摘要:

Mendeleev Communications Electronic Version, Issue 4, 1999 (pp. 129–170) Enantiomeric NMR analysis of organic acids with the Corey chiral controller Margarita A. Lapitskaya, Georgy V. Zatonsky and Kasimir K. Pivnitsky* N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 117913 Moscow, Russian Federation. Fax: +7 095 135 5328; e-mail: li@ioc.ac.ru (R,R)-1,2-Di-(2,4,6-trimethylbenzylamino)-1,2-diphenylethane (the Corey chiral controller) was found to be an effective chiral NMR shift reagent for the determination of the enantiomer ratio in chiral carboxylic and sulfonic acids and cyclic b-diketones. Determination of an enantiomer ratio (enantiomeric analysis) in the mixtures of enantiomers is a difficult but unavoidable procedure in any chiral total synthesis so widespread in the present days.There are several more or less general solutions of the problem. The most general solutions are NMR analysis with chiral lanthanide shift reagents and chromatography on chiral columns. The NMR analysis of diastereomeric mixtures of esters, amides and amine salts with chiral acids is by far the most popular substrate-specific method for enantiomeric analysis of alcohols and amines.1 The best method for the enantiomeric analysis of carboxylic acids is NMR analysis of diastereomeric salt mixtures formed in situ with (R,R)-1,2-diphenylethane-1,2-diamine (DPDAE).2 However, this diamine was found to be inapplicable to the analysis of ketoacid 1 because of rapid formation of Schiff bases in CDCl3 solution.As ketoacid 1 was important for us as a key intermediate in the total synthesis of eicosanoids3 so we were looking for a substitute of DPDAE devoid of its reactivity.Enantiomeric (R,R)- and (S,S)-1,2-di-(2,4,6-trimethylbenzylamino)- 1,2-diphenylethanes (DADPE) are excellent chiral controllers in an enantioselective olefin dihydroxylation reaction.4 The structure of DADPE has been tailored by E.J. Corey5 specially for this purpose. A complex of DADPE with osmium tetroxide binds olefins in a stereospecific manner due to the existence of an asymmetric groove in the predominant conformation of DADPE. It is believed that other types of complex formation with DADPE can be highly stereo- or enantiospecific as well. On the other hand, being hindered bis-secondary diamine, DADPE is much less reactive in comparison with DPDAE.We report here the salt formation of chiral acidic compounds with DADPE and its application to enantiomeric NMR analysis. The acidic compounds studied are presented in Scheme 1. These are chiral carboxylic acids 1–4, 9 and 10, sulfonic acid 8, and cyclic b-diketones 5–7. Acids 1–4 and 8 were used each as a pair of enantiomers or as a racemic mixture and a single enantiomer.Achiral acid 11 was used for comparison purposes. 1H NMR spectra were measured for mixtures of (R,R)-DADPE with the acids taken as racemic mixtures or, if available, as scalemic mixtures with known enantiomeric composition (approximately 4:6). The enantiomeric differences of signal shifts were taken from these spectra (Table 1).† The signal shifts induced by salt formation were calculated by comparison of the spectra of salts and corresponding individual compounds.The interaction of the diamine (R,R)-DADPE with an acid in a solution gives rise to a set of equilibria presented in Scheme 2, where NN and AH are a diamine and an acid, respectively. This interaction can lead to the formation of basic (1:1, acid:diamine) and neutral (2:1) salts depending on the composition of the mixture, existing as ion pairs (or triades), free ions or mixtures of them.In the case of an enantimer mixture, each enantiomer forms its own basic and (homo-)neutral salts, and the formation of a hetero-neutral salt becomes also possible. As the equilibria are rapid in the NMR time scale, the observed chemical shifts, for erxample, of R-acid signals are a weighted average of the chemical shifts in all species containing this enantiomer.This is also true for the S-enantiomer of the acid. Chemical shifts of acid enantiomer residues in the corresponding basic, homo- and hetero-neutral salts, and cations thereof, all diastereomeric by pairs, should be different from each other; therefore, enantiomeric differences for acid signals in the spectrum are possible.‡ The other reason for enantiomeric differences can be the inequality of association constants for the formation or dissociation of diastereomeric salts. This reason is believed to be at least as significant for an enantiomer discrimination in salts of monobasic amines and DPDAE due to anisochronicity.1,2 For DADPE we assume that the association constants for salt formation are sufficient to provide the nearly quantitative salt † Spectra of salts were recorded on a Bruker DRX500 spectrometer (500 MHz) at 30 °C in CDCl3 for the solutions 0.05 M in (R,R)-DADPE and 0.1 M in acidic compounds.Compounds with low solubility in CDCl3 (5–7, 9, 10) are much more soluble in the presence of DADPE and were used as saturated solutions with the acid:diamine ratios shown in Table 1.‡ The situation is quite different for the signals of the diamine (R,R)- DADPE. Although the positions of the signals in the mixtures with acids depend on the acid structure and an acid:diamine ratio, the salt formation with the mixtures of acid enantiomers never induced any enantiomeric splitting of enantiomerically pure diamine signals due to the rapid equilibria of a single diamine residue between all diamine-containing species.Scheme 1 For chiral compounds, only enantiomers with the R-configuration of a chiral centre proximal to an acidic functional group are presented. HN Ph NH Ph Me Me Me Me Me Me (R,R)-DADPE Me O OH COOH OH (R)-1 Ph COOH H OMe (R)-2 Ph COOH MeO CF3 (R)-3 O COOH O 1 2 3 4 5 6 7 8 (R)-4 O (R)-5 X = S (R)-6 X = SO2 O X Ph O (R)-7 O Br Br SO3H Me Me (R)-8 S N Ph COOH (R)-9 Me Me COOH NHCHO (R)-10 COOH 11 OMendeleev Communications Electronic Version, Issue 4, 1999 (pp. 129–170) formation in deuterochloroform solution, and dissociation of the formed salts into ions is insignificant. This assumption is based on the following observations.The induced chemical shifts (Dd = dsalt – dfree acid) of acid (S)-1 in mixtures with the diamine (R,R)-DADPE vary insignificantly with changing acid– base ratios from 0.6:1 to 2:1.§ An analogous result was obtained previously6 with Mosher acid 3. In addition, the substitution of deuterochloroform as a solvent for deuterobenzene does not increase significantly enantiomeric differences in the spectrum of acid 2 (cf.ref. 7). An acid:diamine ratio of 2:1 is most convenient from the practical point of view, and it was used throughout if possible.† At this ratio, acid (S)-1 with (R,R)-DADPE in CDCl3 produces a salt solution stable during several days (NMR data). The NMR spectrum of the salt exhibits significant induced Dd values for both acid and diamine signals.§ These Dd values reach –0.234 ppm for one of the acid signals and +0.91 ppm for one of the diamine signals.The reason of these large Dd values is not only ionization but, in a greater extent, complexation of the molecules due to an additional functionality in the acid residue. This is evident from the spectrum of the salt of model acid 11 where Dd are no higher than +0.04 and +0.23 ppm for the acid and diamine signals, respectively.¶ The spectra of 2:1 salts of enantiomeric acids (R)-1 and (S)-1 have different Dd.†† The enantiomeric differences of Dd (DDd = = DdR-enantiomer – DdS-enantiomer) reach +0.056 ppm for one of the acid signal (Table 1, entry 2).However, the spectra of mixtures of acid enantiomers could differ from the superposition of the spectra of individual enantiomers due to formation of a heteroneutral RS-salt mentioned above (Scheme 2).Indeed, we found that the mixing of two solutions of diastereomerically individual salts produces a new spectrum with single diamine signals, but with enantiomerically splitted signals of the acid with new DDd values. Luckily enough these new DDd values are even larger for some signals (Table 1, entry 1) thus providing an excellent measurement method for acid enantiomer ratios.In a particular case of acid 1, the detection of 1% of minor enantiomer is easy § Dd/ppm for 0.6:1 and 2:1 salts, respectively. (S)-1 residue: –0.23, –0.26 and –0.208 (d, 1H, H2, J 3.6–4.0 Hz, shift from 4.37 ppm), –0.09, –0.14 and –0.138 (br. t, 1H, H3, J 5.8–6.0 Hz, shift from 4.15 ppm), +0.02, 0.00 and +0.03 (q, 2H, C8H2, J 6.4–7.3 Hz, shift from 1.75 ppm), –0.02, –0.06 and –0.04 (s, 3H, C11H3, shift from 2.20 ppm); (R,R)-DADPE residue: +0.26, +0.36 and +0.38 (d, 1H, CHAHB, J 11–13 Hz, shift from 3.47 ppm), +0.27, +0.36 and +0.36 (d, 1H, CHAHB, J 11–13 Hz, shift from 3.53 ppm), +0.19, +0.38 and +0.75 (br.s, 1H, CHN, shift from 3.70 ppm), £ 0.06 (all other).¶ Dd/ppm for 2:1 salt. Acid 11 residue: –0.02 (t, 2H, C2H2, J 7.5 Hz, shift from 2.50 ppm), +0.02 (quint., 2H, C3H2, J 7.5 Hz, shift from 1.84 ppm), +0.04 (td, 2H, C4H2, J 7.5 and 2.5 Hz, shift from 2.26 ppm), +0.03 (t, 1H, H6, shift from 1.95 ppm); (R,R)-DADPE residue: +0.14 (d, 1H, CHAHB, J 12.9 Hz), +0.23 (d, 1H, CHAHB, J 12.9 Hz), +0.12 (br. s, 1H, CHN), £ 0.05 (all other).††Dd/ppm for 2:1 salt. (R)-1 residue: –0.234 (m, 1H, H2), –0.082 (br. t, 1H, H3, J 6.0 Hz), +0.04 (q, 2H, C8H2, J 7.4 Hz), –0.05 (s, 3H, C11H3); (R,R)-DADPE residue: +0.36 (d, 1H, CHAHB, J 11.2 Hz), +0.38 (d, 1H, CHAHB, J 11.2 Hz), +0.91 (br. s, 1H, CHN), £ 0.10 (all other). by measurement of signal intensities of the proton H3 in spite of a multiplet character (W1/2 19 Hz) of this signal reporter.Analogously, with the 2:1 (if possible) salts of the enantiomer mixtures, DDd were measured for all other chiral acids shown in Scheme 1 (entries 3–11 in Table 1). In all cases, with only two exceptions, the enantiomeric differences were observed with DDd values sufficient to measure the ratio of enantiomers. One of the obvious exceptions is acid 9.Amino acid 9 exists as an internal salt and is not transformed into a salt with the (less basic) external base (R,R)-DADPE thus lacking considerable Dd. The second exception, Mosher acid 3, is most probably the result of an accident. The spectrum of the corresponding salt shows substantial Dd for acid signals‡‡ and large Dd values as well as DDd for diamine signals. The latter were used for the analysis of the enantiomer composition of DADPE.6 A specific and sometimes unique property of DADPE as a chiral shift reagent is its long-range action in enantiomeric proton discrimination.Significant DDd are generated for the signals of protons separated from the location of a charge in an anion of the acid by five and even larger number of bonds. In acid 8 (Table 1, entry 9) DADPE produces DDd 0.059 ppm for the signal of one of the methyl groups remote from the charge by more than 5 Å.For comparison, with DPDAE DDd 0.013 ppm was observed in a similar case (methyl group of camphanic acid).2 Thus, acyclic (1, 2 and 10), cyclic (5–7), and threedimensional bicyclic acids (4 and 8) can be analysed with DADPE for the enantiomer ratio. The shifting properties of DADPE are in some contrast with the observation that its close analogue, N,N'-dibenzyl-DPDAE, has greatly reduced enantiodifferentiating properties.2 However, this distinction is in agreement with the remark5 that, in contrast to DADPE, N,N'-dibenzyl-DPDAE was not an effective controller for enantioselective dihydroxylation reaction due to greater rotational flexibility.Another possible application of (R,R)-DADPE (or its equally available enantiomer6) as a chiral shift reagent is the detection of compound chirality. An example is dibromide 7 with an unknown relative configuration of bromine atoms.§§ The observation of large DDd values in the spectrum of its salt (entry 8, ‡‡Dd/ppm for 2:1 salts. (R)- or (S)-3 residues: –0.09 (br. s, 3H, OMe, shift from 3.59 ppm), +0.07 (d, 2H, 2o-HPh, J 7.6 Hz, shift from 7.49 ppm); Dd for (R,R)-DADPE residue see in ref. 6.§§ Dibromide 7 was prepared by partial debromination of the corresponding 2,4,5-tribromide.8 ARH + NN NNH+·AR – NNH2 ++·AR –AR – R-salt RR-salt NNH+ + AR – (or AS –) NNH2 ++·AR –AS – R- or S-anion RS-salt R-cation S-cation NNH2 ++·AR – + AS – (or AR –) NNH2 ++·AS – + AR – (or AS –) ASH + NN NNH+·AS – NNH2 ++·AS –AS – S-salt SS-salt Scheme 2 Salt formation equilibria with the participation of (R,R)-DADPE.ASH ARH ASH ARH aMolar ratios. The sum of enantiomers is taken as an acid concentration. bDDd = d (signal of R-acid) – d (signal of S-acid). Therefore ‘+’ sign means a more pronounced induced shift in low field or a less pronounced shift in high field.cDifferences between two spectra of individual enantiomers. dSome broadening of the OMe signal is observed. eNo sign for DDd is available due to an arbitrary assignment of the enantiomers. Table 1 Enantiomeric differences of chemical shifts induced in the 1H NMR spectra of racemic or scalemic mixtures of acid enantiomers by (R,R)- DADPE. Entry Acid Acid:DADPE ratioa Chemical shift differences of splitted signals (DDd/ppmb) 1 1 2:1 –0.018 (H2), +0.069 (H3) 2 1c 2:1 –0.026 (H2), +0.056 (H3) 3 2 2:1 +0.008 (H2), +0.010 (OMe), +0.032 (o-HPh) 4 3 2:1 No differencesd 5 4 2:1 –0.010 (HA 4 ), –0.027 (HB 4 ), –0.010 (H5), –0.005 (H6) 6 5e 2:1 0.093 (=CH), 0.000 (CHAHB), 0.008 (CHAHB), 0.084 (CHS), 0.040 (o-HPh) 7 6e 0.6:1 0.106 (=CH), 0.000 (CHAHB), 0.042 (CHAHB), 0.360 (CHSO2) 8 7e 1.5:1 0.129 (=CH), 0.064 (CHBr) 9 8 2:1 –0.059 (C9H3), –0.011 (C10H3) 10 9 2:1 No differences 11 10e 0.009 (CHN), 0.016 (CHO), 0.015 (CAH3), 0.000 (CBH3)Mendeleev Communications Electronic Version, Issue 4, 1999 (pp. 129–170) Table 1) proves unambigously the chirality of the molecule and hence the trans-configuration of the bromine atoms. In summary, DADPE enantiomers appear to be a useful addition to a set of chiral shift reagents for the NMR analysis of enantiomer ratio of various acidic substances. This work was supported by the Russian Foundation for Basic Research (grant no. 98-03-32996) and by ASGL Research Laboratories. References 1 D. Parker, Chem. Rev., 1991, 91, 1441. 2 R. Fulwood and D. Parker, J. Chem. Soc., Perkin Trans. 2, 1994, 57. 3 P. M. Demin, T. A. Manukina, C. R. Pace-Asciak and K. K. Pivnitsky, Mendeleev Commun., 1996, 130. 4 H. C. Kolb, M. S. van Nieuwenhze and K. B. Sharpless, Chem. Rev., 1994, 94, 2483. 5 E. J. Corey, P. D. Jardine, S. Virgil, P.-W. Yuen and R. D. Connell, J. Am. Chem. Soc., 1989, 111, 9243. 6 M. A. Lapitskaya and K. K. Pivnitsky, Izv. Akad. Nauk, Ser. Khim., 1997, 101 (Russ. Chem. Bull., 1997, 46, 96). 7 F. J. Villani, M. J. Costanzo, R. R. Inners, M. S. Mutter and D. E. McClure, J. Org. Chem., 1986, 51, 3715. 8 C. H. DePuy and R. D. Thurn, J. Org. Chem., 1962, 27, 744. Received: 16th December 1998; Com. 98/1413

ISSN:0959-9436     

出版商:RSC    

年代:1999

数据来源: RSC

摘要:

Mendeleev Communications Electronic Version, Issue 4, 1999 (pp. 129–170) 3,7-Dimethyl-3,7-diazabicyclo[3.3.1]nonane-2,6-dione-1,5-dicarboxylic acid derivatives: synthesis, structure and resolution Remir G. Kostyanovsky,*a Konstantin A. Lyssenko,b Denis A. Lenev,c Yuri I. El’natanov,a Oleg N. Krutiusa and Irina A. Bronzovaa a N. N. Semenov Institute of Chemical Physics, Russian Academy of Sciences, 117977 Moscow, Russian Federation.Fax: +7 095 938 2156; e-mail: kost@center.chph.ras.ru b A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, 117813 Moscow, Russian Federation. Fax: +7 095 135 5085; e-mail: kostya@xray.ineos.ac.ru c Higher Chemical College, Russian Academy of Sciences, 125047 Moscow, Russian Federation. Fax: +7 095 978 8527; e-mail: lenev@hotmail.com Diamide monohydrate 6 was found to form a conglomerate (space group P21), and it was spontaneously resolved by crystallization; esters 1 and 2 were optically enriched by classical methods; the above compounds were structurally characterised by NMR spectroscopy and X-ray analysis.As we have found recently,1 the crystalline parent dilactam 3,7-diazabicyclo[3.3.1]nonane-2,6-dione forms expected2 homochiral H-bonded helical suprastructures, whereas its 1,5-diethoxycarbonyl derivative1 and the other parent dilactam 3,7-diazabicyclo[ 3.3.0]octane-2,6-dione3 are self-assembled in heterochiral H-bonded tapes of the diagonal zigzag type.Each link of this zigzag is cloned in infinite columns, which are alternated in the direction of the skeleton packing (Scheme 1).It was suggested that homochiral self-assembling can be accomplished through H-bonding of the columns by modified 1,5-substituents with the elimination of the lactamic H-bonding by N-methylation (Scheme 1). In this study, we performed a search for conglomerates in the series of 3,7-dimethyl-3,7- diazabicyclo[3.3.1]nonane-2,6-dione-1,5-dicarboxylic acid derivatives1,4,5 (Scheme 2).Dilactam 1 was prepared by the known method;4 it was partially enriched with dextrorotatory enantiomer (+)-1 (ee ª 9%) using chromatography on a chiral phase. It was shown that 1 readily undergoes transesterification into 2 and saponification into diacid 3.5 The salt of 3 and (S)-(–)-a-phenylethylamine was partially resolved by crystallization and converted into diester (+)-2 (ee ª 2.5%).Dilactam 1 also readily undergoes amidation with the retention of lactam groups to form bismethylamide 4 under the action of MeNH2 or monoamide 5 and diamide monohydrate 6 on treatment with NH3. The structures of the products were confirmed by spectroscopic data† and, in N(4) H(4A) H(4B) H(7A) H(7B) C(7) C(11) O(4) C(4) H(2A) C(2) H(2B) N(1) C(3) O(1) C(8) H(8A) H(8B) H(8C) C(1) C(10) O(3) N(3) H(3A) H(3B) C(5) H(5A) H(5B) N(2) C(6) O(2) C(9) H(9A) H(9B) H(9C) Figure 1 The general view of 6.Selected bond lengths (Å): O(1)–C(3) 1.232(2), O(2)–C(6) 1.237(2), O(3)–C(10) 1.227(2), O(4)–C(11) 1.228(2), N(1)–C(3) 1.341(2), N(1)–C(2) 1.461(3), N(2)–C(6) 1.330(2), N(2)–C(5) 1.466(2), N(3)–C(10) 1.328(3), N(4)–C(11) 1.337(3); selected bond angles (°): C(3)–N(1)–C(2) 124.5(2), C(3)–N(1)–C(8) 117.8(2), C(2)–N(1)–C(8) 117.6(2), C(6)–N(2)–C(9) 120.0(2), C(6)–N(2)–C(5) 124.6(2), C(9)–N(2)– C(5) 115.4(2), C(6)–C(1)–C(7) 113.0(1), C(6)–C(1)–C(2) 106.9(2), C(7)– C(1)–C(2) 107.3(1), C(6)–C(1)–C(10) 107.5(1), C(7)–C(1)–C(10) 112.1(2), C(2)–C(1)–C(10) 110.0(1), O(1)–C(3)–N(1) 122.4(2), O(1)–C(3)–C(4) 119.2(2), N(1)–C(3)–C(4) 118.2(2), C(5)–C(4)–C(7) 107.1(1), C(5)–C(4)– C(3) 107.1(2), C(7)–C(4)–C(3) 114.2(2), C(5)–C(4)–C(11) 109.1(1), C(7)– C(4)–C(11) 112.8(2), C(3)–C(4)–C(11) 106.3(1), O(2)–C(6)–N(2) 122.5(2), O(2)–C(6)–C(1) 117.8(2), N(2)–C(6)–C(1) 119.7(2), C(1)–C(7)–C(4) 106.3(2).Homochiral packing, H-bonding with the skeleton substituents Scheme 1 Heterochiral zigzag, lactamic H-bonding NMe MeN O O Hc Hc EtO2C CO2Et HaH b Hb Ha ' ' ' 1 2 3 4 5 6 7 8 9 NMe MeN MeO2C CO2Me O O NMe MeN HO2C CO2H O O (+)-2 (+)-1 iv i NMe MeN MeHNOC CONHMe O O v ii iii 2 3 1 4 NMe MeN EtO2C CONH2 O O 5 NMe·H 2O MeN H2NOC CONH 2 O O 6 vii (+)-6 or (–)-6 vi Scheme 2 Reagents and conditions: i, chromatography on microcrystalline cellulose triacetate (Fluka), eluent: n-hexane–PriOH (95:5); ii, MeOH, cat.MeONa, 18 h at 20 °C; iii, KOH in EtOH, boiling for 0.5 h, 12 h at 20 °C, then HCl in an H2O–Et2O mixture, evaporation and extraction with MeCN; iv, (S)-(–)-a-phenylethylamine in EtOH, crystallization from MeCN and treatment with CH2N2 in an Et2O–MeOH mixture; v, MeNH2 in EtOH, 72 h at 20 °C; vi, an excess of NH3 in EtOH, cat. EtONa, 6 days at 20 °C; vii, crystallization from H2O.Mendeleev Communications Electronic Version, Issue 4, 1999 (pp. 129–170) the case of 6, X-ray diffraction analysis‡ (Figure 1). Parameters of the NMR spectra are in a good agreement with those described for dilactams of this series.1,4,5 The C2 symmetry of the molecules was confirmed by equivalency of H and C in pairs in the groups 1,5; 2,6; 3,7; 4,8 and 9-CH2.The chirality of molecules was confirmed by non-equivalency of CH2O protons in 1, 5 and by doubling of the signals of 1 in the presence of a chiral shift reagent. The assignment of the spin–spin coupling constants 3JCNCHb = 2.2 Hz, observed for 1, 2, 4 and 6, is based on the average dihedral angles MeNCHb and MeNCHa in 6, which are equal to 38 and 83°, respectively. For 6, the found average dihedral angles between carbon in the 9-position and † Characteristics and spectroscopic data.NMR spectra were measured on a Bruker WM-400 spectrometer (at 400.13 MHz for 1H and at 100.62 MHz for 13C; TMS was an internal standard). Optical rotation was measured on a Polamat A polarimeter, and CD spectra were taken on a JASCO J-500A instrument with a DP-500N data processor. 1 was prepared by the known method,4 yield 75%, mp 103–104 °C. 1H NMR (CDCl3) d: 1.29 (t, 6H, 2MeCH2, 3J 7.3 Hz), 2.66 (t, 2H, 9-CH2, 4JHHb obs 1.2 Hz), 3.00 (s, 6H, 2,7-NMe), 3.67 (dt, 2H, 4,8-CHb, 2J –12.7, 4JH–9-CH2 obs 1.2 Hz), 3.87 (d, 2H, 4,8-CHa, 2J –12.7 Hz), 4.25 (m, 4H, 2CH2Me, ABX3 spectrum, Dn 20.0, 2J –12.2 Hz, 3J 7.3 Hz). 13C NMR (CDCl3) d: 13.62 (qt, MeCH2, 1J 127.3 Hz, 2J 2.5 Hz), 33.12 (tt, 9-CH2, 1J 137.3 Hz, 3JC–Hb 6.7 Hz), 34.48 (qd, 3,7-NMe, 1J 139.5 Hz, 3JCNCHb 2.2 Hz), 49.36 (quint, 1,5-C, 2J 3.7 Hz), 54.76 (ttq, 4,8-CH2, 1J 145.7 Hz, 3JC–9-CH2 = 3JCNMe = 4.4 Hz), 61.68 (tq, CH2O, 1J 148.2 Hz, 2J 4.4 Hz), 166.0 (sh.s, 2,6-CO), 168.4 (sh. s, 1,5-CCO). (+)-1: yield 36%, [a]20 578 = +4.6°; [a]20 546 = +5.1° (c 2.3, MeOH); the positive Cotton effect was observed in the CD spectra (MeOH) at 216 nm.In the 1H NMR spectrum of (+)-1 (CDCl3) in the presence of Eu(tfc)3 the signals from MeCH2, 9-CH2, and MeN groups are split and shifted to the low field; the Dd (Dn) values are 12 (1.8), 520 (5.2) and 24 (5.2) Hz, respectively. In the latter case, the ratio between the integral intensity of the enantiomer signals is ~ 1.2, and hence ee ª 9%. 2: yield 84%, mp 200–202 °C. 1H NMR (CDCl3) d: 2.67 (t, 2H, 9-CH2, 4JHHb vis 1.2 Hz), 3.0 (s, 6H, 3,7-NMe), 3.68 (dt, 2H, 4,8-CHb, 2J –12.8 Hz, 4JH–9-CH2 vis 1.2 Hz), 3.78 (s, 6H, 2MeO), 3.87 (d, 2H, 4,8-CHa, 2J –12.8 Hz). 13C NMR (CDCl3) d: 33.0 (tt, 9-CH2, 1J 137.0 Hz, 3JCHb 7.0 Hz), 34.6 (qd, 3,7-NMe, 1J 139.5 Hz, 3JCHb 2.2 Hz), 49.35 (quint, 1,5-C, 2J 3.6 Hz), 52.66 (q, MeO, 1J 148.2 Hz), 54.68 (ttq, 4,8-CH2, 1J 146.0 Hz, 3JC–9-CH2 = 3JCNMe = 4.4 Hz), 165.9 (sh.s, 2,6-CO), 168.85 (sh. s, 1,5-CCO). (+)-2: yield 68.7%, mp 202–205 °C (MeOH), [a]D 20 = +0.78°, [a]20 546 = +1.3° (c 1.1, MeOH). According to 1H NMR (CDCl3) in the presence of Eu(tfc)3 [like the case of (+)-1], ee ª 2.5%. 3: yield 80%, mp 184–185 °C. 1H NMR (CD3OD) d: 2.72 (t, 2H, 9- CH2, 4JHHb vis 1.2 Hz), 2.97 (s, 6H, 3,7-NMe), 3.58 (dt, 2H, 4,8-CHb, 2J –12.8 Hz, 4JH–9-CH2 vis 1.2 Hz), 3.94 (d, 2H, 4,8-CHa, 2J –12.8 Hz). 4: yield 22%, after sublimation at 230 °C (10 Torr), mp 262–264 °C. 1H NMR (CDCl3) d: 2.71 (t, 2H, 9-CH2, 4JHHb vis 1.2 Hz), 2.81 (d, 6H, 2MeNH, 3JHCNH 4.9 Hz), 2.96 (s, 6H, 3,7-NMe), 3.50 (dt, 2H, 4,8-Hb, 2J –12.2 Hz, 4JH–9-CH2 vis 1.2 Hz), 3.76 (d, 2H, 4,8-Ha, 2J –12.2 Hz), 8.31 (sh.s, 2H, HN). 13C NMR (CDCl3) d: 26.44 (qd, MeNH, 1J 138.1 Hz, 2J 2.9 Hz), 33.11 (tt, 9-CH2, 1J 138.0 Hz, 3JCHb 6.0 Hz), 35.03 (qd, 3,7-NMe, 1J 139.5 Hz, 3JCNCHb 2.2 Hz), 47.86 (quint., 1,5-C, 2J 3.5 Hz), 58.58 (tm, 4,8-CH2, 1J 146.0 Hz), 168.6 (d, CONH, 2J 7.0 Hz), 169.55 (sh. s, 2,6-CO). 5: yield 25%, mp 158–162 °C (EtOH–Et2O, 1:2). 1H NMR (CD3OD) d: 1.26 (t, 3H, MeCH2, 3J 7.0 Hz), 2.66 (ddd, 2H, 9-CH2, ABXY spectrum, Dn 64.0, 2J –13.1 Hz, 4Jbc' = 4Jb'c = 2.7 Hz), 2.96 (s, 3H, 7-NMe), 2.97 (s, 3H, 3-NMe), 3.56 (dd, 1H, H'b , 2J –12.7 Hz, 4Jb'c 2.7 Hz), 3.58 (dd, 1H, Hb, 2J –12.7 Hz, 4Jbc' 2.7 Hz), 3.91 (d, 2H, HaH'a , 2J –12.7 Hz), 4.21 (m, 2H, CH2O, ABX3 spectrum, Dn ª 3.5, 2J –10.7 Hz, 3J 7.0 Hz). 13C NMR (CDCl3) d: 13.6 (qt, 1J 127.0 Hz, 2J 2.5 Hz), 32.72 (tt, 9-CH2, 1J 137.0 Hz, 3JCHb = 3JCH'b = 6.3 Hz), 34.46 (qd, 3-NMe, 1J 139.3 Hz, 3JCNCH'b 2.2 Hz), 34.95 (qd, 7-NMe, 1J 139.0 Hz, 3JCNCH'b 2.1 Hz), 47.9 (s, 5-C), 49.35 (quint., 1-C, 2J 3.7 Hz), 55.06 (tm, 8-CH2, 1J 146.0 Hz), 57.74 (tm, 4-CH2, 1J 147.0 Hz), 61.74 (tq, CH2O, 1J 148.0 Hz, 2J 4.0 Hz), 166.14, 168.61, 168.80 and 170.60 (s, CO). 6: yield 62%, mp 320–325 °C (MeCN). 1H NMR (CD3OD) d: 2.63 (t, 2H, 9-CH2, 4JHHb vis 1.3 Hz), 2.96 (s, 6H, 3,7-NMe), 3.53 (dt, 2H, 4,8-CHb, 2J –12.5 Hz, 4JH–9-CH2 vis 1.3 Hz), 3.90 (d, 2H, 4,8-CHa, 2J –12.5 Hz). 13C NMR (CD3OD) d: 29.17 (tt, 9-CH2, 1J 136.6 Hz, 3JCHb 5.8 Hz), 30.47 (qd, 3,7-NMe, 1J 141.0 Hz, 3JCNCHb 2.2 Hz), 44.90 (quint, 1,5-C, 2J 3.0 Hz), 51.2 (ttq, 4,8-CH2, 1J 146.8 Hz, 3JC–9-CH2 = 3JCNMe = 4.0 Hz), 164.1 (m, 2,6-CO), 168.12 (s, 1,5-CCO).(+)-6: yield 11%, [a]D 18 = +108.5° (c 0.14, H2O), De +7.25 (lmax 215 nm). (–)-6: yield 3%, [a]D 18 = –107.3° (c 0.12, H2O), De –7.25 (lmax 215 nm). protons Hb, H'b and between carbon atoms in the 4,8-positions and protons H'c, Hc are almost equal (173°). However, the spin– spin coupling constants 3J9C-Hb = 5.8–7.0 Hz observed for 1, 2, 4 and 6 are considerably higher than 3J4C-H'c = 4.0–4.4 Hz because of the virtual nature of the latter.5,6 Characteristic virtual long-range spin–spin coupling constants 4JHH of 9-CH2 protons with Hb, H'b were observed for compounds 1–4, 6 (cf.refs. 1 ‡ Crystallographic data for 6: C11H18N4O5, M = 289.29, monoclinic crystals, space group P21, at –120 °C, a = 7.343(2) Å, b = 9.018(2) Å, c = 9.989Å, b = 97.26°, V = 656.2(3) Å3, Z = 2, dcalc = 1.449 g cm–3, m(MoKa) = 1.15 cm–1, F(000) = 304.Intensities of 2564 reflections were measured on a Siemens P3 diffractometer at –120 °C (l MoKa radiation, q/2q scan technique, 2q < 64°) and 2408 independent reflections were used in further calculations and refinement. The structure was solved by the direct method and refined by the full-matrix least-squares technique against F2 in the anisotropic–isotropic approximation. Hydrogen atoms were located from the difference Fourier synthesis and refined in the isotropic approximation.The refinement converged to wR2 = 0.1206 and COF = 1.028 for all independent reflections [R1 = 0.0406 is calculated against F for 1957 observed reflections with I > 2s(I)].The number of the refined parameters is 253. All calculations were performed using SHELXTL PLUS 5.0 on an IBM PC/AT. Atomic coordinates, bond lengths, bond angles and thermal parameters have been deposited at the Cambridge Crystallographic Data Centre (CCDC). For details, see ‘Notice to Authors’, Mendeleev Commun., 1999, Issue 1. Any request to the CCDC for data should quote the full literature citation and the reference number 1135/48.aa' bb' cc' c c' 3.91 3.58 3.56 2.74 2.58 d/ppm aa' bb' Figure 2 1H NMR spectra (in CD3OD) of the ring protons: 5, 4Jbc' = = 4Jb'c = 2.7 Hz (below) and 6, 4Jobs 1.3 Hz (above). 8 6 4 2 0 –2 –4 –6 –8 200 220 240 260 l/nm De Figure 3 CD spectra (in H2O) of (+)-6 (above) and (–)-6 (below).Mendeleev Communications Electronic Version, Issue 4, 1999 (pp. 129–170) and 5). In the desymmetrised system of 5, they disappear and transform into two sets of usual spin–spin coupling constants, which are approximately two times higher in the absolute value than the virtual constants (Figure 2). According to the X-ray diffraction data, diamide monohydrate 6 forms a crystalline conglomerate (space group P21).‡ This fact made it possible to spontaneously resolve 6 by simple crystallization.Racemate (±)-6 (40 mg) was dissolved in H2O (1.5 ml) at 60 °C and kept for 24 h at 20 °C; 13.2 mg (33%) of a precipitate was obtained, and four crystals (1.4–1.5 mg each) were selected. Three of these crystals were found to be dextrorotating with [a]D 18 = +108.5° (c 0.14, H2O), and one was laevorotating with [a]D 18 = –107.3° (c 0.12, H2O); the CD spectra are shown in Figure 3.The mother liquor exhibited no optical activity. The bond lengths and bond angles in the crystal structure of 6 (Figure 1) are very similar to those of the previously investigated derivatives of a dilactam from the bicyclo[3.3.1]nonane series.1 The molecule is characterised by almost ideal C2 local symmetry with small deviations from it for only CONH2 groups.The angle between this C2 local axis and the crystallographic 21 axis is approximately 70°. The bicyclic molecule of 6 is characterised by the double half-chair–half-boat conformation with the deviation of the C(7) atom by 0.7 Å from the planes of the corresponding atoms of the six-membered rings.The rings are twisted with the pseudotorsion angles C(3)–C(4)–C(1)–C(2) and C(5)–C(4)–C(1)–C(6) equal to 17.5 and 17.8°, respectively. The angle between the six-membered rings is 100°. The angles between the C(1)–C(4)–C(7) plane and the planes of the amido groups are 73.8 and 79.4° for C(10)–O(3)–N(3) and C(11)–O(4)–N(4), respectively. All nitrogen atoms have a planar configuration, the maximum deviation (0.13 Å) was found for the N(4) atom; this is probably caused by the formation of H-bonds.In the crystal structure, molecules of 6 are assembled into homochiral H-bonded layers (Figure 4), which are in turn connected by H-bonds with solvate water molecules to form a three-dimensional framework. The corrugated layer (parallel with the crystallographic plane bc) consists of H-bonded helixes (molecules A···B···C).The C(10)–N(3)–O(3) group takes part in the formation of helixes by the H-bond N(3)–H(3A)···O(4') (–1 – x, 1/2 + y, 2 – z) [N(3)···O(4') 3.000(2) Å, N(3)–H(3)– O(4') 170°] and forms the H-bond with an H2O molecule of another layer: N(3)–H(3B)···O(1W) (–1 + x, y, z) [N(3)···O(1W) 2.887(2) Å, N(3)–H(3B)–O(1W) 159°] (Figure 5), whereas the C(11)–N(4)–O(4) group interlinks the molecules (A···C) into helixes by the H-bond N(4)–H(4A)···O(2'') (x, –1 + y, z) [N(4)···O(2'') 2.893(2) Å, N(4)–H(4A)–O(2'') 162°] and associates these helixes into layers by the H-bond N(4)–H(4B)···O(3'') (–1 – x, –1/2 + y, –1 – z) [N(4)···O(3'') 2.988(2) Å, N(4)–H(4B)– O(3'') 170°].Solvate H2O molecules not only interlink the layers into a three-dimensional framework (Figure 5), but also frame the H-layers by additionally linking molecules (A···C) (Figure 4) by H-bonds with C=O groups of the bicyclic molecule of 6: O(1W)–H(1WB)···O(1') (x, 1 + y, z) [O(1W)···O(1' ) 2.923(2) Å, O(1W)–H(1WA)–O(1') 155°] and O(1W)–H(1WA)··· O(2) [O(1W)···O(1) 2.792(2) Å, O(1W)–H(1WA)–O(2) 171°]. This work was supported by the Russian Foundation for Basic Research (grant nos. 97-03-33021, 97-03-33786 and 96- 97367). References 1 R. G. Kostyanovsky, K. A. Lyssenko, Yu. I. El’natanov, O. N. Krutius, D. A. Lenev, I. A. Bronzova, Yu. A. Strelenko and V. R. Kostyanovsky, Mendeleev Commun., 1999, 106. 2 R. G. Kostyanovsky, K. A. Lyssenko, G. K. Kadorkina, O. V. Lebedev, A. N. Kravchenko, I. I. Chervin and V. R.Kostyanovsky, Mendeleev Commun., 1998, 231. 3 R. G. Kostyanovsky, Yu. I. El’natanov, O. N. Krutius, K. A. Lyssenko and Yu. A. Strelenko, Mendeleev Commun., 1999, 70. 4 G. Darnbrough, P. Knowles, S. P. O’Connor and F. J. Tierney, Tetrahedron, 1986, 42, 2339. 5 R. G. Kostyanovsky, Yu. I. El’natanov, I. I. Chervin and V. N. Voznesenskii, Izv. Akad. Nauk, Ser. Khim., 1996, 1037 (Russ. Chem. Bull., 1996, 45, 991). 6 F. A. Bovey, L. Jelinski and P. A. Mirau, Nuclear Magnetic Resonance Spectroscopy, 2nd edn., Academy Press, San Diego, 1988, p. 174. O(4) N(4) O(1) A O(1') N(4') O(4') O(2') N(3') H(3A') O(4'') N(3) H(3A) H(3B) O(1W') H(4A'') N(4'') H(4B'') O(1'') C N(3'') O(2'') O(3'') O(3''') O(1W) H(1WA) O(2) O(3) H(4''') N(4''') B Figure 4 Formation of the H-bonded ‘corrugated’ layers in the crystal structure of 6. H(1WB) layer 1 layer 2 N(3'') H(3B'') O(1W) H(1WB) H(1WA) O(2') O(1') N(3') H(3B') H(1W') H(1W'') O(1W'') O(1'') Figure 5 Formation of the three-dimensional H-bonded framework in the crystal structure of 6. Methyl groups are omitted for clarity. Received: 6th November 1998; Com. 98/1394 (8/08872A)

ISSN:0959-9436     

出版商:RSC    

年代:1999

数据来源: RSC

摘要:

Mendeleev Communications Electronic Version, Issue 4, 1999 (pp. 129–170) Chirality-directed co-crystallization of different configurationally opposite dialkyl 2,5-diazabicyclo[2.2.2]octane-3,6-dione-1,4-dicarboxylates Remir G. Kostyanovsky,*a Konstantin A. Lyssenkob and Denis A. Lenevc a N. N. Semenov Institute of Chemical Physics, Russian Academy of Sciences, 117977 Moscow, Russian Federation. Fax: +7 095 938 2156; e-mail: kost@center.chph.ras.ru b A.N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, 117813 Moscow, Russian Federation. Fax: +7 095 135 5085; e-mail: kostya@xray.ineos.ac.ru c Higher Chemical College, Russian Academy of Sciences, 125047 Moscow, Russian Federation . Fax: +7 095 978 8527; e-mail: lenev@hotmail.com The title procedure gives quasi-racemic optically active (CD) co-crystals of 4 (space group P21) and 5 of the 1:1 composition; in [CD(–)230]-4, molecules of (–)-1 and (+)-2 are joined by amide H-bonds into infinite linear zigzag tapes packed as infinite columns.In racemic bislactams of the C2 symmetry, the chirality-directed stereospecific self-assembling of molecules in the crystal by H-bonding into infinite linear zigzag tapes for A,1,2 (±)-1,3 diagonal zigzags for C,4 D5 and double zigzags (helices) for B4 with the formation of centrosymmetric crystals was observed.Thus, in the case of bislactam diesters 1 and D, it was reasonable to expect the chirality-directed co-crystallization of two different diesters of opposite configurations to form a noncentrosymmetric quasi-racemic co-crystal.This possibility was implemented in this study. Indeed, typical plate-like co-crystals of 4 and 5, respectively, were formed in the co-crystallization of an enantiomerically pure diethyl ester with a dipropyl or dimethyl ester of the bislactam diacid of opposite configuration (Scheme 1). Their composition (1:1) was supported by NMR† and X-ray diffraction studies,‡ and optical activity was detected by the CD method.† According to X-ray diffraction data‡ (Figure 1), a co-crystal of [CD(–)230]-4 is noncentrosymmetric.Molecules of (–)-1 and (+)-2 in this crystal are strictly alternating and joined by amide H-bonds into infinite linear zigzag tapes [Figure 1(B)]. Each of the esters is packed to form its own infinite columns [Figure 1(A)].The unit-cell, structure and packing parameters of 4 are similar to those observed for (±)-13 (Table 1). † Characteristics and spectroscopic data. 1H NMR spectra were measured on a Bruker WM-400 spectrometer at 400.13 MHz with TMS as an internal standard. Optical rotation and CD spectra were measured on a Polamat A polarimeter and a JASCO J-500 A instrument, respectively.(1S,4S)-(+)-1: yield 45%, mp 233–234 °C, the 1H NMR spectrum (CDCl3) is identical to that described earlier,3 in the presence of Eu(tfc)3 the only signal of HN at 6.96 ppm was observed in the spectrum of (+)-1, whereas the signals of HN of enantiomers at 6.94 and 6.97 ppm (Dn = 12 Hz) were observed for (±)-1; [a]D 20 = 38.6° (c 1.9, MeOH); CD spectrum, cell 0.5 mm, De (lmax/nm): in H2O (c 7.8×10–3 M): +0.1 (249), –0.7 (237), +6.9 (220), –4.2 (200); in MeOH (c 10–2 M): +0.7 (248), +15.5 (224), –8.6 (205); in MeCN (c 6.1×10–3 M): +6.0 (227), –5.5 (200).(1R,4R)-(–)-1: yield 27%, mp 230–233 °C, [a]D 20 = –35.7° (c 1.3, MeOH); CD spectrum in MeOH (c 10–2 M), De (lmax/nm): –0.6 (248), –14.3 (224), +8.0 (205). (1S,4S)-(+)-2: yield 60%, mp 180 °C, [a]D 20 = 28.6° (c 0.5, MeOH). 1HNMR (CDCl3) d: 0.99 (t, 6H, 2Me, 3J 7.3 Hz), 1.76 (qt, 4H, 2CH2Me, 3J 7.3 Hz), 2.40 [m, 4H, (CH2)2, AA'BB' spectrum, Dn ª 88 Hz], 4.31 (m, 4H, 2CH2O, ABX2 spectrum, Dn = 15.0 Hz, 2J –10.7 Hz, 3J 7.3 Hz), 6.78 (br. s, 2H, 2HN). (1R,4R)-(–)-2: yield 54%, mp 181 °C, [a]D 20 = –28.8° (c 0.7, MeOH). (1S,4S)-(+)-3: yield 75%, mp 233–234 °C, [a]D 20 = 44.8° (c 0.2, MeOH). (1R,4R)-(–)-3: yield 80%, mp 234 °C, [a]D 20 = –45° (c 0.2, MeOH). 1H NMR spectra of (+)-3 and (–)-3 are identical to those described earlier.4 [CD(–)230]-4: yield ~100%, mp 219–220 °C, [a]D 20 ª 0° (c 0.3, MeOH); CD spectrum in MeOH, cell 2 mm (c 4.5×10–3 M), De (lmax/nm): –0.34 (230). 1H NMR (CDCl3) d: 0.99 (t, 6H, 2MeCH2, 3J 7.2 Hz), 1.37 (t, 6H, 2MeCH2O, 3J 7.4 Hz), 1.75 (qt, 4H, 2CH2Me, 3J 7.2 Hz), 2.40 [m, 8H, (CH2)2, AA'BB' spectrum, Dn ª 88 Hz], 4.30 (m, 4H, CH2CH2O, ABX2 spectrum), 4.40 (m, 4H, 2MeCH2O, ABX3 spectrum, Dn = 13.0Hz, 2J –12.0 Hz, 3J 7.4 Hz), 6.81 (br.s, 2H, 2HN), 6.83 (br. s, 2H, 2HN). [CD(+)230]-4, yield ~100%, mp 223 °C, [a]D 20 ª 0° (c 0.3, MeOH); CD spectrum in MeOH (c 4×10–3 M), De (lmax/nm): 0.36 (230). [CD(–)235]-5: yield 15%, mp 228–229 °C, [a]D 20 ª 0° (c 0.3, MeOH); CD spectrum in MeOH, cell 2 mm (c 1.2×10–3 M), De (lmax/nm): –0.45 (235), +0.25 (220); 1H NMR, d: 1.40 (t, 6H, 2MeCH2O, 3J 7.1 Hz), 2.40 [m, 8H, 2(CH2)2, AA'BB' spectrum, Dn ª 82 Hz], 3.96 (s, 6H, 2MeO), 4.40 (m, 4H, 2CH2O, ABX3 spectrum, Dn = 13.0 Hz, 2J –12.0 Hz, 3J 7.1 Hz), 6.82 (br.s, 2H, 2HN), 6.85 (br. s, 2H, 2HN). N N R R O H O H N N R R O H O H n A R = H B R = CO2H (±)-1 R = CO2Et C R = H, n = 0 D R = CO2Et, n = 1 N N CO2Et EtO2C O H O H N N O H CO2R RO2C H O N N CO2Et EtO2C H O H O N N H O CO2Pr PrO2C O H (1R,4R)-(–)-1 + (1S,4S)-(+)-2 (1R,4R)-(–)-1 + (1S,4S)-(+)-3 i ii n [CD(–)230]-4 [CD(–)235]-5 (R = Pr) (R = Me) n (1S,4S)-(+)-1 + (1R,4R)-(–)-2 [CD(+)230]-4 i Scheme 1 Reagents and conditions: i, equimolar quantities of bislactams in MeCN (0.5 h at 20 °C), and separation of crystals; ii, the same, in MeOH.Table 1 Distances between the centres of C(7)–C(8) bonds in adjacent molecules in a column (d1), a zigzag (d2) and adjacent zigzags (d3). Compound d1/Å d2/Å d3/Å 4 5.597 10.198 11.866 (±)-13 5.568 10.189 11.626Mendeleev Communications Electronic Version, Issue 4, 1999 (pp. 129–170) Enantiomeric bislactam diesters 1–3 were prepared according to Scheme 2.Their structure was supported by spectral data† and X-ray diffraction data‡ for (–)-1 (Figure 2). ‡ Crystallographic data for (1R,4R)-(–)-1 and [CD(–)230]-4 at –120 °C: crystals of C12H16N2O6 (–)-1 are orthorhombic, space group P212121, a = 5.534(3) Å, b = 9.908(4) Å, c = 25.773(10) Å, V = 1413(1) Å3, Z = 4, M= 284.27, dcalc = 1.336 g cm–3, m(MoKa) = 1.08 cm–1, F(000) = 600; crystals of C26H36N4O12 4 are monoclinic, space group P21, a = = 10.199(7) Å, b = 5.597(3) Å, c = 25.11(2) Å, b = 95.96(5)°, V = = 1425(2) Å3, Z = 2, M = 596.59, dcalc = 1.390 g cm–3, m(MoKa) = = 1.11 cm–1, F(000) = 632.Intensities of 1922 independent reflections for (–)-1 and of 3616 reflections for 4 were measured on a Siemens P3 diffractometer at –120 °C (l MoKa radiation, q/2q-scan technique, 2qmax < 55°) and were used in further calculations and refinement.The structures were solved by a direct method and refined by a full-matrix least squares against F2 in the anisotropic–isotropic approximation. The difference Fourier synthesis for (–)-1 revealed additional peaks which were interpreted as the disorder of the ethyl group by two positions with equal occupancies.The hydrogen atoms were located from the difference Fourier synthesis with the exception of the hydrogens of the ethyl groups, the positions of which were calculated from the geometrical point of view. The refinement converged to wR2 = 0.1814 and COF = = 1.168 for all independent reflections [R1 = 0.0615 was calculated against F for the 1712 observed reflections with I > 2s(I)] for the structure of (–)-1 and to wR2 = 0.2848 and COF = 0.918 for all independent reflections [R1 = 0.0761 was calculated against F for the 1973 observed reflections with I > 2s(I)] for the structure of 4.All calculations were performed on an IBM PC/AT using the SHELXTL PLUS 5.0 program.Atomic coordinates, bond lengths, bond angles and thermal parameters have been deposited at the Cambridge Crystallographic Data Centre (CCDC). For details, see ‘Notice to Authors’, Mendeleev Commun., Issue 1, 1999. Any request to the CCDC should quote the full literature citation and the reference number 1135/53. Final enantiomeric purification of (+)- and (–)-1 was performed by crystallization from MeCN.In this case, the racemate was initially precipitated. The optical purity of (+)-1 was determined by 1H NMR using a chiral shift reagent.† The optical purity of (+)-3 was monitored by the value of [a]D (cf. ref. 4). The absolute configuration of the diesters follows from the fact that the consecutive transesterification (+)-1 ® (+)-2 ® (+)-3 gives (1S,4S)-(+)-3, the configuration of which was found by chemical correlation.4 Moreover, the opposite configuration of diesters (–)-1 and (+)-2 (Figure 1) follows from the results of X-ray diffraction analysis of [CD(–)230]-4. The absolute configurations of (1S,4S)-(+)- and (1R,4R)-(–)-1 were independently supported by the CD data.† The Cotton effect at 220–270 nm was attributed to the n–p* transition of the diketopiperazine chromophore on the basis of a typical long-wave shift with decreasing polarity of the solvent.† According to refs. 7–9, the sign of this Cotton effect is associated with the chirality of a fixed conformation of the bislactam. Like the case of (–)-A,2 expected cyclohexamerization2 does not occur in the crystal structure of (–)-1, although similar H-bonded aggregation of molecules was observed previously (trimerization in solution10 and hexamerization in crystals of trimesic acid, isophthalic acid derivatives11 and tetralactams, which form molecular tectones12). Similarly to (–)-B and (±)-B,4 molecules in a crystal of (–)-1 are joined by H-bonds with the participation of CONH and CO2 groups into helical suprastructures which can be considered as infinite double zigzag tapes (Figure 2).In this case, the molecules are packed in infinite columns as well as in crystals of 4, (–)-A2 and (±)-13 with similar values of the parameter d1 = 5.534Å (cf. Table 1). Note that the formation of columns was not observed in (±)-A.2 In the case of (–)-1 and (–)-B,4 the C–H···O contacts13 between hydrogen atoms of the C(7)–C(8) bridge and oxygen atoms of the lactam groups, which are typical of the majority of the bislactams examined [4, (±)-A and (–)-A,2 (±)-13 and (±)-B4], are absent.The results obtained are interesting from two standpoints. First of them is the problem of quasi-racemates,14 the study of which dates back to Pasteur.15 Examples of the use of quasiracemates for separating enantiomers are well known.14 In this respect, we attempt to choose CO2R groups of bislactam diesters, which are appropriate for the formation of a hydrophobic zipper16 in the co-crystallised substance.We anticipate to separate the racemate of one ester by co-crystallization with a half-molar amount of an enantiomer of another ester. Another procedure can consist in the preparation of a conglomerate like 4 by cocrystallization of racemates of two diesters (Scheme 1).The second aspect is intensely developed crystal engineering by co-crystallization.1,13,17–23 Chirality-directed co-crystallization of different bislactams5,6 and bisureas24 is examined from this standpoint. O(3') O(4') O(1') H(2') N(2') N(5') H(5') O(6') O(5') O(2') O(1) O(2) O(3) O(4) O(5) O(6) N(2) H(2) N(5) H(5) O(3') O(4') O(1') N(2') N(5') H(5') O(6') O(5') O(2') O(1) O(2) O(3) O(4) O(5) O(6) N(2) H(2) N(5) H(5) Figure 1 The zigzag tapes in the crystal structure of [CD(–)230]-4 directed along the crystallographic axis a (in projections A and B) and columns directed along the axis b (projection A).In the projection B, the Et and Pr groups are omitted for clarity. The parameters of the H-bonds are: N(2)– H(2)···O(2') (–1 + x, y, z) [H(2)···O(2') 2.13 Å, N(2)–H(2)–O(2') 146°, N(2)···O(2') 2.901(7) Å]; N(5)–H(5)···O(1') [H(5)···O(1') 2.09 Å, N(5)– H(5)–O(1') 152°, N(5)···O(1') 2.893(7) Å]; N(2')–H(2')···O(1) (1 + x, y, z) [H(2')···O(1) 2.15 Å, N(2')–H(2')–O(1) 148°, N(2')···O(1) 2.930(7) Å]; N(5')–H(5')···O(2) [H(5')···O(2) 2.15 Å, N(5')–H(5')–O(2) 149°, N(5')···O(2) 2.940(7) Å]. A B N N CO2R CO2R H O O H (1S,4S)-(+)-1 R = Et (1S,4S)-(+)-2 R = Pr (1S,4S)-(+)-3 R = Me iii iv N H2N CO2Et EtO2C CO2Et O H E N N CO2R CO2R H O O H (1R,4R)-(–)-1 R = Et (1R,4R)-(–)-2 R = Pr (1R,4R)-(–)-3 R = Me iii iv i ii Scheme 2 Reagents and conditions: i, an equimolar amount of (–)-dibenzoyl- L-tartaric acid in MeCN at 20 °C, evaporation to dryness, single crystallization from a MeCN–C6H6 (1:15) mixture and separation from the mother liquor (for using in ii); next, treatment with Et3N in Et2O, separation of the precipitate, evaporation of the solution to dryness, and holding the residue in MeCN with a catalytic amount of DBU (1 week at 20 °C); the removal of the racemate precipitate and separation of DBU by chromatography on silica gel (40/100) with an AcOEt–EtOH (10:1) eluent; ii, evaporation of the mother liquor separated in i and further treatment according to i; iii, PrOH and a catalytic amount of DBU (1.5 months at 20 °C), evaporation and chromatography on silica gel according to i; iv, boiling in MeOH in the presence of DBU (12 h), cooling (10 h at 4 °C) and separation of the precipitate.Mendeleev Communications Electronic Version, Issue 4, 1999 (pp. 129–170) This work was supported by the Russian Foundation for Basic Research (grant nos. 97-03-33021 and 97-03-33786). References 1 J.-M. Lehn, Supramolecular Chemistry, VCH, Weinheim, 1995. 2 M.-J. Brienne, J. Gabard, M. Leclercq, J.-M. Lehn, M. Cesario, C. Pascard, M. Heve and G. Dutruc-Rosset, Tetrahedron Lett., 1994, 35, 8157. 3 R. G. Kostyanovsky, Yu.I. El’natanov, O. N. Krutius, I. I. Chervin and K. A. Lyssenko, Mendeleev Commun., 1998, 228. 4 R. G. Kostyanovsky, Yu. I. El’natanov, O. N. Krutius, K. A. Lyssenko, I. I. Chervin and D. A. Lenev, Mendeleev Commun., 1999, 109. 5 R. G. Kostyanovsky, Yu. I. El’natanov, O. N. Krutius, K. A. Lyssenko and Yu. A. Strelenko, Mendeleev Commun., 1999, 70. 6 R. G. Kostyanovsky, K. A. Lyssenko, Yu.I. El’natanov, O. N. Krutius, I. A. Bronzova, Yu. A. Strelenko and V. R. Kostyanovsky, Mendeleev Commun., 1999, 106. 7 D. W. Urry, Ann. Revs. Phys. Chem., 1968, 19, 477. 8 N. J. Greenfield and G. D. Fasman, Biopolymers, 1969, 7, 595. 9 T.M. Hooker, P.M. Bayley, W. Radding and J. A. Schellman, Biopolymers, 1974, 13, 549. 10 S. C. Zimmerman and B. F. Duerr, J. Org. Chem., 1992, 57, 2215. 11 J. Yang, J.-L. Marendaz, S. J. Geib and A. D. Hamilton, Tetrahedron Lett., 1994, 35, 3665. 12 X. Wang, M. Simard and J. D. Wuest, J. Am. Chem. Soc., 1994, 116, 12119. 13 G. R. Desiraju, Acc. Chem. Res., 1996, 29, 441. 14 J. Jacques, A. Collet and S. H. Wilen, Enantiomers, Racemates, and Resolution, Krieger Publ. Comp., Malabar, Florida, 1994. 15 L. Pasteur, Ann. Chim. (Paris), 1853, 38, 437. 16 M. Vasquez, G. Nemethy and H. A. Schekaga, Chem. Rev., 1994, 94, 2183. 17 M.-J. Brienne, J. Gabard, J.-M. Lehn and I. Stibor, J. Chem. Soc., Chem. Commun., 1989, 1868. 18 J.-M. Lehn, M. Mascal, A. DeCian and J. Fischer, J. Chem. Soc., Chem. Commun., 1990, 479. 19 T. Gulik-Krzywicki, C. Fouquey and J.-M. Lehn, Proc. Natl. Acad. Sci. USA, 1993, 90, 163. 20 J. C. MacDonald and G.M. Whitesides, Chem. Rev., 1994, 94, 2383. 21 J.-P. Mathias, E. E. Simanek, J. A. Zerkowskii and G. M. Whitesides, J. Am. Chem. Soc., 1994, 116, 4326. 22 S. Hanessian, M. Simard and S. Roeleus, J. Am. Chem. Soc., 1995, 117, 7630. 23 W. T. S. Huck, R. Hulst, P. Timmerman, F. C. J. M. van Veggel and D. N. Reinhoudt, Angew. Chem., Int. Ed. Engl., 1997, 36, 1006. 24 R. G. Kostyanovsky, K. A. Lyssenko, G. K. Kadorkina, O. V. Lebedev, A. N. Kravchenko, I. I. Chervin and V. R. Kostyanovsky, Mendeleev Commun., 1998, 231. O(6) O(1) O(5) N(2) H(2N) N(1) H(1N) O(2') O(3) O(1') O(4) O(2) H(1N'') O(1'') O(6'') O(5'') H(2N'') O(2'') O(4'') A B O(1) O(2) O(3) O(4) O(5) O(6) N(1)H(1) N(2) H(2) Figure 2 The homochiral helices in the crystal structure of (1R,4R)-(–)-1 directed along the crystallographic axis b (in projections A and B) and columns directed along the axis a (projection A). In the projection B, the Et groups are omitted for clarity. The parameters of the H-bonds are: N(1)– H(1N)···O(2) (1 – x, 1/2 + y, –3/2 – z) [H(1N)···O(2) 2.08 Å, N(1)–H(1N)– O(2) 156°, N(1)···O(2) 2.883(5) Å]; N(2)–H(2N)···O(3) (1 – x, –1/2 + y, 1/2 – z) [H(2N)···O(3) 2.20 Å, N(2)–H(2N)–O(3) 147°, N(2)···O(3) 2.947(5) Å]. Received: 24th February 1999; Com. 99/1448

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Mendeleev Communications Electronic Version, Issue 4, 1999 (pp. 129–170) Configurations of 1,3-bis(aryl)-1,3-diaza-2-thiaallenes in the crystal state Irina Yu. Bagryanskaya, Yuri V. Gatilov and Andrey V. Zibarev* N. N. Vorozhtzov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russian Federation. Fax: +7 3832 34 4752; e-mail: zibarev@nioch.nsc.ru The s,p-mixing responsible for the Z,Z configuration of the title compounds is indifferent to both withdrawing (NO2) and releasing (OMe) p-electron character of ortho-substituents, and the arrangement of aromatic rings in the Z,E configuration orthogonally to the NSN plane is a universal way to overcome steric hindrances due to bulky (But, Br) ortho-substituents. Azathienes (RN=)2S, which are widely used as reagents and ligands in organoelement, heteroatom and coordination chemistry, prefer Z,E and Z,Z configurations in all states of aggregation (Scheme 1).1 The E,E configuration was found only in the crystal state of some metal complexes2,3 rather than in noncoordinated molecules.With R = Ar, the relative importance of the Z,E4–7 and Z,Z6–9 configurations is determined by a complex stereoelectronic balance.7,8 In particular, as shown by the PM3 calculations,7,8 the Z,Z isomers of (ArN=)2S are stabilised by the s,p-mixing of nN – with p– (where p correlates with the 1e1gS benzene MO) and nN + with p+ (where p correlates with the 1a2u benzene MO). In the case of polyfluorinated (ArN=)2S, fluorine 2p AOs do not participate in the contributing MOs providing only an inductive influence upon them.8 We can suppose the above interaction to be indifferent to both withdrawing and releasing p-electron character of other heteroatom substituents.Indeed, as shown by X-ray structure analysis, compound 2† (Figure 1)‡ possesses the same Z,Z configuration in the crystal as compound 3.6 The only difference is that ortho-MeO groups in 3 are oriented in the same direction, whereas ortho-NO2 groups in 2 are arranged in opposite directions.It was believed that a universal way to overcome steric hindrances induced by bulky ortho-substituents in (ArN=)2S is the arrangement of Ar rings in the Z,E configuration orthogonally to the NSN plane.7 As shown by X-ray structure analysis, sterically hindered compound 4† (Figure 1)‡,§ really exists in the crystal as the Z,E configuration in which the Ar rings are virtually perpendicular to the NSN plane.As parent † Compound 2 was synthesised as transparent orange prisms, mp 141– 142 °C (from benzene–hexane) as described earlier.10 Compound 4 (94%) was prepared from corresponding ArNH2 and SF4 according to a general method11 as transparent orange crystals, mp 208– 209 °C (from toluene).MS, m/z experimental (calculated): 550.4299 (550.4321), [M+]. UV [heptane, lmax/nm (lg e)]: 420 (3.66). 1H NMR (CS2, 20 °C) d: 7.14 (s, 2H), 1.31 (s, 18H), 1.26 (s, 9H). 13C NMR, d: 143.3, 139.1, 122.2, 120.1, 33.8, 32.2, 30.1, 29.3. 15N NMR, d: 334. A single crystal for X-ray diffraction analysis was prepared by slow evaporation of a solution of 4 in 4'-pentyl-4-biphenylcarbonitrile (Aldrich).‡ X-ray crystal data. Compound 2: C12H8N4O4S, M = 304.28, monoclinic, a = 8.159(3) Å, b = 12.444(4) Å, c = 12.867(4) Å, b = 94.56(3)°, V = = 1302.3(8) Å3, space group P21/n, Z = 4, dc = 1.552 g cm–3, m(CuKa) = = 2.446mm–1, F(000) = 624. Compound 4: C36H58N2S, M = 550.90, triclinic, a = 9.979(3) Å, b = = 10.089(3) Å, c = 20.648(4) Å, a = 91.39(3)°, b = 101.91(3)°, g = = 119.26(3)°, V = 1755.4(8) Å3, space group P , Z = 2, dc = 1.042 g cm–3, m(CuKa) = 0.979 mm–1, F(000) = 608.Data were measured on a Syntex P21 diffractometer with graphite monochromated CuKa radiation using q/2q scans. A correction for absorption was made for 2 according to the crystal faces (transmission: 0.25–0.58), and for 4 by the azimuthal scan method (transmission: 0.73– 0.93).The structure of 2 was solved by the direct method and that of 4, by the heavy atom method using the SHELXS-86 program. The structures were refined in the full-matrix anisotropic (isotropic for H atoms) approximation by the SHELXL-97 program. R, S, the number of independently observed reflections [|F0| > 4s|F0|], 2q < (°): 2, 0.0533, 1.038, 1544, 140; 4, 0.0447, 1.053, 3847, 114.The parameters of the hydrogen atoms were given geometrically. Atomic coordinates, bond lengths, bond angles and thermal parameters have been deposited at the Cambridge Crystallographic Data Centre (CCDC). For details, see ‘Notice to Authors’, Mendeleev Commun., 1999, issue 1. Any request to the CCDC for data should quote the full literature citation and the reference number 1135/50.S(1) N(1) N(2) N(3) N(4) O(1) O(2) O(3) O(4) C(1) C(2) C(3) C(4) C(5) C(6) C(7) C(8) C(9) C(10) C(11) C(12) S(1) N(1) N(2) C(1) C(2) C(3) C(4) C(5) C(6) C(7) C(12) C(11) C(10) C(9) C(8) 2 4 Figure 1 Molecular structure of 2 and 4.§ For 2, selected bond lengths (Å): S(1)–N(1) 1.515(3), S(1)–N(2) 1.514(3), N(1)–C(1) 1.410(4), N(2)–C(7) 1.416(4); selected bond angles (°): N(1)–S(1)–N(2) 123.44(15), S(1)– N(1)–C(1) 130.0(2), S(1)–N(2)–C(7) 129.4(2).For 4, selected bond lengths (Å): S(1)–N(1) 1.528(2), S(1)–N(2) 1.527(2), N(1)–C(1) 1.433(3), N(2)–C(7) 1.425(3); selected bond angles (°): N(1)–S(1)–N(2) 117.0(1), S(1)–N(1)–C(1) 125.9(2), S(1)–N(2)–C(7) 122.3(2); selected torsional angles (°): S(1)–N(1)–C(1)–C(6) 72.4(3), S(1)–N(2)–C(7)–C(8) –60.6(3), N(2)–S(1)–N(1)–C(1) 16.3(2), N(1)–S(1)–N(2)–C(7) –165.3(2).N R S N R N R S N R N R S N R Z,Z 2,3 Z,E 1,4,5 E,E 1 R = 4-MeC6H4 2 R = 2-NO2C6H4 3 R = 2-MeOC6H4 4 R = 2,4,6-But 3C6H2 5 R = 2,4,6-Br3C6H2 Scheme 1 1Mendeleev Communications Electronic Version, Issue 4, 1999 (pp. 129–170) compound 1 (taken as a 4,4'-dimethyl derivative) exists in the crystal as a nearly planar Z,E isomer,4 we can conclude that bulky ortho-substituents such as But (Figure 1) and Br (compound 5)7 induce only conformational, not configurational, reorganization.Thus, this work gives new important evidence in favour of our earlier conclusions.7,8 This work was supported by the Russian Foundation for Basic Research (grant nos. 96-03-33276 and 96-07-89181). References 1 I. Yu. Bagryanskaya, Yu. V. Gatilov and A. V. Zibarev, Zh. Strukt. Khim., 1997, 38, 988 [J. Struct. Chem. (Engl. Transl.), 1997, 38, 829]. 2 R. Meij and K. Olie, Cryst. Struct. Commun., 1975, 4, 515. § The equality of S=N bond lengths found for 4 is not typical of all other (Z,E)-(ArN=)2S with known real geometry in which the E-bond is slightly longer [by 0.009(2)–0.065(16) Å]6–8 than the Z-bond.Another feature is that N=S=N bonds are twisted (for torsional angles, see Figure 1). The aromatic rings adopt a boat-like conformation typical of 1-R-2,4,6-(But)3C6H2 compounds12 with the E-ring being less distorted than the Z-ring (cf. the X-ray data on structurally related phosphorus heterocumulenes).13,14 3 C.Mahabiersing, W. G. J. de Lange, K. Goublitz and D. J. Stufkens, J. Organomet. Chem., 1993, 461, 127. 4 G. Leandri, V. Busetti, G. Valle and M. Mammi, J. Chem. Soc., Chem. Commun., 1970, 413. 5 V. Busetti, Acta Crystallogr., B, 1982, 38, 665. 6 V. Busetti, G. Cevasco and G. Leandri, Z. Kristallogr., 1991, 197, 41. 7 I. Yu. Bagryanskaya, Yu. V. Gatilov, M. M. Shakirov and A. V. Zibarev, Mendeleev Commun., 1994, 136. 8 I. Yu. Bagryanskaya, Yu. V. Gatilov, M. M. Shakirov and A. V. Zibarev, Mendeleev Commun., 1994, 167. 9 I. Yu. Bagryanskaya, Yu. V. Gatilov and A. V. Zibarev, Zh. Strukt. Khim., 1999, 40, 790 (in Russian). 10 A. V. Zibarev, A. O. Miller, Yu. V. Gatilov and G. G. Furin, Heteroatom Chem., 1990, 1, 443. 11 J. Kuyper and K. Vreize, J. Organomet. Chem., 1975, 86, 127. 12 F. H. Allen and O. Kennard, Chemical Automation Design News, 1993, 8, 31. 13 R. Appel, P. Folling, L. Krieger, M. Siray and F. Knoch, Angew. Chem., Int. Ed. Engl., 1984, 23, 970. 14 A. N. Chernega, A. A. Korkin and V. D. Romanenko, Zh. Obshch. Khim., 1995, 65, 1823 (Russ. J. Gen. Chem., 1995, 1674). Received: 24th March 1999; Com. 99/1467

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Mendeleev Communications Electronic Version, Issue 4, 1999 (pp. 129–170) Synthesis and stereochemical features of 2-oxo-3-cyano-1,2-thiaphosphorinanes Irina L. Odinets,* Natalya M. Vinogradova, Oleg I. Artyushin, Pavel V. Petrovskii, Konstantin A. Lyssenko, Michail Yu. Antipin and Tatyana A. Mastryukova A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, 117813 Moscow, Russian Federation.Fax: +7 095 135 5085; e-mail mastr@ineos.ac.ru The intramolecular Pishchimuka rearrangement of 3-halopropyl-substituted thiophosphorylacetonitriles results in the corresponding 2-oxo-3-cyano-1,2-thiaphosphorinanes as a statistical mixture of two diastereomers, which transforms to an individual diastereomer with time; in benzene solution, the latter turns again into an equilibrium mixture of diastereomers.It is well known that 3- and 4-chloro-substituted O,O-diethylthiophosphonates on heating with sodium iodide in acetone form corresponding iodo derivatives, which undergo the intramolecular Pishchimuka rearrangement to yield 2-O-ethyl-2-oxo- 1,2-thiaphosphacyclanes (so-called thiolphostones).1,2 We prepared 3-chloropropyl-substituted thiophosphorylacetonitriles 1 by alkylation of thiophosphorylacetonitriles with 1,3- bromochloropropane under phase-transfer catalysis conditions.3 Unlike non-functionalised O,O-diethyl-w-chloroalkylthiophosphonates, these compounds are rather reactive.They partially undergo the intramolecular Pishchimuka rearrangement to corresponding 2-oxo-3-cyano-1,2-thiaphosphorinanes 3 under vacuum distillation (Scheme 1).Apparently, the formation of compounds 3 proceeds via corresponding phosphonium salts similarly to the previously suggested intramolecular S-alkylation in the series of non-functionalised w-haloalkyl-substituted thiophosphoryl compounds.2 The fact that for the 3-chloropropylsubstituted thiophosphorylacetonitriles with a diphenylthiophosphoryl group we detected (by NMR spectroscopy) the formation of the corresponding phosphonium salt (dP 39.4 ppm) in a MeCN solution at room temperature supports this assumption.Using different 3-chloropropyl-substituted methyl(alkoxy)- thiophosphorylacetonitriles 1b–d as an example, we found that the yield of thiophosphorinane 3b obtained by distillation depends on the radical R1 in the alkoxy group at the phosphorus atom.As should be expected, this yield decreased with increasing volume of the radical and especially when going to the compounds in which R1 is a secondary alkyl (the yield was about 50% at R1 = Et, about 32% at R1 = Bui and as low as 7% at R1 = Pri). Although thiaphosphorinanes 3a,b are sparingly soluble in usual organic solvents and can be recovered from distillates by precipitation, nevertheless it is much more suitable to prepare compounds 3 through corresponding iodo derivatives 2 (Scheme 1).On heating a MeCN solution of 1 with NaI, the cyclization was completed in 6–8 h.† The formation of 2 during the reaction and the structure of the compound were confirmed by NMR spectroscopy (31P and 1H). Note that in a MeCN solution the cyclization of iodopropyl-substituted thiophosphorylacetonitriles 2 proceeds slowly even at room temperature (the yield of 3 was 60–65% after 6 months).This cyclization is not stereoselective, and compounds 3 are formed as a statistical mixture of two diastereomers A and B,‡ which exhibit two closely located signals in the 31P NMR spectra. 1,2-Thiaphosphorinanes 3a,b were precipitated as solids with the same ratio between diastereomers on addition of diethyl ether to distillates (Hal = Cl) or to reaction mixtures (Hal = I).At the same time, in the absence of the solvent in distillates or in concentrated reaction mixtures, the slow transformation of equilibrium mixtures to the preferable individual diastereomers was observed. The relative configuration of chiral atoms in the diastereomers was determined by X-ray diffraction.For 2-ethoxy-substituted 1,2-thiaphosphorinane 3a, the configuration of asymmetric centres was found to be identical, while it was opposite for compound 3b with a methyl group at the phosphorus atom. A comparison of 31P NMR and X-ray diffraction data allows us to conclude that diastereomer † General procedure for the synthesis of 3a,b.Compounds 1 (obtained according to ref. 3) were heated with a 10% molar excess of NaI in a MeCN solution. After 1.5 h, the NaCl precipitate was filtered off, and heating was continued for 5–6 h. The mixture was evaporated, CHCl3 was added to the residue, and the mixture was filtered once again. The filtrate was evaporated under reduced pressure, the residue was either crystallised from Et2O (diastereomer mixture) or allowed to stand for spontaneous crystallization (individual diastereomer) followed by washing with benzene.The yield of 3a,b separated was about 73–78%. Compounds 3a,b had the satisfactory elemental analysis regardless of the isolation procedure. Selected data for 3a. D = 160–190 (1 mmHg), mp 65–70 °C (Et2O, A:B = 1:1).Diastereomer A: 1HNMR (CDCl3) d: 1.05 (t, 3H, MeCH2OP, 3JHH 7.0 Hz), 1.75–1.95 and 2.12–2.23 (2m, 1H + 1H, SCH2CH2), 2.24– 2.33 and 2.43–2.60 [2m, 1H + 1H, C(CN)CH2], 2.92–3.06 (m, 2H, SCH2), 3.02 (ddd, CHCN, 3JHH 4.0 Hz, 3JHH 10.4 Hz, 2JPH 19.0 Hz). 13C NMR (CDCl3) d: 15.7 (Me, 3JPC 7.0 Hz), 23.1 [C(5), 3JPC 6.1 Hz], 29.1 [C(6), 2JPC 5.8 Hz], 30.2 [C(4), 2JPC 3.6 Hz], 31.7 [C(3), 1JPC 100.8 Hz], 62.4 (OCH2, 2JPC 6.7 Hz), 115.2 (CN, 3JPC 4.5 Hz). 31P NMR, d: 36.6 (CDCl3), 34.9 (C6D6). Diastereomer B: mp 116–118 °C. 1H NMR (CDCl3) d: 1.13 (t, 3H, MeCH2OP, 3JHH 7.0 Hz), 1.86–1.90 and 2.15–2.20 (2m, 1H + 1H, SCH2CH2), 2.26–2.32 and 2.50–2.54 [2m, 1H + 1H, C(CN)CH2], 2.92–3.06 (m, 2H, SCH2), 3.16 (ddd, CHCN, 3JHH 3.8 Hz, 3JHH 10.0 Hz, 2JPH 18.4 Hz). 13C NMR (CDCl3) d: 15.9 (Me, 3JPC 6.2 Hz), 25.6 [C(5), 3JPC 4.5 Hz], 29.7 [C(6), 2JPC 5.8 Hz], 30.2 [C(4), 2JPC 3.6 Hz], 32.2 [C(3), 1JPC 96.8 Hz], 62.8 (OCH2, 2JPC 7.1 Hz), 114.9 (CN, 3JPC 11.2 Hz). 31P NMR, d: 36.2 (CDCl3), 34.0 (C6D6). For 3b: D = 170–190 °C (1 mmHg). Diastereomer A: mp 136–137 °C; 1H NMR (CDCl3) d: 1.98 (d, 3H, MeP, 2JPH 13.4 Hz), 2.12–2.19 (m, 2H, SCH2CH2), 2.25–2.39 and 2.52–2.56 [2m, 1H + 1H, C(CN)CH2], 2.87–2.92 and 3.36–3.28 (2m, 1H + 1H, SCH2), 3.25 (dt, CHCN, 3JHH 3.88 Hz, 2JPH 16.66 Hz). 31P NMR, d: 42.5 (CDCl3), 39.4 (C6D6). Diastereomer B: 31P NMR, d: 40.01 (CDCl3), 37.4 (C6D6). ‡ The diastereomer having a downfield signal in the 31P NMR spectra was designated as diastereomer A. P(S)CHCN R1O R (CH2)3Cl P R1O R S NC Cl P(S)CHCN R1O R (CH2)3I P R1O R S NC I NaI/MeCN reflux 1a–d 2a–d D MeCN P O R S NC 3a,b – R1Cl – R1I 1,2: a R = OEt, R1 = Et b R = Me, R1 = Et c R = Me, R1 = Bui d R = Me, R1 = Pri 3: a R = OEt b R = Me Scheme 1 The synthesis of 2-oxo-3-cyano-1,2-thiaphosphorinanes.Mendeleev Communications Electronic Version, Issue 4, 1999 (pp. 129–170) A is characterised by the configuration (2S*,3R*) with the fully staggered disposition of the cyano group and the oxygen atom of the P=O group, while the identical configuration of asymmetric centres, i.e.(2R*,3R*), with the skew arrangement of the above groups corresponds to isomer B. Note that in spite of different surroundings at the phosphorus atom (phosphonate and phosphinate structures in 3a and 3b, respectively) the signals in the 31P NMR spectra of these compounds are close to one another and upfield shifted with respect to the signals of linear compounds with similar surroundings at the phosphorus.Thus the chemical shift primarily depend on the presence of a 1,2-thiaphosphorinane ring in the molecule. According to X-ray diffraction data,§ bond lengths and angles in both molecules (Figures 1 and 2) exhibit expected values.4,5 The phosphorus atoms are characterised by a slightly distorted tetrahedral configuration with the endocyclic angles 105.1(1)° and 103.9(1)° in the structures of 3a(B) and 3b(A), respectively.In both molecules, six-membered rings exhibit a slightly distorted chair conformation. In both structures, the CN group occupies an axial position, while the positions of oxygen atoms of the phosphoryl group are different.In 1,2-thiaphosphorinane 3a(B) (R = OEt), it occupies an equatorial position with the torsion angle O(1)–P(1)– C(4)–C(5) equal to 48.9°, while it is in an axial position in 3b(A) (R = Me) and is fully staggered to the CN group with the torsion angle equal to 170.6°. Evidently, the strength of the possible stereoelectronic n–s* interaction between the lone electron pair of sulfur and the antibonded orbital of the axial group at the phosphorus atom [P(1)–O(2) in 3a(B) and § Crystallographic data for 3a and 3b at –80 °C: crystals of C7H12N2PS 3a are monoclinic, space group C2/c, a = 21.034(9) Å, b = 6.076(4) Å, c = 18.015(9) Å, b = 118.16(2)°, V = 2030(2) Å3, Z = 8, M= 205.21, dcalc = 1.343 g cm–3, m(MoKa) = 4.39 cm–1, F(000) = 864; crystals of C6H10NOPS 3b are triclinic, space group P , a = 6.978(7) Å, b = = 7.132(3) Å, c = 9.813(6) Å, V = 414.7(5) Å3, a = 101.72(4)°, b = = 101.79(6)°, g = 113.77(5)°, Z = 2, M= 175.17, dcalc = 1.403 g cm–3, m(MoKa) = 5.16 cm–1, F(000) = 184.Intensities of 3049 reflections for 3a and 1445 reflections for 3b were measured with a Syntex P21 diffractometer at –80 °C (l MoKa radiation, q/2q scan technique, 2qmax < 60° for 3a and 50° for 3b) and 2977 for 3a and 980 for 3b independent reflections were used in further calculations and refinement.The structures were solved by a direct method and refined by a fullmatrix least-squares against F2 in the anisotropic-isotropic approximation. Hydrogen atoms were located from the difference Fourier synthesis and refined in the isotropic approximation. The refinement converged to wR2 = 0.2615 and COF = 0.869 for all independent reflections [R1 = = 0.0736 for 1102 observed reflections with I > 2s(I)] for structure 3a and to wR2 = 0.1629 and COF = 1.059 for all independent reflections [R1 = 0.0437 for 880 observed reflections with I > 2s(I)] for structure 3b.All calculations were performed using the SHELXTL PLUS 5.0 program on an IBM PC/AT.Atomic coordinates, bond lengths, bond angles and thermal parameters have been deposited at the Cambridge Crystallographic Data Centre (CCDC). For details, see ‘Notice to Authors’, Mendeleev Commun., 1999, Issue 1. Any request to the CCDC should quote the full literature citation and the reference number 1135/51.P(1)=O(1) in 3b(A)] is different in these two cases.6 This n–s* interaction will result in shortening the P(1)–S(1) bond. Taking into account that the P(1)–S(1) bond in 3a(B) is significantly shorter [2.044(2) Å] than that in 3b(A) [2.062(2) Å], we can conclude that the above interaction is more pronounced in the case of the P(1)–O(2) antibonded orbital in diastereomer B of 1,2-thiaphosphorinane 3a.The appreciable shortening of the P(1)=O(1) bond length up to 1.456(2) Å in the above structure in comparison with 3b(A) [1.488(2) Å] is not only due to the difference in the n–s* interaction, but also due to the alteration of the coordination sphere of the phosphorus atom (replacement of OEt with Me).7 Note that P–S bond lengths in cyano-substituted 1,2-thiaphosphorinanes 3 are similar to those [2.048(2)–2.068(2) Å] in the series of 2,2-diphenyl-1,2l4-thiaphospholanium and 2,2-diphenyl- 1,2l4-thiaphosphorinanium salts.2 Furthermore, the S(1)– C(1) bond in the crystal structure of 3b(A) is significantly elongated up to 1.835(1) Å as compared with that in 3a(B) [1.807(5) Å] and also is very similar to the corresponding bond in the above thiaphosphorinanium salts [1.837(5) Å].The P(1)– C(4) bonds in 1,2-thiaphosphorinanes 3a,b are significantly longer [1.817(4) Å]. Thus, the phosphorus atom in the crystal structures of 3a,b possesses a significant positive charge which is larger in 3b(A), where the n–s* interaction is less pronounced. In both of the crystal structures of 3, molecules are assembled by the C(4)–H(4)···O(1)=P(1) H-bonds in two centrosymmetric dimers, which in turn are interlinked by the C–H···O=P bonds in double H-bonded layers (Figures 3 and 4).Note that, from the geometrical point of view (C···O and H···O distances), the C–H···O=P H-bonds in 3b(2S*,3R*) molecules are significantly stronger than those in the crystal structure of 3a(2R*,3R*). This Figure 1 The general view of diastereomer B (2R*,3R*) of 3a.Selected bond lengths (Å): P(1)–O(1) 1.456(3), P(1)–O(2) 1.573(3), P(1)–C(4) 1.817(4), P(1)–S(1) 2.044(2), S(1)–C(1) 1.807(6); selected bond angles (°): O(1)–P(1)–O(2), 116.7(2), O(1)–P(1)–C(4) 117.0(2), O(2)–P(1)–C(4) 98.2(2), O(1)–P(1)–S(1) 109.4(2), O(2)–P(1)–S(1) 109.0(1), C(4)–P(1)– S(1) 105.5(1), C(1)–S(1)–P(1) 99.2(2), C(6)–O(2)–P(1) 119.0(3), C(2)– C(1)–S(1) 114.3(3), C(5)–C(4)–P(1) 109.5(3), C(3)–C(4)–P(1) 113.2(3).C(7) C(6) O(2) P(1) O(1) S(1) C(1) C(2) C(3) C(4) C(5) N(1) 1 Figure 2 The general view of diastereomer A (2S*,3R*) of 3b. Selected bond lengths (Å): P(1)–O(1) 1.488(2), P(1)–C(6) 1.785(3), P(1)–C(4) 1.838(4), P(1)–S(1) 2.062(2), S(1)–C(1) 1.835(3); selected bond angles (°): O(1)–P(1)–C(6) 114.6(1), O(1)–P(1)–C(4) 108.3(1), C(6)–P(1)–C(4) 109.1(2), O(1)–P(1)–S(1) 116.4(1), C(6)–P(1)–S(1) 103.8(1), C(4)–P(1)– S(1) 103.9(1), C(1)–S(1)–P(1) 97.9(2), C(2)–C(1)–S(1) 113.7(3), C(5)– C(4)–P(1) 112.1(2), C(3)–C(4)–P(1) 108.7(3).S(1) P(1) C(6) C(1) C(2) C(3) C(4) C(5) N(1) O(1) Figure 3 The doubly bonded layers in the crystal structure of 3a(B). The shortened contacts are: C(4)–H(4)···O(1') (–x, 1 – y, –z) [H(4)···O(1') 2.31 Å, C(4)···O(1') 3.266(4) Å, C(4)–H(4)···O(1') 147°]; C(3)–H(3A)···O(1'') (x, –1 + y, z) [H(3A)···O(1'') 2.36 Å, C(3)···O(1'') 3.345(4) Å, C(3)– H(3A)···O(1'') 153°].P(1'') O(1'') Et O(2) C(2) C(1) S(1) P(1) O(1) N(1) C(5) C(4) H(4) C(3) H(3A) H(4') C(4') P(1') O(1')Mendeleev Communications Electronic Version, Issue 4, 1999 (pp. 129–170) can be due to additional accumulation of the negative charge at the phosphoryl oxygen atom O(1). These O···H contacts, according to Desiraju,8 can be considered as medium-strength contacts, which play an important role in the crystal packing. It is likely that the formation of these contacts in the crystals of preferential individual diastereomers of 1,2-thiaphosphorinanes 3a,b resulted in the crystallization from concentrated reaction mixtures.At the same time, an equilibrium mixture of both diastereomers is formed in solutions where these contacts are impossible. In benzene solutions, slow reverse transformation of individual diastereomers 3a(B) and 3b(A) to the corresponding equilibrium mixtures, where the ratio A:B = 1:1 was achieved in about 3 months, was observed.Evidently, mutual transformations of the diastereomers proceed through opening of the six-membered ring (at either a P–S or S–C bond), inversion of the configuration of one of the asymmetric centres and subsequent recyclization. This work was supported by the Russian Foundation for Basic Research (grant nos. 96-03-32992a and 96-15-97367). References 1 O.V. Bykhovskaya, I. M. Aladzheva, D. I. Lobanov, P. V. Petrovskii, T. A. Mastryukova and M. I. Kabachnik, Abstratcs of the XI International Conference on Chemistry of Phosphorus Compounds (ICCPC-XI), Kazan, 1996, p. 155. 2 I. M. Aladzheva, O. V. Bykhovskaya, D. I. Lobanov, P. V. Petrovskii, K. A. Lyssenko, T. A. Mastryukova and M. I. Kabachnik, Zh. Obshch. Khim., 1998, 68, 1421 (Russ. J.Gen. Chem., 1998, 68, 1356). 3 N. M. Vinogradova, I. L. Odinets, O. I. Artyushin, P. V. Petrovskii, K. A. Lyssenko, M. Yu. Antipin and T. A. Mastryukova, Zh. Obshch. Khim., 1998, 68, 1434 (Russ. J. Gen. Chem., 1998, 68, 1368). 4 D. G. Gilheany, The Chemistry of Organophosphorus Compounds, ed. F. R. Harley, Wiley–Interscience, Chichester, 1992, vol. 2, p. 1. 5 Cambridge structural database, release 1998. 6 D. G. Gorenstein, Chem. Rev., 1987, 37, 1047. 7 I. L. Odinets, O. I. Artyushin, R. M. Kalyanova, A. G. Matveeva, P. V. Petrovskii, K. A. Lyssenko, M. Yu. Antipin, T. A. Mastryukova and M. I. Kabachnik, Zh. Obshch. Khim., 1997, 67, 922 (Russ. J. Gen. Chem., 1997, 67, 862) and references therein. 8 G. R. Desiarju, Acc. Chem. Res., 1996, 29, 441. Figure 4 The doubly bonded layers in the crystal structure of 3b(A). The shortened contacts are: C(4)–H(4)···O(1') (–x, 1 – y, 1 – z) [H(4)···O(1') 2.22 Å, C(4)···O(1') 3.246(4) Å, C(4)–H(4)···O(1') 161°]; C(6)–H(6B)···O(1'') (1 – x, 1 – y, 1 – z) [H(6B)···O(1'') 2.42 Å, C(3)···O(1'') 3.469(4) Å, C(3)– H(3A)···O(1'') 167°]. P(1'') O(1'') C(2) C(1) S(1) P(1) O(1) N(1) C(5) C(4) H(4) C(3) H(4') C(4') P(1') O(1') C(6) H(6B) C(6'') H(6B'') Received: 24th March 1999; Com. 99/1468

ISSN:0959-9436     

出版商:RSC    

年代:1999

数据来源: RSC

摘要:

Mendeleev Communications Electronic Version, Issue 4, 1999 (pp. 129–170) Amidine function in constructing novel types of phosphorus-containing heterocycles Gennady V. Oshovsky,* Alexander M. Pinchuk and Andrei A. Tolmachev Institute of Organic Chemistry, National Academy of Sciences of Ukraine, 253660 Kiev, Ukraine. Fax: +7 044 573 2643; e-mail: oshovsky@carrier.kiev.ua Novel pyrazolo[5,4-b]azaphosphinine and pyrazolo[4,5-e]diazaphosphinine ring systems have been synthesised from 4-phosphorylated 5-formamidinopyrazoles.We have previously found that the amidine substituent (–N=CH– NMe2) is a convenient protecting group in electrophilic reactions involving trivalent phosphorus halides, in which classical acetamide protection is not suitable. In this way, it was possible to introduce phosphorus substituents into the 4-position of thiazole and thiadiazole amidines.Subsequent removal of the amidine protecting group was found to lead to promising phosphorylated amino heterocycles.1 Here we report the use of the amidine substituent in heterocyclization reactions. Initially, the amidine group provides protection and activation (s° = –0.25)2 for the introduction of a dihalophosphine moiety into the neighbouring position in the ring system. Next, an appropriate transformation of the phosphorus-containing moiety can result in an intramolecular nucleophilic substitution reaction to produce a phosphoruscontaining heterocycle.A dichlorophosphino moiety was successfully introduced into the 4-position of the pyrazole ring using N1,N1-dimethyl-N2-5- pyrazolylformamidine 1 as the model system (Scheme 1).Note that 1 is considerably more reactive towards phosphorylation than other pyrazoles.3 This fact illustrates the strong electrondonating properties of the amidine substituent. Dichlorophosphine 2 was then transformed into bis(dialkylamino)phosphines 3a,b under mild conditions. Imidophosphonic diamide 6 (X = N), which was prepared from 3 by chlorination with hexachloroethane followed by reaction with NH3, undergoes cyclization in situ to give the novel pyrazolo[4,5-e]diazaphosphinine ring system† of 7a,b.Dimorpholinophosphine 3a was transformed into phosphonium salts 5 and 5' by the action of methyl iodide and p-nitrobenzyl bromide, respectively. Reactions of salts 5 and 5' give phosphorus ylides 6 (X = HC or 4-NO2C6H4C), which undergo intramolecular nucleophilic substitution in situ to form pyrazolo- † 4-[5-(3-Methyl-1,3-diazabut-1-enyl)-3-methyl-1-phenyl]pyrazolyldichlorophosphine 2.To a solution of 2.28 g of 1 (0.01 mol) in pyridine (23 ml), 1.31 ml of PCl3 (0.015 mol) was added with cooling (0 °C) and stirring. The reaction mixture was allowed to stand for 1.5 h.Next, 2.8 ml of NEt3 (0.02 mol) was added with cooling and stirring; after standing for 5 min, the salts were filtered off, and the reaction mixture was evaporated to dryness in vacuo. The product was crystallised from dry octane. 4-[5-(3-Methyl-1,3-diazabut-1-enyl)-3-methyl-1-phenyl]pyrazolyldimorpholinophosphine 3a and 4-[5-(3-methyl-1,3-diazabut-1-enyl)-3- methyl-1-phenyl]pyrazolyl[bis(diethylamino)phosphine] 3b.A secondary amine (morpholine or diethylamine) (0.021 mol) was added to a mixture of 2 (0.01 mol) and NEt3 (0.03 mol) in 30 ml of benzene with cooling and stirring. The reaction mixture was allowed to stand for 2 h. The salts formed were filtered off, and the reaction mixture was evaporated to dryness in vacuo. Product 3a was crystallised from dry octane, and 3b was extracted with dry hexane. 3-Methyl-4,4-bis(1-morpholino)-1-phenylpyrazolo[4,5-e]-1,3,4l5-diazaphosphinine 7a and 3-methyl-4,4-bis(diethylamino)-1-phenylpyrazolo- [4,5-e]-1,3,4l5-diazaphosphinine 7b. Amide 3a or 3b (0.01 mol) was dissolved in dry benzene (30 ml); next, C2Cl6 (0.01 mol) in 10 ml of benzene was added with cooling and stirring. The reaction mixture was allowed to stand overnight and then evaporated to dryness in a vacuum.The residue was dissolved in CH2Cl2, the solution was saturated with gaseous NH3 during 4 h and then allowed to stand for 24 h. The salts were filtered off, and the reaction mixture was evaporated to dryness. Compound 7a was recrystallised from octane and isopropanol. Compound 7b was recrystallised from hexane.[5,4-b]azaphosphinines 8 and 8'. The formation of the ylides from the salts is a rate-limiting step in the overall transformation. This results in a considerable decrease in the reaction rate when the methylphosphonium salt is used in the heterocyclization in place of the p-nitrobenzylphosphonium salt. Although the a-C–H proton in methylphosphonium salt 5 exhibits low acidity, nevertheless, the steady-state concentration of non-stabilised methylide 6 (X = CH) produced by EtONa is sufficient to perform the heterocyclization.‡ N N Ph Me N CH Me2N 1.PCl3, Py 2. NEt3 – NEt3·HCl N N Ph Me N CH Me2N Cl2P 1 2 R2NH, NEt3 – NEt3·HCl N N Ph Me N CH Me2N (R2N)2P 3a,b 1. C2Cl6 2. NH3 or XH2Hal N N Ph Me N CH Me2N (R2N)2P 4a,b; 5,5' XH2 Hal NH3 – NH3·HHal or EtONa – NaHal N N Ph Me N CH Me2N P 6 NR2 R2N HX intramolecular heterocyclization – Me2NH X N P N N NR2 R2N Ph Me 7a,b; 8,8' O N a NR2 = b NR2 = NEt2 4 X = N, Hal = Cl O N 5 NR2 = , X = CH, Hal = I O N 5' NR2 = , X = , Hal = Br NO2 C 7 X = N O N 8 NR2 = , X = CH O N 8' NR2 = , X = NO2 C Scheme 1Mendeleev Communications Electronic Version, Issue 4, 1999 (pp. 129–170) The ease of the cyclizations is caused by a significant polarization of P=XH bonds in both phosphazocompounds (X = N) and ylides (X = CR).An electron-rich nitrogen or carbon atom attacks the spatially adjacent electron-deficient carbon atom in the amidine group resulting in the replacement of a dimethylamino group and the formation of a heterocyclic ring.§ Nucleophilic substitution at a formamidine carbon atom is a promising approach which can be used in constructing heterocycles. 4 However, most of the systems containing active functional groups in the position adjacent to the amidine substituent are difficult to obtain. Only o-formylamidines can be easily prepared from the corresponding amines by reactions with an excess of the Vilsmaier reagent.5 ‡ 4-[5-(3-Methyl-1,3-diazabut-1-enyl)-3-methyl-1-phenyl]pyrazolyldimorpholinomethylphosphonium iodide 5 and 4-[5-(3-methyl-1,3-diazabut- 1-enyl)-3-methyl-1-phenyl]pyrazolyldimorpholino-p-nitrobenzylphosphonium bromide 5'.Dimorpholinophosphine 3a (0.01 mol) was dissolved in 25 ml of benzene, and a benzene solution (15 ml) of MeI (0.01 mol) or p-nitrobenzyl bromide (0.01 mol) was added. The reaction mixture was allowed to stand for 4 days.The product was filtered and recrystallised from isopropanol. 3-Methyl-4,4-bis(1-morpholino)-1-phenylpyrazolo[5,4-b]-1,4l5-azaphosphinine 8 and 3-methyl-4,4-bis(1-morpholino)-5-(4-nitrophenyl)-1- phenylpyrazolo[5,4-b]-1,4l5-azaphosphinine 8'. A mixture of 5 or 5' (0.01 mol) and EtOH (10 ml) was added to EtONa (0.015 mol) in EtOH (20 ml). The reaction mixture was stirred for 12 (5) or 2 days (5').Compound 8 was isolated by evaporating the reaction mixture to dryness, washing with water and recrystallization from ethanol. Compound 8' was isolated by filtration, washing with water and then with dry diethyl ether. § 31P, 13C and 1H NMR spectra were measured on a Varian VXR-300 instrument (131.313, 63.6 and 300 MHz, respectively) using TMS as an internal standard (13C and 1H) or 85% H3PO4 as an external standard (31P). Elemental analysis data correspond to the calculated values to within 0.25%. 2: yield 88%, mp 88–89 °C. 1H NMR (C6D6) d: 8.04 (d, 2H, Ph, o-H, J 7.8 Hz), 7.17 (2H, Ph, m-H), 7.10 (d, 1H, NCHN, JPH 6.9 Hz), 6.99 (t, 1H, Ph, p-H, J 7.5 Hz), 2.77 (s, 3H, MeHet), 2.27, 1.92 (6H, Me2N). 13C NMR (C6D6) d: 156.97 (NCHN, JCP 11.6 Hz), 156.93 (Het, 5-C, JCP 36.7 Hz), 153.15 (Het, 3-C, JCP 11.6 Hz), 140.76 (Ph, N–C), 129.24 (Ph, m-C), 126.97 (Ph, p-C), 124.29 (Ph, o-C), 105.43 (Het, 4-C, JCP 57.2 Hz), 39.84, 34.57 (NMe2), 15.52 (MeHet, JCP 4.5 Hz). 31P NMR (C6D6) d: 148.04 (d, JPH 6.9 Hz). 3a: yield 90%, mp 102–103 °C. 31P NMR (pyridine) d: 88.42. 3b: yield 81%, oil. 31P NMR (pyridine) d: 87.53. 5: yield 79%, mp 188–189 °C. 31P NMR (EtOH) d: 48.78. 5': yield 77%, mp 160–162 °C. 31P NMR (acetone) d: 46.14 (br. m). 7a: yield 84%, mp 134–135 °C. 1H NMR (CDCl3) d: 8.01 (d, 1H, NCHN, JPH 46.2 Hz), 7.96 (d, 2H, Ph, o-H, J 8.1 Hz), 7.47 (t, 2H, Ph, m-H), 7.29 (t, 1H, Ph, p-H, J 7.2 Hz), 3.71 (8H, CH2N), 3.15 (s, 8H, CH2O), 2.42 (s, 3H, MeHet). 13C NMR (CDCl3) d: 160.13 (Het, 5-C, JCP 6.9 Hz), 157.36 (NCHN, JCP 15.4 Hz), 145.69 (Het, 3-C, JCP 1.1 Hz), 139.17 (Ph, N–C), 128.85 (Ph, m-C), 126.34 (Ph, p-C), 122.99 (Ph, o-C), 82.80 (Het, 4-C, JCP 142.79 Hz), 66.97 (CH2N, JCP 10.6 Hz), 44.39 (CH2O), 15.11 (MeHet, JCP 2 Hz). 31P NMR (CHCl3) d: 26.55 (d, JPH 46.2 Hz). MS, m/z: 400 [M+]. 7b: yield 77%, mp 76–77 °C. 1H NMR (CDCl3) d: 8.01 (d, 1H, NCHN, JPH 45.9 Hz), 8.00 (d, 2H, Ph, o-H, J 8.4 Hz), 7.45 (t, 2H, Ph, m-H), 7.25 (t, 1H, Ph, p-H, J 7.5 Hz), 3.13 (m, 8H, NCH2Me), 2.41 (s, 3H, MeHet), 1.08 (t, 12H, NCH2Me, J 6.9 Hz). 31P NMR (CH2Cl2) d: 28.61 (m). MS, m/z: 372 [M+]. 8: yield 74%, mp 246–247 °C. 1H NMR (CDCl3) d: 8.34 (dd, 1H, HCCP, JPH 5.1 Hz, JHH 9.9 Hz), 7.76–7.58 (m, 4H, Ph, o-H, m-H), 7.50 (t, 1H, Ph, p-H, J 7.2 Hz), 5.38 (dd, 1H, HCP, JPH 38 Hz, JHH 9.9 Hz), 3.74 (8H, CH2N), 3.19 (s, 8H, CH2O), 2.48 (s, 3H, MeHet). 13C NMR (CD3OD) d: 150.45 (Het, 5-C, JCP 7.6 Hz), 147.54 (PCHCHN, JCP 12 Hz), 145.73 (Het, 3-C, JCP 1.1 Hz), 138.06 (Ph, N–C), 131.48 (Ph, m-C), 131.15 (Ph, p-C), 126.78 (Ph, o-C), 85.23 (Het, 4-C, JCP 113.4 Hz), 80.58 (PCHCHN, JCP 96.86 Hz), 68.01 (CH2N, JCP 7 Hz), 46.40 (CH2O), 15.12 (MeHet, JCP 1 Hz). 31P NMR (CHCl3) d: 29.89 (dm, JPCH 38 Hz). MS, m/z: 399 [M+]. 8': yield 72%, mp 241–243 °C. 1H NMR (CDCl3) d: 8.26 (d, 2H, o-NO2–H, J 12.3 Hz), 8.19 (d, 2H, m-NO2–H), 8.03 (HCCP, JPH 5.1 Hz), 7.60–7.40 (4H, Ph, o-H, m-H), 7.30 (t, 1H, Ph, p-H, J 7.2 Hz), 3.61 (8H, CH2N), 3.11 (s, 8H, CH2O), 2.97 (s, 3H, MeHet). 31P NMR (CH2Cl2) d: 30.32 (br. m). We found that C-phosphorylation of N1,N1-dimethyl-N2- hetarylformamidines can proceed at the heterocyclic moiety, in contrast to N1,N1-dimethyl-N2-arylformamidines in which the formamidine carbon is the site of attack.6 Thus, systems containing phosphorus and amidine groups at neighbouring positions can be produced.Appropriate modification of the phosphoruscontaining substituent provides means for achieving subsequent cyclization.This strategy is promising for the synthesis of a wide range of phosphorus-containing heterocycles. G. V. Oshovsky is grateful to the International Science Educational Program (ISEP) of the International Science Foundation and to the International Renaissance Foundation for partial financial support of this work (grant nos. PSU073017 and PSU083047). References 1 (a) G.V. Oshovsky, A. A. Tolmachev, A. A. Yurchenko, A. S. Merkulov and A. M. Pinchuk, Izv. Akad. Nauk, Ser. Khim., 1999, 1353 (in Russian); (b) A. A. Tolmachev, G. V. Oshovsky, A. S. Merkulov and A. M. Pinchuk, Khim. Geterotsikl. Soedin., 1996, 1288 [Chem. Heterocycl. Compd. (Engl. Transl.), 1996, 1109]; (c) G. V. Oshovsky, A. A. Tolmachev, A. S. Merkulov and A. M. Pinchuk, Khim.Geterotsikl. Soedin., 1997, 1422 [Chem. Heterocycl. Compd. (Engl. Transl.), 1997, 1242]. 2 E. D. Raczynska and M. Drapala, J. Chem. Res. (S), 1993, 54. 3 A. A. Tolmachev, A. I. Sviridon, A. N. Kostyuk and A. M. Pinchuk, Heteroatom Chemistry, 1995, 6, 449. 4 (a) V. G. Granik, Usp. Khim., 1983, 52, 669 (Russ. Chem. Rev., 1983, 52, 377); (b) O. L. Acevedo, S. H. Krawczyk and L. B. Townsend, J.Heterocycl. Chem., 1985, 22, 349; (c) R. Troschuetz, Arch. Pharm., 1991, 324, 485; (d) E. N. Dozorova, A. V. Kadushkin, G. A. Bogdanova, N. P. Solov’eva and V. G. Granik, Khim. Geterotsikl. Soedin., 1991, 754 [Chem. Heterocycl. Compd. (Engl. Transl.), 1991, 590]; (e) A. V. Komkov, A. M. Sakharov, V. S. Bogdanov and V. A. Dorokhov, Izv. Akad. Nauk., Ser. Khim., 1995, 1324 (Russ. Chem. Bull., 1995, 44, 1278). 5 (a) O. Meth-Cohn and B. Norine, Synthesis, 1980, 133; (b) V. S. Velezheva, S. V. Simakov, V. N. Dymov and N. N. Suvorov, Khim. Geterotsikl. Soedin., 1980, 851 (in Russian). 6 (a) G. V. Oshovsky, A. M. Pinchuk, A. N. Chernega, I. I. Pervak and A. A. Tolmachev, Mendeleev Commun., 1999, 38; (b) A. A. Tolmachev, A. S. Merkulov, G. V. Oshovsky and A. B. Rozhenko, Zh. Obshch. Khim., 1996, 66, 1930 [J. Gen. Chem. (Engl. Transl.), 1996, 66, 1877]; (c) A. A. Tolmachev, A. S. Merkulov and G. V. Oshovsky, Khim. Geterotsikl. Soedin., 1997, 1000 [Chem. Heterocycl. Compd. (Engl. Transl.), 1997, 877]. Received: 9th February 1999; Com. 99/1440

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Mendeleev Communications Electronic Version, Issue 4, 1999 (pp. 129–170) Addition of secondary phosphines to phenylcyanoacetylene as a route to functional phosphines Boris A. Trofimov, Svetlana N. Arbuzova,* Anastasiya G. Mal’kina, Nina K. Gusarova, Svetlana F. Malysheva, Mikhail V. Nikitin and Tamara I. Vakul’skaya Irkutsk Institute of Chemistry, Siberian Branch of the Russian Academy of Sciences, 664033 Irkutsk, Russian Federation.Fax: +7 3952 35 6046; e-mail: gusarova@irioch.irk.ru Bis(2-phenylethyl)phosphine 1a and bis(2-phenylpropyl)phosphine 1b react chemo- and regioselectively with phenylcyanoacetylene to give [bis(2-phenylalkyl)](1-phenyl-2-cyanoethenyl)phosphines 2 and 3 in quantitative total yields. Amphiphilic functional phosphines with polar hydrophilic groups and hydrophobic branched chains are promising ligands for the design of metal complex catalysts that combine the properties of phase-transfer and micellar catalysts.The synthesis of these phosphines is a topical problem. Here we report an approach to the synthesis of a new family of ternary arylalkylphosphines bearing an acrylonitrile substituent. The nucleophilic addition of bis(2-phenylethyl)phosphine 1a and bis(2-phenylpropyl)- phosphine 1b, which can be easily prepared from elemental phosphorus and arylalkenes,1 to phenylcyanoacetylene is used as an example.It is well known that cyanoacetylenes (primarily phenylcyanoacetylene) easily add N-, O- and S-nucleophiles [ammonia,2 piperidine,2 N-(tert-butyl)hydroxylamine,3 azoles,4 imidazolethiones5 and mercaptoquinolines6] to form, in most cases, Z-isomers of 3-substituted acrylonitriles.The reaction of secondary phosphines with cyanoacetylene proceeds in the same direction.7 However, there are no data on the interaction of phenylcyanoacetylene with PH species, while this reaction makes it possible not only to solve the above problem and to synthesise new functional organophosphorus compounds, but also to obtain additional information on the reactivity of disubstituted acetylenes. The aim of this work was to study the reaction of activated disubstituted acetylenes with secondary phosphines in order to determine its mechanism and chemo-, regio- and stereoselectivity.Scheme 1 demonstrates that phosphines 1a and 1b add readily to phenylcyanoacetylene giving new [bis(2-phenylalkyl)]- (1-phenyl-2-cyanoethenyl)phosphines 2 and 3 in almost quantitative total yields.† The process is chemo- and regioselective: neither 2-substituted acrylonitriles nor products of further addition of starting phosphine 1 to the double bond of compounds 2 and 3 (even with an excess of 1) were formed.The reaction of bis(2-phenylethyl)phosphine 1a with phenylcyanoacetylene proceeds stereoselectively to afford 2a; corresponding E-isomer 3a was formed in negligible amounts (~5%).This fact is in agreement with the trans-mode of nucleophile addition (in particular, P-nucleophiles7,8) to activated acetylenes.9 In contrast to phosphine 1a, more branched bis(2-phenylpropyl) phosphine 1b reacts with phenylcyanoacetylene to form not only the Z-isomer of [bis(2-phenylpropyl)](1-phenyl-2-cyanoethenyl) phosphine 2b, but also a considerable amount of the E-isomer of 3b (the ratio 2b:3b = 3:2).It is unlikely that phosphine 3b resulted from post-isomerization of phosphine 2b, which was formed initially, because the configurational transformation of Z-isomer 2b into E-isomer 3b has been found to occur on heating at 180–200 °C for 5 h.Therefore, the successful competition between the trans- and cis-addition to a triple bond occurs in the case of phosphine 1b because of steric hindrances. Note that the EPR spectrum of the reaction mixture of bis(2- phenylethyl)phosphine 1a and phenylcyanoacetylene in dioxane exhibits a high-resolution signal as a doublet of multiplets with g = 2.0029 and a doublet hyperfine structure constant of ~3 mT.This signal can be attributed10 to the interaction of an unpaired electron with the phosphorus nucleus; this fact indicates that the reaction can proceed via a stage of one-electron transfer. This presumption was also confirmed by UV spectra of the reaction mixture. These spectra exhibited a charge-transfer absorption band at 412 nm, which varied with time.11 At the same time, the addition of small amounts of hydroquinone (up to 3 wt%) to the reaction mixture had almost no effect on the product yields and the reaction time.This fact suggests that the reaction is a nucleophilic addition rather than a chain-radical process. It is likely that the reaction proceeds † General experimental techniques. 31P and 1H NMR spectra were measured on a Jeol-90Q spectrometer.IR spectra were recorded on a Specord 75-IR spectrometer. EPR spectra were studied on an SE/X-2547 EPR spectrometer equipped with an NMR magnetometer and a microwave frequency meter (Radiopan, Poland) at room temperature. UV spectra were recorded on a Specord UV-Vis spectrometer. For 2a (oil): 1H NMR (CDCl3) d: 1.96 (m, 4H, CH2P), 2.65 (m, 4H, CH2Ph), 5.81 (d, 1H, HC=C, 3JPH 16.2 Hz), 7.07–7.37 (m, 15H, Ph). 31P NMR (CDCl3) d: –13.2. For 3a: 31P NMR (CDCl3) d: –9.9. For 2b: 1H NMR (CDCl3) d: 1.23 (m, 6H, Me), 1.70 (m, 4H, CH2P), 2.66 (m, 2H, CHPh), 5.74 (d, 1H, HC=C, 3JPH 17.9 Hz), 7.19–7.35 (m, 15H, Ph). 31P NMR (CDCl3) d: –21.4, –22.4, –23.3. For 3b (oil): 1H NMR (CDCl3) d: 1.20 (m, 6H, Me), 1.72 (m, 4H, CH2P), 2.70 (m, 2H, CHPh), 5.34 (d, 1H, HC=C, 3JPH was too small to be determined), 7.20–7.35 (m, 15H, Ph). 31P NMR (CDCl3) d: –16.7, –16.8, –17.1. Three signals in the 31P NMR spectra of 2b and 3b can be explained by the presence of two asymmetrical centres in the molecules of these compounds). Satisfactory elemental analyses were obtained for phosphines 2 and 3. For 4 (it was identified in the mixture with 2a by 1H and 31P NMR spectroscopy): 1H NMR (CDCl3) d: 2.42 (m, 4H, CH2P), 2.90 (m, 4H, CH2Ph), 6.02 (d, 1H, HC=C, 3JPH 29.2 Hz), 7.19–7.37 (m, 15H, Ph). 31P NMR (CDCl3) d: 38.8. For 5: yield 71%, mp 70–74 °C (CHCl3–Et2O). 1HNMR ([2H6]acetone) d: 2.70 (d, 3H, Me, 2JPH 13.6 Hz), 3.00–3.50 (m, 8H, CH2P, CH2Ph), 6.93–7.61 (m, 16H, HC=C, Ph). 31P NMR ([2H6]acetone) d: 34.53. Found (%): C, 61.88; H, 5.80; I, 23.47; N, 2.73; P, 5.06.Calc. for C26H27INP (%): C, 61.07; H, 5.32; I, 24.83; N, 2.74; P, 6.06. In the IR spectra of compounds 1–5, an absorption band at 2210 cm–1 (nCºN) was present, and no absorption corresponding to CºC and CºN bonds of the initial phenylcyanoacetylene (2270 cm–1 with a shoulder) was observed. Scheme 1 Reagents and conditions: molar ratio 1:PhCºCCN = 1:1, dioxane, room temperature, 1.5 h (for 1a), 5 h (for 1b).(PhCHCH 2)2PH R PhC CCN C C H CN Ph (PhCHCH 2)2P C C CN H Ph (PhCHCH 2)2P R 3 2 a R = H b R = Me R 1Mendeleev Communications Electronic Version, Issue 4, 1999 (pp. 129–170) via an intermediate ion-radical pair which dissociates to only a small extent. The structure and configuration of phosphines 2 and 3 were confirmed by 1H and 31P NMR spectroscopy (from the 31P–1H coupling of an ethenyl group12) and also by chemical transformations.Thus, phosphine 2a was oxidised in air to [bis(2-phenylethyl)]( Z-1-phenyl-2-cyanoethenyl)phosphine oxide 4. In contrast to the majority of ternary phosphines, the oxidation of 2a proceeds slowly; this is probably due to a decrease in the electron density at the phosphorus atom as a result of the conjugation of its lone electron pair with the carbon-carbon double bond and next with the nitrile group.Upon the treatment of phosphine 2a with methyl iodide in dioxane at room temperature, methyl[bis(2-phenylethyl)](Z-1-phenyl-2-cyanoethenyl) phosphonium iodide 5 was prepared. This work was supported by the Russian Foundation for Basic Research (grant no. 98-03-32925a). References 1 B. A. Trofimov, L. Brandsma, S. N. Arbuzova, S. F. Malysheva and N. K. Gusarova, Tetrahedron Lett., 1994, 35, 7647. 2 Ch. Moyreu and M. Bongrad, Ann. Chim., 1920, 14, 5. 3 H. G. Aurich and K. Hahm, Chem. Ber., 1979, 112, 2769. 4 A. G. Mal’kina, Yu. M. Skvortsov, B. A. Trofimov, D.-S. D. Taryashinova, N. N. Chipanina, A. N.Volkov, V. V. Keiko, A. G. Proidakov, T. N. Aksamentova and E. S. Domnina, Zh. Org. Khim., 1981, 17, 2438 [J. Org. Chem. USSR (Engl. Transl.), 1981, 17, 2178]. 5 G. G. Skvortsova, N. D. Abramova, A. G. Mal’kina, Yu. M. Skvortsov, B. V. Trzhtsinskaya and A. I. Albanov, Khim. Geterotsikl. Soedin., 1982, 963 [Chem. Heterocycl. Compd. (Engl. Transl.), 1982, 736]. 6 L. V. Andriyankova, A. G. Mal’kina, A. I. Albanov and B. A. Trofimov, Zh. Org. Khim., 1997, 33, 1408 (Russ. J. Org. Chem., 1997, 1332). 7 R. G. Kostyanovsky and Yu. I. El’natanov, Izv. Akad. Nauk SSSR, Ser. Khim., 1983, 2581 (Bull. Acad. Sci. USSR, Div. Chem. Sci., 1983, 32, 2322). 8 B. A. Trofimov, N. K. Gusarova and L. Brandsma, Main Group Chemistry News, 1996, 4, 18. 9 J. I. Dickstein and S. I. Miller, in The Chemistry of the Carbon–Carbon Triple Bond, ed. S. Patai, Wiley, Chichester, 1978, part 2, p. 813. 10 V. V. Pen’kovskii, Usp. Khim., 1975, 44, 969 (Russ. Chem. Rev., 1975, 44, 449). 11 C. N. R. Rao, in Ultra-violet and Visible Spectroscopy Chemical Applications, Butterworths, London, 1961, p. 230. 12 M. Duncan and M. J. Gallagher, Org. Magn. Res., 1981, 15, 37. Received: 14th October 1998; Com. 98/1381 (8/08243J)

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Mendeleev Communications Electronic Version, Issue 4, 1999 (pp. 129–170) Synthesis and regioselective cycloaddition reactions of 2,4,6-triazido-3,5-dichloropyridine Sergei V. Chapyshev Institute of Problems of Chemical Physics, Russian Academy of Sciences, 142432 Chernogolovka, Moscow Region, Russian Federation. Fax: +7 096 515 3588; e-mail: chap@icp.ac.ru 2,4,6-Triazido-3,5-dichloropyridine, obtained by the reaction of pentachloropyridine with sodium azide, readily adds two molecules of dimethyl acetylenedicarboxylate to the azide groups at the 2- and 6-positions, whereas, in the reaction with norbornene, it forms a cycloadduct only at the azido group in the 4-position.Selective derivatization of azide groups in polyazides is of considerable interest from both theoretical and practical points of view.Recently we have shown1(a)–(e) that cycloaddition of electron-rich dipolarophiles such as norbornene, ButCºCH and ButCºP to 2,4,6-triazidocyanopyridines proceeds regioselectively at the azido group in the 4-position of the pyridine ring to give the corresponding monoadducts as intermediates. However, because of the very low reactivity of these triazides toward electron-deficient dipolarophiles, the cycloadditions of this type have not been studied.To perform these experiments under mild conditions, it was tempting to have a model triazide containing no cyano group at the pyridine ring. Here, the synthesis of 2,4,6-triazido-3,5-dichloropyridine 3 and its reactions with norbornene and dimethyl acetylenedicarboxylate (DMAD) are considered. The reaction of pentachloropyridine 1 with sodium azide was studied earlier.2(a)–(d) The reaction was carried out in aprotic polar solvents such as DMSO or DMF which allowed the authors to obtain only monoazide 2 in 22–62% yield. Although Pannell in his patents2(a),(b) also claimed the preparation of triazide 3, no detail concerning the synthesis and physical characteristics of this compound were reported.Our investigation showed that when pyridine 1 is allowed to react with an excess (molar ratio 1:4) of sodium azide in aqueous acetone (1:10) at room temperature the yield of 2 is increased to 98%. Furthermore, the same reaction at 70 °C for 72 h gave triazide 3† in 84% yield. Figure 1 shows the distribution of the orbital density in the HOMO and the LUMO of triazide 3 computed by the PM3 method.3 The high orbital density on the a-azido groups and almost the lack of it on the g-azido group in the HOMO of 3 indicate4–6 that cycloaddition of electron-deficient dipolarophiles to this triazide occurs at the a-azido groups.By contrast, the higher orbital density on the g-azido group in the LUMO of 3 suggests that this group should be most reactive toward electron-rich dipolarophiles.The reaction of 3 with an excess (1:4) of norbornene was carried out in diethyl ether in the dark at room temperature for two weeks. In contrast to 2,4,6-triazido-3,5-dicyanopyridine, † Characteristic data for compound 3: mp 78–79 °C (decomp.). 13C NMR (CDCl3) d: 109.1 (C-3, C-5), 144.6 (C-4), 148.7 (C-2, C-6).IR (KBr, n/cm–1): 2148, 2131, 2099, 1576, 1559, 1555, 1544, 1541, 1427, 1413, 1387, 1258, 1169, 1111, 936, 832, 778. MS (70 eV), m/z: 270 (M+, 43%). Found (%): C, 22.26; N, 51.57. Calc. for C5Cl2N10 (%): C, 22.16; N 51.68. which readily added three molecules of norbornene under similar conditions,1(e) triazide 3 reacted only with one molecule of this dipolarophile to give cycloadduct 4‡ in 88% yield.The presence of only three signals at d 107.7, 148.2 and 155.2 ppm for the carbon atoms of the pyridine ring in the 13C NMR spectrum of 4 proves that the cycloaddition of norbornene to triazide 3 occurs regioselectively at the g-azido group. Apart from that, the absence of coupling between the endo-protons at d 2.71 and the bridgehead protons at d 2.59 ppm in the 1H NMR spectrum of 4 indicates1(e) stereospecificity of the reaction, which yields only the less hindered exo-adduct.The high orbital density on the azido groups in the LUMO of 4 (Figure 2) testifies that reactions of these groups with electron-rich dipolarophiles are not forbidden by the orbital selection rules.4–6 An explanation of the very low reactivity of this compound toward norbornene comes from an analysis of the frontier orbital energies of ‡ Characteristic data for compound 4: mp 144–145 °C (decomp.). 1HNMR (CDCl3) d: 0.81 (d, 1H, 8-Hsyn, J 10.2 Hz), 1.21 (d, 2H, 6- and 7-Ha, J 7.5 Hz), 1.35 (d, 1H, 8-Hanti, J 10.2 Hz), 1.48 (d, 2H, 6- and 7-He, J 7.5 Hz), 2.59 (s, 2H, bridgehead-H), 2.71 (s, 2H, NCH). 13C NMR (CDCl3) d: 26.5 (CH2CH2), 29.1 (CH2), 37.3 (CH), 45.0 (NCH), 107.8 (C-3, C-5), 148.5 (C-2, C-6), 155.2 (C-4).IR (KBr, n/cm–1): 2970, 2935, 2884, 2148, 1612, 1572, 1418, 1390, 1371, 1286, 1226, 1109, 1066, 975, 827. MS (70 eV), m/z: 336 (M+, 55%). Found (%): C, 42.86; H, 3.12; N, 33.11. Calc. for C12H10Cl2N8 (%): C, 42.75; H, 2.99; N 33.24. aExperimental ionization potential (IP) from ref. 9. bExperimental electron affinity (EA) from ref. 10. Table 1 The HOMO and LUMO energies of azides 3–6, norbornene and DMAD. Compound HOMO/eV LUMO/eV 3 –8.882 –1.176 4 –8.753 –0.802 5 –9.350 –1.615 6 –10.012 –2.098 Norbornene –8.97a 1.70b DMAD –12.077 –0.941 N Cl Cl Cl Cl Cl N Cl Cl N3 Cl Cl NaN3 N N3 Cl N3 Cl N3 NaN3 1 2 3 Et2O, room temperature N N3 Cl N Cl N3 4 DMAD N N Cl N3 Cl N3 N N CO2Me CO2Me 5 room temperature Et2O, room temperature DMAD N N Cl N3 Cl N N N CO2Me CO2Me 6 N N CO2Me CO2MeMendeleev Communications Electronic Version, Issue 4, 1999 (pp. 129–170) reactants.This analysis shows that, due to the presence of an electron-donating aziridine substituent at the pyridine ring, the LUMO energy of 4 is higher by 8.6 kcal mol–1 than that for 3 (Table 1) and by 16.0 kcal mol–1 than the LUMO energy for the 3,5-dicyano derivative of 4.1(e) No surprise that the latter readily reacts with norbornene at room temperature to give the corresponding tris-adduct.The synthesis of 4 demonstrates that despite the moderate reactivity of 3 toward electron-rich dipolarophiles the cycloadditions of this type can be successfully used for mild and selective derivatization of the g-azido group of this triazide.The reaction of 3 with an excess (molar ratio 1:4) of DMAD was carried out in diethyl ether in the dark at room temperature for two weeks. Compound 6§ was obtained as a single product in 75% yield. The presence of only three signals at d 114.7, 142.9 and 149.8 ppm for the carbon atoms of the pyridine ring in the 13C NMR spectrum of 6 testifies that triazole substituents are placed at the 2- and 6-positions of this compound.The spectral characteristics of triazole fragments in 6 are in good agreement with published data.7,8 The formation of bis-adduct 6 shows that in full accord with theoretical predictions the cycloaddition of DMAD to triazide 3, indeed, proceeds at one of the a-azido groups. Intermediate monoadduct 5, in turn, adds another molecule of DMAD to the a-azido group, which also has the highest HOMO orbital density (Figure 2).By comparison of the HOMO energies of 3, 5 and 6 (Table 1) one can find that the addition of one molecule of DMAD to 3 decreases the HOMO energy of azide by 10.8 kcal mol–1 while the addition of two molecules of DMAD, by 25.1 kcal mol–1. It is obvious that the very low reactivity of 6 toward DMAD is explained by the low HOMO energy of this azide.At the same time, straight conversion of 5 into 6 demonstrates that in comparison with reactions of electron-rich dipolarophiles the cycloadditions of electron-deficient dipolarophiles to azides are less sensitive to changes in the frontier orbital energy of azides and can proceed § Characteristic data for compound 6: mp 139–140 °C (decomp.). 1HNMR (CDCl3) d: 3.83 (s, 3H, CO2Me), 3.95 (s, 3H, CO2Me). 13C NMR (CDCl3) d: 53.6 and 54.5 (OMe), 114.7 (C-3, C-5), 131.7 (C-5'), 140.2 (C-4'), 142.9 (C-4), 149.8 (C-2, C-6), 157.4 and 160.1 (C=O). IR (KBr, n/cm–1): 2956, 2144, 1736, 1560. Found (%): C, 36.89; H, 2.32; N, 25.07. Calc. for C17H12Cl2N10O8 (%): C, 36.77; H, 2.18; N 25.23.efficiently at considerably larger energy gaps between the frontier orbitals of addends. Successive selective cycloaddition of electron-rich and/or electron- deficient dipolarophiles to 2,4,6-triazidopyridines provides ample opportunities to synthesise a great variety of novel compounds. References 1 (a) S. V. Chapyshev and T. Ibata, Heterocycles, 1993, 36, 2185; (b) S. V. Chapyshev, Khim.Geterotsikl. Soedin., 1993, 1560 [Chem. Heterocycl. Compd. (Engl. Transl.), 1993, 29, 1426]; (c) S. V. Chapyshev, U. Bergstrasser and M. Regitz, Khim. Geterotsikl. Soedin., 1996, 67 [Chem. Heterocycl. Compd. (Engl. Transl.), 1996, 32, 59]; (d) S. V. Chapyshev and V. M. Anisimov, Khim. Geterotsikl. Soedin., 1997, 676 [Chem. Heterocycl. Compd. (Engl. Transl.), 1997, 33, 587]; (e) S.V. Chapyshev and V. M. Anisimov, Khim. Geterotsikl. Soedin., 1997, 1521 [Chem. Heterocycl. Compd. (Engl. Transl.), 1997, 33, 1315]. 2 (a) C. E. Pannell, US Patent, 3773774, C07d, 1973 (Chem. Abstr., 1974, 80, 59869v); (b) C. E. Pannell, US Patent, 3883542, C07d, 1975 (Chem. Abstr., 1975, 83, 58670y); (c) I. R. A. Bernard, G. E. Chivers, R. J. W. Cremlyn and K. G.Mootoosamy, Aust. J. Chem., 1974, 27, 171; (d) R. A. Abramovitch, S. R. Challand and Y. Yamada, J. Org. Chem., 1975, 40, 1541. 3 (a) J. J. P. Stewart, J. Comput. Chem., 1989, 10, 209; (b) Spartan version 4.0, Wavefunction, Inc., USA, 1995. 4 H. Fujimoto and K. Fukui, in Chemical Reactivity and Reaction Paths, ed. G. Klopman, Wiley–Interscience, New York, 1974, ch. 3. 5 W. Lwowski, in 1,3-Dipolar Cycloaddition Chemistry, ed. A. Padwa, Wiley, New York, 1984, vol. 1, ch. 5. 6 K. N. Houk, Acc. Chem. Res., 1975, 8, 361. 7 T. Sasaki, S. Eguchi, M. Yamaguchi and T. Esaki, J. Org. Chem., 1981, 46, 1800. 8 A. Hassner, M. Stern and H. E. Gottlieb, J. Org. Chem., 1990, 55, 2304. 9 P. Bischof, Helv. Chim. Acta, 1970, 53, 1677. 10 H. Morrison, T. Singh, L. de Cardenas and D. Severance, J. Am. Chem. Soc., 1986, 108, 3862. HOMO of 3 LUMO of 3 Figure 1 The orbital density distribution in the HOMO and the LUMO of 3. LUMO of 4 HOMO of 5 Figure 2 The orbital density distribution in the LUMO of 4 and the HOMO of 5. Received: 4th March 1999; Com. 99/1456

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Mendeleev Communications Electronic Version, Issue 4, 1999 (pp. 129–170) Selective derivatization of 2,4,6-triazidopyridines by the Staudinger reaction Sergei V. Chapyshev Institute of Problems of Chemical Physics, Russian Academy of Sciences, 142432 Chernogolovka, Moscow Region, Russian Federation. Fax: +7 096 515 3588; e-mail: chap@icp.ac.ru The selective addition of triphenylphosphine to the g-azido group of 2,4,6-triazidopyridines has been developed.Selective derivatization of the azide groups in polyazides is of considerable interest. Recently we have shown1–3 that 2,4,6-triazidopyridines 1a–c add electron-rich dipolarophiles to the azido group at the 4-position of the pyridine ring, whereas in reactions with electron-deficient dipolarophiles cycloadducts are formed at the azido groups in the 2- and 6-positions.To extend the synthetic methods of selective derivatization of the azido groups in 2,4,6-triazidopyridines, the nucleophilic additions of triphenylphosphine (Staudinger reaction4) to the azido groups of 1a–c were studied. In the reactions† of 1a–c with an equimolar amount of PPh3 in diethyl ether at 0 °C, only iminophosphoranes 3a–c were formed as the final products in quantitative yields.The structures of 3a–c are supported by the data of elemental analysis and spectroscopic investigations.‡ Thus, for instance, the presence of only three signals at d 111.5 (d, 3JPC 10.2 Hz), 147.0 (s) and 155.2 (d, 2JPC 3.6 Hz) ppm for the carbon atoms of the pyridine ring in the 13C NMR spectrum of 3a unambiguously indicates that the addition of a molecule of PPh3 to triazide 1a occurs regioselectively at the g-azido group.Based on literature analogies, 4 it seems reasonable to assume that the mechanism of the reactions involves initial nucleophilic attack by a molecule of PPh3 on the azide terminus in the g-azido group of 1a–c and formation of phosphazides 2a–c as intermediate products.Compounds 2a–c are obviously unstable at 0 °C and readily lose a molecule of nitrogen to form 3a–c. The reason for the selective nucleophilic addition of PPh3 to the g-azido groups of 1a–c can be rationalised from the analysis of the charge distribution in the azido groups of starting triazides. Thus, as can be seen in Table 1, the g-azido groups of 1a–c have the † A typical procedure for the synthesis of 2,6-diazido-4-iminophosphoranopyridines 3a–c.A diethyl ether solution of triphenylphosphine (2 mmol, 50 ml) was added dropwise to a solution, cooled at 0 °C, of triazide 1a–c (2 mmol) in 100 ml of the ether with stirring. The mixture was kept at 0 °C for 1 h and then warmed to room temperature. The solvent was evaporated under reduced pressure, and the solid residue was recrystallised from hexane. Yields (%): 3a, 93; 3b, 95 and 3c, 97.‡ Characteristic data for 3a: mp 151–152 °C (decomp.). 1HNMR (CDCl3) d: 7.47 (m, 6H, C3'–H), 7.55 (m, 3H, C4'–H), 7.77 (m, 6H, C2'–H). 13C NMR (CDCl3) d: 111.5 (d, C-3, C-5, 3JPC 10.2 Hz), 128.5 (d, C-3', 3JPC 13.1 Hz), 131.4 (d, C-1', 1JPC 106.1 Hz), 131.9 (d, C-4', 4JPC 2.2 Hz), 132.4 (d, C-2', 2JPC 10.2 Hz), 147.0 (s, C-2, C-6), 154.5 (d, C-4, 2JPC 3.6 Hz).IR (KBr, n/cm–1): 2140 (N3), 1630 and 1570 (C=N, C=C). Found (%): C, 54.86; H, 3.17; N, 22.01; P 5.88. Calc. for C23H15Cl2N8P (%): C, 54.68; H, 2.99; N 22.17; P, 6.13. 3b: mp 176–177 °C (decomp.). 1H NMR (CDCl3) d: 7.46 (m, 6H, C3'–H), 7.53 (m, 3H, C4'–H), 7.75 (m, 6H, C2'–H). 13C NMR (CDCl3) d: 92.3 (d, C-5, 3JPC 15.2 Hz), 108.5 (d, C-3, 3JPC 7.3 Hz), 115.8 (CºN), 128.6 (d, C-3', 3JPC 13.1 Hz), 130.5 (d, C-1', 1JPC 106.1 Hz), 131.9 (d, C-4', 4JPC 2.2 Hz), 132.3 (d, C-2', 2JPC 10.2 Hz), 152.0 (s, C-6), 154.1 (s, C-2), 159.2 (d, C-4, 2JPC 2.2 Hz).IR (KBr, n/cm–1): 2225 (CºN), 2145 (N3), 1640 and 1565 (C=N, C=C). Found (%): C, 58.32; H, 3.28; N, 27.98; P 6.04. Calc. for C24H15ClN9P (%): C, 58.14; H, 3.05; N 28.24; P, 6.25. 3c: mp 190–191 °C (decomp.). 1H NMR (CDCl3) d: 7.56 (m, 6H, C3'–H), 7.67 (m, 3H, C4'–H), 7.80 (m, 6H, C2'–H). 13C NMR (CDCl3) d: 89.8 (d, C-3, C-5, 3JPC 12.4 Hz), 115.1 (CºN), 128.9 (d, C-3', 3JPC 13.1 Hz), 129.0 (d, C-1', 1JPC 106.1 Hz), 132.5 (d, C-2', 2JPC 10.9 Hz), 132.7 (d, C-4', 4JPC 2.2 Hz), 159.1 (s, C-2, C-6), 163.4 (d, C-4, 2JPC 2.2 Hz). IR (KBr, n/cm–1): 2230 (CºN), 2150 (N3), 1640 and 1565 (C=N, C=C).Found (%): C, 61.97; H, 3.32; N, 28.55; P 6.16. Calc. for C25H15N10P (%): C, 61.74; H, 3.11; N 28.78; P, 6.37. most electrophilic azide termini. By comparing the charges at the azido groups of 1a–c and their derivatives 3a–c (Table 1), one can also find that the transformation of the g-azido groups of 1a–c into a strong electron-donating N=PPh3 substituent leads to a decrease in the electrophilicity of azide termini in the a-azido groups of pyridines.Therefore, no surprise that the addition of PPh3 to all three azido groups of 1b has been achieved only on prolonged boiling of the reaction mixture in a benzene solution.7 To our knowledge, compounds 3a–c are the first representatives of azides containing an active phosphaza group in the molecule.According to PM3 computations, among three resonance forms 3, 4 and 5 the last one most closely fits the structure of such compounds. This conclusion is in full accord with the published data8,9 on the structure of aryliminophosphoranes. Taking into account the fact that azido and phosphaza groups can be easily modified in numerous fashions4,10 into other N-containing functions, compounds 3a–c can be considered as very promising synthons for the preparation of novel pyridine derivatives.Table 1 The charge distribution on the Ng atoms in azido groups of 1a–c and 3a–c computed by the PM3 and RHF/3-21 G* methods.5,6 Compound 2-N3 4-N3 6-N3 PM3 3-21 G* PM3 3-21 G* PM3 3-21 G* 1a –0.30 — –0.28 — –0.30 — 1b –0.28 0.10 –0.26 0.14 –0.28 0.10 1c –0.27 0.11 –0.24 0.15 –0.26 0.11 3a –0.34 — — — –0.33 — 3b –0.32 — — — –0.32 — 3c –0.31 — — — –0.31 — N R2 N3 N3 N3 R1 N R2 N N3 N3 R1 N N P Ph Ph Ph PPh3 1a–c 2a–c – N2 N R2 N3 N3 R1 N P Ph Ph Ph 3a–c N R2 N3 N3 R1 N P Ph Ph Ph 5a–c N R2 N3 N3 R1 N P Ph Ph Ph 4a–c a R1 = R2 = Cl b R1 = Cl, R2 = CN c R1 = R2 = CNMendeleev Communications Electronic Version, Issue 4, 1999 (pp. 129–170) References 1 S. V. Chapyshev, U. Bergstrasser and M. Regitz, Khim. Geterotsikl. Soedin., 1996, 67 [Chem. Heterocycl. Compd. (Engl. Transl.), 1996, 32, 59]. 2 S. V. Chapyshev and V. M. Anisimov, Khim. Geterotsikl. Soedin., 1997, 1521 [Chem. Heterocycl. Compd. (Engl. Transl.), 1997, 33, 1315]. 3 S. V. Chapyshev, Mendeleev Commun., 1999, 164. 4 (a) Yu. G. Gololobov, I.N. Zhmurova and L. F. Kazukhin, Tetrahedron, 1981, 37, 437; (b) Yu. G. Gololobov and L. F. Kazukhin, Tetrahedron, 1992, 48, 1353. 5 (a) J. J. P. Stewart, J. Comput. Chem., 1989, 10, 209; (b) Spartan version 4.0, Wavefunction, Inc., USA, 1995. 6 M. W. Schmidt, K. K. Baldrige, J. A. Boatz, S. T. Elbert, M. S. Gordon, J. H. Jensen, S. Koseki, N. Matsunaga, K. A. Nguyen, S. J. Su, T. L. Windus, M. Dupius, J. A. Montgomery, J. Comput. Chem., 1993, 14, 1347. 7 S. V. Chapyshev and T. Ibata, Heterocycles, 1993, 36, 2185. 8 M. Pomerantz, D. S. Marynick, K. Rajeshwar, W.-N. Chou, L. Throckmorton, E. W. Tsai, P. C. Y. Chen and T. Cain, J. Org. Chem., 1986, 51, 1223. 9 T. A. Albright, W. J. Freeman and E. E. Schweizer, J. Am. Chem. Soc., 1975, 97, 940. 10 E. Scriven and K. Turnbull, Chem. Rev., 1988, 88, 297. Received: 4th March 1999; Com. 99/1457

ISSN:0959-9436     

出版商:RSC    

年代:1999

数据来源: RSC

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Mendeleev Communications Electronic Version, Issue 4, 1999 (pp. 129–170) Simple synthesis of natural polyketides, 2-dodecanoyl-5-hydroxycyclohexane-1,3-dione and 2-dodecanoylresorcinol Vladimir G. Zaitsev,* Pavel M. Philipchenko and Fedor A. Lakhvich Institute of Bioorganic Chemistry, National Academy of Sciences of Belarus, 220141 Minsk, Belarus. Fax: +375 172 63 7274; e-mail: prostan@ns.iboch.ac.by The title compounds were synthesised in two and three steps, respectively, starting from 5-hydroxycyclohexane-1,3-dione. 2-Dodecanoyl-5-hydroxycyclohexane-1,3-dione 1 was identified1 as the major component of the secretions of Stephanitis takeyai. It was prepared by a complex multistage synthesis including the construction of the cyclohexane ring containing a phenyldimethylsilyl substituent as a masked hydroxy group.2 The authors reported the easy aromatization of hydroxytriketone 1 due to the known succeptibility of b-hydroxyketones to dehydration.Recently, we reported the first synthesis of 5-hydroxycyclohexane- 1,3-dione 2.3 We have found that 5-hydroxydiketone 2 exists in solution mainly in the enolic form, and it takes part in reactions through its enol group.It gives little or no by-product aromatics in the absence of an acid. Based on this finding, we carried out a simple two-step synthesis of target compound 1 by the method developed earlier4 for regioisomeric 2-acyl-4- hydroxycyclohexane-1,3-diones. Acylation of 5-hydroxydiketone 2 with dodecanoyl chloride proceeds regiospecifically, affording enolacylate 3. The latter was then subjected to a smooth O–C isomerization into triketone 1† under the CN– catalysis. This method can be used as a general procedure for the synthesis of other 2-acyl-5-hydroxycyclohexane-1,3-diones.Moreover, these 5-hydroxyketones are the immediate synthetic precursors of natural bioactive 2-acylresorcinols.5 Thus, hydroxytriketone 1 was entirely converted into 2-dodecanoylresorcinol 4‡ when treated with a mineral acid.This work was supported by the Byelarussian Foundation for Basic Research (grant no. X97-109). † 2-Dodecanoyl-5-hydroxycyclohexane-1,3-dione 1. To a stirred solution of 0.39 g (3 mmol) of anhydrous 5-hydroxycyclohexane-1,3-dione 2 (mp 95–96 °C) and 0.25 ml (3.1 mmol) of pyridine in 30 ml of dioxane, 0.60 ml (2.5 mmol) of dodecanoyl chloride in 20 ml of dioxane was added dropwise, over 1 h at room temperature.The solvent was evaporated in vacuo, and 20 ml of CHCl3 was added to the residue. The solution was washed with 0.2 M HCl, H2O, brine, and then dried over MgSO4. The crude product after solvent evaporation was recrystallised from hexane giving 0.71 g (92%) of 3-dodecanoyl-5-hydroxycyclohex-2-en-1-one 3.Mp 43–44 °C. 1H NMR (200 MHz, CDCl3) d: 0.88 (t, 3H, Me, J 6.5 Hz), 1.27 (m, 16H, 4'–11'-CH2), 1.67 (m, 2H, 3'-CH2), 2.48 (t, 2H, 2'-CH2, J 7.5 Hz), 2.55 and 2.64 (2dd, 2H, 4,6-Ha, J 6.5 and 17 Hz), 2.70 (dd, 1H, 4- or 6-He, J 4 and 17 Hz), 2.88 (dd, 1H, 4- or 6-He, J 4 and 17 Hz), 4.43 (m, 1H, 5-H), 5.98 (s, 1H, 2-H). IR (KBr, n/cm–1): 3440 (br.), 1765, 1680, 1660, 1480, 1420, 1380, 1145, 1135, 1115, 1070.To a solution of 0.17 g (0.55 mmol) of enolacylate 3 and 0.24 ml (2.5 mmol) of Et3N in 30 ml of acetonitrile, 0.06 ml (0.6 mmol) of acetone cyanohydrin was added. The reaction mixture was allowed to stand for 3 h at room temperature, then the solvent was evaporated in vacuo, and the residue was worked up as above giving, after recrystallization from hexane, 0.16 g (94%) of 2-dodecanoyl-5-hydroxycyclohexane-1,3-dione 1.Mp 55–56 °C. Physical and chemical characteristics of synthetic 1 are the same as those published.2 ‡ 2-Dodecanoylresorcinol 4 was obtained by dehydration in an acid medium (2 drops of conc. HCl in 20 ml of acetone) of crude hydroxytriketone 1 synthesised as described above from 0.30 g (0.97 mmol) of enolacylate 3.After completing the dehydration reaction (3 h, control by TLC), the solvent was evaporated. The residue was dissolved in CHCl3, washed with H2O and brine, dried over MgSO4, and the solvent was evaporated giving, after recrystallization of the residue from hexane, 0.25 g (88%) of 2-dodecanoylresorcinol 4. Mp 85–86 °C. Physical and chemical characteristics of synthetic 4 are the same as those published.6 References 1 J.E. Oliver, W. R. Lusby and J. W. Neal, Jr., J. Chem. Ecol., 1990, 16, 2243. 2 J. E. Oliver, R. M. Waters and W. R. Lusby, Tetrahedron, 1990, 46, 1125. 3 V. G. Zaitsev and F. A. Lakhvich, Mendeleev Commun., 1998, 20. 4 V. G. Zaitsev, G. I. Polozov and F. A. Lakhvich, Tetrahedron, 1994, 50, 6377. 5 (a) R. A. Jurenka, J. W. Neal, Jr., R. W. Howard, J. E. Oliver and G. I. Blomquist, Comp. Biochem. Physiol., 1989, 93C, 253; (b) Y. Tsuda, Sh. Hosoi and Y. Goto, Chem. Pharm. Bull., 1991, 39, 18; (c) V. G. Zaitsev and F. A. Lakhvich, Mendeleev Commun., 1995, 224. 6 K. K. Purushotaman, A. Sarada and J. D. Connolly, J. Chem. Soc., Perkin Trans. 1, 1977, 587. O O HO OH O HO C11H23COCl; Py dioxane, 1 h, room temperature O O HO O H23C11 O O HO C11H23 O CN OH; Et3N MeCN HCl acetone OH OH C11H23 O 2 3 1 4 Received: 18th December 1999; Com. 98/1414

ISSN:0959-9436     

出版商:RSC    

年代:1999

数据来源: RSC