摘要:

Cl CO2H NH2 Cl HO2C Cl CO2H 1 i,ii O O O Cl Cl O Cl Cl iii iv 2 3 72% 73% O Cl Cl O R2N NR2 3 4 5 NH2 O Me2N NMe2 i,ii iii,iv 35-71% 65% J. CHEM. RESEARCH (S), 1997 183 J. Chem. Research (S), 1997, 183 J. Chem. Research (M), 1997, 1252–1261 A Convenient Route to 3,6-Diaminofluoren-9-ones Stephane G. R. Guinot, John D. Hepworth* and Mark Wainwright Department of Chemistry, University of Central Lancashire, Preston PR1 2HE, UK The synthesis of fluoren-9-ones having a 3,6-bis(tertiary amino) functionality is described, in which the amino groups are introduced using either cyclic secondary amines or their N-formylated derivatives to effect nucleophilic displacement of the halogen from 3,6-dichlorofluoren-9-one, which is derived from 4-chloroanthranilic acid.As part of our studies of di- and tri-arylmethane dyes, we have reported the synthesis of some 4,4p-diaminobenzophenones, 16 analogues of Michler’s ketone, the 4,4p-bis(dimethylamino) derivative. We now describe the preparation of some cyclic analogues, 3,6-diaminofluoren-9-ones, from the commercially available 4-chloroanthranilic acid.On treatment with a cuprammonium reagent, diazotised 4-chloroanthranilic acid underwent a self-coupling process which yielded 5,5p-dichlorobiphenyl-2,2p-dicarboxylic acid (1). Conversion into the anhydride 2, achieved by boiling with acetic anhydride, was followed by in situ pyrolysis at ca. 400 °C to give 3,6-dichlorofluoren-9-one (3) in 53% overall yield (Scheme 1).The nucleophilic displacement of halides in an aromatic environment is known to be promoted by the presence of electron-withdrawing functionalities. However, unless such activation is particularly efficient, as for example in Sanger’s reagent where the preferred halogen,15 fluorine, is activated by two nitro groups, quite severe conditions are necessary. Cyclic secondary amines provide not only a good nucleophilic centre but also enable high reaction temperatures to be achieved and react with 4,4p-difluorobenzophenone to give the corresponding diamino ketone.16 Although not a powerfully activated halogen, both chlorine atoms were displaced from 3,6-dichlorofluoren-9-one by a variety of amine nucleophiles in boiling sulfolane.The aminofluorenones 4b–d were also obtained when the aminating species was derived from the corresponding N-formylamines under basic conditions19 (Scheme 2). Although halide displacement from activated chloro compounds by boiling with N,N-dimethylformamide is well documented, 20 3,6-bis(dimethylamino)fluoren-9-one (4a) could not be obtained in this manner.Similar failure attended the use of N,N-diethylformamide. 3,6-Bis(dimethylamino)fluoren-9-one (4a) was obtained in good yield from 2-amino-4,4p-bis(dimethylamino)benzophenone (5) via diazotisation and intramolecular coupling of the derived radicals under acidic conditions. Careful control of the conditions are essential to the success of the reaction.Techniques used: 1H NMR, flash chromatography References: 25 Schemes: 2 Received, 24th January 1997; Accepted, 27th February 1997 Paper E/7/00560A References cited in this synopsis 15 N. B. Chapman and R. E. Parker, J. Chem. Soc., 1951, 3301; H. Bader, A. R. Hansen and F. J. McCarty, J. Org. Chem., 1966, 31, 2319. 16 S. F. Beach, J. D. Hepworth, P. Jones, D. Mason, J. Sawyer, G. Hallas and M. M. Mitchell, J. Chem. Soc., Perkin Trans. 2, 1989, 1087. 19 T. Watanabe, Y. Tanaka, K. Sekida, Y. Akita and A. Ohta, Synthesis, 1980, 39. 20 N. D. Heindel and P. D. Kennewell, J. Chem. Soc., Chem. Commun., 1969, 38. *To receive any correspondence. Scheme 1 Reagents and conditions: i, HCl, NaNO2 (aq.), 0 °C; ii, CuSO4 (aq.), NH3 (aq.), NH2OH.HCl (aq.), NaOH (aq.); iii, Ac2O, heat; iv, 400 °C Scheme 2 Reagents and conditions: i, R2NH, sulfolane, heat; ii, R2NCHO, KOH, heat; iii, H2SO4, NaNO2, dil. H2SO4, 0–5 °C; iv, Cu bronze, Na2SO4, 90 °C

ISSN:0308-2342    

DOI:10.1039/a700560a

出版商:RSC    

年代:1997

数据来源: RSC

摘要:

N O R1 OR2 R3 O H CMe2, R3 = H 1 H CMe2, R3 = Me R1 = H, R2 = Me, R3 = Me R1 = H, R2 = SiMe2But, R3 = H R1 = H, R2 = CH2Ph, R3 = Me R1 = H, R2 = CH2C R1 = H, R2 = THP, R3 = H R1 = H, R2 = THP, R3 = Me R1 = H, R2 = THP, R3 = CH2OAc R1 = OMe, R2 = Me, R3 = Me R1 = H, R2 = CH2C R1 = H, R2 = H, R3 = CH2OAc R1 = H, R2 = H, R3 = Me R1 = H, R2 = CH2Ph, R3 = H R1 = H, R2 = H, R3 = H R1 = OMe, R2 = Me, R3 = H R1 = H, R2 = Me, R3 = H a b c d e f g h i j k l m n o NH OH R3 O OR2 R1 N O OMe 2 O OH OH Me R1 = OMe, R2 = Me, R3 = H R1 = H, R2 = Me, R3 = H R1 = H, R2 = CH2Ph, R3 = H R1 = H, R2 = H, R3 = H R1 = H, R2 = Me, R3 = CH2Ph 3 a b c d e 184 J.CHEM. RESEARCH (S), 1997 J. Chem. Research (S), 1997, 184–185 J. Chem. Research (M), 1997, 1201–1215 Synthesis of Pyrano[3,2-c]quinolin-5-one Alkaloids: Veprisine, 7-Dimethylallyloxy-N-methylflindersine and cis- 3,4-Dihydroxy-7-methoxy-2,2,6-trimethyl-3,4,5,6-tetrahydro- 2H-pyrano[3,2-c]quinolin-5-one William H. Watters and Venkataraman N.Ramachandran* School of Applied Biological and Chemical Sciences, University of Ulster at Coleraine, Cromore Road, Coleraine, Northern Ireland BT52 1SA, UK Condensation of the appropriate 4-hydroxyquinolin-2-ones with 3-methylbut-2-enal gave pyrano[3,2-c]quinolin-5-ones which were further elaborated to the three alkaloids named in the title. Veprisine (1a), 7-dimethylallyloxy-N-methylflindersine (1b), 7-hydroxy-N-acetyloxymethylflindersine (1c) and the cis-diol of 7-methoxyflindersine (3) are examples of pyrano[3,2- c]quinolin-5-ones which have been isolated in recent years from plant species of the Rutaceae family.1–4 Most of the viable syntheses of these alkaloids involve the cyclisation of the corresponding 3-prenyl-4-hydroxyquinolin-2-ones. We now report the successful synthesis of the pyrano[3,2- c]quinolin-5-one alkaloids named in the title from the 4-hydroxyquinolin-2-ones 2 and 3-methylbut-2-enal by utilisation of the method of De Groot and Jansen7 for the formation of 2H-pyrans by one-step condensation of an a,b-unsaturated aldehyde with 1,3-diketones.The two starting 8-methoxy- and 7,8-dimethoxy-4-hydroxyquinolin- 2-ones (2b and 2a respectively) were prepared by the condensation of the corresponding aromatic amines and malonic acid in the presence of phosphorus oxychloride.8 The 8-benzyloxy-4-hydroxyquinolin-2-one (2c) could not be prepared this way since the acidic reaction conditions would result in the removal of the benzyl group.The alternative method to prepare 8-benzyloxy-4-hydroxyquinolin-2-one by the condensation of 2-benzyloxyaniline with diethyl malonate was unsuccessful. The modified scheme involved the synthesis of 7-hydroxy- flindersine (1f) which could be prepared by the condensation of 3-methylbut-2-enal with 4,8-dihydroxyquinolin-2-one (2d). Demethylation of 8-methoxy-4-hydroxyquinolin-2-one (2b) to 2d was unsuccessful. Synthesis of 2d was finally achieved by the aluminium chloride demethylation and debenzylation of 8-methoxy-3-benzyl-4-hydroxyquinolin-2-one (2e).9 Condensation of quinolin-2-ones 2a, 2b and 2d with 3-methylbut-2-enal in refluxing pyridine in the presence of anhydrous magnesium sulfate gave the desired pyrano[3,2- c]quinolin-5-ones 1g, 1h and 1f in yields ranging from 44 to 69%.N-Methylation of 7,8-dimethoxyflindersine (1g) using NaH–MeI gave veprisine (1a) in 90% yield. This synthesis is the most efficient to date with an overall yield of 51% for the three-step synthesis.The spectral data obtained for 1a corresponded to literature values.1 The cis-diol 3 was synthesised by the osmium tetroxide oxidation of 7-methoxy-N-methylflindersine (1i), formed by the methylation of 7-methoxyflindersine (1h). The spectral data obtained corresponded to the structure 3 for the oxidation product. No literature data are available in order to make a comparison. Since the synthesis of 7-dimethylallyloxy-N-methylflindersine (1b) from 7-hydroxyflindersine (1f) would involve Oalkylation and N-methylation and methylation by most conditions would result in a dimethylated product, protection of the hydroxy group is necessary prior to N-methylation.The first-choice protecting group was the tert-butyldimethylsilyl group and under normal silylating conditions 1f gave 7-tertbutyldimethylsilyloxyflindersine (1j) in 42% yield. N-Methylation with LDA and MeI was unsuccessful and methylation under more basic conditions resulted in desilylation giving 1f as the major product.The benzyl group was the second-choice protecting group and 7-benzyloxyflindersine (1e) was prepared in a modest 20% yield with NaOEt–PhCH2Cl. N-Methylation of 1e with NaH–MeI yielded 7-benzyloxy-N-methyflindersine (1k) but *To receive any correspondence. Fig. 1 Fig. 2J. CHEM. RESEARCH (S), 1997 185 deprotection by triphenylmethyl fluoroborate could not be achieved.At this stage it was decided that direct dimethylallylation might yield a reasonable amount of the O-allylated derivative which could then be N-methylated to give 1b. Treatment of 1f with 1-bromo-3-methylbut-2-ene in the presence of sodium methoxide gave 7-dimethylallyloxyflindersine (1l) in very low yield which was N-methylated to 1b. Spectral data confirmed the formation of 1l and 1b. Since the overall yield for the synthesis of 1b by the above method was very poor, it was decided to look for another protecting group for the hydroxy function and the tetrahydropyranyl group was an obvious choice.Tetrahydropyranylation of 1f with dihydropyran and toluene-p-sulfonic acid was achieved in 59% yield. 7-Tetrahydropyranyloxyflindersine (1m) was N-methylated nearly quantitatively to 7-tetrahydropyranyloxy- N-methylflindersine (1n). Deprotection of 1n was achieved by stirring in a 5% solution of methanolic hydrochloric acid to yield 7-hydroxy-N-methylflindersine (1d). 1b was finally prepared by reaction of 1d with 1-bromo- 3-methylbut-2-ene and anhydrous K2CO3 in dry acetone. All the structures for the intermediates and the final product were established by mass spectroscopy and 1H NMR. The spectral data were in complete agreement with literature values reported for the natural product.2 Synthesis of 7-hydroxy-N-acetyloxymethylflindersine (1c) could not be achieved since N-alkylation of 1m with chloromethyl acetate under a number of different conditions was unsuccessful. Techniques used: 1H NMR, IR, MS References: 10 Figures: 2 Received, 2nd December 1996; Accepted, 19th February 1997 Paper E/6/08110J References cited in this synopsis 1 J. F. Ayafor, B. L. Sondengam and B. T. Ngadjui, Phytochemistry, 1982, 21, 2733. 2 S. A. Khalid and P. G. Waterman, J. Nat. Prod., 1977, 45, 343. 3 F. R. Stermitz and I. A. Sharifi, Phytochemistry, 1977, 16, 2003. 4 A. I. Gray and J. J. O’Sullivan, unpublished data cited by I. Mester in Chemistry and Chemical Taxonomy of the Rutales, ed. P. G. Waterman and M. F. Grundon, Academic Press, London, 1983, p. 31. 7 A. De Groot and B. J. M. Jansen, Tetrahedron Lett., 1975, 3407. 8 T. Kappe and E. Ziegler, Tetrahedron Lett., 1968, 1947. 9 T. H. Kappe, H. Schmidt and E. Ziegler, Z. Naturforsch., Teil B, 1970, 25, 328.

ISSN:0308-2342    

DOI:10.1039/a608110j

出版商:RSC    

年代:1997

数据来源: RSC

摘要:

N N N N N O– Ni N 2+ I 186 J. CHEM. RESEARCH (S), 1997 J. Chem. Research (S), 1997, 186–187 J. Chem. Research (M), 1997, 1216–1236 Kinetics of the Oxidation of Thioglycolic and Thiomalic Acids by a Nickel(III) Oxime–Imine Complex Amitava Dutta, Basudeb Saha, Mahammad Ali and Pradyot Banerjee* Department of Inorganic Chemistry, Indian Association for the Cultivation of Science, Jadavpur, Calcutta-700 032, India The kinetics of the oxidation of thioglycolic and thiomalic acids by [NiIIIL1]2+ (where HL1=15-amino-3-methyl- 4,7,10,13-tetraazapentadec-3-en-2-one oxime) have been investigated at 30.0 °C; an inner-sphere mechanism for both the reactions has been proposed except for the fully deprotonated species of thiomalic acid which follows an outer-sphere route.Studies on the thiol–disulfide interchange reactions are of immense importance in biochemistry.1,2 However this type of transformation by metal complexes has received much less attention. In this investigation we present the kinetic results on the oxidation of thioglycolic acid (H2A) and thiomalic acid (H3A) by the nickel(III) oxime–imine complex I.Spectrophotometric determination at 498 nm (lmax for [NiIII(L1)]2+, hereafter designated as NiIII) revealed a 1:1 stoichiometric ratio for both the reactions leading to the disulfide products [eqn. (1)]. 2NiIII+2RSHh2NiII+RSSR+2H+ (1) RSH and RSSR represent respectively the thiols and the corresponding disulfide products. Generation of free radicals and characterisation of disulfide products were achieved by reported9,24 methods.Under pseudo-first-order conditions with varied concentrations of reductants, a plot of kobs vs. [H2A]T gives a straight line passing through the origin whereas that for H3A is a limiting curve of decreasing slope with nearly zero intercept (Table 1). The corresponding rate laws are given by eqns. (2) and (3) respectively. µd/dt[NiIII] =k[H2A][NiIII] =kobs[NiIII] (2) µd/dt[NiIII] = kQ[H3A]T[NiIII] 1+Q[H3A]T =kobs[NiIII] (3) Q k NiIII+H3AMNiIII.H3AhProducts (3a) Q is the association constant as defined by eqn.(3a) and represents the oxidation of thiomalic acid. The effect of acidity on the reaction rates was investigated in the pH range 2.51–8.05 for H2A and 2.71–8.25 for H3A as shown in Figs 1(a) and (b). Dependence on acidity can best be explained by considering the pK values of H2A and H3A.25 In the experimental pH range, the existing thioglycolic acid species are H2A, HAµ and A2µ.Their reactions can be portrayed as: NiIII+H2AhNiII+radical (4) NiIII+HAµhNiII+radical (5) NiIII+A2hNiII+radical (6) radical+radicalhdisulfide (7) The general rate law derived from the above is: kox= k4[H+]2+k5K1[H+]+k6K1 [H+]2+K1[H+]+K1K2 (8) Considering the pH range 2.51–6.70, the parameters k4, k5 and K1 were evaluated by a non-linear least-squares programme: k4=(22.5�2.8) dm3 molµ1 sµ1, k5=(3.05 �0.10)Å102 dm3 molµ1 sµ1 and K1=(5.36�0.13) *To receive any correspondence.Fig. 1 Variation of kox as a function µlog[H+] for the reduction of [NiIII(L1)]2+ by (a) thioglycolic acid and (b) thiomalic acid at 30.0 °C with [NiIII(L1)]2+=5.0Å10µ5 mol dmµ3, I=0.20 mol dmµ3 (NaClO4) and [buffer] =0.02 mol dmµ3: the solid line represents calculated values, points represent experimental values Table 1 Pseudo-first-order rate constants at various reductant concentrations for the oxidations of thioglycolic acid and thiomalic acid by [NiIII(L1)]2+ with [[NiIII(L1)]2+] =5.0Å10µ5 mol dmµ3, I=0.2 mol dmµ3 (NaClO4), [OAcµ] =0.02 mol dmµ3 and temperature=30.0 °C kobs/sµ1 102[Reductant]/ Reductant mol dmµ3 pH 4.75 pH 5.90 Thioglycolic acid 0.10 0.30 0.50 0.70 0.90 0.10 0.27 0.41 0.56 0.69 Thiomalic acid 0.05 0.10 0.20 0.30 0.50 0.70 1.00 0.75 1.25 1.79 2.33 2.94 3.44 4.11J.CHEM. RESEARCH (S), 1997 187 Å10µ6 mol dmµ3 (pK1=5.23, reported 3.58). Similarly from the pH range 7.0–8.05, the values of k5=(2.86� 0.1)Å102 dm3 molµ1 sµ1 and k6=(5.36�0.13)Å 103 dm3 molµ1 sµ1 were obtained using K2=1.66Å10–10 mol dmµ3.The reacting species of thiomalic acid in the experimental pH range are H3A, H2Aµ, HA2µ and A3µ. Their reactions towards the NiIII complex can be represented by: NiIII+H3AhNiII+radical (12) NiIII+H2AµhNiII+radical (13) NiIII+HA2µhNiII+radical (14) NiIII+A3µhNiII+radical (15) The corresponding rate law is: kox= k12[H+]3+k13K1[H+]2+k141K2[H+]+k15K1K2K3 [H+]3+K1[H+]2+K1K2[H+]+K1K2K3 (16) In suitable pH ranges, the values of the evaluated parameters are: k12=(1.72�0.3)Å102 dm3 molµ1 sµ1, k13=(4.10 �0.2)Å102 dm3 molµ1 sµ1, k14=(1.24�0.5)Å103 dm3 molµ1 sµ1, k15=(2.53�0.09)Å105 dm3 molµ1 sµ1, K1=(4.15�0.03)Å10µ4 mol dmµ3 (pK1=3.38, reported 3.64) and K2=(9.77�0.05)Å10µ6 mol dmµ3 (pK2=5.01, reported 4.64). Putting the corresponding evaluated parameters in eqns.(8) and (16), kox values at different experimental [H+] were obtained and these showed an excellent agreement with the experimental values for both thiols.The low spin (t2g 6eg 1) nickel(III) complexes having an unpaired electron in the dz2 orbital are generally substitutionally inert, although there is no experimental estimate of the ligand exchange rate for [NiIII(L1)]2+ and thereby reactions involving this complex are likely to follow an outersphere route. However, the formation of a hydrogen bonded intermediate in many of the electron transfer reactions of NiIII/IV oxime–imine complexes17,20–22 has been proposed.The initial rapid increase in the absorbance in the 20–30 ms timescale of thioglycolic acid oxidation points to inner-sphere coordination of the thiol molecule to the metal centre, probably by the partial release of one of the nitrogen atoms of the coordinated N6-oxime–imine frame. In the oxidation of thiomalic acid and other carboxylic acids (glycolic and malic acid), no such initial rise in absorbance was noted but the former oxidation was found to proceed through rate saturation. The higher reactivity of H2A towards [NiIII(L1)]2+ (E°=0.49 V, kex=102 dm3 molµ1 sµ1) is higher than that towards [MnIII(cdta)]µ (E°=0.81 V, kex=4.4Å108 dm3 molµ1 sµ1).This can be explained by considering the hydrogen bond formation between the carboxylato hydrogen atom and the oximato oxygen atom (�N·Oµ), which may substantially increase the lability of the metal centre through the sulfur atom and thereby provide a lower energy pathway for the electron transfer process.The lack of a carboxylato proton in HAµ and A2µ species explains their lower reactivity towards [NiIII(L1)]2+ than [MnIII(cdta)]µ. For the oxidation of thiomalic acid, a higher formation constant obtained from kinetics indicates that the reaction proceeds either through the initial formation of a hydrogen bonded adduct or through the coordination of the ligand to the metal centre by the SH group. In the oxidation of A3µ, no hydrogen bonding effect is possible and so an outer-sphere mechanism is more likely.We acknowledge the CSIR (New Delhi) for financial assistance. Techniques used: UV–VIS, elemental analysis, pH-metry References: 29 Table 2: Pseudo-first-order rate constants at various concentrations of glycolic acid and malic acid Table 3: Decomposition rate of [NiIII(L1)]2+ as a function of pH at 40.0 °C Fig. 2: kox vs. µlog[H+] for malic acid oxidation by [NiIII(L1)]2+ Schemes: 2 Received, 10th January 1997; Accepted, 21st February 1997 Paper E/7/00249A References cited in this synopsis 1 H. F. Gilbert, Adv. Enzymol., 1995, 63, 69. 2 R. Singh and G. M. Whitesides, The Chemistry of Sulfur Containing Functional Groups, ed. S. Patai and Z. Rappoport, Wiley, London, 1993. 9 S. Gangopadhyay, M. Ali, A. Dutta and P. Banerjee, J. Chem. Soc., Dalton Trans., 1994, 841. 17 A. McAuley, C. J. d P. R. West, J. Chem. Soc., Dalton Trans., 1988, 2279. 20 S. Bhattacharya, M. Ali, S. Gangopadhyay and P. Banerjee, J. Chem. Soc., Dalton Trans., 1994, 3733. 21 B. Saha, S. Gangopadhyay, M. Ali and P. Banerjee, Proc. Acad. Sci. (Chem. Sci.), 1995, 107, 393. 22 S. Bhattacharya, M. Ali, S. Gangopadhyay and P. Banerjee, J. Chem. Soc., Dalton Trans., 1996, 2645. 24 W. R. Cullen, B. C. Mcbride and J. R. Reglinski, J. Inorg. Biochem., 1984, 21, 45. 25 Stability Constants of Metal Ion Complexes, ed. L. G. Sillen and A. E. Martell, The Chemical Society, London, Special Publ. No. 17, 1964, pp. 376, 423, 367 and 411.

ISSN:0308-2342    

DOI:10.1039/a700249a

出版商:RSC    

年代:1997

数据来源: RSC

摘要:

O O N O O O N O O OH N O OH 1 MeO OMe MeO OMe 2 3 188 J. CHEM. RESEARCH (S), 1997 J. Chem. Research (S), 1997, 188–189 J. Chem. Research (M), 1997, 1237–1251 The X-Ray Crystal Structures of Two Derivatives of 2,6-Bis{[2-(dimethoxymethyl)phenoxy]methyl}pyridine Harry Adams, David E. Fenton,* Yuh-Shan Ho, Blanca A. Najera and Cecilia O. Rodriguez de Barbarin Department of Chemistry, Dainton Building, The University of Sheffield, Sheffield S3 7HF, UK The X-ray crystal structures of 2,6-bis{[2-dimethoxymethyl)phenoxy]methyl}pyridine and 2,6-bis{[2-(hydroxymethyl)- phenoxy]methyl}pyridine are reported.We have previously reported that the reaction of 2,2p- [pyridine-2,6-diylbis(methyleneoxy)]dibenzaldehyde (1) and bis(2-aminoethyl) ether, in the presence of barium cations as a templating device, can yield a [1+1] macrocyclic Schiff base.1 Reaction of this macrocycle with cerium nitrate led to the isolation of the complex [Ce(1)2](NO3)3 .2H2O, hydrolysis of the macrocycle having occurred.2 Consequently we have investigated the potential complexation properties of 1 towards the lanthanides3 and have shown that whilst [Ce(1)2](NO3)3 .2H2O can be formed by the reaction of cerium nitrate with 1 in a mixed methanol–acetonitrile medium a very different white crystalline product is formed when the reaction is carried out in methanol alone.Spectroscopic analysis of this product suggested that acetal formation had occurred to give 2,6-bis{[2-(dimethoxymethyl)- phenoxy]methyl}pyridine (2), as we had previously noted in the reaction of 1 with lead(II) salts.1 Recrystallisation of 1 from methanol alone gave no acetal formation, suggesting that 2 is produced as a result of a metal ion activated reaction. A single crystal X-ray crystal structure determination con- firmed the nature of 2 (Fig. 1). The bond angles and distances in the ligand are comparable to those reported for the related compound, pyridine-2,6-dimethanol.7 Crystal Data for 2.·C25H29NO6, Mr=439.49, colourless oblong crystals from methanol, crystal dimensions 0.66Å 0.44Å0.25 mm, monoclinic, a=9.609(3), b=9.327(2), c=26.101(3) Å, b=96.101(2)°, U=2326.0(9) Å3, Z=4, Dc=1.255 g cmµ3, space group P21/n, Mo-Ka radiation (�l =0.71069 Å), m(Mo-Ka)=0.90 cmµ1, F(000)=936.Three-dimensional, room temperature X-ray data were collected in the range 3.5s2ys45° on a Siemens P4 diffractometer by the omega scan method. Of the 4186 reflections measured, all of which were corrected for Lorentz and polarisation effects (but not for absorption), 2250 independent reflections exceeded the significance level |F|/s(|F|)a4.0.The structure was solved by direct methods and refined by full matrix least squares on F2. Hydrogen atoms were included in calculated positions and refined in riding mode. Refinement converged at a final R=0.0571 (wR2=0.1700, for all 3024 data, 289 parameters, mean and maximum d/s 0.000, 0.000), with allowance for the thermal anisotropy of all non-hydrogen atoms.Minimum and maximum final electron density µ0.312 and 0.390 e ŵ3. A weighting scheme w=1/[s2(Fo2)+(0.0895P)2+1.1610P] where P=(Fo2+2Fc2)/ 3 was used in the latter stages of refinement. Complex scattering factors were taken from the program package SHELXL935 as implemented on the Viglen 486dx computer. The structure of 2 may be compared with that of the dialcohol, 2,6-bis{[2-(hydroxymethyl)phenoxy]methyl}pyridine (3) (Fig. 2), prepared by reduction of 1 using NaBH4.5 The dialcohol is isolated as the monohydrate 3.H2O, and the water molecule helps augment three dimensional molecular aggregation, bridging adjacent molecules of 3 by hydrogen bonding to a pyridine nitrogen atom from one molecule and to an alcoholic oxygen atom from an adjacent molecule. Crystal Data for 3. H2O.·C21H23NO5, Mr=369.42, pale yellow prismatic crystals from acetonitrile, crystal dimensions 0.25Å0.85Å0.08 mm, triclinic, a=11.222(4), b=11.308(4), c=7.588(9) Å, a=81.277(12)°, b=105.718(20)°, g= 87.139(6)°, U=912.0(11) Å3, Z=2, Dc=1.350 g cmµ3, space group P�1 (C1i , no. 2), Mo-Ka radiation (�l =0.71069 Å), m(Mo-Ka)=0.90 cmµ1, F(000)=391.95. The experimental data were collected at room temperature in the range 6.5s2ys50.0° on a Stoe Stadi 2 diffractometer by the omega scan method (h from µ15 to 15, k from µ15 to 15, l from 0 to 8). The 1575 independent reflections (of 3187 measured) for which I/s(I)a3.0 were corrected for Lorentz and polarisation effects but not for absorption.The structure was solved by direct methods. Hydrogen atoms were detected and *To receive any correspondence. Fig. 1 X-Ray crystal structure of 2 Fig. 2 X-Ray crystal structure of 3J. CHEM. RESEARCH (S), 1997 189 placed in calculated positions and refined in riding mode with isotropic thermal vibrational parameters related to those of the supporting atoms. One of the alcoholic H atoms was found to be disordered between sites with necessarily equal population.These hydrogens were constrained with an O·H distance of 1.00 Å and refined in riding mode. Refinement by block cascade least-squares methods converted to a final R of 0.0516 (Rw=0.0595) for 244 parameters, with allowance for thermal anisotropy of all non-hydrogen atoms. A weighting scheme wµ1=[s(2(F)+0.0035 F2] was used in the final stages of refinement. The maximum value of d/s in the final cycle was 0.009 (mean value 0.001).The final difference electron density map showed maximum and minimum of 0.194 and µ0.221 e ŵ3. Complex scattering factors were taken from the program package SHELXTL6 as implemented on the Data General DG30 computer. We thank the EPSRC and the Royal Society for funds towards the purchase of the diffractometer and CONACYT for support to B. A. N. and C. O. R. Techniques used: X-ray diffraction References: 7 Figures: 3 Tables 1 and 3: Atomic coordinates and equivalent isotropic displacement parameters for 2 and 3 respectively Tables 2 and 4: Bond lengths (Å) and bond angles (°) for 2 and 3 respectively Tables 5–8: Anisotropic displacement parameters, hydrogen coordinates and isotropic parameters Received, 30th January 1997; Accepted, 21st January 1997 Paper E/7/00690J References cited in this synopsis 1 H.Adams, N. A. Bailey, R. Bastida, D. E. Fenton, Y.-S. Ho and P. D. Hempstead, J. Chem. Res., 1992, (S) 190; (M) 1501. 2 H. Adams, C. O. Rodriguez de Barbarin, D. E. Fenton, Y.-S. Ho and G. J. Humber, Inorg. Chim. Acta, 1995, 232, 227. 3 B. A. Najera, unpublished results, 1996 5 G. M. Sheldrick, SHELXL93 Program for crystal structure refinement, University of Gottingen, Germany, 1993. 6 G. M. Sheldrick, SHELXTL, An integrated system for solving, refining and displaying crystal structures from diffraction data (Revision 5.1), University of Gottingen, Germany 1985. 7 W. Bell, P. I. Coupar, G. Ferguson and C. Glidewell, Acta Crystallogr., Sect. C, 1996, 52,

ISSN:0308-2342    

DOI:10.1039/a700690j

出版商:RSC    

年代:1997

数据来源: RSC

摘要:

Me Me Me Me Br H [CH2] n PhCH2NMe3Br3 – Br in CH2Cl2 room temp. (5 min) H b; n = 3 c; n = 4 [CH2] n 1 b; n = 3 c; n = 4 cis-3 + (2) Me Me Br H Br H Me Me OAc H Br H Me Me H AcO OAc H [CH2] n b; n = 3 c; n = 4 cis-5 Me cis-3 Me b; n = 3 c; n = 4 OAc H OAc [CH2] n H 4 [CH2] n trans-5c + AgOAc– HOAc b; n = 3 c; n = 4 [CH2] n + 190 J. CHEM. RESEARCH (S), 1997 J. Chem. Research (S), 1997, 190–191 J. Chem. Research (M), 1997, 1301–1322 Medium-sized Cyclophanes. Part 42.1 Synthesis of [2.n]Metacyclophan-1-ones and [2.n]Metacyclophane- 1,2-diones Takehiko Yamato,*a Koji Fujita,a Seiji Idea and Yoshiaki Naganob aDepartment of Applied Chemistry, Faculty of Science and Engineering, Saga University, Honjo-machi 1, Saga-shi, Saga 840, Japan bTohwa Institute of Science, Tohwa University, 1-1 Chikushigaoka, Minami-ku, Fukuoka 815, Japan Acetolysis of 10-endo, 11-exo-dibromo-6,14-di-tert-butyl-9,17-dimethyl[3.2]metacyclophane cis-3b afforded the corresponding 10,11-diacetoxy derivative cis-5b with retention of configuration, whereas in the case of [4.2]metacyclophane cis-3c the same stereoselectivity was not observed: the diacetoxy derivatives 5 were converted into a 10,11-dione 10b and a 11,12-dione 10c via hydrolysis followed by Swern oxidation of dihydroxy derivatives 7b and 7c.For many years various research groups have been attracted by the chemistry and spectral properties of the [2.2]MCP ([2.2]MCP=[2.2]metacyclophane) skeleton.2,3 Its conformation, which has been elucidated by X-ray measurements,4 is frozen into a chair-like non-planar form. Many attempts have been made directly to introduce functional groups into the methylene groups of [2.2]MCPs, but these have failed because of deviation of the benzyl carbon atom from the plane of the benzene ring.5g Singler and Cram have reported that bromination of [2.2]paracyclophan-1-ene with bromine affords the corresponding cis-adduct.6 Recently, we have reported that di-tertbutyl( dimethyl)[2.n]MCP-1-enes 1b,c when treated with an equimolar amount of benzyltrimethylammonium tribromide (BTMA Br3) in methylene dichloride9a afford the cis-adducts 3b,c to the bridged double bond in 90 and 95% yield, respectively [eqn. (2)].These results indicate the first success in the introduction of two bromo groups into the methylene groups of dimethyl[n.2]MCPs. We undertook the present work in order to extend the novel reaction mentioned above. We report here on the acetolysis of bromine adducts with silver acetate in acetic acid and the conversion into the 10,11-dione 10b and 11,12-dione 10c via hydrolysis followed by Swern oxidation of the dihydroxy derivatives 7.Acetolysis of 10-endo,11-exo-dibromo-6,14-di-tert-butyl- 9,17-dimethyl[3.2]MCP cis-3b with silver acetate in acetic acid at 60 °C for 30 min afforded the corresponding 10-acetoxy derivative 4b with complete retention of configuration in 90% yield. A prolonged reaction time (to 12 h) and higher reaction temperature (to 90 °C) furnished complete acetolysis to afford 10-endo,11-exo-diacetoxy-6,14-di-tert-butyl- 9,17-dimethyl[3.2]MCP cis-5b with complete retention of configuration at the 10,11 positions in the bridged cyclophane ring.In contrast, in the case of the [4.2]metacyclophane cis-3c the same stereoselectivity was not observed under either set of reaction conditions. Thus, 11,12-bis(endo-acetoxy)- 7,15-di-tert-butyl-10,18-dimethyl[4.2]MCP trans-5c was obtained in 30 and 40% yields along with 4c and cis-5c, respectively.These results can be attributed to the nature of the cyclophane structure, like in the acetolysis of 1,2-dibromo[2.2]paracyclophane. 10a The stereoselectivity of the acetolysis decreases with increasing the length of the methylene bridges and the distances between the two aromatic rings. Acetates 4 and cis-5 were easily converted into the corresponding alcohols 6 and cis-7 by hydrolysis with alcoholic KOH at 50 °C for 15 min in almost quantitative yields.Attempted oxidation of monools 6b and 6c with pyridinium chlorochromate12 carried out in a methylene dichloride *To receive any correspondence (e-mail: yamatot@cc.saga-u. ac.jp). Table 1 Acetolysis of cis-3 with AgOAc in acetic acida Temp. Time Run Substrate (T/°C) (t/h) Products (%) 1234 cis-3b cis-3b cis-3c cis-3c 60 90 60 90 0.5 12 0.5 12 4b (90) cis-5b (87) 4c (60), trans-5c (30) cis-5c (50), trans-5c (40) aIsolated yields are shown. Scheme 1Me Me OH H X H [CH2] n b X = Br, n = 3 c X = Br, n = 4 6 b X = OH, n = 3 c X = OH, n = 4 cis-7 Me Me [CH2] n b X = Br, n = 3 c X = Br, n = 4 8 b X = H, n = 3 c X = H, n = 4 9 Me Me O [CH2] n b n = 3 c n = 4 10 O X H O Me N N Me H2N H2N in EtOH, room temp., 24 h (quant.) 10b 12b J.CHEM. RESEARCH (S), 1997 191 solution at room temperature for 1 h led to the expected monoketones 8b and 8c as a single product in 61 and 90% yields, respectively.Monoketones 8b and 8c were easily converted into the corresponding 9b and 9c by reduction with zinc powder in acetic acid at 80 °C for 15 min. In contrast, an attempted oxidation of the cis-diol cis-7b to the 11,12-dione 10b with pyridinium chlorochromate carried out in a methylene dichloride solution under the same reaction conditions as described above failed. Only the cleavage reaction product, 1,3-bis(5-tert-butyl-3-formyl-2-methylphenyl) propane 11b, was obtained in quantitative yield.This finding seems to support the strained nature of the diketone 10b compared to the monoketones 8b and 9b, in spite of these having the same ring size. Fortunately, Swern oxidation13 of cis-7b succeeded in affording the desired [3.2]diketone 10b in quantitative yield. However, 10b was found to be labile during silica gel column chromatography, and on refluxing in hexane it gave only intractable mixtures. Thus, a trapping reaction of diketone 10b with o-phenylenediamine was attempted, in which the crude diketone 10b was treated with o-phenylenediamine in ethanol at room temperature for 24 h to afford in almost quantitative yield the desired [3.2]MCP 12b having a quinoxaline skeleton (Scheme 3).Similarly, in the case of [4.2]MCP, Swern oxidation of the cis-diol cis-7c also succeeded in affording the desired diketone 10c in 70% yield as stable colourless prisms. This finding seems to support the notion that the strain of the [3.2]diketone 10b compared to the [4.2]diketone 10c increases as the length of the methylene bridge decreases.The low frequency in the IR spectrum (1700 cmµ1 for 9b and 1696 cmµ1 for 9c) in comparison with that of the reference compound, 5-tert-butyl-2,3-dimethylbenzyl 5-tert-butyl- 2,3-dimethylphenyl ketone (1685 cmµ1), presumably and in analogy with the corresponding paracyclophane analogue, 10a,14 reflects expanded OCC bond angles rather than conjugation. Bathochromic shifts were observed in the cyclophane ketones 9b,c and the diketone 10b, which are ascribed to a transannular interaction between the two benzene rings and an increase in the strain of these systems.15 The lack of an acetophenone-type chromophore in the UV spectrum of the MCP ketones confirms the non-planarity of the aromatic ring and carbonyl group. In conclusion, we have demonstrated that acetolysis o f 1 0 - e n d o , 1 1 - e x o - d i b r o m o - 6 , 1 4 - d i - t e r t- b u t y l - 9 , 1 7 - d i m e t h y l - [3.2]MCP cis-3b affords the corresponding 10,11-diacetoxy derivative 5b with retention of configuration, whereas in the case of [4.2]MCP 3c the same stereoselectivity is not observed.The present results of the stereoselective acetolysis of bromine adducts of [2.n]MCP-1-enes will open up new mechanistic aspects for cyclophane chemistry. Also, diacetoxy derivatives 5 were converted into the 10,11-dione 10b and the 11,12-dione 10c via hydrolysis followed by Swern oxidation of the dihydroxy derivatives 7.Further studies on the chemical properties of the monoketone 9 and diketone 10 are now in progress. Techniques used: 1H NMR, IR, mass spec. References: 15 Schemes: 3 Fig. 1: UV absorption spectra of [n.2]MCP ketones 9b, 9c and reference compound 13 in cyclohexane Fig. 2: UV absorption spectra of [n.2]MCP diketone 10c and reference compound benzil 14 in cyclohexane Table 2: 1H NMR data for [2.n]MCP-1-ones 8, 9 and [2.4]MCP- 1,2-dione 10c Received, 2nd September 1996; Accepted, 3rd March 1997 Paper E/6/06019F References 1 Part 41: T. Yamato, K. Fujita, N. Shinoda, K. Noda, Y. Nagano, T. Arimura and M. Tashiro, Research on Chemical Intermediates, 1996, 22, 871. 2 R. W. Griffin, Jr., Chem. Rev., 1963, 63, 45. 3 D. J. Cram, Acc. Chem. Res., 1971, 4, 204. 4 C. J. Brown, J. Chem. Soc., 1953, 3278. 5 (g) B. H. Smith, Bridged Aromatic Compounds, Academic Press, New York, 1964. 6 R. E. Singler and D. J. Cram, J. Am. Chem. Soc., 1972, 94, 3512. 9 (a) T. Yamato, J. Matsumoto, S. Ide, K. Suehiro, K. Kobayashi and M. Tashiro, Chem. Ber., 1993, 126, 447. 10 (a) R. E. Singer and D. J. Cram, J. Am. Chem. Soc., 1971, 93, 4443. 12 G. Piancatelli, A. Scettri and M. D’Auria, Synthesis, 1982, 245. 13 A. J. Mancuso, S. L. Huang and D. Swern, J. Org. Chem., 1978, 43, 2480. 14 D. J. Cram and R. C. Helgeson, J. Am. Chem. Soc., 1966, 88, 3515. 15 Cyclophanes, ed. P. M. Keehn and S. M. Rosenfield, Academic Press, New York, 1983, vol. 1, ch. 6, p. 428. Scheme 3

ISSN:0308-2342    

DOI:10.1039/a606019f

出版商:RSC    

年代:1997

数据来源: RSC

摘要:

R¢ S R¢ 15 S 6 S 9 R S syn-conformer R 18 anti-conformer XCH2 CH2X R HSCH2 CH2SH OMe + S 3 4a 15 6 S 18 OMe syn-5 9 R R = H, X = Br (67%) i R = Me, X = Br R = Br, X = Cl R = NO2, X = Br R = But, X = Br a b c d e R = H R = Me R = Br R = NO2 R = But a b c d e (61%) (41%) (67%) (60%) 192 J. CHEM. RESEARCH (S), 1997 J. Chem. Research (S), 1997, 192–193 J. Chem. Research (M), 1997, 1323–1343 Medium-sized Cyclophanes. Part 44.1 Synthesis and Stereochemical Assignments of 9-Substituted 2,11-Dithia[3.3]metacyclophanes Takehiko Yamato,*a Mitsuaki Shigekuni,a Hidetsugu Kunugidaa and Yoshiaki Naganob aDepartment of Applied Chemistry, Faculty of Science and Engineering, Saga University, Honjo-machi, Saga-shi, Saga 840, Japan bTohwa Institute of Science, Tohwa University, 1-1 Chikushigaoka, Minami-ku, Fukuoka 815, Japan Various syn- and anti-9-substituted 2,11-dithia[3.3]metacyclophanes are obtained by the coupling reaction of the corresponding 2,6-bis(bromomethyl)benzenes and 1-substituted 2,6-bis(sulfanylmethyl)-4-tert-butylbenzenes under highly diluted conditions in 10% ethanolic KOH in the presence of a small amount of NaBH4.For many years various research groups have been attracted by the structures of the [3.3]MCP ([3.3]MCP=[3.3]metacyclophane) skeleton.2,3c When both internal substituents of a [3.3]phane are H, the molecule may be mobile. Mitchell and his co-workers demonstrated in 1970 that 9,18-dimethyl- 2,11-dithia[3.3]MCP exists in syn- and anti-conformers (see Fig. 1), which do not interconvert below 200 °C.4a V�ogtle and Schunder5 have made extensive studies of syn–anti conversions in other dithia[3.3]MCPs, especially in relation to the size of the substituents. When electron-withdrawing groups such as halo, nitro and cyano are present, the yields of the syn isomers increase substantially. Very bulky groups, such as tert-butyl, decrease the yields of syn isomers. Although the effect on the ratio of syn and anti conformers of dithia[3.3]MCPs was reported, it is still not clear what the effects are, not only with respect to the properties of the internal substituents, but also of having unsymmetrically substituted benzene rings arising from charge-transfer-type interactions between the two benzene rings as well as from the steric effects of the substituents at the 6- and 15-positions.All the previously studied compounds have been internally unsubstituted or methyl-substituted dithia[3.3]MCPs and it is surprising that there are very few reports on the preparation of 9-methoxy analogues.We report here the synthesis and stereochemical assignments of 9-methoxy-2,11-dithia[3.3]- MCPs. The substituent effects on the syn and anti conformations are also discussed. The cyclizations of 5-substituted 1,3-bis(halomethyl)benzenes 3a–e with 4-tert-butyl-2,6-bis(sulfanylmethyl)anisole 4a6,7a,b,e were carried out at high dilution in 10% ethanolic KOH and in the presence of a small amount of NaBH4, giving syn-9-methoxy-2,11-dithia[3.3]MCPs 5a–e in 41–67% yields, respectively (Scheme 1).In contrast, when the cyclizations of 5-substituted 1,3-bis (halomethyl)benzenes 3a–e with 4-tert-butyl-2,6-bis(sulfanylmethyl) toluene 4b were carried out under similar conditions, 3a–c and 3e gave exclusively the anti-9-methyl- 2,11-dithia[3.3]MCPs 6a–c and 6e in 60–71% yields, respectively whereas 3d gave only syn-9-methyl-15-nitro- 2,11-dithia[3.3]MCP syn-6d.Depending on the OMe and Me substitution, different yields (inversion of selectivity) of antiand syn-conformers were formed. Thus 9-methoxy analogues are exclusively formed as syn-conformers, but 9-methyl analogues are formed as anti-conformers. On treatment of 4-substituted 2,6-bis(bromomethyl)anisoles 8a–d with 4a, mixtures of anti- and syn-2,11- dithia[3.3]MCPs 5h–k were obtained, except for 6,15-di-tertbutyl- 2,11-dithia[3.3]MCP 5l. By careful column chromatography (silica gel, Wako C-300), two conformers, anti (anti- 5) and syn-2,11-dithia[3.3]MCP (syn-5), were easily *To receive any correspondence (e-mail: yamatot@cc.saga-u.ac.jp). Fig. 1 Syn- and anti-conformers of dithia[3.3]metacyclophanes Scheme 1 Reagents and conditions: i, KOH, EtOH, NaBH4, high dilutionMeO S S OMe OMe S S OMe anti-5 R R OMe CH2X XCH2 R syn-5 a b c d e 8 R = H, X = Br R = Me, X = Cl R = Cl, X = Cl R = Br, X = Br R = But, X = Cl + 4a i h i j k l R = H R = Me R = Cl R = Br R = But (17%) (31%) (12%) (25%) (56%) (74%) (40%) (27%) (13%) (0%) 19 : 81 56 70 34 0 anti : syn + 44 : 30 : 66 : 100 : R S– K+ S R O Me K+ –S X R S Me K+ –S R¢ X R¢ R S Steric interaction and p–p stacking interaction X Through-space interaction CH–p interaction J.CHEM. RESEARCH (S), 1997 193 separated. The 1H NMR spectrum of 5l shows this product to exist exclusively as the anti conformer. This result might be attributed to the bulkiness of the tert-butyl groups which would inhibit formation of syn-5l.Accordingly, the proportion of syn conformer is observed to increase with decreasing bulkiness of the substituents at the 15-position. These findings suggest that in the case of the 9-methoxy analogues the through-space interaction between the nonbonding electron pairs of the oxygen atom of the methoxy group and the opposite aromatic p-electrons of the anticonformer may disfavour the formation of this conformer. In contrast, in the case of a 9-methyl analogue the aromatic p–p interaction between the two opposite benzene rings and the steric crowding at the internal positions 9 and 18 may inhibit the formation of the syn-conformer in the [3.3]MCP system, while in turn the CH–p interaction9 between the methyl and the opposite aromatic p-electrons may favour the formation of an anti-conformer during the cyclization process.CH–p interactions involving aliphatic CH moieties are well documented9 as being either conformation-controlling intramolecular processes or involving crystal-structure-controlling intermolecular forces, especially for inclusion complexes of calixarene derivatives.10g In conclusion, we have demonstrated for the first time a through-space interaction between the non-bonding electron pairs of the oxygen atom of the methoxy group and the opposite aromatic p-electrons which may disfavour the formation of the anti-conformer during the coupling reaction of the corresponding 2,6-bis(bromomethyl)benzenes and 4-tertbutyl- 2,6-bis(sulfanylmethyl)anisole 4a to afford syn- 9-methoxy-2,11-dithia[3.3]MCPs 5 exclusively.Techniques used: 1H NMR, IR, mass. spec. References: 10 Schemes: 5 Fig. 2: Steric effect on the reaction intermediate for the cyclization to form syn-2,11-dithia[3.3]MCPs Received, 18th November 1996; Accepted, 4th March 1996 Paper E/6/07798F References cited in this synopsis 1 Part 43: T. Yamato, H. Kamimura, T. Furukawa, F. Zhang and Y. Nagano, J. Org. Chem., submitted for publication. 2 K. Meurer and F. V�ogtle, Top. Curr. Chem., 1985, 127, 1. 3 (c) F. V�ogtle, Cyclophane Chemistry, Wiley, Chichester, 1993. 4 (a) R. H. Mitchell and V. Boekelheide, Tetrahedron Lett., 1970, 1197. 5 F. V�ogtle and L. Schunder, Chem. Ber., 1969, 102, 2677. 6 M. Tashiro and T. Yamato, Org. Prep. Proced. Int., 1981, 13, 1. 7 (a) M. Tashiro and T. Yamato, J. Org. Chem., 1981, 46, 1543; (b) M. Tashiro, K. Koya and T. Yamato, J. Am. Chem. Soc., 1982, 104, 3707; (e) M. Tashiro, A. Tsuge, T. Sawada, T. Makishima, S. Horie, T. Arimura, S. Mataka and T. Yamato, J. Org. Chem., 1990, 55, 2404. 9 M. Nishio and M. Horita, Tetrahedron, 1989, 45, 7201. 10 (g) K. Kobayashi, Y. Asakawa, Y. Kikuchi, H. Toi and Y. Aoyama, J. Am. Chem. Soc., 1993, 115, 2648. Scheme 4 Reagents and conditions: i, KOH, EtOH, NaBH4, high dilution Fig. 3 Reaction intermediate for the cyclization to form [

ISSN:0308-2342    

DOI:10.1039/a607798f

出版商:RSC    

年代:1997

数据来源: RSC

摘要:

R S R¢ R S R¢ + CrO2BrOpyH + O CrOBrOpyH (1) R S R¢ S O R¢ Cr O–pyH+ O Br R S R¢ CrO2BrO–pyH+ + R + O CrOBrO–pyH+ # (20) d+ d– 194 J. CHEM. RESEARCH (S), 1997 J. Chem. Research (S), 1997, 194–195 J. Chem. Research (M), 1997, 1262–1285 Kinetics and Mechanism of the Oxidation of Organic Sulfides by Pyridinium Bromochromate Kavita Loonker, Pradeep K. Sharma and Kalyan K. Banerji* Department of Chemistry. J.N.V. University, Jodhpur 342 005, India The oxidation of organic sulfides by pyridinium bromochromate proceeds through an acyclic sulfurane transition state.Pyridinium bromochromate (PBC) is a mild oxidizing agent.3 In the oxidation of organic sulfides, PCC10 exhibits Michaelis–Menten type kinetics with respect to the reductant whereas a first-order dependence is obtained in the oxidation by PFC.11 There do not appear to be any reports on the kinetics of the oxidation of sulfides by PBC. We now report the kinetics of the oxidation of 34 organic sulfides by PBC.A probable mechanism is proposed. PBC was prepared by a reported method.3 The reactions were studied under pseudo-first-order conditions by using an excess (15Å or greater) of the sulfide. N,N-Dimethylformamide (DMF) was used a solvent unless otherwise stated. The reactions were followed by monitoring the decrease in the concentration of PBC at 356 nm for up to 80% of the reaction duration. Pseudo-first-order rate constants, kobs, were evaluated from linear plots (ra0.990) of log[PBC] against time. The oxidation of organic sulfides by PBC resulted in the formation of the corresponding sulfoxides.Product analysis indicated the following overall reaction [eqn. (1)]. The reactions are first-order with respect to PBC and the sulfide. The oxidation of methyl phenyl sulfide, in an atmosphere of nitrogen, failed to induce the polymerization of acrylonitrile. The reaction is catalysed by hydrogen ions, the dependence on which has the form: kobs=c+d[H+].This suggests protonation of PBC in a pre-equilibrium with both PBC and PBCH+, PBCH+ being the reactive oxidizing species. The oxidation of MeSPh was studied in 19 different organic solvents. The kinetics were similar in all the solvents. However, the rate constants for the oxidation in 18 of the solvents (CS2 was not considered, as the complete range of solvent parameters was not available) did not show a satisfactory correlation in terms of the linear solvation energy relationship of Kamlet et al.21 The solvent effect data exhibited excellent correlation in terms of Swain’s equation23 of the cation- and anion-solvating abilities of the solvents [eqn.(8)], with the cation-solvating power being slightly more important [eqn. (9)]. log k2=aAµbB+C (8) log k2=1.72(�0.06)A+1.99(�0.05)Bµ6.86 (9) R2=0.9934; sd=0.05; n=19 The solvent polarity, represented by (A+B), also accounted for ca. 99% of the data. However, the correlations individually with A and B were poor (r2=0.2179 and 0.6842 respectively).The rates of oxidation of a number of ortho-, meta- and para-substituted methyl phenyl sulfides, alkyl phenyl sulfides, dialkyl sulfides and diphenyl sulfides were determined at different temperatures and the activation parameters were calculated. The rates of the oxidation of meta- and para-substituted aryl methyl sulfides were correlated in terms of Charton’s27 triparametric LDR equation [eqn. (13)]. log k2=Ls1+Dsd+Rse+h (13) Here, s1 is a localized effect parameter, sd is the intrinsic delocalized electrical effect parameter when active site electronic demand is minimal and se represents the sensitivity of the substituent to changes in electronic demand by the active site.The latter two substituent parameters are related by eqn. (13) sD=nse+sd (14) where n represents the electronic demand of the reaction site which is given by n=R/D, and sD represents the delocalized electrical parameter of the diparametric LD equation.For ortho-substituted compounds, the LDR equation was modified to the LDRS equation [eqn. (15)],27 where V is the well known Charton’s steric parameter based on van der Waals radii.28 log k2=Ls1+Dsd+Rse+SV+h (15) The rates of oxidation of the ortho-, meta- and para-substituted sulfides show excellent correlations with their structures in terms of the LDR/LDRS equations with all the three regression coefficients, L, D and R, being negative. This indicates an electron-deficient sulfur centre in the transition state of the rate-determining step.The positive value of n adds a negative increment to sd [eqn. (14)], thereby increasing the electron-donating power of the substituent and its capacity to stabilize a cationic species. The negative value of S indicates that the reaction is sterically hindered by the ortho-substituent. This may be due to steric hindrance to the approach of the oxidizing species by the ortho-substituent.The oxidation rates of the alkyl phenyl sulfides showed excellent correlations in terms of the Pavelich–Taft37 dual substituent-parameter (DSP) equation [eqn. (18)]. The negative polar reaction constant confirms that the electron-donating power of the alkyl group enhances the reaction rate. The steric effect plays a minor inhibitory role. log k2=r*s*+dEs+log k0 (18) The experimental results can be accounted for in terms of the rate-determining electrophilic oxygen transfer from PBC to the sulfide [eqn.(20)]. The nucleophilic attack of a sulfidesulfur on a PCB-oxygen may be viewed as an SN2 process. Low magnitudes of the polar reaction constants support a transition state depicted in eqn. (20) rather than a sulfonium ion as shown in eqn. (21). The observed solvent effect also supports an SN2-like transition state. *To receive any correspondence.R S R¢ S+ O Cr O–pyH+ O– R R¢ Br + CrO2BrO–pyH+ (21) R S R¢ S O Cr O R¢ Br S O Cr O R¢ O–pyH+ R CrO2BrO–pyH+ + R Br O–pyH+ or Products (22) J.CHEM. RESEARCH (S), 1997 195 The oxidation of sulfides by PBC may involve a cyclic intermediate as has been suggested in many reactions of CrVI.40 The cyclic transition state will be highly strained in view of the apical position of a lone pair of electrons or an alkyl group [eqn. (22)]. The steric requirements of the reaction (22) will be higher as compared to those of reaction (20) and the observed small magnitudes of the steric reaction constants are thus consistent with the proposed acyclic mechanism.The formation of a cyclic transition state entails a more exacting specificity of orientation and should result in a much larger negative entropy of activation than that observed. Thanks are due to the Council of Scientific and Industrial Research (India) and the University Grants Commission (India) for financial support. Techniques used: Spectrophotometry, correlation analysis References: 41 Equations: 22 Table 1: Rate constants for the oxidation of methyl phenyl sulfide by PBC at 313 K Table 2: Solvent effect on the oxidation of MeSPh by PBC at 293 K Table 3: Dependence of the reaction rate on hydrogen-ion concentration Table 4: Rate constants and activation parameters for the oxidation of sulfides by PBC Table 5: Temperature dependence of the reaction constants for the oxidation of organic sulfides by PBC Table 6: Correlation of rate of oxidation of alkyl phenyl sulfides with the Pavelich–Taft equation Received, 23rd July 1996; Accepted, 4th March 1997 Paper E/6/05129D References cited in this synopsis 3 N.Narayanan and T. R. Balasubramanian, Indian J. Chem., 1986, 25B, 229; J. Chem. Res., 1991, (S) 336; (M) 3052. 10 G. P. Panigrahi and D. D. Mahapatro, Int. J. Chem. Kinet., 1981, 13, 85. 11 K. K. Banerji, J. Chem. Soc., Perkin Trans 2, 1988, 2065. 21 M. J. Kamlet, J. L. M. Abboud, M. H. Abraham and R. W. Taft, J. Org. Chem., 1983, 48, 2877 and references cited therein. 23 C. G. Swain, M. S. Swain, A. L. Powel and S. Alunni, J. Am. Chem. Soc., 1983, 105, 502. 27 M. Charton and B. Charton, Bull. Soc. Chim. Fr., 1988, 199 and references cited therein. 28 M. Charton, J. Org. Chem., 1975, 40, 407. 37 W. H. Pavelich and R. W. Taft, J. Am. Chem. Soc., 1956, 79, 4935 Y. W. Chang and F. H. Westheimer, J. Am. Chem. Soc., 1960, 82, 1401; J. Rocek and F. H. Westheimer, J. Am. Chem. Soc., 1962, 84, 2241.

ISSN:0308-2342    

DOI:10.1039/a605129d

出版商:RSC    

年代:1997

数据来源: RSC

摘要:

N N N OMe O NPri OH N N HN S(O)Me OMe N N HN OMe OMe X N N HN OMe OMe O PriN 1 2 OH 9 H H 5 X = H 6 X = OCH2CH(OH)CH2OH 7 X = OCH2CH(OH)CH2N(H)Pri N NH2 NO2 Cl O NPri HO O N NH2 NO2 O O NPri O N NH2 HN O O NPri O O OMe OMe N NH2 NH2 O O NPri O N N HN OMe OMe O N O O N N N OMe OMe + i O PriN N N N OMe OMe 10 11 ii 14 12 PriN 13 iii RO Pri H H 3 5 O H RO– 5 N N HN OMe OMe 6 17 R = H 18 R = CH2CH2OH iv H O 19 PriN v,vi or vii 15 16 + 6¢ H + 7 N NH2 NO2 NMe2 N NH2 NO2 OR Cl HN O N HN OMe OMe – 20 21 22 196 J.CHEM. RESEARCH (S), 1997 J. Chem. Research (S), 1997, 196–197 J. Chem. Research (M), 1997, 1359–1376 Synthesis of ‘A’ Ring Isomazole Oxypropanolamines via Hydrolysis of 1H-Imidazo[4,5-c]pyridine Oxazolidin-2-ones Paul Barraclough,*a Janet Gillam,b W. Richard King,a Malcolm S. Nobbs*a,† and Susan J. Vinea aDepartment of Medicinal Chemistry, Wellcome Research Laboratories, Langley Court, Beckenham, Kent BR3 3BS, UK bDepartment of Physical Sciences, Wellcome Research Laboratories, Langley Court, Beckenham, Kent BE3 3BS, UK The base-catalysed hydrolysis of oxazolidin-2-one 15 gives an oxypropanolamine 7 and 4,5-dihydro-1H-imidazo[4,5-c]- pyridin-4-ones (17–19) and may occur by a BAL mechanism.BW567C, (�)-1,1 is a combined inotrope–b-adrenoceptor antagonist. In connection with our studies of the structure– activity relationships of 1, isomazole (2) and its analogue (5),2 we wished to synthesise and evaluate the pharmacological properties of the oxypropanolamines (�)-7 and (�)-9.Attempts to convert (�)-63 into (�)-7 via monomethanesulfonate or epoxide intermediates were unsuccessful. An alternative route (Scheme 1) utilising the racemic oxazolidinone precursor 15 was therefore employed. The first and last stages in this synthesis, however, proved problematical. Reaction of 104–6 and racemic 117–9 in N,N-dimethylformamide, containing an equivalent of NaOMe at 50 °C, gave the diamine 20 (55%) and 12 (5%).The poor conversion into 12, and the distinctive deep-red colour of the reaction mixture, was attributed to the formation of either the sodium salt of 10 or a Meisenheimer complex 21. To suppress these side reactions we reacted 10 and 11 in ButOH at 80 °C in the presence of ButOK and obtained a 60% yield of 12. Attempted deprotection10 of the oxazolidinone 15 by reaction with 10 M NaOH in ethane-1,2-diol (1:10) at 120 °C gave the 4,5-dihydro-1H-imidazo[4,5-c]pyridin-4-ones 17 and 18 as the major products.When the above reaction was carried out using Ba(OH)2 as the base, 17 and 18 were again formed along with a third product, assigned structure 19. *To receive any correspondence. †Current address: Glaxo Wellcome Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK. Scheme 1 Reagents and conditions: i, KOBut, ButOH, 80 °C (64%); ii, H2, 10% Pd–C, MeOH (84%); iii, 2,4-dimethoxybenzoyl chloride, pyridine (58%); iv, POCl3, pyridine (63%); v, 10 M NaOH–ethane-1,2-diol (1:10), 120 °C, 15h17 (20%), 18 (26%); vi, Ba(OH)2, ethane- 1,2-diol, 120 °C, 15h17 (26%), 18 (24%), 19 (16%); vii, 10 M NaOH–ethane-1,2-diol (1:1), 120 °C, 15h7 (24%), 17 (14%), 22 (5%)N O N N OMe NPri OMe HN O N N OMe NPri OMe H 15 OR H 23 24 R = H 25 R = CH2CH2OH N O2N NH2 Cl N O2N NH2 O O NPri O N N HN OMe OMe O PriN O O N N HN OMe OMe + 11 i PriN O OH ii,iii iv 26 27 H v 31 O 32 +9 N N NH OMe OMe O NPri O O N N N OMe OMe O NPri 33 34 H i J.CHEM. RESEARCH (S), 1997 197 The formation of 17–19 may be explained by deprotonation of 15 to give the anion which reacts at the pyridyl rather than the imidazo nitrogen. Intramolecular nucleophilic attack at C-5 of the oxazolidinone with concomitant oxygen– alkyl ring cleavage would give a carbamate anion which would readily lose carbon dioxide to produce 16. Reaction of 16 with µOH or HO[CH2]2Oµ may then proceed by a similar, although intermolecular, mechanism (BAL2, Ingold notation15) but with two possible regiochemical outcomes.Intermolecular nucleophilic attack at C-5 and oxygen–alkyl ring cleavage would give 17 and 18, while 7 would be the product arising from C-6 attack. The azetidine 19 would result from 16 by intramolecular attack at C-5 by the side-chain amine. Products such as 23–25 (Scheme 2), arising from intramolecular nucleophilic attack by imidazo nitrogen on the oxazolidinone group of 15, were not detected.We also postulated that increasing the [µOH]: [HOCH2CH2Oµ] ratio would favour attack at C-6 of the 5,6-dihydroimidazo[4,5-c]oxazolo[3,2-a]pyridine intermediate 16 by µOH since this pathway should be the least susceptible to steric hindrance. When we carried out the deprotection of 15 using 10 M NaOH–ethane-1,2-diol (1:1, i.e. just enough solvent to solubilise the mixture) the products were 7 (25%), 17 (14%) and 22 (5%). While a pathway via 16 explains this product distribution, 7 may also be derived, at least in part, from 15 by the ‘normal’ hydrolysis mechanism BAC2,15,16 i.e., nucleophilic attack at the carbonyl carbon and oxygen–acyl ring cleavage. With the knowledge gained from this reaction sequence the preparation of the isomeric BW567C analogue, 9, proved straightforward.Thus, hydrolysis of oxazolidinone 31 gave 9 along with the rearrangement product 32 (Scheme 5). Interestingly, however, base-catalysed hydrolysis of oxazolidin- 2-one 3324 gave a tricycle 34 as the sole product (Scheme 6).This reaction probably occurs by a similar BAL mechanism and will be described in detail elsewhere. Oxypropanolamines 7 and 9 were found to be inactive as inotropic agents (cf. diol 6 and oxazolidinone 15, which are moderately potent inotropes). 7 was also devoid of b-blocking properties but 9 was found to be a b-adrenoceptor antagonist (pKB 5.9). We are indebted to J. W. Black, R. A. Hull and P. Randall (James Black Foundation, London) for provision of pharmacological data, to the staff in the Department of Physical Sciences, Wellcome Research Laboratories, for spectroscopic data, and to Jenny Lane for preparation of this manuscript.Techniques used: IR, mass spectrometry, 1H NMR, NOE, spin decoupling References: 25 Schemes: 6 Received, 16th December 1996; Accepted, 5th March 1997 Paper E/6/08407I References and notes cited in this synopsis 1 P. Barraclough, W. R. King, M. S. Nobbs and S.Smith, J. Chem. Res., 1996, (S) 408; (M) 2336. 2 P. Barraclough, J. W. Black, D. Cambridge, D. Collard, D. Firmin, V. P. Gerskowitch, R. C. Glen, H. Giles, A. P. Hill, R. A. D. Hull, R. Iyer, W. R. King, C. O. Kneen, J. C. Lindon, M. S. Nobbs, P. Randall, G. P. Shah, S. Smith, S. J. Vine, M. V. Whiting and J. M. Williams, J. Med. Chem., 1990, 33, 2231. 3 Prepared by a similar route to that shown in Scheme 1 involving reaction of 10 with solketal. 4 T. Talik and E. Plazek, Roczn.Chem., 1955, 29, 1019. 5 Z. Talik and E. Plazek, Roczn. Chem., 1956, 30, 1139. 6 R. J. Rousseau and R. K. Robins, J. Heterocycl. Chem., 1965, 2, 196. 7 Fujimoto Pharm. Co., Jap. Pat., 81 40,674 (Chem. Abstr., 1981, 85, 115521z). 8 S. Hamaguchi, M. Asada, J. Hasegawa and K. Watanabe, Eur. Pat. Appl., 123,719 (Chem. Abstr., 1985, 102, 132025w). 9 G. Cardillo, M. Orena and S. Sandri, J. Org. Chem., 1986, 51, 713. 10 M. E. Dyen and D. Swern, Chem. Rev., 1967, 67, 197 and references cited therein. 15 Physical and Mechanistic Organic Chemistry, ed. R. A. Y. Jones, Cambridge University Press, Cambridge, 1979, pp. 227–233. 16 J. O. Branstad, Acta Pharm. Suecica, 1969, 6, 49 (Chem. Abstr., 1969, 70, 114325k). 24 Prepared via reaction of 11 with 4-chloro-3-nitropyridin- 2-amine. Scheme 2 Scheme 5 Reagents and conditions: i, KOBut, ButOH, 80 °C (36%); ii, H2 10% Pd–C, MeOH (60%); iii, 2,4-dimethoxybenzoyl chloride, pyridine (73%); iv, POCl3, pyridine (74%); v, 10 M NaOH–ethane-1,2-diol (1:1), 120 °C, 31h9 (36%), 32 (12%) Scheme 6 Reagent: i, 10 M NaOH–ethane-1,2-diol (1:10), 120 &d

ISSN:0308-2342    

DOI:10.1039/a608407i

出版商:RSC    

年代:1997

数据来源: RSC

摘要:

PhCH2 CN N O NHPh 4 O Ph CN H NMe2 5 PhCH2CO2Et + CH3CN PhCH2COCH2CN NaH OH NH2 6 + O PhCH2 CH CO2Et Ph 8 PhCH2 CN N O NHPh N NH N N Ph Ph NH2 1 N N N N Ph Ph NH2 9 N N Ph CN O Ph 10 NH2NH2•H2O PhNHNH2•HCl DMF DMA 1,4-Dioxane 4 Ph N N NC NH Ph NH2 N N CN Ph NH2 NH or N N NC N Ph N N N CN Ph N O Me2N DMF DMA 13 14 15 16 N N N Me CN Ph Ph O CN H NMe2 + N NH Me NH2 2 5 AcOH AmOAc–AcOH CH2(CN)2 4 198 J. CHEM. RESEARCH (S), 1997 J. Chem. Research (S), 1997, 198–199 J. Chem. Research (M), 1997, 1377–1389 Studies with 3-Oxoalkanenitriles: Synthesis of New Pyrazolo[1,5-a]pyrimidines and Pyrazolo[5,1-c]-1,2,4- triazines and Reactivity of 4-Phenyl-3-oxobutanenitrile Derivatives Mervat Mohammed Abdel Khalik Department of Chemistry, College of Women, Faculty of Science, Ain Shams University, Cairo, Egypt 4-Phenyl-3-oxobutanenitrile is synthesized via the reaction of ethyl phenylacetate with acetonitrile in the presence of sodium hydride and identified by isolating its 2-phenylhydrazone and dimethylaminomethylidene derivatives; both the hydrazone and dimethylaminomethylidene derivatives prove versatile starting materials for the synthesis of a variety of polyfunctionally substituted heterocycles.The synthesis of 4-phenyl-3-oxobutanenitrile 6 and its characterization in the form of its hydrazone 4 and its dimethylaminomethylidene derivative 5 are reported. The utility of both derivatives for the synthesis of a variety of new heterocycles of potential biological activity is also described.Ethyl phenylacetate reacted with acetonitrile in refluxing toluene in the presence of sodium hydride to yield an oily mixture consisting of two major products. Triturating this oily mixture with ethanol afforded ethyl 2,4-diphenyl-3-oxobutanoate 8 in 30% yield as a solid, which was separated by filtration. Evaporation of the ethanol afforded an oil consisting mainly of 3-phenyl-3-oxobutanenitrile 6. Although this compound could not be obtained in pure form, it could be utilized to produce the phenylhydrazone derivative 4 and the dimethylaminomethylidene derivative 5 via treatment with benzenediazonium chloride and N,N-dimethylformamide dimethyl acetal (DMF DMA), respectively. Both 4 and 5 were characterized by elemental and spectral data.Treatment of the phenylhydrazone 4 with hydrazine hydrate afforded 5-amino-3-benzyl-4-phenylazopyrazole 1 in quantitative yield. Similar treatment of 4 with phenylhydrazine resulted in isomerization of the phenylhydrazone into another compound for which no simple structure could be deduced.However, when 4 was treated with phenylhydrazine hydrochloride in refluxing ethanol, 5-amino-3-benzyl- 1-phenyl-4-phenylazopyrazole 9 was obtained. Reaction of 4 with DMF DMA yielded the pyridazinone 10. A similar pyridazine synthesis has been recently reported by Elnagdi and co-workers.6 Reaction of 4 with malononitrile afforded a product of condensation that may be formulated as 13 or 14.Structure 14 is preferred over 13 based on the observation that treatment of the product with DMF DMA did not afford the tetracyclic derivative 15 but rather gave 16. Treatment of 5 with 5-amino-3-methylpyrazole in acetic acid afforded the benzylpyrazolo[1,5-a]pyrimidine 2 in quantitative yield. Compound 1 afforded the 5-aminopyrazolo[1,5-a]pyrimidine derivative 17 on treatment with acrylonitrile. Structure 17 was also established for the product from the reaction of the hydrazone 4 with (2-cyanoethyl)hydrazine.N N N N PhN NH2 Ph N HN N N PhN Ph 17 19 O Me 1 CH2COCH2CO2Et NH2NHCH2CH2CN 4 N N N N N PhN 22 NH2 Ph COPh N N N N N PhN 23 Ph N N N N N PhN 24 Ph OH NH N N PhN Ph N N+Cl– 20 N– N N PhN Ph N N+ 21 Ph O CN OH OH OH CN J.CHEM. RESEARCH (S), 1997 199 Compound 1 reacted with ethyl acetoacetate in ethanol to afford the 5-oxopyrazolo[1,5-a]pyrimidine derivative 19. Structure 19 is based on literature precedent7 and on the IR spectrum which revealed a characteristic carbonyl absorption for a 5-oxopyrazolo[1,5-a]pyrimidine at 1674 cmµ1.The behaviour of 1 towards ethyl acetoacetate is in parallel with that reported for 5-aminopyrazoles towards the same reagent under similar conditions.8 Compound 1 was readily diazotized utilizing Elnagdi’s diazotization procedure.8 Although the diazonium salt 20 could not be isolated in pure form, it coupled readily with benzoylacetonitrile, yielding 7-aminopyrazolo[1,5-a]triazines 22. The diazonium salt 20 also reacted under the coupling conditions with 2-naphthol and with resorcinol affording the pyrazolotriazine derivative 23 and the pyrazolotriazine 24 respectively. Techniques used: IR, 1H and 13C NMR, mass spectrometry References: 10 Received, 2nd January 1997; Accepted, 7th March 1997 Paper E/7/00024C References cited in this synopsis 6 H. Al-Awadhi, F. Al-Omran, M. H. Elnagdi, L. Infantes, C. Foces- Foces, N. Jagerovic and J. Elguero, Tetrahedron, 1995, 51, 12745. 7 M. H. Elnagdi, M. R. H. Elmoghayar and G. E. H. Elgemeie, Adv. Heterocycl. Chem., 1987, 41, 319. 8 A. A. El-Agamey, S. O. Abdullah and M. R. H. Elmoghayar, Monatsh. Chem., 1994, 115, 1413. 9 K. U. Sadek, N. S. Ibrahim and M. H. Elnagdi, Arch. Pharm. (Weinheim), 1988, 321, 141.

ISSN:0308-2342    

DOI:10.1039/a700024c

出版商:RSC    

年代:1997

数据来源: RSC

摘要:

–O2C HN SH O NH O H3 +N –O2C HN O N CO2H O H3 +N S Me Me H H 2 1 O2 2H2O IPNS CO2H S O COR S O HN O CO2R¢ 13 R = OH 14 R = Cl 7a,b R¢ = But R¢HN NHR CO2R¢¢ 8 R = R¢ = R¢¢ = H 10 R = Z, R¢ = R¢¢ = H 9 R = Z, R¢ = Boc, R¢¢ = H 11 R = Z, R¢ = Boc, R¢¢ = But 12 R = H, R¢ = Boc, R¢¢ = But HN ButO O NH CO2But O O HN Boc SH HN ButO O NH CO2But O O HN Boc S-)2 20a,b 21 –O2C HN NH CO2H O O +H3N S-)2 22 –O2C HN NH O SH CO2H O H3 +N 6a,b 200 J. CHEM. RESEARCH (S), 1997 J. Chem. Research (S), 1997, 200–201 J.Chem. Research (M), 1997, 1401–1411 Studies on Side Chain Interactions during the Isopenicillin N Synthase Catalysed Biosynthesis of Penicillins Florine Cavelier, Andrew T. Russell, Christopher J. Schofield and Jack E. Baldwin* The Dyson Perrins Laboratory and the Oxford Centre for Molecular Sciences, South Parks Road, Oxford OX1 3QY, UK The role of the L-d-(a-aminoadipoyl)–L-cysteinyl amide bond in isopenicillin N synthase catalysis is probed by the synthesis of two analogues of its tripeptide substrate L-d-a-aminoadipoyl-L-cysteinyl-D-valine.Isopenicillin N synthase (IPNS) catalyses the reaction of dioxygen and the tripeptide L-d-a-aminoadipoyl-L-cysteinyl- D-valine (ACV, 1) to give isopenicillin N (IPN, 2) and two water molecules (Scheme A).1,2 The L-d-a-aminoadipoyl side chain of IPNS may be replaced with a variety of analogues,1,2 but for efficient conversion to a penicillin a linear 6-carbon chain (or equivalent) is required.4 The puckered nature of the penicillin products and presumably intermediates during IPNS catalysis may place the L-d-a-aminoadipoyl–cysteinyl amide link proximate to the reactive iron centre and it was considered possible that this amide plays a catalytic role.The analogue 6 in which the NH of the amide link is 1,3-transposed into the side chain of ACV may thus act as a mechanistic probe for the involvement of the L-d-a-aminoadipoyl-L-cysteinyl amide link in catalysis. Diaminobutyric acid (8) was sequentially N-protected with benzyloxycarbonyl (Z) and tert-butyloxycarbonyl (Boc) groups, on its d- and a-amino groups respectively to give 9 via 10.8 tert-Butyl ester 11 formation using tert-butyl alcohol and dimethylformamide neopentyl acetal,9,10 followed by hydrogenolysis of the d-amino protecting group gave 12.Racemic thioparaconic acid (13), synthesised7 from itaconic acid, was activated as its acid chloride 14 and reacted with D-valine tertbutyl ester to give the lactones 7a,b (70%).Diprotected L-diaminobutyric acid (12) was treated (EtOH, Cairos tube, 110 °C, overnight)13 with the lactones 7a,b to give the epimeric thiols 20a,b in low yield (16%). Thiols 20a,b were oxidised [PhI(OAc)2] to a mixture of disulfides 21 (36%) in order to prevent intramolecular attack of the thiol on the side chain amide link resulting in reformation of thiolactones 7a, b and 12 (Scheme B). Acid mediated deprotection gave the desired epimeric peptides as a mixture of disulfides 22 (98%), which were subsequently reduced using dithiothreitol to give crude epimeric thiols 6a,b which were purified by HPLC.Neither 6a nor 6b were found to be substrates or inhibitors of IPNS. The influence of the substrate side chain linkage in IPNS catalysis was also investigated by removal of the carbonyl of the side chain amide link, i.e. by the synthesis and incubation of 24. Since the amino group of the L-d-a-aminoadipoyl side chain is not required for IPNS turnover,4 the synthetic target was simplified to 25.Thus, aldehyde 2614 and S-benzhydrylcysteine (27) were reacted under reductive amination conditions (NaBH3CN, NaOH, MeOH) to give acid 28 (40%), which was coupled with D-valine tert-butyl ester to give 29 (62%) (Scheme C). Deprotection via basic cleavage of the methyl ester, followed by acid mediated removal of the benzhydryl and ester groups gave tripeptide 25 (97% prior to HPLC). Incubation of 25 with IPNS led again only to recovered starting material with no evidence for the formation of products (by 1H NMR, bioassay, or HPLC analyses).Preincubation experiments of 25 with IPNS did not lead to any increased inactivation relative to controls with ACV 1. However, preliminary kinetic studies indicated that amine 25 *To receive any correspondence. Scheme A Scheme BMeO H O O 26 +H3N O– O SBzh 27 MeO NH OH O O SBzh 28 MeO NH HN O O SBzh 29 Bzh = CHPh2 CO2Bu HO2C HN NH O SH R CO2H 24 R = NH2 25 R = H J.CHEM. RESEARCH (S), 1997 201 reversibly inhibited IPNS with an IC50 of between 35 and 45 mM. Techniques used: IR, 1H and 13C NMR, MS, TLC, polarimetry, elemental analysis References: 14 Schemes: 1 Received, 29th January 1997; Accepted, 11th March 1997 Paper E/7/00662D References cited in this synopsis 1 J. E. Baldwin and C. J. Schofield, in The Chemistry of b-lactams, ed. M. I. Page, Blackie, London, 1992, ch. 1, pp. 1–78 and references cited therein. 2 J. E. Baldwin and M. Bradley, Chem. Rev., 1990, 90, 1079 and references cited therein. 4 J. E. Baldwin, E. P. Abraham, R. M. Adlington, G. A. Bahadur, B. Chakravarti, B. P. Domayne-Hayman, L. D. Field, S. I. Flitsch, G. S. Jayatilake, A. Spakovskis, H.-H. Ting, N. J. Turner, R. L. White and J. J. Usher, J. Chem. Soc., Chem. Commun., 1984, 1225. 7 B. Holmberg and E. Schjånberg, Ark. Kemi, Min. Geol., 1940, 14A, 1. 8 J. Leclerc and L. Benoiton, Can. J. Chem., 1968, 46, 1047. 9 J. E. Baldwin, C. N. Farthing, A. T. Russell, C. J. Schofield and A. C. Spivey, Tetrahedron Lett., 1996, 37, 3761. 10 T. R. Welter, US Pat., 5 087 288, 1992. 13 J. Megnan, M. Colin and G. Lang, Eur. Pat., 368 763A1, 1990. 14 A. W. Burgstahler, L. O. Weigeland and C. G. Sheifer, Synthesis, 1976, 767. Scheme C

ISSN:0308-2342    

DOI:10.1039/a700662d

出版商:RSC    

年代:1997

数据来源: RSC