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Amidine function in constructing novel types of phosphorus-containing heterocycles

 

作者: Gennady V. Oshovsky,  

 

期刊: Mendeleev Communications  (RSC Available online 1999)
卷期: Volume 9, issue 4  

页码: 161-162

 

ISSN:0959-9436

 

年代: 1999

 

出版商: RSC

 

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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