Mendeleev Communications Electronic Version, Issue 1, 1999 (pp. 1–44) Novel heterocyclizations of N,N'-diarylformamidines: 1,4,2,5-diazadiphosphorinanes Gennady V. Oshovsky,* Alexander M. Pinchuk, Alexander N. Chernega, Igor I. Pervak and Andrey A. Tolmachev Institute of Organic Chemistry, National Academy of Sciences of Ukraine, 253660 Kyiv, Ukraine. Fax: +7 044 543 6843; e-mail: oshovsky@carrier.kiev.ua The heterocyclization of N,N'-diarylformamidines with phosphorus trichloride to form 1,4,2,5-diazadiphosphorinanes was found to proceed via the key stage of aliphatic electrophilic ylide substitution at the formamidine carbon atom.The first examples of aliphatic electrophilic substitution at the formamidine carbon atom in reactions with trivalent phosphorus halides were found recently.1 There is no published data on similar reactions of formamidines with other electrophilic agents.C-Substitution in N,N,N'-trisubstituted formamidines is an extension of well-studied N-phopshorylation of NH-amidines.2 In this work, we report a novel approach to N,N'-diarylformamidines as N,C-bifunctional compounds, in which classical substitution at the nitrogen atom is followed by the formation of a bond with the formamidine carbon atom.This is a new feature of using formamidines in syntheses of heterocyclic compounds. Using a model reaction of the title compounds with phosphorus trichloride, we implemented a new promising synthesis of 1,4,2,5-diazadiphosphorinane3 (Scheme 1). The first step of the reaction leads to N-phosphorylated2 amidines 2.Compounds 2 are transformed into 3 only in a basic medium (a mixture of pyridine and NEt3).† This fact suggests that the transformation occurs via the ylide mechanism4 of electrophilic C-substitution at the HCXY moiety (X, Y = NR, N, S, O) of heterocyclic compounds and is similar to acylation5 and phosphorylation6 of azoles. The transformation of 2 into 3 can be easily monitored by 31P NMR. This process is considerably slower than the formation of 2 from amidine and PCl3.The 31P NMR spectrum of 3 exhibits two signals as a result of two possible isomers of 3. These isomers are interconvertable in solution; it is likely that this conversion is caused by the presence of trace acids.‡ The mixture of isomers 3 reacts smoothly with secondary amines and sulfur leading to a mixture of stable isomers 5.The difference in solubility allows the separation of stable isomers 5a and 5a'. X-ray analysis confirmed the structure of 5a' (Figure 1).§,¶ Compound 5a' corresponds to the cis isomer, and the diazadiphosphorinane ring has a boat conformation in crystals. The second isomer 5a is trans. Both cis and trans isomers are sterically hindered.Judging from very wide signals in the 1H NMR spectra corresponding to Ar bonded to endocyclic nitrogen and amide moieties at phosphorus,†† one can conclude that the energy difference between conformers of each isomer should be insignificant. This is not surprising, because the 1,4,2,5-diazadiphosphorinane ring involves sp2 carbons. Therefore, there is a dynamic equilibrium between the conformers, instead of an excess of one of them, in contrast with less sterically hindered phosphaheteroannelated cyclohexanes.7 † General method for the synthesis of 3, 4a–c, 5a,a': 0.005 mol of an amidine was dissolved in 10 ml of pyridine and 0.0125 mol of NEt3; next 0.005 mol of PCl3 was added to this reaction mixture cooled to –70 °C. The reaction mixture was allowed to stand for 7 h at room temperature.Next, (A) to prepare compounds 3, the reaction mixture was filtered and evaporated to dryness. By-products were extracted with dry acetonitrile (up to 100 ml). (B) To prepare compounds 4a–c, 5a, 0.015 mol of NEt3 was added to the reaction mixture, and, after cooling to –50 °C, 0.006 mol of a secondary amine was added. The reaction mixture was allowed to stand for 1 h, then 0.005 mol of S was added.After standing for 2 h, the precipitate was filtrered off and washed three times with hot benzene; the solvent was evaporated to dryness in a vacuum, and by-products were extracted with acetonitrile (up to 100 ml). The solid residue was recrystallised from toluene (crystallisation from dioxane is also acceptable). To prepare 5a', the acetonitrile extract was evaporated to dryness, and the product was crystallised from octane and ethyl acetate.‡ 2b (R = Me): d31P = 152.3 ppm (Py); 3b d31P = 67.31 (prevailing isomer), d31P = 67.61 (minor isomer), yield of the isomers mixture 42%. The yields of isomers strongly depend on the temperature and the nature of substituents at phosphorus and of aryl substituents at nitrogens.§ To confirm the structure of isomers 4a, 4b and 5a, mass spectroscopy (molecular desorption) was used: 4a, 690±5 (calc. 686.48); 4b, 747±5 (calc. 742.85); 5a, 660±5 (calc. 658.78). Elemental analysis corresponds to the calculated data to within 0.25%. ¶ Crystallographic data for 5a'. A crystal of compound 5a' as a transparent prism (crystal dimensions 0.16×0.34×0.62 mm) was grown from ethyl acetate, C34H40N6P2S2, M = 658.80, monoclinic, a = 8.723(3), b = 38.29(1), c = 10.938(5) Å, b = 109.06(3)°, V = 3453.4 Å3 (by the least-squares refinement of the setting angles for 24 automatically centered reflections), space group P21, Z = 4, Dc = 1.27 g cm–3, m = = 2.70 cm–1.‘Enraf-Nonius CAD4’ diffractometer was used, w/2q scan mode with the w scan width 0.71 + 0.34tg q, w scan speed 1.7–6.7 ° min–1, graphite-monochromated MoKa radiation (l = 0.71069 Å), 6338 reflections were measured (2 < q < 30°), 5473 unique (merging R = 0.017), giving 4044 with I > 3s(I).The structure was solved using direct methods, full-matrix least-squares refinement against F with all non-hydrogen atoms in anisotropic approximation (793 variables, observations/variables = 5.1).All crystallographic calculations were carried out using the CRYSTALS program package. Atomic coordinates, bond lengths, bond angles and thermal parameters have been deposited at the Cambridge Crystallographic Data Centre. For details, see Mendeleev Commun., Issue 1, 1999. Any request to the CCDC for data should quote the full literature citation and the reference number 1135/37.Ar NH CH N Ar + PCl3 Py, NEt3 – NEt3·HCl Ar N CH N Ar PCl2 NEt3 – NEt3·HCl N P N P Cl Ar N Cl Ar N Ar Ar i, R2NH, NEt3 ii, S N P N P Ar N Ar N Ar Ar S NR2 S R2N 1a–c 2 3a–c 4a–c, 5a,a' R' Ar = a R' = H b R' = Me c R' = Br 4 R2N = N O 5 R2N = Et2N Scheme 1Mendeleev Communications Electronic Version, Issue 1, 1999 (pp. 1–44) †† Spectral data: 3b (prevailing isomer): 1HNMR (C6D6) d: 7.43 (d, 4H, a, Jag 7.2 Hz), 6.76–6.92 (m, 12H, bgd), 1.96 (s, 12H, et, Me). 4a: yield 56%, mp 302–303 °C. 1H NMR (C6D6) d: 7.45 (br. s, 4H, a), 7.015 (d, 4H, b, Jbd 7.5 Hz), 6.90 (t, 4H, d), 6.70 (t, 2H, t, Jtd 7.2 Hz), 6.63 (br. s, 6H, ge), 3.36, 3.08 and 2.72 (br. s, 16H, Y = NR2). 31P NMR (pyridine) d: 67.2. 4b: yield 49%, mp 295–296 °C. 1H NMR (C6D6) d: 7.45 (br. s, 4H, a), 7.06 (d, 4H, b, Jbd 8.1 Hz), 6.77 (d, 4H, d), 6.62 (br. s, 4H, g), 3,40, 3.16 and 2.83 (br. s, 16H, Y = NR2), 2.00 and 1.84 (s, 12H, et). 31P NMR (pyridine) d: 68.4. 4c: yield 37%, mp > 350 °C. 1H NMR (C6D6) d: 7.29 and 7.10 (br. s, 8H, ag), 7.22 and 6.62 (d, 8H, bd, Jbd 7.8 Hz), 3.37, 3.21 and 3.06 (br. s, 16H, Y = NR2). 31P NMR (benzene) d: 57.3. 5a (trans): yield 48%, mp 260–262 °C. 1HNMR (C6D6) d: 7.52 and 7.43 (br. s, 4H, a), 7.07 (d, 4H, b, Jbd 7.2 Hz), 6.91 (t, 4H, d, Jtd 7.2 Hz), 6.8–6.6 (br. s, 8H, get), 3.39 and 3.18 [br. s, 8H, Y = NR2:(CH2)], 0.58 [br. s, 12H, Y = NR2:(Me)]. 31P NMR (C6D6) d: 61.42. 5a' (cis): yield 12%, mp 208–209 °C. 1HNMR (C6D6) d: 7.72 (br. s, 4H, a), 6.9–7.2 (br. s, 6H, ge), 6.99 (t, 4H, d), 6.82 (t, 2H, t, Jtd 7.5 Hz), 6.40 (d, 4H, b, Jbd 6.8 Hz), 3.42 [br.s, 8H, Y = NR2:(CH2)], 1.15 [br. s, 12H, Y = NR2:(Me)]. 31P NMR (MeCN) d: 60.72. 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) A. A. Tolmachev, A. S. Merkulov, G. V. Oshovsky and A. B. Rozhenko, Zh. Obshch. Khim., 1996, 66, 1930 (Russ. J. Gen. Chem., 1996, 66, 1877); (b) A. A. Tolmachev, A. S. Merkulov and G. V. Oshovsky, Khim. Geterotsikl. Soedin., 1997, 1000 [Chem. Heterocycl. Compd. (Engl. Transl.), 1997, 877]. 2 (a) V. I. Shevchenko, A. D. Sinitsa and V. I.Kal’chenko, Zh. Obshch. Khim., 1976, 46, 541 [J. Gen. Chem. USSR (Engl. Transl.), 1976, 46, 535]; (b) V. V. Negrebetskiy, V. I. Kal’chenko and L. I. Atamas’, Zh. Obshch. Khim., 1990, 60, 517 [J. Gen. Chem. USSR (Engl. Transl.), 1990, 60, 450] and references therein; (c) L. N. Markovsky, V. I. Kal’chenko and V. V. Negrebetskiy, New. J. Chem., 1990, 14, 339 and references therein. 3 (a) Yu.G. Gololobov and L. I. Nesterova, Zh. Obshch. Khim., 1977, 47, 1422 [J. Gen. Chem. USSR (Engl. Transl.), 1977, 47, 1303]; (b) A. M. Kibardin, T. Kh. Gazizov, K. M. Enikeev and A. N. Pudovik, Izv. Akad. Nauk SSSR, Ser. Khim., 1983, 432 (Bull. Acad. Sci. USSR, Div. Chem. Sci., 1983, 32, 390). 4 L. I. Belenkii and N. D. Chuvylkin, Khim. Geterotsikl. Soedin., 1996, 1535 [Chem.Heterocycl. Compd. (Engl. Transl.), 1996, 1319] and references therein. 5 (a) E. Regel, K.-H. Büchel, Liebigs Ann. Chem., 1977, 145; (b) E. Anders, H.-G. Boldt, R. Fuchs and T. Gassner, Tetrahedron Lett., 1984, 1715. 6 (a) 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]; (b) A.A. Tolmachev, A. A. Yurchenko, M. G. Semenova and N. G. Feschenko, Zh. Obshch. Khim., 1993, 63, 714 [J. Gen. Chem. USSR (Engl. Transl.), 1993, 63, 714]. 7 (a) L. D. Quin and J. H. Sommers, J. Org. Chem., 1972, 37, 1217; (b) D. B. Cooper, I. D. Inch and G. L. Lewis, J. Chem. Soc., Perkin Trans. 1, 1974, 1043; (c) G. D. Macdonnel, K. D. Berlin, J. R. Baker, S. E. Ealick, D.van der Helm and K. L. Marsi, J. Am. Chem. Soc., 1978, 100, 4535. N P N P N N X Y X Y R R R R a b g d t e a a a b b b g g g d d d e t C(1) C(2) C(3) C(4) C(5) C(6) C(7) C(8) C(9) C(10) C(11) C(12) C(13) C(14) C(15) C(16) C(17) C(18) C(19) C(20) C(21) C(22) C(23) C(24) C(25) C(26) C(27) C(28) C(29) C(30) C(31) C(32) C(33) C(34) N(1) N(2) N(3) N(4) N(5) P(1) P(2) S(1) S(2) Figure 1 Crystal structure of 1,4,2,5-diazadiphosphorinane 5a'. Selected bond lengths (Å): P(1)–S(1) 1.924(3), P(2)–S(2) 1.915(3), P(1)–N(1) 1.643(7), P(1)–N(2) 1.712(6), P(2)–N(4) 1.706(6), P(2)–N(6) 1.638(7), P(1)–C(5) 1.856(8), P(2)–C(6) 1.828(8); selected bond angles (°): N(2)– P(1)–C(5) 101.1(3), N(4)–P(2)–C(6) 102.0(3), C(5)–N(3)–C(13) 122.2(7), C(6)–N(5)–C(25) 125.9(7). The C(5)–P(1)–N(2)–C(6) and C(5)–N(4)– P(2)–C(6) groups are planar to within 0.06 Å, and the dihedral angle between these planes is 39.5°. N(6) Received: Moscow, 20th July 1998 Cambridge, 26th November 1998; Com. 8/06223D