A simple one-pot synthesis of N-alkyl-2,5-diaryl-1,3-dioxol-4-amines

Article abstract of DOI:10.1002/hlca.201100052

An efficient procedure for the synthesis of N-alkyl-2,5-diaryl-1,3-dioxol- 4-amines 3 via a one-pot reaction of aromatic aldehydes 2 and alkyl isocyanides 1 at room temperature in good yields is described (Scheme 1, Table). Copyright

Full text of DOI:10.1002/hlca.201100052

Helvetica Chimica Acta – Vol. 94 (2011)
1657
A Simple One-Pot Synthesis of N-Alkyl-2,5-diaryl-1,3-dioxol-4-amines
by Mohammad Bayat* and Shima Nasri
Chemistry Department, Imam Khomeini International University, Qazvin, Iran
(phone/fax: þ 98-281-3780040; e-mail: bayat_mo@yahoo.com)
An efficient procedure for the synthesis of N-alkyl-2,5-diaryl-1,3-dioxol-4-amines 3 via a one-pot
reaction of aromatic aldehydes 2 and alkyl isocyanides 1 at room temperature in good yields is described
(Scheme 1, Table).
Introduction. – The 1,3-dioxole moiety is an important substructure found in
numerous natural alkaloids [1] (e.g., in hydrastine). Many condensed heterocyclic
systems, especially when linked to a 1,3-dioxole ring, play important roles as potent
anti-HIV (e.g., AHE) [2][3], anticancer (e.g., podophyllotoxin and etoposide) [4][5],
anticonvulsant [6], antidepressive [6], antitumor [7], and antipyretic [6] agents, as well
as in the treatment of cardiovascular diseases [8] and lung cancer [9].
A number of synthetic routes for 1,3-benzodioxoles have been reported [7 – 10],
and many syntheses of 1,3-dioxoles via the reaction of a-diazo ketones with carbonyl
derivatives have been described [11]. As part of our ongoing studies on the
development of simple synthetic methods in heterocyclic chemistry, for e.g., the
synthesis of iminospiro-g-lactones, 2H-pyrano[2,3-d]pyrimidine derivatives, and 2,5-
diaminofuran derivatives [12], and our interest in isocyanide-based reactions, we report
herein an efficient synthesis of N-alkyl-2,5-diaryl-1,3-dioxol-4-amines, starting from
simple and readily available precursors. To the best of our knowledge, there are no
reports on the synthesis of these compounds via isocyanide-based reactions.
Results and Discussion. – The reaction of alkyl isocyanides 1 and aromatic
aldehydes 2 proceeds smoothly in dry CH2Cl2 in the absence of any catalyst and at room
temperature to produce the 1,3-dioxolamines 3 in excellent yields (Scheme 1, Table).
As shown in the Table, aromatic aldehydes 2 with electron-withdrawing or donating
groups gave excellent yields of the corresponding product 3.
Scheme 1
The structures of the products 3 were deduced from their elemental analyses and IR
and 1H- and 13C-NMR spectra. In the 1H- and 13C-NMR spectra of the crude reaction
ꢀ 2011 Verlag Helvetica Chimica Acta AG, Zꢁrich

1658
Helvetica Chimica Acta – Vol. 94 (2011)
Table. Synthesis of 1,3-Dioxole Derivatives 3a – 3h
Aldehyde 2
Isocyanide 1
Cy-NꢀC
Product 3
Yield [%]
96
PhCHO
4-MeC6H4CHO
4-ClC6H4CHO
2,6-Cl2C6H3CHO
Cy-NꢀC
Cy-NꢀC
Cy-NꢀC
94
92
85
4-BrC6H4CHO
Cy-NꢀC
92
PhCHO
tBuNꢀC
tBuNꢀC
90
95
4-ClC6H4CHO
4-MeC6H4CHO
tBuNꢀC
90

Helvetica Chimica Acta – Vol. 94 (2011)
1659
mixture, no products other than 3 could be detected. The mass spectra of compounds 3
displayed molecular-ion peaks at appropriate m/z values, though of low intensity. The
1H-NMR spectrum of 3a (Ar¼ Ph, R ¼ cyclohexyl) consisted of a m for the cyclohexyl
group (d(H) 1.01 – 2.01), a broad signal for the CHꢁN group (d(H) 3.77 – 3.87), a s at
d(H) 6.30 for the acetal H-atom and a d (d(H) 6.10 (3J ¼ 7.5 Hz)) for the NH group, in
1
agreement with the suggested structure. The H-decoupled 13C-NMR spectrum of 3a
showed 17 distinct signals in agreement with the proposed structure. In this case, the
molecule is chiral owing to the acetal stereogenic C-atom, consequently the five CH2
groups of the cyclohexyl moiety are noneqivalent, and they gave separate resonances.
The characteristic signal of the acetal C-atom was observed at d(C) 75.93, and the
olefinic C-atoms of the 1,3-dioxole ring appeared at d(C) 164.95 and 167.37. The 1H- and
13C-NMR spectra of compounds 3b – 3h were similar to that of 3a, except for the signals
of the substituted alkyl and aryl moieties, which exhibited characteristic resonances
with appropriate chemical shifts (see Exper. Part).
A plausible mechanism for the formation of 1,3-dioxolamines 3 is shown in
Scheme 2. On the basis of the well-established chemistry of isocyanides [13][14], it is
reasonable to assume that the reaction between the alkyl isocyanide and the aldehyde
involves initial formation of a 1,3-dipolar intermediate 4, which undergoes addition to
the C¼O group of another aldehyde molecule to give 5. This intermediate is converted
into product 3 via H-atom transfer.
Scheme 2
In conclusion, we have reported a simple method for the synthesis of potentially
interesting N-alkyl-2,5-diaryl-1,3-dioxol-4-amines from readily available aromatic
aldehydes and alkyl isocyanides. The present procedure has the advantage that the
reaction occurs under neutral conditions, and, moreover, the substances can be mixed
without any further activation or modification.
Experimental Part
General. Alkyl isocyanides, aromatic aldehydes, and solvents used in this work were obtained from
Fluka (Buchs, Switzerland) and used without further purification. M.p.: Gallenkamp-9100 electro-
thermal apparatus; uncorrected. IR Spectra: Bruker-Tensor-27 spectrometer; KBr; ˜n in cmꢁ1. NMR
Spectra: Bruker-DRX-300-Avance instrument, CDCl3 solns.; d in ppm rel. to Me4Si as internal standard, J
in Hz. MS: Shimadzu-QP-GC-5050 spectrometer; at 70 eV; in m/z (rel. %). Elemental analyses:
Heraeus-CHN-O-Rapid analyzer.
Compounds 3: General Procedure. To a magnetically stirred soln. of benzaldehyde (0.212 g, 2 mmol)
in CH2Cl2 (3 ml) was added, at r.t. within 10 min via
a syringe, cyclohexyl isocyanide
(¼ isocyanocyclohexane; 0.109 g, 1 mmol) or tert-butyl isocyanide (¼2-isocyano-2-methylpropane;
0.083 g, 1 mmol) in CH2Cl2 (2 ml). The mixture was stirred at r.t. for 3 d. The solvent was evaporated,
and the residue washed with hexane/AcOEt 9 :1: the product 3.

1660
Helvetica Chimica Acta – Vol. 94 (2011)
N-Cyclohexyl-2,5-diphenyl-1,3-dioxol-4-amine (3a): Yield 0.308 g (96%). Pale orange solid. M.p.
116 – 1188. IR: 3440, 3311, 3100, 1733, 1655, 1545, 1256, 1113. 1H-NMR: 1.01 – 2.01 (m, 10 H of Cy); 3.77 –
3.87 (m, CHꢁN); 6.10 (d, 3J ¼ 7.5, NH); 6.30 (s, CH); 7.35 – 7.64 (m, 6 arom. H); 8.10 (d, 3J ¼ 7.4, 4 arom.
H).13C-NMR: 24.68, 24.71, 25.43, 32.85, 32.95 (Cy); 48.24 (CHꢁN); 75.93 (CH); 127.42, 128.65, 128.77,
130.03, 128.95, 133.63 (10 arom. C); 129.34, 135.78 (arom. C); 164.95, 167.37 (C¼C). EI-MS: 321 (1), 273
(2), 82 (4), 58 (44), 42 (100). Anal. calc. for C21H23NO2 (321.41): C 78.47, H 7.21, N 4.36; found: C 78.42,
H 7.14, N 4.33.
N-Cyclohexyl-2,5-bis(4-methylphenyl)-1,3-dioxol-4-amine (3b): Yield 0.328 g (94%). Yellow solid.
M.p. 164 – 1668. IR: 3444, 3292, 2928, 1728, 1658, 1256, 1107. 1H-NMR: 1.09 – 1.98 (m, 10 H of Cy); 2.34,
2.42 (2 s, 2 Me); 3.78 – 3.88 (m, CHꢁN); 6.03 (d, 3J ¼ 7.5, NH); 6.26 (s, CH); 7.18 (d, 3J ¼ 7.8, 2 arom. H);
3
3
3
7.27 (d, J ¼ 7.8, 2 arom. H); 7.40 (d, J ¼ 8.1, 2 arom. H); 7.97 (d, J ¼ 8.1, 2 arom. H).13C-NMR: 21.13,
21.63 (2 Me); 24.63, 24.67, 25.34, 32.67, 32.79 (Cy); 48.10 (CHꢁN); 75.55 (CH); 126.59 (arom. C); 127.27,
129.21, 129.27, 129.71 (arom. C); 132.95, 138.58, 144.26 (arom. C); 165.07, 167.58 (C¼C). EI-MS: 349
(0.6), 315 (1), 240 (10), 119 (100), 104 (19), 91 (27), 58 (23), 42 (65). Anal. calc. for C23H27NO2 (349.47):
C 79.07, H 7.79, N 4.01; found: C 79.11, H 7.76, N 4.08.
2,5-Bis(4-chlorophenyl)-N-cyclohexyl-1,3-dioxol-4-amine (3c): Yield 0.358 g (92%). White solid.
M.p. 199 – 2018. IR: 3446, 3279, 2930, 2358, 1732, 1657, 1253, 1100. 1H-NMR: 1.10 – 1.98 (m, 10 H of Cy);
3.76 – 3.85 (m, CHꢁN); 5.95 (d, 3J ¼ 8.1, NH); 6.22 (s, CH); 7.36 (d, 3J ¼ 8.4, 2 arom. H); 7.47 – 7.53 (2d,
3J ¼ 8.2, 4 arom. H); 8.10 (d, 3J ¼ 8.4, 2 arom. H).13C-NMR: 24.67, 24.70, 25.39, 32.86, 32.96 (Cy); 48.40
(CHꢁN); 75.39 (CH); 128.85, 129.06, 129.10, 131.14 (arom. C); 129.48, 134.03, 135.13, 140.36 (arom. C),
164.11, 166.69 (C¼C). EI-MS: 390 (0.9), 363 (1), 273 (2), 139 (100), 111 (46), 57 (34), 42 (52). Anal. calc.
for C21H21Cl2NO2 (390.30): C 64.62, H 5.42, N 3.59; found: C 64.55, H 5.34, N 3.62.
N-Cyclohexyl-2,5-bis(2,6-dichlorophenyl)-1,3-dioxol-4-amine (3d): Yield 0.390 g (85%). Pale orange
paste. IR: 3430, 2931, 2854, 1650, 1529, 1489, 1090. 1H-NMR: 1.11 – 1.97 (m, 10 H of Cy); 3.76 – 3.86 (m,
CHꢁN); 5.91 (d, 3J ¼ 7.4, NH); 6.22 (s, CH); 7.38 (2t, 3J ¼ 7.6, 2 arom. H); 7.46 (d, 3J ¼ 7.6, 2 arom. H); 8.02
(d, 3J ¼ 7.2, 2 arom. H).13C-NMR: 24.66, 24.70, 25.39, 32.87, 32.95 (Cy); 48.49 (CHꢁN); 76.59 (CH);
128.85, 129.07, 129.11, 131.14 (arom. C); 129.42, 130.08, 130.45, 140.35 (arom. C); 164.11, 166.69 (C¼C).
EI-MS: 459 (3), 370 (11), 281 (6), 212 (30), 185 (38), 105 (100), 83 (33), 57 (70). Anal. calc. for
C21H19Cl4NO2 (459.19): C 54.93, H 4.17, N 3.05; found: C 54.85, H 4.27, N 3.12.
2,5-Bis(4-bromophenyl)-N-cyclohexyl-1,3-dioxol-4-amine (3e): Yield 0.440 g (92%). Yellow oil. IR:
3449, 3268, 2932, 2354, 1731, 1659, 1249, 1123. 1H-NMR: 1.08 – 1.95 (m, 10 H of Cy); 3.75 – 3.85 (m,
CHꢁN); 5.93 (d, 3J ¼ 7.2, NH); 6.20 (s, CH); 7.39 (d, 3J ¼ 8.4, 2 arom. H); 7.52 (d, 3J ¼ 8.4, 2 arom. H); 7.63
(d, 3J ¼ 6.8, 2 arom. H); 7.93 (d, 3J ¼ 6.8, 2 arom. H).13C-NMR: 24.67, 24.71, 25.39, 32.86, 32.95 (Cy); 48.40
(CHꢁN); 75.45 (CH); 123.34, 127.97 (arom. C); 129.12, 131.24, 132.02, 132.10 (arom. C); 132.46, 134.51
(arom. C); 164.25, 166.59 (C¼C). EI-MS: 479 (1), 370 (14), 316 (4), 199 (8), 183 (66), 97 (34), 83 (50), 71
(53), 57 (100). Anal. calc. for C21H21Br2NO2 (479.20): C 52.63, H 4.42, N 2.29; found: C 52.55, H 4.48, N
2.36.
N-(tert-Butyl)-2,5-diphenyl-1,3-dioxol-4-amine (3f): Yield 0.266 g (90%). Yellow solid. M.p. 144 –
1458. IR: 3435, 3290, 1724, 1655, 1555, 1450, 1263, 1113. 1H-NMR: 1.37 (s, Me3C); 6.02 (br. s, NH);
3
6.23 (s, CH); 7.35 – 7.63 (m, 8 arom. H); 8.08 (d, J ¼ 8.1, 2 arom. H).13C-NMR: 28.71 (Me3C); 51.61
(Me3C); 76.06 (CH); 127.45, 128.65, 128.78, 128.91, 129.76 (8 arom. C); 129.39, 135.96 (2 arom. C); 133.60
(2 arom. C); 164.90, 167.38 (C¼C). EI-MS: 295 (0.8), 212 (34), 190 (8), 162 (9), 105 (100), 77 (28), 57
(18). Anal. calc. for C19H21NO2 (295.38): C 77.26, H 7.17, N 4.74; found: C 77.29, H 7.18, N 4.71.
N-(tert-Butyl)-2,5-bis(4-chlorophenyl)-1,3-dioxol-4-amine (3g): Yield 0.345 g (95%). White solid.
M.p. 148 – 1508. IR: 3450, 3291, 1725, 1656, 1555, 1258, 1103. 1H-NMR: 1.36 (s, Me3C); 5.89 (br. s, NH);
6.14 (s, CH); 7.30 (d, 3J ¼ 8.2, 2 arom. H); 7.82 (d, 3J ¼ 8.2, 2 arom. H); 7.83 (d, 3J ¼ 8.4, 2 arom. H); 8.00
(d, 3J ¼ 8.4, 2 arom. H).13C-NMR: 28.76 (Me3C); 51.80 (Me3C); 75.71 (CH); 128.86, 129.07, 129.38, 131.11
(8 arom. C); 127.60, 134.20, 135.08, 140.32 (4 arom. C); 164.09, 166.72 (C¼C). EI-MS: 307 (1), 280 (12),
141 (45), 139 (100), 11 (16), 57 (40). Anal. calc. for C19H19Cl2NO2 (364.27): C 62.65, H 5.26, N 3.85;
found: C 62.64, H 5.32, N 3.83.
N-(tert-Butyl)-2,5-bis(4-methylphenyl)-1,3-dioxol-4-amine (3h): Yield 0.290 g (90%). Pale yellow
solid. M.p. 127 – 1288. IR: 3480, 3291, 1720, 1656, 1555, 1113. 1H-NMR: 1.36 (s, Me3C); 2.34, 2.42 (2 Me);
6.00 (br. s, NH); 6.18 (d, 3J ¼ 7.8, 2 CH); 7.26 (d, 3J ¼ 7.8, 2 arom. H); 7.40 (d, 3J ¼ 7.8, 2 arom. H); 7.96 (d,

Helvetica Chimica Acta – Vol. 94 (2011)
1661
3
3J ¼ 7.8, 2 arom. H); 8.00 (d, J ¼ 8.4, 2 arom. H).13C-NMR: 21.21, 21.70 (2 Me); 28.71 (Me3C); 51.50
(Me3C); 75.81 (CH); 127.89, 127.41, 129.18, 129.31, 129.78 (arom. C); 126.74, 133.16, 138.70, 144.34
(arom. C); 164.95, 167.67 (C¼C). EI-MS: 273 (0.7), 240 (22), 119 (100), 104 (15), 91 (18), 42 (20). Anal.
calc. for C21H25NO2 (323.43): C 77.98, H 7.79, N 4.33; found: C 78.06, H 7.82, N 4.31.
REFERENCES
[1] J. R. Falck, S. Manna, Tetrahedron Lett. 1981, 22, 619.
[2] W. W. Epstein, D. F. Netz, J. L. Seidel, J. Chem. Educ. 1993, 70, 598.
[3] R. Ikan, ꢂNatural Products, A Laboratory Guideꢃ, Academic Press, New York, 1991, pp. 55 – 60.
[4] T. Utsugi, J. Shibata, Y. Sugimoto, K. Aoyagi, K. Wierzba, T. Kobunai, T. Terada, T. Oh-hara, T.
Tsuruo, Y. Yamada, Cancer Res. 1996, 56, 2809.
[5] C. Bardelle, D. Cross, S. Davenport, J. G. Kettle, E. J. Ko, A. G. Leach, A. Mortlock, J. Read, N. J.
Roberts, P. Robins, E. J. Williams, Bioorg. Med. Chem. Lett. 2008, 18, 2776.
[6] O. J. Kokas, M. G. Banwell, A. C. Willis, Tetrahedron 2008, 64, 6444; Y.-S. Cho, C.-G. Cho,
Tetrahedron 2008, 64, 2172.
˜
[7] D. R. de Magalhaes Moreira, A. C. L. Leite, P. M. P. Ferreira, P. M. da Costa, L. V. C. Lotufo, M. O.
´
de Moraes, D. J. Brondani, C. do O Pesso, Eur. J. Med. Chem. 2007, 42, 351.
[8] N. Ishizuka, K.-i. Matsumura, J. Kikuchi, H. Nakai, Bioorg. Med. Chem. Lett. 2002, 10, 3965.
[9] A. Rodina, M. Vilenchik, K. Moulick, J. Aguirre, J. Kim, A. Chiang, J. Litz, C. C. Clement, Y. Kang,
Y. She, N. Wu, S. Felts, P. Wipf, J. Massague, X. Jiang, J. L. Brodsky, G. W. Krystal, G. Chiosis, Nat.
Chem. Biol. 2007, 3, 498.
[10] A. E. Shchekotikhin, Y. N. Luzikov, V. N. Buyanov, M. N. Preobrazhenskaya, Chem. Heterocycl.
Compd. (N.Y., NY, U.S.) 2009, 45, 151; N. M. Boshta, M. Bomkamp, S. R. Waldvogel, Tetrahedron
2009, 65, 3773.
[11] M. E. Alonso, A. W. Chitty, Tetrahedron Lett. 1981, 22, 4181; M. Avataneo, W. Navarrini, U. De
Patto, G. Marchionni, J. Fluorine Chem. 2009, 130, 933; C. Batsila, G. Kostakis, L. P. Hadjiarapoglou,
Tetrahedron Lett. 2002, 43 5997; A. Guirado, A. Zapata, R. Andreu, C. R. de Arellano, P. G. Jones, J.
´
Galvez, Tetrahedron 2009, 65, 3886; A. Russo, W. Navarrini, J. Fluorine Chem. 2004, 125, 73; A.
Milani, M. Tommasini, C. Castiglioni, G. Zerbi, S. Radice, G. Canil, P. Toniolo, F. Triulzi, P.
Colaianna, Polymer 2008, 49, 1812; A. Padwa, J. Boonsombata, P. Rashatasakhon, Tetrahedron Lett.
2007, 48, 5938; V. V. Nikolaev, A. Linden, H. Heimgartner, Helv. Chim. Acta 2007, 90, 2330; V.
Nikolaev, L. Hennig, H. Heimgartner, B. Schulze, V. Nikolaev, Tetrahedron Lett. 2006, 47, 2643; V. V.
Nikolaev, H. Heimgartner, A. Linden, I. S. Krylov, V. A. Nikolaev, Eur. J. Org. Chem. 2006, 4737;
V. V. Nikolaev, B. Schulze, H. Heimgartner, V. A. Nikolaev, Heterocycles 2007, 73, 433.
[12] M. Bayat, H. Imanieh, E. Hossieninejad, Synth. Commun. 2008, 38, 2567; M. Bayat, H. Imanieh, N.
Zabarjad Shiraz, M. S. Qavidel, Monatsh. Chem. 2010, 141, 333; M. Bayat, H. Imanieh, H. Abbasi,
Helv. Chim. Acta. 2010, 93, 757; M. Bayat, N. Zabarjad Shiraz, S. S. Asayesh, J. Heterocycl. Chem.
2010, 74, 857.
[13] A. Dçmling, Chem. Rev. 2006, 106, 17; L. Banfi, R. Riva, Org. React. 2005, 65, pp. 1 – 140; A.
Dçmling, Curr. Opin. Chem. Biol. 2000, 4, 318; L. F. Tietze, A. Modi, Med. Res. Rev. 2000, 20, 304.
[14] I. Ugi, Angew. Chem., Int. Ed. 1982, 21, 810; S. Marcaccini, T. Torroba, Org. Prep. Proced. Int. 1993,
25, 141; H. M. Walborsky, M. P. Presiasamy, ꢂThe Chemistry of Functional Groups. Suppl. Cꢃ, Eds. S.
Patai, Z. Rappaport, Wiley, New York, 1993, Chapt. 20, p. 835.
Received February 2, 2011