Microwave-assisted facile synthesis of dispiro 4-imino-1,3-dioxolanes

Article abstract of DOI:10.1081/SCC-200050361

The condensation reactions of isocyanides 1 with 1,3-dimethyl alloxan 2 to afford dispiro 4-imino-1,3-dioxolane heterocycles, in excellent yields under microwave irradiation, are reported.

Full text of DOI:10.1081/SCC-200050361

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Microwave‐Assisted Facile Synthesis of
Dispiro 4‐Imino‐1,3‐Dioxolanes
Mohammad Bagher Teimouri a
a Gas Conversion Department , Iran Polymer and Petrochemical Institute ,
Tehran, Iran
Published online: 20 Aug 2006.
To cite this article: Mohammad Bagher Teimouri (2005) Microwave‐Assisted Facile Synthesis of Dispiro
4‐Imino‐1,3‐Dioxolanes, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 35:5, 675-682, DOI: 10.1081/SCC-200050361
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Synthetic Communicationsw, 35: 675–682, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1081/SCC-200050361
Microwave-Assisted Facile Synthesis of
Dispiro 4-Imino-1,3-Dioxolanes
Mohammad Bagher Teimouri
Gas Conversion Department, Iran Polymer and Petrochemical Institute,
Tehran, Iran
Abstract: The condensation reactions of isocyanides 1 with 1,3-dimethyl alloxan 2 to
afford dispiro 4-imino-1,3-dioxolane heterocycles, in excellent yields under
microwave irradiation, are reported.
Keywords: Alloxan, dispiro, iminodioxolane, isocyanide, microwave-assisted reaction
INTRODUCTION
Organic isocyanides are useful reagents for organic synthesis.[1,2] They enter
cycloaddition reactions giving different types of heterocycles.[3,4] The reaction
of isocyanides with carbon-centered double bonds occurs in a stepwise
manner and is initiated by a zwitterionic intermediate, whose ultimate fate
appears to be dictated by the nature of the original double bond in the
substrate.[5,6] Isocyanides can insert preferentially into the carbon-oxygen
double bond of electron-deficient carbonyl compounds.[7–9]
Alloxan and its derivatives have four electrophilic C55O sites. The
alloxan molecule is biologically a highly important molecule, since it
destroys pancreatic insulin-producing beta cells and causes diabetes in
animals. The toxicity of a number of N-substituted alloxan derivatives has
Received in Poland October 21, 2004
Address correspondence to Mohammad Bagher Teimouri, Gas Conversion Depart-
ment, Iran Polymer and Petrochemical Institute, P.O. Box 14965-115, Tehran, Iran.
E-mail: m.teimouri@ippi.ac.ir

676
M. B. Teimouri
been studied and it has been shown that comparatively small changes to the
alloxan molecule have a major impact upon diabetogenicity.[10]
The central carbonyl group of the cyclic vicinal triones such as alloxan
derivatives is sufficiently reactive to participate in different reactions. This
highly electron-deficient moiety is entered in Diels-Alder reactions, Friedel-
Crafts reactions, ene reactions, photochemical conversions, and reactions
with active methylene compounds.[11] Numerous examples of reactions of
alloxan that produce heterocycles have been described.[11,12]
In continuation of my interest on microwave-assisted organic transform-
ation[13] and chemistry of isocyanides leading to the spiro-fused heterocycles
synthesis,[9,14] herein I describe an efficient and high yielding protocol for the
preparation of dispiro iminodioxolane derivatives.
Wallach’s compound has been assigned the 4-imino-1,3-dioxolane
structure.[15] A few natural products intramolecularly incorporating a spiro
1,3-dioxolane ring are known,[16] while its usefulness as a building block in
asymmetric organic synthesis has been often reported.[17] In recent years,
1,3-dioxolan-4-one derivatives have served as precursors to a variety of
synthetic targets. They have been used as substrates for the total synthesis
of (S)-oxybutynin,[18] eicosanoids,[19] beta lactams,[20] and a muscarinic
receptor antagonist.[21]
RESULTS AND DISCUSSION
The pseudo three-component condensation reactions of alkyl or aryl isocya-
nides 1 with 1,3-dimethyl alloxan 2 proceeded spontaneously in dimethyl
formamide (DMF) under microwave irradiation and were completed within
1
2 min. The H and 13C nuclear magnetic resonance (NMR) spectra of the
crude products clearly indicated the formation of Cs symmetry dispiro imino-
dioxolanes 3. Any product other than 3 could not be detected by NMR spec-
troscopy. The structure of these adducts were established as 3 by their
1
elemental analysis and their infrared (IR), H NMR, and 13C NMR spectra.
The nature of these compounds as 1 : 2 adduct was also apparent from the
elemental analysis as well as from the mass spectra. The mass spectra of
compounds 3a–g displayed molecular ion peaks at the appropriate m/z values.
1
The H NMR spectrum of 3a exhibited three single sharp lines readily
recognized as arising from tert-butyl (d 1.44 ppm) and two N-methyl
1
(d 3.32 and 3.42 ppm) protons. The H decoupled 13C NMR spectrum of 3a
showed 11 distinct resonances that are in agreement with Cs symmetry of
the structure, and the characteristic signals due to two spiro carbons were dis-
cernible at d 80.64 and 96.01 ppm.
1
The H decoupled 13C NMR spectra of 3b–g are similar to those of 3a
except for the alkyl or arylimino group, which exhibit characteristic signals
with appropriate chemical shifts.

Microwave-Assisted Facile Synthesis
677
Although I have not established a mechanism for the formation of the
compounds 3 in an experimental manner, a possible explanation is shown in
Scheme 1. The first step may involve addition of the isocyanide to the 1,3-
dimethyl alloxan and formation of the 1 : 1 adduct 4. Subsequent nucleophilic
attack of this adduct to another molecule of the 1,3-dimethyl alloxan would
yield zwitterionic intermediate 5 that can be cyclized to product 3.
The starting 1,3-dimethylalloxan is conveniently prepared from its hydrate
by either chemical removal of the water (acetic anhydride in boiling acetic acid)
or by azeotropic drying using chlorobenzene as solvent but I prepared it from
the thermal decomposition of 1,3-dimethyl-5,5-dinitrobarbituric acid[22] by a
novel, effective, and facile procedure (see EXPREMENTAL).
CONCLUSION
In summary, I found that the reaction of isocyanides with two equivalents of
1,3-dimethyl alloxan leads to facile synthesis of dispiro 4-imino-1,3-dioxolane
derivatives in excellent yields under microwave irradiation and without any
catalyst after two minutes.
EXPERIMENTAL
¨
Melting points were measured on a BUCHI 535 apparatus and are uncor-
rected. Elemental analyses were performed using a Heraeus CHN-O-Rapid
Scheme 1.

678
M. B. Teimouri
analyzer. Mass spectra were recorded on a FINNIGAN-MAT 8430 mass spec-
trometer operating at an ionization potential of 70 eV. The infrared (IR)
spectra were recorded on a Shimadzu IR-470 spectrometer. 1H and 13C
NMR spectra were recorded on a BRUKER DRX-500 AVANCE spec-
1
trometer at 500.13 and 125.77 MHz, respectively. The H and 13C NMR
spectra were obtained on solutions in CDCl3. Microwave irradiation were
carried out in a National domestic oven, model 5250 (700 W). The reagents
and solvents used in this work except for benzyl isocyanide were purchased
from Fluka (Buchs, Switzerland) chemical company and the benzyl isocya-
nide was obtained from Aldrich Chemical Company.
Preparation of 1,3-Dimethyl Alloxan 2
Thermolysis of (2.461 g, 10 mmol) 1,3-dimethyl-5,5-dinitrobarbituric acid at
1708C for 20 min, after elimination of N2O and NO resulted in 1,3-dimethyl
alloxan 2 as a pure product (1.667 g, 9.8 mmol, 98%). Yellow powder, Mp
284–2868C. IR (KBr) (nmax, cm21): 1762, 1700 and 1666 (C55O).
1H NMR (DMSO-d6, 400 MHz): dH 3.17 (6 H, s, 2 NMe). 13C NMR
(DMSO-d6, 100 MHz): dC 28.91 (2 NMe), 151.09(NCON), 156.67 (2
NCOC), 168.58 (OCCOCO). MS (m/z, %) 170 (Mþ, 68), 142 (100). Anal.
Calcd. for C6H6 N2O4 (170.12): C, 42.36; H, 3.55; N, 16.47%. Found: C,
42.4; H, 3.5; N, 16.4%.
Typical Procedure
Synthesis of 2,4,10,12-tetramethyl-15-(tert-butylimino)-7,14-dioxa-2,4,
10,12-tetraazadispiro[5.1.5.2]pentadecane-1,3,5,9,11,13-hexone (3a)
To a solution of 1,3-dimethyl alloxan (0.341 g, 2.0 mmol) in DMF (1 mL) in a
screw-capped vial, tert-butyl isocyanide (0.084 g, 1.0 mmol) was added via a
syringe and subjected to microwave irradiation at medium high power for
2 min. After cooling, the reaction mixture was poured onto cold water
(10 mL) and stirred for 5 min. The separated solid was filtered under
suction, washed with water (20 mL) and then diethyl ether (10 mL) to afford
the pure product. Light pink powder (0.377 g, 89%). Mp 241–2438C. IR
(KBr) (nmax, cm21): 1732 and 1684 (C55O), 1573 (N55C). 1H NMR
(CDCl3, 400 MHz): dH 1.26 (9 H, s, C(CH3)3), 3.32 and 3.42 (12 H, 2 s, 4
NCH3). 13C NMR (CDCl3, 100 MHz): dC 29.43 (CMe3), 29.70 and 29.73
(4 NMe), 56.22 (CMe3), 80.64 and 96.01 (2 spiro carbons), 142.98 (N55C),
149.74 and 150.63 (2 NCON), 162.12 and 162.45 (4 NCOC). MS (EI,
70 eV) (m/z, %) 423 (Mþ, 24), 57 (100). Anal. Calcd. for C17H21N5O8
(423.38): C, 48.23; H, 5.00; N, 16.54%. Found: C, 48.3; H, 5.1; N, 16.5%.

Microwave-Assisted Facile Synthesis
679
2,4,10,12-Tetramethyl-15-(cyclohexylimino)-7,14-dioxa-2,4,10,
12-tetraazadispiro [5.1.5.2]pentadecane-1,3,5,9,11,13-hexone (3b)
Creamy powder. (0.418g, 93 %). Mp 195–1978C. IR (KBr) (nmax, cm21): 1735
and 1700 (C55O), 1564 (N55C). H NMR (CDCl3, 400 MHz): dH 1.26–1.72
1
(10 H, m, 5 CH2), 3.33 and 3.43 (12 H, 2 s, 4 NCH3), 3.66 (1 H, m, N-CH).
13C NMR (CDCl3, 100 MHz): dC 23.77, 25.55 and 32.68 (5 CH2), 29.74 and
29.83 (4 NMe), 57.01 (N-CH), 80.28 and 95.57 (2 spiro carbons), 145.54
(N55C), 149.64 and 150.53 (2 NCON), 162.12 and 162.24 (4 NCOC). MS
(EI, 70eV) (m/z, %) 449 (Mþ, 8), 55 (100). Anal. Calcd. for C19H23N5O8
(449.41): C, 50.78; H, 5.16; N, 15.58%. Found: C, 50.7; H, 5.2; N, 16.0%.
2,4,10,12-Tetramethyl-15-(benzylimino)-7,14-dioxa-2,4,10,
12-tetraazadispiro [5.1.5.2]pentadecane-1,3,5,9,11,13-hexone (3c)
Light pink powder. (0.403 g, 88%). Mp 238–2408C. IR (KBr) (nmax, cm21):
1762, 1727, 1688, and 1668 (C55O), 1529 (N55C). 1H NMR (CDCl3,
400 MHz): dH 3.32 and 3.44 (12 H, 2 s, 4 NCH3), 4.65 (2 H, s, CH2), 7.20–
7.33 (5 H, m, C6H5). 13C NMR (CDCl3, 100 MHz): dC 29.81 and 29.92
(4 NMe), 52.28 (NCH2), 80.54 and 95.96 (2 spiro carbons), 127.06, 127.14,
128.53 and 137.63 (arom.), 148.29 (N55C), 149.58 and 150.35 (2 NCON),
161.87 and 161.93 (4 NCOC). MS (EI, 70 eV) (m/z, %) 457 (Mþ, 15), 91
(100). Anal. Calcd. for C20H19N5O8 (457.39): C, 52.52; H, 4.19; N,
15.31%. Found: C, 52.6; H, 4.3; N, 15.2%.
2,4,10,12-Tetramethyl-15-(2,6-dimethylphenylimino)-7,14-dioxa-
2,4,10,12-tetra azadispiro[5.1.5.2]pentadecane-1,3,5,9,11,13-hexone (3d)
Light pink powder. (0.429 g, 91%). Mp 278–2798C. IR (KBr) (nmax, cm21):
1769, 1729, and 1697 (C55O), 1586 (N55C). H NMR (CDCl3, 400 MHz):
1
dH 2.09 (6 H, s, C6H3Me2), 3.39 and 3.41 (12 H, 2 s, 4 NCH3), 6.93–7.00
(3 H, m, arom.). 13C NMR (CDCl3, 100 MHz): dC 17.59 (C6H3Me2), 29.73
and 29.91 (4 NMe), 80.90 and 96.23 (2 spiro carbons), 124.90, 127.56,
127.85, and 141.40 (arom.), 147.54 (N55C), 149.43, and 150.19 (2 NCON),
161.40 and 161.65 (4 NCOC). MS (EI, 70 eV) (m/z, %) 471 (Mþ, 10), 104
(100). Anal. Calcd. for C21H21N5O8 (471.42): C, 53.50; H, 4.49; N,
14.86%. Found: C, 53.5; H, 4.5; N, 14.8%.
Ethyl[(2,4,10,12-tetramethyl-1,3,5,9,11,13-hexaoxo-7,14-dioxa-2,4,10,
12-tetraaza dispiro[5.1.5.2]pentadec-15-ylidene)amino]acetate (3e)
Pink powder. (0.409 g, 90%). Mp 221–2238C. IR (KBr) (nmax, cm21): 1765,
1728, 1720, and 1687 (C55O), 1584 (N55C). 1H NMR (CDCl3, 400 MHz): dH
3
1.27 (3 H, t, JHH ¼ 7.1 Hz, CH3 of Et), 3.34 and 3.44 (12 H, 2 s, 4 NCH3),

680
M. B. Teimouri
4.20 (2 H, q, 3JHH ¼ 7.1 Hz, OCH2), 4.77 (2 H, s, NCH2). 13C NMR (CDCl3,
100 MHz): dC 14.10 (CH3 of Et), 29.74 and 29.83 (4 NMe), 55.23 (NCH2),
59.84 (OCH2), 80.61 and 95.94 (2 spiro carbons), 149.12 (N55C), 149.78
and 150.38 (2 NCON), 162.03 and 162.18 (4 NCOC). MS (EI, 70 eV) (m/z,
%) 453 (Mþ, 6), 73 (100). Anal. Calcd. for C17H19N5O10 (453.36): C,
45.04; H, 4.22; N, 15.45%. Found: C, 45.1; H, 4.2; N, 15.5%.
2,4,10,12-Tetramethyl-15-(f[(4-methylphenyl)sulfonyl]methylgimino)-
7,14-dioxa-2,4,10,12-tetraazadispiro[5.1.5.2]pentadecane-
1,3,5,9,11,13-hexone (3f)
Pink powder. (0.461 g, 86%). Mp 241–2438C. IR (KBr) (nmax, cm21): 1753,
1725, and 1691 (C55O), 1565 (N55C), 1384 and 1170 (SO2). 1H NMR
(CDCl3, 400 MHz): dH 2.47 (3 H, s, CH3), 3.31 and 3.46 (12 H, 2 s, 4
3
NCH3), 4.98 (2 H, s, NCH2SO2), 7.34 and 7.91 (4 H, 2 d, JHH ¼ 8.6 Hz,
C6H4). 13C NMR (CDCl3, 100 MHz): dC 21.60 (CH3), 29.83 and 29.85
(4 NMe), 73.47 (NCH2SO2), 80.95 and 96.68 (2 spiro carbons), 127.70,
132.02, 138.83, and 144.47 (C6H4), 147.81 (N55C), 149.61 and 150.84
(2 NCON), 162.11 and 163.02 (4 NCOC). MS (EI, 70 eV) (m/z, %) 535
(Mþ, 2), 91 (100). Anal. Calcd. for C21H21N5O10S (535.48): C, 47.10; H,
3.95; N, 13.08%. Found: C, 47.2; H, 4.0; N, 13.1%.
2,4,10,12-Tetramethyl-15-(2-morpholinoethylimino)-7,14-dioxa-
2,4,10,12-tetraaza dispiro[5.1.5.2]pentadecane-1,3,5,9,11,13-hexone (3g)
Dark pink powder. (0.370 g, 77%). Mp 212–2148C. IR (KBr) (nmax, cm21):
1760, 1724, and 1683 (C55O), 1576 (N55C). H NMR (CDCl3, 400 MHz):
1
3
dH 2.43 (4 H, m, CH2NCH2), 2.56 (2 H, t, JHH ¼ 5.7 Hz, NCH2), 3.33 and
3
3.41 (12 H, 2 s, 4 NCH3), 3.45 (2 H, t, JHH ¼ 5.7 Hz, ¼ NCH2), 3.67 (4 H,
m, CH2OCH2). 13C NMR (CDCl3, 100 MHz): dC 29.79 and 29.83 (4 NMe),
45.03 (NCH2), 53.34 (CH2NCH2), 57.91 (¼NCH2), 67.11 (CH2OCH2),
80.71 and 96.22 (2 spiro carbons), 146.69 (N55C), 149.37 and 150.81
(2 NCON), 162.09 and 162.57 (4 NCOC). MS (EI, 70 eV) (m/z, %) 480
(Mþ, 10), 87 (100). Anal. Calcd. for C19H24N6O9 (480.43): C, 47.50; H,
5.04; N, 17.49%. Found: C, 47.6; H, 5.0; N, 17.5%.
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