A mild and efficient method for the synthesis of 2,5-dihydro-5-imino-2-methylfuran-3,4-dicarboxylates via an isocyanide-based multicomponent reaction

Article abstract of DOI:10.1016/j.tetlet.2009.01.069

The zwitterion formed from an alkyl or aryl isocyanide and dialkyl acetylenedicarboxylate reacts with acetic anhydride or phthalic anhydride to form 2,5-dihydro-5-imino-2-methylfuran-3,4-dicarboxylates or benzo-fused spirolactones in relatively good yield

Full text of DOI:10.1016/j.tetlet.2009.01.069

Tetrahedron Letters 50 (2009) 1456–1458
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A mild and efficient method for the synthesis of 2,5-dihydro-5-imino-2-
methylfuran-3,4-dicarboxylates via an isocyanide-based multicomponent
reaction
*
Ahmad Shaabani , Ali Hossein Rezayan, Sabrieh Ghasemi, Afshin Sarvary
Department of Chemistry, Shahid Beheshti University, PO Box 19396-4716, Tehran, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
The zwitterion formed from an alkyl or aryl isocyanide and dialkyl acetylenedicarboxylate reacts with
acetic anhydride or phthalic anhydride to form 2,5-dihydro-5-imino-2-methylfuran-3,4-dicarboxylates
or benzo-fused spirolactones in relatively good yields at room temperature without using a catalyst.
Ó 2009 Published by Elsevier Ltd.
Received 1 December 2008
Revised 29 December 2008
Accepted 13 January 2009
Available online 19 January 2009
Keywords:
Multicomponent reaction
Isocyanide
2,5-Dihydro-5-imino-2-methylfuran
derivatives
Furans and their derivatives play an important role in organic
chemistry due to their presence as key structural units in many
natural products and pharmaceuticals, and as essential building
blocks for the total synthesis of complex naturally occurring
metabolites. Furthermore, polyfunctionalized furans are versatile
synthetic starting materials for the preparation of a variety of het-
erocyclic and acyclic compounds,1–9 and especially 2,5-disubsti-
tuted furan-3,4-dicarboxylates which are very important starting
materials in the synthesis of natural products containing tetrahy-
drofuran rings.10 For these reasons, the development of new and
efficient methods for the synthesis of furan derivatives remains
an area of current interest.
Due to atom economy, simplicity, and amenability to auto-
mated synthesis, multicomponent condensation reactions (MCRs)
have an advantageous position among other reactions. The devel-
opment of new MCRs is an interesting research topic in applied sci-
ences.11–13 Although isocyanide-based multicomponent reactions
have been applied to the synthesis of various furan and furan
derivatives,14–19 our literature survey revealed that the reactions
of isocyanides and dialkyl acetylenedicarboxylates with acetic
anhydride have not been investigated.
dicarboxylates 4 via the reaction of an isocyanide 1 with a dialkyl
acetylenedicarboxylate 2 and acetic anhydride 3 at room tempera-
ture without using any catalyst (Scheme 1).
As indicated in Table 1, the 1:1:1 addition reaction of isocyanides
1 with dialkyl acetylenedicarboxylates 2 and acetic anhydride 3
occurssmoothlyinCH2Cl2 atroomtemperaturetoproduce2,5-dihy-
dro-5-imino-2-methylfuran-3,4-dicarboxylates 4. The structures of
CO2R2
O
R2O2C
R1
CO2R2
O
O
C
CH2Cl2
r.t., 12 h
R1
N
C
+
Me
+
O
Me
Me
C
N
O
Me
CO2R2
O
1
2
3
4a-h
47-60%
Scheme 1. Synthesis of 2,5-dihydro-5-imino-2-methylfuran-3,4-dicarboxylates.
Table 1
Synthesis of 2,5-dihydro-5-imino-2-methylfuran-3,4-dicarboxylates
Entry
R1
R2
Product
Yield (%)
As part of our research on the development of new synthetic
methods in heterocyclic chemistry and our interest in isocya-
nide-based multicomponent reactions,20–25 herein, we describe
an efficient synthesis of 2,5-dihydro-5-imino-2-methylfuran-3,4-
1
2
3
4
5
6
7
8
Cyclohexyl
Cyclohexyl
tert-Butyl
tert-Butyl
Me
Et
Me
Et
C(Me)3
Me
Et
4a
4b
4c
4d
4e
4f
60
55
53
49
53
47
52
58
tert-Butyl
1,1,3,3-Tetramethylbutyl
1,1,3,3-Tetramethylbutyl
2,6-(Me)2C6H4
4g
4h
* Corresponding author. Tel.: +98 2129902800; fax: +98 2122431663.
E-mail address: a-shaabani@cc.sbu.ac.ir (A. Shaabani).
Et
0040-4039/$ - see front matter Ó 2009 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2009.01.069

A. Shaabani et al. / Tetrahedron Letters 50 (2009) 1456–1458
1457
R1
In conclusion, a convenient, one-pot, three-component method
for the synthesis of 2,5-dihydro-5-imino-2-methylfuran-3,4-dicar-
boxylates from readily accessible precursors has been developed.
These compounds are important starting materials in the synthesis
of natural products containing tetrahydrofuran rings.10 The present
procedure has advantages such as good functional group tolerance
and neutral reaction conditions.
O
O
CO2R2
C
N
Me
O
Me
C
R1
N
C
3
C
R2O2C
CO2R2
CO2R2
5
R1
CO2R2
O
R2O2C
R1
O
N
O
Me
Me
C
Acknowledgments
O
Me
N
O
Me
O
R2O2C
CO2R2
We gratefully acknowledge financial support from the Research
Council of Shahid Beheshti University and from the Iran National
Science Foundation (INSF).
6
4a-h
Scheme 2. Proposed mechanism.
the products were deduced from their IR, mass, 1H NMR, and 13C
NMR spectra. The mass spectra of these compounds displayed
molecular ion peaks at the appropriate m/z values. The 1H NMR spec-
trum of 4a consisted of a multiplet for the cyclohexyl ring (d 1.18–
1.62), two singlets for the methyl groups (d 1.76 and 1.96), a multi-
plet for the N–CH cyclohexyl proton (d 3.51), two singlets for the
methoxy groups (d 3.74 and 3.80). The 1H decoupled 13C NMR spec-
trum of 4a showed 17 distinct resonances, partial assignments of
these resonances are given in the typical procedure.26
To explore the scope and limitations of this reaction further, we
extended our studies to the reaction of various dialkyl acetylenedi-
carboxylates and alkyl and aryl isocyanides with acetic anhydride.
As indicated in Table 1, the reactions proceeded very efficiently in
relatively good yields.
Although the mechanism of this reaction has not been estab-
lished, a plausible rationalization can be advanced to explain prod-
uct formation, Scheme 2. On the basis of the well-established
chemistry of isocyanides,11,27–29 it is reasonable to assume that
zwitterionic intermediate 5 produced by reaction between the iso-
cyanide and the dialkyl acetylenedicarboxylate adds to acetic
anhydride 3 resulting in the formation of 6, which undergoes cycli-
zation to deliver the 2,5-dihydro-5-imino-2-methylfuran-3,4-
dicarboxylates 4a–h.
The versatility of this multicomponent reaction with respect to
the active carbonyl component was also studied (Scheme 3). As
indicated in Table 2, reaction of phthalic anhydride 7 and dialkyl
acetylenedicarboxylates with alkyl isocyanides in CH2Cl2 led to
the formation of benzo-fused spirolactones18 8a–d in good yields
at room temperature.30
Supplementary data
Experimental procedures and mass, IR, 1H NMR, and 13C NMR
spectral data for compounds 4a–h and 8a–d are available. Supple-
mentary data associated with this article can be found, in the
online version, at doi:10.1016/j.tetlet.2009.01.069.
References and notes
1. Dean, F. M.. In Advances in Heterocyclic Chemistry; Katritzky, A. R., Ed.;
Academic: New York, 1982; Vol. 30, pp 167–238.
2. Dunlop, A. P.; Peters, F. N. The Furans; Reinhold: New York, 1953.
3. Corey, E. J.; Cheng, X. M. The Logic of Chemical Synthesis; Wiley: New York, 1989.
4. Benassi, R.. In Comprehensive Heterocyclic Chemistry II; Katritzky, A. R., Rees, C.
W., Scriven, E. F. V., Eds.; Pergamon: Oxford, 1996; Vol. 2, pp 259–295.
5. Onitsuka, S.; Nishino, H. Tetrahedron 2003, 59, 755–765.
6. Yao, T.; Zhang, X.; Larock, R. C. J. Am. Chem. Soc. 2004, 126, 11164–11165.
7. Fan, M.; Guo, L.; Liu, X.; Liu, W.; Liang, Y. Synthesis 2005, 391–396.
8. Jung, C. K.; Wang, J. C.; Krische, M. J. J. Am. Chem. Soc. 2004, 126, 4118–4119.
9. Lo, C. Y.; Guo, H.; Lian, J. J.; Shen, F. M.; Liu, R. S. J. Org. Chem. 2002, 67, 3930–
3932.
10. Pei, W. P.; Pei, J.; Li, S. H.; Ye, X. L. Synthesis 2000, 2069–2072.
11. Domling, A. Chem. Rev. 2006, 106, 17–89.
12. Multi-component Reactions; Zhu, J., Bienayme, H., Eds.; Wiley-VCH: Weinheim,
2005.
13. Tietze, L. F. Chem. Rev. 1996, 96, 115–136.
14. Teimouri, M. B.; Mansouri, F. J. Comb. Chem. 2008, 10, 507–510.
15. Yavari, I.; Mokhtarporyani-Sanandaj, A.; Moradi, L.; Mirzaei, A. Tetrahedron
2008, 64, 5221–5225.
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17. Esmaeili, A. A.; Zendegani, H. Tetrahedron 2005, 61, 4031–4034.
18. Shaabani, A.; Teimouri, M. B.; Mirzaei, P.; Bijanzadeh, H. R. J. Chem. Res. (S)
2003, 82–83.
19. Yavari, I.; Hossaini, Z.; Sabbaghan, M. Mol. Divers. 2006, 10, 479–482.
20. Shaabani, A.; Soleimani, E.; Sarvary, A.; Rezayan, A. H. Bioorg. Med. Chem. Lett.
2008, 18, 3968–3970.
21. Shaabani, A.; Soleimani, E.; Rezayan, A. H.; Sarvary, A.; Khavasi, H. R. Org. Lett.
2008, 10, 2581–2584.
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49, 1469–1472.
R1
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3925–3927.
N
CO2R2
O
CO2R2
O
CO2R2
C
C
CH2Cl2
r.t., 2 h
R1
N
C
+
+
O
O
26. Typical procedure for the preparation of (5Z)-dimethyl 2-acetoxy-5-
(cyclohexylimino)-2,5-dihydro-2-methylfuran-3,4-dicarboxylate (4a): To
a
CO2R2
O
magnetically stirred solution of acetic anhydride (0.11 g, 1.0 mmol) and
dimethyl acetylenedicarboxylate (0.14 g, 1.0 mmol) in CH2Cl2 (10 mL) was
added, dropwise, a solution of cyclohexyl isocyanide (0.11 g, 1 mmol) in CH2Cl2
(2 mL) at room temperature over 10 min. The mixture was stirred for 12 h. The
solvent was removed under vacuum, and the residue was separated by column
chromatography (silica gel, hexane/EtOAc, 4:1) to give the product as a yellow oil
8a-d
O
1
2
7
75-85%
Scheme 3. Synthesis of benzo-fused spirolactones.
(0.21 g, yield 60%). IR (KBr) (m
max/cmÀ1): 2933, 2855, 1754, 1734, 1692. MS, m/z
(%): 333 (M+À20, 2), 293 (2), 182 (20), 98 (30), 59 (30), 43 (100). 1H NMR
(300 MHz, CDCl3): dH (ppm) 1.18–1.62 (10H, m, 5CH2 of cyclohexyl), 1.76 (3H, s,
CH3), 1.96 (3H, s, CH3), 3.51 (1H, m, CH–N), 3.74 (3H, s, O–CH3), 3.80 (3H, s, O–
CH3). 13C NMR (75 MHz, CDCl3): dC (ppm) 21.48 (CH3), 24.50 (CH3), 24.22, 24.57,
25.56, 33.02, 33.18 (C-cyclohexyl), 52.71, 52.97 (2O–CH3), 56.75 (CH–NH),
106.90 (O–C–O), 137.52, 139.90 (C-olefin), 152.00 (C-imine), 160.36, 161.93,
168.41 (3C@O). Anal. Calcd for C17H23NO7: C, 57.78; H, 6.56; N, 3.96. Found: C,
57.81; H, 6.50; N, 3.89.
Table 2
Synthesis of various benzo-fused spirolactones
Entry
R1
R2
Product
Yield (%)
1
2
3
4
Cyclohexyl
tert-Butyl
tert-Butyl
1,1,3,3-Tetramethylbutyl
Me
Me
Et
8a
8b
8c
8d
82
75
85
80
27. Ugi, I. Isonitrile Chemistry; Academic Press: London, 1971.
28. Domling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168–3210.
Me

1458
A. Shaabani et al. / Tetrahedron Letters 50 (2009) 1456–1458
29. Nair, V.; Rajesh, C.; Vinod, A. U.; Bindu, S.; Speekanth, A. R.; Mathen, J. S.;
Balagopal, L. Acc. Chem. Res. 2003, 36, 899–907.
30. Typical procedure for the preparation of compound (8a): To a magnetically stirred
solution of phthalic anhydride (0.15 g, 1.0 mmol) and dimethyl
acetylenedicarboxylate (0.14 g, 1.0 mmol) in CH2Cl2 (10 mL) was added,
8a was obtained as a white powder (0.33 g, yield 82%). IR (KBr) (m
max/cmÀ1):
2930, 2852, 1785, 1722, 1700. MS, m/z (%): 399 (M+, 20), 367 (20), 302 (100), 243
(30), 163 (70), 97 (35). 1H NMR (300 MHz, CDCl3): dH (ppm) 1.14–1.85 (10H, m,
5CH2 of cyclohexyl), 3.69 (1H, m, CH–N), 3.61 (3H, s, O–CH3), 3.95 (3H, s, O–CH3),
7.45–8.03 (4H, m, arom). 13C NMR (75 MHz, CDCl3): dC (ppm) 24.43, 24.46, 25.49,
33.04, 33.14 (C-cyclohexyl), 52.96, 53.42 (2O–CH3), 57.46 (CH–N), 109.08 (spiro
carbon), 122.42, 125.70, 126.96, 131.25, 131.87, 134.64, 136.11, 143.48 (C-olefin
and C-arom), 150.69 (C-imine), 159.36, 161.27, 166.41 (3C@O). Anal. Calcd for
C21H21NO7: C, 63.15; H, 5.30; N, 3.51. Found: C, 63.23; H, 5.20; N, 3.46.
dropwise,
a solution of cyclohexyl isocyanide (0.11 g, 1 mmol) in CH2Cl2
(2 mL) at room temperature over 10 min. The mixture was stirred for 2 h. The
solvent was removed under vacuum, and the residue was crystallized from n-
hexane/dichloromethane (2:1) and washed with ether (3 Â 5 mL). The product