Stereoselective synthesis of 2-carbamoyl-2-cyanocyclopropanecarboxylates by tandem oxidative cyclization and neighboring group-assisted decarboxylation

Article abstract of DOI:10.1021/jo1014245

In this paper, we report a facile synthesis of 2-carbamoyl-2- cyanocyclopropanecarboxylates through a tandem iodosobenzene/tetrabutylammonium iodide-induced oxidative cyclization and a subsequent neighboring group-assisted decarboxylation of the Michael adducts of 2-cyanoacetamides with α,β-unsaturated malonates. This method affords the desired highly functionalized cyclopropanes in moderate to good yields and with excellent diastereoselectivities. In addition, the reaction proceeds smoothly under mild conditions and with good functional group tolerance.

Full text of DOI:10.1021/jo1014245

pubs.acs.org/joc
the area of cyclopropane synthesis,4 new and straightfor-
Stereoselective Synthesis of
2-Carbamoyl-2-cyanocyclopropanecarboxylates
by Tandem Oxidative Cyclization and Neighboring
Group-Assisted Decarboxylation
ward methods to access these highly constrained cycloal-
kanes are always highly desirable. In this paper, we introduce
an efficient synthesis of 2-carbamoyl-2-cyanocyclopropane-
carboxylates with excellent diastereoselectivities via tandem
iodine(III)-induced oxidative cyclization and subsequent
neighboring group assisted decarboxylation.
Hua Wang† and Renhua Fan*,†,‡
2-Carbamoyl-2-cyanocyclopropanecarboxylates have been
used as templates for the preparation of many useful function-
alized cyclopropanes due to their reactive functionalities.5 For
example, they have been used as key intermediates in the
synthesis of cryptophycin analogues, which exhibit high activ-
ity against a broad spectrum of solid tumors.6 The Charette
group has reported the reaction of alkenes with R-cyanodiazo-
acetamide in the synthesis 1-cyanocyclopropane-1-carboxy
derivatives.7 Similarly, Zhang and co-workers developed a
cobaltcatalyzed cyclopropanation of various electron-deficient
alkenes with diazoacetate to afford 2-cyanocyclopropane
carboxylates.8 However, when a double bond with two electron-
withdrawing groups at the same carbon was employed, no
reaction occurred (path b, Scheme 1). This kind of reaction with
an R,β-unsaturated carbonyl compound has never been
addressed in previous literature (path a, Scheme 1). In our
previous studies, we found that 2-benzoylcyclopropane- 1,1-
dicarboxylate could be prepared through oxidative cycliza-
tion of the Michael adducts of malonates with chalcones in
the presence of iodosobenzene and tetrabutylammonium iodide.9
The success of such a procedure encouraged us to investigate this
as a novel method for the synthesis of 2-carbamoyl-2-cyanocy-
clopropanecarboxylates from 2-cyanoacetamides and R,β-
unsaturated esters (path c, Scheme 1).
†Department of Chemistry, Fudan University,
220 Handan Road, Shanghai 200433, China, and
‡Shanghai Key Laboratory of Molecular Catalysts and
Innovative Materials, Department of Chemistry,
Fudan University, 220 Handan Road, Shanghai 200433, China
rhfan@fudan.edu.cn
Received July 28, 2010
In this paper, we report a facile synthesis of 2-carbamoyl-
2-cyanocyclopropanecarboxylates through a tandem
iodosobenzene/tetrabutylammonium iodide-induced oxidative
cyclization and a subsequent neighboring group-assisted
decarboxylation of the Michael adducts of 2-cyanoace-
tamides with R,β-unsaturated malonates. This method
affords the desired highly functionalized cyclopropanes
in moderate to good yields and with excellent diastereo-
selectivities. In addition, the reaction proceeds smoothly
under mild conditions and with good functional group
tolerance.
The 2-cyanoacetamide 2a was prepared as described in the
literature in 92% yield.10 In our initial experiments, we found
the Michael addition of 2-cyanoacetamide 2a to ethyl cinnamate
€
(4) (a) Salaun, J. Chem. Rev. 1989, 89, 1247. (b) Padwa, A.; Krumpe, K. E.
Tetrahedron 1992, 48, 5385. (c) Doyle, M. P. In Catalytic Asymmetric
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Angew. Chem., Int. Ed. 1996, 35, 971. (e) Lautens, M.; Klute, W.; Tam, W.
Chem. Rev. 1996, 96, 49. (f ) Li, A. H.; Dai, L. X.; Aggarwal, V. K. Chem. Rev.
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(h) Davies, H. M. L.; Antoulinakis, E. Org. React. 2001, 57, 1. (i) Donaldson,
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C.; Charette, A. B. Chem. Rev. 2003, 103, 977. (k) Pietruszka, J. Chem. Rev.
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Chem. 2007, 72, 1058.
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Andis, S. L.; Corbett, T. H.; Gossett, L. S.; Janisse, S. K.; Martinelli, M. J.;
Moher, E. D.; Schultz, R. M.; Toth, J. E. Bioorg. Med. Chem. Lett. 1999, 9,
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(9) Ye, Y.; Zheng, C.; Fan, R. Org. Lett. 2009, 11, 3156.
As the smallest cycloalkanes, cyclopropanes1 not only
appear as basic skeltons in a wide range of biologically active
natural and unnatural compounds2 but also as versatile
intermediates for the synthesis of various cyclic and acyclic
compounds.3 Despite the considerable amount of effort in
(1) For selected reviews on cyclopropanes, see: (a) Patai, S.; Rappoport,
Z. The Chemistry of the Cyclopropyl Group; Wiley & Sons: New York, 1987.
(b) Houblen-Weyl Methods of Organic Chemistry; Thieme: Stuttgart, 1997;
Vol. E17c. (c) Small Ring Compounds in Organic Synthesis VI; de Meijere, A.,
Ed.; Springer: Berlin, 2000; Vol. 207.
(2) (a) de Meijere, A. Angew. Chem., Int. Ed. 1979, 18, 809. (b) Suckling,
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Chem. 1990, 14, 713. (d) Wiberg, K. B. Acc. Chem. Res. 1996, 29, 229. (e) Salaun,
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40, 2251.
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Tetrahedron 1993, 49, 5203. (g) Nonhebel, D. C. Chem. Soc. Rev. 1993, 347.
6994 J. Org. Chem. 2010, 75, 6994–6997
Published on Web 09/21/2010
DOI: 10.1021/jo1014245
r
2010 American Chemical Society

Wang and Fan
JOCNote
SCHEME 1
TABLE 1
entry
conditions
4a (%)a
7a (%)a
8a (%)a
1
2
25 °C, 1 h
75
31
0
0
5
61
81
0
52
23
trace
0 °C, 1 h
SCHEME 2
3
-15 °C, 1 h
-15 °C, 0.5 h
4b
0
aIsolated yield. b1 equiv of PhIO and Bu4NI were used.
SCHEME 4
SCHEME 3
Under the optimized Michael addition conditions, the reac-
tion of 2-cyanoacetamide 2a with 2-benzylidenemalonate 5a
afforded adduct 6a in 78% yield (Scheme 3, eq 2). Interest-
ingly, when the combination of PhIO and Bu4NI was used as
the oxidative reagent, 2-carbamoyl-2-cyanocyclopropane-
1,1-dicarboxylate 7a was not detected, but the desired
2-carbamoyl-2-cyanocyclopropanecarboxylate 4a was iso-
lated in 51% yield (Scheme 3, eq 3). In our previous studies,
cyclopropane derivatives were normally formed as trans
diastereoisomers, in which the coupling constants between
the two methine protons of the cyclopropanes were 6-7 Hz.9
However, the observed corresponding coupling constant for pro-
duct 4a was 10.4 Hz, which is larger than those for the trans-
cyclopropane derivatives, and indicates a cis configuration
for compound 4a. The cis configuration of 4a was also con-
firmed by its single-crystal diffraction analysis.
Further studies were conducted to set up the optimal cy-
clization conditions [PhIO (2 equiv), Bu4NI (2 equiv), THF,
25 °C, 1 h] to afford product 4a in 75% yield (Table 1, entry 1).
When the reaction was carried out at 0 °C, besides product
4a, two byproducts formed. They were isolated and assigned
as 2-carbamoyl-2-cyanocyclopropane-1,1-dicarboxylate 7a and
ethyl 5-cyano-2,4-dioxo-6-phenyl-3-azabicyclo[3.1.0]hexane-1-
carboxylate 8a, respectively (Table 1, entry 2). When the
reaction was further decreased to -15 °C, compound 7a
formed as the major product (Table 1, entry 3). When the
proceeded sluggishly.11 After the optimization of reaction
conditions, Michael adduct 3a was finally obtained in low
yield (Scheme 2, eq 1). However, the subsequent oxidative
cyclization of 3a with the combination of iodosobenzene and
tetrabutylammonium iodide failed (Scheme 2, eq 2).
To increase the reactivity for both the R,β-unsaturated
ester in Michael addition and the corresponding adduct in
oxidative cyclization, another ester group was introduced
into the structure of the substrate. The desired 2-carbamoyl-
2-cyanocyclopropanecarboxylate was expected to be formed
through the decarboxylation of a resultant 2-carbamoyl-
2-cyanocyclopropane-1,1-dicarboxylate 7 (Scheme 3, eq 1).
(10) (a) Ried, W.; Schleimer, B. Angew. Chem. 1958, 70, 164. (b) Gorobets,
N. Y.; Yousefi, B. H.; Belaj, F.; Kappe, C. O. Tetrahedron 2004, 60,
8633.
(11) For selected examples on the reactions of 2-cyanoacetmides, see:
(a) Girgis, A. S.; Hosni, H. M.; Barsoum, F. F. Bioorg. Med. Chem. 2006, 14,
4466. (b) Bheemanapalli, L. N.; Akkinepally, R. R.; Pamulaparthy, S. R.
Chem. Pharm. Bull. 2008, 56, 1342. (c) Rosati, O.; Curini, M.; Marcotullio,
M. C.; Oball-Mond, G.; Pelucchini, C.; Procopio, A. Synthesis 2010, 239.
J. Org. Chem. Vol. 75, No. 20, 2010 6995

Wang and Fan
JOCNote
TABLE 2
SCHEME 5. Plausible Reaction Pathway
entry
R1
R2
R3
4
yielda (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
C6H5
C6H5
C6H5
4-NO2C6H4
C6H5
C6H5
4-CF3C6H4
C6H5
4-MeOC6H4
Bn
Et
Et
Et
Et
Me
Bn
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
4a
4b
4c
4d
4e
4f
4g
4h
4i
75
65
87
40
61
76
80
65
70
52
70
80
66
62
60
65
73
47
53
trace
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-FC6H4
4-ClC6H4
2-ClC6H4
2,4-di-Cl-C6H3
4-BrC6H4
4-CNC6H4
4-CF3C6H4
4-NO2C6H4
4-MeOC6H4
4-MeC6H4
1-naphthyl
2-furan
4j
4k
4l
4m
4n
4o
4p
4q
4r
4s
4t
the same conditions only afforded 2-carbamoyl-2-cyanocy-
clopropane-1,1-dicarboxylate 10 as the product (eq 1).
2-thiophene
n-Bu
aIsolated yield.
amounts of PhIO and Bu4NI were decreased to 1 equiv, the
reaction only afforded compound 7a after 30 min (Table 1,
entry 4). When compounds 7a and 8a were treated with the
combination of PhIO and Bu4NI again, both of them were
converted into product 4a with good yields. Moreover, the
conversions also proceeded well by treatment with 1 equiv of
NaOAc (Scheme 4, eqs 1 and 2). When D2O was introduced
into the reaction mixture, the reaction was monitored by
observing the disappearance of the R proton signal of the
ester group of compound 6a in 1H NMR (Scheme 4, eq 3).
The reaction scope was then investigated under the opti-
mized conditions, and the results are summarized in Table 2.
Michael adducts 6 were prepared from corresponding addi-
tions of 2-cyanoacetamides with R,β-unsaturated malonates in
yields ranging from 62 to 91%. In most cases, 2-carbamoyl-
2-cyanocyclopropanecarboxylates 4 were formed in good
yields. With respect to the R2 groups on the nitrogen, both
electron-poor and electron-rich aromatic rings afford good
yields, while reaction of the substrate with a benzyl group as
the R2 group also afforded the corresponding product 4d
(Table 2, entries 1-4). Michael adducts derived from di-
methyl and dibenzyl malonates were also suitable substrates
(Table 2, entries 5 and 6). Additionally, the reaction was
found to tolerate a range of different groups with different
electronic demands on the R1 aromatic rings (Table2, entries
7-17). 2-Furan- or 2-thiophene-substituted Michael ad-
ducts were also utilized as substrates to afford the desired
product 4r or 4s in 47 or 53% yield, respectively (Table 2,
entries 18 and 19). Only trace amounts of product were
detected for the reaction of the substrate with butyl as the
R1 group (Table 2, entry 20). All products were formed with
excellent diastereoselectivities (cis/trans >95:5, determined
by 1H NMR).
A plausible reaction mechanism is outlined in Scheme 5.
Due to the polymeric structure of iodosobenzene, a hydrox-
ylic solvent or a catalyst is normally required to depolymerize
(PhIO)n to generate the reactive species.12 Besides the useful
oxidative nature, a notable feature of the resultant iodine-
(III) compounds is their ability to undergo ligand exchange
reaction and reductive elimination reaction like transition
metals.13 In the presence of the reactive iodine(III) species I,
which is generated from the depolymerization of iodosoben-
zene by tetrabutylammonium iodide, an R hyperiodination
of Michael adduct 6 yields an intermediate II. After an intra-
molecular attack by the activated methine carbon and a
subsequent reductive elimination of PhI, intermediate II is
converted into 2-carbamoyl-2-cyanocyclopropane-1,1-di-
carboxylate 7.14 The diastereomer 7I is the favored product
due to steric effects, in which one ester group and one amide
group are located on the same side of the plane of the cyclo-
propane moiety. Subsequently, compound 7I undergoes an
intramolecular cyclization which eventually generates 5-cyano-
2,4-dioxo-6-phenyl-3-azabicyclo[3.1.0]hexane-1-carboxylate 8.15
(12) (a) Moriarty, R. M.; Duncan, M. P.; Prakash, O. J. Chem. Soc.,
Perkin Trans. 1 1987, 1781. (b) Moriarty, R. M.; Rani, N.; Condeiu, C.;
Duncan, M. P.; Prakash, O. Synth. Commun. 1997, 27, 3273. (c) Tohma, H.;
Takizawa, S.; Maegawa, T.; Kita, Y. Angew. Chem., Int. Ed. 2000, 39, 1306.
(d) Francisco, C. G.; Freire, R.; Gonzalez, C. C.; Leon, E. I.; Riesco-
Fagundo, C.; Suarez, E. J. Org. Chem. 2001, 66, 1861. (e) Tohma, H.;
Maegawa, T.; Takizawa, S.; Kita, Y. Adv. Synth. Catal. 2002, 344, 328.
(f ) Francisco, C. G.; Herrera, A. J.; Suarez, E. J. Org. Chem. 2002, 67, 7439.
(g) Francisco, C. G.; Herrera, A. J.; Suarez, E. J. Org. Chem. 2003, 68, 1012.
(13) For selected reviews, see: (a) Moriarty, R. M.; Vaid, R. K. Synthesis
1990, 431. (b) Stang, P. J.; Zhdankin, V. V. Chem. Rev. 1996, 96, 1123.
(c) Zhdankin, V. V.; Stang, P. J. In Chemistry of Hypervalent Compounds;
Akiba, K., Ed.; VCH Publishers: New York, 1999; Vol. 11, p 327. (d) Grushin,
V. V. Chem. Soc. Rev. 2000, 29, 315. (e) Zhdankin, V. V.; Stang, P. J. Chem.
Rev. 2002, 102, 2523. (f ) Stang, P. J. J. Org. Chem. 2003, 68, 2997. (g) Moriarty,
R. M. J. Org. Chem. 2005, 70, 2893. (h) Zhdankin, V. V.; Stang, P. J. Chem.
Rev. 2008, 108, 5299.
When the amide group of Michael adduct 6b was pro-
tected by a methyl group, the corresponding reaction under
6996 J. Org. Chem. Vol. 75, No. 20, 2010

Wang and Fan
JOCNote
Although we are not certain of the true pathway involving
the generation of the cis-2-carbamoyl-2-cyanocyclopro-
panecarboxylate 4 from compound 8, a possible rationalization
could be the selective hydrolysis of compound 8 and the
decarboxylation of the resultant intermediate III.
The future direction for the research will be extending the
scope and potential synthetic applications, as well as inves-
tigation of asymmetric transformations.
Experimental Section
Finally, the treatment of 2-carbamoyl-2-cyanocyclopro-
panecarboxylate 4b with K2CO3 and H2O2 in DMSO16 led to
the generation of 2,4-dioxo-N,6-diphenyl-3-azabicyclo-
[3.1.0]hexane-1-carboxamide 11 in 55% yield (eq 2).
General Experimental Procedure. The mixture of Michael
adduct 6 (0.2 mmol) with PhIO (88 mg, 0.4 mmol) in THF
(2 mL) was treated with Bu4NI (148 mg, 0.4 mmol). The reaction
was allowed to stir at 25 °C for 1 h. Upon completion by TLC,
the reaction mixture was quenched with saturated Na2S2O3 (25
mL) and extracted by ethyl acetate (25 mL ꢀ 3). The organic
layer was dried over Na2SO4 and concentrated in vacuo. The
residue was purified by column chromatography on silica gel
(15% ethyl acetate in hexanes) to provide 2-carbamoyl-2-
cyanocyclopropane carboxylate 4.
Product 4a: colorless solid; mp 148-150 °C; 1H NMR (400 MHz,
CDCl3) δ8.61 (s, 1 H), 7.70 (d, J= 8.7 Hz, 2 H), 7.64 (d, J=8.7 Hz,
2 H), 7.36-7.40 (m, 5 H), 4.18-4.21 (m, 2 H), 3.61 (d, J = 10.4 Hz,
In conclusion, we have developed a novel method for
stereoselective synthesis of 2-carbamoyl-2-cyanocyclopro-
panecarboxylates by tandem iodine(III)-induced oxidative
cyclization, followed by a neighboring group-assisted de-
carboxylation. This reaction proceeds smoothly to afford the
desired highly functionalized cyclopropane in good yield
under mild conditions with good functional group tolerance.
1 H), 3.17 (d, J = 10.4 Hz, 1 H), 1.20 (t, J = 7.1 Hz, 3 H); 13
C
NMR (100 MHz, CDCl3) δ 165.4, 161.9, 139.6, 130.4, 129.1,128.8,
128.6, 128.4, 126.5, 126.4, 120.2, 115.7, 62.1, 37.1, 34.6, 27.5, 13.9;
IR (KBr) 2955, 2924, 2843, 2249, 1736, 1697, 1605, 1535, 1409
cm-1; HRMS m/z calcd for C21H17F3N2NaO3 ([M þ Na]þ)
425.1089, found 425.1051.
(14) For selected examples on MIRC reactions, see: (a) Zwanenburg, B.;
De Kimpe, N. In Houben-Weyl, 4th ed.; de Meijere, A., Ed.; Thieme:
Stuttgart, 1997; Vol. E17a, p 69. (b) Lebel, H.; Marcoux, J.-F.; Molinaro, C.;
Charette, A. B. Chem. Rev. 2003, 103, 977. (c) Kozhushkov, S. I.; Leonov, A.;
De Meijere, A. Synthesis 2003, 956. (d) Giubellina, N.; De Kimpe, N. Synlett
2005, 976. (e) Peppe, C.; das Chagas, R. P.; Burrow, R. A. J. Organomet.
Chem. 2008, 693, 3441. (f ) Pellissier,H. Tetrahedron2008, 64, 7041. (g) Bagnoli,
L.; Scarponi, C.; Testaferri, L.; Tiecco, M. Tetrahedron: Asymmetry 2009, 20,
1506. (h) Marini, F.; Sternativo, S.; Del Verme, F.; Testaferri, L.; Tiecco, M.
Adv. Synth. Catal. 2009, 351, 1801.
Acknowledgment. Financial support from the National
Natural Science Foundation of China (20702006) and Shanghai
Key Laboratory of Molecular Catalysts and Innovative Materials,
Department of Chemistry, Fudan University (2009KF02), is
gratefully acknowledged.
Supporting Information Available: Experimental proce-
dures, characterization data, copies of 1H NMR and 13C NMR
of new compounds, and crystallographic data of compound 4a
(CIF). This material is available free of charge via the Internet at
http://pubs.acs.org.
(15) Shchepin, V. V.; Silaychev, P. S. Chem. Heterocycl. Compd. 2005, 41,
1545.
(16) Nagata, K.; Sano, D.; Shimizu, Y.; Miyazaki, M.; Kanemitsu, T.;
Itoh, T. Tetrahedron: Asymmetry 2009, 20, 2530.
J. Org. Chem. Vol. 75, No. 20, 2010 6997