Metal iodide mediated ring expansion of cyclopropanecarboxylic thioesters with imines

Article abstract of DOI:10.1016/j.tetlet.2006.05.019

Metal iodide mediated three-component reactions of cyclopropanecarboxylic thioesters 1, aldehydes, and amines were developed. The initial products, pyrrolidines 2 were obtained in 39-73% yields, which could further be converted to lactams 4, via sequentia

Full text of DOI:10.1016/j.tetlet.2006.05.019

Tetrahedron Letters 47 (2006) 4911–4915
Metal iodide mediated ring expansion
of cyclopropanecarboxylic thioesters with imines
Wenwei Huang,* Janice Chin, Luke Karpinski, Gary Gustafson,
Carmen M. Baldino and Libing Yu
ArQule, Inc., 19 Presidential Way, Woburn, MA 01801, USA
Received 13 April 2006; revised 3 May 2006; accepted 4 May 2006
Available online 30 May 2006
Abstract—Metal iodide mediated three-component reactions of cyclopropanecarboxylic thioesters 1, aldehydes, and amines were
developed. The initial products, pyrrolidines 2 were obtained in 39–73% yields, which could further be converted to lactams 4,
via sequential reactions of a retro-aza-Michael addition and an intramolecular cyclization. This methodology provided facile access
to analogs of both pyrrolidines 2 and lactams 4.
ꢀ 2006 Elsevier Ltd. All rights reserved.
Metal iodide mediated ring expansion of activated
cyclopropanes has recently attracted much attention
because it provides an efficient method for the prepara-
tion of heterocyclic compounds.1 Although many
carbonyl groups have been used to activate cyclopro-
pane, we are interested in thioesters recognizing that
they can be easily prepared and the transformations of
thioesters in organic synthesis are well documented.2
In particular, direct amidation of thioesters and
reductive alkylation of amines by thioesters under mild
conditions allow further derivation of the products
in a parallel fashion for compound library generation.
Recently, Olsson and co-workers developed a conve-
nient three-component reaction of cyclopropylketones,
aldehydes, and amines for the synthesis of pyrrolidine
derivatives.1f Since pyrrolidines are found in a variety
of natural products and biologically active compounds,
we envisioned that ring expansion of cyclopropanecarb-
oxylic thioesters with imines would provide versatile
synthetic intermediates not only for the construction
Table 1. Metal iodide mediated three-component reaction
Cl
Cl
O
O
NH2
CHO
Cl
O
S
S
+
+
+
N
S
N
F
F
F
1a
2a
3a
Entry
Metal iodide
Solvent
Temp (ꢁC)
Time (h)
Ratio of 2a/3aa
Yieldb (%)
1
2
3
4
MgI2 (2 equiv)
Et2AlI (2 equiv)
Et2AlI (1 equiv)
ZnI2 (2 equiv)
CH3CN
85
80
80
85
20
5
20
20
0.9/1.0
>99/1
59
57
<5
0
CH2ClCH2Cl
CH2ClCH2Cl
CH3CN
a The ratios were determined by proton NMR of the crude reaction products.
b Isolated yield.
Keywords: Pyrrolidine; Three-component reaction; Thioester; Retro-aza-Michael addition.
*
Corresponding author. Tel.: +1 781 994 0610; fax: +1 781 994 0678; e-mail: whuang@arqule.com
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.05.019

4912
W. Huang et al. / Tetrahedron Letters 47 (2006) 4911–4915
of b-proline combinatorial libraries, but also for the
synthesis of some pyrrolidine alkaloids.
When other metal iodides (ZnI2 and Et2AlI) were inves-
tigated, 2 equiv of Et2AlI was found to push the reaction
to completion in 5 h at 80 ꢁC and gave 2a as a predo-
minate product in a 57% isolated yield,3 as shown in
Table 1.
Our studies began with heating a mixture of thioester 1a,
4-fluorobenzaldehyde, and 4-methylbenzylamine in the
presence of 2 equiv of MgI2 in acetonitrile at 85 ꢁC.
After 20 h, the reaction gave the desired pyrrolidines
as a pair of isomers (2a and 3a) in about a 1 to 1 ratio.
To explore the scope of the reaction, the optimal Et2AlI
conditions were applied to various thioesters, aldehydes,
Table 2. Et2AlI mediated three-component reaction4
O
Et2AlI DCE, 80 o
C
R1
O
S
+
+
R3NH2
R2CHO
R1
S
N
R2
R3
1a-c
2a-j
Entry
Substrates
Time (h)
Product
Yield (%)a
R1
R2
R3
1
5
2a
57
Cl
F
1a
2
3
5
5
2b
2c
2d
2e
2f
2g
2h
2i
73
59
56
61
64
49
45
43
68
39
50
1b
MeO
1c
4
5
Cl
Cl
Cl
Cl
Cl
Cl
Cl
5
5
OMe
6
5
NC
7
5
8
5
9
5
10
11
12
5
2j
Cl
24
5
2k
2l
MeO
Cl
a Isolated yields and all compounds were characterized by 1H NMR and 13C NMR.

W. Huang et al. / Tetrahedron Letters 47 (2006) 4911–4915
4913
Cl
R2
O
Cl
Cl
O
O
O
- p-ClPhSH
Et2AlI
S
S
S
N
R1
+
Al
N
Al
N
R2
R2
N
R1
R2
R1
R1
2
4
Scheme 1.
and amines as summarized in Table 2. Both aliphatic
and aromatic thioesters worked under the set of condi-
tions while aliphatic thioester 1c gave a better yield in
comparison with aromatic thioesters 1a and 1b (entries
2, 3, and 4). In addition, both aromatic and aliphatic
aldehydes performed well in this reaction although elec-
tronic rich aldehydes, such as 4-methoxybenzaldehyde,
reacted slowly and required a longer reaction time (entry
11). In all cases, the reaction gave one predominate
isomer.
the Lewis acid underwent an intramolecular cyclization
to give lactams 4.
Recognizing that lactams 4 were important synthetic
intermediates,6 we focused our efforts on optimizing
reaction conditions to generate lactams 4 exclusively.
The three-component reaction was carried out using
3 equiv of Et2AlI at 80 ꢁC for 3 h followed by further
heating the reaction mixture at 90 ꢁC for 21 h. Under
the new set of conditions, pyrrolidines 2, the initial
product of the reaction, were converted to lactams 4
completely in moderate to good yields, as shown in
Table 3. It was noteworthy that only a single isomer
of 4 was generated from the reactions as determined as
E isomer by NOE analysis.7
Along with pyrrolidines 2, the reactions gave a small
amount of lactams 4. Further studies revealed that
increasing either the amount of Et2AlI used in the reac-
tion or the reaction temperature increased the amount
of lactams 4. These side products came from the decom-
position of pyrrolidines 2, which was similar to the
observation5 we reported on the cyclopropylketone sys-
tem. A mechanism was proposed in Scheme 1 to illus-
trate how pyrrolidines 2 were converted to lactams 4.
Acyclic intermediates generated from pyrrolidines 2
via a retro-aza-Michael addition reaction catalyzed by
In conclusion, a novel metal iodide mediated ring expan-
sion of cyclopropanecarboxylic thioesters with imines
was developed, by which pyrrolidines 2 or lactams 4
were prepared easily under two different sets of condi-
tions by varying the amount of Et2AlI, reaction temper-
ature and time, starting from the same set of reagents.
Table 3. Lactam 4 formation8
R2
Cl
3 equiv Et2AlI
O
R2CHO
R1NH2
+
+
N
O
S
DCE, 80-90 ºC, 24 h
R1
1a
4a-d
Entry
Substrates
Product
Yield (%)a
Mp (ꢁC)
R1NH2
R2CHO
NH2
CHO
1
2
3
4
4a
4b
4c
4d
64
71
40
42
77–78
134–135
67–68
64–65
NH2
NH2
CHO
CHO
NH2
CHO
a Isolated yields and all compounds were characterized by 1H NMR and 13C NMR.

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W. Huang et al. / Tetrahedron Letters 47 (2006) 4911–4915
benzylamine (60.6 mg, 0.5 mmol, 1.0 equiv) in anhydrous
1,2-dichloroethane (1 mL) at room temperature and the
resulting mixture was shaken at 80 ꢁC. After 5 h, the
reaction was cooled to room temperature and then
quenched with 2 mL of 0.5 M ethylenediaminetetraacetic
acid disodium salt solution. The mixture was extracted with
EtOAc (2 · 5 mL). The combined organic layer was dried
over MgSO4, filtered, and concentrated under reduced
pressure. The crude reaction product was purified by
preparative thin-layer chromatography (10% ethyl acetate
in hexanes) to yield 2a (124.8 mg, 57%) as a viscous oil.
TLC (silica gel, 10% ethyl acetate in hexanes, Rf = 0.42); 1H
NMR (CDCl3, 400 MHz) d 2.09–2.15 (m, 1H), 2.21–2.29
(m, 1H), 2.33 (s, 3H), 2.38–2.43 (m, 1H), 3.04 (d,
J = 12.9 Hz, 1H), 3.08–3.13 (m, 1H), 3.16–3.22 (m, 1H),
3.69 (d, J = 8.2 Hz, 1H), 3.73 (d, J = 12.9 Hz 1H), 7.06–
7.14 (m, 6H), 7.26–7.28 (m, 2H), 7.36–7.38 (m, 2H), 7.46–
7.50 (m, 2H); 13C NMR (CDCl3, 75 MHz) d 21.1, 28.0,
52.3, 57.1, 61.1, 71.6, 115.5 (JC–F = 21.4 Hz), 126.0, 128.5,
128.9, 129.3, 129.4, 135.6, 135.7, 135.8, 136.5, 136.8
(JC–F = 3.1 Hz), 162.4 (JC–F = 245.7 Hz), 198.4.
The application of this methodology in the syntheses of
b-proline libraries will be reported in due course.
Acknowledgments
We thank Dr. Feng Li for the NOE analysis.
References and notes
1. (a) Alper, P. B.; Meyers, C.; Lerchner, A.; Siegel, D. R.;
Carreira, E. M. Angew. Chem., Int. Ed. 1999, 38, 3186; (b)
Fischer, C.; Meyers, C.; Carreira, E. M. Helv. Chim. Acta
2000, 83, 1175; (c) Han, Z.; Uehira, S.; Tsuritani, T.;
Shinokubo, H.; Oshima, K. Tetrahedron 2001, 57, 987–995;
(d) Lautens, M.; Han, W.; Liu, H.-C. J. Am. Chem. Soc.
2003, 125, 4028–4029; (e) Lautens, M.; Han, W. J. Am.
Chem. Soc. 2002, 124, 6312–6316; (f) Bertozzi, F.; Gustafs-
son, M.; Olsson, R. Org. Lett. 2002, 4, 3147–3150; (g) Li,
G.; Xu, X.; Chen, D.; Timmons, C.; Carducci, M. C.;
Headley, A. D. Org. Lett. 2003, 5, 329–331; (h) Timmons,
C.; Guo, L.; Liu, J.; Cannon, J. F.; Li, G. J. Org. Chem.
2005, 70, 7634–7639.
2. (a) Liebeskind, L. S.; Srogl, J. J. Am. Chem. Soc. 2000, 122,
11260–11261; (b) Fukuyama, T.; Lin, S. C.; Li, L. J. Am.
Chem. Soc. 1990, 112, 7050–7051; (c) Crich, D.; Hao, X.
J. Org. Chem. 1997, 62, 5982–5988; (d) Sugoh, K.;
Kuniyasu, H.; Ohtaka, A.; Takai, Y.; Tanaka, A.; Mach-
ino, C.; Kambe, N.; Kurosawa, H. J. Am. Chem. Soc. 2001,
123, 5108–5109; (e) Arrastia, I.; Lecea, B.; Cossio, F. P.
Tetrahedron Lett. 1996, 37, 245–248; (f) Danheiser, R. L.;
Choi, Y. M.; Menichincheri, M.; Stoner, E. J. J. Org. Chem.
1993, 58, 322–327; (g) Han, Y.; Chorev, M. J. Org. Chem.
1999, 64, 1972–1978.
5. Huang, W.; O’Donnell, M.-M.; Bi, G.; Liu, J.; Yu, L.;
Baldino, C. M.; Bell, A. S.; Underwood, T. J. Tetrahedron
Lett. 2004, 45, 8511.
6. Some recent examples for preparing 3-alkylidenyl-pyrrol-
idin-2-one derivatives: (a) Hutton, T. K.; Muir, K. W.;
Procter, D. J. Org. Lett. 2003, 4811; (b) Kitbunnadaj, R.;
Zuiderveld, O. P.; De Esch, I. J. P.; Vollinga, R. C.; Bakker,
R.; Lutz, M.; Spek, A. L.; Cavoy, E.; Deltent, M.-F.;
Menge, W. M. P. B.; Timmerman, H.; Leurs, R. J. Med.
Chem. 2003, 46, 5445; (c) Fielding, M. R.; Grigg, R.; Urch,
C. J. Chem. Commun. 2000, 2239.
7. The assignment of the stereochemistry was based upon an
NOE analysis of lactam 4d.
2.4% nOe
H
3. When MgI2 was used to promote the reaction, 2a and 3a
were formed as an inseparable mixture. These thioesters
were converted to the phenylketones under Liebeskind’s
condition.2a When a mixture of 2a and 3a was used, the
reaction gave phenylketones 5 and 6 as a pair of cis–trans
isomers (Eq. 1). The proton NMR spectra of the phenylk-
etones were compared with those of the authentic samples.
Under the same condition, thioester 2a gave phenylketone
5, the trans isomer (Eq. 2). Based on these observations, 2a
was tentatively assigned as trans configuration.
H
H
H
N
O
8. General procedure: To a 7 mL vial, benzaldehyde (53.1 mg,
0.5 mmol in 1.0 mL ClCH2CH2Cl, 1.0 equiv), Et2AlI
(1.5 mL, 25 wt % solution in toluene, 1.0 mmol, 3.0 equiv),
O
O
O
O
PhB(OH)2
Ph
Ph
+
(
p
-Cl)PhS
F
(p
-Cl)PhS
F
+
N
N
CuTc
Pd(PPh3)4
N
N
ð1Þ
ð2Þ
F
F
5
2a
3a
6
O
O
PhB(OH)2
(p
-Cl)PhS
F
Ph
N
N
CuTc
Pd(PPh3)4
F
2a
5
4. General procedure: To a 7 mL vial, 4-fluorobenzaldehyde
(62.1 mg, 0.5 mmol in 1.0 mL ClCH2CH2Cl, 1.0 equiv),
Et2AlI (1.0 mL, 25 wt % solution in toluene, 1.0 mmol,
2.0 equiv), and cyclopropanecarboxylic 4-chlorophenyl thio-
ester (1a) (106.2 mg, 0.5 mmol in 1.0 mL ClCH2CH2Cl,
1.0 equiv) were added sequentially to a solution of 4-methyl
and cyclopropanecarboxylic 4-chlorophenyl thioester (1a)
(106.2 mg, 0.5 mmol in 1.0 mL ClCH2CH2Cl, 1.0 equiv)
were added sequentially to a solution of butylamine
(36.5 mg, 0.5 mmol, 1.0 equiv) in anhydrous 1,2-dichloro-
ethane (1 mL) at room temperature and the resulting
mixture was shaken first at 80 ꢁC for 3 h, then at 90 ꢁC

W. Huang et al. / Tetrahedron Letters 47 (2006) 4911–4915
4915
for 21 h. The reaction was cooled to room temperature and
then quenched with 3 mL of 1.0 M NaOH aqueous
solution. The mixture was extracted with EtOAc
(2 · 10 mL). The combined organic layer was dried over
MgSO4, filtered, and concentrated under reduced pressure.
The crude reaction product was purified by preparative
thin-layer chromatography (20% ethyl acetate in hexanes)
to yield 4a (73.3 mg, 64%) as a solid. TLC (silica gel, 20%
ethyl acetate in hexanes, Rf = 0.18); 1H NMR (CDCl3,
400 MHz) d 0.94 (t, J = 7.2 Hz, 3H), 1.29–1.42 (m, 2H),
1.52–1.62 (m, 2H), 3.06 (dt, J = 6.1 Hz, 2.8 Hz, 2H), 3.41–
3.51 (m, 4H), 7.26–7.50 (m, 6H). 13C NMR (CDCl3,
75 MHz) d 13.7, 20.1, 24.4, 29.4, 42.9, 44.5, 128.2, 128.6,
129.4, 129.7, 131.3, 136.0, 169.0.