An Efficient Access to Selenazoline-4-Carboxylate Derivatives Incorporating Cyclopropyl Groups

Article abstract of DOI:10.1055/s-2003-44969

5-Spirocyclopropane-annulated selenazoline-4-carboxylates were synthesized in good yield via Michael addition of selenoamide to 2-bromo-2- cyclopropylideneacetate followed by an intramolecular substitution under basic conditions (NaHCO₃, MeCN).

Full text of DOI:10.1055/s-2003-44969

LETTER
329
An Efficient Access to Selenazoline-4-Carboxylate Derivatives Incorporating
Cyclopropyl Groups
Efficient
A
ccess to
i
Selena
a
zoline-4-C
n
arboxylate
D
erivat
H
ives uang,*a,b Wan-Li Chen,a Hong-Wei Zhoua
a
Department of Chemistry, Zhejiang University, Xixi Campus, Hangzhou, P. R. China
Fax +86(571)88807077; E-mail: huangx@mail.hz.zj.cn
b
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai,
P. R. China
Received 17 September 2003
O
S
O
S
Abstract: 5-Spirocyclopropane-annulated selenazoline-4-carboxy-
lates were synthesized in good yield via Michael addition of sele-
noamide to 2-bromo-2-cyclopropylideneacetate followed by an
intramolecular substitution under basic conditions (NaHCO3,
MeCN).
formal
Tol
R1
COOEt
R1
Tol
O
[3+2] cycloaddition
O
Br
+
O
O
NH
Bn
N
COOEt
Bn
Key words: Michael addition, selenoamide, selenium heterocycles
Scheme 1
cleophile, so we prepared to synthesize a new kind of se-
lenium heterocycles containing cyclopropane by using
selenoamide and 2-bromo-2-cyclopropylideneacetate.
A variety of simple cyclopropane-containing compounds
have been of synthetic interest due to their biological ac-
tivity.1 These include cyclopropylamine, cyclopropyl-
methanols, cyclopropyl-substituted ketones, and
especially the cyclopropane-derived amino acids, which
have attractive attention as photochemical agents, en-
zyme, inhibitors, or probes in metabolism studies.2
At the first attempt, we examined the reaction of 2-bromo-
2-cyclo-propylideneacetates 1 with phenylselenoamide
2a in THF in the presence of Et3N. After workup and iso-
lation, the desired product, 5-spirocyclopropane-annulat-
ed selenazoline-4-carboxylates 4a was obtained in 65%
The selenium heterocycles are of marked interest because
of their antitumor, antibacterical and other notable
activities.3 Among our efforts devoted to the chemistry of
selenium,4 we were interested in the synthesis of spirocy-
clopropane-annulated selenium heterocyclic compounds.
At present, this kind of selenium compounds was not
available in literatures. It is expected that this kind of het-
erocycles can be used as biologically active compounds.
1
yield. The structure was assigned on the basis of its H
NMR, 13C NMR, IR spectra, MS data and microanalyses.
The possible mechanism may involve a Michael addition
followed by an intramolecular nucleophilic substitution
(Scheme 2). Further screening demonstrated anhydrous
MeCN and NaHCO3 were more suitable conditions for the
mentioned reaction and the yield of 4a could be improved
up to 85%. Under the same condition, a series of seleno-
amides were chosen as substrates and 5-spirocyclo-
propane-annulated selenazoline-4-carboxylates were
obtained in good yields (Table 1). However, owing to the
instability and the difficulty of purification of alkylseleno-
carboxamide,13 we succeeded in our experiment using 2i,
which was added directly to the reaction system without
purification, and obtained 4i in 70% yield.
Methylenecyclopropanes (MCPs), which are highly
strained but readily accessible molecules, have served as
useful building blocks in organic synthesis.5 They can un-
dergo a variety of reactions because the relief of ring
strain provides a potent thermodynamic driving force for
this process. Over the last decades, increasing attention
has been paid to the synthesis transformation of MCPs,
which have been employed for the construction of com-
plex organic molecules.6 Also many unnatural molecules
containing cyclopropane, which exhibit some interesting
characters, had been synthesized by MCPs through ring-
untouched reactions.7
Se
Br
NaHCO3, MeCN
80 °C, 1–2 h
+
CO2Et
R
NH2
2
Recently, Chang has reported a base-induced coupling/
cyclization reaction of a-sulfonylacetamide with ethyl
(Z)-2-bromo-2-propenoates (Scheme 1).8
1
NH
R
Se
R
In the above reaction, a-sulfonylacetamide was used as an
Se
efficient dinucleophile. Selenoamide9 is also a good dinu-
N
Br
EtO2C
CO2Et
SYNLETT 2004, No. 2, pp 0329–0331
0
2.
0
2.
2
0
0
4
4
3
Advanced online publication: 04.12.2003
DOI: 10.1055/s-2003-44969; Art ID: U18603ST
© Georg Thieme Verlag Stuttgart · New York
Scheme 2

330
X. Huang et al.
LETTER
Table 1 One Pot Synthesis of selenazoline-4-carboxylates10
References
(1) (a) Liu, H. W.; Walsh, C. T. In The Chemistry of the
Cyclopropyl Group, Vol. 2; Rappoport, Z., Ed.; Wiley &
Sons: New York, 1987, 959. (b) Burger, A. Progr. Drug
Res. 1971, 15, 227. (c) Baldwin, J. E.; Parker, D. W. J. Org.
Chem. 1987, 52, 1475. (d) Baldwin, J. E.; Parker, D. W.
Chem. Rev. 2003, issue 4.
(2) (a) Gnad, F.; Reiser, O. Chem. Rev. 2003, 103, 1603.
(b) Wessjohann, L.; Krass, N.; Yu, D.; de Meijere, A. Chem.
Ber. 1992, 125, 867; and references therein.
(3) (a) Shafiee, A.; Mazloumi, A.; Cohen, V. I. J. Heterocycl.
Chem. 1979, 16, 1563. (b) Shafiee, A.; Shafaati, A.;
Khamench, B. H. J. Heterocycl. Chem. 1989, 26, 709.
(c) Shafieem, A.; Khashayarmanesh, Z.; Kamal, F. J. Sci.
Islamic Rep. Iran 1990, 1, 111; Chem. Abstr. 1991, 115:
49544.
(4) (a) Huang, X.; Xie, M. H. Org. Lett. 2002, 4, 1331.
(b) Huang, X.; Xie, M. H. J. Org. Chem. 2002, 67, 8895.
(c) Huang, X.; Sun, A. J. Org. Chem. 2000, 65, 6561.
(5) Synthesis of MCPs: (a) Brandi, A.; Cicchi, S.; Cordero, F.
M.; Goti, A. Chem. Rev. 2003, 103, 1213. (b) Brandi, A.;
Goti, A. Chem. Rev. 1998, 98, 598. (c) Yamago, S.;
Nakamura, E. Org. React. 2002, 61, 1. (d) Nakamura, E.;
Yamago, S. Acc. Chem. Res. 2002, 35, 867. (e)Yamago, S.;
Takeichi, A.; Nakamura, E. Synthesis 1996, 1380.
(6) Reviews: (a) Binger, P.; Buch, H. M. Top. Curr. Chem.
1987, 135, 77. (b) Ohta, T.; Takaya, H. In Comprehensive
Organic Synthesis, Vol. 5; Trost, B. M., Ed.; Pergamon:
Oxford, 1991, 1185.
Entry
R
Product
4a
Yield (%)a
1
2
3
4
5
6
7
8
9
Ph
85
83
75
82
79
88
84
81
70
p-ClC6H4
p-BrC6H4
m-BrC6H4
p-CH3C6H4
m-CH3C6H4
p-FC6H4
3,4-(OCH2O)C6H3
4b
4c
4d
4e
4f
4g
4h
b
PhCH2
4i
a Overall yields based on ethyl 2-bromo-2-cyclopropylideneacetate.
b Prepared from PhCH2CN (5 mmol) + NaSeH (10 mmol)
Recently, our group reported a CuX2-mediated cycliza-
tion reaction of cyclopropylideneacetic acids or esters and
a CuX2-mediated halogenation of alkylidenecyclopro-
panes.11 Considering the structure of 4a, which has a cy-
clopropyl group, we presumed that the cyclopropyl ring
could be opened and be halogenated under the same con-
ditions.11 As excepted, we obtained compound 5a in 82%
(Scheme 3).12 It has two different kind of bromine atoms
in one molecular unit, which could be further transformed.
Further applications are being investigated in our labora-
tory.
(7) (a) Salaün, J. Top. Curr. Chem. 1999, 207, 1. (b) Salaün, J.;
Baird, M. S. Curr. Med. Chem. 1995, 2, 511. (c) Huang, Z.;
He, Y. B.; Raynor, K.; Tallent, M.; Reisine, T.; Goodman,
M. J. Am. Chem. Soc. 1992, 114, 9390. (d) Zhu, Y. F.;
Yamazaki, T.; Tsang, J. W.; Lok, S.; Goodman, M. J. Org.
Chem. 1992, 57, 1074. (e) Notzel, M. W.; Tamm, M.;
Labahn, T.; Noltemeyer, M.; Es-Sayed, M.; de Meijere, A. J.
Org. Chem. 2000, 65, 3850. (f) Nötzel, M. W.; Labahn, T.;
Es-Sayed, M.; de Meijere, A. Eur. J. Org. Chem. 2001,
3025.
Br
Se
Se
Ph
CuBr2
Ph
(8) Sun, P. P.; Chang, M. Y.; Chiang, M. Y.; Chang, N. C. Org.
Lett. 2003, 5, 1761.
N
MeCN 80 °C
N
Br
(9) For recent examples of selenoamides, see: (a) Pan, B. C.;
Chen, Z. H.; Piras, G.; Dutschman, G. E.; Rowe, E. C.;
Cheng, Y. C.; Ch, S. H. J. Heterocycl. Chem. 1994, 177.
(b) Koketsu, M.; Senda, T.; Yoshimura, K.; Ishihara, H. J.
Chem. Soc., Perkin Trans. 1 1999, 453. (c) Attanasi, O. A.;
Filippone, P.; Perrulli, F. R.; Santeusanio, S. Eur. J. Org.
Chem. 2002, 2323. (d) Koketsu, M.; Takenaka, Y.;
Hiramatsu, S.; Ishihara, H. Heterocycles 2001, 55, 1181.
(e) Koketsu, M.; Hiramatsu, S.; Ishihara, H. Chem. Lett.
1999, 485. (f) Zhang, P. F.; Chen, Z. C. Synthesis 2000,
1219. (g) Koketsu, M.; Kanoh, M.; Itoh, E.; Ishihara, H. J.
Org. Chem. 2001, 66, 4099. (h) Koketsu, M.; Takenaka, Y.;
Ishihara, H. Synthesis 2001, 38, 503. (i) Zhang, P. F.; Chen,
Z. C. J. Heterocycl. Chem. 2001, 38, 503. (j) Ishihara, H.;
Koketsu, M.; Fukuta, Y.; Nada, F. J. Am. Chem. Soc. 2001,
123, 8408. (k) Bhattacharyya, P.; Woollins, J. D.
Tetrahedron Lett. 2001, 42, 5949. (l) Koketsu, M.;
Okayama, Y.; Aoki, H.; Ishihara, H. Heteroat. Chem. 2002,
13, 195. (m) Zhao, H.-R.; Zhao, X.-J.; Huang, X. Synth.
Commun. 2002, 32, 3383.
EtOOC
5a
EtOOC
4a
82%
Scheme 3
In summary, we have developed an efficient method for
the preparation of 5-spirocyclopropane-annulated selen-
azoline-4-carboxylate derivatives. It is expected that this
kind of selenazoline derives could be used as biologically
active compounds.3
Acknowledgment
The project 20272050 was supported by the National Nature
Science Foundation of China.
(10) Typical Procedure for the Synthesis of 4: A solution of the
respective ethyl-2-bromo-2-cyclopropylideneacetate2 (1)
(0.5 mmol), selenoamide13 2 (0.5mmol), and NaHCO3 (1.00
g, 11.9 mmol) in freshly distilled MeCN (10 mL) was heated
under reflux for 1–2 h. After filtration, the solvent was
Synlett 2004, No. 2, 329–331 © Thieme Stuttgart · New York

LETTER
evaporated in vacuo. The residue was subjected to
Efficient Access to Selenazoline-4-Carboxylate Derivatives
331
H). 13C NMR (CDCl3): d = 171.40, 168.25, 138.49, 135.14,
132.71, 129.32, 128.56, 126.54, 85.38, 61.43, 31.89, 21.22,
16.81, 14.29, 9.23. MS (EI): m/z = 323 (3.83) [M+(Se80)],
250 (100).; Anal. Calcd for C15H17NO2Se: C, 55.91; H, 5.32;
N, 4.35. Found: C, 56.08; H, 5.21; N, 4.42.
preparative TLC (eluent: petroleum ether–Et2O, 3:1) to
afford the product 4.
4a: IR (film): 3062, 2981, 1747, 1729, 1255, 1180 cm–1. 1H
NMR (CDCl3): d = 7.76–7.78 (m, 2 H), 7.46–7.48 (m, 1 H),
7.39–7.43 (m, 2 H), 4.83 (s, 1 H), 4.20–4.25 (q, J = 7.1 Hz,
4g: IR (film): 3063, 2982, 1732, 1253, 1182 cm–1. 1H NMR
(CDCl3): d = 7.75–7.79 (m, 2 H), 7.08–7.12 (m, 2 H), 4.81
(s, 1 H), 4.20–4.24 (q, J = 7.1 Hz, 2 H), 1.28–1.32 (t, J = 7.1
Hz, 3 H), 1.14–1.18 (m, 4 H). 13C NMR (CDCl3): d = 171.27,
168.36, 164.73 (d, J = 250.9 Hz), 131.96 (d, J = 3.1 Hz),
131.03 (d, J = 8.7 Hz), 115.66 (d, J = 22 Hz), 85.96, 61.37,
32.58, 16.57, 14.27, 9.32; MS (EI): m/z = 327 (2.60)
[M+(Se80)], 254 (100). Anal. Calcd for C14H14FNO2Se: C,
51.54; H, 4.33; N, 4.29. Found: C, 51.69; H, 4.40; N, 4.13.
4h: IR (film): 3064, 2981, 1747, 1727, 1254, 1037 cm–1. 1H
NMR (CDCl3): d = 7.35 (s, 1 H), 7.21–7.24 (m, 1 H), 6.80–
6.82 (d, J = 8.0 Hz, 1 H), 6.02 (s, 2 H), 4.78 (s, 1 H), 4.18–
4.25 (q, J = 7.1 Hz, 2 H), 1.27–1.31 (t, J = 7.1 Hz, 3 H), 1.13–
1.16 (m, 4 H). 13C NMR (CDCl3): d = 170.02, 168.56,
150.50, 147.98, 130.08, 125.00, 108.17, 108.04, 101.73,
85.81, 61.30, 32.22, 16.60, 14.29, 9.27. MS (EI): m/z = 353
(1.03) [M+(Se80)], 84 (100), 280 (17.15). Anal. Calcd for
C15H15NO4Se: C, 51.15; H, 4.29; N, 3.98 Found: C, 51.00;
H, 4.38; N, 4.08.
2 H), 1.27–1.31 (t, J = 7.1 Hz, 3 H), 1.13–1.17 (m, 4 H). 13
C
NMR (CDCl3): d = 171.27, 168.44, 135.60, 131.60, 128.96,
128.60, 86.01, 61.34, 32.13, 16.63, 14.30, 9.36. MS (EI):
m/z: 309 (4.64) [M+(Se80)], 236 (100). Anal. Calcd for
C14H15NO2Se: C, 54.55, H, 4.91, N, 4.54. Found: C, 54.70;
H, 4.98; N, 4.50.
4b: IR (film): 3067, 2981, 1747, 1730, 1181, 1092 cm–1. 1H
NMR (CDCl3): d = 7.69–7.72 (d, J = 8.8 Hz, 2 H), 7.38–7.40
(d, J = 8.8 Hz, 2 H), 4.82 (s, 1 H), 4.21–4.26 (q, J = 7.1 Hz,
2 H), 1.31–1.28 (t, J = 7.1 Hz, 3 H), 1.14–1.18 (m, 4 H). 13
C
NMR (CDCl3): d = 169.93, 168.27, 137.68, 134.08, 130.16,
128.83, 85.97, 61.41, 32.57, 16.57, 14.29, 9.36. MS (EI):
m/z = 343 (5.43) [M+(Se80,Cl35)], 270 (100). Anal. Calcd for
C14H14ClNO2Se: C, 49.07; H, 4.12; N, 4.09. Found: C,
48.81; H, 4.20; N, 4.20.
4c: IR (film): 3065, 2980, 1745, 1729, 1179, 1096 cm–1. 1H
NMR (CDCl3): d = 7.63–7.65 (d, J = 8.4 Hz, 2 H), 7.54–7.56
(d, J = 8.4 Hz, 2 H), 4.81 (s, 1 H), 4.20–4.26 (q, J = 7.1 Hz,
2 H), 1.28–1.31 (t, J = 7.1 Hz, 3 H), 1.14–1.17 (m, 4 H). 13
C
4i: IR (film): 3065, 2980, 1746, 1728, 1252, 1105 cm–1. 1H
NMR (CDCl3): d = 7.29–7.40 (m, 5 H), 4.81 (s, 1 H), 4.30
(s, 2 H), 4.20–4.25 (q, J = 7.1 Hz, 2 H), 1.27–1.31 (t, J = 7.1
Hz, 3 H), 1.14–1.18 (m, 4 H). 13C NMR (CDCl3): d = 171.11,
168.40, 135.35, 129.10, 128.45, 127.78, 85.98, 61.29, 43.10,
32.04, 16.53, 14.29, 9.35. MS (EI): m/z = 323 (3.60)
[M+(Se80)]. Anal. Calcd for C15H17NO2Se: C, 55.91; H, 5.32;
N, 4.35; Found: C, 55.80; H, 5.40; N, 4.20.
NMR (CDCl3): d = 170.05, 168.23, 134.54, 131.80, 130.33,
126.16, 86.02, 61.41, 32.57, 16.57, 14.27, 9.37. MS (EI):
m/z = 387 (4.23) [M+(Se80,Br79)], 97 (100), 314 (23.72).
Anal. Calcd for C14H14BrNO2Se: C, 43.43; H, 3.65; N, 3.62.
Found: C, 43.55; H, 3.72; N, 3.60.
4d: IR (film): 3065, 2891, 1746,1730, 1245, 1281 cm–1. 1H
NMR (CDCl3): d = 7.96–7.97 (t, J = 1.7 Hz, 1 H), 7.59–7.66
(m, 2 H), 7.27–7.31 (t, J = 7.8 Hz, 1 H), 4.83 (s, 1 H), 4.19–
4.25 (q, J = 7.1 Hz, 2 H), 1.28–1.32 (t, J = 7.1 Hz, 3 H) 1.14–
1.18 (m, 4 H). 13C NMR (CDCl3): d = 169.73, 168.17,
137.45, 134.44, 131.39, 130.07, 127.81, 122.75, 85.96,
61.45, 32.57, 16.55, 14.28, 9.39. MS (EI): m/z = 387 (4.23)
[M+(Se80,Br79)], 314 (100). Anal. Calcd for C14H14BrNO2Se:
C, 43.43; H, 3.65; N, 3.62. Found: C, 43.23; H, 3.73; N, 3.60.
4e: IR (film): 3063, 2980, 1747, 1728, 1255, 1179 cm–1. 1H
NMR (CDCl3): d = 7.65–7.67 (d, J = 8.1 Hz, 2 H), 7.20–7.22
(d, J = 8.1 Hz, 2 H), 4.81 (s, 1 H), 4.17–4.23 (q, J = 7.1 Hz,
2 H), 2.39 (s, 3 H), 1.27–1.31 (t, J = 7.1 Hz, 3 H), 1.13–1.17
(m, 4 H). 13C NMR (CDCl3): d = 171.05, 168.57, 142.07,
133.03, 129.26, 128.94, 86.00, 61.28, 32.00, 21.52, 16.62,
14.28, 9.34. MS (EI): m/z = 323 (3.28) [M+(Se80)], 250(100).
Anal. Calcd for C15H17NO2Se: C, 55.91; H, 5.32; N, 4.35.
Found: C, 55.79; H, 5.40; N, 4.41.
(11) (a) Huang, X.; Zhou, H. W. Org. Lett. 2002, 4, 4419.
(b) Zhou, H. W.; Huang, X.; Chen, W. L. Synlett 2003, 2080.
(12) Typical procedure: A solution of 4a (171 mg, 0.5 mmol)
with CuBr2 (450 mg, 2 mmol) in MeCN (10 mL) was stirred
under reflux and was monitored by TLC. After the reaction
was completed, the mixture was diluted with 20 mL of sat.
NH4Cl and then extracted with Et2O (3 ×). The Et2O phases
were combined and dried over MgSO4. After evaporation,
the residue was subjected to preparative TLC (eluent:
petroleum ether–Et2O, 3:1) to afford 5a 192mg (82%).
IR(film): 3061, 2980, 1735 cm–1. 1H NMR (CDCl3): d =
7.99–8.01 (m, 2 H), 7.52–7.56 (m, 1 H), 7.42–7.48 (m, 2 H),
5.00 (s, 1 H), 4.25–4.34 (m, 2 H), 3.70–3.90 (m, 4 H), 1.33–
1.37 (t, J = 7.1 Hz, 3 H). 13C NMR (CDCl3): d = 169.22,
165.13, 132.78, 129.19, 128.88, 126.62, 86.62, 74.59, 62.55,
36.50, 32.39, 14.47. MS (EI): m/z = 467 (0.58)
[M+(Se80,Br79,Br79)]. Anal. Calcd for C14H15Br2NO2Se: C,
35.93; H, 3.23; N, 2.99. Found: C, 36.90; H, 3.41; N, 3.10.
(13) (a) Lai, L. L.; Reid, D. H. Synthesis 1993, 870. (b) Zhao, H.
R.; Ruan, M. D.; Fan, W. Q.; Zhou, X. J. Synth. Commun.
1994, 24, 1761.
4f: IR (film): 3065, 2981, 1746,1729, 1265, 1181 cm–1. 1H
NMR (CDCl3): d = 7.64 (s, 1 H), 7.55–7.56 (m, 1 H), 7.29–
7.30 (m, 2 H), 4.83 (s, 1 H), 4.22–4.25 (q, J = 7.1 Hz, 2 H),
2.39 (s, 3 H), 1.28–1.31 (t, J = 7.1 Hz, 3 H), 1.14–1.17 (m, 4
Synlett 2004, No. 2, 329–331 © Thieme Stuttgart · New York