New synthesis of substituted cyclopentanes via reactions of γ-chlorocarbanions with electron-deficient alkenes

Article abstract of DOI:10.1055/s-2004-815441

Carbanions of 3-chloropropyl pentachlorophenylsulfone, although they undergo fast cyclization to the corresponding cyclopropyl sulfone, can be trapped with electrondeficient alkenes to produce carbanionic adducts that enter intramolecular substitution to

Full text of DOI:10.1055/s-2004-815441

LETTER
717
New Synthesis of Substituted Cyclopentanes via Reactions of g-Chloro-
carbanions with Electron-deficient Alkenes
New
S
ynthesis of Subs
i
tituted
e
Cyclopenta
c
nes zysław Mąkosza,* Marek Judka
Institute of Organic Chemistry, Polish Academy of Sciences, ul. Kasprzaka 44, 01-224 Warszawa 42, POB 58, Poland
Fax +48(22)6326681; E-mail: icho-s@icho.edu.pl
Received 21 November 2003
sulfone and t-butyl acrylate, with t-BuOK or LDA result-
ed in polymerization of the acrylate and the only isolable
product was phenylsulfonyl cyclopropane. The failure of
the Michael addition to t-butyl acrylate when the carban-
ion is generated in the presence of the acceptor could be
due to the moderate rate of deprotonation of the carbanion
precursor, the base induced polymerization of the accep-
tor thus becoming the dominating process.
Abstract: Carbanions of 3-chloropropyl pentachlorophenylsul-
fone, although they undergo fast cyclization to the corresponding
cyclopropyl sulfone, can be trapped with electrondeficient alkenes
to produce carbanionic adducts that enter intramolecular substitu-
tion to form substituted cyclopentanes.
Key words: carbanions, cyclization, cyclopentane, Michael accep-
tors, sulfone
Deprotonation of the more acidic 3-chloropropylaryl sul-
fone should proceed faster whereas its corresponding car-
banion should cyclize more slowly, thus its addition to an
electrondeficient alkene should be feasible. Indeed the
carbanion of 3-chloropropyl pentachlorophenyl sulfone
(1, readily prepared from pentachlorothiophenol via its re-
action with 1,3-bromochloropropane followed by oxida-
tion) cyclizes much slower than that of 3-chloropropyl
phenyl sulfone. Treatment of 1 in THF with t-BuOK at
–70 °C, followed by quench with aqueous NH4Cl after 10
seconds resulted in only partial cyclization and a sub-
stantial part of 1 was recovered. Only after 25 seconds at
–70 °C the cyclization was completed. The lifetime of the
g-chlorocarbanion is affected by the kind of counterion.
The lithium salt, generated by treatment of 1 with LDA,
cyclized substantially slower (Scheme 1). On the other
hand, under these conditions cyclization of 3-chloro-
propyl phenyl sulfone carbanion, even as a lithium salt, is
complete within 1–2 seconds.
g-Halocarbanions are considered to be short lived inter-
mediates undergoing rapid intramolecular substitution to
cyclopropanes.1 Numerous reported examples of reac-
tions of g-halocarbanions generated via deprotonation of
appropriate precursors or by addition of a-halocarbanions
to Michael acceptors2,3 invariably resulted in formation of
three-membered rings: cyclopropane derivatives or the
Favorski4 and Ramberg–Bäcklund reactions.5
Recently, we have shown that g-chlorocarbanions gener-
ated from g-chlorobutyronitrile, t-butyl g-chlorobutyrate
and 3-chloropropyl phenyl sulfone, albeit they undergo
very fast intramolecular replacement of the halogen to
form substituted cyclopropanes can be efficiently trapped
by active electrophilic partners, e.g. aldehydes. The
produced aldol type anions undergo rapid cyclization via
intramolecular replacement of the halogen to give substi-
tuted tetrahydrofurans.6
In this communication we present a new simple method
for the construction of substituted cyclopentane ring via
reaction of g-chlorocarbanions with electrondeficient al-
kenes – Michael acceptors. The cyclopentane ring is
present in many natural products, pharmaceuticals etc.,
thus synthetic methods for substituted cyclopentanes are
of great interest.7 There are a few major strategies to
achieve this goal: functionalization of an existing cyclo-
pentene or a cyclopentadiene ring,8 cyclization of an
appropriate precursors,9 or ring contraction.10
In analogy to the synthesis of tetrahydrofurans via addi-
tion of g-chlorocarbanions to aldehydes6 followed by in-
tramolecular substitution, we have expected that addition
of the g-chlorocarbanions to electrondeficient alkenes
should produce intermediate w-chlorocarbanions, under-
going rapid intramolecular substitution to cyclopentane
derivatives. However, treatment of 3-chloropropyl phenyl
Scheme 1 Estimation of cyclization rate of carbanion of 1
As we had expected, the carbanion of 1 can be trapped by
moderately active Michael acceptors and the produced
carbanionic adducts undergo intramolecular substitution
giving substituted cyclopentanes. Thus, when a THF solu-
tion of 1 was treated with t-BuOK at –70 °C and t-butyl
acrylate (three equiv) was added immediately, two
SYNLETT 2004, No. 4, pp 0717–0719
0
9.
0
3.
2
0
0
4
Advanced online publication: 29.01.2004
DOI: 10.1055/s-2004-815441; Art ID: G32603ST
© Georg Thieme Verlag Stuttgart · New York

718
M. Mąkosza, M. Judka
products were obtained: cyclopropyl arylsulfone (2, 41%) This new and simple synthetic method of substituted cy-
and t-butyl 3-arylsulfonylcyclopentane-carboxylate (3, clopentanes appears to have general character. The pres-
24%), as a mixture of two geometric isomers. Much better ence of a variety of functional groups in the cyclopentane
results were obtained when a solution of 1 and the Micha- ring offers a wide-range of possibilities for further trans-
el acceptor (molar ratio 1:3) was treated with LDA, then formations. Scope of this reaction and its stereochemical
the yield of 3 was 64%. Alternative protocol – addition of course are under investigation.
the electrophile to the carbanion of 1 generated by treat-
ment of 1 with LDA 1–2 seconds earlier, gave usually
similar or better results. According to this protocol the re-
Acknowledgment
This work was supported by the State Committee for Scientific
Research, KBN Grant 4 T09A05625.
action of 1 with a series of Michael acceptors gave expect-
ed substituted cyclopentanes (Scheme 2, Table 1).11
The substituted cyclopentanes 3–10 can be formed as two
or more stereoisomers (see Table 1). On the basis of NMR
spectral analysis including NOE experiments, compounds
6 and 7, formed as single isomers, were shown to have a
cis-relation of the COOEt (and COPh) and Ph groups,
whereas the Ph and ArSO2 groups were in trans-relation.
Major isomers of 3, 4, 5, and 10 have the substituents in
cis-relation whereas 9 is formed as a single trans-isomer
and 8 as a mixture of trans- and cis- isomers close to 1:1.
So far, it is not completely clear whether the composition
of the stereoisomers is determined in the addition and sub-
stitution steps (kinetic control), or there is equilibration of
some stereogenic centers under the reaction conditions.
References
(1) (a) Gronert, S.; Azizian, K.; Friedman, M. A. J. Am. Chem.
Soc. 1998, 120, 3220. (b) Habusha, U.; Rozental, E.; Hoz, S.
J. Am. Chem. Soc. 2002, 124, 15006.
(2) (a) McCoy, L. J. Am. Chem. Soc. 1960, 82, 6416.
(b) Wendish, D. In Houben–Weyl, Methoden der
organischen Chemie, Vol. IV 3; , Thieme: Stuttgart, 1971,
89. (c) Fleming, F. F.; Shook, B. C. Tetrahedron 2002, 58, 1.
(3) Zwanenburg, B.; De Kimpe, N. In Houben–Weyl, Methoden
der organischen Chemie, Vol. E17a; Thieme: Stuttgart,
1997, 45.
(4) Mann, J. Comprehensive Organic Synthesis, Vol. 3; Trost,
B., Ed.; Pergamon: Oxford, 1991, 839.
Scheme 2 Formation of substituted cyclopentanes
Table 1 Substituted Cyclopentanes Obtained as in Scheme 2a
R
Z
Y
Product
Yield [%]
cis–trans Ratio Yield of 2b
1
2
3
4
5
6
7
8
H
H
COOt-Bu
SO2Ph
COOMe
COOEt
COPh
CN
3
4
64
49
32
33
77
82
70
85
60:40c
11
36
15
52
5
H
H
65:35c
H
Me
H
5
65:35c
Ph
6
1 isomer
1 isomer
44:56 d
0:100c
Ph
H
7
Ph
CN
CN
CN
8
–
2-ClPh
2-Furyl
CN
9
–
CN
10
66:34c
–
a Notation as in Scheme 2.
b Yield of cyclopropane 2 formed as a side product.
c Separated, ratio of cis- and trans-isomers.
d Estimated on the basis of 1H NMR spectra.
Synlett 2004, No. 4, 717–719 © Thieme Stuttgart · New York

LETTER
New Synthesis of Substituted Cyclopentanes
719
(5) (a) Paquette, L. A. Org. React. 1971, 25, 1. (b) Clough, J.
M. Comprehensive Organic Synthesis, Vol. 3; Trost, B., Ed.;
Pergamon: Oxford, 1991, 861.
(6) (a) Mąkosza, M.; Przyborowski, J.; Klajn, R.; Kwast, A.
Synlett 2000, 1773. (b) Mąkosza, M.; Judka, M. Chem.–Eur.
J. 2002, 8, 4234.
CDCl3): d = 2.17–2.33 (m, 2 H), 2.89 [dt, 3J(H,H) = 6.60,
14.43 Hz, 1 H], 3.03–3.20 (m, 2 H), 4.26–4.41 (m, 1 H),
4.72–4.84 (m, 1 H), 5.47–5.54 (m, 1 H), 7.54–7.93 (m, 5 H).
13C NMR (100 MHz, CDCl3): d = 25.57, 27.74, 66.91,
68.88, 75.46, 128.42, 129.46, 129,82, 132.96, 133.98,
134.57, 135.18, 138.78.
(7) (a) Collins, S. P. W.; Djuric, W. Chem. Rev. 1993, 93, 1533.
(b) Mathew, J. Recent Progress in the Chemical Synthesis of
Antibiotics, Lucas G., Vol. II; Springer Verlag: Heidelberg,
1993, 435. (c) Mikolajczyk, M.; Mikina, M.; Jankowska, A.
J. Org. Chem. 2000, 65, 5127. (d) Ghosh, S.; Patra, D. Pure
Appl. Chem. 1996, 68, 597.
Comound 5: cis-isomer, mp 197 °C; 1H NMR (400 MHz,
CDCl3): d = 1.98 (s, 3 H), 2.17–2.38 (m, 2 H), 2.64 [dd,
3J(H,H) = 2.39, 15.96 Hz, 1 H], 2.94 [dd, 3J(H,H) = 9.36,
15.96 Hz, 1 H], 3.17–3.25 (m, 1 H), 3.73 (s, 3 H), 4.64 [dt,
3J(H,H) = 2.38, 8.62 Hz, 1 H]. 13C NMR (100 MHz, CDCl3):
d = 26.91, 29.61, 34.58, 53.11, 54.36, 64.93, 73.21 133.67,
133.75, 138.16, 175.53.
(8) Hanselaer, R.; Samson, M.; Vandewalle, M. Tetrahedron
1978, 34, 2393.
Compound 5: trans-isomer, mp 148 °C; 1H NMR (400 MHz,
CDCl3): d = 2.01 (s, 3 H), 2.15–2.22 (m, 2 H), 2.60 [dd,
3J(H,H) = 4.22, 15.77 Hz, 1 H], 2.92 [dd, 3J(H,H) = 7.7,
15.59 Hz, 1 H], 3.09–3.16 (m, 1 H), 3.73 (s, 3 H), 4.19–4.25
(m, 1 H), 4.64–4.69 (m, 1 H). 13C NMR (100 MHz, CDCl3):
d = 28.01, 29.54, 34.22, 53.03, 54.36, 64.72, 73.94, 133.65,
133.77, 138.16, 138.58, 175.65.
(9) (a) Hudlicky, T.; Price, J. D. Chem. Rev. 1989, 89, 1467.
(b) Thebtaranonth, C.; Thebtaranonth, Y. Tetrahedron 1990,
46, 1385. (c) Survey of cyclopentane ring formation, see:
Larock, R. L. Comprehensive Organic Transformations, 2nd
ed.; Wiley-VCH: New York, 1999, 168–174. (d) Du, Y.;
Lu, X.; Zhang, C. Angew. Chem. Int. Ed. 2003, 42, 1035.
(e) Huart, C.; Ghosez, L. Angew. Chem., Int. Ed. Engl. 1997,
36, 634.
Compound 6: mp 167 °C; 1H NMR (200 MHz, CDCl3):
d = 1.18 [t, 3J(H,H) = 7.16 Hz, 3 H], 2.00–2.14 (m, 1 H),
2.38–2.60 (m, 1 H), 3.60 [dd, 3J(H,H) = 6.00, 11.68 Hz, 1
H], 4.14 [dq, 3J(H,H) = 2.56, 7.14 Hz, 2 H], 4.25–4.57 (m, 2
H), 4.87–4.96 (m, 2 H), 7.20–7.37 (m, 5 H). 13C NMR (50
MHz, CDCl3): d = 13.89, 26.05, 44.83, 53.03, 61.62, 72.27,
128.19, 128.98, 130.38, 133.48, 134.47, 135.41, 137.77,
169.33.
(10) Silva, L. F. Jr. Tetrahedron 2002, 58, 9137.
(11) Typical Procedure. All reactions were performed in oven-
dried glassware under argon. THF was freshly distilled from
potassium-benzophenone. To a solution of 1 (117 mg, 0.3
mmol) in THF (5 mL) at –70 °C LDA (0.22 mL of 1.8 M
solution, 0.4 mmol) was added in one portion. After 1–2 sec
Michael acceptor dissolved in THF was added: 0.45 mmol in
0.5 mL of THF for the synthesis of 4, 7, 8, 9, 10; 0.6 mmol
for 6, and 3 mmol for 5. The mixture was stirred for 5 min,
warmed to r.t., quenched with aq NH4Cl, extracted and
purified by column and preparative TLC chromatography
(hexane/EtOAc as eluent).
Compound 7: mp 232 °C; 1H NMR (400 MHz, CDCl3):
d = 1.90–2.07 (m, 1 H), 2.44–2.55 (m, 1 H), 3.65–3.74 (m, 1
H), 4.41–4.47 (m, 2 H), 4.86 [t, 3J(H,H) = 7.89 Hz, 1 H],
5.46 [d, 3J(H,H) = 5.32 Hz, 1 H], 7.23–7.61 (m, 10 H). 13
C
NMR (100 MHz, CDCl3): d = 26.09, 45.26, 56.95, 71.99,
76.27, 127.55, 128.16, 128.27, 128.69, 132.58, 133.25,
133.78, 134.70, 136.20, 136.79, 196.14.
Compound 1: mp 124 °C; 1H NMR (200 MHz, CDCl3):
d = 2.31–2.46 (m, 2 H), 3.67–3.78 (m, 4 H). 13C NMR (50
MHz, CDCl3): d = 25.93, 43.12, 53.77, 134.51, 135.67,
135.97, 139.83.
Compound 9: trans-isomer, mp 234 °C; 1H NMR (400 MHz,
CDCl3): d = 2.67–2.88 (m, 3 H), 2.92–2.98 (m, 1 H) 4.72 [d,
3J(H,H) = 9.72 Hz, 1 H], 4.76–4.86 (m, 1 H), 7.23–7.28 (m,
3 H), 7.33–7.38 (m, 1 H). 13C NMR (50 MHz, CDCl3):
d = 23.62, 38.26, 42.20, 50.90, 64.25, 112.81, 113.18,
127.28, 128.11, 128.59, 130.03.61, 130.61, 132.91, 133.76,
135.06, 135.12, 139.48.
Compound 2: mp 169 °C; 1H NMR (400 MHz, CDCl3):
d = 1.12–1.16 (m, 2 H), 1.50–1.55 (m, 2 H), 3.20 [tt,
3J(H,H) = 4.77, 7.88 Hz, 1 H]. 13C NMR (100 MHz, CDCl3):
d = 6.06, 32.69, 133.20, 134.87, 137.45, 138.47.
Compound 3: cis-isomer, mp 125 °C; 1H NMR (400 MHz,
CDCl3): d = 1.42 (s, 9 H), 2.13–2.26 (m, 3 H), 2.90–3.08 (m,
2 H), 4.59 [dd, 3J(H,H) = 6.97, 7.43 Hz, 1 H], 4.75–4.80 (m,
1 H). 13C NMR (100 MHz, CDCl3): d = 26.53, 27.81, 28.28,
48.83, 66.23, 75.09, 82.76, 132.48, 133.21, 136.81, 168.86.
Compound 3: trans-isomer, mp 120 °C. 1H NMR (400 MHz,
CDCl3): d = 1.42 (s, 9 H), 2.20–2.31 (m, 1 H), 2.33–2.41 (m,
2 H), 2.76–2.83 (m, 1 H), 3.12–3.21 (m, 1 H), 4.27–4.34 (m,
1 H), 4.62 [t, 3J(H,H) = 6.87 Hz, 1 H], 4.73 [dt,
Compound 10: trans-isomer, mp 216 °C; 1H NMR (500
MHz, CDCl3): d = 1.92 [dddd, 3J(H,H) = 3.40, 6.80, 9.15
Hz, 2J(H,H) = 15.50 Hz, 1 H], 2.60 [dddd, 3J(H,H) = 4.95,
5.80, 8.80 Hz, 2J(H,H) = 15.50 Hz, 1 H], 3.61 [ddd,
3J(H,H) = 6.80, 4.95 Hz, 2J(H,H) = 11.50 Hz, 1 H], 3.82
[ddd, 3J(H,H) = 5.85, 9.10 Hz, 2J(H,H) = 11.50 Hz, 1 H],
4.26 [ddd, 3J(H,H) = 12.00, 8.80, 3.40 Hz, 1 H], 4.42 [d,
3J(H,H) = 12.00 Hz, 1 H], 6.57 [dd, 3J(H,H) = 1.90, 3.40 Hz,
1 H], 6.83 [d, 3J(H,H) = 3.35 Hz, 1 H], 7.65 [d,
3J(H,H) = 2.20, 8.72 Hz, 1 H]. 13C NMR (100 MHz, CDCl3):
d = 26.64, 27.82, 28.59, 49.27, 67.58, 74.68, 82.78, 132.77,
133.28, 136.65, 169.19. Anal. calcd (%) for C16H17Cl5O4S
(482.63): C, 39.82; H, 3.55; Cl, 36.73; S, 6.64. Found: C,
39.93; H, 3.63; Cl, 36.82; S, 6.60.
3J(H,H) = 1.55 Hz, 1 H]. 13C NMR (100 MHz, CDCl3):
d = 28.21, 40.87, 42.65, 45.02, 56.77, 110.04, 111.03,
111.56, 114.71, 123.84, 132.18, 133.96, 136.57, 139.98,
140.18, 143.53, 145.29.
Compound 10: cis-isomer, mp 158 °C; 1H NMR (400 MHz,
CDCl3): d = 2.60–2.89 (m, 4 H), 4.17 [d, 3J(H,H) = 10.08
Hz, 1 H], 4.87–4.95 (m, 1 H), 6.19 [dd, 3J(H,H) = 1.47, 3.30
Hz, 1 H], 6.29 [d, 3J(H,H) = 3.29 Hz, 1 H], 7.24 [d,
3J(H,H) = 1.28 Hz, 1 H]. 13C NMR (100 MHz, CDCl3):
d = 23.03, 37.23, 41.77, 50.53, 62.59, 110.68, 110.86,
112.73, 113.34, 133.55, 133.78, 135.04, 139.56, 144.15,
144.28.
Compound 4: cis-isomer, mp 156 °C; 1H NMR (200 MHz,
CDCl3): d = 2.21–2.33 (m, 2 H), 2.78–2.83 (m, 2 H), 3.31 [t,
3J(H,H) = 10.01 Hz, 1 H], 4.26–4.44 (m, 1 H), 4.72–4.82 (m,
1 H), 5.57–5.65 (m, 1 H), 7.56–7.94 (m, 5 H). 13C NMR (100
MHz, CDCl3): d = 25.02, 28.28, 65.95, 67.85, 75.30, 128.23,
129.35, 129.50,134.17, 134.52, 135.43, 135.84, 139.21.
Compound 4: trans-isomer, oil. 1H NMR (200 MHz,
Synlett 2004, No. 4, 717–719 © Thieme Stuttgart · New York