Facile Ring Expansions of α-Halomethyl β-Keto Esters Mediated with SmI2

Article abstract of DOI:10.1055/s-2001-16064

Treatment of α-halomethyl β-keto esters with SmI2 afforded their corresponding one-carbon expanded products with the aids of HMPA or NiI2.

Full text of DOI:10.1055/s-2001-16064

1266
LETTER
Facile Ring Expansions of -Halomethyl -Keto Esters Mediated with SmI2
So Hee Chung, Min Seok Cho, Jun Young Choi, Doo Won Kwon, Yong Hae Kim*
Center for Molecular Design and Synthesis, Department of Chemistry, Korea Advanced Institute of Science and Technology, 373-1,
Kusong Dong, Yusong Gu, Taejon, 305-701, Korea
Fax +82-42-869-5818; E-mail: kimyh@mail.kaist.ac.kr
Received 7 May 2001
in DMF.15 A typical experimental procedure is as follows.
Abstract: Treatment of -halomethyl -keto esters with SmI2 af-
A THF solution of 2 (0.23 mmol) was diluted in THF (4.5
forded their corresponding one-carbon expanded products with the
mL) and then slowly added to a SmI2 solution (0.5 mmol
in 5 mL THF) in the presence of NiI2 (0.015 mmol) or
HMPA (1.38 mmol) at 78 °C. The reaction mixture was
stirred at 78 °C for ca. 10 min and then quenched with a
saturated NH4Cl solution (5 mL). The product was ex-
tracted with ether, dried over MgSO4, and then concen-
aids of HMPA or NiI2.
Key words: SmI2, ring expansion, bicyclic compounds, -keto es-
ters, NiI2
Ring expansion reactions give useful carbocyclic or het-
trated to give a crude product 3 which was purified by
erocyclic intermediates in organic chemistry. Epoxide1
silica gel chromatography (silica gel: 230 400 mesh,
and aziridines2 were expanded to 5- or 6- membered het-
erocyclic compounds through cycloaddition or coupling
reactions. Nitrogen or oxygen atom insertions in carbonyl
derivatives are also well known to give the corresponding
ethyl acetate : n-hexane = 1: 5).16
O
O
lactones3 or lactams.4 The ring expansions of many car-
bocyclic substrates have been also examined to result in
one to three carbon-expanded products.5 Especially, the
carbon expanding reactions have been focussed to gener-
ate medium and large rings. For the synthetic utility, me-
dium and larger rings have become important to explore
and develop new avenues of approach to appropriately
functionalized rings.6 The general methods of medium
and larger ring expansions have been studied by various
groups. Most of them proceed via anionic procedure.7 Re-
cently, Dowd and his coworkers reported the radical pro-
cedure for the ring expansion using tin reagent.8 Later, the
mechanistic study of this free-radical reaction has been es-
tablished.9 Ring expansion reaction of cyclobutanone was
reported via addition of diiodomethane.10
1) NaH, DMF
SmI2, HMPA or NiI2
THF, –78 °C
CO2Et
CO2Et
I
2) CH2I2, reflux
n
n
n = 1, 2, 3
2
O
1
CO2Et
n
3
Scheme 1
The additives of HMPA,17 DMPU,18 Fe(DBM)3,19 and
NiI2 are known as the activators in SmI2 reactions.
HMPA is well used, but not promising because it is highly
toxic. Thus, these four activators are compared in this ring
expansion reaction. The results are shown in Table 1.
20
Samarium diiodide which is a strong one-electron donor
have resulted in versatile synthetic utility in organic syn-
thesis.11, 12 Formation of a ketyl radical13 of a ketone with
SmI2 and a radical or an anion of an alkyl halide with
SmI211 has been well known. In our earlier work,14 we re-
ported that functionalized cyclopropyl ketones underwent
reductive ring opening with SmI2 in the presence of pro-
ton source. On the supposition that formation of a cyclo-
propane intermediate by radical-radical coupling or
through anion and then provides some interesting prod-
ucts by cleavage of cyclopropane, -iodomethyl -keto
ester derivatives have been examined to react with SmI2.
Treatment of -iodomethyl -keto esters with SmI2 in the
presence of catalytic amount of NiI2 in THF afforded one
carbon-ring expanded products in good yields under mild
reaction conditions at 78 °C in short reaction time.
Table 1 SmI2 Mediated Ring Expansion Reaction with Additives
O
O
O
SmI2
OEt
Br
Additive, THF
OEt
O
(eq.) Temp (°C) Time(min) Yield (%)a
Run
SmI2 (eq.)
2.15
Additives
HMPA
1
2
–78
–20
10
85
85
76
99
6.0
6.0
DMPU
2.15
30
180
10
Fe(DBM)3
NiI2
3
4
2.15
–20
–78
0.1
0.1
2.15
The -iodomethyl -keto ester derivatives 2 were readily
synthesized by alkylation of commercially available
-keto esters with diiodomethane in the presence of NaH
a) Yields were determined by 1H NMR.
Synlett 2001, No. 8, 1266–1268 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Facile Ring Expansions of -Halomethyl -Keto Esters Mediated with SmI2
1267
A catalytic amount of Fe(DBM)3 works well, but the reac-
tion time is long (180 min) and the yield is low (76%).
Some data obtained from the reactions using catalytic
amount of NiI2 were added. The results obtained are sum-
marized in Table 2.
O
O
Br
SmI2
2 SmI2, HMPA
THF, –78 °C
CO2Et
CO2Et
4
5
OSmI2
OH
H+
Table 2 Ring Expansions of -Iodomethyl -Keto Esters with
a
SmI2
CO2Et
CO2Et
O
O
7
O
6
SmI2
OEt
X
THF, –78 °C
OEt
Scheme 2
n
n
O
Yield (%)a
Run
1
Substrates
Additive
Time (min)
Recently, a mechanism on the ring-expansion of -bro-
momethyl benzocyclic -keto ester with SmI2 has been
proposed.21 Although the reaction mechanism is not clear,
there are two possible pathways. The first is a radical
pathway similar to the tin induced radical ring expansion.8
Two equivalent of SmI2 may generate the ketyl radical
and the alkyl radical. The cyclopropane intermediate A is
generated by coupling of two radicals each other. The in-
termediate A may rearrange to the product via cleavage of
bicyclic C-C bond due to a cyclopropane C-C bond acti-
vation by CO2Et group.14 The other is an anionic pathway.
The alkyl radical reduced to an anion of samarium Grig-
nard type, which attack the cyclopropane intermediate
like the case of Scheme 3. The present reaction may be
widely available for constructing medium- and large-
sized ring compounds and has an advantage that NiI2
(0.05 equiv) is the better activator than HMPA in this re-
action.
O
O
none
10
10
27
80
OEt
2
HMPAb
I
O
O
99c
87
3
4
NiI2 (10 mol%)
NiI2 (5 mol%)
10
10
OEt
Br
O
O
O
O
5
6
OEt
HMPA
10
15
71
I
82d
NiI2 (5 mol%)
OEt
I
O
O
7
8
HMPA
10
10
94
92
OEt
I
NiI2 (5 mol%)
OSmI2
O
O
O
CO2Et
I
2SmI2
PhCH2
OEt
I
HMPA
HMPA
87
71
10
O
CO2Et
9
SmI2
O
O
CO2Et
H+
O
O
SmI2
O
OEt
I
120
10
CO2Et
CO2Et
CO2Et
a) Isolated yields. b) The amount of HMPA is 6 eq. c) 1H NMR yield.
d) The ratio of the seven membered ring and the reduced alcohol is ca.
90: 10 by 1H NMR.
A
Scheme 3
Without using an additive, the yield was low (run 1, 27%).
In the most of reactions, the reduced side product of alco-
hol could not be obtained. But the ratio of the ring-ex-
panded seven membered ring and the reduced alcohol was
Acknowledgement
This work was generously supported by the Korea Research Foun-
dation.
1
determined by H NMR (ca. 90:10 in run 7). An acyclic
-halomethyl- -ketoester did not give a chain extension
product; only reduction occurred to give an alcohol.
Reference and Notes
(1) (a) Kihara, N.; Nakawaki, Y.; Endo, T. J. Org. Chem. 1995,
60, 473. (b) Itoh, A.; Hirose, Y.; Kashiwagi, H.; Masaki, Y.
Heterocycles 1994, 38, 2165. (c) Karikomi, M.; Yamazaki, T.;
Toda, T. Chem. Lett. 1993, 1965. (d) Piotti, M. E.; Alper, H.
J. Org. Chem. 1997, 62, 8484.
It is noteworthy that under the same reaction conditions,
ethyl( -iodopropyl) pentyl -keto ester 4 reacted with
SmI2 to afford a bicyclic compound 7 as shown in Scheme
2.
Synlett 2001, No. 8, 1266–1268 ISSN 0936-5214 © Thieme Stuttgart · New York

1268
S. H. Chung et al.
LETTER
(c) Molander, G. A.; Harris, C. R. Tetrahedron 1998, 54,
(2) (a) Wolf, M. S.; Patta, D.; Auke, J. J. Org. Chem. 1997, 62,
654. (b) Colham, J.; Collis, A. J.; Moald, R. L. Tetrahedron
Lett. 1995, 36, 3557. (c) Nada, U. K.; Busu, N. Tetrahedron
1993, 49, 7787.
(3) (a) Chida, N.; Tobe, T.; Ogawa, S. Tetrahedron Lett. 1994, 35,
7249. (b) Genicot, C.; Ghosez, L. Tetrahedron Lett. 1992, 33,
7357.
(4) (a) Laurent, A.; Jaquqnt, P.; Di Martino, J. L.; Hamelin, Chem.
Commun. 1995, 1105. (b) Gracia, G. L.; Milligan, J. A. J. Am.
Chem. Soc. 1995, 118, 8047.
(5) (a) Tsukayama, M.; Utsumi, H.; Kunugi, A. Chem. Commun.
1995, 615. (b) Rude, B. M.; Kulkarni, V. R. J. Org. Chem.
1995, 60, 3084. (c) Kulinkovich, G.; Sorokin, V. L. Russ. J.
Org. Chem. 1994, 30, 196. (d) Zhang, W.; Hua, Y.; Geib, S.
J.; Dowd, P. Tetrahedron 1994, 50, 12579. (e) Feldmann, K.
S.; Berven, H. M.; Weinreb, P. H. J. Am. Chem. Soc. 1993,
115, 11364. (f) Lee, P. H.; Kim, J. S.; Shim, Y. C. Tetrahedron
Lett. 1993, 34, 7583. (g) Booker, K. I.; Thompson, D. F.
Tetrahedron Lett. 1993, 34, 7291. (h) Mitani, M.; Kobayashi,
Y. Bull. Chem. Soc. Jpn. 1994, 67, 284. (i) Herndon, J. W.;
Zora, M. Synlett 1993, 363.
(6) Dowd, P.; Zhang, W. Chem. Rev. 1993, 93, 2091.
(7) Trost, B. M.; Fleming, I. Eds. Comprehensive of Organic
Chemistry, Oxford 1991, Vol 1, 33.
(8) Dowd, P.; Choi, S. C. J. Am. Chem. Soc. 1987, 109, 3493.
(9) Chatgilialogh, C.; Timikhin, V. T.; Ballestri, M. J. Org. Chem.
1998, 63, 1327.
3321.
(13) (a) Curran, D. P.; Fevig, T. L.; Jasperse, C. P.; Totleben, M. J.
Synlett 1992, 943. (b) Kagan, H. B.; Namy, J. L. Tetrahedron
1986, 42, 6573.
(14) Kim, Y. H.; Lee. I. S. Heteroatom Chemistry 1992, 3, 509.
(15) For the synthesis of starting material 2, see; Beckwith, A. L.
J.; O’Shea, D. M.; Westwood, S. W. J. Am. Chem. Soc. 1988,
110, 2565.
(16) Ethyl 3-oxocyclohexanone carboxylate, 3: 1H NMR
(400MHz, CDCl3, TMS) 1.21-1.25 (t, 3H), 1.71-1.82 (m,
2H), 2.01- 2.07 (m, 2H), 2.29-2.35 (m, 2H), 2.51-2.53 (m,
2H), 2.75-2.82 (m, 1H), 4.10-4.16 (q, 2H); 13C NMR
(100MHz, CDCl3, TMS) 14.1, 24.4, 27.7, 40.9, 43.1, 43.2,
60.9, 173.7, 209.3. Ethyl 3-oxocycloheptanone carboxylate, 3:
1H NMR (400MHz, CDCl3, TMS) 1.21-1.25 (t, 3H), 1.55-
2.10 (m, 6H), 2.45-2.49 (m, 2H), 2.64-2.69 (m, 2H), 2.74-2.82
(m, 1H), 4.09-4.15 (q, 2H); 13C NMR (100MHz, CDCl3,
TMS) 14.1, 23.9, 28.3, 33.2, 41.3, 43.9, 45.5, 60.9, 174.5,
212.2.
(17) Inanaga, J.; Ishikawa, M.; Yamaguchi, M. Chem. Lett. 1987,
1485.
(18) Hasegawa, E.; Curran, D. P. J. Org. Chem. 1993, 58, 5008.
(19) Molander, G. A.; McKie, J. A. J. Org. Chem. 1991, 56, 4112.
(20) (a) Machrouhi, F.; Hamann, B.; Namy, J. L.; Kagan, H. B.
Synlett 1996, 633. (b) Krief, A.; Laval, A.-M.; Chem. Rev.
1999, 99, 745.
(10) Fukuzawa, S.; Tsuchimoto, T. Tetrahedron Lett. 1995, 36,
5937.
(21) Hasegawa, E.; Kitazume, T.; Suzuki, K.; Tosaka, E.
Tetrahedron Lett. 1998, 39, 4059.
(11) (a) Girard, P.; Namy, J. L.; Kagan. H. B. J. Am. Chem. Soc.
1980, 102, 2693. (b) Kagan, H. B.; Namy, J. L. Tetrahedron
Lett. 1986, 27, 3243.
Article Identifier:
(12) (a) Molander, G. A. Chem. Rev. 1992, 92, 307. (b) Trost, B.
M. Comprehensive of Organic Synthesis 1991, vol 1, 253.
1437-2096,E;2001,0,08,1266,1268,ftx,en;Y09601ST.pdf
Synlett 2001, No. 8, 1266–1268 ISSN 0936-5214 © Thieme Stuttgart · New York