Intramolecular Carbolithiation of 3-Lithioxy-5-alkenyllithiums as a Platform for Cyclopentanols and Cyclopentanones

Article abstract of DOI:10.1055/s-0035-1560170

Intramolecular carbolithiation of 3-lithioxy-5-hexenyllithiums was studied. Unlike the case of 5-hexenyllithium, the cyclization of 3-lithioxy-5-hexenyllithium was very sluggish. Acceleration was observed when lithium chloride was added, suggesting that i

Full text of DOI:10.1055/s-0035-1560170

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Intramolecular Carbolithiation of 3-Lithioxy-5-alkenyllithiums as a
Platform for Cyclopentanols and Cyclopentanones
Ilhyong Ryu*a
OH
OLi
Go-hei Yamamurab
Satoshi Minakatab
Mitsuo Komatsub
Haruka Kuboa
LiO
Li
O
Br
5-exo
Swern
THF
Li
Mitsuhiro Uedaa
SiMe3
SiMe3
SiMe3
SiMe3
a Department of Chemistry, Graduate School of Science,
Osaka Prefecture University, Sakai, Osaka 599-8531,
Japan
ryu@c.s.osakafu-u.ac.jp
b Department of Applied Chemistry, Graduate School of
Engineering, Osaka University, Suita, Osaka 565-0871,
Japan
Received: 17.05.2015
Accepted after revision: 21.07.2015
Published online: 01.09.2015
Bailey's work
Li
DOI: 10.1055/s-0035-1560170; Art ID: st-2015-s0369-c
5-exo
El+
Abstract Intramolecular carbolithiation of 3-lithioxy-5-hexenyllithi-
ums was studied. Unlike the case of 5-hexenyllithium, the cyclization of
3-lithioxy-5-hexenyllithium was very sluggish. Acceleration was ob-
served when lithium chloride was added, suggesting that intramolecu-
lar lithioxy coordination would hinder the cyclization. Introduction of a
silyl or thiophenyl group at the olefin terminus caused smooth cycliza-
tion. The resulting dianions having a cyclopentane framework are sub-
jected to C–C bond-forming reaction with electrophiles to give 3-sub-
stituted cyclopentanols. Coupled with the Swern oxidation, the overall
protocol served as a platform for 3-substituted cyclopentanones.
(1)
Li
El
newly formed C–C bond
this work
OLi
O
OH
LiO
Li
El+
[ox.]
5-exo
(2)
Key words intramolecular carbolithiation, dianion, cyclopentanols,
cyclopentanones
Li
El
El
Five-membered carbocycles are frequently found in
both natural and unnatural compounds.1 Two decades ago,
Bailey and co-workers reported that 5-hexenyllithium un-
dergoes 5-exo cyclization leading to cyclopentylmethyllith-
ium on warming at 25 °C (Scheme 1, eq. 1).2 This finding
has triggered a number of useful studies of intramolecular
carbolithiation leading to five-membered rings,3 which in-
volve asymmetric carbolithiation based on (–)-sparteine.4
During the course of our study on ketone dilithio dianion
chemistry,5 it occurred to us that intramolecular carbolithi-
ation, when applied to the lithioxy-tethered 5-alkenyllithi-
ums, the synthetic usefulness would be further expanded,
since the resulting five-membered-ring products are ready
to be transformed into cyclopentanols and cyclopenta-
nones, a basically important class of building blocks in or-
ganic synthesis (Scheme 1, eq. 2). Herein we report the re-
activity of 3-lithioxy-5-alkenyllithums towards the intra-
molecular carbolithiation.
Scheme 1 Concept: Carbocyclization of 3-lithioxy-5-hexenyllithium as
a platform for 3-substituted cyclopentanols and cyclopentanones
Firstly we examined the reaction of the simplest dilithio
dianion, 3-lithioxy-5-hexenyllithium (2a), which was gen-
erated from 1-tributylstannyl-5-hexen-3-ol (1a) and n-BuLi
(2.1 equiv) in THF (Scheme 2). Tin–lithium exchange reac-
tion was carried out at –78 °C, and then the reaction mix-
ture was allowed to warm to 0 °C. Disappointingly, recool-
ing the mixture to –78 °C and quenching by TMSCl resulted
in the formation of uncyclized product 4a in 73% yield, and
only 5% yield of the cyclized product 5a was obtained. Tin-
containing 5a would be formed by the reaction of the cy-
clized dianion 3a with tetrabutyltin. The observed reluctant
carbolithiation of 2a led us to posturate intramolecular co-
ordination of a lithioxy group to alkyllithium in 2a. To alter
the unfavorable intramolecular Li–O–Li coordination, we
examined the experiment in the presence of LiCl (5 equiv),6
which resulted in the increase of the yield of 5a to 32% yield
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2413–2417

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with 85:15 (cis/trans) ratio. The promotion of the cycliza-
tion and cis preference may be due to chairlike conforma-
tion allowed by LiCl-caused liberation of the intramolecular
Li–O–Li coordination (Scheme 2).
13a did not occur at all even when the LiCl was added. On
the other hand, the cyclization reaction of 13b having a vi-
nylsilane moiety did proceed, yet sluggish, giving a 2:1 mix-
ture of uncyclized 15b and cyclized 16b. The addition of
LiCl was effective to accelerate the cyclization, giving 76%
yield of 16b with an 82:18 diastereomeric ratio. The Swern
oxidation of 16b gave the corresponding 2,3-dihydro-1-in-
denone 16b′ in quantitative yield.
We then examined aryllithium 13c having a vinyl sul-
fide moiety (Scheme 5). Again the addition of LiCl was nec-
essary to promote the carbocyclization of 13c leading to
14c. In this case, however, the expected cyclization product
16c was detected in a trace amount and instead 17c, in
which a butyl group was incorporated at α position to the
PhS group, was obtained as the cyclization product (57%
with 5 equiv of LiCl, –78 °C, 30 min). This could be formed
by the cyclized anion 14c with n-BuBr, in situ formed by
Li–Br exchange reaction between 12c and n-BuLi. Since no
such reaction with n-BuBr was observed in TMS-attached
anion 14b, the observed reactivity difference is intriguing,
and we are now examining the generality.
In summary, we have studied the intramolecular carbo-
lithiation of 3-lithioxy-5-hexenyllithiums. In contrast to the
case of Bailey’s 5-hexenyllithium, the cyclization was gen-
erally inefficient presumably due to the intramolecular co-
ordination. With an exception of aryllithium 13a, the addi-
tion of LiCl was effective to promote the cyclization and this
is due to dissociation of the intramolecular coordination.
Introduction of a silyl group at the olefin terminus pushed
smooth intramolecular carbolithiation, and the resulting
Since carbolithiation of ketone dilithio α,β-dianions
onto vinylsilane proceeds efficiently,5e,7 we next examined
dianion 2b having a silane moiety (Scheme 3). Unlike the
parent 2a, the cyclization of 2b leading to 3b proceeded
smoothly even without the addition of LiCl to give the de-
sired cyclopentanol 5b in 85% isolated yield with 94:6
(cis/trans) ratio after aqueous treatment.8 We then exam-
ined the reaction of thus generated 3b with carbon electro-
philes, such as allyl bromide, benzyl bromide, and benzal-
dehyde, which gave good yields of the corresponding
3-functionalized cyclopentanols 6, 7, and 8. Swern oxi-
dation was examined to convert cyclopentanols 5b and
6 into the corresponding cyclopentanones 5b′ and 6′,
which worked quite well. Acidic treatment (sulfuric acid in
THF) of the diastereomer mixture (23:23) of diol 8 caused
Peterson olefination to give 91% yield of 8′. The reaction of
3b with CO was also carried out in the hope of causing acyl-
lithium to lithium enolate conversion accompanied by 1,2-
Si shift.9 As our expectation, after aqueous treatment, the
desired acylsilane 11 was obtained in 63% yield.
To extend the present dianion-based cyclization strate-
gy to the construction of 2,3-dihydro-1-indenols, we
turned our attention to aryllithiums having an ortho-lithi-
oxy tether (Scheme 4).10 The dianion 13a was prepared
from aryl bromide 12a and n-BuLi via Li–Br exchange, how-
ever, unlike the case of the dianion 2a, the cyclization of
OLi
OLi
OH
LiO
Li
n-BuLi
(2.1 equiv)
n-Bu4Sn
n-BuLi
SnBu3
THF
–78 to 0 °C
1 h
Li
3a
SnBu3
2a
1a
OSiMe3
Me3SiCl
(3 equiv)
OSiMe3
+
SiMe3
–78 to 0 °C
30 min
SnBu3
5a
4a
additive
none
LiCl (5 equiv)
5%
73%
56%
32% (cis/trans = 85:15)
LiCl
–Cl
Li
LiO
LiO
Li+
Li
–Cl
LiO
Li
OLi
Li
Li+
Scheme 2 Carbocyclization of 3-lithioxy-5-hexenyllithium (2a)
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2413–2417

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dianions are subjected to C–C bond-forming reaction with
electrophiles to give the corresponding 3-substituted cyclo-
pentanols. Coupled with the subsequent Swern oxidation,
the overall protocol served as a platform for β-substituted
cyclopentanones.
Acknowledgment
This work was supported by a Grant-in-Aid for Scientific Research
from the JSPS and the MEXT, Japan.
OLi
LiO
Li
OH
n-BuLi
(2.1 equiv)
SnBu3
THF
–78 to 0 °C
Li
SiMe3
2b
1 h
SiMe3
SiMe3
1b
3b
O
Br
(1.5 equiv)
H2O
Ph
(1.5 equiv)
Br
Ph
H
(1.5 equiv)
OH
OH
OH
OH
HO
Me3Si
Ph
Ph
SiMe3
SiMe3
SiMe3
7
8
5b
85%
(cis/trans = 94:6)
6
80%
62%
58%
60:40
60:40
23:23:27:27
for cis isomer
for cis isomer
for cis isomer
DMSO, (COCl)2
Et3N, CH2Cl2
DMSO, (COCl)2
Et3N, CH2Cl2
H2SO4, THF
20 °C, 12 h
–60 to 20 °C
12 h
–60 to 20 °C
12 h
O
OH
O
Me3Si
Ph
SiMe3
5b'
6'
8'
97%
90% (62:38)
91% (from 23:23)
OLi
OLi
OH
CO
(1 atm)
H2O
1,2-Si
3b
O
LiO
Me3Si
O
Me3Si
0 to 15 °C
3 h
Li
SiMe3
9
10
11
63%
(cis/trans = 94:6)
Scheme 3 Carbocyclization of 3-lithioxy-6-trimethylsilyl-5-hexenyllithium (2b) and the use as a platform for 3-substituted cyclopentanols and cyclo-
pentanones
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Li
OLi
OLi
Li
OLi
OLi
Br
OH
n-BuLi
Br
OH
n-BuLi
(3.2 equiv)
(3.2 equiv)
THF
–78 °C
10 or 30 min
THF
–78 °C, 10 min
Li
SPh
Li
OH
PhS
SPh
12a
13a
14a
12c
(E/Z = 33:67)
13c
14c
OH
1) warm to 20 °C
24 h
OH
OH
+
OH
1) warm to 20 °C
4 h
2) H2O
+
+
15a
16a
additive
none
2) H2O
89%
85%
0%
0%
n-Bu
LiCl (5 equiv)
SPh
PhS
17c
PhS
15c (E/Z)
16c
additive
none
LiCl (5 equiv, 10 min)
LiCl (5 equiv, 30 min)
33% (63:37)
21% (63:37)
15% (63:37
25% (34:30:23:13)
46% (38:27:20:15)
57% (30:27:23:15)
trace
trace
trace
Li
OLi
OLi
Br
OH
n-BuLi
(3.2 equiv)
THF
–78 °C, 10 min
n-BuLi
H2O
12c
13c
14c
17c
Li
SiMe3
Me3Si
14b
SiMe3
12b
(E/Z = 100:0)
13b
n-BuBr
OH
OH
Scheme 5 Carbocyclization of aryllithium 13c having an o-lithioxy-
butenyl tether
1) warm to 20 ºC
3 h
+
2) H2O
SiMe3
SiMe3
References and Notes
15b
16b
additive
none
LiCl (5 equiv)
(1) For reviews, see: (a) Mehta, G.; Srikrishna, A. Chem. Rev. 1997,
97, 671. (b) Biellmann, J.-F. Chem. Rev. 2003, 103, 2019. (c) Das,
S.; Chandrasekhar, S.; Yadav, J. S.; Grée, R. Chem. Rev. 2007, 107,
3286. (d) Manna, M. S.; Mukherjee, S. Org. Biomol. Chem. 2015,
13, 18.
25% (77:23)
76% (82:18)
58%
12%
DMSO,(COCl)2
Et3N, CH2Cl2
(2) Bailey, W. F.; Patricia, J. J.; DelGobbo, V. C.; Jarret, R. M.; Okarma,
P. J. J. Org. Chem. 1985, 50, 1999.
–60 to 20 °C
12 h
(3) For selected reviews and recent references on the intramolecu-
lar carbolithiation leading to five-membered rings, see:
(a) Mealy, M. J.; Bailey, W. F. J. Organomet. Chem. 2002, 646, 59.
(b) Fañanás, F. J.; Sanz, R. In The Chemistry of Organolithium
Compounds; Vol. 2; Rappoport, Z.; Marek, I., Eds.; Wiley: Chich-
ester, 2006, 295. (c) Hogan, A.-M. L.; O’Shea, D. F. Chem.
Commun. 2008, 3839. (d) Girard, A.-L.; Lhermet, R.; Fressigné,
C.; Durandetti, M.; Maddaluno, J. Eur. J. Org. Chem. 2012, 2895.
(e) Bailey, W. F.; Bakonyi, J. M. J. Org. Chem. 2013, 78, 3493.
(f) Bailey, W. F.; Fair, J. D. Beilstein J. Org. Chem. 2013, 9, 537.
(g) Fressigné, C.; Lhermet, R.; Girard, A.-L.; Durandetti, M.;
Maddaluno, J. J. Org. Chem. 2013, 78, 9659. (h) Rodríguez, C.;
Nudelman, N. S. Synth. Commun. 2014, 44, 772. (i) Rodríguez, C.;
Nudelman, N. S. J. Phys. Org. Chem. 2014, 27, 322.
O
SiMe3
16b'
100%
Scheme 4 Carbocyclization of aryllithiums 13a and 13b having an
o-lithioxybutenyl tether
Supporting Information
(4) For reviews on the asymmetric intramolecular carbolithiation
in the presence of (–)-sparteine, see: (a) Marek, I. J. Chem. Soc.,
Perkin Trans. 1 1999, 535. (b) Clayden, J. Organolithiums: Selec-
tivity for Synthesis; Pergamon Press: New York, 2002, 273.
(c) Normant, J. F. In Organolithiums in Enantioselective Synthe-
sis; Vol. 5; Hodgson, D. M., Ed.; Springer: Berlin, 2003, 287.
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1560170.
S
u
p
p
ortioInfgrmoaitn
S
u
p
p
ortiInfogrmoaitn
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(d) Gómez-SanJuan, A.; Sotomayor, N.; Lete, E. Beilstein J. Org.
Chem. 2013, 9, 313. (e) Tian, L.; Du, W.; Zhang, Y.; Tang, S. Chin. J.
Org. Chem. 2014, 34, 507.
resulting solution was quenched with H2O and extracted with
Et2O twice. The combined organic solution was washed with
sat. aq NH4Cl and dried over MgSO4 and then concentrated
under reduced pressure. Purification by flash chromatography
(elution with hexane–Et2O, 2:1) provided the desired 3-tri-
methylsilylmethylcyclopentanol (5b, 70 mg, 85%) with 94:6
(cis/trans) ratio as a colorless oil. Rf = 0.2 (hexane–Et2O, 3:1).
1H NMR (270 MHz, CDCl3 for cis isomer): δ = –0.01 (s, 9 H), 0.71
(d, 2 H, J = 7.3 Hz), 1.06–1.16 (m, 1 H), 1.33–1.43 (m, 1 H), 1.60–
1.90 (m, 5 H), 2.16–2.26 (m, 1 H), 4.25–4.29 (m, 1 H). 13C NMR
(68 MHz, CDCl3 for cis isomer): δ = –0.74, 24.53, 33.99, 35.06,
35.70, 45.90, 73.78. MS (EI): m/z (%) = 157 (13) [M+ – CH3], 139
(5) For our work on ketone α,β-dianions, see: (a) Nakahira, H.; Ryu,
I.; Ikebe, M.; Kambe, N.; Sonoda, N. Angew. Chem., Int. Ed. Engl.
1991, 30, 177. (b) Ryu, I.; Nakahira, H.; Ikebe, M.; Sonoda, N.;
Yamato, S.; Komatsu, M. J. Am. Chem. Soc. 2000, 122, 1219.
(c) Ryu, I.; Ikebe, M.; Sonoda, N.; Yamato, S.; Yamamura, G.;
Komatsu, M. Tetrahedron Lett. 2000, 41, 5689. (d) Ryu, I.; Ikebe,
M.; Sonoda, N.; Yamato, S.; Yamamura, G.; Komatsu, M. Tetrahe-
dron Lett. 2002, 43, 1257. (e) Nakahira, H.; Ikebe, M.; Oku, Y.;
Sonoda, N.; Fukuyama, T.; Ryu, I. Tetrahedron 2005, 61, 3383.
(f) Yamato, S.; Yamamura, G.; Komatsu, M.; Arai, M.; Fukuyama,
T.; Ryu, I. Org. Lett. 2005, 7, 2489. (g) Ryu, I.; Yamamura, G.;
Omura, S.; Minakata, S.; Komatsu, M. Tetrahedron Lett. 2006, 47,
2283.
(29), 91 (32), 73 (Me3Si, 100). IR (KBr): 837, 1248, 3348 cm–1
.
HRMS: m/z calcd for C8H17OSi [M+ – CH3]: 157.1049; found:
157.1037. Anal. Calcd for C9H20OSi3: C, 62.72; H, 11.70. Found:
C, 62.48; H, 11.69.
(6) (a) Komine, N.; Tomooka, K.; Nakai, T. Heterocycles 2000, 52,
1071. (b) Bailey, W. F.; Jiang, X. Tetrahedron 2005, 61, 3183.
(c) Bailey, W. F.; Jiang, X. ARKIVOC 2005, (vi), 25.
(7) Bailey, W. F.; Gavaskar, K. V. Tetrahedron 1994, 50, 5957.
(8) 3-Trimethylsilylmethylcyclopentanol (5b); Typical Proce-
dure
(9) For conversion of acyllithium into lithium enolates, see:
(a) Murai, S.; Ryu, I.; Iriguchi, J.; Sonoda, N. J. Am. Chem. Soc.
1984, 106, 2440. (b) Ryu, I.; Hayama, Y.; Hirai, A.; Sonoda, N.;
Orita, A.; Ohe, K.; Murai, S. J. Am. Chem. Soc. 1990, 112, 7061.
(c) Ryu, I.; Yamamoto, H.; Sonoda, N.; Murai, S. Organometallics
1996, 15, 5459. (d) Fukuyama, T.; Totoki, T.; Ryu, I. Org. Lett.
2014, 16, 5632.
To a solution of γ-stannylalcohol 1b (221 mg, 0.48 mmol) in THF
(3 mL) was added n-BuLi (0.63 mL, 1.57 M solution in hexane,
1.01 mmol) dropwise over a period of 5 min at –78 °C. This
solution was allowed to warm to 0 °C and stirred for 1 h. The
(10) Ross, G. A.; Koppang, M. D.; Bartak, D. E.; Woolsey, N. F. J. Am.
Chem. Soc. 1985, 107, 6742.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2413–2417