Construction of cyclopentyl carbinols from ω-tosyloxy-1-alkenyl boronate esters and grignard reagents

Article abstract of DOI:10.3987/COM-08-S(F)69

Addition of RMgCl (R = n-Bu, Ph) to pinacol esters of 6-tosyloxy-l-alkenyl boronic acids at -78 °C gave the borates, which upon warming to room temperature underwent migration of R on boron to C(1) carbon and concomitant ring construction C-C bond formati

Full text of DOI:10.3987/COM-08-S(F)69

HETEROCYCLES, Vol. 77, No. 2, 2009
787
ETEROCYCLES, Vol. 77, No. 2, 2009, pp. 787 – 791. © The Japan Institute of Heterocyclic Chemistry
Received, 28th July, 2008, Accepted, 30th September, 2008, Published online, 2nd October, 2008
DOI: 10.3987/COM-08-S(F)69
CONSTRUCTION
OF
CYCLOPENTYL
CARBINOLS
FROM
ω-TOSYLOXY-1-ALKENYL BORONATE ESTERS AND GRIGNARD
REAGENTS†
Yuichi Kobayashi,* Moriteru Asano, and Yohei Kiyotsuka
Department of Biomolecular Engineering, Tokyo Institute of Technology, B52,
Nagatsuta-cho 4259, Midori-ku, Yokohama 226-8501, Japan
ykobayas@bio.titech.ac.jp
Abstract – Addition of RMgCl (R = n-Bu, Ph) to pinacol esters of
6-tosyloxy-1-alkenyl boronic acids at –78 °C gave the borates, which upon
warming to room temperature underwent migration of R on boron to C(1) carbon
and concomitant ring construction C–C bond formation between C(2) and C(6),
eventually producing cyclopentyl alkyl (or aryl) carbinols after oxidative workup
of the borane intermediates with 35% H2O2. Eight examples are presented and the
reaction was applied to construction of a cyclohexyl carbinol.
Esters of organoboronic acids with a diol (organoboronate esters) are chemically stable neutral
compounds that are easily purified by chromatography and/or by distillation, whereas organoborates
derived by reaction with organometallics are reactive anions that undergo coupling reactions with allylic
acetates, alkenyl bromides, and aryl halides.1 Examples of such coupling reactions are shown in eqs (1)2,3
and (2)4,5 of Scheme 1.6 Importantly, low reactivity of the substrates due to steric reasons are compensated
by the high reactivity of the borates. We then envisioned another reaction delineated in Scheme 2, in
which borate B undergoes migration of R3 to the olefinic carbon and concomitant cyclization as
illustrated in E to produce cyclopentyl alkyl (or aryl) carbinol D after oxidative workup of the borane
intermediate C. Previously, an anion and a radical, generated at the C-L (L = I, Br) carbon of
organoboranes of similar structures to A, have been shown to undergo cyclization.7,8 Herein, we report
preliminary results of the migration/cyclization.
First, effect of metal cations (M+) of n-Bu-M on the proposed reaction was examined using boronate
† This paper is dedicated to Professor Emeritus Keiichiro Fukumoto on the occasion of his 75th birthday.

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HETEROCYCLES, Vol. 77, No. 2, 2009
HO
OAc
–
R1
n-BuLi
R1
O
O
O
O
HO
Li+
(1)
R1
B
B
n-Bu
Ni cat.
allylic coupling
boronate esters
lithium borates
R
TBSO
Br
–
R
R1
O
O
MeLi
Li+
(2)
R1
TBSO
R1
B
B
Me
Ni cat.
sp2-C and sp2-C coupling
O
O
Scheme 1. Previous coupling reactions using lithium borates
–
R3
R3
R3
R2
R2
R2
R2
–
O
O
O
B
R3 M+
B
B
OH
H2O2
M+
O
O
O
R1
R1
R1
R1
R
R
R
L
L
D
C
A
B
(L : Leaving group)
R3
R2
O
B
O
R
R1
L
E
Scheme 2. Formation of cyclopentane ring through migration of R3 and cyclization on borates B
esters 2a–d (L = OTs, OMs, Br, I) possessing a 2,2-dimethylpropane-1,3-diol ligand (examination of diol
ligands is described in a later section). The esters 2a and 2b were synthesized through hydroboration of
acetylenes 1a and 1b with HBBr2, hydrolysis, and subsequent esterification of the resulting boronic acid
with the diol in good yields. The TsO group in 2a was replaced by halogen atoms to afford bromide 2c
and iodide 2d, respectively. Addition of n-Bu-M (M = Li, ZnCl, MgCl) to 2a–d were carried out at
–78 °C for 30–60 min. The resulting borates were warmed slowly to room temperature and, after stirring
overnight, the products were treated with 35% H2O2 in order to produce alcohol 3. As summarized in
Table 1, reaction of tosylate 2a with slightly excess n-BuLi (1.2 equiv) in THF and Et2O gave
unidentified products (entries 1, 2). On the other hand, 2a and excess n-BuZnCl (6 equiv) in THF
produced the tosylate of 5-hexen-1-ol (entry 3), indicating that the zinc borate was indeed formed, but
remained unchanged before the aqueous work up. Next, n-BuMgCl (6 equiv) in THF was investigated
O
NaBr, Bu4NBr
O
1) HBBr2 then H2O
2)
B
B
;
2a
O
O
or NaI
HO
OH
L
L
L
acetone
1a, L = OTs
1b, L = OMs
2a, L = OTs (77%)
2b, L = OMs (69%)
2c, L = Br (91%)
2d, L = I (89%)
Scheme 3. Synthesis of substrates 2a–d

HETEROCYCLES, Vol. 77, No. 2, 2009
789
Table 1. Reaction of boronate esters 2a–d with n-Bu-M.
OH
n-Bu
O
1) n-BuM, –78 °C then rt
2) 35% H2O2, 0 °C
B
O
L
3
2a–d
n-BuM
yield
of 3 (%)
entry substrate
L
M
equiv
solvent
THF
Et2O
THF
THF
Et2O
THF
THF
THF
THF
a
1
2
3
4
5
6
7
8
9
2a
2a
2a
2a
2a
2a
2b
2c
2d
OTs
OTs
OTs
OTs
OTs
OTs
OMs
Br
Li
1.2
1.2
6
–
a
Li
–
b
ZnCl
MgCl
MgCl
MgCl
MgCl
MgCl
MgCl
–
c
6
69
c
6
69
c
2.5
2.5
6
53
d
41
d
28
d
I
6
29
a
b
c
A mixture of unidentified compounds was produced. Tosylate of 5-hexen-1-ol was obtained.
1
d
Isolated yield. Determined by H NMR spectroscopy using pyridine as a reference.
to afford the desired alcohol 3 in 69% yield after oxidative workup (entry 4). Reaction in Et2O proceeded
with a comparable yield (entry 5). Use of 2.5 equiv of n-BuMgCl in THF resulted in decrease in yield
(53%, entry 6). In contrast to tosylate 2a, mesitylate 2b, bromide 2c, and iodide 2d produced alcohol 3 in
lower yields (entries 7–9).
Table 2. Further optimization of the reaction using 2e–g.
OH
1) n-BuMgX (3.2 equiv)
–78 °C then rt
O
B
n-Bu
O
R
2) 35% H2O2, 0 °C
OTs
3
2e–g
entry
substrate
ligand
reagent
yield (%)
1
2
3
4
2e
2f
O(CH2)3O
n-BuMgCl
n-BuMgCl
n-BuMgCl
n-BuMgBr
53
58
74
48
OCH(Me)CH(Me)O
OC(Me)2C(Me)2O
OC(Me)2C(Me)2O
2g
2g

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HETEROCYCLES, Vol. 77, No. 2, 2009
Further optimization of the reaction was executed with boronate esters 2e–g, which were prepared by a
method similar to 2a. Reactions with n-BuMgX (3.2 equiv) are summarized in Table 2. The pinacol ester
2g gave product 3 in good yield (entry 3), while 2e and 2f showed comparable reactivities to 2a (entries 1,
2; cf. Table 1, entry 6 with 2.5 equiv of BuMgCl). We then tested n-BuMgBr, which demonstrated no
advantage over n-BuMgCl (entry 4).
The conditions developed for the migration/cyclization were applied to various cases to clarify the scope
and limitations (Scheme 4). Substrates 2h–j were synthesized by hydroboration of the corresponding
acetylenes with HB(c-Hex)2 followed by oxidation of the boranes with Me3NO and subsequent ligand
exchange with pinacol,9 while 2k was synthesized through hydroboration with HBBr2 similar to 2a and
2g. Reaction of 2g with PhMgCl (3.2 equiv) afforded 4 in 52% yield, while lower yields were obtained
with c-HexMgCl and t-BuMgCl, indicating a limitation toward steric hindrance at the reagent side (eq 3).
On the other hand, bulkiness at the TsO carbon seems less sensitive as indicated by reaction of 2h with
RMgCl (R = n-Bu, Ph), giving 7 and 8, respectively (eq 4). Two more examples are shown in eqs 5 and 6,
in which 9 and 10 were formed in moderate to good yields. The reaction was also applicable to
cyclohexane ring formation as shown in eq 7.
OH
R
O
1) RMgCl (3.2 equiv)
B
(3)
4, R = Ph, 52%
5, R = c-Hex, 26%
6, R = t-Bu, 3%
O
OTs
2) 35% H2O2
2g
OH
O
1) RMgCl (3.2 equiv)
2) 35% H2O2
*
*
B
R
(4)
(5)
O
OTs
7, R = n-Bu, t / c = 84 : 16, 78%
8, R = Ph, t / c = 45 : 55, 52%
2h
OH
O
1) n-BuMgCl (3.2 equiv)
2) 35% H2O2
B
*
n-Bu
MOMO
O
OTs
MOMO
HO
*
2i
9, t / c = 57 : 43, 49%
O
n-Bu
B
1) n-BuMgCl (3.2 equiv)
2) 35% H2O2
O
(6)
(7)
OTs
2j
10, 76%
OH
n-Bu
O
1) n-BuMgCl (3.2 equiv)
2) 35% H2O2
B
O
OTs
11, 63%
2k
Scheme 4. Scope and limitations of the reaction

HETEROCYCLES, Vol. 77, No. 2, 2009
791
In summary, we have developed a new construction of cyclopentyl alkyl (or aryl) carbinols by reaction of
pinacol alkenylboronate esters and RMgCl through migration of R group and cyclization. The
stereochemical outcome was, however, controlled little by the existing chiral centers. We are continuing
investigation to control the stereochemistry of the reaction.
ACKNOWLEDGEMENTS
This work was supported by a Grant-in-Aid for Scientific Research from the Ministry of Education,
Science, Sports, and Culture, Japan.
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