Construction of a quaternary carbon at the carbonyl carbon of the cyclohexane ring

Article abstract of DOI:10.1039/c0cc00653j

High S_N2′ selectivity in the allylic substitution of cyclohexylidene ethyl picolinates with copper reagents prepared from RMgBr and CuBr·Me₂S was realized by addition of ZnX₂ (X = I, Br, Cl). Furthermore, ZnX₂ accelerated the reaction with the bulky iPr reagent. The Royal Society of Chemistry 2010.

Full text of DOI:10.1039/c0cc00653j

View Article Online / Journal Homepage / Table of Contents for this issue
COMMUNICATION
www.rsc.org/chemcomm | ChemComm
Construction of a quaternary carbon at the carbonyl carbon
of the cyclohexane ringw
Yuki Kaneko, Yohei Kiyotsuka, Hukum P. Acharya and Yuichi Kobayashi*
Received 29th March 2010, Accepted 9th June 2010
First published as an Advance Article on the web 29th June 2010
DOI: 10.1039/c0cc00653j
High SN20 selectivity in the allylic substitution of cyclo-
hexylidene ethyl picolinates with copper reagents prepared from
RMgBr and CuBrꢀMe2S was realized by addition of ZnX2
(X = I, Br, Cl). Furthermore, ZnX2 accelerated the reaction
with the bulky iPr reagent.
envisioned a sequence of reactions shown in eqn (2) though
the regioselectivity at the g carbon over the a carbon in the
allylation of picolinates 4 was uncertain as the g and a carbons
are, respectively, more and less congested than the substrates
examined in eqn (1). Furthermore, the influence of the
substituent(s) attached to the cyclohexane ring on stereo-
selectivity was unprecedented. In practice, regioselectivity with
the original reagent system (R3MgBr, CuBrꢀMe2S) was low or
reverse, whereas reaction in the presence of a zinc halide
was found to be highly regioselective. On the other hand,
stereoselectivity was high irrespective of zinc halides. Herein,
we report the results of the investigation.
Addition of two alkyl groups to the carbonyl group of the
cyclohexanones would be a convenient strategy for formation
of a quaternary carbon on the cyclohexane ring, and provides
an access to several kinds of biologically important natural
compounds such as the steroids, morphine, taxol, etc.
Previously, this concept was investigated by using a sequence
of reactions, which consists of addition of CH2QCHMgBr to
Initially, MeMgBr and CuBrꢀMe2S were mixed in a 2 : 1
ratio at 0 1C for 30 min to prepare the copper reagent of the
supposed structure, Me2CuMgBrꢀMgBr2, which (1.5 equiv.)
was subjected to reaction with 4-tert-butylcyclohexylidene
derivative 4A at 0 1C for 1 h according to the published
procedure4a,b to afford the regioisomer 6a as the major
product (Table 1, entry 1). We supposed that the chelation
of the picolinoxy group to MgBr2, one of the effective activations,
is insufficient for the present substrate. We then directed our
attention to zinc halides. Fortunately, ZnBr2 (1.5 equiv.) was
found to afford the desired product 5a with 95% regio-
selectivity by 1H NMR spectroscopy (entry 2). Reaction at
lower temperatures resulted in higher regioselectivity (99%,
entry 3). Use of ZnBr2 in larger quantity (4 equiv.) provided a
similar selectivity (entry 4), whereas insufficient selectivity was
obtained with 0.5 equiv. of ZnBr2 (entry 5). High efficiency
was also observed with ZnI2 and ZnCl2 (entries 6 and 7). In
contrast to Me2CuMgBrꢀMgBr2, another copper reagent,
MeCuꢀMgBr2, (1.5 equiv.) was 89% SN20 selective (entry 8).
However, the selectivity was not improved by ZnBr2
(1.5 equiv.), which rather retarded the reaction (entry 9 and
footnote e). In addition, leaving groups other than the picolinoxy
group were examined. The o-(PPh2)C6H4CO2, C6F5CO2, and
AcO leaving groups showed no reactivity, while the MeOCO2
group gave 5a in o24% yield.
4-tert-butyl-cyclohexanone and
a nickel-catalyzed allylic
substitution of the resulting allylic alcohol with MeMgBr,
producing 4-tert-butyl-1-methyl-1-vinylcyclohexane.1 Although
the stereoselectivity is quite high (ca. 95%), the reaction suffers
from somewhat low regioselectivity (81–86%), indicating
difficulty in controlling the reaction site of the p-allylnickel
intermediates. Furthermore, according to the authors, this
method is not applicable to Grignard reagents possessing a
b-hydrogen.2,3 Recently, we found highly regio- and stereo-
selective substitution of allylic picolinates with classes of
organocopper reagents to afford the anti SN20 products 2
(Scheme 1, eqn (1)).4 With this substitution in mind, we
Next, the above protocol was applied to Et2CuMgBrꢀMgBr2
and Bu2CuMgBrꢀMgBr2. Different from Me2CuMgBrꢀMgBr2,
these reagents as such were of slight SN20 selectivity, which was
substantially improved by addition of ZnI2 to produce 5b and
5c in good yields (entries 11 and 13 vs. entries 10 and 12).
The cis stereochemistry regarding the tBu and the vinyl
group of 5a was unambiguously established by comparison of
the 13C NMR spectrum with the literature data for the cis and
trans isomers.1 The assignment indicates that the stereochemical
course of the reaction depicted by heavy arrow A in Fig. 1
is controlled to avoid the steric interaction with the axial
hydrogens in the chair conformation. This consideration is
Scheme 1 The previous (eqn (1)) and the present investigation
(eqn (2)). Py = 2-pyridyl.
Department of Biomolecular Engineering, Tokyo Institute of
Technology, Japan. E-mail: ykobayas@bio.titech.ac.jp
w Electronic supplementary information (ESI) available: The details of
the results of Chart 1, full experimental detail, spectroscopic data,
stereochemical correlation, and copies of NMR spectra. See DOI:
10.1039/c0cc00653j
ꢁc
This journal is The Royal Society of Chemistry 2010
5482 | Chem. Commun., 2010, 46, 5482–5484

View Article Online
Table 1 Reactions under various conditions
Copper reagenta
Formula
Additive
Entry
Temp.,1C
Regioselectivity (5 : 6)b
Stereoselectivity of 5b,c
Yield, %d
Equiv.
ZnX2
Equiv.
1
2
3
4
5
6
7
8
Me2CuMgBrꢀMgBr2
Me2CuMgBrꢀMgBr2
Me2CuMgBrꢀMgBr2
Me2CuMgBrꢀMgBr2
Me2CuMgBrꢀMgBr2
Me2CuMgBrꢀMgBr2
Me2CuMgBrꢀMgBr2
MeCuꢀMgBr2
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
3.0
—
—
0
0
22 : 78
95 : 5
99 : 1
99 : 1
59 : 41
100 : 0
98 : 2
89 : 11
85 : 15
56 : 44
98 : 2
62 : 38
99 : 1
—
98 : 2
93 : 7
97 : 3
98 : 2
98 : 2
100 : 0
98 : 2
94 : 6
94 : 6
99 : 1
98 : 2
100 : 0
100 : 0
—
nd
nd
94
88
nd
85
86
nd
nd
81
86
nd
94
0f
ZnBr2
ZnBr2
ZnBr2
ZnBr2
ZnI2
ZnCl2
—
ZnBr2
—
ZnI2
—
1.5
1.5
4.0
0.5
1.5
1.5
—
1.5
—
1.5
—
ꢂ40 to ꢂ10
ꢂ40 to 0
ꢂ40 to 0
ꢂ40 to ꢂ10
ꢂ40 to ꢂ10
0
9
MeCuꢀMgBr2
0 to rte
10
11
12
13
14
15
Et2CuMgBrꢀMgBr2
Et2CuMgBrꢀMgBr2
Bu2CuMgBrꢀMgBr2
Bu2CuMgBrꢀMgBr2
iPr2CuMgBrꢀMgBr2
iPr2CuMgBrꢀMgBr2
ꢂ40 to 0
ꢂ40 to 0
ꢂ40 to ꢂ10
ꢂ40 to ꢂ10
ꢂ40 to ꢂ10
ꢂ40 to 0
ZnI2
—
ZnI2
1.5
—
3
99 : 1
99 : 1
93
a
b
The copper reagents were prepared from RMgBr (R = Me, Et, Bu, iPr) and CuBrꢀMe2S in 2 : 1 and 1 : 1 ratios, respectively. Determined by
1H NMR spectroscopy. For 5a (R = Me) the cis relation regarding the tBu and the vinyl groups is confirmed by 13C NMR spectroscopy, while
c
d
e
f
the same stereochemistry was assigned for 5b–d by analogy. Isolated, combined yields of 5 and 6. nd: Not determined. 18 h at rt. The
corresponding alcohol and 4A were obtained in 75 and 25% yields, respectively.
observed with the Me reagent was inverted to SN20 selective by
addition of ZnX2 (X = I, Br) (rs 95% and 100%, respectively).
The low level of SN20 preference with Et and Bu reagents
(rs 82%, 70%) was substantially improved (rs 100% both
cases), while >95% ss was recorded independent of ZnX2
Fig. 1 Stereochemical course and the assigned stereochemistry of 5a.
(X = I, Br). Reaction with the iPr reagent afforded a mixture
of the regioisomer 6h, the corresponding alcohol and 4B in a
29 : 61 : 10 ratio, whereas ZnBr2 accelerated the SN20 allylic
substitution selectively to produce 5h as observed in the case of
4A. ZnI2 gave a similar result.
later proved to be applicable to other cases. The same stereo-
chemistry was assigned to 5b–d by analogy.
Allylation with a bulky copper reagent derived from
iPr2CuMgBrꢀMgBr2 disclosed another effect of ZnX2. In the
absence of a zinc halide, the SN20 reaction was suppressed
apparently by the steric reason. Alternatively, attack at the
carbonyl carbon of the picolinoxy group took place to produce
the corresponding alcohol (entry 14 and footnote f). In
contrast, ZnI2 (3 equiv.) led the SN20 allylation to completion,
giving 5d in high yield with high regio- and stereoselectivities
(entry 15). It should be noted that ZnX2 accelerated the
reaction with the cuprate (iPr2CuMgBrꢀMgBr2) or retarded
the reaction with the copper reagent (MeCuꢀMgBr2).
2-Methyl substrate 4C, prepared as a 4 : 1 mixture of the
E/Z isomers, was subjected to reaction with the Me and Bu
reagents. High selectivity was observed as well to produce the
SN20 products 5i and 5j, respectively. The results indicate that
stereocontrolled synthesis or separation of the olefin isomers
of the substrate is not a requirement for attaining high
selectivity, thus demonstrating another advantage of the
present strategy. The stereochemistry of 5i was established as
drawn in Chart 1 by transformation to the known acid, 1,2-
dimethylcyclohexanecarboxylic acid,5 by oxidation of the
double bond (see ESIw). The outcome was consistent with
the stereochemical course illustrated in Fig. 1.
The SN20 allylation optimized above with ZnX2 was further
examined by using a variety of substrates and reagents to
establish the generality of the reaction. Substrate–product
relationship, regioselectivity (rs), stereoselectivity (ss) and
yields (y) are summarized in Chart 1, in which the
selectivities were determined by 1H NMR spectroscopy. In
the cases of 5i and 5k, yields were somewhat low due to the
volatile property. The details of the results and those carried
out without ZnX2 are presented in Table S1 in the electronic
supplementary information (ESIw). 4-Phenyl derivative 4B
showed similar reactivity and selectivity to 4-t-butyl
substrate 4A. Thus, the SN2 (a) selectivity (5e/6e = 1 : 99)
Next, ZnI2-assisted reaction of 3-methyl and 3,5,5-trimethyl
derivatives 4D and 4E with the Et and Bu reagents afforded
the corresponding SN20 products 5k–m with similarly high
selectivities (rs >99%, >97%). ZnI2-assisted substitution of
the 2-methoxy derivative 4F with the Bu reagent proceeded
similarly to furnish the SN20 product 5n in 70% yield. The SN20
selectivity (100%) was not diminished by the Lewis basic MeO
group. The piperidine derivative 4G, chosen as a heterocyclic
substrate, upon reactions with the Me and Bu reagents
produced the SN20 products 5o and 5p with high selectivities
ꢁc
This journal is The Royal Society of Chemistry 2010
Chem. Commun., 2010, 46, 5482–5484 | 5483

View Article Online
Chart 1 Substrates, products, regio- and stereoselectivities (rs, ss) and yields.
(rs 98%, ss >98%). It should be noted that high regio- and
stereoselectivities were independent of the E/Z stereochemistry
of 4D–4G as in the case of 4C.
activates the leaving group effectively for the reaction to
proceed at the g carbon.
In conclusion, the SN20 selective allylation of 4 was attained
by adding ZnX2 (X = I, Br), and the generality of the reaction
was established by sacrificing a number of the substituted
cyclohexyl derivatives. In all cases, the stereoselectivity was at
high levels and the stereochemical course of the reaction is
now predictable by using the chair conformer of the cyclo-
hexane ring. Furthermore, ZnX2 was found to accelerate the
allylation with the bulky iPr reagent.
The allylation was applied to the trans decaline derivative
4H, which was prepared from the corresponding ketone6 as a
1 : 1 mixture of the olefin isomers. The methylation without a
zinc halide was moderately SN2 selective (5q/6q = 25 : 75),
whereas reaction in the presence of ZnI2 was SN20 selective,
giving 5q with rs 99% and ss 100%. Substitution with the Bu
reagent afforded 5r.
Finally, the protocol established above (with ZnX2) was
applied to the steroid derivative 4I (E/Z = 1 :1), which afforded
5s and 5t upon reaction with the Et and Bu reagents, respectively.
The regio- and stereoselectivities (rs 100%, ss >98%) were as
high as those recorded with other picolinate derivatives. Once
again, the stereochemistry of 5t, confirmed by derivation to
the known compound7 (see ESIw for the transformation), is
consistent with the model depicted in Fig. 1.
Notes and references
1 B. L. Buckwalter, I. R. Burfitt, H. Felkin, M. Joly-Goudket,
K. Naemura, M. F. Salomon, E. Wenkert and P. M. Wovkulich,
J. Am. Chem. Soc., 1978, 100, 6445.
2 Breit succeeded in constructing
a quaternary carbon on the
cyclohexane ring by applying his syn SN20 protocol to 3-alkyl-
2-cyclohexen-1-ol derivatives with the o-(PPh2)C6H4CO2 leaving
group, which are a structurally different class of substrates:
A copper reagent derived from Et2Zn and CuBrꢀMe2S in a
1 : 1 ratio upon reaction with 4A afforded 5b with a similarly
high regioselectivity, indicating Et2Cu(ZnBr) is also an effective
reagent to give 5b in 70% yield though the reagent suffers from
the co-production of alcohol 7 as shown in eqn (3).
B. Breit, P. Demel and C. Studte, Angew. Chem., Int. Ed., 2004,
43, 3786.
3 Formation of the quaternary carbon on the cyclopentane ring:
D. Soorukram and P. Knochel, Org. Lett., 2007, 9, 1021.
4 (a) Y. Kiyotsuka, H. P. Acharya, Y. Katayama, T. Hyodo and
Y. Kobayashi, Org. Lett., 2008, 10, 1719; (b) Y. Kiyotsuka,
Y. Katayama, H. P. Acharya, T. Hyodo and Y. Kobayashi,
J. Org. Chem., 2009, 74, 1939; (c) Y. Kiyotsuka and
Y. Kobayashi, Tetrahedron Lett., 2008, 49, 7256.
5 E. Wenkert, P. M. Wovkulich, R. Pellicciari and P. Ceccherelli,
J. Org. Chem., 1977, 42, 1105.
ð3Þ
6 R. J. Abraham, H. A. Bergen and D. J. Chadwick, Tetrahedron,
1982, 38, 3271.
7 B. T. Ngatcha, V. Luu-The, F. Labrie and D. Poirier, J. Med.
Chem., 2005, 48, 5257.
The data obtained with ZnX2 and ZnEt2 suggest that stronger
coordination of the picolinoxy group to more acidic Zn2+
ꢁc
This journal is The Royal Society of Chemistry 2010
5484 | Chem. Commun., 2010, 46, 5482–5484