Construction of a chiral quaternary carbon center by catalytic asymmetric alkylation of 2-arylcyclohexanones under phase-transfer conditions

Article abstract of DOI:10.1021/ja403340r

In this paper, we present an asymmetric alkylation of modified 2-arylcyclohexanones that employs a novel chiral ammonium bromide as a phase-transfer catalyst and an achiral auxiliary as a controller to improve the enantioselectivity to afford optically enriched products having a chiral quaternary carbon center.

Full text of DOI:10.1021/ja403340r

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Communication
Construction of a Chiral Quaternary Carbon Center by Catalytic Asymmetric
Alkylation of 2-Arylcyclohexanones under Phase-transfer Conditions
Taichi Kano, Yumi Hayashi, and Keiji Maruoka
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja403340r • Publication Date (Web): 01 May 2013
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Construction of a Chiral Quaternary Carbon Center by Cata-
lytic Asymmetric Alkylation of 2-Arylcyclohexanones under
Phase-transfer Conditions
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Taichi Kano, Yumi Hayashi, and Keiji Maruoka*
Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo, Kyoto 606-8502, Japan
Supporting Information Placeholder
Scheme 1. 2-Arylcyclohexanone Modified with N,N-
ABSTRACT: In this paper, we present an asymmetric alkyla-
Diphenylaminomethylene
tion of modified 2-arylcyclohexanones that employs a novel
chiral ammonium bromide as a phase-transfer catalyst and
(S)-1 (1 mol%)
BnBr
KOH, H2O
O
O
O
an achiral auxiliary as a controller for improving enantiose-
lectivity to afford optically enriched products having a chiral
quaternary carbon center.
Bn
Ph
Bn
Ph
Ph
CPME, 0 °C, 24 h
(S)-1a: 76%, 11% ee
(S)-1b: 78%, 19% ee
80%, 38% ee
Cyclohexane rings containing a chiral quaternary carbon
center are frequently found in natural products and consid-
ered as an important and useful building block in organic
synthesis.1–4 Among them, 1-alkyl-1-arylcyclohexane is an
attractive structural motif that constitutes the core structure
of biologically active compounds represented by morphine
O
Ar
Ph2N
N,N-diphenylaminomethylene group
· steric and electronic tuning
· ease of removal
and
strychnine.5
Asymmetric
alkylation
of
2-
arylcyclohexanone is a simple and direct method to con-
struct such chiral quaternary carbon centers;5a however, only
a few reports on the catalytic asymmetric synthesis of 2-
alkyl-2-arylcyclohexanones have appeared to date with lim-
ited success (e.g., Mukaiyama aldol reaction, Pd-catalyzed
allylation and arylation).5,6 In contrast to the previous at-
tempts, phase-transfer-catalyzed asymmetric alkylation is
undoubtedly one of the most reliable methods to introduce
alkyl substituents in an enantioselective fashion, though such
an approach has not reached to a synthetically useful level.7,8
Here, we wish to disclose our initial results on this study.
· synthetic handle for
further transformations
The reaction between 2-phenylcyclohexanone and benzyl
bromide under phase-transfer conditions gave the benzylat-
ed product in low enantioselectivity (Scheme 1), and a chiral
phase-transfer catalyst (S)-1 was found to be unsuitable for
the relatively small substrate such as 2-phenylcyclohexanone,
probably due to the difficulty of the enantioface discrimina-
tion. On the other hand, asymmetric benzylation of 2-
phenyltetralone with a fused benzene ring gave the product
in somewhat higher enantioselectivity (Scheme 1). Based on
these results, we installed N,N-diphenylaminomethylene as a
tunable achiral auxiliary at the 6-position of 2-
phenylcyclohexanone with the expectation that the structur-
al modification in the cyclic ketone would result in an effi-
cient enantioface discrimination leading to a higher enanti-
oselectivity (Scheme 1).9,10 Indeed, a significant improvement
of enantioselectivity was observed in the reaction of modified
2-phenylcyclohexanone 2a (Table 1, entry 3). We then tuned
the structure of a catalyst and found that replacing butyl
groups on the ammonium nitrogen to isobutyl groups was
effective for achieving high enantioselectivity (entry 4).11 Fi-
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ne-tuning of the catalyst and lowering the reaction tempera-
tivity (entry 7). We then tested the scope of the reaction by
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5
6
7
8
9
ture to –10 °C led to a slight increase in enantioselectivity,
while a longer reaction time was required (entries 5 and 6). It
should be noted that even with the optimized catalyst (S)-1d,
the reaction between 2-phenylcyclohexanone and benzyl
bromide under similar conditions gave the benzylated prod-
uct in low enantioselectivity, implying the importance of the
achiral auxiliary for the high asymmetric induction (entry 7).
varying the substituents on the phenyl ring of the modified
2-arylcyclohexanone (entries 8–12). While para and/or meta-
substituents did not significantly affect the enantioselectivity
(entries 8–11), ortho-substitution resulted in no conversion
(entry 12). The electronic nature of the aryl group has some
effect on the reaction rate and yield. Since the electron-
withdrawing group on the phenyl ring significantly slowed
the reaction, a large excess of benzyl bromide was required
for completion of the reaction (entry 11). Unfortunately, the
reaction of 2a with ethyl iodide as an unactivated alkyl halide
did not afford the desired product. When 2-
phenylcyclopentanone having N,N-diphenylaminomethylene
moiety at the 5-position of cyclopentanone was used instead
of 2a, a significant decrease in enantioselectivity was ob-
served (93% yield, 38% ee).
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Table
2.
Asymmetric
Alkylation
of
2-
Arylcyclohexanone 2a
Table
1.
Asymmetric
Benzylation
of
2-
Phenylcyclohexanone 2aa
entry Ar
1
RCH2
yield (%)b ee (%)c
90
85
94
85
78
94
67
92
80
95
92
0
92
92
93
90
91
entry
1d
catalyst
temp. (°C) yield (%)b ee (%)c
2
(S)-1a
0
80
–3
67
67
87
89
92
9
2d
(S)-1b
(S)-1b
(S)-1c
(S)-1d
(S)-1d
(S)-1d
0
99
3
3
0
85
4
4
0
90
5
5
0
89
6e
7f
–10
0
91 (90)
50
6
95
80
96
92
92
91
aThe reaction of 2-phenylcyclohexanone 2a (0.10 mmol) with
benzyl bromide (0.12 mmol) was carried out in the presence
of a catalyst (0.001 mmol), KOH (0.50 mmol) and H2O (0.10
mmol) in CPME (1.0 mL) at room temperature for 48 h.
bConversion yield based on the ratio of 2a and 3a determined
by 1H-NMR. Isolated yield was indicated in parenthesis.
cDetermined by HPLC using chiral column. dThe reaction
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e
was performed in t-BuOMe for 24 h. The reaction was per-
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12
13
formed for 72 h. fUnder similar conditions, the reaction of 2-
phenylcyclohexanone instead of 2a was carried out for 24 h.
With the optimized conditions in hand, we examined the
substrate scope and the results are shown in Table 2. In the
presence of 1 mol% of (S)-1d, the reactions between 2-
phenylcyclohexanone 2a with various alkyl bromides gave
the corresponding products in good yield and enantioselec-
tivity (entries 1–6). Use of a propargyl bromide, 1-bromo-2-
butyne resulted in a decrease in both yield and enantioselec-
-
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aThe reaction of 2-arylcyclohexanone 2 (0.10 mmol) with
Figure 1. Plausible Transition State Model
alkyl bromide (0.12 mmol) was carried out in the presence of
(S)-1d (0.001 mmol), KOH (0.50 mmol) and H2O (0.10 mmol)
in CPME (1.0 mL) at –10 for 72 h. bIsolated yield. cDetermined
d
6
by HPLC using chiral column. Use of 5 equiv of benzyl bro-
7
mide.
8
9
N
Introduction of N-methylanilinomethylene group to ke-
tones is a well-known method for blocking the α-position of
a ketone.9 This blocking group can be removed by hydrolysis
with aqueous HCl followed by a retro-Claisen reaction of the
formylated ketone under basic conditions. Accordingly, we
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O
applied
this
procedure
to
remove
N,N-
diphenylaminomethylene group in 3a after the asymmetric
alkylation. However, a significant amount of the starting
material 3a was recovered after the acidic hydrolysis. Fortu-
nately, treatment of 3a with 1M KOH in 1,4-dioxane under
reflux afforded 2-benzyl-2-phenylcyclohexanone 4a directly
in quantitative yield without loss of enantiopurity (Scheme 2).
On the other hand, ozonolysis of 3a gave the corresponding
enol 5a as a useful building block, which is amenable to fur-
ther transformation. The absolute configuration of the allyla-
tion product 3b was determined to be S by conversion to 2-
allyl-2-phenylcyclohexanone 4b and comparison of its opti-
cal rotation to the literature value (Scheme 3):5b the alkylat-
ing agent (allyl bromide) should approach from the Si face of
the enolate anion generated from 2-phenylcyclohexanone 2a
under the influence of chiral phase-transfer catalyst (S)-1d as
shown in Figure 1.
Further synthetic utility of the present asymmetric alkyla-
tion was successfully demonstrated in the synthesis of an
Amaryllidaceae alkaloid, crinane,12 as shown in Scheme 4.
Optically enriched cyclohexanone 4c was prepared by the
asymmetric alkylation of 2c with cinnamyl bromide and the
following removal of N,N-diphenylaminomethylene group.
The styryl group of 4c was converted to the formyl group by
OsO4 and NaIO4. Reductive amination of γ-keto aldehyde 6
afforded octahydroindole 7, which was treated with Eschen-
moser’s salt to gave (+)-crinane according to the literature
procedure.12b
Scheme 4. Asymmetric Synthesis of (+)-Crinane
Scheme 2. Removal of N,N-Diphenylaminomethylene
Group
Scheme 3. Determination of Absolute Configuration
In summary, we have realized a highly enantioselective al-
kylation of 2-arylcyclohexanones by installing an achiral aux-
iliary, N,N-diphenylaminomethylene group at the 6-position
of cyclohexanones. The auxiliary was readily removed from
the alkylation product by simple basic hydrolysis. This meth-
odology certainly expands the synthetic utility of chiral
phase-transfer-catalyzed alkylation and provides a practical
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(5) For representative reports on the catalytic asymmetric synthe-
entry to the construction of chiral quaternary carbon centers
in organic synthesis.
sis of 2-alkyl-2-arylcyclohexanones, see: (a) Nerinckx, W.; Vande-
walle, M. Tetrahedron: Asymmetry 1990, 1, 265. (b) Trost, B. M.;
Schroeder, G. M.; Kristensen, J. Angew. Chem. Int. Ed. 2002, 41, 3492.
(c) Ishikawa, S.; Hamada, T.; Manabe, K.; Kobayashi, S. J. Am. Chem.
Soc. 2004, 126, 12236. (d) Liao, X.; Weng, Z.; Hartwig, J. F. J. Am.
Chem. Soc. 2008, 130, 195.
(6) For representative reports on the asymmetric synthesis of 2-
alkyl-2-arylcyclohexanes using chiral auxiliaries, see: (a) Hashimoto,
S.; Koga, K. Tetrahedron Lett. 1978, 19, 573. (b) Enders, D.; Zamponi,
A.; Schäfer, T.; Nübling, C.; Eichenauer, H.; Demir, A. S.; Raabe, G.
Chem. Ber. 1994, 127, 1707.
ASSOCIATED CONTENT
Supporting Information
Experimental procedure and spectral data for all new com-
pounds and computational details. This material is available
free of charge via the Internet at http://pubs.acs.org.
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(7) For recent reviews on the phase-transfer catalysis, see: (a)
Maruoka, K.; Ooi, T. Chem. Rev. 2003, 103, 3013. (b) O’Donnell, M. J.
Acc. Chem. Res. 2004, 37, 506. (c) Lygo, B.; Andrews, B. I. Acc. Chem.
Res. 2004, 37, 518. (d) Ooi, T.; Maruoka, K. Angew. Chem. Int. Ed.
2007, 46, 4222. (e) Hashimoto, T.; Maruoka, K. Chem. Rev. 2007, 107,
5656. (f) Jew, S.-s.; Park, H.-g. Chem. Commun. 2009, 7090.
(8) For selected reports of phase-transfer-catalyzed alkylations
forming a chiral quaternary carbon center, see: (a) Dolling, U. H.;
Davis, P.; Grabowski, E. J. J. J. Am. Chem. Soc. 1984, 106, 446. (b) Lee,
T. B. K.; Wong, G. S. K. J. Org. Chem. 1991, 56, 872. (c) Nibbs, A. E.;
Baize, A.-L.; Herter, R. M.; Scheidt, K. A. Org. Lett. 2009, 11, 4010. (d)
Moss, T. A.; Alonso, B.; Fenwick, D. R.; Dixon, D. J. Angew. Chem. Int.
Ed. 2010, 49, 568. (e) Hong, S.; Lee, J.; Kim, M.; Park, Y.; Park, C.;
Kim, M.-h.; Jew, S.-s.; Park, H.-g. J. Am. Chem. Soc. 2011, 133, 4924;
see also ref 4.
(9) N-Methylanilinomethylene group is used for blocking the α-
position of a ketone, see: (a) Birch, J.; Robinson, R. J. Chem. Soc. 1944,
501. (b) Woodward, R. B.; Sondheimer, F.; Taub, D.; Heusler, K.;
McLamore, W. M. J. Am. Chem. Soc. 1947, 74, 4223. (c) Hamada, T.;
Chieffi, A.; Åhman, J.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124,
1261.
(10) The benzylation of 2-phenylcyclohexanone having N-
methylanilinomethylene group at the 6-position with (S)-1d in
CPME at 0 °C gave the product in lower yield and enantioselectivity
(53% yield, 57% ee) than that shown in Table 1.
AUTHOR INFORMATION
Corresponding Author
maruoka@kuchem.kyoto-u.ac.jp
ACKNOWLEDGMENT
This work was supported by a Grant-in-Aid for Scientific
Research from MEXT, Japan.
REFERENCES
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(11) Chiral phase-transfer catalysts having other N-alkyl groups
such as isopropyl, neopentyl, cyclohexylmethyl and isopentyl
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(3) For selected reports on the catalytic asymmetric synthesis of
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Ar
Br
1.
(S)- (1 mol%)
1d
O
O
RCH2Br, KOH
H2O, CPME
R
Ar
Ar
iPr
iPr
Ph2N
N
2. 1M KOH
dioxane
· steric and electroni tuning
· ease of removal
synthetic handle for
further transformations
9
up to 96% ee
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Ar
(S)-1d
(Ar = 3,5-(3,5-F2C6H3)2C6H3)
·
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