Highly regioselective alkylation at the more-hindered α-site of unsymmetrical ketones by the combined use of aluminum tris(2,6-diphenylphenoxide) and lithium diisopropylamide

Full text of DOI:10.1021/ja963274o

J. Am. Chem. Soc. 1997, 119, 611-612
611
Communications to the Editor
Scheme 1
Highly Regioselective Alkylation at the
More-Hindered r-Site of Unsymmetrical Ketones by
the Combined Use of Aluminum
Tris(2,6-diphenylphenoxide) and Lithium
Diisopropylamide
Susumu Saito, Masahiro Ito, and Hisashi Yamamoto*
Graduate School of Engineering, Nagoya UniVersity
CREST, Japan Science and Technology Corporation (JST)
Furo-cho, Chikusa, Nagoya 464, Japan
ReceiVed September 17, 1996
An unsymmetrical dialkyl ketone can form two regioisomeric
enolates upon deprotonation.1 To exploit the synthetic potential
of enolate ions, the regioselectivity of their formation must be
controlled. By adjusting the conditions under which an enolate
mixture is formed from a ketone, it is possible to establish either
kinetic or thermodynamic control. Ideal conditions for kinetic
control of the formation of less-substituted enolate are those in
which deprotonation is irreversible, such as those with lithium
diisopropylamide (LDA). On the other hand, at equilibrium,
the more-substituted enolate is the dominant species with
moderate selectivity.2 Although there exists a method to
generate the more-substituted enolate using magnesium re-
agents,3 the selectivity is not always high. We report here a
third, hitherto unknown, method for the kinetically controlled
generation of the more-substituted enolate by the combined use
of aluminum tris(2,6-diphenylphenoxide) (ATPH)4 and LDA
(Scheme 1).
LDA in tetrahydrofuran and methyl trifluoromethanesulfonate5
(MeOTf), furnished, after 2 h, 2,2-dimethylcyclohexanone (2a)
and 2,6-dimethylcyclohexanone (3a) in an isolated yield of 53%
in a ratio of 32:1.6 Other alkylating agents, such as octyl triflate7
(OctOTf), allyl bromide (Allyl-Br), allyl iodide (Allyl-I), and
propargyl bromide, were also used for highly selective alkylation
at the more encumbered R-site of 1a to give 2b-d exclusively
(entries 2-5). In general, the reaction with the halides required
Precomplexation of ATPH with methylcyclohexanone (1a)
at -78 °C in toluene, followed by sequential treatment with
(1) (a) House, H. O. In Modern Synthetic Reactions; Breslow, R., Ed.;
W. A. Benjamin, INC.: Menlo Park, NY 1972; Chapter 9 and references
cited therein. (b) Evans, D. A. In Asymmetric Synthesis; Morrison, J. D.,
Ed.; Academic Press: San Diego, CA, 1984; Vol. 3, Chapter 1 and
references cited therein. (c) Caine, D. In ComprehensiVe Organic Synthesis;
Trost, B. M., Ed.; Pergamon Press: Oxford, 1991; Vol. 3, Chapter 1.1 and
references cited therein. (d) Mekelburger, H. B.; Wilcox, C. S. In
ComprehensiVe Organic Synthesis; Trost, B. M., Ed.; Pergamon Press:
Oxford, 1991; Vol. 2, Chapter 1.4 and references cited therein. (e)
Heathcock, C. H. In Modern Synthetic Methods 1992; Scheffold, R., Ed.;
VHCA and VCH: Basel, Weinheim, and New York, 1992; Vol. 6, Chapter
1 and references cited therein.
(2) Recent methods for the generation of more-substituted enolates have
been reported. KH and BEt3 system: (a) Negishi, E.; Chatterjee, S.
Tetrahedron Lett. 1983, 24, 1341. (b) Negishi, E.; Matsushita, H.; Chatterjee,
S.; John, R. A. J. Org. Chem. 1982, 47, 3190. Unsymmetrical imines with
RLi; (c) Hosomi, A.; Araki, Y.; Sakurai, H. J. Org. Chem. 1982, 104, 2081.
The regiochemistry of R-alkylation of unsymmetrical ketones depends on
the combination of the metal cation and electrophiles rather than on
regioselective enolate formation: (d) Duhamel, P.; Cahard, D.; Quesnel,
Y.; Poirier, J.-M. J. Org. Chem. 1996, 61, 2232. Preparation of thermody-
namic trimethylsilyl enol ethers: (e) Krafft, M. E.; Holton, R. A. J. Org.
Chem. 1984, 49, 3669. (f) Stork, G.; Hudrlik, P. F. J. Am. Chem. Soc. 1968,
90, 4462. (g) House, H. O.; Czuba, L. J.; Olmstead, H. D. J. Org. Chem.
1969, 34, 2324. (h) Nakamura, E.; Murofushi, T.; Shimizu, M.; Kuwajima,
I. J. Am. Chem. Soc. 1976, 98, 2346. (i) Miller, R. D.; Mckean, D. R.
Synthesis 1979, 730. (j) Brown, C. A. J. Org. Chem. 1974, 39, 3913.
(3) (a) Krafft, M. E.; Holton, R. A. Tetrahedron Lett. 1983, 24, 1345.
(b) Crisp, G. T.; Scott, W. J.; Stille, J. K. J. Am. Chem. Soc. 1984, 106,
7500. A referee has suggested that in the Krafft-Holton procedure,
complexation of an acidic Mg species with the carbonyl groups of ketones
might occur prior to deprotonation, based on our results described here. In
fact, they used more than 1 equiv of the magnesium reagent (<1.25 equiv)
for deprotonation.
a higher temperature (-20 to 0 °C) than that with the alkyl
triflates (-78 to -40 °C). This alkylation method was also
successfully applied to other unsymmetrical ketones, and the
results are summarized in Table 1. It should be emphasized
that a high level of discrimination of R-methine over R-meth-
ylene (entries 1-8), R-methylene over R-methyl (entries 9 and
10), and R-methine over R-methyl (entry 11) was achieved using
ATPH to give 2b-i in reasonable yields.
The generation of the kinetically deprotonated more-
substituted enolate could be interpreted in terms of the influence
(a) Maruoka, K.; Ito, M.; Yamamoto, H. J. Am. Chem. Soc. 1995, 117,
9091. (b) Maruoka, K.; Saito, S.; Yamamoto, H. Ibid. 1995, 117, 1165. (c)
Maruoka, K.; Imoto, H.; Yamamoto, H. Ibid. 1994, 116, 12115. (d)
Maruoka, K.; Imoto, H.; Saito, S.; Yamamoto, H. Ibid. 1994, 116, 4131.
(5) For alkylation of ketone enolates with alkyl triflates, see: (a) Bates,
R. B.; Taylor, S. R. J. Org. Chem. 1993 58, 4469. (b) Bates, R. B.; Taylor,
S. R. Ibid. 1994, 59, 245.
(6) Monitoring the reaction by GC-MS analysis using dodecane as an
internal standard revealed that 2a (94%) and 3a (0.5%) were generated
along with unreacted 1a (5%) after 1 h at -78 °C. The relatively low isolated
yield with low observed regioselectivity (entry 1, Table 1) should be due
to more volatile nature of 2a. The tri- and tetramethylated products could
not be detected by the GC-MS analysis.
(4) ATPH was prepared as follows: To a solution of 2,6-diphenylphenol
(3 equiv) in toluene was added a 1 M hexane solution of Me3Al (1 equiv)
at room temperature under argon. The resulting pale yellow solution was
stirred at this temperature for 30 min and used without further purification.
(7) Prepared as described in the literature procedure: Stang, P. J.; Hanack,
M.; Subramanian, L. R. Synthesis 1982, 85.
S0002-7863(96)03274-X CCC: $14.00 © 1997 American Chemical Society

612 J. Am. Chem. Soc., Vol. 119, No. 3, 1997
Communications to the Editor
Table 1. Regioselective Alkylation of Unsymmetrical Ketonesa
Figure 1. Space-filling model of the ATPH-1a complex. LDA
attacking is more feasible at the more substituted R-carbon.
obstructing the trajectory of the nucleophilic LDA attacking at
this position (Scheme 1 and Figure 1).
Figure 1 also shows that upon anti complexation with ATPH,
the R-methylene proton of 1a lays behind the R-methine proton,
which is more accessible for deprotonation. The crucial role
of the pocket in obtaining the present regioselectivity and high
yields was further demonstrated by an alkylation experiment
with 1a in the presence of methylaluminum bis(2,6-di-tert-butyl-
4-methylphenoxide) (MAD),10 a less-hindered aluminum reagent
lacking a pocket. Complexation of 1a with MAD at -78 °C
was followed by addition of LDA. After 1 h, the resulting
enolate was treated with MeOTf, and the mixture was stirred
continuously for 19 h at the same temperature to give 2a and
3a in a ratio of ∼1:1.
In conclusion, the synthetically useful, highly selective
alkylation at the more-substituted R-carbon of unsymmetrical
ketones was realized by extending the Lewis acid-base
complexation system to the ordinary ketone alkylation method
using LDA and electrophilic alkylating agents.
a Unless otherwise noted, deprotonation of ketones with LDA in the
presence of ATPH at -78 °C for 30 min was followed by treatment
with alkylating agent (R′X), and the mixture was stirred at -78 °C to
room temperature. bThe carbons indicated with arrows are the more-
hindered R-site. c Yields are of isolated, purified products. d Product
1
ratios are determined by 300 MHz H NMR, HPLC, or GC analysis
Acknowledgment. Partial financial support from the Ministry of
Education, Science, and Culture of Japan is gratefully acknowledged.
against authentic samples.
Supporting Information Available: A representative experimental
procedure, spectral data for all new compounds, and the determination
of regioisomeric ratios (5 pages). See any current masthead page for
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of ATPH on the inherent coordination preferences of unsym-
metrical ketones. The X-ray crystal structure of the ATPH-
dimethylformamide complex4d revealed that the three arene rings
of ATPH form a propeller-like arrangement around the alumi-
num, producing a pocket for accepting a carbonyl compound.
It is reasonable to suggest that the bulky aluminum reagent
ATPH prefers coordination with one of the lone pairs of the
carbonyl oxygen anti to the more-hindered R-carbon of the
unsymmetrical ketone.8,9 As a consequence, the pocket sur-
rounds the less-hindered site of the carbonyl group, thus
JA963274O
(9) The MM2 calculation for the ATPH-1a complex using the CAChe
system indicates that the anti coordination of ATPH to 1a is 7.6 kcal/mol
more stable than the syn coordination.
(10) The bulky Lewis acid methylaluminum bis(2,6-di-tert-butyl-4-
methylphenoxide) (MAD) selectively chelates to the less-hindered oxygen
functionalities of ethers, ketones, and esters. (a) MAD for ethers: Maruoka,
K.; Nagahara, S.; Yamamoto, H. Tetrahedron Lett. 1990, 31, 5475. (b) MAD
for ketones: Maruoka, K.; Araki, Y.; Yamamoto, H. J. Am. Chem. Soc.
1988, 110, 6225. (c) MAD for esters: Maruoka, K.; Saito, S.; Yamamoto,
H. Ibid. 1992, 114, 1089. (d) Selective coordination to one of the lone pairs
of the epoxide oxygen anti to the migration group, with the MAD analogue
(8) Coordination aptitude of a variety of Lewis acids toward carbonyl
compounds is discussed in the following review: (a) Schreiber, S. L. In
ComprehensiVe Organic Synthesis; Trost, B. M., Ed.; Pergamon Press:
Oxford, 1991; Vol. 1, Chapter 1.10 and references cited therein. (b)
Shambayati, S.; Crowe, W. E.; Schreiber, S. L. Angew. Chem., Int. Ed.
Engl. 1990, 29, 256.
methylaluminum
bis(4-bromo-2,6-di-tert-butyl-4-methylphenoxide)
(MABR): Maruoka, K.; Ooi, T.; Yamamoto, H. Tetrahedron 1994, 50,
6505.