Asymmetric synthesis of α,α-diaryl and α-aryl-α-heteroaryl alkylamines by organometallic additions to N-tert-butanesulfinyl ketimines

Article abstract of DOI:10.1016/S0040-4039(01)01513-1

Organometallic addition to tert-butanesufinyl ketimines derived from diaryl and aryl-heteroaryl ketones provided the corresponding α,α-diaryl and α-aryl-α-heteroaryl alkylamines in good yield with high diastereoselectivity. In many cases, imine facial selectivity is reversed on changing the organometallic counterion.

Full text of DOI:10.1016/S0040-4039(01)01513-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 7173–7176
Asymmetric synthesis of a,a-diaryl and a-aryl-a-heteroaryl
alkylamines by organometallic additions to N-tert-butanesulfinyl
ketimines
Anthony W. Shaw* and S. Jane deSolms
Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA
Received 2 August 2001; accepted 13 August 2001
Abstract—Organometallic addition to tert-butanesufinyl ketimines derived from diaryl and aryl-heteroaryl ketones provided the
corresponding a,a-diaryl and a-aryl-a-heteroaryl alkylamines in good yield with high diastereoselectivity. In many cases, imine
facial selectivity is reversed on changing the organometallic counterion. © 2001 Published by Elsevier Science Ltd.
The amine functionality is an important component of
many bioactive compounds. In pursuit of farnesyl
protein transferase (FPTase) inhibitors possessing a
diaryl ether moiety1 we observed that the presence of a
primary amine attached to a quaternary carbon in
compound 1 enhanced cell activity without compromis-
ing intrinsic potency (Fig. 1).2
describe our preliminary findings on the asymmetric
syntheses of chiral a,a-diaryl and a-aryl-a-heteroaryl
alkylamines from N-tert-butanesulfinyl ketimines.
Notably, reversal of diastereoselectivity was observed in
most cases when the substrate was treated with either
Grignard or organolithium reagents in THF. To carry
out these studies, we required an efficient method for
the large scale preparation of the key ketimine interme-
diate 6 (Scheme 1). Aldehyde 3 was prepared in four
To aid in SAR studies we required intermediates which
contained a chiral nitrogen-substituted quaternary car-
bon. Methods for the synthesis of a-branched chiral
amines employing organometallic addition to sulfen-
imines have been described by Davis3 and Ellman.4
Most of the work has focussed on addition to
aldimines. Limited studies have been carried out on
ketimines5 derived from unsymmetrical ketones. The
diastereoselective 1,2-addition of organometallic
reagents to the N-tert-butanesulfinyl ketimines of diaryl
or aryl-heteroaryl ketones seemed an appropriate
method for the preparation of 1. In this paper we
Scheme 1. Reagents and conditions: (a) KMnO4, pyridine,
H2O, reflux, 40 h, 94%; (b) BH3–THF, 5°C to rt, 24 h, 92%;
(c) Zn(CN)2, Pd(Ph3P)4, DMF, 95°C, 18 h, 66%; (d) pyridine–
SO3, DMSO, Et3N, 0°C, 2 h, 100%; (e) 1-methylimidazole,
n-BuLi, Et3SiCl, THF, −78°C to rt, 18 h; sec-BuLi, THF,
−78°C to rt, 2 h; (f) MnO2, CH2Cl2, CH3CN, 3 h, 48%; (g)
Figure 1.
(R)-(+)-2-methyl-2-propanesulfinamide,
Ti(OEt)4,
THF,
* Corresponding author. Tel.: 215-652-1097; fax: 215-652-7310;
e-mail: anthony shaw@merck.com
reflux, 72 h, 76%.
–
0040-4039/01/$ - see front matter © 2001 Published by Elsevier Science Ltd.
PII: S0040-4039(01)01513-1

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A. W. Shaw, S. J. deSolms / Tetrahedron Letters 42 (2001) 7173–7176
steps from commercially available 2. Alkylation of alde-
hyde was achieved with 5-lithio-1-methyl-2-
additions required many equivalents (ꢀ6 equiv.) at 0°C
to consume all of the starting material, whereas alkyl
lithium additions required only 1–1.5 equiv. at −78°C.
The addition was selective for the ketimine over the
nitrile when the organometallic was added to the sub-
strate, but not under inverse conditions. Good to excel-
lent yields were obtained in all cases except for 8f and
8g (entries 10–13), presumably due to the instability of
the pyridyllithium reagents. Aryl organometallic addi-
tion was consistently more selective than aliphatic
organometallic addition probably due to the steric bulk
of the nucleophile (entries 4,5 versus 1,2). Grignard
versus alkyllithium additions to the R-ketimine gave
opposite stereoselectivity (entries 1 versus 2 and 4 ver-
sus 5). Thus, with the proper choice of organometallic
reagent or chiral ketimine, either enantiomer of 8 could
be synthesized.
3
triethylsilylimidazole6 to give alcohol 4 which was
oxidized to ketone 5. The ketimine 6 was prepared by
Ti(OEt)4 mediated condensation of 5 with either com-
mercially available R- or S-sulfinamide following Ell-
man’s procedure.7 Compound 6 was isolated in 76%
yield after refluxing for 3 days in THF with the mass
balance recovered as unreacted ketone 5. Addition of
more sulfinamide, Ti(OEt)4, molecular sieves, and
longer reaction times were unsuccessful in driving the
reaction to completion. Variable temperature NMR
studies of 6 at −40 to 25°C indicates the presence of
both E and Z isomers which rapidly interconvert.8
Attempts at further structural characterization using
NOE experiments were unsuccessful due to rapid
exchange.
The versatility of ketimine 6 was evidenced by the
introduction of a wide variety of alkyl, alkynyl, and
aryl substituents in good to excellent diastereoselectivity
(Table 1). The chirality of the amine could be con-
trolled by the choice of organometallic reagent or chiral
sulfinamide. Treatment of 6 with a Grignard reagent or
alkyllithium in THF, followed by cleavage of the tert-
butanesulfinyl group with 4 M HCl in dioxane and
CH3OH, liberated the amines 8a–g. THF was the sol-
vent of choice due to the insolubility of the ketimine
substrate in diethyl ether or CH2Cl2. Reactions were
run for 5–15 min, then quenched with water. Grignard
To determine whether the facile and diastereoselective
addition to the (R)-ketimine 6 was unique to this
particular compound, a series of diaryl and aryl-het-
eroaryl ketimines were examined.10 Examples were cho-
sen (Table 2) to determine the role of the 4-cyano group
as well as the imidazole moiety on reactivity and selec-
tivity. As before, Grignard additions were generally
performed at 0°C whereas organolithium additions
were performed at −78°C.
With aryl-heteroaryl ketimines (entries 1–4), a reversal
in selectivity is observed suggesting imidazole is not
Table 1. 1,2-Addition of organometallic reagents to 6a
Entry
Substrate
R-Metal
T (°C)
Product
Ratio (−):(+)b
Yield (%)c
1
2
3
4
5
6
7
8
R-6
R-6
S-6
R-6
R-6
S-6
R-6
R-6
S-6
R-6
S-6
R-6
S-6
CH3MgBr
CH3Li
CH3Li
(C6H5)MgBr
(C6H5)Li
4-F-C6H4MgBr
4-OCH3-C6H5MgBr
(C3H5)CꢀCMgBr
(C3H5)CꢀCMgBr
3-Pyr Li
3-Pyr Li
2-OCH3-5-Pyr Li
2-OCH3-5-pyr Li
0
8a
8a
8a
8b
8b
8c
8d
8e
8e
8f
(80:20)
13:87
(94:6)
6:94
94:6
96:4
74
82
65
78
83
−78
−78
0
−78
0
0
0
0
−78
−78
−78
−78
86
83
7:93
21:79
78:22
3:97
96:4
5:95
(100)
(100)
35
9
10
11
12
13
8f
8g
8g
31
57d
57d
96:4
a Reactions were performed by slow addition of organometallic solution to a solution of 6 in THF (see Ref. 9).
b Enantiomeric ratios of amine 8 (−):(+) determined by chiral HPLC (ratios in parenthesis are for diastereomeric ratios of precursor sulfinamides
7 determined by reverse-phase HPLC).
c Isolated yields (−/+ combined) of sulfinamide 7 (crude yields are in parenthesis) are based on ketimine 6, and are not optimized.
d Isolated yields of amine 8.

A. W. Shaw, S. J. deSolms / Tetrahedron Letters 42 (2001) 7173–7176
Table 2. 1,2-Addition of organometallic reagents to 10a
7175
Entry
Substrate
Ar1
Ar2
CH3MgBr (−):(+)b
Yield 11 (%)c
CH3Li (−):(+)b
Yield 11 (%)c
1
2
3
4
5
6
7
8
9
R-6
10a
10b
10c
10d
10e
10f
1-CH3Im
1-CH3Im
3-py
3-py
Ph
4-OCH3Ph
4-OCH3Ph
2-CH3Ph
2-CH3Ph
3-F-4-CNPh
Ph
3-F-4-CNPh
Ph
4-CNPh
4-CNPh
Ph
80:20
77:23
73:27
60:40
73:27
63:37
39:61
100:0
95:5
74
52
89
100
100
93
13:87
7:93
82
48
88
100
88
72
45:55
36:64
30:70
14:86
27:73
100:0
85:15
90
95
10g
10h
Ph
76d
92
38e
64
3-F-4-CNPh
a Reactions were performed by slow addition of organometallic solution to a solution of 10 in THF.
b Enantiomeric ratios of (−) and (+)-11 were determined by using chiral HPLC.
c Isolated yields of (−) and (+)-11 are based on ketimine 10 and are not optimized.
d No reaction at 0°C, allowed to warm to rt.
e No reaction at −78°C, allowed to warm to rt.
critical for this effect. Furthermore, selectivity is
observed regardless of whether an electron withdrawing
group is on the aryl ring or not. With diaryl ketimines,
turnover is observed, but only if an electron withdraw-
ing group is on one of the aryl rings (entries 5,6 versus
7). Replacement of the 4-methoxy group with an o-tolyl
group (entries 8 versus 7), retains lack of turnover in
selectivity even when an electron withdrawing group is
present (entries 9 versus 6). A boost in selectivity is also
observed (entries 8 versus 7). This phenomenon could
be due, in part, to conformational effects analogous to
observations by Corey in oxazaborolidine-catalyzed
enantioselective carbonyl reductions11. The inability to
accurately determine the structure of our ketimines by
NOE experiments8 makes mechanistic interpretation of
these subtle trends difficult.
ham and Christopher J. Dinsmore for helpful
discussions.
References
1. MacTough, S. C.; deSolms, S. J.; Shaw, A. W.; Abrams,
M. T.; Ciccarone, T. M.; Davide, J. P.; Hamiliton, K. A.;
Hutchinson, J. H.; Koblan, K. S.; Kohl, N. E.; Lobell, R.
B.; Robinson, R. G.; Graham, S. L. Bioorg. Med. Chem.
Lett. 2001, 11, 1257–1260.
2. deSolms, S. J.; Ciccarone, T. M.; MacTough, S. C.;
Shaw, A. W.; Abrams, M. T.; Buser-Doepner, C.;
Davide, J. P.; Hamiliton, K. A.; Huber, H. E.; Kohl, N.
E.; Lobell, R. B.; Robinson, R. G.; Tsou, N. N.; Gra-
ham, S. L.; Beese, L. S.; Taylor, J. S.; manuscript in
preparation.
The addition of organometallic reagents to chiral diaryl
sulfinimines is a useful tool for the asymmetric synthesis
of a,a-diaryl and a-aryl-a-heteroaryl alkylamines.
Reversal of chirality with change in counterion is
observed with aryl-heteroaryl ketimines and with diaryl
ketimines containing electron withdrawing groups, but
not electron rich or neutral diaryl ketimines. o-Tolyl
ketimines are highly selective, but chirality does not
reverse with a change in counterion, possibly a result of
a strong conformational bias. Elucidation of the mech-
anisms accounting for these reversals in diastereoselec-
tivity will require additional studies.
3. Davis, F. A.; Zhou, P.; Chen, B.-C. Chem. Soc. Rev.
1998, 27, 13–18.
4. Cogan, D. A.; Liu, G.; Ellman, J. A. Tetrahedron 1999,
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5. Cogan, D. A.; Liu, G.; Ellman, J. A. J. Am. Chem. Soc.
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Lett. 1996, 37, 9353–9356.
7. Liu, G.; Cogan, D. A.; Owens, D. O.; Tang, T. P.;
Ellman, J. A. J. Org. Chem. 1999, 64, 1278–1284.
8. Ketimine 10e was found to exist as a 85:15 mixture of
isomers at −40°C using a Double Pulse Field Gradient
NOE run on an INOVA 600 spectrometer. Ketimines
R-6, 10c, d, h were found to be exchanging too fast at
−40°C to see a mixture of isomers.
Acknowledgements
9. General procedure: Compound 6 (1.50 g, 4.51 mmol) was
dissolved in anhydrous THF (30 mL) at 0°C to which a
3.0 M solution of MeMgBr (4.50 mL, 13.5 mmol) in Et2O
was added. The reaction was quenched with aq. NH4Cl
solution, diluted with saturated NaHCO3 solution and
The authors would like to thank Joan S. Murphy and
Steven M. Pitzenberger for NMR experiments, Carl F.
Homnick for chiral HPLC work, and Samuel L. Gra-

7176
A. W. Shaw, S. J. deSolms / Tetrahedron Letters 42 (2001) 7173–7176
extracted with CH2Cl2 (3X). The combined organic layers
10. Ketones 9b, c, d, and h were obtained from commercial
sources. The remaining ketones 9a, e, f, and g were
prepared by addition of the requisite Ar1 Grignard
reagent or aryl lithium and the appropriate Ar2 aldehyde
followed by oxidation.
were dried (MgSO4), filtered, and concentrated to give
1.57 g (99%) of an 80:20 mixture of 7. To a solution of
this crude product (0.880 g, 2.51 mmol) dissolved in
MeOH (50 mL) was added a cold methanolic HCl solu-
tion (50 mL) with stirring for 1 h at rt. After concentra-
tion and purification 0.47 g (59%) of 8 was obtained.
11. Corey, E. J.; Helal, C. Tetrahedron Lett. 1996, 37, 5675–
5678.