Highly stereoselective addition of organometallic reagents to N-tert-butanesulfinyl imines derived from 3- and 4-substituted cyclohexanones

Article abstract of DOI:10.1021/ol0495220

Addition of alkyl or aryl Grignard reagents to N-sulfinyl imines derived from 3- and 4-substituted cyclohexanones proceeds with good yields and with excellent diasteroselectivity. The selectivity of the reaction is controlled by the ring substituent rathe

Full text of DOI:10.1021/ol0495220

ORGANIC
LETTERS
2004
Vol. 6, No. 10
1645-1647
Highly Stereoselective Addition of
Organometallic Reagents to
N-tert-Butanesulfinyl Imines Derived
from 3- and 4-Substituted
Cyclohexanones
Jeffrey P. McMahon and Jonathan A. Ellman*
Center for New Directions in Organic Synthesis, Department of Chemistry,
UniVersity of California, Berkeley, California 94720
jellman@uclink.berkeley.edu
Received March 12, 2004
ABSTRACT
Addition of alkyl or aryl Grignard reagents to N-sulfinyl imines derived from 3- and 4-substituted cyclohexanones proceeds with good yields
and with excellent diasteroselectivity. The selectivity of the reaction is controlled by the ring substituent rather than the sulfinyl group
stereochemistry, and therefore racemic tert-butanesulfinamide can be employed.
The synthesis of chiral amines is of great interest due to their
prevalence in biologically active molecules. Over the past
several years, our laboratory has developed several methods
for the asymmetric synthesis of amines using tert-butane-
sulfinamide as a chiral amine source.1 tert-Butanesulfinamide
can be condensed with aldehydes and ketones to form
N-sulfinyl imines in good yields. The chiral tert-butanesulfi-
nyl group directs the addition of nucleophiles to the imine
and also minimizes competitive deprotonation at the R
carbon. Subsequent cleavage of the sulfinamide under acidic
conditions provides the chiral amines.
despite the prevalence of R-substituted cyclohexylamines in
drugs and drug candidates, additions to N-sulfinyl ketimines
derived from cyclic ketones have not yet been reported.
Prompted by a number of inquiries on the feasibility of
preparing R-substituted cyclohexylamines using tert-butane-
sulfinamide chemistry, we report here on the efficient
preparation of this compound class by the addition of
organometallic reagents to N-sulfinyl imines derived from
3- and 4-substituted cylcohexanones.3 This study further
provides the first examples of nucleophilic attack upon
N-sulfinyl cyclic imines where both ring substituents and
the sulfinyl group have the potential to control reaction
diastereoselectivity.4
Organolithium reagents have been reported to add to tert-
butanesulfinyl ketimines with high diastereoselectivity and
good yields to provide one of the few general and efficient
methods for the synthesis of tertiary carbinamines.2 However,
(3) (a) Katritzky, A. R.; Najzarek, Z.; Dega-Szafran, Z. Synthesis 1989,
66. (b) Pai, K. P. P.; Volk, F.-J.; Khaliq-uz-Zaman, S. M.; Bisel, P.; Frahm,
A. W. Tetrahedron: Asymmetry 2002, 13, 2241. (c) Alonso, F.; Mico, I.;
Najera, C.; Sansano, J. M.; Yus, M. Tetrahedron 1995, 51, 10259. (d)
Vinick, F. J.; Nowakowska, J.; Jung, S. Tetrahedron Lett. 1987, 28, 741.
(e) Jirgensons, A.; Kauss, V.; Kalvinsh, I.; Gold, M. R.; Danysz, W.;
Parsons, C. G.; Quack, G. Eur. J. Med. Chem. 2000, 35, 555.
(1) Ellman, J. A.; Owens, T. D.; Tang, T. P. Acc. Chem. Res. 2002, 35,
984.
(2) Cogan, D. A.; Ellman, J. A. J. Am. Chem. Soc. 1999, 121, 268.
10.1021/ol0495220 CCC: $27.50 © 2004 American Chemical Society
Published on Web 04/20/2004

Condensation of (R)-tert-butanesulfinamide with 4-tert-
butylcyclohexanone employing Ti(OEt)4 in THF at room
temperature provided imine 1 (R1 ) t-Bu) in 72-81% yield
as a 1:1 mixture of imine isomers on the NMR time scale.
When the imine was treated with BuLi using the previously
reported conditions for organolithium additions to N-sulfinyl
ketimines, a 94:6 ratio of diastereomers was obtained in 77%
yield (entry 1, Table 1). The selectivity of the addition can
Table 2. Addition of Grignard Reagents to
N-tert-Butanesulfinyl Imines 1
Table 1. Addition of Organolithiums to N-tert-Butanesulfinyl
Imines 1
entrya
R1
R2
additive
yield
2:3c,d
1
2
3
4
5
6b
7
8
9
t-Bu
Me
Ph
Me
Ph
Bu
Me
Me
Ph
Me
Ph
Bu
Me3Al
Me3Al
none
none
none
80
76
78
69
59
77
80
76
79
62
57
98:2
95:5
98:2
95:5
97:3
>96:4e
95:5
95:5
95:5
93:7
96:4
none
Me
Me3Al
Me3Al
none
none
none
entry
R1
R2
additive
solvent
toluene
2:3a,b
10
11
1
2
3
4
5
t-Bu
Me
t-Bu
t-Bu
t-Bu
Bu
Bu
Me
Ph
Bu
Me3Al
Me3Al
Me3Al
Me3Al
Me3Al
94:6
86:14
2:1
3:2
7:3
toluene
a Unless otherwise indicated, (R)-tert-butanesulfinamide was employed.
b Racemic tert-butanesulfinamide was employed. c Unless otherwise indi-
cated, the diastereomeric ratio was determined by HPLC analysis. d Relative
stereochemistry of 2 (R1 ) Me, R2 ) Ph) was determined by X-ray
crystallography, and the stereochemistry of the other addition products was
inferred by analogy. e Diastereomeric ratio was determined by NMR of the
amine hydrochloride salt after cleavage of the sulfinyl group.
toluene/Et2O
toluene/Et2O
toluene/Et2O
a Diastereomeric ratio was determined by HPLC analysis. b Stereochem-
istry for 2 (R1 ) Me, R2 ) Ph) was determined by X-ray crystal structure.
The stereochemistry of the other amine products was determined by analogy.
Encouraged by these preliminary results, we next evaluated
other organolithium reagents. Unfortunately, the selectivity
of the reaction suffered when MeLi and PhLi were used as
nucleophiles (entries 3 and 4, Table 1). The dramatically
lower selectivities for these reactions likely resulted from
an altered aggregation state of the lithium reagents.7 While
n-BuLi is sold as a solution in hexanes, neither MeLi nor
PhLi are soluble in hydrocarbon solvents. The experiments
were therefore performed using commercially available
solutions of MeLi and PhLi in diethyl ether and cyclohexane/
ether, respectively. The deleterious effect of the diethyl ether
cosolvent was confirmed by addition of BuLi to 1 (R1 )
t-Bu) in toluene with a small amount of diethyl ether, equal
to the percentage in the experiment in entry 4. A considerable
drop in selectivity was observed (entry 5). A range of
additives such as TMEDA and BF3-Et2O and solvents were
evaluated, but reaction conditions for achieving high selec-
tivities were not identified.
best be rationalized if equatorial attack were to occur on the
lowest energy chair conformation, which has the 4-tert-butyl
group located equatorially.5 The chirality at sulfur is very
unlikely to play a significant role in the addition selectivity
because a 1:1 ratio of diastereomeric imine isomers was
observed (Figure 1).6 As could be expected, when imine 1
Poor selectivity was previously observed for the addition
of Grignard reagents to acyclic N-sulfinyl ketimines.2
However, the selectivity for additions to cyclic imines
appears to depend on the low-energy chair conformation
enforced by the ring substituent rather than the chirality of
the sulfinyl group. We therefore explored the addition of
Grignard reagents to N-sulfinyl-substituted cyclohexyl imines
1 (Table 2). As shown in entries 1-5, very high selectivities
and good yields were observed for additions to imine 1 (R1
) t-Bu), regardless of the Grignard reagent added. Due to
the symmetry of 4-substituted imines 1, racemic tert-
Figure 1. Equilibrium of Diastereomeric Imine Isomers 1.
(R1 ) Me) was employed, the addition product was obtained
in similar yield (72%) but with a modest drop in selectivity
(entry 2).
(4) Evans, J. W.; Ellman, J. A. J. Org. Chem. 2003, 68, 9949.
(5) Similar rationale is used to explain the selectivity of organometallic
additions to cyclic ketones; see: Carey, F. A.; Sundberg, R. J. AdVanced
Organic Chemistry; Kluwer Academic: New York, 2001; Part B, p 457.
(6) Although the individual imine isomers cannot be isolated, they can
be observed on the NMR time scale.
1646
Org. Lett., Vol. 6, No. 10, 2004

provided imines 4 and 5, respectively, in good yields.
Addition of MeMgBr to imines 4 and 5 each proceeded with
very high (99:1) diastereoselectivity and gave comparable
yields for the addition products 6 and 7. The relative
stereochemistry of 6 was established by X-ray crystal-
lography, and the relative stereochemistry of 7 was deter-
mined by conversion of 6 and 7 to the common amine
hydrochloride product 8.3e The stereoselectivity of the
addition reaction clearly is controlled by equatorial attack
upon the low-energy chair conformation enforced by the ring
substituent rather than by the chirality at sulfur.
Scheme 1. Grignard Reagent Additions to
N-tert-Butanesulfinyl Imines 4 and 5a
In summary, we have shown that alkyl and aryl Grignard
reagents add with high diastereoselectively and good yields
to N-sulfinyl imines derived from 3- and 4-substituted
cyclohexanones. The diastereoselectivity of the reaction is
determined by equatorial attack upon the low-energy chair
conformation and is independent of the stereochemistry of
the sulfinyl group. Consequently, the less expensive racemic
tert-butanesulfinamide can practically be employed for these
reactions.
a Reagents and Conditions: (i) (R)-tert-butanesulfinamide, Ti(O-
Et)4, THF; (ii) (S)-tert-butanesulfinamide, Ti(OEt)4, THF; (iii)
MeMgBr, Et2O, -78 to 25 °C.
Acknowledgment. The NSF is gratefully acknowledged
for support of this work. We thank Dr. Allen G. Oliver and
Dr. Frederick J. Hollander of the Berkeley CHEXray facility
for solving the X-ray crystal structures. The Center for New
Directions in Organic Synthesis is supported by Bristol-
Myers-Squibb as a sponsoring member and Novartis as a
supporting member.
butanesulfinamide can be employed to prepare the imines
without any loss in selectivity being observed in the addition
reaction (entry 6). Grignard reagent additions to imine 1 (R1
) Me) also proceeded in good yields and with high
selectivities for all of the Grignard reagents employed (entries
7-11).
We next evaluated Grignard reagent additions to N-sulfinyl
imines derived from 3-substituted cyclohexanones (Scheme
1). Condensations of both (R)- and (S)-tert-butanesulfinamide
with commercially available (R)-3-methyl cyclohexanone
Supporting Information Available: Crystallographic
data, full experimental details, and characterization for all
new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
(7) Clayden, J. Organolithiums: SelectiVity for Synthesis; Pergamon
Press: New York, 2002; pp 2-5.
OL0495220
Org. Lett., Vol. 6, No. 10, 2004
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