Asymmetric synthesis of α,α-dibranched amines by the trimethylaluminum-mediated 1,2-addition of organolithiums to tert- butanesulfinyl ketimines [12]

Full text of DOI:10.1021/ja983217q

268
J. Am. Chem. Soc. 1999, 121, 268-269
Table 1. Condensations of Ketones with Sulfinamide 1
Asymmetric Synthesis of r,r-Dibranched Amines by
the Trimethylaluminum-Mediated 1,2-Addition of
Organolithiums to tert-Butanesulfinyl Ketimines
Derek A. Cogan and Jonathan A. Ellman*
ketimine 2
R1
R2
yield (%)
(E:Z)b
Department of Chemistry
UniVersity of California
Berkeley, California 94720
2a
2b
2c
2d
2e
2f
Me
Me
Bu
Bu
Me
Me
i-Pr
Ph
i-Pr
Ph
i-Bu
Bu
84
87
66
77
88
77
one isomer
one isomer
one isomer
one isomer
6:1
ReceiVed September 9, 1998
5:1
Asymmetric induction in the synthesis of chiral quaternary
centers has been a formidable challenge in synthetic chemistry.
In fact, only recently have practical and elegant routes to certain
classes of quaternary centers been developed.1 However, despite
the prevalence of the amine functionality in natural products,
synthetic pharmaceuticals, catalysts, and materials, no direct
method has yet been reported for the asymmetric synthesis of
the large class of nitrogen-substituted quaternary centers, the R,R-
dibranched amines. To this end, the 1,2-addition of nucleophiles
to ketimines has great potential as a general and direct approach.2,3
Unfortunately, competitive R-deprotonation has prohibited the
general use of aryl or alkyl carbanions.2,4 Thus, the asymmetric
synthesis of R,R-dibranched amines has been limited to allylation
of ketimines2 and additions to R-pyridyl-substituted ketimines.5
Herein, we report the first direct method for the asymmetric
synthesis of a broad range of R,R-dibranched amines by the
unprecedented 1,2-addition of organolithium reagents to ketimines.
Specifically, we report the highly diastereoselective 1,2-addition
of organolithium reagents to N-tert-butanesulfinyl ketimines,
which are prepared in high yield in one step from the corre-
sponding ketones.
Although a variety of amines have been prepared by the
diastereoselective addition of nucleophiles to N-sulfinyl aldi-
mines,6 far fewer transformations of N-sulfinyl ketimines have
been reported.7 This is likely due to the unavailability of most
N-sulfinyl ketimine derivatives, which have traditionally been
synthesized by the reaction of chiral sulfinate esters with imine
anions prepared in situ by the 1,2-addition of organometallics to
nitriles.3,8 This approach is limited by the small number of readily
available, nonenolizable nitriles.
a Reactions were run with 2.0 equiv of Ti(OEt)4 in THF at 60-75
1
°C. b Ratios were determined by H NMR recorded in CDCl3.
1; R1 ) H).9 To prepare R,R-dibranched amines, the analogous
condensation of 1 with ketones to provide N-sulfinyl ketimines
would clearly be desirable. Unfortunately, attempted condensation
of acetophenone and methyl isopropyl ketone with 1 employing
Mg(SO4) was not successful. By exploring a number of different
dehydrating agents and catalysts, Cu(SO4) was found to be a more
effective agent for the direct condensation of aldehydes with 1,10
but still did not effect the ketone condensations. Titanium(IV)
salts have been successfully employed in the condensations of
ketones with amines11 and ureas.12 Therefore, a number of
inexpensive Ti(IV) reagents, including Ti(O-i-Pr)4, Ti(OEt)4, and
various TiCln(O-i-Pr)4-n derivatives were investigated, with Ti-
(OEt)4 most efficiently providing N-sulfinyl ketimines 2a and 2b
(84% and 87% yield) upon heating in THF (eq 1). Significantly,
1
only the E isomer was detected by H and 13C NMR in CDCl3.
A number of ketones with varying steric and electronic demand
about the carbonyl were submitted to these same conditions to
investigate generality (Table 1). Although ketones with more
substantial steric demand required longer reaction times and
slightly higher temperatures, all ketones submitted to these
conditions condensed in good yields. The ratio of E:Z isomers,
1
as determined by H NMR in CDCl3, were excellent when R1
and R2 were dissimilarly branched (2a-d). Considering the
modest steric difference between methyl and butyl substituents,
the E:Z ratio of 5 observed for sulfinyl ketimine 2f is remarkable.
Sulfinyl ketimine 2e, with â-substitution as the remote source of
steric demand, favored the E isomer to an even greater degree.
The 1,2-addition of organometallic reagents to N-sulfinyl
ketimines 2 was next explored for the preparation of R,R-
dibranched amines. First, N-sulfinyl ketimine 2a was added to
phenylmagnesium bromide under the conditions that we had
previously developed for 1,2-additions to N-sulfinyl aldimines
(-48 °C in CH2Cl2).9a A 2:3 mixture of (RS,R)-3a and (RS,S)-3a
was obtained in 21% yield, with the difference in mass isolated
as unreacted 2a, likely resulting from competitive deprotonation.
The 1,2-addition of phenyllithium to 2a in toluene was consider-
ably more promising, affording 3a in 65% yield with a 94:6 ratio
of (RS,R)-3a to (RS,S)-3a (Table 2; entry 1). Interestingly, this
highly stereoselective reaction favored the diastereomer opposite
that observed for the Grignard addition. The 1,2-addition of
butyllithium to 2b was considerably less satisfying, affording
(RS,S)-3b in only 26% yield, albeit with an excellent diastereo-
We recently reported the practical two-step preparation of
enantiomerically pure tert-butanesulfinamide (1) in 71-75%
overall yield from tert-butyl disulfide. We also described the Mg-
(SO4)-mediated condensation of 1 with aldehydes (eq 1 in Table
(1) (a) Corey, E. J.; Guzman-Perez, A. Angew. Chem., Int. Ed. Engl. 1998,
37, 388-401. (b) Fuji, K. Chem. ReV. 1993, 93, 2037-2066.
(2) (a) Bloch, R. Chem. ReV. 1998, 98, 1407-1438. (b) Enders, D.;
Reinhold: U. Tetrahedron: Asymmetry 1997, 8, 1895-1946.
(3) Allylmetal additions are a special case because they presumably proceed
through a concerted mechanism. Hua, D. H.; Miao, S. W.; Chen, J. S.; Iguchi,
S. J. Org. Chem. 1991, 56, 4-6.
(4) For the synthesis of racemic or achiral R,R-disubstituted amines see:
(a) Barbot, F.; Miginiac, L. Synth. Commun. 1997, 27, 2601-2614. (b)
Calderwood, D. J.; Davies, R. V.; Rafferty, P.; Twigger, H. L.; Whelan, H.
M. Tetrahedron Lett. 1997, 38, 1241-1244. (c) Ciganek, E. J. Org. Chem.
1992, 57, 4521-4527. (d) Charette, A. B.; Gagnon, A.; Janes, M.; Mellon,
C. Tetrahedron Lett. 1998, 39, 5147-5150.
(5) Spero, D. M.; Kapadia, S. R. J. Org. Chem. 1997, 62, 5537-5541.
(6) (a) Davis, F. A.; Zhou, P.; Chen, B.-C. Chem. Soc. ReV. 1998, 27, 13-
18. (b) Davis, F. A.; Portonovo, P. S.; Reddy, R. E.; Reddy, G. V.; Zhou, P.
Phosphorus, Sulfur, Silicon Relat. Elem. 1997, 120, 121, 291-303.
(7) (a) Davis, F. A.; Reddy, R. T.; Reddy, R. E. J. Org. Chem. 1992, 57,
6387-6389. (b) Hua, D. H.; Lagneau, N.; Wang, H.; Chen, J. Tetrahedron:
Asymmetry 1995, 6, 349-352. (c) Annunziata, R.; Cinquini, M.; Cozzi, F. J.
Chem. Soc., Perkin Trans. 1 1982, 341-343.
(9) (a) Liu, G.; Cogan, D.; Ellman, J. A. J. Am. Chem. Soc. 1997, 119,
9913-9914. (b) Cogan, D. A.; Liu, G.; Kim, K.; Backes, B. J.; Ellman, J. A.
J. Am. Chem. Soc. 1998, 120, 8011-8019.
(10) Guangcheng Liu, unpublished results.
(11) Selva, M.; Tundo, P.; Marques, C. A. Synth. Commun. 1995, 23, 369-
378 and references therein.
(8) Annunziata, R.; Cinquini, M.; Cozzi, F. J. Chem. Soc., Perkin Trans.
1 1982, 341-343.
(12) Armstrong, I. J. D.; Wolfe, C. N.; Keller, J. L.; Lynch, J.; Bhupathy,
L. M.; Volante, R. P. Tetrahedron Lett. 1997, 38, 1531-1532.
10.1021/ja983217q CCC: $18.00 © 1999 American Chemical Society
Published on Web 12/19/1998

Communications to the Editor
J. Am. Chem. Soc., Vol. 121, No. 1, 1999 269
Table 2. 1,2-Additions of Organolithiums to N-Sulfinyl Ketimines
2
Figure 1. Model consistent with observed stereoselection for the Me3-
Al-mediated 1,2-addition of RLi to 2.
product
state with the bulky tert-butyl group preferring the equatorial
position (Figure 1). This model is supported by two pieces of
experimental data. First, the treatment of sulfinyl ketimine 2a with
a mixture of Me3Al and PhLi in toluene did not afford any 1,2-
addition product, even at room temperature after 12 h. This
indicates that the imine addition does not proceed via an alkyl
transfer from an aluminate intermediate, but likely occurs from
the organolithium species to a 2a-Me3Al complex. Second, the
use of coordinating ethereal solvents resulted in dramatic reduc-
tions in yields and drs, consistent with both Lewis acid activation
of the imine as well as organolithium coordination.
Me3Al
(equiv)
(config)a
yield
(%)
entry
2
R3
-3
dr
1
2
3
4
5
6
7
8
9
2a
2a
2b
2b
2f
Ph
Ph
Bu
Bu
Ph
0
1.1
0
1.1
0
1.1
1.1
1.1
0
(R)-3a
(R)-3a
(S)-3b
(S)-3b
(R)-3b
(R)-3b
(R)-3b
(S)-3ce
(R)-3ce
(R)-3ce
65
93
26
86
67
93
quant
61
54
94:6b
97:3b
99:1c
98:2c
63:37c
89:11c
99:1c
2f
Ph
2d
2a
2c
2c
Me
Bu
Me
Me
99:1d
82:18d
91:9d
10
1.1
82
a Refers to the configuration at the new stereocenter. b Diastereose-
lection determined by HPLC analysis of 3a. c Diastereoselection
determined by chiral HPLC analysis of benzamide derivative formed
after sulfinyl cleavage. d Diastereoselection determined by HPLC
analysis of (R)-MTPA derivatives formed after sulfinyl cleavage.
e Absolute configuration tentatively assigned on the basis of consistent
diastereofacial selectivity for entries 1-8.
The surprising selectivity for the 1,2-addition of PhLi to sulfinyl
ketimine 2f provides further insights into the mechanism. The
barriers for E:Z isomerization for arenesulfinyl imines have been
determined to be between 13 and 17 kcal/mol.14 Thus, due to
rapid isomerization, Me3Al-2f complexes may prefer one
isomeric conformation to an extent more in line with the observed
diastereoselection (9:1) than the parent sulfinyl ketimine (5:1).
However, 1H NMR experiments performed in toluene-d8 indicate
that the E:Z ratio is unaffected by the presence of Me3Al at both
+23 and -78 °C. The only observable change in the spectra upon
addition of Me3Al is a slight broadening of the R-protons of 2f.
The selectivity most likely arises from a difference in reaction
rates between the two Me3Al-2 isomers that are in rapid
equilibrium under the reaction conditions.
meric ratio (dr) (Table 2, entry 3). Again, the balance of the mass
was isolated as unconsumed N-sulfinyl ketimine 2b.
To enhance the product yield, the effect of Lewis acids,
including Al(O-i-Pr)3, trialkylaluminums, BF3-Et2O, and Et2Zn,
was investigated. Trialkylaluminums, such as Me3Al and i-Bu3-
Al, had the most dramatic effect on the 1,2-additions. Thus, the
slow addition of a toluene solution of Me3Al and N-sulfinyl
ketimines 2 to organolithiums consistently afforded 1,2-addition
products in higher yields, and typically with higher drs than the
same 1,2-additions performed in the absence of Me3Al (Table
2). One of the most striking results was the diastereocontrol
achieved for the Me3Al-mediated 1,2-addition of butyllithium to
ketimine 2f (R1 ) Me, R2 ) Bu). Despite the similar steric size
of the methyl and butyl substituents, the product was isolated in
a 9:1 ratio of (RS,S)-3b to (RS,R)-3b, which exceeds the substrates
initial E:Z ratio of 5.
In summary, the first general method for the asymmetric
synthesis of chiral acyclic R,R-dibranched amines is reported. The
1,2-addition substrates, tert-butanesulfinyl ketimines 2, are pre-
pared by the first direct condensation of a sulfinamide with
ketones, providing straightforward access to a wide variety of
sulfinyl ketimines. In the presence of Me3Al, tert-butanesulfinyl
ketimines react with organolithiums to provide tert-butanesulfi-
namides, 3, in high yields and with drs >9:1, and as high as 99:
1. Moreover, by the addition of Me3Al, the diastereoselection can
exceed the E:Z ratio of the sulfinyl ketimine substrate. Removal
of the sulfinyl group is achieved with stoichiometric HCl at room
temperature in less than 5 min, to afford the desired R,R-
dibranched amines. As will be reported in due course, tert-
butanesulfinyl ketimines are useful synthetic intermediates not
only for the addition of organolithiums to provide R,R-dibranched
amines, but also for the synthesis of other hindered amines by
the 1,2-addition of other nucleophiles.
Brief treatment of sulfinamides 3 with methanolic HCl provided
the amine hydrochlorides 4, which were isolated as the corre-
sponding benzamides 5 in high overall yields (eq 3). Although
stereochemical assignments of the amines 4 were complicated
by the inaccessibility of these amines by other sources, assign-
ments for 4a and 4b could be accomplished by chemical
correlation.13 Additions to N-sulfinyl ketimines 2a,b,d,f occur
consistently to the same face (entries 1-7; vide infra). This
provides for a reliable method for predicting the stereochemical
outcome of these 1,2-additions, and allows for the tentative
assignment of sulfinamide 3c, for which straightforward chemical
correlation was not possible.
Acknowledgment. We thank Guangcheng Liu for important contribu-
tions. The support of the NSF, Abbott Laboratories, and Berlex Bio-
sciences is gratefully acknowledged. D.A.C. thanks Pharmacia & Upjohn
for a graduate fellowship.
Supporting Information Available: Experimental details for all
procedures, as well as stereochemical assignments (9 pages, print/PDF).
See any current masthead page for ordering information and Web access
instructions.
The source of diastereocontrol is not yet rigorously understood,
but the product stereochemistry can be predicted by a sulfinyl-
directed alkyl transfer model via a cyclic six-membered transition
JA983217Q
(13) As described in the Supporting Information, 3a is converted to the
benzamide, and 3b is converted to the methyl ester of N-benzoyl R-meth-
ylvaline.
(14) (a) Davis, F. A.; Friedman, A. J.; Kluger, E. W. J. Am. Chem. Soc.
1974, 96, 5000-5001. (b) Davis, F. A.; Kluger, E. W. J. Am. Chem. Soc.
1976, 98, 302-303.