Stereoselective synthesis of α-silylamines by the direct addition of silyl anions to activated imines

Article abstract of DOI:10.1021/ol050244u

(Chemical Equation Presented) A highly efficient stereoselective synthesis of unusual α-silylamines via a direct silyl anion addition reaction is reported. This approach is convergent and avoids any problematic aza-Brook shifts of the anionic intermediate

Full text of DOI:10.1021/ol050244u

ORGANIC
LETTERS
2005
Vol. 7, No. 7
1403-1406
Stereoselective Synthesis of
-Silylamines by the Direct Addition of
Silyl Anions to Activated Imines
r
David M. Ballweg, Rebecca C. Miller, Danielle L. Gray, and Karl A. Scheidt*
Department of Chemistry, Northwestern UniVersity, 2145 Sheridan Road,
EVanston, Illinois 60208
scheidt@northwestern.edu
Received February 4, 2005
ABSTRACT
A highly efficient stereoselective synthesis of unusual
r-silylamines via a direct silyl anion addition reaction is reported. This approach is
convergent and avoids any problematic aza-Brook shifts of the anionic intermediates. The use of enantiopure tert-butanesulfinyl imines as the
electrophiles affords exceedingly high levels of diastereocontrol for the newly formed stereogenic carbon.
The stereoselective incorporation of silicon into molecules
is an important goal in organic synthesis due to the utility
of the resulting organosilanes. An unusual class of these
molecules is R-silylamines, and the efficient access to these
compounds is becoming increasingly significant due to their
unique biological1 and pharmacological properties.2 Surpris-
ingly, in light of the potential benefits of these chiral
compounds, there are relatively few stereoselective syntheses
of R-silylamines. In this paper, we report a highly diaste-
reoselective synthesis of protected R-silylamines (3) from
the addition of silyl anions to activated imines (1) by the
attenuation of potential aza-Brook processes of the anionic
intermediate 2 (eq 1).
these compounds, such as the additions of amines to
halomethylsilanes3 or by reduction of amides,4 involve
circuitous approaches that preclude asymmetric induction.
The palladium-catalyzed disilylation of an imine at elevated
temperatures has been reported, but this process remains very
limited in scope.5 A recently reported stereoselective ap-
proach to R-silylamines utilizing reverse aza-Brook rear-
rangements can be accomplished with high levels of enan-
tioselectivity in the presence of (-)-sparteine.6
In connection with our focus on investigating new methods
to incorporate silicon into organic molecules,7 we reasoned
that a convergent and flexible route to construct the desired
(2) (a) Chen, C. A.; Sieburth, S. M.; Glekas, A.; Hewitt, G. W.; Trainor,
G. L.; Erickson-Viitanen, S.; Garber, S. S.; Cordova, B.; Jeffry, S.; Klabe,
R. M. Chem. Biol. 2001, 8, 1161-1166. (b) Showell, G. A.; Mills, J. S.
Drug Discuss. Today 2003, 8, 551-556. (c) Kim, J.; Glekas, A.; Sieburth,
S. M. Bioorg. Med. Chem. Lett. 2002, 12, 3625-3627. (d) Mutahi, M. W.;
Nittoli, T.; Guo, L. X.; Sieburth, S. M. J. Am. Chem. Soc. 2002, 124, 7363-
7375.
(3) For a seminal example, see: Noll, J. E.; Speier, J. L.; Daubert, B. F.
J. Am. Chem. Soc. 1951, 3867-3871. For a representative synthesis, see:
Mariano, P. S.; Zhang, X.; Xu, W. J. Am. Chem. Soc. 1991, 113, 8863-
8878.
(4) (a) Shono, T.; Kise, N.; Kunimi, N.; Nomura, R. Chem. Lett. 1991,
2191-2194. (b) Kashimura, S.; Ishifune, M.; Muria, Y.; Murase, H.;
Shimomura, M.; Shono, T. Tetrahedron Lett. 1998, 39, 6199-6202. (c)
Fleming, I.; Mack, S. R.; Clark, B. P. Chem. Commun. 1998, 713-714.
(5) Tanaka, M.; Uchimaru, Y.; Williams, N. A. J. Chem. Soc., Dalton
Trans. 2003, 236-243.
Although amines possessing R-silyl groups have been
known for over 50 years, the established routes to synthesize
(1) (a) Banik, G. M.; Silverman, R. B. J. Am. Chem. Soc. 1990, 112,
4499-4507. (b) Tacke, R.; Kornek, T.; Heinrich, T.; Burschka, C.; Penka,
M.; Pulm, M.; Keim, C.; Mutschler, E.; Lambrecht, G. J. Organomet. Chem.
2001, 640, 140-165.
10.1021/ol050244u CCC: $30.25
© 2005 American Chemical Society
Published on Web 03/05/2005

Table 1. Optimization of Silyl Anion Addition
Table 2. Dimethylphenylsilyllithium Additions to Iminesa
entry
X
solvent equiv aniona yieldb (%) product
1
2
3
4
5
6
7
Ph (4a)
Benzyl (4b)
SO2Ph (4c)
P(O)Ph2 (4d)
P(O)Ph2 (4d)
P(O)Ph2 (4d)
THF
THF
THF
THF
toluene
THF
3
3
3
2
2
3
3
mixture
mixture
63
entry
R
yieldb (%)
product
6
7
7
7
8
1
2
3
4
5
6
7
8
9
Ph
88
64
61
74
75
90
86
77
55
83
91
58
7
9
52
1-naphth
2-naphth
3-MePh
39
10
11
12
13
14
15
16
17
18
19
88
P(O)(OEt)2 (4e) THF
53
4-MePh
a Relative to imine. b Isolated yield after chromatographic purification.
2-OMe-Ph
4-OMe-Ph
4-F-Ph
2-Cl-Ph
4-Cl-Ph
N-C-Si bonding triad of R-silylamines would involve the
direct addition of a silyl nucleophile to an appropriately
activated CdN system. Astonishingly, this convergent bond-
forming strategy has not been disclosed.8 The advantages
of this approach include high modularity with regard to
electrophile and nucleophile, potential control of the newly
formed stereogenic center, and ease of further synthetic
elaboration of the resulting protected amine. The main
potential problem with this direct approach is that the
resulting anion after silyl nucleophile addition could undergo
a 1,2-silyl shift (aza-Brook rearrangement), thereby locating
the silyl group on nitrogen and thus generating a carbanion.9
If this migratory aptitude of silicon can be controlled, then
the realization of this strategy is possible.
10
11
12
2-furyl
PhCH2dCH2
a Reaction at 0.2 M and 3 equiv of 5b. b Isolated yields after purification.
surveying various activating substituents on nitrogen, N-
diphenylphosphinylimines12 emerged as optimal substrates
for the silyl anion additions. Further optimization of the
reaction, including nucleophilic equivalents and the use of
additives, culminated in a general high-yielding procedure
employing 3 equiv of the silyllithium species in THF (entry
6).13
The exploration of this desired bond forming reaction was
initiated by surveying various imine electrophiles (Table 1,
eq 2). We anticipated that the nitrogen substituent would
play crucial roles of activating the carbon center and
subsequent localization of the resulting anion on the nitrogen
to avoid any aza-Brook rearrangements. At the outset of our
studies, we chose dimethylphenylsilyllithium as the nucleo-
phile due to its stability and ease of preparation.10 Initially,
complex mixtures were generated when the N-phenyl- and
N-benzylimines were employed (entries 1 and 2).11 We
postulated that a stronger electron-withdrawing group was
needed to delocalize the nitrogen anion generated in situ,
thereby potentially minimizing the aza-Brook pathway. After
With the optimized conditions identified, the scope of the
process with regard to electrophile structure has been
examined (Table 2, eq 3).14 The reaction affords good yields
of the protected R-silylamines when aryl aldimines are
employed.15 Furthermore, this methodology is relatively
insensitive to the position of substituents on the aromatic
ring.16 The use of an R,â-unsaturated imine (entry 12)
provides the 1,2-addition product (19) in moderate yield
(58%). Attempts to expand the scope of the reaction by
employing imines with enolizable protons (e.g., derived from
ketones and saturated aldehydes) have met with limited
success to date.17
We have also investigated the influence of silyl anion
structure on the reaction. Fortunately, a variety of silyl anions
could be added (Table 3, eq 4). Trimethylsilyllithium was
(6) (a) Sieburth, S. M.; Somers, J. J.; OHare, H. K. Tetrahedron 1996,
52, 5669-5682. (b) Barberis, C.; Voyer, N. Tetrahedron Lett. 1998, 39,
6807-6810. (c) Sieburth, S. M.; O’Hare, H. K.; Xu, J.; Chen, Y.; Liu, G.
Org. Lett. 2003, 5, 1859-1861. (d) Sieburth, S. M.; Liu, G. Org. Lett. 2003,
5, 4677-4679.
(7) (a) Clark, C. T.; Lake, J. F.; Scheidt, K. A. J. Am. Chem. Soc. 2004,
126, 84-85. (b) Clark, C. T.; Milgram, B. C.; Scheidt, K. A. Org. Lett.
2004, 6, 3977-3980.
(8) An approach with N,N′-dialkyliminium ions prepared in situ using
10 equiv of LiClO4 (5 M in Et2O) has been reported: Saidi, M. R.; Ipaktschi,
J.; Mojtahedi, M. M.; Naimi-Jamal, M. R. J. Chem. Soc., Perkin Trans. 1
1999, 3709-3711. (b) Strohmann, C.; Abele, B. C. In Organosilicon
Chemistry III; Auner, N., Weis, J., Eds.; VCH: Weinheim, 1997; pp 206-
210.
(12) (a) Krzyzanowska, B.; Stec, W. J. Synthesis 1982, 270-273. (b)
Jennings, W. B.; Lovely, C. J. Tetrahedron 1991, 47, 5561-5568.
(13) Fewer equivalents of silyl anion result in lower isolated yields.
(14) A Representative Proceedure. To a 25 mL Schlenk flask was
added 1 equiv of imine and THF (0.2 M), and the mixture was cooled to
-78 °C. To this solution was added 3 equiv of silyllithium (approximately
1 M in THF). After being stirred at -78 °C for 20 min, the reaction was
quenched with 5% acetic acid in methanol (10 mL) at -78 °C. The mixture
was diluted with ethyl acetate and then washed with water and brine. After
drying, the remaining residue was purified using flash chromatography to
yield pure protected R-silylamines.
(9) Duff, J. M.; Brook, A. G. Can. J. Chem. 1977, 55, 2589-2600.
(10) Fleming, I.; Roberts, R. S.; Smith, S. C. J. Chem. Soc., Perkin
Trans. 1 1998, 1209-1214. Solutions of 4 in THF can be stored at -30 °C
under nitrogen for several months.
(11) Preliminary data suggests that reductive coupling products are the
predominant species from these reactions. This intriguing possibility is
currently under investigation.
(15) The structures of these unusual compounds have been confirmed
by X-ray crystallography. See the Supporting Information for details.
(16) The use of nitro aromatic imines afforded no products, presumably
due to complications resulting from incompatibilities with the silyl anion.
(17) The acetophenone-derived imine afforded only 11% yield of desired
product (42% recovered imine). Studies to attenuate of the basicity of the
silyl anions to successfully engage this class of imine are currently underway.
1404
Org. Lett., Vol. 7, No. 7, 2005

Table 3. Survey of Silyl Anion Nucleophile Structurea
Table 4. Stereoselective Silyl Anion Additions
entry
R
yieldb (%) selectivity (dr)a product
entry anion
R1
R2
R3
yielda (%) product
1
2
3
4
5
6
7
Ph
4-Me-Ph
73
72
75
60
90
70
72
95:5
95:5
95:5
90:10
95:5
95:5
95:5
25
26
27
28
29
30
31
1
2
3
4
5
6
5a
5b
5c
5d
5e
5f
CH3 CH3 CH3
CH3 CH3 Ph
CH3 Ph
Ph Ph
CH3 CH3 2,4-Me2Ph
CH3 CH3 5-Me-2-furyl
67
86
80
8
20
14
21
22
23
24
4-MeO-Ph
1-naphthyl
2-naphthyl
PhCH2dCH2
t-Bu
Ph
Ph
53
28
a Determined by 500 MHz 1H NMR. b Isolated yields after purification.
a Reaction at 0.2 M and 3 equiv of 5. b Isolated yields after purification.
sulfinyl oxygen and silicon atom in the solid state.23 The
sizable substituents around the central C11 carbon promote
significantly large bond distortions from ideal sp3 bond
angles. To our surprise, the C11 (R)-diastereomer favored
in this process (with the (R)-sulfinyl imine) is the opposite
isomer than the one predicted via the closed transition-state
model suggested by Ellman for the majority of organome-
tallic additions.24,25 Although unusual, it has been observed
previously that the selectivity for nucleophilic additions to
these N-butanesulfinylimines is highly dependent on the
organometallic species and reaction conditions.26
added in moderate yield (67%, entry 1), but we turned our
attention to silyl nucleophiles possessing aryl groups since
arylsilanes have the potential to undergo further synthetic
manipulations.18 The silyl anion can accommodate up to two
phenyl substituents in these additions (entries 2 and 3), but
the triphenylsilyllithium anion is presumably too hindered
to undergo nucleophilic addition and thus affords a low yield
of the desired amide 22. The 2,4-dimethylphenyl-dimethyl-
silyl anion and the furyl silyl anion undergo smooth addition
(entries 5 and 6), although the yields in these cases are only
moderate at best. It is well documented that the structure of
the aryl component of these anions greatly impacts their
stability and utility in synthesis as nucleophiles.19
With the above information in hand, we turned our
attention to developing a stereoselective variant of our direct
silyl group installation. Although the development of chiral
versions of N-diphenylphosphinyl imines was initially pur-
sued, we rapidly discovered that the exposure of tert-
butanesulfinyl imines20 to silyl anions (such as 5b) provides
good yields and excellent levels of diastereoselection (>90:
10) for the R-silylamine products (Table 4, eq 5).21 The
reaction provides uniformly high selectivities for sulfinyl
imines derived from aromatic aldehydes, but like the
N-diphenylphosphinylimines, saturated imines are not viable
substrates for this reaction, presumably due to the presence
of enolizable protons.
To determine the absolute configuration of the newly
formed stereocenter in this process, single crystals of 31 were
grown and subjected to X-ray diffraction (Figure 1).22
Interestingly, the highly unusual S-N-C-Si bonding ar-
rangement shows no interaction between the Lewis basic
Figure 1. ORTEP structure of 31 at 50% ellipsoid probability.
Selected bond distances (Å) and angles (deg): N-S, 1.63; Si-
C11, 1.91; N-C11, 1.49; N-C11-Si, 102.8; S-N-C11, 117.9;
Si-C11-C15, 121.0.
(18) For selected examples of transformations of arylsilanes, see: (a)
Bonini, B. F.; Comes-Franchini, M.; Fochi, M.; Laboroi, F.; Mazzanti, G.;
Ricci, A.; Varchi, G. J. Org. Chem. 1999, 64, 8008-8013. (b) Denmark,
S. E.; Sweis, R. F. Chem. Pharm. Bull. 2002, 50, 1531-1541. (c) Ichikawa,
J.; Ishibashi, Y.; Fukui, H. Tetrahedron Lett. 2003, 44, 707-710.
(19) Corey, E. J.; Lee, T. W. Org. Lett. 2001, 3, 3337-3339 and
references therein.
(20) For reviews of sulfinyl imines in synthesis, see: (a) Zhou, P.; Chen,
B.-C.; Davis, F. A. Tetrahedron 2004, 60, 8003-8030. (b) Davis, F. A.;
Zhou, P.; Chen, B. C. Chem. Soc. ReV. 1998, 27, 13-18. (c) Ellman, J. A.;
Owens, T. D.; Tang, T. P. Acc. Chem. Res. 2002, 35, 984-995.
(21) For a related approach utilizing trialkylstannane nucleophiles, see:
Kells, K. W.; Chong, J. M. Org. Lett. 2003, 5, 4215-4218.
With a direct method for the stereoselective synthesis of
these unusual polyatomic molecules in hand, we are currently
exploring their synthetic potential. The phosphorus- and
sulfur-based activating groups for these reactions can be
removed easily in good yield by exposure to acidic conditions
(Scheme 1). Furthermore, the resulting primary amines can
be further elaborated to the carbamate (32), notably without
Org. Lett., Vol. 7, No. 7, 2005
1405

nylphosphinyl and N-tert-butanesulfinyl functional groups
attenuates potentially competing aza-Brook rearrangements
and therefore facilitates high yields of R-silylamines. The
overall process currently accommodates nonenolizable imines
and various silyl anion structures. Further investigations to
delineate the synthetic utility of these unique compounds are
underway in our laboratory and will be reported in due
course.
Scheme 1. Synthetic Transformations of R-Silyl Compounds
7 and 25a
a Key: (a) 4 N HCl in dioxane; (b) (t-BuOCO)2O, THF; (c) concd
HCl.
Acknowledgment. Financial support for this work has
been provided by Northwestern University and the NSF
(CHE-0348979). We thank Amgen for unrestricted support
in the form of a New Investigator Award and R.C.M. thanks
NU for a Summer Undergraduate Research Fellowship. We
acknowledge Dr. Joern Winterfeld (Wacker Chemical Corp.)
for providing organosilanes used in this work.
loss of the silyl group and in the case of 25, without
epimerization of the newly formed stereogenic center.
In conclusion, the addition of silyl nucleophiles to activated
imines is a direct and highly stereoselective route to the
synthesis of chiral R-silylamines. The use of N-diphe-
Supporting Information Available: Experimental pro-
cedures and characterization data for new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(22) Information regarding the X-ray analysis of 31 is as follows: crystal
system: orthorhombic, space group P212121, unit cell dimensions 6.4 ×
16.6 × 18.3 Å. Data were collected on a Bruker Smart 1000 CCD with
Mo KR radiation. CCDC 257698 (ent-25), CCDC 257699 (31), and CCDC
257700 (11) contain the supplementary crystallographic data for these
structures. These data can be obtained online free of charge (or from the
Cambridge Crystallographic Data Centre, 12, Union Road, Cambridge CB2
1EZ, U.K.; fax (+44) 1223-336-033; deposit@cdc.cam.ac.uk). For an X-ray
structure of a related R-silylamine, see: Bolm, C.; Kasyan, A.; Drauz, K.;
Gunther, K.; Raabe, G. Angew. Chem., Int. Ed. 2000, 39, 2288-2290.
(23) For an example of Si-O interactions in the solid state, see: Dixon,
D. A.; Hertler, W. R.; Chase, D. B.; Farnham, W. B.; Davidson, F. Inorg.
Chem. 1988, 27, 4012-4018 and references therein. For a review of
hypervalent silicon, see: Chuit, C.; Corriu, R. J. P.; Reye, C.; Young, J. C.
Chem. ReV. 1993, 93, 1371-1448.
OL050244U
(24) Liu, G. C.; Cogan, D. A.; Ellman, J. A. J. Am. Chem. Soc. 1997,
119, 9913-9914.
(25) The X-ray crystallographic structure of ent-25 also displays a high
preference for this unusual diastereomeric pattern. In contrast, the opposite
diastereoselectivity is observed with seemingly related tralkylstannyl anion
additions, see ref 19.
(26) (a) Cogan, D. A.; Liu, G. C.; Ellman, J. Tetrahedron 1999, 55,
8883-8904. (b) For an example of diastereoselective phosphite additions
to enantiopure sulfinylimines, see: Lefebvre, I. M.; Evans, S. A., Jr. J.
Org. Chem. 1997, 62, 7532-7533.
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Org. Lett., Vol. 7, No. 7, 2005