Highly selective α-acylvinyl anion additions to imines

Article abstract of DOI:10.1021/ol802227t

α-Hydroxypropargylsilanes undergo rearrangement to form reactive lithium allenolates. The resulting ∞-acylvinyl anion equivalents undergo highly selective additions to N-tert-butanesulfinyl imines generating/β- substituted aza-MBH-type products. High yields are achieved for a wide range of α-hydroxypropargylsilanes as well as for a diverse selection of imines. The reactions proceed with good to excellent diastereoselectivity and regioselectivity (8-20:1 major/Σ minor) favoring the Z-isomer of the alkene.

Full text of DOI:10.1021/ol802227t

ORGANIC
LETTERS
2008
Vol. 10, No. 22
5227-5230
Highly Selective r-Acylvinyl Anion
Additions to Imines
Troy E. Reynolds, Michael S. Binkley, and Karl A. Scheidt*
Department of Chemistry, Northwestern UniVersity, EVanston, Illinois 60208
scheidt@northwestern.edu
Received September 24, 2008
ABSTRACT
r-Hydroxypropargylsilanes undergo rearrangement to form reactive lithium allenolates. The resulting r-acylvinyl anion equivalents undergo
highly selective additions to N-tert-butanesulfinyl imines generating ꢀ-substituted aza-MBH-type products. High yields are achieved for a wide
range of r-hydroxypropargylsilanes as well as for a diverse selection of imines. The reactions proceed with good to excellent diastereoselectivity
and regioselectivity (8-20:1 major/∑ minor) favoring the Z-isomer of the alkene.
Optically active, chiral amines are valuable and ubiquitous
compounds found abundantly in many biologically active
natural products and pharmaceutical agents.1 Consequently,
synthetic methods that access these useful amines in a
modular and stereocontrolled manner are exceedingly im-
portant. One such approach is the aza-Morita-Baylis-
Hillman (aza-MBH) reaction, which involves the Lewis base-
catalyzed addition of an electron-deficient alkene and an
activated imine (Scheme 1).2 This formal R-acylvinyl anion
addition generates highly functionalized, allylic amines
efficiently and in an atom-economical fashion.3-5 Recently,
the aza-MBH reaction has been the subject of many synthetic
advances. Particularly, the development of enantioselective
variants has allowed for the rapid generation of optically
active amines in a highly convergent manner.6 Unfortunately,
this reaction remains limited in many aspects. Useful
asymmetric aza-MBH reactions are reported only for aromatic-
substituted imines, and the electron deficient olefin (e.g.,
vinyl ketone or acrylate) is typically unsubstituted at the
ꢀ-position of the alkene, thus further restricting the substrate
scope. Due to these problematic restrictions and the sub-
stantial value of the chiral amine products, alternative
methods that access allylic amines with similar substitution
patterns as the aza -MBH reaction with far greater substrate
scope are essential.7
Our research group has focused on the development of
new reactions utilizing nontraditional nucleophiles for the
construction of unconventional carbon-carbon bonds.8 One
particular area of current interest is the addition of R-acylvi-
(1) For recent reviews, see: (a) Bloch, R. Chem. ReV. 1998, 98, 1407.
(b) Enders, D.; Reinhold, U. Tetrahedron: Asymmetry 1997, 8, 1895. (c)
Kobayashi, S.; Ishitani, H. Chem. ReV. 1999, 99, 1069. (d) Friestad, G. K.;
Mathies, A. K. Tetrahedron 2007, 63, 2541.
(6) For examples of enantioselective aza-MBH reactions, see: (a) Shi,
M.; Xu, Y.-M. Angew. Chem., Int. Ed. 2002, 47, 4507. (b) Kawahara, S.;
Nakano, A.; Esumi, T.; Iwabuchi, Y.; Hatakeyama, S. Org. Lett. 2003, 5,
3103. (c) Balan, D.; Adolfsson, H. Tetrahedron Lett. 2003, 44, 2521. (d)
Shi, M.; Chen, L. H. Chem. Comm. 2003, 1310. (e) Shi, M.; Xu, Y. M.;
Shi, Y. L. Chem.-Eur. J. 2005, 11, 1794. (f) Raheem, I. T.; Jacobsen,
E. N. AdV. Synth. Catal. 2005, 347, 1701. (g) Matsui, K.; Takizawa, S.;
Sasai, H. J. Am. Chem. Soc. 2005, 127, 3680. (h) Shi, M.; Chen, L. H.; Li,
C. Q. J. Am. Chem. Soc. 2005, 127, 3790. (i) Liu, Y. H.; Chen, L. H.; Shi,
M. AdV. Synth. Catal. 2006, 348, 973. (j) Vesely, J.; Dziedzic, P.; Cordova,
A. Tetrahedron Lett. 2007, 48, 6900. Also, see ref 2d.
(2) Reviews of aza-MBH reaction, see: (a) Basavaiah, D.; Rao, A. J.;
Satyanarayana, T. Chem. ReV. 2003, 103, 811. (b) Basavaiah, D.; Rao, K. V.;
Reddy, R. J. Chem. Soc. ReV. 2007, 36, 1581. (c) Shi, Y. L.; Shi, M. Eur.
J. Org. Chem. 2007, 2905. (d) Masson, G.; Housseman, C.; Zhu, J. P.
Angew. Chem., Int. Ed. 2007, 46, 4614.
(3) Chinchilla, R.; Najera, C. Chem. ReV. 2000, 100, 1891
(4) Trost, B. M. Science 1991, 254, 1471
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.
.
.
10.1021/ol802227t CCC: $40.75
Published on Web 10/30/2008
2008 American Chemical Society

nyl anion equivalents from easily accessible precursors. We
have demonstrated that silyloxyallenes, which can be pre-
pared directly from R-hydroxypropargylsilanes via a base-
initiated rearrangement, serve as latent allenolates and
valuable R-acylvinyl anion equivalents. In the presence of
catalytic Lewis acid or base, silyloxyallenes undergo addi-
tions to aldehydes in excellent yields for a wide range of
substrates.9,10 These reactions are highly selective forming
Z-substituted R,ꢀ-unsaturated carbinol products exclusively.
Excellent enantioselectivities can be achieved as well using
a Cr(III)-catalyst.11 Herein, we address the limitations of the
aza-MBH reaction by adding silyloxyallene-derived
R-acylvinyl anion equivalents to imines to afford allylic
amines with excellent levels of selectivity and yield (Scheme
1, bottom).
allenolate 3, and addition to imine 4 in a single-flask
operation (Scheme 2). If successful, this method would
generate ꢀ-substituted aza-MBH-type products rapidly with
exquisite stereocontrol in a single flask.
Scheme 1. R-Acylvinyl Anion Additions to Imines
Our synthetic strategy explored the diastereoselective
R-acylvinyl anion additions to N-tert-butanesulfinyl imines.
Elegant work by Davis and Ellman has previously demon-
strated that metal reagents (e.g., Grignard and organolithium
reagents, metal enolates) undergo 1,2-additions to optically
active sulfinyl imines with excellent stereocontrol.12 Due to
the mild nucleophilicity of silyloxyallenes, we postulated that
more reactive lithium allenolates, which can be prepared
readily from the silyloxyallene via the House-Stork desi-
lylation method, should undergo addition to the N-tert-
butanesulfinyl imine.13 More desirably, we sought to begin
directly from R-hydroxypropargylsilane 1, conducting the
rearrangement to silyloxyallene 2, desilylation to lithium
Scheme 2
.
Addition of R-Hydroxypropargylsilanes to
N-tert-Butane Sulfinylimines
(7) For alternative approaches to aza-MBH-type products, see: (a) Wei,
H. X.; Hook, J. D.; Fitzgerald, K. A.; Li, G. G. Tetrahedron: Asymmetry
1999, 10, 661. (b) Li, G. G.; Wei, H. X.; Whittlesey, B. R.; Batrice, N. N.
J. Org. Chem. 1999, 64, 1061. (c) Trost, B. M.; Oslob, J. D. J. Am. Chem.
Soc. 1999, 121, 3057. (d) Reginato, G.; Mordini, A.; Valacchi, M.; Piccardi,
R. Tetrahedron: Asymmetry 2002, 13, 595. (e) Mori, M.; Nakanishi, M.;
Kajishima, D.; Sato, Y. J. Am. Chem. Soc. 2003, 125, 9801. (f) Cho, C. W.;
Kong, J. R.; Krische, M. J. Org. Lett. 2004, 6, 1337. (g) Trost, B. M.;
Chung, C. K. J. Am. Chem. Soc. 2006, 128, 10358. (h) Nemoto, T.;
Fukuyama, T.; Yamamoto, E.; Tamura, S.; Fukuda, T.; Matsumoto, T.;
Akimoto, Y.; Hamada, Y. Org. Lett. 2007, 9, 927. (i) Utsumi, N.; Zhang,
H. L.; Tanaka, F.; Barbas, C. F. Angew. Chem., Int. Ed. 2007, 46, 1878. (j)
Yamaguchi, A.; Aoyama, N.; Matsunaga, S.; Shibasaki, M. Org. Lett. 2007,
9, 3387
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(8) (a) Mattson, A. E.; Bharadwaj, A. R.; Scheidt, K. A. J. Am. Chem.
Soc. 2004, 126, 2314. (b) Myers, M. C.; Bharadwaj, A. R.; Milgram, B. C.;
Scheidt, K. A. J. Am. Chem. Soc. 2005, 127, 14675. (c) Chan, A.; Scheidt,
K. A. Org. Lett. 2005, 7, 905. (d) Mattson, A. E.; Zuhl, A. M.; Reynolds,
T. E.; Scheidt, K. A. J. Am. Chem. Soc. 2006, 128, 4932. (e) Mattson,
A. E.; Scheidt, K. A. J. Am. Chem. Soc. 2007, 129, 4508. (f) Chan, A.;
Starting with R-hydroxypropargylsilane 1a, we examined
the reaction with tert-butanesulfinyl imine 4a. Lithium
allenolate 3a was prepared in situ using n-BuLi in THF at 0
°C followed by addition of imine 4a. Gratifyingly, the
ꢀ-substituted aza-MBH-type product was obtained in 70%
yield (Table 1, entry 1). Unfortunately, the stereoselectivity
of the addition is low (2:1 major/sum of minor). The
selectivity of the addition can be improved by lowering the
temperature prior to the addition of the imine (entries 2-3).
However, the stereoselectivity is still only 5:1 at -78 °C
(entry 3). A variety of additives were examined to enhance
the selectivity. While forming different metal allenolates via
transmetallation led to low yields and selectivities, the
addition of hexamethylphosphoramide (HMPA) to the reac-
tion mixture improves the stereolectivity of the addition
(entry 4-6). In fact, increasing the amount of HMPA (5:1
HMPA/n-BuLi, entry 6) gives the optimal results. The
product was obtained exclusively as the Z-isomer in 75%
yield and 20:1 dr.
Scheidt, K. A. J. Am. Chem. Soc. 2007, 129, 5334
.
(9) (a) Reynolds, T. E.; Bharadwaj, A. R.; Scheidt, K. A. J. Am. Chem.
Soc. 2006, 128, 15382. (b) Reynolds, T. E.; Stern, C. A.; Scheidt, K. A.
Org. Lett. 2007, 9, 2581
.
(10) For previous examples of silyloxyallenes as R-acylvinyl anion
equivalents, see: (a) Merault, G.; Bourgeoi, P.; Dunogues, S.; Duffaut, N.
J. Org. Chem. 1974, 76, 17. (b) Fleming, I.; Perry, D. A. Tetrahedron 1981,
37, 4027. (c) Kato, M.; Kuwajima, I. Bull. Chem. Soc. Jpn. 1984, 57, 827.
(d) Reich, H. J.; Eisenhart, E. K.; Olson, R. E.; Kelly, M. J. J. Am. Chem.
Soc. 1986, 108, 7791. (e) Stergiades, I. A.; Tius, M. A. J. Org. Chem. 1999,
64, 7547. (f) Yoshizawa, K.; Shioiri, T. Tetrahedron 2007, 63, 6259. (g)
Mueller, A. J.; Jennings, M. P. Org. Lett. 2007, 9, 5327
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(11) Reynolds, T. E.; Scheidt, K. A. Angew. Chem., Int. Ed. 2007, 46,
7806.
(12) For reviews, see: (a) Zhou, P.; Chen, B.-C.; Davis, F. A. In
AdVances in Sulfur Chemistry; Raynor, C. M.; Ed.; JA Press: Stamford,
CT, 2000; Vol 2, pp 249-282. (b) Ellman, J. A.; Owens, T. D.; Tang,
T. P. Acc. Chem. Res. 2002, 35, 984.
(13) (a) Stork, G.; Hudrlik, P. F. J. Am. Chem. Soc. 1968, 90, 4462. (b)
House, H. O.; Czuba, L. J.; Gall, M.; Olmstead, H. D. J. Org. Chem. 1969,
34, 2324.
5228
Org. Lett., Vol. 10, No. 22, 2008

Table 1. Optimization of Reactiona
Table 2. R-Hydroxypropargylsilane Scopea
entry
R1
R2
Ph (1a)
n-Bu (1b)
t-Bu (1c)
(CH2)3OTBS (1d)
Ph (1e)
Ph (1f)
yield (%)b major/Σ minorc
1
2
3
4
Me
Me
Me
Me
Et
75
77
83
85
70
70
86
20:1 (5)
17:1 (6)
20:1 (7)
13:1 (8)
20:1 (9)
20:1 (10)
20:1 (11)
entry
conditions
yield (%)b major/Σ minorc
1
2
3
4
5
6
0 °C
-40 °C
-78 °C
-78 °C, 2.5 equiv HMPA
-78 °C, 5.0 equiv HMPA
-78 °C, 12.5 equiv HMPA
70
61
64
64
73
75
2:1
3:1
5:1
6:1
7:1
5
6
i-Pr
t-Bu Ph (2g)
7d
20:1
a Two equivalents of R-hydroxypropargylsilane, 2.5 equiv of n-BuLi,
12.5 equiv of HMPA, 1 equiv of 4a. b Yield of isolated product after column
chromatography. c Determined by 1H NMR spectroscopy (500 MHz).
d Reaction was conducted starting from the silyloxyallene, see Supporting
Information for details.
a Two equivalents of 1a, 2.5 equiv of n-BuLi, 1 equiv of 4a. b Yield of
isolated product after column chromatography. Determined by H NMR
spectroscopy (500 MHz).
c
1
With the optimized bond-forming conditions in hand, the
scope of the R-acylvinyl anion addition was investigated.
First, various R-hydroxypropargylsilanes were studied (Table
2). The reaction was discovered to be general for the
propargylsilane component. A wide range of ꢀ-substituents
(R2) is accommodated. Aryl and alkyl substituted propar-
gylsilanes give good yields and selectivities (entries 1 and
2). A bulky tert-butyl group can be incorporated as well as
a TBS-protected alcohol (entries 3 and 4). Substitution at
R1 was also explored. Ethyl, iso-propyl, and tert-butyl
substituted lithium allenolates are all quality substrates
(entries 5-7). Each of the ꢀ-substituted products is formed
in high yields with good to excellent stereoselectivity
(13-20:1). The effect of the imine on the reaction was
investigated as well (Table 3). Various electron-rich and
electron-poor aromatic imines react with R-hydroxypropar-
gylsilane 1b (entries 1-5). Excellent yields are achieved as
well as regio- and diastereoselectivities. Selective 1,2-
addition is observed with cinnamyl imine 4g in 71% yield,
20:1 Z/E, and 20:1 dr (entry 6). Aliphatic imines are also
tolerated (entries 7-10). Notably, R-substituted imines are
reactive partners. Both iso-propyl and cyclohexyl imines
undergo additions in good yields and stereoselectivity (entries
8 and 9). R-Hydroxypropargylsilane 1b even reacts with tert-
butyl imine 4j with good results (entry 10). Upon examining
the scope of the transformation, we explored the stereo-
chemical aspects of the R-acylvinyl anion addition. First, the
absolute stereochemistry of the addition product 21 was
determined to be S after single crystal X-ray crystallography
(Scheme 3).
Table 3. tert-Butane Sulfinylimine Scopea
entry
R
yield (%)b
major/Σ minorc
1
2
3
4
5
6
7
8
9
10
Ph (4b)
84
85
77
81
83
71
77
94
84
74
13:1 (12)
14:1 (13)
11:1 (14)
20:1 (15)
13:1 (16)
20:1 (17)
17:1 (6)
10:1 (18)
8:1 (19)
8:1 (20)
4-Cl-Ph (4c)
4-Br-Ph (4d)
4-OMe-Ph (4e)
2-Cl-Ph (4f)
PhCH)CH (4g)
PhCH2CH2 (4a)
i-Pr (4h)
CyHex (4i)
t-Bu (4j)
a Two equivalents of 1b, 2.5 equiv of n-BuLi, 12.5 equiv of HMPA, 1
equiv of imine. b Yield of isolated product after column chromatography.
c
1
Determined by H NMR spectroscopy (500 MHz).
explore this potential reaction pathway, two equivalents of
the lithium allenolate, prepared from silyloxyallene 2g, and
a single equivalent of imine 4a were combined under the
optimized conditions. After full consumption of the imine
(as measured by thin layer chromatography), chlorodimeth-
ylphenylsilane (2 equiv) was added and the reaction mixture
was allowed to warm to 0 °C to silylate the unreacted
allenolate (Scheme 4, top). The reaction was quenched with
pH ) 7 phosphate buffer and, after an extraction with ethyl
acetate, the unreacted silyloxyallene was purified by flash
chromatography on silica gel. Analysis of the remaining
silyloxyallene (as determined by HPLC with a Chiralcel-
Since the reaction involves two chiral reagents (racemic
lithium allenolate and optically active imine), a kinetic
resolution of the allene during the reaction is possible.14 To
(14) Masamune, S.; Choy, W.; Petersen, J. S.; Sita, L. R. Angew. Chem.,
Int. Ed. 1985, 24, 1.
Org. Lett., Vol. 10, No. 22, 2008
5229

Scheme 3
.
Absolute Stereochemistry and ORTEP of 21
Scheme 4. Mechanistic Studies
The resulting R-acylvinyl anion equivalent undergoes highly
selective additions to N-tert-butanesulfinyl imines generating
ꢀ-substituted aza-MBH-type products. High yields are
achieved for a wide range of R-hydroxypropargylsilanes as
well as for a diverse selection of imines. The reactions
proceed with good to excellent stereoselectivity (8-20:1)
favoring the Z-isomer of the alkene. Further studies of
R-hydroxypropargylsilanes and silyloxyallenes as R-acylvinyl
anion equivalents and applications of these ꢀ-substituted aza-
MBH-type products are currently ongoing.
OD column) indicated that 2g was optically enriched at 32%
ee. From this result, one enantiomer of the allene appears to
undergo preferential reaction with the chiral imine.
To explain the high stereoselectivity exhibited in this
reaction, we propose the R-acylvinyl anion addition to go
through two diastereoconvergant transition states exhibiting
slightly different rates (Scheme 4, bottom). In the presence
of HMPA, we postulate that a noncoordinated allenolate is
formed which will then proceed through open transition states
via synclinal disposition minimizing dipole-dipole interac-
tions.15,16 The high diastereoselectivity of the addition is
achieved since the “naked” allenolate will most likely attack
the imine opposite the bulky tert-butyl group. The high
regioselectivity favoring the Z-alkene product is then due to
the electrophiles preferential approach away from the R2
substituent. Interactions with the R1 substituent lead to the
difference in rates of addition of each enantiomer of allene.
In conclusion, R-hydroxypropargylsilanes undergo facile
rearrangement to form reactive lithium allenolates in situ.
Acknowledgment. Financial support for this work has
been provided in part by the NSF (CAREER). We thank
Abbott Laboratories, Amgen, GlaxoSmithKline, AstraZen-
eca, and Boerhinger-Ingelheim for generous research support
and Wacker Chemical Corp. and FMCLithium for reagent
support. K.A.S. is a fellow of the A. P. Sloan Foundation.
Funding for the NU Integrated Molecular Structure Education
and Research Center (IMSERC) has been furnished in part
by the NSF (CHE-9871268). T.E.R. is a recipient of a
2007-2008 ACS Division of Organic Chemistry fellowship
sponsored by Bristol-Myers Squibb. M.S.B. thanks North-
western University for a Summer Research Fellowship.
Supporting Information Available: Experimental pro-
cedures and spectral data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
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Org. Lett., Vol. 10, No. 22, 2008