Lewis base activation of Lewis acids. Addition of silyl ketene acetals to aldehydes

Article abstract of DOI:10.1021/ja0282947

The weak Lewis acid silicon tetrachloride can be activated by catalytic amounts of the chiral bisphosphoramide (R,R)-3 to form a highly reactive, chiral trichlorosilyl cation which is an extremely effective promoter of aldol addition reactions between ald

Full text of DOI:10.1021/ja0282947

Published on Web 10/19/2002
Lewis Base Activation of Lewis Acids. Addition of Silyl Ketene Acetals to
Aldehydes
Scott E. Denmark,* Thomas Wynn, and Gregory L. Beutner
Roger Adams Laboratory, Department of Chemistry, UniVersity of Illinois, Urbana, Illinois 61801
Received August 27, 2002
Table 1. Aldol Addition with
Chiral Lewis acids are widely used in asymmetric catalysis for
the selective activation of electrophilic functional groups, in
particular, carbonyls.1 The vast array of reactions that are susceptible
to chiral Lewis acid catalysis2 are guided by a common design
principle: an achiral metal species is transformed by ligand
substitution with a chiral adjuvant into a chiral metal complex. A
consequence of ligand binding, however, is a decrease in the
inherent electrophilicity of the metal atom, thus requiring either a
high association constant or preformation of the complex to avoid
competition from an achiral background reaction.3 Interestingly,
not all Lewis acid-base interactions lead to diminished electro-
philicity.4 In a recent communication, we described the activation
of the weak Lewis acid SiCl4 by a strongly Lewis basic phosphor-
amide.5 Binding of the phosphoramide polarizes the silicon-
chlorine bonds, leading to ionization of a chloride and formation
of a catalytically active, pentacoordinate trichlorosilyl cation i (eq
1).6
1-(tert-Butyldimethylsilyloxy)-1-methoxyethene (1)a
entry
R
product
yield, %b
erc
1
2
3
4
5
6
7
8
9
C6H5 (2a)
4ad
4b
4c
4d
4e
4f
4g
4h
4i
97e
98
98
97
97
96.5:3.5
90:10
97:3
1-naphthyl (2b)
2-naphthyl (2c)
4-CH3C6H4 (2d)
4-CH3OC6H4 (2e)
4-CF3C6H4 (2f)
(E)-PhCHdCH (2g)
(E)-PhCHdC(CH3) (2h)
2-furyl (2i)
97:3
98.5:1.5
95.5:4.5
97:3
72.5:27.5
93.5:6.5
94:6
97
95e
98
94e
86e
72e
10
11
cyclohexyl (2j)f
PhCH2CH2 (2k)f
4j
4k
90.5:9.5
a All reactions employed 1.1 equiv of SiCl4, 1.2 equiv of 1, and 0.05
equiv of (R,R)-3 at 0.2 M in CH2Cl2 at -78 °C for 15 min. b Yield of
analytically pure material. c Determined by CSP-SFC. d R absolute config-
uration.9 e Chromatographically homogeneous material. f Reaction time
6 h.
In the Lewis-base-catalyzed reactions of trichlorosilyl enolates
and allyltrichlorosilanes,7 the nucleophilic fragment is attached to
the electrophilic silicon atom. Association of the electrophile and
the chiral activator generates a single species which contains all of
the reaction partners organized about the silicon center for a
selective reaction via a closed transition structure. However, the
scope of the process is limited by the ability to synthesize a given
trichlorosilyl nucleophile. The use of SiCl4 as an exogenous Lewis
acid releases this synthetic constraint and allows for the conscription
of many structurally diverse, main group organometallic nucleo-
philes.5 To expand the scope of this Lewis-base-activated, SiCl4-
mediated process, we have begun to explore the reactivity and
selectivity of other main group nucleophiles. Guided by the
nucleophilicity scales developed by Mayr and co-workers,8 we were
particularly intrigued by the high reactivity of silyl ketene acetals.
Herein, we report our initial studies into the highly enantio- and
diastereoselective addition of acetate and propanoate derived silyl
ketene acetals to a variety of aromatic, olefinic, propargylic, and
aliphatic aldehydes.
provided 4a in good yield and selectivity (Table 1, entry 1). ReactIR
studies revealed that complete consumption of the aldehyde
occurred in under 5 min. In contrast, the reaction of allyltributyl-
stannane under similar conditions required almost 1 h. Furthermore,
it was determined that the absolute configuration of the newly
formed stereocenter is R,9 in agreement with the sense of asym-
metric induction observed in the allylation reaction.
Table 1 contains the results of an aldehyde survey for this
reaction. In almost all cases, equally high reactivity and, more
importantly, selectivity are maintained. Both electron-rich and
electron-poor aromatic aldehydes react rapidly (entries 4-6),
yielding products with comparable selectivity to benzaldehyde.
Different aromatic structures, such as naphthyl and furyl, also
provide products in good yields and high selectivities (entries 2, 3,
9). Olefinic aldehydes show high selectivity, although the presence
of an R substituent did lead to an erosion in selectivity (entries 7,
8). Most importantly, aliphatic aldehydes reacted, albeit at a slightly
slower rate, producing the aldol adducts in good yields and
selectivities (entries 10, 11). These results are particularly note-
worthy because aliphatic aldehydes have typically failed as useful
substrates in the reactions with other trichlorosilyl-based nucleo-
philes.7,10
Initial investigations focused on the simple, but highly reactive,
ketene acetal 1. The addition to benzaldehyde (2a) in the presence
of 5 mol % of the dimeric phosphoramide (R,R)-3 at -78 °C
* To whom correspondence should be addressed. E-mail: denmark@scs.uiuc.edu.
9
10.1021/ja0282947 CCC: $22.00 © 2002 American Chemical Society
J. AM. CHEM. SOC. 2002, 124, 13405-13407
13405

C O M M U N I C A T I O N S
Table 2. Aldol Reaction with Propanoate-Derived
Table 3. Aldol Reaction with
tert-Butyldimethylsilyl Ketene Acetalsa
(E)-1-(tert-Butoxy-propenyl)-tert-butyldimethylsilane (5d)a
yield, %b
drc
erd
entry
R
E:Zb
product
yield, %c
erd
drb
entry
R
product
1
2
3
4
5
Me (5a)
Et (5b)
Ph (5c)
t-Bu (5d)
t-Bu (5d)
82:18
95:5
94:6
95:5
12:88
6a
98
78
98
93f
73
86:14
88:12
94:6
>99:1
>99:1
99:1
98:2
94:6
99:1
99:1
1
2
3
4
5
6
7
8
C6H5 (2a)
1-naphthyl (2b)
2-naphthyl (2c)
4-CH3OC6H4 (2e)
4-CF3C6H4 (2f)
(E)-PhCHdCH (2g)
(E)-PhCHdC(CH3) (2h)
phenyl propargyl (2l)
6dae
6db
6dc
6de
6df
6dg
6dh
6dl
93
98
95
88
93
98
90
92
99:1 >99:1
96:4 97:3
>99:1 >99:1
6be
6c
6de
6de
>99:1
>99:1
99:1
96:4
>99:1 >99:1
a All reactions employed 1.1 equiv of SiCl4, 1.2 equiv of 5a-d, and
0.01 equiv of (R,R)-3 at 0.2 M in CH2Cl2 at -78 °C for 3 h. b Determined
by 1H NMR analysis. c Chromatographically homogeneous material. d De-
termined by CSP-SFC. e 2S,3R absolute configuration.11 f Analytically pure
material.
>99:1
96:4
96:4
84:16
a Reactions employed 1.1 equiv of SiCl4, 1.2 equiv of (E)-5d, and 0.01
equiv of (R,R)-3 at 0.2 M in CH2Cl2 at -78 °C for 3 h. b Yields of
analytically pure material. c Determined by 1H NMR analysis. d Determined
by CSP-SFC. e 2S,3R absolute configuration.9
In light of the initial success of the addition reactions of the
acetate-derived ketene acetal, the reactions of propanoate-derived
ketene acetals were investigated to assess both enantio- and
diastereoselectivity. Addition of the (E)-tert-butyldimethylsilyl
ketene acetal (E)-5b derived from ethyl propanoate to benzaldehyde
in the presence of 1 mol % of the catalyst (R,R)-3 provided anti-
6b with high enantio- and diastereoselectivity. The configuration
of the product was determined to be (2S,3R)-6b,11 the same absolute
configuration observed in the acetate addition reactions.
Table 4. Aldol Reaction of
(E)-1-(Ethoxy-propenyl)-tert-butyldimethylsilane ((E)-5b) with
Aliphatic Aldehydes
A survey of ketene acetal structure revealed that the alkoxy
substituent had little effect on the diastereoselectivity, although it
did have a major influence on enantioselectivity, such that er
increased with the steric bulk of the alkoxy substituent in the order
of Me < Et < Ph , t-Bu (Table 2). In the case of the (E)-tert-
butyldimethylsilyl ketene acetal (E)-5d derived from tert-butyl
propanoate, nearly complete selectivity is observed in the addition
to benzaldehyde (entry 4). Surprisingly, it is also observed that
enantio- and diastereoselectivity are not affected by the geometrical
integrity of the nucleophile. The addition of (Z)-tert-butyldimethyl-
silyl ketene acetal (Z)-5d derived from tert-butyl propanoate also
yielded the anti adduct with similar yield and selectivity (entry 5).
The observation of a stereoconvergent, anti-selective aldol process
strongly supports reaction through an open transition structure.12
NMR investigations on the stability of the ketene acetals to the
combination of SiCl4 and HMPA revealed that little or no
isomerization or metathesis is occurring. This rules out a cyclic,
Zimmerman-Traxler type transition structure.13 This result is
particularly intriguing because there are few examples of stereo-
convergent anti aldol processes.14 Most ketene acetal aldol processes
afford syn selectivities, and, in general, the (Z)-ketene acetal is
unreactive and/or yields products with poor selectivities.
The scope of the reaction was again explored with a variety of
aldehydes (Table 3). As was observed with the acetate-derived
ketene acetal 1, both electron-rich and electron-poor substrates react
with high selectivities (entries 4, 5). For olefinic aldehydes,
selectivities were also high (entries 6, 7). The propargylic aldehyde,
which is the problematic case in many catalyst systems, has a
slightly lower selectivity (entry 8). However, aliphatic aldehydes
did not react with the sterically hindered ketene acetal 5d!
To enhance the reactivity of the propanoate derived ketene
acetals, less sterically demanding esters were tested with the
aliphatic aldehyde substrates. Whereas (E)-5d yielded a trace of
product after 24 h at -78 °C, a moderate yield could be ob-
tained through the use of the less sterically demanding (E)-5b (Table
4).
entry
R
product
yield, %
dra
erb
1
2
3
4
PhCH2CH2 (2k)c
PhCH2CH2 (2k)e
cyclohexyl (2j)e
cyclohexyl (2j)g
6bk
6bk
6bj
6bj
55d
71f
29d
49f
93:7
91:9
92:8
89:11
94.5:5.5
94:6
ND
67.8:32.2
a Determined by 1H NMR analysis. b Determined by CSP-SFC. c Reac-
tion employed 1.1 equiv of SiCl4, 1.2 equiv of (E)-5b, and 0.05 equiv of
(R,R)-3 at 0.4 M in CH2Cl2 at -78 °C for 24 h. d Chromatographically
homogeneous material. e Reactions employed 1.1 equiv of SiCl4, 1.2 equiv
of (E)-5b, 0.05 equiv of (R,R)-3, and 0.1 equiv of TBAI at 0.4 M in CH2Cl2
at -78 °C for 24 h. f Yield of analytically pure material. g Reaction
employed 1.1 equiv of SiCl4, 1.2 equiv of (E)-5b, 0.1 equiv of (R,R)-3,
and 0.1 equiv of TBAI at 0.8 M in CH2Cl2 at -40 °C for 24 h.
To further increase the reaction rate, the use of tetrabutyl-
ammonium iodide (TBAI) as an additive was investigated. Earlier
reports demonstrated that addition of ammonium salts increased
the rate of chlorosilyl nucleophile additions by increasing the ionic
strength of the medium.15 It was thought that increasing the ionic
strength of the solution could similarly favor the ionization of SiCl4
to form species i. Hydrocinnamaldehyde 2k reacted with good yield
and selectivity after 24 h in the presence of 5 mol % of (R,R)-3
and 10 mol % of TBAI at -78 °C. However, the R branched
cyclohexanecarboxaldehyde 2j could not be induced to react under
these conditions. Use of a higher catalyst loading of 10 mol % and
higher temperature could provide the product 6bj in moderate yield
and selectivity.
In an effort to better understand the decreased reactivity of
aliphatic aldehydes under these reaction conditions, careful ReactIR
and 1H NMR investigations were undertaken. Upon mixing
equimolar amounts of cyclohexanecarboxaldehyde 2j and SiCl4 in
1
the presence of a catalytic amount of HMPA at -78 °C, the H
NMR signals corresponding to the aldehyde immediately dis-
appeared! The disappearance of the signal corresponding to the
aldehydic proton coincides with the appearance of a new signal at
5.78 ppm (eq 2). This signal was assigned as the R chloro silyl
ether 7 by analogy to related compounds.16 Similar experiments
9
13406 J. AM. CHEM. SOC. VOL. 124, NO. 45, 2002

C O M M U N I C A T I O N S
with benzaldehyde only reveal a slight broadening of the aldehydic
proton without the appearance of any new signals. The resistance
of such conjugated aldehydes to chloride addition may be due to
the unfavorable loss of resonance stabilization in the extended,
conjugated system.
only is this a rare example of such a catalytic process, it attests to
the powerful influence of the Lewis basic catalyst over the carbon-
carbon bond forming transition structure. Further studies are
currently underway to expand the scope of this reaction with respect
to both the aldehyde and ketene acetal components.
Acknowledgment. We are grateful to the National Science
Foundation for generous financial support (NSF CHE 0105205).
G.L.B. thanks the Pharmacia Corp. and Johnson and Johnson
Pharmaceutical Research Institute for graduate fellowships.
Supporting Information Available: Full characterization of the
catalyst and all products along with representative procedures for the
addition reactions (PDF). This material is available free of charge via
the Internet at http://pubs.acs.org.
With this new piece of information in hand, a working model
for the catalytic cycle, including an unproductive equilibrium
between the activated aldehyde ii and the R chloro silyl ether iii,
can be formulated (eq 3). It can also be concluded that this
equilibrium strongly favors the unreactive species iii. The nucleo-
phile must intercept a small, equilibrium amount of the activated
aldehyde ii for the reaction to proceed. Hence, more powerful
nucleophiles are required to compensate for this effective loss in
reactivity. This can explain why allylstannanes proved unreactive,
propanoate-derived ketene acetals such as 5 have moderate reactiv-
ity, and acetate-derived ketene acetals 1 react at a reasonable rate.8
References
(1) Modern Carbonyl Chemistry; Otera, J., Ed.; Wiley-VCH: Weinheim, 2000.
(2) Lewis Acids in Organic Synthesis; Yamamoto, H., Ed.; Wiley-VCH:
Weinheim, 2001.
(3) (a) Santelli, M.; Pons, J.-M. Lewis Acids and SelectiVity in Organic
Synthesis; CRC Press: Boca Raton, FL, 1996. (b) Gauthier, D. R.; Carreira,
E. M. Angew. Chem., Int. Ed. Engl. 1996, 35, 2363.
(4) (a) Gutmann, V. The Donor-Acceptor Approach to Molecular Inter-
actions; Plenum Press: New York, 1978. (b) Jensen, W. B. The Lewis
Acid-Base Concept; Wiley-Interscience: New York, 1980; Chapter 4.
(c) Nelson, S. G.; Wan, Z. Org. Lett. 2000, 2, 1883. (d) Nelson, S. G.;
Kim, B.-K.; Peelen, T. J. J. Am. Chem. Soc. 2000, 122, 9318.
(5) Denmark, S. E.; Wynn, T. J. Am. Chem. Soc. 2001, 123, 6199.
(6) For a discussion of the generation of trichlorosilyl cations, see: Bassindale,
A. R.; Glynn, S. J.; Taylor, P. G. In The Chemistry of Organosilicon
Compounds; Rappoport, Z., Apeloig, Y., Eds.; Wiley: Chichester, 1998;
Vol. 2, pp 495-511.
(7) (a) Denmark, S. E.; Stavenger R. A. Acc. Chem. Res. 2000, 33, 432. (b)
Denmark, S. E.; Stavenger R. A. J. Am. Chem. Soc. 2000, 122, 8837.
(8) Mayr, H.; Bug, T.; Gotta, M. F.; Hering, N.; Irrang, B.; Janker, B.; Kempf,
B.; Loos, R.; Ofial, A. R.; Remennikov, G.; Schimmel, H. J. Am. Chem.
Soc. 2001, 123, 9500.
(9) Lutz, G. P.; Du, H.; Gallagher, D. J.; Beak, P. J. Org. Chem. 1996, 61,
4542.
(10) Denmark, S. E.; Fu, J. Org. Lett. 2002, 4, 1951.
(11) Van Draanen, N. A.; Arseniyadis, S.; Crimmins, M. T.; Heathcock, C. H.
J. Org. Chem. 1991, 56, 2499.
(12) (a) Carriera, E. M. In ComprehensiVe Asymmetric Catalysis; Jacobsen,
E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer-Verlag: Heidelberg, 1999;
Chapter 29, Vol. III. (b) Heathcock, C. H.; Davidsen, S. K.; Hug, K. T.;
Flippin, L. A. J. Org. Chem. 1986, 51, 3027.
(13) Zimmerman, H. E.; Traxler, M. D. J. Am. Chem. Soc. 1957, 79, 1920.
(14) Yamashita, Y.; Ishitani, H.; Shimizu, H.; Kobayashi, S. J. Am. Chem.
Soc. 2002, 124, 3292.
(15) (a) Denmark, S. E.; Su, X.; Nishigaichi, Y. J. Am. Chem. Soc. 1998, 120,
12990. (b) Short, J. D.; Attenoux, S.; Berrisford, D. J. Tetrahedron Lett.
1997, 38, 2351.
(16) Several R-chloro ethers have been reported previously: (a) Lokensgard,
J. P.; Fisher, J. W.; Bartz, W. J. J. Org. Chem. 1985, 50, 5609. (b)
Gundersen, L.-L.; Benneche, T. Acta Chem. Scand. 1991, 45, 975.
In conclusion, we have developed a highly selective, Lewis-base-
catalyzed reaction for the addition of ketene acetals to a variety of
aldehydes. Catalyst loadings as low as 1 mol % can be employed
without the requirement of long reaction times. In contrast to earlier
methods involving trichlorosilyl enolates, aliphatic aldehydes react
to provide products with good yields and high selectivities. Studies
revealed that the lack of reactivity observed with aliphatic aldehydes
may be due to unproductive formation of an R chloro silyl ether.
The stereoconvergent, anti selective nature of the addition of
propanoate-derived ketene acetals is particularly noteworthy. Not
JA0282947
9
J. AM. CHEM. SOC. VOL. 124, NO. 45, 2002 13407