Lewis base-catalyzed additions of alkynes using trialkoxysilylalkynes

Article abstract of DOI:10.1021/ol051030f

(Chemical Equation Presented) The Lewis base-catalyzed additions of alkynyl nucleophiles to aldehydes, ketones, and imines is described. Mechanistic studies strongly indicate that the use of new triethoxysilylalkynes facilitates access of a reactive hyper

Full text of DOI:10.1021/ol051030f

ORGANIC
LETTERS
2005
Vol. 7, No. 15
3227-3230
Lewis Base-Catalyzed Additions of
Alkynes Using Trialkoxysilylalkynes
Robert B. Lettan II and Karl A. Scheidt*
Department of Chemistry, Northwestern UniVersity, EVanston, Illinois 60208
scheidt@northwestern.edu
Received May 4, 2005
ABSTRACT
The Lewis base-catalyzed additions of alkynyl nucleophiles to aldehydes, ketones, and imines is described. Mechanistic studies strongly
indicate that the use of new triethoxysilylalkynes facilitates access of a reactive hypervalent silicate intermediate. This activated carbon
nucleophile subsequently undergoes rapid addition to carbonyl compounds and imines, thus affording the secondary and tertiary propargyl
systems in moderate to high yield.
Chemical reactions catalyzed by nucleophilic species (Lewis
bases) possess significant potential for new bond-forming
strategies. Over the past decade, many advances in Lewis
base-catalyzed processes have been realized, including
asymmetric acylations,1 aldol reactions,2 and the enantiose-
lective synthesis of â-lactams and â-lactones.3 However,
Lewis base-catalyzed reactions have not been explored to
the same extent as Lewis acid or transition-metal-promoted
processes, and consequently, these organocatalytic nucleo-
philic manifolds possess considerable promise. Many Lewis
base-catalyzed reactions involve the judicious incorporation
of a silyl group that can facilitate access to a hypervalent
silicate species which ultimately undergoes delivery of a
nucleophile.4 Based on this principle, we reasoned that the
mild and general addition of an alkynyl unit to various
electrophiles might be accomplished employing Lewis base
catalysts. In this paper, we report that trialkoxysilylalkynes
(1) are novel alkynyl nucleophiles in the presence of catalytic
Lewis bases and undergo mild and efficient addition to
aldehydes and ketones (2) to cleanly afford propargyl
alcohols (3, eq 1).
Many highly stereoselective metal-promoted additions of
alkynes to aldehydes have been reported, most notably by
Carreira and co-workers,5 However, there are fewer general
strategies for the addition of alkynes to both aldehydes and
ketones under mild catalytic conditions.6 Inspired by the
silicon-based allyl additions,7 carbonyl reductions,8 that are
catalyzed by Lewis bases, we envisioned that appropriately
(1) (a) Fu, G. C. Acc. Chem. Res. 2000, 33, 412-420. (b) Vedejs, E.;
Daugulis, O.; MacKay, J. A.; Rozners, E. Synlett 2001, 1499-1505.
(2) (a) Denmark, S. E.; Stavenger, R. A.; Su, X. P.; Wong, K. T.;
Nishigaichi, Y. Pure Appl. Chem. 1998, 70, 1469-1476. (b) Denmark, S.
E.; Stavenger, R. A. Acc. Chem. Res. 2000, 33, 432-440.
(3) (a) France, S.; Weatherwax, A.; Taggi, A. E.; Lectka, T. Acc. Chem.
Res. 2004, 37, 4245-4255. (b) Wynberg, H.; Staring, E. G. J. J. Am. Chem.
Soc. 1982, 104, 166-168 and references therein. (c) Orr, R. K.; Calter, M.
A. Tetrahedron 2003, 59, 3545-3565.
(4) (a) Chuit, C.; Corriu, R. J. P.; Reye, C.; Young, J. C. Chem. ReV.
1993, 93, 1371-1448. (b) Holmes, R. R. Chem. ReV. 1996, 96, 927-950.
(c) Brook, M. A. Silicon in Organic, Organometallic, and Polymer
Chemistry; Wiley-Interscience: New York, 1999.
(5) (a) Frantz, D. E.; Fassler, R.; Carreira, E. M. J. Am. Chem. Soc. 2000,
122, 1806-1807. (b) Anand, N. K.; Carreira, E. M. J. Am. Chem. Soc.
2001, 123, 9687-9688. (c) Pu, L. Tetrahedron 2003, 59, 9873-9886 and
references therein. (d) Li, X. S.; Lu, G.; Kwok, W. H.; Chan, A. S. C. J.
Am. Chem. Soc. 2002, 124, 12636-12637.
(6) (a) Cozzi, P. G. Angew. Chem., Int. Ed. 2003, 42, 2895-2898. For
specific asymmetric alkynyl additions to acetophenone derivatives, see: (b)
Lu, G.; Li, X. S.; Jia, X.; Chan, W. L.; Chan, A. S. C. Angew. Chem., Int.
Ed. 2003, 42, 5057-5058. (c) Saito, B.; Katsuki, T. Synlett 2004, 1557-
1560.
10.1021/ol051030f CCC: $30.25
© 2005 American Chemical Society
Published on Web 06/28/2005

functionalized alkynes might productively interact with an
electron-rich catalyst to generate a reactive nucleophilic
species. 9,10
To test this hypothesis, electron-deficient trialkoxysilyl-
alkynes (such as 5a) were easily accessed from the corre-
sponding terminal alkynes11 and subjected to various nu-
cleophilic species in the presence of an aldehyde (4, Table
1, eq 2). The alkoxy substitutents were placed on the silicon
function of increasing reaction time and Lewis base con-
centration. Gratifyingly, catalytic reaction conditions with
only 10 mol % of KOEt at 0 °C generated alcohol 6 in good
yield (entry 5). In addition, sterically hindered tertiary and
secondary alkoxides can also be employed as catalysts
(entries 6 and 7).13
With catalytic conditions identified for this process, the
structure of the alkyne nucleophile was varied (Table 2, eq
Table 1. Lewis Base-Catalyzed Additions of Alkynesa
Table 2. Scope of Alkyne Addition
entry
Lewis base
equiv time (h) ((T (°C))b yieldc (%)
1
2
3
4
5
6
7
n-Bu4N‚F2SiPh3
LiOMe
NaOMe
KOEt
KOEt
KO-t-Bu
1.0
1.0
1.0
1.0
0.1
0.2
16 (23)
24 (23)
19 (23)
1 (23)
2 (0)
50
NRd
50
57
84
2 (0)
2 (0)
75
75
(()-KOCH(CH3)Ph 0.2
a All reactions were performed under inert atmosphere at 0.2 M.
b Reactions halted after 100% conversion. c Isolated yields after purification.
d No reaction.
to induce significant hypervalency in the presence of a Lewis
base catalyst while maintaining ease of synthetic accessibil-
ity.12 Fluoride sources were initially surveyed as potential
catalysts, but stoichiometric quantities of various salts
resulted in limited success (entry 1). Prompted by the strong
Si-O bond strength, we examined simple alkoxides with
various counterions. Interestingly, while LiOMe afforded no
product (entry 2), the use of alkoxides with more electro-
positive counterions (Na and K) cleanly provided the desired
propargyl alcohol 6, with KOEt affording a significant rate
enhancement over NaOMe (entries 3 and 4). During these
early investigations, we noticed product decomposition as a
3). The reaction is facile at 0 °C, and the alkyne can
accommodate linear or branched alkyl groups (entries 1-3)
as well as aryl substitution (entry 4). Propargyl systems
employing benzyl and triisopropylsilyl protecting groups
smoothly afford the desired carbinols in good yields.
Under Lewis base-catalyzed conditions (10 mol % of
KOEt), triethoxysilylalkyne 5a undergoes facile addition to
various aldehydes in good yields (eq 4, Table 3). The reaction
is high yielding with numerous electron-rich and electron-
deficient aromatic aldehydes, is mild enough to accommodate
enolizable aldehydes (entries 9 and 10), and notably affords
selective additions in the presence of esters (entry 11).14
A distinctive and important attribute of this process is the
capability of this new alkynyl nucleophilic reagent to undergo
(7) (a) Kobayashi, S.; Nishio, K. Tetrahedron Lett. 1993, 34, 3453-
3456. (b) Nakajima, M.; Saito, M.; Shiro, M.; Hashimoto, S. J. Am. Chem.
Soc. 1998, 120, 6419-6420. (c) Iseki, K.; Mizuno, S.; Kuroki, Y.;
Kobayashi, Y. Tetrahedron 1999, 55, 977-988. (d) Denmark, S. E.; Fu, J.
P. J. Am. Chem. Soc. 2001, 123, 9488-9489 and references therein.
(8) (a) Kobayashi, S.; Yasuda, M.; Hachiya, I. Chem. Lett. 1996, 407-
408. (b) Schiffers, R.; Kagan, H. B. Synlett 1997, 1175-1178. (c) LaRonde,
F. J.; Brook, M. A. Tetrahedron Lett. 1999, 40, 3507-3510. (d) Iwasaki,
F.; Onomura, O.; Mishima, K.; Maki, T.; Matsumura, Y. Tetrahedron Lett.
1999, 40, 7507-7511. (e) Nishikori, H.; Yoshihara, R.; Hosomi, A. Synlett
2003, 561-563.
(9) For early contributions in this area, see: (a) Nakamura, E.; Kuwajima,
I. Angew. Chem., Int. Ed. Engl. 1976, 15, 498-499. (b) Kuwajima, I.;
Nakamura, E.; Hasimoto, K. Tetrahedron 1983, 39, 975-982.
(10) With trialkylsilylalkynes, see: (a) Busch-Petersen, J.; Bo, Y.; Corey,
E. J. Tetrahedron Lett. 1999, 40, 2065-2068. (b) Baldwin, J. E.; Pritchard,
G. J.; Rathmell, R. E. J. Chem. Soc., Perkin Trans. 1 2001, 2906-2908.
(c) Kraus, G. A.; Bae, J. Tetrahedron Lett. 2003, 44, 5505-5506.
(11) See the Supporting Information for details.
(13) The control experiment with 1-hexyne, KOEt, and aldehyde does
not produce desired propragyl alcohol under the reaction conditions. The
addition of Si(OEt)4 in this system yields no product either. See the
Supporting Information for details.
(12) The use of trialkylsilylalkynes with KOEt afforded minimal amounts
of alkynyl addition products with aldehydes and was not pursued.
(14) In contrast, the lithium alkyne addition to methyl 4-formylbenzoate
affords a complex mixture from the addition to both carbonyl carbons.
3228
Org. Lett., Vol. 7, No. 15, 2005

Table 3. Triethoxysilylhexyne (5a) Additions to Aldehydes
Table 4. Triethoxysilylhexyne (5a) Additions to Ketones
a 20 mol % of 18-crown-6. b Isolated yields after chromatography.
c >95% (E)-chalcone. d Only 1,2-addition product observed.
basicity of these new reagents is attenuated relative to
standard alkynyl organometallic reagents.
Our preliminary investigations of this process have
provided important clues about the operative reaction mech-
anism. We propose that the active alkynyl nucleophile is a
hypervalent silicate intermediate resulting from reversible
addition of alkoxide. Evidence for this species was obtained
by the low-temperature 29Si NMR experiment of combining
trialkoxysilylalkyne 5a, 1.0 equiv of KOEt, and 1.0 equiv
of 18-crown-6 (Figure 1). A new and distinct signal at -126
a Isolated yields after chromatography. b >95% (E)-cinnamaldehyde.
Figure 1. 29Si NMR (-60 °C) of 5a, KOEt, and 18-crown-6
(1:1:1).
addition to ketones (Table 4, eq 5). The conditions that afford
the best yields employ a higher catalyst loading (20 mol %)
and a crown ether (18-crown-6).15 By utilizing these Lewis
basic conditions, undesired aldol products are not observed
with enolizable ketones as substrates, indicating that the
ppm is similar to previously studied pentavalent silicate
intermediates such as (EtO)4SiPh‚K (-117 ppm).16
An intriguing aspect of the reaction is that the propargyl
product is initially an alkoxide and may well activate the
(15) The addition of 18-crown-6 allows for catalytic KOEt to be used
and presumably promotes turnover of the nucleophilic alkoxide product.
See the Supporting Information for details.
(16) Swamy, K. C. K.; Chandrasekhar, V.; Harland, J. J.; Holmes, J.
M.; Day, R. O.; Holmes, R. R. J. Am. Chem. Soc. 1990, 112, 2341-2348.
Org. Lett., Vol. 7, No. 15, 2005
3229

trialkoxysilylalkyne in a manner similar to KOEt. To probe
this product-activation possibility, the potassium salt of
propargyl alcohol 6 was added (10 mol %) to silylalkyne 5a
and benzaldehyde (Scheme 1). Interestingly, propargyl
for catalytic turnover in the addition to ketones, where a more
sterically congested tertiary propargyl alkoxide (I) is gener-
ated.15
The unique properties and synthetic potential of these
trialkoxysilylalkynes can be observed in the formation of
secondary propargylamines18 (Scheme 3). The combination
Scheme 1
Scheme 3
alcohol 14 is isolated in good yield after aqueous workup
(74%).
Drawing from the data observed in both Figure 1 and
Scheme 1, we propose a plausible mechanistic description
of this reaction involving Lewis base initiation of an
autocatalytic cycle (Scheme 2). The addition of a Lewis base
of 5a and tert-butylsulfinyl imine 3019 affords alkyne 31 in
exceptional yield (95%) with high selectivity (20:1) favoring
the (SS,R) diastereomer. Surprisingly, alternative alkynyl
organometallic nucleophiles are either less selective (Met )
K) or prefer the opposite stereoisomer (Met ) Li or MgEt).11
In conclusion, we have reported an efficient nucleophile-
catalyzed addition reaction of alkynes. This new strategy
utilizes trialkoxysilylalkynes as stable nucleophile precursors
with preliminary mechanistic data implicating a hypervalent
organosilane as the active reagent. The new alkynyl species
accessed by the addition of a Lewis base possess reactivity
to undergo smooth, and in some cases highly selective,
additions to aldehydes, ketones, and imines. Mechanistic
investigations and applications of this Lewis base-catalyzed
strategy based on trialkoxyorganosilane activation are cur-
rently underway.
Scheme 2
Acknowledgment. This work has been partially sup-
ported by Northwestern University and the NSF (CAREER
Award to K.A.S.). We are grateful to Abbott Laboratories,
Amgen, 3M, and Boehringer-Ingelheim for research support
and to FMCLithium for providing organolithium reagents
used in this research. We thank Mr. David Ballweg for
assistance with preparing this manuscript.
to 5 would lead to formation of a pentavalent silicon
intermediate II, which could mediate the transfer of an
alkynyl nucleophile via hexacoordinate organization (III).
The resulting silated alkyne-addition product (IV) could
dissociate, leading to generation of alkoxide base I, thereby
perpetuating the reaction. Further evidence for self-promotion
was the direct observation of V by gas chromotography under
catalytic reaction conditions.17 A mechanism involving self-
promotion is also supported by the necessity of crown ether
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.
OL051030F
(18) Asymmetric alkyne additions to imines: (a) Gommermann, N.;
Knochel, P. Chem. Commun. 2004, 2324-2325. (b) Fassler, R.; Frantz, D.
E.; Oetiker, J.; Carreira, E. M. Angew. Chem., Int. Ed. 2002, 41, 3054-
3056. (c) Traverse, J. F.; Hoveyda, A. H.; Snapper, M. L. Org. Lett. 2003,
5, 3273-3275.
(19) Ellman, J. A.; Owens, T. D.; Tang, T. P. Acc. Chem. Res. 2002,
35, 984-995.
(17) Generation of V is not observed in the presence of stoichiometric
amounts of potassium ethoxide.
3230
Org. Lett., Vol. 7, No. 15, 2005