An unusual dianion equivalent from acylsilanes for the synthesis of substituted β-keto esters

Article abstract of DOI:10.1039/b801597j

The reaction of lithiated diazo esters with acylsilanes generates a remarkable intermediate en route to highly substituted β-keto esters. The Royal Society of Chemistry.

Full text of DOI:10.1039/b801597j

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An unusual dianion equivalent from acylsilanes for the synthesis of
substituted b-keto estersw
Chris V. Galliford and Karl A. Scheidt*
Received (in College Park, MD, USA) 29th January 2008, Accepted 20th February 2008
First published as an Advance Article on the web 10th March 2008
DOI: 10.1039/b801597j
The reaction of lithiated diazo esters with acylsilanes generates a
remarkable intermediate en route to highly substituted b-keto
esters.
Reactions that combine multiple starting materials in a single
The resulting intermediate could undergo sequential additions
flask are efficient methods for the rapid synthesis of target
to two different electrophiles to generate substituted b-keto
compounds.1 Our own interest in developing new and efficient
esters (3) in a single flask. In this communication, we report
routes to biologically active or topologically diverse structures
the realization of this multiple bond-forming reaction that
has led us to investigate processes with potential for construct-
accesses new and unusual dianion equivalent reactivity. The
ing multiple carbon–carbon bonds in a single reaction flask.2
reactions of a-metallated diazoacetates with electrophiles are
Diazo compounds have wide-ranging reactivity patterns and
well known.12 The deprotonation can be accomplished using
synthetic utility that are potentially useful in the design of new
several bases13 and the analogous zinc salt has also been
multicomponent reactions. For example, many cycloaddition,
employed in nucleophilic additions to aldehydes.14
cyclopropanation and C–H insertion processes involve metal-
To explore the potential reaction between diazo esters and
locarbenoid species derived from diazo decomposition cata-
acylsilanes, we treated benzoyltrimethylsilane 1a with a-lithio-
lyzed by a transition metal salt.3 Diazo esters and ketones have
ethyl diazoacetate (a-Li-2) at ꢀ78 1C (Scheme 1). Gratifyingly,
also been employed as nucleophiles in a variety of reaction
ethyl benzoylacetate 3 was the sole product of this reaction
manifolds. In this vein, Holmquist and Roskamp reported a
(99% yield, entry 1). In contrast to the cases of ethyl diazo-
stannous chloride-promoted homologation of aldehydes to
acetate anion additions to aldehydes and ketones, the normal
unsubstituted b-ketoesters using diazoesters.4 Employing diazo
carbinol product is not observed with acylsilanes. The tetra-
compounds bearing alternative electron-withdrawing substi-
hedral intermediate most likely formed after the initial addi-
tuents including phosphoryl, phosphinoyl and toluenesulfo-
tion can undergo a 1,2-Brook rearrangement, which then
nyl-groups has expanded the scope of this reaction. Padwa
precipitates the elimination of N2 and potentially affords a
et al. have also disclosed the synthesis of 1,3-diketones by a
novel b-silyloxy allenolate intermediate. This intriguing inter-
similar method.5 The groups of Wang, Terada and more
mediate can be considered to be a new type of formal dianion
recently Hashimoto and Maruoka have all reported elegant
equivalent.
and selective additions of diazo compounds to imines using
Using this new process, various unsubstituted b-ketoesters
chiral acid catalysis.6 In a related process the reaction of
can be prepared rapidly (Table 1, entries 1–5). We were
imines with diazo compounds yield aziridines as products.7
pleased to discover that the substrate scope for the reaction
Yao and Wang have also reported additions to aldehydes
accommodates three different diazo esters, (entries 1, 2 and 5)
catalyzed by a zirconium-BINOL complex, while Nishida and
and both alkyl and aryl acylsilanes (entries 3 and 4). A novel
co-workers have independently reported the use of phase
aspect of this new process is the ability to utilize the dianion
transfer catalysis to effect the addition of diazo esters to
equivalent in carbon–carbon bond forming reactions. For
aldehydes.8
In connection with our research accessing unusual nucleo-
philic species, we became interested in pursuing the combina-
tion of acylsilanes (1) with the distinctive reactivity of diazo
compounds (2).9 Our hypothesis was that the addition of a
deprotonated diazo ester should induce a 1,2-Brook rearran-
gement10 followed by loss of dinitrogen.11
Department of Chemistry, Northwestern University, 2145 Sheridan
Road, Evanston, Illinois 60208, USA. E-mail:
scheidt@northwestern.edu
w Electronic supplementary information (ESI) available: Experimental
procedures and spectral data for new compounds. See DOI: 10.1039/
b801597j
Scheme 1 Dianion equivalents from acylsilanes and diazo esters.
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Table 1 Multicomponent synthesis of b-ketoestersa
We were also able to prepare b-ketoesters possessing
quaternary centers by utilizing two electrophilic partners
(Table 2). Using an excess of allyl iodide or tethered alkyl
bis-halides constructs three new carbon–carbon bonds at the
same time in high yield (Table 2, entries 1–3). To highlight the
versatility of the putative b-silyloxy allenolate, differentially
substituted b-ketoesters can be accessed in a single-flask
operation by the sequential addition of electrophiles (Table 2,
entries 4 and 5).
Entry
R
R1
R2–X
Yieldb (%) Compound
While the a-deprotonation of vinyl or allenyl ketones lead-
ing to allenolate or cumulenolate intermediates is precedented,
this approach does not work when active protons are present.15,16
This restriction underscores the potential utility of accessing a
b-silyloxyallene from simple starting materials as described
herein. To probe the identity of the potential intermediate(s) in
our reaction, we combined p-methyl benzoylsilane 1b and
a-lithio-ethyl diazoacetate (a-Li-2) in C6D6 at 5 1C, and added
a proton source (2,6-bis(1,1-dimethylethyl)-4-methylphenol
(BHT) for 30 min). The 1H NMR spectrum of the reaction
mixture provides data consistent with both silylketene acetal
isomers (16, eqn (1)).17 This observation supports a b-silyloxy
allenolate intermediate and suggests that silyl transfer between
oxygen atoms is also operative under these conditions.
1
2
3
4
5
6
7
8
a
Ph
Ph
Et
t-Bu
H–OM
99
3a
4
5
6
7
8
9
10
H–OMeb 98
H–OMe 98
H–OMe 79
4-CH3C6C4 Et
CH3
Ph
Ph
Ph
CH3
Et
Cinnamyl H–OMe 95
Et
Et
Et
Me–I
Bn–Br
Bn–Br
b
93
95
76
See ESIw for further reaction details. Isolated yield.
example, the addition of MeI to the reaction in place of a
proton results in 93% yield of monomethyl b-ketoester 8
(entry 6). The addition of a variety of alkylating agents (entries
6–10) allows for the three-component preparation of substi-
tuted b-ketoesters in a single flask.
Table 2 Double alkylation of dianion equivalenta
Entry
1
Electrophile
Product
Yieldb (%)
91
Compound
11
2
3
84
77
12
13
4
5
Mel, followed by allyl iodide
BnBr, followed by Mel
81
69
14
15
a
b
See ESIw for further reaction details. Isolated yield.
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(c) C. V. Galliford and K. A. Scheidt, J. Org. Chem., 2007, 72,
1811–1813.
3 For selected reviews, see: (a) D. F. Taber, in Comprehensive
Organic Synthesis, ed. G. Pattenden, Pergamon Press,
Oxford, 1991, vol. 3; (b) H. M. L. Davies, Curr. Org. Chem.,
1998, 2, 463–488; (c) M. P. Doyle and D. C. Forbes, Chem. Rev.,
1998, 98, 911–935; (d) M. P. Doyle, M. A. McKervey and
T. Ye, Modern Catalytic Methods for Organic Synthesis with Diazo
Compounds: From Cyclopropanes to Ylides, Wiley, New York,
1998.
4 (a) C. R. Holmquist and E. J. Roskamp, J. Org. Chem., 1989, 54,
3258–3260; (b) C. R. Holmquist and E. J. Roskamp, Tetrahedron
Lett., 1992, 33, 1131–1134.
5 A. Padwa, S. F. Hornbuckle, Z. Zhang and L. Zhi, J. Org. Chem.,
1990, 55, 5297–5299.
ð1Þ
ð2Þ
Further evidence for a b-silyloxy allenolate generated in this
process is obtained when silyl enol ether 17 was treated with
LDA and then exposed to MeI (eqn (2)), with compound 8
isolated as the product. Additionally, when we employ cinam-
myl diazoacetate 2c in the reaction, smooth conversion to the
b-ketoester 7 is obtained in 95% yield with no products
resulting from a possible carbenoid intermediate (Table 1,
entry 5).
6 (a) Y. H. Zhao, Z. H. Ma, X. M. Zhang, Y. P. Zou, X. L. Jin and J.
B. Wang, Angew. Chem., Int. Ed., 2004, 43, 5977–5980; (b) D.
Uraguchi, K. Sorimachi and M. Terada, J. Am. Chem. Soc., 2005,
127, 9360–9361; (c) T. Hashimoto and K. Maruoka, J. Am. Chem.
Soc., 2007, 129, 10054–10055.
7 (a) L. Casarrubios, J. A. Perez, M. Brookhart and J. L. Templeton,
J. Org. Chem., 1996, 61, 8358–8359; (b) H.-J. Ha, K.-H. Kang, J.-
M. Suh and Y.-G. Ahn, Tetrahedron Lett., 1996, 37, 7069–7070; (c)
K. G. Rasmussen and K. A. Jørgenson, J. Chem. Soc., Perkin
Trans. 1, 1997, 1287–1292; (d) S. Nagayama and S. Kobayashi,
Chem. Lett., 1998, 27, 685–686; (e) J. C. Antilla and W. D. Wulff,
J. Am. Chem. Soc., 1999, 121, 5099–5010; (f) J. C. Antilla and W.
D. Wulff, Angew. Chem., Int. Ed., 2000, 39, 4518–4521.
8 (a) W. G. Yao and J. B. Wang, Org. Lett., 2003, 5, 1527–1530; (b)
S. Arai, K. Hasegawa and A. Nishida, Tetrahedron Lett., 2004, 45,
1023–1026.
9 (a) A. E. Mattson, A. R. Bharadwaj and K. A. Scheidt, J. Am.
Chem. Soc., 2004, 126, 2314–2315; (b) A. E. Mattson, A. R.
Bharadwaj, A. M. Zuhl and K. A. Scheidt, J. Org. Chem., 2006,
71, 5715–5724; (c) R. B. Lettan II, T. E. Reynolds, C. V. Galliford
and K. A. Scheidt, J. Am. Chem. Soc., 2006, 128, 15566–15567; (d)
T. E. Reynolds, A. R. Bharadwaj and K. A. Scheidt, J. Am. Chem.
Soc., 2006, 128, 15382–15383; (e) T. E. Reynolds, C. Stern and K.
A. Scheidt, Org. Lett., 2007, 7, 2581–2584; (f) T. E. Reynolds and
K. A. Scheidt, Angew. Chem., Int. Ed., 2007, 46, 7806–7809; (g) R.
B. Lettan, II, C. C. Woodward and K. A. Scheidt, Angew. Chem.,
Int. Ed., 2008, 120, 2326–2329.
The combination of lithiated diazo esters and acylsilanes
provides a new and general way to access a useful and
unprecedented dianion equivalent. This straightforward com-
bination is presumed to generate a b-silyloxy allenolate inter-
mediate by a 1,2-Brook rearrangement followed by loss of
nitrogen gas. The addition of two electrophiles, either simul-
taneously or sequentially, results in a multicomponent synth-
esis of substituted b-keto esters. The dual anion aspects of this
process are unique and have potential for the efficient synthesis
of highly functionalized 1,3-carbonyl compounds. The combi-
nation of reactive nucleophiles and acylsilanes continues to
provide innovative routes to atypical nucleophiles which
facilitate the synthesis of target molecules by unconventional
means.
10 A. G. Brook, Acc. Chem. Res., 1974, 7, 77–84.
11 For reviews of acylsilane chemistry, see: (a) A. Ricci and A.
Degl’Innocenti, Synthesis, 1989, 647–660; (b) P. F. Cirillo and J.
S. Panek, Org. Prep. Proced. Int., 1992, 24, 553–582.
12 For early examples, see: (a) D. Hoppe, Angew. Chem., Int. Ed.
Engl., 1970, 9, 300–306; (b) E. Wenkert, J. Am. Chem. Soc., 1972,
94, 8084–8090.
13 (a) N. F. Woolsey and M. H. Khalil, J. Org. Chem., 1972, 37,
2405–2408; (b) R. Pellicciari and B. Natalini, J. Chem. Soc., Perkin
Trans. 1, 1977, 1822–1824; (c) R. Pellicciari, B. Natalini, B. M.
Sadeghpour, M. Marinozzi, J. P. Snyder, B. L. Williamson, J. T.
Kuethe and A. Padwa, J. Am. Chem. Soc., 1996, 118, 1–12; (d) D.
F. Taber, R. J. Herr and D. M. Gleave, J. Org. Chem., 1997, 62,
194–198.
Support has been provided in part by the NSF (CHE-
0348979), the PRF (Type G) and the Elizabeth Tuckerman
Foundation (fellowship to C. V. G.). We thank Abbott
Laboratories, Amgen, AstraZeneca, GlaxoSmithKline and
Boehringer-Ingelheim for generous research support and
Wacker Chemical Corp. and FMCLithium for reagent sup-
port. Funding for the NU Integrated Molecular Structure
Education and Research Center (IMSERC) has been furn-
ished in part by the NSF (CHE-9871268). K. A. S. is an Alfred
P. Sloan fellow.
14 (a) C. J. Moody and C. N. Morfitt, Synthesis, 1998, 1039–1042; (b)
F. Sarabia and F. J. Lopez-Herrera, Tetrahedron Lett., 2001, 42,
8801–8804.
Notes and references
15 (a) J. F. Arnett and H. Walborsky, J. Org. Chem., 1972, 37, 3678;
(b) N. A. Petasis and K. A. Teets, J. Am. Chem. Soc., 1992, 114,
10328–10334.
1 (a) G. Dyker, Angew. Chem., Int. Ed. Engl., 1997, 36, 1700–1702;
(b) I. Ugi, Pure Appl. Chem., 2001, 73, 187–191, and references
cited therein; (c) W. H. Moser, Tetrahedron, 2001, 57, 2065–2084;
(d) Multicomponent Reactions, ed. J. Zhu and H. Bienayme, Wiley-
VCH, Weinheim, 2005.
2 (a) C. V. Galliford, M. A. Beenen, S. T. Nguyen and K. A. Scheidt,
Org. Lett., 2003, 5, 3487–3490; (b) C. V. Galliford, J. S. Marten-
son, C. Stern and K. A. Scheidt, Chem. Commun., 2007, 631–633;
16 2,2-Dimethyl-4-methylene-1,3-dioxolane has been used as a pre-
cursor to an a-vinyl enolate, see: (a) M. A. Tius, D. P. Astrab and
X. Q. Gu, J. Org. Chem., 1987, 52, 2625–2627; (b) M. A. Tius and
H. Hu, Tetrahedron Lett., 1998, 39, 5937–5940.
17 See ESIw for details.
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1928 | Chem. Commun., 2008, 1926–1928