pubs.acs.org/joc
asymmetric version has recently been reported4l using Sc(OTf)3
and a bis-N-oxide chrial ligand.
Synthesis of β-Keto Esters In-Flow and Rapid Access
to Substituted Pyrimidines
Although this approach constitutes an elegant method for
the synthesis of β-keto esters, the use of diazo compounds is
potentially hazardous and this is particularly an issue when
working on a larger scale. We considered that if it was pos-
sible to adapt this reaction for use “in-flow” this might offer
several potential benefits over the “batch” process as exo-
thermic processes, the release of gases, and the use of toxic or
hazardous reagents are well tolerated.5 To illustrate the
synthetic utility of the in-flow process, we planned to use
the resulting β-keto ester products to synthesize a range of
substituted pyrimidines.
Our initial efforts focused upon selecting a suitable Lewis
acid that could be used for catalyzing the addition of ethyl
diazoacetate to aldehydes (the Roskamp reaction) under
flow conditions. Roskamp originally reported that SnCl2
was the catalyst of choice under batch conditions, but he also
Hannah E. Bartrum,† David C. Blakemore,‡ Christopher
J. Moody,*,† and Christopher J. Hayes*,†
†School of Chemistry, University of Nottingham, University
Park, Nottingham, NG7 2RD, United Kingdom, and
‡Pfizer Global Research and Development, Ramsgate Road,
Sandwich, Kent, CT13 9NJ, United Kingdom
chris.hayes@nottingham.ac.uk; c.j.moody@nottingham.ac.uk
Received September 10, 2010
reported that BF3 OEt2 could be used, albeit with slightly
3
diminished yields. As the BF3 OEt2-catalyzed reaction re-
3
mains homogeneous throughout, we chose to use this as our
basis for the development of an in-flow process. We began
our studies by comparing the effectiveness of BF3 OEt2 and
3
SnCl2 as catalysts for the batch-wise addition of ethyl dia-
zoacetate (2) to hydrocinnamaldehyde (1), in order to select
an optimum catalyst loading for initial use under flow con-
ditions (Table 1).
This preliminary study showed that BF3 OEt2 was an
3
effective catalyst for the batch-wise production of the desired
β-keto ester product 3(76% yield at 10 mol % loading, entry 5),
and this was comparable to the results obtained using either
We have developed an in-flow process for the synthesis of
β-keto esters via the BF3 OEt2-catalyzed formal C-H
3
SnCl2 (83% yield at 10 mol % loading, entry 1) or SnCl2
2H2O (81% yield at 10 mol % loading, entry 3). Further-
3
insertion of ethyl diazoacetate into aldehydes. The β-keto
esters were then condensed with a range of amidines to
give a variety of 2,6-substituted pyrimidin-4-ols.
more, we found that the loading of BF3 OEt2 could be
3
lowered to 1 mol % (entry 6) without affecting either yield
or conversion. Lowering the loading of either SnCl2 (entry 2)
or SnCl2 2H2O (entry 4) to 1 mol % resulted in significant
3
reductions in yield of the β-keto ester 3.
We next investigated adapting this batch reaction into a
β-Keto esters are versatile intermediates in organic synthe-
sis, and have been extensively used in the construction of
natural products and other biologically active heterocyclic
molecules.1 As the number of commercially available func-
tionalized β-keto esters is limited, a number of methods have
been developed for their preparation.2 One of the simplest
approaches involves an acid-catalyzed formal C-H inser-
tion of ethyl diazoacetate into an aldehyde3 and since the
original report by Roskamp,3a various Lewis acids have been
flow process (Scheme 1). We used a Vaportec R2þ/R4 reactor
(4) (a) Nomura, K.; Iida, T.; Hori, K.; Yoshii, E. J. Org. Chem. 1994, 59,
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2009, 5153. (f) Jeyakumar, K.; Chand, D. K. Synthesis 2008, 11, 1685.
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ChemMedChem. 2007, 2, 768. (b) Ley, S. V.; Baxendale, I. R. Chimia 2008,
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used (SnCl2,3 TiCl4,4a ZrCl4,4a BF3 OEt2,4b NbCl5,4c
3
Ag(TPA),4d [IPrAu(NCMe)]BF4,4e MoO2Cl2,4f activated alu-
mina,4g mesoporous silica,4h zeolites,4i,j clay4k) and the first
(1) (a) Hill, M. D.; Movassaghi, M. Chem.;Eur. J. 2008, 14, 6836.
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(b) The formal C-H insertion of R-diazoketones into aldehydes has also
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Chem. 1990, 55, 5297.
8674 J. Org. Chem. 2010, 75, 8674–8676
Published on Web 11/17/2010
DOI: 10.1021/jo101783m
r
2010 American Chemical Society