The formation of various alpha-diazo acetoacetic esters can be obtained in a single transformation with good to excellent yields using readily available 2-diazoacetoacetic acid

Ferreira, Eric M.

Meyer, Michael E.

Stoltz, Brian M.

English

Caltech Authors - Main

2-Diazoacetoacetic acid, an efficient and convenient reagent for the
synthesis of a-diazo-b-ketoesters{
Michael E. Meyer, Eric M. Ferreira and Brian M. Stoltz*
Received (in Bloomington, IN, USA) 13th December 2005, Accepted 27th January 2006
First published as an Advance Article on the web 15th February 2006
DOI: 10.1039/b517719g
The formation of various a-diazo acetoacetic esters can be
obtained in a single transformation with good to excellent yields
using readily available 2-diazoacetoacetic acid.
Diazo carbonyl compounds are versatile building blocks in organic
synthesis.1 The unique reactivity of these compounds allows them
to undergo a variety of synthetic transformations that include C–H
insertions,2 Wolff rearrangements,3 cyclopropanations,4 and other
useful transformations.5 Over the past three decades, the utility
and scope of diazo carbonyl compounds have vastly increased due
to the development of various transition metal catalysts that can
control the chemoselectivity and regioselectivity of a given
reaction.6
In the course of recent synthetic studies, we required compounds
of the general type 2. We envisioned that accessing enone 2 from
alcohol 1 via standard protocols would be difficult due to
conjugate addition reactions of the enone to form undesired
products. Indeed, initial attempts to prepare 2 were unsuccessful
using known protocols (Fig. 1). For instance, coupling of alcohol 1
with diketene, followed by diazotization using pABSA7 with TEA
led only to decomposition.8 The synthesis of 2 via a transester-
ification route was also explored. However, treatment of alcohol 1
with methyl diazoacetoacetate (3) and dimethylaminopyridine
(DMAP) in toluene at 110 uC produced none of the desired
diazoester 2.9,10
It thus became apparent that compound 2 could not be
produced under basic conditions using known methods, and an
alternate strategy was required. We envisioned that 2-diazoace-
toacetic acid (4) could, in principle, be coupled to alcohols using
standard carbodiimide chemistry. A related system has been
employed by Kato for the preparation of nonsymetrical
diazomalonates by implementation of the mono-acid derived from
ethyl diazomalonate.11 Attempts to saponify ethyl diazoacetoace-
tate under identical conditions to those reported by Kato led only
to decomposition. As an alternative, we hypothesized that it could
be possible to obtain 2-diazoacetoacetic acid (4) by careful
hydrogenolysis of a benzyl ester without loss of N2. Gratifyingly,
hydrogenolysis under neutral conditions occurred smoothly in
THF at room temperature using 10% Pd/C (7% w/w) as catalyst to
provide a crude solution of diazoacetoacetic acid (4) and ca. 2–5%
of acetoacetic acid after filtration (Fig. 2).12
With diazo acid 4 in hand, we hoped that direct coupling under
neutral conditions would afford ester 2 in high yield. To our
delight, coupling of 4 with alcohol 1 proceeded rapidly upon
treatment with DCC and a catalytic amount of DMAP to provide
ester 2 in 77% yield (Table 1, entry 1). We then investigated the
scope of the esterification with a number of alcohols.13 As shown
in Table 1, esterification occurs efficiently for a variety of alcohols.
Primary and allylic alcohols couple with diazoacetoacetic acid in
good to excellent yields (entries 3–7). Secondary alcohols are also
competent substrates and lead to their respective a-diazo-
b-ketoesters in good yields (entries 1, 2, 9–11).14 As shown in
entry 8, 3-methoxyphenol undergoes esterification with 4 in 75%
yield. Amines are also tolerated under these conditions, as
illustrated by the coupling of 4 with phenethylamine to afford
the a-diazo-b-ketoamide in 95% yield (entry 12).15
In conclusion, a general method for obtaining a-diazoacetoa-
cetic esters using 2-diazoacetoacetic acid (4) has been described.
The latter reagent is readily generated, and can be synthesized on
reasonable scale (ca. 5.0 mmol) in a straightforward manner from
available starting materials. Coupling with acid 4 offers several
advantages over known methods. Mainly, it allows diazo
incorporation under neutral conditions into base-sensitive sub-
strates that could not be diazotized under known basic conditions.
Furthermore, esterification with 4 is more convergent than the
general method of acylation with diketene followed by diazotiza-
tion, as the substrate undergoes only a single transformation to
obtain the diazo dicarbonyl. The coupling of 2-diazoacetoacetic
acid (4) provides the desired products in good to excellent yields
Division of Chemistry and Chemical Engineering, California Institute of
Technology, 1200 East California Boulevard, MC 164-30, Pasadena,
CA, 91125, USA. E-mail: stoltz@caltech.edu; Fax: 626 564 9297;
Tel: 626 395 6064
{ Electronic supplementary information (ESI) available: experimental
details and characterization data for all compounds. See DOI: 10.1039/
b517719g
Fig. 1 Initial attempts toward 2.
Fig. 2 Generation of 2-diazoacetoacetic acid.
COMMUNICATION www.rsc.org/chemcomm | ChemComm
1316 | Chem. Commun., 2006, 1316–1318 This journal is  The Royal Society of Chemistry 2006
Table 1 Coupling of 2-diazoacetoacetic acida
Entry Substrate Product Yieldb
1c,d 77
2 95
3 92
4 85
5 82
6 80
7 77
8d 75
9d 77
10d 81
11d 87
12 95
a Standard conditions: 0.50 mmol substrate, 2-diazoacetoacetic acid (2.2 equiv), DCC (2.0 equiv), DMAP (0.10 equiv), 3.30 mL CH2Cl2, 23 uC,
60–90 min. b Isolated yield. c 0.30 mmol substrate. d Reaction at 40 uC, 60–90 min.
This journal is  The Royal Society of Chemistry 2006 Chem. Commun., 2006, 1316–1318 | 1317
and tolerates a wide range of alcohols. In addition, amines can be
used as substrates for the amidation with 4, thus providing access
to a-diazo-b-ketoamides. The use of diazo ketoacids as coupling
partners in various synthetic efforts is currently being employed in
our laboratory.
The authors gratefully acknowledge the NSF (predoctoral
fellowship for E.M.F.), Bristol-Myers Squibb (Graduate
Fellowship in Synthetic Organic Chemistry to E.M.F.),
AstraZeneca, Boehringer Ingelheim, Johnson & Johnson, Pfizer,
Merck, Amgen, Research Corporation, Roche, the Dreyfus
Foundation, and GlaxoSmithKline for generous funding.
Notes and references
1 For reviews, see: (a) M. P. Doyle, M. A. McKervey and T. Ye, Modern
Catalytic Methods for Organic Synthesis with Diazo Compounds from
Cyclopropanes to Ylides; Wiley-Interscience: New York, New York,
1998; (b) T. Ye and M. A. McKervey, Chem. Rev., 1994, 94, 1091–1160;
(c) A. Padwa and D. Austin, Angew. Chem., Int. Ed. Engl., 1994, 33,
1797–1815; (d) M. P. Doyle, Chem. Rev., 1986, 86, 919–939.
2 For a recent review of C–H activation using diazo compounds, see:
H. M. L. Davies and R. E. J. Beckwith, Chem. Rev., 2003, 103,
2861–2904.
3 For recent examples of Wolff rearrangements, see: (a) R. Sarpong,
J. T. Su and B. M. Stoltz, J. Am. Chem. Soc., 2003, 125, 13624–13625;
(b) H. Yang, K. Foster, C. R. J. Stephenson, W. Brown and E. Roberts,
Org. Lett., 2000, 2, 2177–2179; (c) R. R. Julian, J. A. May, B. M. Stoltz
and J. L. Beauchamp, Angew. Chem., Int. Ed., 2003, 42, 1012–1015; (d)
A. Bogdanova and V. Popik, J. Am. Chem. Soc., 2003, 125, 1456–1457;
(e) J. Podlech and M. R. Linder, J. Org. Chem., 1997, 62, 5873–5883.
4 For a review of cyclopropanation, see: H. Lebel, J.-F. Marcoux,
C. Molinaro and A. B. Charette, Chem. Rev., 2003, 103, 977–1050.
5 For selected examples, see: (a) S. Kitagaki, M. Anada, O. Kataoka,
K. Matsuno, C. Umeda, N. Watanabe and S.-I. Hashimoto,
J. Am. Chem. Soc., 1999, 121, 1417–1418; (b) J. A. May and
B. M. Stoltz, J. Am. Chem. Soc., 2002, 124, 12426–12427; (c)
J. L. Wood, G. A. Moniz, D. A. Pflum, B. M. Stoltz, A. A. Houbec
and H.-J. Dietrich, J. Am. Chem. Soc., 1999, 121, 1748–1749; (d)
A. Padwa, M. A. Brodney, J. P. Marino, Jr., M. H. Osterhout and
A. T. Price, J. Org. Chem., 1997, 62, 67–77.
6 (a) A. Padwa, D. J. Austin and S. F. Hornbukle, J. Org. Chem., 1996,
61, 63–72; (b) C. H. Yoon, M. J. Zaworotko, B. Moulton and
K. W. Jung, Org. Lett., 2001, 3, 3539–3542; (c) A. G. H. Wee, B. Liu
and L. Zhang, J. Org. Chem., 1992, 57, 4404–4414; (d) A. Padwa,
D. J. Austin, A. T. Price, M. A. Semones, M. P. Doyle,
M. N. Protopopova, W. R. Winchester and A. Tran, J. Am. Chem.
Soc., 1993, 115, 8669–8680.
7 J. S. Baum, D. A. Shook, H. M. L. Davies and D. H. Smith, Synth.
Commun., 1987, 17, 1709–1716.
8 We have tentatively assigned the product of this reaction sequence to be:
.
9 A similar transesterification on a 2u alcohol was recently described, see:
J. Lim, D.-J. Choo and Y. H. Kim, Chem. Commun., 2000, 553–554.
10 When alcohol 5 was subjected to the identical reaction conditions, the
only isolated product arose from a Wolff Rearrangement of 3, followed
by addition of 5 into the resulting ketene to provide ii
.
11 F. Kido, K. Yamaji, T. Abiko and M. Kato, J. Chem. Res. (S), 1993,
18–19.
12 For a typical hydrogenolysis, see Supporting Information.
13 For a typical esterification procedure, see Supporting Information.
14 It is known that a-diazoacetoacetates can be converted to a-diazoace-
tates under basic conditions. For a general procedure, see: M. P. Doyle,
R. E. Austin, A. S. Bailey, M. P. Dwyer, A. B. Dyatkin, A. V. Kalinin,
M. M. Y. Kwan, S. Liras, C. J. Oalmann and R. J. Pieters, et al.,
J. Am. Chem. Soc., 1995, 117, 5763–5775.
15 For examples of a-diazo-b-ketoamides, see: (a) A. Padwa and L. Zhi,
J. Am. Chem. Soc., 1990, 112, 2037–2038; (b) A. Jeganathan,
S. K. Richardson, R. S. Mani, B. E. Haley and D. S. Watt,
J. Org. Chem., 1986, 51, 5362–5367; (c) A. Padwa, D. C. Dean,
D. J. Fairfax and S. L. Xu, J. Org. Chem., 1993, 58, 4646–4655.
1318 | Chem. Commun., 2006, 1316–1318 This journal is  The Royal Society of Chemistry 2006


2-Diazoacetoacetic acid, an efficient and convenient reagent for the synthesis of alpha-diazo-beta-ketoesters

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2-Diazoacetoacetic acid, an efficient and convenient reagent for the synthesis of alpha-diazo-beta-ketoesters

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