A simple one-pot preparation of diazoacetoacetate derivatives from aldehydes

Article abstract of DOI:10.1021/jo8017523

(Chemical Equation Presented) Diazoacetoacetate derivatives can be simply and efficiently prepared from aldehydes in a one-pot process involving initial DBU-promoted "aldol" condensation with ethyl diazoacetate followed by in situ oxidation with IBX. Aryl, alkyl, and unsaturated aldehydes are all viable substrates.

Full text of DOI:10.1021/jo8017523

SCHEME 1
A Simple One-Pot Preparation of
Diazoacetoacetate Derivatives from Aldehydes
Marvis O. Erhunmwunse†,‡ and Patrick G. Steel*,†
Department of Chemistry, UniVersity of Durham, Science
Laboratories, South Road, Durham DH1 3LE, U.K., and
Department of Chemistry, Faculty of Physical Sciences,
UniVersity of Benin, PMB 1154 Benin City, Nigeria
p.g.steel@durham.ac.uk
ReceiVed August 6, 2008
generic, one-pot method for the conversion of aldehydes to
diazoacetoacetate derivatives.
As part of a wider program directed toward heterocycle
synthesis through C-H insertion chemistry, we wished to
transform aldehyde 1 into diazoacetoacetate 4, Scheme 1.
Although this can be achieved by classical diazo transfer, the
preparation of the precursor ꢀ-ketoester 3 was rather protracted
and inefficient. Consequently, we explored more direct routes
involving condensation reactions of the anion of ethyl diazoac-
etate. While the reaction of the anion of ethyl diazoacetate with
acid chlorides is precedented,8 attempts to reproduce these with
1 afforded only complex mixtures, and we then turned to a more
stepwise process involving condensation with an aldehyde and
subsequent oxidation. Although initial attempts using lithio
diazoacetates, generated through the action of LDA at -78 °C,
provided the desired aldol product, it proved to be simpler and
more efficient to follow the precedents established by Wang et
al.7 and use a substoichiometric amount of 1,8-diazobicyclo-
[5.4.0]undec-7ene (DBU) as the base in acetonitrile at room
temperature. This simple modification allowed the R-diazo-ꢀ-
hydroxy carbonyl compound to be obtained in good yield (Table
1, entry 1). At this stage, all that remained was to oxidize this
product to the diazodicarbonyl function. In view of the interest
in diazocarbonyl compounds, it is rather surprising that relatively
few oxidants have been reported for this transformation,
presumably due to the fact that the diazo group itself can be
easily oxidized.9 In these cases, the reagents which have been
Diazoacetoacetate derivatives can be simply and efficiently
prepared from aldehydes in a one-pot process involving initial
DBU-promoted “aldol” condensation with ethyl diazoacetate
followed by in situ oxidation with IBX. Aryl, alkyl, and
unsaturated aldehydes are all viable substrates.
R-Diazocarbonyl compounds are useful intermediates in
organic synthesis that undergo a broad spectrum of reactions
catalyzed by various transition-metal salts.1 In particular,
diazoacetoacetate derivatives have been employed in cyclopro-
panation, ylide formation, and assorted X-H insertion reactions
(X ) C, N, O, Si, etc.). Such diazoacetoacetate derivatives not
only provide for simpler methods than the parent diazoacetates
but also result in increased functionality in the products. A major
challenge in the use of such compounds is in their preparation.
This is most commonly achieved by diazo transfer to a pre-
formed ꢀ-dicarbonyl function.2 An alternative, more convergent,
process is to exploit the latent nucleophilicity of an R-diazoac-
etate and combine the associated anion with a suitable elec-
trophile.3,4 For example, a conceptually simple two-step se-
quence involves the addition of a metalated R-diazoester to an
aldehyde followed by oxidation of the R-diazo-ꢀ-hydroxy car-
bonyl adducts.5 While the nucleophilic addition of acyldiaz-
omethanes to aldehydes and ketones is well precedented,3,6,7
reports of the oxidation of the aldol products to diazodicarbonyl
compounds are surprisingly rare and this sequence has not been
widely utilized. In this paper, we describe how these two steps
may be carried out in a single operation providing a simple,
(6) (a) Schollkopf, U.; Banhidai, B.; Frasnelli, H.; Meyer, R.; Beckhaus, H.
Liebigs Ann. Chem. 1974, 1767–1783. (b) Schollkopf, U.; Frasnelli, H.; Hoppe,
D. Angew. Chem., Int. Ed. 1970, 9, 301–302. (c) Pellicciari, R.; Natalini, B.
J. Chem. Soc., Perkin Trans. 1 1977, 1822–1824. (d) Pellicciari, R.; Natalini,
B.; Sadeghpour, B. M.; Marinozzi, M.; Snyder, J. P.; Williamson, B. L.; Kuethe,
J. T.; Padwa, A. J. Am. Chem. Soc. 1996, 118, 1–12. (e) Moody, C. J.; Taylor,
R. J. Tetrahedron Lett. 1987, 28, 5351–5352. (f) Burkoth, T. L. Tetrahedron
Lett. 1969, 5049–5052. (g) Woolsey, N. F.; Khalil, M. H. J. Org. Chem. 1972,
37, 2405–2408.
† University of Durham.
‡ University of Benin.
(1) Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic Methods for
Organic Synthesis with Diazo Compounds; Wiley-Interscience: New York, 1998.
(2) Regitz, M. Angew. Chem., Int. Ed. 1967, 6, 733–749.
(3) Wenkert, E.; McPherson, C. A. J. Am. Chem. Soc. 1972, 94, 8084–8090.
(4) Wenkert, E.; McPherson, C. A. Synth. Commun. 1972, 2, 331.
(5) Li, P. H.; Majireck, M. M.; Korboukh, I.; Weinreb, S. M. Tetrahedron
Lett. 2008, 49, 3162–3164.
(7) Jiang, N.; Wang, J. Tetrahedron Lett. 2002, 43, 1285–1287.
(8) Looker, J. H.; Hayes, C. H. J. Org. Chem. 1963, 28, 1342–1347.
(9) (a) Curci, R.; Difuria, F.; Ciabatto, J.; Concannon, P. W. J. Org. Chem.
1974, 39, 3295–3297. (b) Ihmels, H.; Maggini, M.; Prato, M.; Scorrano, G.
Tetrahedron Lett. 1991, 32, 6215–6218. (c) Ursini, A.; Pellicciari, R.; Tamburini,
B.; Carlesso, R.; Gaviraghi, G. Synthesis 1992, 363–364.
10.1021/jo8017523 CCC: $40.75
Published on Web 10/08/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 8675–8677 8675

TABLE 1. Conversion of Aldehydes to Diazoacetoacetates
(Table 1). Moreover, the oxidation reaction is very clean
requiring minimal purification, which in many cases simply
involves the removal of excess IBX through an aqueous workup.
The only limitation is that highly electron-rich and R,ꢀ-
unsaturated aldehydes give only moderate conversions in the
initial condensation step (Table 1, entries 6 and 7).
Since only a catalytic amount of DBU is required for the
synthesis of the R-diazo-ꢀ-hydroxyl carbonyl intermediate and
the presence of small quantities of DBU is not deleterious to
the action of IBX, we speculated that this two-step procedure
could have the potential to be conducted in a one-pot fashion.
This requires a common solvent, and since IBX has limited
solubility in acetonitrile we opted to explore the use of DMSO.
Pleasingly, treatment of a DMSO solution of aldehyde 1 with
ethyl diazoacetate and DBU for 8 h, followed by the addition
of a solution of IBX (1.1-1.5 equiv) in DMSO, afforded the
desired diazodicarbonyl compound 4 in good to excellent yields.
Having established the compatability of all the reagents, we then
examined the possibility of further telescoping the procedure
by adding the oxidant at the outset of the reaction. Again this
proved successful, providing the diazoacetoacetates in good
yields that are equal to or greater than that obtained by the
standard two-step protocol. Importantly, this one-pot procedure
allows both electron-rich and R,ꢀ-unsaturated aldehydes to be
converted to the desired diazoacetoacetates in moderate to good
yields.
In conclusion, we have identified a simple, mild, and efficient
one-pot process for the conversion of aldehydes to diazoac-
etoacetates.
Experimental Section
Representative Procedure for the Preparation of r-Diazo-
ꢀ-hydroxyl Esters. Ethyl 2-Diazo-3-hydroxy-3-(2′-methyl-5′-
phenyl-1′,3′-dioxan-2′-yl)propanoate (Table 1, Entry 1). To a
solution of ethyl diazoacetate (0.65 mL, 6.17 mmol) in anhydrous
CH3CN (12 mL) at room temperature under nitrogen was added
successively a solution of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)
(0.08 mL, 0.52 mmol) in anhydrous CH3CN (6 mL) and 2-methyl-
5-phenyl-1,3-dioxane-2-carbaldehyde (1.06 g, 5.15 mmol) in an-
hydrous CH3CN (12 mL) via cannula. After the mixture was stirred
at room temperature for 15 h, the reaction was quenched with
saturated aqueous NaHCO3 and then extracted with CH2Cl2 (3 ×
20 mL). The solvent was removed in vacuo, and the crude product
obtained was purified by flash column chromatography on silica
gel (ethyl acetate/petroleum ether 2/8) to afford the title diazoketol
(Table 1, entry 1) (1.37 g, 86%) as a shiny yellow oil. νmax (neat):
3520-3410, 2980, 2875, 2096, 1683, 1496, 1394, 1107, 1050, 870,
701 cm-1. δH (500 MHz; CDCl3): 7.41 (2H, d, J 7.6), 7.35 (2H, t,
J 7.6), 7.27 (1H, t, J 7.6), 4.85 (1H, bs), 4.29-4.26 (2H, m),
4.25-4.19 (2H, m), 4.15 (2H, dd, J 11.7, 5.4), 2.94-2.90 (1H,
m), 2.84 (1H, bs), 1.50 (3H, s), 1.28 (3H, t, J 7.0). δC (125 MHz;
CDCl3): 166.4, 140.0, 128.9, 127.8, 126.9, 100.4, 67.8, 65.1, 64.2,
60.8, 39.1, 17.6, 14.4. m/z (ES+): 663 (2M + Na+, 35), 417 (100),
343 (M + Na+, 60). HRMS (ES+): found 343.1262 (C16H20O5N2Na
requires 343.1264).
Representative Procedure for the Oxidation of r-Diazo-ꢀ-
hydroxy Esters. Ethyl 2-Diazo-3-(2′-methyl-5′-phenyl-1′,3′-di-
oxan-2′-yl)-3-oxopropanoate (Table 1, Entry 1). Iodoxybenzoic
acid (IBX) (0.34 g, 1.22 mmol) was dissolved in DMSO (5 mL)
over 20 min at room temperature. To this was added a solution of
the above alcohol (0.26 g, 0.81 mmol) in DMSO (4 mL) via
cannula, and the solution was stirred for 4 h at room temperature.
The reaction mixture was quenched with aqueous NaHCO3 and
then extracted with DCM (3 × 10 mL), the combined organic layers
were copiously washed with aqueous NaHCO3 (×3) and finally
a All yields refer to purified products following chromatography.
b Yields of individual steps in parentheses. c Yield of 85% based on
recovered starting material.
used for the oxidation of R-diazo-ꢀ-hydroxy compounds are
limited to manganese dioxide,10 barium permanganate,11 and
2-iodoxybenzoic acid (IBX).12 While initial attempts to use
activated MnO2 were successful giving over 80% yield of the
desired diazoacetoacetate, the reaction was both slow and
inefficient requiring large excesses of the oxidant. Much faster
oxidation could be achieved using the Swern conditions,
although at some cost to the yield (76%). Ultimately, a highly
efficient (g90%) and rapid oxidation was achieved using IBX
in DMSO following the precedents established by Moody (Table
1). This two-step sequence proved to be general with a variety
of aliphatic, aromatic, and heterocyclic aldehydes being con-
verted in good yield to the corresponding diazoacetoacetate
(10) Deng, G.; Xu, B.; Wang, J. Tetrahedron 2005, 61, 10811–10817.
(11) (a) Moody, C. J.; Taylor, R. J. Tetrahedron 1990, 46, 6525–6544. (b)
Padwa, A.; Dean, D. C.; Osterhout, M. H.; Precedo, L.; Semones, M. A. J. Org.
Chem. 1994, 59, 5347–5357.
(12) (a) Bagley, M. C.; Hind, S. L.; Moody, C. J. Tetrahedron Lett. 2000,
41, 6897–6900. (b) Davies, J. R.; Kane, P. D.; Moody, C. J. J. Org. Chem.
2005, 70, 7305–7316. (c) Davies, J. R.; Kane, P. D.; Moody, C. J.; Slawin,
A. M. Z. J. Org. Chem. 2005, 70, 5840–5851.
8676 J. Org. Chem. Vol. 73, No. 21, 2008

with water, and the mixture was then dried with MgSO4, filtered,
and concentrated in vacuo. The resulting crude product was purified
by flash column chromatography on silica gel (ethyl acetate/
petroleum ether 2/8) to afford the title diazoacetoacetate (Table 1,
entry 1) (0.23 g, 90%) as a yellow solid. Mp: 60-62 °C. νmax (neat):
2127, 1732, 1666, 1305, 1186, 1015, 856, 702, 629 cm-1. δH (500
MHz; CDCl3): 7.28-7.25 (2H, m), 7.23-7.19 (1H, m), 7.08 (2H,
d, J 7.4), 4.31 (2H, q, J 7.4), 4.06 (2H, dd, J 11.9, 4.8), 3.91 (2H,
t, J 11.9), 3.25-3.18 (1H, m), 1.53 (3H, s), 1.31 (3H, t, J 7.1). δC
(125 MHz; CDCl3): 188.6, 161.2, 136.7, 128.8, 127.61, 127.58,
mixture was quenched with aqueous NaHCO3 and then extracted
with DCM (3 × 20 mL), the combined organic layers were
copiously washed with aqueous NaHCO3 (×3) and finally with
water, and the mixture was then dried with MgSO4, filtered, and
concentrated in vacuo. The resulting crude product purified by flash
column chromatography on silica gel (ethyl acetate/petroleum ether)
afforded the title diazoacetoacetate (0.14 g, 89%) identical in all
respects to that obtained above.
Acknowledgment. We thank Dr. A. M. Kenwright for as-
sistance with NMR experiments, Dr. M. Jones for mass spectra,
and The Association of Commonwealth Universities (NGCA-
2006-64) and University of Benin, Nigeria, for financial support
(scholarship to M.O.E.).
100.5, 67.8, 62.0, 40.1, 25.0, 14.3. m/z (ES+): 382 (M + Na+
+
CH3CN, 20), 341 (M + Na+, 100), 319 (M + H+, 30). Anal.
[Found: C, 60.8; H, 5.7; N, 7.3. C16H18O5N2 requires C, 60.4; H,
5.7; N, 8.0].
Representative Procedure for the One-Pot Synthesis of Diazo-
dicarbonyl Compounds. Ethyl 2-Diazo-3-(2′-methyl-5′-phenyl-1′,
3′-dioxan-2′-yl)-3-oxopropanoate (Table 1, Entry 1). To a solution
of ethyl diazoacetate (0.06 mL, 0.58 mmol) in DMSO (4 mL) at
room temperature were added in succession DBU (0.007 mL, 0.05
mmol), 2-methyl-5-phenyl-1,3-dioxane-2-carbaldehyde (0.10 g, 0.49
mmol), and a solution of IBX (0.27 g, 0.97 mmol) in DMSO (5
mL). After being stirred for 10 h at room temperature, the reaction
Supporting Information Available: Experimental proce-
dures, product characterization, and copies of NMR spectra for
all new products. This information is available free of charge
via the Internet at http://pubs.acs.org.
JO8017523
J. Org. Chem. Vol. 73, No. 21, 2008 8677