Ethyl Diazoacetate (28). Use of commercially available
8 in the â-ketoester-forming reaction gave good results, but
additional studies determined that 28 prepared by published
procedures16 was undesirable. These methods use haloge-
Table 1. Lewis acid-catalyzed reaction of 28 with 29
2
product ratio
b
Lewis
acid
time temp
30:33:34
30
c
entrya
solvent
(h) (°C) (HPLC area %) (%)
nated solvents and gave rise to lower than desired yields.
Therefore, extensive work within Monsanto18 led to the
development of a new method of preparation of 28 from
ethyl glycinate hydrochloride (eq 1: preparation of 28 from
ethyl glycinate hydrochloride).
1
2
3
4
5
6
7
BF
AlCl
FeCl3
GeCl
ZrCl
TiCl
SnCl
3
‚OEt
3
2
diethyl ether
toluene
2
2
5
25
25
2
-5
0
25
22
22
-14
23
32:27:4
30:6:1
27:21:2
-
42
-
CH Cl2
2
-
4
2
CH Cl
2
18
30
inc
47
4
cumene
toluene
27:18:1
-
d
4
2
2
CH Cl
2
3
30:50:4
a
All reactions were run as 2 wt % of 29 in the listed solvent with 10 mol %
b
Lewis acid and 1.5 equiv of 28. Ratio determined by HPLC analysis and
c
corrected for relative molar extinction coefficients of 1:1:2.45, respectively. The
yields reported are for product isolated via chromatography or by HPLC analysis
d
against an analytical standard of 30. Incomplete conversion observed due to
competing ethyl diazoacetate decomposition.
The procedure was based on a biphasic system of
preparation. An aqueous solution of 27 was prepared in a
sodium acetate-hydrochloric acid buffer with a pH ) 3.5.
This pH was found to be optimum. A decrease or increase
in pH negatively affected 28 yield. To this solution was then
added a predetermined amount of toluene. Typically, solu-
tions prepared in-house ranged from 10 to 11% 28 by weight,
with respect to toluene. Working at this concentration
addressed in-house safety concerns. On the other hand,
extensive studies on the thermostability and detonation
properties20 of 28 suggested that higher concentrations,
perhaps up to 30 wt %, may be employed safely.
Once the biphasic system was in place, an aqueous
solution of sodium nitrite was added at such a rate that the
temperature of the mixture was e15 °C. This mixture was
stirred for 1-3 h, and the phases were separated. This
afforded 28 in yields of 89-92%, which was used without
further purification.
Our optimization research began by subjecting 28 and 29
1
4,16
to a variety of catalyst in several solvents.
Some of the
results are depicted in Table 1. One difficulty observed was
2
7
the relative insolubility of 29 in the solvents tested.
In addition to monitoring the desired conversion, another
2
8
product being formed was pyrazole 33. Trace amounts of
the pyrazole regioisomer 34 were also isolated and identi-
2
9
fied. The ratio of 30 to 33 to 34, respectively, is provided
19
in Table 1. Thus, another factor considered in our evaluation
30
was the selectivity of the catalyst for 30.
Believing the relative insolubility of 29 to be in part
responsible for incomplete conversion, a variety of solvents
â-Ketoester 30. One of the most intriguing techniques
31
were tested with SnCl
2
as the catalyst. A few of the results
was not very
21
reported for preparation of â-ketoesters is the reaction of
are summarized in Table 2. Interestingly, SnCl
2
14
an aldehyde with ethyl diazoacetate. This homologation
effective in most solvents, resulting mostly in incomplete
conversion. However, moderate success was obtained in
2
2
16,23
may be achieved thermally or by means of Lewis acid,
24
25
zeolite, or alumina catalysis. In a program directed toward
preparing â-ketoester 30, the reaction of aldehyde 29 with
8 was studied extensively.
26
(26) (a) Clark, J. D.; Shah, A. S.; Peterson, J. C. Thermochim. Acta 2002, 392-
393, 177. (b) Clark, J. D.; Shah, A. S.; Peterson, J. C.; Gorgan, K. M.;
2
Camden, S. Thermochim. Acta 2001, 367-368, 75. (c) Clark, J. D.
Proceedings, 28th Annual Conference of the North American Thermal
Analysis Society; Therm. Anal. Appl. 2000, 346. (d) Clark, J. D. Proceedings,
27th Annual Conference of the North American Thermal Analysis Society;
Therm. Anal. Appl. 1999, 119. (e) Clark, J. D.; Shah, A. Proceedings of the
9th RC User Forum...USA Scientific and Technical Program, October 27,
1998.
(19) Clark, J. D.; Shah, A. S.; Peterson, J. C.; Patelis, L.; Kersten, R. J. A.;
Heemskerk, A. H.; Gorgan, M.; Camden, S. Thermochim. Acta 2002, 386(1),
6
5.
(20) Clark, J. D.; Shah, A. S.; Peterson, J. C.; Patelis, L.; Kersten, R. J. A.;
Heemskerk, A. H. Thermochim. Acta 2002, 386(1), 73.
(
21) For alternative â-ketoester preparative methods, see: (a) Clasien, L.;
(27) For example, the solubility of 29 in toluene was measured at approximately
0.70 wt % at 20 °C.
Lowman, O. Ber. 1887, 20, 651. (b) Schaefer, J.; Bloomfield, J. Org. React.
1
8
967, 15, 1. (c) Wenkert, E.; McPherson, A. J. Am. Chem. Soc. 1972, 94,
664. (d) Balasubrahmanyam, S. N.; Balasubrahmanyam, M. Organic
(28) Pyrazole 33 was shown to be identical to material derived from a literature
procedure. See: (a) Beck, J. R.; Gajewski, R. P.; Lynch, M. P.; Wright, F.
L. J. Heterocycl. Chem. 1987, 24(1), 267. (b) Holzer, W.; Seiringer, G. J.
Heterocycl. Chem. 1993, 30(4), 865.
(29) Pyrazole 34 was shown to be identical to material derived from a literature
procedure. (a) Holzer, W.; Seiringer, G. J. Heterocycl. Chem. 1993, 30(4),
865. (b) El Khadem, H.; Rateb, L.; Mokhtar, H. J. Chem. Soc., C 1968,
1845.
Syntheses; Wiley: New York, 1973: Vol. V, p 439. (e) I. Rathko, M. Org.
React. 1975, 22, 423. (f) Pallicciari, R.; Fringualli, R.; Ceccherelli, P.; Sisani,
E. J. Chem. Soc., Chem. Commun. 1979, 959. (g) Ikota, N.; Takamura, N.;
Young, S.; Ganem, B. Teterahedron Lett. 1981, 22(42), 4163. (h) Pallicciari,
R.; Natalini, B.; Fringualli, R.; Ceccherelli, P. J. Chem. Soc., Perkin Trans.
1
1985, 493. (i) Kocienski, P.; Stocks, M.; Donald, D.; Cooper, M.; Mannera,
A. Tetrahedron Lett. 1988, 29(35), 4481. (j) Benetti, S.; Romagnoli, R.;
De-Risi, C.; Spalluto, G.; Zanirato, V. Chem. ReV. 1995, 95, 1065.
(30) A study of the reaction of 28 with 29 by NMR analysis indicated that 30,
33, and 34 form independently, with no build up of a common intermediate.
The relative rate of formation of 30 verses 33 was approximately 10:1,
respectively. A clean transformation was observed displaying resonances
consistent with the reaction of 28 and 29 to products 30, 33, and 34 only.
No transient R-formyl ester was observed, suggesting that a 1,2-rearrange-
ment similar to that reported by Kanemasa was not in operation.
(31) For the effect of solvents on the reactivity of imines with ethyl diazoacetate
see: Casarrubios, L.; Perez, J. A.; Brookhart, M.; Templeton, J. L. J. Org.
Chem. 1996, 61, 8358.
(
(
(
(
22) (a) Buchner, E.; Curtlus, T. Ber. 1883, 18, 2371. (b) Schlotterbeck, F. Ber.
1
907, 40, 479, 3000. (c) Dieckmann, W. Ber. 1910, 43, 1024.
23) Kanemasa, S.; Kanai, T.; Araki, T.; Wada, E. Tetrahedron Lett. 1999, 40,
055.
5
2
3
24) Sudrik, S. G.; Balaji, B. S.; Singh, A. P.; Mitra, R. B.; Sonawane, H. R.
Synlett 1996, 369.
25) Dhavale, D. D.; Patil, P. N.; Mali, R. S. J. Chem. Res., Synop. 1994, 4,
1
52.
180
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Vol. 8, No. 2, 2004 / Organic Process Research & Development