Metalation of α-diazocarbonyl compounds using Grignard reagents. A convenient synthesis of α-diazo-β-ketoesters and mixed esters of α-diazomalonate

Article abstract of DOI:10.1016/j.tetlet.2004.01.074

α-Diazocarbonyl compounds react with methylmagnesium bromide at -78°C generating the corresponding α-diazo-α-bromomagnesio species, which can be intercepted by various electrophilic reagents. For example, with alkyl chloroformates α-diazo-β-ketoesters or mixed esters of α-diazomalonate are obtained in good yields.

Full text of DOI:10.1016/j.tetlet.2004.01.074

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 2417–2419
Metalation of a-diazocarbonyl compounds using Grignard reagents.
A convenient synthesis of a-diazo-b-ketoesters and mixed esters
of a-diazomalonate
a,
b
a,z
*
Erick Cuevas-Ya n~ ez, Joseph M. Muchowski and Raymundo Cruz-Almanza
a
Instituto de Qu ꢀı mica, UNAM. Organic synthesis, Circuito Exterior, Ciudad Universitaria, Coyoac ꢀa n, 04510 M ꢀe xico DF, Mexico
Chemistry, Roche Palo Alto, 3431 Hillview Avenue, Palo Alto, CA 94304-1320, USA
b
Received 7November 2003; revised 15 January 2004; accepted 16 January 2004
Abstract—a-Diazocarbonyl compounds react with methylmagnesium bromide at )78 ꢀC generating the corresponding a-diazo-a-
bromomagnesio species, which can be intercepted by various electrophilic reagents. For example, with alkyl chloroformates a-diazo-
b-ketoesters or mixed esters of a-diazomalonate are obtained in good yields.
ꢁ
2004 Elsevier Ltd. All rights reserved.
a-Diazo-b-ketoesters are of considerable importance as
precursors of carbonyl ylides, and recently have also
been used to prepare furo[3,4-c]furan derivatives.
diazoacetate with methylmagnesium iodide and the
subsequent generation of ethyl a-diazopropionate upon
reaction of the a-iodomagnesio species with methyl
iodide. This report describes the successful adaptation
of this methodology to the synthesis of a-diazo-b-
ketoesters from a-diazoketones and alkyl chlorofor-
mates.
1
2
In connection with a current synthetic study, we
required an array of a-diazo-b-ketoesters in which the
acyl portion of the molecule was widely varied. The
3
diazo transfer reaction to b-ketoesters, which is one of
the most frequently used syntheses of these compounds,
was inappropriate for our purposes because the required
b-ketoesters were not readily accessible. The direct
acylation of diazoacetic esters although attractive, is
In a model study, an equimolar amount of methyl-
magnesium bromide in THF was added to a THF
solution of ethyl diazoacetate at )78 ꢀC (inert atmo-
sphere). After 30 min at )78 ꢀC an equimolar amount of
ethyl chloroformate was added and after an additional
30 min at )78 ꢀC, the reaction was quenched with
4
limited in scope to reactive acyl halides and anhydrides
5
(
diazoacetic acid esters react with aldehydes and imines
e.g., trifluoroacetic anhydride). It is known that a-
aqueous NH Cl. Column chromatographic purification
4
6
7
in the presence of NaOH or DBU. In addition, a-
metalated diazo compounds based on lithium, silver,
on silica gel gave diethyl diazomalonate in 81% yield.
Not only was this process readily applicable to the
synthesis of mixed esters of a-diazomalonate (Table 1,
entries 9–11), it could also be used to prepare a-diazo-
8
9
10
11
mercury, or zinc are easily generated and react with
various electrophilic reagents. We attempted to adapt
several of these methods to the synthesis of a-diazo-b-
ketoesters from a-diazoketones and alkyl chloro-
formates, but they either failed completely, or were of
limited generality. We were attracted by the report of
13
b-ketoesters from a-diazoketones (entries 1–7).
Further-more, electrophilic reagents such as di-tert-
butyldicarbonate, MEM chloride, p-toluenesulfonyl
chloride, and piperonal produced the new a-diazo-b-
substituted carbonyl compounds shown in entries 11–14.
12
Sch o€ llkopf et al. concerning the deprotonation of ethyl
This synthesis of functionalized a-diazocarbonyl com-
pounds has one important limitation. Substrates with
acidic hydrogens a to the carbonyl moiety are deprot-
onated at this site and the carbanionic species so pro-
duced cyclizes. For example, the diazoketone 1 is
converted into the enolate 2, which on acidification gives
Keywords: Diazoketone; Grignard reagent; Diazoketoester; Diazomal-
onate.
*
Corresponding author. Tel.: +52-56-224408; fax: +52-56-162217;
e-mail: erick.cuevas@correo.unam.mx
Deceased, October 2003.
18
z
0
040-4039/$ - see front matter ꢁ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.01.074

2418
E. Cuevas-Ya ~n ez et al. / Tetrahedron Letters 45(2004) 2417–2419
Table 1. Diazocompounds prepared from a-diazocarbonyl compounds, methylmagnesiumbromide and diverse electrophiles
O
O
O
THF
EX
E
CH
3
MgBr
MgBr
R
+
R
R
-78 °C
N
2
N
2
N
2
Entry
R
Electrophile Diazocompound
Yield
(
Entry
R
Electrophile
ClCOOEt
Diazocompound
Yield
(%)
%)
O
O
O
O
O
14
15
1
Ph
ClCOOEt
7
9
8E tO
81
Ph
OEt
EtO
OEt
N
2
N
2
O
O
O
O
O
O
O
4
d
6
7
2
3
4
5
6
7
Ph
ClCOOi-Bu Ph
OiBu
98
68
58
45
42
42
9
EtO
EtO
EtO
EtO
EtO
Ph
ClCOOBn
82
73
63
44
88
97
EtO
EtO
EtO
EtO
OBn
OiBu
OtBu
O
N
N
N
2
N
N
2
2
O
O
O
O
O
O
O
Ph
(BOC)
2
O
10
ClCOOi-Bu
Ph
Ph
Ph
Ph
Ph
OtBu
O
2
O
1
PhCH
PhCH
PhCH
2
2
2
2
CH
CH
CH
CH
2
2
2
2
ClCOOEt
ClCOOBn
ClCOOi-Bu
11
12
13
14
2
(BOC) O
OEt
N
2
2
O
O
ClMEM
OBn
OiBu
OtBu
N
N
N
2
N
2
O
O
1
SO
2
C
6
H
4
CH
3
ClSO
2
C
6
H
4
CH
3
EtO
Ph
N
2
2
2
O
OH
OHC
O
O
O
O
PhCH
2
(BOC) O
N
2
the very unstable, but spectroscopically characterizable
pyrazolinone 3. If the enolate solution is left at room
temperature (12 h), acidification gives crystalline 3-phe-
Acknowledgements
19
Financial support from CONACyT (No. 37312-E) is
gratefully acnowledged. The authors would also like to
thank R. Pati n~ o, M. Adaya, A. Pe n~ a, N. Zavala,
E. Huerta, J. P ꢀe rez, and L. Velasco for the technical
support.
20
nyl-4-hydroxypyrazole 4 (75% yield). This route to
-hydroxypyrazoles has ample literature precedent
4
21
(
Scheme 1).
In summary, a-diazo-b-keto esters, mixed esters of
a-diazomalonates, and other b-substituted a-diazo-
carbonyl compounds are easily prepared from a-diazo-
a-bromomagnesio carbonyl compounds and the
appropriate electrophilic reagent. The simplicity of
the method suggests that this route to b-functionalized
a-diazocarbonyl compounds will enjoy widespread
application.
References and notes
1
. Hodgson, D. M.; Glen, R.; Grant, G. H.; Redgrave, A.
J. Org. Chem. 2003, 68, 581, and references cited therein.
. Padwa, A.; Straub, C. S. J. Org. Chem. 2003, 68, 227.
. Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Synthetic
Methods Using Diazocompounds: From Cyclopropanes to
Ylides; John Wiley and Sons: New York, 1998.
2
3
THF
o
OMgBr
O
O
H
3
O+
+
3
CH MgBr
4
. (a) Bestmann, H. J.; Kolm, H. Chem. Ber. 1963, 96, 1948;
(b) Staudinger, H.; Becker, J.; Hirzel, H. Chem. Ber. 1916,
o
-
78 C
-78 C
N
2
N
N
N N
2
3
4
1
4
1
9, 1978; (c) Looker, J. H.; Thatcher, D. N. J. Org. Chem.
958, 23, 403; (d) Marino, J. P.; Osterhout, M. H.; Price,
A. T.; Sheehan, S. M.; Padwa, A. Tetrahedron Lett. 1994,
5, 849.
5. Weygand, F.; Schwenke, W.; Bestmann, H. J. Angew.
OH
1
)
R.T.
3
2
3
) H O+
N NH
Chem. 1958, 70, 506.
6. Wenkert, E.; McPherson, A. J. Am. Chem. Soc. 1972, 94,
8084.
Scheme 1. Generation of pyrazolinone 3 and hydroxypyrazole 4
from 1.

E. Cuevas-Ya ~n ez et al. / Tetrahedron Letters 45(2004) 2417–2419
2419
7
8
. Jiang, N.; Wang, J. Tetrahedron Lett. 2002, 43, 1285.
. (a) Jiang, N.; Qu, Z.; Wang, J. Org. Lett. 2001, 3, 2989; (b)
Ye, T.; McKervey, M. A. Tetrahedron 1992, 48, 8007; (c)
Moody, C. J.; Taylor, R. J. Tetrahedron 1990, 46, 6525; (d)
Schollkopf, U.; Frasnelli, H. Angew. Chem., Int. Ed. Engl.
29.1, 31.3, 42.0, 72.9, 75.3, 126.1, 128.4, 128.4, 130.4,
þ
130.4, 139.0, 177.2, 213.3; MS [EI+] m=z (RI%): 274 [M]
þ
ꢀ1
(8), 91 [PhCH
2
1
]
(100). Entry 10: IR (CHCl
2141, 1713; H NMR (CDCl , 200 MHz) d 0.94 (d,
6H),1.28 (t, 3H), 3.85 (d, 2H), 4.24 (q, 2H); C NMR
3
, cm ) 2964,
3
1
3
1
970, 9, 301; (e) Aggarwal, V. K.; Sheldon, C. G.;
Macdonald, G. J.; Martin, W. P. J. Am. Chem. Soc.
002, 124, 10300.
(CDCl
3
, 50 MHz) d 14.3, 19.0, 19.0, 27.0, 72.2, 73.7, 74.6,
þ
177.1, 177.9; MS [EI+] m=z (RI%): 214 [M] (5), 0.73
þ
ꢀ1
2
[CO
2141, 1713; H NMR (CDCl
3.40 (s, 3H); 3.57 (t, 2H), 3.72 (t, 2H), 4.24 (q, 2H); 4.76 (s,
2
CH
2
CH
3
1
]
(100). Entry 12: IR (CHCl
3
, cm ) 2975,
9
. (a) Regitz, M.; Liedhegener, A.; Eckstein, U.; Martin, M.;
Anschutz, W. Leibigs Ann. Chem. 1971, 748, 207; (b)
Schollkopf, U.; Rieber, N. Chem. Ber. 1969, 102, 488.
0. (a) Demaree, P.; Doria, M. C.; Muchowski, J. M.
J. Heterocycl. Chem. 1978, 15, 1295; (b) Demaree, P.;
Doria, M. C.; Muchowski, J. M. Can. J. Chem. 1977, 55,
3
, 200 MHz) d 1.33 (t, 3H),
1
3
2H); C NMR (CDCl
3
, 50 MHz) d 14.3, 58.5, 58.7, 68.2,
þ
1
1
70.5, 72.8,171.4; MS [EI+] m=z (RI%): 202 [M] (5), 0.29
þ
ꢀ1
)
[CH
3360, 2909, 2090, 1686; H NMR (CDCl
d 6.06 (s, 2H), 6.74 (s, 1H), 6.94 (d, 1H), 6.97–7.63
2
CH
3
]
(100). Entry 14: p.f. 62 ꢀC; IR (CHCl
3
, cm
1
3
, 200 MHz)
2
1. (a) Sarabia, F.; Lopez-Herrera, F. J. Tetrahedron Lett.
43.
1
3
3
(m, 7H); C NMR (CDCl , 50 MHz) d 65.2, 69.7,
2
1
001, 42, 8801; (b) Moody, C. J.; Morfitt, C. N. Synthesis
998, 1039.
123.8, 123.8, 125.7, 125.7, 126.8, 126.8, 127.8, 127.8,
133.2, 135.4, 136.1, 139.7, 189.7; MS [EI+] m=z (RI%):
þ
þ
þ
1
2. Schollkopf, U.; Banhidai, B.; Frasnelli, H.; Meyer, R.;
Beckhaus, H. Liebigs Ann. Chem. 1974, 1767.
296 [M] (5), 268 [M)N
2
] (5), 251 [M)N )OH] (5), 151
2
þ
[M)CN
2
COC
6
H
5
]
(100).
1
3. Typical procedure for the synthesis of a-diazo-b-keto-
esters. 3.0 M Ethereal MeMgBr (0.33 mL, 1 mmol) was
added to a stirred solution of the diazoketone (1 mmol) in
14. Zeller, K. P.; Meier, H.; Muller, E. Liebigs Ann. Chem.
1971, 749, 178.
15. Rosenberg, M.; Yates, P.; Hendrickson, J. B.; Wolf, W.
Tetrahedron Lett. 1964, 2285.
16. Koskinen, A. M. P.; Mu n~ oz, L. J. Chem. Soc., Chem.
Commun. 1990, 652.
dry THF cooled to )78 ꢀC (N
2
atmosphere). The requisite
electrophilic reagent was then added neat at )78 ꢀC and
thereafter stirring was continued at this temperature for an
additional 30 min. Saturated aqueous NH
4
Cl (15 mL) was
then added to the reaction mixture and the product was
17. Regitz, M.; Bartz, W. Chem. Ber. 1970, 103, 1477.
18. McKervey, M. A.; Ratananukul, P. Tetrahedron Lett.
1982, 23, 2509.
extracted with ether (3 · 10 mL). The extract was dried
over Na
product was purified by column chromatography (SiO
2
SO
4
, the solvent was removed in vacuo and the
19. Preparation of compound 3. A THF solution of the
2
,
hexane/AcOEt 9:1). Selected spectral data. Entry 2: IR
bromomagnesio derivative of the a-diazoketone
(1 mmol) was prepared as described above, and after
30 min at )78 ꢀC saturated aqueous NH Cl (15 mL) was
added to the reaction mixture. The product was extracted
4
SO ,
1
ꢀ1
1
(
CHCl
3
, cm ) 2962, 2091, 1713; H NMR (CDCl
3
,
4
2
7
1
1
00 MHz) d 0.96 (d, 6H), 1.91 (m, 1H), 3.85 (d, 2H),
1
3
.09–7.70 (m, 5H); C NMR (CDCl
3
, 50 MHz) d 19.3,
9.3, 27.0, 72.2, 74.6, 126.8, 126.8, 127.8, 127.8, 135.5,
with ether (3 · 10 mL), the extract was dried over Na
2
and the solvent was removed in vacuo to give compound 3
as a very unstable, red oil (62%). Selected spectral data for
þ
36.1, 169.4, 183.2; MS [EI+] m=z (RI%): 246 [M] (5), 105
þ
ꢀ1
1
[
Ph)CO] (100). Entry 3: IR (CHCl
3
, cm ) 2984, 2110,
, 200 MHz) d 1.52 (s, 9H), 7.09–
.70 (m, 5H); C NMR (CDCl , 50 MHz) d 29.1, 29.1,
compound 3: H NMR (CDCl
3
, 300 MHz) d 5.13 (s, 2H),
1
13
1
7
2
1
720; H NMR (CDCl
3
3
6.19 (s, 1H), 7.19–7.36 (m, 5H); C NMR (CDCl ,
1
3
3
75 MHz) d 55.0, 68.0, 127.1, 128.7, 128.7, 129.2, 129.2,
þ
9.1, 72.9, 75.3, 126.4, 126.4, 127.7, 127.7, 135.2, 136.0,
þ
134.3, 197.8; MS [EI+] m=z (RI%): 160 [M] (25), 77
6 5
[C H ] (100); IR (film, cm ) 2108, 1732.
þ ꢀ1
70.1, 183.1 MS [EI+] m=z (RI%): 246 [M] (10), 105
þ
ꢀ1
[
1
Ph)CO] (100). Entry 4: IR (CHCl
3
, cm ) 2982, 2089,
, 200 MHz) d 1.33 (t, 3H),
.77 (t, 2H), 3.61 (t, 2H), 4.29 (q, 2H), 6.97–7.33 (m, 5H);
20. Preparation of compound 4. A solution of the bromo-
magnesio derivative of 1 (1 mmol) was prepared as
described above. After 30 min at )78 ꢀC, the cooling bath
was removed, and after 12 h at room temperature, the
reaction mixture was worked up as described for the
synthesis of 3 above. The crude product was purified by
1
762, 1709; H NMR (CDCl
3
3
1
3
C NMR (CDCl , 50 MHz) d 14.3, 31.1, 41.5, 63.0, 74.9,
3
1
26.5, 126.5, 127.7, 127.7, 135.3, 136.4, 177.8, 212.5; MS
þ
[
EI+] m=z (RI%): 246 [M]
(2), 91 [PhCH
Et] (100). Entry 5: IR (CHCl
2
,
,
þ
M)CH
2
COCN
2
CO
2
3
column chromatography (SiO
2
, hexane/AcOEt 8:2) to
ꢀ1
1
cm ) 3029, 2092, 1716; H NMR (CDCl , 200 MHz) d
3
afford a yellow solid (75%), mp 128–130 ꢀC. Selected
1
2
.99 (t, 2H), 3.39 (t, 2H), 5.11 (s, 2H), 6.97–7.33 (m, 10H);
C NMR (CDCl , 50 MHz) d 31.1, 41.5, 67.1, 75.4, 126.1,
3
spectral data for compound 4: H NMR (CDCl
3
,
1
3
300 MHz) d 5.10 (br s, 1H), 7.12 (s, 1H), 7.23 (m, 1 H),
7.29 (m, 2H), 7.32 (m, 2H), 7.88 (br s, 1H); C NMR
1
3
1
1
28.4, 128.4, 128.5, 130.4, 130.4,131.3, 131.3 135.2, 138.1,
þ
77.1, 213.3; MS [EI+] m=z (RI%): 308 [M] (5), 91
(CDCl
3
, 75 MHz) d 126.1, 127.6, 128.1, 128.1, 129.4,
þ
ꢀ1
þ
[
1
1
PhCH
2
]
(100). Entry 6: IR (CHCl
770; H NMR (CDCl , 200 MHz) d 0.96 (d, 6H), 1.91 (m,
H), 3.85 (d, 2H), 3.01 (t, 2H), 3.38 (t, 2H), 6.97–7.33 (m, 5
3
, cm ) 2963, 2117,
129.4, 138.1, 140.6, 142.9; MS [EI+] m=z (RI%): 160 [M]
(30), 143 [M] (50), 77 [C
1650.
1
þ
þ
ꢀ1
3
6
H
5
] (100); IR (film, cm ) 3321,
1
3
H); C NMR (CDCl , 50 MHz) d 19.0, 19.0, 27.0, 31.1,
41.2, 72.2, 74.6, 126.1, 128.4, 128., 130.4, 130.4, 139.0,
3
21. Chen, X.; Schneller, S. W. J. Med. Chem. 1993, 36, 3727;
See also (a) Yates, P.; Mayfield, R. J. Can. J. Chem. 1977,
55, 145; (b) Crain, P. F.; McCloskey, J. A.; Lewis, A. F.;
Schram, K. H.; Townsend, L. B. J. Heterocycl. Chem.
1973, 10, 843; (c) Bertho, A.; Nussel, H. Liebigs Ann.
Chem. 1927, 457, 278.
þ
1
IR (CHCl
77.1, 213.3; MS [EI+] m=z (RI%): 274 [M] (10). Entry 7:
1 1
ꢀ
3
, cm ) 2951, 2103, 1739; H NMR (CDCl
3
,
2
7
00 MHz) d 1.51 (s, 9H), 3.66 (d, 2H), 2.95 (t, 2H), 6.97–
.33 (m, 5 H); C NMR (CDCl , 50 MHz) d 29.1, 29.1,
3
13