A three-step preparation of MAC reagents from malononitrile

Article abstract of DOI:10.1016/S0040-4039(02)02483-8

An alternative method for the preparation of MAC reagents, H-C(CN)₂O-R, was developed. Using the proposed method, MAC reagents with acyl moiety were synthesized from malononitrile in more than 60% overall yields in three steps.

Full text of DOI:10.1016/S0040-4039(02)02483-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 73–75
A three-step preparation of MAC reagents from malononitrile
Hisao Nemoto,a,* Xinming Li,b Rujian Ma,a Ichiro Suzukia and Masayuki Shibuyaa
aFaculty of Pharmaceutical Sciences, The University of Tokushima, Sho-machi 1-78, Tokushima 770-8505, Japan
bDepartment of Chemistry, East China University of Science and Technology, Shanghai 200237, China
Received 30 September 2002; revised 4 November 2002; accepted 6 November 2002
Abstract—An alternative method for the preparation of MAC reagents, H-C(CN)2O-R, was developed. Using the proposed
method, MAC reagents with acyl moiety were synthesized from malononitrile in more than 60% overall yields in three steps.
© 2002 Elsevier Science Ltd. All rights reserved.
−
A number of researchers have developed various COX
synthon (X=OH, or the equivalent), which are useful
umpolung agents.1,2 The masked acyl cyanides [1, H-
Indirect (two-step) activation of the methylene group of
malononitrile was then examined via 2-(1-hydroxy-eth-
ylidene)malononitrile 7, which was prepared according
to the standard method10 in almost quantitative yield
from malononitrile (Scheme 3).
MAC-R3 (MAC=-C(CN)2O-)], a COX synthon, was
−
developed by us,4 and then we reported several syn-
thetic applications by using 1 (Scheme 1).5–8
Treatment of 7 (208 mg, 1.93 mmol) with 1.2 equiv. of
acetic peracid (9% in acetic acid solution, 5 ml, 6.04
mmol) in water (5 ml) for 2 h at room temperature gave
All of the transformation reactions from 1 to 4 proceed
under mild conditions, and a one-portion reaction can
be carried out in some cases.5,6 However, the availabil-
ity of 1 has until recently been limited because (i)
synthesis from diethyl malonate to 1 requires seven
steps and results in less than 10% overall yield (Scheme
2), (ii) conversion from 5 to 6 in ammonia takes up to
10 days when the R group is large, (iii) a basic labile
protecting group cannot be introduced as R because
one of the seven steps (from 5 to 6) requires ammonia
as a solvent, and (iv) an expensive condensation
reagent9 is required for the final step (from 6 to 1).
In this paper, we report an alternative method for the
preparation of 1 in three steps, and present the synthe-
sis of new MAC reagents 1 with an acyl moiety, one of
labile groups under basic conditions. To address the
numerous problems outlined above, we examined a
synthetic route starting from malononitrile which
would eliminate the need for an expensive condensation
reagent and ammonia. Direct oxidation of the active
methylene of malononitrile was initially attempted
using bromine, peroxides, peracids. However, none of
these approaches were successful.
Scheme 1.
Keywords: masked acyl cyanide; acyl anion equivalents; alkoxy-
malononitrile; oxidation; peracids.
* Corresponding author.
Scheme 2.
0040-4039/03/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02483-8

74
H. Nemoto et al. / Tetrahedron Letters 44 (2003) 73–75
new compound 1c (H-MAC-Ac) was obtained in 63%
overall yield from 7. It is noteworthy that this is the
first reported introduction of a basic labile protecting
group as R of MAC reagents. Synthesis of the benzoyl
derivative 1d (H-MAC-Bz) and the undecanoyl deriva-
tives 1e, (H-MAC-COC10H23) was also successful, both
afforded in 55% overall yield from 7.
The reaction mechanism for 7 to 8 is proposed as
shown in Figure 1. Although reaction course via 9 and
1c (Baeyer–Villiger type), was initially thought reason-
able, that route can be discounted because (i) careful
1
analysis of 7 by H and 13C NMR failed to detect the
keto form 9, (ii) not even trace 1c was obtained as
expected for a major Baeyer–Villiger type product, (iii)
acidic hydrolysis of 1c prepared from 8 was not
observed at all for more than 24 h under the same
reaction conditions as from 7 to 8. Therefore, the
proposed route is considerably via 10 and 11 (epoxida-
tion–ring opening type). After generation of the epox-
ide 10, which could be unstable in the presence of large
amount of acetic acid, 11 should be produced by ring
opening step. Since the product 11 has three electron-
withdrawing groups on one carbon, deacetylation
would easily occur to give 8.
Scheme 3.
the crude product 8. The resulting solution was concen-
trated in vacuo to eliminate excess of acetic peracid,
water and acetic acid (Caution: during concentration,
keep below 35°C in a hood with a hard shield since
acetic peracid is explosive). Purification of 8 was unsuc-
cessful because 8 was partially decomposed during silica
gel column chromatography. The crude product 8 was
then mixed with t-butyldimethylsilyl chloride (TBS-Cl,
436.3 mg, 2.90 mmol), and imidazole (197.4 mg, 2.90
mmol) in N,N-dimethylformamide (5 ml) and stirred
for 5 min at 0°C. The resulting mixture was diluted
with ethyl acetate, washed with an aqueous solution of
sodium hydrogen carbonate/sodium thiosulfate, fol-
lowed by washing with brine, then dried over magne-
sium sulfate, and concentrated in vacuo. The residue
was purified by column chromatography on silica gel
eluted with hexane/ethyl acetate (8/1) to give H-MAC-
TBS (1a, 299.3 mg, 1.72 mmol, 79% overall yield from
7). The ethoxyethyl derivative 1b (H-MAC-EE) was
obtained from the crude 8 using ethyl vinyl ether in the
presence of a catalytic amount of 4-toluenesulfonic acid
in benzene for 1 h at 0°C in 75% overall yield from 7.
When acetic anhydride was treated to the crude 8 in the
presence of pyridine in methylene chloride at 0°C, a
In conclusion, a novel method for the synthesis of
MAC reagents with very high overall yield has been
developed, allowing the various derivatives of MAC
reagents to be obtained within several hours using 7,
which is stable and storable for more than 1 month
according to the present observation. This advantage
will facilitate the development of further synthetic
applications using 1.
Acknowledgements
This work was supported in part by research grants
from the Faculty of Pharmaceutical Sciences of The
University of Tokushima, and Eisai Co. Ltd.
Figure 1.

H. Nemoto et al. / Tetrahedron Letters 44 (2003) 73–75
Yamamoto, Y. J. Org. Chem. 1990, 55, 4515–4516.
75
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