Synthesis of α-ketoamides from a carbamoylsilane and acid chlorides

Article abstract of DOI:10.1021/jo040164o

Treatment of acid chlorides with a carbamoylsilane affords α-ketoamides. In some instances, in situ reaction of additional carbamoylsilane with these products yielded α-organyl-α- siloxymalonamides.

Full text of DOI:10.1021/jo040164o

TABLE 1. Rea ction of Acid Ch lor id es [2, RC(Cl)dO]
Syn th esis of r-Ketoa m id es fr om a
w ith Ca r ba m oylsila n e 1
Ca r ba m oylsila n e a n d Acid Ch lor id es
entry
R of 2
conditionsa
11 h
product (% yield)b
1
2
3
4
5
6
7
8
Me
Me
Me
Me
tBu
3a (72)
3a (68)
3a (81)
3a (35) + 4a (64)
3b (91)
3c (52) + 4c (24)
J ianxin Chen† and Robert F. Cunico*
6 h, THF
12 hc
Department of Chemistry and Biochemistry,
Northern Illinois University, DeKalb, Illinois 60115
11 hd
1 week
7 h
rfc@marilyn.chem.niu.edu
n-C3F7
n-C3F7
n-C3F7
7 h, THF, -78 °C 3c (66)
11 hd
4c (89)
Received April 2, 2004
9
Ph
Ph
22 h
3d (87)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
69 hd, 60 °C
21 h
3d (20) + 4d (70)
3e (70) + 4d (13)
3e (61) + 4d (0)
3e (9) + 4e (88)
3f (42) + 4f (26)
E-PhCHdCH
E-PhCHdCH
E-PhCHdCH
PhCtC
PhCtC
PhCtC
ClCH2
Abstr a ct: Treatment of acid chlorides with a carbamoyl-
silane affords R-ketoamides. In some instances, in situ
reaction of additional carbamoylsilane with these products
yielded R-organyl-R-siloxymalonamides.
19 h, THF
40 hd
10 h
8 h, THF, -78 °C 3f (39) + 4f (33)
23 hd
4f (94)
3g (56)
3h (77)
3i (65)
3j (75)
3j (88)
3k (82)
3l (0)
10 h, 0 °C
R-Ketoamides are known to have important roles as
protease inhibitors1 and serve as precursors to pharma-
cologically important structures such as oxazolidinones,2
â-lactams,2,3 and chiral R-hydroxyamides.4 Due to such
interests, numerous methods for the synthesis of R-ke-
toamides have been reported. Earlier approaches have
been summarized,5 and new methodologies have contin-
ued to appear,6 with the palladium-catalyzed amino
(double) carbonylation of organic halides arguably rep-
resenting the most commercially useful approach.7 The
latter, however, is attendant with drawbacks associated
with the use of toxic carbon monoxide, usually employed
under elevated temperatures and high pressures.8 Most
recently, the reaction of acid chlorides with a carbam-
oylstannane has been reported to afford good yields of
R-ketoamides, for the most part under ambient condi-
tions.9 Unfortunately, this approach does not remove
carbon monoxide from the synthetic stream, as it is
MeO2CCH2CH2 10 h
MeO2C
5 h, 0 °C
36 h
28 h, THF
40 h
3 h
3 days, 60 °C
6 h, 0 °C
6 h, THF, -78 °C 5 (47)
o-AcetoxyPh
o-AcetoxyPh
iPrO
MeO2CCH2
Et2NCdO
ClCdO
No reaction
5 (50)
ClCdO
a
Ratio of 1:2 was 1.1:1, benzene solvent, rt, unless otherwise
indicated. b Isolated yield based on acid chloride. c 1.4:1 ratio. 2.1:
d
1 ratio.
required for the preparation of the carbamoylstannane.10
In addition, the toxicity of organotin compounds,11 and
the possibility of trace organotin contamination in phar-
maceutical applications, limit the appeal of this method.
Herein, we present an alternative entry to R-ketoamides
which avoids these problems.
When 1.1 equiv of a carbamoylsilane (1)12 was allowed
to react with acid chlorides (2) in benzene or THF solution
under anhydrous conditions at ambient conditions or
below, good yields of R-ketoamides (3) were obtained,
generally within a matter of hours (eq 1). Results are
† Current Address: DaTong Medical College, DaTong, Shanxi,
China.
(1) (a) Wada, C. K.; Frey, R. R.; J i, Z.; Curtin, M. L.; Garland, R. B.;
Holms, J . H.; Li, J .; Pease, L. J .; Guo, J .; Glaser, K. B.; Marcotte, P.
A.; Richardson, P. L.; Murphy, S. S.; Bouska, J . J .; Tapang, P.; Magoc,
T. J .; Albert, D. H.; Davidsen, S. K.; Michaelides, M. R. Bioorg. Med.
Chem. Lett. 2003, 13, 3331-3335. (b) Wasserman, H. H.; Petersen, A.
K.; Xia, M. Tetrahedron 2003, 59, 6771-6784. (c) Otto, H. H.;
Schirmeister, T. Chem. Rev. 1997, 97, 133-171.
(2) Aoyama, H.; Hasegawa, T. Watabe, M.; Shiraishi, H,; Omote, Y.
J . Org. Chem. 1978, 43, 419-422.
(3) Hashizume, D.; Kogo, H.; Sekine, A.; Ohashi, Y.; Miyamoto, H.;
Toda, F. J . Chem. Soc., Perkin Trans. 2 1996, 61-66.
(4) (a) Youn, S. W.; Kim, Y. H.; Hwang, J .-W.; Do, Y. Chem.
Commun. 2001, 996-997. (b) Solodin, I.; Goldberg, Y.; Zelcans, G.;
Lukevics, E. J . Chem. Soc., Chem. Commun. 1990, 1321-1322.
(5) Takahashi, K.; Shibasaki, K.; Ogura, K.; Iida, H. Chem. Lett.
1983, 859-862.
(6) (a) Chen, J . J .; Deshpande, S. V. Tetrahedron Lett. 2003, 44,
8873-8876. (b) Yang, Z.; Zhang, Z.; Meanwell, N. A.; Kadow, J . F.;
Wang, T. Org. Lett. 2002, 4, 1103-1105. (c) Wong, M.-K.; Yu, C.-W.;
Yuen, W.-H.; Yang, D. J . Org. Chem. 2001, 66, 3606-3609. (d)
Katritsky, A. R.; Oniciu, D. C.; Ghiviriga, I.; Soti, F. J . Org. Chem.
1998, 63, 2110-2115. (d) Wasserman, H. H.; Ho, W.-B. J . Org. Chem.
1994, 59, 4364-4366. (e) Tsuda, T.; Miwa, M. Saegusa, T. J . Org.
Chem. 1979, 44, 3734-3736.
(7) (a) Yamamoto, A.; Lin, Y.-S. Organometallics 1998, 17, 3466-
3478 and references therein. (b) Yamamoto, A.; Yamamoto, T.; Ozawa,
F. Pure Appl. Chem. 1985, 57, 1799-1808
(8) Recent protocols have employed carbon monoxide under one
atmosphere pressure and at room temperature: (a) Uozumi, Y.; Arii,
T.; Watanabe, T. J . Org. Chem. 2001, 66, 5272-5274. (b) Zhou, T.;
Chen, Z.-C. J . Chem. Res., Synop. 2001, 116-117.
displayed in Table 1. Entries 1-4 are indicative of the
behavior encountered. The reaction was typically allowed
to proceed in benzene solvent until all of 1 was consumed,
affording a mixture of unreacted 2 (if present), product
3, small amounts of DMF, and TMSCl. Purification was
then carried out by distillation or chromatography. The
appearance of DMF is due to protonolysis of 1 by either
adventitious protonic sources and/or enolizable C-H
(9) Hua, R.; Takeda, H.; Abe, Y.; Tanaka, M. J . Org. Chem. 2004,
69, 974-976.
(10) Lindsay, C. M.; Widdowson, D. A. J . Chem. Soc., Perkin Trans.
1 1988, 596-573.
(11) Pereyre, M.; Quintard, J .-P.; Rahm, A. Tin in Organic Synthesis;
Butterworths: London, 1987.
(12) Cunico, R. F.; Chen, J . Synth. Commun. 2003, 33, 1963-1968.
10.1021/jo040164o CCC: $27.50 © 2004 American Chemical Society
Published on Web 07/10/2004
J . Org. Chem. 2004, 69, 5509-5511
5509

SCHEME 1
moieties in the acid chloride (see later). Use of THF
instead of benzene (entry 2) accelerated the reaction, but
had little effect on yield. In entry 3, the 1 to 2 ratio was
increased to 1.4:1 in an attempt to compensate for DMF
formation and this did increase the yield of 3 to some
extent. However, small absorptions were noted in the
NMR of the crude reaction mixture suggesting the
presence of a second, minor, amide product. Entry 4
outlines the result of increasing the 1:2 ratio to 2.1:1.
Under these conditions, some of the initially formed
R-ketoamide undergoes addition of a second molecule of
1 (eq 2) to give the R-methyl-R-siloxymalonamide (4a ).
N,N-Dimethylcarbamoyl chloride, containing an electron-
rich carbonyl group, proved to be totally inert even at 60
°C for 3 days (entry 24). The double carbamoylation of
oxalyl chloride was only partially successful (entries 25
and 26), in that it was accompanied by decarbonylation
to only give 5 (eq 3).15
This was not unexpected behavior, as we have previously
shown that 1 will add in this fashion to isolated carbonyl
groups in aldehydes and ketones, albeit under more
elevated temperatures.13 It seems reasonable to assume
that those keto functions in 3 which would be considered
to be more reactive on steric and/or electronic grounds
would exhibit this reactivity under less forcing conditions.
The antithesis of this possibility is represented by entry
5, where only 3b is formed slowly, but in high yield,
because of steric inhibition to carbonyl attack. In con-
trast, entry 6, in which 2c contains the electron-
withdrawing perfluoropropyl group, affords a 2:1 mixture
of 3c and 4c with the standard 1.1 equiv of 1 at room
temperature. Keto addition could be suppressed, how-
ever, by carrying out the reaction at -78 °C (entry 7), or
alternatively, completely favored by using 2.1 equiv of 1
(entry 8). Only R-ketoamide 3d was obtained under
standard conditions from benzoyl chloride, but with the
use of excess 1, a higher temperature, and longer reaction
time, the diadduct could be made the major product
(entry 10). Other conjugated systems were found to be
more prone to diaddition. The less sterically demanding
cinnamoyl chloride afforded a good yield of 3e, but
accompanied by small amounts of diadduct under stan-
dard conditions (entry 11). The latter could be completely
eliminated by the use of THF as solvent (entry 12) or
made the major product in good yield using excess 1
(entry 13). The ketoamide obtained from phenylpropiolyl
chloride (entry 14) proved more reactive toward further
addition of 1, giving a 2:1 ratio of 3f to 4f. Surprisingly,
an attempt to suppress diaddition by employing the
previously successful techniques of THF solvent and low-
temperature failed to eliminate this competition.
We suggest a mechanism for R-ketoamide formation
as shown in Scheme 1.
O-Acylation of the carbamoylsilane by the acid chloride
is believed to form an isoimidium salt as a transient
intermediate. Although rare, such salts have actually
been isolated as stable species in cyclic systems.16 The
facility of acylation is thus seen to be correlated with the
steric availability and electrophilicity of the carbonyl
group of the acid chloride. Subsequent attack of chloride
ion at the silicon of the TMS group may expel a
resonance-stabilized acyloxy(amino)carbene.17 Similar
species bearing both acyloxy and carbon substituents on
the carbenic carbon are known to rearrange efficiently
to R-diketones,18 and parallel behavior in the present case
would afford R-ketoamides.
Although the current results specifically address the
formation of (tertiary) N,N-dimethyl R-keto amides, our
ability to synthesize carbamoylsilanes bearing other
N-substituents,12 including the easily hydrolyzable meth-
oxymethyl moiety, suggests that primary and secondary
R-ketoamides may also be accessible by this methodology.
In addition, a one-pot entry into certain representatives
Other functionalized acid chlorides could also be
converted to the corresponding R-ketoamides. Substrates
containing chloro (entry 17) and ester functionalities such
as entries 18-21 behaved normally,14 but methyl 3-chloro-
3-oxopropionate quickly converted 1 into DMF, presum-
ably due to its readily enolizable R-protons (entry 23).
(15) Gas evolution could be seen upon adding 1 to oxalyl chloride
at 0 °C. We note that it has been reported that the reaction of oxalyl
chloride with a carbamoylstannane does not lead to decarbonylation
of the tetracarbonyl product.9
(16) Boyd, G. V.; Monteil, R. L. J . Chem. Soc, Perkin Trans. 1 1978,
1338-1350.
(17) For a report of stable amino(oxy)carbenes, see: Alder, R. W.;
Butts, C. P.; Orpen, A. G. J . Am. Chem. Soc. 1998, 120, 11526-11527.
Removal of silicon from the cationic center is analogous to base removal
of a proton from amino(oxy)carbocations, suggested to form amino-
(oxy)carbene intermediates. See: Warkentin, J . In Advances in Carbene
Chemistry; Brinker, U. H., Ed.; J AI Press: Stamford, CT, 1998; pp
253-256.
(13) Cunico, R. F. Tetrahedron Lett. 2002, 43, 355-358.
(14) The yield of 3g was presumably reduced due to competition from
protonolysis. If crude 3i was chromatographed instead of distilled, a
solid was obtained having 1H NMR (C6D6) absorptions at δ 5.59 (2H),
3.29 (3H), 2.57 (3H), and 2.48 (3H). This material may have been a
hydrate, but was not investigated further.
(18) Moss, R. A.; Xue, S.; Liu, W.; Krogh-J espersen, K. J . Am. Chem.
Soc. 1996, 118, 12588-12597.
5510 J . Org. Chem., Vol. 69, No. 16, 2004

Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures. This material is available free of charge via the
Internet at http://pubs.acs.org.
of R-substituted tartronic acid (R-hydroxymalonic acid)
amides has been demonstrated.
Ack n ow led gm en t. This work was supported by
NIH Grant No. R15 GM065864.
J O040164O
J . Org. Chem, Vol. 69, No. 16, 2004 5511