Reactions of a Carbamoylstannane with Acid Chlorides: Highly Efficient Synthesis of α-Oxo Amides

Article abstract of DOI:10.1021/jo035572r

Treatment of acid chlorides with a carbamoylstannane under mild conditions (mostly rt for a few hours) affords α-oxo amides in high yields. Vicinal polycarbonyl compounds are also obtained, although spontaneous decarbonylation occasionally occurs.

Full text of DOI:10.1021/jo035572r

TABLE 1. r-Oxo Am id e Syn th esis by th e Rea ction of
Rea ction s of a Ca r ba m oylsta n n a n e w ith
Acid Ch lor id es: High ly Efficien t Syn th esis
of r-Oxo Am id es
Acid Ch lor id es w ith Ca r ba m oylsta n n a n e 1a
entry
R
conditions
1 h, rt
1 h, rt
1 h, rt
1 h, rt
product, yield (%)b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
CH3
3a , 96 (83)
3b, 95 (87)
3c, 91 (72)
3d , 90 (72)
3e, 92 (85)
3f, 94 (81)
3g, 95 (76)
3h , 97 (85)
3i, 95 (78)
3j, 92 (85)
3k , 93 (76)
3l, 82 (70)
3m , 97 (78)
3n , 31 (22)
3p , 56 (39)
Ruimao Hua,† Hide-aki Takeda,‡,§ Yoshimoto Abe,‡ and
Masato Tanaka*,‡,§,
(CH3)2CH
C6H5CH2
CH2dC(CH3)
trans-C6H5CHdCH 1 h, rt
Department of Chemistry, Tsinghua University,
Beijing 100084, China, Department of Industrial
Engineering Chemistry, Tokyo University of Science,
Noda, Chiba 278-8510, J apan, National Institute of
Advanced Industrial Science and Technology (AIST),
Tsukuba Central 5, Tsukuba, Ibaraki 305-8565, J apan, and
Chemical Resources Laboratory, Tokyo Institute of
Technology, 4259 Nagatsuta, Midori-ku,
ClCH2
C3F7
C6H5
3 h, 80 °C
1 h, 60 °C
3 h, rt
3 h, rt
3 h, rt
8 h, rt
10 h, rt
3 h, 80 °C
5 h, 120 °Cc
5 h, -45 °C to rt
p-CH3C6H4
p-BrC6H4
2-furyl
2-thienyl
C2H5O
Yokohama 226-8503, J apan
(CH3)2N
C2H5OCO
m.tanaka@res.titech.ac.jp
Received October 27, 2003
a
Reactions were carried out in a 1.0-mmol scale with benzene
(2.0 mL) as solvent. RCOCl/Me3SnCONiPr2 ) 1.0:1.1 (molar ratio).
b
GLC yield based on the amount of acid chloride charged. The
figures in parentheses are isolated yields. c Run in a sealed glass
tube.
Abstr a ct: Treatment of acid chlorides with a carbamoyl-
stannane under mild conditions (mostly rt for a few hours)
affords R-oxo amides in high yields. Vicinal polycarbonyl
compounds are also obtained, although spontaneous decar-
bonylation occasionally occurs.
During our study on the addition reaction of carbam-
oylstannane 17 to alkynes catalyzed by transition metal
complexes,8 we came across the high reactivity of the Sn-
CONR2 bond. This finding prompted us to investigate the
intrinsic reactivity of 1 in the absence of transition metal
complexes. We wish to disclose in this paper that
compound 1 indeed reacts very rapidly with acid chlo-
rides affording R-oxo amides, some of which are not easy
to synthesize by conventional methods (eq 1).
R-Oxo amides are an important class of compounds,
which have been exploited in organic syntheses mainly
for pharmaceutical applications.1 The synthetic methods
of R-oxo amides have been rather well established as
exemplified by the reaction of oxamates with Grignard
reagents,2 amidation of R-oxo acid derivatives with amine
nucleophiles,3 transition-metal-catalyzed double carbo-
nylation reaction of organic halides in the presence of
primary or secondary amines,4 and oxidation of R-hy-
droxy amides.5 However, exploration into more general
and efficient methods that work under mild conditions
still is a subject of research interest.6
In a representative experiment, a benzene solution of
acetyl chloride and carbamoylstannane 1 (1.1 equiv) was
stirred at room temperature for 1 h. GLC analysis of the
reaction mixture showed the formation of N,N-diisopro-
pyl-2-oxo-propionamide 3a in 96% yield (Table 1, entry
1).9 Branched aliphatic and aralkyl acid chlorides such
as isobutyryl chloride and phenylacetyl chloride react
similarly to furnish high yields of the corresponding R-oxo
amides (entries 2 and 3). The reactions of olefinic acid
chlorides such as methacryloyl chloride and cinnamoyl
chloride with 1 also proceed very cleanly to afford the
products in more than 90% yields (entries 4 and 5).
However, chloroacetyl chloride displays lower reactivity
than the foregoing acid chlorides, which is peculiar from
a view that the reaction proceeds via electrophilic sub-
stitution at the Sn-C bond.10 Thus, the reaction of
† Tsinghua University.
‡ Tokyo University of Science.
§ National Institute of Advanced Industrial Science and Technology.
Tokyo Institute of Technology.
(1) For representative publications, see: (a) Andersen, K.; Liljefors,
T.; Hytted, J .; Perregaard, J . J . Med. Chem. 1996, 39, 3723. (b) Ogawa,
H.; Aoyama, T.; Shioiri, T. Heterocycles 1996, 42, 75. (c) Axten, M.;
Krim, L.; Kung, H. F.; Winkler, D. J . Org. Chem. 1998, 63, 9628. (d)
Singh, R. P.; Kirchmeier, R. L.; Shreeve, J . M. J . Org. Chem. 1999,
64, 2579. (e) Toda, F.; Miyamoto, H.; Inoue, M.; Yasaka, S.; Matijasic,
I. J . Org. Chem. 2000, 65, 2728. (f) Meng, C. Q.; Rakhit, S.; Lee, D. K.
H.; Kamboj, R.; McCallum, K. L.; Mazzocco, L.; Dyne, K.; Slassi, A.
Bioorg. Med. Chem. Lett. 2000, 10, 903. (g) Heaney, F.; Fenlon, J .;
McArdle, P.; Cunningham, D. Org. Biomol. Chem. 2003, 1, 1122.
(2) Barre, R. Ann. Chim. Phys. 1928, 9, 237; Chem. Abstr. 1928,
22, 2268.
(3) Li, Z.; Patil, G. S.; Chu, D.-L.; Foreman, J . E.; Eveleth, D. D.;
Powers, J . C. J . Med. Chem. 1996, 39, 4089.
(4) (a) Review: des Abbayes, H.; Salau¨n, J .-Y. Dalton Trans. 2003,
1041. (b) Kobayashi, T.; Tanaka, M. J . Organomet. Chem. 1982, 23,
C64. (c) Ozawa, F.; Soyama, T.; Yamamoto, T.; Yamamoto, A. Tetra-
hedoron Lett. 1982, 23, 3383.
(5) Harbeson, S. L.; Abelleira, S. M.; Akiyama, A.; Barrett, R.;
Straub, J . A.; Tkacz, J . N.; Wu, C.; Musso, G. F. J . Med. Chem. 1994,
37, 2918.
(6) (a) Parlow, J . J .; Dice, T. A.; South, M. S. In High-Throughput
Synthesis; Sucholeiki, I., Ed.; Marcel Dekker: New York, 2001, p 143.
(b) Kobayashi, N.; Koji, T.; Fujita, T.; Nishimura, T.; Hosoda, A. PCT
Int. Appl. WO 2002002546 A1, 2002. (c) Singh, R. P.; Shreeve, J . M.
J . Org. Chem. 2003, 68, 6063.
(7) For the preparation of 1 and palladium-catalyzed cross-coupling
reactions of 1 with organic halides, see: Lindsay, C. M.; Widdowson,
D. A. J . Chem. Soc., Perkin Trans. 1 1988, 569.
(8) Hua, R.; Onozawa, S-y.; Tanaka, M. Organometallics 2000, 9,
3269. See also: Shirakawa, E.; Yamasaki, K.; Yoshida, H.; Hiyama,
T. J . Am. Chem. Soc. 1999, 121, 10221.
(9) In a preliminary experiment, treatment of (N,N-diisopropylcar-
bamoyl)tributylstannane with acetyl chloride over 1 h at room tem-
perature without a solvent afforded 95% GC yield of 3a .
(10) For the mechanism of substitution reactions of organostan-
nanes, see: (a) Wardell, J . L. In Chemistry of Tin; Smith, P. J ., Ed.;
Blackie Academic & Professional: London, UK, 1998; p 121. (b) Davies,
A. G. Organotin Chemistry; VCH: Weinheim, Germany, 1997; p 51.
10.1021/jo035572r CCC: $27.50 © 2004 American Chemical Society
Published on Web 01/06/2004
974
J . Org. Chem. 2004, 69, 974-976

SCHEME 1. Rea ction of Eth oxa lyl Ch lor id e w ith
Ca r bom oylsta n n a n e 1
chloroacetyl chloride with 1 run at room temperature for
2 h gave the corresponding R-oxo amide only in 44% yield.
To obtain a satisfactory yield (94%), heating at 80 °C for
3 h was needed (entry 6).11 On the other hand, perfluoro
acid chlorides, highly substituted by the electronegative
fluorine substituent, react normally, i.e., more readily
than chloroacetyl chloride; when a mixture of 1 and
heptafluoro-n-butyryl chloride in benzene was heated at
60 °C for 1 h, the corresponding heptafluoro R-oxo amide
3g was obtained in 95% yield (entry 7). In addition, the
reaction of bifunctional hexafluoropentanedioyl dichloride
with 2 equiv of 1 at room temperature for 1 h gave the
corresponding product 4 in 79% GC yield (60% isolated
yield; eq 2). Fluorine-containing R-oxo amides have
no)propionate 3p and ethyl N,N-diisopropyloxamate 3m
were formed in 23% and 74% GC yield, respectively
(Scheme 1). The latter product is envisioned to have
arisen from decarbonylation of 3p ,14c which is substanti-
ated by the change of the 3p /3m ratio from 64/36 to 34/
66, observed when the mixture was kept standing in
CDCl3 at room temperature for 2 days. Accordingly in
another reaction of ethoxalyl chloride with 1 run at -45
°C to room temperature for 5 h, the yield of 3p increased
to 56% (GC) at the expense of 3m (35%, entry 15).
The ease of the decarbonylation appears to be very
much dependent on the structure. Rather unexpectedly,
for instance, the reaction of oxalyl chloride with 2 equiv
of 1 afforded the corresponding tetracarbonyl compound,
N,N,N′,N′-tetraisopropyl-2,3-dioxosuccinamide 5, as an
exclusive amide product (95% GC and 72% isolated yield)
(eq 3). The result suggests that the new methodology with
1 provides a very simple and efficient access to vicinal
polycarbonyl compounds.
proved to be the useful intermediates for the syntheses
of agrochemicals and pharmaceuticals, but there are only
a few publications disclosing the preparation of these
compounds.12
The reactions of aromatic and heteroaromatic acid
chlorides with 1 proceed somewhat slowly as compared
with aliphatic acid chlorides and prolonged reaction times
are required at room temperature to achieve acceptable
yields in excess of 90% (entries 8-12). Unlike aliphatic
ones, however, benzoyl chloride, 4-bromobenzoyl chloride,
and p-toluoyl chloride display similar reactivity despite
the difference in the electronic nature of the para
substituent.
Ethyl chloroformate and N,N-dimethylcarbamoyl chlo-
ride are also reactive although their reactivity is much
less than acid chlorides (entries 13 and 14). The reaction
of the former needed heating at 80 °C for 3 h to furnish
the corresponding product 3m in 97% yield, whereas the
latter gave only a trace of product 3n under the same
conditions, and heating at 120 °C for 5 h afforded 3n in
only 31%.13
Synthesis and reactivity of vicinal polycarbonyl com-
pounds [R-(CO)n-R, n g 3] continue to be a vital area
of research since the first review article appeared in
1975.14 In view of the foregoing high reactivity of the
carbamoylstannane species, it appeared promising to
synthesize the polycarbonyl compounds in one step. In
practice, the reaction of ethoxalyl chloride with 1 indeed
proceeded readily at room temperature to almost comple-
tion within 1 h. Ethyl 2,3-dioxo-3-(N,N-diisopropylami-
In all of the foregoing reactions, benzene was used as
the solvent. However, the reaction of 1 with acetyl
chloride in toluene (otherwise identical conditions) worked
as well to result in 93% GC yield of 3a , suggesting that
toluene may be used for the reactions with other acid
chlorides. In addition, when the starting acid chloride is
liquid, the reaction can be effected without using a
solvent, as exemplified by the reaction of 1 with acetyl
chloride affording 98% GC yield of 3a (room temperature,
1 h).
In conclusion, the reaction of the carbamoylstannane
species with acid chlorides has proved to offer a general
and efficient route to R-oxo amides, some of which are
not easily prepared via other routes.
Exp er im en ta l Section
(11) The chloro substituent at the R-carbon remained intact.
(12) Urata, H.; Ishii, Y.; Fuchikami, T. Tetrahedron Lett., 1989, 30,
4407 and references therein.
(13) The reaction was very clean; GLC and GC-MS analyses showed
that, besides the corresponding R-oxo amide and Me3SnCl, no other
byproduct was formed and that both of the starting materials
remained.
(14) For the synthesis and synthetic applications of vicinal polycar-
bonyl compounds, see: (a) Rubin, M. B. Chem. Rev. 1975, 75, 177. (b)
Rubin, M. B.; Gleiter, R. Chem. Rev. 2000, 100, 1121. (c) Wasserman,
H. H.; Lee, K.; Xia, M. Tetrahedron Lett. 2000, 41, 2511.
A Typ ica l P r oced u r e for th e Rea ction of Ca r ba m oyl-
sta n n a n e w ith Acid Ch lor id es. At room temperature, to a
solution of (N,N-diisopropylcarbamoyl)trimethylstannane (1,1.1
mmol) and docosane (0.37 mmol, as an internal standard for
GLC analysis) in 2.0 mL of benzene was added 1.0 mmol of acetyl
chloride by a macrosyringe over 10 min and the resulting
solution was stirred at room temperature for 1 h. The GLC
analysis of the reaction mixture revealed that acetyl chloride
was almost completely consumed (>99%) and that the product
J . Org. Chem, Vol. 69, No. 3, 2004 975

2
N,N-diisopropyl-2-oxo-propionamide 3a was formed in 96% yield.
After removal of the volatiles in vacuo, the residue was subjected
to column chromatography on silica gel with hexane and then
CH2Cl2 as the eluting solvent. 3a was obtained as a colorless
oil (142.0 mg, 0.83 mmol, 83% yield).
) 6.6 Hz). 13C NMR (CDCl3) δ 181.6 (t, J CF ) 32.0 Hz), 161.5,
1
2
1
110.1 (tquint, J CF ) 267.0 Hz; J CF ) 34.0 Hz), 109.6 (tt, J CF
) 270.0 Hz; J CF ) 34.0 Hz), 50.4, 46.6, 20.5, 19.8. 19F NMR
2
(CDCl3) δ 26.1 (s(br), 2F), 22.1 (s(br), 2F). IR (neat) 2982, 2944,
1750, 1657, 1475, 1452, 1377, 1348, 1209, 1183, 1139 cm-1
.
N,N-Diisop r op yl-2-oxop r op ion a m id e 3a : Colorless oil,
isolated yield 83%, bp 100 °C. 1H NMR (CDCl3) δ 3.72 (hept,
1H, J ) 6.6 Hz), 3.51 (hept, 1H, J ) 6.8 Hz), 2.35 (s, 3H), 1.42
(d, 6H, J ) 6.8 Hz), 1.20 (d, 6H, J ) 6.6 Hz). 13C NMR (CDCl3)
δ 198.8, 167.4, 49.7, 45.9, 27.3, 20.8. IR (neat) 2976, 2942, 1715,
1686, 1450, 1375, 1199 cm-1. GCMS m/z (% rel intensity) 171
(M+, 0.5), 128 (31), 86 (100), 58 (11). Anal. Calcd for C9H11NO2:
C, 63.16; H, 9.94; N, 8.19. Found: C, 62.62; H, 10.0; N, 7.91.
E t h yl 3-(N,N-d iisop r op yla m in o)-2,3-d ioxop r op ion a t e
3p : Colorless product, isolated yield 39%, mp 79.0-80.0 °C
GCMS m/z (% rel intensity) 424 (M+ - 2F, 1), 334 (0.6), 264 (3),
216 (2), 128 (55), 86 (100), 70 (4), 58 (4). HRMS calcd for
C19H28F6N2O4 462.1951, found 462.1958.
N,N,N′,N′-Tetr a isop r op yl-2,3-d ioxosu ccin a m id e 5: Col-
orless product, isolated yield 72%, mp 88.0-89.5 °C (recrystal-
lization in hexane). 1H NMR (CDCl3) δ 4.11 (hept, 1H, J ) 6.6
Hz), 3.53 (hept, 1H, J ) 6.8 Hz), 1.44 (d, 6H, J ) 6.8 Hz), 1.26
(d, 6H, J ) 6.6 Hz). 13C NMR (CDCl3) δ 181.6, 166.2, 50.4, 46.0,
20.6, 20.1. IR (neat) 2976, 2942, 1717, 1636, 1458, 1365, 735,
592 cm-1. GCMS m/z (% rel intensity) 312 (M+, 0.3), 213 (3),
128 (30), 100 (2), 86 (100), 70 (4), 58 (3). HRMS calcd for
C15H28N2O3 (M+ - CO) 284.2098, found 284.2099.
1
(recrystallization in hexane). H NMR (CDCl3) δ 4.28 (q, 2H, J
) 7.1 Hz), 3.94 (hept, 1H, J ) 6.6 Hz), 3.47 (hept, 1H, J ) 6.8
Hz), 1.42 (d, 6H, J ) 6.8 Hz), 1.32 (t, 3H, J ) 7.1 Hz), 1.14 (d,
6H, J ) 6.6 Hz). 13C NMR (CDCl3) δ 179.8, 170.3, 160.2, 63.1,
50.1, 46.3, 20.5, 19.9, 13.9. IR (neat) 2978, 2946, 1742, 1647,
1421, 1379, 1292, 1261, 1145, 1129, 1089, 1040, 592 cm-1. GCMS
m/z (% rel intensity) 229 (M+, 0.1), 201 (0.1), 128 (38), 86 (100),
70 (6), 58 (4). HRMS calcd for C11H20NO4 (MH+) 230.1391, found
230.1393.
Ack n ow led gm en t. We thank the J apan Science and
Technology Corporation (J ST) for financial support
through the CREST program.
Su p p or tin g In for m a tion Ava ila ble: Detailed experi-
mental procedure and characterization data of products 3a -
p , 4, and 5. This material is available free of charge via the
Internet at http://pubs.acs.org.
N,N,N′,N′-Tet r a isop r op yl-3,3,4,4,5,5-h exa flu or o-2,6-d i-
oxop im ela m id e 4: Colorless oil, isolated yield 60%, bp 85 °C
(0.15 Torr). 1H NMR (CDCl3) δ 3.67 (hept, 1H, J ) 6.6 Hz), 3.56
(hept, 1H, J ) 6.8 Hz), 1.46 (d, 6H, J ) 6.8 Hz), 1.24 (d, 6H, J
J O035572R
976 J . Org. Chem., Vol. 69, No. 3, 2004