Convenient method for the preparation of secondary α-ketoamides via aminocarbonylation of acid chlorides with carbamoylsilane

Article abstract of DOI:10.1016/j.tetlet.2016.10.040

The convenient transformation of acid chlorides into corresponding secondary α-ketoamides by the aminocarbonylation of acid chlorides with N-methoxymethyl-N-methylcarbamoyl(trimethyl)silane is described. The use of carbamoylsilane containing methoxymethyl

Full text of DOI:10.1016/j.tetlet.2016.10.040

Accepted Manuscript
Convenient method for the preparation of secondary α-ketoamides via amino-
carbonylation of acid chlorides with carbamoylsilane
Fei Ma, Hui Liu, Jianxin Chen
PII:
S0040-4039(16)31353-3
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.10.040
TETL 48210
Reference:
Tetrahedron Letters
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4 October 2016
12 October 2016
Please cite this article as: Ma, F., Liu, H., Chen, J., Convenient method for the preparation of secondary α-ketoamides
via aminocarbonylation of acid chlorides with carbamoylsilane, Tetrahedron Letters (2016), doi: http://dx.doi.org/
10.1016/j.tetlet.2016.10.040
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Fei Ma, Hui Liu and Jianxin Chen 

1
Tetrahedron Letters
Convenient method for the preparation of secondary α-ketoamides via
aminocarbonylation of acid chlorides with carbamoylsilane
Fei Ma, Hui Liu and Jianxin Chen 
College of Chemistry and Materials Science, Shanxi Normal University, Linfen 041004, PR China.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The convenient transformation of acid chlorides into corresponding secondary α-ketoamides by
the aminocarbonylation of acid chlorides with N-methoxymethyl-N-methylcarbamoyl(trime-
thyl)silane is described. The use of carbamoylsilane containing methoxymethyl group avoids
the reaction of products α-ketoamides with carbamoylsilane in situ in the aminocarbonylation
reaction. The methoxymethyl group was used as an amino protecting group and could be easily
converted into hydrogen atom by simple acid hydrolysis.
Available online
Keywords:
Ketoamides
2009 Elsevier Ltd. All rights reserved.
Carbamoylsilane
Hydrolysis
Aminocarbonylation
Acid chlorides
1. Introduction
this methodology was effective in generating α-ketoamides,
however, in some instances, in situ reaction of additional carba-
α-Ketoamides are an important class of organic compounds,
which have been widely used in developing inhibitors of
peptidases,1 serine or cysteine protease,2 DACs,3 p38,4 peptidyl
prolyl isomerases,5 cathepsin S,6 and human cytosolic phospholi-
pase A2.7 Their moiety can be found in a number of natural prod-
ucts, biologically relevant molecules, and marketed drugs.8 Fur-
thermore, they also served as useful synthetic intermediates in
various functional group transformations9 and in the elaboration
of important heterocycles.10 For these reasons, numerous metho-
ds for the synthesis of α-ketoamides have been developed. Earlier
approaches have been summarized,11 and new methodologies
have continued to be reported.12 The common routes involve the
direct oxidation of the corresponding α-hydroxyamides,11g
arylacetamides,12h acrylic amides,12c or α-amino-α-cyanoket-
ones,11d the oxidative coupling of arylglyoxals,12d aryl methyl
ketones,12f toluene12a or terminal alkynes12e with amines or
amides, and the reaction of acylchlorides with α-isocyanoacet-
amides.12g However, these methods suffer from some disadv-
antages such as the use of oxidants, the high costs of heavy
metals, the restricted scope of substrates, and needing more steps.
So search for a simple and practical method remains a challenge
for the synthetic chemists.
moylsilane with α-ketoamides yielded α-organyl-α-siloxymal-
onamides, leading to α-ketoamides decrease in yields. In
addition, the scope of this protocol is limited to the synthesis of
only the N,N-dimethylsubstituted α-ketoamides derivatives, for
efficient application within these areas, synthesizing secondary α-
keto-amides and expanding the scope of synthesizing tertiary α-
ketoamides are required. We now found that the reaction of N-
methoxymethyl-N-methylcarbamoyl(trimethyl)silane with acid
chlorides could conveniently afford good yields of exclusive α-
ketoamides, which avoids the reaction of additional carbamoyl-
silane with α-ketoamides in situ. Furthermore, because the meth-
oxymethyl of these α-ketoamides can be readily converted into
hydrogen by acid hydrolysis, present protocol is applicable for
synthesizing secondary α-ketoamides, and also expand the scope
of synthesizing tertiary α-ketoamides. The developed methodolo-
gy tolerated a wide rang of functionnal groups with an additional
advantage of free oxidants and higher yields as compared to
earlier protocols. We report here on the successful attempt in this
regard.
2. Results and discussion
We have recently addressed in other contexts by using
carbamoylsilanes as an amide source to carry out a series of
aminocarbonylation reactions, including the addition of carbam-
oylsilanes to the C=N bond of imines,13 the addition of carbam-
oylsilanes to the C=O bond of aldehydes, ketones, α-ketoamides
or a-ketoesters,14 and selective C-H functionalization of aroma-
tics by carbamoylsilanes.15 The aminocarbonylation of acid
Scheme 1. The reaction of N-methoxymethyl-N-methylcarbamoyl(trimeth-
yl)silane 2 with acid chlorides 1
chlorides with carbamoylsilanes have been found previously16,
———
 Corresponding author. E-mail address: jjxxcc2002@yahoo.com

2
Tetrahedron Letters
Table 1 Solvent effect on aminocarbonylation of butanoyl chloride with N-
methoxymethyl-N-methylcarbamoyl(trimethyl)silane
When acid chlorides 1 were allowed to react with 1.2 equiv
of N-methoxymethyl-N-methylcarbamoyl(trimethyl)silane (2)17
under anhydrous conditions at ambient condition, good yields of
α-ketoamide 3 were achieved, generally within a matter of hours
(Scheme 1). Initial experiments were carried out to investigate
the effects of solvents on aminocarbonylation reaction. The ami-
nocarbonylation of butanoyl chloride with N-methoxymethyl-N-
methylcarbamoyl(trimethyl)silane was chosen as a model reacti-
on. A significant solvent effect was observed: when the reaction
was conducted in benzene, the product was obtained in high yield
and the reaction time was short. Several other solvents, including
toluene, acetonitrile, dichloromethane and THF, gave inferior
results compared to benzene (Table 1).
Entry
Solvent
Temp (℃)
Timea (h)
Yieldb,c (％)
1
2
3
4
5
dichloromethane
acetonitrile
THF
toluene
benzene
35
75
60
75
60
46
30
28
26
25
10
73
69
78
86
aTo complete consumption of carbamoylsilane.
b
Isolated yield after chromatography on silica gel based on butanoyl
chloride. c1:1.2 mol ratio of butanoyl chloride and carbamoylsilane.
Table 2
α-Ketoamides 3 from acid chlorides 1 and carbamoylsilane 2
Entry
Acid chloride
Product
Timea (h)
25
Yieldb,c (%)
1
3
1
86
1a
3a
2
3
4
96
87
89
80
1b
1c
1d
3b
3c
3d
106
61
5
6
21
43
82
89
1e
1f
3e
3f
7
8
25
20
82
79
1g
1h
3g
3h
9
16
71
1i
3i
10
11
18
36
84
87
1j
3j
1k
3k
12
40
88
1l
3l
aTo complete consumption of carbamoylsilane 2 in benzene at 60 ˚C.
b Isolated yield after chromatography on silica gel based on acid chlorides. Characterization data are given.19
c 1:1.2 mol ratio of acid chlorides and carbamoylsilane.
To explore the reaction scope of acid chlorides with carbam-
oylsilane 2 under optimal conditions to furnish the α-ketoamides,
we tested the representative acid chlorides bearing aliphatic
group, aryl or heteroaryl. Experimental results were summarized
in Table 2. For all of acid chlorides, the reactions gave good to
exicellent yields. Linear and branched aliphatic acid chlorides
reacted with carbamoylsilane 2 to furnish high yields of the
corresponding α-ketoamides (Table 2, entries 1–3). The cyclohe-
xyl formoyl chloride (1d) also proceed very cleanly to afford the
products in 80% yields (Table 2, entry 4). A comparison of the

3
results obtained from 1a–d indicates that the reaction is sensitive
to steric factors, the bigger the aliphatic group, the slower the
reaction rate is. Substrate 1a containing linear propyl substituent
reacted essentially quicker than others with more bulky ones.
While 1c was the slowest (106 h) since there is the biggest steric
inhibition, but in high yield.
In order to understand the reaction of additional carbamoyl-
silane with products α-ketoamides in situ in aminocarbonylation
of acid chlorides with carbamoylsilane, and determine the reacti-
vity of carbamoylsilane 2 to α-ketoamides, 2.2 equiv of carbamo-
ylsilane 2 was allowed to react with cinnamoyl chloride 1j in
benzene solution. We found only product 3j was obtained even
lengthening reaction time to 72 h. However, we have previously
found that the reaction of 1j with N,N-dimethylcarbamoyl(trim-
ethyl)silane easily afforded a mixture of α-ketoamides and
reaction products of α-ketoamides with carbamoylsilane in situ.16
This may reflect weaker reactivity of carbamoylsilane 2 with α-
ketoamide 3 compared to N,N-dimethylcarbamoyl(trimethyl)si-
lane. We now have confirmed that the N, N-dimethylcarbamoyl-
(trimethyl)silane can easily react with α-ketoamides, however,
the carbamoylsilane 2 poorly proceed.14c
Subsequently, these α-ketoamides ware hydrolyzed in a
mixture of concentrated hydrochloric acid and dichloromethane
at room temperature. Because methoxymethyl on the N atom can
be easily replaced by hydrogen in acid conditions, the α-keto-
amides 3 could be transformed into the secondary α-ketoamides 8.
So methoxymethyl of these α-ketoamides could be used as an
amino protecting group. We selected representative aliphatic α-
ketoamides 3d and aromatic α-ketoamides 3e–l to be hydrolyzed
in a mixture of concentrated hydrochloric acid and dichlorome-
thane at room temperature. Results are listed in Table 3, all of
reaction formed secondary α-ketoamides in high yields.
Examining the reactivity of aromatic acid chlorides with
carbamoylsilane 2 (Table 2, entries 5–9), we found that the reac-
tions proceed somewhat fast as compared with aliphatic acid
chlorides under the same condition. Entries 5–9 indicate that
electronic consideration plays a significant role in the reaction,
the stronger electron–donating ability of the substituent on the
aromatic ring, the slower the process, the higher the yield was
obtained. Aromatic acid chlorides 1f and 1g possessing an
electron-donating group, methyl and methoxy, reacted slower
than 1e, gave the desired coupling products in high yields (Table
2, entries 6 and 7). Aromatic acid chlorides 1h and 1i possessing
an electron-withdrawing group, chloro and nitro, reacted faster
than 1e, afforded the coupling products in moderate yields (Table
2, entries 8 and 9). We conclude that, in general, aryl acid
chlorides possessing an electron-donating group gave a better
yield than those having an electron–withdrawing group. As
expected, the less sterically demanding cinnamoyl chloride (1j)
exhibited faster reaction rates than aryl acid chlorides since
shorter reaction time was needed in case of 1j than in case of 1e–
h, afforded a good yield of 3j (Table 2, entry 10). Acid chlorides
1k and 1l containing the electron–rich heteroaryl, furyl and
thienyl, are also reactive although their reactivity is much less
than phenyl acid chloride 1e (Table 2, entries 11, 12). The
reaction of the former needed heating at 60 ˚C for 36 h to afford
the corresponding product 3k in 87% yield, the latter needed 40 h
to afford 88% yield of product 3l under the same conditions.
In addition, the reaction of bifunctional hexanedioyl dichlo-
ride 4 with 2.4 equiv of carbamoylsilane 2 in the standard condi-
tions for 6 h gave the corresponding product 5 in 82% isolated
yield (Scheme 2).
Table 3
The formation of secondary α-ketoamides 8 by acid hydrolysis of 3
Entry
1
3
Product
8
Yield (%)a, b
96
3d
8d
2
83
3e
8e
Scheme 2. The reaction of carbamoylsilane 2 with hexanedioyl dichloride 4
3
4
5
79
84
89
3f
8f
Synthesis and reactivity of vicinal tricarbonyl compounds is a
vital area of research since there is a highly electrophilic nature
due to the three contiguous carbonyl groups, which are activated
by the adjacent two carbonyl groups. They are of interest from a
viewpoint of their chemical properties that could lead to the
application to crosslinking agents and polymer systems.18 The
reaction of ethoxalyl chloride 6 with carbamoylsilane 2 can
directly achieve the vicinal tricarbonyl compound 7 at 0 ˚C in
86% isolated yield (Scheme 3).
3g
3h
8g
8h
6
7
80
93
3i
3j
8i
8j
Scheme 3. The reaction of carbamoylsilane 2 with ethoxalylchloride 6

4
Tetrahedron Letters
This research was supported by Shanxi Province Foundation
for Returness (No. 0713), the Natural Science Foundation of
Shanxi Province (No. 2012011046-9) and Foundation of Shanxi
Normal University (No. SD2015CXXM-83), China.
8
87
3k
3l
8k
8l
References and notes
9
95
1. Ocain, T. D.; Rich, D. H. J. Med. Chem. 1992, 35, 451–456.
2. (a) Schreiber, S. L. Science 1991, 251, 283–285. (b) Tanaka, H.;
Kuroda, A.; Marusawa, H.; Kino, T.; Goto, T.; Hashimoto, M.; Taga, T.
J. Am. Chem. Soc. 1987, 109, 5031–5033.
3. (a) Curtin, M.; Glaser, K.; Curr. Med. Chem. 2003, 10, 2373–2392. (b)
Wada, C. K.; Frey, R. R.; Ji, 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.
a
Stirring 24 h at room temperature in a mixture of HCl (concd) and
dichloromethane.
b Isolated yield after chromatography on silica gel based on α-ketoamides.
Characterization data are given.19
General procedure for preparation of α-ketoamides 3, 5 and
7
A Schlenk tube fitted with a Teflon vacuum stopcock and
micro stirbar was flame-heated under vacuum and refilled with
Ar. Acid chlorides (0.75 mmol) and anhydrous benzene (1.5 mL)
was added at ice bath temperature. After 20 min, N-methoxyme-
thyl-N-methylcarbamoyl(trimethyl)silane 2 (0.9 mmol) was
added. The sealed reaction mixture was stirred at 60 °C until no
carbamoylsilane 2 could be detected by TLC. Volatiles were
removed in vacuum, and the residue was chromatographed using
petroleum ether–EtOAc as eluent to yield products 3. 3a: IR:
1758, 1725, 1328 cm–1. 1H NMR (600 MHz, CDCl3): δ 4.68, 4.84
(ss, 2 H), 3.30, 3.34 (ss, 3 H), 3.00, 3.03 (ss, 3 H), 2.77 (t, J = 7.2
Hz, 2 H), 1.66–1.71 (m, 2 H), 0.96–1.01 (m, 3 H). 13C NMR (151
MHz, CDCl3): δ 200.7, 168.1, 80.6, 56.2, 55.4, 41.9, 41.8, 33.2,
31.8, 16.3, 13.6. Anal. Calcd for C8H15NO3: C, 55.47; H, 8.73; N,
8.09. found: C, 55.58; H, 8.61; N, 8.15.
4. Montalban, A. G.; Boman, E.; Chang, C. D.; Ceide, S. C.; Dahl, R.;
Dalesandro, D.; Delaet, N. G. J.; Erb, E.; Ernst, J. T.; Gibbs, A.; Kahl,
J.; Kessler, L.; Kucharski, J.; Lum, C.; Lundstroem, J.; Miller, S.;
Nakanishi, H.; Roberts, E.; Saiah, E.; Sullivan, R.; Urban, J.; Wang, Z.;
Larson, C. J. Bioorg. Med. Chem. Lett. 2010, 20, 4819–4824.
5. Wang, X.-J.; Etzkorn, F. A. Biopolymers, 2006, 84, 125–146.
6. Cai, J.; Robinson, J.; Belshaw, S.; Everett, K.; Fradera, X.; Zeeland, M.
van; Berkom, L. van; Rijnsbergen, P. van; Popplestone, L.; Baugh, M.;
Dempster, M.; Bruin, J.; Hamilton, W.; Kinghorn, E.; Westwood, P.;
Kerr, J.; Rankovic, Z.; Arbuckle, W.; Bennett, D. J.; Jones, P. S.; Long,
C.; Martin, I.; Uitdehaag, J. C. M.; Meulemans, T. Bioorg. Med. Chem.
Lett. 2010, 20, 6890–6894.
7. (a) Six, D. A.; Barbayianni, E.; Loukas, V.; Constantinou-Kokotou, V.;
Hadjipavlou-Litina, D.; Stephens, D.; Wong, A. C.; Magrioti, V.;
Moutevelis-Minakakis, P.; Baker, F. S.; Dennis, E. A.; Kokotos, G. J.
Med. Chem. 2007, 50, 4222–4235. (b) Chiou, A.; Markidis, T.;
Kokotou, V. C.; Verger, R.; Kokotos, G. J. Med. Chem. 2002, 45,
2891–2893.
8. (a) Lee, S. H.; Kyung, H.; Yokota, R.; Goto, T.; Oe, T. Chem. Res.
Toxicol. 2015, 28, 59–70. (b) Swindells, N. D. C.; White, P. S.;
Findlay, J. A. Can. J. Chem. 1978, 56, 2491–2492. (c) Tanaka, H.;
Kuroda, A.; Marusawa, H.; Hatanaka, H.; Kino, T.; Goto, T.;
Hashimoto, M.; Taga, T. J. Am. Chem. Soc. 1987, 109, 5031–5033.
9. (a) Morris, W. J.; Muppalla, K. K.; Cowden, C.; Ball, R. G. J. Org.
Chem. 2013, 78, 706–710. (b) Tomita, D.; Yamatsugu, K.; Kanai, M.;
Shibasaki, M. J. Am. Chem. Soc. 2009, 131, 6946–6948. (c) Bode, J.
W.; Fox, R. N.; Baucom, K. D. Angew. Chem. Int. Ed. 2006, 45, 1248–
1252. (d) Wang, G.-Z.; Mallat, T.; BaiKer, A. Tetrahedron:
Asymmetry 1997, 8, 2133–2140.
10. (a) Tomaszewski, M. J.; Boisvert, L.; Jin, S. Tetrahedron Lett. 2009,
50, 1435–1437. (b) Miyake, F. Y.; Yakushijin, K.; Horne, D. A. Org.
Lett. 2002, 4, 941–943. (c) Taylor, M. J.; Hpffman, T. Z.; Kauhaluoma,
J. T.; Lerner, R. A.; Janda, K. D. J. Am. Chem. Soc. 1998, 120, 12783–
12790.
11. (a) Takahashi, K.; Shibasaki, K.; Ogura, K.; Iida, H. Chem. Lett. 1983,
859–862. (b) Katritsky, A. R.; Oniciu, D. C.; Ghiviriga, I.; Soti, F. J.
Org. Chem. 1998, 63, 2110–2115. (c) Chen, J.-J.; Deshpande, S. V.
Tetrahedron Lett. 2003, 44, 8873–8876. (d) Yang, Z.; Zhang, Z.;
Meanwell, N. A.; Kadow, J. F.; Wang, T. Org. Lett. 2002, 4, 1103–
1105. (e) Hua, R.; Takeda, H.; Abe, Y.; Tanaka, M. J. Org. Chem,
2004, 69, 974–976. (f) Hsung, R. P.; Wei, Y.; Yao, P.-Y.; Liu, R.;
Zhao, K. J. Org. Chem. 2008, 73, 8780–8784. (g) Semple, J. E.;
Owens, T. D.; Nguyen, K.; Levy, O. E. Org. Lett. 2000, 2, 2769–2772.
12. (a) Fan, W.-Z.; Shi, D.-Y.; Feng, B.-N. Tetrahedron Lett. 2015, 56,
4638–4641. (b) Giustiniano, M.; Mercalli, V.; Cassese, H.; Maro, S. D.;
Galli, U.; Novellino, E.; Tron, G. C. J. Org. Chem. 2014, 79, 6006–
6014. (c) Liu, L.; Du, L.; Zhang, D.-N.; Du, Y.-F.; Zhao, K. Org. Lett.
2014, 16, 5772–5775. (d) Shaw, A. Y.; Denning, C. R.; Hulme, C.
Tetrahedron Lett. 2012, 53, 4151–4153. (e) Zhang, C.; Jiao, N. J. Am.
Chem. Soc. 2010, 132, 28–29. (f) Wei, W.; Shao, Y.; Hu, H.-Y.; Zhang,
F.; Zhang, C.; Xu, Y.; Wan, X.-B. J. Org. Chem. 2012, 77, 7157–7165.
(g) Mossetti, R.; Pirali, T.; Tron, G. C.; Zhu, J. Org. Lett. 2010, 12,
820–823. (h) Shao, J.; Huang, X. M.; Wang, S. Y.; Liu, B. X.; Xu, B.
Tetrahedron 2012, 68, 573–579.
General procedure for acid hydrolysis of α-ketoamides 3
Concentrated hydrochloric acid (0.2 mL) was added dropwise
to a solution of 3 (50 mg) in dichloromethane (3 mL). After 24
hours’ stirring at room temperature, the organic layer was decan-
ted. The aqueous phase extracted with dichloromethane (310
mL). The combined organic layers were washed with sodium
bicarbonate solution (10 mL), dried over MgSO4 and evaporated
to afford the crude product which was purified by column chro-
matography on silica gel (petroleum ether/ethyl acetate combin-
ation) to afford secondary α-ketoamides 8. 8e: mp 74.0–75.0 ˚C.
IR: 3350, 1676, 1592, 1468 cm–1. 1H NMR (600 MHz, CDCl3): δ
7.49–8.37 (m, 5 H), 7.13, 7.12 (ss, 1 H), 3.01, 3.00 (ss, 3 H). 13C
NMR (151 MHz, CDCl3): δ 187.7, 162.4, 134.4, 133.3, 131.2,
128.5, 29.7, 26.1. Anal. Calcd for C9H9NO2: C, 66.25; H, 5.56; N,
8.58. found: C, 66.10; H, 5.27; N, 8.32.
3. Conclusions
In summary, we have successfully developed a novel and
highly efficient synthetic method toward secondary α-ketoamides
by aminocarbonylation of acid chlorides using N-methoxymeth-
yl-N-methylcarbamoyl(trimethyl)silane as a secondary amide
source. The methoxymethyl group was used as an amino protec-
ting group and can be easily converted into hydrogen atom by
simple acid hydrolysis. This method is more efficient for prepar-
ation of α-ketoamides compared with our previous reported
ones,13 since which avoids the reaction of carbamoylsilane with
α-ketoamides in situ. The method in general provides good yields
of the products under mild reaction conditions. The mild and
simple procedure, the easy availability of acid chlorides and
impressive yield provides a valuable method for the preparation
of various α-ketoamides. We anticipate that our study may draw
significant attention of chemists working on the development of
synthetic methodologies and will find applications in organic and
medicinal chemistry.
13. (a) Tong, W.-T.; Liu, H.; Chen, J.-X. Tetrahedron Lett. 2015, 56,
1335–1337. (b) Liu, H.; Guo, Q.-L.; Chen, J.-X. Tetrahedron Lett.
2015, 56, 5747–5751.
14. (a) Yao, Y.; Tong, W.-T.; Chen, J.-X. Mendeleev Commun. 2014, 24,
176–177. (b) Yao, Y.; Li, W.-D.; Chen, J.-X. Chin. J. Org. Chem.
2014, 34, 2124–2129. (c) Chen, X.-J.; Chen, J.-X. Mendeleev
Commun. 2013, 23, 106–107. (d) Li, W.-D.; Liu, Y.-H.; Chen, J.-X.
Tetrahedron Lett. 2015, 56, 4328–4330.
Acknowledgments
15. Liu, Y.-H.; Cao, P.; Chen, J.-X. Tetrahedron Lett. 2016, 57, 937–941.
16. Chen, J.-X.; Cunico, R. F. J. Org. Chem. 2004, 69, 5509–5511.

5
17. For the preparation of the carbamoylsilane, see: Cunico, R. F.; Chen,
J.-X. Synth. Commun. 2003, 33, 1963–1968.
122.4, 113.0, 113.1, 80.7, 56.3, 55.4, 33.4, 31.3. Anal. Calcd for
C9H11NO4: C, 54.82; H, 5.62; N, 7.10. Found: C, 54.63; H, 5.46; N,
7.32. 3l: IR: 1672, 1653, 1454 cm–1. 1H NMR: δ 7.81–7.84 (m, 2 H),
18. (a) Rubin, M. B.; Gleiter, R. Chem. Rev. 2000, 100, 1121–1164. (b)
Wasserman, H. H.; Parr, J. Acc. Chem. Res. 2004, 37, 687–701. (c)
Fang, L.; Hmadeh, M.; Wu, J.; Olson, M. A.; Spruell, J. M.; Trabolsi,
A.; Yang, Y.-W.; Elhabiri, M.; Albrecht-Gary, A. M.; Stoddart, J. F. J.
Am. Chem. Soc. 2009, 131, 7126–7134.
7.19–7.20 (m, 1 H), 4.96, 4.74 (ss, 2 H), 3.42, 3.23 (ss, 3 H), 3.13, 3.05
(ss, 3 H). 13C NMR: δ 182.9, 182.7, 167.0, 166.9, 140.4, 140.0, 136.7,
136.4, 136.2, 136.1, 128.8, 128.7, 80.7, 77.1, 56.3, 55.5, 33.5, 31.2.
Anal. Calcd for C9H11NO3S: C, 50.69; H, 5.20; N, 6.57. Found: C,
50.76; H, 5.12; N, 6.84. 5: IR: 1708, 1656, 1452, 1401, 1099 cm–1. 1H
NMR: δ 4.80, 4.64 (ss, 4 H), 3.29, 3.26 (ss, 6 H), 2.99, 2.97 (ss, 6 H),
2.79–2.78 (m, 4 H), 1.67–1.65 (m, 4 H). 13C NMR: δ 200.1, 200.0,
167.9, 167.7, 92.6, 80.6, 56.2, 56.5, 39.6, 33.3, 32.1, 32.0, 22.1, 22.0.
Anal. Calcd for C14H24N2O6: C, 53.15; H, 7.65; N, 8.86. found: C,
53.26; H, 7.48; N, 8.74. 7: Kugelrohr distillation afforded an
19. Characterization data for α-ketoamides 3, 5, 7 and 8. All NMR
spectra were obtained in CDCl3 unless otherwise indicated. 3b: IR:
1763, 1714, 1331 cm–1. 1H NMR: δ 4.80, 4.59 (ss, 2 H), 3.28–3.24 (m,
3 H), 3.13–3.18 (m, 1 H), 3.14–2.91 (m, 3 H), 1.13, 1.10 (dd, J = 7.2
Hz, 6 H). 13C NMR: δ 203.9, 203.8, 169.5, 168.1, 80.4, 76.9, 56.1, 55.4,
37.5, 37.3, 33.0, 31.5, 16.9, 16.5. Anal. Calcd for C8H15NO3: C, 55.47;
H, 8.73; N, 8.09. Found: C, 55.54; H, 8.58; N, 8.19. 3c: IR: 1713,
1662, 1460 cm–1. 1H NMR: δ 4.84, 4.51 (ss, 2 H), 3.33, 3.29 (ss, 3 H),
3.01, 2.88 (ss, 3 H), 1.29, 1.25 (ss, 9 H). 13C NMR: δ 207.8, 168.7,
168.2, 80.6, 76.5, 56.2, 55.5, 42.8, 42.7, 33.1, 31.0, 26.6, 26.4. Anal.
Calcd for C9H17NO3: C, 57.73; H, 9.15; N, 7.48. Found: C, 57.68; H,
9.21; N, 7.55. 3d: IR: 1713, 1662, 1460 cm–1. 1H NMR: δ 4.83, 4.62 (ss,
analytically pure yellowish liquid. IR: 1672, 1655, 1453 cm–1. 1H NMR:
δ 4.87, 4.68 (ss, 2 H), 4.36–4.40 (m, 2 H), 3.34, 3.28 (ss, 3 H), 3.07,
3.01 (ss, 3 H), 1.37 (q, J = 7.2 Hz, 3 H). 13C NMR: δ 180.6, 179.9,
165.6, 165.1, 159.9, 80.6, 76.8, 63.5, 63.3, 56.2, 55.6, 32.7, 31.6, 13.9.
Anal. Calcd for C8H13NO5: C, 47.29; H, 6.45; N, 6.89. Found: C,
47.03; H, 6.53; N, 6.73. 8d: mp 115.0–116.5 ˚C. IR: 3406, 1713, 1662,
1423 cm–1. 1H NMR: δ 3.47 (s, 1 H), 3.14 (s, 3 H), 1.86–1.28 (m, 11 H).
13C NMR: δ 203.3, 160.0, 55.7, 44.1, 32.3, 31.8, 24.7, 22.0. Anal.
Calcd for C9H15NO2: C, 63.88; H, 8.93; N, 8.28. found: C, 63.81; H,
8.71; N, 8.32. 8e: mp 74.0–75.0 ˚C. IR: 3350, 1676, 1592, 1468 cm–1.
1H NMR: δ 7.49–8.37 (m, 5 H), 7.13, 7.12 (ss, 1 H), 3.01, 3.00 (ss, 3
H). 13C NMR: δ 187.7, 162.4, 134.4, 133.3, 131.2, 128.5, 29.7, 26.1.
Anal. Calcd for C9H9NO2: C, 66.25; H, 5.56; N, 8.58. found: C, 66.10;
H, 5.27; N, 8.32. 8f: mp 40.0–42.0 ˚C. IR: 3341, 1657, 1604, 1484 cm–
1. 1H NMR: δ 8.29 (d, J = 8.4 Hz, 2 H), 7.30 (d, J = 8.4 Hz, 2 H), 7.14–
7.11 (m, 1 H), 3.00, 2.99 (ss, 3 H), 2.45 (s, 3 H). 13C NMR: δ 187.1,
162.7, 145.7, 131.4, 130.8, 129.5, 129.3, 29.7, 26.0, 21.9. Anal. Calcd
for C10H11NO2: C, 67.78; H, 6.26; N, 7.90. found: C, 67.54; H, 6.31; N,
7.75. 8g: IR: 3339, 1667, 1588, 1485 cm–1. 1H NMR: δ 8.01–7.18 (m, 4
H), 7.14 (s, 1 H), 3.88 (s, 3 H), 2.99, 2.98 (ss, 3 H). 13C NMR: δ 187.4,
162.5, 159.5, 134.5, 129.6, 124.2, 121.5, 114.6, 55.5, 26.1. Anal. Calcd
for C10H11NO3: C, 62.17; H, 5.74; N, 7.25. found: C, 62.28; H, 5.54; N
7.12. 8h: IR: 3654, 1667, 1589, 1474 cm–1. 1H NMR: δ 7.71–7.37 (m, 4
H), 7.05 (s, 1 H), 3.01, 3.00 (ss, 3 H). 13C NMR: δ 190.0 161.3, 133.9,
133.1, 131.3, 130.9, 130.5, 126.6, 26.3. Anal. Calcd for C9H8ClNO2: C,
54.70; H, 4.08; N, 7.09. found: C, 54.56; H, 4.12; N, 7.21. 8i: mp
102.0–104.0 ˚C. IR: 3298,1708, 1645, 1526, 1489 cm–1. 1H NMR: δ
8.57–8.33 (m, 4 H), 7.19 (s, 1 H), 3.03, 3.02 (ss, 3 H). 13C NMR: δ
186.0, 161.1, 150.9, 137.9, 132.4, 123.5, 26.2. Anal. Calcd for
2 H), 3.31, 3.28 (ss, 3 H), 3.00, 2.94 (ss, 4 H), 1.19–1.93 (m, 10 H). 13
NMR: δ 203.2, 168.5, 168.2, 80.4, 77.0, 56.2, 55.5, 46.9, 46.6, 33.1,
C
31.4, 27.3, 27.0, 25.7, 25.4, 25.3. Anal. Calcd for C11H19NO3: C, 61.95;
H, 8.98; N, 6.58. Found: C, 61.84; H, 8.99; N, 6.68. 3e: IR: 1676, 1592,
1468, 1405 cm–1. 1H NMR: δ 7.51–7.99 (m, 5 H), 4.99, 4.65 (ss, 2 H),
3.46, 3.21 (ss, 3 H), 3.16, 2.98 (ss, 3 H). 13C NMR: δ 190.9, 168.2,
167.8, 134.9, 134.8, 133.2, 132.7, 129.8, 129.7, 129.1, 129.0, 80.7,
56.4, 55.5, 33.3, 30.9. Anal. Calcd for C11H13NO3: C, 63.76; H, 6.32; N,
6.76. Found: C, 63.64; H, 6.35; N, 6.89. 3f: IR: 1657, 1604, 1456 cm–1.
1H NMR: δ 7.31–7.88 (m, 4 H), 4.98, 4.64 (ss, 2 H), 3.45, 3.21 (ss, 3
H), 3.15, 2.97 (ss, 3 H), 2.46, 2.45 (ss, 3 H). 13C NMR: δ 190.9, 190.6,
168.4, 167.6, 146.2, 146.1, 130.8, 130.2, 129.9, 129.8, 129.7, 128.7,
80.7, 56.4, 55.5, 33.3, 30.8, 21.9. Anal. Calcd for C12H15NO3: C, 65.14;
H, 6.83; N, 6.33. Found: C, 65.23; H, 6.93; N, 6.25. 3g: IR: 1676,
1665, 1491 cm–1. 1H NMR: δ 7.20–7.53 (m, 4 H), 4.99, 4.64 (ss, 2 H),
3.89, 3.88 (ss, 3 H), 3.46, 3.22 (ss, 3 H), 3.16, 2.98 (ss, 3 H). 13C NMR:
δ 191.0, 190.8, 168.2, 167.7, 160.2, 160.0, 134.5, 130.2, 130.0, 123.0,
122.8, 121.9, 121.8, 112.9, 112.8, 80.7, 56.4, 55.5, 33.3, 30.9. Anal.
Calcd for C12H15NO4: C, 60.75; H, 6.37; N, 5.90. Found: C, 60.68; H,
6.40; N, 5.82. 3h: IR: 1667, 1589, 1434 cm–1. 1H NMR: δ 7.85–7.37
(m, 4 H), 4.90, 4.69 (ss, 2 H), 3.39, 3.31 (ss, 3 H), 3.07, 3.06 (ss, 3 H).
13C NMR: δ 189.7, 189.4, 168.0, 167.3, 134.5, 133.8, 133.6, 133.2,
133.0, 132.2, 132.2, 131.0, 130.7, 127.4, 127.3, 80.6, 56.7, 55.7, 33.4,
31.2. Anal. Calcd for C11H12NO3Cl: C, 54.67; H, 5.00; N, 5.80. Found:
C, 54.53; H, 5.04; N, 5.71. 3i: mp 73–74 ˚C. IR: 1689, 1648, 1353 cm–1.
1H NMR: δ 8.16–8.40 (m, 4 H), 5.00, 4.69 (ss, 2 H), 3.46, 3.22 (ss, 3
H), 3.21, 3.02 (ss, 3 H). 13C NMR: δ 188.4, 166.6, 151.1, 137.6, 130.9,
130.8, 124.2, 124.0, 80.9, 56.5, 55.7, 33.4, 31.8. Anal. Calcd for
C11H12N2O5: C, 52.38; H, 4.80; N, 11.11. Found: C, 52.65; H, 4.53; N,
11.19. 3j: IR: 1753, 1658, 1636, 1423 cm–1. 1H NMR: δ 7.43–7.70 (m,
6 H), 6.93–6.98 (m, 1 H), 4.94, 4.73 (ss, 2 H), 3.41, 3.28 (ss, 3 H), 3.11,
3.04 (ss, 3 H). 13C NMR: δ 190.6, 190.0, 167.9, 167.8, 148.8, 148.5,
133.9, 133.8, 131.6, 131.5, 129.2, 129.1, 128.9, 123.2, 123.0, 80.7,
77.1, 56.3, 55.5, 33.5, 31.3. Anal. Calcd for C13H15NO3: C, 66.94; H,
6.48; N, 6.00. Found: C, 66.87; H, 6.53; N, 6.12. 3k:IR: 1662, 1645,
1455 cm–1. 1H NMR: δ 7.73–7.75 (m, 1 H), 7.39–7.40 (m, 1 H), 6.62–
6.65 (m, 1 H), 4.94, 4.73 (ss, 2 H), 3.41, 3.25 (ss, 3 H), 3.11, 3.04 (ss, 3
H). 13C NMR: δ 177.6, 166.6, 166.2, 150.3, 150.0, 149.0, 149.1, 122.6,
C9H8N2O4: C, 51.93; H, 3.87; N, 13.46. found: C, 51.78; H, 3.65; N,
13.22. 8j: mp 68.0–70.0 ˚C. IR: 3421, 1753, 1658, 1636, 1423 cm–1. 1H
NMR: δ 7.98–7.44 (m, 7 H), 7.22 (s, 1 H), 2.97, 2.96 (ss, 3 H). 13
C
NMR: δ 185.4, 162.0, 148.0, 134.4, 131.5, 129.2, 129.1, 128.2, 118.6,
26.0. Anal. Calcd for C11H11NO2: C, 69.83; H, 5.86; N, 7.40. found: C,
69.58; H, 5.66; N, 7.23. 8k: mp 118.0–120.0 ˚C. IR: 3386, 1702, 1645,
1467, 1401 cm–1. 1H NMR: δ 8.19–7.76 (m, 2 H), 7.37 (s, 1 H), 7.22–
7.21 (m, 1 H), 2.95–2.94 (m, 3 H). 13C NMR: δ 173.6, 173.4, 160.8,
160.6, 157.4, 149.4, 127.8, 126.9, 113.2, 112.5, 36.5, 25.9. Anal. Calcd
for C7H7NO3: C, 54.90; H, 4.61; N, 9.15. found: C, 54.68; H, 4.39; N,
9.20. 8l: mp 58.0–59.5 ˚C. IR: 3388, 1672, 1653, 1454 cm–1. 1H NMR:
δ 8.44–7.85 (m, 2 H), 7.35 (s, 1 H), 7.22–7.21 (m, 1 H), 3.00, 2.99 (ss,
3 H). 13C NMR: δ 178.3, 161.5, 138.7, 138.1, 136.8, 128.3, 26.1. Anal.
Calcd for C7H7NO2S: C, 49.69; H, 4.17; N, 8.28. found: C, 49.43; H,
4.11; N, 8.15.
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6
Tetrahedron
Highlights
A novel and efficient procedure for the preparation of secondary α-ketoamides. Useing N-
methoxymethyl-N-methylcarbamoyl(trimethyl)silane as an amide source. The aminocarbonylation of acid
chlorides with carbamoylsilane. Avoiding the reaction of α-ketoamides with carbamoylsilane by useing of
methoxymethyl. The methoxymethyl group being used as an amino protecting group.