Novel chromium(VI) catalyzed oxidation of N-alkylamides to imides with periodic acid

Article abstract of DOI:10.1039/b404823g

A novel and practical procedure for preparation of imides is described using chromium(VI) oxide to catalyze the oxidation of N-alkylamides with periodic acid in the presence of acetic anhydride in acetonitrile.

Full text of DOI:10.1039/b404823g

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Novel chromium(VI) catalyzed oxidation of N-alkylamides to imides with
periodic acid
Liang Xu,a Suhong Zhangb and Mark L. Trudell*b
a St Charles Pharmaceuticals, Inc., P.O. Box 850815, New Orleans, Louisiana 70185, USA
b Department of Chemistry, University of New Orleans, New Orleans, Louisiana 70148, USA.
E-mail: mtrudell@uno.edu; Fax: 504 280-6860; Tel: 504 280-7337
Received (in Corvallis, OR, USA) 1st April 2004, Accepted 28th April 2004
First published as an Advance Article on the web 11th June 2004
A novel and practical procedure for preparation of imides is
described using chromium(VI) oxide to catalyze the oxidation of
N-alkylamides with periodic acid in the presence of acetic
anhydride in acetonitrile.
required to keep the reaction mixture anhydrous and thus reduce N-
dealkylation. Only trace amounts of N-dealkylation products were
observed in the oxidation of N-alkylbenzamides. The N-alkylben-
zamides (Table 1, entries 1–10) including N-benzylbenzamides
(Table 1, entries 13–18) were smoothly oxidized to the correspond-
ing imides in high yields.12 The N-benzylbenzamides exhibited the
greatest reactivity. Reactions could be routinely performed at 0 °C
to room temperature with low catalyst loading (1.0 to 2.5 mol%) to
obtain the corresponding imides in high yields. The N-methyla-
mides (Table 1, entries 1–3) containing primary C–H bonds
required higher temperatures (room temperature) and longer
reaction times to achieve similar yields. The chemoselective
oxidation of N-propargylbenzamide (Table 1, entry 10) was
achieved at 210 °C to furnish the benzimide without significant
oxidation of the carbon–carbon triple bond. Although the H5IO6–
CrO6 system has been reported to effect the hydroxylation of
tertiary C–H bonds,13 the oxidation of N-isobutylbenzamide (Table
1, entry 8) and N-(cyclopropyl)methylbenzamide (Table 1, entry 9)
afforded the corresponding imides in high yields without observ-
able competitive oxidation of tertiary C–H bonds. In general the
reactivity of N-a-CH bonds toward oxidation was not significantly
influenced by the nature of the functionality of the group beta to the
amide nitrogen atom. However, no reaction was observed for the N-
2,2,2-trifluoroethylbenzamide (Table 1, entry 12) and only starting
material was recovered. This suggests that strong electron-
withdrawing groups in the b-position deactivate the N-a-CH bonds
toward oxidation.
The imide moiety is a commonly occurring structural unit in
pharmaceutical agents1,2 as well as a useful directing group in
Michael addition and alkylation reactions.3,4 Many methods have
been developed for the preparation of imides,5 however, most
available methods either employ sophisticated reagents or provide
only moderate yields. The direct oxidation of N-alkylamides is the
simplest and most straightforward method for preparation of
imides. Unfortunately, most of the oxidations cited in the literature
suffer from a competitive N-dealkylation reaction and afford the
corresponding imides only as minor products.5b,6 Only the RuO4
oxidation has been proven to be synthetically useful for the
preparation of imide derivatives.7 However, the synthetic scope of
the RuO4 oxidation is limited due to oxidative degradation of
aromatic rings,8 and oxidative cleavage of both carbon–carbon
double bonds9 and carbon–carbon triple bonds.10 During recent
studies of chromium catalyzed periodic acid oxidation,11 we found
that N-alkylamides could be oxidized to imides with chromium(VI
)
oxide and periodic acid in the presence of acetic anhydride in
acetonitrile. Herein, we describe this practical and highly efficient
method for the preparation of imides.
The oxidation of N-alkylbenzamides with periodic acid cata-
lyzed by chromium(VI) oxide in the presence of acetic anhydride in
acetonitrile was initially examined (Table 1). Acetic anhydride was
The anomaly of the benzamide series was the N-allyl derivative
(Table 1, entry 11) The oxidation of N-allylbenzamide cleanly
afforded N-formylbenzimide as the only product in 85% yield.
Presumably the formyl group is derived from oxidative cleavage of
the allyl moiety. It is noteworthy that the propargyl analogue (Table
1, entry 10) did not exhibit similar reactivity at 210 °C.
Table 1 Oxidation of N-alkylbenzamides to imides
The results of the oxidation of a variety of N-alkylamides to the
corresponding imides are summarized in Table 2. This study
demonstrates that the oxidation is sufficiently mild to tolerate a
wide variety of functionality. The N-benzylformamide and N-
benzylacetamide (Table 2, entries 1 and 2) were easily oxidized to
the corresponding benzimides with only 2.5 mol% of CrO3 at 0 °C
for 1 h. Low reaction temperatures facilitated the chemoselectivity
of the oxidation. Although N-allylbenzamide was not tolerant of
this oxidation, the oxidation of N-benzylacrylamides at 210 °C
(Table 2, entries 4 and 5) afforded the corresponding imides in high
yields without affecting the carbon–carbon double bond. Higher
catalyst loading (5–10 mol%) and longer reaction times were
required for the oxidation of the N-alkylacrylamides as well as
several of the N-alkylamides (Table 2, entries 4–6).
The yields of this oxidation were not significantly affected by the
nature of the substituents on the phenyl ring of the benzamide
moiety (Table 2, entries 8–16). In addition, the oxidation was
tolerant of the heteroarylamide as well (Table 2, entry 17).
In summary, we have developed a novel and practical method for
preparation of imides by chemoselective oxidation of N-alkyla-
mides with the H5IO6–CrO3 system. This oxidation is superior to
the RuO4 oxidation offering better functional group tolerance,
higher yields and shorter reaction times. Additional studies directed
toward the elucidation of the scope, mechanism and additional
applications of this reaction are under investigation
Entry
R
CrO3 (mol%)
Time (h)
Yield (%)a
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
H
H
H
Me
1.0
5.0
10.0
5.0
5.0
5.0
10.0
5.0
5.0
10.0
5.0
5.0
1.0
2.5
5.0
1.0
2.5
2.5
c
18b
4b
1.5b
1
87
91
91
92
92
92
84
87
88
90c
0d
Et
1
(CH2)9Me
CH2CO2Me
CH(CH3)2
Cyclo-Pr
HC·C
H2CNCH
F3C
C6H5
C6H5
C6H5
1b
3c
1
1
1
2b
8b
6b
1
0.3
3
1
0e
87
92
92
80
92
92
4-MeC6H4
4-ClC6H4
4-NO2C6H4
1
a Isolated yields. b Room temperature. 210 °C. d 10 equiv. H5IO6, 10
equiv. Ac2O, N-formylbenzimide was obtained (85%). e Starting material
recovered (96%).
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C h e m . C o m m u n . , 2 0 0 4 , 1 6 6 8 – 1 6 6 9
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4

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Table 2 Oxidation of N-alkyl amides to imides
4 (a) S. K. Kim, C. J. Lim, C. Song and W. Chung, J. Am. Chem. Soc.,
2002, 124, 14306; (b) W. Flitsch and M. Hohenhorst, Liebigs Ann.
Chem., 1990, 397.
5 (a) A. Schnyder and A. F. Indolese, J. Org. Chem., 2002, 67, 594 and
references cited therein; (b) H. R. Bjorsvik, F. Fontana, L. Liguori and
F. Minisci, Chem. Commun., 2001, 523; (c) A. Itoh, T. Kodama, S.
Inagaki and Y. Masaki, Chem. Lett., 2000, 542; (d) M. Ochiai, D.
Kajishima and T. Sueda, Tetrahedron Lett., 1999, 40, 5541and
references cited therein (e) A. P. Gledhill, C. J. McCall and M. D.
Threadgill, J. Org. Chem., 1986, 51, 3196; (f) H. Alper and C. P.
Mahatantila, J. Am. Chem. Soc., 1984, 106, 2708; (g) A. R. Doumaux,
J. E. McKeon and D. J. Trecker, J. Am. Chem. Soc., 1969, 91, 3992.
6 (a) T. Sueda, D. Kajishima and S. Goto, J. Org. Chem., 2003, 68, 3307;
(b) F. Minisci, C. Punta, F. Recupero, F. Fontana and G. F. Pedulli, J.
Org. Chem., 2002, 67, 2671; (c) K. V. Reddy, S. J. Jin, P. K. Arora, D.
S. Sfeir, S. C. Feke Maloney, F. L. Urbach and L. M. Sayre, J. Am.
Chem. Soc., 1990, 112, 2332; (d) M. V. Lock and B. F. Sagar, J. Chem.
Soc. (B)., 1966, 690.
7 (a) J. P. N. Papillon and R. J. K. Taylor, Org. Lett., 2000, 2, 1987; (b)
Y. Takeuchi, T. Shiragami, K. Kimura, E. Suzuki and N. Shibata, Org.
Lett., 1999, 1, 1571; (c) C. Altomare, A. Carotti, G. Casini, S.
Cellamare, M. Ferappi, E. Gavuzzo, F. Mazza, G. Pantaleoni and R.
Raffaele Giorgi, J. Med. Chem., 1988, 31, 2153; (d) S. Yoshifuji and Y.
Arakawa, Chem. Pharm. Bull., 1989, 37, 3380 and references cited
therein.
Entry
R1
R2
CrO3 (mol%)
Yield (%)a
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
H
Me
MeO
H2CNCH
Ph
Ph
Ph
Ph
2.5
2.5
5.0
5.0
5.0
10.0
2.5
2.5
10.0
10.0
5.0
5.0
5.0
5.0
5.0
5.0
2.5
92
92
80b
88b
88b
88c
91
H2CNCH
4-Cl–C6H4
Me
Ph
Me(CH2)6
cyclohexyl
4-CN–C6H4
4-tBu–C6H4
4-NO2–C6H4
4-NO2–C6H4
4-NO2–C6H4
3-NO2–C6H4
4-CN–C6H4
4-CF3–C6H4
4-tBu–C6H4
3-pyridinyl
Ph
91
HC·C
HC·C
i-Pr
Me
H
H
H
H
Ph
91b
90b
86
92
90d
90d
91e
88e
84
8 M. T. Nunez and V. S. Martin, J. Org. Chem., 1990, 55, 1928.
9 R. D. Miller, W. Theis, G. Heilig and S. Kirchmeyer, J. Org. Chem.,
1991, 56, 145.
a Isolated yields. b 210 °C. c r.t., 3 h. d r.t., 5 h. e r.t., 4 h.
10 R. Wagner and J. W. Tilley, J. Org. Chem., 1990, 55, 6289.
11 (a) L. Xu, J. Cheng and M. L. Trudell, J. Org. Chem., 2003, 68, 5388;
(b) L. Xu and M. L. Trudell, Tetrahedron Lett., 2003, 44, 2553.
12 Typical procedure for oxidation of N-alkylamides to imides: A mixture
of H5IO6 (6.90g, 30 mmol) and CrO3 (25 mg, 5 mol%) in acetonitrile (70
mL) was stirred at room temperature for 30 min, then acetic anhydride
(3.1 g, 30 mmol) was added. The resulting mixture was cooled to 0 °C.
The N-alkylamide (5 mmol) was added in one portion. After the reaction
was complete (monitored by TLC), the reaction mixture was quenched
by addition of ice-water (70 g), extracted with EtOAc (2 3 70 mL),
washed respectively with sat. NaHCO3 solution (80 mL), sat. Na2S2O3
solution (80 mL) and brine (80 mL). The organic portion was dried over
MgSO4 and the solvent was removed under reduced pressure. The
residue was purified by flash chromatography (SiO2, hexanes: EtOAc =
6 : 1) to give pure imide.
Notes and references
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Commun., 1994, 1379.
2 S. M. Capitosti, T. P. Hansen and M. L. Brown, Org. Lett., 2003, 5,
2865and references cited therein.
3 (a) M. S. Taylor and E. N. Jacobsen, J. Am. Chem. Soc., 2003, 125,
11204and references cited therein (b) I. T Raheem, S. N Goodman and
E. N. Jacobsen, J. Am. Chem. Soc., 2004, 126, 706; (c) M. P. Sibi, N.
Prabagaran, S. G. Ghorpade and C. P Jasperse, J. Am. Chem. Soc., 2003,
125, 11796.
13 S. Lee and P. Fuchs, J. Am. Chem. Soc., 2002, 124, 13978.
C h e m . C o m m u n . , 2 0 0 4 , 1 6 6 8 – 1 6 6 9
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