Copper mediated oxidation of amides to imides by Selectfluor

Article abstract of DOI:10.1016/j.tetlet.2011.02.059

The combination of Selectfluor and copper(I) bromide has shown a strong oxidation ability, readily oxidizing amides into the corresponding imides in acetonitrile at room temperature in less than 1 h. This transformation under mild conditions gives good to excellent chemical yields. A possible reaction mechanism is proposed.

Full text of DOI:10.1016/j.tetlet.2011.02.059

Tetrahedron Letters 52 (2011) 1956–1959
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Copper mediated oxidation of amides to imides by Selectfluor
⇑
Zhuang Jin, Bo Xu , Gerald B. Hammond
Department of Chemistry, University of Louisville, Louisville, KY 40292, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The combination of Selectfluor and copper(I) bromide has shown a strong oxidation ability, readily oxi-
dizing amides into the corresponding imides in acetonitrile at room temperature in less than 1 h. This
transformation under mild conditions gives good to excellent chemical yields. A possible reaction mech-
anism is proposed.
Received 8 December 2010
Revised 9 February 2011
Accepted 14 February 2011
Available online 18 February 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Selectfluor
Copper(I) bromide
Amide
Imides
Oxidation
Imides are core structures in many therapeutic and agrochem-
ical agents.1 Although imides can be prepared through the conden-
sation of carboxylic acid derivatives and ammonia or primary
amine2 or other protocols,3 the most straightforward preparation
would be the direct oxidation of amides into imides. Accordingly,
several methodologies involving the direct oxidation of amides
have been reported over the years.4 Unfortunately, most protocols
suffer from low yields or/and limited substrate scope.4a–h To the
best of our knowledge, there are only two efficient methods to pre-
pare imides from amides.4i,j And they still have some shortcomings
like the use of toxic chromium reagent4j or use of Dess–Martin
periodinane at elevated temperatures.4i We are now pleased to re-
port a very mild synthesis of imides from amides using a combina-
tion of copper(I) bromide and Selectfluor.
Selectfluor is an easy-handling and bench stable electrophilic
fluorinating agent.5 In the course of our works on Selectfluor/gold
mediated oxidative coupling6 and copper mediated amination,7 we
found that a combination of copper(I) bromide and Selectfluor is a
strong oxidation system that efficiently oxidizes amides into imi-
des. First, we chose amide 1a as substrate to find the best oxidation
conditions (Table 1). Amide 1a, Selectfluor (2.2 equiv), and copper
bromide (10%) were mixed in acetonitrile at room temperature for
1 h, and afforded 10% yield of imide 2a, the same yield as the load
of copper salt, together with unreacted starting material (Table 1,
entry 1). When the copper load was increased to 1 equivalent,
we obtained a moderate yield of imide (Table 1, entry 2); however,
1 equivalent of Selectfluor gave a low yield (Table 1, entry 3). En-
tries 4 and 5 showed that both copper bromide and Selectfluor
are indispensable to the oxidation. CuCl2 alone, or together with
Selectfluor (Table 1, entries 6 and 7), has no effect on the transfor-
mation. Similarly, the use of different copper salts, such as CuOTf,
CuBF4, CuCl, CuI, and Cu(OTf)2 gave small amounts of imide (Table
1 entries 8–12). Since the main difference among these copper
salts is the counteranion, which shows remarkably dissimilar re-
sults, and because it has been reported that bromide can be oxi-
dized to bromine cation8 we examined the role of bromide, and
found that bromide itself (KBr) was not the active species (Table
1, entry 13). Inspired by White’s work,9 CuBr was added in five por-
tions over 32 min, improving our results (Table 1, entry 14). Using
a similar portion-wise addition, the highest yield of imide can be
obtained by increasing the amount of both Selectfluor and CuBr
(Table 1, entry 15); hence, this was chosen as our optimized condi-
tion for this oxidation. Although water may be a possible oxygen
source in this oxidation, small amounts of water (Table 1, entry
16) have a deleterious effect on this reaction.
Next, we examined the substrate scope. Amide 1a (Table 2, en-
try 1) was readily oxidized by the combination of copper bromide
and Selectfluor to give imide 2a in excellent yield after 1 h, to-
gether with small amounts of unreacted starting material. Simi-
larly, amides 1b, 1c, 1d, and 1e all afforded the corresponding
imides in high yields (Table 2, entries 2–5). Branched amide 1f
gave moderate yield (Table 2, entry 6); this may be due to steric
hindrance; the unreacted amide can be recycled. Amide 1g also
gave moderate yield of 2g together with small amount of unre-
acted 1g (Table 2, entry 7) and the reason for this lower yield is un-
known. The oxidation of 1h gave 2h in high yield (Table 2, entry 8);
and the reaction with amidoesters 1i, 1j is chemoselective (Table 2,
entries 9 and 10). Unfortunately, a hydroxyl group, double, or triple
bonds are not tolerated due to possible over oxidation.
⇑
Corresponding author.
E-mail address: bo.xu@louisville.edu (B. Xu).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.02.059

Z. Jin et al. / Tetrahedron Letters 52 (2011) 1956–1959
1957
Table 1
Table 2
Screening for best oxidation conditiona
Examination of substrate scopea
O
O
O
O
O
O
N
H
N
H
R1
N
H
R2
R1
N
H
R2
1
2
1a
2a
Entry
1
Amides
% Yieldb (SM)c
Entry
Selectfluor (equiv)
Metal (or other) (equiv)
% Yieldb (SM)c
O
O
O
1
2
3
4
5
6
7
8
2.2
2.2
1.0
2.2
—
CuBr (0.1)
CuBr (1.0)
CuBr (1.0)
10 (90)
66 (33)
12 (88)
0 (100)
0 (100)
0 (100)
0 (100)
25 (75)
0 (100)
7 (93)
N
N
H
H
1a
2a 88 (7)
CuBr (1.0)
CuCl2 (1.0)
CuCl2 (1.0)
CuOTf (1.0)
CuBF4 (1.0)
CuCl (1.0)
CuI (1.0)
Cu(OTf)2 (1.0)
KBr (1.0)
CuBr (1.0)
CuBr (1.0)
CuBr (1.0)
O
O
O
—
N
H
N
2.2
2.2
2.2
2.2
2.2
2.2
2.2
2.2
2.5
2.5
2
3
H
9d
10
11
12
13
14e
15f
16f,g
2b 83
1b
O
O
O
6 (94)
5
N
5
N
19 (81)
0 (100)
83 (17)
92 (8)
H
H
1c
2c 79 (13)
O
O
O
N
H
N
37 (63)
4
5
H
a
b
c
d
e
f
All reactions were conducted in acetonitrile at room temperature for 1 h.
NMR yield. Benzyl bromide as internal standard.
Starting material.
1d
O
2d 77 (10)
O
O
CuBF4 was generated in situ.
N
H
N
H
Copper bromide was added five portions over 32 min.
Copper bromide was added six portions over 40 min.
Acetonitrile/water = 100:3 (v/v).
g
1e
O
2e 84 (11)
O
O
N
H
N
3
3
5
5
6
H
2f 66 (30)
1f
There are two possible sources of oxygen for the newly incorpo-
O
O
O
rated oxygen in imide 2, namely dioxygen in air and trace amounts
of water in the reaction media. We conducted the reaction under
nitrogen, and found that 50% of imide was formed.10 Since com-
mercial Selectfluor always contains trace amounts of water,11 we
could not conduct the reaction under strictly anhydrous condi-
tions. On the other hand, when substrate 1b was oxidized in aceto-
nitrile (dried shortly before use) containing 0.1% H218O, we
observed 18O (45%) incorporation in imide 2b (confirmed by high
resolution mass spectroscopy and 13C NMR of 2b), which clearly
demonstrated that trace water in the reaction acts as the oxygen
source (Eq. (1)).12
N
H
N
7d
H
F
F
F
F
1g
O
2g 50 (10)
O
O
N
H
N
8d
H
2h 80 (5)
1h
O
O
O
O
O
O
N
O
N
H
O
O
O
9
4
4
H
2i 84 (6)
1i
18O (18O 45%)
O
O
O
O
CuBr, Selectfluor
O
N
H
N
N
N
H
10
ð1Þ
CH3CN:H218O=1000:1
H
H
O
1j
2j 82 (6)
1b
2b, 70%
a
Amide 1 (0.25 mmol), Selectfluor (0.625 mmol, 2.5 equiv) and CuBr (0.3 mmol,
Since all amides in Table 2 are secondary amides, a tertiary
amide 1k was employed for examining whether N–H is important
(Eq. (2)). Most of the starting amide 1k was recycled and only small
amounts of oxidation product 2b (20%) could be isolated with
some unknown product, the yield being much lower than a similar
product in entry 2 of Table 1, indicating that N–H probably plays a
role in the oxidation.
1.2 equiv, added in six portions over 40 min) reacted in acetonitrile (5 mL) at room
temperature for 1 h.
b
Isolated yield based on starting material.
Starting material recovered.
c
d
Small amount of impurities were found in imides.
O
O
O
O
CuBr, Selectfluor
CH3CN
added; this phenomenon may be due to the presence of paramag-
netic species in the reaction, which seemed to hint toward the
existence of Cu(II). However, electron paramagnetic resonance
(EPR) analysis showed that there was no Cu(II) formed in the
course the reaction. Also Cu(II) salt along is not an effective oxidant
in this transformation (Table 1, entry 12), so we rule out the possi-
bility that the Cu(II) is the active species in this transformation.
Based on the above observations, we proposed the copper(III)
mechanism (Scheme 1). Recently, we have demonstrated that
Selectfluor has the ability to oxidize gold(I) species to fluorinated
+
N
N
N
H
1k
1k, 60%
2b, 20%
ð2Þ
At first we thought that some of Cu(I)Br could be oxidized into
Cu(II) species, which may disproportionate into Cu(I) and Cu(III).13
Attempts to monitor the reaction by 1H NMR spectroscopy was
complicated by line broadening effects when Selectfluor was

1958
Z. Jin et al. / Tetrahedron Letters 52 (2011) 1956–1959
Cl
-
BF4
Cl
N
N
Cl
N
-
N
2BF4
CuIBr
III
-
.
F
Cu Br BF4
-
CuIBr
+
N
F
BF4
+
Cu(I)
N
fast
N
A
reaction
7
O
H
H
Selectfluor
R2
N
R1
N
-
H
1
BF4
Cl
B:
8
Br
O
H
R2
H
CuIII
O
F
B:
N
R1
+ HBF4
or
H
H
CuIII
Br
R2
N
R1
F
4
3
-HF
-CuIBr
O
18OH
O
18O
R2
O
CuIII
H218O
R2
N
R1
R2
N
R1
N
H
R1
H
5
2
6
Scheme 1. Proposed copper(III) mechanism.
gold(III) species in a gold catalyzed oxidative coupling reaction.6
Considering that copper(I) is a stronger reductant compared to
gold(I), we propose that a similar chemistry will occur in copper(I)
species. The copper(I) salt can be oxidized to generate a fluorinated
copper(III) species A and 7 (Scheme 1).14 Then, copper(III) species A
may coordinate with oxygen or nitrogen in 1 to form complex 3 or
4, followed by elimination of HF and copper(I) from 3 or 4 to give
the imine intermediate 5. Compound 5 may react with water to
generate hemiaminal 6; 6 can be further oxidized by A or Selectflu-
or itself to give the final product 2. Considering that copper(III)
species A may not be very stable (isolable only with specific li-
gands), a multi portion addition of CuBr could reduce the decom-
position of A and thus improve the yield of 2 (Table 1, entries 2
and 14). A premixed solution of CuBr and Selectfluor is still active,
albeit it gives lower yields.15
Supplementary data
Supplementary data (the 1H, 13C NMR spectroscopic data, MS
and analytic data of the compounds shown in Tables 1 and 2,
and the detailed description of experimental procedures) associ-
ated with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2011.02.059.
References and notes
1. Bioactive compounds containing amide group: (a) Maruyama, H. B.; Suhara, Y.;
Suzuki-Watanabe, J.; Maeshima, Y.; Shimizu, N.; Ogura-Hamada, M.; Fujimoto,
H.; Takano, K. J. Antibiot. 1975, 28, 636–647; (b) Suhara, Y.; Maruyama, H. B.;
Kotoh, Y.; Miyasaka, Y.; Yokose, K.; Shirai, H.; Takano, K.; Quitt, P.; Lanz, P. J.
Antibiot. 1975, 28, 648–655; (c) Krohn, K.; Franke, C.; Jones, P. G.; Aust, H. J.;
Draeger, S.; Shulz, B. Liebigs Ann. Chem. 1992, 789–798; (d) Thirkettle, J.;
Alvarez, E.; Boyd, H.; Brown, M.; Diez, E.; Hueso, J.; Elson, S.; Fulston, M.;
Gershater, C.; Morata, M. L.; Perez, P.; Ready, S.; Sanchez-Pulles, J. M.; Sheridan,
R.; Stefanska, A.; Warr, S. J. Antibiot. 2000, 53, 664–669; (e) Ross, L.; Guarino, L.
A. Virology 1997, 232, 105–113.
2. Typical examples of preparation of amide through condensation: (a) Eliel, E. L.;
McBride, R. T.; Kaufmann, St. J. Am. Chem. Soc. 1953, 75, 4291–4296; (b) Ficken,
G. E.; Linstead, R. P. J. Chem. Soc. 1952, 4846–4854.
3. Selected other protocols for preparation of imides: (a) Evans, D. A.; Nagorny, P.;
Xu, R. Org. Lett. 2006, 8, 5669–5671; (b) Schnyder, A.; Indolese, A. F. J. Org.
Chem. 2002, 67, 594–597; (c) Gledhill, A. P.; McCall, C. J.; Threadgill, M. D. J. Org.
Chem. 1986, 51, 3196–3201; (d) Alper, H.; Mahatantila, C. P.; Einstein, F. W. B.;
Willis, A. C. J. Am. Chem. Soc. 1984, 106, 2708–2710; (e) Ochiai, M.; Kajishima,
D.; Sueda, T. Tetrahedron Lett. 1999, 40, 5541–5544; (f) Wang, F.; Liu, H.; Fu, H.;
Jiang, Y.; Zhao, Y. Adv. Synth. Catal. 2009, 351, 246–252.
4. Alkylperoxyiodane oxidation: (a) Sueda, T.; Kajishima, D.; Goto, S. J. Org. Chem.
2003, 68, 3307–3310; Aerobic oxidation catalyzed by N-hydroxyphthlimides
and cobalt(II) salt: (b) Minisci, F.; Punta, C.; Recupero, F.; Fontana, F.; Pedulli, G.
F. . J. Org. Chem. 2002, 67, 2671–2676; (c) Wang, J.; Liu, L.; Wang, Y.; Zhang, Y.;
Deng, W.; Guo, Q. Tetrahedron Lett. 2005, 46, 4647–4651; RuO4 oxidation: (d)
Papillon, J. P. N.; Taylor, R. J. K. Org. Lett. 2000, 2, 1987–1990; (e) Altomare, C.;
Carotti, A.; Casini, G.; Cellamare, S.; Ferappi, M.; Gavazzo, E.; Mazza, F.;
Pantaleoni, G.; Giorgi, R. J. Med. Chem. 1988, 31, 2153–2158; (f) Yoshifuji, S.;
Arakawa, Y. Chem. Pharm. Bull. 1989, 37, 3380–3381; O-Iodooxybenzoic acid
(IBX) oxidation: (g) Gorka, A.; Hazai, L.; Szantary, C.; Hada, V.; Szabo, L.;
Szantary, C. Hetereocycles 2005, 65, 1359–1371; Aerobic oxidation catalyzed by
iodine: (h) Nakayama, H.; Itoh, A. Synlett 2008, 675–768; Dess–Martin
Periodinane (DMP) oxidation: (i) Nicolaou, K. C.; Mathison, C. J. N. Angew.
Chem., Int. Ed. 2005, 44, 5992–5997; Chromium(VI) catalyzed periodic acid
oxidation: (j) Xu, L.; Zhang, S.; Trudell, M. L. Chem. Commun. 2004, 1668–1669.
5. (a) Nyffeler, P. T.; Duron, S. G.; Burkart, M. D.; Vincent, S. P.; Wong, C.-H. Angew.
Chem., Int. Ed. 2005, 44, 192–212; (b) Banks, R. E.; Mohialdin-Khaffaf, S. N.; Lal,
G. S.; Sharif, I.; Syvret, R. G. J. Chem. Soc., Chem. Commun. 1992, 595–596.
6. Wang, W.; Jasinski, J.; Hammond, G. B.; Xu, B. Angew. Chem., Int. Ed. 2010, 49,
7247.
The proposed mechanism also helps to explain why stoichiom-
etric amounts of copper(I) are needed to complete the reaction.
Selectfluor loses its fluorine to generate 7 after oxidation, 7 has a
free amine which may coordinate with copper(I) to generate a
rather stable copper(I) complex 816 thereby losing its catalytic
activity. In theory, the addition of a ligand with a high affinity for
copper(I) should prevent the oxidation of copper(I) to copper(III)
and thus inhibit the reaction. This hypothesis was supported by
the addition of 1,10-phenanthroline, a strong bidentate ligand to
copper(I), which completely suppressed the reaction.
Alternatively, a single electron transfer (SET) mechanism17–19
can also be a viable mechanism, based on the facts that tertiary
amide 1k (Eq. (2)) can also be oxidized into imide (albeit in low
yield).
Cu(II) salts are well known oxidants in many transformations,20
in our case, the combination of copper(I) bromide and Selectfluor
can oxidize the stable amides into imides21. The broader implica-
tions of this oxidation system, including exploring other metal/
Selectfluor combinations, are being investigated by our group.
Acknowledgment
We are grateful to the National Science Foundation for financial
support (CHE-0809683). We also acknowledge the support pro-
vided by the CREAM Mass Spectrometry Facility (University of Lou-
isville) funded by NSF/EPSCoR grant #EPS-0447479.
7. Han, J.; Xu, B.; Hammond, G. B. J. Am. Chem. Soc. 2010, 132, 916–917.

Z. Jin et al. / Tetrahedron Letters 52 (2011) 1956–1959
1959
8. Acetonilide can be brominated on the para-position in the presence of CuBr/
Selectfluor system. The generation of bromine cation through oxidation of
bromide (e.g., KBr) by Selectfluor has been reported: Ye, C.; Shreeve, J. M. J. Org.
Chem. 2004, 69, 8561–8563.
9. Yield could be significantly increased by adding reactants in multi-portion
fashion: (a) Chen, M. S.; White, M. C. Science 2010, 327, 566–571; (b) Chen, M.
S.; White, M. C. Science 2007, 318, 783–787.
10. Amide 1a (1 equiv), copper bromide (1.2 equiv, one portion) and Selectfluor
(2.5 equiv) were stirred in acetonitrile under nitrogen atmosphere for 1 h; a
50% (NMR) yield of imide 2a was recorded, which is comparable to entry 2 in
Table 1.
18. (a) Zhang, X.; Liao, Y.; Qian, R.; Wang, H.; Guo, Y. Org. Lett. 2005, 7, 3877–3880;
(b) Zhang, X.; Wang, H.; Guo, Y. Rapid Commun. Mass Spectrom. 2006, 20, 1877–
1882.
19. Copper salts have been reported to promote single electron transfer in the
presence of several oxidants, such as H2O2 and tBuOOH, see: (a) Li, X.; Li, C.-J. J.
Am. Chem. Soc. 2004, 126, 11810–11811; (b) Li, C.-J.; Li, Z. Pure Appl. Chem.
2006, 78, 935–945; (c) Li, C.-J. Acc. Chem. Res. 2009, 42, 335–344. and references
cited therein.
20. Selected references for oxidation of acyloin by stoichiometric Cu(II) salts: (a)
Pepe, A.; Sun, L.; Zanardi, I.; Wu, X.; Ferlini, C.; Fontana, G.; Bombardelli, E.;
Ojima, I. Bioorg. Med. Chem. Lett. 2009, 19, 3300–3304; (b) Hicks, L. D.; Hyatt, J.
L.; Moak, T.; Edwards, C. C.; Tsurkan, L.; Wierdle, M.; Ferreira, A. M.; Wadkins,
R. M.; Potter, P. M. Bioorg. Med. Chem. Lett. 2007, 17, 3801–3817; (c) Chen, C.;
Lin, J.; Moturu, M. V. R. K.; Lin, Y.; Yi, W.; Tao, Y.; Chien, C. Chem. Commun. 2005,
3980–3982.
11. The trace amount of water in commercial Selectfluor can’t be removed by
50 °C/1 mmHg vacuum overnight.
12. Comparison of 13C NMR and HRMS of 18O containing 2b and regular 2b is
available in the supporting information section.
13. For selected references for Cu(II) disproportionation into Cu(I) and Cu(III), and
Cu(III) activation of a C–H bond see: (a) King, A. E.; Huffman, L. M.; Casitas, A.;
Costas, M.; Ribas, X.; Stahl, S. S. J. Am. Chem. Soc. 2010, 132, 12068–12073; (b)
Huffman, L. M.; Stahl, S. S. J. Am. Chem. Soc. 2008, 130, 9196–9197.
14. The reaction of Selectfluor with copper(I) like CuBr is a fast exothermic process
even at room temperature (acetonitrile as solvent). And electron paramagnetic
resonance (EPR) analysis showed that there was no Cu(II) species formed in the
course the reaction. And also copper(II) species are not active in this
transformation, we tentatively assign the oxidized copper intermediate A as
a copper(III) intermediate.
15. CuBr and Selectfluor were pre-mixed in acetonitrile for 1 h, the resulting
solution still can oxidize amide 1a into imide 2a (50% yield by 1H NMR).
16. Twamley, B.; Gupta, O. D.; Shreeve, J. M. Acta Crystallogr., Sect. E 2002, 58,
m663–m665.
17. Selected examples of Single Electron Transfer by copper salt and oxidant: (a) Li,
X.; Li, C.-J. J. Am. Chem. Soc. 2004, 126, 11810–11811; (b) Li, C.-J.; Li, Z. Pure Appl.
Chem. 2006, 78, 935–945; (c) Li, C.-J. Acc. Chem. Res. 2009, 42, 335–344. and
references cited therein.
21. General procedure for copper mediated oxidation of amides to imides by
Selectfluor: Amide 1a (48 mg, 0.25 mmol, 1 equiv), and Selectfluor (221 mg,
0.625 mmol, 2.5 equiv) were dissolved in 5 mL of acetonitrile at room
temperature, and CuBr (42.6 mg, 0.3 mmol, 1.2 equiv) was added over
a
40 min period in six portions. After all CuBr was added, the resulting mixture
was stirred for extra 20 min, and then acetonitrile was evaporated under
reduced pressure. Then, 20 mL of a saturated ammonium chloride solution was
added into the reaction mixture and extracted by diethyl ether (25 mL ꢀ 4), the
ether layers were combined and dried over Na2SO4, filtered, and evaporated
under reduced pressure to give the crude product. Silica gel flash
chromatography of the crude product (hexanes–ethyl acetate (10:1) to
hexanes–ethyl acetate (4:1)) yielded pure imide 2a (45 mg, 0.22 mmol, 88%
yield) together with unreacted 1a (3.2 mg, 0.017 mmol, 7%). N-(3-Methyl-
butyryl)-benzamide,3a (2a): 1H NMR (400 MHz, CDCl3): d 8.92 (br s, 1H), 7.82
(d, J = 7.6 Hz, 2H), 7.51 (t, J = 6.4 Hz, 1H), 7.42 (t, J = 7.6 Hz, 2H), 2.82 (d,
J = 6.8 Hz, 2H), 2.18 (m, 1H), 0.96 (d, J = 6.4 Hz, 6H). 13C NMR (100 MHz, CDCl3):
d 175.9, 165.6, 133.1, 132.9, 128.9, 127.7, 46.2, 24.8, 22.52.