Oxidation of 4-methoxyanilines to 1,4-benzoquinones using ceric ammonium nitrate (CAN)

Article abstract of DOI:10.1016/j.tetlet.2010.11.070

Treatment of substituted 4-methoxyanilines with ceric ammonium nitrate in a 1:1 mixture of water and acetonitrile resulted in the formation of 1,4-benzoquinones in acceptable yields.

Full text of DOI:10.1016/j.tetlet.2010.11.070

Tetrahedron Letters 52 (2011) 480–482
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Oxidation of 4-methoxyanilines to 1,4-benzoquinones using ceric
ammonium nitrate (CAN)
⇑
Yugang Chen, Weijiang Ying, Michael Harmata
Department of Chemistry, University of Missouri-Columbia, Columbia, MO 65211, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Treatment of substituted 4-methoxyanilines with ceric ammonium nitrate in a 1:1 mixture of water and
acetonitrile resulted in the formation of 1,4-benzoquinones in acceptable yields.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 21 September 2010
Revised 11 November 2010
Accepted 14 November 2010
Available online 18 November 2010
Keywords:
Oxidation
Ceric ammonium nitrate
Aniline
Benzoquinone
Quinone
1. Introduction
2. Results and discussion
In the course of our work on the synthesis of various antituber-
cular terpenes1 and related compounds,2 we were challenged by
the need to oxidize a relatively complex aniline to the correspond-
ing benzoquinone.3 This Letter summarizes our successful devel-
opment of ceric ammonium nitriate for that purpose.
We specifically wanted to accomplish the conversion of 1 into
2 (Eq. 1). To this end, 1 was treated with a variety of oxidants.
After several attempts with known procedures17 that proved
ineffective; we turned to ceric ammonium nitrate and found that
a good yield of the quinone 2 could be obtained simply by stirring
The oxidation of aromatic amines to quinones is a potentially
convenient way to generate the latter, since anilines are readily
available via a number of processes, including the reduction of
nitroarenes. While a number of methods have been reported for
this oxidation,4–12 they can be tedious due to long reaction times,
complicated work-up procedures, or low yields and often work
best when using anilines soluble in water.
Me
Me
Me
Me
Me
Me
CAN
MeO
MeO
O
OH
OH
NH2
MeO
O
1
2
Me
Me
Ceric ammonium nitrate (CAN) is a powerful oxidant that has
many uses in organic synthesis.13 This reagent is well known to
oxidize electron rich aromatic groups. The removal of p-methoxy-
phenyl and related electron rich aromatic groups from amines has
been established.14 For example, electron rich aromatics can be re-
moved from secondary amines and secondary amides by oxidation
with CAN.15 It is likely that such deprotections proceed via the for-
mation of a quinone, but generally in these processes, the quinone
is not the desired organic material. Other electron rich systems are
readily oxidized by CAN to quinones,16 but it appears that the di-
rect oxidation of substituted, unprotected anilines to quinones
has not previously been reported.
ð1Þ
aniline 1 in the presence of the reagent in a 1:1 mixture of water
and acetonitrile. Thus, an acetonitrile solution (4 mL) of
1
(0.6 mmol) was added dropwise into a 16 mL solution (acetoni-
trile/water = 1:1) of ceric ammonium nitrate (4.0 equiv) at room
temperature with vigorous stirring. After 20 min, the reaction
was quenched. Chromatographic work-up afforded a 73% yield of
2. Compound 2 was obtained without any epimerization at the ste-
reocenter adjacent to the quinone ring according to 1H NMR
analysis.
This procedure turned out to be general and was applied to a
small selection of other anilines that were available in our labora-
tories. The results are presented in Table 1. The results suggest that
highly substituted anilines are best for this process, presumably as
⇑
Corresponding author.
E-mail address: harmatam@missouri.edu (M. Harmata).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.11.070

Y. Chen et al. / Tetrahedron Letters 52 (2011) 480–482
481
Table 1
Conversion of anilines to quinones with CAN
Entry
Aniline
Quinone
Yield (%)
Me
Me
Me
Me
Me
O
Me
MeO
MeO
1
73
OH
OH
MeO
NH2
O
2
1
Me
Me
Cl
Cl
MeO
O
2
3
51b
O
NH2
Me
3
4
OMe
OMe
Me
MeO
O
OH
OH
76c
Me
Me
O
NH2
Me
OMe
OMe
OMe
6
5
Me
MeO
O
Me
NH2
Me
4
5
75
69
Me
Me
O
OMe
7
8
Me
Me
MeO
O
Me
Me
NH2
O
9
10
TIPSO
TIPSO
Me
Me
Me
Me
Me
Me
Me
O
MeO
MeO
6
7
57
42
OAc
OAc
MeO
O
NH2
11
12
Me
Me
Me
Me
tBu
tBu
Me
Me
Me
Me
O
Me
O
MeO
MeO
MeO
O
MeO
O
O
O
tBu
tBu
NH2
NH2
O
13
14
Me
Me
8
9
11a
O
16
15
NO2
NO2
Me
Me
O
MOMO
0
Me
Me
O
NH2
17
18
TIPSO
TIPSO
a
b
c
The reaction was conducted at 0.001 M. At 0.03 M, no quinone could be isolated.
See Ref. 18.
See Ref. 19.
that minimizes side reactions that might arise as a result of reac-
tions between the starting materials and the products. Indeed, it
should be noted that in general this reaction not only gave quinone
but also resulted in the formation of a number of colored by prod-
ucts, none of which have been isolated and characterized.
3. Conclusion
We found that treatment of p-methoxyanilines with ceric
ammonium nitrate afforded the corresponding 1,4-quinones in
good yield. The efficacy of CAN as an oxidant suggests its potential

482
Y. Chen et al. / Tetrahedron Letters 52 (2011) 480–482
4. Rao, A. V.; Chavan, S. P.; Sivadasan, L. Tetrahedron 1986, 42, 5065.
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York, 1993.
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8. Fieser, L. F. Org. Synth. 1937, 17, 68.
Acknowledgment
9. Sakave, S.; Tsubakino, T.; Nishiyama, Y.; Ishi, Y. J. Org. Chem. 1993, 58, 3633.
10. Adams, R.; Nagarkatti, A. S. J. Am. Chem. Soc. 1950, 72, 4601.
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13. Nair, V.; Deepthi, A. Chem. Rev. 2007, 107, 1862.
This work was supported by the NIH (1R01-A159000-01A1) to
whom we are very grateful.
14. For examples see: (a) Wuts, P. G. M.; Greene, T. W. Greene’s Protective Groups in
Organic Synthesis, 4th ed.; Wiley: New York, 2007. pp 813–14; (b) Uraguchi, D.;
Nakashima, D.; Ooi, T. J. Am. Chem. Soc. 2009, 131, 7242; (c) Cheemala, M. N.;
Knochel, P. Org. Lett. 2007, 9, 3089.
15. (a) Verniest, G.; Wang, X.; Kimpe, N. D.; Padwa, A. J. Org. Chem. 2009, 75, 424;
(b) McErlean, C. S. P.; Sperry, J.; Blake, A. J.; Moody, C. J. Tetrahedron 2007, 63,
10963.
Supplementary data
Supplementary data (experimental procedures, charaterization
data; 1H and 13C spectra for new compounds) associated with this
article can be found, in the online version, at doi:10.1016/
j.tetlet.2010.11.070.
16. For example, see: Radeke, H. S.; Digits, C. A.; Bruner, S. D.; Snapper, M. L. J. Org.
Chem. 1997, 62, 2823.
17. We focused on using FeCl3 under a variety of conditions giving results ranging
from no reaction to complicated mixtures. Attempts to generate diazonium
ions from nitrite acid or isoamyl nitrite were also not successful. The use of
sodium hypochlorite did not afford the desired quinone and it was after these
initial attempts that we pursued CAN oxidation.
18. Higuchi, T.; Satake, C.; Hirobe, M. J. Am Chem. Soc. 1995, 117, 8879.
19. Ying, W.; Barnes, C. L.; Harmata, M. Tetrahedron Lett. 2010 (in press),
doi:10.1016/j.tetlet.2010.10.109.
References and notes
1. (a) Harmata, M.; Zheng, P. Heterocycles 2009, 77, 279; (b) Harmata, M.; Cai, Z.;
Chen, Y. J. Org. Chem. 2009, 74, 5559; (c) Harmata, M.; Hong, X.; Schreiner, P. R.
J. Org. Chem. 2008, 73, 1290; (d) Harmata, M.; Hong, X. Tetrahedron Lett. 2005,
46, 3847; (e) Harmata, M.; Hong, X. Org. Lett. 2005, 7, 3581–3583.
2. Harmata, M.; Hong, X.; Barnes, C. L. Tetrahedron Lett. 2003, 44, 7261–7264.
3. The work described herein was initiated during a formal total synthesis of
floresolide B, the details of which shall be communicated shortly.