Regiospecific oxidation of an alkyl group of aromatic amine to carbonyl group by DDQ in aq. medium

Article abstract of DOI:10.1016/j.cclet.2011.03.016

The regiospecific oxidation of alkyl group of both sterically hindered and unhindered aromatic amine to corresponding carbonyl compound was done in aq. medium by using DDQ. The optimized reaction protocol was found to be most simple, high yielding and novel method for oxidation of alkyl group of aromatic amine in to its carbonyl compound.

Full text of DOI:10.1016/j.cclet.2011.03.016

Available online at www.sciencedirect.com
Chinese Chemical Letters 22 (2011) 1039–1042
www.elsevier.com/locate/cclet
Regiospecific oxidation of an alkyl group of aromatic amine to
carbonyl group by DDQ in aq. medium
Madhav S. Mane a, Ravi S. Balaskar a, Sandip N. Gavade a, Pramod N. Pabrekar c,
Murlidhar S. Shingare b, Dhananjay V. Mane a,
*
a Organic Research Laboratory, S.C.S. College, Omerga, 413 606, MS, India
b Department of Chemistry, Dr. Babasaheb Ambedkar Marathwada University, Aurangabad, 431 004, MS, India
c V.G. Vaze College, Mulund(E), Mumbai, 400081, MS, India
Received 6 December 2010
Available online 25 June 2011
Abstract
The regiospecific oxidation of alkyl group of both sterically hindered and unhindered aromatic amine to corresponding carbonyl
compound was done in aq. medium by using DDQ. The optimized reaction protocol was found to be most simple, high yielding and
novel method for oxidation of alkyl group of aromatic amine in to its carbonyl compound.
# 2011 Dhananjay V. Mane. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: DDQ; Aq. medium; Regiospecific oxidation; Aromatic amine
The discovery of new environment friendly methods for selective catalytic oxidation of alkyl substrates to aldehyde
and ketone in presence of amine is an important goal in the development of modern methods for chemical synthesis
[1]. With the considerable development of selective organic chemistry in the last few decades; specific reagents have
seen their potential increase dramatically. The spectrum of their applications in modern organic chemistry has been
enlarged to offer new challenging synthesis opportunities [2]. Not an exception, DDQ has been investigated as a
powerful oxidizing agent by several research groups, and was proved to be useful for a wide range of reactions.
Although several uses of DDQ have been mentioned in many patents from the pharmaceutical and chemical specialties
industries, we will restrict this article to regiospecific oxidation by DDQ of an unhindered alkyl group of aromatic
amine.
Amino benzaldehydes are the important key intermediates for synthesis of many biologically active compounds.
They are used for the synthesis of inosine monophosphate dehydrogenase (IMPDH) inhibitors [3] in development of
anticancer drugs [4], Chk1 kinase inhibitors [5] and also in the preparation of an intermediate of one of the major
metabolites of the antihypertensive trequisin [6], novel thyroid hormone receptor antagonists [7].
The oxidation of the sterically hindered aromatic amine has been reported using enzymatic [8], electrochemical [9]
and chemical reactions [10,11]. In the reaction the nitrogen of the molecule is involved in the oxidation and not the
* Corresponding author.
E-mail address: dr_dvmane@rediffmail.com (D.V. Mane).
1001-8417/$ – see front matter # 2011 Dhananjay V. Mane. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2011.03.016

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M.S. Mane et al. / Chinese Chemical Letters 22 (2011) 1039–1042
alkyl group. The 2,3-dichloro-5,6-dicyno-1,4-benzoquinone (DDQ) and related high potential oxidant interact with
aliphatic amino groups and doubts have been raised about the nature of reaction with aromatic amines.
Regiospecific oxidation of mesidine to 4-amino-3,5-dimethylaldehyde was done by using DDQ (3 eq.) in dioxane
[12]. This method has certain drawbacks such as: (1) low yield, long reaction time and tedious workup, (2) failed to
give p-aminobenzaldehyde from p-toludine. (3) 2,6-dimethyl-4-propylaniline to corresponding carbonyl compound
gives very less yield. An aerobic oxidations by using molybdovanadophosphate as a catalyst convert 2,4,6-
trimethylaniline to 4-amino-2,6-dimethylbenzaldehyde in good yield (64%) which is difficult to prepare by
conventional methods. However this reaction was catalyzed by metal and required high temperature with long reaction
time [13]. Oxidation of glycozolinine to 3-formyl-6-methoxycarbazole was reported by DDQ (4.2 eq.) in
methanol:water (16:1) gives 79% yield of corresponding aldehyde within 85 min [14,15]. This method works
beautifully for the tricycle system, however failed to give p-aminobenzaldehyde from p-toludine and required excess
of DDQ.
To overcome these drawbacks we had decided to develop methodology, which is high yielding, short reaction time,
and use of greener protocol.
There are no previous reports, to the best of our knowledge; on the oxidation of an unhindered alkyl group of
unhindered aromatic amines in water by using DDQ.
1. Experimental
1.1. General procedure
Amine (0.111 mol) was dissolved in 5% aq. HCl and DDQ (0.225 mol) was added in it (Scheme 1). The mixture
was stired at rt for 2 h and the residue was treated with dilute sodium hydroxide and extracted with ethyl acetate. The
organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo; the crude
product was purified by silica gel column chromatography using EtOAc–hexane (1:2) as eluent to afford the oxidized
1
product. The identity and purity of the known products was confirmed by H NMR, IR and mass spectroscopic
analysis, and the new products were fully characterized.
4-Amino-3, 5-dimethylbenzaldehyde (Table 2,entry 1): crystalline solid; M.p.78–80 8C; IR (neat) 1677 cmÀ1; 1H
NMR (CDCl3, 400 MHz): d 7.47 (s, 2H, Ar H), 2.23 (s, 6H, CH3), 4.22 (br.s, H, NH2), and 9.71 (s, 1H, CHO); HRMS
(EI, m/z) calcd. for C9H11NO (M+) 149.08, found 149.05. p-Aminobenzaldehyde (Table 2, entry 6): crystalline solid;
1
Mp 41–43 8C; IR (neat) 1670 cmÀ1; H NMR (CDCl3, 400 MHz): d 6.77 (d, 2H, J = 8.5 Hz, Ar H), 7.68 (d, 2H,
J = 8.5 Hz, Ar H), 4.37 (br.s, 2H, NH2), and 9.74 (s, 1H, CHO); HRMS (EI, m/z) calcd. for C7H7NO (M+) 121.14,
found 121.12. 4-Amino3bromobenzaldehyde (Table 2, entry 3): solid; Mp 109–110 8C; IR (neat) 1677, 2747 cmÀ1; 1H
NMR (CDCl3, 400 MHz): d 7.95 (d, 2H, J = 8.2 Hz, ArH), 7.64 (d, 1H, J = 8.2 Hz, ArH), 6.80 (s, 1H, Ar H), 4.73 (br.s,
2H, NH2), and 9.71 (s, 1H, CHO); HRMS (EI, m/z) calcd. for C7H6BrNO (M+) 198.96 found 198.94. 1-(4Amino-3, 5-
dimethylphenyl)propan-1-one (Table 2, entry 8): Mp 81–82 8C; IR (neat) 1718 cmÀ1; 1H NMR (CDCl3, 400 MHz): d
7.47 (s, 2H, Ar H), 2.23 (s, 6H, CH3), 2.122 (q, 2H, CH2), 1.21 (t, J = 6.9 3H, CH3), 4.22 (br.s, 2H, NH2), HRMS (EI,
m/z); calcd. for C10H13NO (M+) 163.10, found 163.09. 3-Formyl-6-methoxycarbazole (Table 2, entry 11): light yellow
solid; Mp 183–184 8C; IR (neat) 1671 cmÀ1; 1H NMR (CDCl3, 400 MHz): d 6.92 (dd, 1H, J = 8.5, 2.2 Hz, ArH), 6.95
(dd, 1H, J = 2.2 Hz, Ar H), 7.45 (d, 1H, J = 8.4 Hz, ArH), 7.89 (dd, 1H, J = 8.4, 1.5 Hz, ArH), 7.98 (d, 1H, J = 8.5 Hz,
Ar H), 8.49 (m, 1H), 8.38 (br.s, 1H, NH), 3.90 (s, 3H, CH3) and 10.07 (s, 1H, CHO); HRMS (EI, m/z) calcd. for
C14H11NO2 (M+) 225.079, found 225.078.
[(Schme_1)TD$FIG]
Me
CHO
NH2
DDQ, rt for 2 hr.
5% aq.HCl
NH2
Scheme 1.

M.S. Mane et al. / Chinese Chemical Letters 22 (2011) 1039–1042
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2. Results and discussion
To continue our interest in conversion of aromatic methyl group into corresponding carbonyl compound we had
selected mesidine (2,4,6-trimethylbenzene amine) as model substrate for further studies. As mention earlier studies
when mesidine was treated with 3 eq. DDQ in 1, 4-dioxane p-methyl group was oxidized to corresponding aldehyde in
49% yield [12]. When above reaction was done with 1 eq. and 2 eq. gives only 12% and 20% yield of product
respectively. To improve yield of reaction we had decided to use different solvent keeping rest of thing constant.
Similar reaction was repeated in solvent such as THF, Acetonitrile and DMF gives almost similar yield. Drastic change
in yield was observed when reaction was done in water; this method gives 70% desired product of aldehyde from
mesidine. Similarly MeOH:water mixture gives 82% yield of desired product [14,15]. Although the amines are
partially soluble in water the advantages of the employment of water as a solvent are numerous: not only it is cheap,
nontoxic, and inflammable, but also it may have the feature of the stability of reaction intermediate in water which
leads to high yield of desired product.
When mesidine treated with DDQ in 5% aq. HCl the 4-methyl group of mesidine was regiospecificaly oxidized to
corresponding aldehyde with 94% yield. It has isolated in pure state and can be stored for longer time. For consistency
of result we have repeated same protocol three times for mesidine and we had got similar result as we done previously.
Mesidine was taken in 5% aq. HCl along with DDQ (2.5 mol eq.) and mixture was stirred for 2 h and monitored by
TLC. After complete disappearance of starting material from TLC, reaction mixture was basified with 10% aq. NaOH
and compound was extracted in ethyl acetate. Ethyl acetate layer was dried over anhydrous sodium sulphate and
concentrated to get white crystalline solid.
We had also observed similar result for the DDQ oxidation of less hindered amines such as p-toludine in dioxane
[12] (Table 1, entry 1) and for THF (Table 1, entry 2). From above observation we conclude that both are not suitable
solvent for DDQ oxidation of less hindered aromatic amine.
Similar reaction gives 30% yield of p-aminobenzaldehyde in (Table 1, entry 4) MeOH:water system [14,15].
Reaction of p-toludine with DDQ in H2O gives only 10% yield of p-aminobenzaldehyde. Whereas 62% yield was
achieved when similar reaction was carried out in (Table 1, entry 5) 5% aq. HCl with DDQ. We believe that this is
Table 1
Reaction of p-toludine with DDQ (2.5 eq.) in different solvent.
No.
Solvent
Yield (%)a
1
2
3
4
5
1,4-Dioxane
THF
0
0
Water
10
30
62
MeOH:Water (10:1)
5% Aq. HCl
a
Isolated yield.
Table 2
Reaction of different aromatic amine with DDQ (2.5 eq.) in 5% aq. HCl.
No. Amine
Product
Physical constant (M.P.) (8C) Yield (%)a
1
2,4,6-Trimethylbenzeneamine
4-Amino-3,5-dimethylbenzaldehyde
4-Amino-3-methylbenzaldehyde
4-Amino-3-bromolbenzaldehyde
4-Amino-3-chlorolbenzaldehyde
4-Amino-2,3-dibromobenzaldehyde
4-Aminobenzaldehyde
78–79
98–100
109–110
104–106
161–163
42–44
94
82
80
75
80
62
80
10
73
95
96
2
2,4-Dimethylbenzeneamine
2-Bromo-4-methylbenzeneamine
2-Chloro-4-methylbenzeneamine
2,3-Dibromo-4-methylbenzeneamine
p-Toludine
3
4
5
6
7
2,3-Dibromo-4,5-dimethylbenzeneamine 4-Amino-2,3-dibromo-6-methylbenzaldehyde
169–170
81–82
8
2-Methyl-4-propylbenzylamine
4-Benzyl-2-methylbenzenamine
1-(4-Amino-3-methylphenyl)propan-1-one
9
(4-Amino-3-methylphenyl)(phenyl)methanone 121–122
10
11
2,3-Dibromo-4,5-dimethylbenzeneamine 4-Amino-2,3-dibromo-5-methylbenzaldehyde
169–170
183–184
7-Methoxy-3-methylcarbazole
3-Formyl-7-methoxy-carbazole
a
Isolated yield.

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M.S. Mane et al. / Chinese Chemical Letters 22 (2011) 1039–1042
novel and more general method for oxidation of p-toludine to p-aminobenzaldehyde in water at ambient temperature.
Steric hindrance certainly plays role in the success of this reaction.
Under optimized reaction condition, the scope of reaction was explored with structurally and electronically diverse
amine.
More the steric hindrance at ortho position of amine gives higher yield of aldehyde. More the steric bulk at ortho
position of amine will give more yield of aldehyde.
Similarly, 2-chloro-4-methylaniline (Table 2, entry 4) gives 4-amino-3-chlorobenzaldehyde in 75% and 2-bromo-
4-methyl aniline (Table 2, entry 3) was successfully oxidized to corresponding aldehyde with very good yield (80%).
While oxidation of 2,4-dimethyl aniline to 4-amino-3-methylbenzaldehyde (Table 2, entry 2) in 72% yield.
Reaction of 4-benzyl-2-methylbenzenamine (Table 2 entry 9) with DDQ under optimized condition gives 73% of
(4-amino-3-methylphenyl)-1-phenylmethanone.
DDQ oxidation of 2-methyl-4propylbenzylamine (Table 2 entry 8) in to respective ketone gives only 10% yield.
The poor yield might be due to a further dehydrogenation of the—CO–CH2CH3 group there by generating very active
species—CO–CH CH2, although this is only our speculation, since we do not have evidence on this matter.
An interesting application of above method was demonstrated in the preparation of 3-formyl-7-methoxy carbazole
from 7-methoxy-3-methylcarbazole, (Table 2, entry 11). Above conversion gives 79% yield in water:MeOH method
[14,15], while under optimized condition 96% of product obtained. 3-Formyl-7-methoxy carbazole is an alkaloid
isolated from the Chinese medicinal plant ‘‘Clausena excavate’’ and it exhibits anti HIV activity.
3. Conclusion
In this communication, we report a simple, economical, efficient, high yielding, method for regiospecific oxidation
of alkyl group of an aromatic amine in to corresponding carbonyl compound depending on nature of substrate. Various
amino benzaldehydes (Table 2) were prepared in high yields under optimized reaction protocol and their spectroscopic
confirmation was achieved.
Acknowledgment
Authors are thankful to Head of Department of Chemistry, S.C.S. College, Omerga for providing the necessary
laboratory facilities.
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