Oxidative coupling of N,N-Dialkylanilines using iodic acid and sodium nitrite

Article abstract of DOI:10.1246/cl.2010.808

A new reagent system, a combination of iodic acid and sodium nitrite has been investigated for oxidative coupling of N,N-disubstituted anilines. A facile para-selective coupling occurs to give benzidines at room temperature in water as a solvent. A tentative mechanism is proposed with some supporting experiments.

Full text of DOI:10.1246/cl.2010.808

doi:10.1246/cl.2010.808
808
Published on the web June 26, 2010
Oxidative Coupling of N,N-Dialkylanilines Using Iodic Acid and Sodium Nitrite
Sameerana N. Huddar, Ulhas S. Mahajan, and Krishnacharya G. Akamanchi*
Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology,
Matunga, Mumbai 400019, India
(Received May 6, 2010; CL-100433; E-mail: kg.akamanchi@ictmumbai.edu.in)
Table 1. Optimization of reaction conditions and screening of various
hypervalent iodine reagentsa
A new reagent system, a combination of iodic acid and
sodium nitrite has been investigated for oxidative coupling of
N,N-disubstituted anilines. A facile para-selective coupling
occurs to give benzidines at room temperature in water as a
H3C
CH3
H3C
CH3
N
N
Reagent system
H2O, rt
H3C
H3C
CH3
N
N
solvent.
A tentative mechanism is proposed with some
+
CH3
supporting experiments.
3a
1a
2a
NO2
Unreacted
recoveredb/%c
1a
Yield/%c
Reagent
combination
Molar Reaction
ratio
Benzidine derivatives have widespread applications in the
field of organic light-emitting diodes,1 organic field-effect
transistors,2 organic solar cells,3 organic photoconductors,4 and
as crosslinking agents used in polyurethane plastics.5 Oxidative
coupling of N,N-dialkylated anilines is an important approach in
organic synthesis for construction of benzidine systems,6 and a
few methods are available, these includes oxidative systems
naphthalen-1,8-diylbis(diphenylmethylium) dication,7 Cu(II),8
CuBr/H2O2,9 TiCl4,10 and CAN.11
Our research group is actively engaged in exploring new
utilities of hypervalent iodine compounds in organic synthe-
sis,12,13 and we would like to report successful use of iodic acid
with sodium nitrite in water, which is considered to be a green
solvent,13 for oxidative coupling of N,N-dialkylanilines to give
benzidines.
Entry
timeb
2a 3a
1
2
3
4
5
6
7
8
HIO3/NaNO2 2.0/2.0
HIO3/NaNO2 0.1/1.0
HIO3/NaNO2 1.0/0.1
HIO3/NaNO2 1.0/1.0
HIO3/NaNO2 1.0/2.0
HIO3/NaNO2 2.0/1.0
IBX/NaNO2 2.0/2.0
5 min
8 h
8 h
8 h
8 h
®
97
90
75
75
70
20
20
70 20
NRe NRe
d
4
14.5
17
®
®
®
d
d
8 h
1 h
22 3.5
30 40
60 10
HIO4/NaNO2 2.0/2.0 30 min
aReaction performed on 5 mmol scale using reagent combination at rt.
bThe reaction was incomplete even after stirring for 8 h in all cases
where ratios of HIO3 and NaNO2 were less than 2:2 equivalent
c
d
e
(Entries 2-6). Isolated yields. Trace amount. NR: No reaction.
Table 2. Oxidative coupling reaction of N,N-dialkylanilines18
Use of HIO3 in organic synthesis has several advantages
like non toxicity, easy handling, and cost effectiveness. It is
employed as an oxidant for many oxidative transformations such
as oxidation of sulfides,14 aromatic iodination,15 nitrosation,16
and deoximation.17
R1
R2
R1
R2
N
N
R1
R1
R2
HIO3, NaNO2
H2O, rt
N
N
+
R2
NO2
Initial experiments were performed with N,N-dimethylani-
line (1a) as model substrate. When 1a was treated with HIO3 (2
equiv) and NaNO2 (2 equiv) in water at room temperature
N,N,N¤,N¤-tetramethylbenzidine (2a) was obtained in 70% yield
along with 20% N,N-dimethyl-4-nitroaniline (3a) in just 5 min
with complete consumption of starting material. To verify the
role of HIO3 and NaNO2, reactions were carried out using
different mole ratios of HIO3/NaNO2, monitoring the reaction
by TLC, and results are summarized in Table 1.
When reaction was carried out with 1:2 equivalent of HIO3
and NaNO2 and vice versa poor yields of 2a were shown
(Entries 4 and 5). Further optimization revealed that the
combination of substrate, HIO3, and NaNO2 in the ratio of
1:2:2 respectively in water at room temperature as the best
reaction conditions for coupling. Use of other hypervalent iodine
reagents like o-iodoxybenzoic acid (IBX) and HIO4 were also
viable, however, imparted 2a in low yields. (Table 1, Entries 7
and 8).
1
2
3
Time
/min
Products,
Yield/%a
Entry Substrate
R1
R2
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
1g
1h
1i
Me
Me
Me
Me
Et
Me
Et
Bu
CH2Ph
Et
Pr
5
5
10
10
5
15
25
30
5
2a/70
2b/72 3b/20
2c/74 3c/15
2d/70 3d/20
3a/20
2e/71
2f/65
2g/60
3e/20
3f/25
3g/30
Pr
(-CH2-)4
(-CH2-)5
allyl
allyl
COCH3
2h/65 3h/30
allyl
Et
Et
2i/70
2j/62
NRb
3i/15
3j/20
NRb
10
11
1j
1k
5
180
aIsolated yields. NR: No reaction.
b
In order to check the generality and utility of the reaction, a
variety of substrates were employed and results are summarized
in Table 2. Inspection of the results reveals that oxidative
coupling of various N,N-disubstituted anilines gave correspond-
ing benzidines (Table 2, Entries 1-10) smoothly in good yields.
When the reaction was performed on N-benzyl-N-methyl-
aniline, N,N-diallylaniline, and N-allyl-N-ethylaniline using the
When reaction of 1a was carried with 1:1 equivalent of
HIO3 and NaNO2 at 100 °C in water, 2a and 3a were formed in
30% and 25% yield, respectively, showing some additional
spots on TLC indicative of by-product formation. Hence
carrying out reaction at higher temperature is not significant.
Chem. Lett. 2010, 39, 808-809
© 2010 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

809
Table 3. Reaction of N-alkylanilnesa
O
I
O
I
Na
O
I
OH
I
R
H
NaIO3
+
OH
+
OH
NaNO2
OH
+
O
O
N
O
OH
O N O
O
O N O
R
N
R
N
N
HIO3, NaNO2
H2O, rt
R2
R1
R2
N
N
N
O
O
R1
R1
N
4
HO OH
R2
R1
R1
N
R2
-H2O
•NO2
5
IO2
O
N
I
O
R2
Time
/min
Product
Yield/%b
2HIO2
R1
O
N
Entry
Substrate
R
•NO2
N
R
2 N
1
2
4a
4b
Me
Et
10
10
5a/92
5b/90
R2 R1
Major
HIO2
2 •NO2
aReaction performed on 5 mmol scale using reagent combination at rt.
bIsolated yields.
HNO2
HNO
3
H2O
NO2
Minor
N2O4
+
+
Table 4. Reaction of para-substituted N,N-dialkylanilinesa
Scheme 1. Proposed mechanism of reaction for benzidine formation.
R
R
H
R
N
N
HIO3, NaNO2
H2O, rt
NO2
One of the authors (S.N.H.) wishes to thank Narotam
Sekhsaria Foundation, Mumbai, for financial support. In
addition, the authors wish to thank the University Grants
Commission (UGC) of India and All India Council for Technical
Education (AICTE) for financial support.
6
X
X
7
Time
/min
Product
Yield/%b
Entry
Substrate
R
X
1
2
3
4
6a
6b
6c
6d
Me
Et
Pr
Cl
Cl
CH3
NO
5
5
10
7a/70
7b/72
7c/74
NRc
References and Notes
1
G. E. Johnson, K. M. McGrane, M. Stolka, Pure Appl. Chem. 1995, 67,
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3
G. Horowitz, Adv. Mater. 1998, 10, 365.
N. S. Sariciftci, L. Smilowitz, A. J. Heeger, F. Wudl, Science 1992, 258,
1474.
Me
120
aReaction performed on 5 mmol scale using reagent combination at rt.
bIsolated yields. NR: No reaction.
c
4
V. Getautis, A. Stanisauskaité, O. Paliulis, S. Uss, V. Uss, J. Prakt. Chem.
2000, 342, 58.
5
6
7
W. A. Rye, P. F. Woolrich, R. P. Zanes, J. Occup. Med. 1970, 12, 211.
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optimized reaction conditions, oxidative coupling occurred
without effecting either benzylic or allylic positions or the
double bond of the substrates. This observation highlights the
chemoselectivity of the reaction (Table 2, Entries 4, 9, and 10).
The coupling of N-ethyl-N-phenylacetamide did not occur and
the starting material was recovered (Table 2, Entry 11).
It was found that, in all cases (Table 2, Entries 1-10), only
benzidines i.e., para-coupled products were selectively formed,
and no ortho-, ortho-para-coupled products9 were observed.
When N-monoalkylated anilines 4 were subjected to the
optimized reaction conditions, N,N¤-dialkyl-N,N¤-dinitrosoben-
zidines 5 were obtained in high yields. The results are
summarized in Table 3.
8
9
Y. Jiang, C. Xi, X. Yang, Synlett 2005, 1381.
10 M. Periasamy, K. N. Jayakumar, P. Bharathi, J. Org. Chem. 2000, 65,
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J. Org. Chem. 2007, 72, 662. b) E. V. Bellale, D. S. Bhalerao, K. G.
Akamanchi, J. Org. Chem. 2008, 73, 9473. c) U. S. Mahajan, K. G.
Akamanchi, Synth. Commun. 2009, 39, 2674. d) T. Dohi, M. Ito, K.
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To get mechanistic insight some investigations were carried
out. Reactions with para-substituted N,N-dialkylated anilines 6
did not provide coupled products, instead ortho-nitrated products
7 with N-monodealkylation were obtained in high yields
(Table 4, Entries 1-3) and interestingly 4-nitroso-N,N-dimethyl-
aniline remained unreacted (Table 4, Entry 4), this is valuable
evidence to indicate that the 4-nitro products 3 are not formed via
nitrosation followed by oxidation. Further substrate 1a failed to
react with HIO3 and NaNO3 under the reaction conditions to form
N,N-dimethyl-4-nitroaniline (3a). This indicates that nitro prod-
ucts 3 are not arising out of simple nitration of 1, through
nitronium ion generated by oxidation of HNO2.
With this preliminary evidence we propose a tentative
mechanism as depicted in Scheme 1.
It can be concluded that iodic acid and sodium nitrite bring
about a facile oxidative coupling of N,N-disubstituted anilines
in water, a green solvent, to form selectively para-coupled
products, benzidines.
14 P. D. Salgaonkar, V. G. Shukla, K. G. Akamanchi, Synth. Commun. 2005,
35, 2805.
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2005, 46, 7179.
16 M. A. Zolfigol, A. G. Choghamarani, F. Shirini, H. Keypour, S.
Salehzadeh, Synth. Commun. 2001, 31, 359.
17 S. Chandrasekhar, K. Gopalaiah, Tetrahedron Lett. 2002, 43, 4023.
18 General procedure for oxidative coupling of N,N-dialkylarylamine: To a
stirred solution of iodic acid (1.76 g, 10 mmol) and sodium nitrite (0.76 g,
10 mmol) in water (20 mL), substrate (5 mmol) was added immediately in
one portion. Stirring continued until complete consumption of starting
material as observed on TLC. After completion of reaction, the reaction
mixture was diluted with water (20 mL) and a small amount of urea was
added to destroy unreacted sodium nitrite and extracted with chloroform
(2 © 15 mL). The organic layer was washed with saturated solution of
sodium bicarbonate (2 © 30 mL) and brine solution (50 mL), dried over
anhydrous sodium sulfate and concentrated under reduced pressure to give
crude product. Pure product was obtained after column chromatography
(silica gel, mesh size 60-120, eluent ethyl acetate:hexane 5:95). Spectral
data of these compounds are available electronically as Supporting
Information, http://www.csj.jp/journals/chem-lett/.
Chem. Lett. 2010, 39, 808-809
© 2010 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/