Selective Aromatic N-Substitution with N-(4-Tolyl)hydroxylamine by Addition of Polar Aprotic or Diethereal Solvent

Article abstract of DOI:10.1002/ejoc.200200576

Amination of anisole and toluene with N-(4-tolyl)hydroxylamine in trifluoroacetic acid was tuned to regioselectively provide the corresponding diarylamine by partial replacement of trifluoroacetic acid with a polar aprotic or a diethereal solvent. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003.

Full text of DOI:10.1002/ejoc.200200576

SHORT COMMUNICATION
Selective Aromatic N-Substitution with N-(4-Tolyl)hydroxylamine by Addition
of Polar Aprotic or Diethereal Solvent
Hiroshi Takeuchi,*[a,b] Jun-ichi Tateiwa,[a] Suguru Hata,[a] Keisuke Tsutsumi,[a] and
Yoshinori Osaki[b]
Keywords: Regioselectivity / Amination / Aromatic substitution / Solvent effects / Amines
Amination of anisole and toluene with N-(4-tolyl)hydroxyla- ( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
mine in trifluoroacetic acid was tuned to regioselectively pro- Germany, 2003)
vide the corresponding diarylamine by partial replacement
of trifluoroacetic acid with a polar aprotic or a diethereal
solvent.
Introduction
tuned the amination by the use of several solvents to re-
gioselectively provide the corresponding diarylamine.
Aromatic compounds are transformed to diarylamines by
treatment with aryl azide[1,2] or N-arylhydroxylamine.[3,4]
Recently, we tried to treat several aromatic compounds with
N-arylhydroxylamine, including N-phenylhydroxylamine[4]
and N-(4-tolyl)hydroxylamine (1),[5] in trifluoroacetic acid
(TFA) in the presence of polyphosphoric acid (PPA) to pro-
duce the corresponding diarylamines by N-substitution as
well as the corresponding aminobiphenyls by C-substi-
tution. In these reactions, an arylnitrenium ion[6,7] should
be a reactive intermediate with a canonical resonance
form[8] wherein the positive charge populates carbon atoms
of the ring and a nitrogen atom, and which then reacts with
the aromatic compounds to give both the diarylamines and
the aminobiphenyls.[3,4] 4-(Nitro and cyano)phenylnitren-
ium ions[2] from the corresponding aryl azides are efficiently
capable of a selective aromatic N-substitution. Diarylam-
ines were regioselectively formed in a case where electron-
rich N,N-dimethylaniline was a nucleophile to arylnitren-
ium ion.[9] We also found that anisole (2a) reacted with 1 to
produce the corresponding diarylamine in a relatively high
proportion, and came across the regioselective formation
of the diarylamine by addition of 1,1,3,3-tetramethylurea
(TMU) as a polar aprotic solvent. In this paper, we have
Results and Discussion
Compound 2a reacted with 1 in a mixture of TFA and
TMU containing PPA at 40 °C for 3 h to give N-(4Ј-tolyl)-
2- and -4-anisidines (3a) and 2-amino-2Ј- and -4Ј-methoxy-
5-methylbiphenyls (4a) accompanied by 4,4Ј-dimethylazoxy-
benzene (5) (Scheme 1).[10] The replacement of TFA with
TMU led to an increase in the yield of 3a and a decrease
in the yield of 4a (Figure 1). For instance, with 30 % (v/v)
TMU, compound 3a was obtained selectively in 72% GLC
yield (Table 1, Entry 2). The yield of 3a then decreased as
the proportion of TFA decreased.
[a]
Department of Molecular Science, Graduate School of Science
Scheme 1
and Technology, Kobe University,
Rokkodai-cho, Nada-ku, Kobe, 657-8501, Japan
Fax: (internat.) ϩ81-78/803-6205
The replacement with polar aprotic solvents with a rela-
tively high dielectric constant such as DMSO, 1,3-dimethyl-
2-imidazolidinone (DMI), acetonitrile (AN) and propio-
nitrile (PN) also led to an increase in the yield of 3a and a
decrease in the yield of 4a, and brought about the regiose-
E-mail: takeuchi@kobe-u.ac.jp
[b]
Department of Chemical Science and Engineering, Faculty of
Engineering, Kobe University, Rokkodai-cho, Nada-ku, Kobe,
657-8501, Japan
Fax: (internat.) ϩ81-78/803-6205
E-mail: takeuchi@kobe-u.ac.jp
3920
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/ejoc.200200576
Eur. J. Org. Chem. 2003, 3920Ϫ3922

Selective Aromatic N-Substitution with N-(4-Tolyl)hydroxylamine
SHORT COMMUNICATION
ino-2Ј,5- and -4Ј,5-dimethylbiphenyl (4b) accompanied by 5
(Scheme 1). The replacement of TFA with TMU produced
3b selectively when the content was 25 % (v/v) (Figure 2),
and this also occurred with AN and PN at 50 % (v/v) of
the content (Table 1, Entries 11Ϫ13). In this reaction, the
replacement with Hx was unsuccessful for amination (Entry
14).These results indicates that a polar aprotic or a dieth-
ereal solvent might be effective for the amination.
Figure 1. Reaction of anisole (2a) with N-(4-tolyl)hydroxylamine
(1) in a mixture of TFA and TMU
Table 1. Reaction of anisole (2a) and toluene (2b) with N-(4-to-
lyl)hydroxylamine (1) in a mixture of TFA and a solvent
Entry[a] Solvent (v/v%)
2
GLC yield (%)[b]
3a[c]
4a[c]
5
1
2
3
4
5
6
7
8
9
Ϫ
Ϫ
2a 52 (7:93)
2a 72 (9:91)
2a 63 (7:93)
2a 75 (3:97)
2a 78 (3:97)
2a 85 (6:94)
2a 79 (7:93)
2a 79 (9:91)
2a 44 (9:91)
22 (19:81)
0
0
0
6
Figure 2. Reaction of toluene (2b) with N-(4-tolyl)hydroxylamine
(1b) in a mixture of TFA and TMU
TMU
DMSO
DMI
AN
PN
DME
DO
30
25
31
63
50
38
25
63
25
18
12
21
1
6
2
0
3 (0:100)
0
4 (0:100)
2 (0:100)
It is not completely clear what factors dictate the regio-
chemistry of the reaction with N-arylhydroxylamine, and the
mechanism of the attack with the nitrogen atom has re-
mained controversial. We suppose that the polar aprotic
solvents might affect the initially formed arylnitrenium ion
itself or the transition states,[4] where the transition state in
the N-substitution is more stabilized by solvation than that
in the C-sustitution due to the higher positive density of the
former transition state, to allow the regiospecific attack by
N-arylhydroxylamine on the aromatic compounds. The ef-
fect of nonpolar Hx on the selectivity of 3a cannot be ex-
plained clearly at this stage, but seemes to arise from the
formation of nearly intimate ion pair with N-positive
charge.
Hx
31
3b[c]
4b[c]
5
10
11
12
13
14
Ϫ
Ϫ
2b 25 (8:92)
2b 43 (13:87)
2b 44 (15:85)
2b 43 (12:88)
18 (42:58) 10
TMU
AN
PN
Hx
25
50
50
50
0
0
0
11
5
4
2b 24 (20:80) 15 (40:60) 13
3c[c]
4c[c]
5
15[d]
16
Ϫ
PN
Ϫ
50
2c
2c
0
28 (0:100)
0
7
12
19 (0:100)
The order, 3a (85%) Ͼ 3b (43%) Ͼ 3c (19%) Ͼ 3d (trace),
for the selective N-substitution using 50 % (v/v) PN
(Table 1, Entries 6, 13, 16, 18) can be interpreted by the
usual effect of the aromatic substitution. In the case where
the total yield of 3Ϫ5 is markedly less than 100%, unidenti-
fied products (black tarry oil not being characterized) were
probably formed by reaction with solvent and by uncertain
reactions. The effect of solvent on the magnitude of the
yield in N-selectivity and the solvent concentration for
attaining the selectivity depend on the power of cationic
solvation and the reactivity with solvent.
3d
4d
5
17[d]
18
Ϫ
PN
Ϫ
50
2d
2
25
0
6
2
2d trace
[a]
1 (1.0 mmol), 2 (2a: 2.0 mL, 17.7 mmol; 2b: 2.0 mL, 18.8 mmol;
2c: 3.0 mmol; 2d: 2.0 mL, 22.4 mmol), a mixture of TFA and a
[b]
solvent (6.0 mL), PPA (1.2 mmol) at 40 °C for 3 h. Based on 1.
[c] Also listed is the isomer ratio for o/p attack in parentheses. [d] The
reaction using 2c or 2d was carried out at 20 °C.
lective formation of 3a (Table 1, Entries 3Ϫ6); however, AN
exerted its effect at 63 % (v/v) of the content (Entry 5). The
replacement with 1,2-dimethoxyethane (DME) and 1,4-di-
oxane (DO), classified as a less polar aprotic solvent with a Conclusion
low dielectric constant, and hexane (Hx), a kind of nonpo-
lar aprotic solvent, was also effective for the amination (En-
In summary, we have clarified that the partial replace-
tries 7Ϫ9); however, Hx exerted its influence at 63 % (v/v) ment of TFA with a polar aprotic or a diethereal solvent
of the content (Entry 9).
brings about the amination of 2a and 2b with N-arylhydrox-
The reaction of toluene (2b) with 1 was similarly carried ylamine to regioselectively produce the corresponding diar-
out to produce 2,4Ј- and 4,4Ј-ditolylamines (3b) and 2-am- ylamine.
Eur. J. Org. Chem. 2003, 3920Ϫ3922
www.eurjoc.org
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3921

H. Takeuchi, J.-i. Tataiwa, S. Hata, K. Tsutsumi, Y. Osaki
SHORT COMMUNICATION
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S. Srivastava, J. P. Toscano, R. J. Moran, D. E. Falvey, J.
Acknowledgments
This work was supported by Ishihara Sangyo Kaisha, Ltd. and
Toyo Kasei Kogyo Co., Ltd.
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Typical experimental procedure: N-(4-tolyl)hydroxylamine (1)
(1.0 mmol) was added to a mixture of polyphosphoric acid
(PPA, 1.2 mmol), anisole (2a) (2.0 mL, 17.7 mmol), TFA (3.6
mL) and TMU (2.4 mL) at 40 °C and stirred at that tempera-
ture for 3 h. After cooling to room temperature, the mixture
was neutralized with aqueous Na2CO3 and extracted with di-
chloromethane (50 mL). The organic layer was separated, dried
with anhydrous Na2SO4 and concentrated under reduced press-
ure. The resulting oil was analyzed by GLC to determine the
yields of N-(4Ј-tolyl)-2- and -4-anisidines (3a), 2-amino-2Ј-
and -4Ј-methoxy-5-methylbiphenyls (4a) and 4,4Ј-dimethylaz-
oxybenzene (5). GLC yield: 3a 72% (2-anisidine/4-anisidine ϭ
9:91); 4a 0%; 5 25%. The oil was subjected to silica gel column
chromatography with hexane and hexane/ethyl acetate as
eluents to provide 3a (129.0 mg, 60%, 2-anisidine/4-anisidine ϭ
0:100) and a mixture of 3a (2-anisidine/4-anisidine ϭ 100:0)
and 5 (18.1 mg, GLC ratio 3a/5 ϭ 62:38).
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Received October 15, 2003
Early View Article
Published Online September 8, 2003
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3922
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 3920Ϫ3922