Copper-catalyzed direct amination of nitrobenzenes with O-alkylhydroxylamines

Full text of DOI:10.1021/jo951903r

442
J . Org. Chem. 1996, 61, 442-443
Ta ble 1. Dir ect Am in a tion of Nitr oben zen e w ith
Cop p er -Ca ta lyzed Dir ect Am in a tion of
Nitr oben zen es w ith O-Alk ylh yd r oxyla m in es
NHROR′a
NHROR′
R′
nitroanilines
entry
R
yieldb (%)
o/pc
Shinzo Seko* and Norio Kawamura
1
2
3
4
5
6
H
H
H
H
Me
H
Me
93 (60)d
68
41
71/29 (65/35)d
68/32
76/24
27/73
0/100
Ete
Bne
t-Bue
Me
Organic Synthesis Research Laboratory, Sumitomo
Chemical Co., Ltd., Tsukahara, Takatsuki,
Osaka 569-11, J apan
40
22f
He
0g
Received October 26, 1995
a
Unless otherwise noted, the reaction of nitrobenzene with
Direct amination of aromatic compounds remains as
a challenging problem of practical importance in organic
synthesis.1 In particular, the amination of nitrobenzenes
via the nucleophilic substitution of hydrogen has recently
attracted considerable interest because it is an environ-
mentally safer route to nitroanilines, since halogenated
nitrobenzenes are not required as substrates. Two
different approaches to this problem have recently been
reported, i.e., the oxidative direct coupling of nitroben-
zene and aniline2 or amide3 and a vicarious nucleophilic
substitution of hydrogen (VNS)4 using 4-amino-1,2,4-
triazole5 or sulfenamides6 as aminating agents. However,
both types of amination occur predominantly at the
4-position with respect to the nitro group of nitroben-
zenes.7 To our knowledge, general and simple or ortho-
selective direct amination of nitrobenzenes has not been
reported.8 In this paper, we describe a new direct
amination of nitrobenzenes with O-alkylhydroxylamines
in the presence of a copper catalyst, producing predomi-
nantly ortho-nitroanilines.
The behavior of primary amines possessing an N-N,
N-O, or N-S bond was examined for the direct amina-
tion of nitrobenzene. Consequently, O-methylhydroxy-
lamine9 was found to efficiently aminate nitrobenzene
under basic conditions at room temperature to give
nitroanilines (o/p ) 65/35) in 60% yield. The yield was
enhanced up to 93% (o/p ) 71/29) by the addition of 10
mol % CuCl (Table 1, entry 1). A similar effect was
observed with the addition of other copper catalysts such
as CuCl2, CuBr, CuI, Cu(acac)2, Cu(NO3)2, and Cu(OAc)2,
whereas CuCN, Cu(OH)2, and CuSO4 were less effective.
The results of the direct amination with various O-
alkylhydroxylamines are shown in Table 1. Ortho-rich
aminated products were obtained when using O-meth-
NHROR′ (1.25 equiv) was performed in the presence of t-BuOK
b
(3.00 equiv) and CuCl (0.1 equiv) in DMF at rt for 1-24 h. GC
yields. c The o/p ratio was determined by GC. No CuCl was
d
added. e Hydrochloric acid salt and an additional base (1.25 equiv)
were used. f N-Methylnitroaniline was obtained. g Starting mate-
rial was recovered.
ylhydroxylamine, O-ethylhydroxylamine, and O-benzyl-
hydroxylamine. However, the reactions with O-tert-
butylhydroxylamine or N,O-dimethylhydroxylamine
exhibited para-selectivity, an outcome attributed to steric
effects. In contrast, no reaction occurred with unsubsti-
tuted hydroxylamine8 under these conditions, and the
starting material was recovered quantitatively (Table 1,
entry 6).
The reaction of nitrobenzenes bearing various substit-
uents with O-methylhydroxylamine gave the correspond-
ing substituted nitroanilines in excellent yields.10 Rep-
resentative results are summarized in Table 2. In
general, the preferential synthesis of a 1,2,3-trisubsti-
tuted aromatic compound from a 1,3-disubstituted aro-
matic compound by conventional intermolecular aromatic
substitution of hydrogen, for example, through nitra-
tion,11 Friedel-Crafts reaction,12 VNS reaction,4 etc., is
extremely difficult because of steric hindrance. However,
the reaction of N,N-dimethyl-3-nitroaniline with O-
methylhydroxylamine in the presence of a copper catalyst
surprisingly gave the most sterically congested 2 (R )
NMe2)13 in 75% yield and 1 (R ) NMe2) and 3 (R ) NMe2)
in 10% and 15% yields, respectively (Table 2, entry 5).
Such regioselectivity was observed when using meta-
substituted nitrobenzenes in which the substituent has
a lone pair of electrons (Table 2, entries 2-4). This result
does not appear to be due to coordination of an unshared
electron pair of the substituent to copper because the
addition of a copper catalyst has no effect on the orienta-
tion of the amination. The observed effects of the
substituents on the reactivity of the 2-position lie in the
order NMe2 > OMe > F > Cl, which is consistent with
the mesomeric effects (+M) in electrophilic aromatic
substitution.14 Hence, it is apparent that electronic
factors must play a dominant role in this regioselectivity.
In the case of p-chloronitrobenzene, the Cl atom is
susceptible to conventional nucleophilic aromatic substi-
tution (SNAr) since it is activated by the p-nitro group.
Nevertheless, no 7 from a typical SNAr could be detected,
(1) (a) Shmerling, L. US 2,948,755 (1960); Chem. Abstr. 1961, 55,
1527. (b) Squire, E. N. GB 1,327,494 (1973). (c) Kovacic, P. In Friedel
Crafts and Related Reactions; Olah, G. A., Ed.; J ohn Wiley & Sons:
New York, 1964; Vol. III, Part 2, pp 1493-1506. (d) Takeuchi, H.;
Adachi, T.; Nishiguchi, H. J . Chem. Soc., Chem. Commun. 1991, 1524-
1525. (e) Minisci, F; Galli, R.; Cecere, M. Tetrahedron Lett. 1965, 4663-
4667 and references cited therein. (f) Mitchell, H.; Leblanc, Y. J . Org.
Chem. 1994, 59, 682-687. (g) Ayyangar, N. R.; Naik, S. N.; Srinivasan,
K. V. Tetrahedron Lett. 1990, 31, 3217-3220. (h) Cadogan, J . I. G.;
Rowley, A. G. J . Chem. Soc., Perkin Trans. 1 1975, 1069-1071. (i)
Abramovitch, R. A.; Beckert, J . M.; Chinnasamy, P.; Xiaohua, H;
Pennington, W.; Sanjivamurthy, A. R. V. Heterocycles 1989, 28, 623-
628.
(2) Stern, M. K.; Hileman, F. D.; Bashkin, J . K. J . Am. Chem. Soc.
1992, 114, 9237-9238.
(3) Stern, M. K.; Cheng, B. K. J . Org. Chem. 1993, 58, 6883-6888.
(4) Makosza, M.; Winiarski, J . Acc. Chem. Res. 1987, 20, 282-289.
(5) Katritzky, A. R.; Laurenzo, K. S. J . Org. Chem. 1986, 51, 5039-
5040.
(10) Typical procedure: A solution of NH2OMe (2.5 mmol) and a
nitroarene (2 mmol) in DMF (3 mL) was added dropwise to a stirred
solution of t-BuOK (6 mmol) and CuCl (0.2 mmol) in DMF (7 mL) over
5 min at room temperature. Then, formation of a deep red color was
observed. After 1 h at room temperature, the reaction was quenched
in saturated NH4Cl, and the products were extracted with CH2Cl2 and
purified by silica gel thin layer chromatography.
(11) Pearson, D. E.; Buehler, C. A. Synthesis 1971, 455-477.
(12) Friedel Crafts and Related Reactions; Olah, G. A., Ed.; J ohn
Wiley & Sons: New York, 1964; Vols. II and III.
(6) Makosza, M.; Bialecki, M. J . Org. Chem. 1992, 57, 4784-4785.
(7) For ortho-amination of 1-nitronaphthalene, see ref 6.
(8) For direct aminations of 1,3-dinitroarenes or bicyclic nitroarenes
with hydroxylamine, see: (a) Mo¨ler, F. In Houben-Weil Methoden der
Organische Chemie; Mu¨ller, E., Ed.; G. Thieme: Stuttgart, 1957; Vol.
11/1, pp 17-19. (b) Baumgarten, H. E. J . Am. Chem. Soc. 1955, 77,
5109-5112. (c) Nasielski-Hinkens, R.; Kotel, J .; Lecloux, T.; Nasielski,
J . Synth. Commun. 1989, 19, 511-514.
(13) New compound (see supporting information).
(14) Taylor, R. Electrophilic Aromatic Substitution; J ohn Wiley &
Sons: Chichester, 1990.
(9) Bissot, T. C.; Parry, R. W.; Campbell, D. H. J . Am. Chem. Soc.
1957, 79, 796-800.
0022-3263/96/1961-0442$12.00/0 © 1996 American Chemical Society

Communications
J . Org. Chem., Vol. 61, No. 2, 1996 443
Ta ble 2. Cop p er -Ca ta lyzed Dir ect Am in a tion of
Sch em e 1
Nitr oa r en es w ith O-Meth ylh yd r oxyla m in ea
complex 1215 derived from a potassium amide and a
copper salt to nitrobenzene is thought to produce 13,
which readily undergoes reductive elimination to give the
Meisenheimer complex 14. Finally, base-induced â-e-
limination gives the red-colored quinoid intermediate 15,
which is protonated through workup to give the nitroa-
niline. We assume that the role of the copper catalyst
differs from that proposed by Nilsson,16 who previously
described stoichiometric copper-mediated vicarious nu-
cleophilic substitution, because a catalytic amount of
copper salt is sufficient for this amination. The details
of this mechanism, particularly the role of the copper
catalyst and the observed regioselectivity, remain to be
explored.
In conclusion, the copper-catalyzed direct amination
of nitrobenzenes with O-alkylhydroxylamine, in particu-
lar O-methylhydroxylamine, has been demonstrated. The
reaction with O-methylhydroxylamine generates metha-
nol as a byproduct that is easier to treat in large-scale
production than the byproducts of the other known
methods.5,6 Since the reaction affords predominantly
o-amino compounds, we believe that this method will
greatly facilitate the synthesis of o-nitroaniline deriva-
tives which are important intermediates in the prepara-
tion of numerous pharmaceuticals and agricultural chemi-
cals containing a benzimidazole moiety. Further studies
along these lines are currently underway.
a
See ref 10 for typical procedure. Results when no CuCl was
used are in parentheses. All isomers were isolated. c Total yields
of all isolated products.
b
and 4 (R ) Cl) was obtained in 86% yield along with 8
(8%) (Table 2, entry 9). On the other hand, with
p-fluoronitrobenzene, the yield of the desired aminated
product 4 (R ) F) was only 17%, and 8 (37%), 9 (14%),
10 (25%), and 11 (7%) were obtained via nucleophilic
Ack n ow led gm en t. We are grateful to Professor Z.
Yoshida, Professor M. Makosza, and Professor Y. Yama-
moto for their valuable comments and discussion. We
also thank Mr. M. Nagase and Miss M. Futagami
(Sumitomo Chemical. Co., Ltd.) for the NMR analysis
of the copper amide species.
substitution of fluorine by t-BuO- derived from the base
or MeO- generated in situ after the amination (Table 2,
entry 10). Again, however, 7 was also apparently not
produced in this case, which does not agree with the
amination with sulfenamide reported by Makosza.6 The
fact that 7 is not produced in both cases clearly indicates
that the direct amination with O-methylhydroxylamine
is faster than SNAr with O-methylhydroxylamine under
these conditions, even when p-fluoronitrobenzene is used
as a substrate.
Su p p or tin g In for m a tion Ava ila ble: Spectral and ana-
lytical data for nitroaniline derivatives (12 pages).
J O951903R
(15) 1H-NMR spectrum (DMSO-d6) of the mixture of NH2OMe,
t-BuOK, and CuCl exhibited two singlets for the methoxy groups of
two different species at δ 3.35 and δ 3.22, although in the absence of
CuCl it indicated only one singlet for the methoxy group at δ 3.34.
(16) Haglund, O.; Nilsson, M. Synthesis 1994, 242-244.
A proposed copper-catalyzed mechanism is illustrated
in Scheme 1. The oxidative addition of copper amide ate