The use of hydroxylamine hydrochloride in the Chan-Lam reaction: A simple access to symmetric diarylamines

Article abstract of DOI:10.1055/s-0029-1218295

A CuBr-catalyzed coupling reaction of hydroxylamine hydrochloride and arylboronic acids is described, providing a simple and efficient methodology for the synthesis of symmetric diaryl amines. The reaction shows good functional group tolerance. Georg Thie

Full text of DOI:10.1055/s-0029-1218295

3198
LETTER
The Use of Hydroxylamine Hydrochloride in the Chan–Lam Reaction:
A Simple Access to Symmetric Diarylamines
Access to
S
ymm
e
h
tric
D
iarylam
a
ines ngfeng Zhou, Dongpeng Yang, Xiaofei Jia, Lixue Zhang, Jiang Cheng*
College of Chemistry and Materials Engineering, Wenzhou University, Wenzhou 325027, P. R. of China
Fax +86(577)88156826; E-mail: jiangcheng@wzu.edu.cn
Received 31 July 2009
drochloride might inhibit the reaction. Thus, K2CO3 was
added to the reaction system. To our delight, in the pres-
ence of 1.5 equivalents of K2CO3, the yield increased to
35% in toluene (Table 1, entry 2). Among the solvents
Abstract: A CuBr-catalyzed coupling reaction of hydroxylamine
hydrochloride and arylboronic acids is described, providing a sim-
ple and efficient methodology for the synthesis of symmetric diaryl
amines. The reaction shows good functional group tolerance.
Key words: copper(I)-catalyzed, arylboronic acids, diaryl amines,
hydroxylamine hydrochloride, coupling reaction
Table 1 Screening for the Optimum Conditionsa
copper source
+
NH2OH⋅HCl
PhB(OH)2
Ph2NH
base, solvent
1a
2a
Aromatic amines are widely used in the synthesis of natu-
ral products, pharmaceutical and agrochemical com-
pounds, as well as polymers and materials.1 Over the past
several decades, extensive efforts have been directed to-
ward C–N bond formation.2 Arylboronic acids have been
widely used in N-arylation of arylamines through the am-
ination strategies developed by the research groups of
Chan and Lam.3 The development of new processes using
cheap and abundant amino sources as feedstocks in the
synthesis of aromatic amines remains a highly desirable
goal. Nevertheless, to the best of our knowledge, few ex-
amples have been reported. The employing of ammonia as
an abundant and inexpensive amino source is attractive in
organic synthesis.4–6 Recently, Fu described copper-cata-
lyzed coupling reaction employing arylboronic acids and
aqueous ammonia as reagents at room temperature afford-
ing primary arylamines.7 We also developed a facile
method to access diarylamine through the copper-cata-
lyzed coupling reaction of arylboronic acids with aqueous
ammonia.8
Entry Copper source Solvent
Base (equiv)
Yield (%)b
1
2
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
Cu2O
Cu(OTf)2
CuF2
Cu(OAc)2
CuBr
CuBr
–
1,4-dioxane K2CO3 (1.5)
<5
35
23
<5
80
56
toluene
MeOH
DMF
K2CO3 (1.5)
K2CO3 (1.5)
K2CO3 (1.5)
K2CO3 (1.5)
Na2CO3 (1.5)
3
4
5
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
6
7
K3PO4·3H2O (1.5) 69
8
Cs2CO3 (1.5)
KOt-Bu (1.5)
Li2CO3 (1.5)
–
<5
15
<5
<5
<5
75
73
52
78
71
<5
70c
58d
<5
9
10
11
12
13
14
15
16
17
18
19
20
21
K2CO3 (0.5)
K2CO3 (1.0)
K2CO3 (2.0)
K2CO3 (1.5)
K2CO3 (1.5)
K2CO3 (1.5)
K2CO3 (1.5)
K2CO3 (1.5)
K2CO3 (1.5)
K2CO3 (1.5)
Based on our previous work, we envisioned that hydroxyl-
amine hydrochloride which is also an inexpensive chemi-
cal commodity might be utilized as an ammonia surrogate
in the N-arylation reaction. Herein, we wish to report a
simple and cheap copper(I)-catalyzed coupling reaction of
hydroxylamine hydrochloride with arylboronic acids,
providing the symmetric diarylamines in moderate to
good yields.
Initial studies were conducted using hydroxylamine hy-
drochloride (1.2 equiv) and phenylboronic acid 1a (0.2
mmol) in toluene as a model reaction under air in the pres-
ence of CuBr (20 mol%). Disappointingly, after the exten-
sive screening of copper sources and solvents, no
synthetically useful results were obtained. We realized
that acid conditions provided by the hydroxylamine hy-
a All reactions were run with phenylboronic acid (0.2 mmol),
NH2OH·HCl (0.24 mmol), copper (20 mol%), indicated base, solvent
(2 mL), 70 °C, 24 h.
SYNLETT 2009, No. 19, pp 3198–3200
Advanced online publication: 21.10.2009
DOI: 10.1055/s-0029-1218295; Art ID: W12109ST
© Georg Thieme Verlag Stuttgart · New York
x
x
.x
x
.2
0
0
9
b Isolated yield.
c CuBr (10 mol%).
d CuBr (5 mol%).

LETTER
Access to Symmetric Diarylamines
3199
tested, acetonitrile was the best, and the yield was sharply
increased to 80% in the presence of 1.5 equivalents of
K2CO3 (Table 1, entry 5). Other bases, such as Na2CO3
and K3PO4·3H2O were also efficient for such transforma-
tion and K2CO3 was the best (Table 1, entries 5–10). Fur-
ther investigations revealed that the amount of K2CO3 had
a significant effect on the reaction (Table 1, entries 11–
14). Several copper(I) or copper(II) sources were also ex-
amined, and CuBr turned out to be better than other ones.
No product was formed in the absence of copper source
(Table 1, entry 19).
Table 2 Reaction of Arylboronic Acids with Hydroxylamine Hydro-
chloridea
CuBr (20 mol%)
ArB(OH)2
+
NH2OH⋅HCl
Ar2NH
K2CO3, MeCN
Entry
1
ArB(OH)2
Ar2NH
Yield (%)b
2a
2b
2c
80
70
82
B(OH)2
2
3
B(OH)2
With the optimized conditions in hand, we turned our at-
tention to study the substrates scope. The results are sum-
marized in Table 2. As expected, a series of functional
groups on the phenyl ring of arylboronic acids, such as
methyl, methoxy, chloro, fluoro, nitro, trifluoromethyl,
acetyl, and carbomethoxy, were compatible under this
procedure, and diaryl amines were isolated in moderate to
good yields. The reaction efficiency was sensitive to the
electronic property of the substituents, as arylboronic ac-
ids possessing electron-donating groups (e.g., Table 2, en-
tries 2–6) generally delivered the products in higher yields
than those of possessing electron-withdrawing groups
(e.g., Table 2, entries 10–13). However, bis(4-methoxy-
phenyl)amine was isolated in moderate yield. ortho-Sub-
stituted substrate failed to deliver the diaryl amines. We
reasoned that the hindrance of the aryl group of arylboron-
ic acids had some effect on the reaction. It is worth noting
that highly electron-deficient arylboronic acids were tol-
erated in the reaction. For example, 2j and 2k were sub-
jected to the procedure, 50% and 55% yield of the diaryl
amines product were isolated (Table 2, entries 8–11). Dis-
appointingly, the feasibility of monoarylation of hydroxyl-
amine hydrochloride failed.
B(OH)2
B(OH)2
4
2d
73
5
6
2e
2f
50
80
MeO
MeO
B(OH)2
B(OH)2
7
8
9
2g
2h
2i
72
55
40
Cl
F
B(OH)2
B(OH)2
Cl
Cl
B(OH)2
B(OH)2
10
11
2j
50
55
A plausible reaction pathway was outlined in Scheme 1.
In step 1, a Chan–Lam reaction of boronic acids with hy-
droxylamine, which released from hydroxylamine hydro-
chloride in the presence of base, formed phenyl
hydroxylamine. Then the formed phenyl hydroxylamine
transformed to aniline.9 Finally, aniline underwent the
Chan–Lam reaction with boronic acids to produce the di-
aryl amines.
F3C
O2N
2k
B(OH)2
12
13
2l
75
84
MeOOC
MeOC
B(OH)2
2m
Cu(I)
base
NH2OH⋅HCl
NH2OH
ArNH2OH
ArB(OH)2
B(OH)2
Cu(I)
ArB(OH)2
a Reaction conditions: arylboronic acid (0.2 mmol), NH2OH·HCl
(0.24 mmol), CuBr (5.7 mg, 20 mol%), K2CO3 (41.4 mg, 0.3 mmol),
MeCN (2 mL), 70 °C, 24 h.
Ar2NH
ArNH2
Scheme 1 Plausible reaction pathway
b Isolated yield.
In summary, we have successfully developed a simple and
facile copper(I)-catalyzed coupling reaction of arylboron-
ic acids with hydroxylamine hydrochloride, providing the
symmetric diaryl amines with moderate to good yields in
one-pot.10 Importantly, this transformation is very practi-
cal as it does not require the use of strong bases or expen-
sive ligands, and the rigorous exclusion of air/moisture is
not required. Ongoing work seeks to gain further insights
into the mechanism of this reaction.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Synlett 2009, No. 19, 3198–3200 © Thieme Stuttgart · New York

3200
C. Zhou et al.
LETTER
(4) Roundhill, D. M. Chem. Rev. 1992, 92, 1.
Acknowledgment
(5) For palladium-catalyzed coupling of aryl halides with
ammonia, see: (a) Shen, Q.; Hartwig, J. F. J. Am. Chem. Soc.
2006, 128, 10028. (b) Surry, D. S.; Buchwald, S. L. J. Am.
Chem. Soc. 2007, 129, 10354. (c) Schulz, T.; Torborg, C.;
Enthaler, S.; Schaffner, B.; Dumrath, A.; Spannenberg, A.;
Neumann, H.; Borner, A.; Beller, M. Chem. Eur. J. 2009, 15,
4528. (d) Vo, G. D.; Hartwig, J. F. J. Am. Chem. Soc. 2009,
131, 11049.
(6) For copper-catalyzed coupling of aryl halides with
ammonia, see: (a) Kim, J.; Chang, S. Chem. Commun. 2008,
3052. (b) Xia, N.; Taillefer, M. Angew. Chem. Int. Ed. 2009,
48, 337. (c) Lang, F.; Zewge, D.; Houpis, I. N.; Volante,
R. P. Tetrahedron Lett. 2001, 42, 3251.
(7) Rao, H.; Fu, H.; Jiang, Y.; Zhao, Y. Angew. Chem. Int. Ed.
2009, 48, 1114.
(8) Zhou, C.; Chen, F.; Yang, D.; Jia, X.; Zhang, L.; Cheng, J.
Chem. Lett. 2009, 38, 708.
(9) For the transformation of phenyl hydroxylamine to aniline,
see: (a) Saha, A.; Ranu, B. J. Org. Chem. 2008, 73, 6867.
(b) Cyr, A.; Huot, P.; Marcoux, J.-F.; Belot, G.; Laviron, E.;
Lessard, J. Electrochimica Acta 1989, 34, 439.
We thank the Key Project of Chinese Ministry of Education (No.
209054) for financial support.
References and Notes
(1) (a) Weissermel, K.; Arpe, H. J. Industrial Organic
Chemistry; Wiley-VCH: Weinheim, 1997. (b) Lawrence,
S. A. Amines: Synthesis Properties and Applications;
Cambridge University Press: Cambridge, 2004.
(c) Schlummer, B.; Scholz, U. Adv. Synth. Catal. 2004, 346,
1599. (d) Suwanprasop, S.; Nhujak, T.; Roengsumran, S.;
Petsom, A. Ind. Eng. Chem. Res. 2004, 43, 4973.
(2) Reviews: (a) Muci, A. R.; Buchwald, S. L. Top. Curr. Chem.
2002, 219, 131. (b) Hartwig, J. F. In Handbook of
Organopalladium Chemistry for Organic Synthesis;
Negishi, E., Ed.; Wiley-Interscience: New York, 2002,
1051. (c) Wolfe, J.; Marcoux, J.-F.; Buchwald, S. L. Acc.
Chem. Res. 1998, 31, 805. (d) Hartwig, J. F. Acc. Chem.
Res. 1998, 31, 853.
(3) For selected references, see: (a) Lam, P. Y. S.; Clark, C. G.;
Saubern, S.; Adams, J.; Winters, M. P.; Chan, D. M. T.;
Combs, A. Tetrahedron Lett. 1998, 39, 2941. (b) Combs,
A.; Saubern, S.; Rafalski, M.; Lam, P. Y. S. Tetrahedron
Lett. 1999, 40, 1623. (c) Lam, P. Y. S.; Clark, C. G.;
Saubern, S.; Adams, J.; Averill, K. M.; Chan, D. M. T.;
Combs, A. Synlett 2000, 674. (d) Lam, P. Y. S.; Vincent, G.;
Clark, C. G.; Deudon, S.; Jadhav, P. K. Tetrahedron Lett.
2001, 42, 3415. (e) Chan, D. M. T.; Monaco, K. L.; Wang,
R.-P.; Winters, M. P. Tetrahedron Lett. 1998, 39, 2933.
(10) General Procedure
Under air, a reaction tube was charged with arylboronic acid
(0.2 mmol), NH2OH·HCl (0.24 mmol), CuBr (5.7 mg, 20
mol%), K2CO3 (41.4 mg, 0.3 mmol), MeCN (2 mL) at 70 °C
for 24 h. After the completion of the reaction, as monitored
by TLC, the solvent was evaporated under reduced pressure,
and the residue was purified by flash column chromatog-
raphy on a silica gel to give the product.
Synlett 2009, No. 19, 3198–3200 © Thieme Stuttgart · New York