Copper-mediated reductive amination of aryl halides with trimethylsilyl azide

Article abstract of DOI:10.1002/chem.200903511

(Chemical equation presented) Look, no azide! Trimethylsilyl azide was reductively cross-coupled with a variety of aryl halides in the presence of a copper species and amines, such as triethylamine or aminoethanol, to give the corresponding primary aryl amine in good yields without the formation of the expected aryl azide (see scheme).

Full text of DOI:10.1002/chem.200903511

DOI: 10.1002/chem.200903511
Copper-Mediated Reductive Amination of Aryl Halides with
Trimethylsilyl Azide
[
a]
[a]
[a]
[a, b]
Yasunari Monguchi, Toshihide Maejima, Shigeki Mori, Tomohiro Maegawa,
and
[
a]
Hironao Sajiki*
Primary arylamines have found many applications in or-
ganic synthesis as synthons for biologically active and other
[1]
functional compounds. Although the discovery of palladi-
um-catalyzed cross-coupling methods, independently by
Buchwald and Hartwig, for the reaction of aryl halides with
a variety of amines made it easy to access secondary and ter-
[2]
Scheme 1. The unanticipated formation of ethyl 4-aminobenzoate (3)
under the Pd/C-catalyzed aromatic-azidation conditions. Ethyl 4-bromo-
benzoate (81.6 mL, 500 mmol) and DMA (1 mL) were used.
tiary arylamines, the direct synthesis of primary arylamines
from aryl halides was not reported until lithium bis(trime-
[3,4]
thylsilyl)amide was employed as the ammonia equivalent.
Subsequently, ammonia and ammonium chloride were effec-
[5]
[6]
tively applied to the palladium- or copper-catalyzed syn-
thesis of primary arylamine derivatives.
and 3) the reaction efficiency was significantly improved at
elevated temperature and by using triethylamine instead of
triphenylphosphine.
The reductive coupling reaction of TMSN3 with 1 also
proceeded with a variety of other copper salts, regardless of
the oxidation state of copper (Table 1, entries 2–9), and
even zero-valence copper metal was an efficient activating
agent (Table 1, entry 10). On the other hand, no reaction
Recently, we demonstrated that palladium on carbon (Pd/
C) is a versatile catalyst for cross-coupling reactions that
[7]
[8]
create carbon–carbon
and carbon–nitrogen bonds.
During the course of our study into the Pd/C-catalyzed azi-
[9–11]
dation of aryl halides,
we found, to our surprise, that the
cross-coupling reaction between ethyl 4-bromobenzoate (1)
[12]
and trimethylsilyl azide (TMSN ), in the presence of CuF2
took place if other metal species, such as FeCl , Fe
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
(OAc) ,
3
3
2
and triphenylphosphine, gave ethyl 4-aminobenzoate (3) as
NiCl , ZnCl , TiCl , and CoBr , were used.
2
2
2
2
the sole product (23%) instead of the expected ethyl 4-azi-
dobenzoate (2; Scheme 1).
We then investigated the effect of solvents on the reaction
[11,13]
using CuF , since it gave the highest yield of 3 (Table 1,
2
Initial optimization of the reaction conditions for this un-
expected, but remarkable, transformation revealed the fol-
entry 2, 84%). Polar aprotic solvents, such as dimethylaceta-
mide (DMA), DMF, DMSO, and N-methylpyrrolidone
(NMP), were found to be effective for the reaction (Table 1,
entries 2 and 11–13), while other organic solvents, as well as
water, tended to reduce the yield (Table 1, entries 14–19).
In addition, the progress of the reaction was suppressed
by the absence of triethylamine or by the use of other terti-
ary or secondary amines (Table 2, entry 2 vs. entries 1 and
[14]
lowing: 1) Pd/C was not required, 2) CuF was essential,
2
[
a] Dr. Y. Monguchi, T. Maejima, Dr. S. Mori, Dr. T. Maegawa,
Prof. Dr. H. Sajiki
Laboratory of Organic Chemistry
Department of Organic and Medicinal Chemistry
Gifu Pharmaceutical University
3
–7), and the reaction was not initiated at all by tetrabutyl-
1
-25-4 Daigaku-nishi, Gifu 501-1196 (Japan)
Fax : (+81)58-230-8109
ACHTUNGTRENaNGNU mmonium bromide (Table 2, entry 8). Diamines and ami-
E-mail: sajiki@gifu-pu.ac.jp
noalcohols were also examined with the expectation that
they would have a bidentate ligand-like effect (Table 2, en-
tries 9–14). Accordingly, 2-aminoethanol, in particular, was
found to be a highly efficient additive for the reaction
[
b] Dr. T. Maegawa
Current address:
Graduate School of Pharmaceutical Sciences
Osaka University, 1–6 Yamada-oka
Suita, Osaka 565-0871 (Japan)
[15]
(
Table 2, entry 11),
although neither N,N,N’,N’-tetrame-
thylethylenediamine nor ethylene glycol exhibited this effect
(Table 2, entries 10 and 15). Furthermore, the reaction utiliz-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200903511.
7372
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 7372 – 7375

COMMUNICATION
Table 1. Evaluation of copper reagents and solvents in the copper-medi-
ated reductive amination of ethyl 4-bromobenzoate (1) with TMSN
Next, we explored the scope of this reductive amination
based upon the cross-coupling of aryl halides with TMSN3
as the amino source under the optimal conditions [CuF2
3
.
(
9
2.0 equiv), amine (2.5 equiv), TMSN3 (2.0 equiv), DMA,
58C] (Table 3). Bromobenzenes containing an electron-
[
a]
Entry
Cu reagent
–
Solvent
Yield [%]
Table 3. Azide and copper-mediated reductive amination of a variety of
aryl halides.
1
2
3
4
5
6
7
8
9
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMF
DMSO
NMP
1,4-dioxane
MeOH
acetone
EtOAc
toluene
0
84
7
CuF
2
CuBr
CuO
2
73
32
82
63
73
75
82
69
70
73
35
55
61
27
15
0
Cu
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
(OTf)
2
CuOAc
CuI
[
a]
Entry
Ar
X
Amine
Yield [%]
CuBr
CuCl
1
2
3
4
5
6
7
8
9
10
11
12
4-NO
2
C
6
H
4
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
I
H
H
H
H
H
H
H
H
H
H
Et
Et
Et
Et
Et
2
2
2
2
2
2
2
2
2
2
N
N
N
N
N
N
N
N
N
N
A
T
N
T
E
N
N
2
2
2
2
2
2
2
2
2
2
)
)
)
)
)
)
)
)
)
)
2
2
2
2
2
2
2
2
2
2
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
95
99
80
76
77
76
75
95
48
81
67
77
66
59
60
32
4-EtO
3-EtO
2-EtO
3-MeO
4-ClC
2-Me-5-NO
4-PhC
2
2
2
CC
CC
CC
6
H
H
H
4
4
4
ACHTUNGTRENNUNG
[
b]
10
11
12
13
14
15
16
17
18
19
Cu
6
ACHTUNGTRENNUNG
CuF
CuF
CuF
CuF
CuF
CuF
CuF
CuF
CuF
2
2
2
2
2
2
2
2
2
6
ACHTUNGTRENNUNG
2
CC
6
H
4
ACHTUNGTRENNUNG
6
H
4
ACHTUNGTRENNUNG
2
C
6
H
3
ACHTUNGTRENNUNG
[
[
[
b]
b]
b]
6
H
4
ACHTUNGTRENNUNG
4-MeOC
3-MeOC
6
6
H
H
4
ACHTUNGTRENNUNG
4
ACHTUNGTRENNUNG
4-CF
4-AcC
4-MeO
4-AcC
4-CF
4-NO
3
C
6
H
4
3
N
3
N
3
N
3
N
3
N
[
c]
H
2
O
6 4
H
CC H
2 6 4
1
1
1
1
3
4
5
6
[
a] Isolated yield. [b] Copper powder was used.
6
H
4
I
I
Cl
3
C
6
H
4
2
C
6
H
4
H
2
N
A
H
U
G
R
N
U
G
2
)
2
OH
0
Table 2. Evaluation of additives for the copper-mediated reductive ami-
nation of ethyl 4-bromobenzoate (1) with TMSN
[a] Isolated yield. [b] Cu powder was used in place of CuF
2 3
. [c] NaN
3
.
was used in place of TMS-N and the reaction was carried out at 1208C.
3
withdrawing group effectively reacted with TMSN , regard-
3
less of the position of the substituent on the aromatic ring,
in the presence of 2-aminoethanol or triethylamine to give
the corresponding aniline derivatives in good to excellent
yields (Table 3, entries 1–7 and 11). In the cases of 4-bromo-
biphenyl and the electron-donating methoxy-substituted aryl
bromides, copper powder was quite effective as the activator
[
a]
Entry
Additive
–
Yield [%]
1
2
3
4
5
6
7
8
9
27
84
55
26
53
26
68
0
69
31
99
89
93
92
44
95
97
Et
(nPr)
(nBu)
Bn
Ph
Et
3
N
A
C
H
T
U
N
G
T
R
N
U
G
3
N
3
N
A
C
H
T
U
N
G
T
R
E
N
N
[16]
(
Table 3, entries 8–10). Sodium azide, which is a cheaper,
3
N
3
N
widely used azido salt, was also suitable for the reductive
coupling (Table 3, entry 12). This protocol was also effec-
tively applied to the amination of iodoarenes (Table 3, en-
tries 13–15). Furthermore, the aniline derivative was also ob-
tained from 4-chloronitrobenzene.
The formation of these aniline derivatives might proceed
stepwise through an intermediary aryl azide, which would
be generated by the copper-mediated cross-coupling reac-
2
NH
A
C
H
T
U
N
G
T
R
N
N
(nBu)
4
NBr
H
2
N
A
H
U
G
R
N
U
2
)
2
NH
NMe
OH
OH
OH
OH
2
10
11
12
13
14
15
16
17
Me
2
N
A
H
U
G
R
N
U
2
)
2
2
H
H
H
H
2
N
2
N
2
N
2
N
A
T
N
T
E
N
N
2
2
2
2
)
)
)
)
2
3
4
5
A
H
U
G
E
N
N
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
2 2
HO ACHTUNGTERNN(NUG CH ) OH
[
[
b]
c]
tion of TMSN with the aryl halides. However, exposure of
3
H
H
2
N
N
A
T
N
T
E
N
N
2
)
)
2
OH
OH
2
A
T
N
T
E
N
N
2
2
the corresponding ethyl 4-azidobenzoate (2) to the amina-
tion conditions scarcely promoted the reduction of the azide
functionality and the corresponding aniline derivative (3)
was only obtained in 5% yield (Scheme 2). This result sug-
gests that the azide/copper-mediated reductive amination of
haloarenes does not chiefly proceed through an aryl azide
intermediate. Furthermore, no reaction took place if a
single-electron acceptor, such as 7,7,8,8-tetracyanoquinodi-
methane (TCNQ) or tetracyanoethene (TCNE), was added
(Scheme 3), suggesting the participation of a single-electron
[
a] Isolated yield. [b] 0.1 mL of DMA was used. [c] 2 mL of DMA was
used.
ing 2-aminoethanol proceeded efficiently in either 0.1 or 2
times the volume of DMA used in the test reactions
Table 2, entries 16 and 17), suggesting that the concentra-
tion of the reaction mixture does not affect the reaction
progress.
(
Chem. Eur. J. 2010, 16, 7372 – 7375
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
7373

H. Sajiki et al.
palladium Chemistry for Organic Synthesis Vol. 1 (Ed.: E. I. Ne-
gishi), Wiley-Interscience, New York, 2002, pp. 1051–1097; c) A. R.
Muci, S. L. Buchwald, Top. Curr. Chem. 2002, 219, 131–209; d) K.
Kunz, U. Scholz, D. Ganzer, Synlett 2003, 2428–2439; e) L. Jiang,
S. L. Buchwald in Metal-Catalyzed Cross-Coupling Reactions, 2nd
ed. (Eds.: A. de Meijere, F. Diederich), Wiley-VCH, Weinheim,
Scheme 2. Exposure of an aryl azide to the amination conditions. Ethyl
-azidobenzoate (95.6 mg, 500 mL) and DMA (1 mL) were used.
2
004, pp. 699–760; f) J. F. Hartwig, Synlett 2006, 1283–1294; g) D. S.
4
Surry, S. L. Buchwald, Angew. Chem. 2008, 120, 6438–6461; Angew.
Chem. Int. Ed. 2008, 47, 6338–6361.
[
3] S. Lee, M. Jørgensen, J. F. Hartwig, Org. Lett. 2001, 3, 2729–2732.
[
2
4] LiHMDS and Zn ACTHUNGTRNEUNG( HMDS) (HMDS=hexamethyldisilazide) were
also used as ammonia equivalents, see: a) X. Huang, S. L. Buchwald,
Org. Lett. 2001, 3, 3417–3419; b) D.-Y. Lee, J. F. Hartwig, Org. Lett.
2
005, 7, 1169–1172.
[
5] a) Q. Shen, J. F. Hartwig, J. Am. Chem. Soc. 2006, 128, 10028–
1
1
1
0029; b) D. S. Surry, S. L. Buchwald, J. Am. Chem. Soc. 2007, 129,
0354–10355; c) G. D. Vo, J. F. Hartwig, J. Am. Chem. Soc. 2009,
31, 11049–11061; d) T. Schulz, C. Torborg, S. Enthaler, B. Schꢂffer,
Scheme 3. Addition of a single electron acceptor to the reductive amina-
tion of ethyl 4-bromobenzoate (1). Ethyl 4-bromobenzoate (81.6 mL,
A. Dumrath, A. Spannenberg, H. Neumann, A. Bçrner, M. Beller,
Chem. Eur. J. 2009, 15, 4528–4533.
5
00 mmol) and DMA (1 mL) were used.
[
[
6] a) J. Kim, S. Chang, Chem. Commun. 2008, 3052–3054; b) N. Xia,
M. Taillefer, Angew. Chem. 2009, 121, 343–345; Angew. Chem. Int.
Ed. 2009, 48, 337–339; c) L. Jiang, X. Lu, H. Zhang, Y. Jiang, D.
Ma, J. Org. Chem. 2009, 74, 4542–4546; d) H. Xu, C. Wolf, Chem.
Commun. 2009, 3035–3037.
7] a) H. Sajiki, T. Kurita, A. Kozaki, G. Zhang, Y. Kitamura, T. Maega-
wa, K. Hirota, J. Chem. Res. 2004, 593–595 [Erratum: H. Sajiki, T.
Kurita, A. Kozaki, G. Zhang, Y. Kitamura, T. Maegawa, K. Hirota,
J. Chem. Res. 2005, 344]; b) H. Sajiki, T. Kurita, A. Kozaki, G.
Zhang, Y. Kitamura, T. Maegawa, K. Hirota, Synthesis 2005, 537–
transfer in the reaction mechanism, although the actual re-
ductive species and hydrogen source are not yet clear.
In conclusion, we have demonstrated that a variety of aryl
[14,17]
halides react with TMSN in the presence of copper species
3
and an amine, in heated DMA, to give aniline derivatives as
the sole products, without the formation of the correspond-
ing aryl azides. The copper-mediated aromatic amination
formally proceeds through both a cross-coupling between
5
42 [Erratum: H. Sajiki, T. Kurita, A. Kozaki, G. Zhang, Y. Kita-
mura, T. Maegawa, K. Hirota, Synthesis 2005, 852]; c) H. Sajiki, G.
Zhang, Y. Kitamura, T. Maegawa, K. Hirota, Synlett 2005, 619–622
TMSN and an aryl halide and a reduction of an azide func-
3
tionality to the corresponding amine in a one-pot manner,
although the detailed reaction mechanism is currently un-
clear. Further studies to expand the scope of the substrates,
as well as to clarify the reaction mechanism, based on seek-
ing the actual reductive species, are now ongoing in our lab-
oratory.
[
Erratum: H. Sajiki, G. Zhang, Y. Kitamura, T. Maegawa, K. Hirota,
Synlett 2005, 1046]; d) T. Maegawa, Y. Kitamura, S. Sako, T. Udzu,
A. Sakurai, A. Tanaka, Y. Kobayashi, K. Endo, U. Bora, T. Kurita,
A. Kozaki, Y. Monguchi, H. Sajiki, Chem. Eur. J. 2007, 13, 5937–
5
943; e) Y. Kitamura, A. Sakurai, T. Udzu, T. Maegawa, Y. Mongu-
chi, H. Sajiki, Tetrahedron 2007, 63, 10596–10602; f) Y. Kitamura, S.
Sako, T. Udzu, A. Tsutui, T. Maegawa, Y. Monguchi, H. Sajiki,
Chem. Commun. 2007, 5069–5071; g) S. Mori, T. Yanase, S. Aoyagi,
Y. Monguchi, T. Maegawa, H. Sajiki, Chem. Eur. J. 2008, 14, 6994–
6
999.
Experimental Section
[
[
8] Y. Monguchi, K. Kitamoto, T. Ikawa, T. Maegawa, H. Sajiki, Adv.
Synth. Catal. 2008, 350, 2767–2777.
9] Organic azides are recognized as valuable intermediates for the syn-
thesis of nitrogen-containing compounds; for reviews, see: a) E. F. V.
Scriven, K. Turnbull, Chem. Rev. 1988, 88, 297–368; b) S. Brꢂse, C.
Gil, K. Knepper, V. Zimmermann, Angew. Chem. 2005, 117, 5320–
General procedure for the copper-mediated reductive amination of aryl
halides with TMSN
the aryl halide (500 mmol), 2-aminoethanol (74.9 mL, 1.25 mmol), and
TMSN (132 mL, 1.00 mmol), in DMA (1.00 mL), in a test tube (15 mL),
3 2
ACHTUNGTRENNUNG( Table 3): A mixture of CuF (102 mg, 1.00 mmol),
3
under Ar, was stirred at 958C for 24 h by using a Chemist Plaza personal
organic synthesizer (Shibata Science Technology Ltd.) and then filtered
through a Celite pad. The pad was then washed with EtOAc (30 mL) and
5
374; Angew. Chem. Int. Ed. 2005, 44, 5188–5240; c) M. Minozzi, D.
Nanni, P. Spagnolo, Chem. Eur. J. 2009, 15, 7830–7840.
[
[
10] Palladium species have never been used as a catalyst for aryl azide
syntheses based on a cross-coupling reaction between aryl halides
and azide sources, although copper-catalyzed aromatic azidations
were recently reported, see: a) W. Zhu, D. Ma, Chem. Commun.
the combined filtrates were successively washed with H
and brine (30 mL), dried (MgSO ), filtered, and concentrated in vacuo.
The residue was purified by flash column chromatography on silica gel
hexane/EtOAc, 5:1 ! 4:1).
2
O (20 mL ꢁ 3)
4
(
2
004, 888–889; b) J. Andersen, U. Madsen, F. Bjçrkling, X. Liang,
Synlett 2005, 2209–2213.
11] During the preparation of this manuscript, an interesting aryl azide
synthesis, which uses a copper-catalyzed cross-coupling reaction be-
tween potassium haloaryltrifluoroborates and sodium azide, was re-
ported as a communication, including the substrate dependent for-
mation of aniline derivatives in a minority of cases (four examples),
see: Y. A. Cho, D.-S. Kim, H. R. Ahn, B. Canturk, G. A. Molander,
J. Ham, Org. Lett. 2009, 11, 4330–4333.
[12] a) L. Birkofer, P. Wegner, Organic Synthesis, Collective Vol. 6, Wiley,
New York, 1988, pp. 1030–1032; b) M. Jafarzadeh, Synlett 2007,
2144–2145.
Keywords: amination · azides · copper · cross-coupling ·
reduction
[
1] a) K. Weissermel, H. J. Arpe, Industry Organic Chemistry, Wiley-
VCH, Weinheim, 1997; b) S. A. Lawrence, Amines: Synthesis Prop-
erties, and Application, Cambridge University Press, Cambridge,
2
004.
[
2] For reviews, see: a) B. H. Yang, S. L. Buchwald, J. Organomet.
Chem. 1999, 576, 125–146; b) J. F. Hartwig in Handbook of Organo-
[13] Olah and Ernst used TMSN
3
for the introduction of an amino group
into aromatic rings through an electrophilic aromatic substitution
7374
www.chemeurj.org
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 7372 – 7375

Reductive Amination
COMMUNICATION
process, in the presence of triflic acid, see: G. A. Olah, T. D. Ernst,
J. Org. Chem. 1989, 54, 1203–1204.
14] The reaction of aryl halides with secondary amines under transition-
metal-free conditions was reported, see: W. Kleist, S. S. Prçckl, M.
Drees, K. Kçhler, L. Djakovitch, J. Mol. Catal. A 2009, 303, 15–22;
see also reference [8] and [17].
[16] Use of copper plate for the reaction of 4-bromobiphenyl was not ef-
fective (36%). Therefore, the morphological properties of the
copper metal appear to be important for a smooth reaction.
[17] No formation of the regioisomers of aminobenzenes was observed,
suggesting that the reaction does not proceed via hydroamination of
a benzyne intermediate, which might be generated by the removal
of hydrogen halide with base in heated polar aprotic solvents.
[
[
15] When 2-aminoethanol was added to a mixture of ethyl 4-bromoben-
2
zoate and CuF in DMA, the mixture turned pale blue. The color
change was, presumably, due to the enhanced solubility of copper
species caused by the formation of a complex with 2-aminoethanol.
The dissolved copper species aids the increase in the reaction effi-
ciency.
Received: December 22, 2009
Published online: May 18, 2010
Chem. Eur. J. 2010, 16, 7372 – 7375
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
7375