One-pot aromatic amination based on carbon-nitrogen coupling reaction between aryl halides and azido compounds

Article abstract of DOI:10.1016/j.tet.2011.12.058

An efficient copper-mediated C-N coupling reaction between various aryl halides and azido compounds to produce the corresponding aromatic primary amines was established. The present amination is apparently involved in both the reduction of an azido functionality to the corresponding primary amino group and its cross-coupling reaction with aryl halides in a one-pot manner. The present amination could be applied to the synthesis of procaine, a local anesthetic drug. A mechanistic study indicated that 2-aminoethanol could work as a major hydrogen donor and the reaction would proceed without the formation of the intermediary aryl azide.

Full text of DOI:10.1016/j.tet.2011.12.058

Tetrahedron 68 (2012) 1712e1722
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
One-pot aromatic amination based on carbonenitrogen coupling reaction
between aryl halides and azido compounds
Toshihide Maejima, Yutaka Shimoda, Kei Nozaki, Shigeki Mori, Yoshinari Sawama,
*
*
Yasunari Monguchi , Hironao Sajiki
Laboratory of Organic Chemistry, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu 501-1196, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient copper-mediated CeN coupling reaction between various aryl halides and azido compounds
to produce the corresponding aromatic primary amines was established. The present amination is ap-
parently involved in both the reduction of an azido functionality to the corresponding primary amino
group and its cross-coupling reaction with aryl halides in a one-pot manner. The present amination could
be applied to the synthesis of procaine, a local anesthetic drug. A mechanistic study indicated that 2-
aminoethanol could work as a major hydrogen donor and the reaction would proceed without the
formation of the intermediary aryl azide.
Received 4 November 2011
Received in revised form 19 December 2011
Accepted 21 December 2011
Available online 24 December 2011
Keywords:
Amination
Reduction
Azides
Ó 2011 Elsevier Ltd. All rights reserved.
Copper
Cross-coupling
1. Introduction
coupling reaction of aryl halides and trimethylsilylazide (TMSN3)
in the presence of CuF2 and triphenylphosphine, we developed the
A metal-catalyzed carbonenitrogen (CeN) bond formation re-
action using aryl halides has attracted attention as a useful meth-
odology for the synthesis of a variety of subunits and precursors of
functional materials, such as pharmaceuticals, natural products,
liquid crystals, etc.1 Although copper-mediated2,3 and palladium-
mediated3,4 CeN bond formation reactions to access secondary or
tertiary arylamines were recently established by many research
groups, the direct syntheses of primary arylamines have hardly
been reported other than methods to use lithium bis(trimethylsilyl)
amide or zinc bis(trimethylsilyl)amide as the ammonia equiva-
lent.5,6 However, highly efficient synthetic methods for the prepa-
ration of primary aromatic amines have very recently been
developed through the palladium-catalyzed coupling between aryl
halides and ammonia or ammonium salts.7,8 Therefore, the appli-
cable metal-mediated synthesis of primary aromatic amines using
a CeN coupling reaction is a rapidly developing area in organic
chemistry. We have established several CeC and CeN bond for-
mations using palladium on carbon (Pd/C) as a heterogeneous
catalyst.9,10 During the course of our research related to the de-
velopment of an aryl azidation method11,12 via a Pd/C-catalyzed
formation of a primary arylamine as the sole product instead of the
desired aryl azide. After a detailed optimization, it was found that
Pd/C and triphenylphosphine were not required, but CuF2 was es-
sential for the reaction progress (Scheme 1).13
Scheme 1. Copper-mediated reductive amination with a variety of aryl halides and
TMSN3.
Molander et al. described that primary amines were obtained
during the course of their research to synthesize potassium azi-
doaryltrifluoroborates starting from the corresponding haloge-
nated aryltrifluoroborates and sodium azide (NaN3) in the presence
of Cs2CO3, CuBr, and N,N-dimethylethylenediamine (DMEDA), al-
though the reactions were substrate-dependent and rare cases.14
Furthermore, the direct amination of aryl chlorides and bromides
possessing an ortho-substituted carboxyl, carboxamido, or amino-
carbonyl group on the aromatic nuclei using an excess amount of
NaN3 and Cs2CO3 together with catalytic CuI and DMEDA was also
reported in the literature,15 where it is proposed that the reaction
proceeds via intermediary arylazides. Helquist et al. also reported
the copper-promoted synthesis of primary arylamines using NaN3
* Corresponding authors. Tel.: þ81 58 230 8100; fax: þ81 58 230 8109; e-mail
addresses: monguchi@gifu-pu.ac.jp (Y. Monguchi), sajiki@gifu-pu.ac.jp (H. Sajiki).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.12.058

T. Maejima et al. / Tetrahedron 68 (2012) 1712e1722
1713
catalyzed by CuI/DMEDA, CuI/proline, or Cu2O/proline.16 A similar
amination of aryl halides using NaN3 as the amino source in the
presence of copper or copper salt together with a ligand was
employed for the synthesis of 3-aminoquinolines and 3-
aminocoumarines as well as anilines.17 A CuSO4-mediated amina-
Table 2
Effect of copper reagents on the reductive amination of 4-bromobiphenyl (1) with
TMSN3
Copper reagent (2.0 equiv)
Br
NH2
H2N(CH2)2OH (2.5 equiv)
DMA, 95 °C, 24 h
TMSN3
(2.0 equiv)
+
Ph
Ph
tion of electron-deficient halobenzenes using NaN3,
sodium ascorbate was also demonstrated.18 Furthermore, the utility
of
-glucosamine as the ligand was recently reported by Sekar.19
We now describe in detail a general synthetic method for the
L-proline, and
1
2
D
Entry
Copper reagent
Yielda (%)
preparation of primary aromatic amines using the cross-coupling
reaction of aryl chlorides, bromides, and iodides with TMSN3 or
NaN3, as well as its mechanistic studies. Combined use of Cu0
powder and 2-aminoethanol in particularly was found to be ef-
fective for the amination of haloarenes using TMSN3.
1
2
3
4
5
6
7
8
d
0
78
17
5
86
80
14
78
68
79
71
77
95
CuF2
CuCl2
CuBr2
Cu(OH)2
Cu(OAc)2
Cu(OTf)2
CuO
CuCl
CuBr
CuI
CuOAc
Cu
2. Results and discussion
9
10
11
12
13
2.1. Copper-mediated reductive amination of aryl halides
with TMSN3
a
Isolated yield.
When 4-bromobiphenyl (1) was treated with CuF2 (2.0 equiv),
2-aminoethanol (2.5 equiv), and TMSN3 (2.0 equiv) in DMA at
95 ꢀC, the desired 4-aminobiphenyl (2) was obtained in 78% yield
(Table 1, entry 9). The addition of trialkylamines, ammonia, ethyl-
ene diamine, or aminoalcohol was crucial for the reaction progress
(Table 1, entries 2, 3, 5, and 8e12 vs entry 1), although triphenyl-
amine, tetraalkylammonium bromide, pyridine, or alkylene diols
indicated no accelerating effect as an additive (entries 4, 6, 7,13, and
14). However, 2-aminoethanol, in particular, was effective as an
additive (entry 9).
The temperature was also a crucial factor for the present re-
ductive amination (Table 3, entries 1e5). The yield of 4-
aminobiphenyl (2) increased temperature-dependently up to
95 ꢀC (95%, entry 3), while it gradually decreased at over 95 ꢀC
(entries 4 and 5). We then investigated the effect of solvents on the
reaction using copper powder and 2-aminoethanol at 95 ꢀC (entries
6e14). The reaction smoothly proceeded in either an aprotic polar
solvent, such as DMA, DMSO, DMF, NMP, and 1,4-dioxane, or
a protic polar solvent, such as MeOH and EtOH (entries 3, 6e9, 11,
and 12), while THF, EtOAc, and water were not suitable as a solvent
for the reaction (entries 10, 13, and 14).
Table 1
Effect of additives on the copper-mediated reductive amination of 4-bromobiphenyl
(1) with TMSN3
CuF2 (2.0 equiv)
Br
NH2
Additive (2.5 equiv)
DMA, 95 °C, 24 h
TMSN3
(2.0 equiv)
+
Table 3
Ph
Ph
Solvent and temperature effects on the copper-mediated reductive amination of 4-
bromobiphenyl (1) with TMSN3
1
2
Cu (2.0 equiv)
Entry
Additive
Yielda (%)
Br
NH2
H2N(CH2)2OH (2.5 equiv)
Solvent, Temp., 24 h
TMSN3
(2.0 equiv)
+
1
2
3
4
5
6
7
8
d
8
62
46
11
27
11
11
70
78
70
69
72
8
Ph
Ph
Et3N
(n-C8H17)3N
Ph3N
1
2
aq 28% NH3
(n-C4H9)4NBr
Pyridine
H2N(CH2)2NH2
H2N(CH2)2OH
H2N(CH2)3OH
H2N(CH2)4OH
H2N(CH2)5OH
HO(CH2)2OH
HO(CH2)3OH
Entry
Solvent
Temp (ꢀC)
Yielda (%)
1
2
3
4
5
6
7
8
DMA
DMA
DMA
DMA
DMA
DMSO
DMF
NMP
1,4-Dioxane
THF
50
80
95
110
120
95
95
95
95
95
27
85
95
89
78
89
69
89
88
49
86
77
30
NRb
9
10
11
12
13
14
4
9
a
Determined by 1H NMR with 1,4-dioxane as an internal standard.
10
11
12
13
14
MeOH
EtOH
EtOAc
H2O
95
95
95
95
Since no reaction took place without copper species (Table 2,
entry 1), the effect of the copper reagents on the amination using 4-
bromobiphenyl (1) and TMSN3 was then investigated in the pres-
ence of 2-aminoethanol in DMA. The yield of 4-aminobiphenyl (2)
was basically increased by the use of divalent copper salts in
agreement with the basicity order of the counter anion of the
copper salts (entries 2e8). On the other hand, monovalent copper
salts were equally effective for the amination regardless of the type
of counter anions (68e78%, entries 9e12). Amazingly, zero-valent
copper powder was finally found to be the most efficient for
completing the reaction (entry 13).
a
Isolated yield.
No reaction.
b
The scope and limitations of the aryl halides for the reductive
amination using TMSN3 (2.0 equiv) in the presence of copper
powder (2.0 equiv) and 2-aminoethanol (2.5 equiv) in DMA at
95 ꢀC were investigated (Table 4). Aryl bromides and iodides
bearing an electron-withdrawing group, such as nitro, ester,

1714
T. Maejima et al. / Tetrahedron 68 (2012) 1712e1722
Table 4
Copper-mediated reductive amination of aryl halides with TMSN3
Cu (2.0 equiv)
H2N(CH2)2OH (2.5 equiv)
TMSN3
(2.0 equiv)
Ar
X
+
Ar NH2
DMA, Ar, 95 °C
Entry
1
AreX
Time (h)
1
Yielda (%)
95
Entry
9
AreX
Time (h)
24b
Yielda (%)
Entry
17
AreX
Time (h)
24b
Yielda (%)
69
Br
Br
Br
Br
84c
66
O2N
O2N
Cl
N
I
Br
2
3
16
5
79
93
10
11
24b
24b
18
19
EtO
3
1
92
96
Me
Me
O
Br
EtO
74
Me
Br
O2N
I
I
O
Br
24b
24b
60
48
20
21
6
92c
49
EtO
4
5
9
86
55
12
13
Br
Cl
Me
O
Br
O
Br
Br
I
OEt
24b
24b
MeO
MeO
MeO
MeO
O2N
24b
10
75
93
14
15
9
89
85
22
23
24b
24b
70
33
MeO
Ph
6
7
Br
I
O
Br
Cl
Br
24b
Ph
Br
Br
8
24b
84
16
24b
54
a
Isolated yield.
The reaction was incomplete within 24 h.
Yield of 4-chloroaniline.
b
c
phenyl, and chlorine functionalities, on the aromatic nucleus were
effectively aminated (Table 4, entries 1e9 and 18e20). In the case
of the electron-donating methyl or methoxy-substituted aryl
bromides, substitution patterns affected the reaction progress.
Aryl bromides and iodides possessing a methyl or methoxy group
at the meta-position of the bromine or iodine were better sub-
strates compared to the ortho- or para-substituted aryl bromides
and iodides (entries 10e14, 21, and 22). The present reaction was
also applicable to fused aromatic bromides including aromatic
heterocycles, such as bromonaphthalenes, and 3-bromoquinoline
(entries 15e17). Furthermore, the highly electron-deficient 4-
chloronitrobenzene could be expected to be aminated under the
present reaction conditions (33% isolated yield), although the
reaction efficiency was not very good and a significant amount of
the 4-chloronitrobenzene remained unchanged (entry 23).
Therefore, aryl chlorides were essentially less reactive as
a substrate.
Scheme 2. Copper-mediated reductive amination of 2-bromochalcone (3) with
TMSN3.
2.2. Synthetic application to procaine (8), a local anesthetic
drug
When 2-bromochalcone (3) was employed as a substrate,
2-phenylquinoline (4) was obtained in 82% yield as the sole
product through the intramolecular nucleophilic addition of the
amino group of the intermediary 2-aminochalcone to the car-
bonyl group within the molecule and subsequent dehydration
(Scheme 2).
Procaine (8) is a local anesthetic drug composed of a primary
aromatic amine and amino ester functionalities. It is used to reduce
the pain of the intramuscular injection of penicillin and has also
been used in dentistry.20 Procaine (8) is conventionally prepared
via the reduction of 2-diethylaminoethyl 4-nitrobenzoate using
21
SnCl2 or the reduction of ethyl 4-nitrobenzoate using Fe powder

T. Maejima et al. / Tetrahedron 68 (2012) 1712e1722
1715
Table 6
followed by the transesterification with 2-diethylaminoethanol in
basic media,22 while no amination method of 4-bromobenzoic acid
derivatives was employed. We now attempted to synthesize pro-
caine by the present reductive amination in DMA at 95 ꢀC (Scheme
3). The esterification of 4-bromobenzoyl chloride (5) with 2-
diethylaminoethanol (6) in the presence of N,N-dimethyl-4-
aminopyridine (DMAP) (0.2 equiv) and Et3N (1.2 equiv) in DMA at
room temperature gave 2-diethylaminoethyl 4-bromobenzoate (7)
in 85% yield. The bromide smoothly underwent the copper-
mediated amination using TMSN3 (2.0 equiv), copper powder
(2.0 equiv), and 2-aminoethanol (2.5 equiv) to afford the desired
procaine (8) in 63% isolated yield.
Effect of copper reagents on the copper-mediated reductive amination of ethyl 4-
bromobenzoates (9) using NaN3
Copper reagent (2.0 equiv)
Br
NH2
H2N(CH2)2OH (2.5 equiv)
DMA, 95 °C, 24 h
NaN3
(2.0 equiv)
+
EtO2C
EtO2C
10
9
Entry
Copper reagent
Yielda (%)
1
2
3
4
5
6
7
8
Cu
CuI
CuBr
CuCl
CuF2
5
52
46
56
91b
85
21
42
Cu(OAc)2
Cu(OH)2
CuCl2
a
Determined by 1H NMR with 1,4-dioxane as the internal standard.
Isolated yield.
b
To explore the scope of the present method using NaN3
(2.0 equiv) together with CuF2 (2.0 equiv), a variety of bromo-
benzenes was used as the substrates. Although an extension of the
reaction period was generally required compared to when using
TMSN3 (Table 7, entries 1e8 vs Table 4, entries 1e14), the corre-
sponding aniline derivatives were obtained in good to excellent
yields regardless of the type of substituents on the benzene nucleus.
The reaction was only affected by the substitution pattern of the
aromatic ring and the ortho-substituted ethyl bromobenzoate was
hardly aminated (Table 7, entry 3). The CuF2 and NaN3-mediated
reductive coupling of aryl iodides similarly and smoothly proceeded
to give the desired aniline derivatives in more than 90% yields
Scheme 3. Synthesis of procaine (8) by the reductive amination.
2.3. Application of other azido compounds to the aromatic
amination
Diphenylphosphoryl azide (DPPA) developed as an organic azide
by Shioiri and Yamada,23 and an inorganic azide, NaN3, were next
employed instead of TMSN3 for the present amination of ethyl 4-
bromobenzoate (9) (Table 5). As the result, DPPA was found to be
quite effective as an amino source, while the desired ethyl 4-
aminobenzoate (10) was only slightly obtained using NaN3. Since
the use of NaN3 would make the reaction more user-friendly be-
cause of its cost and easy access, we reinvestigated the detailed
reaction conditions using NaN3.
Table 7
CuF2-mediated reductive amination of aryl halides with NaN3
CuF2 (2.0 equiv)
H2N(CH2)2OH (2.5 equiv)
NaN3
(2.0 equiv)
Ar
X
+
Ar NH2
DMA, Ar, 95 °C
Entry
AreX
Time (h)
Yielda (%)
Table 5
Application of azido compounds to the copper-mediated reductive amination
Br
Br
Cu (2.0 equiv)
Br
NH2
1
EtO
24
91
H2N(CH2)2OH (2.5 equiv)
DMA, 95 °C, 24 h
azido compound
(2.0 equiv)
+
O
O
EtO2C
EtO2C
9
10
EtO
2
3
24
24
83
11
Entry
Azido compound
Yielda (%)
1
2
DPPA
NaN3
84
5
Br
O
a
Isolated yield.
OEt
Br
2.4. Application of NaN3 as a nitrogen source of the amino
substituent to the copper-mediated reductive amination
4
5
24
24
89
79
75
F3C
Copper reagents were screened in detail for the present re-
ductive amination of ethyl 4-bromobenzoate (9) with NaN3
(2.0 equiv) in the presence of 2-aminoethanol (2.5 equiv) in DMA at
95 ꢀC. Both monovalent and bivalent copper reagents worked well
(Table 6, entries 2e8), although zero-valent copper powder, an
excellent copper reagent for the reaction using TMSN3 (Table 2,
entry 13) and DPPA (Table 5, entry 1), gave a poor result (Table 6,
entry 1). CuF2 was especially effective, leading to the completion of
the reaction to give ethyl 4-aminobenzoate (10) in 91% yield
(entry 5).
Br
O2N
Br
6
7
24
24
Ph
Br
79
MeO
(continued on next page)

1716
T. Maejima et al. / Tetrahedron 68 (2012) 1712e1722
Table 7 (continued )
1.0 equiv of
a
single-electron scavenger, such as 7,7,8,8-
tetracyanoquinodimethane (TCNQ) or tetracyanoethylene (TCNE),
strongly suppressed the reaction efficiency (entry 6), suggesting
that the reaction would be involved in the single-electron transfer
step.
Entry
AreX
Time (h)
Yielda (%)
8
9
24
6
90
92
Ethyl 4-azidobenzoate (11), which is a possible intermediate,
was subjected to the present reductive amination conditions. In the
presence of both copper powder and 2-aminoethanol, ethyl 4-
azidobenzoate was quantitatively reduced to the corresponding
aniline (10) (Table 9, entry 1), while the reduction proceeded with
a low efficiency without the copper powder (8%, entry 2). There-
fore, 2-aminoethanol could also function as a minor reducing re-
agent, although it is not effective. On the other hand, almost no
reaction took place without 2-aminoethanol even in the presence
of the copper powder (entry 3). Since ethyl 4-aminobenzoate (10)
was obtained in 23% yield from ethyl 4-bromobenzoate (9) and
TMSN3 under 2-aminoethanol-free conditions (Table 8, entry 2),
ethyl 4-azidobenzoate (11) would not be an intermediate of the
present reductive amination.24 This assumption was also supported
by the fact that the corresponding arylazides, such as 11, were never
detected during the reductive amination by the TLC analyses as
well as time-course analyses by IR spectroscopy in DMA. The azido
MeO
EtO
Br
I
O
I
10
11
15
24
90b
29
Cl
Cl
O2N
a
Isolated yield.
Yield of 4-chloroaniline.
b
(entries
8 and 9). Furthermore, highly electron-deficient 4-
peak of TMSN3 in the IR spectrum (Fig. 1, spectrum a, 2129 cmꢁ1
)
chloronitrobenzene was also applicable for the present reductive
aminationwith NaN3, although the yield was not satisfactory similar
to the reaction of TMSN3 (entry 10, see also Table 4, entry 23).
was shifted to 2012 cmꢁ1 by the addition of 2-aminoethanol
(spectrum b), and no peaks were detected around
1900e2000 cmꢁ1 in spectrum c of a mixture of the ethyl 4-
bromobenzoate (9) and 2-aminoethanol. In the IR spectrum of ei-
ther the 0.5 or 6 h-reaction of 9 with TMSN3, copper powder, and 2-
aminoethanol at 95 ꢀC in DMA, a peak at 2048 cmꢁ1 was observed
(spectra d and e), which would be derived from the unreacted
excess amount of TMSN3 or possible azido intermediate (11).
Meanwhile, two peaks emerged at 2126 and 2065 cmꢁ1 after the
addition of ethyl 4-azidobenzoate (11) to the reaction mixture after
6 h (spectrum f). Since the peak at 2126 cmꢁ1 was confirmed as that
of ethyl 4-azidobenzoate (spectrum g), the other peak at 2065 cmꢁ1
in spectrum f would be derived from TMSN3. Furthermore, the
product (10) would not give the peak at ca. 2050 cmꢁ1 in its IR
spectrum (spectrum h). Therefore, the peak at 2048 cmꢁ1 of spec-
trum e for the reaction mixture after 6 h-reaction would be due to
the remaining TMSN3 and should shift from 2012 cmꢁ1 during the
reaction.
2.5. Mechanistic studies and plausible reaction mechanism
The role of the additive and DMA as a solvent for the amination
of ethyl 4-bromobenzoate (9) using copper powder and TMSN3 was
explored to determine the reaction mechanism (Table 8). The
amination quantitatively proceeded even without a solvent (entries
3 vs 1), although the yield of ethyl 4-aminobenzoate (10) signifi-
cantly decreased without 2-aminoethanol in DMA (entries 2 vs 1).
These results suggest that 2-aminoethanol was very likely to work
as a major hydrogen source of the amino functionality. When
the
bulky
tert-butyldiphenylsilyl
(TBDPS)-protected
2-
dimethylaminoethanol was used instead of 2-aminoethanol, the
reaction proceeded as equally poor as in the case without the ad-
ditive (entries 4 vs 2), and the reaction scarcely took place without
any solvent (entry 5). Based on these results, the following two
hypotheses could be made: (1) 2-aminoethanol would work as an
activator probably based on the coordination with the copper
species, which would be inhibited by the bulky substituents of 2-
aminoethanol; and (2) DMA could be a minor hydrogen donor
Table 9
The reduction of ethyl 4-azidobenzoate (11)
Cu (2.0 equiv)
N3
NH2
2-aminoethanol (2.5 equiv)
DMA, 95 °C, 24 h
due to the acidity of its a-hydrogen atoms, since the desired aniline
was obtained in about 20% yield without the hydrogen atoms of the
2-aminoethanol (entries 2 and 4). Furthermore, the addition of
EtO2C
EtO2C
11
10
Entry
Cu
2-Aminoethanol
11/10a
Table 8
1
2
3
B
ꢂ
B
B
ꢂ
0:100
92:8
>99:trace
Effect of additives on the reductive amination of ethyl 4-bromobenzoate (9)
Cu (2.0 equiv)
B
Br
NH2
Additive
The ratio was determined by 1H NMR.
TMSN3
(2.0 equiv)
a
+
DMA, 95 °C, 24 h
EtO2C
EtO2C
9
10
A possible reaction mechanism of the present reductive ami-
Entry
Additive
DMA
Yielda (%)
nation is depicted in Scheme 4. We mainly assumed that the oxi-
dative addition of the copper species, which are activated by 2-
aminoethanol, to an aryl halide (A) would produce the copper
complex (B), and the exchange of Xꢁ with N3ꢁ, which would be
inspired by the nucleophilic attack of 2-aminoethanol to TMSN3,
would provide the corresponding aryl azide complex (C). The azido
group of C could be reduced through two single-electron transfer
steps from the zero-valent copper complex with 2-aminoethanol or
1
2
3
4
5
6
H2N(CH2)2OH (2.5 equiv)
d
B
B
d
B
d
B
96
23
97
19
Trace
Trace
H2N(CH2)2OH (2.5 equiv)
Me2N(CH2)2OTBDPS (2.5 equiv)
Me2N(CH2)2OTBDPS (2.5 equiv)
H2N(CH2)2OH (2.5 equiv)
TCNQ or TCNE (1.0 equiv)
a
Determined by 1H NMR with 1,4-dioxane as an internal standard.

T. Maejima et al. / Tetrahedron 68 (2012) 1712e1722
1717
Table 10
Reductive amination of ethyl 4-bromobenzoate or 4-bromoanisole using catalytic
amount of copper powder
Cu (X equiv)
Br
NH2
H2N(CH2)2OH (2.5 equiv)
DMA, 95 °C, 24 h
TMSN3
(2.0 equiv)
+
R
R
Entry
R
Cu (X equiv)
Yielda (%)
1
2
3
4
5
6
7
8
9
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
MeO
2.0
1.0
0.5
0.4
0.3
0.2
0.1
2.0
0.5
96 (93b)
98
94
87
85
77
67
48b
29
MeO
a
The yield was determined by 1H NMR with 1,4-dioxane as an internal standard.
Isolated yield.
b
3. Conclusion
We have developed a novel synthetic method for the prepara-
tion of primary arylamines by the reductive cross-coupling reaction
between aryl halides and azido compounds, such as TMSN3, NaN3,
and DPPA, in the presence of copper reagents and 2-aminoethanol
in heated DMA. The method could be used for synthesis of procaine.
The copper-mediated reductive amination proceeded in a one-pot
manner for both the reduction of the azido functionality and the
cross-coupling between an aryl halide and TMSN3 without the
formation of the aryl azide as an intermediate. Since arylamines
could be effectively and readily obtained from various aryl halides
using only commercially available reagents, the present method
will be in practical use in organic and medicinal chemistries.
Fig. 1. IR spectra in DMA of (a) TMSN3; (b) TMSN3 and 2-aminoethanol; (c) ethyl 4-
bromobenzoate (9) and 2-aminoethanol; (d) the reaction mixture after 30 min [ethyl
4-bromobenzoate (9), TMSN3, copper powder and 2-aminoethanol in DMA at 95 ꢀC];
(e) the reaction mixture after 6 h; (f) the reaction mixture after 6 h and ethyl 4-
azidobenzoate (11); (g) ethyl 4-azidobenzoate (11) and 2-aminoethanol; (h) ethyl 4-
aminobenzoate (10) and 2-aminoethanol.
4. Experimental
4.1. General experimental
TMSN3 was supplied by the Toyobo Co., Ltd. (Osaka, Japan). All
other reagents and solvents were purchased from commercial
sources and used without further purification. Analytical thin-layer
chromatography (TLC) was carried out on pre-coated silica Gel 60
F254 plates (Merck; Art 5715) and visualized with UV light. Flash
column chromatography was used with a Silica Gel 60 N (Kanto
Chemical Co., Inc.; 63e210 mm, spherical, neutral). The IR spectra
were measured bya Bruker FT-IRALPHA. The 1H and13C NMR spectra
were recorded by a JEOL JNM ECA-500 (500 MHz for 1H NMR and
125 MHz for 13C NMR) or JEOL JNM AL-400 spectrometer (400 MHz
Scheme 4. Proposed reaction mechanism.
for 1H NMR and 100 MHz for 13C NMR). The chemical shifts (
d) are
expressed in parts per million and are internally referenced
(0.00 ppm for TMS for 1H NMR and 77.0 ppm for CDCl3 for 13C NMR).
The EI mass spectra were measured by a JEOL JMS-SX 102 A or JEOL
JMS-T100GC AccuTOF at the Gifu Pharmaceutical University.
O-TMS-2-aminoethanol to give the aryl copper amine complex (D).
Reductive elimination of D would lead to the formation of the de-
sired arylamine (E) and copper species.25 The present amination
would require more than a stoichiometric amount of the copper-2-
aminoethanol (O-TMS-2-aminoethanol) complex for the reduction
of the azido group and cross-coupling, if the copper species, which
are generated after the reduction, are not active for further ami-
nation. When ethyl 4-bromobenzoate (9) was used as a substrate
for the amination, the amount of copper powder could be reduced
to 0.5 equiv without a significant loss of the reaction efficiency
(Table 10, entries 1e3), while the use of less than 0.4 equiv of
copper powder dropped the efficiency (entries 4e7). The amination
of 4-bromoanisole using 0.5 equiv of copper powder proceeded
very slowly to afford the corresponding 4-anisidine in only 29%
yield (entries 9). Therefore, a stoichiometric amount of copper
powder should be generally used for the effective synthesis of the
aromatic amines.
4.2. General procedure for the copper-mediated reductive
amination of aryl halides with TMSN3 (Table 4)
A mixture of copper powder (63.5 mg, 1.00 mmol), the aryl ha-
lide (500
mmol), 2-aminoethanol (74.9 mL, 1.25 mmol), and TMSN3
(133 L, 1.00 mmol) in DMA (1 mL) in a 15 mL test tube was stirred
m
under an Ar atmosphere (balloon) at 95 ꢀC using a Chemistation
personal organic synthesizer (EYELA, Tokyo). After complete con-
sumption of the aryl halide was confirmed by TLC analyses or after
24 h (if the reaction was incomplete within 24 h), the mixture was
diluted with EtOAc (10 mL) and then filtered through a Celite pad.
The pad was successively washed with EtOAc (20 mL), H2O (25 mL),

1718
T. Maejima et al. / Tetrahedron 68 (2012) 1712e1722
and concd aq ammonia solution (5 mL). After the two layers were
separated, the aqueous layer was extracted with EtOAc (2ꢂ10 mL).
The combined organic layers were washed with brine (20 mL),
dried over MgSO4, filtered, and concentrated under reduced pres-
sure. The residue was purified by silica-gel column chromatography
with n-hexane/EtOAc or n-pentane/Et2O as the eluent.
J¼2.4, 1.9 Hz, 1H), 7.20 (t, J¼7.7 Hz, 1H), 6.85 (dd, J¼7.7, 2.4 Hz, 1H),
3.88 (s, 3H), 3.80 (br s, 2H); 13C NMR (100 MHz):
d 167.2, 146.5, 131.1,
129.2,119.6,119.3,115.7, 52.0; MS (EI) m/z (%): 151 (Mþ,100),120 (82),
92 (60), 65 (22); HRMS (EI) calcd for C8H9NO2 (Mþ) 151.06333, found
151.06288.
4.2.7. 4-Aminobiphenyl (1) (entry 7)8b. Eluent for column chro-
4.2.1. 4-Nitroaniline (entries 1 and 23)8b. Eluent for column chro-
matography, n-hexane/EtOAc (5:1/4:1). 93% (78.3 mg, 463 mmol)
matography, n-hexane/EtOAc (5:1/2:1). 95% (65.3 mg, 473
for entry 1 and 33% (22.9 mg, 166 mol) for entry 23 as a yellow
solid. Mp 146e147 ꢀC; IR: nmax 3480, 3356, 1628, 1585, 1468, 1442,
mmol)
as a pale brown solid. Mp 57e58 ꢀC; IR: nmax 3422, 3390, 3191,
m
3024, 1599, 1518, 1483, 1418, 1256, 1189, 1130, 1078, 1036, 1002, 830,
786, 759, 692, 562, 549, 493 cmꢁ1 1H NMR (400 MHz):
; d 7.53 (d,
1293, 1110, 837, 752 cmꢁ1; 1H NMR (400 MHz):
d
8.07 (d, J¼9.2 Hz,
J¼7.7 Hz, 2H), 7.36e7.42 (m, 4H), 7.26 (t, J¼8.0 Hz, 1H), 6.74 (d,
2H), 6.63 (d, J¼9.2 Hz, 2H), 4.42 (br s, 2H); 13C NMR (100 MHz):
J¼8.2 Hz, 2H), 3.88 (s, 3H), 3.80 (br s, 2H); 13C NMR (100 MHz):
d
152.5, 139.1, 126.3, 113.4; MS (EI) m/z (%): 138 (Mþ, 100), 108 (50),
d 145.8, 141.1, 131.5, 128.6, 128.0, 126.4, 126.2, 115.4; MS (EI) m/z (%):
92 (36), 65 (47), 52 (6); HRMS (EI) calcd for C6H6N2O2 (Mþ)
138.04293, found 138.04211.
169 (Mþ, 100), 139 (16), 115 (20), 83 (20), 63 (13); HRMS (EI) calcd
for C12H11N (Mþ) 169.08915, found 169.08961.
4.2.2. 5-Nitro-2-toluidine (entry 2)26. Eluent for column chroma-
4.2.8. 2-Aminobiphenyl (entry 8)7a. Eluent for column chromatog-
tography, n-hexane/EtOAc (5:1/4:1). 79% (59.7 mg, 393
mmol) as
raphy, n-hexane/EtOAc (20:1/10:1). 84% (71.4 mg, 422 mmol) as
a yellow solid. Mp 106e107 ꢀC; IR: nmax 3485, 3392, 2922, 2857,
a pale brown solid. Mp 52e54 ꢀC; IR: nmax 3479, 3385, 3023, 1611,
1738, 1625, 1494, 1434, 1380, 1336, 1292, 1277, 1136, 1101, 1030, 995,
1499,1478,1454,1433,1283,1156,1071,1007, 918, 751, 735, 702, 666,
869, 812, 733 cmꢁ1
;
1H NMR (400 MHz):
d
7.51 (dd, J¼8.0, 2.3 Hz,
615, 563, 521, 478, 432 cmꢁ1
;
1H NMR (500 MHz):
d
7.48e7.53 (m,
1H), 7.49 (d, J¼2.3 Hz,1H), 7.14 (d, J¼8.0 Hz, 2H), 3.94 (br s, 2H), 2.23
4H), 7.19e7.24 (m, 2H), 6.89 (t, J¼7.4 Hz, 1H), 6.81 (d, J¼8.0 Hz, 1H),
(s, 3H); 13C NMR (CDCl3):
d
147.3, 145.3, 130.6, 129.5, 113.1, 108.7,
3.79 (br s, 2H); 13C NMR (125 MHz):
d 143.4,139.4,130.3,129.0,128.7,
17.5; MS (EI) m/z (%): 152 (Mþ, 100), 122 (6), 106 (60), 51 (8); HRMS
128.4, 127.1, 118.6, 115.5; MS (EI) m/z (%): 169 (Mþ, 100), 149 (6), 115
(EI) calcd for C7H8N2O2 (Mþ) 152.05858, found 152.05798.
(11); HRMS (EI) calcd for C12H11N (Mþ) 169.08915, found: 169.08849.
4.2.3. Ethyl 4-aminobenzoate (10) (entries 3 and 18)27. Eluent for
column chromatography, n-hexane/EtOAc (5:1/4:1). 93%
4.2.9. 4-Chloroaniline (entries
chromatography, n-hexane/EtOAc (5:1/4:1). 84% (53.4 mg,
419 mol) for entry 9 and 92% (58.7 mg, 460 mol) for entry 20 as
a colorless solid. Mp 71e72 ꢀC; IR: nmax 3469, 3380, 2921, 2853,
1686, 1613, 1491, 1285, 1180, 1088, 1004, 817, 636, 503 cmꢁ1 1H
NMR (400 MHz):
7.09 (d, J¼8.2 Hz, 2H), 6.59 (d, J¼8.2 Hz, 2H),
9
and 20)7a. Eluent for column
(76.8 mg, 465
m
mol) for entry 3 and 92% (76.0 mg, 460
mmol) for
m
m
entry 18 as a pale yellow solid. Mp 92e94 ꢀC; IR: nmax 3416, 3340,
3218, 2983, 2899, 1678, 1631, 1592, 1511, 1473, 1440, 1366, 1309,
;
1272, 1169, 1122, 1023, 844, 770, 699, 638, 501 cmꢁ1
;
1H NMR
d
(400 MHz):
d
7.85 (d, J¼7.9 Hz, 2H), 6.62 (d, J¼7.9 Hz, 2H), 4.31 (q,
3.64 (br s, 2H); 13C NMR (100 MHz):
d 144.9, 129.1, 123.1, 116.2; MS
J¼7.1 Hz, 2H), 4.13 (br s, 2H), 1.35 (t, J¼7.1 Hz, 3H); 13C NMR
(EI) m/z (%): 127 (Mþ, 100), 92 (17), 65 (20), 44 (9); HRMS (EI) calcd
(100 MHz):
d
166.8, 150.9, 131.5, 119.9, 113.8, 60.3, 14.4; MS (EI) m/z
for C6H6ClN (Mþ) 127.01887, found: 127.01915.
(%): 165 (Mþ, 44), 137 (15), 120 (100), 92 (21), 65 (17); HRMS (EI)
calcd for C9H11NO2 (Mþ) 165.07898, found 165.07823.
4.2.10. 4-Toluidine (entry 10)8b. The reaction was carried out
according to the general procedure. Et2O was used for washing the
Celite pad and phase separation instead of EtOAc. Eluent for column
chromatography, n-pentane/Et2O (5:1/2:1). 66% (35.4 mg,
4.2.4. Ethyl 3-aminobenzoate (entry 4)27. Eluent for column chro-
matography, n-hexane/EtOAc (5:1/4:1). 86% (70.8 mg, 429 mmol)
as a pale yellow oil. IR: nmax 3469, 3375, 3229, 2983, 2939, 2904,
330
mmol) as a brown solid. IR: nmax 3421, 3338, 3029, 2925, 2854,
1704, 1622, 1604, 1588, 1460, 1367, 1301, 1234, 1099, 1021, 906, 754,
1624, 1580, 1460, 1380, 1281, 1178, 1075, 1044, 813, 774, 693,
681, 647, 534 cmꢁ1
;
1H NMR (400 MHz):
d
7.43 (ddd, J¼7.8, 1.7,
511 cmꢁ1
;
1H NMR (500 MHz):
d
6.99 (d, J¼8.2 Hz, 2H), 6.63 (d,
1.0 Hz, 1H), 7.35 (dd, J¼2.5, 1.7 Hz, 1H), 7.20 (t, J¼7.8 Hz, 1H), 6.84
J¼8.2 Hz, 2H), 3.37 (br s, 2H), 2.26 (s, 3H); 13C NMR (125 MHz):
(ddd, J¼7.8, 2.5, 1.0 Hz, 1H), 4.34 (q, J¼7.2 Hz, 2H), 3.80 (br s, 2H),
d
143.7,129.7,127.7,115.2, 20.4; MS (EI) m/z (%): 106 (Mþ,100), 77(15),
1.37 (t, J¼7.2 Hz, 3H); 13C NMR (100 MHz):
d
166.7, 146.4, 131.4,
51 (6); HRMS (EI) calcd for C7H9N (Mþ) 107.07350, found 107.07295.
129.1, 119.5, 119.2, 115.6, 60.8, 14.2; MS (EI) m/z (%): 165 (Mþ, 100),
149 (9), 137 (41), 120 (97), 92 (66), 65 (36); HRMS (EI) calcd for
C9H11NO2 (Mþ) 165.07898, found 165.07870.
4.2.11. 3-Toluidine (entry 11)5a. The reaction was carried out
according to the general procedure. Et2O was used for washing the
Celite pad and phase separation instead of EtOAc. Eluent for column
chromatography, n-pentane/Et2O (5:1/4:1). 74% (39.6 mg,
4.2.5. Ethyl 2-aminobenzoate (entry 5)17. Eluent for column chro-
matography, n-hexane/EtOAc (10:1/5:1). 55% (45.3 mg, 274
as a pale yellow oil. IR: nmax 3479, 3370, 2980,1682, 1613,1585, 1559,
m
mol)
370
2859, 1618, 1589, 1492, 1467, 1311, 1291, 1169, 996, 926, 854, 771,
689, 555, 537, 439 cmꢁ1 1H NMR (500 MHz):
7.07 (t, J¼7.5 Hz,
1H), 6.61 (d, J¼7.5 Hz,1H), 6.51e6.54 (m, 2H), 3.62 (br s, 2H), 2.30 (s,
mmol) as a pale brown oil. IR: nmax 3426, 3351, 3218, 3034, 2918,
1486, 1454, 1368, 1291, 1239, 1159, 1096, 1019, 748, 701, 664,
;
d
526 cmꢁ1; 1H NMR (400 MHz):
d
7.87 (dd, J¼8.3, 1.5 Hz,1H), 7.24 (m,
1H), 6.61e6.65 (m, 2H), 5.71 (br s, 2H), 4.32 (q, J¼7.1 Hz, 2H), 1.37 (t,
3H); 13C NMR (125 MHz):
d 146.3, 139.1, 129.1, 119.4, 115.9, 112.2,
J¼7.1 Hz, 3H); 13C NMR (100 MHz):
d
168.1, 150.4, 133.9, 131.1, 116.6,
21.4; MS (EI) m/z (%): 106 (Mþ, 100), 79 (14), 53 (4); HRMS (EI) calcd
116.1,111.0, 60.2,14.3; MS (EI) m/z (%): 165(Mþ, 74),119 (100), 65 (16);
for C7H9N (Mþ) 107.07350, found: 107.07377.
HRMS (EI) calcd for C9H11NO2 (Mþ) 165.07898, found 165.07955.
4.2.12. 2-Toluidine (entry 12)7a. The reaction was carried out
according to the general procedure. Et2O was used for washing the
Celite pad and phase separation instead of EtOAc. Eluent for column
chromatography, n-pentane/Et2O (4:1/2:1). 60% (32.4 mg,
4.2.6. Methyl 3-aminobenzoate (entry 6)28. Eluent for column
chromatography, n-hexane/EtOAc (5:1/4:1). 75% (57.0 mg,
377
1604, 1493, 1461, 1435, 1315, 1293, 1238, 1100, 997, 754, 681, 647,
534 cmꢁ1; 1H NMR (400 MHz):
7.42 (dd, J¼7.7,1.9 Hz,1H), 7.35 (dd,
mmol) as a pale yellow oil. IR: nmax 3467, 3378, 2952, 1711, 1622,
302
mmol) as a pale brown oil. IR: nmax 3451, 3361, 3218, 3019, 2972,
d
2913, 2857, 1619, 1584, 1495, 1467, 1442, 1302, 1268, 1143, 1064,

T. Maejima et al. / Tetrahedron 68 (2012) 1712e1722
1719
1034, 986, 927, 845, 745, 713, 535, 514, 438 cmꢁ1
;
1H NMR
J¼8.1 Hz, 1H), 7.47 (s, 1H), 7.26 (dd, J¼8.1, 8.0 Hz, 1H), 6.94 (d,
(500 MHz):
d
7.05e7.08 (m, 2H), 6.74 (dd, J¼7.5, 7.4 Hz, 2H), 6.70 (d,
J¼8.0 Hz, 1H), 4.02 (br s, 2H); 13C NMR (125 MHz):
d 149.1, 147.4,
J¼7.5 Hz, 1H), 3.54 (br s, 2H), 2.19 (s, 3H); 13C NMR (125 MHz):
129.9, 120.6, 113.1, 108.9; MS (EI) m/z (%) 138 (Mþ, 99), 108 (9), 92
(95), 65 (100), 52 (12); HRMS (EI) calcd for C6H6N2O2 (Mþ)
138.04293, found 138.04348.
d
144.5, 130.4, 126.9, 122.3, 118.6, 114.9, 17.3; MS (EI) m/z (%): 106
(Mþ, 100), 77 (13), 57 (6); HRMS (EI) calcd for C7H9N (Mþ)
107.07350, found 107.07282.
4.3. Copper-mediated reactive amination of
2-bromochalcone with TMSN3 (Scheme 2)
4.2.13. 4-Anisidine (entries 13 and 21)8b. Eluent for column chro-
matography, n-pentane/Et2O (4:1/2:1). 48% (29.7 mg, 241 mmol)
for entry 13 and 49% (30.4 mg, 247
mmol) for entry 21 as a brown
4.3.1. 2-Bromochalcone (3)29. Acetophenone (583
and 2-bromobenzaldehyde (578 L, 5.00 mmol) were added to
mL, 5.00 mmol)
solid. Mp 56e57 ꢀC; IR: nmax 3420, 3345, 3222, 3006, 2958, 2937,
m
2914, 2839, 1628, 1617, 1506,1464, 1456, 1437, 1297, 1271, 1177, 1128,
a mixture of 10% NaOH (2.5 mL) and EtOH (1.5 mL) at 0 ꢀC (ice bath).
The mixture was warmed up to room temperature over 1 h period
and stirring for 24 h. After stirring, the mixture was diluted with
EtOAc (20 mL) and H2O (20 mL). After the two layers were sepa-
rated, the aqueous layer was extracted with EtOAc (2ꢂ10 mL). The
combined organic layers were washed with brine (20 mL), dried
over MgSO4, filtered, and concentrated under reduced pressure.
The residue was purified by silica-gel column chromatography with
n-hexane/EtOAc (20:1/15:1/10:1) as the eluent to give 2-
bromochalcone in 100% yield (1.44 g, 5.00 mmol) as a yellow oil.
IR: nmax 3058, 1661, 1603, 1578, 1560, 1463, 1446, 1437, 1330, 1312,
1269, 1212, 1179, 1160, 1012, 971, 746, 716, 688, 648, 576, 536,
1029, 823, 727, 707, 670, 666, 513 cmꢁ1; 1H NMR (400 MHz):
d
6.73
(d, J¼8.7 Hz, 2H), 6.62 (d, J¼8.7 Hz, 2H), 3.73 (s, 3H), 3.36 (br s, 2H);
13C NMR (100 MHz):
d 152.5, 139.1, 126.3, 113.4, 55.6; MS (EI) m/z
(%): 123 (Mþ, 92), 108 (100), 80 (31), 65 (4), 53 (8); HRMS (EI) calcd
for C7H9NO (Mþ) 123.06842, found 123.06892.
4.2.14. 3-Anisidine (entries 14 and 22)8b. Eluent for column chro-
matography, n-hexane/EtOAc (20:1/10:1). 89% (54.9 mg,
446 mmol) for entry 14 and 70% (43.1 mg, 350 mmol) for entry 22 as
a pale orange oil. IR: nmax 3448, 3360, 3220, 3000, 2958, 2836, 1620,
1587, 1493, 1460, 1439, 1331, 1290, 1203, 1171, 1154, 1034, 992, 942,
922, 832, 760, 736, 686, 574, 523, 453 cmꢁ1
;
1H NMR (400 MHz):
440 cmꢁ1
;
1H NMR (500 MHz):
d
8.13 (d, J¼16.1 Hz, 1H), 8.01 (d,
d
7.06 (t, J¼8.0 Hz, 1H), 6.28e6.34 (m, 2H), 6.24 (s, 1H), 3.76 (s, 3H),
J¼7.5 Hz, 2H), 7.72 (d, J¼7.8 Hz, 1H), 7.62 (d, J¼8.0 Hz, 1H), 7.59 (dd,
J¼7.8, 6.9 Hz,1H), 7.50 (dd, J¼7.8, 7.5 Hz, 2H), 7.42 (d, J¼16.1 Hz,1H),
7.35 (t, J¼7.8 Hz, 1H), 7.24 (dd, J¼8.0, 6.9 Hz, 1H); 13C NMR
3.66 (br s, 2H); 13C NMR (100 MHz):
d
160.7,147.7,130.1,107.9,103.9,
101.1, 55.1; MS (EI) m/z (%): 123 (Mþ, 100), 94 (38), 80 (20), 57 (16);
HRMS (EI) calcd for C7H9NO (Mþ) 123.06842, found 123.06782.
(125 MHz): d 190.3, 143.1, 137.8, 135.0, 133.5, 132.9, 131.3, 128.6,
128.5, 127.8, 127.7, 125.8, 124.9; MS (EI) m/z (%): 286 (Mþ, 15), 207
(100), 178 (30), 130 (5), 102 (34), 77 (41), 51 (20); HRMS (EI) calcd
for C15H11BrO (Mþ) 285.99933, found 285.99988.
4.2.15. 1-Naphtylamine (entry 15)8b. Eluent for column chroma-
tography: n-hexane/EtOAc (5:1/4:1). 85% (61.0 mg, 426 mmol) as
a purple solid. Mp 52e53 ꢀC; IR: nmax 3406, 3339, 3205, 3041, 1620,
1571, 1510, 1457, 1401, 1373, 1287, 1086, 1011, 850, 788, 766, 670,
4.3.2. 2-Phenylquinoline (4)30. A mixture of copper powder
665, 565, 454, 412 cmꢁ1
;
1H NMR (500 MHz):
d
7.74e7.79 (m, 2H),
(63.5 mg, 1.00 mmol), 2-bromochalcone (131
mL, 500
mmol), 2-
7.39e7.44 (m, 2H), 7.24e7.30 (m, 2H), 6.72 (d, J¼8.0 Hz,1H), 4.05 (br
aminoethanol (74.9 L, 1.25 mmol), and TMSN3 (133
m
m
L,
s, 2H); 13C NMR (125 MHz):
d
; MS (EI) m/z (%): 143 (Mþ, 100), 115
1.00 mmol) in DMA (1 mL) in a 15 mL test tube was stirred under an
Ar atmosphere (balloon) at 95 ꢀC using a Chemistation personal
organic synthesizer (EYELA, Tokyo). After 24 h, the mixture was di-
luted with EtOAc (10 mL) and then filtered through a Celite pad. The
pad was successively washed with EtOAc (20 mL), H2O (25 mL), and
concd aq ammonia solution (5 mL). After the two layers were sep-
arated, the aqueous layer was extracted with EtOAc (2ꢂ10 mL). The
combined organic layers were washed with brine (20 mL), dried
over MgSO4, filtered, and concentrated under reduced pressure. The
residue was purified by silica-gel column chromatography with n-
hexane/EtOAc (5:1/2:1) as the eluent to give 2-phenylquinoline in
(39), 89 (5), 63 (5); HRMS (EI) calcd for C10H9N (Mþ) 143.07350,
found 143.07379.
4.2.16. 2-Naphtylamine (entry 16)7a. Eluent for column chroma-
tography: n-hexane/EtOAc (5:1/4:1). 54% (39.0 mg, 272 mmol) as
a purple solid. Mp 111e113 ꢀC; IR: nmax 3391, 3303, 3197, 3047, 1624,
1597,1508,1468,1446,1385,1362,1266,1221,1182, 1144,1121,1013,
954, 882, 853, 843, 813, 739, 705, 636, 616, 473, 425 cmꢁ1; 1H NMR
(500 MHz):
d
7.68 (d, J¼8.0 Hz, 1H), 7.63 (d, J¼8.6 Hz, 1H), 7.57 (d,
J¼8.1 Hz,1H), 7.35 (dd, J¼8.1, 6.9 Hz,1H), 7.21 (dd, J¼8.0, 6.9 Hz,1H),
6.94 (s, 1H), 6.90 (d, J¼8.6 Hz, 1H), 3.78 (br s, 2H); 13C NMR
82% yield (84.2 mg, 410 m
mol) as a yellow solid. 1H NMR (500 MHz):
(125 MHz):
d
144.0,134.8,129.1,127.9,127.7,126.3,125.7,122.4,118.2,
d
8.17e8.24 (m, 4H), 7.86 (d, J¼8.6 Hz, 1H), 7.81 (d, J¼8.1 Hz, 1H),
108.5; MS (EI) m/z (%): 143 (Mþ,100),115 (36),106 (6), 89 (6), 72 (6);
7.73e7.77 (m, 1H), 7.48e7.57 (m, 4H); mp 84e85 ꢀC; IR: nmax 3054,
HRMS (EI) calcd for C10H9N (Mþ) 143.07350, found: 143.07399.
2924, 2853,1614,1595,1552,1507,1489,1445,1422,1317,1281,1240,
1125,1049, 979, 923, 829, 769, 689, 675, 624, 612, 551, 459 cmꢁ1 13C
;
4.2.17. 3-Aminoquinoline (entry 17)7a. Eluent for column chroma-
NMR (125 MHz): d 157.2,148.2,139.6,136.6,129.6,129.5,129.2,128.7,
tography, n-hexane/EtOAc (2:1). 69% (49.5 mg, 343
mmol) as an or-
127.5, 127.4, 127.0, 126.1, 118.8; MS (EI) m/z (%): 205 (Mþ, 100), 176
(10),151 (4),102 (15), 76 (6), 51 (4); HRMS (EI) calcd for C15H11N (Mþ)
205.08915, found 205.08877.
ange solid. Mp 82e84 ꢀC; IR: nmax 3307, 3152, 2919, 2849,1641,1606,
1570, 1494, 1468, 1430, 1378, 1344, 1287, 1236, 1217, 1189, 1126, 1017,
978, 944, 916, 882, 837, 770, 742, 670, 609, 465, 421, 412 cmꢁ1 1H
;
NMR (500 MHz):
d
8.48 (d, J¼7.74e7.79 Hz) (m, 2H), 7.39e7.44 (m,
4.4. Synthesis of procaine with the reductive amination
(Scheme 3)
2H), 7.24e7.30 (m, 2H), 6.72 (d, J¼8.0 Hz,1H), 4.05 (br s, 2H); 13C NMR
(125 MHz): d
; MS (EI) m/z (%): 144 (Mþ,100),117 (20), 89 (22), 63 (9);
HRMS (EI) calcd for C9H8N2 (Mþ) 144.06875, found 144.06792.
4.4.1. 2-Diethylaminoethyl 4-bromobenzoate (7). A mixture of 4-
bromobenzoyl chloride (110 mg, 500
(79.9 L, 600 mol), N,N-dimethylaminopyridine
100 mol), and Et3N (83.2 L, 600 mol) in DMA (1 mL) in a 15 mL
test tube was stirred under an Ar atmosphere at room temperature
for 30 min and then diluted with EtOAc (20 mL) and H2O (20 mL).
After the two layers were separated, the aqueous layer was extracted
m
mol), 2-diethylaminoethanol
4.2.18. 3-Nitroaniline (entry 19)8a. Eluent for column chromatog-
m
m
(12.2 mg,
raphy, n-hexane/EtOAc (5:1/3:1). 96% (66.1 mg, 479
mmol) as
m
m
m
a yellow solid. Mp 114e115 ꢀC; IR: nmax 3426, 3323, 3199, 3076,
1619, 1507, 1482, 1344, 1322, 1306, 1262, 1089, 1063, 994, 929, 867,
815, 792, 734, 666, 539 cmꢁ1 1H NMR (500 MHz):
; d 7.56 (d,

1720
T. Maejima et al. / Tetrahedron 68 (2012) 1712e1722
with EtOAc (2ꢂ10 mL). The combined organic layers were washed
with brine (20 mL), dried over MgSO4, and concentrated under re-
duced pressure. The residue was purified by silica-gel column chro-
matography with n-hexane/EtOAc (2:1/1:1) as the eluent to give 2-
diethylaminoethyl 4-bromobenzoate in 85% yield (128 mg,
4.6. General procedure for the copper-mediated reductive
amination of aryl halides with NaN3 (Table 7)
A
mixture of CuF2 (102 mg, 1.00 mmol), the aryl halide
mol), 2-aminoethanol (74.9 L, 1.25 mmol), and NaN3
(500
m
m
427
1591, 1484, 1398, 1269, 1173, 1116, 1103, 1069, 1012, 847, 757, 683,
648 cmꢁ1 1H NMR (500 MHz):
7.90 (d, J¼8.6 Hz, 2H), 7.57 (d,
m
mol) as a pale yellow oil. IR: nmax 2971, 2935, 2874, 2815, 1715,
(65.0 mg, 1.00 mmol) in DMA (1 mL) was stirred under an Ar at-
mosphere (balloon) at 95 ꢀC using a Chemistation personal organic
synthesizer (EYELA, Tokyo). After complete consumption of the aryl
halide was confirmed by TLC analyses or after 24 h (if the reaction
was incomplete within 24 h), the mixture was diluted with EtOAc
(10 mL) and then filtered through a Celite pad. The pad was suc-
cessively washed with EtOAc (20 mL), H2O (25 mL), and concd aq
ammonia solution (5 mL). After the two layers were separated, the
aqueous layer was extracted with EtOAc (2ꢂ10 mL). The combined
organic layers were washed with brine (20 mL), dried over MgSO4,
filtered, and concentrated under reduced pressure. The residue was
purified by silica-gel column chromatography with n-hexane/
EtOAc or n-pentane/Et2O as the eluent.
;
d
J¼8.6 Hz, 2H), 4.39 (t, J¼6.3 Hz, 2H), 2.84 (t, J¼6.3 Hz, 2H), 2.63 (q,
J¼7.2 Hz, 4H), 1.06 (t, J¼7.2 Hz, 6H); 13C NMR (125 MHz):
d 165.8,
131.6,131.1,129.1,127.9, 63.6, 50.9, 47.7,12.0; MS(EI) m/z (%): 299 (Mþ,
1), 284 (2), 227 (11), 200 (1),183 (15),155 (9), 86 (100), 58 (13); HRMS
(EI) calcd for C13H18BrNO2 (Mþ) 299.05209, found 299.05181; ele-
mental analysis calcd (%) for C13H18BrNO2$0.1H2O: C 51.70, H 6.07, N
4.64, found: C 51.65, H 6.00, N 4.60.
4.4.2. Procaine (8)31. A mixture of copper powder (63.5 mg,
1.00 mmol), 2-diethylaminoethyl 4-bromobenzoate (150 mg,
500
mmol), 2-aminoethanol (74.9
mL, 1.25 mmol), and TMSN3
(133
mL, 1.00 mmol) in DMA (1 mL) in a 15 mL test tube was stirred
4.6.1. For entry 1. Yield 91% (74.8 mg, 453 mmol). The spectra data
under an Ar atmosphere (balloon) at 95 ꢀC using a Chemistation
personal organic synthesizer (EYELA, Tokyo). After 24 h, the mixture
was diluted with EtOAc (10 mL) and then filtered through a Celite
pad. The pad was successively washed with EtOAc (20 mL), H2O
(25 mL), and concd aq ammonia solution (5 mL). After the two layers
were separated, the aqueous layer was extracted with EtOAc
(2ꢂ10 mL). The combined organic layers were washed with brine
(20 mL), dried overMgSO4, filtered, and concentrated under reduced
pressure. The residue was purified by silica-gel column chroma-
tography with n-hexane/EtOAc(1:1) as the eluent to give procainein
were shown for entry 3 in Table 4.
4.6.2. For entry 2. Yield 83% (68.3 mg, 413 mmol). The spectra data
were shown for entry 4 in Table 4.
4.6.3. For entry 3. Yield 11% (9.0 mg, 54.4 mmol). The spectra data
were shown for entry 5 in Table 4.
4.6.4. 4-(Trifluoromethyl)aniline (entry 4)29. Eluent for column
chromatography, n-hexane/EtOAc (4:1/3:1). 89% (72.0 mg,
63% yield (74.1 mg, 314
nmax 3472, 3370, 3222, 2969,1693,1622,1602,1518,1440,1377,1309,
1270, 1170, 1112, 1072, 842, 771, 698, 647, 618, 505 cmꢁ1 1H NMR
(500 MHz):
7.80 (d, J¼8.6 Hz, 2H), 6.58 (d, J¼8.6 Hz, 2H), 4.30 (t,
m
mol) as a yellow solid. Mp 61e62 ꢀC; IR:
447
1318, 1184, 1156, 1098, 1060, 1010, 828, 588, 503 cmꢁ1
(400 MHz):
7.38 (d, J¼8.2 Hz, 2H), 6.67 (d, J¼8.2 Hz, 2H), 3.92 (br s,
2H); 13C NMR (100 MHz):
mmol) as a brown oil. IR: nmax 3488, 3396, 3230, 1625, 1527,
;
1H NMR
;
d
d
d
149.4, 126.7 (q, J¼4.1 Hz), 124.8 (q,
J¼6.0 Hz, 2H), 4.20 (br s, 2H), 2.80 (t, J¼6.0 Hz, 2H), 2.59 (q, J¼7.1 Hz,
J¼270.4 Hz), 120.1 (q, J¼32.8 Hz), 114.2; MS (EI) m/z (%): 161 (Mþ,
100), 142 (44), 111 (36), 65 (10); HRMS (EI) calcd for C7H6NF3 (Mþ)
161.04523, found 161.04480.
4H), 1.03 (t, J¼7.1 Hz, 6H); 13C NMR (125 MHz):
d 166.6, 151.0, 131.4,
119.3,113.6, 62.5, 50.9, 47.6,11.8; MS (EI) m/z (%): 236 (Mþ, 2), 221 (2),
164 (14), 137 (6), 120 (40), 86 (100), 65 (22); HRMS (EI) calcd for
C15H11N (Mþ) 236.15248, found 236.15017.
4.6.5. For entry 5. Yield 79% (54.3 mg, 393 mmol). The spectra data
were shown for entry 1 in Table 4.
4.6.6. For entry 6. Yield 75% (63.3 mg, 374 mmol). The spectra data
4.5. Application of azido compounds to the copper-mediated
reductive amination (Table 5)
were shown for entry 7 in Table 4.
4.6.7. For entry 7. Yield 79% (48.7 mg, 395 mmol). The spectra data
A mixture of copper powder (63.5 mg, 1.00 mmol), ethyl 4-
were shown for entry 13 in Table 4.
bromobenzoate (80.1 mL, 500 mmol), 2-aminoethanol (74.9 mL,
1.25 mmol), and the azido compound (1.00 mmol) in DMA (1 mL)
was stirred under an Ar atmosphere (balloon) at 95 ꢀC using
a Chemistation personal organic synthesizer (EYELA, Tokyo). After
24 h, the mixture was diluted with EtOAc (10 mL) and then filtered
through a Celite pad. The pad was successively washed with EtOAc
(20 mL), H2O (25 mL), and concd aq ammonia solution (5 mL). After
the two layers were separated, the aqueous layer was extracted with
EtOAc (2ꢂ10 mL). The combined organic layers were washed with
brine (20 mL), dried over MgSO4, filtered, and concentrated under
reduced pressure. The residue was purified by silica-gel column
chromatography with n-hexane/EtOAc (5:1/4:1) as the eluent.
4.6.8. For entry 8. Yield 90% (55.6 mg, 451
were shown for entry 14 in Table 4.
m
mol). The spectra data
mol). The spectra data
4.6.9. For entry 9. Yield 92% (75.8 mg, 459
were shown for entry 3 in Table 4.
m
4.6.10. For entry 10. Yield 90% (57.6 mg, 452 mmol). The spectra
data were shown for entry 9 in Table 4.
4.6.11. For entry 11. Yield 29% (20.1 mg, 146 mmol). The spectra data
were shown for entry 1 in Table 4.
4.5.1. For entry 1. Diphenylphosphoryl azide (216
was used as an azido compound. Ethyl 4-aminobenzoate was ob-
tained in 83% yield (68.2 mg, 413 mol).
m
L, 1.00 mmol)
4.7. Effect of additives on the reductive amination of ethyl 4-
bromobenzoate (Table 8)
m
A mixture of copper powder (63.5 mg, 1.00 mmol), ethyl 4-
4.5.2. For entry 2. Sodium azide (65.0 mg, 1.00 mmol) was used as
an azido compound. Ethyl 4-aminobenzoate was obtained in 5%
yield (4.1 mg, 25 mmol).
bromobenzoate (80.1
TMSN3 (133 L, 1.00 mmol) in DMA (1 mL) was stirred under an Ar
atmosphere (balloon) at 95 ꢀC using a Chemistation personal
mL, 500 mmol), the additive (1.25 mmol), and
m

T. Maejima et al. / Tetrahedron 68 (2012) 1712e1722
1721
organic synthesizer (EYELA, Tokyo). After 24 h, the mixture was
dissolved in DMA (1 mL); (c) ethyl 4-bromobenzoate (80.1
500 mol) and 2-aminoethanol (74.9 L, 1.25 mmol) were dis-
solved in DMA (1 mL); (d) A mixture of copper powder (63.5 mg,
1.00 mmol), ethyl 4-bromobenzoate (80.1 L, 500 mol), 2-
aminoethanol (74.9 L, 1.25 mmol), and TMSN3 (133 L,
mL,
diluted with EtOAc (10 mL) and then filtered through a Celite pad.
The pad was successively washed with EtOAc (20 mL), H2O (25 mL),
and concd aq ammonia solution (5 mL). After the two layers were
separated, the aqueous layer was extracted with EtOAc (2ꢂ10 mL).
The combined organic layers were washed with brine (20 mL),
dried over MgSO4, filtered, and concentrated under reduced pres-
sure. The residue was dissolved in CDCl3, and the yield was de-
termined by the 1H NMR analysis in the presence of 1,4-dioxane
m
m
m
m
m
m
1.00 mmol) in DMA (1 mL) was stirred under an Ar atmosphere
(balloon) at 95 ꢀC using a Chemistation personal organic synthe-
sizer (EYELA, Tokyo). After 30 min, the mixture (ca. 50 mL) was
sampled and used for the IR measurement; (e) A mixture of
copper powder (63.5 mg, 1.00 mmol), ethyl 4-bromobenzoate
(8.48 mL, 100 mmol) as the internal standard.
(80.1
TMSN3 (133
atmosphere (balloon) at 95 ꢀC using a Chemistation personal or-
ganic synthesizer (EYELA, Tokyo). After 6 h, the mixture (ca. 50 L)
m
L, 500
m
mol), 2-aminoethanol (74.9
mL, 1.25 mmol), and
4.7.1. For entry 1. The reaction was carried out using 2-
aminoethanol (74.9 L, 1.25 mmol) as an additive in DMA (1 mL).
mL, 1.00 mmol) in DMA (1 mL) was stirred under an Ar
m
m
4.7.2. For entry 2. The reaction was carried out in DMA (1 mL)
without additives.
was sampled and used for the IR measurement; (f) A mixture of
copper powder (63.5 mg, 1.00 mmol), ethyl 4-bromobenzoate
(80.1
mL, 500 mmol), 2-aminoethanol (74.9 mL, 1.25 mmol), and
4.7.3. For entry 3. The reaction was carried out using 2-
TMSN3 (133 mL, 1.00 mmol) in DMA (1 mL) was stirred under an Ar
aminoethanol (74.9
mL, 1.25 mmol) as an additive without DMA.
atmosphere (balloon) at 95 ꢀC using a Chemistation personal or-
ganic synthesizer (EYELA, Tokyo). After 6 h, the mixture was
cooled to room temperature and ethyl 4-azidobenzoate (65.9 mg,
4.7.4. For entry 4. The reaction of ethyl 4-bromobenzoate (16.0
100 mol) and TMSN3 (26.5 L, 200 mol) with copper powder
(12.7 mg, 200 mol) was carried out using O-TBDPS-2-
mL,
m
m
m
500
used for the IR measurement; (g) ethyl 4-azidobenzoate (65.9 mg,
500 mol) and 2-aminoethanol (74.9 L, 1.25 mmol) was used; (h)
ethyl 4-bromobenzoate (82.6 mg, 500 mol) and 2-aminoethanol
(74.9 L, 1.25 mmol) was used.
mmol) was added. The mixture (ca. 50 mL) was sampled and
m
dimethylaminoethanol (89.0
(1 mL).
mL, 250
mmol) as an additive in DMA
m
m
m
m
4.7.5. For entry 5. The reaction of ethyl 4-bromobenzoate (16.0
100 mol) and TMSN3 (26.5 L, 200 mol) with copper powder
(12.7 mg, 200 mol) was carried out using O-TBDPS-2-
mL,
m
m
m
m
4.10. Reductive amination of ethyl 4-bromobenzoate or
4-bromoanisole using catalytic amount of copper powder
(Table 10)
dimethylaminoethanol (89.0
DMA.
mL, 250 mmol) as an additive without
4.7.6. For entry 6. The reaction was carried out using 2-
aminoethanol (74.9 L, 1.25 mmol) and 7,7,8,8-
tetracyanoquinodimethane (TCNQ) (102.1 mg, 500 mol) or tetra-
mol) as the additives in DMA
A mixture of copper powder (63.5 mg, 1.00 mmol for entries 1
m
and 8; 31.8 mg, 500
3; 12.7 mg, 200 mol for entry 4; 9.5 mg, 150
6.4 mg, 100 mol for entry 6; 3.2 mg, 50.0 mol for entries 7 and
9), aryl bromides [ethyl 4-bromobenzoate (80.1 L, 500 mol) or
4-bromoanisole (62.3 L, 500 mol)], 2-aminoethanol (74.9 L,
1.25 mmol), and TMSN3 (133 L, 1.00 mmol) in DMA (1 mL) was
mmol for entry 2; 15.9 mg, 250
mmol for entry
m
m
m
mol for entry 5;
cyanoethylene (TCNE) (64.0 mg, 500
(1 mL).
m
m
m
m
m
m
m
m
4.8. The reduction of ethyl 4-azidobenzoate (Table 9, entry 1)
m
stirred under an Ar atmosphere (balloon) at 95 ꢀC using a Chem-
istation personal organic synthesizer (EYELA, Tokyo). After 24 h,
the mixture was diluted with EtOAc (10 mL) and then filtered
through a Celite pad. The pad was successively washed with EtOAc
(20 mL), H2O (25 mL), and concd aq ammonia solution (5 mL).
After the two layers were separated, the aqueous layer was
extracted with EtOAc (2ꢂ10 mL). The combined organic layers
were washed with brine (20 mL), dried over MgSO4, filtered, and
concentrated under reduced pressure. The residue was dissolved
in CDCl3, and the yield was determined by the 1H NMR analysis in
A mixture of copper powder (63.5 mg, 1.00 mmol), ethyl 4-
azidobenzoate (65.9 mg, 500 mmol), and 2-aminoethanol (74.9 mL,
1.25 mmol) in DMA (1 mL) was stirred under an Ar atmosphere
(balloon) at 95 ꢀC using a Chemistation personal organic synthe-
sizer (EYELA, Tokyo). After 24 h, the mixture was diluted with
EtOAc (10 mL) and then filtered through a Celite pad. The pad was
successively washed with EtOAc (20 mL), H2O (25 mL), and concd
aq ammonia solution (5 mL). After the two layers were separated,
the aqueous layer was extracted with EtOAc (2ꢂ10 mL). The com-
bined organic layers were washed with brine (20 mL), dried over
MgSO4, filtered, and concentrated under reduced pressure. The
residue was dissolved in CDCl3, and the yield was determined by
the presence of 1,4-dioxane (8.48
standard.
mL, 100 mmol) as the internal
the 1H NMR analysis in the presence of 1,4-dioxane (8.48
100 mol) as the internal standard.
mL,
m
Acknowledgements
4.8.1. For entry 2. The reaction was carried out without copper
powder.
T.M. acknowledges the financial support of the Sasakawa Sci-
entific Research Grant from the Japan Science Society. We sincerely
thank Toyobo Co., Ltd., for the kind gift of TMSN3. We also thank Dr.
Tomohiro Maegawa at the Graduate School of Pharmaceutical Sci-
ences, Osaka University, for the thoughtful discussion.
4.8.2. For entry 3. The reaction was carried out without 2-
aminoethanol.
4.9. IR measurement in DMA (Fig. 1)
Supplementary data
The samples were prepared as follows; (a) TMSN3 (133
1.00 mmol) was dissolved in DMA (1 mL); (b) TMSN3 (133
1.00 mmol) and 2-aminoethanol (74.9 mL, 1.25 mmol) was
m
m
L,
L,
Supplementary data related to this article can be found online at
doi:10.1016/j.tet.2011.12.058.

1722
T. Maejima et al. / Tetrahedron 68 (2012) 1712e1722
12. Syntheses of arylazides between arylhalides and azide compounds with
References and notes
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€
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24. Sekar18 and Alami17 proposed a reaction mechanism involving the formation of
aryl azide by the following temperature-dependent reaction experiments. Se-
kar et al. reported that 4-azidoanisole was obtained in 68% yield, when
€
C.; Enthaler, S.; Schaffer, B.; Dumrath, A.; Spannenberg, A.; Neumann, H.;
€
Borner, A.; Beller, M. Chem.dEur. J. 2009, 15, 4528e4533.
8. (a) Kim, J.; Chang, S. Chem. Commun. 2008, 3052e3054; (b) Xia, N.; Taillefer, M.
Angew. Chem., Int. Ed. 2009, 48, 337e339; (c) Jiang, L.; Lu, X.; Zhang, H.; Jiang, Y.;
Ma, D. J. Org. Chem. 2009, 74, 4542e4546; (d) Xu, H.; Wolf, C. Chem. Commun.
2009, 3035e3037.
4-iodoanisole was treated with NaN3 at 90 ꢀC in the presence of CuI,
D
-glu-
cosamine, KI, and KOH in H2O/DMF (1:1). The azide could be reduced to cor-
responding 4-aminoanisole by further treatment with CuI, -glucosamine,
D
KOH, and KI in H2O/DMF (1:1) at higher temperature (120 ꢀC).18 Meanwhile,
Alami et al. could not directly detect the intermediary aryl azide in the ami-
nation of an aryl bromide using NaN3, CuI, pipecolinic acid (ligand), and as-
corbic acid in EtOH at 100 ꢀC. The possible azide intermediate was not even
trapped as the triazole in the presence of 4-ethynylanisole under the above-
mentioned reaction conditions. When an alternatively synthesized aryl azide
was used as the starting material instead of the aryl bromide, Huisgen cycli-
zation took place in the presence of the alkyne at lower temperature 40 ꢀC
under the above reaction conditions to give the corresponding triazole, while
the corresponding arylamine was obtained at higher temperature (100 ꢀC) by
the removal of N2 before the reaction with alkyne.17
9. (a) Sajiki, H.; Kurita, T.; Kozaki, A.; Zhang, G.; Kitamura, Y.; Maegawa, T.; Hirota,
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25. The formation of arylazides was never observed during the present amination
of halobenzenes using NaN3 (Tables 5e7). It suggested that the reaction would
proceed in
arylazides).
a manner similar to that using TMSN3 (not via intermediary
26. Hou, J.; Ma, Y.; Li, Y.; Guo, F.; Lu, L. Chem. Lett. 2008, 37, 974e975.
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