Selective copper-promoted cross-coupling reaction of anilines and alkylboranes

Article abstract of DOI:10.1016/j.tetlet.2011.11.144

Extension of the Chan-Lam N-alkylation of anilines by using alkylboranes as organoboron partners is reported. Alkylboranes, synthesized by hydroboration of styrenes, are effectively coupled with anilines, which comprises a facile method for the synthesis

Full text of DOI:10.1016/j.tetlet.2011.11.144

Tetrahedron Letters 53 (2012) 769–772
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Selective copper-promoted cross-coupling reaction of anilines and alkylboranes
⇑
Leticia Naya, Marta Larrosa, Ramón Rodríguez, Jacobo Cruces
Galchimia, S.L. R&D Department, Cebreiro s/n 15823 O Pino, A Coruña, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Extension of the Chan–Lam N-alkylation of anilines by using alkylboranes as organoboron partners is
reported. Alkylboranes, synthesized by hydroboration of styrenes, are effectively coupled with anilines,
which comprises a facile method for the synthesis of highly functionalized phenethylaniline derivatives.
This is the first time that alkylboranes are used in C–N copper-promoted cross-coupling reactions.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 13 September 2011
Revised 29 November 2011
Accepted 30 November 2011
Available online 9 December 2011
Keywords:
Chan–Lam
Copper
Boranes
Phenylethylamine
Aromatic amines are ubiquitous compounds used in pharma-
ceuticals, crop-protection chemicals, and material science.1 Hence,
the development of new methods for their synthesis is still an ac-
tive area of research.
with the exception of cyclopropylboron derivatives due to the sig-
nificant sp2-character of the carbon atoms.7 Cyclopropyl boronic
acid has been successfully coupled with a range of different NH
containing substrates (most of them being compounds with in-
creased NH acidity like amides and indoles).8
Transition metal-catalyzed cross-coupling reactions are well
established for C–N bond formation.2 In the last decade, Buchwald
and Hartwig have pioneered palladium-catalyzed cross-coupling
reactions of amines with aryl halides, triflates, and tosylates.3
Copper-promoted or catalyzed carbon–nitrogen bond forming
reactions are a useful complement to palladium chemistry, due
to the high stability, low toxicity, and low cost of the copper re-
agents. Among these, the coupling with boronic acids has emerged
as a powerful synthetic method since the initial reports by Chan,
Lam, and Evans.4 This methodology, as compared to classical Ull-
mann reaction or Pd-catalyzed transformations has several advan-
tages: use of very mild reaction conditions, weak base, and that
reactions can be performed in the presence of air. The scope of
the reaction has been extended to NH containing nucleophiles such
as amines, amides, imides, ureas, hydrazines, carbamates, and dif-
ferent classes of aromatic heterocycles (imidazole, pyrazole, indole,
and others). Catalytic versions of several of these processes have
also been reported.5
Even so, we have recently developed a simple copper-promoted
N-monoalkylation of anilines which relies on the use of alkylbo-
ronic acids as the alkylating partner.9 During the last decade, ef-
forts have been expended toward further development of the
most important component of the process, the organoboron itself.
Several types of organoboron reagents have been employed in
Chan–Lam coupling, such as boronic acids, boronate esters,
organotrifluoroborates, boroxines, and aryltriolborates.10 Our
interest in copper-promoted cross-coupling reactions prompted
us to consider the possibility of further expanding the toolbox of
boron reagents by using alkylboranes. Despite the fact that they
have been extensively employed in the Suzuki reaction11 there
are no examples where alkylboranes are involved in C–N cross-
coupling bond forming reactions. We realized that if they could
act as an effective partner in Chan–Lam coupling reactions, N-
alkylation of anilines could be carried out by the use of alkylbor-
anes, which can be synthesized in a highly regioselective manner
by means of the hydroboration of the corresponding olefin.12
In this Letter, we describe the results of our effort aimed at
exploring and developing a novel copper-promoted reaction based
on the use of alkylboranes as organoboron partner. We focused on
the synthesis of phenethylanilines, as these are interesting targets
due to their biological properties but difficult to prepare by direct
alkylation.13
Although tremendous progress has been made in recent years
in the development of effective methods for copper-mediated
cross-couplings of aryl and alkenyl organoboron compounds,6
comparable success has not yet been achieved for alkyl organobo-
ron reagents. Alkyl boronic acids rarely act as effective reagents be-
cause of their low reactivity toward transmetallation with Cu salts,
In previous work we found that optimal reaction conditions for
the coupling between anilines and alkyl boronic acids were the use
of Cu(OAc)2 as the copper source and pyridine as the base in reflux-
⇑
Corresponding author.
E-mail address: jacobo.cruces@galchimia.com (J. Cruces).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.11.144

770
L. Naya et al. / Tetrahedron Letters 53 (2012) 769–772
NH2
H
Cu(OAc)2
py
N
R2B
+
dioxane
reflux, 3-4 h
OtBu
OtBu
3a
hydroboration
1a
OtBu
2a
Scheme 1. Preparation of phenethylamine 3a from aniline 1a and styrene 2a.
ing dioxane, in air-opened reaction flask.9 Under these conditions,
full conversion is achieved in several hours, affording only mono-
alkylated anilines. We decided to apply the same reaction condi-
tions to the coupling of alkylboranes.
We tested the minimal amount of alkylborane that was needed
to achieve full conversion. It was found that aniline was consumed
to furnish coupling product using as low as 0.4 equiv of trialkylbo-
rane (Table 1, entry 3). A twofold raise in yield was achieved by
using 1.1 equiv of trialkylborane (Table 1, entry 5), whereas larger
excess of boron reagent did not result in any yield improvement.
As in other Chan–Lam reactions, the use of some excess of boron
reagent is necessary to avoid competitive side reactions, so we
decided to use 1.1 equiv of trialkylborane in next experiments.16
Trialkylboranes proved to be more reactive than analogous alkyl
BBN reagents or alkyl boronic acids. While the latter reacted only
at high temperature, moderate conversion was observed when tri-
alkyl borane was allowed to react at rt (Table 1, entry 6).
Alkylboranes are not air-stable and so they are usually difficult
to isolate, purify and handle.14 Thus, they were prepared in situ via
hydroboration of appropriate styrenes and used without isolation
or purification. Our research was started by exploring the reaction
of 4-tert-butylaniline (1a) with 4-tert-butoxy styrene (2a) (Scheme
1, Table 1). We used 9-BBN at the beginning as the boron source,
and hydroboration of styrene 2a proceeded smoothly at room tem-
perature. The coupling reaction was performed under conditions
similar to those previously reported: 2.5 equiv of Cu(OAc)2 and
3 equiv of pyridine in dioxane. No reaction took place at rt, even
when 4 equiv of alkyl BBN reagent were used, but it proceeded
to completion after 4 h at reflux, (Table 1, entries 1 and 2). Never-
theless, purification was quite tedious due to the presence of
byproducts from BBN, and yield of pure product was only
moderate.
Several control experiments were carried out to confirm that
copper was promoting the cross-coupling between trialkylborane
and aniline. Coupling product was not formed in the absence of
Cu(OAc)2, although aniline was totally consumed to furnish the
corresponding azobenzene. No product was detected when all
The reaction was regioselective, furnishing the product with the
nitrogen attached to terminal carbon of the styrene, arising from
addition of boron to the less hindered carbon of the olefin. Besides
that, although dialkylated compounds can be formed under forced
reaction conditions (large excess of reagents and long reaction
times), only monoalkylated product was detected.
This result, although not useful from a synthetic point of view,
demonstrated that alkyl boranes were viable reagents in copper-
promoted C–N cross-coupling reactions. We decided to use
BH3ÁTHF complex for the preparation of the alkylborane reagent.
Unlike BBN, when olefins are reacted with BH3 the outcome is
the formation of a trialkylborane (R3B).15
Table 2
Aniline and styrene electronic properties influencea
Entry
1
Aniline
Styrene
Yieldb (%)
86
NH2
OtBu
Cl
1a
2a
Cl
2
1a
90
2b
2c
When the coupling was carried out with trialkylboranes reac-
tions were quite clean, and full conversion was achieved within
3 h. Furthermore, pure samples were obtained after flash chroma-
tography purification.
3
4
1a
89
Table 1
MeO
NH2
Screening of alkylboranes for the coupling between 4-t-butylaniline and 4-t-
2a
68c
butoxystyrenea
1b
Entry
Borane
Equiv
Yieldb (%)
5
6
1b
1b
2b
2c
71d
90
c
1
R-BBN
R-BBN
R3B
R3B
R3B
4
4
0
2
3
4
5
6
7
35
47
73
86
26
0
Cl
NH2
0.4
0.8
1.1
1.1
1.1
7
2a
62
1c
c
R3B
R3B
8
9
1c
1c
2b
2c
47
75
d
a
a
Reagents and conditions: a mixture of borane, 1 mmol of 4-t-butylaniline (1a),
Typical procedure: 1 mmol of aniline (1), 1.1 mmol of trialkylborane, 2.5 mmol
2.5 mmol of Cu(OAc)2 and 3 mmol of pyridine in dioxane (15 mL) was reacted at
reflux.
of Cu(OAc)2 and 3 mmol of pyridine in dioxane (15 mL) were refluxed until aniline
was consumed or for a maximum time of 16 h.
b
b
Isolated yields.
Reaction was run at rt.
Isolated yields.
A 5% of dialkylated compound was detected by LC–MS.
c
c
d
d
Alkylborane was not preformed.
A 7% of dialkylated compound was detected by LC–MS.

L. Naya et al. / Tetrahedron Letters 53 (2012) 769–772
771
the reagents, aniline, copper reagent, styrene, BH3ÁTHF and pyri-
dine were mixed together and refluxed (Table 1, entry 7). As it
should be expected, it is necessary to prepare the alkylborane be-
fore its addition to the reaction mixture. The order of addition of
reagents was important to optimize conversions: slightly higher
yields were obtained when aniline and copper were incubated at
rt for an induction period (10–15 min) before the addition of the
alkylborane.
With the optimal reaction conditions in hand, a broader study
was undertaken. As seen in the previous work, electronic proper-
ties of substrates could dramatically influence the reaction out-
come; thus we decided to test the reaction over three anilines
(4-tert-butyl-, 4-methoxy- and 4-chloroaniline) against alkylbor-
anes derived from three different styrenes (4-tert-butoxy, 4-
methyl and 3,4-dichloro styrene) ranging both partners from elec-
tron rich to electron poor. This exploratory study provided the re-
sults displayed in Table 2.
It was noticed that there is a relationship between the elec-
tronic properties of anilines and their reaction rate: reactions are
faster for electron rich anilines (completed in 1–2 h), and slower
for electron poor ones, which require for longer reaction times
(up to 6 h). However, the yield is similar for electron rich and neu-
tral anilines, and slightly lower for electron deficient substrates.
In some cases, yield was lower with p-anisidine due to the for-
mation of some dialkylated product. It is likely that yields could be
increased by adjusting the general reaction conditions to each type
of substrate.
To study the scope and limitations of our conditions, we further
evaluated the cross-coupling of different trialkylboranes with ani-
lines (Table 3).
The reaction tolerates a variety of functional groups in both ani-
line and styrene fragments, including ester, ketones, alkylether,
thioether, and halides (chlorine and bromine). Chemoselective
coupling of bromoderivatives (entries 7, 10, 16, and 19) is particu-
larly interesting for several reasons. First, it reveals that the N cou-
pling process is favorable over possible C Suzuki or Ullmann type
reactions. Second, this selectivity allows further functionalization
of the product, since the product still bears a bromine atom which
is helpful for additional modifications.
Using the standard protocol, moderate to excellent yields were
obtained for all combinations, except in the reaction of 4-chloroan-
iline with dichlorostyrene, where full conversion was not achieved
even after extending reaction time to 16 h.
Table 3
Scope and limitations of copper-promoted alkylation of anilines with trialkylboranesa
Entry Product
Yieldb
(%)
Entry Product
Yieldb
(%)
Entry Product
Yieldb
(%)
H
N
H
N
H
N
Cl
Cl
Cl
1
26
61
60
62
52
68
50
8
82
51
47
80
50
48
77
15
59
60
76
69
56
CO2Me
Me
Me
MeO
3p
3q
Me
3b
3i
H
N
H
N
H
N
Cl
Cl
2
3
9
16
OMe
MeO
Br
Cl
OMe
3c
3j
H
N
H
N
H
N
Cl
Cl
10
17
Me
Me
MeO
3r
Br
3d
3k
H
N
H
N
H
N
Cl
Cl
4
11
18
Me
Me
MeO
3l
3s
Me
3e
H
N
H
H
N
Cl
Cl
N
Cl
Cl
5
12
19
MeS
Cl
Br
3m
3t
OMe
3f
H
N
H
N
Cl
Cl
6
13
OtBu
OtBu
OMe
O
3g
3n
H
N
H
N
7
14
Me
OtBu
3o
Br
3h
a
Typical procedure: 1 mmol of aniline (1), 1.1 mmol of trialkylborane, 2.5 mmol of Cu(OAc)2 and 3 mmol of pyridine in dioxane (15 mL) were allowed to react at reflux for
1–6 h.
b
Isolated yield.

772
L. Naya et al. / Tetrahedron Letters 53 (2012) 769–772
4. (a) Chan, D. M. T.; Monaco, K. L.; Wang, R.-P.; Winters, M. P. Tetrahedron Lett.
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containing a thioether moiety (entry 12) that proved problematic
in other cross-coupling reactions. Aniline bearing carbonyl groups
were also transformed to the desired products, in moderate yields
for acetyl moiety (entry 13), and low yields for methyl ester (entry
1), although in the last example it can be caused by the location of
the methoxycarbonyl group in ortho position to the amino group.
To summarize, we have developed conditions for a copper-pro-
moted cross-coupling of anilines with trialkylboranes. This new
transformation expands the utility of copper-promoted coupling
reaction to a new type of reagents, not reported before, and com-
plements the use of boronic acid derivatives in the Chan–Lam cou-
pling methodology. The fact that alkyl borane reagents are easily
synthesized in a highly regioselective manner by means of the hyd-
roboration of the corresponding styrenes makes cross-coupling
chemistry using these reagents highly attractive. Efforts to expand
the utility of this reaction for the formal amination of alkenes are
ongoing in our laboratory.
10. (a) Collman, J. P.; Zhong, M. Org. Lett. 2000, 2, 1233–1236; (b) Jouvin, K.;
County, F.; Evano, G. Org. Lett. 2010, 12, 3272–3275; For coupling reactions of
trifluoroborates, see: (c) Quach, T. D.; Batey, R. A. Org. Lett. 2003, 5, 1381–1384;
(d) Quach, T. D.; Batey, R. A. Org. Lett. 2003, 5, 4397–4400; (e) Bolshan, Y.;
Batey, R. A. Angew. Chem., Int. Ed. 2008, 47, 2109–2112; For coupling reactions
of boroxines, see: (f) Zheng, Z.; Wen, J.; Wang, N.; Wu, B.; Yu, X. Beilstein J. Org.
Chem. 2008, 4, 40–46; For coupling reactions of triolborates, see: (g)
Yamamoto, Y.; Takizawa, M.; Yu, X.; Miyaura, N. Angew. Chem., Int. Ed. 2008,
47, 928–931; (h) Yu, X.; Yamamoto, Y.; Miyaura, N. Chem. Asian J. 2008, 3,
1517–1522.
Acknowledgment
We thank the Xunta de Galicia for financing this work through
the INCITE project call (code 10CSA021E).
Supplementary data
11. For reviews see: (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457–2483; (b)
Suzuki, A. In Metal-Catalyzed Cross-Coupling Reactions; Diederich, F., Stang, P. J.,
Eds.; VCH: Weinheim, Germany, 1998; pp 49–97.
12. Miyaura, N.; Ishiyama, T.; Sasaki, H.; Ishikawa, M.; Satoh, M.; Suzuki, A. J. Am.
Chem. Soc. 1989, 111, 314–321.
Supplementary data (experimental procedures, analytical
instrumentation and data) associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2011.11.144.
13. Patrick, G. L. An Introduction to Medicinal Chemistry, Second ed.; Oxford
University Press: Oxford, 2001; For recent synthesis of phenethylamines, see:
(a) Heutling, A.; Pohlki, F.; Bytschkov, I.; Doye, S. Angew. Chem., Int. Ed. 2005, 44,
2951–3954; (b) Hamid, M. H. S. A.; Williams, J. M. J. Chem. Commun. 2007, 725–
727; (c) Munro-Leighton, C.; Delp, S. A.; Alsop, N. M.; Blue, E. D.; Gunnoe, T. B.
Chem. Commun. 2008, 111–113; (d) Iranpoor, N.; Firouzabadi, H.; Nowrouzi, N.;
Khalili, D. Tetrahedron 2009, 65, 3893–3899.
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Wiley-Interscience: New York, 2002; (b) Miyaura, N. Cross-Coupling. Reactions:
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9633–9695.
15. Brown, H. C.; Tsukamoto, A.; Bigley, D. B. J. Am. Chem. Soc. 1960, 82, 4703–4707.
16. General procedure for the preparation of N-alkylboranes 3: A dioxane solution
of trialkylborane was prepared via hydroboration of styrene with BH3ÁTHF
complex (0.4 equiv) in dioxane at rt for 3 h. In a separate vessel, copper(II)
acetate (454 mg, 2.5 mmol) was added to a solution of aniline (1.0 mmol) and
pyridine (238 mg, 3 mmol) in dioxane (15 mL). The mixture was stirred for
15 min, and the trialkylborane solution in dioxane (1.1 mmol) was added. The
reaction mixture was refluxed until aniline was totally consumed (TLC
analysis, 3–4 h). The reaction mixture was allowed to reach rt, poured into
NH4Cl (60 mL, saturated aqueous solution), and extracted with CH2Cl2 (60 mL).
The organic layer was dried over Na2SO4 (anhydrous), filtered, and
concentrated. The crude residue was purified by flash chromatography on
SiO2 (0?50% EtOAc/hexanes) to afford the N-alkylaniline as colorless oil.
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