A Simple Cobalt(II) Chloride Catalyzed N -Alkylation of Amines with Alcohols

Article abstract of DOI:10.1055/s-0036-1589064

A facile cobalt-catalyzed N -alkylation of amines with alcohols using inexpensive, commercially available CoCl ₂ ·6H ₂ O is reported. Employing this readily available cobalt catalyst, a variety of amines with wide functional group tolerance were selectively alkylated under benign conditions.

Full text of DOI:10.1055/s-0036-1589064

SYNTHESIS
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©
Georg Thieme Verlag Stuttgart · New York
2017, 49, A–E
special topic
A
en
Synthesis
S. P. Midya et al.
Special Topic
A Simple Cobalt(II) Chloride Catalyzed N-Alkylation of Amines
with Alcohols
Siba P. Midyaa,b
Akash Mondala,b
Ayesha Beguma
Ekambaram Balaraman*a,b
H
N
NH2
CoCl2·6H2O/PPh3
Base
R1
R
+
R1
OH
R
Readily
available
18 examples
1–73% yield
0
0
0
0
0-
0
0
1
9-
2
4
8
2-
8
0
9
4
*
Simple & Efficient
R = H, F, Cl, Br, Me, OMe, SMe
R1 = Alkyl, Aryl, Heteroaryl
a
* Practical conditions
Broad substrate scope
* Functional group tolerance
Catalysis Division, Dr. Homi Bhabha Road, CSIR-National
Chemical Laboratory (CSIR-NCL), Pune 411008, India
Academy of Scientific and Innovative Research (AcSIR),
New Delhi 110025, India
*
b
eb.raman@ncl.res.in
Dedicated to Professor David Milstein on the occasion of his
th
70
birthday
Published as part of the Special Topic Cobalt in Organic Synthesis
Received: 12.04.2017
Accepted after revision: 30.05.2017
Published online: 11.07.2017
In the final step, the imine intermediate undergoes in situ
hydrogenation with the hydrogen equivalent liberated in
the alcohol oxidation step to afford the N-alkylated amine
DOI: 10.1055/s-0036-1589064; Art ID: ss-2017-c0248-st
(
Scheme 1). This overall hydrogen autotransfer is hydrogen
Abstract A facile cobalt-catalyzed N-alkylation of amines with alcohols
neutral, and water is liberated as a stoichiometric byprod-
uct, which makes the process green and environmentally
benign.
using inexpensive, commercially available CoCl ·6H O is reported. Em-
2
2
ploying this readily available cobalt catalyst, a variety of amines with
wide functional group tolerance were selectively alkylated under benign
conditions.
R1
R
OH
M
R
N
Key words cobalt catalysis, N-alkylation, amines, alcohols, hydrogen
H
autotransfer, dehydrogenation
H2
H2
Hydrogenation
Dehydrogenation
MH
Amines constitute an important class of molecules in
both chemical industry and synthetic biology. In particular,
secondary amines are highly versatile building blocks for
various synthetic targets and are essential pharmacophores
in numerous biologically active compounds. They have
been used as dyes, electrolytes, agricultural chemicals,
H
H
R1
N
Condensation
R
O
R
R1 NH2
H2O
Scheme 1 General overview of the N-alkylation of amines with alco-
hols
1,2
polymers, and functionalized materials. Owing to these
extensive applications, the synthesis of secondary amines
has long been of immense importance in contemporary sci-
ence. Although traditional methods for secondary amine
preparation, including N-alkylation using alkyl halides,
amide reduction, or reductive amination, are fairly reliable,
associated over-alkylation resulting in the formation of un-
desired ammonium halides and/or tertiary amines as by-
products often reduces the application of these procedures.
Recently, transition-metal-catalyzed N-alkylation of amines
using readily available alcohols, generating no inorganic
waste, has emerged as a highly desirable and superior strat-
egy owing to its environmentally benign and atom-eco-
To date, various catalysts based on precious metals, in-
4
5
6
cluding ruthenium, rhodium, and iridium, have been in-
tensively studied for the N-alkylation of amines with alco-
hols. However, the design of new catalytic systems that op-
erate under mild conditions using the naturally more
abundant, and inexpensive, first-row transition metals for
similar or better reactivity in N-alkylation reactions, while
very much in demand, has been rarely reported.7 In recent
times, significant efforts have been made towards the de-
velopment of homogeneous cobalt catalysts for the N-al-
kylation of amines with alcohols. Kempe and co-workers
reported the first cobalt-catalyzed alkylation of amines by
–9
2
a,c,3
nomic pathway.
In this strategy, alcohol is first oxidized
using a triazine-backbone-based cobalt(II)–PNP pincer
8a
to the corresponding carbonyl compound via an acceptor-
less dehydrogenation pathway. Then, the carbonyl com-
pound undergoes condensation with a free amine to give an
imine intermediate with the formation of a water molecule.
complex (Scheme 2). Subsequently, the research group of
Zheng8b and Zhang reported an ionic cobalt(II) alkyl com-
8c
Cy
F
plex [(PNHP )Co(CH SiMe )][BAr ] catalyzed selective al-
2
3
4
kylation of anilines using alcohols and amines as alkylating
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–E

B
Synthesis
S. P. Midya et al.
Special Topic
R1
cat. [Co]
Previous work
CoCl2·6H2O/PPh3
R1
R
N
H
R
OH + H2N
R1
R
N
This work
H
*
Simple & Efficient
cat. [Co]
* Practical conditions
*
*
Broad substrate scope
Functional group tolerance
NH
H
+
BArF –
4
N
N
N
N
N
Cy2P
Co
PCy2
HN
i-Pr)2P
N
NH
(i-Pr) P
Co
Cl
P(i-Pr)2
2
CH2SiMe3
(
Co
P(i-Pr)2
Cl
Cl
Scheme 2 Cobalt-catalyzed N-alkylation of amines with alcohols8a–d
agents, respectively. Of late, Kirchner and co-workers re-
ported the N-alkylation of amines catalyzed by well-de-
fined cobalt(II) complexes which are stabilized by an anion-
ic PCP ligand (N,N′-bis(diisopropylphosphino)-N,N′-dimeth-
yl-1,3-diaminobenzene) based on the 1,3-diaminobenzene
ture was an important factor for the highest yield of 3a (en-
try 13). Analysis of the gas phase by gas chromatography
(GC) revealed the formation of dihydrogen.
Table 1 Screening of the Reaction Conditionsa
8d
scaffold. Importantly, compared with the previous reports
in which the ligands and complexes were synthesized in
multiple steps, we describe herein the efficient alkylation
of aromatic amines with alcohols catalyzed by the simple,
commercially available CoCl ·6H O and triphenylphosphine
cat. [Co]/L
NH2
OH
t-BuOK
N
H
+
Solvent, Δ
1a
2a
3a
2
2
as a ligand. Employing this readily available cobalt catalyst,
a variety of amines with wide functional group tolerance
were selectively alkylated with alcohols in moderate to ex-
cellent yields (Scheme 2).
Entry
Catalyst
Ligand (L) Solvent
Temp (°C) Yield (%)
b
1
2
CoCl
2
2
PPh
PPh
PPh
3
3
3
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
octane
THF
100
100
100
100
100
100
100
100
100
100
100
100
130
110
40
CoCl
·6H
2
O
55
We began our N-alkylation of aromatic amines via the
hydrogen autotransfer strategy with an evaluation of a
range of cobalt salts, ligands, bases, and solvents in the
presence of aniline (1a) and benzyl alcohol (2a) as bench-
mark substrates (Table 1). We found that the use of triphen-
ylphosphine as a ligand in the presence of catalytic
amounts of CoCl ·6H O enabled the desired N-alkylation,
3
Co(OAc)
2
16
4
CoC O
2
4
PPh3
PPh
23
5
Co(acac)
3
3
trace
31
6
CoCl
CoCl
CoCl
CoCl
2
2
2
2
·6H
·6H
·6H
·6H
2
2
2
2
O
O
O
O
dppb
–
7
12
8
BINAP
BPy
trace
trace
44
2
2
providing product 3a in 55% yield (entry 2). The necessity of
each of the key reaction components (cobalt catalyst, li-
gand, and base) was demonstrated through a series of con-
trol experiments. In the absence of a cobalt catalyst, no
product formation was observed in a control reaction with
9
10
CoCl ·6H O
2
2
2
2
2
2
2
2
PPh3
1
1
1
1
2
3
4
CoCl
CoCl
CoCl
–
·6H
·6H
·6H
O
O
O
PPh
PPh
PPh
PPh
3
3
3
3
32
DMF
0
toluene
toluene
67
1a and 2a (entry 14). Significantly, the choice of the base
1
trace
was found to have a dramatic effect on the yield of 3a, with
t-BuOK proving to be optimal for the present strategy. No
formation of 3a was observed in the absence of a base.
Screening of the cobalt precursor revealed that cobalt(II)
species gave promising results, with CoCl ·6H O showing
a
Reaction conditions: 1a (0.25 mmol), 2a (0.275 mmol), cobalt salt (5
mol%), ligand (10 mol%), t-BuOK (0.275 mmol), solvent (0.5 mL), heat, 18
h.
b
Yield determined by GC using 1,4-dibromobutane as an internal standard.
2
2
excellent activity for this transformation (entries 1–5). Ho-
mogeneity of the present catalytic system was confirmed
by a mercury poisoning experiment. Screening of the li-
gands revealed that the use of triphenylphosphine as the li-
gand was beneficial (entries 6–9); a trace amount (only
In order to show the versatility of the N-alkylation reac-
tion catalyzed by a simple cobalt catalyst, various anilines
and alcohols were tested under the optimal conditions.
First, we tried out the reactions of aniline (1a) with various
alcohol derivatives 2a–j under the standard reaction condi-
tions (5 mol% of CoCl ·6H O, 10 mol% of PPh ), and estab-
12%) of 3a was observed in the absence of a ligand. Further
2
2
3
screening of the bidentate phosphine ligands and amine li-
gands revealed slightly lower reactivity under optimal con-
ditions. A series of solvents was examined; among them,
toluene was found to be the optimal solvent for this trans-
formation (entries 10–12). Notably, the reaction tempera-
lished the yield of product after isolation by silica gel col-
umn chromatography (Scheme 3). It was observed that an
electron-donating substituent such as a methoxy or methyl
group at the para position of benzyl alcohol facilitated for-
mation of the N-benzylaniline product, in 66% and 63%
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–E

C
Synthesis
S. P. Midya et al.
Special Topic
yield for 3b and 3c, respectively (Scheme 3). In contrast, a
para-halo substituent on the benzyl alcohol led to slightly
lower yields; in the case of 4-chloro- and 4-bromobenzyl
alcohol, 57% and 55% yield of the respective alkylated ani-
line product 3d and 3e was observed (Scheme 3), which in-
dicated an excellent functional group tolerance. N-Alkyl-
ated product 3f was isolated in a good 59% yield from m-
methylbenzyl alcohol, while for o-methylbenzyl alcohol the
alkylation led to a moderate yield of 3g (41% isolated yield)
due to steric reasons. Interestingly, the present cobalt-cata-
lyzed N-alkylation strategy is applicable for heterocyclic al-
cohols and aliphatic alcohols. Thus, under the standard
conditions, furfuryl alcohol and long-chain fatty alcohols
smoothly underwent N-alkylation with aniline to afford the
desired products 3h–j in moderate to good yields (Scheme
4e and 4f. 2-Halo-substituted anilines (2-fluoro- and 2-bro-
moaniline) were found to be suitable substrates for alkyla-
tion with benzyl alcohol, to provide the corresponding
products 4g and 4h in reasonable 58% and 42% yield, re-
spectively (Scheme 4). However, under the optimized con-
ditions, the secondary amines N-methylaniline and mor-
pholine did not yield the desired products.
CoCl2·6H2O (5 mol%)
PPh3 (10 mol%)
R
NH2
OH
N
R
+
H
t-BuOK, toluene
130 °C, 18 h
1b–i
2a
4a–h
H
H
N
H
N
N
MeO
4a, 73%
4b, 71%
MeS
Cl
4c, 58%
H
N
H
N
H
3).
MeO
N
4e, 65%
4
f, 60%
F
F
4d, 62%
CoCl2·6H2O (5 mol%)
PPh3 (10 mol%)
NH2
Br
Me
N
H
N
+
HO
R
N
H
R
N
t-BuOK, toluene
130 °C, 18 h
H
1a
2a–j
3a–j
4
g, 58%
4h, 42%
4i, 0%
OMe
H
N
H
N
H
Scheme 4 Cobalt-catalyzed N-alkylation of amines: Scope of anilines.
Reagents and conditions: aniline 1b–i (0.5 mmol), 2a (0.55 mmol),
N
CoCl ·6H O (0.025 mmol), PPh (0.05 mmol), t-BuOK (0.55 mmol), tol-
uene (1 mL), 130 °C (bath temperature), 18 h, 10-mL sealed screw cap
tube under argon; yields are of isolated product.
3
a, 64%
3b, 66%
3c, 63%
2
2
3
Cl
Br
H
N
H
N
H
N
3
d, 57%
3e, 55%
3f, 59%
In conclusion, we have revealed a nonprecious metal,
cobalt-catalyzed alkylation of amines with alcohols via the
hydrogen autotransfer strategy for the synthesis of a broad
range of aromatic, aliphatic, and heteroaromatic secondary
amines. Notably, this reaction system is very practical, us-
ing commercially available and inexpensive cobalt precur-
sor and triphenylphosphine ligand. The present cobalt-cat-
alyzed alkylation reaction is a benign process, implements
inexpensive reagents, is operationally simple, and is based
on the acceptorless alcohol dehydrogenation concept.
O
H
H
N
H
N
N
5
3g, 41%
3h, 49%
H
N
7
3i, 53%
3j, 62%
Scheme 3 Cobalt-catalyzed N-alkylation of amines: Scope of alcohols.
Reagents and conditions: 1a (0.5 mmol), benzyl alcohol 2a–j (0.55
mmol), CoCl ·6H O (0.025 mmol), PPh (0.05 mmol), t-BuOK (0.55
2
2
3
mmol), toluene (1 mL), 130 °C (bath temperature), 18 h, 10-mL sealed
screw cap tube under argon; yields are of isolated product.
All catalytic experiments were carried out using standard Schlenk
techniques. All solvents were reagent grade or better. Deuterated sol-
vents were used as received. All non-deutrated solvents were dried
according to standard procedures. All reactions were performed in
normal screw cap reaction tubes (Fisher brand). TLC was performed
on Merck 1.05554 aluminum sheets precoated with silica gel 60 F254,
and the spots were visualized with UV light at 254 nm or under io-
Next, we investigated the substrate scope of anilines
while using benzyl alcohol (2a) as the alkylating reagent
Scheme 4). It was observed that electron-donating 4-meth-
oxy- and 4-methylaniline were excellent substrates for the
N-alkylation reaction, affording the corresponding products
a and 4b in 73% and 71% isolated yield, respectively
Scheme 4). An electron-donating thiomethyl substituent
on aniline, however, led to a significant reduction in the
yield of the desired N-alkylated product 4c (58%), and unre-
acted starting material was recovered. Aniline with an elec-
tron-withdrawing (fluoro) substituent at the para position
underwent efficient dehydrogenative coupling with benzyl
alcohol to give N-benzyl-4-fluoroaniline (4d) in 62% yield.
In addition, meta-substituted anilines showed efficient re-
activity towards alkylation with benzyl alcohol, resulting in
(
4
(
dine. Column chromatography was performed with silica gel. H and
1
1
3
C NMR spectra were recorded on Bruker DRX-200 (200 MHz), DRX-
00 (400 MHz), and DRX-500 (500 MHz) spectrometers, with TMS or
4
CHCl as an internal standard. The peaks were internally referenced to
3
TMS (0.00 ppm) or residual non-deuterated solvent signal (7.27 ppm
1
13
for H NMR, 77.0 ppm for C NMR); abbreviations used: br, broad; s,
singlet; d, doublet; t, triplet; q, quartet; m, multiplet. GC analyses
were carried out using a Carboxen 1000 column on a HP 690 series GC
system, or a HP-5 cross-linked 5% PH ME Siloxane column (30 m ×
0.32 mm × 0.25 μm film thickness, FID) on a HP 6890 series GC sys-
tem.
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–E

D
Synthesis
S. P. Midya et al.
Special Topic
1
Cobalt-Catalyzed N-Alkylation of Amines; General Procedure
H NMR (500 MHz, CDCl ): δ = 7.51–7.44 (m, 1 H), 7.38–7.36 (m, 3 H),
3
7
4
.32–7.31 (m, 1 H), 7.24 (d, J = 8.4 Hz, 2 H), 6.62 (d, J = 8.4 Hz, 2 H),
.35 (s, 2 H), 4.12 (br, 1 H), 2.43 (s, 3 H).
To a 10-mL, clean, oven-dried, screw cap reaction tube were added
CoCl ·6H O (0.025 mmol, 5 mol%), PPh (0.05 mmol, 10 mol%), alcohol
2
2
3
13
2
(0.55 mmol, 1.1 equiv), amine 1 (0.5 mmol), t-BuOK (0.55 mmol),
C NMR (125.8 MHz, CDCl ): δ = 146.94, 139.11, 131.47, 129.12,
3
and toluene (1 mL) under argon atmosphere. The reaction mixture
was stirred at 130 °C (bath temperature) for 18 h. Then, the reaction
128.67, 127.44, 127.31, 113.47, 48.31, 19.12.
mixture was diluted with water (4 mL) and extracted with Et O (3 × 5
N-Benzyl-2-bromoaniline (4h)10
2
mL). The resultant organic layer was dried over anhydrous Na SO and
2
4
Light yellow liquid; yield: 55 mg (42%).
the solvent was evaporated under reduced pressure. The crude mix-
ture was purified by silica gel column chromatography (230–400
mesh size) using petroleum ether/EtOAc as the eluting system.
1
H NMR (500 MHz, CDCl ): δ = 7.48 (d, J = 7.6 Hz, 1 H), 7.40–7.37 (m, 4
3
H), 7.34–7.31 (m, 1 H), 7.16 (t, J = 7.6 Hz, 1 H), 6.65 (d, J = 7.6 Hz, 1 H),
6.61 (t, J = 7.6 Hz, 1 H), 4.80 (br, 1 H), 4.45 (d, J = 6.1 Hz, 2 H).
Details of all products are given in the Supporting Information; ana-
lytical and spectroscopic data for some selected compounds are given
below.
13
C NMR (125.8 MHz, CDCl ): δ = 144.78, 138.68, 133.81, 132.37,
3
128.71, 127.21, 117.95, 111.60, 109.65, 47.99.
N-Benzylaniline (3a)8a
Acknowledgment
Colorless oil; yield: 59 mg (64%).
1
H NMR (200 MHz, CDCl ): δ = 7.39–7.26 (m, 5 H), 7.17 (t, J = 7.3 Hz, 2
This research was supported by the SERB (SB/FT/CS-065/2013). S.P.M.
thanks CSIR and A.M. thanks UGC for fellowships.
3
H), 6.75 (t, J = 7.3 Hz, 1 H), 6.63 (d, J = 8.7 Hz, 2 H), 4.32 (s, 2 H), 4.02
(br, 1 H).
13
C NMR (50.3 MHz, CDCl ): δ = 148.11, 139.40, 129.22, 128.59,
3
Supporting Information
127.47, 127.19, 117.52, 112.80, 48.29.
Supporting information for this article is available online at
N-(4-Methoxybenzyl)aniline (3b)8a
https://doi.org/10.1055/s-0036-1589064.
S
u
p
p
ortioIgnfmr oaitn
S
u
p
p
o
nrtogI
i
f
rm oaitn
Light yellow liquid; yield: 70 mg (66%).
1
H NMR (200 MHz, CDCl ): δ = 7.32 (d, J = 8.7 Hz, 2 H), 7.21 (t, J = 7.4
3
References
Hz, 2 H), 6.91 (d, J = 8.7 Hz, 2 H), 6.76 (d, J = 7.3 Hz, 1 H), 6.66 (d, J = 7.6
Hz, 2 H), 4.28 (s, 2 H), 3.97 (br, 1 H), 3.83 (s, 3 H).
(
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13
C NMR (50.3 MHz, CDCl ): δ = 158.80, 148.13, 131.34, 129.19,
3
128.76, 117.46, 113.96, 112.80, 55.24, 47.74.
(
cation;1-4
V
o.
l
McGuire, J. L., Ed.; Wiley-VCH: Weinheim, 2000.
N-(4-Methylbenzyl)aniline (3c)8a
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1
H NMR (500 MHz, CDCl ): δ = 7.35–7.34 (m, 3 H), 7.24 (t, J = 7.6 Hz, 3
3
H), 6.80 (t, J = 7.2 Hz, 1 H), 6.71 (d, J = 8.0 Hz, 2 H), 4.37 (s, 2 H), 4.20
(
2) (a) Bahn, S.; Imm, S.; Neubert, L.; Zhang, M.; Nuemann, H.;
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13
C NMR (125.8 MHz, CDCl ): δ = 148.04, 136.90, 136.22, 129.30,
3
129.27, 127.55, 117.62, 112.95, 48.18, 21.09.
11022.
N-(Furan-2-ylmethyl)aniline (3h)10
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Colorless liquid; yield: 42 mg (49%).
1
H NMR (200 MHz, CDCl ): δ = 7.38 (s, 1 H), 7.20 (t, J = 7.3 Hz, 2 H),
3
6.76 (t, J = 7.3 Hz, 1 H), 6.69 (d, J = 7.8 Hz, 2 H), 6.34–6.33 (m, 1 H),
(
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6.25–6.24 (m, 1 H), 4.33 (s, 2 H), 4.03 (br, 1 H).
13
C NMR (100 MHz, CDCl ): δ = 152.71, 147.60, 141.91, 129.22,
3
118.02, 113.14, 110.31, 106.97, 41.43.
N-Octylaniline (3i)4i
Colorless liquid; yield: 54 mg (53%).
1
H NMR (200 MHz, CDCl ): δ = 7.19 (t, J = 8.5 Hz, 2 H), 6.70 (t, J = 7.3
3
Hz, 1 H), 6.62 (d, J = 7.6 Hz, 2 H), 3.61 (br, 1 H), 3.12 (t, J = 6.9 Hz, 2 H),
1.70–1.57 (m, 2 H), 1.44–1.30 (m, 10 H), 0.91 (t, J = 4.5 Hz, 3 H).
11197. (h) Fernandez, F. E.; Puerta, M. C.; Valerga, P. Organome-
13
C NMR (50.3 MHz, CDCl ): δ = 148.52, 129.19, 117.04, 112.66, 43.98,
3
tallics 2012, 31, 6868. (i) Celaje, J. J. A.; Zhang, X.; Zhang, F.; Kam,
L.; Herron, J. R. ACS Catal. 2017, 7, 1136.
31.82, 29.56, 29.41, 29.26, 27.17, 22.65, 14.09.
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Colorless liquid; yield: 66 mg (58%).
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Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–E