An Efficient Palladium-Catalysed Aminocarbonylation of Benzyl Chlorides

Article abstract of DOI:10.1055/s-0039-1690786

An improved procedure for the aminocarbonylation of benzyl chloride derivatives using carbon monoxide and either primary or secondary amines has been developed. Studying the competing background alkylation reaction allowed the solvent and base to be selected for a simple catalyst screen, which, in turn, enabled the discovery of a method for the preparation of 2-arylacetamides under mild conditions, with minimal side-products using an inexpensive phosphine ligand. This non-traditional optimisation strategy allowed us to overcome the background alkylation, which has been cited as justification for the development of more complex and less atom-economical approaches.

Full text of DOI:10.1055/s-0039-1690786

SYNLETT
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© Georg Thieme Verlag Stuttgart · New York
2020, 31, A–D
letter
A
en
E. Rilvin-Derrick et al.
Letter
Synlett
An Efficient Palladium-Catalysed Aminocarbonylation of Benzyl
Chlorides
Eloise Rilvin-Derrick
Niall Oram
O
R1
Cl
desired
reaction
N
R2
R1 R2
+
N
H
Jeffery Richardson*
0
0
0
0-
0
0
0
2-4
4
5
0-3
8
2
8
CO (50 psi)
Pd(OAc)2, DPEPhos
EtN(iPr)2, PhMe
70 °C
Discovery Research and Technologies, Eli Lilly and Company,
Erl Wood Manor, Sunninghill Road, Windlesham, Surrey,
GU20 6PH, UK
- non-traditional
optimisation approach
- inexpensive ligand
- gram scale
R2
N
Richardson_jeffery@lilly.com
R1
- 0–97% yield
- 21 examples
undesired background
reaction suppressed by
solvent, base and
catalyst
Received: 09.11.2019
Accepted after revision: 11.12.2019
Published online: 10.01.2019
OH
OH
O
DOI: 10.1055/s-0039-1690786; Art ID: st-2019-v0607-l
N
O
Cl
N
Abstract An improved procedure for the aminocarbonylation of ben-
zyl chloride derivatives using carbon monoxide and either primary or
secondary amines has been developed. Studying the competing back-
ground alkylation reaction allowed the solvent and base to be selected
for a simple catalyst screen, which, in turn, enabled the discovery of a
method for the preparation of 2-arylacetamides under mild conditions,
with minimal side-products using an inexpensive phosphine ligand. This
non-traditional optimisation strategy allowed us to overcome the back-
ground alkylation, which has been cited as justification for the develop-
ment of more complex and less atom-economical approaches.
Cl
Insect repellant
D1 PAM (Lilly)
F
O
N
N
O
N
OMe
N
F
GPR119 agonist (Merck & Co.)
Key words palladium catalysis, carbonylation, amides, reaction opti-
misation
Figure 1 A selection of biologically interesting 2-arylacetamides
2-Arylacetamides are useful synthetic intermediates1
and can be found in some important biologically active
compounds. Examples include the insect repellent N,N-di-
ethylphenylacetamide (Figure 1),2 as well as more highly
elaborated amides from drug discovery projects such as the
Lilly D1 Positive Allosteric Modulator3 and Merck GPR119
agonist.4
During the course of one of our drug discovery pro-
grams a broadly applicable and robust method to prepare
diverse 2-aryl acetamides was sought. Typically, 2-phenyl-
acetamides are prepared from the corresponding acids,
which themselves often require preparation, and so we
sought a more modular method that utilises a broad array
of available building blocks. Other methods are known but
are not as straightforward and modular as was required for
our program.5
amine in the presence of carbon monoxide and a suitable
catalyst.6–14 Only a small number of examples have been re-
ported for the aminocarbonylation of benzylic halides and
those examples demonstrate the main challenge associated
with overcoming the competing background alkylation of
the amine and benzyl halide starting materials. This is fre-
quently cited as justification of the development of alter-
nate methods for the synthesis of 2-arylacetamides
(Scheme 1).15–19 This is in contrast to aminocarbonylation
reactions of aryl halides, where the background amination
is only problematic in substrates that are highly activated
towards nucleophilic aromatic substitution.
R2
N
O
R1
Cl
CO
"LPd(0)"
N
R2
R1
R1 R2
base, solvent
+
N
H
undesired
background
reaction
desired
reaction
Aminocarbonylation is a well-described and syntheti-
cally expedient method for the preparation of aryl amides
from the corresponding aryl halide or pseudohalide and
Scheme 1 Challenges associated with aminocarbonylation of benzyl
halides
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–D
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
E. Rilvin-Derrick et al.
Letter
Synlett
Table 1 Survey of the Background Alkylation Reaction under the Influ-
been reported using 11CO at high catalyst loadings22,23 or CO
surrogates24–27 and were suggestive that a viable solution
could be obtained.
ence of Bases and Solvents Commonly Used in Carbonylation Reactiona
base (1.5 equiv)
solvent (10 mL/g)
80 °C
Our approach for obtaining suitable conditions to effect
this transformation was to study the background alkylation
with various solvents and bases that are commonly em-
ployed in aminocarbonylation reactions6–14 with the intent
of identifying those in which the undesired alkylation is
slowest. This approach afforded a reasonable expectation
that a viable method could be found by subsequent screen-
ing around these conditions to identify potential catalysts
and optimise solvent, base and ligand.
Our studies began by examining the inherent alkylation
of n-butylamine with benzyl chloride (1a) with solvents
and bases relevant to aminocarbonylation reactions (Table
1). This revealed that the extent of the background reaction
was highly dependent on the solvent, and, to a lesser ex-
NH2
NH
N
Cl
+
+
1a
2a
3a
(1.2 equiv)
Entry
Base
Solvent
1 h
3 h
8 h
1
2
Na2CO3
EtN(iPr)2
Na2CO3
EtN(iPr)2
Na2CO3
EtN(iPr)2
Na2CO3
EtN(iPr)2
Na2CO3
EtN(iPr)2
PhMe
83:15:2
85:14:1
69:25:6
73:22:5
78:19:3
79:18:3
11:36:53
4:46:50
6:37:58
4:40:57
79:18:3
83:15:2
49:33:19
56:30:14
67:27:06
70:24:06
3:35:62
0:46:54
0:36:64
0:40:60
72:23:5
82:15:3
29:33:38
37:32:32
53:36:11
59:30:11
0:35:65
0:46:54
0:35:65
0:39:61
PhMe
3
1,4-dioxane
1,4-dioxane
THF
4
5
6
THF
7
MeCN
MeCN
DMF
8
H
N
9
Pd(OAc)2 (2 mol%)
O
L1 (4 mol%)
EtN(iPr)2 (1.5 equiv)
toluene (20 mL/g)
CO (50 psi)
R1
10
DMF
a Ratio = 1a/2a/3a.
4a (R1 = H) 77%
4b (R1 = OMe) 71%
NH2
or
O
Cl
80 °C
+
The conditions described by Troisi et al. demonstrate
that, while this transformation can be achieved, the unpro-
ductive background reaction limits the utility and must be
better controlled.15 Furthermore, the scope of this transfor-
mation was not broadly explored and gaining additional in-
sight into the effect of substitution on the benzylic portion
would be critical for its application to the synthesis of inter-
esting amides. A limited number of other examples20,21 have
R1
N
H
or
O
1b (R1 = H)
1c (R1 = OMe)
N
O
PPh2
Me
O
R1
Me
PPh2
4c (R1 = H) 49%
4d (R1 = OMe) 34%
XantPhos L1
Scheme 2 Proof of concept of aminocarbonylation reactions
Pd(OAc)2 (5 mol%)
O
O
Ligand (10 mol%)
Cl
N
N
+
+
O
EtN(iPr)2 (1.5 equiv)
PhMe (10 mL/g)
N
H
MeO
MeO
O
MeO
CO (50 psi), 80 °C, 16 h
1c
(1.2 equiv)
4d
3b
PPh2
PPh2
PPh2
PPh2
Me
Me
P
O
O
Fe
PPh2
PPh2
XantPhos L1
78:22
L2
dppf L3
95:5
L4
0:100
(DPEPhos)
96:4
Ph
n-Bu
PPh2 PPh2
P
PCy2
P
O
Fe
O
O
PPh2
Josiphos SL-J001-1
SkewPhos L6
L7
CatacXium A L8
L5
33:67
21:79
2:98
2:98
Ratio 4d:3b determined by HPLC analysis of crude reaction mixture.
All reactions reached 100% conversion
Scheme 3 Ligand screening to disfavour background reaction
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–D

C
E. Rilvin-Derrick et al.
Letter
Synlett
tent, the base; we were encouraged to see that over a stan-
dard 8 h time course, the combination of toluene and
EtN(iPr)2 left over 80% of the chloride unreacted (Table 1,
entry 2).
Pd(OAc)2 (2.5 mol%)
DPEPhos (5 mol%)
H
NR2
NR2
R1 Cl
R1
EtN(iPr)2 (1.5 equiv.)
PhMe (20 mL/g)
CO (50 psi), 70 °C, 16 hr
O
4a–v
1a–m
(1.0 g)
2a–j
(1.2 equiv)
When n-butylamine was reacted with 4-methoxyben-
zyl chloride (1c) under the same conditions, only 65% start-
ing material remained after 8 h. Under identical conditions,
benzyl bromide was completely consumed in the same pe-
riod. These results suggested that the focus of our investiga-
tion should be limited to benzyl chlorides and that 4-me-
thoxybenzyl chloride could be a more useful substrate for
development of the aminocarbonylation conditions than
benzyl chloride, as this provided a potentially more chal-
lenging background reaction to overcome.
To confirm the hypothesis that the solvent/base combi-
nation could translate to useful conditions, preliminary
aminocarbonylation reactions were attempted with
Pd(OAc)2 and Xantphos as the catalyst (Scheme 2). As ex-
pected, these performed well for benzyl chloride but with a
lower yield for 4-methoxybenzyl chloride. To optimise this
reaction, the carbon monoxide pressure and reaction tem-
perature were varied (Table 2). These data suggested that
the effects of pressure and temperature were subtle, and
that further improvement of the reaction would likely come
from optimization of the ligand.
The reaction was then further studied using 5 mol% Pd
and a variety of commonly applied ligands to determine
whether a more suitable ligand could be identified to over-
come the background reaction (Scheme 3). DPEPhos (L2)
was identified as the preferred ligand and the reaction was
performed at 1 g scale to afford aminocarbonylation prod-
uct 4d in 72% isolated yield. The catalyst loading could be
lowered to 2.5 mol% Pd without compromising the prod-
uct/alkylation by-product ratio.
O
N
H
N
H
N
O
O
O
O
O
4d, 72% yield
4b, 85% yield
4a, 94% yield
H
H
N
N
N
O
O
O
4e, 85% yield
4f, 92% yield,
4g, 92% yield
100% ee
O
O
O
F
Cl
N
N
N
O
O
O
4h, 83% yield
4i, 75% yield
4j, 69% yield
O
O
O
Br
Cl
Cl
N
N
N
O
O
O
Cl
Cl
4k, 62% yield
4l, 82% yield
4m, 0% yield
5% yielda
OH
O
O
F
N
N
N
N
O
O
MeO2C
O
F
4n, 0% yield
4o, 37% yield
4p, 83% yield
65% yielda
O
O
N
O
N
O
N
O
N
O
N
4q, 85% yield
4r, 77% yielda
4s, 50% yieldb
O
O
H
N
N
N
N
S
With these conditions in hand, we sought to better un-
derstand the scope and limitations of the method (Scheme
4).28 These reactions worked broadly for a variety of (hete-
ro)benzylic chlorides and amines. Electron-withdrawing
and electron-donating groups were tolerated as were aryl
halides. In the case of aryl bromide 4k, some additional car-
bonylation of the ArBr was observed as a by-product.
Notably, while single ortho-substituents were tolerated,
2,6-disubstituted substrates proved challenging (4m). A
range of amines were efficiently incorporated and although
piperidin-4-ol gave a poor yield (4o) under the standard
conditions, this could be overcome by using preformed cat-
alyst. Highly nucleophilic amines, for example as in the
preparation of Weinreb amide 4s gave lower, but still use-
ful, yields, as the rate of the background reaction was sig-
nificantly increased.
N
O
N
O
O
4v, 97% yield
4t, 47% yield
4u, 60% yield
Scheme 4 Scope and limitations of the aminocarbonylation reaction.
Isolated yields given. a PdCl2(DPEPhos) used instead of Pd(OAc)2 + L2.
b HCl salt of amine used + additional EtN(iPr)2 (1.2 equiv).
zylic chlorides that uses an inexpensive ligand and works
for a variety of interesting substrates. This reaction has of-
ten been cited as difficult to achieve efficiently and led to
the development of more complex solutions.
Acknowledgment
The authors gratefully acknowledge Dr Matthew Jones and Dr Craig
Ruble for their helpful comments during the preparation of this man-
uscript.
In conclusion, by employing a non-traditional optimisa-
tion strategy we have successfully developed an efficient
palladium-catalysed aminocarbonylation reaction of ben-
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–D

D
E. Rilvin-Derrick et al.
Letter
Synlett
Table 2 Effect of Temperature and Pressure on the Aminocarbonylation Reactiona
Pd(OAc)2 (2 mol%)
L1 (4 mol%)
EtN(iPr)2 (1.5 equiv)
O
O
toluene (10 mL/g)
N
N
Cl
+
+
O
O
MeO
N
MeO
MeO
H
4d
3b
1c
CO pressure (psi)
Temperature (°C)
80
60
100
20
50
80
70:30
51:49
35:65
78:22
75:25
65:35
68:32
50:50
78:22
a Ratio 4d/3b determined by HPLC analysis of the crude reaction mixture.
Supporting Information
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Supporting information for this article is available online at
https://doi.org/10.1055/s-0039-1690786.
S
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orit
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(28) General Procedure: To a round-bottomed ACE glass pressure
flask containing a magnetic stirrer was added toluene (20 mL),
chloromethylbenzene (1.0 g, 7.9 mmol) and N,N-diisopropyl-
ethylamine (1.5 equiv). The mixture was degassed with subsur-
face nitrogen purge for 5 minutes. Palladium(II) acetate (2.5
mol%) and bis(2-diphenylphosphinophenyl)ether (5 mol%)
were added, followed by the primary or secondary amine (1.2
equiv) to give a pale-yellow solution. The flask was purged with
nitrogen, filled with carbon monoxide to 50 psig and heated at
70 °C with magnetic stirring overnight. The reaction mixture
was cooled to ambient temperature and residual CO vented. The
reaction mixture was partitioned between EtOAc (200 mL) and
10% aq. citric acid (2 × 30 mL). The organic layer was washed
with water then brine, dried over MgSO4, filtered and evapo-
rated. The residue was loaded to the top of a silica gel plug with
CH2Cl2 and eluted with a gradient of EtOAc in isohexane to
afford the amide products.
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–D