Palladium-Catalyzed Aminocarbonylation of Aryl Halides with N,N-Dialkylformamide Acetals

Article abstract of DOI:10.1002/hlca.202100162

We developed a protocol for the palladium-catalyzed aminocarbonylation of aryl halides using less-toxic formamide acetals as bench-stable aminocarbonyl sources under neutral conditions. Various aryl (including heteroaryl) halides reacted with N,N-dialkylformamide acetals in the presence of a catalytic amount of tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct and xantphos to give the corresponding aromatic carboxamides at 90–140 °C without any activating agents or bases in up to quantitative chemical yield. This protocol was applied to aryl bromides, aryl iodides, and trifluoromethanesulfonic acid, as well as to relatively less-reactive aryl chlorides. A wide range of functionalities on the aromatic ring of the substrates were tolerated under the aminocarbonylation conditions. The catalytic aminocarbonylation was used to prepare the insect repellent N,N-diethyl-3-methylbenzamide as well as a synthetic intermediate of the dihydrofolate reductase inhibitor triazinate.

Full text of DOI:10.1002/hlca.202100162

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chimica acta
Accepted Article
Title: Palladium-Catalyzed Aminocarbonylation of Aryl Halides with
N,N-Dialkylformamide Acetals
Authors: Shuichi Hirata, Takao Osako, and Yasuhiro Uozumi
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10.1002/hlca.202100162
Helvetica Chimica Acta
HELVETICA
Palladium-Catalyzed Aminocarbonylation of Aryl Halides with N,N-
Dialkylformamide Acetals
Shuichi Hirata, Takao Osako, and Yasuhiro Uozumi*
Institute for Molecular Science, Myodaiji, Okazaki, 444-8787, Japan (uo@ims.ac.jp)
Dedicated to Professor Peter Kündig on the occasion of his 75th birthday
We developed a protocol for the palladium-catalyzed aminocarbonylation of aryl halides using less-toxic formamide acetals as bench-stable
aminocarbonyl sources under neutral conditions. Various aryl (including heteroaryl) halides reacted with N,N-dialkylformamide acetals in the presence of
a catalytic amount of tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct and xantphos to give the corresponding aromatic carboxamides at
90–140 °C without any activating agents or bases in up to quantitative chemical yield. This protocol was applied to aryl bromides, aryl iodides, and
trifluoromethanesulfonic acid, as well as to relatively less-reactive aryl chlorides. A wide range of functionalities on the aromatic ring of the substrates
were tolerated under the aminocarbonylation conditions. The catalytic aminocarbonylation was used to prepare the insect repellent N,N-diethyl-3-
methylbenzamide as well as a synthetic intermediate of the dihydrofolate reductase inhibitor triazinate..
Keywords: palladium • carbonylation • N,N-dimethylformamide dimethylacetal • aryl carboxamide
1 further improvements are needed for aromatic carboxamide formation
Introduction
using DMF.
The palladium-catalyzed carbonylation of aryl halides is one of the most
Recently, formamide acetals have been recognized as effective precursors
powerful synthetic methods for preparing esters and amides. Since Heck’s
to afford the corresponding oxo-iminium species without requiring an
discovery of the palladium-catalyzed aminocarbonylation of aryl halides
activation reagent and have been widely used in various alkylation and
using CO and amines, [1-2] various catalytic systems for aminocarbonylation
have been developed and widely applied in organic syntheses over the
past half-century (Scheme 1, equation 1).[3-8] However, the typical
aminocarbonylation reaction often requires an excess amount of highly
toxic CO gas, which is handled using specialized high-pressure reactors.
To overcome the drawback of using CO gas, researchers have investigated
various CO surrogates for the aminocarbonylation reaction. For example,
metal carbonyls as well as oxalic acid have been successfully used as
bench-stable agents that generate CO in situ (Scheme 1, equation 2). [9-11]
Cross-coupling reactions of aryl halides and carbamoylsilanes have also
been developed as an alternative aromatic aminocarbonylation route
(Scheme 1, equation 3).[12-13] However, these reaction systems still suffer
drawbacks such as toxic or low-availability reagents or require harsh
reaction conditions.
formylation reactions, including transition-metal-catalyzed reactions.[22-25]
Aminocarbonylation using CO (Heck's carbonylation)
R
R
O
C
CO, HNRR'
(1)
(2)
X
NRR'
[Pd] (cat), base
Aminocarbonylation using CO surrogates; previous works
R
R
O
C
CO (in situ), HNRR'
X
NRR'
[Pd] (cat), base
(CO : in situ generation from Mo(CO)6 or (COOH)2)
O
R
R
O
C
TMS C NMe2
(3)
(4)
X
X
NMe2
NMe2
[Pd] (cat)
O
HCNMe2
R
R
Recently, the use of N,N-dimethylformamide (DMF) for amino-
carbonylation has attracted much attention because it is readily
available.[14-16] Thus, palladium-catalyzed aminocarbonylation using DMF
has typically been performed in the presence of a DMF-activating agent
such as phosphoryl trichloride (POCl3),[18-19] a cyanuric chloride[20] or
WCl6,[21] where iminium intermediates are generated to participate in the
aminocarbonylation to give the corresponding aryl amides (Scheme 1,
equation 4). However, because of the high toxicity of the activating agents,
O
C
+ activating agent
[Pd] (cat)
(activating agent: POCl3, cyanuric chloride, WCl6)
O
Cl
activating agent
HCNMe2
C
NMe2
H
Scheme 1. Palladium-catalyzed amicocarbonylations.
1 The example of toxicity: sigma-Aldrich SDS POCl3 LD50 Oral rat 36 mg/kg, Cyanuric
chloride LD50 Oral rat 315 mg/kg, N,N-dimethylformamide dimethyl acetal LD50 Oral
rat >5000 mg/kg.
1
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10.1002/hlca.202100162
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When Pd(OAc)2 was replaced with tris(dibenzylideneacetone)-
dipalladium(0)-chloroform adduct (Pd2dba3·CHCl3), both the reaction
selectivity and the chemical yield of 3aA were substantially improved
(entry 7).[30-31] Other Pd(II) sources, such as PdCl2 and palladium(II)
trifluoroacetate (Pd(tfa)2), were also investigated, but no improvement in
the yield of 3aA was observed. The use of DMF as a reaction solvent instead
of 1,4-dioxane led to the exclusive formation of the aminocarbonylation
product 3aA (62% isolated yield, 100% selectivity, entry 8). The reactions in
other solvents (toluene, 1,2-dichloroethane, tetrahydrofuran, acetone,
EtOH) afforded the desired product 3aA in less than 40% yield (selected
result in entry 9). The reaction did not take place with DMF in the absence
of DMF-DMA (2A-Me) (entry 10). The best result was obtained with N,N-
dimethylformamide diisopropyl acetal (2A-IP) at 100 °C, where the yield of
3aA was improved to 89%, with exclusive reaction selectivity (entry 11).
Given this background, we speculated that using formamide acetals for
the aminocarbonylation of aryl halides should offer a safe. bench-stable,
and base-free alternative to the Heck-type carbonylation (Scheme 2).
This Work (safe CO surrogates)
OR
HCNR2
R
R
O
C
OR
X
NR2
[Pd] (cat)
Plausible Pathway
RO
OR
C
NR2 OR
HC NR2
OR
H
θ
Pd
θ'
L
L
P
P
Table 1. Condition screening of palladium-catalyzed aminocarbonylation with
DMF-dialkyl acetals.a
Pd
ArPdX
X
ArX
Pd(0)/ligand
N
Ar
Y
Z
C
[Pd] (5 mol%)
ligand (7.5 mol%)
O
C
OR
+ HCNMe2
OR
insertion
F3C
X
F3C
NMe2
solvent, 90 °C, 24 h
3aA
O
C
2A-Me (R = Me)
2A-IP (R = i-Pr)
OR
C
β-hydride elimination
1a-Br
F C
3
OMe
+
Ar
NR2
PdH(X)L2
4
H
PdX(OR)L2
Entry
[Pd]
Ligand
Solvent
Yield (%)
3aA
OR
O
RO
Ar
hydrolysis
(workup)
4
C
NR2 OR
Ar
C
NR2
Ar
C NR2
OR
1
Pd(OAc)2
xantphos
dppb
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
DMF
33
<1
<1
4
18
Scheme 2. Aminocarbonylation using formamide acetals.
2
Pd(OAc)2
<1
<1
3
Results and Discussion
3
Pd(OAc)2
dppf
4
Pd(OAc)2
binap
We initially examined the screening conditions for the palladium-catalyzed
aminocarbonylation of 4-bromobenzotrifluoride (1a-Br) with N,N-
dimethylformamide dimethylacetal (DMF-DMA) (2A-Me) (Table 1). The
reaction of 4-bromobenzotrifluoride (1a) with DMF-DMA (2A-Me)
proceeded in the presence of Pd(OAc)2 and xantphos in 1,4-dioxane at
90 °C for 24 h in 86% conversion, giving the desired N,N-dimethyl(4-
trifluoromethyl)benzamide (3aA) in 33% yield, along with methyl (4-
trifluoromethyl)benzoate 4 (entry 1) in 18% yield. The use of other
phosphine ligands such as 1,4-bis(diphenylphosphino)butane (dppb), 1,1’-
bis(diphenylphosphino)ferrocene (dppf), 2,2’-bis(diphenylphosphino)-
binaphthyl (binap), and triphenylphosphine resulted in poor yields of both
amide 3aA and ester 4 (entries 2–5). In the absence of ligands, the reaction
did not proceed efficiently (entry 6). It has been reported that the values of
the anglea P-Pd-P (q) of palladium(II)-bisphosphine complexes well
correlate with the reactivity of the Pd-catalyzed coupling reactions. Thus,
the coupling ligands (i.e. Y and Z in Scheme 2) are in closer proximity to
each other as the bidentate bisphosphine has larger bite angle (q) to
accelerate the coupling reaction.[26] The results of this ligand screening are
likely attributable to the wide bite angle of xantphos ligand (q = 111 °)[27-29]
which generates arylpalladium(II)-xantphos species exhibiting high
activity toward aminocarbonylation with formamide acetals.
5
Pd(OAc)2
PPh3
<1
<1
67
62
40
<1
89
<1
<1
14
<1
27
<1
<1
6
Pd(OAc)2
none
7
Pd2dba3•CHCl3
Pd2dba3•CHCl3
Pd2dba3•CHCl3
Pd2dba3•CHCl3
Pd2dba3•CHCl3
xantphos
xantphos
xantphos
xantphos
xantphos
8
9
toluene
10b
11c
DMF
DMF
a Reaction conditions: 1a-Br (0.1 mmol), N,N-dimethylformamide dimethylacetal
(DMF-DMA) (2A-Me) (0.2 mmol), Pd source (5 mol% Pd), ligand (7.5 mol%), solvent
(0.5–1.0 mL), 90 °C, 24 h. The conversion and yields were determined by GC-MS
and GC analyses. b The reaction was carried out without DMF-DMA. b The reaction
was carried out with N,N-dimethylformamide diisopropylacetal (2A-IP) at 100 °C.
PPh2
PPh2
PPh2
PPh2
PPh2
Fe
O
PPh2
PPh2
PPh2
xantphos
dppb
dppf
binap
Having determined the optimal conditions, we examined the palladium-
catalyzed aminocarbonylation of various aryl halides 1 with 2A-IP (Scheme
2
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10.1002/hlca.202100162
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HELVETICA
3). para-Trifluoromethylphenyl iodide (1a-I) and triflate (1a-OTf) gave the
aminocarbonylation product 3aA in 82% and 79% yield, respectively,
under the standard conditions. Relatively less-reactive chloride 1a-Cl also
underwent the reaction to give 3aA in 79% yield at 120 °C. Bromobenzene
(1b-Br) and chlorobenzene (1b-Cl) bearing no aromatic substituents gave
3bA in 82% (at 100 °C) and 92% (at 140 °C) yield, respectively.
Halobenzenes bearing electron-withdrawing groups such as cyano (1c),
nitro (1d), phenylketone (1e), and methyl ester (1f) groups at their 4-
in 63% yield. α-Naphthyl and b-naphthyl halides 1n-Br, 1o-Br, and 1o-Cl
were also aminocarbonylated under the standard catalytic conditions.
Although the sterically hindered a-naphthyl 3nA was obtained in a
moderate chemical yield even at 140 °C, b-carboxamides 3oA were
obtained in 78% (from 1o-Br at 100 °C) and 94% (from 1o-Cl at 140 °C) yield.
Fused heterocycles benzodioxolane 1p and benzofuran 1q smoothly
underwent the carbonylation to give 3pA and 3qA in 77% and 50% yield,
respectively. Heteroaryl substrates, 3-pyridyl (1r-Br), 2-thiophenyl (1s-Br
and 1s-Cl), and 3-thiophenyl (1t-Br) halides were also examined for the
catalytic aminocarbonylation using DMF acetal 2A-IP. Pyridine 3-
carboxamide 3rA was obtained in 33%. The reactions of 1s-Br, 1s-Cl, and
1t-Br proceeded under the standard conditions to give thiophene 2-
carboxamide 3sA in 78% (from 1s-Br at 100°C) and 50% (from 1s-Cl at
140°C) yield and 3tA in 63% (from 1t-Br at 100°C) yield, respectively, even
though the substrates 1s and 1t as well as the products 3sA and 3tA might
have coordinated to palladium, thereby disordering the catalytic system.
We next investigated the aminocarbonylation reaction with various
formamide acetals (Scheme 4). Formamide diisopropyl acetals of
diethylamine 2B-IP, pyrrolidine 2C-IP, piperidine 2D-IP, and morpholine
2E-IP were examined for the aminocarbonylation with 4-trifluorophenyl
bromide (1a-Br). The use of DMF as a solvent gave amide-scrambled
dimethyl amide 3aA as a byproduct. The reactions were therefore carried
out in N,N-dimethylacetamide (DMA) as a solvent under otherwise similar
catalytic conditions. The corresponding amides 3aB–E were obtained in
82%, 82%, 58%, 58%, and 79% yield, respectively (Scheme 4). Morpholine
amides are known to work as alternatives to Weinreb amides in the
addition of organometallic reagents.[32-33] Morpholine benzamide 3aE
reacted with PhMgBr to give diarylketone 5 in 83% yield (Scheme 4,
bottom).
positions were converted to the corresponding aryl carboxamides 3cA–
3fA in 74–100% yield. Halobenzenes bearing electron-donating groups
Pd2dba3•CHCl3 (5 mol% Pd)
OPri
HCNMe2
OPri
O
xantphos (7.5 mol%)
Ar
X
+
C
Ar
NMe2
DMF, temp.
24 h
3
1
2A-IP (2 equiv)
O
O
O
C
F3C
C
NMe2
H
C
NMe2
NC
NMe2
3aA
3bA
3cA
88% (X = Br, 100 °C)
79% (X = OTf, 100 °C)
79% (X = Cl,120 ˚C)
82% (X = I, 100 °C)
82% (X = Br, 100 °C)
92% (X = Cl, 140 °C)
81% (X = Br, 90 °C)
80% (X = Cl, 120 ˚C)
O
O
O
O2N
C
NMe2 PhOC
C
NMe2 MeOOC
C NMe2
3dA
3eA
3fA
74% (X = Br, 100 °C)
87% (X = Cl,100 ˚C)
90% (X = Br, 100 °C)
quant (X = Cl, 140 °C)
85% (X = Br, 100 °C)
80% (X = Cl, 120 ˚C)
O
O
O
Me
C
NMe2
C
NMe2
MeO
C NMe2
3gA
3hA
3iA
85% (X = Br, 100 °C)
92% (X = Cl, 140 °C)
88% (X = Br, 100 °C)
74% (X = Cl, 140 °C)
69% (X = Br, 100 °C)
66% (X = Cl, 140 °C)
Me
Me
O2N
O
O
O
C
C
NMe2
C
NMe2
NMe2
3jA
3kA
3lA
78% (X = Br, 100 °C)
84% (X = Cl, 140 °C)
58% (X = Br, 140 °C)
83% (X = Br, 100 °C)
72% (X = Cl, 140 °C)
Pd2dba3•CHCl3 (5 mol% Pd)
OPri
+ HCNR2
OPri
O
C
xantphos (7.5 mol%)
NR2
1a-Br
F3C
F3C
O
O
DMA, 100 °C
24 h
O
C
NMe2
C NMe2
C
NMe2
3aB–3aE
2 (2 equiv)
3nA
3oA
3mA
F3C
78% (X = Br, 100 °C)
94% (X = Cl, 140 °C)
63% (X = Br, 100 °C)
85% (X = Cl, 140 °C)
O
O
C
53% (X = Br, 140 °C)
3aB
82%
3aC
82%
F3C
F3C
C
N
N
F3C
N
O
O
O
O
O
O
C
NMe2
C
NMe2
C
NMe2
O
C
O
C
N
3aD
58%
3aE
79%
3pA
3qA
3rA
F3C
N
O
77% (X = Br, 100 °C)
50% (X = Br, 100 °C)
68% (X = Cl, 140 °C)
33% (X = Br, 100 °C)
O
C
O
C
S
S
NMe2
NMe2
O
PhMgBr (4.0.equiv), THF, 0°C, 18 h
3aE
F3C
C
3sA
3tA
83%
78% (X = Br, 100 °C)
50% (X = Cl, 140 °C)
63% (X = Br, 100 °C)
5
Scheme 4. Aromatic aminocarbonylation with various N,N-dialkylformamide
Scheme 3. Aromatic aminocarbonylation with DMF diisopropyl acetal.
acetals.
such as methyl (1g), tert-butyl (1h), and methoxy (1i) groups were also
tolerated (66–92% yield). In the reaction of halobenzenes bearing a methyl
group at the meta or ortho position, the meta-substituted product 3jA was
obtained in high yield (78% (from 1j-Br), 84% (from 1j-Br)), whereas ortho-
substituted aryl amide 3kA was obtained in moderate yield (58%). The
aminocarbonylation of 3,5-disubstituted substrate 1mA-Br afforded 3mA
3
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10.1002/hlca.202100162
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Me
of the solvent, the crude material was purified with silica gel column
chromatography (ethylacetate : hexane = 1:1-3:1).
Experimental details and spectroscopic data are given in the
Supplementary Materials.
O
C
standard conditions
100 °C, 24 h
(1)
N
1j-Br
+ 2B-IP
3jB 93%
(DEET: insect repellent)
Supplementary Material
Cl
O
Cl
O
standard
conditions
O
C
Experimental detailes and spectroscopic data are available on the WWW
under http://dx.doi.org/10.1002/MS-number.
NMe2
Br
2A-IP
+
100 °C, 18 h
O2N
O2N
1u
3uA 48%
Cl
O
O
C
Acknowledgements
NMe2
H2N
N
(2)
This work was supported by JSPS KAKENHI (Grant Number JP21K18968).
We are grateful to Ms. Aya Tazawa for management of spectroscopic
data.
N
•EtSO3H
N
6
H2N
(Triazinate: dihydrofolate reductase inhibitor)
Scheme 5. Synthetic application of the aminocarbonylation protocol to bioactive
Author Contribution Statement
compounds.
Prof. Yasuhiro Uozumi and Dr. Takao Osako led this project. Drs. Shuichi
Hirata and Takao Osako did most of the experiments.
To demonstrate the synthetic utility of this aminocarbonylation protocol,
we prepared some bioactive compounds (Scheme 4). Thus, N,N-diethyl-3-
methylbenzamide (DEET) (3jB), an insect repellent,[34] was obtained in 92%
yield by the coupling of 4-trifluorophenyl bromide (1j-Br) and N,N-
diethylformamide diisopropyl acetal (2B-IP) (Scheme 4, top). Triazinate (6)
is a dihydrofolate reductase inhibitor.[35-36] 3-Bromobenzyl aryl ether 1u-Br
successfully underwent aminocarbonylation with DMF diisopropyl acetal
2A-IP to give N,N-dimethylamide 3uA, a synthetic key intermediate for
triazinate, in 48% isolated yield.
References
[1]
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3318-3326.
[2]
[3]
[4]
A. Schoenberg, R. F. Heck, ‘Palladium-catalyzed amidation of aryl,
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Conclusions
We developed a palladium-catalyzed method for the aminocarbonylation
of aryl halides using less-toxic formamide acetals as bench-stable
aminocarbonyl sources under neutral conditions. This reaction protocol
was applied to aryl bromides, aryl iodides, and trifluoromethanesulfonic
acid, as well as to relatively less-reactive aryl chlorides. A wide range of
functionalities on the aromatic ring of the substrates were tolerated under
the aminocarbonylation conditions to afford the corresponding aryl
carboxamides in good to excellent yields.
[5]
[6]
[7]
[8]
[9]
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General Procedure of Aminocarbonylation with 2A-IP
Aryl halide (0.1 mmol), DMF-diisopropyl acetal (0.2 mmol, 2.0 equiv),
[10] P. Nordeman, L. R. Odell, M. Larhed, ‘Aminocarbonylations Employing
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11398.
xantphos (0.0075 mmol, 7.5 mol%), Pd2dba3·CHCl3 (0.005 mmol, 5 mol%
Pd) were dissolved in DMF (1 mL). A solution was degassed by a freeze-
pump-thaw method. A solution was stirred at 90-160 °C for 24 h. The
resulting mixture was diluted by ethyl acetate, filtrated through celite. The
filtrate cake was rinsed with ethyl acetate/hexane (1/1). The filtrate was
washed with water (x 1), brine (x 1), and dried over Na2SO4. After removal
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Heteroarylamines Using Conventional Heating’, Eur. J. Org. Chem. 2009,
2820-2827.
4
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10.1002/hlca.202100162
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HELVETICA
[12] R. F. Cunico, B. C. Maity, ‘Direct Carbamoylation of Aryl Halides‘, Org. Lett.
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[13] W. Tong, P. Cao, Y. Liu, J. Chen, ‘Synthesis of Secondary Aromatic Amides via
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Palladium-catalyzed aminocarbonylation of aryl halides using formamide acetals as CO surrogates was developed to offer a safe, neutral,
and bench-stable alternative to the Heck-type carbonylation.
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