Cobalt-catalyzed aminocarbonylation of (hetero)aryl halides promoted by visible light

Article abstract of DOI:10.1039/d0sc02178d

The catalytic aminocarbonylation of (hetero)aryl halides is widely applied in the synthesis of amides but relies heavily on the use of precious metal catalysis. Herein, we report an aminocarbonylation of (hetero)aryl halides using a simple cobalt catalyst under visible light irradiation. The reaction extends to the use of (hetero)aryl chlorides and is successful with a broad range of amine nucleophiles. Mechanistic investigations are consistent with a reaction proceeding via intermolecular charge transfer involving a donor-acceptor complex of the substrate and cobaltate catalyst.

Full text of DOI:10.1039/d0sc02178d

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Cobalt-Catalyzed Aminocarbonylation of (Hetero)Aryl Halides
Promoted by Visible Light
Alexander M. Veatcha and Erik J. Alexanian*a
Received 00th January 20xx,
Accepted 00th January 20xx
The catalytic aminocarbonylation of (hetero)aryl halides is widely applied in the synthesis of amides but relies heavily on the
use of precious metal catalysis. Herein, we report an aminocarbonylation of (hetero)aryl halides using a simple cobalt
catalyst under visible light irradiation. The reaction extends to the use of (hetero)aryl chlorides and is successful with a broad
range of amine nucleophiles. Mechanistic investigations are consistent with a reaction proceeding via intermolecular charge
transfer involving a donor-acceptor complex of the substrate and cobaltate catalyst.
DOI: 10.1039/x0xx00000x
www.rsc.org/
tetracarbonyl cobaltate (Co(CO)4—) in situ as the active
catalyst.6 However, the requirement of alkoxides presents a
challenge in the use of other nucleophiles in this manifold.5
Indeed, there is scant precedent for intermolecular
aminocarbonylation using cobalt catalysis (Figure 1).5a
Moreover, the mechanistic details concerning the activation of
the (hetero)aryl substrate by the cobaltate catalyst remain
unknown.5c
We have recently developed a mild system for the
generation of cobaltate ion from Co2(CO)8 for the catalytic
carbonylative functionalization of alkyl electrophiles.7 We
hypothesized that this system could also unlock a general,
Introduction
Carbonylative transformations of (hetero)aryl halides are
widely utilized across chemical synthesis for the preparation of
functionalized aromatics.1 The aminocarbonylation of
(hetero)aryl halides is a prototypical example in the class, first
reported by Heck in 1974 using palladium catalysis.2 The
significant value of this transformation in amide synthesis has
since led to the development of a range of novel palladium-
catalyzed aminocarbonylations of broad scope.3 While often
efficient, the use of expensive palladium catalysts and
phosphine ligands in these reactions is suboptimal. The
continued lack of catalytic systems for aminocarbonylation
featuring inexpensive, first-row metals hampers further
application of this important synthetic process.4
cobalt-catalyzed
aminocarbonylation
of
(hetero)aryl
electrophiles. Herein, we report the successful development of
such a process using a broad range of electrophiles–including
(hetero)aryl chlorides–and diverse amine nucleophiles. Initial
mechanistic studies support a visible light-promoted electron-
transfer of a donor-acceptor complex involving the substrate
and cobaltate in the critical activation step.
Catalytic aminocarbonylation of bromobenzene using the CoCRACO system: Caubère (1979)
O
20 mol % Co(OAc)2
Br
CO stream
2 equiv 1o or 2o amine
NR2
2 equiv NaH
40 mol % t-amyl-ONa
3 examples reported
40-55% yield
THF, 63 o
C
Results and discussion
This work: Light-promoted, Co-catalyzed aminocarbonylation of (hetero)aryl and vinyl halides
First-row, commercially
available catalyst
5 mol % Co2(CO)8
O
Our studies commenced with the aminocarbonylation of 1-
bromo-4-methoxybenzene (1) using piperidine as the
nucleophile. The use of simple carbonyl complex Co2(CO)8 in
conjunction with 2 equiv of tetramethylpiperidine (TMP) under
visible light irradiation (390 nm LEDs) delivered the desired
aminocarbonylation product in virtually quantitative isolated
yield (Table 1, entry 1). As expected, the substitution of 10 mol
% of a cobaltate catalyst was equally effective (entry 2). The use
of either Mn2(CO)10 or CoCl2 instead of Co2(CO)8 was not
effective in the aminocarbonylation (entries 3 and 4). Switching
from violet LEDs (390 nm) to either blue LEDs (427 nm), ambient
light, or dark conditions significantly lowered the yield (entries
5-7). The use of a balloon of CO (1 atm) instead of 2 atm CO was
suboptimal, although the reaction proceeded in 58% yield
(entry 8). Decreasing the reaction time to 20 h led to incomplete
2 atm CO
X
390 nm LEDs
Efficiently transforms chlorides
and bromides
NR2
R
R
1.3 equiv 1° or 2° amine
or ammonium carbamate
2 equiv TMP, t-amyl-OH
Broad reaction scope
X = Cl or Br
1o, 2o, or 3o amides
Mild reaction conditions
Fig. 1. Cobalt-catalyzed aminocarbonylations of sp2 C–X electrophiles.
Metal carbonyl complexes (e.g., Co2(CO)8) have been shown
to catalyze carbonylative transformations of (hetero)aryl
halides using phase-transfer catalysis or visible light promotion,
most notably in alkoxycarbonylations.5 In these reactions, the
strongly basic reaction conditions are proposed to generate
a. Department of Chemistry, The University of North Carolina at Chapel Hill, Chapel
Hill, North Carolina 27599, United States.
† Electronic Supplementary Information (ESI) available: Experimental details and
characterization data. See DOI: 10.1039/x0xx00000x
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conversion (entry 9). Control experiments indicated that substrate and a few others irradiation at 370 nm slightly
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removing TMP lowered reaction efficiency (entry 10), and no improved reaction efficiency. Electron-pDoOorI: 1a0r.y1l03b9r/oDm0SiCd0e2s17a8rDe
reaction took place in the absence of Co2(CO)8 (entry 11).
also good coupling partners in the aminocarbonylation
(substrates 15-18), with the decreased yield of aryl nitrile 18
attributed to undesired reactivity of the nitrile functionality.
Cyclooctenyl bromide 19 and (E)-(2-bromovinyl)benzene 20
delivered aminocarbonylation products in 94% and 50% yield
(76:24 E:Z), respectively, indicating the viability of vinyl halide
substrates.
Table 1. Cobalt-catalyzed aminocarbonylation of 1-bromo-4-methoxybenzene with
piperidine.
O
5 mol % Co2(CO)8
Br
HN
2 atm CO
+
N
390 nm LEDs
2 equiv TMP
t-amyl-OH, 48 h
MeO
MeO
1
1.3 equiv
We additionally surveyed several classes of common
heterocyclic bromides, with the aminocarbonylations
proceeding in good to excellent yields. Bromopyridines
(substrates 21-23), 3-bromofuran (24), and 6-bromoquinoline
(25) all delivered the corresponding amide products in good
entry
variation from standard conditions above
none
yield (%)a
99b
99
1
2
10 mol % K[Co(CO)4] instead of Co2(CO)8
10 mol % Mn2(CO)10 instead of Co2(CO)8
10 mol % CoCl2 instead of Co2(CO)8
427 nm LEDs instead of 390 nm LEDs
ambient light, 50 oC instead of 390 nm LEDs
no light instead of 390 nm LEDs
1 atm CO (balloon) instead of 2 atm CO
20 h instead of 48 h
3
<2
4
<2
5
10
yield. We also examined the reactions of
a set of
6
<2
7
<2
bromo(aza)indoles (substrates 26-28) which were similarly
successful. We additionally performed the aminocarbonylation
of 1-bromo-4-methoxybenzene (1) on a one-gram scale in 96%
isolated yield with no change in reaction conditions. In short,
Figure 2 (top) clearly indicates that the cobalt-catalyzed
aminocarbonylations of (hetero)aryl and vinyl bromides
proceed with notable efficiency across a broad range of
important substrates.
Owing to their wider availability and lower cost than other
electrophiles, (hetero)aryl chlorides are attractive substrates
for carbonylative processes. These substrates also pose
significant limitations in palladium-catalyzed carbonylations, as
the presence of CO is known to present significant challenges in
the catalytic activation of these substrates.1a,3a We next
explored the use of (hetero)aryl chlorides in the
aminocarbonylation (Figure 2, bottom). While the overall levels
8
58
9
73
10
11
no TMP
69
no Co2(CO)8
<2
Reactions were performed with [1]0 = 0.40 M. aYields determined by 1H NMR
spectroscopy of crude reaction mixture using an internal standard. bIsolated yield.
A diverse array of (hetero)aryl and vinyl electrophiles are
excellent substrates for the aminocarbonylation, as
demonstrated in Figure 2 using piperidine as a representative
nucleophile. Aminocarbonylations of electron-rich and
electronically neutral aryl electrophiles proceed in good to
quantitative yields across a range of substitution patterns, as
demonstrated by the reactions of substrates 1-14. Aryl triflates
react comparably to aryl bromides, as indicated by the
quantitative aminocarbonylation of substrate 8. For this
O
5 mol % Co2(CO)8
X
HN
2 atm CO
+
N
R
390 nm LEDs
2 equiv TMP
t-amyl-OH, 48 h
R
1.3 equiv
Bromide Electrophiles:
X
Br
OMe
Me
Br
Br
Br
Br
Br
MeO
Br
Br
Br
Br
MeO
Me
tBu
OH
Br
7, X = Br, >99% yielda
8, X = OTf, >99% yieldb
6
9
10
91% yield
1
2
3
4
5
99% yield
99% yielda
>99% yield
96% yield
94% yield
99% yield
77% yield
Br
Br
Br
Br
Br
Br
Br
pinB
MeO2C
F3C
PivO
F
NC
13
18
11
12
14
15
88% yielda
16
96% yield
17
19
92% yield
87% yielda
80% yielda
94% yield
84% yieldb
33% yieldb,c
78% yieldb
Br
Br
Br
Br
Br
Br
N
Br
N
N
N
N
Br
O
N
N
N
Boc
Boc
H
20
25
21
22
51% yield
23
24
77% yield
26
27
28
50% yieldb
73% yield
>99% yielda
83% yielda
99% yielda
52% yieldb
77% yieldd
76:24 E:Z
Chloride Electrophiles:
Cl
Cl
Cl
Cl
Cl
Cl
Cl
N
N
N
MeO2C
F3C
NC
29
31
33
30
80% yield
32
59% yielda
34
84% yield
35
59% yield
44% yielde
91% yieldb
43% yieldb,c
Fig. 2. Aminocarbonylation of diverse (hetero)aryl electrophiles. Yields are of isolated product unless otherwise noted. a10 mol % Co2(CO)8 used as catalyst. b10 mol % Co2(CO)8
used as catalyst under 370 nm LEDs. cCyclohexylamine used as the nucleophile, reaction time of 24 h. dSubstrate HCl salt used, 3 equiv of TMP used as base. e20 mol % Co2(CO)8
used as catalyst, reaction time of 144 h.
2 | J. Name., 2012, 00, 1-3
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of reactivity were lower than that of bromides, promising catalyst to deliver benzoic acid 46 in 82% yield (see Supporting
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DOI: 10.1039/D0SC02178D
results were obtained across several substrates. The Information for further details).
aminocarbonylation of chlorobenzene (29) proceeded in
moderate yield (44%) after an extended reaction time and an
increase in catalyst loading, while the reaction of 2-
chloronapthalene (30) proceeded under standard conditions in
good yield (80%). The aminocarbonylations of electron-poor
aryl chlorides were similar to their bromide counterparts
(substrates 31-33), whereas reactions of electron-rich aryl
chlorides gave poor conversions and are a current limitation
likely owing to higher reduction potentials. As expected,
heteroaryl chlorides also reacted efficiently, as 2-chloropyridine
(34) and 2-chloropyrazine (35) delivered aminocarbonylation
products in 84% and 59% yield, respectively.
Fig. 4. UV-vis absorption spectra of bromobenzene and KCo(CO)4 in THF with [10 M].
O
5 mol % Co2(CO)8
Br
2 atm CO
+
R2NH
NR2
390 nm LEDs
2 equiv TMP
t-amyl-OH, 48 h
Despite the clear potential for cobalt catalysis in the
carbonylative functionalization of sp2 C–X electrophiles, the
mechanistic details of this class of transformations remain
obscure. While previous studies have speculated that
photochemical charge transfer of a donor-acceptor complex
MeO
1.3 equiv
MeO
MeO
O
O
O
O
Bn
Cy
N
NEt2
N
N
H
O
Me
MeO
MeO
MeO
36
99% yield
37
81% yield
38
81% yield
39
77% yielda
—
involving the electrophile and Co(CO)4 could be involved,
there is no experimental evidence for such a step.5c In order to
gain insight into this key step, we performed UV-vis
spectroscopic measurements on bromobenzene, KCo(CO)4
(used as a proxy for cobaltate formed in situ under our reaction
conditions, and also a viable catalyst–see Table 1, entry 2), and
the combination of the two in THF at 10 M of the cobaltate
ion. As clearly indicated in Figure 4, we observed an increase in
absorbance (max = 275 nm) upon mixing the two species; this
peak is proposed to arise from the absorption of a donor-
acceptor complex formed from the bromobenzene and the
cobaltate, providing support for such a complex in the light-
promoted activation via cobaltate catalysis.
O
O
O
nHex
N
N
H
Cl
N
H
H
MeO
MeO
MeO
40
41
42
75% yielda
48% yielda
89% yield
O
O
R
O
N
H
N
H
CO2Et
MeO
MeO
MeO
b
NH
43
44
76% yield
45
46
(R = NH2) 46% yield
(R = OH) 82% yield
93% yielda
c
Fig. 3. Cobalt-catalyzed aminocarbonylation of 1-bromo-4-methoxybenzene using
diverse amine nucleophiles. aReaction time of 24 h. b10 mol % Co2(CO)8 used as catalyst
with ammonium carbamate as nucleophile in the presence of 4Å molecular sieves. c10
mol % KCo(CO)4 used as catalyst with 4.0 equiv of KOH as nucleophile.
*
[Co(CO)4]
We continued by evaluating the scope of the amine
nucleophiles permissible in the aminocarbonylation, which was
also quite broad. Cyclic and acyclic secondary amines afforded
benzamides 36-38 in good to excellent yield. Primary amines
were also useful coupling partners, as demonstrated by the
synthesis of products 39-44 using a diverse set of common
amine nucleophiles. We have also obtained a promising
preliminary result indicating the potential for the preparation of
primary amides using our system. Aminocarbonylation using
ammonium carbamate as an in situ source of ammonia
produced amide 45 in moderate yield (46%). Notably, the
catalytic carbonylative coupling of (hetero)aryl electrophiles
with ammonia remains a significant challenge in catalysis, with
few successful systems to date even involving precious
palladium catalysis with tuned phosphine ligands.3a,8 Finally, we
also achieved preliminary results for alkoxycarbonylation and
carboxylation using substrate 1 with only minor changes. The
alkoxycarbonylation proceeded in 69% yield using 2,2,2-
trifluoroethanol with Ph3SiCo(CO)4 as catalyst, and the
carboxylation used KOH as the nucleophile with KCo(CO)4 as
h
ET
Br
-
[Co(CO)4]
[Co(CO)4]
Br
Br
PhBr
R2NH
Br
Co2(CO)8
[Co(CO)3(R2NH)] [Co(CO)4]
O
[Co(CO)4]
Ph
NR2
O
base + R2NH + CO
Ph
Co(CO)3
Co(CO)4
Ph
Scheme 1. Plausible catalytic cycle for the cobalt-catalyzed aminocarbonylation.
A
mechanistic proposal for the cobalt-catalyzed
aminocarbonylation is depicted in Scheme 1.
Octacarbonyldicobalt first disproportionates to the cobaltate
anion by addition of the amine or TMP.9 The active cobaltate
next coordinates to the (hetero)aryl or vinyl electrophile,
followed by a reversible light-promoted charge transfer of the
donor-acceptor complex. Loss of the halide (or triflate) through
an SRN1 mechanism leads to a radical pair which recombines in
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M. Freckmann, T. E. Barder, S. L. Buchwald, J. Org. Chem.
the solvent cage to form a (hetero)aryl or vinyl cobalt
species.5b,10 This intermediate undergoes CO migratory
insertion to generate an acylcobalt which is then substituted by
the amine nucleophile to deliver the product and regenerate
the catalyst.
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2008, 73, 7102–7107; (c) C. F. J. BarDnOarI:d1,0.O10r3g9a/nDo0mSCe0t2a1l7l8icDs
2008, 27, 5402–5422; (d) S. D. Friis, T. Skrydstrup, S. L.
Buchwald, Org. Lett. 2014, 16, 4296–4299; (e) S. N. Gockel, K.
L. Hull, Org. Lett. 2015, 17, 3236–3239.
4
5
For aminocarbonylations not involving simple amine coupling
partners (aryl carbamoylation), see: (a) X.-P. Wen, Y.-L. Han,
J.-X. Chen, RSC Adv. 2017, 7, 45107–45112; (b) C. M. Lindsay,
D. A. Widdowson, J. Chem. Soc. Perkin Trans. 1 1988, No. 3,
569; (c) N. Alandini, L. Buzzetti, G. Favi, T. Schulte, L. Candish,
K. D. Collins, P. Melchiorre, Angew. Chem. Int. Ed. 2020, 59,
5248–5253.
(a) J.-J. Brunet, C. Sidot, B. Loubinoux, P. Caubère, J. Org.
Chem. 1979, 44, 2199–2202; (b) J.-J. Brunet, C. Sidot, P.
Caubère, Tetrahedron Lett. 1981, 22, 1013–1016; (c) J.-J.
Brunet, C. Sidot, P. Caubère, J. Org. Chem. 1983, 48, 1166–
1171; (d) J. Marchal, J. Bodiguel, Y. Fort, P. Caubère, J. Org.
Chem. 1995, 60, 8336–8340; (e) R. Vanderesse, J. Marchal, P.
Caubère, Synth. Commun. 1993, 23, 1361–1370.
J.-J. Brunet, C. Sidot, P. Caubère, J. Organomet. Chem. 1981,
204, 229–241.
B. T. Sargent, E. J. Alexanian, Angew. Chem. Int. Ed. 2019, 58,
9533–9536.
(a) X. Qi, H.-J. Ai, C.-X. Cai, J.-B. Peng, J. Ying, X.-F. Wu, Eur. J.
Org. Chem. 2017, 7222–7225; (b) A. Schnyder, M. Beller, G.
Mehltretter, T. Nsenda, M. Studer, A. F. Indolese, J. Org.
Chem. 2001, 66, 4311–4315.
Conclusions
In conclusion, we have developed a visible-light promoted,
cobalt-catalyzed aminocarbonylation of diverse sp2 C–X
electrophiles. The broad scope of the reaction extends to the
use of (hetero)aryl and vinyl bromides, chlorides, and triflates
with a range of amine nucleophiles, including an ammonia
surrogate. The overall scope of the cobalt-catalyzed
aminocarbonylation rivals that of the common phosphine-
ligated, palladium-catalyzed methods, and proceeds at low CO
pressure, ambient temperatures, and uses common visible light
LEDs. Our mechanistic studies provide evidence for the
important role of a donor-acceptor complex between cobaltate
and (hetero)aryl electrophiles with implications beyond the
present work. We anticipate that the notable practicality of this
inexpensive cobalt-based catalytic system will prove enabling in
carbonylative catalysis. Ongoing efforts will continue to develop
carbonylative transformations for synthesis featuring anionic
metal catalysis.
6
7
8
9
(a) P. L. Pauson, J. P. Stambuli, T.-C. Chou, B.-C. Hong,
Octacarbonyldicobalt. In Encyclopedia of Reagents for
Organic Synthesis; 2014; pp 1–26; (b) J. Guo, H. D. Pham, Y.-B.
Wu, D. Zhang, X. Wang, ACS Catal. 2020, 10, 1520–1527.
10 J. F. Bunnett, Acc. Chem. Res. 1978, 11, 413–420.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
This work was supported by Award No. R35 GM131708 from the
National Institute of General Medical Sciences. We thank the
UNC Department of Chemistry Mass Spectrometry Core
Laboratory for assistance with MS analysis, supported by the
National Science Foundation under award number CHE
1726291. We thank Brendon Sargent (University of North
Carolina—Chapel Hill) for assistance with optimization and
helpful discussions. We also thank Carla Morton (UNC—CH) for
assistance with UV-vis spectroscopic measurements and Xander
Deetz (UNC—CH) for assistance with calculation of the donor-
acceptor binding constant.
Notes and references
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