Visible-Light-Driven alkyne hydro-/carbocarboxylation using CO2 via iridium/cobalt dual catalysis for divergent heterocycle synthesis

Article abstract of DOI:10.1021/jacs.8b01561

We present herein the first visible-light-driven hydrocarboxylation as well as carbocarboxylation of alkynes using CO₂ via an iridium/cobalt dual catalysis. Such transformations provide access to various pharmaceutically important heterocycles in a one-pot procedure from readily available alkynes. Coumarins, 2-quinolones, and 2-benzoxepinones were directly accessed through a one-pot alkyne hydrocarboxylation/alkene isomerization/cyclization sequence in which the Ir photocatalyst serves a dual role to promote single-electron transfer in alkyne hydrocarboxylation and energy transfer in the subsequent alkene isomerization. Moreover, an unprecedented cobalt carboxylation/acyl migration cascade enables alkyne difunctionalization to introduce γ-hydroxybutenolides with high efficiency. We expect that this cascade strategy will inspire new perspectives for alkyne and alkene difunctionalization.

Full text of DOI:10.1021/jacs.8b01561

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Visible-Light-Driven Alkyne Hydro-/Carbocarboxylation Using CO2
via Iridium/Cobalt Dual Catalysis for Divergent Heterocycle Synthesis
Jing Hou, Aloysius Ee, Wei Feng, Jin-Hui Xu, Yu Zhao, and Jie Wu
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b01561 • Publication Date (Web): 29 Mar 2018
Downloaded from http://pubs.acs.org on March 29, 2018
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Journal of the American Chemical Society
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Visible-Light-Driven Alkyne Hydro-/Carbocarboxylation Using CO2
via Iridium/Cobalt Dual Catalysis for Divergent Heterocycle Synthe-
sis
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Jing Hou, Aloysius Ee, Wei Feng, JinꢀHui Xu, Yu Zhao* and Jie Wu*
Department of Chemistry, National University of Singapore, 3 Science Drive 3, Republic of Singapore, 117543.
ABSTRACT: We present herein the first visibleꢀlightꢀdriven hydrocarboxylation as well as carbocarboxylation of alkynes using
CO via iridium/cobalt dual catalysis. Such transformations provide access to various pharmaceutically important heterocycles in a
2
oneꢀpot procedure from readily available alkynes. Coumarins, 2ꢀquinolones, and 2ꢀbenzoxepinones were directly accessed through
a oneꢀpot alkyne hydrocarboxylation/alkene isomerization/cyclization sequence, in which the Ir photocatalyst serves a dual role to
promote single electron transfer in alkyne hydrocarboxylation and energy transfer in the subsequent alkene isomerization. Moreoꢀ
ver, an unprecedented cobaltꢀcarboxylation/acyl migration cascade enables alkyne difunctionalization to introduce γꢀ
hydroxybutenolides in high efficiency. We expect that this cascade strategy will inspire new perspectives for alkyne and alkene
difunctionalization.
3
INTRODUCTION
formations. However, breakthrough for lightꢀdriven CO
2
ꢀ
fixation via C−C bond formation to deliver carboxylic acids
Carbon dioxide is an attractive renewable C feedstock due
to its abundance, low cost, and nontoxicity. Utilization of CO2
1
and derivatives has not been achieved until very recently. In
2
015, Murakami and coꢀworkers reported the first example of
to replace toxic C building blocks, such as phosgene, for fine
3
1
direct carboxylation of benzylic C(sp )−H bonds using CO
under UV or sunlight irradiation. In 2017, the Jamison group
disclosed a straightforward synthesis of αꢀamino acid derivaꢀ
2
chemical synthesis has received considerable momentum in
4
1
the last decade. One particular intriguing transformation is the
catalytic hydrocarboxylation of alkynes with CO , in which
2
tives using amines and CO as cheap feedstocks under UV
2
several catalytic systems have been developed for this transꢀ
formation. However, the patterns of molecular scaffolds acꢀ
cessible by existing protocols are mainly limited to linear
5
light irradiation. Very recently, several groups sequentially
reported studies on visibleꢀlightꢀdriven carboxylation of alꢀ
6
kenes and organo halides, without the usage of metallic reꢀ
2
acrylic acids and 2ꢀpyrones. Moreover, stoichiometric amount
ductants. However, to the best of our knowledge, lightꢀ
of metallic reagents such as Et Zn, silanes, Mn, or Zn powder
2
promoted carboxylation of alkynes with CO has not been
2
are required as the reducing agents in hydrocarboxylation
(Figure 1a). Thus, the introduction of catalytic activation
modes that are environmentally benign and capable of achievꢀ
ing a higher degree of structural diversity are highly desirable.
developed so far. In contrast to conventional carboxylation of
alkynes, we envisioned that photoꢀpromoted transformation
may provide opportunities to access new structural diversity.
For instance, the alkyne carboxylation products, especially
aryl substituted olefins, are prone to undergo E,Zꢀ
isomerization in the presence of a photocatalyst through a
7
tripletꢀtriplet energy transfer process. As part of our ongoing
efforts in developing visibleꢀlightꢀpromoted transformations
8
using inexpensive gaseous feedstocks, we report herein the
carboxylation of alkynes to directly access various types of
compounds including biological important heterocycles using
CO as feedstocks through the synergistic combination of phoꢀ
2
toredox and cobalt catalysis (Figure 1b).
RESULTS AND DISUSSION
Our study was initiated by employing 1ꢀphenylꢀ1ꢀpropyne
1
a as the model substrate to investigate the hydrocarboxylaꢀ
tion under 1 atm of CO in the presence of a photocatalyst and
2
2b,9
a cobalt catalyst with blue LED irradiation. After extensive
optimization (Table 1), we found that the combination of
Ir(ppy) (dtbbpy)PF (1 mol%), CoBr (10 mol%), dcype (10
Figure 1. Transitionꢀmetalꢀcatalyzed carboxylation of alkynes
with CO2.
2
6
2
Photocatalysis has witnessed dramatic developments over
the past decade, which enables previously inaccessible transꢀ
mol%, bis(dicyclohexylphosphino)ethane) and ZnBr (1 equiv)
2
as the additive in the presence of iPr NEt (3 equiv) provided
2
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Page 2 of 7
the best result, affording vinyl acids in 70% combined yield
(2a:2a’:2a’’=3.3:1:6.7, entry 1). It is worth noting that the
duced. Notably, the Ir/Co dual catalysis protocol could be
extended to aliphatic terminal alkynes to produce 2ꢀpyrones
(Scheme 1b, 3aꢀ3c), which represents a rare example of 2ꢀ
pyrone synthesis via intermolecular [2+2+2] cycloaddition
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
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5
5
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hydrocarboxylation proceeded with CO insertion preferentialꢀ
2
ly at the alkylꢀsubstituted site. CoCl catalyst was less effecꢀ
2
tive than CoBr (entry 2). The choice of phosphine ligand was
between two alkynes and CO at ambient pressure and temꢀ
2
2
11
crucial, as employing other ligands such as PCy or 1,2ꢀ
perature. The reaction with phenylacetylene was also tested.
However, less than 10% 2ꢀpyrone product was obtained, with
significant amount of alkyne trimerization byproducts and
starting materials left.
3
bis(diphenylphosphino)ethane (dppe) resulted in complete
suppression
of
the
reaction
(entry
3).
Using
Ir[dF(CF )ppy] (dtbbpy)PF instead of Ir(ppy) (dtbbpy)PF as
3
2
6
2
6
the photocatalyst gave lower yield (entry 4). Only trace
Scheme 1. VisibleꢀLightꢀDriven CobaltꢀCatalyzed Alkyne
Hydrocarboxylation and [2+2+2] Cycloaddition with
amount of products was detected when using MgBr as addiꢀ
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
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7
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0
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3
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5
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9
0
1
2
3
4
5
6
7
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9
0
1
2
3
4
5
6
7
8
9
0
a,b
tive (entry 5). Three equivalent of Hünig’s base was utilized in
place of the metallic reductant, and decrease in loading led to
lower yield (entry 6). Switching the reaction solvent from
CO2
CO2 (1 atm)
Ir(ppy)2(dtbbpy)PF6 (1 mol%)
a)
CoBr2 (10 mol%), dcype (10 mol%)
iPr2NEt (3 equiv), ZnBr2 (1 equiv)
COOH
R1
MeCN to DMF delivered product 2 in decreased yield (entry
o
R2
R1
R2
2a-2f
7
8
). Hydrocarboxylation did not proceed well at 60 C (entry
CH3CN, Blue LED, r.t., 24 h
1
a-1f
COOHHOOC
Me Ph
). Reaction in the absence of ZnBr yielded 26% of acid
2
Me
COOH
C3H7
COOH
C8H17
products with a significant amount of hydrogenated olefin byꢀ
products (entry 9). No product was detected in the absence of
CoBr , dcype, Ir photocatalyst, iPr NEt or light, demonstrating
Ph
MePh
COOH
C3H7
2
a
2a'
2a''
2b
63%
2c
2
2
0% (2a:2a':2a''= 3.5:1:7.1)c
7
52%
the need for all of these components (entries 10 to 13). Despite
our optimization efforts, only moderate E/Zꢀselectivity was
COOH
Me Me
COOH
COOH
COOH
Ph
1
0
O
O
obtained with arylꢀsubstituted alkynes.
Br
O
O
2d
2e
50%
Ph
2f
2f'
Ph
Table 1. Optimization of Alkyne Hydrocarboxyaltion
5
0%
73% (2f:2f' = 2:1)c
CO2 (1 atm)
Ir(ppy)2(dtbbpy)PF6 (1 mol%)
b)
CO2 (1 atm)
Ir(ppy)2(dtbbpy)PF6 (1 mol%)
CoBr2 (10 mol%), dcype (10 mol%)
iPr NEt (3 equiv), ZnBr (1 equiv)
CoBr2 (10 mol%), dcype (10 mol%)
iPr2NEt (3 equiv), ZnBr2 (1 equiv)
Me
COOH HOOC
+
O
O
Ph
Me
+
Ph
Me
Ph
Me Ph
COOH
CH3CN, Blue LED, r.t., 24 h
2
2
R1
H
1
a
2
a
2a'
2a''
CH CN, Blue LED, r.t., 24 h
3
R1
R1
1g-1i
yield (2a:2a':2a'')a
70% (3.3:1:6.7)
58% (2.5:1:6.1)
3a-3c
O
entry
1
deviation
none
O
O
O
2
3
CoCl2 instead of CoBr2
O
O
PCy3 or dppe instead of dcype
< 2%
nBu
nBu
Ph
Ph
MeOOC
COOMe
3a
47%
3b
49%
3c
42%
Ir[df(CF3)ppy]2(dtbbpy)PF6 instead of
Ir(ppy)2(dtbbpy)PF6
4
54% (4.4:1:5.4)
aReaction conditions: alkyne 1 (0.2 mmol), CO2 (1 atm), Ir(ppy)2(dtbbpy)PF6 (1 mol%), CoBr2
(10 mol%), dcype (10 mol%), ZnBr2 (1 equiv), iPr2NEt (3 equiv) and CH3CN (1 mL) at ambient
temperature under blue LED irradiation for 24 hours. bIsolated yields. cIsomer ratios were
determined by analysis of 1H NMR spectra of the crude reaction mixtures.
5
6
7
8
MgBr2 instead of ZnBr2
<10%
41% (3.3:1:6)
46% (5.2:1:5.2)
< 10 %
iPr2NEt 1.5 equiv instead of 3 equiv.
DMF instead of MeCN
60 oC instead of r.t.
Development of OneꢀPot Aryl Alkyne Hydrocarboxylaꢀ
tion/Alkene Isomerization/Cyclization. Our preliminary
investigation suggested that it was difficult to achieve high
E/Zꢀselectivity for visibleꢀlightꢀmediated aryl alkyne hydroꢀ
carboxylation. Furthermore, encouraged by the formation of 2ꢀ
9
Without ZnBr2
26% (9.5:1:2.5)
1
1
0
1
Without CoBr2 or dcype
no reaction
no reaction
Without Ir(ppy)2(dtbbpy)PF6
1
1
2
3
Without iPr2NEt
no reaction
no reaction
pyrones from alkynes and CO , we turned our attention to
2
heterocycle synthesis. We thus envisioned that the introducꢀ
tion of an ancillary substituent in proximity of the alkyne moiꢀ
ety should be able to direct the E/Z isomerization of the acrylic
acid intermediate, in which the ring closure would drive the
Without light
aIsolated combined yields. Isomer ratios were determined by analysis of 1H NMR spectra
of isolated products.
Scope of PhotoꢀDriven Alkyne Hydrocarboxylation and
2+2+2] Cycloaddition. When the optimal hydrocarboxylaꢀ
12
equilibrium to the Zꢀalkene (Figure 2). In this manner, useful
heterocycles such as coumarins and 2ꢀquinolones, which are
important structural motifs in a myriad of pharmaceutical
compounds that display significant biological properties (e.g.,
[
tion protocol was applied to bisꢀaliphatic substituted alkynes,
Eꢀacrylic acid products were obtained exclusively (Scheme
1
a). Alkene E/Z isomerization was not detected for α,βꢀ
1
3
anticancer, antimicrobial, antiviral, and antiꢀinflammatory),
could be directly prepared from substituted alkynes and CO2.
unsaturated acid products under visibleꢀlightꢀirradiation. The
symmetrical alkyne 1b proceeded to give 2b in 63% yield. A
high degree of regioselectivity was achieved when the two
alkyl substituents were sterically differentiated. Products 2cꢀ
2
e were obtained as the sole regioisomer from 1cꢀ1e, where
CO was inserted adjacent to the less sterically hindered subꢀ
2
stituent. It is worth noting that product 2d bearing an aryl
bromide moiety, which was not compatible with metal reductꢀ
ants, was smoothly produced under the photoꢀdriven condiꢀ
tions. However, in the absence of steric bias in the unsymmetꢀ
rical alkyne starting materials 1f, both regioisomers were proꢀ
2
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Figure 2. Proposed oneꢀpot hydrocarboxylation/alkene isomꢀ
or electronꢀwithdrawing groups (5lꢀ5n) on MOM etherꢀ
containing aryl substituents furnished coumarin products in
good yield. The bulky naphthyl alkyne afforded product 5o in
moderate yield. However, 1,2ꢀdiphenyl alkynes resulted in
very low yield of the desired coumarin 5p, with stilbene deꢀ
tected as the major side product. Moreover, this catalytic proꢀ
tocol was successfully applied to aryl alkynes with an NꢀBoc
carbamate substituent. The corresponding 2ꢀquinolones (5qꢀ5t)
were produced in good yield for both electronꢀrich and elecꢀ
tronꢀpoor aryl substituted alkynes.
1
2
3
4
5
6
7
8
9
erization/cyclization transformation.
Our hypothesis was evaluated by employing phenyl alkyne
4
a with a methoxymethyl (MOM) protected hydroxyl group as
the ancillary substituent. Hydrocarboxylation of 4a under the
optimized conditions gave olefins 2g and 2g’ in 28% and 47%
isolated yields respectively (Scheme 2a, entry 1). When the
reaction was conducted in the absence of ZnBr , the combined
2
yield of acid products decreased to 28% (entry 2). Simple inꢀ
jection of TsOH methanol solution to the hydrocarboxylation
reaction mixture followed by irradiation under blue LED for
another 12 hours produced the desired coumarin product 5a in
Notably, the sevenꢀmembered ring 2ꢀbenzoxepinones (7aꢀ
7c) could be selectively produced by changing phenyletherꢀ
substituted alkynes 4 to the benzyletherꢀsubstituted alkynes 6
(Scheme 3b), highlighting the utility of this catalytic method
to access heterocycles with different ring sizes.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
7
3% isolated yield (entry 3). In the absence of light for the
second step, 5a was only obtained in 44% yield, together with
5% yield of MOM cleaved 2h (entry 4). To further support
2
that the E/Z isomerization was induced by lightꢀdriven Ir caꢀ
talysis, conversion of preꢀsynthesized 2g to 5a was attempted
(Scheme 2b). In the presence of both Ir photocatalyst and light,
a full conversion to 5a took place. In the absence of either Ir
catalyst or light, in contrast, no cyclization but complete conꢀ
version of 2g to 2h was observed (Scheme 2b).
Scheme 3. Scope of the OneꢀPot Aryl Alkyne Hydrocarꢀ
a,b
boxylation/Alkene Isomerization/Cyclization
a)
CO2 (1 atm)
R1
Ir(ppy)2(dtbbpy)PF6 (1 mol%)
CoBr2 (10 mol%), dcype (10 mol%)
iPr2NEt (3 equiv), ZnBr2 (1 equiv)
R1
O
R2
TsOH (6 equiv)
R2
PG
Y
CH3CN, Blue LED, r.t., 24 h
MeOH/CH3CN, r.t.
Blue LED, 12 h
Y
Y = O, NH
5a-5t
Y-PG = OMOM, NHBoc
a-4t
Scheme 2. Control Experiments of OneꢀPot Hydrocarꢀ
boxylation/Alkene Isomerization/Cyclization
4
a
coumarin:
a)
CO2 (1 atm)
COOH
nBu
Me
O
nHep
Ph
nBu
Ir(ppy)2(dtbbpy)PF6 (1 mol%)
Ar CoBr2 (10 mol%), dcype (10 mol%)
iPr2NEt (3 equiv), ZnBr2 (1 equiv)
Ar
nBu
TsOH (6 equiv)
MeOH/CH3CN
O
5b
O
O
O
5a
O
O
5c
O
O
O
2g
5d
5a
73%, 71%c
75%
72%
65%
CH3CN, Blue LED, r.t., 24 h
nBu
Blue LED, r.t., 12 h
COOH
nBu
nBu
step 1
step 2
HO
OBn
COOMe
O
Ar
COOH
g'
OMOM
4a
2
O
O
O
O
O
O
O
5h
O
Ar =
5
e
5f
5g
2h
47%
69%
70%
47%
O
2g (%)b
2g' (%)b
5a (%)b
Cy
O
Me
nBu
MeO
nBu
entry
step
deviation
none
nBu
1
2
1
1
28
21
47
7
O
O
O
O
O
O
O
without ZnBr2
none
5i
5j
5k
5l
45%
72%
65%
72%
3
1+2
1+2
73
44
MeOOC
nBu
F
nBu
Ph
4c
without light (the second step)
nBu
aStandard conditions: 4a (0.2 mmol), CO2 (1 atm), Ir(ppy)2(dtbbpy)PF6 (1 mol%), CoBr2 (10 mol%), dcype
O
O
O
O
O
O
O
O
(10 mol%), ZnBr2 (1 equiv), iPr2NEt (3 equiv) and CH3CN (1 mL) at ambient temperature under blue LED
5m
5n
5o
5p
6
2%
72%
51%
<10%
irradiation for 24 hours. Then added TsOH (6 equiv. in MeOH) at ambient temperature under blue LED
irradiation for another 12 hours. bIsolated yields. c2h was isolated as by-product.
2-quinolones:
b)
nBu
Me
O
Me
nBu
F
nBu
COOH Ir(ppy)2(dtbbpy)PF6 (1mol%)
MOMO
MOMO
TsOH (6 equiv)
MeOH/CH3CN
C4H9
O
N
H
O
N
H
N
O
N
O
nBu
H
H
5
q
5r
67%
5s
58%
5t
70%
2-benzoxepinone
Blue LED, r.t., 12 h
O
7
0%
2g
5a, 100% conv.
CO2 (1 atm)
Ir(ppy)2(dtbbpy)PF6 (1 mol%)
COOH
b)
OH
nBu
TsOH (6 equiv)
MeOH/CH3CN
COOH
nBu CoBr2 (10 mol%), dcype (10 mol%)
nBu
O
iPr2NEt (3 equiv), ZnBr2 (1 equiv)
TsOH (6 equiv)
nBu
2h, 100% conv.
OH
O
Blue LED, r.t., 12 h
No Ir catalyst
MeOH/CH CN, r.t.
CH3CN, Blue LED, r.t., 24 h
3
OMOM
R
2g
Blue LED, 12 h
7a: R = H, 50%
7b: R = Me, 51%
7c: R = Ph, 46%
COOH
R
6a-6c
Ir(ppy)2(dtbbpy)PF6 (1mol%)
TsOH (6 equiv)
MOMO
COOH
nBu
MeOH/CH3CN
c)
CO2 (1 atm)
nBu
r.t., 12 h
No light
nBu
nBu
Ir(ppy)2(dtbbpy)PF6 (1 mol%)
CoBr2 (10 mol%), dcype (10 mol%)
iPr2NEt (3 equiv), ZnBr2 (1 equiv)
2g
2h, 100% conv.
nBu
OH
3
CH CN, Blue LED, r.t., 24 h
O
4
u
8,
75% yield
Scope of OneꢀPot Aryl Alkyne Hydrocarboxylaꢀ
tion/Alkene Isomerization/Cyclization. Adopting the optiꢀ
mized oneꢀpot sequential transformation protocol, the generalꢀ
ity of this method was evaluated via a variety of aryl substitutꢀ
ed alkynes bearing a phenyl ether substituent (Scheme 3a).
Replacing the protecting group from MOM to EOM (ethoxy
methyl) did not affect the reactivity, providing 5a in 71% yield.
The sequential transformation proceeded well with various
alkynes bearing different aliphatic substituents to deliver the
corresponding coumarin products, such as methyl (5b), nꢀ
heptyl (5c), or even steric bulky ones like cyclopropyl (5h) or
cyclohexyl (5i). Substrates bearing functional groups such as
phenyl groups (5d), ethers (5e, 5f), or esters (5g) were well
tolerated. Furthermore, alkynes with electronꢀdonating (5j, 5k)
CO2 (1 atm)
Ir(ppy) (dtbbpy)PF6 (1 mol%)
2
CoBr2 (10 mol%), dcype (10 mol%)
nBu
iPr2NEt (3 equiv), ZnBr2 (1 equiv)
NH2
3
CH CN, Blue LED, r.t., 24 h
N
O
H
4v
5q, 63% yield
aReaction conditions: alkyne 4 or 6 (0.2 mmol), CO2 (1 atm), Ir(ppy)2(dtbbpy)PF6 (1 mol%), CoBr2 (10
mol%), dcype (10 mol%), ZnBr2 (1 equiv), iPr2NEt (3 equiv) and CH3CN (1 mL) at ambient
temperature under blue LED irradiation for 24 hours. Then added TsOH (6 equiv, in MeOH) at ambient
temperature under blue LED irradiation for another 12 hours. bIsolated yields. cUsing EOM as the
protection group, EOM = ethoxy methyl.
To achieve a more efficient protocol to access coumarins or
ꢀquinolones, the substrates without protecting group on the
2
phenol or aniline were attempted (Scheme 3c). Alkyne 4u
bearing a free phenol did not incorporate CO but led to the
2
formation of benzofuran 8. This transformation proceeded
3
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Journal of the American Chemical Society
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smoothly as well in the absence of CO . On the other hand,
alkyne 4v with a free aniline directly delivered 2ꢀquinolone 5q
with good yield under the photo hydrocarboxylation condiꢀ
tions, representing a more stepꢀeconomic protocol to access 2ꢀ
quinolone compounds (Scheme 3c).
pounds (e.g. PD 156707), which exhibits important bioactiviꢀ
ties such as antiꢀinflammatory, anticancer, and antimicrobial
activities. Rapid and effective synthesis of highly functionalꢀ
ized γꢀhydroxybutenolides, especially from inexpensive feedꢀ
2
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
15
stock CO , is of considerable importance for both synthetic
2
16
and medicinal chemistry.
Scheme 4. Photosynthesis of γꢀHydroxybutenolides from
a,b
orthoꢀEster Substituted Aryl Alkynes and CO2
The scope of the visibleꢀlightꢀdriven γꢀhydroxybutenolide
synthesis was subsequently investigated. Various alkyl subꢀ
stituents on the alkyne such as methyl (10a), nbutyl (10b),
cyclopropyl (10c), sterically demanding cyclohexyl (10d),
phenylethyl (10e) and methoxymethyl (10f) were well toleratꢀ
ed to deliver γꢀhydroxybutenolides in moderate to good yields.
Importantly, only one regioisomer was generated in all cases.
Reactions with phenyl acetates bearing either an electronꢀ
donating (10gꢀ10i) or an electronꢀwithdrawn substituent (10jꢀ
10l) proceeded effectively. Changing phenyl acetate to naphꢀ
thyl acetate delivered γꢀhydroxybutenolide 10m in moderate
CO2 (1 atm)
HO
R3
a)
R1
Ir(ppy)2(dtbbpy)PF6 (1 mol%)
CoBr2 (10 mol%), dcype (10 mol%)
iPr2NEt (3 equiv), ZnBr2 (1 equiv)
O
O
R3
R2
R2
R1
O
O
CH3CN, Blue LED, r.t., 24 h
OH
9
a-9u
10a-10u
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
HO
Me
HO
Me
HO
Me
HO
Me
HO
Me
O
O
O
O
O
O
O
O
O
O
Me
nBu
Cy
OH
OH
10a
0%
OH
10b
73%
OH
OH
10d
43%
Ph
10c
42%
10e
65%
7
HO
Me
HO
Me
HO
Me
HO
HO
O
O
O
Me
O
O
Me
O
O
O
O
O
O
Me
MeO
nBu
nBu
nBu
nBu
yield. This CO ꢀbased synthetic method can be further exꢀ
OH OMe
0f
47%
HO
OH
10g
63%
Me
OH
10h
65%
OH
O
OH
10j
71%
2
1
10i
50%
panded effectively to include various aliphatic substituted acyl
groups with different steric effects (10nꢀ10t). However, benꢀ
zoic ester was a poor candidate for this cascade transformation
HO
HO
HO
Et
HO
O
Me
O
Me
O
O
Me
O
Ph
O
O
O
O
MeOOC
nBu
nBu
nBu
nBu
nBu
OH
OH
OH
10n
OH
10o
(10u). Notably, the use of 2,6ꢀbisalkynyl phenyl acetates diꢀ
OH
1
0k
10l
10m
7
0%
67%
51%
72%
70%
rectly provided γꢀhydroxybutenolides 10vꢀ10x with a benzofuꢀ
ran moiety, in which one alkyne performed cobaltꢀ
carboxylation/acyl migration cascade, while the other alkyne
substituent underwent intramolecular cyclization with the inꢀ
situ generated phenoxide to form the benzofuran substituent
(Scheme 4b). The structural configuration of 10a was clearly
determined by Xꢀray diffraction using 4ꢀnitrobenzoate derivaꢀ
tive 11a, and those of other products 10 were assigned by
analogy.
HO
HO
HO
tBu
HO
HO
O
O
O
O
O
O
O
Ph
MeOOC
O
O
O
nBu
nBu
nBu
nBu
nBu
OH
OH
10q
66%
OH
10r
65%
OH
10s
70%
OH
1
0p
10t
71%
6
6%
HO
Ph
O2N
O
Me
O
O
O
O
nBu
O
OH
0u
20%
O
Me
1
O
11a
NO2
Scheme 5. GramꢀScale Scale Synthesis of Heterocycles
b)
CO2 (1 atm)
Ir(ppy)2(dtbbpy)PF6 (1 mol%)
CoBr2 (10 mol%), dcype (10 mol%)
R1
O
HO
R3
O
R3
R2
O
iPr2NEt (3 equiv), ZnBr2 (1 equiv)
O
R2
R1
CH3CN, Blue LED, r.t., 24 h
9v-9x
O
1
0v-10x
R1
R1
nBu
HO
OMe
nBu
HO
OMe
nBu
HO
OMe
O
O
O
O
O
O
nBu
nBu
nBu
F
Me
O
Me
10x
42%
1
4
0v
0%
10w
56%
aReaction conditions: alkyne 9 (0.2 mmol), CO2 (1 atm), Ir(ppy)2(dtbbpy)PF6 (1 mol%), CoBr2 (10 mol%), dcype (10
mol%), ZnBr2 (1 equiv), iPr2NEt (3 equiv) and CH3CN (1 mL) at ambient temperature under blue LED irradiation for 24
hours. bIsolated yields.
Development of VisibleꢀLightꢀDriven Difunctionalizaꢀ
To further demonstrate the synthetic utility of this methodꢀ
ology, the synthesis of coumarins and γꢀhydroxybutenolides
were amenable to scaleꢀup to gram quantities (Scheme 5).
However, lower yield was observed compared to the smallꢀ
scale reactions due to the incomplete conversion of starting
materials.
tion of Alkynes with CO to Access γꢀHydroxybutenolides.
2
Based on the formation of 2ꢀpyrones from terminal aliphatic
alkynes (Scheme 1b), we speculated that a fiveꢀmembered
cobaltacycle intermediate derived from the Co species, alꢀ
kynes, and CO might be involved under the optimal reaction
2
2b
conditions. To further expand the application of this aforeꢀ
mentioned strategy, we postulated that the incorporation of an
electrophilic substituent in the alkyne substrate may trigger a
kinetically favored intramolecular addition of the cobaltacycle
intermediate to realize alkyne difunctionalization. Various
electrophilic substituents were therefore evaluated (Figure S1),
and we were delighted to observe that γꢀhydroxybutenolides
Scheme 6. Using Zn Powder as the Reductant and Deuterꢀ
iumꢀLabeling Experiments
could be synthesized using CO with orthoꢀester substituted
2
aryl alkynes 9 under the photoredox/cobalt dual catalytic conꢀ
ditions, featuring an unprecedented intramolecular cobaltꢀ
14
carboxylation/acyl migration cascade reaction (Scheme 4). γꢀ
Hydroxybutenolides are important structural motifs widely
found in natural products (e.g. ianthellidone G, manoalide,
petrosaspongiolide M) and artificial pharmaceutical comꢀ
4
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Journal of the American Chemical Society
a) Using Zinc as the Reductant
nBu
using Zn powder as the reductant. Treatment of alkyne 4a with
stoichiometric amount of CoBr and dcype ligand with two
CO2 (1 atm), Zn (2 equiv)
CoBr2 (1 equiv), dcype (1 equiv)
1
2
3
4
5
6
7
8
9
OMOM
2
(
E)
ZnBr2 (1 equiv)
COOH
equivalent of Zn powder in the presence of CO , without any
2
CH3CN, r.t., 24 h
nBu
2g, 73% yield
hydride or proton source, resulted in product 2g in 73% yield,
exhibiting the same regioselectivity as photoredox conditions
(Scheme 6). Difunctionalization of alkynes was realized based
on this hypothesized cobaltacycle intermediate by incorporatꢀ
ing an intramolecular acyl migration. Moreover, no deuterium
incorporation was observed in the product when the photo
OMOM
4
a
b) Isotopic Experiments
Ir(ppy)2(dtbbpy)PF6 (1 mol%)
CoBr2 (10 mol%), dcype (10 mol%)
iPr2NEt (3 equiv), ZnBr2 (1 equiv)
D/H
3
COOH
nC H
CD3CN, Blue LED, r.t., 24 h
nC H
7
3
7
2b
1% yield (no D incorporated)
hydrocarboxylation was conducted in CD CN, indicating that
6
3
17
CO2
+
nC H
3 7
nC H
3
7
Ir(ppy) (dtbbpy)PF6 (1 mol%)
the hydrogen atom source should arise from iPr NEt. In adꢀ
2
2
1
b
CoBr2 (10 mol%), dcype (10 mol%)
iPr2NEt (3 equiv), ZnBr2 (1 equiv)
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
D/H
COOH
dition, cyclic voltammetry (CV) measurement was conducted
CD3OD, CH3CN, Blue LED, r.t., 24 h
with the complex of CoBr and dcype, which demonstrated
2
II I
nC3H7
nC3H7
d-2b
that the Co complex can be reduced to the Co complex at ꢀ
0.75 V vs SCE in MeCN (Figure S3). The absolute role of
1
5
equiv CD3OD: 40% yield (15% D)
equiv CD3OD: 21% yield (43% D)
ZnBr is unclear at this stage and requires further investigaꢀ
2
Mechanistic Study of Alkyne Hydrocarboxylation. The
production of 2ꢀpyrones with terminal aliphatic alkynes
Scheme 1b) suggested a fiveꢀmembered cobaltacycle interꢀ
mediate derived from the Co species, alkynes, and CO in the
presence of photoredox and cobalt catalysis. The fiveꢀ
membered cobaltacycle intermediate was further supported by
Scheme 7. Proposed Mechanism for Alkyne Carboxylation
tion, even though it has been reported that the ZnBr can stabiꢀ
2
I
18
lize a transient Co species in MeCN, and may facilitate the
regeneration of Co catalyst from the carboxylatocobalt interꢀ
mediate.
(
2
2
b
Tentative mechanistic pathways for alkyne hydrocarboxylaꢀ
tion are proposed in light of all the experimental data (Scheme
give the sevenꢀmembered cobaltacycle G. Subsequent reducꢀ
I
tive elimination will afford 2ꢀpyrone 3 and regenerate Co B
7
,
left). Reductive quenching of visibleꢀlightꢀexcited
When orthoꢀester substituted aryl alkyne 9 is applied as the
Ir(ppy) (dtbbpy)PF by iPr NEt gives rise to an amine radical
substrate (Scheme 7, right), intramolecular addition of the in
2
6
2
II
III II
III
cation and a reduced Ir species, the latter (E [Ir /Ir ] = ꢀ
situ generated C−Co bond to the ester substituent furnishes
1
/2
II
1
(
.51 V vs SCE in MeCN) is then oxidized by Co complex A
E1 = ꢀ0.75 V vs SCE in MeCN) to regenerate Ir . The active
Co species B generated in this step will react with CO and
alkyne substrates to produce the fiveꢀmembered cobaltacycle
the carboꢀcarboxylation intermediate I. The transient complex
III
/2
I
may undergo photoredoxꢀcatalyzed reduction and
I
2
transmetallation with ZnBr to provide zinc complex J and
2
I
regenerate Co species B. Tautomerization of J delivers the γꢀ
2b
III
intermediate C. Subsequent protonolysis of C−Co bond by
cationic amine radicals will deliver the carboxylatocobalt inꢀ
termediate D. The transient complex D may undergo photoreꢀ
keto acrylic zinc species K, which is followed by another tauꢀ
tomerization to accomplish the synthesis of γꢀ
hydroxybutenolide 10.
I
doxꢀcatalyzed reduction to regenerate Co species B, and
Even though the hydrocarboxylation products could be genꢀ
erated without ZnBr , however, in the presence of ZnBr , we
ZnBr may facilitate this step through transmetallation to furꢀ
2
2
2
nish carboxylate E. Finally, the aryl substituted Eꢀ
vinylcarboxylate E can undergo a reversible isomerization to
its Zꢀisomer F through an Irꢀmediated tripletꢀtriplet energy
were unable to exclude the possibility of CoꢀZn transmetallaꢀ
tion of cobaltacycle C to form an alkenylzinc species, which
can undergo subsequent protonation or intramolecular cyclizaꢀ
tion to achieve the same products (Figure S5).
10
transfer process under visibleꢀlightꢀirradiation, following
which an acidꢀmediated intramolecular cyclization delivers
product 5. As for terminal alkynes, insertion of another alkyne
molecule into the fiveꢀmembered cobaltacycle C will occur to
Conclusion
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Journal of the American Chemical Society
Page 6 of 7
In summary, we have disclosed the direct synthesis of variꢀ
ous pharmaceutically important heterocycles, including 2ꢀ
pyrones, coumarines, 2ꢀquinolones, 2ꢀbenzoxepinones, and γꢀ
(5) Seo, H.; Katcher, M. H.; Jamison, T. F. Nat. Chem. 2017, 9,
453.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(
6) (a) Seo, H.; Liu, A.; Jamison, T. F. J. Am. Chem. Soc. 2017,
1
39, 13969. (b) Yatham, V. R.; Shen, Y.; Martin, R. Angew. Chem.,
hydroxybutenolides, from alkynes and CO in a regioꢀ and
2
Int. Ed. 2017, 56, 10915. (c) Ye, J.ꢀH.; Miao, M.; Huang, H.; Yan, S.ꢀ
S.; Yin, Z.ꢀB.; Zhou, W.ꢀJ.; Yu, D.ꢀG. Angew. Chem. Int. Ed. 2017,
56, 15416. (d) Murata, K.; Numasawa, N.; Shimomaki, K.; Takaya,
J.; Iwasawa, N. Chem. Commun. 2017, 53, 3098. (e) Shimomaki, K.;
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M. Chem. Eur. J. 2016, 22, 6524.
stereospecific fashion through the synergistic combination of
photoredox and cobalt catalysis. In the oneꢀpot synthesis of
coumarins and 2ꢀquinolones, the Ir photocatalyst plays a dual
role to promote both the electron transfer in hydrocarboxylaꢀ
tion and the tripletꢀtriplet energy transfer in the subsequent
alkene isomerization. Alkyne difunctionalization has also been
realized through an unprecedented cobaltꢀcarboxylation/acyl
migration cascade to efficiently generate γꢀhydroxybutenolides
(
7) (a) Metternich, J. B.; R. Gilmour, J. Am. Chem. Soc. 2016, 138,
040. (b) Metternich, J. B.; Gilmour R. Synlett 2016, 27, 2541. (c)
Metternich J. B.; Gilmour, R. J. Am. Chem. Soc. 2015, 137, 11254.
d) Singh, K.; Staig, S. J.; Weaver, J. D. J. Am. Chem. Soc. 2014, 136,
275.
(8) Xue, F.; Deng, H.; Xue, C.; Mohamed, D. K. B.; Tang, K. Y.;
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
using CO . We expect that this carbometalation/rearrangement
2
cascade strategy promises to find wide applications with other
types of metallacycles to enable difunctionalization of alkenes
and alkynes.
(
5
Wu, J. Chem. Sci. 2017, 8, 3623.
ASSOCIATED CONTENT
Supporting Information
(9) For an example of the merge of photoredox and Coꢀcatalysis,
see: Ruhl, K. E.; Rovis, T. J. Am. Chem. Soc. 2016, 138, 15527.
(10) (a) Arai, T.; Sakuragi, H.; Tokumaru, K. Bull. Chem. Soc. Jpn.
1982, 55, 2204. (b) Arai, T.; Sakuragi, H.; Tokumaru, K. Chem. Lett.
This material is available free of charge via the Internet at
http://pubs.acs.org.
1
980, 261.
11) For selected examples of Niꢀcatalyzed preparation of pyrones
using CO , see: (a) OliverosꢀCruz, S.; Arevalo, A.; García, J. J. J.
(
2
AUTHOR INFORMATION
Corresponding Author
Organomet. Chem. 2017, 831, 18. (b) Louie, J.; Gibby, J. E.; Farnꢀ
worth, M. V.; Tekavec, T. N. J. Am. Chem. Soc. 2002, 124, 15188. (c)
Tsuda, T.; Kunisada, K.; Nagahama, N.; Morikawa, S.; Saegusa, T.
Synth. Commun. 1989, 19, 1575. (d) Tsuda, T.; Morikawa, S.; Sumiꢀ
ya, R.; Saegusa, T. J. Org. Chem. 1988, 53, 3140. (e) Inoue, Y.; Itoh,
Y.; Hashimoto, H. Chem. Lett. 1978, 633.
zhaoyu@nus.edu.sg; chmjie@nus.edu.sg
Notes
The authors declare no competing financial interests.
(
12) (a) Chen, X.; Qiu, S.; Wang, S.; Wang, H.; Zhai, H. Org. Biꢀ
omol. Chem. 2017, 15, 6349. (b) Zhan, K.; Li, Y. Catalysts 2017, 7,
37.
(13) (a) Medina, F. G.; Marrero, J. G.; MaciasꢀAlonso, M.; Gonzaꢀ
ACKNOWLEDGMENT
3
We are grateful for the financial support provided by the National
University of Singapore and the Ministry of Education (MOE) of
Singapore (Rꢀ143ꢀ000ꢀ645ꢀ112, Rꢀ143ꢀ000ꢀ665ꢀ114), GSKꢀEDB
(Rꢀ143ꢀ000ꢀ687ꢀ592 and Rꢀ143ꢀ000ꢀ564ꢀ592) and A*STAR
RIE2020 AME (Rꢀ143ꢀ000ꢀ690ꢀ305).
lez, M. C.; CordovaꢀGuerrero, I.; Garcia, A. G. T.; OseguedaꢀRobles,
S. Nat. Prod. Rep. 2015, 32, 1472. (b) Bansal, Y.; Sethi, P.; Bansal,
G. Med. Chem. Res. 2013, 22, 3049. (c) Hassanin, H. M.; Elꢀedfawy,
S. M. Heterocycles 2012, 85, 2421. (d) Claassen, G.; Brin, E.;
CroganꢀGrundy, C.; Vaillancourt, M. T.; Zhang, H. Z.; Cai, S. X.;
Drewe, J.; Tseng, B.; Kasibhatla, S. Cancer Lett. 2009, 274, 243. (e)
Kraus, J. M.; Verlinde, C. L. M. J.; Karimi, M.; Lepesheva, G.
I.;Gelb, M. H.; Buckner, F. S. J. Med. Chem. 2009 , 52 , 1639. (f)
Glasnov, T. N.; Stadlbauer, W.; Kappe, C. O. J. Org. Chem. 2005, 70,
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using CO
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