Photochemical Cobalt-Catalyzed Hydroalkynylation to Form 1,3-Enynes

Article abstract of DOI:10.1021/acscatal.9b00248

A photochemical hydroalkynylation is reported employing a metallaphotoredox approach using cobalt catalysis and an organic dye, 4CzIPN. The protocol enables catalysis without the need for stoichiometric metal reductants, normally needed to convert higher

Full text of DOI:10.1021/acscatal.9b00248

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Article
Photochemical Cobalt-Catalyzed Hydroalkynylation to Form 1,3-Enynes.
Jean-Christophe Grenier-Petel, and Shawn K. Collins
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.9b00248 • Publication Date (Web): 27 Feb 2019
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ACS Catalysis
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Photochemical Cobalt-Catalyzed Hydroalkynylation to Form 1,3-
Enynes.
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Jean-Christophe Grenier-Petel and Shawn K. Collins*
Département de Chimie, Centre for Green Chemistry and Catalysis, Université de Montréal, CP 6128 Station Downtown,
Montréal, Québec H3C 3J7, Canada
ABSTRACT: A photochemical hydroalkynylation is reported employing a metallaphotoredox approach using cobalt catalysis and
an organic dye, 4CzIPN. The protocol enables catalysis without the need for stoichiometric metal reductants, normally needed to
convert higher oxidation state cobalt complexes to their more active lower oxidation states. The hydroalkynylation provides 1,3-
enynes in good to high yields and E-selectivity (25-99% yield, 17→>99:1 E:Z, 27 examples). Importantly, “cross-dimerizations” of
terminal alkynes that are typically rare are also possible and occur with unusually high levels of stereoselection. In addition,
macrocyclic hydroalkynylations are reported in good to high yields, affording macrocyclic enyne motifs which are found in numerous
bioactive natural products
KEYWORDS:
Alkynes,
Dimerization,
Cobalt,
halides or organometallic coupling partners. Other routes to 1,3-
enynes include olefinations,10 which typically have the
drawback of producing stoichiometric waste.
Metallaphotoredox, Macrocyclization.
Alkynes are fundamental synthons for organic synthesis,1
whose reactive -systems can be further functionalized by a
host of transformations, particularly in the context of transition-
metal catalysis. Alkyne reactivity often differs from that of
alkenes, and the two functionalities can be exploited to generate
complexity from relatively simple starting materials. The 1,3-
enyne motif is a prominent example,2 as the alkene unit can
participate in a number of asymmetric addition processes,
Past Work/State-of-the-Art: Iron-Catalyzed Cross Dimerization of Alkynes
(Milstein, 2016)
PiPr2
H
N
Fe
H
Ph
Ph
H
H
BH2
PiPr2
H
Ph
(1 mol%)
Ph
TMS
(3 equiv)
TMS
TMS
Ph
THF
rt, 24h
, ,
including copper-catalyzed hydroboration/additions,3 4 5 or both
22%
56%
7%
 Good selectivity for Z-products (typically >7:1)
 Excellent yields (typically >79 %)
-systems can react to form new unsaturation patterns, such as
in the synthesis of enantioenriched allenes,6 alkenes via double
proto-sillyations,7 or in annulations to form new ring systems.8
This Work: Cobalt-Catalyzed Metallaphotoredox (Cross) Dimerization
of Alkynes
Sonogashira/Suzuki/Stille Coupling
 Advantages: Predictable acces to stereodefined enynes
 Disadvantages: Necessary prefunctionalization of precursors
R
H
H
Co
PC
R
R3Si
(2.5 equiv)
R1/2
R3Si
 Good yields and excellent selectivity for E-products
 First demonstration fo macrocyclic hydroalkynylation
[M] or X
R1
R2
R1
R1/2
?
Pd
+
H
X or [M]
Figure 2. Past and present strategies for the cross dimerization of
alkynes.
R1
R1
R1/2
1,3-Enynes can also be formed via various hydrometallation
pathways, including the hydropalladation of allenes,11 or
manganese-catalyzed hydroarylation of 1,3-diynes to access Z-
enynes.12 However, the most direct route would involve the
controlled dimerization of alkynes.13 The process is difficult to
control, as it could form the 2,3- or the 1,3-enyne, and the latter
can exist as the E- or Z-isomers, or mixtures thereof. For
example, Zhao and co-workers reported a dimerization of
terminal aryl alkynes catalyzed by iron pyrazoyl tripodal
complexes, where the E:Z selectivity was controlled by nature
of the base (80:20 to 30:70 E:Z for different compounds).14
Kirchner and co-workers used Fe(II)-pincer complexes to
promote dimerization of alkynes with high Z-selectivity.15
R1
Dimerization of Alkynes
 Advantages: Simple starting materials, atom economy
 Disadvantages: Control of regioselectivity and stereoselectivity
Figure 1. Challenges in the synthesis of enynes.
Given their utility, 1,3-enyne synthesis has attracted
significant attention (Figure 1). In general, cross-coupling
processes such as the Sonogashira coupling between terminal
alkynes and alkenyl halides are used, although examples of
Suzuki or Stille coupling have also been reported.9 While the
stereoselectivity can often be easily predicted in cross-
couplings, it can be difficult to prepare certain stereo-defined
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Table 1. Optimization of a Photochemical Cobalt-Catalyzed
Page 2 of 7
Table 2. Scope of the Photochemical Cobalt-Catalyzed
Homocoupling Hydroalkynylation Process. a
1
Homocoupling Hydroalkynylation Process.
2
3
4
OMe
4CzIPN (2 mol%)
4CzIPN (2 mol%)
Co(BF4)2. 6H2O (5 mol%)
dppp (6 mol%)
Ar
Co(BF4)2. 6H2O (5 mol%)
dppp (6 mol%)
5
6
7
8
DIPEA (30 mol%)
DIPEA (30 mol%)
Ar
2
MeCN [200 mM]
MeCN [200 mM]
MeO
Ar
Blue LEDs, 18 h
Blue LEDs, 18 h
1
9
MeO
R
10
11
12
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Entry
Changes
Yield 2
E:Zb
(%)a
1
2
3
4
5
6
7
-
PPh3 (12 mol%)
BINAP
71
48
53
>99:1
>99:1
>99:1
-
R
c
PCy3 (12 mol%)
[Ir(dF(CF3)ppy)2(dtbpy)]PF6
CoBr2
-
28b
4.3:1
-
7
2
73 %
R = OMe
(4 h)
82 %
(4 h)
3
70 %
R = H
60 %
-
4
R = Me
(4 h)
48 %
5
R = Br
R = F
OMe
1 h irradiation, then 17 h in dark
21
-
>99:1
-
6
90 %
Without light, Co(BF4)•6H2O, or
8
NHR
DIPEA
a
b
1
Yields following chromatography. Determined by H
c
NMR spectroscopy.
[2+2+2]cycloaddition product.
Isolated a 53% yield of the
Cross-dimerizations of terminal alkynes, which are rare, can
form an even more complicated distribution of products (Figure
2). To influence the chemoselectivity of a cross dimerization
process, Okamoto and co-workers demonstrated that cobalt
NHR
8
71 %
MeO
9
51 %)
R = H (
10
83 %
)
R = Boc (
catalysis could promote
a
dimerization between
a Isolated yields. All enynes isolated in >99:1 E:Z selectivity.
In attempting to develop photoredox route to
trimethylsilylacetylene (TMSA) and internal alkynes at
elevated temperatures,16 while Reddy and co-workers
demonstrated cross dimerizations using ynols as coupling
partners.17 Perhaps the state-of-the-art is represented by a cross
dimerization of two terminal alkynes using iron pincer
complexes (Figure 2).18 Milstein and co-workers reported the Z-
selective synthesis of the 1,3-enynes for both homo- and cross
dimerizations, the latter exploited an excess of TMSA to help
favor the formation of cross dimerization products, although
homocoupling of the other acetylene coupling partner was
observed. In examining new routes to the dimerization of
alkynes, the identification of metal catalysts and conditions that
exhibited reactivity with alkynes under mild conditions was
necessary. In particular, recent reports from Rovis and co-
workers described metallaphotoredox cobalt-catalyzed
[2+2+2]cycloadditions under mild conditions.19 In related
reports, they demonstrated that polymerizations using similar
a
hydroalkynylation, a series of base metal complexes, ligands
and photocatalysts were evaluated for their ability to promote
the dimerization of 4-methoxyphenylacetylene 1. The survey
afforded an encouraging result, when a combination of the
photocatalyst
4CzIPN,23
Co(BF4)2•6H2O,
1,3-
bis(diphenylphosphino)propane (dppp), DIPEA in MeCN
afforded the enyne in 71 % isolated yield of enyne 2, with
excellent selectivity for the E-isomer (>99:1 H NMR) (Table
1). Changing the ligand for PPh3 or BINAP afforded lower
yields, while PCy3 resulted in the formation of
[2+2+2]cycloaddition product, previously obtained by Rovis
and co-workers. The Ir-based catalyst
[Ir(dF(CF3)ppy)2(dtbpy)]PF6 did not afford a better yield, but
also reduced the E-selectivity (4.3:1 E:Z for 2).24 In addition,
when the reaction was irradiated for only a single hour and then
left to stir in the dark, no further reaction was observed,
implying the need for constant irradiation throughout the
reaction time. Note that control reactions performed in the
absence of light, Co-catalyst or base afforded none of the
desired enyne 2.
1
a
reaction
conditions
(CoBr2(PCy3),
[Ir(dF(CF3)ppy)2(dtbpy)]PF6, DIPEA, CFL, 24 h),20 as well
reactions with 1,3-dienes,21 proceeded with excellent
selectivities when conducted under a photoredox manifold. In
addition, Wu and co-workers also reported that Ir/Co dual-
catalysis could be used to promote alkyne carboxylations using
CO2.22 Herein we report on the first photoredox approach to
hydroalkynylation affording 1,3-enynes with excellent E-
selectivities, in addition to cross dimerizations with
trialkylsilyl-substituted alkynes as well as the first example of
macrocyclic hydroalkynylation.
The homodimerization of alkynes could be conducted with a
variety of aromatic groups maintaining good to excellent yields
(Table 2). For example, unsubstituted enynes (3) as well those
substituted with methoxy (2), Me (4), Br (5), F (6), NH2 (9) and
NHBoc (10) were isolated in 48-90 % yield. In addition
cyclohexenyl and naphthyl alkynes afforded their
corresponding enynes 7 and 8 in 82 and 71 % yield respectively.
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Importantly, all the enynes were isolated in >99:1 E:Z
dimerization of with a deuterium-labelled derivative of alkyne
1 afforded the enyne 11-d in 73 % yield, where the deuterium
from the alkyne was found to be present only at the alkenyl
position next to the alkyne.
1
selectivity.
2
3
Table 3. Optimization of a Photochemical Cobalt-Catalyzed
Cross Dimerization of Alkynes.
4
5
6
7
8
9
10
11
12
13
Table 4. Scope of the Photochemical Cobalt-Catalyzed
Cross Dimerization Process. a
OMe
4CzIPN (2 mol%)
Co(BF4)2. 6H2O (5 mol%)
dppp (6 mol%)
OMe
4CzIPN (2 mol%)
MeO
DIPEA (30 mol%)
Co(BF4)2. 6H2O (5 mol%)
Ar
1
+
dppp (6 mol%)
MeCN [200 mM]
Ar
DIPEA (30 mol%)
+
TMS
Blue LEDs, 18h
TMS
11
(x equiv)
2
MeCN [200 mM]
R3Si
R3Si
(2.5 equiv)
Blue LEDs, 18 h
MeO
OMe
Me
Entry
x
Time (h)
Yield 11 (%)a
Yield 2 (%)a
14
15
16
17
18
19
20
21
22
23
24
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NH2
1
2
3
4
5
a
1.5
2.0
2.5
3.0
2.5
18
18
18
18
4
23
50
91
92
73
37
10
-
TMS
TIPS
TIPS
TIPS
-
13
14
15
16
-
70 %
98 %
71 %
67 %
Yields following chromatography. No observation of the Z-
OMe
isomer by 1H NMR
F
4CzIPN (2 mol%)
Co(BF4)2 6H2O (5 mol%)
NHR
OBn
TMS
BnO
dppp (6 mol%)
DIPEA (30 mol%)
+
+
MeCN [200 mM]
Blue LEDs, 18h
TMS
TIPS
TIPS
TIPS
TMS
BnO
TMS
(2.5 equiv)
12
64%
17
47 %
19
52 %
20
21
R = Ac
Not observed
18
56 %
64 %
80 %
R = Boc
OMe
4CzIPN (2 mol%)
OR
EtO
D
9
/H
:1
Co(BF4)2 6H2O (5 mol%)
dppp (6 mol%)
C4H9
OR
OEt
4
D
1:
H/
DIPEA (30 mol%)
+
MeO
MeCN [200 mM]
Blue LEDs, 18h
TIPS
TMS
TIPS
TIPS
TMS
(2.5 equiv)
24 93 %
25 61 %
26
22
12 64 % R = Bn
23 58 % R = H
R = Bn
TMS
11-d
73%
70 %
99 %
R = TBS
Scheme 1. Confirming the structure of the enynes formed
via cross dimerization.
a Isolated yields. No observation of the Z-isomer by 1H NMR.
With optimized conditions in hand for the cross dimerization
of alkynes, the scope was investigated with regards to cross
dimerizations with either TMS- or TIPS-protected alkynes with
both aromatic and aliphatic alkynes (Table 4). With regards to
aromatic alkynes, phenyl as well as substituted benzenes
bearing methoxy, amino, methyl, fluoro, N-acetyl and N-Boc
were all found to be compatible. The respective enynes 13→19
were isolated in 47-98 % yield. Enynes such as 20 and 21
having naphthyl or cyclohexenyl groups were also synthesized
in 64 and 80 % yield respectively. Aliphatic alkynes also
underwent cross dimerization effectively, as 1-hexyne afforded
the enyne 22 in near quantitative yield (99 %). A TBS-protected
propargyl alcohol afforded the corresponding 1,3-enyne 23 in
58 % yield, while a Bn-protected propargyl alcohol also
underwent cross-dimerization in good yield (64 % yield). A
homo-propargyl alkynol either as its free hydroxyl, or as a Bn-
protected ether were also compatible couplings partners (24, 61
%, 25, 93 % yields). A diethyl acetal also afforded its
corresponding 1,3-enyne in good yield (26, 70 %).
Given the results from the homodimerization of alkynes, the
cross dimerization of 4-methoxyphenylacetylene with TMSA
was explored (Table 3). When 1.5 equivalents of TMSA were
used in the cross dimerization with 1, only a 23 % yield of the
desired mixed product 11 was isolated, along with 37 % of the
enyne 2 resulting from homocoupling of 1 (Table 3, entry 1).
Increasing the number of equivalents of TMSA from 1.5 to 2.5
increased the yield of the desired cross dimerization product 11
to 91 %, while the homocoupling product 2 was no longer
observed. Further increasing the number of equivalents of
TMSA did not improve the isolated yields of enyne 11, and
decreasing the reaction time to 4 h lowered the yield. Once
again, all the enynes isolated during the optimization were
obtained in >99:1 E:Z selectivity.
To confirm the structure of the enynes formed via cross
dimerization, the hydroalkynylation with TMSA was repeated
and an alkyl-substituted alkyne was used in place of 1 (Scheme
1). The cross dimerization product 12 was isolated in 64 %
yield, and analysis of the 1H NMR confirmed coupling between
the adjacent methylene and alkenyl hydrogens. A cross
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addition of an alkyne (TMSA in the cross dimerization process,
Page 4 of 7
1
2
3
4
5
6
7
8
given that it is present in excess) followed by subsequent
migratory insertion into a second alkyne would afford the
intermediate C. The oxidative addition and migratory insertion
steps are suggested based upon the deuterium labelling
experiment conducted in a cross dimerization process (Scheme
1). Oxidation of the Co(II) intermediate to Co(III) via SET from
the ground state of 4CzIPN, followed by reductive elimination
would afford the enyne product and a Co(I) by-product. To
close both catalytic cycles, the reduction via the excited state of
4CzIPN would regenerate the Co(0) catalyst. It should be noted
that early optimization experiments established the need for
irradiation throughout the reaction time to achieve high yields,
and suggest the intersecting transition-metal and photoredox
catalytic cycles.
Table 5. Macrocyclic Hydroalkynylation.a
4CzIPN (2 mol%)
Co(BF4)2 6H2O (20 mol%)
dppp (24 mol%)
DIPEA (60 mol%)
MeCN [10 mM]
Blue LEDs, 18 h
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
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aryl/aryl substrates
( )2
O
O
O
O
O
O
O
O
18
19
2
2BF4
Ph2
P
II
Co
28
27
P
37 %
(34:1 E:Z)
Ph2
N
91 %
(17:1 E:Z)
alkyl/aryl substrates
NC
CN
N
iPrNEt
iPrNEt
4CzIPN*
2x
N
O
O
N
4CzIPN
17
29
4CzIPN
Ph2
P
0
Co
H
Ph2
I
Co
P
P
Ph2
R
25 %
(>99:1 E:Z)
A
SiR3
P
*
4CzIPN
Ph2
a Isolated yields.
E
R3Si
In an effort to expand the substrate scope, it was decided to
investigate whether a macrocyclic hydroalkynylation was
possible. Such a process would also expand the toolbox of
photochemical macrocyclization processes, which are rare and
underdeveloped, as well as offer a new route to macrocyclic
enynes, a motif found in numerous macrocyclic bioactive
natural products (Table 5). The macrocyclic hydroalkynylation
process required changes to the optimized reaction conditions:
1) the concentration was decreased from 200 mM to 10 mM, to
help prevent oligomerization processes, and as consequently, 2)
to maintain a reaction time of 18 h, the catalyst loadings were
increased to 20 and 24 mol% for the cobalt catalyst and dppp
ligand respectively, and 60 mol % for DIPEA. Gratifyingly,
under these conditions, the macrocyclization of an aromatic
symmetrical diyne afforded the corresponding 18-membered
macrocyclic enyne 27 in 91 % yield as a 17:1 E:Z ratio of
diastereomers, and a 19-membered enyne 28 in 37 % yield (34:1
E:Z ratio) (Table 5). Finally, a mixed alkyl/aryl diyne could be
cyclized to afford the unsymmetrical enyne 29 in 25 % total
yield, but with high regio- and stereoselectivity (>99:1 E:Z).
Ph2
II
Co
P
H
P
4CzIPN
SiR3
Ph2
B
SiR3
H
Ph2
III
Co
P
H
4CzIPN
SiR3
P
H
Ph
2 R
Ph2
II
Co
R
D
P
H
P
H
Ph
2 R
C
Figure 3. Proposed mechanism for the cobalt-catalyzed
photochemical hydroalkynylation (cross dimerization of alkynes).
In summary, a catalyst system employing cobalt catalysis and
an organic dye, 4CzIPN, promotes the first photochemical
hydroalkynylation process. Employing a metallaphotoredox
approach affords the possibility to omit stoichiometric metal
reductants, normally needed to convert higher oxidation state
cobalt complexes to their more active lower oxidation states.
Using the Co/4CzIPN catalytic system, enynes are prepared in
good to excellent yields, with excellent E-selectivity (25-99 %
yield, 17→>99:1 E:Z, 27 examples). In addition to the
dimerization of alkynes, cross-dimerizations of terminal
alkynes are also possible. Such processes are generally scarce
and do not occur with such high levels of stereoselection.
Notably, the first macrocyclic hydroalkynylations are reported
and occur up to 91 % yield, affording macrocyclic enyne motifs
which are found in numerous bioactive natural products.
A
possible
mechanism
for
the
photochemical
hydroalkynylation process is outlined in Figure 3. In many
cobalt-catalyzed reactions, reduction of Co(II) species to Co(I)
or Co(0) oxidation states requires stoichiometric metal
additives, either Zn, Mn or through the use of a Grignard
reagent. It is possible that under the reaction conditions
optimized herein, that the Co(II) species is reduced to Co(0)
through sequential single electron transfers (SETs) from the
excited state of the photocatalyst 4CzIPN.25 In such a manner,
DIPEA is proposed to act as a sacrificial electron donor to
regenerate 4CzIPN, however more data is needed to rule other
roles such as a traditional base of H-atom donor. Oxidative
ASSOCIATED CONTENT
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via the Internet at http://pubs.acs.org.
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Corresponding Author
shawn.collins@umontreal.ca
ACKNOWLEDGMENT
The authors acknowledge the Natural Sciences and Engineering
Research Council of Canada (NSERC), Université de Montréal and
the Centre for Green Chemistry and Catalysis (CGCC) for generous
funding.
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Cobalt-Catalyzed Metallaphotoredox
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 Good yields and excellent selectivity for E-products
 First demonstration of macrocyclic hydroalkynylation
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