A Convergent Synthesis of Functionalized Alkenyl Halides through Cobalt(III)-Catalyzed Three-Component C?H Bond Addition

Article abstract of DOI:10.1002/anie.201705817

A Co^III-catalyzed three-component coupling of C(sp²)?H bonds, alkynes, and halogenating agents to give alkenyl halides is reported. This transformation proceeds with high regio- and diastereoselectivity, and is effective for a broad

Full text of DOI:10.1002/anie.201705817

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Accepted Article
Title: A Convergent Synthesis of Functionalized Alkenyl Halides via
Co(III)-Catalyzed Three-Component C-H Bond Addition
Authors: Jonathan Anthony Ellman and Jeffrey A Boerth
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201705817
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A Convergent Synthesis of Functionalized Alkenyl Halides via
Co(III)-Catalyzed Three-Component C–H Bond Addition
Jeffrey A. Boerth and Jonathan A. Ellman*
Abstract: A Co(III)-catalyzed three-component coupling of C(sp2)–H
bonds, alkynes, and halogenating agents to give alkenyl halides is
reported. This transformation proceeds with high regio- and
diastereoselectivity, and is effective for a broad range of aryl and
alkyl terminal alkynes. Diverse C–H bond partners also exhibit good
reactivity for a range of heteroaryl and aryl systems as well as
synthetically useful secondary and tertiary amide, urea, and pyrazole
directing groups. This multi-component transformation is also
compatible with allenes in place of alkynes to furnish tetra-
substituted alkenyl halides, showcasing the first halo-arylation of
allenes.
allenes and halogenating agents to provide functionalized
alkenyl halides with high regio- and diastereoselectivity (Figure
2b). Notably, alkenyl halides are versatile synthetic handles for
many important transformations.5,6
Transition-metal-catalyzed C–H functionalization has become
a powerful synthetic approach that relies on simple and readily
available starting inputs. In directed C–H bond functionalization,
a C–H bond substrate and a transition-metal catalyst typically
form a nucleophilic metallocycle intermediate that adds across a
single coupling partner to create a functionalized product (Figure
1a).1,2 Three-component C–H functionalization using two
different coupling partners theoretically would provide efficient
entry to an enormous array of diverse and complex products in a
single reaction, especially when one considers the very large
number of potential coupling partner combinations (Figure 1b).3
Figure 2. Co(III)-catalyzed three-component transformations.
We began by exploring terminal alkynes7,8,9 and halogenating
agents as the two coupling partners. Significantly, neither of
these inputs had previously been explored in an intermolecular
three-component C–H bond functionalization. Successful
coupling required initial addition to the alkyne instead of the
more electrophilic halogenating agent.10 More challenging was
the identification of suitable conditions for halogenation of the
alkenyl-metal intermediate while minimizing well-established and
efficient proto-demetallation to give the undesired alkene.7
Additionally, terminal alkynes are susceptible to C–H bond
activation, and this mode of activation needed to be avoided to
prevent
side
reactions
such
as
homocoupling
or
Figure 1. Overview of three-component C–H functionalization approach.
oligomerization.11
A thorough exploration of reaction conditions established that
the preformed air-stable Co(III)-catalyst [Cp*Co(MeCN)3][SbF6]2
in conjunction with sparing amounts of acetic acid (2.5 mol %) at
40 °C provided the desired alkenyl iodide 4a in 71% yield from
Recently our lab published on the Co(III)-catalyzed three-
component diastereoselective synthesis of β-hydroxy ketones,
utilizing enones and aldehydes (Figure 2a).3a To expand upon
this first example of intermolecular multi-component C–H
functionalization,4 we sought to extend this approach to different
C–H functionalization substrates and coupling partners. Herein
we describe a new Co(III)-catalyzed three-component coupling
wherein the C–H bond sequentially adds to terminal alkynes or
thiophene-amide
1a,
phenylacetylene
(2a),
and
N-
iodosuccinimide (NIS) (Table 1) (see Table S1 in SI). Direct C–
H iodination was not observed, suggesting that under the
reaction conditions, alkenylation completely outcompetes
iodination.12-14 Acetic acid has previously been found to be an
effective additive for facilitating Co(III)-catalyzed C–H bond
additions to π-bonds and was crucial to achieving effective
alkyne coupling. However, only sub-stoichiometric amounts of
acetic acid relative to catalyst loading could be used to minimize
undesired proto-demetallation of the alkenyl cobalt intermediate.
It is also noteworthy that Rh(III) catalysts, which often show
parallel reactivity to Co(III), were ineffective for this
transformation.
[*]
J. A. Boerth, Prof. Dr. J. A. Ellman
Department of Chemistry
Yale University
225 Prospect St., New Haven, CT 06520 (USA)
E-mail: jonathan.ellman@yale.edu
Supporting information for this article is given via a link at the end of
the document.
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Once optimal conditions were determined, different
halogenating agents and a wide range of terminal alkynes 2
were evaluated (Table 1). In addition to NIS to give 4a, N-
bromosuccinimide (NBS) provided alkenyl bromide 4b in good
yield (see also 4x in Table 2, vide infra). However, chlorination
with N-chlorosuccinimide was unsuccessful.
protected amine (4l), a propargyl ether (4m), a silyl ether (4n)
and an ester (4o), all in ≥80% yields. Notably, alkenyl iodides 4
were obtained with >95% regio- and diastereoselectivity for
every terminal alkyne examined. However, internal alkynes did
not give three-component products with 1a primarily
recovered.15
A variety of different C–H bond partners were also effective for
coupling with both aryl and alkyl alkynes (Table 2). Thiophenes
with alkyl- or halo-substituents at the 5-position underwent three-
component coupling to give products 4p and 4q in 85% and
75% yields, respectively. Moreover, the thiophene could be
replaced with a furan to provide product 4r in 45% yield. In
addition to the tertiary pyrrolidine amide directing group,
secondary amides with varying steric character were also
effective. For example, N-Me and N-iPr amides furnished
products 4s and 4t in good yields. For 4s, the regio- and
Table 1. Alkyne Scope for the three-component addition cascade.a,b
[Cp*Co(MeCN)3][SbF6]2
N
O
(10 mol %)
N
O
AcOH (2.5 mol %)
+
+
R
R
NXS
Dioxane [0.1 M]
40 °C, 20 h
S
S
X
1a
2
3
4
N
O
N
O
N
O
OMe
Me
stereochemistry
was
rigorously
confirmed
by
X-ray
crystallography.16 Furthermore, pyrrole protected as the N,N-
dimethyl urea also coupled to give 4u. Finally, aromatic C–H
bond functionalization was demonstrated using the pyrazole
directing group as exemplified by alkenyl halides 4v – 4x.
S
S
S
X
I
I
4a (X = I), 71%
4b (X = Br), 66%c
4c
60%d
4d
64%
O
OMe
N
N
N
O
N
O
N
O
Cl
S
Table 2. C–H bond partner scope in the three-component addition cascade.a,b
[Cp*Co(MeCN)3][SbF6]2
(10 mol %)
AcOH (2.5 mol %)
S
S
S
I
I
I
DG
DG
4e
68%
4g
56%
4f
58%
R
+
+
R
NXS
Dioxane [0.1 M]
40 °C, 20 h
X
O
N
O
N
O
1
2
3
4
S
S
S
I
I
I
N
O
N
O
N
O
4h
4i
84%
4j
85%
74%
butyl
butyl
I
S
S
O
I
I
N
O
N
O
O
Me
Cl
4q
75%
4r
45%c
4p
85%
NHBoc
OMe
S
S
S
I
I
I
4k
4l
4m
83%
HN
O
HN
O
23%
80%
butyl
N
O
N
O
S
S
S
I
I
4t
4s
51%
OEt
63%d
OTBS
S
I
I
O
4n
85%
4o
91%
N
N
O
N
N
[a]Conditions: 1a (1.0 equiv at 0.1 M), 2 (1.2 equiv), and 3 (1.5 equiv).
X
I
[b]Isolated yields. [c]Using 10 mol % of AcOH. [d]Using 5 mol % of AcOH.
R
4v (R = H, X = I), 51%
4w (R = Me, X = I), 74%
4x (R = Me, X = Br), 76%d
4u
61%e
Next, a range of substituents was examined on the aryl alkyne
(Table 1). Electron donating substituents furnished alkene
products 4c and 4d in good yields. Alkynes with electron
withdrawing chloro and carboxyester groups also coupling
efficiently to generate alkenyl iodides 4e and 4f in 68% and 58%
yields, respectively. Additionally, a heteroaryl terminal alkyne
coupled to give 4g in 56% yield. A broad range of alkyl alkynes
were also effective substrates. Linear and β-branched alkyl
alkynes gave alkenyl iodides 4h and 4i in high yields, and 4-
phenyl-1-butyne led to product 4j in 74% yield. In contrast, α-
alkyl branching in ethynylcyclohexane provided alkenyl iodide 4k
in lower yield. A variety of heteroatom functionality could be
incorporated on the alkyne coupling partner, including a Boc-
[a]Conditions: 1 (1.0 equiv at 0.1 M), 2 (1.2 equiv), and 3 (1.5 equiv). [b]Isolated
yields. [c]Using 5 mol % of AcOH. [d]Using 10 mol % of AcOH. [e]1 (1.5 equiv), 2
(1.0 equiv), and 3a (1.1 equiv) using 20 mol % of LiOAc at 60 °C.
A number of experiments were conducted to probe the
mechanistic features of this three-component transformation
(Schemes 1-2). The potential participation in catalysis of alkene
5a, an undesired two-component coupling byproduct produced
in minor amounts under the reaction conditions, was initially
investigated. First, alkene product 5a and NIS were subjected to
the standard reaction conditions (Scheme 1a). Excellent
recovery of alkene 5a was observed and no alkenyl iodide 4a
could be detected. Second, substrate 1b, 1-hexyne, and NIS
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were submitted to the standard reaction conditions with one
equiv of 5a as an additive (Scheme 1b). The presence of 5a did
not affect the yield of the three component coupling product 4p,
and again, 5a was not iodinated. Together, these experiments
clearly establish that two-component byproduct 5a is not an
intermediate and does not interfere with the catalytic cycle.
Scheme 3. Proposed mechanism for the Co(III)-catalyzed three-component
transformation.
Allenes were also investigated as possible three-component
coupling partners with NIS to generate tetra-substituted alkenyl
iodides (Table 3).18 Few examples of Co(III)-catalyzed C–H bond
additions to allenes have been reported,19,20 with the first
hydroarylation of allenes appearing only very recently.19 In
Scheme 1. Mechanistic experiments with two-component product 5a
Experiments with deuterated substrate 1a-D also defined key
features of the reaction (Scheme 2). When deuterated product
1a-D was subjected to the optimal reaction conditions for only 1
h, no deuterium exchange was observed in the recovered
starting material. The lack of scrambling at the site of C–H
functionalization is unexpected because extensive deuterium
exchange by reversible orthometallation is almost always
observed for Cp*Co(III)-systems.17 Initial rates were next
independently determined for protio 1a and deuterio 1a-D under
the standard catalyst and acetic acid loadings (See Section 7 of
SI). A primary kinetic isotope effect (KIE) of 2.15 ± 0.16 was
observed, which is consistent with orthometallation as a rate-
determining step.
particular, 1,1-disubstituted allenes
8 were effective three-
component coupling electrophiles to give 9a-c in good yields.
These allylated thiophene amides nicely complement the
alkenylated derivatives obtained with the aforementioned three-
component reactions of terminal alkynes. To the best of our
knowledge, halo-arylation of allenes has not previously been
reported.
Table 3. Synthesis of alkenyl iodides via three-component coupling with
allenes a,b
[Cp*Co(MeCN)3][SbF6]2
N
O
(10 mol %)
AcOH (2.5 mol %)
N
O
R
R
R
+
+
NIS
·
R
Dioxane [0.1 M]
60 °C, 20 h
S
S
X
Me
Me
1b
8
3a
9
N
O
N
O
N
O
butyl
butyl
Me
Scheme 2. No observed H/D exchange for 1a-D under reaction conditions
Me
S
S
I
I
S
I
A possible mechanism for the reaction consistent with the high
regio- and diastereoselectivity and the aforementioned
mechanistic studies is depicted in Scheme 3. First, irreversible
orthometallation of 1 with the cationic Co(III)-catalyst furnishes
Me
Me
Me
9a
65%
9b
50%
9c
64%
[aConditions: 1b (1.0 equiv at 0.1 M), 8 (1.2 equiv), and 3a (1.5 equiv).
[b]Isolated yields.
cobaltacycle 6. Regioselective syn-insertion of
6 into the
In summary, a novel multi-component transformation has been
developed using Co(III) catalysis to form functionalized alkenyl
halides with high regio- and stereoselectivity. This coupling
proceeds with broad alkyne scope, and is applicable to a variety
of C–H bond substrates and directing groups. Additionally, we
have showcased that allenes are suitable reaction partners for
the synthesis of allylated products incorporating tetra-substituted
terminal alkyne then generates alkenyl-cobalt 7. Finally,
intermediate 7 reacts with the halogenating agent 3 to provide
the desired three-component product 4 with release of the
cationic Co(III)-catalyst. An undesired minor pathway for
intermediate 7 is proto-demetallation to give the alkene product
5, also with release of the active catalyst.
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present in products 4 and 9, are well documented to be capable
of undergoing a range of metal-catalyzed transformations. We
are currently investigating the C–H bond three-component
coupling of numerous additional coupling partner combinations
for the synthesis of interesting and useful structures in a
straightforward and convergent manner.
[8]
[9]
This work was supported by the NIH (R35GM122473). We
gratefully acknowledge Dr Brandon Mercado (Yale University)
for solving the crystal structure of 4s, and Joshua Hummel for
helpful input.
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D.-G.Yu, T. Gensch, F. de Azambuja, S. Vasquez-Cespedes, F.Glorius,
J. Am. Chem. Soc. 2014, 136, 17722.
Keywords: C–H activation • homogeneous catalysis •
multicomponent reactions • alkynes • allenes
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by X-ray structural analysis are described in the Supporting Information.
CCDC 1548918 (4s) contain the supplementary crystallographic data
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Cambridge Crystallographic Data Centre.
[3]
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Triple Play: A convergent assembly
of functionalized alkenyl halides is
reported via Co(III)-catalyzed three-
component C–H bond addition across
alkynes and halogenating agents. The
reaction proceeds with high regio- and
diastereoselectivity and is effective for
a wide range of alkynes and C–H
bond substrates. Allenes are also
suitable substrates for the preparation
of tetra-substituted alkenyl halide
products.
Jeffrey A. Boerth, Jonathan A. Ellman*
Page No. – Page No.
A Convergent Synthesis of
Functionalized Alkenyl Halides via
Co(III)-Catalyzed Three-Component
C–H Bond Addition
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