Synthesis of Tetrasubstituted Alkenes by Tandem Metallacycle Formation/Cross-Electrophile Coupling

Article abstract of DOI:10.1021/jacs.8b04637

Nickel-catalyzed cross-electrophile couplings have recently emerged as highly effective and practical methods for the formation of C-C bonds. By merging this process with well-established π-π coupling chemistry, a new method for the synthesis of tetrasubstituted alkenes has been developed. The procedure relies on the use of chlorosilanes as a means of generating reactive vinylnickel intermediates, which are capable of undergoing a reductive cross-electrophile coupling with alkyl halides. The method not only generates highly substituted allylic alcohol derivatives but also obviates the need for stoichiometric organometallic nucleophiles and provides greatly improved scope and functional group tolerance compared with previously developed methods.

Full text of DOI:10.1021/jacs.8b04637

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Communication
Synthesis of Tetrasubstituted Alkenes by Tandem
Metallacycle Formation/Cross-Electrophile Coupling
Kirk Shimkin, and John Montgomery
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b04637 • Publication Date (Web): 25 May 2018
Downloaded from http://pubs.acs.org on May 25, 2018
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Synthesis of Tetrasubstituted Alkenes by Tandem Metallacy-
cle Formation/Cross-Electrophile Coupling
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Kirk W. Shimkin and John Montgomery*
Department of Chemistry, University of Michigan, 930 North University Avenue, Ann Arbor, Michigan, 48109-1055, Unit-
ed States
Supporting Information Placeholder
to a nickel-based catalytic intermediate derived from a
single reactive component (1, Scheme 1).
ABSTRACT: Nickel-catalyzed cross-electrophile cou-
plings have recently emerged as highly effective and
practical methods for the formation of C-C bonds. By
merging this process with well-established π-π coupling
chemistry, a new method for the synthesis of tetrasubsti-
tuted alkenes has been developed. The procedure relies
on the use of chlorosilanes as a means of generating re-
active vinylnickel intermediates, which are capable of
undergoing a reductive cross-electrophile coupling with
alkyl halides. The method not only generates highly sub-
stituted allylic alcohol derivatives, but also obviates the
need for stoichiometric organometallic nucleophiles and
provides greatly improved scope and functional group
tolerance compared with previously developed methods.
The oxidative cyclization of Ni(0) complexes of two
different π-components to form Ni(II) metallacyclic in-
termediates forms the basis of many types of catalytic
processes.6 Whereas the resulting metallacyclic interme-
diates are typically further functionalized by σ-bond
metathesis, transmetallation, or migratory insertion
pathways, we speculated that metallacycles generated
via oxidative cyclization of an alkyne and an aldehyde
(2, Scheme 1b) could participate in a cross-electrophile
coupling via alkyl halide addition mediated by single-
electron processes. The successful realization of this
concept would allow the formation of two new C-C
bonds: one via the initial oxidative cyclization event and
one via the subsequent cross-electrophile coupling.
Herein, we report our initial illustrations of this strategy
in the context of the alkylative cyclization of ynals
(Scheme 1b).
The reductive coupling of two different electrophilic
components, often referred to as “cross-electrophile
couplings,” is a highly useful and practical strategy for
C-C bond construction.1 This approach has been applied
Scheme 1. Proposed Merger of Cross-Electrophile
Coupling and Alkyne-Aldehyde Oxidative Cycliza-
tion
2
3
in a variety of contexts, most often to create Csp -Csp
bonds allowing efficient access to a variety of function-
alized aryl, alkenyl, and acyl derivatives (Scheme 1a).2
Under this reaction manifold, two components that are
electrophilic in nature, such as an aryl halide and alkyl
halide, are coupled with the use of an electron-rich nick-
el catalyst and a stoichiometric reductant.3 The chemose-
lectivity is typically derived from the propensity of the
two electrophilic partners to react with nickel catalysts
in differing oxidation states and the ability of Ni(II) in-
termediates to effectively capture carbon-centered radi-
cals.4 This capability has also led to the merger of nickel
catalysis with photoredox catalysis, a powerful approach
that takes advantage of the ability of photoredox cata-
lysts to generate free radicals from a variety of precur-
sors including boranes, silicates, carboxylic acids, and
C-H bonds, among others.5 A common feature of all of
the above methods is that a carbon-centered radical adds
(a) Cross-electrophile coupling:
L
NiII
I
Ni(0)
R'
reductant
Br
R'
R
R
I
R
1
(b) Alkyne-aldehyde oxidative cyclization/cross-electrophile coupling:
R'
This Work:
NiII
O
R'
Br
R3SiCl, Mn0
R
R
O
OSiR3
R
Ni(0)
X
H
oxidative
cyclization
cross-electrophile
coupling
X
X
2
The above hypothesis was examined with aldehyde-
alkyne couplings, which produce substituted allylic al-
cohols that are ubiquitous in synthesis and natural prod-
ucts.7 Early studies on aldehyde-alkyne couplings and
ynal cyclizations utilized alkylmetal reagents such as
1
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Page 2 of 7
dialkylzinc,8 trialkylaluminum,9 and trialkylboranes10 as
reductants. The alkylmetal reagent can either serve as a
reductant, or it can directly append an alkyl group to the
distal site of the alkyne component.8 Several highly ef-
fective procedures have been developed for H-atom in-
stallation using silanes or boranes as the terminal reduct-
ant,6a,11 but strategies enabling the incorporation of func-
tionalized alkyl fragments through this approach are
rare, much more limited in scope, and require highly
reactive organometallic reagents.8,12
Table 1. Optimization of Reaction Conditions for the Al-
kylative Cyclization Reaction
1
2
3
4
5
6
7
8
Et3SiCl (1.5 equiv)
nPr
Ph
Ni(II) cat. (10 mol %)
ligand (10 mol %)
Mn0 (2.0 equiv)
Ph
O
OSiEt3
+
nPr
X
solvent, rt
H
3
4
Entry Catalyst
Ligand
X
Solvent Yield,
(conc.)
%
9
(E:Z ratio)a
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
To address this limitation, we opted to explore the cy-
clization of ynal 3 utilizing a Ni(0) catalyst, a butyl hal-
ide as the second electrophilic reaction partner, and Mn
as the terminal reductant to furnish tetrasubstituted al-
kene product 4.2a,2d Initial attempts to generate product 4
under these conditions failed, and we reasoned that the
metallacylic structure 2 possessing a cyclic framework
and a Ni-O bond might behave very differently towards
free radical additions compared with other Ni(II) halide
species commonly invoked in cross electrophile cou-
plings. Accordingly, triethylchlorosilane (Et3SiCl) was
explored as an additive, anticipating that its addition
would convert metallacycle 2 into the open chain
alkenyl Ni(II) halide more closely resembling the adduct
derived from oxidative addition of a vinyl halide precur-
sor to Ni(0).13
1
NiBr2·dme
NiBr2·dme
NiBr2·dme
NiBr2·dme
5
5
5
6
-
I
28 (86:14)
57 (82:18)
85 (77:23)
64 (89:11)
86 (73:27)
87 (89:11)d
DMPU
(0.2 M)
2
I
DMF
(0.2 M)
3b
4c
5b
6c
Br
Br
Br
Br
DMF
(0.2 M)
DMF
(1.0 M)
(bipy)NiI2
(7)
DMF
(0.2 M)
-
(bipy)NiI2
(7)
DMF
(1.0 M)
Reactions run on 0.2 mmol scale using ynal 3 (1.0 equiv) and
alkyl halide (2.0 equiv). Yield and E:Z ratio determined by H
NMR using trimethoxybenzene as an internal standard. nBu4NI
(50 mol %) additive used. NaI (50 mol %) additive used. Isolat-
ed yield on 1.0 mmol scale using 5.0 mol % catalyst.
a
1
When commercially available NiBr2·DME was used
as the catalyst with 2,2’-bipyridyl (bipy) (5) as the lig-
and with triethylchlorosilane in DMPU, a modest 28%
yield was observed (Table 1, entry 1). Optimization of
the reaction conditions revealed that Mn was the best
reductant, DMF the optimal solvent, and that other bi-
pyridyl ligands were inferior to the parent 2,2’-
bipyridine, a welcome discovery given the low cost of
this ligand.14 The reaction yield did not exceed ~60%
when 1-iodobutane was used as the alkylating agent. We
hypothesized that this was due to rapid reduction to form
the alkyl radical, which dimerizes at a faster rate than
the productive coupling reaction (dimerization of the
alkyl halide is often observed as a side-product). By us-
ing more stable alkyl bromides in conjunction with an
exogenous iodide salt, the yield was increased to 85%
yield (Table 1, entry 3).15 Finally, the air- and moisture-
b
c
d
R
R
N
I
N
I
N
N
Ni
5: R = H
6: R = tBu
7: (bipy)NiI2
With optimal reaction conditions in hand, we explored
the scope of the alkyl components introduced via the
cross-electrophile coupling approach (Scheme 2). It was
quickly established that a variety of alkyl bromides bear-
ing reactive functional groups such as esters (9), acetals
(11), acetate-protected alcohols (12), and amides (13)
were well tolerated, providing highly functionalized
tetrasubstituted olefins. Trimethylchlorosilane could be
used in place of triethylchlorosilane, giving good yield
of product 8 with a slightly decreased E:Z ratio. Most
reactions proceeded with excellent E:Z selectivity. β-
Branched alkyl halides were introduced in good yield
(14), although this led to a significant decrease in the
E:Z selectivity. Substrate 15 bearing an alkyne substitu-
ent demonstrates the chemoselectivity of the ynal cy-
clization reaction.
stable
single
component
catalyst
(2,2’-
bipyridyl)nickel(II) iodide (7) was discovered to be a
convenient and effective replacement for the in situ
formed catalyst of NiBr2·dme and 2,2’-bipyridine (Table
1, entry 5). Interestingly, we found that the product was
observed as a mixture of E and Z isomers (vide infra),
but increasing the concentration of the reaction mixture
to 1.0 M led to very good selectivity for the formation of
the E isomer (Table 1, entry 6).
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Scheme 2. Substrate Scope of Alkyl Bromides
exocyclic cyclopentene 30. Pyrrolidines could be syn-
1
2
3
4
5
6
7
8
thesized using a nitrogen-bearing ynal (33, 34). Sub-
strate 34 also shows that an alkyl halide bearing an acid-
ic N-H group could be coupled effectively. Extending
the ynal length produced exocyclic cyclohexene 31.
However, examination of the NOE correlations con-
firmed that the Z isomer is the major isomer formed in
this reaction.
R3SiCl (1.5 equiv)
(bipy)NiI2 (5 mol %)
R’
Mn0 (2.0 equiv)
NaI (50 mol %)
R
O
OSiEt3
R
+
R’
Br
H
DMF (1 M), rt
Me
O
O
O
OEt
Scheme 3. Substrate Scope
9
OSiR3
OSiEt3
OSiEt3
OSiEt3
Ph
Ph
Ph
Ph
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Et3SiCl (1.5 equiv)
R’
(bipy)NiI2 (5 mol %)
Mn0 (2.0 equiv)
4, R= Et, 87%
(89:11 E:Z)
8, R= Me, 77%
(82:18 E:Z)
9
83% (88:12 E:Z)
10
83% (88:12 E:Z)
11
70% (87:13 E:Z)
R
O
OSiEt3
R
NaI (50 mol %)
+
R’
Br
X
H
DMF (1 M), rt
O
X
O
N
SiMe3
Me
Me
Me
OAc
Me
Ph
16, R= CF3, 77% (83:17 E:Z)
17, R= OMe, 73% (89:11 E:Z)a
18, R= COMe, 56% (83:17 E:Z)
19, R= CO2Me, 69% (79:21 E:Z)
20, R= CN, 76% (80:20 E:Z)
21, R= B(pin), 77% (87:13 E:Z)
3
OSiEt3
OSiEt3
OSiEt3
Ph
OSiEt3
Ph
Ph
OSiEt3
OSiEt3
R
S
12
65% (88:12 E:Z)
13
64% (88:12 E:Z)
14
68% (51:49 E:Z )
15
65% (88:12 E:Z)
22
84% (91:9 E:Z)
Me
Me
O
Standard conditions: ynal (1.0 mmol), alkyl bromide (2.0 equiv),
chlorosilane (1.5 equiv), Mn0 (2.0 equiv), NaI (0.5 equiv),
(bipy)NiI2 (5.0 mol %) in DMF (1.0 M). Isolated yields after iso-
lation by silica gel chromatography. E:Z ratios were determined
by crude 1H NMR.
Cl
OEt
OSiEt3
O
OSiEt3
OSiEt3
O
TsN
23
24
80% (88:12 E:Z)
25
79% (86:14 E:Z)
73% (81:19 E:Z)
After establishing the substrate scope of the alkyl hal-
ide component, we next turned our attention to varia-
tions of the ynal (Scheme 3). Ynals substituted with both
electron rich (17) and electron-deficient (16, 18, 19, 20)
arenes were well tolerated. Interestingly, the electron
rich substrate 17 (p-OMe) reacted more efficiently with
a lower catalyst loading (1 mol %), although the basis
for this observation is currently unclear. Several func-
tional groups known to be reactive in other nickel-
catalyzed transformations such as an aryl boronic ester16
(21) and an aryl chloride17 (25) underwent the alkylative
coupling smoothly without competing reactivity. Elec-
trophilic functional groups such as ketones (18), esters
(19), and nitriles (20) were also well tolerated. These
functional groups are often problematic in processes
involving silanes or organozincs due to competing hy-
drosilylation and nucleophilic addition processes. Het-
erocycles such as thiophenes (22), protected indoles
(23), and uracils (26) were all tolerated in the reaction,
although the yield is diminished in the case of the uracil
substrate 26.
Me
O
Me
N
OSiEt3
OSiEt3
OSiEt3
Me
O
BnO
N
Me
26
27
28
82% (85:15 Z:E)b
66% (88:12 E:Z)b
28% (96:4 E:Z)
Me
Me
Me
OSiEt3
OSiEt3
OSiEt3
Me
EtO2C CO2Et
O
29
31-Z
65% (36:64 E:Z)
30
63% (89:11 E:Z)
63% (85:15E:Z)
O
Me
NHBoc
OEt
OSiEt3
OSiEt3
O
OSiEt3
O
N
Ts
N
Ts
34
65% (93:7 E:Z)b
32
73% (89:11 E:Z)b,c
33
68% (89:11 E:Z)b
The reaction is not limited to aryl-substituted ynals.
An alkyl-substituted ynal participated smoothly (27), as
did an ynal bearing a propargyl ether (28). For these
alkyl-substituted ynals, tetrabutylammonium iodide was
found to be superior to sodium iodide as an additive. An
enynal also participated smoothly, providing a highly
substituted 1,3-diene product (32). Finally, ynals bearing
different backbone substitution were also tolerated. An
oxygen-substituted ynal gave the exocyclic alkenyl tet-
rahydrofuran 29, while a malonate-derived ynal gave the
Standard conditions: ynal (1.0 mmol), alkyl bromide (2.0 equiv),
chlorosilane (1.5 equiv), Mn0 (2.0 equiv), NaI (0.5 equiv),
(bipy)NiI2 (5.0 mol %) in DMF (1.0 M). Isolated yields after iso-
lation by silica gel chromatography. E:Z ratios were determined
1
a
b
by crude H NMR. 1 mol % (bipy)NiI2 used. nBu4NI used in
place of NaI. c2 mol % (bipy)NiI2 used
A likely mechanism of the alkylative cyclization in-
volves oxidative cyclization of the ynal by the Ni(0)
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catalyst to form nickelacycle 35, generating the first car-
Page 4 of 7
Interestingly, the Z isomer predominates in the case of
secondary alkyl bromides (Scheme 5b). The more exten-
sive isomerization observed when secondary halides are
used is likely driven by the more crowded steric envi-
ronment slowing the rate of additions to 36 or 37 (de-
picted for 37, Scheme 5c). By decreasing the concentra-
tion of the reaction mixture, the proportion of the Z iso-
mer of product 40 derived from isomerization is in-
creased. This concentration effect is also seen with pri-
mary alkyl bromides but to a lesser extent, wherein de-
creasing the concentration of the reaction mixture leads
to an increased proportion of the minor Z isomer of the
product (Scheme 5a). In the case of secondary alkyl hal-
ides, the E/Z selectivity of the reaction can be complete-
ly reversed simply by altering the reaction concentration.
1
2
3
4
5
6
7
8
bon-carbon bond (Scheme 4). Next, the nickel-oxygen
bond is cleaved by the chlorosilane, generating the silyl
ether and the vinylnickel(II) intermediate 36. Based on
analogy to known cross-electrophile coupling mecha-
nisms,4b our original hypothesis suggested that free radi-
cal addition to 36 would lead to product via formation of
Ni(III) intermediate 38 (path a). Alternatively, Mn-
mediated reduction of 36 to Ni(I) intermediate 37,2g,13c,18
followed by oxidative addition of the alkyl halide, would
also generate Ni(III) intermediate 38 (path b). Given that
oxidative additions of alkyl halides to Ni(I) proceed
through single electron transfer (SET) pathways,19
pathways a and b both ultimately involve a free radical
addition to a Ni(II) species. Intermediate 38 is poised for
rapid reductive elimination20 to generate product along
with Ni(I) intermediate 39 which is further reduced by
Mn to complete the catalytic cycle. Experiments with
stoichiometric Ni(0) catalysts indicate that product for-
mation does not occur in the absence of reductant, which
tentatively supports a mechanistic sequence involving
formation of 37 (path b).21
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 5. Effect of Reaction Concentration
Et3SiCl (1.5 equiv)
(bipy)NiI2 (5 mol %)
Mn0 (2.0 equiv)
Conc. (M) yield (E:Z ratio)
a)
Ph
nPr
Ph
nPr
Br
88% (53:47)
0.05
90% (74:26)
82% (82:18)
83% (87:13)
87% (89:11)
OSiEt3 0.1
O
+
NaI (50 mol %)
0.2
0.5
1.0
DMF (X M), rt
H
4
Me
Br
b)
Scheme 4. Mechanistic Proposal
Et3SiCl (1.5 equiv)
(bipy)NiI2 (5 mol %)
Mn0 (2.0 equiv)
Conc. (M) yield (E:Z ratio)
58% (17:83)a
0.1
Me
58% (19:81)a
0.2
OSiEt3
iPr
Ph
O
+
NaI (50 mol %)
0.5
1.0
54% (35:65)
40% (44:56)
N
N
DMF (X M), rt
H
Ni
L=
I
I
40
Mn0
N
N
R
O
c)
L
L
R'
R'
X
NiI
NiIII
H
L—Ni0
Br
Mn0
Br
OSiR3
OSiEt3
R
OSiEt3
R
R
R'
Br
R'
L
R'
L—NiI—Br
39
X
X
38-Z
X
E product
OSiEt3
R
NiII
37-Z
R
O
path (a)
X
L
R'
R'
R
X
R'
R
R'
NiIII
R
Br
OSiEt3
35
R
NiI
OSiEt3
R'
L
OSiEt3
NiIII
Br
OSiEt3
Br
L
Et3Si–Cl
L
X
X
X
X
NiII
Cl
OSiEt3
Z product
L
NiI
37-E
38-E
38
R
Effect of reaction concentration on E/Z ratio using (a) primary
OSiEt3
R
R'
Br
alkyl bromide and (b) secondary alkyl bromide. (c) Proposed
mechanistic pathway for isomerization Reaction performed with
no NaI additive
X
a
path (b)
Mn0
36
X
37
The Z→E isomerization likely does not occur from a
Ni(III) intermediate 38-Z given the fast rate of reductive
eliminations from Ni(III). Furthermore, the unimolecular
nature of the conversion of 38 to product should not ex-
hibit concentration-dependent E/Z selectivity. The strong
dependence of product E:Z ratio on reaction concentra-
tion instead suggests that the rate of isomerization com-
petes with a bimolecular reaction of 36 or 37. Similar
effects were demonstrated in nickel/photoredox cata-
lyzed desymmetrization of meso-anhydrides, in which
the ratio of diastereomeric keto-acid products could be
adjusted by tailoring reaction conditions to favor or dis-
favor rapid capture of a putative Ni(II) intermediate.23
The formation of mixtures of E and Z isomers is likely
a result of the Z→E isomerization of the intermediate 36
or 37 generated after cleavage of the nickelacycle 35 by
the chlorosilane (Scheme 4). It is currently unclear
which intermediate undergoes isomerization, but E/Z
isomerization of vinylnickel intermediates has been pro-
posed in various transformations.2g,13a,22 We found that
increasing the concentration of the reaction mixture to
1.0 M gave optimal E:Z ratios (Scheme 5a). Either oxi-
dative addition of the alkyl halide to Ni(I) intermediate
37 (path b) or radical addition to Ni(II) intermediate 36
(path a) would be favored at high concentration com-
pared with the rate of the isomerization process.
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of
a nickel catalyzed process using radicals generated from
In conclusion, this work demonstrates the combination
of nickel-catalyzed oxidative cyclization and reductive
cross-electrophile coupling as a new approach for the
catalytic union of aldehydes, alkynes, and alkyl halides.
The use of chlorosilanes to generate a reactive vi-
nylnickel(II) intermediate was essential in enabling the
reductive cross-electrophile coupling. The reaction al-
lows for the use of air-stable alkyl halides as alkylating
reagents in place of preformed organometallic reagents
previously employed, which significantly expands the
scope and functional group tolerance of the procedure.
Efforts to expand these findings towards other classes of
cyclizations and multicomponent couplings are in pro-
gress.
hydrometallation with a cobalt catalyst, see: (g) Green, S. A.; Matos,
J. L. M.; Yagi, A.; Shenvi, R. A. J. Am. Chem. Soc., 2016, 138,
12779.
1
2
3
4
5
6
7
8
(5)
(a) Zuo, Z.; Ahneman, D. T.; Chu, L.; Terrett, J. A.; Doyle,
A. G.; MacMillan, D. W. C. Science, 2014, 345, 437. (b) Tellis, J. C.;
Primer, D. N.; Molander, G. A. Science, 2014, 345, 433. (c) Matsui, J.
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Supporting Information
Experimental details, copies of spectra, and additional dis-
cussion of mechanism. This material is available free of
charge via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
*jmontg@umich.edu
Funding Sources
No competing financial interests have been declared. We
are grateful to the National Institutes of Health
(R35GM118133) for support of this work.
ACKNOWLEDGMENT
(14) See supporting information for additional screening,
optimization, and control results.
Michael Robo is acknowledged for useful discussions.
(15) Although previous studies suggest that exogenous iodide
salts are necessary to facilitate electron transfer from manganese to
Ni(II) intermediates (see ref 13c), the cyclization reaction occurs in
the absence of iodide salts, albeit with lower yields and selectivities.
We believe the role of iodide is limited to the in situ Finkelstein
reaction, slowly forming the alkyl iodide and limiting dimerization.
(16) Boit, T. B.; Weires, N. A.; Kim, J.; Garg, N. K. ACS
Catal., 2018, 8, 1003.
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(21) See the Supporting Information for
a more detailed
mechanistic discussion and preliminary mechanistic studies.
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Authors are required to submit a graphic entry for the Table of Contents (TOC) that, in conjunction with the manuscript title,
should give the reader a representative idea of one of the following: A key structure, reaction, equation, concept, or theorem,
etc., that is discussed in the manuscript. Consult the journal’s Instructions for Authors for TOC graphic specifications.
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R3SiCl, Mn0
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~ 30 examples
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