Nickel-catalyzed reductive conjugate addition to enones via allylnickel intermediates

Article abstract of DOI:10.1021/ja309176h

An alternative method to copper-catalyzed conjugate addition followed by enolate silylation for the synthesis of β-disubstituted silyl enol ether products (R¹(R²)HCCH=C(OSiR⁴₃)R ³) is presented. This method uses haloarenes instead of nucleophilic aryl reagents. Nickel ligated to either neocuproine or bipyridine couples an α,β-unsaturated ketone or aldehyde (R²HC=CHC(O)R ³) with an organic halide (R¹-X) in the presence of a trialkylchlorosilane reagent (Cl-SiR⁴₃). Reactions are assembled on the benchtop and tolerate a variety of functional groups (aldehyde, ketone, nitrile, sulfone, pentafluorosulfur, and N-aryltrifluoroacetamide), electron-rich iodoarenes, and electron-poor haloarenes. Mechanistic studies have confirmed the first example of a catalytic reductive conjugate addition of organic halides that proceeds via an allylnickel intermediate. Selectivity is attributed to (1) rapid, selective reaction of LNi⁰ with chlorotriethylsilane and enone in the presence of other organic electrophiles, and (2) minimization of enone dimerization by ligand steric effects.

Full text of DOI:10.1021/ja309176h

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Article
Nickel-Catalyzed Reductive Conjugate Addition
to Enones Via Allylnickel Intermediates
Ruja Shrestha, Stephanie C. M. Dorn, and Daniel John Weix
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja309176h • Publication Date (Web): 27 Dec 2012
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Journal of the American Chemical Society
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Nickel-Catalyzed Reductive Conjugate Addition to Enones
Via Allylnickel Intermediates
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Ruja Shrestha,† Stephanie C. M. Dorn, and Daniel J. Weix*
Department of Chemistry, University of Rochester, Rochester, NY 14627-0216, U.S.A.
Supporting Information Placeholder
ABSTRACT: An alternative method to copper-catalyzed conjugate addition followed by enolate silylation for the synthesis of β-di-
substituted silyl enol ether products (R1(R2)HCCH=C(OSiR4 )R3) is presented. This method uses haloarenes instead of nucleophilic aryl
3
reagents. Nickel ligated to either neocuproine or bipyridine couples an α,β-unsaturated ketone or aldehyde (R2HC=CHC(O)R3) with an
organic halide (R1-X) in the presence of a trialkylchlorosilane reagent (Cl-SiR4 ). Reactions are assembled on the bench-top and tolerate a
3
variety of functional groups (aldehyde, ketone, nitrile, sulfone, pentafluorosulfur, and N-aryltrifluoroacetamide), electron-rich iodoarenes,
and electron-poor haloarenes. Mechanistic studies have confirmed the first example of a catalytic reductive conjugate addition of organic
halides that proceeds via an allylnickel intermediate. Selectivity is attributed to: 1) rapid, selective reaction of LNi0 with chlorotriethylsilane
and enone in the presence of other organic electrophiles, and 2) minimization of enone dimerization by ligand steric effects.
1. Introduction
selectivity observed and shed light on a mechanism for the reduc-
tive conjugate addition of organic halides.
The conjugate addition of aryl and vinyl nucleophiles to an α,β-
A. Nucleophilic Aryl Reagents
unsaturated ketones has been important to organic synthesis for
1
over half a century. The potential to functionalize two adjacent
ꢀ Enol Ether Product
( Nucleophilic Ar
OSiR3
carbons via conjugate addition and trapping of the resultant enolate
O
1c, 1d, 2,
3
has proven especially powerful in synthesis (Figure 1A).
( Limited Functional-
Group Compatibility
Ar–[M]
Cu or Ni cat.
R3SiCl
Trapping with chlorosilanes to form silyl enol ethers enables sub-
Ar
ꢀ Wide Ar-X and Enone Scope
4
sequent regioselective vinylnonaflate formation, enolate for-
2
5
6
2
B. Electrophilic Aryl Reagents Via Reductive Heck
( Ketone Product Only
mation, α-arylation, α-alkylation, aldol reaction, Michael addi-
2
7
7b
O
tion, α-oxygenation, and α-amination. While the conjugate ad-
dition reaction has been continually expanded and refined over the
intervening years, a fundamental weakness of the approach, the
need for pre-formed organometallic reagents, has remained.
O
ꢀ Electrophilic Ar
ꢀ Excellent FG Compatibility
Ar–X
Pd, Co, or Ni
reductant
( Limited Ar-X (Pd) or
Enone (Co, Ni) Scope
Ar
Although great progress has been made in the synthesis and con-
jugate addition of less reactive carbon nucleophiles, such as or-
C. Electrophilic Aryl Reagents Via Allylnickel - This Work
ꢀ Enol Ether Product
ꢀ Electrophilic Ar
OSiR3
8
ganozinc, organotin, or organoboron compounds, functional
O
group compatibility remains a challenge and few of these carbon
nucleophiles are commercially available. Of these approaches, the
Rh-,9 and later Pd-,10 catalyzed conjugate addition of arylboronic
acids has proven to have the broadest functional-group compatibil-
Ar–X
ꢀ Excellent FG Compatibility
ꢀ Promising Ar-X and
Enone Scope
Ni cat.
R3SiCl, reductant
Ar
Figure 1. Comparison of three approaches to conjugate addition
reactions that highlights the advantages of this study (C).
11
ity, but trapping of the enolates has not been demonstrated. Addi-
tionally, 10 to 1000 times fewer arylboronic acids than haloarenes
12
are commercially available. As a consequence, extra synthetic
2. Background
steps may be required to synthesize a molecule of interest due to
the formation of the organometallic reagent or because of protec-
tion and deprotection steps.
The Pd-catalyzed reductive Heck reaction, pioneered by Cacchi
nearly 30 years ago, is the most developed approach towards con-
jugate addition without pre-formed organometallic reagents (Fig-
ure 1B).13 Intermolecular, intramolecular, and even stereoselective
intramolecular applications have been reported by a number of
groups. While good substrate scope has been demonstrated for the
Michael acceptor, all of the intermolecular approaches suffer from
the same limitations: only electron-rich aryl iodides provide high
yields and no addition/enolate trapping sequences have been re-
ported.
The reductive Heck reaction avoids the use of nucleophilic car-
bon reagents; however, trapping of the resultant enolate has not
been demonstrated (Figure 1B). It would be a great advantage in
complex molecule synthesis, to have a method for conjugate addi-
tion, that combines the mildness of the Heck reaction with the
ability to form silyl enol ether products.
We report our development of a reaction that satisfies these
needs (Figure 1C). In addition, our studies explain the cross-
Nickel-14 or cobalt-catalyzed15 reductive Heck reactions have
broader haloarene scope, but only Michael acceptors without β-
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Page 2 of 15
1. Na0, COD
0 °C, 2 h
substitution provide high yields. Ronchi, Beletskaya, and Nédélec
Ph
PhBr
(3 equiv)
Cl
1
2
3
4
5
6
7
8
demonstrated that the nickel-catalyzed reactions tolerated elec-
tron-poor haloarenes, which was an important advance over the
palladium-catalyzed methods. While acrylates, vinyl ketones, and
acrylonitrile provide good yields of product, β-substituted α,β-
unsaturated ketones are rarely used as substrates. For example, the
addition of bromonaphthalene to ethyl crotonate provided only
(1)
[Ni]
(py)4NiCl2
hυ
10 °C
12.5 h
2. cyclopentenone
TBS-Cl, 30 min
OTBS
II
OTBS
82% yield
The catalytic applications of this proposed approach have not
been reported; however, the use of Lewis acids or chlorosilanes to
facilitate the oxidative addition of enones to nickel(0) and palladi-
um(0) has been shown by a number of groups. Mackenzie reported
an allylnickel mechanism to be operative for the nickel-catalyzed
14h
20% of the conjugate addition product. Finally, although Mont-
20
gomery has shown that iodoarenes can be added to acrylates with
trapping of the resultant enolate by an aldehyde,14f, g no examples of
trapping with silicon reagents are known. In fact, the addition of
chlorotrimethylsilane has been reported to favor biaryl formation
9
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conjugate addition of organostannanes to enones. In this case,
15b
over conjugate addition product. In contrast, a host of literature
transmetalation between an allylnickel(II) complex and a nucleo-
philic carbon reagent (e.g. ArSnMe3), followed by reductive elimi-
nation forms the silyl enol ether product. This inverse mechanism
has demonstrated that the conceptually related addition of alkynes
and alkenes to enones in the presence of silicon reagents can form
silyl enol ether products with broad functional group compatibil-
22
23
has been leveraged by Morken, Yoremitsu, and Oshima in the
reaction of enones with organoboranes as well. Lastly, palladium
16
ity.
24
The limitations of the reductive Heck approaches appear to be
related to their common mechanism (Figure 2). Migratory inser-
tion of the arylmetal intermediate (I) into the acceptor is ineffi-
cient, resulting in poor results with electron-poor haloarenes (Pd)
or less electrophilic Michael acceptors (Ni, Co). β-Hydride elimi-
nation from the metal enolate can result in the formation of Heck
reaction products. Finally, trapping of the metal enolate intermedi-
ate is inefficient with chlorosilanes or the chlorosilanes cause unde-
sired reactivity. While adjustment of conditions or catalysts could
be envisioned to overcome these problems, overcoming these limita-
tions may require a reaction with a fundamentally different mechanism
(Figure 3).
was shown to behave similarly by Ogoshi and Kurosawa, and this
has enabled unconventional conjugate additions of carbon nucleo-
25
philes.
While this prior work establishes the viability of each individual
step in a potential “enone-first” catalytic cycle (Figure 3), it was not
clear if each step could be accomplished in the presence of the other
reagents. For instance, if the iodoarene reacted with nickel(0) faster
than enone and chlorosilane, then a reductive Heck mechanism
would result. On the other hand, formation of allylnickel(II) com-
19d, 20b
plexes could result in bis-allyl dimers.
Thus, formation of the
conjugate addition product requires oxidative addition of the
enone first, followed by preferential reaction of allylnickel II with
iodoarene over enone or another equivalent of II.
2X-
Ar-X
[M0]
2e-
Slow migratory
2X-
[Ni0]
O
insertion limits
Ar-X and enone
2e-
+
Et3SiCl
X
[MII]
X
I
Ar [MII]
X
O
[Ni0]
X
X
OSiEt3
HX
O
II
H
[NiII]
Cl
X
X
O
[MII]
O
OSiEt3
Ar
O
[MII]
Product trapping
limited to HX and
RCHO
Ar-X
Ar
Heck reaction can compete
Ar
Ar
Ar
Figure 3. A hypothetical reductive conjugate addition mechanism
with an allylnickel(II) intermediate (II).
Figure 2. The reductive Heck consensus mechanism and its rela-
tionship to the limitations of the methods.
We recently reported the reductive conjugate addition of sec-
ondary, tertiary, and neopentyl halides to enones with trapping as
the silyl enol ether (eq 2), but were unable to confirm the mecha-
Precedent for a different approach can be found in the stoichio-
metric reactivity of nickel(0) with enones and chlorosilanes.17
Mackenzie showed that allylnickel(II) reagents can be formed by
the reaction of Ni0 with an enone and a chlorosilane and that these
26
nism by which the products were formed.
4 mol % Ni(acac)2
OSiEt3
O
allylnickel intermediates will react with aryl bromides when irradi-
4 mol % L1
R
Br
R
+
17a,b
(2)
Alkyl
ated with UV light (eq 1).
Allylnickel(II) species are versatile
Et3SiCl
18
reagents which react with a variety of electrophiles, presumably
2 equiv Mn0 powder
Alkyl
DMF, 40 °C, 2-24 h
via a single-electron transfer mechanism involving nickel(I) inter-
19
L1 = 4,4',4''-tri-tert-butyl-2,2':6',2''-terpyridine
15 examples
42-85% yield
mediates. If Mackenzie’s approach could be made catalytic, it
Alkyl = 3° alkyl, 2° alkyl, neopentyl
would avoid the two problematic steps in the reductive Heck reac-
tion: 1) migratory insertion and 2) enolate trapping.
While we were able to rule out the intermediacy of AlkylMnBr
intermediates, both the reductive Heck (Figure 2) and “enone first”
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Journal of the American Chemical Society
(Figure 3) mechanisms were considered. While L1 was required Application of the best conditions for cyclohexenone to an E-
1
2
3
4
5
6
for the chemistry, stoichiometric studies on in situ-formed
(L1)NiII(η3-1-triethylsilyloxycyclohexenyl)Cl (like II in Figure 3)
did not match the selectivity observed under catalytic conditions.
Due to the instability of (L1)Ni(alkyl)X complexes (like I in Figure
acyclic substrate, 4-hexen-3-one produced a low yield of product
(<40% yield after 3 h, SM consumed). The low selectivity appears
to be related to sterics because we found that the least hindered
ligand, 2,2’-bipyridine (L2), provided the best results (eq 4).
27
Table 1: Ligand Effects on Reductive Conjugate Addition.a
2), we were unable to directly test for the viability of a reductive
Heck mechanism. The poor selectivity observed with L1-ligated
7
8
9
allylnickel led us to favor a reductive Heck mechanism.
O
1 mol % Ni(acac)2
1 mol % L
OSiEt3
OSiEt3
Our previous study, while promising because the reductive con-
jugate additions were not previously possible, was limited to unac-
tivated alkyl halides. Attempts to use the same catalyst to couple
vinyl and aryl halides provided low yields of product (vide infra,
Table 1, entry 3). Furthermore, the demonstrated functional-group
tolerance was limited to an ester and a nitrile. Finally, the limited
mechanistic understanding limited our ability to further improve
the scope of the reaction.
+
+
Ph-Ph
Ph-I (1 equiv)
Ph
R3
Et3SiCl (1.1 equiv)
Mn0 powder (2 equiv)
2 mL DMA, 20 °C
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2
Product
Biaryl Enone Dimer
R3
R3
R3
R2
R2
R2
R2
N
N
N
N
R1
R1
R1
R1
We report here a new catalyst system that broadens the scope of
reductive conjugate addition/enolate trapping to include aryl and
vinyl halides (eq 3). New mechanistic studies on reactions con-
ducted with aryl and alkyl halides reveal a general mechanism for
reductive conjugate addition. Finally, these studies also illuminate
the factors that govern cross-selectivity for these new reactions.
L2: R1 = R2 = R3 = H
L7: R1 = R2 = R3 = H
L3: R1 = R2 = H, R3 = t-Bu
L4: R1 = R2 = H, R3 = OMe
L5: R1 = R3 = H, R2 = Me
L6: 2,2'-biquinoline
L8: R1 = R2 = H, R3 = Ph
L9: R1 = H, R2 = R3 = Me
L10: R1 = Me, R2 = R3 = H
t
P
B
E
PhH
(%)
O
1 mol % Ni(acac)2
1 mol % neocuproine
or bipyridine
OSiR3
entry
ligand (L)
(h)
(%)
(%)
(%)
X
+
Ar
(3)
2 equiv Mn0 powder
1.1 equiv R3SiCl
DMA, rt
1
none
24
28b
39c
24
6
19
1
Ar
1.0
equiv
1.0 or 1.2
equiv
2
py (1 equiv)
15
18
24
24
24
72
24
24
24
24
2
3
14
98
51
38
54
34
47
44
46
36
13
4
3d
L1
L2
L3
L4
L5
L6
L7
L8
L9
L10
42
13
16
36
0
10
6
3. Results
4
67
3.1 Ligands. Initial reaction development was focused on find-
ing a catalyst that would be selective for the cross-coupling of iodo-
benzene with cyclohexenone in presence of chlorotriethylsilane
(Table 1). The combination of three electrophiles could result in
multiple by-products, but we primarily observed biphenyl (B),
benzene (Ph-H), and silylated enone dimer (E). Notably, we did
not observe the formation of desilylated ketone product or prod-
ucts from a Heck-like addition/β-hydride elimination process.
5
41c
41e
60
10
11
0
6
7
8
41c
28c
34f
43e
99
19
12
24
34
0
11
11
11
9
9
Consistent with previous studies using cobalt and nickel,28 reac-
tions of cyclohexenone with iodobenzene did not produce much
product in the absence of a ligand (Table 1, entry 1). When pyri-
dine was used in excess to nickel, selectivity was improved but reac-
tivity remained low (entry 2). Reactions with smaller amounts of
pyridine provided only trace amounts of product. Our previous
10
11
12
4
a
See Supporting Information for full experimental details. Yields for
P, B, and Ph-H are corrected vs internal standard (dodecane). Yields of
26
b
c
studies with haloalkanes had demonstrated the ability of nickel
E are uncorrected. >50% of both enone and PhI remained. >10% of
d
ligated to
a tridentate nitrogen ligand (4,4’,4’’-tri-tert-butyl-
both enone and PhI remained. Reaction run with 10 mol % [Ni] and
L1 in DMF. e>10% of enone remained. f >10% of PhI remained.
2,2’:6’,2’’-terpyridine, L1) to favor conjugate addition over compet-
ing dimerization processes; however, this catalyst primarily formed
biaryl and dimerized enone products in reactions with haloarenes
(entry 3).
1 mol % Ni(acac)2
Ph OSiEt3
1 mol % L
O
(4)
Ph-I (1 equiv)
The observation of strong ligand effects for other reductive cou-
pling reactions29 prompted us to examine various bidentate nitro-
gen-based ligands (L2-L10). While the series of ligands did provide
a wide range of selectivities, the electronics of the ligands appeared
to play only a small role (entries 5 vs 6, 9 vs 10). Substitution, even
substitution remote from the metal center, decreased the amount
of enone dimer (E) formed (entries 5-8 and 9-12). Of the ligands
surveyed, 2,9-dimethyl-1,10-phenanthroline (neocuproine, L10)
provided the highest yield of product, the best selectivity, and the
fastest reaction (complete in 20 min vs >18 h).30
Et3SiCl (1.1 equiv)
Mn0 powder (2 equiv)
DMA, 20 °C
With L10:
With L2:
34% (GC, 3 h)
56% (GC, 12 h)
3.2 Other Reaction Conditions. As we had seen with the con-
jugate addition of haloalkanes to enones, the presence of nickel,
reductant, and trialkylchlorosilane were essential for reactivity.
Reactions conducted without any one of these individual compo-
nents did not consume iodoarene or enone after 30 min of reaction
time. Amide and urea solvents provided the highest yields of prod-
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uct (DMA~NMP~DMPU>DMF>DMI~THF, see Table S1 in the 3.4 Haloarene Scope. A major advantage of reductive conjugate
1
2
3
4
5
6
7
8
Supporting Information). Finally, manganese powder was a more
effective electron source than zinc. Reactions run with zinc pro-
duced more hydrodehalogenated products.
Table 2. Silicon Reagent Reactivitya
addition is the large substrate pool and the potential for broad func-
tional-group compatibility. Given the problems observed in Pd-
catalyzed reductive Heck reactions with electron-poor arenes, we
first examined the effect of electronics on the outcome of these
conjugate addition reactions (Scheme 2).
31
Scheme 1. Acceptor and Silicon Reagent Scopea
OSiR3
O
1 mol % Ni(acac)2
1 mol % L10
+
R3SiX
O
OSiEt3
Ph-I (1 equiv)
Mn0 powder (2 equiv)
1 mol % Ni(acac)2
1 mol % L10 or L2
Ph
9
X
+
2 mL DMA, 20 °C
Ar
10
11
12
13
14
15
16
17
18
19
20
21
22
23
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59
60
Mn powder (2 equiv)
R3SiCl (1.1 equiv)
DMA, rt
Ar
1.0
equiv
1.0
equiv
entry silicon reagent
yield (%)b
1-9
1
Me3SiOTf (TMS-OTf)
Me3SiCl (TMS-Cl)
48
48
0
OSiEt3
OSiEt3
OSiEt3
2
3
(Me3Si)2NH (HMDS)
(Me3Si)NHCHOSiMe3 (BSA)
Et(Me)2SiCl
4
0
1
2
3
5
66
79
94
73
77
95
84
66
36
27
0
75%0
79%b
65%0
Me
6
n-Bu(Me)2SiCl
O
O
Ar
Ar = 4-MeOC6H4-, 4, 48%c
Ar = 4-AcC6H4-, 5, 58%c
OSiR3
7
Et3SiCl (TES-Cl, as in Table 1)
Et3SiOTf (TES-OTf)
i-Pr(Me)2SiCl
Et
Me
8
Ar
O
Ar
9
H
Me
10
11
12
13
14
15
n-Pr3SiCl
Me
R3 = n-Pr3, 8, 91%0
t-Bu(Me)2SiCl (TBS-Cl)
t-Bu(Me)2SiOTf (TBS-OTf)
i-Pr3SiCl (TIPS-Cl)
Ar = 4-AcC6H4-,
6, 51%c,d
Ar = 4-AcC6H4-,
7, 50%c,d
R3 = t-BuMe2, 9, 87%
a
Ratio of enone : Ar-I : R3Si-Cl : catalyst was 1.0 : 1.0 : 1.1 : 0.01.
Yields reported are of isolated, pure material (average of two runs).
Reaction temperature was 40 °C. With ligand L2 and after deprotec-
tion by KF in methanol. Yield reported is for two steps. Products
b
i-Pr3SiOTf (TIPS-OTf)
t-Bu(Ph)2SiCl (TBDPS-Cl)
c
d
a
b
isolated as mixtures of diastereomers: 6, 1:1; 7, 6:1.
Reactions conducted as in Table 1. Yield is an uncorrected GC
yield vs internal standard (dodecane).
Scheme 2. Aryl Halide Electronic Effectsa
A variety of silicon reagents were tested under our optimized re-
action conditions (Table 2). Reactions conducted with the trime-
thylsilyl donors provided only modest yields of product (entries 1-
4) and similarly poor results were obtained with very large silicon
groups: triisopropylsilyl (TIPS) and tert-butyldiphenylsilyl
(TBDPS) (entries 13-15). Most other silicon reagents with moder-
ate reactivity and steric bulk formed product in reasonable yield
(66-95% yield, entries 5-12). Because chlorotriethylsilane (TES-
Cl) was among the most effective reagents and it is available at low
cost, we conducted the majority of our reactions in the following
sections with TES-Cl. If less reactive silyl enol ether products
would be an advantage in synthesis, n-Pr3Si-Cl or TBS-Cl can be
used with only a small change in yield (entries 10 and 11 respec-
tively).
O
OSiEt3
1 mol % Ni(acac)2
1 mol % L10
X
+
Ar
Mn0 powder (2 equiv)
Et3SiCl (1.1 equiv)
DMA, rt
Ar
1.0
equiv
1.0
equiv
10-15
Electron-rich aryl halides
Me
86% yield 10
I
I
OMe
I
NMe2
76% yield 12
86% yield 11
Electron-poor aryl halides
O
I
F
Br
CN
I
Me
3.3 Enone and Silicon Reagent Scope. A variety of α,β-
unsaturated ketones and an α,β-unsaturated aldehydes formed
conjugate addition products under our optimized conditions
(Scheme 1). Five-, six-, and seven-membered α,β-unsaturated cy-
cloalkenones, as well as linear alkenones provided products 1-9 in
reasonable yields. The acyclic silyl enol ethers 4-7 were formed
84% yield 13
84% yield 14b
84% yield 15
a Reactions conducted as in Scheme 1. b With Ar-Br, 58% yield.
Electron-poor and electron-rich aryl halides coupled equally
well, but only electron-poor aryl bromides coupled in high yield.
Reactions with bromobenzene, for example, primarily produced
with modest E:Z ratios (2:1 to 3:1), so the ketone products were
32, 33
34
isolated instead of the silyl enol ethers.
As noted above, tert-
silyl enol ether dimer E (Table 1). This limitation is complemen-
butyldimethylsilyl and tri-n-propylsilyl enol ethers could also be
obtained in good yield (8 and 9).
tary to reductive Heck reactions, which are limited to electron-rich
aryl halides. Despite the poor reactivity with electron-neutral and
electron–rich bromoarenes, the commercially available substrate
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pool is vastly expanded compared to reactions with Grignard rea- bearing aldehydes have appeared in the literature, none have been
1
2
3
4
5
6
7
8
gents or arylboronic acids.
shown to participate in conjugate addition reactions selectively.
Reactions with ortho-substituted aryl halides resulted in lower
yields (Scheme 3). While methoxy and nitrile substituents on the
ortho position were tolerated to form 16 and 17 respectively, reac-
tions run with o-iodotoluene and o-iodoacetophenone did not form
product when ligand L10 was used. Anticipating that this was due
to a steric mismatch similar to what we observed with E-alkenones,
we briefly explored the less hindered ligands L2 and L3. Consistent
with our hypothesis, the reaction conducted with ligand L3 formed
product 18 in better yield than with ligand L10. Further improve-
ments for the addition of sterically hindered haloarenes are re-
quired, but these results demonstrate that ligand design can poten-
tially solve this problem.
Fluorinated arenes are important in the pharmaceutical industry,
but their electron-poor nature would prevent their use in reductive
Heck reactions for their addition to enones. The expected products
25-27 were formed in good yields under our standard conditions.
Aryl halides which could be easily hydrolyzed, such as an aryl es-
ter and a trifluoroacetamide, coupled in high yields to form 30 and
31 respectively. Conditions which utilize strong nucleophiles (cu-
prates) or basic aqueous conditions (Rh-catalyzed conjugate addi-
tion) could be problematic for these substrates. Additionally, the
N-H proton on the N-aryltrifluoracetamide is reported to have a
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
42
pKa of 12.6 in DMSO and can readily protonate most organome-
tallic reagents
Scheme 3. Ortho-Substituted Arenes.a
Finally, a vinyl halide, 2-bromopropene, reacted to form product
33 in good yield. The corresponding boronic acid is reported to be
thermally unstable.43
O
R
OSiEt3
1 mol % Ni(acac)2
1 mol % L
I
R
+
Scheme 4. Functional-Group Compatibility
Mn0 powder (2 equiv)
Et3SiCl (1.1 equiv)
DMA, rt
1.0
equiv
1.0
equiv
O
OSiEt3
1 mol % Ni(acac)2
1 mol % L10
X
+
Ar
L10, R = OMe, 65% yield 16
L10, R = CN, 54% yield 17b
L10, R = Me,
L3, R = Me, 37% yield 18c0
0% yield 18
Mn0 powder (2 equiv)
Et3SiCl (1.1 equiv)
DMA, rt
Ar
1.0
equiv
1.0 or 1.2
equiv
19-34
a
b
c
Reactions conducted as in Scheme 1. With Ar-Br, 44% yield.
Yield based on a single run.
I/X and I/Bpin Chemoselectivity
Cl
76% yield 19
O
O
Functional-group compatibility is further demonstrated in
Scheme 4. While 1 equivalent of aryl halide was generally sufficient,
a small improvement in yield could be obtained for reactions of aryl
iodides when a slight excess of Ar-I was added (1.2 equiv). This
improvement was not observed for reactions of aryl bromides.
I
I
Br
71% yield 20
I
B
69% yield 21b, c
Aryl Halides Containing Additional Reducable Groups
O
H
O
The lower reactivity of aryl bromides and chlorides compared to
aryl iodides enabled the chemoselective coupling of 4-chloro and 4-
bromo-1-iodobenzene (19 and 20 respectively). In addition, a
pinacolato boronic acid ester was not reactive under these condi-
tions (21). As we have found previously, reductive coupling condi-
tions are complementary to reactions that utilize mild carbon nu-
O
I
SF5
71% yield 23b
I
Br
S
54% yield 22b
63% yield 24b
Fluorinated Aryl Halides
I
F
I
CF3
Br
CF3
56% yield 25
Addtional Examples
Br
CO2Me
61% yield 28c
NH
29
cleophiles, such as boronic acid esters.
Me
81% yield 26
78% yield 27
Due to the reducing nature of the reaction conditions, we were
concerned that high-oxidation-state functional groups would pre-
sent a challenge. Although nickel and metal reductant combina-
tions have been reported to reduce or cross-couple high oxidation-
O
I
CO2Et
35
I
O
state sulfur compounds, the sulfone and pentafluorosulfur prod-
ucts (22 and 23 respectively) were obtained in high yield. The
pentafluorosulfur group has found increasing application in elec-
tronics and pharmaceutical applications due to it’s interesting elec-
83% yield 29b
88% yield 30b
I
I
Me
O
O
I
Br
36a,
b
tronic and steric parameters,
but few catalytic reactions have
O
F3C
73% yield 31
been demonstrated to tolerate it’s presence. Indeed, synthesis of
36a
76% yield 32c 79% yield 33
80% yield 34
derivatives remains the “Achille’s heel” of the SF5 group. In this
case, the corresponding boronic acid is not commercially available
a
b
36c
Reactions conducted as in Scheme 1. 1.2 Equiv of aryl iodide was
and is difficult to synthesize.
used instead of 1 equiv. c Product contaminated with a small amount of
hydrodehalogenated arene.
37
The pinacol coupling of aldehydes and ketones is reported to
be catalyzed by nickel under reducing conditions, and manganese
38
dust has been shown to reduce aldehydes to alcohols, but we did
Although the reaction demonstrated good substrate scope and
broad functional group compatibility, we observed two notable
limitations. Firstly, reactions with 4-iodo-nitrobenzene provided
none of the conjugate addition product. In fact, we found 10 mol %
of 4-iodo-nitrobenzene to be inhibitory to reactions with other
iodoarenes. This is probably related to the ease with which the
not observe these side reactions in the formation of products 14
and 24. Both products bear differentially protected carbonyls and
39
would be difficult to synthesize directly by any other method.
40
41
While a few remarkable reports of zinc and copper reagents
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Page 6 of 15
nitroarene accepts electrons. Inhibition by nitroarenes has also examining the reactivity of arylnickel (I) and allylnickel (II) inter-
1
2
3
4
5
6
been proposed as evidence for radical-chain-like reaction mecha-
mediates, we studied their formation and the relative stability of the
two complexes (eq 5 and 6).
19
nisms. We have observed this limitation in other reductive cou-
29
pling reactions. Secondly, reactions with halogenated het-
I
II
L10
PhI
(L10)
Ni
eroarenes (pyridine, thiophene) did not produce acceptable yields
of product and resulted in large amounts of heteroarene dimeriza-
tion.
(L10)Ni0(cod)
(5)
Ni(cod)2
Ph
IA
violet
red-brown solution
7
8
9
+
3.5 Oxidative Addition to Nickel(0). Given the strong prece-
dent for both arylnickel (I) and allylnickel (II) intermediates (Fig-
ures 2 and 3), we studied the rate at which iodobenzene, enone,
and chlorotriethylsilane react with (L10)Ni0(cod) by monitoring
II(L10)
OSiEt3
Cl-
py
Ni
L10
OSiEt3
(6)
NiII
py
Cl
IIA
deep blue-purple solution
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
44
red
the disappearance of the MLCT band at 450 nm (Figure 4). The
results clearly show that iodobenzene reacts much slower than
chlorotriethylsilane and enone, consistent with the “enone-first”
mechanism (Figure 3).
A solution of red-brown complex (L10)NiII(Ph)(I) (IA) was
generated in situ by adding PhI to a pre-stirred, violet solution of L1
and Ni(cod)2 (1:1 ratio), in analogy to preparations reported by
reactant
L10
46
Yamamoto (eq 5).
A solution of blue-purple complex
Ni0(cod)2
(L10)Ni0(cod)
(L10)[NiII]
(py)(L10)Ni(η3-1-triethylsilyloxycyclohex-2-enyl)Cl (IIA) was
generated in situ by the addition of L10 to a red solution of
18 h
monitor
at 450 nm
(py)Ni(η3-1-triethylsilyloxycyclohex-2-enyl)Cl (eq 6).
26
2.5
We made some effort to characterize the complexes in solution
by 1H NMR spectroscopy. Although complete assignment of all
protons proved difficult (Figures S6 and S7 in Supporting Infor-
mation), clear changes to the 1H chemical shifts of ligand L10
could be observed in each case, consistent with L10 coordination
with the pyridine-ligated nickel-allyl complex to form IIA and the
oxidative addition of Ph-I to the (L10)Ni0(cod) complex to form
IA.
B
F
B
2
1.5
1
H
J
F
F
B
F
B
F
B
F
B
F
B
F
B
F
B
F F
B
B
B B
F
F
F
F
F
F
B B B B
The solutions of IA and IIA were stable for at least 10 min at rt
0.5
0
H
J
47
H
J
H
J
H
J
H
J
H
J
H H H
J J
J J
H H
H H H
J J
J J
before significant decomposition into yellow solutions containing
H H
J J
aryl or allyl dimer were observed (monitored by GC analysis). Ex-
periments in the next sections used freshly generated solutions of
48
IA and IIA which were pre-stirred for 10 min before use and
0
0.2 0.4 0.6 0.8
1
1.2 1.4 1.6
Time (min)
monitored for decomposition by their characteristic color changes.
3.7 Stoichiometric Reactivity of Organonickel Intermediates
IA and IIA. After establishing the stability of IA and IIA, the reac-
tivity of each of these reagents was examined in a series of stoichi-
ometric studies (Tables 3 and 4).
Figure 4. Reaction of (L10)Ni(cod) with Ph-I (ꢀ), cyclohex-
enone + Et3SiCl (▲), Et3SiCl (ꢁ), and cyclohexenone (ꢂ) as mon-
itored by UV-Vis at 450 nm. For full UV-Vis spectra and expanded
plots of all four reactions, see Figures S1-S3 in the Supporting In-
formation.
The stoichiometric reaction of in-situ-generated arylnickel IA
with cyclohexenone and chlorotriethylsilane exclusively formed
biphenyl (B in Table 3, entries 1 and 2). When an excess of rea-
gents and a reductant were added, biphenyl was formed in the first
turnover, followed by enone dimer (E) or product (P) formation in
subsequent turnovers (entries 2 vs 3 and 4 vs 5). In comparison,
the standard catalytic reaction produces no measurable biphenyl
(entry 7), making the intermediacy of IA in the catalytic reaction
unlikely.
While no detailed mechanistic study on the Mackenzie allylnick-
el formation has been reported, Kurosawa studied the formation of
allylpalladium by the addition of Lewis acids to enone-palladium
24
complexes. Kurosawa’s results suggested that the chlorosilane
could react with a nickel-enone complex to form the allylnickel
intermediate. While we observe rapid coordination of the enone to
(L10)Ni0(cod) (6) in the absence of chlorosilane (Figure 4, small
shift in UV-Vis spectrum, complete in about 30 s), 6 also reacts
rapidly with Et3SiCl in the absence of enone to form a single new
yellow species. This product appears to be paramagnetic based
Table 3. Stoichiometric Reactivity of Arylnickel IAa
OSiEt3
OSiEt3
1
upon the broadened H NMR peaks and large chemical shifts ob-
rt, 5 min
I
Ph
+
+
II
(L10)
Ni
Ph
served (Figure 4 and Figures S4-S5 in Supporting Information).
While square-planar nickel(II) complexes are diamagnetic, tetra-
hedral nickel(II) complexes are paramagnetic and display chemical
shifts in this range. These results could represent a rare example of
Ph
Ph
2
IA
Product
Biaryl
Enone Dimer
45
rapid Si-Cl bond activation.
entry conditionsb
Yield
Yield
Yield
3.6 Synthesis and Stability of Potential Organonickel Inter-
mediates. Although the allylnickel intermediate was formed faster
than the arylnickel intermediate, either complex could still be on-
cycle if the oxidative addition reactions were reversible. Before
Enone Et3SiCl Mn0 PhI P (%) B (%) E (%)
1
0
0
0
0
0
10
0
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Ni(cod)2, NiCl2(dme)). Both IA and IIA were catalytically compe-
tent and formed product with rates and selectivities comparable to
our standard reaction conditions (Figure S8 in Supporting Infor-
mation). Close examination of reactions catalyzed by IA revealed
that biphenyl is formed at early time points. This is in contrast to
reactions catalyzed IIA or the other nickel precursors, where bi-
phenyl is not observed until significant amounts of product have
been formed (Tables S3-S7 in the Supporting Information).
2
100
100
1.0
110
110
1.1
0
0
0
0
0
116
86
95
96
0
0
1
2
3
4
5
6
7
8
3
200
1.0
1.0
0
>100d
4
5e
200
0
1.0
1.1
200 97
99f
0
13f
6
catalytic reaction with
Ni(acac)2 and L10
a
Nickel complexes were generated in situ at a concentration of 2.5
3.9 Potential Transmetalation Mechanism. In analogy to
mM in DMA and reacted with the noted reagents. Analysis at 5
minutes provided the stated yields (GC, corrected). Yields are calcu-
49
9
Osakada’s mechanism for biaryl formation, we considered wheth-
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
er product could be formed by a transmetalation event between IA
and IIA followed by reductive elimination of product. We observed
only biaryl products from the reaction of a 1:1 mixture of IA and
IIA, suggesting that transmetalation between the two different
b
lated with respect to IA unless otherwise noted. equivalents with
respect to [Ni]. Mn0 powder was pre-stirred with Et3SiCl. Yield was
c
d
37% when calculated with respect to enone. e Reaction monitored at 20
f
minutes instead of 5 minutes. Uncorrected GC yield calculated using
dodecane as internal standard, with respect to enone as the limiting
reagent (0.5 mmol).
50
nickel complexes is slower than disproportionation of IA (eq 7).
+
II(L10)
Cl-
py
Ni
I
Ph
II
(7)
OSiEt3
(L10)
Ni
+
Ph
In contrast, analogous reactions of allylnickel IIA with iodoben-
zene selectively provided the silyl enol ether product (P), albeit in
low yield (Table 4 entries 2 and 3). Increased yield and selectivity
were observed when Mn pre-activated with chlorotriethylsilane was
employed with either excess or equimolar amounts of iodobenzene
(Entries 4 and 5). Selectivity for product formation over biaryl
formation is consistent with the catalytic reaction (entry 7). Of the
two potential intermediates, only allylnickel IIA formed the correct
product and showed selectivity consistent with the catalytic reaction.
Ph
rt
5 min
39%
IA
IIA
3.10 Potential Organomanganese Intermediates. With man-
ganese metal as the terminal reductant, the potential exists for the
intermediacy of arylmanganese reagents. Reactions conducted
without nickel, but with 1.1 equiv of chlorotriethylsilane did not
consume aryl iodide over a period of 24 h (Figures S9 and S10 in
the Supporting Information). Compared to our reaction condi-
tions, the synthesis of arylmanganese iodide reagents is reported to
require different additives, higher temperatures, and longer reac-
Table 4. Stoichiometric Reactivity of Allylnickel IIA.a
51
OSiEt3
+ Cl-
OSiEt3
tion times. Further evidence against the intermediacy of ArMnI is
II(L10)
py
Ni
Ph
that the reaction of IIA with iodobenzene and an organic reduct-
ant, tetrakis(dimethylaminoethylene) (TDAE), produced more
product than the reaction without any reductant (Table 4, entry 6
vs 2). Additionally, organomanganese sensitive functional groups,
such as a free aldehyde and trifluoroacetamide were also tolerated
(Scheme 4, products 24 and 31 respectively).
+
+
OSiEt3
Ph
rt
5 min
Ph
2
Biaryl Enone Dimer
IIA
Product
entry conditionsb
PhI Mn0 Et3SiCl
Yield
Yield
Yield
P (%) B (%) E (%)
3.11 Mechanism of Reactions With Alkyl Halides. In light of
the results of our studies showing that allylnickel(II) intermediates
are key for the conjugate addition of aryl halides, we chose to revisit
our mechanistic studies on the conjugate addition of alkyl halides
that used terpyridine ligand L1 (eq 2).
1
2
3
4
5
6
7
0
0
0
0
0
0
0
0
0
0
0
0
0
0
100
100
0
12
7
0
110
200
200
0
0
100 110
1.0 110
100 0d
71
28
26
99e
0
We first examined the rate at which 2-bromoheptane, chlorotri-
ethylsilane, and cyclohexenone reacted with (L1)Ni0(cod) in a
manner identical to our studies with ligand L10. The results, shown
in Figure 5, show that (L1)Ni0(cod) reacts much faster with enone
and silyl chloride than with 2-bromoheptane. This suggests the
“enone-first” mechanism is operative for reactions with alkyl hal-
0
0
13e
catalytic reaction with
Ni(acac)2 and L10
8
69 e
0
14 e
26
Catalytic reaction with
Ni(acac)2, L10, and pyr
ides as well, in disagreement with our previous report.
Finally, we revisited the reaction of the in-situ formed
(L1)NiII(η3-1-triethylsilyloxycyclohex-2-enyl)Cl
bromoheptane (Scheme 5). Our previous study had shown that
with
2-
a
Nickel complexes were generated in situ at a concentration of 2.5
26
mM in DMA and reacted with the noted reagents. Analysis at 5
minutes (GC, corrected) provided the stated yields. For stoichiometric
reactions (1-6), the yield is calculated from starting nickel complex IIA.
predominantly enone dimer (E) was formed when this complex
26
was reacted with 2-bromoheptane (56 % E vs. 8 % P with 1 equiv,
b
c
Equivalents with respect to [Ni]. Mn0 powder was pre-stirred with
94% E vs. 0% P with 25 equiv in Scheme 5), leading us to doubt the
relevance of allylnickel intermediates. However, the addition of
manganese powder activated with Et3SiCl made a large difference
in reactivity and resulted in a reaction that favored product for-
mation over dimer formation. While the yield is modest, this result,
along with the oxidative addition studies (vide supra) support the
existence of an allylnickel intermediate in the catalytic cycle.
d
e
Et3SiCl. TDAE = tetrakis(dimethylamino)ethylene. Yield calculated
from the amount of enone added to catalytic reactions (0.5 mmol).
3.8 Kinetic Competence of IA and IIA. In order to investigate
if the observed stoichiometric reactivity is relevant to the catalytic
reactions, we compared reactions catalyzed by IA and IIA with
reactions catalyzed by several other nickel precursors (Ni(acac)2,
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Page 8 of 15
reactant
L1
product and homocoupled enone at earlier time points, followed by
eventual biaryl formation. This difference appears to be related to
the steric hindrance of the ligand, even on the periphery. As noted
in Table 1, substitution on any position of bipyridine or phenan-
throline decreases enone homocoupling. In these reactions, more
steric hindrance improved selectivity and yield.
Ni0(cod)2
(L1)Ni0(cod)
(L1)[NiII]
1
2
3
4
18 h
monitor
at 435 nm
1.2
5
6
7
8
B
J
1
0.8
0.6
0.4
0.2
0
B
F
B
F
B
F
B
B
F
B
F
B
F
B
F
F
H
The reaction of an (E)-enone with iodobenzene (eq 4) or a (Z)-
enone with a hindered aryl iodide (Scheme 3) demonstrated that
too much steric encumbrance at the nickel center could prevent
product formation. In both cases, yields could be improved by
changing to a less hindered ligand. Simple bipyridine (L2) suffices
for (E)-enones because enone dimerization is slower than for (Z)-
enones. The reaction of a hindered aryl iodide with a (Z)-enone
requires a ligand with enough bulk on the periphery to slow enone
dimerization, but no steric bulk near the nickel center (L3). These
results lay the foundation for the design of second-generation lig-
ands with increased generality and selectivity.
F
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
H
J
H
J
H
J
H
J
H
J
H
J
H
J
H
J
0
0.2 0.4 0.6 0.8
1
Time (min)
1.2 1.4 1.6
Finally, reactions conducted with neocuproine (L10) were re-
markably fast (~30 min with 1 mol % catalyst at rt) and this rate
advantage was observed for both (Z)- and (E)-enones. At this time,
the origin of this dramatic effect is unclear.
Figure 5. Reaction of (L1)Ni(cod) with 2-bromoheptane (ꢀ),
cyclohexenone + Et3SiCl (▲), Et3SiCl (ꢁ), and cyclohexenone (ꢂ)
as monitored by UV-Vis at 880 nm. For full UV-Vis spectra and an
expanded plot of all four reactions, see Figures S11 and S12 in the
Supporting Information.
4.2 Role of Silicon Reagents. As we observed in our studies on
the conjugate addition of haloalkanes to enones catalyzed by
(L1)Ni complexes, silicon reagents are required for the conjugate
addition reaction to proceed. Unlike our previous studies, most
silicon reagents of moderate steric bulk worked well.
Scheme 5. Reaction of (L1)Ni0(allyl) with 2-bromoheptane.a
The low reactivity observed without added chlorosilane can be
explained by its two roles. One role is in the activation of the Mn
surface, which became evident in our stoichiometric studies. Addi-
tionally, we could observe small amounts of Et3Si-O-SiEt3 formed
at early time points in catalytic reactions, suggesting that the silicon
reagent is removing an oxide layer from the Mn.
OSiEt3
OSiEt3
OSiEt3
L1 (1 equiv)
+
Ni
2-bromoheptane
(25 equiv)
py
Cl
2
P
E
C5H11
:
:
:
94%
ND
26%
without Mn: ND
with activated Mn: 17%
catalytic reaction: 76%
The second role is to completely change the order of reactivity of the
two electrophiles and the mechanism of the reaction. The chlorosilane
and enone react more rapidly with nickel(0) than organic halides.
The enone, which alone reacts slowly with the nickel(0) complex,
is activated by the silane to change the order of reactivity; this reac-
tivity is not limited to neocuproine complexes: examination of the
selectivity data for reactions in Table 1 over time show that regard-
less of the ligand, aryl dimerization remains slow in the presence of
both chlorosilane and enone. Only when enone and chlorosilane
have been consumed does significant biaryl formation occur. Alt-
hough the propensity of Lewis acids and chlorosilanes to allow for
a See Supporting Information for full details. Yields of stoichiometric
reactions are based upon the amount of nickel, yields of catalytic reac-
tion is based upon the amount of 2-bromoheptane. Yields are uncor-
rected vs. dodecane internal standard.
4. Discussion
4.1 Ligand Effects. A major finding of these studies is that the
conjugate addition of organic halides to enones can be improved by
ligand choice (Figure 6). This study, combined with our previous
communication, demonstrates that a complementarity between
substrate and ligand sterics must exist for high yields.
26
17a,b
24
the oxidative addition of enones to both Ni
and Pd is well
documented in the literature, this is the first time that the relative
magnitude of this effect has been reported and exploited for reac-
tion design.
R-X:
2°-, 3°-alkyl
Ar-X
Ar-X
Enone:
cyclic, acyclic
cyclic
acyclic
Our UV-Vis data (Figures 4 and 5) and NMR data (Figures S4
and S5) suggest that the chlorosilane alone can react with the nick-
el(0) complex, resulting in a new, paramagnetic species. At this
time, the structure of this putative complex and its role in the cata-
lytic cycle is unclear. It is important to note that the rapid oxidative
t-Bu
t-Bu
Ligand:
N
N
N
N
N
N
45
addition of a chlorosilane Si-Cl bond is rare. We are currently
t-Bu
N
L1
L10
L2
studying this reaction and will report our results in due course.
4.3 Functional Group Compatibility and Synthetic Utility.
These studies show, for the first time, the potential of reductive
conjugate addition reactions for the formation of functionalized
silyl enol ether products from the union of organic halides, enones,
and chlorosilanes. Functional-group tolerance and chemoselectivi-
Figure 6. Optimal ligand for different substrate combinations.
In the context of an allylnickel mechanism (Figure 3), neocupro-
ine (L10) enables high yields of product by disfavoring enone ho-
mocoupling. Reactions conducted with other ligands produce
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ty are promising. For example, the reaction is highly selective for reduction of allylnickel(II) to allylnickel(I), followed by oxidative
1
2
3
4
5
6
7
8
reaction at the iodine-carbon bond over nearly all other electro-
philes, including C-X and C-O bonds, acidic protons, and carbon-
yls. Compared to copper-catalyzed reactions – the primary method
of forming the same silyl enol ether products – functional group
compatibility is superior.
addition of R-X, and reductive elimination of product, but no sup-
porting data is available.
55a, 56, 57
Scheme 6. Unified Mechanism.
O
(L)Ni0
MnXCl
Rh-catalyzed methods using arylboronic acids have seen wide
Et3Si-Cl
35
9c
application in synthesis due in part to excellent functional-group
Mn0
52
compatibility and broad Michael acceptor scope. The nickel-
9
catalyzed reductive conjugate addition has just as great potential in
synthesis because it combines the functional-group tolerance of the
Rh-catalyzed reactions with (1) a broader pool of aryl substrates
and (2) the ability to form silyl enol ether products.
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
+
Cl-
OSiEt3
(L)NiII(X)Cl
38
NiII(L)
The products in Schemes 1-4 are mostly 3-arylcyclohexanone
derivatives, a frequent motif found in the pharmaceutical patent
literature. Despite their prevalence, relatively few examples of the
OSiEt3
37 or IIA
53
silyl enol ethers of these valuable intermediates have been reported
(24 examples, no patents) and we expect that they would be useful
for drug design.
R
R-X
enone dimer (E)
Differentiating between these mechanisms will require further
studies, but a few observations are worth noting. Stoichiometric
reactions of allylnickel IIA provided more product in the presence
of added reductant (Table 3, entries 11-13), consistent with either
mechanism, but the formation of small amounts of product without
added reductant is harder to explain with an allylnickel(I) interme-
diate. We have looked for radical intermediates using a radical trap,
1,4-cyclohexadiene, but results were inconclusive.
Finally, the ability to form TBS or TES silyl enol ethers provides
some flexibility in synthetic planning because the TBS ethers are
54
much more resistant to cleavage under acidic conditions. Because
the electrophilicity and steric size of the silicon reagent is easily
tuned, the choice of silicon reagent could be used to match or dif-
ferentiate the reactivity of two different substrates or improve selec-
tivity of poorly selective reactions.
4.4 Mechanism. All previous reports on nickel-, cobalt-, and pal-
ladium-catalyzed reductive conjugate addition reactions proposed,
and in many cases provided strong evidence for, reductive Heck-
like mechanisms (Figure 2). Compared to these previous reactions,
our new nickel-catalyzed conditions provide different products
(silyl enol ethers), better results with β-substituted enones than
other Ni- or Co-catalyzed methods, and better results with elec-
tron-poor aryl halides than the Pd-catalyzed methods. Our hypoth-
esis was that these improvements could be the result of a change in
mechanism to one involving an allylnickel intermediate (Figure 3),
but our previous studies on the conjugate addition of alkyl bro-
mides had proven inconclusive.
Hegedus noted that stoichiometric reactions of allylnickel(II)
reagents were accelerated by the addition of reductant (sodium
naphthalenide), irradiation with a tungsten lamp, or the addition of
excess NiBr2. Mackenzie reported on stoichiometric reactions of
allylnickel(II) reagents generated from enones and silyl chlorides
19d
17a,b
which required UV irradiation to react with electrophiles. Con-
sistent with the manganese powder initiating the reaction or reduc-
ing an allylnickel intermediate, a reaction conducted in the dark
proceeded the same as reactions run in the light. Similar to Hege-
dus’s observations, we also found that 10 mol
nitroiodobenzene significantly inhibited product formation.
% of 4-
4.5 Selectivity. The ordered coupling of three electrophiles –
enone, trialkylchlorosilane, and organic halide – requires selectivity
at two different stages. Our results show that selectivity is achieved
because 1) in the presence of a trialkylchlorosilane, (L)Ni0 reacts
more rapidly with enone than with iodoarene; 2) proper ligand
substitution slows the reaction of the allylnickel species with more
enone and facilitates selective formation of product. Our results
demonstrate that the selectivity and reactivity in the second step is
the weakest point of the current catalysts and further improvement
in catalyst design has the potential to allow the use of more hin-
dered substrates and less reactive organic halides.
Our new results point to a new unified, “enone-first” mechanism
that contains an allylnickel intermediate (Scheme 6) and a revision
of our earlier suggestion that an alkyl-first mechanism was likely for
26
reactions of alkyl halides. The key evidence in support of this
result is: 1) allylnickel intermediates are formed faster than either
arylnickel or alkylnickel species, and 2) only the allylnickel inter-
mediates react to form the observed products with the correct se-
lectivity.
While allylmetal intermediates have been postulated in nickel-
and palladium-catalyzed conjugate additions of various organome-
21-22232425
tallic reagents to enones,
they have never been demon-
5. Conclusions
strated to be an intermediate in catalytic coupling reactions of or-
55
The reductive conjugate addition of haloarenes, vinyl halides,
and alkylhalides to α,β-unsaturated ketones or aldehydes forms
silyl enol ether products in good yield. The only other methods
which can form these products require pre-formed organometallic
reagents (R-MgX, R-Ti(OR)3, R-ZnX). These other reactions have
limited functional-group compatibility, usually require cryogenic
temperatures, and almost always require the synthesis of the organ-
ometallic reagent. This new reductive conjugate addition displays
superior functional group compatibility to Cu-catalyzed methods
ganic halides with enones.
At this time, we do not have firm evidence for the mechanism by
which the allylnickel(II) intermediate 37 reacts with iodoarene to
form product. From the literature, two proposals exist for the reac-
tion of allylnickel complexes with electrophiles. Hegedus showed
that stoichiometric reactions of allylnickel(II) reagents proceed via
a complex radical-chain-like process involving reactive nickel(I)
and nickel(III) intermediates as well as less reactive nickel(0) and
19d
nickel(II) intermediates. The other proposal is a single-electron
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Page 10 of 15
and is comparable to the mildest conjugate addition approaches Acknowledgments are made to the University of Rochester, the
1
2
3
4
5
6
7
that cannot form silyl enol ether products (Rh-catalyzed conjugate
NIH (R01 GM097243), and to the Donors of the American Chem-
ical Society Petroleum Research Fund for partial support of this
research. Adam W. Lee (University of Rochester) is acknowledged
for the synthesis of several iodoarenes. Dr. Soumik Biswas (Univer-
sity of Rochester) is acknowledged for helpful mechanis-
tic discussions and assistance with NMR experiments of nickel
complexes.
9
addition of arylboronic acids, and Pd-catalyzed addition of io-
13
doarenes ). We expect that further studies by our group and others
will be able to further expand the scope of the Michael acceptor and
render the reaction enantioselective. Encouragingly, the choice of
ligand has a profound affect on the selectivity and reaction rate,
presenting a clear focus for these future efforts.
8
9
In contrast to all previous reports on reductive conjugate addi-
tion reactions, our studies support a mechanism involving an al-
lylnickel intermediate. Allylnickel(II) intermediates have proven
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17
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14,
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15
). Interestingly, we have shown that the oxidative addition of an
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18
lylnickel reagents with a wide variety of electrophiles, we expect
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addition reactions will soon be possible.
6. Experimental Section
Representative Procedure: Synthesis of triethyl((1,4,5,6-
tetrahydro-[1,1'-biphenyl]-3-yl)oxy)silane (4a). No precautions
were taken to exclude air or moisture besides using anhydrous-
grade N,N-dimethylacetamide (DMA) and oven-dried 1-dram vials
and stir-bars. On the benchtop, Ni(acac)2 (2.56 mg, 0.01 mmol),
neocuproine (2.08 mg, 0.01 mmol), manganese powder (110 mg,
2.00 mmol) were weighed directly into a 1-dram vial equipped with
a teflon-coated stir bar. DMA (3 mL), 2-cyclohexen-1-one (96.8
μL, 1.00 mmol), iodobenzene (111 μL, 1.00 mmol) and chlorotri-
ethylsilane (185 μL, 1.10 mmol) were added using an automatic
pipet. The vial was then capped with a PTFE-faced silicone septum,
and stirred at 1200 rpm at rt. Upon completion, the reaction mix-
ture was purified using silica gel column chromatography on deac-
tivated silica gel (1% EtOAc in hexanes). Silyl enol ether 4a was
obtained as a faint yellow oil (221 mg, 77% yield).
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ASSOCIATED CONTENT
Supporting Information. Supplementary Tables S1-S7, Figures
S1-S10, detailed experimental procedures, and full characterization
of new compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
* daniel.weix@rochester.edu
Present Addresses
†Department of Chemistry, University of California, Berkeley, CA
USA, 94720-1460
ACKNOWLEDGMENT
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stein, D., J. Chem. Soc., Chem. Commun. 1989, 1826; (c) Yamashita, H.;
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Commun. 2005, 4211.
(28) Most previous nickel work used only pyridine as a ligand and were
not able to provide satisfactory yields with β-substituted enones. See ref.
14c, d, f, and h.
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1992, 428, 223.
(47) The yellow complex could be (L10)NiIIX2. The combination of
L10 with 0.5 equiv NiCl2(dme) and 0.5 equiv NiI2 yielded the same yellow
color. See Supporting Information.
(48) A solution of (L10)Ni(cod) stirred with Ph-I for 10 min and
quenched with HCl produced only benzene and unreacted iodobenzene,
but no biphenyl. The allylnickel complex was even more stable. See Sup-
porting Information.
(49) Osakada, K.; Yamamoto, T., Coord. Chem. Rev. 2000, 198, 379.
(50) An aliquot taken at 60 min showed no change in the amount of bi-
phenyl formed and no product or enone dimer was observed.
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(51) Direct insertion with commercial Mn powder requires additives
moto, S.; Nishimata, T.; Ebisawa, M.; Asoh, Y.; Fukushima, Y.; Kato, M.
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4
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(a) Peng, Z.; Knochel, P., Org. Lett. 2011, 13, 3198; for a review on highly
activated Mn powder and applications, see (b) Cahiez, G.; Duplais, C.;
Buendia, J., Chem. Rev. 2009, 109, 1434.
Preparation of N-((1R)-1-arylethyl)-N-(arylcycloalkyl)amine derivatives
as agonists of calcium sensing receptor (CaSR). WO2010021351A1, 2010;
(d) Am Ende, C. W.; Fish, B. A.; Johnson, D. S.; Lira, R.; O'Donnell, C. J.;
Pettersson, M. Y.; Stiff, C. M. Aminocyclohexanes and aminotetrahydropy-
rans as γ-secretase modulators and their preparation and use for the treat-
ment of neurological and psychiatric diseases. WO2011092611A1, 2011.
(54) Guo, Y.; Tao, G.-H.; Blumenfeld, A.; Shreeve, J. M., Organometal-
lics 2010, 29, 1818.
(55) Gong has separately suggested related allylnickel(II) intermediates
for reactions of allylic acetates with alkyl and aryl halides, but without evi-
dence (ref. 20c-d). Our studies support an allylnickel mechanism (ref. 20e).
(56) Ikeda, S.-i.; Suzuki, K.; Odashima, K., Chem. Commun. 2006, 457.
(57) Although ref. 18a-b contain references to both allylnickel(I) and
bis(allyl)nickel(0) complexes, and have been referenced in papers that
suggest allylnickel(I) intermediates, the intermediates drawn in those pa-
pers are best formulated as allylnickel(II) and bis(allyl)nickel(II) complex-
es using current electron-counting methods. See ref. 19, for example.
(52) Clearly, the high enantioselectivity that can be obtained with the
Rh-catalyzed reactions is also a major reason of their use in synthesis. The
development of enantioselective reactions will be reported in due course.
(53) A search of patents containing 3-arylated cyclohexanones returned
375 patents. These intermediates were elaborated into molecules with a
variety of activities, including a monoamine reuptake inhibitor, a CCR2
antagonist, a CaSR agonist, and a γ-secretase modulator. These have the
potential to treat depression, pain, asthma, heart disease, hypercalcemia,
and psychiatric diseases. See: (a) Schoenfeld, R. C. Preparation of diaze-
pine derivatives as monoamine reuptake inhibitors. US 20110136787 A1,
2011; (b) Ebel, H.; Frattini, S.; Gerlach, K.; Giovannini, R.; Hoenke, C.;
Santagostino, M.; Scheuerer, S.; Trieselmann, T. Preparation of dihydropy-
ranmethylaminopyrimidinylcarbonylpiperidine derivatives and analogs for
use as CCR2 receptor antagonists. WO 2011073155 A1, 2011; (c) Maru-
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