Nickel-Catalyzed 1,2-Diarylation of Simple Alkenyl Amides

Article abstract of DOI:10.1021/jacs.8b11942

A nickel-catalyzed conjunctive cross-coupling of simple alkenyl amides with aryl iodides and aryl boronic esters is reported. The reaction is enabled by an electron-deficient olefin (EDO) ligand, dimethyl fumarate, and delivers the desired 1,2-diarylated products with excellent regiocontrol. Under optimized conditions, a wide range of amides derived from 3-butenoic acid, 4-pentenoic acid, and allyl amine are compatible substrates. This method represents the first example of regiocontrolled 1,2-diarylation directed by a native amide functional group. Computational analysis sheds light on the potential substrate binding mode and the role of the EDO ligand in the reductive elimination step.

Full text of DOI:10.1021/jacs.8b11942

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Communication
Nickel-Catalyzed 1,2-Diarylation of Simple Alkenyl Amides
Joseph Derosa, Roman Kleinmans, Van T. Tran, Malkanthi K. Karunananda,
Steven R. Wisniewski, Martin D. Eastgate, and Keary M. Engle
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b11942 • Publication Date (Web): 07 Dec 2018
Downloaded from http://pubs.acs.org on December 7, 2018
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Nickel-Catalyzed 1,2-Diarylation of Simple Alkenyl Am-
ides
Joseph Derosa‡, Roman Kleinmans†‡, Van T. Tran†‡, Malkanthi K. Karunananda‡, Steven R. Wisniewski§, Mar-
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tin D. Eastgate§, and Keary M. Engle‡*
‡
Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States
§Chemical & Synthetic Development, Bristol-Myers Squibb, 1 Squibb Drive, New Brunswick, New Jersey 08903, United States
Supporting
Information
Placeholder
nickel catalysis, showcasing the ability of this method to lead
ABSTRACT: A nickel-catalyzed conjunctive cross-coupling
of simple alkenyl amides with aryl iodides and aryl boronic
esters is reported. The reaction is enabled by an electron-
deficient olefin (EDO) ligand, dimethyl fumarate, and deliv-
ers the desired 1,2-diarylated products with excellent regio-
control. Under optimized conditions, a wide range of amides
derived from 3-butenoic acid, 4-pentenoic acid, and allyl
amine are compatible substrates. This method represents the
first example of regiocontrolled 1,2-diarylation directed by a
native amide functional group. Computational analysis sheds
light on potential substrate binding mode and the role of
EDO ligand in the reductive elimination step.
to complex polyarylated alkanes (Scheme 1A).4
With non-conjugated alkenes it is more difficult to over-
come undesired β-hydride elimination from the alkylmetal
intermediates. As
a consequence, the scope of non-
conjugated alkenes via this mode of reactivity has been clas-
sically limited to special cases, such as norbornene-type sub-
strates.5 In an effort to employ more synthetically useful sub-
strates, several research groups, including our own, have em-
ployed strongly coordinating directing groups tethered to the
alkene to stabilize the putative alkylmetal species and facili-
tate selective 1,2-diarylation under nickel catalysis (Scheme
1B).6 Though this approach has enabled robust 1,2-
difunctionalization, the need to install and then remove the
directing auxiliary detracts from the practicality of these
methods. With more weakly coordinating directing groups,
Alkene starting materials serve as diversifiable chemical feed-
stocks for rapid build-up of molecular complexity.1 From the
perspective of synthetic chemists, the ability to regioselec-
tively install two unique components across an alkene of in-
terest is attractive. One approach toward alkene difunctional-
ization that has rapidly garnered interest in recent years is
conjunctive cross-coupling, a strategy in which alkene start-
ing materials can be used as ambiphilic reagents to unite var-
ious electrophiles and organometallic nucleophiles under
transition metal catalysis.2 In the context of regioselective
1,2-diarylation specifically, this potentially powerful synthet-
ic strategy can be difficult to implement on electronically
unactivated, non-conjugated alkenes.
Scheme 1. Background and Synopsis of Current Work
A. Transition-metal-catalyzed 1,2-diarylation of styrenes
R1
R1
R1
[M]
Ar
cat. [M]
Ar–[M]
R2
R2
R2
Ar–X
Ar
[electronically stabilized]
Ar
[M] = Pd, Ni
B. Nickel-catalyzed 1,2-diarylation of alkenes using a directing group strategy
R2
Si
NPh
NPh
O
R
R1
N
N
R2
H
N
cat. Ni
Ar–ZnX
Ar–X
cat. Ni
Ar–ZnX
Ar–X
cat. Ni + cat. Ag/Cu
Ar–ZnX
cat. Ni
Alkyl–ZnX or Ar–ZnX
[C(sp2)]–X
Ar–X
[Giri, 2017]
[Giri, 2018]
[Giri, 2018]
[Engle, 2017]
[requires installation of strongly coordinating auxiliaries]
C. Nickel-catalyzed 1,3-diarylation of non-conjugated alkenes
Recent advances in transition-metal-catalyzed 1,2-diarylation
of alkenes have generally relied on the formation of a stabi-
lized alkylmetal intermediate after an initial migratory inser-
tion event (Scheme 1). Due to the inherent reactivity of al-
kylmetal species, the alkene substrates are often limited to
1,3-dienes3 or styrenes4 that react to form electronically sta-
cat. Ni(cod)2
cat. dppm
cat. NiBr2
cat. P(OPh)3
NPh
O
Ar Ar
H
H
N
N
N
N
R1
R1
Ar–X
Ar–B(OH)2
Ar–X
Ar–ZnX
R2
R2
N
N
Ar Ar
[Zhao, 2018]
[Giri, 2018] [after H+ workup]
D. Nickel-catalyzed 1,2-diarylation of simple alkenyl amides (this work)
CO2Me
X
MeO2C
NiII Ar
NiII
Ar
O
[Ar–B(OR)2
]
O
O
Ar
Ar
R2N
carbonickelation
R2N
R2N
transmetalation /
reductive elimination
n
n
n
n = 1, 2
bilized π-allyl or π-benzyl intermediates, respectively. In the-
se cases, electronic stabilization allows for regiocontrolled
addition of an aryl organometallic reagent to afford the de-
sired 1,2-diarylated product. Several groups have made major
contributions to styrene 1,2-diarylation under palladium and
• innate directivity • broad aryl scope • diverse amide compatibility • mild conditions • ligand-enabled
alkylnickelacycles are prone to rapid β-hydride elimina-
tion/reinsertion, which the Zhao and Giri groups have clev-
erly exploited in 1,3-diarylation processes (Scheme 1C).6c,7,8
Giri recently reported that 1,2-diarylation can be promoted
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in such systems through addition of copper or silver addi-
benzene and phenylboronic acid neopentyl glycol ester
(PhB(nep)) as coupling partners, and Ni(cod)2 as precata-
lyst (Table 1). Considering the difficulty in promoting pro-
ductive 1,2-diarylation with a weakly coordinating amide, we
reasoned that an electron-withdrawing L-type ligand could
potentially (1) prevent β-hydride elimination, (2) facilitate
C–C reductive elimination, and (3) encourage substrate
binding to the nickel catalyst. Electron-deficient olefins
(EDOs) represent a unique class of ligands that have been
demonstrated to enable various cross-coupling reactions by
tives.6e It is important to note that alkyl radical addition to
alkenes and interception with metalloradical species has also
1
2
3
4
5
6
7
8
been shown to be
a viable strategy toward 1,2-
difunctionalization of non-conjugated alkenes,14 but this
strategy has not been demonstrated in the context of 1,2-
diarylation. The goal of the present study was to develop an
efficient alkene 1,2-diarylation directed by simple monoden-
tate functional groups.
9
Our inspiration for this approach originated from a series of
seminal publications by Fu and coworkers, in which simple
amides and other carbonyl-containing compounds were used
to effectively direct C–X oxidative addition and stabilize the
resulting intermediate for a variety of enantioselective cross-
coupling reactions under nickel catalysis.9 Given our group’s
interest in nickel-catalyzed alkene difunctionalization,10 we
wondered if previously employed, strongly coordinating di-
recting groups such as 8-aminoquinoline (AQ) could be re-
placed with simple amides. Practically speaking, this advance
would be advantageous in that it would allow use of diverse
amide directing groups, including those that are readily
cleavable as well as those that are native to the target com-
pound of interest. Conceptually, it would present the oppor-
tunity to engage weakly coordinating carbonyl directing
groups, rather than more commonly used N(sp2)-based di-
recting groups, and to identify ancillary ligands that can bind
to the open coordination site around nickel to facilitate key
steps in catalysis.
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promoting the reductive elimination step and preventing β-
hydride elimination.11,12 To our delight, the use of dimethyl
fumarate as ligand under optimized reaction conditions de-
livered the desired product in 88% isolated yield (Entry 1).13
Interestingly, removal of the ligand or substitution for more
commonly employed phosphine and bipyridyl-based ligands
did not lead to the formation of the desired product, but in-
stead gave ~25% of the biphenyl Suzuki–Miyaura product
(Entries 2 and 3). Both free boronic acid and pinacol boronic
esters also gave the corresponding product in 78% and 65%
yield, respectively (Entries 5 and 6). Despite numerous at-
tempts to use Ni(II) precatalysts, Ni(cod)2 was ultimately
the most competent nickel source for this reaction (Entries
11 and 12).
Having identified optimal conditions, we next sought to
test the electrophile and nucleophile scope of this nickel-
catalyzed 1,2-diarylation reaction (Table 2). First, we elected
to evaluate the nucleophile scope using iodobenzene as the
electrophile (2a–2m). With respect to the B(nep) compo-
nent, both electron-donating and electron-withdrawing
groups in the para-position gave the desired products in
good to excellent yields (2a–2f). Tethered alcohol- (2e) and
chloride-containing (2f) aryl fragments were also tolerated,
allowing for further downstream diversification. Aryl nucleo-
philes with substituents at the meta-position (2g–2l) were
also competent, including ketones (2i) and sulfones (2k).
Given the potential sensitivity of the steric environment
around the putative metalacycle, we were encouraged by the
compatibility of ortho-Me substituted B(nep), which gave
the desired product in 60% yield (2m).
Next, we explored the electrophile scope using PhB(nep)
as the nucleophile (2n-2z). In general, alkylated aryl iodides
performed well under the optimized conditions (2n–2q).
Electron-rich aryl iodides also gave the desired products in
moderate yields, tolerating O-, S-, and N-heteroatoms (2r–
2t). Interestingly, the presence of a second amide on the
electrophilic component could also be accommodated (2y).
In addition, 1,1-disubstituted vinyl iodides were reactive
under optimized conditions (2z). Electron-poor aryl iodides
were substantially less reactive, and heterocyclic aryl iodides
and boronic esters were not suitable coupling partners in this
reaction (see Supporting Information).
Table 1. Variations from Standard Reaction Conditionsa
15 mol% Ni(cod)2
15 mol% L
2 equiv NaOH
O
Ph
O
R
Ph
R
+
+
Ph
I
B(nep)
N
Ph
N
H
H
i-BuOH, RT, 12 h
1a
(1.5 equiv)
(1.5 equiv)
2aa
O
B
Me
Me
CO2Me
R =
MeO
MeO2C
O
OMe
[B(nep)]
L = dimethyl fumarate
% Yieldb 2aa
Entry
variation from standard conditions
1
2
3
4
5
none
92 (88)c
n.d.
no ligand
PPh3 or PCy3 instead of dimethyl fumarate
bipyridine or phenathroline instead of dimethyl fumarate
bromobenzene instead of iodobenzene
n.d.
n.d.
45
6
7
PhB(OH)2 instead of PhB(nep)
PhBpin instead of PhB(nep)
78
65
8
dioxane instead of i-BuOH
40
9
1.0 equiv of both iodobenzene and PhB(nep) instead of 1.5 equiv
KOAc instead of NaOH
59
10
n.d.
11
12
10 mol% Ni(cod)2
75
NiCl2, NiBr2, Ni(acac)2, or NiI2 instead of Ni(cod)2
n.d.
13
NiCl2, NiBr2, Ni(acac)2, or NiI2 with Mn0 instead of Ni(cod)2
n.d.
aReaction conditions: 1a (0.1 mmol), 0.2 M i-BuOH. bPercentages
represent 1H NMR yields using CH2Br2 as internal standard unless
c
noted otherwise; n.d. = not detected. Parentheses represent isolated
yield.
To initiate our investigation, we surveyed a range of mono-
dentate amides and found that among many that were effec-
tive, electron-rich N-benzyl amides consistently gave high
yields. For this reason, we elected to use 2,4-dimethoxy ben-
zyl amide 1a as the pilot alkene substrate, along with iodo-
After the evaluation of our coupling partner scope, we
turned our attention to other alkene substrates. Gratifyingly,
1,1-disubstituted alkenes could serve as competent sub-
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strates to set all-carbon quaternary centers, albeit in modest
internal alkenes were found to be unreactive at this stage of
1
2
3
4
5
6
7
8
development (3c–3f). In comparison, our previously report-
ed AQ-directed dicarbofunctionalization is compatible with
the last three of those four alkenyl amide subtypes (3d–3f).6a
Gratifyingly, a wide range of N-substituted amides were
suitable substrates under the reaction conditions previously
optimized for amide 1a (Table 3).
yield (3a). Upon treating γ,δ-unsaturated alkene substrate
3b to the standard reaction conditions with iodobenzene and
phenyl B(nep), we were pleased to observe the exclusive
formation of 1,2-diarylation product 4ba in 67% yield. Fur-
thermore, hetero-diarylation could also be achieved (4bb
and 4bc). This method is not without its limitations. In par-
ticular, δ,ε-unsaturated alkenes, α-substituted alkenes, and
9
Table 2. Electrophile, Nucleophile, and Alkene Scopea
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11
12
13
14
15
16
17
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19
20
21
22
23
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27
28
29
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15 mol% Ni(cod)2
15 mol% L
2 equiv NaOH
R2
O
Me
CO2Me
O
O
B
Me
I
R1
R =
MeO
MeO2C
R
R1
+
+
R
N
N
H
OMe
OH
O
L = dimethyl fumarate
H
R2
i-BuOH, RT, 12 h
[B(nep)]
1a
2a–2z
nucleophile scope
O
Ph
Cl
OMe
Me
t-Bu
CF3
R
Ph
N
H
2aa, 88%
O
O
O
O
O
O
homo-diarylation
R
Ph
R
Ph
R
Ph
R
Ph
R
Ph
R
Ph
N
N
N
N
N
H
N
H
H
H
H
H
2f, 79%
2a, 88% (0.2 mmol)
85% (2.0 mmol)
[X-ray]
2b, 92%
2c, 82%
2d, 89%
2e, 63%
O
Me
F
SO2Me
F3C
CF3
Me
O
O
O
O
O
O
Me
Ph
O
R
Ph
R
Ph
R
Ph
R
Ph
R
Ph
R
R
Ph
N
N
N
N
N
N
N
H
H
H
H
H
H
H
2g, 93%
2i, 73%
2j, 90%
2k, [ArB(OH)2] 39%
2l, 80%
2m, 60%
2h, 77%
electrophile scope
O
R
O
Ph
OMe
SMe
N
O
Ph
O
Ph
O
Ph
O
Ph
R
N
H
R
R
R
R
N
N
N
iPr
N
H
H
H
2n, (R = Me) 83%
2o, (R = Et) 80%
2p, (R = i-Pr) 79%
2q, (R = Ph) 75%
Me
H
2r, 67%
2s, 50%
2u, 81%
2t, 59%
NHAc
O
Ph
O
Ph
O
Ph
O
Ph
O
Ph
R
R
R
Me
Me
R
R
N
Me
N
N
H
N
N
H
H
H
H
Me
2v, 87%
2w, 34%
2z, 63%
2x, 92%
2y, 55%
alkene scope
unreactive alkenes
Me
O
O
O
Me
O
Me Ph
N
H
N
H
N
H
N
H
Me
MeO
OMe
MeO
OMe
MeO
OMe
MeO
OMe
3a
4a, 30%
3d
3c
[1,1-disubstituted alkene]
[α-substituted alkene]
[δ,ε-unsaturated alkene]
O
N
O
O
O
H
R2
Me
MeO
OMe
N
H
N
H
N
H
4ba, (R1 = H, R2 = H) 67%
[X-ray]
4bb, (R1 = H, R2 = Me) 44%
4bc, (R1 = Me , R2 = H) 54%
Et
MeO
OMe
MeO
OMe
MeO
OMe
R1
3b
3e
3f
[γ,δ-unsaturated alkene]
[E-internal alkene]
[Z-internal alkene]
aReactions performed on 0.2 mmol scale unless stated otherwise. Percentages represent isolated yields.
Removal of one methoxy group from the standard amide
substrate had only a minor impact on reactivity, as 81%
yield of the desired product 6a was still obtained. Unfortu-
nately, no stereoinduction was observed when using chiral
benzylamine substrates (6b). Cyclopropyl, cyclobutyl-,
cyclohexyl-, and adamantyl-derived amides reacted to give
desired products in good yields (6c–6f). Alkenyl amides
with tethered heteroatoms and heterocycles also per-
formed well (6g–6i). The reaction was found to be
chemoselective in that in exclusively functionalized the
terminal alkene over the distal trisubstituted alkene (6i).
Table 3. β,γ-unsaturated Amide Scopea
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15 mol% Ni(cod)2
15 mol% L
2 equiv NaOH
similar results to the earlier system (8ea–8ed). Non-
Me
O
O
1
2
3
4
5
6
7
8
I
B(nep)
carbonyl-containing Bn-protected allyl amine did not react
(8f). Based on these findings, we concluded that a carbon-
yl-directed model was consistent with the observed reactiv-
ity trends.
+
+
[N]
[N]
Me
i-BuOH, RT, 12 h
5a–5l
6a–6l
amide scope
[N] =
Me
N
N
H
H
N
H
N
N
MeO
H
H
6a, 81%
6b, 73% (1.1:1 d.r.)b
6c, 68%
6d, 80%
6e, 74%
Scheme 2. Initial Rate Trends
O
Ar2
(standard conditions)
+
Ar1–I + Ar2–Bnep
R
Ar1
1a
O
S
PhO
N
N
N
N
H
N
H
H
H
N
H
9
H
6h, 42%c
6i, 86%
coupling partners
initial rates
6f, 75%
6g, 93%
6j, 84%
10
11
12
13
14
15
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17
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19
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22
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43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
I
Bnep
+
Bn
N
Bn
N
Bn
Bn
N
H2N
N
X = OMe ~ Me ~ H ~ Cl ~ CF3
Bn
6l, 74%c
Me
6m, 84%c
Ph
t-Bu
6o, 43%c
X
minimal electronic influence
6k, 19%
6n, 65%c
aReactions performed on 0.2 mmol scale unless stated otherwise.
Percentages represent isolated yields. bThe d.r. by crude 1H NMR
wass 1.0:1; d.r. of isolated compound was 1.1:1. c NaOH (1 equiv)
I
Bnep
+
Y = OMe ~ H ~ Me >> Cl > CF3
substantial electronic influence
Y
The dramatic reactivity enhancement enabled by the EDO
ligand and the broad amide directing group scope prompt-
ed us to examine the reaction mechanism through kinetics
and computation. First, we evaluated reaction rates with a
series of electronically diverse aryl iodides and boronates
(see Scheme 2 and SI). We found that the electronic prop-
erties of the aryl Bnep component had a negligible influ-
ence on rate, while electron-neutral and -rich aryl iodides
reacted faster than electron-poor electrophiles. The former
trend is inconsistent with a scenario in which transmeta-
lation is rate-limiting, while the latter is inconsistent with a
scenario where oxidative addition is rate limiting. One
plausible explanation is that migratory insertion of the ar-
ylnickel intermediate into the alkene is the slow step in the
catalytic cycle.
To shed more light on the preferred coordination mode of
the substrate with nickel and the impact of the EDO ligand
on the reductive elimination step (where it was expected to
play a beneficial role), we performed computational analy-
sis using density functional theory (DFT). Notably, despite
a plethora of elegant experimental evidence regarding the
beneficial effects of EDO ligands in promoting reductive
elimination in nickel-catalyzed cross-coupling, a head-to-
head comparison of the effect of these ligands on reductive
elimination has not been quantified from a computational
perspective.12c,15 Our calculations indicate that for each of
the proposed intermediates, the corresponding carbonyl-
bound nickel species are 3–8 kcal/mol lower in energy
compared to their nitrogen-bound counterparts, support-
ing the hypothesis that the carbonyl group directs catalysis
(see Supporting Information). The computed transition
state for reductive elimination with dimethyl fumarate
Somewhat surprisingly, N,N-dibenzyl amide still delivered
the 1,2-diarylated product in good yield (6l). With other
tertiary amides, we observed that sterically bulky groups
attenuated reactivity (6m–6o). This observation, viewed
in conjunction with the result with the chiral benzyl amine
(i.e., negligible chirality transfer) led us to speculate that
the reaction may be proceed via carbonyl coordination
rather than nitrogen atom coordination.
Table 4. Protected Allylic Amine Scopea
15 mol% Ni(cod)2
15 mol% L
PG
I
B(nep)
N
H
2 equiv NaOH
PG
+
+
N
H
Me
Me
i-BuOH, RT, 12 h
8a–8f
7a–7f
protected allylic amines
PG =
O
O
O
O
O
Me
t-Bu
8b, 70%
t-BuO
Ad
Ph
Ph
8f, n.d.
8c, 29%c
[X-ray]
8ea, 81%
8a, 20%b
8d, 70%
O
O
I
B(nep)
Ph
N
(as above)
R1
H
R1
R2
+
+
Ph
N
H
R2
8ea–8ed
7e
representative coupling partner scope
O
O
O
Ph
N
Ph
N
Ph
N
H
H
H
OMe
8eb, 34%
8ec, 69%
8ed, 75%
F
OMe
aReactions performed on 0.2 mmol scale unless stated otherwise.
b
Percentages represent isolated yield. NaOt-Bu (1 equiv) used in
place of NaOH. c NaOH (1 equiv).
In order to gain further insight into the coordination mode
of the amide directing group and expand the substrate
scope, we next examined substrates in which the nitrogen
atom would be incorporated within the putative nickelacy-
cle intermediate, namely protected allyl amines. Excitingly,
this class of substrates also reacted under standard nickel-
catalyzed 1,2-diarylation conditions in a regiocontrolled
fashion (Table 4). Ac-, Piv-, and Boc-protecting groups
served as competent directing groups in this reaction (8a–
8c). With benzoyl-protected allyl amine, we tested repre-
sentative coupling partner combinations and obtained
(TS1) has an activation energy of ΔG‡ = 2.6 kcal/mol, sig-
nificantly lower than the corresponding transition states for
ethylene-bound nickel (ΔG‡ = 14.6 kcal/mol, TS2)16 and
solvent-bound nickel (ΔG‡ = 37.4 kcal/mol, TS3).
Figure 1. Computed Transition States for Reductive
Elimination
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X-ray data for compound 2a (CIF)
R
O
R
O
R
NH
NH
NH
1
2
3
4
O
NiII
E
X-ray data for compound 4ba (CIF)
X-ray data for compound 8c (CIF)
NMR Data (ZIP)
NiII
NiII
L
E
TS1
E =CO2Me
TS2
TS3
L= i-BuOH
5
6
7
8
9
AUTHOR INFORMATION
Corresponding Author
*keary@scripps.edu
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Author Contributions
† R. K. and V. T. T. contributed equally.
TS1
ΔG = 2.6
kcal/mol
TS2
ΔG = 14.6
kcal/mol
TS3
ΔG = 37.4
kcal/mol
A mechanism consistent with the observations made thus
far is proposed in Scheme 3. First, the nickel catalyst oxida-
tively adds into the aryl iodide and coordinates with the
amide and alkene moieties of the substrate. Next, the ar-
ylnickel(II) species undergoes rate-limiting 1,2-migratory
insertion to yield the corresponding 5- or 6-membered
nickelacycle. Transmetalation with ArB(nep) and subse-
quent reductive elimination, promoted by the EDO ligand,
yields the desired 1,2-diarylation product and regenerates
the catalyst.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This work was financially supported by The Scripps Research
Institute (TSRI), Pfizer, Inc., Bristol-Myers Squibb (Unre-
stricted Grant), and the National Science Foundation (CHE-
1800280). We further acknowledge the NSF for a Graduate
Research Fellowship (NSF/DGE-1346837, J.D.). We thank
Dr. Jacob T. Edwards (Celgene), Tyler G. Saint-Denis (Yu lab,
TSRI), and Vincent A. van der Puyl (Shenvi lab, TSRI) for
helpful discussion. We further thank Prof. Arnold L.
Rheingold, Dr. Milan Gembicky and Dr. Curtis E. Moore for
X-ray crystallographic analysis (UCSD).
Scheme 3. Proposed Catalytic Cycle
O
Ar2
O
Ar1
R
+
I
R
Ar1
N
R
LnNi0
N
R
n
n
oxidative addition/
substrate coordination
reductive
elimination
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NR2
NR2
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O
O
NiII
Ar2
E
n
I
NiII
Ar1
n
Ar1
E
NaOH
NR2
RO Bnep
transmetalation Ar2
O
NiII
E
migratory insertion/
ligand exchange
n
Bnep
NaI
Ar1
OH
E
E = CO2Me
In conclusion, we have developed a regioselective, nickel-
catalyzed 1,2-diarylation of simple, non-conjugated alkenyl
amides using aryl iodides and aryl boronates by employing
dimethyl fumarate as ligand. The reaction was found to
proceed with a broad range of aryl electrophiles and aryl
nucleophiles, and allows for both β,γ- and γ,δ-diarylation
of carbonyl compounds. Computational analysis deter-
mined that an oxygen-bound nickelacycle is energetically
preferred and that the EDO ligand dramatically lowers the
activation energy of the reductive elimination step.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge via the
Internet at http://pubs.acs.org.
Experimental details, analytical data, and 1H, 13C and 19F NMR
spectra (PDF)
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bicy-
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Directed Nickel-Catalyzed 1,2-Dialkylation of Alkenyl Carbonyl Com-
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O
O
Ar1
Ar2
cat. Ni
[N]
[N]
PG
MeO2C
cat.
n
n
CO2Me
n = 1, 2
or
or
Ar1–B(OR)2
Ar2–I
[>50 examples]
PG
N
H
Ar2
N
H
Ar1
8
9
• innate directivity • diverse amide compatibility
• mild conditions • ligand-enabled
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