Diverting c?H annulation pathways: Nickel-Catalyzed dehydrogenative homologation of aromatic amides

Article abstract of DOI:10.1021/acscatal.6b02477

Direct homologation of aromatic amides with internal alkynes has been accomplished via a nickel-catalyzed sequential C?H activation reaction. The use of a rigid chelating group and a strong aprotic polar solvent successfully divert the classical [4 + 2] annulation to the [2 + 2 + 2] homologation pathway. This transformation is promoted by a simple nickel catalyst without the need of stoichiometric metal oxidants. Mechanistic studies support an unusual substrate-assisted ligand exchange process. NMR and X-ray data suggest a [5,5] Ni-bridged metallacycle as the catalyst resting state. Substrate assisted directing group swap plays an important role for the subsequent meta-C-H insertion. In contrast, [4 + 2] annulation can be accomplished using a bulky, electron-rich phosphine ligand, which favors rapid reductive C?N elimination.

Full text of DOI:10.1021/acscatal.6b02477

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Article
Diverting C-H Annulation Pathways: Nickel-Catalyzed
Dehydrogenative Homologation of Aromatic Amides
Zhiqi He, and Yong Huang
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.6b02477 • Publication Date (Web): 04 Oct 2016
Downloaded from http://pubs.acs.org on October 7, 2016
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Diverting CꢀH Annulation Pathways: Nickelꢀ
Catalyzed Dehydrogenative Homologation of
Aromatic Amides
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Zhiqi He, Yong Huang*
Key Laboratory of Chemical Genomics, Peking University, Shenzhen Graduate School,
Shenzhen, 518055, China
O
Q
C-N reductive elimination
N
O
NHQ
H
L = Cy3P
R
O
R'
4+2]
Ni
N
N
[
Ni
R
H
L
+
R'
NHQ
O
R'
R'
QHN
O
R'
R
L = substrate
R
R'
R'
R
'
N
Ni
Q =
L
R
R'
2+2+2]
[
ABSTRACT Direct homologation of aromatic amides with internal alkynes has been
accomplished via a nickelꢀcatalyzed sequential CꢀH activation reaction. The use of a rigid
chelating group and a strong aprotic polar solvent successfully divert the classical [4+2]
annulation to the [2+2+2] homologation pathway. This transformation is promoted by a simple
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nickel catalyst without the need of stoichiometric metal oxidants. Mechanistic studies support an
unusual substrateꢀassisted ligand exchange process. NMR and Xꢀray data suggest a [5,5] Niꢀ
bridged metallacycle as the catalyst resting state. Substrate assisted directing group swap plays
an important role for the subsequent metaꢀCꢀH insertion. In contrast, [4+2] annulation can be
accomplished using a bulky, electronꢀrich phosphine ligand, which favor rapid reductive CꢀN
elimination.
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KEYWORDS Nickel catalysis, CꢀH activation, dehydrogenative homologation, phosphine,
directing group
Introduction
1
Nickelꢀcatalyzed reactions have rapidly advanced over the last decade. This abundant and
cheap firstꢀrow transition metal is shown capable of promoting many valuable, yet challenging
crossꢀcoupling reactions involving secondary and tertiary alky halides, ethers and phenol
10
2
derivatives, which distinguish Ni from second and third row d transition metals. Recently,
Nickelꢀcatalyzed direct functionalization of inert CꢀH bonds also enjoyed rapid evolution. Early
reports primarily dealt with reactions involving Ni insertion into acidic CꢀH bonds, such as
3
azoles, perfluorobenzenes and pyridine derivatives. Subsequent studies revealed that Ni(II) can
2
3
insert into electronically unbiased sp or sp CꢀH bonds selectively with the help of a bidentate
4
directing group (DG) and phosphine ligands. In 2011, Chatani and coꢀworkers reported the first
4d
Niꢀcatalyzed [4+2] CꢀH annulation of arenes and alkynes via chelation control. In 2013,
4
e
directed orthoꢀ alkylation of benzamides via Ni(II) catalysis was reported by the same group. It
is believed that a strong, bidentate directing group is essential for the rateꢀlimiting CꢀH
5
nickelation step, which generally requires higher temperature than Pd catalyzed processes.
3
Recently, CꢀC bond formation via sp CꢀH activation were reported by Chatani and Ge groups
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4g,4j,4k,4m
independently.
Although these pioneering work demonstrated the feasibility of nickel to
activate and functionalize an inert CꢀH bond, the types of new bond formation remains scarce
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compared to the more mature Pd and Rh catalysis. For example, reaction involving multiple Cꢀ
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4a,4h
H activation remains challenging for this unique and intriguing metal.
Recently, polycyclic aromatic hydrocarbons (PAHs) have attracted much attention due to their
unique electroꢀ and photochemical properties as organic semiꢀconductors and luminescent
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materials. Various synthetic methods have been developed to access this particular chemical
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space. Arguably, transitionꢀmetalꢀcatalyzed [2+2+2]ꢀtype aromatic homologation by CꢀH
9
activation is an efficient and modular strategy to extend aromaticity of arenes. In 2008, Miura
and Satoh first reported an Rh(III)ꢀcatalyzed oxidative annulation reaction using phenylazoles or
2ꢀphenylpyridine and diarylacetylenes via double CꢀH activation that avoids preactivation of the
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aryl CꢀHs. In 2008, Wu and coꢀworker reported Pd(II) catalyzed homologation of benzene
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1
derivatives. Cramer and coꢀworkers developed a Rh(III) catalyzed homologation reaction of
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2
naphthalenes and related compounds. The oxidative nature of this chemistry demands
stoichiometric amounts of external oxidants, such as copper and silver salts, to turn over the
metal catalyst. This limitation becomes increasingly burdensome for large scale production and
substrates sensitive to oxidants. In contrast, [2+2+2] annulation using cheap Ni or Fe catalysts
4
u,8i,13
has been scarce,
due to the predominant [4+2] reaction pathway. In this article, we report
our recent mechanistic findings that led to precise control of these cyclization pathways.
Scheme 1. Two Reaction Pathways of Ni-catalyzed C-H Annulation Reactions involving
Alkynes.
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Results and Discussion
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4
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4d
Reports by Matsubara, Murakami, Cheng and Chatani demonstrated that Ni catalyzed
areneꢀalkyne annulation reactions proceed via a [4+2] pathway due to facile C/N reductive
elimination from a Ni(II) center. Isoquinolones were exclusively obtained. This CꢀN bond
formation requires compression of the CꢀNiꢀN bond angle of intermediate A in order to pull the
carbon and nitrogen atoms together (Scheme 1). Consequently, the NꢀNiꢀN bond angle needs to
expand to accommodate this conformational change. This calls for N,Nꢀchelating groups with
stretchable bite angles. In Chatani’s case, 2ꢀpyridinylmethylamine was found as a good DG for
this purpose. In order to divert the [4+2] annulation to the [2+2+2] homologation pathway, we
envisioned a more rigid DG would prohibit significant bite angle change and disfavor CꢀN bond
formation leading to the [4+2] product. In addition, a rigid DG would dissociate more readily
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from the strained [5,7] Ni bridge (intermediate A), setting stage for bond rotation and second Cꢀ
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u
H insertion. This design echo a recent report by Chatani using the similar rigid DG strategy.
Considering reductive elimination is more difficult for electronꢀrich metal centers, we also
proposed using an electronꢀrich phosphine ligand or solvent to further discourage the CꢀN bond
formation.
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Impact of solvent and directing group. To verify this proposal, we first examined
benzamide/alkyne annulation reactions using various DGs in DMA (Table 1). Phosphine ligand
was used to facilitate CꢀH metalation as suggested by previous reports on Ni catalyzed CꢀH
3,4
activation reactions. As expected, 2ꢀpyridinylmethylamine substrate (Table 1, DG A, Chatani’s
substrate for the [4+2] annulation) resulted the [4+2] product exclusively. No [2+2+2] product
was observed. The low yield (8%) was likely attributed polar solvent DMA, which might serve
as an ligand and increase the electron density of Ni(II). The starting material decomposed when
2ꢀ(methylthio)aniline was used as the DG (B), due to poor stability of the CꢀS bond under the
reaction condition. The use of 2ꢀ(diphenylphosphino)aniline as DG (C) resulted in no reaction,
suggesting a N,Nꢀchelating DG is essential for CꢀH insertion. Interestingly, orthoꢀ
dihydrooxazolyl aniline (D) was found to be a competent DG. A mixture of [2+2+2] and [4+2]
products were obtained (42% vs 16%). Improved yield and selectivity was obtained by using a
directing group with higher rigidity: 8ꢀaminoquinoline (E). The desired homologation product
was obtained in 78% NMR yield with moderate [2+2+2] vs [4+2] selectivity. The reaction did
not take place for both 8ꢀhydoxyquinoline ester (F) and Nꢀ2ꢀnaphthyl benzamide (G) substrates,
indicating both nitrogen atoms are required. As predicted, lower ratio of [2+2+2]/[4+2] was
observed in nonꢀpolar solvent such as toluene. In aprotic polar solvents, the reaction afforded
much higher conversions to [2+2+2] homologation product 3aa. The best result was obtained
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when 8ꢀaminoquinoline was used as DG in NMP or DMPU. The desired polysubstituted
naphthalene product 3aa was obtained 80% yield, along with 13% isoquinolone (Table 1, entry
12).
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a
Table 1. Impact of solvent and directing group on the [2 + 2 + 2] pathway
b
b
entry
DG
A
solvent
DMA
DMA
yield (%)
3 : 4
1
2
8
0
0 : 100
—
B
3
C
DMA
0
—
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5
6
D
E
F
DMA
DMA
DMA
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78
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—
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G
DMA
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E
E
Toluene
DMSO
DMF
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15
1 : 1
7 : 1
6.5 : 1
1
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E
E
NMP
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93
6.7 : 1
6.2 : 1
1
DMPU
a
Reactions were conducted using 0.125 mmol 1, 0.5 mmol diphenylacetylene 2a, 10 mol%
b
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Ni(acac) , 20 mol% PPh in 1 mL solvent under Ar at 140 °C for 8 hours. Determined by H
2 3
NMR integration against 1,3,5ꢀTrimethoxybenzene as the external standard.
Impact of ligand and catalyst. Having identified the promising DG and solvent, we next
examined the effects of the phosphine ligands and nickel catalysts. We initially expected that
electronꢀrich phosphine ligands would increase the electron density on the nickel center of
intermediate A (Scheme 1) and slow down the terminating C/N bond reductive elimination. In
turn, it might facilitate DG disassociation from Ni and trigger the second CꢀH metalation.
However, moderate [2+2+2]/[4+2] ratio (Table 2, entries 1ꢀ3, 3aa/4aa) was observed for
electronꢀrich triarylphosphines. On the other hand, phosphines bearing electronꢀwithdrawing
fluoro or trifluoromethyl aryls led to improved selectivity towards homologation (entry 4 and 5).
Following this trend, we removed phosphine ligand from the reaction. To our delight, the [4+2]
pathway leading to 4aa was completely suppressed (Table 2, entry 6). We suspected this
“
2
ligandꢀfree” reaction would be sensitive to Ni species. The use of cationic NiCl and Ni(OTf)2
resulted much lower conversions compared to Ni(acac) . The best result was obtained using low
2
valent Ni(cod) . Polysubstituted naphthalene 3aa was obtained in 92% isolated yield. In these
2
reactions, diphenyl acetylene serves as the terminal oxidant for the initial Ni oxidation and
4
d
subsequent catalyst turnover. The corresponding stilbene byproduct was isolated in good yield.
a
Table 2. Impact of ligand and catalyst on the [2 + 2 + 2] C-H annulation
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entry
Ni source
Ni(acac)2
Ni(acac)2
Ni(acac)2
Ni(acac)2
Ni(acac)2
Ni(acac)2
Ni(OTf)2
NiCl2
ligand
PPh3
yield (%)
3 : 4
1
2
3
4
5
6
93
6.2 : 1
5.1 : 1
4.1 : 1
7.0 : 1
15 : 1
P(4ꢀMeC H )
97
6
4 3
P(4ꢀMeOC H )
86
6
4 3
P(4ꢀFC H )
96
6
4 3
P(4ꢀCF C H )
4 3
80
3
6
none
none
none
none
70
>20 : 1
>20 : 1
>20 : 1
>20 : 1
c
7
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8
31
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Ni(cod)2
95 (92)
a
Reactions were conducted using 0.125 mmol 1a, 0.5 mmol diphenylacetylene 2a, 10 mol%
b
1
Ni catalyst, 20 mol% ligand in 1 mL solvent under Ar at 140 °C for 8 hours. Determined by H
NMR integration against 1,3,5ꢀTrimethoxybenzene as the external standard. The number in
c
parentheses is the isolated yield. The reaction was carried out for 48 h. Q = 8ꢀaminoquinolinyl
Substrate scope for alkyne and aryl amide. With the optimized reaction condition in hand,
we explored the substrate scope for both alkyne and aryl amide. Various arylꢀaryl, alkylꢀalkyl
and alkylꢀaryl disubstituted acetylenes were tolerated. We observed serious precipitation of Ni
black for dialkyl acetylenes under the standard reaction condition, indicating attenuated redox
1
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potential for these more electronꢀrich substrates. Nevertheless, increasing Ni loading to 20 mol%
and the reaction temperature to 160 °C was sufficient to overcome the decomposition of the Ni
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catalyst. Moderate to good yields were obtained (Table 3, product 3ab, 3ac). For asymmetrically
substituted alkylꢀaryl acetyenes, single regioisomer out of 4 possibilities was isolated (Table 3,
product 3ad, 3ae). Interestingly, although we observed CꢀS bond decomposition when using DG
B (Table 2), 4ꢀMeSPh was not affected by this homologation reaction condition (Table 3,
product 3ah). The reaction became complicated when acetylenes bearing two electronically
different aryl groups were attempted. A mixture of regioisomers was formed.
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a,b
Table 3. Substrate Scope for Internal Alkyne
b
entry
R
R’
product
3ab
3ac
yield (%)
63
c
1
nBu
nPr
nBu
nPr
c
2
53
c
3
Me
Ph
3ad
3ae
57
c
4
nBu
4ꢀMeOPh
Ph
60
c
5
4ꢀMeOPh
3af
66
6
7
8
9
4ꢀCF ꢀPh
4ꢀCF ꢀPh
3ag
3ah
3ai
77
3
3
4ꢀMeSꢀPh
4ꢀMeꢀPh
4ꢀCNꢀPh
2ꢀthiophenyl
4ꢀMeOPh
4ꢀFꢀPh
4ꢀMeSꢀPh
4ꢀMeꢀPh
4ꢀCNꢀPh
2ꢀthiophenyl
4ꢀCNꢀPh
4ꢀFꢀPh
57
81
3aj
70
10
11
12
3ak
3al
69
d
d
67
3am
86
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Reaction condition: amide (0.125 mmol), alkyne (0.5 mmol), Ni(cod) (0.0125 mmol) in 0.5
2
b
c
ml DMPU, at 150 °C for 24 h. Isolated yields; average of two runs. Ni(cod) (0.025 mmol)
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d
was used and run at 160 °C. The ratio of 4 isomers is 1:1:1.6:1.6
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The scope of aryl amide was studied as well (Table 4). Orthoꢀ, metaꢀ and paraꢀ substituted
aryls undergoes the desired homologation with similar efficiency. No rate difference was
observed between sterically more hindered oꢀtolyl substrate vs its metaꢀ analogue (Table 4,
products 3bc and 3ca). Both electronꢀrich and electionꢀpoor aryl amides worked well. This
reaction has a broad functional group tolerance. In particular, a B(pin) substituted benzamide
2
substrate afforded the corresponding boron containing polynathphalene 3ja in 71% yield which
could undergo further crossꢀcoupling reactions to introduce versatile substituents to the PAH
scaffolds. Interestingly, when an orthoꢀfluoro benzamide was used, the reaction afforded a 1:1
mixture of the desired product 3ma and defluorinated product 3aa. Presumably, 8ꢀ
aminoquinoline directed a CꢀF activation process that occurred with similar efficiency. The
structures of these products were elucidated by Xꢀray crystallography. Substituents on the central
naphthalene are all twisted out of planarity into a propellerꢀlike conformation.
a,b
Table 4. Substrate Scope of Arenes
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a
Amide (0.125 mmol), alkyne (0.5 mmol), Ni(cod) (0.0125 mmol) using Condition A: in 1
2
b
ml DMPU, at 140 °C for 8 h or Condition B: in 0.5 ml DMPU, at 150 °C for 18 h. Isolated
c
d
yields; average of two runs. Run at 150 °C. Run at 160 °C.
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We also attempted a reaction using 1,8ꢀbis(phenylethynyl)naphthalene as substrate. An
interesting sequential annulation occurred to yield a fluoranthene product 5, which is a popular
scaffold in organoelectronic devices and fullerene chemistry (Scheme 2). This protocol provides
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a straightforward method to access this family of useful polyaromatic system.
Scheme 2. Homologation using a dialkyne substrate
Deuterium Labeling Experiments. In order to probe the reaction mechanism, we carried out
detailed isotope labelling experiments (Scheme 3). When d ꢀbenzamide substrate was subjected
5
to the reaction condition for a short period, the unreacted starting material was recovered without
H contamination. However, 28% H incorporation was observed at the orthoꢀ position of the
product. This result suggests the initial NꢀH insertion by Ni(0) is irreversible. Hydrogen
contamination in the product indicates the orthoꢀCꢀH metalation step might be reversible. In
contrast, no H/D exchange was observed at the metaꢀ positions for product 3aa-d . A large
3
primary isotope effect was observed for substrate 1a-d (Scheme 2, b, KIE = 3.4). Smaller, yet
5
very similar KIE values (2.0 and 1.9) were observed using metaꢀ and orthoꢀ deuterated substrates
1
a-d and 1a-d (Scheme 2, c and d). Considering the substrate contains two orthoꢀ and two
m o
metaꢀ CꢀHs, we also determined the KIE values for substrates containing only one orthoꢀ or one
metaꢀ CꢀH bond (Scheme 3, e and f). Again, both substrates showed significant primary isotope
effect (KIEmeta = 4.0, KIEortho = 2.8). These data indicate both orthoꢀ and metaꢀCꢀH metallation
steps contribute to the overall reaction rate. The orthoꢀ CꢀH cleavage occurs before the rateꢀ
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determining step (RDS) and exhibits an equilibrium isotope effect. The meta- CꢀH activation is
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likely the slowest step in the catalytic cycle. The combination of a rigid DG and a strong
aprotic polar solvent contributes to both slow C/N reductive elimination and fast DG dissociation,
delivering the [2+2+2] homologation product exclusively.
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Scheme 3. Deuterium Labeling Experiments
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NMR Spectroscopic Study and Isolation of Ni Complexes. As discussed above, the orthoꢀ Cꢀ
H insertion is reversible. Therefore, the overall reaction carries a simplified kinetic profile
illustrated in Scheme 4a. According to this analysis, there should be a stable Ni resting state
between the two CꢀH nickelation events. In order to confirm this speculation, we followed the
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1
reaction between 1a and 2a at 120 °C using H NMR. A new species was observed that remained
at constant concentration (ca. 6%) throughout the course of the reaction (Scheme 4b). Upon
approaching full conversion, the amount of this species started to decrease and eventually was
consumed completely (see SI). We believe this newly identified “intermediate” is likely the
catalyst resting state.
Scheme 4. Proposed Kinetic Profile and Evidence of a Catalyst Resting State
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(
a)
meta C-H
activation
k2
ortho C-H
activation
G
kobs=k k /(k +k )
1 2
-1
2
k1
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k-1
stable
intermediate
reaction coordinate
O
O
N
N
Ni
L
Ni
Ph
INT-Q2
N
N
Ph
INT-Q1
[5,5] Ni-bridged
[5,7] Ni-bridged
metallacycle
metallacycle
possible catalyst resting states
(b)
QHN
O
O
NHQ
H
Ph
10 mol% Ni(cod)2
Ph
Ph
+
Ph
Ph
DMPU, 120°C
2a
H
Ph
3aa
1
a
3
0%
5.9%
6
0 min
0 min
2
3%
5.3%
5
17%
1a
5.9%
40 min
30 min
1a
3aa
cat. resting state
.9%
3aa, 11%
5
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The first CꢀH activation step involves two key Ni bridged intermediates INT-Q1 and INT-Q2
Scheme 4a). In order to determine which one is the catalyst resting state, we attempted to
(
isolate and determine the structure of the most stable Ni complex. The reaction of 1a and 2a was
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carried out at 120 °C using a stoichiometric amount of Ni(cod) . The reaction was stopped after
2
40 min. A dark red solid was isolated. The structure of this compound was determined as a Ni(III)
complex 6 (Scheme 5), which was likely a oxidation product during isolation. This result
suggests that the [5,5] Niꢀbridged metallacycle INT-Q1 is likely the catalyst resting state. Since
the C/N reductive elimination is suppressed, the persistence of INT-Q1 implies that the
corresponding [5,7] Niꢀbridged metallacycle INT-Q2 is relatively unstable and DG
dissociation/metaꢀCꢀH insertion is imminent. This argument is consistent with a condition
involving a rigid DG and strong polar solvent.
Scheme 5. Isolation of Nickelcycle Complex
2
0
LFER between Ligand Electronics and Selectivity. Intrigued by the electronic effect of
phosphine ligands on the selectivity of [4+2] vs [2+2+2], we investigated the linear freeꢀenergy
relationship (LFER) between paraꢀsubstituted triarylphosphines and the ratio of [4+2]/[2+2+2]
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(
Table 5). The positive slope indicates that DG dissociation/mꢀCꢀH metallation, compared to
C/N reductive elimination, is more sensitive to the electronics of the phosphine ligand. Electronꢀ
deficient phosphines favor [2+2+2] over [4+2], inspired by complex 6 structure, it likely due to
decreased positive charge on the nickel by the coordination of the second substrate.
Table 5. LFER between Ligand Electronics and Selectivity
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QHN
O
Q
N
Ni cat. ( 10 mol % )
ligand ( 20 mol % )
O
NHQ
H
Ph
O
Ph
Ph
Ph
Ph
+ Ph
Ph
+
°
DMPU, 140 C, 8 h
2
H
Ph
H
1a
ligand:
3
4
R
P
3
Based on this information, we proposed a substrateꢀassisted ligand exchange pathway leading
to the [2+2+2] product 3 (Scheme 6). The first alkyne insertion reaction generates intermediate
INT-Q2. The rigidity of the 8ꢀaminoquinoline ligand prohibits direct CꢀN bond formation from
INT-Q2. INT-Q2 is a 16ꢀelectron Ni(II) complex, which is coordinated by another substrate to
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yield an 18ꢀelectron intermediate INT-Q2’. The increased electron density at the Ni center of
INT-Q2’ triggers ligand exchange/reorganization to give INT-Q3, setting stage for the second
alkyne insertion. In this process, electronꢀpoor phosphine is a better leaving group than electronꢀ
rich ones and favors the ligand exchange.
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Scheme 6. Substrate Assisted Ligand Dissociation
Following this analysis, we proposed that a bulky electronꢀrich phosphine might divert the
reaction pathway back to [4+2]. A large phosphine would discourage coordination of a second
substrate molecule by creating a crowded Ni center. An electronꢀrich PAr would disfavor ligand
3
displacement. We were pleased to find that PCy is an effective ligand for the [4+2] reaction
3
under otherwise identical conditions. Product 4ab was preferentially formed over 3ab in 7:1 ratio
(
Scheme 7). In this reaction, PCy blocks second 1a from coordinating to Ni center and the
3
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strong trans effect of this phosphine assists C/N reductive elimination by prolonging NꢀNi bond.
In comparison, standard ligandꢀfree condition yielded the [2+2+2] product 3ab only.
Scheme 7. Diverting Reaction Pathways Using A Bulky and Electron-rich Phosphine
Ligand.
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The complete catalytic cycle for the [2+2+2] reaction is proposed in Scheme 8. Ni(cod) is
2
readily oxidized by the acidic amide bond to give nickel hydride INT-Q0. This oxidative
addition step is likely irreversible as supported by the H/D exchange experiment (Scheme 3a).
OrthoꢀCꢀH nickelation occurs via σꢀbond metathesis. The H bonded nickelacycle INT-Q1-H is
2
consumed by alkyne to give key CꢀH insertion intermediate INT-Q1, which is the catalyst
resting state. Stilbene was observed in 76% by GC. Alternatively, nickelation could occur after
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alkyne insertion via INT-Q1-V (σꢀbond metathesis). Fast alkyne insertion into INT-Q1
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9
generates INT-Q2. In the absence of an external ligand, substrate amide 1a acts as a
monodentate ligand to stabilize both INT-Q1 and INT-Q2. Intramolecular ligand exchange/DG
swap gives INT-Q3. Second σꢀbond metathesis results metaꢀ CꢀH nickelation (INT-Q4), which
is likely the slowest step. The second alkyne insertion, followed by CꢀC bond reductive
elimination, releases homologation product 3aa. This mechanistic proposal also supports recent
finding by the Chatani group. In their case, the same rigid 8ꢀaminoquinoline was used as DG. In
contrast to our ligandꢀfree condition, a NHC ligand was used to prevent premature CꢀN bond
reductive elimination. In their case, substrate assisted DG dissociation is unlikely to operate. As
a result, higher temperature and concentrations were employed for the reaction. In addition, a
close to 1 KIE value is consistent with DG dissociation being the rate determining step.
Scheme 8. Proposed Mechanism for the [2+2+2] Reaction Pathway
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Conclusion
In summary, we developed a Niꢀcatalyzed dehydrogenative homologation reaction of arenes and
alkynes. Polycyclic aromatic hydrocarbon scaffolds were synthesized in one step using a simple,
ligandꢀfree procedure. The common [4+2] reaction pathway is diverted to [2+2+2] using a rigid
8
ꢀaminoquinoline directing group. Detailed mechanistic studies suggest a substrateꢀassisted
ligand exchange pathway leading to [2+2+2] products. A stable Ni resting state between two Cꢀ
H activation events was identified experimentally. The selectivity of [2+2+2] vs [4+2] is
influenced by both DG and ligand. A bulky, electronꢀrich phosphine can revert this reaction back
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to the [4+2] pathway. We expect insights gained in this endeavor would stimulate development
of sophisticated CꢀH functionalization cascades by mechanism inspired rationale design.
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ASSOCIATED CONTENT
Supporting Information. Experimental procedures, analytical and spectroscopic data for new
compounds, copies of NMR spectra. This material is available free of charge via the Internet at
http://pubs.acs.org
AUTHOR INFORMATION
Corresponding Author
huangyong@pkusz.edu.cn
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
This work is financially supported by the National Natural Science Foundation of China
(21372013, 21572004), the Guangdong Province Special Branch Program (2014TX01R111), the
Guangdong Natural Science Foundation (2014A030312004) and the Shenzhen Basic Research
Program (JCYJ20160226105602871, JSGG20140717102922014).
REFERENCES
(1) For selected recent reviews on nickelꢀcatalyzed reactions, see: (a) Tasker, S. Z.; Standley, E.
A.; Jamison, T. F. Nature 2014, 509, 299ꢀ309. (b) Hoshimoto, Y.; Ohashi, M.; Ogoshi, S. Acc.
Chem. Res. 2015, 48, 1746ꢀ1755. (c) Jackson, E. P.; Malik, H. A.; Sormunen, G. J.; Baxter, R.
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D.; Liu, P.; Wang, H.; Shareef, A. R.; Montgomery, J. Acc. Chem. Res. 2015, 48, 1736ꢀ1745. (d)
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(2) For selected recent reviews see: (a) Phapale, V. B.; Cárdenas, D. J. Chem. Soc. Rev. 2009, 38,
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W.; Wilson, D. A.; Zhang, N.; Resmerita, A. M.; Garg, N. K.; Percec, V. Chem. Rev. 2011, 111,
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Itami, K. Eur. J. Org. Chem. 2013, 19ꢀ30.
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N. D.; Cavell, K. J. Angew. Chem., Int. Ed. 2004, 43, 3845ꢀ3847. (b) Nakao, Y.; Kanyiva, K. S.;
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A.; Jeftic, T.; Modi, S.; Johnson, S. A. J. Am. Chem. Soc. 2010, 132, 11923ꢀ11925. (l) Hachiya,
H.; Hirano, K.; Satoh, T.; Miura, M. Angew. Chem., Int. Ed. 2010, 49, 2202ꢀ2205. (m) Nakao,
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