Ni-Catalyzed Regioselective Alkylarylation of Vinylarenes via C(sp3)-C(sp3)/C(sp3)-C(sp2) Bond Formation and Mechanistic Studies

Article abstract of DOI:10.1021/jacs.8b05374

We report a Ni-catalyzed regioselective alkylarylation of vinylarenes with alkyl halides and arylzinc reagents to generate 1,1-diarylalkanes. The reaction proceeds well with primary, secondary and tertiary alkyl halides, and electronically diverse arylzinc reagents. Mechanistic investigations by radical probes, competition studies and quantitative kinetics reveal that the current reaction proceeds via a Ni(0)/Ni(I)/Ni(II) catalytic cycle by a rate-limiting direct halogen atom abstraction via single electron transfer to alkyl halides by a Ni(0)-catalyst.

Full text of DOI:10.1021/jacs.8b05374

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Communication
Ni-Catalyzed Regioselective Alkylarylation of Vinylarenes via C(sp3)-
C(sp3)/C(sp3)-C(sp2) Bond Formation and Mechanistic Studies
Shekhar KC, Roshan K Dhungana, Bijay Shrestha, Surendra Thapa,
Namrata Khanal, Prakash Basnet, Robert W. Lebrun, and Ramesh Giri
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 26 Jul 2018
Downloaded from http://pubs.acs.org on July 26, 2018
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Ni-Catalyzed Regioselective Alkylarylation of Vinylarenes via C(sp3)-
C(sp3)/C(sp3)-C(sp2) Bond Formation and Mechanistic Studies
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Shekhar KC, Roshan K. Dhungana, Bijay Shrestha, Surendra Thapa, Namrata Khanal, Prakash Basnet,
Robert W. Lebrun, and Ramesh Giri*
Department of Chemistry & Chemical Biology, The University of New Mexico, Albuquerque, NM 87131, USA.
Supporting Information Placeholder
ABSTRACT: We report a Ni-catalyzed regioselective alkylaryla-
tion of vinylarenes with alkyl halides and arylzinc reagents to gen-
erate 1,1-diarylalkanes. The reaction proceeds well with primary,
secondary and tertiary alkyl halides, and electronically diverse ar-
ylzinc reagents. Mechanistic investigations by radical probes, com-
petition studies and quantitative kinetics reveal that the current re-
action proceeds via a Ni(0)/Ni(I)/Ni(II) catalytic cycle by a rate-
limiting direct halogen atom abstraction via single electron transfer
(SET) to alkyl halides by a Ni(0) catalyst.
Scheme 1. Bioactive 1,1-diarylalkanes
We began our studies by attempting to alkylarylate 2-vinylnaph-
thalene with cyclohexyl iodide and PhZnI with different transition
metal catalysts (Table 1). We were pleased to find that the reaction
Regioselective difunctionalization of olefins by intercepting
Heck C(sp3)-[M] intermediates with organometallic reagents1 is a
powerful method to construct complex molecules2 rapidly from
readily available starting materials.3 However, the development of
such a method is generally hindered by facile -H elimination from
the C(sp3)-[M] species leading to Heck products.4 Recently, strate-
gies to stabilize C(sp3)-[M] species in situ via -allyl-[M] for-
mation5 and heteroatom coordination6 have been successfully im-
plemented to overcome the complications from -H elimination,7
which enabled their subsequent interception with organometallic
reagents.8 An alternative approach that proceeds by reductive cou-
pling via radical intermediates9 is also emerging as a powerful
method for olefin dicarbofunctionalization.10
was efficiently catalyzed by 5 mol% NiBr2 in NMP at room tem-
perature affording the alkylarylated product 2 in 81% yield with 2
equiv each of cyclohexyl iodide and PhZnI (entry 1).17 Lowering
the amount of cyclohexyl iodide or PhZnI decreased the yield (en-
tries 2-3). Alkyl fluoride did not form any product (entry 4).16c The
reaction is also catalyzed by Ni(cod)2 and (Ph3P)4Ni in similar
yields (entries 5-6). While CoCl2 also catalyzed the reaction in
moderate yields (entry 7), Fe, Cu and Pd-catalysts did not form any
product (entry 8). The reaction also did not proceed in the absence
of NiBr2 (entry 9). While the reaction proceeded in a similar yield
in DMA, only a small amount of the product 2 was formed in THF
or toluene (entries 10-11).
Table 1. Optimization of reaction conditionsa
Vinylarenes serve as one of the most synthetically valuable
sources of olefins, which could attenuate the effects of -H elimi-
nation by in situ formation of -benzyl-[M] species.11 Dicarbofunc-
tionalization of such olefins could afford a concise synthetic dis-
connection to construct 1,1-diarylalkanes, which show strong bio-
activity against breast cancer (MCF-7), lung cancer (H-460), brain
cancer (SF-268), and membrane protein FLAP (5-Lipoxygenase
Acting Protein) (Scheme 1).12 However, methods to dicarbofunc-
tionalize vinylarenes are rare. The limited known examples of re-
actions proceed for homodicarboalkoxylation,13 homodiaryla-
tion/homodivinylation,11a trifluoromethylarylation,14 trifluoro-
methylcyanation15 and vinylarylation.11b To the best of our
knowledge, there is no general catalytic method for a three-compo-
nent alkylarylation of vinylarenes to furnish 1,1-diarylalkanes.16
Herein, we report a Ni-catalyzed alkylarylation of vinylarenes with
primary, secondary and tertiary alkyl halides, and arylzinc reagents
that furnishes diversely substituted 1,1-diarylalkanes via the for-
mation of two C(sp3)-C(sp3) and C(sp3)-C(sp2) bonds in one step.
Mechanistic studies indicate that the reaction proceeds by a rate-
limiting direct halogen atom abstraction via single electron transfer
(SET) from a Ni(0) catalyst to alkyl halides.
b
a0.1 mmol scale reactions. Isolated yield (0.5 mmol scale) in
parenthesis.
With the optimized conditions, we examined the scope of the al-
kylarylation of 2-vinylnaphthalene with a variety of alkyl halides
and arylzinc reagents (Table 2).18 The reaction proceeds well with
primary and secondary alkyl halides (I, Br), and generates products
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Table 3. Scope with vinylarenes, RX and ArZnIa
with secondary and tertiary carbon centers. The reaction also toler-
ates various functional groups such as OTBS (5), phthalimide (6),
CF3 (7-8) and OMe (4, 10), and ArZnI bearing ortho-OMe (4).
Table 2. Scope with RX and ArZnIa
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a0.5 mmol scale reactions. Letters in parenthesis indicate X in
Alkyl-X. b5 mol% Ni(cod)2. c8 h.
The current alkylarylation reaction can be conducted with a wide
range of vinylarenes (Table 3).18 The reaction can be performed
with vinylarenes containing various functional groups such as Cl
(15-17, 21, 22), Ph (18), OMe (19, 32), esters (20, 25) and ketones
(30). Alkyl halides containing functional groups such as Cl (12),
OEt (13), OTBS (16), olefins (17) and NCbz (24) can be used as
coupling partners. ArZnI containing sensitive functional groups
like esters (22) and CN (29) are tolerated. The reaction also pro-
ceeds with vinyl bromides (25).
The reactions of tert-alkyl halides proved more challenging than
those of the primary and secondary alkyl halides. The reaction with
tertiary alkyl halides typically produced products in low yields ex-
cept for the coupling of tert-BuBr and PhZnI with 2-vinylnaphtha-
lene (26). Further catalyst optimization showed that (Ph3P)2NiCl2
was an excellent catalyst for the coupling with tert-alkyl halides,
which afforded products with quaternary carbon centers in good to
excellent yields (26-32).
We have also demonstrated the synthetic utility of the alkylary-
lation reaction in modified drug derivatives (34-36). Vinylarenes
built on the backbones of two non-steroidal anti-inflammatory
drugs (NSAIDs), indometacin and tolmetin, were alkylarylated ef-
ficiently with ArZnI and primary and secondary alkyl halides,
which afforded the corresponding products 34-36 in 46-67% yields.
We also conducted mechanistic studies to understand the process
of alkylarylation. Since the current reaction is also catalyzed by
Ni(cod)2 and (Ph3P)4Ni similar to NiBr2 (Table 1), we believe that
Ni(0) is the active catalyst wherein NiBr2 is reduced by ArZnI to
Ni(0). In order to examine this possibility, we performed a reaction
of NiBr2•DME with access of 4-FC6H5ZnI in the presence of 2-
vinylnaphthalene and analyzed the dark solution formed instanta-
neously upon mixing by 19F NMR. The reaction furnished 4,4’-
difluorobiphenyl in a near stoichiometric molar ratio to that of
NiBr2•DME immediately and the concentration of the biaryl re-
mained constant over time (Scheme 2). This experiment indicates
that NiBr2 is instantaneously reduced to Ni(0) in the presence of
ArZnI reagents under our reaction conditions via fast double
transmetalation with ArZnI and reductive elimination of biaryls.
a0.5 mmol scale reactions. Letters in parenthesis indicate X in
e
Alkyl-X. b8 h. c10 mol% NiBr2. d5 mol% Ni(cod)2. 50 °C, 12 h.
We then conducted a radical clock experiment using iodoethox-
ypropene as a radical probe (Scheme 3).10m When iodoethoxypro-
pene was reacted with 4-chlorostyrene and PhZnI under the stand-
ard reaction condition, cyclized product 37 was generated in 38%
yield. In addition, we also isolated the dimer 38 along with the
Scheme 2. Reduction of Ni(II) to Ni(0) by ArZnI
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expected product 26 in 14% and 55% yields, respectively, when
olefin 1 was reacted with tBuBr and PhZnI (Scheme 4). The prod-
uct 38 arises from dimerization of the benzylic radical 39. These
results indicate that the alkylarylation of vinylarenes proceeds by a
single electron transfer (SET) process.
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3
4
5
6
7
Scheme 7. Competition experiments with ArZnI
8
9
rates of the reactions. Plots of kin versus the concentrations of cy-
clohexyl iodide and the catalyst gave linear curves (slope = 1.61 ×
10-4 M s-1; 7.3 × 10-3 M s-1) indicating a first order rate dependence
on RX and the catalyst (Fig. 1a-b). Similar kinetic studies by vary-
ing the concentration of PhZnI, however, showed no change in kin
(Fig. 1c) suggesting that the reaction is zero order on ArZnI. Meas-
urements of reaction progress with increasing concentrations of 2-
vinylnaphthalene showed that the reaction rates were slightly af-
fected negatively (Fig. 1d). These qualitative and quantitative ki-
netic studies suggest that the reaction with alkyl halides by direct
halogen atom abstraction is rate-limiting, and that the increased
concentration of 2-vinylnaphthalene interferes with the reaction
rate by multiple ligation to the Ni(0)-catalyst, which depletes coor-
dination sites for complexing alkyl halides at the transition state
required for inner sphere electron transfer during direct halogen
atom abstraction.19
Scheme 3. Radical clock experiment
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Scheme 4. Formation of radically dimerized product
We also performed competition experiments with different alkyl
halides. Competitions between n-octyl iodide and cyclohexyl io-
dide, and between cyclohexyl bromide and t-butyl bromide showed
that t-alkyl halides reacted faster than s-alkyl halides, and s-alkyl
halides reacted faster than n-alkyl halides (t-RX > s-RX > n-RX)
(Scheme 5). Similar competition between s-alkyl iodide and s-alkyl
bromide, and s-alkyl bromide and s-alkyl chloride indicated that
alkyl iodides reacted faster than alkyl bromides, and alkyl bromides
reacted faster than alkyl chlorides (RI > RBr > RCl) (Scheme 6).
These results are consistent with the reaction proceeding by a rate-
limiting direct halogen atom abstraction from alkyl halides via in-
ner sphere electron transfer from a Ni-catalyst.19
0.00012
0.0001
y = -1.1548e-5 + 0.0073463x
R2= 0.99398
0.0001
y = -3.8e-6 + 0.0001609x
R2= 0.98744
8 10-5
6 10-5
4 10-5
2 10-5
0
(a)
(b)
8 10-5
6 10-5
4 10-5
2 10-5
0
We also performed a competition between 4-CF3C6H4ZnI and 4-
MeOC6H4ZnI, which produced the corresponding alkylarylated
products 8 and 10 in nearly a 1:1 ratio (Scheme 7). This result in-
dicated that the reaction experienced no rate difference towards
electronically biased ArZnI and that ArZnI reagents were less
likely involved in the rate-determining step (RDS).
0
0.0045
0.009
0.0135
0.018
0
0.1 0.2 0.3 0.4 0.5 0.6 0.7
[cyclohexyl iodide] (M)
[NiBr ] (M)
2
8 10-5
6 10-5
4 10-5
2 10-5
0
0.08
0.07
0.06
0.05
0.04
0.03
0.02
0.01
0
y = 3.8719e-5 - 2.56e-7x
R2= 0.0015704
0.15 M olefin 1
0.30 M olefin 1
0.60 M olefin 1
(d)
(c)
0
0.1 0.2 0.3 0.4 0.5 0.6 0.7
[PhZnI] (M)
0
2000
4000
6000
8000
time (s)
Figure 1. (a) A plot of kin vs. cyclohexyl iodide concentrations. (b)
A plot of kin vs. NiBr2 concentrations. (c) A plot of kin vs. PhZnI
concentrations. (d) A plot of product yields vs. olefin 1 concentra-
tions.
Scheme 5. Competition experiments with 1°, 2° and 3° R-X
We finally conducted quantitative kinetic studies in order to de-
termine the roles of ArZnI, alkyl halides and vinylarenes at the
RDS. Measurements of the initial rates (kin) for the reaction of 2-
vinylnaphthalene and PhZnI with different concentrations of cyclo-
hexyl iodide and the catalyst showed a corresponding rise in the
Scheme 8: Proposed catalytic cycle
Based on these mechanistic studies, we propose a catalytic cycle
(Scheme 8). Herein, the reaction is initiated by a solvent/olefin-sta-
bilized Ni(0)-catalyst, which reduces alkyl halides by SET and gen-
erates alkyl radicals (R•) by a rate-limiting halogen atom abstrac-
tion process. The alkyl radicals then undergo addition to olefins to
Scheme 6. Competition experiments with RI, RBr and RCl
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(6) (a) Trejos, A.; Fardost, A.; Yahiaoui, S.; Larhed, M. Chem. Commun.
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1
2
3
4
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7
8
In summary, we have developed a Ni-catalyzed regioselective
alkylarylation of vinylarenes to generate 1,1-diarylalkanes via the
formation of two C(sp3)-C(sp3) and C(sp3)-C(sp2) bonds in one
step. The reaction works well with primary, secondary and tertiary
alkyl halides, and a variety of arylzinc reagents. Mechanistic stud-
ies by radical probes, competition experiments and quantitative ki-
netics indicate that the reaction proceeds by a rate-limiting halogen
atom abstraction via SET from a Ni(0) catalyst to alkyl halides.
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ASSOCIATED CONTENT
Supporting Information
Experimental procedures and characterization data for all
compounds. This material is available free of charge via the
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AUTHOR INFORMATION
Corresponding Author
rgiri@unm.edu
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
We thank the University of New Mexico (UNM) and the National
Science Foundation (NSF CHE-1554299) for financial support,
and upgrades to the NMR (NSF grants CHE08-40523 and CHE09-
46690) and MS Facilities.
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M. P.; Morken, J. P. Science 2016, 351, 70.
(3) For reviews on olefin difunctionalization to form C-C/C-O,N bonds,
see: (a) Chemler, S. R.; Karyakarte, S. D.; Khoder, Z. M. J. Org. Chem.
2017, 82, 11311; (b) Gockel, S. N.; Buchanan, T. L.; Hull, K. L. J. Am.
Chem. Soc. 2018, 140, 58; (c) Wolfe, J. P. Synlett 2008, 2008, 2913.
(4) For Ni-catalyzed Heck reactions, see: (a) Matsubara, R.; Gutierrez,
A. C.; Jamison, T. F. J. Am. Chem. Soc. 2011, 133, 19020; (b) Harris, M.
R.; Konev, M. O.; Jarvo, E. R. J. Am. Chem. Soc. 2014, 136, 7825; (c)
Gøgsig, T. M.; Kleimark, J.; Nilsson Lill, S. O.; Korsager, S.; Lindhardt, A.
T.; Norrby, P.-O.; Skrydstrup, T. J. Am. Chem. Soc. 2012, 134, 443; (d)
Desrosiers, J.-N.; Hie, L.; Biswas, S.; Zatolochnaya, O. V.; Rodriguez, S.;
Lee, H.; Grinberg, N.; Haddad, N.; Yee, N. K.; Garg, N. K.; Senanayake,
C. H. Angew. Chem. Int. Ed. 2016, 55, 11921; (e) Maity, S.; Dolui, P.;
Kancherla, R.; Maiti, D. Chem. Sci. 2017, 8, 5181; (f) Huihui, K. M. M.;
Shrestha, R.; Weix, D. J. Org. Lett. 2017, 19, 340.
(5) (a) Mizutani, K.; Shinokubo, H.; Oshima, K. Org. Lett. 2003, 5, 3959;
(b) Liao, L.; Jana, R.; Urkalan, K. B.; Sigman, M. S. J. Am. Chem. Soc.
2011, 133, 5784; (c) McCammant, M. S.; Liao, L.; Sigman, M. S. J. Am.
Chem. Soc. 2013, 135, 4167; (d) Wu, X.; Lin, H.-C.; Li, M.-L.; Li, L.-L.;
Han, Z.-Y.; Gong, L.-Z. J. Am. Chem. Soc. 2015, 137, 13476; (e) Iwasaki,
T.; Fukuoka, A.; Yokoyama, W.; Min, X.; Hisaki, I.; Yang, T.; Ehara, M.;
Kuniyasu, H.; Kambe, N. Chem. Sci. 2018, 9, 2195; (f) Jun, T.; Shinsuke,
N.; A., C. F.; Akifumi, N.; Nobuaki, K. Adv. Synth. Catal. 2004, 346, 905.
(18) The mass balance is accounted for by the remaining vinylarenes and
5-10% of the alkyl Heck and hydroarylated products.
(19) Huber, T. A.; Macartney, D. H.; Baird, M. C. Organometallics
1995, 14, 592.
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