Nickel-Catalyzed Stereoselective Diarylation of Alkenylarenes

Article abstract of DOI:10.1021/jacs.8b05680

A three-component coupling of aryl bromides, arylboron reagents, and alkenylarenes is presented. The method tolerates a variety of substitution patterns on all of the components. In particular, 1,2-disubstituted alkenylarenes are suitable and undergo highly diastereoselective diarylation.

Full text of DOI:10.1021/jacs.8b05680

Communication
pubs.acs.org/JACS
Cite This: J. Am. Chem. Soc. XXXX, XXX, XXX−XXX
Nickel-Catalyzed Stereoselective Diarylation of Alkenylarenes
Pin Gao,†,‡,§ Liang-An Chen,‡,§ and M. Kevin Brown*,‡
†Department of Chemistry, School of Science, and MOE Key Laboratory for Nonequilibrium Synthesis and Modulation of
Condensed Matter, Xi’an Jiaotong University, Xi’an 710049, China
‡Department of Chemistry, Indiana University, 800 East Kirkwood Avenue, Bloomington, Indiana 47405, United States
S
* Supporting Information
Scheme 1. Intermolecular 1,2-Diarylation of Alkenes
ABSTRACT: A three-component coupling of aryl
bromides, arylboron reagents, and alkenylarenes is
presented. The method tolerates a variety of substitution
patterns on all of the components. In particular, 1,2-
disubstituted alkenylarenes are suitable and undergo
highly diastereoselective diarylation.
lkenes represent an appealing class of molecules for
Achemical synthesis because of their wide availability and
ease of preparation.1 While alkene difunctionalization is
known, reactions that incorporate two distinct carbon-based
groups are more rare.2 In particular, addition of two different
aryl groups across an alkene represents an attractive goal for
method development because of the prevalence of polyar-
ylalkanes in natural products and pharmaceutical agents.
One strategy to achieve alkene diarylation is to interrupt a
cross-coupling reaction with a migratory insertion event.2
However, challenges with this strategy lie in competing direct
cross-coupling and β-hydride elimination of alkylmetal
intermediates (Mizoroki−Heck reaction). To mitigate these
concerns, methods involving intramolecular variants,2,3 sub-
strates with coordinating groups,4 and/or use of select classes
of activated alkenes have been developed.5 Several examples of
related intermolecular aryl/alkenylation of activated alkenes
are known.6 In addition, intermolecular aryl/alkylation by
metalloradical processes have been reported.7
As noted above, while several classes of activated alkenes are
known to undergo diarylation, three examples of diarylation of
vinylarenes have been reported. The first is a homodiarylation
of vinylarenes with aryltin reagents.5d The other two examples
involve heterodiarylation; while one requires the use of a
coordinating group,4a the second necessitates substrates with
extended conjugation (Scheme 1A), thus limiting the reaction
scope.5g Furthermore, reactions of 1,2-alkenylarenes are not
known yet particularly important, as the opportunity for
stereocontrol becomes apparent. Only two examples of
diarylation of 1,2-disubstituted alkenes are known and are
limited to norbornene derivatives5a−c and 1,3-cyclohexadiene
(Scheme 1B).5e It is evident that despite the significant
advances outlined above, heterodiarylation of simple styrene
derivatives and reactions of 1,2-disubstituted alkenylarenes are
lacking. Herein we disclose a stereoselective Ni-catalyzed
diarylation of mono-, 1,1-di-, and 1,2-disubstituted alkenylar-
enes with aryl bromides and arylboron reagents (Scheme 1C).8
The method is notable in that it is stereoselective, a range of
substitution patterns are tolerated, and gram-scale synthesis
can be achieved.
In the context of recent efforts from our lab on Ni-catalyzed
carboboration of unactivated alkenes9 and Cu-catalyzed alkene
diarylation reactions,10 we discovered a novel diarylation of
styrene (1) with p-tolB(neop)11 (2) and 3,5-dimethylbromo-
benzene (3). The optimized reaction conditions (Table 1,
entry 1) utilize inexpensive NiCl2 at 80 °C in toluene. Under
these conditions, triarylethane 4 was formed in 77% yield,
accompanied by the direct cross-coupling product in ∼25%
yield (<2% yield of products derived from β-hydride
elimination was observed).12 Key to the development of this
reaction was the identification of 0.1 equiv of (Bpin)2 in the
presence of KOEt as a suitable reductant for NiCl2, presumably
to generate a Ni(0) complex.13 Use of the common reductants
Zn and Mn (Table 1, entry 4) was ineffective. In addition, use
Received: May 30, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.8b05680
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
a
a
Table 1. Change from Standard Conditions
Scheme 2. Evaluation of Various Alkenes
yield
b
entry
change from standard conditions
(%)
1
2
no change
no (Bpin)2
77
<2
d
3
4
5
6
7
8
0.1 equiv of (Bneop)2 instead of 0.1 equiv of (Bpin)2
1.0 equiv of Zn0 or Mn0 instead of 0.1 equiv of (Bpin)2
Ni(COD)2 instead of NiCl2 and (Bpin)2
Ni(COD)2 instead of NiCl2
NiCl2(PCy3)2 instead of NiCl2
NiCl2(bpy) instead of NiCl2
70
<2
c
53
54
d
<2
<2
d
9
NiCl2(DME) instead of NiCl2
1.2 equiv of ArBr instead of 1.7 equiv of ArBr
1.8 equiv of ArB(neop) instead of 2.0 equiv of ArB(neop)
73
68
72
10
11
12
d
NaOEt instead of KOEt
16
a
b
The reactions were run on a 0.2 mmol scale. Yields were
determined by GC analysis with a calibrated internal standard. The
conversion of styrene was >98%, except where noted otherwise.
c
d
>80% of the styrene was recovered. ∼50% of the styrene was
recovered.
of Ni(COD)2 (with or without (Bpin)2) allowed for product
formation, albeit in reduced yield, thus confirming that Ni(0)
is a competent catalyst (Table 1, entries, 5 and 6). Phosphine-
and amine-based ligands suppressed the alkene functionaliza-
tion and allowed only direct cross-coupling to occur (Table 1,
entries 7 and 8). When lower amounts of ArBr or ArB(neop)
were employed, slightly lower yields were observed (compare
Table 1, entries 10 and 11 with entry 1). Finally, for reasons
that are unclear at this time, the reaction is sensitive to the
counterion of the base, as NaOEt was significantly less effective
than KOEt (compare Table 1, entry 12 with entry 1).
After the optimized conditions were established, the scope
of the diarylation was evaluated. With respect to the alkene
component, styrene derivatives bearing electron-donating
(products 7 and 10) and electron-withdrawing substituents
(products 8 and 9) worked well (Scheme 2). Sterically
demanding 2-methylstyrene was tolerated; however, the yield
was slightly diminished (product 11). Substrates that have
extended conjugation also allowed for product formation
(products 12 and 13).
a
The reactions were run on a 0.5 mmol scale. “NMR yield” refers to
1
yields determined by H NMR analysis of the unpurified reaction
mixtures with an internal standard; “yield” refers to yields of isolated
products after silica gel column chromatography. Diastereomeric
ratios were determined by 1H NMR analysis of the unpurified
reaction mixtures. The conversion of styrene was >98%, except where
b
c
noted. Ar1 = 4-MeC6H4 and Ar3 = 4-OMeC6H4. 27% of the alkene
was recovered.
One of the most notable aspects of this method is that 1,1-
and 1,2-disubstituted alkenylarenes were also tolerated
(Scheme 2). For example, reaction of α-methylstyrene allowed
for formation of 14, which bears a quaternary carbon (see also
products 15 and 16). Reaction of 1,2-disubstituted alkenylar-
enes occurred with control of the stereoselectivity; in all cases,
syn addition of the aryl group was observed as the major
product regardless of the alkene geometry (compare products
21 and 22, from trans- and cis-stilbene, respectively). In the
case of cis-stilbene, slightly lower levels of diastereoselectivity
were observed relative to trans-stilbene. Substitution at the β-
position could be varied to a silyl-protected hydroxyalkyl group
(product 19), i-Pr (product 20) or Ph (products 21 and 22).
With respect to known limitations, attempted diarylation of a
trisubstituted alkene and an unactivated alkene did not lead to
product formation.12
Reactions with a variety of aryl bromides were investigated
and found to tolerate electron-donating (products 29, 30, and
34), electron-withdrawing (products 27 and 32), and sterically
demanding (product 33) substituents (Scheme 3A). The
functional group tolerance was also evaluated and included
esters (product 32), amides (product 28), and tertiary amines
(products 29 and 35). The moderate yield observed in the
formation of 35 is likely due to the Lewis basic nitrogen, which
partially inhibits catalysis. It should also be noted that
heterocyclic aryl bromides, such as 3-bromopyridine, are not
B
DOI: 10.1021/jacs.8b05680
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
a
Scheme 3. Evaluation of ArBr and ArB(neop)
Scheme 4. Utility of the Method
a representative target (Scheme 4B). The established approach
toward rac-lasofoxifene involves hydrogenation of a tetrasub-
stituted double bond, wherein the exocyclic aryl groups are
installed at an earlier stage in the synthesis.14,15 The strategy
outlined herein is orthogonal but has the advantage that the
exocyclic aryl groups are installed at a late stage by the
convergent assembly of simple components. This is significant
when modular approaches to molecules are desired, such as in
early-stage drug discovery chemistry. In practice, diarylation of
6-methoxy-3,4-dihydronaphthalene (50) with PhBr and ArB-
(neop) 49 allowed for the formation of a known precursor to
rac-lasofoxifene with >20:1 dr in 36% yield. As noted
previously with product 35, the moderate yield observed for
the formation of 52 is likely due to the presence of the Lewis
basic nitrogen.
A reasonable catalytic cycle for the diarylation reaction is
illustrated in Scheme 5.4a It is proposed that NiCl2 is reduced
to Ni(0) with (Bpin)2 and KOEt, perhaps via reductive
elimination of EtOBpin from complex 54.13 Oxidative addition
of Ni(0) and Ar2Br generates NiIIBrAr2 (56), which upon
migratory insertion provides π-benzyl−Ni complex 57 (this is
likely why alkenyl arenes, as opposed to unactivated alkenes,
are required). Transmetalation with Ar1B(neop) assisted by
KOEt generates 58, which undergoes reductive elimination to
form the diarylation product. The process likely does not
involve radical intermediates, as reaction of (E)- and (Z)-
alkene isomers gave rise to different major diastereomers
a
b
See footnote a of Scheme 2. 24 was used instead of 25.
tolerated in the reaction, likely for similar reasons.12 A similar
scope with respect to the arylboron reagent compared to the
aryl bromide was observed, with electron-donating, electron-
withdrawing, and sterically demanding substituents being
tolerated (Scheme 3B). In addition, an alkenylB(neop) could
be used to access 47, thus demonstrating an example of aryl/
alkenylation. However, mono- or disubstituted alkenylboranes
did not function well and resulted only in direct cross-
coupling.12
The reaction was performed on a gram scale with similar
yield and selectivity as in the smaller-scale reactions (Scheme
4A). It should be emphasized that the reaction conditions
employ inexpensive and readily available reagents, making for a
practical synthesis of polyarylalkanes.
To compare this method with existing strategies for
polyarylalkane synthesis, rac-lasofoxifene (48) was chosen as
C
DOI: 10.1021/jacs.8b05680
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
ORCID
Scheme 5. Proposed Catalytic Cycle
M. Kevin Brown: 0000-0002-4993-0917
Author Contributions
§P.G. and L.-A.C. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Indiana University and the NIH (5R01GM114443)
for financial support. P.G. thanks the China Scholarship
Council and the National Natural Science Foundation of
China (21602168) for generous financial support. This project
was partially funded by the Vice Provost for Research through
the Research Equipment Fund.
resulting from syn diarylation (Scheme 2, products 21 and 22).
It should be noted that this process might involve a
heterogeneous/surface reaction, as strongly donating ligands
are absent.
REFERENCES
■
(1) For reviews, see: (a) Saini, V.; Stokes, B. J.; Sigman, M. S. Angew.
Chem., Int. Ed. 2013, 52 (43), 11206−11220. (b) Coombs, J. R.;
Morken, J. P. Angew. Chem., Int. Ed. 2016, 55 (8), 2636−2649.
(2) For reviews, see: (a) Jensen, K. H.; Sigman, M. S. Org. Biomol.
Chem. 2008, 6 (22), 4083−4088. (b) Giri, R.; KC, S. J. Org. Chem.
2018, 83 (6), 3013−3022. (c) Derosa, J.; Tran, V. T.; van der Puyl, V.
A.; Engle, K. M. Aldrichimica Acta 2018, 51, 21−32.
(3) Zeni, G.; Larock, R. C. Chem. Rev. 2006, 106 (11), 4644−4680.
(4) (a) Shrestha, B.; Basnet, P.; Dhungana, R. K.; KC, S.; Thapa, S.;
Sears, J. M.; Giri, R. J. Am. Chem. Soc. 2017, 139 (31), 10653−10656.
(b) Derosa, J.; Tran, V. T.; Boulous, M. N.; Chen, J. S.; Engle, K. M. J.
Am. Chem. Soc. 2017, 139 (31), 10657−10660. (c) Li, W.; Boon, J.
K.; Zhao, Y. Chem. Sci. 2018, 9, 600−607. (d) Thapa, S.; Dhungana,
R. K.; Magar, R. T.; Shrestha, B.; KC, S.; Giri, R. Chem. Sci. 2018, 9,
904−909.
(5) (a) Catellani, M.; Chiusoli, G. P.; Concari, S. Tetrahedron 1989,
45 (16), 5263−5268. (b) Kang, S.-K.; Kim, J.-S.; Choi, S.-C.; Lim, K.-
H. Synthesis 1998, 1998 (09), 1249−1251. (c) Shaulis, K. M.; Hoskin,
B. L.; Townsend, J. R.; Goodson, F. E.; Incarvito, C. D.; Rheingold, A.
L. J. Org. Chem. 2002, 67 (16), 5860−5863. (d) Urkalan, K. B.;
Sigman, M. S. Angew. Chem., Int. Ed. 2009, 48 (17), 3146−3149.
(e) Zhang, X.; Larock, R. C. Tetrahedron 2010, 66 (24), 4265−4277.
(f) Stokes, B. J.; Liao, L.; de Andrade, A. M.; Wang, Q.; Sigman, M. S.
Org. Lett. 2014, 16, 4666−4669. (g) Kuang, Z.; Yang, K.; Song, Q.
Org. Chem. Front. 2017, 4 (7), 1224−1228.
(6) (a) Liao, L.; Jana, R.; Urkalan, K. B.; Sigman, M. S. J. Am. Chem.
Soc. 2011, 133 (15), 5784−5787. (b) McCammant, M. S.; Liao, L.;
Sigman, M. S. J. Am. Chem. Soc. 2013, 135 (11), 4167−4170.
(c) McCammant, M. S.; Sigman, M. S. Chem. Sci. 2015, 6, 1355−
1361. (d) Kuang, Z.; Yang, K.; Song, Q. Org. Lett. 2017, 19 (10),
2702−2705.
(7) (a) Gu, J.-W.; Min, Q.-Q.; Yu, L.-C.; Zhang, X. Angew. Chem.,
Int. Ed. 2016, 55 (40), 12270−12274. (b) García-Domínguez, A.; Li,
Z.; Nevado, C. J. Am. Chem. Soc. 2017, 139 (20), 6835−6838.
(8) For a review regarding Ni catalysis, see: Tasker, S. Z.; Standley,
E. A.; Jamison, T. F. Nature 2014, 509 (7500), 299−309.
(9) Logan, K. M.; Sardini, S. R.; White, S. D.; Brown, M. K. J. Am.
Chem. Soc. 2018, 140 (1), 159−162.
(10) (a) You, W.; Brown, M. K. J. Am. Chem. Soc. 2014, 136 (42),
14730−14733. (b) You, W.; Brown, M. K. J. Am. Chem. Soc. 2015,
137 (46), 14578−14581.
(11) neop = neopentylglycolate.
(12) See the Supporting Information for details.
(13) (a) Fujita, T.; Arita, T.; Ichitsuka, T.; Ichikawa, J. Dalton Trans.
2015, 44 (45), 19460−19463. (b) For a potential reductive
elimination of MeOBpin from a Ni(III) complex, see: Xu, H.; Zhao,
C.; Qian, Q.; Deng, W.; Gong, H. Chem. Sci. 2013, 4 (10), 4022−
4029.
(14) (a) Umareddy, P.; Arava, V. R. Synth. Commun. 2016, 46 (4),
309−313. (b) Khan, M. A.; Trivedi, N. R.; Kandasamy, N. N.; Patil,
The conditions outlined herein allow for diarylation in
preference to direct cross-coupling or Mizoroki−Heck
reaction, likely for several reasons. The first is the absence of
strongly donating ligands (e.g., phosphines and amines), which
allows for alkene coordination and subsequent migratory
insertion. In the presence of strongly donating ligands, alkene
coordination is likely to be inhibited, and thus, direct cross-
coupling dominates. The second is the use of arylboronic
esters, which reduces the rate of cross-coupling because of
slower transmetalation relative to other nucleophiles. For
example, if an arylzinc reagent is used in place of ArB(neop),
the cross-coupling product is the major product observed.12 In
addition, the use of 1.7 equiv of ArBr and 2.0 equiv of
ArB(neop) is required not because of competing direct cross-
coupling, as the cross-coupling product is formed in <25%
yield, but rather to ensure rapid capture of intermediates 55
and 57 prior to off-cycle reactions (e.g., Ni−C bond homolysis
or Ni aggregation). Finally, use of Ni catalysts results in the
formation of π-benzyl−Ni complexes, which are less prone to
β-hydride elimination compared with π-benzyl−Pd com-
plexes.16 In the latter case, β-hydride elimination is known to
be rapid.5g
In summary, a Ni-catalyzed diarylation of alkenylarenes has
been developed. The method represents a substantial
departure from known methods for reaction of vinylarenes in
that specialized substrates are not required and the process is
uniquely effective for diarylation of 1,2-disubstituted alkenylar-
enes. Such advances allow for the efficient and modular
synthesis of a wide variety of polyarylalkanes.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.8b05680.
■
S
Crystallographic data for 21 (CIF)
Crystallographic data for 22 (CIF)
Crystallographic data for 37 (CIF)
Experimental procedures and analytical data for all
compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
*brownmkb@indiana.edu
■
D
DOI: 10.1021/jacs.8b05680
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
D. G.; Pandey, V. K.; Sinha, S. Process for the Preparation of
Lasofoxifene Tartrate. U.S. Patent US8937188B2, 2015.
(15) (−)-Lasofoxifene is obtained from the racemate by fractional
crystallization with D-tartaric acid (see ref 14b). However, a recent
report details an enantioselective hydrogenation approach. See:
̌
́
́
Zanotti-Gerosa, A.; Gazic Smilovic, I.; Casar, Z. Org. Chem. Front.
2017, 4 (12), 2311−2322.
(16) Lin; Liu, L.; Fu, Y.; Luo, S.-W.; Chen, Q.; Guo, Q.-X.
Organometallics 2004, 23 (9), 2114−2123.
E
DOI: 10.1021/jacs.8b05680
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX