Potassium-Zincate-Catalyzed Benzylic C?H Bond Addition of Diarylmethanes to Styrenes

Article abstract of DOI:10.1002/anie.201713165

Direct functionalization of the benzylic C?H bond of diarylmethanes is an important strategy for the synthesis of diarylmethine-containing compounds. However, the methods developed to date for this purpose require a stoichiometric amount (usually more) of either a strong base or an oxidant. Reported here is the first catalytic benzylic C?H bond addition of diarylmethanes to styrenes and conjugated dienes. A potassium zincate complex, generated from potassium benzyl and zinc amide, acts as a catalyst and displays good activity and chemoselectivity. Considering the atom economy of the reaction and the ready availability of the catalyst, this reaction constitutes a practical, efficient method for diarylalkane synthesis.

Full text of DOI:10.1002/anie.201713165

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Accepted Article
Title: Potassium-Zincate-Catalyzed Benzylic C-H Bond Addition of
Diarylmethanes to Styrenes
Authors: Yu-Feng Liu, Dan-Dan Zhai, Xiang-Yu Zhang, and Bing-Tao
Guan
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10.1002/anie.201713165
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Potassium-Zincate-Catalyzed Benzylic C–H Bond Addition of
Diarylmethanes to Styrenes
Yu-Feng Liu[a], Dan-Dan Zhai[a], Xiang-Yu Zhang[a] and Bing-Tao Guan*[a, b]
Dedication ((optional))
Abstract: Direct functionalization of the benzylic C–H bond of
diarylmethanes is an important strategy for the synthesis of
diarylmethine-containing compounds. However, the methods
developed to date for this purpose require a stoichiometric amount
(usually more) of a strong base or an oxidant. Herein, we report the
first catalytic benzylic C–H bond addition of diarylmethanes to
styrenes and conjugated dienes. A potassium zincate complex
generated from potassium benzyl and zinc amide acted as the
Figure 1. Medicinally Important Diarylalkanes.
catalyst and displayed good activity and chemoselectivity.
Considering the atom economy of the reaction and the ready
availability of the catalyst, this reaction constitutes a practical, efficient
method for diarylalkane synthesis.
Diarylalkane motifs are widespread in pharmaceuticals and
natural products,[1,2] and compounds with this unique fragment
tend to have interesting biological activities. For example, a
diarylmethine motif is present in several drug candidates,
including the phosphodiesterase inhibitor CDP480[2a] and the
endothelin receptor antagonist SB-209670,[2b] and in some
marketed drugs, such as (R)-tolterodine[2c–e] and (+)-sertraline[2f]
(Figure 1). Owing to the reactivity of benzylic C–H bonds, direct
functionalization of diarylalkanes is also a direct and effective
synthetic method. For example, the deprotonation of
diarylmethane with a strong base such as BuLi or NaNH2/NH3 has
frequently been used to generate a benzylic carbanion for a
subsequent nucleophilic substitution or addition reaction (Scheme
1, eq 1).[3] The research groups of Walsh, Oshima, Trost, and
others have reported arylation and allylation of diarylalkanes via
transition-metal-catalyzed cross-coupling reactions (Scheme 1,
eq 2).[4] Li, Powell, Klussmann, Shi, and their colleagues have
reported the direct functionalization of diarylalkanes with terminal
alkynes, ketones, arenes, carboxylicacids, and amides via direct
oxidative coupling reactions (Scheme 1, eq 3).[5] However, these
direct C–H bond transformations have the disadvantages of
requiring harsh reaction conditions and stoichiometric amounts of
strong bases or oxidants. Therefore, the development of a mild,
atom-economical method for the synthesis of diarylalkanes would
be highly desirable.
Scheme 1. C–H Functionalization of Diarylmethanes.
Brønsted-base-catalyzed C–C bond formation reactions, such
as the aldol, Mannich, and Michael reactions, have been
extensively used in organic synthesis, owing to their reliability,
efficiency, and ideal atom economy.[6] However, the nucleophiles
that can be used for these reactions are limited to compounds with
relatively acidic hydrogen atoms (pKa = 18–25), such as
aldehydes, malonates, nitroalkanes, and ketones. For less acidic
compounds, such as esters, nitriles, amides, and alkylazaarenes
(pKa > 30), a stoichiometric amount of a strong Brønsted base is
necessary to generate the carbanion nucleophile. In pioneering
work, Pines and Knochel and their colleagues achieved KOBut-
catalyzed additions of alkylazaarenes, cyclic amides, nitriles,
ketones, and imines to styrenes.[7] Kobayashi and Schneider and
their co-workers reported catalytic additions of simple esters,
amides, alkylnitriles, alkylazaarenes, alkanesulfonamides and
allylbenzenes to imines and ɑ,β-unsaturated carbonyl compounds
by using a strong Brønsted base such as KH, KHMDS or
NaHMDS as a catalyst.[8] Recently, we achieved the KHMDS-
catalyzed benzylic C–H addition of alkylpyridines to styrenes.[9]
[a]
[b]
Y.-F. Liu, D.-D. Zhai, X.-Y. Zhang, and Prof. Dr. B.-T. Guan
State Key Laboratory and Institute of Elemento-Organic Chemistry,
College of Chemistry, Nankai University, Tianjin 300071, China
E-mail: guan@nankai.edu.cn
Prof. Dr. B.-T. Guan
Collaborative Innovation Center of Chemical Science and
Engineering, Nankai University, Tianjin 300071, China
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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Table 1. Optimization of Reaction Conditions[a]
Entry
1
Catalyst (10 mol %)
KBn
Yield (%)[b]
<5[c]
2
KOBut
<5
3
LiHMDS
<5
4
NaHMDS
<5
5
Zn(HMDS)2
KHMDS
<5
6
11
7[d]
KBn + Zn(HMDS)2
KZn(HMDS)2Bn
NaBn + Zn(HMDS)2
LiBn + Zn(HMDS)2
ZnBn2
88
8
90
9[d]
10[d]
11
12
13
<5
<5
<5
BnZnCl
<5
96 (93)[e]
Scheme 2. Reactions of Diphenylmethane with Styrenes and Conjugated
KZn(HMDS)2Bn
Dienes. Conditions: diphenylmethane 1a (0.75 mmol),
2 (0.5 mmol),
KZn(HMDS)2Bn (10 mol %), benzene (0.5 mL), 80 °C, 24 h; yields are based
on the amount of styrene. [a] 20 mol % catalyst was used. [b] 72 h. [c]
Diphenylmethane 1a (0.5 mmol), conjugated diene (1.5 mmol), hexane as
solvent; yields are based on the amount of 1a. [d] Ratio determined by 13C NMR.
[e] About 15 % of 4,1-addtion product was observed.
[a] Conditions: diphenylmethane 1a (1.0 mmol), styrene 2a (0.5 mmol), catalyst
(10 mol % of 2a), benzene (1.0 mL), 70 °C, 12 h. [b] 1H NMR yields based on
styrene with 2-methoxynaphthalene as an internal standard. [c] Oligomerization
of styrene was observed. [d] The catalyst precursors were firstly stirred in
benzene at rt for 0.5 h. [e] Catalyst (5 mol %), 80 ˚C, isolated yield in
parentheses.
To our knowledge, diphenylmethane, the benzylic C–H bond of
which has an acidity (pKa(C6H6) = 35) similar to that of
alkylpyridines and allylbenzenes,[10] has never been utilized in
similar transformations. Herein, we report the first catalytic
addition of the benzylic C–H bond of diarylmethanes to alkenes
(Scheme 1, eq 4). The catalyst was a potassium zincate complex,
analogues of which are widely used in directed deprotonative
metalation reactions,[11] and it displayed unique catalytic activity.
Drawing on recent work on catalytic C–H bond functionalization
reactions of alkylpyridines and allylbenzenes,[8e, 8g, 9] we began by
structure of the potassium zincate complex played a critical role
in the catalytic alkylation reaction (entries 9-12). Further
conditions optimization increased the yield to 96% (93% isolated
yield), even when the catalyst loading was decreased to 5 mol %
(entry 13).
We then carried out alkylation reactions between
diphenylmethane and various other styrenes (Scheme 2).
Reaction with 4-methylstyrene afforded 3ab under the optimized
conditions (table 1, entry 8), but the yield was lower than that for
styrene. However, after some simple modifications of the
standard conditions (see Supporting Information), reaction of 4-
methylstyrene in the presence of 10 mol % catalyst at 80 °C for
24 h afforded 3ab in good yield (86%). Under these modified
conditions, reactions of 2-methylstyrene, 4-tert-butylstyrene, 4-
phenylstyrene, 4-methoxylstyrene, and 2-methoxylstyrene
afforded the corresponding alkylation products (3ac–3ag) in good
to high yields. The good reactivities of 2-methylstyrene and 2-
methoxylstyrene hinted that the steric bulk of the styrene
substrate had little effect on the reaction. We also evaluated
various halogenated styrenes. Alkylation of diphenylmethane with
4-chlorostyrene to afford 3ah could not be achieved catalytically.
However, 3-chlorostyrene underwent catalytic alkylation to give
the desired addition product (3ai) in moderate yield (55%). The
yield could be improved to 73% by increasing the reaction time to
72 h. In contrast, 2-chlorostyrene underwent the reaction
efficiently and afforded 3aj in high yield (83%). The order of the
exploring
Brønsted-base-catalyzed
reactions
between
diphenylmethane and styrene (Table 1). The use of Brønsted
base such as KBn, KOBut, LiHMDS, NaHMDS and Zn(HMDS)2,
as a catalyst failed to give the desired alkylation product (entries
1–6). KHMDS afforded 3aa in only 11% yield (entry 7). However,
we were pleased to find that the combination of potassium benzyl
(KBn)[12] and Zn(HMDS)2 was an excellent catalyst, affording 3aa
in 88% yield (entry 7). This combined catalyst displayed excellent
selectivity for the C–H bond alkylation reaction: neither double
alkylation nor styrene oligomerization was observed. To better
understand how the combined catalyst worked, we carried out a
reaction in which KBn was slowly added to a benzene solution of
Zn(HMDS)2. Under these conditions, the red solid KBn slowly
disappeared, and a white solid precipitated from the solution. The
white solid was identified as the potassium zincate complex
KZn(HMDS)2Bn (92 % yield, see Supporting Information), which
has been synthesized by Mulvey et al. via deprotonation of
toluene with KZn(HMDS)3.[13] The potassium zincate complex
features an amide-bridging four-membered ring (KN2Zn), and
showed equal catalytic efficiency with the catalyst generated in
situ (entry 8). Control experiments suggested that the bridging
reactivities of the chlorostyrenes (2-chlorostyrene
>
3-
chlorostyrene > 4-chlorostyrene) was the same as that of the
corresponding fluoro-substituted styrenes (3ak–3am). The
catalytic reaction of diphenylmethane and 2-vinylnaphthalene
could also be achieved, affording 3an in 76% yield. Reaction of
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Scheme 4. Control Experiments
Scheme 3. Reactions of Diarylmethanes with Styrene. Conditions: 1 (0.75
mmol), 2a (0.5 mmol), KZn(HMDS)2Bn (10 mol %), benzene (0.5 mL), 80 °C,
24 h; yields are based on the amount of styrene. [a] 20 mol % catalyst was used.
1,1-diphenylethene and diphenylmethane gave 3ao in high yield
(88%). Conjugated dienes such as butadiene and isoprene were
also suitable substrates; their reactions in hexane afforded 1,4-
addition products 3ap and 3aq in 91% and 98% yields,
respectively. The double bonds in these products have potential
utility for further transformations. We also tested some other
olefins, including norbornene, 1-hexene, and 1,3-cyclohexadiene,
in the potassium-zincate-catalyzed alkylation reaction, but these
substrates failed to give the expected alkylation products.
Scheme 5. Plausible Reaction Pathway
Next, we evaluated various diarylmethanes in potassium-
zincate-catalyzed alkylation reactions with styrene (Scheme 3). 4-
Benzyltoluene and 3-benzyltoluene smoothly reacted with styrene
to produce alkylation products 3ba and 3ca in comparable good
yields. 2-Benzyltoluene also reacted with styrene to give 3da, but
the yield was slightly lower (75%). 4-Benzylbiphenyl gave 3ea in
high yield (96%). 2-Benzylnaphthalene and 1-benzylnaphthalene
underwent the reaction, and the corresponding products (3fa and
3ga) were obtained in 90% and 81% yields, respectively. The
slightly lower yields for 2-benzyltoluene and 1-benzylnaphthalene
(compare 3ba with 3da and 3fa with 3ga) suggest that the steric
bulk of the diarylmethane had a slight impact on the reaction.
When 4-benzylanisole and 2-benzylanisole were allowed to react
with styrene, the corresponding alkylation products (3ha and 3ia)
were obtained in comparable moderate yields. 2-
Benzylchlorobenzene and 2-benzylfluobenzene smoothly
afforded 3ka and 3ma in good yields (83% and 81%, respectively).
However, 4-benzylchlorobenzene and 4-benzylfluorobenzene
showed much poorer reactivity under the same conditions;
alkylation products 3ja and 3la were obtained in very low yields,
even when the catalyst loading was increased to 20 mol %. The
halogen effect of the diarylmethanes was similar to that of
to styrene to give alkylation products 3na–3qa. 4-Benzylpyridine
was also subjected to the reaction but failed to give the alkylation
product. The distinct reactivity between 2-benzylpyridine and 4-
benzylpyridine revealed that the strong coordination between
pyridine and the catalyst could facilitate or prevent the alkylation
reaction. Indene and fluorene failed to undergo the catalytic
alkylation reaction either, mainly because of the formation of less
nucleophilic indenyl and fluorenyl metal intermediates. To test the
practicability further, we carried out the reaction between
diphenylmethane and styrene on a gram scale, and the product
was obtained in high yield (88%, see Supporting Information).
We were intrigued by the fact that a para halogen substituent
greatly inhibited the potassium-zincate-catalyzed C–H bond
alkylation reaction, whereas an ortho halogen had little effect. We
suspected that the inhibitory effect of a para halogen was due
mainly to an electronic or coordination effect rather than to a steric
effect. To explore this possibility, chlorobenzene was added as an
additive and the catalytic alkylation reaction between
diphenylmethane and styrene was greatly suppressed (Scheme
4a). This result could rule out the electronic effect, suggesting that
coordination of chlorobenzene to the catalyst might account for
the inhibitory effect. Competitive reactions indicated that 2-
benzylpyridine and 2-benzylchlorobenzene reacted faster than
diphenylmethane (see Supporting Information). A coordinative
interaction could well explain these behaviors of the ortho-
substituted
styrenes
(3ah–3am).
Diarylmethanes
with
heterocyclic moieties were also allowed to react with styrene.
Specifically, xanthene, benzylferrocene, 2-benzylpyridine and 2-
benzylthiophene smoothly underwent catalytic C–H bond addition
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rate-determining step.
On the basis of the above-described results, we propose the
reaction pathway shown in Scheme 5. The potassium zincate
complex KZn(HMDS)2Bn synthesized by the reaction between
potassium benzyl and zinc amide deprotonates diphenylmethane
to afford the actual catalytic species (intermediate A), a
diphenylmethine potassium zincate species. Reaction between
styrene and A generates new potassium zincate complex B.
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Subsequent
deprotonation
of
another
molecule
of
diphenylmethane by B releases the alkylation product and
regenerates intermediate A for another catalytic cycle. The nature
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with regard to the synergic interaction between zinc and
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In summary, we have achieved the first catalytic C–H bond
addition of diarylmethanes to styrenes. A potassium zincate
complex generated from potassium benzyl and zinc amide shows
unique catalytic activity. Because no bases or oxidants were
required, this reaction represents a practical, atom-economical
process for diarylalkane synthesis. Exploration of additional
catalytic applications of the potassium zincate complex and
mechanistic studies are currently underway in our laboratory.
Acknowledgements ((optional))
We gratefully acknowledge the State Key Laboratory of
Elemento-Organic Chemistry for generous start-up financial
support. We are also thankful for support from National Program
for Support of Top-notch Young Professionals. This project was
supported by the NSFC (21372123).
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Keywords: potassium zincate • catalysis • diparylmethane •
alkylation • styrenes
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Arene Chemistry: Reaction Mechanisms and Methods for Aromatic
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10.1002/anie.201713165
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[13] The NMR spectra consistent well with the potassium zincate complex
synthesized by Mulvey. W. Clegg, G. C. Forbes, A. R. Kennedy, R. E. Mulvey,
S. T. Liddle, Chem. Commun. 2003, 406-407.
123, 9968–9999.
[12] KBn was synthesized by deprotonation of toluene by KOBut/nBuLi. This
deep red powder could be well kept and easily handled under inert
atmospheres, such as nitrogen and argon. a) L. Lochmann, J. Trekoval, J.
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10.1002/anie.201713165
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COMMUNICATION
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Potassium zincate catalyzed: A catalytic addition of benzylic C-H bond of
diarylmethanes to styrenes and conjugated dienes was achieved for the first time by
using a potassium zincate catalyst.
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