Dimeric Potassium Amide-Catalyzed α-Alkylation of Benzyl Sulfides and 1,3-Dithianes

Article abstract of DOI:10.1021/acs.orglett.9b01994

The first catalytic α-alkylation reaction of benzyl sulfides and 1,3-dithianes with styrenes and conjugated dienes was developed under mild conditions by using a readily available Br?nsted base potassium bis(trimethylsilyl)amide (KHMDS) as catalyst. The reaction displayed good functional group tolerance, high efficiency, and excellent chemoselectivity. A series of desired alkylation products were obtained in good to high yield. Preliminary mechanism studies suggested that two of the potassium amide catalyst molecules worked together in the catalytic cycle.

Full text of DOI:10.1021/acs.orglett.9b01994

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Dimeric Potassium Amide-Catalyzed α-Alkylation of Benzyl Sulfides
and 1,3-Dithianes
Yu-Feng Liu,† Lei Zheng,† Dan-Dan Zhai,† Xiang-Yu Zhang,† and Bing-Tao Guan*,†,‡
†State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry and ‡Collaborative Innovation Center of
Chemical Science and Engineering (Tianjin), Nankai University, Tianjin 300071, China
S
* Supporting Information
ABSTRACT: The first catalytic α-alkylation reaction of benzyl
sulfides and 1,3-dithianes with styrenes and conjugated dienes
was developed under mild conditions by using a readily
available Brønsted base potassium bis(trimethylsilyl)amide
(KHMDS) as catalyst. The reaction displayed good functional
group tolerance, high efficiency, and excellent chemoselectivity.
A series of desired alkylation products were obtained in good to
high yield. Preliminary mechanism studies suggested that two of the potassium amide catalyst molecules worked together in the
catalytic cycle.
electrophiles. For the limited electron-withdrawing effect from
s one of the most important functional groups, a sulfide
Amotif exists widely and plays crucial roles in many a single sulfur atom, the α-H of simple sulfides is much less
acidic than that of 1,3-dithianes. Therefore, simple sulfides are
always considered even less reactive under basic conditions.5
Despite the weakly acidic nature, the α-H of sulfides could
undergo dehydrogenative coupling reactions6 or addition
reactions with activated alkenes7 via a radical mechanism
(Scheme 1, eq 2). However, the radical generation via a
homolytic cleavage strategy always needs stoichiometric
amounts of peroxide, oxidant, or photoirradiation in the
presence of a photocatalyst. Very recently, Hou and co-workers
made a significant breakthrough in the α-functionalization of
sulfides. Using a cationic scandium catalyst, they achieved the
selective C−H alkylation of methyl sulfides with various
alkenes (Scheme 1, eq 3).8 However, styrenes failed to
undergo the catalytic alkylation of methyl sulfides. The
polymerization of styrene took place easily mainly because of
the excellent activity of the scandium catalyst.
bioactive compounds, natural products, organocatalysts, and
functional materials.1 The sulfide synthesis, however, usually
needs complicated processes. Therefore, it is highly desirable
to develop efficient methods for the synthesis and function-
alization of sulfide compounds. Among various synthetic
approaches, α-functionalization of sulfides represents an
important and widely used strategy. For example, the 1,3-
dithiane unit, often considered as a masked carbonyl or
methylene group, was extensively employed in the construction
of many important organic compounds (Scheme 1, eq 1).2−4
Generally, a stoichiometric amount of strong base or more was
necessary to deprotonate the acidic C−H bond to produce the
2-lithio-1,3-dithiane intermediate, which could then undergo
nucleophilic addition or substitution reactions with various
Scheme 1. C−H Functionalization of Sulfides
Brønsted-base-catalyzed C−C bond formation reactions
have been extensively explored for their reliability, efficiency,
and ideal atom economy.9 However, both scopes of the
nucleophiles and the electrophiles are very limited. Pioneering
work of Pines and Knochel achieved the use of styrenes as
electrophiles.10 By using a strong Brønsted base such as KH,
KHMDS, or NaHMDS as a catalyst, Kobayashi and Schneider
further broadened the scope of nucleophiles to weakly acidic
compounds such as esters, nitriles, amides, and alkylazaar-
enes.11 With potassium amide and potassium zincate catalysts,
we recently reported the catalytic benzylic C−H addition of
alkylpyridines and diarylmethanes to styrenes and conjugated
dienes.12 Very recently, the catalytic addition reactions of very
weakly acidic alkylarenes such as toluene were achieved by
Received: June 10, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01994
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Kobayashi and Walsh.13 Generally, 1,3-dithianes and benzyl
sulfides have relative acidic C−H bonds (pKa = 29−39),14 and
their deprotonation with stoichiometric amounts of strong
bases is widely used in various transformations. However, to
the best of our knowledge, no catalytic reaction of 1,3-
dithianes and benzyl sulfides was reported with a catalytic
amount of base. Herein, we for the first time reported a
potassium-amide-catalyzed alkylation of sulfides, including
benzyl sulfides and 1,3-dithianes, with styrenes and conjugated
dienes (Scheme 1, eq 4).
We first examined the reaction between benzyl phenyl
sulfide and styrene with KHMDS catalyst in benzene under 80
°C (Table 1). The alkylation product 3aa was obtained in 86%
Table 1. Optimization of Reaction Conditionsa
Figure 1. Scope of styrenes. (a) Conditions: benzyl phenyl sulfide 1a
(0.6 mmol), 2 (0.5 mmol), KHMDS (0.05 mmol), Et2O (0.5 mL), 40
°C, 24 h. Yields are based on the amount of styrenes. (b) 1a (0.5
mmol), 2p (2.5 mmol), Et2O (0.5 mL), and toluene (0.8 mL), 80 °C,
60 h. Yields are based on the amount of 1a. (c) Ratio determined by
1H NMR. (d) 1a (0.5 mmol), 2q (2.5 mmol), neat, 40 °C, 60 h.
About 28% of 4,1-addition product was observed.
b
entry
catalyst
solvent
temp (°C)
yield (%)
1
2
3
4
5
6
7
8
9
KHMDS
NaHMDS
LiHMDS
KHMDS
KHMDS
KHMDS
KHMDS
KHMDS
KHMDS
KHMDS
benzene
benzene
benzene
toluene
n-hexane
THF
dioxane
Et2O
Et2O
80
80
80
80
80
80
80
80
40
40
86 (80)
<5
<5
85
61
70
63
99
99
in 90% and 93% yields, respectively (3ap−3aq). Some other
olefins including norbornene, 1-hexene, 1-octene, and 1,3-
cyclohexadiene failed to give any alkylation products.
c
10
Et2O
99 (95)
Various substituted benzyl sulfides were then evaluated in
the potassium-amide-catalyzed alkylation reactions with
styrene (Figure 2). The sulfides bearing various substituents,
such as phenyl, tert-butyl, methyl, flouro, methoxyl, and chloro
a
Conditions: Benzyl phenyl sulfide 1a (0.75 mmol), styrene 2a (0.5
b
mmol), catalyst (0.05 mmol), solvent (0.5 mL), 12 h. NMR yields
based on styrene with 2-methoxynaphthalene as an internal standard.
Isolated yields in parentheses. 1a (0.6 mmol), 24 h.
c
yield (entry 1). Sodium or lithium amides failed to afford any
alkylation products (entries 2 and 3). The reaction in toluene
gave the product in a comparative yield (entry 4). The use of
n-hexane, THF, and dioxane as solvents led to lower yields of
61−70% (entries 5−7). It was gratifying that diethyl ether as a
solvent afforded the alkylation product in 99% yield, even
under a lower temperature (entries 8 and 9). With decreasing
amount of sulfide, the catalytic alkylation reaction smoothly
took place under 40 °C in Et2O to give the alkylation product
in 95% yield with prolonged reaction time (entry 10). The
reaction was easily scalable to gram scale in high yield (1.38 g,
91%, see Supporting Information).
With the optimized conditions in hand, we explored an array
of substituted styrenes to test the generality of the reaction
(Figure 1). The reactions of 2-vinylnaphthalene, 4-phenyl-
styrene, 4-tert-butylstyrene, 4-methylstyrene, 3-methylstyrene,
and 2-methylstyrene with benzyl phenyl sulfide took place
smoothly and afforded the desired alkylation products in good
yields (3ab−3ag). Halogenated styrenes including chlorostyr-
enes and fluorostyrenes gave the alkylation products in good to
high yields (3ah−3am). It seems that the alkylation reaction of
sulfides was not so sensitive to halogen atoms as the reaction of
alkylpyridines and diarylmethanes.12 2-Methoxylstyrene could
react with benzyl phenyl sulfide efficiently to give the desired
product 3ao in 96% yield. 4-Methoxylstyrene, however, was
not so reactive and afforded the alkylation product in a much
lower yield (3an). Besides, conjugated dienes such as
butadiene and isoprene successfully gave allylation products
Figure 2. Scope of benzyl sulfides. (a) Conditions: 1 (0.6 mmol), 2a
(0.5 mmol), KHMDS (0.05 mmol), Et2O (0.5 mL), 40 °C, 24 h.
Yields are based on the amount of styrene. (b) 1 (0.75 mmol), THF
(0.5 mL) as solvent, 80 °C.
B
DOI: 10.1021/acs.orglett.9b01994
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
groups, on the benzylic ring smoothly underwent the catalytic
reaction to give the alkylation products in good to high yields
(3ba−3ia). Substituted aryl benzyl sulfides were also allowed
to react with styrene, and the corresponding alkylation
products were obtained in good yields (3ja−3qa). The methyl
group on either ortho- or para-position of the phenyl ring
showed little effect (3la−3ma). However, the chloro and
methoxyl group on the ortho-position resulted in much better
yields (3na vs 3oa, 3pa vs 3qa). It is possible that the bidentate
coordination from the ortho-heteroatom and sulfur atom to the
metal catalyst would facilitate the catalytic alkylation reaction.
Benzyl alkyl sulfides, which were supposed to have much less
acidic benzylic C−H bonds than benzyl aryl sulfides,5f were
also subjected to the catalytic alkylation. The reaction of
benzyl methyl sulfide under the same conditions, however,
gave the alkylation product in 23% yield. Under 80 °C in THF
(see Supporting Information), benzyl alkyl sulfides proved to
be good substrates, providing the expected alkylation products
(3ra−3ua) in good yields.
aromatic rings including 2-naphthyl, 2-ferrocenyl, 2-pyridyl,
and 2-thienyl could undergo the catalytic reactions and afford
the alkylation products in high yields (5ja−5ma). 1,3-Dithiane
with much weaker acidic α-C−H bond (pKa = 39 in DMSO)
could also undergo the catalytic reaction to afford the
alkylation product in high yield under an elevated temperature
of 110 °C in toluene (5na, see Supporting Information).
Bis(methylthio)methane and bis(phenylthio)methane were
also available substrates and gave the alkylation products in
moderate yields (5oa−5pa). To further expand the applica-
tion, we carried out the deprotection reactions of 3aa and 5aa
to get 1,3-diphenylpropane and 1,3-diphenylpropan-1-one in
high yield (87% and 94%, see Supporting Information). Thus,
combined with the reduction of sulfides and deprotection of
1,3-dithianes, this method could provide a traceless directing
strategy for the synthesis of aryl alkyl ketones and
alkylbenzenes, whose synthesis usually needs transition metal
catalysts and redox process.15
To gain further insight into the reaction process, we
measured the reaction rates with sulfide (1a) and the
deuterated sulfide (1a-d7) under the exactly same conditions
(Scheme 2, eqs 5−6). The observed typical primary kinetic
Considering the wide application of 2-phenyl-1,3-dithiane
and also its acidic C−H bonds (pKa = 30.7 in DMSO), we
further tested it in the catalytic reaction. The reaction between
2-aryl-1,3-dithianes and styrene smoothly took place with 5
mol % of KHMDS catalyst, providing the alkylation product in
high yield (Figure 3, 5aa). Various 2-aryl-1,3-dithianes bearing
Scheme 2. Control Experiments
isotope effect (KIE) value of 2.3 suggested that the cleavage of
the benzylic C−H bond of sulfide is involved in the rate-
determining step.8 No obvious deprotonation reaction was
detected with the reaction between benzyl phenyl sulfide and
KHMDS (see Supporting Information). However, a red oil
formed during removing the volatiles from the mixture. The
NMR analysis suggested that to be a deprotonation
intermediate, it must contain an amide anion (Scheme 2, eq
7). The deprotonation of sulfide (1a) with BuLi and KOtBu in
n-hexane gave an orange precipitate (Scheme 2, eq 8, K-1a),
which was subjected to the reaction as a catalyst but failed to
achieve the alkylation reaction. Once treated with KHMDS,
the undissolved orange solid was dissolved in Et2O and
afforded a red solution. After removing the solvent, a red oil
was obtained and proved to be the same intermediate (K-1a·
KHMDS) as found in eq 7, which could successfully catalyze
the alkylation reaction and might be the true catalyst. The two
intermediates (K-1a and K-1a·KHMDS) were further
demonstrated to be alkyl potassium intermediates for their
protonation in C6D6 with HMDS and gave mixtures of sulfide
(1a) and KHMDS. We have made great efforts to get the
crystal but unfortunately made little headway so far. In an
Figure 3. Scope of 1,3-dithianes. (a) Conditions: 4 (0.5 mmol), 2a
(0.75 mmol), KHMDS (0.025 mmol), Et2O (0.5 mL), 40 °C, 24 h.
Yields are based on the amount of 4. (b) 2a (0.5 mmol), 4n (0.75
mmol), KHMDS (0.1 mmol), toluene (0.5 mL), 110 °C, 48 h. Yields
are based on the amount of styrene. (c) 2a (0.5 mmol), 4o or 4p
(0.75 mmol), KHMDS (0.1 mmol), THF (0.5 mL), 80 °C, 48 h.
Yields are based on the amount of styrene.
either electron-donating or electron-withdrawing groups
smoothly underwent the catalytic alkylation reactions, and
the corresponding products were obtained in high yields
(5aa−5ia). On the contrary to the excellent reactivity of 2-(p-
tolyl)-1,3-dithiane (5ba), 2-(o-tolyl)-1,3-dithiane failed to give
any alkylation product, suggesting that the steric hindrance
from the 2-aryl-1,3-dithiane completely inhibited the catalytic
alkylation reaction. 2-Aryl-1,3-dithianes with some other
C
DOI: 10.1021/acs.orglett.9b01994
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
effort to gain more information on the intermediate (K-1a·
KHMDS), the 1H-DOSY NMR spectrum were performed and
suggested that the KHMDS species and K-1a species did
belong to the same molecule (see Supporting Information).
On the basis of the above-described results, we propose the
reaction pathway shown in Scheme 3. The deprotonation most
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: guan@nankai.edu.cn.
ORCID
Bing-Tao Guan: 0000-0003-0686-4945
Notes
Scheme 3. Plausible Reaction Pathway
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge support from the State Key
Laboratory of Elemento-Organic Chemistry and National
Program for Support of Top-notch Young Professionals. This
project was supported by the NSFC (21372123).
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■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b01994.
Experimental details and characterization data (PDF)
D
DOI: 10.1021/acs.orglett.9b01994
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