Lithium Diisopropylamide Catalyzed Allylic C-H Bond Alkylation with Styrenes

Article abstract of DOI:10.1021/acs.orglett.8b03108

Allylic substitution reactions, a well-established approach for new bond construction, often need transition-metal catalysts and stoichiometric amounts of organometallic reagents, strong bases, or oxidants. Lithium diisopropylamide (LDA), a widely used and commercially available Br?nsted base, is herein reported to catalyze the allylic C-H bond addition of 1,3-diarylpropenes to styrenes. Preliminary mechanism studies have provided a solid structure of the π-allyllithium intermediate and revealed the unique catalytic roles of LDA and its conjugate acid diisopropylamine.

Full text of DOI:10.1021/acs.orglett.8b03108

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Lithium Diisopropylamide Catalyzed Allylic C−H Bond Alkylation
with Styrenes
Xiang-Yu Zhang,† Lei Zheng,† and Bing-Tao Guan*,†,‡
†State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin 300071,
China
‡Collaborative Innovation Center of Chemical Science and Engineering, Nankai University, Tianjin 300071, China
S
* Supporting Information
ABSTRACT: Allylic substitution reactions, a well-established
approach for new bond construction, often need transition-
metal catalysts and stoichiometric amounts of organometallic
reagents, strong bases, or oxidants. Lithium diisopropylamide
(LDA), a widely used and commercially available Brønsted
base, is herein reported to catalyze the allylic C−H bond
addition of 1,3-diarylpropenes to styrenes. Preliminary mechanism studies have provided a solid structure of the π-allyllithium
intermediate and revealed the unique catalytic roles of LDA and its conjugate acid diisopropylamine.
reagents such as Zn, In, SnCl2, SmI2, Et2Zn, and Et3B (Scheme
1c).5 These reagents are incompatible with the oxidation
conditions of allylic C−H bond activation, and so the
umpolung reactions prefer to take place with substrates
bearing a leaving group at the allylic position rather than a
simple alkene. Allyl stannanes, allyl silanes, and allyl boron
compounds have also been reported to undergo transition-
metal-catalyzed electrophilic substitution reactions via nucle-
ophilic π-allyl intermediates.6,7 The direct synthesis of the
nucleophilic π-allyl metal intermediates can also be achieved
via either the metalation of allyl halides with main group metals
or the deprotonation of an allylic C−H bond with strong base
reagents (Scheme 1d,e).8−10 Even though versatile approaches
have been reported for the allylation reactions, these methods
have the disadvantages of requiring transition-metal catalysts
and stoichiometric amounts of organometallic reagents, strong
bases, or oxidants. Therefore, mild, atom-economical methods
for allylation would be highly desirable.
ransition-metal-catalyzed allylic substitution reactions are
Twell established as one of the most important and reliable
methods for C−C and C−X bond construction reactions.1
Generally, an olefin bearing an allylic leaving group is necessary
for oxidative addition with a low-valent transition-metal
complex to produce an electrophilic π-allyl intermediate,
which then undergoes nucleophilic substitution with release of
the catalyst (Scheme 1a).2 The electrophilic transition-metal π-
allyl intermediates can also be obtained via direct allylic C−H
bond activation (Scheme 1b). However, a stoichiometric
amount of an oxidant is indispensable to achieve the catalytic
transformation.3,4 The umpolung of electrophilic π-allyl metal
species can actually take place via the reactions with
stoichiometric amounts of reductants or organometallic
Scheme 1. Allylic C−H Bond Functionalization Reactions
Brønsted base-catalyzed C−C bond formation reactions
have been extensively used in organic synthesis for their
reliability, high efficiency, and ideal atom economy.11
Kobayashi and co-workers have broadened the scope of the
nucleophiles to simple esters, amides, alkylnitriles, alkylazaar-
enes, and alkanesulfonamides by using a strong Brønsted base
such as KH or KHMDS as catalyst.12 Schneider and co-
workers recently reported the first catalytic C−H addition of
allylbenzenes to imines with NaHMDS as a catalyst (Scheme
1f).13 The catalytic alkylation of weakly acidic C−H bonds was
also reported by Pines, Knochel, and Kobayashi with styrenes
as electrophiles.14 Very recently, we investigated the base-
catalyzed alkylation of alkylpyridines and diarylmethanes.15
Received: September 29, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03108
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Herein, we further report the catalytic allylic C−H bond
alkylation reaction with styrenes (Scheme 1g).
Scheme 2. Substrate Scope of Styrenes
We first investigated the reaction of 1,3-diphenylpropene
(1a) with styrene (2a) in toluene with 10 mol % of KHMDS
or potassium zincate, which were efficient catalysts in the
alkylation of alkylpyridines or diarylmethanes.15,16 After being
heated at 40 °C for 48 h, the reactions gave the desired
alkylation product but in low yields (Table 1, entries 1 and 2).
a
Table 1. Optimization of Reaction Conditions
b
entry
catalysts
KHMDS
KZn(HMDS)2Bn
KOtBu
NaHMDS
LiHMDS
KTMP
solvent
yield (%)
1
2
3
4
5
6
7
8
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
benzene
hexane
THF
17
19
<5
<5
<5
<5
<5
23
11
9
92
<5
91
78
8
NaTMP
LiTMP
a
Conditions: 1,3-diphenylpropene (1a) (0.3 mmol), styrenes (2)
(0.36 mmol), LDA (10 mol %), toluene (0.5 mL), 40 °C, 60 h;
9
KNiPr2
10
11
12
13
14
15
NaNiPr2
b
c
d
isolated yields are based on the amount of 1a. 72 h. 96 h. LDA (20
LiNiPr2 (LDA)
LiCH2SiMe3
LiNiPr2 (LDA)
LiNiPr2 (LDA)
LiNiPr2 (LDA)
mol %).
c
also attempted to raise the reaction temperature to accelerate
the reaction, but multiple styrene insertion products were
detected. The synthesis of the allylic alkylation product 3aa
was reported by coupling reactions but needed allylic
carbonate substrates, transition-metal catalysts, and phosphine
ligands.18
d
a
Conditions: 1,3-diphenylpropene (1a) (0.3 mmol), styrene (2a)
b
(0.36 mmol), catalyst (10 mol %), solvent (0.5 mL), 40 °C, 48 h. 1H
NMR yields based on 1a with 1,3,5-trimethoxybenzene as an internal
standard. Oligomerization of styrene was observed. 64% conversion
of 1a, double and triple styrene insertion products were detected with
GC−MS. HMDS = bis(trimethylsilyl)amide, TMP = 2,2,6,6-
tetramethylpiperidide.
c
d
Having the optimized conditions in hand, we examined the
styrene scope of the LDA-catalyzed alkylation of 1,3-
diphenylpropene (Scheme 2). 2-Vinylnaphthalene, 4-phenyl-
styrene, 4-tert-butylstyrene, 2-methoxylstyrene, 4-methoxylstyr-
ene, 2-methylstyrene, 3-methylstyrene, and 4-methylstyrene all
smoothly underwent the reaction and afforded the correspond-
ing alkylation products (3ab−ai) in good to high yields. 2-
Methylstyrene and 2-methoxystyrene displayed similar good
reactivity with their para-substituted analogues, which means
that the steric hindrance in the styrenes has little effect on the
reaction. Chlorostyrenes were also subjected to the alkylation
reaction but showed poor reactivity. By prolonging the
reaction time, 3-chlorostyrene and 2-chlorostyrene provided
the alkylation products in moderate and good yields (3aj−ak).
4-Chlorostyrene, however, failed to achieve the alkylation
catalytically (3al). The possible reason might be the inhibitory
effect resulting from the coordination interaction between the
chlorine atom and the lithium metal center.15b
Various substituted 1,3-diarylpropenes were evaluated in the
LDA-catalyzed allylic C−H alkylation reaction with styrene
(Scheme 3). 1,3-Di-p-tolylpropene, 1,3-di-m-tolylpropene, 1,3-
di-o-tolylpropene, and 1,3-bis(4-tert-butylphenyl)propene
smoothly reacted with styrene and afforded the alkylation
products in good to high yields (3ba−ea). Rather than leading
to a sluggish reaction due to increased steric hindrance, the o-
methyl group of 1,3-diarylpropene actually gave the alkylation
product in an even better yield (3da). 1,3-Di(thiophene-2-
yl)propene and 1,3-di(naphthalen-1-yl)propene could also
undergo the catalytic reaction under enhanced conditions
Some other widely used Brønsted bases were also tested as
catalysts in the reaction. KOtBu, NaHMDS, LiHMDS, KTMP,
and NaTMP failed to provide any alkylation product (entries
3−7). Compared with KTMP and NaTMP, LiTMP could
catalyze the alkylation reaction and gave the product in 23%
yield (entries 6−8). Using KDA and NaDA as catalyst, the
alkylation products were obtained only in yields of about 10%
(entries 9 and 10). We were pleased to find that LDA (lithium
diisopropylamide) efficiently catalyzed the reaction and gave
the alkylation product in a high yield of 92% (entry 11). Since
it is a commonly encountered reagent, LDA was extensively
studied but mostly used as a reagent rather a catalyst.17 Even
stronger Brønsted base alkyllithium reagents were studied as
reaction catalysts. However, the styrene underwent oligome-
rization easily but left the 1,3-diphenylpropene intact (entry
12). The LDA-catalyzed alkylation reaction also took place in
benzene to give a yield comparable to that of toluene (entry
13). Hexane could achieve the catalytic alkylation but not as
efficiently as toluene or benzene (entry 14). In THF, 64% of
1,3-diphenylpropene was consumed, but the desired product
was produced in only 8% yield. The double styrene insertion
product could also be detected with GC−MS, which suggested
the easy multiple insertion of styrene (entry 15). Prolonging
the reaction time to 60 h actually led to the alkylation product
in an even higher isolated yield of 94% (Scheme 2, 3aa). We
B
DOI: 10.1021/acs.orglett.8b03108
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 3. Substrate Scope of 1,3-Diarylpropenes
Scheme 4. Control Experiments
shown in Figure 1. In the solid state, the complex is composed
of a 1,3-diphenylallyl anion and a cationic [Li(THF)]+ moiety.
a
Conditions: 1 (0.3 mmol), styrene (2a) (0.36 mmol), LDA (10 mol
%), toluene (0.5 mL), 40 °C, 60 h; isolated yields are based on the
b
c
d
amount of 1. LDA (20 mol %). 96 h. 100 °C.
and gave the alkylation products in moderate yields (3fa−ga).
1,3-Bis(4-methoxyphenyl)propene and 1,3-bis(3-methoxy-
phenyl)propene were subjected to the reaction, and the
alkylation products were obtained in moderate and low yields
even under elevated temperature (3ha−ia). 1,3-Bis(2-
methoxyphenyl)propene was also tested but failed to provide
any alkylation product. 1-(2-Methoxyphenyl)-3-phenylpropene
and 3-(2-methoxyphenyl)-1-phenylpropene smoothly reacted
with styrene, and both isomers gave the same alkylation
product 3ja with good efficiency and regioselectivity. This
result suggested that the deprotonation of the allylic C−H
bond took place easily to provide a delocalized allylic lithium
species, which could be a key intermediate in the catalytic
alkylation reaction. Allylbenzene was also subjected into the
reaction with styrene but failed to provide alkylation product
selectively.19 To evaluate the practicability of this reaction, the
catalytic allylic C−H alkylation of 1,3-diphenylpropene (1a)
was carried out on gram scale with styrene (2a), and the
alkylation product was obtained in 80% yield (Supporting
Information).
We measured the initial rates of the catalytic alkylation
reaction of 1-(2-methoxyphenyl)-3-phenylpropene (1j) and its
deuterated analogue (1j-d7) under exactly the same conditions
(Scheme 4). The kinetic isotope effect value (kH/kD = 2.0)
suggested that the cleavage of the allylic C−H bond is the rate-
determining step. To gain insight of this catalytic trans-
formation, we further carried out the control experiments and
monitored them with 1H NMR and 7Li NMR. The
deprotonation reaction of 1,3-diphenylpropene with LDA in
C6D6 took place slowly at room temperature. After about 4 h,
the deprotonation was complete and produced a mixture of
diisopropylamine and an allyllithium intermediate. Further
addition of styrene into this mixture gave alkylation product
3aa in 78% yield after 19 h and regenerated LDA (see the
Supporting Information). The allyllithium intermediate was
prepared, isolated, and characterized by NMR. A red crystal
suitable for X-ray crystallographic study was obtained from
crystallization in toluene/THF (10/1), and its structure is
Figure 1. Molecular unit of 1a−Li·THF with H atoms omitted for
clarity. Thermal ellipsoids are set at 50% probability. Selected bond
lengths (Å) and angles (deg): Li(1)−O(1) 1.894(3), Li(1)−C(8)
2.302(3), Li(1)−C(9) 2.327(3), Li(1)−C(7) 2.534(3), C(7)−C(8)
1.387(2), C(8)−C(9) 1.397(2); C(1)−C(6)−C(7)−C(8) 3.1(2),
C(8)−C(9)−C(10)−C(11) 2.8(2).
The intermolecular interaction between the lithium atom with
diphenylallyl anion of another unit extends the structure
supramolecularly (see the Supporting Information). All of the
carbon atoms of the two phenyl group are located in the allylic
plane. The lithium atom lies above the plane and coordinates
with the allylic anion in an η3 fashion. It is interesting that this
allyllithium intermediate smoothly underwent the deprotona-
tion reaction with HMDS to produce LiHMDS and 1,3-
diphenylpropene (see the Supporting Information). These
results hint that the basicity of the allyllithium intermediate is
located between that of LDA and LiHMDS. The basicity
difference well explains the quite different behaviors in the
catalytic alkylation reactions (Table 1, entry 5 vs 11). As a
widely used intermediate, allyllithium species have been
extensively studied with NMR analysis. The exact structures,
to our best knowledge, have not been determined.20 Herein,
we reported the first solid structure of a π-allyllithium complex.
The isolated allyllithium intermediate itself could not catalyze
the alkylation reaction but led to the formation of styrene
oligomers. However, in the presence of the diisopropylamine,
the allyllithium species smoothly achieved the catalytic
reaction. These results suggest that the diisopropylamine
generated via deprotonation also plays an important role in the
catalytic transformation.
C
DOI: 10.1021/acs.orglett.8b03108
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Notes
According to the results described above, we propose the
possible mechanism shown in Scheme 5. The catalyst LDA
The authors declare no competing financial interest.
Scheme 5. Proposed Mechanism
ACKNOWLEDGMENTS
■
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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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
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Accession Codes
CCDC 1849989 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: guan@nankai.edu.cn.
ORCID
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Bing-Tao Guan: 0000-0003-0686-4945
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DOI: 10.1021/acs.orglett.8b03108
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