Taming living carbocations in catalytic direct conjugate addition of simple alkenes to α,Enones

Article abstract of DOI:10.1002/chem.201402246

A Lewis acid in the presence of an anionic phosphate ligand enables the addition of alkenes to α,enones. The ligand facilitates selective proton elimination by suppressing competing pathways, thus leading to vinylation adducts in high yields (up to 99%) for a broad range of substrates.

Full text of DOI:10.1002/chem.201402246

DOI: 10.1002/chem.201402246
Communication
&
Conjugate Addition
Taming Living Carbocations in Catalytic Direct Conjugate Addition
of Simple Alkenes to a,b-Enones
Jian Lv,[a, b] Xingren Zhong,[a] and Sanzhong Luo*[a, b]
Abstract: A Lewis acid in the presence of an anionic phos-
phate ligand enables the addition of alkenes to a,b-
enones. The ligand facilitates selective b-proton elimina-
tion by suppressing competing pathways, thus leading to
vinylation adducts in high yields (up to 99%) for a broad
range of substrates.
Carbocationic processes of alkenes are widely utilized in the
petrochemical and material industries.[1] In contrast to these
bulk industrial processes, selective CÀC bond formation
through a carbocationic process remains a challenging issue in
organic synthesis, particularly regarding intermolecular reac-
tions with simple alkenes.[2] Under acid catalysis, most elec-
tron-rich/neutral alkenes, including those from industrial feed-
stocks, tend to oligomerize or polymerize (Figure 1A).[3] Ac-
cordingly, cationic functionalizations of alkenes are typically
conducted in the presence of nucleophiles, resulting in electro-
Figure 1. Cationic transformation of simple alkenes.
philic-addition products with Markovnikov selectivity (Fig-
ure 1B).[4] In this context, a long-standing challenge in cationic
functionalization of alkenes is achieving selective b-proton
arranged products instead of vinylation adducts.[6] Previously,
elimination of the carbocationic intermediate whilst suppress-
ing cationic polymerization and nucleophilic interception (Fig-
ure 1C). Such a process would lead to synthetically appealing
vinylation products and has the potential of becoming a very
effective method for the introduction of an alkenyl group at
the b-position of ketones derived from abundant and inexpen-
sive alkenes.[5,6a]
a stoichiometric amount of Lewis acid was reported to pro-
mote the addition of alkenes to a,b-enones to give also
double-bond-shifted products.[7] Recently, an intermolecular
version was realized with a special class of enones and in this
case a silyl group was introduced onto the b-position of
enones in order to facilitate b-proton elimination.[8] General
methods for the intermolecular addition of simple alkenes to
a,b-enones remains elusive so far.
As well as the aforementioned pitfalls, the low nucleophilici-
ty of alkenes in acid-mediated processes has caused them to
be seldom utilized as nucleophiles in acid-catalyzed conjugate
additions. Advances along this line are mainly achieved with
transition metals, such as Pd, Ni, and Ru, but the use of such
metals in these reactions sometimes leads to double-bond re-
Herein, we present strategy whereby an anionic ligand is
used to tame living carbocations in Lewis-acid-catalyzed direct
conjugate addition of alkenes to enones. In this strategy, the
anionic ligand has two roles: it tunes the Lewis acidity of the
metal center and it stabilizes the developing carbocations
through an ion-pair effect. We hypothesized that such a stabi-
lizing effect would help suppress the polymerization or nucleo-
philic interception processes, thereby facilitating selective b-
proton elimination. This concept bears origins in other carbo-
cationic processes such as electrophilic polyene cyclization cat-
alyzed by terpene cyclases, wherein phosphate and carboxyl-
ate serve as ligands and balancing anions.[9] A similar counter-
anion effect has also been well utilized in living cationic poly-
merizations.[1a,10] However, the use of anionic ligands in carbo-
cationic CÀC bond formation has not been reported so far. In
our studies, the use of a phosphate ligand has been found to
[a] Dr. J. Lv,+ X. Zhong,+ Prof. Dr. S. Luo
Beijing National Laboratory for Molecular Sciences (BNLMS)
CAS Key Laboratory of Molecular Recognition and Function
Institute of Chemistry, Chinese Academy of Sciences
Beijing, 100190 (P.R. China)
[b] Dr. J. Lv,+ Prof. Dr. S. Luo
Collaborative Innovation Center of Chemical Science and
Engineering (Tianjin), Tianjin, 300071 (P.R. China)
E-mail: luosz@iccas.ac.cn
[+] These authors contributed equally to this work.
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201402246.
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Communication
enable direct alkene addition to a,b-enones, affording vinyla-
tion adducts through selective b-proton elimination mecha-
nism.
Table 2. Scope of a,b-unsaturated ketones 2.[a]
Direct conjugate addition of styrene 2a to chalcone 3a was
chosen as a model reaction to test the catalytic activity of the
Lewis acid/anionic ligand complex. We were able to identify
a viable complex composed of FeCl3 and phosphate 1a.[11]
Under optimized conditions, the desired vinylation adduct 4aa
can be isolated in quantitative yield (>99% yield, Table 1,
Entry
R1
R2
Product
Yield [%][b]
1
2
3
4
5
6
7
8
Ph
Ph
Ph
4-MeC6H4
Ph
4-ClC6H4
Ph
Ph
CH3
CH3
CH3
CH3
CH3
4aa
4ba
4ca
4da
4ea
4 fa
4ga
4ha
4ia
4ja
4ka
4la
4ma
4na
99
99
99
99
81
93
77
76
62
48
86
99
90
86
4-ClC6H4
4-MeC6H4
Ph
4-ClC6H4
4-BrC6H4
4-MeC6H4
3-MeC6H4
2-ClC6H4
CH3
Table 1. Influence of reaction parameters on the catalytic conjugate addi-
tion of styrene 3a to enones 2a.
9
10
11
12
13
14
CH3
Ph
CH3
CH3
CH3
nC3H7
Entry
Variation from standard conditions[a]
Yield [%][b]
[a] Reaction conditions: FeCl3 (10 mol%), 1a (10 mol%), 2a (0.2 mmol)
and 3a (2.0 mmol) at 1008C in PhCH3 (2.0 mL). Reaction time: entries 1–5
and 12 for 24 h; entries 6–11, 13, and 14 for 48 h. [b] Yields of isolated
products.
1
2
3
4
5
6
7
standard conditions
no FeCl3
no 1a
>99
NR
NP
<10
58
20 mol% 1a
1b instead of 1a
sodium citrate instead of 1a
NaBArF
64
71
plied to give the desired vinylation adducts in good yields
(Table 2, entries 1–5). Methyl styryl ketones and phenyl propen-
yl ketone work well in the reactions (Table 2, entries 6–12), al-
though enones bearing an electron-donating aryl moiety gave
relatively low yields (Table 2, entries 9 and 10). Moreover, ali-
phatic a,b-unsaturated ketones, such as (E)-3-penten-2-one
(2m) and (E)-3-hepten-2-one (2n), also reacted smoothly with
styrene to give the expected adducts in good yields (Table 2,
entries 13 and 14). Unfortunately, for Z-configured a,b-
enones,[12] such as cyclohex-2-enone or cyclopent-2-enone,
only trace amounts of product were detected.
8
9
10
11
12
13
NaBF4 instead of 1a
1c instead of 1a
1c instead of 1a (30 mol% of 1c)
DCE
EtOH
808C
28
65
trace
21
NR
54
[a] Standard reaction condition: FeCl3 (10 mol%), 1a (10 mol%), 2a
(0.1 mmol), and 3a (1.0 mmol) at 1008C in PhCH3 (1.0 mL) for 24 h.
[b] Determined by 1H NMR analysis with an internal standard, 1,3,5-trime-
thoxybenzene. NaBArF =sodium tetrakis[3,5-bis(trifluoromethyl)phenyl]bo-
rate. NR=no reaction. NP=no product.
Variation of the alkene partner was also explored (Table 3).
Different styrenes bearing either electron-withdrawing or elec-
tron-donating groups are applicable in the reactions, with the
latter affording generally lower yields owing to polymerization,
a consequence of their electron-rich nature (Table 3, entries 9
and 10). Notably, electron-rich styrenes reacted more cleanly
with aliphatic enones to give the expected adducts in high
yields (Table 3, entries 11 and 12). Furthermore, 1,1-diphenyl-
ethylene (Table 3, entry 13) and indene (Table 3, entry 14) can
also be applied to give vinylation adducts in high yields. In the
case of 1,1-diphenylethylene, only 2 mol% of catalyst loading
was sufficient to promote a smooth reaction in CH2Cl2 at room
temperature. Unfortunately, industrial-feedstock alkenes, such
as isobutene, showed low reactivity (<10% yield, as deter-
entry 1). Virtually no reaction occurred in the absence of FeCl3
(Table 1, entry 2) or by using other Lewis acids (see Table S1 in
the Supporting Information). Polymerization occurred in the
absence of 1a (Table 1, entry 3). When the loading of 1a was
increased to 20 mol%, the reaction was seriously retarded
likely due to the attenuated Lewis acidity (<10% yield,
Table 1, entry 4). The use of free acid 1b was found to be infe-
rior to its sodium salt 1a (Table 1, entry 5). Other anionic li-
gands such as sodium citrate or simple salts such as NaBArF
and NaBF4, were less effective under these conditions (<71%
yield, Table 1, entries 6–8). The exchange of ClÀ for phosphate
was also examined by mixing FeCl3 and silver phosphate 1c in
situ; the obtained phosphate complex was found to be less ef-
fective than FeCl3/1a (Table 1, entries 9 and 10 versus entry 1).
The reaction was optimized in terms of solvent and reaction
temperature; the use of toluene as solvent and a reaction tem-
perature less than 1008C was found to be optimal (Table 1, en-
tries 11–13 versus 1).
1
mined by H NMR spectroscopy).
In order to define the roles of anionic ligand 1a, kinetic
studies were carried out by monitoring the reactions by using
in situ IR (Figure 2). Styrene polymerized easily by using FeCl3
in the absence of ligand 1a, the polymerization being com-
plete within five minutes (Figure 2A, a). In comparison, in the
presence of ligand 1a, the polymerization was five times
slower (Figure 2A, b). In the reaction with enone 2a, significant
With optimized conditions established, we next explored the
substrate scope. As shown in Table 2, chalcones bearing either
electron-withdrawing or -donating groups can be equally ap-
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Table 3. Scopes of alkenes 3.[a]
Entry
R1
R2
3
Product
Yield [%][b]
1
2
3
4
Ph
4-ClC6H4
CH3
nC3H7
2o
Ph
4-MeC6H4
Ph
Ph
3b
3b
3b
3b
3b
3c
3d
3e
3 f
3 f
3 f
3g
3h
3i
4ab
4 db
4lb
4nb
4ob
4ac
4ad
4ae
4df
4lf
85
97
77
64
95
52
83
58
52
52
98
82
97
89
CH3
5
6[c,d]
7
4-MeC6H4
4-MeC6H4
4-MeC6H4
Ph
Ph
CH3
CH3
4-ClC6H4
4-ClC6H4
Ph
Ph
8[c]
9[e]
10[e]
11[e]
12
13[f]
14
4-ClC6H4
CH3
nC3H7
nC3H7
Ph
4nf
4 ng
4ch
4ci
Ph
[a] Reaction conditions: FeCl3 (10 mol%), 1a (10 mol%), 2a (0.2 mmol),
and 3 (1.0 mmol) at 1008C in PhCH3 (2.0 mL). Reaction time: entries 1–5,
9–12, and 14 for 24 h, entries 6–8 and 13 for 48 h. [b] Yields of isolated
products. [c] With
3 (2.0 mmol). [d] At 1208C. [e] At 608C. [f] FeCl3
(2 mol%), 1a (2 mol%), 2a (0.2 mmol), and 3 (0.6 mmol) at room temper-
ature in CH2Cl2 (2.0 mL).
polymerization was still observed particularly upon gradual
consumption of enone 3a (Figure 2B, a). Polymeric adduct
4aa’ (Mn =1.38ꢁ103, Mw/Mn =1.54) was isolated as the major
product from the reaction mixture. As can be seen from Fig-
ure 2B, the effect of ligand is also quite evident and the poly-
merization can be largely inhibited in the presence of 1a. Fur-
ther inspection of the kinetic behavior of both styrene 3a (Fig-
ure 2B) and enone 2a (see Figure S2 in the Supporting Infor-
mation) reveal that the reaction appears to be zero order in
both substrates. This result indicates that CÀC bond formation
is not the rate limiting step, which likely resides prior to or
after CÀC bond formation. In control reactions, isolated vinyla-
tion adduct 4ab was subjected to the catalytic conditions in
the presence of styrene 3b (Figure 2C). With only FeCl3, the
polymerization of adduct 4ab and para-chlorostyrene oc-
curred, reaching 100% conversion in 24 h and no 4ab can be
recovered. When phosphate 1a was added, 95% of the initial
product 4ab was recovered. Taken together, these results high-
light the critical role of the anionic ligand in suppressing the
polymerization of both the starting alkenes and the resulted vi-
nylation products.
Figure 2. Conversion of styrene 3a tracked by the changes of the peak at
1632 cmÀ1 (nC of styrene): (A) without the enone 2a. (B) with the enone
2a. (C) Control reactions with isolated vinylation adduct 4ab.
=
C
Scheme 1. The proposed catalytic cycle.
To account for the experimental observations, preferential
stabilization of the carbocationic intermediate with phosphate
anion has been proposed for the direct conjugate addition
(Scheme 1). The reaction occurs through direct nucleophilic ad-
dition of alkene to a rapidly equilibrated Lewis acid–enone
complex, which generates carbocationic intermediate I. The
carbocation I undergoes selective b-proton elimination, likely
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mediated by the phosphate anion (Figure 1C), followed by
protonation to deliver adduct 4. In this catalytic cycle, phos-
phate, for example, 1a, has two roles, namely, that of a ligand
that modulates the Lewis acidity of the metal and that of an
anionic nucleophile stabilizing the developing living carbocat-
ion. The critical stabilizing effect of the FeCl3/1a complex in
maintaining a living carbocation can be further verified by
a deuterium-exchange experiment. When isolated adduct 4ab
was treated with [D2]-3a (10 equiv) under catalytic conditions,
substantial deuterium incorporation in 4ab was observed
(Scheme 2, eq. 1), and meanwhile 4ab can be recovered quan-
foundation for the explorations of other cationic alkene func-
tionalization and as well as their catalytic asymmetric ver-
sions.[13]
Experimental Section
General procedure for the preparation of product 4
To a dry reaction tube was added FeCl3 (10 mol% loading), 1a
(10 mol%), enone 2a (0.2 mmol), and anhydrous PhCH3 (2.0 mL).
While the reaction mixture was being stirred, styrene 3a
(2.0 mmol) was added in one portion. The reaction mixture was
stirred for 24 h at 1008C. After cooling to room temperature, the
mixture was purified by flash chromatography on silica gel to
afford the desired product 4aa as clear, colorless oil.
Acknowledgements
We gratefully acknowledge the Natural Science Foundation of
China (21390400, 21025208 and 21202170) and the Ministry of
Science and Technology (2012CB821600) for financial supports.
Keywords: alkenes · anionic ligands · iron · vinylation
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[13] The use of 1a gave racemic products. Initial examinations with 3,3’-sub-
stituted 1a ligands led to product moderate 35% ee. Further work is
underway.
Scheme 2. Deuterium-labelling experiments.
titatively. In this context, the small amount of polymerization
of [D2]-3a provides the deuterium ion for proton exchange.
The proton elimination step in the catalytic cycle was further
investigated in labelling experiments. We first measured the ki-
netics for the reactions of enone 2a with styrene 3a and sty-
rene [D2]-3a, respectively, by in situ IR. A large primary kinetic
isotope effect, kH/kD =2.6, was obtained (see Figure S3 in the
Supporting Information), which is consistent with a rate-limit-
ing b-proton elimination. The observation of zero-order kinet-
ics for both styrene and enone is clearly in line with this con-
clusion. Styrenes (Z)-[D1]-3a and (E)-[D1]-3a were also prepared
and allowed to react with enone 2a under the standard condi-
tions (Scheme 2, eq. 2 and 3). The deuterium-labeled adducts
were obtained with similar deuterium incorporation ratios and
in the Z position for both reactions, irrespective of the starting
deuterium geometry (Scheme 2, eq. 2 and 3). These results in-
dicated that the b-proton elimination is not stereospecific, con-
sistent with a carbocation intermediate and the observed pref-
erence of proton elimination over deuteron elimination adds
further support to the rate-limiting proton elimination scenar-
io.
In summary, we have demonstrated herein an anionic ligand
effect in cationic alkene transformations. The use of phosphate
as an anionic ligand has been found to facilitate selective b-
proton elimination by suppressing cationic olefin polymeri-
zation in direct alkene addition to enone. This study lays the
Received: February 19, 2014
Published online on May 26, 2014
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ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim