Mild rhodium(III)-catalyzed C-H allylation with 4-vinyl-1,3-dioxolan-2-ones: Direct and stereoselective synthesis of (E)-allylic alcohols

Article abstract of DOI:10.1021/ol503229c

A rhodium(III)-catalyzed C-H direct allylation reaction with 4-vinyl-1,3-dioxolan-2-ones has been developed. The reaction provides a facile and stereoselective access to substituted-(E)-allylic alcohols under mild and redox-neutral reaction conditions. Olefinic C-H activation is applicable, giving multifunctionalized skipped dienes in good yields. Minimal double-bond migration was observed.

Full text of DOI:10.1021/ol503229c

Letter
pubs.acs.org/OrgLett
Mild Rhodium(III)-Catalyzed C−H Allylation with 4‑Vinyl-1,3-
dioxolan-2-ones: Direct and Stereoselective Synthesis of (E)‑Allylic
Alcohols
Shang-Shi Zhang, Jia-Qiang Wu, Ye-Xing Lao, Xu-Ge Liu, Yao Liu, Wen-Xin Lv, Dong-Hang Tan,
Yao-Fu Zeng, and Honggen Wang*
School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
S
* Supporting Information
ABSTRACT: A rhodium(III)-catalyzed C−H direct allylation
reaction with 4-vinyl-1,3-dioxolan-2-ones has been developed. The
reaction provides a facile and stereoselective access to substituted-
(E)-allylic alcohols under mild and redox-neutral reaction
conditions. Olefinic C−H activation is applicable, giving multi-
functionalized skipped dienes in good yields. Minimal double-bond
migration was observed.
llylic alcohols are undoubtedly among the most syntheti-
cally useful building blocks in organic synthesis.1 Therefore,
Scheme 1. Different Strategies toward Allyl Arenes or Skipped
Dienes Bearing an Allylic Hydroxyl Group
A
the incorporation of an allylic alcohol functional group into a
molecule is of great value. In addition, allyl arenes and skipped
dienes are pervasive structural elements in biologically active
compounds, as displayed by natural product lobatamide A,2
antifilarial agent corallopyronin A,3 the bacterial RNA-polymer-
ase inhibitor ripostatin A,4 and the well-known omega-3-acid
ethyl ester (Figure 1). Reported methods for accessing allyl
Figure 1. Allyl arenes (in red) and skipped dienes (in blue) in
biologically active compounds.
synthetic applications. A Friedel−Crafts-type allylation with
vinyl epoxide was also documented (Scheme 1b).6 However, this
reaction is only applicable to electron-rich arenes. Besides, low
regioselectivity and overreaction are unaddressed issues.
In recent years, transition-metal-catalyzed C−H activation
reaction has provided an attractive and straightforward method
for the construction of C−C and C−heteroatom bonds.7 Thus,
arenes or skipped dienes bearing a hydroxyl group at the allylic
position generally necessitate the use of preactivated starting
materials. For instance, the nucleophilic ring-opening of vinyl
epoxide with a variety of organometallic reagents has been well
established (Scheme 1a).5 Nevertheless, the instability and/or
toxicity of the corresponding organometallic reagents, associated
with the usually observed poor stereoselectivities in the
formation of mixtures of E/Z isomers, might hamper their
Received: November 6, 2014
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ol503229c | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
the direct C−H allylation has been achieved under the catalysis
of various metals such as Rh(III),8,9 Ir(I),10 Ni,11 Ru,12 Re,13
Pd,14 and Cu.15 Very recently, the group of Li reported an elegant
Rh(III)-catalyzed C−C coupling of arenes with vinyl epoxide for
the synthesis of allylic alcohols under the assistance of 2-pyridyl,
2-pyrimidyl, pyrazol-1-ol, oxime, and N-nitroso directing groups
(Scheme 1c).16 Unfortunately, in their reactions, low stereo-
selectivities (up to 6.1:1) were observed. In addition, no
examples on the allylation of benzoic acid derivatives were
reported. Given the widespread occurrence of carboxyl groups in
functional molecules, for instance, in lobatamides A and
ripostatin A (Figure 1, in pink), and their easily transformable
ability to other functional groups, it would be highly interesting
to develop a method for the elaboration of benzoic acid
derivatives. Herein, we disclose our realization of a highly chemo-
and stereoselective Rh(III)-catalyzed C−H allylation of
benzamides with 4-vinyl-1,3-dioxolan-2-ones. The utilization of
4-vinyl-1,3-dioxolan-2-ones as coupling partners is key to success
(vide infra).17 Various substituted vinyl-1,3-dioxolan-2-ones
were successfully applied. Importantly, this method is applicable
to olefinic C−H activation reaction, generating skipped dienes
functionalized with an allylic hydroxyl group.
allylic alcohol 4a in 45% yield in the presence of CsOAc as
additive in MeOH at 0 °C (entry 2). Screening of different
solvents revealed CF3CH2OH to be the best (entries 2−7),
giving 4a in 81% isolated yield with excellent stereoselectivity (E/
Z > 20:1). It should be noted that no double-bond migration
isomers of 4a were detected probably due to the rather mild
reaction conditions. Substitution of CsOAc with K2CO3 gave a
diminished yield (entry 8). The use of PivOH as additive shut
down the reactivity completely (entry 9). It has been shown that
the combined use of an insoluble carbonate base and a catalytic
amount of soluble base is beneficial for C−H activations.18
Indeed, in our cases, the use of K2CO3/PivOH or Cs2CO3/
PivOH as additive provided better yields (entries 10 and 11 vs
entry 8), but not better than CsOAc (entry 7). The lowering of
catalyst loading from 5 to 2 mol % resulted in a slightly lower
yield of 76% (entry 12). [Cp*RhCl2]2 (2.5 mmol %) also showed
good reactivity (79%, entry 13). A control experiment showed
that rhodium is essential for the reactivity as its absence resulted
in no reaction (entry 14). The efficacy of 2-vinyloxirane 3 as
coupling partner was reexamined under the optimized conditions
(entry 15). The reaction led to complex reaction products with
the isolation of 4a in only 18% yield. Notably, the reaction is easy
to handle as no special exclusion of air and moisture is needed. A
7 mmol scale reaction was conducted with 2 mol % rhodium
catalyst to give 1.23 g of 4a in 75% yield, demonstrating the
reaction is practical (entry 16).
With the optimized reaction condition established (Table 1,
entry 7), we next explored the scope of this method. Gratifyingly,
the reaction was compatible with a variety of commonly
encountered functional groups such as fluoro (4n), chloro (4b
and 4l), bromo (4c and 4t), iodo (4d), methoxyl (4i and 4s),
trifluoromethyl (4g), nitro (4k and 4o), ester (4e and 4u), amino
(4f), and cyano (4r), giving the corresponding products in
generally good-to-excellent yields (Scheme 2). With meta-
substituted substrates, reactions at the less hindered position
were exclusively observed (4a−k). Importantly, ortho-substitu-
ents did not hamper the reactivities (4l−o) with one exception
compound 4p. We suspected the oxygen atom of the methoxyl
group together with the carbonyl group might act as a bidentate
ligand, thereby directing the rhodium catalyst far away from the
desired C−H bond. Not surprisingly, the reaction of para-
substituted benzamide derivatives also gave significant amounts
of diallylation products due to the remarkably high reactivities of
the monoallylation products (4q−u). Fortunately, the separation
of the mono- and diallylation products could be easily realized by
using flash column chromatography. The reaction was also
applicable to electron-rich heterocycles such as thiophene (4w),
furan (4x), and indole (4y). The reaction of furan occurred
exclusively at the α position. We also explored the feasibility of an
olefinic C−H activation for the synthesis of skipped dienes. To
our delight, the reaction of acrylic acid derivatives bearing a
methyl or phenyl substituent at the α position both delivered the
desired products in good yields with excellent stereoselectivities
(5a and 5b). Furthermore, the cyclic olefinic substrates also
underwent reaction smoothly (5c and 5d). Other benzamide
derivatives such as N-propylbenzamide 6, N,N-diisopropylben-
zamide 7, and Weinreb amide N-methoxy-N-methylbenzamide 8
showed no reactivities under the standard reaction conditions.
To extend the scope of this transformation further, substituted
vinyl-1,3-dioxolan-2-one 2 were synthesized and subjected to the
reaction. We were pleased to find that the reaction occurred
without difficulty regardless of an aromatic or aliphatic
substituent at the fourth position (Scheme 3). However, the
We initiated our investigation by using N-methoxy-3-
methylbenzamide 1a as a substrate. We first tested the feasibility
of the desired reaction under Li’s conditions (3 mol % of
[Cp*Rh(CH3CN)3](SbF6)2, 1.2 equiv of 3, 1.0 equiv of PivOH
in ClCH2CH2Cl, rt).16 However, no desired product was
obtained (Table 1, entry 1). After extensive studies, we were
able to determine that the commercially available 4-vinyl-1,3-
dioxolan-2-one 2a is a highly reactive coupling partner, providing
a
Table 1. Reaction Optimization
entry
solvent
2a/3
additive (1 equiv)
yield (%)
b
1
ClCH2CH2Cl
MeOH
3
PivOH
0
c
c
c
c
c
,
,
,
,
,
d
d
d
d
d
2
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
3
CsOAc
45
50
59
45
55
81
57
0
3
EtOH
CsOAc
4
CH3CN
CsOAc
5
ClCH2CH2Cl
toluene
CsOAc
6
CsOAc
d
d
7
CF3CH2OH
CF3CH2OH
CF3CH2OH
CF3CH2OH
CF3CH2OH
CF3CH2OH
CF3CH2OH
CF3CH2OH
CF3CH2OH
CF3CH2OH
CsOAc
8
K2CO3
9
PivOH
c
c
c
c
,
,
,
,
d
d
d
d
,
,
,
,
e
e
f
10
11
12
13
14
15
16
K2CO3/PivOH
Cs2CO3/PivOH
CsOAc
74
65
76
79
0
g
CsOAc
h
c
CsOAc
CsOAc
18
75
d,i
2a
CsOAc
a
1a (0.2 mmol), 2a, or 3 (0.24 mmol), additive (1.0 equiv), [RhIII] (5
b
mol %), solvent (1.0 mL), 0 °C, 12 h, isolated yields. [RhIII] (3 mol
c
d
%), rt. 1H NMR yield. E/Z > 20:1 was observed, determined by 1H
e
f
NMR. Carbonate (1.1 equiv) and PivOH (30 mol %). [RhIII] (2 mol
g
h
%) was used. [Cp*RhCl2]2 (2.5 mmol %) was used. No rhodium
i
was used. Gram-scale reaction: 1a (7.0 mmol), 2a (8.4 mmol), CsOAc
(7.0 mmol), [RhIII] (2 mol %), CF3CH2OH (35.0 mL), 12 h, 1.23 g of
4a was isolated.
B
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Organic Letters
Letter
of the E isomer. On the other hand, the cis-substituted 2 gave the
Z isomer preferentially, probably because of the steric issues
leading to selective facial coordination of the alkene to the metal
in the reaction mechanism (vide infra). 4,4-Dimethyl-substituted
2 delivered the corresponding product in moderate yield, but
with excellent stereoselectivity (4ad).
Scheme 2. Rhodium(III)-Catalyzed C−H Allylation
Reactions with 4-Vinyl-1,3-dioxolan-2-one 2a
The allylation of indoles bearing a pyrimidine directing group
were extensively explored in Li’s work.16 Disappointingly, when
9a was reacted with 2a under our standard reaction conditions, a
low E/Z ratio of 1.7:1 was also observed (eq 1). Interestingly,
however, by using a modified conditions of Li’s,16 the
stereoselectivities were improved significantly to 15−20:1 (vs
1.8−4.2:1 in Li’s work) (eq 2). A 3-methyl group was well
tolerated (10c).
On the basis of literature precedent,8a−f a tentative mechanism
was proposed for this transformation (Scheme 4). The active
Scheme 4. Mechanistic Rationale
a
b
c
At 30 °C. At 80 °C. DCE was used as solvent.
Scheme 3. Substrate Scope on the Use of Substituted Vinyl-
1,3-dioxolan-2-one 2
catalyst Cp*Rh(OAc)2 is generated by a ligand exchange from
[Cp*Rh(CH3CN)3](SbF6)2 with CsOAc. C−H activation takes
place under the assistance of the directing group to give a
rhodacycle A. The coordination of the alkene 2 to the metal is
followed by a migratory insertion to generate intermediate B.
The π-facial-selectivity of this step, which might be greatly
influenced by the substituent of 2, determines the E/Z ratio of
the final product. Subsequently, a β-oxygen elimination occurs to
form the new double bond bearing an allylic hydroxyl group
while releasing one molecule of CO2. The resulting allylic alcohol
4 is then released with the concurrent regeneration of the
rhodium catalyst.
In summary, by using vinyl-1,3-dioxolan-2-one 2 as a novel
coupling partner, we have developed a rhodium(III)-catalyzed
C−H allylation reaction for the synthesis of functionalized allylic
alcohols. The reaction is applicable to both aromatic and olefinic
substrates, giving allylarenes and skipped dienes, respectively, in
good to excellent yields. While unsubstituted vinyl-1,3-dioxolan-
2-one was used, excellent E/Z ratios were observed. The reaction
E/Z ratio varies depending on the stereochemistry of the
coupling partner. Thus, with trans-substituted vinyl-1,3-
dioxolan-2-one 2, the reactions slightly favored the formation
C
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Letter
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proceeded under rather mild reaction conditions and is very easy
to handle. Broad substrate scope and good functional group
tolerance were found. A gram-scale reaction was performed to
showcase the practicability of this transformation. Given the
great importance of allylic alcohols in bioactive compounds and
synthetically valuable building blocks, we anticipate this method
will find applications.
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̈
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures and full analytical data. This material is
available free of charge via the Internet at http://pubs.acs.org.
(10) Zhang, Y. J.; Skucas, E.; Krische, M. J. Org. Lett. 2009, 11, 4248.
(11) Cong, X.; Li, Y.; Wei, Y.; Zeng, X. Org. Lett. 2014, 16, 3926.
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(13) Kuninobu, Y.; Ohta, K.; Takai, K. Chem. Commun. 2011, 47,
10791.
■
S
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AUTHOR INFORMATION
Corresponding Author
■
*E-mail: wanghg3@mail.sysu.edu.cn.
Notes
(16) Yu, S.; Li, X. Org. Lett. 2014, 16, 1200.
(17) For use of 4-vinyl-1,3-dioxolan-2-one in metal-catalyzed
reactions, see: (a) Zhang, Y. J.; Yang, J. H.; Kim, S. H.; Krische, M. J.
J. Am. Chem. Soc. 2010, 132, 4562. (b) Kang, S.-K.; Park, D.-C.; Park, C.-
H.; Hong, R.-K. Tetrahedron Lett. 1995, 36, 405. (c) Kang, S.-K.;
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(18) Lafrance, M.; Gorelsky, S. I.; Fagnou, K. J. Am. Chem. Soc. 2007,
129, 14570.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for the support of this work by a Start-up Grant
from Sun Yat-sen University and the National Natural Science
Foundation of China (81402794 and 21472250)
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