Enantioselective Phosphine-Catalyzed Allylic Alkylations of mix-Indene with MBH Carbonates

Article abstract of DOI:10.1021/acs.orglett.7b02895

The first enantioenriched synthesis of 1,1,3-trisubstituted (trifluoromethyl)indene derivatives, bearing a quaternary stereogenic carbon center, is reported using a simple chiral sulfinamide phosphine-catalyzed asymmetric allylic alkylation of a mixture of indenes with Morita-Baylis-Hillman carbonates. The resulting derivatives can serve as a valuable synthetic building block for some drugs and natural products. Broad substrate scope and high regio- and enantioselectivity of this reaction were particularly remarkable.

Full text of DOI:10.1021/acs.orglett.7b02895

Letter
Cite This: Org. Lett. XXXX, XXX, XXX-XXX
pubs.acs.org/OrgLett
Enantioselective Phosphine-Catalyzed Allylic Alkylations of mix-
Indene with MBH Carbonates
Junyou Zhang, Hai-Hong Wu,* and Junliang Zhang*
Shanghai Key Laboratory of Green Chemistry and Chemical Processes, School of Chemistry and Molecular Engineering, East China
Normal University, 3663 N. Zhongshan Road, Shanghai 200062, P. R. China
*
S Supporting Information
ABSTRACT: The first enantioenriched synthesis of 1,1,3-
trisubstituted (trifluoromethyl)indene derivatives, bearing a
quaternary stereogenic carbon center, is reported using a
simple chiral sulfinamide phosphine-catalyzed asymmetric
allylic alkylation of a mixture of indenes with Morita−Baylis−
Hillman carbonates. The resulting derivatives can serve as a
valuable synthetic building block for some drugs and natural
products. Broad substrate scope and high regio- and
enantioselectivity of this reaction were particularly remarkable.
he indene core is a privileged framework in numerous
afford tertiary 1H-indene-1-amine compounds (Scheme 1a). In
2016, Jørgensen first realized a formal [4 + 2] cycloaddition of
benzofulvenes with 2,4-dienals through trienamine catalysis,
1
T
natural products. Chiral, nonracemic indenes that bear a
2
stereogenic center are valuable in pharmaceutical research.
5a
However, methods for enantioselective syntheses of these
compounds are limited, particularly for indene molecules
enantioenriched with a quaternary center. Few efforts have
been made for building different chiral indene derivatives over
the years. Among the methods that are available, there are two
providing a facile method to spiroindene derivatives (Scheme
1b-left). The same group also demonstrated an asymmetric
cyclopropanation of benzofulvenes with dimethyl bromomalo-
nate to construct cyclopropane spiroindenes by the employing
5b
chiral phase-transfer catalysis (PTC) (Scheme 1b-right).
Undoubtedly, asymmetric hydrogenation is also a powerful
3
4,5
typical efficient strategies based on intra- and intermolecular
cyclization. Representative intramolecular methods focus on C−
6b
6c
tool to obtain chiral indene derivatives catalyzed by Co, Ir,
3a,b
4a
6d
6e
H activation via Pd(II) catalysis. Cramer et al. developed an
enantioselective Rh(I)-catalyzed intermolecular tandem cycliza-
tion of unsaturated aromatic ketimines with internal alkynes to
Rh, and Zr complexes.
Due to its salient strong electron-acceptor characteristics, the
CF group can enhance robustness against metabolic oxidation.
3
Therefore, the construction of organic compounds bearing a
7
Scheme 1. Synthesis of Indene Derivatives and MBH
Carbonates Utilized in Asymmetric Allylic Alkylation
Reactions
trifluoromethyl group has attracted much attention. However,
to the best of our knowledge, the synthesis of optically active
(trifluoromethyl)indene derivatives, especially with all carbon
C1-quaternary carbon stereocenters, has not so far been reported.
The asymmetric allylic alkylation is an effective method for
controlling the facial access of nucleophiles to double bonds and
allows carbon−carbon and carbon−heteroatom bonds to often
be formed rapidly. Morita−Baylis−Hillman (MBH) carbonates
have been developed to react with a range of nucleophiles via this
reaction mode, especially under the catalysis of chiral
8
phosphines. Very recently, our group has devised an umpolung
addition of trifluoromethyl ketimines to MBH carbonates
catalyzed by Peng-Phos to produce valuable α-methylene-γ-
8k
lactams. Inspired by this work, we became interested in
defining whether chiral indenes with a trifluoromethylated
quaternary stereocenter could be efficiently constructed by the
phosphine-catalyzed asymmetric allylic alkylation of mix-
indenes. However, this method poses considerable challenges
Received: September 15, 2017
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02895
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a
Table 1. Optimization of Reaction Conditions
Scheme 2. Substrate Scope of the Aryl Ring of Indenes
3
a
b
c
entry
1
cat.*
solvent
yield [%]
ee [%]
1
2
3
4
5
6
7
8
9
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
P1
P2
P3
P4
P5
P6
P7
P8
P9
P10
P8
P8
P8
P8
P8
P8
P8
P8
P8
P8
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
DCM
88
85
87
43
85
85
82
85
88
78
87
86
71
53
46
71
47
35
84
87
96
95
95
66
92
89
45
97
89
8
10
11
12
13
14
15
16
17
18
19
20
94
96
94
97
93
96
96
96
96
95
DCE
THF
Et O
2
CH CN
3
d
e
f
toluene
toluene
toluene
toluene
toluene
1a′
1a+1a′
g
a
Unless otherwise specified, all reactions were carried out with 1 (0.1
mmol), 2a (0.15 mmol), chiral phosphine catalyst (10 mol %) in
solvent (2 mL), rt, 3a/3a′ > 49:1 (see Supporting Information for
a
b
c
Unless otherwise specified, all reactions were performed with 1 (0.1
details). Isolated yield. Determined by HPLC analysis using a chiral
d
e
f
mmol), 2 (0.15 mmol), and P8 (10 mol %) in toluene (2 mL) under
argon, rt; isolated yields were reported; ee was determined by chiral
stationary phase. 7.5 mol % P8 used. 5 mol % P8 used. 2.5 mol %
g
P8 used. 1a/1a′ = 1:1.
b
HPLC analysis. Isomer ratio of starting material (see SI for details).
c
1
5 mol % P8 used.
derived from aliphatic sulfinimines were then investigated.
Disappointingly, low enantioselectivity of the product arose
with the P7 with a bulky tert-butyl group, even though the
reaction gave rise to a good yield (Table 1, entry 7). To our
delight, P8 with a less sterically demanding isopropyl proved to
be a promising catalyst, incredibly furnishing an 85% yield with
9
7% ee. Further simplification of the skeleton from isopropyl to
methyl led to a slightly lower ee (Table 1, entry 9). Next, the
influence of solvent was also evaluated, and no solvents were
better than toluene (Table 1, entries 11−15). Further
investigations into lowering the catalyst loading from 10% to
Figure 1. Screened chiral phosphine catalysts.
7
.5%, 5%, and 2.5% did not adversely affect the enantioselectivity,
9
due to the easy fluoride elimination of indene carbanion
intermediates.
but the yield declined significantly (Table 1, entries 16−18).
Interestingly, 3-phenyl-1-(trifluoromethyl)-1H-indene 1a′, the
isomer of 1a, also reacted smoothly to give product in 84% yield
with 96% ee (Table 1, entry 19), proving that a mixture of 1a and
1a′ could be used directly (Table 1, entry 20).
With this in mind, the reaction of 1-phenyl-3-(trifluorometh-
yl)-1H-indene 1a and carbonate 2a in toluene was investigated in
the presence of a series of (R)-tert-butylsulfinamide derived chiral
phosphine catalysts (Figure 1) at room temperature. Gratify-
ingly, the product 3a was obtained in 88% yield with 96% ee with
less than a 2% NMR yield of a byproduct 3a′ when P1 was used
With the optimal reaction conditions in hand, we next
examined the substrate scope of this highly regio- and
enantioselective allylic alkylation. In general, the aryl ring of
indenes bearing electron-donating or electron-withdrawing
groups at the 5-position were well tolerated. For instance, 5-
Me-substituted 3b and 5-MeO-substituted 3c were exclusively
formed in good yields and with excellent enantioselectivity
(Scheme 2; 3b, 88% yield, 94% ee, and 3c, 83% yield, 94% ee). In
(
Table 1, entry 1). Motivated by this result, a systematic
screening of related catalysts was conducted. Whether with an
aryl substituent at the ortho-position of the phenyl ring, such as
P2, P3, and P6, good enantioselectivities and high yields were
obtained. Wei-Phos P5 also gave a favorable result, but Xiao-
Phos P4 delivered only moderate ee. Several simpler catalysts
particular, a strong electron-withdrawing substituent CF at the
3
B
DOI: 10.1021/acs.orglett.7b02895
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3. Substrate Scope of Indenes Functionalized at the 3-
Position
Scheme 4. Gram-Scale Synthesis of 3g and Transformations
a
a
Unless otherwise specified, all reactions were performed with 1 (0.1
mmol), 2 (0.15 mmol), and P8 (10 mol %) in toluene (2 mL) under
argon, rt; isolated yields were reported; ee was determined by chiral
b
HPLC analysis. Isomer ratio of starting material (see SI for details).
high yields with excellent enantioselectivities (3w−3z). Never-
theless, ether substituted carbonates derived from acrylate-
benzaldehyde (2f) or acetaldehyde (2g) were not compatible in
this catalysis mode (eq 1; see SI for details). Finally, it is
5
-position had no negative influence on the yield and ee (3d).
Halogen-substituents were also compatible with the reaction to
give high ee values and moderate to excellent yields (3e−3h).
When the 7-position of the indene was bearing a methyl group,
the corresponding 3i could be also produced in 77% yield with
noteworthy that when the CF group was functionalized with an
3
ester, for instance, this delivered the corresponding asymmetric
allylic alkylation product in 97% yield and 90% ee (eq 2).
9
6% ee.
Additionally, a disubstituted indene ring could be used, such as
,6-dimethyl, 5,6-dimethoxy, and 5,6-dioxole, with the corre-
4
sponding (trifluoromethyl)indenes products being exclusively
obtained in high yield (82%−94%) with high enantioselectivities
(
90%−94% ee) (3j−3l). To our delight, a naphthalene ring could
be used instead of the benzene ring of indene, leading to the
corresponding products in good yields with excellent enantio-
selectivity (3m−3n).
We next investigated the scope of different substituents at the
3
-position of indenes under the standard reaction conditions.
Indenes containing electron-rich (3o), electron deficient (3p−
r), or electron-neutral (3u−3v) substituents all proved to be
3
suitable reaction partners with favorable yields and excellent ee
values (Scheme 3). Moreover, bromo-compounds were well-
tolerated, furnishing the corresponding products in similar
enantioselectivities and yields (3s, 3t). Additionally, when the
ester group of the MBH carbonate was replaced by other
substituents, the corresponding products were still obtained in
To illustrate the practical applicability of this protocol, a Gram-
scale reaction under the standard conditions was conducted
without loss of efficiency and enantioselectivity (3g: 91% yield,
96% ee). Besides, several transformations of these chiral allylic
alkylation products were carried out (Scheme 4). For example,
C
DOI: 10.1021/acs.orglett.7b02895
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
hydrolysis of ester 3g provided efficient access to the carboxylic
acid 6. Treatment of 3g with DIBAL-H delivered chiral allyl
alcohol product 7 smoothly. The highly efficient and stereo-
selective palladium-catalyzed Heck reaction of 3g with
iodobenzene generated alternative access to multiple valuable
9559. (c) Egi, M.; Shimizu, K.; Kamiya, M.; Ota, Y.; Akai, S. Chem.
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009, 11, 1405. (c) Yang, L.; Zheng, H.; Luo, L.; Nan, J.; Liu, J.; Wang,
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and optically active alkenyl compounds. Cycloaddition of 3g
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Y.; Luan, X. J. Am. Chem. Soc. 2015, 137, 4876. (d) Reddy Chidipudi, S.;
Burns, D. J.; Khan, I.; Lam, H. W. Angew. Chem., Int. Ed. 2015, 54, 13975.
11
ing natural products. The hydroxyl of 7 could easily undergo
oxidation to acrolein, and the phenyl hydrazine 10 was obtained
via condensation with phenylhydrazine. The absolute stereo-
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12
analogy (see the SI for details).
(
1
In summary, we have developed a mild, highly efficient, and
regio-/enanotioselective allylic alkylation that provides optically
enriched 1,1,3-trisubstituted (trifluoromethyl)indene deriva-
tives, which employ a simple chiral sulfinamide phosphine
catalyst. Further efforts toward the transformation of these
optically active trifluoromethylindene compounds are currently
in progress in our laboratory, and these results will be reported in
due course.
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ASSOCIATED CONTENT
Supporting Information
■
*
S
(c) Hagmann, W. K. J. Med. Chem. 2008, 51, 4359. (d) O’Shea, P. D.;
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b02895.
Chen, C.-Y.; Gauvreau, D.; Gosselin, F.; Hughes, G.; Nadeau, C.;
Volante, R. P. J. Org. Chem. 2009, 74, 1605.
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Experimental procedures; spectroscopic date for catalyst,
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X-ray data for (R)-8 (CIF)
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2
014, 43, 2927. For selected examples of AAA reactions utilizing MBH
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Krische, M. J. Angew. Chem., Int. Ed. 2004, 43, 6689. (f) Jiang, Y.-Q.; Shi,
Y.-L.; Shi, M. J. Am. Chem. Soc. 2008, 130, 7202. (g) Deng, H.-P.; Wei,
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AUTHOR INFORMATION
Corresponding Authors
■
*
*
E-mail: hhwu@chem.ecnu.edu.cn.
E-mail: jlzhang@chem.ecnu.edu.cn.
(i) Zhao, S.; Zhao, Y.-Y.; Lin, J.-B.; Xie, T.; Liang, Y.-M.; Xu, P.-F. Org.
ORCID
Lett. 2015, 17, 3206. (j) Zhan, G.; Shi, M.-L.; He, Q.; Lin, W.-J.; Ouyang,
Q.; Du, W.; Chen, Y.-C. Angew. Chem., Int. Ed. 2016, 55, 2147. (k) Chen,
P.; Yue, Z.; Zhang, J.; Lv, X.; Wang, L.; Zhang, J. Angew. Chem., Int. Ed.
Hai-Hong Wu: 0000-0001-6266-8290
Junliang Zhang: 0000-0002-4636-2846
Notes
2
016, 55, 13316.
(9) For reviews, see: (a) Amii, H.; Uneyama, K. Chem. Rev. 2009, 109,
The authors declare no competing financial interest.
2119. (b) Chelucci, G. Chem. Rev. 2012, 112, 1344. For selected
examples about fluoride elimination of the carbanion intermediate of α-
CF compounds, see: (c) Kitazume, T.; Ohnogi, T.; Miyauchi, H.;
Yamazaki, T.; Watanabe, S. J. Org. Chem. 1989, 54, 5630. (d) Ichikawa,
J.; Wada, Y.; Fujiwara, M.; Sakoda, K. Synthesis 2002, 2002, 1917.
ACKNOWLEDGMENTS
We are grateful to the 973 Program (2015CB856600), the
National Natural Science Foundation of China (21373088,
1425205, 21672067), and the Changjiang Scholars and
Innovative Research Team in University (PCSIRT) for financial
3
■
(e) Yang, J.; Mao, A.; Yue, Z.; Zhu, W.; Luo, X.; Zhu, C.; Xiao, Y.; Zhang,
2
J. Chem. Commun. 2015, 51, 8326. (f) Yang, J.; Zhou, X.; Zeng, Y.;
Huang, C.; Xiao, Y.; Zhang, J. Chem. Commun. 2016, 52, 4922.
(10) (a) Zhou, W.; Su, X.; Tao, M.; Zhu, C.; Zhao, Q.; Zhang, J. Angew.
Chem., Int. Ed. 2015, 54, 14853. (b) Zhou, W.; Chen, P.; Tao, M.; Su, X.;
Zhao, Q.; Zhang, J. Chem. Commun. 2016, 52, 7612.
support.
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DOI: 10.1021/acs.orglett.7b02895
Org. Lett. XXXX, XXX, XXX−XXX