Chemo- and Stereoselective Cross Rauhut–Currier-Type Reaction of Tri-substituted Alkenes Containing Trifluoromethyl Groups

Article abstract of DOI:10.1002/chem.201705010

A chemoselective cross Rauhut–Currier-type reaction has been developed involving a tri-substituted alkene (trifluoromethyl-containing acrylonitrile derivative) with a di- or tri-substituted alkene to yield tetra-substituted double bonds in RC-type products. This approach can support the synthesis of trifluoromethylated tetra-substituted olefins and synthetically important, structurally complex 3-allylic-type oxindole skeletons. The asymmetric version of this RC-type reaction can be realized by combining a Br?nsted acid and Lewis base for bifunctional H-bonding-tertiary amine catalysis. Subsequent transformation of multi-functionalized RC-type product leads to pharmacologically interesting cyclohexane-based spiro-pyrazolones bearing six contiguous chiral centers and two highly congested, vicinal quaternary carbon centers.

Full text of DOI:10.1002/chem.201705010

A Journal of
Accepted Article
Title: Chemo- and Stereoselective Cross Rauhut-Currier-Type
Reaction of Tri-substituted Alkenes Containing Trifluoromethyl
Groups
Authors: Xiang-Hong He, Lei Yang, Yan-Ling Ji, Qian Zhao, Ming-
Cheng Yang, Wei Huang, Cheng Peng, and Bo Han
This manuscript has been accepted after peer review and appears as an
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To be cited as: Chem. Eur. J. 10.1002/chem.201705010
Link to VoR: http://dx.doi.org/10.1002/chem.201705010
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Chemo- and Stereoselective Cross Rauhut-Currier-Type Reaction
of Tri-substituted Alkenes Containing Trifluoromethyl Groups
Xiang-Hong He, Lei Yang, Yan-Ling Ji, Qian Zhao, Ming-Cheng Yang, Wei Huang, Cheng Peng* and
Bo Han*
Dedication ((optional))
Abstract: A chemoselective cross Rauhut-Currier-type reaction has
been developed involving a tri-substituted alkene (trifluoromethyl-
containing acrylonitrile derivative) with a di- or tri-substituted alkene
to yield tetra-substituted double bonds in RC-type products. This
approach can support the synthesis of trifluoromethylated tetra-
substituted olefins and synthetically important, structurally complex
3-allylic-type oxindole skeletons. The asymmetric version of this RC-
type reaction can be realized by combining a Brønsted acid and
Lewis base for bifunctional H-bonding-tertiary amine catalysis.
Subsequent transformation of multi-functionalized RC-type product
leads to pharmacologically interesting cyclohexane-based spiro-
pyrazolones bearing six contiguous chiral centers and two highly
congested, vicinal quaternary carbon centers.
Introduction
The Rauhut-Currier (RC) reaction, first described by Rauhut and
Currier in 1963 and also known as the vinylogous Morita-Baylis-
Hillman reaction,1 is an efficient, atom-economic approach to
multi-substituted alkenes. This powerful method for forming C-C
bonds has been applied to the synthesis of several biologically
important targets and natural products.2 Much more challenging
is the so-called “cross Rauhut-Currier” reaction between two
different activated alkenes, which normally proceeds with poor
selectivity.3 Cross RC reactions have been extensively explored
between a mono-substituted alkene and another electron-
deficient alkene (Scheme 1a),4 as well as between a 1,2-
disubstituted alkene and another electron-deficient alkene
(Scheme 1b).5 Previous studies have demonstrated that 1,2,2-
Scheme 1. The Application of RC Reaction in Building Multi-substituted
Alkenes
tri-substituted alkenes are poor donors in cross RC reactions,
likely because of steric hindrance, which means that few
methods exist to generate tetra-substituted RC-type products
(Scheme 1c).6,7 In 2009, Christmann and co-workers generated
cyclization of 1,2,2-tri-substituted alkenes and α,β-unsaturated
RC-type products with a tetra-substituted alkene via dienamine-
aldehydes in the presence of secondary amine catalyst.6 More
activated intramolecular enantioselective Michael/isomerization
recently, Alemán’s group generated tetra-substituted RC-type
products via intermolecular regioselective Mukaiyama reaction in
the presence of bifunctional catalyst.7 While these advances are
Dr. X.-H. He, Dr. L. Yang, Dr. Y.-L. Ji, Dr. Q. Zhao, Dr. M-C. Yang, Dr. W.
important, many types of tetra-substituted RC-type products
remain inaccessible.
Huang, Prof. C. Peng, Prof. B. Han
State Key Laboratory Breeding Base of Systematic Research,
Development and Utilization of Chinese Medicine Resources
School of Pharmacy, Chengdu University of Traditional Chinese Medicine
Chengdu 611137 (P.R. China)
Trifluoromethyl (CF3) is a privileged structural motif playing a
crucial role in many drugs,8 so organic chemists continue to
spend considerable efforts on constructing CF3-containing
organic compounds.9 Trifluoromethylated alkenes,10 especially
3,3,3-trifluoropropene derivatives, are particularly attractive
E-mail: pengcheng@cdutcm.edu.cn;
hanbo@cdutm.edu.cn
Supporting information for this article is given via a link at the end of the
document.
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Table 1. Optimization of reaction conditions.[a]
Figure 1. Representative examples of multisubstituted CF3-alkenes.
organic skeletons because of their significant usefulness as
pharmaceuticals or functional molecules (Figure 1).11
Time
[h][b]
Yield
[%][c]
Z/E
Entry
Solvent
Catalyst
[3a:3a’][d]
For the foregoing reasons, coupled with our own recent
success developing organocatalytic reactions to assemble
synthetically important and structurally complex molecules,12 we
have designed a novel multi-functionalized CF3-alkene 1a with
two different reactive sites, which we hypothesized could serve
as a Michael donor or as an RC donor via the strong electron
withdrawing groups on the substrate (Scheme 2).
1
CH2Cl2
Toluene
MeCN
THF
TEA
3
75
64
57
46
37
65
54
28
75
68
79
82:18
69:31
78:22
60:40
63:37
74:26
67:23
55:45
81:19
73:27
90:10
2
TEA
2
3
TEA
4
4
TEA
6
5[e]
6[f]
7
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
TEA
1
TEA
6
DIPEA
DBU
DABCO
DMAP
PPh3
0.5
0.5
4
8
9
10
11
4
6
[a] Unless noted otherwise, reactions were performed with 0.30 mmol of 1a,
0.20 mmol of 2a, and 0.04 mmol of base catalyst in 1 mL of solvent at room
temperature. For the relative configuration of 3a and 3a’, see entry 9 in Table
2. [b] Indicates the time after which total yield of 3a and 3a’ did not increase.
[c] Total yield of isolated 3a and 3a’. [d] Calculated based on 1H NMR analysis
of the crude reaction mixture. [e] Reaction performed at 50 oC. [f] Reaction
performed at 0 oC.
Scheme 2. Synthetic strategy.
Results and Discussion
DABCO and DMAP led to slower reaction but better yield and
Z/E ratio (entries 9-10). Interestingly, using the traditional
nucleophilic reagent PPh3 as base catalyst led to good yield and
Z/E ratio (entry 11).
We probed the reactivity and selectivity of ethyl (E)-4-cyano-3-
(trifluoromethyl)-but-3-enoate 1a by reacting it initially with
nitrostyrene 2a in dichloromethane at room temperature for 3 h
in the presence of 20 mol% trimethylamine. We were pleased to
obtain exclusively the RC-type product in 75% yield with a
moderate Z/E ratio of 82:18 (Table 1, entry 1). Next, we
optimized the reaction by screening additional parameters in the
presence of trimethylamine (Table 1). Various solvents
supported the reaction, allowing formation of the desired RC-
type product (entries 1-4), with dichloromethane showing the
highest efficiency (entry 1). Raising the reaction temperature
substantially improved the reaction rate but significantly
decreased yield and Z/E ratio (entry 5), while lowering the
temperature decreased the reaction rate without improving yield
or Z/E ratio (entry 6). Using the relatively strong base catalysts
DIPEA and DBU supported rapid reaction but at a cost of lower
yield and Z/E ratio (entries 7-8). Using the weak base catalysts
Under optimal reaction conditions, various alkaline or
nucleophilic catalysts promoted the reaction (Table 1). We
postulate two reaction pathways that could explain the highly
chemoselective RC-type products observed (Scheme 3). The
more likely reaction pathway is a traditional RC reaction in the
presence of nucleophilic reagent (path a). Another possible
pathway is a complicated deprotonation-isomerization-Michael-
isomerization cascade (path b). When we conducted the
reaction using PPh3 or DABCO (entries 9 and 11), which are
poor bases but good nucleophiles, ESI-MS revealed the
presence of intermediates consistent with path a. 13 On the other
hand, conducting the reaction with the weakly nucleophilic base
DIPEA (entry 7) accelerated the reaction to afford the desired
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Table 2. Substrate scope of the RC-type reaction.[a]
Time
[h][b]
Yield
[%][c]
Z/E
[3:3’][d]
Entry
R
Product
1
Ph
6
8
7
7
7
7
7
7
8
5
5
5
5
5
5
5
2
4
5
6
6
3a/3a’
3b/3b’
3c/3c’
3d/3d’
3e/3e’
3f/3f’
79
72
83
81
85
83
84
82
87
68
76
78
80
74
76
75
64
71
57
79
83
90:10
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
92:8
2
2-CH3C6H4
3-CH3C6H4
4-CH3C6H4
3-OMeC6H4
4-OMeC6H4
4-t-BuC6H4
4-i-PrC6H4
3,4-(OMe)2C6H3
2-FC6H4
3
4
5
6
7
3g/3g’
3h/3h’
3i[e]/3i’[f]
3j/3j’
8
9
10
11
12
13
14
15
16
17
18
19
20
21
>95:5
>95:5
>95:5
>95:5
>95:5
91:9
3-FC6H4
3k/3k’
3l/3l’
4-FC6H4
3-ClC6H4
3m/3m’
3n/3n’
3o/3o’
3p/3p’
3q/3q’
3r/3r’
4-ClC6H4
Scheme 3. Proposed catalytic cycle to yield the RC-type product with high
selectivity.
3-BrC6H4
4-BrC6H4
4-NO2C6H4
3,4-Cl2C6H3
2-thienyl
86:14
>95:5
>95:5
>95:5
88:12
>95:5
product, which is consistent with path b. We conclude that the
reaction probably proceeds via an RC pathway, but we cannot
exclude the possibility that it also proceeds via a Michael
cascade at least under certain conditions.
3s/3s’
3t/3t’
Having established the optimal conditions (Table 1, entry 11),
we examined the scope of the reaction. Substrates with nearly
any substitution at the ortho-, meta-, or para-position on the
aromatic groups of nitroolefin 2 gave the desired products in
moderate to good yields and high Z/E ratios (Table 2, entries 2-
18). Higher yields and Z/E ratios were obtained when the
nitroolefin 2 bearing electron-donating groups (entries 3-9)
rather than electron-neutral or -withdrawing groups (entries 1
and 11-18). Substitutions at the ortho-position of nitroolefin led
to relatively inefficient reaction (entries 2 and 10), perhaps as a
result of steric hindrance. Heteroaryl nitroolefin gave the target
product 3s, albeit in slightly lower yield (entry 19).
Naphthaldehyde nitroolefin also afforded the corresponding
products in good yields and with moderate to high Z/E ratios
(entries 20 and 21).
α-naphthyl
β-naphthyl
3u/3u’
[a] See entry 11 and footnote a in Table 1. [b] Indicates the time after which
total yield of 3 and 3’ did not increase. [c] Total yield of isolated 3 and 3’. [d]
Calculated based on 1H NMR analysis of the crude reaction mixture. [e] The
relative configuration of compound 3i was confirmed by X-ray
crystallographic analysis (Figure 2),14 and the relative configurations of other
products
3 were tentatively assigned by analogy. [f] The relative
configuration of compound 3i’ was confirmed by X-ray crystallographic
analysis (Figure 2),15 and the relative configurations of other products 3’
were tentatively assigned by analogy.
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Table 3. Extensive substrate scope of the RC-type reaction.[a]
Entry
R
PG
Bn
Time [h][b]
Product
5a
Yield [%][c]
Figure 2. ORTEP drawing of compounds 3i and 3i’. Ellipsoids are shown at
the 50% probability level.
1
2
3
4
5
6
7
H
1
1
1
1
2
1
1
69
61
64
67
71
42
47
5-Cl
5-Br
7-F
5-Me
H
Bn
5b[d]
5c
Subsequently, we attempted to use a 1,2,2-tri-substituted
alkene as RC-type acceptor. Our goal was to determine whether
Bn
Bn
5d
such
a substrate could complement traditional strategies
(Scheme 4a)16-19 to efficiently generate a multi-functionalized 3-
allylic-type oxindole derivatives (Scheme 4b). Such a skeleton is
an important synthon used to prepare many natural products or
pharmaceutical lead compounds.20
Bn
5e
Me
Allyl
5f
H
5g
We began our studies using the potential RC-type acceptor 3-
ylideneoxindole 4. The base catalyst PPh3 did not lead to
satisfactory results, while tertiary amines, especially DABCO,
promoted the reaction smoothly to afford a major RC-type
product together with minor complex by-products, which likely
contain the diastereoisomer, Z/E-isomers and double-bond
migration products of 5. Meanwhile we explored whether the
reaction would tolerate substitutions on the oxindole core of the
major RC-type product. Changing the functional group on the R
[a] Unless noted otherwise, reactions were performed with 0.30 mmol of 1a,
0.20 mmol of 4, and 0.04 mmol of DABCO in 1 mL CH2Cl2 at 0 oC. [b]
Indicates the time after which yield of 5 did not increase. [c] Yield of isolated
major product 5. [d] The relative configuration of compound 5b was
confirmed by X-ray crystallographic analysis (Figure 3),21 and the relative
configurations of other products 5 were tentatively assigned by analogy.
of the oxindole core slightly affected the reaction, particularly
halides (Table 3, entries 1-5). The reaction did not tolerate a Boc
group but it did tolerate methyl and allyl groups, although yields
were substantially lower (Table 3, entries 6 and 7). Unfortunately,
we failed to purify the target products of these reactions from the
complex by-products. Nevertheless, we did manage to isolate a
small amount of double-bond migration products 5a’’ and 5e’’
obtained when the R group was H or 5-Me, respectively (see
NMR and HRMS spectra in Electronic Supplementary
Information).
To explore the reaction scope further, we tested the ability of
phenyl-substituted alkene 1b to serve as an RC donor. PPh3
failed to catalyze this reaction, so we screened the base
catalysts DBU, DIPEA, DABCO, DMAP and TEA. DABCO led to
the most efficient reaction, which generated the conventional
Michael addition product 6a rather than the predicted RC-type
product (Scheme 5). This result indicates that the CF3 group is
essential for obtaining highly chemoselective RC-type products
in our reaction.
Scheme 4. Strategies to access 3-allyl oxindole derivatives.
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recent success using a Brønsted acid and neutral coordinate
bifunctional organocatalyst (Figure 4, middle).7
We attempted the asymmetric version of our reaction in the
presence of numerous chiral catalysts (Table 4). The Cinchona
alkaloids quinine (C1), cinchonine (C2) and β-isocupreidine (β-
ICD, C3) provided the desired product in good yield but with
poor enantioselectivity (entries 1-3). Various kinds of bifunctional
catalysts were also tested, including Takemoto’s catalysts (C4,
C5), thiourea-based tertiary amine derivatives (C6, C7), and
squaramide-based
cinchona
alkaloid
derivative
(C8).
Nevertheless, only poor to moderate ee values were obtained
(entries 4-8), with alkaloid catalyst C8 providing the best results
of 72% yield and 83% ee (entry 8). Combining bisthiourea
catalyst C9 with alkaloids C1 or C8 did not improve
enantioselectivity (entries 9-10), nor did stereoselectivity
improve with different solvents (entries 11-14), reaction
temperatures or catalyst loadings (entries 15-17).
Figure 3. ORTEP drawing of compound 5b. Ellipsoids are shown at the 50%
probability level.
We propose that the asymmetric RC-type reaction in the case
of the most powerful bifunctional H-bonding-tertiary amine
catalyst involves the transition state shown in Figure 5, reflecting
a possible Brønsted acid-Lewis base activation mode. ESI-MS
analysis of reaction mixtures revealed intermediates of catalyst
C8 predicted by our catalytic cycle.25 However, as mentioned
above, we cannot totally repudiate the possibility that it also
proceeds via a catalytic strategy combining a Brønsted acid with
a Brønsted base.
Scheme 5. The Michael addition reaction between phenyl substituted alkene
1b and nitroolefin 2a.
To extend the synthetic usefulness of our RC-type approach,
we attempted to achieve the asymmetric version in the presence
of an appropriate organocatalyst.22 We also focused on
exploring the unusual activation modes of bifunctional hydrogen-
bonding-tertiary amine organocatalysis because of our
continuing efforts to expand the repertoire of organocatalytic
tools.23 For the same reason, instead of the more common
bifunctional catalytic strategy of combining a Brønsted acid with
a Brønsted base (Figure 4, left),24 we planned to combine a
Brønsted acid and Lewis base (Figure 4, right) on the basis of
Figure 5. The proposed transition state of a Brønsted acid-Lewis base
activation mode.
Figure 4. Three activation modes of bifunctional H-bonding-tertiary amine catalysts.
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chiral stationary phase. [f] 0.02 mmol of C9 and 0.02 mmol of C1 were
used. [g] 0.02 mmol of C9 and 0.02 mmol of C8 were used. [h] Reaction
performed at 0 oC. [i] Reaction performed at -20 oC. [j] 0.08 mmol of C8 was
used.
Table 4. Optimization of conditions for the asymmetric RC-type reaction.[a]
Using optimized reaction conditions (Table 4, entry 8), we
succeeded in generating typical asymmetric RC-type products in
good yields and with excellent Z/E ratios (Table 5).
Enantioselectivity was greater when the nitroolefin 2 carried
electron-donating groups (entries 3-6) than when it carried
electron-withdrawing groups (entries 8-10). Enantioselectivity up
to 91% ee was obtained with nitroolefin 2 bearing a methoxy
group (entries 3, 4 and 6). Slightly lower enantioselectivity was
obtained when the nitroolefin was substituted at the ortho-
position (entries 2 and 7), perhaps as a result of steric hindrance.
Heteroaryl nitroolefin gave the target product 3s, albeit in slightly
lower yield and poorer ee (entry 11). Naphthaldehyde nitroolefin
afforded the corresponding products in good yield but with poor
enantioselectivity (entry 12). Using 3-alkenyl-substituted
oxindole 4a, a tri-substituted alkene, instead of nitroolefin 2 led
to lower enantioselectivity,26 probably because 4a lacks the
hydrogen bond-accepting nitro group.
The synthetic usefulness of our RC-type reaction lies in its
ability to generate a tetra-substituted alkene containing an
activated methylene group and an activated alkene. This
Time
[h][b]
Yield
[%][c]
Z/E
[3a:3a’][d]
ee
[%][e]
Entry
Cat.
Solvent
Table 5. Substrate scope of the asymmetric RC-type reaction.[a]
1
C1
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Toluene
MeCN
THF
4
76
73
62
65
62
70
68
72
74
70
68
65
56
67
64
53
69
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
41
29
65
44
51
41
-45
83
53
76
67
64
55
79
81
80
82
2
C2
4
3
C3
12
6
4
C4
En
try
Time
[h][b]
Yield
[%][c]
Z/E
[3:3’][d]
ee
[%][e]
R
Product
5
C5
8
1
Ph
8
chiral 3a
chiral 3b
chiral 3e
chiral 3f
chiral 3h
chiral 3i
chiral 3j
chiral 3m
chiral 3p
chiral 3r
chiral 3s
chiral 3u
72
73
75
77
76
78
57
65
69
64
60
67
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
83
75
87
88
83
91
72
82
82
83
77
56
6
C6
12
12
8
2
2-CH3C6H4
3-OMeC6H4
4-OMeC6H4
4-i-PrC6H4
3,4-(OMe)2C6H3
2-FC6H4
12
12
12
12
12
6
7
C7
3
8
C8
9[f]
10[g]
11
12
13
14
15[h]
16[i]
17[j]
C9+C1
C9+C8
C8
6
4
5
10
8
6
7
C8
8
8
3-ClC6H4
6
C8
10
10
24
36
4
9
4-BrC6H4
6
C8
CHCl3
10
11
12
3,4-Cl2C6H3
2-thienyl
6
C8
CH2Cl2
CH2Cl2
CH2Cl2
8
C8
β-naphthyl
8
C8
[a] See entry 8 and footnote a in Table 3. [b] Indicates the time after which
the yield of 3 did not increase. [c] Yield of isolated chiral 3. [d] Calculated
based on 1H NMR analysis of the crude reaction mixture. [e] Determined by
HPLC using a chiral stationary phase.
[a] Unless noted otherwise, reactions were performed with 0.30 mmol of 1a,
0.20 mmol of 2a, and 0.04 mmol of chiral catalyst in 1 mL of solvent at room
temperature. [b] Indicates the time after which yield of chiral 3a did not
increase. [c] Yield of isolated chiral 3a. [d] Calculated based on 1H NMR
analysis of the crude reaction mixture. [e] Determined by HPLC using a
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the RC-type products served as 1,4-synthons in [4+2] cyclization
to provide elegant access to fully substituted spirocyclohexane-
based pyrazolones bearing two highly congested contiguous
quaternary carbon centers.
Experimental Section
General Methods. NMR data were obtained for 1H at 400 MHz or 600
MHz, and for 13C at 100 MHz or 150 MHz. Chemical shifts were reported
in ppm from tetramethylsilane using solvent resonance in CDCl3 solution
as the internal standard. ESI HRMS was performed on a Waters
SYNAPT G2. Enantiomeric ratios were determined by comparing HPLC
analysis of products on chiral columns with results obtained using
authentic racemates. The following Daicel Chiralpak columns were used:
AS-H (250 x 4.6 mm), AD-H (250 x 4.6 mm), IC (250 x 4.6 mm) or IE
(250 x 4.6 mm). UV detection was performed at 220 nm or 254 nm.
Optical rotation values were measured with instruments operating at λ =
Scheme 6. Asymmetric synthesis of fully substituted cyclohexane-based
spiropyrazolone.
species can serve as a 1,4-synthon in a [4+2] cyclization
reaction to provide cyclohexane-fused drug-like scaffolds. To
illustrate this synthetic potential, we reacted this tetra-substituted
alkene 3i with pharmacologically interesting pyrazolone27 7a in
the presence of 20 mol% trimethylamine in dichloromethane at
room temperature (Scheme 6). To our delight, we obtained a
spirocyclohexane-based pyrazolone28 8a containing six
contiguous chiral centers and two highly congested, vicinal
quaternary stereocenters in 43% yield and 90% ee.
589 nm, corresponding to the sodium
D
line at 20 oC. Column
chromatography was performed on silica gel (200-300 mesh) using an
eluent of ethyl acetate and petroleum ether. Melting points were
determined on a Mel-Temp apparatus and were not corrected. All
reactions were monitored by thin layer chromatography (TLC) with silica
gel-coated plates and products were visualized using UV light and I2.
The absolute configuration of 8a was determined by X-ray
crystallographic analysis (Figure 6),29 and from this we also
tentatively inferred the absolute configuration of chiral 3i. The
absolute configurations of the other chiral RC-type products 3
were tentatively assigned by analogy.
General Procedure for the Synthesis of RC-type Tetra-substituted
Alkenes 3 and 3’. The reaction was carried out with 1a (62.15 mg, 0.30
mmol) and nitroolefin 2 (0.20 mmol) in the presence of PPh3 (10.49 mg,
0.04 mmol) in CH2Cl2 (1.0 ml) at room temperature. The reaction was
monitored by TLC until no further increase in the total yield of 3 and 3’
was observed. When the reaction was completed, the resulting mixture
was directly subjected to flash chromatography on silica gel (eluted by
petroleum ether/ethyl acetate = 14:1) to give the product 3 and 3’, which
were dried under vacuum and further analyzed by 1H NMR, 13C NMR,
HRMS analysis.
General Procedure for the Synthesis of 3-Allylic Type Oxindole
Derivatives 5. The reaction was carried out with 1a (62.15 mg, 0.30
mmol) and 3-alkenyl substituted oxindole 4 (0.20 mmol) in the presence
of DABCO (4.49 mg, 0.04 mmol) in CH2Cl2 (1.0 ml) at 0oC. The reaction
was monitored by TLC until no further increase in the yield of 5 was
observed. When the reaction was completed, the resulting mixture was
directly subjected to flash chromatography on silica gel (eluted by
petroleum ether/ethyl acetate = 13:1) to give the major RC-type product 5,
which was dried under vacuum and further analyzed by 1H NMR, 13C
NMR, HRMS analysis.
Figure 6. ORTEP drawing of compound 8a. Ellipsoids are shown at the 50%
probability level.
Conclusions
General Procedure for the Synthesis of Chiral RC-type Tetra-
substituted Alkene 3. The reaction was carried out with 1a (31.07 mg,
0.15 mmol) and nitroolefin 2 (0.1 mmol) in the presence of catalyst C8
(12.61 mg, 0.02 mmol) in dry CH2Cl2 (1.0 ml) at room temperature. The
reaction was monitored by TLC until no further increase in the yield of 3
was observed. When the reaction was completed, the resulting mixture
was directly subjected to flash chromatography on silica gel (eluted by
petroleum ether/ethyl acetate = 14:1) to give the product chiral 3, which
was dried under vacuum and further analyzed by 1H NMR, 13C NMR,
HRMS and chiral HPLC analysis.
In conclusion, we have presented an efficient chemo- and regio-
selective cross RC-type reaction in which a tri-substituted alkene
serves as an RC-type donor. Using this strategy, we easily
obtained multi-functionalized, tetra-substituted RC-type products.
Both 1,2-disubstituted and 1,2,2-trisubstituted alkenes
participated as RC-type acceptors in the reaction. When 3-
ylidene oxindole was employed as RC-type acceptor, we
obtained a 3-allylic-type oxindole skeleton, widely used in the
synthesis of various natural products or pharmaceutical lead
compounds. We also achieved the asymmetric version of this
RC-type reaction using the possible combination of a Brønsted
acid and Lewis base, extending the applications of bifunctional
H-bonding-tertiary amine organocatalysts. More interestingly,
Asymmetric Synthesis of Fully Substituted Cyclohexane-based
Spiropyrazolone 8a. The reaction was carried out with chiral 3i (41.64
mg, 0.10 mmol) and (Z)-4-benzylidene-3-methyl-1-phenyl-1H-pyrazol-
5(4H)-one 7a (31.48 mg, 0.12 mmol) in the presence of triethylamine
(2.02 mg, 0.02 mmol) in CH2Cl2 (1.0 ml) at room temperature for 8 h. The
This article is protected by copyright. All rights reserved.

10.1002/chem.201705010
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reaction was monitored by TLC. When the reaction was completed, the
resulting mixture was directly subjected to flash chromatography on silica
gel (eluted by petroleum ether/ethyl acetate = 12:1) to give the product
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8a, which was dried under vacuum and further analyzed by 1H NMR, 13
C
NMR, HRMS and chiral HPLC analysis. Compound 8a was obtained as a
white solid in 44% yield (38.02 mg) for two steps after flash
chromatography. The dr value was calculated to be 10:1 from 1H NMR
analysis. The enantiomeric excess was determined to be 90% by HPLC
(Chiralpak AD-H column, 20% 2-propanol/n-hexane, flow rate 1 ml/min,
UV 254 nm): tminor = 7.83 min, tmajor = 10.36 min. m.p. 171-173 oC; [α]D20: -
33.84 (c 0.09 in CH2Cl2). 1H NMR (600 MHz, CDCl3): δ = 7.44-7.41 (m,
2H), 7.39-7.36 (m, 2H), 7.25-7.23 (m, 2H), 7.22-7.17 (m, 2H), 7.07-6.95
(m, 4H), 6.86 (d, J = 8.4 Hz, 1H), 5.98 (t, J = 12.0 Hz, 1H), 5.31 (d, J =
12.0 Hz, 1H), 4.43-4.37 (m, 1H), 4.34-4.28 (m, 2H), 4.09 (d, J = 11.4 Hz,
1H), 3.93 (s, 3H), 3.84 (s, 3H), 3.51 (d, J = 13.8 Hz, 1H), 3.23 (d, J = 13.8
Hz, 1H), 2.22 (s, 3H), 1.38 (t, J = 7.2 Hz, 3H) ppm; 13C NMR (150 MHz,
CDCl3): δ = 170.57, 167.67, 156.57, 149.86, 149.72, 136.08, 130.72,
130.02, 129.32, 129.05, 127.00, 125.77, 125.26 (d, JCF = 286.5 Hz),
120.65, 115.21, 111.71, 88.75, 62.88, 59.63, 56.12, 55.84, 52.88 (q, JCF
= 23.7 Hz), 47.16, 44.92, 34.38, 32.06, 18.32, 13.94 ppm. ESI HRMS:
calcd. For C35H33F4NO7Na+ 701.2199, found 701.2198.
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Acknowledgements
We are grateful for financial support from the National Natural
Science Foundation of China (81573588, 81630101 and
81773889), the Science & Technology Department of Sichuan
Province (2017JQ0002), the Foundation for the Author of
National Excellent Doctoral Dissertation of PR China (201487)
and the China Postdoctoral Science Foundation.
Keywords: cross Rauhut-Currier-type reaction; organocatalysis;
tri-substituted alkene; asymmetric synthesis; bifunctional H-
bonding-tertiary amine
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[13] For ESI-MS spectra indicating the existence of intermediates predicted
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Supporting Information.
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10.1002/chem.201705010
Chemistry - A European Journal
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Yang, W. Sun, C. Zhang, Q. Wang, Z. Guo, B. Mao, J. Liao, H. Guo,
ACS Catal. 2017, 7, 3142-3146.
[29] CCDC 1571411 (8a) contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre.
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10.1002/chem.201705010
Chemistry - A European Journal
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Entry for the Table of Contents
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Xiang-Hong He, Lei Yang, Yan-Ling Ji,
Qian Zhao, Ming-Cheng Yang, Wei
Huang, Cheng Peng* and Bo Han*
Page No. – Page No.
Chemo- and Stereoselective Cross
Rauhut-Currier-Type Reaction of Tri-
substituted Alkenes Containing
Trifluoromethyl Groups
A chemoselective cross RC-type reaction has been developed involving a tri-
substituted alkene (CF3-containing acrylonitrile derivative) is described. This
approach can support the synthesis of trifluoromethylated tetra-substituted olefins
and 3-allylic-type oxindole skeletons. The transformation of multi-functionalized
chiral RC-type product leads to pharmacologically interesting cyclohexane-based
spiro-pyrazolones bearing six contiguous chiral centers.
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