Enantioselective Mannich-Type Reactions to Construct Trifluoromethylthio-Containing Tetrasubstituted Carbon Stereocenters via Asymmetric Dual-Reagent Catalysis

Article abstract of DOI:10.1002/adsc.201700321

An approach to construct tetrasubstituted carbon stereocenters bearing both a trifluoromethylthio (SCF₃) group and a cyano group has been realized, through asymmetric organophosphine-catalyzed Mannich-type reactions. The products were obtained

Full text of DOI:10.1002/adsc.201700321

Title: Enantioselective Mannich-type Reactions to Construct
CF3S-containing Tetrasubstituted Carbon Stereocenters via
Asymmetric Dual-Reagent Catalysis
Authors: Gang Zhao, Lijun Xu, Changwu Zheng, and Hongyu Wang
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10.1002/adsc.201700321
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Enantioselective Mannich-type Reactions to Construct CF3S-
containing Tetrasubstituted Carbon Stereocenters via
Asymmetric Dual-Reagent Catalysis
Lijun Xu,a Hongyu Wang,a Changwu Zheng,a Gang Zhaoa*
a
Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese
Academy of Sciences, 345 Lingling Lu, Shanghai 200032, China.
[E-mail: zhaog@sioc.ac.cn]
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract: An approach to construct tetrasubstituted carbon Keywords: CF3S-containing building blocks; Mannich-
stereocenters bearing both a SCF3 group and a cyano group type reactions; Nucleophilic phosphines; The dual-reagent
has been realized, through asymmetric organophosphine- catalysis
catalyzed Mannich-type reactions. The products were
obtained in high yields and moderate to high
enantioselectivities. Two diastereoisomers could be isolated
from each reaction (25 overall examples), rendering this
approach a viable opportunity for molecular diversity
generation and improvement of the bioactivity of related
drug candidates.
using CF3S-containing building blocks have been
Introduction
reported.
Asymmetric catalysis with nucleophilic phosphines
The incorporation of fluorine-containing groups into
organic molecules often modifies their chemical and
physicochemical properties.[1] Trifluoromethylthio
(SCF3) containing compounds are frequently found in
pharmaceuticals and agrochemicals because of the
high lipophilicity and electron-withdrawing character
of the SCF3 moiety.[2] Recently, tremendous progress
for the introduction of SCF3 group into organic
compounds using nucleophilic or electrophilic SCF3
transfer reagents has been achieved.[3] Alternatively,
strategies for the formation of trifluoromethyl-
thiolated compounds through the transformation from
SCF3-containing building blocks have drawn
attention due to their high atom economy. So far,
several examples related to CF3S-containing building
blocks of type I-IV (Scheme 1, eq. a) have been
independently reported by Ponticello and Wakselman
for the synthesis of heteroaryl trifluoromethyl
sulfides.[4] Other than these methods, very recently,
an enantioselective trifluoromethylthiolation of β-
ketoesters has been developed by Rueping,[5] Shen[6]
and Tan[7] using cinchona alkaloid as the catalyst.
Zhao and co-workers also revealed an efficient
has captured considerable interest due to the
effectivity for the synthesis of chiral organic
molecules.[9] Recently, we have developed novel
asymmetric dual-reagent catalysis to expand the
application of the asymmetric nucleophilic phosphine
to Mannich-type reactions between N-Boc imines and
nucleophilic reagents such as dimethyl 2-fluoro-mal-
approach
for
enantioselective
trifluoro-
methylthiolating lactonization catalyzed by an
indane-based chiral sulfide.[8] However, until now, no
reports for the construction of stereogenic centers
Scheme 1. a) Reported CF3S-containing building blocks.
b) Asymmetric dual-reagent catalysis. c) Enantioselective
Mannich-type reactions involving CF3S-pronucleophiles.
1
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10.1002/adsc.201700321
Advanced Synthesis & Catalysis
onate, nitroalkanes and β-ketoesters (Scheme 1, eq.
b).[10] Besides, the zwitterion generated in situ could
also serve as an efficient Lewis base catalyst for the
asymmetric cyanation of ketimines derived from
isatins (Scheme 1, eq. b). [11] Inspired by the above-
mentioned process, we envisaged that an appropriate
CF3S-containing pro-nucleophile could be utilized in
the asymmetric dual-reagent catalysis. Herein, we
erous natural products and marketed drugs.[12] The
acidity of the proton alpha to the nitrile group may
play a key role in favoring the deprotonation of 1h,
even if other factors such as steric and/or solvent
effects could be relevant for the success of the
reaction (for details, see the Supporting
Information).[13]
Encouraged by this result, a series of chiral
report an enantioselective Mannich-type reaction bifunctional catalysts derived from amino acids
between N-Boc imines and CF3S-containing building were synthesized and evaluated. The reaction was
blocks. This transformation offers an expeditious
first performed in DCM at room temperature
approach to enantioenriched CF3S-containing without methyl acrylate (MA) in the presence of
tetrasubstituted carbon stereocenters (Scheme 1, eq. 4b to give trace of product. On the other hand,
c).
when MA was added to the reaction mixture, the
yield and enantioselectivity drastically improved
to 85% and 65%/33% ee for the two
diastereomers, respectively (Table 1, entries 1
and 2). Various reaction temperatures were then
investigated and it was found that the reaction
was much more enantioselective at low
temperature without the need for extending
reaction time (Table 1, entries 3 and 4).
Results and Discussion
The initial stages of the study revolved around
finding an appropriate CF3S-containing building
block for the Mannich-type reaction with N-Boc
imine (2a) to get the desired product in acceptable
yield. Unfortunately, under previously used
conditions, no products were observed with a variety
of CF3S-containing pro-nucleophiles (Figure 1, 1a–
1g) (for details, see the Supporting Information). To
our delight, the more reactive pronucleophile 1h
Table 1. Optimization of chiral catalystsa
provided the desired product bearing
a
tetrasubstituted carbon stereocenters as a mixture of
two diastereomers (3a + 3a′) in 96% yield, as
determined by 19F NMR spectroscopy (Figure 1). In
contrast, compound 1f, which differs from 1h by
containing an ester group instead of the cyano group,
produced traces of the product, indicating that the
cyano group is quite important for reaction efficiency.
It is worth mentioning that nitriles are ubiquitous in
organic synthesis and aryl nitriles are present in num-
Yield
(%)b
trace
85
83
82
80
82
85
81
83
82
82
82
82
81
81
48
drc
(3a : 3a′)
－
ee(%)c
(3a/3a′)
Entry
Catalyst
Solvent T/oC
1d
2
3
4
5
6
7
8
4b
4b
4b
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Toluene
EtOAc
CH2Cl2
r.t.
r.t.
－
59:41
62:38
70:30
57:43
58:42
67:33
59:41
57:43
68:32
72:28
69:31
78:22
74:26
66:34
55:45
64:36
65(33)
75(44)
86(63)
31(-21)
32(-6)
37(-17)
46(-49)
18(0)
62(14)
66(13)
59(19)
90(73)
66(45)
43(68)
82(52)
76(81)
Figure 1. Screening of CF3S-containing building blocks as
pronucleophiles
-30
-72
-72
-72
-72
-72
-30
-72
-72
-72
-72
-72
-72
-72
-72
9
10
11
12
13
14
15
16
17e
4k
4k
4k
82
[a] Unless otherwise noted, the reactions were performed
with 1h (0.05 mmol), 2a (0.10 mmol) and methyl acrylate
(10 mol%) in the presence of chiral phosphine 4 (10 mol%)
in solvent (0.5 mL) for 0.5 h. [b] Total isolated yields of 3a
and 3a′. [c] The dr values were determined by chiral
HPLC analysis and the ee values of the minor diastereomer
3a′ were shown in parentheses. [d] The reaction was
performed without methyl acrylate. [e] The reaction was
performed with 4k (5 mol%) and methyl acrylate (5 mol%).
[a] Unless otherwise noted, all reactions were carried out
with 1 (0.05 mmol), 2a (0.10 mmol), 4a (10 mol%),
methyl acrylate (10 mol%) in CH2Cl2 (0.5 mL) at r.t. for 5
h and monitored by 19F NMR spectroscopy. [b] Reaction
was stirred for 0.5 h. Yield of the isolated products.
2
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10.1002/adsc.201700321
Advanced Synthesis & Catalysis
Among the several catalysts screened, the chiral
skeleton derived from L-phenylalanine performed
the Mannich-type reaction, however no improvement
in enantioselectivity was found (Table 1, entries 15
and 16). Additionally, reducing the catalyst loading to
5 mol% led to a loss of stereoselectivity (Table 1,
entry 17).
After optimized reaction conditions were found,
we next turned our attention to exploring the CF3S-
containing building block (1h) and various N-Boc
imines (2) in this Mannich-type reaction. As
summarized in Table 2, all of the N-Boc imines
examined provided the corresponding products in
high isolated yields within 0.5 hour regardless of the
electronic nature and the steric effect of substituents
on the aryl ring of imines. In general, substituted
aromatic imines bearing electron-donating groups
(such as Me, Et, i-Pr, and t-Bu) afforded the major
diastereomer products with high levels of enantiose-
best
in
terms
of
enantioselectivity
and
diastereoselectivity (Table 1, entry 4 versus 5 and 6).
The acyl group of bifunctional chiral phosphine
catalysts seemed crucial for the enantiocontrol.
Replacement of this moiety with thiourea (4e) or urea
(4f) led to inferior results (Table 1, entries 7 and 8).
Further investigations indicated that the electronic
effect of different substitutent groups of the acyl
moiety were also crucial to the enantioselectivity
(Table 1, entries 9 to 14). Catalyst 4k, which contains
strongly electron-withdrawing nitro-groups, turned
out to be the best under the same reaction conditions
providing products with 82% isolated yield and
higher enantioselectivity (90% ee and 73% ee, for the
two diastereomers, respectively) (Table 1, entry 13).
We also investigated the effect of various solvents on
Table 2. Scope of the Mannich-type reaction catalyzed by the dual-reagent catalysisa
[a] Isolated yields of the major diastereomer 3 on a 0.1 mmol scale. Isolated yields and the ee values of the minor
diastereomer 3´ were shown in parentheses. The dr values were determined by chiral HPLC analysis. The dr value of 3n
and 3n′ was determined by 1H NMR spectroscopic analysis of the crude product.
lectivity and moderate levels of diastereoselectivity
(3a–3h). Particularly, imine bearing meta-methyl
group on the aryl ring reacted efficiently, producing
3g in 94% ee. Aromatic imines with electron-
withdrawing groups (such as F, Cl and Br) provided
the addition products 3i–3n with moderate
stereoselectivity. Additionally, heteroaryl and poly-
cyclic aromatic imines also worked under the reaction
conditions, furnishing the products 3o–3r in
moderate to good enantioselectivities. Moreover, the
cyclohexyl
containing
imine
afforded
the
corresponding product in 96% ee (3s). The absolute
configuration of 3m was confirmed by X-ray
crystallographic analysis after recrystallization
3
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10.1002/adsc.201700321
Advanced Synthesis & Catalysis
(Figure 2); additionally, the absolute configuration of
the minor diastereomer (3n′) was also determined,
supporting the notion that the diastereoisomeric
couples 3/3′ are epimeric at C2 (see the Supporting
Information for details). [14]
desired products while N-Cbz imine could provide
the the corresponding major diastereomeric product
in 53% ee (see the SI). We also investigated
substituents other than a trifluoromethyl group on the
sulfide, as shown in scheme 2. With the electron-
donating methyl group (1q), the reaction also worked
under the similar conditions at ambient temperature,
although extended time was required. However, the
yield and enantioselectivity were low. To our delight,
the reaction proceeded smoothly with the
trifluoroethyl substituted sulfide (1r) to give the the
major diastereomeric product 7 in 58% yield and
72% ee (20% yield and 56% ee for the minor
diastereomer). The trifluoroethylthio group (-
SCH2CF3) has been proved to be an important moiety
in several agrochemical and pharmaceutical
compounds.[15]
Figur 2. X-ray crystal structure of 3m
Table 3. Substrate Scope of the CF3S-containing
buildingsa
Scheme 2. Related R3CS-building blocks in the Mannich-
type reaction
Scheme 3. The representative transformation of 3a
To demonstrate the utility of the products, compound
3a (90% ee) was converted to the useful amide 8
(85% ee) under the condition of Pd(OAc)2 and
acetaldoxime (Scheme 3).[16]
[a] Isolated yields of the major diastereomers 5 on a 0.1
mmol scale; Isolated yields and the ee values of the minor
diastereomer 5′ were shown in parentheses. The dr values
were determined by chiral HPLC analysis. The dr value of
5e and 5e′ was determined by H NMR spectroscopic
analysis of the crude product.
A possible mechanism for the reaction is shown in
Figure 3. First, the chiral phosphine adds to the
methyl acrylate, forming phosphonium enolate A,
which was confirmed by ESI-MS (m/z for (M + H)+:
600.2). This zwitterion, which acts a mild Brønsted
base, deprotonates 1h to generate the ion-pair B. This
ion-pair can then react with imine 2a to form
intermediates D (via transition state C). A proton
exchange then occurs to produce the product (3a +
3a′) and regenerate the ion-pair B. A possible
transition state C can be considered to control the
stereoselectivity. The N-Boc imine is activated by the
amide moiety of the catalyst through hydrogen
bonding and the pronucleophile seems to be
controlled via the ion pair generated in situ. Further
mechanistic studies to elucidate the reaction
mechanism will be explored.
1
We next examined the scope of the CF3S-
containing reagent (1) in the reaction to show the
variety of tolerated pronucleophiles (Table 3). In
general, good isolated yields (of the two
diastereomers) were obtained with a range of aryl
containing pronucleophiles (5a–5f). Electronic
effects and steric effects on the aryl ring of 2-
(trifluoromethylthio) phenylacetonitrile 1 showed a
negative influence on the enantioselectivity compared
to 3a. Reactions afforded the products with moderate
to high enantioselectivities.
Changing the protecting group of the imine to p-
toluenesulfonyl, 1,1-diphe-nylmethenyl, p-methoxy-
phenyl and diphenylphos-phinyl did not furnish the
4
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10.1002/adsc.201700321
Advanced Synthesis & Catalysis
Figure 3. Possible reaction mechanism and transition state
water (2 mL). The aqueous phase was extracted with DCM
(3 × 2 mL), and the combined organic layers were dried
over anhydrous Na2SO4 and concentrated in vacuo. The
crude product was purified by PTLC to afford two
diastereomers. The diastereomer ratio was determined by
Conclusion
In summary, we have developed the enantio-selective
Mannich-type reaction of the CF3S-containing
building blocks via a dual-reagent catalysis system
consisting of a bifunctional phosphine derived from
an amino acid and methyl acrylate as the additive.
This catalyst system can offer an efficient approach to
1
HPLC, H NMR and 19F NMR at this stage. The major
isomer and the minor isomer were isolated with PTLC for
data collection.
construct the chiral stereocenters bearing a SCF3 Acknowledgements
group and a cyano group in good yields and moderate
This work was supported by the National Natural Science
to high enantioselectivities. These moieties might
modulate the physicochemical properties of some
drug candidates by enhancing the lipophilicity. Our
Foundation of China (21272247, 21572247 and 21290184) and
Chinese Academy of Sciences (XDB 20020100). The authors
gratefully acknowledge Mr. Farid W. van der Mei (Boston
future research is directed at exploring the bioactivity College) for manuscript proofreading.
of these unique molecules. Additionally, the full
potential of this asymmetric dual-reagent catalysis
will be further explored.
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General procedure for the symmetric dual-reagent
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10.1002/adsc.201700321
Advanced Synthesis & Catalysis
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10.1002/adsc.201700321
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