Catalytic Asymmetric Mukaiyama-Mannich Reaction of Cyclic C-Acylimines with Difluoroenoxysilanes: Access to Difluoroalkylated Indolin-3-ones

Article abstract of DOI:10.1021/acs.orglett.7b03213

A catalytic enantioselective Mukaiyama-Mannich reaction of cyclic C-acylimines with difluoroenoxysilanes is reported. (S)-TRIP enables the enantioselective synthesis of a series of novel difluoroalkylated indolin-3-ones bearing a quaternary stereocenter i

Full text of DOI:10.1021/acs.orglett.7b03213

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX-XXX
Catalytic Asymmetric Mukaiyama−Mannich Reaction of Cyclic
C‑Acylimines with Difluoroenoxysilanes: Access to Difluoroalkylated
Indolin-3-ones
Jin-Shan Li, Yong-Jie Liu, Guang-Wu Zhang, and Jun-An Ma*
Department of Chemistry, Tianjin Key Laboratory of Molecular Optoelectronic Sciences, Tianjin University, and Collaborative
Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300072, P. R. China
S
* Supporting Information
ABSTRACT: A catalytic enantioselective Mukaiyama−Man-
nich reaction of cyclic C-acylimines with difluoroenoxysilanes
is reported. (S)-TRIP enables the enantioselective synthesis of
a series of novel difluoroalkylated indolin-3-ones bearing a
quaternary stereocenter in up to 97% yield and 98% ee. The
synthetic utility of this protocol is highlighted by efficient
conversion of the products to the corresponding indolin-3-one
derivatives without any erosion of the enantiopurity.
xindoles are prominent scaffolds in natural products with
Scheme 1. Strategies for Enantioselective Synthesis of
Difluoroalkylated Indolin-2-ones and Indolin-3-ones
O
diverse biological activities.1 Therefore, the development
of convenient synthetic methods for the enantioselective
assembly of oxindoles has become the subject of intensive
research in the field of synthetic organic chemistry.2 Likewise, the
selective incorporation of a fluoroalkyl group into a target organic
molecule often significantly changes the properties of the
molecule, such as the metabolic stability, bioavailability,
lipophilicity, and membrane permeability, which have extensive
applications in pharmaceutical research.3 Consequently, the
synthesis of fluoroalkyl-substituted oxindoles has gained great
attention.4 Most of the recent developments in this context have
focused on the trifluoromethylation of oxindoles, whereas the
catalytic enantioselective difluoroalkylation of oxindoles is still
less exploited (Figure 1).5 In 2012, Zhou and co-workers
ones bearing a quaternary stereocenter could be constructed
through the Mukaiyama−Mannich reaction of cyclic C-
acylimines (2-substituted-3H-indol-3-ones) with difluoroenox-
ysilanes in the presence of chiral phosphoric acids (Scheme 1b).
Herein, we report our preliminary results on this subject.
2-Aryl-3H-indol-3-ones 1, important cyclic ketimines acti-
vated by the coplanar carbonyl group, are useful synthetic
intermediates for the synthesis of 2,2-disubstituted indolin-3-one
derivatives.8 However, 2-aryl-3H-indol-3-ones are not easily
accessible and have to be prepared through a troublesome
stepwise transformation.9 One recent report by Sperry and co-
workers has addressed one example involving one-pot multistep
synthesis of indolone.10 According to this procedure, we
prepared a series of 2-aryl-3H-indol-3-ones on a gram-scale in
moderate to good yields (Scheme 2).
Figure 1. Structure motifs of trifluoromethylated and difluoroalkylated
oxindoles.
reported the first example of highly enantioselective organo-
catalytic synthesis of 3-difluoroalkyl-substituted 3-hydroxyindo-
lin-2-ones by employing a hydroquinine-derived urea catalyst
(Scheme 1a).6 However, to the best of our knowledge, no
attempt has been reported for the installation of a difluoroalkyl
group into the indolin-3-one framework, and the resulting
difluoroalkylated products might be interesting for medicinal
studies (Figure 1, highlighted in red). Encouraged by this
interesting investigation, along with our interest in the Brønsted
acid-catalyzed asymmetric construction of fluorinated organic
compounds,7 we envisioned that difluoroalkylated indolin-3-
With 3H-indol-3-ones 1 in our hands, we first examined the
reaction between 2-phenyl-3H-indol-3-one 1a and difluo-
roenoxysilane 2a by using a series of chiral phosphoric acids
4a−k (Table 1). We were delighted to find that the reaction
Received: October 14, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03213
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. General Procedure for the Preparation of 2-Aryl-
3H-indol-3-ones 1
Scheme 3. Scope of the Enantioselective Mukaiyama−
Mannich Reaction of 2-Aryl-3H-indol-3-ones 1 with
Difluoroenoxysilanes 2
a
Table 1. Catalyst Screening and Condition Optimization
b
c
entry
catalyst
solvent/temp (°C)/time (h)
yield (%)
ee (%)
1
4a
4a
4a
4a
4a
4a
4a
4b
4c
4d
4e
4f
THF/25/48
86
93
80
46
32
96
0
89
91
85
62
35
93
2
THF/0/60
3
Et2O/0/48
4
toluene/0/72
CH2Cl2/0/72
THF/−20/72
THF/−40/144
THF/−20/24
THF/−20/72
THF /−20/24
THF /−20/72
THF/−20/24
THF/−20/36
THF/−20/24
THF/−20/84
THF/−20/36
THF/−20/36
THF/−20/96
5
6
7
8
89
87
84
93
81
88
86
84
79
82
87
70
67
54
84
57
85
84
73
70
77
89
9
10
11
12
13
14
15
16
17
4g
4h
4i
the phenyl ring could be well tolerated in the reaction with
difluoroenoxysilane 2a, affording the corresponding products
3a−j in good yields and with high enantioselectivities. 1- and 2-
Naphthyl-substituted 3H-indol-3-ones 1k and 1l also delivered
the Mannich products 3k and 3l with high enantioselectivity, a
similar results were obtained for 2-phenyl-3H-indol-3-ones 1
with both electron-donating and -withdrawing groups on the
indolone ring (3m−p). X-ray crystallographic analysis of 3p
allowed the absolute configuration of the stereogenic center to be
assigned as R. Several aryl-substituted difluoroenoxysilanes 2q−u
also gave corresponding products 3q−u in good yields with good
to high ee values. In addition, we investigated the Mannich
reaction of 2-phenyl-3H-indol-3-one 1a with benzyl-substituted
difluoroenoxysilane. This alkyl-substituted difluoroenoxysilane
substrate was found to be unsuitable for this asymmetric
transformation, and no desired product was observed.
Apart from 2-aryl-3H-indol-3-ones, a series of indolones,
1′H,3H-[2,3′-biindol]-3-ones 5 (indoxyl red derivates, which
were isolated from the glycoside indicant with a strong purple-
red color),12 were also viable substrates under the established
conditions (Scheme 4). C2−C3′ bisindole-3-ones with electron-
donating or withdrawing groups on the indole ring all worked
well, and the reactions were all completed within 48−72 h to give
the products 6a−l in good yields with good to excellent
enantioselectivities. Difluoroenoxysilanes 2 with different
substituents on the phenyl ring also gave the corresponding
products 6m−s in good yields with excellent ee values. It should
be noted that a higher temperature was required for the Mannich
reaction, probably due to the lower reactive activities of these
substrates.
4j
4k
4a
d
18
a
General reaction conditions: 1a (0.1 mmol), 2a (0.2 mmol), and
catalyst 4 (10 mol %) in solvent (1 mL) at the given temperature for
b
c
the stated time. Isolated yield. Enantiomeric excess (ee) was
determined by chiral HPLC analysis. 5 mol % of catalyst was used.
d
proceeded smoothly to afford the desired product 3a in good
yield with 89% ee in the presence of the catalyst (S)-TRIP 4a11 in
THF at room temperature (entry 1). Lowering the reaction
temperature to 0 °C improved the yield and enantioselectivity
slightly (entry 2). Subsequently, the solvent was found to have a
pronounced effect on the reactivity and selectivity (entries 3−5).
Among the solvents tested, THF was found to be the best with
respect to the asymmetric induction. Further improvement in
enantioselectivity was achieved by decreasing reaction temper-
ature with a prolonged reaction time (entry 6). Subsequent
attempts to conduct the reaction at −40 °C failed (entry 7).
Other chiral phosphoric acids 4b−k were then tested at −20 °C
(entries 8−17), and we found that phosphoric acid 4a proved to
be the best (entry 6). Reducing the catalyst loading from 10 to 5
mol % had a deleterious effect on both yield and ee (entry 18).
With the optimized reaction conditions in hand, a series of 2-
aryl-substituted 3H-indol-3-one derivatives 1 was reacted with
various difluoroenoxysilanes 2 to probe the generality of the
reaction (Scheme 3). In general, 2-phenyl-3H-indol-3-ones 1
bearing electron-donating or electron-withdrawing groups on
B
DOI: 10.1021/acs.orglett.7b03213
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 4. Scope of the Enantioselective Mukaiyama−
Mannich Reaction of 1′H,3H-[2,3′-Biindol]-3-ones 5 with
Difluoroenoxysilanes 2
Scheme 6. Reaction of 5,5′-Dibromo-1′-tosyl-1′H,3H-[2,3′-
biindol]-3-one 5k′ with Difluoroenoxysilane 2a
Figure 2. Proposed transition state for the reaction of difluoroenox-
ysilanes with 3H-indol-3-ones.
hydrogen bonding interaction, therefore creating a chiral
environment wherein the enol silyl ethers attack the Si face of
the CN group preferentially. Further studies are required to
fully elucidate the detailed mechanism of this Mukaiyama−
Mannich reaction.
In summary, we have successfully developed a chiral
phosphoric acid-catalyzed enantioselective Mukaiyama−Man-
nich reaction of cyclic C-acylimines with difluoroenoxysilanes.
This method tolerates a series of 2-aryl-substituted 3H-indol-3-
ones, affording the difluoroalkylated indolin-3-ones bearing a
quaternary stereocenter in high yields (up to 97%) and
enantioselectivities (up to 98% ee). Moreover, the products
obtained can be readily converted into optically active esters and
α-CF2H derivatives by simple modifications. Further develop-
ment and applications of this Mannich reaction, as well as the
one-pot procedure for the synthesis of compounds containing
CF2H groups, is ongoing in our laboratory.
To demonstrate the synthetic utility of this protocol, we
conducted further manipulation by using the product 3e
(Scheme 5). The Baeyer−Villiger oxidation13 of 3e (>99.9% ee
Scheme 5. Further synthetic transformations
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b03213.
after one recrystallization) gave corresponding ester 7 in 92%
yield without any loss of ee. Of particular interest, we found that
the C−C bond adjacent to the carbonyl group in these α,α-
difluoroketones could be readily cleaved to afford the optically
pure indolin-3-one 8 bearing CF2H group in the presence of 2.0
equiv of NaOH at room temperature.14 The resulting CF2H-
containing molecules are biologically interesting because of their
frequent use in medicinal chemistry, owing to the fact that the
CF2H group often acts as a bioisostere for alcohols and thiols.15
To probe the substitution effect of the remote N-protecting
group on the indole ring, the reaction between N-tosylated
1′H,3H-[2,3′-biindol]-3-one 5k′ and difluoroenoxysilane 2a was
performed to give the comparable enantioselectivity with
unprotected indol-3-one 5k, indicating that the hydrogen on
the N atom of the indole moiety is not essential for the activation
of the reactant by the phosphoric acid catalyst in this reaction
(Scheme 6). Based on this result and the stereochemical
outcome of the Mannich adduct with the R configuration, a
potential transition state was proposed. As shown in Figure 2, the
phosphoric acid could activate cyclic ketimine through the
Experimental details, spectral data of all the new
compounds, and HPLC analytic results for 3a−u, 6a−
6s, 7, and 8 (PDF)
Accession Codes
CCDC 1575423 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_
request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: majun_an68@tju.edu.cn.
ORCID
Jun-An Ma: 0000-0002-3902-6799
C
DOI: 10.1021/acs.orglett.7b03213
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National Natural Science
Foundation of China (No. 21225208, 21472137, and
21532008), the National Basic Research Program of China
(973 Program, 2014CB745100), and Tianjin Municipal Science
& Technology Commission (14JCZDJC33400).
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DOI: 10.1021/acs.orglett.7b03213
Org. Lett. XXXX, XXX, XXX−XXX