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Letter
Enantioselective Alkynylation of Isatin Derivatives Using a
Chiral Phase-Transfer/Transition Metal Hybrid Catalyst System
Suva Paria, Hyo-Jun Lee, and Keiji Maruoka
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.8b04949 • Publication Date (Web): 05 Feb 2019
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Page 1 of 8 ACS Catalysis

1
2
3
4
5
6
7 Enantioselective Alkynylation of Isatin Derivatives Using a Chiral
8 Phase-Transfer/Transition Metal Hybrid Catalyst System
9
10 Suva Paria,† Hyo-Jun Lee,† and Keiji Maruoka*†‡
11
†
12 Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo, Kyoto 606-8502, Japan
13 ‡
School of Chemical Engineering and Light Industry, Guangdong University of Technology, No.100, West Waihuan Road,
14 HEMC, Panyu District, Guangzhou, 510006, China
15
16
17 ABSTRACT: An enantioselective alkynylation of isatin derivatives can be realized by using a hybrid catalyst system consisting of
18 chiral phase-transfer catalyst and transition metal catalyst. The chiral alkynylation products can be used as versatile intermediates
19 for further synthetic transformations.
20
21
22 KEYWORDS: phase-transfer catalyst, hybrid catalyst, asymmetric alkynylation, isatin, silver acetate
23
24 Among the different modes of asymmetric induction in organic   Y
3
25 synthesis, chiral phase-transfer catalysis represents a powerful and MX
R1R2
26 versatile tool to engage prochiral anionic nucleophiles and elec- R M (Y = O, NR 3)
27 trophiles by forming a chiral ion pair with enolates. This approach chiral
Path A low 2a Brønsted or R
produces high levels of enantioselectivity in a wide range of reac-
28 nucleophilicity Lewis acid
tions that include enolate alkylations, conjugate additions, cyclo- HY
29 propanations, oxidative cyclizations, and aminations.1 The pronu- R H 4
R1 * 2
30 cleophiles used in this context generally contain an enolizable 1 Path B enhanced Y R
3
31 proton that is deprotonated under basic conditions. In order to MX
nucleophilicity
R1 R2
32 stabilize the chiral ion pair with the quaternary ammonium cation R ML*
33 of chiral phase-transfer catalysts, oxygen anions derived from L* 2b
enolates are usually chosen. In marked contrast, examples of
34 M = transition metal; L* = chiral ligand
enantioselective transformations that involve carbanion-based
35 nucleophiles under chiral phase-transfer catalysis remain scarce in
36 The dearth of reports using chiral phase-transfer catalysts for
the scientific literature.2,3
37 asymmetric alkynylations probably arises from the instability of
The asymmetric alkynylation of ketones and imines is a versatile the ion pair (5a), which consists of a carbanion and a quaternary
38 process to prepare chiral propargylic alcohols and amines. Conse- ammonium cation (Scheme 2). We hypothesized that transition-
39 quently, a plethora of transformations that afford these target mo- metal alkynylides (2a), which are soft in nature, should generate a
40 lecules has been reported,4 including the pioneering work of Mu- more stable ion pair (5b) with chiral phase-transfer catalyst
41 kaiyama on the addition of Li-acetylides to aldehydes5 and later (QX).11,12 Once formed, 5b should be expected to react smoothly
that of Carreira.6 Many of these processes use functionalized al- with ketone-based electrophiles (3a) to furnish enantioenriched
42
kynes to generate the alkyne nucleophile, even though terminal tertiary alcohols (4a).
43 alkynes (1) have also been reported as alkynylide sources under
44 transition-metal catalysis in the presence of Cu,7 Zn,8 Rh,9 and
45 Ag10 complexes with chiral ligands. Generally, such transition Scheme   2.   Working   Hypothesis   for   Asymmetric   Alkynyla-­‐
46 metal alkynylides (2) are considered to be insufficiently nucle- tions  Catalyzed  by  Chiral  PTCs.  
47 ophilic to attack unactivated ketones or imines. However, the low
48 nucleophilicity of transition-metal alkynylides (2a) has been used
to render these reactions enantioselective. In Scheme 1, the two
49 main approaches to asymmetric alkynylation are shown. Path A
50 illustrates the enantioselective alkynylation of ketones or imines
51 (3) with 2a via an activation based on chiral Brønsted or Lewis
52 acids, which affords enantioenriched tertiary alcohols or amines
53 (4). Path B shows that the nucleophilicity of the metal alkynylide
54 (2a) can be enhanced by covalent or coordinative bonding bet-
ween the metal center and the chiral ligands, which also leads to
55 enantioenriched 4.
56
57
58 Scheme  1.   The  State  of  the  Art  of  Enantioselective  Alkynyla-­‐
59 tions.  
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Our hypothesis was inspired by the work of Tan, who have repor- AgOAc mesitylene
1 ted elegant asymmetric transformations based on the chiral-
2 counter-cation strategy.13 However, asymmetric alkynylations (S,S)-8d, Cs2CO3,
based on this strategy had not been available until recently, when 6 93 87
3 AgOAc mesitylene
the same group used a chiral cation/cuprate complex for the dy-
4
namic kinetic enantioselective allylic alkynylation of racemic (S,S)-8d, K2CO3,
5 bromides.14 So far, enantioselective alkynylations of ketones that 7 91 96
AgOAc mesitylene
6 capitalize on the chiral-counter-cation strategy have not been
7 reported. Herein we report the successful implementation of this (S,S)-8d, no base,
8 strategy for the synthesis of chiral tertiary alcohols in high stere- 8
AgOAc mesitylene
trace ––
9 ofidelity.
10 Given their biological activity, we identified 3-substituted 3- (S,S)-8d, K2CO3, mesity-
11 hydroxyoxindoles as attractive targets.15 A subclass of these in- 9
AgOAc lene, 40 °C
43 96
doles, 3-alkynyl-3-hydroxyoxindoles, which are analogues of
12
efavirenz, is biologically active on Echinococcus multilocularis no PTC, K2CO3, me-
13 metacestodes.16 Even though several examples of the achiral syn- 10 <5 ––
14 AgOAc sitylene
thesis of this class of oxindoles have been reported,17 the enanti-
15 oselective alkynylation of isatin remains confined to two reports.
(S,S)-8d, K2CO3,
16 Both studies use copper salts and chiral ligands to promote the 11
no AgOAc mesitylene
trace ––
17 enantioselectivity by means of nucleophilicity enhancement of the
metal alkynylide via covalent bonding with the chiral ligands
18 a
Reaction conditions (unless otherwise noted): 6a (0.05 mmol),
(Path B, Scheme 1).18
19 1a (0.1 mmol), metal salt (5 mol%), chiral PTC 8 (5 mol%), base
We started our investigation by using trityl-protected isatin (6a) as
20 (0.5 equiv) in solvent (0.4 M) at 60 ºC. bIsolated yield after col-
the electrophile and phenylacetylene (1a) as the nucleophile. The umn chromatography on silica gel. cThe ee was determined by
21 results of the optimization are summarized in Table 1 (for the chiral HPLC analysis. dOpposite absolute configuration.
22 details of the optimization, including other N-protected isatin
23 derivatives, metal salts, bases, solvents and PTCs, see the Sup- When the reaction of 6a and 1a was carried out in the presence of
24 porting Information). copper(I) triflate, Cs2CO3, and the Simplified Maruoka Catalyst®
25 (S)-8a as the chiral PTC at 60 ºC, alkynylation product 7aa was
26 Table 1. Optimization of the Reaction Conditions for the obtained in good yield with low enantioselectivity (32% ee; entry
27 Enantioselective Alkynylation of 6a.a 1). The use of silver acetate under otherwise similar reaction con-
28 ditions improved the enantioselectivity to 49% ee, whereas
MX (5 mol%) Ph switching the solvent from toluene to mesitylene furnished 7aa in
29 O PTC (S)-8 (5 mol%) HO 54% ee (entries 2 and 3). At this stage, we decided to screen other
30 Base (0.5 equiv) chiral PTCs to improve the enantioselectivity, and the spiro-type
O + Ph H * O
31 N solvent (0.4 M) N chiral PTC (S,S)-8d as Maruoka Catalyst® delivered 7aa in 87%
32 1a 60 °C, 8 h ee (entry 6). When K2CO3 was used instead of Cs2CO3, the enan-
CPh3 CPh3
33 6a 7aa tioselectivity increased to 96% ee (entry 7). The addition of the
34 base is crucial for this reaction to proceed (entry 8), and decreas-
Ar Ar ing the temperature resulted in a decreased product yield (entry 9).
35
Br Br In the absence of a PTC or AgOAc under otherwise identical reac-
36 Bu tion conditions, the conversion was very low (entries 10 and 11),
N N
37 Bu which probably explains the high enantioselectivity of this proc-
38 ess. The absolute stereochemistry of 7aa was determined to be R
39 Ar Ar after comparing the optical rotation with a known derivative (cf.
40 (S)-8a (Ar = 3,4,5-F3C6H 2) (S,S)-8c (Ar = 3,4,5-F3C6H 2) Supporting Information).
(S)-8b (Ar = 3,5-(CF3) 2C6H 3) (S,S)-8d (Ar = 3,5-(3,5-(CF3) 2C6H 3) 2C6H 3)
41
42 yield ee Table 2. Reaction Scope with Respect to Isatin Deriva-
43 entry hybrid catalyst base & solvent
(%)b (%)c tives.a
44 AgOAc (5 mol%) Ph
O (S,S)-8d (5 mol%) HO
45 1 (S)-8a, CuOTf
Cs2CO3,
87 32 d K 2CO3 (0.5 equiv)
46 toluene R
N
O + Ph H
mesitylene (0.4 M)
R
N
O

47 CPh3
1a 60 °C
CPh3
Cs2CO3, 6a~i 7
48 2 (S)-8a, AgOAc 90 49d
toluene Ph Ph Ph
49 HO HO HO
Me
50 Cs2CO3, O O O
51 3 (S)-8a, AgOAc 90 54d N N Cl N
mesitylene
52 7aa
CPh3
7ba
CPh3
7ca
CPh3

53 (S)-8b, Cs2CO3, 8 h, 91%, 96% ee 24 h, 92%, 94% ee 6 h, 87%, 93% ee

4 96 44d
54 AgOAc mesitylene (88%, 95% ee)b
Ph Ph Ph
55 HO HO Br HO
F
56 5 75 17d
(S,S)-8c, Cs2CO3, O O O
57 Br N N N
CPh3 CPh3 CPh3
58 7da 7ha 7ia
59 6 h, 88%, 92% ee 4 h, 97%, 93% ee 5 h, 93%, 94% ee
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a
Reaction conditions: 6 (0.05 mmol), 1a (0.1 mmol), AgOAc (5 The chiral tertiary alcohols 7, thus obtained, can be used as versa-
1 mol%), (S,S)-8d (5 mol%), K2CO3 (0.5 equiv) in mesitylene (0.4 tile intermediates for further transformations (Scheme 3). For
2 M) at 60 ºC. bThe reaction was carried out on a 0.5-mmol scale. example, the reduction of the alkyne moiety in 7ha with Pd/C
3 under an atmosphere of hydrogen, followed by removal of the
trityl group of 8 furnished oxindole 9 in good yield as virtually a
4 Having optimized the reaction conditions, we examined the scope single enantiomer. Furthermore, deprotection of the TMS group
5 of this alkynylation. Initially, we evaluated the scope with respect from 7bh with TBAF, followed by azide-alkyne cycloaddition
6 to isatin derivatives (Table 2). In general, the products were ob- afforded triazole 11 in high yield without any erosion of enanti-
7 tained in high yield with excellent enantioselectivity. Longer reac- oselectivity.
tion times (24 h) were required to achieve the full conversion of a
8 5-methylisatin derivative (7ba), whereas the full conversion of a
9 5-fluoroisatin (7ha) was accomplished within 4 h. Scheme   3.   Transformation   of   the   Obtained   Alkynylation  
10 After establishing the scope of this reaction with respect to isatin Products.  
11 derivatives, we examined different alkynes (Table 3). The reac-
12 tion tolerates a wide range of functionalities in aromatic alkynes,   Ph
Ph Ph
HO HO HO
13 including cyano, ester, nitro and halogen groups, affording the F Pd/C, H 2 F Et 3SiH, TFA F
14 desired products (7) in moderate to high yield and invariably high   O O O
N EtOAc N DCM, rt, 4 h N
15 enantioselectivity. Slightly lower ee values were obtained only in 2 h, rt H
case of an ester-substituted phenylacetylene (7bc). Concerning 7ha CPh3 8 CPh3 9
16 aliphatic alkynes, the reaction was compatible with cyclohexeny-
(93% ee) ~100% 83%, 99% ee

17 lacetylene, which furnished 7bg in 94% ee. Trimethylsilylacety-

Ph

18 lene and sterically hindered tert-butylacetylene produced the cor- HO

SiMe3
HO HO
N
N
PhCH 2N 3
19 responding tertiary alcohols 7hh and 7hi, respectively, in high F TBAF F CuSO 4·5H 2O F N
yields with excellent enantioselectivity. Cyclopropylacetylene O O O
20 N THF N Na-ascorbate N
21 also reacted smoothly with the isatin derivative to furnish 7hj in 0 °C, 1 h DCM/H 2O H
7hh CPh3 10 CPh3 11
94% ee. Conventional alkyl chains and an ester group were also rt, 0.5 h
22 (96% ee) ~100% 92%, 96% ee
well tolerated in this reaction.
23 Although the exact mechanism of this asymmetric transformation
24 a remains elusive at present, a plausible catalytic cycle is proposed
25 Table 3. Reaction Scope with Respect to Alkynes. in Scheme 4. It seems feasible to expect that the interaction be-
26 AgOAc (5 mol%) R1
tween AgOAc and the chiral quaternary ammonium salt generates
27 O (S,S)-8d (5 mol%) HO chiral ion-pair 12, which could furnish the chiral silver alkynylide
28 R O + R1 H
K 2CO3 (0.5 equiv)
R O
13 in the presence of a base and alkyne 1.11 The stable ion pairing
N mesitylene (0.4 M) N between the silver anion and the chiral ammonium salt should
29 CPh3
1b~l 60 °C CPh3 help to discriminate the two enantiotopical faces of the substrate
7
30 6b or 6h
ketone 6a during the nucleophilic attack to generate 14 with high
31 CN CO 2Me stereoselectivity. Upon protonation, most likely from another
32 molecule of alkyne 1, the final product (7) could be furnished
33 HO HO under concomitant regeneration of chiral silver-ammonium ion
Me Me
34 O O
pair 13.
N N
35 7bb CPh3 7bc CPh3
36 24 h, 72%, 93% ee 24 h, 67%, 86% ee
Scheme  4.  Plausible  Reaction  Mechanism.  
37 Me Br NO 2

38 + AgOAc Q [ Ag(OAc)Br ]
HO HO HO Q Br
39 F F F 12
O O O K 2CO3
40 N N N
R H
41 7hd CPh3 7he CPh3 7hf CPh3
R
1
HO KHCO 3 + KX
42 16 h, 86%, 92% ee 6 h, 96%, 97% ee 6 h, 87%, 95% ee
(X = Br or OAc)
43 O
R AgX Q
44 SiMe3
N
HO HO HO 13
45 Me F F 7 CPh3

46 O O
N
O
N N O
47 7bg CPh3 7hh CPh3 7hi CPh3
48 24 h, 84%, 94% ee 24 h, 93%, 96% ee 6 h, 92%, 96% ee
Q XAg O R O
N
49 HO HO
Pr
HO OCOPh
R H
F F F 6a CPh3
50 O O O 1
O
N
51 N N N
7hj CPh3 7hk 7hl CPh3 CPh3
52 CPh3 14
6 h, 91%, 94% ee 10 h, 80%, 95% ee 4 h, 94%, 93% ee
53
a
54 Reaction conditions: 6 (0.05 mmol), 1a (0.1 mmol), AgOAc (5 In conclusion, we have developed a hybrid catalytic process that
55 mol%), (S,S)-8d (5 mol%), K2CO3 (0.5 equiv) in mesitylene (0.4 involves a chiral phase-transfer/transition-metal catalyst for the
M) at 60 ºC. enantioselective alkynylation of isatin derivatives. The thus ob-
56
57 tained alkynylation products were generally obtained in very high
58
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yield with excellent enantioselectivity. The attractive synthetic Walsh, P. J. Development of the First Practical Catalyst for the
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AUTHOR INFORMATION
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The authors declare no conflict of interest. Soc. 2001, 123, 9687.
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(9) (a) Ohshima, T.; Kawabata, T.; Takeuchi, Y.; Kakinuma, T.; (17) (a) Fu, X.-P.; Liu, L.; Wang, D.; Chen, Y.-J.; Li, C.-J. “On
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α-Ketoesters. Angew. Chem., Int. Ed. 2011, 50, 6296. (b) Wang, T.; ethynylindolin-2-ones. Green Chem. 2011, 13, 549. (b) Lazreg, F.;
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4 NCN Pincer Rhodium(III) Complexes with Bis(imidazolinyl)phenyl N-Heterocyclic Carbene Catalysts for the Alkynylation of Ketones in
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20
Aldehydes. J. Am. Chem. Soc. 2003, 125, 2054. (b) Ooi, T.; Doda, K.;
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Selective Asymmetric Synthesis of β-Hydroxy-α-amino Acid Esters
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2017, 359, 1772.
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(16) Sarciron, M. E.; Audin, P.; Delabre, I.; Gabrion, C.; Petavy, A.
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4 cat. R2
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5 (S,S)-1 AgOAc
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7 R1 O + R2 H R1 O
8 N mesitylene, K 2CO3, 60 °C N
9 CPh3 Ar CPh3
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