Synthesis of Optically Active 2,3-Disubstituted Indoline -Derivatives through Cycloaddition Reactions between Benzynes and α,β-Unsaturated γ-Aminobutyronitriles

Article abstract of DOI:10.1055/s-0036-1591722

We report a method for synthesizing optically active 2,3-disubstituted indolines by the cycloaddition reaction of benzynes with various 4-[(4-toluenesulfonyl)amino]-(E)-but-2-enenitriles, which are readily prepared from the corresponding l -amino acid der

Full text of DOI:10.1055/s-0036-1591722

SYNLETT
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© Georg Thieme Verlag Stuttgart · New York
2018, 29, A–G
letter
A
en
T. Ikawa et al.
Letter
Synlett
Synthesis of Optically Active 2,3-Disubstituted Indoline
Derivatives through Cycloaddition Reactions between Benzynes
and α,β-Unsaturated γ-Aminobutyronitriles
NC
NC
HN
CN
R2
R1
Takashi Ikawa*
Yuta Sumii
0
0
0
0
0-
0
0
2
1-
6
4
2
3-
2
7
3
OTf
R2
F–
R2
+
R1
R1
Shigeaki Masuda
Ding Wang
N
SiMe3
R
HN
Ts
R
R
Ts
Ts
Yuto Emi
12 examples
up to 93% yield
up to >20:1 dr
up to 99% ee
R1 = alkyl, CH2OTBDMS, (CH2)4NHBoc
R1, R2 = –(CH2)4–
Akira Takagi
Shuji Akai*
0
0
0
0
0-
0
0
1
9-
1
4
9
8-
7
4
5
Graduate School of Pharmaceutical Sciences, Osaka University,
1-6 Yamadaoka, Suita, Osaka 565-0871, Japan
ikawa@phs.osaka-u.ac.jp
akai@phs.osaka-u.ac.jp
Received: 18.09.2017
Accepted after revision: 17.10.2017
Published online: 04.01.2018
ring through C–C bond formation at the (a) or (b) bonds or
C–N bond formation at the (c) or (d) bonds (Scheme 1).4
However, only a few methods have been reported for the
direct enantio- and diastereoselective construction of the
C2 and C3 stereogenic centers of substituted indolines
without the need for prior synthesis of the indole moiety.
Consequently, the development of a novel synthetic route
to optically active indolines by using an alternative stereo-
selective cyclization approach is of particular interest.
In this context, many reactions of benzynes with novel
arynophiles have been reported in the past few decades.5
One particular benefit of such reactions is the simultaneous
formation of two sigma bonds at adjacent positions of a
benzene ring,5 so that these efficient transformations have
the potential to render molecular syntheses more concise
and attractive. Despite such advances, examples of stereo-
selective bond-forming reactions involving benzyne are
limited.6 Here, we present novel syntheses of optically
active 2,3-disubstituted indolines 1 through a cycloaddition
protocol between benzynes 2 and optically active (E)-4-
aminobut-2-enenitriles 3,7–9 which are readily available
DOI: 10.1055/s-0036-1591722; Art ID: st-2017-u0697-l
Abstract We report a method for synthesizing optically active 2,3-
disubstituted indolines by the cycloaddition reaction of benzynes with
various 4-[(4-toluenesulfonyl)amino]-(E)-but-2-enenitriles, which are
readily prepared from the corresponding L-amino acid derivatives.
Keywords indolines, benzynes, cycloaddition, asymmetric synthesis,
nucleophilic addition, amino acids
The indoline framework is one of the most important
skeletons present in biologically active natural products.1
Currently, two general approaches exist for the synthesis of
indolines. The first of these methods is based on the dearo-
matization of indoles by polyfunctionalization of the C2–C3
double bond.2 This type of strategy has been applied to a
number of stereoselective syntheses of complex natural
products; however, it requires the corresponding indoles to
be prepared in advance.3 The second route to the indoline
framework is based on the construction of the pyrrolidine
NHBoc
Et
H2NBoc
+
OMs
I
N
R
R
(a)
OTf CO2Me
Me
R1
N
R2
b
a
d
F3C
Me
Br
R3
R4
Pd/L*
(a)
LDA
+
N
Tol
PMP
c
(b, d)
S
N
R
R
R
R5
CO2Me
O
O
Br
(c)
Ph
optically active
indolines
+
O
NH2
NHCbz
R
R
Me
The letters in parenthesis indicate the position of bond formation.
Scheme 1 Reported syntheses of the indoline framework based on cyclization reactions.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–G

B
T. Ikawa et al.
Letter
Synlett
through a three-step telescoping process from commercial-
CN
CN
H
ly available L-amino acid methyl ester derivatives
(Scheme 2).
4
R2
⋅HCl
CO2Me
Amino acid derivatives 4
R2
R2
H2N
We initially examined the feasibility of the cycloaddition
protocol by generating benzyne (2a, R1 = H) from 2-(tri-
methylsilyl)phenyl triflate (5a, R1 = H; 1.0 equiv) and CsF
(2.0 equiv), and reacting it with (2E,4S)-4-benzylamino-5-
methylhex-2-enenitrile (3a, R2 = i-Pr; R3 = H; Pg = Bn;
1.5 equiv), a process that involves the nucleophilic addition
of the amino group of 3a to 2a, and subsequent intra-
molecular Michael addition to the α,β-unsaturated nitrile
moiety to produce indoline 1a (Pg = Bn) (Table 1). The reac-
tion in MeCN at room temperature for one hour produced
1a in 47% isolated yield with good diastereoselectivity
(dr = 6.7:1), with the trans-product being the major isomer
(Table 1, entry 1). A single-addition product 6a (41%)10 was
also produced in this reaction. However, the application of
these reaction conditions to nitriles 3 (R2 = i-Pr; R3 = H)
bearing various protecting groups [Pg = Boc (3b), Ac (3c), 4-
O2NC6H4SO2 (Ns) (3d), Ms (3e), Ts (3f)] produced signifi-
cantly different results. More specifically, neither the addi-
tion product 6 nor the cycloaddition product 1 were formed
from 3b bearing a tert-butoxycarbonyl (Boc) group or from
3c bearing an Ac group (entries 2 and 3). In contrast, nitriles
N
HN
R1
R1
2
Pg
Pg
1
3
Scheme 2 Strategy for the stereoselective syntheses of indolines
through cycloaddition reactions of benzynes
3d–f bearing sulfonyl-type protecting groups gave 1 with
high diastereoselectivities (dr = >20:1) and in 32–54% yields
(entries 4–6).11,12 The use of alternative solvents or other
fluoride sources, such as KF/18-crown-6 (18-c-6) or tetra-
butylammonium difluorotriphenylsilicate (TBAT), produced
varied yields of the cycloaddition product 1f and addition
product 6f, in addition to giving good diastereomeric ratios
of 1f (entries 7–13). The optimal yield of 1f (71%) was ob-
tained in the presence of CsF and 18-c-6 in THF at room
temperature (entry 10). The reaction carried out at a lower
temperature (−40 °C) gave a similar result (entry 11). Fur-
thermore, the presence of larger protecting groups
(Pg = SO2Mes; 3g) lowered the diastereoselectivity of 1g
(dr = 6.9:1, entry 14).
Table 1 Optimization of the Reaction Conditionsa
NC
CN
CN
CN
OTf
F–
i-Pr
i-Pr
N
N
i-Pr
SiMe3
rt
HN
HN
Pg
3a–3g
i-Pr
Pg
Pg
Pg
2a
5a
trans-1a–1g
6a–6g
3a–3g
Entry
Pg
F– source
Solvent
Reactant
Products
Yield of 1
Yield of 6
drc
(%)b
(%)b
1
Bn
Boc
Ac
Ns
Ms
Ts
CsF
CsF
CsF
CsF
CsF
CsF
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
THF
3a
3b
3c
3d
3e
3f
1a, 6a
1b, 6b
1c, 6c
1d, 6d
1e, 6e
1f, 6f
1f, 6f
1f, 6f
1f, 6f
1f, 6f
1f, 6f
1f, 6f
1f, 6f
1g, 6g
47
ndd
ndd
54
32
44
54
55
19
71
69
50
48
69
41
ndd
ndd
32
30
36
37
36
13
22
15
16
12
20
6.7:1
–
2
3
–
4
19:1
15:1
>20:1
12:1
13:1
–
5
6
7
Ts
CsF/18-crown-6
KF/18-crown-6
TBAT
3f
8
Ts
3f
9
Ts
3f
10
11e
12
13
14
Ts
CsF/18-crown-6
CsF/18-crown-6
KF/18-crown-6
TBAT
3f
16:1
17:1
>20:1
>20:1
6.9:1
Ts
THF
3f
Ts
THF
3f
Ts
THF
3f
SO2Mes
CsF/18-crown-6
THF
3g
a Reaction conditions: 5a (1.0 equiv), 3 (1.5 equiv), F– source (3.0 equiv), solvent (0.05 M), r.t., 1.0 h.
b Determined by 1H NMR analysis with DMF as the internal standard.
c dr = ratio of trans- and cis-diastereomers of 1.
d nd = not detected.
e Conducted at −40 °C.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–G

C
T. Ikawa et al.
Letter
Synlett
We also found that the optically pure α,β-unsaturated
nitrile 3f was the most suitable for production of the opti-
cally pure indoline 1f (R2 = i-Pr; R3 = H; 75% isolated yield,
trans/cis = 18:1, 99% ee of trans-1f) (Table 2, entry 1).
Similar reactions also proceeded with the corresponding
γ-amino α,β-unsaturated ester 3h (EWG = CO2Me; entry 2)
and ketone 3i (EWG = COMe; entry 3), but with lower opti-
cal purities (95% ee for 1h and 84% ee for 1i). These differ-
ences were probably caused by changes in the optical puri-
ties of 3h and 3i under the reaction conditions employed.
Indeed, although the optical purity of 3f remained >99% ee
under these reaction conditions after 12 hours, those of 3h
(98% ee) and 3i (96% ee) decreased significantly to 68% and
48% ee, respectively, and unidentified decomposition prod-
ucts were observed (see Supporting Information). These re-
sults indicate that the appropriate electron-withdrawing
ability of the cyano group determined the optical integrity
and reactivity of 3, whereas the more-strongly electron-
withdrawing ester and keto groups caused partial racemi-
zation. Furthermore, the reaction carried out by using the
nitro substrate 3j (EWG = NO2) gave indoline 1j with a low-
er yield of 64%, probably due to the instability of 3j under
the basic reaction conditions (entry 4).
various steps. It is worth noting that the chiral integrity
of L-valine (4a) as a starting amino acid was maintained un-
der these reaction conditions, yielding 3f in an excellent
enantiomeric excess of >99% (entry 1).14
Table 3 Telescoping Synthesis of γ-Amino α,β-Unsaturated Nitriles 3
from Amino Acids 4a
R2
1) PgCl
2) DIBAL
R2
·HCl
CO2Me
PgHN
3f, 3g, 3k–3p
CN
H2N
3) HWE reagent
4
Entry Reactant
R2
Pg
Ts
Product Yield (%)b
1
2
3
4
5
6
7
8
4a
4a
4b
4c
4d
4d
4e
4f
i-Pr
3f
63c
55
i-Pr
SO2Mes
3g
3k
3l
Me
Ts
Ts
Ts
Ns
Ts
Ts
36
Bn
82
i-Bu
3m
3n
3o′
3p
67
i-Bu
55
CH2OH
(CH2)4NHBoc
30d
69e
a Reaction conditions: (1) 4 (1.0 equiv), PgCl (1.2 equiv), Et3N (2.5 equiv),
CH2Cl2 (0.50 M), r.t.; (2) DIBAL (2.5 equiv), CH2Cl2 (0.50 M), −80 °C, 2 h;
(3) NCCH2PO(OEt)2 (1.0 equiv), DIPEA (1.0 equiv), LiCl (1.5 equiv), MeCN
Table 2 Effects of Varying the Electron-Withdrawing Groupa
(0.20 M), r.t.
b Isolated yield.
EWG
EWG
EWG
c >99% ee.
CsF
18-c-6
OTf
d Silylation was conducted by using TBDMSCl following the tosylation of
i-Pr
4e.
THF
rt
e Synthesized from commercial Fmoc-Lys(Boc)-OH in five steps.
SiMe3
N
HN
Ts
3f, 3h–3j
i-Pr
N
Ts
i-Pr
Ts
trans-1f, 1h–1j
5a
6f, 6h–6j
We then applied the optimized reaction conditions to a
range of γ-amino α,β-unsaturated nitriles 3k–p (Table 4). In
all cases, the corresponding indolines 1 were obtained in
good to moderate yields. Although less-bulky R2 substitu-
ents such as Me (Table 4, entries 1 and 2), Bn (entry 3), i-Bu
(entries 4 and 5), CH2OTBDMS (entries 8 and 9), CH2OH
(entry 10), or (CH2)4NHBoc (entry 11) rendered the reaction
less diastereoselective (c.f., i-Pr; Table 2, entry 1), higher
selectivities were observed at lower temperatures (−40 °C;
entries 2, 7, and 9). Under these conditions, silyloxy
(entry 9), hydroxy (entry 10), and N-Boc functional
groups (entry 11) were also tolerated. In addition, when
Ns was employed as an amine-protecting group instead
of Ts, a lower yield was obtained (c.f., 1n and 1m, entries
4–7). It should also be noted that the reaction of 3f with
3-methoxybenzyne (2b) (R1 = OMe, entry 12)15 and with
3-TBDMS-benzyne 2c (R1 = TBDMS, entry 13)16 provided
the desired products 1q and 1r with excellent regioselec-
tivities. In these transformations, the initial addition of the
amino group took place at the position meta to the OMe
and silyl groups.
Entry
EWG (3)
Yield of 1 (%)b
Yield of 6 (%)b
drc
ee (%)d
1
2
3
4
CN (3f)
75 (1f)
75 (1h)
79 (1i)
64 (1j)
20 (6f)
6 (6h)
10 (6i)
19 (6j)
18:1
17:1
12:1
15:1
>99
94
84
–
CO2Me (3h)
COMe (3i)
NO2 (3j)
a Reaction conditions: 5a (1.5 equiv), 3 (1.0 equiv), CsF (3.0 equiv),
18-crown-6 (3.0 equiv), THF (0.05 M), r.t., 1.0 h.
b Determined by 1H NMR analysis with DMF as the internal standard.
c dr = ratio of trans- and cis-diastereomers 1.
d ee = enantiomeric excess of the major diastereomer trans-1.
An efficient three-step telescoping synthesis13 of vari-
ous γ-amino α,β-unsaturated nitriles 3 from commercially
available L-amino acid methyl esters 4 is shown in Table 3.
After protection of the amino groups of 4, the resulting
esters were reduced by using DIBAL-H to give the corre-
sponding aldehydes, and the resulting mixtures were sub-
jected to reaction with the Horner–Wadsworth–Emmons
(HWE) reagent [NCCH2PO(OEt)2] to produce γ-amino a, b-
unsaturated nitriles 3f, 3g, and 3k–p in good to moderate
overall yields (30–82%) without isolation between the
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–G

D
T. Ikawa et al.
Letter
Synlett
Table 4 Substrate Scope of the Reactiona
NC
HN
R1
R1
OMe
R3
R1
CN
R3
CsF
18-c-6
OTf
SiMe3
OTf
PgHN
CN
R3
or
SiMe3
+
R2
THF
temp
R2
R2
N
3f, 3k–3p
Pg
3f, 3k–3p
5a: R1 = R2 = H
5c: R1 = TBDMS, R2 = Me
5b
2
Pg
trans-1k–1r
Entry
Reactants
Benzyne
Temp
(°C)
Product
1
Yield (%)b
drc,d
19
1
2
5a, 3k
r.t.
CN
1.1:1
2.3:1
Me
trans-1k
trans-1l
N
5a, 3k
–40
76
2a
Ts
CN
Bn
3
5a, 3l
2a
r.t.
93
5.0:1
N
Ts
4
5
5a, 3m
5a, 3m
r.t.
73
72
2.3:1
2.4:1
CN
2a
2a
i-Bu
trans-1m
–40
N
Ts
6
7
5a, 3n
5a, 3n
0
58
24
4.2:1
4.8:1
CN
i-Bu
trans-1n
N
–40
Ns
8
9
r.t.
70
65
2.5:1
4.0:1
CN
5a, 3o’
2a
trans-1o’
N
–40
OTBDMS
Ts
CN
OH
10
11
5a, 3o
5a, 3p
2a
2a
–40
–40
trans-1o
trans-1p
57
63
2.4:1
3.5:1
N
Ts
CN
4
N
NHBoc
Ts
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–G

E
T. Ikawa et al.
Letter
Synlett
Entry
Reactants
Benzyne
Temp
(°C)
Product
1
Yield (%)b
drc,d
OMe
CN
OMe
i-Pr
12
13
5b, 3f
5c, 3f
–40
r.t.
trans-1q
72
>20:1
>20:1
N
Ts
2b
TBDMS
CN
TBDMS
i-Pr
trans-1r
68
N
Me
Me
Ts
2c
a Conditions: 5 (1.5 equiv), 3 (1.0 equiv), CsF (3.0 equiv), 18-crown-6 (3.0 equiv), THF (0.05 M), 1 h.
b Isolated yield.
c dr = ratio of trans- and cis-diastereomers 1.
d Determined by 1H NMR measurements.
As outlined in Scheme 3, the hexahydrocarbazole 1s
was also synthesized by this method. More specifically, the
reaction of 5a with cyclic tosylamide (±)-3q provided (±)-1s
(33%) with high diastereoselectivity17 at 50 °C, although a
lower yield was obtained than when the acyclic substrates 3
were employed, due to the formation of a significant
amount (20%) of the monoaddition product 6s.
Funding Information
This work was financially supported by the JSPS KAKENHI (grants
numbers 23790017, 24390005, and 25460018) and by a Grant-in-Aid
for JSPS (grant number 15J06024), as well as by the Platform Project
for Supporting Drug Discovery and Life Science Research funded by
the Japanese Agency for Medical Research and Development (AMED),
the Research Foundation for Pharmaceutical Sciences, the Kobayashi
International Scholarship Foundation, and the Hoansha Foundation.
a
Jp
a
nS
o
eciyfotrhePor
m
o
itnoSefcin
c
e(2
3
7
9
0
0
1
72()4
3
9
0
0
0
52()5
4
6
0
0
1
81()5
0
J
6
0
2
4)
CN
CN
CN
CsF
18-c-6
OTf
Acknowledgment
+
+
THF
50 °C
SiMe3
NHTs
N
Ts
N
H
We thank Daicel Co. for providing us with their new chiral column.
Ts
)-1s (33%)
single stereoisomer
5a
(
)-3q
(
)-6s (20%)
(
Supporting Information
Scheme 3 Synthesis of hexahydrocarbazole (±)-1s from cyclic
tosylamide (±)-3q
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1591722.
S
u
p
p
o
nrtogI
f
rmoaitn
S
u
p
p
ortiInfogrmoaitn
In summary, we successfully developed a synthesis of
optically active 2,3-disubstituted indolines through cy-
cloaddition reactions between benzynes and γ-amino α,β-
unsaturated nitriles,18–20 in which the use of a cyano group
as the electron-withdrawing group gave superior results to
the use of an ester8a or carbonyl group, resulting in reten-
tion of the optical integrity of the arynophile. This method
is of particular importance in the area of synthetic chemis-
try, as the nitrile group of the indoline products can be
transformed into a range of other functional groups. As
such, our protocol opens a potential new route that permits
synthetic and/or medicinal chemists to prepare biologically
active compounds bearing the indoline moieties. Studies on
applications of this transformation and detailed mechanis-
tic investigations are now underway in our laboratory.
References and Notes
(1) For biologically active indoline papers, see: (a) Bechle, B. M.;
Didiuk, M. T.; Fritzen, E. L.; Garigipati, R. S. WO 2006032987,
2006. (b) Goodman, F. R.; Weiss, G. B.; Hurley, M. E. Cardiovasc.
Drug Rev. 1985, 3, 57. (c) Poondra, R. R.; Kumar, N. N.; Bijian, K.;
Prakesch, M.; Campagna-Slater, V.; Reayi, A.; Reddy, P. T.;
Choudhry, A.; Barnes, M. L.; Leek, D. M.; Daroszewska, M.;
Lougheed, C.; Xu, B.; Schapira, M.; Alaoui-Jamali, M. A.; Arya, P.
J. Comb. Chem. 2009, 11, 303. (d) Gan, Z.; Reddy, P. T.; Quevillon,
S.; Couve-Bonnaire, S.; Arya, P. Angew. Chem. Int. Ed. 2005, 44,
1366. (e) Nicolaou, K. C.; Roecker, A. J.; Pfefferkorn, J. A.; Cao,
G.-Q. J. Am. Chem. Soc. 2000, 122, 2966. (f) Rakhit, A.; Hurley,
M. E.; Tipnis, V.; Coleman, J.; Rommel, A.; Brunner, H. R. J. Clin.
Pharmacol. 1986, 26, 156. (g) Xiang, L.; Xing, D.; Wang, W.;
Wang, R.; Ding, Y.; Du, L. Phytochemistry 2005, 66, 2595.
(h) Yang, Z.; Liu, C.; Xiang, L.; Zheng, Y. Phytother. Res. 2009, 23,
1032.
(2) For selected reviews on syntheses of indolines by dearomatiza-
tion of indoles, see: (a) Zhang, D.; Song, H.; Qin, Y. Acc. Chem.
Res. 2011, 44, 447. (b) Zi, W.; Zuo, Z.; Ma, D. Acc. Chem. Res.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–G

F
T. Ikawa et al.
Letter
Synlett
2015, 48, 702. For selected papers on indoline syntheses by
dearomatization reactions, see. (c) Kuwano, R.; Sato, K.;
Kurokawa, T.; Karube, D.; Ito, Y. J. Am. Chem. Soc. 2000, 122,
7614. (d) Kubota, K.; Hayama, K.; Iwamoto, H.; Ito, H. Angew.
Chem. Int. Ed. 2015, 54, 8809. (e) He, F.; Bo, Y.; Altom, J. D.;
Corey, E. J. J. Am. Chem. Soc. 1999, 121, 6771. (f) Kobayashi, S.;
Ueda, T.; Fukuyama, T. Synlett 2000, 883. (g) Ishikawa, H.;
Elliott, G. I.; Velcicky, J.; Choi, Y.; Boger, D. L. J. Am. Chem. Soc.
2006, 128, 10596. (h) Jones, S. B.; Simmons, B.; Mastracchio, A.;
MacMillan, D. W. C. Nature 2011, 475, 183. (i) Mizoguchi, H.;
Oikawa, H.; Oguri, H. Nat. Chem. 2014, 6, 57. (j) Awata, A.; Arai,
T. Angew. Chem. Int. Ed. 2014, 53, 10462.
(10) For studies discussing the addition of nitrogen nucleophiles to
benzynes, see: (a) Liu, Z.; Larock, R. C. J. Am. Chem. Soc. 2005,
127, 13112. (b) Liu, Z.; Larock, R. C. J. Org. Chem. 2006, 71, 3198.
(c) Liu, Z.; Larock, R. C. Org. Lett. 2003, 5, 4673. (d) Li, L.; Qiu, D.;
Shi, J.; Li, Y. Org. Lett. 2016, 18, 3726.
(11) The use of our newly developed precursor, 2-(trimethyl-
silyl)phenyl trimethylsilyl ether (see Ref. 12) instead of 5a also
gave trans-1f (46%, dr = 14:1) and 6f (39%), which was very
similar to Table 1, entry 6. The reaction was performed with the
silyl ether (1.5 equiv), nonaflourobutane-1-sulfonyl fluoride
(2.3 equiv), 3f (1.0 equiv), and CsF (4.5 equiv) in MeCN (0.10 M)
at 60 °C for 26 h.
(3) For selected reviews on indole synthesis, see: (a) Wu, H.; He,
Y.-P.; Shi, F. Synthesis 2015, 47, 1990. (b) Zi, W.; Zuo, Z.; Ma, D.
Acc. Chem. Res. 2015, 48, 702. (c) Taber, D. F.; Tirunahari, P. K.
Tetrahedron 2011, 67, 7195. (d) Miller, K. A.; Williams, R. M.
Chem. Soc. Rev. 2009, 38, 3160.
(12) Ikawa, T.; Masuda, S.; Nakajima, H.; Akai, S. J. Org. Chem. 2017,
82, 4242.
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(a) Nishimura, K.; Saitoh, T. Chem. Pharm. Bull. 2016, 64, 1043.
(b) Anderson, N. G. Practical Process Research & Development;
Academic Press: San Diego, 2000. (c) Ikemoto, T. In Process
Chemistry of Pharmaceuticals; Kagaku-Dojin Publishing: Kyoto,
2013, (in Japanese).
(4) For reviews on syntheses of indolines through the formation of
pyrrolidine rings, see: (a) Anas, S.; Kagan, H. B. Tetrahedron:
Asymmetry 2009, 20, 2193. (b) Liu, D.; Zhao, G.; Xiang, L. Eur. J.
Org. Chem. 2010, 3975. For selected papers, see: (c) Dounay, A.
B.; Overman, L. E.; Wrobleski, A. D. J. Am. Chem. Soc. 2005, 127,
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Angew. Chem. Int. Ed. 2011, 50, 7438. (e) Miyaji, R.; Asano, K.;
Matsubara, S. Org. Lett. 2013, 15, 3658. (f) Minatti, A.; Buchwald,
S. L. Org. Lett. 2008, 10, 2721. (g) Ruano, J. L. G.; Alemán, J.;
Catalán, S.; Marcos, V.; Monteagudo, S.; Parra, A.; del Pozo, C.;
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Buchwald, S. L. Angew. Chem. Int. Ed. 2008, 47, 177. (i) Pian, J.-X.;
He, L.; Du, G.-F.; Guo, H.; Dai, B. J. Org. Chem. 2014, 79, 5820.
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Prep. Proced. Int. 2008, 40, 215. (b) Kitamura, T. Aust. J. Chem.
2010, 63, 987. (c) Bhunia, A.; Yetra, S. R.; Biju, A. T. Chem. Soc.
Rev. 2012, 41, 3140. (d) Tadross, P. M.; Stoltz, B. M. Chem. Rev.
2012, 112, 3550. (e) Wu, C.; Shi, F. Asian J. Org. Chem. 2013, 2,
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Biomol. Chem. 2013, 11, 191. (g) Yoshida, H. In Comprehensive
(14) Sudalai and co-workers reported that γ-amino α,β-unsaturated
nitriles could not be obtained (see Ref. 8a).
(15) For selected examples related to 3-methoxybenzyne, see:
(a) Shi, J.; Qiu, D.; Wang, J.; Xu, H.; Li, Y. J. Am. Chem. Soc. 2015,
137, 5670. (b) Umezu, S.; dos Passos Gomes, G.; Yoshinaga, T.;
Sakae, M.; Matsumoto, K.; Iwata, T.; Alabugin, I.; Shindo, M.
Angew. Chem. Int. Ed. 2017, 56, 1298. (c) Matsumoto, T.; Hosoya,
T.; Katsuki, M.; Suzuki, K. Tetrahedron Lett. 1991, 32, 6735.
(d) Yoshida, H.; Shirakawa, E.; Honda, Y.; Hiyama, T. Angew.
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Bugga, P.; Virgil, S. C.; Stoltz, B. M. Org. Lett. 2010, 12, 1224.
(16) For selected recent papers on silylbenzynes, see: (a) Akai, S.;
Ikawa, T.; Takayanagi, S.-i.; Morikawa, Y.; Mohri, S.;
Tsubakiyama, M.; Egi, M.; Wada, Y.; Kita, Y. Angew. Chem. Int.
Ed. 2008, 47, 7673. (b) Dai, M.; Wang, Z.; Danishefsky, S. J. Tetra-
hedron Lett. 2008, 49, 6613. (c) Diemer, V.; Begaud, M.; Leroux,
F. R.; Colobert, F. Eur. J. Org. Chem. 2011, 341. (d) Ikawa, T.;
Nishiyama, T.; Shigeta, T.; Mohri, S.; Morita, S.; Takayanagi, S.-i.;
Terauchi, Y.; Morikawa, Y.; Takagi, A.; Ishikawa, Y.; Fujii, S.; Kita,
Y.; Akai, S. Angew. Chem. Int. Ed. 2011, 50, 5674. (e) Ikawa, T.;
Tokiwa, H.; Akai, S. J. Synth. Org. Chem., Jpn. 2012, 70, 1123.
(f) Bronner, S. M.; Mackey, J. L.; Houk, K. N.; Garg, N. K. J. Am.
Chem. Soc. 2012, 134, 13966. (g) Ikawa, T.; Takagi, A.; Goto, M.;
Aoyama, Y.; Ishikawa, Y.; Itoh, Y.; Fujii, S.; Tokiwa, H.; Akai, S. J.
Org. Chem. 2013, 78, 2965. (h) Yoshida, H.; Yoshida, R.; Takaki, K.
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Fukumoto, Y.; Sumii, Y.; Nishiyama, T.; Akai, S. Chem. Eur. J.
2014, 20, 16228. (j) Ikawa, T.; Masuda, S.; Takagi, A.; Akai, S.
Chem. Sci. 2016, 7, 5206.
Organic Synthesis II;
C
4hV,4a0po.l9
.
Knochel, P.; Molander, G. A., Eds.; Elsevier:
Amsterdam, 2014, 517. (h) Yoshida, S.; Hosoya, T. Chem. Lett.
2015, 44, 1450. (i) Karmakar, R.; Lee, D. Chem. Soc. Rev. 2016, 45,
4459. (j) Zeng, Y.; Hu, J. Synthesis 2016, 48, 2137.
(6) For stereoselective benzyne reactions, see: (a) Webster, R.;
Lautens, M. Org. Lett. 2009, 11, 4688. (b) Peña, D.; Pérez, D.;
Guitián, E. Chem. Rec. 2007, 7, 326. (c) Caeiro, J.; Peña, D.; Cobas,
A.; Párez, D.; Guitián, E. Adv. Synth. Catal. 2006, 348, 2466.
(d) Dockendorff, C.; Sahli, S.; Olsen, M.; Milhau, L.; Lautens, M.
J. Am. Chem. Soc. 2005, 127, 15028.
(7) For indoline syntheses through reactions with benzynes, see:
(a) Guo, J.; Kiran, C. I. N.; Gao, J.; Reddy, R. S.; He, Y. Tetrahedron
Lett. 2016, 57, 3481. (b) Gilmore, C. D.; Allan, K. M.; Stoltz, B. M.
J. Am. Chem. Soc. 2008, 130, 1558.
(17) The corresponding diastereomer of (±)-1s was below the detec-
tion limit of 1H NMR (>50:1).
(8) During the preparation of this manuscript (see Ref. 9), closely
related work was published by the groups of Sudalai and She:
(a) Aher, R. D.; Suryavanshi, G. M.; Sudalai, A. J. Org. Chem. 2017,
82, 5940. (b) Xu, D.; Zhao, Y.; Song, D.; Zhong, Z.; Feng, S.; Xie,
X.; Wang, X.; She, X. Org. Lett. 2017, 19, 3600.
(9) For preliminary work carried out in relation to this study, see:
Ikawa, T.; Sumii, Y.; Takagi, A.; Akai, S. The 135th Annual Meeting
of the Pharmaceutical Society of Japan (Kobe, March, 2015),
Abstract Book No. 2. Pharmaceutical Society of Japan: Tokyo: 83
(18) Indolines 1a–r; General Procedure
A test tube was charged with the appropriate benzyne precur-
sor 5 (1.5 equiv) and a magnetic stir bar. THF (1.0 mL, 50 mM),
which did not have to be anhydrous, was added to the tube and
the mixture was stirred for a few minutes to dissolve 5. The γ-
tosylamino α,β-unsaturated nitrile 3 (1.0 equiv) and 18-crown-
6 (3.0 equiv) were added to the solution, and the flask was
equipped with a screw cap. (This solution was stirred for 10 min
at the indicated temperature when the reaction was conducted
at 0 °C or below.) CsF (3.0 equiv) was quickly added to the test
tube, which was then resealed with the screw cap, and the
mixture was stirred at the appropriate temperature until either
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–G

G
T. Ikawa et al.
Letter
Synlett
the α,β-unsaturated nitrile 3 or the benzyne precursor 5 was
consumed (TLC). The mixture was then passed through a short
pad of silica gel with elution by EtOAc, and solvents were
removed under reduced pressure. The residue was subjected to
1H NMR analysis to determine the ratio of the two diastereo-
mers (trans-1 and cis-1). The crude product was purified by
flash column chromatography (silica gel) or by preparative TLC
(hexane–EtOAc, hexane–CH2Cl2, or EtOAc) to afford the required
substituted indoline 1 and the single-addition product 6.
(19) {(2S,3R)-2-Isopropyl-1-tosyl-2,3-dihydro-1H-indol-3-yl}ace-
tonitrile (trans-1f)
1 H), 2.36 (s, 3 H), 3.05–3.09 (m, 1 H), 3.77 (dd, J = 5.0, 2.0 Hz,
1 H), 7.08 (dd, J = 7.5, 7.5 Hz, 1 H), 7.14 (d, J = 7.5 Hz, 1 H), 7.22
(d, J = 8.0 Hz, 2 H), 7.32 (ddd, J = 7.5, 7.5, 1.0 Hz, 1 H), 7.57 (d,
J = 8.0 Hz, 2 H), 7.75 (d, J = 7.5 Hz, 1 H). 13C NMR (125 MHz,
CDCl3): δ = 16.4, 18.1, 21.5, 24.0, 33.3, 39.2, 72.1, 117.3, 117.5,
124.5, 125.1, 127.0, 129.5, 129.8, 132.9, 134.6, 141.6, 144.5.
HRMS (MALDI): m/z [M
377.1294; found: 377.1291.
+
Na]+ calcd for C20H22N2NaO2S:
All spectroscopic data for product (2S,3R)-1f were in good
agreement with those for (±)-trans-1f, synthesized from (±)-3f.
(20) {(2S,3S)-2-Isopropyl-1-tosyl-2,3-dihydro-1H-indol-3-yl}ace-
tonitrile (cis-1f)
According to the general procedure, a mixture of CsF (91 mg,
0.60 mmol), 18-crown-6 (0.16 g, 0.60 mmol), triflate 5a (90 mg,
0.30 mmol), and sulfonamide 3f (56 mg, 0.20 mmol) was stirred
in THF (2.0 mL, 0.10 M) for 1 h at r.t. The crude product (trans-
1f/cis-1f = 16:1, determined by 400 MHz 1H NMR analysis) was
purified by column chromatography [silica gel, hexane–
EtOAc (20:1 to 4:1)] to give a colorless solid; yield: 51 mg (72%,
>99% ee); mp 139–141 °C; [α]D25 –137.4 (c 0.12, CHCl3).
Obtained from above-mentioned crude reaction mixture as a
colorless solid; yield: 2.4 mg (3%); mp 131–133 °C; [α]D20 –2.4 (c
0.12, CHCl3). The relative stereochemistry was determined by
NOESY spectroscopy. IR (neat): 2967, 2371, 1597 cm–1. 1H NMR
(500 MHz, CDCl3): δ = 0.51 (d, J = 7.0 Hz, 3 H), 1.22 (d, J = 7.0 Hz,
3 H), 1.96 (sept d, J = 7.0, 2.5 Hz, 1 H), 2.37 (s, 3 H), 2.54 (dd,
J = 17.0, 9.0 Hz, 1 H), 2.68 (dd, J = 17.0, 7.0 Hz, 1 H), 2.97–3.02
(m, 1 H), 4.33 (dd, J = 8.5, 2.5 Hz, 1 H), 7.03 (d, J = 8.0 Hz, 1 H),
7.10–7.15 (m, 1 H), 7.14 (d, J = 8.0 Hz, 2 H), 7.30 (dd, J = 8.0, 8.0
Hz, 1 H), 7.44 (d, J = 8.0 Hz, 2 H), 7.66 (d, J = 8.0 Hz, 1 H). 13C
NMR (125 MHz, CDCl3): δ = 15.8, 17.4, 21.0, 21.6, 29.0, 40.7,
69.3, 118.2, 119.5, 121.8, 126.1, 126.9, 128.9, 129.7, 134.9,
135.2, 142.8, 144.2. HRMS (MALDI): m/z [M + Na]+ calcd for
The relative stereochemistry was determined by NOESY
spectroscopy, and the optical purity was determined by HPLC.
HPLC: CHIRALCEL AD-3 [hexane–i-PrOH (80:20), 1.0 mL/min,
20 °C]; tr = 12.7 min (2S,3R), 9.1 min (2R,3S). IR (neat): 3446,
2964, 2251, 1597 cm–1 1H NMR (500 MHz, CDCl3): δ = 0.81 (d,
.
J = 7.0 Hz, 3 H), 1.01 (d, J = 7.0 Hz, 3 H), 1.11 (dd, J = 17.0, 9.5 Hz,
1 H), 1.68 (dd, J = 17.0, 7.0 Hz, 1 H), 2.15 (sept d, J = 7.0, 5.0 Hz,
C
20H22N2NaO2S: 377.1294; found: 377.1294.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–G