Transition-Metal-Free Terminal Alkyne Addition to Isatins

Article abstract of DOI:10.1055/s-0035-1562611

A 'direct' alkynylation of isatins, which uses potassium tert-butoxide to provide the desired 3-hydroxy-3-ethynyl-2-oxindoles in good to high yields, is reported. This protocol proceeds smoothly for both electron-rich and electron-deficient alkynes in com

Full text of DOI:10.1055/s-0035-1562611

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2016, 48, A–I
paper
A
K. Dhara et al.
Paper
Synthesis
Transition-Metal-Free Terminal Alkyne Addition to Isatins
Kalyan Dhara
Ajoy Kapat
R2
O
Tridev Ghosh
Jyotirmayee Dash*
Transition–metal–free
OH
O
R2
H
O
Versatile synthon
N
R1
N
R1
27 examples up to
79% yield
KOtBu, toluene, rt
Department of Organic Chemistry, Indian Association
for the Cultivation of Science, Jadavpur, Kolkata
700032, India
ocjd@iacs.res.in
Received: 20.05.2016
Accepted after revision: 11.07.2016
Published online: 24.08.2016
hydroxy-5-methylindolin-2-one F is more active than the
anti-HIV drug efavirenz (Figure 1).4 Ethynylindolin-2-ones
can also serve as versatile synthons in a wide variety of
synthetic applications to prepare biologically important
compounds.
DOI: 10.1055/s-0035-1562611; Art ID: ss-2016-n0175-op
Abstract A ‘direct’ alkynylation of isatins, which uses potassium tert-
butoxide to provide the desired 3-hydroxy-3-ethynyl-2-oxindoles in
good to high yields, is reported. This protocol proceeds smoothly for
both electron-rich and electron-deficient alkynes in comparable reac-
tion rates and does not require any specially design ligand or expensive
transition-metal catalysts.
In this context, we were interested in developing a di-
rect alkynylation of isatins 1 for the synthesis of 3-hydroxy-
3-ethynylindolin-2-one derivatives under transition-metal-
free conditions. Despite several methods having been re-
ported for direct terminal alkyne addition to a carbonyl
group,5–8 only a few studies have used isatins as the electro-
philic partners (Scheme 1, a–c).9–11 We have previously re-
ported that KOtBu can transform organonitriles to the cor-
responding amides via activation of the nitrile groups by
potassium ions.12 We hypothesised that if the carbonyl
group of isatins could be activated by coordination with po-
tassium ions, an alkoxide-promoted alkynylation would be
possible (Scheme 1, d).
In order to test our proposed methodology, N-benzyli-
satin (1a) was used as a model substrate to optimize the di-
rect alkynylation using phenylacetylene (2a) as the alkyne
precursor (Table 1). Babler and co-workers reported that
alkoxide can catalyze the addition of terminal alkynes to
ketones in DMSO.13 We first attempted the alkynylation of
Key words alkynes, 3-hydroxy-3-ethynylindolin-2-ones, HIV, isatins,
nucleophiles, addition, transition-metal-free
The addition of a carbon-centered nucleophile to the
electrophilic carbonyl group is one of the important atom-
economical methods1 to construct complex molecules from
simple starting materials. Recently, we have developed an
‘on-water’-promoted aldol reaction of N-substituted thi-
azolidinediones with isatin derivatives to afford a new class
of pharmacologically important thiazolidinedione-linked
3-hydroxy-2-oxindole derivatives.2 The 3-hydroxy-2-oxin-
dole motif is widely distributed in several biologically ac-
tive natural products such as the celogentins,3a convolut-
amidine A to E (Figure 1)3b and donaxaridine.3c–e Further-
more, it has been reported that 3-(cyclopropylethynyl)-3-
Br
HO
R
A R = CH2COMe
B R = CH2CH2Cl
C R = Me
D R = CH=CH2
E R = CH2CH2OH
HO
CF3
R
*
Cl
O
O
O
N
Br
N
N
H
O
H
Me
F R = Me
G R = Br
Convolutamidine
Efavirenz
Figure 1 Naturally occurring and biologically active 3-hydroxy-2-oxindole derivatives
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

B
K. Dhara et al.
Paper
Synthesis
isatin 1a using catalytic KOtBu in DMSO (Table 1, entry 1);
however, 1a did not show any reactivity under these condi-
tions. Next, a stoichiometric amount of KOtBu was used,
and the desired product 3aa was obtained in poor yield (Ta-
ble 1, entry 2). No further improvement in yield was ob-
served upon reaction in N,N-dimethylformamide and no
product formation was detected in acetonitrile (Table 1, en-
tries 3 and 4). Then, different polar aprotic solvents were
tested, but only electron-rich aromatic solvents provided
the desired product (Table 1, entries 5–12). Toluene was the
best solvent among the tested electron-rich aromatic sol-
vents (Table 1, entry 7). Furthermore, alkynylation in protic
solvents, such as tBuOH and MeOH, proved to be inefficient
(Table 1, entries 13 and 14).
Previous work (eq. a–c):
(2)
Ar
H
(a)
(b)
nucleophilic sites
Ar
Zn(Et)2-mediated addition
O
HO
NHC–Ag-catalysed alkyne
addition
O
O
N
N
Bn
Cu-catalysed addition
KOtBu, toluene, rt
3
1a
Bn
(c)
(d)
versatile synthon
This work (eq. d):
Scheme 1 Addition of alkynes to isatins
Table 2 Addition of Alkynes to Isatinsa
Table 1 Optimization of Phenylacetylene Addition to N-Benzylisatina
R2
O
HO
KOtBu
O
+
O
O
HO
H
R2
N
toluene, rt
N
R1
R1
2a
Bn
Bn
O
O
base, solvent, rt
N
N
1a–f
3
2a–l
Bn
Bn
3aa
1a
Entry
R1
R2
2a, H
Product
Yield (%)
Entry
Base (mol%)
KOtBu (10)
Solvent
Yieldb (%)
1
2
1a, H
1a, H
1b, H
1a, H
1a, H
1a, H
1a, H
1a, H
1a, H
1a, H
1a, H
1a, H
1a, H
3aa
3ab
3bb
3ac
3ad
3ae
3af
3ag
3ah
3ai
79
62
47
48
76
68
50
40
69
48
46
70
55
62
76
42
56
52
50
46
42
2b, 3-OMe
2b, 3-OMe
2c, 3-Me
2d, 4-Me
2e, 4-tBu
2f, 2,4,6-Me3
2g, 3,5-(OMe)2
2h, 4-C5H11
2i, 4-COOMe
2j, 3-F
1
2
DMSO
DMSO
DMF
–
3b
4
KOtBu (100)
KOtBu (100)
KOtBu (100)
KOtBu (50)
30
30
NR
40
52
79
56
42
trace
NR
NR
NR
trace
70
–
3
5
4
MeCN
toluene
toluene
toluene
xylene
6
5
6
KOtBu (75)
7
7
KOtBu (100)
KOtBu (100)
KOtBu (100)
KOtBu (100)
KOtBu (100)
KOtBu (100)
KOtBu (100)
KOtBu (100)
NaOtBu (100)
LiOtBu (100)
K2CO3 (100)
Cs2CO3 (100)
KOH (100)
8
9
8
10
11
12
13
14
15
16
17
18
19
20
21
9
mesitylene
3aj
10
11
12
13
14
15
16
17
18
19
20
nitrobenzene
DCE
2k, 3,5-F2
2l, 4-CF3
2a, H
3ak
3al
CH2Cl2
tBuOH
1c, 5-Cl
1d, 5-F
3ca
3da
3ea
3fa
3cd
3ce
3cl
2a, H
MeOH
1e, 5-OCF3
1f, 5,7-Me2
1c, 5-Cl
1c, 5-Cl
1c, 5-Cl
1c, 5-Cl
2a, H
toluene
toluene
toluene
toluene
toluene
toluene
2a, H
2d, 4-Me
2e, 4-tBu
2l, 4-CF3
2b, 3-OMe
–
–
–
3cb
NaOH (100)
–
a Reaction conditions: 1 (1.0 equiv), 2 (1.2 equiv), KOtBu (1.0 equiv), tolu-
ene, rt, 0.5–3 h.
a Reaction conditions: 1a (0.4 mmol), 2a (0.5 mmol), N2 atmosphere.
b Isolated yield; NR = no reaction.
b N-Methylisatin was used.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

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K. Dhara et al.
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Synthesis
To investigate counterion effects, NaOtBu and LiOtBu
were also used (Table 1, entries 15 and 16). Surprisingly,
only NaOtBu provided the desired product in a synthetically
useful yield. This result indicates that the size of the posi-
tive counterion plays a significant role in activation of the
electrophile. At this point we were curious as to whether
any other base with a different counter anion could pro-
mote this transformation. We found that K2CO3 and Cs2CO3
could not provide the desired product 3aa (Table 1, entries
17 and 18). In addition, the reaction was unsuccessful when
KOH or NaOH was used (Table 1, entries 19 and 20). The op-
timized protocol is straightforward and uses commercially
available reagents. No special experimental setup is neces-
sary to perform this transformation.
Having established optimized reaction conditions, we
explored the substrate scope of this methodology with re-
spect to the nucleophile using commercially available anhy-
drous toluene (Table 2). Electron-rich alkynes 2a–h provid-
ed the corresponding products 3aa–ah in moderate to good
yields in comparable reaction rates (Table 2, entries 1–9).
Next, electron-deficient alkynes 2i–2l were used as the
nucleophile, and the corresponding alkynylation products
3ai–3al were obtained in 46–70% yield (Table 2, entries 10–
13). Then, both electron-rich and electron-deficient isatins
were examined as the electrophilic partner. Thus, addition
of phenylacetylene (2a) to both electron-deficient and elec-
tron-rich isatins was investigated (Table 2, entries 14–17).
Since the 5-chloro- and 5-fluoroisatins 1c and 1d are highly
electrophilic in nature, the corresponding alkyne addition
products 3ca and 3da were isolated in 62% and 76% yield,
respectively. As expected, the electron-rich isatin 1f, due to
its poor electrophilicity, afforded the corresponding addi-
tion product 3fa in 56% yield. Since isatin 1c was a good
electrophilic partner in the direct alkyne addition, the nuc-
leophilic addition of different alkynes (2d, 2e, 2l and 2b)
was also performed (Table 2, entries 18–21). The corre-
sponding products 3cd, 3ce, 3cl and 3cb were isolated in
synthetically useful yields.
The reaction of aliphatic alkynes 2o and 2p with isatin
1a afforded the corresponding addition products 3ao and
3ap in 53% and 50% yield, respectively (Scheme 2). Encour-
aged by these results, we attempted the direct addition of
ethynylcyclopropane (2q) to N,5-dimethylisatin and 5-bro-
mo-N-methylisatin. To our delight, the anti-HIV drug ana-
logues F and G were synthesised in a single step starting
from commercially available materials in synthetically use-
ful yields. Efficient synthesis of 3an (78% yield) using
alkyne 2n containing the heterocyclic thiophene ring sys-
tem and successful addition of the more complex alkyne
2m demonstrate the synthetic utility of this protocol for
the diversity oriented synthesis14 of biologically active mol-
ecules (Scheme 2).
OH
N
Bn
OMe
O
S
MeO
3am 46%
HO
HO
O
OMe
O
2m
N
O
N
OMe
S
Bn
3ao 53%
Bn
2o
2n
R1
3an 78%
O
Me
N
1
R3
3
Me
Br
HO
HO
2p
2q
O
N
O
2q
N
Bn
Me
3ap 50%
Me
G 60%
HO
Biologically active
compound
O
N
Me
F 51%
Biologically active
compound
Scheme 2 Addition of aromatic, heteroaromatic and aliphatic alkynes to isatins
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

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K. Dhara et al.
Paper
Synthesis
To examine whether this alkynylation process involves
the formation of any radicals, the reaction of isatin 1a with
phenylacetylene (2a) was performed in the presence of
TEMPO or galvinoxyl as a radical scavenger (Scheme 3). No
significant change in the yield of 3aa was observed, indicat-
ing that radical intermediates are not involved in this pro-
cess.
To investigate the role of potassium ion, the alkynyla-
tion of isatin 1a with phenylacetylene (2a) was carried out
using 18-crown-6 as a potassium ion scavenger: only 20%
inhibition of product formation was observed.16 To study
the role of isatin conformation, alkynylations of aromatic
and aliphatic ketones were tested, but none of these ke-
tones afforded the desired product. The same result was
also observed for cyclic and acyclic diketone substrates.17
These data suggest that the lactam functionality plays an
important role in enhancing the electrophilicity of the keto
group of isatin. To clarify this point, the direct alkynylation
of acyclic keto amide 4 was undertaken and, gratifyingly,
the addition product 4a was isolated in 50% yield. This re-
sult provides direct evidence that the presence of an amide
group or lactam is essential for this transformation.
O
KOtBu,
HO
RS (3 equiv)
O
+
toluene
rt
O
N
N
2a
Bn
1a
Bn
3aa
Yield
Radical Scavenger (RS)
Combining these results, the following mechanism is
proposed for the direct alkynylation reaction of isatins
(Scheme 5). Upon treatment of isatin 1d with KOtBu, potas-
sium cation would coordinate with the two carbonyl
groups to form a stable five-membered complex A. In the
proposed complex A, the electrophilicity of the carbonyl
group is increased due to the presence of the electrophilic
iminium ion (resonance form of lactam). This facilitates a
direct nucleophilic attack of in situ formed phenylacetylide
to the most electrophilic carbonyl group to form the corre-
sponding potassium alkoxide, which upon protonation gen-
erates the desired alcohol 3da. Our deuterium labelling ex-
periment showed that alkyne acts as the proton source in
this reaction. X-ray crystal structure18 analysis unambigu-
ously proved the structure of the product 3da. The crystal
packing shows that the two structural units are stacked in
three-dimensional orientations via H-bonding and π–π* in-
teractions (Figure 2).
79%
75%
73%
none
TEMPO
galvinoxyl
Scheme 3 Addition of phenylacetylene to isatin 1a in the presence of a
radical scavenger
A deuterium labelling experiment was then carried out
to evaluate the proton source for protonation of the resul-
tant alkoxide formed during the direct alkyne addition to
isatins. A deuterium atom was incorporated into phenyl-
acetylene upon treatment with K2CO3 and D2O.15 When the
2
alkyne H-2a was employed under our alkynylation condi-
tions with isatin 1a, an excellent level of deuterium incor-
poration was observed to afford 2H-3aa in 59% yield
(Scheme 4). This experimental data indicates that the
alkyne serves as the proton source during protonation of
the resultant alkoxide in this alkynylation method.
Deuterium labelling experiments
D2O, K2CO3
D
H
MeCN, rt
2H-2a 99%
2a
Ph
DO
D
O
2H-2a
O
O
KOtBu, toluene, rt
N
N
Bn
Bn
Figure 2 Crystal packing of the direct alkynylation product 3da
2H-3aa 59%
1a
Ph
H
O
OH
N
In conclusion, a direct alkynylation of isatins mediated
by potassium tert-butoxide has been developed. A wide
range of substrates are compatible under these reaction
conditions, providing the corresponding alkynylation prod-
ucts in good to high yields. The transition-metal-free pro-
cess, inexpensive base reagent and the direct alkynylation
2a
N
KOtBu, toluene, rt
O
O
4a 50%
4
Scheme 4 Deuterium labelling and control experiments
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

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K. Dhara et al.
Paper
Synthesis
O
K
H
F
O
KOtBu
toluene, rt
2a
tBuO
O
O
F
N
N
tBuOH
Bn
1d
A
tBuOH
K
O
OK
3da
O
O
F
F
N
N
tBuOK
B
Scheme 5 Proposed mechanism
of isatins are highlights of this method. This work is prom-
ising for the large-scale synthesis of 3-hydroxy-3-ethynyl-
2-oxindoles from various isatins and alkynes. Studies di-
rected towards the synthetic applications of the ethynylox-
indole products are currently underway in our laboratory,
and the results will be reported in due course.
resulting mixture was extracted with CH2Cl2 (2 × 15 mL). The com-
bined organic phases were washed with a saturated aqueous solution
of sodium chloride, dried over anhydrous sodium sulfate, filtered and
concentrated under reduced pressure. The crude residue was then
purified by column chromatography on silica gel (EtOAc–hexane,
10:90 to 30:70) to give compounds 3.
1-Benzyl-3-hydroxy-3-[(3-methoxyphenyl)ethynyl]indolin-2-one
(3ab)
Following the general procedure, isatin 1a (100 mg, 0.4 mmol), KOtBu
(45 mg, 0.4 mmol) and 3-ethynylanisole (2b) (0.06 mL, 0.5 mmol)
provided compound 3ab (92 mg, 62%) as a grey solid; mp 177–179 °C.
All solvents and reagents were obtained from commercial sources.
Unless stated otherwise, reactions were conducted in oven-dried
glassware under an atmosphere of argon using anhydrous solvents.
N-Protected isatin derivatives 1a–f were prepared following a litera-
ture procedure.2 Reactions were monitored by analytical TLC which
was visualized by exposure to UV light (254 nm). Silica gel (100–200
mesh) was used for flash column chromatography. 1H NMR spectra
were recorded in CDCl3 at 400 or 500 MHz and the data are reported
relative to the residual solvent signals. Data for 1H NMR spectra are
reported as follows: chemical shift, multiplicity, coupling constant(s),
integration. Chemical shifts (δ) and coupling constants (J) are report-
ed in ppm and Hz, respectively. The following abbreviations are used
to indicate the multiplicity in the NMR spectra: s (singlet), d (dou-
blet), t (triplet), q (quartet), m (multiplet). 13C NMR spectra were re-
corded in CDCl3 at 100 or 125 MHz and the data are reported in terms
of chemical shift. IR spectra were recorded on a Perkin Elmer FT-IR
spectrometer and the data are reported in terms of frequency of ab-
sorption (cm–1). High-resolution mass spectrometry was recorded
with a Q-TOF YA263 (Waters Corporation) high-resolution instru-
ment by positive-mode electrospray ionization. Single crystal X-ray
analysis of 3da was recorded on a Bruker Kappa Apex II high-resolu-
tion X-ray diffractometer. Compounds 3aa, 3ca, 3da, 3ea and 3cd are
known compounds and their characterization data match those pre-
viously reported10,11 (see Supporting Information).
IR (KBr): 3270, 2831, 2721, 1410, 1340, 1210, 1108 cm–1
.
1H NMR (400 MHz): δ = 7.63 (d, J = 9.0 Hz, 1 H), 7.32–7.29 (m, 4 H),
7.28–7.24 (m, 2 H), 7.20 (t, J = 10.0 Hz, 1 H), 7.13 (t, J = 9.4 Hz, 1 H),
7.06 (d, J = 9.5 Hz, 1 H), 7.00–6.98 (m, 1 H), 6.90 (dd, J = 10.4, 2.7 Hz, 1
H), 6.74 (d, J = 9.8 Hz, 1 H), 4.94 (s, 2 H), 3.94 (br s, 1 H), 3.77 (s, 3 H).
13C NMR (125 MHz): δ = 174.1, 159.2, 142.1, 135.0, 130.4, 129.3,
128.9, 128.8, 127.8, 127.2, 124.8, 124.6, 123.8, 122.5, 116.6, 116.0,
110.0, 86.5, 85.2, 69.6, 55.3, 44.1.
HRMS (ESI): m/z [M + Na]+ calcd for C24H19NNaO3: 392.1263; found:
392.1201.
3-Hydroxy-3-[(3-methoxyphenyl)ethynyl]-1-methylindolin-2-one
(3bb)
Following the general procedure, isatin 1b (65 mg, 0.4 mmol), KOtBu
(45 mg, 0.4 mmol) and 3-ethynylanisole (2b) (0.06 mL, 0.5 mmol)
provided compound 3bb (55 mg, 47%) as a grey solid; mp 171–173 °C.
IR (KBr): 3285, 2981, 2861, 2740, 2430, 1670, 1208 cm–1
.
1H NMR (400 MHz): δ = 7.61 (d, J = 9.4 Hz, 1 H), 7.36 (dd, J = 14.4, 5.4
Hz, 1 H), 7.15 (dt, J = 9.7, 4.1 Hz, 2 H), 7.00 (d, J = 9.5 Hz, 1 H), 6.94 (d,
J = 1.9 Hz, 1 H), 6.86–6.83 (m, 2 H), 3.72 (s, 3 H), 3.22 (s, 3 H).
13C NMR (125 MHz): δ = 174.1, 159.1, 143.0, 130.4, 129.2, 129.0,
125.0, 125.0, 124.0, 123.0, 116.5, 116.0, 109.0, 86.1, 85.3, 70.0, 55.2,
27.0.
3-Ethynyl-3-hydroxyindolin-2-ones 3; General Procedure
To a solution of an alkyne 2 (1.2 equiv) in anhydrous toluene (3 mL)
under an argon atmosphere, KOtBu (1.0 equiv) was added, and the
mixture was stirred for 10–15 min. Then, an N-protected isatin 1 (1.0
equiv) was added to the reaction mixture, which was stirred for 30
min to 3 h until all the isatin was consumed (confirmed by TLC). The
reaction was finally quenched with a few drops of 1 N HCl and the
HRMS (ESI): m/z [M + Na]+ calcd for C18H15NNaO3: 316.0950; found:
316.1023.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

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K. Dhara et al.
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Synthesis
1-Benzyl-3-hydroxy-3-(m-tolylethynyl)indolin-2-one (3ac)
13C NMR (125 MHz): δ = 174.4, 142.3, 138.4, 138.2, 135.3, 134.0,
133.4, 131.0, 130.4, 129.4, 129.0, 128.0, 127.3, 125.0, 124.0, 119.0,
110.0, 89.0, 86.2, 70.0, 44.2, 20.1, 20.0, 19.1.
HRMS (ESI): m/z [M + Na]+ calcd for C26H23NNaO2: 404.1626; found:
404.1598.
Following the general procedure, isatin 1a (100 mg, 0.4 mmol), KOtBu
(45 mg, 0.4 mmol) and 3-ethynyltoluene (2c) (0.06 mL, 0.5 mmol)
provided compound 3ac (68 mg, 48%) as a white solid; mp 195–
197 °C.
IR (KBr): 3210, 2831, 2831, 2710, 1680, 1370, 1208 cm–1
.
1-Benzyl-3-[(3,5-dimethoxyphenyl)ethynyl]-3-hydroxyindolin-2-
one (3ag)
Following the general procedure, isatin 1a (100 mg, 0.4 mmol), KOtBu
(45 mg, 0.4 mmol) and 1-ethynyl-3,5-dimethoxybenzene (2g) (81 mg,
0.5 mmol) provided compound 3ag (64 mg, 40%) as a white solid; mp
193–195 °C.
1H NMR (400 MHz): δ = 7.62 (d, J = 10.0 Hz, 1 H), 7.46–7.43 (m, 2 H),
7.34–7.24 (m, 6 H), 7.12 (dd, J = 9.6, 2.8 Hz, 3 H), 6.72 (d, J = 9.8 Hz, 1
H), 4.93 (s, 2 H), 2.28 (s, 3 H).
13C NMR (125 MHz): δ = 174.5, 142.0, 138.0, 135.0, 133.0, 130.2,
130.0, 129.1, 129.0, 129.0, 128.1, 128.0, 127.1, 125.0, 124.0, 121.4,
110.0, 87.0, 85.1, 70.0, 44.0, 21.1.
IR (KBr): 3080, 2820, 2621, 1820, 1680, 1470, 1280 cm–1
.
HRMS (ESI): m/z [M + Na]+ calcd for C24H19NNaO2: 376.1313; found:
376.1287.
1H NMR (400 MHz): δ = 7.61 (d, J = 7.3 Hz, 1 H), 7.34–7.30 (m, 4 H),
7.29–7.27 (m, 2 H), 7.13 (t, J = 7.5 Hz, 1 H), 6.73 (d, J = 7.9 Hz, 1 H),
6.61 (d, J = 2.3 Hz, 2 H), 6.45 (t, J = 2.3 Hz, 1 H), 4.94 (s, 2 H), 3.75 (s, 6
H).
13C NMR (125 MHz): δ = 160.5, 142.2, 135.0, 130.5, 129.0, 128.8,
128.7, 128.7, 128.0, 127.2, 125.0, 124.0, 123.0, 119.4, 110.0, 109.8,
103.0, 87.0, 85.0, 70.0, 55.5, 44.2.
1-Benzyl-3-hydroxy-3-(p-tolylethynyl)indolin-2-one (3ad)
Following the general procedure, isatin 1a (100 mg, 0.4 mmol), KOtBu
(45 mg, 0.4 mmol) and 4-ethynyltoluene (2d) (0.06 mL, 0.5 mmol)
provided compound 3ad (107 mg, 76%) as a white solid; mp 199–
201 °C.
HRMS (ESI): m/z [M + Na]+ calcd for C25H21NNaO4: 422.1368; found:
422.1320.
IR (KBr): 3303, 2223, 1705, 1612, 1395, 1256, 1220, 1156 cm–1
.
1H NMR (400 MHz): δ = 7.61 (d, J = 7.3 Hz, 1 H), 7.39 (d, J = 8.1 Hz, 2
H), 7.32–7.21 (m, 6 H), 7.11 (t, J = 7.8 Hz, 1 H), 7.09 (d, J = 8.1 Hz, 2 H),
6.72 (d, J = 7.8 Hz, 1 H), 4.93 (s, 2 H), 3.52 (br s, 1 H), 2.34 (s, 3 H).
13C NMR (125 MHz): δ = 174.1, 142.1, 139.3, 135.0, 132.0, 130.3,
129.0, 128.9, 127.8, 127.1, 124.8, 123.7, 118.5, 109.9, 86.8, 84.7, 69.6,
44.1, 21.5.
1-Benzyl-3-hydroxy-3-[(4-pentylphenyl)ethynyl]indolin-2-one
(3ah)
Following the general procedure, isatin 1a (100 mg, 0.4 mmol), KOtBu
(45 mg, 0.4 mmol) and 1-ethynyl-4-pentylbenzene (2h) (0.09 mL, 0.5
mmol) provided compound 3ah (113 mg, 69%) as a white solid; mp
141–143 °C.
HRMS (ESI): m/z [M + Na]+ calcd for C24H19NNaO2: 376.1313; found:
376.1308.
IR (KBr): 3250, 3040, 2621, 2410, 1820, 1670, 1180 cm–1
.
1H NMR (400 MHz): δ = 7.60 (d, J = 7.4 Hz, 1 H), 7.36 (d, J = 8.0 Hz, 2
H), 7.33–7.29 (m, 4 H), 7.23 (d, J = 7.8 Hz, 2 H), 7.11 (t, J = 7.8 Hz, 3 H),
6.72 (d, J = 8.0 Hz, 1 H), 4.94 (s, 2 H), 3.60 (d, J = 3.5 Hz, 1 H), 2.58 (t, J =
7.7 Hz, 2 H), 1.60–1.57 (m, 2 H), 1.33–1.26 (m, 4 H), 0.88 (t, J = 6.7 Hz,
3 H).
13C NMR (125 MHz): δ = 174.1, 144.4, 142.2, 135.1, 132.0, 130.4,
129.0, 129.0, 128.4, 128.0, 127.2, 125.0, 124.0, 119.0, 110.0, 87.0, 85.0,
70.0, 44.1, 36.0, 31.4, 31.0, 22.5, 14.0.
1-Benzyl-3-[(4-tert-butylphenyl)ethynyl]-3-hydroxyindolin-2-one
(3ae)
Following the general procedure, isatin 1a (100 mg, 0.4 mmol), KOtBu
(45 mg, 0.4 mmol) and 4-tert-butylphenylacetylene (2e) (0.09 mL, 0.5
mmol) provided compound 3ae (107 mg, 68%) as a white solid; mp
188–190 °C.
IR (KBr): 3110, 2931, 2821, 2710, 1680, 1470, 1208 cm–1
.
1H NMR (400 MHz): δ = 7.61 (d, J = 7.2 Hz, 1 H), 7.39 (d, J = 8.3 Hz, 2
H), 7.35–7.28 (m, 6 H), 7.27–7.22 (m, 2 H), 7.12 (t, J = 7.5 Hz, 1 H), 6.71
(d, J = 7.8 Hz, 1 H), 4.93 (s, 2 H), 1.29 (s, 9 H).
HRMS (ESI): m/z [M + Na]+ calcd for C28H27NNaO2: 432.1939; found:
432.1910.
13C NMR (125 Hz): δ = 174.2, 152.4, 142.2, 135.0, 132.0, 130.3, 129.0,
129.0, 128.0, 127.1, 125.2, 125.0, 124.0, 119.0, 110.0, 87.0, 85.0, 70.0,
44.1, 35.0, 31.1, 30.0.
HRMS (ESI): m/z [M + Na]+ calcd for C27H25NNaO2: 418.1783; found:
418.1701.
Methyl 4-[(1-Benzyl-3-hydroxy-2-oxoindolin-3-yl)ethynyl]benzo-
ate (3ai)
Following the general procedure, isatin 1a (100 mg, 0.4 mmol), KOtBu
(45 mg, 0.4 mmol) and methyl 4-ethynylbenzoate (2i) (80 mg, 0.5
mmol) provided compound 3ai (76 mg, 48%) as a white solid; mp
146–148 °C.
1-Benzyl-3-hydroxy-3-(mesitylethynyl)indolin-2-one (3af)
IR (KBr): 3260, 2824, 2220, 1810, 1680, 1470, 1220 cm–1
.
Following the general procedure, isatin 1a (100 mg, 0.4 mmol), KOtBu
(45 mg, 0.4 mmol) and 2-ethynyl-1,3,5-trimethylbenzene (2f) (0.08
mL, 0.5 mmol) provided compound 3af (76 mg, 50%) as a white solid;
mp 219–221 °C.
1H NMR (400 MHz): δ = 7.95 (d, J = 8.4 Hz, 2 H), 7.62 (d, J = 7.4 Hz, 1
H), 7.49 (d, J = 8.4 Hz, 2 H), 7.33–7.28 (m, 6 H), 7.13 (t, J = 7.5 Hz, 1 H),
6.74 (d, J = 7.9 Hz, 1 H), 4.94 (s, 2 H), 3.91 (s, 3 H).
13C NMR (125 MHz): δ = 174.2, 166.4, 142.1, 135.0, 132.0, 131.0,
130.3, 129.4, 129.0, 129.0, 128.0, 127.2, 127.0, 126.2, 125.0, 124.0,
115.0, 110.0, 88.2, 86.0, 70.0, 52.3, 44.2.
IR (KBr): 3240, 3060, 2820, 1810, 1680, 1470, 1230 cm–1
.
1H NMR (400 MHz): δ = 7.61 (d, J = 7.4 Hz, 1 H), 7.31 (d, J = 4.2 Hz, 4
H), 7.27–7.19 (m, 3 H), 7.11 (t, J = 7.5 Hz, 1 H), 6.94 (s, 1 H), 6.71 (d, J =
7.8 Hz, 1 H), 4.99–4.87 (m, 2 H), 2.32 (s, 3 H), 2.21 (s, 3 H), 2.16 (s, 3
H).
HRMS (ESI): m/z [M + Na]+ calcd for C25H19NNaO4: 420.1212; found:
420.1188.
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Synthesis
1-Benzyl-3-[(3-fluorophenyl)ethynyl]-3-hydroxyindolin-2-one
(3aj)
Following the general procedure, isatin 1a (100 mg, 0.4 mmol), KOtBu
(45 mg, 0.4 mmol) and 1-ethynyl-3-fluorobenzene (2j) (0.06 mL, 0.5
mmol) provided compound 3aj (66 mg, 46%) as a brown solid; mp
164–166 °C.
1H NMR (400 MHz): δ = 7.38 (dd, J = 8.0, 1.3 Hz, 2 H), 7.25–7.15 (m, 7
H), 7.09 (d, J = 7.3 Hz, 2 H), 6.74 (s, 1 H), 5.08 (d, J = 7.6 Hz, 2 H), 2.22
(s, 3 H), 2.11 (s, 3 H).
13C NMR (125 MHz): δ = 175.2, 138.0, 137.0, 135.0, 134.0, 133.0,
130.0, 129.0, 128.2, 127.3, 126.0, 123.5, 122.0, 120.4, 86.4, 86.0, 69.2,
45.3, 21.1, 18.5.
IR (KBr): 3210, 2831, 2621, 1710, 1480, 1370, 1208 cm–1
.
HRMS (ESI): m/z [M + Na]+ calcd for C25H21NNaO2: 390.1470; found:
1H NMR (400 MHz): δ = 7.54 (d, J = 7.6 Hz, 1 H), 7.27–7.22 (m, 4 H),
7.21–7.14 (m, 4 H), 7.05 (t, J = 7.7 Hz, 2 H), 6.94–6.79 (m, 1 H), 6.66 (d,
J = 8.4 Hz, 1 H), 4.86 (s, 2 H).
390.1397.
1-Benzyl-3-[(4-tert-butylphenyl)ethynyl]-5-chloro-3-hydroxyin-
dolin-2-one (3ce)
13C NMR (125 MHz): δ = 174.1, 163.4, 161.0, 142.1, 135.0, 130.5,
130.0, 129.8, 129.0, 128.0, 127.8, 127.2, 125.0, 124.0, 119.0, 118.7,
116.5, 116.3, 110.0, 86.4, 85.2, 70.0, 44.1.
HRMS (ESI): m/z [M + Na]+ calcd for C23H16FNNaO2: 380.1063; found:
380.1002.
Following the general procedure, isatin 1c (108 mg, 0.4 mmol), KOtBu
(45 mg, 0.4 mmol) and 4-tert-butylphenylacetylene (2e) (0.09 mL, 0.5
mmol) provided compound 3ce (86 mg, 50%) as a white solid; mp
191–193 °C.
IR (KBr): 3220, 2840, 2721, 2610, 2370, 1870, 1308 cm–1
.
1-Benzyl-3-[(3,5-difluorophenyl)ethynyl]-3-hydroxyindolin-2-
one (3ak)
Following the general procedure, isatin 1a (100 mg, 0.4 mmol), KOtBu
(45 mg, 0.4 mmol) and 1-ethynyl-3,5-difluorobenzene (2k) (0.06 mL,
0.5 mmol) provided compound 3ak (105 mg, 70%) as a white solid;
mp 173–175 °C.
1H NMR (400 MHz): δ = 7.59 (d, J = 1.5 Hz, 1 H), 7.39 (d, J = 8.4 Hz, 2
H), 7.32–7.29 (m, 7 H), 7.20 (dd, J = 2.2, 10.3 Hz, 1 H), 6.62 (d, J = 10.5
Hz, 1 H), 4.91 (s, 2 H), 1.30 (s, 9 H).
13C NMR (125 MHz): δ = 174.0, 153.0, 141.0, 135.0, 132.0, 131.0,
130.2, 129.2, 129.0, 128.0, 127.1, 125.4, 125.3, 118.2, 111.0, 87.4, 84.1,
69.5, 44.2, 35.0, 31.1.
IR (KBr): 3210, 2931, 2881, 2790, 1680, 1370, 1208 cm–1
.
HRMS (ESI): m/z [M + Na]+ calcd for C27H24ClNNaO2: 452.1393; found:
1H NMR (400 MHz): δ = 7.62 (d, J = 6.8 Hz, 1 H), 7.33–7.27 (m, 6 H),
7.24–7.13 (m, 1 H), 6.91 (d, J = 6.9 Hz, 2 H), 6.75 (d, J = 9.2 Hz, 2 H),
4.93 (s, 2 H).
13C NMR (125 MHz): δ = 174.3, 164.0 (d), 161.1 (d), 142.0 (d), 135.0,
131.0, 128.8, 128.6, 128.5, 128.0, 127.1, 127.0, 125.0, 124.0, 115.1,
115.0, 110.0, 105.2, 87.5, 70.0, 44.1.
452.1372.
1-Benzyl-5-chloro-3-hydroxy-3-{[4-(trifluoromethyl)phe-
nyl]ethynyl}indolin-2-one (3cl)
Following the general procedure, isatin 1c (108 mg, 0.4 mmol), KOtBu
(45 mg, 0.4 mmol) and 4-ethynyl-α,α,α-trifluorotoluene (2l) (0.08
mL, 0.5 mmol) provided compound 3cl (81 mg, 46%) as a brown solid;
mp 175–177 °C.
HRMS (ESI): m/z [M + Na]+ calcd for C23H15F2NNaO2: 398.0969; found:
398.1067.
IR (KBr): 3280, 2950, 2820, 2740, 2470, 1670, 1408 cm–1
.
1-Benzyl-3-hydroxy-3-{[4-(trifluoromethyl)phenyl]ethynyl}indo-
lin-2-one (3al)
Following the general procedure, isatin 1a (100 mg, 0.4 mmol), KOtBu
(45 mg, 0.4 mmol) and 4-ethynyl-α,α,α-trifluorotoluene (2l) (0.08
mL, 0.5 mmol) provided compound 3al (90 mg, 55%) as a white solid;
mp 155–157 °C.
1H NMR (400 MHz): δ = 7.52 (d, J = 2.3 Hz, 1 H), 7.48 (br s, 4 H), 7.25–
7.19 (m, 5 H), 7.16 (dd, J = 2.2, 8.4 Hz, 1 H), 6.58 (d, J = 8.4 Hz, 1 H),
4.85 (d, J = 3.1 Hz, 2 H).
13C NMR (125 MHz): δ = 173.7, 140.5, 134.4, 132.3, 130.5, 130.0,
129.4, 129.0, 128.7, 128.1, 127.1, 125.4, 125.2, 111.1, 87.1, 85.5, 69.4,
53.4, 44.3, 30.0.
IR (KBr): 3303, 2223, 1705, 1612, 1493, 1419, 1388, 1272, 1248 cm–1
.
HRMS (ESI): m/z [M + Na]+ calcd for C24H15ClF3NNaO2: 464.0641;
1H NMR (400 MHz): δ = 7.63 (d, J = 9.1 Hz, 1 H), 7.53 (d, J = 1.7 Hz, 4
H), 7.34–7.27 (m, 6 H), 7.14 (t, J = 8.8 Hz, 1 H), 6.74 (d, J = 9.8 Hz, 1 H),
4.94 (s, 2 H), 4.43 (br s, 1 H).
13C NMR (125 MHz): δ = 174.1, 142.1, 134.8, 132.3, 130.6, 128.9,
128.5, 127.9, 127.1, 125.2, 125.1, 124.8, 124.0, 110.0, 87.8, 85.0, 69.5,
44.1, 22.1.
found: 464.0602.
1-Benzyl-5-chloro-3-hydroxy-3-[(3-methoxyphenyl)ethynyl]indo-
lin-2-one (3cb)
Following the general procedure, isatin 1c (108 mg, 0.4 mmol), KOtBu
(45 mg, 0.4 mmol) and 3-ethynylanisole (2b) (0.06 mL, 0.5 mmol)
provided compound 3cb (68 mg, 42%) as a white solid; mp 186–
188 °C.
HRMS (ESI): m/z [M + Na]+ calcd for C24H16F3NNaO2: 430.1031; found:
430.1035.
IR (KBr): 3250, 2822, 2711, 2650, 2270, 1670, 1408 cm–1
.
1-Benzyl-3-hydroxy-5,7-dimethyl-3-(phenylethynyl)indolin-2-
one (3fa)
Following the general procedure, isatin 1f (106 mg, 0.4 mmol), KOtBu
(45 mg, 0.4 mmol) and phenylacetylene (2a) (0.05 mL, 0.5 mmol) pro-
vided compound 3fa (82 mg, 56%) as a white solid; mp 155–157 °C.
1H NMR (400 MHz): δ = 7.52 (d, J = 2.2 Hz, 1 H), 7.24–7.18 (m, 5 H),
7.12 (t, J = 9.7 Hz, 2 H), 6.98 (d, J = 7.6 Hz, 1 H), 6.90 (br s, 1 H), 6.82
(dd, J = 2.6, 10.4 Hz, 1 H), 6.56 (d, J = 8.4 Hz, 1 H), 4.84 (s, 2 H), 3.69 (s,
3 H).
13C NMR (125 MHz): δ = 174.0, 159.2, 141.0, 134.5, 130.3, 130.2,
129.4, 129.2, 129.0, 128.0, 127.1, 125.4, 124.7, 122.2, 116.6, 116.1,
111.0, 87.0, 84.4, 69.4, 55.3, 44.2.
IR (KBr): 3280, 2631, 1821, 1710, 1480, 1270, 1208 cm–1
.
HRMS (ESI): m/z [M + Na]+ calcd for C24H18ClNNaO3: 426.0873; found:
426.0798.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

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Synthesis
1-Benzyl-3-hydroxy-3-[(5-methoxynaphthalen-2-yl)ethynyl]indo-
lin-2-one (3am)
Following the general procedure, isatin 1a (100 mg, 0.4 mmol), KOtBu
(45 mg, 0.4 mmol) and 6-ethynyl-1-methoxynaphthalene (2m) (91
mg, 0.5 mmol) provided compound 3am (77 mg, 46%) as a white sol-
id; mp 205–207 °C.
13C NMR (125 MHz): δ = 174.4, 142.1, 135.1, 130.2, 129.3, 129.0,
128.0, 127.1, 125.0, 124.0, 110.0, 88.4, 86.2, 69.3, 44.0, 31.0, 28.0,
22.1, 19.0, 14.0.
HRMS (ESI): m/z [M + Na]+ calcd for C22H23NNaO2: 356.1626; found:
356.1620.
IR (KBr): 3220, 3031, 2821, 2610, 1880, 1670, 1420 cm–1
.
3-(Cyclopropylethynyl)-3-hydroxy-1,5-dimethylindolin-2-one (F)
1H NMR (400 MHz): δ = 7.92 (s, 1 H), 7.67–7.63 (m, 3 H), 7.45 (dd, J =
8.4, 1.2 Hz, 1 H), 7.33 (d, J = 4.4 Hz, 4 H), 7.28–7.25 (m, 2 H), 7.15–7.13
(m, 2 H), 7.08 (d, J = 2.0 Hz, 1 H), 6.73 (d, J = 7.8 Hz, 1 H), 4.95 (s, 2 H),
3.92 (s, 3 H).
Following the general procedure, 1,5-dimethylindoline-2,3-dione (70
mg, 0.4 mmol), KOtBu (45 mg, 0.4 mmol) and ethynylcyclopropane
(2q) (0.04 mL, 0.5 mmol) provided compound F (49 mg, 51%) as a
white solid; mp 184–186 °C.
IR (KBr): 2880, 2640, 2421, 1810, 1680, 1250, 1160 cm–1
.
13C NMR (125 MHz): δ = 174.2, 159.0, 142.2, 135.1, 135.0, 132.3,
130.4, 129.4, 129.0, 129.0, 129.0, 128.3, 128.0, 127.2, 127.0, 125.0,
124.0, 120.0, 116.4, 110.0, 106.0, 87.2, 85.0, 70.0, 55.4, 44.2.
1H NMR (400 MHz): δ = 7.32 (s, 1 H), 7.13 (d, J = 7.9 Hz, 1 H), 6.71 (d,
J = 7.9 Hz, 1 H), 3.52 (br s, 1 H), 3.18 (s, 3 H), 2.35 (s, 3 H), 1.26 (t, J =
6.6 Hz, 1 H), 0.78–0.69 (m, 4 H).
HRMS (ESI): m/z [M + Na]+ calcd for C28H21NNaO3: 442.1419; found:
13C NMR (125 MHz): δ = 174.1, 141.0, 133.3, 130.4, 129.2, 125.2,
442.1387.
108.4, 91.0, 72.2, 69.3, 29.7, 26.5, 21.0, 8.4 (d).
1-Benzyl-3-hydroxy-3-(thien-3-ylethynyl)indolin-2-one (3an)
HRMS (ESI): m/z [M + Na]+ calcd for C15H15NNaO2: 264.1000; found:
264.0421.
Following the general procedure, isatin 1a (100 mg, 0.4 mmol), KOtBu
(45 mg, 0.4 mmol) and 3-ethynylthiophene (2n) (0.05 mL, 0.5 mmol)
provided compound 3an (108 mg, 78%) as a white solid; mp 161–
163 °C.
5-Bromo-3-(cyclopropylethynyl)-3-hydroxy-1-methylindolin-2-
one (G)
IR (KBr): 2840, 2620, 2421, 2010, 1680, 1470, 1206 cm–1
.
Following the general procedure, 5-bromo-N-methylisatin (96 mg,
0.4 mmol), KOtBu (45 mg, 0.4 mmol) and ethynylcyclopropane (2q)
(0.04 mL, 0.5 mmol) provided compound G (73 mg, 60%) as a white
solid; mp 197–199 °C.
1H NMR (400 MHz): δ = 7.60 (d, J = 7.3 Hz, 1 H), 7.50 (d, J = 2.9 Hz, 1
H), 7.33–7.28 (m, 4 H), 7.25–7.23 (m, 3 H), 7.12 (dd, J = 9.8, 5.1 Hz, 2
H), 6.72 (d, J = 7.8 Hz, 1 H), 4.92 (s, 2 H), 3.72 (s, 1 H).
IR (KBr): 3080, 2730, 2440, 1710, 1680, 1220, 1180 cm–1
.
13C NMR (125 MHz): δ = 174.0, 142.2, 135.0, 130.4, 130.0, 129.0,
129.0, 128.0, 127.2, 125.4, 125.0, 124.0, 121.0, 110.0, 85.1, 82.0, 70.0,
44.1.
1H NMR (400 MHz): δ = 7.61 (d, J = 1.7 Hz, 1 H), 7.47 (dd, J = 8.3, 2.1
Hz, 1 H), 6.71 (d, J = 8.2 Hz, 1 H), 3.19 (s, 3 H), 1.28–1.26 (m, 1 H),
0.81–0.73 (m, 4 H).
HRMS (ESI): m/z [M + Na]+ calcd for C21H15NNaO2S: 368.0721; found:
13C NMR (125 MHz): δ = 173.6, 142.0, 133.0, 131.0, 128.0, 125.0,
368.1011.
116.2, 110.2, 92.0, 71.4, 69.0, 27.0, 8.5 (d).
1-Benzyl-3-hydroxy-3-(3-methoxyprop-1-yn-1-yl)indolin-2-one
(3ao)
Following the general procedure, isatin 1a (100 mg, 0.4 mmol), KOtBu
(45 mg, 0.4 mmol) and 3-methoxyprop-1-yne (2o) (0.04 mL, 0.5
mmol) provided compound 3ao (65 mg, 53%) as a white solid; mp
131–133 °C.
HRMS (ESI): m/z [M + Na]+ calcd for C14H12BrNNaO2: 327.9949; found:
327.9887.
Deuterium Labelling Experiment
To a mixture of phenylacetylene (2a) (1.0 equiv) and K2CO3 (1.5 equiv)
in MeCN (2 mL) under an argon atmosphere was added D2O (500 μL,
~50 equiv). After the mixture was stirred for 1 h, it was diluted with
CH2Cl2 (5 mL) and transferred to a separating funnel. The organic layer
was separated and dried with MgSO4, filtered and concentrated under
reduced pressure. Subsequent NMR analysis showed that phenylacet-
ylene (2a) was deuterated. Then, isatin 1a (100 mg, 0.4 mmol) was
added to a mixture of KOtBu (45 mg, 0.4 mmol) and phenylacetylene-
d (2H-2a) (0.05 mL, 0.5 mmol) in toluene (3 mL), and this mixture was
stirred for 3 h. The crude mixture was dried and purified by column
chromatography (silica gel; EtOAC–hexane, 10:90 to 30:70) to provide
compound 2H-3aa in 59% yield.
IR (KBr): 2880, 2640, 2420, 1810, 1680, 1470, 1240 cm–1
.
1H NMR (400 MHz): δ = 7.55 (d, J = 7.4 Hz, 1 H), 7.33–7.23 (m, 6 H),
7.09 (t, J = 7.5 Hz, 1 H), 6.71 (d, J = 7.9 Hz, 1 H), 4.90 (d, J = 3.8 Hz, 2 H),
4.15 (s, 2 H), 3.35 (s, 3 H).
13C NMR (125 MHz): δ = 174.0, 142.2, 135.0, 130.4, 129.0, 129.0,
128.0, 127.2, 125.0, 124.0, 110.0, 83.1, 83.0, 69.2, 60.0, 58.0, 44.1.
HRMS (ESI): m/z [M + Na]+ calcd for C19H17NNaO3: 330.1106; found:
330.1086.
1-Benzyl-3-(hept-1-yn-1-yl)-3-hydroxyindolin-2-one (3ap)
Following the general procedure, isatin 1a (100 mg, 0.4 mmol), KOtBu
(45 mg, 0.4 mmol) and 1-heptyne (2p) (0.07 mL, 0.5 mmol) provided
compound 3ap (64 mg, 50%) as a white solid; mp 137–139 °C.
2-Hydroxy-2,4-diphenyl-1-(piperidin-1-yl)but-3-yn-1-one (4a)
Following the general procedure, keto amide 4 (100 mg, 0.46 mmol),
KOtBu (52 mg, 0.46 mmol) and phenylacetylene (2a) (0.06 mL, 0.55
mmol) provided compound 4a (74 mg, 50%) as a white solid; mp
171–173 °C.
IR (KBr): 3420, 3230, 2821, 2710, 2480, 2270, 1820 cm–1
.
1H NMR (400 MHz): δ = 7.52 (d, J = 6.6 Hz, 1 H), 7.33–7.25 (m, 5 H),
7.21 (t, J = 7.7 Hz, 1 H), 7.09 (t, J = 7.5 Hz, 1 H), 6.69 (d, J = 7.8 Hz, 1 H),
4.90 (d, J = 4.0 Hz, 2 H), 3.32 (br s, 1 H), 2.25–2.22 (m, 2 H), 1.52–1.50
(m, 2 H), 1.36–1.27 (m, 4 H), 0.89–0.86 (m, 3 H).
IR (KBr): 3300, 2223, 1700, 1610, 1390, 1253, 1210, 1150 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.60 (d, J = 7.4 Hz, 2 H), 7.55–7.53 (m, 2
H), 7.41–7.32 (m, 6 H), 6.15 (s, 1 H), 3.69 (s, 2 H), 3.47–3.43 (m, 1 H),
3.25–3.24 (m, 1 H), 1.60 (s, 4 H), 1.37 (s, 2 H).
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Synthesis
13C NMR (100 MHz, CDCl3): δ = 168.7, 141.0, 132.0, 129.0, 128.9,
128.7, 128.6, 126.4, 122.3, 87.7, 86.8, 72.1, 47.9, 45.6, 25.7, 24.9, 24.3.
HRMS (ESI): m/z [M + H]+ calcd for C21H22NO2: 320.1651; found:
320.1654.
(h) Deng, G.-J.; Li, C.-J. Synlett 2008, 1571. (i) Brummond, K. M.;
Osbourn, J. M. Beilstein J. Org. Chem. 2010, 6, 33. (j) Chinkov, N.;
Warm, A.; Carreira, E. M. Angew. Chem. Int. Ed. 2011, 50, 2957.
(7) For catalytic alkyne addition to ketones, see: (a) Cozzi, P. G.
Angew. Chem. Int. Ed. 2003, 42, 2895. (b) Lu, G.; Li, X.; Jia, X.;
Chan, W. L.; Chan, A. S. C. Angew. Chem. Int. Ed. 2003, 42, 5057.
(c) Saito, B.; Katsuki, T. Synlett 2004, 1557. (d) Cozzi, P. G.; Alesi,
S. Chem. Commun. 2004, 2448. (e) Liu, L.; Wang, R.; Kang, Y.-F.;
Chen, C.; Xu, Z.-Q.; Zhou, Y.-F.; Ni, M.; Cai, H.-Q.; Gong, M.-Z.
J. Org. Chem. 2005, 70, 1084.
Acknowledgment
We thank the Department of Science and Technology (DST) and CSIR-
India for research funding. K.D. thanks UGC and T.G. thanks CSIR for a
research fellowship. We thank Professor Dr Hans-Ulrich Reissig for
useful discussions.
(8) Reference for alkyne addition to aldehydes, see: (a) Viehe, H. G.;
Reinstein, M. Chem. Ber. 1962, 95, 2557. (b) Brandsma, L. Prepar-
ative Acetylenic Chemistry, 2nd ed.; Elsevier: Amsterdam, 1988.
(c) Wang, Q.; Pu, L. Synlett 2013, 24, 1340.
(9) Chen, G.; Wang, Y.; Guo, S.; He, H.-P.; Li, S.-L.; Zhang, J.-X.; Ding,
J.; Hao, X.-J. J. Heterocycl. Chem. 2009, 46, 217.
Supporting Information
(10) Fu, X.-P.; Liu, L.; Wang, D.; Chen, Y.-J.; Li, C.-J. Green Chem. 2011,
13, 549.
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1562611.
S
u
p
p
ortioInfgrmoaitn
S
u
p
p
ortiInfogrmoaitn
(11) Chouhan, M.; Senwar, K. R.; Kumar, K.; Sharma, R.; Nair, V. A.
Synthesis 2014, 46, 195.
(12) Midya, G. C.; Kapat, A.; Maiti, S.; Dash, J. J. Org. Chem. 2015, 80,
4148.
(13) Babler, J. H.; Liptak, V. P.; Phan, N. J. Org. Chem. 1996, 61, 416.
(14) (a) Burke, M. D.; Schreiber, S. L. Angew. Chem. Int. Ed. 2004, 43,
46. (b) O’Connor, C. J.; Beckmann, H. S. G.; Spring, D. R. Chem.
Soc. Rev. 2012, 41, 4444.
References
(1) Trost, B. M. Science 1991, 254, 1471.
(2) Paladhi, S.; Bhati, M.; Panda, D.; Dash, J. J. Org. Chem. 2014, 79,
1473.
(3) (a) Suzuki, H.; Morita, H.; Shiro, M.; Kobayashi, J. Tetrahedron
2004, 60, 2489. (b) Kamano, Y.; Zhang, H.-P.; Ichihara, Y.; Kizu,
H.; Komiyama, K.; Pettit, G. R. Tetrahedron Lett. 1995, 36, 2783.
(c) Kawasaki, T.; Nagaoka, M.; Satoh, T.; Okamoto, A.; Ukon, R.;
Ogawa, A. Tetrahedron 2004, 60, 3493. (d) Miah, S.; Moody, C. J.;
Richards, I. C.; Slawin, A. M. Z. J. Chem. Soc., Perkin Trans. 1 1997,
2405. (e) Rasmussen, H. B.; MacLeod, J. K. J. Nat. Prod. 1997, 60,
1152.
(4) Boechat, N.; Kover, W. B.; Bongertz, V.; Bastos, M. M.; Romeiro,
N. C.; Azevedo, M. L. G.; Wollinger, W. Med. Chem. (Sharjah,
United Arab Emirates) 2007, 3, 533.
(5) For alkyne addition to carbonyls, see: (a) Trost, B. M.; Weiss, A.
H. Adv. Synth. Catal. 2009, 351, 963. (b) Carreira, E. M.; Frantz, D.
E. In Science of Synthesis: Stereoselective Synthesis; Vol. 2;
Molander, G. A., Ed.; Thieme: Stuttgart, 2011, 497. (c) Li, C.-J.
Acc. Chem. Res. 2010, 43, 581.
(6) For alkyne addition to ketones, see: (a) Tzalis, D.; Knochel, P.
Angew. Chem. Int. Ed. 1999, 38, 1463. (b) Chen, C.-Y.; Tiller, R. D.;
Grabowski, E. J. J.; Reider, P. J. Angew. Chem. Int. Ed. 1999, 38,
711. (c) Choudhury, A.; Moore, J. R.; Pierce, M. E.; Fortunak, J.
M.; Valvis, I.; Confalone, P. N. Org. Process Res. Dev. 2003, 7, 324.
(d) Jiang, B.; Tang, X. Org. Lett. 2002, 4, 3451. (e) Dhondi, P. K.;
Chisholm, J. D. Org. Lett. 2006, 8, 67. (f) Dhondi, P. K.; Carberry,
P.; Choi, L. B.; Chisholm, J. D. J. Org. Chem. 2007, 72, 9590.
(g) Motoki, R.; Kanai, M.; Shibasaki, M. Org. Lett. 2007, 9, 2997.
(15) Bew, S. P.; Hiatt-Gipson, G. D.; Lovell, J. A.; Poullain, C. Org. Lett.
2012, 14, 456.
(16) A stoichiometric amount of 18-crown-6 was added to the alky-
nylation reaction of isatin 1a with phenylacetylene (2a) under
the standard reaction conditions. The reaction afforded 3aa in
60% yield, a 20% inhibition of product formation compared to
the reaction in the absence of 18-crown-6 (Table 1, entry 7).
Only partial inhibition of the product yield was observed; possi-
bly toluene is not the best solvent for efficient 1:1 complex for-
mation; see: (a) Izzat, R. M.; Pawlak, K.; Bradshaw, J. S. Chem.
Rev. 1991, 91, 1721. (b) Li, Y.; Huszthy, P.; Móczár, I.;
Szemenyei, B.; Kunsági-Máté, S. Chem. Phys. Lett. 2013, 556, 94.
(17) Different aryl ketones (benzaldehydes, acetophenone, trifluoro-
acetophenone) and aryl diketones (benzil and 9,10-phenan-
threnequinone) were used as the electrophilic partner. As
expected, none of these substrates, except trifluoroacetophe-
none, afforded the corresponding addition products. The aryl
ketone trifluoroacetophenone, due to its high electrophilicity,
provided the desired product in low (30%) yield. Under similar
reaction conditions, the alkynylation of acetone with phenyl-
acetylene did not proceed to give the desired product.
(18) CCDC 1433098 contains the supplementary crystallographic
data for 3da in this paper. The data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/getstructures.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I