Oxidative Cyclization of o-(1-Hydroxy-2-alkynyl)- N-tosylanilides for the Synthesis of 4-Quinolones

Article abstract of DOI:10.1021/acs.joc.0c00245

The treatment of easily accessible o-(1-hydroxy-2-alkynyl)-N-tosylanilides 1 with excess manganese(IV) oxide in the presence of substoichiometric tetrabutylammonium iodide (TBAI) in chloroform (or in the absence of TBAI in dimethylformamide, DMF) promoted a sequential oxidation/intramolecular hydroamination to give 4-quinolones 3 and/or (Z)-2-alkylidene-3-oxindoles (Z)-4 in good yields. Possibly, MnO2 played dual roles as an oxidant and as a Lewis acidic activator of intermediary ynones 2. The product distributions between 3 and (Z)-4 could be controlled by the choice of solvents.

Full text of DOI:10.1021/acs.joc.0c00245

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Article
Oxidative Cyclization of o-(1-Hydroxy-2-alkynyl)-N-
tosylanilides for Synthesis of 4-Quinolones
Jun-ichi Ueda, Yuuki Enomoto, Mizuki Seki, Takuma Konishi, Masamichi Ogasawara, and Kazuhiro Yoshida
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c00245 • Publication Date (Web): 21 Apr 2020
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Page 1 of 10
The Journal of Organic Chemistry
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Oxidative Cyclization of o-(1-Hydroxy-2-alkynyl)-N-tosylanilides for
Synthesis of 4-Quinolones
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Jun-ichi Ueda,† Yuuki Enomoto,‡ Mizuki Seki,† Takuma Konishi,‡ Masamichi Ogasawara,‡,* and Kazuhiro Yo-
shida†,*
†Department of Chemistry, Graduate School of Science, Chiba University, Yayoi-cho, Inage-ku, Chiba 263-8522, Japan
‡Department of Natural Science, Graduate School of Science and Technology and Research Cluster on "Innovative Chemical Sens-
ing", Tokushima University, Tokushima 770-8506, Japan
Supporting Information Placeholder
ABSTRACT: A treatment of easily accessible o-(1-hydroxy-2-alkynyl)-N-tosylanilides 1 with excess manganese(IV) oxide in the presence of
substoichiometric tetrabutylammonium iodide (TBAI) in chloroform (or in the absence of TBAI in DMF) promoted a sequential oxidation/in-
tramolecular hydroamination to give 4-quinolones 3 and/or (Z)-2-alkylidene-3-oxindoles (Z)-4 in good yields. Possibly MnO2 played dual
roles as an oxidant and as a Lewis acidic activator of intermediary ynones 2. The product distributions between 3 and (Z)-4 could be controlled
by the choice of the solvents.
During the course of the studies, we were aware of the potential
usefulness of this reaction sequence; i.e., the hydroamination/cy-
clization of o-propynoyl-(N-tosyl)amidobenzene derivatives could
be a general route to a series of 4-quinolones.3 And indeed, several
examples of somewhat similar reactions have already been described
in literatures and selected examples are shown in Scheme 2.4 In 1991,
Torii reported a palladium-catalyzed reaction between o-iodoaniline
and a terminal acetylene under a carbon monoxide atmosphere. The
carbonylative coupling generated a propynoylaniline and the subse-
quent cyclization gave a 4-quinolone (eq. (a)).4a,b In 2009, Georg de-
scribed an N-deprotection/cyclization protocol starting with the
ynone substrates in which methanol played an important role as a
catalytic nucleophile (eq. (b)).4c,e More recently, Helaja developed a
gold-catalyzed cyclization of N-unprotected ynones leading to anal-
ogous 4-quinolones (eq. (c)).4d
INTRODUCTION
Nitrogen-containing heterocycles are ubiquitous in nature and
have played important roles in pharmaceutical industries. Among
them, 4-quinolone structures are omnipresent in a number of bio-
logically active molecules such as antibiotics.1 Recently, we devel-
oped a method of preparing the ferrocene-fused planar-chiral pyri-
done/pyridine derivatives in an enantioselective fashion (Scheme
1).2 The key reaction step of the synthetic sequence was the intra-
molecular hydroamination/cyclization of 1-propynoyl-2-(N-to-
syl)amidoferrocene derivatives B. Whereas B were found to be rela-
tively susceptible, they were not isolated. Instead, the oxidation of
propargyl alcohols A giving B in situ, and the subsequent hydroami-
nation/cyclization of B were conducted in one-pot. The sequential
reactions took place smoothly under the mild conditions in the pres-
ence of excess manganese(IV) oxide and catalytic tetrabutylammo-
nium iodide (TBAI), and the corresponding ferroco-pyridones C
were obtained in up to 99% yield.
PdCl2(PPh3)2 (5 mol %)
Et2NH
I
(a)
+ CO +
Ph
120 °C, 6 h
NH2
O
Scheme 1. Enantioselective Synthesis of Planar-Chiral Ferroco-
Pyridones/Pyridines.2
O
K2CO3, MeOH
HCl
dioxane
(b)
OH
45-50 °C, 4 days
Ph
CHO
MgBr
NH
N
H
Ph
Boc
Fe NH
Fe NH
Ts
Ts
O
R'5
R'5
(S)-A
O
PPh3AuNTf2 (5 mol %)
MeCN, r.t., 24 h
single-enantiomer
(c)
R' = Me, Ph, Bn
MnO2
TBAI
Ph
NH2
Fe NH
Ts
In spite of these precedence, we still have pursued our protocol as
a potential procedure for 4-quinolone synthesis due to the simple
manipulations and the easy access to the starting compounds. While
the one-pot oxidation/cyclization of o-(1-hydroxy-2-alkynyl)-N-to-
sylanilides 1 were examining, the concomitant formation of 2-alkyli-
dene-3-oxindoles 4,5,6 which are also known as important N-
R'5
NR2
O
(S)-B
Me3SiNR2
TiCl4
Fe
N
Fe
N
iodide-catalyzed
cyclization
Ts
R'5
R'5
(S)-C
up to 99% yield
(from A to C)
NR2 = NMe2, pyrroridyl
NEt2, morpholyl
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The Journal of Organic Chemistry
Page 2 of 10
heterocycles, was detected together with expected 4-quinolones 3. propynyl)-N-tosylanilide 1a as a model substrate (Table 1). Firstly,
1
2
3
4
5
6
7
8
While the formation of 3 was explained by the endo-cyclization of o-
alkynoyl-N-tosylanilides 2 which were generated in situ, the exo-cy-
clization of 2 afforded 4 alternatively (Scheme 2).7 After the exten-
sive tuning of the reaction conditions, it was established that the exo-
versus endo-selectivity on the intramolecular hydroamination of 2
could be controlled to a certain extent. In this report, we describe our
results on the cyclization of o-alkynoyl-N-tosylanilide derivatives 2.
the reaction conditions used in the synthesis of ferroco-pyridone
(S)-C (Scheme 1) were examined. A mixture of 1a, manganese(IV)
oxide (15 equiv to 1a), and TBAI (0.5 equiv to 1a) in CH2Cl2 was
stirred at 35 °C for 2 hours. Although 1a was consumed completely,
expected 6-endo-dig cyclization product 3a was obtained in only 13%
together with 2a in 25% and (Z)-4a in 44% (entry 1). The unex-
pected formation of (Z)-4a could be rationalized by the 5-exo-dig
hydroamination/cyclization of 2a.8 It was found that the reaction
showed a remarkable solvent effect in the product distribution. A re-
action in chloroform under otherwise identical conditions afforded
(Z)-4a predominantly in 94% with a trace amount of 3a (entry 2).
While the reaction in toluene gave the similar results as in chloro-
form (entry 3), the cyclization step was slow in 1,4-dioxane or
MTBE and intermediate 2a was obtained in 72-74% yields (entries
4 and 5). The yields of 3a were slightly increased in THF, acetone,
or acetonitrile, however, the general trend of the predominant for-
mation of (Z)-4a remained unchanged (entries 6-8). The use of
methanol inhibited the oxidation of 1a leading to 29% conversion
(entry 9). On the other hand, the reactions in aprotic polar solvents,
such as DMSO or DMF, drastically changed the product distribu-
tion giving 3a as a major product (entries 10 and 11). A role of TBAI
Scheme 2. Cyclization of o-Alkynoyl-N-tosylanilides 2 Prepar-
ing 4-Quinolones 3 and 2-Alkylidene-3-oxindoles 4.
9
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O
MnO2 (15 equiv.)
DMF
N
R
OH
R'
Ts
3
4
R
NH
Ts
1
O
N
R'
MnO2 (15 equiv.)
TBAI (0.5 equiv.)
CHCl3
R
R'
Ts
O
is a catalytic nucleophile, which bind to the b-sp-carbon of the ynone
moiety in 2 to activate the molecule for the subsequent cyclization.
The presence of TBAI was important in the effective cyclization of
(S)-B forming ferroco-pyridone (S)-C (Scheme 1). On the other
hand, the oxidative cyclization of 1a in DMF proceeded without
TBAI, and both 3a and 4a were obtained in 36% and 23% yields, re-
spectively (entry 12). The effect of TBAI was much more visible in
chloroform and the cyclization was very slow without TBAI (entry
13).
R
NH
R'
Ts
2
RESULTS AND DISCUSSION
At the outset, the intramolecular hydroamination reaction was ex-
amined using readily accessible o-(1-hydroxy-3-phenyl-2-
Table 1. Oxidative Hydroamination/Cyclization of 1a: Optimizing Reaction Conditionsa
OH
O
O
O
MnO2 (15 equiv.)
TBAI
+
+
solvent
35 °C, 2 h
Ph
Ph
N
Ph
NH
Ts
NH
Ts
N
Ph
Ts
Ts
1a
2a
3a
(Z)-4a
entry
1
2
3
4
5
6
7
8
solvent
CH2Cl2
CHCl3
toluene
1,4-dioxane
MTBE
THF
acetone
MeCN
MeOH
DMSO
DMF
TBAI (equiv)
conv. (%)b
100
2a (%)b
25
0
3a (%)b
13
1
4a (%)b
44
94
92
15
13
51
85
79
15
8
35
23
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0
100
100
100
100
100
100
100
29
100
100
100
100
0
3
2
2
74
72
0
0
0
0
12
0
0
83
16
13
12
0
35
42
36
0
9
10
11
12
13
DMF
CHCl3
0
12
a The reaction was carried out with 1a, MnO2 (15 equiv to 1a), and tetrabutylammonium iodide (TBAI) (0 or 0.5 equiv to 1a) in a given solvent at
b
35 °C for 2 h. The conversion and the yields were determined by 1H NMR analysis of the crude mixture using 1,4-bis(trimethylsilyl)benzene as an
internal standard.
The single-crystals of 3a were grown as pale yellow prisms by slow
diffusion of hexane into the concentrated chloroform solution, and
the solid-state structure was clarified by the X-ray crystallographic
analyses (Figure 1).9 The 4-pyridone ring in 3a is not planar and
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The Journal of Organic Chemistry
folded along the O1-C3-N1 axis. The dihedral angle between N1- ratio (entry 2). As with the reaction of 1a, the reaction in DMF pro-
1
2
3
4
5
6
7
8
C1-C2-C3 plane and N1-C9-C4-C3 plane is 24.2(2)°. In accord-
ance with this, the geometry at N1 is trigonal pyramidal, and the sum
of the three angles at N1 involving C1, C9, and S1 is 343.5°. This is
a clear contrast to the structurally characterized 4-pyridone deriva-
tives in which the pyridone rings are nearly planar.2,10
vided 3b predominantly (entry 3), and the effects of TBAI was neg-
ligible (entry 4). Substrate 1c, which is with a p-anisyl substituent at
the alkynyl terminal, was less reactive than 1b in the cyclization, and
the reaction in chloroform required to be conducted at 55 °C (en-
tries 5 and 6). Substrate 1c showed the higher trend of giving the 6-
endo-dig cyclization product with 3c/4c = 26/63 molar ratio in chlo-
roform (entry 6) and 3c/4c = 90/8 molar ratio in DMF (entry 7).
Next, the influences of a chloro substituent at the 5-position of the
phenylene linker were investigated. The cyclization was somewhat
slower with 1d compared to 1a (entry 2 in Table 1 vs entry 9 in Table
2). As with 1c, the 6-endo-dig cyclization was preferred in the reac-
tions of 1d as well (entries 9-12). These results implied that the se-
lectivity between the formation of 3 and 4 was driven to 4-quin-
olones 3 with (i) an electron-rich aryl group at the alkynyl terminal
and (ii) an electron-deficient phenylene linker. To enhance the se-
lectivity of the quinolone formation further, substrates 1 with an al-
kyl substituent at the alkynyl terminal were examined in the present
cyclization reaction. In the reactions of 1e, having a hexyl group at
the alkynyl end, the 5-exo-dig cyclization did not take place irrespec-
tive of the choice of the solvents, and 3e was obtained exclusively ei-
ther in chloroform or in DMF (entries 13-17). The presence of sub-
stoichiometric TBAI was essential in the reaction of 1e in chloro-
form. The cyclization did not proceed without TBAI in chloroform
under otherwise identical conditions, and acyclic 2e was obtained
quantitatively (entries 13 vs 17). Substrate 1f showed the selectivity
similar to that of 1e giving 3f exclusively regardless of the choice of
the solvents (entries 18-20). The reaction of 1g, which is with a
bulky tert-butyl group, became much slower, and heating to 75 °C in
toluene could realize the cyclization giving 3g together with acyclic
2g (entries 21 and 22). The reactions of 1g in DMF were also con-
ducted at 75 °C, and 3g was obtained in good yields exclusively with
or without TBAI (entries 23 and 24). The reactions of 1h, which has
a terminal alkynyl group, also resulted in an exclusive formation of
3h in moderate yields via the 6-endo-dig cyclization in any solvents
examined (entries 25-28). The low mass-balances in the reactions of
1h could be ascribed to the competing intermolecular processes
leading to uncharacterized polymeric/oligomeric materials. This is a
clear contrast to the reaction of (S)-A, in which the reactive substit-
uents are identical to those in 1h, giving 4-pyridone (S)-C in up to
99% yield under the similar conditions as in entry 19 (Scheme 1).11
9
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11
12
13
14
15
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17
18
19
20
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Figure 1. ORTEP drawing of the X-ray structure of 2-phenyl-N-tosyl-4-
quinolone 3a with 30% thermal ellipsoids.
The structure of 2-benzylidene-3-oxindole 4a were unambigu-
ously determined by the X-ray crystallographic analyses (Figure 2).9
Single crystals of 4a were grown from hexane/chloroform and iso-
lated as pale yellow prisms. The compound was obtained as a single
isomer, of which geometry at the exocyclic benzylidene moiety was
clarified to be (Z). The exclusive formation of (Z)-isomer in 4a
could be rationalized to the steric interaction between the carbonyl
group and the terminal phenyl group.
Figure 2. ORTEP drawing of the X-ray structure of (Z)-2-benzylidene-
N-tosyl-3-oxindole (Z)-4a with 30% thermal ellipsoids.
The synthetic practicality of the present protocol was demon-
strated in a 1-mmol scale reaction of substrate 1f as in entry 18. A
mixture of 1f (440 mg, 1.05 mmol), TBAI (189 mg, 0.49 mmol), and
MnO2 (1.31 g, 15.1 mmol) in CHCl3 (20 mL) was stirred at 35 °C
for 3 h. The NMR measurement of the crude reaction mixture
showed the complete consumption of 1f and the exclusive formation
of 3f of which NMR yield being 89%. Silica gel column chromatog-
raphy of the crude product provided the pure sample of 3f in 85%
isolated yield (371 mg, 0.888 mmol).
After the optimization studies shown in Table 1, the conditions in
entries 2, 11, and 12 were chosen and the generality of the present
protocol was examined with various other substrates 1b-h (Table 2).
Substrate 1b, which has a 3-thienyl group instead of a phenyl group
in 1a, the cyclization in chloroform was slower and took longer reac-
tion time for completion (entries 1 and 2). The formation of five-
membered (Z)-4b was dominant in chloroform, but the 6-endo-dig
cyclization competed to a certain extent with 3b/4b = 9/89 molar
Table 2. Reaction Scope of Oxidative Hydroamination/Cyclization of 1a
OH
O
O
O
MnO2 (15 equiv.)
TBAI
+
+
solvent
R
R
N
R
R'
NH
Ts
R'
NH
Ts
R'
N
R
R'
Ts
Ts
1
2
3
(Z)-4
entry
substrate 1
solvent
TBAI (equiv) temp. (°C) time (h) conv. (%)b 2 (%)b 3 (%)b 4 (%)b
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1b
OH
1
2
3
4
5
6
7
CHCl3
CHCl3
DMF
0.5
0.5
0.5
0
0.5
0.5
0.5
0
0.5
0.5
0.5
0
0.5
0.5
0.5
0
35
35
35
35
35
55
35
35
35
35
35
35
35
55
55
55
35
35
35
35
55
75
75
75
35
35
35
35
2
7
2
2
2
4
2
2
2
4
4
4
2
3
3
3
2
3
2
2
2
47
6
6
3
2
2
2
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
79
57
0
0
0
87
0
4
9
28
89
15
16
5
1
2
3
4
5
6
7
8
NH
Ts
68
65
2
26
90
83
4
10
81
73
42
86
98
88
0
89
42
56
0
S
DMF
1c
OH
CHCl3
CHCl3
DMF
63
8
NH
Ts
0
OMe
8
9
DMF
0
22
0
0
0
48
0
0
0
>99
0
6
9
1d
OH
CHCl3
CHCl3
DMF
48
71
6
3
0
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
Cl
NH
Ts
DMF
1e
OH
CHCl3
CHCl3
DMF
0
0
0
0
0
0
Hex
NH
Ts
DMF
CHCl3
CHCl3
DMF
0
1f
OH
0.5
0.5
0
0.5
0.5
0.5
0
0.5
0.5
0.5
0
0
Hex
Cl
NH
Ts
DMF
77
0
0
0
0
0
0
0
1g
OH
CHCl3
toluene
DMF
100
100
100
100
100
100
83
83
11
0
0
0
60
79
91
30
48
56
54
NH
Ts
DMF
1h
OH
CHCl3
CH2Cl2
DMF
0
0
0
0
0
0
H
NH
Ts
DMF
85
a
The reaction was carried out with 1, MnO2 (15 equiv to 1), and tetrabutylammonium iodide (TBAI) (0 or 0.5 equiv to 1) in a given solvent. b The
conversion and the yields were determined by 1H NMR analysis of the crude mixture using 1,4-bis(trimethylsilyl)benzene as an internal standard.
To gain mechanistic insights in the cyclization step, the reactions
of ynone 2a were examined with or without manganese(IV) oxide
and/or TBAI (Table 3). Although the primal role of MnO2 is the ox-
idation of 1 generating 2 in situ, the presence of MnO2 was found to
be essential in the cyclization step as well. Both MnO2 and TBAI are
crucial in the reaction of 2a in chloroform, and the cyclized products,
3a and 4a, were obtained in less than 6 % yields without either of the
two (entries 2-4). On the other hand, the cyclization of 2a took place
without TBAI in DMF, but the presence of MnO2 was essential (en-
tries 5-8).
3
4
5c
6
7
8
CHCl3
CHCl3
DMF
DMF
DMF
DMF
15
0
15
0
15
0
0
0.5
0.5
0
0
0.5
0
0
42
3
53
7
6
0
35
1
29
2
a The reaction was carried out with 2a, MnO2 (0 or 15 equiv), and
tetrabutylammonium iodide (TBAI) (0 or 0.5 equiv) in a given solvent
at 35 °C for 2 h. b The yields were determined by 1H NMR analysis of the
crude mixture using 1,4-bis(trimethylsilyl)benzene as an internal stand-
ard. c Using 1a instead of 2a (taken from Table 1).
Table 3. Effects of Additives in the Cyclization of 2aa
O
O
Plausible reaction pathways of the cyclization are outlined in
Scheme 3. In either chloroform or DMF, ynone 2, which is gener-
ated in situ by the oxidation of 1, is activated by Lewis-acidic MnO2
in intermediates D and E.12 In the reaction in chloroform, a nucleo-
philic attack by an iodide ion derived from TBAI may take place at
the b-carbon of the ynone moiety to give allenoate H, which under-
goes an intramolecular proton shift to form I. When R1 is an aryl
group, the 5-exo-trig cyclization is preferred to form intermediate K,
in which the anionic charge is stabilized by the aryl group. After the
second proton shift (K to L), an elimination of an iodide ion from
O
MnO2
TBAI
solvent
35 °C, 2 h
+
Ph
N
Ph
NH
N
Ph
Ts
(Z)-4a
Ts
2a
Ts
3a
MnO2
TBAI
entry
1c
2
solvent
3a (%)b
4a (%)b
(equiv)
(equiv)
CHCl3
CHCl3
15
0
0.5
0
1
0
94
0
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The Journal of Organic Chemistry
intermediate L gives (Z)-4 as one of the final products. In interme-
CONCLUSIONS
diate L, the sterically demanding R1 substituent on the exocyclic a-
carbon takes the position away from the carbonyl oxygen atom giv-
ing the (Z)-isomer exclusively in 4. On the other hand, when R1 is an
alkyl group or a hydrogen atom, intermediate K no longer forms be-
cause the extra stabilization of the anionic charge by the R1 group
does not exist. Instead, the 6-endo-trig cyclization of I followed by an
elimination of an iodide ion from J gives 3 exclusively.
1
2
3
4
5
6
7
8
In summary, we have developed a method of preparing 4-quin-
olones 3 and/or (Z)-2-alkylidene-3-oxindoles (Z)-4 by the oxida-
tive cyclization of easily accessible o-(1-hydroxy-2-alkynyl)-N-tosyl-
anilides 1. The reaction was assisted by the addition of MnO2 and/or
TBAI. The detailed studies suggested that the roles of the MnO2 ad-
ditive were not only an oxidant but also an activator of intermediary
ynones 2 (probably as a Lewis acid). The product distributions be-
tween 3 and (Z)-4 could be controlled to a certain extent by the
choice of the solvents.
In the reaction in DMF, MnO2 plays an important role on activat-
ing ynone 2, however, the addition of TBAI showed virtually no in-
fluence (Table 3). Whereas the b-carbon atom is more electrophilic
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
than the a-carbon in intermediates D and E, the 6-endo-dig cycliza-
tion should be preferred over the 5-exo-dig cyclization to produce 3
as major products with all the substrates. When R1 is an aryl group,
(Z)-4 was produced as a minor product. This is because the elec-
tron-withdrawing aryl group enhances the electrophilicity of the a-
carbon in intermediates D and E leading to the formation of (Z)-4.
The relative electronic distribution at the alkyne moieties in ynone
2 can be estimated by the 13C-NMR chemical shifts of the sp-carbon
atoms.13 The 13C-NMR resonance of the more nucleophilic sp-car-
bon atom is observed in the upper field, while the signal in the lower
filed corresponds to the more electrophilic carbon atom. In addition,
the degree of the triple bond polarization can be estimated by the
EXPERIMENTAL SECTION
General Information. All anaerobic and/or moisture-sensitive
manipulations were carried out with standard Schlenk techniques
under predried nitrogen or with glovebox techniques under prepur-
1
ified argon. H NMR and 13C NMR chemical shifts are reported in
ppm downfield of internal tetramethylsilane. High-resolution mass
spectra were recorded on a Thermo Fisher Scientific Exactive Or-
bitrap mass spectrometers (DART or ESI) or on a Waters XEVO Q-
TOF MS System (ESI). Tetrahydrofuran and 1,4-dioxane were dis-
tilled from benzophenone−ketyl under nitrogen prior to use. Di-
chloromethane and chloroform were distilled from CaH2 under ni-
trogen and stored in a glass flask with a Teflon stopcock under nitro-
gen. Methanol was distilled from magnesium under nitrogen and
stored in a glass flask with a Teflon stopcock under nitrogen. Man-
ganese(IV) oxide14 and substituted 2-tosylamidebenzaldehydes15
were prepared according to the reported procedure. All other chem-
icals were obtained from commercial sources and used without ad-
ditional purification.
Preparation of o-(1-Hydroxy-2-alkynyl)-N-tosylanilides 1:
General Procedure. To a solution of substituted acetylene (3.2
equiv, 3.20 mmol) in THF (2.85 mL) was added a solution of
EtMgBr (3.0 equiv, 3.00 mmol, 0.95 M, 3.16 mL). The reaction mix-
ture was stirred at 50 °C in an oil bath for 1 h and then added a solu-
tion of substituted 2-tosylamidebenzaldehyde (1.0 equiv, 1.00
mmol) in THF (20 mL) via cannula. The resulting mixture was
stirred at room temperature for 20 min, and then was quenched with
sat. NH4Claq, extracted with EtOAc three times. The combined or-
ganic phases were washed with dilute NH4Claq, water, and brine, suc-
cessively. The organic phase was separated, dried over Na2SO4, fil-
tered, and concentrated on a rotary evaporator to afford compound
1 as a white or pale yellow solid.
chemical shift difference (Dd) between the two sp-carbon atoms.
While the 13C-NMR signals of the alkyne moiety in 2e (R1 = Hex)
were detected at d 79.5 and 99.5 (Dd = 20.0), those in 2a (R1 = Ph)
were observed at d 86.7 and 95.4 (Dd= 8.7). These data suggest that
the b-sp-carbon in 2e is much more electrophilic than that in 2a, and
thus, the reaction of 2e showed the exclusive formation of 6-endo-dig
product 3e. On the other hand, the alkyne moiety in 2a is less polar-
ized and the two cyclization modes are competing in 2a.
Scheme 3. Plausible Reaction Pathways of Cyclization of 2.
[Mn]
O
O
O
[Mn]
R1
[Mn]–
DMF
α
β
R1
NH
NH
N+ R1
H
6-endo-dig
1 = Ar, alkyl, H
Ts
Ts
D
Ts
E
R
F
5-exo-dig
R1 = Ar
CHCl3
DMF
[Mn]
I–
O
O
[Mn]
[Mn]
R1
N-[2-(1-Hydroxy-3-phenylprop-2-ynyl)phenyl]-4-
methylbenzenesulfonamide (1a). Yield: >99% (567 mg, from 413
mg of 2-tosylamidebenzaldehyde). The NMR spectra were con-
sistent with those reported previously.8a
N
R1
N+
[Mn]
H
O–
Ts
3
Ts
G
•
I
R1
N-[2-{1-Hydroxy-3-(3-thienyl)prop-2-ynyl}phenyl]-4-
methylbenzenesulfonamide (1b). Yield: 92% (395 mg, from 310
mg of 2-tosylamidebenzaldehyde). The NMR spectra were con-
sistent with those reported previously.16
N-[2-{1-Hydroxy-3-(4-methoxyphenyl)prop-2-ynyl}phe-
nyl]-4-methylbenzenesulfonamide (1c). Yield: 94% (384 mg,
from 276 mg of 2-tosylamidebenzaldehyde). mp 120-122 °C. H
NH
Ts
H
O–
O
H
I–
R1
N
I
N
R1
Ts
(Z)-4
Ts
J
1
I–
6-endo-trig
R1 = alkyl, H
NMR (400 MHz, CDCl3): d 2.36 (s, 3H), 2.70 (br, 1H), 3.82 (s,
3H), 5.47 (d, J = 3.6 Hz, 1H), 6.84-6.87 (m, 2H), 7.13 (td, J = 7.6
and 1.1 Hz, 1H), 7.18 (d, J = 7.9 Hz, 2H), 7.27 (td, J = 7.7 and 1.6
Hz, 1H) 7.36-7.42 (m, 2H), 7.45 (dd, J = 8.2 and 1.1 Hz, 1H), 7.55
O
I
O
O
H
R1
H
I
R1
N
H
I
R1
Ts
N–
N
5-exo-trig
R1 = Ar
Ts
(dd, J = 7.5 and 1.6 Hz, 1H), 7.69-7.71 (m, 2H), 7.97 (br, 1H). 13
C
Ts
I
K
L
NMR (100 MHz, CDCl3): d21.5, 55.3, 63.5, 85.0, 88.6, 113.8, 114.0,
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The Journal of Organic Chemistry
Page 6 of 10
122.7, 125.1, 127.2, 128.3, 129.6, 129.7, 130.8, 133.3, 135.6, 136.8,
The yield was determined by 1H NMR analysis of the crude mixture
using 1,4-bis(trimethylsilyl)benzene as the internal standard.
143.8, 160.1. HRMS (ESI) calcd for C23H21NNaO4S (M+Na+)
430.1089, found 430.1092.
1
2
3
4
5
6
7
8
2-Phenyl-1-tosylquinolin-4(1H)-one (3a) (Table 1, entries
11-12). The crude mixture was purified by silica gel column chro-
matography (hexane/EtOAc/toluene = 3/1/1) to afford the title
N-[5-Chloro-2-(1-hydroxy-3-phenylprop-2-ynyl)phenyl]-4-
methylbenzenesulfonamide (1d). Yield: >99% (701 mg, from 501
mg of 4-chloro-2-tosylamidebenzaldehyde). mp 119-121 °C. 1H
NMR (400 MHz, CDCl3): d 1.80 (br, 2H), 2.35 (s, 3H), 5.47 (s,
1H), 7.07 (dd, J = 8.4 and 2.0 Hz, 1H), 7.17 (d, J = 7.9 Hz, 2H), 7.30-
7.40 (m, 3H), 7.41-7.47 (m, 3H), 7.51 (d, J = 2.0 Hz, 1H), 7.72 (d, J
= 8.4 Hz, 2H). 13C NMR (100 MHz, CDCl3): d21.5, 63.2, 85.8, 88.7,
121.6, 121.9, 124.7, 127.2, 128.3, 128.4, 129.1, 129.4, 129.8, 131.8,
135.3, 136.3, 136.9, 144.2. HRMS (ESI) calcd for C22H18ClNNaO3S
(M+Na+) 434.0594, found 434.0598.
1
compound as a yellow solid. mp 147-150 °C. H NMR (400 MHz,
CDCl3): d 2.31 (s, 3H), 6.45 (s, 1H), 7.02-7.10 (m, 4H), 7.45 (td, J
= 8.0 and 0.9 Hz, 1H), 7.49-7.53 (m, 3H), 7.69 (td, J = 8.5 and 1.6
Hz, 1H), 7.72-7.77 (m, 2H), 7.94 (dd, J = 8.0 and 1.4 Hz, 1H), 8.34
(d, J = 8.7 Hz, 1H). 13C NMR (100 MHz, CDCl3): d 21.6, 120.7,
125.2, 125.6, 127.2, 127.6, 127.9, 128.5, 129.4, 130.7, 131.1, 132.0,
137.3, 140.7, 145.5, 154.0, 180.5. HRMS (ESI) calcd for
C22H18NO3S (M+H+) 376.1007, found 376.1008.
2-(Thiophen-3-yl)-1-tosylquinolin-4(1H)-one (3b) (Table 2,
entries 3-4). The crude mixture was purified by silica gel column
chromatography (hexane/EtOAc/toluene = 3/1/1) to afford the ti-
tle compound as a yellow solid. mp 137-138 °C. 1H NMR (400 MHz,
CDCl3): d 2.31 (s, 3H), 6.44 (s, 1H), 7.02-7.10 (m, 4H), 7.40-7.46
(m, 3H),7.68 (td, J = 8.5 and 1.6 Hz, 1H), 7.78 (t, J = 2.2 Hz, 1H),
7.92 (dd, J = 8.0 and 1.6 Hz 1H), 8.26 (d, J = 8.5 Hz, 1H). 13C NMR
(100 MHz, CDCl3): d 21.6, 119.2, 125.48, 125.52, 126.2, 127.0,
127.19, 127.24, 127.7, 129.4, 129.5, 130.9, 131.9, 138.4, 140.5, 145.6,
148.8, 180.6. HRMS (DART) calcd for C20H16NO3S2 (M+H+)
382.0572, found 382.0566.
2-(4-Methoxyphenyl)-1-tosylquinolin-4(1H)-one (3c) (Ta-
ble 2, entries 7-8). The crude mixture was purified by silica gel col-
umn chromatography (hexane/EtOAc/toluene = 3/1/1) to afford
the title compound as a yellow solid. mp 125-127 °C. 1H NMR (400
MHz, CDCl3): d 2.31 (s, 3H), 3.90 (s, 3H), 6.39 (s, 1H), 6.98-7.06
(m, 6H), 7.44 (t, J = 7.6 Hz, 1H), 7.64-7.71 (m, 3H), 7.93 (d, J = 8.0
Hz, 1H), 8.30 (d, J = 8.5 Hz, 1H). 13C NMR (100 MHz, CDCl3): d
21.6, 55.4, 114.0, 119.3, 125.5, 127.1, 127.6, 129.3, 129.6, 130.9,
131.8, 140.6, 145.5, 153.9, 161.8, 180.5. HRMS (ESI) calcd for
C23H20NO4S (M+H+) 406.1113, found 406.1114.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N-[2-(1-Hydroxynon-2-ynyl)phenyl]-4-methylbenzenesul-
fonamide (1e). Yield: 99% (430 mg, from 311 mg of 2-tosyla-
midebenzaldehyde). mp 46-47 °C. 1H NMR (400 MHz, CDCl3): d
0.89 (t, J = 7.0 Hz, 3H), 1.25-1.44 (m, 6H), 1.54 (quint, J = 7.4 Hz,
2H), 2.27 (td, J = 7.2 and 2.0 Hz, 2H), 2.38 (s, 3H), 2.40 (br, 1H),
5.20 (d, J = 5.7 Hz, 1H), 7.11 (td, J = 7.6 and 1.4 Hz, 1H), 7.20-7.28
(m, 3H), 7.43-7.50 (m, 2H), 7.70 (d, J = 8.4 Hz, 2H), 7.91 (s, 1H).
13C NMR (100 MHz, CDCl3): d 14.0, 18.8, 21.5, 22.5, 28.4, 28.6,
31.3, 63.1, 90.1, 122.7, 125.0, 127.1, 128.1, 129.5, 129.7, 131.0, 135.5,
+
136.9, 143.8. HRMS (DART) calcd for C22H31N2O3S (M+NH4 )
403.2055, found 403.2052.
N-[5-Chloro-2-(1-hydroxynon-2-ynyl)phenyl]-4-
methylbenzenesulfonamide (1f). Yield: >99% (212 mg, from 156
mg of 4-chloro-2-tosylamidebenzaldehyde). mp 73-74 °C. 1H NMR
(400 MHz, CDCl3): d 0.89 (t, J = 6.8 Hz, 3H), 1.22-1.45 (m, 6H),
1.54 (quint, J = 7.4 Hz, 2H), 2.26 (td, J = 7.1 and 2.0 Hz, 2H), 2.40
(s, 3H), 2.41(br, 1H), 5.17 (d, J = 5.4 Hz, 1H), 7.05 (dd, J = 8.2 and
2.0 Hz, 1H), 7.26 (d, J = 7.9 Hz, 2H), 7.38 (d, J = 8.2 Hz, 1H), 7.51
(d, J = 2.0 Hz, 1H), 7.72 (d, J = 8.4 Hz, 2H), 8.05 (s, 1H). 13C NMR
(100 MHz, CDCl3): d 14.0, 18.8, 21.6, 22.5, 28.3, 28.6, 31.2, 62.8,
90.6, 121.9, 124.6, 127.1, 128.7, 129.2, 129.8, 135.2, 136.6, 136.9,
+
144.1. HRMS (DART) calcd for C22H30ClN2O3S (M+NH4 )
7-Chloro-2-phenyl-1-tosylquinolin-4(1H)-one (3d) (Table 2,
entries 11-12). The crude mixture was purified by silica gel column
chromatography (hexane/EtOAc/toluene = 3/1/1) to afford the ti-
tle compound as a yellow solid. mp 133-134 °C. 1H NMR (400 MHz,
CDCl3): d 2.32 (s, 3H), 6.43 (s, 1H), 7.07-7.15 (m, 4H), 7.40 (dd, J
= 8.4 and 2.1 Hz, 1H), 7.48-7.56 (m, 3H), 7.70 (dd, J = 5.7 and 2.1
Hz, 2H), 7.88 (d, J = 8.5 Hz, 1H), 8.35 (d, J = 1.8 Hz, 1H). 13C NMR
(100 MHz, CDCl3): d 21.7, 120.5, 125.0, 127.0, 127.6, 127.7, 127.7,
127.9, 128.6, 129.6, 130.8, 131.1, 137.0, 138.5, 141.4, 145.9, 154.1,
179.5. HRMS (ESI) calcd for C22H17ClNO3S (M+H+) 410.0618,
found 410.0618.
437.1666, found 437.1660.
N-[2-(1-Hydroxy-4,4-dimethylpent-2-ynyl)phenyl]-4-
methylbenzenesulfonamide (1g). Yield: >99% (356 mg, from 275
1
mg of 2-tosylamidebenzaldehyde). mp 118-119 °C. H NMR (400
MHz, CDCl3): d 1.27 (s, 9H), 2.32, (d, J = 6.3 Hz, 1H), 2.39 (s, 3H),
5.18 (d, J = 6.1 Hz, 1H), 7.11 (td, J = 7.6 and 1.1 Hz, 1H), 7.20-7.30
(m, 3H), 7.42-7.49 (m, 2H), 7.68-7.71 (m, 2H), 7.95 (s, 1H). 13C
NMR (100 MHz, CDCl3): d21.5, 27.6, 30.7, 62.9, 98.2, 122.7, 124.9,
127.1, 128.1, 129.5, 129.7, 131.0, 135.6, 136.9, 143.8. HRMS
+
(DART) calcd for C20H27N2O3S (M+NH4 ) 375.1742, found
375.1742.
2-Hexyl-1-tosylquinolin-4(1H)-one (3e) (Table 2, entries
14-16). The crude mixture was purified by silica gel column chro-
matography (hexane/EtOAc/toluene = 3/1/1) to afford the title
N-[2-(1-Hydroxyprop-2-ynyl)phenyl]-4-methylbenzenesul-
fonamide (1h). Yield: >99% (303 mg, from 277 mg of 2-tosyla-
midebenzaldehyde). The NMR spectra were consistent with those
reported previously.17
1
compound as a white solid. mp 43-44 °C. H NMR (400 MHz,
CDCl3): d0.87 (t, J = 7.2 Hz, 3H), 1.21-1.39 (m, 6H), 1.65-1.79 (m,
2H), 2.31 (s, 3H), 2.99 (t, J = 7.5 Hz, 2H), 6.17 (s, 1H), 7.08 (d, J =
8.0 Hz, 2H), 7.18 (d, J = 8.7 Hz, 2H), 7.40 (t, J = 8.0 Hz, 1H), 7.62
(td, J = 7.9 and 1.6 Hz, 1H), 7.92 (dd, J = 8.0 and 1.4 Hz, 1H), 8.17
(d, J = 8.7 Hz, 1H). 13C NMR (100 MHz, CDCl3): d 14.0, 21.6, 22.5,
28.8, 29.1, 31.4, 37.1, 120.6, 125.0, 125.4, 126.7, 127.1, 128.8, 129.5,
131.6, 132.2, 140.9, 145.4, 157.1, 180.3. HRMS (DART) calcd for
C22H26NO3S (M+H+) 384.1633, found 384.1627.
Oxidative Hydroamination/Cyclization of 1 (Table 1 and 2):
General Procedure. o-(1-Hydroxy-2-alkynyl)-N-tosylanilides 1
(0.10 mmol) and tetrabutylammonium iodide (0 or 0.5 equiv) were
weighed into a Schlenk flask, which was then purged with nitrogen.
To this were added solvent (CHCl3 or DMF) (2.0 mL) and MnO2
(15 equiv) in the order. The reaction mixture was stirred at 35-75 °C
in an oil bath for 2-47 h and then was concentrated in vacuo. The
resulting mixture was passed through a short pad of silica gel
(EtOAc/hexane = 1/1) and concentrated on a rotary evaporator.
7-Chloro-2-hexyl-1-tosylquinolin-4(1H)-one (3f) (Table 2,
entries 18-20). The crude mixture was purified by silica gel column
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The Journal of Organic Chemistry
chromatography (hexane/EtOAc/toluene = 3/1/1) to afford the ti-
129.9, 130.6, 132.2, 135.1, 135.3, 145.0, 150.5, 161.8, 186.5. HRMS
tle compound as a yellow solid. mp 69-70 °C. 1H NMR (400 MHz,
CDCl3): d0.88 (t, J = 6.8 Hz, 3H), 1.21-1.41 (m, 6H), 1.65-1.79 (m,
2H), 2.33 (s, 3H), 2.98 (t, J = 7.6 Hz, 2H), 6.16 (s, 1H), 7.13 (d, J =
8.0 Hz, 2H), 7.23 (d, J = 8.7 Hz, 2H), 7.36 (dd, J = 8.5 and 1.8 Hz,
1H), 7.86 (d, J = 8.5 Hz, 1H), 8.20 (d, J = 1.8 Hz, 1H). 13C NMR
(100 MHz, CDCl3): d 14.0, 21.6, 22.4, 28.8, 29.1, 31.4, 37.1, 120.4,
124.8, 126.8, 127.1, 127.2, 127.3, 129.7, 132.2, 138.1, 141.6, 145.7,
157.2, 179.3. HRMS (DART) calcd for C22H25ClNO3S (M+H+)
418.1244, found 418.1238.
(ESI) calcd for C23H20NO4S (M+H+) 406.1113, found 406.1112.
1
2
3
4
5
6
7
8
(Z)-2-Benzylidene-6-chloro-1-tosylindolin-3-one ((Z)-4d)
(Table 2, entry 10). The crude mixture was purified by silica gel col-
umn chromatography (hexane/EtOAc/toluene = 3/1/1) to afford
the title compound as a yellow solid. mp 133-134 °C. 1H NMR (400
MHz, CDCl3): d 2.30 (s, 3H), 7.07 (d, J = 8.2 Hz, 2H), 7.24-7.28 (m,
3H), 7.42-7.54 (m, 5H), 7.99 (dd, J = 8.2 and 1.4 Hz, 2H), 8.11 (d,
J = 1.6 Hz, 1H). 13C NMR (100 MHz, CDCl3): d 21.6, 121.3, 125.2,
126.0, 127.4, 128.0, 128.3, 129.5, 130.1, 130.7, 130.9, 132.6, 132.9,
133.6, 142.0, 145.4, 151.4, 185.2. HRMS (ESI) calcd for
C22H17ClNO3S (M+H+) 410.0618, found 410.0615.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2-(tert-Butyl)-1-tosylquinolin-4(1H)-one (3g) (Table 2, en-
tries 23-24). The crude mixture was purified by silica gel column
chromatography (hexane/EtOAc/toluene = 3/1/1) to afford the ti-
tle compound as a white solid. mp 102-104 °C. 1H NMR (400 MHz,
CDCl3): d 1.52 (s, 9H), 2.30 (s, 3H), 6.49 (s, 1H), 6.94 (d, J = 8.4
Hz, 2H), 6.99 (d, J = 8.8 Hz, 2H), 7.33 (t, J = 7.8 Hz, 1H), 7.56-7.61
(m, 2H), 7.99 (d, J = 6.8 Hz, 1H). 13C NMR (100 MHz, CDCl3): d
21.6, 31.6, 39.4, 125.1, 125.4, 126.0, 127.2, 128.3, 128.8, 129.1, 130.8,
131.7, 142.5, 145.4, 168.5, 181.5. HRMS (ESI) calcd for
C20H21NNaO3S (M+Na+) 378.1140, found 378.1139.
4-Methyl-N-[2-(3-phenylpropioloyl)phenyl]benzenesulfon-
amide (2a) (Table 1, entry 13). The reaction was performed with-
out tetrabutylammonium iodide. The crude mixture was purified by
silica gel column chromatography (hexane/EtOAc/toluene =
3/1/1) to afford the title compound as a yellow solid. The NMR
spectra were consistent with those reported previously.18 1H NMR
(400 MHz, CDCl3): d 2.36 (s, 3H), 7.12-7.16 (m, 1H), 7.23-7.26
(m, 2H), 7.41-7.45 (m, 2H), 7.49-7.53 (m, 2H), 7.65-7.68 (m, 2H),
7.71-7.73 (m, 1H), 7.77-7.79 (m, 2H), 8.27-8.30 (m, 1H), 11.26 (s,
1H). 13C NMR (100 MHz, CDCl3): d 21.7, 86.7, 95.4, 118.5, 119.7,
122.6, 122.8, 127.4, 128.9, 129.9, 131.4, 133.2, 134.9, 135.9, 136.5,
141.0, 144.2, 180.6. HRMS (ESI) calcd for C22H17NNaO3S
(M+Na+) 398.0827, found 398.0820.
1-Tosylquinolin-4(1H)-one (3h) (Table 2, entries 25-28).
The crude mixture was purified by silica gel column chromatography
(hexane/EtOAc/toluene = 3/1/1) to afford the title compound as
an orangish solid. mp 153-155 °C. The NMR spectra were consistent
with those reported previously.4f
(Z)-2-Benzylidene-1-tosylindolin-3-one ((Z)-4a) (Table 1,
entry 2). The crude mixture was purified by silica gel column chro-
matography (hexane/EtOAc/toluene = 3/1/1) to afford the title
compound as a yellow solid. 1H NMR (400 MHz, CDCl3): d 2.28 (s,
3H), 7.02 (d, J = 8.8 Hz, 2H), 7.19-7.24 (m, 2H), 7.30 (t, J = 7.6 Hz,
1H), 7.40-7.51 (m, 4H), 7.59 (d, J = 7.6 Hz, 1H), 7.70 (t, J = 8.8 Hz,
1H), 8.01-8.05 (m, 2H), 8.09 (d, J = 8.4 Hz, 1H). 13C NMR (100
MHz, CDCl3): d21.6, 121.0, 124.3, 126.7, 127.6, 128.0, 128.2, 129.3,
129.5, 130.6, 130.9, 132.6, 133.1, 133.9, 135.7, 145.1, 150.7, 186.5.
HRMS (DART) calcd for C22H18NO3S (M+H+) 376.1002, found
376.1003.
4-Methyl-N-(2-non-2-ynoylphenyl)benzenesulfonamide
(2e) (Table 2, entry 17). The reaction was performed without tet-
rabutylammonium iodide. The crude mixture was purified by silica
gel column chromatography (hexane/EtOAc = 3/1) to afford the ti-
1
tle compound as pale yellow viscous liquid. H NMR (400 MHz,
CDCl3): d0.90 (t, J = 7.2 Hz, 3H), 1.24-1.37 (m, 4H), 1.41-1.49 (m,
2H), 1.62-1.69 (m, 2H), 2.36 (s, 3H), 2.49 (t, J = 7.2 Hz, 2H), 7.06-
7.10 (m, 1H), 7.22-7.24 (m, 2H), 7.45-7.49 (m, 1H), 7.66-7.69 (m,
1H), 7.74-7.77 (m, 2H), 8.17-8.19 (m, 1H), 11.27 (s, 1H). 13C NMR
(100 MHz, CDCl3): d 14.1, 19.4, 21.7, 22.6, 27.7, 28.7, 31.3, 79.5,
99.5, 118.2, 122.4, 122.6, 127.4, 129.8, 135.1, 135.6, 136.5, 140.9,
144.1, 180.9. HRMS (ESI) calcd for C22H25NNaO3S (M+Na+)
406.1453, found 406.1455.
(Z)-2-(Thiophen-3-ylmethylene)-1-tosylindolin-3-one ((Z)-
4b) (Table 2, entry 2). The crude mixture was purified by silica gel
column chromatography (hexane/EtOAc/toluene = 3/1/1) to af-
ford the title compound as a yellow solid. mp 159-160 °C. 1H NMR
(400 MHz, CDCl3): d 2.27 (s, 3H), 7.01 (d, J = 8.0 Hz, 2H), 7.23 (d,
J = 6.6 Hz, 2H), 7.28 (t, J = 7.3 Hz, 1H), 7.39 (dd, J = 5.2 and 3.0 Hz,
1H), 7.48 (s, 1H), 7.55 (dd, J = 8.4 and 1.4 Hz, 1H), 7.68 (td, J = 7.1
and 1.4 Hz, 1H), 7.93 (dd, J = 5.0 and 1.1 Hz, 1H), 7.97 (dd, J = 2.9
and 1.4 Hz, 1H), 8.05 (d, J = 8.2 Hz, 1H). 13C NMR (100 MHz,
CDCl3): d 21.6, 121.1, 123.6, 124.1, 125.4, 126.8, 127.9, 128.1,
129.3, 130.0, 130.8, 132.5, 134.0, 135.1, 135.5, 145.1, 150.6, 186.8.
HRMS (DART) calcd for C20H16NO3S2 (M+H+) 382.0572, found
382.0567.
Oxidative Hydroamination/Cyclization of 1f in Larger Scale.
Preparation of 7-Chloro-2-hexyl-1-tosylquinolin-4(1H)-one
(3f). The reaction of entry 18 in Table 2 was conducted with a mix-
ture of 1f (440 mg, 1.05 mmol), TBAI (189 mg, 0.49 mmol), and
MnO2 (1.31 g, 15.1 mmol) in CHCl3 (20 mL) at 35 °C for 3 h. Yield:
85% (371 mg, 0.888 mmol).
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Pub-
lications website at DOI: *********.
NMR spectra (1H and 13C) for all the new compounds (PDF).
Crystallographic data for 3a and (Z)-4a (CIF).
(Z)-2-(4-Methoxybenzylidene)-1-tosylindolin-3-one ((Z)-
4c) (Table 2, entry 6). The crude mixture was purified by silica gel
column chromatography (hexane/EtOAc/toluene = 3/1/1) to af-
ford the title compound as a yellow solid. mp 180-181 °C. 1H NMR
(400 MHz, CDCl3): d 2.27 (s, 3H), 3.89 (s, 3H), 6.96-7.03 (m, 4H),
7.21 (d, J = 8.5 Hz, 2H), 7.29 (t, J = 8.4 Hz, 1H), 7.42 (s, 1H), 7.57
(dd, J = 8.0 and 0.7 Hz, 1H), 7.68 (td, J = 8.2 and 1.4 Hz, 1H), 8.03
(d, J = 9.0 Hz, 2H), 8.08 (d, J = 7.6 Hz, 1H). 13C NMR (100 MHz,
AUTHOR INFORMATION
Corresponding Authors
*E-mail: ogasawar@tokushima-u.ac.jp (M.O.)
*E-mail: kyoshida@faculty.chiba-u.jp (K.Y.)
CDCl3): d21.5, 55.4, 113.8, 121.1, 124.1, 125.5, 126.7, 128.1, 129.2,
ORCID
Masamichi Ogasawara: 0000-0002-1893-3306
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Yang, M.-C.; Li, X.; He, G.; Peng, C.; Han, B. Stereoselective Synthesis of
Kazuhiro Yoshida: 0000-0001-5130-9479
Hydropyrano[3,2-b]indoles via Organocatalytic Asymmetric Inverse-Elec-
tron-Demand Oxa-Diels–Alder Reaction. Adv. Synth. Catal. 2016, 358,
2970-2975. (c) Petermayer, C.; Thumser, S.; Kink. F.; Mayer, P.; Dube, H.
Hemiindigo: Highly Bistable Photoswitching at the Biooptical Window. J.
Am. Chem. Soc. 2017, 139, 15060-15067.
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
(6) For reports on the synthesis of 2-alkylidene-3-oxindoles, see: (a)
Hooper, M.; Pitkethly, W. N. 2-Arylmethylideneindolin-3-ones: Stereo-
chemistry and Reduction with Sodium Borohydride. J. Chem. Soc., Perkin
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palladium-catalyzed synthesis of indoxyl derivatives. J. Organomet. Chem.
1990, 397, C31-C32. (c) Shu, C.; Li, L.; Xiao, X.-Y.; Yu, Y.-F.; Ping, Y.-F.;
Zhou, J.-M., Ye, L.-W. Flexible and practical synthesis of 3-oxyindoles
through gold-catalyzed intermolecular oxidation of o-ethynylanilines. Chem.
Commun. 2014, 50, 8689-8692. (d) Li, R.; Qi, X.; Wu, X.-F. A general and
convenient palladium-catalyzed synthesis of benzylideneindolin-3-ones
with formic acid as the CO source. Org. Biomol. Chem. 2017, 15, 6905-6908.
(7) For reports on the selective synthesis of 4-quinolones and 2-alkyli-
dene-3-oxindoles, see: (a) Genelot, M.; Bendjeriou, A.; Dufaud, V.; Dja-
kovitch, L. Optimised procedures for the one-pot selective syntheses of in-
doxyls and 4-quinolones by a carbonylative Sonogashira/cyclisation se-
quence. Appl. Catal. A 2009, 369, 125-132. (b) Genelot, M.; Dufaud, V.;
Djakovitch, L. Heterogeneous metallo-organocatalysis for the selective one-
pot synthesis of 2-benzylidene-indoxyl and 2-phenyl-4-quinolone. Tetrahe-
dron 2011, 67, 976-981.
(8) For reports on related 5-exo-dig cyclization, see: (a) Susanti, D.; Koh,
F.; Kusuma, J. A.; Kothandaraman, P.; Chan, P. W. H. Silver Acetate Cata-
lyzed Hydroamination of 1-(2-(Sulfonylamino)phenyl)prop-2-yn-1-ols to
(Z)-2-Methylene-1-sulfonylindolin-3-ols. J. Org. Chem. 2012, 77, 7166-
7175. (b) Kothandaraman, P.; Lauw, S. J. L.; Chan, P. W. H. Metal-free syn-
thesis of 1H-indole-2-carbaldehydes by N-iodosuccinimide-mediated cy-
clization of 1-(2'-anilinyl)prop-2-yn-1-ols in water. A formal synthesis of
(R)-calindol. Tetrahedron 2013, 69, 7471-7480.
(9) The crystallographic coordinates have been deposited with the Cam-
bridge Crystallographic Data Centre; deposition no. 1980563 (3a) and
1980564 (4a). The data can be obtained free of charge via
http://www.ccdc.cam.ac.uk/conts/retrieving.html (or from The Cam-
bridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 IEZ,
UK; fax (+44) 1223-336-033; E-mail deposit@ccdc.cam.ac.uk).
(10) (a) Masse, R.; Le Fur, Y. Crystal Structure of Bis(4-pyridone)di-
chlorozinc(II), ZnCl2(C5H5NO)2. Z. Kristallogr. NCS 1998, 213, 114. (b)
Nguyen, D. M.; Desikan, V.; Glen, J. A.; Manke, D. R. Crystal Structure of
2,6-Dimethyl-4-pyridone Hemihydrate. Acta Cryst. 2015, E71, o533.
(11) Unexpected oligomerization/polymerization were considered to be
one of the reasons of the moderate yields. Although the dilute conditions
were examined to suppress the side reaction, the yields could not be im-
proved.
This work was supported by JSPS KAKENHI "Precisely Designed Cat-
alysts with Customized Scaffolding" to K.Y. (Grant #18H04236), a
Grant-in-Aid for Scientific Research (C) to K.Y. (Grant
#18K05097), and a Grant-in-Aid for Scientific Research (B) to M.O.
(Grant #18H01979) from MEXT, Japan.
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For Table of Contents
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Oxidative Intramolecular Hydroamination
OH
O
4
MnO2, TBAI, CHCl3
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R
or MnO2, DMF
R’
NH
R’
N
R
8 examples
Ts
Ts
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