Photoinduced intramolecular cyclization of o -ethenylaryl isocyanides with organic disulfides mediated by diphenyl ditelluride

Article abstract of DOI:10.1021/jo200299d

Photoinduced reaction of o-ethenylaryl isocyanides with organic disulfides in the presence of diphenyl ditellurides affords the corresponding bisthiolated indole derivatives via a radical cyclization process. The cyclization can proceed at room temperature upon visible-light irradiation and exhibits good tolerance to functional groups. Several organic disulfides also can be employed for this cyclization, and the corresponding bisthiolated indole derivatives are obtained selectively. In addition, the photoinduced reaction of o-ethenylaryl isocyanides with bis(2-aminophenyl) disulfide affords tetracyclic compounds in one portion.

Full text of DOI:10.1021/jo200299d

ARTICLE
pubs.acs.org/joc
Photoinduced Intramolecular Cyclization of o-Ethenylaryl
Isocyanides with Organic Disulfides Mediated by Diphenyl
Ditelluride
Takenori Mitamura, Kimiyo Iwata, and Akiya Ogawa*
Department of Applied Chemistry, Graduate School of Engineering, Osaka Prefecture University, 1-1 Gakuen-cho, Nakaku, Sakai,
Osaka 599-8531, Japan
S Supporting Information
b
ABSTRACT: Photoinduced reaction of o-ethenylaryl isocya-
nides with organic disulfides in the presence of diphenyl
ditellurides affords the corresponding bisthiolated indole deri-
vatives via a radical cyclization process. The cyclization can
proceed at room temperature upon visible-light irradiation and
exhibits good tolerance to functional groups. Several organic
disulfides also can be employed for this cyclization, and the
corresponding bisthiolated indole derivatives are obtained selec-
tively. In addition, the photoinduced reaction of o-ethenylaryl
isocyanides with bis(2-aminophenyl) disulfide affords tetracyclic
compounds in one portion.
’ INTRODUCTION
’ RESULTS AND DISCUSSION
Indole derivatives are present in a number of natural products
such as alkaloids and many of them indicate valuable bioactivities.
Therefore, the indole derivatives have been often designed and
synthesized as new pharmaceutical active agents.1 Therefore,
development of new methods for the preparation of various indole
derivatives is of great importance in pharmaceutical sciences as
well as organic synthesis.2 Heterocycles having organosulfur
groups are also important in the fields of pharmacology, materials
sciences, and organic synthesis.3,4 We and other groups have
developed a series of photoinduced addition reactions of organic
dichalcogenides to acetylenes,5 allenes,6 conjugated dienes,7 and
alkenes.8 Furthermore, the photoinduced addition to isocyanides
has been attained by the combination of organic disulfides and
organic diselenides (or ditellurides).9 Isocyanides are useful parent
compounds for the synthesis of N-heterocycles. For this purpose,
nucleophilic reactions,10 transition metal-catalyzed reactions,11
radical reactions,12 and photochemical reactions13 have been
reported.14 These results prompted us to examine the synthesis
of N-heterocycles by the photoinduced reaction of o-ethenylaryl
isocyanides with organic disulfides, diselenides, and ditellurides.
Herein, we report a highly selective synthesis of bisthiolated
indole derivatives 315 by the photoinduced intramolecular cycli-
zation of o-ethenylaryl isocyanides 1 with organic disulfides 2 in
the presence of diphenyl ditelluride (Scheme 1). We also report a
novel one-pot preparation of tetracyclic compounds 4 from
o-ethenylaryl isocyanides 1 and bis(2-aminophenyl) disulfide.
The formed tetracyclic compounds 4 consist of both dihydro-
quinazoline and benzothiazole units.
On the basis of our previous work on the photoinduced
thioselenation and thiotelluration of isocyanides,9 we first pro-
pose a possible reaction pathway for the synthesis of bisthiolated
indole derivatives by the photoinduced reaction of o-ethenylaryl
isocyanide 1 with organic disulfide 2 in the presence of diphenyl
ditelluride, as shown in Scheme 2. In the initiation step, the
homolytic dissociation of diphenyl ditelluride upon photoirra-
diation with the light of wavelength over 400 nm generates PhTe•
species selectively, and the sequential SH2 reaction of PhTe• with
organic disulfide forms the ArS• species and the thiotelluride.
The addition reaction of ArS• to the isocyano group gives an
imidoyl radical intermediate (A),16 and the subsequent 5-exo
cyclization forms the radical intermediate (B).17 The generated
radical species B undergoes SH2 reaction with (PhTe)2,18 and the
following tautomerization forms indole derivative (C). The
homolytic cleavage takes place to generate radical species D
due to the instability of the CꢀTe bond of C.19 Finally, the
abstraction of the ArS group from the thiotelluride forms the
corresponding bisthiolated indole 3.
Keeping this proposed pathway in mind, we examined the
photoinduced reaction of isocyanide 1a with diphenyl disulfide
(2a) in the presence of diphenyl ditelluride under several reaction
conditions (Table 1). Upon photoirradiation with a high-pressure
Hglampthrough a glass filter, the reaction of isocyanide 1a (0.4 M)
with 1.5 equiv of (PhS)2 and (PhTe)2 afforded the corresponding
Received: February 9, 2011
Published: April 04, 2011
r
2011 American Chemical Society
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|

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Scheme 1. Preparation of 3 and 4
Table 1. Photoinduced Reaction of Isocyanide 1a with
a
(PhS)2 in the Presence of (PhTe)2
yield (%)b
1a
(PhS)2
(PhTe)2
(equiv)
concn
(M)
time
(h)
entry (equiv)
3a
1
1.5
1.5
1.5
1.0
1.0
1.5
1.5
1.5
1.5
0.40
0.20
0.05
0.20
0.20
0.40
0.40
31
40
24
40
40
24
24
56c
37
0 f
ND
33
97g
2
3d
1.5
Scheme 2. Possible Reaction Pathways for the Synthesis of
Bisthiolated Indoles
4
1.0
18
28
0 f
33
5
0.5
19
6d
7d'e
none
95g
95g
1.5
0 f
a Reaction condition: isocyanide (1a, 0.1 mmol), (PhS)2 (2a), (PhTe)2,
CDCl3, room temperature, hv: irradiation with a high-pressure Hg lamp
through a glass filter (>400 nm). b Determined by 1H NMR.
c Isolated yield. d Methyl 2-(2-isocyanophenyl)acrylate (1b) was used
in place of 1a. e In the dark. f Indole 3b was the desired product.
g Isocyanide 1b was recovered unchanged.
Scheme 3. Photoinduced Cyclization of 1b in Several
Solvents
bisthiolated indole 3a in 56% yield (entry 1).20 When 0.2 M of the
isocyanide 1a was used, the indole 3a was obtained in 37% yield
with the recovery of isocyanide 1a (33%yield) (entry 2). Under the
lower concentration of the substrate (0.05 M), the desired indole
derivative was not formed, and instead, 97% yield of isocyanide 1b
was recovered unchanged (entry 3). The result suggests that the
addition of the thiyl radical generated in situ to the isocyano group
is a key step for this indole synthesis. When the amounts of (PhS)2
and (PhTe)2 were reduced, the yields of the bisthiolated indole 3a
decreased (entries 4 and 5). To clarify the role of diphenyl
ditelluride and photoirradiation, we also examined the control
reactions, i.e., (i) the photoinduced reaction of methyl
2-(2-isocyanophenyl)acrylate (1b) with 2a in the absence of
diphenyl ditelluride and (ii) the reaction of 1b with 2a in the
presence of diphenyl ditelluride in the dark. In each case, the
bisthiolated indole 3b was not formed. Instead, isocyanide 1b
was recovered unchanged (entries 6 and 7). These results suggest
that the photoinduced dissociation of diphenyl ditelluride is
important for the photoinduced synthesis of the bisthiolated
indoles.
We also examined the cyclization reactions in several solvents
(Scheme 3). When isocyanide 1b was treated in CHCl3, MeCN,
and acetone, the corresponding indole 3b was obtained in 47%,
30%, and 42% yields, respectively. The use of THF, AcOEt,
hexane, and benzene as a solvent was ineffective for this indole
synthesis. In the case of protic solvent such as EtOH, 3b was
obtained in 8% yield. Instead, a fragmentation of 1b took place.
In addition, the photoinduced reaction of isocyanide 1b with
2a was attempted in the presence of (PhSe)2 in place of (PhTe)2.
However, a complex mixture including the bisthiolated indole,
the selenothiolated indole, and the acyclic thioselenation product
was obtained (total 20% yield) (Scheme 4).9b Although organic
diselenides also have good carbon radical capturing ability as well
as organic ditelluride,18 the generating CꢀSe bond is more stable
than the CꢀTe bond under photoirradiation condition. There-
fore, the selenium intermediates formed in situ survive under the
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Scheme 4. Photoinduced Reaction of Isocyanide 1b with
(PhS)2 and (PhSe)2
Table 2. Photoinduced Cyclization of Several Isocyanides 1
with (PhS)2 in the Presence of (PhTe)2
a
photoirradiation condition. This resulted in the formation of a
complex mixture. On the other hand, the CꢀTe bond can
reversibly undergo homolytic cleavage under photoirradiation
conditions. Hence, the most stable product was obtained selec-
tively. Indeed, organic tellurides-mediated selective polymeriza-
tion of olefins was achieved in recent years.21 Thus, (PhTe)2 is
not only an effective trapping reagent for carbon radicals but also
a useful precursor for carbon radical intermediates under the
photoirradiation condition.
We next examined the scope and limitation of this indole
synthesis, and the results are summarized in Table 2. Ester,
ketone, and phenyl groups at the terminal position of the vinyl
group are tolerant of the photoinduced reaction condition.
This reaction afforded the corresponding bisthiolated indoles
3b, 3c, and 3d in moderate to good yields (entries 2ꢀ4).
Isocyanides, which have substituents on the phenyl group, also
underwent the photoinduced cyclization to give indole deriva-
tives. 2-Ethenyl-4-methylphenyl isocyanide (1e) gave the bisthio-
lated indole 3e in 33% yield (entry 5). On the other hand, the
photoinduced reaction of isocyanides 1f and 1g, which have
fluoro and trifluoromethyl groups, respectively, gave the corre-
sponding bisthiolated indoles 3f and 3g in 68% and 48% yields
(entries 6 and 7).
In the case of the isocyanide bearing acrylonitrile group, a trace
amount of bisthiolated indole 3h was formed, and 2-thiylindole-
3-carbaldehyde 5a was obtained as the major product in 71%
yield (eq 1). R-Thiylacetonitrile moieties are known to undergo
hydrolysis under acidic/basic conditions (or in the presence of
hydrolase) to convert to the corresponding aldehyde groups.22
Therefore, the indole carbaldehyde 5a was formed via the
formation of bisthiolated indole 3h and the following hydrolysis
of 3h.
a Reaction conditions: isocyanide (1, 0.15 mmol), (PhS)2 (2a, 0.225
mmol), (PhTe)2 (0.225 mmol), CHCl3 (0.4 mL), hv: irradiation with a
high-pressure Hg lamp through a glass filter (>400 nm), room tem-
perature, 24 h. b Isolated yield. c 31 h. d 18 h. e 30 h.
respectively. Unfortunately, the reaction with di-n-butyl disulfide
(2d) did not take place. The bond energies of the SꢀS bond were
listed as follows: PhSꢀSPh = 206 kJ/mol; MeSꢀSMe = 274 kJ/
mol; EtSꢀSEt = 277 kJ/mol.23 These values suggest that the
homolytic cleavage of dialkyl disulfides is somewhat difficult
compared with that of diaryl disulfides.
After the cyclization reactions, a mixture of diphenyl ditelluride,
diphenyl disulfide, and diphenyl thiotelluride was recovered con-
comitantly when the product was purified. When the recovered
dichalcogenides were used for the photoinduced cyclization of
isocyanide 1b with (PhS)2, the corresponding indole 3b was
obtained successfully in 51% yield (eq 2).
We also examined the photoinduced reaction of o-ethenylaryl
isocyanide 1 with several organic disulfides 2 (Scheme 5). When
bis(4-tolyl) disulfide (2b) and bis(4-chlorophenyl) disulfide
(2c) were used for the cyclization, the corresponding bisthiolated
indoles 3i and 3j were obtained in 67% and 53% yields,
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Scheme 5. Photoinduced Cyclization of Isocyanides 1d with
Several Organic Disulfides 2
Table 3. Photoinduced Sequential Cyclization with
Bis(2-aminophenyl) Disulfide (2e) in the Presence of
Diphenyl Ditelluridea
a Reaction conditions: isocyanide (1, 0.1 mmol), bis(2-aminophenyl) disul-
fide (2e, 0.10 mmol), (PhTe)2 (0.15 mmol), CHCl3 (0.25 mL), hv:
irradiation with a high-pressure Hg lamp through a glass filter (>400 nm),
room temperature, 24 h. b Isolated yield.
When the photoinduced reaction of isocyanide 1b with bis(2-
aminophenyl) disulfide (2e) was examined, the desired bisthio-
lated indole was not observed. Surprisingly, however, the tetra-
cyclic compound 4a, which had both dihydroquinazoline
and benzothiazole units, was obtained in 71% yield (Table 3,
entry 1).24 Isocyanide 1h also afforded the similar tetracyclic
compound 4b in 65% yield (entry 2). In contrast, the photo-
induced reactions of isocyanides 1a and 1d with disulfide 2e in
the presence of (PhTe)2 gave benzothiazole derivatives 6a and
6b having unreacted vinyl group in 66% and 58% yields without
the generation of tetracyclic derivative (entries 3 and 4).
When the reaction of isocyanide 1b with disulfide 2e was
examined in the dark, no tetracycle 4a was obtained. In addition,
when the photoirradiated reaction of isocyanide 1b with disul-
fide 2e was conducted in theabsenceof (PhTe)2, no reaction took
place. These results suggest that the formation of the tetra-
cyclic compounds requires the photoirradiation and diphenyl
ditelluride.
Scheme 6. A Plausible Reaction Pathway for the Photoinduced
Cyclization of Isocyanide 1 with Bis(2-aminophenyl) Disulfide (2e)
A plausible reaction pathway for the formation of tetracyclic
compounds 4 is shown in Scheme 6. The reaction pathway may
involve the following steps: (i) the photoinduced thiotelluration
of o-ethenylaryl isocyanide 1 gives an intermediate E; (ii) the
nucleophilic substitution of the phenyltelluro group of E by
the amino group at the ortho-position leads to the formation
of F; and (iii) the intramolecular aza-Michael addition reaction
provides 4.
We have reported the photoinduced thiotelluration of aryl
isocyanides in the presence of (PhS)2 and (PhTe)2.9b Thus, the
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reaction also proceeds via the addition of thiyl radical to the
isocyano group at first. Indeed, the photoinduced reaction of
4-nitrophenyl isocyanide (7a) with (o-H2N-C6H4S)2 (2e) and
(PhTe)2 afforded the corresponding thiotellurated imine 8a,
selectively (eq 3).
3371, 3229, 3057, 2924, 2853, 1719, 1582, 1477, 1439, 1340, 1290, 1242,
1192, 1069, 1024, 997, 739, 689; HRMS (EI) calcd for C21H17NS2
[Mþ] 347.0802, found 347.0820.
2-Phenylsulfanyl-3-(methoxycarbonyl-phenylsulfanyl-
methyl)-1H-indole (3b): slightly yellow oil; H NMR (400 MHz,
1
CDCl3, ppm) δ 3.63 (s, 3H), 5.59 (s, 1H), 7.01ꢀ7.05 (m, 2H),
7.12ꢀ7.28 (m, 9H), 7.31ꢀ7.35 (m, 2H), 8.08 (d, J = 7.8 Hz, 1H),
8.11 (s, 1H); 13C NMR (100 MHz, CDCl3, ppm) δ 49.8, 52.7, 110.9,
117.3, 120.4, 121.5, 123.9, 124.8, 125.8, 126.3, 127.7, 127.8, 128.8, 129.0,
133.3, 133.8, 135.6, 137.0, 170.4; IR (NaCl, cmꢀ1) 3360, 3057, 2950,
1732, 1479, 1439, 1151, 743, 690; HRMS (EI) calcd for C23H19NO2S2
[M]þ 405.0857, found 405.0856.
2-Phenylsulfanyl-3-(acetyl-phenylsulfanylmethyl)-1H-indole
(3c): colorless oil; 1H NMR (400 MHz, CDCl3, ppm) δ 2.08
(s, 3H), 5.63 (s, 1H), 6.95ꢀ7.01 (m, 2H), 7.10ꢀ7.31 (m, 11H),
7.85 (d, J = 7.8 Hz, 1H), 8.16 (s, 1H); 13C NMR (100 MHz, CDCl3,
ppm) δ 28.2, 58.4, 111.0, 116.8, 120.6, 121.1, 124.0, 125.2, 125.8, 126.5,
127.5, 127.7, 128.7, 129.2, 133.5, 133.9, 135.5, 137.0, 202.7; IR
(NaCl, cmꢀ1) 3348, 3055, 3009, 2978, 2916, 1705, 1612, 1582, 1512,
1473, 1443, 1420, 1350, 1296, 1242, 1219, 1150, 1088, 1018, 772, 748,
687; HRMS (FAB) calcd for C23H20NOS2 [M þ H]þ 390.0986, found
390.0986.
’ CONCLUSION
In summary, we have developed the photoinduced intramo-
lecular cyclization of o-ethenylaryl isocyanides with organic
disulfide in the presence of diphenyl ditelluride. This cyclization
reaction affords the bisthiolated indole derivatives under mild
reaction condition (at room temperature) upon photoirradia-
tion. In the cases of bis(2-aminophenyl) disulfide, the photo-
induced reaction afforded the tetracyclic compounds bearing
dihydroquinazoline and benzothiazole units, selectively. Further
studies about the syntheses of N-heterocycles by the photo-
induced intramolecular cyclization of isocyanides having an
unsaturated bond are now in progress.
2-Phenylsulfanyl-3-(phenyl-phenylsulfanylmethyl)-1H-
1
indole (3d): white solid; mp 118ꢀ119 °C; H NMR (300 MHz,
CDCl3, ppm) δ 6.15 (s, 1H), 6.89ꢀ6.96 (m, 2H), 7.06ꢀ7.31 (m, 14H),
7.57 (d, J = 7.7 Hz, 2H), 7.99 (s, 1H), 8.04 (d, J = 8.0 Hz, 1H); 13C NMR
(75 MHz, CDCl3, ppm) δ 50.5, 111.0, 120.0, 121.9, 122.3, 123.5, 123.6,
126.1, 126.3, 126.9, 126.9, 127.5, 128.2, 128.3, 128.6, 129.1, 131.9, 135.8,
135.9, 137.2, 140.5; IR (NaCl, cmꢀ1) 3404, 3057, 3014, 1580, 1477,
1439, 1406, 1340, 1242, 1069, 1024, 739, 689; HRMS (FAB) calcd for
C27H22NS2 [M þ H]þ 424.1194, found 424.1188.
’ EXPERIMENTAL SECTION
General Comments. 1H NMR spectra were recorded at 300 and
400 MHz with CDCl3 as the solvent and tetramethylsilane (TMS) as the
internal standard. 13C NMR spectra were obtained at 75 and 100 MHz
with CDCl3 as the solvent. Chemical shifts in 13C NMR were measured
relative to CDCl3 by using δ 77.0 ppm. Infrared spectra were recorded
with a FT-IR spectrometer. Melting points were determined on a micro
melting point apparatus. High-resolution mass spectra were obtained on
a mass spectrometer (FAB or EI). Diphenyl ditelluride25 and 4-nitro-
phenyl isocyanide (7a)9b,26 were prepared and determined according
to the literature. Other reagents such as anilines as the starting materials
for o-ethenylaryl isocyanides, diphenyl disulfide, bis(4-tolyl) disulfide,
bis(4-chlorophenyl) disulfide, di-n-butyl disulfide, bis(2-aminophenyl)
disulfide, methyl acrylate, methyl vinyl ketone, styrene, acrylonitrile, and
tri-n-butylvinylstannane were commercially available and used without
further purification.
5-Methyl-2-phenysulfanyl-3-phenylsulfanylmethyl-1H-
indole (3e): colorless oil; 1H NMR (400 MHz, CDCl3, ppm) δ 2.46
(s, 3 H), 4.44 (s, 2H), 7.00ꢀ7.24 (m, 10H), 7.33ꢀ7.40 (m, 2H), 7.50
(s, 1H), 7.94 (s, 1H); 13C NMR (75 MHz, CDCl3, ppm) δ 21.5, 29.8,
110.7, 118.2, 119.5, 123.6, 125.5, 126.0, 126.3, 127.2, 128.7, 129.1, 129.5,
130.1, 130.5, 135.3, 136.5, 136.7; IR (NaCl, cmꢀ1) 3285, 2974, 2936,
2878, 1720, 1583, 1556, 1514, 1479, 1408, 1371, 1279, 1204, 1177, 1155,
1123, 1026, 995, 741, 691, 662; HRMS (CI) calcd for C22H20NS2
[M þ H]þ 362.1037, found 362.1040.
5-Fluoro-2-phenylsulfanyl-3-phenylsulfanylmethyl-1H-
indole (3f): white solid; mp 106ꢀ107 °C; 1H NMR (300 MHz,
CDCl3, ppm) δ 4.40 (s, 2H), 6.98 (ddd, J = 2.6, 8.8, 9.2 Hz, 1H),
7.03ꢀ7.09 (m, 2H), 7.14ꢀ7.25 (m, 7H), 7.32ꢀ7.41 (m, 3H), 8.01 (s,
1H); 13C NMR (75 MHz, CDCl3, ppm) δ 29.8, 104.9 (d, JCꢀF = 23.4
Hz), 111.7 (d, JCꢀF = 9.9 Hz), 112.3 (d, JCꢀF = 25.9 Hz), 118.5, 123.3,
125.9, 126.4, 126.6, 127.5, 127.6, 128.8, 129.2, 130.8, 133.4, 136.2, 157.8
(d, JCꢀF = 234.4 Hz); IR (NaCl, cmꢀ1) 3716, 3713, 3051, 1582, 1479,
1445, 1356, 1296, 1232, 1184, 1070, 1024, 997, 970, 854, 829, 799, 739,
689, 604; HRMS (CI) calcd for C21H17FNS2 [M þ H]þ 366.0786,
found 366.0779.
Typical Procedure for the Synthesis of Bisthiolated
Indoles via the Photoinduced Intramolecular Cyclization
of o-Ethenylaryl Isocyanides with Organic Disulfides in the
Presence of Diphenyl Ditelluride. A mixture of 2-styrylphenyl
isocyanide (1d, 31 mg, 0.15 mmol), diphenyl disulfide (2a, 49 mg, 0.225
mmol), and diphenyl ditelluride (92 mg, 0.225 mmol) in CHCl3
(0.4 mL) was irradiated with a high-pressure Hg lamp through a glass
filter (hv > 400 nm) at room temperature for 18 h. After the photoir-
radiation, CHCl3 was removed in vacuo from the resulting mixture.
The crude mixture was purified by PTLC on silica gel (eluent: Hex/
AcOEt = 4/1), and 2-phenylsulfanyl-3-(phenyl-phenylsulfanylmethyl)-
1H-indole (3d, 40 mg, 0.095 mmol, 63%) was obtained as a white solid
(mp 118ꢀ119 °C).
5-Trifluoromethyl-2-phenylsulfanyl-(3-methoxycarbonyl-
phenylsulfanylmethyl)-1H-indole (3g): colorless oil; H NMR
1
(400 MHz, CDCl3, ppm) δ 3.66 (s, 3H), 5.57 (s, 1H), 7.01ꢀ7.05
(m, 2H), 7.16ꢀ7.24 (m, 6H), 7.31ꢀ7.36 (m, 3H), 7.47 (dd, J = 1.4, 8.4
Hz, 1H), 8.24 (s, 1H), 8.36 (s, 1H); 13C NMR (100 MHz, CDCl3, ppm)
δ 49.5, 52.8, 111.3, 118.0, 119.5 (q, JCꢀF = 4.4 Hz), 120.5 (q, JCꢀF = 3.8
Hz), 122.9 (q, JCꢀF = 33.0 Hz), 125.2, 126.8, 127.4, 128.2, 128.2, 128.9,
129.3, 133.2, 133.6, 134.6, 170.1; IR (NaCl, cmꢀ1) 3333, 3055, 3001,
2955, 2839, 1728, 1628, 1582, 1474, 1435, 1358, 1327, 1281, 1157, 1119,
1049, 1003, 941, 903, 810, 741, 687, 648; HRMS (FAB) calcd for
C24H19F3NO2S2 [M þ H]þ 474.0809, found 474.0796.
2-Phenylsulfanyl-3-phenylsulfanylmethyl-1H-indole (3a):
white solid; mp 91ꢀ92 °C; 1H NMR (400 MHz, CDCl3, ppm) δ 4.46
(s, 2H), 7.02ꢀ7.07 (m, 2H), 7.12ꢀ7.30 (m, 9H), 7.33ꢀ7.37 (m, 2H),
7.76 (d, J = 7.8 Hz, 1H), 8.03 (s, 1H); 13C NMR (100 MHz, CDCl3,
ppm) δ 29.8, 110.9, 118.6, 120.0, 120.1, 123.7, 126.1, 126.3, 127.3,
2-Tolylsulfanyl-3-(phenyl-tolylsulfanylmethyl)-1H-indole
1
128.7, 129.1, 129.6, 130.5, 135.1, 136.1, 136.5, 136.9; IR (NaCl, cmꢀ1
)
(3i): slightly yellow oil; H NMR (300 MHz, CDCl3, ppm) δ 2.24
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(s, 6H), 6.10 (s, 1H), 6.79ꢀ6.86 (m, 2H), 6.87ꢀ6.96 (m, 4H),
7.06ꢀ7.27 (m, 8H), 7.56 (d, J = 6.8 Hz, 2H), 7.95 (s, 1H), 8.03 (d,
J = 7.9 Hz, 1H); 13C NMR (75 MHz, CDCl3, ppm) δ 20.9, 21.1, 50.9,
110.9, 119.8, 121.7, 121.8, 123.3, 124.4, 126.3, 126.8, 128.2, 128.2, 128.2,
129.4, 129.8, 132.1, 132.6, 136.2, 136.9, 137.0, 137.1, 140.8; IR
(NaCl, cmꢀ1) 3395, 3263, 3055, 3024, 2970, 2924, 2870, 1697, 1597,
1558, 1489, 1443, 1366, 1342, 1250, 1211, 1180, 1157, 1088, 1018, 964,
802, 748, 694; HRMS (FAB) calcd for C29H26NS2 [M þ H]þ 452.1507,
found 452.1535.
2-Chlorophenylsulfanyl-3-(phenyl-4-chlorophenylsulfan-
ylmethyl)-1H-indole (3j): white solid; mp 110ꢀ111 °C; 1H NMR
(300 MHz, CDCl3, ppm) δ 6.06 (s, 1H), 6.72ꢀ6.81 (m, 2H),
7.02ꢀ7.30 (m, 12H), 7.48ꢀ7.56 (m, 2H), 8.00ꢀ8.09 (m, 2H); 13C
NMR (75 MHz, CDCl3, ppm) δ 51.0, 111.1, 120.2, 121.9, 122.1, 122.9,
123.9, 126.1, 127.2, 128.1, 128.4, 128.4, 128.8, 129.2, 132.2, 133.3, 133.7,
134.0, 134.4, 137.2, 140.0; IR (NaCl, cmꢀ1) 3233, 3355, 3024, 2970,
2932, 1697, 1589, 1473, 1446, 1389, 1366, 1342, 1250, 1204, 1180, 1157,
1088, 1011, 818, 748, 694; HRMS (FAB) calcd for C27H20Cl2NS2 [M þ
H]þ 492.0414, found 492.0440.
694; HRMS (FAB) calcd for C15H13N2S [M þ H]þ 253.0799, found
253.0779.
2-Benzothiazolyl-(2-styrylphenyl)amine (6b): slightly yellow
solid; mp 149ꢀ150 °C; 1H NMR (400 MHz, CDCl3, ppm)
δ 7.05ꢀ7.16 (m, 3H), 7.28ꢀ7.39 (m, 6H), 7.43ꢀ7.48 (m, 2H),
7.54ꢀ7.59 (m, 2H), 7.70 (ddd, J = 1.4, 5.5, 7.8 Hz, 2H); 13C NMR
(100 MHz, CDCl3, ppm) δ 119.3, 120.8, 122.3, 122.9, 124.1, 126.0,
126.4, 126.7, 127.0, 128.1, 128.6, 128.7, 130.4, 132.1, 132.3, 136.8, 137.0,
144.6, 151.5; IR (NaCl, cmꢀ1) 3371, 3171, 3116, 3063, 3024, 2939,
2862, 1690, 1605, 1535, 1450, 1312, 1265, 1250, 1180, 1126, 1096, 1072,
1018, 964, 918, 872, 849, 756, 694; HRMS (FAB) calcd for C21H17N2S
[M þ H]þ 329.1112, found 329.1124.
N-(4-Nitrophenyl) 1-(2-Aminophenylsulfanyl-phenyltel-
1
lanylmethane) Imine (8a): light yellow oil; H NMR (400 MHz,
CDCl3, ppm) δ 4.30 (s, 2H), 6.71ꢀ6.78 (m, 2H), 6.87 (d, J = 8.7 Hz,
2H), 7.23ꢀ7.29 (m, 3H), 7.35 (d, J = 7.8 Hz, 1H), 7.39 (dd, J = 6.9, 7.3
Hz, 1H), 7.87 (d, J = 7.3 Hz, 2H), 8.11 (d, J = 8.7 Hz, 2H); 13C NMR
(100 MHz, CDCl3, ppm) δ 109.4, 113.3, 115.7, 118.7, 120.0, 124.9,
129.4, 129.4, 132.5, 136.5, 137.3, 141.5, 144.3, 152.6, 156.7; IR
(NaCl, cmꢀ1) 3479, 3371, 3217, 3063, 2924, 1589, 1528, 1504, 1443,
1327, 1312, 1258, 1219, 1173, 1111, 856, 772, 687; HRMS (FAB) calcd
for C19H16N3O2STe [M þ H]þ 480.0026, found 480.0001.
2-Phenylsulfanyl-1H-indole-3-carboaldehyde (5a):27 white
solid; mp 182ꢀ183 °C; 1H NMR (400 MHz, CDCl3, ppm) δ 7.24ꢀ7.30
(m, 3H), 7.33ꢀ7.40 (m, 3H), 7.40ꢀ7.44 (m, 2H), 8.24ꢀ8.28 (m, 1H),
8.63 (s, 1H), 10.25 (s, 1H); 13C NMR (100 MHz, CDCl3, ppm) δ 110.8,
118.5, 121.0, 123.1, 124.4, 125.8, 128.6, 129.9, 131.2, 131.7, 136.2, 140.5,
185.3; MS (EI) m/z 253 (Mþ, 100).
Preparation of o-Ethenylaryl Isocyanides 1, e.g., 1a. To a
solution of 2-bromoaniline (11 mL, 101 mmol) in toluene (50 mL) was
added formic acid (ca. 80% aq) (10 mL), and the mixture was stirred at
110 °C for 4 h. Volatiles were removed from the resulting mixture. The
crude solid was recrystallized from toluene to give 2-bromoformanilide
(15.3 g, 76.4 mmol, 76%).
To a 50-mL two-necked flask were added 2-bromoformanilide (1.0 g,
5.0 mmol), tributylvinylstannane (1.5 mL, 5.16 mmol), and tetrakis-
(triphenylphosphine)palladium (120 mg, 0.10 mmol) in toluene (20 mL)
under nitrogen atmosphere, and then the mixture was stirred at 110 °C.
After heating for 16 h, volatiles were removed from the resulting mixture
under the reduced pressure, and the crude mixture was purified bycolumn
chromatography on silica gel (eluent: hexane/AcOEt = 1/1). Then,
2-ethenylformanilide (562 mg, 3.8 mmol, 76%) was obtained.
Procedure for the Synthesis of Tetracyclic Compounds 4.
A mixture of methyl 2-(2-isocyanophenyl)acrylate (1b, 19 mg, 0.10
mmol), bis(2-aminophenyl) disulfide (2e, 25 mg, 0.10 mmol), and
diphenyl ditelluride (61 mg, 0.15 mmol) in CDCl3 (0.25 mL) was
irradiated with a high-pressure Hg lamp through a glass filter (hv >
400 nm) at room temperature for 24 h. After the photoirradiation,
CDCl3 was removed in vacuo from the resulting mixture. The crude
product was purified by PTLC on silica gel (eluent: Hex/AcOEt = 9/1),
and methyl (12H-benzo[4,5]thiazolo[2,3-b]quinazolin-12-yl) acetate
(4a, 22 mg, 0.071 mmol, 71%) was obtained as a slightly yellow oil.
Methyl (12H-Benzo[4,5]thiazolo[2,3-b]quinazolin-12-yl)-
acetate (4a): slightly yellow oil; 1H NMR (400 MHz, CDCl3, ppm) δ
2.80ꢀ2.84 (m, 2H), 3.60 (s, 3H), 5.93ꢀ6.01 (m, 1H), 7.07 (ddd, J = 1.4,
7.3, 7.3 Hz, 1H), 7.11ꢀ7.17 (m, 4H), 7.25ꢀ7.35 (m, 2H), 7.43 (d,
J = 7.8 Hz, 1H); 13C NMR (100 MHz, CDCl3, ppm) δ 40.4, 52.1, 52.7,
109.5, 120.7, 122.4, 123.3, 123.6, 123.9, 124.6, 125.7, 126.4, 129.4, 137.9,
141.5, 159.6, 170.3; IR (NaCl, cmꢀ1) 3063, 3017, 2947, 2924, 1736, 1582,
1558, 1481, 1458, 1335, 1296, 1273, 1242, 1219, 1180, 1026, 980, 748, 694;
HRMS (FAB) calcd for C17H15N2O2S [M þ H]þ 311.0854, found
311.0870.
(12H-Benzo[4,5]thiazolo[2,3-b]quinazolin-12-yl)acetoni-
trile (4b): slightly yellow solid; mp 172ꢀ173 °C; 1H NMR (400 MHz,
CDCl3, ppm) δ 2.81ꢀ2.87 (m, 2H), 5.78ꢀ5.83 (m, 1H), 7.08 (d, J = 8.2
Hz, 1H), 7.14ꢀ7.23 (m, 3H), 7.30ꢀ7.39 (m, 3H), 7.46 (d, J = 7.8 Hz,
1H); 13C NMR (100 MHz, CDCl3, ppm) δ 24.2, 52.4, 109.0, 116.0,
118.1, 122.8, 123.6, 123.8, 124.3, 125.0, 126.3, 126.5, 130.2, 137.2, 141.6,
158.7; IR (NaCl, cmꢀ1) 3071, 3017, 2970, 2932, 2253, 1690, 1589,
1558, 1481, 1458, 1366, 1335, 1304, 1273, 1250, 1204, 1126, 1088, 1018,
980, 935, 918, 872, 849, 756, 687; HRMS (FAB) calcd for C16H12N3S
[M þ H]þ 278.0752, found 278.0746.
To a mixture of methyl 2-ethenylformanilide (147 mg, 1 mmol) and
diisopropylamine (0.20 mL, 1.4 mmol) in chloroform (3.0 mL) was
added phosphoryl chloride (0.13 mL, 1.4 mmol) at 0 °C under nitrogen
atmosphere. The mixture was warmed to room temperature, and then
stirred for 2 h. Saturated aqueous sodium carbonate was poured into the
resulting mixture. The following extraction of the product with diethyl
ether, concentration under the reduced pressure, and the purification
of the resulting crude product by column chromatography on silica
gel (eluent: hexane/AcOEt = 2/1) gave 2-ethenylphenyl isocyanide
(1a, 95.6 mg, 0.74 mmol, 74%) as a colorless oil.
2-Ethenylphenyl isocyanide (1a):28 colorless oil; 1H NMR
(400 MHz, CDCl3, ppm) δ 5.50 (d, J = 11.4 Hz, 1H), 5.87 (d, J =
17.4 Hz, 1H), 7.04 (dd, J = 11.4, 17.4 Hz, 1H), 7.31ꢀ7.41 (m, 4H); 13C
NMR (100 MHz, CDCl3, ppm) δ 119.8, 125.6, 125.7, 127.0, 128.4,
129.3, 130.9, 133.8, 168.3; MS (EI) m/z 129 (Mþ, 100).
2-Ethenyl-4-methylphenyl Isocyanide (1e): colorless oil; 1H
NMR (300 MHz, CDCl3, ppm) δ 2.37 (s, 3H), 5.46 (dd, J = 0.8, 11.2 Hz,
1H), 5.84 (dd, J = 0.8, 17.4 Hz, 1H), 6.94ꢀ7.09 (m, 2H), 7.23 (d, J = 8.0
Hz, 1H), 7.39 (s, 1H); 13C NMR (75 MHz, CDCl3, ppm) δ 21.3, 117.7,
126.0, 126.8, 129.1, 131.0, 133.5, 139.5, 166.1; IR (NaCl, cmꢀ1) 3077,
3031, 2953, 2923, 2855, 2118, 1684, 1558, 1508, 1489, 1458, 1338, 1191,
1163, 1103, 1074, 1038, 989, 918, 860, 816, 754, 719; HRMS (FAB)
calcd for C10H10N [M þ H]þ 144.0813, found 144.0824.
2-Benzothiazolyl-(2-ethenylphenyl)amine (6a): white solid;
mp 172ꢀ173 °C; 1H NMR (400 MHz, CDCl3, ppm) δ 5.39 (dd, J = 0.9,
11.0 Hz, 1H), 5.76 (dd, J = 0.9, 17.4 Hz, 1H), 6.96 (dd, J = 11.0, 17.4 Hz,
1H), 7.13 (ddd, J = 0.8, 7.5, 7.6 Hz, 1H), 7.23ꢀ7.34 (m, 2H), 7.36 (ddd,
J = 1.4, 7.8, 7.8 Hz, 1H), 7.52ꢀ7.60 (m, 3H), 7.69 (dd, J = 0.9, 7.8 Hz,
1H); 13C NMR (100 MHz, CDCl3, ppm) δ 117.8, 119.3, 120.8, 120.9,
122.3, 124.0, 126.1, 126.3, 127.1, 129.0, 131.8, 132.2, 136.7, 136.8, 151.5;
IR (NaCl, cmꢀ1) 3171, 3125, 3062, 3027, 2929, 2831, 1612, 1558, 1481,
1450, 1312, 1265, 1188, 1157, 1126, 1096, 1018, 988, 918, 849, 748, 725,
2-Ethenyl-4-fluorophenyl isocyanide (1f) was too unstable to isolate
and the formation of 1f was determined by 1H NMR with 1,3,5-trioxane
as an internal standard.
Preparation of o-Ethenylaryl Isocyanides 1, e.g., 1b. To a
50-mL two-necked flask were added 2-bromoformanilide (320 mg,
3885
dx.doi.org/10.1021/jo200299d |J. Org. Chem. 2011, 76, 3880–3887

The Journal of Organic Chemistry
ARTICLE
1.6 mmol), palladium(II) acetate (5.6 mg, 0.022 mmol), tris(o-tolyl)-
phosphine (11 mg, 0.035 mmol), methyl acrylate (0.16 mL, 1.8 mmol),
and triethylamine (0.28 mL, 2.0 mmol) in acetonitrile (3 mL) under
nitrogen atmosphere, and then the reaction was conducted at 100 °C.
After heating for 18 h, volatiles were removed from the reaction system
under the reduced pressure, and the crude mixture was purified by
column chromatography on silica gel (eluent: hexane/AcOEt = 1/1).
Then, methyl 3-(2-formamidophenyl)acrylate (230 mg, 1.12 mmol,
72%) was obtained.
’ ACKNOWLEDGMENT
This work was supported by Grant-in-Aid for Scientific
Research (B, 19350095), from the Ministry of Education,
Culture, Sports, Science and Technology, Japan, and in part by
the Leading-edge Research Infrastructure Program (Tohoku
University). We also thank Professor Kiyomi Kakiuchi and Mr.
Shouhei Katao of Nara Institute of Science and Technology in
Kyoto-Advanced Nanotechnology Network. T.M. also thanks
the Japan Society for the Promotion of Science (JSPS) for the
Research Fellowship for Young Scientists.
To a mixture of methyl 3-(2-formamidophenyl)acrylate (205 mg, 1.0
mmol) and diisopropylamine (0.21 mL, 1.5 mmol) in chloroform
(3.0 mL) was added phosphoryl chloride (0.14 mL, 1.5 mmol) at
0 °C under nitrogen atmosphere. The mixture was warmed to room
temperature, and then stirred for 2 h. Saturated aqueous sodium
carbonate was poured into the resulting mixture. The following extrac-
tion of the product with diethyl ether, concentration under the reduced
pressure, and the purification of the obtained crude product by column
chromatography on silica gel (eluent: hexane/AcOEt = 2/1) gave
methyl 3-(2-isocyanophenyl)acrylate (1b, 107 mg, 0.57 mmol, 57%)
as a white solid (mp 56 °C).11d
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Methyl 3-(2-Isocyanophenyl)acrylate (1b):11d white solid;
mp 56 °C; 1H NMR (400 MHz, CDCl3, ppm) δ 3.84 (s, 3H), 6.54 (d,
J = 16.5 Hz, 1H), 7.42ꢀ7.47 (m, 3H), 7.65ꢀ7.69 (m, 1H), 7.98 (d,
J = 16.5 Hz, 1H); 13C NMR (100 MHz, CDCl3, ppm) δ 51.9, 121.9,
125.9, 126.8, 127.6, 129.6, 130.6, 130.7, 137.8, 166.3, 168.6; MS (EI)
m/z 187 (Mþ, 100).
4-(2-Isocyanophenyl)-3-buten-2-one (1c):11d pale yellow oil;
1H NMR (400 MHz, CDCl3, ppm) δ 2.45 (s, 3H), 6.76 (d, J = 16.5 Hz,
1H), 7.43ꢀ7.48 (m, 3H), 7.68ꢀ7.72 (m, 1H), 7.81 (d, J = 16.5 Hz, 1H);
13C NMR (100 MHz, CDCl3, ppm) δ 27.2, 126.2, 126.8, 127.6, 129.7,
130.8, 130.8, 130.9, 136.4, 168.8, 198.0; MS (EI) m/z 129 (Mþ, 100).
Methyl 3-(2-Isocyano-5-trifluoromethylphenyl)acrylate
(1g): white solid; mp 85ꢀ86 °C; 1H NMR (400 MHz, CDCl3, ppm)
δ 3.86 (s, 3H), 6.62 (d, J = 16.0 Hz, 1H), 7.58 (d, J = 8.2 Hz, 1H), 7.68
(d, J = 8.2 Hz, 1H), 7.92 (s, 1H), 7.96 (d, J = 16.0 Hz, 1H); 13C NMR
(100 MHz, CDCl3, ppm) δ 52.2, 122.8 (q, JCF = 270.5 Hz), 123.8, 124.1
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(q, JCF = 3.8 Hz), 127.3 (q, JCF = 3.8 Hz), 128.3, 131.6, 131.7 (q, JCF
=
34.3 Hz), 136.3, 165.7, 171.6; IR (NaCl, cmꢀ1) 3078, 3032, 2955, 2847,
2122, 1713, 1489, 1435, 1335, 1288, 1180, 1165, 1103, 1072, 1034, 988,
926, 864, 841, 772, 702; HRMS (FAB) calcd for C12H9F3NO2 [M þ
H]þ 256.0585, found 256.0873.
3-(2-Isocyanophenyl)acrylonitrile (1h):11d white solid; mp
1
81ꢀ82 °C; H NMR (400 MHz, CDCl3, ppm) δ 6.06 (d, J = 16.5
Hz, 1H), 7.45ꢀ7.53 (m, 3H), 7.60ꢀ7.65 (m, 1H), 7.73 (d, J = 16.5 Hz,
1H); 13C NMR (100 MHz, CDCl3, ppm) δ 100.6, 117.1, 125.5,
126.1, 127.8, 129.5, 129.8, 131.7, 143.9, 169.6; MS (EI) m/z 129
(Mþ, 100).
2-(2-Isocyanophenyl)styrene (1d) was too unstable to isolate and the
formation of 1d was determined by 1H NMR with 1,3,5-trioxane as an
internal standard.
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Supporting Information. 1H and 13C NMR spectra of 3,
S
b
4, 5, 6, and 8, and CIF fires of 4b and 6a. This material is available
free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*Phone: þ81-72-254-9290. Fax: þ81-72-254-9290. E-mail: ogawa@
chem.osakafu-u.ac.jp.
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ARTICLE
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(17) The rate constants for intramolecular 5-exo and 6-endo radical
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2.3 ꢁ 105 sꢀ1; 6-endo cyclization, 4.1 ꢁ 103 sꢀ1, see: (a) Beckwith,
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and (PhTe)2 are 2.6 ꢁ 107 and 1.1 ꢁ 108 Mꢀ1
s
ꢀ1, respectively. For
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(19) For the thermal or photoinduced dissociation of allylic
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(b) Yamago, S.; Hashidume, M.; Yoshida, J. Tetrahedron 2002, 58, 6805.
(20) At the initial stage of this study, the reaction was carried out at
40 °C in CDCl3 solution (0.40 M) by using a tungsten lamp (500 W) as a
light source. This reaction afforded the corresponding indole 3a in 50%
yield. We also examined the reaction using several light sources. When a
Xe lamp was used as light source, the reaction at 40 °C formed indole 3a
in 37% yield; the reaction at room temperature did not afford 3a.
In contrast, the reaction of isocyanide 1a upon photoirradiation with a
high-pressure Hg lamp at room temperature afforded the corresponding
indole 3a in 56% yield.
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(24) Conclusive determination of the tetracyclic compound 4 and
benzothiazole 6 were ascertained by X-ray crystal analysis of 4b and
6a, and the resulting ORTEP diagrams are shown in the Supporting
Information.
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dx.doi.org/10.1021/jo200299d |J. Org. Chem. 2011, 76, 3880–3887