Platinum-catalyzed, one-pot tandem synthesis of indoles and isoquinolines via sequential rearrangement of amides and aminocyclization

Article abstract of DOI:10.1021/jo101347f

By using platinum(II) chloride as a Lewis acid catalyst, concise and efficient syntheses of indole carbamates, 1,2-dihydroisoquinoline carbamates, macrocyclic indole carbamates, indole ureas, and indole phosphoranes have been achieved via tandem Hofmann-t

Full text of DOI:10.1021/jo101347f

pubs.acs.org/joc
Platinum-Catalyzed, One-Pot Tandem Synthesis of Indoles and
Isoquinolines via Sequential Rearrangement of Amides and
Aminocyclization
Noriko Okamoto,†,‡ Kei Takeda,‡ and Reiko Yanada*,†
†Faculty of Pharmaceutical Sciences, Hiroshima International University, 5-1-1 Hirokoshingai, Kure,
Hiroshima 737-0112, Japan, and ‡Department of Synthetic Organic Chemistry, Graduate School of Medical
Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-Ku, Hiroshima 734-8553, Japan
ryanada@ps.hirokoku-u.ac.jp
Received July 28, 2010
By using platinum(II) chloride as a Lewis acid catalyst, concise and efficient syntheses of indole carbamates,
1,2-dihydroisoquinoline carbamates, macrocyclic indole carbamates, indole ureas, and indole phosphor-
anes have been achieved via tandem Hofmann-type rearrangement of 2-alkynylbenzamides and 2-alky-
nylbenzylamides, nucleophilic addition of alcohols and amines to the isocyanate intermediates, and
intramolecular aminocyclization of the thus-formed carbamates and ureas to 2-alkynyl functions. A variety
of nucleophiles such as alcohols, amines, and stable Wittig reagents could be introduced to the highly
electrophilic carbon of the isocyanate intermediates derived from amides. We observed enhancement of the
reaction rates when the reactions were run under microwave irradiation.
Introduction
the construction of these ring systems. Metal-catalyzed ring
closure of 2-alkynylaniline and 2-alkynylbenzylamine deriva-
tives A (Scheme 1) would be one of the most efficient approaches
for the construction of benzo-fused N-containing heterocyclic
compounds.1,2 However, one drawback of the method is
air instability of the amines. We became interested in using
2-alkynylbenzamide and 2-alkynylbenzylamide derivatives
The development of tandem reactions for efficient construc-
tion of complex molecules is an important goal of organic syn-
thesis from the viewpoint of operational simplicity and assembly
efficiency. Since the indole and isoquinoline ring systems are key
structural units for a variety of biologically important com-
pounds, an efficient and expedient method to synthesize a wide
variety of these classes of molecules would be highly desirable.
Among available strategies, metal-catalyzed annulation pro-
cesses have recently been proven to be powerful methods for
(2) Isoquinoline synthesis: (a) Enomoto, T.; Girard, A.-L.; Yasui, Y.;
Takemoto, Y. J. Org. Chem. 2009, 74, 9158–9164. (b) Chen, Z.; Yang, X.;
Wu, J. Chem. Commun. 2009, 3469–3471. (c) Fischer, D.; Tomeba, H.;
Pahadi, N. K.; Patil, N. T.; Huo, Z.; Yamamoto, Y. J. Am. Chem. Soc.
2008, 130, 15720–15725. (d) Obika, S.; Yasui, Y.; Yanada, R.; Takemoto, Y.
J. Org. Chem. 2008, 73, 5206–5209. (e) Enomoto, T.; Obika, S.; Yasui, Y.;
Takemoto, Y. Synlett 2008, 1647–1650. (f) Gao, K.; Wu, J. J. Org. Chem.
2007, 72, 8611–8613. (g) Ding, Q.; Ye, Y.; Fan, R.; Wu, J. J. Org. Chem. 2007,
72, 5439–5442. (h) Su, S.; Porco, J. A., Jr. Org. Lett. 2007, 9, 4983–4986.
(i) Ding, Q.; Wu, J. Org. Lett. 2007, 9, 4959–4962. (j) Obika, S.; Kono, H.;
Yasui, Y.; Yanada, R.; Takemoto, Y. J. Org. Chem. 2007, 72, 4462–4468.
(k) Yanada, R.; Obika, S.; Kono, H.; Takemoto, Y. Angew. Chem., Int. Ed.
2006, 45, 3822–3825. (l) Asao, N.; Yudha, S. S.; Nogami, T.; Yamamoto, Y.
Angew. Chem., Int. Ed. 2005, 44, 5526–5528.
(1) Indole synthesis: (a) Huang, N.-Y.; Liu, M.-G.; Ding, M.-W. J. Org.
Chem. 2009, 74, 6874–6877. (b) Sakai, N.; Annaka, K.; Fujita, A.; Sato, A.;
Konakahara, T. J. Org. Chem. 2008, 73, 4160–4165. (c) Ma, D.; Cai, Q. Acc.
€
Chem. Res. 2008, 41, 1450–1460. (d) Furstner, A.; Davies, P. W. Angew.
Chem., Int. Ed. 2007, 46, 3410–3449. (e) Zhang, Y.; Donahue, J. P.; Li, C.-J.
Org. Lett. 2007, 9, 627–630. (f) Humphrey, G. R.; Kuethe, J. T. Chem. Rev.
2006, 106, 2875–2911. and references therein. (g) Alonso, F.; Beletskaya,
I. P.; Yus, M. Chem. Rev. 2004, 104, 3079–3159. (h) Hiroya, K.; Itoh, S.;
Sakamoto, T. J. Org. Chem. 2004, 69, 1126–1136. (i) Takeda, A.; Kamijo, S.;
Yamamoto, Y. J. Am. Chem. Soc. 2000, 122, 5662–5663.
DOI: 10.1021/jo101347f
r
Published on Web 10/21/2010
J. Org. Chem. 2010, 75, 7615–7625 7615
2010 American Chemical Society

Okamoto et al.
SCHEME 3. Synthesis of Indole Carbamates, Ureas, and
Phosphoranes
JOCArticle
SCHEME 1. Metal-Catalyzed Synthesis of Indoles and Isoqui-
nolines
SCHEME 2. Synthetic Strategy for the Constuction of Indoles
and Isoquinolines
TABLE 1. Examination of Catalysts and Reaction Conditions
as substrates for the reaction since they can be converted to
amine derivatives via a Hofmann-type rearrangement.
We have recently described in a communication the one-
pot, platinum(II)-catalyzed tandem synthesis of indoles and
isoquinolines starting from 2-alkynylbenzamides and 2-
alkynylbenzylamides B (Scheme 2).3 Therein, we described
that isocyanate intermediates C4,5 derived from a Hofmann-
type rearrangement of amides B using hypervalent iodine
reagents were superior substrates for the construction of
heterocycles D through carbamate intermediates A obtained
from the reaction with isocyanate intermediates C and
alcohols; thus, the work showed that stable 2-alkynylamides
B can be used as starting materials for the efficient one-pot
synthesis of indoles and isoquinolines.
yield (%)
2a
entry
catalyst
time (h)
3
1a
2a
3
PtCl2, Et3N (3 equiv)
PtCl2
PtCl2
2.0 þ 3.0
2.0 þ 0.5
0.5
2.5
2.5
3.0
41.0
3.0
9
82
85
84
78
0
64
0
0
0
0
4b
5
PtCl2
PdCl2
InBr3
6
7
8
9
10
92
0
62
84
93
InBr3 (0.2 equiv)
Pd(OAc)2
CuCl2
85
6
3.0
3.0
0
4
Cu(OTf)2
aStepwise procedure. bAt 70 °C.
To further extend our method, we focused on reactions of
different kinds of nucleophiles with isocyanate C. Herein, we
present in greater detail our efforts to achieve platinum(II)-
catalyzed one-pot concise tandem synthesis of indole carba-
mates, 1,2-dihydroisoquinoline carbamates, macrocyclic in-
dole carbamates, indole ureas, and indole phosphoranes
(Scheme 3).
examined: a stepwise procedure based on the formation of
isocyanate C and its subsequent cyclization to D (entries 1
and 2) and a one-pot procedure (entries 3-10). The Hofmann-
type rearrangement reaction of 2-(1-hexynyl)benzamide 1a
with PhI(OAc)2 in 1,2-dichlorobenzene proceeded smoothly
to give 2-(1-hexynyl)phenyl isocyanate C (n = 0, R1 = Bu)
within 2 h.6,7 After completion of the Hofmann-type re-
arrangement was confirmed by thin-layer chromatography,8
PtCl2, ethanol, and triethylamine were added. Et3N was used
to neutralize the acetic acid formed during the reaction. This
reaction did not proceed sufficiently, and a large amount of 3
remained (entry 1). Successful cyclization to indole 2a with
Results and Discussion
Examination of Reaction Conditions. First, we examined
the reaction conditions using 2-(1-hexynyl)benzamide 1a.
The results are shown in Table 1. Two basic procedures were
(3) Okamoto, N.; Miwa, Y.; Minami, H.; Takeda, K.; Yanada, R. Angew.
Chem., Int. Ed. 2009, 48, 9693–9696.
(4) Indole synthesis with 2-alkynylaryl isocyanates: (a) Kamijo, S.;
Yamamoto, Y. J. Org. Chem. 2003, 68, 4764–4771. (b) Kamijo, S.; Yamamoto,
Y. Angew. Chem., Int. Ed. 2002, 41, 3230–3233.
(6) Isocyanates prepared with hypervalent iodine reagents: (a) Liu, W.;
Buck, M.; Chen, N.; Shang, M.; Taylor, N. J.; Asoud, J.; Wu, X.; Hasinoff,
B. B.; Dmitrienko, G. I. Org. Lett. 2007, 9, 2915–2918. (b) Moriarty, R. M.;
Chany, C. J., II; Vaid, R. K.; Prakash, O.; Tuladhar, S. M. J. Org. Chem.
1993, 58, 2478–2482.
(5) Alkylideneoxindole synthesis with 2-alkynylaryl isocyanates: (a) Miura,
T.; Toyoshima, T.; Takahashi, Y.; Murakami, M. Org. Lett. 2009, 11, 2141–
2143. (b) Miura, T.; Toyoshima, T.; Takahashi, Y.; Murakami, M. Org. Lett.
2008, 10, 4887–4889. (c) Miura, T.; Takahashi, Y.; Murakami, M. Org. Lett.
€
2007, 9, 5075–5077. (d) Kamijo, S.; Sasaki, Y.; Kanazawa, C.; Schusseler, T.;
Yamamoto, Y. Angew. Chem., Int. Ed. 2005, 44, 7718–7721.
(7) Isocyanates prepared with triphosgene: (a) Fustero, S.; Chiva, G.;
Piera, J.; Sanz-Cervera, J. F.; Volonterio, A.; Zanda, M.; Ramirez de
Arellano, C. J. Org. Chem. 2009, 74, 3122–3132. (b) Alaoui, A. E.; Schmidt,
F.; Monneret, C.; Florent, J.-C. J. Org. Chem. 2006, 71, 9628–9636.
(8) Isocyanate was used without further purification because of its
instability.
7616 J. Org. Chem. Vol. 75, No. 22, 2010

Okamoto et al.
JOCArticle
TABLE 2. Tandem Indole Formation from 2-Alkynylbenzamide with
Alcohol as Nucleophile
SCHEME 4. Plausible Mechanism for Indole Formation
PtCl2
PdCl2
time
(h)
yield time yield
(%)
entry
1
R1
R2
Et
R3
2
(%)
(h)
1
2
1b n-Bu
1c n-Bu
1d n-Bu
1e Ph
F
2b 2.0
84
91
82
84
66
100
33
0a
2.7
5.5
1.8
6.0
1.7
1.8
6.0
4.0
1.3
1.8
61
48
63
36
62
78
dec
0b
Et
Et
Et
Et
NO2 2c 2.0
OMe 2d 2.0
3
4
H
H
H
H
H
H
H
H
H
2e 2.5
2f 1.0
2g 2.0
2h 6.0
2i 3.0
2j 1.0
2k 3.0
5
1f p-Tol
6
1g -(CH2)3OTs Et
1h
7
H
Et
Et
8
1i TMS
1a n-Bu
1a n-Bu
9
10
Bn
t-Bu
Et
90
34
86
48
-
11c 1e Ph
12d 1e Ph
2e 20 min 83
2e 2.0 97
Et
-
aDesilylated product 2h was obtained in 66% yield. bCarbamate
3 (R1 = TMS, R2 = Et) was produced in 45% yield. cUnder microwave
irradiation at 100 °C. dUnder microwave irradiation in EtOH at 60 °C.
(entry 9), although the use of tert-butyl alcohol resulted in
only 34% yield of 2k, probably due to the steric hindrance
of the bulky nucleophile (entry 10). We previously reported
microwave-promoted tandem one-pot synthesis of isoquino-
lines.10 In expectation of shorter reaction time, microwave
irradiation was applied for this tandem indole synthesis. The
reaction of 1e, PhI(OAc)2, PtCl2, and EtOH in DCB under
microwave irradiation was completed within 20 min at 100 °C
to give the desired indole 2e (entry 11). The reaction in EtOH
under microwaveirradiationat60°C alsogave2ein high yield
(entry 12).
A plausible mechanism for the formation of indoles 2 is
depicted in Scheme 4. Reaction of the 2-alkynylbenzamides 1
with PhI(OAc)2 probably leads to the formation of the
N-(phenyliodonio)intermediates E. Hofmann-type rearrange-
ment generates isocyanate intermediates C, which then
undergo electrophilic addition to alcohols to afford carba-
mates 3. Intramolecular nucleophilic addition of the result-
ing carbamate nitrogen to π-coordinated activated alkyne
with Pt(II) or Pd(II) affords the desired indoles 2 through
intermediate F.
We applied our one-pot tandem reaction to the synthesis
of 2,3-disubstituted indoles. Sakamoto reported the synth-
esis of 2,3-disubstituted indoles from 2-ethynylphenylcarba-
mates and alkenes using Pd(II)-catalyzed cyclization.11 After
carbamate formation derived from amide 1a, PdCl2, CuCl2,
methyl acrylate, and TBAF were added. The solution
was stirred for 18 h at 60 °C. Unfortunately, the desired
2,3-disubstituted indole 4 was obtained only in 26% yield
accompanied by 2-substituted indole 2a in 65% yield
(Scheme 5). The reason why the predominant formation of
2a is unclear.
0.1 equiv of PtCl2 proceeded under an acidic reaction con-
ditions (entry 2). To simplify the method, a one-pot reaction
was developed. When a solution of 1a in DCB in the presence
of PhI(OAc)2, PtCl2, and ethanol was heated at 100 °C for 30
min, 2a was obtained in 85% yield (entry 3). PdCl2 and InBr3
(0.2 equiv) showed catalytic activity similar to that of PtCl2
but required longer reaction times (entry 3 versus entries
5 and 7). Only carbamate 3 was produced when 0.1 equiv of
InBr3 was used in a shorter reaction time (entry 6). The use
of Pd(OAc)2, CuCl2, and Cu(OTf)2, which have been used
in previous studies for intramolecular hydroamination of
2-alkynylaniline derivatives,1,2 gave unsatisfactory results
(entries 8-10).
Tandem Reactions with Alcohols As Nucleophiles. Having
in hand the optimized conditions for the cyclization step, we
next examined the scope of this tandem reaction for various
2-alkynylbenzamides 1a-1i using PtCl2 and PdCl2 as cata-
lysts (Table 2). In comparison with the reaction catalyzed by
PdCl2, the reaction with PtCl2 proceeded smoothly and gave
the corresponding indoles in better yields except for entry 10.
Reaction efficiency was not affected by the substitution
pattern on the aromatic ring in the presence of either
electron-withdrawing groups or electron-donating groups.
The yields of the indole products 2 were within the range of
82-91% (entries 1-3). Alkynylbenzamides 1, bearing aro-
matic or aliphatic substituents on the acetylene terminus,
gave the corresponding indoles 2 in good to excellent yields
(entries 4-6). Unfortunately, terminal alkyne 1h was not
suitable for this reaction, resulting in 33% yield of 2h
(entry 7). This result may be due to the known dimerization
of terminal acetylenes with PhI(OAc)2.9 The reaction of tri-
methylsilyl derivative 1i resulted in desilylation to furnish 2h
in 66% yield (entry 8). Using benzyl alcohol as the nucleo-
phile, N-Cbz-protected indole was obtained in good yield
To further extend our tandem Hofmann-type rearrangement
and cyclization strategy, the procedure was applied to the con-
struction of dihydroisoquinolines 6 from 2-alkynylbenzylamides
5, which are one-carbon homologues of 2-alkynylbenzamides 1.
(10) Okamoto, N.; Sakurai, K.; Ishikura, M.; Takeda, K.; Yanada, R.
Tetrahedron Lett. 2009, 50, 4167–4169.
(9) (a) Zhdankin, V. V.; Stang, P. J. Chem. Rev. 2002, 102, 2523–2584.
(b) Stang, P. J.; Zhdankin, V. V. Chem. Rev. 1996, 96, 1123–1178.
(11) Yasuhara, A.; Takeda, Y.; Suzuki, N.; Sakamoto, T. Chem. Pharm.
Bull. 2002, 50, 235–238.
J. Org. Chem. Vol. 75, No. 22, 2010 7617

Okamoto et al.
JOCArticle
SCHEME 5. Attempted 2,3-Disubstituted Indole Synthesis
TABLE 4. Macrocyclic Bis(yne carbamate) Synthesis
entry
7
conc. (M)
time (h)
8
yield (%)
1
2
3
4
5
6
7
8
7a
7a
7a
7a
7a
7b
7b
7b
0.005
0.01
0.05
0.1
5
5
2
1
1
5
5
3
8a
8a
8a
8a
8a
8b
8b
8b
39
62
62
48
35
39
62
38
0.5
0.005
0.01
0.05
TABLE 3. Tandem Dihydroisoquinoline Formation from 2-Alkynyl-
benzylamide
entry
5
R1
Ph
Ph
Ph
p-Tol
p-Tol
n-Bu
n-Bu
R2
time (h)
6
yield (%)
1
2
3
4
5
6
7
5a
5a
5a
5b
5b
5c
5c
Et
1
1
1
1
1
3
1
6a
6b
6c
6d
6e
6f
86
92
92
82
82
66
73
Me
Bn
Et
Bn
Et
FIGURE 1. B3LYP/6-31G* geometry of intermediate G.
Bn
6g
SCHEME 6. Macrocyclic Bis(indole) Synthesis from
Macrocyclic Bis(yne carbamate)
The reactions of 5 with different alcohols proceeded smoothly
under the same reaction conditions to furnish the desired
isoquinolines 6 in high yields (Table 3, entries 1-7). The
structures of 6 were confirmed by X-ray crystallographic
analysis of compound 6c.12 Cyclization occurred via a
6-endo mode to produce 6 as the sole product; 5-exo-cyclized
products were not obtained at all. The indoles and isoqui-
nolines synthesized contain enecarbamate frameworks, which
are attractive synthetic intermediates owing to their applicability
to synthetic transformations.13
We became interested in determining whether 2-alkynylben-
zamides bearing a ω-(hydroxy)alkyl group 7a and 7b would
undergo intermolecular or intramolecular carbamate formation.
The tandem reaction was examined at 130 °C with various
concentrations of the reactant 7(Table 4). Eighteen- and twenty-
membered ring compounds, bis(yne carbamate) 8, were ob-
tained in 35-62% yields. The optimal concentration for the
production of 8 was found to be between 0.01 and 0.05 M
(entries 2, 3, and 7); the structure of 8a was confirmed by
X-ray crystallography.12 It was found that the reaction using
7 bearing a ω-(hydroxy)alkyl group proceeded with only
intermolecular reaction to give dimerized carbamates 8 with-
out intramolecular carbamate formation.
The facile formation of the dimers led us to search for a stable
ground-state conformation of monocarbamate intermediate G,
a product from the bimolecular coupling process of compound
7a, by quantum chemical calculations. Geometry optimizations
were carried out at the B3LYP level with the 6-31G* basis set
(Figure 1). The hydrogen atom of the hydroxyl group was placed
near the oxygen atom of the isocyanate group of intermediate G
˚
(OfH distance: 2.142 A), providing an easy access to bis(yne
carbamate) 8a.14
(12) CCDC 745937 (6c), CCDC 745938 (8a), CCDC 745939 (9a), and
CCDC 770817 (9f) contain the supplementary crystallographic data for this
paper. These data can be obtained free of charge from the Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
We then confirmed that bis(yne carbamate) 8a and 8b were
converted into bis(indole) 9a and 9b by Pt(II)-catalyzed
transannular hydroaminations (Scheme 6).15
€
(13) (a) Gross, U.; Nieger, M.; Brase, S. Org. Lett. 2009, 11, 4740–4742.
(b) Deng, H.; Yang, X.; Tong, Z.; Li, Z.; Zhai, H. Org. Lett. 2008, 10, 1791–
€
1793. (c) Guin, J.; Frohlich, R.; Studer, A. Angew. Chem., Int. Ed. 2008, 47,
(14) Calculations were performed on the Spartan 06: Spartan 06 (Ver.
1.0.1 for Mac), Wavefunction, Inc, Irvine, CA.
779–782. (d) Sivaguru, J.; Solomon, M. R.; Poon, T.; Jockusch, S.; Bosio,
S. G.; Adam, W.; Turro, N. J. Acc. Chem. Res. 2008, 41, 387–400. (e) Su, S.;
Porco, J. A., Jr. Org. Lett. 2007, 9, 4983–4986. (f) Harrison, T. J.; Patrick,
B. O.; Dake, G. R. Org. Lett. 2007, 9, 367–370. (g) De Faria, A. R.; Salvador,
E. L.; Correia, C. R. D. J. Org. Chem. 2002, 67, 3651–3661. (h) Severino,
E. A.; Correia, C. R. D. Org. Lett. 2000, 2, 3039–3042.
(15) (a) Han, C.; Rangarajan, S.; Voukides, A. C.; Beeler, A. B.; Johnson,
R.; Porco, J. A., Jr. Org. Lett. 2009, 11, 413–416. (b) Fleming, J. J.;
McReynolds, M. D.; Bois, J. D. J. Am. Chem. Soc. 2007, 129, 9964–9975.
(c) Sakai, N.; Ridder, A.; Hartwig, J. F. J. Am. Chem. Soc. 2006, 128, 8134–
8135. (d) Surprenant, S.; Lubell, W. D. Org. Lett. 2006, 8, 2851–2854.
7618 J. Org. Chem. Vol. 75, No. 22, 2010

Okamoto et al.
JOCArticle
SCHEME 7. Macrocyclic Bis(indole) Synthesis
Finally, we applied the stepwise procedure to tandem
macrocyclic bis(indole) synthesis. Treatment of a 0.05 M solu-
tion of amides 7 with PhI(OAc)2 at 130 °C for 1.5 h, followed by
cyclization with PtCl2 at 100-140 °C for 0.5-4.5 h, afforded
the desired indoles 9 via macrocyclic bis(yne carbamate) inter-
mediates 8. The yields of 9a-e were moderate due to the for-
mation of a complex mixture (Scheme 7). For example, trimeric
indole 9f was obtained in 8% yield from 7a. The structures of
compounds 9a and 9f were also confirmed by X-ray crystal-
lography.12 Under microwave irradiation conditions, the tan-
dem one-pot formation of macrocyclic indole 9a from 7a at
130 °C was also completed within 30 min (first step) and within
10 min (second step) in 40% yield. These macrocyclic com-
pounds16 have been the subject of recent interest because of their
potential biological activities.17
TABLE 5. Tandem Indole Formation from 2-Allylbenzamide
additive
(equiv)
entry
catalyst
time (h)
yield (%)
11 (82)
11 (86)
1
2
3
4
5
6
AuClPPh3/AgOTf
PtCl2
PtCl2
2.5
1.0
5.5
4.0
5.0
2.0
11 (84) þ 12 (16)
PdCl2
PdCl2
PdCl2
12 (94)
13 (46)
13 (53)
CuCl2 (1)
CuCl2 (2)
We expected that the same reaction would occur for
2-allylbenzamide 10 in the presence of an oxidant.18
AuClPPh3/AgOTf- or PtCl2-catalyzed reaction in 1,2-di-
chloroethane (DCE) afforded only carbamate 11 (Table 5,
entries 1 and 2). In the case of a longer reaction time with
PtCl2, only isomerization of the double bond of carbamate
11 occurred to give a mixture of 11 and 12 (entry 3). This
isomerization was accelerated by PdCl2 (entry 4). When 1
equiv of CuCl2 was added in order to reoxidize Pd(0), indole
13 was obtained in 46% yield (entry 5). With an increase in
the amount of CuCl2, the reaction was completed within 2 h,
but the yield of 13 remained moderate (53%) (entry 6).19 We
have demonstrated the synthesis of ethyl 2-methyl-1H-in-
dole-1-carboxylate 13 via tandem Hofmann-type rearrange-
ment of 2-allylbenzamide 10, carbamate formation, and
continuous oxidative amino cyclization.
Tandem Reactions with Amines As Nucleophiles. Next, we
investigated the synthesis of indole N-carboxyamide deriva-
tives using amines as nucleophiles toward isocyanates.20
Indole N-carboxyamides are found in biologically active
compounds such as 5-hydroxytryptamine (5-HT3) receptor
antagonists21 and endothelin-A (ET-A) receptor antago-
nists.22 PtCl2 and PdCl2 as catalysts for the aminocyclization
were examined, and the results are shown in Table 6.
Although alcohols were added together with 2-alkynylben-
zamide and the catalyst, amines were added after isocyanate
formation to avoid the amine being oxidized by PhI(OAc)2.
The reaction catalyzed by PtCl2 gave better yields of desired
products than that catalyzed by PdCl2. However, a longer
reaction time than the time for reaction using alcohols was
required. It was assumed that the decrease of catalytic
activity was caused by excess amine. When aniline was used
as the nucleophile, 2-butyl-1H-indole was obtained together
with the desired indole 14a (entry 1). The formation of 1H-
indole was suppressed by addition of CuBr, leading to a
better yield, although the reason is unclear (entry 2). Ben-
zylamine, allylamine, S-methyl-L-cysteine methyl ester,
2-phenylethylamine, and cyclohexylamine also reacted with
the isocyanate intermediate to give indole N-carboxyamides
14b-f in moderate to good yields (entries 3-7). The reaction
(16) (a) Carrick, J. D.; Jennings, M. P. Org. Lett. 2009, 11, 769–772.
(b) Demeter, D.; Blanchard, P.; Allain, M.; Grosu, I.; Roncali, J. J. Org.
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TABLE 6. Tandem Indole N-Carboxyamide Formation from 2-(1-Hexynyl)benzamide
entry
catalyst
RNH2
RNH2 (eq.)
solvent
temp (°C)
time (day)
yield (%) of 14
1
PtCl2
PtCl2
PtCl2
PtCl2
PtCl2
PtCl2
PtCl2
PtCl2
PtCl2
PtCl2
PtCl2
PtCl2
PdCl2
PdCl2
PdCl2
aniline
aniline
benzylamine
allylamine
S-methyl-L-cysteine methyl ester
2-phenylethylamine
cyclohexylamine
diethylamine
2-iodoaniline
2-toluidine
4-aminobenzonitrile
benzylamine
aniline
benzylamine
allylamine
1.2
1.2
3.0
3.0
1.2
3.0
3.0
3.0
1.2
1.2
1.2
3.0
3.0
3.0
3.0
DCB
DCB
DCB
DCB
DCB
DCB
DCE
DCB
DCB
DCE
DCE
DCB
DCB
DCB
DCB
70
70
2.0
1.3
4.0
7.0
5.0
1.6
4.0
2.7
15.0 h
3.0 h
2.5 h
5.0 h
0.3
75 (14a)a
82 (14a)
91 (14b)
63 (14c)
98 (14d)
80 (14e)
87 (14f)
0c
72 (14g)
73 (14h)
75 (14i)
84 (14b)
44 (14a)e
71 (14b)
60 (14c)
2b
3
100
100
100
100
100
100
70
70
70
100
100
100
100
4
5
6
7
8
9b
10b
11b
12d
13
14
15
3.0
1.0
a2-Butyl-1H-indole was obtained in 15% yield. bCuBr (0.1 equiv) was used as additive. c1,1-Diethyl-3-(2-(hex-1-ynyl)phenyl)urea 15 was obtained in
92% yield. dUnder microwave irradiation. e2-Butyl-1H-indole was obtained in 25% yield.
SCHEME 8
SCHEME 9. Synthesis of Carbamoyl Ylide
G-quadruplex ligands by using copper(I)-catalyzed “click”
chemistry.23 Although the second step of the indole formation
was very slow and required an additional 0.1 equivalent of PtCl2,
bis-indole 18 was obtained in 76% yield (Scheme 9).
Tandem Reactions with Phosphonium Ylides As Nucleo-
philes. Finally we tried the reaction using stabilized phospho-
nium ylides as carbon nucleophiles. Since AcOH was formed in
the Hofmann-type rearrangement step, anionic nucleophiles
such as enolate and organometallic reagents (RLi, RMgX) could
not be used. Therefore, we focused on stabilized phosphonium
ylide that could be used without base. It has been reported that
stabilized phosphonium ylides react with phenyl isocyanate to
form the carbamoyl stabilized ylides.24 After formation of the
isocyanate intermediate was complete, phosphonium ylide was
added and the reaction mixture was stirred at 70 °C to give
carbamoyl stabilized ylide 19 in 76% yield (Scheme 9). Next we
also tried the tandem reaction. 2-(1-Hexynyl)benzamide 1a
could be converted into indole ylides 20a-20d in 72-89% yields
by a one-pot tandem procedure, in which PtCl2 catalyst was
used (Table 7, entries 1-4). The reaction with (triphenylphos-
phoranylidene)acetaldehyde gave only a complex mixture
(entry 5). Indole ylide 20a could be converted into the
corresponding β-keto ester with Al/Hg25 or subjected to
ozonolysis to give R,β-diketo ester.26
with diethylamine did not proceed to give only 1,1-diethyl-
3-(2-(hex-1-ynyl)phenyl)urea intermediate 15 in 92% yield
(entry 8). It should be noted that the reactions with 2-iodoaniline,
2-toluidine, and 4-aminobenzonitrile which have ortho or para
substituents were completed in considerably shorter reaction
times than that with other amines (entries 9-11). We observed
enhancement of the rate when the reaction was run under
microwave irradiation as well as in the case of the reaction with
alcohol as the nucleophile (entry 3 versus entry 12).
The same tendency was observed when 2-alkynylaniline was
used. The formation of monoindole 16 was complete in 2.5 h
(Scheme 8). In the absence of PtCl2, indole formation did
not occur, and symmetrical 1,3-bis(ethynylphenyl)urea 17 was
obtained. This urea 17 could be used for the synthesis of
(23) Drewe, W. C.; Neidle, S. Chem. Commun. 2008, 5295–5297.
(24) Aitken, R. A.; Al.-Awadi, N. A.; Dawson, G.; El.-Dusouqi, O. M. E.;
Farrell, D. M. M.; Kaul, K.; Kumar, A. Tetrahedron 2005, 61, 129–135.
(25) Benetti, S.; Romagnoli, R.; Risi, C. D.; Spalluto, G.; Zanirato, V.
Chem. Rev. 1995, 95, 1065–1114.
(26) Rubin, M. B.; Gleiter, R. Chem. Rev. 2000, 100, 1121–1164.
7620 J. Org. Chem. Vol. 75, No. 22, 2010

Okamoto et al.
JOCArticle
TABLE 7. Tandem Indole Ylide Formation from 2-(1-Hexynyl)-
benzamide
Ethyl 2-(3-Tosyloxy)propyl)-1H-indole-1-carboxylate (2g).
The reaction mixture was chromatographed on silica gel [AcOEt-
hexane (1:3)] to afford 2g as a white solid: mp 71-72 °C
(colorless needles from CHCl3); 1H NMR (CDCl3) δ 8.06 (1H,
d, J = 8.2 Hz), 7.79 (2H, d, J = 8.2 Hz), 7.41 (1H, d, J = 6.9 Hz),
7.32 (2H, d, J = 8.2 Hz), 7.26-7.19 (2H, m), 6.23 (1H, s), 4.48
(2H, q, J = 7.2 Hz), 4.11 (2H, t, J = 6.2 Hz), 3.06 (2H, t, J = 7.2
Hz), 2.44 (3H, s), 2.08-2.04 (2H, m), 1.48 (3H, t, J = 7.2 Hz);
13C NMR (CDCl3) δ 151.8, 144.8, 139.8, 136.5, 133.0, 129.8,
129.2, 127.9, 123.7, 123.0, 119.9, 115.7, 108.6, 69.6, 63.2, 28.1,
25.8, 21.7, 14.3; IR (CHCl3, cm-1) 3008, 1730, 1456, 1379, 1360,
1325, 1190, 1175, 1096, 928, 810, 692; MS (EI) m/z = 401 (Mþ);
HRMS (EI) m/z calcd for C21H23NO5S 401.1297, found
401.1297.
entry
R
time (day)
yield (%)
1
2
3
4
5
CO2Me
COPh
COMe
CN
0.6
0.9
1.8
3.5
2.0
89 (20a)
80 (20b)
77 (20c)
72 (20d)
0
CHO
Benzyl 2-Butyl-1H-indole-1-carboxylate (2j). The reaction
mixture was chromatographed on silica gel [AcOEt-hexane
(1:20)] to afford 2j as a pale yellow oil: 1H NMR (CDCl3) δ 8.08
(1H, d, J = 8.9 Hz), 7.49 (2H, d, J = 6.2 Hz), 7.44-7.36 (4H, m),
7.21-7.17 (2H, m), 6.35 (1H, s), 5.45 (2H, s), 2.97 (2H, t, J =
7.6 Hz), 1.65-1.60 (2H, m), 1.39-1.33 (2H, m), 0.91 (3H, t, J =
7.6 Hz); 13C NMR (CDCl3) δ 151.9, 142.6, 136.5, 135.0, 129.6,
128.8, 128.7, 128.7, 123.4, 122.9, 119.7, 115.7, 107.6, 68.7, 31.0,
29.8, 22.5, 14.0; IR (CHCl3, cm-1) 3034, 2959, 2932, 1732, 1570,
1456, 1392, 1325, 1258, 1196, 1119, 1078, 689; MS (EI) m/z =
307 (Mþ); HRMS (EI) m/z calcd for C20H21NO2 307.1572,
found 307.1571.
(E)-Ethyl 2-Butyl-3-(3-methoxy-3-oxoprop-1-enyl)-1H-in-
dole-1-carboxylate (4). A solution of 2-alkynylbenzamide 1a
(0.05 mmol), PhI(OAc)2 (0.06 mmol), and ethanol (0.15 mmol)
in 1,2-dichlorobenzene (0.5 mL) was stirred at 100 °C for 1 h,
and then PdCl2 (0.005 mmol), CuCl2 (0.1 mmol), TBAF (1 M
solution in THF, 0.06 mmol), and methyl acrylate (0.15 mmol)
was added, and the mixture was stirred at 60 °C for 18 h. The
reaction mixture was directly chromatographed on silica gel
[AcOEt-hexane (1:30)] to afford the indole 4 as a yellow oil: 1H
NMR (CDCl3) δ 8.16-8.14 (1H, m), 7.93 (1H, d, J = 16.2 Hz),
7.84-7.83 (1H, m), 7.34-7.31 (2H, m), 6.57 (1H, d, J = 16.2
Hz), 4.55 (2H, q, J = 7.1 Hz), 3.84 (3H, s), 3.20 (2H, t, J =
7.9 Hz), 1.65-1.41 (7H, m), 0.95 (3H, t, J = 7.2 Hz); 13C NMR
(CDCl3) δ 168.2, 151.5, 145.4, 136.4, 136.3, 127.2, 124.5, 123.8,
119.7, 117.0, 115.8, 114.9, 63.6, 51.6, 32.4, 26.6, 22.7, 14.3, 13.9;
IR (CHCl3, cm-1) 3036, 3009, 2959, 1736, 1628, 1545, 1477,
1456, 1435, 1398, 1373, 1342, 1323, 1281, 1238, 1194, 1175, 1163,
1144, 1123, 1015, 976, 810; MS (EI) m/z = 329 (Mþ); HRMS
(EI) m/z calcd for C19H23NO4 329.1627, found 329.1631.
General Procedure for the Preparation of Dihydroisoquinoline
Carbamate. To a solution of 2-alkynylbenzylamide 5 (0.05
mmol), PhI(OAc)2 (0.06 mmol), and PtCl2 (0.005 mmol) in
1,2-dichlorobenzene (0.5 mL) was added alcohol (0.15 mmol),
and the mixture was stirred at 100 °C. The reaction mixture was
directly chromatographed on silica gel to afford the dihydro-
isoquinoline 6.
Conclusions
In summary, we have developed a novel, concise, Pt(II)-
catalyzed, one-pot tandem synthesis of indoles and isoqui-
nolines via nucleophilic addition to isocyanates intermedi-
ates derived from Hofmann-type rearrangement of amides
with a hypervalent iodine reagent and intramolecular ami-
nocyclization. A variety of alcohols, amines, and stable
Wittig reagents as nucleophiles to the isocyanates gave
carbamates, ureas, and carbamoyl-stabilized ylides. Further-
more, C2-symmetrical macrocyclic bis(yne carbamate) was
efficiently synthesized by cyclodimerization of 2-(ω-hydroxy-
1-alkynyl)benzamides. This reaction discovery led to trans-
annular cyclization to provide macrocyclic bis(indole) in
moderate yields. We also noticed a significant enhancement
of the reaction rates of these tandem one-pot reactions under
microwave irradiation.
Experimental Section
General Procedure for the Preparation of Indole Carbamate.
To a solution of 2-alkynylbenzamide (0.05 mmol), PhI(OAc)2
(0.06 mmol), and PtCl2 (0.005 mmol) in 1,2-dichlorobenzene
(0.5 mL) was added the alcohol (0.15 mmol), and the mixture
was stirred at 100 °C. The reaction mixture was directly chro-
matographed on silica gel to afford the indole carbamate 2.
Ethyl 2-Butyl-6-fluoro-1H-indole-1-carboxylate (2b). The re-
action mixture was chromatographed on silica gel [AcOEt-
hexane (1:20)] to afford 2b as a white solid: mp 49-51 °C
1
(colorless plate from CHCl3); H NMR (CDCl3) δ 7.83 (1H,
dd, J = 11.0, 2.1 Hz), 7.34 (1H, dd, J = 8.2, 5.5 Hz), 6.95 (1H,
td, J = 9.1, 2.1 Hz), 6.32 (1H, s), 4.50 (2H, q, J = 7.2 Hz), 2.98
(2H, t, J = 7.6 Hz), 1.69-1.64 (2H, m), 1.49 (3H, t, J = 7.2 Hz),
1.47-1.41 (2H, m), 0.96 (3H, t, J = 7.2 Hz); 13C NMR (CDCl3)
δ 159.5, 151.8, 142.9, 136.7, 125.7, 120.0, 110.9, 107.0, 103.4,
63.2, 31.0, 29.7, 22.6, 14.3, 14.0; IR (CHCl3, cm-1) 3036, 3009,
2961, 2931, 1734, 1599, 1483, 1439, 1379, 1331, 1269, 1194, 1074,
854, 810; MS (EI) m/z = 263 (Mþ); HRMS (EI) m/z calcd for
C15H18FNO2 263.1322, found 263.1317.
Ethyl 3-Phenylisoquinoline-2(1H)-carboxylate (6a). The reac-
tion mixture was chromatographed on silica gel [AcOEt-
hexane (1:10)] to afford 6a as a yellow viscous oil: mp
1
114-115 °C (colorless plate from CHCl3-hexane); H NMR
(CDCl3) δ 7.49 (2H, d, J = 6.9 Hz), 7.37-7.20 (7H, m), 6.53
(1H, s), 4.92 (2H, s), 3.89 (2H, br), 0.74 (3H, br); 13C NMR
(CDCl3) δ 154.4, 140.2, 138.2, 132.5, 131.9, 128.2, 127.9, 127.7,
127.4, 126.0, 125.2, 125.1, 115.8, 61.8, 48.0, 13.8; IR (CHCl3,
cm-1) 3034, 3009, 1699, 1622, 1402, 1379, 1342, 1236, 1198,
1167, 1020, 980; MS (EI) m/z = 279 (Mþ); HRMS (EI) m/z calcd
for C18H17NO2 279.1259, found 279.1265.
Ethyl 2-Butyl-6-nitro-1H-indole-1-carboxylate (2c). The reac-
tion mixture was chromatographed on silica gel [AcOEt-hexane
(1:20)] to afford 2c as a yellow oil: H NMR (CDCl3) δ 9.02
1
(1H, s), 8.11 (1H, d, J = 8.2 Hz), 7.50 (1H, d, J = 8.2 Hz), 6.47
(1H, s), 4.58 (2H, q, J = 7.2 Hz), 3.07 (2H, t, J = 7.9 Hz),
1.74-1.69 (2H, m), 1.55 (3H, t, J = 7.2 Hz), 1.50-1.44 (2H, m),
0.99 (3H, t, J = 7.6 Hz); 13C NMR (CDCl3) δ 151.2, 148.7,
144.2, 135.2, 134.6, 119.5, 118.5, 112.2, 107.3, 63.9, 30.7, 29.9,
22.6, 14.3, 13.9; IR (CHCl3, cm-1) 2959, 1744, 1518, 1339, 1319,
1196, 1099, 837, 808; MS (EI) m/z = 290 (Mþ); HRMS (EI) m/z
calcd for C15H18N2O4 290.1267, found 290.1272.
Methyl 3-Phenylisoquinoline-2(1H)-carboxylate (6b). The re-
action mixture was chromatographed on silica gel [AcOEt-hexane
(1:10)] to afford 6b as a pale yellow solid: mp 113-116 °C (pale
yellow plate from CHCl3); 1H NMR (CDCl3) δ 7.50 (2H, d, J =
7.6 Hz), 7.38 (2H, t, J = 7.6 Hz), 7.33-7.20 (5H, m), 6.58
J. Org. Chem. Vol. 75, No. 22, 2010 7621

Okamoto et al.
JOCArticle
(1H, s), 4.91 (2H, s), 3.46 (3H, br); 13C NMR (CDCl3) δ 155.0,
140.0, 137.6, 132.5, 132.0, 128.3, 128.0, 127.7, 125.8, 125.3,
125.0, 116.2, 52.8, 48.2; IR (CHCl3, cm-1) 1703, 1449, 1360,
1198, 808, 687, 673; MS (EI) m/ z = 265 (Mþ); HRMS (EI) m/ z
calcd for C17H15NO2 265.1103, found: 265.1111.
NMR (CDCl3) δ 8.14 (1H, d, J = 8.2 Hz), 7.65 (1H, s), 7.34 (1H,
dd, J = 7.6, 1.4 Hz), 7.30 (1H, t, J = 7.9 Hz), 6.97 (1H, t, J = 7.6
Hz), 4.46 (2H, t, J = 5.5 Hz), 2.71 (2H, t, J = 6.5 Hz), 2.05-
2.00 (2H, m); 13C NMR (CDCl3) δ 153.0, 139.5, 131.0, 129.3,
122.4, 117.2, 111.6, 95.6, 77.3, 63.0, 26.8, 15.6; IR (CHCl3, cm-1
)
1732, 1601, 1582, 1522, 1454, 1308, 1236, 1198, 771, 746, 727;
MS (EI) m/z = 402 (Mþ); HRMS (EI) m/z calcd for C24H22-
N2O4 402.1580, found 402.1580. Crystals for X-ray diffrac-
tion analysis were obtained by recrystallization from CHCl3-
hexane.
Benzyl 3-Phenylisoquinoline-2(1H)-carboxylate (6c). The re-
action mixture was chromatographed on silica gel [AcOEt-
hexane (1:10)] to afford 6c as a yellow viscous oil: mp 143-
144 °C (colorless plate from CHCl3-hexane); 1H NMR (CDCl3)
δ 7.50 (2H, d, J = 7.6 Hz), 7.36-7.13 (11H, m), 6.55 (2H, br),
4.95 (2H, s), 4.90 (2H, br); 13C NMR (CDCl3) δ 154.3, 139.9,
138.0, 135.4, 132.5, 132.0, 128.5, 128.1, 128.0, 127.7, 127.6, 127.5,
126.1, 125.3, 125.1, 116.3, 67.8, 48.2; IR (CHCl3, cm-1) 3034, 1701,
1622, 1454, 1396, 1344, 1260, 1236, 1161, 1123, 968, 808; MS (EI)
m/z = 341 (Mþ); HRMS (EI) m/z calcd for C23H 19NO2 341.1416,
found 341.1408.
Ethyl 3-p-Tolylisoquinoline-2(1H)-carboxylate (6d). The reac-
tion mixture was chromatographed on silica gel [AcOEt-hexane
(1:10)] to afford 6d as a yellow viscous oil: mp 124-125 °C(colorless
prism from CHCl3-hexane); 1H NMR (CDCl3) δ 7.39 (2H, d, J =
8.2 Hz), 7.27-7.19 (4H, m), 7.17 (2H, d, J = 7.6 Hz), 6.50 (1H, s),
4.90 (2H, s), 3.91 (2H, br), 2.37 (3H, s), 0.79 (3H, br); 13C NMR
(CDCl3) δ 154.4, 140.3, 137.8, 135.2, 132.7, 131.9, 128.9, 127.6,
127.2, 125.9, 125.1, 125.0, 115.2, 61.8, 48.1, 21.3, 13.9; IR (CHCl3,
cm-1) 1697, 1454, 1400, 1377, 1342, 1260, 1117, 689; MS (EI)
m/ z = 293 (Mþ); HRMS (EI) m/ z calcd for C19H19NO2 293.1416,
found 293.1416.
Benzyl 3-p-Tolylisoquinoline-2(1H)-carboxylate (6e). The re-
action mixture was chromatographed on silica gel [AcOEt-hexane
(1:20)] to afford 6e as a yellow viscous oil: 1H NMR (CDCl 3) δ
7.39-7.14 (11H, m), 6.62 (1H, br), 6.52 (1H, s), 4.92 (4H, br),
2.38 (3H, s); 13C NMR (CDCl3) δ 137.9, 132.6, 129.1, 128.0,
127.7, 127.6, 127.3, 126.0, 125.1, 125.0, 115.5, 67.7, 48.2, 21.3;
IR (CHCl3, cm-1) 3034, 1701, 1620, 1512, 1485, 1454, 1441,
1396, 1344, 1310, 1260, 1198, 1161, 966; MS (EI) m/z = 355
(Mþ); HRMS (EI) m/z calcd for C24H21NO2 355.1572, found
355.1579.
Bis-yne Carbamate (8b). A solution of 7b (9.5 mg, 0.05 mmol)
and PhI(OAc)2 (16 mg, 0.05 mmol) in 1,2-dichlorobenzene
(1 mL) was stirred at 130 °C for 3 h. The reaction mixture was
directly chromatographed on silica gel [AcOEt-hexane-CHCl3
(1:20:20)] to afford 8b (3.6 mg, 38%) as a white solid: mp 208-
209 °C (colorless prisms from CHCl3-hexane); 1H NMR (CDCl3)
δ 8.25 (1H, d, J = 8.2 Hz), 7.79 (1H, s), 7.35 (1H, dd, J = 7.6,
1.4 Hz), 7.33-7.30 (1H, m), 6.98 (1H, t, J = 7.6 Hz), 4.42 (2H, t,
J = 5.5 Hz), 2.91 (2H, t, J = 5.2 Hz); 13C NMR (CDCl3) δ
152.7, 139.3, 131.2, 129.4, 122.5, 117.0, 111.2, 94.1, 77.0, 63.4,
20.6; IR (CHCl3, cm-1) 3389, 3036, 3009, 2965, 2928, 2359,
2342, 1734, 1582, 1533, 1518, 1458, 1339, 1308, 1242, 1067, 1042,
810; MS (EI) m/z = 374 (Mþ); HRMS (EI) m/z calcd for
C22H18N2O4 374.1267, found 374.1263.
Bis-indole (9a). A solution of 2-alkynylbenzylamide (10 mg,
0.05 mmol) and PhI(OAc)2 (16 mg, 0.05 mmol) in 1,2-dichloro-
benzene (1 mL) was stirred at 130 °C. After the solution was
stirred for 1 h, PtCl2 (1.3 mg, 0.005 mmol) was added, and
the mixure was stirred for 1 h at 130 °C. The reaction mixture
was directly chromatographed on silica gel [AcOEt-hexane-
CHCl3 (1:20:20)] to afford 9a (4.7 mg, 47%) as a white solid: mp
1
238-239 °C (colorless plates from CHCl3-hexane); H NMR
(CDCl3) δ 8.39 (1H, d, J = 8.2 Hz), 7.48 (1H, d, J = 7.6 Hz),
7.31 (1H, td, J = 7.6, 1.4 Hz), 7.24 (1H, t, J = 7.6 Hz), 6.45
(1H, s), 4.53 (2H, dd, J = 5.2 Hz), 3.27-3.24 (2H, m), 2.23-2.18
(2H, m); 13C NMR (CDCl3) δ 151.8, 139.6, 137.6, 129.3, 124.2,
123.3, 119.8, 116.0, 109.6, 67.8, 30.5, 29.2; IR (CHCl3, cm-1
)
3036, 3009, 1728, 1595, 1572, 1456, 1429, 1398, 1368, 1325, 1258,
1238, 1121, 1098, 1034, 812; MS (EI) m/z = 402 (Mþ); HRMS
(EI) m/z calcd for C24H22N2O4 402.1580, found 402.1584.
Bis-indole (9b). A solution of 2-alkynylbenzylamide (9.5 mg,
0.05 mmol) and PhI(OAc)2 (16 mg, 0.05 mmol) in 1,2-dichlor-
obenzene (1 mL) was stirred at 130 °C. After the solution was
stirred for 1.5 h, PtCl2 (1.3 mg, 0.005 mmol) was added, and the
mixure was stirred for 4.5 h at 130 °C. The reaction mixture was
directly chromatographed on silica gel [AcOEt-hexane-CHCl3
(1:20:20)] to afford 9b (4.2 mg, 45%) as a white solid: mp
Ethyl 3-Butylisoquinoline-2(1H)-carboxylate (6f). The reaction
mixture was chromatographed on silica gel [AcOEt-hexane
1
(1:20)] to afford 6f as a yellow oil: H NMR (CDCl3) δ 7.20
(1H, td, J = 7.4, 1.6 Hz), 7.16-7.12 (2H, m), 7.05 (1H, d, J = 6.9
Hz), 6.08 (1H, s), 4.71 (2H, s), 4.18 (2H, q, J = 7.1 Hz), 2.68 (2H,
t, J = 7.6 Hz), 1.54-1.50 (2H, m), 1.41-1.37 (2H, m), 1.28 (3H,
t, J = 7.2 Hz), 0.93 (3H, t, J = 7.2 Hz); 13C NMR (CDCl3) δ
153.8, 142.3, 132.5, 131.3, 127.6, 126.6, 124.8, 124.1, 114.9, 61.9,
48.0, 34.1, 30.7, 22.4, 14.5, 13.9; IR (CHCl3, cm-1) 1697, 1632,
1464, 1456, 1443, 1402, 1379, 1342, 1186, 1117, 662; MS (EI)
m/z = 259 (Mþ); HRMS (EI) m/z calcd for C16H21NO2
259.1572, found 259.1572.
1
216-217 °C (colorless plate from CHCl3-hexane); H NMR
(CDCl3) δ 8.08 (1H, d, J = 8.1 Hz), 7.47 (1H, d, J = 7.6 Hz),
7.23 (1H, td, J = 8.1, 1.4 Hz), 7.19 (1H, td, J = 7.6, 1.4 Hz), 6.51
(1H, s), 4.78 (2H, br), 3.55 (2H, br); 13C NMR (CDCl3) δ 151.1,
137.6, 137.3, 128.8, 124.3, 123.1, 120.0, 115.3, 110.3, 67.6, 29.3;
IR (CHCl3, cm-1) 3688, 3034, 1736, 1601, 1566, 1456, 1427,
1395, 1329, 1196, 1121, 1098, 1013, 810; MS (EI) m/z = 374
(Mþ); HRMS (EI) m/z calcd for C22H18N2O4 374.1267, found
374.1258.
Benzyl 3-Butylisoquinoline-2(1H)-carboxylate (6g). The reac-
tion mixture was chromatographed on silica gel [AcOEt-hexane
(1:20)] to afford 6g as a yellow oil: 1H NMR (CDCl3) δ
7.36-7.31 (5H, m), 7.22-7.11 (3H, m), 7.04 (1H, d, J = 6.9
Hz), 6.08 (1H, s), 5.16 (2H, s), 4.73 (2H, s), 2.63 (2H, br),
1.47-1.43 (2H, m), 1.30 (2H, br), 0.87 (3H, t, J = 7.2 Hz); 13
C
NMR (CDCl3) δ 153.6, 142.2, 136.0, 132.4, 131.3, 128.5, 128.3,
128.2, 127.6, 126.7, 124.8, 124.2, 115.2, 67.8, 48.2, 34.0, 30.7,
22.3, 13.9; IR (CHCl3, cm-1) 3009, 2959, 2930, 1697, 1634, 1456,
1398, 1344, 1281, 1238, 1184, 1117, 810; MS (EI) m/z = 321
(Mþ); HRMS (EI) m/z calcd for C21H23NO2 321.1729, found:
321.1727.
Bis-indole (9c). A solution of 7c (19 mg, 0.08 mmol) and
PhI(OAc)2 (26 mg, 0.08 mmol) in 1,2-dichlorobenzene (1.6 mL)
was stirred at 130 °C. After the solution was stirred for 1 h, PtCl2
(2.1 mg, 0.008 mmol) was added, and the mixure was stirred for
1 h at 130 °C. The reaction mixture was directly chromatog-
raphed on silica gel [AcOEt-hexane-CHCl3 (1:20:20)] to
Bis-yne Carbamate (8a). A solution of 2-alkynylbenzylamide
(10 mg, 0.05 mmol) and PhI(OAc)2 (16 mg, 0.05 mmol) in 1,2-
dichlorobenzene (5 mL) was stirred at 130 °C for 5 h. 1,2-
Dichlorobenzene was removed by vacuum distillation, and the
residue was purified by column chromatography on silica gel
[hexane-CHCl3 (1:10)] to afford 8a (6.2 mg, 62%) as a white
solid: mp 217 °C (colorless prism from CHCl3-hexane); 1H
1
afford 9c (5.7 mg, 31%) as a white solid: H NMR (CDCl3) δ
8.00 (1H, d, J = 2.1 Hz), 7.34 (1H, d, J = 8.2 Hz), 6.88 (1H, dd,
J = 8.2, 2.1 Hz), 6.37 (1H, s), 4.52 (2H, t, J = 5.2 Hz), 3.89 (3H,
s), 3.23 (2H, dd, J = 10.7, 6.5 Hz), 2.22-2.17 (2H, m); 13C NMR
(CDCl3) δ 157.6, 152.0, 138.5, 138.3, 122.9, 120.1, 112.5, 109.3,
100.4, 67.8, 55.7, 30.6, 29.2; IR (CHCl3, cm-1) 2963, 1724, 1614,
7622 J. Org. Chem. Vol. 75, No. 22, 2010

Okamoto et al.
JOCArticle
1574, 1489, 1441, 1400, 1368, 1323, 1277, 1196, 1238, 1167, 1098,
1034, 918, 810; MS (EI) m/z = 462 (Mþ); HRMS (EI) m/z calcd
for C26H26N2O6 462.1791, found 462.1784.
137.5, 135.4, 129.3, 129.0, 128.0, 122.5, 121.7, 120.3, 111.5,
104.5, 45.2, 31.0, 28.1, 22.5, 14.0; IR (CHCl3, cm-1) 3034,
3008, 2959, 2932, 2872, 1705, 1510, 1454, 1381, 1300, 1196,
779, 719; MS (EI) m/z = 306 (Mþ); HRMS (EI) m/z calcd for
C20H22N2O 306.1732, found 306.1740.
Bis-indole (9d). A solution of 7d (19 mg, 0.08 mmol) and
PhI(OAc)2 (26 mg, 0.08 mmol) in 1,2-dichlorobenzene (1.6 mL)
was stirred at 130 °C. After the solution was stirred for 1 h, PtCl2
(2.1 mg, 0.008 mmol) was added, and the mixure was stirred for
1 h at 130 °C. The reaction mixture was directly chromatog-
raphed on silica gel [AcOEt-CHCl3 (1:20)] to afford 9d (8.8
mg, 50%) as a white solid: 1H NMR (CDCl3) δ 8.13 (1H, dd, J =
10.7, 2.4 Hz), 7.38 (1H, dd, J = 8.2, 5.5 Hz), 7.00 (1H, td, J =
8.9, 2.7 Hz), 6.43 (1H, s), 4.54 (2H, t, J = 5.2 Hz), 3.26-3.23
(2H, m), 2.26-2.17 (2H, m); 13C NMR (CDCl3) δ 160.0, 151.6,
139.9, 125.4, 120.3, 120.2, 111.5, 111.3, 109.1, 103.7, 103.5, 99.9,
67.9, 30.4, 29.1; IR (CHCl3, cm-1) 3690, 1730, 1601, 1483, 1439,
1398, 1368, 1325, 1267, 1238, 1196, 1115, 1094, 926; MS (EI)
m/z = 438 (Mþ); HRMS (EI) m/z calcd for C24H20F2N2O4
438.1391, found 438.1391.
N-Allyl-2-butyl-1H-indole-1-carboxamide (14c): yellow oil;
1H NMR (CDCl ) δ 7.61 (1H, d, J = 8.2 Hz), 7.51 (1H, d,
3
J = 6.9 Hz), 7.21-7.14 (2H, m), 6.35 (1H, s), 6.03-5.97 (1H, m),
5.74 (1H, br), 5.35-5.32 (1H, m), 5.27-5.25 (1H, m), 4.13
(2H, t, J = 5.8 Hz), 2.96 (2H, t, J = 7.6 Hz), 1.72-1.67
(2H, m), 1.46-1.40 (2H, m), 0.95 (3H, t, J = 7.2 Hz); 13C
NMR (CDCl3) δ 152.2, 142.1, 135.4, 133.5, 129.3, 122.4,
121.7, 120.4, 117.5, 111.5, 104.4, 43.5, 31.0, 28.1, 22.5, 14.0;
IR (CHCl3, cm-1) 3445, 3389, 3009, 2961, 2930, 2874, 2862,
2359, 2340, 1709, 1670, 1607, 1585, 1518, 1454, 1381, 1300,
1238, 1175, 1105, 1074, 991, 810, 687; MS (EI) m/z = 256
(Mþ); HRMS (EI) m/z calcd for C16H20N2O 256.1576, found
256.1572.
Bis-indole (9e). A solution of 7e (11 mg, 0.05 mmol) and
PhI(OAc)2 (16 mg, 0.05 mmol) in 1,2-dichlorobenzene (1 mL)
was stirred at 130 °C. After the solution was stirred for 1 h, PtCl2
(1.3 mg, 0.005 mmol) was added, and the mixure was stirred for
1 h at 130 °C. The reaction mixture was directly chromatog-
raphed on silica gel [AcOEt-CHCl3 (1:20)] to afford 9e (5.7
mg, 52%) as a white solid: 1H NMR (CDCl3) δ 8.33 (1H, dd, J =
9.6, 4.8 Hz), 7.13 (1H, dd, J = 8.9, 2.7 Hz), 7.02 (1H, td, J = 9.1,
2.5 Hz), 6.42 (1H, s), 4.54 (2H, t, J = 5.2 Hz), 3.27-3.24 (2H,
m), 2.22 (2H, q, J = 9.2 Hz); 13C NMR (CDCl3) δ 158.8, 151.6,
141.2, 133.8, 130.2, 130.1, 117.00, 116.95, 111.8, 111.6, 109.3,
109.3, 105.3, 67.9, 30.3, 29.2; IR (CHCl3, cm-1) 3690, 1728,
1601, 1474, 1449, 1400, 1368, 1327, 1238, 1196, 1117, 1032, 810;
MS (EI) m/z = 438 (Mþ); HRMS (EI) m/z calcd for C24H20F2-
N2O4 438.1391, found 438.1394.
Trimeric indole (9f): white solid; mp 242 °C (white plates from
hexane-CHCl3); 1H NMR (CDCl3) δ 8.14 (1H, d, J = 8.2 Hz),
7.41 (1H, d, J = 7.6 Hz), 7.26-7.18 (2H, m), 6.39 (1H, s), 4.57
(2H, t, J = 6.5 Hz), 3.19 (2H, t, J = 7.6 Hz), 2.28-2.23 (2H, m);
13C NMR (CDCl3) δ 151.9, 140.1, 136.8, 129.2, 123.9, 123.1,
119.9, 115.7, 108.3, 66.7, 28.3, 26.9; IR (CHCl3, cm-1) 2926,
1730, 1456, 1400, 1325, 1198, 1119, 1094, 685; MS (EI) m/z =
603 (Mþ); HRMS (EI) m/z calcd for C36H33N3O6 603.2369,
found 603.2374.
(R)-Methyl 2-(2-butyl-1H-indole-1-carboxamido)-3-(methylthio)-
propanoate (14d): orange oil; 1H NMR (CDCl 3) δ 7.89 (1H, d,
J = 8.2 Hz), 7.51 (1H, d, J = 7.6 Hz), 7.26-7.23 (1H, m), 7.18
(1H, t, J = 6.9 Hz), 6.57 (1H, d, J = 7.6 Hz), 6.37 (1H, s), 4.98
(1H, td, J = 6.0, 4.6 Hz), 3.84 (3H, s), 3.20 (1H, dd, J = 14.4, 4.6
Hz), 3.10 (1H, dd, J = 14.4, 6.0 Hz), 2.98 (2H, t, J = 7.6 Hz),
2.15 (3H, s), 1.72-1.67 (2H, m), 1.46-1.40 (2H, m), 0.95 (3H, t,
J = 7.2 Hz); 13C NMR (CDCl3) δ 171.2, 151.8, 142.0, 135.6,
129.3, 122.9, 122.0, 120.3, 112.2, 105.2, 52.9, 36.5, 31.0, 28.2,
22.5, 16.2, 14.0; IR (CHCl3, cm-1) 3420, 3034, 3009, 2957, 2930,
2872, 1746, 1701, 1601, 1506, 1456, 1439, 1379, 1346, 1298, 1236,
1196, 1182, 1134, 1020, 833, 754; MS (EI) m/z = 348 (Mþ);
HRMS (EI) m/z calcd for C18H24N2O3S 348.1508, found
348.1504.
2-Butyl-N-phenethyl-1H-indole-1-carboxamide (14e): pale
1
yellow solid; H NMR (CDCl ) δ 7.46 (1H, d, J = 8.2 Hz),
3
7.36-7.33 (2H, m), 7.28-7.25 (3H, m), 7.22 (1H, d, J = 8.2 Hz),
7.10 (1H, t, J = 7.6 Hz), 7.05 (1H, t, J = 7.6 Hz), 6.30 (1H, s),
5.64 (1H, br), 3.79 (2H, q, J = 6.4 Hz), 3.02 (2H, t, J = 6.9 Hz),
2.89 (2H, t, J = 7.6 Hz), 1.68-1.63 (2H, m), 1.43-1.37 (2H, m),
0.94 (3H, t, J = 7.2 Hz); 13C NMR (CDCl3) δ 152.2, 141.9,
138.3, 135.3, 129.1, 128.9, 128.8, 126.9, 122.23, 121.5, 120.12,
111.5, 104.3, 42.0, 35.3, 30.9, 28.0, 22.5, 14.0; IR (CHCl3, cm-1
)
3435, 3036, 2959, 2932, 1705, 1508, 1454, 1381, 1302, 1238, 1194,
1128, 810, 691; MS (EI) m/z = 320 (Mþ); HRMS (EI) m/z calcd
for C21H24N2O 320.1889;, found 320.1881.
General Procedure for the Preparation of Indole Urea. A
solution of 2-alkynylbenzamide (0.05 mmol) and PhI(OAc)2
(0.06 mmol) in 1,2-dichlorobenzene (0.5 mL) was stirred at 70 °C
for 2 h. Then amine and PtCl2 (0.005 mmol) were added, and the
reaction mixture was stirred at the temperature listed in Table 6.
The reaction mixture was directly chromatographed on silica gel
to afford the indole urea.
2-Butyl-N-cyclohexyl-1H-indole-1-carboxamide (14f): white
solid; 1H NMR (CDCl 3) δ 7.57 (1H, d, J = 8.2 Hz), 7.50 (1H, d,
J = 7.6 Hz), 7.18 (1H, t, J = 7.6 Hz), 7.14 (1H, d, J = 7.2 Hz),
6.33 (1H, s), 5.57 (1H, d, J = 7.6 Hz), 3.95-3.90 (1H, m), 2.95
(2H, t, J = 7.6 Hz), 2.15-2.13 (2H, m), 1.81-1.77 (2H, m),
1.70-1.65 (3H, m), 1.49-1.39 (4H, m), 1.35-1.21 (3H, m), 0.94
(3H, t, J = 7.2 Hz); 13C NMR (CDCl3) δ 151.3, 141.9, 135.4,
129.2, 122.3, 121.5, 120.3, 111.3, 104.0, 50.0, 33.2, 31.1, 28.0,
25.4, 24.8, 22.5, 13.9; IR (CHCl3, cm-1) 3426, 3007, 2934, 2859,
1703, 1506, 1454, 1381, 1321, 1294, 1192, 1152, 1128; MS (EI)
m/z = 298 (Mþ); HRMS (EI) m/z calcd for C19H26N2O
298.2045, found 298.2038.
2-Butyl-N-phenyl-1H-indole-1-carboxamide (14a): white so-
lid; mp 110-111 °C (white needles from CHCl3); 1H NMR
(CDCl 3) δ 7.64 (1H, d, J = 7.6 Hz), 7.57 (2H, d, J = 7.6
Hz), 7.55 (1H, d, J = 6.9 Hz), 7.46 (1H, br), 7.42 (2H, t, J = 7.9
Hz), 7.24-7.18 (3H, m), 6.41 (1H, s), 3.01 (2H, t, J = 7.9 Hz),
1.75-1.70 (2H, m), 1.47-1.41 (2H, m), 0.95 (3H, t, J = 7.2 Hz);
13C NMR (CDCl ) δ 149.5, 142.2, 137.1, 135.4, 129.4, 124.9,
3
122.8, 122.1, 120.6, 119.7, 111.4, 105.0, 31.0, 28.0, 22.5, 14.0; IR
(CHCl3, cm-1) 3032, 3011, 2959, 2932, 2874, 1717, 1599, 1524,
1456, 1441, 1381, 1314, 1298, 1234, 1198, 808, 687; MS (EI)
m/z = 292 (Mþ); HRMS (EI) m/z calcd for C19H 20N2O 292.1576,
found 292.1582.
2-Butyl-N-(2-iodophenyl)-1H-indole-1-carboxamide (14g): white
solid; mp 104-108 °C (white needles from hexane-EtOAc); 1H
NMR (CDCl3) δ 8.29 (1H, dd, J = 8.2, 1.4 Hz), 7.92 (1H, br),
7.86 (2H, t, J = 8.2 Hz), 7.55 (1H, d, J = 7.6 Hz), 7.45-7.42
(1H, m), 7.27-7.20 (2H, m), 6.92 (1H, td, J = 7.6, 1.4 Hz), 6.44
(1H, s), 3.04 (2H, t, J = 7.6 Hz), 1.77-1.72 (2H, m), 1.48-1.42
(2H, m), 0.96 (3H, t, J = 7.6 Hz); 13C NMR (CDCl3) δ 149.6,
142.1, 139.3, 137.9, 135.4, 129.5, 129.4, 126.3, 122.9, 122.3,
121.4, 120.5, 112.3, 105.6, 89.5, 30.9, 28.3, 22.5, 14.0; IR
(CHCl3, cm-1) 3032, 1714, 1585, 1518, 1454, 1431, 1234, 1198,
808, 799, 768, 743; MS (EI) m/z = 418 (Mþ); HRMS (EI) m/z
calcd for C19H19IN2O 418.0542, found 418.0533.
N-Benzyl-2-butyl-1H-indole-1-carboxamide (14b): white solid;
1
mp 88-89 °C (white needles from hexane-EtOAc); H NMR
(CDCl ) δ 7.55 (1H, d, J = 8.9 Hz), 7.49 (1H, dd, J = 6.5,
3
2.4 Hz), 7.41-7.37 (4H, m), 7.34-7.31 (1H, m), 7.16-7.11
(2H, m), 6.34 (1H, s), 5.96 (1H, br), 4.67 (2H, d, J = 6.2 Hz),
2.96 (2H, t, J = 7.9 Hz), 1.69-1.64 (2H, m), 1.44-1.38 (2H, m),
0.93 (3H, t, J = 7.2 Hz); 13C NMR (CDCl3) δ 152.3, 142.0,
J. Org. Chem. Vol. 75, No. 22, 2010 7623

Okamoto et al.
JOCArticle
2-Butyl-N-o-tolyl-1H-indole-1-carboxamide (14h): pale yellow
solid; 1H NMR (CDCl3) δ 7.87 (1H, d, J = 7.6 Hz), 7.74 (1H, d,
J = 8.2 Hz), 7.55 (1H, d, J = 6.9 Hz), 7.32-7.15 (6H, m), 6.42
(1H, s), 3.02 (2H, t, J = 7.9 Hz), 2.34 (3H, s), 1.76-1.71 (2H, m),
1.47-1.41 (2H, m), 0.95 (3H, t, J = 7.2 Hz); 13C NMR (CDCl3)
δ 149.9, 142.3, 135.4, 135.1, 130.9, 129.4, 129.1, 127.1, 125.6,
122.7, 122.5, 122.0, 120.6, 111.4, 105.0, 31.0, 28.1, 22.5, 18.1,
13.9; IR (CHCl3, cm-1) 3009, 2959, 2932, 2872, 1717, 1589,
1521, 1489, 1454, 1381, 1304, 1250, 1186, 1123, 764, 691; MS
(EI) m/z = 306 (Mþ); HRMS (EI) m/z calcd for C20H22N2O
306.1732, found 306.1739.
Carbamoyl Ylide (19). A solution of 2-alkynylbenzamide 1a
(0.08 mmol) and PhI(OAc)2 (0.096 mmol) in 1,2-dichloroethane
(0.4 mL) was stirred at 70 °C for 1 h. Then, methyl (triphenyl-
phosphoranylidene)acetate (0.06 mmol) was added, and the
reaction mixture was stirred at 70 °C for 45 min. The reaction
mixture was directly chromatographed on silica gel [AcOEt-
hexane (1:3)] to afford 19 as a orange oil: 1H NMR (CDCl3) δ
11.39 (1H, s), 8.26 (1H, d, J = 8.9 Hz), 7.72 (6H, dd, J = 12.4,
7.6 Hz), 7.52 (3H, t, J = 7.2 Hz), 7.45 (6H, td, J = 7.6, 3.2 Hz),
7.32 (1H, d, J = 7.6 Hz), 7.05 (1H, t, J = 7.9 Hz), 6.80 (1H, t,
J = 7.6 Hz), 3.10 (3H, s), 2.61 (2H, t, J = 7.2 Hz), 1.74-1.69
(2H, m), 1.54-1.48 (2H, m), 0.95 (3H, t, J = 7.2 Hz); 13C NMR
(CDCl3) δ 169.64, 169.55, 168.38, 168.32, 142.2, 133.40, 133.3,
131.59, 131.57, 131.4, 128.5, 128.4, 128.1, 127.7, 127.0, 120.8,
119.1, 112.4, 97.1, 76.9, 57.8, 57.0, 49.2, 30.8, 22.2, 19.6, 13.8; IR
(CHCl3, cm-1) 3009, 1634, 1595, 1568, 1518, 1441, 1325, 1198,
1107; MS (EI) m/z = 533 (Mþ); HRMS (EI) m/z calcd for
C34H32NO3P 533.2120, found 533.2124.
Indole Ylide (20a). A solution of 2-alkynylbenzamide 1a
(0.08 mmol) and PhI(OAc)2 (0.096 mmol) in 1,2-dichloro-
ethane (0.4 mL) was stirred at 70 °C for 1 h, and then
methyl (triphenylphosphoranylidene)acetate (0.06 mmol)
was added. After the solution was stirred for 20 min, PtCl2
(0.008 mmol) was added, and the reaction mixture was stirred
at 70 °C for additional 13 h. The reaction mixture was directly
chromatographed on silica gel [AcOEt-hexane (1:3)] to
afford 20a as a orange oil: orange oil; 1H NMR (CDCl3)
δ 7.87 (1H, d, J = 8.2 Hz), 7.82 (6H, dd, J = 12.7, 7.2 Hz),
7.59-7.49 (9H, m), 7.45 (1H, d, J = 7.6 Hz), 7.11 (1H, t, J =
7.6 Hz), 7.05 (1H, t, J = 7.2 Hz), 6.29 (1H, s), 3.07-3.02 (1H,
m), 3.02 (3H, s), 2.94-2.89 (1H, m), 1.70-1.63 (2H, m),
1.37-1.43 (2H, m), 0.92 (3H, t, J = 7.6 Hz); 13C NMR
(CDCl3) δ 167.6, 167.5, 167.1, 167.0, 142.1, 137.2, 133.6,
133.5, 132.20, 132.18, 128.8, 128.7, 125.6, 125.0, 64.4, 63.6,
50.2, 30.9, 27.9, 22.5, 14.0; IR (CHCl3, cm-1) 3009, 1682,
1599, 1574, 1454, 1437, 1379, 1323, 1105; MS (EI) m/z = 533
(Mþ); HRMS (EI) m/z calcd for C34H32NO3P 533.2120,
found 533.2125.
2-Butyl-N-(4-cyanophenyl)-1H-indole-1-carboxamide (14i):
1
pale yellow solid; H NMR (CDCl3) δ 7.77 (1H, s), 7.70-7.66
(4H, m), 7.56 (2H, dd, J = 15.8, 7.6 Hz), 7.26-7.20 (2H, m), 6.42
(1H, s), 2.98 (2H, t, J = 7.6 Hz), 1.73-1.68 (2H, m), 1.47-1.41
(2H, m), 0.95 (3H, t, J = 7.2 Hz); 13C NMR (CDCl3) δ 149.2,
142.2, 141.3, 135.2, 133.5, 129.6, 123.1, 122.5, 120.8, 119.3,
118.6, 111.5, 107.6, 105.8, 30.8, 28.0, 22.5, 13.9; IR (CHCl3,
cm-1) 3410, 3036, 2961, 2932, 2874, 2228, 1721, 1609, 1589,
1564, 1520, 1514, 1456, 1408, 1377, 1317, 1300, 1240, 1194, 1179,
1119, 1074, 839, 687; MS (EI) m/z = 317 (Mþ); HRMS (EI) m/z
calcd for C20H19IN3O 317.1528, found 317.1536.
1,1-Diethyl-3-(2-(hex-1-ynyl)phenyl)urea (15): pale yellow oil;
1H NMR (CDCl3) δ 8.26 (1H, d, J = 8.2 Hz), 7.41 (1H, br), 7.33
(1H, d, J = 7.6 Hz), 7.25 (1H, t, J = 8.2 Hz), 6.89 (1H, t, J = 7.6
Hz), 3.41 (4H, q, J = 7.3 Hz), 2.47 (2H, t, J = 7.2 Hz), 1.63-
1.59 (2H, m), 1.51-1.45 (2H, m), 1.26 (6H, t, J = 7.2 Hz), 0.95
(3H, t, J = 7.2 Hz); 13C NMR (CDCl3) δ 154.1, 140.6, 131.3,
128.9, 121.3, 117.9, 111.6, 96.9, 76.5, 41.7, 30.9, 22.1, 19.3, 13.8,
13.6; IR (CHCl3, cm-1) 3412, 3007, 2967, 2934, 2874, 1659,
1580, 1524, 1520, 1489, 1447, 1400, 1383, 1364, 1304, 1261, 1163,
1098, 1080, 810, 671; MS (EI) m/z = 272 (Mþ); HRMS (EI) m/z
calcd for C17H24N2O 272.1889, found 272.1880.
2-Butyl-N-(2-(hex-1-ynyl)phenyl)-1H-indole-1-carboxamide
(16): yellow oil; 1H NMR (CDCl3) δ 8.55 (1H, s), 8.45 (1H, d,
J = 8.2 Hz), 7.86 (1H, d, J = 7.6 Hz), 7.54 (1H, d, J = 6.9 Hz),
7.43 (1H, dd, J = 7.6, 1.4 Hz), 7.37 (1H, t, J = 7.9 Hz), 7.22-
7.17 (2H, m), 7.08 (1H, t, J = 7.6 Hz), 6.42 (1H, s), 3.06 (2H, t,
J = 7.9 Hz), 2.30 (2H, t, J = 7.2 Hz), 1.77-1.72 (2H, m), 1.49-
1.36 (4H, m), 1.29-1.23 (2H, m), 0.96 (3H, t, J = 7.2 Hz), 0.78
(3H, t, J = 7.2 Hz); 13C NMR (CDCl3) δ 149.2, 142.4, 138.4,
135.3, 131.8, 129.4, 129.1, 123.6, 122.7, 122.1, 120.4, 118.3,
112.9, 111.8, 105.2, 98.7, 75.7, 30.9, 30.4, 28.2, 22.5, 22.0, 19.3,
14.0, 13.4; IR (CHCl3, cm-1) 3370, 3036, 3009, 2961, 2832, 2874,
2862, 2398, 1712, 1580, 1520, 1449, 1379, 1238, 1196, 1123, 928;
MS (EI) m/z = 372 (Mþ); HRMS (EI) m/z calcd for C25H28N2O
372.2202, found 372.2199.
Indole ylide (20b): brown solid; 1H NMR (CDCl3) δ
7.88 (1H, d, J = 8.2 Hz), 7.82-7.79 (6H, m), 7.58 (3H, t,
J = 7.6 Hz), 7.52-7.49 (6H, m), 7.13-7.05 (4H, m), 6.95 (2H,
q, J = 7.3 Hz), 6.81 (2H, t, J = 6.9 Hz), 5.81 (1H, s), 2.99-
2.94 (1H, m), 2.81-2.75 (1H, m), 1.64-1.54 (2H, m), 1.45-
1.39 (2H, m), 0.95 (3H, t, J = 7.2 Hz); 13C NMR (CDCl3) δ
192.8, 192.8, 167.2, 167.1, 141.6, 141.5, 141.4, 136.8, 133.8,
133.7, 132.2, 132.2, 128.9, 128.9, 128.9, 128.8, 126.6, 126.3,
125.8, 125.2, 121.5, 120.7, 119.0, 113.4, 103.4, 79.0, 78.3,
30.3, 28.8, 22.7, 14.1; IR (CHCl3, cm-1) 3063, 3007, 2959,
2932, 2872, 1624, 1584, 1551, 1539, 1483, 1454, 1439, 1319,
1238, 1194, 1163, 1105, 999, 908, 856, 810; MS (EI) m/z = 579
(Mþ); HRMS (EI) m/z calcd for C39H34NO2P 579.2327,
found 579.2330.
1,3-Bis(2-(hex-1-ynyl)phenyl)urea (17): white solid; mp 162-
1
165 °C (white needle from hexane-EtOAc); H NMR (CDCl3)
δ 8.05 (1H, d, J = 8.2 Hz), 7.38 (1H, d, J = 7.6 Hz), 7.30 (1H, t,
J = 7.9 Hz), 7.24 (1H, br), 7.00 (1H, t, J = 7.6 Hz), 2.39 (2H, t,
J = 7.2 Hz), 1.58-1.53 (2H, m), 1.48-1.42 (2H, m), 0.94 (3H, t,
J = 7.2 Hz); 13C NMR (CDCl3) δ 152.0, 139.1, 132.0, 128.9,
123.0, 119.5, 113.8, 97.7, 76.1, 30.8, 22.1, 19.3, 13.6; IR (CHCl3,
cm-1) 3391, 3007, 3961, 2934, 2874, 2862, 1690, 1605, 1580,
1518, 1317, 1300, 1194, 1105, 1042, 945; MS (EI) m/z = 372
(Mþ); HRMS (EI) m/z calcd for C25H28N2O 372.2202, found
372.2200.
Indole ylide (20c): brown solid; 1H NMR (CDCl3) δ 8.07
(1H, d, J = 7.6 Hz), 7.73 (6H, dd, J = 12.4, 7.6 Hz), 7.56-7.45
(10H, m), 7.16-7.10 (2H, m), 6.35 (1H, s), 3.04-2.89 (2H, m),
1.72-1.61 (2H, m), 1.58 (3H, s), 1.47-1.39 (2H, m), 0.93 (3H, t,
J = 7.2 Hz); 13C NMR (CDCl3) δ 193.1, 193.0, 166.2, 166.1,
141.9, 137.0, 133.4, 133.3, 132.0, 131.9, 129.0, 128.8, 128.7,
126.0, 125.3, 122.1, 121.2, 119.8, 112.6, 104.4, 83.0, 82.3, 30.7,
28.2, 26.5, 26.4, 22.6, 14.0; IR (CHCl3, cm-1) 3032, 3010, 2961,
2932, 2872, 1624, 1547, 1483, 1452, 1437, 1368, 1317, 1198, 1107,
1026, 928, 808; MS (EI) m/z = 517 (Mþ); HRMS (EI) m/z calcd
for C34H32NO2P 517.2171, found 517.2174.
Bis(2-butyl-1H-indol-1-yl)methanone (18): yellow oil; 1H
NMR (CDCl ) δ 7.49 (1H, d, J = 7.6 Hz), 7.13 (1H, t, J =
3
7.6 Hz), 6.99 (1H, t, J = 7.9 Hz), 6.70 (1H, d, J = 8.2 Hz), 6.52
(1H, s), 2.81-2.69 (2H, m), 1.68-1.63 (2H, m), 1.37-1.33 (2H,
m), 0.87 (3H, t, J = 7.6 Hz); 13C NMR (CDCl3) δ 149.1, 141.8,
136.3, 129.3, 123.6, 122.9, 120.1, 112.6, 107.9, 31.0, 27.5, 22.4,
13.7; IR (CHCl3, cm-1) 3078, 2961, 2932, 2874, 2862, 1707,
1568, 1520, 1454, 1379, 1335, 1302, 1196, 810; MS (EI) m/z =
372 (Mþ); HRMS (EI) m/z calcd for C25H28N2O 372.2202,
found 372.2200.
Indole ylide (20d): brown solid; 1H NMR (CDCl3) δ
7.79-7.76 (7H, m), 7.67 (3H, dd, J = 8.2, 6.9 Hz), 7.57 (6H,
td, J=7.9, 3.2 Hz), 7.47 (1H, d, J=7.6 Hz), 7.21 (1H, t, J=7.2
Hz), 7.10 (1H, t, J=6.9 Hz), 6.33 (1H, s), 2.95 (2H, t, J=7.6 Hz),
1.69-1.64 (2H, m), 1.42-1.36 (2H, m), 0.92 (3H, t, J=7.2 Hz);
7624 J. Org. Chem. Vol. 75, No. 22, 2010

Okamoto et al.
JOCArticle
Acknowledgment. This work was supported by a Grant-in-
Aid for Scientific Research(C) from JSPS KAKENHI (20590027).
13C NMR (CDCl3) δ 168.9, 168.8, 141.6, 135.9, 133.8, 133.7,
133.5, 133.5, 129.4, 129.3, 128.8, 122.9, 122.2, 121.8, 120.8,
120.1, 120.0, 119.7, 112.5, 104.1, 45.5, 44.6, 31.3, 27.7, 22.6,
13.9; IR (CHCl3, cm-1) 3063, 3007, 2959, 2932, 2872, 2183,
1610, 1582, 1485, 1454, 1439, 1379, 1329, 1194, 1109, 908; MS
(EI) m/z = 500 (Mþ); HRMS (EI) m/z calcd for C33H29N2OP
500.2018, found 500.2017.
Supporting Information Available: Experimental procedure
for general reaction and spectral data for all new compounds.
Crystallographic data for 6c, 8a, 9a, and 9f. This material is
available free of charge via the Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 75, No. 22, 2010 7625