Direct synthesis of fused indoles by gold-catalyzed cascade cyclization of diynes

Article abstract of DOI:10.1021/jo102507c

A direct, concise, and atom-economical synthetic method for the generation of fused indoles, using a gold-catalyzed cascade cyclization of diynes, has been developed. The reaction gave various fused indoles, such as aryl-annulated[a]carbazoles, dihydrobenzo[g]indoles, and azepino-or oxepinoindole derivatives in good to excellent yields, through an intramolecular cascade 5-endo-dig hydroamination followed by a 6-or 7-endo-dig cycloisomerization, without producing theoretical byproduct. Three of the resulting indoles exhibited potent antifungal activities against T. mentagrophytes and T. rubrum, demonstrating the practical application of the described cascade reaction for drug discovery.(Figure Presented)

Full text of DOI:10.1021/jo102507c

pubs.acs.org/joc
Direct Synthesis of Fused Indoles by Gold-Catalyzed Cascade
Cyclization of Diynes
Kimio Hirano,†,‡ Yusuke Inaba,† Naoya Takahashi,‡ Masanao Shimano,‡ Shinya Oishi,†
Nobutaka Fujii,*,† and Hiroaki Ohno*,†
†Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan, and
‡Central Research Laboratories, Kaken Pharmaceutical Co., Ltd., Yamashina-ku, Kyoto 607-8042, Japan
hohno@pharm.kyoto-u.ac.jp; nfujii@pharm.kyoto-u.ac.jp
Received December 18, 2010
A direct, concise, and atom-economical synthetic method for the generation of fused indoles, using a
gold-catalyzed cascade cyclization of diynes, has been developed. The reaction gave various fused
indoles, such as aryl-annulated[a]carbazoles, dihydrobenzo[g]indoles, and azepino- or oxepinoindole
derivatives in good to excellent yields, through an intramolecular cascade 5-endo-dig hydroamina-
tion followed by a 6- or 7-endo-dig cycloisomerization, without producing theoretical byproduct.
Three of the resulting indoles exhibited potent antifungal activities against T. mentagrophytes
and T. rubrum, demonstrating the practical application of the described cascade reaction for drug
discovery.
Introduction
pyrrole and benzene rings.7 The development of a direct,
concise, and atom-economical synthetic route to this class of
compounds, producing minimum waste/byproduct, would
therefore be of considerable interest for drug discovery and
process chemistry.
In recent years, cascade reactions have been recognized as
an efficient approach to target molecules by minimizing the
number of steps and separation processes and the amount of
time, labor, and waste involved.8 Gold catalysis is an im-
portant and powerful tool for the promotion of cascade
reactions because it can promote several types of nucleo-
philic reaction through the electrophilic activation of
carbon-carbon multiple bonds.9 To develop a more atom-
economical and direct synthetic method to aryl-annulated-
[a]carbazoles 2, we designed a cycloisomerization cascade
The indole moiety is a vital structural unit found in a large
array of natural products and pharmaceuticals.1 Aryl- and
heteroaryl-annulated[a]carbazoles are particularly noted for
their diverse biological activities.2-6 While synthetic methodo-
logies have been developed to generate these compounds,
most include stepwise introduction or construction of the
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2006, 106, 2875–2911.
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€
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Meert, E. M.K.; Cammue, B. P.A. Curr. Med. Chem. 2009, 16, 2205–2211.
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G. C. Chem. Rev. 2005, 105, 1001–1020. (c) Nicolaou, K. C.; Edmonds, D. J.;
Bulger, P. G. Angew. Chem., Int. Ed. 2006, 45, 7134–7186. (d) Kirsch, S. F.
Synthesis 2008, 3183–3204. (e) Nicolaou, K. C.; Chen, J. S. Chem. Soc. Rev.
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1212 J. Org. Chem. 2011, 76, 1212–1227
Published on Web 01/21/2011
DOI: 10.1021/jo102507c
r
2011 American Chemical Society

Hirano et al.
JOCFeatured Article
SCHEME 1. Synthesis of Aryl-Annulated[a]Carbazoles: Our
Strategy
TABLE 1. Reaction of Various Aniline Derivatives under Unoptimized
Conditionsa
entry
1
R
timeb (h)
2
yieldb (%)
strategy on the basis of gold-catalyzed 5-endo-dig hydroami-
nation10 and subsequent 6-endo-dig hydroarylation11 of
diyne 1 (Scheme 1). We now report full details of our study
on the synthesis of aryl-annulated[a]carbazoles based on this
strategy.12 Synthesis of other heterocyclic indoles, such as
dihydrobenzoindole, oxepinoindole, and cycloheptaindole
derivatives and the antifungal activities of these indole
derivatives are also presented.
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
n-Pr
c-Hex
Ph
p-F3CC6H4
p-NCC6H4
p-ClC6H4
p-MeC6H4
p-MeOC6H4
0.75
0.75
1.5
0.5
1.0
0.75
3.5 (0.83)
4.0 (1.5)
2a
2b
2c
2d
2e
2f
87
82
80
84
78
81
42 (65)
29 (45)
1g
1h
2g
2h
aUnless stated otherwise, all reactions were carried out with
Ph3PAuCl (5 mol %) and AgOTf (5 mol %) in MeCN at 80 °C.
bReaction times and yields in parentheses indicate those with 20 mol
% of the catalysts.
Results and Discussion
Synthesis of Aryl-Annulated[a]Carbazoles Using Various
Aniline-Substituted Diethynylarenes. Our preliminary inves-
tigation revealed that 5 mol % of Ph3PAuCl/AgOTf in
MeCN at 80 °C produced carbazoles in good yields from
diyne derivatives bearing an n-propyl, cyclohexyl, phenyl,
and electron-deficient aryl group (p-F3CC6H4, p-NCC6H4,
or p-ClC6H4) at the alkyne terminus (Table 1, entries 1-6).
On the other hand, the reaction of 1g or 1h bearing an
electron-rich aryl group (p-MeC6H4 or p-MeOC6H4) as the
R substituent under identical conditions gave the corre-
sponding carbazoles 2g and 2h in relatively low yields
(42% and 29%, respectively, entries 7 and 8). The yields of
2g and 2h were only moderately improved by increasing the
loading of Ph3PAuCl/AgOTf to 20 mol % (65% and 45%,
respectively). The lower reactivity of these substrates can be
attributed to the predominant coordination of the electron-
rich aryl-substituted alkyne to the active cationic gold com-
plex, which hinders the first cyclization step.
FIGURE 1. Screened gold-phosphine catalysts.
(Figure 1).13 We postulated that the bulky biarylphosphine
ligands might effectively promote dissociation of the gold
catalyst from the substrate, which would improve the chance
of activation of the appropriate alkyne for hydroami-
nation.14-16 Pleasingly, reactions carried out with 5 mol %
of catalysts A-C exhibited significantly increased turnover
of 1g to give 2g, with good yields obtained (Table 2, 71-83%,
entries 2-4).
Using the optimized conditions described in entry 4
(catalyst C, Table 2), the cascade cyclization was extended
to other types of substituted anilines. The results are sum-
marized in Table 3. In contrast to the low yield obtained for
the reaction of aniline 1h having a methoxy group with 5 mol
% of Ph3PAuCl/AgOTf (29% yield, entry 8, Table 1), the
cascade cyclization of 1h with 5 mol % of C/AgOTf pro-
ceeded cleanly to give 2h in 83% yield (entry 2). When using
precursors 1i-k, which bear a meta-substituted phenyl
group at R1, the corresponding products 2i-k were afforded
in good to excellent yields (76-98%, entries 3-5). It should
be noted that an o-cyano group at R1 significantly decreased
We further optimized the reaction conditions for diyne 1g
using highly alkynophilic gold-phosphine catalysts (A-C)
(9) For recent reviews on gold catalysis: (a) Hashmi, A. S. K. Chem. Rev.
2007, 107, 3180–3211. (b) Gorin, D. J.; Toste, F. D. Nature 2007, 446, 395–
ꢀ
ꢀꢁ
403. (c) Jimenez-Nunez, E.; Echavarren, A. M. Chem. Rev. 2008, 108, 3326–
3350. (d) Patil, N. T.; Yamamoto, Y. Chem. Rev. 2008, 108, 3395–3442.
€
(e) Furstner, A. Chem. Soc. Rev. 2009, 38, 3208–3221.
(10) For alkyne hydroamination to give indoles, see: (a) Arcadi, A.;
Bianchi, G.; Marinelli, F. Synthesis 2004, 610–618. (b) Alfonsi, M.; Arcadi,
A.; Aschi, M.; Bianchi, G.; Marinelli, F. J. Org. Chem. 2005, 70, 2265–2273.
(c) Miyazaki, Y.; Kobayashi, S. J. Comb. Chem. 2008, 10, 355–357.
(d) Praveen, C.; Sagayaraj, Y. W.; Perumal, P. T. Tetrahedron Lett. 2009,
50, 644–647. Quite recently, a Pd(II)-catalyzed oxidative halocyclization
cascade using highly related substrates to give benzo[a]carbazoles appeared:
(e) Chen, C.-C.; Chin, L.-Y.; Yang, S.-C.; Wu, M.-J. Org. Lett. 2010, 12,
5652–5655.
(11) For gold-catalyzed electrophilic activation of alkynes toward intra-
molecular nucleophilic attack at the C-3 position of indoles, see: (a) Ferrer,
C.; Echavarren, A. M. Angew. Chem., Int. Ed. 2006, 45, 1105–1109.
(b) Ferrer, C.; Amijs, C. H. M.; Echavarren, A. M. Chem.;Eur. J. 2007,
ꢀ
(13) Nieto-Oberhuber, C.; Lopez, S.; Echavarren, A. M. J. Am. Chem.
Soc. 2005, 127, 6178–6179.
13, 1358–1373. (c) Sanz, R.; Miguel, D.; Rodrı
´
guez, F. Angew. Chem., Int.
(14) For a recent review on ligand effects of gold catalysis, see: Gorin,
D. J.; Sherry, B. D.; Toste, F. D. Chem. Rev. 2008, 108, 3351–3378.
(15) For the impact of the bulky biarylphosphine ligands on gold
catalysis, see: Benitez, D.; Tkatchouk, E.; Gonzalez, A. Z.; Goddard,
W. A., III; Toste, F. D. Org. Lett. 2009, 11, 4798–4801.
(16) While this reference does not refer to a gold-catalyzed reaction, it
discusses the origin of improved reactivity in a Pd-catalyzed C-N bond
formation reaction by bulky and electron-rich monophosphinobiaryl li-
gands; see: Strieter, E. R.; Blackmond, D. G.; Buchwald, S. L. J. Am. Chem.
Soc. 2003, 125, 13978–13980.
Ed. 2008, 47, 7354–7357. (d) England, D. B.; Padwa, A. Org. Lett. 2008, 10,
3631–3634. (e) Lu, Y.; Du, X.; Jia, X.; Liu, Y. Adv. Synth. Catal. 2009, 351,
1517–1522. (f) Verniest, G.; England, D.; Kimpe, N. D.; Padwa, A. Tetra-
hedron 2010, 66, 1496–1502. (g) Liu, Y.; Xu, W.; Wang, X. Org. Lett. 2010,
12, 1448–1451. (h) Li, G.; Liu, Y. J. Org. Chem. 2010, 75, 3526–3528.
(12) A portion of this study (Table 1, entry 1 in Table 2 and Scheme 2) has
already been reported in a preliminary communication: Hirano, K.; Inaba,
Y.; Watanabe, T.; Oishi, S.; Fujii, N.; Ohno, H. Adv. Synth. Catal. 2010, 352,
368–372.
J. Org. Chem. Vol. 76, No. 5, 2011 1213

Hirano et al.
JOCFeatured Article
TABLE 2. Investigation of Gold Catalysts Bearing Bulky Biarylpho-
sphine Ligandsa
TABLE 4. Effect of a Nitrogen Substituent and Various Arene Tethersa
entry
Au catalyst
time (min)
yield (%)
1
2
3
4
Ph3PAuCl
50
45
45
45
42
71
80
83
A
B
C
aAll reactions were carried out with Au catalyst (5 mol %) and AgOTf
(5 mol %) in MeCN at 80 °C.
TABLE 3. Reaction of Various Aniline Derivativesa
aUnless otherwise stated, all reactions were carried out with C (5 mol
%) and AgOTf (5 mol %) in MeCN at 80 °C. bReaction times and yields
in parentheses indicate those with 20 mol % of the catalysts.
entry
1
R1
R2
R3
2
time (min) yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
1g p-MeC6H4
1h p-MeOC6H4
1i m-CF3C6H4
1j m-NCC6H4
1k m-MeC6H4
1l o-NCC6H4
1m o-MeC6H4
1n 3-thienyl
1o c-pentyl
1p Ph
H
H
H
H
H
H
H
H
H
CO2Me
Me
H
H
H
H
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
2q
2r
2s
45
30
40
30
30
250
40
40
40
120
30
40
90
90
83
83
98
79
76
10
82
74
90
68
83
92
96
87
Substitution with a methoxycarbonyl group at the para-
position decreased the reactivity of 1p, and 2p was only
obtained in a moderate yield (68%, entry 10) with prolonged
reaction time. This is presumed to be due to the decreased
nucleophilicity of the amino group in the first step as well as
the indole 3-position in the second step. Reaction of 1q,
containing a p-methyl group, led to 2q in good yield (83%,
entry 11).18 Diynes 1r and 1s, which bear chlorine substitu-
ents, afforded carbazoles 2r and 2s in excellent yields (92%
and 96%, entries 12 and 13), independent of the R1 sub-
stituent. A trifluoromethyl group R3 substituent was also
tolerated (entry 14). From these results, the reaction using
catalyst C, with bulky biaryl phosphine ligand, is applicable
to various substrate types and affords the corresponding
carbazoles in good yields, reducing the importance of sub-
strate electronic effects to reaction outcome.
Next, we investigated nitrogen substitution and other
arene tethers between the two alkynes (Table 4). tert-Butyl
carbamate 1u satisfactorily underwent cascade cyclization in
the presence of gold catalyst C to give 2u in a yield of 89%
(entry 1). The reaction of 1v, which has a methyl group as R1
substituent, also reacted cleanly to afford 2v in excellent yield
(92%, entry 2). Anilines 1w and 1y, which have fluorinated
phenyl or furan groups tethering the alkyne moieties, pro-
vided the desired carbazoles 2w and 2y in 84% and 98%
yields, respectively (entries 3 and 5). However, diyne 1x,
containing a pyridine moiety, proved to be a poor substrate,
H
H
H
H
H
H
H
H
H
H
Cl
Cl
1q Ph
1r Ph
1s c-Hex
1t c-Hex
CF3 2t
aAll reactions were carried out with C (5 mol %) and AgOTf (5 mol
%) in MeCN at 80 °C.
the yield (10%, entry 6), while the effect of p-cyanophenyl
group was less important (Table 1, entry 5). This is presum-
ably because of a coordination effect of the o-cyano group,
which would promote an undesired interaction between the
R1 group substituted triple bond and the catalyst before
hydroamination.17 This explanation is supported by the high
yield obtained with 1m, which bears an R1 o-tolyl group
(82%, entry 7), showing that any steric hindrance of the
reaction by o-substituents on R1 is relatively unimportant.
Diynes 1n and 1o bearing a thienyl and cyclopentyl group as
R1, respectively, were good substrates for the cascade cycli-
zation (entries 8 and 9). We also examined the effect of
substituents R2 and R3 on the aniline moiety (entries 10-14).
(17) For example, N-heterocyclic carbene gold(I) activates a nitrile group,
ꢀ
see: Ramon, R. S.; Marion, N.; Nolan, S. P. Chem.;Eur. J. 2009, 15, 8695–
8697.
(18) It is noteworthy that the reaction of 1p or 1q under the previous
conditions (5 mol % of Ph3PAuCl/AgOTf) gave the corresponding carba-
zoles 2p or 2q in only low yields (35% and 29%, respectively); see ref 12.
1214 J. Org. Chem. Vol. 76, No. 5, 2011

Hirano et al.
JOCFeatured Article
TABLE 5. Synthesis of Seven-Membered Ring Analoguesa
SCHEME 2. Base-Promoted Cascade Cyclization of 1x
Au catalyst time
(mol %)
yield
(%)
entry diyne
Z
(h)
product
SCHEME 3. Synthesis of Dihydrobenzoindole and Dihydro-
naphthofuran
1
2
3
4
5
10a
10a
10a
10b
10c
NTs
NTs
NTs
O
C (5)
2.5
1.5
1
4
2.5
11a
11a
11a
11b
11c
38
42
66
49
63
A (5)
A (20)
C (5)
C(CO2Me)2 C (5)
aAll reactions were carried out with Au catalyst (5 or 20 mol %) and
AgOTf (5 or 20 mol %) in MeCN at 80 °C.
HCl/1,4-dioxane to afford dihydrobenzoindole 5 in 90%
yield.22,23 Similarly, the cyclization of alcohol 8 gave dihy-
dronaphthofuran 9 in 85% yield.23,24 These results show that
tert-butyl carbamates and alcohols can also be used as the
nucleophile in this cascade cyclization. Synthesis of dihydro-
benzo[g]indole derivative such as 5 seems to be especially
important in drug discovery, in terms of improvement of
physiological properties of aryl-annulated[a]carbazoles
(e.g., water solubility, lipophilicity) by removing one benzene
ring from these molecules.25
Synthesis of Azepino- or Oxepino[3,4-b]indole and Cyclo-
hepta[b]indole Derivatives. Indole-fused seven-membered
ring derivatives are attractive drug templates,26 and we
envisioned their synthesis by establishing seven-membered
ring formation as the second step of the cascade cyclization
(Table 5). Three diyne derivatives, sulfonamide 10a, ether
10b, and diester 10c were prepared and subjected to the
standard conditions for the cascade cyclization. Treatment
of 10a with 5 mol % of the gold catalyst C/AgOTf resulted in
azepinoindole 11a in 38% yield (entry 1). This result shows
that intramolecular nucleophilic attack at the C-3 position of
the indole intermediate underwent 7-endo-dig cyclization as
we expected.27 The reaction was also performed by using
5 mol % (entry 2) and 20 mol % (entry 3) of the gold
resulting in a low yield of 2x (15%, entry 4). The yield of 2x
was improved slightly (37%) by the use of increased catalyst
loading (20 mol %, entry 4). Interestingly, the base-
promoted cyclization of 1x using t-BuOK in NMP showed
a dramatic change in cyclization mode, resulting in the
formation of product 3 in 60% yield, as the single E-
isomer,19 through a cascade 5-endo-dig/5-exo-dig cyclization
(Scheme 2).20,21
Synthesis of Dihydrobenzoindole and Dihydronaphthofur-
an. We examined the reactivity of nucleophilic groups other
than anilines (Scheme 3). Unfortunately, the alkyl amine-
derived diyne 4 did not give dihydrobenzoindole 5. We
speculated that unfavorable interactions of the amino group
with the gold catalyst may be responsible for this result, and
therefore tested the Boc-protected amine derivative 6, which
reacted cleanly to afford compound 7 in high yield (99%).
The Boc group of 7 was easily removed by treatment with 2 N
(22) For representative syntheses of dihydrobenzoindole derivatives, see:
(a) Kappe, C. O.; Cochran, J. E.; Padwa, A. Tetrahedron Lett. 1995, 36,
9285–9288. (b) Padwa, A.; Kappe, C. O.; Cochran, J. E.; Snyder, J. P. J. Org.
Chem. 1997, 62, 2786–2797. (c) Ghoral, B. K.; Herndon, J. W. Organome-
tallics 2003, 22, 3951–3957. (d) Kise, N.; Isemoto, S.; Sakurai, T. Org. Lett.
2009, 11, 4902–4905.
(23) For the synthesis of dihydrobenzoindole and dihydronaphthofuran
derivatives, see: Taduri, B. P.; Odedra, A.; Lung, C.-Y.; Liu, R.-S. Synthesis
2007, 2050–2054.
(24) For the representative synthesis of a dihydronaphthofuran deriva-
tive, see: Duperrouzel, P.; Lee-Ruff, E. Can. J. Chem. 1980, 58, 51–54.
(25) Ritchie, T. J.; Macdonald, S. J. F. Drug Discov. Today 2009, 14,
1011–1020.
(26) (a) Putey, A.; Joucla, L.; Picot, L.; Besson, T.; Joseph, B. Tetrahedron
2007, 63, 867–879. (b) Singh, U. S.; Shankar, R.; Yadav, G. P.; Kharkwal, G.;
Dwivedi, A.; Keshri, G.; Singh, M. M.; Moulik, P. R.; Hajela, K. Eur. J.
Med. Chem. 2008, 43, 2149–2158. (c) Keller, L.; Beaumont, S.; Liu, J.-M.;
Thoret, S.; Bignon, J. S.; Wdzieczak-Bakala, J.; Dauban, P.; Dodd, R. H. J.
Med. Chem. 2008, 51, 3414–3421. (d) Feytens, D.; Vlaeminck, M. D.;
(19) NOE analysis indicates that 3 has an E-configuration; see ref 12.
(20) For related base-mediated reactions, see: (a) Wu, M.-J.; Lee, C.-Y.;
Lin, C.-F. Angew. Chem., Int. Ed. 2002, 41, 4077–4079. (b) Lee, C.-Y.; Lin,
C.-F.; Lee, J.-L.; Chiu, C.-C.; Lu, W.-D.; Wu, M.-J. J. Org. Chem. 2004, 69,
2106–2110.
(21) In 2004, Wu reported base-promoted cascade cyclization of aniline-
substituted (Z)-endiyne derivatives to form carbazoles. However, our de-
tailed reinvestigation of the reactions has shown that these reactions generate
pyrido[1,2-a]indole derivatives, not carbazoles; see ref 12.
ꢀ
Cescato, R.; Tourwe, D.; Reubi, J. C. J. Med. Chem. 2009, 52, 95–104. (e)
Putey, A.; Popowycz, F.; Do, Q.-T.; Bernard, P.; Talapatra, S. K.; Kozielski,
F.; Galmarini, C. M.; Joseph, B. J. Med. Chem. 2009, 52, 5916–5925. (f)
Yeung, B. K. S.; Zou, B.; Rottmann, M.; Lakshminarayana, S. B.; Ang,
S. H.; Leong, S. Y.; Tan, J.; Wong, J.; Keller-Maerki, S.; Fischli, C.; Goh, A.;
Schmitt, E. K.; Krastel, P.; Francotte, E.; Kuhen, K.; Plouffe, D.; Henson,
K.; Wagner, T.; Winzeler, E. A.; Petersen, F.; Brun, R.; Dartois, V.; Diagana,
T. T.; Keller, T. H. J. Med. Chem. 2010, 53, 5155–5164.
J. Org. Chem. Vol. 76, No. 5, 2011 1215

Hirano et al.
SCHEME 6. Cyclization of Plausible Intermediate 20
JOCFeatured Article
SCHEME 4. Effect of Methyl Substituent at the Alkyne Ter-
minus
TABLE 6. Antifungal Activities of Indoles
MIC (μM)
SCHEME 5. Plausible Reaction Mechanism
T. mentagrophytes
(SM-110)
T. rubrum
(KD-1137)
compd
LD50 (μM)
2b
2i
3
3.13
3.13
<0.05
25
>100
0.20
5.14
4.53
8.17
providing E-olefin 13 (34%),30 Z-olefin 14 (10%), and
endo-olefin 15 (2%, Scheme 4).31 Thus, the phenyl group at
the alkyne terminus of 10 plays a crucial role in promoting
7-endo-dig cyclization in the second step, and we postulated
that this may be due to activation of the neighboring carbon
by the phenyl group.
Mechanism of the Cascade Cyclization. A plausible me-
chanism for the cascade cyclization is shown in Scheme 5.
First, activation of the alkyne between two arenes of 1c by
the cationic gold complex (as depicted in 16) promotes
5-endo-dig cyclization to form indolylgold intermediate 17.
This is followed by proto-deauration to give the first cycliza-
tion product 18; further activation of the second alkyne by
the gold catalyst to form 18 would lead to 6-endo-dig
cyclization at the C-3 position of the indole and subsequent
rearomatization to give arylgold intermediate 19. Finally,
proto-deauration of 19 would produce fused carbazole 2c to
regenerate the active catalyst. This mechanism, including the
second cyclization after proto-deauration of the vinyl gold
intermediate 17, is supported by the reaction of plausible
intermediate 20: treatment of 20 under the standard reaction
conditions quantitatively proceeded to afford the desired
carbazole 2c (Scheme 6).32
catalyst A/AgOTf to give 11a in 42% and 66% yields,
respectively. The gold-catalyzed cyclization of diynes 10b
and 10c with 5 mol % of C/AgOTf gave oxepinoindole 11b
(49%, entry 4) and cycloheptaindole 11c (63%, entry 5),
respectively, through the same cyclization cascade. While
azepinoindole synthesis has been previously reported by
us,28 the syntheses of 3,10-dihydro-1H-oxepino[3,4-b]indole
and 6,8-dihydrocyclohepta[b]indole derivative are unprece-
dented.
Antifungal Activities of Indoles. The synthesized indoles
were evaluated for antifungal activity against Trichophyton
mentagrophytes and Trichophyton rubrum (Table 6). Among
In contrast to the diester 10c, which bears a phenyl group
at the alkyne terminus, the cyclization of 12, bearing a methyl
group, favors 6-exo-dig cyclization in the second step,29
(30) NOE analysis indicates that (E)-13 has an E-configuration.
(27) For gold-catalyzed electrophilic activation of alkynes toward intra-
molecular nucleophilic attack at the C-3 position of indoles in a 7-endo-dig
manner, see refs 11a and 11b.
(28) For the synthesis of an azepinoindole derivative based on copper-
mediated multicomponent coupling and cyclization, see: (a) Ohno, H.; Ohta,
Y.; Oishi, S.; Fujii, N. Angew. Chem., Int. Ed. 2007, 46, 2295–2298. (b) Ohta,
Y.; Chiba, H.; Oishi, S.; Fujii, N.; Ohno, H. J. Org. Chem. 2009, 74, 7052–
7058.
(29) For gold-catalyzed electrophilic activation of alkynes toward intra-
molecular nucleophilic attack at the C-3 position of indoles in a 6-exo-dig
manner, see ref 11a,11b,11d,11f,11g.
(31) The yields of (E)-13, (Z)-14, and 15 were determined by NMR.
1216 J. Org. Chem. Vol. 76, No. 5, 2011

Hirano et al.
JOCFeatured Article
them, carbazoles 2b and 2i showed good activity against
T. mentagrophytes (minimal inhibitory concentration (MIC)=
3.13 μM in both cases). Compound 2b demonstrated modest
antifungal activity against T. rubrum with an MIC of 25 μM,
while compound 2i showed no activity at 100 μM. Indole 3,
fused with cyclopenta[b]pyridine, exhibited highly potent anti-
fungal activities against T. mentagrophytes and T. rubrum (MIC
<0.05and0.20μM, respectively). The three potent compounds
were tested for in vitro toxicity against human embryonic lung
(HEL) cells, and showed low cytotoxicity (50% lethal dose
(LD50)=4.53-8.17 μM, Table 6). Particularly, selectivity index
of indole 3 was high against both T. mentagrophytes (>163-fold
for MIC) and T. rubrum (41-fold for MIC). The unprecedented
antifungal activities of fused indoles will be useful in future
structure-activity relationships toward the development of this
class of indole derivatives as antifungal therapeutics.
The compounds S5,33 S6,33 S8,34 S10,12 S17,35-37 S20,37
S21,38 S24,39 and S2540 were synthesized according to the liter-
ature procedures. The gold catalyst B was synthesized according
to the literature procedures.13 Other reagents are commercially
available, which were used without further purification.
Preparation of Starting Materials
Conclusions
We have developed an atom-economical, new synthesis of
aryl-annulated[a]carbazoles via gold-catalyzed 5-endo-dig
hydroamination followed by 6-endo-dig hydroarylation of
diynes. The electronic influence of diyne substituents in the
cascade cyclization can be circumvented by using a gold
catalyst with bulky biaryl phosphine ligands. Consequently,
reaction with 5 mol % of catalyst gives not only aryl-
annulated[a]carbazoles but also various other fused indoles
such as dihydrobenzo[g]indole, azepino- or oxepinoindole,
and cycloheptaindole derivatives. Three of the resulting
indoles exhibited good to excellent antifungal activities
against T. mentagrophytes and T. rubrum, demonstrating
the practical application of the described cascade reaction
for drug discovery, including the development of antifungal
agents. Further optimization studies of these antifungal
compounds are now underway.
Synthesis of 2-[(2-Ethynylphenyl)ethynyl]aniline (S1). S1 was
prepared according to the procedure in
a preliminary
communication.12 Characterization data for S1 are as follows:
pale yellow solid; IR (neat) 3454 (NH), 3361 (NH), 2210 (CtC)
cm-1; 1H NMR (400 MHz, CDCl3) δ 3.35 (s, 1H, CtCH), 4.50
(br s, 2H, NH2), 6.73-6.69 (m, 2H, Ar), 7.17-7.13 (m, 1H, Ar),
7.30-7.26 (m, 1H, Ar), 7.34 (td, J=7.6, 1.3 Hz, 1H, Ar), 7.38
(dd, J=7.6, 1.5 Hz, 1H, Ar), 7.54 (dd, J=6.2, 1.6 Hz, 2H, Ar);
13C NMR (125 MHz, CDCl3) δ 81.0, 83.3, 90.7, 93.3, 107.6,
114.3, 117.9, 123.9, 126.7, 127.8, 128.8, 130.2, 131.5, 132.2,
132.8, 148.4; HRMS (FAB) calcd for C16H11N [Mþ] 217.0891,
found 217.0894.
Synthesis of 2-[(2-{[3-(Trifluoromethyl)phenyl]ethynyl}phenyl)-
ethynyl]aniline (1i). A mixture of S1 (0.10 g, 0.46 mmol), CuI
(2.2 mg, 0.012 mmol), PdCl2(PPh3)2 (8.1 mg, 0.012 mmol), Et3N
(0.32 mL, 2.3 mmol), and m-iodobenzotrifluoride (S2a) (66 μL,
0.46 mmol) in THF (1.0 mL) was stirred at room temperature
for 6 h under argon. Concentration under reduced pressure
followed by purification through a pad of silica gel with n-
hexane/EtOAc (5:1) afforded 1i (0.12 g, 70% yield) as a brown
solid, which was recrystallized from n-hexane to give pure 1i as
brown crystals: mp 87-88 °C; IR (neat) 3478 (NH), 3378 (NH),
2205 (CtC) cm-1; 1H NMR (400 MHz, CDCl3) δ 4.34 (br s, 2H,
NH2), 6.69-6.73 (m, 2H, Ar), 7.15 (ddd, J=7.7, 7.7, 1.5 Hz, 1H,
Ar), 7.30-7.41 (m, 3H, Ar), 7.48 (dd, J = 7.7 Hz, 1H, Ar),
7.58-7.61 (m, 3H, Ar), 7.74 (d, J=7.7 Hz, 1H, Ar), 7.86 (s, 1H,
Ar); 13C NMR (125 MHz, CDCl3) δ 90.2, 90.7, 91.5, 93.4, 107.4,
114.2, 117.8, 123.7 (q, J=273.1 Hz), 124.0, 124.4, 125.0 (q, J=
3.6 Hz), 126.1, 127.8, 128.6, 128.7 (q, J=3.6 Hz), 128.9, 130.1,
131.0 (q, J=32.4 Hz), 131.6, 132.0, 132.1, 134.9, 148.0. Anal.
Calcd for C23H14F3N: C, 76.45; H, 3.91; N, 3.88. Found: C,
76.65; H, 4.17; N, 3.91.
Experimental Section
General Methods. 1H NMR spectra were recorded at 400 or
500 MHz. 13C NMR spectra were recorded at 100 or 125 MHz.
Internal references were used for CDCl3, C6D6, and DMSO-d6
1
in H and 13C NMR spectra. Data are presented as follows:
chemical shift (in ppm on the δ scale relative to δTMS = 0),
multiplicity (s=singlet, d=doublet, t=triplet, q=quartet, m=
multiplet, br=broad), coupling constant (J/Hz) and number of
protons. 1H NMR assignments were confirmed by 1H-1H
COSY (PFG) and difference NOE analyses if necessary. Melt-
ing points were measured by a hot stage melting point apparatus
and are uncorrected. For column chromatography, silica gel
(45-75 μm) and amino silica gel (100-200 mesh) were emplo-
yed. The compounds 1a-h,p,q,x, 2a-h,p,q,x, and 3 are known.
Characterization data and NMR spectra for these compounds
were already reported in our preliminary communication.12
3-({2-[(2-Aminophenyl)ethynyl]phenyl}ethynyl)benzonitrile (1j).
By a procedure identical to that described for the preparation of
1i, S1 (0.10 g, 0.46 mmol) was converted into 1j (0.14 g, 96%
yield) as a brown solid using 3-iodobenzonitrile (S2b) (0.11 g,
(32) At present, we cannot rule out an alternative mechanism where the
intermediate 17 attacks the alkyne moiety directly before protonation. For a
related paper describing the formation of an arylgold(III) intermediate in an
SN2-type mechanism, see: Shi, Z.; He, C. J. Am. Chem. Soc. 2004, 126,
13596–13597.
(33) Schmittel, M.; Strittmatter, M. Tetrahedron 1998, 54, 13751–13760.
(34) Larock, R. C.; Yum, E. K.; Refvik, M. D. J. Org. Chem. 1998, 63,
7652–7662.
0.46 mmol): IR (neat) 3474 (NH), 3378 (NH), 2232 (CtC) cm-1
;
1H NMR (400 MHz, CDCl3) δ 4.33 (br s, 2H, NH2), 6.71-6.75
(m, 2H, Ar), 7.14-7.19 (m, 1H, Ar), 7.31-7.40 (m, 3H, Ar), 7.47
(dd, J=7.8, 7.8 Hz, 1H, Ar), 7.59-7.61 (m, 3H, Ar), 7.78 (dt, J=
7.8, 1.7 Hz, 1H, Ar), 7.86-7.87 (m, 1H, Ar); 13C NMR (125
(35) Wills, M. S. B.; Danheiser, R. L. J. Am. Chem. Soc. 1998, 120, 9378–
9379.
(38) Flynn, B. L.; Funke, F. J.; Silveira, C. C.; de Meijere, A. Synlett 1995,
(36) Kang, S.-K.; Baik, T.-G.; Kulak, A. N.; Ha, Y.-H.; Lim, Y.; Park, J.
J. Am. Chem. Soc. 2000, 122, 11529–11530.
(37) Chang, H.-T.; Jeganmohan, M.; Cheng, C.-H. Org. Lett. 2007, 9,
505–508.
1007–1010.
ꢀ
a-Rubın, S.; Varela, J. A.; Castedo, L.; Saa, C. Chem.;Eur. J.
´ ´
(39) Garcı
2008, 14, 9772–9778.
(40) Shen, Z.; Lu, X. Adv. Synth. Catal. 2009, 351, 3107–3112.
J. Org. Chem. Vol. 76, No. 5, 2011 1217

Hirano et al.
JOCFeatured Article
MHz, CDCl3) δ 90.6, 90.7, 91.0, 93.3, 107.4, 112.9, 114.3, 117.9,
117.9, 124.1, 124.6, 126.1, 127.9, 128.8, 129.3, 130.2, 131.6,
131.6, 132.0, 132.1, 135.1, 135.8, 148.0; HRMS (FAB) calcd
for C23H14N2 [Mþ] 318.1157, found 318.1158.
(400 MHz, CDCl3) δ 4.39 (br s, 2H, NH2), 6.68-6.72 (m, 2H, Ar),
7.13 (ddd, J=7.8, 7.8, 1.5 Hz, 1H, Ar), 7.23-7.26 (m, 1H, Ar),
7.28-7.35 (m, 3H, Ar), 7.39 (dd, J = 7.8, 1.5 Hz, 1H, Ar),
7.55-7.59 (m, 3H, Ar); 13C NMR (125 MHz, CDCl3) δ: 88.2,
88.3, 90.4, 93.7, 107.6, 114.1, 117.6, 122.0, 125.0, 125.4, 125.8,
127.7, 128.1, 129.3, 129.9, 130.1, 131.4, 132.0, 132.0, 148.2; HRMS
(FAB) calcd for C20H13NS [Mþ] 299.0769, found 299.0765.
2-{[2-(m-Tolylethynyl)phenyl]ethynyl}aniline (1k). By a proce-
dure identical to that described for the preparation of 1i, S1 (0.10
g, 0.46 mmol) was converted into 1k (0.11 g, 76% yield) as a brown
oil using 1-iodo-3-methylbenzene (S2c) (59 μL, 0.46 mmol): IR
(neat) 3479 (NH), 3378 (NH), 2205 (CtC) cm-1; 1H NMR (400
MHz, CDCl3) δ 2.34 (s, 3H, CH3), 4.36 (br s, 2H, NH2),
6.67-6.71 (m, 2H, Ar), 7.13 (ddd, J=8.5, 7.0, 1.2 Hz, 1H, Ar),
7.16-7.18 (m, 1H, Ar), 7.23-7.26 (m, 1H, Ar), 7.28-7.35 (m, 2H,
Ar), 7.36-7.41 (m, 3H, Ar), 7.57 (ddd, J=7.1, 7.1, 1.6 Hz, 2H,
Ar); 13C NMR (125 MHz, CDCl3) δ 21.2, 88.5, 90.4, 93.3, 93.7,
107.6, 114.0, 117.6, 122.8, 125.2, 125.9, 127.7, 128.1, 128.2, 128.9,
129.5, 129.9, 131.4, 132.0, 132.0, 132.5, 138.0, 148.2; HRMS
(FAB) calcd for C23H16N [M - H]- 306.1283, found 306.1289.
2-({2-[(2-Aminophenyl)ethynyl]phenyl}ethynyl)benzonitrile (1l).
By a procedure identical to that described for the preparation of
1i, S1 (0.11 g, 0.50 mmol) was converted into 1l (0.15 g, 92%
yield) as a brown solid using 2-iodobenzonitrile (S2d) (0.10 g,
0.44 mmol), which was recrystallized from n-hexane-EtOAc to
give pure 1l as pale brown crystals: mp 93-94 °C; IR (neat) 3475
Synthesis of 2-[(2-Bromophenyl)ethynyl]aniline (S3). S3 was
prepared according to the procedure in our preliminary
communication.12 Characterization data for S3 are as follows:
colorless solid; IR (neat) 3406 (NH), 3308 (NH), 2210 (CtC)
cm-1 1H NMR (400 MHz, CDCl3) δ 4.48 (br s, 2H, NH2),
;
(NH), 3370 (NH), 2228 (CtC) cm-1 1H NMR (400 MHz,
;
6.69-6.74 (m, 2H, Ar), 7.13-7.19 (m, 2H, Ar), 7.30 (ddd, J =
7.6, 7.6, 0.9 Hz, 1H, Ar), 7.39 (dd, J = 7.6, 1.2 Hz, 1H, Ar),
7.56 (dd, J=7.6, 1.6 Hz, 1H, Ar), 7.62 (dd, J=8.0, 0.7 Hz, 1H,
Ar); 13C NMR (125 MHz, CDCl3) δ 91.2, 93.4, 107.4, 114.4,
117.9, 125.1, 125.7, 127.3, 129.3, 130.3, 132.2, 132.4, 133.0, 148.5;
HRMS (FAB) calcd for C14H10BrN [Mþ] 270.9997, found
270.9987.
CDCl3) δ 4.38 (br s, 2H, NH2), 6.69-6.73 (m, 2H, Ar),
7.13-7.17 (m, 1H, Ar), 7.32-7.45 (m, 4H, Ar), 7.54-7.60 (m,
2H, Ar), 7.67-7.72 (m, 3H, Ar); 13C NMR (125 MHz, CDCl3) δ
89.1, 90.7, 93.2, 95.0, 107.6, 114.2, 115.4, 117.5, 117.8, 123.9,
125.9, 126.9, 127.9, 128.5, 129.1, 130.0, 131.6, 132.1, 132.4,
132.6, 132.7, 132.9, 148.1. Anal. Calcd for C23H14N2: C, 86.77;
H, 4.43; N, 8.80. Found: C, 86.80; H, 4.72; N, 8.74.
Synthesis of 2-{[2-(Cyclopentylethynyl)phenyl]ethynyl}aniline
(1o). To a solution of S3 (0.27 g, 0.99 mmol) in THF (1.7 mL)
were successively added diisopropylamine (0.69 mL, 4.9 mmol),
CuI (11 mg, 0.059 mmol), PdCl2(PhCN)2 (23 mg, 0.059 mmol),
P(t-Bu)3 (29 μL, 0.12 mmol), and ethynylcyclopentane (S4a)
(0.13 mL, 1.0 mmol) at room temperature under argon. The
mixture was stirred at room temperature for 16 h and quenched
by addition of saturated aqueous NH4Cl at room temperature.
The aqueous mixture was extracted with EtOAc, and the layers
were separated. The organic layer was washed with brine, dried
over Na2SO4, filtrated, and concentrated in vacuo. The residue
was purified by column chromatography on silica gel with
n-hexane/EtOAc (5:1) to afford 1o (0.14 g, 50% yield) as a
brown solid, which was recrystallized from n-hexane to give pure
1o as brown crystals: mp 62-63 °C; IR (neat) 3474 (NH), 3372
2-{[2-(o-Tolylethynyl)phenyl]ethynyl}aniline (1m). By a pro-
cedure identical to that described for the preparation of 1i, S1
(83 mg, 0.38 mmol) was converted into 1m (30 mg, 25% yield) as
a brown oil using 1-iodo-2-methylbenzene (S2e) (49 μL, 0.38
mmol): IR (neat) 3478 (NH), 3378 (NH), 2208 (CtC) cm-1; 1H
NMR (400 MHz, CDCl3) δ 2.50 (s, 3H, CH3), 4.32 (br s, 2H,
NH2), 6.64 (dd, J=8.7, 0.6 Hz, 1H, Ar), 6.68 (ddd, J=7.5, 7.5,
1.0 Hz, 1H, Ar), 7.09-7.14 (m, 1H, Ar), 7.14-7.19 (m, 1H, Ar),
7.21-7.27 (m, 2H, Ar), 7.28-7.34 (m, 2H, Ar), 7.36-7.38 (m,
1H, Ar), 7.52 (d, J=7.8 Hz, 1H, Ar), 7.55-7.60 (m, 2H, Ar); 13
C
NMR (125 MHz, CDCl3) δ: 20.9, 90.3, 92.1, 92.5, 93.7,
107.5, 114.0, 117.5, 122.7, 125.4, 125.5, 125.7, 127.8, 128.0,
128.6, 129.5, 129.9, 131.6, 132.0, 132.1, 132.1, 140.6, 148.2;
HRMS (FAB) calcd for C23H16N [M - H]- 306.1283, found
306.1279.
(NH), 2208 (CtC) cm-1 1H NMR (400 MHz, CDCl3) δ
;
1.57-1.64 (m, 2H, c-pentyl), 1.71-1.80 (m, 4H, c-pentyl),
1.97-2.05 (m, 2H, c-pentyl), 2.84-2.92 (m, 1H, c-pentyl), 4.47
(br s, 2H, NH2), 6.69-6.73 (m, 2H, Ar), 7.12-7.16 (m, 1H, Ar),
7.21-7.27 (m, 4H, Ar), 7.37 (dd, J = 7.7, 1.6 Hz, 1H, Ar),
7.42-7.44 (m, 1H, Ar), 7.47-7.51 (m, 1H, Ar); 13C NMR (125
MHz, CDCl3) δ 25.2 (2C), 31.1, 34.2 (2C), 79.6, 89.7, 94.1, 99.0,
108.0, 114.2, 117.8, 125.6, 126.2, 127.4, 127.8, 129.9, 131.5,
132.1, 132.3, 148.1. Anal. Calcd for C21H19N: C, 88.38; H,
6.71; N, 4.91. Found: C, 88.27; H, 6.70; N, 4.82.
Synthesis of 2-{[2-(Thiophene-3-ylethynyl)phenyl]ethynyl}-
aniline (1n). To a solution of S1 (88 mg, 0.41 mmol) in THF
(1.3 mL) were successively added Et3N (0.27 mL, 1.9 mmol), CuI
(3.7 mg, 0.019 mmol), PdCl2(PPh3)2 (14 mg, 0.019 mmol), and
3-iodothiophene (S2f) (39 μL, 0.39 mmol) at room temperature
under argon. The mixture was stirred for 50 h and quenched by
addition of saturated aqueous NH4Cl and brine, dried over
Na2SO4, filtrated, and concentrated in vacuo. The residue was
purified by column chromatography on silica gel with n-hexane/
EtOAc (3:1) to afford 1n (68 mg, 59% yield) as a pale brown solid:
Synthesis of 5-Chloro-2-{[2-(phenylethynyl)phenyl]ethynyl}-
aniline (1r). To a solution of 5-chloro-2-iodoaniline (S2g) (0.14 g,
0.55 mmol) in THF (0.42 mL) were successively added Et3N
1
IR (neat) 3474 (NH), 3372 (NH), 2206 (CtC) cm-1; H NMR
1218 J. Org. Chem. Vol. 76, No. 5, 2011

Hirano et al.
JOCFeatured Article
(0.38 mL, 2.8 mmol), CuI (2.6 mg, 0.014 mmol), PdCl2(PPh3)2
(9.7 mg, 0.014 mmol), and 1-ethynyl-2-(2-phenylethynyl)-
benzene (S5) (0.11 g, 0.55 mmol) in THF (0.50 mL) at room
temperature under argon. The mixture was stirred at room
temperature for 21 h and quenched by addition of saturated
aqueous NH4Cl at room temperature. The aqueous mixture
was extracted with EtOAc, and the layers were separated. The
organic layer was washed with brine, dried over Na2SO4,
filtrated, and concentrated in vacuo. The residue was purified
by column chromatography on amino silica gel with n-
hexane/EtOAc (6:1) to afford 1r (70 mg, 39% yield) as a
brown solid: IR (neat) 3460 (NH), 3363 (NH), 2200 (CtC)
24.6 (2C), 26.0, 29.7, 32.5 (2C), 79.1, 80.4, 82.5, 99.0, 124.5,
127.0, 127.2, 128.4, 131.7, 132.4; HRMS (FAB) calcd for C16H16
[Mþ] 208.1252, found 208.1251.
Synthesis of 5-Chloro-2-{[2-(cyclohexylethynyl)phenyl]ethynyl}-
aniline (1s). To a solution of S2g (0.12 g, 0.48 mmol) in THF
(0.30 mL) were successively added Et3N (0.34 mL, 2.4 mmol),
CuI (4.6 mg, 0.024 mmol), PdCl2(PPh3)2 (17 mg, 0.024 mmol),
and S7 (0.11 g, 0.55 mmol) in THF (0.50 mL) at room
temperature under argon. The mixture was stirred at room
temperature for 16 h and quenched by addition of saturated
aqueous NH4Cl at room temperature. The aqueous mixture
was extracted with EtOAc, and the layers were separated. The
organic layer was washed with brine, dried over Na2SO4,
filtrated, and concentrated in vacuo. The residue was purified
by column chromatography on amino silica gel with n-hex-
ane/EtOAc (5:1) to afford 1s (0.11 g, 71% yield) as a colorless
solid, which was recrystallized from n-hexane to give pure 1s
as colorless crystals: mp 90-91 °C; IR (neat) 3481 (NH), 3376
1
cm-1; H NMR (400 MHz, CDCl3) δ 4.43 (br s, 2H, NH2),
6.65-6.67 (m, 2H, Ar), 7.28-7.39 (m, 6H, Ar), 7.54-7.60 (m,
4H, Ar); 13C NMR (100 MHz, CDCl3) δ 88.7, 89.4, 93.1, 94.4,
106.0, 113.7, 117.8, 122.8, 125.0, 125.5, 127.9, 128.2, 128.4
(2C), 128.7, 131.4, 131.8 (2C), 132.1, 132.8, 135.5, 149.0;
HRMS (FAB) calcd for C22H13ClN [M - H]- 326.0737,
found 326.0739.
(NH), 2205 (CtC) cm-1 1H NMR (400 MHz, CDCl3) δ
;
1.30-1.40 (m, 2H, Cy), 1.52-1.60 (m, 4H, Cy), 1.73-1.81 (m,
2H, Cy), 1.86-1.92 (m, 2H, Cy), 2.60-2.67 (m, 1H, Cy), 4.53
(br s, 2H, NH2), 6.68 (dd, J=8.2, 1.6 Hz, 1H, Ar), 6.73 (d, J=
2.0 Hz, 1H, Ar), 7.23-7.29 (m, 3H, Ar), 7.43-7.51 (m, 2H,
Ar); 13C NMR (125 MHz, CDCl3) δ 24.9 (2C), 26.0, 30.1, 32.8
(2C), 80.1, 88.6, 94.8, 98.9, 106.6, 113.9, 118.0, 125.2, 126.2,
127.5, 128.0, 131.5, 132.4, 133.0, 135.5, 149.0. Anal. Calcd for
C
22H20ClN: C, 79.15; H, 6.04; N, 4.20. Found: C, 79.14; H,
5.99; N, 4.25.
Synthesis of 2-{[2-(Cyclohexylethynyl)phenyl]ethynyl}-5-(tri-
fluoromethyl)aniline (1t). To a solution of 2-bromo-5-(trifluo-
romethyl)aniline (S2h) (76 μg, 0.54 mmol) in THF (0.54 mL)
were successively added diisopropylamine (0.38 mL, 2.7
mmol), CuI (6.2 mg, 0.032 mmol), PdCl2(PhCN)2 (12 mg,
0.032 mmol), P(t-Bu)3 (16 μL, 0.065 mmol), and S7 (0.13 mL,
1.0 mmol) in THF (0.60 mL) at room temperature under
argon. The mixture was stirred at room temperature for 22 h
and quenched by addition of saturated aqueous NH4Cl at
room temperature. The aqueous mixture was extracted
with EtOAc, and the layers were separated. The organic layer
was washed with brine, dried over Na2SO4, filtrated, and
concentrated in vacuo. The residue was purified by column
chromatography on silica gel with n-hexane/EtOAc (8:1) to
afford 1t (0.14 g, 50% yield) as a brown solid: IR (neat)
1
3481 (NH), 3382 (NH), 2294 (CtC), 2221 (CtC) cm-1; H
NMR (400 MHz, CDCl3) δ 1.31-1.40 (m, 3H, Cy), 1.54-1.58
(m, 3H, Cy), 1.74-1.81 (m, 2H, Cy), 1.87-1.92 (m, 2H,
Cy), 2.61-2.67 (m, 1H, Cy), 4.65 (br s, 2H, NH2), 6.92-6.96
(m, 2H, Ar), 7.26-7.29 (m, 2H, Ar), 7.43-7.53 (m, 3H,
Ar); 13C NMR (125 MHz, CDCl3) δ 25.0 (2C), 26.0, 30.1,
32.9 (2C), 80.0, 88.2, 95.9, 99.1, 110.6, 110.6, 111.2, 114.1,
114.2, 124.9, 126.4, 127.5, 128.4, 131.7, 132.4, 132.5, 148.1;
HRMS (FAB) calcd for C23H20F3N [Mþ] 367.1548, found
367.1553.
Synthesis of 1-(Cyclohexylethynyl)-2-ethynylbenzene (S7). To
a solution of 2-(2-bromophenyl)ethynyltrimethylsilane (S6)
(0.86 g, 3.4 mmol) in THF (6.8 mL) were successively added
diisopropylamine (2.4 mL, 17 mmol), CuI (39 mg, 0.21
mmol), PdCl2(PhCN)2 (79 mg, 0.21 mmol), P(t-Bu)3 (99 μL,
0.41 mmol), and cyclohexylacetylene (S4b) (0.48 mL, 3.8 mmol)
at room temperature under argon. The mixture was stirred at
room temperature for 2 h and concentrated in vacuo. To the
residue were added THF (6.5 mL) and TBAF (1 M solution in
THF; 3.5 mL, 3.5 mmol). The mixture was stirred at room
temperature for 2.5 h and quenched by addition of saturated
aqueous NH4Cl and brine, dried over Na2SO4, filtrated, and
concentrated in vacuo. The residue was purified by column
chromatography on silica gel with n-hexane/EtOAc (20:1) to
afford S7 (0.53 g, 75% yield in two steps) as a brown oil: IR
(neat) 3289 (CtCH), 2224 (CtC) cm-1; 1H NMR (400 MHz,
CDCl3) δ 1.34-1.44 (m, 3H, Cy), 1.50-1.64 (m, 3H, Cy),
1.76-1.91 (m, 4H, Cy), 2.65-2.71 (m, 1H, Cy), 3.27 (s, 1H,
CtCH), 7.18-7.29 (m, 2H, Ar), 7.39-7.41 (m, 1H, Ar), 7.47
(dd, J=7.7, 1.3 Hz, 1H, Ar); 13C NMR (125 MHz, CDCl3) δ
Synthesis of tert-Butyl 2-{[2-(Phenylethynyl)phenyl]ethynyl}-
phenylcarbamate (1u). A mixture of 1c (0.21 g, 0.73 mmol) and
(Boc)2O (0.24 g, 1.1 mmol) in THF (2.0 mL) was refluxed
under stirring for 18 h under argon. Concentration under
reduced pressure followed by purification through a pad of
silica gel with n-hexane/EtOAc (10:1) afforded 1u (0.28 g,
97% yield) as a colorless solid: IR (neat) 3387 (NH), 2294
(CtC), 2256 (CtC) cm-1 1H NMR (400 MHz, CDCl3) δ
;
1.32 [s, 9H, C(CH3)3], 7.00 (td, J = 7.6, 1.0 Hz, 1H, Ar),
7.31-7.38 (m, 6H, Ar), 7.49-7.54 (m, 3H, Ar), 7.57-7.62 (m,
2H, Ar), 8.24 (d, J = 8.5 Hz, 1H, Ar); 13C NMR (125 MHz,
CDCl3) δ 28.1, 80.7, 85.3, 88.2, 88.7, 94.1, 94.9, 111.0, 117.6,
122.1, 123.2, 125.1, 126.0, 128.2, 128.5 (2C), 128.6, 128.6,
130.0, 131.8, 131.8, 132.0 (2C), 132.1, 139.9, 146.9, 152.5;
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Hirano et al.
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HRMS (FAB) calcd for C27H23NO2 [Mþ] 393.1729, found
393.1728.
132.1 (2C), 132.2, 150.1; HRMS (FAB) calcd for C23H16N [M -
H]- 306.1283, found 306.1280.
Synthesis of N-Methyl-2-[(trimethylsilyl)ethynyl]aniline (S9).
To a solution of 2-iodo-N-methylaniline (S8) (0.88 g, 3.8 mmol)
in THF (7.5 mL) were successively added Et3N (2.6 mL, 19
mmol), CuI (18 mg, 0.095 mmol), PdCl2(PPh3)2 (67 mg, 0.095
mmol), and trimethylsilylacetylene (0.55 mL, 4.0 mmol) at room
temperature under argon. The mixture was stirred at room
temperature for 16 h and quenched by addition of saturated
aqueous NH4Cl at room temperature. The aqueous mixture was
extracted with EtOAc, and the layers were separated. The
organic layer was washed with brine, dried over Na2SO4,
filtrated, and concentrated in vacuo. The residue was purified
by column chromatography on silica gel with n-hexane/EtOAc
(10:1) to afford S9 (0.77 g, 100% yield) as a pale yellow oil: IR
Synthesis of 1-(Cyclohexylethynyl)-2-ethynyl-4-fluorobenzene
(S12). To a solution of 1-bromo-4-fluoro-2-iodobenzene (S11)
(0.22 mL, 1.7 mmol) in THF (3.0 mL) were successively added
Et3N (1.2 mL, 8.3 mmol), CuI (16 mg, 0.083 mmol), PdCl2-
(PPh3)2 (58 mg, 0.083 mmol), and trimethylsilylacetylene (0.24
mL, 1.7 mmol) at room temperature under argon. The mixture
was stirred at room temperature for 16 h and quenched by
addition of saturated aqueous NH4Cl at room temperature. The
aqueous mixture was extracted with EtOAc, and the layers were
separated. The organic layer was washed with brine, dried over
Na2SO4, filtrated, and concentrated in vacuo. The residue was
purified by column chromatography on silica gel with n-hexane
to afford [(2-bromo-5-fluorophenyl)ethynyl]trimethylsilane
(0.43 g, 95% yield) as a pale yellow oil. To a solution of this
compound (0.22 g, 0.81 mmol) in THF (1.3 mL) were succes-
sively added diisopropylamine (0.56 mL, 4.0 mmol), CuI (9.2
mg, 0.048 mmol), PdCl2(PhCN)2 (19 mg, 0.048 mmol), P(t-Bu)3
(23 μL, 0.097 mmol), and S4b (0.11 mL, 0.89 mmol) at room
temperature under argon. The mixture was stirred at room
temperature for 17 h and quenched by addition of saturated
aqueous NH4Cl at room temperature. The aqueous mixture was
extracted with EtOAc, and the layers were separated. The
organic layer was washed with brine, dried over Na2SO4,
filtrated, and concentrated in vacuo. The residue was purified
by column chromatography on silica gel with n-hexane/EtOAc
(40:1) to afford {[2-(cyclohexylethynyl)-5-fluorophenyl]ethynyl}-
trimethylsilane (0.25 g, 100% yield) as a brown oil. A mixture
of this compound (0.25 g, 0.81 mmol) and TBAF (1 M
solution in THF; 0.89 mL, 0.89 mmol) in THF (4.0 mL) was
stirred at room temperature for 2 h and quenched by addition
of saturated aqueous NH4Cl and brine, dried over Na2SO4,
filtrated, and concentrated in vacuo. The residue was purified
by column chromatography on silica gel with n-hexane/
EtOAc (40:1) to afford S12 (0.12 g, 61% yield in three steps)
as a brown oil: IR (neat) 3304 (CtCH), 2227 (CtC) cm-1; 1H
NMR (400 MHz, CDCl3) δ 1.34-1.41 (m, 3H, Cy), 1.50-1.62
(m, 3H, Cy), 1.76-1.89 (m, 4H, Cy), 2.63-2.69 (m, 1H, Cy),
3.30 (s, 1H, CtCH), 6.97 (ddd, J=8.4, 8.4, 2.7 Hz, 1H, Ar),
7.16 (dd, J=9.0, 2.7 Hz, 1H, Ar), 7.37 (dd, J=8.4, 5.7 Hz, 1H,
Ar); 13C NMR (125 MHz, CDCl3) δ 24.7 (2C), 26.0, 29.7, 32.5
(2C), 78.1, 81.5 (2C), 98.6, 116.1 (d, J=21.6 Hz), 119.1 (d, J=
24.0 Hz), 123.5, 126.3 (d, J =9.6 Hz), 133.4 (d, J =8.4 Hz),
161.1 (d, J=248.3 Hz); HRMS (FAB) calcd for C16H15F [Mþ]
226.1158, found 226.1163.
(neat) 3422 (NH), 2143 (CtC) cm-1 1H NMR (400 MHz,
;
CDCl3) δ 0.27 [s, 9H, Si(CH3)3], 2.91 (s, 3H, NCH3), 4.64 (s, 1H,
NH), 6.57 (d, J=8.5 Hz, 1H, Ar), 6.59-6.62 (m, 1H, Ar), 7.22
(ddd, J=8.6, 7.0, 1.3 Hz, 1H, Ar), 7.30 (dd, J=7.6, 1.2 Hz, 1H,
Ar); 13C NMR (125 MHz, CDCl3) δ 0.0 (3C), 30.1, 99.8, 101.9,
106.9, 108.6, 115.8, 130.0, 132.1, 150.0; HRMS (FAB) calcd for
C12H17NSi [Mþ] 203.1130, found 203.1126.
Synthesis of N-Methyl-2-{[2-(phenylethynyl)phenyl]ethynyl}-
aniline (1v). A mixture of S9 (0.73 g, 3.6 mmol) and TBAF (1 M
solution in THF; 4.3 mL, 4.3 mmol) in THF (1.8 mL) was stirred
at room temperature for 17 h, quenched by addition of saturated
aqueous NH4Cl and brine, dried over Na2SO4, filtrated, and
concentrated in vacuo. The residue was purified by column
chromatography on silica gel with n-hexane/EtOAc (50:1) to
afford 2-ethynyl-N-methylaniline (0.47 g). To a solution of
1-bromo-2-(2-phenylethynyl)benzene (S10) (0.27 g, 1.1 mmol)
in THF (1.0 mL) were successively added diisopropylamine
(0.74 mL, 5.3 mmol), CuI (12 mg, 0.064 mmol), PdCl2(PhCN)2
(24 mg, 0.064 mmol), P(t-Bu)3 (31 μL, 0.13 mmol), and 2-ethy-
nyl-N-methylaniline (0.15 g, 1.1 mmol) in THF (0.80 mL) at
room temperature under argon. The mixture was stirred at room
temperature for 46 h and quenched by addition of saturated
aqueous NH4Cl at room temperature. The aqueous mixture was
extracted with EtOAc, and the layers were separated. The
organic layer was washed with brine, dried over Na2SO4,
filtrated, and concentrated in vacuo. The residue was purified
by column chromatography on silica gel with n-hexane/Et2O
(50:1) to afford 1v (0.13 g, 40% yield in two steps) as a pale
yellow solid: IR (neat) cm-1 3409 (NH), 2205 (CtC); 1H NMR
(400 MHz, CDCl3) δ 2.51 (d, J=5.1 Hz, 3H, NCH3), 4.97 (d, J=
3.9 Hz, 1H, NH), 6.54 (d, J=8.3 Hz, 1H, Ar), 6.64 (ddd, J=7.5,
7.5, 1.1 Hz, 1H, Ar), 7.20-7.37 (m, 6H, Ar), 7.40 (dd, J=7.5, 1.5
Hz, 1H, Ar), 7.55-7.59 (m, 4H, Ar); 13C NMR (125 MHz,
CDCl3) δ 30.1, 88.8, 90.8, 93.2, 94.0, 107.1, 108.9, 116.0, 122.9,
125.0, 126.1, 127.8, 128.3, 128.5 (2C), 128.7, 130.4, 131.5, 131.9,
Synthesis of 2-{[2-(Cyclohexylethynyl)-5-fluorophenyl]ethynyl}-
aniline (1w). To a solution of S12 (0.10 g, 0.45 mmol) in Et3N
(4.0 mL) were successively added CuI (8.6 mg, 0.045 mmol),
PdCl2(PPh3)2 (16 mg, 0.023 mmol), and 2-iodoaniline (99 mg,
1220 J. Org. Chem. Vol. 76, No. 5, 2011

Hirano et al.
JOCFeatured Article
0.45 mmol) at room temperature under argon. The mixture
was stirred at room temperature for 2.5 h and quenched by
addition of saturated aqueous NH4Cl at room temperature.
The aqueous mixture was extracted with EtOAc, and the
layers were separated. The organic layer was washed with
brine, dried over Na2SO4, filtrated, and concentrated in
vacuo. The residue was purified by column chromatography
on silica gel with n-hexane/EtOAc (5:1) to afford 1w (81 mg,
56% yield) as a brown oil: IR (neat) 3480 (NH), 3377 (NH),
2203 (CtC) cm-1; 1H NMR (500 MHz, CDCl3) δ 1.30-1.38
(m, 3H, Cy), 1.51-1.59 (m, 3H, Cy), 1.73-1.79 (m, 2H, Cy),
1.87-1.89 (m, 2H, Cy), 2.60-2.65 (m, 1H, Cy), 4.45 (s, 2H,
NH2), 6.69-6.73 (m, 2H, Ar), 6.94 (ddd, J=8.4, 8.4, 2.5 Hz,
1H, Ar), 7.15 (dd, J=8.4, 8.4 Hz, 1H, Ar), 7.18 (dd, J=9.2,
2.3 Hz, 1H, Ar), 7.36 (d, J=7.4 Hz, 1H, Ar), 7.40 (dd, J=8.4,
5.7 Hz, 1H, Ar); 13C NMR (125 MHz, CDCl3) δ 24.8 (2C),
25.9, 29.9, 32.7 (2C), 79.0, 90.6, 92.9, 98.2, 107.3, 114.2, 115.3
(d, J=21.6 Hz), 117.7, 118.0 (d, J=24.0 Hz), 122.3 (d, J=2.4
Hz), 127.3 (d, J=10.8 Hz), 130.1, 132.1, 133.9 (d, J=9.6 Hz),
148.1, 161.3 (d, J = 248.3 Hz); HRMS (FAB) calcd for
afford 1y (0.16 g, 34% yield) as a pale brown solid, which was
recrystallized from n-hexane to give pure 1y as pale brown
crystals: mp 68-69 °C; IR (neat) 3479 (NH), 3382 (NH), 2203
(CtC) cm-1; 1H NMR (400 MHz, CDCl3) δ 4.32 (s, 2H, NH2),
6.55 (dd, J=2.0, 0.5 Hz, 1H, Ar), 6.69-6.73 (m, 2H, Ar), 7.14
(td, J=7.7, 1.4 Hz, 1H, Ar), 7.35-7.39 (m, 5H, Ar), 7.54-7.58
(m, 2H, Ar); 13C NMR (125 MHz, CDCl3) δ 78.8, 86.1, 91.6,
97.6, 107.7, 113.1, 113.2, 114.4, 118.0, 122.1, 128.6 (2C), 129.1,
130.0, 131.8 (2C), 131.9, 140.0, 143.5, 148.0. Anal. Calcd for
C20H13NO: C, 84.78; H, 4.62; N, 4.94. Found: C, 85.04; H,
4.59; N, 4.95.
C
22H20FN [Mþ] 317.1580, found 317.1572.
Synthesis of 4-[2-(Phenylethynyl)phenyl]but-3-yn-1-ol (8). To
a solution of S10 (0.52 g, 2.0 mmol) in THF (3.4 mL) were
successively added diisopropylamine (1.4 mL, 10 mmol), CuI
(23 mg, 0.12 mmol), PdCl2(PhCN)2 (47 mg, 0.12 mmol), P(t-
Bu)3 (59 μL, 0.24 mmol), and 3-butyn-1-ol (0.17 mL, 2.1
mmol) at room temperature under argon. The mixture was
stirred at room temperature for 14 h and quenched by addition
of saturated aqueous NH4Cl at room temperature. The aqu-
eous mixture was extracted with EtOAc, and the layers were
separated. The organic layer was washed with brine, dried
over Na2SO4, filtrated, and concentrated in vacuo. The resi-
due was purified by column chromatography on silica gel with
n-hexane/EtOAc (3:1) to afford 8 (0.36 g, 72% yield) as a pale
brown oil: IR (neat) 3359 (OH), 2217 (CtC) cm-1; 1H NMR
(400 MHz, CDCl3) δ 2.07 (t, J=5.9 Hz, 1H, OH), 2.77 (t, J=
6.1 Hz, 2H, CH2CH2OH), 3.82 (td, J = 5.7, 5.7 Hz, 2H,
CH2CH2OH), 7.25-7.28 (m, 2H, Ar), 7.34-7.39 (m, 3H,
Ar), 7.43-7.46 (m, 1H, Ar), 7.51-7.59 (m, 3H, Ar); 13C
NMR (125 MHz, CDCl3) δ 24.1, 61.0, 81.5, 88.3, 90.8, 93.1,
123.0, 125.6, 125.8, 127.7, 128.0, 128.4 (2C), 128.5, 131.6 (2C),
131.7, 131.9; HRMS (FAB) calcd for C18H14O [Mþ] 246.1045,
found 246.1046.
Synthesis of 1-(4-Azidobut-1-ynyl)-2-(phenylethynyl)benzene
(S15). To a solution of 8 (0.26 g, 1.1 mmol) in CH2Cl2 (5.5
mL) were successively added Et3N (0.18 mL, 1.3 mmol)
and MsCl (87 μL, 1.1 mmol) at 0 °C for 1.5 h under argon.
The mixture was stirred at room temperature for 24 h. The
aqueous mixture was extracted with EtOAc, and the layers
were separated. The organic layer was washed with brine,
dried over Na2SO4, filtrated, and concentrated in vacuo. To
the residue were added DMSO (2.5 mL) and NaN3 (0.11 g, 1.6
mmol). The mixture was stirred at room temperature for 18 h
and quenched by addition of saturated aqueous NaHCO3 and
brine, dried over Na2SO4, filtrated, and concentrated in
vacuo. The residue was purified by column chromatography
on silica gel with n-hexane/EtOAc (10:1) to give S15 (0.18 g,
62% yield in two steps) as a pale yellow oil: IR (neat) 2217
(CtC), 2102 (N3) cm-1; 1H NMR (400 MHz, CDCl3) δ 2.80
Synthesis of 3-Bromo-2-(phenylethynyl)furan (S14). To a so-
lution of 2,3-dibromofuran (S13) (1.0 g, 4.6 mmol) in THF
(9.3 mL) were successively added diisopropylamine (3.2 mL, 23
mmol), CuI (53 mg, 0.28 mmol), PdCl2(PhCN)2 (0.11 g, 0.28
mmol), P(t-Bu)3 (0.14 mL, 0.56 mmol), and phenylacetylene
(0.56 mL, 5.1 mmol) at room temperature under argon. The
mixture was stirred at room temperature for 15 h and quenched
by addition of saturated aqueous NH4Cl at room temperature.
The aqueous mixture was extracted with EtOAc, and the layers
were separated. The organic layer was washed with brine, dried
over Na2SO4, filtrated, and concentrated in vacuo. The residue
was purified by column chromatography on silica gel with
n-hexane/EtOAc (20:1) to give S14 (0.45 g, 39% yield) as a
colorless oil: IR (neat) cm-1: 2217 (CtC); 1H NMR (500 MHz,
CDCl3) δ 6.51 (d, J=2.3 Hz, 1H, Ar), 7.35-7.37 (m, 4H, Ar),
7.54-7.57 (m, 2H, Ar); 13C NMR (125 MHz, CDCl3) δ 81.5,
97.1, 105.8, 114.7, 121.9, 128.4 (2C), 129.0, 131.6 (2C), 136.5,
143.7; HRMS (FAB) calcd for C12H7BrO [Mþ] 245.9680; found
245.9680.
Synthesis of 2-{[2-(Phenylethynyl)furan-3-yl]ethynyl}aniline
(1y). To a solution of S14 (0.41 g, 1.7 mmol) in THF (1.6
mL) were successively added diisopropylamine (1.2 mL, 8.4
mmol), CuI (19 mg, 0.10 mmol), PdCl2(PhCN)2 (38 mg, 0.10
mmol), P(t-Bu)3 (49 μL, 0.20 mmol), and 2-ethynylaniline (0.27
mL, 2.3 mmol) in THF (1.2 mL) at room temperature under
argon. The mixture was stirred at room temperature for 14 h
and quenched by addition of saturated aqueous NH4Cl at
room temperature. The aqueous mixture was extracted with
EtOAc, and the layers were separated. The organic layer was
washed with brine, dried over Na2SO4, filtrated, and concen-
trated in vacuo. The residue was purified by column chroma-
tography on amino silica gel with n-hexane/EtOAc (5:1) to
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Hirano et al.
JOCFeatured Article
(t, J = 7.0 Hz, 2H, CH2CH2N3), 3.50 (t, J = 7.0 Hz, 2H,
CH2CH2N3), 7.23-7.30 (m, 2H, Ar), 7.34-7.38 (m, 3H, Ar),
7.44-7.46 (m, 1H, Ar), 7.50-7.57 (m, 3H, Ar); 13C NMR (125
MHz, CDCl3) δ 20.7, 50.0, 81.3, 88.2, 90.0, 93.1, 123.3, 125.6,
125.8, 127.8, 127.9, 128.4 (2C), 128.4, 131.6 (2C), 131.8, 131.9;
HRMS (FAB) calcd for C18H13N3 [Mþ] 271.1109, found
271.1104.
155.7; HRMS (FAB) calcd for C23H23NO2 [Mþ] 345.1729,
found 345.1719.
Synthesis of 2,2,2-Trifluoro-N-{4-[2-(phenylethynyl)phenyl]-
but-3-ynyl}acetamide (S16). To a solution of S15 (0.34 g, 1.2
mmol) in THF (2.0 mL) were successively added PPh3 (0.33 g,
1.2 mmol) in THF (1.0 mL) and H2O (45 μL, 2.5 mmol) at
room temperature. The mixture was stirred at room tempera-
ture for 23 h and concentrated in vacuo. To the residue
were added pyridine (5.0 mL) and TFAA (0.19 mL, 1.4 mmol).
The mixture was stirred at room temperature for 12 h
and quenched by addition of H2O and brine, dried over
Na2SO4, filtrated, and concentrated in vacuo. The residue
was purified by column chromatography on silica gel
with n-hexane/EtOAc (3:1) to afford S16 (0.22 g, 53% yield
in two steps) as a colorless solid, which was recrystallized
from n-hexane/EtOAc to give pure S16 as colorless crystals:
mp 80-81 °C; IR (neat) 3323 (NH), 2217 (CtC), 1697
Synthesis of N-[3-(2-Aminophenyl)prop-2-ynyl]-4-methyl-N-
[3-(trimethylsilyl)prop-2-ynyl]benzenesulfonamide (S18). To a
solution of 4-methyl-N-prop-2-ynyl-N-(3-trimethylsilylprop-2-
ynyl)benzenesulfonamide (S17) (0.28 g, 0.86 mmol) in THF
(2.7 mL) were successively added Et3N (0.57 mL, 4.1 mmol), CuI
(4.7 mg, 0.025 mmol), PdCl2(PPh3)2 (17 mg, 0.025 mmol), and
2-iodoaniline (0.18 g, 0.82 mmol) at room temperature under
argon. The mixture was stirred at room temperature for 16 h and
quenched by addition of saturated aqueous NH4Cl at room
temperature. The aqueous mixture was extracted with EtOAc,
and the layers were separated. The organic layer was washed
with brine, dried over Na2SO4, filtrated, and concentrated in
vacuo. The residue was purified by column chromatography on
silica gel with n-hexane/EtOAc (5:1) to afford S18 (0.17 g, 50%
yield) as a brown solid: IR (neat) 3482 (NH), 3382 (NH), 2175
(CdO) cm-1 1H NMR (400 MHz, CDCl3) δ 2.76-2.81
;
(m, 2H, CtCCH2CH2), 3.58-3.64 (m, 2H, CtCCH2-
CH2), 6.70 (br s, 1H, NH), 7.24-7.27 (m, 1H, Ar), 7.28-
7.31 (m, 1H, Ar), 7.34-7.37 (m, 3H, Ar), 7.41-7.45 (m, 1H,
Ar), 7.49-7.55 (m, 3H, Ar); 13C NMR (125 MHz, CDCl3) δ
20.1, 38.6, 81.9, 88.1, 89.5, 93.0, 115.5 (q, J = 286.7 Hz),
122.9, 125.2, 125.8, 128.0, 128.1, 128.5 (2C), 128.6, 131.5 (2C),
131.8, 131.9, 162.0 (q, J = 34.4 Hz). Anal. Calcd for
C20H14F3NO: C, 70.38; H, 4.13; N, 4.10. Found C, 70.54; H,
4.12; N, 4.08.
Synthesis of 4-[2-(Phenylethynyl)phenyl]but-3-yn-1-amine (4).
To a solution of S16 (0.13 g, 0.38 mmol) in MeOH (3.4 mL)
were successively added K2CO3 (0.26 g, 1.9 mmol) and
H2O (0.21 mL) at room temperature for 12 h. The reaction
mixture was filtrated, and concentrated in vacuo. The residue
was purified by column chromatography on amino silica gel
with n-hexane/EtOAc (1:2) to give 4 (89 mg, 97% yield) as
a pale yellow oil: IR (neat) 3359 (NH), 3287 (NH), 2216 (CtC)
1
(CtC), 1349 (SdO), 1160 (SdO) cm-1; H NMR (400 MHz,
CDCl3) δ 0.06 [s, 9H, Si(CH3)3], 2.38 (s, 3H, C6H4CH3), 4.10 (br
s, 2H, NH2), 4.23 (s, 2H, CH2), 4.40 (s, 2H, CH2), 6.60-6.65 (m,
2H, Ar), 7.05 (dd, J=7.7, 1.6 Hz, 1H, Ar), 7.08-7.12 (m, 1H,
Ar), 7.28 (d, J=8.5 Hz, 2H, Ar), 7.75 (d, J=8.3 Hz, 2H, Ar); 13
C
NMR (100 MHz, CDCl3) δ 0.0 (3C), 21.8, 37.7, 37.8, 82.9, 87.2,
91.6, 98.1, 107.1, 114.6, 117.9, 128.3 (2C), 130.0 (2C), 130.3,
132.6, 135.6, 144.2, 148.6; HRMS (FAB) calcd for C22H27-
N2O2SSi [M þ H]þ 411.1563, found 411.1557.
cm-1 1H NMR (400 MHz, CDCl3) δ 2.64 (t, J = 6.2 Hz,
;
2H, CH2CH2NH2), 2.94 (t, J = 6.2 Hz, 2H, CH2CH2NH2),
7.25-7.29 (m, 2H, Ar), 7.33-7.38 (m, 3H, Ar), 7.42-7.46
(m, 1H, Ar), 7.51-7.56 (m, 3H, Ar); 13C NMR (CDCl3)
δ 24.8, 41.2, 80.9, 88.4, 92.3, 92.9, 123.2, 125.7, 126.0,
127.5, 128.0, 128.4 (2C), 128.4, 131.6 (2C), 131.8, 131.8;
HRMS (FAB) calcd for C18H16N [M þ H]þ 246.1283, found
246.1279.
Synthesis of N-[3-(2-Aminophenyl)prop-2-ynyl]-4-methyl-
N-(prop-2-ynyl)benzenesulfonamide (S19). A mixture of S18
(0.15 g, 0.36 mmol) and TBAF (1 M solution in THF; 0.39
mL, 0.39 mmol) in THF (1.8 mL) was stirred at room tempera-
ture for 40 min and quenched by addition of saturated aqueous
NH4Cl and brine, dried over Na2SO4, filtrated, and concen-
trated in vacuo. The residue was purified by column chroma-
tography on silica gel with n-hexane/EtOAc (3:1) to give S19
(0.17 g, 50% yield) as a brown solid: IR (neat) 3478 (NH), 3380
(NH), 3285 (CtCH), 2216 (CtC), 1348 (SdO), 1160 (SdO)
Synthesis of tert-Butyl 4-(2-(Phenylethynyl)phenyl)but-3-ynyl-
carbamate (6). To a solution of 4 (78 mg, 0.32 mmol) in THF
(0.50 mL) were successively added Et3N (44 μL, 0.32 mmol) and
(Boc)2O (0.10 g, 0.47 mmol) in THF (1.0 mL) at room tempera-
ture under argon. The mixture was stirred at room temperature
for 23 h and quenched by addition of H2O at room temperature.
The aqueous mixture was extracted with EtOAc, and the layers
were separated. The organic layer was washed with brine, dried
over Na2SO4, filtrated, and concentrated in vacuo. The residue
was purified by column chromatography on silica gel with n-
hexane/EtOAc (3:1) to afford 6 (96 mg, 88% yield) as a colorless
solid: IR (neat) 3358 (NH), 2294 (CtC), 2217 (CtC), 1698
1
cm-1; H NMR (400 MHz, CDCl3) δ 2.19 (t, J=2.3 Hz, 1H,
CtCH), 2.38 (s, 3H, C6H4CH3), 4.07 (br s, 2H, NH2), 4.21 (d,
J=2.3 Hz, 2H, CH2), 4.44 (s, 2H, CH2), 6.60-6.65 (m, 2H, Ar),
7.01 (d, J=7.6 Hz, 1H, Ar), 7.07-7.12 (m, 1H, Ar), 7.26-7.30
(m, 2H, Ar), 7.76 (d, J=8.3 Hz, 2H, Ar); 13C NMR (100 MHz,
CDCl3) δ 21.5, 36.5, 37.4, 74.0, 82.8, 86.6, 100.6, 106.6, 114.2,
117.6, 127.9 (2C), 129.6 (2C), 130.0, 132.3, 135.2, 144.0, 148.2;
HRMS (FAB) calcd for C19H18N2O2S [Mþ] 338.1089, found
338.1095.
Synthesis of N-[3-(2-Aminophenyl)prop-2-ynyl]-4-methyl-N-
(3-phenylprop-2-ynyl)benzenesulfonamide (10a). To a solution
of S19 (76 mg, 0.22 mmol) in Et3N (2.2 mL) were successively
added CuI (4.2 mg, 0.022 mmol), PdCl2(PPh3)2 (7.8 mg, 0.011
mmol), and iodobenzene (25 μL, 0.22 mmol) at room tempera-
ture under argon. The mixture was stirred at room temperature
for 14 h and quenched by addition of saturated aqueous NH4Cl
(CdO) cm-1 1H NMR (400 MHz, CDCl3) δ 1.40 [s, 9H,
;
(CH3)3], 2.69 (t, J= 6.3 Hz, 2H, CtCCH2CH2), 3.39 (td, J =
5.9, 5.9 Hz, 2H, CtCCH2CH2), 4.94-5.02 (br m, 1H, NH),
7.24-7.29 (m, 2H, Ar), 7.34-7.37 (m, 3H, Ar), 7.43-7.45 (m,
1H, Ar), 7.51-7.56 (m, 3H, Ar); 13C NMR (125 MHz, CDCl3) δ
21.2, 28.3 (3C), 39.5, 79.3, 80.8, 88.3, 91.6, 93.0, 123.2, 125.8,
125.8, 127.7, 128.0, 128.4 (2C), 128.4, 131.6 (2C), 131.8, 131.9,
1222 J. Org. Chem. Vol. 76, No. 5, 2011

Hirano et al.
JOCFeatured Article
at room temperature. The aqueous mixture was extracted with
EtOAc, and the layers were separated. The organic layer was
washed with brine, dried over Na2SO4, filtrated, and concen-
trated in vacuo. The residue was purified by column chroma-
tography on silica gel with n-hexane/EtOAc (3:1) to afford 10a
(70 mg, 75% yield) as a brown solid: IR (neat) 3474 (NH), 3382
room temperature. The aqueous mixture was extracted with
EtOAc, and the layers were separated. The organic layer was
washed with brine, dried over Na2SO4, filtrated, and concen-
trated in vacuo. The residue was purified by column chroma-
tography on silica gel with n-hexane/EtOAc (3:1) to afford S22
(0.23 g, 62% yield) as a pale brown solid: IR (neat) 3477 (NH),
1
(NH), 2212 (CtC), 1349 (SdO), 1161 (SdO) cm-1; H NMR
3383 (NH), 2179 (CtC), 1737 (CdO) cm-1 1H NMR (400
;
(400 MHz, CDCl3) δ 2.33 (s, 3H, C6H4CH3), 4.09 (br s, 2H,
NH2), 4.45 (s, 2H, CH2), 4.47 (s, 2H, CH2), 6.59-6.64 (m, 2H,
Ar), 7.05 (dd, J=7.7, 1.3 Hz, 1H, Ar), 7.09 (td, J=7.7, 1.5 Hz,
1H, Ar), 7.18-7.32 (m, 7H, Ar), 7.78-7.81 (m, 2H, Ar); 13C
NMR (100 MHz, CDCl3) δ 21.4, 37.5, 37.7, 81.7, 82.7, 85.9,
87.0, 106.7, 114.2, 117.6, 122.1, 127.9 (2C), 128.2 (2C), 128.5,
129.6 (2C), 130.0, 131.6 (2C), 132.3, 135.3, 143.9, 148.2; HRMS
(FAB) calcd for C25H22N2O2S [Mþ] 414.1402, found 414.1404.
MHz, CDCl3) δ 0.14 [s, 9H, Si(CH3)3], 3.06 (s, 2H, CH2), 3.24
(s, 2H, CH2), 3.77 (s, 6H, 2 ꢀ CO2CH3), 4.21 (br s, 2H, NH2),
6.61-6.66 (m, 2H, Ar), 7.06-7.10 (m, 1H, Ar), 7.21 (dd, J =
7.8, 1.5 Hz, 1H, Ar); 13C NMR (100 MHz, CDCl3) δ 0.0 (3C),
24.2, 24.4, 53.1 (2C), 57.2, 80.6, 88.8, 89.0, 100.8, 107.7, 114.2,
117.6, 129.5, 132.2, 148.2, 169.6 (2C); HRMS (FAB) calcd for
C
20H24NO4Si [M - H]- 370.1475, found 370.1485.
Synthesis of Dimethyl 2-[3-(2-Aminophenyl)prop-2-ynyl]-2-
(prop-2-ynyl)malonate (S23). A mixture of S22 (0.22 g, 0.58
mmol) and TBAF (1 M solution in THF; 0.64 mL, 0.64 mmol) in
THF (3.0 mL) was stirred at room temperature for 1.5 h and
quenched by addition of saturated aqueous NH4Cl and brine,
dried over Na2SO4, filtrated, and concentrated in vacuo. The
residue was purified by column chromatography on silica gel
with n-hexane/EtOAc (3:1) to give S23 (0.12 g, 69% yield) as a
pale brown solid: IR (neat) 3476 (NH), 3381 (NH), 3288
(CtCH), 2260 (CtC), 1734 (CdO) cm-1 1H NMR (400
;
Synthesis of 2-[3-(3-Phenylprop-2-ynyloxy)prop-1-ynyl]aniline
(10b). To a solution of 2-iodoaniline (0.40 g, 1.8 mmol) in THF
(2.0 mL) were successively added Et3N (1.3 mL, 9.2 mmol),
CuI (8.7 mg, 0.046 mmol), PdCl2(PPh3)2 (32 mg, 0.046 mmol),
and [3-(prop-2-ynyloxy)prop-1-ynyl]benzene (S20) (0.33 g, 1.9
mmol) in THF (1.0 mL) at room temperature under argon. The
mixture was stirred at room temperature for 4 h and quenched
by addition of saturated aqueous NH4Cl at room temperature.
The aqueous mixture was extracted with EtOAc, and the layers
were separated. The organic layer was washed with brine, dried
over Na2SO4, filtrated, and concentrated in vacuo. The residue
was purified by column chromatography on silica gel with
n-hexane/EtOAc (3:1) to give 10b (0.18 g, 37% yield) as a brown
MHz, CDCl3) δ 2.05 (t, J=2.7 Hz, 1H, CtCH), 3.06 (d, J=
2.7 Hz, 2H, CH2), 3.27 (s, 2H, CH2), 3.79 (s, 6H, 2 ꢀ CO2CH3),
4.20 (br s, 2H, NH2), 6.62-6.67 (m, 2H, Ar), 7.06-7.11 (m, 1H,
Ar), 7.21 (dd, J =7.8, 1.5 Hz, 1H, Ar); 13C NMR (100 MHz,
CDCl3) δ 23.0, 24.1, 53.2 (2C), 56.8, 71.8, 78.4, 80.7, 88.7, 107.5,
114.2, 117.6, 129.4, 132.1, 148.1, 169.5 (2C); HRMS (FAB)
calcd for C17H17NO4 [Mþ] 299.1158, found 299.1151.
Synthesis of Dimethyl 2-[3-(2-Aminophenyl)prop-2-ynyl]-2-(3-
phenylprop-2-ynyl)malonate (10c). To a solution of S23 (94 mg,
0.32 mmol) in Et3N (3.0 mL) were successively added CuI (6.0
mg, 0.032 mmol), PdCl2(PPh3)2 (11 mg, 0.016 mmol), and
iodobenzene (35 μL, 0.32 mmol) at room temperature under
argon. The mixture was stirred at room temperature for 6 h and
quenched by addition of saturated aqueous NH4Cl at room
temperature. The aqueous mixture was extracted with EtOAc,
and the layers were separated. The organic layer was washed
with brine, dried over Na2SO4, filtrated, and concentrated in
vacuo. The residue was purified by column chromatography on
silica gel with n-hexane/EtOAc (3:1) to afford 10c (0.11 g, 93%
yield) as a pale brown solid: IR (neat) 3482 (NH), 3384 (NH),
1
oil: IR (neat) 3475 (NH), 3380 (NH), 2246 (CtC) cm-1; H
NMR (400 MHz, CDCl3) δ 4.21 (s, 2H, NH2), 4.55 (s, 2H, CH2),
4.60 (s, 2H, CH2), 6.66-6.69 (m, 2H, Ar), 7.11-7.15 (m, 1H,
Ar), 7.28-7.34 (m, 4H, Ar), 7.45-7.47 (m, 2H, Ar); 13C NMR
(100 MHz, CDCl3) δ 57.3, 57.5, 83.6, 84.3, 86.8, 89.6, 107.0,
114.3, 117.8, 122.4, 128.3 (2C), 128.5, 130.0, 131.8 (2C), 132.5,
148.2; HRMS (FAB) calcd for C18H15NO [Mþ] 261.1154, found
261.1158.
1
2295 (CtC), 2222 (CtC), 1729 (CdO) cm-1; H NMR (400
MHz, CDCl3) δ 3.27 (s, 2H, CH2), 3.32 (s, 2H, CH2), 3.81 (s, 6H,
2 ꢀ CO2CH3), 4.25 (br s, 2H, NH2), 6.62-6.67 (m, 2H, Ar),
7.07-7.11 (m, 1H, Ar), 7.22 (dd, J = 7.6, 1.2 Hz, 1H, Ar),
7.26-7.29 (m, 3H, Ar), 7.36-7.39 (m, 2H, Ar); 13C NMR (100
MHz, CDCl3) δ 24.0, 24.3, 53.1 (2C), 57.2, 80.7, 83.7, 83.9, 88.9,
107.6, 114.2, 117.6, 123.0, 128.1, 128.2 (2C), 129.4, 131.7 (2C),
132.1, 148.1, 169.6 (2C); HRMS (FAB) calcd for C23H22NO4 [M
þ H]þ 376.1549, found 376.1553.
Synthesis of Dimethyl 2-[3-(2-Aminophenyl)prop-2-ynyl]-
2-[3-(trimethylsilyl)prop-2-ynyl]malonate (S22). To a solution
of 2-iodoaniline (0.22 g, 1.0 mmol) in THF (2.0 mL) were
successively added Et3N (0.71 mL, 5.1 mmol), CuI (9.7 mg,
0.051 mmol), PdCl2(PPh3)2 (36 mg, 0.051 mmol), and dimethyl
2-(prop-2-ynyl)-2-[3-(trimethylsilyl)prop-2-ynyl]malonate (S21)
(0.30 g, 1.1 mmol) in THF (2.0 mL) at room temperature under
argon. The mixture was stirred at room temperature for 14 h
and quenched by addition of saturated aqueous NH4Cl at
Synthesis of Dimethyl 2-[3-(2-Aminophenyl)prop-2-ynyl]-
2-(but-2-ynyl)malonate (12). To a solution of 2-iodoaniline
(0.13 g, 0.59 mmol) in THF (1.2 mL) were successively added
Et3N (0.41 mL, 3.0 mmol), CuI (5.6 mg, 0.030 mmol), PdCl2-
(PPh3)2 (21 mg, 0.030 mmol), and dimethyl 2-(but-2-ynyl)-
2-(prop-2-ynyl)malonate (S24) (0.14 g, 0.62 mmol) in THF
J. Org. Chem. Vol. 76, No. 5, 2011 1223

Hirano et al.
JOCFeatured Article
(1.2 mL) at room temperature under argon. The mixture was
stirred at room temperature for 20 h and quenched by addition
of saturated aqueous NH4Cl at room temperature. The aqueous
mixture was extracted with EtOAc, and the layers were sepa-
rated. The organic layer was washed with brine, dried over
Na2SO4, filtrated, and concentrated in vacuo. The residue was
purified by column chromatography on silica gel with n-hexane/
EtOAc (3:1) to give 12 (68 mg, 37% yield) as a brown oil: IR
stirred at 60 °C for 18 h, and MeONa (32 mg, 0.60 mmol) was
added at 80 °C. The reaction mixture was stirred at 80 °C for 19 h
and quenched by addition of H2O at room temperature. The
aqueous mixture was extracted with EtOAc, and the layers were
separated. The organic layer was washed with brine, dried over
Na2SO4, filtrated, and concentrated in vacuo. The residue was
purified by column chromatography on silica gel with n-hexane/
EtOAc (6:1) to give 20 (40 mg, 68% yield) as a pale yellow solid:
IR (neat) 3430 (NH), 2249 (CtC) cm-1; 1H NMR (400 MHz,
CDCl3) δ 7.00 (d, J=1.5 Hz, 1H, Ar), 7.11-7.15 (m, 1H, Ar),
7.19-7.23 (m, 1H, Ar), 7.28 (td, J = 7.6, 1.0 Hz, 1H, Ar),
7.36-7.41 (m, 5H, Ar), 7.52-7.55 (m, 2H, Ar), 7.63 (dd, J=7.8,
1.0 Hz, 1H, Ar), 7.66 (d, J=7.8 Hz, 1H, Ar), 7.78 (dd, J=7.8, 0.5
Hz, 1H, Ar), 9.60 (br s, 1H, NH); 13C NMR (125 MHz, CDCl3)
δ 89.6, 93.6, 102.1, 110.9, 118.7, 120.1, 120.7, 122.5, 122.7, 127.2,
128.0, 128.4, 128.6 (2C), 128.8, 129.0, 131.3 (2C), 133.4, 134.0,
136.3, 136.8; HRMS (FAB) calcd for C22H15N [Mþ] 293.1204,
found 293.1205.
(neat) 3481 (NH), 3382 (NH), 2253 (CtC), 1734 (CdO) cm-1
;
1H NMR (400 MHz, CDCl3) δ 1.77 (t, J = 2.4 Hz, 3H,
CtCCH3), 2.99 (q, J = 2.4 Hz, 2H, CH2), 3.24 (s, 2H, CH2),
3.78 (s, 6H, 2 ꢀ CO2CH3), 4.22 (br s, 2H, NH2), 6.61-6.66 (m,
2H, Ar), 7.06-7.10 (m, 1H, Ar), 7.21 (dd, J=7.6, 1.0 Hz, 1H,
Ar); 13C NMR (100 MHz, CDCl3) δ 3.5, 23.3, 24.1, 53.0 (2C),
57.1, 72.8, 79.4, 80.4, 89.1, 107.6, 114.1, 117.5, 129.3, 132.1,
148.1, 169.8 (2C); HRMS (FAB) calcd for C18H19NO4 [Mþ]
313.1314, found 313.1310.
Gold-Catalyzed Cascade Cyclization of Diynes. General Pro-
cedure for Synthesis of Fused Indoles. Synthesis of 6-p-Tolyl-
11H-benzo[a]carbazole (2g) (Table 2, Entry 4). A mixture of the
gold catalyst C (5.0 mg, 7.1 μmol, 5 mol %) and AgOTf (1.8 mg,
7.1 μmol, 5 mol %) in acetonitrile (0.71 mL) was stirred at room
temperature under argon. After aniline 1g (43 mg, 0.14 mmol)
was added, the mixture was stirred at 80 °C for 45 min. The
reaction mixture was diluted with EtOAc, washed with satu-
rated aqueous NH4Cl and brine, dried over Na2SO4, filtrated,
and concentrated in vacuo. The residue was purified by column
chromatography on amino silica gel with n-hexane/Et2O (2:3) to
afford 2g (36 mg, 83% yield) as a brown oil. 1H NMR spectra of
2g were in good agreement with those previously reported.12
Synthesis of 6-(4-Methoxyphenyl)-11H-benzo[a]carbazole
(2h) (Table 3, Entry 2). By a procedure similar to that described
for the preparation of carbazole 2g, 1h (36 mg, 0.11 mmol) was
converted into 2h (30 mg, 83% yield) as a pale brown solid by
treatment with C (3.9 mg, 5.6 μmol) and AgOTf (1.4 mg, 5.6
Synthesis of N-(2-{[2-(Phenylethynyl)phenyl]ethynyl}phenyl)-
methanesulfonamide (S26). To a solution of S10 (0.31 g, 1.2
mmol) in THF (2.0 mL) were successively added diisopropyla-
mine (0.85 mL, 6.1 mmol), CuI (14 mg, 0.073 mmol), PdCl2-
(PhCN)2 (28 mg, 0.073 mmol), P(t-Bu)3 (35 μL, 0.15 mmol) and
S25 (0.24 g, 1.3 mmol) at room temperature under argon. The
mixture was stirred at room temperature for 19 h, filtrated, and
concentrated in vacuo. The residue was purified by column
chromatography on silica gel with n-hexane/EtOAc (3:1) to give
S26 (0.22 g, 48% yield) as a pale brown sold: IR (neat) 3329
(NH), 2256 (CtC), 2215 (CtC), 1338 (SdO), 1155 (SdO)
1
μmol) in acetonitrile (0.56 mL) at 80 °C for 30 min. H NMR
spectra of 2h were in good agreement with those previously
reported.12
1
cm-1; H NMR (400 MHz, CDCl3) δ 2.88 (s, 3H, CH3), 7.16
Synthesis of 6-[3-(Trifluoromethyl)phenyl]-11H-benzo[a]car-
bazole (2i) (Table 3, Entry 3). By a procedure similar to that
described for the preparation of carbazole 2g, 1i (31 mg, 0.087
mmol) was converted into 2i (31 mg, 98% yield) as a brown oil
by treatment with C (3.1 mg, 4.3 μmol) and AgOTf (1.1 mg, 4.3
μmol) in acetonitrile (0.43 mL) at 80 °C for 40 min: IR (neat)
3472 (NH) cm-1; 1H NMR (500 MHz, C6D6) δ 7.01-7.07 (m,
2H, Ar), 7.22 (d, J=8.0 Hz, 1H, Ar), 7.27 (s, 1H, Ar), 7.30 (dd
J=7.4, 7.4 Hz, 1H, Ar), 7.37-7.41 (m, 2H, Ar), 7.46 (d, J=7.4
Hz, 1H, Ar), 7.55-7.58 (m, 2H, Ar), 7.62 (d, J=8.6 Hz, 1H, Ar),
(td, J=7.7, 1.1 Hz, 1H, Ar), 7.22 (br s, 1H, NH), 7.32-7.41 (m,
6H, Ar), 7.53-7.62 (m, 6H, Ar); 13C NMR (125 MHz, CDCl3) δ
39.5, 87.5, 87.9, 94.0, 95.3, 114.3, 119.8, 122.7, 124.2, 124.7,
126.0, 128.2, 128.4 (2C), 128.7, 128.9, 130.2, 131.8, 131.8 (2C),
132.3, 132.4, 137.8; HRMS (FAB) calcd for C23H17NO2S [Mþ]
371.0980, found 371.0983.
Synthesis of 1-(Methylsulfonyl)-2-[2-(phenylethynyl)phenyl]-
1H-indole (S27). To a solution of S26 (0.20 g, 0.54 mmol) in
NMP (2.5 mL) were added N,N-diisopropylethylamine (0.47
mL, 2.7 mmol). The mixture was stirred at 80 °C for 15 h and
quenched by addition of H2O at room temperature. The aqu-
eous mixture was extracted with EtOAc, and the layers were
separated. The organic layer was washed with brine, dried over
Na2SO4, filtrated, and concentrated in vacuo. The residue was
purified by column chromatography on silica gel with n-hexane/
EtOAc (3:1) to give S27 (0.18 g, 90% yield) as a pale yellow oil:
IR (neat) 2294 (CtC), 2254 (CtC), 1370 (SdO), 1171 (SdO)
cm-1; 1H NMR (400 MHz, CDCl3) δ 2.94 (s, 3H, CH3), 6.85 (s,
1H, Ar), 7.13-7.26 (m, 5H, Ar), 7.34-7.46 (m, 4H, Ar),
7.51-7.53 (m, 1H, Ar), 7.63-7.66 (m, 2H, Ar), 8.11 (dd, J =
8.0, 0.7 Hz, 1H, Ar); 13C NMR (125 MHz, CDCl3) δ 39.7, 88.5,
93.2, 113.2, 115.0, 121.1, 122.7, 123.6, 124.2, 125.0, 127.6, 128.3
(2C), 128.4, 128.7, 129.9, 131.3 (2C), 131.5, 131.7, 134.7, 137.0,
139.2; HRMS (FAB) calcd for C23H17NO2S [Mþ] 371.0980,
found 371.0978.
7.78-7.79 (m, 1H, Ar), 7.92 (br s, 1H, NH), 7.96 (s, 1H, Ar); 13
C
NMR (125 MHz, C6D6) δ 111.4, 116.6, 120.2, 120.9, 121.0,
121.6, 122.0, 123.9, 124.4 (q, J = 3.6 Hz), 125.0, 125.0 (q,
J=272.3 Hz), 125.6, 125.9, 126.5 (q, J=3.6 Hz), 129.0, 129.3,
131.0 (q, J=32.0 Hz), 132.5, 133.1, 135.1, 135.7, 139.1, 142.6;
HRMS (FAB) calcd for C23H14F3N [Mþ] 361.1078, found
361.1068.
Synthesis of 3-(11H-Benzo[a]carbazol-6-yl)benzonitrile (2j)
(Table 3, Entry 4). By a procedure similar to that described for
the preparation of carbazole 2g, 1j (33 mg, 0.10 mmol) was
converted into 2j (26 mg, 79% yield) as a yellow solid by
treatment with C (3.7 mg, 5.2 μmol) and AgOTf (1.3 mg, 5.2
μmol) in acetonitrile (0.52 mL) at 80 °C for 30 min: IR (neat)
1
3344 (NH), 2234 (CtN) cm-1; H NMR (500 MHz, C6D6) δ
6.81 (dd, J=7.7, 7.7 Hz, 1H, Ar), 7.03 (dd, J=7.7, 7.7 Hz, 1H,
Ar), 7.11-7.15 (m, 2H, Ar), 7.27-7.34 (m, 2H, Ar), 7.38-7.45
(m, 4H, Ar), 7.50 (s, 1H, Ar), 7.69 (d, J=6.9 Hz, 1H, Ar), 7.81
(dd, J=6.9, 2.3 Hz, 1H, Ar), 8.09 (br s, 1H, NH); 13C NMR (125
MHz, C6D6) δ 111.5, 113.2, 116.4, 118.9, 120.2, 121.0, 121.1,
Synthesis of 2-[2-(Phenylethynyl)phenyl]-1H-indole (20). To a
solution of S27 (74 mg, 0.20 mmol) in MeOH (2.0 mL) was
added MeONa (65 mg, 1.2 mmol) at 60 °C. The mixture was
1224 J. Org. Chem. Vol. 76, No. 5, 2011

Hirano et al.
JOCFeatured Article
121.5, 121.8, 123.8, 125.1, 125.7, 126.0, 128.9, 129.2, 131.0,
132.4, 132.8, 133.6, 134.3, 135.7, 139.1, 142.6; HRMS (FAB)
calcd for C23H14N2 [Mþ] 318.1157, found 318.1149.
treatment with C (4.2 mg, 6.0 μmol) and AgOTf (1.5 mg,
6.0 μmol) in acetonitrile (0.60 mL) at 80 °C for 40 min, which
was recrystallized from n-hexane/EtOAc to give pure 2o as pale
brown crystals: mp: 147-149 °C; IR (neat) cm-1: 3417 (NH); 1H
NMR (500 MHz, CDCl3) δ 1.85-2.00 (m, 6H, c-pentyl),
2.29-2.35 (m, 2H, c-pentyl), 4.07-4.13 (m, 1H, c-pentyl), 7.31
(dd, J=7.4, 7.4 Hz, 1H, Ar), 7.42 (dd, J=7.4, 7.4 Hz, 1H, Ar),
7.48-7.50 (m, 3H, Ar), 7.57 (d, J=8.0 Hz, 1H, Ar), 7.94 (dd, J=
6.3, 3.4 Hz, 1H, Ar), 8.04 (dd, J=6.3, 3.2 Hz, 1H, Ar), 8.24 (d,
J=8.0 Hz, 1H, Ar), 8.80 (br s, 1H, NH); 13C NMR (125 MHz,
CDCl3) δ 25.0 (2C), 32.6 (2C), 42.9, 111.0, 115.2, 117.7, 119.6,
119.9, 120.1, 122.5, 124.1, 124.2, 124.7, 125.3, 128.4, 132.4,
135.1, 138.6, 140.4. Anal. Calcd for C21H19N: C, 88.38; H,
6.71; N, 4.91. Found C, 88.18; H, 6.60; N, 4.91.
Synthesis of 6-m-Tolyl-11H-benzo[a]carbazole (2k) (Table 3,
Entry 5). By a procedure similar to that described for the
preparation of carbazole 2g, 1k (33 mg, 0.11 mmol) was con-
verted into 2k (26 mg, 76% yield) as a brown oil by treatment
with C (3.8 mg, 5.3 μmol) and AgOTf (1.4 mg, 5.3 μmol) in
acetonitrile (0.53 mL) at 80 °C for 30 min: IR (neat) 3469 (NH)
cm-1; 1H NMR (500 MHz, C6D6) δ 2.21 (s, 3H, CH3), 7.06 (dd,
J=7.4, 7.4 Hz, 1H, Ar), 7.13 (d, J=7.4 Hz, 1H, Ar), 7.23 (d, J=
8.0 Hz, 1H, Ar), 7.27 (dd, J=7.4, 7.4 Hz, 1H, Ar), 7.32 (dd, J=
7.4, 7.4 Hz, 1H, Ar), 7.36-7.41 (m, 2H, Ar), 7.49 (s, 1H, Ar),
7.53-7.55 (m, 2H, Ar), 7.64 (d, J=8.6 Hz, 1H, Ar), 7.82-7.85
(m, 2H, Ar), 7.89 (br s, 1H, NH); 13C NMR (125 MHz, C6D6) δ
21.4, 111.2, 117.4, 120.0, 120.7, 121.0, 121.3, 122.6, 124.5, 124.8,
125.1, 125.7, 126.9, 128.5, 128.5, 129.2, 130.5, 132.8, 135.6,
137.4, 138.1, 139.2, 141.8; HRMS (FAB) calcd for C23H16N
[M - H]- 306.1283, found 306.1285.
Synthesis of Methyl 6-Phenyl-11H-benzo[a]carbazole-8-car-
boxylate (2p) (Table 3, Entry 10). By a procedure similar to that
described for the preparation of carbazole 2g, 1p (43 mg, 0.12
mmol) was converted into 2p (29 mg, 68% yield) as a pale brown
solid by treatment with C (4.4 mg, 6.2 μmol) and AgOTf (1.6 mg,
1
Synthesis of 2-(11H-Benzo[a]carbazol-6-yl)benzonitrile (2l)
(Table 3, Entry 6). By a procedure similar to that described for
the preparation of carbazole 2g, 1l (41 mg, 0.13 mmol) was
converted into 2l (4.2 mg, 10% yield) as a yellow solid by
treatment with C (4.6 mg, 6.5 μmol) and AgOTf (1.7 mg, 6.5
μmol) in acetonitrile (0.65 mL) at 80 °C for 250 min: IR (neat)
3365 (NH), 2228 (CtN) cm-1; 1H NMR (400 MHz, DMSO-d6)
δ 6.81 (d, J=7.7 Hz, 1H, Ar), 6.98 (dd, J=7.7, 7.7 Hz, 1H, Ar),
7.36 (dd, J=7.7, 7.7 Hz, 1H, Ar), 7.57 (s, 1H, Ar), 7.62-7.80 (m,
5H, Ar), 7.94 (dd, J=7.7, 7.7 Hz, 1H, Ar), 8.10-8.12 (m, 2H,
Ar), 8.61 (d, J=8.3 Hz, 1H, Ar), 12.49 (br s, 1H, NH); 13C NMR
(125 MHz, CDCl3) δ: 111.1, 113.0, 116.1, 118.4, 119.7, 120.5,
120.7, 120.8, 121.2, 123.1, 124.7, 125.8, 126.1, 128.2, 129.0,
131.0, 131.6, 131.7, 132.6, 133.1, 135.3, 138.6, 145.1; HRMS
(FAB) calcd for C23H14N2 [Mþ] 318.1157, found 318.1157.
Synthesis of 6-o-Tolyl-11H-benzo[a]carbazole (2m) (Table 3,
Entry 7). By a procedure similar to that described for the
preparation of carbazole 2g, 1m (30 mg, 0.096 mmol) was
converted into 2m (24 mg, 82% yield) as a brown solid by
treatment with C (3.4 mg, 4.8 μmol) and AgOTf (1.2 mg, 4.8
μmol) in acetonitrile (0.48 mL) at 80 °C for 40 min: IR (neat)
6.2 μmol) in acetonitrile (0.62 mL) at 80 °C for 120 min. H
NMR spectra of 2p were in good agreement with those pre-
viously reported.12
Synthesis of 8-Methyl-6-phenyl-11H-benzo[a]carbazole (2q)
(Table 3, Entry 11). By a procedure similar to that described
for the preparation of carbazole 2g, 1q (29 mg, 0.096 mmol) was
converted into 2q (24 mg, 83% yield) as a brown solid by
treatment with C (3.4 mg, 4.8 μmol) and AgOTf (1.2 mg, 4.8
1
μmol) in acetonitrile (0.48 mL) at 80 °C for 30 min. H NMR
spectra of 2q were in good agreement with those previously
reported.12
Synthesis of 9-Chloro-6-phenyl-11H-benzo[a]carbazole (2r)
(Table 3, Entry 12). By a procedure similar to that described
for the preparation of carbazole 2g, 1r (30 mg, 0.092 mmol) was
converted into 2r (28 mg, 92% yield) as a yellow solid by
treatment with C (3.3 mg, 4.6 μmol) and AgOTf (1.2 mg, 4.6
μmol) in acetonitrile (0.46 mL) at 80 °C for 40 min: IR (neat)
3416 (NH) cm-1; 1H NMR (500 MHz, CDCl3) δ 6.98 (dd, J=
8.6, 1.7 Hz, 1H, Ar), 7.31 (d, J=8.6 Hz, 1H, Ar), 7.48-7.59 (m,
7H, Ar), 7.63 (dd, J=8.0, 1.7 Hz, 2H, Ar), 7.97 (d, J=7.4 Hz,
1H, Ar), 8.07 (d, J=8.0 Hz, 1H, Ar), 8.82 (br s, 1H, NH); 13
C
1
3431 (NH) cm-1; H NMR (500 MHz, CDCl3) δ 2.11 (s, 3H,
NMR (125 MHz, CDCl3) δ 110.8, 116.3, 120.1, 120.2, 120.3,
121.3, 122.4, 122.8, 125.7, 125.9, 127.7, 128.4 (2C), 128.9, 129.2
(2C), 130.3, 132.2, 135.6, 136.2, 139.1, 140.8; HRMS (FAB)
calcd for C22H13ClN [M - H]- 326.0737, found 326.0740.
Synthesis of 9-Chloro-6-cyclohexyl-11H-benzo[a]carbazole
(2s) (Table 3, Entry 13). By a procedure similar to that described
for the preparation of carbazole 2g, 1s (34 mg, 0.10 mmol) was
converted into 2s (33 mg, 96% yield) as a pale yellow solid by
treatment with C (3.6 mg, 5.1 μmol) and AgOTf (1.3 mg, 5.1
μmol) in acetonitrile (0.51 mL) at 80 °C for 90 min: IR (neat)
3416 (NH) cm-1; 1H NMR (500 MHz, CDCl3) δ 1.36-1.45 (br
m, 1H, Cy), 1.58-1.68 (m, 4H, Cy), 1.89-1.91 (br m, 1H, Cy),
1.96-2.01 (br m, 2H, Cy), 2.22-2.29 (br m, 2H, Cy), 3.43-3.47
(br m, 1H, Cy), 7.26 (dd, J=8.6, 1.7 Hz, 1H, Ar), 7.46 (s, 1H,
Ar), 7.50-7.52 (m, 3H, Ar), 7.93 (dd, J=6.0, 3.2 Hz, 1H, Ar),
7.99-8.00 (m, 2H, Ar), 8.72 (br s, 1H, NH); 13C NMR (125
MHz, CDCl3) δ 26.5, 27.2 (2C), 33.1 (2C), 41.1, 110.9, 115.8,
116.7, 119.5, 120.1, 120.6, 122.4, 123.0, 124.9, 125.6, 128.6,
129.9, 132.6, 135.4, 139.0, 141.9; HRMS (FAB) calcd for
C22H20ClN [Mþ] 333.1284, found 333.1277.
CH3), 6.95 (d, J=8.0 Hz, 1H, Ar), 7.00 (dd, J=8.0, 8.0 Hz, 1H,
Ar), 7.32-7.36 (m, 2H, Ar), 7.39-7.45 (m, 4H, Ar), 7.52-7.60
(m, 3H, Ar), 7.99 (d, J=8.0 Hz, 1H, Ar), 8.14 (d, J=8.0 Hz, 1H,
Ar), 8.85 (br s, 1H, NH); 13C NMR (125 MHz, CDCl3) δ 19.9,
110.8, 117.4, 120.0, 120.2, 120.2, 120.4, 121.2, 124.1, 124.6,
125.3, 125.5, 125.9, 127.8, 128.9, 129.6, 129.9, 132.2, 134.8,
135.9, 136.7, 138.5, 140.7; HRMS (FAB) calcd for C23H16N
[M - H]- 306.1283, found 306.1289.
Synthesis of 6-(Thiophen-3-yl)-11H-benzo[a]carbazole (2n)
(Table 3, Entry 8). By a procedure similar to that described for
the preparation of carbazole 2g, 1n (28 mg, 0.093 mmol) was
converted into 2n (21 mg, 74% yield) as a yellow solid by
treatment with C (3.3 mg, 4.7 μmol) and AgOTf (1.2 mg, 4.7
μmol) in acetonitrile (0.47 mL) at 80 °C for 40 min: IR (neat)
cm-1: 3410 (NH); 1H NMR (500 MHz, CDCl3) δ 7.10 (dd, J=
7.4, 7.4 Hz, 1H, Ar), 7.37 (dd, J=7.4, 7.4 Hz, 1H, Ar), 7.42 (dd,
J=4.6, 1.1 Hz, 1H, Ar), 7.50-7.57 (m, 6H, Ar), 7.60 (d, J=7.4
Hz, 1H, Ar), 7.96 (d, J=7.4 Hz, 1H, Ar), 8.09 (d, J=8.0 Hz, 1H,
Ar), 8.85 (br s, 1H, NH); 13C NMR (125 MHz, CDCl3) δ 110.9,
117.0, 119.7, 120.3, 120.3, 121.0, 122.0, 123.0, 123.8, 124.7,
125.4, 125.5, 125.7, 128.8, 129.3, 131.2, 132.0, 135.2, 138.6,
141.7; HRMS (FAB) calcd for C20H13NS [Mþ]: 299.0769;
found: 299.0767.
Synthesis of 6-Cyclohexyl-9-(trifluoromethyl)-11H-benzo-
[a]carbazole (2t) (Table 3, Entry 14). By a procedure similar to
that described for the preparation of carbazole 2g, 1t (32 mg,
0.088 mmol) was converted into 2t (28 mg, 87% yield) as a pale
brown solid by treatment with C (3.1 mg, 4.4 μmol) and AgOTf
(1.1 mg, 4.4 μmol) in acetonitrile (0.44 mL) at 80 °C for 90 min:
Synthesis of 6-Cyclopentyl-11H-benzo[a]carbazole (2o) (Table 3,
Entry 9). By a procedure similar to that described for the
preparation of carbazole 2g, 1o (34 mg, 0.12 mmol) was con-
verted into 2o (31 mg, 90% yield) as a pale brown solid by
IR (neat) 3495 (NH) cm-1 1H NMR (500 MHz, CDCl3) δ
;
1.36-1.45 (br m, 1H, Cy), 1.60-1.69 (m, 4H, Cy), 1.90-1.93 (br
J. Org. Chem. Vol. 76, No. 5, 2011 1225

Hirano et al.
JOCFeatured Article
m, 1H, Cy), 1.99-2.01 (br m, 2H, Cy), 2.21-2.31 (br m, 2H, Cy),
3.46-3.50 (br m, 1H, Cy), 7.47 (s, 1H, Ar), 7.50-7.58 (m, 3H,
Ar), 7.80 (s, 1H, Ar), 7.94 (dd, J=5.7, 2.9 Hz, 1H, Ar), 8.02 (dd,
J=7.5, 3.2 Hz, 1H, Ar), 8.17 (d, J=8.6 Hz, 1H, Ar), 8.89 (br s,
1H, NH); 13C NMR (125 MHz, CDCl3) δ 26.5, 27.2 (2C), 33.2
(2C), 41.1, 108.3 (q, J=4.8 Hz), 116.1, 116.5, 116.7 (q, J=3.6
Hz), 119.4, 120.3, 122.4, 124.8 (q, J=241.9 Hz), 125.1, 125.9 (q,
J = 32.4 Hz), 126.0, 126.2, 128.6, 133.0, 136.5, 137.5, 142.2;
HRMS (FAB) calcd for C23H20F3N [Mþ] 367.1548, found
367.1556.
Synthesis of tert-Butyl 6-Phenyl-11H-benzo[a]carbazole-11-
carboxylate (2u) (Table 4, Entry 1). By a procedure similar to
that described for the preparation of carbazole 2g, 1u (41 mg,
0.10 mmol) was converted into 2u (36 mg, 89% yield) as a yellow
oil by treatment with C (3.7 mg, 5.2 μmol) and AgOTf (1.3 mg,
5.2 μmol) in acetonitrile (0.52 mL) at 80 °C for 2 h: IR (neat)
1730 (CdO) cm-1; 1H NMR (500 MHz, CDCl3) δ 1.71 [s, 9H,
C(CH3)3], 7.07 (dd, J=8.0, 8.0 Hz, 1H, Ar), 7.16 (d, J=8.0 Hz,
1H, Ar), 7.35-7.39 (m, 1H, Ar), 7.49-7.56 (m, 5H, Ar),
7.59-7.61 (m, 2H, Ar), 7.65 (s, 1H, Ar), 7.93 (d, J = 8.0 Hz,
1H, Ar), 8.19 (d, J=8.0 Hz, 1H, Ar), 8.26 (d, J=8.0 Hz, 1H, Ar);
13C NMR (125 MHz, CDCl3) δ 28.2 (3C), 84.5, 114.8, 122.0,
122.1, 122.6, 122.8, 124.9, 125.0, 125.6, 126.0, 126.1, 126.2,
127.8, 128.5, 128.5 (2C), 128.7, 129.4 (2C), 133.0, 135.3, 140.6,
140.6, 151.9; HRMS (FAB) calcd for C27H23NO2 [Mþ]
393.1729, found 393.1731.
preparation of carbazole 2g, 1y (34 mg, 0.12 mmol) was con-
verted into 2y (33 mg, 98% yield) as a colorless solid by
treatment with C (4.2 mg, 5.9 μmol) and AgOTf (1.5 mg, 5.9
μmol) in acetonitrile (0.59 mL) at 80 °C for 75 min, which was
recrystallized from n-hexane to give pure 2y as colorless crystals:
1
mp 120-121 °C; IR (neat) 3443 (NH) cm-1; H NMR (500
MHz, CDCl3) δ 6.98-7.01 (m, 2H, Ar), 7.29-7.32 (m, 2H, Ar),
7.36 (d, J=8.0 Hz, 1H, Ar), 7.44-7.54 (m, 4H, Ar), 7.63-7.64
(m, 2H, Ar), 7.69 (d, J=2.3 Hz, 1H, Ar), 8.38 (br s, 1H, NH); 13
C
NMR (125 MHz, CDCl3) δ 103.4, 105.7, 110.6, 110.9, 115.7,
119.4, 121.8, 123.7, 124.4, 127.5, 128.4 (2C), 129.4 (2C), 132.6,
134.6, 139.1, 141.3, 144.1, 154.6. Anal. Calcd for C20H13NO: C,
84.78; H, 4.62; N, 4.94. Found: C, 84.55; H, 4.65; N, 4.78.
Synthesis of tert-Butyl 4-Phenyl-2,3-dihydro-1H-benzo[g]-
indole-1-carboxylate (7) (Scheme 3). By a procedure similar to
that described for the preparation of carbazole 2g, 6 (42 mg, 0.12
mmol) was converted into 7 (41 mg, 99% yield) as a pale yellow
solid by treatment with C (4.3 mg, 6.0 μmol) and AgOTf (1.5 mg,
6.0 μmol) in acetonitrile (0.60 mL) at 80 °C for 25 min: IR (neat)
1698 (CdO) cm-1; 1H NMR (500 MHz, CDCl3) δ 1.55 [s, 9H,
C(CH3)3], 3.16 (t, J=7.7 Hz, 2H, CH2), 4.24 (t, J=7.7 Hz, 2H,
CH2), 7.36-7.51 (m, 7H, Ar), 7.63 (s, 1H, Ar), 7.83 (d, J=8.0
Hz, 1H, Ar), 7.98 (d, J=8.0 Hz, 1H, Ar); 13C NMR (125 MHz,
CDCl3) δ 28.4 (3C), 30.0, 51.9, 81.1, 124.0, 124.8, 125.2, 125.4,
125.5, 127.3, 128.2, 128.4 (2C), 128.6 (2C), 129.6, 134.0, 136.5,
139.5, 140.4, 154.5; HRMS (FAB) calcd for C23H23NO2 [Mþ]
345.1729, found 345.1734.
Synthesis of 11-Methyl-6-phenyl-11H-benzo[a]carbazole (2v)
(Table 4, Entry 2). By a procedure similar to that described for
the preparation of carbazole 2g, 1v (32 mg, 0.11 mmol) was
converted into 2v (30 mg, 92% yield) as a colorless solid by
treatment with C (3.7 mg, 5.3 μmol) and AgOTf (1.3 mg, 5.3
μmol) in acetonitrile (0.53 mL) at 80 °C for 40 min, which was
recrystallized from n-hexane to give pure 2v as colorless crystals:
mp 194-195 °C; 1H NMR (500 MHz, C6D6) δ 3.54 (s, 3H, CH3),
7.04 (dd, J=7.4, 7.4 Hz, 1H, Ar), 7.13 (d, J=8.6 Hz, 1H, Ar),
7.27-7.34 (m, 5H, Ar), 7.38 (dd, J=5.7, 3.2 Hz, 1H, Ar), 7.52 (s,
1H, Ar), 7.66-7.71 (m, 3H, Ar), 7.88 (dd, J=5.7, 2.9 Hz, 1H,
Ar), 8.37 (dd, J = 5.7, 3.4 Hz, 1H, Ar); 13C NMR (125 MHz,
C6D6) δ 33.4, 109.1, 117.9, 119.6, 121.8, 122.4, 122.5, 122.5,
123.3, 124.7, 124.9, 125.1, 127.7, 128.6 (2C), 129.6, 129.8 (2C),
133.8, 136.3, 136.9, 141.4, 142.1. Anal. Calcd for C23H17N: C,
89.87; H, 5.57; N, 4.56. Found: C, 89.61; H, 5.79; N, 4.60.
Synthesis of 6-Cyclohexyl-2-fluoro-11H-benzo[a]carbazole
(2w) (Table 4, Entry 3). By a procedure similar to that described
for the preparation of carbazole 2g, 1w (33 mg, 0.11 mmol) was
converted into 2w (28 mg, 84% yield) as a brown solid by
treatment with C (3.7 mg, 5.3 μmol) and AgOTf (1.3 mg, 5.3
μmol) in acetonitrile (0.53 mL) at 80 °C for 50 min: IR (neat)
3457 (NH) cm-1; 1H NMR (500 MHz, CDCl3) δ 1.35-1.44 (br
m, 1H, Cy), 1.59-1.70 (m, 4H, Cy), 1.89-2.00 (m, 3H, Cy),
2.27-2.28 (br m, 2H, Cy), 3.51-3.55 (br m, 1H, Cy), 7.22-7.26
(m, 1H, Ar), 7.32 (dd, J=7.4, 7.4 Hz, 1H, Ar), 7.42-7.45 (m,
2H, Ar), 7.55 (d, J=8.0 Hz, 1H, Ar), 7.62 (dd, J=9.7, 1.7 Hz,
1H, Ar), 7.89 (dd, J=8.9, 5.4 Hz, 1H, Ar), 8.14 (d, J=8.0 Hz,
1H, Ar), 8.64 (br s, 1H, NH); 13C NMR (125 MHz, CDCl3) δ 26.6,
27.2 (2C), 33.2 (2C), 41.0, 104.3 (d, J=22.8 Hz), 111.1, 115.1, 115.1,
119.9, 120.0, 122.5, 123.7, 124.6, 129.3, 130.8, 130.8, 134.6 (d, J=4.8
Hz), 138.7, 141.4, 160.1 (d, J=244.7 Hz); HRMS (FAB) calcd for
C22H20FN [Mþ] 317.1580, found 317.1575.
Synthesis of 4-Phenyl-2,3-dihydro-1H-benzo[g]indole (5)
(Scheme 3). To a solution of 7 (40 mg, 0.12 mmol) in 1,4-dioxane
(0.50 mL) was added 4 N HCl/1,4-dioxane (0.50 mL, 2.0 mmol)
at room temperature. The mixture was stirred at room tempera-
ture for 19 h and quenched by addition of saturated aqueous
NaHCO3 at room temperature. The aqueous mixture was
extracted with EtOAc, and the layers were separated. The
organic layer was dried over Na2SO4, filtrated, and concen-
trated in vacuo. The residue was purified by column chroma-
tography on amino silica gel with n-hexane/EtOAc (5:1) to
afford 5 (26 mg, 90% yield) as a red oil: IR (neat) 3373 (NH)
1
cm-1; H NMR (400 MHz, CDCl3) δ 3.27 (t, J=8.5 Hz, 2H,
CH2), 3.73 (t, J = 8.5 Hz, 2H, CH2), 3.95 (br s, 1H, NH),
7.32-7.46 (m, 6H, Ar), 7.52-7.55 (m, 2H, Ar), 7.62-7.66 (m,
1H, Ar), 7.79-7.83 (m, 1H, Ar); 13C NMR (125 MHz, CDCl3) δ
30.8, 48.0, 118.8, 120.1, 121.3, 121.8, 124.8, 125.5, 127.0, 128.3
(2C), 128.5 (2C), 128.6, 133.8, 137.4, 141.2, 147.4; HRMS (FAB)
calcd for C18H15N [Mþ] 245.1204, found 245.1206.
Synthesis of 4-Phenyl-2,3-dihydronaphtho[1,2-b]furan (9)
(Scheme 3). By a procedure similar to that described for the
preparation of carbazole 2g, 8 (42 mg, 0.17 mmol) was converted
into 9 (36 mg, 85% yield) as a pale yellow solid by treatment with
C (6.1 mg, 8.6 μmol) and AgOTf (2.2 mg, 8.6 μmol) in acetoni-
trile (0.86 mL) at 80 °C for 40 min: 1H NMR (500 MHz, CDCl3)
δ 3.42 (t, J=8.9 Hz, 2H, CH2), 4.76 (t, J=8.9 Hz, 2H, CH2), 7.36
(dd, J=7.4, 7.4 Hz, 1H, Ar), 7.42-7.46 (m, 5H, Ar), 7.54-7.55
(m, 2H, Ar), 7.82 (dd, J=6.0, 3.2 Hz, 1H, Ar), 7.96 (dd, J=6.0,
3.4 Hz, 1H, Ar); 13C NMR (125 MHz, CDCl3) δ 30.7, 71.9,
118.7, 119.7, 119.8, 121.4, 125.2, 126.1, 127.2, 127.9, 128.3 (2C),
128.5 (2C), 134.2, 137.0, 140.8, 155.8; HRMS (FAB) calcd for
C18H14O [Mþ] 246.1045, found 246.1050.
Synthesis of 5-Phenyl-2-tosyl-1,2,3,10-tetrahydroazepino[3,4-b]-
indole (11a) (Table 5, Entry 2). By a procedure similar to that
described for the preparation of carbazole 2g, 10a (33 mg, 0.079
mmol) was converted into 11a (14 mg, 42% yield) as a brown
solid by treatment with A (2.1 mg, 4.0 μmol) and AgOTf (1.0 mg,
4.0 μmol) in acetonitrile (0.40 mL) at 80 °C for 1.5 h: IR (neat)
Synthesis of 6-Phenyl-11H-pyrido[3,2-a]carbazole (2x) (Table 4,
Entry 4). By a procedure similar to that described for the
preparation of carbazole 2g, 1x (41 mg, 0.14 mmol) was con-
verted into 2x (17 mg, 37% yield) as a brown solid by treatment
with C (20 mg, 0.028 mmol) and AgOTf (7.1 mg, 0.028 mmol) in
acetonitrile (0.69 mL) at 80 °C for 24 h. 1H NMR spectra of 2x
were in good agreement with those previously reported.12
Synthesis of 5-Phenyl-10H-furo[3,2-a]carbazole (2y) (Table 4,
Entry 5). By a procedure similar to that described for the
3369 (NH), 1331 (SdO), 1157 (SdO) cm-1 1H NMR (500
;
MHz, CDCl3) δ 2.32 (s, 3H, C6H4CH3), 3.92 (d, J=6.9 Hz, 2H,
CH2), 4.60 (s, 2H, CH2), 5.97 (t, J=6.9 Hz, 1H, CdCHCH2),
6.63 (d, J=8.0 Hz, 1H, Ar), 6.86 (dd, J=7.4, 7.4 Hz, 1H, Ar),
1226 J. Org. Chem. Vol. 76, No. 5, 2011

Hirano et al.
JOCFeatured Article
7.12 (dd, J=7.4, 7.4 Hz, 1H, Ar), 7.17 (d, J=8.0 Hz, 2H, Ar),
7.25-7.34 (m, 6H, Ar), 7.71 (d, J=8.0 Hz, 2H, Ar), 8.63 (br s,
1H, NH); 13C NMR (125 MHz, CDCl3) δ 21.4, 44.5, 45.8, 111.3,
114.0, 119.7, 120.0, 120.8, 122.4, 126.2, 127.3 (2C), 128.0, 128.1
(2C), 128.2 (2C), 129.7 (2C), 134.2, 135.7, 135.8, 139.6, 143.2,
143.5; HRMS (FAB) calcd for C25H22N2O2S [Mþ] 414.1402,
found 414.1408.
Synthesis of 5-Phenyl-3,10-dihydro-1H-oxepino[3,4-b]indole
(11b) (Table 5, Entry 4). By a procedure similar to that described
for the preparation of carbazole 2g, 10b (38 mg, 0.14 mmol) was
converted into 11b (18 mg, 49% yield) as a brown oil by
treatment with C (5.1 mg, 7.2 μmol) and AgOTf (1.8 mg, 7.2
μmol) in acetonitrile (0.72 mL) at 80 °C for 4 h: IR (neat) 3282
(NH) cm-1; 1H NMR (500 MHz, CDCl3) δ 4.11 (d, J=6.3 Hz,
2H, CH2), 4.83 (s, 2H, CH2), 6.29 (t, J=6.3 Hz, 1H, CdCHCH2),
6.75 (d, J=8.0 Hz, 1H, Ar), 6.91 (ddd, J=7.7, 7.7, 1.1 Hz, 1H,
Ar), 7.16 (ddd, J=7.7, 7.7, 1.1 Hz, 1H, Ar), 7.35-7.38 (m, 4H,
Ar), 7.44-7.46 (m, 2H, Ar), 8.34 (br s, 1H, NH); 13C NMR (125
MHz, CDCl3) δ 63.7, 64.8, 111.2, 114.6, 120.0, 121.1, 122.3,
124.1, 126.4, 127.9, 128.2 (2C), 128.2 (2C), 135.9, 138.7, 140.2,
143.5; HRMS (FAB) calcd for C18H15NO [Mþ] 261.1154, found
261.1153.
(2C); HRMS (FAB) calcd for C18H19NO4 [Mþ] 313.1314, found
313.1305.
Synthesis of 6-Phenyl-11H-benzo[a]carbazole (2c) (Scheme 6).
By a procedure similar to that described for the preparation of
carbazole 2g, 20 (30 mg, 0.102 mmol) was converted into 2c (31
mg, quant) as a yellow solid by treatment with Ph3PAuCl (2.5
mg, 5.1 μmol) and AgOTf (1.3 mg, 5.1 μmol) in acetonitrile (0.51
1
mL) at 80 °C for 40 min. H NMR spectra of 2c were in good
agreement with those previously reported.12
Antifungal Susceptibility Tests. Antifungal susceptibility assay
was performed by the CLSI M38-A2 microdilution method.41
Compounds were assayed at 0.05-100 μM concentrations (2-fold
serial dilutions). The inoculum size was 1 ꢀ 103 to 3 ꢀ 103 CFU/mL
as a final concentration. Ninety-six-well microplates were incubated
at 35 °C for 4 days. MICs were determined as the minimal inhibitory
concentration of drug that produced visually 80% reduction of
turbidity compared to that of the growth control (drug-free
medium). T. mentagrophytes KD-1031 (MYA-4439) and T.
rubrum KD-1137 (MYA-4438) were used as quality control
strains recommended for use in CLSI method (M38-A2).
Cytotoxicity Assays. Cytotoxicity to human embryonic lung
cell (HEL cell) was determined with the MTT assay. Cells were
seeded into 96-well microplates at 1 ꢀ 105 cells/mL as a final
concentration. Then, cells were treated with 0.05 to 100 μM
concentration of each compound. Microplates were incubated
at 37 °C for 72 h under 5% CO2. After incubation, the medium
was removed from the cells. The MTT solution (Eagle’s MEM
supplemented with 0.45 mg/mL MTT and 1% fetal bovine serum)
were added into 96-well microplates and incubated for 4 h. After
incubation, the medium was removed, and formazan crystalswere
solubilized with DMSO. Its optical density was measured at 540
nm, and then the LD50 (lethal doses 50%) was calculated.
Synthesis of Dimethyl 10-Phenyl-6,8-dihydrocyclohepta[b]-
indole-7,7(5H)-dicarboxylate (11c) (Table 5, Entry 5). By a
procedure similar to that described for the preparation of
carbazole 2g, 10c (35 mg, 0.092 mmol) was converted into 11c
(22 mg, 63% yield) as a colorless solid by treatment with C (3.3
mg, 4.6 μmol) and AgOTf (1.2 mg, 4.6 μmol) in acetonitrile (0.46
mL) at 80 °C for 2.5 h: IR (neat) 3329 (NH), 1726 (CdO) cm-1
;
1H NMR (500 MHz, CDCl3) δ 2.62 (d, J=6.9 Hz, 2H, CH2),
3.31 (s, 2H, CH2), 3.74 (s, 6H, 2 ꢀ CO2CH3), 6.43 (t, J=6.9 Hz,
1H, CdCHCH2), 6.85 (d, J=7.4 Hz, 1H, Ar), 6.91 (dd, J=7.4,
7.4 Hz, 1H, Ar), 7.12 (dd, J=7.4, 7.4 Hz, 1H, Ar), 7.30-7.31 (br
m, 3H, Ar), 7.36 (d, J=8.0 Hz, 1H, Ar), 7.40-7.42 (br m, 2H,
Ar), 8.55 (br s, 1H, NH); 13C NMR (125 MHz, CDCl3) δ 31.4,
33.4, 52.8 (2C), 70.3, 110.9, 112.6, 119.7, 120.3, 121.5, 122.9,
126.6, 127.5, 127.6 (2C), 128.1 (2C), 135.6, 138.1, 139.8, 141.1,
171.7 (2C); HRMS (FAB) calcd for C23H21NO4 [Mþ] 375.1471,
found 375.1471.
Acknowledgment. This work was supported in part by the
Japan Science and Technology Agency (JST). We are grate-
ful for a Grant-in-Aid for Scientific Research on Innovative
Areas “Integrated Organic Synthesis” (H.O.) and the Tar-
geted Proteins Research Program from the Ministry of
Education, Culture, Sports, Science and Technology of
Japan, as well as the Program for Promotion of Fundamen-
tal Studies in Health Sciences of the National Institute of
Biomedical Innovation (NIBIO).
Synthesis of (E)-Dimethyl 4-Ethylidene-3,4-dihydro-1H-car-
bazole-2,2(9H)-dicarboxylate [(E)-13] (Scheme 4). By a proce-
dure similar to that described for the preparation of carbazole
2g, 12 (31 mg, 0.099 mmol) was converted into (E)-13 (17 mg,
34% yield) as a pale yellow solid by treatment with C (3.5 mg, 5.0
μmol) and AgOTf (1.3 mg, 5.0 μmol) in acetonitrile (0.50 mL) at
80 °C for 3 h: IR (neat) 3423 (NH), 1739 (CdO) cm-1; 1H NMR
(400 MHz, C6D6) δ: 1.84 (d, J=6.8 Hz, 3H, CH3CHdC), 3.26
(s, 2H, CH2), 3.28 (s, 6H, 2 ꢀ CO2CH3), 3.35 (s, 2H, CH2), 6.25
(q, J=6.9 Hz, 1H, CH3CH=C), 6.68 (br s, 1H, NH), 6.99-7.03
Supporting Information Available: 1H and 13C NMR spec-
tra of all new compounds are provided. This material is available
free of charge via the Internet at http://pubs.acs.org.
(m, 1H, Ar), 7.15-7.20 (m, 2H, Ar), 7.91-7.94 (m, 1H, Ar); 13
NMR (125 MHz, C6D6) δ 13.3, 30.0, 32.5, 52.4 (2C), 55.6, 111.3,
111.9, 116.2, 120.5, 120.7, 121.9, 125.5, 129.1, 132.5, 137.1, 171.2
C
(41) Clinical and Laboratory Standards Institute (CLSI). Reference
method for broth dilution antifungal susceptibility testing of filamentous fungi;
Approved standard, 2nd ed.; M38-A2; Clinical and Laboratory Standards
Institute: Wayne, PA, 2008.
J. Org. Chem. Vol. 76, No. 5, 2011 1227