Development of an Efficient Procedure for Indole Ring Synthesis from 2-Ethynylaniline Derivatives Catalyzed by Cu(II) Salts and Its Application to Natural Product Synthesis

Article abstract of DOI:10.1021/jo035528b

The development of efficient methods for the indole synthesis catalyzed by Cu(II) salts and its applications were investigated. Cu(OAc)₂ has been proved to be the best catalyst for the synthesis of various 1-p-tolylsulfonyl or 1-methylsulfonylindoles, which have both electron-withdrawing and electron-donating groups on the aromatic ring and C2 position of indoles. For the primary aniline derivatives, Cu(OCOCF ₃)₂ showed good activities, while Cu(OAc)₂ was a good catalyst for the cyclization of secondary anilines. This methodology could be applied to the sequential cyclization reaction for the compounds which have the electrophilic part in the same molecule. By prior treatment with KH, the sequential cyclization was realized to provide the tricyclic ring systems, but it was limited to five- and six-membered rings for the second cyclization. Finally, formal and total synthesis of hippadine with the Cu(II)-promoted indole synthesis as the key step was accomplished.

Full text of DOI:10.1021/jo035528b

Develop m en t of a n Efficien t P r oced u r e for In d ole Rin g Syn th esis
fr om 2-Eth yn yla n ilin e Der iva tives Ca ta lyzed by Cu (II) Sa lts a n d
Its Ap p lica tion to Na tu r a l P r od u ct Syn th esis
Kou Hiroya,* Shin Itoh, and Takao Sakamoto
Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba-ku, Sendai 980-8578, J apan
hiroya@mail.tains.tohoku.ac.jp
Received October 16, 2003
The development of efficient methods for the indole synthesis catalyzed by Cu(II) salts and its
applications were investigated. Cu(OAc)2 has been proved to be the best catalyst for the synthesis
of various 1-p-tolylsulfonyl or 1-methylsulfonylindoles, which have both electron-withdrawing and
electron-donating groups on the aromatic ring and C2 position of indoles. For the primary aniline
derivatives, Cu(OCOCF3)2 showed good activities, while Cu(OAc)2 was a good catalyst for the
cyclization of secondary anilines. This methodology could be applied to the sequential cyclization
reaction for the compounds which have the electrophilic part in the same molecule. By prior
treatment with KH, the sequential cyclization was realized to provide the tricyclic ring systems,
but it was limited to five- and six-membered rings for the second cyclization. Finally, formal and
total synthesis of hippadine with the Cu(II)-promoted indole synthesis as the key step was
accomplished.
In tr od u ction
sequential C3 functionalization9-13 and polymer-sup-
ported reactions14 also have been established recently.
However, not only the palladium-mediated reactions, but
also other reagents are known to have some disadvan-
tages depending on the nature of the reagents, namely,
(i) metal alkoxide mediated reactions cannot be applied
to the alkaline-sensitive substrates,6 (ii) the carbonyl or
sulfonyl groups have to be on the nitrogen atom for most
procedures (e.g., sulfonamides, amides, and carbamates
are usually used),15 and (iii) there have been no efficient
Heterocyclic compounds, particularly indoles, are of
interest because they widely occur in nature as partial
structures of alkaloids and having unique biological
activities.1 As the synthetic procedures for the function-
alized 2-ethynylaniline derivatives already have been
established,2 the methods for indole syntheses with these
compounds as the starting materials are some of the most
efficient procedures. Thus far, many kinds of reagents
have been reported for indole syntheses from 2-ethynyl-
aniline derivatives.2-9 Among these reagents, the most
frequently used reagents (catalysts) are the palladium
complexes,2-5 and many applications including both
(6) (a) Sakamoto, T.; Kondo, Y.; Iwashita, S.; Yamanaka, H. Chem.
Pharm. Bull. 1987, 35, 1823. (b) Sakamoto, T.; Kondo, Y.; Yamanaka,
H. Heterocycles 1986, 24, 1845. (c) Sakamoto, T.; Kondo, Y.; Yamanaka,
H. Heterocycles 1986, 24, 31.
* Corresponding author.
(7) Yasuhara, A.; Kanamori, Y.; Kaneko, M.; Numata, A.; Kondo,
Y.; Sakamoto, T. J . Chem. Soc., Perkin Trans. 1 1999, 529.
(8) (a) Koradin, C.; Dohle, W.; Rodriguez, A. L.; Schmid B.; Knochel,
P. Tetrahedron 2003, 59, 1571. (b) Rodriguez, A. L.; Koradin, C.; Dohle,
W.; Knochel, P. Angew. Chem., Int. Ed. 2000, 39, 2488. (c) Dai, W. M.;
Sun, L. P.; Guo, D. S. Tetrahedron Lett. 2002, 43, 7699. (d) Dai, W.
M.; Guo, D. S.; Sun, L. P. Tetrahedron Lett. 2001, 42, 5275.
(9) For review, see: Battistuzzi, G.; Cacchi, S.; Fabrizi, G. Eur. J .
Org. Chem. 2002, 2671.
(10) (a) Cacchi, S.; Fabrizi, G.; Pace, P. J . Org. Chem. 1998, 63, 1001.
(b) Iritani, K.; Matsubara, S.; Uchimoto, K. Tetrahedron Lett. 1988,
29, 1799.
(11) (a) Cacchi, S.; Fabrizi, G.; Marinelli, F.; Moro, L.; Pace, P.
Synlett 1997, 1363. (b) Arcadi, A.; Cacchi, S.; Carnicelli, V.; Marinelli,
F. Tetrahedron 1994, 50, 437.
(12) Yasuhara, A.; Kaneko, M.; Sakamoto, T. Heterocycles 1998, 48,
1793.
(13) (a) Cacchi, S.; Fabrizi, G.; Pace, P.; Marinelli, F. Synlett 1999,
620. (b) Kondo, Y.; Shiga, F.; Murata, N.; Sakamoto, T.; Yamanaka,
H. Tetrahedron 1994, 50, 11803.
(14) (a) Dai, W.-M.; Guo, D.-S.; Sun, L.-P.; Huang, X.-H. Org. Lett.
2003, 5, 2919. (b) Yamazaki, K.; Nakamura, Y.; Kondo, Y. J Org. Chem.
2003, 68, 6011. For review, see: (c) Bra¨se, S.; Kirchhoff, J . H.;
Ko¨bberling, J . Tetrahedron 2003, 59, 885.
(15) Only a limited number of examples for unsubstituted aniline
cyclization reactions have been reported. See refs 3c, 5b,d-f, 8, and
10b.
(1) (a) Gribble, G. W. J . Chem. Soc., Perkin Trans. 1 2000, 1045. (b)
Gribble, G. W. Comprehensive Heterocyclic Chemistry II; Katritzky,
A. R., Rees, C. W., Scriven, E. F. V., Ed.; Pergamon Press: Oxford,
UK, 1996;, Vol. 2, p 207.
(2) (a) Kondo, Y.; Kojima, S.; Sakamoto, T. J . Org. Chem. 1997, 62,
6507. (b) Ezquerra, J .; Pedregal, C.; Lamas, C.; Barluenga, J .; Pe´rez,
M.; Garc´ıa-Mart´ın, M. A.; Gonza´lez, J . M. J . Org. Chem. 1996, 61, 5804.
(c) Kondo, Y.; Kojima, S.; Sakamoto, T. Heterocycles 1996, 43, 2741.
(d) Rudisill, D. E.; Stille, J . K. J . Org. Chem. 1989, 54, 5856.
(3) (a) Barluenga, J .; Trincado, M.; Rubio, E.; Gonza´lez, J . M. Angew.
Chem., Int. Ed. 2003, 42, 2406. (b) Arcadi A.; Cacchi, S.; Fabrizi, G.;
Marinelli, F. Synlett 2000, 647. (c) McDonald, F. E.; Chatterjee, A. K.
Tetrahedron Lett. 1997, 38, 7687.
(4) Recent review for palladium-catalyzed cyclization reactions,
see: Larock, R. C. J . Organomet. Chem. 1999, 576, 111.
(5) (a) Kamijo, S.; Yamamoto, Y. J . Org. Chem. 2003, 68, 4764. (b)
Esseveldt, B. C. J .; Delft, F. L.; Gelder, R.; Rutjes, F. P. J . T. Org.
Lett. 2003, 5, 1717. (c) Kamijo. S.; Yamamoto Y. Angew. Chem., Int.
Ed. 2002, 41, 3230. (d) Takeda, A.; Kamijo. S.; Yamamoto, Y. J . Am.
Chem. Soc. 2000, 122, 5662. (e) Yu, M. S.; Leon, L. L.; McGguire, M.
A.; Botha, G. Tetrahedron Lett. 1998, 39, 9347. (f) Larock, R. C.; Yum,
E. K.; Refvik, M. D. J . Org. Chem. 1998, 63, 7652. (g) Cacchi, S.;
Carnicelli, V.; Marinelli, F. J . Organomet. Chem. 1994, 475, 289. (h)
Sakamoto, T.; Kondo, Y.; Iwashita, S.; Nagano, T.; Yamanaka, H.
Chem. Pharm. Bull. 1988, 36, 1305. (i) Arcadi, A.; Cacchi, S.; Marinelli,
F. Tetrahedron Lett. 1989, 30, 2581.
10.1021/jo035528b CCC: $27.50 © 2004 American Chemical Society
Published on Web 01/16/2004
1126
J . Org. Chem. 2004, 69, 1126-1136

Indole Ring Synthesis from 2-Ethynylaniline Derivative
F IGURE 1.
F IGURE 2.
TABLE 1. Lew is Acid P r om oted Cycliza tion Rea ction s
of th e Su lfon a m id e 1a
reagents developed for the cyclization reaction of 2-ethy-
nylaniline derivatives which have an electron-withdraw-
ing group on the acetylene terminal. Recently, Knochel
et al.8a,b reported the efficient indole formation of unsub-
t
stituted aniline derivatives mediated by BuOK, KH, or
tBuOCs in NMP. Although the cyclization reactions can
occur at room temperature based on their conditions and
that can be applied for the various substrates which
contain hydroxyl groups, acetals, amino groups, and
amides (for the linker with resin), it seems to be an
unsolved problem as to whether alkaline-sensitive func-
tional groups can be tolerated under the reaction condi-
tions.
From the background described above, we decided to
develop an efficient and general procedure that can be
applied to a wide variety of molecules, especially those
that have never been cyclized to indoles. Herein, we now
report the mild, applicable, and versatile method for
indole cyclization catalyzed by Cu(II) salts and its ap-
plication to the sequential cyclization reaction (Figure
1).16
temp
(°C)
time
(h)
yield
(2a ) (%) (1a ) (%)
recovery
entry Lewis acid (equiv)
1
2
3
4
5
6
7
BF3‚OEt2 (1.5)
TiCl4 (3)
100
100
reflux 24
reflux 72
17
22
13
14
8
12
dec
28
89
87
69
92
86
Ti(OiPr)4 (3)
ZnCl2 (3)
AlCl3 (3)
Sn(OTf)2 (3)
Cu(OTf)2 (3)
60
2.5
reflux 24
reflux 10
13
0
effectively promote the cyclization reaction and 1a was
mainly recovered (entries 1-4). AlCl3 and Sn(OTf)2
induced the decomposition of the substrate (entries 5 and
6). Among the tested Lewis acids, Cu(OTf)2 showed an
effective promotion of the cyclization reaction (entry 7).
In 1995, Saulnier et al. reported the Cu(OAc)2-promoted
indole formation reaction, when they tried to react
2-ethynyltrifluroacetanilide to synthesize the homo coupled
product.17 To the best of our knowledge, there has been
no report about Cu(II) salt-mediated indole cyclization
reactions except for this report.18
We next investigated the effect of the counteranion and
the catalytic version of this reaction (Table 2). In the
presence of 20 mol % of Cu(OTf)2, indole 4a was afforded
in 74% yield together with 19% of recovered 3a (entry
1). Surprisingly, both Cu(OMs)219 and Cu(OTs)219 did not
show any catalytic activities (entries 2 and 3). Arduini
et al. reported that the nature of the Cu(II)-oxygen atom
bond for Cu(II) sulfate is highly dependent on the acidity
of the conjugated acid of the counteranion, which means
Resu lts a n d Discu ssion
Th e Su r vey a n d th e Op tim iza tion of th e Rea ction
Con d ition s. For the effective catalytic cyclization reac-
tion starting from 2-ethynylaniline derivatives, the triple
bond first has to be activated by Lewis acids, which must
not form a strong complex with the nitrogen atom. When
the bond between the nitrogen and carbon atoms has
been made, the metal-carbon bond at C3 (indole number)
will be cleaved by the proton originally bound to the
nitrogen atom, then the catalytic cycle will be ac-
complished (Figure 2).
Therefore, one of the key features to realize this
reaction is finding some compound(s) that can selectively
activate the triple bond. For this purpose, we decided to
start surveying various Lewis acids employing the sul-
fonamides as the substrate which have the highest
reactivity toward these kinds of the cyclization reactions
(Table 1). BF3‚OEt2, TiCl4, Ti(OiPr)4, and ZnCl2 did not
(17) Saulnier, M. G.; Frennesson, D. B.; Deshpande, M. S.; Vyas,
D. M. Tetrahedron Lett. 1995, 36, 7841.
(18) Cyclization reactions of 2,3-allenoic acid and allenamide pro-
moted by CuX2 (X ) Cl or Br) have been reported: (a) Ma, S.; Xie, H.
Org. Lett. 2000, 2, 3801. (b) Ma, S.; Wu, S. J . Org. Chem. 1999, 64,
9314.
(16) Part of this work has been communicated previously: Hiroya,
K.; Itoh, S.; Ozawa, M.; Kanamori, Y.; Sakamoto, T. Tetrahedron Lett.
2002, 43, 1277.
(19) Arduini, A. L.; Garnett, M.; Thompson, R. C.; Wong, T. C. T.
Can. J . Chem. 1975, 53, 3812.
J . Org. Chem, Vol. 69, No. 4, 2004 1127

Hiroya et al.
TABLE 2. Cycliza tion Rea ction of 1a or 3a Ca ta lyzed by Va r iou s Cu (II) Sa lts
entry
substrate
catalyst
time (h)
yield (%)
recovery (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
1a
1a
1a
Cu(OTf)2
Cu(OMs)2
Cu(OTs)2
Cu(OBz)2
Cu(OAc)2
48
48
48
48
27
48
40
46
48
48
48
48
48
48
72
48
74 (4a )
0
0
19 (3a )
quant. (3a )
quant. (3a )
67 (3a )
33 (4a )
98 (4a )
56 (4a )
94 (4a )
0
trace
8 (4a )
trace
0
0
Cu(OCOCF3)2‚xH2O
Cu(OCHO)2‚xH2O
Cu[CH(OH)COO]2‚xH2O
Cu(ClO4)2‚6H2O
44 (3a )
0
quant. (3a )
61 (3a )
92 (3a )
Cu(BF4)2‚xH2O
Cu(NO3)2‚3H2O
85 (3a )
Cu[Et2NCSS]2
quant. (3a )
quant. (3a )
quant. (1a )
93 (1a )
Cu bis(8-hydroxyquinolinate)
CuBr2 (10 mol %)
CuF2 (10 mol %)
0
0
7 (2a )
0
CuCl2 (400 mol %)
quant. (1a )
TABLE 3. Cycliza tion Rea ction of th e Va r iou s
Su bstr a tes Ca ta lyzed by Cu (OAc)2
that the Cu(II)-oxygen bond will have a more ionic
character when the oxygen comes from the conjugated
base of a stronger sulfonic acid.19 According to their
argument, the Cu(II)-O character of Cu(OMs)2 and Cu-
(OTs)2 will be more covalent than that of Cu(OTf)2 and
it seems likely that the trifluoromethanesulfonic anion
can easily be eliminated when the Cu(II) atom coordi-
nates to the acetylene. Therefore, we speculated that the
elimination of the counteranion must be essential for
these reactions.
sub-
time yield recovery
entry strate R1
R2
R3
R4 (h)
(%)
(%)
On the other hand, Cu(II) carboxylates tended to show
higher catalytic activities than Cu(OTf)2. Cu(OAc)2 is the
best catalyst for this substrate among the tested Cu(II)
salts (entry 5). However, a lower reaction rate was
observed when Cu(OBz)2 was used as the catalyst (entry
6). The reason for the difference between Cu(OAc)2 and
Cu(OBz)2 has not yet been clarified, but one possibility
is the difference in the solubility in 1,2-dichloroethane.
Before starting the reactions, we expected the salts,
which contain crystalline water, will have either lower
or no catalytic activities. Although Cu(II) tartrate hydrate
did not show any activities, Cu(OCOCF3)2‚xH2O and Cu-
(OCHO)2‚xH2O catalyzed the reaction, especially the
latter showed an almost comparable activity as Cu(OAc)2
(entries 6, 7, and 8). These results suggest that this
reaction was not sensitive for moisture to the solvent,
which will be a great advantage for practical uses. As
the structures of the Cu(II) carboxylates are known to
be dimeric,20 it seems likely that one copper atom assists
in the elimination of the carboxylate residue from the
other copper atom. Again, it is also suggested that the
elimination of the counteranion from the copper atom is
crucial for these cyclization reactions to occur.
1
2
3
4a
5
6
7
8
9
1a
1b
1c
1d
1e
1f
1g
1h
1i
H
H
H
H
H
H
H
Br
CN
H
H
Ph
Bu
H
Ms 18
Ms 20
94 (2a )
91 (2b)
0
H
H
H
H
H
H
H
H
0
0
0
0
Ms
1.5 87 (2c)
CH2OH Ts
2
76 (2d )
79 (2e)
22 (2f) 74 (1f)
9 (2g) 64 (1g)
76 (2h )
74 (2i)
95 (2j)
97 (2k )
CO2Me Ms 24
tBu
TMS
Ph
Ms 72
Ms 72
Ms
7
0
0
0
0
Ph
Ms 50
Ms 38
10
11
1j
1k
OMe Ph
Ph
Me
H
Ms
6
a
20 mol % of Cu(OAc)2 was used.
The other Cu(II) salts, which include the inorganic and
halogen counteranions, did not afford satisfactory results
(entries 9-16).
At this stage, we concluded that Cu(OAc)2 is the best
catalyst for the sulfonamide. We next applied this condi-
tion to the functionalized substrates and these results
are summarized in Table 3. The chemical properties of
substituents on the acetylene terminal (R3) did not affect
the yields of the indoles, even if the hydroxyl group is
present in the molecule (entries 1-5). However, the
balkiness of the substituents has significant effect on the
yield of the indoles. Namely, when the substituents are
too big to inhibit the approach of the catalyst and/or
(20) (a) Cotton, F. A.; Wilkinson, G.; Murillo, C. A.; Bochmann, M.
Advanced Inorganic Chemistry, 6th ed.; J ohn Wiley & Sons: NewYork,
1999; p 870. (b) Crystal structure of Cu(OCOCF3)2‚xH2O: Karpova,
E. V.; Boltalin, A. I.; Zakharov, M. A.; Sorokina, N. I.; Korenev, Y. M.
Z. Anorg. Allg. Chem. 1998, 624, 741. (c) Crystal structure of Cu-
(OCHO)2‚xH2O: Kiriyama, R.; Ibamoto, H.; Matsuo, K. Acta Crystallogr.
1954, 7, 482.
t
nitrogen atom such as Bu and TMS, the yields signifi-
cantly decreased (entries 6 and 7). The remarkable
feature of the Cu(II) salt-catalyzed reaction is the ability
to synthesize the indole, which has an electron-with-
1128 J . Org. Chem., Vol. 69, No. 4, 2004

Indole Ring Synthesis from 2-Ethynylaniline Derivative
TABLE 4. Cycliza tion Rea ction of th e Ca r ba m a tes Ca ta lyzed by Cu (II) Sa lts
entry
substrate
R1
R2
catalyst (mol %)
Cu(OAc)2 (10)
time (h)
yield (%)
20 (6a )
recovery (%)
1
2
3
4
5
5a
5a
5a
5a
5a
Ph
Ph
Ph
Ph
Ph
OEt
OEt
OEt
OEt
OEt
72
48
48
48
28
65 (5a )
quant. (5a )
quant. (5a )
38 (5a )
0
Cu(OBz)2 (20)
0
0
Cu(OCHO)2‚xH2O (20)
Cu(OCOCF3)2‚xH2O (20)
Cu(OTf)2 (10)
33 (6a ), 28 (9a )a
88 (6a )
6
7
8
9
10
11
5b
5c
5d
5g
7a
7a
Bu
H
CH2OH
TMS
Ph
OEt
OEt
OEt
OEt
Me
Cu(OTf)2 (10)
Cu(OTf)2 (10)
Cu(OTf)2 (20)
Cu(OTf)2 (20)
Cu(OAc)2 (20)
Cu(OTf)2 (20)
48
48
19
21
48
48
81 (6b)
35 (6c)
0
4 (5c)
0
0
quant. (7a )
0
dec
28 (R1 ) H) (6c)
0
dec
Ph
Me
a
9a : 2-phenylindole.
drawing group at C-2 (indole number) (entry 5). In this
case, the dimeric product was not observed at all and only
2-carbomethoxylindole 2e was isolated. To the best of our
knowledge, the cyclization reactions of such substrates
have not been reported with use of any other reagents.
The functional group(s) on the aromatic ring also did
not affect the reaction efficiency, namely, in the presence
of either electron-withdrawing groups (bromine and
nitrile; entries 8 and 9) or electron-donating groups
(methoxyl and methyl; entries 10 and 11), the yield of
the indoles were within 70-95%.
To investigate the scope and limitations of the Cu(II)-
catalyzed indole syntheses, we next tried to use a series
of carbamates and acetate as the substrates (Table 4).
In contrast to the sulfonamides, the Cu(II)-carboxylates
did not give satisfactory results, only recovery of the
starting material (entries 2 and 3) or a yield only twice
the amount of the catalyst (entry 1). Only Cu(OCOCF3)2‚
xH2O gave the indole in 61% yield, but almost half of the
product was decarboethoxylated 9a (entry 4). The best
catalyst for the carbamates 5a and 5b was Cu(OTf)2,
which catalyzed the cyclization reaction in 81-88% yield
(entries 5 and 6), but it is apparent that even this salt
did not show general application properties for the other
substrates (e.g., entries 8 and 9). Furthermore, the
corresponding acetamide 7a was negative toward this
cyclization reaction by any tested Cu(II) salts and only
the recovered starting materials were observed (entries
10 and 11).21
and the acidity of the hydrogen atom on the nitrogen
seems to be not high enough. Thus, we tested the reaction
using the five different Cu(II) salts and 2-phenylethynyl-
aniline 8a as the substrates (Table 5). As a result, Cu-
(OTf)2, Cu(OBz)2, and the Cu(OCOCF3)2‚xH2O catalyzed
the cyclization reactions, especially, the third compound
produced the fastest and cleanest reaction (entries 2, 3,
and 5). This compound can also be applied to other
substrates which have various substituents on the aro-
matic ring (entries 6-9). The secondary amines 10a ,c,m
also could be cyclized into the corresponding indole rings
by Cu(OAc)2 catalysis in good yield (entries 10, 11, and
12).
Rea ction Mech a n ism . From the results described
above, it is likely that the reactivity of the substrates was
highly dependent on the acidity of the proton on the
nitrogen atom. This hypothesis was confirmed by the
reactions in the presence of an extra base (Scheme 1).
When the cyclization reaction was performed in the
presence of 2 equiv of 1-ethylpiperidine, the reaction rate
was highly accelerated and the corresponding indole was
afforded even at room temperature. As we have already
confirmed that the reaction did not progress at all in the
absence of Cu(OAc)2, it is apparent that the amine base
might facilitate the reaction by assistance with the
deprotonation from the nitrogen atom.
Therefore, we speculate that the mechanism of the Cu-
(II)-catalyzed cyclization reaction for the sulfonamides
and carbamates is as shown in Figure 3.
The catalytic process starts from the ligation of the
acetylene moiety to the copper atom (A f B). From
intermediate B, two different pathways can be considered
depending on the counteranion (X-). If the counteranion
is not a strong enough base to remove the proton on the
nitrogen atom, the lone pair may attack the activated
acetylene to produce D, next the proton will be eliminated
by the counteranion (B f C f D). On the other hand, if
the counteranion is strong enough to remove the proton
on the nitrogen atom, deprotonation will occur first,
followed by cyclization (B f E f F ). Finally, the C3
position of the indole is protonated and the catalyst is
regenerated (F f G). For this reaction, more electrophilic
We next investigated the application of the Cu(II)-
catalyzed cyclization reactions to the unsubstituted
aniline derivatives. In general, the cyclization of the
unsubstituted aniline derivatives seems to be useful
because the substituents on the nitrogen atom do not
have to be added and there have been only a few reports
about the cyclization of such substrates.15 However,
before starting the investigation, we had doubts about
the possibility of these reactions, because the Cu(II) salt
could bind tightly to the lone pair of the nitrogen atom
(21) The same observation has been reported for the solid-phase
reaction. See ref 14a.
J . Org. Chem, Vol. 69, No. 4, 2004 1129

Hiroya et al.
TABLE 5. Cycliza tion Rea ction of Un su bstitu ted An ilin es Ca ta lyzed by Cu (II) Sa lts
entry
substrate
catalyst
Cu(OAc)2
Cu(OTf)2
Cu(OBz)2
Cu(OCHO)2‚xH2O
Cu(OCOCF3)2‚xH2O
R1
R2
R3
R4
time (h)
yield (%)
1
2
3
4
5
8a
8a
8a
8a
8a
H
H
H
H
H
H
Ph
Ph
Ph
Ph
Ph
H
H
H
H
H
48
1.5
48
48
2
32 (9a )a
63 (9a )
79 (9a )
32 (9a )b
72 (9a )
H
H
H
H
6
7
8
9
8h
8j
8k
8l
Cu(OCOCF3)2‚xH2O
Cu(OCOCF3)2‚xH2O
Cu(OCOCF3)2‚xH2O
Cu(OCOCF3)2‚xH2O
Br
H
Me
H
H
OMe
H
Ph
Ph
Ph
Ph
H
H
H
H
4
6
2.5
24
83 (9h )
58 (9j)
71 (9k )
84 (9l)
CN
PMBd
PMBd
iPr
48
48
48
92 (11a )
89 (11c)
100 (11m )
c
10
11
12
10a
10c
10m
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
H
H
H
H
H
H
Ph
H
(CH2)4OTBS
a
b
d
67% of 8a was recovered. 64% of 8a was recovered (yields were calculated from 1H NMR). c 40 mol % of Cu(OAc)2 was used. PMB:
p-methoxybenzyl
have been developed with use of Pd(II) catalysts.9 How-
ever, the reactants for this reaction were limited to the
allyl halides,10 aryl halides,11 vinyl triflates,11b olefin
(Heck reaction),12 and carbon monoxide (carbonylation).13
In the Cu(II)-catalyzed reaction, the catalyst was regen-
erated by quenching of the C3-CuX species by the proton
that was originally bound on the nitrogen atom. There-
fore, we tried to examine our cyclization reaction of the
compounds having the electrophilic part in the same
molecule that was treated with base to remove the proton
on the nitrogen group to realize the sequential cyclization
reaction that cannot be done by the Pd catalysis.
Three kinds of substrates were synthesized from 12
in the same way by the standard 4-step sequences
(Scheme 2). The aldehyde 20 was synthesized from 13a
in 5 steps and in good overall yield.
For developing the optimum conditions, we chose 16a
as the substrate and surveyed the reaction conditions
(Table 6). For the reaction without the base treatment,
the monocyclized indole was obtained almost quantita-
F IGURE 3.
tively as the sole product (entry 1). The base-promoted
cyclization reaction can be neglected (entry 2). The
SCHEME 1
combination of KH and Cu(OAc)2 seems to be essential
for this reaction, but the amount of Cu(OAc)2 is impor-
tant, namely, the excess amount of copper salts produced
a lower yield, but a smaller amount of the reagent needed
a longer reaction time and the yield was also disappoint-
ing (entries 4, 5, and 6). The high reaction temperature
also caused the low yield (entry 7). The solvent is another
important factor for this reaction and 1,2-dichloroethane
copper might favor the activation of the acetylene moiety
was the best solvent among those tested (entries 5, 8,
toward nucleophilic attack, but a stronger base could be
more efficient in the cyclization step on the pathway B
f F f G. The different reactivity depending on the
copper salts and the nature of R1 might depend on a
different balance between these two effects. For the
group. The yields of the tricyclic compounds were de-
unsubstituted and secondary anilines, the coordination
of the copper atom between acetylene moiety and nitro-
gen atom cannot be ruled out.
and 9).
To clarify the scope and limitation of this reaction, we
tested both substrates which have longer carbon chains
than 16a and a carbonyl group instead of a tosyloxy
pressed corresponding to the length of the carbon chain
and only the monocyclized compound 22c was isolated
when 16c was reacted. As a consequence, it appeared
that the second cyclization reaction can be applied for
only five- and six-membered-ring syntheses (Scheme 3).
Sequ en tia l Cycliza tion Rea ction s. The spontaneous
indole cyclization and C-3 functionalization reactions
1130 J . Org. Chem., Vol. 69, No. 4, 2004

Indole Ring Synthesis from 2-Ethynylaniline Derivative
SCHEME 2
TABLE 6. Th e Sequ en tia l Cycliza tion Rea ction s
yield (%)
22a
entry
Lewis acid (mol %)
Cu(OAc)2 (50)
base
solvent
toluene
toluene
toluene
toluene
toluene
toluene
toluene
temp. (°C)
time (h)
21a
1
2
3
4
5
6
7
8
9
70
70
70
70
70
70
reflux
70
70
48
48
48
48
48
72
20
48
48
100
9
KH
KH
KH
KH
KH
KH
KH
KH
7
46
26
51
20
40
28
67
Cu(OTf)2 (50)
Cu(OAc)2 (120)
Cu(OAc)2 (50)
Cu(OAc)2 (20)
Cu(OAc)2 (50)
Cu(OAc)2 (50)
Cu(OAc)2 (50)
trace
trifluorotoluene
1,2-dichloroethane
SCHEME 3
SCHEME 4
(Scheme 4). Further studies on the other kind of sequen-
tial reactions are now in progress.
Syn th esis of Hip p a d in e. Hippadine 24 was one of
the lycorine alkaloids isolated from various species of
Amaryllidaceae and known to have inhabitation effects
on fertility in male rats.22 Due to its unique structure,
hippadine 24 had been synthesized by many organic
chemists using independent approaches.23 As we wanted
to synthesize the indole part of hippadine 24 at the later
Not only the application to larger ring formations but
also the trapping reaction by the carbonyl was disap-
pointing. The only indole aldehyde 23 was isolated when
even a stoichiometric amount of Cu(OAc)2 was used
(22) Ghosal, S.; Rao, P. H.; J aiswal, D. K.; Kumar, Y.; Frahm, A.
W. Phytochemistry 1981, 20, 2003.
J . Org. Chem, Vol. 69, No. 4, 2004 1131

Hiroya et al.
SCHEME 5
F IGURE 4.
stage of the synthesis, we have to first construct the
bisaromatic compound. To realize this basic idea, we
considered synthesizing 26 by the palladium-catalyzed
Suzuki-Miyaura coupling reaction between the boronic
ester 27 and iodide 28. The iodine atom of 28 could be
introduced to the ortho position of the nitrogen function
of 29 by using a regioselective lithiation reaction2b,c
(Figure 4).
N-Boc-2-iodoaniline 31, which was synthesized from
commercially available 2-iodoaniline 30 with a standard
procedure, was subjected to the Sonogashira coupling
reaction with TMS-acetylene to afford 32 in a good
overall yield. The regioselective lithiation reaction of 32
t
was successful by reacting with BuLi in Et2O at -20 °C
subjected to the Bischler-Napieralski reaction with
(TfO)2O and DMAP23f,25 that directly provided hippadine
24 via the cyclic acetal 36, followed by an air oxidation
reaction, although the yield has to be improved (Scheme
6).
and the resulting lithium salt was trapped by the iodine
atom at -100 °C using 1,2-diiodoethane to afford 282c in
82% yield. The palladium-catalyzed Suzuki-Miyaura
coupling reaction between the iodide 28 and easily
available 27 (which contains some amounts of anhydride)
was carried out under standard conditions to produce the
bisaromatic compound 33 in 72% yield, followed by the
TMS group that was eliminated under solvolysis condi-
tions (Scheme 5).
Con clu sion
We have developed a relatively general and efficient
method for indole cyclization reactions from 2-ethynyl
aniline derivatives. The distinctive features of our reac-
tions are the following:
(1) The Cu(II)-catalyzed reaction can be applied to not
only the sulfonamides, but also the unsubstituted pri-
mary and secondary aniline derivatives. The yield of the
Cu(II)-promoted cyclization reaction is not affected by the
chemical properties of the substituted groups on both the
aromatic ring and acetylene terminal. However, the
yields of the indoles are dependent on the bulkiness of
the substituents on the acetylene terminal.
(2) It is possible to realize the sequential cyclization
reaction of the 2-ethynyl aniline derivatives which have
a leaving group in the same molecule. However, the
product for this reaction is limited to the five- and six-
membered rings for the second cyclization.
Thus, we could demonstrate the application of the Cu-
(II)-promoted cyclization reaction for the hippadine syn-
thesis. Further studies including the synthesis of the
As the substrate for the indole synthesis had been
furnished in good overall yield, we next examined the
cyclization reaction of 26. When a solution of 26 in 1,2-
dichloroethane in the presence of a stoichiometric amount
of Cu(OAc)2 was refluxed for 5 h, the 1-Boc-indole 25 was
produced in 80% yield. The Boc group of 25 was elimi-
nated under acidic conditions to provide indole 34, which
was converted to hippadine 24 by Banwell et al.23g in 4
steps, thus formal synthesis of hippadine 24 was ac-
complished. On the other hand, 34 was converted to
formamide 35 by the reaction between the sodium salt
of 34 and acetic formic anhydride.24 Finally, 35 was
(23) (a) Hartung, C. G.; Fecher, A.; Chapell, B.; Snieckus, V. Org.
Lett. 2003, 5, 1899. (b) Boger, D. L.; Wolkenberg, S. E. J . Org. Chem.
2000, 65, 9120. (c) Padwa, A.; Brodney, M. A.; Liu, B.; Satake, K.; Wu,
T. J . Org. Chem. 1999, 64, 3595. (d) Harrowven, D. C.; Lai, D.; Lucas,
M. C. Synthesis 1999, 1300. (e) Miki, Y.; Shirokoshi, H.; Matushita,
K. Tetrahedron Lett. 1999, 40, 4347. (f) Hutchings, R. H.; Meyers, I.
A. J . Org. Chem. 1996, 61, 1004. (g) Banwell, M. G.; Bissett, B. D.;
Busato, S.; Cowden, C. J .; Hockless, D. C. R.; Holman, J . W.; Read, R.
R.; Wu, A. W. J . Chem. Soc., Chem. Commun. 1995, 2551. (h)
Sakamoto, T.; Yasuhara, A.; Kondo, Y.; Yamanaka, H. Heterocycles
1993, 36, 2597. (i) Grigg, R.; Teasdale, A.; Sridharan, V. Tetrahedron
Lett. 1991, 32, 3859. (j) Siddiqui, M. A.; Snieckus, V. Tetrahedron Lett.
1990, 31, 1523. (k) Hayakawa, K.; Yasukouchi, T.; Kanematsu, K.
Tetrahedron Lett. 1987, 28, 5895.
(24) Krimen, L. I. Organic Syntheses; Wiley: New York, 1988;
Collect Vol. VI, p 8.
(25) (a) Banwell, M. G.; Havey, J . E.; Hockless, D. C. R. J . Org.
Chem. 2000, 65, 4241. (b) Banwell, M. G.; Cowden, C. J .; Gable, R. W.
J . Chem. Soc., Perkin Trans. 1 1994, 3515.
1132 J . Org. Chem., Vol. 69, No. 4, 2004

Indole Ring Synthesis from 2-Ethynylaniline Derivative
SCHEME 6
1-p-Tolylsu lfon yl-2-h yd r oxym eth ylin d ole (2d ) (Ta ble
3, en tr y 4). A solution of 1d (100.7 mg, 0.33 mmol) and Cu-
(OAc)2 (12.5 mg, 0.069 mmol) in anhydrous 1,2-dichloroethane
(10 mL) was refluxed for 2 h. The residue was chromato-
graphed on silica gel [AcOEt-hexane (1:3)] to afford 2d (76.2
mg, 76%) as a colorless solid; mp 91-92 °C (colorless needles
from AcOEt-hexane); IR (film, cm-1) 3566, 3425, 1367, 1173;
1H NMR (400 MHz, CDCl3) δ 2.34 (3H, s), 3.11 (1H, t, J ) 7.4
Hz), 4.90 (2H, d, J ) 7.4 Hz), 6.64 (1H, s), 7.20 (2H, d, J ) 8.6
Hz), 7.22 (1H, t, J ) 7.7 Hz), 7.29 (1H, t, J ) 7.7 Hz), 7.48
(1H, d, J ) 7.7 Hz), 7.71 (2H, d, J ) 8.6 Hz), 7.04 (1H, d, J )
7.7 Hz); MS m/z 301 (M+, 68.4), 129 (100). Anal. Calcd for
biologically active compounds with our methodology are
now in progress in our laboratory.
Exp er im en ta l Section
Gen er a l P r oced u r e for th e Selected En tr ies for Ta bles
3 a n d 5. A solution of 2-ethynylaniline derivatives in anhy-
drous toluene or 1,2-dichloroethane was added to a suspension
of Lewis acid in anhydrous toluene or 1,2-dichloroethane, then
the mixture was heated at the temperature and for the
reaction time listed in the tables. Water was added to the
mixture and extracted with AcOEt (three times). The combined
organic solution was washed with saturated aqueous NaCl
solution and dried over anhydrous MgSO4, and the solvent was
evaporated.
C
16H15NO3S: C, 63.77; H, 5.02; N, 4.65. Found: C, 63.82; H,
5.02; N, 4.46.
Meth yl 1-Meth ylsu lfon yl-2-in dolecar boxylate (2e)(Table
3, en tr y 5). A solution of 1e (43.6 mg, 0.17 mmol) and Cu-
(OAc)2 (3.0 mg, 0.017 mmol) in anhydrous 1,2-dichloroethane
(8 mL) was refluxed for 24 h. The residue was chromato-
graphed on silica gel [AcOEt-hexane (1:5)] to afford 2e (34.5
mg, 79%) as a colorless solid; mp 89-91 °C (colorless prisms
from AcOEt-hexane); IR (film, cm-1) 1728, 1435, 1367, 1352,
1-Meth ylsu lfon yl-2-p h en ylin d ole (2a ) (Ta ble 3, en tr y
1). A solution of 1a (100.2 mg, 0.37 mmol) and Cu(OAc)2 (6.7
mg, 0.037 mmol) in anhydrous 1,2-dichloroethane (10 mL) was
refluxed for 18 h. The residue was chromatographed on silica
gel [AcOEt-hexane (1:10)] to afford 2a (94.1 mg, 94%) as a
colorless solid; mp 115-117 °C (colorless needles from AcOEt-
1
1205; H NMR (300 MHz, CDCl3) δ 3.71 (3H, s), 3.96 (3H, s),
1
hexane, lit.7 mp 115-116 °C); IR (film, cm-1) 1367, 1171; H
7.30 (1H, s), 7.31 (1H, br t, J ) 8.0 Hz), 7.45 (1H, td, J ) 8.0,
1.1 Hz), 7.65 (1H, br d, J ) 8.0 Hz), 8.05 (1H, br d, J ) 8.0
Hz); 13C NMR (100 MHz CDCl3) δ 43.5, 52.7, 115.0, 117.2,
122.7, 123.8, 127.18, 127.22, 130.4, 138.5, 161.3; MS m/z 253
(M+, 49.2), 175 (100), 141 (92.1); HRMS calcd for C11H11NO4S
253.0409, found 253.0406.
NMR (300 MHz, CDCl3) δ 2.74 (3H, s), 6.72 (1H, s), 7.35-
7.45 (5H, m), 7.56-7.62 (3H, m), 8.13 (1H, d, J ) 7.1 Hz); MS
m/z 271 (M+, 51.3), 192 (100), 165 (51.8); HRMS calcd for
C
15H13NO2S 271.0667, found 271.0673.
1-Meth ylsu lfon yl-2-bu tylin d ole (2b) (Ta ble 3, en tr y 2).
A solution of 1b (103.2 mg, 0.41 mmol) and Cu(OAc)2 (7.4 mg,
0.041 mmol) in anhydrous 1,2-dichloroethane (10 mL) was
refluxed for 20 h. The residue was chromatographed on silica
gel [AcOEt-hexane (1:10)] to afford 2b (94.4 mg, 91%) as a
colorless solid; mp 80-81 °C (colorless needles from AcOEt-
hexane, lit.7 mp 81-82 °C); IR (film, cm-1) 1366, 1171; 1H NMR
(300 MHz, CDCl3) δ 0.98 (3H, t, J ) 7.7 Hz), 1.46 (2H, sex, J
) 7.7 Hz), 1.75 (2H, quint, J ) 7.7 Hz), 2.96 (2H, t, J ) 7.7
Hz), 3.00 (3H, s), 6.46 (1H, s), 7.23-7.30 (2H, m), 7.47-7.52
(1H, m), 8.00 (1H, d, J ) 8.1 Hz); MS m/z 251 (M+, 36.8), 209
(39.5), 130 (100); HRMS calcd for C13H17NO2S 251.0980, found
251.1012.
1-Meth ylsu lfon yl-2-(1,1-dim eth yleth yl)in dole (2f) (Table
3, en tr y 6). A solution of 1f (99.7 mg, 0.40 mmol) and Cu-
(OAc)2 (7.6 mg, 0.042 mmol) in anhydrous 1,2-dichloroethane
(10 mL) was refluxed for 72 h. The residue was chromato-
graphed on silica gel [AcOEt-hexane (1:10)] to afford 2f (22.1
mg, 22%) as a yellow oil. From the later fraction, 1f (73.3 mg,
74%) was recovered. 2f: IR (neat, cm-1) 1371, 1176; 1H NMR
(300 MHz, CDCl3) δ 1.56 (9H, s), 2.94 (3H, s), 6.62 (1H, s),
7.23-7.32 (2H, m), 7.49 (1H, d, J ) 6.9 Hz), 8.08 (1H, d, J )
7.1 Hz); 13C NMR (100 MHz CDCl3) δ 30.9, 34.8, 39.5, 110.1,
115.3, 120.5, 123.8, 124.5, 129.4, 138.5, 151.8; MS m/z 251 (M+,
42.4), 236 (50.7), 172 (100); HRMS calcd for C13H17NO2S
251.0980, found 251.0966.
1-Meth ylsu lfon yl-2-tr im eth ylsilylin d ole (2g) (Ta ble 3,
en tr y 7). A solution of 1g (101.3 mg, 0.38 mmol) and Cu(OAc)2
(7.2 mg, 0.040 mmol) in anhydrous 1,2-dichloroethane (10 mL)
was refluxed for 72 h. The residue was chromatographed on
silica gel [AcOEt-hexane (1:10)] to afford 2g5h (9.0 mg, 9%)
as a yellow oil. From the later fraction, 1g (64.5 mg, 64%) was
recovered. 2g: IR (neat, cm-1) 1366, 1170; 1H NMR (300 MHz,
CDCl3) δ 0.41 (9H, s), 3.01 (3H, s), 6.95 (1H, s), 7.28 (1H, td,
J ) 8.1, 0.9 Hz), 7.36 (1H, td, J ) 8.1, 0.9 Hz), 7.59 (1H, br d,
J ) 8.1 Hz), 8.00 (1H, br d, J ) 8.1 Hz); MS m/z 267 (M+,
1-Meth ylsu lfon ylin d ole (2c) (Ta ble 3, en tr y 3). A solu-
tion of 1c (90.6 mg, 0.47 mmol) and Cu(OAc)2 (8.6 mg, 0.047
mmol) in anhydrous 1,2-dichloroethane (10 mL) was refluxed
for 1.5 h. The residue was chromatographed on silica gel
[AcOEt-hexane (1:5)] to afford 2c7 (79.1 mg, 87%) as a yellow
1
oil; IR (neat, cm-1) 1361, 1170; H NMR (300 MHz, CDCl3) δ
3.09 (1H, s), 6.72 (1H, d, J ) 3.7 Hz), 7.30 (1H, td, J ) 7.8, 1.2
Hz), 7.37 (1H, td, J ) 7.8, 1.2 Hz), 7.44 (1H, d, J ) 3.7 Hz),
7.63 (1H, br d, J ) 7.8 Hz), 7.92 (1H, dd, J ) 7.8, 0.7 Hz); MS
m/z 195 (M+, 54.6), 116 (100); HRMS calcd for C9H9NO2S
195.0354, found 195.0359.
J . Org. Chem, Vol. 69, No. 4, 2004 1133

Hiroya et al.
27.7), 252 (100), 189 (55.3); HRMS calcd for C12H17NO2SSi
267.0749, found 267.0710.
acetone-hexane, lit.7 mp 171-172 °C); IR (KBr, cm-1) 3394;
1H NMR (400 MHz, CDCl3) δ 3.85 (3H, s), 6.74 (1H, d, J ) 2.0
Hz), 6.79 (1H, dd, J ) 8.5, 2.0 Hz), 6.88 (1H, d, J ) 2.0 Hz),
7.28 (1H, t, J ) 7.7 Hz), 7.41 (2H, t, J ) 7.7 Hz), 7.48 (1H, br
d, J ) 8.5 Hz), 7.60 (2H, d, J ) 7.7 Hz), 8.25 (1H, br); MS m/z
223 (M+, 91.7), 208 (100); HRMS calcd for C15H13NO 223.0997,
found 223.1004.
5-Br om o-1-m eth ylsu lfon yl-2-p h en ylin d ole (2h ) (Ta ble
3, en tr y 8). A solution of 1h (35.0 mg, 0.10 mmol) and Cu-
(OAc)2 (1.8 mg, 0.010 mmol) in anhydrous 1,2-dichloroethane
(10 mL) was refluxed for 7 h. The residue was chromato-
graphed on silica gel [AcOEt-hexane (1:7)] to afford 2h (26.7
mg, 76%) as a colorless solid; mp 186-187 °C (colorless needle
from AcOEt-hexane); IR (film, cm-1) 1361, 1177; 1H NMR (300
MHz, CDCl3) δ 2.76 (3H, s), 6.65 (1H, s), 7.40-7.50 (4H, m),
7.50-7.58 (2H, m), 7.74 (1H, d, J ) 1.4 Hz), 8.01 (1H, d, J )
8.8 Hz); MS m/z 351 (M+ + 2, 66.4), 349 (M+, 65.3), 272 (98.8),
270 (100), 191 (94.3). Anal. Calcd for C15H12NO2BrS: C, 51.44;
H, 3.45; N, 4.00. Found: C, 51.39; H, 3.47; N, 3.86.
5-Meth yl-2-p h en ylin d ole (9k ) (Ta ble 5, en tr y 8). A
solution of 8k (97.3 mg, 0.47 mmol) and Cu(OCOCF3)2‚xH2O
(6.2 mg, 0.021 mmol) in anhydrous 1,2-dichloroethane (10 mL)
was refluxed for 2.5 h. The residue was chromatographed on
silica gel [AcOEt-hexane (1:5)] to afford 9k (68.7 mg, 71%)
as a pale yellow solid; mp 217 °C (colorless needles from Et2O-
1
hexane, lit.26 mp 218-219 °C); IR (film, cm-1) 3435; H NMR
(400 MHz, CDCl3) δ 2.40 (3H, s), 6.74 (1H, s), 7.01 (1H, d, J )
8.2 Hz), 7.26-7.33 (2H, m), 7.39-7.45 (3H, m), 7.64 (2H, d, J
) 7.2 Hz), 8.24 (1H, br); MS m/z 207 (M+, 100); HRMS calcd
for C15H13N2 207.10480, found 207.1014.
6-Cya n o-2-p h en ylin d ole (9l) (Ta ble 5, en tr y 9). A solu-
tion of 8l (109.9 mg, 0.50 mmol) and Cu(OCOCF3)2‚xH2O (29.2
mg, 0.101 mmol) in anhydrous 1,2-dichloroethane (10 mL) was
refluxed for 24 h. The residue was chromatographed on silica
gel [AcOEt-hexane (1:5)] to afford 9l (92.1 mg, 84%) as a pale
yellow solid; mp 226-227 °C (colorless needle from hexane);
IR (KBr, cm-1) 3368, 2210; 1H NMR (400 MHz, CDCl3) δ 6.88
(1H, d, J ) 2.2 Hz), 7.30-7.51 (4H, m), 7.65-7.74 (4H, m),
8.69 (1H, br); MS m/z 218 (M+, 100). Anal. Calcd for
5-Cya n o-1-m eth ylsu lfon yl-2-p h en ylin d ole (2i) (Ta ble
3, en tr y 9). A solution of 1i (34.9 mg, 0.12 mmol) and Cu-
(OAc)2 (2.4 mg, 0.013 mmol) in anhydrous 1,2-dichloroethane
(7 mL) was refluxed for 50 h. The residue was chromato-
graphed on silica gel [AcOEt-hexane (1:7)] to afford 2i (25.9
mg, 74%) as a colorless solid; mp 213-214 °C (colorless needle
from AcOEt-hexane); IR (film, cm-1) 2226, 1371, 1175; 1H
NMR (300 MHz, CDCl3) δ 2.87 (3H, s), 6.74 (1H, s), 7.41-
7.59 (5H, m), 7.64 (1H, d, J ) 8.5 Hz), 7.95 (1H, s), 8.25 (1H,
d, J ) 8.5 Hz); MS m/z 296 (M+, 58.4), 217 (100), 190 (62.5).
Anal. Calcd for C16H12N2O2S: C, 64.85; H, 4.08; N, 9.45.
Found: C, 64.94; H, 4.26; N, 9.28.
1-Meth ylsu lfon yl-6-m eth oxy-2-ph en ylin dole (2j) (Table
3, en tr y 10). A solution of 1j (103.6 mg, 0.34 mmol) and Cu-
(OAc)2 (5.7 mg, 0.031 mmol) in anhydrous 1,2-dichloroethane
(10 mL) was refluxed for 38 h. The residue was chromato-
graphed on silica gel [AcOEt-hexane (1:5)] to afford 2j (98.8
mg, 95%) as a colorless solid; mp 134-135 °C (colorless prisms
from AcOEt-hexane); IR (film, cm-1) 1612, 1367, 1180; 1H
NMR (300 MHz, CDCl3) δ 2.72 (3H, s), 3.91 (3H, s), 6.64 (1H,
s), 6.98 (1H, dd, J ) 8.5, 2.2 Hz), 7.38-7.44 (3H, m), 7.47 (1H,
d, J ) 8.6 Hz), 7.52-7.60 (2H, m), 7.69 (1H, d, J ) 2.2 Hz);
C
15H10N2: C, 82.55; H, 4.62; N, 12.84. Found: C, 82.26; H,
4.86; N, 12.59.
1-(p-Meth oxyben zyl)-2-p h en ylin d ole (11a ) (Ta ble 5,
en tr y 10). A solution of 10a (95.7 mg, 0.31 mmol) and Cu-
(OAc)2 (22.1 mg, 0.12 mmol) in anhydrous 1,2-dichloroethane
(10 mL) was refluxed for 48 h. The residue was chromato-
graphed on silica gel [AcOEt-hexane (1:9)] to afford 11c (88.4
mg, 92%) as a yellow solid; mp 156-157 °C (yellow prisms from
Et2O-AcOEt); IR (film, cm-1) 1510, 1460, 1246; 1H NMR (400
MHz, CDCl3) δ 3.76 (3H, s), 5.31 (2H, s), 6.63 (1H, s), 6.79
(2H, d, J ) 8.7 Hz), 6.94 (2H, d, J ) 8.7 Hz), 7.10-7.22 (3H,
m), 7.34-7.46 (5H, m), 7.63-7.67 (1H, m); 13C NMR (100 MHz,
CDCl3) δ 47.2, 55.2, 102.2, 110.5, 114.0, 120.0, 120.4, 121.8,
127.1, 127.9, 128.2, 128.4, 129.1, 130.1, 132.7, 137.8, 141.7,
158.6; MS m/z 313 (M+, 44.5), 121 (100); HRMS calcd for
MS m/z 301 (M+, 40.6), 222 (100). Anal. Calcd for C16H15
-
NO3S: C, 63.77; H, 5.02; N, 4.65. Found: C, 63.73; H, 4.95;
N, 4.60.
1-Meth ylsu lfon yl-5-m eth yl-2-p h en ylin d ole (2k ) (Ta ble
3, en tr y 11). A solution of 1k (71.6 mg, 0.25 mmol) and Cu-
(OAc)2 (4.8 mg, 0.026 mmol) in anhydrous 1,2-dichloroethane
(10 mL) was refluxed for 6 h. The residue was chromato-
graphed on silica gel [AcOEt-hexane (1:7)] to afford 2k (69.1
mg, 97%) as a colorless solid; mp 137-138 °C (colorless needles
from AcOEt-hexane); IR (film, cm-1) 1366, 1173; 1H NMR (300
MHz, CDCl3) δ 2.47 (3H, s), 2.70 (3H, s), 6.66 (1H, s), 7.20
(1H, d, J ) 8.6 Hz), 7.38-7.46 (4H, m), 7.54-7.60 (2H, m),
7.99 (1H, d, J ) 8.5 Hz); 13C NMR (100 MHz, CDCl3) δ 21.3,
39.0, 113.0, 115.5, 120.9, 126.4, 127.6, 128.7, 130.0, 130.5,
132.0, 142.2, 136.2, 142.1; MS m/z 285 (M+, 47.5), 206 (100);
HRMS calcd for C16H15NO2S 285.0824, found 285.0848. Anal.
Calcd for C16H15NO2S: C, 67.34; H, 5.30; N, 4.91. Found: C,
67.35; H, 5.43; N, 4.52.
C
22H19NO 313.1467, found 313.1449.
1-(p-Meth oxyben zyl)in d ole (11c) (Ta ble 5, en tr y 11).
A solution of 10c (134.8 mg, 0.57 mmol) and Cu(OAc)2 (22.1
mg, 0.12 mmol) in anhydrous 1,2-dichloroethane (10 mL) was
refluxed for 48 h. The residue was chromatographed on silica
gel [AcOEt-hexane (1:9)] to afford 11c (119.9 mg, 89%) as a
yellow oil; IR (neat, cm-1) 1512, 1248; 1H NMR (400 MHz,
CDCl3) δ 3.77 (3H, s), 5.26 (2H, s), 6.52 (1H, d, J ) 3.2 Hz),
6.82 (2H, d, J ) 8.7 Hz), 7.06 (2H, d, J ) 8.7 Hz), 7.08-7.12
(2H, m), 7.16 (1H, td, J ) 8.0, 1.2 Hz), 7.29 (1H, d, J ) 8.0
Hz), 7.63 (1H, d, J ) 8.0 Hz); 13C NMR (100 MHz CDCl3) δ
49.6, 55.3, 101.5, 109.6, 114.0, 119.4, 120.9, 121.5, 128.0, 128.1,
128.6, 129.4, 136.1, 158.9; MS m/z 237 (M+, 42.4), 121 (100);
HRMS calcd for C16H15NO 237.1154, found 237.1120.
5-Br om o-2-p h en ylin d ole (9h ) (Ta ble 5, en tr y 6). A
solution of 8h (108.3 mg, 0.40 mmol) and Cu(OCOCF3)2‚xH2O
(23.0 mg, 0.079 mmol) in anhydrous 1,2-dichloroethane (10
mL) was refluxed for 4 h. The residue was chromatographed
on silica gel [AcOEt-hexane (1:5)] to afford 9h (89.5 mg, 83%)
as a pale yellow solid; mp 194-195 °C (colorless plates from
2-(4-ter t-Bu t yld im et h ylsilyloxyb u t yl)-1-isop r op ylin -
d ole (11m ) (Ta ble 5, en tr y 12). A solution of 10m (134.3 mg,
0.39 mmol) and Cu(OAc)2 (14.5 mg, 0.080 mmol) in anhydrous
1,2-dichloroethane (10 mL) was refluxed for 48 h. The residue
was chromatographed on silica gel [AcOEt-hexane (1:9)] to
1
Et2O-hexane, lit.7 mp 196-198 °C); IR (film, cm-1) 3435; H
afford 11m (134.0 mg, 100%) as a yellow oil; IR (neat, cm-1
)
NMR (400 MHz, CDCl3) δ 6.75 (1H, s), 7.24-7.29 (2H, m), 7.34
(1H, t, J ) 7.5 Hz), 7.44 (2H, t, J ) 7.7 Hz), 7.64 (2H, d, J )
7.8 Hz), 7.74 (1H, s), 8.38 (1H, br); MS m/z 273 (M+ + 2, 95.7),
271 (M+, 100); HRMS calcd for C14H10NBr 270.9997, found
270.9994.
1312, 1105; 1H NMR (400 MHz, CDCl3) δ 0.06 (6H, s), 0.90
(9H, s), 1.62 (6H, d, J ) 7.1 Hz), 1.58-1.60 (2H, m), 1.60-
1.83 (2H, m), 2.75 (2H, t, J ) 7.7 Hz), 3.67 (2H, t, J ) 6.0 Hz),
4.62 (1H, septet, J ) 7.1 Hz), 6.21 (1H, s), 7.02 (1H, td, J )
7.7, 1.4 Hz), 7.08 (1H, td, J ) 7.7, 1.4 Hz), 7.48 (1H, br d, J )
7.7 Hz), 7. 52 (1H, br d, J ) 7.7 Hz); 13C NMR (100 MHz CDCl3)
δ -5.2, 18.4, 21.5, 25.5, 26.0, 27.5, 32.6, 46.8, 62.8, 99.2, 111.4,
6-Meth oxy-2-p h en ylin d ole (9j) (Ta ble 5, en tr y 7). A
solution of 8j (98.2 mg, 0.44 mmol) and Cu(OCOCF3)2‚xH2O
(24.1 mg, 0.083 mmol) in anhydrous 1,2-dichloroethane (10
mL) was refluxed for 6 h. The residue was chromatographed
on silica gel [AcOEt-hexane (1:7)] to afford 9j (56.8 mg, 58%)
as a pale yellow solid; mp 169-171 °C (colorless plates from
(26) Smith, A. B.; Visnick, M.; Haseltine, J . N.; Sprengeler, P. L.
Tetrahedron 1986, 42, 2957.
1134 J . Org. Chem., Vol. 69, No. 4, 2004

Indole Ring Synthesis from 2-Ethynylaniline Derivative
118.7, 119.8, 119.9, 128.8, 134.9, 140.5; MS m/z 345 (M+, 100);
HRMS calcd for C21H35NOSi 345.2488, found 345.2458.
Th e Cycliza tion Rea ction in th e P r esen ce of 1-Eth -
ylp ip er id in e (Sch em e 1). F or 2a : A suspension of 1a (98.6
mg, 0.36 mmol), Cu(OAc)2 (6.4 mg, 0.035 mmol), and 1-eth-
ylpiperidine (0.10 mL, 0.73 mmol) in anhydrous 1,2-dichloro-
ethane (10 mL) was stirred for 72 h at room temperature. H2O
was added to the mixture and extracted with AcOEt (3 times).
The combined organic solution was washed with saturated
aqueous NaCl solution and dried over anhydrous MgSO4, and
the solvent was evaporated. The residue was purified by silica
gel column chromatography [AcOEt-hexane (1:9)] to afford
2a (75.3 mg, 76%) as a colorless solid.
F or 2c: A suspension of 1c (105.3 mg, 0.54 mmol), Cu(OAc)2
(10.0 mg, 0.055 mmol), and 1-ethylpiperidine (0.15 mL, 1.09
mmol) in anhydrous 1,2-dichloroethane (10 mL) was stirred
for 48 h at room temperature. H2O was added to the mixture
and extracted with AcOEt (3 times). The combined organic
solution was washed with saturated aqueous NaCl solution
and dried over anhydrous MgSO4, and the solvent was
evaporated. The residue was purified by silica gel column
chromatography [AcOEt-hexane (1:5)] to afford 2c (81.0 mg,
77%) as a yellow oil.
(1H, s), 7.17 (2H, d, J ) 8.2 Hz), 7.18-7.30 (2H, m), 7.32 (2H,
d, J ) 8.2 Hz), 7.39 (1H, d, J ) 8.3 Hz), 7.57 (2H, d, J ) 8.2
Hz), 7.78 (2H, d, J ) 8.2 Hz), 8.13 (1H, d, J ) 8.1 Hz); MS m/z
497 (M+, 9.0), 170 (100). Anal. Calcd for C26H27NO5S2: C,
62.75; H, 5.47; N, 2.81. Found: C, 62.90; H, 5.61; N, 2.57.
1-(p-Tolylsu lfon yl)-2-[3-(p-tolylsu lfon yloxy)p en tyl]in -
d ole (22c). A solution of 16c (151.9 mg, 0.30 mmol), KH (18.4
mg, 0.46 mmol), and Cu(OAc)2 (17.6 mg, 0.10 mmol) in
anhydrous 1,2-dichloroethane (13 mL) was reacted. The crude
product was chromatographed on silica gel [AcOEt-hexane
(1:7)] to afford 22c (88.9 mg, 59%) as a yellow solid; mp 122-
123 °C (colorless needles from AcOEt-hexane); IR (film, cm-1
)
1
1362, 1175; H NMR (400 MHz, CDCl3) δ 1.40-1.49 (2H, m),
1.65-1.74 (4H, m), 2.33 (3H, s), 2.42 (3H, s), 2.93 (2H, t, J )
7.4 Hz), 4.03 (2H, t, J ) 6.3 Hz), 6.33 (1H, s), 7.17 (2H, d, J )
8.2 Hz), 7.19-7.29 (2H, m), 7.32 (2H, d, J ) 8.2 Hz), 7.39 (1H,
d, J ) 7.7 Hz), 7.58 (2H, d, J ) 8.2 Hz), 7.78 (2H, d, J ) 8.2
Hz), 8.14 (1H, d, J ) 8.0 Hz); 13C NMR (100 MHz, CDCl3) δ
21.6, 21.7, 25.1, 28.4, 28.6, 28.9, 70.4, 108.9, 114.8, 120.0, 123.5,
123.8, 126.1, 127.8, 129.6, 129.72, 129.74, 133.0, 136.0, 137.1,
141.6, 144.59, 144.62; MS m/z 511 (M+, 44.7), 356 (100); HRMS
calcd for C27H29NO5S2 511.1487, found 511.1492.
ter t-Bu t yl 6-(3,4-Met h ylen ed ioxyp h en yl)-2-(t r im et h -
ylsilyleth yn yl)p h en ylca r ba m a te (33). 4-Bromo-1,2-(meth-
ylenedioxy)benzene (3.0 mL, 24.9 mmol) was added to a
mixture of Mg (0.67 g, 27.5 mmol) in anhydrous THF (20 mL)
at room temperature and refluxed for 19 h. B(OMe)3 (3.3 mL,
28.0 mmol) was added to the mixture at -78 °C. After the
solution was stirred for 3 h at the same temperature, 3 N HCl
was added at room temperature and stirred for 15 h. H2O was
added and extracted with AcOEt (3 times). The combined
organic solution was washed with saturated aqueous NaCl
solution and dried over anhydrous MgSO4. The solvent was
evaporated to afford 27 (2.40 g) as a pale yellow solid, which
was used in the next reaction without purification.
Gen er a l P r oced u r e for Sch em e 3. A solution of 2-ethy-
nylaniline derivatives in anhydrous 1,2-dichloroethane was
added to a suspension of KH in anhydrous 1,2-dichloroethane
at 0 °C and the mixture was stirred for 1 h at the same
temperature and for another 1 h at room temperature. The
mixture was added to a suspension of Cu(OAc)2 (50 mol %) in
anhydrous 1,2-dichloroethane and then the mixture was
heated at 70 °C. After the mixture was stirred for 48 h,
saturated aqueous ammonium chloride solution was added to
the mixture and extracted with AcOEt (3 times). The combined
organic solution was washed with saturated aqueous NaCl
solution and dried over anhydrous MgSO4, and the solvent was
evaporated.
Pd(PPh3)4 (95.5 mg, 0.08 mmol) and a solution of 27 (1.26
g, 2.8 mmol) in EtOH (6 mL) were added to a solution of 28
(1.20 g, 2.9 mmol) in a mixed solution of aqueous 2 N Na2CO3
(5.8 mL) and benzene (18 mL) at room temperature and
refluxed for 3 h. H2O was added to the mixture and extracted
with AcOEt. The combined organic solution was washed with
saturated aqueous NaCl solution and dried over anhydrous
MgSO4, and the solvent was evaporated. The residue was
purified by silica gel column chromatography eluting with
AcOEt-hexane(1:9) to afford 33 (0.85 g, 72%) as a yellow
4-(p-Tolu en esu lfon yl)-1,2,3,4-tetr a h yd r ocyclop en ta [b]-
in d ole (21a ). A solution of 16a (169.2 mg, 0.35 mmol), KH
(23.6 mg, 0.59 mmol), and Cu(OAc)2 (32.0 mg, 0.18 mmol) in
anhydrous 1,2-dichloroethane (13 mL) was reacted. The crude
product was chromatographed on silica gel [AcOEt-hexane
(1:7)] to afford 21a (73.3 mg, 67%); mp 165-166 °C (colorless
needles from Et2O-hexane); IR (film, cm-1) 1366, 1178; 1H
NMR (400 MHz, CDCl3) δ 2.48 (2H, quint, J ) 6.7 Hz), 2.31
(3H, s), 2.71 (2H, t, J ) 6.7 Hz), 3.13 (2H, t, J ) 6.7 Hz), 7.14-
7.24 (4H, m), 7.30 (1H, dd, J ) 8.0, 1.6 Hz), 7.70 (2H, d, J )
8.5 Hz), 8.01 (1H, dd, J ) 7.2, 1.6 Hz); 13C NMR (100 MHz,
CDCl3) δ 21.6, 24.1, 27.5, 28.1, 114.3, 118.9, 123.1, 123.2, 126.4,
126.5, 127.1, 129.7, 135.7, 140.1, 143.5, 144.5; MS m/z 311 (M+,
58.5), 156 (100). Anal. Calcd for C18H17NO2S: C, 69.43; H, 5.50;
N, 4.50. Found: C, 69.51; H, 5.69; N, 4.31.
1
viscous oil; IR (neat, cm-1) 2154, 1719, 1491, 1227, 1163; H
NMR (400 MHz, CDCl3) δ 0.26 (9H, s), 1.36 (9H, s), 5.96 (2H,
s), 6.19 (1H, br), 6.80-6.93 (3H, m), 7.18 (1H, t, J ) 7.7 Hz),
7.26 (1H, dd, J ) 7.3, 2.0 Hz), 7.42 (1H, dd, J ) 7.6, 1.7 Hz);
13C NMR (100 MHz CDCl3) δ 0.0, 28.1, 80.0, 99.6, 100.8, 101.6,
108.1, 108.9, 121.2, 121.8, 126.0, 130.9, 131.2, 133.2, 135.9,
138.6, 146.6, 147.3, 152.9; MS m/z 409 (M+, 5.7), 57 (100);
HRMS calcd for C23H27NO4Si 409.1709, found 409.1736.
N-p-Tolylsu lfon yl-1,2,3,4-tetr ah ydr ocar bazole (21b) an d
1-(p -Tolylsu lfon yl)-2-[3-(p -t olylsu lfon yloxy)b u t yl]in -
d ole (22b). A solution of 16b (150.8 mg, 0.30 mmol), KH (18.1
mg, 0.45 mmol), and Cu(OAc)2 (29.0 mg, 0.16 mmol) in
anhydrous 1,2-dichloroethane (13 mL) was reacted. The crude
product was chromatographed on silica gel [AcOEt-hexane
(1:7)] to afford 21b (63.4 mg, 64%) and 22b (20.3 mg, 13%),
both as a yellow solid. 21b: mp 116-117 °C (pale yellow
ter t-Bu tyl 6-(3,4-Meth ylen edioxyph en yl)-2-eth yn ylph en -
ylca r ba m a te (26). A suspension of 33 (753.9 mg, 1.84 mmol)
and K2CO3 (392.1 mg, 2.84 mmol) in MeOH (15 mL) was
stirred at room temperature for 14 h. H2O was added to the
mixture and extracted with AcOEt. The combined organic
solution was washed with saturated aqueous NaCl solution
and dried over anhydrous MgSO4, and the solvent was
evaporated. The residue was chromatographed on a silica gel
column [AcOEt-hexane (1:5)] to afford 26 (566.3 mg, 91%) as
a pale red solid; mp 110-112 °C (pale red prisms from Et2O-
hexane); IR (film, cm-1) 3391, 3292, 1717, 1491; 1H NMR (400
MHz, CDCl3) δ 1.36 (9H, s), 3.30 (1H,s), 5.96 (2H, s), 6.14 (1H,
br), 6.84-6.95 (3H, m), 7.21 (1H, t, J ) 7.7 Hz), 7.28 (1H, td,
J ) 7.7, 1.2 Hz), 7.47 (1H, dd, J ) 7.7, 1.2 Hz); 13C NMR (100
MHz, CDCl3) δ 28.1, 80.3, 80.5, 82.1, 101.0, 108.3, 109.1, 120.6,
122.0, 126.2, 131.1, 131.9, 133.0, 136.1, 138.9, 146.8, 147.5,
153.1; MS m/z 337 (M+, 13.6), 237 (100); HRMS calcd for
prisms from Et2O-hexane, lit.27 mp 93-96 °C); IR (film, cm-1
)
1
1369, 1178; H NMR (300 MHz, CDCl3) δ 1.70-1.95 (4H, m),
2.30 (3H, s), 2.57 (2H, d, J ) 6.0 Hz), 3.00 (2H, t, J ) 6.0 Hz),
7.15 (2H, d, J ) 8.4 Hz), 7.18-7.29 (2H, m), 7.32 (1H, d, J )
7.1 Hz), 7.64 (2H, d, J ) 8.4 Hz), 8.15 (1H, d, J ) 8.2 Hz); MS
m/z 325 (M+, 54.3), 170 (100); HRMS calcd for C19H19NO2S
325.1137, found 325.1140. 22b: mp 126-127 °C (colorless
prisms from Et2O-hexane); IR (film, cm-1) 1362, 1175; 1H
NMR (400 MHz, CDCl3) δ 1.70-1.80 (4H, m), 2.33 (3H, s), 2.43
(3H, s), 2.95 (2H, t, J ) 6.4 Hz), 4.07 (2H, t, J ) 6.4 Hz), 6.32
(27) Fleming, I.; Farckenpohl, J .; Ila, H. J . Chem. Soc., Perkin Trans.
1 1998, 1229.
C
20H19NO4 337.1314, found 337.1338.
J . Org. Chem, Vol. 69, No. 4, 2004 1135

Hiroya et al.
1-ter t-Bu toxyca r bon yl-7-(3,4-m eth ylen ed ioxyp h en yl)-
in d ole (25). A solution of 26 (566.3 mg, 1.68 mmol) in
anhydrous 1,2-dichloroethane (20 mL) was added to a suspen-
sion of Cu(OAc)2 (310.3 mg, 1.71 mmol) in anhydrous 1,2-
dichloroethane at room temperature and the mixture was
refluxed for 5 h. H2O was added to the mixture and extracted
with AcOEt. The combined organic solution was washed with
saturated aqueous NaCl solution and dried over anhydrous
MgSO4, and the solvent was evaporated. The residue was
chromatographed on a silica gel column [AcOEt-hexane (1:
9)] to afford 25 (452.7 mg, 80%) as a colorless viscous oil; IR
residue was chromatographed on a silica gel column [AcOEt-
hexane (1:9)] to afford 35 (26.7 mg, 51%) as a yellow viscous
1
oil; IR (neat, cm-1) 1701; H NMR (400 MHz, CDCl3) δ 6.04
(2H, s), 6.76 (1H, d, J ) 3.4 Hz), 6.84-6.93 (2H, m), 7.13 (1H,
d, J ) 7.3 Hz), 7.20-7.30 (2H, m), 7.57 (1H, d, J ) 7.8 Hz),
7.83 (1H, d, J ) 3.4 Hz), 8.82 (1H, s); 13C NMR (100 MHz
CDCl3) δ 101.4, 109.0, 109.2, 110.3, 120.7, 122.1, 123.0, 123.2,
127.0, 127.3, 131.8, 132.8, 133.2, 147.5, 148.2, 158.3; MS m/z
265 (M+, 100); HRMS calcd for C16H11NO3 265.0739, found
265.0743. 34 (21.1 mg, 45%) was recovered from the later
fraction.
1
(neat, cm-1) 1751, 1728, 1153; H NMR (400 MHz, CDCl3) δ
Hip p a d in e (24). Tf2O (0.15 mL, 0.89 mmol) was added to
a solution of 35 (47.2 mg, 0.18 mmol) and DMAP (56.9 mg,
0.47 mmol) in CH2Cl2 (5 mL) at 0 °C and the mixture was
stirred for 4 h at room temperature. Saturated aqueous
NaHCO3 solution was added to the mixture and extracted with
AcOEt. The combined organic solution was washed with
saturated aqueous NaCl solution, dried over anhydrous Mg-
SO4, and concentrated. The residue was purified by prepara-
tive TLC [AcOEt-hexane (1:2)] to provide hippadine (24) (8.4
mg, 18%) as a pale yellow solid; mp 213-215 °C (pale red
1.36 (9H, s), 5.96 (2H, s), 6.60 (1H, d, J ) 3.7 Hz), 6.85 (1H, d,
J ) 7.8 Hz), 6.94-6.99 (2H, m), 7.22 (1H, d, J ) 7.6 Hz), 7.28
(1H, d, J ) 7.6 Hz), 7.51 (1H, d, J ) 7.6 Hz), 7.53 (1H, d, J )
3.7 Hz); 13C NMR (100 MHz, CDCl3) δ 22.7, 83.5, 100.9, 107.0,
108.2, 108.3, 119.7, 120.7, 123.1, 126.5, 128.6, 129.4, 132.4,
132.6, 136.1, 146.2, 147.5, 149.0; MS m/z 337 (M+, 26.2), 237
(100); HRMS calcd for C20H19NO4 337.1314, found 337.1329.
7-(3,4-Meth ylen ed ioxyp h en yl)in d ole (34). A solution of
25 (671.1 mg, 1.99 mmol) and 3 N HCl (4 mL) in AcOEt (15
mL) was refluxed for 2 h. H2O was added to the mixture and
extracted with AcOEt. The combined organic solution was
washed with saturated aqueous NaCl solution and dried over
anhydrous MgSO4, and the solvent was evaporated. The
residue was chromatographed on a silica gel column [AcOEt-
hexane (1:5)] to afford 34 (397.2 mg, 84%) as a yellow solid;
mp 118-119 °C (colorless prisms from Et2O-hexane, lit.23f mp
needles from CHCl3, lit.23g mp 215-217 °C); IR (film, cm-1
)
1670, 1310; 1H NMR (400 MHz, CDCl3) δ 6.15 (2H, s), 6.89
(1H, d, J ) 2.3 Hz), 7.46 (1H, t, J ) 7.4 Hz), 7.64 (1H, s), 7.74
(1H, d, J ) 7.4 Hz), 7.90 (1H, d, J ) 7.4 Hz), 7.97 (1H, s), 8.03
(1H, d, J ) 2.3 Hz); MS m/z 263 (M+, 100); HRMS calcd for
C
16H9NO3 263.0582, found 263.0555.
1
119-121 °C); IR (film, cm-1) 3423, 1229; H NMR (400 MHz,
Ack n ow led gm en t. This work was supported by
CDCl3) δ 6.02 (2H, d, J ) 2.4 Hz), 6.61 (1H, s), 6.93 (1H, d, J
) 8.3 Hz), 7.05-7.25 (5H, m), 7.61 (1H, d, J ) 6.6 Hz), 8.39
(1H, br); MS m/z 237 (M+, 100); HRMS calcd for C15H11NO2
237.0790, found 237.0814.
Grants-in Aid for Scientific Research (No. 13672206 and
No. 14044007) from the Ministry of Education, Culture,
Sports, Science and Technology of J apan.
1-F or m yl-7-(3,4-m eth ylen ed ioxyp h en yl)in d ole (35). 34
(47.1 mg, 0.20 mmol) was added to a suspension of NaH (60%
in oil, 15.6 mg, 0.39 mmol) in anhydrous DMF (5 mL) at 0 °C
and the solution was stirred for 30 min at the same temper-
ature and for another 30 min at room temperature. The
mixture was cooled at 0 °C, then acetic formic anhydride24 (35.1
mg, 0.66 mmol) was added. After the solution was stirred for
22 h at room temperature, H2O was added to the mixture and
extracted with AcOEt. The combined organic solution was
washed with saturated aqueous NaCl solution and dried over
anhydrous MgSO4, and the solvent was evaporated. The
Su p p or tin g In for m a tion Ava ila ble: The experimental
procedures and compound characterization data for 1a -k , 2a ,
3a , 4a , 5a -d ,g, 6a -c, 7a , 8a ,b, e-l, 10a ,c,m , 13a -c, 14a -
c, 15a -c, 16a -c, 17-20, 22a , 23, 28, 31, 32, Table 1 (entries
1-4, 6, 7), Table 2 (entries 1, 4-7), Table 4 (entries 1, 4-7,
9), Table 5 (entries 1-4), and Table 6 (entries 1-8). This
material is available free of charge via the Internet at
http://pubs.acs.org.
J O035528B
1136 J . Org. Chem., Vol. 69, No. 4, 2004