Efficient synthesis of indoles using [3,3]-sigmatropic rearrangement of N-trifluoroacetyl enehydrazines

Article abstract of DOI:10.1016/j.tet.2006.01.087

[3,3]-Sigmatropic rearrangement of N-trifluoroacetyl enehydrazines provides a novel method for the construction of indoles. N-Trifluoroacetyl enehydrazine having a cyclopentene ring smoothly underwent [3,3]-sigmatropic rearrangement followed by cyclizatio

Full text of DOI:10.1016/j.tet.2006.01.087

Tetrahedron 62 (2006) 3629–3647
Efficient synthesis of indoles using [3,3]-sigmatropic
rearrangement of N-trifluoroacetyl enehydrazines
Okiko Miyata,a Norihiko Takeda,a Yasuo Kimura,a Yoshiji Takemoto,b
Norimitsu Tohnai,c Mikiji Miyatac and Takeaki Naitoa,
*
aKobe Pharmaceutical University, Motoyamakita, Higashinada, Kobe 658-8558, Japan
bGraduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan
cGraduate School of Engineering, Osaka University, Yamadaoka, Suita, Osaka 565-0871, Japan
Received 28 June 2005; revised 23 January 2006; accepted 25 January 2006
Available online 28 February 2006
Abstract—[3,3]-Sigmatropic rearrangement of N-trifluoroacetyl enehydrazines provides a novel method for the construction of indoles.
N-Trifluoroacetyl enehydrazine having a cyclopentene ring smoothly underwent [3,3]-sigmatropic rearrangement followed by cyclization to
give indolines in excellent yield. On the other hand, both cyclohexenyl N-trifluoroacetyl enehydrazine and acyclic N-trifluoroacetyl
enehydrazine gave indoles in good yield. Additionally, the substituent effect on the benzene ring was also studied. The rearrangement of
N-trifluoroacetyl enehydrazines proceeded smoothly even under either aqueous or solvent-free conditions.
q 2006 Elsevier Ltd. All rights reserved.
1. Introduction
enehydrazines 1 proceed smoothly under mild conditions
(without acids and at below 90 8C) to give the indolines 2
and indoles 3.9,10a
Indole ring systems are the core structural elements in
natural and synthetic organic compounds possessing a wide
diversity of important biological activities. Therefore, there
is continuously a need for developing concise and practical
synthetic methods of indoles and the related compounds.
Despite recently developed methodologies,1 such as metal-
catalyzed transformations and radical cyclization, the
venerable Fischer indole synthesis has maintained its
prominent role as a route to indoles. However, two major
drawbacks to the Fischer indole synthesis are that yields are
sometimes low2–4 with numerous by products being formed.
And the reactions involving unsymmetrical hydrazines or
ketones often give products with low regioselectivity.2,5–8
Particularly, the low yields are a persistent problem in the
Fischer indole synthesis. Although the Fischer indolization
is usually carried out in the presence of an acid catalyst, the
acid may cause decomposition of the indole produced and,
therefore, thermal cyclization in the absence of a catalyst
appears to offer advantages over the acid-catalyzed
procedure. However, high temperature (180–250 8C) is
required for such cyclization.
The [3,3]-sigmatropic rearrangement of N-trifluoroacetyl
enehydrazines having either a methoxy or a methyl group on
the benzene ring gave dienylimines 4 which correspond
to the proposed intermediates of Fischer indolization.10b
Recently, we found that the [3,3]-sigmatropic rearrange-
ment and subsequent cyclization of N-trifluoroacetyl
Keywords: [3,3]-Sigmatropic rearrangement; N-Trifluoroacetyl enehydraz-
ines; Indole; Indoline; Dienylimine.
*
Corresponding author. Tel.: C81 78 441 7554; fax: C81 78 441 7556;
e-mail: taknaito@kobepharma-u.ac.jp
Scheme 1.
0040–4020/$ - see front matter q 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.01.087

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O. Miyata et al. / Tetrahedron 62 (2006) 3629–3647
This reaction provides a new entry to the Fischer indole
synthesis and was applied to not only one-pot synthesis of
various types of indoles11a but also synthesis of natural
indole products.11b We disclose herein the full details of the
[3,3]-sigmatropic rearrangement of N-trifluoroacetyl enehy-
drazines which are indispensable in the synthesis of indoles
(Scheme 1).10
Table 2. The conversion of N-acyl enehydrazines 6a–c into the indolines
7a–c
Entry
Substrate
R
Conditions
(8C)
Time
(h)
Yield
(%)
1
2
3
6a
6b
6c
COCF3
COCCl3
COCH3
THF (65)
THF (65)
Xylene (140)
5
5
3
99
56
65
7b in 56% yield (entry 2). However, in the case of 6c,
higher reaction temperature (140 8C) was required for
the successful rearrangement and cyclization (entry 3).
These results suggest that strong electron-withdrawing
group is suitable as the substituent on the nitrogen.
2. Results and discussion
2.1. The substituent effects on the nitrogen atom in [3,3]-
sigmatropic rearrangement of enehydrazines bearing
a cyclopentene ring
We next examined the rearrangement of the enehydrazine
6d carrying a trifluoromethanesulfonyl group which has
higher electron-withdrawing ability (Scheme 4, Table 3).
The sulfonylation of hydrazone 5a with trifluoromethane-
sulfonic anhydride was carefully carried out in the
presence of g-collidine at 0 8C. However, the reaction
gave not the desired product 6d but the rearranged
product 8d in low yield, along with the decomposition of
5a (entry 1).
At first, we investigated the substituent effects on the
nitrogen atom. Three types of N-acyl enehydrazines 6a, 6b,
and 6c having a cyclopentene ring were employed as the
substrate (Scheme 2, Table 1). The hydrazone 5a,12
prepared by condensation of cyclopentanone with N,N-
diphenylhydrazine was subjected to acylation with trifluoro-
acetic anhydride (TFAA) in the presence of g-collidine to
give the corresponding N-trifluoroacetyl enehydrazines 6a
in excellent yield (entry 1). Similarly, N-trichloroacetyl
enehydrazine 6b and N-acetyl enehydrazine 6c were
prepared from 5a (entries 2 and 3).
Scheme 2.
Scheme 4.
Table 1. The acylation of 5a with various acylating agents
Entry
Acylating
reagent
Temperature
(8C)
Product
Yield
(%)
Table 3. The treatment of 5a with (CF3SO2)2O
Entry
Base
Temperature (8C)
Yield (%)
1
2
3
TFAA
(CCl3CO)2O
AcCl, DMAP
0
0
25
6a
6b
6c
99
99
99
1
2
3
g-Collidine
g-Collidine
Et3N
0
K78
K78
5
25
70
When a solution of 6a in THF was heated at 65 8C for 5 h,
indoline 7a was obtained in 99% yield (Scheme 3, entry 1 in
Table 2). Similarly, the reaction of N-trichloroacetyl
enehydrazine 6b at the same temperature gave indoline
At lower reaction temperature of K78 8C, 8d was obtained
in 25% yield (entry 2). Replacement of g-collidine to
triethylamine as a base improved the yield to 70% (entry 3).
Thus, this result suggests that the enehydrazine 6a bearing a
trifluoroacetyl group is the best substrate for our indole
synthesis.
Similarly, the reaction of N-monophenylenehydrazine 6e,
prepared from 5b,13 proceeded smoothly in toluene at 90 8C
to give the indoline 7e along with the unreacted starting
material 6e (Scheme 5).
Scheme 3.

O. Miyata et al. / Tetrahedron 62 (2006) 3629–3647
3631
due to too low temperature (K78 8C). Therefore, 8d was an
isolable product in the reaction of 5a with trifluoromethane-
sulfonic anhydride.
2.2. The substituent effect on the ene part in [3,3]-
sigmatropic rearrangement of enehydrazines
We next investigated the substituent effects on the ene part.
At first, N-trifluoroacetyl enehydrazines 6a and 6f having a
cyclic enamine part was employed as substrate (Scheme 7,
Table 4). As mentioned above, the reaction of enehydrazine
6a having a cyclopentene ring gave the indoline 7a in
excellent yield (entry 1). Surprisingly, the reaction also
proceeded at room temperature but required prolonged
reaction time (entry 2). When the reaction of 6a was carried
out in toluene at 90 8C, a mixture of indoline 7a and indole
11a14 was obtained (entry 3). The reaction of 6a in xylene at
140 8C gave the indole 11a as the sole product (entry 4).
In the case of cyclohexenehydrazine 6f,15 the indole 11f16
was exclusively obtained without formation of the indoline
7f (entry 5).
Scheme 5.
Considering our results obtained above and the related
known Fischer indolization, we propose a plausible reaction
pathway that is shown in Scheme 6. At first, [3,3]-
sigmatropic rearrangement of the N-acyl enehydrazines
6a–c followed by isomerization proceeds to form
N-acylimines 10a–c which then cyclized intramolecularly
to give the indoline 7a–c.
Scheme 7.
Table 4. The thermal reaction of enehydrazines 6a and 6f under various
conditions
Entry
Substrate
Conditions (8C) Time (h)
Yield (%)
7
11
1
2
3
4
5
6a
6a
6a
6a
6f
THF (65)
5
480
3
4
11
99
98
61
—
—
—
—
30
92
53
CDCl3 (25)
Toluene (90)
Xylene (140)
THF (65)
Upon heating at 140 8C, the indoline 7a was converted
into the indole 11a in quantitative yield as a result of the
elimination of trifluoroacetamide (Scheme 8). Reductive
deamination of 7a with sodium cyanoborohydride
proceeded smoothly to give the corresponding indoline
1217 in 71% yield that is unsubstituted at the 3a-position
(Scheme 8).
Scheme 6.
In sulfonylation of hydrazone 5a, N-trifluoromethansulfonyl
enehydrazine 6d could not be isolated. Probably, the [3,3]-
sigmatropic rearrangement of 6d that would be transiently
formed from hydrazone 5a would take place easily even at
K78 8C because a trifluoromethanesulfonyl group has a
very strong electron-withdrawing property. The following
cyclization of rearranged intermediate 10d was prevented
In general, it is difficult to isolate 2-aminoindolines which is
proposed as an intermediate of Fischer indolization. To our
knowledge, there has been only a few works18–20 achieving
the isolation of 2-aminoindoline derivatives.

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O. Miyata et al. / Tetrahedron 62 (2006) 3629–3647
Table 5. The thermal reaction of enehydrazines 6g and 6h
Entry
Substrate
Conditions
(8C)
Time
(h)
Yield (%)
7
11
1
2
6g
6h
THF (65)
Toluene (90)
5
7
76
—
—
99
hand, the reaction of 6h in toluene at 90 8C gave the indole
11h22 in excellent yield (entry 2).
It is known5 that the classical Fischer indolization of
hydrazone prepared from unsymmetrical ketone gives a
mixture of substituted indoles with no regioselectivity.
Therefore, this regioselective formation of indolines and
indoles from unsymmetrical hydrazones 5c,d would be
useful for the synthesis of variously substituted polycyclic
indole alkaloids.
Scheme 8.
The difference between the structures of products (indolines
7a from cyclopentenehydrazine 6a and indoles 11f from
cyclohexenehydrazines 6f) could be explained as follows.
The indole double bond is not readily accommodated in
a fused system such as 1,2,3,3a,4,8b-hexahydrocyclopent-
[b]indoles in which the two rings are five-membered and
rather rigid. On the other hand, it is clear that no comparable
difficulty exists in the elimination of trifluoroacetamide
when the more flexible six-membered cyclohexane ring
is present.
The stereostructures of indolines 7a, 7g, and 12 were
established by NOESY of 1H NMR spectra. The assignment
of those configurations is based on the observed NOE
correlations as shown in Figure 1. In the case of 7a, NOE
was observed between 8b-H and NH. NOE in 7g was
observed between 3-Me and 8b-H, 3-Me and NH, and NH
and 8b-H. The stereostructures of 7b,c,e were deduced from
comparison of the 1H NMR spectra with those of 7a. In the
case of 12, NOE was observed between 8b-H and 3a-H.23
Next, the reaction of enehydrazines 6g and 6h having a
methyl group on the cyclopentene ring was examined
(Scheme 9, Table 5). The enehydrazines 6g and 6h were
prepared by the treatment of hydrazones 5c and 5d21 with
TFAA without formation of the regioisomer 13. The
enehydrazine 6g was subjected to the heating at 65 8C to
give the indoline 7g in 76% yield (entry 1) while the
indoline 7h could not be isolated from 6h under the same
conditions probably because of its instability. On the other
Figure 1. NOE correlations of compounds 7a, 7g and 12.
Furthermore, the stereostructure of 12 was firmly estab-
lished by the single-crystal X-ray analysis of the dibromide
14 which was prepared by bromination of 12 with NBS
(Scheme 10, Fig. 2).
Scheme 10.
We propose the possible reaction pathway for the formation
of 7g as shown in Scheme 11. The rearrangement of 6g
would proceed via a stable conformation A of 6g to give
the intermediate B which was converted into the stable
product 7g.
Scheme 9.

O. Miyata et al. / Tetrahedron 62 (2006) 3629–3647
Table 6. The thermal reaction of enehydrazines 6i–k
3633
Entry
Substrate
Conditions (8C) Time (h)
Yield (%)a
1
2
3
4
5
6i
6i
6j
6j
6k
THF (65)
CDCl3 (25)
THF (65)
Toluene (90)
THF (65)
4
480
10
6
69
50
24 (38)
77
79
10
a Yield in parenthesis is for recovered starting material.
gave a 3:1 mixture of enehydrazines 6j and 6k. The
stereostructures of 6i,k have not been established.
The enehydrazine 6i was heated at 65 8C to afford the
corresponding indoles 11i as the sole product (entry 1).
The thermal reaction of 6j at 90 8C gave indole 11j in 77%
yield (entry 4). Similarly, 11k25 was obtained from 6k
(entry 5). Since the rearrangement and cyclization of 6i–k
occurred with no isomerization of the olefin part under mild
conditions, the substituted indoles such as 2-mono- and 2,3-
disubstituted indoles would be selectively obtained as the
sole product.
Figure 2. The single-crystal X-ray analysis of 14.
2.3. The substituent effects on benzene ring in [3,3]-
sigmatropic rearrangement of enehydrazines bearing
cycloalkene ring
To demonstrate the generality of the rearrangement and
cyclization of N-trifluoroacetyl enehydrazines, we next
investigated the substituent effects on the benzene ring.
We chose methoxyl, methyl, nitro, and chloro groups as a
substituent. At first, the reaction of enehydrazine having a
substituent at the p-position on the benzene ring was
examined (Scheme 13, Table 7).
Scheme 11.
We then investigated the reaction of enehydrazine with an
acyclic chain on the ene part (Scheme 12, Table 6). The
enehydrazine 6i was prepared by the acylation of hydrazone
5e with TFAA. The acylation of hydrazone 5f24 with TFAA
Scheme 12.
Scheme 13.

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O. Miyata et al. / Tetrahedron 62 (2006) 3629–3647
Table 7. The thermal reaction of enehydrazines 6l–o
while in the case of an electron-withdrawing group, harsh
conditions were required for successful reaction.
Entry
Substrate
Conditions (8C) Time (h)
Yield (%)
7
11
We next investigated the thermal reaction of m-substituted
enehydrazines 6p–s, prepared from m-substituted phenyl-
hydrazines 15k–n (Scheme 14, Table 8). The reaction of 6p
bearing an m-methoxy group proceeded in toluene at
90 8C to give the 8-substituted indoline 7p and indole
11p, and 6-substituted indoline 70p and indole 110p
(entry 2).
1
2
3
4
5
6
7
6l
THF (65)
THF (65)
5
12
8
15
15
29
6
99
—
68
25
—
48
54
—
—
—
20
—
25
19
6m
6m
6n
6o
6o
6o
Toluene (90)
Toluene (90)
Toluene (90)
Toluene (110)
Xylene (140)
The condensation of hydrazines 15g–i with cyclopentanone
gave the corresponding unstable hydrazones 5g–i, which
without isolation were acylated to give enehydrazines 6l–n
in 52–69% yield. On the other hand, in the case of 6o
having a nitro group, the hydrazone 5j26 could be isolated
and then acylated to give the desired product 6o and
diacylated product 16 in 38 and 44% yields, respectively.
The substrate 6l having a methoxy group underwent
cyclization at lower temperature (65 8C) than the reaction
of unsubstituted enehydrazine 6e at 90 8C (see Scheme 5).
The indoline 7l was produced in excellent yield (entry 1).
Similarly, the substrate 6m with a methyl group gave the
indoline 7m at 90 8C (entry 3). On the other hand, in the
case of the enehydrazines 6n and 6o having an electron-
withdrawing group, prolonged reaction time and high
reaction temperature were required (entries 4–7). These
substituent effects are almost in agreement with those
obtained in the classical Fischer indolization.2 The
existence of an electron-donating group on a benzene
ring makes the thermal reaction relatively easy to occur
Table 8. The thermal reaction of enehydrazines 6p–s
Entry
Substrate Conditions
(8C)
Time
(h)
Yield (%)
70
110
7
11
1
2
3
4
5
6
6p
6p
6q
6r
6s
THF (65)
5
11
8
15
15
—
11
15
17
—
14
—
24
6
—
6
15
12
—
14
—
20
6
—
—
5
Toluene (90)
Toluene (90)
Toluene (90)
Toluene (90)
8
—
66
6s
Toluene (110) 29
Similarly, m-methyl enehydrazine 6q gave the 8-substituted
products 7q and 11q, and 6-substituted products 70q and
110q (entry 3). In the case of enehydrazine 6s with a nitro
group, four products 7s, 11s,27 70s, and 110s27 were obtained
after prolonged reaction time (entry 6). Thus, the [3,3]-
sigmatropic rearrangement of m-substituted enehydrazines
proceeded with low regioselectivity.
We next investigated the reaction of o-substituted enehy-
drazines (Scheme 15, Table 9). At first, [3,3]-sigmatropic
rearrangement of 6t having an o-methoxy group was
Scheme 14.
Scheme 15.

O. Miyata et al. / Tetrahedron 62 (2006) 3629–3647
Table 9. The thermal reaction of enehydrazines 6t–x
3635
Entry
Substrate
R
n
Conditions (8C)
Time (h)
Yield (%)
17 (cis-syn:cis-anti)
7
11
1
2
3
4
5
6
7
8
6t
6t
6t
6t
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
Me
1
1
1
1
1
2
2
2
1
1
1
1
THF (65)
10
5
7
22
6
10
10
10
8
63
51
69
75
—
—
—
—
30
14
66
31
—
—
—
—
24
34
52
75
37
42
—
—
36 (5:1)
48 (5:1)
29 (4:1)
24 (4:1)
15 (7:1)
3 (2:1)
17 (2:1)
9 (2:1)
32 (7:1)
18 (14:1)
—
MeCN (80)
Toluene (90)
Hexane (70)
MeOH (65)
THF (65)
MeCN (80)
Toluene (90)
MeCN (80)
Toluene (90)
Toluene (90)
Toluene (110)
6t
6u
6u
6u
6v
6v
6w
6x
9
10
11
12
Me
Cl
NO2
8
15
29
—
examined. 6t was heated in THF at 65 8C to give a mixture
of indoline 7t and two dienylimines 17t in 63 and 36%
yields, respectively (entry 1). The dienylimines 17t were
obtained as the result of the rearrangement at the root of a
methoxy group. Furthermore, 17t was easily separated into
two diastereomers, cis-syn-17t and cis-anti-17t, in a 5:1
ratio. Interestingly, the polarity of the organic solvent used
influences both the product ratio of the indoline and
dienylimine and the reaction time. In MeCN, the reaction
proceeded smoothly to give a 1:1 mixture of 7t and 17t in
99% yield (entry 2). On the other hand, in a less polar
solvent, such as toluene and hexane, 7t was obtained as a
major product in 69–75% yield, although prolonged
reaction time was required for complete consumption of
6t (entries 3 and 4). In methanol, the indole 11t and the
dienylimines 17t were obtained with no formation of
indoline 7t (entry 5). The reaction of cyclohexenyl
hydrazine 6u proceeded slowly under similar mild
conditions to give 7-methoxyindole 11u28 and dienylimines
17u (entries 6–8).
based on the observed NOE correlations as shown in
Figure 3. In the case of cis-syn-17t, NOE was observed
between MeO and 8b-H, 8b-H and NH, NH and MeO. On
the other hand, NOE in cis-anti-17t was observed only
between 8b-H and NH.
The stereostructure of cis-syn-17t was established unam-
biguously by single-crystal X-ray analysis.30 Furthermore,
heating the dienylimines, cis-syn-17t and cis-anti-17t,
in xylene at 140 8C afforded exclusively indole 11e31
(Scheme 16). This reaction pathway is ambiguous at the
moment.
Next, we turned our attention to the corresponding
o-methyl-N-trifluoroacetyl enehydrazine. The reaction of
6v proceeded smoothly in MeCN and toluene at 80–90 8C to
give the indoline 7v, indole 11v,29 cis-syn-17v, and cis-anti-
17v (entries 9 and 10). When an electron-withdrawing
group such as a chlorine or nitro group was present in the
o-position, the indolization occurred regioselectively at
the unsubstituted position to give 5-substituted products
(entries 11 and 12).
Scheme 16.
We have now succeeded in the isolation and structure
determination of the dienylimine intermediate in the
thermal reaction of the o-methoxyenehydrazine. Addition-
ally, the cis-syn-isomer was obtained as the major product
among dienylimines.
The stereostructures of cis-syn-17t–v and cis-anti-17t–v
were firmly established by NOESY of the 1H NMR
spectra (Fig. 3). Taking cis-syn-17t and cis-anti-17t as a
typical example, the assignment of those configurations is
It is well-known2–4,32,33 that Fischer indolization of (2-
methoxyphenyl)hydrazone gives 7-methoxyindole as a
minor product and the abnormal 6-substituted indole as a
major product without the isolation of dienylimine. The
isolation and determination of the dienylimine intermedi-
ates in the Fischer indolization of o-methoxy and o-methyl
enehydrazines provides good evidence for the postulated
reaction mechanism, including a stereochemical rationaliz-
ation, particularly for the [3,3]-sigmatropic rearrangement
Figure 3. NOE correlations of compounds cis-syn-17t and cis-anti-17t.

3636
O. Miyata et al. / Tetrahedron 62 (2006) 3629–3647
Scheme 17.
step. To the best of our knowledge, there has been only one
paper34 pertaining to the isolation of a pure dienylimine
having a methyl group at the 3a-position in which the
relative configurations at the 2-, 3- and 3a-position remain to
be established. Additionally, Brown35 has reported that
attempts to isolate a tricyclic dienylimine having a methyl
group were unsuccessful. Therefore, our result is the first
example of isolation and structure determination of the
tricyclic dienylimine with a methyl group.
The thermal reaction of o-substituted enehydrazine can be
summarized as follows. The reaction of enehydrazines
having an electron-donating group proceeded to give
indolines, indoles, and dienylimines. The cis-syn-dienyli-
mines were formed in preference to cis-anti-isomers. The
degree of regioselectivity on [3,3]-sigmatropic rearrange-
ment was shown to be dependent on the reaction solvent.
Thus, in a polar solvent, ca. 1:1 mixture of indolines or
indoles and dienylimines was obtained, while the reaction
employing a less polar solvent gave the indole or indoline as
a major product. In the case of enehydrazine bearing
an electron-withdrawing group, prolonged reaction time and
higher reaction temperature were required and no formation
of dienylimines was observed.
We next propose the possible reaction pathway for the
formation of dienylimines 17t–v (Scheme 17). The
enehydrazines 6t–v would exist in three different confor-
mations C, D, and E. The indolines 7t–v were obtained via
Scheme 18.

O. Miyata et al. / Tetrahedron 62 (2006) 3629–3647
3637
[3.3]-sigmatropic rearrangement of C. In the case of 7u,v,
they were converted into the indoles 11u,v by the elimination
of the trifluoroacetamido group. On the other hand, the
rearrangement of D and E followed by the cyclization of
the resulting imines F and G gave cis-syn-17t–v and cis-anti-
17t–v, respectively. The conversion of D into cis-syn-17t–v
proceeded more readily than that into cis-anti-17t–v because
conformation E is less stable than conformation D due to the
steric hindrance between a methoxy group and methylene on
a cyclopentene or cyclohexene ring in E. The rearrangement
of 6w,x gave the indolines 7w,x as the sole product. We are
unable at this time to offer an explanation of the difference
in regioselectivity between enehydrazine having an electron-
donating group and enehydrazine having an electron-
withdrawing group.
2.4. [3,3]-Sigmatropic rearrangement of enehydrazines
under both aqueous and solvent-free conditions
Due to the natural abundance of water as well as the inherent
advantages of using water as a solvent, much interest has
been recently growing in developing organic synthetic
reactions in water.37 We next investigated the [3,3]-
sigmatropic rearrangement of enehydrazines 6a,l,o,t,x in
aqueous media (Scheme 19, Table 10). Suspension of
enehydrazine 6a in water was heated at 65 8C. Extraction
and purification of the product by chromatography gave the
indoline 7a and indole 11a in 61 and 33% yield, respectively
(entry 1). The reaction of enehydrazine 6l having a
p-methoxy group gave the indole 11l as the sole product.
When a methoxy group exists at the o-position on the
benzene ring, the dienylimines 17t were obtained in
addition to indoline 7t and indole 11t. The reaction of
enehydrazines 6o and 6x bearing a nitro group on the
benzene ring did not occur even at 100 8C.
We next examined the reaction of acyclic enehydrazine 6y
having the o-methoxy group (Scheme 18). The conden-
sation of 15o with 2-butanone followed by acylation of
the resulting hydrazone gave the enehydrazine 6y and
C-acylated product 18. The isolated enehydrazine 6y was
heated at 80 8C to give cis-dienylimines 17y and indole
11y36 in 27% and 68% yields, respectively.
Finally, the rearrangement of enehydrazines was examined
under solvent-free conditions (Scheme 19, Table 10). The
reaction of enehydrazine 6a at 65 8C afforded the indoline
7a as a major product while the enehydrazine 6l having a
p-methoxy group gave the indole 11l as the sole product
(entries 6 and 7). In the case of enehydrazine 6o and 6x
having a nitro group which did not undergo the reaction at
100 8C, heating at from 120 to 160 8C allowed the reaction
to proceed but inefficiently (entries 8 and 10). The reaction
of o-methoxy substituted enehydrazine 6t gave 7t, 11t, and
17t in favor of 7t (entry 9). It is worth mentioning that the
indoles 11 are predominantly obtained under both aqueous
and solvent-free conditions except the case of o-methoxy
substituted enehydrazine 6t. Particularly, the enehydrazine
6l having a p-methoxy group gave the indole 11l even at
65 8C under these conditions while the reaction of 6l
proceeded at 65 8C in a solvent to give the indoline 7l as
the sole product (entry 1 in Table 7, Scheme 13).
3. Conclusion
We have established a novel [3,3]-sigmatropic rearrange-
ment of N-trifluoroacetyl enehydrazines for synthesis of
indolines and indoles. At below 100 8C, N-trifluoroacetyl
enehydrazine having a cyclopentene ring smoothly under-
went [3,3]-sigmatropic rearrangement followed by cycliza-
tion to give indolines in excellent yield. On the other hand,
both cyclohexenyl N-trifluoroacetyl enehydrazine and
Scheme 19.
Table 10. The thermal reaction of enehydrazines 6 under aqueous and solvent-free conditions
Entry
Substrate
R1
R2
Solvent
Temperature (8C)
Time (h)
Yield (%)
17 (cis-syn:cis-anti)
7
11
1
2
3
4
5
6
7
8
9
10
6a
6l
6o
6t
6x
6a
6l
6o
6t
H
Ph
H
H
H
H
Ph
H
H
H
H
H2O
H2O
H2O
H2O
H2O
Neat
Neat
Neat
Neat
Neat
65
65
100
65
100
65
65
160
65
120
5
0.5
7
7
7
4
5
5
5
10
61
—
—
8
—
83
—
—
51
5
33
60
—
39
—
4
89
41
10
17
—
—
—
29 (14:1)
—
—
—
—
p-OMe
p-NO2
o-OMe
o-NO2
H
p-OMe
p-NO2
o-OMe
o-NO2
25 (4:1)
—
6x

3638
O. Miyata et al. / Tetrahedron 62 (2006) 3629–3647
Scheme 20.
acyclic N-trifluoroacetyl enehydrazine gave indoles in good
yield under the almost same conditions. The rearrangement
of enehydrazine having an o-methoxy or an o-methyl group
on the benzene ring gave dienylimines that were clearly
characterized for the first time. The N-trifluoromethane-
sulfonyl enehydrazine was converted into the rearranged
product at low temperature (Scheme 20).
4.2.2. Trichloroacetic acid 1-(1-cyclopenten-1-yl)-2,2-
diphenylhydrazide (6b). According to the general pro-
cedure (A) given for preparation of N-acyl enehydrazine,
the treatment of hydrazone 5a12 (2.5 g, 10 mmol) with
trichloroacetic anhydride (4.1 mL, 20 mmol) in the presence
of g-collidine (3.8 mL, 30 mmol) gave the enehydrazine 6b
1
(3.90 g, 99%) as a yellow oil; IR (CHCl3) 1699 cmK1; H
NMR (300 MHz, CDCl3) d 1.85 (2H, br quint, JZ8 Hz),
2.28 and 2.58 (each 2H, m), 5.81 (1H, br s), 7.01–7.39 (10H,
m); HRMS (EI, m/z) calcd for C19H Cl3N2O (MC)
394.0406, found 394.0406.
35
17
4. Experimental
4.1. General
4.2.3. Acetic acid 1-(1-cyclopenten-1-yl)-2,2-diphenyl-
hydrazide (6c). To a solution of hydrazone 5a12 (500 mg,
2.0 mmol) and g-collidine (727 mg, 6.0 mmol) in CH2Cl2
(15 mL) was added acetyl chloride (314 mg, 4.0 mmol) and
dimethylaminopyridine (DMAP) (12.2 mg, 0.1 mmol)
under a nitrogen atmosphere at room temperature. After
being stirred at the same temperature for 24 h, the reaction
mixture was concentrated under reduced pressure. Purifi-
cation of the residue by FCC (n-hexane/ethyl acetate 10:1)
gave the N-acetyl enehydrazine 6c (548 mg, 99%) as a
1
Melting points are uncorrected. H and 13C NMR spectra
were recorded at 200, 300, or 500 MHz and at 125 MHz,
respectively. IR spectra were recorded using FTIR
apparatus. Mass spectra were obtained by EI method.
Flash column chromatography (FCC) was preformed using
E. Merck Kieselgel 60 (230–400 mesh). Medium-pressure
column chromatography (MCC) was performed using
¨
Lober Große B (E. Merck 310-25, Lichroprep Si60).
1
yellow oil; IR (CHCl3) 1680 cmK1; H NMR (300 MHz,
4.2. General procedure (A) for preparation of N-acyl
enehydrazines 6
CDCl3) d 1.82 (2H, br quint, JZ7.5 Hz), 2.04 (3H, s), 2.29
and 2.66 (each 2H, m), 5.70 (1H, br s), 6.99–7.33 (10H, m);
HRMS (EI, m/z) calcd for C19H20N2O (MC) 292.1575,
found 292.1576.
To a solution of hydrazone (10 mmol) in CH2Cl2 (100 mL)
were added g-collidine (30 mmol) and the corresponding
acid anhydride (20 mmol) at 0 8C. After being stirred at the
same temperature for 1.5–5.5 h, the reaction mixture was
concentrated under reduced pressure. Purification of the
residue by FCC (hexane/AcOEt 20:1–7:1) gave the N-acyl
enehydrazine 6.
4.3. General procedure for thermal reaction of N-acyl
enehydrazines 6
A solution of enehydrazines 6 (0.12–0.50 mmol) in solvent
(5–15 mL) was heated while monitoring the reaction by
TLC. The reaction mixture was concentrated under reduced
pressure. Purification of the residue by MCC (hexane/
AcOEt 20:1–5:1) gave the products.
4.2.1. Trifluoroacetic acid 1-(1-cyclopenten-1-yl)-2,2-
diphenylhydrazide (6a). According to the general pro-
cedure (A) given for preparation of N-acyl enehydrazine,
the treatment of hydrazone 5a12 (2.5 g, 10 mmol) with
TFAA (2.8 mL, 20 mmol) in the presence of g-collidine
(3.8 mL, 30 mmol) gave the enehydrazine 6a (3.43 g, 99%)
4.4. Thermal reaction of 6a–c (Table 2)
as a yellow oil; IR (CHCl3) 1711 cmK1 1H NMR
;
According to the general procedure given for the reaction of
6, the enehydrazines 6a–c were heated under the conditions
shown in Table 2 to give the indoline 7a–c in the yield
shown in Table 2.
(300 MHz, CDCl3) d 1.85 (2H, br quint, JZ8 Hz), 2.28
and 2.58 (each 2H, m), 5.80 (1H, br s), 7.01–7.39 (10H, m);
HRMS (EI, m/z) calcd for C19H17F3N2O (MC) 346.1292,
found 346.1273.

O. Miyata et al. / Tetrahedron 62 (2006) 3629–3647
3639
4.4.1. cis-3a-[(Trifluoroacetyl)amino]-1,2,3,3a,4,8b-
hexahydro-4-phenylcyclopent[b]indole (7a). Colorless
crystals, mp 137–140 8C (hexane/AcOEt); IR (CHCl3)
(entry 3) To a solution of hydrazone 5a (35.0 mg,
0.14 mmol) in CH2Cl2 (4 mL) was added triethylamine
(14.2 mg, 0.14 mmol) and Tf2O (39.5 mg, 0.14 mmol) at
K78 8C. The reaction mixture was stirred at the same
temperature for 1.5 h, monitoring the reaction by TLC. The
reaction mixture was purified without concentration by FCC
(n-hexane/ethyl acetate 20:1) to give 8d (37.5 mg, 70%) as
a yellow oil.
3425, 1725 cmK1
;
1H NMR (300 MHz, CDCl3) d
1.59–1.65 (1H, m), 1.79–1.86 (2H, m), 2.14–2.27 (2H, m),
2.35–2.42 (1H, m), 3.96 (1H, br dd, JZ9.5, 3 Hz), 6.58 (1H,
br d, JZ8 Hz), 6.74 (1H, br s), 6.81 (1H, br t, JZ8 Hz), 7.06
(1H, br t, JZ8 Hz), 7.15 (1H, br d, JZ8 Hz), 7.23 (1H, br t,
JZ8 Hz), 7.26 (2H, br d, JZ8 Hz), 7.40 (2H, br t, JZ8 Hz).
NOE was observed between 8b-H (d 3.96) and NH (d 6.74)
in NOESY spectroscopy. 13C NMR (125 MHz, CDCl3) d
24.6, 34.9, 36.4, 52.9, 90.9, 108.7, 115.4 (q, CF3), 119.7,
124.5, 125.1, 125.8, 127.5, 129.7, 132.1, 140.2, 148.1, 155.7
(q, COCF3); HRMS (EI, m/z) calcd for C19H17F3N2O (MC)
346.1292, found 346.1277. Anal. Calcd for C19H17F3N2O:
C, 65.89; H, 4.95; N, 8.09, found: C, 65.93; H, 5.13; N, 8.14.
4.4.5. Trifluoroacetic acid 1-(1-cyclopenten-1-yl)-2-
phenylhydrazide (6e). According to the general procedure
(A) given for the preparation of enehydrazine 6, the
acylation of hydrazone 5b13 (348 mg, 2 mmol) with
TFAA (0.6 mL, 4 mmol) gave enehydrazine 6e (400 mg,
1
74%) as a yellow oil; IR (CHCl3) 3421, 1721 cmK1; H
NMR (300 MHz, CDCl3) d 1.89 (2H, br quint, JZ8 Hz),
2.36 and 2.69 (each 2H, m), 5.72 (1H, br s), 6.17 (1H, br s),
6.75 (2H, br d, JZ8.5 Hz), 6.88 (1H, br t, JZ8.5 Hz), 7.28
(2H, br d, JZ8.5 Hz); HRMS (EI, m/z) calcd for
C13H13F3N2O (MC) 270.0980, found 270.0994.
4.4.2. cis-3a-[(Trichloroacetyl)amino]-1,2,3,3a,4,8b-
hexahydro-4-phenylcyclopent[b]indole (7b). A yellow
1
oil; IR (CHCl3) 3424, 1714 cmK1; H NMR (300 MHz,
CDCl3) d 1.56 (1H, br s), 1.63 (2H, m), 1.83 (1H, m),
2.16–2.42 (3H, m), 4.00 (1H, dd, JZ9.5, 3 Hz), 6.60 (1H, d,
JZ8 Hz), 6.80 (1H, br t, JZ8 Hz), 6.93 (1H, br t, JZ8 Hz),
7.06 (1H, m), 7.15–7.42 (5H, m); HRMS (EI, m/z) calcd for
4.4.6. cis-3a-[(Trifluoroacetyl)amino]-1,2,3,3a,4,8b-
hexahydrocyclopent[b]indole (7e). According to the
general procedure given for the thermal reaction of 6, 6e
(30 mg, 0.11 mmol) was heated in toluene (15 mL) at 90 8C
to give the indoline 7e (17 mg, 56%) as a colorless oil; IR
C19H Cl3N2O (MC) 394.0406, found 394.0406.
35
17
1
(CHCl3) 3424, 1720 cmK1; H NMR (300 MHz, CDCl3) d
4.4.3. cis-3a-Acetylamino-1,2,3,3a,4,8b-hexahydro-4-
phenylcyclopent[b]indole (7c). Colorless crystals, mp
1.66 (1H, m), 1.74–1.88 (2H, m), 2.20 (1H, m), 2.31–2.42
(2H, m), 3.69 (1H, dd, JZ8.5, 2 Hz), 4.67 (1H, br s), 6.57
(1H, dd, JZ7, 1 Hz), 6.78 (1H, td, JZ7, 1 Hz), 6.79 (1H, br
s), 7.07 (2H, m); HRMS (EI, m/z) calcd for C13H13F3N2O
(MC) 270.0980, found 270.0962.
1
218–221 8C (AcOEt); IR (CHCl3) 3436, 1678 cmK1; H
NMR (300 MHz, CDCl3) d 1.55 (1H, m), 1.70–1.81 (2H,
m), 1.90 (3H, s), 2.08 (1H, m), 2.20–2.38 (2H, m), 3.96 (1H,
dd, JZ9.5, 3 Hz), 6.02 (1H, br s), 6.62 (1H, d, JZ8 Hz),
6.76 (1H, br t, JZ8 Hz), 7.02 (1H, br t, JZ8 Hz), 7.13 (1H,
m), 7.16–7.49 (5H, m); HRMS (EI, m/z) calcd for
C19H20N2O (MC) 292.1575, found 292.1576. Anal. Calcd
for C19H20N2O$1/100H2O: C, 77.45; H, 6.77; N, 9.47,
found: C, 77.28; H, 6.93; N, 9.49.
4.4.7. Thermal reaction of 6a at 140 8C (entry 4, Table 4).
According to the general procedure given for the thermal
reaction of 6, 6a was heated in xylene at 140 8C to give
1,2,3,4-tetrahydro-4-phenylcyclopent[b]indole
11a14
(165 mg, 92%) as a yellow oil; 1H NMR (300 MHz,
CDCl3) d 2.55 (2H, br quint, JZ7 Hz), 2.91 (4H, t-like,
JZ7 Hz), 7.10–7.52 (9H, m); HRMS (EI, m/z) calcd for
C17H15N (MC) 233.1203, found 233.1177.
4.4.4. Reaction of hydrazone 5a with triflic anhydride
(Table 3). (entry 1) According to the general procedure (A)
given for the preparation of enehydrazine 6, the hydrazone
5a (2.50 g, 10 mmol) was treated with Tf2O (5.64 g,
20 mmol) in the presence of g-collidine (3.46 g, 30 mmol)
at 0 8C. After being stirred at the same temperature for 3 h,
the reaction mixture was concentrated under reduced
pressure. Purification of the residue by FCC (hexane/ethyl
acetate 20:1) gave N-[2-[2-(phenylamino)phenyl]cyclo-
penten-1-yl]trifluoromethanesulfonamide (8d) (191 mg,
4.4.8. Trifluoroacetic acid 1-(1-cyclohexen-1-yl)-2,2-
diphenylhydrazide (6f). According to the general pro-
cedure (A) given for the preparation of enehydrazine 6, the
acylation of diphenylhydrazone15 (2.64 g, 10 mmol) of
cyclohexanone with TFAA (2.8 mL, 20 mmol) gave
enehydrazine 6f (3.38 g, 94%) as a yellow oil; IR (CHCl3)
1711 cmK1; 1H NMR (300 MHz, CDCl3) d 1.44–1.80 (4H,
m), 2.04 and 2.35 (each 2H, m), 5.55 (1H, br s), 7.00–7.24
(10H, m); HRMS (EI, m/z) calcd for C20H19F3N2O (MC)
360.1448, found 360.1423.
1
5%) as a yellow oil; IR (CHCl3) 3327, 1603 cmK1; H
NMR (300 MHz, CDCl3) d 1.92 (2H, br quint, JZ8 Hz),
2.26 (1H, br s), 2.79 (4H, m), 7.05–7.38 (9H, m), 8.56 (1H,
br s); HRMS (EI, m/z) calcd for C18H17F3N2O2S (MC)
382.0962, found 382.0959.
(entry 2) To a solution of hydrazone 5a (52.8 mg,
0.21 mmol) in CH2Cl2 (7 mL) was added g-collidine
(38.8 mg, 0.32 mmol) and Tf2O (59.2 mg, 0.21 mmol) at
K78 8C. The reaction mixture was stirred at the same
temperature for 1.5 h, monitoring the reaction by TLC. The
reaction mixture was purified without concentration by FCC
(n-hexane/ethyl acetate 20:1) to give 8d (20.1 mg, 25%) as a
yellow oil.
4.4.9. 1,2,3,4-Tetrahydro-9-phenyl-9H-carbazole (11f)
(entry 5, Table 4). According to the general procedure
given for the thermal reaction of 6, 6f (75 mg, 0.21 mmol)
was heated in THF (10 mL) at 65 8C to give the indole 11f16
(27.5 mg, 53%) as a yellow oil; 1H NMR (200 MHz,
CDCl3) d 1.89 (4H, br quint, JZ3 Hz), 2.60 and 2.80 (each
2H, m), 7.02–7.54 (9H, m); HRMS (EI, m/z) calcd for
C18H17N (MC) 247.1360, found 247.1357.

3640
O. Miyata et al. / Tetrahedron 62 (2006) 3629–3647
4.4.10. Conversion of indoline 7a into indole 11a. A
solution of indoline 7a (82.3 mg, 0.24 mmol) in xylene
(4 mL) was refluxed, monitoring the reaction by TLC. After
being refluxed at the same temperature for 4 h, the reaction
mixture was concentrated under reduced pressure. Purifi-
cation of the residue by MCC (hexane/ethyl acetate 9:1)
gave 11a (35.4 mg, 92%).
performed at 93 K. The independent four molecules are in a
unit cell. Crystallographic data of: C68 H60 Br8 N4; space
˚
˚
˚
group P1; aZ8.371(1) A, bZ12.564(2) A, cZ13.862(2) A,
aZ86.99(1)8, bZ81.07(1)8, gZ89.91(1)8; VZ
3
1438.2(4) A ZZ1; TZ93.2 K; mZ7.044 mmK1; reflection
total: 14240, unique: 4774, observed: 4774(IOK10.0s(I));
parameters refined:721; R1Z0.067, RwZ0.181; GOFZ
1.81. Crystallographic data for the structure in this paper
have been deposited with the Cambridge Crystallographic
Data Centre as supplementary publication number
CCDC-292640. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/conts/retrieving.html (or from the
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: C44 1223 336 033; or
deposit@ccdc.cam.uk).
˚
4.4.11. cis-1,2,3,3a,4,8b-Hexahydro-4-phenylcyclopent-
[b]indole (12).17 To a stirred solution of indoline 7a
(187 mg, 0.54 mmol) in AcOH (3 mL) was added NaBH3-
CN (67.9 mg, 1.08 mmol) at 0 8C. After being stirred at
room temperature for 19 h, the reaction mixture was
neutralized with 4 M-NaOH and extracted with CHCl3.
The organic phase was washed with H2O, dried over
MgSO4, and concentrated under reduced pressure. Purifi-
cation of the residue by MCC (hexane/AcOEt 9:1) afforded
indoline 12 (129 mg, 71%) as a yellow oil; 1H NMR
(500 MHz, CDCl3) d 1.53 and 1.64 (each 1H, m), 1.80–1.96
(3H, m), 2.03 (1H, dddd, JZ12.5, 11, 8.5, 6.5 Hz), 3.83
(1H, td, JZ8.5, 3 Hz), 4.73 (1H, ddd, JZ8.5, 6.5, 3 Hz),
6.73–7.31 (9H, m); NOE was observed between 8b-H (d
3.83) and 3a-H (d 4.75) in NOESY spectroscopy. 13C NMR
(125 MHz, CDCl3) d 24.5, 34.0, 34.8, 45.5, 68.7, 108.2,
118.7, 119.0, 121.1, 124.7, 127.1, 129.1, 135.0, 143.4,
147.3; HRMS (EI, m/z) calcd for C17H17N (MC) 235.1360,
found 235.1361.
4.4.13. Trifluoroacetic acid 2,2-diphenyl-1-[1-(5-methyl-
cyclopenten-1-yl)]hydrazide (6g). According to the
general procedure (A) given for the preparation of
enehydrazine 6, the acylation of hydrazone 5c (528 mg,
2 mmol) with TFAA (0.6 mL, 4 mmol) gave enehydrazine
6g (520 mg, 72%) as a yellow oil; IR (CHCl3) 1709 cmK1
;
1H NMR (300 MHz, CDCl3) d 0.86 (3H, d, JZ8.5 Hz), 2.20
(4H, m), 3.56 (1H, m), 5.49 (1H, br s), 6.98–7.38 (10H, m);
HRMS (EI, m/z) calcd for C20H19F3N2O (MC) 360.1448,
found 360.1458.
4.5. General procedure (B) for preparation of N-acyl
enehydrazines 6
4.4.12. cis-7-Bromo-4-(4-bromophenyl)-1,2,3,3a,4,8b-
hexahydrocyclopent[b]indole (14). To a solution of
1,2,3,3a,4,8b-hexahydro-4-phenylcyclopent[b]indole 12
(105.2 mg, 0.45 mmol) in acetone (4.5 mL) was added
N-bromosuccinimide (NBS) (159.4 mg, 0.90 mmol) at 0 8C
under a nitrogen atmosphere in the dark. After being stirred
at the same temperature for 2 h, the reaction mixture was
quenched with H2O and extracted with CHCl3. The organic
phase was washed with brine, dried over MgSO4 and
concentrated at reduced pressure. The crude solid obtained
was recrystallized from n-hexane to afford 14 (169.8 mg,
To a solution of hydrazine (10 mmol) in EtOH (50 mL) was
added ketone (20 mmol) at room temperature. After being
stirred at the same temperature for 3–5 h, the reaction
mixture was concentrated under reduced pressure to give the
crude hydrazone. To a stirred solution of crude hydrazone in
CH2Cl2 (100 mL) was added g-collidine (30 mmol) and
TFAA (20 mmol) at 0 8C. After being stirred at the same
temperature for 1–5 h, the reaction mixture was concen-
trated under the reduced pressure. Purification of the residue
by FCC (hexane/AcOEt 20:1–5:1) gave the enehydrazine 6.
1
97%) as colorless crystals, mp 151–153 8C (hexane): H
NMR (500 MHz, CDCl3) d 1.56–1.69 (2H, m), 1.81–1.88
(3H, m), 1.97–2.10 (1H, m), 3.80 (1H, br td, JZ8.5, 3 Hz),
4.71 (1H, ddd, JZ8.5, 6.5, 3 Hz), 6.80 (1H, d, JZ8 Hz),
7.11 (2H, br d, JZ8 Hz), 7.12 (1H, dd, JZ8, 2.5 Hz), 7.19
(1H, dd, JZ2.5, 1.5 Hz), 7.41 (2H, br d, JZ8 Hz); HRMS
(EI, m/z) calcd for C17H15Br2N (MC) 390.9574, found
390.9570. NOE was observed between 8b-H (d 3.80) and
3a-H (d 4.71) in NOESY spectroscopy.
4.5.1. Trifluoroacetic acid 1-[1-(5-methylcyclopenten-1-
yl)]-2-phenylhydrazide (6h). According to the general
procedure (B) given for the preparation of 6, the
condensation of phenylhydrazine with 2-methylcyclo-
pentanone (1.02 g, 10.4 mmol) followed by acylation of the
resulting hydrazone with TFAA (2.9 mL, 20.8 mmol) gave
enehydrazine 6h (2.20 g, 75%) as a yellow oil; IR (CHCl3)
3354, 1720 cmK1; 1H NMR (300 MHz, CDCl3) d 1.09 (3H,
d, JZ8.5 Hz), 2.19 (4H, m), 3.30 (1H, m), 5.53 (1H, br s),
6.05 (1H, br s), 6.71–7.32 (5H, m); HRMS (EI, m/z) calcd for
C14H15F3N2O (MC) 284.1136, found 284.1142.
Determination of single-crystal structures by X-ray
crystallography: the dibromide 14 was recrystallized from
acetone to give single crystals suitable for X-ray single
crystallographic analysis. X-ray diffraction data was
collected on a Rigaku RAPID imaging plate with two-
dimensional area detector and graphite-monochromatized
4.5.2.
(3a,3aa,8ba)-3a-[(Trifluoroacetyl)amino]-
1,2,3,3a,4,8b-hexahydro-3-methyl-4-phenyl-cyclopent-
[b]indole (7g). According to the general procedure given for
the thermal reaction of 6, 6g (75.6 mg, 0.21 mmol) was
heated in THF (10 mL) at 65 8C to give the indoline 7g
(57.5 mg, 76%) as colorless crystals, mp 92–94 8C (hexane/
˚
Cu Ka radiation (lZ1054186A). The crystallographic
calculation was performed with the TEXSAN software
package from the Molecular Structure Corporation. The
crystal structure was solved by direct methods (SIR-92), and
refined by the full-matrix least-squares method. All non-
hydrogen atoms were anisotropically refined. Hydrogen
atoms were located in idealized positions and were not
subjected to further refinement. X-ray diffraction study was
AcOEt); IR (CHCl3) 1740 cmK1 1H NMR (500 MHz,
;
CDCl3) d 0.95 (3H, d, JZ7.5 Hz), 1.62–1.67 (2H, m), 1.91–
1.96 (1H, m), 2.41–2.51 (2H, m), 4.13 (1H, br dd, JZ9.5,
6 Hz), 6.40 (1H, br d, JZ8 Hz), 6.71 (1H, br s), 6.78 (1H, br

O. Miyata et al. / Tetrahedron 62 (2006) 3629–3647
3641
t, JZ8 Hz), 7.02 (1H, br t, JZ8 Hz), 7.14 (1H, br d, JZ
8 Hz), 7.24 (2H, br d, JZ8 Hz), 7.28 (1H, br t, JZ8 Hz),
7.41 (2H, br t, JZ8 Hz). NOE were observed between 3-Me
(d 0.95) and 8b-H (d 4.13), 3-Me (d 0.95) and NH (d 6.71),
NH (d 6.71) and 8b-H (d 4.13) in NOESY spectroscopy. 13C
NMR (125 MHz, CDCl3) d 15.0, 32.6, 33.3, 43.9, 52.6,
91.3, 108.0, 115.7 (q, CF3), 119.2, 123.8, 126.6, 127.1,
127.5, 129.8, 131.8, 140.3, 148.5, 156.1 (q, COCF3); HRMS
(EI, m/z) calcd for C20H19F3N2O (MC) 360.1448, found
360.1455. Anal. Calcd for C20H19F3N2O: C, 66.66; H, 5.31;
N, 7.77, found: C, 66.71; H, 5.42; N, 7.79.
7.32 (2H, m), 7.49 (4H, m); HRMS (EI, m/z) calcd for
C17H17N (MC) 235.1360, found 235.1374.
1
4.6.2. 2-Ethyl-1-phenyl-1H-indole (11j). A yellow oil; H
NMR (200 MHz, CDCl3) d 1.22 (3H, t, JZ8 Hz), 2.63 (2H,
q, JZ8 Hz), 6.42 (1H, br s), 7.08 (3H, m), 7.35 (2H, m),
7.43–7.61 (4H, m); HRMS (EI, m/z) calcd for C16H15N
(MC) 221.1203, found 221.1226.
4.6.3. 2,3-Dimethyl-1-phenyl-1H-indole (11k).25 A yellow
oil; 1H NMR (200 MHz, CDCl3) d 2.24 and 2.32 (each 3H,
s), 7.10 (3H, m), 7.32 (2H, m), 7.41–7.59 (4H, m); HRMS
(EI, m/z) calcd for C16H15N (MC) 221.1203, found
221.1208.
4.5.3. 1,2,3,4-Tetrahydro-3-methylcyclopent[b]indole
(11h). According to the general procedure given for the
thermal reaction of 6, 6h (59.6 mg, 0.21 mmol) was heated
in toluene(10 mL) at 90 8C to give the indole 11h (35.5 mg,
4.7. Preparation of N-trifluoroacetyl enehydrazines 6l–n
1
99%) as a yellow oil; IR (CHCl3) 3475 cmK1; H NMR
According to the general procedure (B) given for the
preparation of enehydrazine 6, the condensation of
corresponding hydrazines 15g–i with cyclopentanone
followed by acylation of hydrazones 5g–i gave 6l–n in the
yield shown in Table 7.
(300 MHz, CDCl3) d 1.29 (3H, d, JZ7 Hz), 2.05 (2H, m),
2.64–2.90 (3H, m), 6.95–7.48 (4H, m), 7.78 (1H, br s);
HRMS (EI, m/z) calcd for C12H13N (MC) 171.1047, found
171.1065.
4.5.4. Trifluoroacetic acid 2,2-diphenyl-1-(1-ethyl-1-
propenyl)hydrazide (6i). According to the general pro-
cedure (A) given for the preparation of 6, the acylation of
hydrazone 5e (2.52 g, 10 mmol) with TFAA (2.8 mL,
20 mmol) gave the enehydrazine 6i (1.67 g, 48%) as a
4.7.1. Trifluoroacetic acid 1-(1-cyclopenten-1-yl)-2-(4-
methoxyphenyl)hydrazide (6l). A yellow oil; IR (CHCl3)
3478, 1720 cmK1; 1H NMR (300 MHz, CDCl3) d 1.90 (2H,
br q, JZ8 Hz), 2.34 and 2.66 (each 2H, m), 3.77 (3H, s),
5.71 (1H, br s), 5.92 (1H, br s), 6.72 (2H, br d, JZ8.5 Hz),
6.84 (2H, br d, JZ8.5 Hz); HRMS (EI, m/z) calcd for
C14H15F3N2O2 (MC) 300.1085, found 300.1101.
1
yellow oil; IR (CHCl3) 1709 cmK1; H NMR (300 MHz,
CDCl3) d 1.17 (3H, t, JZ8 Hz), 1.64 (3H, d, JZ6 Hz), 2.37
(2H, br q, JZ8 Hz), 5.28 (1H, br q, JZ6 Hz), 7.02 and 7.32
(each 5H, m); HRMS (EI, m/z) calcd for C19H19F3N2O
(MC) 348.1449, found 348.1451.
4.7.2. Trifluoroacetic acid 1-(1-cyclopenten-1-yl)-2-(4-
methylphenyl)hydrazide (6m). A yellow oil; IR (CHCl3)
3354, 1717 cmK1; 1H NMR (300 MHz, CDCl3) d 1.88 (2H,
br quint, JZ7.5 Hz), 2.28 (3H, s), 2.34 and 2.68 (each
2H, m), 5.70 (1H, br s), 5.94 (1H, br s), 6.64 and 7.07
(each 2H, br d, JZ8 Hz); HRMS (EI, m/z) calcd for
C14H15F3N2O (MC) 284.1135, found 284.1113.
4.5.5. Acylation of hydrazone 5f with TFAA. According
to the general procedure given for the preparation of
enehydrazine 6, acylation of 5f24 (2.38 g, 10 mmol) with
TFAA (2.8 mL, 20 mmol) gave 6j (2.07 g, 62%) and 6k
(668 mg, 20%).
4.7.3. Trifluoroacetic acid 2-(4-chlorophenyl)-1-(1-cyclo-
penten-1-yl)hydrazide (6n). A yellow oil; IR (CHCl3)
3353, 1721 cmK1; 1H NMR (300 MHz, CDCl3) d 1.90 (2H,
br quint, JZ7.5 Hz), 2.35 and 2.67 (each 2H, m), 5.64 (1H,
4.5.6. Trifluoroacetic acid 1-(1-methylenepropyl)-2,2-
diphenylhydrazide (6j). A yellow oil; IR (CHCl3)
1
1713 cmK1; H NMR (300 MHz, CDCl3) d 1.12 (3H, m),
2.24 (2H, br q, JZ8 Hz), 4.09 and 5.07 (each 1H, br s), 7.04
and 7.32 (each 5H, m); HRMS (EI, m/z) calcd for
C18H17F3N2O (MC) 334.1292, found 334.1285.
br s), 6.13 (1H, br s), 6.69 (2H, br d, JZ8.5 Hz), 7.24 (2H,
35
br d, JZ8.5 Hz); HRMS (EI, m/z) calcd for C13H ClF3N2O
12
(MC) 304.0590, found 304.0602.
4.5.7. Trifluoroacetic acid 1-(1-methyl-2-propenyl)-2,2-
diphenylhydrazide (6k). A yellow oil; IR (CHCl3)
4.7.4. Conversion of hydrazine 15j into 6o. According to
the general procedure (B) given for the preparation of 6, the
condensation of hydrazine 15j (3.06 g, 20 mmol) with
cyclopentanone (1.68 g, 40 mmol) followed by acylation of
the resulting hydrazone 5j with TFAA (5.6 mL, 40 mmol)
gave the enehydrazine 6o (315 mg, 10%) and 5j (3.9 g,
89%). According to the general procedure (A) given for
preparation of 6, the acylation of 5j (3.9 g, 17.8 mmol) with
TFAA (5 mL, 35.6 mmol) gave the enehydrazine 6o
(1.74 g, 31% from 15j) and diacylated enehydrazine 16
(3.58 g, 49% from 15j).
1
1712 cmK1; H NMR (300 MHz, CDCl3) d 1.61 (3H, br
d, JZ7 Hz), 1.98 (3H, s), 5.33 (1H, br q, JZ7 Hz), 7.07 and
7.35 (each 5H, m); HRMS (EI, m/z) calcd for C18H17F3N2O
(MC) 334.1292, found 334.1291.
4.6. Thermal reaction of enehydrazines 6i–k
According to the general procedure for thermal reaction of
enehydrazine 6, 6i–k was heated at temperature shown in
Table 6 to afford 11i–k in the yield shown in Table 6.
4.7.5. Trifluoroacetic acid 1-(1-cyclopenten-1-yl)-2-(4-
nitrophenyl)hydrazide (6o). A yellow oil; IR (CHCl3)
3310, 1727, 1525, 1342 cmK1; 1H NMR (300 MHz, CDCl3)
d 1.94 (2H, br quint, JZ7 Hz), 2.38 and 2.71 (each 2H, m),
4.6.1. 2-Ethyl-3-methyl-1-phenyl-1H-indole (11i). A
yellow oil; H NMR (200 MHz, CDCl3) d 0.98 (3H, t, JZ
8 Hz), 2.34 (3H, s), 2.68 (2H, q, JZ8 Hz), 7.07 (3H, m),
1

3642
O. Miyata et al. / Tetrahedron 62 (2006) 3629–3647
5.71 (1H, br s), 6.62 (1H, br d, JZ8.5 Hz), 6.82 (1H, d, JZ
8.5 Hz), 6.83 (1H, br s), 8.20 (2H, d, JZ8.5 Hz); HRMS
(EI, m/z) calcd for C13H12F3N3O3 (MC) 315.0830, found
315.0828.
4.8.5. cis-3a-[(Trifluoroacetyl)amino]-1,2,3,3a,4,8b-
hexahydro-7-nitrocyclopent[b]indole (7o). A yellow oil;
IR (CHCl3) 3439, 1725, 1518, 1330 cmK1 1H NMR
;
(300 MHz, CDCl3) d 1.68 (1H, m), 1.78–1.94 (2H, m),
2.18 and 2.32 (each 1H, m), 2.44 (1H, m), 3.68 (1H, dd, JZ
9, 2 Hz), 5.59 (1H, br s,), 6.49 (1H, d, JZ8.5 Hz), 6.99 (1H,
br s), 7.95 (1H, br s), 8.19 (1H, dd, JZ8.5, 2 Hz); HRMS
(EI, m/z) calcd for C13H12F3N3O3 (MC) 315.0830, found
315.0848.
4.7.6. Cyclopentanone 4-nitrophenylhydrazone (5j).26
A
yellow oil; IR (CHCl3) 3602, 1521, 1211 cmK1; H NMR
(300 MHz, CDCl3) d 1.80 and 1.93 (each 2H, quint, JZ
7 Hz), 2.31 and 2.51 (each 2H, br td, JZ7, 2 Hz), 7.01 (2H,
br d, JZ9 Hz,), 7.30 (1H, br s), 8.13 (2H, br d, JZ9 Hz);
HRMS (EI, m/z) calcd for C11H13N3O2 (MC) 219.1007,
found 219.1014.
1
4.8.6. 1,2,3,4-Tetrahydro-7-nitrocyclopent[b]indole
(11o). A yellow oil; IR (CHCl3) 3468, 1519, 1334 cmK1
;
1H NMR (300 MHz, CDCl3) d 2.59 (2H, br quint, JZ8 Hz),
2.88 (4H, t-like, JZ8 Hz), 7.31 (1H, dd, JZ8.5, 1 Hz), 8.05
(1H, dd, JZ8.5, 2.5 Hz), 8.28 (1H, br s), 8.39 (1H, br d, JZ
2.5 Hz); HRMS (EI, m/z) calcd for C11H10N2O2 (MC)
202.0742, found 202.0748.
4.7.7. Trifluoroacetic acid 1-(1-cyclopenten-1-yl)-2-tri-
fluoroacetyl-2-(4-nitrophenyl) hydrazide (16). A yellow
1
oil; IR (CHCl3) 1725, 1752, 1535, 1348 cmK1; H NMR
(300 MHz, CDCl3) d 2.10 (2H, m), 2.46 (4H, m), 5.85 (1H,
br s), 7.63 (2H, br d, JZ8.5 Hz), 8.34 (2H, br d, JZ8.5 Hz);
HRMS (EI, m/z) calcd for C15H11F6N3O4 (MC) 411.0652,
found 411.0654.
4.9. Preparation of N-trifluoroacetyl enehydrazines 6p–s
4.8. Thermal reaction of N-trifluoroacetyl enehydrazines
6l–o
According to the general procedure (B) given for the
preparation of enehydrazine 6, the condensation of
corresponding hydrazines 15k–n with cyclopentanone
followed by acylation of the corresponding hydrazones
gave 6p–s in 36–99% yields.
According to the general procedure given for the thermal
reaction of 6, enehydrazines 6l–o were heated at the
temperature shown in Table 7 to give indoline 7l–o and
indole 11l–o in the yield shown in Table 7.
4.9.1. Trifluoroacetic acid 1-(1-cyclopenten-1-yl)-2-(3-
methoxyphenyl)hydrazide (6p). A yellow oil; IR (CHCl3)
3355, 1721 cmK1; 1H NMR (300 MHz, CDCl3) d 1.89 (2H,
br quint, JZ7.5 Hz), 2.35 and 2.68 (each 2H, m), 3.77 (3H,
s), 5.73 (1H, br s), 6.09 (1H, br s), 6.29 (1H, br s), 6.34 (1H,
br d, JZ8.5 Hz), 6.51 (1H, ddd, JZ8.5, 2.5, 1 Hz), 7.17
(1H, t, JZ8.5 Hz); HRMS (EI, m/z) calcd for
C14H15F3N2O2 (MC) 300.1085, found 300.1079.
4.8.1. cis-3a-[(Trifluoroacetyl)amino]-1,2,3,3a,4,8b-
hexahydro-7-methoxycyclopent[b]indole (7l). A yellow
1
oil; IR (CHCl3) 3478, 1750 cmK1; H NMR (300 MHz,
CDCl3) d 1.66 (1H, m), 1.82 (2H, m), 2.08 (1H, m), 2.40
(2H, m), 3.72 (1H, br d, JZ8 Hz), 3.75 (3H, s), 4.31 (1H, br
s), 6.52 (1H, br d, JZ8 Hz), 6.65 (1H, dd, JZ8, 2 Hz), 6.67
(1H, d, JZ2 Hz), 6.78 (1H, br s); HRMS (EI, m/z) calcd for
C14H15F3N2O2 (MC) 300.1085, found 300.1095.
4.9.2. Trifluoroacetic acid 1-(1-cyclopenten-1-yl)-2-(3-
methylphenyl)hydrazide (6q). A yellow oil; IR (CHCl3)
3455, 1718 cmK1; 1H NMR (300 MHz, CDCl3) d 1.88 (2H,
br quint, JZ7.5 Hz), 2.31 (3H, s), 2.35 and 2.68 (each 2H,
m), 5.70 (1H, br s), 6.02 (1H, br s), 6.52 (1H, br d, JZ8 Hz),
6.56 (1H, br s), 6.78 (1H, br d, JZ8 Hz), 7.16 (1H, br t, JZ
8 Hz); HRMS (EI, m/z) calcd for C14H15F3N2O (MC)
284.1135, found 284.1154.
4.8.2. cis-3a-[(Trifluoroacetyl)amino]-1,2,3,3a,4,8b-
hexahydro-7-methylcyclopent[b]indole (7m). A yellow
1
oil; IR (CHCl3) 3423, 1721 cmK1; H NMR (300 MHz,
CDCl3) d 1.66 (1H, m), 1.81 (2H, m), 2.13 (1H, m), 2.26
(3H, s), 2.38 (2H, m), 3.68 (1H, dd, JZ10, 1 Hz), 4.49 (1H,
br s), 6.49 (1H, br d, JZ8.5 Hz), 6.74 (1H, br s), 6.86–6.91
(2H, m); HRMS (EI, m/z) calcd for C14H15F3N2O (MC)
284.1135, found 284.1153.
4.9.3. Trifluoroacetic acid 2-(3-chlorophenyl)-1-(1-cyclo-
penten-1-yl)hydrazide (6r). A yellow oil; IR (CHCl3)
3408, 1728 cmK1; 1H NMR (300 MHz, CDCl3) d 1.90 (2H,
br quint, JZ7.5 Hz), 2.36 and 2.69 (each 2H, m), 5.74 (1H,
br s), 6.47 (1H, br s), 6.63 and 6.93 (each 1H, m), 6.76 (1H,
br s), 7.19 (1H, br dd, JZ8.5, 8 Hz); HRMS (EI, m/z) calcd
4.8.3.
1,2,3,3a,4,8b-hexahydrocyclopent[b]indole (7n).
yellow oil; IR (CHCl3) 3424, 1720 cmK1 1H NMR
cis-7-Chloro-3a-[(trifluoroacetyl)amino]-
A
;
(300 MHz, CDCl3) d 1.66 (1H, m), 1.72–1.90 (2H, m),
2.20 (1H, m), 2.28–2.38 (2H, m), 3.67 (1H, dd, JZ10.5,
2.5 Hz), 4.66 (1H, br s), 6.47 (1H, br d, JZ8.5 Hz), 6.81
(1H, br s), 7.00–7.04 (2H, m); HRMS (EI, m/z) calcd for
for C13H ClF3N2O (MC) 304.0590, found 304.0589.
35
12
C13H ClF3N2O (MC) 304.0590, found 304.0595.
35
12
4.9.4. Trifluoroacetic acid 1-(1-cyclopenten-1-yl)-2-(3-
nitrophenyl)hydrazide (6s). A yellow oil; IR (CHCl3)
3315, 1725, 1515, 1340 cmK1; 1H NMR (300 MHz, CDCl3)
d 1.94 (2H, br quint, JZ7.0 Hz), 2.37 and 2.72 (each 2H,
m), 5.68 (1H, br s), 6.37 (1H, br s), 7.06 (1H, br dd, JZ8,
2 Hz), 7.46 (1H, br t, JZ8 Hz), 7.61 (1H, br s), 7.84 (1H, dd,
JZ8, 2 Hz); HRMS (EI, m/z) calcd for C13H12F3N3O3
(MC) 315.0830, found 315.0841.
4.8.4. 7-Chloro-1,2,3,4-tetrahydrocyclopent[b]indole
1
(11n).38 A yellow oil; IR (CHCl3) 3475 cmK1; H NMR
(300 MHz, CDCl3) d 2.53 (2H, br quint, JZ8 Hz), 2.76–
2.88 (4H, t-like, JZ8 Hz), 7.03 (1H, dd, JZ8.5, 2 Hz), 7.18
(1H, br d, JZ8.5 Hz), 7.39 (1H, br d, JZ2 Hz), 7.84 (1H, br
s); HRMS (EI, m/z) calcd for C11H ClN (MC) 191.0501,
35
10
found 191.0516.

O. Miyata et al. / Tetrahedron 62 (2006) 3629–3647
3643
1
4.10. Thermal reaction of N-trifluoroacetyl enehydraz-
ines 6p–s
oil; IR (CHCl3) 3425, 1721 cmK1; H NMR (300 MHz,
CDCl3) d 1.70 (1H, m), 1.82–1.88 (2H, m), 2.27–2.40 (3H,
m), 3.72 (1H, dd, JZ10, 2.5 Hz), 4.81 (1H, br s), 6.44 and
According to the general procedure given for the thermal
reaction of 6, enehydrazines 6p–s were heated at the
temperature shown in Table 8 to give indoline 7p–s, 70p–s
and indole 11p–s, 110p–s in the yield shown in Table 8.
6.71 (each 1H, br d, JZ8 Hz), 6.82 (1H, br s, NH), 7.00 (1H,
35
t, JZ8 Hz); HRMS (EI, m/z) calcd for C13H ClF3N2O
12
(MC) 304.0590, found 304.0569.
4.10.8.
1,2,3,3a,4,8b-hexahydrocyclopent[b]indole (70r).
yellow oil; IR (CHCl3) 3426, 1721 cmK1 1H NMR
cis-6-Chloro-3a-[(trifluoroacetyl)amino]-
4.10.1. cis-3a-[(Trifluoroacetyl)amino]-1,2,3,3a,4,8b-
hexahydro-8-methoxycyclopent[b]indole (7p). A yellow
A
;
1
oil; IR (CHCl3) 3425, 1721 cmK1; H NMR (300 MHz,
(300 MHz, CDCl3) d 1.66 (1H, m), 1.71–1.89 (2H, m),
2.23–2.36 (3H, m), 3.62 (1H, br dd, JZ9.5, 2 Hz), 4.78 (1H,
br s), 6.53 (1H, d, JZ2 Hz), 6.72 (1H, dd, JZ8, 2 Hz), 6.78
(1H, br s, NH), 6.95 (1H, dd, JZ8, 1 Hz); HRMS (EI, m/z)
CDCl3) d 1.67 (1H, m), 1.84 (2H, m), 2.14–2.35 (3H, m),
3.68 (1H, dd, JZ8, 2 Hz), 3.81 (3H, s), 4.72 (1H, br s), 6.23
and 6.32 (each 1H, d, JZ8 Hz), 6.76 (1H, br s), 7.05 (1H, t,
JZ8 Hz); HRMS (EI, m/z) calcd for C14H15F3N2O2 (MC)
300.1085, found 300.1073.
calcd for C13H ClF3N2O (MC) 304.0590, found 304.0604.
35
12
4.10.9. 8-Chloro-1,2,3,4-tetrahydrocyclopent[b]indole
1
4.10.2. 1,2,3,4-Tetrahydro-8-methoxycyclopent[b]indole
;
(11r).39 A yellow oil; IR (CHCl3) 3686 cmK1; H NMR
(11p). A yellow oil; IR (CHCl3) 3479 cmK1
1H NMR
(300 MHz, CDCl3) d 2.53 (2H, br quint, JZ7 Hz), 2.85 and
3.04 (each 2H, t-like, JZ7 Hz), 6.96 (1H, t, JZ8 Hz), 7.03
(300 MHz, CDCl3) d 2.51 (2H, m), 2.83 and 2.96 (each 2H,
t-like, JZ7 Hz), 3.90 (3H, s), 6.49 (1H, dd, JZ8, 1 Hz),
6.92 (1H, dd, JZ8, 1 Hz), 6.99 (1H, t, JZ8 Hz), 7.81 (1H,
br s); HRMS (EI, m/z) calcd for C12H13NO (MC) 187.0996,
found 187.1001.
and 7.17 (each 1H, dd, JZ8, 1 Hz), 7.92 (1H, br s); HRMS
10
35
(EI, m/z) calcd for C11H ClN (MC) 191.0501, found
191.0504.
4.10.10. cis-3a-[(Trifluoroacetyl)amino]-1,2,3,3a,4,8b-
hexahydro-8-nitrocyclopent[b]indole (7s). A yellow oil;
4.10.3. cis-3a-[(Trifluoroacetyl)amino]-1,2,3,3a,4,8b-
hexahydro-6-methoxycyclopent[b]indole (70p). A yellow
IR (CHCl3) 3424, 1724, 1532, 1346 cmK1 1H NMR
;
1
oil; IR (CHCl3) 3424, 1720 cmK1; H NMR (300 MHz,
(300 MHz, CDCl3) d 1.76–1.89 (3H, m), 2.22 (1H, ddd,
JZ13.5, 10, 7.5 Hz), 2.48 (2H, m),4.21 (1H, dd, JZ12,
2 Hz), 5.30 (1H, br s), 6.80 and 7.55 (each 1H, dd, JZ8.5,
1 Hz), 6.91 (1H, br s), 7.22 (1H, t, JZ8.5 Hz); HRMS (EI,
m/z) calcd for C13H12F3N3O3 (MC) 315.0830, found
315.0847.
CDCl3) d 1.60–1.88 (3H, m), 2.15–2.46 (3H, m), 3.61 (1H,
br d, JZ8 Hz), 3.75 (3H, s), 5.72 (1H, br s), 6.15 (1H, d, JZ
3 Hz), 6.31 (1H, dd, JZ8, 3 Hz), 6.78 (1H, br s), 6.94 (1H,
d, JZ8 Hz); HRMS (EI, m/z) calcd for C14H15F3N2O2
(MC) 300.1085, found 300.1094.
4.10.4. 1,2,3,4-Tetrahydro-6-methoxycyclopent[b]indole
4.10.11. cis-3a-[(Trifluoroacetyl)amino]-1,2,3,3a,4,8b-
hexahydro-6-nitrocyclopent[b]indole (70s). A yellow oil;
1
(110p). A yellow oil; IR (CHCl3) 3477 cmK1; H NMR
(300 MHz, CDCl3) d 2.51 (2H, m), 2.80 (4H, br m), 3.82
(3H, s), 6.74 (1H, dd, JZ8.5, 2.5 Hz), 6.83 (1H, d, JZ
2.5 Hz), 7.30 (1H, d, JZ8.5 Hz), 7.70 (1H, br s); HRMS
(EI, m/z) calcd for C12H13NO (MC) 187.0996, found
187.1011.
IR (CHCl3) 3426, 1724, 1527, 1339 cmK1 1H NMR
;
(300 MHz, CDCl3) d 1.65 (1H, m), 1.76–1.92 (2H, m), 2.30
(2H, m), 2.38 (1H, m), 3.74 (1H, dd, JZ9.5, 2 Hz), 4.99 (1H,
br s), 6.82 (1H, br s), 7.16 (1H, d, JZ8 Hz), 7.32 (1H, d, JZ
2 Hz), 7.65 (1H, dd, JZ8, 2 Hz); HRMS (EI, m/z) calcd for
C13H12F3N3O3 (MC) 315.0830, found 315.0850.
4.10.5. cis-3a-[(Trifluoroacetyl)amino]-1,2,3,3a,4,8b-
hexahydro-8-methylcyclopent[b]indole (7q) and cis-3a-
[(trifluoroacetyl)amino]-1,2,3,3a,4,8b-hexahydro-6-
methylcyclopent[b]indole (70q). The indolines 7q and 70q
are inseparable: a yellow oil; 1H NMR (300 MHz, CDCl3) d
1.61–1.86 and 2.13–2.45 (6H, m), 2.23 and 2.27 (each 3/2H,
s), 3.63 and 3.66 (each 1/2H, dd, JZ8, 2 Hz), 4.63 and 4.66
(each 1/2H, br s), 6.41 (1/2H, br s), 6.43 (1/2H, br d, JZ
8 Hz), 6.59 (1H, br d, JZ8 Hz), 6.94 (1/2H, br d, JZ8 Hz),
6.99 (1/2H, t, JZ8 Hz).
4.10.12. 1,2,3,4-Tetrahydro-8-nitrocyclopent[b]indole
(11s).27 A yellow oil; IR (CHCl3) 3471, 1514, 1327 cmK1
;
1H NMR (300 MHz, CDCl3) d 2.53 (2H, quint, JZ7 Hz),
2.94 and 3.22 (each 2H, t-like, JZ7 Hz), 7.11 (1H, t, JZ
8 Hz), 7.55 and 8.02 (each 1H, dd, JZ8, 1 Hz), 8.28 (1H, br
s); HRMS (EI, m/z) calcd for C11H10N2O2 (MC) 202.0742,
found 202.0768.
4.10.13. 1,2,3,4-Tetrahydro-6-nitrocyclopent[b]indole
(110s).27 A yellow oil; IR (CHCl3) 3468, 1513, 1323 cmK1
;
4.10.6. 1,2,3,4-Tetrahydro-8-methylcyclopent[b]indole
(11q) and 1,2,3,4-tetrahydro-6-methylcyclopent[b]indole
(110q). The indoles 11q and 110q are inseparable: a yellow
1H NMR (300 MHz, CDCl3) d 2.59 (2H, quint, JZ7 Hz),
2.86 and 2.94 (each 2H, t-like, JZ7 Hz), 7.43 (1H, d, JZ
8.5 Hz), 8.01 (1H, dd, JZ8.5, 2 Hz), 8.26 (1H, d, JZ2 Hz),
8.30 (1H, br s); HRMS (EI, m/z) calcd for C11H10N2O2 (MC)
202.0742, found 202.0760.
1
oil; H NMR (300 MHz, CDCl3) d 2.43 and 2.57 (each 3/
2H, s), 2.82 (4H, m), 3.04 (2H, m), 6.82, 6.89 and 7.09 (each
1/2H, br d, JZ8 Hz), 6.97 (1/2H, t, JZ7.5 Hz), 7.10 (1/2H,
br s), 7.32 (1/2H, br d, JZ8 Hz).
4.11. Preparation of N-trifluoroacetyl enehydrazines 6t–x
4.10.7. cis-8-Chloro-3a-[(trifluoroacetyl)amino]-
1,2,3,3a,4,8b-hexahydrocyclopent[b]indole (7r). A yellow
According to the general procedure (B) given for the
preparation of enehydrazine 6, the condensation of

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O. Miyata et al. / Tetrahedron 62 (2006) 3629–3647
corresponding hydrazines 15o–r with cyclopentanone or
cyclohexanone followed by acylation of the corresponding
hydrazones gave 6t–x in 63–96% yields.
(EI, m/z) calcd for C14H15F3N2O2 (MC) 300.1085, found
300.1086.
4.12.2. (3aa,8aa,8ba)-3a-[(Trifluoroacetyl)amino]-
1,2,3,3a,8a,8b-hexahydro-8a-methoxycyclopent[b]-
indole (cis-syn-17t). Colorless crystals, mp 140–141 8C
4.11.1. Trifluoroacetic acid 1-(1-cyclopenten-1-yl)-2-
(2-methoxyphenyl)hydrazide (6t). A yellow oil; IR
1
(CHCl3) 3418, 1720 cmK1; H NMR (300 MHz, CDCl3) d
(hexane); IR (CHCl3) 1732 cmK1 1H NMR (500 MHz,
;
1.86 (2H, br quint, JZ7.5 Hz), 2.32 and 2.64 (each 2H, m),
3.89 (3H, s), 5.67 (1H, br s), 6.65–6.94 (5H, m); HRMS (EI,
m/z) calcd for C14H15F3N2O2 (MC) 300.1085, found
300.1101.
CDCl3) d 1.28–1.36 (2H, m), 1.75 (1H, m, 2-H), 1.90 (1H,
m), 2.38 (1H, ddd, JZ17, 9.5, 7.5 Hz), 2.47 (1H, m, 3-H),
2.82 (1H, dd, JZ10.5, 5 Hz), 3.18 (3H, s), 6.12 (1H, dt, JZ
9.5, 1 Hz), 6.45 (1H, dt, JZ9.5, 3.5 Hz), 6.53 (2H, dd, JZ
3.5, 1 Hz), 7.24 (1H, br s); NOE was observed between NH
(d 7.24) and 8a-OMe (d 3.18), NH (d 7.24) and 8b-H (d
2.82), and 8a-OMe (d 3.18) and 8b-H (d 2.82) in NOESY
spectroscopy. HRMS (EI, m/z) calcd for C14H15F3N2O2
(MC) 300.1085, found 300.1110. The crystal data of cis-
syn-17t was shown in previous communication.30
4.11.2. Trifluoroacetic acid 1-(1-cyclohexen-1-yl)-2-
(2-methoxyphenyl)hydrazide (6u). A yellow oil; IR
1
(CHCl3) 3421, 1710 cmK1; H NMR (300 MHz, CDCl3) d
1.50–1.63 (4H, m), 2.07–2.17 (4H, m), 3.81 (3H, s), 5.88
(1H, br s), 6.78 (1H, br s), 6.77–6.92 (4H, m); HRMS (EI,
m/z) calcd for C15H17F3N2O2 (MC) 314.1241, found
314.1252.
4.12.3. (3aa,8ab,8ba)-3a-[(Trifluoroacetyl)amino]-
1,2,3,3a,8a,8b-hexahydro-8a-methoxycyclopent[b]indole
(cis-anti-17t). Colorless crystals, mp 140–141 8C (hexane);
4.11.3. Trifluoroacetic acid 1-(1-cyclopenten-1-yl)-2-
(2-methylphenyl)hydrazide (6v). A yellow oil; IR
1
IR (CHCl3) 1731 cmK1; H NMR (500 MHz, CDCl3) d
1
(CHCl3) 3455, 1718 cmK1; H NMR (300 MHz, CDCl3) d
1.94–2.21 (6H, m), 3.06 (1H, br dd, JZ9, 2 Hz), 3.16 (3H,
s), 6.03 (1H, dt, JZ9.5, 1 Hz), 6.41 (1H, ddd, JZ9.5, 5.5,
1 Hz), 6.52 (1H, ddd, JZ9.5, 5.5, 1 Hz), 6.61 (1H, br dt, JZ
9.5, 1 Hz), 6.71 (1H, br s); NOE was observed between NH
(d 6.71) and 8b-H (d 3.06) in NOESY spectroscopy. HRMS
(EI, m/z) calcd for C14H15F3N2O2 (MC) 300.1085, found
300.1098.
1.89 (2H, br quint, JZ7.5 Hz), 2.35 and 2.67 (each 2H, m),
2.23 (3H, s), 5.68 (1H, br s), 5.96 (1H, br s), 6.65 (1H, br d,
JZ8 Hz), 6.89 (1H, td, JZ7.5, 1 Hz), 7.10–7.17 (2H, m);
HRMS (EI, m/z) calcd for C14H15F3N2O (MC) 284.1135,
found 284.1154.
4.11.4. Trifluoroacetic acid 2-(2-chlorophenyl)-1-
(1-cyclopenten-1-yl)hydrazide (6w). A yellow oil; IR
4.12.4. 1,2,3,4-Tetrahydro-5-methoxycyclopent[b]indole
(CHCl3) 3402, 1719 cmK1; H NMR (300 MHz, CDCl3) d
(11t). A yellow oil; IR (CHCl3) 3479 cmK1 1H NMR
;
1
1.89 (2H, br quint, JZ7.5 Hz), 2.34 and 2.67 (each 2H, m),
5.68 (1H, br s), 6.71 (1H, br s), 6.75 (1H, br dd, JZ8,
0.5 Hz), 6.91 (1H, ddd, JZ8, 7.5, 1.5 Hz), 7.20 (1H, dddd,
JZ8.5, 8, 1.5, 0.5 Hz), 7.32 (1H, dd, JZ8, 1.5 Hz); HRMS
(300 MHz, CDCl3) d 2.53 (2H, br quint, JZ7.5 Hz), 2.83
(4H, t-like, JZ7.5 Hz), 3.94 (3H, s), 6.60 (1H, br dd, JZ9,
1 Hz), 7.12 (2H, m), 8.05 (1H, br s); HRMS (EI, m/z) calcd
for C12H13NO (MC) 187.0996, found 187.0997.
(EI, m/z) calcd for C13H ClF3N2O (MC) 304.0590, found
35
12
304.0588.
4.12.5. 1,2,3,4-Tetrahydro-8-methoxy-9H-carbazole
1
(11u).28 A yellow oil; IR (CHCl3) 3422 cmK1; H NMR
4.11.5. Trifluoroacetic acid 1-(1-cyclopenten-1-yl)-2-
(2-nitrophenyl)hydrazide (6x). A yellow oil; IR (CHCl3)
3259, 1728, 1533, 1337 cmK1; 1H NMR (300 MHz, CDCl3)
d 1.93 (2H, br quint, JZ7.5 Hz), 2.39 and 2.71 (each 2H,
m), 5.78 (1H, br s), 6.93 (1H, br d, JZ8.5 Hz), 7.03 and 7.58
(each 1H, td, JZ8.5, 1 Hz), 8.25 (1H, dd, JZ8.5, 1 Hz),
9.24 (1H, br s); HRMS (EI, m/z) calcd for C13H12F3N3O3
(MC) 315.0830, found 315.0836.
(300 MHz, CDCl3) d 1.87 (4H, m), 2.70 (4H, m), 3.93 (3H,
s), 6.59 (1H, dd, JZ8, 1 Hz, 7-H), 6.98 (1H, t, JZ8 Hz),
7.07 (1H, dd, JZ8, 1 Hz), 7.92 (1H, br s); HRMS (EI, m/z)
calcd for C13H15NO (MC) 201.1153, found 201.1160.
4.12.6. (4aa,4ba,9aa)-9a-[(Trifluoroacetyl)amino]-
1,2,3,4,4a,9a-hexahydro-4b-methoxy-4bH-carbazole
(cis-syn-17u). Colorless crystals, mp 139–140 8C (hexane/
AcOEt); IR (CHCl3) 1732 cmK1 1H NMR (500 MHz,
;
4.12. Thermal reaction of N-trifluoroacetyl enehydraz-
ines 6t–x
CDCl3) d 0.65 (1H, dtd, JZ13.5, 12, 4 Hz), 1.12 (1H, qt,
JZ13.5, 3.5 Hz), 1.22–1.33 (1H, qt, JZ13.5, 3.5 Hz), 1.57
(1H, m), 1.63–1.71 (2H, m), 2.16 (1H, td, JZ13.5, 4.5 Hz),
2.63 (1H, dd, JZ12, 7 Hz), 3.15 (1H, dtd, JZ13.5, 3.5, 2 Hz),
3.17 (3H, s), 6.08 (1H, dt, JZ9.5, 1 Hz), 6.43 (1H, ddd, JZ
9.5, 5.5, 1 Hz), 6.56 (1H, ddd, JZ9.5, 5.5, 1 Hz), 6.63 (1H, br
d, JZ9.5 Hz), 7.41 (1H, br s); NOE was observed between
NH (d 7.41) and 4b-OMe (d 3.17), and NH (d 7.41) and 4a-H
(d 2.63) in NOESY spectroscopy. HRMS (EI, m/z) calcd for
C15H17F3N2O2 (MC) 314.1241, found 314.1252.
According to the general procedure given for the thermal
reaction of 6, enehydrazines 6t–x were heated at the
temperature shown in Table 9 to give indoline 7t–x, indole
11t–x, and dienylimine 17t–v in the yield shown in Table 9.
4.12.1. cis-3a-[(Trifluoroacetyl)amino]-1,2,3,3a,4,8b-
hexahydro-5-methoxycyclopent[b]indole (7t). A yellow
1
oil; IR (CHCl3) 3490, 1625 cmK1; H NMR (300 MHz,
CDCl3) d 1.65 (1H, m), 1.83 (2H, m), 2.10 (1H, m),
2.33–2.53 (2H, m), 3.80 (1H, br d, JZ9.5 Hz), 3.84 (3H, s),
4.48 (1H, br s), 6.69 (1H, br d, JZ8 Hz), 6.72 (1H, br d,
JZ8 Hz), 6.79 (1H, br s), 6.80 (1H, t, JZ8 Hz); HRMS
4.12.7. (4aa,4bb,9aa)-9a-[(Trifluoroacetyl)amino]-
1,2,3,4,4a,9a-hexahydro-4b-methoxy-4bH-carbazole
(cis-anti-17u). Colorless crystals, mp 138–140 8C (hexane/
AcOEt); IR (CHCl3) 1720 cmK1 1H NMR (500 MHz,
;

O. Miyata et al. / Tetrahedron 62 (2006) 3629–3647
3645
CDCl3) d 1.44 (1H, qt, JZ13.5, 3 Hz), 1.60 (1H, m), 1.65–
1.87 (4H, m), 2.10 (1H, dm, JZ13.5 Hz), 2.35 (1H, dm,
JZ13.5 Hz), 2.78 (1H, br dt, JZ8, 1 Hz), 3.07 (3H, s), 6.11
(1H, dt, JZ9.5, 1 Hz), 6.41 (1H, br s), 6.44 (1H, ddd, JZ
9.5, 5.5, 1 Hz), 6.54 (1H, ddd, JZ9.5, 5.5, 1 Hz), 6.66 (1H,
dt, JZ9.5, 1 Hz); NOE was observed between NH (d 6.41)
and 4a-H (d 2.78) in NOESY spectroscopy. HRMS (EI, m/z)
calcd for C15H17F3N2O2 (MC) 314.1241, found 314.1260.
4.83 (1H, br s), 6.70 (1H, t, JZ8 Hz), 6.88 (1H, br s), 6.94
and 7.06 (each 1H, br d, JZ8 Hz); HRMS (EI, m/z) calcd
12
for C13H ClF3N2O (MC) 304.0590, found 304.0571.
35
4.12.13. cis-3a-[(Trifluoroacetyl)amino]-1,2,3,3a,4,8b-
hexahydro-5-nitrocyclopent[b]indole (7x). A yellow oil;
IR (CHCl3) 3436, 1729, 1518, 1331 cmK1 1H NMR
;
(300 MHz, CDCl3) d 1.65 (1H, m), 1.81–1.91 (2H, m),
2.24–2.44 (3H, m), 3.83 (1H, br d, JZ9.5 Hz), 6.72 (1H, t,
JZ8 Hz), 6.86 (1H, br s), 7.16 (1H, br s), 7.25 and 7.87
(each 1H, br d, JZ8 Hz); HRMS (EI, m/z) calcd for
C13H12F3N3O3 (MC) 315.0830, found 315.0842.
4.12.8. cis-3a-[(Trifluoroacetyl)amino]-1,2,3,3a,4,8b-
hexahydro-5-methylcyclopent[b]indole (7v). A yellow
1
oil; IR (CHCl3) 3423, 1721 cmK1; H NMR (300 MHz,
CDCl3) d 1.66 (1H, m), 1.74–1.89 (2H, m), 2.13 (3H, s),
2.18 (1H, m), 2.30–2.48 (2H, m), 3.72 (1H, dd, JZ10,
1 Hz), 4.43 (1H, br s), 6.73 (1H, t, JZ8 Hz), 6.78 (1H, br s),
6.90–6.94 (2H, m); HRMS (EI, m/z) calcd for C14H15F3N2O
(MC) 284.1135, found 284.1142.
4.12.14. 1,2,3,4-Tetrahydrocyclopent[b]indole (11e)
(conversion of dienylimines cis-syn-17t and cis-anti-17t
into indole 11e). A solution of cis-syn-17t (27 mg,
0.09 mmol) in xylene (5 mL) was heated at 140 8C for
23 h. After the reaction mixture was concentrated under the
reduced pressure, purification of the residue by MCC (n-
hexane/ethyl acetate 2:1) gave the indole 11e31 (9.9 mg,
70%). Similarly, cis-anti-17t (27 mg, 0.09 mmol) was
converted into indole 11e31 (5.9 mg, 42%) as a yellow oil,
IR (CHCl3) 3477 (NH) cmK1; 1H NMR (300 MHz, CDCl3)
d 2.52 (2H, br quint, JZ8 Hz), 2.84 (4H, t-like, JZ8 Hz),
7.07 (2H, m), 7.28 and 7.42 (1H, m,), 7.76 (1H, br s); HRMS
(EI, m/z) calcd for C11H11N (MC) 157.0891, found
157.0891.
4.12.9. (3aa,8aa,8ba)-3a-[(Trifluoroacetyl)amino]-
1,2,3,3a,8a,8b-hexahydro-8a-methylcyclopent[b]indole
(cis-syn-17v). Colorless crystals, mp 139–140 8C (hexane/
AcOEt); IR (CHCl3) 1721 cmK1 1H NMR (500 MHz,
;
CDCl3) d 1.24 (3H, s), 1.29 (1H, m), 1.51 (1H, m), 1.78 (1H,
m), 1.99 (1H, br ddd, JZ13, 7, 4 Hz), 2.07 (1H, dtd, JZ13,
9.5, 6.5 Hz), 2.42 (1H, ddd, JZ13, 9.5, 7 Hz), 2.90 (1H, dd,
JZ9.5, 5 Hz), 6.06 (1H, ddd, JZ9.5, 5.5, 1 Hz), 6.23 (1H,
br d, JZ9.5 Hz), 6.27 (1H, dt, JZ9.5, 1 Hz), 6.51 (1H, ddd,
JZ9.5, 5.5, 1 Hz), 8.11 (1H, br s); NOE was observed
between NH (d 8.11) and 8a-Me (d 1.24), NH (d 8.11) and
8b-H (d 2.90), and 8a-Me (d 1.24) and 8b-H (d 2.90) in
NOESY spectroscopy. HRMS (EI, m/z) calcd for
C14H15F3N2O (MC) 284.1135, found 284.1125. Anal.
Calcd for C14H15F3N2O: C, 59.15; H, 5.32; N, 9.85,
found: C, 59.03; H, 5.31; N, 9.85.
4.13. Condensation of hydrazine 15o followed
by acylation
According to the general procedure (B) given for the
preparation of enehydrazine 6, the condensation of
corresponding hydrazine 15o (2.76 g, 20 mmol) with
2-butanone (1.79 mL, 20 mmol) followed by acylation of
the corresponding hydrazone gave 6y (1.29 g, 23%) and
C-acylated product 18 (3.44 g, 62%).
4.12.10. (3aa,8ab,8ba)-3a-[(Trifluoroacetyl)amino]-
1,2,3,3a,8a,8b-hexahydro-8a-methylcyclopent[b]indole
(cis-anti-17v). Colorless crystals, mp 138–139 8C (hexane/
AcOEt); IR (CHCl3) 1724 cmK1 1H NMR (500 MHz,
;
4.13.1. Trifluoroacetic acid (Z)-2-(2-methoxyphenyl)-1-
(1-ethyl-1-propenyl)hydrazide (6y). A yellow oil; IR
CDCl3) d 1.18 (3H, s), 1.78 (1H, br dquint, JZ13, 8 Hz),
1.89 (1H, m), 1.97 (1H, ddd, JZ13, 8, 5.5 Hz), 2.05 (1H,
m), 2.21–2.29 (2H, m), 3.04 (1H, br dd, JZ9, 2 Hz), 5.99
(1H, ddd, JZ9.5, 5.5, 1 Hz), 6.26 (1H, dt, JZ9.5, 1 Hz),
6.41 (1H, br dt, JZ9.5, 1 Hz), 6.48 (1H, ddd, JZ9.5, 5.5,
1.5 Hz), 6.73 (1H, br s); NOE was observed between NH (d
6.73) and 8b-H (d 3.04) in NOESY spectroscopy. HRMS
(EI, m/z) calcd for C14H15F3N2O (MC) 284.1135, found
284.1151. Anal. Calcd for C14H15F3N2O: C, 59.15; H, 5.32;
N, 9.85, found: C, 59.13; H, 5.31; N, 9.83.
1
(CHCl3) 3357, 1720 cmK1; H NMR (500 MHz, CDCl3) d
1.07 (3H, t, JZ7.5 Hz), 2.32 (2H, br q, JZ7.5 Hz), 3.89
(3H, s), 5.09 (2H, br d, JZ15 Hz), 6.68 (1H, br s), 6.77–6.95
(4H, m); HRMS (EI, m/z) calcd for C13H15F3N2O2 (MC)
288.1087, found 288.1079.
4.13.2. 1,1,1-Trifluoro-2,4-hexanedione 4-(2-methoxy-
phenyl)hydrazone (18). A yellow oil; IR (CHCl3) 3372,
1711 cmK1; 1H NMR (200 MHz, CDCl3) d 1.15 (3H, t, JZ
7.5 Hz), 2.04 (2H, br s), 2.41 (2H, br q, JZ7.5 Hz), 3.85
(3H, s), 6.95–7.02 (2H, m), 7.29–7.42 (2H, m); HRMS (EI,
m/z) calcd for C13H15F3N2O2 (MC) 288.1085, found
288.1079.
4.12.11. 1,2,3,4-Tetrahydro-5-methylcyclopent[b]indole
1
(11v).29 A yellow oil; IR (CHCl3) 3480 cmK1; H NMR
(300 MHz, CDCl3) d 2.46 (3H, s, Me), 2.55 (2H, br quint,
JZ7.5 Hz), 2.79–2.90 (4H, t-like, JZ7.5 Hz), 6.90 (1H, br
d, JZ8 Hz), 7.00 (1H, t, JZ8 Hz), 7.29 (1H, br d, JZ8 Hz),
7.66 (1H, br s); HRMS (EI, m/z) calcd for C12H13N (MC)
171.1048, found 171.1069.
4.14. Thermal reaction of N-trifluoroacetyl enehydraz-
ine 6y
4.12.12.
1,2,3,3a,4,8b-hexahydrocyclopent[b]indole (7w).
yellow oil; IR (CHCl3) 3424, 1720 cmK1 1H NMR
(300 MHz, CDCl3) d 1.64 (1H, m), 1.73–1.90 (2H, m),
2.22 (1H, m), 2.29–2.43 (2H, m), 3.80 (1H, dd, JZ8, 1 Hz),
cis-5-Chloro-3a-[(trifluoroacetyl)amino]-
According to the general procedure given for the thermal
reaction of 6, the enehydrazine 6y (51.2 mg, 0.18 mmol)
was heated at 80 8C in MeCN. After the reaction mixture
was concentrated under reduced pressure, the residue was
purified by MCC (hexane/AcOEt 10:1) to give the
A
;

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O. Miyata et al. / Tetrahedron 62 (2006) 3629–3647
dienylimine 17y (13.7 mg, 27%) and indole 11y36 (21.2 mg,
68%).
Gilchrist, T. L. J. Chem. Soc., Perkin Trans. 1 1999, 2848. (d)
Gribble, G. W. J. Chem. Soc., Perkin Trans. 1 2000, 1045.
2. Reviews of Fischer indole synthesis: (a) Robinson, B. Chem.
Rev. 1963, 63, 373. (b) Robinson, B. Chem. Rev. 1969, 69, 227.
(c) Robinson, B. The Fischer Indole Synthesis; Wiley: New
York, 1982. (d) Hughes, D. L. Org. Prep. Proced. Int. 1993,
25, 609.
4.14.1. cis-2-Ethyl-2-[(trifluoroacetyl)amino]-2,3-dihy-
dro-3a-methoxy-3aH-indole (17y). Colorless crystals, mp
117–118 8C (hexane/Et2O); IR (CHCl3) 3416, 1725 cmK1
;
1H NMR (500 MHz, CDCl3) d 1.06 (3H, t, JZ7.5 Hz), 1.98
(1H, dq, JZ15, 7.5 Hz), 2.23 and 2.86 (each 1H, AB q, JZ
13.5 Hz), 2.47 (1H, dq, JZ15, 7.5 Hz), 3.14 (3H, s), 6.19
(1H, br d, JZ9.5 Hz), 6.41 (1H, br ddd, JZ9.5, 5.5, 1 Hz),
6.57 (1H, br ddd, JZ9.5, 5.5, 1 Hz), 6.61 (1H, br d, JZ
9.5 Hz), 6.96 (1H, br s); 13C NMR (125 MHz, CDCl3) d 9.0,
32.5, 49.9, 51.9, 82.3, 88.1, 115.6 (q, CF3), 123.1, 126.5,
132.2, 134.5, 155.6 (q, COCF3), 174.9; HRMS (EI, m/z)
calcd for C13H15F3N2O2 (MC) 288.1084, found 288.1091.
Anal. Calcd for C13H15F3N2O2: C, 54.17; H, 5.24; N, 9.72,
found: C, 54.37; H, 5.33; N, 9.68; NOE was observed
between 3a-OMe (d 3.14) and NH (d 6.96) in NOESY
spectroscopy.
3. Kelly, A. H.; McLeod, D. H.; Parrick, J. J. Chem. Soc. 1965,
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9. Although the Fischer indolization of N-acetyl enehydrazine
has previously been reported, it required either an elevated
temperature (170 8C) or an acid catalysis (dichloroacetic acid)
to achieve successful cyclization. Schiess, P.; Sendi, E. Helv.
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4.14.2. 2-Ethyl-7-methoxyindole (11y). Colorless oil; IR
1
(CHCl3) 3372 cmK1; H NMR (200 MHz, CDCl3) d 1.32
10. (a) Miyata, O.; Kimura, Y.; Muroya, K.; Hiramatsu, H.; Naito, T.
Tetrahedron Lett. 1999, 40, 3601. (b) Miyata, O.; Kimura, Y.;
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(3H, t, JZ7.5 Hz), 2.76 (2H, q, JZ7.5 Hz), 3.94 (3H, s),
6.21 (1H, br s), 6.58 (1H, br d, JZ8 Hz), 6.97 (1H, br t, JZ
8 Hz), 7.14 (1H, br d, JZ8 Hz), 8.11 (1H, br s); HRMS (EI,
m/z) calcd for C11H13NO (MC) 175.0997, found 175.0984.
11. (a) Miyata, O.; Kimura, Y.; Naito, T. Synthesis 2001, 1635. (b)
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4.15. Thermal reaction of N-trifluoroacetyl
enehydrazines 6a,l,o,t,x in water
A suspended solution of enehydrazines 6a,l,o,t,x (0.18–
0.25 mmol) in H2O (10–15 mL) was heated under the
conditions shown in Table 10. The reaction mixture was
extracted with CHCl3 and the organic phase was washed
with H2O, dried over Na2SO4, and concentrated under the
reduced pressure. Purification of the residue by MCC
(hexane/AcOEt 20:1–5:1) afforded the indoline 7, indole 11,
dienylimine 17 in the yield shown in Table 10.
14. Odera, T.; Sato, M. Patent JP 2000169446, 2000; Chem. Abstr.
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4.16. Thermal reaction of N-trifluoroacetyl enehydraz-
ines 6a,l,o,t,x under solvent-free conditions
17. Torizuka, K. Patent JP 2001175012; Chem. Abstr. 2001, 135,
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The enehydrazines 6a,l,o,t,x (0.18–0.25 mmol) was heated
directly under the conditions shown in Table 10. Purifi-
cation of the residue by MCC (hexane/AcOEt 20:1–5:1)
afforded the indoline 7, indole 11, dienylimine 17 in the
yield shown in Table 10.
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Acknowledgements
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We acknowledge Grants-in Aid for Scientific Research (B)
(T.N.) and Scientific Research (C) (O.M.) from Japan
Society for the Promotion of Science. Our thanks are also
directed to the Science Research Promotion Fund of the
Japan Private School Promotion Foundation for a research
grant.
26. (a) Zhang, G.-S.; Chai, B. Synth. Commun. 2000, 30, 1849. (b)
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30. The crystal data and figure of cis-syn-17t were shown in a
previous communication.10b
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