Unambiguous characterisation of dienylimines as intermediates in Fischer indolisation of o-substituted N-trifluoroacetyl enehydrazines

Article abstract of DOI:10.1039/a907539i

Thermal cyclisation of o-substituted N-trifluoroacetyl enehydrazines was systematically investigated and found to proceed via dienylimine intermediates, which were unambiguously characterised by X-ray and spectral analysis.

Full text of DOI:10.1039/a907539i

Unambiguous characterisation of dienylimines as intermediates in Fischer
indolisation of o-substituted N-trifluoroacetyl enehydrazines
Okiko Miyata, Yasuo Kimura and Takeaki Naito*
Kobe Pharmaceutical University, Motoyamakita, Higashinada, Kobe 658-8558, Japan.
E-mail: taknaito@kobepharma-u.ac.jp
Received (in Cambridge, UK) 17th September 1999, Accepted 1st November 1999
Thermal cyclisation of o-substituted N-trifluoroacetyl ene-
hydrazines was systematically investigated and found to
proceed via dienylimine intermediates, which were unambi-
guously characterised by X-ray and spectral analysis.
Fischer indolisation. o-Substituted hydrazones are generally
known to react more sluggishly than the m- and p-substituted
analogs and sometimes give low yields of the desired indoles
accompanied with side reactions.1
We first examined the thermal cyclisation of N-trifluoro-
acetyl enehydrazine 3a having an o-methoxy group (Table 1).
The Fischer indole synthesis provides a versatile and con-
1
1,5
vergent route to a wide variety of indoles. Although today the
Previously, characterisation of the dienylimine intermediate
key step in Fischer indolisation is regarded as a [3,3]-sigma-
tropic rearrangement of the enehydrazines, which is related to
the Cope and Claisen rearrangements,1 there have been only a
few reports on the isolation and characterisation of the
dearomatised dienylimine (1 or 2) intermediates because of
with a methoxy group had been attempted but found to be
unsuccessful. A solution of 3a in THF was heated at 65 °C for
10 h to give a mixture of indoline 4a and two dienylimines 6a
in 63 and 36% yields, respectively (entry 1). Furthermore, 6a
was easily separated into two diastereomers, cis-syn-6a and cis-
anti-6a, in a 5 : 1 ratio. The stereostructure of cis-syn-6a was
,2
6
established unambiguously by single-crystal X-ray analysis
(
Fig. 1) and then the relative configuration of the isomeric cis-
1
13
anti-6a was deduced from comparison of its H and C NMR
spectra with those of cis-syn-6a. Therefore, we have now
succeeded in the isolation and structure determination of the
dienylimine intermediate in the Fischer indolisation of the o-
methoxy enehydrazine. Additionally, the cis-syn-isomer was
obtained as the major product.
their instability. To the best of our knowledge, there has been
only one paper 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-positions remain to be
established.
3
Interestingly, the polarity of the organic solvent used
influences both the product ratio of 4a and 6a and the reaction
time (entries 2–4). In MeCN, the reaction proceeded smoothly
to give a 1+1 mixture of 4a and 6a in 98% yield (entry 3). On
the other hand, in non-polar hexane, 4a was obtained as the
major product in 75% yield, although prolonged reaction time
was required for complete consumption of 3a (entry 4). Heating
the indoline 4a in xylene at 138 °C afforded the corresponding
indole 5a in quantitative yield as a result of the elimination of
During the course of our investigation on reactivity of N-
4
trifluoroacetyl enamine moieties, we investigated the thermal
cyclisation of o-substituted N-trifluoroacetyl enehydrazines
under mild conditions and succeeded in the isolation and
structure determination of the dienylimine intermediates in the
Table 1 Thermal cyclisation of N-trifluoroacetyl enehydrazines 3
Conditions
Yield (%)
Entry
Substrate
R
n
Solvent
T/°C
t/h
Total
4
5
6 (cis-syn+cis-anti)
1
2
3
4
5
6
7
8
9
3a
3a
3a
3a
3b
3b
3c
3c
3d
3d
3e
3f
MeO
MeO
MeO
MeO
MeO
MeO
Me
Me
Me
Me
Cl
1
1
1
1
2
2
1
1
2
2
1
1
THF
65
90
80
80
90
80
90
110
110
110
90
10
7
5
22
10
10
8
99
98
98
99
84
73
74
99
78
87
74
63
69
51
75
—
—
14
30
—
—
70
—
—
—
—
75
54
42
37
71
76
4
36 (5+1)
29 (4+1)
47 (5+1)
24 (4+1)
9 (2+1)
19 (2+1)
18 (14+1)
32 (7+1)
7 (7+1)
11 (6+1)
—
PhMe
MeCN
hexane
PhMe
MeCN
PhMe
MeCN
PhMe
MeCN
PhMe
PhMe
8
10
10
15
29
1
1
1
0
1
2
NO
2
110
31 (85)a 31 (85)a
—
—
a
Yields in parentheses are for the recovered starting material.
Chem. Commun., 1999, 2429–2430
This journal is © The Royal Society of Chemistry 1999
2429

anti-6a,b. Brown 9 has reported that attempts to isolate a
tricyclic dienylimine having a methyl group were unsuccessful.
Therefore, our result is the first example of the isolation and
structure determination of the tricyclic dienylimine with a
methyl group.
When an electron-withdrawing group such as a chlorine or
nitro group was present in the o-position, the indolisation
occurred regioselectively at the unsubstituted position to give
7
-substituted products (entries 11 and 12).
Finally, the isolation and structure determination of the
dienylimines intermediates in the Fischer indolisation of o-
methoxy and o-methyl enehydrazines provides good evidence
for the postulated reaction mechanism, including a ster-
eochemical rationalisation, particularly for the [3,3]-sigma-
tropic rearrangement step.
This work was supported in part by a Grant-in-Aid for
Scientific Research (No. 09672293) from the Ministry of
Education, Science, Sports and Culture, Japan and a research
grant from the Science Research Promotion Fund of the Japan
Private School Promotion Foundation. We thank Dr K. Aoe
Fig. 1 ORTEP drawing of the molecule cis-syn-6a at the 50% probability
level. The structure depicted is one of the independent molecules with the
major component of the disordered CF group.
3
(
Analytical Research Laboratory, Tanabe Seiyaku) for the X-
ray crystallographic structure determination of 6a.
trifluoroacetamide. Under the same conditions, both cis-syn-6a
and cis-anti-6a were converted into indole 7. Reaction of
cyclohexene hydrazines 3b proceeded slowly under similar
mild conditions to give 7-methoxyindole 5b as the major
product with no detection of indoline 4b (entries 5 and 6).
Notes and references
1
Reviews of Fischer indole synthesis: B. Robinson, Chem. Rev., 1963, 63,
73; B. Robinson, Chem. Rev., 1969, 69, 227; B. Robinson, The Fischer
3
Indole Synthesis, Wiley, New York, 1982; D. L. Hughes, Org. Prep.
Proced. Int., 1993, 25, 609.
2
K. Bast, T. Durst, R. Huisgen, K. Lindner and R. Temme, Tetrahedron,
1
998, 54, 3745.
3
4
G. S. Bajwa and R. K. Brown, Can. J. Chem., 1969, 47, 785.
Recently we found a novel synthetic route for indoles (or indolines) via
thermal cyclisation of N-trifluoroacetyl enehydrazines. O. Miyata. Y.
Kimura, K. Muroya, H. Hiramatsu and T. Naito, Tetrahedron Lett., 1999,
40, 3601.
It is well-known that Fischer indolisation of (2-methoxy-
phenyl)hydrazone gives 7-methoxyindole as a minor product
and the abnormal 6-substituted indole as a major product,
respectively. 1 On the other hand, our results indicate that the
indolisation reaction of 3 proceeds preferentially at the
unsubstituted position to give 7-methoxyindole as the major
product. Consequently, the thermal cyclisation of 3 has
provided a practical synthetic method for the 7-oxygenated
indoles, which are known to be potential intermediates for the
synthesis of biologically active compounds.
5
6
C. S. Barnes, K. H. Pausacker and C. I. Schubert, J. Chem. Soc., 1949,
1
381.
The crystal contains two independent molecules in the asymmetric unit.
Both molecules have disordered CF groups with occupancy factor of
.67/0.33 and 0.81/0.19, respectively and one of the molecules has
additional disorder at the fused cyclopentane (C17-C18) with occupancy
,7,8
3
0
15 3 2 2
factors of 0.56 and 0.44. Crystal data for cis-syn-6a: C14H F N O , mp
140–141 °C, triclinic, P ¯1 , a = 11.277(2), b = 12.015(2), c = 11.056(2)
3
Å, a = 97.87 (1), b = 94.66(2), g = 71.73(1)°, V = 1408.1(4) Å , Z =
2
1
23
c
4, m = 1.056 mm , D = 1.416 mg m , F000 = 624, T = 293 K. Final
R value was 0.0684 for 4788 reflections. CCDC 182/1467. See http:/
www.rsc.org/suppdata/cc/1999/2429/ for crystallographic data in .cif
Next, we turned our attention to the corresponding o-methyl
N-trifluoroacetyl enehydrazines 3c,d. Reaction of 3d proceeded
smoothly at a high temperature (110 °C) to give 5d with
moderate regioselectivity, while 3c afforded a mixture of 4c, 5c,
cis-syn-6c and cis-anti-6c (entries 7, 8, 9 and 10). The cis-syn
and cis anti-dienylimines 6c,d were obtained as minor products.
Their stereostructures were deduced from comparisons of their
/
format.
7
8
H. Ishii, Acc. Chem. Res., 1981, 14, 275.
Y. Murakami, H. Yokoo, Y. Yokoyama and T. Watanabe, Chem. Pharm.
Bull., 1999, 47, 791.
9
G. S. Bajwa and R. K. Brown, Can. J. Chem., 1970, 48, 2293.
1
13
H and C NMR spectra with those of cis-syn-6a,b and cis-
Communication 9/07539I
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Chem. Commun., 1999, 2429–2430