One-pot synthesis of N-substituted 2-methyl-4,5,6,7-tetrahydroindole derivatives

Article abstract of DOI:10.1016/j.tetlet.2004.10.145

We describe the preliminary results of one-pot syntheses of various N-substituted 2-methyl-4,5,6,7-tetrahydroindole derivatives from 2-(2-bromoallyl)cyclohexanone and the corresponding primary amines in good yields. Aliphatic amines were directly converted to tetrahydroindoles, whereas aromatic amines needed an extra base treatment step to complete the transformation.

Full text of DOI:10.1016/j.tetlet.2004.10.145

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 9627–9629
One-pot synthesis of N-substituted
2-methyl-4,5,6,7-tetrahydroindole derivatives
_
Cihangir Tanyeli,* Idris M. Akhmedov* and Emre Y. Yazıcıog˘lu
Department of Chemistry, Middle East Technical University, 06531 Ankara, Turkey
Received 23 August 2004; revised 19 October 2004; accepted 26 October 2004
Available online 11 November 2004
Abstract—We describe the preliminary results of one-pot syntheses of various N-substituted 2-methyl-4,5,6,7-tetrahydroindole
derivatives from 2-(2-bromoallyl)cyclohexanone and the corresponding primary amines in good yields. Aliphatic amines were
directly converted to tetrahydroindoles, whereas aromatic amines needed an extra base treatment step to complete the
transformation.
Ó 2004 Elsevier Ltd. All rights reserved.
1. Introduction
ene (1equiv) was reacted with 2,3-dibromopropene
(1.2equiv) in dry dioxane, with the addition of 1equiv
of triethylamine and the mixture was refluxed for 6h.
The resultant mixture was subsequently refluxed with
1N HCl for an additional 3h to afford 1 with an
improved yield of 65%. Mixing 1 with 1.5equiv of vari-
ous primary amines and a drying agent (MgSO4) in dry
toluene under argon at room temperature did not afford
any condensation product. Next, the starting compound
1 was mixed with 1.5equiv of ( )-methylbenzylamine in
dry toluene, with the addition of p-toluenesulfonic acid
(PTSA) (10mg, 0.06mmol) under an argon atmosphere
and the mixture was refluxed for 14h using a Dean–
Stark trap. After evaporation of the solvent in vacuo
and purification of the crude product by flash column
chromatography, a yellow oil (42%) was obtained,
which proved to be N-(1-phenylethyl)-2-methyl-4,5,6,7-
tetrahydroindole 2b10 instead of the anticipated enamine
product (Scheme 1). Using this procedure we were also
able to obtain the N-substituted 2-methyl-4,5,6,7-tetra-
hydroindole derivatives 2a, 2c and 2d (Ômethod AÕ).
The results are given in Table 1. In entries 5–7 with aro-
matic amines, Ômethod AÕ failed to give the desired
2-methyl-4,5,6,7-tetrahydroindoles affording only the
corresponding enamines. Using more than 0.1equiv of
PTSA resulted in formation of p-toluene sulfonate salts
of the amine.
The biological activity of some pyrrole derivatives has
prompted the development of new synthetic pathways
for 4,5,6,7-tetrahydroindoles with various substitution
patterns.1a–m Different tetrahydroindoles are found in
the structures of many biologically active compounds,
such as antibiotics,2 antipsychotic agents3 and blood-
platelet aggregation inhibitors.4a,b They can also be used
as ligands for transition metals.5 Various multistep syn-
thetic procedures have been described in the literature,
including reduction of indoles6a–c or annulation reac-
tions.1e Although there are several methods for the syn-
thesis of 4-oxo-4,5,6,7-tetrahydroindoles from 1,3-
dicarbonyl compounds,7a,b the synthesis of tetrahydro-
indoles without a carbonyl group in the cyclohexane
ring requires multistep procedures.8 The factors outlined
above directed our efforts towards the development of a
one-pot procedure for the synthesis of various N-substi-
tuted 2-methyl-4,5,6,7-tetrahydroindoles. Here we
report the results obtained from our work.
2. Results and discussion
2-(2-Bromoallyl)cyclohexanone 1 was chosen as starting
compound and was prepared according to slightly modi-
fied literature procedures.7b,9 1-Pyrrolidino-1-cyclohex-
In order to complete the transformation of the enamines
to the corresponding tetrahydroindole derivatives, we
applied Ômethod BÕ.11 In this method, the enamines were
subsequently treated with potassium tert-butoxide in
Keywords: 4,5,6,7-Tetrahydroindoles; Enamines.
*
Corresponding authors. Tel.: +90 312 210 3222; fax: +90 312 210
1280; e-mail addresses: tanyeli@metu.edu.tr; mecid@metu.edu.tr
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.10.145

9628
C. Tanyeli et al. / Tetrahedron Letters 45 (2004) 9627–9629
, toluene, PTSA
R'
NH2
Ar, 7-14 h, 110 o
C
Br
Br
N
O
NH
R'
1
R'
RNH2, PTSA, toluene
Ar, 110 oC, 3-4 h
2a-d
DMSO, t-BuOK, 80 oC, 3h
Br
NH
R
N
R
3a-c
R= aromatic group
Scheme 1.
Table 1. Synthesis of N-substituted 4,5,6,7-tetrahydroindoles
Entry
1
Amine
Method
A
Product
2 or 3
Time (h)
Yield (%)
2a8
1250
NH2
N
N
N
2
3
A
A
2b
2c
14
42
NH2
H2N
7
2
2
EtO
OEt
EtO
N
OEt
4
5
A
B
2d13
13
31
98
NH2
N
N
3a
7
NH2
6
7
B
B
3b
3c
6
6
74
72
NH2
NH2
N
N
N
dimethyl sulfoxide to afford N-substituted 2-methyl-
4,5,6,7-tetrahydroindole derivatives 3a,12 3b and 3c.
tetrahydroindole formation from aliphatic amines, we
tried to develop a transamination procedure. The reac-
tion between freshly distilled 1-pyrrolidinyl-1-cyclohex-
ene with 1equiv of 2,3-dibromopropene in dioxane
yielded a white waxy solid, which could not be charac-
terized due to its sensitivity to air. Subsequently, this
solid was reacted with 1.5equiv of benzylamine, chosen
as an example of a primary aliphatic amine, applying
Ômethod AÕ, hoping that the pyrrolidine would behave
as a better leaving group than protonated oxygen. A
12% increase in yield was observed when compared with
the reaction between 1 and benzylamine (Scheme 3).
The following mechanistic scheme is consistent with
these results (Scheme 2). The reaction presumably pro-
ceeds through the formation of allenes 5 under basic
conditions from the enamines 4. The resultant interme-
diate 5 affords 2-methyl-4,5,6,7-tetrahydroindoles via a
cyclization–aromatization reaction.
Yields using aromatic amines were much higher than
with aliphatic amines. In order to increase the yield of

C. Tanyeli et al. / Tetrahedron Letters 45 (2004) 9627–9629
9629
.
RNH2
Br
Br
N
-HBr
NH
R
5
NH
R
O
R
2 or 3
1
4
Scheme 2.
2. Remers, W. A.; Weiss, M. J. J. Org. Chem. 1965, 30,
5232.
3. Masaguer, C. F.; Ravina, E. Tetrahedron Lett. 1996, 37,
5171.
1
Br
dioxane, reflux
Br
N
(62% yield)
2a
toluene, reflux
2
NH2
4. (a) Sun, L.; Tran, N.; Liang, C.; Hubbard, S.; Tang, F.;
Lipson, K.; Schreck, R.; Zhou, Y.; McMahon, G.; Tang,
C. J. Med. Chem. 2000, 43, 2655; (b) Oba, T.; Tanaka, T.;
Okamura, N.; Watanabe, K.; Bannai, K.; Ohtsu, A.;
Naruchi, T.; Kurozumi, S.; Toru, T. Eur. Pat. Appl., 1981,
145 pp; Chem. Abstr. 1981, 95:24812.
5. McComas, C. C.; Van Vranken, D. L. Tetrahedron Lett.
1999, 40, 8039.
6. (a) OÕBrien, S.; Smith, D. C. C. J. Chem. Soc. 1960, 4609;
(b) Young, D. V.; Snyder, H. R. J. Am. Chem. Soc. 1961,
83, 3160; (c) Greenhouse, R.; Ramirez, C.; Muchowski, J.
M. J. Org. Chem. 1985, 50, 2962.
Scheme 3.
In conclusion, we have demonstrated the versatility of 2-
(2-bromoallyl)cyclohexanone 1 as a starting material for
the one-pot synthesis of N-substituted 2-methyl-4,5,6,7-
tetrahydroindoles. We have improved the yields from
primary aliphatic amines by utilising a transamination
procedure. In the future, we plan to use various chiral
amines to afford the corresponding chiral N-substituted
2-methyl-4,5,6,7-tetrahydroindoles.
7. (a) De Kimpe, N.; Keppens, M. Tetrahedron 1996, 52,
3705; (b) Mori, M.; Washioka, Y.; Urayama, T.; Yoshi-
ura, K.; Chiba, K.; Bon, Y. J. Org. Chem. 1983, 48, 4058.
8. Arcadi, A.; Rossi, E. Tetrahedron 1998, 54, 15253.
9. Nagano, H.; Ohtani, Y.; Odake, E.; Nakagawa, J.; Mori,
Y.; Yajima, T. J. Chem. Res. (S) 1999, 5, 338.
Acknowledgements
1
10. Spectroscopic data for 2b H NMR (400MHz, CDCl3) d
We thank the Middle East Technical University for grants
no. BAP-2003-07-02-00-93, the Turkish Scientific and
Technical Research Council for a grant [no. TBAG-
2244(102T169)], and the Turkish State Planning Organiza-
tion for a grant (no. BAP-07-02-DPT-2002 K120540-04).
(ppm): 1.57–1.63 (m, 4H), 1.76 (d, J = 7.2Hz, 3H), 2.02(s,
3H), 2.41 (br s, 4H), 5.35 (q, J = 7.1Hz, 1H), 5.62(s, 1H),
6.96 (d, J = 8.4Hz, 2H), 7.14–7.25 (m, 3H); 13C NMR
(100.6MHz, CDCl3) d (ppm): 143.1, 128.8, 127.7, 127.6,
127.2, 126.5, 116.8, 106.3, 52.8, 24.2, 24.1, 23.6, 20.0, 13.8,
1.4; MS(CI+): 240 ([M+H]+, 100%), 238 (52%), 226 (11%);
HRMS calcd for C17H22N (M+H)+, 240.1752. Found
240.1746.
References and notes
11. General procedure for ÔMethod B: Starting compound 1
(0.31g, 1.43mmol) was mixed with 1.1equiv of aniline
(0.15g, 1.57mmol) in dry toluene (30mL), with p-tolu-
enesulfonic acid (10mg, 0.06mmol) under argon and the
mixture was refluxed for 3h using a Dean–Stark trap.
After evaporation of the solvent in vacuo, dry dimethyl
sulfoxide (3mL) was added together with 1.1equiv of
potassium tert-butoxide (0.28g, 2.46mmol) and the reac-
tion mixture was kept at 80°C for 4h. The reaction
mixture was allowed to reach room temperature and
purification by flash column chromatography afforded
compound 3a as a yellow oil (0.27g, 98%).
1. (a) Stetter, H.; Siehnhold, E. Chem. Ber. 1955, 88, 271; (b)
Patterson, J. M.; Soedigdo, S. J. Org. Chem. 1967, 32,
2969; (c) Hershenson, F. M. J. Org. Chem. 1975, 40, 1260;
(d) Dhanak, D.; Reese, C. B.; Romana, S.; Zappia, G. J.
Chem. Soc., Chem. Commun. 1986, 12, 903; (e) Chelucci,
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Tetrahedron Lett. 1995, 36, 8007; (g) Lim, S.; Jabin, I.;
Revial, G. Tetrahedron Lett. 1999, 40, 4177; (h) Ferraz, H.
M. C.; Pereira, F. L. C.; Leita, F. M.; Nunes, M. R. S.;
Payret-Arrua, M. E. Tetrahedron 1999, 55, 10915; (i)
Ferraz, H. M. C.; Oliviera, E. O.; Payret-Arrua, M. E.;
Brandt, C. A. J. Org. Chem. 1995, 60, 7357; (j) Mori, M.;
Akashi, M.; Nishida, M. Chem. Lett. 1999, 465; (k)
Fukumoto, S.; Imamiya, E.; Kusumoto, K.; Watanabe,
T.; Shiraishi, M. J. Med. Chem. 2002, 45, 3009; (l) Demir,
1
12. Spectroscopic data for 3a H NMR (400MHz, CDCl3) d
(ppm): 1.91 (t, J = 2.9Hz, 4H), 2.24 (s, 3H), 2.49 (br s,
2H), 2.62 (br s, 2H), 5.99 (s, 1H), 7.37 (d, J = 7.3Hz, 2H),
7.49 (t, J = 7.4Hz, 1H), 7.57 (t, J = 7.3Hz, 2H); 13C NMR
(100.6MHz, CDCl3) d (ppm): 139.3, 129.4, 128.5, 128.3,
127.7, 117.3, 106.3, 24.4, 24.1, 23.6, 23.5, 13.2.
_
A. S.; Akhmedov, I. M.; Sesenoglu, O. Tetrahedron 2002,
58, 9793; (m) Mori, M.; Uozumi, Y.; Shibasaki, M.
Heterocycles 1992, 33, 819.
13. For spectroscopic data of 2d see: Ahlbrecht, H.; Von
Daacke, A. Synthesis 1984, 7, 610.