A novel one-step efficient method for the synthesis of tetrahydroindoles from 1-(1-pyrrolidino)cyclohexene and chloropyruvates

Article abstract of DOI:10.1016/j.tetlet.2008.05.044

A highly efficient, one-step, versatile method for the synthesis of tetrahydroindoles has been developed on the basis of new ring formation in the reactions of 1-(1-pyrrolidino)cyclohexene with chloropyruvates.

Full text of DOI:10.1016/j.tetlet.2008.05.044

Tetrahedron Letters 49 (2008) 4658–4660
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A novel one-step efficient method for the synthesis of tetrahydroindoles
from 1-(1-pyrrolidino)cyclohexene and chloropyruvates
0
*
Vakhid A. Mamedov , Tat yana N. Beschastnova, Nataliya A. Zhukova, Aidar T. Gubaidullin,
Rustem A. Isanov, Il0dar Kh. Rizvanov
A. E. Arbuzov Institute of Organic and Physical Chemistry, Kazan Research Center of the Russian Academy of Sciences, Arbuzov Str. 8, 420088 Kazan, Russian Federation
a r t i c l e i n f o
a b s t r a c t
Article history:
A highly efficient, one-step, versatile method for the synthesis of tetrahydroindoles has been developed
on the basis of new ring formation in the reactions of 1-(1-pyrrolidino)cyclohexene with chloropyruvates.
Ó 2008 Published by Elsevier Ltd.
Received 22 March 2008
Revised 30 April 2008
Accepted 8 May 2008
Available online 13 May 2008
Keywords:
1-(1-Pyrrolidino)cyclohexene
Chloropyruvates
Chloroglycidates
Ring recyclization
Ring formation
Tetrahydroindoles
Indoles are one of the most widespread heterocyclic com-
pounds in Nature. The total number of known indole alkaloids is
ca. 1500.1 The potent physiological properties of many of them
have led to their use in medicine, but in most instances, they have
at present to be supplanted by synthetic substances.2 Natural
indole alkaloids applicable in medicine are varied, and it is not
always possible to obtain their synthetic analogues using known
methods for indole synthesis. This appears to be the reason why
the numerous known reactions, beginning with the classical
Fischer reaction,3 refer to the synthesis of indole derivatives, most
of these reactions having been discovered only recently. Some of
these methods4–8 are suitable for the synthesis of indole deriva-
tives with substituents on the carbon atoms of the five-membered
ring, whilst others9,10 are convenient for indoles with substituents
on the carbon atoms of the six-membered ring. Other methods 11,12
are used successfully for the synthesis of indole derivatives with
substituents on the carbon atoms of both rings of the indole. How-
ever, a method for producing indole derivatives with substituents
on both the carbon and the nitrogen atoms of the five-membered
ring is not available in the literature.
obtained according to this approach can be transformed easily into
various tetrahydroindole derivatives (Scheme 1).
Despite the well-known chemistry of enamines14 in general,
and of 1-(1-pyrrolidino)cyclohexene15 1 in particular, the reaction
of the latter with chloropyruvates appears not to proceed via initial
nucleophilic substitution of the halogen atom in these highly elec-
trophilic compounds, but via nucleophilic addition to the carbonyl
group. This is followed by cascade conversions involving (a) an
intramolecular nucleophilic substitution of the SN2 type with the
formation of an epoxide ring and elimination of Clꢀ, (b) opening
of the pyrrolidine ring on exposure to Clꢀ, see Scheme 2, A, (c)
imino-enamine tautomerism B¢C, (d) opening of the epoxide ring
O
N
OR
Ar
Cl
O
+
Ar
OR
H2O
Cl
N
O
1
2
3
In this Letter, a direct, efficient and operationally convenient
approach to the synthesis of 1,2 and 3-substituted tetrahydroin-
doles based on the cascade reactions of 1-(1-pyrrolidino)cyclohex-
ene 1 and chloropyruvates13 is presented. The tetrahydroindoles
2,3 Ar
R
% yield of 3 2,3
Ar
R
% yield of 3
a
b
c
Ph Me
Ph Et
Ph Pr-i
Ph Pr-n
85
77
72
80
e
f
g
4-O2NC6H4 Me
3-O2NC6H4 Me
90
80
70
74
4-ClC6H4
4-BrC6H4
Me
Me
d
h
* Corresponding author. Tel.: +7 843 2727304; fax: +7 843 2732253.
E-mail address: mamedov@iopc.kcn.ru (V. A. Mamedov).
Scheme 1.
0040-4039/$ - see front matter Ó 2008 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2008.05.044

V. A. Mamedov et al. / Tetrahedron Letters 49 (2008) 4658–4660
4659
Cl
Cl
_
Cl
Ar
O
..
Ar
O
Ar
O
+
O
N
N
NH
OR
4
4
OR
OR
OR
2
OH
Ar
3
1
O
H
O
O
H2O
N
Cl
B
D
A
C
4
Scheme 2.
the same tetrahydroindole 3f,20 which indicated that the rear-
rangement of chloroglycidate 2f0 to chloropyruvate 2f proceeds
faster than the electrophilic attack of enamine 1 on the C(3) carbon
atom of chloroglycidate 2f0 (Schemes 2 and 3). The expected tetra-
hydroindole derivative 3f0 isomeric to 3f is not formed.
The presented tetrahydroindole synthesis complements other
recognized methods and offers significant advantages for the syn-
thesis of indoles with various types of acid sensitive (easily trans-
formable) functional groups. Application of this methodology to
the synthesis of tetrahydroindoles using other cyclic enamines
and chloroketones is currently under study and the results will
be published in due course.
Acknowledgement
We thank the Russian Foundation for Basic Research (Grant No.
07-03-00613-a) for financial support.
References and notes
1. Hesse, M. Alkaloids, Nature’s Curse or Blessing?; VHCA, Verlag (Helvetica
Chimica Acta, Zurich, Switzerland), WILEY-VCH: Weinheim, Germany, 2002,
413.
Figure 1. ORTEP drawing of compound 3e.
2. Negwer, N.; Scharnow, H.-G., 8th, extensively enlarged ed.. In Organic-Chemical
Drugs and Their Synonyms; WILEY-VCH: Weinheim, New York, Chichester,
Brisbane, Singapore, Toronto, 2001; Vols. 1–6.
with concomitant formation of the new pyrrolidine ring, D, and (e)
elimination of water leading to formation of tetrahydroindole
derivatives 3 (Scheme 2).
3. Fischer, E.; Jourdan, F. Ber. Dtsch. Chem. Ges. 1883, 16, 2241.
4. (a) Gassman, P. G.; van Bergen, T. J.; Gilbert, D. P.; Cue, B. W. J. Am. Chem. Soc.
1974, 96, 5495; (b) Ishikawa, H.; Uno, T.; Miyamoto, H.; Ueda, H.; Tamaoka, H.;
Tominaga, M.; Nakagawa, K. Chem. Pharm. Bull. 1990, 38, 2459.
5. (a) Larock, R. C.; Yum, E. K. J. Am. Chem. Soc. 1991, 113, 6689; (b) Larock, R. C.;
Yum, E. K.; Refvik, M. D. J. Org. Chem. 1998, 63, 7652; (c) Larock, R. C. J.
Organomet. Chem. 1999, 576, 111; (d) Walsh, T. F.; Toupence, R. B.; Ujjainwalla,
F.; Young, J. R.; Goulet, M. T. Tetrahedron 2001, 57, 5233.
The structures of compounds 3a–h were deduced from their
elemental analyses and 1H and 13C NMR data.16 The mass spectra
of these compounds displayed molecular ion peaks at appropriate
m/z values. Initial fragmentation patterns involved cleavage of the
tetrahydroindole ring system.17 The molecular structure of com-
pound 3e was confirmed by single-crystal X-ray analysis (Fig. 1).18
In addition, it should be pointed out that the reactions of the
chloroglycidates (isomeric with chloropyruvates) with enamine 1
proceed in the same way with the formation of tetrahydroindoles
3. In these cases, the rearrangement of chloroglycidates to isomeric
chloropyruvates in boiling dioxane occurs initially19 (Scheme 3).
For example, the reaction of chloroglycidate 2f0 and its isomeric
chloropyruvate 2f with enamine 1 proceeds with formation of
6. (a) Smith, A. B., III; Haseltine, J. N.; Visnick, M. Tetrahedron 1989, 45, 2431; (b)
Wacker, D. A.; Kasireddy, P. Tetrahedron Lett. 2002, 43, 5189.
7. (a) Mori, M.; Chiba, K.; Ban, Y. Tetrahedron Lett. 1977, 12, 1037; (b) Ban, Y.;
Wakamatsu, T.; Mori, M. Heterocycles 1977, 6, 1711; (c) Amatore, C.; Azzabi, M.;
Jutand, A. J. Am. Chem. Soc. 1991, 113, 8375; (d) Li, J. J. Org. Chem. 1999, 64,
8425; (e) Gelpke, A. E. S.; Veerman, J. J. N.; Goedheijt, M. S.; Kamer, P. C. J.; Van
Leuwen, P. W. N. M.; Hiemstra, H. Tetrahedron 1999, 55, 6657; (f) Sparks, S. M.;
Shea, K. J. Tetrahedron Lett. 2000, 41, 6721; (g) Bosch, J.; Roca, T.; Armengol, M.;
Fernandez-Forner, D. Tetrahedron 2001, 57, 1041.
8. (a) Coic, J. P.; Saint-Ruf, G. J. Heterocycl. Chem. 1978, 75, 1367; (b) Henry, J. R.;
Dodd, J. H. Tetrahedron Lett. 1998, 39, 8763.
9. (a) Bartoli, G.; Leardini, R.; Medici, A.; Rosini, G. J. Chem. Soc., Perkin Trans. 1
1978, 892; (b) Bartoli, G.; Bosco, M.; Dalpozzo, R.; Todesco, P. E. J. Chem. Soc.,
Chem. Commun. 1988, 807; (c) Bartoli, G.; Palmieri, G.; Bosco, M.; Dalpozzo, R.
Tetrahedron Lett. 1989, 30, 2129; (d) Dobbs, A. P. J. Org. Chem. 2001, 66, 638; (e)
Pirrung, M. C.; Wedel, M.; Zhao, Y. Synlett 2002, 143; (f) Garg, N. K.; Sarporg, R.;
Stoltz, B. J. Am. Chem. Soc. 2002, 124, 13179.
10. (a) Bhattacharya, G.; Su, T.-L.; Chia, C.-M.; Chen, K.-T. J. Org. Chem. 2001, 66,
426; (b) Kozmin, S. A.; Iwama, T.; Huang, Y.; Rawal, V. H. J. Am. Chem. Soc. 2002,
124, 4628; (c) Pete, B.; Parlagh, G. Tetrahedron Lett. 2003, 44, 2537.
11. (a) Mukhanova, T. I.; Panisheva, E. K.; Lyubchanskaya, V. M.; Alekseeva, L. M.;
Sheinker, Y. N.; Granik, V. G. Tetrahedron 1997, 53, 177; (b) Ketcha, D. M.;
Wilson, L. J.; Portlock, D. E. Tetrahedron Lett. 2000, 41, 6253; (c) Brase, S.; Gil, C.;
Knepper, K. Bioorg. Med. Chem. Lett. 2002, 10, 2415.
12. (a) Hegedus, L. S.; Alien, G. F.; Waterman, E. L. J. Am. Chem. Soc. 1976, 98, 2674;
(b) Hegedus, L. S.; Alien, G. F.; Bozell, J. J.; Waterman, E. L. J. Am. Chem. Soc.
1978, 100, 5800; (c) Hegedus, L. S.; Winton, P. M.; Varaprath, S. J. Org. Chem.
1981, 46, 2215; (d) Hegedus, L. S. Angew. Chem., Int. Ed. Engl. 1988, 27, 1113; (e)
Kondo, T.; Okada, T.; Mitsudo, T. J. Am. Chem. Soc. 2002, 124, 186.
13. Mamedov, V. A.; Berdnikov, E. A.; Tsuboi, S.; Hamamoto, H.; Komiyama, T.;
Gorbunova, E. A.; Gubaidullin, A. T.; Litvinov, I. A. Russ. Chem. Bull. 2006, 55,
1455.
Ar
O
1
Cl
O
OMe
dioxane,
~ 100 oC
N
OMe
O2N
Cl
O
O
2f'
3f'
4
Not formed
dioxane,
~ 100 oC
1
O
3f
OMe
dioxane,
~ 100 oC
O2N
Cl
2f
Scheme 3.

4660
V. A. Mamedov et al. / Tetrahedron Letters 49 (2008) 4658–4660
14. Enamines: Synthesis, Structure, and Reactions; Cook, A. G., Ed.; Dekker: New
York, 1969; p 515.
331(13); 327(10); 313(11); 267(14); 194(10); 91(13); 81(11); 69(16); 55(30);
41(6)).
15. (a) Stork, G.; Terrel, R.; Szmuszkovicz, J. J. Am. Chem. Soc. 1954, 76, 2029; (b)
Stork, G.; Brizzolara, A.; Landesman, H.; Szmuszkovicz, J.; Terrel, R. J. Am. Chem.
Soc. 1963, 85, 207; (c) Szablewski, M. J. Org. Chem. 1994, 59, 954; (d) Li, J. J.;
Trivedi, B. K.; Rubin, J. R.; Roth, B. D. Tetrahedron Lett. 1998, 39, 6111; (e) Yehia,
N. A. M.; Polborn, K.; Muller, T. J. J. Tetrahedron Lett. 2002, 43, 6907.
18. The X-ray diffraction data for the crystal structure of 3e were collected on a
Bruker AXS Kappa Apex diffractometer at 293 K. Crystallographic data for 3e.
C
20H23ClN2O4, pink prismatic crystal, formula weight 390.85, monoclinic, P21/
c, a = 9.3894(7), b = 21.7976(15), c = 10.5986(7) Å, b = 114.755(1)°, V =
1969.8(2) Å3, Z = 4, qcalc = 1.318 g cmꢀ3, l (kMoKa 0.71073 Å) = 0.222 mmꢀ1
.
16. Typical procedure for the preparation of 3.
A
solution of 1-(1-
F(000) = 824, reflections collected = 16434, unique = 4687, Rint = 0.0268, full-
matrix least-squares on F2, parameters = 281, restraints = 14. Final indices
R1 = 0.0567, wR2 = 0.1573 for 3275 reflections with I > 2r(I); R1 = 0.0788,
wR2 = 0.1760 for all data, goodness-of-fit on F2 = 1.040, the largest difference
in peak and hole (0.257 and ꢀ0.300 e Åꢀ3). Crystallographic data (except
structure factors) for structure 3e in this Letter have been deposited with the
Cambridge Crystallographic Data Centre as supplementary publication number
CCDC 681280. Copies of these data can be obtained free of charge on
application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK, (fax: +44-
(0)1223-336033 or e-mail: deposit@ccdc.cam.ac.uk).
pyrrolidino)cyclohexene (1.5 g, 10 mmol) and chloropyruvate 2e (2.6 g,
1
10 mmol) in dioxane (25 mL) was refluxed for 6 h during which time the colour
of the reaction mixture changed from dark green to dark red. The reaction
mixture was cooled to ca. 20 °C and a solution of NaOAc (0.27 g, 3.3 mmol) in
AcOH (6 mL) was added and the reaction mixture was refluxed for another 2 h
and then cooled to ca. 20 °C for 3 h. The reaction solution was evaporated to
one-half of the initial volume in vacuo and then washed with 25% aqueous
NaCl (4 ꢁ 25 mL). The organic extract was dried over MgSO4 and the solvent
was removed in vacuo.
A crude brown oil was obtained, which after
crystallization from i-PrOH gave 3.5 g (90%) of an analytically pure sample of
19. Thermal isomerization of methyl 2-chloro-3-(4-nitrophenyl)-2,3-epoxy-
propionate[13] 2f into methyl 3-chloro-3-(4-nitrophenyl)-2-oxopropionate
2f0. A solution of 2f (10 mmol) in dioxane (15 mL) was refluxed for 3 h. The
solvent was removed in vacuo. The chloropyruvate was obtained as a brown
oil, which had satisfactory analytical characteristics, including 1H NMR
(600 MHz, DMSO-d6) spectroscopic data, d 3.96 (3H, s, OCH3); 6.22 (1H, s,
CH); 7.73 (1H, dd, aromatic, J = 8.5, 8.5 Hz); 7.81 (1H, d, aromatic, J = 8.5 Hz);
8.25 (1H, d, aromatic, J = 8.5 Hz); 8.72 (1H, s, aromatic).
1-chlorobutyl-2-(4-nitrophenyl)-3-methoxycarbonyl-4,5,6,7- tetrahydroindole
3e: mp 117–119 °C. 1H NMR (600 MHz, DMSO-d6),
d 1.56–1.66 (4H, m,
CH2CH2); 1.81–1.88 (2H, m, CH2); 1.90–1.94 (2H, m, CH2); 2.60 (2H, t, CH2,
J = 6.1 Hz); 2.79 (2H, t, CH2, J = 6.1 Hz); 3.38 (2H, t, CH2, J = 6.1 Hz); 3.62 (3H, s,
OCH3); 3.68 (2H, t, CH2, J = 7.3 Hz); 7.51 (2H, d, aromatics, J = 7.0 Hz); 8.29 (2H,
d, aromatics, J = 7.0 Hz). The tetrahydroindoles 3a–d,f–h were obtained in the
same way using the corresponding a-chloropyruvates.
17. Analytical and other spectroscopic data of tetrahydroindole 3e (13C NMR, IR,
MS) were in good agreement with the proposed structures. MS (EI), m/z (I (%):
M+Å37Cl 392 (19); 391 (13); M+Å35Cl 390 (53); 375(10); 356(32); 355(100);
20. Analytical and other spectroscopic data (1H NMR, IR, MS) of tetrahydroindole
3f obtained from chloropyruvate 2f and chloroglycidate 2f0 were identical as
were the mp’s 93.5–95 °C.