Efficient synthesis of 2,6-dioxo-1,2,3,4,5,6-hexahydroindoles based on the synthesis and reactions of (2,4-dioxocyclohex-1-yl)acetic acid derivatives

Article abstract of DOI:10.1016/j.tetlet.2008.02.027

Acetal-protected (2,4-dioxocyclohex-1-yl)acetic acid derivatives were prepared by the allylation of dilithiated 1,3-cyclohexane-1,3-diones, by the protection of the carbonyl groups and by the oxidation of the alkene. The products were then transformed, by

Full text of DOI:10.1016/j.tetlet.2008.02.027

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Tetrahedron Letters 49 (2008) 2272–2274
Efficient synthesis of 2,6-dioxo-1,2,3,4,5,6-hexahydroindoles based
on the synthesis and reactions of (2,4-dioxocyclohex-1-yl)acetic
acid derivatives
Benard Juma a, Muhammad Adeel a,b, Alexander Villinger a, Peter Langer a,b,
*
a Institut fu¨r Chemie, Universita¨t Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany
b Leibniz-Institut fu¨r Katalyse e. V. an der Universita¨t Rostock, Albert-Einstein-Str. 29a, 18059 Rostock, Germany
Received 4 December 2007; revised 2 February 2008; accepted 5 February 2008
Available online 9 February 2008
Abstract
Acetal-protected (2,4-dioxocyclohex-1-yl)acetic acid derivatives were prepared by the allylation of dilithiated 1,3-cyclohexane-1,3-
diones, by the protection of the carbonyl groups and by the oxidation of the alkene. The products were then transformed, by amide
formation and subsequent cyclization, into 2,6-dioxo-1,2,3,4,5,6-hexahydroindoles, which represent important intermediates for the
synthesis of various alkaloids.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Cyclizations; Dianions; N-Heterocycles; Indoles; Oxindoles
2,6-Dioxo-1,2,3,4,5,6-hexahydroindoles represent impor-
tant key intermediates for the synthesis of various alkaloids
including the Erythrina and the Amaryllidaceae family.1,2
Haruna and co-workers reported the synthesis of 1-[2-(3-
hydroxy-4-methoxyphenyl)ethyl]-3a,4-dihydro-1H-indole-
2(3H),6(5H)-dione (based on the Birch reduction) and its
transformation into 3-oxoerythrinan.3 Mariano reported
a different strategy based on the aza-Claisen rearrangement
of an isoquinuclidine derivative.4 Recently, Padwa and
co-workers reported the synthesis5 of 2,6-dioxo-1,2,3,4,5,
6-hexahydroindoles (based on Diels–Alder reactions of
2-imidofurans) and their transformation6 into spirocyclic
alkaloids (e.g., dimethoxyerythratidinone, erysotramidine
and epi-zephyranthine). Despite their synthetic utility, the
scope of these methods is limited to specific examples.
Herein, we report what is, to the best of our knowledge,
a new strategy for the preparation of 2,6-dioxo-1,2,3,4,
5,6-hexahydroindoles. Our approach is based on the syn-
thesis of hitherto unknown (2,4-dioxocyclohex-1-yl)acetic
acid derivatives, which represent potentially useful building
blocks. The straightforward strategy reported herein allows
the synthesis of a variety of 2,6-dioxo-1,2,3,4,5,6-hexahydro-
indoles in good yields.
Our initial attempts to prepare (2,4-dioxocyclohex-1-
yl)acetic acid proved to be unsuccessful: the reaction of
the dianion7,8 of cyclohexane-1,3-dione with 1-bromo-2,2-
diethoxyethane and epibromohydrin afforded products 2
and 3, albeit, in low yields (Scheme 1). All attempts to
transform 2 and 3 into (2,4-dioxocyclohex-1-yl)acetic acid
(4) failed. Deslongchamps and Guay recently reported
the synthesis of 4-(3-oxopropyl)cyclopentane-1,3-dione by
ozonolysis of 4-(but-3-en-1-yl)cyclopentane-1,3-dione.9
Inspired by this report, we explored a related strategy for
the synthesis of acid 4.
The reaction of the dianion of 1 with allylbromide gave
the known10 product 5 (Scheme 2). Unexpectedly, the
ozonolysis of 5 afforded triacid 10 rather than the desired
product 11 (Scheme 3). Triacid 10 was also isolated when
the oxidation was carried out under different conditions
(KMnO4 or KMnO4/NaIO4 in acetone, KMnO4/
CuSO4Á5H2O in CH2Cl2/tBuOH/H2O). The problem was
*
Corresponding author. Tel.: +49 381 4986410; fax: +49 381 4986412.
E-mail address: peter.langer@uni-rostock.de (P. Langer).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.02.027

B. Juma et al. / Tetrahedron Letters 49 (2008) 2272–2274
2273
of KMnO4/NaIO4 (in acetone) afforded acid 7. Although
the latter could be transformed into acid 4 in good yield,
it proved to be advantageous to directly use diacetal 7
for further transformations. The DCC-mediated reaction
of 7 with various primary amines gave amides 8a–i in good
yields.11 Reflux of an acetone solution of 8a–i in the pres-
ence of p-toluenesulfonic acid (PTSA) afforded the desired
2,6-dioxo-1,2,3,3a,4,5-tetrahydroindoles 9a–i in good
yields (Scheme 2, Table 1).12
Tetrahydroindole 9j was prepared from 7 and enantio-
merically pure (R)-(+)-1-phenylethylamine in 49% overall
yield (Fig. 1). The diastereomers could be successfully sep-
arated on analytical scale to give the two enantiomerically
pure isomers (GC, 30m HP5 column, 190 °C, isotherm,
retention times: 49.75 and 51.05 min). Derivative 9k was
prepared from di-medone by the application of the strategy
outlined above for the synthesis of 9a–i (Fig. 1).
The structure of all products was established by spectro-
scopic methods. The structure of 9a was independently
confirmed by X-ray crystal structure analysis (Fig. 2).13
In conclusion, we have reported a new synthetic
approach to 2,6-dioxo-1,2,3,4,5,6-hexahydroindoles, which
represent important key intermediates for the synthesis of
various alkaloids. The preparative scope of our strategy
and its application to the synthesis of alkaloids is currently
being studied.
O
OEt
i
O
OEt
OEt
Br
EtO
O
HO
i
2 (8%)
1
CrO3
O
Br
H2SO4
O
O
Pb(OAc)4
OH
O
O
O
O
4
3 (8%)
Scheme 1. Attempted synthesis of 4. Reagents and conditions: (i) (1) 2.5
LDA, HMPTA, THF, À78 °C, 1 h, (2) electrophile, À40?20 °C, 12 h.
O
O
i
HO
HO
5 (72%)
1
ii
O
O
O
O
OH
iii
O
O
O
Table 1
Synthesis of 9a–i
O
O
7 (84%)
6 (100%)
% (8)a
% (9)a
vi
8, 9
R
iv
4 (70%)
a
b
c
d
e
f
Ph(CH2)2
[3,4-(MeO)2C6H3] (CH2)2
Allyl
Ph
Bn
HO(CH2)2
cHex
cPr
64
65
65
70
67
72
65
67
57
85
82
93
78
86
83
80
62
64
O
R
N
O
O
v
NHR
O
O
g
h
i
O
O
8a-i
9a-i
nHept
a
Yields of isolated products.
Scheme 2. Synthesis of 9a–i. Reagents and conditions: (i) (1) 2.5 LDA,
HMPTA, THF, À78 °C, 1 h, (2) allylbromide, À40?20 °C, 12 h; (ii)
HO(CH2)2OH, toluene, p-TsOH; (iii) NaIO4, KMO4, acetone; (iv) (1)
DCC, N-hydroxysuccinimide, CH2Cl2, 1 h, 0 °C, then 12 h, 20 °C, (2)
RNH2, 2 h, 20 °C; (v) PTSA, acetone, 6 h, reflux; (vi) HCl (5%), acetone,
reflux, 3 h.
Me
Me
O
H
O
H
Ph
O
Ph
O
N
N
+
CO2H
CO2H
9j
OMe
HO2C
O
10
oxidation
O
MeO
O
O
O
5
N
O
11
Scheme 3. Oxidation of 5; conditions: see text.
Me
Me
O
9k
finally solved by the protection of the carbonyl groups of 5
to give diacetal 6 (Scheme 2). The oxidation of 6 by means
Fig. 1.

2274
B. Juma et al. / Tetrahedron Letters 49 (2008) 2272–2274
4. Chen, Y.; Huesmann, P. L.; Mariano, P. S. Tetrahedron Lett. 1983,
24, 1021.
5. (a) Padwa, A.; Ginn, J. D. J. Org. Chem. 2005, 70, 5197; (b) Padwa,
A.; Bur, S. K.; Zhang, H. J. Org. Chem. 2005, 70, 6833; (c) Zhang, H.;
Padwa, A. Org. Lett. 2006, 8, 247.
6. (a) Wang, Q.; Padwa, A. Org. Lett. 2006, 8, 601; (b) Padwa, A.;
Wang, Q. J. Org. Chem. 2006, 71, 7391.
7. (a) Berry, N. M.; Darey, M. C. P.; Harwood, L. M. Synthesis 1986,
476. See also: (b) Vassilikogiannakis, G.; Margaros, I.; Tofi, M. Org.
Lett. 2004, 6, 205.
8. For a recent review of dianions, see: Langer, P.; Freiberg, W. Chem.
Rev. 2004, 104, 4125 and references cited therein.
9. Guay, B.; Deslongchamps, P. J. Org. Chem. 2003, 68, 6140.
10. Zhang, W.; Pugh, G. Tetrahedron 2003, 59, 4237.
11. Typical procedure for the synthesis of amides 8a–f: To a CH2Cl2
solution (20 mL) of 7 (200 mg, 0.77 mmol) were added N-hydroxy-
succinimide (88 mg, 0.78 mmol) and dicyclohexylcarbodiimide
(162 mg, 0.78 mmol) at 0 °C and the mixture was stirred for 1 h at
the same temperature. After stirring for 12 h, the mixture was filtered,
1-amino-2-phenylethane (0.01 mL, 0.85 mmol) was added to the
filtrate and the mixture was stirred for 2 h. The mixture was filtered
and washed for several times with water (50 mL for each washing).
The organic layer was dried (NaSO4), filtered and the filtrate was
concentrated in vacuo. The residue was purified by column chromato-
graphy (silica gel, heptanes–EtOAc) to give 8a (180 mg, 64%) as a
colourless solid.
12. General procedure for the synthesis of 9a–f: An acetone solution of
amide 8 and of a catalytic amount of p-toluenesulphonic acid was
heated under reflux for 6 h. The solution was cooled to 20 °C and
concentrated to give a solid residue, which was purified by flash
chromatography (silica gel, heptanes–EtOAc) to give compounds
9a–f. Starting with 8a (0.58 mmol), PTSA (5 mg, 0.02 mmol) and
acetone (15 mL), 9a was isolated (90 mg, 85%) as a slightly yellow
solid, mp = 168 °C. Spectroscopic data of 9a: 1H NMR (CDCl3,
250 MHz): d 7.20 (m, 1H, Ar), 7.15 (m, 2H, Ar), 7.10 (m, 2H, Ar),
5.42 (d, J = 1.7 Hz, 1H, C@CH), 3.74 (ddd, J = 13.7, 8.3, 7.6 Hz, 1H,
CH2), 3.59 (ddd, J = 13.8, 8.4, 7.1 Hz, 1H, CH2), 2.96 (m, 1H, CH),
2.78 (t, J = 8.1 Hz, 2H, CH2), 2.64 (dd, J = 17.2, 8.7 Hz, 1H, CH2),
2.54 (dd, J = 17.3, 5.0, 2.0 Hz, 1H, CH2), 2.34 (dd, J = 13.4, 4.9 Hz,
1H, CH2), 2.19 (m, 1H, CH2), 2.16 (dd, J = 17.3, 8.5 Hz, 1H, CH2),
1.69 (ddd, J = 24.8, 12.2, 4.9 Hz, 1H, CH2). 13C NMR (CDCl3,
62.9 MHz): dC = 196.9 (C), 175.0 (C), 165.9 (C), 137.2 (C), 128.7
(CH), 128.6 (CH), 126.9 (CH), 101.9 (CH), 41.6 (CH2), 37.5 (CH2),
34.8 (CH2), 34.7 (CH), 32.8 (CH2), 28.0 (CH2). IR (KBr, cmÀ1):
~m = 3322 (s), 2931 (m), 1733 (m), 1600 (br). MS (EI, 70 eV): m/z
(%) = 255 (M+, 46), 164 (10), 151 (10), 136 (41), 123 (22), 108 (22),
104 (100), 103 (5), 77 (9). HRMS (EI, 70 eV): calcd for C16H17O2N
[M+]: m/z = 255.12538; found, 255.12593.
Fig. 2. ORTEP plot of 9a.
Acknowledgement
Financial support by the Alexander-von-Humboldt
foundation (Georg-Forster-scholarship for B.J.) is grate-
fully acknowledged.
References and notes
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Z.; Manson, A. J.; Stonner, F. W. J. Am. Chem. Soc. 1955, 77, 675;
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A.; Rodig, O.; Ternbah, M. Helv. Chim. Acta 1959, 42, 1301; (d)
Mondon, A.; Nestler, H. J. Angew. Chem. 1964, 76, 651; (e) Stevens,
R. V.; Wentland, M. P. J. Chem. Soc., Chem. Commun. 1968,
1104.
2. (a) Namsa-aid, A.; Ruchirawat, S. Org. Lett. 2002, 4, 2633; (b) Rigby,
J. H.; Cavezza, A.; Heeg, M. J. J. Am. Chem. Soc. 1998, 120, 3664; (c)
Schwenker, G.; Metz, G. J. Chem. Res. (Synopses) 1985, 1247.
3. Ito, K.; Haruna, M.; Furukawa, H. J. Chem. Soc. Chem. Commun.
1975, 681.
13. CCDC 677344 contains all crystallographic details of this publication
and are available free of charge at www.ccdc.cam.ac.uk/conts/
retrieving.html or can be ordered from the following address:
Cambridge Crystallographic Data Centre, 12 Union Road, GB-
Cambridge CB21EZ; Fax: (+44)1223-336-033; or deposit@ccdc.
cam.ac.uk.