Synthesis of 2,6-dioxo-1,2,3,4,5,6-hexahydroindoles by acid-catalyzed cyclization of acetal-protected (2,4-dioxocyclohex-l-yl)acetamides and their transformation into 5,8,9,10-tetrahydro-6H-indolo[2,1-a]isoquinolin-9-ones

Article abstract of DOI:10.1002/adsc.200800691

Acetal-protected (2,4-dioxocyclohex-1-yl)-acetic acids were prepared by allylation of dilithiated 1,3-cyclohexane-1,3-diones, protection of the carbon-yl groups and oxidation of the alkene moiety. Their reaction with amines afforded the corresponding amides which were transformed, by acid-catalyzed cyclization, into various 2,6-dioxo-1,2,3,4,5,6-hexahy-droindoles. The reaction of the latter with triflic acid resulted in the formation of novel 5,8,9,10-tetrahy-dro-6H-indolo[2,1-a]isoquinolin-9-ones.

Full text of DOI:10.1002/adsc.200800691

FULL PAPERS
DOI: 10.1002/adsc.200800691
Synthesis of 2,6-Dioxo-1,2,3,4,5,6-hexahydroindoles by Acid-
Catalyzed Cyclization of Acetal-Protected (2,4-Dioxocyclohex-1-
yl)acetamides and their Transformation into 5,8,9,10-Tetrahydro-
6H-indolo[2,1-a]isoquinolin-9-ones
G
Benard Juma,a Muhammad Adeel,a Alexander Villinger,a Helmut Reinke,a
Anke Spannenberg,b Christine Fischer,b and Peter Langera,b,*
a
Institut fꢀr Chemie, Universitꢁt Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany
Fax : (+49)-381-498-6412; e-mail: peter.langer@uni-rostock.de
Leibniz-Institut fꢀr Katalyse e. V. an der Universitꢁt Rostock, Albert-Einstein-Str. 29a, 18059 Rostock, Germany
b
Received: November 9, 2008; Published online: February 2, 2009
Dedicated to Professor Armin de Meijere on the occasion of his 70th birthday.
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200800691.
Abstract: Acetal-protected (2,4-dioxocyclohex-1-yl)- droindoles. The reaction of the latter with triflic acid
acetic acids were prepared by allylation of dilithiated resulted in the formation of novel 5,8,9,10-tetrahy-
1,3-cyclohexane-1,3-diones, protection of the carbon- dro-6H-indolo
ACHTUNGTRENNUNG
yl groups and oxidation of the alkene moiety. Their
reaction with amines afforded the corresponding
amides which were transformed, by acid-catalyzed Keywords: alkaloids; amides; C C bond formation;
ꢀ
cyclization, into various 2,6-dioxo-1,2,3,4,5,6-hexahy- cyclization; nitrogen heterocycles
Introduction
Erythrina alkaloids occur in various tropical and sub-
tropical plants[1] and show a wide range of interesting
biological properties.[2] This includes, for example,
curare-like, hypotensive, sedative, anticonvulsive, and
CNS-depressive activity.[3] Erythrina alkaloids have
been prepared, for example, using photochemical [2+
2]cycloadditions or Diels–Alder reactions as the key
steps.[4] An important strategy for the synthesis of Er-
ythrina alkaloids relies on the acid-catalyzed domino
reaction of (2-oxocyclohex-1-yl)acetic amides.[4–6] This
transformation proceeds by acid-catalyzed cyclization
of the amide to give an N-(2-arylethyl)-2-oxo-
1,2,3,4,5,6-hexahydroindole which is transformed in
situ into the Erythrina-type spirocyclic product by a
Scheme 1. Strategy for the synthesis of the novel Erythrina-
type spiro-compound III containing an additional carbonyl
group.
Pictet–Spengler reaction. For example, spirocycle I
has been directly prepared from the amide II under
various conditions (use of acids or Lewis acids) the aryl group and the nitrogen atom, etc.). This is a
(Scheme 1). Despite its utility, the preparative scope severe limitation because the synthesis of specific
of this reaction is very narrow and its success strongly target molecules heavily relies on functional group
depends on the structure of the substrate (substitution transformations of the spiro compounds obtained by
pattern of the aryl group, length of the linker between the domino process.
Adv. Synth. Catal. 2009, 351, 1073 – 1079
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1073

Benard Juma et al.
FULL PAPERS
To address this problem, we planned to prepare the
unknown Erythrina derivative III, which contains an
additional carbonyl group, from the corresponding
amide IV (Scheme 1). The carbonyl group of III was
expected to be a useful tool for the synthesis of Eryth-
rina-type natural products and their non-natural ana-
logues. It was planned to prepare the required starting
material IV from (2,4-dioxocyclohex-1-yl)acetic acid
which, therefore, represents an important key inter-
mediate of the present study.
Recently, we have reported[7] preliminary results re-
lated to the synthesis of (2,4-dioxocyclohex-1-yl)acetic
amides, such as IV. Their cyclization, in the presence
of catalytic amounts of para-toluenesulfonic acid
(PTSA), resulted in the formation of 2,6-dioxo-
1,2,3,4,5,6-hexahydroindoles rather than the expected
Erythrina-type spiro compounds. Herein, we report a
full account of the preparative scope of this method-
ology which provides, to the best of our knowledge,
the as yet most general approach to 2,6-dioxo-
1,2,3,4,5,6-hexahydroindoles.[8] In addition, we report
for the first time the reaction of 2,6-dioxo-1,2,3,4,5,6-
hexahydroindoles with triflic acid which results in the
Scheme 2. Synthesis of 7a,b. Conditions: i, 1) 2.5 equiv.
LDA, HMPTA, THF, ꢀ788C, 1 h, 2) allyl bromide, ꢀ40 !
formation of novel 5,8,9,10-tetrahydro-6H-indolo
a]isoquinolin-9-ones.
ACHTUNGTNER[NUNG 2,1-
208C, 12 h. ii, HOACHTNUGTRNEG(UN CH2)2OH, toluene, PTSA (6 mol%). iii,
NaIO4, KMnO4, acetone. iv, 1) O3, 2) Me2S or other condi-
tions (see text).
Results and Discussion
The synthesis of (2,4-dioxocyclohex-1-yl)acetic acid cyclohex-1-yl)acetic acid (4) which, however, proved
(4) has, to the best of our knowledge, not been report- to be unstable. Therefore, bis(acetals) 7a and b were
ed to date. The synthesis of 4 proved to be very diffi- used directly for all further transformations.
cult in our hands, despite its structural simplicity. The
AHCTUNGTRENNUNG
The DCC-mediated reaction of 7a and b with vari-
reaction of the dianion[9,10] of cyclohexane-1,3-dione ous amines afforded the amides 10a–v (Scheme 3,
(1) with 1-bromo-2,2-diethoxyethane and epibromo-
hydrin resulted in attack onto the carbon attached to
the bromide and gave the corresonding products 2
and 3, albeit, in low yields, respectively. The low
yields can be explained by the b-oxygen effect. All at-
tempts to prepare 4 by oxidation of 2 and 3 failed.
Deslongchamps and Guay reported the synthesis of
4-(3-oxopropyl)cyclopentane-1,3-dione by ozonolysis
of 4-(homoallyl)cyclopentane-1,3-dione.[11] However,
the ozonolysis of 4-allylcyclohexane-1,3-dione (5a),
prepared by reaction of the dianion of 1a with allyl
bromide,[12] afforded the triacid 9 rather than the de-
sired aldehyde 8 (Scheme 2). The triacid 9 was also
isolated when the oxidation was carried out using
KMnO4, KMnO4/NaIO4 in acetone, or KMnO4/
CuSO4·5H2O in CH2Cl2/t-BuOH/H2O. The formation
of 9 can be explained by oxidative cleavage of the
enolic double bond. The problem was solved by pro-
tection of the carbonyl groups of 5a to give the bis-
ACHTUNGTRENNUNG
Scheme 3. Synthesis of 11a–v. Conditions: i, 1) DCC, N-hy-
droxysuccinimide, CH2Cl2, 1 h, 08C, then 12 h, 208C, 2)
AHCTUNGTRENNUNG
7a can be deprotected to give the desired (2,4-dioxo- R2NH2, 2 h, 208C. ii, PTSA (2–7 mol%), acetone, 6 h, reflux.
1074
asc.wiley-vch.de
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2009, 351, 1073 – 1079

Synthesis of 2,6-Dioxo-1,2,3,4,5,6-hexahydroindoles by Acid-Catalyzed Cyclization
FULL PAPERS
Table 1. Synthesis of 11a–v.
10, 11 R1 R2
% [10][a] % [11][a]
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
q
r
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
n-Hept
i-Bu
62
57
76
65
86[b]
46
65
67
79
–
90
64
81
51
91
73
93
86
Figure 1. ORTEP plot of 10o (50% probability level).
c-Pr
c-Pent
c-Hex
Allyl
PhCH2
T
71
49[c]
85
G
R
E
E
64
–
(CH2)2
R
E
45[c]
53
89[b]
85
72
65
83
78
N
G
(CH2)2 64
G
73
70
–
–
–
Me [3-
Me
E
43[c]
86[c]
58[c]
84
Figure 2. ORTEP plot of 11o (50% probability level).
The reaction of 7a with 1,4-bis(aminomethyl)ben-
s
t
u
v
R
R
N
A
E
N
90
A
A
(CH2)2 74[b]
65
zene afforded the bisACTHNUTRGNE(NUG amide) 10w which was trans-
[a]
[b]
Yields of isolated products.
formed, by two-fold acid-catalyzed cyclization, into
the bis(2,6-dioxo-1,2,3,3a,4,5-tetrahydroindole) 11w
(Scheme 4).
For comparison, we studied the PTSA-catalyzed
cyclization of amide 10x which contains only one car-
These products were prepared from mono-7a, b and
were isolated in the form of mono-10e, m, v (structures
see above).
[c]
Overall yield based on 7a, b.
Table 1). Reflux of an acetone solution of 10a–v in
the presence of catalytic amounts of para-toluenesul-
fonic acid (PTSA, 2–7 mol%) afforded the 2,6-dioxo-
1,2,3,3a,4,5-tetrahydroindoles 11a–v. The formation of
an Erythrina-type spiro compound, such as III (see
Scheme 1), was not observed. The formation of 11a–v
presumably proceeds by acid-catalyzed deacetaliza-
tion and subsequent acid-catalyzed attack of the ni-
trogen atom onto the neighboring carbonyl group and
extrusion of water. In contrast to all other products,
11e, m and v were prepared from mono-10e, m and v
containing only one (rather than two) acetal groups.
The amides mono-10e, m and v were prepared from
the corresponding acids (mono-7a,b). The latter are
available by acetalization of 5a and b using only one
(rather than two) equivalents of glycol.
The structures of all products were established by
spectroscopic methods. The structures of 10o, 11o,
and 11e were independently confirmed by X-ray crys-
tal structure analyses (Figure 1 and Figure 2).[13]
Scheme 4. Synthesis of 11w. Conditions: i, 1) DCC, N-hy-
droxysuccinimide, CH2Cl2, 1 h, 08C, then 12 h, 208C, 2)
RNH2, 2 h, 208C. ii, PTSA (10 mol%), acetone, 6 h, reflux.
Adv. Synth. Catal. 2009, 351, 1073 – 1079
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1075

Benard Juma et al.
FULL PAPERS
Scheme 6. Synthesis of 11y,z. Conditions: i, 1) DCC, N-hy-
droxysuccinimide, CH2Cl2, 1 h, 08C, then 12 h, 208C, 2)
RNH2, 2 h, 208C. ii, PTSA (2 mol%), acetone, 6 h, reflux.
tion of an iminium ion which might be subsequently
attacked by a nucleophile.
Heating of 2,6-dioxo-1,2,3,4,5,6-hexahydroindole
11o in the presence of PTSA for an extended period
of time (48 h) or using stoichiometric amounts of
PTSA did not result in any conversion. Therefore, we
chosed triflic acid (TfOH) as a more reactive reagent.
The reaction of 11o, l and v with triflic acid (TfOH)
Scheme 5. Synthesis of 12. Conditions: i, 1) DCC, N-
hydroxy
ACHTUNGTRENNUNGsuccinimide, CH2Cl2, 1 h, 08C, then 12 h, 208C, 2)
RNH2, 2 h, 208C. ii, PTSA (2 mol%), acetone, 6 h, reflux.
afforded the 5,8,9,10-tetrahydro-6H-indoloACHTNUTRGNE[UNG 2,1-a]iso-
quinolin-9-ones 14a–c rather than the Erythrina-type
spirocycles 13 (Scheme 7, Table 2). The formation of
bonyl group (Scheme 5). Amide 10x was prepared by 14a–c can be explained by protonation of the amide
DCC-mediated reaction of 2-(3,4-dimethoxyphenyl)- oxygen atom to give the cationic intermediate E, cy-
A
ACHTUNGTRENcNUGN lization via the electron-rich aryl group (intermedi-
10x with PTSA afforded the Erythrina-type spiro ate F), and subsequent extrusion of water and double
compound 12 in excellent yield. Tietze and co-work- bond migration. In contrast, the reaction of TfOH
ers recently reported the synthesis of 12 by AlMe3/In- with 11k resulted in the formation of a complex mix-
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
tion of 12 can be explained, as outlined in the intro-
duction, by acid-catalyzed reaction of the keto group
with the electron-rich phenyl group to give intermedi-
ate C, protonation of the enamine moiety to give imi-
nium salt D, and subsequent Pictet–Spengler reaction.
It is important to note that this reaction is not gener-
al: The reaction of PTSA (2 mol%) with amides 10y
and z, which were again prepared from 7c in good
yields, afforded the 2-oxo-1,2,3,4,5,6-hexahydroindoles
11y and z rather than the expected spirocyclic prod-
ucts (Scheme 6). This result can be explained by the
higher strain of a 5,5,6- compared to a 5,6,6-spirocy-
clic system.
Our next plan was to study the transformation of
2,6-dioxo-1,2,3,4,5,6-hexahydroindoles 11 into Erythri-
na-type spirocycles, such as III, under more forcing
conditions. 2,6-Dioxo-1,2,3,4,5,6-hexahydroindoles 11
represent polyfunctionalized heterocycles containing
an enone, enamine, and lactam moiety. In principle, a
nucleophilic attack might occur at the enone moiety
(1,2- or 1,4-addition) or at the amide group. Protona-
Scheme 7. Possible mechanism of the formation of 14a. Con-
tion of the enamine moiety might result in the forma- ditions: i, TfOH, CH2Cl2, reflux, 4 h.
1076
asc.wiley-vch.de
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2009, 351, 1073 – 1079

Synthesis of 2,6-Dioxo-1,2,3,4,5,6-hexahydroindoles by Acid-Catalyzed Cyclization
FULL PAPERS
Table 2. Synthesis of 14a–c.
4-Allylcyclohexane-1,3-dione (5a)
To a THF solution (98 mL) of 1,3-cyclohexanedione 1a
(5.0 g, 44.6 mmol) and of anhydrous HMPA (20 mL) was
added a THF solution of LDA which was prepared from n-
BuLi (2.5M solution in hexane, 40 mL, 98.2 mmol) and di-
11
14
R1
R2
R3
% (14)[a]
o
l
v
a
b
c
H
H
Me
H
OMe
H
OMe
H
OMe
84
32
57
A
mixture was allowed to warm to ꢀ408C and 2-methylallyl
bromide (4.1 mL, 44.6 mmol) was added rapidly. The mix-
ture was slowly warmed to room temperature and stirred
for additional 10 h at 208C. The reaction mixture was con-
centrated, diluted with hydrochloric acid (5%), and extract-
ed with diethyl ether (3ꢄ100 mL). The organic layer was
washed with hydrochloric acid (3%) and with brine, dried
(MgSO4), filtered and concentrated under vacuum. The
crude product was purified by flash column chromatography
(silica gel, heptanes/EtOAc=1:1) to give 5a as a pale yellow
oil; yield: 5.90 g (87%). 1H NMR (300 MHz, CDCl3): d=
5.77 (m, 1H, C=CH), 5.45 (s, 1H, CH), 5.03 (m, 2H, C=
CH2), 2.67 (m, 3H, CH, CH2), 2.43 (m, 2H, CH2), 2.23 (m,
2H, CH2), 1.7 (m, 1H, CH2); 13C NMR (75 MHz, CDCl3):
d=196.7 (C=O), 189.5 (C=COH), 136.2 (C=CH), 117.9 (C=
[a]
Yields of isolated products.
phenyl group. This can be explained by the high reac-
tivity of activated, electron-rich arenes in electrophilic
substitution reactions. The reaction of TfOH with 11s
also gave a complex mixture. This can be explained
by the higher strain of 5,5,6- compared to 5,6,6-tricy-
clic products.
Padwa and Wang have recently reported the
TfOH-mediated transformation of
1,2,3,4,5,6-hexahydroindole into a 5,6-dihydroindolo-
ACHTUNGTRENNUNG
[2,1-a]isoquinolin-9-ol.[6,15] This reaction, which in-
volves a cyclization, decarboxylation and an aromati-
zation step, presumably proceeds by a mechanism
similar to that suggested for the formation of 5,8,9,10-
tetrahydro-6H-indolo
The synthesis of 5,8,9,10-tetrahydro-6H-indoloAHCTUNGTRENNUNG
a]isoquinolin-9-ones has, to the best of our knowl-
edge, not been reported to date.[16]
a
2,6-dioxo-
CH2), 104.3 (CH), 41.9 (CH), 34.8 (CH2), 30.2 (CH2), 25.7
ꢀ1
˜
(CH2); IR (neat, cm ): n=3076 (m), 2934 (w), 2664 (w),
1598 (s, br), 1413 cmꢀ1 (m); MS (GC, 70 eV): m/z (%)=152
[M]+· (13), 124 (16), 123 (27), 110 (46), 109 (24), 96 (26), 95
(52), 92 (10), 83 (42), 82 (62), 81 (33), 79 (15), 69 (22), 68
(56), 67 (100); HR-MS (EI, 70 eV): m/z=152.08318, calcd.
for C9H12O2 [M+C]: 152.08367.
ACHTUNGTRENNUNG
In conclusion, we have reported the synthesis of
the first (2,4-dioxocyclohex-1-yl)acetic amides. Their
reaction with PTSA provides a general method for
the synthesis of 2,6-dioxo-1,2,3,4,5,6-hexahydroin-
doles. The reaction of the latter with triflic acid af-
12-Allyl-1,4,8,11-tetraoxadispiro
(6a)
ACHTUNGERTN[NUNG 4.1.4.3]tetradecane
A
mixture of 5a (6.08 g, 40.0 mmol), ethylene glycol
(5.0 mL, 85.0 mmol) and p-toluenesulfonic acid monohy-
drate (50 mg, 2.6 mmol, 6.5 mol%) in toluene (300 mL) was
stirred under reflux for 4 h using Dean–Stark conditions.
Approximately 1.6 mL of water were collected in the Dean–
Stark trap. The toluene solution was washed with a saturat-
ed aqueous solution of NaHCO3 (40 mL) and with brine
(60 mL). The solution was dried (MgSO4), filtered and the
solvent of the filtrate was removed under vacuum. The resi-
due was purified by chromatography (silica gel) to give 6a
forded
5,8,9,10-tetrahydro-6H-indoloACTHUNGTERNNU[G 2,1-a]isoqui-
nolin-9-ones rather than Erythrina-type spirocycles.
Experimental Section
General Remarks
1
1
Chemical shifts of the H and 13C NMR spectra are reported
as a colourless oil; yield: 3.65 g (18.6 mmol, 90%). H NMR
in parts per million using the solvent internal standard
(chloroform, 7.26 and 77.0 ppm, respectively). Infrared spec-
tra were recorded on an FT-IR spectrometer. Mass spectro-
metric data (MS) were obtained by electron ionization (EI,
70 eV), chemical ionization (CI, isobutane) or electrospray
ionization (ESI). Melting points are uncorrected. Analytical
thin layer chromatography was performed on 0.20 mm 60 A
silica gel plates. Column chromatography was performed
using 60 A silica gel (60–200 mesh). All cyclization reactions
were carried out in Schlenk tubes under an argon atmos-
phere. The bis(silyl enol ethers) were prepared as described
in the literature. Crystallographic data were collected on a
Bruker X8Apex with MoKa radiation (l=0.71073 ꢃ). The
structures were solved by direct methods using SHELXS-97
and refined against F2 on all data by full-matrix least-
squares with SHELXL-97. All non-hydrogen atoms were re-
fined anisotropically, all hydrogen atoms were refined in the
model at geometrically calculated positions and refined
using a riding model.
(CDCl3, 300 MHz): d=5.92 (m, 1H, CH), 5.15 (m, 2H,
CH2), 4.06 (m, 8H, OCH2), 2.58 (m, 1H, CH), 2.18–1.86 (m,
6H, CH2), 1.69 (m, 2H, CH2); 13C NMR: (CDCl3,
75.4 MHz): d=137.8 (C=CH), 116.1 (C=CH2), 110.5 (C),
109.3 (C), 65.6 (OCH2), 65.0 (OCH2), 64.9 (OCH2), 64.2
(OCH2), 43.8 (CH), 43.1 (CH2), 33.5 (CH2), 32.7 (CH2), 24.9
(CH2); MS (GC, 70 eV): m/z (%)=240 ([M+1]+·, 1), 157
(35), 154 (22), 139 (15), 138 (10), 126 (26), 125 (14), 113 (5),
99 (35), 87 (12), 86 (100), 55 (11), 42 (10); HRMS (EI,
70 eV): m/z=240.13589, calcd. for C13H20O4 [M+1]+C:
240.13561.
2-(1,4,8,11-Tetraoxadispiro
acetic acid (7a)
ACHTUNGTNER[NUNG 4.1.4.3]tetradec-12-yl)-
To a stirred water solution (250 mL) of NaIO4 (15.00 g,
196.0 mmol) and KMnO4 (0.63 g, 3.9 mmol) was added an
acetone solution (39 mL) of 6a (2.30 g, 11.7 mmol). The so-
lution was stirred at room temperature until a colour change
Adv. Synth. Catal. 2009, 351, 1073 – 1079
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1077

Benard Juma et al.
FULL PAPERS
from violet to red was observed. The solution was then ex-
tracted with EtOAc (3ꢄ100 mL) and the combined organic
layers were dried (MgSO4). The solution was filtered and
the filtrate was concentrated under vacuum to give 7a as a
light brown gummy substance which required no further pu-
concentrated under vacuum to give a solid residue which
was purified by column chromatography (silica gel, hep-
tanes/EtOAc).
3,3a,4,5-Tetrahydro-1H-indole-2,6-dione (11a): Starting
with 10a (70 mg, 0.27 mmol), PTSA (5 mg, 0.02 mmol) and
dry acetone (40 mL), 11a was isolated as a white solid;
yield: 31 mg (90%); 1H NMR (CDCl3, 250 MHz): d=9.05
(br, 1H, NH), 5.51 (d, J=2.0 Hz, 1H, CH), 3.14 (m, 1H,
CH), 2.66 (dd, J=17.3, 8.8 Hz, 1H, CH2), 2.49 (ddd, J=
17.3, 6.8, 2.3 Hz, 1H, CH2), 2.38 (dd, J=13.3, 4.8 Hz, 1H,
CH2), 2.26 (dd, J=17.3, 8.8 Hz, 1H, CH2), 2.24 (m, 1H,
CH2), 1.77 (ddd, J=27.3, 14.8, 6.3 Hz, 1H, CH2); 13C NMR
(CDCl3, 62.9 MHz): d=197.8 (C=O), 177.0 (NC=O), 165.3
(NC=C), 103.1 (CH), 37.4 (CH2), 36.2 (CH), 35.4 (CH2),
1
rification; yield: 1.61 g (65%). H NMR (300 MHz, CDCl3):
d=10.09 (brs, 1H, COOH), 3.86 (m, 8H, OCH2), 2.51 (dd,
J=15.0, 4.5 Hz, 1H), 2.21 (m, 1H), 2.05 (dd, J=14.7,
8.1 Hz, 1H), 1.90 (dd, J=12.5, 1.8 Hz, 2H), 1.69 (m, 2H),
1.50 (brd, d, J=8.7, 2H); 13C NMR (75 MHz, CDCl3): d=
178.7 (C=O), 109.7 (C), 109.0 (C), 65.5 (OCH2), 65.4
(OCH2), 64.9 (OCH2), 64.1 (OCH2), 42.6 (CH2), 40.9 (CH),
33.8 (CH2), 33.5 (CH2), 26.0 (CH2); MS (EI, 70 eV): m/z
(%) 258 [M]+· (2), 215 (8), 172 (18), 157 (87), 152 (6), 144
(32), 128 (8), 113 (32), 100 (9), 99 (93), 87 (20), 86 (100), 85
(15), 83 (22); HR-MS (EI, 70 eV): m/z=258.109219, calcd.
for C12H18O6 [M]+C: 258.10979.
˜
27.9 (CH2); IR (neat): n=3098 (w), 2991 (w), 2950 (w), 2799
(w), 1746 (s, br), 1574 cm<-M>1 (a, br); MS (GC, 70 eV): m/z
(%)=151 ([M]+·, 51), 124 (7), 123 (100), 122 (7), 95 (35), 68
(16), 67 (21); HR-MS (EI, 70 eV): m/z=151.06278, calcd.
for C8H9O2 [M]+C: 151.063012.
Typical Procedure for the Synthesis of Amides 10
2,3-Dimethoxy-5,8,10,11-tetrahydroindoloACHTNUGTREN[NUNG 2,1-a]isoquino-
To a CH2Cl2 solution (20 mL) of 7a (200 mg, 0.8 mmol) was
added N-hydroxysuccinimide (88 mg, 0.78 mmol) and dicy-
clohexylcarbodiimide (162 mg, 0.8 mmol) at 08C and the
mixture was stirred for 1 h at the same temperature. After
stirring for 12 h, the mixture was filtered, 1-amino-2-phenyl-
ethane (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 wash-
ing). The organic layer was dried (NaSO4), filtered and the
filtrate was concentrated under vacuum. The residue was
purified by column chromatography (silica gel, heptanes/
EtOAc) to give 10k as a colourless solid; yield: 180 mg
(64%).
AHCTUNGTRElGNNUN in-9(6H)-one (14a): A CH2Cl2 solution (16 mL) of 11o
(150 mg, 0.5 mmol) and of TfOH (0.7 mL) was heated under
reflux for 4 h, cooled to room temperature, and quenched
with water. The aqueous layer was extracted with CHCl3
(3ꢄ80 mL) and the combined organic layers were dried
(MgSO4). The solution was filtered and the solvent of the
filtrate was removed under reduced pressure. The residue
was purified by flash chromatography (silica gel, heptanes/
EtOAc) to give 14a as white crystals which proved to be un-
1
stable at room temperature; yield: 120 mg (84%); H NMR
(CDCl3, 250 MHz): d=6.91 (s, 1H, ArH), 6.62 (s, 1H,
ArH), 6.18 (s, 1H), 3.83 (s, 3H, OCH3), 3.80 (s, 3H, OCH3),
3.76 (dd, J=5.6, 5.3 Hz, 2H, NCH2), 3.40 (s, 2H, CH2), 2.90
(dd, J=5.5, 5.3 Hz, 2H, CH2), 2.83 (dd, J=5.6, 5.5 Hz, 2H,
CH2), 2.61 (dd, J=5.4, 5.7 Hz, 2H, CH2); 13C NMR (CDCl3,
62.9 MHz): d=207.6 (C=O), 147.3 (C, Ar), 146.3 (C, Ar),
129.3 (C), 122.7 (C), 121.5 (C, Ar), 121.3 (C, Ar), 116.0 (C),
110.3 (CH, Ar), 104.7 (CH, Ar), 99.3 (CH), 55.1 (OCH3),
55.0 (OCH3), 39.6 (CH2), 39.1 (CH2), 36.3 (CH2), 27.6
2-(1,4,8,11-Tetraoxadispiro
acetamide (10a)
ACHTUNGTNER[NUNG 4.1.4.3]tetradec-12-yl)-
Starting with CH2Cl2 (40 mL), 7a (340 mg, 1.3 mmol), N-hy-
droxysuccinimide (178.4 mg, 1.6 mmol), dicyclohexylcarbo-
diimide (328.8 mg, 1.6 mmol) and ammonia (25% aqueous
solution, 0.12 mL, 1.6 mmol), 10a was isolated as a white
solid; yield: 210 mg (62%); mp 149–1528C; 1H NMR
(CDCl3, 250 MHz): d=5.81 (brs, 1H, NH), 5.69 (brs, 1H,
NH), 3.89 (m, 8H, OCH2), 2.46 (dd, J=14.5, 4.5 Hz, 1H,
CH2), 2.16 (m, 1H, CH), 1.98 (dd, J=8.5, 2.5 Hz, 1H, CH2),
1.92 (dd, J=7.5, 5.3 Hz, 1H, CH2), 1.77 (m, 2H, CH2), 1.70
(br, J=13.8 Hz, 1H, CH2), 1.53, (dd, J=11.0, 2.0 Hz, 1H,
CH2), 1.49 (dd, J=11.2, 2.7 Hz, 1H, CH2); 13C NMR
(CDCl3, 62.9 MHz): dC =175.4 (NC=O), 109.7 (C), 108.6
(C), 65.0 (OCH2), 64.7 (OCH2), 64.6 (OCH2), 63.9 (OCH2),
42.3 (CH2), 40.6 (CH), 35.0 (CH2), 33.2 (CH2), 25.8 (CH2);
˜
(CH2), 20.8 (CH2); IR (neat): n=2961 (w), 2911 (w), 2857
(w), 2837 (w), 1711 (s, br), 1526 cmꢀ1 (s); MS (EI, 70 eV):
m/z (%)=297 ([M]+·, 100), 295 (15), 269 (41), 255 (11), 254
(56), 224 (7), 211 (6); HR-MS (ESI, 70 eV): m/z=
320.12542, calcd. for C18H19NO3 [M+Na]+C: 320.12571,
m/z=298.14340, calcd. for [M+H]+C: 298.14377.
1,4,5,10,11,12,13,13a-Octahydro-7,8-dimethoxy-2H-indolo-
AHCTUNGTREG[NNUN 7a,1-a]isoquinolin-2-one (12): The synthesis was carried out
following the procedure as given for the synthesis of 14a.
Starting with 10x (380 mg, 1.2 mmol), PTSA (5 mg,
0.02 mmol) and dry acetone (70 mL), 12 was isolated as a
colourless viscous oil; yield: 309 mg (86%); 1H NMR
(CDCl3, 250 MHz): d=6.80 (s, 1H, ArH), 6.51 (s, 1H,
ArH), 4.02 (ddd, J=13.3, 7.0, 3.3 Hz, 1H, NH), 3.81 (s, 3H,
OCH3), 3.77 (s, 3H, OCH3), 3.15 (ddd, J=15.8, 10.3, 5.8 Hz,
1H), 2.90 (ddd, J=16.5, 9.8, 7.3 Hz, 1H), 2.63 (m, 1H, CH),
2.50 (m, 1H, CH2), 2.30 (brd, J=8.0 Hz, 2H, CH2), 1.95 (m,
1H, CH2), 1.80 (d, J=6.0 Hz, 1H, CH2), 1.77 (d, J=5.5 Hz,
1H, CH2), 1.69 (dd, J=10.0, 5.0 Hz, 1H, CH2), 1.58 (m, 2H,
CH2), 1.46 (dd, J=10.3, 4.5 Hz, 2H, CH2); 13C NMR
(CDCl3, 62.9 MHz): d=174.2 (NC=O), 147.8 (C, Ar), 147.3
(C, Ar), 134.7 (C, Ar), 125.7 (C, Ar), 111.9 (CH, Ar), 108.2
(CH, Ar), 62.3 (C), 56.1 (OCH3), 55.8 (OCH3), 37.7 (CH),
˜
IR (neat): n=3411 (w), 3175 (w), 2946 (w), 2966 (w), 2946
(w), 2880 (w), 1669 (s, br), 1625 cmꢀ1 (m); MS (GC, 70 eV):
m/z (%)=257 ([M]+·, 2), 214 (5), 212 (5), 199 (9), 171 (19),
157 (69), 143 (16), 127 (6), 113 (13), 99 (67), 87 (14), 86
(100); HR-MS (EI, 70 eV): m/z= 257.12577, calcd. for
C12H19O5 [M]+C: 257.125885.
General Procedure for the Synthesis of 11a–z
An acetone solution of amide 10 and of a catalytic amount
(2–10 mol%) of p-toluenesulfonic acid (PTSA) was heated
under reflux for 6 h. The solution was cooled to 208C and
1078
asc.wiley-vch.de
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2009, 351, 1073 – 1079

Synthesis of 2,6-Dioxo-1,2,3,4,5,6-hexahydroindoles by Acid-Catalyzed Cyclization
FULL PAPERS
36.5 (CH2), 35.8 (CH2), 34.9 (CH2), 27.1 (CH2), 27.0 (CH2),
[8] For other syntheses of 2,6-dioxo-1,2,3,4,5,6-hexahy-
droindoles, see: a) Birch reaction: K. Ito, M. Haruna,
H. Furukawa, J. Chem. Soc. Chem. Commun. 1975,
681; b) aza-Claisen rearrangement of isoquinuclidines:
Y. Chen, P. L. Huesmann, P. S. Mariano, Tetrahedron
Lett. 1983, 24, 1021; c) Diels–Alder reaction of 2-imido-
furans: A. Padwa, J. D. Ginn, J. Org. Chem. 2005, 70,
5197; d) A. Padwa, S. K. Bur, H. Zhang, J. Org. Chem.
2005, 70, 6833.
[9] a) N. M. Berry, M. C. P. Darey, L. M. Harwood, Synthe-
sis 1986, 476; see also: b) G. Vassilikogiannakis, I. Mar-
garos, M. Tofi, Org. Lett. 2004, 6, 205.
[10] For a recent review of dianions, see: P. Langer, W. Frei-
berg, Chem. Rev. 2004, 104, 4125, and references cited
therein.
˜
20.6 (CH2), 20.3 (CH2); IR (neat): n=2930 (m), 2854 (w),
2250 (w), 2799 (m), 1673 (s, br), 1512 cmꢀ1 (s); MS (GC,
70 eV): m/z (%)=301 ([M]+C, 26), 259 (17), 258 (100), 245
(12), 244 (15), 216 (9), 67 (21); HR-MS (EI, 70 eV): m/z=
301.166580, calcd. for C18H23NO3 [M]+C: 301.16725.
Acknowledgements
We are grateful for an experimental contribution by Mr. Olu-
mide Fatunsin. Financial support from the Alexander-von-
Humboldt Foundation (Georg-Forster scholarship for B. J.)
is gratefully acknowledged.
[11] B. Guay, P. Deslongchamps, J. Org. Chem. 2003, 68,
6140.
References
[12] W. Zhang, G. Pugh, Tetrahedron 2003, 59, 4237.
[13] CCDC 716534, CCDC 670738, and CCDC 716346 con-
tain the supplementary crystallographic data for this
paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
[14] We have prepared 7c by oxidation of 2-allylcyclohexa-
none (5c) which is readily available from cyclohexa-
none (see below). This approach to 7c has, to the best
of our knowledge, not yet been reported. For a differ-
ent synthesis of 7c, see for example: S. M. Allin, S. L.
James, M. R. Elsegood, W. P. Martin, J. Org. Chem.
2002, 67, 9464.
[1] B. A. Krukoff, R. C. Barneby, Mem. N. Y. Bot. Gard.
1970, 20, 1.
[2] a) A. S. Chawla, V. K. Kapor, in: Handbook of Plant
and Fungal Toxicants, (Ed.: J. F. D’Mello), CRC Press,
New York, 1997, p 37; b) A. J. Lehman, J. Pharmacol.
1937, 69; c) M. Williams, J. L. Robinson, J. Neurosci.
1984, 4, 2906; d) M. W. Decker, D. J. Anderson, J. D.
Brioni, D. L. Donnelly-Roberts, C. H. Kang, A. B.
OꢅNeil, M. Piattoni-Kaplan, S. Swanson, J. P. Sullivan,
Eur. J. Pharmacol. 1995, 79.
[3] For reviews, see: a) V. Boekelheide, in: The Alkaloids,
Vol. 7, (Ed.: R. H. F. Manske), Academic Press, New
York, 1960, p 201; b) R. K. Hill, in: The Alkaloids, Vol.
9, (Ed.: R. H. F. Manske), Academic Press, New York,
1967, p 483; c) S. F. Dyke, S. N. Quessy, in: The Alka-
loids, Vol. 18, (Ed.: R. G. A. Rodrigo), Academic Press,
New York, 1981, p 1; d) A. H. Jackson, in: Chemistry
and Biology of Isoquinoline Alkaloids, (Eds.: J. D. Phil-
lipson, M. F. Margaret, M. H. Zenk), Springer, Berlin,
1985, p 62; e) A. S. Chawla, A. H. Jackson, Nat. Prod.
Rep. 1984, 1, 371; for early original reports, see: f) K.
Wiesner, Z. Valenta, A. J. Manson, F. W. Stonner, J.
Am. Chem. Soc. 1955, 77, 675; g) V. Prelog, Angew.
Chem. 1957, 69, 33; h) V. Prelog, A. Langemann, O.
Rodig, M. Ternbah, Helv. Chim. Acta 1959, 42, 1301;
i) A. Mondon, H. J. Nestler, Angew. Chem. 1964, 76,
651.
[15] The following reaction has been reported by Padwa
and Wang (ref.[6]).
[4] a) P. C. Stanislawski, A. C. Willis, M. G. Banwell, Org.
Lett. 2006, 8, 2143; b) A. Padwa, Q. Wang, J. Org.
Chem. 2006, 71, 7391; c) A. K. Ganguly, C. H. Wang, D.
Biswas, J. Misiaszek, A. Micula, Tetrahedron Lett. 2006,
47, 5539; d) S. Gao, Y. Q. Tu, X. Hu, S. Wang, R. Hua,
Y. Jiang, Y. Zhao, X. Fan, S. Zhang, Org. Lett. 2006, 8,
2373; e) H. Fukumoto, K. Takahashi, J. Ishihara, S. Ha-
takeyama, Angew. Chem. 2006, 118, 2797; Angew.
Chem. Int. Ed. 2006, 45, 2731; f) J. H. Rigby, A. Cavez-
za, M. Heeg, J. Am. Chem. Soc. 1998, 120, 3664.
[5] L. F. Tietze, N. Tçlle, C. Noll, Synlett 2008, 525.
[6] A. Padwa, Q. Wang, J. Org. Chem. 2006, 71, 7391.
[7] B. Juma, M. Adeel, A. Villinger, P. Langer, Tetrahedron
Lett. 2008, 49, 2272.
[16] For related heterocycles, such as 5,8,9,10-tetrahydro-
6H-indoloACTHNUTRGNEUG[N 2,1-a]isoquinolin-11-ones, see: a) H. Meyer,
Liebigs Ann. Chem. 1981, 1534; b) Z. Vincze, P. Nemes,
ꢅB. Balazs, G. Toth, P. Scheiber, Synlett 2004, 1023;
c) M. Menes-Arzate, R. Martinez, R. Cruz-Almanza,
J. M. Muchowski, Y. M. Osornio, L. D. Miranda, J. Org.
Chem. 2004, 69, 4001.
Adv. Synth. Catal. 2009, 351, 1073 – 1079
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1079