Intramolecular N-acyliminium ion versus Friedel-Crafts cyclization onto 3-indoles: synthesis of the novel rings pyrrolizino[2,1-b]indole and homologues

Article abstract of DOI:10.1016/j.tet.2009.02.036

Acid treatment of indole-2-carboxylic acid β- and γ-oxoamides causes Friedel-Crafts intramolecular cyclization to β-carbolinones and dihydro-2H-azepino[3,4-b]indol-1-ones, in contrast to secondary δ-,ε-, and ζ-oxoamides, which cyclize to the novel heteroc

Full text of DOI:10.1016/j.tet.2009.02.036

Tetrahedron 65 (2009) 3465–3472
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Intramolecular N-acyliminium ion versus Friedel–Crafts cyclization onto
3-indoles: synthesis of the novel rings pyrrolizino[2,1-b]indole and homologues
*
Raffaella Cincinelli , Sabrina Dallavalle, Lucio Merlini, Raffaella Nannei, Leonardo Scaglioni
`
Dipartimento di Scienze Molecolari Agroalimentari, Universita di Milano, Via Celoria 2, 20133 Milano, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Acid treatment of indole-2-carboxylic acid
b
- and
g
-oxoamides causes Friedel–Crafts intramolecular
-, -,
-oxoamides, which cyclize to the novel heterocyclic rings pyrrolizino[2,1-b]indole, indolizino[2,1-
Received 21 November 2008
Received in revised form 25 January 2009
Accepted 13 February 2009
Available online 24 February 2009
cyclization to
and
b-carbolinones and dihydro-2H-azepino[3,4-b]indol-1-ones, in contrast to secondary d 3
z
b]indole, and 9a,11-diaza-indeno[1,2-a]azulene, via an intermediate N-acyliminium ion. Tertiary amides
lead only the Friedel–Crafts ring closure, thus allowing the synthesis of larger fused rings.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Friedel–Crafts
Acyliminium ion
Indole-fused heterocycles
Synthesis
1. Introduction
Compared to the syntheses of the azepino[3,4]indole scaffold
reported in the literature,3–5 our procedure required simpler re-
agents and conditions, and could give easy access to aryl and alkyl
substituted azepino[3,4-b]indol-1-ones.
In this paper we report the results of the application of the
intramolecular Friedel–Crafts cyclization to the synthesis of higher
homologues.
In a recent paper1 we reported that the intramolecular Friedel–
Crafts cyclization of indole-2-carboxylic acids -oxoamides (1),
catalyzed by trifluoroacetic acid (TFA) or InCl3, represents a simple,
b
straightforward synthesis of b-carbolin-1-ones (2) (Scheme 1).
R5
2. Results and discussion
R4
O
R5
N
R4
NH
O
R1
R2
R1
R2
TFA
NH
To investigate the scope and aim of the TFA catalyzed annulation
process, indole-2-carboxylic acid oxoamides with increasing chain
length were subjected to intramolecular Friedel–Crafts cyclization.
Interestingly, when the ring-closure reaction was attempted on
(or InCl3)
N
O
R3
R3
1
2
a
d-oxoamide (8), a compound with the mass expected for an
Scheme 1.
azocino[3,4-b]indol-1-one (9) was obtained in good yield (75%).
However, careful analysis of the 1H and 13C NMR spectra of this
product indicated that they were more consistent with a tetracyclic
pyrrolizino[2,1-b]indol-9-one structure (10a) (Scheme 3).
Due to the simplicity and efficiency of the synthesis, we decided
to extend its scope to the preparation of indole-fused larger rings,
such as azepino[3,4-b]indol-1-ones and higher homologues.
The disappearance of the proton in position 3b of the indole
nucleus, together with H-10/C-8a, H-10/C-3c, and H-3/C-8a long
range correlations, clearly demonstrated the occurrence of a cycli-
zation process (Table 1). However, in the 13C spectra, no further
olefinic carbon was present, apart from those of the indole ring,
suggesting that the condensation did not give the expected azo-
cino[3,4-b]indol-1-one nucleus. The 1H NMR spectrum revealed the
presence of well-separated protons belonging to the three CH2
groups, as clearly demonstrated by the 1H-COSY, DEPT, and HSQC
experiments. The different chemical shifts of the protons of each
To this purpose, indole-2-carboxylic acid
g-oxoamides were
synthesized by condensation of the acids (3) with the appropriate
3-aminoalcohols (4), followed by oxidation of the hydroxyl with
IBX, and cyclization with TFA to the expected 3,10-dihy-
droazepino[3,4-b]indol-1-ones (7) in good yields (Scheme 2).2
* Corresponding author. Tel.: þ390250316816; fax: þ390250316801.
E-mail address: raffaella.cincinelli@unimi.it (R. Cincinelli).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.02.036

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R. Cincinelli et al. / Tetrahedron 65 (2009) 3465–3472
R
HO
R
H3CO
H3CO
H3CO
NH
O
IBX
EDC, HOBt
+
COOH
HO
DMSO or EtOAc
THF
N
N
CH3
H3CO
NH2
CH3
4a R= H
4b R= CH3
5a R= H
5b R= CH3
3a
R
R
O
H3CO
H3CO
H3CO
H3CO
NH
O
TFA
CH3CN
NH
N
CH3
N
CH3
O
7a R= H
7b R= CH3
6a R= H
6b R= CH3
7c R= 4-OCH3C6H4
6c R=4-OCH3C6H4
Scheme 2.
methylene group and the coupling constants were an evidence of
a small-size ring system. Moreover, the amidic NH proton was ab-
sent, and H-3 showed a coupling only with the adjacent H-2. The
13C and DEPT spectra showed the presence of two methyl groups,
H3C
H3CO
H3CO
O
NH
one linked to a nitrogen atom (
24.00 ppm) attached to a sp3 quaternary carbon.
All this information, together with the value of 67.08 ppm for
d 30.29 ppm) and the other
N
CH3
O
(d
H3C
N
9
TFA
H3CO
H3CO
N
the chemical shift of the quaternary carbon C-3a, most likely due to
the linkage to a nitrogen atom, clearly support the proposed
tetracyclic structure.
As the reaction appeared a useful method for the synthesis of
novel heterocyclic rings, its scope was explored by extending the
study to the preparation of compounds with six- and seven-
membered distal rings, differently substituted on the ring junction
(Table 2).
To the best of our knowledge, only two examples of indolizi-
dino[2,1-b]indoles, both with a distal aromatic ring, and obtained
via Fischer indole synthesis6 or Nazarov reaction,7 have been
reported recently, whereas no examples of pyrrolizidino[2,1-b]in-
doles or of 9a,11-diaza-indeno[1,2-a]azulenes have been reported
so far.
H
O
CH3
TFA
8
H3C
N
H3CO
O
N
H3CO
CH3
10a
Scheme 3.
The amides 8 were prepared by condensing the appropriate
indole-2-carboxylic acid 3 with the corresponding aminoalcohols
or aminoketone hydrochlorides or toluenesulfonates in the pres-
ence of EDC and HOBt (Scheme 4, routes A and B). In the former
case, the alcohols 12 were oxidized to the corresponding aldehydes
with IBX in DMSO. Alternatively, amide 8g was obtained by acyla-
tion of valerolactam with 2-indolecarboxylic acid chloride,
Table 1
1H, 13C, and HMBC NMR data for compound 10a (DMSO-d6)
2
3
10
1
H3C
3a
4
7
N
H3CO
H3CO
3c
5
6
9
3b
8
8a
O
7a
N
CH3
Table 2
10a
C
dC
41.56
28.86
35.03
67.08
113.55
130.91
94.78
145.86
149.24
101.93
137.87
136.34
166.11
24.00
30.29
56.21
dH
HMBC
R3
m
1
2
3
3a
3b
3c
4
5
6
7
7a
8a
9
10
NMe
5-OMe
6-OMe
3.48–3.20
2.38–2.25
2.12–1.40
C-2; C-3; C-3a; C-9
C-3; C-3a
C-10; C-2; C-1; C-3a; C-8a
N
R1
R2
O
N
CH3
10
7.10
7.19
C-3a; C-7; C-3b; C-8a; C-7a; C-5; C-6
C-4; C-8a; C-7a; C-5; C-6; NCH3; C-3c
Entry
m
R1
R2
R3
Method
Yield (%)
a
b
c
d
e
f
1
1
1
1
1
2
2
3
OCH3
OCH3
H
OCH3
OCH3
H
CH3
H
H
4-CH3O-Ph
4-CH3O-Ph
H
CH3
H
B
A
A
B
B
A
C
A
76
10
10
75
93
20
57
40
H
H
1.54
3.81
3.85
3.80
C-3; C-3a; C-3c; C-8a
C-3c; C-7a; C-9
C-4; C-6
OCH3
OCH3
H
OCH3
OCH3
H
g
h
OCH3
OCH3
56.39
C-7; C-5

R. Cincinelli et al. / Tetrahedron 65 (2009) 3465–3472
3467
HO
R1
HN
m
HO
R2
route A
N
CH3
O
NHm2
IBX
DMSO or AcOEt
11
12
EDC, HOBt,
THF
R3
O
R1
R2
O
R1
R2
NH3+
HN
m
R3
13
COOH
TFA
route B
10
N
EDC/HOBt
DIPEA
N
O
CH3
CH3
3
8
O
R3MgX
R1
R2
SeeTable 2 for the meaning of R1,R2,R3 and m.
CO N
route C
N
CH3
14
Scheme 4.
H
O
+
CH3
H3C
HO
N
H3C
N
H3CO
H3CO
N
H3CO
H3CO
N
O
H3CO
H3CO
H+
-H2O
+
H
TFA
N
8
10a
N
CH3
O
O
CH3
CH3
Scheme 5.
O
R3
R3
R1
R2
TFA
N
R4
R1
R2
N
R4
N
O
CH3
N
O
CH3
9a R1, R2 = OMe R3 = H,
R4 = nBu
8i R1, R2 = OMe R3 = H,
R4 = nBu
9b R1, R2 = H, R3 = pOMePh R4 = Me
8l R1, R2 = H R3 = pOMePh R4 = Me
Scheme 6.
followed by preferential lactam ring-opening with a Grignard
reagent8 (Scheme 4, route C).
The cyclization was performed with TFA in acetonitrile to obtain
compounds 10. The results are reported in Table 2.
a hydroxylactam. This latter can be readily converted to the
N-acyliminium ion by protonation. The intramolecular cyclization
of this ion onto the indole nucleus gives rise to the final product
(Scheme 5).10
The yields of the cyclization range from good to excellent in the
case of ketones, especially when activating groups are present on
the indole ring. The low yields of ring closure by aldehydes are most
probably due to the lower stability of the intermediates, or to
competitive reactions, such as the easier formation of
intermolecular products.9
The formation of the tetracyclic compound can be explained by
an acid-catalyzed activation of the carbonyl group, which un-
dergoes a nucleophilic attack by the amide nitrogen, to give
Intramolecular N-acyliminium cyclizations of indoles are well-
known, and a large number of examples of their use in the
synthesis of alkaloids have been reported.11 However, almost all of
them involve the cyclization onto the 2-position of indole of a N-
acyliminium ion tethered to position 3. In some cases, attack at
position 3 gave a spirocyclization. The exhaustive survey of Mar-
yanoff et al.11 reports only one case12 where the reaction has been
exploited in the reverse sense, to cyclize onto position 3 a N-acyl-
iminium ion tethered at position 2.

3468
R. Cincinelli et al. / Tetrahedron 65 (2009) 3465–3472
Support to the mechanism proposed for the formation of the
(m, 4H, NHCH2(CH2)2). dC (75 MHz, DMSO-d6) 166.8, 153.4, 150.4,
138.5, 135.5, 123.1, 109.2, 107.6, 98.3, 65.5, 60.9, 60.5, one peak
missing due to the overlapping with solvent signal, 36.3, 35.0, 31.0.
HRMS (ESIþ): [MþNa]þ found 329.1476, C16H22N2NaO4 requires
329.1472.
tetracyclic compounds comes from the restoration of the Friedel–
Crafts product, when the cyclization conditions were applied to
a tertiary amide, which would not give an iminium ion. In fact, with
tertiary amides, azocino[3,4-b]indol-1-ones
9 were obtained
(Scheme 6).
4.2.2. 1-Methyl-1H-indole-2-carboxylic acid (4-hydroxybutyl)-
amide (12c)
3. Conclusion
Yield 74%, mp 99 ꢁC; Rf (20% hexane/ethyl acetate) 0.36; nmax
(KBr): 3600, 3400, 3300, 3050, 2900, 1650, 1540, 1470, 1440, 1390,
In conclusion, the acid-catalyzed intramolecular reaction of in-
dole-2-carboxylic acid secondary oxoamides takes place with two
different mechanisms, depending on the length of the chain be-
tween the amide and the oxo group. One pathway, which follows
1040 cmꢂ1
;
dH (300 MHz, DMSO-d6) 8.47 (t, J¼5.95 Hz, 1H, NH),
7.63 (d, J¼8.6 Hz, 1H, ArH), 7.52 (d, J¼8.6 Hz, 1H, ArH), 7.25 (dd,
J¼8.6, 7.4 Hz, 1H, ArH), 7.08 (dd, J¼8.6, 7.4 Hz, 1H, ArH), 7.04 (s, 1H,
ArH), 4.45 (t, J¼5.2 Hz, 1H, OH), 3.98 (s, 3H, NMe), 3.43 (dt, J¼6.3,
5.2 Hz, 2H, CH2OH), 3.26 (m, 2H, NHCH2), 1.63–1.40 (m, 4H,
NHCH2(CH2)2). dC (75 MHz, DMSO-d6) 161.9, 138.5, 132.7, 125.9,
123.6, 121.7, 120.3, 110.7, 104.2, 60.7, one peak missing due to the
overlapping with solvent signal, 31.5, 30.3, 26.1. HRMS (ESIþ):
[MþNa]þ found 268.1265, C14H18N2NaO2 requires 269.1261.
a Friedel–Crafts mechanism, gives rise to
b-carbolinones and
dihydro-2H-azepino[3,4-b]indol-1-ones; the other one leads to
a tetracyclic pyrrolizino[2,1-b]-indole and homologues with larger
rings via a N-acylium ion. Both pathways represent a simple and
straightforward method for the synthesis of these classes of het-
erocycles. Tertiary amides give only the Friedel–Crafts ring closure,
thus allowing the synthesis of larger rings.
4.2.3. 5,6-Dimethoxy-1-methyl-1H-indole-2-carboxylic acid
(5-hydroxypentyl)-amide (12f)
4. Experimental
4.1. General
Yield 81%, mp 155–157 ꢁC; Rf (30% hexane/ethyl acetate) 0.21;
nmax (KBr) 3600, 3300, 3060, 2900, 1630, 1560, 1470, 1460, 1250,
1210, 1100 cmꢂ1; UV (methanol) lmax nm (log
3) 316 (4.29). dH
All reagents and solvents were reagent grade or were purified by
standard methods before use. Melting points were determined in
open capillaries on a melting point apparatus and are uncorrected.
Column chromatography was carried out on flash silica gel (Merck
230–400 mesh). TLC analysis was conducted on silica gel plates
(Merck 60F254). 1H and 13C NMR spectra were recorded, re-
(300 MHz, DMSO-d6) 8.26 (t, J¼5.5 Hz, 1H, NH), 7.07 (s, 1H, ArH),
7.03 (s, 1H, ArH), 6.93 (s, 1H, ArH), 4.35 (t, J¼5.3 Hz, 1H, OH), 3.94 (s,
3H, OMe), 3.83 (s, 3H, OMe), 3.76 (s, 3H, NMe), 3.44–3.35 (m, 2H,
CH2OH), 3.27–3.15 (m, 2H, NHCH2), 1.61–1.26 (m, 6H,
NHCH2(CH2)3). dC (75 MHz, DMSO-d6) 162.2, 148.8, 145.8, 133.9,
130.9, 118.5, 104.5, 103.0, 93.8, 61.1, 56.2, 56.1, one peak missing due
to the overlapping with solvent signal, 32.7, 31.9, 29.6, 23.5. HRMS
(ESIþ): [MþNa]þ found 343.1633, C17H24N2NaO4 requires 343.1629.
spectively, at 300 MHz and 75 MHz. Chemical shifts (d values) and
coupling constants (J values) are given in parts per million and
hertz, respectively. High-resolution mass spectra were recorded on
an APEX II ICR-FTMS spectrometer using electrospray ionization
(ESI). The IR spectra were measured on a Perkin–Elmer 177 spec-
trophotometer. Solvents were routinely distilled prior to use; an-
hydrous tetrahydrofuran (THF) was obtained by distillation from
sodium-benzophenone ketyl; dry methylene chloride was obtained
by distillation from phosphorus pentoxide; DMF was dried over 4 Å
molecular sieves. All reactions requiring anhydrous conditions
were performed under a positive nitrogen flow, and all glassware
was oven-dried and/or flame dried. The synthesis of compounds
7a–c was performed as described in Ref. 2.
4.2.4. 5,6-Dimethoxy-1-methyl-1H-indole-2-carboxylic acid
(6-hydroxyhexyl)-amide (12h)
Yield 87%, mp 160–161 ꢁC; Rf (20% hexane/ethyl acetate) 0.8;
nmax (KBr) 3350, 3250, 3080, 2850, 1690, 1580, 1480, 1410, 1380,
1230, 930 cmꢂ1; UV (methanol) lmax nm (log
3) 212 (4.48), 316
(4.23). dH (300 MHz, DMSO-d6) 8.27 (t, 1H, J¼5.6 Hz, NH), 7.07
(s, 1H, ArH), 7.02 (s, 1H, ArH), 6.93 (s, 1H, ArH), 4.35 (t, 1H, J¼5.2 Hz,
OH), 3.94 (s, 3H, OMe), 3.83 (s, 3H, OMe), 3.76 (s, 3H, NMe), 3.44–
3.35 (m, 2H, CH2OH), 3.27–3.13 (m, 2H, NHCH2), 1.59–1.23 (m, 8H,
NHCH2(CH2)4). dC (75 MHz, DMSO-d6) 162.1, 148.8, 145.8, 133.8,
130.8, 118.5, 104.4, 103.0, 93.8, 61.0, 56.1 (2C), 32.9, 31.9, 29.7, 26.8,
25.7, one peak missing due to overlapping with solvent signal.
HRMS (ESIþ): [MþNa]þ found 357.1790, C18H26N2NaO4 requires
357.1785.
4.2. General procedure for the synthesis of indole-2-
carboxylic acid hydroxyalkylamides (route A)
The appropriate aminoalcohol (1.59 mmol) was dissolved in dry
THF (5.8 mL), then EDC (1.59 mmol), HOBt (1.59 mmol), and the
appropriate indole-2-carboxylic acid (1.06 mmol) were added se-
quentially at room temperature. After the resulting mixture was
stirred overnight, the solvent was removed and the crude product
was poured into saturated aqueous NaHCO3 (30 mL) and extracted
with ethyl acetate (20ꢀ2 mL). The combined organic layers were
washed with 1 N HCl, saturated aqueous NaHCO3, brine, dried over
Na2SO4, and concentrated in vacuo to give the product.
4.3. General procedure for the oxidation of
hydroxyalkylamides (route A)
To a solution of IBX (1.37 mmol) in DMSO (1.85 mL) was added
the hydroxyalkylamide (0.684 mmol) and the solution was stirred
2 h at room temperature under nitrogen. The solution was diluted
with water (20 mL) and extracted with ethyl acetate (25ꢀ2 mL).
The combined organic layers were washed with saturated aqueous
NaHCO3 (30ꢀ2 mL), water (50 mL), dried over Na2SO4, and evap-
orated. The compounds were purified by crystallization from ethyl
acetate or by flash chromatography (hexane/ethyl acetate).
4.2.1. 5,6-Dimethoxy-1-methyl-1H-indole-2-carboxylic acid
(4-hydroxybutyl)-amide (12b)
Yield 85%, mp 170–171 ꢁC; Rf (20% hexane/ethyl acetate) 0.14;
nmax (KBr) 3600, 3350, 3300, 3050, 2900, 1640, 1560, 1460, 1410,
4.3.1. 5,6-Dimethoxy-1-methyl-1H-indole-2-carboxylic acid
(6-oxohexyl)-amide (8f)
1390, 1250, 1230 cmꢂ1
; dH (300 MHz, DMSO-d6) 8.27 (t, 1H,
J¼5.6 Hz, NH), 7.06 (s, 1H, ArH), 7.02 (s, 1H, ArH), 6.93 (s, 1H, ArH),
4.42 (t, 1H, J¼5.2 Hz, OH), 3.93 (s, 3H, OMe), 3.83 (s, 3H, OMe), 3.75
(s, 3H, NMe), 3.42 (m, 2H, CH2OH), 3.22 (m, 2H, NHCH2), 1.62–1.40
Yield 40%, mp 85 ꢁC; Rf (20% hexane/ethyl acetate) 0.57; nmax
(KBr) 3350, 3080, 2995, 1735, 1680, 1630, 1240 cmꢂ1
;
dH (300 MHz,
acetone-d6) 9.76 (s, 1H, CHO), 7.60 (br s, 1H, NH), 7.06 (s, 1H, ArH),

R. Cincinelli et al. / Tetrahedron 65 (2009) 3465–3472
3469
7.02 (s, 1H, ArH), 6.93 (s, 1H, ArH), 4.02 (s, 3H, OMe), 3.88 (s, 3H,
OMe), 3.80 (s, 3H, NMe), 3.20 (dd, J¼7.1, 5.9 Hz, 2H, NHCH2), 2.52
(t, J¼7.0 Hz, 2H, CH2CHO), 1.80–1.50 (m, 4H, NHCH2(CH2)2). HRMS
(ESIþ): [MþNa]þ found 341.1477, C17H22N2NaO4 requires 341.1472.
nitrogen, for 3 h. The appropriate aminoketone trifluoro-
methanesulfonate13 or hydrochloride14 (0.404 mmol) was added,
followed by N-ethyldiisopropylamine (0.404 mmol). After the
mixture was stirred 1 h at room temperature, the solvent was
evaporated and the crude product was poured into saturated
NaHCO3 (25 mL) and extracted with ethyl acetate (25ꢀ2 mL). The
combined extracts were then washed with 1 N HCl (30 mL), satu-
rated aqueous NaHCO3 (30 mL), dried over Na2SO4, and concen-
trated in vacuo. The crude product was purified by flash
chromatography (hexane/ethyl acetate) to give the product.
4.3.2. 5,6-Dimethoxy-1-methyl-1H-indole-2-carboxylic acid
(6-oxo-hexyl)-amide (8h)
Yield 37%, mp 124–125 ꢁC; Rf (20% hexane/ethyl acetate) 0.53;
nmax (KBr) 3340, 3080, 2990, 1730, 1680, 1630, 1540, 1230 cmꢂ1
; dH
(300 MHz, DMSO-d6) 9.66 (s, 1H, CHO), 8.27 (t, 1H, J¼5.6 Hz, NH),
7.06 (s, 1H, ArH), 7.02 (s, 1H, ArH), 6.92 (s, 1H, ArH), 3.93 (s, 3H,
OMe), 3.83 (s, 3H, OMe), 3.75 (s, 3H, NMe), 3.26–3.15 (m, 2H,
NHCH2), 2.42 (t, 2H, J¼7.07 Hz, CH2CHO), 1.64–1.24 (m, 6H,
NHCH2(CH2)3). dC (75 MHz, DMSO-d6) 203.9, 162.2, 148.8, 145.8,
133.8, 130.8, 118.5, 104.4, 103.0, 93.8, 56.1 (2C), 43.4, 38.8, 31.9, 29.4,
26.4, 21.7. HRMS (ESIþ): [MþNa]þ found 355.1633, C18H24N2NaO4
requires 355.1629.
4.4.1. 5,6-Dimethoxy-1-methyl-1H-indole-2-carboxylic acid
(4-oxopentyl)-amide (8a)
Yield 69%, mp 143–144 ꢁC; Rf (30% hexane/ethyl acetate) 0.23;
nmax (KBr) 3450, 3350, 3080, 2990, 2900, 1720, 1660, 1540, 1470,
1410, 1390, 1260, 1220, 1160, 1110, 1010 cmꢂ1; UV (methanol) lmax
nm (log 3) 212 (4.45), 315 (4.15). dH (300 MHz, DMSO-d6) 8.28 (t,1H,
J¼5.58 Hz, NH), 7.07 (s, 1H, ArH), 7.02 (s, 1H, ArH), 6.94 (s, 1H, ArH),
3.94 (s, 3H, OMe), 3.83 (s, 3H, OMe), 3.76 (s, 3H, NMe), 3.26–3.14
(m, 2H, NHCH2), 2.49 (t, 2H, J¼7.1 Hz, COCH2), 2.09 (s, 3H, COMe),
1.76–1.62 (m, 2H, COCH2CH2). dC (75 MHz, DMSO-d6) 208.5, 162.3,
148.8, 145.8, 133.9, 130.7, 118.5, 104.5, 103.0, 93.7, 56.1 (2C), 38.3,
31.9, 30.2, 23.8, one peak missing due to overlapping with solvent
signal. HRMS (ESIþ): [MþNa]þ found 341.1476, C17H22N2NaO4 re-
quires 341.1472.
4.3.3. 5,6-Dimethoxy-1-methyl-1H-indole carboxylic acid
butyl-(4-oxobutyl)amide (8i)
To a stirred mixture of n-butanol (1.471 g, 20.4 mmol), 4-ami-
nobutanol (2 g, 22.4 mmol), and crushed/dried 4 Å molecular
sieves in methanol (10 mL) at room temperature under nitrogen
was added pyridine-borane complex (1.580 g, 17.0 mmol). After
being stirred overnight, the mixture was filtered and the solvent
evaporated in vacuo. The residue was purified by flash chroma-
tography using CH2Cl2/MeOH/Et3N 90:10:0.5 to give 890 mg (30%)
of 4-butylaminobutan-1-ol (yellow oil); Rf (95% CH2Cl2/MeOH)
0.32; nmax (liquid film) 3320, 2900, 1540, 1480, 1390, 1310,
4.4.2. 1-Methyl-1H-indole-2-carboxylic acid [4-(4-methoxy-
phenyl)-4-oxo-butyl]-amide (8d)
Yield 76%, mp 115 ꢁC; Rf (60% hexane/ethyl acetate) 0.22; nmax
(KBr) 3450, 3340, 3080, 2990, 2900, 1680, 1640, 1540, 1290, 1270,
1080 cmꢂ1
;
dH (300 MHz, CDCl3) 3.95–3.74 (br s, 2H, OHþNH),
3.65–3.53 (m, 2H, CH2OH), 2.80–2.60 (m, 4H, CH2NHCH2), 1.80–1.25
(m, 8H, (CH2)2CH2NHCH2(CH2)2), 0.92 (t, J¼7.1 Hz, 3H, Me). dC
(75 MHz, CDCl3) 62.0, 49.0, 48.7, 31.8, 30.8, 27.5, 20.14, 13.7. HRMS
(ESIþ): [MþNa]þ found 168.1354, C8H19NNaO requires 168.1359.
This compound was reacted as described in the general procedure
to give 5,6-dimethoxy-1-methyl-1H-indole carboxylic acid butyl-
(4-hydroxybutyl)amide, yield 54%, oil; Rf (5% hexane/ethyl acetate)
0.45; nmax (liquid film) 3610, 3450, 3080, 2990, 2900, 1630, 1540,
1180 cmꢂ1
;
dH (300 MHz, DMSO-d6) 8.51 (t, 1H, J¼5.0 Hz, NH), 7.94
(d, 2H, J¼8.3 Hz, 2ArH), 7.61 (d, 1H, J¼7.8 Hz, ArH), 7.50 (d, 1H,
J¼7.8 Hz, ArH), 7.25 (t, 1H, J¼7.8 Hz, ArH), 7.13–6.97 (m, 4H, 4ArH),
3.95 (s, 3H, OMe), 3.82 (s, 3H, NMe), 3.39–3.27 (m, 2H, NHCH2), 3.05
(t, 2H, J¼7.2 Hz, COCH2), 1.96–1.89 (m, 2H, COCH2CH2). dC (75 MHz,
DMSO-d6) 198.4, 163.4, 162.3, 138.7, 132.8, 130.5 (2C), 130.1, 126.0,
123.7, 121.8, 120.4, 114.2 (2C), 110.8, 104.4, 55.9, 38.7, 35.4, 31.6, 24.3.
HRMS (ESIþ): [MþNa]þ found 373.1528, C21H22N2NaO3 requires
373.1523.
1470, 1430, 1390, 1220, 1100 cmꢂ1
; dH (300 MHz, acetone-d6) 7.10
(s,1H, ArH), 7.00 (s,1H, ArH), 6.50 (s,1H, ArH), 3.88 (s, 3HOMe), 3.80
(s, 3H, NMe), 3.72 (s, 3H, NMe), 3.65–3.45 (m, 6H, CH2NCH2þOCH2),
1.80–1.22 (m, 8H, (CH2)2CH2NCH2(CH2)2), 0.89 (t, J¼6.7 Hz, 3H, Me).
dC (75 MHz, acetone-d6) 163.9, 148.6, 145.9, 132.6, 131.7, 119.2, 103.2,
101.6, 93.4, 61.0, 55.6, 55.4, 30.5, 29.7, two peaks missing due to the
overlapping with solvent signal, 28.2, 24.6, 19.8, 13.2. HRMS (ESIþ):
[MþNa]þ found 385.2096, C20H30N2NaO4 requires 385.2098.
Oxidation of 5,6-dimethoxy-1-methyl-1H-indole carboxylic
acid butyl-(4-hydroxybutyl)amide with IBX, as described in the
general procedure, afforded the title compound as a yellow oil,
yield 93%; Rf (5% hexane/ethyl acetate) 0.37; nmax (liquid film) 3080,
4.4.3. 5,6-Dimethoxy-1-methyl-1H-indole-2-carboxylic acid
[4-(4-methoxyphenyl)-4-oxobutyl]-amide (8e)
Yield 43%, mp 182 ꢁC; Rf (20% hexane/ethyl acetate) 0.37; nmax
(KBr) 3340, 3080, 2990, 1680, 1630, 1540, 1270 cmꢂ1
; dH (300 MHz,
DMSO-d6) 8.34 (t, 1H, J¼5.6 Hz, NH), 7.95 (d, 2H, J¼8.9 Hz, ArH),
7.07 (s, 1H, ArH), 7.04 (d, 2H, J¼8.9 Hz, 2ArH), 7.03 (s, 1H, ArH), 6.95
(s, 1H, ArH), 3.92 (s, 3H, OMe), 3.83 (s, 3H, OMe), 3.76 (s, 3H, OMe),
3.32–3.25 (m, 2H, NCH2), 3.04 (t, 2H, J¼7.1 Hz, COCH2), 1.90–1.82
(m, 2H, COCH2CH2). dC (75 MHz, DMSO-d6) 163.4, 162.3, 156.7,
148.8, 145.8, 133.9, 133.9, 131.7, 130.5, 128.5, 127.4, 118.5, 114.2,
104.6, 103.0, 93.8, 56.1 (2C), 55.9, 55.8, 38.6, 35.4, 31.9, 24.4. HRMS
(ESIþ): [MþNa]þ found 433.1738, C23H26N2NaO5 requires 433.1734.
2990, 1730, 1660, 1630, 1540, 1270 cmꢂ1
; dH (300 MHz, CDCl3) 9.80
(s, 1H, CHO), 7.05 (s, 1H, ArH), 6.77 (s, 1H, ArH), 6.49 (s, 1H, ArH),
3.89 (s, 3H, OMe), 3.83 (s, 3H, OMe), 3.78 (s, 3H, NMe), 3.60–3.46
(m, 4H, CH2NCH2), 2.60–2.41 (m, 2H, CH2CHO), 2.04–1.25 (m, 8H,
(CH2)2CH2NCH2(CH2)2), 0.90 (t, J¼6.75 Hz, 3H, Me). dC (75 MHz,
CDCl3) 202.3, 162.3, 149.0, 145.7, 134.2, 130.9, 118.7, 104.6, 103.2,
94.2, 56.2, 56.1, 47.5 (2C), 42.5, 33.9, 31.8, 21.6, 20.5, 14.2. HRMS
(ESIþ): [MþNa]þ found 383.1947, C20H28N2NaO4 requires 383.1942.
4.4.4. 1H-Indole-2-carboxylic acid butyl-[4-(4-methoxy-
phenyl)-4-oxo-butyl]-amide (8l)
Trifluoromethanesulfonic acid (4 mL) was ice-cooled and 4-
(methylamino)butyric acid hydrochloride (1.62 g, 10.53 mmol) and
anisole (1 g, 9.25 mmol) were added. The mixture was heated and
stirred at 80 ꢁC for 50 min. The mixture was cooled to room tem-
perature, water (16 mL) was added under ice-cooling and the
aqueous phase was extracted with ethyl acetate (25 mL). The or-
ganic phase was dried over Na2SO4, filtered, and concentrated in
vacuo to give 1-(4-methoxyphenyl)-4-methylaminobutan-1-one
trifluoromethanesulfonate as a sticky solid (2.49 g, 79%); nmax (film)
4.4. General procedure for the synthesis of indole-2-
carboxylic acid oxoamides by condensation with
the appropriate aminoketone (route B)
To a suspension of the appropriate carboxylic acid (0.20 mmol)
in dry THF (1.09 mL) were added EDC (0.30 mmol) and HOBt
(0.30 mmol). The mixture was stirred at room temperature, under
2800,1680,1630,1230 cmꢂ1
; dH (300 MHz, DMSO-d6) 8.45 (br s, 2H,
NHþ2 ), 7.95 (d, J¼8.6 Hz, 2H, 2ArH), 7.06 (d, J¼8.6 Hz, 2H, 2ArH), 3.85

3470
R. Cincinelli et al. / Tetrahedron 65 (2009) 3465–3472
(s, 3H, OMe), 3.12 (s, 3H, NMe), 3.12 (t, J¼7.06 Hz, 2H, NCH2), 2.94 (t,
J¼7.6 Hz, 2H, COCH2), 1.98–1.84 (m, 2H, NCH2CH2). This compound
was reacted as described in the general procedure (route B) to give
the title compound: yield 72%, mp 125 ꢁC; Rf (30% hexane/ethyl
mixture was refluxed until the starting material disappeared (TLC).
The solvent was evaporated and the crude product was purified by
flash column or preparative layer chromatography (hexane/ethyl
acetate).
acetate) 0.17; nmax (KBr) 3080, 2990,1680,1640,1530,1230 cmꢂ1
; dH
(300 MHz, acetone-d6) 7.97 (m, 2H, 2ArH), 7.59 (d, J¼8.0 Hz, 1H,
ArH), 7.43 (d, J¼8.4 Hz, 1H, ArH), 7.25 (dd, J¼8.0, 8.2 Hz, 1H, ArH),
7.14–6.95 (m, 4H, 4ArH), 6.66 (s, 1H, ArH), 3.89 (s, 3H, OMe), 3.78 (s,
3H, NMe), 3.67 (t, J¼7.2 Hz, 2H, NCH2), 3.20 (s, 3H, NMe), 3.19 (m, 2H,
COCH2), 2.05 (m, 2H, COCH2CH2). dC (75 MHz, acetone-d6) 197.2,
163.3, 137.4, 132.9, 129.9 (2C), 126.5, 122.7, 122.3, 121.1, 120.9, 119.8,
119.4, 113.7, 113.2, 109.5, 54.8, 34.5, 30.1, two peaks missing due to
the overlapping with signal solvent, 21.5. HRMS (ESIþ): [MþNa]þ
found 387.1685, C22H24N2NaO3 requires 387.1680.
4.6.1. 2-Butyl-8,9-dimethoxy-11-methyl-2,3,4,6a,11,11a-
hexahydroazocino[3,4-b]indol-1-one (9a)
Yield 10%, yellow oil, Rf (95% ethyl acetate/hexane) 0.27; nmax
(liquid film) 3080, 2900, 1660, 1460, 1430, 1380, 1260 cmꢂ1
; dH
(300 MHz, acetone-d6) 7.08 (s, 1H, ArH), 7.02 (s, 1H, ArH), 6.57
(dt, J¼12.6, 2.1 Hz, 1H, CH]), 5.71 (dt, J¼12.6, 4.2 Hz, 1H, CH]),
3.90 (s, 3H, OMe), 3.85 (s, 3H, OMe), 3.79 (s, 3H, NMe), 3.22–3.00
(m, 4H, NCH2þNCH2CH2), 2.78–2.50 (m, 2H, NCH2), 1.80–1.61 (m,
2H, CH2CH2CH3), 1.52–1.34 (m, 2H, CH2CH3), 0.98 (t, J¼7.44 Hz, 3H,
Me). dC (75 MHz, acetone-d6) 166.1, 149.8, 146.1, 133.8, 129.6, 125.7,
117.7, 117.0, 101.8, 101.1, 97.3, 56.5, 56.4, 47.7, 47.6, 34.5, 32.1, 26.3,
20.4, 13.6. HRMS (ESIþ): [MþNa]þ found 365.1832, C20H26N2NaO3
requires 365.1836.
4.5. Synthesis of indole-2-carboxylic acid oxoamides by
Grignard reaction on N-acyllactams (route C)
4.5.1. 1-(1-Methyl-1H-indole-2-carbonyl)-piperidin-2-one (14)
To a solution of n-BuLi (0.6 mL, 1.6 mmol, 2.7 M in heptane) at
4.6.2. 6-(4-Methoxyphenyl)-2,11-dimethyl-2,3,4,6a,11,11a-
hexahydroazocino[3,4-b]indol-1-one (9b)
ꢂ78 ꢁC was added a solution of
d-valerolactam (139 mg, 1.4 mmol)
in THF (4 mL). After 20 min at ꢂ78 ꢁC, 1-methyl-1H-indole-2-car-
bonyl chloride15 (271 mg, 1.4 mmol) was added and the solution
was slowly warmed to room temperature and stirred for 48 h. The
reaction was then quenched with aq NH4Cl (10 mL) and extracted
with ethyl acetate (10ꢀ2 mL). The organic phase was washed with
satd aq NaHCO3 (20 mL), dried over Na2SO4, filtered, and concen-
trated under reduced pressure to give 14 (127 mg, 35%) as a brown
oil. Yield 35%; Rf (20% hexane/ethyl acetate) 0.52; nmax (liquid film)
3300, 2900, 2800, 1680, 1520, 1470, 1390, 1270, 1220, 1190, 1150,
Yield 21%, mp 85 ꢁC; Rf (60% ethyl aceatate/hexane) 0.23; nmax
(KBr) 3080, 2995, 1690, 1620, 1570, 1520, 1470, 1260 cmꢂ1
; dH
(300 MHz, CDCl3) 7.32 (d, J¼8.4 Hz,1H, ArH), 7.22–7.14 (m,1H, ArH),
7.10 (d, J¼8.6 Hz, 2H, 2ArH), 6.90–6.81 (m, 1H, ArH), 6.73 (d,
J¼8.6 Hz, 2H, 2ArH), 5.89 (dd, J¼6.3, 2.8 Hz, 1H, CH]), 4.33 (dt,
J¼13.9, 2.8 Hz, 1H, NCH2CHaCHb), 3.87 (s, 3H, OMe), 3.76 (s, 3H,
NMe), 3.18 (s, 3H, NMe), 3.14–3.03 (m, 1H, NCH2CHaCHb), 2.98–2.79
(m, 1H, NCHaCHb), 2.61–2.48 (m, 1H, NCHaCHb). dC (75 MHz, CDCl3)
163.8, 159.8, 148.3, 140.5, 140.1, 132.1, 125.2 (3C), 122.1, 121.5, 121.1
(2C), 116.3, 114.2 (2C), 110.3, 56.0, 50.2, 34.3, 33.0, 25.2. HRMS
(ESIþ): [MþNa]þ found 369.1571, C22H22N2NaO2 requires 369.1574.
980 cmꢂ1
;
dH (300 MHz, CDCl3) 7.60 (d, 1H, J¼7.5 Hz, ArH), 7.42–
7.30 (m, 2H, 2ArH), 7.15–7.05 (m, 1H, ArH), 6.85 (s, 1H, ArH), 3.95 (s,
3H, NMe), 3.82–3.70 (m, 2H, NCH2), 2.70–2.55 (m, 2H, COCH2),
2.02–1.90 (m, 4H, NCH2(CH2)2). dC (75 MHz, CDCl3) 174.0, 163.2,
139.4, 138.8, 134.0, 125.6, 123.6, 120.5, 110.8, 107.4, 46.1, 34.3, 31.7,
31.2, 22.2. HRMS (ESIþ): [MþNa]þ found 279.1108, C15H16N2NaO2
requires 279.1104.
4.6.3. 3a-Methyl-5,6-dimethoxy-1,2,3,3a,9,9a-
hexahydropyrrolizino[1,2-b]indol-9-one (10a)
Yield 76%, mp 152–153 ꢁC; Rf (20% hexane/ethyl acetate) 0.42;
nmax (KBr) 3000, 2930, 1680, 1560, 1510, 1480, 1430, 1340, 1280,
1220, 1040 cmꢂ1; UV (methanol) lmax nm (log
3) 321 (4.38); dH
4.5.2. 1-Methyl-1H-indole-2-carboxylic acid (6-oxohexyl)-
amide (8g)
(300 MHz, DMSO-d6) 7.19 (s, 1H, ArH), 7.10 (s, 1H, ArH), 3.85 (s, 3H,
OMe), 3.81 (s, 3H, NMe), 3.80 (s, 3H, OMe), 3.48–3.20 (m, 2H, NCH2–
), 2.38–2.25 (m, 2H, NCH2CH2), 2.12–1.40 (m, 2H, NCH2CH2CH2),
1.54 (s, 3H, Me). dC (75 MHz, DMSO-d6) 166.1, 149.2, 145.8, 137.8,
136.3, 130.9, 113.5, 101.9, 94.7, 67.0, 56.3, 56.2, 41.5, 35.0, 30.2, 28.8,
24.0. HRMS (ESIþ): [MþNa]þ found 323.1366, C17H20O3N2Na re-
quires 323.1363; [2MþNa]þ found 623.2838, C34H40O6N4Na re-
quires 623.2840; [3MþNa]þ found 923.4332, C51H60O9N6Na
requires 923.4314.
In a three-necked round bottomed flask equipped with an
nitrogen inlet and
a thermometer, compound 14 (100 mg,
0.390 mmol) was dissolved in dry THF (1.37 mL). To this solution
cooled at ꢂ78 ꢁC was added dropwise CH3MgI (0.546 mL of a 1 M
solution in isoamyl ether, 0.546 mmol). The mixture was warmed
to room temperature and 2 M HCl was added until pH was 1–3. The
organic phase was extracted with diethyl ether (15ꢀ2 mL), dried
over Na2SO4, and concentrated in vacuo. The product 8g was iso-
lated by flash chromatography eluting with hexane/ethyl acetate
65:35 (14 mg, 14%, yellow oil); Rf (40% hexane/ethyl acetate) 0.32;
nmax (liquid film) 3350, 3080, 2990, 1710, 1650, 1530, 1470, 1230,
4.6.4. 5,6-Dimethoxy-1,2,3,3a,9,9a-hexahydropyrrolizino-
[1,2-b]indol-9-one (10b)
Under a stream of nitrogen, 2-iodoxybenzoic acid (298 mg,
1.1 mmol) was dissolved in DMSO (1.55 mL), and then the alcohol
12b (168 mg, 0.55 mmol) was added. The mixture was stirred at
room temperature for 4 h. Water (10 mL) was added and the
product was extracted with ethyl acetate (10ꢀ2 mL). The organic
phase was washed with water (20 mL), dried over Na2SO4, and
concentrated in vacuo. The crude aldehyde 8b (150 mg) was dis-
1100 cmꢂ1
; dH (300 MHz, acetone-d6) 7.76 (br s, 1H, CONH), 7.59
(d, J¼8.0 Hz, 1H, ArH), 7.48 (d, J¼8.4 Hz, 1H, ArH), 7.28 (dd, J¼8.0,
8.2 Hz, 1H, ArH), 7.09 (dd, J¼8.2, 8.4 Hz, 1H, ArH), 7.04 (s, 1H, ArH),
4.06 (s, 3H, NMe), 3.40 (m, 2H, NHCH2), 2.53 (t, J¼7.1 Hz, 2H,
COCH2), 2.10 (s, 3H, COMe), 1.70–1.50 (m, 4H, COCH2(CH2)2). dC
(75 MHz, acetone-d6) 207.3, 162.1, 138.8, 126.3, 123.4, 121.4, 120.0,
110.0, 103.5, 42.3, 38.6, 38.5, 30.73, one peak missing due to the
overlapping with solvent signal, 20.8. HRMS (ESIþ): [MþNa]þ found
295.1422, C16H20N2NaO2 requires 295.1417.
solved in 2.5 mL of CH3CN, and then TFA (56 mL, 0.73 mmol) was
added. The solution was refluxed for 1 h. The solid formed was
filtered and dried under vacuum to give 16 mg of the desired
product. Yield 10%, mp >300 ꢁC; Rf (20% hexane/ethyl acetate) 0.45;
nmax (KBr) 3080, 2800, 1650, 1460, 1430, 1380, 1340, 1260,
4.6. General procedure for the cyclization of
indole-2-carboxylic acid oxoamides
900 cmꢂ1
; dH (300 MHz, TFA) 7.60 (s, 1H, ArH), 7.44 (s, 1H, ArH),
6.43 (d, J¼8.0 Hz,1H, NCH), 4.47 (s, 3H, OMe), 4.46 (s, 3H, OMe), 4.17
(s, 3H, NMe), 4.11–4.06 (m, 1H, NCHaCHb), 3.91–3.85 (m, 1H,
NCHaCHb), 3.02–2.95 (m, 1H, NCH2CHaCHb), 2.81–2.76 (m, 1H,
Trifluoroacetic acid (0.258 mmol) was added to a solution of the
appropriate oxoalkylamide (0.172 mmol) in CH3CN (3.2 mL) and the

R. Cincinelli et al. / Tetrahedron 65 (2009) 3465–3472
3471
NCH2CHaCHb), 2.64–2.56 (m, 1H, NCH2CH2CHaCHb), 2.45–2.39 (m,
1H, NCH2CH2CHaCHb). dC (75 MHz, TFA) 169.9, 151.9, 147.8, 137.5,
135.4, 128.1, 115.1, 104.6, 95.7, 62.6, 58.5, 57.5, 52.7, 34.8, 31.7, 23.8.
HRMS (ESIþ): [MþNa]þ found 309.1207, C16H18O3N2Na requires
309.1210.
extracted with ethyl acetate. The organic phase was washed twice
with water, dried over Na2SO4, and concentrated in vacuo. To give
a crude product (115 mg), that was dissolved in 6.6 mL of CH3CN,
then TFA (42 mL, 0.542 mmol) was added. The solution was refluxed
for 5 h. The solvent was evaporated in vacuo and the crude product
was purified by flash chromatography (hexane/ethyl acetate 20:80)
to give 22 mg (20%) of 10f as a yellow solid. Mp 162–163 ꢁC; Rf (20%
hexane/ethyl acetate) 0.47; nmax (KBr) 3080, 2850, 1650, 1465, 1430,
4.6.5. 8-Methylpyrrolizino[2,1-b]indol-9-one (10c)
Under a stream of nitrogen, 2-iodoxybenzoic acid (145 mg,
0.536 mmol) was dissolved in DMSO, and then alcohol 12c (66 mg,
0.268 mmol) was added. The mixture was stirred at room tem-
perature for 1 h. Water was added and the product was extracted
with ethyl acetate. The organic phase was washed with water, dried
over Na2SO4, and concentrated in vacuo. The crude aldehyde 8c
1380, 1320, 1250 cmꢂ1
; dH (300 MHz, DMSO-d6) 7.18 (s, 1H, ArH),
7.11 (s, 1H, ArH), 4.33 (dd, J¼3.8, 12.0 Hz, 1H, NCH), 4.16 (dd, J¼13.0,
5.0 Hz, 1H, NCHaCHb), 3.86 (s, 3H, OMe), 3.85 (s, 3H, OMe), 3.78
(s, 3H, NMe), 2.96 (td, J¼13.0, 13.0, 3.6 Hz, 1H, NCHaCHb), 2.60–2.56
(m,1H, NCH2CHaCHb),1.89–1.85 (m,1H, NCH2CHaCHb),1.79–172 (m,
1H, NCH2CH2CHaCHb), 1.65–1.59 (m, 1H, NCH2CH2CHaCHb), 1.23–
1.29 (m, 1H, N(CH2)3CHaCHb), 0.90–1.09 (m, 1H, N(CH2)3CHaCHb). dC
(75 MHz, DMSO-d6) 159.3, 148.1, 145.0, 136.5, 131.9, 128.1, 113.2,
101.5, 55.7, 55.5, 54.4, 38.9, 32.2, 29.6, 25.5, 22.6. HRMS (ESIþ):
[MþNa]þ found 323.1363, C17H20O3N2Na requires 323.1366;
[2MþNa]þ found 623.2838, C34H40O6N4Na requires 623.2840;
[3MþNa]þ found 923.4326, C51H60O9N6Na requires 923.4314.
(55 mg) was dissolved in 1.6 mL of CH3CN, and then TFA (36 mL,
0.47 mmol) was added. The solution was refluxed for1 h. The solid
formed was filtered and dried under vacuum to give 8 mg of the
desired product. Yield 10%, mp >300 ꢁC; Rf (10% hexane/ethyl ac-
etate) 0.55; nmax (KBr) 3060, 2980, 1650, 1460, 1430, 1400,
920 cmꢂ1
;
dH (300 MHz, TFA) 8.03 (d, J¼7.8 Hz, 1H, ArH), 7.83–7.-75
(m, 2H, 2ArH), 7.69–7.-60 (m, 1H, ArH), 6.49 (d, J¼5.2 Hz, 1H, NCH),
4.20 (s, 3H, NMe), 4.10–4.05 (m, 1H, NCHaCHb), 3.95–3.83 (m, 1H,
NCHaCHb), 3.08–2.90 (m, 1H, NCH2CHaCHb), 2.86–2.76 (m, 1H,
NCH2CHaCHb), 2.70–2.51 (m, 1H, NCH2CH2CHaCHb), 2.47–2.34 (m,
1H NCH2CH2CHaCHb). HRMS (ESIþ): [MþH]þ found 227.1181,
C14H15N2O requires 227.1186; [2MþH]þ found 453.2284,
C28H29N4O2 requires 453.2281; [2MþNa]þ found 475.2104,
C28H28N4NaO2 requires 475.2110; [4MþH]þ found 905.4463,
C56H57N8O4 requires 905.4483; [4MþNa]þ found 927.4302,
C56H56N8NaO4 requires 927.4284.
4.6.9. 4a-Methyl-1,2,3,4,4a,4b,4c-hexahydro-9H-indolizino-
[1,2-b]indol-10-one (10g)
Yield 57%, mp 118 ꢁC; Rf (50% hexane/ethyl acetate) 0.41; nmax
(KBr) 3050, 2900, 1680, 1460, 1430, 1380 cmꢂ1
; dH (300 MHz, ace-
tone-d6) 7.72 (d, J¼8.4 Hz, 1H, ArH), 7.54 (d, J¼8.4 Hz, 1H, ArH), 7.33
(dd, J¼8.0, 8.4 Hz,1H, ArH), 7.16 (dd, J¼8.0, 8.4 Hz,1H, ArH), 4.25 (m,
1H, NCHaCHb), 3.97 (s, 3H, NMe), 2.99 (m,1H, NCHaCHb), 2.39 (m,1H,
NCH2CHaCHb), 1.80–1.67 (m, 2H, NCH2CHaCHbþNCH2CH2CHaCHb),
1.59 (s, 3H, Me), 1.43–1.21 (m, 3H, NCH2CH2CHaCHbþN(CH2)3CH2).
dC (75 MHz, acetone-d6) 165.4,143.4,141.8,135.4,123.3,120.9,119.8,
119.6,110.8, 57.9, 36.9, 35.9, one peak missing due to the overlapping
with solvent signal, 25.9, 20.4, 19.7. HRMS (ESIþ): [MþNa]þ found
277.1309, C16H18N2NaO requires 277.1312.
4.6.6. 4-Methoxyphenyl-1,2,3,3a,9,9a-hexahydropyrrolizino-
[1,2-b]indol-9-one (10d)
Yield 75%, mp 130 ꢁC; Rf (65% hexane/ethyl acetate) 0.41; nmax
(KBr) 3080, 2995, 1700, 1620, 1570, 1520, 1470, 1340, 1260, 1190,
1050, 905, 840 cmꢂ1; UV (methanol) lmax nm (log
3) 230 (4.52), 302
(4.17); dH (300 MHz, CDCl3) 7.65 (d, 1H, J¼7.8 Hz, ArH), 7.56 (d, 2H,
J¼8.6 Hz, 2ArH), 7.41–7.25 (m, 2H, 2ArH), 7.14 (t, 1H, J¼7.8 Hz, ArH),
6.90 (d, 2H, J¼8.6 Hz, ArH), 3.96 (s, 3H, OMe), 3.88–3.73 (m, 4H,
OMeþNCHaCHb), 3.46–3.34 (m, 1H, NCHaCHb), 2.84–2.72 (m, 1H,
NCH2CHaCHb), 2.45–2.30 (m, 1H, NCH2CHaCHb), 2.24–2.07 (m, 1H,
NCH2CH2CHaCHb), 1.86–1.70 (m, 1H, NCH2CH2CHaCHb). dC (75 MHz,
CDCl3) 166.7, 158.8, 142.48, 135.3, 132.9, 126.3 (3C), 124.2, 120.7,
120.3, 120.0, 114.1 (2C), 110.9, 73.0, 55.2, 41.2, 36.2, 29.9, 28.7. HRMS
(ESIþ): [MþNa]þ found 355.1410, C21H20N2NaO2 requires 355.1417.
4.6.10. 2,3-Dimethoxy-11-methyl-4c,6,7,8,9,11-hexahydro-5H-
9a,11-diaza-indeno[1,2-a]azulen-10-one (10h)
Yield 40%, mp 156–157 ꢁC; Rf (30% hexane/ethyl acetate) 0.28;
nmax (KBr) 3060, 2980, 1660, 1460, 1420, 1380, 1350, 1260 cmꢂ1
; dH
(300 MHz, DMSO-d6) 7.15 (s, 1H, ArH), 7.10 (s, 1H, ArH), 4.67 (t, 1H,
J¼5.2 Hz, NCH), 3.84 (s, 6H, 2 OMe), 3.78 (s, 3H, NMe), 3.73–3.65 (m,
1H, NCHaCHb), 3.35–3.20 (m, 1H, NCHaCHb), 2.40–2.24 (m, 1H,
NCH2CHaCHb), 1.84–1.40 (m, 6H, NCH2CHaCHbþN(CH2)2CH2CH2
þN(CH2)4CHaCHb), 1.39–1.19 (m, 1H, N(CH2)4CHaCHb). dC (75 MHz,
DMSO-d6) 162.6, 148.7, 145.7, 137.5, 132.7, 128.9, 113.9, 101.7, 94.8,
57.3, 56.2, 56.1, 43.5, 33.7, 30.3, 29.2, 27.1. HRMS (ESIþ): [MþNa]þ
found 337.1519, C18H22O3N2Na requires 337.1522; [2MþNa]þ found
651.3146, C36H44O6N4Na requires 651.3153; [3MþNa]þ found
965.4765, C54H66O9N6Na requires 965.4783.
4.6.7. 4-Methoxyphenyl-5,6-dimethoxy-1,2,3,3a,9,9a-
hexahydropyrrolizino[1,2-b]indol-9-one (10e)
Yield 93%, mp 88 ꢁC; Rf (35% hexane/ethyl acetate) 0.33; nmax
(KBr) 3050, 2930, 1685, 1510, 1470, 1430, 1320, 1240, 1030,
900 cmꢂ1
;
dH (300 MHz, DMSO-d6) 7.59 (d, 2H, J¼8.93 Hz, 2ArH),
7.11 (s,1H, ArH), 7.07 (s,1H, ArH), 6.91 (d, 2H, J¼8.9 Hz, ArH), 3.82 (s,
3H, OMe), 3.81 (s, 3H, OMe), 3.77 (s, 3H, OMe), 3.71 (s, 3H, NMe),
3.65–3.51 (m,1H, NCHaCHb), 3.27–3.15 (m,1H, NCHaCHb), 2.83–2.69
(m, 1H, NCH2CHaCHb), 2.36–2.21 (m, 1H, NCH2CHaCHb), 1.98–1.79
(m, 1H, NCH2CH2CHaCHb), 1.71–1.56 (m, 1H, NCH2CH2CHaCHb). dC
(75 MHz, DMSO-d6) 166.2, 158.5, 149.2, 145.8, 137.8, 136.0, 133.7,
130.0, 126.7 (2C), 114.3 (2C), 113.27, 102.0, 94.7, 72.7, 56.4, 56.1, 55.4,
41.6, 36.4, 30.3, 28.8. HRMS (ESIþ): [MþNa]þ found 415.1625,
C23H24N2NaO4 requires 415.1629.
Acknowledgements
This work was supported by the University of Milano (FIRST
funds).
References and notes
1. Cincinelli, R.; Dallavalle, S.; Merlini, L. Synlett 2008, 1309–1312.
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cinardi, T.; Martinelli, A.; Penco, S.; Zunino, F. J. Med. Chem. 2008, 51, 7777–7787.
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D.; Beller, M.; Tse, M. K. J. Org. Chem. 2007, 72, 8847–8858.
4.6.8. 6,7-Dimethoxy-1,2,3,4,4a,9,10,10a-octahydro-9H-
indolizino[1,2-b]indol-10-one (10f)
4. Chacun-Lefe`vre, L.; Joseph, B.; Me´rour, J.-Y. Tetrahedron 2000, 56, 4491–4499.
´
5. Montagne, C.; Laurent, N.; Joseph, B.; Merour, J.-Y. J. Heterocycl. Chem. 2005, 42,
1433–1441.
Under a stream of nitrogen, 2-iodoxybenzoic acid (330 mg,
1.22 mmol) was dissolved in DMSO (1.7 mL), and then alcohol 12f
(196 mg, 0.61 mmol) was added. The mixture was stirred at room
temperature for 4 h. Water was added and the product was
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R. Cincinelli et al. / Tetrahedron 65 (2009) 3465–3472
10. A referee (whom we thank) has suggested an alternative mechanism, i.e., that
the Friedel–Crafts might take place first, followed by the transannular attack of
the poorly nucleophilic amide nitrogen onto the alcohol (or its protonated
state) to give 10.
11. Maryanoff, B. E.; Zhang, H. C.; Cohen, J. H.; Turchi, I. J.; Maryanoff, C. A. Chem.
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9. From the reaction of 8i, the bis-indole 15, apparently deriving from both intra
and intermolecular reaction of the aldehyde with two indole nuclei, was
isolated in a 10% yield.
OCH3
OCH3
H3C
OHC
N
15
N
C
O
H3CO
N
H3CO
N
O
CH3