Application of 7-endo-trig Pictet-Spengler cyclization to the formation of the benzazepine ring: Synthesis of benzazepinoindoles

Article abstract of DOI:10.1002/ejoc.200801201

The preparation of benzazepinoindoles, fused heterocycles with a benzazepine moiety, was accomplished through an intramolecular 7-endo-tring Pictet-Spengler cyclization. The precursors comprising C-3- or C-2-linked o-aminobenzyl-indoles required for the c

Full text of DOI:10.1002/ejoc.200801201

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200801201
Application of 7-endo-trig Pictet–Spengler Cyclization to the Formation of the
Benzazepine Ring: Synthesis of Benzazepinoindoles[‡]
Sudhir K. Sharma,[a] Sunil Sharma,[a] Piyush K. Agarwal,[a] and Bijoy Kundu*[a]
Keywords: Fused-ring systems / Nitrogen heterocycles / Cyclization / Polycycles
The preparation of benzazepinoindoles, fused heterocycles
with a benzazepine moiety, was accomplished through an in-
tramolecular 7-endo-trig Pictet–Spengler cyclization. The
precursors comprising C-3- or C-2-linked o-aminobenzyl-
indoles required for the cyclization were obtained either by
treating indoles with o-nitrobenzyl bromide followed by re-
duction of the nitro group or by treating 2-nitrophenylacetic
acid with DCC/DMAP followed by reduction of the aryl nitro
functionality. Resulting substrates 5 and 6 were then sub-
jected to the 7-endo-trig Pictet–Spengler reaction with a vari-
ety of aldehydes and ketones to furnish new polycyclic struc-
tures benzazepinoindoles.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
Introduction
The azepinoindole template has been found to be present
in the marine sponge metabolite hymenialdisine[1] (1) and in
paullone[2] (2), a synthetic benzazepinoindolone undergoing
clinical trials[3] as an anticancer agent. Both compounds
were found to be a potent kinase inhibitor of several related
cyclin-dependent kinases (CDKs),[4] and hymenialdisine
also exhibits potent antiproliferative, antineurodegenerative,
and anti-inflammatory activities in various cell lines and
animal models (Figure 1).[5]
Recently, we reported a straightforward and easy syn-
thetic route for annulated quinolines and quinoxalines
by using a 6-endo-trig cyclization following our modified
Pictet–Spengler strategy.[6] The methodology involved con-
densation of carbonyl-containing compounds to arylamine
substrates linked to an activated heterocycle, which pro-
ceeded through the intramolecular attack of a π nucleo-
philic carbon atom from the activated heterocycle onto the
carbon atom of the iminium ion. In contrast, examples for
the formation of the corresponding seven-membered ring
Figure 1. Polycyclic structures based on the azepinoindole tem-
plate.
through
a 7-endo-trig Pictet–Spengler cyclization are
Results and Discussion
scarce,[7] probably because generation of such rings still re-
mains a challenge in organic synthesis.[8] In this paper, we
wish to apply a 7-endo-trig cyclization based on our modi-
fied Pictet–Spengler methodology for the synthesis of
benzazepinoindoles 3 and 4 and some derivatives thereof
hitherto not reported in the literature.
Our synthetic strategy involved regioselective linkage of
a benzylamine moiety to either the 2- or 3-position of the
indole followed by the 7-endo-trig Pictet–Spengler cycliza-
tion with various carbonyl compounds (Scheme 1).
Thus, the key step in our strategy involves synthesis of
substrates 5 and 6, in which a benzylamine moiety is at-
tached to C-3 and C-2 of the indole ring, respectively
(Scheme 2). Synthesis of substrate 5a,b was carried out by
treating indole with 2-nitrobenzyl bromide in the presence
of Na2CO3 by using a modified procedure published in the
literature.[9] Resulting nitro intermediates 7a,b were then re-
duced with Fe/HCl to give corresponding substrates 5a,b.
[‡] CDRI Communication No. 7688
[a] Medicinal Chemistry Division, Central Drug Research Insti-
tute,
Lucknow 226001, India
Fax: +91-522-2623405
E-mail: bijoy_kundu@yahoo.com
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Eur. J. Org. Chem. 2009, 1309–1312
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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S. K. Sharma, S. Sharma, P. K. Agarwal, B. Kundu
SHORT COMMUNICATION
Scheme 1. Retrosynthetic route for benzazepinoindoles 3 and 4 by
the 7-endo-trig Pictet–Spengler cyclization involving arylamine sub-
strates 5 and 6 as precursors.
Synthesis of substrate 6 was carried out in two steps from
2-nitrophenyl acetic acid by a protocol published in the lit-
erature.[10] Once we had substrates 5 and 6, we next investi-
gated their abilities to undergo 7-endo-trig Pictet–Spengler
cyclizations with structurally diverse aldehydes and ketones.
For the Pictet–Spengler cyclization (Scheme 2), substrate 5a
(X = H) was initially treated with 4-chlorobenzaldehyde un-
der the traditional Pictet–Spengler protocols involving 2%
TFA in DCM at both 0 °C and at room temperature. Inter-
estingly, 7-endo-trig cyclization resulting in benzazepino-
indole 3a occurred under both sets of conditions, but the
best results were obtained in 2% TFA in DCM at room
temperature; the reaction was complete in 45 min (Table 1).
The crude product obtained after workup was purified
by silica-gel column chromatography with the use of
EtOAc/hexane as the eluent; it was isolated in 79% yield.
The scope and limitation of our strategy with substrates
5a,b was established by synthesizing benzazepinoindoles
3b–l; a variety of aldehydes and ketones were tolerated
(Table 2). For the Pictet–Spengler cyclization, 2% TFA/
DCM at room temperature was used and for the condensa-
tion involving aldehydes, in general, the cyclization was
found to be complete within 45 min. On the contrary, con-
densation with ketones was found to be sluggish (10–30 h)
and afforded products in 20–72% yields (Table 2). Alde-
hydes with electron-donating groups had no adverse effect
on the rate of cyclization. This is in contrast to the typical
Pictet–Spengler reaction, where aldehydes with electron-
withdrawing groups had favorable affects on endo cycliza-
tion, whereas aldehydes with electron-donating substituents
failed to undergo π-cyclization.[11] After successfully estab-
lishing the Pictet–Spengler reaction on substrates 5a,b, we
shifted our attention to substrate 6. The substrate was ini-
tially treated with salicyldehyde with the use of 2% TFA/
DCM at room temperature. The progress of the reaction
was monitored by TLC and HPLC. As expected, cyclization
of substrate 6 to afford 4a was found to be complete within
Scheme 2. Synthesis of compounds 3 and 4. Reagents and condi-
tions: (i) Na2CO3, acetone/water (4:1), 70 °C, 36 h; (ii) Fe, HCl/
EtOH (1:4), 100 °C, 1.5 h (iii) DCC/DMAP, dry THF, r.t., 3 h (iv)
Fe–CH3COOH/C2H5OH (1:1), 3 h; (v) R1R2CO, 2% TFA in
DCM, r.t.
Table 1. Optimization of the reaction conditions for conversion of
substrate 5a into 3a.
Entry Reaction conditions
T [°C]
Time [h]
Yield of 3a [%][a]
1
2
3
4
5
2% TFA in DCM
2% MSA/CH3CN
2% TFA in CH3CN
2% TFA in DCM
Yb(OTf)3 in DCM
0
12
2
2
0.75
8
45
51
55
79
42
r.t.
r.t.
r.t.
r.t.
[a] Isolated yield.
20 min. The scope and limitation of our strategy with sub- the rate of the π-cyclization reactions for both substrates
strate 6 was established by synthesizing benzazepinoindoles with structurally diverse carbonyl groups varied from
4b–j, substrates containing both aromatic and aliphatic al- 10 min to 30 h and followed the order of reactivity aromatic
dehydes and ketones were tolerated (Table 2). In general, aldehydes Ͼ aliphatic aldehydes Ͼ ketones.
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Pictet–Spengler Cyclization for the Synthesis of Benzazepinoindoles
Table 2. Physicochemical characteristics of compounds 3 and 4.
Entry
Substrate
Product
R1
R2
Time
Isolated Yield
[%]
MS (ES)
Retention time[a]
[min]
[M + H]+
1
2
3
4
5
6
7
8
5a
5a
5a
5a
5a
5a
5a
5a
5b
5b
5b
5b
6
6
6
6
6
6
6
6
6
3a
3b
3c
3d
3e
3f
3g
3h
3i
4-ClC6H4
H
H
H
H
H
CH3
CH3
45 min
30 min
35 min
40 min
50 min
10 h
79
94
72
62
75
72
46
50
85
79
73
76
76
42
90
85
54
75
48
55
20
30
345.2
356.2
325.2
341.2
263.1
263.0
325.1
303.1
390.3
379.2
405.1
370.2
327.2
350.2
336.2
325.2
371.2
263.1
339.2
263.1
303.2
325.1
22.175
20.708
20.855
19.697
18.108
17.069
14.540
19.705
22.271
23.770
21.688
22.008s
17.628
20.190
17.600
26.582
20.700
16.996
21.759
18.494
27.291
19.519
4-O2NC6H4
4-CH3C6H4
4-CH3OC6H4
C3H5
CH3
C6H5
30 h
30 h
R1 and R2 = C6H10
4-O2NC6H4
4-ClC6H4
9
H
H
H
H
H
H
H
H
H
H
H
CH3
20 min
25 min
30 min
25 min
20 min
45 min
15 min
20 min
15 min
25 min
35 min
3 h
10
11
12
13
14
15
16
17
18
19
20
21
22
3j
3k
3l
3,4-(CH3O)2C6H3
4-NCC6H4
2-HOC6H4
indol-3-yl
4-NCC6H4
4-CH3C6H4
3,4-(CH3O)2C6H3
C3H5
4a
4b
4c
4d
4e
4f
4g
4h
4i
C6H5CH2CH2
CH3
R1 and R2 = C6H10
C6H5
30 h
30 h
6
4j
CH3
[a] Retention time on HPLC (C18 reverse-phase column; 150ϫ4.8 mm; 5 µm) with a linear gradient of 10–100% CH3CN in water over
30 min, flow rate of 1.0 mLmin–1, and UV detection at 220/254 nm.
2-(1H-Indol-2-ylmethyl)aniline (6): Prepared by the procedure re-
Conclusions
ported in ref.[10] Yield: 72%; white solid; m.p. 110–112 °C [ref.[10]
In conclusion, we have described an efficient method for
110–112 °C]; R = 0.40 (EtOAc/hexane, 1:4). IR (KBr): ν = 3380,
˜
f
generating the indole-annulated benzazepine ring through 3312, 2905, 2841, 1619 cm–1. H NMR (300 MHz, [D6]DMSO): δ
1
= 10.8 (br. s, 1 H, NH), 7.40 (d, J = 7.6 Hz, 1 H, ArH), 7.27 (d, J =
7.6 Hz, 1 H, ArH), 6.99–6.85 (m, 4 H, ArH), 6.64 (dd, J = 7.0 Hz, J
= 0.9, Hz, 1 H, ArH), 6.50–6.49 (m, 1 H, ArH), 6.16 (s, 1 H, ArH),
4.87 (br. s, 2 H, NH2), 3.89 (s, 2 H, CH2) ppm. MS (ES+): m/z =
223.0 [M + 1]+. C15H14N2 (222.29): calcd. C 81.05, H 6.35, N 12.60;
found C 81.12, H 6.27, N 12.61.
a 7-endo-trig Pictet–Spengler cyclization. Our methodology
allows rapid access to benzazepinoindoles with different
substitution patterns and could be suitable for the prepara-
tion of a wide library of compounds. The indole-linked
arylamine precursors used in the present investigation for
the 7-endo-trig cyclizations are new additions to the reper-
toire of “second-generation substrates” for the Pictet–
Spengler reaction reported earlier by us.
General Procedure for the 7-endo-trig Cyclization: A mixture of 5
or 6 (0.45 mmol) and benzaldehyde/ketone (0.49 mmol) in DCM
(2 mL) was treated with 2% TFA in DCM, and the progress of
the reaction was monitored by TLC. The reaction mixture, upon
completion, was concentrated, and the residue so obtained was trit-
urated with aqueous NaHCO3 (10 mL). The suspension was then
extracted with EtOAc (20 mL), washed with brine (10 mL), and
dried with anhydrous Na2SO4. The organic layer was concentrated
to dryness under reduced pressure, and the crude material obtained
was purified by column chromatography (hexane/ethyl acetate, 9:1)
to afford 3 or 4.
Experimental Section
General Procedure for the Synthesis of Key Intermediate 5: A solu-
tion of 7 (3.2 mmol) and Fe (9.52 mmol) in acidic ethanol (HCl/
EtOH, 1:4) was heated at reflux under a nitrogen atmosphere for
1.5 h. The solution was cooled down and then poured into ice; the
pH was made slightly basic (pH 8) by the addition of 5% aqueous
NaHCO3. EtOAc (50 mL) was added to the mixture, and the mix-
ture was filtered through a bed of Celite. The organic layer was
finally washed with water (50 mL) and brine (50 mL) and dried
with anhydrous Na2SO4. The organic layer was evaporated to dry-
ness under reduced pressure. The crude product was purified on a
silica gel column (hexane/ ethyl acetate, 9:1) to afford 5.
6-(4-Chlorophenyl)-5,6,7,12-tetrahydroindolo[2,3-c][1]benzazepine
(3a): Yield: 79%; white solid; m.p. 176–178 °C; Rf = 0.50 (EtOAc/
1
hexane, 1:3). IR (KBr): ν = 3422, 2927, 2848, 1637, 754 cm–1. H
˜
NMR (300 MHz, CDCl3): δ = 7.69–7.66 (m, 1 H, ArH), 7.30–7.27
(m, 3 H, ArH), 7.23–7.16 (m, 2 H, ArH), 7.13–7.00 (m, 4 H, ArH),
6.98–6.96 (m, 1 H, ArH), 6.70 (d, J = 7.5 Hz, 1 H, ArH), 5.46 (s,
1 H, CH), 4.29 (d, J = 15.5 Hz, 1 H, CH2), 4.08 (d, J = 15.5 Hz,
1 H, CH2) ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 146.3, 142.3,
136.8, 135.4, 134.6, 131.6, 129.8, 128.1, 127.8, 126.9, 126.5, 123.4,
122.0, 120.7, 118.2, 117.6, 110.7, 109.0, 59.5, 28.1 ppm. MS (ES+):
m/z = 345.2 [M + 1]+. C22H17ClN2 (344.84): calcd. C 76.63, H 4.97,
N 8.12; found C 76.58, H 4.99, N 8.15.
2-(1H-Indol-3-ylmethyl)aniline (5a): Yield: 64%; white solid; m.p.
110–112 °C; R = 0.40 (EtOAc/hexane, 1:9). IR (KBr): ν = 3020,
˜
f
2920, 2846 cm–1. 1H NMR (300 MHz, CDCl3): δ = 7.95 (br. s, 1
H, NH), 7.57 (d, J = 7.8 Hz, 1 H, ArH), 7.33 (d, J = 8.0 Hz, 1 H,
ArH), 7.23–7.05 (m, 4 H, ArH), 6.82–6.78 (m, 2 H, ArH), 6.74 (d,
J = 8.1 Hz, 1 H, ArH), 4.00 (s, 2 H, CH2), 3.50 (br. s, 2 H, NH2)
ppm. MS (ES+): m/z = 223.0 [M + 1]+. C15H14N2 (222.29): calcd. 2-(5,6,11,12-Tetrahydroindolo[3,2-c][1]benzazepin-12-yl)phenol (4a):
C 81.05, H 6.35, N 12.60; found C 81.16, H 6.43, N 12.41. Yield: 76%; white solid; m.p. 167–169 °C; Rf = 0.53 (EtOAc/hex-
Eur. J. Org. Chem. 2009, 1309–1312
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S. K. Sharma, S. Sharma, P. K. Agarwal, B. Kundu
SHORT COMMUNICATION
ane, 1:3). IR (KBr): ν = 3463, 2926, 2842 cm–1. 1H NMR
[4] Y. Wan, W. Hur, C. Y. Cho, Y. Liu, F. J. Adrian, O. Lozach, S.
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˜
(300 MHz, CDCl3): δ = 7.90 (br. s, 1 H, OH), 7.45 (dd, J = 5.9 Hz,
J = 1.6, Hz, 1 H, ArH), 7.22–7.17 (m, 3 H, ArH), 7.14–7.11 (m, 1
H, ArH), 7.07–6.95 (m, 3 H, ArH), 6.93–6.81 (m, 4 H, ArH), 5.65
(s, 1 H, CH), 4.68 (d, J = 15.9 Hz, 1 H, CH2) 3.70 (d, J = 16.0 Hz,
1 H, CH2) ppm. 13C NMR (100 MHz, CDCl3): δ = 145.1, 135.4,
131.9, 129.7, 129.5, 128.4, 128.1, 127.6, 125.7, 124.7, 123.8, 122.8,
121.6, 120.0, 119.6, 118.8, 117.5, 112.2, 110.7, 61.8, 33.0 ppm. MS
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H 5.56, N 8.58; found C 80.78, H 5.65, N 8.52.
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Acknowledgments
The authors are grateful to SAIF, CDRI, Lucknow for spectro-
scopic data. S. K. S., S. S., and P. K. A. are grateful to CSIR, New
Delhi, India for fellowships.
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Published Online: February 13, 2009
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