Stereoselective intramolecular hetero Diels-Alder reactions of 1-oxa-1,3-butadienes: Synthesis of novel annelated pyrrolo[1,2-a]indoles

Article abstract of DOI:10.1016/j.tetlet.2005.03.091

Novel classes of pyrano-1,3-dioxane-, pyranopyrimidine- and pyranopyrazole-fused pyrrolo[1,2-a]indoles are synthesised via stereoselective intramolecular 1-oxa-1,3-butadiene hetero Diels-Alder reactions.

Full text of DOI:10.1016/j.tetlet.2005.03.091

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 3391–3393
Stereoselective intramolecular hetero Diels–Alder reactions of
1
-oxa-1,3-butadienes: synthesis of novel annelated
pyrrolo[1,2-a]indoles
Harsha N. Borah, Mohit L. Deb, Romesh C. Boruah and Pulak J. Bhuyan*
Medicinal Chemistry Division, Regional Research Laboratory, Jorhat 785006, Assam, India
Received 23 December 2004; revised 11 March 2005; accepted 15 March 2005
Available online 1 April 2005
Abstract—Novel classes of pyrano-1,3-dioxane-, pyranopyrimidine- and pyranopyrazole-fused pyrrolo[1,2-a]indoles are synthesised
via stereoselective intramolecular 1-oxa-1,3-butadiene hetero Diels–Alder reactions.
Ó 2005 Elsevier Ltd. All rights reserved.
The mitomycins are an important class of naturally
occurring heterocyclic antitumour antibiotics that pos-
sess a 2,3,9,9a-tetrahydro-1H-pyrrolo[1,2-a]indole unit
pyrimidine- and pyranopyrazole-fused pyrrolo[1,2-
a]indoles as mitomycin analogues via intramolecular
oxabutadiene hetero Diels–Alder reactions (Scheme 1).
1
as the basic skeleton. Subsequent to the discovery and
total synthesis of mitomycin C, a number of compounds
have been synthesised by molecular modifications at the
pyrrolo[1,2-a]indole without significant loss of biologi-
2-Formyl-3-methyl-N-allylindole 2 was synthesised from
3-methylindole 1 by N-allylation with allyl bromide un-
der phase transfer catalytic conditions followed by Vils-
meier formylation. Treatment of 2 with MeldrumÕs acid
3a in the presence of a catalytic amount of piperidine in
2
5
cal activity. Therefore, large efforts have been directed
towards the synthesis of functionalised pyrrolo[1,2-a]in-
dole derivatives as mitomycin analogues and as a result,
numerous heterocycle-annelated pyrrolo[1,2-a]indole
ethanol afforded the 1-oxa-1,3-butadiene 4a in high
9
yield. The structure of 4a was confirmed from spectro-
scopic data. Heating 4a in refluxing toluene for 6 h.
afforded the cis hetero Diels–Alder cycloadduct 5a as
3
derivatives have been reported. Substituted indoles
and hydroxybenzenes are typically used as the starting
4
10
materials for the synthesis of these molecules. In an ear-
5
lier publication we reported the synthesis of novel dihy-
the sole adduct in excellent yield. The structure of
the compound was ascertained from spectroscopic data
and elemental analysis. The stereochemistry was deter-
mined as cis from the coupling constant of proton H-
5b (J = 3) with H-11a. The mass spectrum of compound
dro- and tetrahydroisoxazole fused pyrrolo[1,2-a]indoles
as mitomycin analogues via intramolecular 1,3-dipolar
cycloaddition reactions, which could be subsequently
transformed into azirdines.
+
5a exhibited a strong ion at 326 (M+H) .
Hetero Diels–Alder reactions are becoming a mainstay
6
The reaction was then extended by generating the
oxabutadienes 4b–d from the condensation of 2 with
barbituric acids 3b–d in the presence of HCl. On reflux-
ing in toluene, 4b–d afforded the cis hetero Diels–Alder
adducts 5b–d in high yields (Table 1). The structures of
the cycloadducts were confirmed from spectroscopic
data and elemental analysis. The reaction was further
extended by reacting 1-phenyl-3-methylpyrazol-5-one 6
with 2 in the presence of piperidine as catalyst. The iso-
lated oxabutadiene 7 (80% yield), on refluxing in tolu-
ene, gave the cycloadduct 8, but only in a poor yield
(48%). However, when the reaction was performed in
xylene, a better yield of the cycloadduct was obtained
of heterocyclic and natural product synthesis. Among
these reactions the oxa-butadiene Diels–Alder reaction
provides a means for the construction of functionalised
7
heterocycles in a regio- and stereoselective manner. As
8
part of our interest in this area, we report here the syn-
thesis of novel classes of pyrano-1,3-dioxane-, pyrano-
Keywords: Mitomycins; Antitumour; Antibiotic; Hetero Diels–Alder
reactions; Oxabutadienes.
*
Corresponding author. Tel.: +91 376 2370121; fax: +91 376
370011; e-mail: pulak_jyoti@yahoo.com
2
0
040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.03.091

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H. N. Borah et al. / Tetrahedron Letters 46 (2005) 3391–3393
Me
References and notes
1
. Carter, S. K.; Crooke, S. T. In Mitomycin C, Current
status and New Development; Academic: New York, 1979.
. Kinoshita, S.; Uzu, K.; Nakano, K.; Takahashi, T. J.
Med. Chem. 1971, 14, 103–109, and references cited
therein.
N
H
1
2
1
. Allyl bromide
2
. DMF+POCl3
Me
PTC/NaOH
3. (a) Padwa, A.; Gascaska, J. R. J. Am. Chem. Soc. 1986,
08, 1104–1106; (b) Rebek, J.; Shaber, S. H., Jr.; Shue,
Y.-K.; Gehret, J.-C.; Zimmerman, S. J. Org. Chem. 1984,
1
N
CHO
Me
4
2
9, 5164–5174; (c) Prajapati, D.; Gadhwal, S. Tetrahedron
004, 60, 4909–4913.
2
O
4. (a) Nakatsubo, F.; Cocuzza, A. J.; Keeley, D. E.; Kishi, Y.
J. Am. Chem. Soc. 1977, 99, 4835–4836; (b) Rebek, J., Jr.;
Shaber, S. H.; Shue, Y. K.; Gehret, J. C.; Zimmerman, S.
J. Org. Chem. 1984, 49, 5164–5174; (c) Dijksman, W. C.;
Egberink, R. J. M.; Verboom, W.; Reinhoudt, D. N. J.
Org. Chem. 1985, 50, 3791–3797; (d) Shaw, K. J.; Luly, J.
R.; Rapoport, H. J. Org. Chem. 1985, 50, 4515–4523; (e)
Danishefsky, S.; Berman, E. M.; Ciufolini, M.; Etheredge,
S. J.; Segmuller, B. E. J. Am. Chem. Soc. 1985, 107, 3891–
3
a.X=Z=O; Y=CMe2
N
z
b-d.X=NMe,NH;Y= C=O
N Ph
6
Me Me
Z=NMe,NH
Y
X
O
O
Me
O
z
Y
N
X
N Ph
N
N
O
O
3
898.
5
. Bhuyan, P. J.; Boruah, R. C.; Sandhu, J. S. Tetrahedron
Lett. 1989, 30, 1421–1422.
4a-d
7
6
. For leading references, see: (a) Daly, J. W.; Spande, T. F.
In Alkaloids: Chemical and Biological Perspectives; Pelle-
tier, S. W., Ed.; Wiley: New York, 1986; Vol. 4, pp 1–274;
(b) Foder, G. B.; Colasanti, B. In Alkaloids: Chemical and
Biological Perspectives; Pelletier, S. W., Ed.; Wiley: New
York, 1985; Vol. 3, pp 1–90; (c) Boger, D.; Weinreb, S. M.
Hetero Diels–Alder Methodology in Organic Synthesis;
Academic: San Diego, 1987, Chapter 2, pp 34–70; (d)
Buomora, P.; Olsen, J. C.; Oh, T. Tetrahedron 2001, 57,
4
1
Me
Me Me
O
z
7
3
6
8
Y
X
4
N
4
a
5
2
3
2
4a
11b
11a
5
H
H
6
7
9
5
c
8NPh
2
12a
N
1
1
1
2b
5a
5c
5a
9a
N
5b 8a
5b
1
1a
11
10a10 9O
1
1
O10
H
H
8
5a-d
6
099–6138.
Scheme 1.
Table 1.
7
8
. Demising, G.; Tacconi, G. Chem. Rev. 1975, 75, 651–692.
. Devi, I.; Borah, H. N.; Bhuyan, P. J. Tetrahedron Lett.
2
. An equimolar amount of 1-allyl-2-formyl-3-methylindole
2
4
ethanol (15 mL) was stirred at room temperature for 4 h.
The solid product appeared in the clear solution while
stirring. The reaction mixture was cooled in ice water,
filtered, the precipitate washed with a small amount of
004, 45, 2405–2408.
9
(0.796 g, 4 mmol) and MeldrumÕs acid 3a (0.576 g,
mmol) in the presence of one drop of piperidine in
Compound
X
O
Y
Z
Reaction Mp °C Yield
time (h)
5
5
5
5
8
a
b
c
CMe
2
O
6
8
225
32
85
NMe C@O NMe
NH C@O NH
NMe C@O NH
8
85
8
>330
>330
315
80
78
48
cold ethanol and dried to give 4a (1.15 g, 90%). Mp.
1
d
8
10
135 °C. H NMR (90 MHz, CDCl ): d 1.50 (s, 6H), 2.30 (s,
3
—
—
—
3H), 4.20 (d, J = 9.0, 2H), 5.30 (m, 2H), 5.80–6.20 (m, 2H),
6
À1
.75–7.20 (m, 4H). mmax (KBr): 1780 cm . m/z 326
M+H) .
+
(
1
0. Compound 4a (500 mg) was heated at reflux in toluene
(15 mL) for 6 h. After completion of the reaction (mon-
itored by TLC), the solvent was removed under reduced
pressure. The solid compound obtained was purified by
column chromatography (silica gel 60–120 mesh) using
(63%). The structure of the compound was confirmed
from spectroscopic data and elemental analysis.
In conclusion, the results delinesated here demonstrates
the synthesis of novel classes of annulated pyrrolo[1,2-
a]indoles in excellent yields via stereoselective intramo-
lecular hetero Diels–Alder reactions of oxa-butadienes.
The presence of the C-5 methyl group in the annelated
pyrrolo[1,2-a]indoles enhances their importance due to
the possibility of side chain manipulations. Further
study of the reaction is in progress.
chloroform as eluent, giving 5a (0.425 g, 85%) Mp 225 °C.
1
3
H NMR (300 MHz, CDCl ): d 1.40 (s, 3H), 1.50 (s, 3H),
2
.36 (s, 3H), 3.25 (m, 1H), 4.02 (d, J = 4.0, 2H), 4.20
13
(d, J = 3.8, 2H), 4.65 (d, J = 3.0, 1H), 6.75–7.46 (m, 4H).
NMR (75 MHz, CDCl
C
3
): d 162.0 (C-12b), 157.1 (C-9a),
152.4 (C-6), 132.8 (C-5a), 126.6, 124.4, 122.0, 120.4 (Ph),
120.2 (C-4a), 112 (C-5), 90.3 (C-5c), 63.5 (C-11), 52.0 (C-
8), 37.4 (C-12), 29.6 (C-11a), 28.5 (C-5b), 27.2, 26.5, 23.0
À1
+
(
(
CH
calcd %) C, 70.15; H, 5.84; N, 4.30; (C19
) C, 70.23; H, 5.70; N, 4.50%. Compound 8, mp 315 °C.
3
). mmax (KBr): 1775 cm . m/z 326 (M+H) . Analysis
H
19NO ) (found
4
%
Acknowledgements
1
H NMR (300 MHz, CDCl
3
): d 2.36 (s, 3H), 2.95 (s, 3H),
3
4.68 (d, J = 3.0, 1H), 6.70–7.46 (m, 9H). C NMR
.18 (m, 1H), 4.05 (d, J = 4.2, 2H), 4.23 (d, J = 3.9, 2H),
1
3
M.L.D. thanks CSIR (India) for the award of a Junior
Research Fellowship.
(75 MHz, CDCl ): d 161.8 (C-11b), 153.2(C-8a), 135.1
3

H. N. Borah et al. / Tetrahedron Letters 46 (2005) 3391–3393
3393
+
). m/z 356 (M+H) .
Analysis (calcd %) C, 77.74; H, 5.90; N, 11.83;
(C H N O) (found %) C, 77.70; H, 5.87; N, 11.85.
(
1
(
C-6), 132.8 (C-5a), 126.6, 126.3, 125.2, 124.8, 124.3,
23.8, 123.4, 122.6, 122.0, 120.4 (Arom), 120.5 (C-4a), 112
C-5), 89.5 (C-5c) 64.0 (C-10), 38.4 (C-11), 31.5 (CH3),
30.1 (C-10a), 29.0 (C-5b), 23.2 (CH
3
23
21
3