From 1,4-diketones to N-vinyl derivatives of 3,3′-bipyrroles and 4,8-dihydropyrrolo[2,3-f]indole in just two preparative steps

Article abstract of DOI:10.1016/j.tetlet.2004.03.084

Dioximes of hexane-2,5-dione and cyclohexane-1,4-dione react with acetylene in an autoclave (KOH/DMSO, 100°C, 1h, initial pressure 14atm) to give 2,2′-dimethyl-1,1′-divinyl-[3,3′]bipyrrole and 1,5-divinyl-4,8-dihydropyrrolo[2,3-f]indole in 12% and 6% yiel

Full text of DOI:10.1016/j.tetlet.2004.03.084

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 3789–3791
From 1,4-diketones to N-vinyl derivatives of 3,30-bipyrroles and
4,8-dihydropyrrolo[2,3-f]indole in just two preparative steps
Boris A. Trofimov, Alexey B. Zaitsev, Elena Yu. Schmidt, Alexander M. Vasil’tsov,
Al’bina I. Mikhaleva,* Igor’ A. Ushakov, Alexander V. Vashchenko and
Nadezhda V. Zorina
A. E. Favorsky Irkutsk Institute of Chemistry, Siberian Branch of the Russian Academy of Sciences, 1 Favorsky Str.,
Irkutsk 664033, Russian Federation
Received 27 January 2004; revised 3 March 2004; accepted 12 March 2004
Abstract—Dioximes of hexane-2,5-dione and cyclohexane-1,4-dione react with acetylene in an autoclave (KOH/DMSO, 100 ꢀC, 1 h,
initial pressure 14 atm) to give 2,20-dimethyl-1,10-divinyl-[3,30]bipyrrole and 1,5-divinyl-4,8-dihydropyrrolo[2,3-f]indole in 12% and
6% yields, respectively, thus exemplifying a very simple, straightforward route to inaccessible or unknown pyrrolic assemblies.
ꢁ 2004 Elsevier Ltd. All rights reserved.
Bipyrrolic structures are widespread in Nature and are
constituents of prodigiosins and corrins, including
vitamin B12 and its analogs.1 However, this refers mainly
to 2,20-bipyrrole derivatives, whereas other pyrrolic
assemblies, particularly 3,30-bipyrroles, have remained
understudied for a long time whilst having only minor
importance among the bipyrroles.1;2 Interest in these
bipyrroles appeared as recently as the 1980’s due to the
need for the synthesis of the antitumor agent CC-1065,
where 3,30-bipyrroles were building blocks.3;4 The
strategy for their synthesis was based on a sequential
building up of the pyrrole rings using several preparative
steps.3
cyclic members of the series, and subjected their dioxi-
mes, 27 and 10,8 to the reaction with acetylene.9
A number of alternative pathways to the required
reaction could interfere. Thus, in the case of dioxime 2,
three bipyrroles could be formed (Scheme 1) due to the
rearrangements5;10 involving both the methylene and
methyl groups in the intermediates 3–5.
The target 2,20-dimethyl-1,10-divinyl-[3,30]bipyrrole 6
was isolated by column chromatography in 12% yield
(not optimized) as the major product.11 The structurally
isomeric bipyrroles 7 and 8 were only minor components
of the reaction mixture, because they would have been
built up with the participation of the methyl groups of
the intermediates 3–5, which are less reactive compared
to the competing methylene groups.5;10 Thermodynam-
ics may also contribute to the product distribution, since
the major isolated isomer 6 is the most conjugated.
Meanwhile, a straightforward approach to 3,30-bipyr-
role assemblies could be achieved using the known two
step transition from ketones to pyrroles via the reaction
of ketoximes with acetylene in the presence of the KOH/
DMSO system, often referred to as the Trofimov reac-
tion.5;6
In the case of cyclohexane-1,4-dione dioxime 10, under
the same conditions, the unconjugated bipyrrolic cyclo-
phane 13 was isolated in 6% yield (not optimized),12
instead of the expected conjugated 3,30-linked bipyrrole
system 14 (Scheme 2).
To prove the feasibility of this approach, we chose two
1,4-diketones, namely hexane-2,5-dione 1 and cyclo-
hexane-1,4-dione 9, as representing open chain and
The structure of the 1,5-divinyl-4,8-dihydropyrrolo[2,3f]-
indole 13 followed from a 2D NOESY experiment,
which showed cross-peaks between the protons H3 and
H4 (H7 and H8). Quantum chemical calculations
Keywords: 3,30-Bipyrroles; Pyrroloindoles; Dioximes; Acetylene;
Superbases.
* Corresponding author. Fax: +7-3952-41-93-46; e-mail: mikh@
irioch.irk.ru
0040-4039/$ - see front matter ꢁ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.03.084

3790
B. A. Trofimov et al. / Tetrahedron Letters 45 (2004) 3789–3791
OH
N
H
N
O
N
O
Me
H2NOH
-H2O
[1,3]
Me
HO
O
H
Me
Me
12
O
15
N
N
N
1
2
16
H
H
[3,3]
[3,3]
O
N
HC CH
Me
O
2
Me
KOH/DMSO
3
14
13
N
[1,3]
[3,3]
-
H2O
Scheme 3.
Me
mechanical calculation, 13 is planar including the two
vinyl groups, the latter deviating out of the plane by no
more than 1ꢀ. The thermodynamic stabilization of 13
may originate from transannular interactions of the
pyrrole moieties as supported by the absence of nodes in
N
O
N
O
Me
Me
N
H
-
N
H
4
5
[1,3]
[3,3]
HC CH
[1,3]
[3,3]
HC CH
0
0
0
the HOMO of 13 between C3 –C8 kcal molꢀ1 and C4 –
-
H2O
H2O
0
C7 .
Interestingly, of the two key intermediate vinyl-
oxyhydroxylamines 16 and 15 (Scheme 3),5;10 the former
one (16) leading to 13 is 0.47 kcal molꢀ1 less stable than
its isomer 15 [B3LYP/6-311þþG(d,p) calculations for
the most stable conformations], that is, this particular
kinetic factor works against the experimental result.
N
Me
Me
Me
N
N
N
N
N
6
7
8
12%
minor products
In conclusion, the reaction of 1,4-diketone dioximes with
acetylene in the KOH/DMSO system provides a direct
access to N-vinyl-3,30-bipyrroles and 4,8-dihydropyr-
rolo[2,3-f]indoles, which are promising pharmacophores,
monomers, and building blocks for biologically impor-
tant molecules.
Scheme 1.
OH
H2NOH
-H2O
O
O
N
N
HO
9
10
Acknowledgements
N
O
O
[1,3], [3,3]
- H2O
HC CH
N
N
10
KOH/DMSO
N
The authors are grateful to the Russian Foundation for
Basic Research (Grants No 03-03-32472 and No
2241.2003.3) for financial support.
O
H
12
11
12
[1,3]
[3,3]
- H2O
HC CH
References and notes
8
7
1. Comprehensive Organic Chemistry; Sammes, P. G., Ed.;
Pergamon: Oxford, New York, Toronto, Sydney, Paris,
Frankfurt, 1979; Vol. 4, Chapter 17.
2. Gossauer, A. Der Chemie der Pyrrole; Springer: Berlin,
Heidelberg, New York, 1974; pp 330–331.
1
2
'
8
'
7
N
N
N
6
N
'
'
3
4
3
5
4
14
not isolated
13
3. Magnus, P.; Or, Y.-S. J. Chem. Soc., Chem. Commun.
1983, 26–27.
Scheme 2.
4. (a) Magnus, P.; Gallagher, T. J. Chem. Soc., Chem.
Commun. 1984, 389–390; (b) Halazy, S.; Magnus, P.
Tetrahedron Lett. 1984, 25, 1421–1424; (c) Magnus, P.;
Halazy, S. Tetrahedron Lett. 1985, 26, 2985–2989; (d)
Carter, P.; Fitzjohn, S.; Magnus, P. J. Chem. Soc., Chem.
Commun. 1986, 1162–1164; (e) Magnus, P.; Gallagher, T.;
Schultz, J.; Or, Y.-S.; Ananthanarayan, T. P. J. Am.
Chem. Soc. 1987, 109, 2706–2711; (f) Carter, P.; Fitzjohn,
S.; Halazy, S.; Magnus, P. J. Am. Chem. Soc. 1987, 109,
2711–2717.
[B3LYP/6-311þþG(d,p)] confirmed the higher stability
13
(DE ¼ 1:33 kcal molꢀ1
isomer 14.
)
of isomer 13 as compared to
The reason why structure 14 becomes thermodynami-
cally less favorable relative to structure 13 may be due to
the H–H repulsion between the two adjacent methylene
groups in the cyclohexane ring, which distorts the
coplanarity of the whole tricyclic skeleton [B3LYP/
6-311þþG(d,p) data], thus decreasing the pyrrole–pyrrole
conjugation. It turns out that, according to the quantum
5. Trofimov, B. A.; Mikhaleva, A. I. N-Vinylpyrroles;
Nauka: Novosibirsk, 1984; p 264 (in Russian).
6. (a) Pozharsky, A. F.; Anisimova, V. A.; Tsupak, E. B. In
Prakticheskie Raboty po Khimii Geterotsiklov (Manual for

B. A. Trofimov et al. / Tetrahedron Letters 45 (2004) 3789–3791
3791
Heterocyclic Chemistry); Izd. Rostovskogo Universiteta:
Rostov, 1988, p 9; (b) Bean, G. P. In The Chemistry of
Heterocyclic Compounds. Part 1: Pyrroles; Jones, R. A.,
Ed.; Wiley: New York, 1990; Vol. 48, p 153; (c) Tedeschi,
R. J. Acetylene In Encyclopedia of Physical Science and
Technology; Academic: San Diego, 1992; Vol. 1, p 27; (d)
Mikhaleva, A. I.; Schmidt, E. Yu In Selected Methods for
Synthesis and Modification of Heterocycles; Kartsev,
V. G., Ed.; IBS: Moscow, 2002; Vol. 1, pp 331–352.
7. Compound 2. NH2OHÆHCl (7.59 g, 109 mmol) and
CH3COONa (8.94 g, 109 mmol) in MeOH (20 mL) were
stirred for 20 min at room temperature. Then hexane-2,5-
dione 1 (5.00 g, 44 mmol) was added, and stirring was
continued for 3 h. The NaCl precipitate was filtered off and
washed with Et2O. The filtrate and the ether solution were
combined and neutralized with an excess of a concentrated
aqueous solution of K2CO3. After addition of ether
(50 mL) and vigorous shaking, the organic layer was
separated, washed with water (2 · 5 mL), and dried over
anhyd K2CO3. After removal of solvents in vacuo (water-
jet pumped rotary evaporator), dioxime 2 (2.05 g, 32%) was
obtained as a white powder, mp 144 ꢀC (from MeOH). 1H
NMR (DMSO-d6): d 10.32 (s, 2H, OH), 2.29 (s, 4H, CH2),
1.73 (s, 6H, CH3). 13C NMR (DMSO-d6): d 155.07 (C@N),
32.70 (CH2), 13.74 (Me). IR (KBr) mmax: 3246, 2922, 1673,
1576, 1429, 1375, 1308, 1203, 945, 825, 762, 731, 616,
9. General procedure for the synthesis of 2,20-dimethyl-1,10-
divinyl-[3,30]bipyrrole 6 and 1,5-divinyl-4,8-dihydropyr-
rolo[2,3-f]indole 13. Into a steel 0.5-L rotating autoclave,
the dioxime (14 mmol), KOHÆ0.5H2O (15% water content)
(1.80 g, 28 mmol) and DMSO (50 mL) were loaded. The
mixture was saturated with acetylene from a cylinder
(14 atm) and heated at 100 ꢀC whilst rotating for 1 h. After
cooling to room temperature, the autoclave was dis-
charged, and the reaction mixture was diluted with water
(up to 100 mL) and extracted with Et2O (4 · 30 mL). The
ether extracts were washed with water (3 · 20 mL), dried
over anhyd K2CO3 and filtered. After distilling off the
ether, the products were isolated by column chromato-
graphy (basic Al2O3, hexane–ether, 2:1).
10. (a) Trofimov, B. A. In Advances in Heterocyclic Chemistry;
Katritzky, A. R., Ed.; Academic: San Diego, 1990; Vol.
51, pp 177–301; (b) Trofimov, B. A. In The Chemistry of
Heterocyclic Compounds. Part 2: Pyrroles; Jones, R. A.,
Ed.; Wiley: New York, 1992; Vol. 48, pp 131–298.
11. Compound 6. Yield 12%. Light yellow transparent liquid,
n2D3 1.5780. 1H NMR (CDCl3):
d 6.96 (d, 2H,
3J4–5 ¼ 3:1 Hz, H5), 6.89 (dd, 2H, 3JAX ¼ 8:9 Hz,
3JBX ¼ 15:6 Hz, HX), 6.16 (d, 2H, H4), 5.07 (dd, 2H,
3JAB ¼ ꢀ0:9 Hz, HB), 4.63 (dd, 2H, HA), 2.20 (s, 6H, Me).
13C NMR (CDCl3): d 130.88 (Ca), 125.07 (H2), 117.38
(H5), 115.15 (H4), 111.39 (H3), 97.33 (Hb), 10.74 (Me). IR
(thin film) mmax: 2920, 1638 (mC@Cvin), 1560 (C–Cpyr), 1488
(C–Cpyr), 1424, 1378 (C–Cpyr), 1305 (N–Cvin), 1284, 961
(sHC@CH), 889, 857 (xCH2), 709 (dC–Hpyr), 589
483 cmꢀ1
.
8. Compound 10. To the mixture of cyclohexane-1,4-dione 9
(7.00 g, 62 mmol), NH2OHÆHCl (10.84 g, 156 mmol),
EtOH (35 mL), and water (3 mL), finely ground NaOH
(6.24 g, 156 mmol) was gradually added while stirring.
After addition of the NaOH, stirring was continued for
30 min, then mixture was poured into cold water (150 mL),
and the precipitate was filtered off and washed with water.
After drying under vacuum (1 Torr) dioxime 10 (6.90 g,
78%) was obtained as a white powder, mp 192–196 ꢀC
(xHC@CH) cmꢀ1
12. Compound 13. Yield 6%. Yellowish needles, mp 188 ꢀC
.
(from Et2O). 1H NMR (CDCl3):
d 7.00 (d, 2H,
3J4–5 ¼ 2:8 Hz, H5), 6.86 (dd, 2H, 3JAX ¼ 9:2 Hz,
3JBX ¼ 15:8 Hz, HX), 6.17 (d, 2H, H4), 5.08 (dd, 2H,
HB), 4.63 (dd, 2H, HA), 3.74 (s, 4H, CH2). 13C NMR
0
0
(CDCl3): d 130.48 (Ca), 126.44 (C4 ,8 ), 116.19 (C2;6),
1
0
0
(from Et2O). H NMR (DMSO-d6): d 10.40, 10.38 (s, 2H,
115.31 (C3 ,7 ), 109.04 (C3,7), 96.77 (Cb), 21.87 (CH2). IR
(KBr) mmax: 1640 (mC@Cvin), 1572 (C–Cpyr), 1486 (C–Cpyr),
1377 (C–Cpyr), 1306 (N–Cvin), 1262, 964 (sHC@CH), 862
OH), 2.51 (m, 4H, Hsyn), 2.39 (m, 4H, Hanti). 13C NMR
(DMSO-d6): d 156.21, 155.72 (C@N), 29.23, 26.49, 23.44,
20.99 (CH2). IR (KBr) mmax: 3198, 3075, 2861, 1659, 1487,
1418, 1324, 1275, 1212, 1175, 1121, 1055, 1001, 974, 953,
(xCH2), 711 (dC–Hpyr), 585 (xHC@CH) cmꢀ1
.
13. The computational and structural details of the com-
pounds 13 and 14 will be considered elsewhere.
926, 843, 778, 711, 642, 534 cmꢀ1
.