An unusual boron tribromide-mediated, one-pot bromination/cyclization reaction. Application to the synthesis of a highly strained cyclopenta[1,3] cyclopropa[1,2-b]pyrrolizin-8-one

Article abstract of DOI:10.1016/j.tetlet.2012.12.056

Performing Jefford's cyclization of ethyl 2-pyrrol-1-ylcyclohex-2-ene-1- carboxylate (5) using boron tribromide in refluxing dichloromethane led to a trans-cis bromopyrrolohydrindolone 7 whose debromination in alkaline medium afforded a highly strained cy

Full text of DOI:10.1016/j.tetlet.2012.12.056

Tetrahedron Letters 54 (2013) 1133–1136
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Tetrahedron Letters
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An unusual boron tribromide-mediated, one-pot bromination/cyclization
reaction. Application to the synthesis of a highly strained
cyclopenta[1,3]cyclopropa[1,2-b]pyrrolizin-8-one
⇑
Jean-Pierre Jourdan, Christophe Rochais, Remi Legay, Jana Sopkova de Oliveira Santos, Patrick Dallemagne
Université de Caen Basse-Normandie, UFR des Sciences Pharmaceutiques, Centre d’Etudes et de Recherche sur le Médicament de Normandie (CERMN) EA 4258, FR CNRS 3038 INC3M,
SF 4206 ICORE, Boulevard Becquerel, 14032 Caen cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Performing Jefford’s cyclization of ethyl 2-pyrrol-1-ylcyclohex-2-ene-1-carboxylate (5) using boron tri-
bromide in refluxing dichloromethane led to a trans–cis bromopyrrolohydrindolone 7 whose debromin-
ation in alkaline medium afforded a highly strained cyclopenta[1,3]cyclopropa[1,2-b]pyrrolizin-8-one 6.
Compound 7 and two of its diastereoisomers were synthesized in order to better understand this unusual
reaction and more generally the reactivity of these systems.
Received 20 November 2012
Revised 11 December 2012
Accepted 14 December 2012
Available online 28 December 2012
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Tripentone
Jefford’s reaction
Cyclopentacyclopropapyrrolizinone
Pyrrolohydrindolone
O
Tripentones constitute a heterocyclic family bearing some very
interesting biological properties widely studied by several teams
around the world.1–8 Among these activities, antineoplastic prop-
erties are particularly displayed by some tripentones such as com-
O
O
S
Ar
N
N
N
pound MR22388 which appears as
a very potent cytotoxic
tripentones
derivative9 with specific FLT3-ITD kinase inhibitor activities and
a great potential interest in the treatment of acute myeloid leuke-
mia. During the course of our work aiming at developing some no-
vel tripentones, we wished to synthesize the hitherto unknown
tetrahydropyrroloindolone 1 (Fig. 1).
1
O
OH
MR22388
Figure 1. Structure of tripentones, MR22388, and compound 1.
To achieve this goal we started from ethyl 2-oxocyclohexane-
carboxylate (2) which was submitted to ammonium carbamate
in refluxing methanol.10 The reaction led quantitatively to ethyl
2-aminocyclohexenecarboxylate (3) which was involved in a pyrr-
olation reaction under Clauson-Kaas conditions.11 The reaction
afforded in 50% yield a mixture of pyrrole derivatives 4 and 5 in
2:1 proportions respectively, whereas the starting material 2, is-
sued from the hydrolysis of 3, was mainly recovered (Scheme 1).
Compounds 4 and 5, which were not separable, were both en-
gaged in a cyclization reaction using boron tribromide according
to Jefford’s method.12 Beside ketone 2 and the desired tetrahydro-
pyrroloindolone 1, this reaction afforded, after an alkaline treat-
ment, an unexpected tetracyclic compound. The latter was
identified using 2D NMR experiments as 1,2,3,3a-tetrahydrocyclo-
penta[1,3]cyclopropa[1,2-b]pyrrolizin-8(3bH)-one (6) (Scheme 2).
The structure of the latter was confirmed by X-ray diffractometry
(Fig. 2).
In order to understand this surprising synthesis, we investi-
gated the reaction carried out under conditions deprived from
the alkaline treatment. In this case, formation of trans–cis bro-
mopyrrolohydrindolone 7 was observed, which was isolated in
30% yield and its relative configuration was unambiguously con-
firmed by NOE experiments (Scheme 3). The following plausible
mechanistic rationale addressing the formation of the observed
products could be proposed. We believe that the aromaticity of
the pyrrole ring in 8 is not restored as usual through the elimina-
tion of BBr3 and EtOH but through the formation of another inter-
mediate
9 bearing a cationic carbon. The latter could be
⇑
Corresponding author. Tel.: +33 2 31 56 68 13; fax: +33 2 31 56 68 03.
E-mail address: patrick.dallemagne@unicaen.fr (P. Dallemagne).
diastereoselectively brominated by the OBBr3 group13 leading to
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.12.056

1134
J.-P. Jourdan et al. / Tetrahedron Letters 54 (2013) 1133–1136
O
O
O
2,5-diOMeTHF
O
N
O
N
H
NH2CO2NH4
4-Clpyridine, HCl
OEt
OEt
NH2
OEt
OEt
+
MeOH
97%
dioxane
50%
3
(2:1)
2
4
5
Scheme 1. Synthesis of compounds 3–5.
into 6 after HBr elimination. More classically, isomer 4 would af-
ford at the same time the cyclization into 1.
4
5
+
To the best of our knowledge, the use of boron tribromide had
never led to such a one-pot bromination/cyclization reaction. In or-
der to confirm this surprising reaction and the structure of its
products, we undertook the unequivocal synthesis of compounds
6 and 7. We started with the bromination of 2 using bromine in
Et2O which led selectively to the monobromo derivative 11
(Scheme 4).14 Under treatment with ammonium carbamate in
EtOH, the latter gave then quantitatively enamine 12.
1) BBr3 / CH2Cl2
2) NaOH / H2O
O
O
N
N
H
6
H
1
O
Scheme 2. Synthesis of compounds 1 and 6.
O
O
O
Br2
NH2CO2NH4
OEt
OEt
OEt
NH
Et2O
97%
2
OH
EtOH
96%
Br
Br
2
11
12
Scheme 4. Synthesis of compounds 11 and 12.
O
O
N
NaBH3CN
H
2,5-diOMeTHF
H
OEt
NH2
OEt
12
EtOH
AcOH
Figure 2. Crystal structure of compound 6.
4-Clpyridine, HCl
dioxane
Br
Br
60%
13
83%
the more stable bromo derivative 10. The latter would be finally
hydrolyzed into 7 whose deprotonation in alkaline medium in
the alpha position of its carbonyl group, would lead to a cyclization
14a, b
Scheme 5. Synthesis of compounds 13 and 14a,b.
Br
B
Br
Br
Br
Br
Br
Br
–
Br
Br
B
–
B
O
N
O
C
O
OEt
H
+
OEt
OEt
+
N
N
5
8
H-OH
Br
Br
Br
Br
Br
B
–
B
O
O
H
H
O
H
H
H-OH
OEt
OEt
H2O
NaOH
6
N
N
N
+
Br
Br
7
10
9
Scheme 3. Hypothetical mechanism proposed for the synthesis of compounds 1 and 7.

J.-P. Jourdan et al. / Tetrahedron Letters 54 (2013) 1133–1136
1135
Compound 12 was then reduced with sodium cyanoboro-hy-
O
O
O
H
H
tBuOK/ Et2O
80%
dride in EtOH in the presence of acetic acid to give in 60% yield
the aminobromocarboxylate 13. The latter was obtained as a mix-
ture in equal parts of all-cis and cis–trans diastereo-isomers identi-
fied through NOE experiments (Scheme 5). The pyrrolation of 13
led in 83% yield to a mixture in equal parts of the corresponding
compounds 14a,b from which we isolated the all-cis derivative
14a. The structure of the latter was confirmed by its X-ray diffrac-
tometry (Fig. 3).
+
N
N
N
H
H
Br
Br
15
18
(1:1)
16
Scheme 8. Synthesis of compounds 16 and 18 starting from 15.
Applying Jefford’s procedure to the diastereoisomeric mixture
of 14, gave then in 50% yield a (2:1) mixture of two cyclized com-
pounds whereas a great amount of the all-cis starting material 14a
was recovered intact (Scheme 6). The cyclized compounds were
identified through NOE experiments. Among them were separated
a cis–trans derivative 15 as a major product and a trans–cis deriva-
tive identical to compound 7 previously obtained.15 A third prod-
uct, present in very low proportion was identified as an all-cis
derivative 16.
O
O
H
H
tBuOK/ Et2O
96%
N
N
H
Br
H
7
6
Scheme 9. Synthesis of compound 6 starting from 7.
Whereas 15 and 16 appeared to be obviously formed by the
cyclization of 14b and 14a respectively, the synthesis of 7 in this
sequence was quite surprising. The hypothesis, we invoked to ex-
plain it, is the same previously postulated in Scheme 3. Compound
14a would lead diastereoselectively to the more stable intermedi-
ate 17, which would undergo an intramolecular SN2 substitution
giving the same intermediate 10 as previously reported, and 7 as
the final result of this epimerization sequence (Scheme 7).
Treatment of compounds 15 and 7 with potassium tert-butylate
in ether at room temperature did not afford the same products.
H
tBuOK/ Et2O
O
O
R
H
R
Br
20
19
Scheme 10. Literature synthesis of compounds 19 starting from 20.
Compound 15 underwent a classical elimination of its bromine
atom to give tetrahydropyrroloindolone 18 and also an epimeriza-
tion into 16, allowed by its enolizable ketone. Compound 16 was
identified by comparison with the minor product of the cyclization
of 14a (Scheme 8).
O
OEt
N
Br
On the other hand, compound 7, contrary to 15 and 16, lent it-
self to an exclusive intramolecular cyclization into the cyclo-
14a
penta[1,3]cyclopropa[1,2-b]pyrrolizin-8-one
6
in quantitative
Figure 3. Crystal structure of compound 14a.
yield (Scheme 9).16 No traces of 17 were observed in this reaction.
This intramolecular cyclization, which seems to confirm the
conclusions hypothetically deduced from the treatment of com-
pound 5 by boron tribromide and then by NaOH (Scheme 1), is very
rarely reported in the literature and only one related example de-
scribes the access to some tricycloctanones 19 starting from bro-
mobicycloctanones 20 (Scheme 10).17,18
O
O
O
H
H
H
H
BBr3 / CH2Cl2
50%
+
14a,b
+
N
N
N
In conclusion, we have finalized the synthesis using Jefford’s
methodology of novel bromopyrrolohydrindolones 7, 15, and 16.
H
H
Br
Br
Br
15
(2:1)
7
16 (traces)
The intramolecular cyclization of
7 led further to a cyclo-
penta[1,3]cyclopropa[1,2-b]pyrrolizinone 6. The latter can be also
obtained through an unusual boron tribromide directed one-pot
bromination/cyclization sequence. The scope of these reactions,
as well as the reactivity and the potential biological interest of
these novel tripentones are currently under investigation.
Scheme 6. Synthesis of compounds 7, 15, and 16 starting from 14a,b.
Br
Br
Br
B
O
N
References and notes
O
N
H
OEt
OEt
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7
+
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Br
Br
14a
17
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6. Aiello, F.; Garofalo, A. Tetrahedron Lett. 2011, 52, 5824–5826.
Scheme 7. Hypothetical mechanism proposed for the synthesis of 7 starting from
14a.

1136
J.-P. Jourdan et al. / Tetrahedron Letters 54 (2013) 1133–1136
7. Perri, V.; Rochais, C.; Legay, R.; Cresteil, T.; Dallemagne, P.; Rault, S. Eur. J. Med.
Chem. 2010, 45, 1146–1150.
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9. Lisowski, V.; Léonce, S.; Kraus-Berthier, L.; Sopkova-de Oliveira Santos, J.;
Pierré, A.; Atassi, G.; Caignard, D. H.; Renard, P.; Rault, S. J. Med. Chem. 2004, 47,
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3908.
m
3435, 2924, 2854, 1704, 1528, 1456, 1367, 1297, 1084, 741 cmꢀ1. Compound
15 (enantiomers (4aR,8R,8aS) and (4aS,8R,8aR)): TLC (3:1/CHX: EtOAc)
Rf = 0.43; HREIMS [M+] m/z 253.01059 (calcd for C11H12NOBr 253.12642); 1H
NMR (400 MHz, CDCl3): d 0.85–0.88 (m, 1H, H70), 1.16–1.60 (m, 3H, H8, H700),
1.75–1.84(m, 1H, H60), 2.04–2.21(m, 1H, H600), 3.14 (ddd, J = 4.88 J = 4.88,
J = 4.90, 1H, H8a), 4.09–4.15 (m, 1H, H5), 4.56–4.61 (m, 1H, H4a), 6.41 (dd,
J = 3.92, J = 2.20, 1H, H2), 6.72 (m, 1H, H1), 7.02 (m, 1H, H3) ppm; 13C NMR
(100 MHz, CDCl3): d 20.5, 23.5, 32.7, 49.0, 52.0, 62.6, 108.4, 115.5, 120.6, 133.2
189.2 ppm; IR (KBr):
745 cmꢀ1
16. 1,2,3,3a-Tetrahydrocyclopenta[1,3]cyclopropa[1,2-b]pyrrolizin-8
m 3436, 2924, 2853, 1696, 1524, 1463, 1310, 1027,
.
(3bH)-one
13. Nordvik, T.; Brinker, U. H. J. Org. Chem. 2003, 68, 9394–9399.
14. Marinko, P.; Kastelic, J.; Krbavcic, A.; Kikilj, D. Tetrahedron Lett. 2001, 42, 8911–
8913.
15. 8-Bromo-4a,5,6,7,8,8a-hexahydropyrrolo[1,2-a]indol-4-ones (7) and (15).To a
solution of diastereoisomers 14a,b in equal parts (700 mg, 2.33 mmol) in
CH2Cl2 (40 mL) and cooled with stirring to 0 °C under N2, was added a 1 M
solution of BBr3 in CH2Cl2 (4.7 mL, 4.70 mmol). The resulting suspension was
refluxed for 6 h. The reaction mixture was then washed with water, dried and
evaporated to dryness to give a brown oil from which were separated by
column chromatography the compounds 7 (65 mg, 13%) and 15 (187 mg, 37%).
(6). To a solution of 7 (35 mg, 0.14 mmol) in diethyl ether (5 mL), was added
potassium tert-butylate (30.9 mg, 0.28 mmol). The resulting suspension was
stirred at room temperature for 2 h. The reaction mixture was washed with
water, dried and evaporated to dryness to give 23 mg (96%) of 6 as a pale
yellow oil. Crystal was obtained by slow evaporation of 6 in a mixture CHX/
DCM (1:1) at room temperature. TLC (3:1/CHX: EtOAc) Rf = 0.20; HREIMS [M+]
m/z 173.08385 (calcd for C11H11NO 173.21448); 1H NMR (400 MHz, CDCl3): d
1.27–1.38 (m, 1H, H20), 1.81 (m, 3H, H200, H3), 2.08 (dd, J = 7.8, J = 12.8, 1H, H10),
2.32–2.35 (m, 1H, H3a), 2.38–2.44 (m, 1H, H100), 4.09 (s, 1H, H4), 6.23 (dd,
J = 3.8, J = 2.4, 1H, H6), 6.51 (m, 1H, H7), 6.91 (m, 1H, H5) ppm; 13C NMR
(100 MHz, CDCl3): d 22.7, 23.9, 27.5, 43.9, 46.6, 50.2, 108.1, 114.4, 122.3, 132.3,
Compound
7 (enantiomers (4aS,8S,8aS) and (4aR,8R,8aR)): TLC (3:1/
CHX:EtOAc) Rf = 0.33; HREIMS [M+] m/z 253.01059 (calcd for C11H12NOBr
190.0 ppm; IR (KBr): m .
3436, 2924, 2855, 1689, 1361, 1021, 731 cmꢀ1
1
253.12642); H NMR (400 MHz, CDCl3): d 1.21 (dt, J = 12.4, J = 2.9, 1H, H70),
17. Cotterill, I. C.; Finch, H.; Reynolds, D. P.; Roberts, S. M.; Rzepa, H. S.; Short, K.
M.; Slawin, A. M. Z.; Wallis, C. J.; Williams, D. J. J. Chem. Soc., Chem. Commun.
1988, 7, 470–472.
18. Cotterill, I. C.; Finch, H.; Highcock, R. M.; Holt, R. A.; Mahon, M. F.; Molloy, K. C.;
Morris, J. G.; Roberts, S. M.; Short, K. M.; Sik, V. J. Chem. Soc., Perkin Trans. 1
1990, 5, 1353–1366.
1.66 (m, 2H, H80, H700), 1.80 (dq, J = 12.9, J = 3.2, 1H, H60), 2.16(dq, J = 12.9, J =
3.2, 1H, H600), 2–39–2.43 (m, 1H, H800), 3.25 (m, 1H, H8a), 3.51–3.57 (m, 1H, H5),
4.76 (t, J = 7.6, 1H, H4a), 6.41 (dd, J = 3.9, J = 2.4, 1H, H2), 6.69 (dd, J = 3.9, J = 1.0,
1H, H1), 7.37 (dd, J = 2.4, J = 1.0, 1H, H3) ppm; 13C NMR (100 MHz, CDCl3): d
21.7, 23.3, 34.4, 52.8, 55.5, 62.5, 108.6, 115.5, 124.0, 130.8, 188.8 ppm; IR (KBr):