Synthesis of 3,4-fused cycloalkanopyrroles by 1,3-dipolar cycloaddition

Article abstract of DOI:10.1016/j.tetlet.2011.12.013

The synthesis of a number of 3,4-fused cycloalkanopyrroles bearing substituents on the cycloalkane ring was accomplished by 1,3-dipolar cycloaddition. The yield of the cyclization appeared to depend on the base-sensitivity of the Michael acceptor, but the method is applicable across a broad range of cyclic α,β-unsaturated ketone esters. Functional group transformations can be undertaken following pyrrole synthesis to increase the diversity of cycloalkanopyrroles accessible by this method. One pyrrole thus made is a diester of a conformationally-constrained analogue of porphobilinogen, the precursor of the natural tetrapyrroles.

Full text of DOI:10.1016/j.tetlet.2011.12.013

Tetrahedron Letters 53 (2012) 819–821
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of 3,4-fused cycloalkanopyrroles by 1,3-dipolar cycloaddition
⇑
James M. Kelly, Finian J. Leeper
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of a number of 3,4-fused cycloalkanopyrroles bearing substituents on the cycloalkane ring
was accomplished by 1,3-dipolar cycloaddition. The yield of the cyclization appeared to depend on the
base-sensitivity of the Michael acceptor, but the method is applicable across a broad range of cyclic
Received 31 October 2011
Revised 22 November 2011
Accepted 2 December 2011
Available online 8 December 2011
a,b-unsaturated ketone esters. Functional group transformations can be undertaken following pyrrole
synthesis to increase the diversity of cycloalkanopyrroles accessible by this method. One pyrrole thus
made is a diester of a conformationally-constrained analogue of porphobilinogen, the precursor of the
natural tetrapyrroles.
Keywords:
Cycloalkanopyrrole
1,3-Dipolar cycloaddition
Michael acceptor
TosMIC
Ó 2011 Elsevier Ltd. All rights reserved.
Br
3,4-Disubstituted pyrroles can be found in natural product alka-
loids,1,2 enzyme inhibitors,3–6 fungicides,7 pharmaceutical agents,8
and modified tetrapyrroles and porphyrins,9,10 as well as molecular
catalysts11 and electroluminescent materials.12,13 These compounds
are challenging targets, as modification of the b-positions of the
H
H
Br
H
H
H
H
a
b
HO
O
O
HO
HO
O
c
O
O
1
2
3
pyrrole ring is difficult in the presence of the more reactive a-free
H
CO2R
forg
CO2H
d, e
positions.14,15 Recent investigations have identified diverse multi-
component syntheses of pyrroles bearing substituents at both the
3- and 4-positions, including those for which the two substituents
are contributed by the same reaction component,16–20 and for which
the two substituents are contributed by separate components.21
Pyrroles bearing cross-linked substituents at the 3- and 4-posi-
tions have been reported recently as assembly blocks for novel por-
phyrins12,22 and as precursors to compounds of therapeutic
interest,5,6,17 but remain an underexplored synthetic target. Fused
cycloalkanopyrroles of this class have typically been symmetri-
cal20,22 or simply substituted on the cycloalkane ring,5,16,17 but
there are few unsymmetrical, highly functionalized pyrroles of this
class that we are aware of. These compounds represent appealing
leads towards new chemotherapeutics and natural product
analogues.
O
O
O
H
4
6(R=Me)
5
7(R=Bn)
Scheme 1. Synthesis of cyclopentenone esters. Reagents and conditions: (a) NBS,
Me2CO/H2O, 97%; (b) H2O2, AcOH, CH2Cl2, 90%; (c) Bu3SnH, AIBN, PhMe, 57%; (d)
DMSO, (CF3CO)2O, CH2Cl2, then NEt3; (e) NEt3, 69% over two steps; (f) K2CO3, MeI,
DMF, 55%; (g) BnOH, DCC, DMAP, CH2Cl2, 63%.
Cyclopentenone ester 6 was synthesized in six steps from
commercially available ( )-cis-bicyclo[3.2.0]hept-2-en-6-one (1)
as described (without full experimental details) by Corey and
Carpino26 (Scheme 1) and the benzyl ester 7 was also made by
esterification of cyclopentenone acid 5 with benzyl alcohol and
DCC.
Multicomponent pyrrole syntheses offer the advantage of gener-
ating diverse families of related pyrroles from a single set of reaction
conditions. Not all reactions show a high degree of functional group
tolerance. One method that has been shown to be compatible with a
range of functional groups is the 1,3-dipolar cycloaddition between
isonitrile anions and Michael acceptors.17,23–25 We have therefore
prepared a number of cyclic Michael acceptors as precursors for
the assembly of families of 3,4-fused cycloalkanopyrroles.
A second family of cyclic Michael acceptors was synthesised
from 2-cyclopenten-1-one (8) (Scheme 2). The Wohl–Ziegler
bromination of cyclopentenone 827 was carried out in a 75% yield
and the resulting bromide 9 was treated with anions of malonate
diesters28 to give cyclopentenone diesters 10, 11 and 12. Substitu-
tion reactions with dimethyl malonate were found to generate a
significant proportion of a tetraester double addition product,
formed by the overall displacement of bromide and conjugate
addition by the malonate anion, but there was minimal double
addition when the more sterically congested methyl t-butyl mal-
onate and dibenzyl malonate were used.
⇑
Corresponding author. Tel.: +44 1223 336403; fax: +44 1223 336362.
E-mail address: fjl1@cam.ac.uk (F.J. Leeper).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.12.013

820
J. M. Kelly, F. J. Leeper / Tetrahedron Letters 53 (2012) 819–821
Table 1
CO2R2
CO2R1
10 (R1=R2=Me)
11 (R1=Me, R2=tBu)
12 (R1=R2=Bn)
Synthesis of 3,4-fused cycloalkanopyrroles32
O
Br
O
a
O
b
O
X
O
X
NaH, Et2O/DMSO
11%-81%
n
n
Ts
N
8
9
C
TosMIC
N
H
Scheme 2. Synthesis of cyclopentenone diesters for 1,3-dipolar cycloaddition.
Reagents and conditions: (a) NBS, AIBN, CCl4, 75%; (b) NaOMe, R1O2CCH2CO2R2,
MeOH/THF, 51% for 10, 80% for 11, 67% for 12.
Entry
1
Michael acceptor
Pyrrole product
Yield (%)
8
72
42
O
N
18
19
H
Cyclohexenone ester 16a was prepared in near-quantitative
yield from Danishefsky’s diene (13) and methyl acrylate (14a) via
a Diels–Alder reaction29 (Scheme 3). The silyl enol ether adduct
15a was converted, under acidic conditions at 0 °C,30 into a mixture
of unsaturated enones 16a and 17a in a 3:1 ratio. However it was
possible to selectively convert 15a into 16a, the desired Michael
acceptor, with zinc chloride in dichloromethane at room tempera-
ture.31 Benzyl analogue 16b was prepared in a 90% yield by a
similar route from benzyl acrylate.
2
O
O
N
H
3
4
5
6
81
57
45
O
O
CO2Me
20
The cyclic a,b-unsaturated ketone esters were all tested (apart
N
H
from 10) as Michael acceptors for pyrrole formation by 1,3-dipolar
cycloaddition. Reactions were carried out with p-toluene-sulfo-
nylmethyl isocyanide (TosMIC) and sodium hydride in a 3:1
solution of diethyl ether and dimethyl sulfoxide at room tempera-
ture. The results are summarized in Table 1.
7
CO2Bn
21
N
H
Esters 6 and 7 (entries 3 and 4) gave 3,4-fused bicyclic pyrroles
in yields comparable to those obtained for cyclopentenone (8) it-
self and 2-cyclohexen-1-one (entries 1 and 2), which were them-
selves comparable to the literature reports.17 In contrast, esters
12, 16a and 16b were significantly poorer 1,3-dicycloaddition
components (entries 6, 7 and 9) and gave yields of pyrroles of only
32%, 11% and 12%. It seems likely that the decrease in yield was a
consequence of an acidic proton on the Michael acceptor, the pro-
ton adjacent to both the ester substituent and the alkene of 16a/b
and the proton adjacent to both ester groups in the case of 12.
However, diester 11 did give a more reasonable yield of 45%, de-
spite its acidic proton. There was no significant difference in the
yield of pyrrole from enone 16a or from the mixture of enones
16a and 17a (entries 7 and 8).
We next demonstrated that the ketone group of the bicyclic
pyrroles can be transformed into other functional groups of inter-
est. It was necessary to activate the ketone towards nucleophilic
addition by installing a N-tosyl group on the pyrroles. This was
achieved by using sodium hydroxide and p-toluenesulfonyl chlo-
ride33 (Scheme 4). A Horner–Wadsworth–Emmons reaction with
N-tosyl pyrrole ketone 26 and triethyl phosphonoacetate gave
the pyrrole diester 27 as a mixture of E- and Z-isomers. The reac-
tion was difficult to drive to completion with sodium salt of the
phosphonate, whereas the lithium salt, surprisingly, gave no
detectable conversion. The tosyl group was cleaved with caesium
carbonate34 and the alkene was hydrogenated over palladium-
on-charcoal to give unsymmetrically substituted cyclohexanopyr-
11
CO2Me
O
t
CO2 Bu
N
H
22
6
7
12
32
11
CO2Bn
CO2Bn
O
O
N
H
23
16a
CO2Me
N
24
H
8
9
16a, 17a
24
11
12
16b
O
CO2Bn
N
H
25
EtO2C
CO2Me
CO2Me
O
CO2Me
a
24
O
b
N
N
H
N
OMe
OMe
26
27
Ts
Ts
CO2R
a
CO2R
b or c
CO2R
c
+
16
EtO2C
EtO2C
TMSO
TMSO
O
O
CO2Me
CO2Me
13 14
+
15
a ,R = Me; b, R = Bn
CO2R
d
N
N
H
17
H
29
28
Scheme 3. Synthesis of cyclohexenone compounds for 1,3-dipolar cycloaddition.
Reagents and conditions: (a) PhMe, 91–99%; (b) 1 M HCl, THF, 72% for 16a and 24%
for 17a; (c) ZnCl2, CH2Cl2, 94–98% 16a/b.
Scheme 4. Synthesis of an unsymmetrical pyrrole diester. Reagents and conditions:
(a) NaOH, CH2Cl2, then TsCl, 59%; (b) (EtO)2POCH2CO2Et, NaHMDS, THF, 47%; (c)
Cs2CO3Á2H2O, THF/EtOH, 53%; (d) H2, Pd/C, EtOH, 99%.

J. M. Kelly, F. J. Leeper / Tetrahedron Letters 53 (2012) 819–821
TMSO
821
Supplementary data
O
O
a
b
NC
Supplementary data (full experimental procedures and com-
pound characterizations) associated with this article can be found,
in the online version, at doi:10.1016/j.tetlet.2011.12.013.
N
H
N
N
18
30
31
Ts
Ts
c
MeO2C
NC
d, e
References and notes
N
N
33
32
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Ts
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Scheme 5. Single carbon homologation. Reagents and conditions: (a) NaOH, CH2Cl2,
then TsCl, 97%; (b) TMSCN, TBAF, 39%; (c) p-TsOH, MeCN; 36%; (d) 6 M HCl, 1,4-
dioxane; (e) SOCl2, MeOH, 39% over two steps.
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the NOESY spectrum suggested that the two side-chains were trans
oriented.
Diester 29 is an analogue of opsopyrrole dicarboxylic ester in
which the side-chains at the 3- and 4-positions are linked by
a
–CH2CH2– bridge, which conformationally constrains these
side-chains. It is of interest, therefore, as a precursor of conforma-
tionally-constrained analogues of porphobilinogen (the monopyrr-
olic precursor) and the natural tetrapyrroles (e.g., uro-, copro- and
proto-porphyrins and haem).
Single carbon homologation reactions of simple cyclopentano-
pyrrole ketone 18 proved to be more difficult. However, transfor-
mation of the ketone into an
a,b-unsaturated ester 33 was
achieved in four steps from N-tosyl pyrrole 30 in a 5% yield
(Scheme 5). Addition of trimethylsilyl cyanide across the carbonyl
bond was accomplished in the presence of tetrabutylammonium
fluoride,35 although the reaction was not as efficient as the corre-
sponding treatment of pyrrole 18. The silyl ether was eliminated
by heating with p-toluenesulfonic acid in acetonitrile to give the
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a,b-unsaturated nitrile 32 in a 36% yield. Conversion into methyl
ester 33 was achieved by hydrolysis of the nitrile under acidic
conditions at 80 °C and esterification with thionyl chloride in
methanol.36
In conclusion we have demonstrated that the 1,3-dipolar cyclo-
addition of the TosMIC anion to a variety of cycloalkenones is a
practical route to families of cycloalkano[c]-pyrroles containing
ester groups. These pyrroles can undergo various functional group
transformations to enable the synthesis of a number of highly
functionalized bicyclic pyrroles of interest.
32. Typical procedure: NaH (60% in mineral oil, 0.67 mmol) was washed with
hexane under argon and then stirred at room temp in Et2O (4 mL). A solution of
cyclopentenone
6 (0.42 mmol) and TosMIC (0.45 mmol) in Et2O/DMSO
(4:2 mL) was added slowly. After 2 h the mixture was poured into H2O
(10 mL) and stirred for a further 20 min. Extraction and chromatography gave
pyrrole 20 (81%) as an oil.
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Acknowledgement
36. Wallace, G. A.; Gordon, T. A.; Hayes, M. E.; Konopacki, D. B.; Fix-Stenzel, S. R.;
Zhang, X.; Grongsaard, P.; Cusack, K. P.; Schaffter, L. M.; Henry, R. F.; Stoffel, R.
H. J. Org. Chem. 2009, 74, 4886.
The authors wish to thank Statoil (UK) for financial assistance
(J.M.K.).