One-pot synthesis of asymmetric annulated bis(pyrrole)s

Article abstract of DOI:10.1021/ol202457n

Condensation of activated functionalized pyrroles with acetone results in asymmetric bis(pyrrole)s, formed via ring annulation. The methodology is somewhat general and can be applied to a variety of ketones, as well as to a range of pyrrolic substrates that do not bear electron-withdrawing groups directly adjacent to the pyrrole ring.

Full text of DOI:10.1021/ol202457n

ORGANIC
LETTERS
2011
Vol. 13, No. 21
5846–5849
One-Pot Synthesis of Asymmetric
Annulated Bis(pyrrole)s
Deborah A. Smithen, T. Stanley Cameron, and Alison Thompson*
Department of Chemistry, Dalhousie University, 6274 Coburg Road, P.O. Box 15000,
Halifax, Nova Scotia, B3H 4R2, Canada
Alison.Thompson@Dal.Ca
Received September 9, 2011
ABSTRACT
Condensation of activated functionalized pyrroles with acetone results in asymmetric bis(pyrrole)s, formed via ring annulation. The methodology
is somewhat general and can be applied to a variety of ketones, as well as to a range of pyrrolic substrates that do not bear electron-withdrawing
groups directly adjacent to the pyrrole ring.
Dipyrromethanes are well-known for their role in the
synthesis of naturally occurring porphyrins and other
Scheme 1. Synthesis of 5,5-Dimethyldipyrromethanes
polypyrrolic compounds. In recent years, meso- or
5-substituted dipyrromethanes have attracted much
attention as precursors to synthetic porphyrins, as well
as dipyrrins, chlorins, corroles, and calixpyrroles.1
During the course of ongoing investigations into the
synthesis and use of polypyrrolic compounds, we
became interested in 5,5-dimethyldipyrromethanes
Our initial work with reactions of this type focused on
(2, Scheme 1). Their synthesis generally involves the
the use of pyrroles (1) bearing conjugated (and thereby
condensation of an excess of a pyrrole with acetone in
deactivating) esters in the 2- or 3-positions and resulted in
the presence of catalytic TFA.1 Although there are
the corresponding dimethyldipyrromethanes as hoped.
many reported conditions for this reaction, generally
However, employing a pyrrole that is not deactivated by
such conjugation (3a) (Scheme 2) gave an asymmetric
employing TFA or boron trifluoride diethyl etherate as
the catalyst, the majority of literature examples focus
on the reaction of pyrrole itself, with limited examples
involving substituted pyrroles.2À5
material containing two unique pyrrolic rings. Although
an azafulvene/pyrrole dimer was previously suggested as a
minor byproduct in an analogous reaction,5 the spectro-
scopic data did not support this assignment in our case.
Reaction of pyrrole 3a with deuterated acetone gener-
ated the analogous deuterated product. Comparison
of the 1H NMR spectra obtained for both compounds
(Figure 1) revealed the acetone-derived peaks for the two
compounds.
(1) Laha, J. K.; Dhanalekshmi, S.; Taniguchi, M.; Ambroise, A.;
Lindsey, J. S. Org. Process Res. Dev. 2003, 7, 799–812.
(2) Boev, N. V.; Ustynyuk, Y. A. Russ. J. Org. Chem. 2007, 43, 297–
304.
(3) Reisinger, A.; Bernhardt, P. V.; Wentrup, C. Org. Biomol. Chem.
2004, 2, 246–256.
(4) Swartz, D. L., II; Odom, A. L. Organometallics 2006, 25, 6125–
6133.
(5) Xie, H.; Leung, S. H.; Smith, K. M. J. Porphyrins Phthalocyanines
2002, 6, 607–616.
Successful crystallization of the deuterated product
enabled analysis of the new compound using X-ray crystal-
lography (Figure 2). This revealed the structure of the
r
10.1021/ol202457n
Published on Web 10/12/2011
2011 American Chemical Society

opposed to silica gel, as 5a was observed to be acid-
sensitive.
Scheme 2. Unexpected Formation of Annulated Product
Table 1. Application of Annulation to Various Pyrrolesa
entry
R1
R2
yield (%)b
1
CH2CO2Me
H
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
86 (5a)
85 (5b)
79 (5c)
85 (5d)
87 (5e)
56 (5f)
51 (5g)
65 (5h)
51 (5i)
83 (5j)
51 (5k)
2
3
Me
4
Et
5
(CH2)2CO2Me
(CH2)4CH3
(CH2)7CH3
(CH2)7CO2Me
(CH2)8OH
Me
6
7
8
9
10
11
Et
Et
a All reactions involve a 1:1 ratio of pyrrole/acetone, with 0.5 equiv
TFA. b Isolated yield.
Figure 1. 1H NMR spectra obtained from reaction of 3a with
acetone (top) and deuterated acetone (bottom).
To examine the scope of this unusual annulation reac-
tion, we examined a variety of activated R-free pyrroles. In
all cases, thenow expected annulation reaction successfully
generated annulated bis(pyrrole)s in generally very good
yields (5aÀk, Table 1). However, it is important to note
that these compounds are somewhat unstable and begin to
show visible signs of degradation from a yellow to a brown
oil within 24 h of purification unless dried thoroughly and
stored at À20 °C under nitrogen. Our immediate purifica-
tion of the crude products over neutral alumina ensured
accurate yields.
asymmetric product to be that of 5a; in essence,
two equivalents of acetone had condensed with two
equivalents of the pyrrole to generate an asymmetric
bis(pyrrole) featuring a fused pyrroleÀpyrrolidine ring
system akin to that found in the naturally occurring
antiparasitic bis(indolic) alkaloids isoborreverine and
dimethylisoborreverine.6
With this success, we investigated whether the presence
of an acyl stabilizing group would allow for this unusual
annulation to take place or whether a meso-dimethyldi-
pyrromethane would result. We also investigated the
effectiveness of indole in this reaction. In both cases, the
corresponding dipyrromethane (6 and 7) was found to
result in yields of 75 and 68%, respectively (Figure 3). This
was surprising in the case of indole, because substituted
indoles have been reported to undergo a similar type of
annulation to that described here, under conditions of
excess HCl in isopropyl alcohol,7 with there being no
previous reports of the dipyrromethane analog 7 (i.e.,
indole itself has not previously been employed as a
substrate). The indole-based substrates in the literature
examples possess several electron-donating groups. It is
thus logical to conclude that the electron-rich nature of the
Figure 2. Confirmed structure of isolated compound (ellipsoid
diagram, 50%; H/D atoms removed for clarity).
Confirmation of the structure allowed for the optimiza-
tion of the reaction by using the necessary stoichiometry of
reactants. Using a 1:1 ratio of pyrrole 3a and acetone
thus resulted in a significantly improved yield of 5a (86%,
Table 1, entry 1) after purification over neutral alumina as
(6) Fernandez, L. S.; Sykes, M. L.; Andrews, K. T.; Avery, V. M. Int.
J. Antimicrob. Agents 2010, 36, 275–279.
(7) Wood, K.; Black, D. S.; Kumar, N. Aust. J. Chem. 2010, 63, 761–
770.
Org. Lett., Vol. 13, No. 21, 2011
5847

starting material is imperative for a substrate to undergo
this annulation reaction.
Table 2. Reaction of 3e with Various Carbonyl Compounds
product
yield (%)a
recovered starting
material (%)
Figure 3. Dipyrromethanes resulting from use of a stabilized
pyrrole and indole.
entry
R
1
2
H
0
0b
0
CH3
CF3
Et
tBu
87 (5e)
The final substrate examined was pyrrole itself, which
was of interest after reading a report that an unusual
annulation reaction was observed following reaction with
acetylacetone.8 However, we found that reaction with
acetone gave the calix[4]pyrrole (8a) in a 61% yield along
with the confused calix[4]pyrrole (8b)9 and a linear tetra-
pyrrole (8c)10 as minor products (Scheme 3).
3
48c,d (9, 1.0:0.7)
0
4
60d (10)
0
5
0
19b,e
34b,e
91b,f
0
6
NMeOMe
NMePy
0
7
0
8
C6H5
91d (11, 1.0:0.8)
87d (12, 1.0:0.9)
76d (13, 1.0:0.6)
9
4-OMe-C6H4
4-Cl-C6H4
0
10
0
a Isolated yield. b Decomposition observed. c Reaction carried out at
À10 °C. d Mixture of isomers. e Pyrrole 3e recovered. f Ketone recovered.
Scheme 3. Reaction of Pyrrole with Acetone
conditions aldehydes and activated R-free pyrroles have
the propensity to polymerize. Maintaining the acetone
skeleton but varying one of the methyl groups to a
trifluoromethyl group was successful (Table 2, entry 3).
Slightly increasing the steric bulk on one side of the ketone
to an ethyl group met with a lack of regioselectivity
(Table 2, entry 4), with two products isolated in a com-
bined yield of 43%; the complexity of the 1H NMR spectra
prevented assignment of the respective structures. Further
increasing the size of the substituent group was not suc-
cessful (Table 2, entries 5À7), with the starting material
recovered in all cases. We then examined the use of
acetophenone (Table 2, entry 8), which has been reported
to be successful in the annulation of electron-rich indoles.7
Pleasingly, we obtained the desired fused bis(pyrrole) (11),
isolated in a 91% yield. Analysis of this arylated analogue
(11) using 1H NMR spectroscopy revealed the presence of
two diastereoisomers (see the Supporting Information),
and these were not separable using column chromatogra-
phy. Further aryl substituents were examined, bearing
electron-donating (Table 2, entry 9) and electron-with-
drawing (Table 2, entry 10) groups. In both cases, the
expected annulation gave good yields, with the products
again appearing to be a mixture of stereoisomers. It was
also noted that while the presence of an electron-with-
drawing group seemed to enhance the stability of the
product (13), electron-rich substituents greatly reduced
the stability of the products (11 and 12), resulting in visible
degradation beginning within an hour of purification: this
observation is consistent with the nature of R-free pyrroles,
because electron-withdrawing groups provide significantly
enhanced stability.
We next turned our attention to the nature of the
carbonyl compound (Table 2). We chose to use pyrrole
3e as our model substrate, as this had given the best yield
in earlier studies (Table 1, entry 5), and it also appeared to
be among the most stable, being one of the few R-free
pyrroles examined that existed in the solid state at room
temperature.
This study established the scope of carbonyl compounds
ableto bring aboutthisunusualtype ofpyrroleannulation.
Following our previous success with acetone (Table 2,
entry 2) and cognizant that a methyl group was required
to install the pyrrolidine-type ring, we examined acetyl-
based carbonyl compounds. The simplest of these was
acetaldehyde (Table 2, entry 1), which did not react in a
similar manner. This was not surprising, as under acidic
(8) Mahanta, S. P.; Panda, P. K. Tetrahedron Lett. 2009, 50, 890–892.
(9) Nishiyabu, R.; Palacios, M. A.; Dehaen, W.; Anzenbacher, P. J. J.
Am. Chem. Soc. 2006, 128, 11496–11504.
(10) Raghavan, K. V.; Kulkarni, S. J.; Kishan, M. R.; Srinivas, N.;
(Council of Scientific and Industrial Research, India). Preparation
of substituted calyx[4]pyrroles over molecular sieve catalysts. WO
2002068426 A1 20020906, 2002.
5848
Org. Lett., Vol. 13, No. 21, 2011

the major isolated product in reasonable yield. However,
TFA remained optimal with regard to this transformation.
The effect of reducing the amount of TFA to just 0.1 equiv
was also examined (Table 3, entry 2), whereby the desired
product was still obtained in high yield. In summary, an
unusual annulation of a range of activated pyrroles with
acetone has been observed. The resulting asymmetric
annulated bis(pyrrole)s, not previously described, were
obtained in good to excellent yield and the reaction was
found to be applicable to various ketones. The core struc-
ture of these compounds is similar to that of the naturally
occurring indolic alkaloids isoborreverine and dimethyli-
soborreverine, recently shown to have antiparasitic activity.6
Mechanistic studies are underway.
Table 3. Variation of Acid Catalyst
entry
acid
TFA
equiv
yield (%)a
1
0.5
0.1
0.5
0.5
0.5
87
85
48
52
81
2
TFA
3
MsOH
Conc. HCl
Acknowledgment. This work was supported by the
Natural Sciences and Engineering Research Council of
Canada (NSERC).
4
5b
BF3 OEt2
3
a Isolated yield. b Anhydrous reaction conditions employed.
Supporting Information Available. Experimental pro-
cedures, NMR characterization data for all previously
unpublished compounds, and crystal data. This material
is available free of charge via the Internet at http://pubs.
acs.org.
Our final study concerned the nature of the acid used to
catalyze the reaction. We examined the reaction of pyrrole
3e with acetone in the presence of various acids (Table 3).
In all four cases, the annulated bis(pyrrole) (5a) was
Org. Lett., Vol. 13, No. 21, 2011
5849