Synthesis of symmetric meso-H-dipyrrin hydrobromides from 2-formylpyrroles

Article abstract of DOI:10.1055/s-0033-1341066

The reaction of 2-formylpyrroles in acidic methanol gives the corresponding symmetric, meso-H-4,6-dipyrrin hydrobromides. This convenient strategy involves initial deformylation under the acidic conditions, followed by immediate in situ reaction of the re

Full text of DOI:10.1055/s-0033-1341066

1142▌
LETTER
lSetyternthesis of Symmetric meso-H-Dipyrrin Hydrobromides from 2-Formyl-
pyrroles
Synthesis of meso-H-Dipyrrin Hydrobromides
Kate-lyn A. R. Lund, Alison Thompson*
Department of Chemistry, Dalhousie University, 6274 Coburg Road, PO BOX 15000, Halifax, Nova Scotia, B3H 4R2, Canada
Fax +1(902)4941310; E-mail: Alison.Thompson@Dal.ca
Received: 16.01.2014; Accepted after revision: 04.03.2014
R1
R2
Abstract: The reaction of 2-formylpyrroles in acidic methanol
gives the corresponding symmetric, meso-H-4,6-dipyrrin hydrobro-
mides. This convenient strategy involves initial deformylation un-
der the acidic conditions, followed by immediate in situ reaction of
the resulting α-free pyrrole with the remaining 2-formylpyrrole in
solution to give the dipyrrin hydrobromide salt in good yield.
H
NH
asymmetric
HN
fast
H
R2
R1
+
CHO
H
N
N
H
H
Key words: pyrrole, condensation, coupling, conjugation, dipyrrin
R1
R1
self-
condensation
NH
symmetric
HN
The conjugated π-system of dipyrrins1,2 consists of two
pyrrolic units linked by a methine bridge. Traditionally of
interest as a building block for porphyrins, the dipyrrinato
unit is now appreciated as a useful chromophore by which
to invoke desirable features such as energy transfer and
storage by the corresponding complexes.3,4 Beyond the
established utility of F-BODIPYs, i.e. –BF2 complexes of
dipyrrins,5–8 the luminescence properties9 of the ligand
and other dipyrrinato complexes have fostered the recent
use of this framework as a component of dye-sensitized
solar cells.10,11 Furthermore, Fe and Co dipyrrinato com-
plexes have recently been shown to catalyze the amination
of C–H bonds,12,13 following earlier work regarding Ir and
Rh dipyrrinato complexes as hydrogenation catalysts.14
Indeed, there are numerous recent reports describing the
use of dipyrrinato complexes in applications as diverse as
biological stains/probes, light harvesters and anticancer
agents,15–20 all pointing towards a promising future for this
underdeveloped ligand.
Scheme 1 MacDonald coupling to generate an asymmetric dipyrrin
(top); when R2 = electron-withdrawing group, the MacDonald cou-
pling is uncompetitive and a symmetric dipyrrin forms (bottom)
Symmetrical dipyrrins are usually prepared via: a) react-
ing two equivalents of an α-free pyrrole with formic acid;
b) acid-catalyzed hydrolysis, decarboxylation and con-
densation of pyrrole-2-carboxylates in formic acid; or c) a
MacDonald coupling in which the α-free component and
the 2-formylpyrrole have the same substitution pattern.24
Wu and Burgess reported the preparation of symmetric F-
BODIPYs from 2-formylpyrroles, eliminating the use of
an α-free pyrrole.25 BODIPYs were isolated via in situ
trapping of the dipyrrin, demonstrating the one-pot syn-
thesis of BODIPYs from 2-formylpyrroles. As such, just
as α-free pyrroles can be generated via the acid-catalyzed
decarboxylation of 2-carboxylate pyrroles so the prece-
dent was demonstrated for the deformylation of 2-formyl-
pyrroles.
The most common synthetic route to dipyrrins is the Mac-
Donald coupling,21,22 an acid-catalyzed condensation of a
2-formylpyrrole with a pyrrole that is unsubstituted in the
2-position, i.e., α-free (Scheme 1).1,2 Upon the addition of
aqueous HBr to a 2-formylpyrrole and an α-free pyrrole, a
dramatic color change typically ensues, turning the solu-
tion an immediate orange/brown/brick-red color depen-
dent upon the nature of the substrates. Rapid precipitation
of the dipyrrin hydrobromide salt occurs (Scheme 1, top).
Both the color change and the precipitation are delayed
when the α-free pyrrole is electron-poor; the presence of
electron-withdrawing substituents decreases the nucleo-
philicity of the pyrrole.23 In some cases, an undesired
symmetric dipyrrin forms under these conditions, result-
ing from competitive self-condensation of the 2-formyl-
pyrrole (Scheme 1, bottom).2
We herein report the efficient synthesis and isolation of
symmetric, meso-H-dipyrrins formed from 2-formylpyr-
roles in the presence of acids (Scheme 2). As well as being
extremely convenient, this strategy complements existing
methods by enabling the high-yielding synthesis of sym-
metric dipyrrins where the α-free pyrrole has electron-
withdrawing functional groups or may not be easily ac-
cessed.
HBr, MeOH
CHO
N
HBr
HN
70 °C, 1 h
N
H
Scheme 2 Dipyrrin hydrobromides from 2-formylpyrroles
SYNLETT 2014, 25, 1142–1144
Advanced online publication: 03.04.2014
DOI: 10.1055/s-0033-1341066; Art ID: ST-2014-S0047-L
© Georg Thieme Verlag Stuttgart · New York
To investigate the formation of dipyrrins via acid-cata-
lyzed deformylation (Scheme 2), 3,5-dimethyl-4-ethyl-2-
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6

LETTER
Synthesis of meso-H-Dipyrrin Hydrobromides
1143
formylpyrrole (1a) was chosen as a test substrate (Table
1). First, a methanolic solution of 1a and 1.1 equivalents
of 48% aqueous HBr were stirred at room temperature.
Although analysis using TLC indicated that some dipyrrin
had formed after 48 hours, significant amounts of starting
material remained (entry 1). Elevating the reaction tem-
perature to 40 °C induced a gradual color change and the
precipitation of the product after five hours (entry 2).
However, heating the reaction mixture at 70 °C for just
two hours returned a 72% yield of the required dipyrrin
hydrobromide (entry 3), and the yield was elevated to
84% after just one hour with the use of excess HBr (entry
4). The use of acetic acid, acetonitrile or dichloroethane
was also somewhat effective, but longer reaction times
were required and lower yields resulted (entries 5–7). The
use of TFA as acid was effective (entry 8), but for conve-
nience we decided to pursue the more crystalline hydro-
bromide salts. Presumably,25 the mechanism involves
(some of) the 2-formylpyrrole undergoing deformylation
to give the α-free analogue which immediately undergoes
rapid condensation, at 40 °C, with the remaining unreact-
Table 2 Dipyrrin Hydrobromide Salts from 2-Formylpyrroles
R1
R1
R1
R2
R2
HBr, MeOH
70 °C, 1 h
R2
N
HN
R3
CHO
N
H
HBr
R3
R3
1a–l
2a–l
Dipyrrin R1
R2
R3
Isolated
yield (%)
2a
2b
2c
2d
2e
2f
Me
Et
Me
Me
H
84
72
63a
79
75
83
79
50
65
84
79
90
Me
Me
Me
Me
Me
Et
Me
Et
(CH2)4Me
(CH2)6Me
Ac
Me
Me
Me
Me
Me
Me
Me
Me
Me
2g
2h
2i
COCH2CH2CO2Me
CO(CH2)4CO2Me
CH2CO2Me
Et
1
ed 2-formylpyrrole; this was supported using H NMR
spectroscopy to monitor a reaction in MeOD. However,
the regioselective formation of 2c potentially points to
some concerted character.
Me
Me
Me
Me
2j
CH2CH2CO2Me
CO2Bu
2k
2l
Table 1 Examining the Effect of Acid, Temperature and Solvent on
the Conversion of 1a into 2a
CO2Bn
a Ratio of symmetric:asymmetric dipyrrins = 9:1.
Entry Solvent
Temp Time
(°C) (h)
Acid
(equiv)
Isolated
yield (%)
anol, is convenient and high yielding at elevated
temperatures.26,27
1
2
3
4
5
6
7
8
MeOH
MeOH
MeOH
MeOH
AcOH
MeCN
DCE
r.t.
40
70
70
70
70
70
70
>48
5
HBr (1.1)
incomplete
HBr (1.1)
70
78
84
67
50
70
74
2
HBr (1.1)
Acknowledgment
1
HBr (excess)
HBr (excess)
HBr (excess)
HBr (excess)
TFA (excess)
This work was supported by the Natural Sciences and Engineering
Research Council of Canada (NSERC).
4
2.5
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnuIpofoiprmntgirStanoIuifpog
r
t
iornat
4.5
24
MeOH
References and Notes
(1) Wood, T. E.; Thompson, A. Chem. Rev. 2007, 107, 1831.
(2) Wood, T. E.; Uddin, I. M.; Thompson, A. In Handbook of
Porphyrin Science; Kadish, K. M.; Smith, K.; Guilard, R.,
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496.
A variety of 2-formylpyrroles were then subjected to the
optimized reaction conditions to evaluate the scope of the
methodology (Table 2). Analogues bearing alkyl (2a–e),
keto (2f–h), alkanoate (2g–j) and conjugated ester (2k,l)
substituents all reacted as expected to give the requisite
dipyrrin salts. For the cases where yields are only moder-
ate, the microcrystallinity of these dipyrrins hampered
isolation, e.g. 2h. Furthermore, the ethoxy groups of 1g
and 1h inevitably underwent exchange in acidic methanol,
and gave the methyl ester-containing dipyrrins 2g and 2h,
respectively.
Overall, the synthesis of symmetric dipyrrins via the re-
spective 2-formylpyrrole under acidic conditions in meth-
(9) Baudron, S. A. Dalton Trans. 2013, 42, 7498.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 1142–1144

1144
K.-l. A. Lund, A. Thompson
LETTER
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(26) General Procedure for the Synthesis of meso-H-4,6-
Dipyrrin Hydrobromides: Aqueous HBr (48%, 1 mL) was
added to a solution of 2-formylpyrrole (100 mg, 1 equiv) in
MeOH (2 mL). The reaction mixture was then heated at
reflux temperature, with stirring, for 1 h or until all starting
material was consumed, monitored using thin layer
chromatography (30% EtOAc–hexanes). The precipitated
product was collected using suction filtration and the residue
was washed with Et2O to yield the respective meso-H-4,6-
dipyrrin hydrobromide.
(27) 1,3,7,9-Tetramethyl-2,8-diethyl-4,6-dipyrrinHydrobromide
(2a): The title compound was isolated as a red solid (93 mg,
84% yield); mp 225 °C (dec.). 1H NMR (300 MHz, CDCl3):
δ = 12.90 (br s, 2 H), 7.01 (s, 1 H), 2.65 (s, 6 H), 2.41 (q, 4
H), 2.25 (s, 6 H), 1.06 (t, 6 H). 13C NMR (125 MHz, CDCl3):
δ = 153.9, 141.4, 130.7, 126.3, 118.8, 17.4, 14.6, 13.0, 10.2.
HRMS (ESI): m/z [M + H]+ calcd for C17H25N2: 257.2012;
found: 257.2018.
(20) McLean, T. M.; Moody, J. L.; Waterland, M. R.; Telfer, S.
G. Inorg. Chem. 2012, 51, 446.
Synlett 2014, 25, 1142–1144
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