On-water synthesis of dipyrromethanes via bis-hetero-diels-alder reaction of azo- and nitrosoalkenes with pyrrole

Article abstract of DOI:10.1055/s-0033-1340300

An unprecedented one-pot approach to 5-substituted dipyrromethanes based on the hetero-Diels-Alder reaction of azo- and nitrosoalkenes is described. The on-water reaction conditions led to the target compounds in higher yields with significantly shorter r

Full text of DOI:10.1055/s-0033-1340300

LETTER
▌423
letter
On-Water Synthesis of Dipyrromethanes via Bis-Hetero-Diels–Alder Reaction
of Azo- and Nitrosoalkenes with Pyrrole
Synthesis of Dipyrromethanes
Nelson A. M. Pereira,a Susana M. M. Lopes,a Américo Lemos,*b Teresa M. V. D. Pinho e Melo*a
a
Department of Chemistry, University of Coimbra, 3004-535 Coimbra, Portugal
E-mail: tmelo@ci.uc.pt
b
CIQA, FCT, University of Algarve, Campus de Gambelas, 8005-139 Faro, Portugal
Received: 17.09.2013; Accepted after revision: 28.10.2013
derivatives with pyrroles1,7 and the acid-catalyzed con-
Abstract: An unprecedented one-pot approach to 5-substituted di-
densation of α-acetoxymethylpyrroles with other pyrrole
pyrromethanes based on the hetero-Diels–Alder reaction of azo-
derivatives or self-condensation.8 Dipyrromethanes bear-
ing a hydroxyalkyl or aminoalkyl substituent at C-5 have
and nitrosoalkenes is described. The on-water reaction conditions
led to the target compounds in higher yields with significantly
shorter reaction times and simpler purification procedures than also been prepared by the reaction of pyrrole with cyclic
carrying out the reaction in dichloromethane or in the absence of
solvent.
vinyl ethers and cyclic enecarbamates, respectively, in the
presence of indium bromide.9 A two-step approach to di-
Key words: dipyrromethane, Diels–Alder reactions, on-water reac-
tions, azoalkenes, nitrosoalkenes
pyrromethanes based on the Michael addition of pyrrole
to 2-alkenylpyrroles is also known.10 On the other hand,
pyrrole adds to alkynes to give dipyrromethanes, using a
catalytic amount of In(OTf)3 or dinuclear ruthenium com-
Dipyrromethanes are of wide interest as building blocks in plexes.11,12 5-(Trifluoromethyl)dipyrromethanes have
organic synthesis, namely in the synthesis of porphyrins been prepared starting from 1-bromo-1-chloro-2,2,2-tri-
and porphyrin analogues such as meso-substituted cor- fluoroethane and pyrrole or N-methylpyrrole in the pres-
roles, chlorins, expanded porphyrins, and calix[4]pyr- ence of sodium dithionite acting as free-radical initiator.13
roles.1 These porphyrin-type macrocycles have Despite the available synthetic methodologies there is still
remarkable photo- and biochemical properties. They have demand for wider structural diversity due to the large
a rich pattern of absorption bands particularly in the red range of applications of dipyrromethanes.
and near-infrared region of the spectra which makes them
Over the past decades the impressive role of conjugated
ideal to be used in light-energy conversion processes such
nitroso- and azoalkenes in the preparation of new hetero-
as in the mimicking of photosynthetic processes2 or in
cyclic systems, used either as Michael-type acceptors in
electric energy production by dye-sensitized solar cells.3
conjugate 1,4-additions or in cycloaddition reactions, has
In medicine, the most relevant applications of porphyrin
been consolidated.14 Our own contribution included the
derivatives are in medical imaging and in photodynamic
functionalization of dipyrromethanes by the Diels–Alder
therapy.4 More recently, there has been a growing interest
reaction with these heterodienes.15 In fact, 5,5′-diethyl-
and 5-phenyldipyrromethanes participated in cycloaddi-
in various other applications of dipyrromethanes. In fact,
dipyrromethanes are the precursors of BODIPY dyes (4,4-
tions with azo- and nitrosoalkenes giving dipyrrometh-
difluoro-4-bora-3a,4a-diaza-s-indacenes) whose photo-
anes with side chains containing open-chain oximes and
physical properties make them the ideal fluorescent scaf-
hydrazones. Controlling reaction stoichiometry it is possi-
fold for the development of high-performance imaging
ble to obtain mono- or 1,9-disubstituted derivatives.
probes, also finding application as photonic organic-based
Despite their widespread use as synthetic intermediates,
the vast majority of the known reports explore the reactiv-
ity of nitroso- and azoalkenes having C-bonded groups at
the 4-position or 4-unsubstituted derivatives. The pres-
ence of a good leaving group at this position, namely a
chlorine or bromine atom, provides an extra functionality
to be explored in a subsequent functionalization of ad-
ducts and cycloadducts.
materials.5 Functionalized dipyrromethanes are also po-
tentially attractive structures for the development of new
optical anion sensors, for application in biological sys-
tems and in the settling of environmental problems.6
Dipyrromethanes can be obtained from the acid-catalyzed
condensation of aldehydes (or ketones) with pyrrole. The
drawbacks of this approach are the competitive formation
of tripyrromethanes and higher oligopyrromethanes, as
well as N-confused dipyrromethane derivatives. There-
fore, over the years, significant efforts have been made to
overcome this problem.1 Alternative approaches to dipyr-
romethanes include the condensation of pyrrole carbinol
Nevertheless, 4-halo-nitrosoalkenes have been used in cy-
cloadditions with electron-rich alkenes, but surprisingly
the literature reports are scarce.16 There are also only
a few reports on the chemistry of 4-haloazoalkenes and
4,4-dihaloazoalkenes.17 We envisaged that the base-medi-
ated dehydrohalogenation of α,α-dihalohydrazones or
α,α-dihalooximes in the presence of pyrrole would lead to
SYNLETT 2014, 25, 0423–0427
Advanced online publication: 04.12.2013
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DOI: 10.1055/s-0033-1340300; Art ID: ST-2013-D0887-L
© Georg Thieme Verlag Stuttgart · New York

424
N. A. Pereira et al.
LETTER
two consecutive Diels–Alder reactions giving dipyrro-
methanes in a one-pot procedure (Scheme 1).
Table 1 Synthesis of Dipyrromethanes from α,α-Dichlorohydra-
zones and Pyrrole
NHCO2t-Bu
R
N
NYH
NHCO2t-Bu
Y
HYN
N
H
N
– HX
base
X
N
R1
R1
(excess)
R1
N
Cl
H
X
R
X
Na2CO3 (5 equiv)
r.t.
NH
HN
X
N
Cl
Y = O or NR2
X = Cl or Br
H
1a R = Me
1b R = Ph
2a R = Me
2b R = Ph
– HX
1c R = 4-BrC6H4
2c R = 4-BrC6H4
R1
NYH
R1
Entry
Pyrrole
Reaction conditions
Isolated yield
(equiv)
(%)
N
N
Y
H
N
NH
HN
1
2
3
4
5
6
9
17
87
87
87
87
CH2Cl2, 24 h
2a 10
2a 18
2a 34
2a 75
2b 17b
2c 38
H
CH2Cl2, 66 ha
Scheme 1 Synthetic strategy for the synthesis of dipyrromethanes
without solvent, 24 h
without solvent, 66 h
without solvent, 66 h
without solvent, 66 h
In this communication, this novel approach to 5-substituted
dipyrromethanes is described.
Initially, the reactivity of pyrrole towards α,α-dichlorohy-
drazone 1a was explored (Table 1). Usually, the transient
azoalkenes are slowly generated at room temperature
from the corresponding α-halohydrazones by the action of
sodium carbonate whose low solubility in dichlorometh-
ane ensures a slow rate of dehydrohalogenation and con-
sequently a low concentration of the heterodiene thus
preventing or diminishing dimerization reactions. There-
fore, the reaction of α,α-dichlorohydrazone 1a with pyr-
role (9 equiv) was carried out under these reaction
conditions with a reaction time of 24 hours which gave the
target compound 2a in low yield (Table 1, entry 1). Using
a larger excess of pyrrole and longer reaction time, a slight
improvement of the yield was observed (Table 1, entry 2).
Then, the reaction of hydrazone 1a was carried out with
excess of pyrrole (87 equiv) without solvent, a strategy
used in the synthesis of dipyrromethanes via acid-cata-
lyzed condensation of aldehydes and pyrroles to avoid the
formation of oligopyrromethanes.18 Under these reaction
conditions, dipyrromethane 2a could be obtained after 24
hours in moderate isolated yield (Table 1, entry 3). The
unreacted pyrrole was recovered by distillation followed
by purification of the product by flash chromatography.
Interestingly, increasing the reaction time to 66 hours the
expected 5-substituted dipyrromethane 2a was isolated in
75% yield (Table 1, entry 4). These optimized reaction
conditions were also applied to the synthesis of dipyrro-
methane 2b from α,α-dichlorohydrazone 1b and pyrrole
(Table 1, entry 5). However, the target dipyrromethane 2b
was obtained in low yield (17%), and an azoalkene self-
condensation product was also isolated. In fact, treatment
of α,α-dichlorohydrazone 1b with sodium carbonate at
room temperature led to the synthesis of the same product
which was identified as being 1,4-dihydro-1,2,3,4-tetra-
zine 3 (Scheme 2, see Supporting Information). Finally,
the synthesis of dipyrromethane 2c was also achieved in a
a Conditions: 10 equiv of Na2CO3 were used.
b Azoalkene self-condensation product 3 was also isolated.
CO2t-Bu
NHCO2t-Bu
N
CO2t-Bu
N
HN
N
Cl
Na2CO3
r.t.
NH
Ph
Ph
Cl
1b
3
Scheme 2 Self-condensation of hydrazone 1b
moderate 38% yield by reacting pyrrole with α,α-dichlo-
rohydrazone 1c (Table 1, entry 6).
The study was extended to the Diels–Alder reaction of
pyrrole with nitrosoalkenes generated from α,α-dihaloox-
imes (Scheme 3). Starting from α,α-dichlorooxime 4a un-
der the optimized reaction conditions, dipyrromethane 5a
could be obtained in only 25% yield. From the reaction of
α,α-dichlorooxime 4b with pyrrole the two isomeric ox-
imes 6a and 6b were obtained in 17% overall yield. The
assignment of the structure of compounds 6a and 6b was
supported by two-dimensional NOESY spectra (400
MHz). Connectivity was observed between the OH proton
and protons of the phenyl group in the NOESY spectrum
of compound 6a, whereas no such correlation was detect-
ed in the case of oxime 6b. On the other hand, in the 1H
NMR spectrum of dipyrromethane 6b the meso proton is
identified at higher chemical shift than the value observed
1
for derivative 6a. The same features are seen in the H
NMR spectra of the isomeric oximes 4b.19 These observa-
tions allowed us to assign the stereochemistry of other di-
pyrromethanes bearing the oxime substituent.
Dehydrobromination of α,α-dibromooxime 4c in the pres-
ence of pyrrole led to dipyrromethane 7a in low yield
(11%).
Synlett 2014, 25, 423–427
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Dipyrromethanes
425
OH
N
Table 2 On-Water Synthesis of Dipyrromethanes from α,α-Dichlo-
rohydrazones and Pyrrole22
R
N
R
N
H
OH
NOH
NHCO2t-Bu
(87 equiv)
X
+
R
N
R
N
H
NHCO2t-Bu
NH
HN
Na2CO3
(5 equiv)
r.t., 66 h
NH
HN
X
(excess)
N
Cl
4a R = Me, X = Cl
4b R = Ph, X = Cl
4c R = 4-BrC6H4, X = Br
5
R = Me
6a R = Ph
25%
14%
7a R = 4-BrC6H4 11%
---
NH
HN
R
Na2CO3 (10 equiv)
H2O, r.t.
6b R = Ph 3%
---
Cl
1a R = Me
1b R = Ph
1c R = 4-BrC6H4
2a R = Me
2b R = Ph
2c R = 4-BrC6H4
Scheme 3 Synthesis of dipyrromethanes from α,α-dihalooximes and
pyrrole
Entry
Pyrrole (equiv) Time (h)
Isolated yield (%)
The above results show that dipyrromethanes can be pre-
pared from dehydrohalogenation of α,α-dichlorohydra-
zones or α,α-dihalooximes in the presence of pyrrole.
However, the target compounds were obtained in moder-
ate to low yields, which led us to explore other reaction
conditions. Recently, on-water reactions have generated
much interest.20 Water is a desirable solvent, not only be-
cause it is inexpensive and environmentally benign, but
also because it can give completely new reactivity. On the
other hand, Diels–Alder reactions can be greatly acceler-
ated and can lead to higher selectivity and higher yield
by using water as solvent instead of organic solvents.
Attanasi et al. have demonstrated that Diels–Alder reac-
1
2
3
4
5
6
7
8
10
20
20
20
20
20
20
20
2
2a 16a
2a 25a
2a 46a
2a 82b
2b 21a,c
2b 21b,c
2c 54a
2c 79b
0.75
4
4
4
4
4
4
tions of azoalkenes with electron-rich dienophiles were a Purified by flash chromatography.
b Purified by crystallization.
faster and gave higher yields in the heterogeneous aque-
c Azoalkene self-condensation product 3 was also isolated.
ous medium in comparison to the homogeneous organic
solvents.21 Thus, the on-water reactivity of α,α-dichloro-
hydrazones 1 and α,α-dihalooximes 4 towards pyrrole was
explored (Table 2 and Scheme 4).
ence of pyrrole led to two consecutive Diels–Alder reac-
tions affording 5-substituted dipyrromethanes in a novel
one-pot procedure. These hetero-Diels–Alder reactions
are accelerated and give higher yields using water as sol-
vent allowing simpler purification procedures than carry-
ing out the reaction in dichloromethane or in the absence
of solvent.
The optimized conditions for the synthesis of dipyrro-
methanes 2 bearing hydrazone substituents proved to be
the use of 20 equivalents of pyrrole, carrying out the reac-
tion at room temperature for four hours. From the reaction
of hydrazones 1a and 1c the target dipyrromethanes 2a
and 2c could be isolated in 82% and 79% yield, respec-
tively (Table 2, entries 4 and 8). It is noteworthy that the
on-water reactions allow the synthesis of the dipyrrometh-
anes in significantly shorter reaction times and lower pyr-
role excess, leading to higher yields than the solvent-free
conditions. Furthermore, the products could be purified
by crystallization. The reaction of α,α-dichlorohydrazone
1b with pyrrole was less efficient due to the competitive
formation of the self-condensation product 3 (Table 2, en-
tries 5 and 6).
OH
R
N
NH
HN
5a R = Me
6a R = Ph
7a R = 4-BrC6H4
N
H
NOH
X
(20 equiv)
X
+
R
Na2CO3 (10 equiv)
H2O, r.t., 4 h
H
R N
OH
4a R = Me, X = Cl
4b R = Ph, X = Cl
4c R = 4-BrC6H4, X = Br
The optimized on-water conditions were also applied to
the synthesis of dipyrromethanes 5–7 from α,α-dihaloox-
imes 4 and pyrrole (Scheme 4). Starting from oxime 4a
the corresponding dipyrromethane 5a was isolated in 74%
yield. The reaction of α,α-dihalooximes 4b and 4c afford-
ed mixtures of isomers in 57% and 76% overall yield, re-
spectively. The two isomers could be separated by flash
chromatography.
NH
HN
6b R = Ph
7b R = 4-BrC6H4
isolated yields
5a, 74%
6a/6b, 57% (40:60)
7a/7b, 76% (28:72)
In conclusion, the base-mediated dehydrohalogenation of
α,α-dihalohydrazones and α,α-dihalooximes in the pres-
Scheme 4 On-water synthesis of dipyrromethanes from α,α-dihalo-
oximes and pyrrole22
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 423–427

426
N. A. Pereira et al.
LETTER
V.; Petrushenko, K. B.; Ushakov, I. A.; Mikhaleva, A. I.;
Meallet-Renault, R.; Trofimov, B. A. Eur. J. Org. Chem.
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Acknowledgment
Thanks are due to Fundação para a Ciência e a Tecnologia
(PEst-C/QUI/UI0313/2011,
SFRH/BD/61573/2009) for financial support. We acknowledge the
Nuclear Magnetic Resonance Laboratory of the Coimbra Chemistry
Center (www.nmrccc.uc.pt), University of Coimbra for obtaining
the NMR data.
SFRH/BPD/84413/2012
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(22) General Procedure for the Synthesis of Dipyrromethanes
Hydrazone 1 (0.83 mmol) or oxime 4 was added to a solution
of Na2CO3 (8.30 mmol) in H2O (11 mL) and pyrrole (16.6
mmol). The reaction mixture was stirred at r.t. for 4 h. After
this time the mixture was extracted with CH2Cl2 (3 × 20 mL)
and dried over Na2SO4. After filtration, the solvent and the
excess pyrrole were removed under reduced pressure. The
product was crystallized with Et2O–n-hexane, filtered,
washed with hexane and dried under vacuum.
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Org. Lett. 2011, 13, 2524. (c) Sobenina, L. N.; Petrova, O.
Synlett 2014, 25, 423–427
© Georg Thieme Verlag Stuttgart · New York

LETTER
5-(1′-tert-Butoxycarbonylhydrazonoethyl)-
Synthesis of Dipyrromethanes
427
(E)-5-(1′-Hydroxyiminoethyl)dipyrromethane (5a)
dipyrromethane (2a)
Yield 74%; mp 142–144 °C (Et2O–n-hexane). IR (KBr): νmax
= 3338, 1403, 1218, 1095, 1029, 948, 728 cm–1. 1H NMR
(400 MHz, CDCl3/DMSO-d6): δ = 10.02 (s, 1 H, OH), 9.37
(s, 2 H, NH), 6.67 (br s, 2 H, α-H pyrrolic), 6.06 (br s, 2 H,
β-H pyrrolic), 5.97 (br s, 2 H, β-H pyrrolic), 5.00 (s, 1 H,
meso), 1.84 (s, 9 H, Me) ppm. 13C NMR (100 MHz, CDCl3/
DMSO-d6): δ = 157.0, 129.5, 117.2, 107.6, 106.5, 44.3, 12.3
ppm. ESI-HRMS: m/z calcd for C11H14N3O [M + H]+:
204.1131; found: 204.1132.
Yield: 82%; mp 137–138 °C (Et2O–n-hexane). IR (KBr):
νmax = 3337, 2979, 1720, 1529, 1369, 1245, 1164, 715 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.74 (br s, 2 H, NH), 7.51
(s, 1 H, NH), 6.70 (br s, 2 H, α-H pyrrolic), 6.13 (br s, 2 H,
β-H pyrrolic), 6.05 (br s, 2 H, β-H pyrrolic), 5.05 (s, 1 H,
meso), 1.83 (s, 3 H, Me), 1.53 (s, 9 H, t-Bu) ppm. 13C NMR
(100 MHz, CDCl3): δ = 156.0, 152.9, 129.1, 117.6, 108.3,
106.9, 81.4, 46.4, 28.3, 13.9 ppm. ESI-HRMS: m/z calcd for
C16H23N4O2 [M + H]+: 303.1815; found: 303.1813.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 423–427

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