Synthesis of pentabromopseudilin and other arylpyrrole derivatives via Heck arylations

Article abstract of DOI:10.1016/j.tetlet.2012.01.086

Pentrabromopseudilin and other 2 and 3-arylpyrrole derivatives were synthesized through the Heck-Matsuda reaction involving endocyclic enecarbamates and N-protected 3-pyrrolines, respectively. The overall processes permitted an easy and efficient access t

Full text of DOI:10.1016/j.tetlet.2012.01.086

Tetrahedron Letters 53 (2012) 1660–1663
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of pentabromopseudilin and other arylpyrrole derivatives via Heck
arylations
Cristiane S. Schwalm a, Ilton B.D. de Castro a, Jailton Ferrari b, Fábio L. de Oliveira a, Ricardo Aparicio a,
Carlos Roque D. Correia a,
⇑
a Instituto de Química, Universidade Estadual de Campinas, UNICAMP, 13084-917 Campinas, São Paulo, Brazil
b Departamento de Química, CCEN, Universidade Federal da Paraíba, 58051-970 João Pessoa, Paraíba, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
Pentrabromopseudilin and other 2 and 3-arylpyrrole derivatives were synthesized through the Heck–
Matsuda reaction involving endocyclic enecarbamates and N-protected 3-pyrrolines, respectively. The
overall processes permitted an easy and efficient access to these structural motifs present in several bio-
active compounds. Attempts to synthesize the compound isopentabromopseudilin led to a tribromo aryl
maleimide. We hypothesize that this latter compound is the putative product arising from the unusual
thermal instability of isopentabromopseudilin.
Received 19 December 2011
Revised 18 January 2012
Accepted 20 January 2012
Available online 28 January 2012
Keywords:
Ó 2012 Elsevier Ltd. All rights reserved.
Heck–Matsuda
Pentabromopseudilin
Arylpyrrole
Introduction
the aromatic substituent to a pre-formed pyrroline scaffold
through an efficient Heck–Matsuda (HM) reaction.
The arylpyrrole unit is a widespread structural motif among
biologically active compounds. For example, it is present on the
The HM reaction, which employs arenediazonium salts as
arylating agents, presents several advantages over conventional
protocols, such as its practicality as an easy to perform protocol,
and as a phosphine-free and air tolerant process. The more reactive
nature of the arylating agent usually implies in shorter reaction
times and milder reaction conditions, making this a greener and
more practical alternative for the arylation of olefins.15–17
Previous studies from our group have already demonstrated
that both 2 and 3-aryl dihydropyrroles could be obtained from
the Heck–Matsuda reactions involving enecarbamates and N-pro-
tected 3-pyrrolines, respectively (Scheme 1).18–20 These structures
represent direct precursors to arylpyrroles, and could be trans-
formed in these aromatic derivatives in a straightforward manner.
Herein we describe the construction of both 2 and 3-arylpyrrole
cores, the application of this methodology in the total synthesis of
structures of two commercial compounds, Chlorfenapyr (1),1
a
potent pro-insecticide, and Fludioxonil (2), an antifungal antibiotic
used for seed treatment (Fig. 1). The latter compound was designed
based on the natural product pyrrolnitrin (3), isolated from Pseudo-
monas sp., which displays excellent antifungal activity but unsuc-
cessful field performance.2
Among the natural arylpyrrole compounds we also find pentab-
romopseudilin (4), a compound first isolated from Pseudomonas
bromoutilis in 19663,4 and later from Chromobacteria,5 Alteromonas
luteoviolaceus6, and Pseudoalteromonas sp.7 This interesting poly-
brominated natural product displays a variety of in vitro biological
activities such as antibiotic, antitumor, antifungal, and phytotoxic,8
including remarkable inhibition of human lipoxygenases9 and
myosin-dependent processes.10–12 It’s also worth mentioning that
pentabromopseudilin also displays a high in vitro activity against
MRSA (IC50 = 0.1 l
M).7
F
Several syntheses of pentabromopseudilin (4) have been re-
ported, and all of them share as a common feature the construction
of the pyrrole nucleus from an aliphatic intermediate already con-
taining the aromatic substituent.6,9,12–14 Herein, we disclose a new
strategy to the synthesis of this class of compounds, by attaching
O
F
Cl
Br
Br
NC
Br
CF3
OEt
Chlorfenap yr ( )
OH
O
NO2
Cl
Br
CN
Br
N
H
N
Cl
N
H
N
Br
H
Fludioxonil ( ) Pyrrolnitrin ( ) Pentabromopseudilin ( )
2
3
4
1
⇑
Corresponding author. Tel.: +55 19 3521 0000.
E-mail address: roque@iqm.unicamp.br (C.R.D. Correia)
Figure 1. Biologically active arylpyrroles.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2012.01.086

C. S. Schwalm et al. / Tetrahedron Letters 53 (2012) 1660–1663
1661
R
6 under the same conditions described in entry 8 of Table 1. Unfor-
tunately, no conversion was observed either in acetonitrile (at rt or
under heating) or in benzonitrile.
With the desired Heck adduct 7 in hand, it was subjected to aro-
matization with DDQ in toluene, leading to the corresponding aryl-
N
N
R
R
N2BF4
O
OR
HM
O
OR
HM
N
N
O
OR
O
OR
pyrrole
8 in high yields (Scheme 3). A simple filtration of
arylpyrrole 8 on a short pad of silica gel provided the desired prod-
uct with enough purity to be used in the next step without further
purification. Compound 8 was then deprotected under basic condi-
tions to afford the free pyrrole compound 9 in an 85% isolated
yield.
Compound 9 is a known intermediate in the synthesis of pen-
tabromopseudilin (4), and we were able to successfully perform
its conversion into the final product through demethylation and
bromination procedures as described in the literature.14 Overall,
we have accomplished a new total synthesis of pentabromopseudi-
lin in a 28% overall yield, over 5 steps.
Using a similar strategy, we moved toward the total synthesis of
the 3-aryl compound isopentabromopseudilin (19). Initially, we
performed the Heck–Matsuda reaction between ortho-methoxy
benzenediazonium salt 5 and 3-pyrroline 11, available from the
ring closing metathesis reaction of the appropriated N-protected
diallylamine.20
To carry out the arylation of 3-pyrroline 11, we used a proce-
dure described previously by us, using Pd(OAc)2 as the pre-catalyst
in a mixture of acetonitrile and water as the solvent.20 Under these
conditions the reaction went to completion in only 15 min. The
crude reaction product was then subjected to dehydration leading
to the desired arylated enecarbamate 13 in a 73% isolated yield
(Scheme 4).
Scheme 1. Preparation of aryl dihydropyrroles by HM reaction.
pentabromopseudilin (4), as well as in studies toward its 3-arylated
regioisomer, isopentabromopseudilin (see compound 19 ahead).
Results and discussion
Aiming at the synthesis of the 2-arylpyrrole natural product 4,
we first investigated the Heck–Matsuda reaction between
enecarbamate 621 and the ortho-methoxy benzenediazonium salt
5 (Scheme 2).
Based on our own previous results, we initiated this study
employing Pd(dba)2 as the catalyst and 3 equiv of NaOAc as the
base, in acetonitrile as the solvent.18 Firstly, we investigated the
stoichiometry of the reaction to find out that the use of 1.5 equiv
of the olefin led to improved yields of the desired 2-arylpyrroline
7 (entries 1–3, Table 1). Larger excesses of the olefin did not lead
to improvements in yields (entry 4).
Secondly, we tested benzonitrile as the solvent, since it proved
to be beneficial in many other Heck–Matsuda reactions.22–24 In
benzonitrile the reaction took place very quickly, but only decom-
position of the starting materials was observed (entry 5). Perform-
ing the reaction at lower temperature led to lower yields (entry 6).
The use of PhCN as an additive in CH3CN did not bring any
improvement in yields when compared to CH3CN alone (entry 7).
Finally, we observed that using freshly macerated NaOAc as the
base resulted in cleaner and faster reactions (entries 8–9). In these
cases, only a slight excess of the olefin (1.2 equiv) was necessary to
obtain good yields of the desired Heck adduct 7 after just 10 min
(78% isolated yield). It is worth mentioning that no isomerized
Heck adducts were detected in any of these experiments.
As pentabromopseudilin (4) bears a free phenol in its structure,
we also prepared the o-hydroxybenzenediazonium tetrafluorobo-
rate (see compound 14 ahead) and reacted it with enecarbamate
OMe
OMe
OMe
DDQ
NaOH
N
N
MeOH
r.t.
PhMe, Δ
N
H
sealed tube
O
OBn
O
OBn
7
8
9
(92-97%)
(82-85%)
Br
Br
OH
OH
Br
Na2S
py .HBr
r
3
Br
N
H
EtOH, r.t.
N
NMP, Δ
H
10
4
(95%)
(46%)
Br
OMe
OMe
Pd(dba)2
Scheme 3. Synthesis of pentabromopseudilin (4) from Heck adduct 7.
+
N
N
N2BF4
NaOAc (3 eq.)
r.t.
O
OBn
O
OBn
5
6
7
OMe
OMe
Scheme 2. Preparation of 7 by means of the HM reaction.
TFAA
2,4-Lut
Pd(OAc)2
1.5%
OMe
+
N
PhMe
OH
OEt
CH3CN/H2O
OEt
r.t.
N2BF4
N
N
Table 1
O
O
OEt
13
(73%, 2 steps)
O
Optimization of HM reaction conditions for preparation of 7
5
11
12
Entry 5 (equiv) 6 (equiv) Pd(dba)2 (mol %) Solvent
Yield 7 (%)
Scheme 4. Preparation of 13 through a HM/dehydration sequence.
1
2
3
4
1.5
1.5
1
1
1
1
1
4
8
4
4
4
4
4
CH3CN
CH3CN
CH3CN
CH3CN
PhCN
46–47
43–46
67
66
Decomp.
43
1.5
2
1.5
1.5
1.5
5
6a
7b
1
1
PhCN
H
O
PhCN/
CH3CN
CH3CN
CH3CN
61
OH
O
- H+
Pd(OAc)2, 5%
N
8c
9c
1
1
1.5
1.2
4
4
71–73
78
+
N
CH3CN/H2O
OEt
5h, r.t.
N2BF4
EtO
O
O
N
a
b
c
14
11
15
(96%)
Reaction performed at 0 °C.
PhCN used as an additive, 10% v/v.
Freshly macerated NaOAc employed.
O
OEt
Scheme 5. Formation of the unprecedent tricycle 15 under HM reaction.

1662
C. S. Schwalm et al. / Tetrahedron Letters 53 (2012) 1660–1663
Figure 2. Ortep diagram for tricyciclic compound 15. Displacement ellipsoids are drawn at 50% probability level. H atoms are shown as small spheres of arbitrary radius.
In spite of the formation of lactamol 12 in the process—due to
the acidification of the reaction medium—its intermediacy in the
overall process is beneficial, since previous attempts to drive the
reaction to the endocyclic enecarbamate in this kind of transforma-
tion proved to be troublesome.19,20 This difficulty is probably
related to the high reactivity of the enecarbamate product under
the Heck–Matsuda conditions, leading to undesired byproducts
and diarylated compounds, for instance.
OMe
OMe
OMe
OH
BBr3
NaOH
DDQ
CH2Cl2
xylene, Δ
MeOH
r.t.
N
N
sealed tube
N
N
-78ºC - r.t.
H
H
EtO
O
EtO
O
13
16 (83%)
17 (95-98%)
18 (72%)
Scheme 6. Preparation of arylpyrrole 18 from Heck adduct 13.
Interestingly, when the o-hydroxyl benzenediazonium salt 14
was subjected to the Heck–Matsuda reaction (5 mol % of Pd, 5 h)
the tricyclic compound 15 was obtained in a 96% isolated yield
(Scheme 5). This curious compound results from the intramolecu-
lar attack of the free phenol group onto the transient N-acylimini-
um ion formed in the course of reaction.
This new tricyclic compound, an unusually thermostable N,O-
acetal, was fully characterized by spectroscopic methods and its
structure was confirmed by X-ray crystallography (Fig. 2 see
details in the supplementary data).
Br
Br
OH
Br
OH
OH
Br
Br
Br
pyr.HBr3
EtOH
Br
Br
O
O
N
N
N
H
H
H
18
Isopentabromopseudilin (19)
20
(66%)
Scheme 7. Attempted preparation of isopentabromopseudilin (19).
Continuing our efforts toward the synthesis of isopentabrom-
opseudilin (19), the Heck adduct 13 was then subjected to aroma-
tization employing DDQ in xylene (Scheme 6), leading to the 3-
arylpyrrole derivative 16 in ꢀ83% yield.25 As before, the reaction
was very clean and a simple filtration on a short pad of silica gel
afforded compound 16 with enough purity to be used in the next
step without further purification.
The N-carboethoxy arylpyrrole 16 was then deprotected under
basic conditions to afford the arylpyrrole 17 in excellent yield and
purity, after a simple extractive work-up. Demethylation of arylpyr-
role 17 proved challenging, and after much experimentation, we
found out that the use of 5 equiv of BBr3 as the demethylating agent
leads to the desired phenol derivative 18 in a 72% isolated yield.
For the completion of the synthesis of isopentabromopseudilin
(19), a final bromination step was required. With this objective in
mind several reaction conditions employing Pyr.HBr3 and trib-
romoisocianuric acid (TBCA) as bromination agents were evalu-
ated.26 However, under all conditions tested only the maleimide
derivative 20 was obtained, probably due to a very facile pyrrole
oxidation after bromination of the putative intermediates, or from
the direct oxidation of the rather unstable isopentabromopseudilin
(Scheme 7).27
In view of this unexpected result, the brominated aryl malei-
mide 20 was fully characterized by spectroscopic methods. We
were able to obtain a single crystal derived from co-crystallization
of maleimide 20 with the pyr.HBr. The structure of this complex
was elucidated by X-ray diffraction, and is shown below (Fig. 3
see details in the supplementary data).
Conclusion
This work illustrates the viability of the HM reaction as a key
step in the synthesis of a variety of valuable arylpyrrole deriva-
tives. The versatility of this approach was demonstrated by the
effective synthesis of both 2 and 3-arylpyrroles. Moreover, a new
total synthesis of the natural product pentabromopseudilin (4)
was also developed. An attempted synthesis of isopentabromopse-
udilin (19) led to the exclusive formation of an interesting trib-
romo arylmaleimide. Isopentabromopseudilin is reported as an
unstable compound which decomposes expontaneously.27 We
hypothesize that maleimide 20 is the main oxidation product
resulting from the decay of isopentabromopseudilin.

C. S. Schwalm et al. / Tetrahedron Letters 53 (2012) 1660–1663
1663
Figure 3. Ortep diagram for a co-crystal of compound 20 with pyr.HBr. Displacement ellipsoids are drawn at 50% probability level. H atoms are shown as small spheres of
arbitrary radius.
10. Fedorov, R.; Bohl, M.; Tsiavaliaris, G.; Hartmann, F. K.; Taft, M. H.; Baruch, P.;
Acknowledgments
Brenner, B.; Martin, R.; Knolker, H. J.; Gutzeit, H. O.; Manstein, D. J. Nat. Struct.
Mol. Biol. 2009, 16, 80.
The authors thank the Brazilian National Research Council
(CNPq) and the Research Supporting Foundation of the State of
São Paulo (FAPESP) for fellowships and financial support.
11. Preller, M.; Chinthalapudi, K.; Martin, R.; Knolker, H. J.; Manstein, D. J. J. Med.
Chem. 2011, 54, 3675.
12. Martin, R.; Jager, A.; Bohl, M.; Richter, S.; Fedorov, R.; Manstein, D. J.; Gutzeit, H.
O.; Knolker, H. J. Angew. Chem., Int. Ed. 2009, 48, 8042.
13. Hanessian, S.; Kaltenbronn, J. S. J. Am. Chem. Soc. 1966, 88, 4509.
14. Xu, Z. R.; Lu, X. Y. J. Org. Chem. 1998, 63, 5031.
15. Roglans, A.; Pla-Quintana, A.; Moreno-Mañas, M. Chem. Rev. 2006, 106, 4622.
16. Taylor, J. G.; Moro, A. V.; Correia, C. R. D. Eur. J. Org. Chem. 2011, 1403.
17. Felpin, F.-X.; Nassar-Hardy, L.; Le Callonnec, F.; Fouquet, E. Tetrahedron 2011,
67, 2815.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2012.01.086.
18. Garcia, A. L. L.; Correia, C. R. D. Tetrahedron Lett. 2003, 44, 1553.
19. Carpes, M. J. S.; Correia, C. R. D. Synlett 2000, 1037.
20. de Oca, A.; Correia, C. R. D. Arkivoc 2003, 390.
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