Palladium-catalyzed hydrodehalogenation of butenolides: An efficient and sustainable access to β-arylbutenolides

Article abstract of DOI:10.1016/j.tetlet.2017.06.016

Several α-unsubstituted β-arylbutenolides have been prepared in 69–92% yield by reductive dehalogenation of α-halo-β-arylbutenolides. The latter were assembled in a single-step from α,β-dihalobutenolides, which are accessible on a large-scale from biomass-derived furfural. Our dehalogenation protocol is illustrated by a new synthesis of the marine antibiotics rubrolide E and F, and 3″-bromorubrolide F.

Full text of DOI:10.1016/j.tetlet.2017.06.016

Accepted Manuscript
Palladium-Catalyzed Hydrodehalogenation of Butenolides: An Efficient and
Sustainable Access to β-Arylbutenolides
Milandip Karak, Luiz C.A. Barbosa, Celia R.A. Maltha, Thiago M. Silva, John
Boukouvalas
PII:
S0040-4039(17)30737-2
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.06.016
TETL 49008
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
4 April 2017
25 May 2017
6 June 2017
Please cite this article as: Karak, M., Barbosa, L.C.A., Maltha, C.R.A., Silva, T.M., Boukouvalas, J., Palladium-
Catalyzed Hydrodehalogenation of Butenolides: An Efficient and Sustainable Access to β-Arylbutenolides,
Tetrahedron Letters (2017), doi: http://dx.doi.org/10.1016/j.tetlet.2017.06.016
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Palladium-Catalyzed Hydrodehalogenation of
Butenolides: An Efficient and Sustainable Access to β-Arylbutenolides
Milandip Karak,a,b Luiz C. A. Barbosa,a,b * Celia R. A. Maltha,b Thiago M. Silva,a and John Boukouvalasa,c

1
Tetrahedron Letters
journal homepage: www.els evier.com
Palladium-Catalyzed Hydrodehalogenation of Butenolides: An Efficient and
Sustainable Access to β-Arylbutenolides
Milandip Karak,a,b Luiz C. A. Barbosa,a,b ∗ Celia R. A. Maltha,b Thiago M. Silva,a John Boukouvalasa,c
aDepartment of Chemistry, Universidade Federal de Minas Gerais, Av. Pres. Antônio Carlos, 6627, Campus Pampulha, CEP 31270-901, Belo Horizonte, Brazil.
bDepartment of Chemistry, Universidade Federal de Viçosa, Av. Peter Henry Rolfs, s/n Campus Universitário, CEP 36570-900, Viçosa, MG, Brazil.
cDepartment of Chemistry and Centre for Green Chemistry and Catalysis, Université Laval, 1045 Av. de la Médecine, Quebec City, Quebec G1V 0A6, Canada.
ARTICLE INFO
ABSTRACT
Several α-unsubstituted β-arylbutenolides have been prepared in 69-92% yield by reductive
dehalogenation of α-halo-β-arylbutenolides. The latter were assembled in a single-step from α,β-
dihalobutenolides, which are accessible on a large-scale from biomass-derived furfural. Our
dehalogenation protocol is illustrated by a new synthesis of the marine antibiotics rubrolide E
and F, and 3”-bromorubrolide F.
Article history:
Received
Received in revised form
Accepted
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Reductive dehalogenation
Suzuki cross-coupling
Vinylogous aldol condensation
Rubrolides synthesis
1. Introduction
relevant compounds.9 For example, replacement of the hydroxyl
group in mucochloric acid 4a by amines provided a series of
The α-unsubstituted β-arylbutenolide unit is found in several
natural1 and unnatural products2 endowed with significant
biological activities. For instance, the synthetic drug benfurodil
(Eucilat®, 1) is used in the treatment of congestive heart failure2a
while β-(2,5-dihydroxyphenyl) butenolide (2),2c a synthetic
analogue of the natural product amisnolide (3),1c displays
antitumor activity comparable to that of Adriamycin®.2c
γ−amino derivatives displaying activity against Trypanosoma
cruzi.10 On the other hand, 4a-b can be easily reduced with
sodium borohydride in the presence of sulfuric acid to afford α,β-
dihalobutenolides 5a-b in high yields.11 These butenolides are
also versatile, stable building blocks frequently employed in site-
selective cross-coupling reactions leading to α-halo-β-aryl/alkyl
butenolides. The latter have served as intermediates in the
synthesis of a variety of bioactive compounds,12 including the
well-known COX-2 inhibitor rofecoxib (Vioxx®).12a,d
HO
HO
OH
acid
acid
O
OH
Figure 1. Synthetic and natural β-arylbutenolides
O
furfural
O
-H2O
X2
+H2O
Given the medicinal value and demonstrated utility of β-
arylbutenolides as synthetic intermediates, a number of methods
for their preparation have been developed.3-6 Among the most
versatile are those involving transition metal catalyzed cross-
coupling of tetronic acid derivatives.4a,5 In this regard,
inexpensive mucohalic acids 4a-b (ca. 0.20–1 US$/gram)
represent an attractive starting point as they are readily available
on a large scale from furfural,7 obtained from raw biomass via
acid-catalyzed dehydration of xylose8 (Scheme 1). Addition of
chlorine or bromine to furfural affords the corresponding
xylose
Raw biomass
H2O, heat
X
X
X
X
NaBH4
H2SO4
O
HO
O
O
O
mucohalic acids
5a
5b
X= Cl
X= Br
4a
4b
X= Cl
X= Br
Scheme 1. Sustainable access to α,β-dihalobutenolides from biomass
mucohalic acids7 that can be used in the synthesis of medicinally
———
∗ Corresponding author. Tel.: +55 31 38993068; fax: +55 31 38993065; e-mail: lcab@ufmg.br

2
Tetrahedron
Given the ready availability α-halo-β-arylbutenolides from
Table 1. Optimization of the Reductive Dehalogenation of 6a
5a-b,12 access to their α-unsubstituted counterparts would simply
entail removal of the superfluous halogen.
Although many methods are available for the dehalogenation
of aromatic halides,13 few have been shown to be applicable to α
or β-halobutenolides.12a,14,15 Further, only two α-halo-β-
arylbutenolides have been dehalogenated thus far, notably by
Rossi.12a Both of them bear an α-bromo substituent. Their
dehalogenation was carried out using either an excess of
activated zinc powder (4 equiv) or Pd(OAc)2/PPh3 (3 mol% each)
in the presence of HCOOH/Et3N, affording the desired products
in yields of 74% and 41%, respectively.12a
Entry
Catalysta
Ligandb
Hydrogen
Sourcec
Et3Nd
Solvent
Yieldf
(%)
29
1
2
Pd(OAc)2
PPh3
-
DMF
Pd(PPh3)4
Et3Nd
DMF
21
3
PdCl2(PPh3)2
-
Et3N
DMF
26
Reported herein is a broader investigation of the latter process
along with the development of a new procedure, applicable to a
range of α-bromo and chloro-β-arylbutenolides. In addition, we
describe an application of this chemistry to the synthesis of three
4
Pd(PhCN)2Cl2
Pd(MeCN)2Cl2
Pd(MeCN)2Cl2
Pd(MeCN)2Cl2
Pd(MeCN)2Cl2
Pd(MeCN)2Cl2
Pd(MeCN)2Cl2
Pd(MeCN)2Cl2
Pd(MeCN)2Cl2
Pd(MeCN)2Cl2
Pd(MeCN)2Cl2
PPh3
PPh3
PPh3
AsPh3
dppf
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
Et3Nd
Et3Nd
DMF
58
5
DMF
59
6
Et3N
Et3Nd
DMF
47
rubrolide antibiotics, notably rubrolides E,
F
and 3”-
7
DMF
31
bromorubrolide F.16
8
Et3N
DMF
22
9
DIPEAd
DIPEAd
DIPEAd
DIPEAd
DIPEAd
DIPEAd
DIPEAd
DMF
61
2. Results and discussion
10
11
12
13
14
15e
MeCN
Toluene
DCM
DMSO
Dioxane
MeCN
64
The quest to find optimal conditions for effecting Pd-
catalyzed hydrodehalogenation of α-halo-β-arylbutenolides
began with 6a as a model substrate. This compound was prepared
in 76% yield by Suzuki-Miyaura coupling of α,β-
dibromobutenolide 5b with phenylboronic acid using a literature
procedure.12k Bromobutenolide 6a was then subjected to
reduction using different catalysts, ligands, amines/hydrogen
sources and solvents, as outlined in Table 1.
At first, we tried the reaction conditions reported by Rossi12a
and found that the dehalogenated product 7a was obtained in
only 29% yield (Table 1, entry 1). Next, we investigated the
effect of the palladium salt (Table 1, entries 2–5). The use of
Pd(PPh3)4 or PdCl2(PPh3)2 in the presence or absence of formic
acid resulted in low product yields (21-26%, entries 2-3).
However, switching to other Pd-salts, such as Pd(PhCN)2Cl2 or
Pd(MeCN)2Cl2, led to a substantial improvement in yield (58-
59%, entries 4-5). A control experiment further revealed that the
use of a mixture of an equimolar amount of formic acid and
triethylamine resulted in a better yield than the use triethylamine
56
33
58
47
Pd(OAc)2/
Pd(MeCN)2Cl2
Pd(OAc)2
b
81
16
PPh3
DIPEAd
MeCN
46
a
c
Catalyst (5.0 mol%); Ligand (10.0 mol%); Hydrogen source/base (5.0
d
equiv.); Mixture of equimolar amount of HCOOH and base (5.0 equiv.
each); e Each catalyst was used in 2.5 mol%; f Isolated yield after purification
by column chromatography; no other compound(s) could be isolated or
identified from the crude reaction mixture.
Having uncovered an efficient procedure for converting 6a to
7a, the next task was to investigate the substrate scope. To this
end, a range of α-halo-β-arylbutenolides were prepared in good
yields by Suzuki cross-coupling12k (Table 2, entries 1-8, 67-
89%). For the sake of comparison, we also included in our study
a known α-halo-β-alkylbutenolide (6j), synthesized from 5b by
cuprate addition-ellimination,18 as well as the starting α,β-
dihalobutenolides 5a-b (entries 9-10).
alone as
a hydrogen source (entry 5 vs 6). Replacing
triphenylphosphine by other ligands (cf. triphenylarsine or dppf)
did not improve yields (entries 7–8). Likewise, Hünig’s base and
triethylamine gave comparable yields (entry 5 vs 9). In terms of
solvent, acetonitrile turned out to be the best choice, with DMF
coming a close second (entries 9–14). Ultimately, it was found
that the yield of 7a could be significantly improved (81%) by
using a combination of palladium salts, notably equimolar
quantities of Pd(OAc)2 and Pd(MeCN)2Cl2, along with Hünig’s
base and formic acid in acetonitrile (entry 15). Given the elusive
nature of the catalytic species involved in such processes,17 it is
difficult to account for the enhanced performance of this
particular procedure. That said, control experiments have shown
that when either of the two palladium salts is used alone, the
yield of 7a is substantially lower (Table 1, entry 15 vs entries 10
and 16).
As seen from the results, our dehalogenation protocol worked
well with all α-halo-β-arylbutenolides tried (Table 2, entries 1-8,
69-92%). However, the highest yields were obtained with
substrates bearing an α-bromo substituent (cf. entry 1, 6b vs 6b’).
Importantly, the butenolide halogen could be selectively removed
in substrates equipped with a chloro or bromoaryl moiety (entries
3-6). Moreover, the nature of the aromatic substituent(s) had little
impact to the yield of 7 (entries 1-8).
In contrast, replacement of the aryl substituent by an alkyl of
similar steric bulk (cf. isopropyl) led to a modest yield of
dehalogenated product 7j (47%, entry 9). Further, attempts at
removing the β-halogen from dihalobutenolides 5a-b led to
complex product mixtures containing only traces of the
completely dehalogenated butenolide 5 (entry 10).

3
Table 2. Substrate scope.
Entry
Yield of 6 (%)a
Yield of 7 (%)a
Entry
Yield of 6 (%)a
Yield of 7 (%)a
Cl
MeO
MeO
1
6
X
H
Cl
MeO
O
O
O
O
O
O
7b
6b
(from , 92%)
6b
6b'
X= Br (89%)
X= Cl (76%)
6g
(74%)
6b'
(from
, 76%)
F
F
F
2
3
4
5
7
Cl
Br
H
MeO
MeO
O
O
O
O
O
O
6c
7h
(78%)
Cl
(86%)
6h
(67%)
Cl
Cl
Me
Me
8
H
H
Br
MeO
MeO
O
O
O
O
O
O
O
O
6d
7d
(73%)
(79%)
7i
(90%)
6i
6j
(72%)
Cl
Br
9
Br
O
O
O
b
(93%)
O
6e
(86%)
H
H
O
10c
O
5
5a
5b
(from
(from
<1%)
<3%)
a All yields refer to isolated products after purification by column chromatography. b 6j was prepared by cuprate addition-ellimination
(ref. 18). c In both cases (5a/5b) decomposition of starting material was observed and no monohalogenated compound was detected by
GC-MS analysis of the crude reaction mixture.
R
R
+
R
Next, we briefly explored the possibility of performing the
Suzuki cross-coupling/dehalogenation sequence in one-pot
fashion (Scheme 2). However, these efforts turned out to be only
partially successful. Although we were able to generate 7b or 7c
directly from dibromobutenolide 5b, the formation of several
side-products, including triphenylphosphine oxide and the
corresponding α,β-diarylbutenolides (cf. 7b’ or 7c’) made
purification difficult. Thus, 7b could be isolated in a fairly
modest 57% yield when compared to that previously obtained by
the 2-step route (cf. 82% overall, entry 1, Table 2).
ꢀꢁꢂꢃꢄꢃꢁꢅꢆꢇꢄꢈꢉ ꢆꢉ ꢊꢋꢌꢍꢎꢏꢈꢐ
ꢑꢒꢆꢓꢊꢂꢔꢈꢉꢂꢕꢉ ꢆꢉꢏꢖ ꢗꢘꢕꢙꢈꢐ
ꢑꢑꢚꢛ ꢆꢜꢝ ꢗꢘꢕꢙꢈꢐ ꢂꢞꢟ ꢆꢉ ꢊꢋꢌꢍꢎꢏꢈꢐ
ꢠꢘꢕꢌꢊꢡꢊꢢꢄꢉꢇ ꢆꢜꢝꢢꢜꢈꢐ ꢃꢝ ꢘꢂꢐ ꢣ ꢚꢤ
H
Br
Br
O
O
ꢑꢒꢆꢇꢥꢦꢈꢉ ꢆꢉꢏꢖ ꢗꢘꢕꢙꢈꢐ
O
O
O
O
iꢑꢧꢉꢔꢨꢩ ꢆꢖ ꢊꢋꢌꢍꢎꢏꢈꢐ ꢄꢂꢇꢇꢄ
ꢆꢉ ꢊꢋꢌꢍꢎꢏꢈꢐ ꢓꢊꢂꢔꢐ ꢃꢝ ꢘꢂꢐ ꢃ ꢚ
5b
7b' R= OMe (8%)
7c' R= F (6%)
7b R= OMe (57%)
7c R= F (39%)
One-pot procedure
Scheme 2. One-pot Suzuki coupling and reductive dehalogenation.

4
Tetrahedron
At this point, we turned our attention to the synthesis of the
Supplementary Material
marine antibiotics rubrolide E, F and 3”-bromorubrolide F (9-11,
Scheme 3). Besides antimicrobial activities,16 compounds 9-11
were recently shown to inhibit NO production, at concentrations
of 10.53, 8.53 and 11.91 µmol/L, respectively.4f The simplest
member of the family, rubrolide E 9 has been synthesized on
numerous occasions in the past.4a-f However, there is only one
synthesis of rubrolides 10-11, reported in early 2017 by Jun and
co-workers.4f Jun’s route begins from p-methoxyacetophenone
and involves Wittig-Horner olefination and tandem SeO2
Supplementary data (detailed experimental procedures,
compounds characterization data, and copies of 1H and 13C NMR
spectra for all new compounds) associated with this article can be
found, in the online version.
References and notes
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Acknowledgments
We thank the Brazilian agencies Conselho Nacional de
Desenvolvimento Científico e Tecnológico (CNPq) for a research
fellowship (LCAB, TMS), a Visiting Researcher Fellowship
(JB), Coordenação de Aperfeiçoamento de Pessoal de Nível
Superior (CAPES) for a PhD fellowship (MK), and Fundação de
Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG) for
financial support. We are grateful to Ms. Cristiane Cerceau for
technical assistance with the NMR experiments.

5
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Highlights
ꢀ An efficient reductive dehalogenation of α-
halo-β-arylbutenolides was developed
ꢀ A protecting group free synthesis of
rubrolides E and F is described
ꢀ β-arylbutenolides were obtained by one-pot
process from α,β-dihalobutenolides
ꢀ A regioselective dehalogenation of α-halo-
β-arylfuran-2(5H)-ones was developed