Synthesis of Multisubstituted Allenes, Furans, and Pyrroles via Tandem Palladium-Catalyzed Substitution and Cycloisomerization

Article abstract of DOI:10.1021/acs.orglett.6b03561

A palladium-catalyzed propargyl substitution reaction of propargyl acetates with indium organothiolates is developed for the synthesis of multisubstituted allenyl sulfides. This procedure can be applied to the synthesis of multisubstituted furans and pyrroles via tandem palladium-catalyzed propargyl substitution and cycloisomerization reaction in one pot.

Full text of DOI:10.1021/acs.orglett.6b03561

Letter
pubs.acs.org/OrgLett
Synthesis of Multisubstituted Allenes, Furans, and Pyrroles via
Tandem Palladium-Catalyzed Substitution and Cycloisomerization
Taekyu Ryu,† Dahan Eom,† Seohyun Shin, Jeong-Yu Son, and Phil Ho Lee*
Department of Chemistry, Kangwon National University, Chuncheon 24341, Republic of Korea
S
* Supporting Information
ABSTRACT: A palladium-catalyzed propargyl substitution reaction of propargyl acetates with indium organothiolates is
developed for the synthesis of multisubstituted allenyl sulfides. This procedure can be applied to the synthesis of multisubstituted
furans and pyrroles via tandem palladium-catalyzed propargyl substitution and cycloisomerization reaction in one pot.
urans1 and pyrroles2 are ubiquitous scaffolds in a large
Scheme 1. Synthesis of Multisubstituted Allenyl Sulfides,
Furans, and Pyrroles
Fnumber of natural products, pharmaceuticals, and materials
science.3 As a consequence, their synthesis has been an active
area of research for over a century, and many methods for the
streamlined synthesis of furans and pyrroles have been reported,
including classical procedures such as the Paal−Knorr,
Hantzsch, and Feist−Ben
́
ary syntheses.4 In addition, the
intramolecular cyclizations catalyzed by transition metals,
including Cu, Ag, Pd, and Zn, have attracted increasing
attention from the viewpoint of atom economy or environ-
mental concern.5 Although these reactions are advantageous,
most of the methods still require investigation in terms of the
substrate scope and limitations, regioselective introduction of
substituents, catalyst loadings, yields, and reaction conditions.
Recently, an efficient synthetic method toward multi-
substituted furans and pyrroles bearing heterosubstituents was
reported through metal-catalyzed 1,2-shifts of diverse migrating
groups in allenyl systems.6 However, the introduction of a wide
variety of substituents at the 4-position of furans and pyrroles is
impossible due to requirement of a [1,3]-H shift in these
methods. Therefore, the development of an efficient synthetic
method for multisubstituted furans and pyrroles bearing 3-
heteroatom substituents as well as substituents at the 4-position
has been a continuing challenge. Recently, we reported that
indium organothiolate is an effective nucleophilic coupling
partner in Pd-catalyzed C−S cross-coupling reactions.7 On the
basis of these results, we envisioned that if Pd-catalyzed
propargyl substitution reactions of propargyl acetates with
indium organothiolates proceed, multisubstituted allenyl
sulfides might be produced, and as a result, multisubstituted
furans and pyrroles could be produced via tandem Pd-catalyzed
propargyl substitution and cycloisomerization reactions.8 Here-
in, we report Pd-catalyzed propargyl substitution reactions of
propargyl acetates with indium organothiolates for the synthesis
of multisubstituted allenyl sulfides (Scheme 1, eq 1). This
procedure employed tandem Pd-catalyzed propargyl substitu-
tion and cycloisomerization reactions from indium organo-
thiolates and propargyl acetates bearing acyl and imidoyl groups
for the synthesis of multisubstituted furans and pyrroles in one
pot (Scheme 1, eq 2).
We began our investigations by examining the reaction of 2-
phenylbut-3-yn-2-yl acetate (2a) with indium 4-methylbenze-
nethiolate (1e) using palladium catalysts and ligands in DMF
(N,N-dimethylformamide) (Table 1). Pd(PPh3)4 (4.0 mol %) is
ineffective in DMF at 25 °C for 5 h (entry 1). Thus, various
ligands were screened in the presence of 2.0 mol % of
Pd2dba3CHCl3 (entries 2−9). DPEphos gave the best result
among the ligands (entry 9). Among the catalytic systems
examined, the best results were obtained with Pd2dba3CHCl3
(2.0 mol %) and DPEphos (8.0 mol %) in DMF at 25 °C for 5 h
under a nitrogen atmosphere, leading to the formation of allenyl
sulfide 3ae in 74% isolated yield (entry 9). The fact that 0.34
equiv of 1e gave the best results indicates that all of the 4-
methlybenzenethiolate groups attached to the indium metal are
efficiently transferred to 2a. Efficient transfer of the three
organic groups attached to indium to electrophiles can be
explained in connection with the weak bond strength between
sulfur and indium. In addition, the large differences in the heats
of formation between In−S and In−O support the present
results.9
Received: November 29, 2016
© XXXX American Chemical Society
A
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Organic Letters
Letter
a
to the present transformation, providing the corresponding alkyl
allenyl sulfides. For example, 1a and 1b took part in propargyl
substitution reactions with 2a to afford 3aa (90%) and 3ab
(88%). tert-Butyl allenyl sulfide 3ac was obtained in 86% yield
even if the sterically hindered 1c was used. It is noteworthy that
indium alkylthiolates generated from volatile alkyl thiols
operated as efficient nucleophiles, resulting in the formation
of alkyl allenyl sulfides. Acetoxy groups on the aryl ring were
tolerated in the propargyl substitution reaction, producing 3bc
(75%) and 3bd (78%). Moreover, substrate (2c) bearing a
bromide group on the aryl ring was smoothly converted to the
desired allenyl sulfides (3cb, 3cd, and 3cf) in high yields. These
results exhibited the preference of the propargyl substitution
reaction over the cross-coupling reaction. Because sterically
congested alkynes were less reactive, the propargyl substitution
reactions did not proceed even at prolonged reaction time at
room temperature. The propargyl substitution reactions of 2d
with 1 occurred at 100 °C for 1 h, affording the desired allenyl
sulfides (3db, 3dd, 3de, and 3df) in good yields. Internal
propargyl acetates (2e and 2f) were found to be compatible with
the propargyl substitution reaction using 1 at 100 °C for 1 h.
When 2e was reacted with 1b and 1f, tetrasubstituted allenyl
sulfides 3eb and 3ef were obtained in 84% and 83% yields,
respectively. To our delight, the Pd-catalyzed propargyl
substitution reactions of 2f with 1d and 1f took place to give
tetrasubstituted allenyl sulfides 3fd and 3ff in good yields.
Encouraged by these results, we envisioned that if propargyl
acetates bearing acyl groups underwent a propargyl substitution
reaction with indium organothiolates, allenyl ketones bearing
sulfenyl groups might be produced and the sequential
cycloisomerization reaction might occur, leading to the
formation of multisubstituted furans in one pot. To our delight,
reaction of 3-methyl-2-oxonon-4-yn-3-yl acetate (5a) with 1d
(0.34 equiv) in the presence of Pd2dba3CHCl3 (4.0 mol %) and
DPEphos (16.0 mol %) furnished 6ad in 75% yield in DMF at
150 °C within a short time (30 min) (see the Supporting
Information). Having established the tandem Pd-catalyzed
propargyl substitution and cycloisomerization reactions, we
next explored the scope of both propargyl acetates 5 bearing acyl
groups and indium reagents 1 (Scheme 3). Various moieties of
propargyl acetates, such as methyl, ethyl, tert-butyl, cyclohexyl,
Table 1. Reaction Optimization
b
entry
cat.
ligand
yield (%)
c
1
Pd(PPh3)4
0
0
0
0
0
0
0
0
2
3
4
Pd2dba3CHCl3
Pd2dba3CHCl3
Pd2dba3CHCl3
Pd2dba3CHCl3
Pd2dba3CHCl3
Pd2dba3CHCl3
Pd2dba3CHCl3
Pd2dba3CHCl3
Pd2dba3CHCl3
Pd(OAc)2
DPPE
DPPP
DPPF
d
5
P[(2,6-(MeO)2C6H3]3
P(4-CF3C6H4)3
Xantphos
d
6
7
d
8
P(biphenyl)Cy2
DPEphos
e
9
86 (74)
f
g
10
DPEphos
16 (60)
c
11
DPEphos
24
a
Reactions were carried out with 2a (0.3 mmol, 1 equiv) and 1e (0.34
equiv) in the presence of 2.0 mol % of catalyst and 8.0 mol % of ligand.
NMR yield using CH2Br2 as an internal standard. 4.0 mol % catalyst
b
c
d
e
f
was used. 16.0 mol % ligand was used. Isolated yield of 3ae. THF
g
was used. Recovered yield of 2a.
To demonstrate the scope and limitations of the present
method, we applied this catalytic system to diverse propargyl
acetates 2 and indium organothiolates 1 (Scheme 2). The
various indium reagents 1 bearing alkyl and aryl thiolates
showed little effect on the product yield as well as the reaction
rate. Under the optimized conditions, treatment of 2a with 1d
and 1f produced the desired allenyl sulfides 3ad and 3af in 83%
and 86% yields, respectively. Indium alkylthiolates are applicable
a
Scheme 2. Preparation of Multisubstituted Allenyl Sulfides
a
Scheme 3. Synthesis of Tetrasubstituted Furans
a
a
Reactions were carried out with 2 (0.3 mmol, 1 equiv) and 1 (0.34
Reactions were carried out with 5 (0.3 mmol, 1 equiv) and 1 (0.34
equiv) in the presence of 2.0 mol % of Pd2dba3CHCl3 and 8.0 mol %
of DPEphos in DMF at 25 °C. For 1 h at 100 °C.
equiv) in the presence of 4.0 mol % of Pd2dba3CHCl3 and 16.0 mol %
of DPEphos in DMF at 150 °C.
b
B
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Letter
a
cyclohexen-1-yl, phenyl, and phenanthrenyl groups, demon-
strated similar efficiencies. Substrate 5a was found to react with
1b and 1f to afford the corresponding furans 6ab and 6af in 82%
and 76% yields, respectively. Treatment of propargyl acetate
(5b) with 1a furnished the desired furan 6ba in 71% yield.
However, benzoyl- and phenyl-substituted propargyl acetate 5e
was less effective, resulting in the production of 6ea in 42%
yield. In addition, substrate 5f is applicable to the present
transformation with sterically hindered 1c, affording the
corresponding bicyclic furan 6fc. Propargyl acetate (5g) bearing
a sterically hindered tert-butyl group with 1a and 1e is
compatible to the tandem reactions to provide the desired
furans 6ga and 6ge in good yields. The present method worked
equally well with cyclohexen-1-yl-substituted propargyl acetate
(5h) and 1b to give 6hb in 73% yield. When 5i was reacted with
a sterically congested 1c in the presence of palladium catalyst,
allenyl ketone 7ic bearing a tert-butylsulfenyl group was
obtained in 52% yield in DMF at 150 °C for 30 min (eq 3).
Scheme 4. Synthesis of Multisubtituted Pyrroles
A full conversion was observed with a prolonged reaction time
(16 h), leading to furan 6ic in 55% yield. These results indicate
that tetrasubstituted furan 6ic is produced through the
formation of allenyl ketone 7ic. Easily accessible propargyl
acetate 5j from phenanthrene-9,10-dione was found to be
compatible with the reaction conditions.
a
Reactions were carried out with 8 (0.3 mmol, 1 equiv) and 1 (0.34
In addition, propargyl acetates 5c and 5d bearing benzoyl and
acetyl groups easily prepared from nonsymmetrical 1-phenyl-
1,2-propanedione are applicable to the present transformation,
providing 6ca and 6da in 80% and 82% yields, respectively (eqs
4 and 5). These transformations afforded an efficient strategy to
synthesize selectively isomeric tetrasubstituted furans.
equiv) in the presence of 4.0 mol % of Pd2dba3CHCl3 and 16.0 mol %
of DPEphos in DMF at 150 °C (step 1). After step 1, reaction
mixture was cooled to 100 °C and then, Cu(OTf)2 (0.5 equiv) was
added and reactions performed at 100 °C.
b
with 1b, 1e, 1f, and 1g to provide the corresponding pyrroles in
high yields.
When terminal propargyl acetate (8a) bearing a methoxy
imidoyl group was treated with 1f, a mixture of imidoyl allenyl
sulfide 10af and pyrrole 9af was produced in 55% yield (27:73)
(eq 6, see the SI). Thus, a variety of additives for the
We applied the optimized conditions for the synthesis of
multisubstituted furans in tandem Pd-catalyzed propargyl
substitution and cycloisomerization reactions using imidoyl
propargyl acetates 8 for the synthesis of multisubstituted
pyrroles (Scheme 4). Propargyl acetates 8 bearing a wide
range of substituents such as methyl, ethyl, tert-butyl, and phenyl
were investigated under the optimized conditions, producing
multisubstituted pyrroles in good yields. For example, when R1,
R2, and R3 are n-Bu, Me, and Me, respectively, tandem reactions
using 1a and 1b smoothly proceeded in the presence of
Pd2dba3CHCl3 (4.0 mol %) and DPEphos (16.0 mol %),
providing pyrroles 9da (71%) and 9db (73%). The present
method worked equally well with 1d and 1e, producing 9dd
(74%) and 9de (94%) in one pot. In addition, n-pentyl- and
methyl-substituted propargyl acetates 8g were found to react
cycloisomerization from 8a were screened (see the SI). The
modified optimized conditions were obtained from the
propargyl substitution reaction of 8a with 1f in the presence
of Pd2dba3CHCl3 (4.0 mol %) and DPEphos (16.0 mol %),
producing allenyl sulfides 10af in DMF at 25 °C for 5 h, and
then the addition of Cu(OTf)2 (0.5 equiv) to the reaction
mixture provided 9af in 68% yield in one pot (eq 7). Moreover,
treatment of 10af with Cu(OTf)2 in DMF at 100 °C for 1 h
produced the desired pyrrole 9af in 80% yield (eq 8, see the SI).
These results indicate that Cu(OTf)2 was involved in the
cycloisomerization reactions of allenyl sulfides.
C
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Iminopropargyl acetate (8a) was treated with 1d to produce
the desired pyrrole 9ad (52%). When R1, R2, and R3 were n-Bu,
H, and Me, respectively, the tandem reactions proceeded
smoothly, affording pyrroles 9ca, 9cb, and 9cd in good yields. In
the case of propargyl acetate 8b derived from glyoxal, pyrrole
9bd was produced in 31% yield due to the instability of the
substrate. In the reaction with 1f, propargyl acetate 8e having n-
butyl, methyl, and phenyl groups was smoothly converted to the
desired pyrrole 9ef in 81% yield. Exposure of propargyl acetates
8f to 1c and 1e led to the formation of 9fc (82%) and 9fe (94%).
Sterically hindered tert-butyl-substituted propargyl acetate 8h
was reacted with 1b, producing 9hb in 63% yield. Imino
propargyl acetate (8i) was smoothly engaged in a tandem
reaction with 1a and 1e to give the corresponding pyrroles 9ia
(83%) and 9ie (92%).
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: phlee@kangwon.ac.kr.
ORCID
Phil Ho Lee: 0000-0001-8377-1107
Author Contributions
†T.R. and D.E. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by the National Research Foundation
of Korea (NRF, 2011-0018355).
■
A plausible mechanism for the tandem Pd-catalyzed propargyl
substitution and cycloisomerization reactions of propargyl
acetates (5 and 8) bearing acyl and imidoyl groups is described
in Scheme 5. First, the σ-propargyl palladium(II) complex A is
DEDICATION
■
This paper is dedicated to Professor Jaiwook Park (POSTECH)
on the occasion of his 60th birthday.
Scheme 5. Plausible Mechanism
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propargyl acetates with indium organothiolates is developed for
the synthesis of multisubstituted allenyl sulfides. This procedure
can be successfully applied to tandem Pd-catalyzed propargyl
substitution and cycloisomerization reactions from indium
organothiolates and propargyl acetates bearing acyl and imidoyl
groups for the synthesis of multisubstituted furans and pyrroles
in one pot.
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ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b03561.
Experimental procedures, characterization data, and
NMR spectra for all of the products (PDF)
D
DOI: 10.1021/acs.orglett.6b03561
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