Benzofuran derivatives from alkynyl-substituted benzynes and aryl halides

Article abstract of DOI:10.1021/ol4032254

A palladium(0)-catalyzed cascade reaction for the efficient synthesis of 2,3-disubstituted benzofuran derivatives 3 containing a 3-trisubstituted alkene functional group in moderate yields from alkynyl-substituted benzynes 1 and aryl halides 2 has been developed. This method provides an efficient and alternative approach to benzofurans which are very useful heterocyclic compounds with biological and pharmacological potentials. A plausible mechanism involving intramolecular ene reaction, intermolecular insertion, and β-H elimination is proposed.

Full text of DOI:10.1021/ol4032254

Letter
pubs.acs.org/OrgLett
Benzofuran Derivatives from Alkynyl-Substituted Benzynes and
Aryl Halides
Weiming Yuan† and Shengming Ma*,†,‡
†Shanghai Key Laboratory of Green Chemistry and Chemical Process, Department of Chemistry, East China Normal University,
3663 North Zhongshan Lu, Shanghai 200062, P. R. China
‡State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
345 Lingling Lu, Shanghai 200032, P. R. China
S
* Supporting Information
ABSTRACT: A palladium(0)-catalyzed cascade reaction for the efficient synthesis of 2,3-disubstituted benzofuran derivatives 3
containing a 3-trisubstituted alkene functional group in moderate yields from alkynyl-substituted benzynes 1 and aryl halides 2
has been developed. This method provides an efficient and alternative approach to benzofurans which are very useful heterocyclic
compounds with biological and pharmacological potentials. A plausible mechanism involving intramolecular ene reaction,
intermolecular insertion, and β-H elimination is proposed.
Scheme 1. Concept for the Efficient Synthesis of Substituted
Benzofurans F
enzofurans are a class of very important heterocyclic com-
Bpounds existing widely in natural products and unnatural
compounds with biological and pharmacological potentials;1
thus, much attention has been paid to the development of the
synthetic methods.2−7 Although numerous synthetic appro-
aches to this family of compounds have been developed in the
past decades, general protocols for the synthesis of these
compounds are still of high interest. On the other hand, arynes
have proven to be one of the most important building blocks in
organic synthesis.8 As a highly active species, they have been
widely used in various carbon−carbon and carbon−heteroatom
bond-forming reactions, such as cycloaddition reactions,9
nucleophilic addition reactions,10 and transition-metal-catalyzed
cyclization and carbometalation reactions.11 Intermolecular
carbopalladation, in particular, shows a powerful potential for
ortho-difunctionalization of arynes through multicomponent
coupling reactions (Scheme 1).12−15 Herein, we hypothesize
that if a benzyne precursor and an alkyne are preinstalled in the
same molecule A, subsequent intermolecular carbopalladation
of ArPdX with B followed by an intramolecular insertion
reaction would form intermediate D, if the regioselectivity
allows. Subsequent β-H elimination would produce allene E,
which may easily isomerize to benzofuran derivatives F
(Scheme 1). Such an approach would provide an efficient
and alternative approach for the construction of the benzocyclic
compounds.
2.0 equiv of K3PO4, and 2.0 equiv of PhI in CH3CN at 50 °C
for 3 h, to our surprise, the desired product 4-aryl-substituted
benzofuran-type F (Ar = Ph) was not formed. Instead, a new
To test our hypothesis, we initially synthesized substrate 1a
as the benzyne precursor to explore this reaction: when we
treated 1a with 5 mol % of Pd(PPh3)4, 3.0 equiv of CsF,
Received: November 9, 2013
Published: December 10, 2013
© 2013 American Chemical Society
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dx.doi.org/10.1021/ol4032254 | Org. Lett. 2014, 16, 193−195

Organic Letters
Letter
product, which was identified as 3a with the phenyl group from
phenyl iodide located in a different place, was detected in 39%
NMR yield (Table 1, entry 1).
Thus, we defined 5 mol % of Pd(PPh3)4, 3.0 equiv of CsF, 1.2
equiv of ArI in CH3CN under reflux as the standard conditions
to explore the feasibility. The scope of the reaction using
differently substituted iodobenzene with 1a is showed in Table 2:
a
Table 1. Optimization of the Reaction Conditions
Table 2. Reaction of Different Substituted Iodobenzenes
a
with Benzyne Precursor 1a
b
entry
1
base
temp (°C)
time (h)
yield of 3a (%)
K3PO4
K3PO4
Ag2CO3
K3PO4
−
50
3
39
34
34
23
49
57
60
60
entry
Ar
time (min)
isolated yield of 3 (%)
c
2
50
3
1
Ph (2a)
50
45
60
60
65
50
70
70
60
80
60
70
55 (3a)
46 (3b)
53 (3c)
46 (3d)
47 (3e)
53 (3f)
46 (3g)
43 (3h)
47 (3i)
43 (3j)
45 (3k)
46 (3l)
3
4
5
6
7
50
3
2
p-MeC6H4 (2b)
m-MeC6H4 (2c)
p-i-Pr-C6H4 (2d)
p-AcC6H4 (2e)
p-EtO2CC6H4 (2f)
p-F-C6H4 (2g)
p-ClC6H4 (2h)
p-BrC6H4 (2i)
3,5-Cl2C6H3 (2j)
1-naphthyl (2k)
2-thienyl (2l)
25
5
3
50
3
4
−
−
−
70
45 min
40 min
40 min
5
reflux
reflux
6
d
8
7
a
The reaction was conducted with 0.1 mmol of 1a in 2 mL of solvent.
8
b
The yield was determined by 1H NMR analysis of the crude product
9
c
using 1,3,5-trimethylbenzene as the internal standard. THF was used
as the solvent. PhI 1.2 equiv was used.
10
11
12
d
A rationale for the formation of 3 is shown in Scheme 2:
first, the benzyne intermediate 4 was formed in situ upon the
treatment of 1a with CsF; an instant intramolecular ene reac-
tion produces readily allene intermediate 5 obviously due to
the aromaticity of the benzene ring; insertion reaction with
ArPdI forms a π-allylic palladium intermediate 6 and sub-
sequent β-H elimination would afford the unexpected isomeric
benzofuran derivative 3.16
a
The reaction conditions: 0.3 mmol of 1a, 0.015 mmol of Pd(PPh3)4,
0.9 mmol of CsF, and 0.36 mmol of PhI in 5 mL of CH3CN under
reflux.
not only the electron-donating substituted aryl iodides but also
electron-withdrawing ones may react smoothly to afford the
corresponding products in moderate yields within 1 h (entries 2−6),
showing this reaction is not sensitive to the electronic effect;
substrates containing a synthetically versatile F-, Cl-, or Br- sub-
stituent to the Ar moiety may also be applied (entries 7−10);
1-naphthyl or heteroaryl substituent, such as 2-thienyl were also
tolerated (entries 11 and 12); the structure of 3j was further
confirmed by the X-ray single-crystal diffraction studies17
(Figure 1).
Scheme 2. Proposed Mechanism
Figure 1. ORTEP representation of 3j.
Inspired by this result, some reaction parameters such as
solvent, base, and temperature effects were investigated for the
purpose of improving the yield. First, changing the solvent to
THF led to a slightly lower yield of 34% (entry 2); Ag2CO3
failed to provide better results (entry 3); the reaction at room
temperature afforded 3a in only 23% yield with a longer time
(entry 4); in fact, this reaction could also proceed smoothly in
absence of any base (entry 5); raising temperature afforded the
product 3a in better yields within 1 h (entries 6 and 7); 1.2
equiv of PhI were enough to complete this reaction (entry 8).
Furthermore, substrates 1b and 1c containing a methyl or
n-C5H11 substituent may also work with the introduction of new
alkyl substituent to the 2-position of benzofuran to produce
2,3-disubstituted benzofurans with practicable yields (eq 1).
Finally, substrates 1d and 1e with longer carbon-chain
substituents were also applied to afford the products E-3o and
E-3p highly stereoselectively in the yields of 41% and 34%,
respectively, and the geometry of the double bond of 3o was
determined to be E, based on NOESY experiment (eq 2).
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Letter
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In conclusion, we have developed an efficient approach to
synthesize benzofuran derivatives from alkynyl-substituted ben-
zynes and aryl halides via the intermediacy of allene. Further
studies including synthetic application are underway in this
laboratory.
ASSOCIATED CONTENT
* Supporting Information
Detailed experimental procedures and characterization data.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(13) Henderson, J. L.; Edwards, A. S.; Greaney, M. F. J. Am. Chem.
Soc. 2006, 128, 7426.
■
S
(14) (a) Jeganmohan, M.; Cheng, C.-H. Org. Lett. 2004, 6, 2821.
(b) Jayanth, T. T.; Jeganmohan, M.; Cheng, C.-H. Org. Lett. 2005, 7,
2921. (c) Jeganmohan, M.; Cheng, C.-H. Synthesis 2005, 10, 1693.
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15716.
AUTHOR INFORMATION
Corresponding Author
(16) Jayanth, T. T.; Jeganmohan, M.; Cheng, M. J.; Chu, S.-Y.;
Cheng, C.-H. J. Am. Chem. Soc. 2006, 128, 2232.
■
(17) Crystal data for compound 3j: C16H10Cl2O; MW = 289.14,
monoclinic space group P2(1)/c, final R indices [I > 2σ(I)], R1 =
0.0396, wR2 = 0.1022, R indices (all data) R1 = 0.0436, wR2 = 0.1062, a
= 7.8959(11) Å, b = 13.1930(18) Å, c = 25.493(4) Å, α = 90°, β = 90°,
γ = 90°, V = 2655.6(6) Å3, T = 173(2) K, Z = 8, reflections collected/
unique 27306/2345 (Rint = 0.0602), number of observations [>2σ(I)]
2345, parameters: 180. Supplementary crystallographic data have been
deposited at the Cambridge Crystallographic Data Center. CCDC
966889.
*E-mail: masm@sioc.ac.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the National Basic Research Program of
China (No. 2011CB808700) and the National Natural Science
Foundation of China (No. 21232006) is greatly appreciated.
We thank Mr Yulin Han in this group for reproducing the
results of 3f, 3n, and E-3o presented in this study.
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