A Palladium-Catalyzed Domino Approach to 2,3-Disubstituted Benzofurans via an Intermolecular Carbopalladation/C(sp3)?H Functionalization/Isomerization Sequence

Article abstract of DOI:10.1002/adsc.201600356

A palladium-catalyzed domino strategy has been developed for the synthesis of 2,3-disubstituted benzofuran derivatives. This cascade reaction sequence involves intermolecular carbopalladation and C(sp³)?H functionalization followed by isomerization. (Figure presented.).

Full text of DOI:10.1002/adsc.201600356

UPDATES
DOI: 10.1002/adsc.201600356
A Palladium-Catalyzed Domino Approach to 2,3-Disubstituted
3
À
Benzofurans via an Intermolecular Carbopalladation/C(sp ) H
Functionalization/Isomerization Sequence
Siva Senthil Kumar Boominathan,a Ruei-Jhih Hou,a Wan-Ping Hu,b Po-Jui Huang,a
and Jeh-Jeng Wanga,*
a
Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
Fax : (+886)-7-312-5339; phone: (+886)-7-312-1101; e-mail: jjwang@kmu.edu.tw
Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
b
Received: April 4, 2016; Revised: May 12, 2016; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201600356.
2
À
Abstract: A palladium-catalyzed domino strategy
has been developed for the synthesis of 2,3-disubsti-
tuted benzofuran derivatives. This cascade reaction
C(sp ) H activation.[8] Despite the significant progress
made in this field, this active palladium species has
not yet been intercepted with C(sp ) H bonds. En-
3
À
sequence involves intermolecular carbopalladation
couraged by our continuing interest on metal-cata-
3
À
and C(sp ) H functionalization followed by isomer-
ization.
lyzed cascade reactions,[9] we envisioned that the
active vinyl Pd(II) species from intermolecular carbo-
palladation could be trapped with C(sp ) H bonds to
construct 2,3-disubstituted benzofurans [Scheme 1,
Eq. (c)].
Benzofurans are a ubiquitous class of heterocycles,
which are embedded in numerous pharmaceuticals,
natural products, unnatural compounds possessing
bio-activity and materials.[10] Consequently, tremen-
dous efforts have been made towards the synthesis of
3
À
3
À
Keywords: benzofurans; C(sp ) H functionaliza-
tion; domino reaction; palladium; vinyl palladium
species
The development of simple and straightforward syn- benzofuran and its derivatives.[11] The reported meth-
thetic methodologies towards the construction of val- ods to prepare the 2,3-disubstituted benzo[b]furans
uable heterocycles has an essential role in organic are less represented in the literature. The available
synthesis. In recent years, the domino reaction has re- methods are frequently suffering from multistep syn-
ceived significant attention due to its convenience in thesis and harsh reaction conditions. The scope of the
assembling multiple bonds in a one-pot process, thus present cascade reaction involves simple starting ma-
providing an efficient and step-economical route for terials and relatively tolerable reaction conditions.
the synthesis of complex heterocycles.[1] One repre-
We commenced our optimization studies using 1-
sentative strategy is the generation of transient vinyl phenyl-2-(2-(phenylethynyl)phenoxy)ethan-1-one (1a)
palladium(II) species from the intermolecular or in- with iodobenzene (2a) in the presence of various pal-
tramolecular carbopalladation of alkynes (or alkenes) ladium catalysts, ligands, and bases as shown in
and aryl halides, which can be further captured by Table 1. We were pleased to obtain an encouraging
any nucleophile in a cascade sequence.[2] The seminal outcome of desired product with Pd(PPh3)4 and
work describes the trapping of in situ vinyl palladium NaOAc in DMF (Table 1; entry 1). With the initial
species with alkenes,[3] or boronic acids[4] and leads to success, we evaluated different Pd(II) and Pd(0) sour-
tetrasubstituted alkenes. Inspired by these works, sub- ces with or without ligands and among them
stantial advances have been made by capturing this Pd(OAc)2 in combination with PPh3 furnished the
active species with anions, nucleophiles,[5] organome- maximum yield of 55% (Table 1; entries 2–7). Inferior
2
tallic reagents,[6] and C(sp ) H/(sp)-H functionaliza- performance was observed, when the reaction was
À
tion reactions[7] [Scheme 1, Eqs. (a) and (b)]. Recent- screened with other phosphine ligands (entries 8–11).
ly, our group has also developed the Pd/Ni-catalyzed Next, the feasibility of the reaction was investigated
stereoselective synthesis of tetrasubstituted olefins via with several inorganic bases (entries 12–17). With the
intermolecular carbopalladation followed by triazole strong bases such as LiO-t-Bu and KO-t-Bu it under-
Adv. Synth. Catal. 0000, 000, 0 – 0
1
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÞÞ
These are not the final page numbers!

UPDATES
asc.wiley-vch.de
Scheme 1. Domino reactions via vinyl palladium species: previous and present approaches.
goes the intramolecular carbanion-yne cyclization to base plays a crucial role and NaOAc was found to be
give undesired compound 4a predominantly (en- the optimum base in this transformation. Changing
tries 12 and 13)[12] and relatively mild bases were inef- the solvent did not improve the reaction yield (en-
ficient (entries 14–17). These results indicated that the tries 18–22). Reactions were performed at different
Scheme 2. Proposed reaction mechanism.
Adv. Synth. Catal. 0000, 000, 0 – 0
2
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÞÞ
These are not the final page numbers!

UPDATES
asc.wiley-vch.de
Table 1. Optimization of the reaction conditions.[a]
Entry
Catalyst
Ligand
Base
Solvent
Time/Temp. [oC]
Yield [%] 3a/4a
1
2
3
4
5
6
7
8
Pd(PPh3)4
Pd(OAc)2
Pd2(dba)3
Pd(dba)2
–
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
LiO-t-Bu
KO-t-Bu
KOPiv
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMSO
ACN
16/100
16/100
16/100
16/100
16/100
16/100
16/100
16/100
16/100
16/100
16/100
16/100
16/100
16/100
16/100
16/100
16/100
16/100
16/reflux
16/reflux
16/reflux
16/120
20/80
26/traces
55/traces
35/traces
40/traces
–
PPh3
–
–
PdCl2
PPh3
PPh3
PPh3
TFP
dppf
P(cy)3
P(nBu)3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
Pd(TFA)2
Pd(PPh3)2Cl2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
–
–
28/10
40/–
–
–
–/85
–/78
15/60
–
traces/25
28/traces
50/traces
15/–
–/traces
–/traces
38
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25[b]
26[c]
K2CO3
Cs2CO3
KOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
toluene
dioxane
DMA
DMF
DMF
DMF
DMF
72/traces
–
65/traces
76/traces
20/60
30/80
20/80
[a]
Reaction conditions: 1a (0.29 mmol), 2a (0.43 mmol), catalyst (0.1 equiv.), ligand (0.2 equiv.), base (3 equiv.), solvent
(1.5 mL).
[b]
[c]
Catalyst (0.05 equiv.) and ligand (0.1 equiv.) used.
4 equiv. of base.
temperatures and the best yield was accomplished at dides (R3) and the respective compounds were isolat-
808C (entries 23 and 24). Decreasing the catalyst ed (3h–k). Of note, substrates in which R2 substituted
loading results in a longer time to complete the reac- with aryl, alkyl, or cycloalkyl groups, the reaction gen-
tion and slightly decreased the reaction yield erally worked well (3l–3p). The scope of the reaction
(entry 25). Increasing the equivalents of base im- at R4 was also examined with different groups such as
proved the reaction yield to 76% and we fixed this as methyl, chloro and fluoro, the corresponding benzo-
optimized conditions for further studies (entry 26).
furans were obtained in good yields (3q–t). However,
After establishing the suitable set of reaction condi- the attempts to extend the strategy to indole deriva-
tions, we probed the scope and limitations of this cas- tives were failed (3u). The carbonyl groups replaced
cade reaction and summarized the results in Table 2. with ester and cyano groups did not provide the ex-
A variety of different aryl-substituted groups at the pected molecules (3v–w). The structure of the com-
R1 position such as phenyl, p-anisyl, p-tolyl, and 4- pound 3g was confirmed by X-ray analysis.[13]
chlorophenyl were successfully converted into desired
On the basis of observed results and literature prec-
products in moderate to good yields (Table 2; 3a–3d). edence,[6,7,8] a plausible mechanistic pathway has been
Interestingly, the R1 replaced with naphthyl, furan proposed in Scheme 2. Initially the aryl iodide under-
and thiophene substrates were smoothly converted goes oxidative addition with in situ generated Pd(0)
into corresponding benzofurans (3e–g). The scope of catalyst and subsequently react with compound 1 via
the reaction was demonstrated with different aryl io- intermolecular carbopalladation gives complex B.[14]
Adv. Synth. Catal. 0000, 000, 0 – 0
3
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÞÞ
These are not the final page numbers!

UPDATES
asc.wiley-vch.de
Table 2. Substrate scope and limitations.[a]
[a]
General reaction conditions: 1 (0.29 mmol), 2 (0.43 mmol), Pd(OAc)2 (0.1 equiv.), PPh3 (0.2 equiv.), NaOAc (4 equiv.),
DMF (1.5 mL) at 808C for 20 h.
Reaction mixture decomposed.
No reaction.
[b]
[c]
Then the complex B activates the sp3 carbon with the ans has been developed. This method can provide
assistance of base gives six-membered palladacycle C. a synthetic route to disubstituted benzofurans in an
The reductive elimination of complex C delivers efficient manner. The cascade reaction proceeds via
3
À
alkene intermediate 4 and expels catalyst for the next an intermolecular carbopalladation, C(sp ) H func-
cycle. Finally, the intermediate D isomerize via [1,3]- tionalization and isomerization sequence. The salient
H shift to desired 2,3-disubstituted benzofurans (3).
features of this work include mild reaction conditions,
An alternative reaction mechanism via deprotona- good substrate scope and moderate to high yields.
tive palladation of methylene carbon has been out-
lined in Scheme 3.[15] Initially the starting material
1 will convert into corresponding enolate E with the
Experimental Section
aid of base. Next the enolate E reacts with the arylat-
ed palladium species A to give intermediate F. Subse-
quently, it undergoes intramolecular carbopalladation
with alkynes followed by reductive elimination to give
the intermediate 4 which then isomerizes into 3.
In conclusion, a palladium-catalyzed domino ap-
General Procedure for the Synthesis 2,3-
Disubstituted Benzofurans (3a–t)
An oven-dried 15-mL glass tube with screw cap was charged
with 1a (0.29 mmol) in DMF (1.5 mL) and then 2a
proach to the synthesis of 2,3-disubstituted benzofur- (0.43 mmol), Pd(OAc)2 (0.1 equiv.), PPh3 (0.2 equiv.), and
Adv. Synth. Catal. 0000, 000, 0 – 0
4
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÞÞ
These are not the final page numbers!

UPDATES
asc.wiley-vch.de
Scheme 3. Alternative reaction pathway.
NaOAc (4 equiv.) were added. The reaction mixture was
heated to 808C for 20 h. After the reaction was completed
(monitored by TLC), the reaction mass was partitioned be-
tween water and ethyl acetate, then the combined organic
phases washed with brine solution, dried over sodium sulfate
and evaporated under vacuum. The resulting crude material
was purified by flash column chromatography on silica gel
(100–200 mesh) with suitable ratios of hexane and ethyl ace-
tate to afford the desired product (3). The identity and
purity of the compounds were determined by 1HNMR,
13CNMR, DEPT and HR-MS data.
B. Movassagh, H. R. Bijanzadeh, J. Org. Chem. 2010,
75, 2806–2812.
[6] a) F. Xue, J. Zhao, T. S. A. Hor, T. J. Hayashi, J. Am.
Chem. Soc. 2015, 137, 3189–3192; b) L. F. Tietze, A.
Dꢁfert, F. Lotz, L. Sçlter, K. Oum, T. Lenzer, T. Beck,
R. Herbst-Irmer, J. Am. Chem. Soc. 2009, 131, 17879–
17884; c) T. Castanheiro, M. Donnard, M. Gulea, J.
Suffert, Org. Lett. 2014, 16, 3060–3063.
[7] a) N. Chernyak, D. Tilly, Z. Li, V. Gevorgyan, Chem.
Commun. 2010, 46, 150–152; b) M. Pawliczek, B. Milde,
P. G. Jones, D. B. Werz, Chem. Eur. J. 2015, 21, 12303–
12307; c) L. L. Suarez, M. F. Greaney, Chem. Commun.
2011, 47, 7992–7994; d) H. Liu, M. El-Salfiti, D. I. Chai,
J. Auffret, M. Lautens, Org. Lett. 2012, 14, 3648–3651;
e) M. Leibeling, M. Pawliczek, D. Kratzert, D. Stalke,
D. B. Werz, Org. Lett. 2012, 14, 346–349; f) M.-B. Zhou,
X.-C. Huang, Y.-Y. Liu, R.-J. Song, J.-H. Li, Chem. Eur.
J. 2014, 20, 1843–1846; g) A. Bunescu, T. Piou, Q.
Wang, J. Zhu, Org. Lett. 2015, 17, 334–337; h) U. K.
Sharma, N. Sharma, Y. Kumar, B. K. Singh, E. V. Van
der Eycken, Chem. Eur. J. 2016, 22, 481–485; i) L. F.
Tietze, T. Hungerland, C. Eichhorst, A. Dꢁfert, C.
Maaß, D. Stalke, Angew. Chem. Int. Ed. 2013, 52, 3668–
3671; j) K. M. Gericke, D. I. Chai, N. Bieler, M. Laut-
ens, Angew. Chem. 2009, 121, 1503–1506; Angew.
Chem. Int. Ed. 2009, 48, 1475–1479.
Acknowledgements
We gratefully acknowledge the financial support from the
Ministry of Science and Technology (MOST), Taiwan and
thank the Centre for Research Resources and Development
of Kaohsiung Medical University for NMR analyses.
References
[1] a) T. Mꢁller, C. Aubert, Metal Catalyzed Cascade Reac-
tions, Springer, Berlin, 2006; b) H. Pellissier, Chem.
Rev. 2013, 113, 442–524.
[8] G. C. Senadi, W.-P. Hu, S. S. K. Boominathan, J.-J.
Wang, Adv. Synth. Catal. 2013, 355, 3679–3693.
[9] a) S. S. K. Boominathan, J.-J. Wang, Chem. Eur. J. 2015,
21, 17044–17050; b) G. C. Senadi, W.-P. Hu, A. M. Gar-
khedkar, S. S. K. Boominathan, J.-J. Wang, Chem.
Commun. 2015, 51, 13795–13798; c) G. C. Senadi, W.-P.
Hu, S. S. K. Boominathan, J.-J. Wang, Chem. Eur. J.
2015, 21, 998–1003; d) S. S. K. Boominathan, G. C.
Senadi, J. K. Vandavasi, J. Y.-F. Chen, J.-J. Wang,
Chem. Eur. J. 2015, 21, 3193–3197; e) S. S. K. Boomina-
than, W.-P. Hu, G. C. Senadi, J.-J. Wang, Adv. Synth.
Catal. 2013, 355, 3570–3574.
[2] a) R. Chinchilla, C. Nꢂjera, Chem. Rev. 2014, 114,
1783–1826; b) Y. Luo, X. Pan, X. Yu, J. Wu, Chem. Soc.
Rev. 2014, 43, 834–846.
[3] a) A. N. Thadani, V. H. Rawal, Org. Lett. 2002, 4, 4317–
4320; b) L. F. Tietze, K. Kahle, T. Raschke, Chem. Eur.
J. 2002, 8, 401–407.
[4] a) C. Zhou, D. E. Emrich, R. C. Larock, Org. Lett.
2003, 5, 1579–1582.
[5] a) D. Chernyak, V. Gevorgyan, Org. Lett. 2010, 12,
5558–5560; b) M. Bararjanian, S. Balalaie, F. Rominger,
Adv. Synth. Catal. 0000, 000, 0 – 0
5
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÞÞ
These are not the final page numbers!

UPDATES
asc.wiley-vch.de
[10] a) H. Khanam, Shamsuzzaman, Eur. J. Med. Chem.
2015, 97, 483–504; b) G. Khodarahmi, P. Asadi, F. Has-
sanzadeh, E. Khodarahmi, J. Res. Med. Sci. 2015, 20,
1094–1104; c) A. Hiremathad, M. R. Patil, C. K. R. K.
Chand, M. Amelia Santos, R. S. Keri, RSC Adv. 2015,
5, 96809–96828; d) R. Naik, D. Harmalkar, X. Xu, K.
Jang, K. Lee, Eur. J. Med. Chem. 2015, 90, 379–393;
e) A. Radadiya, A. Shah, Eur. J. Med. Chem. 2015, 97,
356–376; f) P. J. Zimetbaum, N. Engl. J. Med. 2009, 360,
1811–1813; g) H. Tsuji, C. Mitsui, L. Ilies, Y. Sato, E.
Nakamura, J. Am. Chem. Soc. 2007, 129, 11902–11903;
h) S. O. Simonetti, E. L. Larghi, A. B. J. Braccaa, T. S.
Kaufman, Nat. Prod. Rep. 2013, 30, 941–969.
[11] a) Y. Kommagalla, K. Srinivas, C. Ramana, Chem. Eur.
J. 2014, 20, 7884–7889; b) C. Chen, P. Dormer, J. Org.
Chem. 2005, 70, 6964–6967; c) M. Willis, D. Taylor, A.
Gillmore, Org. Lett. 2004, 6, 4755–4757; d) J. Hu, L.
Wu, X. Wang, Y. Hu, Y. Niu, X. Liu, S. Yang, Y. Liang,
Adv. Synth. Catal. 2010, 352, 351–356; e) D. J. Paymode,
C. V. Ramana, J. Org. Chem. 2015, 80, 11551–11558;
f) I. Nakamura, Y. Mizushima, Y. Yamamoto, J. Am.
Chem. Soc. 2005, 127, 15022–15023; g) A. Fꢁrstner,
P. W. Davies, J. Am. Chem. Soc. 2005, 127, 15024–
15025.
[12] a) P.-Y. Chen, T.-P. Wang, K.-S. Huang, C.-L. Kao, J.-C.
Tsai, E.-C. Wang, Tetrahedron 2011, 67, 9291–9297;
b) The structure of 4a was confirmed by X-ray analysis
(CCDC 1471981; these data can be obtained free of
charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif).
[13] CCDC 1471975 (3g) contains the supplementary crys-
tallographic data for this paper. These data can be ob-
tained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_re-
quest/cif.
[14] The rationalization for the regioselective insertion of
aryl palladium species into alkynes has been explained
in the Supporting Information.
[15] a) N. Chernyak, S. I. Gorelsky, V. Gevorgyan, Angew.
Chem. 2011, 123, 2390–2393; Angew. Chem. Int. Ed.
2011, 50, 2342–2345; b) S. W. Youn, B. S. Kim, A. R.
Jagdale, J. Am. Chem. Soc. 2012, 134, 11308–11311.
Adv. Synth. Catal. 0000, 000, 0 – 0
6
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÞÞ
These are not the final page numbers!

UPDATES
A Palladium-Catalyzed Domino Approach to 2,3-
7
Disubstituted Benzofurans via an Intermolecular
3
À
Carbopalladation/C(sp ) H Functionalization/Isomerization
Sequence
Adv. Synth. Catal. 2016, 358, 1 – 7
Siva Senthil Kumar Boominathan, Ruei-Jhih Hou,
Wan-Ping Hu, Po-Jui Huang, Jeh-Jeng Wang*
Adv. Synth. Catal. 0000, 000, 0 – 0
7
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÞÞ
These are not the final page numbers!