Pd-catalyzed cyclization and carbene migratory insertion: New approach to 3-vinylindoles and 3-vinylbenzofurans

Article abstract of DOI:10.1021/ol402368h

A Pd-catalyzed stereoselective synthesis of 3-vinylindoles and 3-vinylbenzofurans has been developed. The reaction merges the alkyne-based Pd-catalyzed cyclization and Pd carbene migratory insertion in a single catalytic cycle, generating a C-C single bond and a C=C double bond in one operation.

Full text of DOI:10.1021/ol402368h

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Pd-Catalyzed Cyclization and Carbene
Migratory Insertion: New Approach to
3‑Vinylindoles and 3‑Vinylbenzofurans
Zhenxing Liu,† Ying Xia,† Shiyi Zhou,† Long Wang,† Yan Zhang,*,† and Jianbo Wang*,‡
Beijing National Laboratory of Molecular Sciences (BNLMS) and Key Laboratory of
Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of
Chemistry, Peking University, Beijing 100871, China, and State Key Laboratory of
Organometallic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China
yan_zhang@pku.edu.cn; wangjb@pku.edu.cn
Received August 18, 2013
ABSTRACT
A Pd-catalyzed stereoselective synthesis of 3-vinylindoles and 3-vinylbenzofurans has been developed. The reaction merges the alkyne-based
Pd-catalyzed cyclization and Pd carbene migratory insertion in a single catalytic cycle, generating a CꢀC single bond and a CdC double bond in
one operation.
Indoles and benzofurans represent privileged structure
motifs in many areas, and numerous synthetic methods
have been developed related to those structures.1,2 In
particular, 3-vinylindoles and 3-vinylbenzofurans are ver-
satile building blocks in organic synthesis.3 Moreover, they
have been reported to show interesting biological prop-
erties.4 During the past decades, many effective methods
have been developed to construct these structures,
particularly Pd-catalyzed reactions which have attracted
great attention. As summarized in the retrosynthetic
representation shown in Scheme 1, the most common
approach is the functionalization of a preformed indole
system by Pd-catalyzed Heck coupling reactions using
3-halo or 3-OTf indoles with alkenes (Scheme 1, a). One
of the drawbacks of this approach is that the N-unprotected
3-haloindoles are usually not stable. More recently, direct
alkenylation of indoles with alkenes through CꢀH bond
functionalization has emerged as an alternative approach
(Scheme 1, a0).5,6 In2005, Gaunt and co-workers reported a
Pd(II)-catalyzed solvent-controlled FujiwaraꢀMoritaniꢀ
Heck coupling of free indoles and alkenes using Cu(OAc)2
as the oxidant.5 The reaction affords 3-vinylindoles when
a DMFꢀDMSO mixture is used as the solvent. However,
† Peking University.
‡ Chinese Academy of Sciences.
(1) Selected reviews on indoles, see: (a) Cacchi, S.; Fabrizi, G. Chem.
Rev. 2005, 105, 2873–2920. (b) Bandini, M.; Eichholzer, A. Angew.
Chem., Int. Ed. 2009, 48, 9608–9644. (c) Cacchi, S.; Fabrizi, G. Chem.
Rev. 2011, 111, PR215–PR218. (d) Kochanowska-Karamyan, A. J.;
Hamann, M. T. Chem. Rev. 2010, 110, 4489–4497. (e) Shiri, M. Chem.
Rev. 2012, 112, 3508–3549. (f) Bandini, M. Org. Biomol. Chem. 2013, 11,
5206–5212.
(2) For a recent review on benzofurans, see: Yeung, K.-S. Top.
Heterocycl. Chem. 2012, 29, 47–76.
(5) Grimster, N. P.; Gauntlett, C.; Godfrey, C. R. A.; Gaunt, M. J.
Angew. Chem., Int. Ed. 2005, 44, 3125–3129.
(3) For reviews, see: (a) Sundberg, R. J. Indoles; Academic: New York,
€
1996. (b) Knolker, H.-J.; Reddy, K. R. Chem. Rev. 2002, 102, 4303–4427.
(6) (a) Djakovitch, L.; Rouge, P. J. Mol. Catal. A: Chem. 2007, 273,
230–239. (b) Maehara, A.; Tsurugi, H.; Tsurugi, T.; Miura, M. Org.
Lett. 2008, 10, 1159–1162. (c) Djakovitch, L.; Rouge, P. Catal. Today
2009, 140, 90–99. (d) Ueyama, T.; Mochida, S.; Fukutani, T.; Hirano,
K.; Satoh, T.; Miura, M. Org. Lett. 2011, 13, 706–708. (e) Mochida, S.;
Hirano, K.; Satoh, T.; Miura, M. J. Org. Chem. 2011, 76, 3024–3033. (f)
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Y.-Q. Org. Lett. 2012, 14, 5920–5923.
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3193–3328.
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Harada, H.; Ito, T. Bioorg. Med. Chem. Lett. 2010, 20, 3916–3919. (b)
Robinson, M. W.; Overmeyer, J. H.; Young, A. M.; Erhardt, P. W.;
Maltese, W. A. J. Med. Chem. 2012, 55, 1940–1956. (c) Venkatesan, P.;
Sumathi, S. J. Heterocycl. Chem. 2010, 47, 81–84.
r
10.1021/ol402368h
XXXX American Chemical Society

the direct vinylation of benzofuran by this method is
always at the 2-position, since the electrophilic palladation
of benzofuran is more favored at the 2-position.
We conceived that, in combination with Pd-catalyzed
cyclization of alkynes, such a type of CdC bond forming
reaction may be applied to the synthesis of 3-vinylindoles
and 3-vinylbenzofurans (Scheme 1, c þ d).
As demonstrated in Scheme 2, the key step involved in
this approach is the migratory insertion of the Pd carbene
B to form intermediate C, which is followed by β-hydride
elimination. Notably, in this transformation, CꢀC single
bond formation (the cyclization) and CdC double bond
formation (carbene coupling) are achieved in a single
catalytic cycle.
Scheme 1. Retrosynthetic Representation of the Pd-Catalyzed
Synthesis of 3-Vinylindoles
Scheme 2. Synthesis of 3-Vinylindoles and 3-Vinylbenzofurans
Based on Pd Carbene Reaction
Pd-catalyzed cyclization represents another powerful
approach for the construction of an indole structure,
among which the alkyne-based Pd-catalyzed synthesis
of indoles has been extensively investigated.7 In 2000,
Yamamoto and co-workers reported an efficient synthesis
of 3-vinylindoles by Pd-catalyzed intramolecular cycliza-
tion of alkynylimines (Scheme 1, b).8 Since the imine
moiety can be generated in situ from the correspond-
ing amine and aldehyde, this reaction has also been ex-
tended to a three-component coupling for 3-vinylindole
synthesis.
Although significant progress has been made for the
synthesis of 3-vinylindoles, some drawbacks exist for the
existing methods. For example, the alkene substrates used
in the coupling reactions are often limited to those contain-
ing electron-withdrawing substituents, and the 3-vinylin-
dole products obtained are usually limited to those bearing
a disubstituted alkene moiety. Moreover, little attention
has been paid to the synthesis of 3-vinylbenzofurans.
Therefore, it is desirable to further develop novel methods
for the synthesis of 3-vinylindoles and 3-vinylbenzofurans.
In recent years, we and several other groups have
reported a series of Pd-catalyzed CdC bond forming reac-
tions based on a Pd carbene migratory insertion process.9
At the outset of this investigation, we employed the
N-tosylhydrazone 2 as the precursor for in situ generation
of a nonstabilized diazo compound (BamfordꢀStevens
reaction).10 We examined the reaction of N-acetyl-N-(3-
phenylprop-2-ynyl)-2-iodoaniline 1a with N-tosylhydrazone
2 in the presence of the Pd(PPh3)4 catalyst and Cs2CO3 in
toluene at 80 °C. The reaction worked well to afford the
desired 3-vinylindole 3a in good yield (eq 1). To further
simplify the reaction, we attempted a one-pot reaction
starting directly from benzadehyde 4a. Thus, the benzade-
hyde 4a was heated with TsNHNH2 at 60 °C in toluene for
10 min, and then N-acetyl-N-(3-phenylprop-2-ynyl)-2-
iodoaniline 1a, Pd(PPh3)4 catalyst, and Cs2CO3 were added
and heating was continued for another 3 h. To our delight,
the one-pot reaction afforded the desired 3-vinylindole 3a
in slightly improved yield (eq 2).
The one-pot reaction was then applied to a series of aro-
matic aldehydes/ketones 4aꢀk and 2-iodoanilines 1aꢀe
(Scheme 3). The reaction is not markedly affected by the
substituents on the aromatic aldehydes. The aromatic
aldehydes including those bearing an electron-donating
group (4b,c) and electron-withdrawing group (4dꢀf),
as well as those sterically hindered aldehydes (4h) and
heteroaromatic aldehyde (4i), all gave the corresponding
3-vinylindoles in moderate to good yields. However,
ketones (4j, k) gave relatively lower yields, which may be
attributed to the lower reactivity of the corresponding
N-tosylhydrazones than these derived from the corre-
sponding aldehydes. The other reaction component, the
2-iodoanilines 1aꢀe, were then examined. It turned out
(7) For selected reviews, see: (a) Alonso, F.; Beletskaya, I. P.; Yus, M.
Chem. Rev. 2004, 104, 3079–3159. (b) Zeni, G.; Larock, R. C. Chem. Rev.
2006, 106, 4644–4680. (c) Patil, N. T.; Yamamoto, Y. Chem. Rev. 2008,
108, 3395–3442. (d) Vlaar, T.; Ruijter, E.; Orru, R. V. A. Adv. Synth.
Catal. 2011, 353, 809–841. (e) Abbiati, G.; Marinelli, F.; Rossi, E.;
Arcadi, A. Isr. J. Chem. 2013, 53, DOI: 10.1002/ijch.201300040. For
related approaches, see: (f) Le Strat, F.; Maddaluno, J. Org. Lett. 2002,
ꢀ
4, 2791–2793. (g) Fressigne, C.; Girard, A.; Durandetti, M.; Maddaluno,
J. Eur. J. Org. Chem. 2009, 721–729. (h) Durandetti, M.; Hardou, L.;
ꢀ
Clement, M.; Maddaluno, J. Chem. Commun. 2009, 4753–4755. (i)
Durandetti, M.; Hardou, L.; Lhermet, R.; Rouen, M.; Maddaluno, J.
Chem. Eur. J. 2011, 17, 12773–12783. (j) Arcadi, A.; Blesi, F.; Cacchi, S.;
Fabrizi, G.; Goggiamani, A.; Marinelli, F. J. Org. Chem. 2013, 78, 4490–
4498.
(8) Takeda, A.; Kamijo, S.; Yamamoto, Y. J. Am. Chem. Soc. 2000,
122, 5662–5663.
(9) For reviews, see: (a) Zhang, Y.; Wang, J. Eur. J. Org. Chem. 2011,
ꢀ
1015–1026. (b) Barluenga, J.; Valdes, C. Angew. Chem., Int. Ed. 2011, 50,
7486–7500. (c) Shao, Z.; Zhang, H. Chem. Soc. Rev. 2012, 41, 560–572.
(d) Xiao, Q.; Zhang, Y.; Wang, J. Acc. Chem. Res. 2013, 46, 236–247. (e)
Zhang, Y.; Wang, J. Top. Curr. Chem. 2012, 327, 239–269.
(10) Bamford, W. R.; Stevens, T. S. J. Chem. Soc. 1952, 4735–4740.
Org. Lett., Vol. XX, No. XX, XXXX
B

that a terminal alkyne (R4 = H) was not a suitable sub-
strate for the reaction, affording the product in low yield
(3l). This is attributed to the side reactions of the terminal
alkyne under the reaction conditions. In contrast, substitu-
tion on the aromatic ring does not markedly affect the
reaction (3mꢀo).
Scheme 3. Pd-Catalyzed Synthesis of 3-Vinylindolesa
Interestingly, this reaction shows excellent stereoselec-
tivity. All the 3-vinylindole products were formed as a
single isomer judged by 1H and 13C NMR spectra. For one
of the products (3e), the E configuration was unambigu-
ously confirmed by X-ray diffraction (Figure 1). We
assume that all the products have the same E configuration
based on the comparison of their NMR spectra.
Figure 1. X-ray structure of 3e and 6g.
Furthermore, we applied this methodology to the synth-
esis of 3-vinylbenzofurans. To our delight, the reactions
occurred smoothly under the similar reaction conditions,
affording the corresponding 3-vinylbenzofurans 6aꢀp in
moderate to good yields (Scheme 4). The substrate scope
is similar to the synthesis of 3-vinylindoles shown in
Scheme 3.11 Notably, 3-vinylfuro[3,2-b]pyridine (6p)
could also be obtained in 74% yield. Again, in all the
reactions the 3-vinylbenzofuran products were formed
as a single isomer as indicated by their 1H and 13C NMR
spectra. For one of the products (6g), the E configuration
was unambiguously confirmed by X-ray diffraction
(Figure 1).
a The reaction was carried out in 0.25 mmol scale; the yields refer to
the products after isolation by silica gel column. b For the second step,
the reaction needed another 2 h at 110 °C after heating 3 h at 80 °C. c The
reaction was carried out by isolating the tosylhydrazone and then
submitting it to the second step.
for this 3-vinylindole/3-vinylbenzofuran synthesis (Scheme 5).
First, 1a undergoes oxidative addition to Pd(0) to form
Pd(II) species A, from which 5-exo-dig cyclization occurs
toaffordPd(II) intermediateB.7 Then A decomposesthe in
situ formeddiazo compound to givePd carbene C, which is
followed by migratory insertion to produce intermediate
D. As there is no β-H for palladium in D, the palladium
Based on our knowledge of Pd-catalyzed cyclization and
Pd carbene reactions, we proposed a reaction mechanism
(11) Aliphatic aldehydes do not work under the current conditions.
Substrates bearing a substituent on the propargylic position lead to a
mixture of E/Z isomers.
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 4. Pd-Catalyzed Synthesis of 3-Vinylbenzofuransa
Scheme 5. Proposed Reaction Mechanism
Scheme 6. Rationalization of Stereoselectivity
elimination to afford the final product 3a with E config-
uration in the formed CdC double bond.
In conclusion, we have developed a Pd-catalyzed synth-
esisof 3-vinylindolesand 3-vinylbenzofurans. This method
combines alkyne-based Pd-catalyzed cyclization and Pd
carbene chemistry and generates a CꢀC single bond and
a CdC double bond in a single catalytic cycle.14 This
transformation further demonstrates the generality of the
incorporation of Pd carbene migratory insertion in various
Pd-catalyzed reactions. From the viewpoint of practical
applications, the reaction uses easily available start-
ing materials and tolerates various functional groups.
Moreover, the reaction shows excellent stereoselectivity.
With these features, we expect that this reaction will
find applications in the synthesis of 3-vinylindoles and
3-vinylbenzofurans.
a The reaction was carried out in 0.25 mmol scale, and isolated yields
are given. b The reaction was carried out by isolating the tosylhydrazone
and then submitting it to the second step.c The reaction temperature
was 100 °C.
undergoes a 1,3-migration to form intermediate E through
allylpalladium η1ꢀη3 interconversion.12 From E, β-H
elimination occurs to afford the final product 3a.
The excellent stereoselectivity observed for the CdC
double bond formation in this reaction may be interpreted
by the equilibrium shown in Scheme 6. In the allylpalla-
dium η1ꢀη3 interconversion, G is favored over F due
to the A (1,3) interaction in the latter case.13 G rearranges
to η1-allylpalladium complex E, which undergoes β-H
Acknowledgment. The project is supported by 973
Program (No. 2012CB821600) and NSFC (No. 21332002).
(12) For a similar carbene migration process involving π-allylpalla-
dium intermediates, see: (a) Chen, S.; Wang, J. Chem. Commun. 2008,
4198–4200. (b) Barluenga, J.; Tomas-Gamasa, M.; Aznar, F.; Valdes, C.
Adv. Synth. Catal. 2010, 352, 3235–3240. (c) Xiao, Q.; Wang, B.; Tian,
L.; Yang, Y.; Ma, J.; Zhang, Y.; Chen, S.; Wang, J. Angew. Chem., Int.
Ed. 2013, 52, 9305–9308.
(13) Hoffmann, R. W. Chem. Rev. 1989, 89, 1841–1860.
(14) For a recent report on a similar Pd-catalyzed cascade reaction,
see: Liu, X.; Ma, X.; Gu, Z. Org. Lett. 2013, 15, 4814–4817.
Supporting Information Available. Experimental pro-
cedures, characterization data and NMR spectra of all
products, X-ray crystallographic data of 3e and 6g
(CIF file). This material is available free of charge via
the Internet at http://pubs.acs.org.
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The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX