Palladium-catalyzed oxidative cross-coupling of N-tosylhydrazones with indoles: Synthesis of N-vinylindoles

Article abstract of DOI:10.1021/ol401217h

A general and efficient palladium-catalyzed oxidative cross-coupling reaction of N-tosylhydrazones with indoles providing N-vinylindoles has been developed. The reaction proceeds smoothly with various indoles and N-tosylhydrazones in a stereocontrolled ma

Full text of DOI:10.1021/ol401217h

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Palladium-Catalyzed Oxidative Cross-
Coupling of N-Tosylhydrazones with
Indoles: Synthesis of N-Vinylindoles
Xiaobao Zeng, Guolin Cheng, Jinhai Shen, and Xiuling Cui*
Engineering Research Center of Molecular Medicine, Ministry of Education, Key
Laboratory of Xiamen Marine and Gene Drugs, Institutes of Molecular Medicine and
School of Biomedical Sciences, Huaqiao University, Xiamen, 361021, China
cuixl@hqu.edu.cn
Received April 30, 2013
ABSTRACT
A general and efficient palladium-catalyzed oxidative cross-coupling reaction of N-tosylhydrazones with indoles providing N-vinylindoles has
been developed. The reaction proceeds smoothly with various indoles and N-tosylhydrazones in a stereocontrolled manner, and a wide variety of
N-vinylindoles were obtained up to 99% yields for 26 examples.
In recent years, intense efforts have been devoted to the
direct functionalization of indole cores for the synthesis of
active indole derivatives owing to their ubiquity in natural
products, pharmaceuticals, and functional material.1 In
particular, N-vinylindoles are of increasing importance in
material science as monomers for the synthesis of poly-
(N-vinylindoles),2 which can be used as semiconductors
and photosensitive materials.2a,e Among the various syn-
thetic strategies to construct N-vinylindoles, the transition
metal catalyzed cross-coupling reaction of indoles with
prefunctionalized alkenes, such as vinyl triflates3a and
vinyl halides,3b,c is a powerful and reliable method.3
A straightforward and atom-efficient approach was devel-
oped by Li and co-workers via the gold(III)-catalyzed
tandem reaction of o-alkynylanilines with terminal al-
kynes, affording 2-substituted N-vinylindole scaffolds
in moderate yields.4a More recently, the hydroamination
of alkynes was reported by Verma and co-workers and
gave N-vinylindoles in a mixture of Z- and E-forms.4bÀd
Acid-promoted condensations of alkyl or aryl R-branched
aldehydes with indole derivatives could provide N-vinyl-
indoles.5 Although these protocols provided access to
N-vinylindoles, the narrow scope of substrates, high cost,
and harsh reaction conditions have limited their applica-
tions. Considering the importance of N-vinylindoles and
the drawbacksofthe existing methods, the exploration and
development of an alternative method to construct such a
desirable framework is still attractive.
(1) For reviews on indole chemistry, see: (a) Sundberg, R. L. Indoles;
Academic: London, 1996. (b) Hegedus, B. L. S. Angew. Chem., Int. Ed.
1988, 27, 1113. (c) Cacchi, S.; Fabrizi, G. Chem. Rev. 2005, 105, 2873.
(d) Humphrey, G. R.; Kuethe, J. T. Chem. Rev. 2006, 106, 2875.
(e) Joucla, L.; Djakovitch, L. Adv. Synth. Catal. 2009, 351, 673.
(f) Bandini, M.; Eichholzer, A. Angew. Chem., Int. Ed. 2009, 48, 9608.
(g) Cacchi, S.; Fabrizi, G. Chem. Rev. 2011, 111, 215. (h) Shiri, M. Chem.
Rev. 2012, 112, 3508.
(2) (a) Brustolin, F.; Castelvetro, V.; Ciardelli, F.; Ruggeri, G.;
Colligiani, A. J. Polym. Sci., A: Polym. Chem. 2001, 39, 253. (b) Oshiro,
Y.; Shirota, Y.; Mikawa, H. J. Polym. Sci. Polym. Chem. Ed. 1974, 12,
2199. (c) Priola, A.; Gatti, G.; Cesca, S. Makromol. Chem. 1979, 180, 1.
(d) Gipstein, E.; Hewett, W. A. Macromolecules 1969, 2, 82. (e) Maki, Y.;
Mori, H.; Endo, T. Macromolecules 2007, 40, 6119.
On the other hand, Barluenga’s first employment of
N-tosylhydrazones in the Pd-catalyzed cross-coupling re-
action in 2007, which proceeded via the BamfordÀStevens
intermediate,6,7 has significantly reinvigorated the use of
(4) (a) Zhang, Y. H.; Donahue, J. P.; Li, C. J. Org. Lett. 2007, 9, 627.
(b) Verma, A. K.; Joshi, M.; Singh, V. P. Org. Lett. 2011, 13, 1630.
(c) Joshi, M.; Tiwari, R.; Verma, A. K. Org. Lett. 2012, 14, 1106. (d) Joshi,
M.; Patel, M.; Tiwari, R.; Verma, A. K. J. Org. Chem. 2012, 77, 5633.
(5) Fridkin, G.; Boutard, N.; D. Lubell, W. J. Org. Chem. 2009, 74,
5603.
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Q.; Wang, Y.; Zhang, L.; Xi, C. J. Org. Chem. 2009, 74, 6371.
(c) Artyom, Y.; Lebedev, V. V. I; Denis, N.; Kazyul’kin; Beletskaya,
I. P.; Voskoboynikov, A. Z. Org. Lett. 2002, No. 4, 623. (d) Bogdal, D.;
Jaskot, K. Synth. Commun. 2000, 30, 3341. (e) Deagostino, A.; Prandi,
C.; Zavattaro, C.; Venturello, P. Eur. J. Org. Chem. 2007, 8, 1318.
r
10.1021/ol401217h
XXXX American Chemical Society

readily available N-tosylhydrazones, which were derived
from the corresponding aldehydes or ketones, as the
precursors of in situ-generated nonstabilized diazo com-
pounds in the formation of CÀC,8 CÀO,9 CÀP,10 CÀS,11
CÀB,12 and CÀN13 bonds through both metal-catalyzed
and metal-free processes.14 Migratory insertion involving
a palladium carbene was proposed to constitute the key
step in these processes.15 Although impressive progress
has been achieved, however, to the best of our knowledge,
CÀN bond formation using N-tosylhydrazone as a carbo-
nyl surrogate has been rarely reported.13 Based on that, we
report herein a novel approach to N-vinylindoles via Pd-
catalyzed oxidative cross-coupling of N-tosylhydrazones
with indoles.
The condensation of indole 1a with N-tosylhydrazone
2a was initially chosen as a model reaction to screen the
reaction parameters. The desired product 3a was obtained
in 56% yield using 10 mol % Pd(OAc)2/PPh3 as a catalyst,
3.0 equiv of LiOtBu as a base, in toluene at 110 °C (Table 1,
entry 1). Inspired by the preliminary results, the solvents
were examined first (entries 1À4). N,N-Dimethyl forma-
mide (DMF) gave unparalleled performance in this reac-
tion, providing the desired product in 82% yield (entry 3).
When the loading of catalyst was reduced to 5 mol %, the
product 3a was afforded in 80% yield (entry 5). While,
complete inactivity of this reaction system was observed in
the absence of the palladium acetate (entry 6). The base
and the reaction temperature are critical for this transfor-
mation. Of the temperature tested, 80 °C appeared to be
the most favorable (entry 5 vs 7). Whereas, the yield was
decreased to 75% by continuous lowering of the tempera-
ture to 60 °C (entry 7 vs 8). Further fine-tuning of the
reaction conditions has revealed that LiOtBu was superior
to other inorganic bases, such as K2CO3, NaOAc, and
KOtBu (entries 7, 10À13). The yield was not improved
significantly by using Pd(PPh3)2Cl2 as a catalyst instead
of Pd(OAc)2 in the presence of 10 mol % PPh3 (entry 13 vs
14). However, the yield of 3a could reach 94% without
adding PPh3 (entry 15). Interestingly, the reaction pro-
ceeded to completion within 36 h when 2.5 mol % of
Pd(PPh3)2Cl2 was loaded and gave a 92% isolated yield
(entry 17). The controlled experiments were carried out
under air or N2, which led to lower yields of 3a (entries 19,
20). After additional evaluations of palladium catalysts,
bases, temperatures, and catalyst loadings, a combination
of 1a:2a = 1:1.5, 5 mol % Pd(PPh3)2Cl2, and 2.0 equiv of
LiOtBu in DMF at 80 °C were found to be optimal, and 3a
was isolated in 99% yield within 4 h (entry 16).
With the optimized reaction conditions established
(Table 1, entry 16), the scope of the substrates for this reac-
tion was investigated. As shown in Scheme 1, this catalytic
system exhibited highly catalytic activity for a large range
of N-tosylhydrazones and indoles and afforded the main
products 3 in up to 99% yields for 26 examples. A wide
variety of functional groups including nitro, halogens,
ether, aryl, and trifloromethyl groups were tolerated under
the optimal reaction conditions. N-Tosylhydrazones with
both electron-donating and -withdrawing substituents
were compatible with this reaction system, providing
the corresponding coupling products in good to excellent
yields (87À99%, Scheme 1, 3aÀg). This reaction was not
affected significantly by the steric hindrance in N-tosylhy-
drazones. The variation of substituents at the ortho, meta,
and para position in N-tosylhydrazones could afford the
desired products in 92À96% yields (3b, 3h, 3i). Tosylhy-
drazones derived from 1-(naphthalen-2-yl) ethanone and
dihydronaphthalen-1(2H)-one were also good partners for
this transformation. The desired products 3k and 3l were
obtained in 92% and 91% yields, respectively.
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Additionally, nonterminal olefins 3m, 3n, and 3r could
be obtained in 99%, 94%, and 83% yields, respectively.
Normally, the substrates with a halogen easily undergo the
arlyation reaction with N-tosylhydrazones to afford biaryl
derivatives.6,8gÀj To our delight, the presence of halides on
the aromatic ring of N-tosylhydrazones did not interfere with
the formation of the desired products (3bÀd, 3hÀi, 3o),
which provided opportunities for further synthetic elabora-
tion. The substrate scope could be extended to N-tosylhy-
drazone derived from 1-(2,4-dichlorophenyl) ethanone to
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Chem. 2011, 9, 6200. (b) Barluenga, J.; Tomas-Gamasa, M.; Valdes, C.
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B
Org. Lett., Vol. XX, No. XX, XXXX

Table 1. Optimization of Reaction Conditionsa
Scheme 1. N-Vinylation of Indoles with N-Tosylhydrazonesa
catalyst
(mol %)
t
base
yield
(%)c
entry
solvent (°C)
(equiv)
1
2
Pd(OAc)2 (10)
Pd(OAc)2 (10)
toluene 110 LiOtBu (3.0)
56
58
1,4-
110 LiOtBu (3.0)
dioxane
DMF
DMSO
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
3
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (5)
À
110 LiOtBu (3.0)
110 LiOtBu (3.0)
110 LiOtBu (3.0)
110 LiOtBu (3.0)
82
20
80
0
4
5
6
7
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(PPh3)2Cl2 (5)
Pd(PPh3)2Cl2 (5)
80
60
80
80
80
80
80
80
80
80
80
80
80
80
LiOtBu (3.0)
LiOtBu (3.0)
LiOtBu (3.0)
KOtBu (3.0)
NaOtBu (3.0)
K2CO3 (3.0)
NaOAc (3.0)
LiOtBu (3.0)
LiOtBu (3.0)
LiOtBu (2.0)
LiOtBu (2.0)
LiOtBu (2.0)
LiOtBu (2.0)
LiOtBu (2.0)
91
75
77
78
72
70
89
86
94
99
92
93
85
42
8
9b
10
11
12
13
14
15b
16b
17b
Pd(PPh3)2Cl2 (5) DMF
Pd(PPh3)2Cl2 (2.5) DMF
18b,c Pd(PPh3)2Cl2 (5)
19b,d Pd(PPh3)2Cl2 (5)
20b,e Pd(PPh3)2Cl2 (5)
DMF
DMF
DMF
a Reaction conditions: 1a (0.5 mmol), 2a (0.75 mmol), solvent (2 mL),
PPh3 (10 mol %), under O2. b Without ligand. c Isolated yields based
on 1a. 1a:2a = 1:1.2. d Under air atmosphere. e Under N2. DMSO =
Dimethyl sulfoxide.
a Reaction conditions: Indole (0.5 mmol), N-tosylhydrazone deriva-
tives (1.5 equiv), Pd(PPh3)2Cl2 (5 mol %), LiOtBu (2.0 equiv), DMF
(2 mL) under O2, 80 °C. Isolated yields based on indoles.
deliver 3o with reasonable yields (70%). As a limitation of
this transformation, we found that N-tosylhydrazones de-
rived from cyclohexanone, 1-methylpiperidin-4-one, and
tetrahydropyran-4-one failed to yield the desired products,
probably due to the relative less stability of the corresponding
carbene intermediates derived from aliphatic ketones.
Scheme 2. Proposed Mechanistic Pathway
Moreover, the reaction tolerated electronically and
sterically diverse substituents at the indole moiety. Both
mono- and disubstituted indoles effectively participated in
this reaction (3pÀy). More sterically congested substrates
delivered the target products with moderate yields (3pÀt).
A series of 5-substituted-1-(1-phenylvinyl)-1H-indole scaf-
folds could be readily prepared under the standard reac-
tion conditions (3vÀx). Notably, the halide moieties on
the aromatic ring of indoles also remained intact under the
present PdII/Pd0 catalytic cycle (3uÀw). Encouragedby the
successwithvarioussubstitutedindoles, wewerepleasedto
observe that carbazole could also be employed as a sub-
strate to furnish the corresponding product in 99% yield
(3z).16 1H-Imidazole, 1H-benzo[d]imidazole, 1H-pyrrole,
and 1H-indazole were also probed, and the corresponding
products were not observed. The stereochemistry of 3r was
further confirmed by 1H NMR and NOESY spectra and
assigned as the E isomer (for details, see the Supporting
Information).
Based on the experimental results obtained and in the
literature on transition metal catalyzed cross-coupling
reactions of N-tosylhydrazones,3c,6,17 a plausible mechanism
was proposed (shown in Scheme 2). An initial reaction
(16) During our preparation of the manuscript, the synthesis of N-
vinyl carbazole was reported by: Takeda, D.; Hirano, K.; Satoh, T.;
Miura, M. Org. Lett. 2013, 15, 1242.
Org. Lett., Vol. XX, No. XX, XXXX
C

of the diazocompound A (generated in situ from
N-tosylhydrazones in the presence of base) with palladium
gave a palladium-carbene B species. Then base-assisted
ligand exchange of palladium-carbene B with lithated
indole provided an indolyl palladium C species. Next,
the indolyl palladium C species underwent a migratory
insertion process to give intermediate D. Finally, syn
β-hydrogen elimination of D produced the olefin 3
and Pd(0) species in the presence of base. Oxidation of
the Pd(0) species by O2 regenerated the active Pd(II)
species.
In conclusion, we have developed a novel type of
Pd-catalyzed oxidative cross-coupling reaction to access
N-vinylindoles using cheap and readily available starting
materials as well as the environmentally benign oxidant via
a sequential palladium carbene migratory insertion and
β-H elimination process, which formed a CÀN and a CdC
bond spontaneously. This transformation provided an
easy and efficient method for the synthesis of N-vinylin-
doles derivatives and exhibited good functional group
tolerance and a remarkably wide scope. Further investiga-
tions to gain detailed mechanistic insight into this reaction
and extension of the coupling reaction to other types
of CÀN bond-forming reactions are currently underway
in our group.
Acknowledgment. This work was supported by the
NSF of China (21202048), Program for Minjiang Scholar
program (10BS216), Science Research Item of Science and
Technology of Xiamen City (3502z201014), and Funda-
mental Research Funds of Huaqiao University.
Supporting Information Available. Synthesis procedure,
1
characterization, H and 13C NMR spectra of products
3aÀz. This material is available free of charge via the
Internet at http://pubs.acs.org.
(17) Satoh, J.; Sakurada, J. Tetrahedron 2007, 63, 3806.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX