Nucleopalladation triggering the oxidative heck reaction: A general strategy to diverse β-indole ketones

Article abstract of DOI:10.1021/ol4027683

A simple and efficient palladium-catalyzed oxidative coupling between 2-alkynyl anilines and allylic alcohols is described by using cheap and green dioxygen as the oxidant. These cross-couplings have a large functional group tolerance and are of higher re

Full text of DOI:10.1021/ol4027683

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Nucleopalladation Triggering the
Oxidative Heck Reaction: A General
Strategy to Diverse β‑Indole Ketones
Qian Wang,† Liangbin Huang,† Xia Wu, and Huanfeng Jiang*
School of Chemistry and Chemical Engineering, South China University of Technology,
Guangzhou 510640, P. R. China
jianghf@scut.edu.cn
Received September 24, 2013
ABSTRACT
A simple and efficient palladium-catalyzed oxidative coupling between 2-alkynyl anilines and allylic alcohols is described by using cheap and green
dioxygen as the oxidant. These cross-couplings have a large functional group tolerance and are of higher reactivity toward electron nonbaised allylic
alcohols. The resultant β-indole ketones are readily converted to pharmaceutically significant β-indole alcohol/amine and pyrrolo[2,1-a]isoquinolines.
In recent decades, the alkyne-directed transformations
catalyzed by palladium have become a powerful tool
to construct highly functionalized products.1 In this re-
gard, nucleopalladation of CÀC triple bonds arguably
represents one of the most attractive strategies to form
multiple carbonÀcarbon and carbonÀheteroatom bonds,
thus leading to various significant organic molecules in one
step.2À5 Generally, different kinds of nucleophiles includ-
ing halides,2 acetates,3 amines,4 and electron-rich carbon
nucleophiles5 have attacked alkynes activated by PdII to
afford the vinyl-Pd species, which could be captured by CO
and olefins.3,6,7 However, olefins used to capture the vinyl-Pd
species have usually been the electron-biased olefins, such as
R,β-unsaturated olefins and styrenes [eq 1].3,7 This has been
due to electron nonbiased olefins having sluggish reactivity
and facing the dilemma of selective β-H elimination.8,9
Lei and Kommu respectively reported the Pd-catalyzed
oxidative coupling between benzoboric acid and allyic
† These authors contributed equally.
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r
10.1021/ol4027683
XXXX American Chemical Society

Table 1. Impact of Reaction Parametersa
Scheme 1. Scope of 2-Alkynyl Anilinesa,b
entry
catalyst
additive
oxidant
O2 (1 atm)
yield [%]b
1
PdCl2
KI
60
2
Pd(TFA)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
À
KI
O2 (1 atm)
O2 (1 atm)
O2 (1 atm)
O2 (1 atm)
O2 (1 atm)
O2 (1 atm)
Ag2CO3 (1 equiv)
CuBr2 (1 equiv)
O2 (1 atm)
À
54
3
KI
85 (80)
13
4
Cs2CO3
TBAI
K2CO3
À
5
34
6
55
7
63
8
KI
trace
20
9
KI
10
11
KI
n.r.
n.d.
Pd(OAc)2
KI
a Reaction was carried out with 1a (0.5 mmol), 2a (1.0 mmol),
additive (0.5 mmol), catalyst (0.025 mmol), DMF (1.5 mL), 90 °C for
8 h. b Determined by GC using dodecane as the internal standard. The
value in parentheses is the yield of isolated product.
alcohols to afford β-aryl ketones and aldehydes [eq 2].10
Very recently, Glorius and our group achieved the Rh-
or Ru-catalyzed highly efficient CÀH alkylation and a
palladium-catalyzed decarbonxylative alkylation using
allylic alcohols as the alkylation reagents.11 And in continua-
tion of our persistent focus on Pd-catalyzed alkynesÀalkenes
coupling initiated by nucleopalladation of alkynes,12 we here-
in report the intramolecular nucleopalladation of alkynes,
using oxygen as the sole oxidant,13 followed by an oxida-
tive Heck-type reaction with another allyic alcohol to afford
the β-heterocycle ketones [eq 3].
a Reaction was carried with 1 (0.5 mmol), 2 (1.0 mmol), KI (0.5 mmol),
Pd(OAc)2 (0.025 mmol), DMF (1.5 mL), 90 °C for 8 h. b Isolated yield.
the presence of palladium catalyst under various condi-
tions (Table 1). We briefly studied the solvent effects
and results illustrated by the high performance of DMF
in terms of yield and reaction time, and we found polar
solvents displayed much better activity (see Supporting
Information for details). Palladium-catalyst investigation
revealed that Pd(OAc)2 showed a higher reactivity (Table 1,
entries 1À3). Then we explored the influence of several
additives, and 1 equiv of KI gave the best result, which
afforded the desired product 3aa in 85% yield (Table 1,
entries 3À6). Furthermore, 3aa was also obtained in 63%
yield when the reaction proceeded without KI (Table 1,
entry 7), which suggested KI played a beneficial role in this
process.3c Among the oxidants screened, metal oxidants
showed a lower yield than that with only O2. Only a trace
The effort was initiated by using 2-(phenylethynyl)-
aniline (1a) and allyl alcohol (2a) as a model reaction in
(9) (a) Chen, M. S.; White, M. C. J. Am. Chem. Soc. 2004, 126, 1346.
(b) Kubota, A.; Emmert, M. H.; Sanford, M. S. Org. Lett. 2012, 14,
1760.
(10) (a) Chen, M.; Wang, J.; Chai, Z.; You, C.; Lei, A. Adv. Synth.
Catal. 2012, 354, 341. (b) Vellakkaran, M.; Andappan, M. M. S.;
Kommu, N. Eur. J. Org. Chem. 2012, 4694.
(11) (a) Huang, L.; Wang, Q.; Qi, J.; Wu, X.; Huang, K.; Jiang, H.
Chem. Sci. 2013, 4, 2665. (b) Shi, Z.; Boultadakis-Arapinis, M.; Glorius,
F. Chem. Commun. 2013, 49, 6489. (c) Qi, J.; Huang, L.; Wang, Z.; Jiang,
H. DOI: 10.1039/C3OB41590B.
(12) (a) Huang, L.; Wang, Q.; Liu, X.; Jiang, H. Angew. Chem., Int.
Ed. 2012, 51, 5696. (b) Zhou, P.; Huang, P.; Jiang, H.; Wang, A.; Li, X.
J. Org. Chem. 2010, 75, 8279. (c) Wen, Y.; Huang, L.; Jiang, H.; Chen, H.
J. Org. Chem. 2012, 77, 2029. (d) Li, Y.; Liu, X.; Jiang, H.; Liu, B.; Chen,
Z.; Zhou, P. Angew. Chem., Int. Ed. 2011, 50, 6341. (e) Wen, Y.; Huang,
H.; Jiang, H. J. Org. Chem. 2012, 77, 5418.
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S. S. Angew. Chem., Int. Ed. 2004, 43, 3400.
B
Org. Lett., Vol. XX, No. XX, XXXX

Scheme 2. Scope of Allylic Alcoholsa,b
Scheme 3. Proposed Mechanism
product 3ab, and the hydroxy was successfully transformed
into the more active aldehyde. And 2-methyl-2-propen-1-ol
was tested, although only a 56% yield of 3ac was isolated.
To our disappiontment, nonterminal allylic alcohol reacted
with 2-alkynyl aniline, giving the desired product of 3ai in
very low GC yield. In addition, the phenyl substituted allyl
alcohols with electron-donating groups (ÀMe, ÀOMe), the
halide functional group (ÀCl), and the electron-withdrawing
group (ÀCN) also proceeded well in this reaction system.
All of them could be converted to 2,3-disubstituted indoles
3adÀ3ah in moderate yields. However, compounds 3adÀ3ag
were isolated after methylation, except for 3ah.
a Reaction was carried with 1 (0.5 mmol), 2 (1.0 mmol), KI (0.5
mmol), Pd(OAc)2 (0.025 mmol), DMF (1.5 mL), 90 °C for 8 h. b Isolated
yield. c Isolated yield after methylation.
amount of product was obtained when using Ag2CO3 as the
oxidant (Table 1, entries 8, 9). Additionally, control experi-
ments showed that the reaction failed to give the desired
product 3aa without a Pd catalyst or O2 (entries 10, 11).
With the optimal conditions in hand, we investigated the
substrate scope of 2-alkynyl anilines for this transformation
(Scheme 1). First, N-methyl-2-(phenylethynyl)aniline was
treated with 2a, and an 84% yield of 3ba was obtained. To
our delight, the substrates with electron-donating groups
(R = Me, OMe), or electron-withdrawing groups (R = F,
Cl, Br, NO2), could proceed well in the reaction and afford the
corresponding products in good isolated yields (3caÀ3ha).
Encouraged by these promising results, some 2-alkynyl
anilines containing meta- and ortho-substituted groups re-
acted with 2a and gave a high yield of 3iaÀ3la, respectively.
Moreover, 3ma and 3na were also successfully formed, which
greatly expanded the scope of the products. Besides, sub-
strates 1oÀ1r including electron-donating or -withdrawing
groups on the benzene ring performed well in this transfor-
mation and gave the corresponding products 3oaÀ3ra
in moderate to excellent yields. In addition, the halide
functional groups, such as ÀF, ÀCl, ÀBr, were well tolerated
in this reaction, which gave the expected products (3saÀ3va)
in excellent yields. It is noteworthy that the 2-alkynl anilines
including functional groups of biological activity, such as
CF3 or COOMe, could be transformed to the desired
products 3pa and 3qa in 90% and 78% yields, respectively.
Next, we tried to further expand the scope of allylic
alcohols for the indole synthesis (Scheme 2). The simplest
allyl alcohol was first tested which gave a moderate yield of
Naturally occurring and synthetic indole rings are both
biologically active. Our products have a similar framework
to that of tryptamine.14 So it greatly inspired us to synthe-
size the β-indole ketones. Then through a simple reduction
or reductive amination, β-aryl alcohol (4aa) or amine (5aa)
could be obtained in 88% and 85% yields, respectively [eq 4].
More importantly, the indole ring can be also used as a useful
oriented functional group for CÀH activation via the nucleo-
palladation process. Consequently, under Ackermann’s
conditions,15 the corresponding 2-arylpyrrole 6aa, which
is a kind of bioactive compound and functional material,
was successfully formed in 64% yield in two steps [eq 5].
On the basis of the above results, we proposed a mecha-
nism for Pd-catalyzed oxidative couplings between 2-alkynyl
anilines and allylic alcohols (Scheme 3). This transformation
pathway was initiated by aminopalladation of 2-alkynyl
(14) Preciado, S.; Mendive-Tapia, L.; Albericio, F.; Lavilla, R.
J. Org. Chem. 2013, 78, 8129.
(15) Ackermann, L.; Wang, L.; Lygin, A. V. Chem. Sci. 2012, 3, 177.
Org. Lett., Vol. XX, No. XX, XXXX
C

anilines to afford vinyl palladium intermediate I. Subse-
quently allylic alcohols that were 1,2-migratory were inserted
into the CÀPd bond to produce the intermediate II,3cwhich
easily transformed to the alkyl palladium species III by β-H
elimination. This selective β-H elimination occurred fol-
lowed by an enol isomerization between III and IV and
finally gave the β-indole ketones.11a In addtion, the PdII
active species was regenerated with O2.
In conclusion, we have developed the vinyl-Pd species
which were produced though nucleopalladation captured
by allylic alcohols to obtain β-indole ketones. It is a simple
and efficient method for constructing 2-substituted and
3-substituted indoles. Notable features of this transforma-
tion include the readily available materials, high reactivity,
and broad functional group tolerance. Furthermore, mo-
lecular oxygen as the oxidant makes the reaction practical
and environmentally friendly. Moreover, the products can
also be converted into pyrrolo[2,1-a]isoquinolines. We
believe that this method should provide a new and eco-
friendly approach to functional indole synthesis.
Acknowledgment. We thank the National Basic Re-
search Program of China (973 Program) (2011CB808600),
the National Nature Science Foundation of China (20932002
and 21172076), the Guangdong Natural Science Foundation
(10351064101000000), and the Fundamental Research
Funds for the Central Universities (2010ZP0003) for
financial support.
Supporting Information Available. Experimental pro-
cedure and characterization of compounds 3aaÀ3va,
3abÀ3ah, 4aaÀ6aa. This material is available free of
charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX