Efficient synthesis of 2-substituted indoles based on palladium(II) acetate/tri-tert-butylphosphine-catalyzed alkynylation/amination of 1,2-dihalobenzenes

Article abstract of DOI:10.1002/adsc.200606022

A simple, efficient palladium(II) acetate/tri-tert-butylphosphine-catalyzed indole synthesis from o-alkynylhalobenzenes, readily available from 1,2-dihalobenzenes, has been achieved in good to excellent yields. A one-pot, Pd(OAc)₂/t-Bu₃P-catalyzed sequential reaction from 1-chloro-2-iodobenzene, phenylacetylene and amines has also been achieved in good yields.

Full text of DOI:10.1002/adsc.200606022

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DOI: 10.1002/adsc.200606022
Efficient Synthesis of 2-Substituted Indoles Based on
Palladium(II) Acetate/Tri-tert-butylphosphine-Catalyzed
Alkynylation/Amination of 1,2-Dihalobenzenes
Zhen-Yu Tang, Qiao-Sheng Hu*
Department of Chemistry, College of Staten Island and the Graduate Center of the City University of New York,
Staten Island, New York 10314, U.S.A.
Fax: (þ1)-718-982-3910, e-mail: qiaohu@mail.csi.cuny.edu
Received: January 22, 2006; Accepted: March 18, 2006
Supporting Information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: A simple, efficient palladium(II) acetate/
tri-tert-butylphosphine-catalyzed indole synthesis
from o-alkynylhalobenzenes, readily available from
1,2-dihalobenzenes, has been achieved in good to ex-
cellent yields. A one-pot, Pd(OAc)2/t-Bu3P-catalyzed
sequential reaction from 1-chloro-2-iodobenzene,
phenylacetylene and amines has also been achieved
in good yields.
cient synthesis of heterocycles including indoles from
readily available starting materials. Based on our analy-
sis of possible routes to the key intermediate o-alkynyl-
anilines for the synthesis of 2-substituted indoles, we
reasoned that readily available 1,2-dihalobenzenes
could be suitable starting materials to access o-alkynyl-
anilines via an alkynylation followed by an amination se-
quence (Scheme 1). This possible route appeared to be
very attractive considering: (a) due to the electronic na-
ture of alkynyl groups, o-alkynylhalobenzenes are ex-
pected to be more reactive than strong deactivating ami-
no group-containing o-haloanilines, and are thus expect-
ed to behave similarly like other o-substituted haloben-
zenes for the Buchwald–Hartwig aminations[6] and (b)
o-alkynylhalobenzenes, especially o-alkynylchloroben-
Keywords: alkynylation; amination; 1,2-dihaloben-
zenes; indoles; palladium; phosphane ligands
Many natural products and biologically active com- zenes, have been well-established to be readily accessi-
pounds contain indole skeleton as their structural sub- ble from the monoalkynylation of 1,2-dihaloben-
units.[1] Such a prevalence stimulated the development zenes.[7,8] Based on the fact that enormous progress has
of a number of methods for indole synthesis in past deca- been achieved in Pd(0)-catalyzed amination reactions
des.[1–3] Among the methods developed, the palladi- in recent years and different types of aryl halides includ-
um-catalyzed transformations of o-haloanilines via al- ing aryl chlorides have been demonstrated as suitable
kynylation to form o-alkynylanilines followed by intra- substrates,[6,9] we believed that the amination of o-alky-
molecular hydroamination have been studied intensive- nylhalobenzenes including o-alkynylchlorobenzenes
ly and represent a fruitful strategy to access 2-substitut- could be possible and the strategy of alkynylation fol-
ed indoles.[2,3] As part of our program directed to devel- lowed by amination of 1,2-dihalobenzenes would pro-
op new sequential and tandem reactions based on pow- vide us an efficient and general method to access 2-sub-
erful cross-coupling reactions,[4,5] we became interested stituted indoles.[10] Herein our results are reported.
in developing sequential/tandem reactions for the effi-
Scheme 1. Possible routes for the preparation of 2-substituted indoles.
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Synthesis of 2-Substituted Indoles
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Table 1. Ligand screening.[a]
Although the monoalkynylation of 1,2-dihaloben-
zenes with terminal alkynes to form o-alkynylhaloben-
zenes has been well-established,[7,8] we were surprised
to find that the amination of o-alkynylhalobenzenes
for the synthesis of 2-substituted indoles was rarely stud-
ied.[10,11] We thus began our study to identify palladium
catalyst systems that could efficiently catalyze the ami-
nation reaction of o-alkynylhalobenzenes. 1-Chloro-2-
(2-phenylethynyl)benzene was chosen as the model sub-
strate because of (a) its high yield, selective formation
from readily available 1-bromo-2-chlorobenzene
(81%) and 1-chloro-2-iodobenzene (95%),[8] and (b)
the consideration that catalyst systems that work for 1-
chloro-2-(2-phenylethynyl)benzene which contains a
À
very inert C Cl bond should also work for other more
reactive o-alkynylhalobenzenes. A number of commer-
cially available ligands that have been demonstrated as
suitable for the amination of aryl halides were screened
for the Pd(0)-catalyzed amination of 1-chloro-2-(2-phe-
nylethynyl)benzene with benzylamine, which yielded 1-
benzyl-2-phenylindole as the final product after intra-
molecular hydroamination reaction (Table 1). We found
that under the conditions of KO-t-Bu as base and tol-
uene as solvent at 1108C, bidentate bis(2-diphenylphos-
phinophenyl) ether (DPEphos) and 9,9-dimethyl-4,5-
bis(diphenylphosphino)xanthene (XantPhos) were in-
effective ligands (Table 1, entries 1 and 2).[12] Buch-
waldꢁs aryldialkylphosphines proved to be excellent li-
gands for the reaction (Table 1, entries 3 and 4).[13] An
N-heterocyclic carbene, in situ generated from 1,3-
bis(2,4,6-trimethylphenyl)imidazolium chloride, was
also tested and a moderate yield was observed (Table 1,
entry 5).[9c, d] We found that the best result was obtained
when (t-Bu)3P was employed as ligand (Table 1, en-
try 6). Other monodentate ligands such as (Cy)3P and
(sec-Bu)3P were also tested and no desired cyclization
product was observed (Table 1, entry 7).
[a]
Alkyne (1 mmol), amine (1.2 mmol), 3% Pd(OAc)2, 6%
ligands.
Reaction conditions: A: t-BuOK (3 equivs.), toluene
(2 mL), 110–1208C. B: K3PO4 (3 equivs.), DMA
(2 mL), 1308C.
[b]
[c]
Yields of isolated products.
With Pd(0)/P(t-Bu)3 as the catalyst system,[14] several
o-alkynylhaloarenes, which were prepared from 1-bro- than the phenyl group, likely through the triple bond, re-
mo-2-iodobenzene, 1-bromo-2-chlorobenzene and 1- tarded the amination reaction and also slowed down the
chloro-2-iodobenzene by following reported meth- intramolecular hydroamination process.
ods,[7,8] were tested for the amination followed by the in-
With Pd(0)/P(t-Bu)3 as the catalyst system, we have
tramolecular hydroamination and our results are listed also carried out the indole synthesis in a sequential fash-
in Table 2. We found that 1-bromo-2-(2-phenylethynyl)- ion from 1-chloro-2-iodobenzene, alkynes and
benzene and 1-chloro-2-(2-phenylethynyl)benzene re- amines.[10] We found that conditions for the first alkyny-
acted smoothly with both alkylamines and anilines to lation step playedan importantrole for the successful se-
give 2-substitued indoles in excellent isolated yields (Ta- quential reactions. When Et3N was employed as base for
ble 2, entries 1–6). We also found that although o-chloro- the first alkynylation step, no cyclization product was
octynylbenzene and o-chlorohexynylbenzene also re- obtained. Fortunately, when inorganic bases such as
acted with benzylamine and octylamine to give 2-substi- Cs2CO3 or t-BuOK were used, 2-substituted indoles
tuted indoles with satisfactory results, they appeared to were obtained in good yields for phenylacetylene as
be less reactive than 1-chloro-2-(2-phenylethynyl)ben- the alkyne source (Table 3). However, with 1-octyne as
zene (Table 2, entries 7–10). In the reaction of aniline the alkyne source, lower yields of 2-substituted indoles
with o-chlorohexynylbenzene, the uncyclized product were observed, along with significant amounts of un-
2-(1-hexynyl)-N-phenylaniline was isolated as the cyclized N-benzyl-2-(1-octynyl)aniline. Such lower
main product (Table 2, entry 11). Our results suggested yield observation was probably due, at least in part, to
that alkyl groups, which are more electron-donating the electron-donating alkyl group which might make
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847

Zhen-Yu Tang, Qiao-Sheng Hu
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Table 2. Pd(0)-catalyzed synthesis of 2-substituted indoles from o-alkynyl-
halobenzenes.[a]
[a]
3% Pd(OAc)2, 6% (t-Bu)3P, 1 mmol alkyne, 1.2 mmol amine.
Method A: t-BuOK (3 equivs.), toluene (2 mL), 110–128C, 14 h; Meth-
[b]
od B: K3PO4 (3 equivs.), DMA (2 mL), 1308C, 14 h.
Yields of isolated products.
5% Pd(OAc)2 and 10% (t-Bu)3P were used.
2-(1-Hexynyl)-N-phenylaniline was obtained in 55% yield.
[c]
[d]
[e]
the amination and hydroamination less effective. We lene and amines has also been developed. Further inves-
have also attempted to carry out the reaction by loading tigations on Pd(0)-catalyzed sequential/tandem reac-
1-chloro-2-iodobenzene, phenylacetylene and benzyl- tions of 1,2-dihalobenzenes for the synthesis of other
amine at the same time, but no desired indole product types of heterocyclic compounds are currently under-
was observed.
way.
In summary, based on our analysis that readily availa-
ble o-alkynylhalobenzenes would be more reactive than
strong deactivating amino group-containing o-haloani-
lines and would behave similarly like other o-substituted
halobenzenes for the Buchwald–Hartwig aminations,
we have successfully developed a simple, efficient
Pd(OAc)2/(t-Bu)3P-catalyzed indole synthesis from o-
alkynylhalobenzenes including o-alkynylchloroben-
zenes. A one-pot, Pd(OAc)2/(t-Bu)3P-catalyzed sequen-
Experimental Section
General Procedures for Pd(0)/(t-Bu)3P-Catalyzed
Indole Synthesis from o-Alkynylchlorobenzene
Method A: Under an N2 atmosphere, to a mixture of o-alkynyl-
chlorobenzene (1 mmol), t-BuOK (3 mmol), Pd(OAc)2
tial reaction from 1-chloro-2-iodobenzene, phenylacety- (0.03 mmol) and (t-Bu)3P (0.06 mmol) were added an amine
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Synthesis of 2-Substituted Indoles
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Table 3. Indole synthesis in an one-pot, sequential fashion.
Acknowledgements
We gratefully thankthe NIH (GM69704) for their generous
funding. Partial support from the PSC-CUNY Research Award
Programs, and GRTI (The Graduate Research and Technology
Initiative) grants are also gratefully acknowledged. ZYT thanks
the CUNY for Mario Capelloni Dissertation Fellowships. We
also thankFrontier Scientific for its generous gifts of palladiu-
m(II) acetate and Combiphos Catalysts, Inc for its generous gifts
of tri-tert-butylphosphine.
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Preparation of 2-Substituted Indoles
Under an N2 atmosphere, to a mixture of 1-iodo-2-chlorobenze
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quenching with water, the reaction mixture was extracted with
ethyl acetate and the organic layer was washed with brine.
Rota-evaporation and flash chromatography on silica gel (hex-
ane: ethyl acetate¼5:95 to 15:85) gave 2-substituted indoles
as the product.
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À
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active than that of Pd(OAc)2/1,3-bis(2,6-diisopropylphe-
nyl)imidazolium chloride system for the preparation of
2-substituted indoles from o-alkynylhalobenzenes and
1,2-dihalobenzenes because comparable yields were ob-
served from a 3% Pd(OAc)2/(t-Bu)3P catalyst loading
or a 5–10% Pd(OAc)2/1,3-bis(2,6-diisopropylphenyl)-
imidazolium chloride catalyst loading (ref.[10]). In addi-
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À
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lyzed amination reaction has also been reported: H. Sie-
hindered
1,3-bis(2,6-diisopropylphenyl)imidazolium
chloride: For example, the prices from the 2004–2006
Stremꢁs catalog: tri-tert-phosphine: $ 37.0/g; 1,3-bis(2,6-
diisopropylphenyl)imidazolium chloride: $ 58.0/500 mg.
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