A Catalytic Reaction of Alkynes via Multiple-Site Functionalization

Article abstract of DOI:10.1021/ja0304188

The first multiple-site activation of alkynes with amine/halogen functionalities has been established. The reaction was performed by treating alkyne with N,N-dichlorobenzenesulfonamide at 80 °C in the presence of palladium acetate catalyst. A new mechanism was proposed which involves the novel formation of β-halovinyl palladium and π-allylpalladium species. Excellent regio- and stereoselectivities were achieved with the absolute structure determined by X-ray structural analysis. Copyright

Full text of DOI:10.1021/ja0304188

Published on Web 10/14/2003
A Catalytic Reaction of Alkynes via Multiple-Site Functionalization
‡
Subramanian Karur, S. R. S. Saibabu Kotti, Xin Xu, John F. Cannon, Allan Headley,* and
Guigen Li*
Department of Chemistry and Biochemistry, Texas Tech UniVersity, Lubbock, Texas 79409-1061,
and Department of Chemistry and Biochemistry, Brigham Young UniVersity, ProVo, Utah 84602-5700
Received July 9, 2003; E-mail: guigen.li@ttu.edu
The study of transition metal-catalyzed addition reactions of
alkenes and alkynes, particularly those involving amino function-
alities, has been an important topic in organic chemistry because
these reactions can convert common unsaturated petroleum products
into chemically and biologically important precursors.1 Unfor-
tunately, a multiple-site activation of alkynes by using amino and
halogen moieties has not been discovered thus far. Over the past
few years, we have been actively involved in the development of
new aminohalogenation and diamination reactions of alkenes. These
reactions have resulted in versatile building blocks such as
Scheme 1
-4
Table 1. Results of the Regio- and Stereoselective Reaction of
BsNCl2 with arylalkynesa
5
6
haloamines, R,â-differentiated diamines and imidazolines. In this
communication, we report our preliminary results on the regiose-
lective activation of nonsymmetric alkynes and simultaneous
halogenation on their adjacent alkyl position (Scheme 1).7
-11
To
the best of our knowledge, this reaction serves as the first example
of a three-site activation of alkynes with important amine/halogen
functionalities.
The reaction takes place only in nitrile-containing solvents such
as acetonitrile and propionitrile. Several palladium catalysts such
as Pd(PPh
for this catalytic reaction.
3
)
4
, Pd(dba)
2
, and Pd(OAc)
2
were found to be effective
1
2,13
Among these catalysts, palladium
acetate gave the best yields. It is crucial to generate palladium (0)
prior to the reaction by mixing the palladium acetate with the alkyne
in acetonitrile over 1 h. During this period the reaction mixture
turned black, which indicates the in situ reduction of palladium
(II) to palladium (0). However, other palladium (II) salts such as
PdCl
2
and Pd(CF COO) failed to give any products, which is
3
2
probably due to the fact that they cannot be easily reduced to the
palladium (0) state under the current condition.
The reaction was carried out by stirring the pretreated solution
containing the catalyst and alkyne with N,N-dichlorobenzene-
sulfonamide at 82 °C over a period of 24 h. The crude product
was subjected to purification via flash column chromatography
without quenching. Among the three halogen/nitrogen sources we
examined, N,N-dichlorobenzenesulfonamide, N,N-dichloro-p-tolu-
enesulfonamide, and N,N-dibromo-p-toluenesulfonamide, the first
one gave the best yields. A slight excess amount of N,N-
dichlorobenzenesulfonamide (1.1 equiv) was necessary to achieve
optimal yields. Interestingly, increasing the amount of halogen/
nitrogen source led to lower yields due to the N-chlorination of
the product which decomposes on silica gel during column
chromatography.
a
Into a dry vial was added (4-bromophenyl)-1-propyne (97.5 mg, 0.50
mmol) and freshly distilled acetonitrile (0.80 mL). The mixture was stirred
and then loaded with palladium acetate (11.2 mg, 10 mol %) to give a
homogeneous brownish solution. This solution was stirred at room
temperature for 1 h until the brownish color changed to black before N,N-
dichlorobenzenesulfonamide (124 mg, 0.55 mmol, 1.1 equiv) was added.
The resulting mixture was heated to 80-82 °C and stirred at this temperature
for 24 h. It was then cooled to room temperature, and the solvent was
evaporated at reduced pressure. The crude residue was directly purified by
flash column chromatography using ethyl acetate in hexane as the eluent
(hexane/EtOAc, 4:1) to give product 2 as a white solid (148 mg, 70% yield).
b
c
No regio- and stereominor isomers were detected. Yields after purification
via column chromatography. d X-ray structure of the product was obtained
Figure 1).
(
propynes we examined except for entry 7 where a low yield was
obtained. Different substituents on aromatic rings have no effect
on both regio- and stereoselectivity. Two terminal extended
substrates, 1-phenyl-1-hexyne and 1-(4-nitrophenyl)-1-hexyne, have
been examined. Interestingly, the reaction was found to stop at the
stage of 1,2-addition adducts which are also very useful in organic
synthesis. Much work is needed to search for new conditions,
catalysts, and halogen/nitrogen sources to improve yields and the
scope of this multiple-site activation.
The structure of the product (1 of Table 1) was unambiguously
determined by X-ray structural analysis (Figure 1). The crystals
were obtained by slow evaporation of a methanol solution of the
pure product, 1. The results of this new reaction are listed in Table
1
. A good scope was observed for the phenyl-substituted aromatic
‡
Department of Chemistry and Biochemistry, Brigham Young University, Provo,
UT 84602-5700.
13340
9
J. AM. CHEM. SOC. 2003, 125, 13340-13341
10.1021/ja0304188 CCC: $25.00 © 2003 American Chemical Society

C O MMU N I C A T I O N S
of methyleneaziridine derivatives16 is currently being studied in our
laboratories.
In summary, a novel catalytic stereo- and regioselective multiple-
site activation of alkynes has been discovered. A new mechanism
was proposed which involves the novel formation of â-halovinyl
palladium and π-allylpalladium species. The resulting multiple
functionalized haloenamines will find extensive applications in
organic chemistry.
Acknowledgment. We gratefully acknowledge financial support
from NIH (CA 99995-1) and the Robert A. Welch Foundation
(Grant No. D-1361, D-1460). We thank Professor John Marx, Mr.
David Chen, and Mr. Cody Timmons for helpful discussions and
assistance. Its contents are solely the responsibility of the authors
and do not necessarily represent the official views of the National
Cancer Institute.
Figure 1. X-ray structure of product 1.
Scheme 2
Supporting Information Available: Typical procedure, X-ray data,
1H and 13C NMR spectra of all pure products and CIF data for 1. This
material is available free of charge via the Internet at http://pubs.acs.org.
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1
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(
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