Gold(III) chloride-catalyzed three-component reaction: A facile synthesis of alkynyl derivatives of 1,2-dihydroquinolines and isoquinolines

Article abstract of DOI:10.1021/jo8007034

(Chemical Equation Presented) Gold(III) chloride is found to be an effective catalyst for the addition of alkynes on activated quinoline/ isoquinolines to produce a series of alkynyl-substituted 1,2-dihydroquinolines and isoquinolines in a single-step operation. The easy availability of starting materials, convenient synthetic procedure, operational simplicity, and high regioselectivity makes this strategy very useful for the preparation of enyne derivatives of aza-aromatic compounds.

Full text of DOI:10.1021/jo8007034

Activated aza-aromatic systems such as quinolines and
isoquinolines are useful building blocks in organic synthesis,
especially for the synthesis of various biologically active
nitrogen-containing alkaloids.3,4
Gold(III) Chloride-Catalyzed Three-Component
Reaction: A Facile Synthesis of Alkynyl
Derivatives of 1,2-Dihydroquinolines and
Isoquinolines†
Jhillu S. Yadav,*,‡ Basi V. Subba Reddy,‡
Nagendra Nath Yadav,‡ Manoj K. Gupta,‡ and
Balasubramanian Sridhar§
DiVision of Organic Chemistry, and Laboratory of X-ray
Crystallography, Indian Institute of Chemical Technology,
Hyderabad, India
yadaVpub@iict.res.in
ReceiVed April 2, 2008
FIGURE 1. Structure of biologically active dynemicin A (I) and its
analogues (II and III).
In particular, addition of alkynes to activated aza-aromatic
systems is an important carbon-carbon bond-forming reaction
for the synthesis of enediyne alkaloids such as dynemicin A
and its analogues (Figure 1).5 However, only a few methods
are reported for the alkynylation of activated aza-aromatic
systems.3c,5a,6 In most cases, alkynyl Grignard reagents, alky-
nyltin, and alkynylsilanes have been utilized to introduce alkynyl
functionality into quinoline systems.7,8 Generally, chlorofor-
mates or acid chlorides are used as activating agents for
quinolines and isoquinolines.3
Gold(III) chloride is found to be an effective catalyst for
the addition of alkynes on activated quinoline/isoquinolines
to produce a series of alkynyl-substituted 1,2-dihydroquino-
lines and isoquinolines in a single-step operation. The easy
availability of starting materials, convenient synthetic pro-
cedure, operational simplicity, and high regioselectivity
makes this strategy very useful for the preparation of enyne
derivatives of aza-aromatic compounds.
Huisgen et al.9a,b have reported the formation of 1,4-dipoles
from isoquinoline and dimethyl acetylenedicarboxylate (DMAD)
and their trapping by phenyl isocyanate, diethyl mesoxalate, and
dimethyl azodicarboxylate to generate six-membered hetero-
cycles. Recently, we have also found that dimethyl acetylene-
dicarboxylate is an effective reagent for the coupling of indoles
with quinolines and isoquinolines.10 This result provided an
The use of gold salts has been dramatically increased in
organic syntheses due to their unique Lewis acidic nature.1
Especially, gold(III) compounds are being considered as po-
tential Lewis acids to activate alkynes under extremely mild
conditions.2 In particular, gold(III) chloride has been widely
used for a variety of organic transformations.2
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* Address correspondence to this author. Fax: 91-40-27160512.
† Dedicated to Prof. E. J. Corey on the occasion of his 80th birthday.
‡ Division of Organic Chemistry.
§ Laboratory of X-ray Crystallography.
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10.1021/jo8007034 CCC: $40.75
Published on Web 07/29/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 6857–6859 6857

TABLE 1. Gold(III) Chloride-Catalyzed Three-Component
Coupling Reactiona,b
SCHEME 1. Preparation of Product 4a
SCHEME 2. A Plausible Reaction Mechanism for the
Alkynylation of Isoquinoline
inspiration to study the annulation of aryl alkynes with quinoline
and isoquinoline activated by dimethylacetylene dicarboxylate.
However, attempted annulation of isoquinoline (1) with dimethyl
acetylenedicarboxylate (2) and phenylacetylene (3) in the
presence of 2 mol % gold(III) chloride led to formation of alkyne
addition product instead of the anticipated cyclization. The
reaction was complete in 8 h to furnish dimethyl 2-(1-
(phenylethynyl)isoquinolin-2(1H)-yl)maleate 4a in 72% yield
(Scheme 1).
The structure of 4a was established by using various 1H, 13
C
NMR, IR, and HRMS. This result provided incentive for an
extensive study. Interestingly, various ethynylbenzenes such as
1-ethynyl-4-methylbenzene, 1-tert-butyl-4-ethynylbenzene, 1-ethy-
nyl-4-fluorobenzene, and 1-ethynyl-4-methoxybenzene under-
went smooth coupling with activated isoquinoline to produce
the corresponding 1-alkynyl-substituted 1,2-dihydroisoquinolines
in good to excellent yields (entries b-e, Table 1).
Like DMAD, diethyl acetylenedicarboxylate also participated
in this reaction to afford the corresponding alkynyl derivatives
of 1,2-dihydroisoquinolines (entries f-h, Table 1). However,
in case of 4-bromoisoquinoline, the desired products were also
obtained in fairly good yield (entries i and j, Table 1).
Mechanistically, the reaction may proceed via the formation
of a zwitterionic intermediate,11 which reacts subsequently with
phenylacetylene activated by Au(III) to furnish the desired
product (Scheme 2).
Like isoquinolines, quinoline also coupled effectively with
dimethylacetylene dicarboxylate and ethynylbenzene under
identical conditions. The reaction went to completion in 9.0 h
and the desired alkyne addition product, 6a, was obtained in
82% yield (Scheme 3, Table 2)
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a All products were characterized by NMR, IR, and mass spectrometry.
b Isolated yields after purification.
Similarly, various ethynylbenzenes were coupled effectively
with activated quinolines to furnish the corresponding adducts
6858 J. Org. Chem. Vol. 73, No. 17, 2008

SCHEME 3. Preparation of Product 6a
to give the best results. Among various Lewis acid catalysts
such as GaCl3, InCl3, BiCl3, NbCl5, ZrCl4, TaCl5, and
CeCl3 ·7H2O, AuCl3 was found to be the most effective catalyst
in terms of conversion. In the absence of catalyst, no desired
product was obtained. However, aliphatic alkynes failed to
undergo addition under similar conditions.
The structure and configuration of product 6e was also
confirmed by single-crystal X-ray analysis.12 The scope and
generality of this process is illustrated with respect to various
isoquinolines, quinolines, and ethynylbenzenes and the results
are presented in Tables 1 and 2.
TABLE 2. Gold(III) Chloride-Catalyzed Three-Component
Coupling Reactiona,b
In summary, we have developed a novel three-component
reaction capable of coupling of ethynylbenzenes with quinoline
and isoquinolines activated by acetylenedicarboxylate at room
temperature using 2 mol % of gold(III) chloride catalyst. In
addition to its simplicity and mild reaction conditions, this
method provides good yields of products with high regioselec-
tivity, which makes it a useful and attractive process for the
alkynylation of quinolines and isoquinolines in a single-step
operation.
Experimental Section
Typical Procedure. To a stirred solution of dialkyl acetylene-
dicarboxylate (1.2 mmol), ethynylbenzene (1.0 mol), and gold(III)
chloride (2 mol %) in CH2Cl2 (5 mL) at 0 °C under nitrogen
atmosphere for 30 min was added quinoline/isoquinoline (1.0 mmol)
and the resulting mixture was stirred at room temperature for the
appropriate time (see Tables 1 and 2). After completion of the
reaction, as indicated by TLC, the reaction mixture was quenched
with H2O (10 mL) and extracted with CH2Cl2 (2 × 10 mL). The
combined organic extracts were washed with water followed by
brine and dried over anhydrous Na2SO4, which was filtered off.
Removal of solvent followed by purification on silica gel column
with a mixture of EtOAc-hexanes (10%) afforded pure product.
Solid compounds were recrystallized with CH2Cl2-hexane (5%).
Dimethyl 2-(1-(Phenylethynyl)isoquinolin-2(1H)-yl)maleate
(4a; Table 1). Pale yellow solid, mp 143-145 °C; IR (KBr) ν
2924, 2363, 1733, 1597, 1445, 1381, 1163, 1036, 978, 904, 811,
762, 691, 537 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.62 (dd, J )
1.5, 7.5 Hz, 1H), 7.37-7.31 (m, 2H), 7.25-7.18 (m, 5H),
7.09-7.05 (m, 1H), 6.29 (d, J ) 7.5 Hz, 1H), 5.91 (d, J ) 7.5 Hz,
1H), 5.74 (s, 1H), 5.43 (s, 1H), 3.95 (s, 3H), 3.71 (s, 3H); 13C
NMR (proton decoupled, 75 MHz, CDCl3) δ 167.1, 165.0, 149.1,
131.8, 128.9, 128.6, 128.1, 127.6, 126.2, 125.1, 124.9, 121.9, 108.9,
92.4, 86.0, 84.6, 53.2, 51.3, 50.5; LCMSD m/z 396 (M + Na)+;
HRMS (ESI) calcd for C23H19NaNO4 396.1211, found 396.1207.
Acknowledgment. N.N.Y. and M.K.G. thank CSIR, New
Delhi for the award of fellowships.
a All products were characterized by NMR, IR, and mass spectrometry.
b Isolated yields after purification.
Supporting Information Available: Characterization data
and 1H and 13C NMR spectra for compounds 4a-j and 6a-h),
experimental procedure for general reactions, and X-ray data
of compound 6e. This material is available free of charge via
the Internet at http://pubs.acs.org.
in good to excellent yields (entries b-h, Table 2). This method
worked well for both electron-rich as well as electron-deficient
substrates. Various functional groups such as bromo, fluoro, and
methoxy derivatives are well tolerated under the reaction
conditions (Tables 1 and 2). This method offers several
advantages such as high yields of products, mild reaction
conditions, greater regioselectivity, cleaner reaction profiles, and
operational simplicity. As solvent, dichloromethane appeared
JO8007034
(12) Please see the Supporting Information.
J. Org. Chem. Vol. 73, No. 17, 2008 6859