Pd/C-mediated coupling of aryl halides with terminal alkynes in water

Article abstract of DOI:10.1016/j.tet.2005.06.056

2-Aminoethanol facilitated the alkynylation of aryl halides (Sonogashira reaction) under palladium/charcoal-copper catalysis in water affording a mild and practical method for the synthesis of arylalkynes. A variety of terminal alkynes were coupled with a

Full text of DOI:10.1016/j.tet.2005.06.056

Tetrahedron 61 (2005) 9869–9877
Pd/C-mediated coupling of aryl halides with terminal alkynes
in water
*
Venkateswara Rao Batchu, Venkataraman Subramanian, Karuppasamy Parasuraman,
*
Nalivela Kumara Swamy, Sanjeev Kumar and Manojit Pal
Chemistry-Discovery Research, Dr. Reddy’s Laboratories Ltd, Bollaram Road, Miyapur, Hyderabad 500049, AP, India
Received 5 January 2005; revised 17 March 2005; accepted 10 June 2005
Available online 14 July 2005
Abstract—2-Aminoethanol facilitated the alkynylation of aryl halides (Sonogashira reaction) under palladium/charcoal–copper catalysis in
water affording a mild and practical method for the synthesis of arylalkynes. A variety of terminal alkynes were coupled with aryl iodides and
bromides possessing no hydrophilic functional groups to give the coupled products in good to excellent yields.
q 2005 Elsevier Ltd. All rights reserved.
1
homocoupling of the terminal alkynes, polymer supported
1
1
. Introduction
12a
Pd-triazine complex, solid supported Pd-catalyst
12b
etc.
In addition to the copper salts use of other metal co-catalysts
such as zinc, tin, boron or aluminium has also been
Transition metal-catalyzed cross-coupling reactions rank
among the most important processes for constructing new
carbon–carbon bonds. Over the past 25 years, palladium-
1
13a–c
reported. Very recently microwave mediated transition-
metal free Sonogashira coupling has been reported.
1
4
catalyzed coupling of terminal alkynes with the aryl halide
2
Sonogashira coupling) has become a most attractive and
a
(
powerful tool for C(sp )–C(sp) bond forming reaction.
2
2b
The use of aqueous media in palladium-catalyzed reactions
1
5
This reaction can be applied to the substrates carrying
various functional groups (thereby eliminating the protec-
tion–deprotection sequences as well as functional group
transformations) and has found wide application in the
synthesis of valuable compounds such as natural products
and drugs including the construction of complex enediyne
have become popular because water based synthetic
processes are inherently safer (water is non-toxic and non-
flammable) as well as inexpensive. Moreover, it does not
require dry solvents and products can easily be isolated by
extraction, which greatly facilitates the operation. Thus the
use of water in palladium-catalyzed reactions represents one
of the most economically and environmentally viable
options for many organic transformation. Its use is
particularly more beneficial in the cross coupling reaction
of peptides (e.g., 4-IC H CONHR, where R represents a
2
c–e
antibiotics.
The reaction, in general, is carried out with a
large excess of a secondary or tertiary alkyl amine as a
solvent/co-solvent and therefore, application of this proto-
col especially to large scale preparations often leads to
environmental pollution due to the volatile nature of these
6
5
peptide chain) with alkyne ligands for the construction of
biomolecule-based systems where poor solubility of the
reactants often prevent the reaction to be performed in
3
a
amines. Moreover, the use of copper salts often led to
Glaser-type homocoupling of the terminal alkyne.
3
b–f
1
5n
Nevertheless, this palladium-catalyzed reaction has been
investigated extensively to improve the reaction conditions
common organic solvents. Thus, the use of water-soluble
catalysts
4
15g
and water-soluble phosphine ligands, for
1
5f
and an impressive variety of modifications have been
reported thus far. This includes the use of a variety of
additives, solvents, phase-transfer catalysts, new cata-
example, sulfonated phosphines has been investigated.
The initial account of palladium-catalyzed alkylations of
small molecules in aqueous media was reported by
5
6
7
8
9
15g
lysts system including copper-free versions, biphasic
versions, use of hydrogen atmosphere to suppress the
Casalnuovo and Calabrese in 1990.
examples of cross-coupling reactions have been demon-
strated in aqueous media.
Since then several
1
0
1
5l–m
Generally these reactions
*
DRL publication number 461.
were found to be effective with aryl iodides and activated
aryl bromides, typically at high temperature. While a variety
of Pd(II) complexes in combination with triarylphosphines,
sterically demanding trialkylphosphines, sterically demand-
ing N-heterocyclic carbenes or ligands that form
Keywords: Aryl halides; Palladium catalyst; 2-Aminoethanol; Aqueous
media.
*
Corresponding author. Fax: C91 40 23045438/23045007;
e-mail: manojitpal@drreddys.com
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.06.056

9870
V. R. Batchu et al. / Tetrahedron 61 (2005) 9869–9877
palladacycles have been successfully employed for the
coupling of aryl halides with terminal alkynes in common
organic solvents at room temperature, the use of Pd/C–CuI–
Table 1. Effect of amine bases on the Pd/C-mediated coupling reaction of
a
1
a with 2a in water
b
Entry
Base (reaction time)
Et N (12 h)
(S)-Prolinol (12 h)
2-Aminoethanol (9 h)
4-Hydroxypiperidine (9 h)
2-Aminoethanol (9 h)
2-Aminoethanol (24 h)
Temp. (8C) Yield (%)
1
6
PPh as catalyst system for efficient Sonogashira coupling
3
c
1
7
1
2
3
4
5
6
3
80
80
80
80
80
60
59
81
78
76
n.d.
34
has not been exploited well until recently. When
compared with the most frequently used expensive
palladium catalysts [e.g., Pd(PPh ) , (PPh ) PdCl ,
3
4
3 2
2
d
e
Pd(OAc) /PPh etc.], Pd/C-based methods have an econ-
2
3
omic advantage and hence remain attractive in large or
industrial scale applications. Nevertheless, most of the
aqueous Pd-catalyzed reactions are usually carried out in an
aqueous-organic media and a co-solvent, such as acetoni-
a
Reactions were carried out by using 1a (1.0 equiv), 2a (1.5 equiv), Pd/C
0.04 equiv), PPh (0.20 equiv), CuI (0.05 equiv), base (3 equiv) in water.
(
3
b
c
d
e
Isolated yields.
Three equivalents of Et
3
N was used.
1
5f
17g
trile or DME.
Due to our continuing interest in the
The reaction was performed in the absence of CuI.
n.d., not detected.
1
8
palladium-catalyzed reactions we have recently shown
that Sonogashira coupling could be carried out in water in
the presence of (PPh ) PdCl and CuI at 25 8C affording a
high yield of arylalkyne (Scheme 1). Subsequently, we
have developed a mild and efficient method for the synthesis
of 2-substituted benzo[b]furans via Pd/C-catalyzed C–C
3
2
2
amine base for efficient Sonogashira coupling in water. We
therefore, studied the influence of amine bases possessing
hydroxyl group on the coupling of iodobenzene (1a) with
2-methylbut-3-yn-2-ol (2a) in the presence of Pd/C–PPh3–
CuI as a catalyst system in water (Table 1). We reasoned
that due to the presence of hydrophilic group these amines
would exhibit better water miscibility as well as lower
volatility than triehylamine and would facilitate the
coupling reaction in water. Accordingly, the model coupling
reaction of 1a with 2a was performed in the presence of few
hydroxy amines chosen based on their physical properties as
well as triethylamine. Triethylamine, known to give high
yields of coupled product when the Sonogashira reaction is
carried out in an organic solvent (e.g., THF, dioxane,
acetonitrile or DMF), afforded only low yield of product in
our case (Entry 1, Table 1). However, an essential
improvement in yield was achieved when (S)-prolinol
1
8c
1
9a
bond forming reaction in water.
These procedures,
however, involve the use of an expensive and chiral reagent,
that is, (S)-prolinol. Moreover, for our ongoing drug
discovery program on the development of various alkynyl
1
9b
substituted heterocyclic structures
we required an
efficient and practical method for the synthesis of arylalk-
1
9c
ynes, especially 3-aryl substituted alkynols. Accordingly,
we now wish to report a general Pd/C catalyzed synthesis of
2
0a–b
arylalkynes using 2-aminoethanol
base in water. Since arylalkynes are useful intermediates
as a cheaper amine
2
0c
2
1
for the synthesis of various biologically active compounds
as well as drugs, for example, HMG-CoA reductase inhibitor
or COX-2 inhibitor rofecoxib
Fig. 1) for the treatment of hypercholesterolemia and
2
1c
21d
Atrovastatin lactone
(
(Entry 2, Table 1) or 2-aminoethanol (Entry 3, Table 1)
inflammatory diseases, respectively, we envisioned that this
process could offer an increased scope of aryl and
heteroaromatic alkyne formation to the researchers working
especially in the field of medicinal and process chemistry.
was used in place of triethylamine. The halide 1a was
consumed completely after 9 h in both cases and the coupled
product 3a was isolated in 81 and 78% yield, respectively.
The use of 4-hydroxypiperidine was also found to be equally
effective (Entry 4, Table 1) as 3a was isolated in 76% yield
in this case. Nevertheless, we preferred to choose
2
-aminoethanol to continue our investigation further
2
. Results and discussion
because of its lower cost. Although copper-free Sonogashira
reaction has been realized using appropriate palladium
complexes, no product was detected in the present Pd/C-
mediated coupling of 1a with 2a in the absence of CuI
Our initial effort was devoted to the selection of a suitable
(Entry 5, Table 1).
The absence of PPh also retarded the coupling reaction
3
significantly under the conditions studied. The reaction was
carried out at 80 8C as decrease in temperature afforded low
yield (34%) of product even after 24 h (Entry 6, Table 1).
No coupled product was detected when the reaction was
3 2 2
Scheme 1. (PPh ) PdCl –CuI catalyzed reaction of iodobenzene with
terminal alkyne 2a in water.
Figure 1. Uses of arylalkynes in drug synthesis.

V. R. Batchu et al. / Tetrahedron 61 (2005) 9869–9877
9871
performed at room temperature even for 2 days. These
observations clearly indicate in situ generation of a new
Pd(0) species from Pd/C–PPh at higher temperature, which
actually catalyzed the cross-coupling reaction. Notably, the
present coupling reaction in water was found to be selective
as no significant dimerization of terminal alkynes was
observed during the course of our reaction.
bromides towards the palladium-mediated alkynylation of
arenes that have been reported in organic solvents.
However, chlorobenzene failed to react with terminal alkynes
when employed under the present reaction conditions.
1
8b
3
While most of the terminal alkynes used for the present
coupling reaction in water alone were hydrophilic in nature,
the use of at least one hydrophobic alkyne, for example,
phenyl acetylene was examined and was found to afford
good yield of products (Entries 2 and 10, Table 2). The
overall process displays generality as well as good
functional group tolerability. Base sensitive functional
groups like ester, ketone and aldehyde group is well
tolerated under the condition studied and the reaction is
relatively insensitive to the electronic characteristics of a
substitutent.
Having optimized the present methodology, we chose to
investigate the coupling of a variety of terminal alkynes
with aryl halides in water. When aryl halide 1 was treated
with 1–2 equiv of terminal alkyne (2, RZalkyl, hydro-
xyalkyl, aryl etc.) in water in the presence of 10% Pd/C
(
2
0.04 equiv), PPh3 (0.20 equiv), CuI (0.05 equiv) and
-aminoethanol (3 equiv) under nitrogen, aryl alkynes 3
were obtained as desired products in good to excellent
yields. Results of this study are summarized in Table 2.
Of the several examples shown in Table 2, compound 3k is
the precursor of (S)-2-(6-methoxy-2-naphthyl)propanoic
acid, a non-steroidal anti-inflammatory agent commonly
known as naproxen, used for the treatment of inflammatory
In general we have chosen aryl halides that do not possess
hydrophilic functional groups. This clearly ruled out the
possibility of effective Sonogashira coupling aided by
the enhanced solubility of the aryl halides in water in the
presence of a base. Thus, aryl iodides/bromides were
reacted with terminal alkynes under the present reaction
conditions (Table 2). Remarkably, the base sensitive ester
group was not affected in this aqueous Sonogashira coupling
2
1a
diseases.
However, its preparation via conventional
2
1a
Sonogashira coupling was incompatible to the industrial
production. Our procedure reported herein should find
application for the synthesis of 3k in large scale thereby in
the preparation of various types of 2-arylpropenoic acids.
Similarly, compound 3e has been utilized for the synthesis
of incrustoporin [3-(p-tolyl)-5-ethyl-5H-furan-2-one, an
antifungal antibiotic isolated from Incrustoporia carneola]
(
Entry 2, Table 2). Aryl iodides are known to react readily
under the normal Sonogashira coupling condition and were
found to be the same in the present case. However, aryl
bromides are available in far greater number and their use
more economical. We thus employed an array of commer-
cially available aryl bromides bearing a variety of
substituents (Entries 3–10, Table 2), for example, electron
2
1g
and was prepared via a multi-step procedure. We have
also investigated the Pd/C-mediated coupling-cyclization of
o-iodophenol with phenylacetylene in the presence of
2-aminoethanol where effective Sonogashira coupling was
favored due to the enhanced solubility of the aryl halides in
water in the presence of a base to produce a 75% yield of
donating (Me, SMe) or withdrawing groups (COCH , CHO)
3
for the coupling reactions. We were particularly interested
in the synthesis of 4-acyl substituted arylalkynes as this
moiety was found to be an integral part of biologically
active compound such as human farnesyltransferase
22
-phenyl benzo[b]furan. To demonstrate the applicability
2
of this process in the large scale preparation of aryl alkynes
23
we prepared compounds 6 and 7 on 5 g scale using the
conditions used for the synthesis of 3c (Table 1), as a key
synthetic step (Scheme 2).
0
inhibitor 4-[1-hydroxy-3-(3 -methoxy-5-pentanoyl-biphe-
nyl-2-yl)-1-(3-methyl-3H-imidazol-4-yl)-prop-2-ynyl]-ben-
2
1f
zonitrile. Like aryl iodides, all the bromides used were
found to be equally effective in terms of yields and the
respective substituents were well tolerated in this coupling
reaction. Yields were not affected drastically due to the
presence of either electron-donating (Entries 3–5 and 11, 12,
Table 2) or withdrawing groups (Entries 6–10, Table 2).
Notably, aryl bromides were found to be less reactive in the
solventless, microwave-assisted Sonogashira coupling
3
. Conclusion
In conclusion, we have described a general and practical
procedure for the synthesis of a variety of arylalkynes via
Pd/C-mediated cross-coupling in water. Application and
scope of the methodology along with its limitations has
also been described. The process is free from the use of
expensive palladium complexes, hazardous as well as
expensive organic co-solvents and volatile amine bases.
The methodology is equally effective for the Sonogashira
coupling of aryl iodides and bromides. The reaction
proceeds well with activated and electron rich aryl
1
2b
using Pd–CuI–PPh /KF–Al O as catalyst system. Their
3
2 3
reactivity was also found to be low in t-Bu-Amphos/
Pd(OAc) mediated Sonogashira coupling in water
1
5k
or
dependent on the choice of the base in (PPh ) Pd–CuI
2
3
4
2
0c
mediated coupling reaction in water. Thus we have
achieved similar levels of reactivity with aryl iodides and
Scheme 2. Synthesis of arylalkynes 6 and 7.

9872
V. R. Batchu et al. / Tetrahedron 61 (2005) 9869–9877
a
Table 2. Pd/C catalyzed synthesis of aryl alkynes in aqueous media
c
Products (3)
d
Entry
1
Substrate (1); ArXZ
Alkynes (2); RZ
C(CH OH 2a
Reaction
b
time (h)
Yield (%)
78
3
)
2
9
(
1a)
(3a)
2
C
6
H
5
2b
15
93
(
1b)
(
3b)
3
4
5
2a
2a
8
9
6
77
84
77
(
1c)
(
3c)
(
1d)
(
3d)
(1d)
CH(OH)CH
CH(OH)CH
2
3
CH 2c
(
3e)
6
7
8
3
2d
10
85
59
69
(1e)
(
3f)
(1e)
CH(OH)C
6
H
5
2e
9
(3g)
2a
9
(1f)
(
3h)
9
(1f)
CH
2
CH OH 2f
2
5.5
85
(
3i)

V. R. Batchu et al. / Tetrahedron 61 (2005) 9869–9877
9873
Table 2 (continued)
c
Products (3)
d
Entry
Substrate (1); ArXZ
(1f)
Alkynes (2); RZ
Reaction
b
time (h)
Yield (%)
10
2b
5
72
(
3j)
e
1
1
2
2a
2c
15
15
80
82
(
1g)
(
3k)
e
1
(1g)
(
3l)
a
b
c
d
e
All reactions were carried out by using 1 (1.0 equiv), 2 (1.5 equiv), 1:5:1 ratio of Pd/C:PPh
The reaction was monitored by TLC.
Identified by H NMR, C NMR, IR, MS.
Isolated yields.
3
:CuI, 2-aminoethanol (3 equiv) in water.
1
13
2
1:1 acetonitrile–H O was used.
bromides. Both hydrophobic and hydrophilic terminal
alkynes reacted well and no significant side reaction such
as dimerization of terminal alkynes was observed during the
course of our reaction. As far as we know, in spite of a large
number reports on useful and effective modifications of
Sonogashira reaction, no successful examples of Pd/C-
mediated synthesis of arylalkynes in water have been
reported. Due to the operational simplicity as well as easy
isolation and purification procedures for the products the
methodology appears to be a useful alternative to the
conventional Sonogashira reaction. The process is also
expected to be useful in the construction of novel
biomolecule-based systems via transition metal
mediated cross-coupling strategy in water. Current
work is focused on extending the scope and generality
of this methodology.
are given as s (singlet), d (doublet), t (triplet) and m
(multiplet) as well as b (broad). Coupling constants (J) are
given in Hertz. Infrared spectra were recorded on a Perkin-
Elmer 1650 FT-IR spectrometer. UV spectra were recorded
on Shimadzu UV 2100S UV–vis recording spectropho-
tometer. Melting points were determined using a Buchi
melting point B-540 apparatus and are uncorrected. Thermal
analysis data was generated with the help of Shimadzu
DSC-50 detector. MS spectra were obtained on a HP-5989A
mass spectrometer. Purity was determined by HPLC
(AGIL-AUTO) using the condition specified in each case:
column, mobile phase (range used), flow rate (range used),
detection wavelength, retention times. Microanalyses were
performed using Perkin-Elmer 2400 C H N S/O analyzer.
All the aryl halides and terminal alkynes used are
commercially available.
4
.1.1. Synthesis of arylalkynes: a typical procedure for
the synthesis of 4-(3-hydroxybut-1-ynyl)benzaldehyde
3f). A mixture of p-bromobenzaldehyde (0.5 g, 2.7 mmol),
10% Pd/C (0.11 g, 0.103 mmol), PPh (0.14 g, 0.53 mmol),
CuI (0.025 g, 0.13 mmol) and 2-aminoethanol (0.48 g,
8 mmol) in H O (10 mL) was stirred at 25 8C for 30 min
under nitrogen. To this was added butyn-2-ol (0.2 g,
4.0 mmol) slowly and the mixture was then stirred at
80 8C for 10 h. The mixture was cooled to room
temperature, diluted with EtOAc (60 mL) and filtered
through Celite. The filtrate was collected, washed with
4
. Experimental
(
4
.1. General methods
3
Unless stated otherwise, reactions were performed in dried
glassware under a nitrogen atmosphere. All the solvents
used were commercially available and distilled before use.
Reactions were monitored by thin layer chromatography
2
(
TLC) on silica gel plates (60 F254; Merck), visualizing
with ultraviolet light or iodine spray. Flash chromatography
was performed on silica gel (SRL 230–400 mesh) using
distilled petroleum ether, ethyl acetate, dichloromethane,
chloroform and methanol. H and C NMR spectra were
determined in CDCl , DMSO-d or MeOH-d solutions on
cold water (2!50 mL), dried over Na SO , filtered and
2 4
concentrated under vacuum. The residue thus obtained was
purified by column chromatography (hexane–EtOAc) to
afford the desired product as yellow oil (85% yield); H
1
13
1
3
6
4
Varian Gemini 200 MHz spectrometers. Proton chemical
shifts (d) are relative to tetramethylsilane (TMS, dZ0.00) as
internal standard and expressed in ppm. Spin multiplicities
NMR (200 MHz, CDCl ) d 10.0 (s, 1H, CHO), 7.82 (d, JZ
8.3 Hz, 2H), 7.56 (d, JZ7.9 Hz, 2H), 2.29 (q, JZ7.5 Hz,
1H, CH), 1.75 (s, 1H exchangeable, OH), 1.58 (d, JZ
3

9874
V. R. Batchu et al. / Tetrahedron 61 (2005) 9869–9877
K1
.6 Hz, 3H, CH ); IR (KBr, cm ) 3385, 1700 (CHO); MS
6
138.3, 131.5 (2C), 128.9 (2C), 119.5, 89.3 (C ), 84.9 (C ),
sp sp
64.1 (CH), 30.9 (CH ), 21.3 (CH ), 9.4 (CH ); HPLC
2 3 3
3
C C
CI, i-Butane) 175 (M C1, 100%), 157 (M K17);
13
(
NMR (50 MHz, CDCl ) d 191.7 (CHO), 135.3, 132.0 (2C),
C
98.18%, Inertsil ODS 3V (250!4.6 mm), mobile phase
0.01 M KH PO /CH CN, 1.0 mL/min, UV 210 nm, reten-
tion time 8.9 min.
3
1
29.4 (2C), 128.9, 95.2 (C ), 82.8 (C ), 58.5 (CH), 23.7
sp
sp
2
4
3
(
mobile phase 0.01 M KH PO /CH CN, 1.0 mL/min, UV
CH ); HPLC 98.9%, Inertsil ODS 3V (250!4.6 mm)
3
2
4
3
280 nm, retention time 9.02 min; found C, 75.79; H, 5.80;
C H O requires C, 75.84; H, 5.79%.
4.1.7.
dehyde (3g). Yellow liquid; yield 59%; H NMR
200 MHz, CDCl ) d 10.00 (s, 1H, CHO), 7.78 (d, JZ
4-{3-Hydroxy-3-phenyl-1-propynyl}-benzal-
1
1
1 10 2
(
3
1
8c
4
.1.2. 2-Methyl-4-phenyl-3-butyn-2-ol
yellow solid; yield 78%; DSC 51.8 8C; H NMR
200 MHz, CDCl ) d 7.46–7.41 (m, 2H), 7.33–7.27 (m,
(3a) Light
15.0 Hz, 2H), 7.63–7.37 (m, 7H), 5.73 (s, 1H, CH); IR (neat,
cm ) 3414, 1701; MS (CI, i-Butane) 237 (M C1, 100%),
1
K1
C
C 13
219 (M K17); C NMR (50 MHz, CDCl ) d 191.6
(
3
3
3
H), 1.94 (br s, exchangeable with D O, 1H, OH), 1.64
2
(CHO), 140.2, 135.5, 132.1 (2C), 129.4 (2C), 128.6 (2C),
128.4, 128.2, 126.6 (2C), 92.9 (C ), 85.3 (C ), 64.8 (CH);
HPLC 94.97%; Hichrom KR100 C18 (250!4.6 mm),
K1
(
s, 6H, 2CH ); IR (KBr, cm ): 3357, 2982; MS (CI,
3
sp
sp
C
13
i-Butane): 143 (M K17, 100%); C NMR (50 MHz,
CDCl ) d 131.5 (2C), 128.1 (2C), 128.0, 122.7, 93.9 (C ),
mobile phase 0.01 M KH PO /CH CN, 1.0 mL/min, UV
4
3
sp
2
3
8
Inertsil ODS 3V (250!4.6 mm), mobile phase 0.01 M
1.9 (C ), 65.4 (CMe OH), 31.3 (2C, CH ); HPLC 99.60%,
280 nm, retention time 10.6 min; found C, 81.23; H, 5.15;
C H O requires C, 81.34; H, 5.12%.
sp
2
3
1
6 12 2
KH PO /CH CN, 1.0 mL/min, UV 240 nm, 14.6 min.
3
2
4
4.1.8. 1-[4-(3-Hydroxy-3-methyl-1-butynyl)-phenyl]-1-
ethanone
2
4c–d
1
(3h) Light brown liquid; yield 69%; H
4
.1.3. (2-Phenylethynylphenyl)acetic acid ethyl ester
3b). Low melting solid; yield 93%; H NMR (200 MHz,
1
(
CDCl ) d 7.57–7.50 (m, 2H), 7.38–7.25 (m, 7H), 4.16
NMR (200 MHz, CDCl ) d 7.89 (d, JZ8.3 Hz, 2H), 7.49 (d,
3
JZ8.3 Hz, 2H), 2.6 (s, 3H, CH ), 2.18 (br s, exchangeable
3
3
K1
(
q, J Z14.1 Hz, J Z7.1 Hz, 2H), 3.90 (s, 2H, CH ), 1.22
with D O, 1H, OH), 1.64 (s, 6H, 2CH ); IR (KBr, cm
)
3417, 2981, 1681 (C]O); MS (CI, i-Butane) 203 (M ,
1
2
2
2
3
K1
C
(
t, JZ3.7, 3.3 Hz, 3H, CH ); IR (KBr, cm ): 2215 (w,
3
C
C^C–), 1735 (C]O); MS (CI, i-Butane) 265 (M C1,
13
100%); C NMR (50 MHz, CDCl ) d 198.0 (C]O), 136.1,
–
1
1
1
3
1
00%); C NMR (50 MHz, CDCl ) d 171.2 (C]O), 136.4,
3
131.6 (2C), 128.1 (2C), 127.7, 97.3 (C ), 81.2 (C ), 65.4
sp
3
sp
31.9, 131.5 (2C), 129.8, 128.5, 128.3 (2C), 127.1, 126.5,
23.5, 123.3, 93.8 (C ), 87.4 (C ), 60.8 (CMe OH), 40.2
(CMe OH), 31.2 (2C, CH ), 26.5 (CH ); HPLC 95.10%,
2 3 3
Inertsil ODS 3V (250!4.6 mm), mobile phase 0.01 M
KH PO /CH CN, 1.0 mL/min, UV 215 nm, retention time
11.4 min.
sp
sp
2
(CH ), 14.1 (CH ); found C, 81.58; H, 6.18; C H O
18 16
requires C, 81.79; H, 6.10%.
2
3
2
2
4
3
4
ol
.1.4. 2-Methyl-4-(4-methylsulfanylphenyl)-3-butyn-2-
4.1.9. 1-[4-(4-Hydroxy-1-butynyl)phenyl]-1-ethano-
ne.
2
4a
1
(3c) Yellow solid; yield 77%; DSC 71.20 8C; H
18b,24e
1
(3i) White solid; yield 85%; DSC 75.47 8C; H
NMR (200 MHz, CDCl ) d 7.32 (d, JZ8.3 Hz, 2H), 7.16 (d,
NMR (200 MHz, CDCl ) d 7.88 (d, JZ8.3 Hz, 2H), 7.48 (d,
3
3
JZ8.3 Hz, 2H), 2.48 (s, 3H, SCH ), 2.03 (br s, 1H, OH),
JZ8.4 Hz, 2H), 2.72 (t, JZ6.4 Hz, 2H, CH ), 3.84 (t, JZ
3
2
K1
.66 (s, 6H, 2CH ); IR (KBr, cm ): 2987; MS (CI, i-Butane)
1
6.4 Hz, 2H, CH ), 2.59 (s, 3H, CH ), 1.90 (br s, 1H, OH); IR
3
2
3
C
07 (M ), 189 (M K17,100%); C NMR (50 MHz,
C
13
K1
(KBr, cm ) 3324, 1680 (C]O); MS (CI, i-Butane) 189
2
CDCl ) d 139.1, 131.8 (2C), 125.7 (2C), 118.9, 93.8 (C ),
C 13
(M C1, 100%); C NMR (50 MHz, CDCl ) d 197.5
3
sp
3
8
HPLC 99.40%, Inertsil ODS 3V (250!4.6 mm), mobile
1.7 (C ), 65.5 (CMe OH), 31.4 (2C, CH ), 15.2 (CH );
(C]O), 135.7, 131.6 (2C), 128.4, 128.1 (2C), 90.5 (Csp),
81.4 (C ), 60.8 (CH OH), 26.4 (CH ), 23.7 (CH ); HPLC
sp
2
3
3
sp
2
3
2
phase 0.01 M KH PO /CH CN, 1.0 mL/min, UV 210,
2
retention time 17.9 min.
99.89%, Inertsil ODS 3V (4.6!250 mm), mobile phase
0.01 M KH PO /CH CN, 1.0 mL/min, UV 276 nm, reten-
tion time 13.1 min.
4
3
2
4
3
1
7a
4
Yellow liquid; yield 84%; H NMR (200 MHz, CDCl ) d
.1.5. 2-Methyl-4-(4-methylphenyl)-3-butyn-2-ol
(3d)
1
14,24f
4.1.10. 1-(4-Phenylethynyl-phenyl)-ethanone.
Off white solid, yield 72%; DSC 99.25 8C (lit.
(3j)
96–
3
2
4f
7
.31 (d, JZ8.1 Hz, 2H), 7.19 (d, JZ8.1 Hz, 2H), 2.34 (s,
1
3
(
H, CH ), 1.91 (br s, exchangeable with D O, 1H, OH), 1.61
98 8C); H NMR (200 MHz, CDCl ) d 7.93 (d, JZ8.5 Hz,
3
2
3
K1
s, 6H, 2CH ); IR (KBr, cm ): 3356, 2981, 2228 (w,
2H), 7.63–7.52 (m, 5H), 7.36 (t, JZ3.4 Hz, 2H), 2.61 (s, 3H,
3
C1
C^C–); MS (CI, i-Butane) 157 (M K17, 100%);
13
K1
CH ); IR (KBr, cm ) 2217, 1679 (C]O); MS (CI,
–
NMR (50 MHz, CDCl ) d 138.2, 131.4 (2C), 128.9 (2C),
C
3
C
i-Butane) 221 (M , 100%); C NMR (50 MHz, CDCl ) d
13
3
3
1
CH ), 21.3 (CH ); HPLC 99.4%, Inertsil ODS 3V (250!
19.6, 93.0 (C ), 82.1 (C ), 65.5 (CMe OH), 31.4 (2C,
197.2 (C]O), 136.2, 131.7 (2C), 131.6 (2C), 128.8 (2C),
128.4 (2C), 128.2 (2C), 122.6, 92.7 (C ), 88.6 (C ), 26.5
sp
sp
2
3
3
sp
sp
4
min, UV 240 nm, retention time 17.6 min.
.6 mm), mobile phase 0.01 M KH PO /CH CN, 1.0 mL/
3
(CH ); HPLC 99.9%, Inertsil ODS 3V (250!4.6 mm),
3
2
4
0.01 M KH PO /CH CN, 1.0 mL/min, UV 303 nm,
2
4
3
1
2.5 min.
2
4b
4
.1.6. 1-{4-Methylphenyl}-1-pentyn-3-ol
liquid, yield 77%; H NMR (200 MHz, CDCl ) d 7.33 (d,
(3e) Yellow
1
4.1.11. 4-(6-Methoxy-naphthalen-2-yl)-2-methylbut-3-
(3k) White solid; yield 80%; mp 118–119 8C
1
3
2
1a
JZ8.0 Hz, 2H), 7.12 (d, JZ8.3 Hz, 2H), 4.56 (t, JZ5.9 Hz,
yn-2-ol
(lit. 119–121 8C); H NMR (200 MHz, CDCl ) d 7.87 (s,
2
1a
1
1
3
2
H, CH), 2.35 (s, 3H, CH ), 1.82 (m, 2H, CH ), 1.64 (br s,
H, OH), 1.08 (t, JZ7.3 Hz, 3H, CH ); IR (KBr, cm
3
2
3
K1
)
358, 2231 (w, –C^C–); MS (CI, i-Butane) 175 (M ,
1H), 7.65 (d, JZ3.5 Hz, 1H), 7.67 (d, JZ3.2 Hz, 1H), 7.42
(d, JZ8.2 Hz, 1H), 7.20 (s, 1H), 7.10 (d, JZ3.8 Hz, 1H),
3.90 (s, 3H, OCH ), 1.90 (br s, 1H, OH), 1.57 (s, 6H, 2CH ).
3
C
C 13
0%), 157 (M K17, 100%); C NMR (50 MHz, CDCl ) d
3
3
3

V. R. Batchu et al. / Tetrahedron 61 (2005) 9869–9877
9875
4
.1.12. 4-{6-Methoxy-2-naphthyl}-3-butyn-2-ol (3l).
4.3.1. 1-(4-Methylsulfonylphenyl)-2-phenylacetylene (6).
Light yellow solid; yield 78%; mp 157–158 8C (lit.
1
24h
White solid; yield 82%; DSC 99.64 8C; H NMR
200 MHz, CDCl ) d 7.88 (s, 1H), 7.69 (d, JZ3.6 Hz,
1
162.5–163.5 8C); H NMR (200 MHz, CDCl ) d 7.95 (d,
(
3
3
1
(
H), 7.66 (d, JZ3.0 Hz, 1H), 7.43 (d, JZ8.3 Hz, 1H), 7.17
s, 1H), 7.11 (d, JZ3.9 Hz, 1H), 4.80 (q, JZ6.3 Hz, 1H,
CH), 3.92 (s, 3H, OCH ), 1.95 (br s, 1H, OH), 1.58 (d, JZ
JZ8.8 Hz, 2H), 7.72 (d, JZ8.8 Hz, 2H), 7.57–7.28 (m, 5H),
K1
3.09 (s, 3H, SO CH ); IR (neat, cm ) 1461, 1377; MS (CI,
2
3
C
i-Butane) 256 (M , 100%); HPLC 98.5%; Inertsil ODS 3V
(250!4.6 mm), mobile phase H O/CH CN (40: 60),
1.2 mL/min, UV 308 nm, retention time 11.0 min.
3
K1
6
.6 Hz, 3H, CH ); IR (KBr, cm ) 3385; MS (CI, i-Butane)
3
2
3
C
27 (M C1), 209 (M K17, 100%); C NMR (50 MHz,
C
13
2
CDCl ) d 158.2, 134.1, 131.3, 129.2, 128.9, 128.3, 126.7,
3
1
5
19.3, 117.4, 105.7, 90.4 (C ), 84.4 (C ), 58.8 (OCH ),
sp sp 3
5.2 (CH), 24.4 (CH ); HPLC 99.93%, Inertsil ODS 3V
3
4.3.2. 4-(4-Methylsulfonylphenyl)-3-butyn-1-ol (7).
White solid; yield 68%; mp 94–96 8C; H NMR
1
(
250!4.6 mm), mobile phase 0.01 M KH PO /CH CN,
2 4 3
(200 MHz, CDCl ) d 7.90 (d, JZ7.8 Hz, 2H), 7.60 (d, JZ
3
1
7
.0 mL/min, UV 250 nm, retention time 15.5 min; found C,
9.80; H, 6.22; C H O requires C, 79.62; H, 6.24%.
8
.3 Hz, 2H), 3.80 (t, JZ6.3 Hz, 2H, CH ), 3.0 (s, 3H,
2
1
5
14
2
SO CH ), 2.70 (t, JZ6.3 Hz, 2H, CH ), 1.75 (br s,
2 3 2
K1
exchangeable with D O, 1H, OH); IR (neat, cm ) 3440,
2
C
C
4
.2. Preparation of compound 4 and 5
1465; MS (CI, i-Butane) 224 (M , 50%), 194 (M K31,
00%); HPLC 98.67%; Shimpak CLC C8 (250!4.6 mm),
mobile phase 0.01 M KH PO /CH CN (60:40), 1.0 mL/
min, UV 256 nm, retention time 5.59 min; found C, 58.72;
1
General procedure. A mixture of p-bromothioanisole (5.5 g,
2
2
4
3
7.0 mmol), 10% Pd/C (1.1 g, 1.03 mmol), PPh (1.4 g,
3
5
.3 mmol), CuI (0.25 g, 1.3 mmol) and 2-aminoethanol
H, 5.40; C11
H
12
O
3
S requires C, 58.91; H, 5.39%.
(
4.8 g, 80.0 mmol) in H O (75 mL) was stirred at 25 8C for
2
3
2
0 min under nitrogen. To this was added terminal alkyne
b or 2f (40.0 mmol) slowly and the mixture was then
Acknowledgements
stirred at 80 8C for 8–10 h. The mixture was cooled to room
temperature, diluted with EtOAc (200 mL) and filtered
through Celite. The filtrate was collected, washed with cold
The authors thank Dr. A. Venkateswarlu, Dr. R. Rajagopa-
lan, Prof. J. Iqbal of Dr. Reddy’s Laboratories, Hyderabad,
India and Dr. U. Saxena of Reddy US Therapeutics,
Norcross, GA, USA for their constant encouragement.
Authors also thank Dr. K. Vyas and his group for analytical
and spectral support. MP thanks DRL for allowing him to
attend the A.C.S. meeting, Anaheim, CA, March 28–April
1, 2004.
water (2!150 mL), dried over Na SO , filtered and
2
4
concentrated under vacuum. The residue thus obtained
was purified by crystallization (hexane–EtOAc) to afford
the desired product.
2
4g
4
(
8
.2.1. 1-(4-Methylsulfanylphenyl)-2-phenylacetylene
4) Light brown solid, yield 59%; mp 80–82 8C (lit.
2
4g
1
3–84 8C); H NMR (200 MHz, CDCl ) d 7.50 (m, 2H),
3
7
SCH ); IR (neat, cm ) 1460, 1375; MS (CI, i-Butane) 224
(
.41 (d, JZ8.3 Hz, 2H), 7.31–7.20 (m, 5H), 2.49 (s, 3H,
K1
3
References and notes
C
M , 100%).
1
. For selected references, see: (a) Tamao, K. In Trost, B. M.,
Fleming, I., Eds.; Comprehensive Organic Synthesis; Pergamon:
Elmsford, NY, 1991; Vol. 3, pp 435–480. (b) Knight, D. W. In
Trost, B. M., Fleming, I., Eds.; Comprehensive Organic Synthesis;
Pergamon: Elmsford, NY, 1991; Vol. 3, pp 481–520.
(c) Sonogashira, K. In Trost, B. M., Fleming, I., Eds.;
Comprehensive Organic Synthesis; Pergamon: Elmsford, NY,
4
.2.2. 4-(4-Methylsulfanylphenyl)-3-butyn-1-ol (5).
1
Yellow solid; yield 45%; mp 80–82 8C; H NMR
200 MHz, CDCl ) d 7.30 (d, JZ8.3 Hz, 2H), 7.11 (d, JZ
(
8
3
.3 Hz, 2H), 3.80 (t, JZ6.3 Hz, 2H, CH ), 2.70 (t, JZ
2
6
with D O, 1H, OH); IR (neat, cm ) 3400, 1461; MS (CI, i-
.3 Hz, 2H, CH ), 2.47 (s, 3H), 1.97 (br s, exchangeable
2
K1
2
C
C
Butane) 192 (M , 60%), 161 (M K31, 100%); HPLC
7.6%; Symmetry C18 (250!4.6 mm), mobile phase H O/
CH CN (40:60), 1.0 mL/min, UV 279 nm, retention time
1991; Vol. 3, pp 521–549. (d) Tamao, K.; Kumada, M. In Hartley,
9
2
F. R., Ed.; The Chemistry of the Metal–Carbon Bond; Wiley:
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3
5
.08 min; found C, 68.68; H, 6.30; C H OS requires C,
11 12
2. (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett.
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6
8.71; H, 6.29%.
1
Metal Catalyzed Cross-Coupling Reactions; Diederich, F.,
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4
.3. Preparation of compound 6 and 7
General procedure. To a solution of compound 4 or 5
36.0 mmol) in acetone (40 mL) was added a solution of
(
oxone (44.0 g, 71.5 mmol) in water (20 mL). The reaction
mixture was stirred vigorously for 4 h at 25 8C. After
completion of the reaction the solvent was removed under
reduced pressure and water (100 mL) was added to the
reaction mixture. The mixture was then stirred for 15 min
and the solid precipitated was filtered. The crude product
was purified by crystallization from hexane–EtOAc to give
the desired compound.
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3
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(
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1
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1
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1
1
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2
0. (a) The use of 2-aminoethanol in the Pd/C mediated synthesis
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M. Presented at the International Conference on Chemistry
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this manuscript was under preparation a paper describing
(
Tetrahedron Lett. 2000, 41, 5151–5154.
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1
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