Regioselective synthesis of 4-substituted-1-aryl-1-butanones using a Sonogashira-hydration strategy: Copper-free palladium-catalyzed reaction of terminal alkynes with aryl bromides

Article abstract of DOI:10.1055/s-2002-35587

A simple one-pot procedure has been developed for the synthesis of 4-substituted-1-aryl-1-butanones through copper-free Sonogashira reaction of aryl bromides with terminal alkynes in DMF under inert atmosphere, followed by the treatment with acid in the p

Full text of DOI:10.1055/s-2002-35587

1976
LETTER
Regioselective Synthesis of 4-Substituted-1-Aryl-1-butanones Using a
Sonogashira-Hydration Strategy: Copper-Free Palladium-Catalyzed Reaction
of Terminal Alkynes with Aryl Bromides1
C
opper-Free Palladium
a
-Catalyzed
n
R
eaction of
o
Terminal
A
l
j
kynes
w
ithAr
t
yl BromidesPal,* Karuppasamy Parasuraman, Shalabh Gupta, Koteswar Rao Yeleswarapu
Chemistry-Discovery Research, Dr. Reddy’s Laboratories Ltd., Bollaram Road, Miyapur, Hyderabad 500050, India
Fax +91(40)3045438 ; E-mail: manojitpal@drreddys.com
Received 11 October 2002
volves the reaction of nucleophilic aryl lithium with elec-
Abstract: A simple one-pot procedure has been developed for the
synthesis of 4-substituted-1-aryl-1-butanones through copper-free
Sonogashira reaction of aryl bromides with terminal alkynes in
DMF under inert atmosphere, followed by the treatment with acid
trophilic lactone carbonyl moiety of -butyrolactone
followed by treatment with ammonium chloride.13 Al-
though the method has been utilized successfully for the
in the presence of oxygen. A variety of aryl bromides was reacted preparation of compounds having biological importance,6
with 3-butyn-1-ol according to this procedure to give the expected
the protocol suffers from several limitations, the most im-
compounds in good yield. The mechanism of the reaction and appli-
cations of the methodology are discussed.
portant being the difficulties in the preparation of organo-
lithium reagents when applied to more complex systems
(especially in the presence of an acidic functional group).
Key words: 1-aryl-1-butanones, aryl bromide, 3-butyn-1-ol, palla-
dium catalyst, hydration
As a part of our current research program directed toward
the synthesis of compounds for biological testing in dif-
ferent therapeutic areas,14 we required a simple procedure
1-Aryl-1-butanones of the structure ArCOCH2CH2CH2Z
for the synthesis of a variety of 1-aryl-1-butanones 1.
[I, where Ar and Z are (hetero) aryl and hydroxy, halo etc.
Since the existing routes to obtain 1 were either inappro-
respectively] are extremely useful intermediates2 needed
priate (due to the non-availability of the required starting
for various synthetic strategies, especially for the prepara-
material) or unattractive due to the complicated synthetic
tion of agrochemicals and drugs. This is exemplified by
procedure we therefore became interested to develop an
their use in the preparation of biologically active com-
alternative method for the synthesis of 1. Our synthetic
pounds such as 2-( -aroylalkyl)-4-biaryloxobutyric acids
strategy, which relied on umpolung15 of the usual reactiv-
as matrix metalloprotease inhibitors3 for tumor cell inva-
7a–d,13
ity pattern associated with the earlier method
shown in Scheme 2.
is
sion and angiogenesis or 2-(3-aryloxy/aroylpropyl)ami-
no-1,3-thiazoles4 as anti-inflammatory agents or naphtho-
thiazole-substituted piperidine derivatives5 as inhibitors
of stomach acid secretion. They are also useful precursors
for the preparation of quinoline-4-carboxamide deriva-
tives (3, Scheme 1) as NK2 and NK3 receptor
antagonists6 for the treatment of asthma.
Of the variety of transition-metal mediated reactions, Son-
ogashira coupling reaction of aryl halides with terminal
acetylenes provides a powerful tool for C–C bond forma-
tion.16 This palladium–copper-catalyzed reaction is typi-
cally carried out in the presence of catalytic amounts of a
palladium(II) complex as well as copper(I) iodide in an
amine as solvent. Although extensive applications of
Sonogashira coupling of aryl iodides (as the order of ha-
lide reactivity is I > Br >> Cl) with terminal alkynes have
been reported in the literature since 1975, effective use of
aryl bromides17 has only recently been explored.18 Thus
In view of the importance of 1-aryl-1-butanones, a num-
ber of methods have been developed for their synthesis7–
11including the use of transition metal complexes.12
Amongst the various methods reported for the preparation
of 1 (I, Ar = C6H5, Z = OH), the most straightforward in-
O
N
NR
O
O
NR
N
OH
N
N
2
3
1
Scheme 1 Synthesis of quinoline-4-carboxamides as NK2 and NK3 receptor antagonists.
Synlett 2002, No. 12, Print: 02 12 2002.
Art Id.1437-2096,E;2002,0,12,1976,1982,ftx,en;D20402ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

LETTER
Copper-Free Palladium-Catalyzed Reaction of Terminal Alkynes with Aryl Bromides
1977
O
O
OH
OH
-
+
Z
O
Ref 13
-
Br
+
or
7a-d
OH
Scheme 2 Synthetic strategy for the preparation of 1.
Krause et al. reported an improved procedure for the tion of the resultant alkyne in the presence of palladium
coupling of aryl bromides, which are less expensive and catalyst and atmospheric oxygen in aqueous acid.
easy to prepare compared to aryl iodides, with terminal
When aryl halide (II, X = Br, I) was treated with 2 equiv-
alents of 3-butyn-1-ol (III) in DMF in the presence of
PdCl2(PPh3)2 (0.03 equiv) and triethylamine (8 equiv)
under nitrogen atmosphere at 80 °C for 8 hours, 4-aryl-3-
butyn-1-ol (IV, Method A, Scheme 3) was obtained in
good yield. However, we have observed that 1-aryl-1-
butanones (I, Ar = substituted aryl group, Z = OH or
OCHO) were formed as the major product when the same
alkynes using THF as solvent.18aUse of an efficient cata-
lyst i.e. Pd(PhCN)2Cl2/P(t-Bu)3 for Sonogashira reactions
of aryl bromides has been reported by Buchwald and et al.
very recently.19 Although substantial improvement in re-
action conditions has been observed in these cases, all
these procedures require the use of variable amounts (2–4
mol%) of copper(I)iodide for efficient coupling. It is well
known that dimerization of terminal alkynes to the corre-
reaction was performed using aryl bromides followed by
sponding diyne is often a side reaction under the Sono-
the treatment with 20% hydrochloric acid in the presence
gashira coupling conditions18,20 and this oxidative
of aerial oxygen for 8 hours at 25–30 ºC in the same pot
homocoupling (Glaser coupling) predominates21 in the
(Method B, Scheme 3). Our results are summarized in
presence of oxygen or other reagents. CuI in the presence
Table 1.
of excess amine base seemed to have a significant role in
By use of this tandem coupling-hydration protocol a wide
such oxidative homocoupling of terminal acetylenes.
variety of butanones have been prepared (Table 1).23 Thus
Since the separation of diynes from the desired product is
3-butyn-1-ol was reacted with an array of commercially
often cumbersome, copper-free Sonogashira reactions22
available aryl bromides bearing a variety of substituents
have significant advantages over the original method.
(Table 1, Entries 1, 4, 6, 7, 9, 10) e.g. either electron do-
Very recently Ryu et al. reported a copper-free Sono-
nating (Me, SMe) or withdrawing groups (COCH3, NO2,
gashira coupling of aryl iodides with terminal alkynes in
CHO) and all these substituents were well tolerated in this
single pot reaction. Hydroxyketone I was isolated as the
major product in most of the cases along with the internal
alkyne IV in a few cases (Entries 1, 7, 9). However, the
nature of the product (I or IV) formed in this coupling-hy-
dration protocol was affected by the duration of the treat-
ment with acid (Entry 1, Step 2, Table 1) and I was
isolated as the major product when the hydration (Step 2)
was carried out for 8 hours. Further increase in time in
Step 2 led to the generation of product that seemed to re-
sulted from O-formylation of the hydroxy ketone I (Entry
5, 8, 11, Table 1). It is pertinent to note that no oxidative
homocoupled product of terminal alkynes was detected in
all these cases. Another important point to note about the
present coupling-hydration protocol is the regiospecific
formation of ketone (Entry 6 vs 7, Table 1). Since the
alkynylation occurs only at the bromine bearing carbon of
the aromatic ring therefore, whilst the electronic effects
(resonance and inductive) may influence the rates of
the reactions, as a consequence of Pd-mediated reaction
an ionic liquid.22aTo the best of our knowledge, however,
only few descriptions of copper-free Sonogashira coup-
ling employing aryl bromides are available in the litera-
ture17a,17c–d,17h–i and none of them describe the use of
electron rich or unactivated19 aryl bromides. Use of di-
methylformamide (DMF) as a co-solvent for efficient
Sonogashira reaction (especially where the aryl halide is
insoluble in other solvent) is not very common.16c In this
connection we have observed that DMF could be utilized
as an effective solvent for the synthesis of compounds of
potential biological interest via Sonogashira-hydration
strategy. We thought this process could be a means to pro-
mote the equivalent of a Friedel–Crafts acylation
reaction7a–dof deactivated aryl derivatives, which is a de-
manding transformation and is not readily achieved even
in the presence of most effective Lewis acid catalysts.
Herein, we disclose regioselective one-pot synthesis of I
via copper-free Sonogashira coupling of aryl bromides
with a terminal alkyne in DMF followed by in situ hydra-
(X = Br)
(X = Br, I)
ArX
Pd
or
O
1. Pd-catalyst
Pd-Cu catalysis
II
Z
Ar
Ar
+
or
OH
2. HCl, O2
OH
Pd/C -PPh3-CuI
(Method A)
I (Z = OH, OCHO)
(Method B)
IV
III
Scheme 3 Palladium-catalyzed coupling of 3-butynol with aryl halides.
Synlett 2002, No. 12, 1976–1982 ISSN 0936-5214 © Thieme Stuttgart · New York

1978
M. Pal et al.
LETTER
Table 1 Synthesis of 1-Aryl-1-butanones (I)a
1. PdCl2(PPh3)2
O
Ar
Et3N, DMF, 80 °C
ArX
+
+
Z
OH
Ar
OH
2. 20 %HCl, 25–30 °C
III
II
IV
I
(Method B)
Entry
1
ArX
Productsb
Time (h)
Step 1
% Yieldc
(II)
I
IV
Step 2
8
I
IV
8
59
16
O
O
O
O
Br
OH
OH
IIa
IVa
IVa
IVa
n.d.
Ia
2
3
4
IIa
IIa
n.d.e
8
8
8
8
1
8
–
89d
84
n.d.
–
44
21
CH3
O
O2N
OH
Br
CH3
O2N
Ib
IIb
IIb
5
n.d.
n.d.
8
16
47
–
O
O2N
OCHO
CH3
O
Ibb
6
7
8
8
8
8
56
46
–
H3C
H3C
OH
OH
Br
IIc
Ic
13
O
H3C
Br
H3C
OH
IId
IVd
H3C
Id
8
9
IId
n.d.
8
8
8
8
16
8
43
37
61
55
–
O
O
O
O
OCHO
H3C
Idd
19
–
OHC
OHC
OHC
OH
HO
HO
Br
OH
HO
IIe
IVe
Ie
10
11
n.d.
8
H3CS
Br
OH
IIf
H3CS
If
IIf
n.d.
16
–
OCHO
H3CS
Iff
a Reactions were carried out by using II (1.0 equiv), III (2.0 equiv), PdCl2(PPh3)2 (0.03 equiv), Et3N (8 equiv) in DMF. b Identified by 1H NMR,
IR, Mass.
c Isolated yields.
d Reaction was performed using Pd/C:PPh3:CuI, 1:4:2, 2.5 equivalents of 3-butyn-1-ol in DME:H2O (see Ref.17g).
e n.d. = not detected.
Synlett 2002, No. 12, 1976–1982 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Copper-Free Palladium-Catalyzed Reaction of Terminal Alkynes with Aryl Bromides
1979
directing the key transformation, the composition of ke- tion of the ketone I as major product in most of the cases.
tone remains unaffected by the nature and the position of Use of other catalysts such as Pd(PPh3)4 was also investi-
substituent in the starting bromide. This is in sharp con- gated and was found to be less effective (Entry 5, Table 2)
trast to the result using Friedel–Crafts acylation reaction implicating the better efficacy of Pd(0) complex generat-
where reactivity and orientation of electrophilic substitu- ed in situ in the present case. Interestingly, bromobenzene
tion reaction is influenced by the nature of the group in the presence of Pd(PPh3)4-NaOMe catalyst system,
present in the starting aromatics.
when treated with terminal alkyne, afforded biphenyl in
low yield instead of desired alkyne.22b No rearranged
product was detected when the catalyst system
PdCl2(PPh3)2-Et3N (Method B) was replaced by 10% Pd/
C-PPh3-CuI-K2CO3 (Method A)17g and normal coupled
product was isolated in good yield (entry 2, Table 1) even
after treatment with 20% HCl solution for 8 hours in the
presence of air. However, to gain further evidence on the
nature of the hydration reaction, the isolated alkyne24b was
treated separately with 20% HCl at 25–30 ºC but no sig-
nificant change was observed even after stirring for 3 days
in open air and 80% of the reactant alkyne was recovered.
Hydration of a triple bond is a well-known reaction,25
which is catalyzed by Hg salts, its Nafion modification, or
strong acid such as H2SO4, trifluoromethanesulfonic acid
or trifluoromethanesulfonimide25a in the presence of wa-
ter. However, hydration in the presence of HCl at room
temperature is not known in the literature whereas palla-
dium-catalyzed hydration of alkyne is a known process.26
Thus literature reports as well as our observations indicate
that the palladium complex present in the reaction mixture
has a significant role in the hydration of the resultant
alkyne when exposed to acid and air simultaneously.
The copper-free Sonogashira coupling was carried out in
DMF using triethylamine as a base. The advantage in the
use of DMF as solvent is its ability to solubilize a wide va-
riety of aryl bromides and palladium catalysts as well as
its miscibility with aqueous HCl and therefore facilitates
the coupling-hydration reaction well. However, the use of
other solvents such as THF and dioxane was also investi-
gated and was found to be less effective in terms of yield.
The coupling reaction (Step 1) was usually carried out at
80 ºC whereas hydration of the resultant alkyne (Step 2)
proceeded well at 25–30 ºC. The effect of temperature,
time, catalyst and the nature of aryl halide used on product
distribution are summarized in Table 2. Lowering of reac-
tion temperature in Step 1 completely suppressed the
product formation (Entry 1, Table 2) confirming the need
of higher temperature for the conversion of Pd(II) to
Pd(0). Although the increase in time in Step 2 altered the
product distribution drastically (Entry 2 vs 3, Table 2) the
conversion rate however, remained unaffected even after
further increase in time (Entry 2-4, Table 2). Quantitative
conversion was achieved using aryl iodide in place of aryl
bromide but in this case, alkyne was isolated as the major
product under identical reaction conditions (Entry 5,
Table 2). Appearance of a palladium mirror on the wall of
the reaction flask in this case may offer an explanation for
such observation.24a
The Sonogashira coupling-hydration reaction was found
to be highly regioselective in view of product formation as
only 1-aryl-1-butanones (I) and no other regioisomers
were detected under the reaction conditions employed. All
the products isolated were well characterized by their 1H
NMR, Mass and IR spectra (carbonyl stretching frequen-
cies in the region of 1690–1670 cm–1).
The coupling-hydration method proceeded well in the
presence of PdCl2(PPh3)2 as catalyst leading to the forma-
Table 2 Effect of Reaction Conditions on Product Distributiona
O
O
OH
X
1. III, Pd catalyst
OH
+
OCHO
+
H3COC
H3COC
2.HCl
IVa
Iaa
Ia
H3COC
IIa
H3COC
Entry
X
Catalyst
Condition [T (ºC); t (h)]
Conv.b (%)
Product Distributionc (%)
Step 1
35–40; 8
80; 8
Step 2
Ia
–
Iaa
–
IVa
–
1
2
3
4
5
6
Br
Br
Br
Br
I
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)4
–
0
>80
>85
>80
100
>50
20–30; 8
20–30; 16
20–30; 24
20–30; 8
20–30; 8
59
19
12
10
–
n.d.d
51
55
n.d.
–
16
80; 8
n.d.
n.d.
70
80; 8
80; 8
Br
80; 8
39
a Reactions were carried out by using II (1.0 equiv), III (2.0 equiv), PdCl2(PPh3)2 (0.03 equiv), Et3N (8 equiv) in DMF.
b Conversion was determined on the basis of the isolated yield of product and recovered starting material.
c Product distributions were calculated based on the isolated yield of each product.
d n.d. = not detected.
Synlett 2002, No. 12, 1976–1982 ISSN 0936-5214 © Thieme Stuttgart · New York

1980
M. Pal et al.
LETTER
The mechanism of the reaction could be envisaged as (Scheme 5).30b Compound 1a was converted to the corre-
shown in Scheme 4. The alkyne IV generated via usual sponding bromide, which is useful precursor for the syn-
palladium(0) [generated from palladium(II)complex]- thesis of potential antipsychotic agents, using the reported
catalyzed27a,b coupling of aryl bromide II with 3-butyn-1- method.32
ol III subsequently participates in Pd(II) mediated hydra-
To conclude, the present communication deals with a con-
venient one-pot procedure for the regioselective synthesis
tion reaction. Generation of Pd(II) from Pd(0) is catalyzed
by molecular oxygen27c–d in the presence of Et3NHX. Par-
of 1-aryl-1-butanones. To the best of our knowledge this
ticipation of the terminal hydroxyl group of the resultant
is the first example for the synthesis of 1-aryl-1-butanones
alkyne during the hydration process seemed to have the
employing such a methodology. The method involves the
key role in the formation of a particular regioisomer.28
use of readily available aryl bromides in the absence of
The Pd(II)-alcoholate V22b thus formed may lead to the
copper salts, thereby preventing the formation of diynes
as side product. Due to the mild reaction conditions and
functional group tolerability the present protocol is cer-
tainly superior to the existing methods, particularly in that
formation of ketone I (when quenched with excess water)
or formylated product VI (when allowed to stir for longer
period in DMF–HCl)29 depending on the reaction condi-
tions employed. Further study on this mechanistic se-
it allows the regiospecific functionalization of the activat-
quence is in progress.
ed and deactivated aromatics to afford substituted bu-
We have demonstrated that a variety of 1-aryl-1-bu- tanones having a wide range of aryl residues. More
tanones (I), having a substituent (especially hydroxy) at importantly the present protocol is safer than other meth-
the 4-position, can be synthesized via palladium-cata- ods, which involve use of pyrophoric organolithium re-
lyzed alkynylation of aryl bromides followed by subse- agent or environmentally harmful AlCl3, or toxic Hg salts.
quent hydration of internal alkynes generated in situ. This The methodology has been utilized for the preparation of
is worthwhile in comparison to other one-pot reactions compounds of biological interest and its further applica-
(e.g. SnCl2–EtOH–H2O or Fe–NH4Cl–CH3COOH as re- tion in organic synthesis is presently under investigation.
ductive hydrating agent) where hydration of acetylene
moiety was found to be inconsistent.25d Notably, regiose-
Acknowledgment
lectivity of the triple bond hydration in the present case
The authors would like to thank Dr. A. Venkateswarlu, Dr. R. Ra-
jagopalan and Prof. J. Iqbal for their constant encouragement and
the Analytical Department for spectral support. SG thanks to the
Department of Chemistry, I.I.T., Delhi, India for allowing him to
pursue part of this work under summer training program. The au-
thors also thank Mr. P. Vijayaraghavan, Mr. P. Srinivas and Mr. V.
V. Rao for their help in manuscript preparation and Mr. I. Nages-
wara Rao, Dyson Perrins Laboratory, Oxford University, U.K. for
literature research.
was not affected by the nature of the aryl group attached
to it.25e Thus the present Sonogashira-hydration technique
represents a general and versatile method for the synthesis
of I and offers a significant tactical advantage over tradi-
tional Lewis acid-catalyzed acylation reactions. The
methodology has been utilized for the synthesis30 of com-
pounds of potential biological interest.6,30a,b Compound
1d was converted to VI, which is known to be useful for
the treatment of atherosclerosis via raising the level of
HDL cholesterol,31according to the known procedure
H
+
O
ArBr
+
Ar
Ar
Pd(0)
OH
Pd(II)
OH
IV
III
II
(II)Pd
Et3N/ heat
O
2 /Et3NHX
H2O
Pd(II)
Pd(0)
O
O
O
Ar
DMF-HCl
O Pd(II)
OCHO
Ar
Ar
(II)Pd
O
V
H
H2O (excess)
I
Scheme 4 Mechanism of the base promoted oxidative cyclization reaction.
C6H5HNOCO
O
O
OH
H
a
b
N
NH2
N
H3C
H3C
S
H3C
OCONHC6H5
1d
VI
Scheme 5 Reagents and conditions: a) C6H5NCO, Et3N, C6H6, 80 °C, 4 h; b) NH2NHC(S)NH2, MeOH, 1 N HCl, 25 °C, 24 h.
Synlett 2002, No. 12, 1976–1982 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Copper-Free Palladium-Catalyzed Reaction of Terminal Alkynes with Aryl Bromides
1981
(17) For earlier reports on the occasional use of aryl bromide,
see: (a) Dieck, H. A.; Heck, R. F. J. Organomet. Chem.
1975, 93, 259. (b) Takahashi, S.; Kuroyama, Y.;
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7839.
Tetrahedron 1999, 55, 1017. (d) Kimura, N.; Tukamuku, S.
Bull. Chem. Soc. Jpn. 1991, 64, 2433.
(8) For synthesis via chemoselective oxidation of alcohols see:
(a) Singh, J.; Sharma, M.; Chhibber, M.; Kaur, J.; Kad, G. L.
Synth. Commun. 2000, 30, 3941. (b) Zhang, G.; Li, W.; Cai,
K.; Li, Z. Huaxue Tongbao 1992, 4, 34; Chem. Abstr. 1992,
118, 123774. (c) Muzart, J.; Ajjou, A. N. Synth. Commun.
1992, 22, 1993.
(23) Typical procedure for the synthesis of 4-substituted 1-
aryl-1-butanones: Preparation of Ia: To a solution of 4-
bromoacetophenone (1 g, 5.03 mmol) in DMF (10mL) was
added PdCl2(PPh3)2 (0.10 g, 0.15 mmol)and Et3N (4.06 g,
40.20 mmol) under nitrogen atmosphere. The mixture was
stirred for 15 min at 25 C and then 3-butyn-1-ol (0.71 g,
10.05 mmol) was added very slowly via syringe to the stirred
reaction mixture. The temperature of the mixture was
increased slowly to 80 °C and stirring continued for 8 h.
During the reaction, which was followed by TLC,
precipitation of Et3N HBr as crystalline solid was observed.
After the complete consumption of the aryl bromide, the
reaction mixture was cooled to r.t. and 20% HCl solution
(100 mL) was added to it with vigorous stirring. After
stirring for 8 h the mixture was diluted with water and
EtOAc (150 mL), filtered through a small pad of celite
(EtOAc). The organic layer was collected, washed with H2O
(2 100 mL), dried over anhyd Na2SO4, filtered and
concentrated under low vacuum. The residue thus obtained
was purified by flash chromatography to afford the desired
compound. Compound Ia was isolated in 59% yield as light
yellow solid, mp 91–92 °C (hexane); IR (KBr): 3342 (br,
OH), 1678 (C=O), 1502 cm–1; 1H NMR (200 MHz, CDCl3):
= 8.04 (m, 4 H, ArH), 3.76 (t, J = 5.91 Hz, 2 H, CH2OH),
3.16 (t, J = 6.98 Hz, 2 H, CH2CO), 2.65 (s, 3 H, CH3), 2.09–
1.97 (m, 2 H, CH2), 1.65 (br s, D2O exchangeable, 1 H, OH);
M (CI, I-butane): m/z (%) = 207 (100) [MH+]; 13C NMR:
199.89, 197.61, 139.94, 139.87, 128.37 (2 C), 128.13 (2 C),
61.71, 35.42, 26.74, 26.62.
(9) For synthesis via chemoselective reduction see: (a)Barrero,
A. F.; Alvarez-Manzaneda, E. J.; Chahboun, R.; Meneses, R.
Synlett 2000, 197. (b) Isobe, K.; Mohri, K.; Sano, H.; Taga,
J.; Tsuda, Y. Chem. Pharm. Bull. 1986, 34, 3029.
(10) For synthesis via acyl transfer reactions with phosphine
oxides see: (a) Wallace, P.; Warren, S. J. Chem. Soc., Perkin
Trans. 1 1988, 2971. (b) Wallace, P.; Warren, S.
Tetrahedron Lett. 1985, 26, 5713.
(11) For other methods see: (a) Fuji, K.; Node, M.; Usami, Y.
Chem. Lett. 1986, 6, 961. (b) Fuji, K.; Usami, Y.; Kiryu, Y.;
Node, M. Synthesis 1992, 852. (c) Bretsch, W.; Reissig, H.
U. Liebigs Ann. Chem. 1987, 3, 175.
(12) (a) Niita, M.; Yi, A.; Kobayashi, T. Bull. Chem. Soc. Jpn.
1985, 58, 991. (b) Echavarren, A. M.; Perez, M.; Castano,
A. M.; Cuerva, J. M. J. Org. Chem. 1994, 59, 4179.
(13) (a) Taura, Y.; Tanaka, M.; Wu, X. M.; Funakoshi, K.; Sakai,
K. Tetrahedron 1991, 47, 4879. (b) O’Connor, J. M.; Pu, L.;
Rheingold, A. L. J. Am. Chem. Soc. 1990, 112, 6232.
(14) (a) Pal, M.; Rao, Y. K.; Rajagopalan, R.; Misra, P.; Kumar,
P. M.; Rao, C. S. World Patent WO 01/90097, 2001; Chem.
Abstr. 2002, 136, 5893. (b) Pattabiraman, V. R.; Padakanti,
P. S.; Veeramaneni, V. R.; Pal, M.; Yeleswarapu, K. R.
Synlett 2002, 947. (c) For a brief overview see: Scrip 2002,
112, 43.
(15) For a recent example, see: Shuki, A.; Keiko, K.; Jiro, T.;
Tsunehisa, H.; Hatsuo, Y.; Masao, K. J. Org. Chem. 2001,
66, 7919.
(16) (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron
1975, 16, 4467. (b) Sonogashira, K. In Comprehensive
Organic Synthesis, Vol. 3; Trost, B. M.; Fleming, I., Eds.;
Pergamon Press: New York, 1991, 521. (c) Pal, M.; Kundu,
N. G. J. Chem. Soc., Perkin Trans. 1 1996, 449.
Spectral data for 1d: pale yellow oil; IR (KBr): 3420 (br,
OH), 1679 (C=O), 1607 cm–1; 1H NMR (200 MHz, CDCl3):
= 7.90 (d, J = 7.81 Hz, 2 H, ArH), 7.29 (d, J = 7.80 Hz,
2 H, ArH), 3.76 (t, J = 5.86 Hz, 2 H, CH2OH), 3.13 (t,
J = 6.84 Hz, 2 H, CH2CO), 2.43 (s, 3 H, CH3), 2.09–1.97
(m, 2 H, CH2), 1.80 (br s, D2O exchangeable, 1 H, OH); MS
(CI, I-butane): m/z (%) = 179 (100) [MH+]; 13C NMR:
Synlett 2002, No. 12, 1976–1982 ISSN 0936-5214 © Thieme Stuttgart · New York

1982
M. Pal et al.
LETTER
199.12, 143.87, 134.27, 129.20 (2 C), 128.15 (2 C), 62.28,
35.21, 27.00, 21.64.
Kataoka, H.; Watanabe, K.; Miyazaki, K.; Tahara, S.; Ogu,
K.; Matsuoka, R.; Goto, K. Chem. Lett. 1990, 1705. (d)
See also: Kataoka, H.; Watanabe, K.; Goto, K. Tetrahedron
Lett. 1990, 31, 4181.
Spectral data for 1ff: IR (KBr): 1719 (OCHO), 1665 (C=O),
1588 cm–1; 1H NMR (200 MHz, CDCl3): = 8.07 (s, 1 H,
CHO), 7.88 (d, J = 8.33 Hz, 2 H, ArH), 7.27 (d, J = 8.30 Hz,
2 H, ArH), 4.28 (t, J = 6.31 Hz, 2 H, CH2O), 3.05 (t, J = 7.13
Hz, 2 H, CH2CO), 2.53 (s, 3 H, SCH3), 2.16–2.09 (m, 2 H,
CH2); MS (CI, I-butane): m/z (%) = 239 (100) [MH+].
(28) For hydration of alkynes controlled by neighboring group
participation, see: (a) Stork, G.; Borch, R. J. Am. Chem. Soc.
1964, 86, 935. (b) Hooz, J.; Layton, R. B. Can. J. Chem.
1970, 50, 1105; See also ref. 26.
(24) (a) Palladium metal deposited on the wall of the reaction
flask perhaps did not participate in the hydration step.
(b) The alkyne was purified carefully using column
chromatography in order to ensure the removal of the traces
amount of Pd-catalyst.
(25) (a) Tsuchimoto, T.; Joya, T.; Shirakawa, E.; Kawakami, Y.
Synlett 2000, 1777; and references therein. (b) Olah, G. A.;
Meidar, D. Synthesis 1978, 671. (c) Noyce, D. S.; Matesich,
A. M.; Peterson, E. J. Am. Chem. Soc. 1967, 89, 6225.
(d) Bosch, E.; Jeffries, L. Tetrahedron Lett. 2001, 42, 8141.
(e) Yamanaka, H.; Shiraiwa, M.; Sakamoto, T.; Konno, S.
Chem. Pharm. Bull. 1981, 29, 3548.
(29) O-Formylation of alcohols using DMF in the presence of
other reagents has been reported, see for example:
(a) Barluenga, J.; Campos, P. J.; Gonzalez-Nunez, E.;
Asensio, G. Synthesis 1985, 426. (b) Luca, L. D.;
Giacomelli, G.; Porcheddu, A. J. Org. Chem. 2002, 67,
5152.
(30) (a) Commons, T. J.; Musial, C. L.; Christman, S. WO
9857928 A1, 1998; Chem. Abstr. 1998, 130, 81279.
(b) Commons, T. J.; Christman, S. US 5977170 A, 1999;
Chem. Abstr. 1999, 131, 310456. (c) Tomita, Y.;
Kabashima, S.; Okawara, T.; Yamasaki, T.; Furukawa, M.
J. Heterocycl. Chem. 1990, 27, 707.
(26) Imi, K.; Imai, K.; Utimoto, K. Tetrahedron Lett. 1987, 28,
3127.
(31) (a) Miller, N. E.; Hammett, F.; Saltissi, S.; Rao, S.; Van
Zeller, H.; Coltart, J.; Lewis, B. Br. Med. J. 1981, 282,
1741. (b) Picardo, M.; Massey, J. B.; Kuhn, D. E.; Gotto, A.
M. Jr.; Gianturco, S. H.; Pownall, H. J. Arteriosclerosis
1986, 6, 434; Chem. Abstr. 1986, 105 188171.
(32) Mewshaw, R. E.; Silverman, L. S.; Mathew, R. M.; Kaiser,
C.; Sherrill, R. G.; Cheng, M.; Tiffany, C. W.; Karbon, E.
W.; Bailey, M. A.; Borosky, S. A.; Ferkany, J. W.; Abreu,
M. E. J. Med. Chem. 1993, 36, 1488.
(27) (a) For a discussion on generation of Pd(0) from Pd(II) salts
in Et3N, see: Hegedus, L. S. Angew. Chem., Int. Ed. Engl.
1988, 27, 1113. (b) See also: Jeevanandam, A.; Narkunan,
K.; Ling, Y.-C. J. Org. Chem. 2001, 66, 6014. (c) For
oxidation of Pd(0) to Pd(II) in the presence of oxygen, see:
Synlett 2002, No. 12, 1976–1982 ISSN 0936-5214 © Thieme Stuttgart · New York