Pd/C-catalyzed alkynylation of β-chloroacroleins

Article abstract of DOI:10.1016/j.tet.2007.10.013

The first Pd/C-mediated Sonogashira coupling of β-chloroacroleins with terminal alkynes is described here. Pd/C-CuI-PPh₃ was found to be an efficient catalyst system for this coupling reaction. Using this economic and general process a variety

Full text of DOI:10.1016/j.tet.2007.10.013

Available online at www.sciencedirect.com
Tetrahedron 63 (2007) 13018–13023
Pd/C-catalyzed alkynylation of b-chloroacroleins
Rabin Bera,a Nalivela Kumara Swamy,b G. Dhananjaya,a J. Moses Babu,b
P. Rajender Kumar,a K. Mukkantic and Manojit Palb,
*
aCustom Pharmaceutical Services, Dr. Reddy’s Laboratories Ltd, Bollaram Road, Miyapur,
Hyderabad 500049, Andhra Pradesh, India
bDiscovery Research, Dr. Reddy’s Laboratories Ltd, Bollaram Road, Miyapur, Hyderabad 500049, Andhra Pradesh, India
cChemistry Division, Institute of Science and Technology, JNT University, Kukatpally, Hyderabad 500072, Andhra Pradesh, India
Received 29 June 2007; revised 19 September 2007; accepted 4 October 2007
Available online 6 October 2007
Abstract—The first Pd/C-mediated Sonogashira coupling of b-chloroacroleins with terminal alkynes is described here. Pd/C–CuI–PPh3 was
found to be an efficient catalyst system for this coupling reaction. Using this economic and general process a variety of 4-alkynyl-2H-chro-
mene-3-carbaldehydes and 5-alkynyl-2,3-dihydro benzo[b]oxepine-4-carbaldehydes were prepared in good yields.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
for the alkynylation of b-chloroacroleins under Pd/C–copper
catalysis.
Transition metal mediated cross-coupling reactions are
among the most powerful carbon–carbon bond forming reac-
tions in organic synthesis. Among them, those involving pal-
ladium catalysis especially alkynylation of sp2 species such
as aryl and alkenyl halides (the Sonogashira coupling)1 are
particularly useful for the preparation of arylalkynes or con-
jugated enynes, owing to excellent levels of selectivity and
high functional group compatibility. Based onvarious halides
used in Sonogashira reactions the general reactivity order of
the sp2 species can be presented as vinyl iodideꢀvinyl trifla-
te>vinyl bromide>vinyl chloride>aryl iodide>aryl triflate-
ꢀaryl bromideꢀaryl chloride.1b Thus the Sonogashira
alkynylation process usually proceeds smoothly when the
more reactive but more expensive vinyl and aryl iodides
are used. Notably, vinyl chloride although less reactive
amongst the vinyl halides is more reactive than aryl iodides
and therefore has been utilized in the synthesis of natural
products and numerous biologically active compounds.2
Despite its potential utility, the use of b-chloroacroleins
(–CCl]CCHO–) in cross-coupling reaction has not been ex-
plored until recently3 and to the best of our knowledge only
four examples involving the use of b-chloroacroleins under
Sonogashira condition have been reported.4 Because of its
cheap availability and high catalytic activity,5 Pd/C has
been used in Sonogashira coupling by us and several other
groups.6 Herein we report a very facile and general method
2. Results and discussion
To determine the feasibility of this approach, 4-chloro-2H-
chromene-3-carbaldehyde (1, n¼1, Z¼H) was treated with
terminal alkynes (2, R¼alkyl, hydroxyalkyl, aryl, etc.) in
acetonitrile in the presence of 10% Pd/C (0.026 equiv),
PPh3 (0.12 equiv), CuI (0.05 equiv), and Et3N (3.0 equiv)
under nitrogen. The reaction proceeded well and 4-al-
kynyl-2H-chromene-3-carbaldehydes (3, n¼1, Z¼H) were
obtained in good to excellent yields (Scheme 1). The results
are summarized in Table 1.
CHO
CHO
n
10% Pd/C, PPh3, CuI
n
O
R
HC
C R
+
Cl
O
Et3N, CH3CN
80 °C, 2-3h
n = 1, 2
Z = H, Br
Z
Z
1
2
3
Scheme 1. Pd/C-mediated alkynylation of b-chloroacroleins.
While acetonitrile was used as a solvent in the present cou-
pling reaction (entry 1, Table 1), the use of aqueous media
such as dimethoxyethane (DME)/H2O (4:1) was also found
to be effective (entry 2, Table 1). The use of pure water as
a solvent did not provide any product perhaps due to the
poor solubility of the halide 1 in water alone. The use of
an inorganic base, e.g., K2CO3 in place of triethylamine
provided the desired product albeit in lower yield (entry 3,
Table 1). As outlined in Table 1, 4-chloro-2H-chromene-3-
Keywords: b-Chloroacroleins; Terminal alkynes; Palladium catalyst.
* Corresponding author at present address: New Drug Discovery, R & D
Center, Matrix Laboratories Limited, Bollaram 502 325, Andhra Pradesh,
India. Fax: +91 8458279447; e-mail: manojitpal@rediffmail.com
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.10.013

R. Bera et al. / Tetrahedron 63 (2007) 13018–13023
13019
Table 1. Synthesis of 4-alkynyl-2H-chromene-3-carbaldehydes (3a–k) and 5-alkynyl-2,3-dihydro benzo[b]oxepine-4-carbaldehydes (3l–m)a
Entry
b-Chloroacroleins (1)
Alkynes (2), R¼
Productsb (3)
Yieldc (%)
CHO
O
OH
H
O
1
–C(CH3)2OH 2a
3a
85
Cl
O
1a
2d
3e
1a
1a
2a
2a
3a
3a
80
30
CHO
CHO
OH
3b
O
O
4
5
6
7
8
1a
1a
1a
1a
1a
–(CH2)2OH 2b
–(CH2)3OH 2c
–CH(OH)CH3 2d
80f
81f
77f
87
OH
3c
CHO
OH
O
3d
CH3
CHO
CHO
HO
HO
O
3e
2e
Cl
82f
O
–(CH2)3Cl 2f
3f
CHO
CHO
CN
3g
79f
79f
O
9
1a
1a
–(CH2)3CN 2g
–(CH2)3CH3 2h
O
10
3h
CHO
CHO
11
1a
–(CH2)5CH3 2i
3i
90f
O
O
12
13
1a
1b
–C6H5 2j
3j
80
2i
60f
CHO
Br
O
3k
(continued)

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R. Bera et al. / Tetrahedron 63 (2007) 13018–13023
Table 1. (continued)
Entry
b-Chloroacroleins (1)
Alkynes (2), R¼
–C6H5 2k
Productsb (3)
Yieldc (%)
CHO
O
14
3l
70
O
O
CHO
Cl
1c
CHO
15
1c
–(CH2)3CH3 2l
3m
79f
a
All the reactions were carried out using 1 (1.0 equiv), 2 (2.0 equiv), 10% Pd/C (0.026 equiv), PPh3 (0.12 equiv), CuI (0.05 equiv), and Et3N (3.0 equiv) at
80 ꢁC for 2–3 h.
Identified by 1H NMR, IR, and MS.
Isolated yields.
b
c
d
e
f
DME/H2O (4:1) was used as solvent.
K2CO3 was used as a base.
This product was stored at 0 ꢁC due to its apparent instability at room temperature.
carbaldehyde (1a) showed good reactivity toward the pres-
step (Scheme 3). Nevertheless, the high reactivity showed
by b-chloroacroleins toward Pd/C-mediated alkynylation
reaction is due to the presence of electron withdrawing alde-
hyde group, which activated the vinyl chloride moiety and
allowed C–C coupling reaction under mild condition.
ent coupling reaction and a variety of terminal alkynes
were employed under the conditions studied (entries 4–12,
Table 1). Various functional groups including both hydro-
phobic and hydrophilic substitutents, e.g., aryl, alkyl,
hydroxy, ether, etc., present in the terminal alkynes were
well tolerated. This allowed the preparation of a variety of
4-alkynyl-2H-chromene-3-carbaldehyde (3a–k) under mild
condition. Generally, yields of products were not affected
by the nature of alkynes used. The greater reactivity of the
vinyl chloride moiety over an aryl bromide that is also
present in the molecule allowed us to prepare the corre-
sponding 6-bromo derivative (3k) in good yields (entry 13,
Table 1). The use of an alternate b-chloroacrolein derivative
containing a seven membered ring, e.g., 5-chloro-2,3-dihy-
dro benzo[b]oxepine-4-carbaldehyde (1c, n¼2) was also in-
vestigated and it afforded good yields of the desired products
when coupled with terminal alkynes under the condition
employed (entries 14 and 15, Table 1).
H
CHO
Pd
O
R
n
n
O
R
O
Pd
Cl
CuI
Et3N
Z
Z
X
Scheme 3. Effect of neighboring group on the coupling of X with a terminal
alkyne.
3. Conclusion
In conclusion, we have demonstrated that Pd/C–CuI–PPh3
can be used as an efficient catalyst system for Sonogashira
coupling of b-chloroacroleins with terminal alkynes. The
reactions proceed well to afford a variety of 4-alkynyl-
2H-chromene-3-carbaldehydes and 5-alkynyl-2,3-dihydro
benzo[b]oxepine-4-carbaldehydes in good yields. This is a
general and economical process and opens an easy way to
access alkynyl substituted acroleins. Since the development
of effective methods for the functionalization of oxygen con-
taining heterocycles represents a major synthetic challenge
toward the synthesis of biologically important heterocycles
the present process would find wide usage.
b-Chloroacroleins(1a–c) are readily prepared from the cor-
responding ketones by a Vilsmeier–Haack–Arnold reaction7
according to Scheme 2. All the terminal alkynes used are
commercially available.
CHO
n
n
POCl3
DMF
O
Cl
O
O
n = 1, 2
Z = H, Br
Z
1a-c
Z
Scheme 2. Preparation of b-chloroacroleins.
4. Experimental
Mechanistically, the reaction seems to proceed via genera-
tion of Pd(0) species in situ from Pd/C and PPh3. This then
catalyzes the coupling of b-chloroacrolein 1 with copper(I)
acetylide (generated in situ from the terminal alkyne) via in-
termediate X leading to the corresponding alkynyl deriva-
tives. This coupling reaction is perhaps favored because of
the intramolecular coordination of the neighboring carbonyl
oxygen to the palladium during the chloride displacement
4.1. General methods
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
(TLC) on silica gel plates (60 F254; Merck), visualizing

R. Bera et al. / Tetrahedron 63 (2007) 13018–13023
13021
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. 1H and 13C NMR spectra were de-
termined in CDCl3 or DMSO-d6 solutions on Varian Gemini
200 MHz spectrometers. Proton chemical shifts (d) are rela-
tive to tetramethylsilane (TMS, d¼0.00) as internal standard
and expressed in parts per million. Spin multiplicities are
given as s (singlet), d (doublet), t (triplet), and m (multiplet)
aswellasbr(broad). Couplingconstants(J)aregiveninHertz.
Infrared spectra were recorded on a Perkin–Elmer 1650 FTIR
spectrometer. UV spectra were recorded on Shimadzu UV
2100S UV–vis recording spectrophotometer. Melting points
were determined using a Buchi melting point B-540 apparatus
and are uncorrected. Thermal analysis data were 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.
All the terminal alkynes used are commercially available.
156.0, 133.5, 132.4, 131.7, 127.5, 122.2, 120.7, 116.4,
103.9, 72.5, 62.5 (CH2), 59.2 (CH2OH), 23.7 (CH2); IR
(cmꢂ1, CHCl3) 3401, 2225 (–C^C–), 1658; m/z (ES
Mass) 229.2 (M+1, 100%); HPLC 99.0%, column: Luna
C18 (2) (150ꢃ4.6) mm, mobile phase A: 0.05% TFA in
water, mobile phase B: 0.05% TFA in acetonitrile, gradient
(T/%B): 0/35, 25/90, 30/90, 31/35; flow rate: 1 mL/min; UV
210 nm, retention time: 7.57 min; HRMS (ESI): calcd for
C14H11O3[(M–H)+] 227.0708, found 227.0702.
4.1.1.3. 4-(5-Hydroxy-pent-1-ynyl)-2H-chromene-3-
carbaldehyde (3c). Pale yellow oil; Rf (20% ethyl acetate/
light petroleum) 0.09; 1H NMR (DMSO-d6, 400 MHz)
d 10.15 (s, 1H), 7.64 (dd, J¼7.8, 1.6 Hz, 1H), 7.34–7.32
(m, 1H), 7.04–7.0 (m, 1H), 6.88 (dd, J¼8.3, 1.07 Hz, 1H),
4.98 (s, 2H), 3.85 (t, J¼6.2 Hz, 2H), 2.73 (t, J¼7.3 Hz,
2H), 1.96–1.92 (m, 2H); 13C NMR (DMSO-d6, 200 MHz)
d 189.7 (–CHO), 155.7, 133.2, 131.6, 129.5, 127.6, 121.8,
120.1, 116.5, 104.2, 72.7, 62.9 (CH2), 61.2 (CH2), 30.9
(CH2), 16.3 (CH2); IR (cmꢂ1, CHCl3) 3409, 2219 (–C^C–),
1659, 1042; m/z (ES Mass) 243.1 (M+1, 100%); HPLC
98.76%, column: Luna C18 (2) (150ꢃ4.6) mm, mobile phase
A: 0.05% TFA in water, mobile phase B: 0.05% TFA in aceto-
nitrile, gradient (T/%B): 0/35, 25/90, 30/90, 31/35, flow rate:
1 mL/min; UV 210 nm, retention time: 8.49 min; HRMS
(ESI): calcd for C15H13O3[(M–H)+] 241.0865, found 241.0859.
4.1.1. Synthesis of 4-alkynyl-2H-chromene-3-carbalde-
hydes. In a typical procedure a mixture of 4-chloro-2H-
chromene-3-carbaldehyde (0.5 g, 2.57 mmol), 10% Pd/C
(85 mg, 0.08 mmol), PPh3 (81 mg, 0.30 mmol), CuI (26.4 mg,
0.13 mmol), and triethylamine (780 mg, 7.71 mmol) in aceto-
nitrile (20 mL) was stirred at 25–30 ꢁC for 30 min under nitro-
gen. The acetylenic compound (5.14 mmol) was added,
and the mixture was initially stirred at room temperature
for 1 h and then at 80 ꢁC for 2–3 h. After completion of
the reaction (as indicated by TLC), the mixture was cooled
to room temperature, diluted with EtOAc (50 mL), and fil-
tered through Celite. The organic layers were collected
and concentrated. The crude residue was purified by column
chromatography on silica gel, using light petroleum (60–
80 ꢁC)/ethyl acetate (19:1) to afford the desired product.
4.1.1.4. 4-(3-Hydroxy-but-1-ynyl)-2H-chromene-3-
carbaldehyde (3d). Brown oil; Rf (40% ethyl acetate/light
petroleum) 0.17; H NMR (DMSO-d6, 400 MHz) d 10.14
1
(s, 1H), 7.63 (dd, J¼7.7, 1.6 Hz, 1H), 7.36–7.31 (m, 1H),
7.05–7.02 (m, 1H), 6.90 (dd, J¼8.1, 1.1 Hz, 1H), 4.99
(s, 2H), 4.89 (m, 1H), 1.64 (s, 3H); IR (cmꢂ1, CHCl3)
3391, 2219 (–C^C–), 1661, 1217; m/z (ES Mass) 229.1
(M+1, 100%); HPLC 98.2%, column: Luna C18 (2)
(150ꢃ4.6) mm, mobile phase A: 0.05% TFA in water, mo-
bile phase B: 0.05% TFA in acetonitrile, gradient (T/%B):
0/35, 25/90, 30/90, 31/35, flow rate: 1 mL/min; UV
210 nm, retention time: 8.22 min; HRMS (ESI): calcd for
C14H12O3Na[(M+Na)+] 251.0684, found 251.0680.
4.1.1.1. 4-(3-Hydroxy-3-methyl-but-1-ynyl)-2H-chro-
mene-3-carbaldehyde (3a). Pale yellow oil; Rf (25% ethyl
acetate/light petroleum) 0.38; 1H NMR (DMSO-d6,
400 MHz) d 10.06 (s, 1H), 7.65 (dd, J¼7.5, 1.6 Hz, 1H),
7.44–7.40 (m, 1H), 7.14–7.10 (m, 1H), 6.94 (dd, J¼8.1,
0.8 Hz, 1H), 5.75 (br s, D2O exchangeable, 1H, –OH),
4.94 (s, 2H), 1.54 (s, 6H, 2CH3); 13C NMR (DMSO-d6,
200 MHz) d 189.1 (–CHO), 155.1, 133.5, 131.8, 131.6,
127.3, 122.2, 120.3, 116.4, 109.6, 72.0, 62.5, 63.9 (CH2),
31.0 (2CH3); IR (cmꢂ1, CHCl3) 3427, 2211 (–C^C–),
1646, 1041; m/z (ES Mass) 243.1 (M+1, 100%); HPLC
98.0%, column: Luna C18 (2) (150ꢃ4.6) mm, mobile phase
A: 0.05% TFA in water, mobile phase B: 0.05% TFA in ace-
tonitrile, gradient (T/%B): 0/35, 25/90, 30/90, 31/35, flow
rate: 1 mL/min; UV 210 nm, retention time: 9.93 min;
HRMS (ESI): calcd for C15H14O3Na[(M+Na)+] 265.0841,
found 265.0851.
4.1.1.5. 4-(1-Hydroxy-cyclohexylethynyl)-2H-chro-
mene-3-carbaldehyde (3e). Off white solid, mp 97.5–
1
98.9 ꢁC; Rf (40% ethyl acetate/light petroleum) 0.31; H
NMR (DMSO-d6, 400 MHz) d 10.09 (s, 1H, CHO), 7.67
(dd, J¼7.8, 1.6 Hz, 1H), 7.45–7.40 (m, 1H), 7.15–7.1 (m,
1H), 6.65 (dd, J¼8.1, 0.8 Hz, 1H), 5.76 (br s, 1H, OH),
4.95 (s, 2H, CH2), 1.98–1.23 (m, 10H); 13C NMR (CDCl3,
200 MHz) d 189.4 (–CHO), 155.7, 133.4, 133.0, 132.0,
127.6, 122.0, 120.7, 116.6, 106.8, 82.9, 69.3, 62.9 (CH2),
39.6 (2C, CH2), 24.9 (CH2), 23.3 (2C, CH3); IR (cmꢂ1
,
KBr) 3485, 2929, 2852, 2213 (–C^C–), 1662 (C]O),
1073; m/z (ES Mass) 283.4 (M+1, 100%); HPLC 99.7%, col-
umn: Luna C18 (2) (150ꢃ4.6) mm, mobile phase A: 0.05%
TFA in water, mobile phase B: 0.05% TFA in acetonitrile,
gradient (T/%B): 0/35, 25/90, 30/90, 31/35, flow rate:
1 mL/min; UV 210 nm, retention time: 14.2 min; HRMS
(ESI): calcd for C18H19O3 (M+H)+ 283.1334, found
283.1337.
4.1.1.2.
4-(4-Hydroxy-but-1-ynyl)-2H-chromene-3-
carbaldehyde (3b). Pale yellow oil; Rf (40% ethyl acetate/
light petroleum) 0.14; 1H NMR (DMSO-d6, 400 MHz)
d 10.07 (s, 1H), 7.69 (dd, J¼7.8, 1.6 Hz, 1H), 7.43–7.39
(m, 1H), 7.12–7.08 (m, 1H), 6.95 (dd, J¼8.1, 0.8 Hz, 1H),
4.93 (s, 2H), 3.67 (t, J¼6.5 Hz, 2H), 2.74 (t, J¼6.5 Hz,
2H); 13C NMR (DMSO-d6, 200 MHz) d 189.3 (–CHO),
4.1.1.6. 4-(5-Chloro-pent-1-ynyl)-2H-chromene-3-carb-
aldehyde (3f). Brown oil; Rf (25% ethyl acetate/light petro-
leum) 0.47; H NMR (CDCl3), 400 MHz) d 10.14 (s, 1H),
1

13022
R. Bera et al. / Tetrahedron 63 (2007) 13018–13023
7.64 (dd, J¼7.8, 1.6 Hz, 1H), 7.35–7.32 (m, 1H), 7.04–7.0 (m,
1H), 6.88 (dd, J¼8.1, 0.8 Hz, 1H), 4.98 (s, 2H), 3.73–3.7 (m,
2H), 2.8 (t, J¼6.7 Hz, 2H), 2.17–2.10 (m, 2H); 13C NMR
(DMSO-d6, 200 MHz) d 189.4 (–CHO), 155.7, 133.4, 133.1,
131.9, 127.5, 121.9, 121.0, 116.6, 102.4, 73.3, 62.9 (CH2),
43.4 (CH2), 30.9 (CH2), 17.2 (CH2); IR (cmꢂ1, CHCl3) 3312,
2221 (–C^C–), 1661; m/z (ES Mass) 261.1 (M+1), 263.1
(M+3); HPLC 99.6%, column: Luna C18 (2) (150ꢃ4.6) mm,
mobile phase A: 0.05% TFA in water, mobile phase B:
0.05% TFA in acetonitrile, gradient (T/%B): 0/35, 25/90, 30/
90, 31/35; flow rate: 1 mL/min; UV 210 nm, retention time:
17.09 min; HRMS (ESI): calcd for C15H14ClO2 (M+H)+
261.0682, found 261.0687.
acetonitrile, gradient (T/%B): 0/35, 25/90, 30/90, 31/35;
flow rate: 1 mL/min; UV 210 nm, retention time:
23.9 min; HRMS (ESI): calcd for C18H21O2 (M+H)+
269.1542, found 269.1548.
4.1.1.10. 4-Phenylethynyl-2H-chromene-3-carbalde-
hyde (3j). Yellow solid; mp 132.6–134.1 ꢁC; Rf (25% ethyl
acetate/light petroleum) 0.53; 1H NMR (DMSO-d6,
400 MHz) d 10.22 (s, 1H), 7.83–7.77 (m, 3H), 7.57–7.43
(m, 4H), 7.17 (m, 1H), 6.98 (dd, J¼8.3, 1.1 Hz, 1H), 5.00
(s, 2H); 13C NMR (DMSO-d6, 200 MHz) d 188.9 (–CHO),
155.1, 133.5, 132.1 (2C), 131.9, 131.2, 130.3, 128.8 (2C),
127.4, 122.3, 120.7, 120.2, 116.5, 102.1, 80.5, 62.6 (CH2);
IR (cmꢂ1, CHCl3) 2203 (–C^C–), 1664, 1216; m/z (ES
Mass) 275.2 (M+1, 100%); HPLC 99.8%, column: Luna
C18 (2) (150ꢃ4.6) mm, mobile phase A: 0.05% TFA in water,
mobile phase B: 0.05% TFA in acetonitrile, gradient (T/%B):
0/35, 25/90, 30/90, 31/35; flow rate: 1 mL/min; UV 210 nm,
retention time: 19.2 min. Elemental analysis: found C, 83.15;
H, 4.62; C18H12O2 requires C, 83.06; H, 4.65.
4.1.1.7. 6-(3-Formyl-2H-chromen-4-yl)hex-5-yneni-
trile (3g). Brown oil; Rf (40% ethyl acetate/light petroleum)
0.40; 1H NMR (DMSO-d6, 400 MHz) d 10.13 (s, 1H), 7.60
(dd, J¼7.8, 1.6 Hz, 1H), 7.35–7.33 (m, 1H), 7.05–7.01 (m,
1H), 6.89 (dd, J¼8.1, 0.8 Hz, 1H), 4.98 (s, 2H), 2.78 (t,
J¼7.0 Hz, 2H), 2.57 (t, J¼7.0 Hz, 2H), 2.09–2.02 (m, 2H);
13C NMR (CDCl3, 200 MHz) d 189.2 (–CHO), 155.7,
133.3, 132.1, 131.7, 127.4, 121.9, 120.7, 118.5 (CN),
116.7, 101.1, 74.0, 62.9 (CH2), 24.2 (CH2), 18.8 (CH2),
16.4 (CH2); IR (cmꢂ1, CHCl3) 3312, 2221 (–C^C–),
1661; m/z (ES Mass) 252.1 (M+1, 100%); HPLC 98.9%, col-
umn: Luna C18 (2) (150ꢃ4.6) mm, mobile phase A: 0.05%
TFA in water, mobile phase B: 0.05% TFA in acetonitrile,
gradient (T/%B): 0/35, 25/90, 30/90, 31/35; flow rate:
1 mL/min; UV 210 nm, retention time: 11.97 min; HRMS
(ESI): calcd for C16H13NO2K[(M+K)+] 290.0583, found
290.0593.
4.1.1.11. 6-Bromo-4-oct-1-ynyl-2H-chromene-3-carb-
aldehyde (3k). Brown oil; Rf (25% ethyl acetate/light petro-
leum) 0.65; 1H NMR (DMSO-d6, 400 MHz) d 10.04 (s, 1H),
7.69 (d, J¼2.4 Hz, 1H), 7.59 (dd, J¼8.4, 2.4 Hz, 1H), 7.29–
7.26 (m, 2H), 6.95 (d, J¼8.4 Hz, 1H), 4.96 (s, 2H), 2.65 (t,
J¼6.8 Hz, 2H), 1.66–1.59 (m, 2H), 1.5–1.43 (m, 2H), 1.35–
1.23 (m, 4H), 0.90–0.81 (m, 3H); 13C NMR (DMSO-d6,
200 MHz) d 189.9 (–CHO), 156.0, 134.2, 133.5, 131.7, 127.7,
121.9, 116.5, 115.9, 105.5, 73.1, 63.2 (CH2), 31.7 (CH2), 29.0
(CH2), 28.7 (CH2), 23.0 (CH2), 19.6 (CH2), 14.0 (CH3); IR
(cmꢂ1, CHCl3) 2216 (–C^C–), 1663, 1216; m/z (ES Mass)
347.0 (M+1, 100%); HRMS (ESI): calcd for C18H20BrO2
(M+H)+ 347.0647, found 347.0649.
4.1.1.8. 4-Hex-1-ynyl-2H-chromene-3-carbaldehyde
(3h). Brown oil; Rf (25% ethyl acetate/light petroleum) 0.58;
1H NMR (CDCl3, 400 MHz) d 10.15 (s, 1H), 7.65 (dd,
J¼7.8, 1.6 Hz, 1H), 7.33–7.3 (m, 1H), 7.25–7.01 (m, 1H),
6.87 (dd, J¼8.1, 1.1 Hz, 1H), 4.97 (s, 2H), 2.56
(t, J¼7.0 Hz, 2H), 1.7–1.63 (m, 2H), 1.55–1.5 (m, 2H), 0.97
(t, J¼7.3 Hz, 3H); 13C NMR (DMSO-d6, 200 MHz) d 189.7
(–CHO), 155.8, 134.0, 133.1, 131.5, 127.7, 121.8, 121.3,
116.5, 105.1, 72.5, 63.0 (CH2), 30.4 (CH2), 22.1 (CH2), 19.5
(CH2), 13.5 (CH3); IR (cmꢂ1, CHCl3) 2219 (–C^C–),
1659, 1216; m/z (ES Mass) 241.2 (M+1, 100%); HPLC
98.9%, column: Luna C18 (2) (150ꢃ4.6) mm, mobile phase
A: 0.05% TFA in water, mobile phase B: 0.05% TFA in aceto-
nitrile, gradient (T/%B): 0/35, 25/90, 30/90, 31/35, flow rate:
1 mL/min; UV 210 nm, retention time: 20.11 min; HRMS
(ESI): calcd for C16H17O2 (M+H)+ 241.1229, found 241.1226.
4.1.2. Synthesis of 5-alkynyl-2,3-dihydro benzo[b]oxe-
pine-4-carbaldehyde. A mixture of 4-chloro-2H-chro-
mene-3-carbaldehyde (0.536 g, 2.57 mmol), 10% Pd/C (85 mg,
0.08 mmol), PPh3 (81 mg, 0.30 mmol), CuI (26.4 mg,
0.13 mmol), and triethylamine (780 mg, 7.71 mmol) in aceto-
nitrile (20 mL) was stirred at 25–30 ꢁC for 30 min under
nitrogen. The acetylenic compound (5.14 mmol) was added,
and the mixture was initially stirred at room temperature for
1 h and then at 80 ꢁC for 2–3 h. After completion of the reac-
tion (as indicated by TLC), the mixture was cooled to room
temperature, diluted with EtOAc (50 mL), and filtered
through Celite. The organic layers were collected and con-
centrated. The crude residue was purified by column chroma-
tography on silica gel, using light petroleum (60–80 ꢁC)/
ethyl acetate (9.5:0.5) to afford the desired product.
4.1.1.9. 4-Oct-1-ynyl-2H-chromene-3-carbaldehyde
(3i). Greenish yellow oil; Rf (25% ethyl acetate/light petro-
leum) 0.60; H NMR (CDCl3, 400 MHz) d 10.15 (s, 1H),
1
4.1.2.1. 5-Phenylethynyl-2,3-dihydro benzo[b]oxepine-
4-carbaldehyde (3l). Brown oil; Rf (25% ethyl acetate/light
petroleum) 0.51; 1H NMR (DMSO-d6, 400 MHz) d 10.47 (s,
1H), 7.99 (dd, J¼7.8, 1.6 Hz, 1H), 7.7–7.68 (m, 1H), 7.51–
7.44 (m, 3H), 7.31–7.26 (m, 2H), 7.14–7.12 (m, 1H), 6.95–
6.93 (m, 1H), 4.43 (t, J¼5.6 Hz, 2H), 2.68 (t, J¼5.6 Hz, 2H);
13C NMR (DMSO-d6, 200 MHz) d 188.9 (–CHO), 155.1,
133.6, 132.1 (2C), 131.9, 131.2, 130.3, 128.8 (2C), 127.4,
122.3, 120.7, 120.2, 116.5, 102.1, 80.5, 62.6 (CH2); IR
(cmꢂ1, CHCl3) 2203 (–C^C–), 1664, 1216; m/z (ES
Mass) 275 (M+1, 100%); HRMS (ESI): calcd for
C19H15O2 (M+H)+ 275.1072, found 275.1081.
7.66 (dd, J¼7.8, 1.6 Hz, 1H), 7.33–7.3 (m, 1H), 7.03–6.99
(m, 1H), 6.88 (dd, J¼8.1, 0.8 Hz, 1H), 4.97 (s, 2H), 2.57
(t, J¼7.0 Hz, 2H), 2.43–2.34 (m, 2H), 1.70–1.64 (m, 2H),
1.58–1.26 (m, 4H), 0.93–0.87 (m, 3H); 13C NMR (DMSO-
d6, 200 MHz) d 189.7 (–CHO), 155.8, 134.0, 133.0, 131.5,
127.7, 121.8, 121.2, 116.5, 105.1, 72.5, 62.9 (CH2), 31.2
(CH2), 28.6 (CH2), 28.3 (CH2), 22.5 (CH2), 19.8 (CH2),
13.9 (CH3); IR (cmꢂ1, CHCl3) 2219 (–C^C–), 1659,
1217; m/z (ES Mass) 269.2 (M+1, 100%); HPLC 92.65%,
column: Luna C18 (2) (150ꢃ4.6) mm, mobile phase A:
0.05% TFA in water, mobile phase B: 0.05% TFA in

R. Bera et al. / Tetrahedron 63 (2007) 13018–13023
13023
4.1.2.2. 5-Hex-1-ynyl-2,3-dihydro benzo[b]oxepine-4-
carbaldehyde (3m). Brown oil; Rf (25% ethyl acetate/light
petroleum) 0.59; H NMR (CDCl3, 400 MHz) d 10.4 (s,
References and notes
1
1. (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett.
1975, 16, 4467; (b) For a recent review, see: Chinchilla, R.;
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2. (a) Burdon, J.; Coe, P. L.; Marsh, C. R.; Tatlow, J. C. J. Chem.
Soc., Chem. Commun. 1967, 1259; (b) Konig, B.; Pitsch, W.;
Dix, I.; Jones, P. G. Synthesis 1996, 446; (c) Joshi, M. C.;
Joshi, P.; Rawat, D. S. ARKIVOC 2006, xvi, 65–74.
1H, CHO), 7.86 (dd, J¼7.8, 1.6 Hz, 1H), 7.37–7.33 (m,
1H), 7.18–7.14 (m, 1H), 7.06 (dd, J¼8.1, 1.2 Hz, 1H),
4.44 (t, J¼6.0, 2H), 2.67 (t, J¼6.0 Hz, 2H), 2.52 (t,
J¼7.6 Hz, 2H), 1.67–1.60 (m, 2H), 1.55–1.50 (m, 2H),
0.96 (t, J¼7.2 Hz, 3H); 13C NMR (CDCl3, 200 MHz)
d 192.2 (–CHO), 157.0, 142.5, 139.3, 131.4, 130.8, 129.4,
123.1, 122.2, 103.0, 76.5 (2C), 30.3 (CH2), 25.9 (CH2),
22.0 (CH2), 19.4 (CH2), 13.5 (CH3); IR (cmꢂ1, CHCl3)
3020, 2962, 2215 (–C^C–), 1661 (C]O), 1216; m/z (ES
Mass) 255 (M+1, 100%); HPLC 99.3%, column: Luna
C18 (2) (150ꢃ4.6 mm), mobile phase A: 0.05% TFA in
water, mobile phase B: 0.05% TFA in acetonitrile, gradient
(T/%B): 0/35, 25/90, 30/90, 31/35; flow rate: 1 mL/min;
UV 210 nm, retention time: 19.35 min; HRMS (ESI): calcd
for C17H19O2(M+H)+ 255.1385, found 255.1374.
3. (a) Hesse, S.; Kirsch, G. Synthesis 2001, 755; (b) Hesse, S.;
Kirsch, G. Tetrahedron Lett. 2002, 43, 1213.
4. (a) Hesse, S.; Kirsch, G. Synthesis 2003, 717; (b) Recently,
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tylene using Pd/MgLa mixed oxide has been reported, see:
Cwik, A.; Hell, Z.; Figueras, F. Tetrahedron Lett. 2006, 47, 3023.
5. On several occasions it has been observed that the use of Pd/C
provided normal Sonogashira products where homogenous pal-
ladium catalysts either failed or yielded unexpected products,
see for example: (a) Yin, L.; Erdmann, F.; Liebscher, J.
J. Heterocycl. Chem. 2005, 42, 1369; (b) Marrison, L. R.;
Dickinson, J. M.; Ahmed, R.; Fairlamb, I. J. Tetrahedron Lett.
2002, 43, 8853; (c) Pal, M.; Parasuraman, K.; Gupta, S.;
Yeleswarapu, K. R. Synlett 2002, 1976.
Acknowledgements
The authors thank Dr. V. Dahanukar and Mr. A. Mukherjee
for their encouragement and the analytical group for spec-
tral data. R.B. thank CPS-DRL, Hyderabad, India for al-
lowing him to pursue this work as a part of his Ph.D.
program.
6. For a review, see: Yin, L. X.; Liebscher, J. Chem. Rev. 2007, 107,
133–173.
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