Pd/C-Catalyzed coupling and cyclization of β-bromo-α,β- unsaturated carboxylic acids with terminal alkynes leading to alkylidenefuranones

Article abstract of DOI:10.1016/j.jorganchem.2011.06.044

Palladium-catalyzed coupling of β-bromo-α,β-unsaturated carboxylic acids with terminal alkynes and subsequent regioselective 5-exo-dig cyclization produces (Z)-alkylidenefuranones in good yields.

Full text of DOI:10.1016/j.jorganchem.2011.06.044

Journal of Organometallic Chemistry 696 (2011) 3264e3267
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Note
Pd/C-Catalyzed coupling and cyclization of b-bromo-a,b-unsaturated carboxylic
acids with terminal alkynes leading to alkylidenefuranones
*
Chan Sik Cho , Hyo Bo Kim
Department of Applied Chemistry, Kyungpook National University, Daegu 702-701, South Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
Palladium-catalyzed coupling of b-bromo-a,b-unsaturated carboxylic acids with terminal alkynes and
Received 28 April 2011
Received in revised form
3 June 2011
subsequent regioselective 5-exo-dig cyclization produces (Z)-alkylidenefuranones in good yields.
Ó 2011 Elsevier B.V. All rights reserved.
Accepted 9 June 2011
Keywords:
Alkylidenefuranones
Alkynes
b
-Bromo-
Coupling
Cyclization
a,b-unsaturated carboxylic acids
Palladium catalyst
1. Introduction
compounds [6e25]. It has been reported by us that several carbo-
and heterocyclic compounds can be synthesized from b-bromo-a,b-
Palladium-catalyzed carbonecarbon bond formation by the
cross-coupling of terminal alkynes with organo-electrophiles such
as aryl- and vinyl-halides and triflates is known as Sonogashira
coupling reaction [1,2]. This protocol has been recognized as an
attractive tool in synthetic organic chemistry and effectively
applied to the synthesis of conjugated acetylenic compounds.
Among them, the coupling reaction followed by intramolecular
cyclization has been used for the construction of various hetero-
cyclic compounds [2]. In connection with this report, several groups
have reported that 2-iodobenzoic acids are coupled and cyclized
with terminal alkynes in the presence of a palladium catalyst to
give 5-exo-dig cyclized phthalides or 6-endo-dig cyclized iso-
coumarins and the product yield and distribution are varied by
reaction conditions (Scheme 1) [3,4]. For example, the reactions
under the conditions of Pd/CNTs-NaOAc-DABCO-DMF-H2O and Pd/
C-PPh3-CuI-Et3N-EtOH preferentially afforded 5-exo-dig cyclized
phthalides and 6-endo-dig cyclized isocoumarins, respectively. On
unsaturated aldehydes and their derivatives in the presence of
a palladium catalyst [26e32]. The present work was disclosed
during the course of the extension of the palladium-catalyzed
Sonogashira coupling and cyclization protocol to the reaction
with
describes a palladium-catalyzed tandem coupling and cyclization
of -bromo- -unsaturated carboxylic acids with terminal alkynes
b-bromo-a,b-unsaturated carboxylic acids. This report
b
a,b
leading to alkylidenefuranones.
2. Results and discussion
The starting materials 3 were synthesized by initial conversion
of the corresponding
a-methylene containing ketones 1 into b-
bromovinyl aldehydes 2 under bromination conditions of Vils-
meiereHaack reaction (PBr3/DMF/CHCl3) [5] followed by oxidation
of 2 into b-bromo-a,b-unsaturated carboxylic acids 3 by treating
with NaClO2eH2O2 [33] (Scheme 2).
the other hand,
b-bromo-a,b-unsaturated aldehydes and their
The results of several attempted coupling and cyclization of 2-
bromocyclohex-1-enecarboxylic acid (3a) with 1-octyne (4a)
under various reaction conditions are listed in Table 1. Treatment of
3a with two equivalents of 4a in 1-propanol in the presence of 10%
Pd/C (5 mol% based on 3a) and CuI (10 mol% based on 3a) along
with Bu3N afforded (3Z)-4,5,6,7-tetrahydro-3-heptylideneiso-
benzofuran-1(3H)-one (5a) in 50% isolated yield (entry 1). The
derivatives, which are readily prepared from the corresponding
ketones by VilsmeiereHaack reaction [5] and subsequent trans-
formation, have been introduced for the synthesis of versatile cyclic
* Corresponding author. Tel.: þ82 53 950 5586; fax: þ82 53 950 6594.
E-mail address: cscho@knu.ac.kr (C.S. Cho).
0022-328X/$ e see front matter Ó 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.jorganchem.2011.06.044

C.S. Cho, H.B. Kim / Journal of Organometallic Chemistry 696 (2011) 3264e3267
3265
R
5-exo-dig cyclization
O
R
I
O
R
+
COOH
COOH
R
6-endo-dig cyclization
O
O
Scheme 1. 5-Exo-dig and 6-endo-dig cyclizations.
reaction with terminal alkynes 4 in order to investigate the reaction
scope, and several representative results are summarized in Table 2.
O
CHO
Br
NaClO2/H2O2
PBr3/DMF/CHCl3
OH
The
b-bromo-a,b-unsaturated carboxylic acid 3a was readily
O
coupled and cyclized with several terminal alkynes (4aed) having
linear and branched alkyl chains and phenyl group. Here again no
6-endo-dig cyclized products were formed at all. Methyl and phenyl
Br
3
1
2
Scheme 2. Synthesis of
b
-Bromo-
a
,
b
-unsaturated carboxylic acids.
substituted six-membered
b-bromo-a,b-unsaturated carboxylic
acids (3b and 3c) were also coupled and cyclized with 1-hexyne
(4b) to give the corresponding alkylidenefuranones (5e and 5f) in
reaction seems to proceed via initial Sonogashira coupling between
3a and 4a to form usual sp2-carbon-sp-carbon coupled product and
subsequent regioselective 5-exo-dig cyclization of the coupling
product. No 6-endo-dig cyclized product was formed at all. The
stereochemistry of 5a was unequivocally assigned by comparing
the chemical shift of vinyl proton signal in 1H NMR with that of
known (3Z)-4,5,6,7-tetrahydro-3-butylideneisobenzofuran-1(3H)-
one [34,35]. As will be shown later, the configuration was also
identified by the direct comparison of 1H and 13C NMR spectrum
and GC retention time of 5b with the authentic sample prepared by
our recent report [32]. Performing the reaction for a longer reaction
time (40 h) gave no significant improvement in the yield of 5a
(entry 2). The reaction carried out at higher temperature in
a stainless autoclave also resulted in similar yield of 5a (entry 3).
Among solvent examined under the employment of Bu3N as base,
1-propanol and dioxane revealed to be the solvent of choice in
terms of product 5a yield (entries 1, 4e6). When the reaction was
carried out with other bases such as K2CO3, NaOAc and DBU
combined with 1-propanol, the synthesis of 5a did not occur
effectively (entries 7e9).
similar yields. With
b-bromo-a,b-unsaturated carboxylic acids
(3deg) having various ring sizes, the coupled and cyclized alkyli-
denefuranones (5gej) were formed in the range of 48e68% yields
without any identifiable side product, and the product yield was
not significantly affected by the ring size of 3deg. Regioisomers (3h
and 3i) exhibited different rates, and the reaction of 3h proceeded
more slowly to result in 24% yield of 5k in 40 h reaction time. The
low reactivity of 3h is ascribable to slow Sonogashira coupling
reaction because the corresponding carboxylic acid was not
observed in the crude mixture.
3. Conclusion
In summary, we have demonstrated that b-bromo-a,b-unsatu-
rated carboxylic acids undergo coupling with terminal alkynes and
subsequent regioselective 5-exo-dig cyclization in the presence of
Pd/C and CuI to give (Z)-alkylidenefuranones in good yields. The
present reaction provides a new route for (Z)-alkylidenefuranones
from readily available starting ketones. Further study of synthetic
applications to heterocycles by using this ketone as starting
compound is in progress.
After the reaction conditions had been optimized, various b-
bromo-a,b-unsaturated carboxylic acids 3 were subjected to the
Table 1
Optimization of conditions for the reaction of 3a with 4a.a
O
10% Pd/C
PPh3, CuI
OH
Hex
O
Br
O
3a
4a
5a
Entry
Base
Solvent
Temp (ꢀC)
Time (h)
Isolated yield (%)
1
2
3b
4
5
6
7
8
9
Bu3N
Bu3N
Bu3N
Bu3N
Bu3N
Bu3N
NaOAc
K2CO3
DBU
1-propanol
1-propanol
1-propanol
DMF
HOCH2CH2OH
dioxane
1-propanol
1-propanol
1-propanol
110
110
135
110
110
110
110
110
110
20
40
20
20
20
20
20
20
20
50
51
52
40
0
51
18
0
0
a
Reaction conditions: 3a (0.5 mmol), 4a (1 mmol), 10% Pd/C (0.25 mmol), PPh3 (0.1 mmol), CuI (0.05 mmol), base (2.5 mmol), solvent (8 mL).
The reaction was carried out in autoclave.
b

3266
C.S. Cho, H.B. Kim / Journal of Organometallic Chemistry 696 (2011) 3264e3267
Table 2
Palladium-catalyzed coupling and cyclization of
b
-bromo-
a
,
b
-unsaturated carboxylic acids 3 with 1-alkynes 4.a
b
-Bromo-
Br
COOH
a
,
b
-unsaturated carboxylic acids 3
1-Alkynes 4 Alkylidenefuranones 5
Yield (%)
51
3a
4a
Hex
5a
O
O
O
O
4b
Bu
5b
57
43
52
4c
5c
O
O
O
O
Ph
5d
4d
Ph
Br
COOH
3b
4b
4b
4b
4b
4b
5e
68
51
57
53
50
O
O
Ph
Br
Ph
3c
5f
O
COOH
O
Br
3d
5g
O
COOH
O
Br
3e
3f
5h
O
COOH
O
Br
5i
O
COOH
O
Br
3g
COOH
4b
5j
48
O
O
O
Br
3h
4b
4b
5k
24b
COOH
O
Br
3i
5l
42
O
COOH
O
a
Reaction conditions: 3 (0.5 mmol), 4 (1 mmol), 10% Pd/C (0.25 mmol), PPh3 (0.1 mmol), CuI (0.05 mmol), Bu3N (2.5 mmol), dioxane (8 mL), 110 ꢀC, 20 h.
For 40 h.
b

C.S. Cho, H.B. Kim / Journal of Organometallic Chemistry 696 (2011) 3264e3267
3267
4. Experimental
21.00, 21.34, 22.57, 25.75, 28.26, 28.55, 29.86; HRMS (FAB) Anal.
Calc. for C14H21O2 ([M þ H]þ): 221.1542. Found: 221.1544.
1H and 13C NMR (400 and 100 MHz) spectra were recorded on
a Bruker Avance Digital 400 spectrometer using TMS as an internal
standard. IR spectra were measured on a Shimadzu FT IR-8400S
spectrophotometer. Melting points were determined on a Stand-
ford Research Inc. MPA100 automated melting point apparatus. GLC
analyses were carried out with Shimadzu GC-17A (FID) equipped
with CBP10-S25-050 column (Shimadzu, a silica fused capillary
column, 0.33 mm ꢁ 25 m, 0.25
carrier gas. The isolation of pure products was carried out via thin
layer chromatography (silica gel 60 GF254, Merck). -Bromo-a,b-
4.1.5. (3Z)-4,5,6,7-Tetrahydro-6-phenyl-3-pentylideneisobenzofuran-
1(3H)-one (5f)
Solid, m.p. 113e114 ꢀC (from hexane); 1H NMR (CDCl3):
d 0.93 (t,
J ¼ 7.2 Hz, 3H), 1.32e1.49 (m, 4H), 1.83e1.93 (m, 1H), 2.12e2.16 (m,
1H), 2.36e2.61 (m, 5H), 2.68e2.73 (m, 1H), 2.87e2.94 (m, 1H), 5.16
(t, J ¼ 7.8 Hz, 1H), 7.22e7.26 (m, 3H), 7.32e7.36 (m, 2H); 13C NMR
m
m film thickness) using N2 as
(CDCl3): d 14.07, 21.69, 22.59, 25.83, 27.79, 29.28, 31.51, 39.85,
111.56, 126.86, 126.98, 127.00, 128.87, 144.94, 149.00, 151.08, 169.77;
HRMS (FAB) Anal. Calc. for C19H23O2 ([M þ H]þ): 283.1698. Found:
283.1696.
b
unsaturated carboxylic acids 3 were synthesized by two steps,
initial treatment of ketones 1 with PBr3/DMF/CHCl3 [5] to produce
b
-bromovinyl aldehydes 2 and oxidation of 2 under NaClO2eH2O2
4.1.6. (3Z)-4,5-Dihydro-3-pentylidenenaphtho [1,2-c]furan-1(3H)-
[33]. Commercially available organic and inorganic compounds
were used without further purification.
one (5l)
Solid, m.p. 63e65 ꢀC (from hexane); 1H NMR (CDCl3):
d 0.94
(t, J ¼ 7.2 Hz, 3H), 1.34e1.53 (m, 4H), 2.45 (q, J ¼ 7.6 Hz, 2H),
2.71 (t, J ¼ 8.1 Hz, 2H), 3.02 (t, J ¼ 8.1 Hz, 2H), 5.35 (t,
J ¼ 8.0 Hz, 1H), 7.20e7.30 (m, 3H), 8.06e8.08 (m, 1H); 13C NMR
4.1. General experimental procedure
To a 50 mL stainless steel autoclave were added
b
-bromo-
a
,b
-
(CDCl3): d 14.06, 19.98, 22.63, 26.21, 27.65, 31.48, 114.05, 123.59,
unsaturated carboxylic acid (0.5 mmol), terminal alkyne (1 mmol),
10% Pd/C (0.027 g, 0.025 mmol), PPh3 (0.026 g, 0.1 mmol), CuI
(0.010 g, 0.05 mmol), Bu3N (0.463 g, 2.5 mmol) and dioxane (8 mL).
The reaction mixture was allowed to react at 110 ꢀC for 20 h. The
reaction mixture was filtered through a short silica gel column
(ethyl acetate-hexane mixture) to eliminate black precipitate.
Removal of the solvent left a crude mixture, which was separated
by thin layer chromatography (silica gel, ethyl acetate-hexane
mixture) to give (Z)-alkylidenefuranones 5. Except for 5a, 5cef,
5l, all products prepared by the above procedure were character-
ized by GLC and spectroscopic comparison with authentic samples
synthesized by our recent report [32].
124.51, 127.35, 127.62, 128.08, 128.89, 135.06, 148.15, 149.28,
167.56; HRMS (EI) Anal. Calc. for C17H18O2 (Mþ): 254.1307.
Found: 254.1307.
Acknowledgements
This research was supported by Basic Science Research Program
through the National Research Foundation of Korea (NRF) funded
by the Ministry of Education, Science and Technology (2011-
0005123).
References
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one (5a)
Oil; IR (neat) 2924, 2855, 1759, 1674, 1643 cmꢂ1
;
1H NMR
0.88 (t, J ¼ 7.0 Hz, 3H), 1.26e1.35 (m, 6H), 1.41e1.48 (m,
2H), 1.72e1.79 (m, 4H), 2.30e2.39 (m, 6H), 5.11 (t, J ¼ 7.8 Hz, 1H);
13C NMR (CDCl3):
14.28, 20.19, 21.24, 21.64, 21.91, 22.79, 26.07,
(CDCl3):
d
d
29.19, 29.40, 31.81, 110.98, 127.00, 149.28, 151.32, 170.27; HRMS (EI)
Anal. Calc. for C15H22O2 (Mþ): 234.1620. Found: 234.1618.
4.1.2. (3Z)-4,5,6,7-Tetrahydro-3-(3-methylbutylidene)isobenzofuran-
1(3H)-one (5c)
Oil; 1H NMR (CDCl3):
d
0.94 (d, J ¼ 6.6 Hz, 6H), 1.71e1.80 (m, 5H),
2.24e2.32 (m, 4H), 2.37e2.40 (m, 2H), 5.13 (t, J ¼ 8.1 Hz, 1H); 13C
NMR (CDCl3): d 20.15, 21.24, 21.61, 21.88, 22.56, 28.85, 34.90, 109.70,
127.04, 149.75, 151.26, 170.32; HRMS (FAB) Anal. Calc. for C13H19O2
([M þ H]þ): 207.1385. Found: 207.1382.
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4.1.3. (3Z)-4,5,6,7-Tetrahydro-3-benzylideneisobenzofuran-1(3H)-
one (5d)
Solid, m.p. 116e117 ꢀC (from hexane) (lit [36]. 123e125 ꢀC); 1H
NMR (CDCl3):
(m, 2H), 5.87 (s, 1H), 7.27e7.32 (m, 1H), 7.36e7.40 (m, 2H); 13C NMR
(CDCl3): 20.34, 21.36, 21.69, 21.83, 108.03, 126.84, 128.71, 128.92,
d 1.75e1.86 (m, 4H), 2.35e2.38 (m, 2H), 2.48e2.52
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73.
1(3H)-one (5e)
Oil; 1H NMR (CDCl3):
d
0.91 (t, J ¼ 7.2 Hz, 3H), 1.07 (d, J ¼ 6.3 Hz,
3H), 1.31e1.48 (m, 5H), 1.76e1.89 (m, 3H), 2.32e2.40 (m, 3H),
2.44e2.51 (m, 2H), 5.11 (t, J ¼ 7.8 Hz, 1H); 13C NMR (CDCl3):
d 14.06,