Palladium-catalyzed carbonylative cyclization of 3-bromoallyl alcohols leading to furan-2(5H)-ones

Article abstract of DOI:10.1002/aoc.2864

3-Bromoallyl alcohols are carbonylatively cyclized under carbon monoxide pressure in toluene in the presence of a catalytic amount of Pd(OAc)₂ and PPh₃ along with Na₂CO₃ to give furan-2(5H)-ones in good yields.

Full text of DOI:10.1002/aoc.2864

Full Paper
Received: 27 February 2012
Revised: 16 March 2012
Accepted: 22 March 2012
Published online in Wiley Online Library
(wileyonlinelibrary.com) DOI 10.1002/aoc.2864
Palladium-catalyzed carbonylative cyclization
of 3-bromoallyl alcohols leading to furan-2
(5H)-ones
Hye Kyung Lee and Chan Sik Cho*
3-Bromoallyl alcohols are carbonylatively cyclized under carbon monoxide pressure in toluene in the presence of a
catalytic amount of Pd(OAc)2 and PPh3 along with Na2CO3 to give furan-2(5H)-ones in good yields. Copyright © 2012
John Wiley & Sons, Ltd.
Keywords: 3-bromoallyl alcohol; carbon monoxide; cyclization; furan-2(5H)-one; palladium catalyst
with saturated aqueous ammonium chloride solution to afford
Introduction
3-bromoallyl alcohols 3.[41]
Transition metal-catalyzed carbonylation followed by cyclization
(carbonylative cyclization) has been widely explored and
used as a promising synthetic tool for the construction of the
structural core of many pharmacologically and biologically active
lactones and lactams.[1–7] During the course of our ongoing
studies on palladium-catalyzed cyclization reactions using
b-bromo-a, b-unsaturated aldehydes and their derivatives,[8–11]
which are readily prepared from the corresponding ketones by
Vilsmeier–Haack reaction[12,13] and subsequent transformation
and used as a building block for the construction of versatile
cyclic compounds,[14–36] we recently reported on the synthesis
of several heterocycles via such a carbonylative cyclization. For
example, b-bromovinyl aldehydes were found to be cyclized
under carbon monoxide pressure in MeCN and alcohols in the
presence of a palladium catalyst to give furan-2(5H)-ones.[37,38]
Such a similar palladium-catalyzed carbonylative cyclization was
also exemplified by the reaction of b-bromo-a, b-unsaturated
ketones under carbon monoxide pressure to give (Z)-alkylidene-
furanones.[39] It is also disclosed that 2-bromocyclohex-1-
enecarbaldehydes react with anilines under carbon monoxide
pressure in the presence of a palladium catalyst to afford
hydroisoindol-1-ones.[40] Prompted by these findings, such an
intrinsic palladium-catalyzed carbonylative cyclization protocol
led us to seek for a promising route for other heterocyclic
compounds using b-bromovinyl aldehyde and its derivatives.
Herein, this report describes palladium-catalyzed carbonylative
cyclization of 3-bromoallyl alcohols leading to furan-2(5H)-ones.
To investigate the effect of reaction variants such as CO
pressure, reaction temperature and time for the carbonylative
cyclization, 1-(2-bromocyclohex-1-enyl)pentan-1-ol (3a) was chosen
as a model substrate. Treatment of 3a in toluene at 150ꢀC in
the presence of Pd(OAc)2 and PPh3 along with Na2CO3 under
carbon monoxide pressure (10 atm) afforded 4a in 28% isolated
yield with 51% conversion of 3a (entry 1). Either higher carbon
monoxide pressure or longer reaction time resulted in an
increased yield of 4a with increased conversion of 3a (entries
2 and 3). However, no significant synergic effect was observed
with both conditions (entry 4). Performing the reaction at lower
reaction temperature produced a slightly decreased yield of 4a
(entry 5). In spite of further elaboration for the optimization of
reaction conditions, the best result in terms of the conversion
of 3a and the yield of 4a is best accomplished under the
standard set of condition shown in entry 4 of Table 1.
After the reaction conditions have been established, various
3-bromoallyl alcohols 3 were subjected to carbonylative cycliza-
tion in order to investigate the reaction scope and several
representative results are summarized in Table 2. 3-Bromoallyl
alcohol 3b having phenyl group at allylic position was also
cyclized under the employed conditions to give 3-phenyl-
4,5,6,7-tetrahydroisobenzofuran-1(3H)-one (4b) in 47% yield.
With cyclic 3-bromoallyl alcohols (3a, 3c–f) having various ring
sizes, the carbonylative cyclized products (4a, 4c–f) were
formed in the range of 31–85% yields and the product yield
was considerably affected by the ring size of 3a and 3c–f. Lower
reaction rate and yield were observed with 3e and 3f, having
larger ring size. To test for the effect of the position of bromide
and carbinol group on 3-bromoallyl alcohols, 3g and 3h were
Results and Discussion
The starting 3-bromoallyl alcohols 3 were synthesized by initial
conversion of the corresponding a-methylene containing
cyclic and acyclic ketones 1 into b-bromovinyl aldehydes 2 under
bromination conditions of Vilsmeier–Haack reaction (PBr3/DMF/
CHCl3) (Scheme 1).[12,13] This is followed by the reaction with
organomagnesium bromides in THF and subsequent quenching
*
Correspondence to: Chan Sik Cho, Department of Applied Chemistry,
Kyungpook National University, Daegu 702–701, South Korea.
E-mail: cscho@knu.ac.kr
Department of Applied Chemistry, Kyungpook National University, Daegu,
702-701, South Korea
Appl. Organometal. Chem. (2012)
Copyright © 2012 John Wiley & Sons, Ltd.

H. Y. Lee and C. S. Cho
Scheme 1. Synthesis of 3-bromoallyl alcohols
Table 1. Optimization of conditions for the carbonylative cyclization of 3aa
OH
Pd(OAc)2, PPh3
O
Na2CO3, CO
Br
O
3a
4a
Entry
Pressure of CO (atm)
Temp. (ꢀC)
Time (h)
Conv. of 3a (%)
Yield (%)
1
2
3
4
5
10
10
20
20
20
150
150
150
150
120
20
40
22
40
20
51
83
75
86
69
28
72
64
77
57
aReaction conditions: 3a (0.5 mmol), Pd(OAc)2 (0.05 mmol), PPh3 (0.1 mmol), Na2CO3 (2 mmol), toluene (5 ml).
employed. The present carbonylative cyclization readily took
place with both 3g and 3h irrespective of their position.
Experimental
1H and 13C NMR (400 and 100 MHz) spectra were recorded on a
Bruker Avance Digital 400 spectrometer using Me4Si as an internal
standard. The isolation of pure products was carried out via column
(silica gel 60, 70–230 mesh, Merck) chromatography. 3-Bromoallyl
Similar treatment of acyclic 3-bromoallyl alcohols (3i and 3j)
under the employed conditions also afforded the carbonylative
cyclized products (4i and 4j), however, the yield was lower
than that when previously described cyclic 3-bromoallyl alcohols
were used, except for 3e and 3f. In the reaction of 3j, since the
product 4j was not possible to separate from the reaction
mixture using column or thin-layer chromatography, the yield
was analyzed from the intensity of the clearly separated allylic
proton signal of 4j based on anisole as an internal standard in
1H NMR spectrum.[42]
alcohols 3 were synthesized in two steps: initial treatment of
[12,13]
ketones 1 with PBr3/DMF/CHCl3
to produce b-bromovinyl
aldehydes 2 and subsequent conversion of 2 into 3 by Grignard
addition.[41] Commercially available organic and inorganic
compounds were used without further purification.
The reaction seems to proceed as shown in Scheme 2. Oxidative
addition of the carbon–bromide bond of 3-bromoallyl alcohol 3
to palladium(0) produces a vinylpalladium(II) complex 5, where
carbon monoxide coordination to palladium and then vinyl
migration from palladium to the carbon of carbon monoxide
occurs to give an acylpalladium(II) intermediate 6. The elimination
of HBr by a base occurs in intermediate 6 to produce a palladacycle
intermediate 7, which can reductively eliminate to give 4.
General Experimental Procedure
To a 50 ml stainless steel autoclave were added 3-bromoallyl
alcohol (0.5 mmol), Pd(OAc)2 (0.011 g, 0.05 mmol), PPh3 (0.026 g,
0.1 mmol), Na2CO3 (0.212 g, 2 mmol), and toluene (5 ml). After
the system was flushed and then pressurized with carbon
monoxide to 10–20 atm, the reaction mixture was allowed to react
at 120–150ꢀC for 20–40 h. The reaction mixture was filtered
through a short silica gel column (ethyl acetate) to eliminate the
precipitate. Removal of the solvent left
a crude mixture,
which was separated by column chromatography (hexane/ethyl
acetate= 10/1) to give furan-3(5H)-ones. Except for known 4a,[43]
4b,[44] 4g,[45]4h[46] and 4i,[47] all new products prepared by the above
procedure were characterized spectroscopically as shown below.
Conclusion
In summary, we have demonstrated that 3-bromoallyl alcohols,
which are readily prepared from a-methylene containing ketones
in two steps, are carbonylatively cyclized to furan-3(5H)-ones in
the presence of a palladium catalyst along with a base. The present
reaction provides a promising route for the synthesis of valuable
heterocycles from readily available starting ketones. Further study
of synthetic applications to heterocycles by using this ketone as
starting compound is in progress.
3-Butyl-5,6-dihydro-3H-cyclopenta[c]furan-1(4H)-one (4c)
Oil. 1H NMR (400 MHz, CDCl3) d 0.91 (t, JHH = 6.9 Hz, 3H, CH3),
1.31–1.45 (m, 4H, 2CH2), 1.58–1.67 (m, 1H, 1/2CH2), 1.75–1.83
(m, 1H, 1/2CH2), 2.42–2.54 (m, 4H, 2CH2), 2.56–2.61 (m, 2H,
CH2), 4.92–4.95 (m, 1H, CH). 13C NMR (100 MHz, CDCl3) d 14.02
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Appl. Organometal. Chem. (2012)

Palladium-catalyzed carbonylative cyclization
Table 2. Palladium-catalyzed carbonylative cyclization of
3-bromoallyl alcohols 3 leading to furan-3(5H)-ones 4a
3-bromoallyl alcohols 3
furan-3(5H)-ones 4
Isolated yield (%)
37
3a
4a
Scheme 2. A catalytic cycle
(CH3), 22.57 (CH2), 25.13 (CH2), 27.02 (CH2), 28.84 (CH2), 28.95
(CH2), 32.54 (CH2), 80.74 (OCH), 137.41 (¼CCO), 169.78 (¼C),
177.30 (C¼O). Anal. Calcd for C11H16O2: C, 73.30; H, 8.95. Found:
C, 73.10; H, 8.87.
4b
4c
3b
3c
47
80
3-Butyl-5,6,7,8-tetrahydro-3H-cyclohepta[c]furan-1(4H)-one (4d)
Solid; m.p. 38–39ꢀC (from hexane–ethyl acetate). 1H NMR (400 MHz,
CDCl3) d 0.90 (t, JHH = 7.1 Hz, 3H, CH3), 1.24–1.50 (m, 6H, 3CH2),
1.53–1.94(m, 8H, 4CH2), 2.34–2.37 (m, 2H, CH2), 4.70–4.72
(m, 1H, CH). 13C NMR (100 MHz, CDCl3) d 14.07 (CH3), 22.63
(CH2), 25.06 (CH2), 26.92 (CH2), 26.95 (CH2), 27.09 (CH2), 28.44
(CH2), 30.80 (CH2), 31.78 (CH2), 82.66 (OCH), 129.30 (¼CCO),
165.77 (¼C), 174.81 (C¼O). Anal. Calcd for C13H20O2: C, 74.96; H,
9.68. Found: C, 75.04; H, 9.73.
3d
85
4d
3-Butyl-4,5,6,7,8,9-hexahydrocycloocta[c]furan-1(3H)-one (4e)
4e
4f
36
31
Oil. 1H NMR (400 MHz, CDCl3) d 0.91 (t, JHH = 7.1 Hz, 3H, CH3), 1.28–1.62
(m, 9H, 9/2CH2), 1.63–1.74 (m, 2H, CH2), 1.76–1.83 (m, 2H, CH2), 1.85–1.95
(m, 1H, 1/2CH2), 2.43–2.48 (m, 4H, 2CH2), 4.72–4.74 (m, 1H, CH). 13C NMR
(100 MHz, CDCl3) d 14.08 (CH3), 22.14 (CH2), 22.64 (CH2), 25.43 (CH2),
25.94 (CH2), 26.13 (CH2), 26.71 (CH2), 27.08 (CH2), 27.23 (CH2), 32.19
(CH2), 82.83 (OCH), 127.25 (¼CCO), 164.37 (¼C), 174.74 (C¼O). Anal.
Calcd for C14H22O2: C, 75.63; H, 9.97. Found: C, 75.45; H, 9.97.
3e
3f
3-Butyl-4,5,6,7,8,9,10,11,12,13-decahydrocyclododeca[c]furan-1(3H)-one (4f)
Solid; m.p. 88–89ꢀC (from hexane–ethyl acetate). 1H NMR (400 MHz,
CDCl3) d 0.90 (t, JHH = 6.9 Hz, 3H, CH3), 1.12–1.70 (m, 20H,
10CH2), 1.76–1.81(m, 1H, 1/2CH2), 1.87–1.91 (m, 1H, 1/2CH2),
2.05–2.13 (m, 1H, 1/2CH2), 2.25–2.36 (m, 2H, CH2), 2.64–2.71
(m, 1H, 1/2CH2), 4.83–4.85 (m, 1H, CH). 13C NMR (100 MHz, CDCl3)
d 14.09 (CH3), 21.00 (CH2), 21.77 (CH2), 22.64 (CH2), 22.87 (CH2),
23.49 (CH2), 23.52 (CH2), 24.49 (CH2), 25.30 (CH2), 25.34 (CH2),
25.38 (CH2), 26.77 (CH2), 32.10 (CH2), 81.69 (OCH), 127.19 (¼CCO),
164.43 (¼C), 174.64 (C¼O). Anal. Calcd for C18H30O2: C, 77.65; H,
10.86. Found: C, 77.66; H, 10.96.
3g
4g
4h
4i
94
3h
3i
84
52
48
Acknowledgments
This research was supported by the Basic Science Research
Program through the National Research Foundation of Korea
(NRF) funded by the Ministry of Education, Science and Technology
(2011–0005123).
3j
4j
aReaction conditions: 3 (0.5 mmol), Pd(OAc)2 (0.05 mmol), PPh3 (0.1 mmol),
Na2CO3 (2 mmol), CO (20 atm), toluene (5 ml), 150ꢀC, for 40 h.
bDetermined by 1H NMR.
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