Palladium-catalyzed carbonylative cyclization of β-Bromo-α, β-unsaturated ketones leading to alkylidenefuranones

Article abstract of DOI:10.1007/s10562-010-0457-2

β-Bromo-α,β-unsaturated ketones are carbonylatively cyclized to (Z)-alkylidenefuranones in good yields under carbon monoxide pressure in DMF in the presence of a catalytic amount of a palladium catalyst along with Et₃N.

Full text of DOI:10.1007/s10562-010-0457-2

Catal Lett (2010) 140:116–120
DOI 10.1007/s10562-010-0457-2
Palladium-Catalyzed Carbonylative Cyclization
of b-Bromo-a,b-Unsaturated Ketones Leading
to Alkylidenefuranones
•
Chan Sik Cho Hyo Bo Kim
Received: 1 September 2010 / Accepted: 22 September 2010 / Published online: 6 October 2010
Ó Springer Science+Business Media, LLC 2010
Abstract b-Bromo-a,b-unsaturated ketones are carbony-
latively cyclized to (Z)-alkylidenefuranones in good yields
under carbon monoxide pressure in DMF in the presence of
a catalytic amount of a palladium catalyst along with Et3N.
proposed for these catalytic processes (Scheme 1). The
present work was disclosed during the course of the
extension of this carbonylative cyclization protocol to
the reaction with b-bromo-a,b-unsaturated ketones in order
to synthesize 3-substituted lactams. Herein, as an example
for the application of b-bromovinyl aldehydes to the con-
struction of versatile cyclic compounds [9, 10, 15, 16,
18–38], this report describes a palladium-catalyzed car-
bonylative cyclization of b-bromo-a,b-unsaturated ketones
leading to alkylidenefuranones.
Keywords Alkylidenefuranones Á b-Bromo-a,b-
unsaturated ketones Á Carbon monoxide Á Cyclization Á
Palladium catalyst
1 Introduction
Transition metal-catalyzed carbonylation followed by
cyclization (carbonylative cyclization) has been used as
convenient and efficient synthetic tool for the construction
of the structural core of many pharmacologically and bio-
logically active lactones and lactams [1–6]. During the
course of our ongoing studies on palladium-catalyzed
cyclization reactions [7–12], we also developed on the
synthetic methods for several lactones and lactams via such
an intrinsic palladium-catalyzed carbonylative cyclization
[13–16]. Among them, in connection with this report,
2-bromobenzaldehyde and 2-bromocyclohex-1-enecarbal-
dehydes were found to be carbonylatively cyclized with
primary amines in the presence of a palladium catalyst
under carbon monoxide pressure to afford isoindol-1-ones
and hydroisoindol-1-ones, respectively [17, 18]. A reaction
pathway involving initial condensation to form an imine,
carbonylation and subsequent intramolecular acylpallada-
tion to carbon–nitrogen double bond and reduction was
2 Results and Discussion
The substrates 4 were synthesized by three steps from the
corresponding a-methylene containing cyclic and acyclic
ketones 1 (Scheme 2). b-Bromovinyl aldehydes 2 were
prepared by treating 1 under the reaction condition of the
bromo analogue of Vilsmeier reaction (PBr3/DMF/CHCl3)
[39]. Allyl alcohols 3 synthesized by the reaction with
pentylmagnesium bromide in THF and subsequent quench-
ing with saturated aqueous ammonium chloride solution
were easily oxidized to b-bromo-a,b-unsaturated ketones 4
under PCC (pyridinium chlorochromate) [40].
Based on our recent report on palladium-catalyzed syn-
thesis of isoindol-1-ones and hydroisoindol-1-ones by the
reaction of 2-bromobenzaldehyde and 2-bromocyclohex-1-
enecarbaldehydes with primary amines [17, 18], we
attempted similar carbonylative cyclization of b-bromo-a,b-
unsaturated ketone 4a with aniline (5) in order to produce 3-
alkyl substituted hydroisoindol-1-one 6 (Scheme 3). How-
ever, when 4a was treated with equimolar amount of 5 under
the reaction condition used for synthesis of isoindol-1-ones
and hydroisoindol-1-ones [PdCl2(PhCN)2 (4 mol%), CO
(10 atm), DMF, 100 °C, 20 h], the desired carbonylative
C. S. Cho (&) Á H. B. Kim
Department of Applied Chemistry, Kyungpook National
University, Daegu 702-701, South Korea
e-mail: cscho@knu.ac.kr
123

Palladium-Catalyzed Carbonylative Cyclization
117
Scheme 1 A reaction pathway
for the synthesis of isoindol-1-
ones and hydroisoindol-1-ones
PdBr
R'
R
CHO
Br
R
R'
R
R
N
H2N R'
Pd,CO
N
N R'
Br
O
O
Scheme 2 Synthesis of
b-bromo-a,b-unsaturated
ketones
OH
CHO
Br
PBr3/DMF/CHCl3
BrMg
Ether
O
Br
1
2
3
O
PCC/NaOAc
CH2Cl2
Br
4
Scheme 3 Palladium-catalyzed
reactions of 4a with 5
PdCl2(PhCN)2
DMF,CO
N
Ph
O
O
O
6
+
H2N Ph
Br
PdCl2(PPh3)2,PPh
Et3N,MeCN,CO
3
4a
5
O
7a
cyclized product 6 was not formed at all. The present reaction
was found during the course of continuous attempts to realize
the carbonylative cyclization toward 6. For an example,
treatment of 4a with 2 equiv. of 5 under carbon monoxide
pressure (15 atm) in acetonitrile at 120 °C for 20 h in the
presence of PdCl2(PPh3)2 (4 mol%), PPh3 (10 mol%) and
Et3N (6 equiv.) afforded pentylidenefuranone 7a, rather than
6, in 52% isolated yield with 69% conversion of 4a. The
configuration of the product was determined by comparing
the chemical shift of vinyl proton signal in 1H NMR with that
of a compound having a similar structural backbone. It is
known that the chemical shift of vinyl proton of naturally
occurring 6,7-dihydroligustilide (Z)-butylidene analogue of
7a appears at d 5.11 ppm [41]. It appears that the configu-
ration of the product is (Z)-isomer as this chemical shift is
exactly in accordance with that of the vinyl proton of 7a and
it is also known that the chemical shift of vinyl proton of (E)-
isomer is shifted downfield from that of (Z)-isomer [42].
After further elaborated tuning on reaction conditions,
the best result in terms of both product 7a yield and
effective conversion of 4a was best accomplished by the
standard set of reaction conditions shown in footnote of
Table 1. Various cyclic and acyclic b-bromo-a,b-unsatu-
rated ketones 4 were subjected to the reaction under the
optimized conditions in order to investigate the reaction
scope and several representative results are summarized in
Table 1. With cyclic b-bromo-a,b-unsaturated ketones
(4a–g), the carbonylative cyclized pentylidenefuranones
(7a–g) were formed in the range of 38–70% yields without
any identifiable side product. Here again, all pentylide-
nefuranones were produced with (Z)-configuration. The
ring size of 4a–g had some relevance to the product yield.
Lower reaction rate and yield were observed with five and
twelve membered cyclic b-bromo-a,b-unsaturated ketones
(4b and 4g). The reaction proceeds likewise with benzo-
fused cyclic b-bromo-a,b-unsaturated ketone 4h to give the
corresponding carbonylative cyclized product 7h in similar
yield. Similar treatment of acyclic b-bromo-a,b-unsatu-
rated ketone 4i under the employed conditions also affor-
ded the carbonylative cyclized product 7i, however, the
yield was lower than that when previously described
b-bromo-a,b-unsaturated ketones were used except for 4g.
3 Experimental
3.1 General
1H and 13C NMR (400 and 100 MHz) spectra were
recorded on a Bruker Avance Digital 400 spectrometer
123

118
C. S. Cho, H. B. Kim
Table 1 Palladium-catalyzed carbonylative cyclization of b-bromo-a,b-unsaturated ketones
O
PdCl2(PPh3)2, Et3N
O
CO (20 atm), DMF
120 oC, 20 h
Br
O
b-Bromo-a,b-unsaturated ketones 4
Alkylidenefuranones 7
Yield (%)
O
O
O
4a
7a
66
Br
O
O
O
4b
4c
7b
7c
49
66
Br
O
O
O
Br
O
Ph
Ph
4d
7d
70
O
O
Br
O
4e
4f
7e
7f
70
66
O
O
Br
O
O
O
Br
O
4g
4h
7g
7h
38
65
O
O
Br
O
Br
O
O
O
Ph
O
4i
7i
43
Ph
Br
O
Reaction conditions: 4 (0.5 mmol), PdCl2(PPh3)2 (0.025 mmol), Et3N (1 mmol), DMF (5 mL)
CO (20 atm), at 120 °C, for 20 h
123

Palladium-Catalyzed Carbonylative Cyclization
119
using TMS as an internal standard. IR spectra were mea-
sured on a Shimadzu FT IR-8400S spectrophotometer.
Melting points were determined on a Standford Research
Inc. MPA100 automated melting point apparatus. The
isolation of pure products was carried out via thin layer
chromatography (silica gel 60 GF254, Merck). b-Bromo-
vinyl aldehydes 2 were synthesized from the corresponding
ketones by treatment of PBr3/DMF/CHCl3 [39]. The
aldehydes 2 were transformed to b-bromo-a,b-unsaturated
ketones 4 through Grignard addition followed by oxidation
with PCC [40]. Commercially available organic and inor-
ganic compounds were used without further purification.
110.95, 126.74, 149.13, 151.36, 170.08. Anal. (C14H20O2)
calcd: C, 76.33; H, 9.15. Found: C, 76.13; H, 9.14.
(3Z)-4,5,6,7-Tetrahydro-3-pentylidene-5-phenylisoben-
zofuran-1(3H)-one (7d): Solid; MP 72.8–73.3 °C (from
1
hexane-EtOAc); H NMR (CDCl3) d 0.91 (t, J = 7.2 Hz,
3H), 1.31–1.47 (m, 4H), 1.80–1.90 (m, 1H), 2.09–2.15 (m,
1H), 2.35–2.57 (m, 5H), 2.70–2.76 (m, 1H), 2.90–2.97 (m,
1H), 5.12 (t, J = 7.8 Hz, 1H), 7.23–7.28 (m, 3H),
7.33–7.37 (m, 2H); 13C NMR (CDCl3) d 14.02, 20.73,
22.54, 25.76, 29.20, 29.51, 31.47, 39.73, 111.37, 126.78,
126.97, 126.98, 128.92, 144.97, 148.86, 151.18, 169.80.
Anal. (C19H22O2) calcd: C, 80.82; H, 7.85. Found: C,
80.57; H, 7.80.
3.2 General Experimental Procedure
(3Z)-5,6,7,8-Tetrahydro-3-pentylidene-3H-cyclohepta[c]
furan-1(4H)-one (7e): Oil; IR (neat) 2924, 2855, 1751,
1667, 1636 cm-1; 1H NMR (CDCl3) d 0.91 (t, J = 7.2 Hz,
3H), 1.31–1.48 (m, 4H), 1.60–1.72 (m, 4H), 1.80–1.86 (m,
2H), 2.34–2.40 (m, 2H), 2.46–2.51 (m, 4H), 5.25 (t,
J = 7.8 Hz, 1H); 13C NMR (CDCl3) d 14.06, 22.59, 25.00,
26.09, 26.22, 26.82, 26.92, 31.04, 31.56, 111.42, 129.70,
149.26, 153.24, 170.93. Anal. (C14H20O2) calcd: C, 76.33;
H, 9.15. Found: C, 76.09; H, 9.17.
To a 50 mL stainless steel autoclave were added b-bromo-
a,b-unsaturated ketone (0.5 mmol), PdCl2(PPh3)2 (0.018 g,
0.025 mmol), Et3N (0.101 g, 1 mmol) and DMF (5 mL).
After the system was flushed and then pressurized with
carbon monoxide to 20 atm, the reaction mixture was
allowed to react at 120 °C for 20 h. The reaction mixture
was filtered through a short silica gel column (ethyl ace-
tate–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 7.
All products prepared by the above procedure were char-
acterized spectroscopically as shown below.
(3Z)-4,5,6,7,8,9-Hexahydro-3-pentylidenecycloocta[c]
furan-1(3H)-one (7f): Oil; 1H NMR (CDCl3) d 0.92 (t,
J = 7.2 Hz, 3H), 1.33–1.38 (m, 2H), 1.40–1.47 (m, 2H),
1.48–1.53 (m, 4H), 1.68–1.76 (m, 4H), 2.35–2.41 (m, 2H),
2.48–2.51 (m, 2H), 2.56–2.59 (m, 2H), 5.22 (t, J = 8.0 Hz,
1H); 13C NMR (CDCl3) d 14.06, 22.46, 22.58, 23.46,
25.70, 25.83, 25.98, 27.89, 28.10, 31.55, 111.06, 128.08,
149.12, 151.90, 170.89. Anal. (C15H22O2) calcd: C, 76.88;
H, 9.46. Found: C, 76.69; H, 9.40.
3.3 Characterization Data
(3Z)-4,5,6,7-Tetrahydro-3-pentylideneisobenzofuran-1(3H)-
one (7a): Oil; IR (neat) 2932, 2862, 1759, 1674, 1643,
(3Z)-4,5,6,7,8,9,10,11,12,13-Decahydro-3-pentylidene
cyclododeca[c]furan-1(3H)-one (7g): Oil; 1H NMR
(CDCl3) d 0.92 (t, J = 7.3 Hz, 3H), 1.24–1.48 (m, 16H),
1.64–1.75 (m, 4H), 2.32–2.40 (m, 4H), 2.44–2.48 (m, 2H),
5.22 (t, J = 7.8 Hz, 1H); 13C NMR (CDCl3) d 14.09,
21.35, 22.05, 22.17, 22.51, 22.62, 24.42, 24.75, 24.95,
25.67, 25.75, 25.98, 27.70, 31.59, 112.04, 128.44, 149.45,
151.74, 170.98. Anal. (C19H30O2) calcd: C, 78.57; H,
10.41. Found: C, 78.48; H, 10.35.
1
1018 cm-1; H NMR (CDCl3) d 0.91 (t, J = 7.2 Hz, 3H),
1.31–1.47 (m, 4H), 1.75–1.76 (m, 4H), 2.30–2.39 (m, 6H),
5.11 (t, J = 7.8 Hz, 1H); 13C NMR (CDCl3) d 14.04, 20.17,
21.23, 21.62, 21.89, 22.56, 25.73, 31.51, 110.93, 126.98,
149.28, 151.32, 170.26. Anal. (C13H18O2) calcd: C, 75.69;
H, 8.80. Found: C, 75.48; H, 8.75.
(3Z)-5,6-Dihydro-3-pentylidene-3H-cyclopenta[c]furan-
1(4H)-one (7b): Oil; 1H NMR (CDCl3)
d
0.92
(1Z)-4,5-Dihydro-1-pentylidenenaphtho[2,1-c]furan-3
(1H)-one (7h): Oil; 1H NMR (CDCl3) d 0.94 (t,
J = 7.2 Hz, 3H), 1.36–1.45 (m, 2H), 1.49–1.56 (m, 2H),
2.48–2.53 (m, 2H), 2.58 (t, J = 7.8 Hz, 2H), 2.93 (t,
J = 7.8 Hz, 2H), 5.79 (t, J = 7.8 Hz, 1H), 7.29–7.38 (m,
3H), 7.56–7.58 (m, 1H); 13C NMR (CDCl3) d 14.08, 18.41,
22.65, 26.56, 28.67, 31.55, 115.72, 125.46, 126.67, 127.21,
127.96, 129.12, 130.50, 138.74, 146.68, 146.91, 169.01.
Anal. (C17H18O2) calcd: C, 80.28; H, 7.13. Found: C,
80.02; H, 7.08.
(t, J = 7.2 Hz, 3H), 1.31–1.48 (m, 4H), 2.32–2.38 (m, 2H),
2.43–2.50 (m, 2H), 2.57–2.60 (m, 2H), 2.63–2.67 (m, 2H),
5.09 (t, J = 8.0 Hz, 1H); 13C NMR (CDCl3) d 14.04,
22.56, 25.56, 25.94, 26.74, 28.97, 31.40, 113.64, 137.53,
146.05, 164.68, 166.06. Anal. (C12H16O2) calcd: C, 74.97;
H, 8.39. Found: C, 74.80; H, 8.30.
(3Z)-4,5,6,7-Tetrahydro-5-methyl-3-pentylideneisobenzo-
furan-1(3H)-one (7c): Oil; 1H NMR (CDCl3) d 0.91
(t, J = 7.2 Hz, 3H), 1.08 (d, J = 6.6 Hz, 3H), 1.31–1.46
(m, 5H), 1.79–2.00 (m, 3H), 2.21–2.30 (m, 1H), 2.33–2.53
(m, 4H), 5.11 (t, J = 7.8 Hz, 1H); 13C NMR (CDCl3) d
14.03, 19.96, 21.35, 22.55, 25.72, 28.28, 29.33, 30.19, 31.50,
(5Z)-4-Methyl-5-pentylidene-3-phenylfuran-2(5H)-one
1
(7i): Oil; H NMR (CDCl3) d 0.94 (t, J = 7.2 Hz, 3H),
1.35–1.44 (m, 2H), 1.46–1.53 (m, 2H), 2.24 (s, 3H),
123

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C. S. Cho, H. B. Kim
8. Cho CS, Lim DK, Zhang JQ, Kim T-J, Shim SC (2004) Tetra-
hedron Lett 45:5653
2.42–2.48 (m, 2H), 5.41 (t, J = 7.8 Hz, 1H), 7.35–7.39 (m,
1H), 7.43–7.46 (m, 2H), 7.52–7.54 (m, 2H); 13C NMR
(CDCl3) d 11.13, 14.07, 22.64, 26.21, 31.52, 113.44,
126.66, 128.73, 128.75, 129.22, 130.19, 146.86, 150.09,
169.39. Anal. (C16H18O2) calcd: C, 79.31; H, 7.49. Found:
C, 79.15; H, 7.40.
9. Cho CS, Patel DB, Shim SC (2005) Tetrahedron 61:9490
10. Cho CS, Patel DB (2006) Tetrahedron 62:6388
11. Cho CS, Kim JU (2007) Tetrahedron Lett 48:3775
12. Cho CS, Kim TG, Kim HW (2009) Catal Commun 10:1482
13. Cho CS, Lee JW, Lee DY, Shim SC, Kim TJ (1996) Chem
Commun 2115
14. Cho CS, Chu DY, Lee DY, Shim SC, Kim TJ, Lim WT, Heo NH
(1997) Synth Commun 27:4141
15. Cho CS, Shim HS (2006) Tetrahedron Lett 47:3835
16. Cho CS, Kim JU, Choi H-J (2008) J Organomet Chem 693:3677
17. Cho CS, Ren WX (2009) Tetrahedron Lett 50:2097
18. Cho CS, Kim HB, Lee SY (2010) J Organomet Chem 695:1744
19. Ray JK, Haldar MK, Gupta S, Kar GK (2000) Tetrahedron
56:909
20. Zhang Y, Herndon JW (2003) Org Lett 5:2043
21. Mal SK, Ray D, Ray JK (2004) Tetrahedron Lett 45:277
22. Ray D, Mal SK, Ray JK (2005) Synlett 2135
23. Some S, Dutta B, Ray JK (2006) Tetrahedron Lett 47:1221
24. Ray D, Ray JK (2007) Tetrahedron Lett 48:673
25. Some S, Ray JK, Banwell MG, Jones MT (2007) Tetrahedron
Lett 48:3609
4 Conclusion
In summary, it has been shown that various cyclic and
acyclic b-bromo-a,b-unsaturated ketones, which are read-
ily prepared from ketones, undergo carbonylation and
intramolecular cyclization under carbon monoxide pressure
in the presence of a catalytic amount of PdCl2(PPh3)2 along
with Et3N to give the corresponding (Z)-alkylidenefura-
nones in good yields. The present reaction is a straight-
forward methodology for the synthesis of valuable
heterocycles from readily available starting ketones. Fur-
ther study of synthetic applications to N-heterocycles using
b-bromo-a,b-unsaturated ketones is in progress.
26. Some S, Ray JK (2007) Tetrahedron Lett 48:5013
27. Ray D, Paul S, Brahma S, Ray JK (2007) Tetrahedron Lett
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28. Ray D, Ray JK (2007) Org Lett 9:191
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31. Jana R, Chatterjee I, Samanta S, Ray JK (2008) Org Lett 10:4795
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Acknowledgments 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 (2010-0007563).
33. Karthikeyan P, Meena Rani A, Saiganesh R, Balasubramanian
KK, Kabilan S (2009) Tetrahedron 65:811
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