Palladium-catalyzed carbonylative cycloisomerization of γ-propynyl-1,3-diketones: A concise route to polysubstituted furans

Article abstract of DOI:10.1021/jo9020634

(Chemical Equation Presented) Di- and trisubstituted furan derivatives have been efficiently synthesized via palladium(II)-catalyzed intramolecular carbonylative cycloisomerization of γ-propynyl-1,3-diketones with aryl iodides and carbon monoxide. The mec

Full text of DOI:10.1021/jo9020634

pubs.acs.org/joc
R-propargyl β-ketoesters have been known for construction
Palladium-Catalyzed Carbonylative
Cycloisomerization of γ-Propynyl-1,3-diketones: A
Concise Route to Polysubstituted Furans
of polysubstituted furans.6 Although these methods have
been successfully applied in the synthesis of furan deriva-
tives, they are usually used with limitation such as the
difficulty accessing polyfunctionalized furans. Thus, synth-
esis of polysubstituted furans remains a challenge in organic
synthesis. As a continuation of our interest in the carbony-
lative coupling of alkynes and 1,3-dicarbonyl compounds,7
we investigated the carbonylation of γ-propynyl-1,3-dicar-
bonyl compounds with carbon monoxide in the presence of
an organic halide. Herein, we report synthesis of di- and
trisubstituted furans through concise carbonylative cyclo-
isomerization of γ-propynyl-1,3-diketones.
Yu Li† and Zhengkun Yu*,†,‡
†Dalian Institute of Chemical Physics, Chinese Academy of
Sciences, 457 Zhongshan Road, Dalian, Liaoning 116023,
P. R. China, and ‡State Key Laboratory of Organometallic
Chemistry, Shanghai Institute of Organic Chemistry, Chinese
Academy of Sciences, 354 Fenglin Road, Shanghai 200032,
P. R. China
In our initial study, carbonylation of 1,3-diketone 1a in the
presence of iodobenzene 2a was tried in THF with 3 mol %
Pd(PPh3)2Cl2 as the precatalyst (Table 1, entries 1-4),
affording the desired product 3a in up to 73% yield, while
the possible product of type 3a0 was not detected.6a With
6 mol % catalyst, 3a was obtained in 77% yield (entry 5).
Decreasing the base amount from 5 to 1 equiv led to 3a in a
lower yield (72%, entries 5-7). A CO pressure of 200 psi
seems to be suitable for the reaction, and the expected
reaction worked less efficiently with atmospheric CO
(entry 11). Unexpectedly, the reaction proceeded more
efficiently at a relatively low temperature such as 30 °C
(entry 13). Under the same conditions, PdCl2, PdCl2/PPh3,
and Pd(OAc)2 exhibited no catalytic activity (entries 14-16).
The first and the last precatalysts failed presumably as a
result of the absence of ligand, and the middle case may have
resulted from the incorrect stoichiometry of ligand and/or
inadequate time for an active catalytic species to form before
addition of the substrates. Pd(0) precatalysts Pd(dba)2 and
Pd(PPh3)4 showed no or very poor activity for the desired
reaction. In the presence of dppb ligand, Pd(OAc)2 exhibited
a low activity in water (entry 19), and in ionic liquid
[bmin]PF6, Pd(PPh3)2Cl2 could only demonstrate a poor
catalytic activity (entry 20). It is worth noting that the
reaction of 1a and 2a to form 3a should be carried out under
CO atmosphere, and a catalyst and base such as Et3N are
essential for the reaction.
To define the protocol scope, different types of γ-propy-
nyl-1,3-diketones were applied as the substrates. γ-Functio-
nalization8 was employed to modify the skeleton of a 1,3-
diketone. Thus, treatment of a 1,3-diketone with 2 equiv of
LDA followed by reaction with an electrophile, e.g., pro-
pargyl bromide, may produce two new isomeric γ-functio-
nalized 1,3-diketones via the in situ generated doubly
enolized dianions (see Experimental Section). Starting from
symmetrical 1,3-dialkyl-1,3-diones and unsymmetrical
1-aryl-3-alkyl-1,3-diones, only one type of γ-functionalization
products such as 1a, 1m, and 1n were obtained (Table 2).9
zkyu@dicp.ac.cn
Received September 24, 2009
Di- and trisubstituted furan derivatives have been effi-
ciently synthesized via palladium(II)-catalyzed intramo-
lecular carbonylative cycloisomerization of γ-propynyl-
1,3-diketones with aryl iodides and carbon monoxide.
The mechanism suggests that in situ generated acylpalla-
dium species from the carbonylation of aryl iodide initi-
ates the reaction followed by cyclization of the enolized
isomer of a 1,3-diketone substrate via carbon-carbon
triple bond activation.
Highly substituted furans have been found as key struc-
tural units in many biologically important natural products
and pharmaceuticals.1 Substituted furans are usually synthe-
sized by functionalization of an existing furan ring,2 through
cycloisomerization of alkynyl- and allenyl-functionalized
compounds,3 or by means of alkyne- and allene-involved
reactions.4 1,3-Dicarbonyl compounds have also been used
in the synthesis of furans,5 but only a few examples involving
(1) Hou, X. L.; Yang, Z.; Wong, H. N. C. Progress in Heterocyclic
Chemistry; Gribble, G. W.; Gilchrist, T. L., Eds.; Pergamon: Oxford, UK,
2003; Vol. 15, pp 167.
(2) Alberico, D.; Scott, M. E.; Lautens, M. Chem. Rev. 2007, 107, 174.
(3) Selected recent reports, see: (a) Yoshida, M.; Al-Amin, M.; Matsuda,
K.; Shishido, K. Tetrahedron Lett. 2008, 49, 5021. (b) Xia, Y. Z.; Dudnik,
A. S.; Gevorgyan, V.; Li, Y.-H. J. Am. Chem. Soc. 2008, 130, 6940. (c) Ma, S.;
Zhang, J. J. Am. Chem. Soc. 2003, 125, 12386.
(4) For selected recent examples, see: (a) Xiao, Y. J.; Zhang, J. L. Angew.
Chem., Int. Ed. 2008, 47, 1903. (b) Barluenga, J.; Riesgo, L.; Vicente, R.;
Lopez, L. A.; Tomas, M. J. Am. Chem. Soc. 2008, 130, 13528. (c) Dai, L.-Z.;
Shi, M. Tetrahedron Lett. 2008, 49, 6437.
(5) Selected recent reports, see: (a) Arcadi, A.; Cacchi, S.; Fabrizi, G.;
Marinelli, F.; Parisi, L. M. Tetrahedron 2003, 59, 4661. (b) Duan, X. H.; Liu,
X. Y.; Guo, L. N.; Liao, M. C.; Liu, W. M.; Liang, Y. M. J. Org. Chem. 2005,
(6) (a) Cacchi, S.; Fabrizi, G.; Moro, L. J. Org. Chem. 1997, 62, 5327. (b)
MaGee, D. I.; Leach, J. D. Tetrahedron Lett. 1997, 38, 8129. (c) Marshall,
J. A.; Zou, D. Tetrahedron Lett. 2000, 41, 1347.
(7) Li, Y.; Yu, Z. K.; Alper, H. Org. Lett. 2007, 9, 1647.
(8) Hayakawa, K.; Yodo, M.; Ohsuki, S.; Kanematsu, K. J. Am. Chem.
Soc. 1984, 106, 6735.
´
70, 6980. (c) Cadierno, V.; Dıez, J.; Gimeno, J.; Nebra, N. J. Org. Chem.
2008, 73, 5852.
(9) Kel’in, A. V.; Maioli, A. Curr. Org. Chem. 2003, 7, 1855.
8904 J. Org. Chem. 2009, 74, 8904–8907
Published on Web 10/20/2009
DOI: 10.1021/jo9020634
r
2009 American Chemical Society

Li and Yu
JOCNote
TABLE 1. Screening of Reaction Conditionsa
TABLE 2. Carbonylative Cycloisomerization of 1 with PhIa
solvent
(5 mL)
NEt3 P(CO) temp yieldb
entry catalyst/mol %
(equiv) (psi)
(°C)
(%)
1
2
3
4
5
6
7
8
Pd(PPh3)2Cl2/3
Pd(PPh3)2Cl2/3
Pd(PPh3)2Cl2/3
Pd(PPh3)2Cl2/3
Pd(PPh3)2Cl2/6
Pd(PPh3)2Cl2/6
Pd(PPh3)2Cl2/6
Pd(PPh3)2Cl2/6
Pd(PPh3)2Cl2/6
Pd(PPh3)2Cl2/6
Pd(PPh3)2Cl2/6
Pd(PPh3)2Cl2/6
Pd(PPh3)2Cl2/6
PdCl2/6
CH3CN
DME
NEt3
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
5
5
36
5
5
2
1
2
2
2
2
2
2
2
2
2
2
2
200
200
200
200
200
200
200
400
100
50
100
100
100
100
100
100
100
100
100
100
60
60
30
30
30
30
30
30
100
36
55
66
73
77
76
72
75
73
69
62
78
79
0
9
10
11
12
13
14
15
16
17
18
19
14.7
200
200
200
200
200
200
200
200
PdCl2/6; PPh3/12 THF
<1
0
0
<10
40
Pd(OAc)2/6
Pd(dba)2/6
Pd(PPh3)4/6
Pd(OAc)2/6;
dppb/6
THF
THF
THF
H2O
2
20
Pd(PPh3)2Cl2/6
[bmin]PF6
5
200
100
31
aConditions: 1a, 1.0 mmol; 2a, 1.0 mmol; 4 h. bIsolated yields of 3a.
dppb = 1,4-bis(diphenylphosphino)butane.
Using unsymmetical 1,3-dialkyl-1,3-diones, which can be de-
protonated at two different γ-positions, their γ-functionaliza-
tion usually afforded a mixture of two inseparable isomers
such as 1d/1d0, 1e/1e0, and 1f/1f0 (substrates for entries 4-6,
Table 2). A bulky substituent such as isopropyl and cyclopentyl
at the γ-position excluded double γ-functionalization, exclusively
leading to a mono-γ-functionalization product, e.g., 1b and 1c
(substrates for entries 2 and 3, Table 2).10 Only in one case,
isomeric 1g and 1h were successfully separated by flash silica gel
column chromatography (substrates for entries 7 and 8, Table 2).
Under the optimized conditions for carbonylative cyclo-
isomerization, the reactions of 1b and 1c afforded the desired
products 3b and 3c in 43-57% yields (Table 2, entries 2 and
3). Although a mixture of two inseparable γ-stereoisomers
was used as the substrate, both of the isomers were reactive to
undergo the expected reactions, forming two separable
products in moderate to good yields (entries 4-6). The
reactions of isomeric 1g and 1h gave the desired products
3g and 3h in 56-67% yields (entries 7 and 8), respectively.
Fused furan 3i was obtained from the reaction of cyclic
substrate 1i11 (entry 9). The enamine of 1a, i.e., 1j, also
underwent the reaction to form 3a as the product (entry 10).
No reaction was observed for internal alkyne 1k and β-
ketoester 1l (entries 11 and 12), presumably due to the steric
hindrance of the terminal alkyl of 1k and change of the
enolization of 1l by replacing acetyl with an ester moiety.
Carbonylation products 3m and 3n instead of the desired
products were obtained in 36% and 38% yields from the
reactions of 1m and 1n with CO and PhI, respectively (eq 1),
suggesting that the linker between a carbonyl and its adjacent
aConditions: 1, 1.0 mmol; PhI, 1.0 mmol; Pd(PPh3)2Cl2, 6 mol %;
NEt3, 2.0 mmol; THF, 5.0 mL; P(CO), 200 psi; 30 °C; 8 h. bIsolated
yields. c4 h. d100 °C.
alkynyl plays a key role in directing formation of the
target products, and the linker length should be two
CH2 groups. Substrate 1o was decomposed to the cycliza-
tion product 3o (eq 2), revealing that replacement of
1-alkyl with an aryl changes the enolization mode of a
1,3-diketone moiety in the substrate and thus alters the
reaction pathway.
(10) Kel’in, A. V. Curr. Org. Chem. 2003, 7, 1691.
~
as, M.; Rodrıguez, J. R.; Castedo, L.; Mascarenas, J. L. Org.
´ ´
(11) Gulı
Lett. 2003, 5, 1975.
J. Org. Chem. Vol. 74, No. 22, 2009 8905

Li and Yu
JOCNote
TABLE 3. Carbonylative Cycloisomerization of 1a with ArIa
Next, the synthetic procedure was extended to the reactions
of 1a with a variety of aryl iodides, producing 2,5-disubsti-
tuted furans 4b-p in good to excellent yields (Table 3). An
electron-donating substituent such as a methyl in ArI facil-
itates formation of the desired products 4b-d (71-84%),
whereas electron-withdrawing substituents decreased the
reaction efficiency, leading to 4j-o in lower yields
(27-62%). The steric hindrance from a 2-substituent in
ArI retarded the reactions. The reaction of 2-iodothiophene
gave the target product 4p in 74% yield.
SCHEME 1. Proposed Mechanism
aConditions: 1a, 1.0 mmol; ArI, 1.0 mmol; Pd(PPh3)2Cl2, 6 mol %;
NEt3, 2.0 mmol; THF, 5.0 mL; P(CO), 200 psi; 100 °C, 8 h. Isolated
yields in parentheses. b4 h. c30 °C.
In conclusion, a concise protocol has been developed to
synthesize di- and trisubstituted furans. The proposed me-
chanism suggests that the reaction proceeds through Pd-
catalyzed carbonylation of an aryl iodide followed by cycli-
zation of the enolized isomer of γ-propynyl-1,3-diketone via
carbon-carbon triple bond activation.
A plausible mechanism is demonstrated by the reaction of
1a, 2a, PhI, and CO in Scheme 1.5a,6a The reaction is
presumably initiated by reduction of Pd(PPh3)2Cl2 to the
Pd(0) species,12 followed by oxidative addition of aryl iodide
2a to form intermediate A, which undergoes CO insertion to
generate acylpalladium complex B. Enolized 1a, i.e., 1a0, is
then activated through coordination to the metal by its CtC
bond to form species C. Intramolecular nucleophilic attack
of the enolic oxygen across the activated CtC bond gives
Pd(II) species D. Subsequent reductive elimination affords
dialkylidene intermediate E and regenerates the Pd(0) spe-
cies.13 Spontaneous isomerization of E5a,6a forms the carbo-
nylative cycloisomerization product, i.e., 2,5-disubstituted
furan 3a. The carbonylative cycloisomerization of 1 in the
presence of 2 may also proceed through other mechanisms.
Carbonylative Sonogashira reactions of aryl iodides and term-
inal alkynes have been known to form alkynyl aryl ketones,14
and ynones can be transformed to furans under gold15 or acid16
catalysis. In our case, the target products could be produced
from the cyclization of the presumably generated ynone species
similar to 3m or 3n with a (CH2)2 linker.
Experimental Section
γ-Functionalization of 1,3-Diketones. γ-Propynyl-1,3-dike-
tones were synthesized using the reported procedures as shown
in Scheme 2.8 Treatment of 1,3-diketone I with 2 equiv of LDA
at low temperature produces double enolization dianions II/II0,
which can be further reacted with an electrophile such as
propargyl bromide (III) to form two isomeric γ-functionalized
1,3-diketone products IV and IV0.
SCHEME 2. γ-Functionalization of 1,3-Diketones
Typical Procedure for the Palladium-Catalyzed Carbonylative
Cycloisomerization Reactions. Synthesis of 3a. Pd(PPh3)2Cl2 (42
mg, 0.06 mmol), THF (5.0 mL), diketone 1a (138 mg, 1.0 mmol),
(12) Amatore, D.; Jutand, A.; M’Barki, M. Organometallics 1992, 11,
3009.
8906 J. Org. Chem. Vol. 74, No. 22, 2009

Li and Yu
JOCNote
iodobenzene 2a (204 mg, 1.0 mmol), and triethylamine (202 mg,
2.0 mmol) were successively added to a 45 mL autoclave. The
reactor was closed, purged three times with carbon monoxide,
pressurized with 200 psi CO, and then heated at 30 °C for 4 h.
The CO pressure was discharged at room temperature. All
volatiles were removed under reduced pressure, and the resul-
tant residue was purified by flash silica gel column chromato-
graphy (eluent, petroleum ether (60-90 °C)/EtOAc = 10:1 v/v)
to afford 2,5-disubstituted furan 3a as a pale yellow oil (190 mg,
7.43 (t) (2:1:2 H, Ph), 6.18 (dd, J = 2.8 Hz, 1H, furyl CH), 6.14
(dd, J = 19.4 Hz, 1 H, furyl CH), 4.26 and 3.63 (s each, 2:2 H,
2 ꢀ CH2), 2.09 (s, 3 H, CH3). 13C{1H} NMR (100 MHz, CDCl3):
δ 204.2 and 194.8 (Cq each, CdO), 147.8 and 147.7 (Cq each,
furyl C-O), 135.9 (Cq, i-C, Ph), 133.2, 128.5, and 128.3 (1:2:2
CH), 109.3 and 109.2 (1:1 CH, furyl), 43.0 and 38.2 (2 ꢀ CH2),
28.8 (CH3). HRMS (EI) calcd for C15H14O3 [Mþ] 242.0943,
found 242.0949.
1
79%). H NMR (400 MHz, CDCl3): δ 7.97 (d), 7.54 (t), and
Acknowledgment. We are grateful to the National Natur-
al Science Foundation of China (20772124, 20972157) and
the National Basic Research Program of China
(2009CB825300) for support of this research.
(13) Tamaru, Y.; Kimura, M. Handbook of Organopalladium Chemistry
for Organic Synthesis; Wiley: New York, 2002; pp 2425.
(14) (a) Ahmed, M. S. M.; Mori, A. Org. Lett. 2003, 5, 3057. (b) Liang, B.;
Huang, M. W.; You, Z. J.; Xiong, Z. C.; Lu, K.; Fathi, R.; Chen, J. H.; Yang,
Z. J. Org. Chem. 2005, 70, 6097.
Supporting Information Available: Spectroscopic data and
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Rodrıguez, F. Org. Lett. 2007, 9, 727.
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copies of H, 13C{1H} and 2D NMR spectra. This material is
available free of charge via the Internet at http://pubs.acs.org.
ꢀ
J. Org. Chem. Vol. 74, No. 22, 2009 8907