Palladium-catalyzed cyclocotrimerization of propargyl alcohols with aryl halides

Article abstract of DOI:10.3987/COM-05-S(K)51

Tertiary propargyl alcohols react with aryl halides in the presence of K₂CO₃ and a catalytic amount of palladium(0) complex affording 2:1 cyclocotrimerization products, 3-benzylidene-2,3-dihydrofuranes (3).

Full text of DOI:10.3987/COM-05-S(K)51

HETEROCYCLES, Vol. 66, 2005
621
HETEROCYCLES, Vol. 66, 2005, pp. 621 – 625. © The Japan Institute of Heterocyclic Chemistry
Received, 6th September, 2005, Accepted, 11th October, 2005, Published online, 14th October, 2005. COM-05-S(K)51
PALLADIUM-CATALYZED CYCLOCOTRIMERIZATION OF
PROPARGYL ALCOHOLS WITH ARYL HALIDES
Shuichi Oi,* Hideki Orihara, Hiroshi Kawai, and Yoshio Inoue*
Department of Biomolecular Engineering, Graduate School of Engineering,
Tohoku University, 6-6-11 Aramaki-Aoba, Aoba-ku, Sendai 980-8579, Japan
E-mail: oishu@aporg.che.tohoku.ac.jp
Abstract – Tertiary propargyl alcohols react with aryl halides in the presence of
K
2
3
CO and a catalytic amount of palladium(0) complex affording 2:1 cyclocotri-
merization products, 3-benzylidene-2,3-dihydrofuranes (3).
Palladium-catalyzed reaction of terminal acetylenes with aryl halides, referred to as the Sonogashira
1
,2
coupling reaction, has been recognized to be a good synthetic method for arylacetylenes. The
Sonogashira coupling reaction has been typically performed in the presence of copper salts and
appropriate organic bases such as tertiary amines. There has been some reports that the reaction proceeds
3
-10
in the absence of copper salts when appropriate base or ligand is used.
palladium-catalyzed reaction of tertiary propargyl alcohols with aryl halides in the presence of inorganic
bases such as K CO gives not the Sonogashira coupling products but 2:1 cyclocotrimerization products,
-benzylidene-2,3-dihydrofuranes (3) (Scheme 1).
We have found that the
2
3
3
O
Pd(PPh ) , K CO
3
4
2
3
Ar
OH
+
Ar
X
DMF, 100°C, 6 h
OH
1
2
3
Scheme 1
When 2-methyl-3-butyn-2-ol (1a, 10.0 mmol) and iodobenzene (2a, 5.0 mmol) were reacted in the
presence of 0.1 mmol of Pd(PPh and 10 mmol of triethylamine in DMF at 100°C for 6 h, the
3 4
)
Sonogashira coupling product (4a) was obtained predominantly together with a small amount of the
cyclocotrimerization product (3a) (Table 1, Entry 1). On the contrary, the use of inorganic bases reversed

622
HETEROCYCLES, Vol. 66, 2005
Table 1. Cyclocotrimerization of 2-methyl-3-butyn-2-ol (1a) with iodobenzene (2a).
NOE
CH CH
3
3
H
Catalyst, Base
O
+
OH
Ph
OH
+
Ph
I
Ph
Solvent, 100°C, 6 h
OH
4
a
3
a
1
a
2a
Yield (%)
Entry
Catalyst
Base
Solvent
3
a
4a
48
4
0
10
0
8
0
0
0
1
2
3
4
5
6
7
8
9
Pd(PPh
Pd(PPh
Pd(PPh
Pd(PPh
3
3
3
3
)
)
)
)
4
4
4
4
Et
3
N
DMF
DMF
DMF
9
K
3
PO
4
44
43
31
11
24
22
32
21
0
K
K
2
CO
CO
3
2
3
DMSO
THF
acetonitrile
toluene
DMF
Pd(PPh3)4
Pd(PPh
Pd(PPh3)4
Pd(dba) /2PPh
Pd(dba) /2P(Bu-n)
Pd(dba) /2P(OEt)
2
K CO3
3
)
4
K
2
CO
3
2
K CO3
2
3
K
K
2
CO
CO
3
2
3
2
3
DMF
DMF
DMF
1
1
0
1
2
K CO3
0
0
2
3
Pd(dba)
2
/dppe
K
2
CO
3
32
the selectivity of the products. The reaction using K
of 4a (Entry 2). Moreover, the use of K CO resulted in the exclusive formation of 3a in 43% yield (Entry
). The geometry of 3-benzylidene moiety of 3a was determined to be E by NOE experiments. It is noted
that the reaction gave only E-form selectively. The reaction was then examined in various solvents
Entries 3-7). Among the solvent examined, DMF showed the best result. The combination of Pd(dba)
3 4
PO as base gave 44% yield of 3a and only 4% yield
2
3
3
(
2
with some phosphine ligands also exhibited the catalytic activity (Entries 8-11), however, the yields were
lower than the reaction with Pd(PPh ) .
3
4
Using the optimized reaction conditions (Table 1, Entry 3), reactions of propargyl alcohols with various
aryl halides were examined (Table 2). A primary propargyl alcohol (1b) did not react with iodobenzene
under the reaction conditions and a secondary propargyl alcohol (1c) gave only the Sonogashira product
(
4b) (Entries 1 and 2). Although a reason has not yet been clear, the cyclocotrimerization thus proved to
be particular to the tertiary propargyl alcohols such as 1a (Entry 3). The reaction of 1a with
bromobenzene gave the product in a better yield of 65% than that with iodobenzene, while the reaction
with chlorobenzene did not give the product (Entries 4 and 5). Bromobenzenes substituted with either
electron-donating or electron-withdrawing group (2d-f) reacted with 1a affording the products in
moderate yields (Entries 6-8). Bromonaphtharenes (2g and 2h) also reacted well with 1a affording the
products in good yields (Entries 9 and 10).

HETEROCYCLES, Vol. 66, 2005
623
Table 2. Cyclocotrimerization of propargyl alcohols (1) with aryl halides (2).
R R2
1
1
R R2
1
2
R R
OH
O
Pd(PPh ) , K CO
Ar
3
4
2
3
+
OH
+
Ar
X
Ar
DMF, 100°C, 6 h
OH
R1
R2
4
3
1
2
1
2
Yield (%)
Entry
R , R
Ar-X
3
0
0
4
1
2
1
2
3
4
5
6
7
8
9
R = R = H (1b)
Ph-I (2a)
0
1
2
R = H, R = Me (1c)
2a
2a
23 (4b)
1
2
R = R = Me (1a)
43 (3a)
65 (3a)
0
45 (3b)
22 (3c)
50 (3d)
59 (3e)
56 (3f)
0
5
0
8
0
1a
1a
1a
1a
1a
1a
1a
Ph-Br (2b)
Ph-Cl (2c)
4-Me-C
6
H
4
-Br (2d)
4-MeO-C
6
4
H -Br (2e)
4-F-C H -Br (2f)
trace
6
4
1-Naphthyl-Br (2g)
2-Naphthyl-Br (2h)
5
6
1
0
Although there is little experimental evidence at present to determine the exact reaction pathway for the
cyclocotrimerization, a possible reaction mechanism is shown in Scheme 2. A palladium(0) complex
reacts with an aryl halide to give an arylpalladium(II) species. Sequential insertion of two propargyl
O
Ar
OH
Ar
X
Pd(0)
O
Pd
Ar Pd
X
Ar
OH
6
OH
HX
OH
Pd X
OH
Ar
Ar
Pd X
OH
5
OH
Scheme 2. Possible reaction mechanism

624
HETEROCYCLES, Vol. 66, 2005
alcohols to the palladium-carbon bond affords the alkenylpalladium intermediate (5). Cyclization of 5
accompanied by elimination of HX then gives the palladacycle (6). The cyclocotrimerization product (3)
is formed through reductive elimination from 6, with the simultaneous regeneration of palladium(0)
complex.
In conclusion, palladium-catalyzed cyclocotrimerization of tertiary propargyl alcohols with aryl halides is
2 3
described. The use of inorganic bases such as K CO is important to promote the cyclization. The reaction
affords 3-benzylidene-2,3-dihydrofuranes in one step.
EXPERIMENTAL
General. Infrared (IR) spectra were recorded on JASCO FT/IR-350 Fourier transform infrared
spectrophotometer. NMR spectra were recorded on Bruker AC-250, spectrometer. EIMS spectra were
measured on Shimadzu GCMS-QP5050. All reactions were performed in Schlenk tubes under a N
atmosphere. Propargyl alcohols (1a-c), aryl halides (2a-h), Pd(PPh , and anhydrous DMF was
2
purchased and used as received. K CO was dried at 250 °C under reduced pressure and stored under N .
2
3 4
)
2
3
Flash chromatographies were performed using spherical silica gel (40-100 μm, Kanto Chemical).
Elemental analyses were performed by the Microanalytical Laboratory of the Institute for Chemical
Reaction Science, Tohoku University.
General procedure for the reaction of propargyl alcohols with aryl halides. A mixture of propargyl
alcohol (10.0 mmol), aryl halide (5.0 mmol), K
mmol) in 15 mL of dried and degassed DMF was stirred at 100 °C for 6 h. The reaction mixture was
diluted with 30 mL of Et O, washed with water (30 mL x 3), and dried over MgSO . After the solvent
2 3 3 4
CO (1.38 g, 10.0 mmol), and Pd(PPh ) (116 mg, 0.10
2
4
was removed in vacuo, the residue was purified by silica gel flash chromatography (hexane-EtOAc, 10:1)
to give the product. All reactions were performed using the same procedure.
1
3
1
2
a. Colorless oil. H-NMR (CDCl ): δ (ppm) 7.29-7.32 (m, 5H), 6.03 (s, 1H), 5.68 (s, 1H), 2.11 (s, 1H),
3
1
3
.47 (s, 6H), 1.45 (s, 6H). C-NMR (CDCl ): δ(ppm) 171.4, 150.8, 138.7, 128.4, 127.4, 110.9, 95.6, 89.8,
3
-1
8.1, 27.9. IR (neat): 3400, 2960, 1600, 1500, 1380 cm . MASS (EI): m/z 115, 143, 185, 211, 226, 244
+
(
M ). Anal. Calcd for C16
H
20
O
2
: C, 78.65; H, 8.25. Found: C, 78.65; H, 8.01.
1
3
1
1
b. Colorless oil. H-NMR (CDCl
3
): δ (ppm) 7.19 (d, J = 5.1 Hz, 2H), 7.09 (d, J = 5.1 Hz, 2H), 5.99 (s,
1
3
H), 5.63 (s, 1H), 2.32 (s, 1H), 1.44 (s, 6H), 1.41 (s, 6H). C-NMR (CDCl
3
): δ(ppm) 170.8, 149.8, 135.8,
-1
29.7, 129.2, 127.3, 110.8, 95.6, 89.7, 69.3, 28.0, 27.9, 21.1. IR (neat): 3400, 2980, 1600, 1510 cm .
+
MASS (EI): m/z 105, 157, 161, 185, 199, 225, 243, 258 (M ). Anal. Calcd for C H O : C, 79.03; H,
1
7
22
2
8
3
1
.58. Found: C, 78.92; H, 8.38.
1
c. Colorless oil. H-NMR (CDCl
3
): δ (ppm) 7.35 (d, J = 8.8 Hz, 2H), 6.84 (d, J = 8.8 Hz, 2H), 6.19 (s,
1
3
H), 5.67 (s, 1H), 3.36 (s, 3H), 1.96 (s, 1H), 1.39 (s, 6H), 1.37 (s, 6H). C-NMR (CDCl ): δ(ppm) 170.3,
3

HETEROCYCLES, Vol. 66, 2005
625
1
1
56.7, 147.8, 127.6, 126.9, 126.5, 126.1, 109.4, 94.5, 88.2, 67.8, 53.3, 26.7. IR (neat): 3370, 2970, 1600,
-1
+
510, 1380, 1250, 1030 cm . MASS (EI): m/z 121, 173, 187, 215, 241, 259, 274 (M ). Anal. Calcd for
C
17
H
22
O
3
: C, 74.42; H, 8.08. Found: C, 74.32; H, 7.96.
1
3
1
9
2
3
d. Colorless oil. H-NMR (CDCl ): δ (ppm) 7.32-7.24 (m, 2H), 7.07-6.95 (m, 2H), 5.96 (s, 1H), 5.63 (s,
3
13
H), 1.68 (s, 1H), 1.46 (s, 6H), 1.44 (s, 6H). C-NMR (CDCl ): δ(ppm) 128.8, 128.7, 115.3, 115.0, 109.6,
3
-1
5.1, 89.8, 69.3, 28.0, 27.9. IR (neat): 3410, 2980, 1600, 1510, 1230 cm . MASS (EI): m/z 157, 161, 189,
+
03, 229, 247, 262 (M ). Anal. Calcd for C16
H
19
O
2
F: C, 73.26; H, 7.30. Found: C, 73.12; H, 7.41.
1
e. Colorless oil. H-NMR (CDCl ): δ (ppm) 8.03 (d, J = 5.2 Hz, 1H), 7.82 (d, J = 6.2 Hz, 1H), 7.70 (d, J
3
=
8.3 Hz, 1H), 7.50-7.40 (m, 4H), 6.23 (s, 1H), 5.78 (s, 1H), 2.15 (s, 1H), 1.56 (s, 6H), 1.43 (s, 6H).
1
3
C-NMR (CDCl ): δ(ppm) 170.8, 152.9, 136.0, 133.7, 131.7, 128.5, 126.5, 125.7, 125.6, 125.5, 124.4,
3
-
1
1
2
3
1
1
7
8
08.1, 95.7, 89.3, 69.3, 28.3, 27.9. IR (neat): 3400, 1620, 800 cm . MASS (EI): m/z 141, 165, 193, 207,
+
35, 261, 279, 294 (M ). Anal. Calcd for C20
H
22
O
2
: C, 81.60; H, 7.53. Found: C, 81.75; H, 7.56.
1
f. Colorless oil. H-NMR (CDCl
3
): δ (ppm) 7.77-7.62 (m, 5H), 7.43-7.35 (m, 2H), 6.14 (s, 1H), 5.81 (s,
1
3
H), 2.22 (s, 1H), 1.48 (s, 12H). C-NMR (CDCl
3
): δ(ppm) 170.8, 151.3, 136.3, 133.8, 131.7, 127.8,
27.64, 127.55, 126.3, 126.04, 125.57, 125.1, 111.0, 95.7, 90.0, 69.4, 28.1, 27.9. IR (neat): 3400, 1620,
-1
+
50 cm . MASS (EI): m/z 141, 165, 193, 207, 235, 261, 279, 294 (M ). Anal. Calcd for C20
1.60; H, 7.53. Found: C, 81.38; H, 7.22.
22 2
H O : C,
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