Microwave-assisted palladium-catalyzed allylation of aryl halides with homoallyl alcohols via retro-allylation

Article abstract of DOI:10.1016/j.tet.2007.03.165

The palladium-catalyzed allylation of aryl halides with homoallyl alcohols via retro-allylation proceeds at 200-250 °C in a toluene-DMF mixed solvent using microwave heating. Even at such high temperatures, the regio- and stereospecificity of the allyl tr

Full text of DOI:10.1016/j.tet.2007.03.165

Tetrahedron 63 (2007) 5200–5203
Microwave-assisted palladium-catalyzed allylation of aryl
halides with homoallyl alcohols via retro-allylation
*
Masayuki Iwasaki, Sayuri Hayashi, Koji Hirano, Hideki Yorimitsu and Koichiro Oshima
*
Department of Material Chemistry, Graduate School of Engineering, Kyoto University, Kyoto-daigaku Katsura,
Nishikyo-ku, Kyoto 615-8510, Japan
Received 17 February 2007; revised 29 March 2007; accepted 29 March 2007
Available online 4 April 2007
Abstract—The palladium-catalyzed allylation of aryl halides with homoallyl alcohols via retro-allylation proceeds at 200–250 ꢀC in a tolu-
ene–DMF mixed solvent using microwave heating. Even at such high temperatures, the regio- and stereospecificity of the allyl transfer
reaction is still satisfactory. The amount of the palladium catalyst can be reduced to 0.5 or 0.05 mol %.
Ó 2007 Elsevier Ltd. All rights reserved.
R5
R2 R1 R5
HO
1. Introduction
cat. Pd, Cs2CO3
R3
Ar
+
Ar–X
2
toluene, reflux
6–24 h
R4 R6
3
Recently we reported the use of homoallyl alcohols as the al-
lyl sources in the palladium-catalyzed allylations of organic
halides instead of allylmetal reagents (Scheme 1).1 The allyl-
ation reaction would proceed as follows: (1) oxidative
addition of aryl halide 2, (2) ligand exchange with homoallyl
alcohol 1 to afford alkoxy(aryl)palladium B, (3) retro-
allylation reaction of B providing s-allyl(aryl)palladium
C, and (4) reductive elimination to yield 3. Since the oxida-
tive addition, the ligand exchange, and the reductive elimi-
nation would occur even at ambient temperature, the
retro-allylation seems to be the rate-determining step of
this reaction. Due to the slow retro-allylation, the allylation
of aryl halides in refluxing toluene required prolonged reac-
tion time, ca. 6–24 h. Shorter reaction time is preferable to
improve the productivity of the reaction and to enable
high-throughput screenings. Here we report the micro-
wave-assisted allylation reactions of aryl halides with homo-
allyl alcohols, which proceed to completion within 15 min in
most cases.2,3
R3 R4 R6
1
2
3
Pd
1)
4)
Pd Ar
X
R5
A
R3
Pd–Ar
R4 R6
2)
C
1
R5
3)
R1
O
R1 R2
Pd–Ar
R3
O
R2
R6
R4
B
Scheme 1.
2. Results and discussions
provided 1-methallylnaphthalene (3a) in excellent yield
(Table 1, entry 1). Instead of toluene alone,1 a toluene–N,N-
dimethylformamide (DMF) mixed solvent was used to
improve the efficiency of microwave heating. Not only di-
isopropyl-substituted 1a but also dimethyl-substituted 1b
participated in the methallyl transfer reaction (entry 2).
Aryl bromides having substituents at the ortho positions
were smoothly methallylated to yield the corresponding
products in high yields (entries 3 and 4). The yields were
comparable to those previously reported.1a When the reac-
tions were performed at 250 ꢀC, the amount of the palladium
Treatment of 1-bromonaphthalene (2a) with homoallyl alco-
hol 1a in the presence of cesium carbonate at 200 ꢀC for
15 min under microwave irradiation and palladium catalysis
Keywords: Palladium; Allylation; Microwaves; Carbon–carbon bond cleav-
age.
* Corresponding authors. Tel.: +81 75 383 2441; fax: +81 75 383 2438;
e-mail addresses: yori@orgrxn.mbox.media.kyoto-u.ac.jp; oshima@
orgrxn.mbox.media.kyoto-u.ac.jp
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.03.165

M. Iwasaki et al. / Tetrahedron 63 (2007) 5200–5203
5201
Table 1. Allylation of aryl halides with homoallyl alcohols under microwave irradiation
OH
R
Pd catalyst
R
Ar
0.60 mmol Cs2CO3
1 (0.50 mmol)
toluene/DMF
+
Ar–X
MW, temp., 15 min
3
2 (0.60 mmol)
Entry
1
1a
2
Pd(OAc)2/mmol
Ligand, mmol
Tempb/ꢀC
200
3, Yieldc/%
3a, 90 (86)
Br
1a
0.025
P(p-tol)3, 0.10
2a
2
3
1b
1a
2a
0.025
0.025
P(p-tol)3, 0.10
P(p-tol)3, 0.10
200
200
3a, 94
3b, 87 (90)
2b
Br
Ph
4
1a
0.025
P(p-tol)3, 0.10
200
3c, 100 (91)
2c
Br
5
6
1a
1a
2b
2c
0.0025
0.0025
P(p-tol)3, 0.010
P(p-tol)3, 0.010
250
250
3b, 62
3c, 95
7
8
9
1a
1a
1a
0.025
0.025
0.025
P(p-tol)3, 0.10
PCy3, 0.050
PCy3, 0.050
200
200
200
3d, 41 (34)
3d, 61 (83)
3e, 53 (86)
2d
Ph
Br
2d
Br
2e
EtO
2f
10
11
1b
1a
Br
0.025
0.025
PCy3, 0.15
250
220
3f, 97d
O
EtO
2g
Cl
PCy3, 0.050
3f, 72 (79)
O
12
13
1a
1a
2g
2g
0.0025
0.00025
PCy3, 0.015
PCy3, 0.0015
250
250
3f, 86
3f, 78
14
1a
0.025
PCy3, 0.15
250
3g, 98 (70)
MeO
Cl 2h
Compound 1a: R¼iPr, 1b: R¼Me.
a
b
The reactions at 200 ꢀC and at 220 ꢀC were performed in a mixed solvent of toluene (2.0 mL) and DMF (0.20 mL). The reactions at 250 ꢀC were performed in
toluene (2.0 mL) and DMF (0.40 mL) to improve the efficiency of microwave heating further.
The yields reported in the literature1 by performing the reactions in refluxing toluene for 8 h are in parentheses.
Performed for 20 min.
c
d
catalyst could be reduced from 5 mol % of Pd(OAc)2 and
20 mol % of P(p-tol)3 to 0.5 mol % and 2 mol %, respec-
tively (entries 5 and 6). The reaction of 4-bromobiphenyl
(2d), which has no substituent at the ortho position, resulted
in a moderate yield of the coupling product (entry 7). To
improve the yield of 3d, tricyclohexylphosphine (PCy3)
was used as ligand (entry 8).1b PCy3 also allowed the use
of aryl chlorides as substrates (entries 11–14). Electron-
rich as well as electron-deficient aryl chlorides underwent
methallylation. It is worth noting that only 0.05 mol %
of Pd(OAc)2 functioned to catalyze the reaction wherein
the turnover number was 1.6ꢁ103 (entry 13). The best
Pd(OAc)2/PCy3 ratio was 1:6 at 250 ꢀC under microwave
irradiation, whereas a Pd(OAc)2/PCy3 ratio of 1:2 was
effective at 200 ꢀC (entries 8 and 9) as well as in the previous
report1b performed in refluxing toluene. When we used a 1:2
ratio at 250 ꢀC under microwave irradiation, palladium
black was likely to be generated during the heating. The pal-
ladium black would be heated extremely by microwaves,
causing the reaction vial to shatter.4
Microwave heating was applicable to the arylative ring-
opening reactions of endocyclic homoallyl alcohols (Table
2). In most cases, the yields were higher than those obtained
by the conventional heating at 140 ꢀC.1b The reactions of
aryl halides having ortho substituents proceeded at 200 ꢀC
(entries 1–3 and 5). The reaction of p-bromotoluene (2j) re-
quired heating at 250 ꢀC to attain satisfactory yield (entry 4).

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M. Iwasaki et al. / Tetrahedron 63 (2007) 5200–5203
Table 2. Arylative ring-opening reaction using microwave heating
Np
0.025 mmol Pd(OAc)2
0.10 mmol PCy3
0.60 mmol Cs2CO3
0.60 mmol Ar–X 2
O
(E)-7
(Z)-7
OH
OH
HO
R
2a
2a
R
t
t
+
Np
Bu
Bu
93%
92%
toluene/DMF
Ar
n
n
E/Z = 95:5
E/Z < 1:99
MW, temp., 15 min
threo-6a
erythro-6a
4 (0.50 mmol)
5
Np = 1-naphthyl
Entry
1
4
2
Tempa/ꢀC Yieldb/%
6a (0.50 mmol), 2a (0.60 mmol), Pd(OAc)2 (0.0025 mmol),
PCy3 (0.0050 mmol), Cs2CO3 (0.60 mmol), toluene (2.0 mL),
DMF (0.40 mL), MW, 250 °C, 15 min
HO
t
Bu
2b
200
5a, 88 (80)
4a
2b (0.30 mmol)
Cs2CO3 (0.30 mmol)
Ar
OH
Pd(OAc)2 (0.00125 mmol)
PCy3 (0.00375 mmol)
O
2
3
4a
4a
2c
200
200
5b, 76 (68)
5c, 94 (70)
toluene (2.0 mL), DMF (0.40 mL)
MW, 250 °C, 15 min
2i
threo-6b
Br
(E)-8
(0.25 mmol)
51%, only E
Ar = 2,6-Me2C6H3
4c
5
4a
4a
250
200
250
5d, 75 (65)
5a, 83
2j
Br
2b (0.60 mmol)
Cs2CO3 (0.60 mmol)
Pd(OAc)2 (0.0025 mmol)
PCy3 (0.0075 mmol)
OH
O
Ar
2k
Cl
toluene (2.0 mL), DMF (0.40 mL)
MW, 250 °C, 15 min
erythro-6b
(Z)-8
HO
i
Pr
(0.50 mmol)
61%, only Z
6
2b
5e, 36 (20)
4b
Scheme 2.
HO
OH
7d
2b
250
5f, 47 (59)
t
0.025 mmol Pd(OAc)2
0.10 mmol P(p-tol)3
0.60 mmol Cs2CO3
Bu
4c
i
Pr
i
Pr
Ar
1a (0.50 mmol)
a
The reactions at 200 ꢀC were performed in a mixed solvent of toluene
(2.0 mL) and DMF (0.20 mL). The reactions at 250 ꢀC were performed
in toluene (2.0 mL) and DMF (0.40 mL).
dimethylnaphthalene (2.0 mL)
N-methylpyrrolidinone (0.20 mL)
+
Ar–X
3b
2b (0.60 mmol)
The yields reported in the literature1b by performing the reactions in re-
fluxing xylene for 12 or 24 h are in parentheses.
0.15 mmol of PCy3 was used.
b
MW heating,
200 °C, 15 min : 90%
classical heating, 200 °C, 15 min : <5%
classical heating, 110 °C, 11 h : 65%
c
d
0.050 mmol of PCy3 was used.
Scheme 3.
Unfortunately, the reactions of 4b and 4c at 250 ꢀC were still
unsatisfactory by using microwave heating.
3. Conclusion
Microwave heating promotes the palladium-catalyzed allyl-
ation of aryl halides with homoallyl alcohols. The micro-
wave heating easily allowed us to perform the reactions at
200–250 ꢀC. Even at such high temperatures, the regio-
and stereospecificity of the allyl transfer reaction are excel-
lent. In addition, the amount of the palladium catalyst can be
reduced to 0.5 or 0.05 mol %.
Treatment of 2a with threo-6a in the presence of 0.5 mol %
of palladium acetate and 1.0 mol % of PCy3 at 250 ꢀC
afforded (E)-1-crotylnaphthalene (E)-7 stereoselectively
(Scheme 2). Similar treatment with erythro-6a afforded
(Z)-7 exclusively. Stereospecificity was thus observed even
at 250 ꢀC. Stereospecificity was also observed in the reac-
tions of alkenylcyclohexanol, threo- and erythro-6b.
It was reported that microwave heating is not only a simple
heating method but also can have so-called nonthermal
microwave effects.2,5 This was also the case for the present
reaction (Scheme 3). The reaction of 1a with 2b completed
smoothly within 15 min in a dimethylnaphthalene (bp: ca.
260 ꢀC)/N-methylpyrrolidinone (bp: 202 ꢀC) mixed solvent
by using microwave heating at 200 ꢀC, whereas the same
reaction was sluggish by classical heating for 15 min at
200 ꢀC. We cannot explain how nonthermal microwave
effects operated. Possible nonthermal microwave effects
may include: (1) microwave-assisted activation of the polar
transition state of the retro-allylation step, (2) preventing the
formation of palladium black, and (3) intervention of local-
ized microscopic high temperatures.
4. Experimental section
4.1. General
Unless otherwise noted, all the reactions were carried out
using a focused microwave unit (Biotage InitiatorÔ). The
maximum irradiation power is 400 W. Each reaction was
run in a 5-mL glass pressure vial, which is a commercially
available vial specially for the Biotage InitiatorÔ. It took
2 min and 6 min to reach 200 ꢀC and 250 ꢀC, respectively.
After reaching the indicated temperatures, controlled micro-
wave irradiation started and continued for 15 min, keeping
the reaction temperature constant. The classical heating at
200 ꢀC shown in Scheme 3 was performed in a Kugelrohr

M. Iwasaki et al. / Tetrahedron 63 (2007) 5200–5203
5203
distillation apparatus (Shibata, GTO-250RS). With the appa-
ratus, it took 5 min to reach 200 ꢀC and additional heating
continued for 15 min. The classical heating at 110 ꢀC shown
in Scheme 3 was done in an oil bath.
4.3.1. 2,2-Dimethyl-6-(2,6-dimethylphenyl)-7-octen-3-
1
one (5f). IR (neat) 2967, 1705, 1453, 1367, 769 cmꢂ1; H
NMR (CDCl3) d 1.05 (s, 9H), 2.02–2.09 (m, 1H), 2.14–
2.22 (m, 1H), 2.32 (s, 6H), 2.34–2.47 (m, 2H), 3.84–3.89
(m, 1H), 5.05 (dt, J¼10.5, 2.0 Hz, 2H), 6.08 (ddd, J¼17.5,
10.5, 5.5 Hz, 1H), 6.96–7.02 (m, 3H); 13C NMR (CDCl3)
d 21.67, 26.54, 26.59, 34.54, 43.27, 44.25, 114.47, 126.28,
129 (br s), 136.95, 139.51, 140.29, 215.87. Anal. Calcd for
C18H26O: C, 83.67; H, 10.14%. Found: C, 83.66; H, 10.09%.
1H NMR (300 MHz and 500 MHz) and 13C NMR (75.3 MHz
and 125.7 MHz) spectra were taken on Varian Mercury 300
and UNITY INOVA 500 spectrometers and were recorded
in CDCl3. Chemical shifts (d) are in parts per million relative
to tetramethylsilane at 0.00 ppm for 1H and relative to CDCl3
at 77.0 ppm for 13C unless otherwise noted. IR spectra were
determined on a SHIMADZU FTIR-8200PC spectrometer.
TLC analyses were performed on commercial glass plates
bearing 0.25-mm layer of Merck Silica gel 60F254. Silica
gel (Wakogel 200 mesh) was used for column chromato-
graphy. Elemental analyses were carried out at the Elemental
Analysis Center of Kyoto University.
Acknowledgements
This work is supported by Grants-in-Aid for Scientific Re-
search and COE Research from the Ministry of Education,
Culture, Sports, Science, and Technology, Japan. K.H.
acknowledges JSPS for financial support.
Unless otherwise noted, materials obtained from commer-
cial suppliers were used without further purification. Tolu-
ene, DMF, and N-methylpyrrolidinone were purchased
from Wako Pure Chemical Co. Dimethylnaphthalene (mix-
ture of regioisomers) was obtained from TCI. Toluene was
stored over slices of sodium. Dimethylnaphthalene, DMF,
and N-methylpyrrolidinone were used as received. Tri(p-
tolyl)phosphine and cesium carbonate were purchased from
Wako Pure Chemical Co. Palladium acetate and tricyclo-
hexylphosphine were obtained from TCI and Acros, respec-
tively. The homoallyl alcohols 1, 4, and 6 were prepared
according to the literature.1b
References and notes
1. (a) Hayashi, S.; Hirano, K.; Yorimitsu, H.; Oshima, K. J. Am.
Chem. Soc. 2006, 128, 2210–2211; (b) Iwasaki, M.; Hayashi,
S.; Hirano, K.; Yorimitsu, H.; Oshima, K. J. Am. Chem. Soc.
2007, 129, 4099–4104.
2. Reviews for microwave-assisted organic reactions: (a)
Microwave Assisted Organic Synthesis; Tierney, J. P.,
€
Lidstrom, P., Eds.; Blackwell: Victoria, 2005; (b) Larhed, M.;
Olofsson, K. Microwave Methods in Organic Synthesis;
Springer: Berlin, 2006; (c) Roberts, B. A.; Strauss, C. R. Acc.
Chem. Res. 2005, 38, 653–661; (d) Tokuyama, H.; Nakamura,
M. J. Synth. Org. Chem. Jpn. 2005, 63, 523–538; (e) de la
Hoz, A.; Diaz-Ortiz, A.; Moreno, A. Chem. Soc. Rev. 2005,
34, 164–178; (f) Kappe, C. O. Angew. Chem., Int. Ed. 2004,
4.2. Typical procedure
The reaction of entry 1 in Table 1 is representative. Cesium
carbonate (0.20 g, 0.60 mmol), palladium acetate (5.6 mg,
0.025 mmol), and tri(p-tolyl)phosphine (30 mg, 0.10 mmol)
were placed in a 5-mL glass pressure vial. The vial was
flushed with argon and sealed with a PTFE–silicon septum.
Toluene (2.0 mL) and DMF (0.20 mL) were added, and the
mixture was stirred for 1 min. Homoallyl alcohol 1a (85 mg,
0.50 mmol)and1-bromonaphthalene(2a, 83 mL, 0.60 mmol)
were added. The suspension was heated at 200 ꢀC with stir-
ring for 15 min in the microwave reactor. The mixture was
then cooled to room temperature. Hydrochloric acid (1 M,
3 mL) was added. The organic layer formed was then washed
with brine (5 mL), and dried over anhydrous sodium sulfate.
The solvent was evaporated. Silica gel column purification
with hexane as an eluent afforded 1-methallylnaphthalene
(3a, 82 mg, 0.45 mmol) in 90% yield.
€
43, 6250–6284; (g) Lidstrom, P.; Tierney, J.; Wathey, B.;
Westman, J. Tetrahedron 2001, 57, 9225–9283; (h) Caddick,
S. Tetrahedron 1995, 51, 10403–10432; (i) Mingos, D. M. P.;
Baghurst, D. R. Chem. Soc. Rev. 1991, 20, 1–47.
3. Microwave-assisted carbon–carbon bond cleavage has rarely
been reported: (a) Tanner, D. D.; Kandanarachchi, P.; Ding,
Q.; Shao, H.; Vizitiu, D.; Franz, J. A. Energy Fuels 2001, 15,
197–204; (b) Ahn, J.-A.; Chang, D.-H.; Park, Y. J.; Yon, Y. R.;
Loupy, A.; Jun, C.-H. Adv. Synth. Catal. 2006, 348, 55–58.
4. Caution: the black precipitate resulted in extreme microwave
absorption that caused reaction vial to shatter. Although the mi-
crowave reactor is explosion-proof, proper precautions should
be taken.
5. (a) Garbacia, S.; Desai, B.; Lavastre, O.; Kappe, C. O. J. Org.
Chem. 2003, 68, 9136–9139; (b) Perreux, L.; Loupy, A.
Tetrahedron 2001, 57, 9199–9223; (c) Kuhnert, N. Angew.
Chem., Int. Ed. 2002, 41, 1863–1866; (d) Strauss, C. R.
Angew. Chem., Int. Ed. 2002, 41, 3589–3590.
4.3. Characterization data
Spectral data for 3, 5, 7, and 8 were found in the literature1,6
except for 5f.
6. For 3c: Thatia, T.; Jayanth, T.; Jeganmohan, M.; Cheng, C.-H.
Org. Lett. 2005, 7, 2921–2924.