Synthesis of (2-arylethylidene)cyclobutanes by palladium-catalyzed reactions of aryl halides with homoallyl alcohols bearing a trimethylene group at the allylic position

Article abstract of DOI:10.1055/s-0029-1217703

Treatment of aryl bromides with homoallyl alcohols bearing a trimethylene group at the allylic position in the presence of cesium carbonate under palladium catalysis affords (2-arylethylidene) cyclobutanes selectively. The selective formation of the alkylidenecyclobutane skeleton results from regiospecific retroallylation of the homoallyl alcohols, which accompanies the transposition of the double bonds. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1217703

LETTER
2177
Synthesis of (2-Arylethylidene)cyclobutanes by Palladium-Catalyzed
Reactions of Aryl Halides with Homoallyl Alcohols Bearing a Trimethylene
Group at the Allylic Position
Synthesis of
A
lkyliden
a
ecyclobuta
s
Department of Material Chemistry, Graduate School of Engineering, Kyoto University, Kyoto-daigaku Katsura, Nishikyo,
Kyoto 615-8510, Japan
Fax +81(75)3832438; E-mail: yori@orgrxn.mbox.media.kyoto-u.ac.jp; E-mail: oshima@orgrxn.mbox.media.kyoto-u.ac.jp
Received 12 May 2009
regioselective formation of alkylidenecyclobutanes with-
Abstract: Treatment of aryl bromides with homoallyl alcohols
out generating the regioisomer, (1-trimethylene-2-prope-
nyl)arene (Step D). Advantageously, alcohols 2 were
bearing a trimethylene group at the allylic position in the presence
of cesium carbonate under palladium catalysis affords (2-aryl-
ethylidene)cyclobutanes selectively. The selective formation of the
readily prepared in a few steps from commercially avail-
alkylidenecyclobutane skeleton results from regiospecific retro- able ethyl cyclobutanecarboxylate.8
allylation of the homoallyl alcohols, which accompanies the trans-
position of the double bonds.
Ar
Key words: palladium, methylenecyclobutanes, homoallyl alco-
hols, cleavage reactions, allylation
ArX
1
R
Pd
O
3–5
A
D
EtO
Alkylidenecyclobutanes are interesting due to their
strained skeleton and reactive double bonds and are hence
useful compounds in organic synthesis.1 Uncatalyzed2
and catalyzed3 cycloaddition reactions of allenes with ac-
tivated alkenes represent the most useful conventional
method for the synthesis of alkylidenecyclobutanes. How-
ever, the use of activated alkenes, such as acrylonitrile and
styrene, limits the scope of the reactions. The Wittig alky-
lidenation reactions of cyclobutanone are usually effec-
tive, unfortunately they can suffer from moderate yields.4
Titanium reagents have been used in the preparation of
alkylidenecyclobutanes, although the strong oxophilicity
of the reagents leads to limited functional group compati-
bility.1b,5 For these reasons, a new, efficient method for
constructing this intriguing strained skeleton has been
awaited.
Ar
Ar
Pd
Pd
a few
steps
X
R
OH
B
Ar
Pd
C
Ph
Ph
R
O
O
2
Ph
Ph
R
Ph
Ph
Scheme 1 Proposal for the construction of alkylidenecyclobutanes
Treatment of 2-bromonaphthalene (1a) with alcohol 2a in
the presence of cesium carbonate and catalytic amounts of
palladium acetate and tri(4-tolyl)phosphine in toluene at
reflux, provided alkylidenecyclobutane 3a in 94% yield
(Table 1, entry 1). Sterically demanding compounds 1b
and 1c also participated in the reaction (entries 2 and 3),
as did electron-deficient aryl bromides 1f and 1g, which
reacted smoothly to afford the corresponding products in
excellent yields (entries 6 and 7). The reaction of aryl bro-
mide 1h, bearing an electron-donating 4-methoxy group,
provided 3h in 66% yield (entry 8). Carbon–carbon bond
formation took place predominantly at the brominated
carbon of 1i, leaving the chloro moiety intact (entry 9).
The reaction of ethyl 2-bromobenzoate (1j) gave rise to a
modest yield of product 3j (entry 10). The reactions of
3,5-dimethylbromobenzene (1d) and 2-bromoanisole (1k)
yielded the corresponding alkylidenecyclobutanes 3d and
3k, respectively, although the products were contaminat-
ed with 5% of regioisomers 6 (entries 4 and 11). Vinyl
bromide 1l also underwent the reaction to yield the corre-
sponding 1,4-diene (entry 12). The methyl group of 2a
was not essential, since phenyl-substituted 2b as well as
We have been interested in palladium-catalyzed reactions
of aryl halides with homoallyl alcohols that result in high-
ly regiospecific generation of allylarenes.6,7 We envi-
sioned that the allylation reaction of aryl halides would be
applicable to the synthesis of alkylidenecyclobutanes by
using homoallyl alcohol 2 bearing a trimethylene group at
the allylic position (Scheme 1 and Table 1). After oxida-
tive addition (Step A), alkoxide–halide exchange between
the arylpalladium halide and 2 would occur to yield
aryl(alkoxy)palladium (Step B). The subsequent retro-
allylation of the palladium alkoxide would afford
aryl(3-trimethylene-2-propenyl)palladium regioselective-
ly, whilst releasing benzophenone (Step C). Finally, im-
mediate reductive elimination would lead to the
SYNLETT 2009, No. 13, pp 2177–2179
x
x
.x
x
.2
0
0
9
Advanced online publication: 15.07.2009
DOI: 10.1055/s-0029-1217703; Art ID: U05009ST
© Georg Thieme Verlag Stuttgart · New York

2178
M. Iwasaki et al.
LETTER
Table 1 Synthesis of (2-Arylethylidene)cyclobutanes
of methylenecyclopropane (40.9 kcal/mol) was calculated
to be much larger than that of cyclopropane (27.5 kcal/
mol). The retro-allylation of 7 would thus require a higher
activation-energy than for 2. Heating the reaction mixture
at 250 °C under microwave irradiation afforded the de-
sired product 8 exclusively, albeit in modest yield (entry
2).
5 mol% Pd(OAc)2
20 mol% P(4-tolyl)3
1.4 equiv Cs2CO3
OH
Ar
+
ArBr
Ph
Ph
R
toluene, reflux
R
1
2
3–5
(1.2 equiv)
Entry Ar
1
R
2
Time 3–5 Yield
(h)
13
13
9
(%)
94
94
67
61a
70
87
97
66
66
53
71a
60
75
82
78
62
87
Table 2 Synthesis of (2-Arylethylidene)cyclopropanes
5 mol% Pd(OAc)2
1
2
3
4
5
6
7
8
9
2-naphthyl
1-naphthyl
2-PhC6H4
1a
1b
1c
1d
1e
1f
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Ph
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2b
2b
2c
2c
3a
3b
3c
3d
3e
3f
20 mol% ligand
1-NpBr
1-Np
1.4 equiv Cs2CO3
1b
+
OH
1-Np
+
toluene
9
8
Ph
Ph
3,5-Me2C6H3
4-PhC6H4
9
7
(1.2 equiv)
9
Entry Heating
Time (h) Ligand
8 (%) 9 (%)
4-CF3C6H4
4-EtO2CC6H4
4-MeOC6H4
4-ClC6H4
10
13
13
10
12
12
10
11
16
16
18
18
1
2
3
conventional 11 h (4-tolyl)3P
(110 °C)
<26
41
0
0
1g
1h
1i
3g
3h
3i
microwave
(250 °C)
15 min
15 min
(4-tolyl)3P
0
microwave
(250 °C)
Me3P
59
10 2-EtO2CC6H4
11 2-MeOC6H4
12 (CH2=CBrPh)
13 2-naphthyl
1j
3j
1k
1l
3k
3l
Interestingly, the use of trimethylphosphine, instead of
tri(4-tolyl)phosphine, reversed the regioselectivity and 9
was solely obtained (entry 3). We assume that the small
and electron-donating trimethylphosphine retarded the
smooth reductive elimination from intermediate 10
(Scheme 2). This reductive elimination would lead to the
isomerization of 10 to the thermodynamically more stable
11, from which reductive elimination would occur. Unfor-
tunately, such a drastic change in regioselectivity was not
observed in the reactions of 2.
1a
1g
1h
1a
1g
4a
4g
4h
5a
5g
14 4-EtO2CC6H4
15 4-MeOC6H4
16 2-naphthyl
Ph
Ph
H
17 4-EtO2CC6H4
H
a Contaminated with regioisomer 6 (5%).
1-Np
1-Np
Pd
Pd
PMe3
Ar
8
9
R
PMe3
11
6
10
Scheme 2 Isomerization of (3-ethylene-2-methyl-2-propenyl)palla-
2c, bearing no substituents on the vinyl group, also under-
went the reaction (entries 13–17).
In summary, we have developed a new access to (2-aryl-
ethylidene)cyclobutanes, using the palladium-catalyzed
retro-allylation of homoallyl alcohols 2 as a method for
the transposition of the double bond.11
We attempted the synthesis of alkylidenecyclopropane by
applying the present strategy (Table 2). However, the re-
action with 7 under the standard reaction conditions was
sluggish (entry 1). The rigid cyclopropane moiety of alco-
hol 7 would hamper the retro-allylation step, probably due
to the wider, fixed C(hydroxylated)–C(cyclopropyl)–
C(vinylic) angle (calculated to be 114°)9 compared to the
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
calculated
C(hydroxylated)–C(cyclobutyl)–C(vinylic)
angle of 2a (110°),9 as well as the typical unstrained C–
C(sp3)–C angle (~110°). The high strain-energy of meth-
ylenecyclopropane skeleton is also responsible for the dif-
ficulty. According to the literature,10 the strain-energy of
methylenecyclobutane (26.9 kcal/mol) is close to that of
cyclobutane (26.5 kcal/mol). In contrast, the strain-energy
Acknowledgment
This work was supported by Grants-in-Aid for Scientific Research
and GCOE Research from JSPS. M.I. acknowledges JSPS for finan-
cial support. H.Y. thanks Eisai and Kyoto University for financial
support.
Synlett 2009, No. 13, 2177–2179 © Thieme Stuttgart · New York

LETTER
Synthesis of Alkylidenecyclobutanes
2179
(7) For studies from other groups, see: (a) Berthiol, F.; Doucet,
H.; Santelli, M. Synthesis 2005, 3589. (b) Oh, C. H.; Jung,
S. H.; Bang, S. Y.; Park, D. I. Org. Lett. 2002, 4, 3325.
(8) Hama, T.; Hartwig, J. F. Org. Lett. 2008, 10, 1545; see also
Supporting Information.
References and Notes
(1) (a) Chen, L.; Shi, M.; Li, C. Org. Lett. 2008, 10, 5285; and
references cited therein. (b) Fujiwara, T.; Iwasaki, N.;
Takeda, T. Chem. Lett. 1998, 27, 741; and references cited
therein.
(2) For historically important examples, see: (a) Alder, K.;
Ackermann, O. Chem. Ber. 1957, 90, 1697. (b) Cripps,
H. N.; Williams, J. K.; Sharkey, W. H. J. Am. Chem. Soc.
1959, 81, 2723.
(3) For selected examples, see: (a) Hosomi, A.; Miura, K. Bull.
Chem. Soc. Jpn. 2004, 77, 835. (b) Hojo, M.; Murakami, C.;
Nakamura, S.; Hosomi, A. Chem. Lett. 1998, 27, 331.
(c) Narasaka, K.; Hayashi, K.; Hayashi, Y. Tetrahedron
1994, 50, 4529. (d) Luzung, M. R.; Mauleón, P.; Toste, F. D.
J. Am. Chem. Soc. 2007, 129, 12402.
(4) (a) Wu, Z.; Nguyan, S. T.; Grubbs, R. H.; Ziller, J. W. J. Am.
Chem. Soc. 1995, 117, 5503. (b) Vedejs, E.; Meier, G. P.;
Snoble, K. A. J. J. Am. Chem. Soc. 1981, 103, 2823.
(5) Morlender-Vais, N.; Solodovnikova, N.; Marek, I. Chem.
Commun. 2000, 1849.
(6) (a) Hayashi, S.; Hirano, K.; Yorimitsu, H.; Oshima, K.
J. Am. Chem. Soc. 2006, 128, 2210. (b) Iwasaki, M.;
Hayashi, S.; Hirano, K.; Yorimitsu, H.; Oshima, K. J. Am.
Chem. Soc. 2007, 129, 4463. (c) Iwasaki, M.; Hayashi, S.;
Hirano, K.; Yorimitsu, H.; Oshima, K. Tetrahedron 2007,
63, 5200. (d) Hayashi, S.; Hirano, K.; Yorimitsu, H.;
Oshima, K. J. Am. Chem. Soc. 2007, 129, 12650.
(e) Hayashi, S.; Hirano, K.; Yorimitsu, H.; Oshima, K.
J. Am. Chem. Soc. 2008, 130, 5048. (f) Iwasaki, M.;
Yorimitsu, H.; Oshima, K. Bull. Chem. Soc. Jpn. 2009, 82,
249. (g) Imoto, J.; Hayashi, S.; Hirano, K.; Yorimitsu, H.;
Oshima, K. Bull. Chem. Soc. Jpn. 2009, 82, 393.
(9) Optimized at the B3LYP/6-31G* level. For the optimized
structures, see Supporting Information.
(10) Wiberg, K. B. Angew. Chem., Int. Ed. Engl. 1986, 25, 312.
(11) Typical Procedure. Cs2CO3 (0.12 g, 0.36 mmol) was placed
in a 20 mL two-necked reaction flask equipped with a
Dimroth condenser. The Cs2CO3 was dried in vacuo with
heating with a hair dryer for 2 min. Pd(OAc)2 (2.8 mg,
0.0125 mmol) and tri(4-tolyl)phosphine (15 mg, 0.050
mmol) were added to the reaction flask. The flask was then
filled with argon using standard Schlenk techniques.
Toluene (2.0 mL), homoallyl alcohol 2a (79 mg, 0.30
mmol), and 2-bromonaphthalene (1a; 52 mg, 0.25 mmol)
were sequentially added at ambient temperature. The
resulting mixture was heated at reflux for 13 h. After the
mixture was cooled to room temperature, water (20 mL) was
added. The product was extracted with hexane (3 × 20 mL)
and the combined organic layer was dried over sodium
sulfate, and concentrated in vacuo. Silica gel column
purification with hexane as an eluent gave 2-(2-cyclobutyl-
idenepropyl)naphthalene (3a; 52.0 mg, 94% yield).
Characterization data for 3a: IR (neat): 2826, 1600, 1508
cm–1; 1H NMR (CDCl3): d = 1.44 (s, 3 H), 1.95–2.01 (m, 2
H), 2.68–2.72 (m, 2 H), 2.80–2.82 (m, 2 H), 3.35 (s, 2 H),
7.30–7.32 (m, 1 H), 7.40–7.47 (m, 2 H), 7.60 (s, 1 H), 7.75–
7.81 (m, 3 H); 13C NMR (CDCl3): d = 15.68, 15.86, 29.26,
29.43, 38.95, 124.83, 125.02, 125.78, 126.69, 127.42,
127.53, 127.58, 127.76, 132.02, 133.59, 134.38, 138.40.
Anal. Calcd for C17H18: C, 91.84; H, 8.16. Found: C, 91.57;
H, 8.06.
Synlett 2009, No. 13, 2177–2179 © Thieme Stuttgart · New York

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