Palladium-catalyzed coupling reaction of propargylic oxiranes with arylboronic acids in aqueous media

Article abstract of DOI:10.1016/j.tetlet.2005.07.134

A novel type of coupling reaction has been developed by the palladium-catalyzed reaction of propargylic oxiranes with arylboronic acids, in which anti-substituted 4-aryl-2,3-allenols were produced in a highly diastereoselective manner. A chiral-substitute

Full text of DOI:10.1016/j.tetlet.2005.07.134

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 6705–6708
Palladium-catalyzed coupling reaction of propargylic oxiranes
with arylboronic acids in aqueous media
Masahiro Yoshida,a,* Hirofumi Uedab and Masataka Iharab,*
aGraduate School of Pharmaceutical Sciences, The University of Tokushima, 1-78-1 Sho-machi, Tokushima 770-8505, Japan
bGraduate School of Pharmaceutical Sciences, Tohoku University, Aobayama, Sendai 980-8578, Japan
Received 27 June 2005; revised 25 July 2005; accepted 26 July 2005
Available online 10 August 2005
Abstract—A novel type of coupling reaction has been developed by the palladium-catalyzed reaction of propargylic oxiranes with
arylboronic acids, in which anti-substituted 4-aryl-2,3-allenols were produced in a highly diastereoselective manner. A chiral-substi-
tuted allene has been synthesized from the reaction of a chiral propargylic oxirane without loss of the chirality.
Ó 2005 Elsevier Ltd. All rights reserved.
The functionalized allenes are versatile building blocks
for organic synthesis because of the inherent reactivity
for their axially chiral backbones.1 Furthermore, a large
number of natural products containing an allene moiety
have been isolated, and most of these have axial chiral-
ity.2 Extensive studies for the synthesis of allenes have
been undertaken from these reasons,1 and SN20-type
reactions of propargylic oxiranes are one of the most
successful procedures to afford 2,3-allenols.3 Propargylic
oxiranes generally reacted with organocopper,4 magne-
sium5 and metal hydride6 to produce the substituted
2,3-allenols in moderate to high diastereoselectivity. It
is also known that palladium complexes catalyze the
reactions of propargylic oxiranes with organozinc,7
stannane8 and carbon monooxide9 yielding the corre-
sponding 2,3-allenols. These reactions are normally
required to be carried out under anhydrous conditions,
and some of the organometallic reagents are unstable,
expensive and toxic. Organoboronic acids are widely
used reagents in organic synthesis because of their
stability, commercial availability and nontoxicity.
However, to the best of our knowledge, there are no
examples about the reaction of propargylic oxiranes
with organoboronic acids.
dium catalyst. The reactions can be carried out in aque-
ous media to produce the aryl-substituted 2,3-allenols
with high anti-diastereoselectivity.
The initial reactions were carried out using phenyl-
substituted propargylic oxirane 1a10 and 2-methyl-
phenylboronic acid (2a).11 When a mixture of 1a and
2a were subjected to the reaction with 10 mol%
Pd(PPh3)4 in dioxane at 80 °C for 2 h, the aryl-substi-
tuted 2,3-allenol 3aa having anti-geometry was obtained
in 81% yield (Table 1, entry 1). The stereochemistry of
3aa was determined unambiguously by NOESY correla-
tion of dihydrofuran 4aa, which was produced from the
reaction of 3aa with AgNO53 (Scheme 1). The similar
result was obtained by using Pd2(dba)3ÆCHCl3 with
P(o-Tol)3 (entry 2), but poor results were obtained in
the presence of bidentate phosphine ligands (entries 3–
5). It was found that the yields of 3aa were increased
in the presence of water (entries 6–8), and the product
was produced in 92% yield when the reaction was
employed in dioxane–H2O (2:1) (entry 7). Since the
obtained 2,3-allenol had all anti-geometry in any condi-
tions, it was ascertained that this addition reaction
proceeds in a high diastereoselective manner.
Herein, we describe a novel type of coupling reaction of
propargylic oxiranes with arylboronic acids by palla-
A series of substituted arylboronic acids 2b–f were then
subjected to the reaction. The corresponding products
3ab and ac were obtained in good yields by the reactions
of 1a with 2- and 4-methoxyphenylboronic acids (2b
and c) (Table 2, entries 1 and 2). 1-Naphthalene- and
phenylboronic acids (2d and e) were also efficiently
transformed to the coupled products 3ad and ae (entries
Keywords: Palladium; Addition; Oxiranes; Boronic acids; Propargylic
compounds.
*
Corresponding authors. Fax: +81 88 6337294; e-mail: yoshida@
ph.tokushima-u.ac.jp
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.07.134

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M. Yoshida et al. / Tetrahedron Letters 46 (2005) 6705–6708
Table 1. Palladium-catalyzed coupling of propargylic oxirane 1a with
2-methylphenylboronic acid (2a)
Table 3. Reactions of various propargylic oxiranes 1b–g with
2-methylphenylboronic acid (2a)a
Entry Substrate
Productb
Yield (%)
OH
Ar
O
Ph
Ph
OH
O
·
1
64
10 mol % Pd(0)
B(OH)2
Ph
3bac
·
+
Ph
solvent, 80 ˚C
2 h
1b
Ar
1a
2a
3aa
Ph
OH
O
Ph
·
Entry Palladium catalyst
Solvent
Yield
(%)
2
83
77
85
43
50
1c
3cac
1
Pd(PPh3)4
Pd2(dba)3ÆCHCl3, P(o-Tol)3 Dioxane
Pd2(dba)3ÆCHCl3, dppe
Pd2(dba)3ÆCHCl3, dppp
Pd2(dba)3ÆCHCl3, dppf
Pd(PPh3)4
Dioxane
81
73
16
38
42
2a
3b
4b
5b
6
Ar
Bu
OH
OH
Dioxane
Dioxane
Dioxane
Dioxane–H2O = 9:1 91
Dioxane–H2O = 2:1 92
Dioxane–H2O = 1:2 61
O
·
·
Bu
3dac
3
1d
7
8
Pd(PPh3)4
Pd(PPh3)4
Ar
Ar
O
OMe
OMe
a 5 mol% palladium and 40 mol% ligand were used.
b 5 mol% palladium and 20 mol% ligand were used.
4
1e
3eac
TMS
OH
O
·
H
5
NOE
H
3fad
Ar
1f
H
OH
AgNO3, CaCO3
O
·
Ph
Ph
aq. acetone, 60 ˚C
63%
OH
Ph
4aa
O
H
6
·
Ph
Ph
3aa
Ph
H
3gac
1g
Scheme 1.
a Reactions were carried not with 2-methylphenylboronic acid (2a) in
the presence of 10 mol% Pd(PPh3)4 in dioxane–H2O (2:1) at 80 °C.
b Ar = 2-methylphenyl.
c The stereochemistry of each product was tentatively assigned by
comparison of its NMR spectra with 3aa, af and fa.
d The stereochemistry was determined unambiguously by NOESY
correlation of dihydrofuran 4fa, which was produced from the
reaction of 3fa with AgNO3 and CaCO3.
Table 2. Palladium-catalyzed coupling of propargylic oxirane 1a with
arylboronic acids 2b–f
Ar
Ph
OH
O
10 mol % Pd(PPh3)4
·
Ph
+ ArB(OH)2
dioxane/H2O (2 : 1)
80 ˚C, 1-3 h
1a
2b-2f
3ab-3af
possessing a five- and a seven-membered ring were
carried out, the coupled 2,3-allenols 3ba and ca were
obtained in 64% and 83% yields, respectively (entries 1
and 2). Substrates 1d and e, having a butyl and a
methoxymethyl group at the terminal position, were
uneventfully reacted with 2a to afford the corresponding
products 3da and 3ea in good yields (entries 3 and 4).
When TMS-substituted propargylic oxirane 1f was
subjected to the reaction, the desilylated 2,3-allenol 3fa
was predominantly produced (entry 5). The reaction of
acyclic substrate 1g also uneventfully proceeded to yield
the corresponding coupled product 3ga in moderate
yield (entry 6).
Entry Boronic acid
Producta Yield
(%)
1
2
3
4
5
2-Methoxyphenylboronic acid (2b) 3aba
4-Methoxyphenylboronic acid (2c)
1-Naphthaleneboronic acid (2d)
Phenylboronic acid (2e)
77
81
86
55
38
3aca
3ada
3aea
3afb
3-Nitrophenylboronic acid (2f)
a The stereochemistry of each product was tentatively assigned by
comparison of its NMR spectra with 3aa and af.
b The stereochemistry was determined unambiguously by NOESY
correlation of dihydrofuran 4af, which was produced from the
reaction of 3af with AgNO3 and CaCO3.
We further attempted the reaction of enantiomerically
enriched propargylic oxirane (1R,2R)-1a (Scheme 2).
When (1R,2R)-1a12 (92% ee) was reacted with 2-meth-
ylphenylboronic acid (2a), the corresponding chiral cou-
pled product (1R,2R)-3aa13 was provided in 92% yield.
The enantiomeric excess of (1R,2R)-3aa was determined
as 92%, and the result showed that the reaction pro-
ceeded with complete transferring chirality.
3 and 4). When 3-nitrophenylboronic acid (2f) having an
electron-withdrawing group was subjected to the reac-
tion, the yield of the resulting product 3af was slightly
lowered (entry 5).
Results of reactions of various propargylic oxiranes 1b–
g with 2-methylphenylboronic acid (2a) are summarized
in Table 3. When the reactions of substrates 1b and c

M. Yoshida et al. / Tetrahedron Letters 46 (2005) 6705–6708
6707
References and notes
10 mol %
Pd(PPh3)4
Ph
1. For selected reviews, see: (a) Marshall, J. A. Chem. Rev.
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nan, E.; Khan, F. A. Chem. Rev. 2000, 100, 3067; (c) Ma,
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Angew. Chem., Int. Ed. 2000, 39, 3590; (e) Hoffmann-
Ro¨der, A.; Krause, N. Angew. Chem., Int. Ed. 2002, 41,
2933; (f) Krause, N.; Hoffmann-Ro¨der, A.; Canisius, J.
Synthesis 2002, 1759; (g) Hoffmann-Ro¨der, A.; Krause, N.
Angew. Chem., Int. Ed. 2004, 43, 1196.
OH
O
B(OH)2
·
+
Ph
solvent, 80 C
˚
2 h
2a
(1R,2R)-1a
92% ee
(1R,2R)-3aa
92%, 92% ee
Scheme 2.
2. (a) Krause, N.; Hoffmann-Ro¨der, A. Allenic Natural
Products and Pharmaceuticals. In Modern Allenic Chem-
istry; Krause, N., Hashmi, A. S. K., Eds.; Wiley-VCH:
Weinheim, 2004, p 997; (b) Landor, S. R. Naturally
Occurring Allenes. In The Chemistry of the Allenes;
Landor, S. R., Ed.; Academic Press: London, 1982,
p 679; (c) Claesson, A. Biologically Active Allenes. In
The Chemistry of the Allenes; Landor, S. R., Ed.;
Academic Press: London, 1982, p 709; (d) Robinson, C.
H.; Covey, D. F. Biological Formation and Reactions. In
The Chemistry of Ketenes, Allenes and Related Compounds;
Patai, S., Ed.; Wiley: Chichester, 1980, p 451.
Ar
OH
Ph
O
·
Ph
3
1
Pd(0)
Ar
Pd
Pd
OH
O
·
·
Ph
Ph
3. Alexakis, A.; Marek, I.; Mangeney, P.; Normant, J. F.
Tetrahedron 1991, 47, 1677.
5
8
4. (a) Vermeer, P.; Meijer, J.; De Graaf, C.; Schreures, H.
Rec. Trav. Chim. Pays-Bas 1974, 93, 46; (b) Oehlschlager,
A. C.; Czyzewska, E. Tetrahedron Lett. 1983, 24, 5587; (c)
Johnson, C. R.; Dhanoa, D. S. J. Org. Chem. 1987, 52,
1885; (d) Marshall, J. A.; Pinney, K. G. J. Org. Chem.
1993, 58, 1885; (e) Bertozzi, F.; Crotti, P.; Macchia, F.;
Pineschi, M.; Arnold, A.; Feringa, B. L. Tetrahedron Lett.
1999, 40, 4893.
B(OH)4
H2O
OH
Ph
Pd
OH
·
ArB(OH)3
7
6
´
5. Furstner, A.; Mendez, M. Angew. Chem., Int. Ed. 2003,
¨
Scheme 3.
42, 5355.
6. (a) Mori, K. Tetrahedron 1974, 30, 1065; (b) Ito, M.;
Hirata, Y.; Tsukida, K.; Tanaka, N.; Hamada, K.; Hino,
R.; Fujiwara, T. Chem. Pharm. Bull. 1988, 36, 3328; (c)
Braumeler, A.; Brade, W.; Haag, A.; Eugster, C. H. Helv.
Chim. Acta 1990, 73, 700.
Plausible mechanism for the formation of aryl-substi-
tuted 2,3-allenols 3 is shown in Scheme 3. In the first
step, regio- and stereoselective anti-SN20 attack of palla-
dium catalyst14 on the propargylic oxirane 1 takes place
to yield the twitter ionic allenylpalladium species 5,
which was further hydrated in the presence of H2O to
form the allenylpalladium hydroxide 6.15 Transmetalla-
tion of 6 with arylborate 7,16 derived from arylboronic
acid 2 and H2O, and then reductive elimination of
palladium from the resulting intermediate 8 diastereo-
selectively produces anti-coupled 4-aryl-2,3-allenol 3.
7. Kleijn, H.; Meijer, J.; Overbeek, G. C.; Vermeer, P. Rec.
Trav. Chim. Pays-Bas 1982, 101, 97.
´
´
8. Kjellgren, J.; Sunden, H.; Szabo, K. J. J. Am. Chem. Soc.
2005, 127, 1787.
9. Knight, J. G.; Ainge, S. W.; Baxter, C. A.; Eastman, T. P.;
Harwood, S. J. J. Chem. Soc., Perkin Trans. 1 2000, 3788.
10. Substrate 1 was easily prepared by the epoxidation of the
corresponding known eneyne with m-CPBA in moderate
to good yields.
11. Typical procedure: to a stirred solution of propargylic
oxirane 1a (45.0 mg, 0.227 mmol) in 1,4-dioxane (2.0 ml)
and H2O (1.0 ml) were added 2-methylphenylboronic acid
(2a) (92.8 mg, 0.682 mmol) and Pd(PPh3)4 (26.3 mg,
22.7 lmol) at rt, and the stirring was continued for 1.5 h
at 80 °C. After filtration of the reaction mixture using
small amount of silica gel, the mass was extracted with
AcOEt. The combined filtrates were washed with 10%
aqueous NaOH and brine, and the residue upon workup
was chromatographed on silica gel with hexane–AcOEt
(90:10, v/v) as eluent to give the 4-aryl-2,3-allenol 3aa
(60.3 mg, 92%) as colourless crystals; mp 98–99 °C; IR
In conclusion, the effort described above has led to the
discovery of a palladium-catalyzed coupling reaction
occurring between propargylic oxiranes and arylboronic
acids. The process can be carried out in aqueous condi-
tions to yield anti-substituted 4-aryl-2,3-allenols in a
highly diastereoselective manner. Furthermore, the
chiral-substituted allene has been synthesized from the
chiral propargylic oxirane without loss of the chirality.
Continuing studies probing the scope and synthetic
applications of this reaction are now in progress.
1
(neat) 3342, 2933, 1948, 1595 cmꢀ1; H NMR (400 MHz,
CDCl3) d 7.30–7.15 (9H, m), 4.12–4.05 (1H, m), 2.62–2.55
Acknowledgement
(1H, m), 2.20 (3H, s), 2.24–2.05 (2H, m), 1.95–1.85 (1H,
m), 1.92 (1H, s), 1.85–1.75 (1H, m), 1.62–1.38 (3H, m); 13
C
This study was supported in part by a Grant-in-Aid for
the Encouragement for Young Scientists (B) from the
Japan Society for the Promotion of Science (JSPS) (for
M.Y.).
NMR (100 MHz, CDCl3) d 195.4, 137.3, 136.5, 136.5,
130.3, 130.2, 128.3, 127.5, 126.7, 126.5, 125.8, 111.5, 110.9,
69.6, 36.6, 30.1, 27.1, 23.9, 20.2; MS m/z 290 (M+); HRMS
m/z calcd for C21H22O: 290.1671 (M+). Found: 290.1688.

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M. Yoshida et al. / Tetrahedron Letters 46 (2005) 6705–6708
12. Chiral substrate (1R,2R)-1a was prepared by the asym-
metric epoxidation of the corresponding eneyne using
Shiꢀs fructose-derived chiral ketone with oxone; Wang,
Z.-X.; Cao, G.-A.; Shi, Y. J. Org. Chem. 1999, 64, 7646.
13. Enantiomeric excess of the obtained (1R,2R)-3aa was
determined by HPLC analysis (DAICEL CHIRALCEL
AD).
14. It is known that chiral allenes can be synthesized from the
palladium-catalyzed reaction of chiral propargylic com-
pounds via stereoselective SN20 attack of palladium
catalyst: (a) Elsevier, C. J.; Stehouwer, P. M.; Westmijze,
H.; Vermeer, P. J. Org. Chem. 1983, 48, 1103; (b)
Marshall, J. A.; Adams, N. D. J. Org. Chem. 1997, 62,
367; (c) Dixneuf, P.; Guyot, T.; Ness, M. D.; Roberts, S.
M. Chem. Commun. 1997, 2083; (d) Konno, T.; Tanikawa,
M.; Ishihara, T.; Yamanaka, H. Chem. Lett. 2000, 1360.
15. From the results that the reaction smoothly proceeded in
the absence of water (Table 1, entries 1–5), the direct
transmetallation of cationic allenylpalladium 5 to inter-
mediate 8 would also be possible.
16. Kotha, S.; Lahri, K.; Kashinath, D. K. Tetrahedron 2002,
58, 9633.