Regioselective ring-opening reaction of unsymmetrical 2,3-diaryl epoxides via catalytic hydrogenolysis with Pd(0)EnCatTM

Article abstract of DOI:10.1055/s-0030-1259505

A series of unsymmetrical 2,3-diaryl epoxides were hydrogenated under transfer-hydrogenation conditions using the polyurea-encapsulated palladium catalyst [Pd(0)EnCat^TM]. The position of the cleaved C-O bond was determined by ¹H NMR analysis of the ring-opened products derived from the epoxide, in which one of the two benzylic methyne protons is deuterated. The ratio of ring-opened products of the unsymmetrically substituted 2,3-diaryl epoxides was affected by the degree of the steric bulkiness on the aromatic ring. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0030-1259505

LETTER
365
Regioselective Ring-Opening Reaction of Unsymmetrical 2,3-Diaryl Epoxides
via Catalytic Hydrogenolysis with Pd(0)EnCatTM
Ring-Opening
R
e
e
action of
t
U
nsym
s
metrical
2
u
,3-Diaryl Ep
t
oxidesaro Kimachi,* Hiroyo Nagata, Yusuke Kobayashi, Kaori Takahashi, Eri Torii, Motoharu Ju-ichi
School of Pharmaceutical Sciences, Mukogawa Women’s University, 11-68 Koshien Kyuban-cho, Nishinomiya 663-8179, Hyogo, Japan
Fax +81(798)459952; E-mail: tkimachi@mukogawa-u.ac.jp
Received 28 October 2010
on the synthesis of novel biologically active natural prod-
Abstract: A series of unsymmetrical 2,3-diaryl epoxides were hy-
ucts,5 we report here the regioselective ring-opening reac-
drogenated under transfer-hydrogenation conditions using the poly-
urea-encapsulated palladium catalyst [Pd(0)EnCatTM]. The position
of the cleaved C–O bond was determined by 1H NMR analysis of
tion of unsymmetrical trans-2,3-diaryl epoxides via
catalytic hydrogenolysis with Pd(0)EnCatTM and propose
the ring-opened products derived from the epoxide, in which one of a rational explanation for the manner of the C–O cleavage
the two benzylic methyne protons is deuterated. The ratio of ring-
which was not controlled by electronic effects but rather
opened products of the unsymmetrically substituted 2,3-diaryl ep-
by the steric bulkiness of the aromatic substituents. The
oxides was affected by the degree of the steric bulkiness on the
position of the cleaved C–O bond was determined by 1H
aromatic ring.
NMR analysis of the ring-opened products derived from
the epoxides, in which one of the two benzylic methyne
protons was deuterated.
Initially, Pd(0)EnCatTM-catalyzed transfer hydrogenation
Key words: reductive ring-opening reaction, polyurea-encapsul-
ated palladium catalyst [Pd(0)EnCatTM], 2,3-diary epoxide, Darzens
reaction
of racemic trans-2-phenyl-3-(4-trifluoro-methylphe-
nyl)oxirane (rac-1) was carried out according to the liter-
We have recently reported a highly enantioselective
Darzens-type epoxidation via chiral ammonium ylides to
ature procedure3 (Scheme 1). The hydrogenolysis of rac-
afford unsymmetrical trans-2,3-diaryl epoxides.1 Optical-
ly active epoxides are important functional organic mole-
cules that can be converted to chiral amino alcohols, diols,
alcohols by the corresponding nucleophilic, acidic and re-
ductive ring-opening reactions. The ring-opened products
are used as important intermediates for the synthesis of bi-
ologically active molecules.2 Among the wide variety of
studies on the ring-opening reactions of epoxides, Ley et
al. have recently shown that the polyurea-encapsulated
palladium catalyst [Pd(0)EnCatTM] is an efficient transfer-
hydrogenation catalyst for the reductive ring-opening
reaction of various benzylic epoxides.3
1 with 4 equivalents of Et3N and HCOOH in EtOAc at
room temperature reached completion after 5 hours to af-
ford the corresponding alcohol 2 or 3 in 96% yield as a
single product without obtaining any other isomers. How-
ever, we were unable to determine which C–O bond fis-
sion had predominantly occurred – that between C-2 and
oxygen (leading to 2) or that between C-3 and oxygen
1
(leading to 3) – by H NMR analysis (Scheme 1). Ley et
al. proposed that the hydrogen delivered from the Pd for-
mate species has a much stronger hydridic nature com-
pared to that from the Pd hydride species.3 In order to
unequivocally solve this problem, we tried to carry out the
reductive ring-opening reaction of a deuterium-labeled
epoxide to clarify which C–O bond was cleaved.
Most recently, Lupattelli et al. reported the regioselective
reductive ring-opening reaction of unsymmetrical 2,3-di-
aryl epoxides under the usual hydrogenation conditions
(H2, Pd/C, MeOH) and found a nonrationalized ring-
opening selectivity in which an unsubstituted benzylic
carbon–oxygen (C–O) bond was predominantly cleaved
in competition with any substituted benzylic C–O bonds
even though the substituents were electron-donating or
electron-withdrawing groups.4 Although their studies
were encouraging, they were unable to provide a convinc-
ing explanations for the regioselective C–O bond cleav-
age in their article.
We have independently focused our attention on the na-
ture of the ring-opening reaction of the unsymmetrical
trans-2,3-diaryl epoxides including differently substituted
trans-2,3-diaryl epoxides. As part of our ongoing studies
SYNLETT 2011, No. 3, pp 0365–0368
x
x.
x
x.
2
0
1
1
Advanced online publication: 25.01.2011
DOI: 10.1055/s-0030-1259505; Art ID: U09710ST
© Georg Thieme Verlag Stuttgart · New York
Scheme 1 Reductive ring-opening reaction of racemic trans-2-
phenyl-3-(4-trifluoromethylphenyl)oxirane (rac-1)

366
T. Kimachi et al.
LETTER
Deuterated compounds are powerful tools for structural an isomeric mixture in the ratios shown in Table 1 (entry
investigation by NMR. Thus, rac-1-d was prepared using 8). These results indicate that the ease of the C–O cleav-
PhCDO and subjected to the same hydrogenolysis condi- age seems to be affected by the degree of the steric bulki-
tions. In this case, we were able to easily determine the ness on the aromatic ring. The 4-cyanophenyl group,
preferential C-2–O bond fission of rac-1-d to afford 2-d as being linear, can coordinate more tightly with the Pd met-
shown in Scheme 2.
al than the 4-trifluoromethyl phenyl group. On the other
hand, the steric bulkiness of the trifluoromethyl and meth-
oxy groups seems to be almost the same, but the slight dif-
ference in steric hindrance between them is reflected in
the slight difference in the ratio of the products. Judging
from the experimental result, in which a larger amount of
18-d than 19-d was obtained, the trifluoromethyl group
seems to be slightly bulkier than the methoxy group. Fur-
ther investigations are needed to verify whether the pres-
ence of an oxygen atom between the methyl group and the
aromatic ring in the 4-anisyl group permits a flat orienta-
tion of the aromatic ring on the Pd-metal surface in the
[Pd(0)EnCatTM] that is better than that of the 4-trifluoro-
methyl phenyl group.
F3C
F3C
Pd0EnCat (5 mol%)
R
Ph
S
S
HCOOH, Et3N
EtOAc
Ph
Scheme 2 Reductive ring-opening reaction of racemic trans-2-
deuterio-2-phenyl-3-(4-trifluoromethylphenyl)oxirane (rac-1-d)
OH
O
93%
(R)-2
(2S,3S)-1
90% ee
89% ee
[α]2D5.4 + 7.8 (c 1.0 CHCl3)
This result prompted us to investigate the relationship be-
tween the various substituents in 2,3-diaryl epoxides and
their C–O cleaving sites. We modified our reported proce-
dure and prepared a series of deuterated unsymmetrical
trans-2,3-diaryl epoxides (4-d–11-d).6 The thus prepared
epoxides (4-d–11-d) were subjected to the reductive ring-
opening reaction, and the results are shown in Table 1.7
Substitution of both electron-donating and electron-with-
drawing groups onto the aromatic ring did not facilitate
cleavage of the C–O bond. The unsubstituted benzylic C–
O bond underwent the preferential cleavage in competi-
tion with the substituted benzylic C–O bonds (entries 1–
5). Sterically demanding 4-tert-butylphenyl group obvi-
ously interferes to arrange the planar geometry on the Pd-
metal surface to result the exclusive cleavage of the un-
substituted benzylic C–O bond (entry 5). 4-Cyanophenyl
group, having linear substituent, partly competed the C–O
cleavage with the unsubstituted phenyl group (entry 6).
These results suggest that the reductive ring-opening reac-
tion is promoted more effectively when the aromatic ring
is flatly oriented on the Pd-metal surface and that the sub-
stituents on the aromatic ring have an adverse steric effect
that interferes with the planar geometry required for effec-
tive coordination.8 4-Cyanophenyl group seems to be able
to coordinate with Pd metal by the help of the p-electrons
in a cyano group to some extent.
Scheme 3
We also focused our attention on the stereochemistry of
this reductive ring-opening reaction. Enantioenriched
trans-2,3-diaryl epoxide [(2S,3S)-1 90% ee] was subject-
ed to the reductive ring-opening reaction. As shown in
Scheme 3, optically active benzylic alcohol (R)-2 was ob-
tained with complete retention of the configuration.
In conclusion, a series of unsymmetrical 2,3-diaryl ep-
oxides were hydrogenated under transfer-hydrogenation
conditions using the polyurea-encapsulated palladium
catalyst [Pd(0)EnCatTM]. The regioselectivity of the C–O
cleavage was identified by 1H NMR analysis of the ring-
opened products of deuterium-labeled epoxides. The
cleavage of the unsubstituted benzylic C–O bond was
shown to occur predominantly in competition with other
substituted benzylic C–O bonds, and the ratio of the ring-
opened products of the differently substituted 2,3-diaryl
epoxides appeared to be affected by the degree of the ster-
ic bulkiness on the aromatic rings. We suggest that the flat
orientation of the aromatic ring component on the Pd-
metal surface in the Pd(0)EnCatTM-catalyzed epoxide-
opening reaction is the reason for the more effective C–O
bond cleavage.
Next, the reductive ring-opening reaction of the two dif-
ferently substituted trans-2,3-diaryl epoxides (10-d and
11-d) was carried out. Ring-opening reaction of 10-d pro-
ceeded regioselectively to furnish compound 19-d in high
yield (entry 7). Ring-opening reaction of epoxide 11-d af-
forded the corresponding compounds (20-d and 21-d) as
Acknowledgment
We thank Professor Yoshiji Takemoto (Graduate School of Phar-
maceutical Sciences, Kyoto University, Japan) for informative dis-
cussion and advice.
Synlett 2011, No. 3, 365–368 © Thieme Stuttgart · New York

LETTER
Ring-Opening Reaction of Unsymmetrical 2,3-Diaryl Epoxides
367
Table 1 Reductive Ring-Opening Reaction of Racemic trans-2- or 3-Deuterio-2,3-diaryl Epoxides (4-d–11-d)
R1
R1
R2
Y
X
Pd0EnCat (5 mol%), HCOOH
Et3N, EtOAc, r.t., 5 h
X
Y
OH
R2
O
4-d–11-d
12-d–21-d
X, Y = H, D or D, H
Entry
Epoxide
R1
R2
X
Y
D
H
D
D
D
Product
12-d
Yield (%)
1
2
3
4
5
6
4-d
5-d
6-d
7-d
8-d
9-d
Me
H
H
H
H
H
H
D
H
H
H
75
95
97
96
80
MeO
Et2NCO
t-BuOCO
t-Bu
13-d
14-d
15-d
16-d
NC
H
H
NC
H
D
D
H
17-d
18-d
68
20
7
8
10-d
11-d
F3C
NC
D
H
19-d
83
F3C
MeO
MeO
F3C
H
D
D
H
20-d
21-d
70
23
(7) Typical Procedure for the Reductive Ring-Opening
References and Notes
Reaction of the Epoxides 4–11 and Deuterated Epoxides
(4-d–11-d)
(1) Kinoshita, H.; Ihoriya, A.; Ju-ichi, M.; Kimachi, T. Synlett
2010, 2330.
Pd(0) catalyst [Pd(0)EnCatTM, 50 mg, 0.02 mmol] was added
to a solution of the epoxide (0.38 mmol) in EtOAc (0.75 mL)
at r.t. under argon atmosphere. The mixture was cooled to
0 °C, Et3N (0.28 mL, 4 mmol) and formic acid (0.07 mL, 4
mmoL) were added. After 5 h stirring at r.t., the mixture was
worked up as follows. The resulting Pd(0) was filtered off,
then filtrate was concentrated under reduced pressure. The
remaining residue was purified by flash chromatography to
afford the product.
(2) Alcoholysis: (a) Tamami, B.; Iranpoor, N.; Razaei, R. Synth.
Commun. 2004, 34, 2789. (b) Iranpoor, N.; Salehi, P.
Synthesis 1994, 1152. (c) Surendra, K.; Krishnaveni, N. S.;
Nageswar, Y. V. D.; Rao, K. R. J. Org. Chem. 2003, 68,
4994 . Aminolysis: (d) Murai, T.; Sano, H.; Kawai, H.; Aso,
H.; Shibahara, F. J. Org. Chem. 2005, 70, 8148.
(e) Mirkhani, V.; Tangestaninejad, S.; Yadollahi, B.;
Alipanah, L. Catal. Lett. 2005, 101, 93. (f) Lupi, V.;
Albanese, D.; Landini, D.; Scaletti, D.; Penso, M.
Tetrahedron 2004, 60, 11709. (g) Sundararajan, G.;
Vijayakrishna, K.; Varghese, B. Tetrahedron Lett. 2004, 45,
8253 . Azidolysis: (h) Marie, J.-C.; Courillon, C.; Malarcia,
M. Synlett 2002, 553. Reductive ring opening (i) Ley, S. V.;
Mitchell, C.; Pears, D.; Ramarao, C.; Yu, J.-Q.; Zhou, W.
Org. Lett. 2003, 5, 4665 . Lewis acid catalyzed ring opening
of epoxides: (j) Blum, S. A.; Rivera, V. A.; Ruck, R. T.;
Michael, F. E.; Bergman, R. G. Organometallics 2005, 24,
1647. (k) Asandei, A. D.; Moran, I. W. J. Am. Chem. Soc.
2004, 126, 15932.
1H NMR Spectra of the Ring-Opened Products 12–21
Product 12: 1H NMR (400 MHz, CDCl3): d = 1.65 (s, 1 H),
2.35 (s, 3 H), 2.91–3.06 (m, 2 H), 4.85–4.89 (m, 1 H), 7.10–
7.36 (m, 9 H).
Product 13: 1H NMR (400 MHz, CDCl3): d = 1.90 (s, 1 H),
3.00 (m, 2 H), 3.80 (s, 3 H), 4.84 (dd, 1 H, J = 5.9, 7.3 Hz),
6.85–6.89 (m, 2 H), 7.16–7.34 (m, 7 H).
Product 14: 1H NMR (500 MHz, CDCl3): d = 1.11 (m, 3 H),
1.22 (m, 3 H), 2.97 (dd, 1 H, J = 8.2, 13.7 Hz), 3.03 (dd, 1 H,
J = 5.0, 13.7 Hz), 3.25 (m, 2 H), 3.53 (m, 2 H), 4.91 (dd, 1
H, J = 5.0, 8.2 Hz), 7.16–7.36 (m, 9 H).
Product 15: 1H NMR (400 MHz, CDCl3): d = 1.60 (s, 9 H),
2.97 (dd, 1 H, J = 8.4, 13.9 Hz), 3.04 (dd, 1 H, J = 4.8, 13.9
Hz), 4.95 (m, 1 H), 7.16–7.18 (m, 2 H), 7.22–7.32 (m, 3 H),
7.38 (d, 2 H, J = 8.4 Hz), 7.95 (d, 2 H, J = 8.4 Hz).
Product 16: 1H NMR (400 MHz, CDCl3): d = 1.32 (s, 9 H),
1.89 (s, 1 H), 2.97 (dd, 1 H, J = 10.2, 13.5 Hz), 3.04 (dd, 1
H, J = 4.4, 13.5 Hz), 4.86 (m, 1 H), 7.20–7.30 (m, 5 H), 7.31
(d, 2 H, J = 8.4 Hz), 7.37 (d, 2 H, J = 8.4 Hz).
(3) Ley, S. V.; Mitchell, C.; Pears, D.; Ramarao, C.; Yu, J.-Q.;
Zhou, W. Org. Lett. 2003, 5, 4665.
(4) Blasio, N. D.; Lopardo, M. T.; Lupattelli, P. Eur. J. Org.
Chem. 2009, 938.
(5) (a) Shirota, O.; Pathak, V.; Sekita, S.; Satake, M.;
Nagashima, Y.; Hirayama, Y.; Hakamata, Y.; Hayashi, T.
J. Nat. Prod. 2003, 66, 1128. (b) Watanabe, M.; Date, M.;
Kawanishi, K.; Hori, T.; Furukawa, S. Chem. Pharm. Bull.
1991, 39, 41. (c) Watanabe, M.; Kawanishi, K.; Akiyoshi,
R.; Furukawa, S. Chem. Pharm. Bull. 1991, 39, 3123.
(6) (a) Kimachi, T.; Kinoshita, H.; Kusaka, K.; Takeuchi, Y.;
Aoe, M.; Ju-ichi, M. Synlett 2005, 842. (b) All new
Product 17: 1H NMR (400 MHz, CDCl3): d = 2.1 (d, 1 H,
J = 3.0 Hz), 2.94 (dd, 1 H, J = 8.4, 13.5 Hz), 3.03 (dd, 1 H,
J = 4.8, 13.5 Hz), 4.95 (m, 1 H), 7.14–7.36 (m, 5 H), 7.43 (d,
2 H, J = 8.0 Hz), 7.61 (d, 2 H, J = 8.0 Hz).
compounds show analytical and spectral (1H NMR, 13
NMR, HRMS) data consistent with the depicted structure.
C
Product 18: 1H NMR (400 MHz, CDCl3): d = 1.98 (m, 1 H),
3.05 (m, 1 H), 3.13 (m, 1 H), 4.90 (m, 1 H), 7.24–7.36 (m, 5
Synlett 2011, No. 3, 365–368 © Thieme Stuttgart · New York

368
T. Kimachi et al.
LETTER
H), 7.27 (d, 2 H, J = 8.3 Hz), 7.54 (d, 2 H, J = 8.3 Hz).
Product 19: 1H NMR (500 MHz, CDCl3): d = 3.07 (d, 2 H,
J = 6.4 Hz), 5.00 (t, 1 H, J = 6.4 Hz), 7.27 (d, 2 H, J = 8.2
Hz), 7.42 (d, 2 H, J = 8.2 Hz), 7.57 (d, 2 H, J = 8.2 Hz), 7.60
(d, 2 H, J = 8.2 Hz).
1.99 (d, 1 H, J = 3.2 Hz), 3.02 (d, 1 H, J = 4.6 Hz), 4.95 (m,
1 H), 7.15–7.18 (m, 2 H), 7.22–7.32 (m, 3 H), 7.38 (d, 2 H,
J = 8.2 Hz), 7.95 (d, 2 H, J = 8.2 Hz).
Product 16-d: 1H NMR (400 MHz, CDCl3): d = 1.31 (s, 9 H),
1.89 (s, 1 H), 3.04 (d, 1 H, J = 4.4 Hz), 4.86 (d, 1 H, J = 4.4
Hz), 7.20–7.30 (m, 5 H), 7.31 (d, 2 H, J = 8.4 Hz), 7.37 (d, 2
H, J = 8.4 Hz).
Product 20: 1H NMR (400 MHz, CDCl3): d = 2.89 (dd, 1 H,
J = 8.4, 13.9 Hz), 2.99 (dd, 1 H, J = 4.8, 13.5 Hz), 3.79 (s, 3
H), 4.91 (m, 1 H), 6.84 (d, 2 H, J = 8.4 Hz), 7.08 (d, 2 H,
J = 8.4 Hz), 7.45 (d, 2 H, J = 8.1 Hz), 7.59 (d, 2 H, J = 8.1
Hz).
Product 17-d: 1H NMR (400 MHz, CDCl3): d = 2.07 (d, 1 H,
J = 3.2 Hz), 3.01 (m, 1 H), 4.95 (m, 1 H), 7.27–7.40 (m, 5 H),
7.43 (d, 2 H, J = 8.3 Hz), 7.62 (d, 2 H, J = 8.3 Hz).
Product 18-d: 1H NMR (400 MHz, CDCl3): d = 2.00 (br s, 1
H), 3.05 (m, 1 H), 3.10 (m, 1 H), 7.37 (m, 5 H), 7.30 (d, 2 H,
J = 8.3 Hz), 7.55 (d, 2 H, J = 8.3 Hz).
Product 21: 1H NMR (400 MHz, CDCl3): d = 3.04–3.08 (m,
2 H), 3.81 (s, 3 H), 4.86 (m, 1 H), 6.87 (d, 2 H, J = 8.8 Hz),
7.22–7.28 (m, 4 H), 7.52 (d, 2 H, J = 8.1 Hz).
1H NMR Spectra of Deuterated Ring-Opened Products
12-d–21-d
Product 19-d: 1H NMR (400 MHz, CDCl3): d = 1.96 (s, 1 H),
3.07 (s, 2 H), 7.27 (d, 2 H, J = 8.1 Hz), 7.42 (d, 2 H, J = 8.1
Hz), 7.56–7.65 (m, 4 H).
Product 12-d: 1H NMR (400 MHz, CDCl3): d = 2.34 (s, 3 H),
2.94–3.01 (m, 1 H), 4.83–4.85 (m, 1 H), 7.06–7.36 (m, 10
H).
Product 20-d: 1H NMR (400 MHz, CDCl3): d = 1.98 (d, 1 H,
J = 3.3 Hz), 2.98 (m, 1 H), 3.79 (s, 3 H), 4.91 (s, 1 H), 6.85
(d, 2 H, J = 8.1 Hz), 7.08 (d, 2 H, J = 8.1 Hz), 7.45 (d, 2 H,
J = 8.4 Hz), 7.59 (d, 2 H, J = 8.4 Hz).
Product 13-d: 1H NMR (400 MHz, CDCl3): d = 3.00 (s, 2 H),
3.80 (s, 3 H), 6.87 (d, 2 H, J = 8.8 Hz), 7.26 (d, 2 H, J = 8.8
Hz), 7.16–7.30 (m, 5 H).
Product 21-d: 1H NMR (400 MHz, CDCl3): d = 1.81 (s, 1 H),
3.06 (dd, 2 H, J = 13.5, 23.8 Hz), 3.81 (s, 3 H), 6.88 (d, 2 H,
J = 8.8 Hz), 7.24 (d, 2 H, J = 8.8 Hz), 7.27 (d, 2 H, J = 8.1
Hz), 7.53 (d, 2 H, J = 8.1 Hz).
Product 14-d: 1H NMR (400 MHz, CDCl3): d = 1.14 (m, 3
H), 1.22 (m, 3 H), 2.05 (s, 1 H), 3.02 (d, 1 H, J = 4.4 Hz),
3.27 (m, 2 H), 3.53 (m, 2 H), 4.92 (d, 1 H, J = 4.4 Hz), 7.17–
7.38 (m, 9 H).
(8) Gaunt, M. J.; Yu, J.; Spencer, J. B. J. Org. Chem. 1998, 63,
4172.
Product 15-d: 1H NMR (400 MHz, CDCl3): d = 1.60 (s, 9 H),
Synlett 2011, No. 3, 365–368 © Thieme Stuttgart · New York

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