Palladium-catalyzed kinetic resolution of tert-cyclobutanols via C-C bond cleavage

Article abstract of DOI:10.1016/S0040-4039(02)00413-6

Palladium-catalyzed kinetic resolution of tert-cyclobutanols with bromobenzene affords chiral ketones via C-C bond cleavage as well as chiral tert-cyclobutanols with moderate to good enantioselectivity.

Full text of DOI:10.1016/S0040-4039(02)00413-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 3037–3039
Palladium-catalyzed kinetic resolution of tert-cyclobutanols via
CꢀC bond cleavage
Takahiro Nishimura, Satoshi Matsumura, Yasunari Maeda and Sakae Uemura*
Department of Energy and Hydrocarbon Chemistry, Graduate School of Engineering, Kyoto University, Sakyo-ku, Kyoto
606-8501, Japan
Received 23 January 2002; revised 21 February 2002; accepted 22 February 2002
Abstract—Palladium-catalyzed kinetic resolution of tert-cyclobutanols with bromobenzene affords chiral ketones via CꢀC bond
cleavage as well as chiral tert-cyclobutanols with moderate to good enantioselectivity. © 2002 Elsevier Science Ltd. All rights reserved.
involving CꢀC bond cleavage proceeded to give both
chiral ketones and unreacted chiral alcohols. Enzymatic
kinetic resolution of rac-benzoin via CꢀC bond cleavage
was reported quite recently.11 On the other hand, non-
enzymatic kinetic resolution of alcohols via CꢀC bond
cleavage has scarcely been reported, and also kinetic
resolution of tert-alcohols has not yet been described in
the literature so far.4 We wish to report here the results
of the Pd-catalyzed kinetic resolution of tert-
cyclobutanols.
Many useful and excellent methods for non-enzymatic
kinetic resolution1 of racemic alcohols, such as acylation,2
epoxidation3 and oxidation of a hydroxyl group,4 has
appeared in recent years.5 Among them the metal-cata-
lyzed oxidative kinetic resolution of secondary alcohols
is one of the attractive techniques, the successful results
of which being obtained using Ru(II) and Pd(II) com-
plexes. Forexample, Noyori etal. reported theRu(II)-cat-
alyzed kinetic resolution of sec-alcohols by hydrogen
transfer.4b Chiral Ru-porphyrin catalysis was studied by
Gross et al.4c Our group also reported highly effective
kinetic resolution of various sec-alcohols using chiral
Ru(II) complex under hydrogen transfer conditions.6
Quite recently, Pd(II)-catalyzed oxidative kinetic resolu-
tion of sec-alcohols using oxygen as a sole oxidant was
reported by two groups, independently.4g,h
As chiral ferrocene-based ligand was disclosed to be
effective for the enantioselective CꢀC bond cleavage of
tert-cyclobutanols in our previous study,10 we first exam-
ined the arylation of racemic alcohol 1a (0.1 mmol) with
bromobenzene (0.06 mmol) in toluene in the presence of
a catalytic amount of Pd(OAc)2, (R)-(S)-PPFA I {(R)-
N,N-dimethyl-1-[(S)-2-(diphenylphosphino)ferrocenyl]-
ethylamine}, and Cs2CO3 (Eq. (1)). The results obtained
under several conditions are listed in Table 1. As a result,
1awasconsumedintheoreticalamounttogiveanarylated
ketone 2a in 52% yield with 34% ee and 40% of the alcohol
1a was recovered with 49% ee (entry 1). The selectivity
factor (krel values)12 did not depend much on the concen-
tration of the reaction mixture (entries 1–3). The increase
of the amount of base (0.2 mmol) slightly increased the
krel value (entry 4), while the reduction of the amount of
the ligand I slightly decreased it (entry 5). Among
analogous ligands I–III,13 the best krel value (5.5) was
obtained when the reaction was carried out using the
ligand III at 50°C (entry 8).
Recently, we have been studying the Pd(II)-catalyzed
oxidative transformation of primary, secondary and
tertiary alcohols.7,8 We also reported Pd(0)-catalyzed
arylation of tert-cyclobutanols with aryl bromide involv-
ing CꢀC bond cleavage9 and its asymmetric version10
(Scheme 1). During these studies we found that the kinetic
resolution of racemic tert-cyclobutanols via the arylation
cat. Pd(OAc)2
chiral ligand
R1
R1
R2
R3
R3
ArBr
Ar
*
base
OH
R2
O
β-carbon
elimination
R1
R2
R3
R1
COR3
R2
OPdArL*
PdArL*
Scheme 1.
* Corresponding author.
(1)
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00413-6

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T. Nishimura et al. / Tetrahedron Letters 43 (2002) 3037–3039
Table 1. Palladium-catalyzed kinetic resolution of tert-cyclobutanol 1aa
Entry
Ligand
(mmol)
Cs2CO3
(mmol)
Toluene
(mL)
Temp. (°C)
Time (h)
Product 2a
Recovered alcohol 1a krel
Yield (%)b
Ee (%)c
Yield (%)b
ee (%)c
1
2
3
4
5
6
I (0.02)
I (0.02)
I (0.02)
I (0.02)
I (0.01)
II (0.02)
III (0.02)
III (0.02)
0.1
0.1
0.1
0.2
0.2
0.2
0.2
0.2
0.5
1.0
1.5
1.0
1.0
1.0
1.0
0.5
80
80
80
80
80
80
80
50
36
36
52
33
36
36
39
48
52
48
42
50
52
60
59
54
34
35
31
43
35
28
37
47
40
43
48
40
34
26
31
43
49
42
38
52
42
54
70
65
3.1
2.8
2.9
3.3
2.2
2.3
3.7
5.5
7
8d
a Reaction conditions: alcohol 1a (0.1 mmol), Pd(OAc)2 (0.005 mmol), PhBr (0.06 mmol).
b GLC yield based on 1a.
c Determined by HPLC. Absolute configuration of a rich enantiomer was not determined.
d PhBr (0.055 mmol) was used.
Me
R, R' = Me: (R)-(S)-PPFA, I
alcohol 3 (entries 6–9), which has H atoms at angular
positions, total material balance was not kept well
because of the formation of dehydrogenated ring-open-
ing ketone (a phenyl group is not introduced),7g which
may be formed by b-hydrogen elimination from the
intermediate alkylpalladium species produced via b-car-
bon elimination of an alkoxypalladium species. In addi-
tion, we confirmed that 3 gradually decomposed even in
the absence of bromobenzene under similar conditions
to produce the same dehydrogenated product together
with a small amount of unidentified products.14 Even in
such a case, the recovered alcohol was found to be
optically active (after 23 h, 55% recovery, 20% ee). The
reduction of the amount of base improved the balance
of the total yield (entry 7). When the reaction was
carried out using bromobenzene (0.2 mmol), the
improvement of both total yield and krel value was
observed, although competitive side reaction could not
be completely avoided (entry 8). The resolution of 3
Fe
PPh2
R
R, R' = -CH2CH2OCH2CH2-: (R)-(S)-II
R = Me, R' = cyclohexyl: (R)-(S)-III
N
R'
O
H
H
Ar
OH
Ar
Ph
n
n
R
R
1: n = 1, R = Me
3: n = 1, R = H
5: n = 2, R = H
2: n = 1, R = Me
4: n = 1, R = H
6: n = 2, R = H
Table 2 shows the results of the kinetic resolution of
some racemic tert-cyclobutanols. The tert-cyclobu-
tanols 1 bearing different aryl substituents also served
as substrates, significant substituent effects of which
being not observed (entries 1–5). In the case of the
Table 2. Palladium-catalyzed kinetic resolution of tert-cyclobutanols 1a–1e, 3 and 5a
Entry
Alcohol
(0.2 mmol)
Ar
Product
ketone
Temp. (°C)
Time (h)
Product ketone
Recovered alcohol
krel
Yield (%)b
ee (%)
Yield (%)b
ee (%)
1
2
3
4
5
6
1
1
1
1
1
3
3
3
3
5
a: Ph
b: 4-ClC6H4
c: 4-MeC6H4
d: 4-MeOC6H4
2a
2b
2c
2d
2e
4
4
4
4
6
50
50
50
50
50
50
50
50
Rt
50
24
35
36
36
35
24
28
15
65
48
48
45
36
27
39
45
47
58
35
55
56
60
67
68
67
50
64
51
77
68
46
54
63
72
61
25
38
31
61
43
59
46
28
26
40
82
62
92
37
84
5.3
4.9
3.7
6.5
6.4
3.9
4.0
7.1
5.3
11.4
e: 2-naphthyl
Ph
Ph
Ph
Ph
Ph
7c
8d
9d
10
a Reaction conditions: alcohol (0.2 mmol), Pd(OAc)2 (0.01 mmol), ligand III (0.04 mmol), PhBr (0.11 mmol), Cs2CO3 (0.4 mmol), toluene (1 mL)
under N2.
b Isolated yield based on the alcohol employed.
c Cs2CO3 (0.11 mmol) was used.
d PhBr (0.2 mmol) was used.

T. Nishimura et al. / Tetrahedron Letters 43 (2002) 3037–3039
3039
could be performed even at room temperature (ca. 28°C)
after 65 h (entry 9). The best krel value was obtained using
the alcohol 5 as a substrate, which reached 11.4.
M.; Yoshihisa, H.; Cortona, M. N.; Kawakami, Y.; Gao,
Z.; Tanaka, H. Tetrahedron Lett. 2000, 41, 8131; (f)
Masutani, K.; Uchida, T.; Irie, R.; Katsuki, T. Tetra-
hedron Lett. 2000, 41, 5119; (g) Jensen, D. R.; Pugsley, J.
S.; Sigman, M. S. J. Am. Chem. Soc. 2001, 123, 7475; (h)
Ferreira, E. M.; Stoltz, B. M. J. Am. Chem. Soc. 2001,
123, 7725.
In summary, we have demonstrated the palladium-cata-
lyzed kinetic resolution of tert-cyclobutanols via CꢀC
bond cleavage. This resolution can produce the chiral
ketones and alcohols, in which the ketones include a
quaternary chiral carbon center. Our efforts to improve
the selectivity and to expand the scope of this resolution
are now in progress.
5. Another method, see: Sekar, G.; Nishiyama, H. J. Am.
Chem. Soc. 2001, 123, 3603.
6. Nishibayashi, Y.; Takei, I.; Uemura, S.; Hidai, M.
Organometallics 1999, 18, 2291.
7. (a) Nishimura, T.; Onoue, T.; Ohe, K.; Uemura, S.
Tetrahedron Lett. 1998, 39, 6011; (b) Nishimura, T.; Ohe,
K.; Uemura, S. J. Am. Chem. Soc. 1999, 121, 2645; (c)
Nishimura, T.; Onoue, T.; Ohe, K.; Uemura, S. J. Org.
Chem. 1999, 64, 6750; (d) Nishimura, T.; Kakiuchi, N.;
Inoue, M.; Uemura, S. Chem. Commun. 2000, 1245; (e)
Nishimura, T.; Maeda, Y.; Kakiuchi, N.; Uemura, S. J.
Chem. Soc., Perkin Trans. 1 2000, 4301; (f) Kakiuchi, N.;
Nishimura, T.; Inoue, M.; Uemura, S. Bull. Chem. Soc.
Jpn. 2001, 74, 165; (g) Nishimura, T.; Ohe, K.; Uemura,
S. J. Org. Chem. 2001, 66, 1455.
8. Pd(II) complex-catalyzed kinetic resolution of sec-alco-
hols: Miyake, Y.; Iwata, T.; Chung, K.-G.; Nishibayashi,
Y.; Uemura, S. Chem. Commun. 2001, 2584.
9. Nishimura, T.; Uemura, S. J. Am. Chem. Soc. 1999, 121,
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