Chiral terpene auxiliaries IV: new monoterpene PHOX ligands and their application in the catalytic asymmetric transfer hydrogenation of ketones

Article abstract of DOI:10.1016/j.tetasy.2017.02.003

New PHOX ligands, derived in three steps from (1R, 2S, 3R, 5R)-3-amino-apopinan-2-ol 1 and (1R, 2R, 3S, 5R)-3-amino-pinan-2-ol 2 were applied as chiral ligands for the formation of ruthenium catalysts. The catalysts were used in asymmetric transfer hydrogenations of prochiral ketones producing the corresponding alcohols in moderate to high yields and enantioselectivity.

Full text of DOI:10.1016/j.tetasy.2017.02.003

Tetrahedron: Asymmetry xxx (2017) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Chiral terpene auxiliaries IV: new monoterpene PHOX ligands and
their application in the catalytic asymmetric transfer hydrogenation
of ketones
⇑
Anna Kmieciak, Marek P. Krzemi n´ ski
Faculty of Chemistry, Nicolaus Copernicus University in Toru n´ , 7 Gagarin St., Toru n´ , Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
New PHOX ligands, derived in three steps from (1R,2S,3R,5R)-3-amino-apopinan-2-ol 1 and
Received 11 January 2017
Revised 23 January 2017
Accepted 7 February 2017
Available online xxxx
(
1R,2R,3S,5R)-3-amino-pinan-2-ol 2 were applied as chiral ligands for the formation of ruthenium cata-
lysts. The catalysts were used in asymmetric transfer hydrogenations of prochiral ketones producing the
corresponding alcohols in moderate to high yields and enantioselectivity.
Ó 2017 Elsevier Ltd. All rights reserved.
1
. Introduction
OH
HO
H
2
N
2
H N
Chiral phosphine-oxazoline (PHOX) ligands, introduced inde-
pendently by Pfaltz, Helmchen2 and Williams,3 are efficient,
1
(
1S,5S)-β-pinene (1S,5S)-α-pinene
1
2
non-C
2
-symmetric, P,N-chelating ligands. They have been applied
4
in various catalytic asymmetric reactions, such as hydrogenation
of olefins, ketones and imines, transfer hydrogenations of
ketones, allylic alkylations, different types of allylations, Heck
5
6
7
Scheme 1. Amino alcohols from b- and a-pinene.
8
9
10
11
13
1
2
and Diels–Alder
reactions, conjugate additions to enones,
Baeyer–Villiger oxidations,14 and Mannich reaction.
15
In continuation of our studies on the synthesis and applications
of monoterpene derived ligands, we have utilized amino alcohols 1
and 2 to the synthesis of PHOX ligands, and used them for the
asymmetric transfer hydrogenation of ketones. To the best of our
knowledge, only Masamune used the monoterpene amino alcohol,
Enantiomerically pure oxazolines with a stereogenic carbon
atom next to the nitrogen have been synthesized by several meth-
1
6
ods. The synthesis usually involves the preparation of 2-(2-halo-
geno-phenyl)oxazolines and then the formation of phosphine
derivatives via substitution of the halogen. The most utilized pre-
3
-amino-isoborneol, derived from camphor, for the synthesis of
bis-oxazoline (BOX) ligands.
2
2
cursors, b-amino alcohols, readily derived from
a-amino acids,
17
can be condensed with substituted benzoic acids,
2-substi-
18
tuted-benzonitriles in the presence of ZnCl
2
.
PHOX ligands can
2. Results and discussion
also be synthesized in three steps from b-amino alcohols and sub-
stituted benzoyl chlorides.19 Modifications of PHOX ligands can be
(1R,2S,3R,5R)-3-Amino-apopinan-2-ol 1 was reacted with 2-flu-
orobenzoyl chloride to give 2-fluoro-N-((1R,2S,3R,5R)-2-hydroxy-
6,6-dimethyl-bicyclo[3.1.1]heptan-3-yl)benzamide 3 in 90% yield.
made at the carbon atom
aryl groups on phosphorus.
a to the oxazoline nitrogen and at the
16
1
9b
Recently, we synthesized (1R,2S,3R,5R)-3-amino-apopinan-2-ol
By applying the Masamune protocol,
3 was cyclized in the
1
from readily available (1S,5S)-b-pinene20 and (1R,2R,3S,5R)-3-
presence of dibutyltin dichloride in refluxing p-xylene to
fluorophenyloxazoline 4 in 96% yield. Substitution of the fluorine
atom with a diphenylphosphino group led to the final product –
PHOX ligand 5 in 55% yield (Scheme 2). Ligand 5 in combination
amino-pinan-2-ol 2 from (1S,5S)-
a-pinene (Scheme 1). We applied
20a
1
and 2 for the synthesis of oxazaborolidines
and spiroborate
2
1
esters, which proved to be convenient catalysts for the enantios-
elective reductions of aryl–alkyl ketones with borane.
3 3 2
with [Ph P] RuCl was applied for the preparation of chiral
ruthenium catalyst Ru-5.
3 3 2
The reaction of 5 with [Ph P] RuCl in toluene, followed by
evaporation, dissolution and filtration of the crude complex in
⇑
Corresponding author.
E-mail address: mkrzem@umk.pl (M.P. Krzemi n´ ski).
http://dx.doi.org/10.1016/j.tetasy.2017.02.003
957-4166/Ó 2017 Elsevier Ltd. All rights reserved.
0
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tetasy.2017.02.003

2
A. Kmieciak, M. P. Krzemi n´ ski / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
applying the best conditions for the asymmetric transfer
hydrogenation of acetophenone catalyzed by Ru-5 in isopropanol.
Asymmetric transfer hydrogenation reactions were carried out
OH
OH
H
N
2
H N
Et
CH
90%
3
N
+
Cl
2
COCl
2
F
O
using 0.05 mol% of Ru-5 catalyst, NaOH or t-BuOK as
base in refluxing isopropanol with 0.25 M ketone concentration
Table 2).
Changing the methyl group in acetophenone to an ethyl group
a
F
1
3
(
2 2
Bu SnCl
9
6%
p-xylene
in propiophenone resulted in a decrease in the reaction yield but
the enantiomeric purity of the product alcohol was maintained
O
N
O
2
Ph PK
(Table 2, entries 1–2). The reduction of bromoacetophenone
THF
5%
N
caused in situ cyclization of the intermediate bromohydrin to
phenyloxirane in a slightly lower yield and ee compared to
acetophenone (Table 2, entry 3). A strong electronegative group
PPh
2
F
5
5
4
(
trifluoromethyl) on the alkyl side of ketone led to a dramatic
Scheme 2. Synthesis of chiral oxazoline 5.
decrease in the enantiomeric excess of the alcohol (6–8% ee).
Transfer hydrogenation of acetophenone derivatives substituted
on the aromatic ring with methoxy groups led to alcohols with
enantiomeric excesses of 75–89% ee regardless of the substituent
position. Acetophenone derivatives with strong deactivating ring
isopropanol to a volumetric flask, afforded a solution of chiral
ruthenium catalyst Ru-5 of known concentration.
Initially, we examined the catalytic activity of Ru-5 in the
asymmetric transfer hydrogenation of acetophenone as a model
ketone. Reductions were carried out in the presence of 1.0, 0.5,
2 3
substituents (NO , CF ) were not reduced or the racemic product
was obtained. In the case of ketones with weakly deactivating
aromatic ring substituents (fluorine), the reduction occurred in
low yields and enantiomeric excess. 1-Indanone and 1-tetralone
were reduced with similar enantioselectivity, 78–87% ee (Table 2,
entries 11, 12).
The reduction of 1- and 2-acetonaphthylene to the correspond-
ing naphthylethanols proceeded with high selectivity (82–85% ee)
while the yield depended on the acetyl group position (Table 3,
entries 13, 14).
Unfortunately, ketones with two groups of a similar size or alkyl
alkyl ketones were reduced with low selectivity, e.g. 2-octanone
gave 2-octanol in 92% yield and 32% ee. 2-Naphthyl phenyl ketone
and 2-benzofuryl-phenyl ketone gave the corresponding racemic
alcohols in 14–32% yield (Table 2, entries 15–17).
0
.1, 0.075, 0.05, 0.025, and 0.01 mol% of Ru-5. The catalyst was stir-
red with a solution of sodium hydroxide in degassed isopropanol
for 15 min. Acetophenone was added and the solution was refluxed
for 0.5 h. The reaction mixture was concentrated and (S)-1-pheny-
lethanol was isolated by column chromatography on silica gel. The
results are summarized in Table 1. The reduction of acetophenone
was completed within 0.5 h in almost all cases except for the low-
est loads of catalyst (0.025 and 0.01 mol%, Table 1, entries 6, 7).
Lowering the catalyst load from 1 to 0.05 mol% increased the ee
value of the product to 90% (Table 1, entries 1–5).
The transfer hydrogenation of ketones carried out in iso-
propanol is a reversible process, therefore the reactions are con-
ducted in dilute solutions. To check the influence of ketone
concentration, the reductions were carried out in 0.25 M and
The influence of the monoterpene structure on the enantiose-
0
.1 M solutions of acetophenone in isopropanol in the presence
lectivity of reduction was also examined. Thus, (1S,5S)-
a-pinene
of 0.05 mol% of Ru-5 and sodium hydroxide or potassium tert-
butoxide (Table 1, entries 5–8). We found that the concentration
of ketone and the type of the base play insignificant roles in the
reaction. From an economic point of view, we decided to conduct
all reactions in more concentrated solutions (0.25 M) of ketones.
The enantioselectivity of the reduction of various prochiral
aryl–alkyl, aryl–aryl, and alkyl–alkyl ketones was explored by
was transformed into amino alcohol 2 in three steps using known
2
3
procedures. It was reacted with 2-bromobenzoyl chloride to give
amide 6 in 64% yield, which was cyclized in the presence of dibu-
tyltin dichloride to 2-bromophenyloxazoline 7 in 62% yield. In the
last step, 7 was treated with n-butyl lithium followed by the reac-
tion with chlorodiphenylphosphine to give PHOX ligand 8 in 63%
yield (Scheme 3).
Table 1
Asymmetric transfer hydrogenation of acetophenone catalyzed by complex Ru-5
O
OH
Ru-5, base
i-PrOH
reflux
Ph
Ph
Entry
1e
Ru-5a (mol%)
Base
Yieldb (%)
eec,d (%)
1
0.5
0.1
0.075
0.05
0.05
0.05
0.05
0.025
0.001
NaOH
NaOH
NaOH
NaOH
NaOH
t-BuOK
NaOH
t-BuOK
NaOH
NaOH
93
98
84
84
98
99
98
94
34
3
78
75
76
80
90
90
93
91
85
71
e
2
e
3
e
4
e
5
e
6
7
f
f
8
e
9
1
0e
a
b
c
d
e
f
The preparation of Ru-5 is described in the Experimental.
Isolated yield.
TM
ee determined by GC analyses on a chiral column, Supelco beta-DEX 325 , 30 m ꢀ 0.25 mm.
The S configuration of 1-phenylethanol was assigned by comparison of the sign of the rotation with the literature data.
The reaction was carried out with acetophenone concentration of 0.25 M.
The reaction was carried out with acetophenone concentration of 0.1 M.
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A. Kmieciak, M. P. Krzemi n´ ski / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
3
of catalyst to 0.1 mol% increased the yield to 72% and selectivity
to 37% ee. The reduction of propiophenone led to 1-phenyl-
propanol in very good yield (93%) and enantiomeric excess of
HO
HO
H
N
2
H N
Et
CH
84%
3
N
2
Cl
2
Br
O
5
1%. From all methoxy acetophenone derivatives, the correspond-
COCl
2
6
ing 1-arylethanols were obtained with average yields (49–66%)
and low enantiomeric excesses (10–39% ee) (Table 3, entries
3–5). The reduction of 2-acetonaphthylene, in contrast to the reac-
tion catalyzed by Ru-5, gave the product with a low enantiomeric
excess (28% ee) in good yield (88%) (Table 3, entry 6).
Br
Bu SnCl
2 2
6
2%
p-xylene
O
N
1
) n-BuLi
2) Ph PCl
THF
3%
O
2
N
3
. Conclusion
PPh
2
Br
6
8
7
Terpene PHOX ligands have been synthesized by simple meth-
ods in good yields. Ligand 5, obtained from 3-amino-apopinan-2-
ol 1 and complexed with [Ph P] RuCl , catalyzed the asymmetric
Scheme 3. Synthesis of chiral oxazoline 8.
3
3
2
transfer hydrogenation of various prochiral ketones with iso-
propanol as a source of hydrogen. The stereochemistry of the
precursor amino alcohols is a key factor in influencing the enan-
tioselectivity of the obtained ligands and catalysts. Catalyst Ru-5
gives much better results in the asymmetric transfer hydrogena-
tion of ketones than Ru-8, and reductions proceed with higher
yields and higher enantiomeric excesses. Much lower amounts of
Ru-5 than Ru-8 can be used. The lower reactivity and enantioselec-
tivity of Ru-8 may be the consequence of the trans-position of the
The reaction of [Ph
the same procedure as for Ru-5, and the stock solution of Ru-8
0.05 M) in isopropanol was prepared.
Employing the best conditions for the asymmetric transfer
hydrogenation of ketones catalyzed by Ru-5, acetophenone was
reduced in the presence of Ru-8 to 1-phenylethanol with only
7% yield and 24% ee (Table 3., entry 1). Increasing the amount
3 3 2
P] RuCl with ligand 8 was carried out using
(
2
Table 2
Asymmetric transfer hydrogenation of ketones with Ru-5 as catalyst
a
O
Ru-5, base
OH
R1
R2
i-PrOH
reflux
R1
R2
Entry
1
R1
R2
Base
Yieldb (%)
eec (%)
Conf.d
Ph
Me
NaOH
t-BuOK
NaOH
t-BuOK
NaOH
NaOH
t-BuOK
NaOH
t-BuOK
NaOH
t-BuOK
NaOH
t-BuOK
NaOH
t-BuOK
NaOH
NaOH
98
99
88
89
90
90
90
93
(S)
2
Ph
Et
(S)
e
e
(S)e
(R)
3
4
Ph
Ph
CH
CF
2
Br
68
81
3
68
70
99
57
35
63
66
99
19
35
88
8
5
5
6
7
8
9
2-MeOC
3-MeOC
4-MeOC
6
6
6
H
H
H
4
4
4
Me
Me
Me
Me
82
87
75
89
81
77
61
43
rac
—
(S)
(S)
(S)
(S)
3-FC
3-CF
6
H
4
3
C
6
H
4
Me
Me
—
—
f
1
0
1
4-NO
2
C
6
H
4
Nr
1
1-Indanone
1-Tetralone
NaOH
t-BuOK
NaOH
97
96
53
67
78
87
79
87
(S)
1
2
(S)
t-BuOK
13
14
15
16
1-Naph
Me
Me
Ph
NaOH
t-BuOK
NaOH
t-BuOK
NaOH
t-BuOK
NaOH
39
45
95
96
14
20
25
32
82
82
85
83
2
8
rac
2
(S)
(S)
—
2-Naph
2-Naph
2-Benzo-furyl
Ph
—
t-BuOK
1
7
2-Octanone
NaOH
92
32g
(S)
a
b
c
d
e
f
The solution of Ru-5 is described in the Experimental.
Isolated yield.
TM
Determined by GC or HPLC analyses on a chiral columns, Supelco beta-DEX 325 , 30 m ꢀ 0.25 mm or Chiraldex OD-H, 250 ꢀ 4.6 mm, 5
lm.
Assigned by comparison of the sign of the specific rotation with the literature data.
For phenyloxirane.
No reaction was observed.
Assigned for p-nitrobenzoate derivative.
g
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A. Kmieciak, M. P. Krzemi n´ ski / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
Table 3
Asymmetric transfer hydrogenation of ketones catalyzed with Ru-8
O
OH
Ru-8, NaOH
R1
R2
R1
R2
i-PrOH
reflux
Entry
1
R1
R2
Ru-8 (mol%)a
Yieldb (%)
eec (%)
Conf.d
Ph
Me
0.05
27
72
66
93
53
49
66
88
24
37
36
51
10
32
39
28
(R)
0
0
.1
.5
2
3
4
5
6
Ph
Et
0.1
0.1
0.1
0.1
0.1
(R)
(R)
(R)
(R)
(R)
2-MeOC
3-MeOC
4-MeOC
2-Naph
6
H
6
H
6
H
4
4
4
Me
Me
Me
Me
a
b
c
The solution of Ru-8 was prepared according to the Experimental.
Isolated yield.
TM
Determined by GC or HPLC analyses on a chiral columns, Supelco beta-DEX 325 , 30 m ꢀ 0.25 mm or Chiraldex OD-H, 250 ꢀ 4.6 mm, 5
lm.
d
Assigned by comparison of the sign of the specific rotation with the literature data.
2
D
0
oxazoline ring to the gem-dimethyl bridge in the pinane ring
system.
white crystals, mp 128–130 °C, ½
a
ꢁ
¼ þ9:1 (c 1.01, CHCl
3
). IR:
m
.
ꢂ1
3398, 3313, 2905, 1625, 1611, 1513, 1479, 1030, 761, 521 cm
1
H NMR (CDCl
1H), 1.74 (dd, J = 13.6, 7.8 Hz, 1H), 1.98 (q, J = 5.1 Hz, 1H), 2.16–
.24 (m, 1H), 2.24–2.32 (m, 1H), 2.53 (br. s., 1H), 2.65 (ddd,
J = 13.9, 9.2, 4.9 Hz, 1H), 4.49 (dd, J = 8.4, 4.8 Hz, 1H), 4.63 (m,
H), 7.08 (ddd, J = 12.0, 8.3, 1.2 Hz, 1H), 7.22 (td, J = 7.6, 1.2 Hz,
1H), 7.38–7.48 (m, 1H), 7.57–7.71 (m, 1H), 8.05 (td, J = 7.9,
3
): d 1.07 (s, 3H), 1.23 (s, 3H), 1.33 (d, J = 10.1 Hz,
4
4
. Experimental
2
.1. General
1
Experiments with air and moisture sensitive materials were
1
3
carried out under an argon atmosphere. Glassware was oven dried
3
1.8 Hz, 1H). C NMR (CDCl ): d 22.6, 25.2, 27.2, 33.2, 38.2, 40.5,
1
for several hours, assembled hot, and cooled in a steam of argon. H
43.8, 46.8, 71.7, 115.9 (d, J = 24.6 Hz), 121.3 (d, J = 11.4 Hz), 124.6
(d, J = 3.3 Hz), 131.8 (d, J = 2.1 Hz), 133.0 (d, J = 9.2 Hz), 160.6 (d,
1
3
and C NMR spectra were recorded on a Bruker AMX 300 MHz
instrument. Optical rotations were measured on an Optical Activity
PolAAr 3000 automatic polarimeter. GC analyses were performed
on a Perkin–Elmer Auto System XL chromatograph, and HPLC anal-
yses on a Shimadzu LC-10AT chromatograph. Melting points were
determined in an open glass capillaries and are uncorrected.
Elemental analyses were performed on Vario MACRO CHN,
ELEMENTAR Analysensysteme GmbH instrument.
1
9
J = 246 Hz), 163.0 (d, J = 3.3 Hz). F NMR (CDCl
ꢂ37.23. Anal. Calcd for C16 20FNO : C, 69.29; H, 7.27; N, 5.05.
Found: C, 69.15; H, 7.18; N, 5.00.
3
): d ꢂ37.44 to
H
2
4.4. (3aR,5R,7R,7aS)-2-(2-Fluorophenyl)-6,6-dimethyl-3a,4,5,6,7,
7a-hexahydro-5,7-methanobenzo[d]oxazole 4
Amide 3 (1.109 g, 4 mmol) was suspended in p-xylene (80 mL)
and heated at reflux with a Dean–Stark trap for 30 min under
nitrogen. The reaction was cooled below boiling point and dibutyl
tin dichloride (61 mg, 0.2 mmol) was added. The mixture was then
refluxed for 24 h. After evaporation of the solvent on a rotary evap-
orator under vacuum, the residue was purified by flash column
chromatography on silica gel (hexane/ethyl acetate = 80:20).
4
.2. Materials
Silica Gel 60, Merck 230–400 mesh was used for preparative
column chromatography. Macherey–Nagel Polygram Sil G/UV254
.2 mm plates were used for analytical TLC. Tetrahydrofuran was
freshly distilled from sodium benzophenone ketyl. (1R,2S,3R,5R)-
0
20
3
2
-Amino-apopinan-2-ol 1 and (1R,2R,3S,5R)-3-amino-pinan-2-ol
Oxazoline 4 (0.996 g, 96% yield) was obtained as colorless oil,
2
3
20
D
were prepared according to the literature.
½
a
1
ꢁ
¼ ꢂ34:2 (c 0.91, CHCl
3
). IR: m 2921, 1643, 1456, 1349, 1219,
ꢂ1
1
3
057, 1027, 1012, 982, 761, 743 cm . H NMR (CDCl ): d 0.87 (s,
4
.3. 2-Fluoro-N-((1R,2S,3R,5R)-2-hydroxy-6,6-dimethylbicyclo
3H), 1.07 (d, J = 10.3 Hz, 1H), 1.24 (s, 3H), 1.98–2.11 (m, 2H),
2.32–2.43 (m, 1H), 2.43–2.56 (m, 2H), 4.59 (td, J = 10.8, 4.9 Hz,
[
3.1.1]heptan-3-yl)benzamide 3
1
H), 5.00 (dd, J = 10.9, 4.5 Hz, 1H), 7.09–7.20 (m, 2H), 7.38–7.47
1
3
(
1R,2S,3R,5R)-3-Amino-apopinan-2-ol 1 (3.105 g, 20.0 mmol)
3
(m, 1H), 7.84 (td, J = 7.5, 2.0 Hz, 1H). C NMR (CDCl ): d 20.8,
and triethylamine (3.036 g, 30 mmol) were dissolved in dichloro-
methane (20 mL) under a nitrogen atmosphere and cooled in an
ice bath to 0 °C. 2-Fluorobenzoyl chloride (3.171 g, 20 mmol) in
dichloromethane (10 mL) was added dropwise with vigorous stir-
ring. The reaction mixture was stirred at 0 °C for 30 min, at rt for
27.6, 28.3, 33.1, 37.9, 40.6, 43.4, 59.6, 84.2, 116.6 (d, J = 10.6 Hz),
116.6 (d, J = 21.9 Hz), 123.8 (d, J = 3.8 Hz), 130.9 (d, J = 1.9 Hz),
132.5 (d, J = 8.7 Hz), 160.9 (d, J = 5.5 Hz), 161.0 (d, J = 256 Hz). 19
F
NMR (CDCl
3
): d ꢂ33.70 to ꢂ33.83 (m). Anal. Calcd for C16
H18FNO:
C, 74.11; H, 7.00; N, 5.40. Found: C, 74.24; H, 7.37; N, 5.59.
1
h, and water (15 mL) was added to quench the reaction. Layers
were separated, aqueous layer was extracted with dichloro-
methane (3 ꢀ 15 mL). The combined organic layers were washed
with 0.5 M solution of hydrochloric acid (15 mL), a saturated solu-
tion of sodium bicarbonate (15 mL) and brine (20 mL). The solution
was dried over anhydrous magnesium sulfate (VI). After filtration,
the solvent was removed on a rotary evaporator under reduced
pressure and the resulting oil was purified by crystallization
4.5. (3aR,5R,7R,7aS)-2-(2-(Diphenylphosphino)phenyl)-6,6-di-
methyl-3a,4,5,6,7,7a-hexahydro-5,7-methanobenzo[d]oxazole 5
A solution of oxazoline 4 (0.970 g, 3.75 mmol) in dry and
degassed THF (10 mL) was added dropwise to potassium
diphenylphosphide (8 mL 0.5 M in THF, 4.0 mmol) in THF (8 mL)
at room temperature, under nitrogen. The reaction mixture was
stirred at reflux overnight. The reaction was quenched with
(
cyclohexane–toluene) to yield 4.992 g (90%) of the amide 3 as
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A. Kmieciak, M. P. Krzemi n´ ski / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
5
degassed water (10 mL) and the mixture was extracted with ethyl
acetate (3 ꢀ 10 mL). The combined organic layers were dried over
anhydrous magnesium sulfate (VI). After filtration and evaporation
of the solvent, the residue was purified by flash column chro-
matography on silica gel (hexane/ethyl acetate = 80:20). Recrystal-
lization from n-hexane gave 5 (0.89 g, 55%) as white crystals, mp
121.7, 127.0, 130.5, 131.1, 131.2, 133.6, 161.3. Anal. Calcd
for C17 20BrNO: C, 61.09; H, 6.03; N, 4.19. Found: C, 61.26; H,
6.19; N, 4.30.
H
4
.8.
(3aS,5R,7R,7aR)-2-(2-(Diphenylphosphino)phenyl)-6,6,7a-
trimethyl-3a,4,5,6,7,7a-hexahydro-5,7-methanobenzo[d]oxazole 8
2
0
6
1
3
2
1
7–69 °C, ½
a
ꢁ
¼ þ90:3 (c 1.00, CHCl
3
). IR:
m
2911, 1639, 1433,
D
ꢂ1
1
010, 740, 694, 683, 484, 454 cm
.
H NMR (CDCl ): d 0.87 (s,
3
At first, n-BuLi (2.5 M solution in hexane, 0.84 mL, 2.1 mmol)
was added dropwise to a solution of oxazoline 7 (0.334 g, 1 mmol)
in dry THF (1 mL) at ꢂ78 °C under argon. The resulting solution
was stirred at ꢂ78 °C for 30 min and chlorodiphenylphosphine
H), 1.07 (d, J = 10.3 Hz, 1H), 1.24 (s, 3H), 1.98–2.11 (m, 2H),
.32–2.43 (m, 1H), 2.43–2.56 (m, 2H), 4.59 (td, J = 10.8, 4.9 Hz,
H), 5.00 (dd, J = 10.9, 4.5 Hz, 1H), 7.09–7.20 (m, 12H), 7.38–7.47
(
m, 1H), 7.84 (td, J = 7.5, 2.0 Hz, 1H). 13C NMR (CDCl
3
): d 21.0,
(
0.420 g, 1.9 mmol) in dry THF (2 mL) was added at the same tem-
2
1
7.6, 28.2, 32.7, 37.9, 40.5, 43.4, 59.6, 84.0, 127.9, 128.3, 128.4,
28.4, 128.4, 128.6, 129.7 (d, J = 2.4 Hz), 130.2, 131.8 (d,
perature. The mixture was stirred 4 h at ꢂ78 °C and then a
degassed solution of NaOH (2 M, 1 mL, 2 mmol) was added. Stirring
was continued overnight at room temperature. After dilution with
THF (10 mL), the solution was dried over anhydrous magnesium
sulfate (VI). After filtration, the solvent was removed on a rotary
evaporator, the residue was purified by flash column chromatogra-
phy on silica gel (petroleum ether/ethyl acetate = 80:20). Product 8
J = 17.5 Hz), 133.0 (d, J = 19.7 Hz), 133.7 (d, J = 1.8 Hz), 133.8,
1
34.1, 134.4, 134.6, 138.2 (d, J = 9.3 Hz), 138.4 (d, J = 13.0 Hz),
31
1
39.0 (d, J = 25.6 Hz), 163.5 (d, J = 3.8 Hz).
28NOP: C, 79.24; H, 6.67; N, 3.59.
Found: C, 79.11; H, 6.49; N, 3.71.
3
P NMR (CDCl ):
d ꢂ5.40. Anal. Calcd for C28
H
(
0.276 g, 63%) was obtained as a white solid, mp 94–95 °C.
4
.6. 2-Bromo-N-((1R,2R,3S,5R)-2-hydroxy-2,6,6-trimethylbicyc-
20
½
a
ꢁ
¼ ꢂ30:8 (c 1.00 CHCl
3
). IR:
H NMR (CDCl
m
2928, 1619, 1435, 1013, 767,
): d 0.75 (d, J = 10.5 Hz, 1H),
D
lo[3.1.1]heptan-3-yl)benzamide 6
ꢂ1
1
7
0
1
3
22, 692, 542 cm
.
3
.82 (s, 3H), 1.18 (s, 3H), 1.22 (s, 3H), 1.40–1.53 (m, 1H), 1.73 (m,
2
-Bromobenzoyl chloride (2.195 g, 10 mmol) in dichloro-
methane (5 mL) was added dropwise, under nitrogen atmosphere
at 0 °C, to solution of (1R,2R,3S,5R)-3-amino-pinan-2-ol
1.693 g, 10 mmol) and triethylamine (1.518 g, 15 mmol) in
dichloromethane (10 mL). The solution was stirred at 0 °C for
0 min and at rt for 1 h. Water (15 mL) was added to quench the
H), 1.93–2.08 (m, 2H), 2.10–2.23 (m, 1H), 3.92 (dd, J = 10.0,
13
.0 Hz, 1H), 6.82 (m, 1H), 7.23–7.38 (m, 12H), 7.89 (m, 1H).
C
a
2
3
NMR (CDCl ): d 23.4, 25.7, 26.8, 26.9, 33.0, 38.5, 39.1, 50.3, 65.8,
(
7
1
1
7.2, 127.9, 128.3, 128.3, 128.3, 128.4, 128.4, 128.6, 129.7, 130.3,
31.8, 133.5, 133.7, 133.8, 134.4, 134.7, 138.3 (d, J = 13.8 Hz),
3
31
3
38.5 (d, J = 10.6 Hz), 138.8 (d, J = 26.0 Hz), 161.5. P NMR (CDCl ):
reaction. Layers were separated, aqueous layer was extracted with
dichloromethane (3 ꢀ 15 mL). The combined organic layers were
washed with 0.5 M solution of hydrochloric acid (15 mL), saturated
solution of sodium bicarbonate (15 mL) and brine (20 mL). The
solution was dried with anhydrous magnesium sulfate (VI). After
filtration, the solvent was removed on rotary evaporator under
reduced pressure and the residue was purified by crystallization
d ꢂ5.72. Anal. Calcd for C29
H30NOP: C, 79.25; H, 6.88; N, 3.19.
Found: C, 79.37; H, 6.71; N, 3.25.
4
.9. Catalyst solution Ru-5 and Ru-8
In a one neck flask equipped with a magnetic stirrer and a sep-
tum cap, dichloro tetrakis(triphenylphosphine) ruthenium (II)
(0.479 g, 0.5 mmol) was placed under an argon atmosphere. A
solution of PHOX ligand (0.5 mmol) in dry toluene (5 mL) was then
added. The mixture was stirred for 15 h at room temperature
under argon. The solvent was evaporated under vacuum, and the
solid product was dissolved in anhydrous degassed isopropanol
(
cyclohexane–toluene) to yield 2.960 g (84%) of 6 as white crystals,
2
0
mp 158–159 °C, ½
a
ꢁ
¼ ꢂ1:9 (c 1.03, CHCl
3
). IR:
m
3399, 3349,
D
ꢂ1
1
2
1
1
913, 1631, 1590, 1512, 1453, 757, 597 cm
.
H NMR (CDCl ): d
3
.11 (s, 3H), 1.30 (s, 3H), 1.39 (d, J = 10.3 Hz, 1H), 1.40 (s, 3H),
.62–1.69 (m, 2H) 1.95–2.05 (m, 2H), 2.18–2.30 (m, 1H), 2.69
(
dd, J = 13.1, 10.7 Hz, 1H), 4.53 (dt, J = 9.9, 7.5 Hz, 1H), 6.83 (d,
(
10 mL) and filtered through a syringe filter into a volumetric flask
J = 7.2 Hz, 1H), 7.22–7.30 (m, 1H), 7.35 (td, J = 7.5, 1.2 Hz, 1H),
1
3
(10 mL), where it was stored under argon.
7
3
1
3
.48–7.61 (m, 2H). C NMR (CDCl
8.9, 40.6, 48.8, 54.6, 74.5, 119.3, 127.5, 129.4, 131.0, 133.2,
38.4, 167.3. Anal. Calcd for C17 22BrNO : C, 57.96; H, 6.29; N,
.98. Found: C, 57.89; H, 6.31; N, 3.90.
3
): d 23.7, 28.1, 28.7, 30.1, 36.2,
4
.10. Transfer hydrogenation of acetophenone. General
H
2
procedure
In a two-neck flask (25 mL), under an inert atmosphere, were
placed a catalyst solution (0.05 M in isopropanol, 100 L, 5 mol),
4
3
.7.
(3aS,5R,7R,7aR)-2-(2-Bromophenyl)-6,6,7a-trimethyl-
l
l
a,4,5,6,7,7a-hexahydro-5,7-methanobenzo[d]oxazole 7
a degassed 0.125 M solution of sodium hydroxide or potassium
tert-butoxide in isopropanol (1 mL, 0.125 mmol), and degassed iso-
propanol (4 mL). After stirring for 15 min. at room temperature
acetophenone (120 mg, 1 mmol) was added and the reaction
mixture was refluxed for 30 min. Isopropanol was removed on
rotary evaporator and 1-phenylethanol was isolated by flash col-
umn chromatography on silica gel (eluent: n-hexane:ethyl acetate
Amide 6 (0.704 g, 2 mmol) was suspended in p-xylene (40 mL)
and heated at reflux with a Dean–Stark trap for 30 min under
nitrogen. The reaction was cooled below boiling point and dibutyl
tin dichloride (30 mg, 0.1 mmol) was added. The mixture was
refluxed for 24 h. After evaporation of the solvent on rotary evap-
orator under reduced pressure, the resulting oil was purified by
flash column chromatography on silica gel (hexane/ethyl acet-
ate = 80:20). Oxazoline 7 (0.414 g, 62% yield) was obtained as a
8
0:20).
2
D
0
colorless oil, ½
a
ꢁ
¼ ꢂ29:7 (c 1.21, CHCl
3
). IR:
m
2911, 1644, 1433,
Acknowledgements
ꢂ1
1
1
0
1
2
(
(
336, 1245, 1027, 1014, 863, 759, 730 cm
.
H NMR (CDCl
3
): d
.94 (s, 3H), 1.27 (d, J = 9.6 Hz, 1H), 1.33 (s, 3H), 1.51 (s, 3H),
.87–1.95 (m, 1H), 1.99 (dd, J = 5.6, 2.7 Hz, 1H), 2.20–2.32 (m,
H), 2.37–2.49 (m, 1H), 4.14 (dd, J = 10.0, 3.0 Hz, 1H), 7.23–7.30
Financial support from the Ministry of Science and Higher
Education, Warsaw, grant 2683/B/H03/2010/38, is acknowledged.
Anna Kmieciak acknowledge financial support from the European
Social Fund and National Budget, grant ‘‘Stypendia dla dok-
torantów 2008/2009 – ZPORR”.
1
3
m, 1H), 7.34 (td, J = 7.5, 1.3 Hz, 1H), 7.60–7.67 (m, 2H). C NMR
CDCl ): d 23.4, 26.1, 26.9, 27.2, 33.7, 38.7, 39.2, 50.3, 66.0, 90.5,
3
Please cite this article in press as: Kmieciak, A. ; Krzemi n´ ski, M. P. Tetrahedron: Asymmetry (2017), http://dx.doi.org/10.1016/j.
tetasy.2017.02.003

6
A. Kmieciak, M. P. Krzemi n´ ski / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
1
2. Carmona, D.; Vega, C.; Garcia, N.; Lahoz, F. J.; Elipe, S.; Oro, L. A.; Lamata, M. P.;
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tetasy.2017.02.003