Development of asymmetric nickel-catalyzed arylation of aromatic aldehydes with arylboron reagents

Article abstract of DOI:10.1055/s-0028-1083216

The development of the nickel-catalyzed 1,2-addition of triarylboroxins to aromatic aldehydes in the presence of a phosphine ligand is described. This development allowed the asymmetric nickel-catalyzed 1,2-addition of arylboron reagents to aromatic aldehydes. The enantioselectivity is synthetically acceptable (up to 81 % ee) using 1-naphthaldehyde and 2-substituted aromatic aldehydes as substrates. The results have enantioselectivity comparable to the best results reported by us for the rhodium-catalyzed arylation of aromatic aldehydes. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0028-1083216

PAPER
3585
Development of Asymmetric Nickel-Catalyzed Arylation of Aromatic
Aldehydes with Arylboron Reagents
Asymmetric
N
icke
a
l-Catalyzed
n
A
rylation a Yamamoto, Kaori Tsurumi, Fumie Sakurai, Kazuhiro Kondo,* Toyohiko Aoyama*
Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya 467-8603, Japan
E-mail: kazuk@phar.nagoya-cu.ac.jp; E-mail: aoyama@phar.nagoya-cu.ac.jp
Received 14 July 2008
Initially our studies focused on the determination of the
conditions for Ni(cod)2-catalyzed phenylation using vari-
ous phosphine ligands, phenylboronic acid, and triphenyl-
boroxin. As can be seen in Table 1, the dramatic effect of
Abstract: The development of the nickel-catalyzed 1,2-addition of
triarylboroxins to aromatic aldehydes in the presence of a phosphine
ligand is described. This development allowed the asymmetric
nickel-catalyzed 1,2-addition of arylboron reagents to aromatic
aldehydes. The enantioselectivity is synthetically acceptable (up to the boron reagent and ligand was observed. When phenyl-
81% ee) using 1-naphthaldehyde and 2-substituted aromatic alde-
boronic acid was used as the boron reagent, the results for
hydes as substrates. The results have enantioselectivity comparable
phenylation were not promising (Table 1, entries 1 and 2).
to the best results reported by us for the rhodium-catalyzed arylation
Next, the use of triphenylboroxin as the boron reagent was
of aromatic aldehydes.
examined. After intensive screening of ligands, we found
that the chemical yield was brought to an acceptable level
Key words: arylation, arylboron, aromatic aldehyde, triarylboroxin
by using ( )-Et-Duphos (6b) (Table 1, entry 10). Very in-
terestingly, other five-membered chelating ligands such
The asymmetric arylation of aromatic aldehydes is one of
the most important C–C bond-forming reactions, because
optically active diarylmethanols are important intermedi-
ates for the synthesis of biologically active compounds.1
Among various arylmetal reagents used, arylboron re-
agents are desirable due to the recent demand for safe and
sustainable organic synthesis, as their reagents are less
toxic and they are air-stable. Miyaura’s group has report-
ed that rhodium(I) complexes catalyze the 1,2-addition of
arylboronic acids to aldehydes giving the corresponding
products with 41% ee.2 Although, later attention focused
on asymmetric arylation with the combination of a rhodi-
um catalyst and an arylboronic acid,3 our method, exhib-
iting up to 85% enantioselectivity, gave the best results.3c,f
Recently, Ohta and Ito,4a our group,4b and others4c–e re-
ported the use of a less expensive palladium catalyst for
the 1,2-addition of arylboronic acids to aromatic alde-
hydes. However, our method using a palladium catalyst
gave no enantioselectivity. From the viewpoint of cost
and practical convenience, the use of a more economical
and naturally abundant metal catalyst such as nickel, rath-
er than rhodium or palladium, is desirable.5 To date, only
one successful example of the nickel-catalyzed arylation
of aldehydes with arylboron reagents has been reported by
Shirakawa.5a However, according to Shirakawa’s report,5a
in the presence of a phosphine ligand, the arylation does
not proceed at all, hence the extension to an asymmetric
version of the nickel-catalyzed arylation seemed to be
very difficult. Herein, we would like to report the devel-
opment of an asymmetric nickel-catalyzed 1,2-addition of
arylboron reagents to aromatic aldehydes.6
as dppe (3), dppben (5), and i-Pr-Duphos (6c), were not
good ligands. Thus, the best reaction conditions were de-
termined to be Ni(cod)2 (10 mol%), ( )-Et-Duphos (6b,
10 mol%), triphenylboroxin (0.66 mol equiv), and sodium
tert-butoxide (0.5 mol equiv) in 1,2-dimethoxyethane–
water (5:1) at 100 °C for 48 hours. Other bases, such as
KOt-Bu, LiOt-Bu, NaOMe, KHMDS, and Et3N, gave less
satisfactory results. To our knowledge, this is the first ex-
ample of the nickel-catalyzed arylation of an aldehyde
with a boron reagent in the presence of a phosphine
ligand.
The generality of the substrate and triarylboroxin in this
reaction under the optimal conditions is shown in Table 2.
From a wide range of aromatic aldehydes, good chemical
yields were generally produced, although the use of tris(4-
methoxyphenyl)boroxin was not good (Table 2, entry 3).
Next, our attempts to extend this reaction with (R,R)-Et-
Duphos [(R,R)-6b] to an asymmetric version were exam-
ined (Table 3). 1-Naphthaldehyde and other 2-substituted
aromatic aldehydes exhibited 65–78% enantioselectivity
with good chemical yields (Table 3, entries 1–6). On the
other hand, the enantioselectivity of the aromatic alde-
hydes without a 2-substituted group was low or moderate.
Furthermore, asymmetric arylations with commercially
available and convenient potassium aryltrifluoroborates,7
in view of their easy handling and greater stability to wa-
ter than triarylboroxins, were performed. Initial studies
focused on ligand screening for the nickel-catalyzed ary-
lation of 1-naphthaldehyde (1a) with potassium 4-tert-bu-
tylphenyltrifluoroborate (this borate was chosen as an
initial candidate because it is relatively inexpensive
among other commercially available potassium aryltri-
fluoroborates). The selected results are summarized in
Table 4. As can be seen in entries 1–4, we found that the
chiral five-membered chelating ligands such as Chiraphos
SYNTHESIS 2008, No. 22, pp 3585–3590
x
x.
x
x
.
2
0
0
8
Advanced online publication: 10.11.2008
DOI: 10.1055/s-0028-1083216; Art ID: F16108SS
© Georg Thieme Verlag Stuttgart · New York

3586
K. Yamamoto et al.
PAPER
Table 1 Optimization of Phenylation
Table 2 Substrate and Triarylboroxin Generality
HO
Ph
Ni(cod)2 (10 mol%)
( )-Et-Duphos (10 mol%)
(Ar2BO)3 (2/3 mol equiv)
Ni(cod)2 (20 mol%)
achiral ligand (20 mol%)
boron reagent (2.0 mol equiv)
CHO
OH
Ar2
Ar1CHO
Ar1
NaOt-Bu (0.5 mol equiv)
DME–H2O = 5:1, 100 °C, 48 h
NaOt-Bu (2 mol equiv)
DME–H2O = 5:1, 100 °C, 24 h
1
2
2a
1a
Entry
Ar1
Ar2
Product
2a
Yield (%)
Entry
1
Achiral ligand
Boron reagent
PhB(OH)2
Yielda (%)
1
2
1-naphthyl
1-naphthyl
1-naphthyl
1-naphthyl
2-MeC6H4
2-MeOC6H4
3-MeC6H4
3-MeOC6H4
4-FC6H4
Ph
93
90
nra
94
91
99
92
99
93
87
86
PPh2
trace
4-FC6H4
4-MeOC6H4
2b
PPh2
3
3
2c
PPh2
PPh2
4
4-i-PrOC6H4 2d
2
PhB(OH)2
7
5
Ph
Ph
Ph
Ph
Ph
Ph
Ph
2e
2f
4
Ph3P
6
3
4
5
(PhBO)3
(PhBO)3
(PhBO)3
trace
trace
trace
7
2g
2h
2i
Cy3P
8
t-BuPh2P
9
PPh2
6
7
8
(PhBO)3
(PhBO)3
(PhBO)3
trace
trace
65
10
11
4-MeC6H4
4-MeOC6H4
2j
PPh2
3
2k
PPh2
a No reaction occurred.
PPh2
5
Table 3 Asymmetric Arylation Reaction Using Triarylboroxins
PPh2
PPh2
( )-
4
Ni(cod)2 (10 mol%)
(R,R)-Et-Duphos (10 mol%)
OH
(Ar2BO)3 (2/3 mol equiv)
Ar1CHO
Ar2
Ar1
NaOt-Bu (0.5 mol equiv)
DME–H2O = 5:1, 100 °C, 48 h
*
R
R
1
2
R
R
P
Entry Ar1
Ar2
Ph
Product Yielda (%) ee (%)
( )-
9
(PhBO)3
68
P
1
2
1-naphthyl
2a
2d
93
94
68 (R)
1-naphthyl
4-i-
PrOC6H4
49
6
6a R = Me
10
11
6b R = Et
(PhBO)3
(PhBO)3
80
3
4
5
6
7
8
9
1-naphthyl
2-MeC6H4
4-FC6H4 2b
87
65
6c R = i-Pr
trace
Ph
2e
2l
91
78 (R)
75
PPh2
2-Me-3-FC6H3 Ph
93
12
(PhBO)3
trace
2-PhC6H4
4-FC6H4
Ph
Ph
Ph
Ph
2m
2i
83a
93
72
PPh2
7
55 (S)
33 (S)
32 (S)
13
14
15
( )-BINAP
(PhBO)3
(PhBO)3
(PhBO)3
trace
trace
trace
4-MeC6H4
4-MeOC6H4
2j
85a
82a
(R)-Segphos
(S,S)-DIOP
2k
a Remainder of mass balance was the starting aldehyde.
a Remainder of mass balance was the starting 1-naphthaldehyde (1a).
Secondly, solvent screening was performed as shown in
Table 5. From the viewpoint of both chemical yield and
enantioselectivity, the best solvent was dioxane–water
(5:1) (Table 5, entry 3). The effect of base and tempera-
ture was then performed as follows: in the case of 100 °C,
no base (96%, 66% ee), NaOt-Bu (93%, 65% ee), KOt-Bu
(4) and Duphos derivatives 6a–c afforded the desired
product 2. When Et-Duphos [(R,R)-6b] was used, the
chemical yield and enantioselectivity were brought to an
acceptable level (76%, 61% ee, Table 4, entry 3).
Synthesis 2008, No. 22, 3585–3590 © Thieme Stuttgart · New York

PAPER
Asymmetric Nickel-Catalyzed Arylation
Table 5 Solvent Effect
3587
Table 4 Ligand Screening
HO
Ar
Ni(cod)2 (20 mol%)
(R,R)-Et-Duphos (20 mol%)
K(4-t-Bu-C6H4)BF3 (2.0 mol equiv)
Ni(cod)2 (20 mol%)
CHO
chiral ligand (20 mol%)
K(4-t-Bu-C6H4)BF3 (2.0 mol equiv)
1a
2n
NaOt-Bu (2 mol equiv)
solvent, 100 °C, 24 h
NaOt-Bu (2 mol equiv)
DME–H2O = 5:1, 100 °C, 24 h
1a
2n: 4-t-Bu-C6H4
Entry
Solvent
Yield (%)
51b
eea (%)
Entry
1b
Chiral ligand
Yield (%) eea (%)
1
2
3
4
5
toluene–H2O (5:1)
CF3C6H5–H2O (5:1)
dioxane–H2O (5:1)
dioxane
62
67
66
–
PPh2
77b
43c
32
60
PPh2
90
(R,R)-4
traceb
nrc
R
R
R
P
P
DMF–H2O (5:1)
–
a Determined by HPLC analysis.
2
58c
b Remainder of mass balance was the starting aldehyde.
c No reaction occurred.
R
6
(R,R)-6a R = Me
(R,R)-6b R = Et
Table 6 Asymmetric Arylation Reaction Using Potassium Aryltri-
fluoroborates
3
4
76c
58c
61
45
(S,S)-6c R = i-Pr
Ni(cod)2 (10 mol%)
(R,R)-Et-Duphos (10 mol%)
OH
KAr2BF3 (2 mol equiv)
Ar1CHO
R
Ar2
Ar1
*
dioxane–H2O = 5:1, 80 °C, 20 h
R
R
P
P
1
2
5
3c
2
Entry Ar1
Ar2
Ph
Product Yield (%) eea (%)
R
1
2
1-naphthyl
2a
97
84b
93
87
95
86
87
89
65b
92
88
90
45b
72 (R)
68
8
1-naphthyl
2-MeC6H4
2-MeC6H4
2-MeC6H4
2-MeC6H4
2-MeC6H4
2-MeC6H4 2o
4-t-BuC6H4 2p
4-MeC6H4 2q
(R,R)-8a R = Et
(S,S)-8b R = Ph
6
7
8
9
nrd
nrd
nrd
nrd
–
–
–
3
81 (R)
78 (R)
81 (R)
75 (R)
66 (R)
78
(S)-Segphos
(S)-BINAP
(S,S)-DIOP
4
5
Ph
2e
2r
6
4-FC6H4
a Determined by HPLC analysis.
b Dppe, tol-BINAP, Ph3P, t-BuPh2P, and Cy3P resulted in no reaction.
c Remainder of the mass balance was the starting aldehyde.
d No reaction occurred.
7
4-MeOC6H4 2s
8
2-Me-3-FC6H3 Ph
2l
9
2-PhC6H4
2-EtOC6H4
4-FC6H4
Ph
Ph
Ph
Ph
Ph
2m
2t
76
(66%, 64% ee), LiOt-Bu (73%, 65% ee), RbOH (76%,
63% ee); in the case of 80 °C without base (97%, 72% ee).
Thus, the best conditions were determined to be dioxane–
H2O (5:1) without base at 80 °C. Using 10 mol% catalyst,
synthetically acceptable catalyst loading, gave good re-
sults.
10
11
12
13
63
2i
67 (S)
41 (S)
17 (S)
4-MeC6H4
4-MeOC6H4
2j
2k
The scope of this asymmetric reaction under the optimal
conditions is summarized in Table 6. 1-Naphthaldehyde
and 2-substituted aromatic aldehydes afforded good enan-
tioselectivity, although reactivity of the 2-substituted
arylborate was slightly low (entry 2). Unfortunately, the
aromatic aldehydes with 4-methyl and 4-methoxy substit-
uents (entries 12 and 13) showed low enantioselectivity.
As shown in Scheme 1, (R)-phenyl-2-tolylmethanol [(R)-
2e] was transformed into anti-histamic and cholinergic
(R)-orphenadrine1 (9).
a Determined by HPLC analysis.
b Remainder of mass balance was the starting aldehyde.
We are tempted to assume the mechanism for these aryla-
tion is as follows (Scheme 2). A nickel(0) complex initial-
ly reacts enantiodiscriminatively with an aromatic
aldehyde to generate a h2-coordinated complex8 10 and/or
its resonance type 11. Subsequent transmetalation with
boron reagent and/or its ate complex by the action of OH–
affords the intermediate 12. In this step, enantiodiscrimi-
Synthesis 2008, No. 22, 3585–3590 © Thieme Stuttgart · New York

3588
K. Yamamoto et al.
PAPER
(R)-(1-Naphthyl)phenylmethanol [(R)-2a, Table 3, Entry 1];
O
NMe2
1)
Cl
Typical Procedure
Me
O
Me
OH
Ph
NMe2
To a stirred soln of (R,R)-Et-Duphos (8.0 mg, 0.022 mmol) in
DME–H2O (5:1, 0.55 mL) was added Ni(cod)2 (6.1 mg, 0.022
mmol), NaOt-Bu (10.6 mg, 0.110 mmol), (PhBO)3 (45.9 mg, 0.147
mmol), and 1-naphthaldehyde (1a, 30 mL, 34.5 mg, 0.221 mmol).
The mixture was stirred at 100 °C for 48 h and allowed to cool. Af-
ter the usual workup, purification by column chromatography (sili-
ca gel, hexane–EtOAc, 20:1 to 4:1) afforded 2a (48.1 mg, 93%) as
a colorless oil; 68% ee (HPLC (Daicel Chiralcel OD-H, hexane–i-
PrOH, 1.0 mL/min). The spectral data were comparable to those re-
ported.2 The absolute configuration was determined by comparison
with the reported specific rotation.2
NaH, DMF
Ph
2) LiAlH4, THF
70% (2 steps)
9
(R)-2e
81% ee
Scheme 1 Conversion into (R)-orphenadrine (9)
*
OH
Ar1CHO
H2O
P
P
Ni
Ar1
Ar2
IR (neat): 3381 cm–1.
1H NMR (CDCl3): d = 2.42 (s, 1 H), 6.48 (s, 1 H), 7.21–7.48 (m, 8
BX2
P
*
P
P
P
H), 7.59 (d, J = 7.1 Hz, 1 H), 7.74–7.86 (m, 2 H), 7.98–8.02 (m, 1
O
H
O
O
Ni
Ni
H
P
P
*
H).
Ar1
Ar1
12
Ni
Ar2
*
Ar1
13C NMR (CDCl3): d = 73.50, 123.86, 124.48, 125.17, 125.44,
125.98, 126.90, 127.48, 128.29, 128.35, 128.60, 130.54, 133.75,
138.63, 142.94.
10
11
MS (EI): m/z = 234 (M+), 217, 157, 129, 128, 105, 77.
boron reagent and/or
its ate complex
Anal. Calcd for C17H14O: C, 87.15; H, 6.02. Found: C, 86.95; H,
5.99.
Scheme 2 Plausible reaction mechanism
(R)-(1-Naphthyl)phenylmethanol [(R)-2a, Table 6, Entry 1];
Typical Procedure
nation of 10 and/or 11 might be kept, although further in-
vestigation is needed, and so this asymmetric arylation
would give good enantioselectivity. Finally, reductive
elimination and protonolysis furnishes the diarylmethanol
and regenerates the nickel(0) complex. However, the rea-
son that 1-naphthaldehyde and 2-substituted aromatic al-
dehydes exhibited good enantioselectivity, is not clear at
the present time.
To a stirred soln of (R,R)-Et-Duphos (8.0 mg, 0.022 mmol) in diox-
ane–H2O (5:1, 0.60 mL) were added Ni(cod)2 (12.2 mg, 0.0442
mmol), KPhBF3 (81.3 mg, 0.442 mmol), and 1-naphthaldehyde (1a,
30 mL, 34.5 mg, 0.221 mmol). The mixture was stirred at 80 °C for
20 h and allowed to cool. After the usual workup, purification by
column chromatography (silica gel, hexane–EtOAc, 20:1 to 4:1) af-
forded 2a (50.2 mg, 97%) as a colorless oil; 72% ee. The spectral
data were comparable to those reported.2 The absolute configura-
tion was determined by comparison with the reported specific rota-
tion.2
In summary, we have found that 1-naphthaldehyde and 2-
substituted aromatic aldehydes as substrates exhibited ac-
ceptable enantioselectivity with good chemical yields in
the asymmetric nickel-catalyzed 1,2-addition of arylbo-
ron reagents to aromatic aldehydes. In view of their easy
handling and greater stability to water, the use of potassi-
um aryltrifluoroborates is better than triarylboroxins. To
the best of our knowledge, this is the first example of
asymmetric nickel-catalyzed 1,2-addition of arylboron re-
agents to aromatic aldehydes. In order to catch up with
and outrun the successful asymmetric arylation methods
of Shibasaki9 and Kanai, and Bolm,10 we have really fo-
cused on tuning Duphos.11
(+)-(4-Fluorophenyl)(1-naphthyl)methanol [(+)-2b]
Colorless oil.
IR (neat): 3236 cm–1.
1H NMR (CDCl3): d = 2.25–2.40 (br, 1 H), 6.52 (br s, 1 H), 6.99 (d,
J = 8.7 Hz, 1 H), 7.02 (d, J = 8.7 Hz, 1 H), 7.29–7.53 (m, 5 H), 7.63
(d, J = 6.8 Hz, 1 H), 7.79–7.91 (m, 2 H), 7.95–8.02 (m, 1 H).
13C NMR (CDCl3): d = 73.03, 115.24 (d, J = 21.2 Hz), 123.73,
124.42, 125.21, 125.58, 126.11, 128.53, 128.62 (d, J = 8.4 Hz),
128.72, 130.40, 133.83, 138.44, 138.70 (d, J = 3.4 Hz), 162.00 (d,
J = 245.4 Hz).
MS (FAB): m/z = 253 (M+ + 1).
Anal. Calcd for C17H13FO: C, 80.93; H, 5.19. Found: C, 81.11; H,
5.43.
IR spectra were measured on a Shimadzu FT-IR-8100 diffraction
grating IR spectrophotometer. 1H and 13C NMR spectra were mea-
sured on a Jeol JNM-EX-270 NMR spectrometer, operating at 270
MHz for 1H NMR and at 68 MHz for 13C NMR. 1H and 13C NMR
spectra were reported downfield from TMS (d = 0). EI- and FAB-
MS spectra were measured on a Jeol JMS-SX-102A instrument.
The enantiomeric excess was determined by HPLC analysis (Daicel
chiralcel OD-H, hexane–i-PrOH) unless otherwise mentioned.
(+)-(4-Isopropoxyphenyl)(1-naphthyl)methanol [(+)-2d]
Colorless oil.
[a]D20 +22 (c 0.98, EtOH).
IR (neat): 3408 cm–1.
1H NMR (CDCl3): d = 1.29 (d, J = 6.1 Hz, 6 H), 2.38 (br, 1 H), 4.48
(sept, J = 6.1 Hz, 1 H), 6.44 (s, 1 H), 6.80 (d, J = 8.7 Hz, 2 H), 7.25
(d, J = 8.7 Hz, 2 H), 7.35–7.52 (m, 3 H), 7.67 (d, J = 7.1 Hz, 1 H),
7.74–7.89 (m, 2 H), 7.91–7.99 (m, 1 H).
13C NMR (CDCl3): d = 22.10, 69.77, 73.16, 115.62, 123.87, 124.00,
125.21, 125.40, 125.91, 128.14, 128.33, 128.59, 130.44, 133.71,
134.97, 138.79, 157.24.
All aromatic aldehydes, potassium aryltrifluoroborates, reagents,
and solvents were available from commercial sources and used
without further purification. In general, all reactions were per-
formed under an argon atmosphere. Silica gel column chromatogra-
phy was performed on Fuji silysia BW200.
Synthesis 2008, No. 22, 3585–3590 © Thieme Stuttgart · New York

PAPER
Asymmetric Nickel-Catalyzed Arylation
3589
MS (EI): m/z = 292 (M+), 121 (bp).
The physical data were comparable to those reported.6
HRMS: m/z (M+) calcd for C20H20O2: 292.1463; found: 292.1481.
(+)-(Biphenyl-2-yl)phenylmethanol [(+)-2m]
[a]D22 +107 (c 1.23, THF).
(R)-Phenyl(2-tolyl)methanol [(R)-2e]
The absolute configuration was determined by comparison with the
The physical data were comparable to those reported.6
reported specific rotation.12
(4-tert-Butylphenyl)(1-naphthyl)methanol (2n)
Colorless oil.
IR (neat): 3342 cm–1.
[a]D22 +11 (c 1.33, THF).
IR (neat): 3173 cm–1.
1H NMR (CDCl3): d = 2.16 (s, 1 H), 2.24 (s, 3 H), 6.00 (s, 1 H),
7.07–7.38 (m, 8 H), 7.46–7.56 (m, 1 H).
13C NMR (CDCl3): d = 19.50, 73.37, 126.03, 126.10, 126.99,
127.44, 127.49, 128.38, 130.43, 135.23, 141.26, 142.66.
MS (EI): m/z = 198 (M+), 181, 77.
HRMS: m/z (M+) calcd for C14H14O: 198.1045; found: 198.1041.
1H NMR (CDCl3): d = 1.32 (s, 9 H), 2.52–2.41 (br, 1 H), 6.53 (br s,
1 H), 7.28–7.37 (br, 4 H), 7.38–7.55 (m, 3 H), 7.68 (d, J = 7.0 Hz,
1 H), 7.75–7.92 (m, 2 H), 7.99–8.08 (m, 1 H).
13C NMR (CDCl3):d = 31.39, 34.58, 73.36, 123.89, 124.22, 125.27,
125.39, 125.44, 125.98, 126.69, 128.23, 128.64, 133.75, 138.77,
139.98.
MS (EI): m/z = 292 (M+), 275, 161.
HRMS: m/z (M+) calcd for C21H22O: 290.1671; found: 290.1669.
(2-Methoxyphenyl)phenylmethanol (2f)
Colorless oil.
IR (Nujol): 3403 cm–1.
(+)-(1-Naphthyl)(2-tolyl)methanol [(+)-2o]
The physical data were comparable to those reported.4b
1H NMR (CDCl3): d = 3.04 (d, J = 5.4 Hz, 1 H), 3.82 (s, 3 H), 6.06
(d, J = 5.4 Hz, 1 H), 6.90 (d, J = 8.5 Hz, 1 H), 6.94 (dd, J = 7.6, 7.6
Hz, 1 H), 7.19–7.43 (m, 7 H).
13C NMR (CDCl3): d = 55.32, 72.06, 110.54, 120.61, 126.37,
126.96, 127.62, 127.98, 128.52, 131.72, 143.04.
(R)-(4-tert-Butylphenyl)(2-tolyl)methanol [(R)-2p]
The assignment of the absolute configuration was determined by
comparison with the CD spectrum of known (R)-phenyl(2-
tolyl)methanol.12
[a]D23 +1 (c 1.69, THF).
IR (neat): 3327 cm–1.
1H NMR (CDCl3): d = 1.29 (s, 9 H), 2.12 (br s, 1 H), 2.24 (s, 3 H),
5.98 (br s, 1 H), 7.03–7.40 (m, 7 H), 7.57 (br d, J = 7.3 Hz, 1 H).
13C NMR (CDCl3): d = 19.53, 31.39, 34.56, 73.08, 125.31, 125.89,
125.98, 126.74, 127.28, 130.32, 135.10, 139.67, 141.42, 150.39.
MS (EI): m/z = 214 (M+), 196, 195, 135, 105, 77.
Anal. Calcd for C14H14O2: C, 78.48; H, 6.59. Found: C, 78.79; H,
6.80.
Phenyl(3-tolyl)methanol (2g)
The spectral data were comparable to those of a commercially avail-
able authentic sample.
MS (EI): m/z = 254 (M+), 237, 119.
HRMS: m/z (M+) calcd for C18H22O: 254.1671; found: 254.1070.
(3-Methoxyphenyl)phenylmethanol (2h)
Colorless oil.
IR (neat): 3417 cm–1.
1H NMR (CDCl3): d = 2.21 (br s, 1 H), 3.78 (s, 3 H), 5.81 (s, 1 H),
6.77–6.84 (m, 1 H), 6.92–6.99 (m, 2 H), 7.21–7.40 (m, 6 H).
13C NMR (CDCl3): d = 55.24, 76.16, 112.07, 112.92, 118.82,
126.43, 127.49, 128.38, 129.39, 143.56, 145.34, 159.62.
MS (EI): m/z = 214 (M+, base peak), 135, 109, 77.
HRMS: m/z (M+): calcd for C14H14O2: 214.09938; found:
(R)-(2-Tolyl)(4-tolyl)methanol [(R)-2q]
The assignment of the absolute configuration was determined by
comparison with the CD spectrum of known (R)-phenyl(2-
tolyl)methanol.12
[a]D22 +8 (c 1.20, THF).
IR (neat): 3328 cm–1.
1H NMR (CDCl3): d = 2.12 (s, 1 H), 2.22 (s, 3 H), 2.32 (s, 3 H), 5.95
(s, 1 H), 7.07–7.34 (m, 7 H), 7.49–7.59 (m, 1 H).
214.09867.
13C NMR (CDCl3): d = 19.47, 21.20, 73.19, 125.95, 125.98, 126.98,
(S)-(4-Fluorophenyl)phenylmethanol [(S)-2i]
The physical data were comparable to those reported.13 The abso-
lute configuration was determined by comparison with the reported
specific rotation.13
127.30, 129.06, 130.36, 135.13, 137.19, 139.78, 141.41.
MS (EI): m/z = 212 (M+), 195, 119 (bp).
HRMS: m/z (M+) calcd for C15H16O: 212.1201; found: 212.1209.
(S)-(4-Tolyl)phenylmethanol [(S)-2j]
(R)-(4-Fluorophenyl)(2-tolyl)methanol [(R)-2r]
The ee was determined by HPLC analysis (Daicel Chiralcel AD-H
and OD-H, hexane–i-PrOH, 0.2 mL/min).
The physical data were comparable to those reported.13 The abso-
lute configuration was determined by comparison with the reported
specific rotation.13
The assignment of the absolute configuration was determined by
comparison with the CD spectrum of known (R)-phenyl(2-
tolyl)methanol.12
[a]D22 +9 (c 0.96, THF).
(S)-(4-Methoxyphenyl)phenylmethanol [(S)-2k]
The physical data were comparable to those reported.13 The abso-
lute configuration was determined by comparison with the reported
specific rotation.13
IR (neat): 3178 cm–1.
1H NMR (CDCl3): d = 2.17 (br s, 1 H), 2.22 (s, 3 H), 5.98 (br s, 1
H), 6.98 (d, J = 8.6 Hz, 1 H), 7.01 (d, J = 8.6 Hz, 1 H), 7.08–7.35
(m, 5 H), 7.43–7.55 (m, 1 H).
(–)-(3-Fluoro-2-methylphenyl)phenylmethanol [(–)-2l]
[a]D22 –3 (c 1.30, THF).
Synthesis 2008, No. 22, 3585–3590 © Thieme Stuttgart · New York

3590
K. Yamamoto et al.
PAPER
13C NMR (CDCl3): d = 19.44, 72.74, 115.05, 115.37, 125.98,
126.12, 127.59, 128.64, 128.77, 130.54, 135.14, 138.39, 138.44,
141.10, 160.16, 163.78.
MS (EI): m/z = 216 (M+), 199, 137.
HRMS: m/z (M+) calcd for C14H13FO: 216.0951; found: 216.0951.
Acknowledgement
We thank the Ministry of Education, Culture, Sports, Science and
Technology, Japan for support. K.K. was financially supported by
the Takeda Science Foundation.
References
(R)-(4-Methoxyphenyl)(2-tolyl)methanol [(R)-2s]
The assignment of the absolute configuration was determined by
comparison with the CD spectrum of known (R)-phenyl(2-
tolyl)methanol.12
(1) For a recent review, see: Schmidt, F.; Stemmler, R. T.;
Rudolph, J.; Bolm, C. Chem. Soc. Rev. 2006, 35, 454.
(2) Sakai, M.; Ueda, M.; Miyaura, N. Angew. Chem. Int. Ed.
1998, 37, 3279.
[a]D26 –10 (c 0.94, THF).
(3) Other asymmetric Rh-catalyzed arylations of aromatic
aldehydes with arylboronic acids: (a) Moreau, C.; Hague,
C.; Weller, A. S.; Frost, C. G. Tetrahedron Lett. 2001, 42,
6957. (b) Focken, T.; Rudolph, J.; Bolm, C. Synthesis 2005,
429. (c) Suzuki, K.; Ishii, S.; Kondo, K.; Aoyama, T. Synlett
2006, 648. (d) Suzuki, K.; Kondo, K.; Aoyama, T. Synthesis
2006, 1360. (e) Arao, T.; Sato, K.; Kondo, K.; Aoyama, T.
Chem. Pharm. Bull. 2006, 54, 1576. (f) Arao, T.; Suzuki,
K.; Kondo, K.; Aoyama, T. Synthesis 2006, 3809. (g) For a
Rh-catalyzed asymmetric arylation of a ketone group in
isatins, see: Shintani, R.; Inoue, M.; Hayashi, T. Angew.
Chem. Int. Ed. 2006, 45, 3353.
(4) (a) Yamamoto, T.; Ohta, T.; Ito, Y. Org. Lett. 2005, 7, 4153.
(b) Suzuki, K.; Arao, T.; Ishii, S.; Maeda, Y.; Kondo, K.;
Aoyama, T. Tetrahedron Lett. 2006, 47, 5789. (c) He, P.;
Lu, Y.; Dong, C.-G.; Hu, Q.-S. Org. Lett. 2007, 9, 343.
(d) Novodomska, A.; Dudicova, M.; Leroux, F. R.; Colobert,
F. Tetrahedron: Asymmetry 2007, 18, 1628. (e) Shirai, R.;
Shimazawa, R.; Kuriyama, M. J. Org. Chem. 2008, 73,
1597.
IR (neat): 3380 cm–1.
1H NMR (CDCl3): d = 2.08 (br s, 1 H), 2.20 (s, 3 H), 3.78 (s, 3 H),
5.94 (br s, 1 H), 6.84 (d, J = 8.5 Hz, 2 H), 7.08–7.32 (m, 5 H), 7.56
(d, J = 7.3 Hz, 1 H).
13C NMR (CDCl3): d = 19.42, 55.29, 72.96, 113.78, 125.79, 125.96,
127.27, 128.37, 130.37, 134.97, 135.05, 141.48, 158.89.
MS (EI): m/z = 228 (M+, bp), 211, 119.
HRMS: m/z (M+) calcd for C15H16O2: 228.1150; found: 228.1150.
(+)-(2-Ethoxyphenyl)phenylmethanol [(+)-2t]
[a]D22 +53 (c 1.17, THF).
The physical data were comparable to those reported.14
(R)-Orphenadrine (9)
To a stirred soln of (R)-phenyl(2-tolyl)methanol [(R)-2e, 201 mg,
1.01 mmol, 81% ee] and 2-chloro-N,N-dimethylacetamide (247 mg,
2.03 mmol) in DMF (5.0 mL) was added NaH (143 mg, 5.97 mmol,
60% in mineral oil) at 0 °C. The mixture was stirred at r.t. for 30
min, quenched with H2O, and extracted with EtOAc. The combined
extracts were washed with brine, dried (Na2SO4), and concentrated.
The residue was purified by column chromatography (silica gel,
EtOAc–hexane, 1:14 to 1:1) to give the crude acetamide (472 mg).
The acetamide was dissolved in THF (6.0 mL). LiAlH4 (77.0 mg,
2.03 mmol) was stirred to this soln at 0 °C. The mixture was stirred
at r.t. for 1 h; Na2SO4·10 H2O was gradually added to the mixture.
The whole mixture was stirred at r.t. for 6 h, filtered to remove the
white precipitates, and concentrated. The residue was purified by
column chromatography (NH silica gel purchased by Fuji Silysia
Chemical Ltd., hexane–EtOAc, 3:1) to give 9 (192 mg, 70%, 2
steps); 81% ee [HPLC (Daicel Chiralcel OD-H, hexane–i-PrOH,
10:1, 1.0 mL/min)].
(5) (a) Takahashi, G.; Shirakawa, E.; Tsuchimoto, T.;
Kawakami, Y. Chem. Commun. 2005, 1459. (b) For recent
contributions of Ni-catalyzed addition to aldehydes, see: Ni-
catalyzed alkylation of aldehydes with trialkylborane: Hirao,
K.; Yorimitsu, H.; Oshima, K. Org. Lett. 2005, 7, 4689.
(c) Mahandru, G. M.; Liu, G.; Montgomery, J. J. Am. Chem.
Soc. 2004, 126, 3698. (d) Miller, K. M.; Huang, W.-S.;
Jamison, T. F. J. Am. Chem. Soc. 2003, 125, 3442.
(6) For our preliminary communication see: Arao, T.; Kondo,
K.; Aoyama, T. Tetrahedron Lett. 2007, 48, 4115.
(7) For a recent review, see: Darses, S.; Genet, J. P. Chem. Rev.
2008, 108, 288.
(8) h2-Coordinated nickel complexes with aldehydes have been
reported: (a) Ogoshi, S.; Oka, M.; Kurosawa, H. J. Am.
Chem. Soc. 2004, 126, 11802. (b) Ogoshi, S.; Kamada, H.;
Kurosawa, H. Tetrahedron 2006, 62, 7583.
[a]D27 +11 (c 3.61, THF).
IR (neat): 1117, 1095, 1074 cm–1.
(9) (a) Tomita, D.; Wada, R.; Kanai, M.; Shibasaki, M. J. Am.
Chem. Soc. 2005, 127, 4138. (b) Tomita, D.; Kanai, M.;
Shibasaki, M. Chem. Asian J. 2006, 1-2, 161.
(10) Bolm, C.; Rudolph, J. J. Am. Chem. Soc. 2002, 124, 14850.
(11) For new tuned Duphos derivatives, see: Oisaki, K.; Zhao, D.;
Suto, Y.; Kanai, M.; Shibasaki, M. Tetrahedron Lett. 2005,
46, 4325.
(12) Ohkuma, T.; Koizumi, M.; Ikehira, H.; Yokozawa, T.;
Noyori, R. Org. Lett. 2000, 2, 659.
(13) Wu, X.; Liu, X. X.; Zhao, G. Tetrahedron: Asymmetry 2005,
16, 2299.
1H NMR (CDCl3): d = 2.25 (s, 9 H), 2.58 (t, J = 6.1 Hz, 2 H), 3.56
(br t, J = 5.9 Hz, 2 H), 5.53 (s, 1 H), 7.09–7.44 (m, 9 H).
13C NMR (CDCl3): d = 19.47, 46.01, 59.03, 67.54, 81.27, 125.79,
126.95, 127.16, 127.21, 127.41, 128.05, 130.32, 135.69, 139.64,
140.99.
MS (FAB): m/z = 270 (M+ + 1).
Anal. Calcd for C18H23NO: C, 80.26; H, 8.61; N, 5.20. Found: C,
79.84; H, 8.77; N, 5.00.
(14) Sharshira, E. M.; Okamura, M.; Hasegawa, E.; Horaguchi,
T. J. Heterocycl. Chem. 1997, 34, 861.
Synthesis 2008, No. 22, 3585–3590 © Thieme Stuttgart · New York