Enantioselective Synthesis of 4,4′-Biaryl-BINOLs from Arynes and β-Diketones

Article abstract of DOI:10.1055/s-0034-1380452

The reaction of 2-(trimethylsilyl)phenyl triflate with aroylacetones in the presence of CsF gave the corresponding 4-aryl-2-naphthols. Substituted triflates also reacted with aroylacetones to afford 4-aryl-2-naphthols regioselectively. The enantioselectiv

Full text of DOI:10.1055/s-0034-1380452

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2015, 47, 2937–2944
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special topic
K. Okuma et al.
Special Topic
Synthesis
Enantioselective Synthesis of 4,4′-Biaryl-BINOLs from Arynes and
β-Diketones
Ar
Kentaro Okuma*
R
Kenta Horigami
chiral
oxovanadium
complex
Ar
Ar
Noriyoshi Nagahora
Kosei Shioji
CsF
MeCN
R
TMS
OTf
O
O
R
OH
OH
+
R
O2
r.t., 2–4 d
reflux
Department of Chemistry, Fukuoka University,
Jonan-ku, Fukuoka 814-0180, Japan
kokuma@fukuoka-u.ac.jp
OH
Ar
26–67%
85–98%
Received: 30.04.2015
Accepted after revision: 24.05.2015
Published online: 17.07.2015
lyzed ring closure of diazoacetate,8 and the palladium-cata-
lyzed direct arylation of naphthyl carbamate.9 All these re-
actions, however, generally require many steps. To do away
with tedious procedures, we designed the synthesis of 4-
aryl-2-naphthols from β-diketones and benzyne by using
carbon–carbon single bond cleavage and carbon–carbon
binding reactions.10 We herein describe the full details of
the synthesis of 4-aryl-2-naphthols and enantiomerically
pure 4,4′-biaryl-1,1′-binaphthols (4,4′-biaryl-BINOLs) from
triflate 1 and β-diketones (Scheme 1).
DOI: 10.1055/s-0034-1380452; Art ID: ss-2015-c0278-st
Abstract The reaction of 2-(trimethylsilyl)phenyl triflate with aroyl-
acetones in the presence of CsF gave the corresponding 4-aryl-2-naph-
thols. Substituted triflates also reacted with aroylacetones to afford 4-
aryl-2-naphthols regioselectively. The enantioselective oxidation of 4-
aryl-2-naphthols with a chiral tridentate oxovanadium(IV) complex fur-
nished the corresponding 4,4′-biaryl-1,1′-binaphthols in good yields.
Key words aryne, β-diketone, carbon–carbon bond insertion, 4-aryl-
2-naphthol, BINOL
Ar
R
Ar
Arynes have received considerable attention over the
last decades because of the important role they play as in-
termediates.1 The chemistry of arynes has shown extensive
progress because of the development of the benzyne pre-
cursor, 2-(trimethylsilyl)phenyl triflate (1a), which forms
benzyne under very mild conditions.2 Arynes are extremely
electron-poor reactive intermediates that exhibit a highly
electrophilic character; even neutral nucleophiles can easi-
ly add to arynes to produce zwitterions that act as key in-
termediates in the subsequent transformation to yield a va-
riety of benzoannulated compounds.3 Stoltz et al. and
Yoshida et al. reported that the reaction of 1a with β-keto
esters or β-diketones provided ortho-substituted benzoyl
compounds via carbon–carbon single bond insertion,4
which has opened the door to carbon–carbon single bond
cleavage reactions using an aryne intermediate. Naphtha-
lene derivatives are commonly found in many organic ma-
terials, such as natural products, pharmaceuticals, agro-
chemicals, and functional organic materials, and are useful
synthetic building blocks.5 Whereas the synthesis of 4-sub-
stituted 2-naphthols is generally difficult,6 the synthesis of
4-aryl-2-naphthols is relatively unknown. Reported exam-
ples include the Friedel–Crafts reaction,7 the rhodium-cata-
OH
OH
R
OH
R
oxidative coupling reaction
Ar
Ar
O
O
R
aryne insertion and
intramolecular aldol reaction
Scheme 1 Retrosynthetic analysis of 4,4′-biaryl-BINOLs
We first attempted to perform the reaction of 2-
(trimethylsilyl)phenyl triflate (1a) with benzoylacetone
(2a) in the presence of CsF. Treatment of benzoylacetone
(2a) with triflate 1a in the presence of CsF in refluxing
MeCN resulted in the formation of 4-phenyl-2-naphthol
(3aa) and 3-phenyl-1-naphthol (4aa) in 52–58% and 9–12%
yields, respectively (Table 1, entries 1 and 2). When the re-
action was carried out by using 1.6 equivalents of triflate
1a, 2-naphthol 3aa and 1-naphthol 4aa were isolated in
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2937–2944

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K. Okuma et al.
Special Topic
Synthesis
53% and 10% yield, respectively (entry 3). Use of excess 1a
resulted in low yields of the naphthols due to the formation
of inseparable side products (entry 4).
A
Ph
O
O
O
O
A
O
Ph
CH2
H
Table 1 Reaction of Triflate 1a with β-Diketone 2a
CH3
B
Ph
O
SiMe3
Ph
anion of 5a
B
OTf
Ph
CsF
1a
+
O
Ph
O
+
MeCN
reflux
OH
O
Ph
OH
4aa
O
O
3aa
CH3
Ph
CH2
C
O
O
Ph
2a
O
Entry
1a (equiv)
Time (h)
Product 3aa Yield (%) of 4aa
anion of 5a'
1
2
3
4
1.0
1.2
1.6
2.0
3.0
6.0
3.0
6.0
52
58
53
48
9
12
10
8
O
3aa
Ph
4aa
O
Scheme 2 Reaction mechanism
The reaction was surmised to proceed as follows: fluo-
ride-induced enolate anion attacks benzyne to give a zwit-
terion, and this in turn reacts with the benzoyl carbon to
furnish an enolate anion of 5a (route A). Another pathway
would be that the anion attacks acetyl carbon to give an
enolate anion of 5a′ (route B). The obtained enolates react
intramolecularly with carbonyl carbon to afford aldol reac-
tion products, and the products are dehydrated and aroma-
tized to give 3aa and 4aa (Scheme 2).
To confirm the reaction mechanism, compound 1a was
treated with 2a at room temperature for 5 hours to give 5a
in 58% yield. When 5a was further treated with CsF in re-
fluxing MeCN, 2-naphthol 3aa was obtained. Thus, the an-
ion of 5a would be the intermediate for the formation of
3aa (Scheme 3).
Table 2 Synthesis of Aryl-Substituted Naphthols
R3
R3
Ar
R3
OH
O
O
R1
R2
TMS
OTf
R2
R1
R1
R2
CsF
+
+
MeCN
reflux
Ar
OH
Ar
1
2
3
4
Entry
1a
1a
R1
R2
R3
2
Ar
Ph
3
Yield (%)
4
Yield (%)
1
2
3
4
5
6
7
8
9
H
H
H
H
H
H
H
H
2a
3aa
3ab
3ac
3ad
3ae
3af
58
37
65
67
44
30
33
26
30
4aa
4ab
4ac
4ad
4ae
4af
12
25
15
0
1a
1a
1a
1a
1a
1b
1c
1d
H
H
H
H
H
H
H
H
H
H
H
2b
2c
2d
2e
2f
4-MeC6H4
4-ClC6H4
4-O2NC6H4
1-naphthyl
2-thienyl
4-ClC6H4
4-ClC6H4
4-ClC6H4
31
25
11
13
20
OCH2O
H
2c
2c
2c
3bc
3cc
3dc
4bc
4cc
4dc
H
OMe
H
Me
Me
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Synthesis
Table 3 (continued)
Table 3 Synthesis of 4,4′-Biaryl-BINOLS 6
3
6
Yield (%)
Ar
Cl
Ar
PhCH2CH2NH2
CuCl2
OH
OH
MeOH
r.t., 2 d
3cc
6g
72
MeO
OH
3
Ar
OH
6
Cl
3
6
Yield (%)
75
Ph
3dc
6h
73
3aa
3ab
6a
6b
OH
OH
Me
After determining the optimum conditions (1.2 equiv of
80
1, reflux in MeCN), substituted 2-arylnaphthols 3 were syn-
thesized from substituted triflates 1b–d and aroylacetones
2b–f in the presence of CsF. Treatment of triflate 1a with 4-
chlorobenzoylacetone (2c) in the presence of CsF gave the
corresponding 4-(4-chlorophenyl)-2-naphthol (3ac) and 3-
(4-chlorophenyl)-1-naphthol (4ac) in 65% and 15% yield,
respectively (Table 2, entry 3). In the presence of an elec-
tron-donating group in the aryl group of the substrate 2b,
the reaction afforded also the 1-naphthol 4ab in moderate
yield (entry 2). Substrates 2 substituted with electron-
withdrawing groups at the para position of the aryl group
afforded 2-naphthols 3 in comparatively high yields (en-
tries 3, 4, 7, and 8). In particular, the nitro substituent af-
forded only 2-naphthol 3ad (entry 4). When 1-(1-naphth-
yl)butane-1,3-dione (2e) and 1-(2-thienyl)butane-1,3-di-
one (2f) were used as substrates, corresponding 4-(1-
naphthyl)-2-naphthol (3ae) and 4-(2-thienyl)-2-naphthol
(3af) were obtained in moderate yields (entries 5 and 6).
Thus, naphthols 3 and 4 were synthesized in one pot start-
ing from easily available substituted aroylacetones 2 and
benzyne precursor 1.
OH
Cl
3ac
6c
76
OH
NO2
3ad
6d
6e
6f
65
72
70
OH
S
3af
Axially dissymmetric 1,1′-binaphthol (BINOL) and its
derivatives are important chiral auxiliaries in asymmetric
catalyses.11 Although many substituted BINOLs have ap-
OH
Cl
O
2a
and CsF
OH
SiMe3
OTf
Me
Ph
3bc
CsF
O
MeCN
r.t., 5 h
MeCN
refllux, 5 h
O
Ph
O
OH
1a
5a
3aa
Scheme 3 Reaction of 5a with CsF
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2937–2944

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Synthesis
peared in the literature, the synthesis of 4,4′-biaryl-BINOLs
6 remains a very difficult task. Until the publication of our
preliminary communication,10 4,4′-biaryl-BINOLs 6 had
been synthesized by bromination of the alkyl ethers of
BINOL followed by the Suzuki–Miyaura coupling reaction
and dehalogenation.12 We synthesized the 4,4′-biaryl-
BINOLs 6 according to the method described by Brussee et
al.13 When 2-naphthol 3aa was treated with copper(II)
chloride and phenethylamine in ethanol at room tempera-
ture for 2 days, 4,4′-biphenyl-BINOL (6a) was obtained in
75% yield. Other reactions were carried out in a similar
manner (Table 3).
Next, the enantioselective synthesis of 4,4′-biaryl-
BINOLs 6 was tried by adopting the method of Chen et al.,14
who used a chiral tridentate oxovanadium(IV) catalyst for
the enantioselective synthesis of BINOLs. Treatment of 2-
naphthol 3aa with tridentate oxovanadium catalyst in the
presence of oxygen gave the corresponding BINOL 6a in 85%
yield with 65% ee (Table 4).
The yields of the reported synthesis of enantiomerically
pure BINOLs by simple recrystallization were low.14 There-
fore, a BINOL-proline complex was prepared to separate en-
antiomerically pure isomers.15 Treatment of BINOL 6a with
proline gave the corresponding 1:1 complex that was easily
separated by filtration. The filtrate was washed with water
and extracted with ethyl acetate to afford enantiomerically
pure (R)-4,4′-biphenyl-BINOL [(R)-6a] (ee >96%) in 47%
yield. Other enantiomerically pure BINOLs were synthe-
sized in a similar manner (Scheme 4).
L-proline
EtOH
reflux
(R)-6a 47%, 96% ee
(R)-6b 58%, 99% ee
(R)-6c 69%, 98% ee
(R)-6e 82%, 98% ee
(R)-6g 17%, 98% ee
(R)-6h 12%, 98% ee
EtOAc–H2O
(1:1)
agitation, 2 h
(S)-6–proline
complex
6a–h
+
(R)-6
Scheme 4 Synthesis of enantiomerically pure 6
The results clearly suggest that enantiomerically pure
4,4′-biaryl-BINOLs 6 could be obtained in short-step opera-
tions via three C–C bond cleavage and C–C bond forming re-
actions: aryne insertion, intramolecular aldol condensa-
tion, and oxidative coupling reaction.
In summary, we have accomplished the synthesis of 4-
aryl-substituted naphthols 3 from aryne precursors and
aroylacetones in one pot. Oxidative coupling of the naph-
thols 3 by using a chiral tridentate oxovanadium(IV) com-
plex afforded substituted 4,4′-biaryl-BINOLs 6 in excellent
yields. This method is expected to pave the way for the con-
struction of new four carbon–carbon bonds in short-step
operations and the efficient synthesis of various 4,4′-biaryl-
BINOLs 6 in moderate yields.
All chemicals were obtained from commercial suppliers and used
without further purification. Analytical TLC was carried out on pre-
coated plates (Merck silica gel 60, F254), and flash column chroma-
tography was performed with silica gel (Merck, 70–230 mesh). NMR
spectra (1H at 400 MHz; 13C at 100 MHz) were recorded in CDCl3, and
chemical shifts are expressed in ppm relative to internal TMS for 1H
and 13C NMR. Melting points are uncorrected.
Table 4 Enantioselective Synthesis of 4,4′-Biaryl-BINOLs 6
R3
Ar
N
O
R1
V
O
O
R3
Ar
O
R1
R2
R2
R2
OH
OH
(10 mol%)
O2, r.t.
CCl4 or ClCH2CH2Cl
OH
R1
3
R3
Ar
6
Entry
3
R1
R2
R3
Ar
Time (d)
Product
Yield (%)
ee (%)
1
2
3
4
5
6
3aa
3ab
3ac
3af
3cc
3dc
H
H
H
Ph
2
4
4
3
3
2
6a
6b
6c
6e
6g
6h
85
90
95
98
97
98
65
74
71
80
56
23
H
H
H
H
H
H
H
4-MeC6H4
4-ClC6H4
2-thienyl
4-ClC6H4
4-ClC6H4
H
H
H
H
OMe
Me
OMe
Me
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Synthesis
Reaction of 2-(Trimethylsilyl)phenyl Triflates 1 with Aroylace-
tones 2; 4-Aryl-2-naphthols 3 and 3-Aryl-1-naphthols 4; General
Procedure
4-(4-Nitrophenyl)-2-naphthol (3ad)
Yield: 0.59 g (0.67 mmol, 67%); yellow crystals; mp 192–193 °C.
1H NMR (CDCl3): δ = 8.36 (d, J = 8.8 Hz, 2H, HAr), 7.77(d, J = 8.0 Hz, 1H,
HAr), 7.67 (t, J = 8.8 Hz, 3H, HAr), 7.48 (t, J = 8.0 Hz, 1H, HAr), 7.32 (t, J =
8.0 Hz, 1H, HAr), 7.25 (s, 1H, HAr), 7.08 (s, 1H, HAr), 5.13 (br s, 1H, OH).
13C NMR (CDCl3): δ = 153.0, 147.7, 147.3, 140.2, 135.6, 131.2, 127.4,
127.3, 126.9, 125.5, 124.8, 124.0, 119.2, 110.8.
To a suspension of aroylacetone 2 (10 mmol) and CsF (5.5 g, 36 mmol)
in MeCN (15 mL) was added a solution of triflate 1 (12 mmol) in
MeCN (15 mL). After refluxing for 6 h, the reaction mixture was
poured into H2O (15 mL). The resulting suspension was extracted
with CH2Cl2 (3 × 10 mL), dried (Na2SO4), filtered, and evaporated to
give colorless oil, which was chromatographed over silica gel, eluting
with hexane–EtOAc (3:1), to give 3 and 4 (Table 2).
HRMS: m/z [M+] calcd for C16H11NO3: 265.0739; found: 265.0731.
4-(1-Naphthyl)-2-naphthol (3ae)
4-Phenyl-2-naphthol (3aa)6a
Yield: 1.2 g (4.4 mmol, 44%); colorless crystals; mp 158–160 °C.
1H NMR (CDCl3): δ = 7.94 (d, J = 8.4 Hz, 1 HAr) 7.93 (d, J = 8.0 Hz, 1 HAr),
7.76 (d, J = 8.0 Hz, 1 HAr), 7.53 (t, J = 8.4 Hz, 1 HAr), 7.49–7.39 (m, 4
HAr), 7.31–7.25 (m, 3 HAr), 7.14–7.10 (m, 2 HAr), 5.10 (br s, 1 H, OH).
13C NMR (CDCl3): δ = 152.8, 140.9, 137.9, 135.0, 133.6, 132.8, 128.7,
128.3, 128.2, 127.8, 126.8, 126.7, 126.7, 126.6, 126.2, 126.0, 125.5,
123.9, 119.8, 109.6.
Yield: 1.3 g (5.8 mmol, 58%); pale yellow oily crystals.
1H NMR (CDCl3): δ = 7.79 (d, J = 8.4 Hz, 1 HAr), 7.74 (d, J = 8.0 Hz, 1 HAr),
7.49–7.41 (m, 6 HAr), 7.27 (t, J = 7.6 Hz, 1 HAr), 7.18 (s, 1 HAr), 7.07 (s, 1
HAr), 5.02 (br s, 1 H, OH).
3-Phenyl-1-naphthol (4aa)
Yield: 0.26 g (1.2 mmol, 12%); colorless crystals; mp 92–93 °C (Lit.16
HRMS: m/z [M+] calcd for C20H14O: 270.1044; found: 270.1055.
mp 97–98 °C)
1H NMR (CDCl3): δ = 8.19 (d, J = 8.4 Hz, 1 HAr), 7.87 (d, J = 6.8 Hz, 1 HAr),
7.70–7.67 (m, 3 HAr), 7.55–7.46 (m, 4 HAr), 7.39 (t, J = 7.6 Hz, 1 HAr),
7.09 (s, 1 HAr), 5.47 (br s, 1 H, OH).
3-(1-Naphthyl)-1-naphthol (4ae)
Yield: 0.84 g (3.1 mmol, 31%); reddish oil.17
1H NMR (CDCl3): δ = 8.29–8.26 (m, 1 HAr), 7.98 (d, J = 8.4 Hz, 1 HAr)
7.94 (d, J = 8.0 Hz, 1 HAr), 7.90 (d, J = 8.0 Hz, 1 HAr), 7.88–7.86 (m, 1
HAr), 7.57–7.48 (m, 6 HAr), 7.43 (t, J = 8.4 Hz, 1 HAr), 6.94 (s, 1 HAr), 5.48
(br s, 1 H, OH).
4-(4-Methylphenyl)-2-naphthol (3ab)
Yield: 0.87 g (0.37 mmol, 37%); pale brown oily crystals.
1H NMR (CDCl3): δ = 7.81 (d, J = 8.4 Hz, 1 HAr), 7.74 (d, J = 8.0 Hz, 1 HAr),
7.42 (t, J = 7.6 Hz, 1 HAr), 7.37 (d, J = 8.0 Hz, 2 HAr), 7.30–7.24 (m, 3
HAr), 7.16 (s, 1 HAr), 7.04 (s, 1 HAr), 4.94 (br s, 1 H, OH), 2.46 (s, 3 H,
CH3).
13C NMR (CDCl3): δ = 152.9, 142.7, 137.5, 137.4, 135.5, 130.0, 129.3,
127.7, 127.1, 126.7, 126.4, 123.9, 118.9, 103.3, 21.51.
4-(2-Thienyl)-2-naphthol (3af)
Yield: 0.68 g (3.0 mmol, 30%); colorless crystals; mp 65–66 °C (Lit.18
mp 67 °C).
1H NMR (CDCl3): δ = 8.12 (d, J = 8.4 Hz, 1 HAr), 7.73 (d, J = 8.4 Hz, 1 HAr),
7.47–7.43 (m, 2 HAr), 7.34 (s, J = 7.6 Hz, 1 HAr), 7.26 (s, 1 HAr), 7.21 (s, 1
HAr), 7.19–7.17 (m, 2 HAr) 5.03 (br s, 1 H, OH).
HRMS: m/z [M+] calcd for C17H15O: 234.1044; found: 234.1048.
3-(4-Thienyl)-1-naphthol (4af)
3-(4-Methylphenyl)-1-naphthol (4ab)
Yield: 0.57 g (0.25 mmol, 25%): colorless crystals; mp 115–116 °C
(Lit.17 mp 115–116 °C).
Yield: 0.59 g (0.25 mmol, 25%); colorless crystals; mp 148–149 °C
(Lit.17 mp 145–146 °C).
1H NMR (CDCl3): δ = 8.15 (d, J = 8.4 Hz, 1 H), 7.82 (d, J = 8.0 Hz, 1 HAr),
7.68 (s, 1 HAr), 7.52–7.44 (m, 2 HAr), 7.38 (d, J = 3.6 Hz, 1 HAr), 7.31 (d,
J = 5.2 Hz, 1 HAr), 7.12–7.10 (m, 2 HAr), 5.63 (br s, 1 H, OH).
1H NMR (CDCl3): δ = 8.19 (d, J = 8.8 Hz, 1 HAr), 7.86 (d, J = 8.4 Hz, 1
HAr), 7.65 (s, 1 HAr), 7.59 (d, J = 8.0 Hz, 2 HAr), 7.54–7.47 (m, 2 HAr), 7.29
(d, J = 8.0 Hz, 2 HAr), 7.08 (s, 1 HAr), 5.40 (br s, 1 H, OH), 2.43 (s, 3 H,
CH3).
4-(4-Chlorophenyl)-6,7-methylenedioxy-2-naphthol (3bc)
4-(4-Chlorophenyl)-2-naphthol (3ac)
Yield: 0.99 g (3.3 mmol, 33%); colorless crystals; mp 139–140 °C.
1H NMR (CDCl3): δ = 7.43 (d, J = 8.4 Hz, 2 HAr), 7.40 (d, J = 8.4 Hz, 2 HAr),
7.05 (s, 1 HAr), 7.01 (s, 2 HAr), 6.86 (s, 1 HAr), 5.98 (s, 2 H, OCH2O), 5.08
(br s, 1 H, OH).
13C NMR (CDCl3): δ = 152.0, 148.2, 146.7, 140.1, 139.1, 133.6, 132.5,
131.1, 128.7, 123.7, 116.7, 110.0, 103.1, 102.3, 101.18.
Yield: 1.65 g (0.65 mmol, 65%); colorless crystals; mp 84–85 °C.
1H NMR (CDCl3): δ = 7.74 (d, J = 8.4 Hz, 2 HAr), 7.47–7.39 (m, 5 HAr),
7.29 (t, J = 8.0 Hz, 1 HAr), 7.19 (s, 1 HAr), 7.04 (s, 1 HAr), 5.19 (br s, 1 H,
OH).
13C NMR (CDCl3): δ = 152.9, 141.3, 138.7, 135.4, 133.8, 132.6, 131.4,
HRMS: m/z [M+] calcd for C17H11ClO3: 298.0397; found: 298.0391.
128.8, 127.1, 126.9, 125.9, 124.2, 119.0, 109.76.
HRMS: m/z [M+] calcd for C17H14ClO2: 254.0498; found: 254.0490.
3-(4-Chlorophenyl)-6,7-methylenedioxy-1-naphthol (4bc)
3-(4-Chlorophenyl)-1-naphthol (4ac)
Yield: 0.33 g (1.1 mmol, 11%); colorless crystals; mp 234–236 °C.
1H NMR (CDCl3): δ = 7.56 (d, J = 8.4 Hz, 2 HAr), 7.45 (s, 1 HAr), 7.43 (s, 1
HAr), 7.41 (d, J = 8.4 Hz, 2 HAr), 7.13 (s, 1 HAr), 6.91 (s, 1 HAr), 6.06 (s, 2
H, OCH2O), 5.22 (br s, 1 H, OH).
13C NMR (CDCl3): δ = 151.5, 148.7, 147.7, 139.6, 136.5, 133.5, 132.5,
129.1, 128.5, 120.3, 118.2, 107.3, 104.2, 101.3, 98.7.
Yield: 0.38 g (1.5 mmol, 15%); colorless crystals; mp 159–160 °C
(Lit.17 mp 160–161 °C).
1H NMR (CDCl3): δ = 8.18 (d, J = 8.8 Hz, 1 HAr), 7.86 (d, J = 8.0 Hz, 1 HAr),
7.61–7.48 (m, 5 HAr), 7.43 (d, J = 8.8 Hz, 2 HAr), 7.02 (s, 1 HAr), 5.45 (br
s, 1 H, OH).
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Special Topic
Synthesis
HRMS: m/z [M+] calcd for C17H11ClO3: 298.0397; found: 298.0404.
Reaction of 5a with CsF in Refluxing MeCN; 4-Phenyl-2-naphthol
(3aa)
4-(4-Chlorophenyl)-5-methoxy-2-naphthol (3cc)
A mixture of 5a (0.12 g, 0.50 mmol) and CsF (0.15 g, 1.0 mmol) in
MeCN (5 mL) was refluxed for 5 h, and the reaction mixture was
poured into H2O and extracted with CH2Cl2 (3 × 3 mL). The combined
extracts were dried (Na2SO4), filtered, and evaporated to give almost
pure 4-phenyl-2-naphthol (3aa); yield: 0.088 g (0.40 mmol, 80%).
Yield: 0.74 g (2.6 mmol, 26%); colorless crystals; mp 112–114 °C.
1H NMR (CDCl3): δ = 7.38–7.34 (m, 2 HAr), 7.31 (d, J = 8.4 Hz, 2 HAr),
7.22 (d, J = 8.4 Hz, 2 HAr), 7.12 (s, 1 HAr), 6.83 (s, 1 HAr), 6.65 (d, J = 7.2
Hz, 1 HAr), 5.29 (br s, 1 H, OH), 3.49 (s, 3 H, CH3).
13C NMR (CDCl3): δ = 156.9, 152.6, 143.3, 140.1, 137.4, 132.0, 130.0,
127.1, 126.9, 120.5, 120.1, 119.0, 109.9, 104.3, 55.1.
HRMS: m/z [M+] calcd for C17H13ClO2: 284.0604; found: 284.0614.
Synthesis of BINOLs by Copper-Amine Complex Catalyzed Oxida-
tion; General Procedure
To a solution of 6 (0.2 mmol) in EtOH was added CuCl2 (5 mg, 0.4
mmol) and phenethylamine (194 mg, 1.6 mmol). After stirring in an
O2 atmosphere for 2 days, the reaction mixture was added to a solu-
tion of aq HCl (0.5 mL) in MeOH (5 mL). The resulting suspension was
extracted with CH2Cl2 (3 × 3 mL), dried (Na2SO4), filtered, and evapo-
rated to give colorless crystals, which were chromatographed over sil-
ica gel, eluting with hexane–CH2Cl2 (1:1), to afford BINOL 6.
3-(4-Chlorophenyl)-8-methoxy-1-naphthol (4cc)
Yield: 0.37 g (1.3 mmol, 13%), yellow crystals; mp 151–153 °C.
1H NMR (CDCl3): δ = 9.37 (br s, 1 H, OH), 7.62 (d, J = 8.4 Hz, 2 HAr), 7.48
(s, 1 HAr), 7.47–7.41 (m, 3 HAr), 7.33 (t, J = 8.4 Hz, 1 HAr), 7.12 (s, 1 HAr),
6.78 (d, J = 7.6 Hz, 1 HAr), 4.07 (s, 3 H, CH3).
13C NMR (CDCl3): δ = 156.2, 155.1, 139.3, 139.2, 137.1, 133.7, 129.0,
128.6, 126.4, 122.3, 116.9, 114.5, 109.5, 104.3, 56.3.
HRMS: m/z [M+] calcd for C17H13ClO2: 284.0604; found: 284.0613.
4,4′-Biphenyl-1,1′-BINOL (6a)
Yield: 0.033 g (0.075 mmol, 75%); colorless crystals; mp 145–146 °C
(Lit.10b mp 147–148 °C).
1H NMR (CDCl3): δ = 7.96–7.94 (m, 2 HAr), 7.62 (d, J = 8.0 Hz, 4 HAr),
7.56 (t, J = 7.2 Hz, 4 HAr), 7.50 (t, J = 7.2 Hz, 2 HAr), 7.38 (s, 2 HAr), 7.36–
7.31 (m, 6 HAr), 5.16 (br s, 2 H, OH)
4-(4-Chlorophenyl)-6,7-dimethyl-2-naphthol (3dc)
Yield: 0.85 g (3.0 mmol, 30%); colorless crystals; mp 125–127 °C.
1H NMR (CDCl3): δ = 7.49 (s, 1 HAr), 7.46 (d, J = 8.4 Hz, 2 HAr), 7.45 (s, 1
HAr), 7.40 (d, J = 8.4 Hz, 2 HAr), 7.08 (s, 1 HAr), 6.92 (s, 1 HAr), 5.01 (br s,
1 H, OH), 2.34 (s, 3 H, CH3), 2.31 (s, 3 H, CH3).
4,4′-Bis(4-methylphenyl)-1,1′-BINOL (6b)
Yield: 0.037 g (0.080 mmol, 80%); colorless crystals; mp 230–231 °C
(Lit.19 mp 224–225 °C).
13C NMR (CDCl3): δ = 152.1, 140.2, 139.0, 136.6, 134.2, 133.7, 133.5,
131.2, 128.6, 126.7, 126.1, 125.2, 117.9, 108.9, 20.3, 20.2.
HRMS: m/z [M+] calcd for C18H15ClO: 282.0811; found: 282.0821.
1H NMR (CDCl3): δ = 8.00–7.97 (m, 2 HAr), 7.52 (d, J = 8.0 Hz, 4 HAr),
7.38 (d, J = 7.6 Hz, 6 HAr), 7.36–7.30 (m, 6 HAr), 5.15 (br s, 2 H, OH),
2.51 (s, 6 H, CH3)
3-(4-Chlorophenyl)-6,7-dimethyl-1-naphthol (4dc)
4,4′-Bis(4-chlorolphenyl)-1,1′-BINOL (6c)
Yield: 0.57 g (2.0 mmol, 20%); colorless crystals; mp 179–180 °C.
1H NMR (CDCl3): δ = 7.90 (s, 1 HAr), 7.60 (s, 1 HAr), 7.58 (d, J = 8.4 Hz, 2
HAr), 7.50 (s, 1 HAr), 7.41 (d, J = 8.4 Hz, 2 HAr), 6.94 (s, 1 HAr), 5.30 (br s,
1 H, OH), 2.46 (s, 3 H, CH3), 2.44 (s, 3 H, CH3).
Yield: 0.039 g (0.076 mmol, 76%); colorless crystals; mp 263–265 °C.
1H NMR (CDCl3): δ = 7.90–7.88 (m, 2 HAr), 7.55 (m, 8 HAr), 7.38–7.30
(m, 8 HAr), 5.12 (br s, 2 H, OH).
13C NMR (CDCl3): δ = 151.4, 139.8, 137.0, 136.8, 135.6, 134.1, 133.4,
13C NMR (CDCl3): δ = 152.3, 142.7, 138.4, 134.1, 131.4, 128.8, 127.9,
129.05, 128.6, 127.9, 122.5, 121.0, 118.0, 107.4, 20.5, 20.3.
127.7, 126.6, 124.5, 118.8, 110.9.
HRMS: m/z [M+] calcd for C18H15ClO: 282.0811; found: 282.0831.
Anal. Calcd for C32H20Cl2O2 + ½ H2O: C, 74.43; H, 4.10. Found: C, 74.29;
H, 4.19.
Reaction of 1a with 2a in the Presence of CsF at Room Tempera-
ture; 1-(2-Benzoylpenyl)acetone (5a)
4,4′-Bis(4-nitrophenyl)-1,1′-BINOL (6d)
Triflate 1a (0.36 g, 1.2 mmol) in MeCN (5 mL) was added to a mixture
of 2a (0.16 g, 1.0 mmol) and CsF (0.55 g, 3.6 mmol) in MeCN (5 mL).
After stirring for 5 h at r.t., the reaction mixture was poured into H2O
and extracted with CH2Cl2 (3 × 5 mL). The combined extracts were
dried (Na2SO4), filtered, and evaporated to give a pale yellow oil,
which was chromatographed over silica gel, eluting with hexane–
EtOAc (5:1), to afford 5a4b a colorless oil; yield: 0.13 g (0.55 mmol,
58%).
Yield: 0.035 g (0.065 mmol, 65%): yellow crystals; mp 275 °C (dec.).
1H NMR (CDCl3): δ = 7.84–7.79 (m, 8 HAr), 7.42–7.32 (m, 8 HAr), 5.21
(br s, 2 H, OH).
13C NMR (CDCl3): δ = 152.28, 147.8, 146.8, 141.7, 134.1, 131.1, 128.2,
127.6, 126.3, 125.2, 125.0, 124.0, 119.1, 111.71.
Anal. Calcd for C32H20N2O6 + 2 H2O: C, 68.08; H, 4.28; N, 4.96. Found:
C, 68.00; H, 4.41; N, 4.94.
1H NMR (CDCl3): δ = 2.29 (s, 3 H, CH3), 2.58 (s, 3 H, CH3), 4.02 (s, 2 H,
CH2), 7.18 (d, J = 7.6 Hz, 1 HAr), 7.38 (t, J = 7.6 Hz, 1 HAr), 7.45 (t, J = 7.6
Hz, 1 HAr), 7.97 (d, J = 7.6 Hz, 1 HAr).
4,4′-Bi(2-thienyl)-1,1′-BINOL (6e)
Yield: 0.032 g (0.072 mmol, 72%); colorless crystals; mp 166–168 °C.
1H NMR (CDCl3): δ = 8.29 (d, J = 7.6 Hz, 2 HAr), 7.52–7.51 (m, 4 HAr),
7.42–7.34 (m, 6 HAr), 7.31–7.29 (m, 6 HAr), 5.10 (br s, 2 H, OH).
13C NMR (CDCl3): δ = 152.1, 140.9, 136.4, 134.2, 128.3, 128.1, 127.9,
127.6, 124.8, 119.9, 111.3.
Anal. Calcd for C28H18O2S2: C, 74.64; H, 4.03. Found: C, 74.82; H, 4.22.
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Synthesis
4,4′-Bis(4-chlorophenyl)-6,7,6′,7′-bi(methylenedioxy)-1,1′-BINOL
(6f)
HPLC: Chiralcel AD-H, hexane–i-PrOH (50:50), temp 27 °C, flow rate:
1.1 mL/min, λ = 254 nm; tR (minor) = 30.6 min, tR (major) = 55.1 min;
ee 80%.
Yield: 0.041 g (0.070 mmol, 70%); colorless crystals; mp >300 °C.
1H NMR (DMSO-d6): δ = 9.25 (br s, 2 H, OH), 7.62 (d, J = 8.4 Hz, 4 HAr),
7.57 (d, J = 8.4 Hz, 4 HAr), 7.07 (s, 2 HAr), 6.97 (s, 2 HAr), 6.36 (s, 2 HAr),
5.99 (s, 2 H, OCH2O), 5.96 (s, 2 H, OCH2O).
(R)-BINOL (R)-6g
Yield: 0.60 g (1.1 mmol, 97%); colorless crystals; mp 151–153 °C.
13C NMR (DMSO-d6): δ = 151.6, 147.6, 145.4, 139.3, 138.0, 132.3,
131.6, 131.3, 128.6, 121.9, 117.2, 116.1, 101.4, 101.1, 101.03.
HPLC: Chiralcel AD-H, hexane–i-PrOH (40:60), temp 27 °C, flow rate:
1.1 mL/min, λ = 254 nm; tR (minor) = 17.4 min, tR (major) = 33.2 min;
ee 56%.
Anal. Calcd for C34H20Cl2O6 + ½ H2O: C, 67.56; H, 3.50. Found: C, 67.72;
H, 3.68.
(R)-BINOL (R)-6h
Yield: 0.67 g (1.2 mmol, 98%); yellow crystals; mp 274–275 °C.
4,4′-Bis(4-chlorophenyl)-5,5′-dimethoxy-1,1′-BINOL (6g)
HPLC: Chiralcel AD-H, hexane–i-PrOH (40:60), temp 27 °C, flow rate:
1.1. mL/min, λ = 254 nm; tR (major) = 6.18 min, tR (minor) = 7.4 min;
ee 23%.
Yield: 0.041 g (0.072 mmol, 72%); colorless crystals; mp 178–180 °C.
1H NMR (CDCl3): δ = 7.40–7.32 (m, 8 HAr), 7.28–7.24 (m, 4 HAr), 6.88
(d, J = 8.4 Hz, 2 HAr), 6.67 (d, J = 7.2 Hz, 2 HAr), 5.05 (br s, 2 H, OH), 3.54
(s, 6 H, CH3).
Enantiomerically Pure 1,1′-Biaryl-BINOL 6c; Typical Procedure
13C NMR (CDCl3): δ = 157.4, 152.1, 143.4, 141.6, 136.1, 132.2, 129.9,
A solution of 4,4′-bis(4-chlorophenyl)-BINOL (6c; 0.41 g, 0.81 mmol)
in EtOH (22 mL) was added to a solution of L-proline (0.026 g, 0.23
mmol) in EtOH (10 mL) at r.t. After refluxing for 3 h, the reaction mix-
ture was cooled to r.t. The resulting crystals were filtered, and the fil-
trate was agitated for 2 h and evaporated to give a colorless solid. The
solid was added to H2O (5 mL), extracted with EtOAc (3 × 5 mL), dried
(Na2SO4), filtered, and evaporated to give the enantiomerically pure
(R)-4,4′-bi(4-chlorophenyl)-BINOL [(R)-6c] as colorless crystals; mp
128.2, 127.1, 120.4, 119.5, 117.5, 111.3, 104.8, 55.2.
Anal. Calcd for C34H24Cl2O2 + H2O: C, 69.75; H, 4.48. Found: C, 69.58;
H, 4.70.
4,4′-Bis(4-chlorophenyl)-6,6′,7,7′-tetramethyl-1,1′-BINOL (6h)
Yield: 0.041 g (0.073 mmol, 73%); colorless crystals; mp 282–284 °C.
1H NMR (CDCl3): δ = 7.62 (s, 2 HAr), 7.58–7.54 (m, 8 HAr), 7.24 (s, 2
HAr), 7.08 (s, 2 HAr), 5.00 (br s, 2 H, OH), 2.32 (s, 6 H, CH3), 2.23 (s, 6 H,
CH3).
20
268–270 °C; yield: 0.28 g (0.56 mmol, 69%); [α]D +79.2 (c = 1.00,
THF); ee >98% .
Other reactions were carried out in a similar manner.
13C NMR (CDCl3): δ = 151.6, 141.6, 138.9, 137.7, 134.1, 133.8,
132.8,131.4, 128.8, 126.7, 126.1, 124.4, 117.9, 110.4, 20.4, 20,2.
Anal. Calcd for C36H28Cl2O2: C, 76.73; H, 5.01. Found: C, 76.69; H, 5.15.
Supporting Information
Enantioselective Synthesis of BINOL 6a; Typical Procedure
Supporting information for this article is available online at
To a solution of 4-phenyl-2-naphthol (3aa; 0.22 g, 1.0 mmol) in CCl4
(15 mL) was added naphthoaldehyde-valine vanadium oxide complex
(0.033 g, 0.10 mmol), and O2 was applied for 10 min. After stirring for
2 days at r.t., the reaction mixture was evaporated to give brown oily
crystals, which were chromatographed over silica gel, eluting with
CH2Cl2, to afford (R)-BINOL (R)-6a as colorless crystals; mp 135–139
°C; yield: 0.18 g (0.43 mmol, 85%).
http://dx.doi.org/10.1055/s-0034-1380452.
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(R)-BINOL (R)-6e
Yield: 0.72 g (1.6 mmol, 98%); colorless crystals; mp 161–162 °C.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2937–2944

2944
K. Okuma et al.
Special Topic
Synthesis
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2937–2944