Direct Asymmetric Friedel-Crafts Reaction of Naphthols with Acetals Catalyzed by Chiral Bronsted Acids

Article abstract of DOI:10.1055/s-0035-1561279

The Friedel-Crafts method synthesis of chiral ethers from various acetals and naphthols catalyzed by chiral Bronsted acids with acetic acid as an effective additive is described. We found that the chiral phosphoric acid (R)-TRIP could efficiently catalyze the asymmetric Friedel-Crafts reaction of naphthols with acetals affording chiral ethers in good enantioselectivity and yield.

Full text of DOI:10.1055/s-0035-1561279

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Direct Asymmetric Friedel–Crafts Reaction of Naphthols with
Acetals Catalyzed by Chiral Brønsted Acids
Long Qina,1
Pei Wanga,1
Yixin Zhanga
Zhengxiang Rena
Xin Zhanga
MeO
R
*
TRIP (20 mol%)
OH
OH
OMe
AcOH (20 mol%)
R1
R1
+
R
C2H4Cl2, 35 °C,15 h
OMe
R = Ar
15 examples,42–72% yield
20–71% ee
Chao-Shan Da*a,b
a Institute of Biochemistry & Molecular Biology, School of Life
Sciences, Lanzhou University, Lanzhou 730000, P. R. of China
b State Key Laboratory of Applied Organic Chemistry, Lanzhou
University, Lanzhou 730000, P. R. of China
dachaoshan@lzu.edu.cn
Received: 01.09.2015
Accepted after revision: 14.11.2015
Published online: 23.12.2015
Acetals are widely used in carbon–carbon bond-forming
reactions with a variety of nucleophiles for the synthesis of
ethers. Already used nucleophiles include vinyl ethers and
arylboronic esters,3 alkynes,4 allyl acetates,5 indoles6 and al-
lyltrimethylsilanes.7 However, the asymmetric substitute of
naphthols as nucleophiles to acetals have not been reported
so far. We were very interested in developing an effective
approach to realize the Friedel–Crafts8 reaction of phenols
and acetals for chiral ethers. Chiral Brønsted acid catalysis
has been widespread in asymmetric synthesis over the past
decade because of it being easy to handle, generally stable
toward oxygen and water, and friendly to environment.9
Many organic chemists have focused their attention on the
development of chiral binaphthol-derived phosphoric acids
as the chiral Brønsted acidic catalysts in a variety of organic
transformations,10 such as nucleophilic addition to aldi-
mines,11 aza Diels–Alder reactions,12 transfer hydrogena-
tions13 and as a result have been actively investigated.
Therefore, we chose chiral BINOL-based phosphoric acids as
catalysts to promote the enantioselective Friedel–Crafts re-
action of naphthols with acetals for chiral ethers. Herein,
we disclose results on this study.
DOI: 10.1055/s-0035-1561279; Art ID: st-2015-w0669-l
Abstract The Friedel–Crafts method synthesis of chiral ethers from
various acetals and naphthols catalyzed by chiral Brønsted acids with
acetic acid as an effective additive is described. We found that the chiral
phosphoric acid (R)-TRIP could efficiently catalyze the asymmetric Frie-
del–Crafts reaction of naphthols with acetals affording chiral ethers in
good enantioselectivity and yield.
Key words Friedel–Crafts reaction, chiral ethers, acetals, chiral Brønst-
ed acid, asymmetric organocatalysis
Chiral ethers are ubiquitous in natural products and
pharmaceutical candidates, show beneficial effects in hu-
man health, such as anticancer, antiobesity, antidiabetes ef-
fects, antibacterial, antioxidative, and antihypercholesterol-
emic properties (Figure 1).2
OH
OH
OH
OH
HO
O
HO
O
In initial experiments, various solvents were investigat-
ed in the model Friedel–Crafts reaction of β-naphthol and
the dimethyl acetal of benzaldehyde by using 20 mol% chi-
ral phosphoric acid 1d at 50 °C without any additive (Table
1, entries 1–5). The results showed that the enantioselectiv-
ities were very low; both toluene and 1,2-dichloroethane
achieved the similar enantioselectivity values higher than
other solvents. Toluene gave 15% ee and 71% isolated yield
(Table 1, entry 1) while 1,2-dichloroethane achieved 13% ee
and 75% isolated yield (Table 1, entry 3). For increase of the
enantioselectivity, we chose toluene and 1,2-dichlo-
roethane as solvents for further optimization of the other
reaction conditions. A series of acidic additives that could
also affect the pKa were introduced to raise the enantiose-
lectivity (Table 1, entries 6–16). The results indicated that
only in 1,2-dichloroethane, acetic acid was an optimal acid-
ic additive with increased yield (up to 77%) and enantiose-
OH
OH
OH
OH
catechin
epicatechin
O
O
O
H
H
O
O
O
asarinin
Figure 1 Structures of chiral ethers
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Table 1 The Optimization of the Reaction Conditionsa
R
Ph
OMe
*
cat. (x mol%)
additive (y mol%)
O
P
OH
O
O
OH
1a: R = H
1b: R = Ph
OH
+
1c: R = 3,5-(CF3)2C6H3 1d: R = biphenyl
1e: R = 2,4,6-(i-Pr)3C6H2
R1
R1
O
O
R
2a
3a
4a
Entry
Solvent
Additiveb
Cat.
R1
x
y
Temp (°C)
Time (h)
Yield (%)c
ee (%)d
1
toluene
THF
–
–
–
–
–
1d
1d
1d
1d
1d
1d
1d
1d
1d
1d
1d
1d
1d
1d
1d
1d
1a
1b
1c
1e
1e
1e
1e
1e
1e
1e
1e
1e
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
20
–
–
–
–
–
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
35
20
35
27
25
25
26
30
22
25
24
10
10
12
7
71
21
75
56
43
78
65
79
77
76
58
55
76
68
63
75
76
72
54
61
55
58
64
60
70
64
46
58
15
5
2
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
5
3
C2H4Cl2
dioxane
DMF
13
4
4
5
5
6
toluene
toluene
toluene
C2H4Cl2
C2H4Cl2
C2H4Cl2
C2H4Cl2
C2H4Cl2
C2H4Cl2
C2H4Cl2
C2H4Cl2
C2H4Cl2
C2H4Cl2
C2H4Cl2
C2H4Cl2
C2H4Cl2
C2H4Cl2
C2H4Cl2
C2H4Cl2
C2H4Cl2
C2H4Cl2
C2H4Cl2
C2H4Cl2
CF3COOH
Et3N
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
30
100
20
20
20
15
11
25
40
31
35
15
33
35
31
15
<1
12
21
61
33
49
58
54
56
68
58
66
7
8
AcOH
9
AcOH
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
BrCH2COOH
EtCOOH
DNPe
PhCOOH
11
11
9
4-MeOC6H4COOH
4-O2NC6H4COOH
Al(OAc)3
AcOH
5
18
20
18
10
13
11
10
9
AcOH
AcOH
AcOH
AcOH
AcOH
10
25
20
20
20
20
20
AcOH
AcOH
AcOH
7
AcOH
15
46
28
AcOH
AcOH
a Unless otherwise specified, the reaction was carried out with 2a (0.4 mmol) and 3a (0.2 mmol) in the presence of catalysts 1, additives and solvent (1 mL).
b Additive was used in entries 6–27.
c Isolated yield.
d Determined by HPLC analysis.
e DNP = 2,4-dinitrophenol.
lectivity (up to 40%; Table 1, entry 9).14 Then we found that
phosphoric acid 1e showed the highest enantioselectivity
(61%) among the investigated five catalysts (Table 1, entries
17–20). Changing the loading of the catalyst not only in-
creased the enantioselectivity but also shortened the reac-
tion time (Table 1, entries 21–23). Increase of the acetic
acid load could accelerate the reaction but did not lead to
significant improvement in enantioselectivity. At last the
reaction temperature was observed. Decreasing the reac-
tion temperature to 35 °C slightly improved the enantio-
selectivity (from 61% to 68%). But at the decreased tempera-
ture of 20 °C, both the enantioselectivity and the yield of
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L. Qin et al.
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the transformation were sharply reduced (Table 1, entries
26 and 27). When we used (diethoxymethyl)benzene as the
substrate, yield and ee of the reaction decreased slightly
(Table 1, entry 28).
thol and m-methoxyphenol were utilized in the reaction.
The reaction proceeded with 2-naphthols (Table 2, entries
11–13). However, 1-naphthol completed the reaction very
fast but with very low enantioselectivity (Table 2, entry 14).
And m-methoxyphenol failed to give the chiral ether (Table
2, entry 15). When cinnamic aldehyde was used, the reac-
tion became complicated and the desired product was not
found (Table 2, entry 16).
Regarding the reaction mechanism, we speculate that
the acetal 3 first loses methanol catalyzed by the chiral
phosphoric acid 1 to result in the reactive oxocarbonium in-
termediate A,15 which is coupled with the anionic phos-
phoric acid 1. The hydrogen atom of acetic acid forms H-
bonding with the basic oxygen atom of the chiral phosphor-
ic acid 1, thus greatly increasing the catalyst acidity. The
subsequent H-bonding interaction of basic oxygen atom of
the chiral phosphoric acid 1 with the hydroxyl group of β-
naphthol increases the nucleophilicity of β-naphthol. The
nucleophilic attack of 2-naphthol to the oxocarbonium in-
termediate A yields the chiral ether 4 and the heterodimeric
catalyst 1 is regenerated to catalyze the next cycle Friedel–
Crafts reaction (Scheme 1).
With the optimized reaction conditions in hand, the
scope of substrates for various acetals with naphthols was
explored. As the results in Table 2 show, the reactions pro-
ceeded smoothly and the acetals with electron-donating
substituents afforded higher levels of enantioselectivities
(Table 2, entries 2–5) while acetals with electron-with-
drawing groups in the benzene rings slightly lowered the
enantioselectivity (Table 2, entries 6–9). m-Tolualdehyde
dimethyl acetal produced the highest ee value (71%) with
good 61% yield (Table 2, entry 3). m-Methoxybenzaldehyde
dimethyl acetal afforded the highest yield of up to 68% (Ta-
ble 2, entry 5). Similarly, 2-naphthaldehyde dimethyl acetal
achieved a moderate 66% ee (Table 2, entry 10). To extend
the scope of the naphthol, 6-bromo-2-naphthol, 1-naph-
Table 2 Direct Asymmetric Substitute Reactions of Various Acetals
with Naphthol
OH
MeO
R
R1
*
OAr
P
*
1e (20 mol%)
Me
R
OH
OH
2
+
AcOH (20 mol%)
MeOH
O
O
OAr
R1
O
C2H4Cl2, 35°C
H
OMe
HOAc
2
4a–n
R
A
OMe
3a–j
OMe
OMe
R
Entry
2
R
Yield (%)a ee (%)b
O
H
3
1
2-naphthol (2a)
2-naphthol (2a)
2-naphthol (2a)
2-naphthol (2a)
2-naphthol (2a)
2-naphthol (2a)
2-naphthol (2a)
2-naphthol (2a)
2-naphthol (2a)
2-naphthol (2a)
Ph (3a)
64
58
61
54
68
55
71
63
63
40
58
33
50
66
57
66
66
20
H
O
O
OAr
P
*
2
o-MeC6H4 (3b)
O
ArO
Me
R
P
O
O
OAr
*
3
m-MeC6H4 (3c)
p-MeC6H4 (3d)
ArO
O
4
H
1
H
AcOH
5
m-MeOC6H4 (3e) 68
O
6
o-ClC6H4 (3f)
p-ClC6H4 (3g)
p-BrC6H4 (3h)
p-FC6H4 (3i)
42
55
51
46
44
57
58
R
OMe
OH
*
7
8
B
9
10
11
12
13
14
15
16
2-naphthyl (3j)
4
6-bromo-2-naphthol (2b) Ph (3a)
Scheme 1 Proposed mechanism of the reaction
6-bromo-2-naphthol (2b) m-MeC6H4 (3c)
6-bromo-2-naphthol (2b) m-MeOC6H4 (3e) 54
In summary, we have reported for the first time an ef-
fective asymmetric Friedel–Crafts reaction of the naphthol
with acetals under mild reaction conditions in the catalysis
of the chiral BINOL-based phosphoric acid in good yields
and enantioselectivities.16 A series of optically active ethers
can be easily synthesized with this approach.
1-naphthol (2c)
Ph (3a)
Ph (3a)
styryl
72
c
c
m-methoxyphenol (2d)
2-naphthol (2a)
–
–
c
c
–
–
a Isolated yield.
b Determined by chiral HPLC analysis.
c Not determined.
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Acknowledgment
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Angew. Chem. 2006, 118, 7996.
We are greatly thankful for the financial support from the National
Natural Science Foundation of China (No. 21072087).
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Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1561279.
S
u
p
p
ortioInfgrmoaitn
S
u
p
p
ortiInfogrmoaitn
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(16) General Catalytic Enantioselective Reaction of the Naphthol
with Acetals: Into a 5-mL dry round bottom flask containing a
magnetic stirring bar were added the catalyst (0.04 mmol) and
the naphthol (0.4 mmol) under argon. Anhydrous 1,2-dichlo-
roethane (1 mL), acetals (0.2 mmol) and AcOH (0.04 mmol)
were added sequentially at r.t. The reaction mixture was stirred
at 35 °C until the reaction was complete (checked by TLC). Then
the reaction was cooled to 0 °C and a few drops of sat. NaHCO3
were added to quench the reaction. After extraction with CH2Cl2
(3 × 2 mL), the combined organic phases were dried with anhyd
Na2SO4 and concentrated under vacuum to give the crude prod-
uct. Finally purification by column chromatography afforded
the expected chiral ethers.
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1-[Methoxy(o-tolyl)methyl]naphthalen-2-ol (4b): white crys-
20
tal; mp 85–87 °C; [α]D +23 (c 1.0, CHCl3). 1H NMR (400 MHz,
CDCl3): δ = 2.65 (s, 3 H), 3.60 (s, 3 H), 6.35 (s, 1 H), 6.88–6.90 (d,
J = 6.0 Hz, 1 H), 6.97–7.01 (m, 1 H), 7.18–7.35 (m, 5 H), 7.41–
7.43 (m, 1 H), 7.78–7.81 (m, 2 H), 9.23 (s, 1 H). 13C NMR (100
MHz, CDCl3): δ = 19.3, 58.2, 81.6, 119.4, 121.1, 123.0, 126.3,
126.8, 127.8, 128.8, 128.9, 130.3, 130.8, 154.9. HRMS (ESI, +ve):
m/z [M – H] calcd for C19H17O2: 277.1234; found: 277.1228. ee =
55%, determined by chiral HPLC with an OD-H column (hexane–
i-PrOH, 99:1); flow rate = 1.0 mL/min; tR = 7.26 (major), tR = 8.97
(minor).
2-[Methoxy(phenyl)methyl]naphthalen-1-ol (4n): yellow oil;
[α]D20 +3 (c 1.0, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 3.52 (s, 3
H), 5.57 (s, 1 H), 6.96–6.98 (d, J = 8.4 Hz, 1 H), 7.28–7.38 (m, 6
H), 7.46–7.47 (m, 2 H), 7.73–7.75 (m, 1 H), 8.29–8.31 (m, 1 H),
9.04 (s, 1 H). 13C NMR (100 MHz, CDCl3): δ = 57.4, 87.6, 119.2,
122.3, 125.2, 125.4, 126.2, 126.4, 127.2, 127.4, 128.3, 128.6,
134.0, 140.0, 150.9. ee = 20%, determined by chiral HPLC with
an OD-H column (hexane–i-PrOH, 99:1); flow rate: 1.0 mL/min;
tR = 8.70 (major), tR = 12.30 (minor).
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, 571–574