A novel Friedel-Crafts alkylation of naphthols without Lewis acid

Article abstract of DOI:10.1016/j.tetlet.2015.07.024

Abstract A novel Friedel-Crafts alkylation of α- or β-naphthols with a variety of β-haloketones is described. The reaction was environmentally-friendly performed under mild conditions without any Lewis acid and in good to excellent yields.

Full text of DOI:10.1016/j.tetlet.2015.07.024

Tetrahedron Letters xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A novel Friedel–Crafts alkylation of naphthols without Lewis acid
Yijun Zhu a,b, Kuaile Lin a, Deyong Ye b, Weicheng Zhou a,
⇑
a State Key Lab of New Drug & Pharmaceutical Process, Shanghai Key Lab of Anti-Infectives, Shanghai Institute of Pharmaceutical Industry, State Institute of Pharmaceutical
Industry, Shanghai 200437, China
b School of Pharmacy, Fudan University, No. 826, Zhangheng Rd., Shanghai 201203, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel Friedel–Crafts alkylation of
reaction was environmentally-friendly performed under mild conditions without any Lewis acid and in
good to excellent yields.
a- or b-naphthols with a variety of b-haloketones is described. The
Received 27 May 2015
Revised 3 July 2015
Accepted 6 July 2015
Available online xxxx
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
Friedel–Crafts alkylation
Naphthols
b-Haloketones
Catalyst-free
Introduction
In fact, compound 1a was a product of Friedel–Crafts alkylation
of naphthol, although the reaction was carried out in the absence
Friedel–Crafts alkylation of aromatic substrates with halides is a
very important method for the carbon–carbon bond formation.1
of Friedel–Crafts catalysts. This unexpected result spurred us to
study the Friedel–Crafts alkylation free from Lewis acids with var-
ious naphthol compounds as the substrate. As illustrated in
Table 1, actually 1-naphthol not only yielded the major product
A
significant number of Lewis acid catalysts, such as AlCl3, SnCl4, and
BF3 have been shown to be very efficient and necessary.2 However,
since the application of Lewis acid, it not only needs strictly anhy-
drous conditions but also generates vast amounts of corrosive
wastes and leads to serious environmental concerns.3 For these
reasons, during the past decade, the study on more ecocompatible
Friedel–Crafts reactions has become a fundamental goal of green
chemistry. The exploitation of recyclable and environmental
friendly catalysts or even abolishment of the traditional Lewis acid
has been one of the important topics in organic synthesis.4
1a, but also gave the
(entry 1). The reaction of 2-naphthol, the isomer of 1-naphthol pro-
ceeded smoothly to afford the -substituted product 1b in good
a,b-dialkylation product 1aa in 18% yield
a
yield (entry 2) and the reaction went well even in toluene with
K2CO3 (entry 3). However, when the organic base DBU was used,
no reaction took place. The naphthols with electron-donating
(OH, OMe, entries 4 and 5) or electron-withdrawing groups (Br,
CN, entries 6 and 7) resulted in the desired Friedel–Crafts alkyla-
tion products (in entry 5, the dialkylated compound was obtained
Results and discussion
In our study on the process of Dapoxetine, a serotonin re-uptake
inhibitor, 3-(1-naphthoxy)propiophenone 1a0 was needed as a key
intermediate.5 It was expected to be prepared by the condensation
of 3-chloro-propiophenone with 1-naphthol under NaOH aq THF
solution (Fig. 1). But the reaction gave 3-(4-hydroxynaphthalen-
1-yl)propiophenone (1a) as the main product (in a yield of 61%)
instead of the proposed compound 1a0. When the iodide 10 with
the better leaving ability was applied in the reaction, the same pro-
duct (63% yield) was obtained.
O
O
OH
O
1a'
X
O
1 (X=Cl)
1' (X=I)
a
HO
1a
Figure 1. Reaction conditions: 1(10) (5 mmol), a (6 mmol), NaOH (7.5 mmol), THF
(6 ml)/H2O (1.5 ml), room temperature, 1 h.
⇑
Corresponding author. Tel.: +86 21 55514600; fax: +86 21 35052484.
E-mail address: zhouweicheng58@163.com (W. Zhou).
http://dx.doi.org/10.1016/j.tetlet.2015.07.024
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Zhu, Y.; et al. Tetrahedron Lett. (2015), http://dx.doi.org/10.1016/j.tetlet.2015.07.024

2
Y. Zhu et al. / Tetrahedron Letters xxx (2015) xxx–xxx
Table 1
Screen of naphthol compoundsa
O
NaOH
Cl
Products
Naphthols
THF/H2O
RT
1
Entry
1
Naphthols
Product
Yieldb (%)
O
OH
61 for 1a
18 for 1aa
O
HO
O
HO
a
1a
1aa
OH
O
2
82
78
60
b
OH 1b
OH
O
3c
b
OH
1b
OH
O
4
OH
OH 1c
HO
c
OH
O
OH
OMe
5
63
OCH3
d
O
1d
OH
Br
O
Br
6
7
58
44
e
f
OH
1e
OH
NC
O
NC
OH1f
OH
O
N
N
8
9
10
87
g
OH 1g
SH
O
S
h
1h'
a
All reactions were conducted by adding naphthols (6 mmol) in 3 ml THF to the mixture of NaOH (7.5 mmol) in 1.5 ml
water, and then the reaction mixture was stirred for 15 min, followed by adding 1 (5 mmol) in 3 ml THF and reacted for 2 h.
b
Isolated yield.
c
The reaction was conducted in toluene with K2CO3 at refluxing temperature.
as the main product), although those with the electron-withdraw-
ing groups gave a lower yield (entries 6 and 7). Moreover,
6-hydroxyl quinoline, the 2-naphthol analogues produced 1g in a
very low yield (10%, entry 8) while 2-naphthalenethiol yielded
the S-alkylation instead of the Friedel–Crafts product.
In light of the novel methodology, a variety of phenolic com-
pounds were further tested to investigate the scope of this
Friedel–Crafts alkylation. The results are summarized in Table 2.
The reaction of phenol (entry 1) or hydroquinone (entry 2) with
compound 1 did not give the Friedel–Crafts alkylation, but the
O-alkylation products were encountered in around 80% yields.
Please cite this article in press as: Zhu, Y.; et al. Tetrahedron Lett. (2015), http://dx.doi.org/10.1016/j.tetlet.2015.07.024

Y. Zhu et al. / Tetrahedron Letters xxx (2015) xxx–xxx
3
Table 2
Screen of phenolsa
O
NaOH
Cl
Products
Phenols
THF/H2O
RT
1
Entry
1
Phenols
Product
Yieldb (%)
82
OH
O
O
i
1i'
HO
HO
O
2
3
80
OH
O
j
1j'
O
O
MeO
MeO
HO
OMe
MeO
OH
15c
kOH
1k'
1k''
4
NA
NA
0d
OMe
l
MeO
5
0d
OMe
m
a
All reactions were conducted by adding phenols (6 mmol) in 3 ml THF to the mixture of NaOH (7.5 mmol) in 1.5 ml water, and then
the reaction mixture was stirred for 15 min, followed by adding 1 (5 mmol) in 3 ml THF and reacted for 2 h.
b
Isolated yield.
c
Calculated from 1k0 plus 1k00.
d
No product was detected by TLC.
Table 3
Screen of chloralkanesa
OH
NaOH
chloralkanes
Products
THF/H2O
RT
Entry
1
Chloralkanes
Product
Yieldb (%)
O
Cl
O
93
O
2
2a'
O
O
Cl
2
3
84
0c
3
3a'
Cl
NA
4
O
O
Cl
4
64
F
HO
F
5
5a
(continued on next page)
Please cite this article in press as: Zhu, Y.; et al. Tetrahedron Lett. (2015), http://dx.doi.org/10.1016/j.tetlet.2015.07.024

4
Y. Zhu et al. / Tetrahedron Letters xxx (2015) xxx–xxx
Table 3 (continued)
Entry
Chloralkanes
Product
Yieldb (%)
58
O
O
H3C
Cl
CH3
5
6
HO
HO
6a
7a
O
O
S
S
Cl
6
56
7
a
All reactions were conducted by adding 1-naphthol (6 mmol) in 3 ml THF to the mixture of NaOH (7.5 mmol) in 3 ml water, and then the
reaction mixture was stirred for 15 min, followed by adding chloralkanes (5 mmol) in 3 ml THF and reacted for 2 h.
b
Isolated yield.
No product was detected by TLC.
c
Tautomerization
OH
O
O
Cl
O
Cl
O
O
1
1a
I
Figure 2. The plausible mechanism of Friedel–Crafts alkylation of naphthols with b-haloketone.
Only 3-methoxyl phenol (entry 3) afforded the trace Friedel–Crafts
alkylation products while neither 1,4-dimethoxybenzene (entry 4)
nor 1,3-dimethoxybenzene (entry 5) reacted with compound 1.
Meanwhile a range of chloralkanes were screened for this Lewis
acid-free Friedel–Crafts reaction by choosing 1-naphthol as the
substrate. As shown in Table 3, when 2-chloro-1-phenylethanone
was used as alkylation agent, the O-alkylation product 2a0 was
obtained (entry 1), while 4-chloro-1-phenylbutan-1-one gave the
elimination product, cyclopropyl (phenyl) methanone (entry 2).
However when the compound (2-chloroethyl)benzene was used,
no reaction took place (entry 3). These results suggested that the
b-haloketone was necessary for this Friedel–Crafts alkylation of
naphthols without catalysts. To further verify this finding, the
reactions of 3-chloro-1-(4-fluorophenyl)propan-1-one (entry 4),
4-chlorobutan-2-one (entry 5) and 3-chloro-1-(thiophen-2-yl)pro-
pan-1-one (entry 6) were tested and the desired Friedel–Crafts
products were obtained in 56–64% yields.
3-methoxyl phenol afforded a low yield of Friedel–Crafts product.
The high aromatic character of the conjugated rings in naphthol
seemed to increase the possibility of the tautomeric carbanion
compared with phenols.8 This may explain why phenols did not
follow the Friedel–Crafts alkylation.
Conclusions
In conclusion, we discovered a novel and facile method for the
Friedel–Crafts alkylation of naphthols with b-haloketone in aque-
ous solvent without any Lewis acid. The yields are good to excel-
lent, and the work-up is very easy and environmentally friendly.
Acknowledgment
We are grateful to the Science and Technology Commission of
Shanghai for financial support (15ZR 1440200).
It was assumed that in the reaction, b-haloketone might form
the oxonium ion transition resulting from the neighboring-group
(carbonyl) participation in the departure of the halo leaving group
Supplementary data
(Fig. 2).6 However
a-haloketone and c-haloketone could not show
Supplementary data (experimental procedures and 1H NMR and
MS data of 1a0–7a) associated with this article can be found, in the
online version, at http://dx.doi.org/10.1016/j.tetlet.2015.07.024.
the neighboring-group effect. The former yielded O-alkylation via a
simple SN2 reaction (Table 2, entry 1) while the latter eliminated a
hydrogen chloride to form the cyclopropane (Table 2, entry 2).
And (2-chloroethyl)benzene did not react with 1-naphthol
(Table 2, entry 3) because of lack of the neighboring carbonyl
group. When the b-haloketone framework was retained, either ali-
phatic (entry 5 in Table 3) or heteroaromatic (entry 6 in Table 3)
ketone could yielded the Friedel–Crafts alkylation products.
The catalyst-free Friedel–Crafts alkylation went well for naph-
thols. Because under the basic aqueous condition naphtholate
existed mainly in the form of its tautomeric carbanion (Fig. 2),7
and the soft base carbanion tended to be attacked by the soft elec-
trophile of transition I from b-haloketone to afford the C-alkylation
product even without the Lewis acid. In entry 5 (Table 1), the elec-
tron-donating methoxy made the naphthol easier for the reaction
so that the di-alkylation took place. However neither phenol nor
hydroquinone followed the Friedel–Crafts alkylation except the
References and notes
1. (a) Olah, G. A. Friedel–Crafts and Related Reactions In ; Wiley-Interscience: New
York, 1965; Vols. I–IV,; (b) Olah,
Interscience: New York, 1973.
G A. Friedel–Crafts Chemistry; Wiley-
2. (a) Liguori, L.; Bjørsvik, H. R.; Fontana, F. J. Org. Chem. 1999, 64, 8812; (b)
Anderson, K. W.; Tepe, J. J. Org. Lett. 2002, 4, 459; (c) Chong, Hyun-Soon; Chen,
Yunwei Org. Lett. 2013, 15, 5912; (d) Kim, H. Y.; Oh, K. Org. Lett. 2014, 16, 5934.
3. Rueping, M.; Nachtsheim, B. J. Beilstein J. Org. Chem. 2010, 6, 6.
4. Sartori, G.; Maggi, R. Chem. Rev. 2006, 106, 1077.
5. Mahale, R. D.; Chaskar, S. P.; Patil, K. E.; Maikap, G. C.; Gurjar, M. K. Org. Process
Res. Dev. 2012, 16, 710.
6. (a) Bouchoux, G.; Hoppilliard, Y. J. Phys. Chem. 1988, 92, 5869; (b) Bégué, J. P.;
Malissard, M. Tetrahedron 1978, 34, 2095.
7. (a) Gut, I. G.; Scheibler, L. C.; Wirz, J. Photochem. Photobiol. Sci. 2010, 9, 901; (b)
Korth, H. G.; Mulder, P. J. Org. Chem. 2013, 78, 7674.
8. Osmialowski, B.; Raczynska, E. D. J. Org. Chem. 2006, 71, 3727.
Please cite this article in press as: Zhu, Y.; et al. Tetrahedron Lett. (2015), http://dx.doi.org/10.1016/j.tetlet.2015.07.024