A new synthesis of 2-fluoro-1-naphthols

Article abstract of DOI:10.1016/j.jfluchem.2004.11.006

A general synthesis of 2-fluoro-1-naphthols in two steps from 1-indanones is reported. The 1-indanones are first converted to difluoromethyl 2-fluoro-1-napthyl ethers by reaction with difluorocarbene source, trimethylsilyl 2-fluorosulfonyl-2,2-difluoroacetate (TFDA). These ethers are then converted in high yield to the respective naphthols by heating with a mixture of acetic acid and 48% HBr.

Full text of DOI:10.1016/j.jfluchem.2004.11.006

Journal of Fluorine Chemistry 126 (2005) 479–482
www.elsevier.com/locate/fluor
A new synthesis of 2-fluoro-1-naphthols
*
Xiaohong Cai, Kai Wu, William R. Dolbier Jr.
Department of Chemistry, University of Florida, P.O. Box 117200, Gainesville FL 32611-7200, USA
Received 7 September 2004; received in revised form 28 October 2004; accepted 10 November 2004
Available online 15 December 2004
Dedicated to Prof. R.D. (Dick) Chambers on the occasion of his 70th birthday.
Abstract
A general synthesis of 2-fluoro-1-naphthols in two steps from 1-indanones is reported. The 1-indanones are first converted to
difluoromethyl 2-fluoro-1-napthyl ethers by reaction with difluorocarbene source, trimethylsilyl 2-fluorosulfonyl-2,2-difluoroacetate
(TFDA). These ethers are then converted in high yield to the respective naphthols by heating with a mixture of acetic acid and 48% HBr.
# 2004 Elsevier B.V. All rights reserved.
Keywords: Difluorocarbene; Indanone; Fluoroaromatics
1. Introduction
2. Results and discussion
The only reported syntheses of 2-fluoro-1-naphthol (1a)
appear to be those that involve electrophilic fluorina-
tion of 1-naphthol by various electrophilic fluorination
reagents, which include fluoroxytrifluoromethane [1],
CsSO4F [2,3], N-fluoro-N-alkylsulfonamides [4], N-fluoro-
pyridinium triflate [5], 1-chloromethyl-4-fluoro-1,4-diazo-
niabicyclo[2.2.2]octane bis(tetrafluoroborate) (also known
as F-TEDA) [6–8], and 4,6-bis(trifluoromethyl) N-fluor-
opyridinium-2-sulfonate (2) [9]. These reactions generally
lead to preferential formation of the 2-fluoro isomer,
although mixtures of both the 2-fluoro and the 4-fluoro
isomers were usually reported (Scheme 1). In one
contrary example, only the 2-fluoro isomer (in 63% yield),
along with a small amount of 2,2-difluoro-3,4-dihydro-2H-
naphthalen-1-one, was obtained when 1-naphthol was
treated with Umemoto’s counteranion-bound N-fluoro-
pyridinium reagent (2) (Scheme 2) [9].
Recently, we reported the sequential reaction of aryl alkyl
ketones with two equivalents of difluorocarbene, generated
thermally (under fluoride catalysis) from acid free
trimethylsilyl fluorosulfonyldifluoroacetate (TFDA) [10],
to form difluoromethyl 2,2-difluorocyclopropyl ethers, via
the intermediate formation of difluoromethyl enol ethers
(Scheme 3) [11].
2.1. Synthesis of 2-fluoro-1-naphthyl difluoromethyl ethers
In principle, when the reaction depicted in Scheme 3 is
carried out using 1-indanone (3a) as substrate, the analogous
product (5a) should be formed (Scheme 4). However, it is
well known that difluorocarbene adducts of both cyclopen-
tadiene [12,13] and indene [14] undergo relatively facile
aromatization reactions via thermal dehydrofluorination
processes. As indicated in Table 1, a small amount of
intermediate compound 5a with the difluorocyclopropane
ring intact could be observed when the reaction with TFDA
was carried out in refluxing toluene, but when it was carried
out in refluxing xylene none was observed. Under these
conditions, the reaction led directly to the aromatized,
dehydrofluorinated product, (6a) in a very good yield.
When carried out using substituted 1-indanones as
substrates, the reaction provides a convenient, general
In the present paper, we report a novel method for the
specific synthesis of 2-fluoro-1-naphthols. It will be shown
that two different aspects of difluorocarbene chemistry
combine to provide an efficient and broadly applicable
synthesis of 2-fluoro-1-naphthols from 1-indanones.
* Corresponding author. Tel.: +1 3523920591; fax: +1 3528461962.
E-mail address: wrd@chem.ufl.edu (W.R. Dolbier Jr.).
0022-1139/$ – see front matter # 2004 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2004.11.006

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X. Cai et al. / Journal of Fluorine Chemistry 126 (2005) 479–482
Scheme 1.
Scheme 4.
Scheme 2.
Table 1
Conversions of 1-indanones to difluoromethyl 2-fluoro-1-naphthyl ethers
synthesis of difluoromethyl ethers of 2-fluoro-1-naphthols,
as can be seen in Scheme 5 and Table 1. Together with
formation of major fluoronaphthol product 6, small amounts
of intermediate enol ethers 4 or difluorocyclopropanes 5
(generally detected in the NMR spectra of the crude product)
were sometimes detected in these reactions.
Indanone R group
substrate
Solvent TFDA
(equiv.)
Product Yield Side
(%)
product
3a
3a
3b
3b
3c
3c
3d
3d
3e
H
Toluene
Xylene
Toluene
Xylene
Xylene
Xylene
6
8
6
6
6
8
6
8
6
6a
6a
6b
6b
6c
6c
6d
6d
6e
35
77
38
80
20
39
53
45
37
5a (6%)
–
H
6-methyl
6-methyl
5-chloro
5-chloro
–
–
An analogous reaction with 1,3-indanedione proceeded
to give enol ether 7 as the major product, together with small
amounts of cyclopropane product 8 (Scheme 6). Unlike the
case for the indanone-derived cyclopropane products 5,
product 8 has no mechanistically viable aromatization
process accessible to it.
–
–
5-methoxy Toluene
5-methoxy Xylene
–
–
2-methyl
Xylene
4e (13%)
It has also been found that 2-indanones undergo
chemistry analogous to that of the 1-indanones, but this
work is still in the preliminary stages and will be reported
separately.
2.2. Conversion of difluoromethyl ethers to naphthols
Finding a good method for conversion of the difluoro-
methyl ether products, 6, to their naphthol analogues, 1,
proved to be an experimental challenge, with these ethers
being stable to highly acidic conditions such as refluxing
6 M HCl and 48% HBr. Use of electrophilic catalysis, such
as refluxing aqueous AgNO3, treatment with solid AlCl3,
Scheme 5.
BF3 in refluxing THF or SbF3 in CH2Cl2 led either to no
reaction or decomposition.
Finally, it was found that heating difluoromethyl ethers
6a–c in a sealed tube containing a mixture of acetic acid and
48% aqueous HBr at 120 8C overnight led to formation of
Scheme 3.
Scheme 6.

X. Cai et al. / Journal of Fluorine Chemistry 126 (2005) 479–482
481
additional 3 h at reflux. After the solvent was removed under
reduced pressure, the residue was purified by column
chromatography on silica gel (hexanes/AcOEt: 20/1) to give
the desired products, 6a–e.
4.2.1. Reaction of 3a
Scheme 7.
In the case of its reaction in toluene, a mixture of 1-
difluoromethoxy-2-fluoro-naphthalene, 6a (35%) and 1a-
difluoromethoxy-1,1-difluoro-1,1a,6,6a-tetrahydro-cyclo-
propa[a]indene, 5a (6%) (6a:5a = 100:17) was obtained, in
addition to recovered 1-indanone. In the case of its reaction
in xylene, only 6a was obtained.
the respective 2-fluoro-1-naphthols, 1a–c in yields ranging
from 75 to 89% (Scheme 7). The methoxy-substituted
difluoromethyl ether, 6d, did not give satisfactory results in
this reaction, whereas 6e was not attempted.
1
1-Difluoromethoxy-2-fluoronaphthalene (6a): H NMR,
d: 6.73 (dd, J = 74.6 and 73.5 Hz, 1H), 7.34 (t, J = 9.7 Hz,
1H), 7.52 (t, J = 7.6 Hz, 1H), 7.62 (t, J = 7.7 Hz, 1H), 7.70–
7.78 (m, 1H), 7.85 (d, J = 8.2 Hz, 1H), 8.18 (d, J = 8.5 Hz,
1H); 19F NMR, d: À80.9 (dd, J = 73.2 and 6.1 Hz, 2F),
À131.5 (m, 1F); HRMS (EI) calculated: C11H7F3O, M+,
212.0449, found: 212.0500.
3. Conclusion
In conclusion, a two step, regiospecific synthesis of
2-fluoro-1-naphthols from 1-indanones is reported. This
synthesis should be broadly applicable to the synthesis of
most substituted 2-fluoro-1-naphthols for which the appro-
priate 1-indanone precursors are available.
1a-Difluoromethoxy-1,1-difluoro-1,1a,6,6a-tetrahydro-
cyclopropa[a]indene (5a): 1H NMR d: 2.80 (dd, J = 7.4 and
17.3 Hz, 1H), 3.15 (d, J = 17.2 Hz, 1H), 3.50 (dd, J = 7.7
and 17.7 Hz, 1H), 6.35 (dd, J = 71.8 and 75.8 Hz, 1H), 7.21–
7.26 (m, 1H), 7.29–7.36 (m, 2H), 7.48–7.56 (m, 1H); 19F
NMR, d: À82.4 (m, 2F), À137.5 (dd, Jd(F–F) = 155.6 Hz,
4. Experimental
4.1. General
J
d(F–H) = 18.3 Hz, 1F), À149.9 (d, Jd(F–F) = 155.6 Hz, 1F);
HRMS (EI), calculated: C11H8F4O2, M+, 232.0511, found:
232.0514.
1H and 13C NMR spectra were obtained at 300 MHz (1H),
75 MHz (13C) and 282 MHz (19F) using CDCl3 as solvent,
tetramethylsilane as an internal reference standard for H and
C and CFCl3 as external reference for F. Toluene and xylene
were distilled from sodium metal under nitrogen immedi-
ately before their use as solvents. FSO2CF2COOSiMe3
(TFDA) was prepared according to the literature [10].
Sodium fluoride (NaF) was oven dried before use. All other
reagents and solvents were obtained from commercial
sources and were used without additional purification.
4.2.2. Reaction with 3b
1-Difluoromethoxy-2-fluoro-7-methylnaphthalene (6b):
yellow oil; 1H NMR (CDCl3), d: 2.38 (s, 3H), 6.55 (t,
1
J = 74.5 Hz, 1H) 7.06 (dd, J = 9.4 and 10.6 Hz, H), 7.15
1
(dd, J = 8.5 and 1.8 Hz, H), 7.47 (dd, J = 4.9 and 9.0 Hz,
1H), 7.54 (d, J = 8.5 Hz, 1H), 7.77 (s, 1H); 13C NMR, d:
22.3, 115.5 (d, J = 11.3 Hz), 117.2 (t, J = 265 Hz), 120.6 (d,
J = 6 Hz), 127.4, 127.5, 127.9, 128.6 (d, J = 3 Hz), 129.6,
138.0, 150.0, 153.5; 19F NMR, d: À80.7 (dd, J = 73.3 and
6.1 Hz, 2F), À131.8 (m, 1F); HRMS (EI) calculated:
C12H9F3O, M+, 226.0605, found: 226.0607.
4.2. General procedure for preparation of
1-difluoromethoxy-2-fluoronaphthalenes from substituted
1-indanones, 3a–e
4.2.3. Reaction with 3c
A 15 mL three-necked, round-bottomed flask was
equipped with a magnetic stirrer, an addition funnel, and
a water-cooled condenser bearing a nitrogen (N2) inlet. The
flask was charged with solvent (either toluene or p-xylene),
sodium fluoride (0.06 equiv.) and 1.0 mmol of the appro-
priate 1-indanone, 3a–e. The solution was heated to reflux
and slow N2 bubbling was initiated and continued for 1 h.
Then, TFDA (0.50 g, 2 mmol, 2.0 equiv.) (free of acid
according to 19F NMR) was added slowly using a syringe
pump via a Teflon1 needle at the rate of 0.25 mL/h. After
3 h, an additional two batches of acid-free TFDA (0.50 g,
2.0 mmol, 2.0 equiv.) were added. (Alternatively, two
batches of 1.0 g, 4 mmol, 4.0 equiv. were added, according
to Table 1). The reaction mixture was then heated for an
6-Chloro-1-difluoromethoxy-2-fluoronaphthalene (6c):
white needles; mp 59–61 8C; 1H NMR, d: 6.73 (t,
J = 74.0 Hz, 1H), 7.37 (dd, J = 9.0 and 9.9 Hz, 1H), 7.54
(dm, J = 9.1 Hz, 1H), 7.65 (dd, J = 4.7 and 9.1 Hz, 1H), 7.83
(d, J = 2.0 Hz, 1H), 8.11 (d, J = 9.1 Hz, 1H); 19F NMR, d:
À81.1 (dd, J = 73.2 and 9.2 Hz, 2F), À130.6 (m, 1F); LRMS
calculated: C11H6ClF3O M+, 246, 196 M–CF2.
4.2.4. Reaction with 3d
1-Difluoromethoxy-2-fluoro-6-methoxynaphthalene
(6d): yellow needles; mp 62–64 8C; 1H NMR, d: 3.91
(s, 3H), 6.70 (t, J = 74.6 Hz, 1H) 7.11 (d, J = 2.4 Hz, 1H),
7.22–7.32 (m, 2H), 7.58 (dd, J = 4.6 and 9.0 Hz, 1H),
8.05 (d, J = 9.3 Hz, 1H); 13C NMR, d: 55.6, 106.0, 117.1

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X. Cai et al. / Journal of Fluorine Chemistry 126 (2005) 479–482
(t, J = 266 Hz), 117.0 (d, J = 22.5 Hz), 120.7, 123.4 (k,
J = 6 Hz), 124.3, 126.1 (d, J = 2.6 Hz), 132.6, 148.7, 151.9,
158.0 (d, J = 2.5 Hz); 19F NMR, d: À81.0 (dd, J = 73.3 and
6.1 Hz, 2F), À135.4 (m, 1F); HRMS (EI) calculated:
C12H9F3O2, M+, 242.0555, found: 242.0561.
The pure naphthol products, 1a–c, were obtained by flash
chromatography.
2-Fluoro-1-naphthol (1a): white solid, 52 mg (85%); mp
1
72–74 8C (lit 71–73 8C) [1]; H NMR 5.91 (s, 1H), 7.22–
7.32 (m, 1H), 7.34–7.47 (m, 1H), 7.53–7.62 (m, 1H), 7.72–
7.83 (m, 2H), 8.02–8.11 (m, 1H); 19F NMR À145.8 (m, 1F);
IR(CH2Cl2) 3562, 3044, 2966, 1605, 1058, 941, 867, 816;
MS: 162 (M+, 83), 149(50), 133(100), 114(29), 85(23).
6-Methyl-2-fluoro-1-naphthol (1b): white solid, yield
4.2.5. Reaction with 3e
Following the procedure described above, 110 mg of a
light yellow oil mixture of products, 1-difluoromethoxy-2-
fluoro-2-methylnaphthalene, 6e (37%) and 3-difluoro-
methoxy-2-methyl-1H-indene, 4e (13%) (6e:4e = 100:36)
was obtained.
1
75%; mp 83–85 8C; H NMR 2.58 (s, 3H), 5.42 (s, 1H),
7.16–7.36 (m, 3H), 7.68 (d, 15 Hz, 1H), 7.94–7.98 (m, 1Hz);
19F NMR À145.0 (dd, 7.6 Hz, 29.6 Hz, 1F); 13C NMR
22.19, 114.50, 114.79, 116.04, 120.33, 120.43, 120.57,
120.66, 127.74, 128.09, 135.99; MS: 176(M+, 100), 147(38),
133(66), 128(36), 64(18); HRMS: 176.0629, required,
C11H9FO, 176.0637.
1-Difluoromethoxy-2-fluoro-2-methylnaphthalene (6e):
1H NMR d 2.49 (t, J = 1.1 Hz, 3H), 6.72 (t, J = 74.6 Hz,
1H), 7.45–7.58 (m, 3H), 7.76 (d, J = 7.7 Hz, 1H), 8.12 (d,
J = 8.2 Hz, 1H); 19F NMR d À80.7 (dd, J = 73.2 and 6.1 Hz,
2F), À135.3 (m, 1F); HRMS (EI) calculated: C12H9F3O, M+,
226.0605, found: 226.0663.
5-Chloro-2-fluoro-1-naphthol (1c): white solid, yield
1
89%; mp 96–98 8C; H NMR 5.56 (s, 1H), 7.24–7.32 (m,
3-Difluoromethoxy-2-methyl-1H-indene (4e): 1H NMR
d 2.11 (s, 3H), 3.30 (s, 2H), 6.50 (t, J = 74.6 Hz, 1H), 7.17–
7.40 (m, 4H); 19F NMR d À79.7 (d, J = 74.2 Hz, 2F); HRMS
(EI) calculated: C11H10F2O, M+, 196.0700, found:
196.0707.
2H), 7.41–7.46 (m, 1H), 7.77–7.79 (m, 1H), 8.10–8.16 (m,
1H); 19F NMR À145.3 (m, 1F); 13C NMR (CDCl3), 116.7,
117.1, 119.7, 119.8, 123.6, 123.7, 126.5, 126.5, 126.5,
127.0; MS, 196 (M+, 100), 198(33), 148(9), 133(46),
113(12); HRMS: 196.0091, required, C10H6FClO, found
196.0091.
4.3. Reaction of TFDA with 1,3-indandione
Following the general procedure described above, 15 mg
1a-difluoromethoxy-1,1-difluoro-1a,6a-dihydro-1H-
Acknowledgment
of
cyclopropa[a]inden-6-one (8) and 66 mg of 3-difluoro-
methoxy-inden-1-one (7) were obtained.
The support of this work in part by the National Science
Foundation is gratefully acknowledged.
1a-Difluoromethoxy-1,1-difluoro-1a,6a-dihydro-1H-
cyclopropa[a]indene-6-one (8): yellow oil, yield 6%;
1H NMR d 6.32 (dd, J = 13.4 and 2.3 Hz, 1H), 6.82
(ddd, J1 = 70.7 Hz, J2 = 71.9 Hz, J3 = 1.2 Hz, 1H), 7.64–
7.71 (m, 1H), 7.76–7.90 (m, 2H), 8.12 (d, J = 7.8 Hz, 1H);
19F NMR d À82.0 (m, 2F), À110.4 (dm, J = 354.0 Hz, 2F);
HRMS (EI) calculated: C11H6F4O2, M+, 246.0304, found:
246.0295.
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