Synthesis of functionalized difluoronaphthalenes by regioselective C—H functionalization of 2,3-difluoronaphthalene

Article abstract of DOI:10.1007/s11172-020-2756-0

2,3-Difluoronaphthalene (1) was selectively converted into 1-methyl-, 1,4-dimethyl-, 1-acetyl-, 1-acetyl-4-methyl-, 1-formyl-, and 1-carboxyl-substituted 2,3-difluoronaphthalenes using lithiation with BuLi as a key step. Nitration and bromination of compound 1 predominantly gave 6,7-difluoro-1-nitronaphthalene and 1-bromo-6,7-difluoronaphthalene, respectively. Regioselectivity of acylation of compound 1 and 2,3-difluoro-1,4-dimethylnaphthalene with AcCl in the presence of AlCl3 dramatically depended on the order of mixing and addition of the reagents. Under the optimized conditions, the yields of 1-(6,7-difluoronaphthalen-1-yl) ethanones and 1-(6,7-difluoronaphthalen-2-yl)ethanones reached 68–93%.

Full text of DOI:10.1007/s11172-020-2756-0

Russian Chemical Bulletin, International Edition, Vol. 69, No. 2, pp. 270—279, February, 2020
270
Synthesis of functionalized difluoronaphthalenes by
regioselective C—H functionalization of 2,3-difluoronaphthalene
N. V. Volchkov, M. B. Lipkind, and O. M. Nefedov
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (495) 135 6390. E-mail: volchkov@ioc.ac.ru
2,3-Difluoronaphthalene (1) was selectively converted into 1-methyl-, 1,4-dimethyl-,
1-acetyl-, 1-acetyl-4-methyl-, 1-formyl-, and 1-carboxyl-substituted 2,3-difluoronaphthalenes
using lithiation with BuLi as a key step. Nitration and bromination of compound 1 predomi-
nantly gave 6,7-difluoro-1-nitronaphthalene and 1-bromo-6,7-difluoronaphthalene, respec-
tively. Regioselectivity of acylation of compound 1 and 2,3-difluoro-1,4-dimethylnaphthalene
with AcCl in the presence of AlCl3 dramatically depended on the order of mixing and addition
of the reagents. Under the optimized conditions, the yields of 1-(6,7-difluoronaphthalen-1-
yl)ethanones and 1-(6,7-difluoronaphthalen-2-yl)ethanones reached 68—93%.
Key words: difluoronaphthalenes, electrophilic substitution, metalation, regioselectivity,
difluoronitronaphthalenes, difluoronaphthoic acids, (difluoronaphthalenyl)ethanones.
difluoronaphthalene skeleton is so far limited to the brief
survey of our studies given in the review.33 In the present
work, we describe a general approach for the regioselective
synthesis of differently substituted 2,3-difluoronaphthal-
enes via a one-pot co-pyrolysis of CHClF2 and styrene to
give 2,3-difluoronaphthalene (1) and its subsequent C—H
functionalization using electrophilic substitution and
metalation reactions.
2,3-Difluoronaphthalene (1) was synthesized as earlier
described32,34 by gaseous co-pyrolysis of styrene (2) and
CHClF2 in a flow tube reactor at 640—645 °C (contact
time of 1—3 s). The obtained pyrolyzate contained
34—35% of difluoronaphthalene 1, which was isolated by
distillation and freezing in 15% yield (Scheme 1). Despite
the low yield of difluoronaphthalene 1, the suggested ap-
proach is the most attractive to date being advantageous
in terms of commercial availability and low price of the
starting materials and accessibility and simplicity of the
single-stage procedure.
In contrast to fluorinated benzenes widely used in the
synthesis of medications, agrochemicals, and advanced
materials,1—7 fluorinated naphthalenes are less accessible
and less studied class of organofluorine compounds.
However, in recent years rapidly growing attention has
been devoted to the development of synthetic procedures
towards functionalized mono- and difluoronaphthalenes
as promising building blocks to access new biologically
active substances and electronic materials.8—28
Unlike monofluoronaphthalenes, which can be rela-
tively easy synthesized by dediazofluorination of naph-
thylamines under the Balz—Schiemann conditions,29—31
difluoronaphthalenes are still hardly commercially avail-
able. It should be noted that 2,3-fluoronaphthalene de-
rivatives are less studied due to difficulties in their synthe-
sis by common procedures for introducing the fluorine
atom into the arene skeleton. For the synthesis of 2,3-di-
fluoronaphthalene (1), only three peculiar methods are
known, namely, the gaseous co-pyrolysis of CHClF2
and styrene,32—34 the pyrolysis of 2,2,3,3-tetrafluoro-1-
phenylcyclobutane,35 and the reaction of perchloryl fluor-
ide with lithium 2-fluoronaphthalenide.36 The yields of
the target difluoronaphthalene achieved by all these meth-
ods do not exceed 20%. Several examples of the synthesis
of functionalized and polysubstituted derivatives of 2,3-flu-
oronaphthalene by annulation of 1,2-disubstituted 4,5-di-
fluorobenzenes via cycloaddition or intramolecular cycli-
zation reactions have been described.8—22 At the same
time, information on the synthesis of functionalized
2,3-difluoronaphthalenes by methods common for the
arene chemistry using direct functionalization of the
Scheme 1
Conditions: 640—645 °C, a flow tube reactor, contact time 1—3 s.
It was found that lithiation of compound 1 with BuLi
at –70 °C in THF proceeds selectively at the α position
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 2, pp. 0270—0279, February, 2020.
1066-5285/20/6902-0270 © 2020 Springer Science+Business Media LLC

2,3-Difluoronaphthalene derivatives
Russ. Chem. Bull., Int. Ed., Vol. 69, No. 2, February, 2020
271
Scheme 2
Reagents and conditions: i. BuLi, THF, –70÷–78 °C, ii. 1) CO2, 2) NaOH, 3) HCl; iii. MeI; iv. 1) DMF, 2) AcOH; v. 1) CuCN, 2) AcCl.
Scheme 3
of the fluorinated ring to give the corresponding lithium
difluoronaphthalenide 3. Subsequent carboxylation of
derivative 3 with CO2 or its alkylation with iodomethane
lead to 2,3-difluoro-1-naphthoic acid (4) in 93% yield or
2,3-difluoro-1-methyl-naphthalene (5) in 86% yield,
respectively (Scheme 2).
Lithiated derivative 3 readily reacts with DMF to give
2,3-difluoro-1-naphthaldehyde (6). Treatment of deriva-
tive 3 with copper cyanide followed by acylation with AcCl
provides 1-(2,3-difluoronaphthalen-1-yl)ethanone (7) in
87% yield.
Similar functionalization reactions are typical of
2,3-difluoro-1-methylnaphthalene (5), lithiation of which
with BuLi followed by either carbonylation, methyl-
ation or acylation of the intermediate lithium di-
fluoromethylnaphthalenide give, respectively, 2,3-di-
fluoro-4-methyl-1-naphthoic acid (8), 2,3-difluoro-1,4-
dimethylnaphthalene (9) or 1-(2,3-difluoro-4-methyl-
naphthalen-1-yl)ethanone (10) in the yields of 82—91%
(Scheme 3).
In contrast to the above described reactions involving
intermediate metalation, the common electrophilic sub-
stitution reactions (bromination, nitration, and acylation)
of 2,3-difluoronaphthalene (1) occur exclusively on the
non-fluorinated ring.
Reagents: i. 1) BuLi, THF, 2) CO2, 3) NaOH, 4) HCl; ii. 1) BuLi,
THF, 2) MeI; iii. 1) BuLi, THF, 2) CuCN, 3) AcCl.
mixture provide 1-bromo-6,7-difluoronaphthalene (11)
in 52% yield.
Scheme 4
Thus, bromination of compound 1 proceeds selectively
at positions 5 and 8 and affords either monobromo de-
rivative 11 or dibromo derivative 12 depending on the
amount of bromine used (Scheme 4). Note that dibromo-
naphthalene 12 can be easily prepared in 88% yield by
bromination of compound 1 with three-fold excess of
bromine in CH2Cl2 at room temperature. When equi-
molar amounts of naphthalene 1 and bromine were used,
a mixture containing 71% of monobromide 11, 9% of
dibromide 12, and 19% of the starting difluoronaphthal-
ene 1 was obtained. Distillation and crystallization of this
Reagents: Br2, CH2Cl2.
Nitration of difluoronaphthalene 1 with a mixture of
HNO3 and H2SO4 gives a 91 : 9 mixture of isomeric

Volchkov et al.
272
Russ. Chem. Bull., Int. Ed., Vol. 69, No. 2, February, 2020
Scheme 6
difluoronitronaphthalenes 13a and 14a (Scheme 5). The
main isomer, 2,3-difluoro-5-nitronaphthalene (13a) was
isolated in 76% yield by crystallization form ethanol.
Scheme 5
R = H (1, 16a, 17a), Me (9, 16b, 17b)
Table 1. Regioselectivity of acylation of 2,3-difluoronaphthalene
(1) and the yields of (difluoronaphthalene)ethanones 16a and
17a depending of the reaction procedurea
Solvent
Composition of
Isolated
yields (%)
the reaction mixtureb (%)
1
16a
17a
16а
17а
Method A
CH2Cl2
11
54
32
89
14
28
8
30
37
84c (76)d
—
—
—
R = H (1, 13a, 14a, 15a), Me (9, 13b, 14b, 15b)
С6H5NO2e
—
—
С6H5NO2
Nearly the same regioselectivity was observed in the
nitration of difluorodimethylnaphthalene 9 providing an
11 : 1 mixture of α and β nitration products 13b and 14b
(see Scheme 5). The main product 13b was isolated in 81%
yield by crystallization from ethanol.
The synthesized difluoronitronaphthalenes 13a,b can
be converted into the corresponding difluoronaphthyl-
amines 15a,b under the catalytic hydrogenation conditions
in the presence of Pd/C in the yields of 77—81%.
Similarly to acylation of unsubstituted naphthal-
ene,37—39 the regioselectivity of acylation of difluoronaphth-
alenes 1 and 9 with AcCl in the presence of AlCl3 strongly
depends on the reaction conditions, the order of mixing
the reagents, and their current concentrations in the reac-
tion mixture (Scheme 6, Tables 1 and 2).
Method B
CH2Cl2
13
51
6
14
13
29
81
34
65
—
—
—
76c (56)d
С6H5NO2e
—
—
С6H5NO2
Method C
CH2Cl2
12
47
10
50
19
28
46
41
59
41c
—
—
36c
—
—
С6H5NO2e
С6H5NO2
Method D
CH2Cl2
12
43
10
86
17
27
10
37
58
82c (71)d
—
—
—
С6H5NO2e
—
—
С6H5NO2
Method E
65 29
CH2Cl2
3
57c
21c
Thus, addition of a solution of difluoronaphthalene 1
and AcCl in CH2Cl2 to a suspension of AlCl3 in CH2Cl2
(method A) gives predominantly 1-(6,7-difluoronaphth-
alen-1-yl)ethanone (16a) and small amounts of iso-
meric 1-(6,7-difluoronaphthalene-2-yl)ethanone (17a)
(16a : 17a = 88 : 9). Isomers 16a and 17a can be easily
separated by chromatography. The main isomer 16a can
a Conditions: molar ratio 1 : AcCl : AlCl3 = 1 : 1.1 : 1.1, 22—25 °C,
reaction time 4 h.
b
GC data on the composition of the reaction mixture after
workup without solvent.
c Isolated yield after chromatography.
d Isolated yield after recrystallization from n-hexane.
e Reaction time was 24 h.

2,3-Difluoronaphthalene derivatives
Russ. Chem. Bull., Int. Ed., Vol. 69, No. 2, February, 2020
273
Table 2. Regioselectivity of acylation of 2,3-difluoro-1,4-
dimethylnaphthalene (9) and the yields of products 16b and 17b
depending on the reaction procedurea
naphthalene (1) when nitrobenzene was used as a solvent
instead of CH2Cl2 (see Table 1). Note that the regioselec-
tivity of acylation of compound 1 in nitrobenzene, unlike
the acylation in CH2Cl2, almost independent on the pro-
cedure used. Also, acylation of compound 1 in nitro-
benzene proceeds much slower than in CH2Cl2.
Method
Composition of
Isolated
yield (%)
the reaction mixtureb (%)
9
16b
17b
16b
17b
The importance of the steric effects in acylation of
naphthalenes is supported by the results obtained upon
acylation of 2,3-difluoro-1,4-dimethylnaphthalene (9).
As compared with acylation of difluoronaphthalene 1,
the regioselectivity of acylation of difluoronaphthalene 9
is noticeably shifted towards the β acylation product
(see Table 2). Acylation of compound 9 using meth-
ods B, C, and E proceeds almost regioselectively to
give 1-(6,7-difluoro-5,8-dimethyl-2-yl)ethanone (17b).
Compound 17b can be easily isolated from the reac-
tion mixture in 88—93% yields by crystallization from
hexane. Acylation of compound 9 by methods A and D
gives mainly α acylation product 16b; however, in this
case the regioselectivity (69—73%) observed is significantly
lower than that of acylation of compound 1 under similar
conditions.
A
<1
1
<1
1
1
73
<1
2.5
69
23
97
95
26
95
68с
18c
93d
87d
15с
92d
B
C
D
E
58с
1.5
a Conditions: molar ratio 9 : AcCl : AlCl3 = 1 : 1.1 : 1.2, CH2Cl2,
22—25 °C, reaction time 4 h.
b
GC data on the composition of the reaction mixture without
solvent.
c Isolated yield after chromatography.
d Isolated yield after recrystallization from n-hexane.
also be separated in 76% yield by crystallization of the
isomeric mixture from hexane.
The change in the order of the reagent mixing, namely,
addition of a solution of a complex AcCl and AlCl3 in
CH2Cl2 to a solution of difluoronaphthalene 1 in CH2Cl2
(method B) leads to the reverse regioselectivity with
(difluoronaphthalene-2-yl)ethanone 17a being the main
product. In this case, compound 17a was isolated in 76%
yield by column chromatography and in 56% by crystal-
lization from hexane.
When compound 1 was added to a solution of a com-
plex of AcCl and AlCl3 in CH2Cl2 (method C), the ac-
ylation products at α and β positions were obtained in
almost equal amounts (16a : 17a = 50 : 46). In the case of
addition of AcCl to a solution of a complex of 1 and AlCl3
in CH2Cl2, the regioselectivity depends on the rate of
addition of acetyl chloride. Thus, slow addition of a solu-
tion of AcCl (over 2 h) (method D) that assumes the low
current concentration of free acetyl chloride in the reac-
tion mixture provides regioselectivity of acylation similar
to that in method A (16a : 17a = 84 : 9). Rapid addi-
tion (over 2 min) of the same amount of AcCl to a mixture
of difluoronaphthalene 1 and AlCl3 (method E) signifi-
cantly increases the yield of the β acylation product 17a
(16a : 17a = 62 : 28).
Found by us simple possibility of turning the regio-
selectivity of acylation of difluoronaphthalenes 1 and 9 by
changing the reaction conditions as well as the ability of
the acyl group to be easily transformed into other func-
tional groups open up the prospects to convenient regio-
selective synthesis of 5- and 6-functionalized 2,3-difluoro-
naphthalenes and complete the above discussed regioselec-
tive synthesis of 1- and 4-substituted 2,3-difluoronaph-
thalenes via metalation reactions. As an example, we
demonstrated the possibility to synthesize 6,7-difluoro-
naphthoic acids 18 and 19 from the corresponding (di-
fluoronaphthalenyl)ethanones 16a and 17a by the haloform
reaction (Scheme 7).
Scheme 7
It is known39 that acylation of unsubstituted naphth-
alene with AcCl—AlCl3 in CH2Cl2 and dichloroethane
occurs exclusively as α acylation; while, in nitrobenzene
the β acylation product is predominantly formed. This fact
is due to complexing ability of nitrobenzene and its parti-
cipation in the formation of active acylation complex, the
large size of which hampers the attack at the sterically
hindered α position of naphthalene. A similar albeit less
pronounced solvent-dependent shift in the regioselectiv-
ity toward β acylation was also observed for 2,3-difluoro-
Reagents: i. Br2, NaOH, 1,4-dioxane, water.
In summary, the obtained results allow us to draw the
conclusions that one-pot pyrolytic synthesis of 2,3-diflu-
oronaphthalene from readily available starting compounds

Volchkov et al.
274
Russ. Chem. Bull., Int. Ed., Vol. 69, No. 2, February, 2020
Synthesis of 2,3-difluoro-1-naphthoic acids 4 and 8. To
a stirred solution of difluoronaphthalene 1 (8.2 g, 50.0 mmol) in
anhydrous THF (100 mL) cooled to –75÷–70 °C (dry ice—
propan-2-ol), 1.6 M BuLi in n-hexane (32 mL, 51.2 mmol) was
added dropwise over 1 h under argon. The reaction mixture was
stirred at –75÷–65 °C for 1 h and poured into a suspension of
dry ice in diethyl ether. After warming up to room temperature,
the mixture was extracted with 1 M aqueous NaOH and the
obtained basic solution was acidified with 1 M HCl to pH < 2.
The precipitate formed was collected by filtration, washed with
water, and air dried to afford 9.67 g (93%) of 2,3-difluoro-1-
naphthoic acid (4) as white crystals, m.p. 185—186 °C.
2,3-Difluoro-4-methyl-1-naphthoic acid (8) was synthesized
similarly from 2,3-difluoro-1-methyl-naphthalene (5) (4.40 g,
24.7 mmol) by lithiation with BuLi (27.2 mmol) in THF (50 mL)
and subsequent carboxylation with CO2. Yield 5.02 g (91%),
white crystals, m.p. 207—210 °C.
2,3-Difluoro-1-naphthoic acid (4). M.p. 185—186 °C.
1H NMR (200.1 MHz, DMSO-d6), δ: 7.52—7.78 (m, 2 H, Ar);
7.91—8.22 (m, 3 H, Ar); 13.9 (br.s, 1 H, COOH). 13C NMR
(DMSO-d6), δ: 115.72 (d, C(4), J = 17.3 Hz); 119.77 (d, C(1),
J = 12.8 Hz); 124.71 (d, C(8), J = 5.3 Hz); 126.51 (br.s, C(8a));
126.97 (s, C(6)); 127.65 (br.s, C(7)); 128.02 (d, C(5), J = 4.4 Hz);
129.81 (d, C(4a), J = 7.9 Hz); 146.50 (dd, C(2), J = 250.0 Hz,
J = 14.3 Hz); 148.21 (dd, C(3), J = 247.4 Hz, J = 15.1 Hz);
164.92 (d, (HO)C=O, J = 2.1 Hz). 19F NMR (188.3 MHz,
DMSO-d6), δ: –136.4 (dd, 1 F, J = 22.2 Hz, J = 8.1 Hz); –136.9
(dd, 1 F, J = 22.2 Hz, J = 11.2 Hz). MS, m/z (Irel (%)): 208 [M]+
(100), 191 [M – OH]+ (51), 163 [M – CO2H]+ (35), 143 (10).
Found (%): C, 63.36; H, 2.96. C11H6F2O2. Calculated (%):
C, 63.47; H, 2.91.
2,3-Difluoro-4-methyl-1-naphthoic acid (8). M.p. 206—
210 °C (decomp.). 1H NMR (200.1 MHz, DMSO-d6), δ: 2.55
(s, 3 H, CH3); 7.40—7.80 (m, 2 H, Ar); 7.88—8.30 (m, 2 H, Ar);
14.0 (br.s, 1 H, COOH). 13C NMR (DMSO-d6), δ: 10.17 (br.s,
CH3); 117.10 (d, C(1), J = 12.4 Hz); 123.24 (d, C(4), J = 12.1 Hz);
124.55 (d, C(5), J = 5.6 Hz); 125.22 (d, C(8), J = 5.2 Hz);
126.19 (br.s, C(8a)); 126.74 (br.s, C(6)); 127.36 (br.s, C(7));
129.19 (d, C(4a), J = 4.4 Hz); 146.15 (dd, C(3), J = 244.2 Hz,
J = 15.8 Hz); 146.56 (dd, C(2), J = 252.5 Hz, J = 18.1 Hz);
165.08 (d, (HO)C=O, J = 3.2 Hz). 19F NMR (188.3 MHz,
DMSO-d6), δ: –136.2 (d, 1 F, J = 20.2 Hz); –139.4 (d, 1 F,
J = 20.2 Hz). MS, m/z (Irel (%)): 222 [M]+ (100), 205 [M – OH]+
(77), 177 [M – CO2H]+ (30), 157 (14), 151 (20). Found (%):
C, 64.60; H, 3.67. C12H8F2O2. Calculated (%): C, 64.87;
H, 3.63.aaaaaaa
Synthesis of methyldifluoronaphthalenes 5 and 9. To a stirred
solution of difluoronaphthalene 1 (16.4 g, 0.10 mol) in anhydrous
THF (200 mL) cooled to –75÷–70 °C (dry ice—propane-2-ol),
1.6 M BuLi in n-hexane (65 mL, 0.108 mol) was added dropwise
over 1 h under argon. The mixture was stirred at –75÷–65 °C
for 1 h and then the obtained solution of lithium difluoronaph-
thalenide was treated dropwise with a solution of MeI (21.3 g,
0.15 mol) in anhydrous THF (40 mL) over 2 h. After 1 h stirring
at –75÷–65 °C, the cooling bath was removed and stirring was
continued until room temperature was reached. The obtained
mixture was concentrated in vacuo to remove excess of THF and
hexane, the residue was diluted with dichloromethane (150 mL),
washed with water, and dried with CaCl2. Vacuum distillation
of this solution afforded 15.3 g (86%) of 2,3-difluoro-1-methyl-
naphthalene (5), b.p. 76—78 °C (4 Torr).
in the combination with developed regioselective ap-
proaches to its C—H functionalization via metalation and
electrophilic substitution reactions enables the rational
synthesis of different difluoronaphthalenes bearing various
functional groups in almost any desired position of
2,3-difluoronaphthalene skeleton.
Experimental
Commercially available chlorodifluoromethane (99.9%)
(Poly-Trade LTd., Russia), styrene (98.5%), acetyl chloride
(98.5%), AlCl3 (99%), CH2Cl2 (99.9%), bromine (99%), nitric
acid (70%), sulfuric acid (95—98%), 1.6 M BuLi in hexane, THF
(99.9%, water content <0.002%), DMF (99.8%, water content
<0.005%), MeI (99%), and CuCN (99%) (all Merck or Acros)
were used as purchased.
The GC analysis was performed using Kristall 2000M chrom-
atograph (capillary column Macherey-Nagel OPTIMA-1,
30 m×0.25 mm, carrier gas was helium, flame ionization detector).
1H NMR spectra were run on Bruker AC-200, Bruker WM 250,
and Bruker AM 300 spectrometers (working frequencies of 200.1,
250.1, and 300.1 MHz, respectively) in CDCl3 and DMSO-d6.
13C NMR spectra were recorded with a Bruker AVANCE III-600
spectrometer (working frequency of 150.9 MHz) in CDCl3 and
DMSO-d6. 19F NMR spectra were obtained on Bruker AC-200
(working frequency of 188.3 MHz) and Bruker AM 300 (working
frequency of 282.4 MHz) spectrometers in CDCl3 and DMSO-d6.
The 1H and 13C NMR chemical shifts are given relative to Me4Si
(an internal standard, 0.05%), the 19F NMR chemical shifts,
relative to CFCl3 (an external standard). Electron impact (EI,
70 eV) mass spectrometry was performed with a Finnigan MAT
INCOS-50 instrument using a direct inlet. Elemental analysis
was performed with a Perkin—Elmer Series II 2400 CHN
Analyzer. Melting points were measured with a Stuart SMP10
apparatus.
Pyrolytic synthesis of 2,3-difluoronaphthalene (1)34. A steady
stream of CHClF2 (flow rate of 300 mL min–1) was passes for
14 h through a flow tube reactor (length 350 mm, outside dia-
meter 24 mm) heated to 640—645 °C together with a stream of
styrene (2) at a flow rate of 0.50 g min–1 controlled by a micro-
dosing pump. The pyrolysis products leaving the reactor were
condensed in a water condenser and in two series-connected
traps cooled with an ice—water mixture. The obtained pyrolyzate
was neutralized with aqueous NH4OH and steam distilled to
remove resinous products, gaseous components, and inorganic
products. The resulting distillate was washed with water and
dried with CaCl2 to give 465.14 g of a product mixture con-
taining 25% of styrene (2) and 34% of difluoronaphthalene 1
(GC data). Freezing and crystallization of this mixture from
ethanol afforded 101.51 g (15%) of difluoronaphthalene (1) with
a purity of 98%.
2,3-Difluoronaphthalene (1)34. M.p. 61—63 °C (from ethan-
ol). 1H NMR (200.1 MHz, CDCl3), δ: 7.48—7.63 (m, 4 H, Ar);
7.71—7.83 (m, 2 H, Ar). 13C NMR (CDCl3), δ: 114.23 (dd, C(1)
and C(4), J = 13.1 Hz, J = 4.7 Hz); 126.85 (s, C(6) and C(7));
127.90 (s, C(5) and C(8)); 130.91 (t, C(4a) and C(8a), J = 4.7 Hz);
150.71 (dd, C(2) and C(3), J = 251.7 Hz, J = 17.4 Hz). 19F NMR
(188.3 MHz, CDCl3), δ: –137.2 (m, 2 F). MS, m/z (Irel (%)):
164 [M]+ (100), 40(15). Found (%): C, 72.78; H, 3.41. C10H6F2.
Calculated (%): C, 73.17; H, 3.68.

2,3-Difluoronaphthalene derivatives
Russ. Chem. Bull., Int. Ed., Vol. 69, No. 2, February, 2020
275
2,3-Difluoro-1,4-dimethylnaphthalene (9) was synthesized
similarly from lithium difluoromethylnaphthalene 5 (8.80 g,
49.4 mmol) by lithiation with BuLi (54.5 mmol) in THF (100 mL)
and subsequent alkylation of the resulting lithium difluoromethyl-
naphthalenide with MeI. Yield 7.96 g (83%), yellow crystals,
m.p. 60—63 °C.
2,3-Difluoro-1-methylnaphthalene (5). B.p. 76—78 °C (4 Torr).
1H NMR (200.1 MHz, CDCl3), δ: 2.60 (d, 3 H, CH3, J = 2.5 Hz);
7.41 (dd, 1 H, Ar, J = 10.6 Hz, J = 8.0 Hz); 7.47—7.58 (m, 2 H,
Ar); 7.75 (dd, 1 H, Ar, J = 8.0 Hz, J = 2.2 Hz); 7.92 (dd, 1 H,
Ar, J = 7.6, Hz J = 1.8 Hz). 13C NMR (CDCl3), δ: 10.03 (dd,
CH3, J = 5.0 Hz, J = 2.7 Hz); 110.86 (d, C(4), J = 16.3 Hz);
120.78 (d, C(1), J = 12.3 Hz); 123.73 (d, C(8), J = 6.2 Hz);
125.74 (d, C(7), J = 2.4 Hz); 125.79 (d, C(6), J = 2.1 Hz); 127.81
(dd, C(5), J = 5.1 Hz, J = 1.8 Hz); 129.81 (br.s, C(4a)); 129.86
(d, C(8a), J = 4.2 Hz); 147.78 (dd, C(2), J = 245.5 Hz, J = 15.8 Hz);
149.91 (dd, C(3), J = 249.3 Hz, J = 17.2 Hz). 19F NMR
(188.3 MHz, CDCl3), δ: –137.1 (dd, 1 F, J = 20.1 Hz, J = 10.6 Hz);
–139.6 (d, 1 F, J = 20.1 Hz). MS, m/z (Irel (%)): 178 [M]+ (98),
177 [M – H]+ (100), 151 (30). Found (%): C, 74.07; H, 4.57.
C11H8F2. Calculated (%): C, 74.15; H, 4.53.
2,3-Difluoro-1,4-dimethylnaphthalene (9). M.p. 60—63 °C.
1H NMR (200.1 MHz, CDCl3), δ: 2.60 (br.s, 6 H, 2 CH3); 7.53
(dd, 2 H, Ar, J = 6.4 Hz, J = 3.3 Hz); 7.92 (dd, 2 H, Ar,
J = 6.4 Hz, J = 3.3 Hz). 13C NMR (CDCl3), δ: 10.63 (t, 2 Me,
J = 3.6 Hz); 118.44 (dd, C(1) and C(4), J = 9.1 Hz, J = 4.1 Hz);
124.93 (s, C(5) and C(8)); 127.90 (s, C(6) and C(7)); 130.39
(t, C(4a) and C(8a), J = 3.4 Hz); 148.57 (dd, C(2) and C(3),
J = 246.8 Hz, J = 18.6 Hz). 19F NMR (188.3 MHz, CDCl3), δ:
–139.8 (br.s, 2 F). MS, m/z (Irel (%)): 192 [M]+ (100), 177 (93),
170 (37), 151 (30), 113 (20). Found (%): C, 74.96; H, 5.29.
C12H10F2. Calculated (%): C, 75.00; H, 5.21.
Synthesis of 2,3-difluoro-1-naphthalenecarbaldehyde (6). To
a stirred solution of difluoronaphthalene 1 (0.501 g, 3.1 mmol)
in anhydrous THF (10 mL) cooled to –78 °C, 1.6 M BuLi in
n-hexane (1.9 mL, 3.1 mmol) was added dropwise over 5 min
and stirring was continued for 1 h. Then anhydrous DMF
(0.28 mL, 3.7 mmol) was added, the mixture was stirred at –78 °C
for 3 h, and a solution of glacial AcOH (0.5 mL, 9 mmol) in
anhydrous THF (2 mL) was added. Cooling was removed and
stirring was continued until room temperature was reached. The
mixture was diluted with water (100 mL) and extracted with
EtOAc (3×10 mL). The combined organic layers were dried with
Na2SO4, the drying agent was filtered off, and the filtrate was
concentrated in vacuo to dryness. Crystallization of the residue
from n-hexane afforded 0.435 g (74%) of product 6, colorless
needles, m.p. 44—45 °C. 1H NMR (300.1 MHz, CDCl3), δ:
7.50—7.70 (m, 2 H, Ar); 7.75—7.90 (m, 2 H, Ar); 9.17 (d, 1 H,
Ar, J = 8.5 Hz); 10.8 (s, 1 H, CHO). 13C NMR (CDCl3), δ:
118.71 (br.s, C(1)); 120.79 (dd, C(4), J = 16.0 Hz, J = 2.2 Hz);
125.51 (dd, C(8), J = 5.5 Hz, J = 2.2 Hz); 127.29 (d, C(8a),
J = 5.0 Hz); 127.40 (s, C(6)); 127.80 (dd, C(5), J = 5.5 Hz,
J = 2.2 Hz); 129.40 (d, C(7), J = 2.8 Hz); 130.01 (dd, C(4a),
J = 6.6 Hz, J = 2.2 Hz); 148.70 (dd, C(3), J = 252.0 Hz,
J = 15.9 Hz); 156.5 (dd, C(2), J = 265.9 Hz, J = 16.6 Hz); 187.92
(dd, CHO), J = 13.3 Hz, J = 3.9 Hz). 19F NMR (282.4 MHz,
CDCl3), δ: –138.6 (dd, 1 F, J = 19.1 Hz, J = 8.5 Hz); –143.0
(dd, 1 F, J = 19.1 Hz, J = 8.5 Hz). Found (%): C, 68.65; H, 3.27.
C11H6F2O. Calculated (%): C, 68.75; H, 3.15.
anhydrous THF (20 mL) cooled to –75÷–70 °C (dry ice—
propan-2-ol), 1.6 M BuLi in n-hexane (6.5 mL, 10.8mol) was
added dropwise over 15 min under argon and the mixture was
stirred at –75÷–65 °C for 1 h. The obtained solution of lithium
difluoronaphthalenide 9 was transferred via a Teflon cannula to
a suspension of CuCN (0.99 g, 11.0 mmol) in THF (10 mL)
cooled to –75 °C. The mixture was stirred at –75÷–65 °C for
1 h, then the cooling bath temperature was gradually raised from
–75 to –10 °C during 1 h. The reaction mixture was again cooled
to –50÷–60 °C and acetyl chloride (0.98 g, 12.5 mmol) was
added via syringe. The mixture was stirred at –50÷–60 °C for
30 min, then the reaction temperature was gradually raised to
room temperature during 30 min. The mixture was poured into
a mixture of CH2Cl2 (80 mL) and water (100 mL) and stirred for
2 h. The precipitate formed was filtered off. The organic filtrate
was washed with water (3×20 mL) and dried with Na2SO4.
Removal of the solvent in vacuo afforded 1.98 g of yellowish
liquid containing 95% of 1-(2,3-difluoronaphthalen-1-yl)ethan-
one (7) and 4% of difluoronaphthalene 1 (GC and NMR spec-
troscopy data). Vacuum distillation of this mixture gave 1.79 g
(87%) of 1-acetyl-2,3-difluoronaphthalene 7, b.p. 123—124 °C
(2 Torr).
1-(2,3-Difluoro-4-methylnaphthalen-1-yl)ethanone (10)
was synthesized similarly from difluoromethylnaphthalene 5
(1.78 g). Yield 1.83 g (83%), yellowish liquid, b.p. 144—145 °C
(2 Torr).
1-(2,3-Difluoronaphthalen-1-yl)ethanone (7). B.p. 123—124 °C
(2 Torr). 1H NMR (300.1 MHz, CDCl3), δ: 2.75 (d, 3 H, CH3,
J = 2.9 Hz); 7.50—7.57 (m, 2 H, Ar); 7.66 (dd, 1 H, Ar,
J = 10.2 Hz, J = 8.3 Hz); 7.78 (dd, 1 H, Ar, J = 7.8 Hz,
J = 2.8 Hz); 7.98 (dd, 1 H, Ar, J = 8.1 Hz, J = 2.5 Hz). 13C NMR
(CDCl3), δ: 32.91 (d, CH3, J = 4.1 Hz); 115.83 (d, C(4),
J = 16.2 Hz); 124.74 (d, C(8), J = 5.4 Hz); 125.39 (d, C(1),
J = 12.7 Hz); 126.67 (br.s, C(4a)); 126.73 (br.s, C(7)); 127.47
(br.s, C(6)); 127.64 (d, C(5), J = 4.8 Hz); 130.33 (d, C(8a),
J = 6.9 Hz); 147.90 (dd, C(3), J = 252.8 Hz, J = 16.5 Hz); 148.83
(dd, C(2), J = 251.9 Hz, J = 16.7 Hz); 199.26 (s, MeC=O).
19F NMR (282.4 MHz, CDCl3), δ: –137.1 (d, 1 F, J = 21.0 Hz);
–138.1 (dd, 1 F, J = 21.0 Hz, J = 10.2 Hz). Found (%): C, 69.78;
H, 4.07. C12H8F2O. Calculated (%): C, 69.90; H, 3.91.
1-(2,3-Difluoro-4-methylnaphthalen-1-yl)ethanone (10). B.p.
144—145 °C (2 Torr). 1H NMR (300.1 MHz, CDCl3), δ: 2.64
(d, 3 H, CH3, J = 2.5 Hz); 2.74 (d, 3 H, CH3, J = 3.2 Hz);
7.52—7.59 (m, 2 H, Ar); 7.92—7.98 (m, 1 H, Ar); 8.02—8.08
(m, 1 H, Ar). 13C NMR (CDCl3), δ: 10.42 (dd, CH3, J = 4.7 Hz,
J = 2.3 Hz); 33.03 (d, CH3, J = 4.3 Hz); 122.70 (d, C(1),
J = 12.1 Hz); 123.81 (d, C(4), J = 12.3 Hz); 123.95 (d, C(5),
J = 6.6 Hz); 125.30 (d, C(8), J = 5.9 Hz); 126.35 (br.s, C(4a));
126.40 (br.s, C(6)); 127.17 (d, C(7), J = 2.4 Hz); 129.98
(d, C(8a), J = 4.0 Hz); 146.75 (dd, C(3), J = 246.9 Hz,
J = 16.3 Hz); 148.15 (dd, C(2), J = 252.6 Hz, J = 18.1 Hz);
199.35 (s, MeC=O). 19F NMR (282.4 MHz, CDCl3), δ: –136.4
(d, 1 F, J = 21.1); –140.6 (d, 1 F, J = 21.1 Hz). Found (%):
C, 70.80; H, 4.84. C13H10F2O. Calculated (%): C, 70.90; H, 4.58.
Bromination of 2,3-difluoronaphthalene (1). To a solution of
difluoronaphthalene 1 (8.20 g, 50 mmol) in chloroform (30 mL),
the iron turnings (0.2 g) were added followed by dropwise addi-
tion of a solution of bromine (8.0 g, 50 mmol) in chloroform
(30 mL) over 1 h at 3—0 °C. The mixture was stirred at room
temperature for 36 h, washed with water, and dried with CaCl2.
Removal of the excess chloroform in vacuo afforded 10.66 g of
Synthesis of 1-(difluoronaphthalenyl)ethanones 7 and 10. To
a stirred solution of difluoronaphthalene 1 (1.64 g, 10 mmol) in

Volchkov et al.
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Russ. Chem. Bull., Int. Ed., Vol. 69, No. 2, February, 2020
a mixture containing 15% of difluoronaphthalene 1, 71% of
1-bromo-6,7-difluoronaphthalene (11), and 9% of 1,4-dibromo-
6,7-difluoronaphthalene (12). Distillation of this mixture gave
1.80 g of difluoronaphthalene 1. Crystallization of the bottom
product from ethanol afforded 6.26 g (56%) of 1-bromo-6,7-
difluoronaphthalene (11).
Bromination of difluoronaphthalene 1 (8.20 g, 50 mmol)
with bromine (23.9 g, 0.150 mol) at room temperature within
24 h gave 14.34 g of a mixture containing 96% of dibromo-
difluoronaphthalene 12. Crystallization of this mixture from
ethanol afforded 13.53 g (90%) of 1,4-dibromo-6,7-difluoro-
naphthalene (12).
J = 9.1 Hz, J = 8.1 Hz); 7.69 (dd, 1 H, Ar, J = 10.2 Hz, J = 8.1 Hz);
8.08 (d, 1 H, Ar, J = 9.1 Hz); 8.31 (d, 1 H, Ar, J = 8.1 Hz); 8.49
(dd, 1 H, Ar, J = 11.2 Hz, J = 7.8 Hz). 13C NMR (CDCl3), δ:
111.66 (d, C(4), J = 21.4 Hz); 115.34 (d, C(1), J = 16.9 Hz);
123.16 (d, C(4a), J = 8.8 Hz); 125.61 (br.s, C(6) and C(7));
132.35 (d, C(8a), J = 7.5 Hz); 134.88 (br.s, C(8)); 146.28 (br.s,
C(5)); 151.21 (dd, C(2), J = 255.2 Hz, J = 16.2 Hz); 152.87 (dd,
C(3), J = 253.9 Hz, J = 15.3 Hz). 19F NMR (188.3 MHz, CDCl3),
δ: –129.9 (m, 1 F); –133.7 (m, 1 F). MS, m/z (Irel (%)): 209
[M]+ (43), 163 [M – NO2]+ (95), 151 (100), 143 (78), 123 (25),
46 (22). Found (%): C, 57.48; H, 2.33; N, 6.72. C10H5F2NO2.
Calculated (%): C, 57.42; H, 2.39; N, 6.70.
1-Bromo-6,7-difluoronaphthalene (11)14. M.p. 57—58 °C
(from ethanol). 1H NMR (250.1 MHz, CDCl3), δ: 7.31 (t, 1 H,
Ar, J = 8.3 Hz); 7.65 (dd, 1 H, Ar, J =10.9 Hz, J = 8.1 Hz); 7.71
(d, 1 H, Ar, J = 8.3 Hz); 7.76 (d, 1 H, Ar, J =8.3 Hz); 8.02 (dd,
1 H, Ar, J =11.8 Hz, J = 8.1 Hz). 13C NMR (CDCl3), δ: 114.60
(d, C(8), J = 19.5 Hz); 114.83 (d, C(5), J = 16.8 Hz); 122.35
(d, C(1), J = 5.0 Hz); 127.41 (br.s, C(3)); 127.85 (d, C(4),
J = 4.7 Hz); 129.95 (d, C(8a), J = 7.8 Hz); 130.87 (d, C(2),
J = 2.5 Hz); 131.89 (d, C(4a), J = 7.7 Hz); 151.10 (dd, C(7),
J = 252.3 Hz, J = 16.0 Hz); 151.50 (dd, C(6), J = 251.4 Hz,
J = 15.9 Hz). 19F NMR (188.3 MHz, CDCl3), δ: –134.1 (m, 1 F);
–135.9 (m, 1 F). Found (%): C, 49.88; H, 2.22. C10H5BrF2.
Calculated (%): C, 49.42; H, 2.07.
1,4-Dibromo-6,7-difluoronaphthalene (12). M.p. 131—132 °C.
1H NMR (200.1 MHz, CDCl3), δ: 7.63 (s, 2 H, Ar); 8.05 (dd, 2 H,
Ar, J = 9.7 Hz, J = 9.3 Hz). 13C NMR (CDCl3), δ: 115.39 (dd,
C(5) and C(8), J = 15.3 Hz, J = 6.0 Hz); 121.93 (s, C(1) and
C(4)); 130.73 (t, C(4a) and C(8a), J = 4.6 Hz); 131.12 (br.s,
C(2) and C(3)); 151.92 (dd, C(6) and C(7), J = 255.7 Hz,
J = 17.6 Hz). 19F NMR (188.3 MHz, CDCl3), δ: –132.9 (m, 2 F).
MS, m/z (Irel (%)): 324, 322, 320 [M]+ (32, 64, 32), 243, 241
[M – Br]+ (12, 12), 162 [M – 2 Br]+ (81), 106 (100), 81 (44).
Found (%): C, 37.98; H, 1.32. C10H4Br2F2. Calculated (%):
C, 37.31; H, 1.25.
2,3-Difluoro-6-nitronaphthalene (14a). 1H NMR (250.1 MHz,
CDCl3), δ: 7.69 (dd, 1 H, Ar, J = 10.3 Hz, J = 7.6 Hz); 7.77 (dd,
1 H, Ar, J = 10.3 Hz, J = 7.7 Hz); 7.91 (d, 1 H, Ar, J = 9.2 Hz);
8.23 (dd, 1 H, Ar, J = 9.2 Hz, J = 1.9 Hz); 8.71 (d, 1 H, Ar,
J = 1.9 Hz). 19F NMR (188.3 MHz, CDCl3), δ: –129.7 (m, 1 F);
–132.8 (m, 1 F).
2,3-Difluoro-1,4-dimethyl-5-nitronaphthalene (13b). M.p.
90—91 °C (from ethanol). 1H NMR (300.1 MHz, CDCl3), δ:
2.40 (d, 3 H, CH3, J = 2.8 Hz); 2.63 (d, 3 H, CH3, J = 2.0 Hz);
7.55 (dd, 1 H, Ar, J = 8.4 Hz, J = 7.4 Hz); 7.70 (d, 1 H, Ar,
J = 7.4 Hz); 8.15 (d, 1 H, Ar, J = 8.4 Hz). 13C NMR (CDCl3),
δ: 11.10 (d, CH3, J = 7.3 Hz); 11.25 (br.s, CH3); 117.46 (d, C(4),
J = 14.8 Hz); 119.89 (d, C(1), J = 12.6 Hz); 121.66 (d, C(4a),
J = 4.7 Hz); 122.94 (br.s, C(6)); 124.85 (br.s, C(7)); 128.91
(d, C(8), J = 6.1 Hz); 132.05 (d, C(8a), J = 4.7 Hz); 149.19 (dd,
C(2), J = 249.3 Hz, J = 17.4 Hz); 149.71 (br.s, C(5)); 150.47
(dd, C(3), J = 248.6 Hz, J = 16.6 Hz). 19F NMR (282.4 MHz,
CDCl3), δ: –133.2 (d, 1 F, J = 20.9 Hz); –136.3 (d, 1 F,
J = 20.9 Hz). MS, m/z (Irel (%)): 237 [M]+ (53), 220 (100),
191 [M – NO2]+ (37), 189 (38), 170 (51), 164 (55), 151 (37).
Found (%): C, 60.74; H, 3.31; N, 5.88. C12H9F2NO2. Calculat-
ed (%): C, 60.76; H, 3.82; N, 5.91.
2,3-Difluoro-1,4-dimethyl-6-nitronaphthalene (14b). 1H NMR
(300.1 MHz, CDCl3), δ: 2.57 (d, 3 H, CH3, J = 2.2 Hz); 2.68
(d, 3 H, CH3, J = 2.6 Hz); 8.07 (d, 1 H, Ar, J = 9.3 Hz); 8.28
(dd, 1 H, Ar, J = 8.9 Hz, J = 2.2 Hz); 8.90 (d, 1 H, Ar, J = 2.2 Hz).
19F NMR (282.4 MHz, CDCl3), δ: –133.1 (d, 1 F, J = 19.4 Hz);
–136.1 (d, 1 F, J = 19.4 Hz).
Synthesis of difluoronaphthalenes 15a,b. A mixture of 2,3-di-
fluoro-5-nitronaphthalene (13a) (2.01 g, 9.6 mmol), MeOH
(25 mL), and 10% Pd/C (0.12 g) was vigorously stirred at
20—30 °C for 10 h under a hydrogen atmosphere. Filtration of
the reaction mixture and removal of the volatiles in vacuo af-
forded 1.69 g of light-brown powder, which was recrystallized
from petroleum ether to give 1.39 g (81%) of 6,7-difluoro-1-
naphthylamine (15a), m.p. 59—60 °C.
Nitration of difluoronaphthalenes 1 and 9. A stirred mixture
of difluoronaphthalene 1 (5.10 g, 0.031 mol), water (1.5 g), and
concentrated H2SO4 (6.0 g, d = 1.84 g mL–1) was treated por-
tionwise with a nitrating mixture containing HNO3 (4.0 g,
d = 1.41 g mL–1) and H2SO4 (5.0 g, d = 1.84 g mL–1) over 30 min
maintaining the reaction temperature at 3—0 °C. The mixture
was stirred at room temperature for 24 h and poured into cold
water (200 mL). The obtained organic products were extracted
with diethyl ether, the combined organic layers were washed with
water and dried with Na2SO4. Removal of the solvent in vacuo
afforded 6.35 g of light-yellow powder. The crude product con-
tained 6% of difluoronaphthalene 1, 83% of 2,3-difluoro-5-nitro-
naphthalene (13a), and 7% of 2,3-difluoro-6-nitronaphthalene
(14a) (GC and NMR spectroscopy data). Recrystallization of
this mixture from ethanol afforded 4.91 g (76%) of difluoro-
nitronaphthalene 13a, greyish powder, m.p. 94—96 °C.
Nitration of compound 9 (5.94 g, 0.031 mol) under similar
conditions gave 7.28 g of a mixture containing 86% of 2,3-di-
fluoro-1,4-dimethyl-5-nitronaphthalene (13b) and 7% of 2,3-di-
fluoro-1,4-dimethyl-6-nitronaphthalene (14b) (GC and NMR
spectroscopy data). Recrystallization of this mixture from ethanol
afforded 5.81 g (79%) of difluoronitronaphthalene 13b, greyish
powder, m.p. 90—91 °C.
Similar reaction of 2,3-difluoro-1,4-dimethyl-5-nitronaphth-
alene (13b) (2.28 g, 9.6 mmol) followed by crystallization of the
crude product from petroleum ether gave 1.53 g (77%) of
6,7-difluoro-5,8-dimethyl-1-naphthylamine (15b), light orange
powder, m.p. 64—65 °C.
6,7-Difluoro-1-naphthylamine (15a). M.p. 59—60 °C. 1H NMR
(250.1 MHz, CDCl3), δ: 4.05 (br.s, 2 H, NH2); 6.74—6.82
(m, 1 H, Ar); 7.20—7.34 (m, 2 H, Ar); 7.47—7.60 (m, 2 H, Ar).
13C NMR (CDCl3), δ: 107.62 (d, C(8), J = 17.4 Hz); 110.15
(br.s, C(2)); 114.09 (d, C(5), J = 16.1 Hz); 118.30 (dd, C(4),
J = 4.7 Hz, J = 1.5 Hz); 120.31 (d, C(8a), J = 6.1 Hz); 126.84
(br.s, C(3)); 131.39 (d, C(4a), J = 4.7 Hz); 141.69 (d, C(1),
J = 4.7 Hz); 149.23 (dd, C(6), J = 251.1 Hz, J = 18.2 Hz); 149.86
2,3-Difluoro-5-nitronaphthalene (13a). M.p. 94—96 °C (from
1
ethanol). H NMR (250.1 MHz, CDCl3), δ: 7.57 (dd, 1 H, Ar,

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Russ. Chem. Bull., Int. Ed., Vol. 69, No. 2, February, 2020
277
(dd, C(7), J = 265.8 Hz, J = 20.9 Hz). 19F NMR (188.3 MHz,
CDCl3), δ: –137.1÷–138.2 (m, 2 F). MS, m/z (Irel (%)): 179
[M]+ (100), 151 (52), 90 (14). Found (%): C, 67.09; H, 4.00;
N, 7.85. C10H7F2N. Calculated (%): C, 67.04; H, 3.94; N, 7.82.
6,7-Difluoro-5,8-dimethyl-1-naphthylamine (15b). M.p.
64—65 °C. 1H NMR (200.1 MHz, CDCl3), δ: 2.48 (d, 3 H, CH3,
J = 2.1 Hz); 2.83 (d, 3 H, CH3, J = 2.7 Hz); 4.20 (br.s, 2 H,
NH2); 6.67—6.72 (m, 1 H, Ar); 7.22—7.34 (m, 2 H, Ar).
19F NMR (CDCl3), δ: –139.4 (d, 1 F, J = 21.0 Hz); –140.3
(d, 1 F, J = 21.0 Hz). MS, m/z (Irel (%)): 207 [M]+ (100), 192
[M – CH3]+ (45), 191 [M – NH2]+ (17), 177 [M – 2 CH3]+
(12), 164 (13), 103 (11). Found (%): C, 69.62; H, 5.39; N, 6.78.
C12H11F2N. Calculated (%): C, 69.55; H, 5.35; N, 6.76.
Acylation of difluoronaphthalenes 1 and 9. Method A. To
a stirred mixture of AlCl3 (2.85 g, 21.34 mmol) and CH2Cl2 (15 mL),
a solution of 2,3-difluoronaphthalene 1 (3.15 g, 19.20 mmol)
and acetyl chloride (1.67 g, 21.27 mmol) in CH2Cl2 (15 mL) was
slowly added dropwise over 2 h at room temperature and stirring
was continued for 2 h. The mixture was poured into ice-water
and vigorously stirred until complete decomposition of the com-
plex. The organic products were extracted with CH2Cl2 (50 mL),
the organic layer was washed with water and dried with Na2SO4.
Removal of the solvent in vacuo afforded 3.81 g of a product
mixture containing 0.6% g of compound 1, 89.2% of 1-(6,7-di-
fluoronaphthalen-1-yl)ethanone (16a), and 7.8% of 1-(6,7-di-
fluoronaphthalen-2-yl)ethanone (17a) (GC and NMR spectro-
scopy data). A part of the crude product (0.51 g) was subjected
to silica gel (40—63 μm, 50/1) column chromatography (elution
with n-hexane—EtOAc (10 : 1)) to afford 0.44 g (84%) of
1-(6,7-difluoronaphthalen-1-yl)ethanone (16a). Crystallization
of the remaining part of the crude product (3.30 g) from n-hex-
ane gave 2.64 g (76%) of (difluoronaphthalenyl)ethanone 16a,
yellowish powder, m.p. 78—79 °C.
Similar reaction of dimethylnaphthalene 9 (3.69 g, 19.20 mmol)
gave 4.37 g of a mixture containing 0.8% of naphthalene 9, 73.3%
of (naphthalenyl)ethanone 16b, and 23.1% (naphthalenyl)ethan-
one 17b. Purification by silica gel column chromatography (elu-
tion with n-hexane—EtOAc (10 : 1)) afforded 3.05 g (68%) of
1-(6,7-difluoro-5,8-dimethylnaphthalen-1-yl)ethanone (16b)
and 0.81 g (18%) of 1-(6,7-difluoro-5,8-dimethylnaphthalen-2-
yl)ethanone (17b).
Method B. To a stirred solution of difluoronaphthalene 1
(4.20 g, 25.60 mmol) in CH2Cl2 (20 mL), a solution of a complex
prepared from AcCl (2.22 g, 28.28 mmol), AlCl3 (3.80 g,
28.46 mmol), and CH2Cl2 (20 mL) was slowly added dropwise
over 2 h at room temperature and then stirring was continued
for 2 h. The reaction mixture was poured into ice-water and
worked up as described in method A. Removal of the volatiles
in vacuo afforded 5.08 g of the product mixture containing 2.1%
of compound 1, 14.1% of (difluoronaphthalenyl)ethanone 16a,
and 81.4% of (difluoronaphthalenyl)ethanone 17a (GC and NMR
spectroscopy data). A part of the crude product (0.60 g) was
subjected to silica gel (40—63 μm, 50/1) column chromatography
(elution with n-haxane—EtOAc (10 : 1)) to give 0.38 g (76%) of
ketone 17a. Crystallization of the remaining part of the crude
product (4.48 g) from n-hexane afforded 2.64 g (56%) of (di-
fluoronaphthalenyl)ethanone 17a.
(93%) of 1-(6,7-difluoro-5,8-dimethylnaphthalen-2-yl)ethanone
(17b), light orange powder, m.p. 112—113 °C.
Method C. To a stirred solution of AcCl (0.73 g, 9.25 mmol)
and AlCl3 (1.24 g, 9.29 mmol) in CH2Cl2 (6 mL), a solution of
difluoronaphthalene 1 (1.38 g, 8.41 mmol) in CH2Cl2 (6 mL)
was slowly added over 2 h at room temperature and then stirring
was continued for 2 h. The mixture was poured into ice-water
and worked up as described above to give 1.59 g of a product
mixture containing 0.9% of compound 1, 49.8% of ketone 16a,
and 46.2% of ketone 17a. Purification of this mixture by silica
gel column chromatography (elution with n-hexane—EtOAc
(10 : 1)) afforded 0.71 g (41%) of ketone 16a and 0.33 g (36%)
of ketone 17a.
Similar reaction of naphthalene 9 (1.63 g, 8.49 mmol) gave
1.92 g of a product mixture containing 2.5% of naphthalene 9,
94.9% of ketone 17b, and 0.7% of ketone 16b. Crystallization of
this mixture from n-hexane afforded 1.72 g (87%) of ketone 17b.
Method D. To a stirred mixture of AlCl3 (3.80 g, 28.46 mmol)
and difluoronaphthalene 1 (4.20 g, 25.60 mmol) in CH2Cl2
(20 mL), a solution of AcCl (2.20 g, 28.02 mmol) in CH2Cl2
(20 mL) was slowly added over 2 h at room temperature and then
stirring was continued for 2 h. The mixture was poured into ice-
water and worked up as described above. Removal of the volatiles
in vacuo afforded 5.06 g of a product mixture containing 1.6% of
compound 1, 86.7% of ketone 16a, and 9.2% of ketone 17a.
A part of the crude product (0.60 g) was subjected to silica gel
(40—63 μm, 50/1) column chromatography (elution with n-hex-
ane—EtOAc (10 : 1)) to afford 0.51 g (82%) of ketone 16a.
Crystallization of a remaining part of the crude product (4.46 g)
from n-hexane gave 2.64 g (71%) of ketone 16a.
Similar reaction of dimethylnaphthalene 9 (1.61 g, 8.41 mmol)
gave 1.85 g of a product mixture containing 0.9% of naphthalene
9, 69.1% of ketone 16b, and 26% of ketone 17b. Purification of
this mixture by silica gel column chromatography (elution with
n-hexane—EtOAc (10 : 1)) afforded 1.15 g (58%) of ketone 16b
and 0.29 g (15%) of ketone 17b.
Method E. To a stirred mixture of AlCl3 (1.90 g, 14.23 mmol)
and difluoronaphthalene 1 (2.10 g, 12.80 mmol) in CH2Cl2
(10 mL) cooled to –40 °C, a solution of AcCl (1.10 g, 14.01 mmol)
in CH2Cl2 (10 mL) was added rapidly (over 2 min) and stirring
was continued at –40÷–30 °C for 2 h. Then an aliquot was
taken and analyzed by GC and stirring was continued at room
temperature for 4 h. The mixture was poured into ice-water and
worked up as described above to afford 2.54 g of a product mixture
containing 2.8% of compound 1, 64.7% of ketone 16a, and 29.2% of
ketone 17a. Purification of this mixture by silica gel column
chromatography (elution with n-hexane—EtOAc (10 : 1)) afford-
ed 1.52 g (57%) of ethanone 16a and 0.56 g (21%) of ketone 17a.
Similar reaction of difluorodimethylnaphthalene 9 (2.46 g,
12.80 mmol) gave 2.96 g of a product mixture containing 0.9%
of naphthalene 9, 1.5% of ketone 16b, and 95.2% of ketone 17b.
Crystallization of this mixture from n-hexane afforded 2.75 g
(92%) of 1-(6,7-difluoro-5,8-dimethylnaphthalen-2-yl)ethan-
one (17b).
Similar procedures were used to acylate difluoronaphthalene
1 in nitrobenzene. Composition of the product mixtures was
analyzed by GC.
Similar reaction of difluorodimethylnaphthalene 9 (4.92 g,
25.60 mmol) gave 5.89 g of a product mixture containing 0.6%
of naphthalene 9, 0.7% of ketone 16b, and 97.2% of ketone 17b.
Crystallization of this mixture from n-hexane afforded 5.58 g
1-(6,7-Difluoronaphthalen-1-yl)ethanone (16a). M.p. 78—79 °C
(from hexane). 1H NMR (250.1 MHz, CDCl3), δ: 2.75 (s, 3 H,
CH3); 7.53 (t, 1 H, Ar, J = 8.2 Hz); 7.59 (dd, 1 H, Ar, J = 10.0 Hz,
J = 7.2 Hz); 7.94 (d, 1 H, Ar, J = 8.2 Hz); 8.05 (d, 1 H, Ar,

Volchkov et al.
278
Russ. Chem. Bull., Int. Ed., Vol. 69, No. 2, February, 2020
J = 8.2 Hz); 8.80 (dd, 1 H, Ar, J = 11.2 Hz, J = 7.7 Hz). 13C NMR
(CDCl3), δ: 29.38 (s, CH3); 113.29 (d, C(8), J = 20.0 Hz); 113.79
(d, C(5), J = 16.3 Hz); 124.82 (br.s, C(3)); 127.28 (d, C(8a),
J = 8.7 Hz); 129.72 (br.s, C(2)); 131.30 (d, C(4a), J = 7.1 Hz);
132.46 (d, C(4), J = 4.5 Hz); 133.72 (s, C(2)); 149.95 (dd, C(7),
J = 251.8 Hz, J = 16.2 Hz); 151.40 (dd, C(6), J = 251.0 Hz,
J = 15.7 Hz); 200.75 (s, MeC=O). 19F NMR (188.3 MHz, CDCl3),
δ: –133.2 (m, 1 F); –135.7 (m, 1 F). MS, m/z (Irel (%)): 206
[M]+ (46), 191 [M – CH3]+ (97), 163 [M – CH3CO]+ (100),
143 [M – CH3CO – HF]+ (25), 43 (30). Found (%): C, 69.77;
H, 3.94. C12H8F2O. Calculated (%): C, 69.90; H, 3.91.
0 °C (ice-water), Br2 (4.60 g, 30 mmol) was added followed by
dropwise addition of a solution of 1-(6,7-difluoronaphthalen-1-
yl)ethanone (16a) (1.64 g, 8 mmol) in 1,4-dioxane (12 mL) over
30 min maintaining the reaction temperature at 5—10 °C. After
2 h stirring at room temperature, bromoform that formed was
extracted with dichloromethane. The aqueous layer was acidified
with 30% aqueous HCl to pH < 2, the precipitate formed was
collected by filtration using a sintered disc filter funnel, washed
with water, and air dried. Yield 1.25 g (75%) of almost pure
6,7-difluoro-1-naphthoic acid (18), white powder.
Similarly reaction of 1-(6,7-difluoronaphthalen-2-yl)ethan-
one (17a) (1.64 g, 8 mmol) gave 1.30 g (78%) of 6,7-difluoro-2-
naphthoic acid (19), white powder.
1-(6,7-Difluoronaphthalen-2-yl)ethanone (17a). M.p. 83—85 °C
(from hexane). 1H NMR (300.1 MHz, CDCl3), δ: 2.71 (s, 3 H,
CH3); 7.61 (dd, 1 H, Ar, J = 10.5 Hz, J = 7.9 Hz); 7.70 (dd, 1 H,
Ar, 3JH,F = 10.4 Hz, J = 8.1 Hz); 7.83 (d, 1 H, J = 8.7 Hz); 8.03
6,7-Difluoro-1-naphthoic acid (18).15,16 M.p. 255 °C (de-
comp.). 1H NMR (300.1 MHz, DMSO-d6), δ: 7.65 (t, 1 H, Ar,
J = 7.8 Hz); 8.14 (dd, 1 H, Ar, J = 9.0 Hz, J = 8.4 Hz); 8.19—8.29
(m, 2 H, Ar); 8.90 (dd, 1 H, Ar, J = 8.9 Hz, J = 8.4 Hz); 13.9
(br.s, 1 H, COOH). 19F NMR (282.4 MHz, DMSO-d6), δ:
–135.8 (m, 1 F); –138.4 (m, 1 F). MS, m/z (Irel (%)): 208 [M]+
(100), 191 [M – OH]+ (49), 163 [M – CO2H]+ (32), 143 (10).
Found (%): C, 63.58; H, 2.97. C11H6F2O2. Calculated (%):
C, 63.47; H, 2.91.
3
(d, 1 H, Ar, JH,H = 8.7 Hz); 8.39 (s, 1 H, Ar). 13C NMR
(CDCl3), δ: 26.60 (s, CH3); 113.64 (d, C(5), J = 16.9 Hz); 115.12
(d, C(8), J = 16.7 Hz); 124.37 (br.s, C(3)); 127.69 (d, C(4),
J = 5.0 Hz); 129.04 (d, C(1), J = 4.2 Hz); 129.31 (d, C(4a),
J = 7.6 Hz); 132.55 (d, C(8a), J = 8.2 Hz); 134.78 (s, C(2));
150.41 (dd, C(7), J = 252.1 Hz, J = 16.3 Hz); 151.35 (dd, C(6),
J = 254.7 Hz, J = 16.0 Hz); 197.47 (s, MeC=O). 19F NMR (282.4
MHz, CDCl3), δ: –132.3 (m, 1 F); –135.0 (m, 1 F). MS, m/z
(Irel (%)): 206 [M]+ (27), 191 [M – CH3]+ (83), 163 [M –
– CH3CO]+ (100), 143 [M – CH3CO – HF]+ (30), 43 (73).
Found (%): C, 69.57; H, 3.84. C12H8F2O. Calculated (%):
C, 69.90; H, 3.91.
1-(6,7-Difluoro-5,8-dimethylnaphthalen-1-yl)ethanone (16b).
M.p. 108—109 °C (from hexane). 1H NMR (300.1 MHz, CDCl3),
δ: 2.35 (d, 3 H, CH3, J = 3.1 Hz); 2.55 (d, 3 H, CH3, J = 2.5 Hz);
2.71 (s, 3 H, COCH3); 7.45—7.49 (m, 2 H, Ar); 7.98—8.02
(m, 1 H, Ar). 13C NMR (CDCl3), δ: 10.22 (dd, CH3, J = 4.8 Hz,
J = 2.5 Hz); 14.10 (dd, CH3, J = 7.3 Hz, J = 2.4 Hz); 31.53 (br.s,
CH3); 118.05 (d, C(8), J = 13.1 Hz); 118.57 (d, C(5), J = 12.0 Hz);
124.03 (d, C(2), J = 2.3 Hz); 124.71 (d, C(3), J = 2.3 Hz); 126.41
(d, C(8a), J = 4.8 Hz); 126.68 (dd, C(4), J = 6.3 Hz, J = 2.2 Hz);
130.73 (d, C(4a), J = 4.3 Hz); 140.83 (dd, C(1), J = 6.4 Hz,
J = 2.1 Hz); 147.96 (dd, C(6), J = 246.9 Hz, J = 17.2 Hz); 149.17
(dd, C(7), J = 248.6 Hz, J = 16.6 Hz); 205.11 (s, MeC=O).
19F NMR (282.4 MHz, CDCl3), δ: –134.5 (d, 1 F, J = 21.5 Hz);
–137.9 (d, 1 F, J = 21.5 Hz). MS, m/z (Irel (%)): 234 [M]+ (53),
219 [M – CH3]+ (100), 191 [M – CH3CO]+ (57), 170 (24),
43 (22). Found (%): C, 71.86; H, 5.17. C14H12F2O. Calculat-
ed (%): C, 71.78; H, 5.16.
1-(6,7-Difluoro-5,8-dimethylnaphthalen-2-yl)ethanone (17b).
M.p. 112—113 °C. 1H NMR (200.1 MHz, CDCl3), δ: 2.50
(d, 3 H, CH3, J = 2.2 Hz); 2.57 (d, 3 H, CH3, J = 2.2 Hz); 2.72
(s, 3 H, COCH3); 7.88 (d, 1 H, Ar, J = 9.0 Hz); 7.97 (d, 1 H,
Ar, J = 9.0 Hz); 8.47 (s, 1 H, Ar). 13C NMR (CDCl3), δ: 10.22
(br.s, 2 CH3); 26.66 (s, CH3); 118.05 (d, C(5), J = 12.7 Hz);
119.56 (d, C(8), J = 12.7 Hz); 123.79 (br.s, C(3)); 124.68
(d, C(4), J = 6.0 Hz); 125.74 (d, C(1), J = 5.9 Hz); 128.93 (d, C(8a),
J = 5.4 Hz); 132.22 (d, C(4a), J = 5.4 Hz); 133.87 (br.s, C(2));
148.26 (dd, C(7), J = 247.2 Hz, J = 17.2 Hz); 149.26 (dd, C(6),
J = 249.4 Hz, J = 16.9 Hz); 197.84 (s, MeC=O). 19F NMR (188.3
MHz, CDCl3), δ: –135.0 (d, 1 F, J = 20.1 Hz); –137.6 (d, 1 F,
J = 20.1 Hz). MS, m/z (Irel (%)): 234 [M]+ (46), 219 [M – CH3]+
(100), 191 [M – CH3CO]+ (50), 170 (20), 43 (50). Found (%):
C, 71.84; H, 5.15. C14H12F2O. Calculated (%): C, 71.78; H, 5.16.
Synthesis of dufluoronaphthoic acids 18 and 19. To a stirred
solution of NaOH (3.60 g, 90 mmol) in water (20 mL) cooled to
6,7-Difluoro-2-naphthoic acid (19). M.p. 235—237 °C (de-
comp.). 1H NMR (300.1 MHz, DMSO-d6), δ: 7.98—8.03 (m, 2 H,
Ar); 8.08 (dd, 1 H, Ar, J = 11.0 Hz, J = 9.1 Hz); 8.22 (dd, 1 H,
Ar, J = 10.5 Hz, J = 9.2 Hz); 8.62 (s, 1 H, Ar); 13.2 (br.s, 1 H,
COOH). 13C NMR (DMSO-d6), δ: 113.90 (d, C(5), J = 17.0 Hz);
115.33 (d, C(8), J = 16.7 Hz); 125.74 (s, C(3)); 127.77 (d, C(4),
J = 4.7 Hz); 128.69 (s, C(2)); 129.34 (d, C(8a), J = 8.0 Hz);
129.93 (d, C(1), J = 4.7 Hz); 132.27 (d, C(4a), J = 8.2 Hz);
149.34 (dd, C(6), J = 248.7 Hz, J = 15.8 Hz); 150.26 (dd, C(7),
J = 250.9 Hz, J = 16.3 Hz); 167.13 (s, (HO)C=O). 19F NMR
(282.4 MHz, DMSO-d6), δ: –135.2 (m, 1 F); –137.6 (m, 1 F).
MS, m/z (Irel (%)): 208 [M]+ (100), 191 [M – OH]+ (48), 163
[M – CO2H]+ (30), 143 (10). Found (%): C, 63.56; H, 2.95.
C11H6F2O2. Calculated (%): C, 63.47; H, 2.91.
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Received May 17, 2019;
in revised form October 22, 2019;
accepted November 5, 2019