Synthesis of mono- and difluoronaphthoic acids

Article abstract of DOI:10.1021/jo0160322

Aryl carboxamides are useful structural units found in several biologically active compounds. Unlike their benzoic acid counterparts, fluorinated versions of naphthoic acids are relatively unknown. In connection with a recent project, we needed viable syntheses of several mono- and difluorinated naphthoic acids. Herein we describe the synthesis of 5-, 6-, 7-, and 8-fluoro-1-naphthalenecarboxylic acids and 5,7-, 5,8-, 6,7-, and 4,5-difluoro-1-naphthalenecarboxylic acids. The 5-fluoro derivative 1 was obtained from the corresponding 5-bromo compound via electrophilic fluorination of the lithio-intermediate. The rest of the monofluoro (2, 3, and 4) and the difluoro acids (5, 6, and 7) were prepared by a new, general route which entailed the elaboration of commercial fluorinated phenylacetic acids to 2-(fluoroaryl)glutaric acids with differential ester groups; selective hydrolysis to a mono acid, intramolecular Friedel-Crafts cyclization, and aromatization furnished the target structures. An alternative process to assemble a naphthalene skeleton is also presented for the difluoro acids 5 and 6. Finally, 4,5-difluoro-1-naphthalenecarboxylic acid (8) was prepared expeditiously from 1,8-diaminonaphthalene by adapting classical reactions.

Full text of DOI:10.1021/jo0160322

J . Org. Chem. 2002, 67, 1171-1177
1171
Syn th esis of Mon o- a n d Diflu or on a p h th oic Acid s
J ayaram R. Tagat,* Stuart W. McCombie, Dennis V. Nazareno, Craig D. Boyle,
J oseph A. Kozlowski, Samuel Chackalamannil, Hubert J osien, Yuguang Wang, and
Guowei Zhou
Chemical Research, Schering-Plough Research Institute, 2015, Galloping Hill Road, K-15-2B-2800,
Kenilworth, New J ersey 07033-0539
jayaram.tagat@spcorp.com
Received August 15, 2001
Aryl carboxamides are useful structural units found in several biologically active compounds. Unlike
their benzoic acid counterparts, fluorinated versions of naphthoic acids are relatively unknown. In
connection with a recent project, we needed viable syntheses of several mono- and difluorinated
naphthoic acids. Herein we describe the synthesis of 5-, 6-, 7-, and 8-fluoro-1-naphthalenecarboxylic
acids and 5,7-, 5,8-, 6,7-, and 4,5-difluoro-1-naphthalenecarboxylic acids. The 5-fluoro derivative 1
was obtained from the corresponding 5-bromo compound via electrophilic fluorination of the lithio-
intermediate. The rest of the monofluoro (2, 3, and 4) and the difluoro acids (5, 6, and 7) were
prepared by a new, general route which entailed the elaboration of commercial fluorinated
phenylacetic acids to 2-(fluoroaryl)glutaric acids with differential ester groups; selective hydrolysis
to a mono acid, intramolecular Friedel-Crafts cyclization, and aromatization furnished the target
structures. An alternative process to assemble a naphthalene skeleton is also presented for the
difluoro acids 5 and 6. Finally, 4,5-difluoro-1-naphthalenecarboxylic acid (8) was prepared
expeditiously from 1,8-diaminonaphthalene by adapting classical reactions.
In tr od u ction
Several biologically active natural products and phar-
maceuticals contain substituted naphthoic acids or the
derived amides as structural features of interest.1 In
connection with a recent project, we found that the
naphthamide moiety that is required for eliciting a
selective biological response is also rapidly metabolized.
F igu r e 1.
LCMS studies of the metabolites showed an M + 34 peak
perhaps indicating arene oxide formation and hydrolysis.
This was a major problem for the parent naphthamide
but was much less significant for the 4-fluoro derivative
(Figure 1), both prepared from commercially available
1-naphthalenecarboxylic acids.
Since it is reasonable to expect that such a process may
occur more readily in the unsubstituted B-ring, we set
out to prepare naphthamides that contain one or more
fluorine atoms in the B-ring in order to block the
oxidative metabolism. To this end, the fluorinated 1-naph-
thalenecarboxylic acids 1-8 were targeted (Figure 2).2
Resu lts a n d Discu ssion
F igu r e 2.
In addition to direct modification of available naph-
thalene derivatives, other useful routes to substituted
naphthalenes in general involve either the Diels-Alder
reaction or the Michael addition/intramolecular cycliza-
tion sequence.3 In the Diels-Alder route, the diene or
the dienophile must be symmetrical to control regio-
chemistry. The Michael addition route has been mainly
used to make naphthols with either a ketone or an ester
functionality at the 2-position. A search for the desired
1-naphthoic acids 1-8 revealed that only the 6- and
7-fluoronaphthoic acids 2 and 3 were previously known.4
The 5-bromo derivative 10 was prepared by a reported
* Corresponding author. Phone: (908)-740-3461. Fax: (908)-740-
7152.
(1) (a) Lowe, J . A. U.S. Patent 4,891,375, 1990. (b) Hollinshead, S.
P.; Huff, B. E.; WO 9 904 778, 1999. (c) Barnett, S. F.; Heimbrook, D.
C. WO 9 910 523, 1999. (d) Ding, C. Z.; Bhide, R. S.; WO 9 918 951,
1999. (e) Kozlowski, J . A.; McCombie, S. W.; Tagat, J . R.; Vice, S. F.
U. S. Patent 6,066,636. 2000.
(2) A preliminary account of this work has been presented as a
poster: Tagat, J . R.; McCombie, S. W.; Nazareno, D. V.; Kozlowski, J .
A.; Boyle, C. D.; J osien, H.; Wang, Y.; Zhou, G. Abstracts of Papers,
36th National Organic Chemistry Symposium, Madison, WI, 1999,
NOS 259.
(3) Katritzky, A. R.; Zhang, G.; Xie, L. J . Org. Chem. 1997, 62, 721
(and references therein).
(4) (a) Fujita et al. Agric. Biol. Chem. 1961, 25, 719. (b) Adcock, W.;
Dewar, M. J . S. J . Am. Chem. Soc. 1967, 89, 386.
10.1021/jo0160322 CCC: $22.00 © 2002 American Chemical Society
Published on Web 01/23/2002

1172 J . Org. Chem., Vol. 67, No. 4, 2002
Tagat et al.
Sch em e 1
Sch em e 2
procedure.5 It was converted to the tert-butyl ester 11
by Widmer’s method.6 Halogen-metal exchange followed
by quenching with an electrophilic fluorinating agent7
gave a 2:1 mixture of the 5-F/5-H products. They were
separated by careful chromatography and the 5-fluoro
ester 13 was treated with trifluoroacetic acid to obtain
5-fluoro-1-naphthalenecarboxylic acid 1 (Scheme 1).
The inherent problems in the Br f F exchange as
noted for the synthesis of 1 prompted us to choosefluo-
rine-containing starting materials for an alternative
route. Thus, base-catalyzed Michael addition of ap-
propriately (o-, m-, p-) fluorinated phenylacetic esters (14)
to tert-butyl acrylate gave 2-(fluorophenyl)glutaric esters
15 (90%) with differential ester groups. Selective cleavage
of the tert-butyl ester and Friedel-Crafts cyclization of
the derived acid chloride produced the tetralone 16
(∼50%). During the reductive elimination of 16 to a
dihydronaphthalene (19), longer reaction times (>1 h)
gave significant amounts of the bicyclic lactone 18 which
was reconverted to 17. DDQ-mediated aromatization and
saponification of the ethyl ester completed the synthesis.
In this seven-step sequence, only the tetralones 16 and
the penultimate naphthalene ester required chromato-
graphic purification. The mono-fluoro-1-naphthalenecar-
boxylic acids 2, 3, and 4 were obtained in 25-30% overall
yield (Scheme 2).
The slightly higher cost of difluorophenyl acetic acids
as starting materials in a sequence analogous to Scheme
2 led us to explore the use of difluoroacetophenones as
precursors in a similar strategy for preparing difluo-
ronaphthoic acids (Scheme 3). 2,4-Difluoroacetophenon-
ewas elaborated to the 4-arylbutanoic acid derivative 22,8
which was cyclized to the tetralone 23 (∼30% overall
yield) in the usual manner. Cyanohydrin formation9 and
a two-step aromatization process provided the naph-
thonitrile 26. Hydrolysis of 26 under strongly acidic
conditions afforded the target 5,7-difluoro-1-naphthal-
enecarboxylic acid 5.
On the other hand, the 5,8-difluoro-1-naphthonitrile
28 prepared by a similar sequence of reactions from 2,5-
difluoroacetophenone 27 could only be partially hydro-
lyzed under acidic or basic conditions, stopping at the
stage of the amide 29 (Scheme 4). However, we were able
to reduce the naphthonitrile 28 to the corresponding
(8) Attempted deoxygenation of 21 using EtSiH3/TFA resulted in
the formation of 5-(2,4-difluorophenyl)-γ-butyrolactone.
(9) Harusawa, S.; Yoneda, R.; Kurihara, T.; Hamada, T.; Shioiri, T.
Tetrahedron Lett. 1984, 25, 427.
(5) Short, W. F.; Wang, H. J . Chem. Soc. 1950, 991.
(6) Widmer, U. Synthesis 1983, 135.
(7) Differding, E.; Ofner, H. Synlett 1991, 187.

Synthesis of Mono- and Difluoronaphthoic Acids
J . Org. Chem., Vol. 67, No. 4, 2002 1173
Sch em e 3
Sch em e 4
Sch em e 5
aldehyde (30) and then oxidize it to the desired 5,8-
difluoro-1-naphthalencarboxylic acid 6.
the 6,7-difluoro-1-naphthoic acid 7 (Scheme 5).10 Later,
this sequence of reactions was also used to prepare the
difluoro-1-naphthalenecarboxylic acids 5 and 6 (2-10 g).
The final target, 4,5-difluoro-1-naphthoic acid (8) was
The lower cost of the starting difluoroacetophenones
was off set by the extra steps needed to introduce the
acidic group and the additional chromatographic purifi-
cation needed in the above sequence. We, therefore,
revisited the first route starting with 31 and prepared
(10) In this route, the Friedel-Crafts cyclization of 32 gave only
the 6,7-difluoro-1-tetralone (33) and none of the alternative 7,8-
difluoro-1-tetralone as confirmed by NOE experiments.

1174 J . Org. Chem., Vol. 67, No. 4, 2002
Tagat et al.
Sch em e 6
5-F lu or o-1-n a p h th a len eca r boxylic Acid , 1,1-Dim eth -
yleth yl Ester (13). A stirred solution of 11 (0.42 g; 1.4 mmol)
in THF (14 mL) was cooled to -78 °C under nitrogen.
n-Butyllithium (1.6 M in hexanes, 1.1 mL, 1.8 mmol) was
added, and the resulting solution was stirred for 1.5 min,
followed by addition of N-fluorobenzenesulfonimide (0.86 g; 2.7
mmol). After stirring for 30 min, the reaction was quenched
with saturated aqueous ammonium chloride. The aqueous
component was extracted with Et2O, and the combined organ-
ics were dried over magnesium sulfate and concentrated in
assembled from the inexpensive 1,8-diaminonaphthalene
(37) by a short sequence. Thus, diazotization of 37 and
reaction with fluoroboric acid yielded the 1,8-difluoro
naphthalene 38.11 Acetylation and oxidation12 afforded
4,5-difluoro-1-naphthalenecarboxylic acid 8 (Scheme 6).
In summary, we have described general, scalable
methods for the preparation of four monofluoro and four
difluoro-1-naphthoic acids from readily available precur-
sors. The wide spread occurrence of naphthamides and
other naphthoic acid derivatives in biologically active
substances warrants the general utility of the title
compounds described in this paper.13
1
vacuo. The crude product 12 was identified by H NMR as a
2/1 mixture of 5-F/5-H compounds. FSGC (toluene as eluent)
resulted in 157 mg of 13 (46% yield). 1H NMR (400 MHz,
CDCl3): δ 8.64 (d, J ) 8.4 Hz, 1H), 8.29 (d, J ) 8.4 Hz, 1H),
8.13 (dd, J ) 1.0, 7.2 Hz, 1H), 7.52 (m, 2H), 7.19 (ddd, J )
1.0, 8.4, 10.0 Hz, 1H), 1.68 (s, 9H). MS (M-t-Bu): 191 (100%).
Exp er im en ta l Section
5-F lu or o-1-n a p h th a len eca r boxylic Acid (1). Trifluoro-
acetic acid (0.3 mL, 3.9 mmol) was added to a stirred meth-
ylene chloride (4 mL) solution of 13 (96.5 mg, 0.39 mmol) at
room temperature. After stirring for several hours, the solution
was concentrated in vacuo and stored under high vacuum for
12 h, yielding 73 mg of pure 1 (98% yield). 1H NMR (400 MHz,
CD3OD): δ 8.73 (d, J ) 8.4 Hz, 1H), 8.31 (d, J ) 8.8 Hz, 1H),
8.27 (d, J ) 7.6 Hz, 1H), 7.63 (dd, J ) 7.2, 8.4 Hz, 1H), 7.56
(m, 1H), 7.26 (dd, J ) 7.2, 10.0 Hz, 1H). Anal. Calcd for C11H7-
FO2: C, 69.47, H, 3.71. Found: C, 69.32; H, 3.76.
2-(2-F lu or op h en yl)p en ta n ed ioic Acid , 5-(1,1-Dim eth -
yleth yl)-1-eth yl Ester (15). o-Fluorophenyl ethyl acetate (14)
was prepared from commercially available o-fluorophenylacetic
acid. tert-Butyl acrylate was added to a solution of 14 (6.3 g;
34.62 mmol) in 30 mL of tert-butyl alcohol cooled in a cold
water bath (5 °C) and treated with oil-free sodium hydride (0.3
g). After the initial effervescence ceased, the resulting clear,
pale yellow solution was stirred at 5 °C for 30 min and allowed
to warm to room temperature (45 min). The reaction mixture
was quenched with 1 mL of glacial acetic acid. The organic
products were extracted into ether and washed with water
(4×), 10% aqueous NaHCO3 solution, and brine. Concentration
in vacuo gave 10 g of a crude product. FSGC (5% ether-
hexane) served to isolate compound 15 (7.6 g; 83% yield) as
colorless oil. 1H NMR (CDCl3): δ 1.20 (t, J ) 7.0 Hz, 3H), 1.43
(s, 9H), 2.05 (m, 1H), 2.2 (t, J ) 7.0 Hz, 2H), 2.35 (m, 1H),
3.96 (t, J ) 7.5 Hz, 1H), 4.15 (m, 2H), 7.0-7.15 (m, 2H), 7.2-
7.35 (m, 2H).
8-F lu or o-1, 2,3,4-tetr a h yd r o-4-oxo-1-n a p h th a len eca r -
b oxylic Acid , E t h yl E st er (16). (a) 4-(Ethyl)-3-(2-fluoro-
phenyl)-1-glutaric acid: Trifluoroacetic acid (TFA; 10 mL) was
added to a solution of 15 (6.6 g; 21.29 mmol) in 25 mL of CH2-
Cl2 and stirred at room temperature until the starting material
was fully consumed (∼7 h). The solvent and most of the TFA
were removed in vacuo. The residue was dissolved in ethyl
acetate (100 mL) and washed with water (4×) and brine. After
concentrating in vacuo, the residue was evaporated with
toluene (2 × 10 mL) to remove the last traces of TFA. The
residue was concentrated overnight under high vacuum to
afford 5.35 g (∼100%) of the monoacid as a colorless oil. 1H
NMR (CDCl3): δ 1.2 (t, J ) 7 Hz, 3H), 2.1 (m, 1H), 2.3-2.45
(m, 3H), 3.95 (t, J ) 7 Hz, 1H), 4.15 (m, 2H), 7.0-7.15 (m,
2H), 7.15-7.35 (m, 2H) and 8.25 (br-s, 1H).
Gen er a l. Melting points were determined on a Mel-Temp
apparatus and are uncorrected. Elemental analyses were
performed by the Physical-Analytical Chemistry department,
Schering-Plough Research Institute, on either a Leeman CE
440 or a Fisons EA 1108 elemental analyzer. Mass spectra
were recorded using either Extrel 401 (Chemical Ionization),
J EOL or MAT-90 (FAB), VG ZAB-SE (SIMS) or Finnigan
MAT-CH-5 (Electron Impact) spectrometer. The 1H and 13C
NMR spectra were obtained on either Varian Gemini-300 (300
MHz, 1H; 75.5 MHz 13C) or XL-400 (400 MHz 1H; 100 MHz
13C) and are reported as ppm downfield from Me4Si with
number of protons, multiplicities, and coupling constants in
hertz indicated in parentheses. For 13C NMR, a Nalorac probe
was used. The compound purity was checked using thin-layer
chromatography (TLC) and LC/MS analysis using Applied
Biosystems API-100 mass spectrometer and Shimadzu SCL-
10A LC column: Allech platinum C18, 3 mµ, 33 mm × 7 mm
ID. Abbreviations used: dichloromethane (DCM), tetrahydro-
furan (THF), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide
(EDCI), 1-hydroxybenzotriazole (HOBt), flash silica gel chro-
matography (FSGC).
5-Br om o-1-n a p h th a len eca r boxylic Acid , 1,1-Dim eth -
yleth yl Ester (11). A suspension of 5-bromo-1-naphthoic acid5
10 (2.00 g, 7.97 mmol) in toluene (12 mL) was heated to 80
°C. N,N-Dimethylformamide di-tert-butyl acetal (7.6 mL, 31.9
mmol) was added dropwise, and the resulting mixture was
heated at 80 °C for an additional 30 min. After cooling to room
temperature, the organic solution was washed consecutively
with H2O, saturated aqueous NaHCO3, and brine. The solution
was dried over sodium sulfate and concentrated in vacuo,
resulting in 1.2 g of desired product 11 as a yellow oil (49%
yield). 1H NMR (400 MHz, CDCl3): δ 8.82 (d, J ) 8.4 Hz, 1H),
8.45 (d, J ) 8.8 Hz, 1H), 8.09 (d, J ) 7.2 Hz, 1H), 7.83 (d, J )
7.6 Hz, 1H), 7.59 (dd, J ) 7.2, 8.8 Hz, 1H), 7.42 (dd, J ) 7.6,
8.4 Hz, 1H), 1.67 (s, 9H). HRMS calculated for C15H16BrO2
(MH+): 307.0329, found 307.0334.
(11) Mallory, F. B.; Mallory, C. W.; Fedarko, M.-C. J . Am. Chem.
Soc. 1974, 96, 3536.
(12) Bachmann, W. E.; Cronyn, M. W.; Struve, W. S. J . Org. Chem.
1947, 12, 603.
(13) For examples of fluorinated naphthamides prepared from all
of the new fluoronaphthoic acids described in this paper and their
effects on pharmacokinetic parameters, see: Boyle, C. D.; Chackala-
mannil, S.; Clader, J . C.; Greenlee, W. J .; J osien, H. B.; Kaminski, J .
J .; Kozlowski, J . A.; McCombie, S. W.; Nazareno, D. V.; Tagat, J . R.;
Wang, Y.; Zhou, G.; Billard, W.; Binch, H., III; Crosby, G.; Cohen-
Williams, M.; Coffin, V. L.; Cox, K. A.; Grotz, D. E.; Duffy, R.; Ruperto,
V.; Lachowicz, J . E. Bioorg. Med. Chem. Lett. 2001, 11, 2311.
(b). Formation of the acid chloride and cyclization to the title
compound (16): Oxalyl chloride (2.3 mL; 25.8 mmol) was added
to a solution of the mono-acid (5.3 g) prepared above and
dimethylformamide (0.3 mL) in 30 mL of DCM at 0 °C. The
reaction mixture was stirred at ice-bath temperature for 45

Synthesis of Mono- and Difluoronaphthoic Acids
J . Org. Chem., Vol. 67, No. 4, 2002 1175
min and then at room temperature for 1.5 h. The solvent and
7-F lu or o-1-n a p h th a len eca r boxylic Acid (3).4b Prepara-
1
acidic byproducts were removed on
a
rotary evaporator.
tion similar to 4. mp: 245 °C. H NMR (DMSO-d6): δ 7.45-
Finally, the residue was concentrated under high vacuum to
yield 6.3 g (∼100%) of a colorless oil.
7.65 (m, 2H), 8.13 (m, 1H), 8.20-8.35 (m, 2H) and 8.67 (d, J
) 13 Hz, 1H).
6-F lu or o-1-n a p h th a len eca r boxylic Acid (2).4a Prepara-
The 4-ethyl-3-(2-fluorophenyl)-1-glutaroyl chloride prepared
above was dissolved in 50 mL of DCM, and solid aluminum
chloride (6.6 g; 50 mmol) was added quickly. After the initial
effervescence, a clear yellow solution is formed and it was
heated to reflux for 6 h. The deep burgundy slurry that
resulted was cooled to room temperature and diluted with
ethyl acetate. The reaction was quenched with 2 M hydrochlo-
ric acid solution (100 mL) to leave a turbid yellow solution.
The layers were separated, and the organic layer was washed
with 2 M HCl aqueous solution (3 × 100 mL) until it was
almost clear and finally with water and brine. Concentration
left a deep red liquid which was purified by FSGC (20% ethyl
acetate in hexane) to obtain 2.1 g (42%) of the tetralone 16 as
a pale yellow syrup. 1H NMR (CDCl3): δ 1.2 (t, J ) 7 Hz, 3H),
2.3-2.45 (m, 1H), 2.5-2.8 (m, 3H), 4.1-4.3 (m, 3H), 7.26 (dd,
J ) 2.7, 8 Hz, 1H), 7.37 (dd, J ) 2.5, 8 Hz, 1H) and 7.87 (d, J
) 8 Hz).
1
tion similar to 4. H NMR: 7.45 (dt, J ) 2.7, 9.4 Hz, 1H), 7.6
(q, J ) 7.5, 16 Hz, 2H), 8.1 (d, J ) 8 Hz, 1H), 8.2 (d, J ) 7.3
Hz, 1H) and 9.05 (dd, J ) 5.7, 9.4 Hz, 1H).
4-(2,4-Diflu or op h en yl)-4-h yd r oxy-bu ta n oic Acid , 1,1-
Dim eth yleth yl Ester (21). A solution of 2,4-difluoroacetophen-
one 20 (7 g; 45.45 mmol) in 50 mL of dry THF was added to a
solution of freshly prepared lithium hexamethyldisilazide in
dry THF (50 mmol in 50 mL) at -78 °C and stirred for 30
min. The resulting yellow solution of the enolate was added
into a solution of tert-butyl iodoacetate (12.1 g; 50 mmol) in
50 mL of dry THF at -78 °C over 15 min. The amber-colored
reaction mixture was allowed to warm to room temperature
over 3 h and quenched with saturated aqueous NH4Cl solution.
Extractive workup in ether gave 14 g of a clear orange liquid.
FSGC (5% ether-hexane) yielded 6 g (∼50%) of the monoalkyl-
ated keto-ester and 1.2 g (∼10%) of the dialkylated keto-ester.
8-F lu or o-1, 2, 3, 4-t et r a h yd r o-4-h yd r oxy-1-n a p h t h a l-
en eca r boxylic Acid , Eth yl Ester (17). A solution of sodium
borohydride (0.21 g; 5.52 mmol) in 4 mL of water was added
to a solution of the tetralone 16 (1.1 g; 4.66 mmol) in 2 mL of
THF and 2 mL of ethanol. The reaction mixture was stirred
at room temperature for 6 h when TLC indicated absence of
starting material. The reaction was quenched with 1 N citric
acid and the product was isolated by extractive workup in
DCM. The carbinol 17 (∼2:1 mixture of epimers) was obtained
A solution of sodium borohydride (0.6 g; 16 mmol) in 5 mL
of water was added to a solution of the keto-ester (4.3 g; 16
mmol) prepared in the first step in 40 mL of THF. The reaction
was allowed to proceed at room temperature for 2.5 h and
quenched with 2 M tartaric acid solution. The organic product
was extracted into DCM and washed with water, 10% NaHCO3
solution, and brine. Concentration in vacuo gave 4.35 g
(∼100%) of the hydroxy ester 21 as a colorless oil. 1H NMR
(CDCl3): δ 1.47 (s, 9H), 2.05 (q, J ) 3, 9 Hz, 2H), 2.4 (t, J )
6 Hz, 2H), 2.5 (br-s, OH), 5.03 (t, J ) 6 Hz, 1H), 6.75 (dt, J )
2, 10 Hz, 1H), 6.9 (t, J ) 9.5 Hz, 1H) and 7.5 (q, J ) 6, 12 Hz,
1H). Anal. Calcd for C14H18F2O3: C, 61.76; H, 6.66; F, 13.95.
Found: C, 61.58; H, 6.78; F, 13.61.
1
as a colorless oil (1.05 g; ∼100%). H NMR (CDCl3): δ 1.2 (t,
J ) 7 Hz, 3H), 1.8-2.15 (m, 4H), 2.25 (m, 2H), 3.85 (t, J ) 6
Hz, 1H), 4.1-4.25 (m, 2H), 4.72 (t, J ) 6 Hz, 1H), 6.96 (t, J )
9 Hz, 1H) and 7.2-7.35 (m, 2H).
8-F lu or o-1, 2-d ih yd r o-1-n a p h th a len eca r boxylic Acid ,
Eth yl Ester (19). The above carbinol 17 was dissolved in 10
mL of 1,2-dichloroethane, treated with p-toluenesulfonic acid
(20 mg), and heated at reflux for 1 h. TLC indicated the
consumption of starting material to form a nonpolar, UV-active
spot. The reaction mixture was cooled to room temperature,
diluted with DCM, and washed with saturated NaHCO3
solution, water, and brine. The product was purified by FSGC
(5-10% EtOAc-hexane) to obtain the olefin 19 (0.65 g; 67%)
as a pale yellow oil. 1H NMR (CDCl3): δ 1.17 (t, J ) 7 Hz,
3H), 2.55 (m, 1H), 2.89-2.98 (dd, J ) 2.5, 2.8 Hz, dd, J ) 2.6,
6 Hz, 1H), 4.0-4.2 (m, 3H), 6.0 (m, 1H), 6.45 (dd, J ) 2, 9.6
Hz, 1H), 6.86-7.0 (m, 2H) and 7.16-7.23 (m, 1H).
8-F lu or o-1-n a p h th a len eca r boxylic Acid (4). Solid 2,3-
dichloro-5,6-dicyano-1,4-benzo quinone (DDQ; 0.73 g; 3.2
mmol) was added to a solution of the dihydronaphthalene 19
(0.65 g; 2.95 mmol) in 6 mL of 1,2-dichoroethane. The reaction
mixture was heated to reflux for 16 h and cooled to room
temperature, and the unreacted DDQ was quenched with
cyclohexadiene. The reaction mixture turned from a dark
brown to muddy tan slurry. After concentration, the residue
was dissolved in a minimum amount of DCM. FSGC of the
crude reaction mixture (25% ether-hexane) provided 8-fluoro-
1-ethyl naphthoate (0.45 g; 71%) as a yellow foam. 1H NMR
(CDCl3): δ 1.42 (t, J ) 7 Hz, 3H), 4.45 (q, J ) 7, 14 Hz, 2H),
7.2-7.26 (dd, J ) 3, 12 Hz, 1H), 7.45 (m, 1H), 7.52 (d, J ) 8
Hz, 1H), 7.60 (d, J ) 16 Hz, 1H), 7.68 (J ) 8 Hz, 1H) and 7.92
(d, J ) 16 Hz, 1H).
4-(2,4- Diflu or op h en yl)bu ta n oic Acid , 1,1-Dim eth yl-
eth yl Ester (22). A solution of the hydroxy ester 21 (4.3 g;
15.8 mmol) in 40 mL of dry DCM was treated with 4-(di-
methylamino)pyridine (0.1 g) and freshly obtained thiocarbonyl
diimidazole (4.2 g; 23.7 mmol). The reaction mixture was
stirred at room temperature until TLC showed disappearance
of the alcohol to form a more polar spot (∼20 h). The reaction
mixture was diluted with DCM and washed with water and
brine. The crude orange oily product was passed through a
short column of FSG (25% EtOAc-hexane) to isolate the
1
xanthate derivative as a pale yellow oil (5.5 g; 92%). H NMR
(CDCl3): δ 1.47 (s, 9H), 2.25-2.45 (m, 4H), 2.5(m, 1H), 6.65
(m, 1H), 6.9 (m, 1H), 7.05 (s, 1H), 7.35 (m, 1H), 7.65 (s, 1H)
and 8.35 (s, 1H).
Tributyltin hydride (5.7 mL; 21.2 mmol) and a catalytic
amount of AIBN were added to a solution of the xanthate
derivative made above in dry toluene (50 mL). The colorless
reaction mixture was heated at reflux for 1.5 h when TLC
indicated complete conversion of the starting material to a less
polar spot. The reaction mixture was diluted with EtOAc,
washed with water, and brine. Concentration to turbid yellow
oil (∼5 g) and FSGC (neat hexane followed by 25% EtOAc-
hexane) of the crude product gave the deoxygenated 4-arylbu-
1
tanoic acid ester 22 (3.25 g; 96%) as a colorless oil. H NMR
(CDCl3): δ 1.47 (s, 9H), 1.9 (m, 2H), 2.25 (t, J ) 9 Hz, 2H),
2.65 (t, J ) 8 Hz, 2H), 6.8 (m, 2H) and 7.1 (q, J ) 7, 12 Hz,
1H). Anal. Calcd for C14H18F2O2: C, 65.61; H, 7.08; F, 14.83.
Found: C, 64.98; H, 6.97; F, 14.40.
To a solution of the ethyl ester isolated above in 6 mL of
ethanol was added 2 mL of 1 M aqueous solution of sodium
hydroxide, and the reaction was heated at reflux for 24 h. After
being cooled to room temperature, the reaction mixture was
acidified with 1 M HCl solution. Extractive workup in DCM
served to isolate 8-fluoro-1-naphthalenecarboxylic acid (4) as
a cream-colored solid (0.33 g; 84%). mp: 140 °C. 1H NMR
(CDCl3): δ 7.27 (m, 1H), 7.45-7.6 (m, 2H), 7.7 (d, J ) 9 Hz,
1H), 7.8 (d, J ) 9 Hz, 1H) and 8.0 (d, J ) 9 Hz, 1H). CI MS
(MH+) ) 191 (100%). HRMS calculated for C11H8O2F: 191.0508.
Found 191.0503. Anal. Calcd for C11H7O2F: C, 69.37; H, 3.71;
F, 9.99. Found: C, 68.94; H, 3.95; F, 9.74.
5,7-Diflu or o-3,4-dih ydr o-1-(2H)-n aph th alen on e (23). Lib-
eration of the acid from 22: A solution of the tert-butyl ester
22 prepared above was dissolved in a mixture of DCM (15 mL)
and trifluoroacetic acid (5 mL) and stirred at room temperature
for 4 h. After removing the solvent and most of TFA on the
rotary evaporator, the residue was dissolved in DCM and
extracted with 1 M sodium hydroxide solution. Acidification
of the aqueous layer and extractive workup in DCM gave
4-(2,4-difluorophenyl)butanoic acid as 2.2 g (88%) of colorless
1
oil. H NMR (CDCl3): δ 1.98 (m, 2H), 2.4 (t, J ) 5.8 Hz, 2H),
2.7 (t, J ) 5.7 Hz, 2H), 6.8 (m, 2H) and 7.17 (q, J ) 4, 9 Hz,
1H).

1176 J . Org. Chem., Vol. 67, No. 4, 2002
Tagat et al.
Friedel-Crafts Reaction. The above acid was converted to
the acid chloride by treatment with oxalyl chloride (2.5 mL)
in DCM containing a trace of DMF followed by concentration
in vacuo. Solid AlCl3 was added to a solution of the acid
chloride prepared above in 40 mL of DCM and heated at reflux
for 4 h. The reaction was then cooled in an ice bath and
quenched with 2 M HCl solution, and the layers were
separated. The DCM layer was washed with water and brine.
Concentration gave ∼ 2 g of a semisolid. FSGC (1:1 ether-
hexane) afforded 1.55 g (74%) of the 5,7-difluorotetralone 23
of ethyl acetate. The reaction mixture was diluted with more
ethyl acetate and quenched with 2 N aqueous HCl solution.
The organic product was extracted into ethyl acetate and
washed with water and brine. Concentration and purification
(FSGC using 10% ether-hexane) afforded 0.75 g (75%) of 5,8-
difluoro naphthaldehyde 30. 1H NMR (CDCl3): δ 7.25 (m, 2H),
7.75 (t, J ) 8 Hz, 1H), 8.4 (dd, J ) 6, 14 Hz, 1H) and 11.0 (s,
1H).
5,8-Difluoro naphthaldehyde 30 (0.75 g; 3.9 mmol) was
dissolved in 10 mL of acetone and treated with a solution of
KMnO4 (1.26 g) in 5 mL of water and 5 mL of acetone and
stirred at 40 °C for 6 h. Inorganic salts were removed by
filtration. The filtrate was concentrated, redissolved in DCM
(50 mL), and washed with water and brine. Concentration in
vacuo gave 0.4 g (∼50%) of 5,8-difluoro-1-naphthalenecarboxyl-
ic acid 6 as beige solid. mp: 260 °C (dec). CI MS (MH+): 209.
1H NMR (CDCl3): δ 7.2 (m, 2H), 7.65 (t, J ) 7 Hz, 1H), 7.85
(d, J ) 8 Hz, 1H) and 8.25 (d, J ) 9 Hz, 1H). Anal. Calcd for
1
as a white solid. mp: 80 °C. H NMR (CDCl3): δ 2.1-2.3 (m,
2H), 2.7 (t, J ) 8 Hz, 2H), 2.95 (t, J ) 7 Hz, 2H), 7.0 (m, 1H)
and 7.55 (d, J ) 9 Hz, 1H). Anal. Calcd for C10H8F2O: C, 65.93;
H, 4.43; F, 20.86. Found: C, 66.08; H, 4.41; F, 20.74.
5,7-Diflu or o-3,4-dih ydr o-1-n aph th alen ecar bon itr ile (25).
A solution of the above tetralone 23 (1.5 g; 8.24 mmol) in 15
mL of dry THF was stirred with lithium cyanide (0.81 g; 24.6
mmol) and diethyl cyanophosphonate (3.75 mL; 24.6 mmol)
for 10 min. Extractive workup in ethyl acetate gave ∼4 g of
red-brown oil. The cyanohydrin 24 obtained above was dis-
solved in benzene (25 mL) and stirred with boron trifluoride
etherate (3 mL; 24. 6 mmol) for 20 h. The mixture was diluted
with more benzene and the reaction mixture quenched with
water. The organic product was extracted with EtOAc and
washed with water and brine. Concentration gave ∼2 g of a
brown gum which was purified by FSGC (20-50% ether-
hexane) to yield 25 (1.47 g; 93%) as an off-white solid. mp: 68
°C. 1H NMR (CDCl3): δ 2.55 (m, 2H), 2.9 (t, J ) 8 Hz, 2H),
6.8 (dt, J ) 2, 10 Hz, 1H), 7.0 (s, 1H) and 7.0-7.1 (t, J ) 10
Hz, 1H). Anal. Calcd for C11H7F2N: C, 69.11; H, 3.69; N, 7.33;
F, 19.87. Found: C, 68.95; H, 3.58; N, 7.28; F, 19.83.
5,7-Diflu or o-1-n a p h th a len eca r bon itr ile (26). DDQ (2.04
g; 9 mmol) was added to a solution of 25 in chlorobenzene (30
mL), and the resulting red heterogeneous mixture was heated
at reflux for 16 h. TLC indicated a slightly less polar,
fluorescent spot. Unreacted DDQ was quenched with 3 mL of
cyclohexadiene. The resulting brown slurry was directly
subjected to FSGC (hexane then 5% ether-hexane) to give 1.25
g (89%) of the naphthonitrile 26 as fibrous white solid. mp:
106 °C. 1H NMR (CDCl3): δ 7.15 (dt, J ) 2, 10 Hz, 1H), 7.6 (t,
J ) 9 Hz, 1H), 7.75 (d, J ) 9 Hz, 1H), 8.0 (d, J ) 8 Hz, 1H)
and 8.35 (d, J ) 8 Hz, 1H). Anal. Calcd for C11H5F2N: C, 69.84;
H, 2.66; F, 20.09; N, 7. 41. Found: C, 69.74; H, 2.55; F, 20.24;
N, 7.46.
5,7-Diflu or o-1-n a p h th a len eca r boxylic Acid (5). The
naphthonitrile 26 (0.5 g; 2.65 mmol) was dissolved in 5 mL of
glacial acetic acid, 4 mL of concentrated sulfuric acid, and 2
mL of water and heated at reflux for 20 h. The heterogeneous
reaction mixture was cooled to room temperature and poured
into ice-water. Upon stirring vigorously, a precipitate formed
which was collected by filtration, washed with water until
clear, and dried in vacuo to leave 0.4 g (73%) of the desired
naphthoic acid 5 as beige solid. mp: 260 °C (dec). 1H NMR: δ
7.0 (dt, J ) 2, 10 Hz, 1H), 7.5 (t, J ) 9 Hz, 1H), 8.25 (d, J )
8 Hz, 1H), 8.4 (d, J ) 8 Hz, 1H) and 8.65 (d, J ) 10 Hz, 1H).
Anal. Calcd for C11H6F2O2: C, 63.47; H, 2.91; F, 18.25.
Found: C, 63.29; H, 2.95; F, 17.91.
C
11H6F2O2: C, 63.47; H, 2.91; F, 18.25. Found: C, 63.29; H,
3.32; F, 18.07.
2-(3,4-Diflu or op h en yl)p en t a n ed ioic Acid , 5-(1,1-Di-
m eth yleth yl)-1-eth yl Ester (32). 3,4-Difluorophenyl ethyl
acetate 31 (4 g; 20 mmol) prepared quantitatively from its
commercial acid was dissolved in 20 mL of tert-butyl alcohol
and treated with tert-butyl acrylate (2.5 mL) in a cold water
bath (5 °C). Oil-free sodium hydride (0.14 g) was added, and
the reaction mixture was stirred at 5 °C for 15 min and at
ambient temperature for 1.5 h. TLC (15% ether-hexane)
indicated the complete formation of a slightly more polar spot.
The reaction was quenched with 2 mL of acetic acid, and the
product was extracted with ether and washed with water, 10%
NaHCO3 solution, and brine. Concentration in vacuo gave 6.23
1
g (95%) of 32 as yellow oil. H NMR (CDCl3): δ 1.25 (t, J ) 6
Hz, 3H), 1.47 (s, 9H), 2.0 (m, 1H), 2.2 (t, J ) 7 Hz, 1H), 2.25-
2.4 (m, 1H), 3.6 (t, J ) 6 Hz, 1H), 4.15 (m, 2H), 7.0 (br-s, 1H)
and 7.05-7.2 (m, 2H). Anal. Calcd for C17H22F2O4: C, 62.18;
H, 6.75; F, 11.57. Found: C, 62.13; H, 6.76; F, 11.84.
6,7-Diflu or o-1, 2, 3, 4-tetr a h yd r o-4-oxo-1-n a p h th a len e-
ca r boxylic Acid , Eth yl Ester (33). Trifluoroacetic acid (10
mL) was added to a solution of the diester 32 (5 g; 15.24 mmol)
in 10 mL of DCM and stirred at ambient temperature for 1.5
h. The solvent and acid were removed on the rotary evaporator;
the residue was dissolved in DCM and washed with water and
brine. Concentration gave 3.9 g (95%) of the carboxylic acid
1
as a yellow gum. H NMR (CDCl3): δ 1.25 (t, J ) 6 Hz, 3H),
2.0-2.2 (m, 1H), 2.2-2.4 (m, 1H), 2.3-2.5 (m, 2H), 3.6 (t, J )
7 Hz, 1H), 4.15 (m, 2H), 6.95-7.05 (br-s, 1H) and 7.05-7.25
(m, 2H).
The glutaric acid monoester obtained above was dissolved
in DCM (20 mL) and treated with two drops of DMF and oxalyl
chloride (1.9 mL; 21.6 mmol). After stirring at ambient
temperature for 2 h, the solvent and unreacted acid chloride
were removed on the rotary evaporator. Traces of acidic vapors
were removed by further evaporating with ethyl acetate, and
the residue was dried under high vacuum.
Aluminum chloride (3.8 g; 28.67 mmol) was added to a
solution of the acid chloride prepared above in 50 mL of DCM
and stirred at ambient temperature for a day. The reaction
was quenched by slow addition of 2 N HCl solution and product
isolated by extractive workup in DCM. FSGC (10-20% ether
in hexane) served to purify the less polar tetralone 33 which
5,8-Diflu or o-1-n a p h th a len eca r bon itr ile (28). Commer-
cially available 2,5-difluoroacetophenone 27 (5.9 g; 37.82 mmol)
was alkylated with tert-butyl iodoacetate (10 g; 41.60 mmol)
and the resulting keto-ester reduced with sodium borohydride
to furnish tert-butyl 4-hydroxy-4 (2,5-difluorophenyl)butyrate
(50% overall) exactly as described for compound 21. This
material was processed as described above for target 26 to
obtain 1.1 g (22% overall yield) of 5,8-difluoro-1-naphthonitrile
(28) as a fibrous white solid. mp: 119 °C. 1H NMR: δ 7.25 (m,
2H), 7.7 (t, J ) 8 Hz, 1H), 8.05 (d, J ) 8 Hz, 1H) and 8.35 (d,
1
was isolated as an amber oil (2.43 g; 52%). H NMR (CDCl3):
δ 1.3 (t, J ) 6 Hz, 3H), 2.2-2.45 (m, 1H), 2.45-2.65 (m, 1H),
2.68 (t, J ) 4 Hz, 1H), 2.9 (dt, J ) 4, 14 Hz, 1H), 3.9 (t, J ) 5
Hz, 1H), 4.2 (q, J ) 6, 12 Hz, 2H), 7.1-7.25 (dd, J ) 8, 10 Hz,
1H), 7.87 (dd, J ) 8, 10 Hz, 1H). Anal. Calcd for C13H12F2O3:
C, 61.42; H, 4.76; F, 14.95. Found: C, 61.51; H, 4.76; F, 15.20.
6,7-Diflu or o-1, 2-dih ydr o-1-n aph th alen ecar boxylic Acid,
Eth yl Ester (35). Sodium borohydride (0.39 g; 10.3 mmol) in
5 mL of water was added to a solution of the tetralone 33 (2.43
g; 9.4 mmol) in 25 mL of THF and stirred at ambient
temperature for 5 h. The reaction was quenched with 2 N
hydrochloric acid and stirred for 20 min. Extractive workup
in DCM gave the 4-hydroxynaphthalene ester 34 (∼2:1 mix-
ture of epimers) as yellow oil (2.4 g; ∼100%). 1H NMR
J
C
) 10 Hz, 1H). CI MS (MH+): 190. Anal. Calcd for
11H5F2N: C, 69.84; H, 2.66; N, 7.41; F, 20.09. Found: C,
69.66; H, 2.51; N, 7.41; F, 20.05.
5,8-Diflu or o-1-n a ph th a len eca r boxylic Acid (6). Diisobu-
tylaluminum hydride (1 M in toluene; 6.4 mL) was added to a
solution of the nitrile 28 (1 g; 5.29 mmol) in toluene (10 mL)
at -78 °C, stirred for 2 h, and then allowed to warm to room
temperature. Excess DIBAL-H was destroyed by the addition

Synthesis of Mono- and Difluoronaphthoic Acids
J . Org. Chem., Vol. 67, No. 4, 2002 1177
(CDCl3): δ 1.3 (t, J ) 6 Hz, 3H), 1.8-1.95 (m, 1H), 1.95-2.15
(m, 2H), 2.2-2.4 (m, 1H), 3.7 (t, J ) 4 Hz, 1H), 3.75 (t, J ) 3
Hz, 0.5H), 4.2 (q, J ) 6, 9 Hz, 2H), 4.65 (t, J ) 5 Hz, 1H),
4.7(t, J ) 3 Hz, 0.5H), 7.05 (dd, J ) 6, 10 Hz, 1H) and 7.25-
7.45 (m, 1H).
The above sequence of reactions (Scheme 5) was also used
to convert 3,5-difluorophenyl acetic acid 36 to 5,7-difluoro-1-
naphthalenecarboxylic acid 5 (5-10 g).
1-(4,5-Diflu or o-1-n a p h th a len yl)eth a n on e (39). Commer-
cial 1,8-diaminonaphthalene was converted to 1,8- difluo-
ronaphthalene by the method of Mallory.11 To a mixture of
aluminum chloride (2.18 g; 16.39 mmol) and lithium chloride
(0.35 g) was added a solution of 1,8-difluoronaphthalene (0.9
g; 5.5 mmol) and acetyl chloride (0.4 mL; 5.6 mmol) in 15 mL
of 1,2-dichloroethane at -35 °C. After stirring for 1 h at low
temperature, the reaction mixture was allowed to warm to
room temperature and stirred for several hours. The reaction
was carefully quenched with 5% hydrochloric acid and ex-
tracted with ethyl acetate. The organic extract was washed
with water, 1 N sodium hydroxide, and brine and dried.
Concentration gave the naphthaleno-ketone 39 (1.04 g; 92%)
The hydroxy ester 34 was dissolved in dichloroethane (20
mL), treated with p-toluenesulfonic acid (0.1 g), and heated
at reflux for 1 h. The reaction mixture was cooled to room
temperature, diluted with DCM, and washed with water, 10%
NaHCO3 solution, and brine. Concentration and FSGC (10-
50% ether in hexane) afforded 35 (1.65 g; 74%) as colorless
1
oil. H NMR (CDCl3): δ 1.25 (t, J ) 7 Hz, 3H), 2.45-2.6 (m,
1H), 2.8-2.9 (two t, J ) 5 Hz, 1H), 3.7 (t, J ) 6 Hz, 1H), 4.15
(q, J ) 6, 12 Hz, 2H), 6.0 (m, 1H), 6.35 (d, 10 Hz, 1H), 6.85
(dd, J ) 7, 9 Hz, 1H) and 7.0 (dd, J ) 7, 9 Hz, 1H). Anal.
Calcd for C13H12F2O2: C, 60.93; H, 5.51; F, 14.83. Found: C,
60.81; H, 5.46; F, 14.58.
1
as a dark brown solid. H NMR (CDCl3): δ 2.75 (s, 3H), 7.1-
6,7-Diflu or o-1-n a p h th a len eca r boxylic Acid (7). DDQ
(1.83 g; 8.06 mmol) was added to a solution of the dihy-
dronaphthalene ester 35 (1.6 g; 6.72 mmol) in 15 mL of
chlorobenzene and heated at reflux for 20 h. Excess DDQ was
destroyed with 1,4-cyclohexadiene (5 mL) forming a turbid tan
solution. The turbid tan solution was directly subjected to
FSGC. Eluting with hexane removed chlorobenzene, and the
nonpolar product was isolated by eluting further with 10%
ether in hexane. Concentration gave 6,7-difluoro-1-ethylnaph-
thoate (1.49 g; 94%) as colorless film. 1H NMR (CDCl3): δ 1.48
(t, J ) 6 Hz, 3H), 4.5 (q, J ) 5, 8 Hz, 2H), 7.5 (t, J ) 6 Hz,
1H), 7.6 (dd, J ) 2, 9 Hz, 1H), 7.9 (d, J ) 8 Hz, 1H), 8.23 (d,
J ) 8 Hz, 1H) and 8.85 (dd, J ) 7, 10 Hz, 1H). FAB MS
(MH+): 237. Anal. Calcd for C13H10F2O2: C, 66.10; H, 4.27; F,
16.09. Found: C, 66.15; H, 4.15; F, 16.23.
The naphthalene ester (1.4 g; 5.93 mmol) was dissolved in
10 mL of ethanol. Aqueous potassium hydroxide solution (1
N; 10 mL) was added and heated at reflux for 8 h. The reaction
mixture was cooled to ambient temperature and carefully
quenched with 2 M hydrochloroic acid. The product was
extracted into DCM (50 mL) and washed with water and brine.
Concentration gave 1 g (81%) of 6,7-difluoro-1-naphthalen-
ecarboxylic acid (7) as a white solid. mp: 260 °C (dec). 1H NMR
(CDCl3): δ 7.5 (t, J ) 6 Hz, 1H), 7.6 (dd, J ) 2, 9 Hz, 1H), 7.9
(d, J ) 8 Hz, 1H), 8.3 (d, J ) 8 Hz, 1H) and 9.0 (dd, J ) 7, 10
Hz, 1H). Anal. Calcd for C11H6F2O2: C, 63.47; H, 2.91; F, 18.25.
Found: C, 63.66; H, 2.98; F, 18.49.
7.3 (m, 2H), 7.6 (dd, J ) 3, 8 Hz, 1H), 8.0 (t, J ) 3 Hz, 1H)
and 8.65 (d, J ) 7 Hz, 1H).
4,5-Diflu or o-1-n a p h th a len eca r boxylic Acid (8). A mix-
ture of 1-acetyl-4,5-difluoro naphthalene 39 (0.28 g; 1.36
mmol), 15 mL of commercial chlorox, and 0.15 g of NaOH was
refluxed for 1 h. The reaction mixture was cooled to room
temperature and filtered. To the filtrate 1 g of sodium
hydrogen sulfite was added, followed by 5% hydrochloric acid
until the pH was 1. The organic product was extracted with
ethyl acetate, washed with water and brine, and concentrated.
The 4,5-difluoro-1-naphthoic acid 8 was obtained as a white
1
solid (0.28 g, ∼100%). mp: 182 °C (dec). H NMR (CDCl3): δ
3.0 (br-s, 1H), 7.0-7.15 (m, 2H), 7.4-7.5 (dd, J ) 3, 8 Hz, 1H),
8.2 (t, J ) 3 Hz, 1H) and 8.8 (d, J ) 7 Hz, 1H). CI MS (MH+):
209. FAB MS: M+ ) 208. FAB HR MS calculated for
C
11H6F2O2 208.0336, found 208.0334.
Ack n ow led gm en t. We would like to thank the
physical and analytical chemistry department at SPRI
for spectral and analytical data on all new compounds.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra of
all the intermediates and the mono- and difluoro-1-naphtha-
lene carboxylic acids (1-8) described herein. This material is
available free of charge via the Internet at http://pubs.acs.org.
J O0160322