Heterosubstituted or functionalized derivatives of 1- and 2-(trifluoro-methyl)naphthalenes emanating from aryne adducts

Article abstract of DOI:10.1055/s-2005-861813

More than two dozen new CF₃-substituted naphthalene derivatives were prepared in an expedient way by employing 3- and 4-(trifluoromethyl)benzyne as the key intermediates. 2- and 4-Chlorobenzotrifluoride were treated with butyllithium and the organometallic species thus generated were allowed to decompose in the presence of furan. The resulting cycloadducts 1 and 14 were reduced to the (trifluoromethyl)naphthalenes 2 and 15, ring- opened to the (trifluoromethyl)naphthols 3,16 and 17 and transformed to the dibromo adducts 5 and 18. The latter were stereoselectively converted into the bromo-1,4-epoxy-1,4-dihydro(trifluoromethyl)naphthalenes 6,7,19 and 20 and, by deoxygenation, into various bromo(trifluoromethyl)naphthalenes 8, 9, 21 and 22. Trifluoromethyl substituted naphthoic acids 10-13 and 23-26 were obtained when the bromo compounds 6-9 and 19-22 were subjected to a halogen/metal permutation followed by carboxylation.

Full text of DOI:10.1055/s-2005-861813

PAPER
791
Heterosubstituted or Functionalized Derivatives of 1- and 2-(Trifluoro-
methyl)naphthalenes Emanating from Aryne Adducts
D
erivatives of
r
1- and
2
é
-(Trifluoro
d
é
Institut des Sciences Chimiques (ISIC-BCh), Ecole Polytechnique Fédérale, 1015 Lausanne, Switzerland
E-mail: manfred.schlosser@epfl.ch
Received 13 October 2004
OCF3
Abstract: More than two dozen new CF3-substituted naphthalene
Br
derivatives were prepared in an expedient way by employing 3- and
4-(trifluoromethyl)benzyne as the key intermediates. 2- and 4-Chlo-
OCF3
OCF3
OCF3
robenzotrifluoride were treated with butyllithium and the organo-
O
metallic species thus generated were allowed to decompose in the
presence of furan. The resulting cycloadducts 1 and 14 were re-
duced to the (trifluoromethyl)naphthalenes 2 and 15, ring-opened to
the (trifluoromethyl)naphthols 3, 16 and 17 and transformed to the
dibromo adducts 5 and 18. The latter were stereoselectively con-
verted into the bromo-1,4-epoxy-1,4-dihydro(trifluorometh-
yl)naphthalenes 6, 7, 19 and 20 and, by deoxygenation, into various
bromo(trifluoromethyl)naphthalenes 8, 9, 21 and 22. Trifluoro-
methyl substituted naphthoic acids 10–13 and 23–26 were obtained
when the bromo compounds 6–9 and 19–22 were subjected to a
halogen/metal permutation followed by carboxylation.
OCF3
Br
Br
OCF3
OCF3
OCF3
OCF3
O
Scheme 1
Key words : arynes, halogen–metal permutation, metalation, naph-
thoic acids, trifluoromethyl groups
drogen fluoride-pyridine.6 2-(Trifluoromethyl)naphtha-
lene was made by the coupling of 2-iodonaphthalene with
transiently formed trifluoromethylcopper.7,8
Introduction
The aryne route9,10 to naphthalenes has been inaugurated
by Wittig et al.11 who set free 1,2-didehydrobenzene
(‘benzyne’) from 1-bromo-2-fluorobenzene with magne-
sium to intercept it in situ with furan and to isomerize the
cycloadduct with acid to 1-naphthol. The practical poten-
tial of the Diels–Alder reaction with furans and congeners
was extensively explored with fluoro,12,13 difluoro,14–16
trifluoro,17–19 and tetrafluoro substituted benzynes.20–24 In
contrast, the intermediacy of a CF3 bearing aryne has so
far been exploited only in a single instance as an entry to
a regioisomeric mixture of triptycenes totaling a yield of
12%.25
Despite all recent progress,1 (trifluoromethoxy)arenes
have remained rare and unfamiliar. For example, until re-
cently, there was not a single OCF3-substituted naphtha-
lene reported in the literature. Meanwhile, we have
disclosed a convenient and expedient access to 1- and 2-
(trifluoromethoxy)naphthalene.2,3 The key step was the
lithium diisopropylamide (LIDA)-promoted generation of
1,2-didehydro-3- and 4-(trifluoromethoxy)benzene from
1-bromo-2- or 3-(trifluoromethoxy)benzene and 1-bro-
mo-4-(trifluoromethoxy)benzene and their trapping with
furan. The resulting Diels–Alder cycloadducts, 1,4-ep-
oxy-1,4-dihydro-5- and 6-(trifluoromethoxy)naphthalene,
were deoxygenated using activated zinc powder4
(Scheme 1).
1-(Trifluoromethyl)naphthalene and Congeners
We wondered whether 1- and 2-(trifluoromethyl)naphtha-
lene could be obtained in the same way with comparable
ease and efficiency. 1-(Trifluoromethyl)naphthalene has
previously been prepared by the acid-catalyzed cycliza-
tion and subsequent dehydrogenation of 3-phenylpropyl-
trifluoromethyl ketone,4 the condensation of 1-iodo-
naphthalene with in situ produced trifluoromethylcopper5
and by the treatment of methyl 1-naphthalenedithiocar-
boxylate with N-bromosuccinimide in the presence of hy-
Attempts to use bromobenzotrifluorides as starting mate-
rials gave inconsistent and mostly poor yields. Contrarily,
when 2-chlorobenzotrifluoride was treated with butyllith-
ium at –75 °C and the mixture was subsequently trans-
ferred into furan kept at ambient temperature,
reproducibly good yields (typically 76%) of 1,4-epoxy-
1,4-dihydro-5-(trifluoromethyl)naphthalene (1) were
achieved (Scheme 2).
SYNTHESIS 2005, No. 5, pp 0791–0797
x
x
.
x
x
.2
0
0
5
Advanced online publication: 09.02.2005
DOI: 10.1055/s-2005-861813; Art ID: T11704SS
© Georg Thieme Verlag Stuttgart · New York

792
F. Bailly et al.
PAPER
CF3
CF3
CF3
CF3
O
O
O
Br
Br
CF3
CF3
CF3
Cl
Cl
a
b
O
1
a
a
CF3
CF3
Li
5a
b
b
O
Scheme 2 Reagents and conditions: a. BuLi in THF at –75 °C for 1
h; b. Added to furan kept at +25 °C.
a
a
Br
Br
Br
Br
6
8
Br
Br
CF3
CF3
5b
5c
Br
The deoxygenation of the epoxynaphthalene (1) was ac-
complished with low-valent titanium to afford 1-(trifluo-
romethyl)naphthalene (2; 83%). The acid-catalyzed ring
opening occurred with amazingly high regioselectivity,
providing only 8-trifluoromethyl-1-naphthol (3; 81%) un-
contaminated by any detectable trace of the 5-isomer 4.
Addition of molecular bromine gave 2,3-dibromo-1,4-ep-
O
7
9
Br
Scheme 4 Reagents and conditions: a. t-BuOK in THF at 0 °C;
b. TiCl4 and Zn powder in THF.
oxy-1,4-dihydro-6-(trifluoromethyl)naphthalene
88%) (Scheme 3).
(5;
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
a
a
b
b
O
O
O
O
O
O
Br
Br
Li
Li
HOOC
HOOC
6
7
10
CF3
11
CF3
a
b
b
Br
Br
Li
Li
HOOC
HOOC
8
9
12
CF3
a
Scheme 3 Reagents and conditions: a. TiCl4 and Zn powder in
THF; b. Ethanolic HCl under reflux for 20 h; c. Br2 in CCl4.
13
Scheme 5 Reagents and conditions: a. BuLi in THF for 45 min;
b. 1. CO2, 2. HCl.
The dibromo compound 5 existed as an approximate 1:1:1
mixture of three stereoisomers, which could be separated
by a combination of column chromatography, preparative
gas chromatography and crystallization. Dehydrobromi-
nation with potassium tert-butoxide converted the 2-endo,
3-exo form 5a and the 2-exo,3-endo form 5c into 2- and 3-
bromo-1,4-epoxy-1,4-dihydro-5-(trifluoromethyl)naph-
thalene (6, 91% and 7, 89%), respectively, whereas the 2-
exo,3-exo form 5b provided an again chromatographically
separable 2:3 mixture (92%) of the isomers 6 and 7. The
epoxides 6 and 7 were deoxygenated to give 6- and 7-bro-
mo-1-(trifluoromethyl)naphthalene (8, 76% and 9, 69%),
respectively, using an in situ generated low-valent titani-
um salt (Scheme 4).
2-(Trifluoromethyl)naphthalene and Congeners
The reactions performed in the 2-trifluoromethyl series
mirrored closely the situation met with the 1-trifluoro-
methyl isomers. Cycloaddition of 1,2-didehydro-4-(tri-
fluoromethyl)benzene, set free from 4-chlorobenzotri-
fluoride, with furan produced the key intermediate 1,4-
epoxy-1,4-dihydro-6-(trifluoromethyl)naphthalene (14)
in excellent yield (75%) (Scheme 6).
The only difference in the behavior of the a-CF3 (see
above) and b-CF3 families was experienced with the acid-
When subjected to consecutive halogen/metal permuta-
tion, carboxylation and neutralization, the bromo-1,4-ep-
oxy compounds 6 and 7 afforded the epoxydihydronaph-
thoic acids (10 and 11; 87% and 72%). In the same way,
the bromo-1-(trifluoromethyl)naphthalenes 8 and 9 were
transformed into the 6- and 7-trifluoromethyl-2-naphthoic
acids (12 and 13; 80% and 81%), respectively
(Scheme 5).
Scheme 6 Reagents and conditions: a. BuLi in THF at –75 °C for 1
h; b. Added to furan kept at +25 °C.
Synthesis 2005, No. 5, 791–797 © Thieme Stuttgart · New York

PAPER
Derivatives of 1- and 2-(Trifluoromethyl)naphthalenes
793
catalyzed ring-opening of the cycloadduct 14 which this The (trifluoromethyl)naphthoic acids 23 (56%), 24
time did not furnish a single isomer but rather a 1:1 mix- (47%), 25 (71%) and 26 (68%), having or not an 1,4-ep-
ture (88%) of 7- and 6-trifluoromethyl-1-naphthols 16 and oxy bridge, were obtained by virtue of the same sequence
17. In contrast, the metal-mediated deoxygenation afford- described above. The heavy halogen in the intermediates
ing 2-(trifluoromethyl)naphthalene (15; 82%) and the re- 19–22 was replaced by lithium using butyllithium and the
action with bromine giving rise to the three stereoisomeric organometallic species thus generated were trapped with
adducts 18 (75%) approximately in a 1:1:1 ratio followed dry ice (Scheme 9).
the familiar pattern (Scheme 7).
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
a
a
b
O
O
O
O
O
O
Br
Br
Li
Li
HOOC
19
20
23
CF3
b HOOC
24
CF3
b
a
Br
Br
Li
Li
HOOC
21
22
25
CF3
b HOOC
a
Scheme 7 Reagents and conditions: a. TiCl4 and Zn powder in
THF; b. Ethanolic HCl under reflux for 20 h; c. Br2 in CCl4.
26
Scheme 9 Reagents and conditions: a. BuLi in THF for 45 min;
b. 1. CO2, 2. HCl.
The base-promoted b-elimination of hydrogen bromide
from the dibromo compounds 18 was presumably again
syn-stereoselective. However, the 1:1 mixture of the 2-en-
do,3-exo and the 2-exo,3-endo forms 18a and 18c proved
to be unseparable. Therefore, it was treated as such with
potassium tert-butoxide to afford a 1:1 mixture (91%) of
2-bromo-1,4-epoxy-1,4-dihydro-6- and 7-(trifluorometh-
yl)naphthalenes 19 and 20, respectively. Again a 1:1 mix-
ture (93%) of these isomers resulted when the 2-exo,3-exo
form 18b served as the substrate. 2-Bromo-6-(trifluoro-
methyl)naphthalene (21; 76%) and 2-bromo-7-(trifluoro-
methyl)naphthalene (22; 60%) were isolated after
reduction of the 1,4-epoxy compounds 19 and 20 with
low-valent titanium (Scheme 8).
Working practices and abbreviations are specified in previous arti-
cles from this laboratory.26–28 1H and (1H-decoupled) 13C NMR
spectra were recorded at 400 and 101 MHz, respectively, relative to
the internal standard tetramethylsilane (chemical shift d = 0.00
ppm). The samples were dissolved in CDCl3 or, if marked by an as-
terisk, in DMSO-d6.
1,4-Epoxy-1,4-dihydro(trifluoromethyl)naphthalenes
1,4-Epoxy-1,4-dihydro-5-(trifluoromethyl)naphthalene (1)
At –75 °C, BuLi (0.30 mol) in hexanes (0.14 L) was added to 2-
chlorobenzotrifluoride (40 mL, 54 g, 0.30 mol) in THF (0.46 L)
over a period of 1 h. The mixture was kept 1 h at –75 °C before be-
ing transferred through teflon tubing into a flask containing furan
(0.22 L, 0.20 kg, 3.0 mol) at 25 °C. The residue left after evapora-
tion of the solvents was suspended in Et2O (0.10 L) and filtered
through a pad of basic alumina (0.40 kg), which was rinsed with
Et2O (0.30 L). After evaporation of the solvents and upon distilla-
tion of the residue, a colorless liquid was collected; yield: 48.4 g
(76%); bp 40–41 °C/0.75 Torr; nD20 1.4903.
1H NMR: d = 7.38 (d, J = 7.0 Hz, 1 H), 7.17 (d, J = 8.0 Hz, 1 H), 7.1
(m, 3 H), 6.00 (s, 1 H), 5.77 (s, 1 H).
13C NMR: d = 150.6, 148.1, 143.7, 142.5, 125.7, 125.5 (q, J = 34
Hz), 124.3 (q, J = 273 Hz), 123.1, 121.1 (q, J = 4 Hz), 82.0, 81.6.
O
Br
CF3
a
Br
18a
CF3
CF3
b
b
O
a
O
Br
Br
Br
Br
19
21
22
Br
Br
CF3
a
18b
Br
CF3
CF3
O
a
O
20
Anal. Calcd for C11H7F3O (212.17): C, 62.27; H, 3.33. Found: C,
61.95; H, 3.71.
CF3
Br
18c
1,4-Epoxy-1,4-dihydro-6-(trifluoromethyl)naphthalene (14)
In the same way, 4-chlorobenzotrifluoride (40 mL, 54 g, 0.30 mol)
gave the isomer 14 as a colorless liquid; yield: 47.7 g (75%); bp 56–
58 °C/0.35 Torr; nD20 1.4930.
Scheme 8 Reagents and conditions: a. t-BuOK in THF at 0 °C; b.
TiCl4 and Zn powder in THF.
Synthesis 2005, No. 5, 791–797 © Thieme Stuttgart · New York

794
F. Bailly et al.
PAPER
1H NMR: d = 7.46 (s, 1 H), 7.33 (d, J = 7.6 Hz, 1 H), 7.29 (d, J = 8.2
Hz, 1 H), 7.06 (dd, J = 3.8, 1.6 Hz, 1 H), 7.04 (dd, J = 5.5, 1.8 Hz,
1 H), 5.76 (s, 2 H).
1H NMR: d = 8.31 (d, J = 8.8 Hz, 1 H), 8.11 (s, 1 H), 7.62 (dd,
J = 8.8, 1.8 Hz, 1 H), 7.52 (d, J = 8.3 Hz, 1 H), 7.40 (t, J = 7.6 Hz,
1 H), 6.92 (dd, J = 7.2, 1.2 Hz, 1 H), 5.34 (s, 1 H).
13C NMR: d = 153.9, 150.3, 143.0, 142.6, 127.6 (q, J = 34 Hz),
124.3 (q, J = 273 Hz), 122.9 (q, J = 4 Hz), 119.9, 116.8 (q, J = 4
Hz), 82.0 (2 C).
13C NMR: d = 151.3, 133.6, 128.3 (q, J = 32 Hz), 127.3, 125.5,
125.3 (q, J = 4 Hz), 124.1 (q, J = 273 Hz), 123.1, 121.5, 120.8 (q,
J = 3 Hz), 110.6.
Anal. Calcd for C11H7F3O (212.17): C, 62.27; H, 3.33. Found: C,
62.16; H, 3.73.
Anal. Calcd for C11H7F3O (212.17): C, 62.27; H, 3.33. Found: C,
62.26; H, 3.27.
Isomer 17
(Trifluoromethyl)naphthalenes
1H NMR: d = 8.54 (s, 1 H), 7.89 (d, J = 8.6 Hz, 1 H), 7.61 (dd,
J = 9.0, 1.8 Hz, 1 H), 7.47 (d, J = 8.3 Hz, 1 H), 7.39 (d, J = 8.3 Hz,
1 H), 6.89 (dd, J = 7.3, 1.0 Hz, 1 H), 5.32 (s, 1 H).
1-(Trifluoromethyl)naphthalene (2)
TiCl4 (8.2 mL, 14 g, 75 mmol) was added in the course of 15 min to
an ice cold suspension of Zn dust (9.8 g, 0.15 mol) in THF (0.13 L).
The mixture was heated under reflux for 15 min, cooled to 0 °C, and
treated with a solution of 1,4-epoxy-1,4-dihydro-5-(trifluorometh-
yl)naphthalene (1; 3.2 g, 15 mmol) in THF (25 mL). The mixture
was kept under reflux for 2 h and poured into 10% HCl (0.10 L) and
extracted with CH2Cl2 (0.20 L). The organic layer was washed with
H2O (0.10 L) and dried. After evaporation of the solvents and upon
distillation of the residue a colorless liquid was collected; yield:
2.44 g (83%); bp 73–75 °C/3 Torr (Lit.8 bp 202–206 °C/760 Torr).
Anal. Calcd for C11H7F3O (212.17): C, 62.27; H, 3.33. Found: C,
62.36; H, 3.31.
2,3-Dibromo-1,4-epoxy-1,4-dihydro(trifluoromethyl)naphtha-
lenes
2,3-Dibromo-1,4-epoxy-1,2,3,4-tetrahydro-5-(trifluorometh-
yl)naphthalene (5)
A solution of 1,4-epoxy-1,4-dihydro-5-(trifluoromethyl)naphtha-
lene (1; 16 g, 75 mmol) in CCl4 (0.10 L) was gently heated to reflux
while Br2 (3.9 mL, 12 g, 75 mmol) in CCl4 (25 mL) was added drop-
wise in the course of 5 min. The heating was continued for 10 min.
According to GC [30 m, DB-WAX, 100 °C (15 min), 100 → 200 °C
(25 °C/min), 200 °C; 30 m, DB-23, 100 °C (15 min), 100 → 200 °C
(25 °C/min), 200 °C], a 7:6:7 mixture of three isomers was present.
Elution from silica gel (0.75 kg) with a 3:7 mixture of CH2Cl2 and
hexanes gave two fractions. The first one (15.6 g, 56%) contained
2-endo,3-exo-5 (5a) and 2-exo,3-endo-5 (5c) in approximately
equal amounts. The isomeric mixture was separated by preparative
GC (3 m, 10% SE-30, 200 °C). A third isomer, 2-exo,3-exo-5 (5b),
was found in the second fraction (8.93 g, 32%) and was purified by
crystallization from hexanes as colorless platelets. The structure as-
signment of the three stereoisomers is based on the constitution and
composition of the dehydrobromination products obtained after
treatment with t-BuOK (see below).
For 1H NMR spectrum, see ref.8
2-(Trifluoromethyl)naphthalene (15)
Prepared analogously starting from 1,4-epoxy-1,4-dihydro-6-(tri-
fluoromethyl)naphthalene (14; 3.2 g, 15 mmol); bp 69–71 °C/2
Torr; yield: 2.41 g (82%); mp 64–65 °C (Lit.8 mp 63–64 °C).
For 1H NMR spectrum, see ref.8
(Trifluoromethyl)naphthols
8-(Trifluoromethyl)-1-naphthol (3)
1,4-Epoxy-1,4-dihydro-5-(trifluoromethyl)naphthalene (1; 5.3 g,
25 mmol) was dissolved in an ethanolic solution (25 mL) of HCl
(0.25 mol). After heating under reflux for 20 h, the mixture was
evaporated to dryness and the residue crystallized from pentanes as
colorless needles; yield: 4.29 g (81%); mp 94–96 °C (Lit.29 mp
97 °C).
Stereoisomer 5a
Mp 61–63 °C.
1H NMR: d = 7.99 (d, J = 8.3 Hz, 1 H), 7.96 (d, J = 7.4 Hz, 1 H),
7.53 (dd, J = 8.1, 1.1 Hz, 1 H), 7.47 (t, J = 8.2 Hz, 1 H), 7.41 (t,
J = 7.7 Hz, 1 H), 7.01 (dd, J = 7.5, 1.2 Hz, 1 H), 5.47 (s, 1 H).
13C NMR: d = 150.4, 136.3, 133.4, 126.9, 126.2 (q, J = 8 Hz), 125.1
(q, J = 273 Hz), 124.4, 123.9 (q, J = 32 Hz), 122.3, 120.1, 113.9.
1H NMR: d = 7.59 (d, J = 7.3 Hz, 1 H), 7.52 (d, J = 7.8 Hz, 1 H),
7.46 (t, J = 7.6 Hz, 1 H), 5.71 (s, 1 H), 5.51 (d, J = 4.7 Hz, 1 H), 4.55
(dd, J = 4.7, 2.0 Hz, 1 H), 3.77 (d, J = 2.6 Hz, 1 H).
13C NMR: d = 143.0, 139.5, 128.3, 126.6, 125.5 (q, J = 4 Hz), 123.5
(q, J = 34 Hz), 123.4 (q, J = 273 Hz), 86.1, 82.8, 51.5, 50.1.
Anal. Calcd for C11H7F3O (212.17): C, 62.27; H, 3.33. Found: C,
62.18; H, 3.24.
Anal. Calcd for C11H7Br2F3O (371.98): C, 35.52; H, 1.90. Found: C,
35.55; H, 2.12.
1
The isomer 4 was not detectable by H NMR and gas chromato-
graphic analysis (DB-1, DB-1701, DB-210, DB-WAX, OV-17 2%,
FFAP 2%).
Stereoisomer 5b
Mp 121–123 °C.
1H NMR: d = 7.56 (d, J = 7.3 Hz, 1 H), 7.49 (d, J = 8.1 Hz, 1 H),
7.42 (t, J = 7.9 Hz, 1 H), 5.77 (s, 1 H), 5.69 (s, 1 H), 4.23 (d, J = 6.7
Hz, 1 H), 4.20 (d, J = 6.7 Hz, 1 H).
13C NMR: d = 144.2, 140.7, 129.1, 124.7 (q, J = 4 Hz), 124.0 (q,
J = 34 Hz), 123.8, 123.4 (q, J = 273 Hz), 87.4, 86.8, 51.2, 50.2.
6-(Trifluoromethyl)-1-naphthol (16) and 7-(Trifluoromethyl)-
1-naphthol (17)
These compounds were obtained as a 1:1 regioisomeric mixture (30
m, DB-1, 125 °C) when an analogous reaction was carried out start-
ing from 1,4-epoxy-1,4-dihydro-6-(trifluoromethyl)naphthalene
(14; 5.3 g, 25 mmol); yield: 4.66 g (88%). The isomer 16 was iso-
lated by fractional crystallization from pentanes as colorless nee-
dles. The regioisomer 17, left after evaporation of the mother
liquors remained contaminated with isomer 16.
Anal. Calcd for C11H7Br2F3O (371.98): C, 35.52; H, 1.90. Found: C,
35.53; H, 2.16.
Stereoisomer 5c
Mp 101–103 °C.
Isomer 16
1H NMR: d = 7.55 (t, J = 7.0 Hz, 2 H), 7.44 (dd, J = 8.0, 7.2 Hz, 1
H), 5.80 (d, J = 4.5 Hz, 1 H), 5.50 (s, 1 H), 4.53 (dd, J = 4.7, 2.5 Hz,
1 H), 3.84 (d, J = 2.4 Hz, 1 H).
Mp 93–95 °C (Lit.29 mp 95 °C).
Synthesis 2005, No. 5, 791–797 © Thieme Stuttgart · New York

PAPER
Derivatives of 1- and 2-(Trifluoromethyl)naphthalenes
795
13C NMR: d = 142.9, 139.5, 129.5, 126.3 (q, J = 32 Hz), 125.0 (q,
J = 4 Hz), 123.5 (q, J = 273 Hz), 123.4, 86.5, 82.5, 52.4, 49.3.
afforded a 2:3 mixture of the elimination products 6 and 7 which
were separated by elution from silica gel (0.20 kg) with a 1:10 mix-
ture of EtOAc and hexanes; total yield: 6.69 g (92%).
Anal. Calcd for C11H7Br2F3O (371.98): C, 35.52; H, 1.90. Found: C,
35.55; H, 2.14.
2-Bromo- and 3-Bromo-1,4-epoxy-1,4-dihydro-6-(trifluoro-
methyl)naphthalenes (19 and 20)
2,3-Dibromo-1,4-epoxy-1,2,3,4-tetrahydro-6-(trifluorometh-
yl)naphthalene (18)
When a 1:1 mixture of compounds 18a and 18c (9.3 g, 25 mmol)
was subjected to the same treatment with t-BuOK as described for
the conversion of the dibromo compound 5a into the elimination
product 6, a 1:1 mixture of the regioisomers 19 and 20, both light
and temperature sensitive, was formed. They were separated by elu-
tion from a column filled with silica gel (0.20 kg) using a 1:10 mix-
ture of EtOAc and hexanes.
The analogous bromination of 1,4-epoxy-1,2,3,4-tetrahydro-6-(tri-
fluoromethyl)naphthalene (14; 16 g, 75 mmol) gave a mixture 7:7:6
of three products [30 m, DB-WAX, 200 °C, 30 m, DB-1, 200 °C (8
min), 200 → 250 °C (25 °C/min), 250 °C]. Elution with a 1:4 mix-
ture of CH2Cl2 and hexanes from silica gel (0.75 kg) gave two frac-
tions. The first one (13.8 g, 49%) contained conjointly 2-endo,3-
exo-18 and 2-exo,3-endo-18 (18a and 18c). The third isomer 2-
exo,3-exo-18 (18b) was isolated from the second fraction (7.25 g,
26%) by crystallization from hexanes as colorless needles.
Regioisomer 19
Yield: 3.42 g (47%).
1H NMR: d = 7.46 (d, J = 8.1 Hz, 2 H), 7.35 (d, J = 7.5 Hz, 1 H),
6.97 (d, J = 2.2 Hz, 1 H), 5.79 (sym. m, 1 H), 5.51 (s, 1 H).
Stereoisomers 18a and 18c
Anal. Calcd for C11H7Br2F3O (371.98): C, 35.52; H, 1.90. Found: C,
35.43; H, 2.11.
Regioisomer 20
Yield: 3.20 g (44%).
1H NMR: d = 7.59 (s, 1 H), 7.37 (d, J = 7.5 Hz, 1 H), 7.34 (d, J = 7.5
Hz, 1 H), 6.95 (d, J = 2.0 Hz, 1 H), 5.78 (s, 1 H), 5.51 (s, 2 H).
Stereoisomer 18b
Mp 107–109 °C.
1H NMR: d = 7.61 (s, 1 H), 7.57 (d, J = 7.7 Hz, 1 H), 7.52 (d, J = 7.7
Hz, 1 H), 5.57 (s, 2 H), 4.25 (d, J = 6.7 Hz, 1 H), 4.21 (d, J = 6.7 Hz,
1 H).
13C NMR: d = 146.4, 143.6, 130.8 (q, J = 33 Hz), 125.9 (q, J = 4
Hz), 123.7 (q, J = 273 Hz), 120.9, 117.7 (q, J = 4 Hz), 87.5, 87.4,
51.1, 51.0.
When treated with t-BuOK (2.8 g, 25 mmol) under the same condi-
tions, the stereoisomer 18b of the dibromo compound (9.3 g, 25
mmol) afforded again a 1:1 mixture of the elimination products 19
and 20 in a total yield of 6.76 g (93%).
The structure assignment of compound 19 and 20 was based on 2D-
NMR experiments (COSY and NOESY) of compound 21 obtained
from compound 19 by reduction with low-valent titanium (see be-
low).
Anal. Calcd for C11H7Br2F3O (371.98): C, 35.52; H, 1.90. Found: C,
35.57; H, 2.08.
Bromo-1,4-epoxy-1,4-dihydro(trifluoromethyl)naphthalenes
Bromo(trifluoromethyl)naphthalenes
2-Bromo-1,4-epoxy-1,4-dihydro-5-(trifluoromethyl)naphtha-
lene (6)
2-Bromo-5-(trifluoromethyl)naphthalene (8)
TiCl4 (8.2 mL, 14 g, 75 mmol) was added during 15 min to an ice-
cold suspension of Zn dust (9.8 g, 0.15 mol) in THF (125 mL). The
mixture was heated under reflux for 15 min, cooled to 0 °C and
treated with a solution of 2-bromo-1,4-epoxy-1,4-dihydro-5-(triflu-
oromethyl)naphthalene (6; 4.4 g, 15 mmol) in THF (25 mL). The
mixture was kept under reflux for 2 h before being poured into 10%
HCl (0.10 L) and extracted with CH2Cl2 (0.20 L). The organic layer
was washed with H2O (0.10 L) and dried. After evaporation of the
solvents and upon distillation of the residue a colorless liquid was
collected. When stored in a freezer (–20 °C) overnight, the product
crystallized; yield: 3.14 g (76%); mp 31–33 °C; bp 74–76 °C/1.5
Torr.
Compound 5a (3.7 g, 10 mmol) was allowed to react with t-BuOK
(1.1 g, 10 mmol) during 15 min at 0 °C in THF (50 mL). H2O (50
mL) was added and the reaction mixture was extracted with EtOAc
(50 mL). The organic layer was washed with brine (50 mL), dried
and evaporated. The residue was crystallized from hexanes to afford
colorless needles; yield: 2.65 g (91%); mp 67–69 °C.
1H NMR: d = 7.52 (d, J = 7.1 Hz, 1 H), 7.26 (d, J = 7.8 Hz, 1 H),
7.15 (t, J = 7.2 Hz, 1 H), 6.94 (d, J = 2.0 Hz, 1 H), 6.01 (s, 1 H), 5.51
(s, 1 H).
13C NMR: d = 148.5, 146.4, 139.0, 137.4, 126.0, 123.9 (q, J = 274
Hz), 123.8 (q, J = 33Hz), 123.7, 122.1 (q, J = 4 Hz), 86.6, 83.5.
1H NMR: d = 8.07 (d, J = 2.1 Hz, 1 H), 8.04 (dd, J = 9.2, 2.2 Hz, 1
H), 7.90 (t, J = 8.3 Hz, 1 H), 7.86 (d, J = 7.3 Hz, 1 H), 7.68 (dd,
J = 9.1, 2.2 Hz, 1 H), 7.52 (t, J = 7.5 Hz, 1 H).
Anal. Calcd for C11H6BrF3O (291.07): C, 45.39; H, 2.08. Found: C,
45.31; H, 2.10.
13C NMR: d = 134.9, 131.6, 130.9, 130.7, 127.3, 126.6 (q, J = 30
Hz), 125.9, 125.3, 124.9 (q, J = 6 Hz), 124.4 (q, J = 274 Hz), 120.8.
The regiochemical identity of the dehydrobromination product 6
followed from 2D-NMR experiments. The hydrogen at the 1-posi-
tion (signal at d = 5.51), readily identified by its nuclear Overhauser
interaction (NOESY) with the hydrogen at the 8-position (signal at
d = 7.52), has no hydrogen neighbor at the vicinal 2-position
(COSY).
Anal. Calcd for C11H6BrF3 (275.07): C, 48.03; H, 2.20. Found: C,
48.07; H, 2.27.
7-Bromo-1-(trifluoromethyl)naphthalene (9)
Prepared from 2-bromo-1,4-epoxy-1,4-dihydro-8-(trifluorometh-
yl)naphthalene (7; 4.4 g, 15 mmol) analogously as described above
for 6-bromo-1-(trifluoromethyl)naphthalene (8); yield: 2.85 g
(69%); mp 51–53 °C; bp 60–62 °C/0.5 Torr.
1H NMR: d = 8.33 (s, 1 H), 7.98 (d, J = 8.3 Hz, 1 H), 7.88 (d, J = 7.3
Hz, 1 H), 7.75 (d, J = 8.8 Hz, 1 H), 7.66 (dd, J = 8.8, 1.8 Hz, 1 H),
7.52 (t, J = 8.1 Hz, 1 H).
3-Bromo-1,4-epoxy-1,4-dihydro-5-(trifluoromethyl)naphtha-
lene (7)
An analogous reaction of compound 5c (3.7 g, 10 mmol) gave the
unstable regioisomer 7; yield: 2.59 g (89%).
1H NMR: d = 7.87 (d, J = 8.4 Hz, 1 H), 7.67 (d, J = 9.6 Hz, 1 H),
7.59 (t, J = 9.5 Hz, 1 H), 7.38 (d, J = 2.5 Hz, 1 H), 6.0 (m, 2 H).
The stereoisomer 5b of the dibromo compound (9.3 g, 25 mmol)
treated with t-BuOK (2.8 g, 25 mmol) under the same conditions,
Synthesis 2005, No. 5, 791–797 © Thieme Stuttgart · New York

796
F. Bailly et al.
PAPER
1,4-Epoxy-1,4-dihydro-8-trifluoromethyl-2-naphthoic Acid
13C NMR: d = 132.6, 132.2, 130.2, 130.1, 129.8, 126.6, 125.6 (q,
J = 5 Hz), 125.1 (q, J = 16 Hz), 124.6, 124.0 (q, J = 273 Hz), 122.3.
(11)
Prepared from 2-bromo-1,4-epoxy-1,4-dihydro-8-(trifluorometh-
yl)naphthalene (7; 1.5 g, 5.0 mmol) analogously as described above
for 1,4-epoxy-1,4-dihydro-5-trifluoromethyl-2-naphthoic acid (10)
as colorless needles; yield: 0.92 g (72%); mp 167–169 °C (dec.).
1H NMR: d = 7.93 (t, J = 7.5 Hz, 1 H), 7.46 (d, J = 7.3 Hz, 1 H),
7.27 (d, J = 7.5 Hz, 1 H), 7.19 (t, J = 7.5 Hz, 1 H), 6.24 (s, 1 H), 5.93
(dd, J = 2.1, 1.1 Hz, 1 H).
13C NMR: d = 166.6, 155.6, 148.5, 148.0, 146.3, 126.5, 124.8 (q,
J = 34 Hz), 124.0, 122.7 (q, J = 274 Hz), 122.4 (q, J = 4 Hz), 83.1,
81.0 (q, J = 2 Hz).
Anal. Calcd for C11H6BrF3 (275.07): C, 48.03;, H, 2.20. Found: C,
48.18; H, 2.30.
2-Bromo-6-(trifluoromethyl)naphthalene (21)
Prepared from 2-bromo-1,4-epoxy-1,4-dihydro-6-(trifluorometh-
yl)naphthalene (19; 2.9 g, 10 mmol) analogously as described above
for 6-bromo-1-(trifluoromethyl)naphthalene (8) with the exception
that compound 21 proved to be too unstable for distillation. Instead,
it was filtered through a pad of silica gel (0.10 kg), which was rinsed
with hexanes (0.20 L). Evaporation of the solvents afforded a color-
less liquid, which crystallized; yield: 2.09 g (76%); mp 62–64 °C.
1H NMR: d = 8.12 (s, 1 H), 8.07 (d, J = 1.7 Hz, 1 H), 7.86 (t, J = 8.7
Hz, 1 H), 7.80 (d, J = 8.8 Hz, 1 H), 7.67 (dd, J = 8.6, 1.8 Hz, 1 H),
7.66 (dd, J = 8.7, 2.0 Hz, 1 H).
Anal. Calcd for C12H7F3O3 (256.18): C, 56.26; H, 2.75. Found: C,
56.04; H, 2.71.
1,4-Epoxy-1,4-dihydro-6-trifluoromethyl-2-naphthoic Acid
(23)
Pepared from 2-bromo-1,4-epoxy-1,4-dihydro-6-(trifluorometh-
yl)naphthalene (20; 1.5 g, 5.0 mmol) analogously as described
above for 1,4-epoxy-1,4-dihydro-5-trifluoromethyl-2-naphthoic
acid (10); yield: 0.72 g (56%).
13C NMR: d = 135.5, 130.7, 130.6, 130.3, 130.0, 128.2 (q, J = 34
Hz), 128.1, 125.7 (q, J = 4 Hz), 124.2 (q, J = 273 Hz), 122.6, 122.4.
Anal. Calcd for C11H6BrF3 (275.07): C, 48.03; H, 2.20. Found: C,
48.24; H, 2.21.
The structure assignment was based on a COSY spectrum, which
revealed the absence of vicinal hydrogen neighbors to both hydro-
gens at the 1- and 5-position (d = 8.12, 8.07).
1H NMR: d = 7.62 (s, 1 H), 7.37 (d, J = 7.3 Hz, 1 H), 7.34 (d, J = 7.5
Hz, 1 H), 6.96 (t, J = 1.9 Hz, 1 H), 5.79 (s, 1 H), 5.50 (s, 1 H).
For obvious reasons, the product 23, like its isomer 24 too, was ther-
mally very labile and therefore did not survive attempts to sublime
it or to purify it elsewise.
2-Bromo-7-(trifluoromethyl)naphthalene (22)
Prepared from 3-bromo-1,4-epoxy-1,4-dihydro-8-(trifluorometh-
yl)naphthalene (20; 2.9 g, 10 mmol) analogously as described above
for 6-bromo-2-(trifluoromethyl)naphthalene (21); yield: 1.65 g
(60%); mp 40–42 °C;.
1,4-Epoxy-1,4-dihydro-7-trifluoromethyl-2-naphthoic Acid
(24)
Prepared from 2-bromo-1,4-epoxy-1,4-dihydro-7-(trifluorometh-
yl)naphthalene (21; 1.5 g, 5.0 mmol) analogously as described
above for 1,4-epoxy-1,4-dihydro-5-trifluoromethyl-2-naphthoic
acid (10); yield: 0.60 g (47%).
1H NMR: d = 7.87 (d, J = 1.9 Hz, 1 H), 7.61 (s, 1 H), 7.41 (d, J = 7.5
Hz, 1 H), 7.35 (d, J = 7.4 Hz, 1 H), 5.95 (s, 1 H), 5.92 (s, 1 H).
1H NMR: d = 8.10 (d, J = 1.7 Hz, 1 H), 8.06 (s, 1 H), 7.93 (d, J = 8.6
Hz, 1 H), 7.78 (d, J = 8.8 Hz, 1 H), 7.68 (dd, J = 9.0, 1.9 Hz, 1 H),
7.66 (dd, J = 9.2, 1.8 Hz, 1 H).
13C NMR: d = 133.2, 132.9, 131.5, 130.8, 129.4, 129.0, 128.8 (q,
J = 34 Hz), 124.7 (q, J = 4 Hz), 124.3 (q, J = 273 Hz), 121.9 (q,
J = 3 Hz), 121.3.
Anal. Calcd for C11H6BrF3 (275.07): C, 48.03; H, 2.20. Found: C,
48.32; H, 2.18.
(Trifluoromethyl)naphthoic Acids
5-Trifluoromethyl-2-naphthoic Acid (12)
1,4-Epoxy-1,4-dihydro(trifluoromethyl)naphthoic Acids
Prepared from 6-bromo-1-(trifluoromethyl)naphthalene (7; 1.4 g,
5.0 mmol) analogously as described above for 1,4-epoxy-1,4-dihy-
dro-5-trifluoromethyl-2-naphthoic acid (10); yield: 0.96 g (80%);
colorless needles (from toluene); mp 193–195 °C.
1,4-Epoxy-1,4-dihydro-5-trifluoromethyl-2-naphthoic Acid
(10)
Freshly prepared 2-bromo-1,4-epoxy-1,4-dihydro-5-(trifluoro-
methyl)naphthalene (6; 1.5 g, 5.0 mmol) in THF (50 mL) was added
to a solution of BuLi (5.0 mmol) in hexanes (2.5 mL) kept in a
MeOH/dry ice bath. After 45 min at –75 °C, the mixture was poured
onto an excess of freshly crushed dry ice. The solvents were evapo-
rated and the residue was partitioned between 1.0 M aq solution of
NaOH (25 mL) and Et2O (25 mL). The aqueous layer was acidified
to pH 1 and extracted with Et2O (3 × 25 mL). The combined organic
layers were dried and evaporated. The residue crystallized from tol-
uene as colorless needles; yield: 1.11 g (87%); mp 146–148 °C
(dec.).
1H NMR: d = 7.86 (d, J = 2.0 Hz, 1 H), 7.55 (d, J = 7.0 Hz, 1 H),
7.25 (s, 1 H), 7.17 (t, J = 7.3 Hz, 1 H), 6.15 (s, 1 H), 5.95 (s, 1 H).
13C NMR: d = 168.0, 154.5, 149.4, 149.2, 145.2 (q, J = 3 Hz),
126.7, 126.6 (q, J = 33 Hz), 123.9, 123.5 (q, J = 274 Hz), 122.0 (q,
J = 4 Hz), 82.9, 81.6.
1H NMR: d = 8.81 (s, 1 H), 8.44 (d, J = 8.3 Hz, 1 H), 8.28 (s, 2 H),
8.14 (d, J = 7.3 Hz, 1 H), 7.78 (t, J = 8.2 Hz, 1 H).
13C NMR: d = 167.2, 135.5, 134.3, 132.6, 131.6, 129.7, 128.3,
128.0 (q, J = 6 Hz), 126.4, 126.3 (q, J = 30 Hz), 125.7 (q, J = 273
Hz), 125.0.
Anal. Calcd for C12H7F3O2 (240.18): C, 60.01; H, 2.94. Found: C,
59.78; H, 2.91.
8-Trifluoromethyl-2-naphthoic Acid (13)
Prepared from 7-bromo-1-(trifluoromethyl)naphthalene (8; 1.4 g,
5.0 mmol) analogously as described above for 1,4-epoxy-1,4-dihy-
dro-5-trifluoromethyl-2-naphthoic acid (10); yield: 0.97 g (81%);
colorless needles (from toluene); mp 231–233 °C.
1H NMR: d = 8.96 (s, 1 H), 8.33 (d, J = 8.3 Hz, 1 H), 8.3 (m, 2 H),
8.10 (d, J = 7.3 Hz, 1 H), 7.81 (t, J = 7.5 Hz, 1 H).
Anal. Calcd for C12H7F3O3 (256.18): C, 56.26; H, 2.75. Found: C,
56.17; H, 2.81.
13C NMR: d = 167.3, 137.0, 134.1, 130.6, 130.4, 128.7, 127.5,
127.3, 127.2, 126.8 (q, J = 6 Hz), 125.7 (q, J = 273 Hz).
Anal. Calcd for C12H7F3O2 (240.18): C, 60.01; H, 2.94. Found: C,
59.65; H, 3.18.
Synthesis 2005, No. 5, 791–797 © Thieme Stuttgart · New York

PAPER
Derivatives of 1- and 2-(Trifluoromethyl)naphthalenes
797
6-Trifluoromethyl-2-naphthoic Acid (25)
(4) Bonnet-Delpon, D.; Charpentier-Morize, M.; Jacquot, R. J.
Org. Chem. 1988, 53, 759.
(5) Long, Z.-Y.; Duan, J.-X.; Lin, Y.-B.; Guo, C.-Y.; Chen,
Q.-Y. J. Fluorine Chem. 1996, 78, 177.
(6) Kuroboshi, M.; Hiyama, T. Chem. Lett. 1992, 827.
(7) Urata, H.; Fuchikami, T. Tetrahedron Lett. 1991, 32, 91.
(8) Le, V. P.; Wells, P. R. Austr. J. Chem. 1992, 45, 1057.
(9) Heaney, H. Chem. Rev. 1962, 62, 81.
(10) Pellissier, H.; Santelli, M. Tetrahedron 2003, 59, 701.
(11) Wittig, G.; Pohmer, L. Chem. Ber. 1956, 89, 1334.
(12) Gribble, G. W.; Kelly, W. J. Tetrahedron Lett. 1981, 22,
2475.
Prepared from 6-bromo-2-(trifluoromethyl)naphthalene (21; 1.4 g,
5.0 mmol) analogously as described above for 1,4-epoxy-1,4-dihy-
dro-5-trifluoromethyl-2-naphthoic acid (10); yield: 0.85 g (71%);
colorless needles (from EtOAc); mp 248–250 °C (Lit.30 mp 273–
275 °C).
1H NMR:* d = 8.70 (s, 1 H), 8.45 (s, 1 H), 8.31 (d, J = 8.6 Hz, 1 H),
8.19 (d, J = 8.6 Hz, 1 H), 8.06 (dd, J = 8.9, 1.6 Hz, 1 H), 7.78 (dd,
J = 8.6, 1.6 Hz, 1 H).
13C NMR:* d = 168.1, 134.8, 134.7, 132.1, 131.5, 131.4, 130.5,
129.2 (q, J = 32 Hz), 127.7, 126.7 (q, J = 5 Hz), 125.4 (q, J = 274
Hz), 123.0 (q, J = 4 Hz).
(13) Caster, K. C.; Keck, C. G.; Walls, R. D. J. Org. Chem. 2001,
66, 2932.
(14) Nakamura, M.; Oki, M.; Nakanishi, H. Tetrahedron 1974,
30, 543.
Anal. Calcd for C12H7F3O2 (240.18): C, 60.01; H, 2.94. Found: C,
59.75; H, 2.92.
(15) Brooke, G. M.; Young, A. C. J. Fluorine Chem. 1976, 8,
223.
(16) Peña, D.; Pérez, D.; Guitián, E.; Castedo, L. J. Org. Chem.
7-Trifluoromethyl-2-naphthoic Acid (26)
Prepared from 6-bromo-2-(trifluoromethyl)naphthalene (22; 1.4 g,
5.0 mmol) analogously as described above for 1,4-epoxy-1,4-dihy-
dro-5-trifluoromethyl-2-naphthoic acid (10); yield: 0.82 g (68%);
colorless needles (from EtOAc); mp 172–174 °C.
1H NMR:* d = 8.77 (s, 1 H), 8.62 (s, 1 H), 8.18 (d, J = 8.6 Hz, 1 H),
8.11 (d, J = 8.9, 1 H), 8.08 (dd, J = 8.2, 1.6 Hz, 1 H), 7.83 (dd,
J = 8.9, 1.9, 1 H).
13C NMR:* d = 168.2, 137.3,132.6, 132.2, 130.7, 130.5, 129.4,
128.8, 128.4 (q, J = 5 Hz), 128.1 (q, J = 32 Hz), 125.4 (q, J = 273
Hz), 124.4 (q, J = 3 Hz).
2000, 65, 6944.
(17) Tamborski, C.; Soloski, E. J. J. Organomet. Chem. 1967, 10,
385.
(18) Harrison, R.; Heaney, H. J. Chem. Soc. C 1968, 889.
(19) Coe, P. L.; Pearl, G. M.; Tatlow, J. C. J. Chem. Soc. C 1971,
604.
(20) Coe, P. L.; Stephens, R.; Tatlow, J. C. J. Chem. Soc. 1962,
3227.
(21) Brewer, J. P. N.; Heaney, H. Tetrahedron Lett. 1965, 6,
4709.
Anal. Calcd for C12H7F3O2 (240.18): C, 60.01; H, 2.94. Found: C,
59.85; H, 2.89.
(22) Calander, D. D.; Coe, P. L.; Tatlow, J. C.; Uff, A. J.
Tetrahedron 1969, 25, 25.
(23) Gribble, G. W.; Easton, N. R.; Eaton, J. T. Tetrahedron Lett.
1970, 11, 1075.
Acknowledgment
(24) Gribble, G. W.; LeHoullier, C. S.; Sibi, M.; Allen, R. W. J.
Org. Chem. 1985, 50, 1611.
(25) Yamamoto, G.; Suzuki, M.; Oki, M. Bull. Chem. Soc. Jpn.
1983, 56, 306.
This work was financially supported by the Schweizerische Natio-
nalfonds zur Förderung der wissenschaftlichen Forschung, Bern
(grants 20-63¢584-00 and 20-100¢336-02).
(26) Bobbio, C.; Schlosser, M. Eur. J. Org. Chem. 2001, 4533.
(27) Heiss, C.; Schlosser, M. Eur. J. Org. Chem. 2003, 447.
(28) Schlosser, M.; Marull, M. Eur. J. Org. Chem. 2003, 1569.
(29) Seiler, P.; Wurz, J. Helv. Chim. Acta 1972, 55, 2693.
(30) Kunshenko, B. V.; Alekseeva, L. A.; Yagupolskii, L. M. Zh.
Org. Khim. 1973, 9, 1954; Russ. J. Org. Chem. (Engl.
Transl.) 1973, 9, 1971; Chem. Abstr. 1973, 79, 146278.
References
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Lausanne: Switzerland, 2001, 24–38. (b) Castagnetti, E.
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Synthesis 2005, No. 5, 791–797 © Thieme Stuttgart · New York