New strategies in the synthesis of regioselectively trifluoromethyl- and trifluoromethoxy-substituted arenes as building blocks for biologically active molecules

Article abstract of DOI:10.1016/S0022-1139(02)00161-6

Regioisomerically pure trifluoromethyl- and trifluoromethoxy-substituted aromatic and heteroaromatic aldehydes and carboxylic acids are valuable building blocks for the synthesis of biologically active molecules. They have been prepared by employing moder

Full text of DOI:10.1016/S0022-1139(02)00161-6

Journal of Fluorine Chemistry 117 (2002) 167±172
New strategies in the synthesis of regioselectively tri¯uoromethyl- and
tri¯uoromethoxy-substituted arenes as building blocks for
biologically active molecules
Stephane Leconte, Renzo Ruzziconi*
Á
Dipartimento di Chimica, Universita di Perugia, via Elce di Sotto 8, I-06123 Perugia, Italy
Received 16 May 2002; received in revised form 28 May 2002; accepted 30 May 2002
Dedicated to Professor Lev M. Yagupolskii on the occasion of his 80th birthday.
Abstract
Regioisomerically pure tri¯uoromethyl- and tri¯uoromethoxy-substituted aromatic and heteroaromatic aldehydes and carboxylic acids are
valuable building blocks for the synthesis of biologically active molecules. They have been prepared by employing modern organometallic
methods. On this basis, a novel access to 2,3-dihydro-5-(tri¯uoromethoxy)indole was developed which represents an intriguing example of
how organometallic and radical chemistry can fecundate each other.
# 2002 Elsevier Science B.V. All rights reserved.
Keywords: Nitrogen heterocycles; Optional site selectivity; Organolithium compounds; Tributyltin hydride; Radical cyclization
1. Introduction
ones are Riluzole [10,11], employed to treat schizophrenia
and amyotropic lateral sclerosis and a-cyano-b-hydroxy-b-
methyl-N-[4-(tri¯uoromethoxy)phenyl]-1-propenamide, an
inhibitor of the epidermal growth factor receptor tyrosine
kinase [12,13]. If OCF3- and even CF3-substituted drug
candidates are still less widespread than one would expect,
this has certainly to do with their poor accessibility. The
purpose of the present investigation was to open new routes
to such attractive classes of compounds.
Health care advances in the past decades have been
tributary to improved diagnosis, and on the other hand, to
a spectacular progress in organic synthesis leading to the
design of extremely selective tailor-made drugs. Fluorine as
a unique tool to ®ne-tune biological activity has played a
major role in this evolution.
Due to its surprising peculiarities [1±6], ¯uorine is
increasingly used as a substituent in the synthesis of impor-
tant pharmacologically active compounds. Fluorinated
drugs include a vast range of pharmaceutical applications
from anesthetics to chemotherapeutics such as corticoids,
neuroleptics, or cardiovascular drugs [7].
Fluorine may be introduced into a target compound as a
single atom or several halogens may be accumulated. For
example, the tri¯uoromethyl group is a favorite structural
feature used to convey both lipophilicity and metabolic
stability. Thus, ¯uordipine [8], diazipine [9] and many other
CF3-substituted 1,4-dihydropyridines (DHPs) have been pre-
pared and evaluated. In contrast, drugs containing a tri¯uoro-
methoxy group are rare. Among them, the most famous
2. Results and discussion
In a recent article, we reported on the use of suitable
¯uoroaryl derivatives as building blocks in the synthesis of
regioselectively ¯uorinated phenanthren-1-ones and 2-acet-
onaphthones (1) [14], which are valuable precursors to
important enzyme inhibitors. The adopted strategy was
based on the CAN-promoted oxidative coupling of easily
accessible 3-(¯uoroaryl)-1-(trimethylsilyloxy)alkenes (2)
with ethyl vinyl ether, followed by acid catalyzed elec-
trophilic aromatic cyclization of the intermediate acetals
(3 and 4) (Scheme 1) [15].
Owing to the weak electrophilic character of a protonated
formyl group, the success of the method depends on the
absence of strongly electron-withdrawing groups in the
aromatic ring of the aryl-1-silyloxyalkene precursor. This
* Corresponding author. Tel.: ‡39-75-585-55-43;
fax: ‡39-75-585-52-62.
E-mail address: ruzzchor@unipg.it (R. Ruzziconi).
0022-1139/02/$ ± see front matter # 2002 Elsevier Science B.V. All rights reserved.
PII: S 0 0 2 2 - 1 1 3 9 ( 0 2 ) 0 0 1 6 1 - 6

168
S. Leconte, R. Ruzziconi / Journal of Fluorine Chemistry 117 (2002) 167±172
Scheme 2.
(LITMP) in tetrahydrofuran at À75 8C. Deprotonation
occurred at the sterically less hindered position adjacent
to bromine (Scheme 3) [17]. The reaction of the lithiated
species (8) with N,N-dimethylformamide afforded, after
hydrolysis, the expected 2-bromo-3,5-bis(tri¯uoromethyl)-
benzaldehyde (9; 64%). Using carbon dioxide as the elec-
trophile, the corresponding benzoic acid (10; 39%) was
obtained.
Scheme 1.
rules out its application to tri¯uoromethyl- or tri¯uoro-
methoxy-substituted substrates. Therefore, we had to adapt
our annulation strategy. In particular, we envisioned to
switch to an intramolecular coupling of a tri¯uormethyl-
or tri¯uoromethoxy-bearing aryl (5) or arylalkyl radical (6)
with a carbon±carbon double bond located in a side-chain
(Scheme 2).
Of course, this requires the availability of suitably func-
tionalized aryl derivatives. In this respect, the concept of
``Shrapnel Reaction Sequences'' disclosed by Schlosser [16]
looks quite attractive as it should provide a convenient entry
to tri¯uoromethyl- or tri¯uoromethoxy-substituted benzal-
dehydes, benzoic acids as well as carbonylated heteroaro-
matics.
With this objective in mind, we have prepared 2,4-bis-
(tri¯uoromethyl)bromobenzene (7; 92%) by the reaction of
2,4-bis(tri¯uoromethyl)phenyllithium with tetrabromo-
methane, to treat it with 2,2,6,6-tetramethylpiperidide
Scheme 3.

S. Leconte, R. Ruzziconi / Journal of Fluorine Chemistry 117 (2002) 167±172
169
Scheme 6.
Scheme 4.
Our work aiming at the regioselective functionalization of
tri¯uoromethyl-substituted pyridines was again inspired by
literature precedents [18,19]. Starting with 2-chloro-4-iodo-
5-(tri¯uoromethyl)pyridine [20] (11) the pyridinecarbalde-
hyde 13 (70%) was obtained by butyllithium-promoted
halogen±metal interconversion followed by the addition
of N,N-dimethylformamide and hydrolysis. Consecutive
treatment of the iodopyridine 11 or its isomer 12 with
butyllithium and dry ice afforded the carboxylic acids 14
(77%) and 15 (45%) (Scheme 4).
tected 4-(tri¯uoromethoxy)aniline (16) was metallated with
2.0 eq. of tert-butyllithium in tetrahydrofuran exclusively at
the 2-position (Scheme 5). The reaction of the resulting 2-
lithiated intermediate with N,N-dimethylformamide pro-
vided the aldehyde 17 (85%). The latter was easily converted
into 2-bromo-5-(tri¯uoromethoxy)benzaldehyde (18; 88%)
by applying a classical Sandmeyer protocol. Finally, Wittig
ole®nation of aldehyde 18 with triphenylphosphoniometha-
nide (methylenetriphenylphosphorane) furnished the 2-
bromo-5-(tri¯uoromethoxy)styrene (19; 52%).
Tri¯uoromethoxy-substituted arenes and anilines were
recently reported to undergo clean metalation and sub-
sequent derivatization [21,22]. The sequence leading to
2-bromo-5-(tri¯uoromethoxy)benzaldehyde (18) from 4-(tri-
¯uoromethoxy)aniline illustrates impressively the potential
inherent in such successive protection/metalation/functio-
nalization/deprotection steps. Owing to the well-known
ortho-directing ability of the amido-group, the BOC-pro-
The synthesis of 1-tert-butoxycarbonyl-2,3-dihydro-3-
methyl-5-(tri¯uoromethoxy)indole (22) described below
emphasizes the synthetic potentialities of the above strategy
by an original combination of organometallic and radical
chemistry. Metalation of the carbamate 16 with tert-butyl-
lithium in THF, followed by the reaction of iodine, gave the
expected 2-iodo-derivative (20). The latter was easily trans-
formed into tert-butyl N-allyl-2-iodo-4-(tri¯uoromethoxy)-
phenylcarbamate (21) by deprotonation with sodium
hydride and successive reaction with allyl bromide in
dimethyl sulfoxide. In a preliminary, not yet optimized
experiment, 21 was re¯uxed with tributyltin hydride in
toluene, in the presence of 2,20-azobis(isobutyronitrile)
(AIBN) to give the indole 22 in 38% of yield (Scheme 6).
3. Experimental
If not speci®ed otherwise, 1H and 13C NMR spectra were
recorded at 400 and 101 MHz, respectively, in CDCl3 solu-
tion using tetramethylsilane as an internal standard. IR
spectra were taken in CHCl3 in the 4000±625 cmÀ1 range.
Gas chromatographic analyses were performed using capil-
lary columns loaded with two different stationary phases:
2 m, 5% UCON LB550X at 110 8C, and 2 m, 5% SE30 at
110 8C. Mass spectra were registered at 70 eV. Melting
points are corrected after calibration performed with authen-
tic standards.
Scheme 5.

170
S. Leconte, R. Ruzziconi / Journal of Fluorine Chemistry 117 (2002) 167±172
All organic reagents were used as purchased. Tetrahy-
needles; yield: 0.90 g (39%). The mp 140±141 8C; 1H NMR
(D3CSOCD3): d 13.6 (1 H, broad s, COOH), 8.42 (1 H, s, H-
6), 8.31 (1 H, s, H-4); 13C NMR (D3CSOCD3): d 161.9,
141.6 (C-1), 132.0 (q, J ˆ 32 Hz, C-3), 130.7 (C-6), 130.1
(q, J ˆ 33 Hz, C-5), 127.0 (C-4), 123.9 (q, J ˆ 273 Hz,
CF3), 123.3 (q, J ˆ 273 Hz, CF3), 122.8 (C-2). Anal. calcd.
for C9H3BrF6O2: C, 32.07; H, 0.90. Found: C, 32.19; H,
0.93.
drofuran and diethyl ether were distilled from potassium
hydroxide in the presence of cuprous chloride and redistilled
from sodium wire in the presence of benzophenone.
3.1. 1-Bromo-2,4-bis(trifluoromethyl)benzene (7)
2,2,6,6-Tetramethylpiperidine (31 g, 0.22 mol) and 1,3-
bis(tri¯uoromethyl)benzene (47 g, 0.22 mol) were consecu-
tively added to butyllithium (0.22 mol) in THF (0.40 l) and
hexane (0.10 l) at À75 8C. After 2 h at this temperature, the
mixture was slowly added to a solution of tetrabromo-
methane (73 g, 0.22 mol) in dichloromethane (0.10 l). The
cold bath was removed and after the temperature reached
25 8C the mixture was washed ®rst with 2 M aqueous
sodium thiosulfate (2Â 0.10 l) and then with brine (2Â
0.10 l) and the organic phase was dried with sodium sulfate.
Upon distillation, the pure product 7 was collected as a
3.4. 2-Chloro-5-(trifluoromethyl)pyridine-4-carbaldehyde
(13)
Butyllithium (6.5 mmol) in hexanes (4.0 ml) was added
dropwise to 2-chloro-4-iodo-5-(tri¯uoromethyl)pyridine
[20] (11, 2.0 g, 6.5 mmol) in tetrahydrofuran (32 ml) at
À75 8C. After 45 min, N,N-dimethylformamide (0.53 ml,
0.50 g, 6.8 mmol) was added and the mixture was made to
react for 45 min. Water (50 ml) was added and the resulting
mixture was washed with a 4.0 M hydrochloric acid and
brine (2Â 0.10 ml). The organic phase was dried over
sodium sulfate and the solvent was evaporated. Chromato-
graphy of the crude product on silica gel (eluent, 4:1 (v/v)
hexanes/DEE) gave aldehyde 13 as a pale yellow oil (0.96 g,
70%). The mp 16±18 8C; bp 68±69 8C/8 mmHg; 1H NMR: d
10.37 (1 H, s, ±CHO), 8.88(1 H, q, J ˆ 1:6 Hz, H-6), 7.92 (1
H, s, H-3); 13C NMR: d 186.4 (±CHO), 157.2 (C-2), 148.2
(C-6), 141.8 (C-4), 123.6 (q, J ˆ 34 Hz, C-5), 123.0
(q, J ˆ 274 Hz, ±CF3), 122.7 (C-3). Anal. calcd. for
C7H3ClF3NO: C, 40.12; H 1.44. Found: C, 39.98; H, 1.21.
1
colorless oil (54 g, 92%). The bp 45±51 8C/15 mmHg; H
NMR: d 7.94 (1 H, s, H-3), 7.88 (1 H, d, J ˆ 8:5, H-6), 7.66
(1 H, dd, J ˆ 8:5 and 1.5 Hz, H-5).
3.2. 2-Bromo-3,5-bis(trifluoromethyl)benzaldehyde (9)
2,2,6,6-Tetramethylpiperidine (2.1 g, 15 mmol) and 2,4-
bis(tri¯uoromethyl)bromobenzene (2.0 g, 6.8 mmol) were
consecutively added dropwise to butyllithium (15 mmol) in
THF (14 ml) and hexane (9.0 ml) at À100 8C. After 45 min
N,N-dimethylformamide (0.53 ml, 0.50 g, 6.8 mmol) was
added and the mixture was kept at À100 8C for 2 h before
being partitioned between water (50 ml) and diethyl ether
(3Â 25 ml). The combined organic layers were washed with
4.0 M hydrochloric acid (0.10 l) and with brine (2Â 0.10 l).
The organic phase was dried with anhydrous sodium sulfate
and the solvent was evaporated. Chromatography of the
crude product on silica gel (0.20 l, eluent, 1:4 (v/v) DEE/
hexanes) gave aldehyde 9 as a pale yellow oil (1.4 g, 64%).
3.5. 2-Chloro-5-(trifluoromethyl)isonicotinic acid (14)
2-Chloro-4-lithio-5-(tri¯uoromethyl)pyridine in tetrahy-
drofuran (32 ml) and hexanes (4 ml), generated as described
in the preceding paragraph, was poured on an excess of
freshly crushed dry ice. The solvents were evaporated and
the residue was dissolved in water (50 ml). The aqueous
layer was washed with diethyl ether (2Â 20 ml) and acidi®ed
with concentrated hydrochloric acid. After extraction with
dichloromethane (3Â 20 ml) and solvent evaporation, the
residue was crystallized from hexanes affording acid 14 as
white needles (0.56 g, 77%). The mp 183±185 8C; 1H NMR:
d 8.76 (1 H, s, H-6), 7.72 (1 H, s, H-3), 6.56 (1 H, COOH);
13C NMR: d 165.4 (COOH), 155.7 (C-2), 148.0 (q,
J ˆ 6:0 Hz, C-6), 142.7 (q, J ˆ 6:8 Hz, C-4), 124.4 (C-
3), 122.6 (q, J ˆ 274 Hz, ±CF3), 122.5 (q, J ˆ 35 Hz, C-5).
Anal. calcd. for C7H3ClF3NO2: C, 37.28; H, 1.34. Found: C,
36.94; H 1.76.
1
The bp 85±90 8C/10 mmHg; H NMR: d 10.52 (1 H, s,
±CHO), 8.32 (1 H, s, H-6), 8.15 (1 H, s, H-4); 13C NMR: d
189.5 (s, ±CHO), 136.1 (s, C-1), 133.0 (q, J ˆ 32 Hz, C-3),
130.9 (q, J ˆ 34 Hz, C-5), 129.8 (C-4), 129.2 (C-6), 128.3
(C-2), 122.5 (q, J ˆ 273 Hz, CF3), 121.9 (q, J ˆ 275 Hz,
CF3). Anal. calcd. for C9H3BrF6O: C, 33.67; H, 0.94. Found:
C, 33.69; H, 1.36.
3.3. 2-Bromo-3,5-bis(trifluoromethyl)benzoic acid (10)
The mixture of 2-lithio-4,6-bis(tri¯uoromethyl)bromo-
benzene, generated as described in the preceding paragraph,
was poured on an excess of freshly crushed dry ice. The
solvent was evaporated and the residue was dissolved in
water (50 ml). The aqueous layer was extracted with diethyl
ether (2 20 ml) and acidi®ed (pH ˆ 1) with concentrated
hydrochloric acid. After extraction with dichloromethane
(3Â 20 ml) and solvent evaporation, the residual solid was
re-crystallized from hexanes to obtain acid 10 as colorless
3.6. 2-Chloro-5-(trifluoromethyl)nicotinic acid (15)
Analogous, as described in the Sections 3.4 and 3.5,
starting with 2-chloro-3-iodo-5-(tri¯uoromethyl)pyridine
[20] (12, 1.0 g, 3.2 mmol). Acid 15 was isolated as colorless
platelets (0.33 mg, 45%) after crystallization from hexanes.
1
The mp 167±168 8C; H NMR: d 8.75 (1 H, dq, J ˆ 2:5,

S. Leconte, R. Ruzziconi / Journal of Fluorine Chemistry 117 (2002) 167±172
171
0.8 Hz, H-6), 8.47 (1 H, dq, J ˆ 2:5, 0.6 Hz, H-4); 13C
NMR: d 165.4 (±COOH), 153.6 (C-2), 148.1 (q, J ˆ 4:0 Hz,
C-6), 137.8 (q, J ˆ 3:0 Hz, C-4), 127.9 (C-3), 125.6 (q,
J ˆ 34 Hz, C-5), 122.7 (q, J ˆ 273 Hz, ±CF3). Anal. calcd.
for C7H3ClF3NO2: C, 37.28; H, 1.34. Found: C, 37.31; H,
0.95.
the residue allowed to collect aldehyde 18 as a pale yellow
1
oil (16.4 g, 88%). The bp 96±98 8C/5 mmHg; H NMR: d
10.32 (1 H, s, ±CHO), 7.76 (1 H, s, H-6), 7.71 (1 H, d,
J ˆ 8:7 Hz, H-3), 7.33 (1 H, dd, J ˆ 8:6 and 2.7 Hz, H-4);
13C NMR: d 190.2 (±CHO), 148.8 (C-5), 135.3 (C-3), 134.7
(C-1), 127.5 (C-4), 124.2 (C-6), 121.7 (C-2), 120.2 (q,
J ˆ 259 Hz, ±CF3). Anal. calcd. for C8H4BrF3O2: C,
35.72; H, 1.50. Found: C, 35.85; H, 1.62.
3.7. tert-Butyl 4-(trifluoromethoxy)phenylcarbamate (16)
Di-tert-butyl dicarbonate (16 g, 72 mmol) and 4-(tri¯uoro-
methoxy)aniline (9.0 ml, 12 g, 0.66 mol) in toluene (0.20 l)
were re¯uxed for 24 h. Evaporation of the solvent and
crystallization from hexanes afforded carbamate 16 as color-
3.10. 2-Bromo-5-(trifluoromethoxy)styrene (19)
A slurry of methyltriphenylphosphonium bromide (20 g,
56 mmol) and sodium amide (2.0 g, 56 mmol) in diethyl ether
(0.10 l) was vigorously stirred for 45 min at 25 8C. 2-Bromo-
5-(tri¯uoromethoxy)benzaldehyde (13.0 g, 50 mmol) was
added at À75 8C. After 2 h at 25 8C, the mixture was washed
with water, extracted with diethyl ether (3Â 0.10 l) and the
combined organic phases were dried with sodium sulfate. The
solvent was evaporated and the residue was distilled. Styrene
19 was collected as a slightly yellow oil; yield: 7.0 g (52%).
The bp 76±77 8C/10 mmHg; 1H NMR: d 7.55 (1 H, d,
J ˆ 8:7 Hz, H-6), 7.38 (1 H, d, J ˆ 2:6 Hz, H-3), 7.00 (1
H, dd, J ˆ 17:3 and 11.0 Hz, CH=CH2), 6.99 (1 H, dd,
J ˆ 8:7 and 2.6 Hz, H-5), 5.72 (1 H, d, J ˆ 17:4 Hz,
CH=CH2,), 5.44 (1 H, d, J ˆ 11:1 Hz, CH=CH2); 13C
NMR: d 148.6 (C-4), 139.2 (C-2), 134.8 (CH=CH2), 134.0
(C-6), 121.4 (C-5), 121.0 (C-3), 120.3 (q, J ˆ 257 Hz, CF3),
119.2 (CH=CH2), 118.2 (C-1). Anal. calcd. for C9H6BrF3O:
C, 40.48; H, 2.28. Found: C, 40.05; H, 2.46.
1
less needles; yield: 15.6 g (85%). The mp 103±104 8C; H
NMR: d 7.37 (2 H, dd, AA0 portion of an AA0BB0 system),
7.14 (2 H, dd, BB0 portion of an AA0BB0 system), 6.50 (1 H,
s), 1.52 (9 H, s); 13C NMR: d 152.6 (C=O), 144.4 (C-4),
137.1 (C-1), 121.8 (C-2, C-6), 120.3 (d, J ˆ 257 Hz, CF3)
119.5 (C-3, C-5), 80.9 (OC(CH3)3), 28.3 (CH3). Anal. calcd.
for C12H14F3NO3: C, 51.99; H 5.09. Found: C, 52.02; H
4.96.
3.8. tert-Butyl 2-formyl-4-
(trifluoromethoxy)phenylcarbamate (17)
tert-Butyllithium (0.20 mol) in hexanes (0.16 l) was
added dropwise to tert-butyl 4-(tri¯uoromethoxy)phenylcar-
bamate (23 g, 84 mmol) in tetrahydrofuran (0.17 l) at
À75 8C. After 6 h, N,N-dimethylformamide (6.5 ml, 6.1 g,
84 mmol) was added and the mixture was made to react at
À75 8C for 45 min. Water (50 ml) was added and the
mixture was washed with a 4 M hydrochloric acid and brine
(2Â 0.10 l). The organic phase was dried with sodium
sulfate, the solvent was evaporated and the residual solid
was crystallized from hexane affording carbamate 17 as
white needles (22.0 g, 85%). The mp 102±104 8C; 1H NMR:
d 10.33 (1 H, s, ±CHO), 9.87 (1 H, s, NH), 8.54 (1 H, d,
J ˆ 9:2 Hz, H-2), 7.48 (1 H, d, J ˆ 2:3 Hz, H-5), 7.43 (1 H,
dd, J ˆ 9:0 and 2.3 Hz, H-3), 1.54 (9 H, s, CH3); 13C NMR:
d 191.3, (±CHO), 152.7 (COOtBu), 142.8 (C-1, C-4), 140.5
(C-2), 127.5 (C-5), 121.5 (C-6), 120.4 (q, J ˆ 235 Hz,
(CF3), 120.0 (C-3), 81.4 (OC(CH3)3), 28.2. Anal. calcd.
for C13H14F3NO4: C, 51.15; H, 4.62. Found C, 51.63; H,
4.67.
3.11. tert-Butyl 2-iodo-4-
(trifluoromethoxy)phenylcarbamate (20)
tert-Butyllithium (60 mmol) in pentanes (35 ml) was
added dropwise to carbamate 16 (6.9 g, 25 mmol) in tetra-
hydrofuran (50 ml) at À75 8C. After 6 h, the mixture was
treated with iodine (6.3 g, 25 mmol) dissolved in tetrahy-
drofuran (20 ml) and worked up as previously described
(Section 3.4). Chromatography of the crude product on silica
gel (eluent, 9:1 (v/v) hexane/diethyl ether) allowed to collect
carbamate 21 as white needles; yield: 8.4 g (84%). The mp
70±71 8C; 1H NMR: d 8.09 (1 H, d, J ˆ 9:1 Hz, H-6), 7.6 (1
H, m, H-3), 7.21 (1 H, dq, J ˆ 9:1 and 2.0 Hz, H-5), 6.81 (1
H, s, NH), 1.54 (9 H, s, tert-C4H9); 13C NMR: d 152.4
(C=O), 144.1 (C-4), 137.9 (C-1), 131.3 (C-3), 120.4 (q,
J ˆ 256 Hz, OCF3), 121.9 (C-6), 120.2 (C-5), 87.6 (C-2),
81.5 (C(CH3)3), 28.2 (CH3). Anal. calcd. for C12H13F3INO3:
C, 35.75; H, 3.25; N, 3.47. Found: C, 35.97; H, 2.78; N, 2.96.
3.9. 2-Bromo-5-(trifluoromethoxy)benzaldehyde (18)
A suspension of the carbamate 17 (22 g, 72 mmol) in 48%
aqueous hydrobromic acid (0.22 l) was re¯uxed for 15 min.
After cooling at 0 8C, sodium nitrite (7.5 g, 108 mmol) in
water (10 ml) and copper bromine (19.5 g, 87 mmol) were
successively added. The mixture was re¯uxed for 45 min,
and after cooling, washed with a 2.0 M sodium thiosulfate
(2Â 0.10 l) and extracted with dichloromethane (3Â 0.10 l).
The combined organic phases were dried with sodium
sulfate and the solvent was evaporated. The distillation of
3.12. tert-Butyl N-allyl-2-iodo-4-
(trifluoromethoxy)phenylcarbamate (21)
Sodium hydride (0.12 g, 3.0 mmol) was added to a solu-
tion of carbamate 21 (1.0 g, 2.5 mmol) in dimethyl sulfoxide
(5 ml) at 25 8C. After 30 min, allyl bromide (0.24 ml, 0.33 g,
2.7 mmol) was added and the reaction was made to go on for

172
S. Leconte, R. Ruzziconi / Journal of Fluorine Chemistry 117 (2002) 167±172
17 h. Water (10 ml) was added, the mixture was extracted
with diethyl ether (3Â 15 ml), the combined extracts were
dried with sodium sulfate and the solvent was evaporated.
Chromatography of the crude product on silica gel (eluent,
9:1 (v/v) hexane/diethyl ether) allowed to collect carbamate
22 as a pale yellow oil (0.84 g, 76%). 1H NMR (200 MHz): d
7.71 (1 H, s, H-3), 7.2 (2 H, m, H-5, H-6), 5.92 (1 H, dddd,
J ˆ 16:9, 10.3, 7.1, and 5.7 Hz, ±CH=CH2), 5.12 (1 H,
d, J ˆ 10:1 Hz, ±CH=CHtHc), 5.09 (1 H, d, J ˆ 17:0 Hz,
±CH=CHtHc), 4.48 (1 H, dd, J ˆ 14:7 and 5.9 Hz,
±CH2CH=CH2), 3.73 (1 H, dd, J ˆ 14:7 and 6.9 Hz,
±CH2CH=CH2), 1.36 (9 H, s, ±C(CH3)3); 13C NMR
(50 MHz): d 153.5 (C=O), 147.5 (C-4), 143.1 (C-1),
133.2 (CH2CH=CH2), 131.4 (C-3), 130.3 (C-6), 120.9
(C-2), 120.2 (q, J ˆ 256 Hz), 118.2 (CH2CH=CH2),
100.5 (C-2), 80.7 (±OC(CH3)3), 51.8 (±CH2CH=CH2),
28.1 (±OC(CH3)3). Anal. calcd. for C12H13F3INO3:
C, 40.65; H, 3.87; N, 3.16. Found: C, 40.80; H, 3.92; N,
3.05.
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1
38%). H NMR: d 7.0 (3 H, m, aromatic H), 4.19 (1 H, t,
J ˆ 10:0 Hz, H-2a), 3.56 (1 H, broad t, J ˆ 10:0 Hz, H-2b),
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Á
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‡
20.0 (±CH3); MS (70 eV), m/z (%): 317 (M , 13), 261 (98),
246 (18), 217 (23), 202 (59), 57 (100). Anal. calcd. for
C12H13F3INO3: C, 56.78; H, 5.72; N, 4.41. Found: C, 56.83;
H, 5.89; N, 4.15.
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 Â
This work was carried out in the context of the Training
and Mobility of Researchers (TMR) European Project
(Contract no. ERBFMRXCT970120) and COST D12
Action. Thanks are due to University of Perugia and to
The European Commission for ®nancial support.
Doctoral Thesis, Ecole Polytechnique Federale, Lausanne, in
preparation.
[21] M. Schlosser, E. Castagnetti, Eur. J. Org. Chem. (2001) 3991±3997.
Â
[22] E. Castagnetti, Doctoral Thesis, Universite de Lausanne, Lausanne,
2001.