A novel synthesis of polysubstituted naphthalenes

Article abstract of DOI:10.1016/S0040-4020(01)00450-1

The reaction of (2-trifluoromethyl)phenyl acetic acid derivatives with anions derived from aromatic acetonitriles furnishes polysubstituted naphthalenes in good yields (30-68%). A solid-phase version of this reaction is reported as well. The transformation is proposed to proceed via the intermediate formation of the quinone methide intermediate.

Full text of DOI:10.1016/S0040-4020(01)00450-1

TETRAHEDRON
Pergamon
Tetrahedron 57 2001) 5321±5326
A novel synthesis of polysubstituted naphthalenes
Alexander S. Kiselyovp
Department of Chemistry, ImClone Systems Incorporated, 180 Varick Street, 6th Floor, New York 10014, USA
Received 9 March 2001; accepted 23 April 2001
AbstractÐThe reaction of 2-tri¯uoromethyl)phenyl acetic acid derivatives with anions derived from aromatic acetonitriles furnishes
polysubstituted naphthalenes in good yields 30±68%). A solid-phase version of this reaction is reported as well. The transformation is
proposed to proceed via the intermediate formation of the quinone methide intermediate. q 2001 Elsevier Science Ltd. All rights reserved.
The anionically activated tri¯uoromethyl group has great
utility in the synthesis of various aromatic, and hetero-
aromatic compounds.1 Representative examples of this
chemistry featuring ortho-tri¯uoromethyl aniline are
summarized in Scheme 1.2±11 It has been suggested that
these transformations are initiated by the proton abstraction
from the anilinic nitrogen to afford the quinone methide
intermediate Q Scheme 1). The subsequent reaction of
this intermediate with various nucleophiles may lead to
the observed array of products. The utility of the CF3-
group in heterocyclic synthesis was further con®rmed by a
facile synthesis of arylbenzimidazoles,12 and cinnolines.13
The corresponding base-induced reactions of the ortho-
tri¯uorotoluene derivatives are studied to a lesser extent.10
naphthalene derivatives 2). The yields of 2 varied
dramatically depending on the reaction conditions Scheme
2). In order to optimize the yield of 2, I studied the effects of
several factors on the outcome of this reaction, including: i)
reaction temperature; ii) ratio of substrate 1) to base; iii)
reaction time; iv) type of solvent, and v) nature of base.
Some of these studies are summarized in Scheme 2.
The temperature was shown to have a profound effect on the
reaction course. For example, treatment of 1 with 1 equiv. of
LDA in THF at 2788C for 24 h followed by aqueous quench
of the reaction mixture with water afforded only the starting
material in quantitative yield. A similar treatment of 1 at
2308C MeCN/ethylene glycol/dry ice mixture) for 12 h
allowed for the isolation of 2 in 13% yield along with the
starting material 1 55%). A further increase in the reaction
temperature to 08C did not improve the yield of 2 22%)
signi®cantly. A decrease in the yield of 2 11%), as well as
the formation of unidenti®ed high-molecular weight
products was observed when the reaction was conducted
at ambient temperature.
In this paper, I report the facile synthesis of 1,2,3,4-tetra-
substituted naphthalenes via the condensation of derivatives
of 2-tri¯uoromethylphenyl)acetic acid with aromatic aceto-
nitriles under basic conditions. In the initial experiment, I
found that the ethyl ester derivative 1 undergoes a facile
self-condensation reaction under basic conditions to afford
Scheme 1.
Keywords: naphthalenes; ¯uorine and compounds; condensations; supported reagents/reactions.
Tel.: 1646-638-5012; fax: 1212-645-2054; e-mail: alexanderk@imclone.com
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020 01)00450-1

5322
A. S. Kiselyov / Tetrahedron 57 *2001) 5321±5326
Scheme 2.
The optimal ratio of 1 to base was found to be 1:4.
Lower ratios resulted in lower yields of 2. Higher ratios
6±8) did not signi®cantly affect the reaction
outcome. THF as well as dimethoxyethane DME)
were the best solvents for the reaction 57±62% yields
of 2), whereas reactions conducted in diethyl ether
afforded only 12±18% isolated yield of 2. Several
amide bases, including LDA, LiTMP 2,2,6,6-tetra-
methylpiperidide), and LiHMDS 1,1,1,3,3,3-hexa-
methyldisilazide) furnished essentially similar yields of
2 52±62%). Reaction times of 12±13 h were essential
to assure the complete conversion of 1 to 2 at 230±
08C. The optimized reaction conditions are indicated in
Scheme 2 bold captions).
although a number of side products were detected in the
reaction mixture along with 2 14% isolated yield).
Application of NaOEt in re¯uxing EtOH 6 equiv.) also
allowed for the isolation of 2 albeit in lower yields 22%)
when compared with lithium amides. In this case, the start-
ing material 1 was the major component of the reaction
mixtures. Longer reaction time did not improve the outcome
of this conversion in EtOH.
The development of the reaction protocol for the self-
condensation reaction of 1 prompted me to attempt a similar
transformation involving 1 and anions derived from
aromatic acetonitriles 4). To my satisfaction, addition of
1 to a solution of 4 2 M equiv.) and LDA 2 M equiv.) at
2308C followed by stirring at rt for 4 h allowed for a
smooth condensation reaction to afford 5 in 37±68%
isolated yields Scheme 3).
The nature of the cation did not affect the yield of 2.
Notably, this reaction was also promoted by EtMgBr,
Scheme 3.

A. S. Kiselyov / Tetrahedron 57 *2001) 5321±5326
5323
Scheme 4.
Scheme 5.
Varying amounts of 2 20±35%) were detected in the
reaction mixtures. Separation of the desired products 5
from 2 via conventional methods including recrystallization
from EtOH, column, and circular chromatography on
silica gel was not ef®cient. Attempts to improve the ratio
of 5 to 2 by changing the experimental conditions were
not successful. The optimal rate of addition of 1 0.01 M
solution in THF) to 4 0.01 M solution in THF) was
reverse-phase preparative HPLC to yield analytically pure
materials as summarized in Scheme 4.
To account for the reported chemistry of 1 under basic
conditions, I propose the mechanism presented below
Scheme 5). It involves the initial deprotonation of 1 to
form 7, which is stable at temperatures below 2308C. At
higher temperatures, 7 undergoes slow elimination of HF to
form the quinone methide intermediate 8. These active
species react with 7 to afford the self-condensation product
2 after a series of addition/elimination steps. Alternatively,
8 reacts with the excess of acetonitrile anion 4 to afford 5.
The indirect support of this mechanism is provided by the
facts that both the dilution of the reaction mixture, as well as
the slow addition of the substrate 1 to assure a large excess
of 4 over 1, and consequently 8) dramatically improves the
yields of 5 vs the self-condensation product 2. Additionally,
higher reaction temperatures allow for the facile elimination
of F2 from 7, shifting the overall equilibrium of the reaction
towards the formation of the key reactive intermediate 8.
Formation of a similar quinone methide intermediate was
suggested in several relevant transformations of 2-tri¯uoro-
methyl)aniline.1
0.25±0.5 mL/min.
condensation product
Signi®cant
2
amounts
of
self-
40±90% conversion) were
observed with faster addition rates, application of a more
concentrated solution of 1, and lower reaction
temperatures. When a larger excess of 4 was used to
facilitate the reaction the overall yield of 5 was not affected
signi®cantly.
In order to avoid the formation of the self-condensation
product 2, I immobilized 2-tri¯uoromethyl)phenyl acetic
acid on Wang resin using a previously reported procedure.14
The resulting resin 250 mg, 0.85 mmol/g loading, as deter-
mined by cleavage of the immobilized acid with 15% TFA
in CH2Cl2 30 min)) was treated with the mixture of
aromatic acetonitrile 3 5 mmol) and LDA 10 mmol) in
THF at 2408C for 1 h and at 08C for 8 h.15 The subsequent
treatment of the reaction mixture with saturated aq. NH4Cl,
followed by a standard work up of the resin,16 and TFA
cleavage of the product afforded the crude 6. Purities of
the resultant product varied between 76 and 91% as deter-
mined by reverse-phase HPLC. The main impurity LC MS)
was the starting 2-tri¯uorometyl)phenyl acetic acid 5±
20%). The naphthalenes 6 were further puri®ed by
In summary, I have described a protocol for the rapid
assembly of 1,2,3,4-tetrasubstituted naphthalenes from the
derivatives of 2- tri¯uoromethyl)phenyl acetic acid and
aromatic acetonitriles. The proposed reaction mechanism
involves the formation of the quinone methide intermediate.
Further synthetic and mechanistic studies of this reaction are
under investigation in my lab.

5324
A. S. Kiselyov / Tetrahedron 57 *2001) 5321±5326
1
1. Experimental
1.1.5. Analytical data for 5d. 68% yield, oil. H NMR
400 MHz, DMSO-d6): d 0.99 t, Jˆ8.0 Hz, 3H), 3.68 t,
Jˆ8.0 Hz, 2H), 6.14 br s, 2H, exch. D2O, NH2), 7.08 dd,
Jˆ8.0, 1.6 Hz, 1H) 7.38 t, Jˆ8.0 Hz, 1H), 7.42 s, 1H),
7.46 t, Jˆ8.0 Hz, 1H), 7.54 d, Jˆ8.0 Hz, 1H), 7.60 t,
Jˆ8.0 Hz, 1H), 7.97 d, Jˆ8.0 Hz, 1H), 8.05 d,
Jˆ8.0 Hz, 1H); 19F NMR 400 MHz, DMSO-d6): d
2115.9; ESI MS: M11) 345, M21) 343. Elemental
analysis, calcd for C19H15ClFNO2: C, 66.38; H, 4.40; N,
4.07. Found: C, 66.18; H, 4.28; N, 3.86.
1.1. Typical experimental procedure for the synthesis of
naphthalenes 5 in solution
A solution of ethyl 2- tri¯uoromethyl)phenyl acetate 1)
232 mg, 1 mmol, prepared by re¯uxing the corresponding
commercially available acid in EtOH with a couple of drops
of concentrated H2SO4 for 5 h) in 100 mL of dry THF was
added via funnel at the rate of 0.25 mL/min to a vigorously
stirred mixture of arylacetonitrile 2 mmol), and LDA
4 mmol, freshly prepared from diisopropylamine and
n-BuLi) in 200 mL of dry THF at 2308C under Ar. After
the addition was ®nished 6±7 h), the dark yellow reaction
mixture was warmed up to room temperature and stirred for
an additional 4 h. The resulting solution was concentrated in
vacuo, and the residue was partitioned between EtOAc and
concentrated aqueous NH4Cl, and the aqueous layer was
extracted with EtOAc. The combined organic extracts
were dried over Na2SO4, concentrated in vacuo, and puri®ed
by column chromatography Silica gel, hexane/
EtOAcˆ2:1) to afford the analytically pure naphthalene 5.
1
1.1.6. Analytical data for 5e. 64% yield, oil. H NMR
400 MHz, DMSO-d6): d 1.03 t, Jˆ8.0 Hz, 3H), 3.63 t,
Jˆ8.0 Hz, 2H), 6.11 br s, 2H, exch. D2O, NH2), 7.12 d,
Jˆ8.0 Hz, 2H), 7.39 d, Jˆ8.0 Hz, 2H), 7.44 t, Jˆ8.0 Hz,
1H) 7.68 t, Jˆ8.0 Hz, 1H), 7.83 d, Jˆ8.0 Hz, 1H), 8.08 d,
Jˆ8.0 Hz, 1H); 19F 400 MHz, DMSO-d6): d 2115.8; ESI
MS: M11) 345, M21) 343. Elemental analysis, calcd for
C19H15ClFNO2: C, 66.38; H, 4.40; N, 4.07. Found: C, 66.20;
H, 4.48; N, 3.95.
1
1.1.7. Analytical data for 5f. 41% yield, oil. H NMR
400 MHz, DMSO-d6): d 1.02 t, Jˆ8.0 Hz, 3H), 3.67 t,
Jˆ8.0 Hz, 2H), 3.76 s, 3H, OMe), 6.03 br s, 2H, exch.
D2O, NH2), 7.06 t, Jˆ8.0 Hz, 1H), 7.17 d, Jˆ8.0 Hz,
1H) 7.23 d, Jˆ8.0 Hz, 1H), 7.36 t, Jˆ8.0 Hz, 1H), 7.54
t, Jˆ8.0 Hz, 1H), 7.71 t, Jˆ8.0 Hz, 1H), 7.72 d,
Jˆ8.0 Hz, 1H), 7.80 d, Jˆ8.0 Hz, 1H); 19F NMR
400 MHz, DMSO-d6): d 2114.0; ESI MS: M11) 340,
M21) 338. Elemental analysis, calcd for C20H18FNO3:
C, 70.78; H, 5.35; N, 4.13. Found: C, 70.51; H, 5.08; N,
4.02.
1
1.1.1. Analytical data for 2. Oil. H NMR 400 MHz,
DMSO-d6): d 0.95 t, Jˆ8.0 Hz, 3H), 3.65 q, Jˆ8.0 Hz,
2H), 7.02 s, 1H, exch. D2O, OH), 7.29 t, Jˆ8.0 Hz, 1H),
7.41 d, Jˆ8.0 Hz, 1H), 7.50±7.66 m, 2H), 7.69±7.75 m,
2H), 7.78±7.90 m, 2H); 19F NMR 400 MHz, DMSO-d6): d
2115.8, 263.3. ESI MS: M11) 379, M21) 377.
Elemental analysis, calcd for C20H14F4O3: C, 65.30; H,
3.73. Found: C, 65.18; H, 3.82.
1
1.1.2. Analytical data for 5a. 37% yield, oil. H NMR
1
1.1.8. Analytical data for 5g. 63% yield, oil. H NMR
400 MHz, DMSO-d6): d 1.02 t, Jˆ8.0 Hz, 3H), 3.69 q,
Jˆ8.0 Hz, 2H), 6.01 br. S, 2H, exch. D2O, NH2), 7.02 t,
Jˆ8.0 Hz, 1H), 7.12±7.21 m, 6H) 7.29 d, Jˆ8.0 Hz, 1H),
7.43 t, Jˆ8.0 Hz, 1H), 7.59 t, Jˆ8.0 Hz, 1H), 7.68 t,
Jˆ8.0 Hz, 1H), 7.75 d, Jˆ8.0 Hz, 1H), 7.94 d,
Jˆ8.0 Hz, 1H); 19F NMR 400 MHz, DMSO-d6): d
2113.2; ESI MS: M11) 386, M21) 384. Elemental
analysis, calcd for C25H20FNO2: C, 77.90; H, 5.23; N,
3.63. Found: C, 77.81; H, 5.29; N, 3.52.
400 MHz, DMSO-d6): d 0.98 t, Jˆ8.0 Hz, 3H), 3.57 t,
Jˆ8.0 Hz, 2H), 3.85 s, 3H, OMe), 6.13 br s, 2H, exch.
D2O, NH2), 6.90 s, 1H), 6.93 d, Jˆ8.0 Hz, 1H), 7.04
dd, Jˆ8.0, 1.6 Hz, 1H) 7.31 t, Jˆ8.0 Hz, 1H), 7.47 t,
Jˆ8.0 Hz, 1H), 7.65 t, Jˆ8.0 Hz, 1H), 7.91 d, Jˆ8.0 Hz,
1H), 7.98 d, Jˆ8.0 Hz, 1H); 19F NMR 400 MHz, DMSO-
d6): d 2115.7; ESI MS: M11) 340, M21) 338. Elemental
analysis, calcd for C20H18FNO3: C, 70.78; H, 5.35; N, 4.13.
Found: C, 70.62; H, 5.16; N, 4.06.
1
1.1.3. Analytical data for 5b. 63% yield, oil. H NMR
1
1.1.9. Analytical data for 5h. 65% yield, oil. H NMR
400 MHz, CDCl3): d 1.02 t, Jˆ8.0 Hz, 3H), 3.68 q,
Jˆ8.0 Hz, 2H), 5.02 br s, 2H, exch. D2O, NH2), 7.08±
7.34 d, 7H), 7.37 t, Jˆ8.0 Hz, 1H), 7.45 d, Jˆ8.0 Hz,
2H), 7.72 t, Jˆ8.0 Hz, 1H), 7.86 d, Jˆ8.0 Hz, 1H), 7.97
d, Jˆ8.0 Hz, 1H); 19F 400 MHz, DMSO-d6): d 2114.9;
ESI MS: M11) 386, M21) 384. Elemental analysis, calcd
for C25H20FNO2: C, 77.90; H, 5.23; N, 3.63. Found: C,
77.76; H, 5.34; N, 3.43.
400 MHz, DMSO-d6): d 1.03 t, Jˆ8.0 Hz, 3H), 3.58 q,
Jˆ8.0 Hz, 2H), 3.88 s, 3H, OMe), 5.98 br s, 2H, exch.
D2O, NH2), 7.04 d, Jˆ8.0 Hz, 2H), 7.26 d, Jˆ8.0 Hz,
2H), 7.35 t, Jˆ8.0 Hz, 1H) 7.62 t, Jˆ8.0 Hz, 1H), 7.81
d, Jˆ8.0 Hz, 1H), 7.89 d, Jˆ8.0 Hz, 1H); 19F 400 MHz,
DMSO-d6): d 2115.9; ESI MS: M11) 340, M21) 338.
Elemental analysis, calcd for C20H18FNO3: C, 70.78; H,
5.35; N, 4.13. Found: C, 70.52; H, 5.11; N, 4.06.
1
1.1.4. Analytical data for 5c. 53% yield, oil. H NMR
400 MHz, DMSO-d6): d 1.01 t, Jˆ8.0 Hz, 3H), 3.63 q,
Jˆ8.0 Hz, 2H), 6.12 br s, 2H, exch. D2O, NH2), 7.03 t,
Jˆ8.0 Hz, 1H), 7.26 d, Jˆ8.0 Hz, 1H) 7.33 d, Jˆ8.0 Hz,
1H), 7.46 t, Jˆ8.0 Hz, 1H), 7.58 t, Jˆ8.0 Hz, 1H), 7.64 t,
Jˆ8.0 Hz, 1H), 7.81 d, Jˆ8.0 Hz, 1H), 7.92 d, Jˆ8.0 Hz,
1H); 19F NMR 400 MHz, DMSO-d6): d 2114.7; ESI MS:
M11) 345, M21) 343. Elemental analysis, calcd for
C19H15ClFNO2: C, 66.38; H, 4.40; N, 4.07. Found: C,
66.11; H, 4.24; N, 3.92.
1.2. Typical experimental procedure for the synthesis of
naphthalenes 6 on solid support
The commercially available 2-tri¯uoromethyl)phenyl ace-
tic acid was immobilized on Wang resin using the reported
DIC/DMAP protocol in dry N-methylpiperidine.14 The
resulting resin was suspended in dry pyridine, concentrated
in vacuo, washed with dry THF followed by dry Et2O, and
dried in the vacuum oven at 408C at 0.1 Torr for 4 h. We

A. S. Kiselyov / Tetrahedron 57 *2001) 5321±5326
5325
found that the drying procedure described above is essential
to obtain good yields of the targeted naphthalenes 6a±h.
Loading of the resin by cleavage of the immobilized acid
with 15% TFA in CH2Cl2 30 min) was determined to be
0.85 mmol/g. The resulting resin 250 mg) was suspended
in dry THF 10 mL) and added to a gently stirred mixture of
aromatic acetonitrile 3 5 mmol) and LDA 10 mmol,
freshly prepared from diisopropylamine and n-BuLi) in
40 mL of dry THF at 2408C ethyleneglycol/water/dry ice
bath) under N2. Immediately upon addition the resin turned
dark yellow. The resulting mixture was stirred at 2408C for
1 h and warmed to 08C cold room). Stirring was continued
at this temperature for an additional 8 h. The resultant
mixture was treated with saturated aq. NH4Cl 40 mL).
The resin was collected and washed with with saturated
aq. NH4Cl, water, DMF, MeOH, and CH2Cl2. The resin
was treated with 15% TFA in CH2Cl2 10 mL, 30 min).
The CH2Cl2 solution was collected, and concentrated. The
crude product was puri®ed by preparative HPLC using a
Phenomenex Prodigy 5m ODS 3) 100A 21.2£250 mm
column on a Waters DeltaPrep4000 HPLC instrument.
The solvent system was MeCN/H2O start: 20:80; ®nish
50:50 ratio; 8 min run; 0.1% of formic acid added) with a
¯ow rate 20 mL/min.
1.2.5. Analytical data for 6e. 67% yield. 1H NMR
400 MHz, DMSO-d6): d 6.08 br s, 2H, exch. D2O, NH2),
7.05 d, Jˆ8.0 Hz, 2H), 7.24 d, Jˆ8.0 Hz, 2H), 7.35 t,
Jˆ8.0 Hz, 1H) 7.65 t, Jˆ8.0 Hz, 1H), 7.81 d, Jˆ8.0 Hz,
1H), 7.97 d, Jˆ8.0 Hz, 1H), 12.98 br s. 1H, exch. D2O,
COOH); 19F 400 MHz, DMSO-d6): d 2114.7; ESI MS:
M11) 317, M21) 315. HRMS ESI calcd for
C17H11ClFNO2: 315.0462. Found: 315.0460.
1.2.6. Analytical data for 6f. 33% yield. 1H NMR
400 MHz, DMSO-d6): d 3.69 s, 3H, OMe), 5.97 br s,
2H, exch. D2O, NH2), 7.03 t, Jˆ8.0 Hz, 1H), 7.08 d,
Jˆ8.0 Hz, 1H) 7.22 d, Jˆ8.0 Hz, 1H), 7.33 t, Jˆ8.0 Hz,
1H), 7.45 t, Jˆ8.0 Hz, 1H), 7.64 t, Jˆ8.0 Hz, 1H), 7.70 d,
Jˆ8.0 Hz, 1H), 7.74 d, Jˆ8.0 Hz, 1H), 12.91 br s. 1H,
exch. D2O, COOH); 19F NMR 400 MHz, DMSO-d6): d
2113.5; ESI MS: M11) 312, M21) 310. HRMS ESI
calcd for C18H14FNO3: 311.0958. Found: 311.0955.
1.2.7. Analytical data for 6g. 61% yield. 1H NMR
400 MHz, DMSO-d6): d 3.81 s, 3H, OMe), 6.09 br s,
2H, exch. D2O, NH2), 6.87 s, 1H), 6.91 d, Jˆ8.0 Hz,
1H), 7.03 dd, Jˆ8.0, 1.6 Hz, 1H) 7.25 t, Jˆ8.0 Hz, 1H),
7.44 t, Jˆ8.0 Hz, 1H), 7.60 t, Jˆ8.0 Hz, 1H), 7.83 d,
Jˆ8.0 Hz, 1H), 7.91 d, Jˆ8.0 Hz, 1H), 12.92 br s. 1H,
exch. D2O, COOH); 19F NMR 400 MHz, DMSO-d6): d
2115.2; ESI MS: M11) 312, M21) 310. HRMS ESI
calcd for C18H14FNO3: 311.0958. Found: 311.0957.
1.2.1. Analytical data for 6a. 30% yield. 1H NMR
400 MHz, DMSO-d6): d 5.89 br. s, 2H, exch. D2O,
NH2), 6.96 t, Jˆ8.0 Hz, 1H), 7.10±7.21 m, 6H) 7.23 d,
Jˆ8.0 Hz, 1H), 7.34 t, Jˆ8.0 Hz, 1H), 7.51 t, Jˆ8.0 Hz,
1H), 7.65 t, Jˆ8.0 Hz, 1H), 7.74 d, Jˆ8.0 Hz, 1H), 7.96
1.2.8. Analytical data for 6h. 66% yield. 1H NMR
400 MHz, DMSO-d6): d 3.87 s, 3H, OMe), 5.95 br s,
2H, exch. D2O, NH2), 7.01 d, Jˆ8.0 Hz, 2H), 7.18 d,
Jˆ8.0 Hz, 2H), 7.33 t, Jˆ8.0 Hz, 1H) 7.57 t, Jˆ8.0 Hz,
1H), 7.74 d, Jˆ8.0 Hz, 1H), 7.83 d, Jˆ8.0 Hz, 1H), 12.94
br s. 1H, exch. D2O, COOH); 19F 400 MHz, DMSO-d6): d
2115.5; ESI MS: M11) 312, M21) 310. HRMS ESI
calcd for C18H14FNO3: 311.0958. Found: 311.0955.
d, Jˆ8.0 Hz, 1H), 12.94 br s. 1H, exch. D2O, COOH); 19
F
NMR 400 MHz, DMSO-d6): d 2112.4; ESI MS: M11)
358, M21) 356. HRMS ESI calcd for C23H16FNO2:
357.1165. Found: 357.1162.
1.2.2. Analytical data for 6b. 55% yield. 1H NMR
400 MHz, DMSO-d6): d 6.02 br s, 2H, exch. D2O, NH2),
7.10±7.35 m, 7H), 7.31 t, Jˆ8.0 Hz, 1H), 7.37 d,
Jˆ8.0 Hz, 2H), 7.73 t, Jˆ8.0 Hz, 1H), 7.79 d, Jˆ8.0 Hz,
1H), 7.85 d, Jˆ8.0 Hz, 1H), 12.86 br s. 1H, exch. D2O,
COOH); 19F 400 MHz, DMSO-d6): d 2114.1; ESI MS:
M11) 358, M21) 356. HRMS ESI calcd for
C23H16FNO2: 357.1165. Found: 357.1163.
References
1. Kiselyov, A. S.; Strekowski, L. Org. Prep. Proc. Int. 1996, 28,
289 and references cited therein.
2. Hojjat, M.; Kiselyov, A. S.; Strekowski, L. Synth.Commun.
1994, 24, 267.
1.2.3. Analytical data for 6c. 47% yield. 1H NMR
400 MHz, DMSO-d6): d 6.04 br s, 2H, exch. D2O, NH2),
7.01 t, Jˆ8.0 Hz, 1H), 7.21 d, Jˆ8.0 Hz, 1H) 7.32 d,
Jˆ8.0 Hz, 1H), 7.46 t, Jˆ8.0 Hz, 1H), 7.58 t, Jˆ8.0 Hz,
1H), 7.64 t, Jˆ8.0 Hz, 1H), 7.73 d, Jˆ8.0 Hz, 1H), 7.92
3. Kiselyov, A. S.; Hojjat, M.; Van Aken, K.; Strekowski, L.
Heterocycles 1994, 37, 775.
4. Wydra, R.; Patterson, S. E.; Strekowski, L. J. Heterocycl.
Chem. 1990, 27, 803.
d, Jˆ8.0 Hz, 1H), 12.88 br s. 1H, exch. D2O, COOH); 19
F
5. Strekowski, L.; Lin, S.-Y.; Nguyen, J.; Redmore, N.; Mason,
J. C.; Kiselyov, A. S. Heterocycl. Commun. 1995, 1, 331.
6. Strekowski, L.; Wydra, R.; Kiselyov, A. S.; Baird, J. H. Synth.
Commun. 1994, 24, 257.
NMR 400 MHz, DMSO-d6): d 2114.3; ESI MS: M11)
317, M21) 315. HRMS ESI calcd for C17H11ClFNO2:
315.0462. Found: 315.0460.
7. a) Strekowski, L.; Patterson, S. E.; Janda, L.; Wydra, R.;
Harden, D. B.; Lipowska, M.; Cegla, M. J. Org. Chem.
1992, 57, 196. b) Janda, L.; Nguyen, J.; Patterson, S. E.;
Strekowski, L. J. Heterocycl. Chem. 1992, 29, 1753.
8. Strekowski, L.; Wydra, R.; Harden, D. B.; Honkan, V. A.
Heterocycles 1990, 31, 1565.
1.2.4. Analytical data for 6d. 64% yield. 1H NMR
400 MHz, DMSO-d6): d 6.07 br s, 2H, exch. D2O, NH2),
6.98 dd, Jˆ8.0, 1.6 Hz, 1H) 7.29 t, Jˆ8.0 Hz, 1H), 7.35 t,
Jˆ8.0 Hz, 1H), 7.40 s, 1H), 7.53 d, Jˆ8.0 Hz, 1H), 7.56 t,
Jˆ8.0 Hz, 1H), 7.83 d, Jˆ8.0 Hz, 1H), 7.98 d, Jˆ8.0 Hz,
1H), 12.89 br s. 1H, exch. D2O, COOH); 19F NMR
400 MHz, DMSO-d6): d 2115.2; ESI MS: M11) 317,
M21) 315. HRMS ESI calcd for C17H11ClFNO2:
315.0462. Found: 315.0459.
9. Strekowski, L.; Kiselyov, A. S.; Hojjat, M. J. Org. Chem.
1994, 59, 5886.
10. Kiselyov, A. S.; Strekowski, L. Tetrahedron Lett. 1994, 35,
7597.

5326
A. S. Kiselyov / Tetrahedron 57 *2001) 5321±5326
11. Kiselyov, A. S. Tetrahedron Lett. 1995, 36, 1383.
12. Kiselyov, A. S. Tetrahedron Lett. 1999, 40, 4119.
13. Kiselyov, A. S.; Dominguez, C. Tetrahedron Lett. 1999, 40,
5111.
with TFA, the LC MS analysis of the resultant mixture
revealed the presence of a product of the formal SNAr of
¯uorine 7) with the anion 4 as shown in Scheme 6. The yields
of this product varied from 15 to 55% depending on the
reaction time. For example, 7 was the major product of this
solid phase reaction at room temperature after 8 h.
14. Kiselyov, A. S.; Smith, L. S.; Armstrong, R. W. Tetrahedron
1998, 54, 5089.
16. Kiselyov, A. S.; Smith, L. S.; Virgilio, A.; Armstrong, R. W.
Tetrahedron 1998, 54, 7987.
15. When the immobilized 2-tri¯uoromethyl)phenyl acetic acid
was treated with the same mixture of reagents at ambient
temperature, followed by a standard work up and cleavage
Scheme 6.