Facile and Efficient Synthesis of 4-Azidotetrafluoroaniline: A New Photoaffinity Reagent

Article abstract of DOI:10.1021/jo000402p

p-Azidotetrafluoroaniline (1) was synthesized in 65-73% yield by two different methods employing a stable carbamate intermediate. The first method trapped the intermediate isocyanate generated via a modified Curtius rearrangement with 2-methyl-2-propanol or 2-(trimethylsilyl)ethanol to form the stable carbamates 2d and 2e, respectively. Benzoic acid 2c was first converted to its acid chloride with PCl₅. Displacement of the chloride by NaN₃ in acetone/water formed the acyl azide. Thermal rearrangement followed by the addition of the appropriate alcohols provided the carbamates. The acid labile carbamate 2d was deprotected with HCl/AcOH to provide 1, while trifluoroacetic acid was required to deprotect 2e and afford 1. In the second path, 1 was synthesized in five steps from pentafluoronitrobenzene (3a) in 65% overall yield. Compound 3a was converted into 4-azidotetrafluoronitrobenzene (3b) with NaN₃ in 93% yield and was used without further purification to form 1,4-diaminotetrafluorobenzene (3c) by Sn/HCl reduction in 85% yield. The mono-9-fiuorenylmethoxycarbonyl (FMOC) derivative 3d was formed from 3c with FMOC-Cl and pyridine in EtOAc in 92% yield. Diazotization of 3d under anhydrous conditions with TFA/NaNO₂ and NaN₃ gave 3e in 87% yield. The aryl azide was formed with concurrent nitration of the 2-position of the fluorenyl system. The protecting group was removed with piperidine to afford 1 in 93% yield. Irradiation of 1 with 254 nm light in cyclohexane gave cyclohexylamine 11, diamine 3c, and azobenzene 12 as the primary products. The formation of C-H insertion product 11 indicates that 1 forms a singlet nitrene upon photolysis. Two heterobifunctional photoaffinity reagents iodoacetamide 9 and dansyl derivative 10 were prepared.

Full text of DOI:10.1021/jo000402p

J . Org. Chem. 2000, 65, 4949-4953
4949
F a cile a n d Efficien t Syn th esis of 4-Azid otetr a flu or oa n ilin e: A New
P h otoa ffin ity Rea gen t†
Kareem A. H. Chehade‡,§ and H. Peter Spielmann*,‡,§,|
Departments of Biochemistry and Chemistry and The Kentucky Center for Structural Biology, University
of Kentucky, Lexington, Kentucky 40536-0084
hps@pop.uky.edu
Received March 20, 2000
p-Azidotetrafluoroaniline (1) was synthesized in 65-73% yield by two different methods employing
a stable carbamate intermediate. The first method trapped the intermediate isocyanate generated
via a modified Curtius rearrangement with 2-methyl-2-propanol or 2-(trimethylsilyl)ethanol to form
the stable carbamates 2d and 2e, respectively. Benzoic acid 2c was first converted to its acid chloride
with PCl5. Displacement of the chloride by NaN3 in acetone/water formed the acyl azide. Thermal
rearrangement followed by the addition of the appropriate alcohols provided the carbamates. The
acid labile carbamate 2d was deprotected with HCl/AcOH to provide 1, while trifluoroacetic acid
was required to deprotect 2e and afford 1. In the second path, 1 was synthesized in five steps from
pentafluoronitrobenzene (3a ) in 65% overall yield. Compound 3a was converted into 4-azidotet-
rafluoronitrobenzene (3b) with NaN3 in 93% yield and was used without further purification to
form 1,4-diaminotetrafluorobenzene (3c) by Sn/HCl reduction in 85% yield. The mono-9-fluorenyl-
methoxycarbonyl (FMOC) derivative 3d was formed from 3c with FMOC-Cl and pyridine in EtOAc
in 92% yield. Diazotization of 3d under anhydrous conditions with TFA/NaNO2 and NaN3 gave 3e
in 87% yield. The aryl azide was formed with concurrent nitration of the 2-position of the fluorenyl
system. The protecting group was removed with piperidine to afford 1 in 93% yield. Irradiation of
1 with 254 nm light in cyclohexane gave cyclohexylamine 11, diamine 3c, and azobenzene 12 as
the primary products. The formation of C-H insertion product 11 indicates that 1 forms a singlet
nitrene upon photolysis. Two heterobifunctional photoaffinity reagents iodoacetamide 9 and dansyl
derivative 10 were prepared.
In tr od u ction
Fluorinated aryl azides have been used extensively as
photoaffinity probes to study protein structure and
function.1 Photolysis of fluorinated aryl azides yields
singlet nitrenes that are capable of inserting into C-H
bonds. Consequently, molecules containing fluorinated
aryl azides are useful in probing reversible biochemical
binding interactions involving nonpolar surfaces.2
A
F igu r e 1.
variety of perfluorophenyl azides bearing functionality
suitable for incorporation of the photoprobe into struc-
tures of interest have been synthesized.2g,h However,
p-azidotetrafluoroaniline (1) is conspicuously absent
among the described perfluorophenyl azides (Figure 1).
In the course of developing a series of heterobifunctional
cross-linking reagents, we required 1 as a synthon and
have developed two routes for the preparation of 1
(Schemes 1 and 2), a new member to the functionalized
perfluorophenyl azide family containing a chemically
reactive electron-donating amino group para to the azido
functionality.
Resu lts a n d Discu ssion
The first route to 1 employed a modified Curtius
reaction, where the intermediate isocyanante was trapped
with 2-methyl-2-propanol or 2-(trimethylsilyl)ethanol to
form the stable carbamates 2d and 2e, respectively
(Scheme 1). Methyl pentafluorobenzoate (2a ) was first
converted into methyl 4-azidotetrafluorobenzoate (2b) by
nucleophilic aromatic substitution with NaN3 in 96%
yield.2g Saponification of 2b with NaOH in aqueous
methanol gave 2c in nearly quantitative yield. Compound
2c was transformed into the intermediate acid chloride,3
followed by conversion to the acyl azide through NaN3
* To whom correspondence should be addressed. Phone: (859) 257-
4790. Fax: (859) 257-8940.
† This work was supported by Kentucky-NSF EPSCoR Program
(Grant EPS-9452895).
‡ Department of Biochemistry.
§ The Kentucky Center for Structural Biology.
| Department of Chemistry.
(1) Schuster, D. I.; Probst, W. C.; Ehrlich, G. K.; Singh, G. Photo-
chem. Photobiol. 1989, 49, 785.
(2) (a) Young, M. J . T.; Platz, M. S. Tetrahedron Lett. 1989, 30, 2199.
(b) Cai, S. X.; Keana, J . F. W. Tetrahedron Lett. 1989, 30, 5409. (c)
Leyva, E.; Munoz, D.; Platz, M. S. J . Org. Chem. 1989, 54, 5938. (d)
Soundararajan, N.; Platz, M. S. J . Org. Chem. 1990, 55, 2034. (e) J anin,
J .; Chothia, C. J . Biol. Chem. 1990, 265, 16027. (f) Poe, R.; Schnapp,
K.; Young, M. J . T.; Grayzar, J .; Platz, M. S. J . Am. Chem. Soc. 1992,
114, 5054. (g) Keana, J . F. W.; Cai, S. X. J . Org. Chem. 1990, 55, 3640.
(h) Keana, J . F. W.; Cai, S. X. J . Fluorine Chem. 1989, 43, 151.
(3) Pinney, K. G.; Katzenellenbogen, J . A. J . Org. Chem. 1991, 56,
3125.
10.1021/jo000402p CCC: $19.00 © 2000 American Chemical Society
Published on Web 07/13/2000

4950 J . Org. Chem., Vol. 65, No. 16, 2000
Chehade and Spielmann
Sch em e 3a
Sch em e 1a
a
Reaction conditions: (a) chloroacetyl chloride, pyridine, EtOAc;
(b) acetone, NaI; (c) dansyl chloride, LiN[Si(CH3)3]2, THF.
perature. Therefore, it is highly desirable to store the
synthon as the stable carbamates 2d or 2e and liberate
1 immediately before use.
The second approach to 1 employed a five-step scheme
via the base-labile 9-fluorenylmethoxycarbonyl (FMOC)
carbamate in an overall yield of 65% from 3a (Scheme
2). Commercially available pentafluoronitrobenzene 3a
was converted into 4-azidotetrafluoronitrobenzene 3b by
nucleophilic aromatic substitution with NaN3 in 93%
yield.2g,5 No ortho isomer was detected in the crude
reaction mixture, and azide 3b was used without further
purification to form the air and light sensitive diamine
3c by Sn/HCl reduction in 85% yield. Previously reported
methods to generate 3c gave either poor yields or
required expensive starting materials.6 We benefited
from the low reactivity of the parent tetrafluorophe-
nylenediamine (3c) to successfully form the mono-FMOC
protected derivative 3d in 92% yield by reacting 3c with
FMOC-Cl and pyridine in EtOAc. Reaction of 3c with
(Boc)2O and Hu¨nig’s base gave no product. Diazotization
of 3d under anhydrous conditions with trifluoroacetic
acid (TFA)/NaNO2 and NaN3 gave 3e in 87% yield.7 One-
a
Reaction conditions: (a) acetone, H2O, NaN3; (b) KOH, MeOH,
H2O; (c) (1) PCl5, Et2O; (2) NaN3; (3) C6H6, ∆; (4) (CH3)3COH or
(CH3)3SiCH2CH2OH; (d) 10d sHCl, HOAc, Et2O; 10esTFA,
CH2Cl2.
Sch em e 2a
1
and two-dimensional and H and 13C NMR, IR, elemental
analysis, and mass spectral data confirm that the aryl
azide was formed with concurrent nitration of the 2-posi-
tion of the fluorenyl system. This was not surprising, as
TFA/NaNO2 has been previously shown to nitrate fluo-
renes at the 2-position.8 The 2-nitro-FMOC protecting
group was removed with piperidine to afford 1 in 93%
yield. As noted above, it is highly desirable to store azide
1 as the stable carbamate 3e and liberate it with
piperidine immediately before use.
a
Reaction conditions: (a) acetone, H2O, NaN3; (b) Sn, HCl,
EtOH; (c) FMOC-Cl, pyridine, EtOAc; (d) CF3CO2H, NaNO2;
NaN3; (e) piperidine.
Irradiation of tetrafluoroaryl azide 1 with 254 nm light
in cyclohexane gave cyclohexylamine 11, diamine 3c, and
azobenzene 12 as the primary products (Figure 2). The
formation of C-H insertion product 11 indicates that
azide 1 forms a singlet nitrene upon photolysis.9 Forma-
tion of diamine 3c is expected from hydrogen abstraction
by the nitrene, and azobenzene 12 is expected because
nitrenes couple with nitrenes to form diazo compounds
much more efficiently than they C-H insert.2d,10
displacement in acetone/water. The crude acyl azide was
isolated, immediately converted into the isocyanate by
thermal rearrangement in dry benzene, and trapped as
the carbamates 2d and 2e by the subsequent addition of
2-methyl-2-propanol or 2-trimethylsilylethanol, respec-
tively. Yields of the purified carbamates ranged between
76 and 88%. This appears to be the first example of a
Curtius rearrangement of a perfluoroaryl compound.
Azide 1 was liberated from the acid labile tert-butyl
carbamate in 83% yield with hydrogen chloride in acetic
acid. Deprotection of 2e required trifluoroacetic acid in
CH2Cl2 to liberate 1 in 86% yield. The normal route for
deprotection of trimethylsilylethyl carbamates using (n-
Bu)4NF in tetrahydrofuran (THF) was not employed
because perfluorinated aryl azides are not compatible
with this reagent.4 Although 1 is stable up to several
months if stored at -20 °C under argon, azide 1 forms
deeply colored contaminants on standing at room tem-
(5) Bolton, R.; Sandall, J . P. B. J . Chem. Soc., Perkin Trans. 2 1978,
1288.
(6) (a) Brooke, G. M.; Burdon, J .; Tatlow, J . C. J . Chem. Soc. 1961,
802. (b) Holland, D. G.; Moore, G. J .; Tamborski, C. Chem. Ind. 1965,
1376. (c) Birchall, J . M.; Haszeldine, R. N.; Kemp, J . E. G. J . Chem.
Soc. C 1970, 449.
(7) Kanakarajan, K.; Haider, K.; Czarnik, A. W. Synthesis 1988, 566.
(8) (a) Uemura, S.; Toshimitsu, A.; Okano, M. J . Chem. Soc., Perkin
Trans. 1 1978, 1076. (b) Klemm, L. H.; Huber, E.; Klopfenstein, C. E.
J . Org. Chem. 1964, 29, 1960.
(9) (a) Reiser, A.; Leyshon, L. J . Am. Chem. Soc. 1971, 93, 4051. (b)
Leyva, E.; Platz, M. S.; Persy, G.; Wirz, J . J . Am. Chem. Soc. 1986,
108, 3783. (c) Shields, C. J .; Falvey, D. E.; Schuster, G. B.; Buchardt,
O.; Nielsen, P. E. J . Org. Chem. 1988, 53, 3501.
(4) Golinski, M.; Heine, M.; Watt, D. S. Tetrahedron Lett. 1991, 32,
1553.
(10) Scriven, E. F. V.; Turnbull, K. Chem. Rev. 1988, 88, 297.

Synthesis of New Photoaffinity Reagent
J . Org. Chem., Vol. 65, No. 16, 2000 4951
F igu r e 2.
onto a silica column, and purified by flash chromatography
(5% EtOAc in hexane).
Two derivatives of azide 1 were prepared to demon-
strate its potential utility in heterobifunctional photo-
affinity reagents (Scheme 3). Azide 9 was synthesized by
reacting aniline 1 with chloroacetyl chloride to provide
chloroacetamide 8 followed by conversion to the corre-
sponding iodide via the Finkelstein reaction in 73%
overall yield. Attempts to synthesize azide 9 directly from
iodoacetyl chloride were unsuccessful. The iodoacetamido
azide 9 is attractive because the chemically reactive
iodoacetamido group is connected to the perfluoroaryl
azide, which can form a singlet nitrene upon UV irradia-
tion. Dansyl derivative 10 is a photoreactive fluorophore
suitable for labeling nonpolar residues and surfaces.
Azide 10 was prepared in 67% yield by condensing dansyl
chloride with aniline 1 in the presence of lithium bis-
(trimethylsilyl)amide in THF.
4-(N-(ter t-Bu t oxyca r b on yl)a m in o)t et r a flu or op h en yl
Azid e (2d ). A 2.29 g amount (88%) of a white crystalline solid.
1H NMR (400 MHz) δ 6.13 (bs, 1H), 1.51 (s, 9H). 13C NMR
(100.7 MHz) δ 152.6, 144.3 (m), 142.4 (m), 141.9 (m), 139.9
(m), 117.9 (m), 113.4 (m), 82.7, 28.4. 19F NMR (376.7 MHz) δ
-153.78 (m), -147.77 (m). IR: 3298, 2976, 2121, 1720, 1535,
1510, 1488, 1445, 1401, 1369, 1252, 1166, 1001, 985 cm-1
.
Sublimation (70 °C/0.5 mm) followed by crystallization from
hexane provided the analytical sample of 10d as colorless
prismatic needles, mp 80 °C. Anal. Calcd for C11H10F4N4O2:
C, 43.14; H, 3.29; N, 18.30. Found: C, 43.31; H, 3.30; N, 18.55.
High-resolution EIMS calcd for
Found: 306.0733.
C11H10F4N4O2: 306.0740.
4-(N-((2-(Tr im eth ylsilyl)eth oxy)ca r bon yl)a m in o)tetr a -
flu or op h en yl Azid e (2e). A 2.74 g amount of pale-yellow
viscous oil (92%). 1H NMR (200 MHz) δ 6.08 (bs, 1H), 4.29 (m,
2H), 1.05 (m, 2H), 0.06 (s, 9H). 13C NMR (50.3 MHz) δ 153.9,
147.9 (m), 146.0 (m), 141.5 (m), 139.9 (m), 139.7 (m), 138.0
(m), 119.4 (m), 105.8 (m), 65.6, 18.0, 1.2. 19F NMR (376.7 MHz)
δ -153.55 (m), -147.65 (m). IR: 3274, 2957, 2901, 2126, 1714,
1652, 1509, 1251, 1179, 1125, 1041, 1002, 932, 839, 770, 743,
696, 671 cm-1. Anal. Calcd for C12H14F4N4O2Si: C, 41.14; H,
4.03; N, 15.99. Found: C, 41.26; H, 4.16; N, 15.90. High-
resolution EIMS calcd for C12H14F4N4O2Si: 350.0822. Found:
350.0820.
Dep r otection of 4-(N-(ter t-bu toxyca r bon yl)a m in o)tet-
r a flu or op h en yl Azid e (2d ) To Give 1. The carbamate 2d
(1.31 g, 4.28 mmol) was dissolved in 5 mL of CH2Cl2 in a 50
mL pear-shaped flask at 0 °C. To the solution was added 15
mL of a 1 N HCl solution in HOAc (Aldrich). The solution was
stirred at 0 °C for 2 h and then stirred at room temperature
overnight. A 20 mL aliquot of H2O was added, and the mixture
was transferred to a separatory funnel containing 150 mL of
hexane/Et2O (1:1 (v/v)) and 20 mL of H2O and shaken. The
aqueous layer was discarded, and the organics were then
washed with 5% NaHCO3 and water, dried (MgSO4), filtered
over a short pad of silica gel, and concentrated to afford 0.73
g (83%) of 1.
Exp er im en ta l Section
Gen er a l P r oced u r es.11 Caution! Organic azides should be
considered explosive, and all manipulations should take place
behind a blast shield! Aryl azides are light sensitive, and all
reactions and flash chromatography procedures should be
conducted under diminished light. All reactions were con-
ducted under dry argon and stirred magnetically except as
noted. Analytical TLC was performed on precoated (0.25 mm)
silica gel 60F-254 plates purchased from E. Merck, developed
with 30% ethyl acetate in hexane, except where noted, and
visualized under UV irradiation. Melting points are uncor-
rected. Chemical shifts are reported in parts per million
downfield using the CDCl3 peak (7.27 ppm, 1H; 77.4 ppm, 13C)
or the DMSO-d6 (2.54 ppm, 1H; 43 ppm, 13C) as an internal
reference. Hexafluorobenzene (C6F6) was used as an internal
reference (-162.9 ppm, 19F). Electron impact, FAB, and
MALDI mass spectra were performed at the University of
Kentucky Mass Spectra Facility. Combustion analyses were
performed by Atlantic Microlabs, Inc., Norcross, GA.
Gen er a l P r oced u r e for Ca r ba m a te Syn th esis. The
carboxylic acid 2c (2.00 g, 8.51 mmol) was dissolved in Et2O
(30 mL) followed by the addition of PCl5 (1.88 g, 9.02 mmol).
The mixture was stirred under argon for 1 h at room temper-
ature. The solvent was removed in vacuo to leave a yellow oil
which was further evaporated for 1 h at 25 °C under vacuum
affording 2.16 g (100%) of a yellow oil. The acid chloride was
dissolved in 45 mL of dry acetone, and the resulting solution
was added dropwise to a rapidly stirred solution of 2.03 g (31.2
mmol) sodium azide in 6.5 mL of water at 0 °C. After the final
addition of the acid chloride, the mixture was stirred for an
additional 15 min at 0 °C. The reaction mixture was poured
into a separatory funnel containing 150 mL of hexane and 100
mL of H2O and shaken. The hexane layer was removed, and
the aqueous layer was extracted with hexane again. The
combined organic layers were dried over MgSO4 (Rf of acyl
azide: 0.64), filtered, and concentrated. The crude acyl azide
was then dissolved in 20 mL of anhydrous benzene and heated
at 70 °C for 1 h (Rf of isocyanate: 0.48) before the addition of
either 5 mL (52.3 mmol) of anhydrous 2-methyl-2-propanol or
2.5 mL (17.4 mmol) of 2-(trimethylsilyl)ethanol. The solution
was stirred at 70 °C for an additional 6 h (Rf’s: 2d , 0.56; 2e,
0.58). The red-violet reaction mixture was concentrated, loaded
Dep r otection of 4-(N-((2-(Tr im eth ylsilyl)eth oxy)ca r -
bon yl)a m in o)tetr a flu or op h en yl Azid e (2e) To Give 1. The
carbamate 2e (1.50 g, 4.28 mmol) was dissolved in 25 mL of
CH2Cl2 at 0 °C. To the solution was added 2.5 mL of TFA.
The solution was allowed to stir at 0 °C for 3 h and then at
room temperature overnight. The reaction was then slowly
quenched by the addition of a saturated NaHCO3 solution. The
reaction mixture was transferred to a separatory funnel
containing 100 mL of Et2O and 20 mL of H2O and shaken and
the aqueous layer discarded. The organics were washed once
more with water, dried (MgSO4), filtered through a pad of silica
gel, and concentrated to afford 0.76 g (86%) of 1.
1,4-Tetr a flu or op h en ylen ed ia m in e (3c). Pentafluoroni-
trobenzene (3a ) was converted into 4-azidotetrafluoronitroben-
zene (3b) with NaN3 as described by Keana and Cai2g in 93%
yield and used without further purification. Into a 1000 mL
three neck round-bottom flask equipped with reflux condenser
was added 200 mL of 95% EtOH, 60 g (0.51 mol) of powdered
tin (325 mesh), and 26.41 g (0.11 mol) of crude 3b dissolved
in 50 mL of 95% EtOH with stirring. A 140 mL aliquot of
concentrated HCl was then added dropwise to the heteroge-
neous mixture over a 30 min period. The mixture was refluxed
for 4 h, cooled to room temperature, and placed into an ice
bath. The mixture was made basic by slow addition of 160 g
(11) For additional information, see supporting information.

4952 J . Org. Chem., Vol. 65, No. 16, 2000
Chehade and Spielmann
of NaOH dissolved in 250 mL of water. The mixture was
warmed to room temperature, and 100 g of NaCl was added.
The mixture was poured into a 2 L separatory funnel contain-
ing 600 mL of Et2O and extracted (3×) with Et2O. The
combined organic extracts were washed with water and brine
and dried over MgSO4. The solution was filtered and evapo-
rated to yield 18.25 g of an off-white/pink solid. The solid was
purified by sublimation (90 °C/0.5 mm) to yield 17.88 g (85%
from 3a ) of 3c as colorless crystals, mp 143-145 °C. These
crystals were stored in a foil-wrapped container under argon
2.34; N, 14.80. Found: C, 53.35; H, 2.37; N, 14.80. Low-
resolution EIMS calcd for C21H11F4N5O4: 473.3. Found: 473.1.
4-Azid otetr a flu or oa n ilin e (1). Into a 250 mL round-
bottom flask was added 3.08 g (6.51 mmol) of 3e and 100 mL
of Et2O. The mixture was then placed in an ice bath, and 10
mL (0.10 mol) of piperidine was added. The solution was
stirred at 0 °C for 50 min and then at room temperature for
10 min. The mixture was then poured into a 1 L separatory
funnel containing 200 mL of ice-cold 2 N HCl and 150 mL of
Et2O. The aqueous layer was discarded, and the organic
solution was then washed with 1 N HCl, water, and brine.
The solution was dried (MgSO4), filtered, and concentrated.
The crude orange-brown solid was purified by sublimation (38
°C/0.5 mm) to yield 1.25 g (93%) of 1 as golden crystals, mp
68-71 °C (dec). The resulting aniline azide is pure enough for
most purposes. TLC: Rf, 0.48. 1H NMR (500 MHz) δ 3.909 (s).
13C NMR (125.7 MHz) δ 142.6 (m), 140.7 (m), 138.3 (m), 136.4
(m), 123.4 (m), 108.4 (m). 19F NMR (470.3 MHz) δ -162.68
(m), -155.10 (m). IR: 3383, 3316, 3284, 3205, 2127, 1510,
1246, 969, 931 cm-1. UV: λmax(MeOH), 262 nm; ꢀmax(MeOH)
19 772; λmax(cyclohexane), 256 nm; ꢀmax(cyclohexane) 16 813.
Low-resolution EIMS calcd for C6H2F4N4: 206. Found 206.
Resublimation (33 °C/0.5 mm) gave the analytical sample of
1 as pale yellow crystals. Anal. Calcd for C6H2F4N4: C, 34.97;
H, 0.98; N, 27.18. Found: C, 35.09; H, 0.94; N, 27.39.
4-(N-(Ch lor oa cetyl)a m in o)tetr a flu or op h en yl Azid e (8).
A 50 mL round-bottom flask was charged with 0.53 g (2.57
mmol) of 1, 0.50 mL (3.78 mmol) of collidine, and 25 mL of
anhydrous EtOAc. After stirring to homogeneity at room
temperature, 3.00 mL (37.7 mmol) of chloroacetyl chloride,
dissolved in 5 mL of dry EtOAc, was added dropwise to the
solution over a 30 min period. The reaction mixture was then
stirred at room temperature for 6 h (TLC of 8: Rf, 0.32). The
mixture was poured into a separatory funnel containing 150
mL of EtOAc, and the organic layer was washed with water,
1 N HCl, water, and 5% NaHCO3. The ethereal layer was then
dried (MgSO4) and concentrated. The residual solid was
purified by flash chromatography (10% EtOAc in hexane) to
yield 0.57 g (79%) of 12 as a white solid, mp 109-110 °C (dec).
1H NMR (500 MHz) δ 7.89 (bs, 1H), 4.28 (s, 2H). 13C NMR
(125.7 MHz) δ 164.9, 144.4(m), 142.5 (m), 140.5 (m), 119.4 (m),
111.5 (m), 4.9. 19F NMR (470.3 MHz) δ -152.79 (m), -145.88
(m). IR: 3225, 2132, 1694, 1651, 1511, 1488, 1245, 1207, 1011,
964, 947 cm-1. An analytical sample was obtained by recrys-
tallization from cyclohexane, yielding 8 as a white fibrous solid.
Anal. Calcd for C8H3F4ClN4O: C, 34.00; H, 1.07; N, 19.83.
Found: C, 33.97; H, 1.20; N, 19.97. High-resolution EIMS calcd
for C8H3F4N4OCl: 281.9932. Found: 281.9936.
4-(N-(Iod oa cet yl)a m in o)t et r a flu or op h en yl Azid e (9).
Into a 50 mL round-bottom flask was added 0.36 g (1.27 mmol)
of 8 followed by 20 mL of dry acetone and 1.91 g (12.7 mmol)
of NaI. The solution was stirred at room temperature over-
night. The mixture was poured into a separatory funnel
containing 150 mL of Et2O, washed once with water, and dried
(MgSO4). Recrystallization from cyclohexane afforded 0.44 g
(93%) of 9 as fine colorless needles, mp 151-153 °C (dec). (TLC
of 9: Rf. 0.38). 1H NMR (500 MHz, DMSO-d6) δ 10.43 (bs, 1H),
3.88 (s, 2H). 13C NMR (125.7 MHz, DMSO-d6) δ 167.3, 143.3
(m), 141.3 (m), 139.3 (m), 117.8 (m), 112.3 (m), -1.7. 19F NMR
(470.3 MHz, DMSO-d6) δ -153.39 (m), -146.85 (m). IR: 3243,
3208, 2132, 1674, 1651, 1488, 1072, 1010, 962 cm-1. Anal.
Calcd for C8H3F4IN4O: C, 25.69; H, 0.81; N, 14.98. Found: C,
25.76; H, 0.83; N, 15.06. High-resolution EIMS calcd for
C8H3F4N4OI: 373.9288. Found: 373.9292.
4-(N-(5-(Dim eth yla m in o)-1-n a p h th a len esu lfon yl)a m i-
n o)tetr a flu or op h en yl Azid e (10). To a solution of 0.206 g
(1.00 mmol) of 1 in 10 mL of anhydrous THF at -78 °C was
added 0.278 g (1.03 mmol) of dansyl chloride immediately
followed by 1 mL (1.00 mmol) of lithium bis(trimethylsilyl)
amide (1 M solution in THF). The solution was stirred at -78
°C for 2 h. The solution was slowly warmed to room temper-
ature and stirred for an additional hour. The solution was
concentrated and purified by flash chromatography (15%
EtOAc in hexane). Fractions containing 10 (TLC: Rf, 0.32)
were combined and concentrated in vacuo to leave a viscous
1
at -20 °C. TLC: Rf 0.42. H NMR (500 MHz) δ 3.49 (s). 13C
NMR (125.7 MHz) δ 139.1 (m), 137.2 (m), 116.5 (m). 19F NMR
(470.3 MHz) δ -162.15 (s). IR: 3430, 3330, 1627, 1516, 1178,
1000, 920 cm-1. Crystallization (1 g of tetrafluorophenylene-
diamine/3 mL of toluene) of the sublimate gave the analytical
sample of 3c as colorless needles, mp 143-144 °C (lit.,6a 143.5-
144 °C). Anal. Calcd for C6H4F4N2: C, 40.01; H, 2.24; N, 15.55.
Found: C, 40.21; H, 2.35; N, 15.64. Low-resolution EIMS calcd
for C6H4F4N2: 180. Found: 180.
4-(N -((9-F lu or e n ylm e t h oxy)ca r b on yl)a m in o)t e t r a -
flu or oa n ilin e (3d ). Into a 250 mL three-neck flask equipped
with a 50 mL addition funnel was introduced 8.35 g (46.4
mmol) of freshly purified 3c, 100 mL of dry EtOAc, and 3.75
mL (46.4 mmol) of anhydrous pyridine. After stirring to
homogeneity at room temperature, the flask was immersed
in an ice bath, and 10.0 g (38.7 mmol) of FMOC-Cl, dissolved
in 35 mL of dry EtOAc, was added dropwise to the solution
over a 30 min period. The mixture was stirred at 0 °C for 4 h
and then at room temperature overnight (TLC of 3d : Rf, 0.26).
The reaction mixture was poured into a separatory funnel
containing 500 mL of EtOAc, and the organic layer was washed
with cold 1 N HCl, water, brine, and dried (Na2SO4) and
concentrated to yield 14.75 g of crude off-white crystals.
Recrystallization from CHCl3/hexane afforded 14.30 g (92%,
two crops) of 3d as fine colorless needles, mp 189 °C. 1H NMR
(500 MHz, 60 °C, DMSO-d6) δ 8.90 (bs, 1H), 7.85 (m, 2H), 7.63
(bs, 2H), 7.41 (t, J ) 7.3 Hz, 2H), 7.32 (m, 2H), 5.80 (m, 1H),
4.68 (m, 0.5H), 4.42 (d, J ) 6.8 Hz, 1.5H), 4.25 (m, 1H), 3.16
(s, 1H). 13C NMR (125.7 MHz, 60 °C, DMSO-d6) δ 157.8, 147.9
(m), 146.9, 146.00 (m), 144.1, 142.7, 141.5 (m), 140.8, 139.9
(m), 139.7 (m), 138.0 (m), 132.1, 130.8, 130.5, 130.3, 130.2,
128.2, 124.5, 123.2, 123.1, 119.4 (m), 112.5, 105.8 (m), 69.7,
49.9. 19F NMR (470.3 MHz, 60 °C, DMSO-d6) δ -162.98 (m),
-162.65 (m). IR: 3419, 1703, 1668, 1541, 1521, 1495, 1452,
1306, 1261, 981, 946, 738 cm-1. Anal. Calcd for C21H14
-
F4N2O2: C, 62.69; H, 3.51; N, 6.96. Found: C, 62.56; H, 3.57;
N, 7.00. Low-resolution EIMS calcd for C21H14F4N2O2 402.3.
Found: 402.2. High-resolution MALDIMS calcd for C21H14
F4N2O2Na: 425.0889. Found: 425.0894.
-
4-(N-(((2-Nitr oflu or en yl)-9-m eth oxy)ca r bon yl)a m in o)-
tetr a flu or op h en yl Azid e (3e). Aniline 3d (6.00 g, 14.9 mmol)
was dissolved in TFA (100 mL) and stirred at 0 °C for 10 min.
Solid NaNO2 (4.12 g, 59.7 mmol) was added in portions over
15 min with stirring, and the stirring was continued for an
additional 15 min. Solid NaN3 (3.27 g, 50.3 mmol) was then
added to the red-violet solution over a 10 min period, and the
mixture was allowed to stir at 0 °C for 80 min. The reaction
was warmed to room temperature over 10 min and then poured
onto 400 mL of ice water (ice is added to the 400 mL mark of
the beaker, followed by addition of water to the same mark)
and stirred for 5 min. The solid was filtered, washed with
water (2×), and dried in vacuo at 40 °C. Two recrystallizations
from CH2Cl2/pentane afforded 6.30 g (89%, two crops) of 3e
1
as an off-white solid, mp 151-152 °C (dec). TLC: Rf, 0.34. H
NMR (500 MHz) δ 8.39 (bs, 1H), 8.35 (dd, J ) 2.0 Hz, 1H),
7.87 (m, 2H), 7.64 (d, J ) 7.3 Hz, 1H), 7.49 (m, 2H), 6.26 (bs,
1H, CONH), 4.82 (m, 1H), 4.39 (m, 2H). 13C NMR (125 MHz)
δ 153.4, 148.1, 147.4, 145.1, 144.8, 144.4 (m), 142.4 (m), 142.1
(m), 140.1 (m), 139.5, 129.7, 129.0, 125.5, 124.6, 121.9, 120.9,
120.5, 119.2 (m), 112.2 (m), 67.6, 47.5. 19F NMR (470.3 MHz)
δ -210.47 (m), -204.86 (m). IR: 3217, 2130, 1708, 1513, 1485,
1337, 1266, 995, 978, 747 cm-1. An analytical sample was
obtained by recrystallization from CH2Cl2/pentane yielding 3e
as a white solid. Anal. Calcd for C21H11F4N5O4: C, 53.29; H,

Synthesis of New Photoaffinity Reagent
J . Org. Chem., Vol. 65, No. 16, 2000 4953
oil which was further evaporated at 25 °C under high vacuum
added 6 mL of a 3.5 × 10-2 M solution of azide 1 in
cyclohexane. The vial was then placed approximately 2 cm
from a 254 nm hand-held light source (UVP Model UVG-11)
and photolyzed for 7 h at 25 °C. Analysis of the reaction
mixture by GC-MS indicated amine 11 (M+ 262, 19%), diamine
3c (M+ 180, 17%), and azobenzene 12 (M+ 356, 29%).
affording 0.295 g (67%) of 10 as an orange glass, mp 42-48
1
°C. H NMR (400 MHz) δ 8.70 (bs, 1H), 8.36 (d, 1H, J ) 8.1
Hz), 8.20 (d, 1H, J ) 7.3 Hz), 7.62 (dd, 1H, J ) 8.6 Hz), 7.54
(t, 1H, J ) 8.6 Hz), 7.28 (bs, 1H), 6.60 (bs, 1H), 2.98 (s, 6H).
13C NMR (100.7 MHz) δ 145.3 (m), 142.8 (m), 142.0 (m), 139.6
(m), 134.7, 131.5, 130.4, 130.0, 129.8, 128.9, 123.9, 119.7 (m),
116.1, 111.8 (m), 46.1. 19F NMR (376.7 MHz) δ -152.74 (m),
-146.58 (m). IR: 3252, 2129, 1499, 1343, 1242, 1165, 1147,
1102, 1000, 949, 789 cm-1. Anal. Calcd for C18H13F4N5O2S: C,
49.20; H, 2.98; N, 15.94; S, 7.30. Found: C, 49.24; H, 3.17; N,
Su p p or tin g In for m a tion Ava ila ble: Figures showing 1H,
13C, 19F NMR, and MS spectra for compounds 1, 2a -e, 3a -e,
and 8-10 and text describing syntheses of compounds 2b and
2c. This material is available free of charge via the Internet
at http://pubs.acs.org.
15.67; S, 7.10. High-resolution EIMS calcd for
F4N5O2S: 439.0726. Found: 439.0722.
C18H13-
P h otolysis of Azid e 1 in Cycloh exa n e. Into a quartz
round-bottom vial equipped with a ground glass stopper was
J O000402P