A convenient synthesis of 4-alkoxy- and 4-hydroxy-2,6-difluoroanilines

Article abstract of DOI:10.1016/j.tetlet.2003.10.109

Two independent synthetic pathways for the preparation of 4-methoxy, 4-benzyloxy and 4-hydroxy-2,6-difluoroanilines, versatile building blocks in medicinal chemistry, based on diazonium coupling or Curtius-type rearrangements are presented.

Full text of DOI:10.1016/j.tetlet.2003.10.109

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 95–98
A convenient synthesis of 4-alkoxy- and 4-hydroxy-
2,6-difluoroanilines
a
Cristina Alonso-Alija, Martin Michels, Karen Peilstocker and Hartmut Schirok
a
b
a,
*
€
aDepartment of Medicinal Chemistry, Bayer HealthCare AG, D-42096 Wuppertal, Germany
bR&D Fluorine Chemistry, Bayer Chemicals AG, D-51368 Leverkusen, Germany
Received 16 September 2003; revised 14 October 2003; accepted 21 October 2003
Abstract—Two independent synthetic pathways for the preparation of 4-methoxy, 4-benzyloxy and 4-hydroxy-2,6-difluoroanilines,
versatile building blocks in medicinal chemistry, based on diazonium coupling or Curtius-type rearrangements are presented.
ꢀ 2003 Elsevier Ltd. All rights reserved.
Fluorinated compounds play a major role in drug dis-
covery, as the bioisosteric replacement of hydrogen by
fluorine has an effect on electronic, lipophilic and steric
parameters, which can critically influence the pharmaco-
dynamic and pharmacokinetic properties of drugs.1
Most importantly, fluoro derivatives are more resistant
to metabolic degradation than their hydrogen counter-
parts. On the other hand, ortho substituents on aromatic
rings have been recognized as conferring important
properties on the molecules that contain them. In con-
formationally restricted systems, they are able to freeze
the conformation, which leads to optimal target inter-
action. Moreover, it has been shown that reduced
molecular flexibility is an important parameter to
achieve good oral bioavailability.2
OH
OR
F
F
F
F
NH2
NH2
1
2a: R = Me
2b: R = Bn
Figure 1.
for 2a were not adequate for multigram synthesis,3 while
the synthesis of 1 and 2b had not been previously
described.4 We herein describe convenient procedures
for the synthesis of these compounds in multigram scale
and with good overall yields.
Within one of our drug discovery programs, we were
confronted with the need to synthesize 4-hydroxy-2,6-
difluoroaniline and several 4-alkoxy-2,6-difluoroanilines
as building blocks (Fig. 1). Literature reported methods
The synthesis of 2a described in the literature3 (Scheme
1) relies on the nucleophilic attack of sodium methanoate
on 2,4,6-trifluoronitrobenzene 3. The drawback of this
F
OMe
F
OMe
a
b
+
F
F
F
F
F
OMe
F
F
NO2
NO2
NO2
NH2
3
4a
4b
2a (14% from 3)
4a + 4b (1:2.2): (93%)
Scheme 1. Reagents and conditions: (a) NaOMe/MeOH, rt, 24 h; (b) H2 (1 atm), Pd/C (10%), MeOH, rt, 12 h.
Keywords: 4-alkoxy-2,6-difluoroanilines; 4-hydroxy-2,6-difluoroaniline; diazo coupling; Curtius rearrangement.
* Corresponding author. Tel.: +49-202-368926; fax: +49-202-364624; e-mail: hartmut.schirok.hs@bayer-ag.de
0040-4039/$ - see front matter ꢀ 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.10.109

96
C. Alonso-Alija et al. / Tetrahedron Letters 45 (2004) 95–98
method is the lack of regioselectivity: an inseparable
1:2.2 mixture of the para and ortho substituted products
4a and 4b is obtained. Separation can only be achieved
after selective demethylation of the ortho methoxy with
boron tribromide. After reduction, the desired aniline 2a
is obtained in less than 20% overall yield.
sen, respectively, depending on the nature of the inter-
mediate species.9 The direct conversion of the carboxylic
acid into the amine, the so-called Schmidt reaction,10 has
been reported for 2,6-difluorobenzoic acid using sodium
azide in sulfuric acid.11 Applying this methodology we
obtained the desired aniline in low yield accompanied by
the 1,4-diamino compound. Using the same reagents
diluted in chloroform12 the reaction resulted in decom-
position of the components. In cases where the acyl
azide is isolated prior to its thermal rearrangement to
yield an isocyanate the reaction is known as the Curtius
rearrangement.13 After generation of the acyl chloride
with thionyl chloride, reaction with sodium azide, ther-
mal rearrangement and treatment with water, we
obtained the desired aniline in about 39% yield.14 Using
trimethylsilyl azide as azide source did not show a
positive effect. A further opportunity was the facile
generation of the intermediate acyl azide directly from
the acid by using diphenyl phosphorylazide (DPPA).15
However, using this convenient method the yield was
also low, probably due to problems during the purifi-
cation of the polar and oxidizable product. On the other
hand, when treated with alcohols instead of water, the
intermediate isocyanates of the Claisen- or Schmidt-
rearrangements form carbamates, which can be purified
more easily than the unprotected p-alkoxyaniline.
Therefore we generated the t-butyl carbamate16 7a with
t-butanol and––more rapidly––the ethyl-carbamate 7b
with ethanol in 47% and 68% yields starting from the
acid (Scheme 2).17 From the carbamates, which can be
stored without decomposition at room temperature in
air, the aniline can be liberated almost quantitatively by
treatment with a base.
In our hands, all efforts to improve the regioselectivity
by using different alcohols or bases failed. We found
that after reduction of the difluoromethoxynitrobenzene
regioisomeric mixture with hydrogen over palladium/
carbon to the corresponding difluoromethoxyanilines,
these could be separated into both regioisomers: the
overall yield was 14% but the method was still limited by
the large amount of undesired isomer isolated in the
process (Scheme 1).
We were interested in an alternative approach leading to
this versatile reagent. It should be highly effective and
applicable to large-scale synthesis forming the desired
regioisomer exclusively. It is well known that fluoro-
arenes undergo smooth ortho metallation when they are
treated with organolithium reagents. A second electro-
negative substituent accelerates the deprotonation con-
siderably, and in the case of 1,3-difluorobenzene the
substrate is acidic enough to react smoothly with n-
butyllithium forming solely the 2-lithiated derivative.5
The resulting organolithium compounds are multipur-
pose reagents, and for example the almost quantitative
conversion of 3,5-difluoroanisole into 2,6-difluoro-4-
methoxybenzoic acid after successive treatment with n-
butyllithium and carbon dioxide has been described.6
Since the degradation of 2,6-difluorobenzoic acid and
analogues into the corresponding anilines using the
Schmidt or Curtius rearrangement has been reported, we
intended to apply this pathway to synthesize the desired
2,6-difluoro-4-alkoxyaniline.
In the course of our investigations we were also inter-
ested in analogues bearing a protecting group on the
oxygen, which can be removed under milder conditions
than the methyl ether in 2a, as for example the benzyl-
oxy ether 2b. Starting from 3,5-difluorophenol we gen-
erated the benzyl ether 5b in 89% yield.18 The lithiation/
carboxylation sequence gave access to the desired car-
boxylic acid 6b (42% yield),19 which was converted into
the ethyl carbamate 7c using DPPA in almost quanti-
tative yield.20 From this compound the aniline 2b could
be obtained under basic conditions (86%).21 Addition-
ally we were interested in a carbamate that liberates the
aniline in an acidic environment. Consequently we used
Starting from 3,5-difluoroanisole,7 lithiation with n-
butyllithium in THF at )78 ꢁC and treatment with solid
or gaseous carbon dioxide smoothly gave the desired
product 6a in 81% yield and with complete regioselec-
tivity (Scheme 2).8
The degradation reaction of a carboxylic acid to the
corresponding amine with one less carbon unit is linked
with the names of Hofmann, Curtius, Schmidt and Los-
OR
OR
OR
OR
a
b
c
F
F
F
F
F
F
F
F
CO2H
HN
OR'
NH2
O
5a: R = Me
5b: R = Bn
6a: R = Me (81%)
6b: R = Bn (42%)
7a: R = Me, R' = tBu (47%)
7b: R = Me, R' = Et (68%)
7c: R = Bn, R' = Et (95%)
7d: R = Bn, R' = TMSE (75%)
2a: R = Me (39% from 6a)
2b: R = Bn (86%)
Scheme 2. Reagents and conditions: (a) 1. nBuLi, THF, )78 ꢁC, 2. CO2, )78 ꢁC to rt; (b) 1. DPPA, NEt3, dioxane, 2. alcohol; (c) KOH, ethanol,
reflux.

C. Alonso-Alija et al. / Tetrahedron Letters 45 (2004) 95–98
97
OH
OH
OH
a
b
+
F
F
F
F
F
F
N+
NH2
N
N
N
Cl-
8: (79%)
1: (73%)
Scheme 3. Reagents and conditions: (a) 2N NaOH, 5–10 ꢁC; (b) Pd/C (10%), H2 (1 atm), ethanol, rt.
2-trimethylsilanyl ethanol as the alcohol component22
and obtained the desired carbamate 7d in 75% yield
(Scheme 2).23
6. Gray, G. W.; Hird, M.; Lacey, D.; Toyne, K. J. Mol.
Cryst. Liq. Cryst. 1989, 172, 165–189.
7. 3,5-Difluoroanisole 5a: To a solution of 25.0 g (192 mmol)
3,5-difluorophenol in 200 mL acetone were added 45.2 g
(327 mmol) potassium carbonate and 20 mL (290 mmol)
methyl iodide. The mixture was warmed to 40 ꢁC for 5 h,
then filtered and evaporated. Diethyl ether was added to
the residue and the solution was washed twice with water.
The organic phase was dried over sodium sulfate and the
solvent removed to yield 27.7 g (100%) of the desired
difluoroanisole. 1H NMR (300 MHz, CDCl3) d ¼ 3:78
(s, 3H), 6.36–6.46 (m, 3H).
8. 2,6-Difluoro-4-methoxybenzoic acid 6a: 28.0 g (194 mmol)
3,5-difluoroanisole in 500 mL THF were cooled to )78 ꢁC
and 77.7 mL of a 2.5 M solution of n-butyllithium in
hexane (194 mmol) was added. After 45 min dry ice was
added. After 2 h the reaction was warmed to rt. The
mixture was evaporated and the residue dissolved in
water. After addition of 30 mL of a 2 M NaOH solution
the aqueous phase was extracted twice with ether, then
acidified with 100 mL 4 M HCl and extracted with diethyl
ether (6 · 150 mL). The combined organic phases were
dried over sodium sulfate and evaporated to yield 29.6 g
(81%) of the desired benzoic acid. 1H NMR (300 MHz,
DMSO-d6) d ¼ 3:83 (s, 3H), 6.81 (m, 2H), 13.4 (br s, 1H);
MS (DCI): m=z 206 [M+NH4]þ.
A different approach was chosen to synthesize 4-
hydroxy-2,6-difluoroaniline 1 (Scheme 3). We envisaged
3,5-difluorophenol as a suitable aromatic substrate for
the coupling with diazonium compounds, a reaction
known to be para-selective with respect to the electron-
donor substituent.24 Indeed, coupling of 3,5-difluoro-
phenol with freshly prepared phenyl diazonium salt
(generated by diazotization of aniline with nitrous acid)
under alkaline conditions regioselectively resulted in the
azo compound 8,25 which could be cleaved to give 1 by
hydrogenation in good yield (73%).26 Aimed at 4-
hydroxy-2,6-difluoroaniline 1, this sequence in terms of
length and yield is obviously superior to alternative
approaches applying the methodologies shown in
Schemes 1 and 2, respectively, as in these cases a final
ether cleavage stepshould be incorporated. However,
the coupling with diazonium ions demands substrates
with strong electron-donor substituents and is therefore
limited to phenols and is not applicable for anisoles or
other alkoxy substituted aryls.
9. Shiori, Y. In Comprehensive Organic Synthesis; Trost, B.
M., Fleming, I., Eds.; Pergamon: Oxford, NY, 1991;
Vol. 6, pp 795–828.
In conclusion, we have developed two independent
synthetic pathways for the preparation of 4-methoxy, 4-
benzyloxy and 4-hydroxy-2,6-difluoroanilines, which
achieve the desired compounds in good overall yields
and have proven to be adequate for multigram scale.
10. Schmidt, K. F. Angew. Chem. 1923, 36, 511.
11. Roe, A. M.; Burton, R. A.; Willey, G. L.; Baines, M. W.;
Rasmussen, A. C. J. Med. Chem. 1968, 4, 814–819.
12. Woodroofe, C. C.; Zhong, B.; Lu, X.; Silverman, R. B.
J. Chem. Soc., Perk. Trans. 2 2000, 55–59.
13. Curtius, T. Ber. Dtsch. Chem. Ges. 1890, 23, 3023–3041.
14. 2,6-Difluoro-4-methoxyphenylamine 2a: 2.00 g (10.6 mmol)
of 6a was dissolved in 16 mL thionyl chloride, one dropof
DMF was added and the mixture was heated to reflux for
2 h. The crude mixture was evaporated to dryness and the
residue was dissolved in 5 mL acetone. A solution of
970 mg (14.9 mmol) sodium azide in 2 mL water was
added dropwise at rt. After 30 min, water (10 mL) was
added and the solution was extracted with toluene
(50 mL). The organic layer was dried over sodium sulfate
and heated to reflux for 30 min. Then 10 mL of a 45%
sodium hydroxide solution was added and the mixture
was heated for a further 30 min. The organic layer was
separated, dried over sodium sulfate and evaporated. The
residue was purified by column chromatography (dichlo-
romethane) to yield 660 mg (39%) of the title compound.
1H NMR (200 MHz, CDCl3) d ¼ 3:39 (br s, 2H), 3.72 (s,
3H), 6.45 (m, 2H); LC-MS: m=z 160 [M+H]þ.
References and Notes
1. Reviews: (a) Ismail, F. J. Fluorine Chem. 2002, 118, 27–33;
(b) Park, B. K.; Kitteringham, N. R.; OÕNeill, P. M. Ann.
Rev. Pharmacol. Toxicol. 2001, 41, 443–470.
2. Veber, D. F.; Johnson, S. R.; Cheng, H.-Y.; Smith, B. R.;
Ward, K. W.; Kopple, K. D. J. Med. Chem. 2002, 45,
2615–2623.
3. (a) Barnard, S.; Storr, R. C.; OÕNeill, P. M.; Park, B. K.
J. Pharm. Pharmacol. 1993, 45, 736–744; (b) OÕNeill,
P. M.; Harrison, A. C.; Storr, R. C.; Hawley, S. R.; Ward,
S. A.; Park, B. K. J. Med. Chem. 1994, 37, 1362–
1370.
4. Compound 1 was obtained by cytochrome P450-catalyzed
4-hydroxylation of 2,6-difluoroaniline; see: Cnubben, N.
H. P.; Vervoort, J.; Boersma, M. G.; Rietjens, I. M. C. M.
Biochem. Pharmacol. 1995, 49, 1235–1248.
15. (a) Ninomiya, K.; Shioiri, T.; Yamada, S. Tetrahedron
1974, 30, 2151–2157; (b) Thomas, A. V. In Encyclopedia
of Reagents for Organic Synthesis; Paquette, L. A., Ed.;
Wiley: New York, 1995; Vol. 4, pp 2242–2245.
5. (a) Tamborski, C.; Soloski, E. J. J. Org. Chem. 1966, 31,
746–749; (b) Mongin, F.; Schlosser, M. Tetrahedron Lett.
1996, 37, 6551–6554, and references cited therein.

98
C. Alonso-Alija et al. / Tetrahedron Letters 45 (2004) 95–98
16. Thornton, T. J.; Jarman, M. Synthesis 1990, 295–299.
17. (2,6-Difluoro-4-methoxyphenyl)carbamic acid tert-butyl
ester 7a: 3.00 g (15.9 mmol) of 6a was heated in 20 mL
thionyl chloride and two drops DMF at reflux for 2 h. The
excess of reagent was removed in vacuo and the residue
was dissolved in 10 mL acetone and cooled to 0 ꢁC. A
solution of 1.45 g (22.3 mmol) sodium azide in water
(3 mL) was added dropwise. A white solid precipitated
and was collected after addition of water by suction. The
residue was dissolved in 50 mL toluene, extracted with
brine and dried over sodium sulfate. After filtration, the
toluene solution was heated to 100 ꢁC for 1 h. Then, at
70 ꢁC, 3.0 mL (32 mmol) of t-butanol was added and the
mixture was heated at 70 ꢁC for 36 h. The mixture was
filtered and evaporated to yield 1.94 g (47%) of the desired
compound. 1H NMR (200 MHz, DMSO-d6) d ¼ 1:41
(s, 9H), 3.77 (s, 3H), 6.76 (m, 2H), 8.50 (br s, 1H); MS
(DCI): m=z 277 [M+NH4]þ. (2,6-Difluoro-4-methoxyphen-
yl)carbamic acid ethyl ester 7b: 509 mg (2.71 mmol) of the
benzoic acid 6a was dissolved in 8 mL dioxane. DPPA
0.70 mL (3.25 mmol) and 0.55 mL (400 mmol) triethyl-
amine were added and the mixture was stirred at rt for
30 min. 2.0 mL (35 mmol) methanol was added and the
reaction was heated to reflux for 2 h. After evaporation
the residue was dissolved in dichloromethane. The solu-
tion was washed with 5% citric acid, 5% sodium
bicarbonate solution and brine, then dried over sodium
sulfate and evaporated. The residue was treated with
cyclohexane and white crystals were collected by suction.
Yield 422 mg (68%). 1H NMR (300 MHz, CDCl3)
d ¼ 1:29 (t, J ¼ 7:1 Hz, 3H), 3.78 (s, 3H), 4.21 (q,
J ¼ 7:1 Hz, 2H), 5.81 (br s, 1H), 6.50 (m, 2H); MS
(ESI): m=z 232 [M+H]þ.
18. 1-Benzyloxy-3,5-difluorobenzene 5b: To a solution of
10.0 g (76.9 mmol) of 3,5-difluorophenol in 100 mL etha-
nol, 31.0 mL of a 10% aqueous sodium hydroxide solution
and subsequently 14.6 g (115 mmol) of benzyl chloride
were added dropwise. Afterwards the mixture was heated
to 100 ꢁC for 1 h. The ethanol was removed and the
residue treated with ethyl acetate/water. The organic
phase was washed twice with water, dried over sodium
sulfate and evaporated to yield 15.1 g (89%) of the desired
product. 1H NMR (300 MHz, DMSO-d6) d ¼ 5:13 (s, 2H),
6.74–6.85 (m, 3H), 7.30–7.47 (m, 5H).
19. 4-Benzyloxy-2,6-difluorobenzoic acid 6b: The compound
was synthesized analogously to 6a in 42% yield. 1H NMR
(200 MHz, DMSO-d6) d ¼ 5:19 (s, 2H), 6.92 (m, 2H),
7.32–7.49 (m, 5H), 13.5 (br s, 1H); MS (DCI): m=z 282
[M+NH4]þ.
(84.3 mmol) of potassium hydroxide was added. The
mixture was heated to reflux for 18 h, evaporated,
dissolved in water and extracted with diethyl ether (3·).
The combined organic phases were dried over sodium
sulfate and evaporated. The residue was purified by
column chromatography (dichloromethane/petroleum
ether 2:1) to yield 1.71 g (86%) of the desired aniline as
1
a yellow oil. H NMR (200 MHz, CDCl3) d ¼ 3:40 (br s,
2H), 4.95 (s, 2H), 6.52 (m, 2H), 7.30–7.42 (m, 5H); LC-
MS (ESI pos.): m=z 236 [M+H]þ.
22. Chehade, K. A. H.; Spielmann, H. P. J. Org. Chem. 2000,
65, 4949–4953.
23. (4-Benzyloxy-2,6-difluorophenyl)carbamic acid 2-trimethyl-
silanylethyl ester 7d: The compound was synthesized from
1
6b analogously to 7b in 75% yield. H NMR (300 MHz,
DMSO-d6) d ¼ 0:00 (s, 9H), 0.94 (dd, J ¼ 8:2, 7.7 Hz,
2H), 4.11 (dd, J ¼ 8:2, 7.7 Hz, 2H), 5.11 (s, 2H), 6.85 (m,
2H), 7.32–7.45 (m, 5H), 8.68 (br s, 1H); MS (ESI): m=z
425 [M+2Na]þ.
24. (a) Szele, I.; Zollinger, H. Top. Curr. Chem. 1983, 112, 1–
66; (b) Hegarty, A. F. In The Chemistry of the Diazonium
and Diazo Groups; Patai, S., Ed.; Wiley: New York, 1978;
pp 545–551.
25. 3,5-Difluoro-4-(phenyldiazenyl)phenol 8: 108 g (1.16 mol)
of aniline was added to 500 g of hydrochloric acid (27%)
at 0 ꢁC. A solution of 95.2 g (1.38 mol) sodium nitrite in
280 mL of water was added dropwise and the temperature
was kept below 5 ꢁC. The precipitate was dissolved by
addition of 200 mL hydrochloric acid (37%) and the
resulting solution was stirred for 1 h at 0 ꢁC. Excess
sodium nitrite was quenched by addition of amidosulfuric
acid. 101 g (0.77 mol) of 3,5-difluorophenol was dissolved
in aqueous sodium hydroxide, prepared from 183 g
(4.57 mol) sodium hydroxide and water (2.2 L). The
solution was cooled to 5 ꢁC and a freshly prepared
solution of the diazonium salt was added dropwise.
During addition the pH was controlled to remain strongly
alkaline. The reaction mixture was stirred for 1 h at room
temperature. The pH was adjusted to 4 by addition of 2 N
hydrochloric acid. The precipitate was filtered and washed
with water to yield 182 g (79%; purity approximately 80%
by GC analysis) of the desired azo compound as an
orange-brown solid. MS-EI: m=z 234 [M]þ. Caution! Solid
diazonium salts are heat and shock sensitive towards
explosion!
26. 4-Amino-3,5-difluorophenol 1: 9.87 g (42 mmol) of 3,5-
difluoro-4-(phenyldiazenyl)phenol was dissolved in etha-
nol. After addition of 100 mg of palladium on carbon
(10%) the mixture was stirred under a hydrogen atmo-
sphere at rt for 12 h. The catalyst was removed by
filtration, the solvent evaporated and the residue was
purified by column chromatography on silica gel (dichlo-
romethane: ethyl acetate 1:1). Recrystallization from
cyclohexane gave 4.5 g (73%) of the desired aminophenol
as a white solid. 1H NMR (300 MHz, DMSO-d6) d ¼ 4:33
(br s, 2H), 6.34 (m, 2H), 9.20 (s, 1H); GC–MS (TOF MS
CIþ): m=z 146 [M+H]þ.
20. (4-Benzyloxy-2,6-difluorophenyl)carbamic acid ethyl ester
7c: The compound was synthesized from 6b analogously
1
to 7b in 95% yield. H NMR (200 MHz, CDCl3) d ¼ 1:29
(t, J ¼ 7:1 Hz, 3H), 4.21 (q, J ¼ 7:1 Hz, 2H), 5.02 (s, 2H),
5.83 (br s, 1H), 5.57 (m, 2H), 7.34–7.42 (m, 5H); MS
(ESI): m=z 308 [M+H]þ.
21. 4-Benzyloxy-2,6-difluorophenylamine 2b: 2.59 g (8.43 mmol)
of 7c was dissolved in 40 mL ethanol and 4.73 g