Straightforward transformation of pentafluorobenzaldehyde into 4-aryloxy-2,3,5,6-tetrafluorobenzaldehydes

Article abstract of DOI:10.1055/s-0028-1083246

A new and practical process leading to 4-aryloxy-2,3,5,6- tetrafluorobenzaldehydes has been developed. The title skeleton is assembled in a convergent fashion from phenols and pentafluorobenzaldehyde via a nucleophilic substitution in the presence of inorganic fluorides. Scope and limitation studies have been conducted, revealing that the methodology is diversity tolerant, facilitating the introduction of various aryl and heteroaryl substituents. Altogether, 12 aldehydes were prepared in 14-93% yield. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1083246

4028
PAPER
Straightforward Transformation of Pentafluorobenzaldehyde into 4-Aryloxy-
2,3,5,6-tetrafluorobenzaldehydes
4
-Aryloxy-2, 3,5, 6-
a
tetrafluorob
n
e
nzaldehyde
i
s
from
e
Pentafluor
l
obenzaldehyd
T
e
. Gryko,* Dagmara Wyrostek, Agnieszka Nowak-Król, Katarzyna Abramczyk, Maciej K. Rogacki
Institute of Organic Chemistry of the Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland
Fax +48(22)6326681; E-mail: daniel@icho.edu.pl
Received 21 August 2008; revised 8 September 2008
the reaction of pentafluorobenzaldehyde with phenols
Abstract: A new and practical process leading to 4-aryloxy-
2,3,5,6-tetrafluorobenzaldehydes has been developed. The title
skeleton is assembled in a convergent fashion from phenols and
pentafluorobenzaldehyde via a nucleophilic substitution in the pres-
showed only one example.13 Thus, methyl 3,5-dihydroxy-
benzoate was converted into the corresponding methyl
3,5-bis(2,3,5,6-tetrafluoro-4-formylphenoxy)benzoate
ence of inorganic fluorides. Scope and limitation studies have been using potassium carbonate as base, in the presence of 18-
conducted, revealing that the methodology is diversity tolerant, fa-
crown-6, in butan-2-one at 15 °C.
cilitating the introduction of various aryl and heteroaryl substitu-
ents. Altogether, 12 aldehydes were prepared in 14–93% yield.
The reaction of pentafluorobenzaldehyde (1) with 4-nitro-
phenol (2) (chosen by us as the first model system for the
Key words: phenols, ethers, fluorine, nucleophilic aromatic substi-
optimization study, Table 1) under these reaction condi-
tution, aldehydes
tions, however, led to a complex and intractable mixture
of products. Consequently, we explored various possible
reaction conditions. It was found that the reaction pro-
Fluorinated aromatic aldehydes constitute an important
ceeds in the presence of potassium hydroxide, instead of
group of organic compounds which are often used in the
potassium carbonate, and 18-crown-6 in tetrahydrofuran
synthesis of dyes, biologically active compounds and in-
to give aldehyde 13 in 58% yield. The same reaction in the
secticides.1 The presence of fluorine atoms can have a
presence of DBU (as a non-nucleophilic base) in tetrahy-
positive influence on the properties of the final com-
drofuran afforded 13 in 42% yield, but in both cases nu-
pound.1 Moreover, in the chemistry of porphyrinoids, per-
merous side products were formed and separation
fluorinated substituents are often incorporated to affect
required careful chromatography. This fact prompted us
the oxidation and reduction potentials and to increase the
to investigate other reaction conditions. We turned to in-
stability of the macrocyclic compound.2 For many
organic fluorides as weak bases. They have been used in
projects related to various porphyrinoids, we were inter-
reactions of fluoronitrobenzenes with phenols.9,14 Given
ested in the transformation of the pentafluorophenyl sub-
the high reactivity of pentafluorobenzaldehyde, we as-
stituent into 4-substituted analogues according to the
sumed that even a weak base such as cesium fluoride
general SNAr mechanism. For the seminal compound in
would facilitate the SNAr reaction. Most importantly, the
the field – 5,10,15,20-tetrakis(pentafluorophenyl)porphy-
use of fluorides as a base would eliminate any competitive
rin – many such SNAr reactions have been reported.3–5 In
reactions with other nucleophiles. We started our experi-
our hands, however, the analogous reactions of 5,15-
ments with cesium fluoride due to its relatively high solu-
bis(pentafluorophenyl)corroles with phenolates as the nu-
bility in polar aprotic solvents. A solution of aldehyde 1
cleophilic partner led only to decomposition of the sub-
and phenol 2 in N,N-dimethylformamide was treated with
strate.
cesium fluoride (2 equiv) for two hours and then the reac-
Consequently, we considered another option, namely the
replacement of a fluorine atom with phenolates at the al-
dehyde level. Different sets of conditions have been pro-
posed for the reaction of 4-fluorobenzaldehyde with
secondary amines6 and phenols.7 SNAr reactions of substi-
tuted 1-fluoro-2-nitrobenzenes with complex phenols me-
diated by potassium carbonate8,9 were extensively used in
the synthesis of vancomycin. Pentafluorobenzaldehyde
has also been reacted with a variety of sulfur10 and
nitrogen11 nucleophiles to replace fluorine in the para-po-
sition, while the kinetics of nucleophilic displacement in
polyhaloaromatic compounds has been extensively stud-
ied.12 On the other hand, a thorough literature search for
tion mixture was poured into water. Subsequent crystalli-
zation of the resulting solid afforded aldehyde 13 in 85%
yield. Since the ratio phenol–cesium fluoride, 1:2, is far
from the reaction stoichiometry, we were interested to see
if the use of a stoichiometric amount of cesium fluoride
would affect the yield of the product. When the amount of
cesium fluoride was decreased to 1.0 equivalent (relative
to phenol 2), the yield of aldehyde 13 decreased to 26%.
Changing the solvent to less polar ones resulted in a de-
crease in the product yield. Furthermore, prolongation of
the reaction time and an increase in the reaction tempera-
ture had a detrimental effect on the yield (numerous side
products were formed).
Having a good procedure in hand [CsF (2 equiv), DMF,
r.t., 1.5 h], scope and limitation studies were conducted;
thus, reactions with different phenols 2–12 were per-
SYNTHESIS 2008, No. 24, pp 4028–4032
Advanced online publication: 01.12.2008
DOI: 10.1055/s-0028-1083246; Art ID: Z19508SS
x
x.
x
x
.
2
0
0
8
© Georg Thieme Verlag Stuttgart · New York

PAPER
4-Aryloxy-2,3,5,6-tetrafluorobenzaldehydes from Pentafluorobenzaldehyde
4029
CHO
Table 1 Results of the Reaction of Pentafluorobenzaldehyde with
Various Phenols
F
F
F
F
CHO
CHO
F
F
F
F
F
F
F
F
CsF or KF
DMF, r.t.
O
+
ArOH
F
F
F
OAr
O
F
F
1
2–12
13–22, 24
Phenol
Ar
Product(s)
Yielda (%)
85 (15)
51 (68)
60 (–)b
67 (68)
59 (93)
77 (90)
45 (–)b
34 (–)b
66 (–)b
CHO
2
3
4-O2NC6H4
4-IC6H4
13
14
15
16
17
18
19
20
21
23
Figure 1
4
4-Tol
used, the reaction afforded doubly substituted 23 as the
sole product. Moreover, we used phenol derivative 1215 as
an example of a more complex system. The reaction of 12
with pentafluorobenzaldehyde led to the corresponding
aldehyde 24 in 55% yield (Table 1). The presence of func-
tional groups such as CHO or NO2 in the starting phenol
did not interfere with the outcome of the studied reaction.
It should be noted that in many cases no chromatography
was needed to purify the product. In five out of 11 cases,
just crystallization was needed to obtain pure product.
5
4-t-BuC6H4
6
2-MeO-4-MeC6H3
2-MeO-4-OHCC6H3
mesityl
7
8
9
naphthalen-2-yl
pyridin-3-yl
10
11
3-HOC6H4
22
23
14c (0)d
64c (72)d
In conclusion, we have developed a mild and comprehen-
sive procedure for the nucleophilic substitution of the
para fluorine atom in pentafluorobenzaldehyde with phe-
nols. This facile procedure opens the way for a variety of
complex aldehydes to be used in materials or medicinal
chemistry. Using optimized conditions, 4-aryloxy-
2,3,5,6-tetrafluorobenzaldehydes could be prepared from
commercially available reagents in one step in 14–93%
yield. Our procedure can be characterized by the follow-
ing advantages: (1) good yields, (2) inexpensive sub-
strates, (3) often chromatography-free and (4) broad
scope.
12
24
55 (–)b
O
N
O
O2N
a CsF was used. Yields obtained with KF are given in parentheses.
b The reaction was not performed.
c 1 equivalent of C6F5CHO relative to resorcinol was used.
d 2 equivalents of C6F5CHO relative to resorcinol were used.
All chemicals were used as received unless otherwise noted. Re-
agent-grade solvents (CH2Cl2, hexane, cyclohexane, EtOAc) were
distilled prior to use. DMF was used as anhydrous (distillation with
MgSO4 under reduced pressure). All reported NMR spectra were
recorded on Varian Gemini 200 MHz, Varian Mercury 400 MHz
and Bruker AM 500 MHz spectrometers. Chemical shifts (d in ppm)
were determined with TMS as the internal reference; J values are
given in Hz. Chromatography was performed on silica gel (Kiesel-
gel 60, 200–400 mesh); dry column vacuum chromatography
(DCVC) was performed on preparative thin-layer chromatography
silica gel (Merck 107747). Mass spectra were obtained via EI-MS
using an AMD-604 Intectra instrument. Phenol 12 was prepared as
described in the literature.15
formed (Table 1). The diverse set of phenols included
phenols 3–5 with substituents of different electronic char-
acter, sterically hindered derivatives such as 6–8, phenol
7 bearing an additional functional group, 2-naphthol (9)
and an example of a heterocyclic phenol 10. In all cases,
the desired products were formed in yields ranging from
34 to 77%. We were delighted to find that cesium fluoride
can be replaced with less expensive potassium fluoride
and, in many cases, the reaction even worked much better
(Table 1). In the case of phenols 6 and 7, the products
were obtained in ~90% yield; however, it is rather diffi-
cult to find the rationale as to why potassium fluoride is
superior in some cases and cesium fluoride in others.
SNAr Reaction of Pentafluorobenzaldehyde (1) with Phenols;
General Procedure
Pentafluorobenzaldehyde (1; 0.62 mL, 5 mmol) and CsF (1.52 g, 10
mmol) were added to a soln of a phenol (5 mmol) in anhyd DMF (5
mL). The reaction mixture was stirred at r.t. for 1.5 h. The mixture
was poured into H2O (30 mL) and extracted with EtOAc (3 × 25
mL). The combined organic extracts were dried (Na2SO4) and the
solvent was removed under reduced pressure. The crude product
was crystallized or chromatographed.
The reaction with resorcinol (11) gave different results de-
pending on the ratio of the substrates. With 1 equivalent
of pentafluorobenzaldehyde relative to resorcinol, both 22
(14% yield) and 23 (Figures 1, 64% yield) were formed.
When 2 equivalents of pentafluorobenzaldehyde were
Synthesis 2008, No. 24, 4028–4032 © Thieme Stuttgart · New York

4030
D. T. Gryko et al.
PAPER
2,3,5,6-Tetrafluoro-4-(4-nitrophenoxy)benzaldehyde (13)
4-Nitrophenol (2; 696 mg, 5 mmol) and pentafluorobenzaldehyde
(1; 0.617 mL, 5 mmol) were dissolved in DMF (5 mL). Subsequent-
ly, CsF (1.52 g, 10 mmol) was added and the reaction mixture was
stirred at r.t. After 2 h, H2O (30 mL) was added. The precipitate was
collected by filtration, washed with H2O (50 mL) and dried under
reduced pressure. The filtrate was extracted with EtOAc (3 × 30
mL). The organic layers were combined, dried (Na2SO4) and con-
centrated. The residue was combined with the collected precipitate.
Crystallization (EtOAc–hexanes) afforded aldehyde 13; yield:
1.339 g (85%); mp 132 °C.
1H NMR (400 MHz, CDCl3): d = 7.13, 8.30 (AA¢BB¢, J = 9.0 Hz, 4
H), 10.33 (s, 1 H, CHO).
13C NMR (100 MHz, CDCl3): d = 112.4, 116.2, 126.2, 137.3, 141.2,
144.3, 147.5, 160.4, 181.6.
1H NMR (200 MHz, CDCl3): d = 1.32 (s, 9 H, CH3), 6.93, 7.36
(AA¢BB¢, J = 7.8 Hz, 4 H), 10.30 (br s, 1 H, CHO).
13C NMR (125 MHz, CDCl3): d = 31.4, 34.4, 111.1, 115.6, 126.8,
139.6, 141.3, 147.5, 147.6, 154.4, 182.0.
HRMS (EI): m/z [M+] calcd for C17H14F4O2: 326.0930; found:
326.0946.
Anal. Calcd for C17H14F4O2: C, 62.58; H, 4.32. Found: C, 62.51; H,
4.41.
2,3,5,6-Tetrafluoro-4-(2-methoxy-4-methylphenoxy)benzalde-
hyde (17)
Pentafluorobenzaldehyde (1; 0.62 mL, 5 mmol) and KF (0.58 g, 10
mmol) were added to a soln of 2-methoxy-4-methylphenol (6; 0.63
mL, 5 mmol) in DMF (5 mL). The reaction mixture was stirred at
r.t. for 1.5 h. The mixture was poured into H2O (30 mL) and extract-
ed with EtOAc (3 × 25 mL). The combined organic extracts were
dried (Na2SO4) and the solvent was removed under reduced pres-
sure. The crude product was chromatographed (EtOAc–hexanes,
1:9). Crystallization (cyclohexane) gave aldehyde 17 as colorless
crystals; yield: 1.454 g (93%); mp 74–75 °C.
1H NMR (200 MHz, CDCl3): d = 2.35 (s, 3 H, CH3), 3.80 (s, 3 H,
OCH3), 6.69–6.78 (m, 2 H, ArH), 6.95 (d, J = 8.2 Hz, 1 H, ArH),
10.26 (br s, 1 H, CHO).
13C NMR (125 MHz, CDCl3): d = 21.3, 26.9, 56.0, 109.7, 113.6,
118.5, 121.2, 136.1, 140.2, 143.0, 147.5, 149.6, 182.1.
19F NMR (376 MHz, CDCl3): d = –144.2, –152.4.
HRMS (EI): m/z calcd for C13H5F4NO4: 315.0155; found:
315.0163.
Anal. Calcd for C13H5F4NO4: C, 49.54; H, 1.60; F, 24.11; N, 4.44.
Found: C, 49.27; H, 1.95; F, 23.78; N, 4.42.
2,3,5,6-Tetrafluoro-4-(4-iodophenoxy)benzaldehyde (14)
4-Iodophenol (3; 2.2 g, 10 mmol) and pentafluorobenzaldehyde (1;
1.23 mL, 10 mmol) were dissolved in DMF (10 mL) and KF (1.162
g, 20 mmol) was added. After 1 h, H2O (50 mL) was added and the
resulting suspension was extracted with EtOAc (3 × 40 mL). The
organic layers were combined, dried (Na2SO4) and concentrated.
The solid was crystallized (cyclohexane) to obtain pure aldehyde
14; yield: 2.67 g (68%); mp 115 °C.
1H NMR (500 MHz, CDCl3): d = 6.79, 7.66 (AA¢BB¢, J = 8.9 Hz, 4
H), 10.30 (s, 1 H, CHO).
13C NMR (125 MHz, CDCl3): d = 87.7, 111.6, 118.3, 138.6, 138.9,
141.2, 147.5, 156.4, 181.8.
HRMS (EI): m/z [M+] calcd for C15H10F4O3: 314.0566; found:
314.0575.
Anal. Calcd for C15H10F4O3: C, 57.33; H, 3.21. Found: C, 57.44; H,
3.20.
2,3,5,6-Tetrafluoro-4-(4-formyl-2-methoxyphenoxy)benzalde-
hyde (18)
4-Hydroxy-3-methoxybenzaldehyde (7; 761 mg, 5 mmol) and pen-
tafluorobenzaldehyde (1; 0.615 mL, 5 mmol) were dissolved in
DMF (5 mL) and KF (0.581 g, 10 mmol) was added. The reaction
mixture was stirred at r.t. for 3 h. The mixture was poured into H2O
(30 mL) and extracted with EtOAc (2 × 30 mL). The organic layer
was washed with H2O (2 × 50 mL), dried (Na2SO4) and filtered,
then concentrated to dryness and chromatographed (EtOAc–hex-
anes, 1:9 to 2.5:7.5) to give pure product as an oil that was crystal-
lized (EtOAc–hexanes); yield: 1.47 g (90%); mp 96.2–96.9 °C.
1H NMR (400 MHz, CDCl3): d = 3.93 (s, 3 H), 7.16 (d, J = 8.2 Hz,
1 H), 7.48 (dd, J = 1.8, 1.9 Hz, 1 H), 7.54 (d, J = 1.8 Hz, 1 H), 9.95
(s, 1 H), 10.29 (t, J = 0.1 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 56.3, 110.7, 111.2, 117.9, 125.1,
134.1, 139.6, 140.7, 147.3, 149.6, 150.3, 181.9, 190.5.
HRMS (EI): m/z calcd for C13H5F4IO2: 395.9270; found: 395.9285.
Anal. Calcd for C13H5F4IO2: C, 39.42; H, 1.27. Found: C, 39.36; H,
1.23.
2,3,5,6-Tetrafluoro-4-(4-methylphenoxy)benzaldehyde (15)
4-Methylphenol (4; 1.135 g, 10.5 mmol) and pentafluorobenzalde-
hyde (1; 1.23 mL, 10 mmol) were dissolved in DMF (10 mL) and
CsF (3.04 g, 20 mmol) was added. After 1.5 h, H2O (50 mL) was
added and the resulting suspension was extracted with EtOAc
(3 × 30 mL). The organic layers were combined, dried (Na2SO4)
and concentrated. The solid was crystallized (cyclohexane) to ob-
tain pure aldehyde 15; yield: 1.68 g (60%); mp 106–107 °C.
1H NMR (500 MHz, CDCl3): d = 2.34 (s, 3 H, CH3), 6.91, 7.15
(AA¢BB¢, J = 8.7 Hz, 4 H), 10.29 (t, J = 1.0 Hz, 1 H, CHO).
13C NMR (125 MHz, CDCl3): d = 20.6, 111.0, 116.0, 130.4, 134.3,
139.7, 141.2, 147.8, 154.6, 182.0.
HRMS (EI): m/z calcd for C15H8F4O4: 328.03587; found:
328.03505.
Anal. Calcd for C15H8F4O4: C, 54.89; H, 2.46; F, 23.15. Found: C,
54.85; H, 2.59; F, 23.17.
HRMS (EI): m/z calcd for C14H8F4O2: 284.0460; found: 284.0469.
Anal. Calcd for C14H8F4O2: C, 59.16; H, 2.84. Found: C, 59.12; H,
2.71.
2,3,5,6-Tetrafluoro-4-(2,4,6-trimethylphenoxy)benzaldehyde
(19)
Pentafluorobenzaldehyde (1; 0.62 mL, 5 mmol) and CsF (1.52 g, 10
mmol) were added to a soln of 2,4,6-trimethylphenol (8; 0.68 g, 5
mmol) in DMF (5 mL). The reaction mixture was stirred at r.t. for
1.5 h. The mixture was poured into H2O (30 mL) and extracted with
EtOAc (3 × 25 mL). The combined organic extracts were dried
(Na2SO4), filtered and concentrated. Unreacted phenol was re-
moved under reduced pressure (70 °C/0.3 mbar). The remaining
yellow oil was crystallized (cyclohexane) to give colorless crystals;
yield: 0.70 g (45%); mp 73–75 °C.
4-(4-tert-Butylphenoxy)-2,3,5,6-tetrafluorobenzaldehyde (16)
Pentafluorobenzaldehyde (1; 0.62 mL, 5 mmol) and CsF (1.52 g, 10
mmol) were added to a soln of 4-tert-butylphenol (5; 0.753 g, 5
mmol) in DMF (5 mL). The reaction mixture was stirred at r.t. for
1.5 h. The mixture was poured into H2O (30 mL) and extracted with
EtOAc (3 × 25 mL). The combined organic extracts were dried
(Na2SO4) and the solvent was removed under reduced pressure. The
crude product was crystallized (cyclohexane) to give colorless crys-
tals; yield: 1.10 g (67%); mp 135.9–137.2 °C.
Synthesis 2008, No. 24, 4028–4032 © Thieme Stuttgart · New York

PAPER
4-Aryloxy-2,3,5,6-tetrafluorobenzaldehydes from Pentafluorobenzaldehyde
4031
1H NMR (500 MHz, CDCl3): d = 2.17 (s, 6 H, CH3), 2.28 (s, 3 H,
CH3), 6.86 (m, 2 H, ArH), 10.22 (t, J = 1 Hz, 1 H, CHO).
1H NMR (500 MHz, CDCl3): d = 6.53–6.57 (m, 2 H, ArH), 6.65
(ddd, J = 8.2, 2.3, 0.7 Hz, 1 H, ArH), 7.20 (t, J = 8.2 Hz, 1 H, ArH),
10.30 (br s, 1 H, CHO).
13C NMR (125 MHz, CDCl3): d = 103.9, 108.2, 111.4, 111.7, 130.7,
139.0, 141.4, 147.6, 157.0, 157.6, 182.0.
13C NMR (125 MHz, CDCl3): d = 16.0, 20.7, 108.7, 128.7, 129.7,
135.5, 139.1, 141.8, 147.7, 150.9, 182.0.
HRMS (EI): m/z [M+] calcd for C16H12F4O2: 312.0773; found:
312.0788.
HRMS (EI): m/z [M+] calcd for C13H6F4O3: 286.0253; found:
286.0260.
Anal. Calcd for C16H12F4O2: C, 61.54; H, 3.87. Found: C, 61.34; H,
3.83.
Anal. Calcd for C13H6F4O3: C, 54.56; H, 2.11. Found: C, 54.56; H,
2.24.
2,3,5,6-Tetrafluoro-4-(naphthalen-2-yloxy)benzaldehyde (20)
2-Naphthol (9; 720 mg, 5 mmol) and pentafluorobenzaldehyde (1;
0.615 mL, 5 mmol) were dissolved in DMF (5 mL) and CsF (1.52
g, 10 mmol) was added. The reaction mixture was stirred at r.t. for
3 h. The mixture was poured into H2O (30 mL) and extracted with
EtOAc (2 × 30 mL). The organic layer was washed with H2O (2 ×
40 mL), dried (Na2SO4), filtered and evaporated. The residue was
chromatographed (CH2Cl2–hexanes, 1:4 to 1:3) to give pure product
as an oil that was crystallized (CH2Cl2–hexanes); yield: 551 mg
(34%); mp 145–146 °C.
1,3-Bis(2,3,5,6-tetrafluoro-4-formylphenoxy)benzene (23)
Mp 147–148 °C.
1H NMR (200 MHz, CDCl3): d = 6.75–6.82 (m, 3 H, ArH), 7.34 (t,
J = 8.2 Hz, 1 H, ArH), 10.31 (br s, 2 H, CHO).
13C NMR (125 MHz, CDCl3): d = 105.5, 111.7, 111.7, 131.0, 138.4,
141.2, 147.5, 157.5, 181.7.
HRMS (EI): m/z [M+] calcd for C20H6F8O4: 462.0138; found:
462.0155.
1H NMR (400 MHz, CD2Cl2): d = 7.25–7.28 (m, 1 H), 7.33 (dd,
J = 2.6, 2.7 Hz, 1 H), 7.43–7.53 (m, 2 H), 7.73 (d, J = 7.7 Hz, 1 H),
7.84–7.92 (m, 2 H), 10.29–10.30 (m, 1 H).
Anal. Calcd for C20H6F8O4: C, 51.97; H, 1.31. Found: C, 51.93; H,
1.21.
13C NMR (100 MHz, CD2Cl2): d = 96.5, 111.4, 111.9, 117.4, 125.9,
127.5, 128.2, 130.8, 131.0, 134.2, 139.3, 141.7, 148.2, 154.8, 182.4.
2,3,5,6-Tetrafluoro-4-[3-(6-nitro-1,3-dioxo-1H-benzo[de]iso-
quinolin-2(3H)-yl)phenoxy]benzaldehyde (24)
Phenol 12 (334 mg, 1 mmol) and pentafluorobenzaldehyde (1;
0.123 mL, 1 mmol) were dissolved in DMF (15 mL). Subsequently,
CsF (304 mg, 2 mmol) was added and the reaction mixture was
stirred at r.t. After 2.5 h, H2O (100 mL) was added. The precipitate
was collected by filtration, washed with H2O (30 mL) and dried un-
der reduced pressure. Dry column vacuum chromatography
(CH2Cl2–hexane, 9:1; then CH2Cl2) afforded pure product; yield:
280 mg (55%); mp 135–137 °C.
1H NMR (400 MHz, DMSO): d = 7.28–7.37 (m, 3 H, ArH), 7.57–
7.64 (m, 1 H, ArH), 8.10–8.16 (dd, J = 8.1, 2.4 Hz, 1 H, ArH), 8.56–
8.67 (m, 3 H, ArH), 8.74–8.78 (dd, J = 8.2, 2.1 Hz, 1 H, ArH), 10.19
(s, 1 H, CHO).
13C NMR (100 MHz, DMSO): d = 111.9, 115.9, 116.9, 122.8,
123.2, 124.3, 125.2, 127.1, 128.7, 129.0, 129.7, 130.2, 130.4, 131.8,
136.9, 137.2, 139.7, 144.4, 148.8, 156.5, 162.3, 163.1, 183.4.
HRMS (EI): m/z [M+] calcd for C25H10F4N2O6: 510.04750; found:
510.04627.
HRMS (EI): m/z calcd for C17H8F4O2: 320.04604; found:
320.04753.
Anal. Calcd for C17H8F4O2: C, 63.76; H, 2.52; F, 23.73. Found: C,
63.61; H, 2.72; F, 23.81.
2,3,5,6-Tetrafluoro-4-(pyridin-3-yloxy)benzaldehyde (21)
Pyridin-3-ol (10; 475 mg, 5 mmol) and pentafluorobenzaldehyde
(1; 0.615 mL, 5 mmol) were dissolved in DMF (5 mL) and CsF
(1.52 g, 10 mmol) was added. The reaction mixture was stirred at
r.t. for 3 h. The mixture was poured into H2O (30 mL) and extracted
with EtOAc (2 × 30 mL). The organic layer was washed with H2O
(2 × 40 mL), dried (Na2SO4) and filtered. The filtrate was concen-
trated to dryness and chromatographed (EtOAc–hexanes, 1:4 to 1:1)
to give pure product as an oil that was crystallized (Et2O–hexanes);
yield: 894 mg (66%); mp 63–64 °C.
1H NMR (500 MHz, CDCl3): d = 7.32–7.38 (m, 2 H), 8.45–8.49 (m,
2 H), 10.31 (s, 1 H).
13C NMR (125 MHz, CDCl3): d = 111.8, 123.4, 124.3, 138.2, 138.8,
141.1, 145.9, 147.5, 153.1, 181.6.
Anal. Calcd for C25H10F4N2O6: C, 58.84; H, 1.97; F, 14.89; N, 5.49.
Found: C, 58.77; H, 1.65; F, 15.11; N, 5.40.
HRMS (EI): m/z calcd for C12H5F4NO2: 271.02564; found:
271.02645.
Acknowledgment
Anal. Calcd for C12H5F4NO2: C, 53.15; H, 1.86; F, 28.02. Found: C,
53.34; H, 1.84; F, 28.61.
We thank the Volkswagen Foundation and the US Air Force for fi-
nancial support.
Reaction of Resorcinol (11) with Pentafluorobenzaldehyde (1)
Pentafluorobenzaldehyde (1; 0.65 mL, 5.3 mmol) and CsF (1.52 g,
10 mmol) were added to a soln of resorcinol (11; 0.58 g, 5.3 mmol)
in DMF (5 mL). The reaction mixture was stirred at r.t. for 2 h, then
it was poured into H2O (30 mL). The resulting colorless precipitate
was collected by filtration and washed with H2O (50 mL). Crystal-
lization of the crude products selectively gave 23, as colorless crys-
tals. The residue was chromatographed (EtOAc–hexanes, 1:19)
affording 23 (total yield: 0.775 g, 64%) and 22 which was crystal-
lized (EtOAc–hexanes) to give colorless crystals (yield: 0.193 g,
14%).
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