Synthesis of alkoxy-substituted pyridines from mono- and tricationic pyridinium salts

Article abstract of DOI:10.1055/s-2005-861827

Nucleophilic substitution reactions on 4-(4-dimethyl-amino)-pyridinium- substituted tetrachloropyridine with oxygen nucleophiles such as alkoxides and phenolates resulted in the formation of 4- or 2,4-alkoxy- or -phenoxy-substituted chloropyridines depend

Full text of DOI:10.1055/s-2005-861827

PAPER
781
Synthesis of Alkoxy-Substituted Pyridines from Mono- and Tricationic
Pyridinium Salts
Synthesis of
A
lkox
n
y-Substitute
d
d
Pyridines reas Schmidt,* Thorsten Mordhorst
Clausthal University of Technology, Institute of Organic Chemistry, Leibnizstrasse 6, 38678 Clausthal-Zellerfeld, Germany
Fax +49(5323)723861; E-mail: schmidt@ioc.tu-clausthal.de
Received 20 October 2004
philes. The (tetrachloropyridin-4-yl)pyridinium chloride
2 and the (3,5-dichloropyridine-2,4,6-triyl)-tris-pyridini-
um trichloride 3 are available in quantitative yields from
pentachloropyridine (1) on reaction with DMAP
Abstract: Nucleophilic substitution reactions on 4-(4-dimethyl-
amino)-pyridinium-substituted tetrachloropyridine with oxygen nu-
cleophiles such as alkoxides and phenolates resulted in the
formation of 4- or 2,4-alkoxy- or -phenoxy-substituted chloropy-
ridines depending on the reaction conditions. Substitution on 2,4,6- (Scheme 1).13
tris(4-dimethylamino)pyridinium-substituted 3,5-dichloropyridine
We were interested in the synthetic potential of 2 and 3, as
they possess two distinct types of leaving groups with dif-
ferent leaving group tendencies.
gave the corresponding 2,4,6-tris-alkoxy- or -phenoxy-substituted
pyridines which are not available by other routes.
Key words: nucleophilic aromatic substitutions, pyridinium salts,
pyridines, trication
Cl
Cl
Cl
Cl
Cl
Substitution reactions on halogenated heteroaromatics are
well-known reactions in organic chemistry. In the case of
pyridines, these reactions lead to numerous biologically,
pharmaceutically or industrially interesting compounds.1
Nucleophilic substitutions on halogen-substituted py-
ridines proceed via the AE-mechanism,1 but SN(AN-
RORC)-,2 EA-3 or SRN1-mechanisms4 are observed as well.
A large number of reports prove that the 2- and 4-posi-
tions of chloropyridines smoothly react with a broad vari-
ety of nucleophiles in high yields,5 whereas the 3-position
is most often inert under these non-catalysed conditions.6
4-Nitro-substituted derivatives are exceptions from this
observation.7 However, substitution reactions on pentaha-
logenopyridines, although widely applied, suffer from
considerable disadvantages. First, they are limited to the
preparation of mono- or disubstituted chloropyridines and
often give mixtures of 2- and 4-substituted tetrachloropy-
ridines as well as 2,4-disubstituted trichloropyridines1,8 on
reaction with alkoxides and other nucleophiles.9 It was de-
scribed earlier that large nucleophiles attack partly or
mainly the 2(6)-position of pentachloropyridine, whereas
small nucleophiles substitute the 4-position.9,10 An addi-
tional problematic issue is that some 4-alkoxy-substituted
tetrachloropyridines decompose to tetrachloro-4-hy-
droxypyridine and alkenes under the reaction conditions
applied,10 so that their isolation is difficult. Consequently,
a large number of simple substituted pyridines have never
been described to date.
N
1
DMAP,1,2-DCB,
DMAP, 1,2-DCB,
2 h, 130 °C (>99%)
2 h, 90 °C (>99%)
NMe2
NMe2
Cl
3 Cl
N
N
Cl
Cl
Cl
Cl
Cl
N
N
N
Cl
N
Me2N
NMe2
2
3
Scheme 1
First, we focused our interest on monocation 2 and found
reaction conditions which allowed the straightforward
syntheses of 4-alkoxy-substituted 2,3,5,6-tetrachloropy-
ridines 5 and 2,4-dialkoxy-substituted 3,5,6-trichloropy-
ridines 6 (Scheme 2). Furthermore, (hetero)aromatic
ethers such as 7–9 were available starting from 2
(Scheme 3). The outcome of the reaction was dependent
on the stoichiometric ratio of the starting materials, the re-
action times, and temperatures, which are presented in
Table 1.
Thus, treatment of pyridinium salt 2 with sodium metha-
nolate yielded either tetrachloro-4-methoxypyridine 5a or
its 2,4-dimethoxy derivative 6a depending on the reaction
conditions. Pyridine 5a is a known compound and had
earlier been prepared by multi-step procedures (via tetra-
chloro-4-methylsulfonylpyridine14 or 4-hydroxy-ethyl-
sulfonamide15). Substitution on pentachloropyridine led
to a mixture of isomers, from which 5a was finally isolat-
ed after morefold recrystallizations.16 The disubstituted
In continuation of our work on oligocationic
heteroaromatics11 and mesomeric betaines12 we report
here our results concerning substitution reactions on pyri-
dinium-substituted pyridines 2 and 3 with oxygen nucleo-
SYNTHESIS 2005, No. 5, pp 0781–0786
x
x
.
x
x
.2
0
0
5
Advanced online publication: 14.02.2005
DOI: 10.1055/s-2005-861827; Art ID: T09804SS
© Georg Thieme Verlag Stuttgart · New York

782
A. Schmidt, T. Mordhorst
PAPER
Table 1 Synthesis of Alkoxy- and Dialkoxy-Substituted Chloropyridines 5–9
Compound
R
Nucleophile (equiv)
MeO– (1)
Solvent
MeOH
MeOH
EtOH
Reaction time (h), Temperature Yield (%)
5a
6a
5b
6b
5c
6c
5d
6d
5e
5f
5g
7
Me
6, reflux
3, reflux
24, r.t.
51
55
Me
MeO– (5)
Et
EtO– (1)
30
Et
EtO– (10)
EtOH
6, reflux
12, r.t.
57
i-Pr
i-PrO– (5)
i-PrOH
i-PrOH
n-PrOH
n-PrOH
t-BuOH
DMFa
73
i-Pr
i-PrO– (10)
n-PrO– (1)
n-PrO– (10)
t-BuO– (8)
n-OctO– (1)
C3H5O– (5)
PhO– (1)
5, reflux
24, r.t.
87
n-Pr
28
n-Pr
6, reflux
5, reflux
18, reflux
12, r.t.
87
t-Bu
33
n-Octyl
Allyl
Ph
23
C3H5OH
DMFa
28
18, 100 °C
5, 100 °C
5, 100 °C
>99
>99
31
8
4-MeOC6H4
Pyridin-3-yl
C7H7O– (10)
C5H4NO– (1)
DMFa
9
DMFa
a Equimolar amounts of NaNH2 were added.
derivative 6a was obtained earlier starting from pen- instabilities of the 4-alkoxy-substituted chloropyridines,
tachloropyridine and sodium methanolate after 22 hours especially of the ethoxy-, n-propoxy-, t-butoxy- and n-oc-
at reflux temperature,16 or by a five-step-procedure via tet- tyloxy derivatives (5b, 5d, 5e, 5f) is reflected in relatively
rachloropyridine-4-sulfenyl chloride.17 The method de- low yields after purification.
scribed here offers some advantages: First, mixtures of
monosubstituted and disubstituted compounds are not
Reaction of 2 with phenol, its 4-methoxy derivative, and
3-hydroxypyridine afforded the addition of a strong base
formed, so that the separation of two species with very
to the DMF solution to generate the corresponding pheno-
similar polarities and solubilities is not necessary. More-
lates, which reacted to 7, 8, and 9 (Scheme 3). Sodium
amide proved to give the best yields. Whereas 7 can also
over, polar by-products such as 2- or 2,6-dialkoxy-substi-
tuted pyridine-4-yl pyridinium salts as well as the leaving
group DMAP can easily be removed by filtration over sil-
ica gel so that the work-up procedure is considerably fa-
be prepared starting from pentachloropyridine followed
by separation from its 2-isomer,21 the ethers 8 and 9 are,
to the best of our knowledge, new compounds.
cilitated.
R
Starting from 2, we were therefore able to prepare the
ethoxy, 1-propoxy, 2-propoxy, t-butoxy, n-octyloxy, and
R
allyloxy derivatives 5b–g and 6b–d under the conditions
O
presented in Table 1. From these, only 5b,18–20 5d18 (alky-
Cl
Cl
Cl
Cl
lation of the pyridin-4-olate in low yields18) and 5e10 have
been described before. The latter was obtained earlier in
low yield on treatment of pentachloropyridine with potas-
sium tert-butoxide as a mixture with its 2-isomer, and
proved to be very sensitive towards the elimination of
isobutene under formation of 4-hydroxypyridine.10a The
OH
N
7: R = H
8: R = OMe
NaNH2
DMF
2
N
O
OR
OR
3-hydroxy-
pyridine
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
RO
2
+
N
Cl
N
OR
N
9
5
6
Scheme 3
Scheme 2
Synthesis 2005, No. 5, 781–786 © Thieme Stuttgart · New York

PAPER
Synthesis of Alkoxy-Substituted Pyridines
783
Table 2 Synthesis of 2,4,6-Trialkoxy-Substituted 3,5-Dichloro-pyridines
Compound
R
Nucleophile
MeO–
Solvent
MeOHa
EtOHa
Yield (%)
10a
Me
>99
55
87
59
55
20
95
28
71
90
38
10b
Et
EtO–
10c
i-Pr
i-PrO–
i-PrOHa
n-PrOHa
n-BuOHa
t-BuOHa
Allyl alcohola
C8H17OHa
DMFb
10d
n-Pr
n-PrO–
10e
n-Bu
t-Bu
n-BuO–
10f
t-BuO–
10g
Allyl
n-Octyl
Ph
CH2=CHCH2O–
CH3(CH2)7O–
PhO–
10h
10i
10j
4-MeOC6H4
Pyridin-3-yl
4-MeOC6H4O–
Pyridin-3-olate
DMFb
10k
DMFb
a Sodium salt.
b Stoichiometric amounts of sodium amide added.
2,4,6-Trisubstitution on pentachloropyridine with nucleo- amide proved to be the most suited solvent for substitu-
philes have very scarcely been described in the literature. tions with phenolates and pyridine-3-olate. The anionic
One example is the preparation of 2,4,6-trimethoxy-pyri- species were generated by stoichiometric amounts of so-
dine 10a which was synthesized from pentachloropyri- dium amide. Thus, 2,4,6-triphenoxypyridine 10i22 and its
dine at high temperature and pressure in an autoclave in p-methoxy derivate 10j,8 as well as the 2,4,6-tri-O-(3-hy-
16% yield.16a By contrast, the trication 3 allows easy prep- droxypyridine) derivative 10k were formed as colored
arations of the hitherto inaccessible symmetrically substi- solids.
tuted pyridines 10a–h (Scheme 4, Tables 2 and 3),
including the trimethoxy derivative, which is formed in
quantitative yield by the method described here. Aliphatic
alcohols can be used as solvents, whereas dimethylform-
It is apparent that the methoxy and the allyloxy derivate
10a and 10g, which cannot eliminate alkenes with con-
comitant formation of 4-hydroxypyridine, give the best
yields. It has generally been supposed that the tert-butox-
ide ion is too large to penetrate to a ring carbon atom, and
OR
even if it does under vigorous conditions, immediate de-
composition to iso-butene occurs.10a These observations
explain the low yield of the 4-t-butoxy-pyridine 10f which
nonetheless could be completely characterized.
Cl
Cl
RO
N
OR
10a–h
RO
The substitutions are not reversible. Thus, no reaction was
observable on treatment of 10a with excess DMAP after
heating at 190 °C in 1,2-dichlorobenzene over a period of
six hours (Scheme 5). The addition of excess TMSOTf
had no influence on the outcome of the reaction.
R´
ROH
O
R´
Cl
O
Cl
O
R´
R´-C6H4-OH
DMF, NaNH2
3
N
DMAP, TMSOTf,
OMe
1,2-dichlorobenzene
6 h, 190 °C
Cl
Cl
10i: R´ = H
10j: R´ = OMe
HO
DMF,
NaNH2
MeO
N
OMe
N
N
10a
O
Cl
O
Cl
Scheme 5
N
N
N
O
10k
Scheme 4
Synthesis 2005, No. 5, 781–786 © Thieme Stuttgart · New York

784
A. Schmidt, T. Mordhorst
PAPER
Table 3 Characterization of New Compoundsa
Compound Mp (°C) 1H NMR (DMSO-d6)
d [ppm], J [Hz]
13C NMR (DMSO-d6)b
d [ppm]
EIMS
m/z (%)
5c
63
4.84 (m, 1 H, CH), 1.33 (d, 3J = 6.1 Hz, 6 H, CH3) 160.5 (C-4), 145.7 (C-2/6), 124.9 (C-3/5), 79.9 (CH), 274 (24)
22.3 (CH3)
[M+], 232
(100)
5fc
Oil
4.19 (t, 3J = 6.4 Hz, 2 H, OCH2), 1.85 (m, over-
lapped, 2 H, 2-CH2), 1.48 (m, overlapped, 2H, 7-
CH2), 1.30 (m, overlapped, 8 H, 3-CH2, 4-CH2, 5- (CH2), 25.6 (CH2), 22.6 (CH2), 14.1 (CH3)
161.7 (C-4), 146.7 (C-2/6), 125.0 (C-3/5), 70.5
(OCH2), 31.8 (CH2), 30.0 (CH2), 29.2 (CH2), 29.1
346 (31)
[M+], 42
(100)
CH2, 6-CH2), 0.89 (s, 3 H, CH3)
5g
6b
6c
6d
8
44
5.81 (m, 1 H, CH), 5.23 (m, 1 H, =CH2), 5.05 (m, 1 156.8 (C-4), 145.6 (C-2/6), 132.3 (=CH), 119.6 (C- 273 (22)
H, =CH2), 4.52 (m, 2 H, CH2)
3/5), 118.2 (=CH2), 75.1 (CH2)
[M+], 41
(100)
Oil
Oil
Oil
61
4.36 (q, 3J = 7.1 Hz, 2 H, CH2), 4.22 (q, 3J = 7.1 Hz, 160.8 (C-4), 157.2 (C-2), 143.1 (C-6), 117.0 (C-3),
271 (58)
2 H, CH2), 1.39 (t, 3J = 7.1 Hz, 3 H, CH3), 1.35 (t, 111.0 (C-5), 70.4 (CH2), 63.9 (CH2), 15.3 (CH3), 14.1 [M+], 254
3J = 7.1 Hz, 3 H, CH3)
(CH3)
(100)
5.20 (h, 3J = 6.2 Hz, 1 H, OCH), 4.78 (h, 3J = 6.2
159.9 (C-4), 156.8 (C-2), 143.2 (C-6), 116.9 (C-3),
299 (74)
Hz, 1 H, OCH), 1.35 (d, 3J = 6.2 Hz, 6 H, CH3), 1.32 111.5 (C-5), 78.7 (CH), 71.1 (CH), 22.3 (CH3), 21.5 [M+], 213
(d, 3J = 6.2 Hz, 6 H, CH3)
(CH3)
(100)
4.26 (t, 3J = 6.6 Hz, 2 H, OCH2), 4.12 (t, 3J = 6.6 Hz, 160.9 (C-4), 157.4 (C-2), 143.1 (C-6), 116.8 (C-3),
298 (72)
2 H, OCH2), 1.77 (m, 4 H, CH2), 1.02 (t, 3J = 6.6
Hz, 3 H, CH3), 0.98 (t, 3J = 6.6 Hz, 3 H, CH3)
110.8 (C-5), 75.8 (OCH2), 69.3 (OCH2), 22.9 (CH2), [M+], 255
21.5 (CH2), 10.1 (2 × CH3)
(100)
6.81 (m, 4 H, PhH), 3.79 (s, 3 H, CH3)
157.9 (C-4), 156.0 (C-4¢), 149.3 (C-2/6), 147.2 (C-
1¢), 125.5 (C-3/5), 116.6 (C-2¢/4¢), 115.0 (C-3¢/5¢),
55.7 (CH3)
329 (100)
[M+]
9c
109
8.36 (d, 5J = 4.8 Hz, 1 H, 2-H), 8.25 (d, 3J = 2.9 Hz, 155.5 (C-4), 150.8 (C-3), 146.4 (C-6¢), 144.4 (C-2/6), 311 (70)
1 H, 6-H), 7.23 (dd, 4J = 8.4 Hz, 5J = 4.8 Hz, 1 H, 137.4 (C-2¢), 124.2 (C-5¢), 123.3 (C-4¢), 121.4 (C- [M+], 273
5-H), 7.07 (dd, 4J = 8.4 Hz, 4J = 2.9 Hz, 1 H, 4-H) 3/5)
(100)
10ac
10bc
10c
86
3.81 (s, 3 H, CH3), 3.80 (s, 6 H, CH3)
157.2 (C-4), 153.0 (C-2/6), 108.5 (C-3/5), 55.3
(CH3), 54.5 (2 × CH3)
237 (100)
[M+]
Oil
32
4.39 (q, 3J = 7.0 Hz, 4 H, CH2), 4.19 (q, 3J = 7.0 Hz, 161.2 (C-4), 156.3 (C-2/6), 103.3 (C-3/5), 69.8
2 H, CH2), 1.43 (m, 9 H, CH3) (CH2), 63.0 (2 × CH2), 15.5 (CH3), 14.5 (2 × CH3)
279 (100)
[M+]
5.19 (m, 2 H, CH), 4.71 (m, 1 H, CH), 1.36 (s, 6 H, 159.9 (C-4), 155.5 (C-2/6), 102.6 (C-3/5), 77.4 (CH), 321 (100)
CH3), 1.33 (s, 12 H, CH3)
70.0 (2 × CH), 22.2 (2 × CH3), 21.7 (4 × CH3)
[M+]
10d
Oil
4.25 (t, 3J = 6.6 Hz, 4 H, OCH2), 4.02 (t, 3J = 6.6 Hz, 160.8 (C-4), 156.0 (C-2/6), 102.1 (C-3/5), 75.2
322 (M+,
100)
2 H, OCH2), 1.74 (m, 6 H, CH2), 1.04 (t, 3J = 6.6
Hz, 6 H, CH3), 0.99 (t, 3J = 6.6 Hz, 3 H, CH3)
(OCH2), 68.3 (2 × OCH2), 22.9 (CH2), 21.7 (2 ×
CH2), 10.2 (3 CH3)
10e
Oil
4.33 (t, 3J = 6.5 Hz, 4 H, OCH2), 4.08 (t, 3J = 6.5 Hz, 160.8 (C-4), 156.0 (C-2/6), 102.2 (C-3/5), 73.4
364 (100)
[M+]
2 H, OCH2), 1.71 (m, 6 H, CH2), 1.43 (m, 6 H,
(OCH2), 66.6 (2 × OCH2), 31.5 (CH2), 30.3 (2 ×
CH2), 18.6 (2 × CH2), 18.5 (CH2), 13.6 (2 × CH3),
13.5 (CH3)
CH2), 0.93 (t, 3J = 6.5 Hz, 9 H, CH3)
10f
10g
10h
41
1.57 (s, 9 H, CH3), 1.50 (s, 18 H, CH3)
164.9 (C-4), 153.9 (C-2/6), 101.1 (C-3/5), 81.9
(CMe3), 75.6 (2 CMe3), 29.3 (3 × CH3), 27.9 (6 ×
CH3)
252 (100)
[M+ – 2 ×
C4H8]
Oil
Oil
6.10 (3 H, =CH), 5.30 (m, 6 H, =CH2), 4.88 (dt, 160.5 (C-4), 155.4 (C-2/6), 132.9 (2 CH=CH2), 132.6 317 (84)
3J = 5.7 Hz, 5J = 1.4 Hz, 4 H, OCH2), 4.67 (dt, 3J = (CH=CH2), 119.2 (2 × =CH2), 118.0 (=CH2), 102.7
[M+], 275
(100)
5.7 Hz, 5J = 1.4 Hz, 2 H, OCH2)
(C-3/5), 74.2 (2 × OCH2), 67.5 (OCH2)
4.32 (t, 3J = 5.7 Hz, 6 H, OCH2), 3.38 (m, 6 H;
158.8 (C-4), 145.8 (C-2/6), 111.2 (C-3/5), 60.6 (3 × 532 (100)
[M+]
CH2), 28.7 (3 × CH2), 25.5 (3 × CH2), 22.1 (3 ×
CH2), 13.9 (3 × CH3)
CH2), 1.71 (m, 6 H, CH2), 1.25 (m, 24 H, CH2), 0.86 OCH2), 32.5 (3 × CH2), 31.2 (3 × CH2), 28.9 (3 ×
(t, 3J = 6.5 Hz, 9 H, CH3)
Synthesis 2005, No. 5, 781–786 © Thieme Stuttgart · New York

PAPER
Synthesis of Alkoxy-Substituted Pyridines
785
Table 3 Characterization of New Compoundsa (continued)
Compound Mp (°C) 1H NMR (DMSO-d6)
d [ppm], J [Hz]
13C NMR (DMSO-d6)b
d [ppm]
EIMS
m/z (%)
10k
149
8.52 (d, 4J = 2.8 Hz, 1 H, 2¢-H), 8.37 (d, 4J = 2.8 Hz, 156.8 (C-4), 155.0 (C-2/6), 152.1 (C-3¢), 149.1 (2 × 428 (100)
3 H, 6¢-H), 8.52 (dd, 4J = 2.8 Hz, 3J = 4.7 Hz, 2 H, C-3¢), 146.2 (2 × C-4¢), 144.8 (C-4¢), 142.4 (2 × C-
2¢-H), 7.63 (dd, 4J = 2.8 Hz, 3J = 4.7 Hz, 1 H; 5¢-H), 2¢), 137.7 (C-2¢), 128.8 (2 × C-5¢), 124.8 (C-5¢),
7.58 (dd, 5J = 2.8 Hz, 3J = 4.7 Hz, 2 H, 5¢-H), 7.48 124.0 (2 × C-6¢), 122.5 (C-6¢), 106.5 (C-3/5)
(d, 3J = 4.7 Hz, 1 H; 4¢-H), 7.32 (d, 3J = 4.7 Hz, 2
[M+]
H, 4´-H)
a Satisfactory microanalyses were obtained for all new compounds, except for 5f, 10c, 10f, 10h which is presumably due to their easy thermal
decomposition.
b Numbering: C-4 corresponds to the 4-position of the pyridine ring; C-4¢ and 4¢-H refers to the 4-positions of phenyl (10i, j) or pyridine rings
(10k), respectively.
c NMR spectra were taken in CDCl3.
Synthesis of the 2,4,6-Trialkoxy-Substituted 3,5-Dichloropy-
ridines 10a–h
1
The H and 13C NMR spectra were recorded on Bruker ARX-400
and DPX-200 spectrometers and were taken in DMSO-d6 at 200
MHz and 400 MHz, respectively, at 20 °C. The chemical shifts are
reported in ppm relative to internal TMS (d = 0.00). Multiplicities
are described by using the following abbreviations: s = singlet, d =
doublet, t = triplet, h = heptet, m = multiplet, br = broad. The mass
spectra (ESIMS) were measured with a Hewlett-Packard HP 5989B
or a Varian SAT2100T with GC3900. Melting points are uncorrect-
ed.
A solution of the trication 3 [6.15 g, 10.0 mmol in alcohol (50 mL)
(cf. Table 2)] was treated with a solution of the sodium alkoxide
(0.2 mol) in the corresponding alcohol (100 mL). Except for the
synthesis of 10g (stirring at r.t. for 24 h), the mixtures were heated
for 6 h at reflux temperature. After completion of the reaction the
alcohols were distilled off in vacuo and the residues were chromato-
graphed on silica gel with EtOAc–petroleum ether (1:1; short col-
umn).
Synthesis of the 4-Alkoxy-2,3,5,6-tetrachloro-pyridines 5a–g
and the 2,4-Dialkoxy-3,4,6-trichloropyridines 6a–d
A solution of 1-(4-dimethylamino)-[2,3,5,6-tetrachloro-pyridin-4-
yl]-pyridinium chloride (2; 10.0 mmol, 3.74 g) in alcohol (30 mL)
was treated with a solution of the sodium alkoxide in the corre-
sponding alcohol (50 mL). The solvents, reaction times and temper-
atures are presented in Table 1. After completion of the reaction the
alcohols were distilled off in vacuo and the residues were chromato-
graphed in a short column on silica gel with EtOAc–petroleum ether
(1:1).
10a
Mp 86 °C.
Synthesis of the 2,4,6-Triphenoxy-Substituted 3,5-Dichloropy-
ridines 10i,j and the 2,4,6-Tri(pyridin-3yl)-oxy-Substituted 3,5-
Dichloropyridine (10k)
Sodium amide (1.30 g, 33 mmol) and trication 3 (6.15 g, 10 mmol)
were suspended in DMF (100 mL). Then, phenol (2.82 g, 30 mmol),
4-methoxyphenol (3.72 g, 30 mmol), or 3-hydroxypyridine (2.85 g,
30 mmol) was added. After the reaction time and temperature as de-
scribed in Table 2, DMF was distilled off in vacuo and the residue
was chromatographed on silica gel with EtOAc–petroleum ether
(1:1).
5a
Mp 114 °C (114–115 °C,16 117–119 °C,16a 113.5 °C16b).
5b
10i
Mp 54 °C (54–56 °C,19 56–58 °C20).
Mp 102 (105–107 °C22).
5d
10j
Mp 145 °C.
The reported mp for 5d is incorrect; mp 83–85 °C (28–29 °C18).
5e
Mp 70 °C (70–72 °C10a).
References
(1) (a) The Chemistry of Heterocyclic Compounds, Vol. 14;
Weissberger, A.; Taylor, E. C., Eds.; Wiley-Interscience:
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Methoden der Organischen Chemie, Vol. E7b; Kreher, E.,
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(2) de Bie, D. A.; Geurtsen, B.; Berg, I. E.; van der Plas, H. C.
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6a
Mp. 117 °C (116.5–117.5 °C16b).
Synthesis of the 4-(Hetero)aryl-Substituted Tetrachloropy-
ridines 7–9
Sodium amide (0.43 g, 11.0 mmol) was suspended in anhyd DMF
(80 mL) and was treated with 1-(4-dimethylamino)-[2,3,5,6-tetra-
chloropyridin-4-yl]pyridi-nium chloride (2; 3.74 g, 10.0 mmol) and
phenol (0.94 g, 10.0 mmol), 4-methoxyphenol (1.24 g, 10.0 mmol),
3-hydroxypyridine (0.95 g, 10.0 mmol), and 1-octanol (1.3 g, 10.0
mmol). The reaction mixture was heated as indicated in Table 1.
DMF was then distilled off and the residue was chromatographed
on silica gel (EtOAc–petroleum ether, 1:2; short column).
Synthesis 2005, No. 5, 781–786 © Thieme Stuttgart · New York

786
A. Schmidt, T. Mordhorst
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Synthesis 2005, No. 5, 781–786 © Thieme Stuttgart · New York