Heteroarenium salts in synthesis. Highly functionalized tetra- and pentasubstituted pyridines

Article abstract of DOI:10.1016/j.tet.2005.11.065

Activation of chloropyridines by heteroarenium substituents allows sequential substitutions by O-, N-, and S-nucleophiles. Reaction of 2,3,5,6-tetrachloropyridine and 4-ethylsulfanyl-2,3,5,6-tetrachloropyridine with 4-(dimethylamino)pyridine, 4-(pyrrolidi

Full text of DOI:10.1016/j.tet.2005.11.065

Tetrahedron 62 (2006) 1667–1674
Heteroarenium salts in synthesis. Highly functionalized
tetra- and pentasubstituted pyridines
a
b
Andreas Schmidt,a, Thorsten Mordhorst and Martin Nieger
*
aClausthal University of Technology, Institute of Organic Chemistry, Leibnizstrasse 6, D-38678 Clausthal-Zellerfeld, Germany
¨
Rheinische Friedrich-Wilhelms-Universitat Bonn, Institute of Inorganic Chemistry, Gerhard-Domagk-Strasse 1, D-53121 Bonn, Germany
b
Received 4 November 2005; revised 24 November 2005; accepted 28 November 2005
Available online 20 December 2005
Abstract—Activation of chloropyridines by heteroarenium substituents allows sequential substitutions by O-, N-, and S-nucleophiles.
Reaction of 2,3,5,6-tetrachloropyridine and 4-ethylsulfanyl-2,3,5,6-tetrachloropyridine with 4-(dimethylamino)pyridine, 4-(pyrrolidin-
1-yl)pyridine, or 4-aminopyridine results in the formation of 2,6-bis-heteroarenium substituted 3,5-dichloropyridines. On nucleophilic
displacement of the heteroarenium substituents by O-, N-, or S-nucleophiles highly functionalized 3,5-dichloropyridines form which possess
N2,S4,N6-, O2,S4,O6-, O2,O6-, N2,N6-, and S2,S6-substitution patterns.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
transition-metal catalysed reactions.20 As a consequence,
the number of reported tetra- and penta-substituted
pyridines is very small. The need for these pyridines,
however, is reflected in recent publications dealing with
sequential controlled substitution reactions on pentafluor-
opyridines as promising avenues for the synthesis of
macrocycles.21
Substitution reactions on halogenated heteroaromatics are
widely applied reactions in organic synthesis. An impress-
ive number of monographs and review articles reflect that
synthetically, biologically, pharmaceutically, or industrially
important pyridines can be synthesized from halogenated
precursors.1–4 Heteroaromatic substitutions proceed by
different mechanisms. Mostly, a two-step AE-mechanism1–3
As part of an ongoing project we recently described the
synthesis and characterization of mono-, tris-, and pentakis-
heteroarenium substituted pyridines bearing up to 10
positive charges within a common p-electron system.22
These heteroarenium salts proved to be valuable starting
materials for the regioselective synthesis of hitherto
unavailable pyridine ethers23 and pyridine thioethers.24
We report here the scope and limitations of reactions leading
to first examples of N2,S4,N6-trisubstituted dichloropyridines,
and to a variety of O2,S4,O6-trisubstituted as well as O2,O6-,
N2,N6-, and S2,S6-disubstituted dichloropyridines, which
are symmetrically (R2ZR3, Fig. 1) or non-symmetrically
substituted (R2sR3).
is observed, but SN(ANRORC)-,5 EA-,6 or SRN1
-
mechanisms7 have also been described. It is also known
that the 2-, 3-, and 4-positions of the pyridine ring system
display different reactivities.1–3 The 3-position is often inert
against nucleophilic attacks,8 unless EA-mechanisms by
amide ions9 or metal-catalyses are applied.10
However, the vast majority of known substitutions was
limited to the synthesis of mono- or bisubstituted pyridines.
Thus, the reaction of pentachloropyridine with aliphatic
amines generates only mono-amino tetrachloropyridines.11
Vigorous reaction conditions are necessary to form
3,4-bisamino substituted trichloropyridines12 or lead to
mixtures of compounds. These limitations cannot be
circumvented by alternative pyridine syntheses such as
2. Results and discussion
13
14
´
¨
Hantzsch synthesis, Krohnke synthesis, gasphase
reactions of aldehydes and ketones with acrolein
and ammonia,15 electrocyclic ring closures,16 ring trans-
formations,17 cycloadditions,18 directed metallations,19 or
2.1. Activation of pentachloropyridine by heteroarenium
substituents
Our earlier work reveals that the 4-chlorine atom of
pentachloropyridine is the most susceptible leaving
group toward substitution reactions with nucleophilic
Keywords: Heteroarenium; Pyridines; Nucleophiles.
*
Corresponding author. Tel.: C49 5323 723861; fax: C49 5323 722858;
e-mail: schmidt@ioc.tu-clausthal.de
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.11.065

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A. Schmidt et al. / Tetrahedron 62 (2006) 1667–1674
Table 1. Preparation of the bis-heteroarenium substituted pyridines
R1
N
R1
N
R
Cl
Cl
Cl
Cl
N
R1
R1
N
2 X
R3
R2
2
Cl
Cl
N
N
Cl
Cl
Cl
Cl
N
2 Cl
R1 = H, SR
R2/R3= NR2, OR, SR
R
R
N
N
in DMF, 120°C
R
R
1 - 9
R
N
N
R1
Cl
R1
R
Bis-hetero- Yield (%)
arenium
salt
Cl
Cl
Cl
Cl
X
Cl
Cl
Cl
Cl
N
N
Cl
Cl
Cl
Cl
1
2
3
4
5
6
7
8
9
S–Et
S–iPr
H
S–Et
S–iPr
H
S–Et
S–iPr
H
–NH2
–NH2
–NH2
–N(CH3)2
–N(CH3)2
–N(CH3)2
Pyrrolidin-1-yl
Pyrrolidin-1-yl
Pyrrolidin-1-yl
1
2
3
4
5
6
7
8
9
54
61
73
90
89
95
65
66
99
Figure 1. Retrosynthesis of substituted pyridines, available by sequential
regioselective substitutions on heteroarenium activated chlorinated
pyridines.
heteroaromatics such as 4-(dimethylamino)pyridine
(DMAP), 4-(pyrrolidino)pyridine, and 1-methylimi-
dazole.22 We therefore focussed our interest on substitution
reactions on pyridines without chlorine in the 4-position. In
view of the interest in 4-sulfanyl-substituted pyridines (most
of which are patented25) and other pyridine thioethers as
bacterizides,26 pesticides,27 and intermediates for the
synthesis of fungicides28 and other biologically active
compounds,29 we focussed our interest on tetrachloro-4-
sulfanylpyridines as starting materials. No substitution,
however, was observable starting from 2,3,5,6-tetrachloro-
pyridine-4-thiol or tetrachloropyridines with oxygen-or
amino-groups in the 4-position under the reaction con-
ditions applied. Deprotonation of acidic groups such as the
SH-group resulted in a considerably decreased leaving
group tendency of the a-chlorine substituents. Thus,
treatment of 2,3,5,6-tetrachloro-pyridine-4-thiol with
DMAP gave the salt 4-(dimethylamino)pyridinium
2,3,5,6-tetrachloropyridine-4-thiolate in quantitative yield
(Scheme 1).
stable on storage in air and on heating to 150 8C. The amino
derivatives (1, 2, 3) are slightly hygroscopic.
Suitable single crystals of the bis-heteroarenium salt 5 as
tetrafluoroborate were obtained by slow evaporation of a
concentrated solution in H2O:EtOH:HBF4 (50% in H2O)Z
1:1:1. The molecular structure and the crystallographic
numbering are shown in Figure 2. The dication 5 crystal-
lized triclinic. The two pyridinium rings are twisted. Two
different dihedral angles N1–C2–N21–C22 [123.4(3)8] and
N1–C6–N61–C66 [115.3(3)8] were determined. The corre-
sponding C2–N21 and C6–N61 bond distances (crystallo-
graphic numbering) are 144.2(3) pm, which corresponds to
long C(sp2)–N bonds. The dimethylamino group is joined to
the pyridinium ring by a shortened C–N bond, the bond
length of which was determined to be 133.2(4) and
133.2(4) pm. Bond distances of C22–C23Z134.6(4) and
C62–C63Z134.9(4) pm do not hint at quinoidal characters
of the pyridinium substituents.
S
N
NMe2
2.2. Reaction of the bis-heteroarenium salts
Cl
Cl
Cl
Cl
Scope and limitations of substitution reactions of bis-
heteroarenium salts to highly functionalized and hitherto
unknown pyridines were investigated by examining first the
reaction with O-, N-, and S-nucleophiles. 4-(Pyrrolidin-
1-yl)pyridine gave the highest yields of the corresponding
bis-heteroarenium salts 7–9, but to our experience
4-(dimethylamino)pyridinium had the best leaving group
tendencies for substitution reactions. Table 2 shows the
reactions of the DMAP derivatives 4, 5, and 6 with oxygen
nucleophiles. Sodium methanolate in methanol changed the
heteroarenium substituents of 4 to methoxy groups to give
10, which is a new substance (Table 2, entry 1). Likewise,
the same reaction conditions converted 5 to 14 and 6 to 18
(entries 5 and 9, respectively). The synthesis of 3,5-
dichloro-2,6-dimethoxypyridine 18 was described earlier.
It was formed on reaction of 2,3,5,6-tetrachloropyridine
with sodium methanolate in moderate yield.30 No reaction
occured on treatment of 4, 5, and 6 with 4-methoxyphenol in
N
H
Scheme 1.
We found that 4-ethylsulfanyl-2,3,5,6-tetrachloropyridine,
prepared regioselectively in 93% yield starting from
4-dimethylamino-(2,3,5,6-tetrachloropyridin-4-yl)pyridi-
nium chloride,24 does react with 4-aminopyridine, 4-
(dimethylamino)pyridine, and 4-(pyrrolidino)pyridine to
the bis-heteroarenium salts 1, 4, and 7, respectively,
(Table 1). Correspondingly, 4-(2-propylsulfanyl)-2,3,5,6-
tetrachloro-pyridine gives 2, 5, and 8. 2,3,5,6-Tetrachloro-
pyridine affords the bis-heteroarenium salts 3, 6, and 9 in
very good to excellent yields. All reactions were conducted
at 120 8C in DMF, from which the salts precipitated in
analytical purity on addition of ethyl acetate. The salts 1–9
are soluble in water, alcohols, amines, thiols, and DMF,

A. Schmidt et al. / Tetrahedron 62 (2006) 1667–1674
1669
Figure 2. Molecular structure of 5.
Table 2. Reaction of the dications 4, 5, and 6 with O-nucleophiles
R1
Cl
Cl
O
2 R2O in R3OH
-2 DMAP
4, 5, 6
R2
R3
O
N
10 - 21
Entry
Starting
material
R1
R2
R3
Base added
Method
Product
Yield (%)
1
2
3
4
5
6
7
8
4
4
4
4
5
5
5
5
6
6
6
6
S–Et
S–Et
S–Et
S–Et
S–iPr
S–iPr
S–iPr
S–iPr
H
Me
Me
Me
iPr
4-MeO-Ph
Me
Me
Na
3 h/64 8C
6 h/64 8C
6 h/82 8C
6 h/82 8C
3 h/64 8C
6 h/64 8C
6 h/82 8C
6 h/82 8C
3 h/64 8C
6 h/64 8C
6 h/82 8C
6 h/82 8C
10
11
12
13
14
15
16
17
18
19
20
21
57
23
20
45
59
43
15
42
55
40
14
43
4-MeO-Ph
4-MeO-Ph
4-MeO-Ph
Me
4-MeO-Ph
4-MeO-Ph
4-MeO-Ph
Me
NaNH2
NaNH2
NaNH2
Na
NaNH2
NaNH2
NaNH2
Na
iPr
4-MeO-Ph
Me
Me
iPr
4-MeO-Ph
9
10
11
12
H
H
H
4-MeO-Ph
4-MeO-Ph
4-MeO-Ph
NaNH2
NaNH2
NaNH2
DMF in the presence of sodium amide. Non-symmetrically
substituted pyridines (R1sR2sR3), however, were
obtained in a one-pot reaction of 4-methoxyphenol and
NaNH2 in methanol, although in moderate to low yields.
Applying this reaction conditions pyridine thioethers with
two different alkoxy groups in the a-positions of
pyridine (11, 15, 19) were obtained. Thus, treatment of
bis-heteroarenium salt 4 with 4-methoxyphenol in the
presence of sodium amide in methanol gave 3,5-dichloro-
4-ethylsulfanyl-2-(4-methoxyphenoxy)-6-methoxypyridine
11 (R3ZMe; entry 2). 2-Propanol as solvent resulted in the
formation of a mixture of symmetrically and non-
symmetrically substituted pyridines. The main products in
the reactions of the bis-heteroarenium salts with
4-methoxyphenol in 2-propanol as solvent are the 2,6-(4-
methoxyphenol)-substituted pyridines 13, 17, and 21
(Table 2, entries 4, 8 and 12), which can easily be separated
from the non-symmetrically substituted a-(2-propoxy)pyr-
idines 12, 16, and 20 (entries 3, 7 and 11) by column
chromatography (silica gel; EtOAC/petrol etherZ1:1),
respectively. To the best of our knowledge, the compounds
10–17 are the first representatives of O2,S4,O6-substituted
3,5-dichloropyridines. Even without chlorine in the b-pos-
itions this substitution pattern is very rare; we found that
only five O2,S4,O6-substituted pyridines have been syn-
thesized by multi-step procedures31 and patented32 to date.
O2,O6-substituted 3,5-dichloropyridines with hydrogen in
the 4-position are pharmacologically interesting

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A. Schmidt et al. / Tetrahedron 62 (2006) 1667–1674
Table 3. Reaction of the bis-heteroarenium salts 4, 5, and 6 with sodium
amide
Finally, we examined thiolates as reagents. In acetone,
methanol, or mixtures of both and triethylamine as base
substitutions were observed, and the pyridinium rings were
replaced. Surprisingly, the ethylsulfanyl- and the 2-propyl-
sulfanyl group at C-4 of 4 and 5 were substituted as well to
yield 25. The bis-heteroarenium salt 6 reacted in low yields
to the bis-sulfanyl derivative 26 (Table 4).
R1
Cl
Cl
+2 NaNH2, morpholine
4, 5, 6
in DMF
H2N
N
NH2
-2 DMAP
22 - 24
In summary, we present an approach to highly functiona-
lized pyridines possessing rare or hitherto unknown
substitution patterns, which are of interest from chemical
and biological viewpoints.
Entry
Starting
material
R1
Product
Yield (%)
1
2
3
4
5
6
S–Et
S–iPr
H
22
23
24
30
55
20
3. Experimental
3.1. General
compounds; some derivatives with a broad variety of
biological activities were prepared by multi-step procedures
earlier.33
1
The H and 13C NMR spectra were recorded on Bruker
Digital FT-NMR Avance 400 and Avance DPX 200
spectrometers. Multiplicities are described by using the
following abbreviations: sZsinglet, dZdoublet, mZmulti-
plet. 15N NMR spectra: reference MeNO2. FT-IR spectra
were obtained on a Bruker Vektor 22 in the range of
400–4000 cmK1 (2.5% pellets in KBr). The electrospray
ionisation mass spectra (ESIMS) were measured with an
Agilent LCMSD Series HP1100 with APIES. Samples were
sprayed from methanol at 0 V fragmentor voltage. Melting
points are uncorrected. Crystallographic data have been
deposited with the Cambridge Crystallographic Data Centre
as supplementary publication no. CCDC 287940. Copies of
the data can be obtained free of charge on application to
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (fax:
C44 1223 336 033; e-mail: deposit@ccdc.cam.ac.uk).
Some crystal data of 5: [C22H27Cl2N5S]2C2 [BF4]K, MZ
638.07; space group P-1 (No. 2); dimensions 0.40!0.20!
We next examined nitrogen nucleophiles. The dications 4
and 5 are attacked by amide in DMF in the presence of
morpholine (or piperidine) to give the 2,6-diamino-4-
sulfanylpyridines 22 and 23 (Table 3). Seemingly, these
compounds are the first examples of N2,S4,N6-substituted
dichloropyridines. The bis-heteroarenium salt 6 affords 2,6-
diamino-3,5-dichloropyridine 24 in low yield, which is also
available starting from tetrachloroisonicotinic acid and
ammonia at 200 8C in a sealed tube,34 or from 2,6-
diaminopyridine and hydrogen peroxide in hydrochloric
acid in 60% yield.35 No traces of the morpholine-substituted
pyridines were isolable.
Table 4. Reaction of the dications with n-butylthiolate
R1
˚
0.10 mm, aZ9.2815(6), bZ9.5981(4), cZ15.9010(9) A;
Cl
Cl
N
aZ93.103(3)8, bZ90.874(3)8; gZ94.325(3)8, VZ
3
1410.16(13) A , DcZ1.503 Mg mK3, ZZ2, m(Mo Ka)Z
2 Cl
˚
N
N
0.380 mmK1; TZ123(2) K; F(000)Z652, 10104 reflections
were collected in a Nonius KappaCD diffractometer
(2QmaxZ508, K11%h%10, K11%k%11, K16%l%18),
4934 symmetry independent reflections (RintZ0.0347) were
used for the structure solution (direct methods)36 and
refinement (full-matrix least-squares on F2,37 365 par-
ameters), non-hydrogen atoms were refined anisotropically,
H atoms localized by difference electron density, and were
defined using a riding model; wR2 (all data)Z0.1182 [R1Z
0.0482 for 3741 IO2s(I)].
Me2N
NMe2
4, 5, 6
+2 nBuSH / NEt3
in MeOH / acetone
-2 DMAP
-2 HCl
R2
Cl
S
Cl
3.2. General procedure for the preparation of dications
(1–9)
N
S
2,3,5,6-Tetrachloropyridine (2.17 g, 10 mmol) or 2,3,5,6-
tetrachloro-4-ethylsulfanylpyridine24 (2.77 g, 10 mmol) or
2,3,5,6-tetrachloro-4-(2-propylsulfanyl)pyridine (2.91 g,
10 mmol) and 4-aminopyridine (1.88 g, 20 mmol) or
4-dimethylaminopyridine (2.44 g, 20 mmol) or 4-(pyrro-
lidin-1-yl)pyridine (2.96 g, 20 mmol) were dissolved in
200 mL of DMF and stirred for 3 h at 120 8C. After cooling
to room temperature 200 mL of ethyl acetate were added
whereupon yellow precipitates formed, which were filtered
off, washed with ethyl acetate, and dried in vacuo.
25, 26
Entry
Starting
material
R1
R2
Product
Yield (%)
1
2
3
4
5
6
S–Et
S–iPr
H
S–nBu
S–nBu
H
25
25
26
46
40
25

A. Schmidt et al. / Tetrahedron 62 (2006) 1667–1674
1671
3.2.1. 1,10-Bis[4-amino-(3,5-dichloro-4-ethylsulfanyl-
pyridine-2,6-diyl)pyridinium]dichloride (1). Yellow
solid, mp 317 8C (Found: C, 43.54; H, 4.56; N, 15.13.
C17H17Cl4N5S requires C, 43.89; H, 3.68; N, 15.05); dH
[D2O–CD3OD (1/1)] 8.34 (d, 3JZ7.9 Hz, 4H), 7.05 (d, 3JZ
7.9 Hz, 4H), 3.32 (q, 2H; JZ7.4 Hz, CH2), 1.33 (d, JZ
7.4 Hz, 3H; CH3), no signals of the amino groups were
detectable due to H/D exchange; dC [D2O–CD3OD (1/1)]
160.3, 153.5, 146.4, 141.7, 132.4, 109.2, 29.9, 14.3; nmax
(KBr) (cmK1) 1655, 1543, 1376, 1202, 843.
12.41; S, 5.02; C25H29Cl4N5S$2H2O requires C, 49.27; H,
5.46; N, 11.49; S, 5.26); dH 3[DMSO–CD3OD (1/1)] 8.68 (d,
3
3JZ7.7 Hz, 4H), 7.31 (d, JZ7.7 Hz, 4H), 4.51 (q, JZ
6.9 Hz, 2H), 3.90–4.10 (m, 8H), 2.40–2.60 (m, 8H), 1.68 (t,
3JZ6.9 Hz, 3H); dC [DMSO–CD3OD (1/1)] 154.2, 146.6,
145.0, 140.8, 129.9, 107.6, 49.2, 29.9, 24.6, 14.2; nmax (KBr)
(cmK1) 1648, 1572, 1430, 1214, 1087, 828.
3
3
3.2.8. 1,10-Bis[4-pyrrolidino-(3,5-dichloro-4-(2-propyl-
sulfanyl)-pyridine-2,6-diyl)-pyridinium]dichloride (8).
Yellow solid, mp 214 8C (Found: C, 47.22; H, 6.15; N,
11.38; S, 4.81; C26H31Cl4N5S$4H2O requires C, 47.35; H,
3.2.2. 1,10-Bis[4-amino-(3,5-dichloro-4-(2-propylsulfanyl)-
pyridine-2,6-diyl)pyridinium]dichloride (2). Yellow
solid, decO260 8C (Found: C, 43.74; H, 4.73; N, 14.60.
C18H19Cl4N5S requires C, 45.11; H, 4.00; N, 14.61); dH
3
5.96; N, 10.62; S, 4.81); dH [DMSO] 8.74 (d, JZ7.7 Hz,
3
3
4H), 7.13 (d, JZ7.7 Hz, 4H), 3.97 (h, JZ6.8 Hz, 1H),
3
3.65 (s, 8H), 2.03 (s, 8H), 1.34 (d, JZ6.8 Hz, 6H); dC
3
[DMSO] 9.47 (s, 4H; NH2), 8.58 (d, JZ7.3 Hz, 4H), 7.16
[DMSO] 153.6, 150.5, 146.3, 141.0, 132.9, 108.3, 49.1,
41.3, 24.5, 23.4; nmax (KBr) (cmK1) 1647, 1571, 1548,
1429, 1215, 1087, 828.
(d, 3JZ7.3 Hz, 4H), 3.94 (h, 3JZ6.6 Hz, 1H), 1.32 (d, 3JZ
6.6 Hz, 6H); dC [DMSO] 160.1, 150.6, 146.3, 141.9, 132.7,
109.0, 41.2, 23.4; nmax (KBr) (cmK1) 3433, 3257, 3095,
1661, 1542, 1376, 1198, 1165, 1103, 846.
3.2.9. 1,10-Bis[4-pyrrolidino-(3,5-dichloro-pyridine-2,6-
diyl)-pyridinium]dichloride (9). Pale yellow solid, mp
232 8C (Found: C, 48.95; H, 5.87; N, 12.82; C23H25Cl4-
N5$3H2O requires C, 48.69; H, 5.51; N, 12.34); dH [DMSO]
9.22 (s, 1H), 8.76 (d, 3JZ7.7 Hz, 4H), 7.15 (d, 3JZ7.7 Hz,
4H), 3.68 (s, 8H), 2.06 (s, 8H); dC [DMSO] 153.6, 146.0,
3.2.3. 1,10-Bis[4-amino-(3,5-dichloro-pyridine-2,6-diyl)-
pyridinium]dichloride (3). Yellow solid, mp 255 8C
(Found: C, 43.72; H, 4.20; N, 17.20. C15H13Cl4N5$1⁄2 H2O
requires C, 43.50; H, 3.41; N, 16.91); dH [DMSO–D2O
3
3
(1/1)] 8.97 (s, 1H), 8.53 (d, JZ7.6 Hz, 4H), 7.11 (d, JZ
7.6 Hz, 4H), no signals of the amino groups detectable due
to H/D exchange; dC [DMSO–D2O (1/1)] 159.7, 145.8,
144.5, 141.8, 127.4, 108.9; nmax (KBr) (cmK1) 3059, 1663,
1542, 1387, 1285, 1189, 1105, 842.
144.4, 140.9, 127.5, 108.3, 49.1, 24.5; nmax (KBr) (cmK1
)
1648, 1573, 1429, 1389, 1351, 1206, 1105, 831.
3.3. General procedure for the reaction of the 1,10-bis[4-
dimethylamino-(3,5-dichloro-pyridine-2,6-diyl)pyridinium]-
dichlorides 4, 5, and 6 with sodium methanolate to 10, 14,
and 18
3.2.4. 1,10-Bis[4-dimethylamino-(3,5-dichloro-4-ethyl-
sulfanyl-pyridine-2,6-diyl)pyridinium]dichloride (4).
Yellow solid, mp 238 8C (Found: C, 45.38; H, 5.14; N,
13.46; S, 5.57. C21H25Cl4N5S$2H2O requires C, 45.25; H,
In 100 mL of methanol were dissolved the salt 4 (5.21 g,
10 mmol), or 5 (5.35 g, 10 mmol), or 6 (4.61 g, 10 mmol)
and sodium methanolate (2.70 g, 50 mmol), respectively.
After 6 h stirring at reflux temperature the solvent was
distilled off, and the residue was worked up by chromatog-
raphy (silica gel 60 HF254 from Merck, ethyl acetate–petrol
ether (1/1)).
3
5.24; N, 12.57; S, 5.75); dH [DMSO] 8.80 (d, JZ7.8 Hz,
3
3
4H), 7.32 (d, JZ7.8 Hz, 4H), 3.37 (q, JZ7.3 Hz, 2H),
3
3.36 (s, 12H), 1.32 (t, JZ7.3 Hz, 3H); dC [DMSO] 156.5,
151.2, 146.1, 141.1, 132.0, 107.6, 40.5, 29.8, 15.3; nmax
(KBr) (cmK1) 1648, 1577, 1543, 1406, 1380, 1219, 829.
3.2.5. 1,10-Bis[4-dimethylamino-(3,5-dichloro-4-(2-propyl-
sulfanyl)-pyridine-2,6-diyl)pyridinium]dichloride (5).
Yellow solid, mp 215 8C (Found: C, 49.34; H, 4.95; N,
12.69; C22H27Cl4N5S requires: C, 49.36; H, 5.08; N, 13.08);
3.3.1. 3,5-Dichloro-4-ethylsulfanyl-2,6-dimethoxypyridine
(10). Colourless liquid; (Found: C, 40.04; H, 3.71; N,
5.14; S, 11.81; C9H11Cl2NO2S requires C, 40.31; H, 4.18;
N, 5.22; S, 11.96); dH3[CDCl3] 4.01 (s, 6H), 3.04 (q, JZ
7.4 Hz, 2H), 1.23 (t, JZ7.4 Hz, 3H); dC [CDCl3] 156.0,
145.8, 113.2, 54.6, 29.1, 14.8; nmax (NaCl) (cmK1) 2984,
2950, 2867, 1562, 1538, 1470, 1448, 1370, 1318, 1200,
1121, 1098, 1031, 787, 746; GC–MS: m/zZ268 (M, 100);
237 (MKC2H5, 9); 199 (MKC5H5–Cl, 13) amu.
3
3
3
dH [DMSO] 8.82 (d, JZ7.8 Hz, 4H), 7.33 (d, JZ7.8 Hz,
3
3
4H), 4.00 (h, JZ6.6 Hz, 1H), 3.36 (s, 12H), 1.37 (d, JZ
6.6 Hz, 6H); dC [DMSO] 156.5, 150.5, 146.2, 141.1, 133.0,
107.6, 48.4, 40.4, 23.4; nmax (KBr) (cmK1) 3409, 1648,
1578, 1407, 1380, 1222, 1163.
3.2.6. 1,10-Bis[4-dimethylamino-(3,5-dichloro-pyridine-
2,6-diyl)pyridinium]dichloride (6). Yellow solid, mp
134 8C (Found: C, 43.45; H, 6.04; N, 14.07; C19H21Cl4-
N5$3,5H2O requires C, 43.57; H, 5.38; N, 13.36); dH
3.3.2. 3,5-Dichloro-2,6-dimethoxy-4-(2-propylsulfanyl)-
pyridine (14). Colourless liquid; (Found: C, 42.58; H,
4.66; N, 4.96; S, 10.93; C10H13Cl2NO2S requires C, 42.56;
H, 4.64; N, 4.96; S, 11.36); dH [CDCl3] 4.02 (s, 6H), 3.74 (h,
3JZ6.7 Hz, 1H), 1.27 (d, 3JZ6.7 Hz, 6H); dC [CDCl3]
3
[DMSO] 9.20 (s, 1H), 8.75 (d, JZ7.8 Hz, 4H), 7.29 (d,
3JZ7.8 Hz, 4H), 3.34 (s, 12H); dC [DMSO] 156.5, 145.9,
144.4, 140.9, 127.5, 107.6, 40.5; nmax (KBr) (cmK1) 1649,
1582, 1562, 1429, 1406, 1230, 1212, 1105, 832.
156.1, 145.9, 113.6, 54.6, 39.4, 23.1; nmax (NaCl) (cmK1
)
2951, 2866, 1558, 1538, 1471, 1446, 1369, 1317, 1244,
1199, 1121, 1097, 786, 749; GC–MS: m/zZ282 (M, 100);
238 (MKC3H7, 5) amu.
3.2.7. 1,10-Bis[4-pyrrolidino-(3,5-dichloro-4-(ethyl-
sulfanyl)-pyridine-2,6-diyl)pyridinium]dichloride (7).
Yellow solid, mp 204 8C (Found: C, 49.99; H, 5.66; N,
3.3.3. 3,5-Dichloro-2,6-dimethoxypyridine (18). White
solid, mp 48 8C (Found: C, 40.41; H, 3.62; N, 6.67;

1672
A. Schmidt et al. / Tetrahedron 62 (2006) 1667–1674
C7H7Cl2NO2 requires C, 40.41; H, 3.39; N, 6.73); dH
[CDCl3] 7.58 (s, 1H), 4.00 (s, 6H); dC [CDCl3] 156.0, 139.9,
107.8, 54.4; nmax (KBr) (cmK1) 1582, 1470, 1398, 1225,
1095, 1009, 786, 739; GC–MS: m/zZ208 (M, 100), 177
(MKCH3O, 52) amu.
chromatographed (silica gel 60, ethyl acetate–petrol ether
(1/1)).
3.5.1. 3,5-Dichloro-4-ethylsulfanyl-2-(4-methoxyphenoxy)-
6-(2-propoxy)-pyridine (12). Colourless liquid; (Found: C,
51.02; H, 4.71; N, 3.70; C17H19Cl2NO3S requires C, 52.58;
H, 4.93; N, 3.61); dH [CDCl3] 7.05 (m, 2H), 6.89 (m, 2H),
4.70 (h, 3JZ6.2 Hz, 1H), 3.83 (s, 3H), 3.09 (h, 3JZ7.3 Hz,
3.4. General procedure for the reaction of the 1,10-bis[4-
dimethylamino-(3,5-dichloropyridine-2,6-diyl)pyridinium]-
dichlorides 4, 5, and 6 with 4-methoxyphenol in methanol to
11, 15, and 19
3
3
2H), 1.28 (t, JZ7.3 Hz, 3H), 1.27 (d, JZ6.2 Hz, 6H); dC
[CDCl3] 160.4, 156.7, 155.2, 147.0, 146.4, 122.5, 122.4,
114.5, 114.1, 70.9, 55.6, 29.2, 21.6, 15.0; nmax (NaCl) (cmK1
2979, 2931, 1557, 1504, 1374, 1246, 1195, 1095, 1036, 945;
)
In 100 mL of methanol were dissolved the salt 4 (5.21 g,
10 mmol), or 5 (5.35 g, 10 mmol), or 6 (4.61 g, 10 mmol),
and 4-methoxyphenol (2.48 g, 20 mmol), respectively.
Then, sodium amide (0.78 g, 20 mmol) was added and the
mixture was heated under reflux for 6 h. After this period the
solvent was distilled off and the residue was worked up
chromatographically (silica gel 60 HF254 from Merck, ethyl
acetate–petrol ether (1/1)).
GC–MS: m/zZ389 (MHC, 100) amu.
3.5.2. 3,5-Dichloro-4-ethylsulfanyl-2,6-bis(4-methoxy-
phenoxy)-pyridine (13). Colourless solid, mp 82 8C;
(Found: C, 55.41; H, 4.42; N, 3.10; S, 6.92; C21H19Cl2NO4S
requires C, 55.76; H, 4.23; N, 3.10; S, 7.09); dH [CDCl3]
6.80–6.87 (m, 4H), 6.64–6.73 (m, 4H), 3.77 (s, 6H), 3.13 (q,
3JZ7.4 Hz, 2H), 1.31 (t, 3JZ7.4 Hz, 3H); dC [CDCl3]
156.6, 155.3, 147.4, 146.5, 122.4, 115.2, 113.9, 55.4, 29.4,
15.0; nmax (KBr) (cmK1) 1559, 1501, 1369, 1249, 1193,
1029, 828; GC–MS: m/zZ452 (M, 100) amu.
3.4.1. 3,5-Dichloro-4-ethylsulfanyl-2-(4-methoxyphenoxy)-
6-methoxypyridine (11). Pale yellow liquid; (Found: C,
49.32; H, 4.29; N, 4.35; C15H15Cl2NO3S requires C, 50.01;
H, 4.20; N, 3.89); dH [CDCl3] 7.07 (d, 3JZ9.2 Hz, 2H), 6.89
(d, 3JZ9.2 Hz, 2H), 3.82 (s, 3H), 3.67 (s, 3H), 3.09 (h, 3JZ
3.5.3. 3,5-Dichloro-2-(4-methoxyphenoxy)-6-(2-propoxy)-
4-(2-propylsulfanyl)pyridine (16). Pale yellow liquid;
(Found: C, 53.34; H, 5.64; N, 3.56; C18H21Cl2NO3S
requires C, 53.73; H, 5.26; N, 3.48); dH [CDCl3] 7.00–
7.10 (m, 2H), 6.85–6.95 (m, 2H), 4.70 (h, 3JZ6.3 Hz, 1H),
3.83 (s, 3H), 3.80 (h, 3JZ6.5 Hz, 1H), 1.31 (d, 3JZ6.3 Hz,
3
7.4 Hz, 2H), 1.27 (t, JZ7.4 Hz, 3H); dC [CDCl3] 157.2,
156.7, 156.0, 146.9, 145.8, 122.4 (overlapped), 114.1,
113.2, 55.5, 54.6, 29.1, 14.9; nmax (NaCl) (cmK1) 2951,
1561, 1504, 1460, 1369, 1247, 1198, 1101, 1033; GC–MS:
m/zZ361 (MHC, 100) amu.
3
6H), 1.17 (d, JZ6.5 Hz, 6H); dC [CDCl3] 156.7, 155.5,
3.4.2. 3,5-Dichloro-2-(4-methoxyphenoxy)-6-methoxy-4-
(2-propylsulfanyl)pyridine (15). Colourless liquid;
(Found: C, 50.46; H, 4.24; N, 3.73; C16H17Cl2NO3S
requires C, 51.34; H, 4.58; N, 3.74); dH [CDCl3] 7.01–
7.11 (m, 2H), 6.82–6.92 (m, 2H), 3.78 (h, 3JZ6.7 Hz, 1H),
155.3, 147.0, 146.5, 122.5, 115.9, 114.2, 113.4, 70.9, 55.6,
39.5, 23.3, 21.6; nmax (NaCl) (cmK1) 2977, 2931, 1558,
1503, 1374, 1246, 1196, 1109, 1037, 946, 832; GC–MS:
m/zZ403 (MHC, 100), 359 (MKC3H7, 15), 317
(MK2C3H7, 28), 280 (MK2C3H7–Cl, 21) amu.
3
3.77 (s, 3H), 3.65 (s, 3H), 1.29 (d, JZ6.7 Hz, 6H); dC
[CDCl3] 156.6, 155.9, 155.4, 146.8, 146.7, 122.3, 115.5,
3.5.4. 3,5-Dichloro-2,6-bis(4-methoxyphenoxy)-4-(2-propyl-
sulfanyl)pyridine (17). Pale yellow solid, mp 52 8C;
(Found: C, 56.22; H, 4.78; N, 3.00; S, 6.80; C22H21Cl2NO4S
requires C, 56.66; H, 4.54; N, 3.00; S, 6.88); dH [CDCl3]
6.86–6.90 (m, 2H), 6.62–6.72 (m, 2H), 3.84 (h, 3JZ6.6 Hz,
114.0, 113.8, 55.3, 54.4, 39.5, 23.1; nmax (NaCl) (cmK1
2951, 1558, 1505, 1462, 1367, 1246, 1196, 1097, 1034, 843;
)
GC–MS: m/zZ389 (M, 100) amu.
3
1H), 3.76 (s, 6H), 1.34 (d, JZ6.6 Hz, 6H); dC [CDCl3]
3.4.3. 3,5-Dichloro-2-(4-methoxyphenoxy)-6-methoxy-
pyridine (19). Colourless liquid; (Found: C, 52.02; H,
3.69; N, 4.67; C13H11Cl2NO3 requires C, 50.57; H, 3.21; N,
4.75); dH [CDCl3] 7.62 (s, 1H), 7.00–7.10 (m, 2H), 6.82–
6.92 (m, 2H), 3.78 (s, 3H), 3.64 (s, 3H); dC [CDCl3] 156.6,
155.8, 155.3, 146.8, 140.5, 122.3, 114.1, 109.9, 108.5, 55.4,
54.4; nmax (NaCl) (cmK1) 2954, 1578, 1506, 1469, 1409,
1380, 1222, 1192, 1095, 1036, 988, 837; GC–MS: m/zZ329
(MHC, 100), 264 (MKC3H7, 83), 108 (C7H7O, 53) amu.
156.6, 155.3, 147.5, 146.5, 122.5, 115.7, 113.9, 55.4, 39.7,
23.3; nmax (KBr) (cmK1) 2957, 2834, 1551, 1505, 1369,
1264, 1193, 1036, 825; GC–MS: m/zZ467 (M, 100) amu.
3.5.5. 3,5-Dichloro-2-(4-methoxyphenoxy)-6-(2-propoxy)-
pyridine (20). Colourless liquid; (Found: C, 54.41; H, 4.39;
N, 4.35; C15H15Cl2NO3 requires C, 54.90; H, 4.61; N, 4.27);
dH [CDCl3] 7.66 (s, 1H), 7.00–7.08 (m, 2H), 6.85–6.93 (m,
3
3
2H), 4.71 (h, JZ6.3 Hz, 1H), 3.82 (s, 3H), 1.17 (d, JZ
6.3 Hz, 6H); dC [CDCl3] 156.7, 155.3, 155.2, 147.0, 140.5,
122.5, 114.1, 110.3, 107.7, 70.7, 55.6, 21.6; nmax (NaCl)
(cmK1) 2980, 1569, 1505, 1436, 1247, 1218, 1191, 1092,
1036, 833; GC–MS: m/zZ329 (MHC, 100) amu.
3.5. General procedure for the reaction of the 1,10-bis[4-
dimethylamino-(3,5-dichloropyridine-2,6-diyl)pyridinium]-
dichlorides 4, 5, and 6 with 4-methoxyphenol in 2-propanole
to 12, 13, 16, 17, 20, and 21
In 100 mL of 2-propanol were dissolved the salt 4 (5.21 g,
10 mmol), or 5 (5.35 g, 10 mmol), or 6 (4.61 g, 10 mmol),
and 4-methoxyphenol (2.48 g, 20 mmol), respectively.
Then, sodium amide (0.78 g, 20 mmol) was dissolved and
the mixture was heated at reflux temperature for 6 h. After
this period the solvent was distilled off and the residue was
3.5.6. 3,5-Dichloro-2,6-bis(4-methoxyphenoxy)pyridine
(21). Colourless solid, mp 104 8C; (Found: C, 58.00; H,
3.49; N, 3.48; C19H15Cl2NO4 requires C, 58.18; H, 3.85; N,
3.57); dH [CDCl3] 7.75 (s, 1H), 6.79–6.89 (m, 4H), 6.63–
6.73 (m, 4H), 3.77 (s, 6H); dC [CDCl3] 156.5, 155.2, 146.6,
141.1, 122.4, 113.9, 110.1, 55.5; nmax (KBr) (cmK1) 2958,

A. Schmidt et al. / Tetrahedron 62 (2006) 1667–1674
1673
1574, 1508, 1428, 1249, 1221, 1180, 1091, 1034, 829;
GC–MS: m/zZ392 (M, 100) amu.
2872, 1492, 1464, 1287, 1209, 1187, 1076, 806; GC–MS: m/
zZ414 (MHC, 80); 376 (MKCl, 100), 334 (MKCl–C3H7,
38) amu.
3.6. General procedure for the reaction of the 1,10-bis[4-
dimethylamino-(3,5-dichloropyridine-2,6-diyl)pyridinium]-
dichlorides 4, 5, and 6 with sodium amide in DMF to 22–24
3.7.2. Preparation of 2,6-bis(n-butylsulfanyl)-3,5-
dichloro-pyridine (26). In 100 mL of methanol were
dissolved 1,10-bis[4-dimethylamino-(3,5-dichloropyridine-
In 100 mL of DMF were dissolved the salt 4 (5.21 g,
10 mmol), or 5 (5.35 g, 10 mmol), or 6 (4.61 g, 10 mmol),
and morpholine (8.2 g, 0.1 mol) as well as sodium amide
(3.9 g, 0.1 mol), respectively. The mixture was stirred at
100 8C for 6 h. Then, the solvent was distilled off and the
residue was chromatographed (silica gel 60, ethyl acetate–
petrol ether (1/1)).
2,6-diyl)pyridinium]dichloride
(5.21 g,
10 mmol),
n-butylthiol (5.4 g, 50 mmol), and triethylamine (5.2 g,
50 mmol). The mixture was stirred for 18 h at room
temperature. Then, the solvent was distilled off and the
residue was chromatographed (silica gel 60, ethyl acetate–
petrol ether (1/1)). Pale yellow liquid; (Found: C, 48.85;
H, 6.22; N, 2.84; C13H19Cl2NS2 requires C, 48.14; H,
5.90; N, 4.32); dH [CDCl3] 7.42 (s, 1H), 3.19 (t, 3JZ
7.4 Hz, 4H), 1.62–1.79 (m, 4H), 1.39–1.54 (m, 4H), 0.95
3.6.1. 2,6-Diamino-3,5-dichloro-4-ethylsulfanylpyridine
(22). Yellow solid, mp 63 8C; (Found: C, 35.83; H, 4.11;
N, 17.09; S, 13.62; C7H9Cl2N3S requires C, 35.31; H, 3.81;
3
(t, JZ7.2 Hz, 6H); dC [CDCl3] 154.2, 135.2, 123.6, 38.8,
31.3, 22.2, 13.7; nmax (NaCl) (cmK1) 2957, 2930, 2873,
1545, 1515, 1464, 1371, 1334, 1218, 1147, 1062;
GC–MS: m/zZ325 (M, 100); 288 (MKCl, 41), 266
(MKC4H9, 10) amu.
3
N, 17.65; S, 13.46); dH [CDCl3] 4.81 (s, 4H), 3.00 (q, JZ
3
7.4 Hz, 2H), 1.24 (t, JZ7.4 Hz, 3H); dC [CDCl3] 152.1,
142.5, 108.0, 29.2, 14.9; nmax (KBr) (cmK1) 3397, 3319,
1605, 1426, 1409, 1263, 746; GC–MS: m/zZ238 (MHC,
100) amu.
Acknowledgements
3.6.2. 2,6-Diamino-3,5-dichloro-4-(2-propylsulfanyl)-
pyridine (23). Yellow solid, mp 64 8C; (Found: C, 38.49;
H, 4.55; N, 15.98; S, 12.61; C8H11Cl2N3S requires C, 38.10;
H, 4.40; N, 16.66; S, 12.72); dH [CDCl3] 4.89 (s, 4H), 3.65
(h, JZ6.6 Hz, 1H), 1.27 (d, JZ6.6 Hz, 6H); dC [CDCl3]
152.1, 142.7, 108.3, 39.3, 23.2; nmax (KBr) (cmK1) 3425,
3323, 1627, 1603, 1531, 1412; GC–MS: m/zZ253 (MHC,
100); 208 (MKC3H7, 31); 175 (MKC3H7S, 43) amu.
The Deutsche Forschungsgemeinschaft (DFG) is greatfully
acknowledged for financial support. We thank Prof. F.
3
3
¨
Vogtle, Prof. K.-H. Dotz, and Prof. E. Niecke (University of
Bonn) for providing the X-ray facilities.
¨
3.6.3. 2,6-Diamino-3,5-dichloropyridine (24). Yellow
solid, mp 202 8C; (Found: C, 33.87; H, 2.70; N, 24.00;
C5H5N3Cl2 requires C, 33.73; H, 2.83; N, 23.60); dH
[CDCl3–CD3OD (1/2)] 7.68 (s, 1H), the protons of the
amino groups gave no signal due to H/D-exchange; dC
[CDCl3–CD3OD (1/2)] 161.1, 140.0, 104.7; nmax (KBr)
(cmK1) 3457, 3409, 3317, 1626, 1458, 1295, 902, 737;
GC–MS: m/zZ180 (MHC, 100) amu.
References and notes
1. Spitzner, D. In Black, D. S. C., Ed.; Science of Synthesis;
Thieme: Stuttgart, 2004; Vol. 15, pp 11–284.
2. Spitzner, D. In Kreher, E., Ed.; Houben-Weyl, Methoden der
Organischen Chemie; Thieme: Stuttgart, 1994; Vol. E7b,
pp 286–686.
3. The Chemistry of Heterocyclic Compounds, Weissberger A.,
Taylor, E. C., Eds.; Vol. 14: Pyridine and its Derivatives,
Suppl. 1–4, Abramovitch, A., Ed., Wiley-Interscience: New
York, 1974 and 1975.
3.7. General procedure for the reaction of the 1,10-bis[4-
dimethylamino-(3,5-dichloro-pyridine-2,6-diyl)pyridinium]-
dichlorides 4, 5, and 6 to 2,4,6-tris(n-butylsulfanyl)-3,5-
dichloropyridine (25)
4. Belen’kii, L. I.; Kruchkovskaya, N. D.; Gramenitskaya, V. N.
Adv. Heterocycl. Chem. 1999, 73, 295.
In 100 mL of methanol were dissolved the salt 4 (5.21 g,
10 mmol) or 5 (5.35 g, 10 mmol), n-butylthiol (5.4 g,
50 mmol) and triethylamine (5.2 g, 50 mmol). The
mixture was then stirred for 18 h at room temperature.
Then, the solvent was distilled off and the residue
was chromatographed (silica gel, ethyl acetate–petrol
ether (1/1)).
5. de Bie, D. A.; Geurtsen, B.; Berg, I. E.; van der Plas, H. C.
J. Org. Chem. 1986, 51, 3209.
6. (a) Hoffmann, R. W. Dehydrobenzene and Cycloalkynes;
Chemie: Weinheim, 1967. (b) Kauffmann, T.; Wirthwein, R.
Angew. Chem. 1971, 83, 21. Angew. Chem., Int. Ed. Engl.
1971, 10, 20. (c) Reinecke, M. G. Tetrahedron 1982, 38, 427.
7. (a) McGill, C. K.; Rappa, A. Adv. Heterocycl. Chem. 1988, 44,
1. (b) Boy, P.; Combellas, C.; Thiebault, A. Synlett 1991, 923.
(c) Beugelmans, R.; Chastanet, J. Tetrahedron 1993, 49, 7883.
8. (a) Jonckers, T. H. M.; Maes, B. U. W.; Lemiere, G. L. F.;
Dommisse, R. Tetrahedron 2001, 57, 7027. (b) Connon, S.-J.;
Hegarty, A. F. J. Chem. Soc., Perkin Trans. 1 2000, 1245. (c)
Kim, C.-S.; Russell, K. C. J. Org. Chem. 1998, 23, 8229. (d)
Barlocco, D.; Cignarella, G.; Tondi, D.; Vianello, P.; Villa, S.
J. Med. Chem. 1998, 41, 674.
3.7.1. 2,4,6-Tris(n-butylsulfanyl)-3,5-dichloropyridine
(25). Colourless liquid; (Found: C, 49.79; H, 6.64; N,
3.05; S, 24.30; C17H27Cl2NS3 requires C, 49.50; H, 6.60; N,
3.40; S, 23.32); dH [CDCl3] 3.17 (t, 3JZ7.5 Hz, 4H), 2.97 (t,
3JZ7.1 Hz, 2H), 1.72 (m, 4H), 1.66 (m, 2H), 1.46 (m, 4H),
1.43 (m, 2H), 0.95 (t, 3JZ7.5 Hz, 6H), 0.89 (t, 3JZ7.1 Hz,
3H); dC [CDCl3] 155.4, 142.4, 127.7, 34.9, 31.8, 31.2, 30.7,
22.2, 21.7, 13.7, 13.5; nmax (NaCl) (cmK1) 2959, 2930,
9. Berry, D. J.; Wakefield, B. J. J. Chem. Soc. C 1969, 2342.

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A. Schmidt et al. / Tetrahedron 62 (2006) 1667–1674
10. (a) Gradel, B.; Brenner, E.; Schneider, R.; Fort, Y.
Tetrahedron Lett. 2001, 42, 568. (b) Sakamoto, T.;
Kondo, Y.; Murata, N.; Yamanaka, H. Tetrahedron Lett.
1992, 33, 5373. (c) Sakamoto, T.; Shiga, F.; Yasuhara, A.;
Uchiyama, D.; Kondo, Y.; Yoshinori, Y. Synthesis 1992, 8,
746. (d) Ji, J.; Li, T.; Brunelle, W. H. Org. Lett. 2003, 5, 4611.
11. (a) Vorbru¨ggen, H. Adv. Heterocycl. Chem. 1990, 49, 117.
(b) Collins, I.; Suschitzky, H. J. Chem. Soc. C 1970, 1523.
(c) Roberts, S. M.; Suschitzky, H. Chem. Commun. 1967, 893.
12. (a) Bratt, J.; Iddon, B.; Mack, A. G.; Suschitzky, H.;
Taylor, J. A.; Wakefield, B. J. J. Chem. Soc., Perkin Trans.
1 1980, 648. (b) Julia, L.; Rius, J.; Suschitzky, H. Heterocycles
1992, 34, 1539.
26. Kyriacou, D. (Dow Chemical Co.). U.S. Patent 3,829,430;
Chem. Abstr. 1975, 82, 43181.
27. Gilmore, C. J.; MacNicol, D. D. Tetrahedron Lett. 1984, 25,
4303.
28. Johnston, H. (Dow Chemical Co.). U.S. Patent 3,364,223;
Chem. Abstr. 1968, 69, 27254.
29. (a) Ugryumov, E. P.; Kaklyugin, V. Y. Agrokhimiya 1995, 2,
73. Chem. Abstr. 1995, 122, 308690. (b) Kukhar, V. P.;
Cherepenko, T. I.; Pavlenko, A. F. Dopov. Akad. Nauk Ukr.
RSR, Ser. B: Geol., Khim. Biol. Nauki 1982, 12, 60. Chem.
Abstr.1983, 98, 121208.(c)Dzyuban, A.D.;Protopopova,G. V.;
Reidalova, L. I.; Sologub, S. L.; Zalesskii, G. A.; Moshchitskii,
S. D.; Pavlenko, A. F. Fiziol. Akt. Veshchestva 1974, 6, 76.
Chem. Abstr. 1975, 82, 165834.
13. Sausins, A.; Duburs, G. Heterocycles 1988, 27, 269.
¨
14. Krohnke, F. Synthesis 1976, 1.
30. Xu, X.; Qian, X.; Li, Z.; Song, G. J. Fluorine Chem. 1998,
88, 9.
15. Beschke, H. Aldrichim. Acta 1981, 14, 13.
16. Jutz, J. C. Top. Curr. Chem. 1978, 73, 125.
31. (a) Efremov, I. V.; Sipyagin, A. M.; Pomytkin, I. A. Chem.
Heterocycl. Compd. (Engl. Transl.) 1996, 32, 796. (b)
Boehme, H.; Ahrens, G. Liebigs Ann. Chem. 1982, 6, 1030.
(c) Tominaga, Y. Chem. Pharm. Bull. 1977, 25, 1519.
32. Yamanouchi Pharm., DE 2727686, 1978; Chem. Abstr. 1978,
88, 136637.
17. Katritzky, A. R. Tetrahedron 1980, 36, 679.
18. Boger, D. L. Chem. Rev. 1986, 86, 781.
19. (a) Queguiner, G.; Marsais, F.; Snieckus, V.; Epsztajn, J. Adv.
Heterocycl. Chem. 1991, 52, 187. (b) Miah, M. A. J.; Snieckus,
V. J. Org. Chem. 1985, 50, 5436. (c) Comins, D. L.; La
Munyon, D. H. Tetrahedron Lett. 1988, 29, 773.
20. Undheim, K.; Benneche, T. Adv. Heterocycl. Chem. 1995,
62, 305.
33. Phillips, G. B.; Buckman, B. O.; Davey, D. D.; Eagen, K. A.;
Guilford, W. J.; Hinchman, J.; Ho, E.; Koovakkat, S.;
Liang, A.; Light, D. R.; Mohan, R.; Ng, H. P.; Post, J. M.;
Shaw, K. J.; Smith, D.; Subramanyam, B.; Sullivan, M. E.;
Trinh, L.; Vergona, R.; Walters, J.; White, K.; Whitlow, M.;
Wu, S.; Xu, W.; Morrissey, M. M. J. Med. Chem. 1998, 41,
3557.
21. (a) Sandford, G. Eur. J. Org. Chem. 2003, 9, 1465. (b)
Chambers, R. D.; Hoskin, P. R.; Sandford, G.; Yufit, D. S.;
Howard, A. A. K. J. Chem. Soc., Perkin Trans. 1 2001, 2788.
(c) Chambers, R. D.; Hoskin, P. R.; Kenwright, A. R.;
Richmond, P.; Sandford, G.; Yufit, M. S.; Howard, J. A. K.
Org. Biomol. Chem. 2003, 1, 2137.
34. (a) Sell, W. J.; Dootson, F. W. J. Chem. Soc. 1897, 71, 1082.
(b) Sell, W. J.; Dootson, F. W. J. Chem. Soc. 1898, 73, 441.
35. Chen, T. K.; Flowers, W. T. J. Chem. Soc., Chem. Commun.
1980, 23, 1139.
22. (a) Schmidt, A.; Mordhorst, T.; Nieger, M. Org. Biomol.
Chem. 2005, 3, 3788. (b) Schmidt, A.; Mordhorst, T.;
Habeck, T. Org. Lett. 2002, 4, 1375.
36. Sheldrick, G. M. SHELXS-97, Acta Crystallogr., Sect. A 1990,
46, 467.
¨
37. Sheldrick, G. M. SHELXL-97, University of Gottingen:
23. Schmidt, A.; Mordhorst, T. Synthesis 2005, 781.
24. Schmidt, A.; Mordhorst, T. Z. Naturforsch. 2005, 60b, 683.
25. Johnston, H. (Dow Chemical Co.). U.S. Patent 3,549,647;
Chem. Abstr. 1971, 75, 5715.
¨
Gottingen, Germany, 1997.