Reactions of 4-(dimethylamino)pyridinium activated pentachloropyridine with nitrogen nucleophiles and hydride

Article abstract of DOI:10.1016/j.tet.2006.04.091

Substitution reactions on 2′,3′,5′,6′-tetrachloro-4-dimethylamino-[1,4]bipyridinyl-1-ylium chloride with nitrogen nucleophiles such as n-propylamine, isopropylamine, glycine, morpholine, and piperidine were examined. Highly functionalized Cl²,Cl³,N⁴,Cl⁵,Cl⁶- and N²,Cl³,N⁴,Cl⁵,Cl⁶-substituted pyridines were obtained, in part possessing unsubstituted 4-amino groups due to dealkylation. Detailed NMR studies were performed in order to elucidate the regiochemistry of these dealkylations.

Full text of DOI:10.1016/j.tet.2006.04.091

Tetrahedron 62 (2006) 6893–6898
Reactions of 4-(dimethylamino)pyridinium activated
pentachloropyridine with nitrogen nucleophiles and hydride
*
Andreas Schmidt, Jan Christoph Namyslo and Thorsten Mordhorst
Institute of Organic Chemistry, Clausthal University of Technology, Leibnizstrasse 6, D-38678 Clausthal-Zellerfeld, Germany
Received 20 March 2006; revised 21 April 2006; accepted 27 April 2006
Available online 19 May 2006
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0
0
0
Abstract—Substitution reactions on 2 ,3 ,5 ,6 -tetrachloro-4-dimethylamino-[1,4]bipyridinyl-1-ylium chloride with nitrogen nucleophiles
such as n-propylamine, isopropylamine, glycine, morpholine, and piperidine were examined. Highly functionalized Cl ,Cl ,N ,Cl ,Cl -
2
3
4
5
6
2
3
4
5
6
and N ,Cl ,N ,Cl ,Cl -substituted pyridines were obtained, in part possessing unsubstituted 4-amino groups due to dealkylation. Detailed
NMR studies were performed in order to elucidate the regiochemistry of these dealkylations.
Ó 2006 Elsevier Ltd. All rights reserved.
1
6
1. Introduction
1. The procedure can be extended to the synthesis of first
representatives of N ,Cl ,S ,Cl ,N -pentasubstituted pyri-
2
3
4
5
6
1
6
Substituted pyridines play a crucial role in organic, bio-
organic, and pharmaceutical chemistry as well as in material
sciences. This is reflected in an impressive number of mono-
graphs and review articles dealing with syntheses and prop-
erties of functionalized pyridines. Numerous synthetic
procedures have been developed during the last decades,
dines (Scheme 1). The preparation of amino-substituted
pyridines, however, remained challenging. 2-Amino-sub-
stituted pyridines are availableby the Chichibabin reaction,
1
7
or by nucleophilic substitutions of suitable leaving groups at
2- or 4-position such as halogen atoms. More than one- or
twofold substitutions afford vigorous reaction conditions due
to the decreased reactivity of chloropyridines substituted
with electron-donating groups. Halogen atoms at C-3 are
inert toward these substitution reactions unless metal-
organic procedures or hetaryne mechanisms are applied.
As a consequence, pentasubstituted pyridines with more
than one amino-substituent are very rare. According to the
1
18
2
among these ring closure reactions from acyclic precursors,
Dimroth rearrangements, ring contractions of 1,2-diazo-
3
4
5
19
cines, multicomponent cascade heterocyclizations, Vils-
meier and the reverse Vilsmeier methods, electrochemical
6
10
20
7
8
methods, pyrimidine–pyridine ring interconversions, metal-
mediated [2þ2þ2]-cycloadditions, and other metal-organic
9
1
0
syntheses. Although nucleophilic substitutions on penta-
fluoropyridine and approaches from ynamines and yna-
1
1
NMe2
1
2
mides have been studied recently and proved to be
promising avenues for the synthesis of highly substituted
pyridines, an astonishing large number of simply functional-
ized pyridines have been unavailable to date. We recently
described mono- and oligocationic hetarenium salts with
NMe2
Cl
Cl
N
N
N
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
N
1
3
up to ten positive charges within the same molecule, and
their broad applicability in heterocyclic synthesis. Thus,
1
0
0
0
0
ylium chloride 1, readily available in quantitative yields
2
,3 ,5 ,6 -tetrachloro-4-dimethylamino-[1,4]bipyridinyl-1-
SR1
X
N
Cl
Cl
Cl
Cl
Cl
Cl
2
3
from pentachloropyridine, can be used to prepare Cl ,Cl ,
O ,Cl ,Cl - and O ,Cl ,O ,Cl ,Cl -pentasubstituted pyri-
4
5
6
2
3
4
5
6
H N
N
NH2
2
14
15
dines as well as their sulfur analogs. Similarly, hitherto
unavailable O ,Cl ,O ,Cl ,O - and biologically interesting
2
3
4
5
6 14
R = OR, SR
2
3
4
5
6
15
S ,Cl ,S ,Cl ,S -pentasubstituted pyridines, as well as a
broad variety of symmetric and non-symmetric O ,Cl ,S ,
Cl ,O -pentasubstituted pyridines are available starting from
SR1
SR1
X
2
3
4
Cl
Cl
Cl
X
Cl
Cl
Cl
Cl
5
6
2
SR2 R O
2
OR3
N
R S
N
N
X = OR, SR
Scheme 1. Synthetic potential of DMAP-activated pentachloropyridine 1.
*
Corresponding author. Tel.: þ49 5323 723861; fax: þ49 5323 722858;
e-mail: schmidt@ioc.tu-clausthal.de
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040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.04.091

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A. Schmidt et al. / Tetrahedron 62 (2006) 6893–6898
Beilstein cross-fire database, less than 10 representatives
of N ,Cl ,N ,Cl ,Cl -pentasubstituted pyridines have been
In a control experiment, the dipropylamino-substituted pyri-
dine 6a indeed reacted with isopropylamine in the presence
of sodium hydride in DMF to give the dealkylated product
5a (Scheme 2). Several mechanisms can be discussed.
The lack of electron-withdrawing groups does not support an
2
3
4
5
6
2
1–26
27
described to date in six publications
and one patent.
We report here our results of studies directed toward the
applicability of our synthetic strategy for the preparation of
functionalized pyridines starting from hetarenium salts to
some nitrogen nucleophiles.
E1 -type mechanism and elimination of propene. Nucleo-
cb
philic attack, however, of propylamide and isopropylamide
2
4
on the 4-propylamino groups in the initially formed N ,N -
dialkyl-pyridine-2,4-diamines 6a and 6b, respectively,
resulted in the formation of N,N-dialkylamines and 4-NH2-
substituted pyridines.
2
. Results and discussion
0
0
0
0
We studied substitution reactions on 2 ,3 ,5 ,6 -tetrachloro-
-dimethylamino-[1,4]bipyridinyl-1-ylium chloride 1 with
4
the nitrogen nucleophiles such as n-propylamine, isopropyl-
amine, glycine, morpholine, and piperidine. Nucleophilic
substitutions on 1 with n-propylamine and isopropylamine
were first performed in the presence of sodium hydride as
base. Mixtures of substituted pyridines were obtained, which
are presented in Table 1, among them new representatives of
HN
H
N
HN
N
i-PrNH , NaH
Cl
Cl
Cl
2
Cl
Cl
Cl
DMF, 4 h, 90°C
N
N
H
N
H
2
3
4
5
6
N ,Cl ,N ,Cl ,Cl -pentasubstituted species.
6a
Surprisingly, n-propylamine as nucleophile resulted in the
formation of 3,5,6-trichloro-N -propyl-pyridine-2,4-diamine
N
H
2
5
was conducted at 50 C over a period of 4 h. 3,5,6-Trichloro-
a as the main product (Table 1, entry 1), when the reaction
ꢀ
NH2
N
HN
2
4
N ,N -dipropyl-pyridine-2,4-diamine 6a was isolated in
very low yields. The 4-isopropylamino-substituted tetra-
chloropyridine 4b was found to be the main product of the
reaction of hetarenium salt 1 with isopropylamine under
analogous reaction conditions (Table 1, entry 3). 3,5,6-
Cl
Cl
Cl
Cl
Cl
Cl
work-up
N
H
N
N
H
5a
2
Trichloro-N -isopropyl-pyridine-2,4-diamine5bwasformed
Scheme 2. Proposed mechanism for dealkylations.
in low yields as a by-product. In either case, unmodified
starting material was easily separated by filtration over
silica gel.
The regiochemistry of this conversion was unambiguously
confirmed by NMR methods. Thus, in the H NMR spectra
1
of 5a, taken in CDCl at rt, two H/D-exchangeable reso-
3
Obviously, the 4-amino groups in 5a and 5b were formed
from propylamino- and isopropylamino groups, respectively.
nance frequencies in a 1:2 ratio are observable at d¼4.82
and 4.95 ppm, which were assigned to the NHR and NH
2
Table 1. Reaction of 1 with amines in the presence of bases
NMe2
Cl
N
NH2
NH2
NHR
NH2
NHR
amine
base
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
+
+
+
+
N
N
N
NH2
N
N
NHR
N
NHR
1
2
3
4
5
6
Entry
1
Amine
Temp/time
Base
NaH
Product
R
Yield %
ꢀ
n-PrNH
2
50 C, 4 h
5a
n-Pr
n-Pr
H
32
5
7
18
0
40
35
6
2
3
4
5
6
a
2
NaNH
2
H
a
a
a
n-Pr
n-Pr
n-Pr
ꢀ
3
4
i-PrNH
2
40 C, 4 h
NaH
4b
i-Pr
i-Pr
H
37
5
5
2
3
4
5
6
b
NaNH
2
10
10
15
30
0
H
b
b
b
i-Pr
i-Pr
i-Pr

A. Schmidt et al. / Tetrahedron 62 (2006) 6893–6898
6895
group, respectively. In agreement to the proposed structure,
the gs-HMBC ( H– C) spectrum displays all the expected
long range C–H couplings as presented in Figure 1.
1
48.0 ± 1.0 ppm
1
13
1
04.7 ± 3.9 ppm
NH2
Cl
Cl
Cl
144.2 ± 0.7 ppm
99.4 ± 5.1 ppm
R
N
N
H
H
H
153.8 ± 2.9 ppm
N
N
Cl
Cl
Cl
13
Figure 3. Peak assignments of the C NMR resonance frequencies.
N
H
to the 4-NH -group of 5a, whereas the signal at ꢁ294.5 ppm
2
is caused by the 2-NHR group. The pyridine nitrogen atom
could not be detected by N NMR spectroscopy.
Figure 1. HMBC-detected long range C–H couplings in 5a.
15
3
Among these, the J coupling of the hydrogen atoms of
CH
Next we used sodium amide as base for the reaction of hetare-
nium salt 1 with amines. This base gave best results on treat-
the NH group with C-5 is diagnostically important. How-
2
ever, a 2D INADEQUATE, performed to unambiguously
1
3–16
ment of 1 with a broad variety of O- and S-nucleophiles.
In these reactions the amide anion never reacted as nucleo-
phile. Indeed, we found a quantitative conversion of the start-
1
3
prove the C peak assignments, suffered from disadvanta-
geous relaxation times of the aromatic carbon atoms due
to the absence of H atoms at the pyridine ring. We solved
the problem by considering very large C–C coupling con-
stants within this special pyridine ring (approx. 70 Hz) and
by addition of 4% chromium(III) acetylacetonate as a relax-
ation reagent, and proved the C–C connectivities as shown in
Figure 2. Analogous results were obtained with 5b.
2
3
4
5
6
ing material 1. Again, the N ,Cl ,N ,Cl ,Cl -substituted
pyridine 5a was isolated as the main product of the reaction
ꢀ
with n-propylamine at 50 C (Table 1, entry 2). The diamine
6a was found in 35% yield. Additional by-products are tetra-
chloropyridin-4-amine 2 and trichloropyridine-2,4-diamine
3, isolated in 7% and 18% yield, respectively. The latter
mentioned compounds formed also on treatment of penta-
1
3
ꢀ
As a result, the C NMR peak assignments of the
N ,Cl ,N ,Cl ,Cl -substituted pyridines presented in this
paper is as shown in Figure 3. A N HMBC measurement
allowed to assign the resonance frequency d at ꢁ310.3 ppm
chloropyridine with ammonia at 170–190 C, in addition
2
3
4
5
6
21,22
to 2-aminotetrachloropyridine. Similar results were
obtained starting from isopropylamine (Table 1, entry 4). A
mixture of 2, 3, 4b, and 5b was formed, with 5b as the
1
5
N
Figure 2. 2D-INADEQUATE of 5a.

6896
A. Schmidt et al. / Tetrahedron 62 (2006) 6893–6898
0
ylium chloride 1 reacts with sodium borohydride to give
0
0
0
main product. All compounds were easily separated and
purified by column chromatography on silica gel.
2 ,3 ,5 ,6 -Tetrachloro-4-dimethylamino-[1,4]bipyridinyl-1-
2
,3,5,6-tetrachlorpyridine 11 (Scheme 4). Best yields and
Glycine as nitrogen nucleophile yielded methyl-(2,3,5,6-
tetrachloro-pyridin-4-yl)-amine 7, which is a known
purities were achieved when 2-propanol was used as sol-
vent. On changing the solvent to ethanol, the yield decreased
from 80 to 5% after reaction at rt over a period of 5 h. In
DMF, the yield is 46% under analogous reaction conditions.
In 2-propanol as solvent, the product was obtained in 95%
purity. The 4-(dimethylamino)pyridine could be recovered.
The chromatographically separable by-product proved to be
2,3,5-trichloropyridine, as evidenced by GC–MS analysis.
Numerous procedures for the preparation of 2,3,5,6-tetra-
chloropyridine 11 exist, among them the reduction of
pentachloropyridine with zinc, ammonium chloride, di-
2
4
2
4
compound, and 3,5,6-trichloro-N ,N -dimethyl-pyridine-
,4-diamine 8 in moderate and low yields, respectively
Scheme 3). Obviously, these compounds were formed on
2
(
decarboxylation of the glycine moieties under the applied re-
action conditions. To the best of our knowledge, 8 has never
been described before. The pyridylamine 7 was obtained
earlier on reaction of pentachloropyridine with methylamine
in 1,4-dioxane as a mixture of 2- and 4-isomers after a reac-
2
4
tion time of 18 h.
ꢀ
29
methylphosphonate in water at 89–90 C, electrochemical
NHMe
Cl
NHMe
Cl
3
0
methods,
with hexachloroethane in the presence of n-Bu NBr in
the chlorination of 2,3,5-trichloropyridine
Cl
Cl
Cl
Cl
HOOCCH2NH2
+
1
4
NaNH , DMF, 130°C
31
2
N
Cl
N
NHMe
aqueous sodium hydroxide, and some patented proce-
dures.
3
2
7
8
Cl
Cl
Cl
Cl
Scheme 3.
NaBH4 / iPrOH
1
N
Morpholine in the presence of sodium amide converted het-
arenium salt 1 into 3,5-dichloro-(2,6-dimorpholin-4-yl)-
pyridin-4-ylamine 9a in 59% yield, which was isolated as
a pure compound (Table 2, entry 2). In accordance with
the structure, the C NMR spectra showed a symmetric
molecule. Sodium hydride as the base gives lower yields
and considerable amounts of 2,3,5-trichloro-6-morpholin-
11
Scheme 4.
1
3
In summary, we supplement our synthetic strategy for the
preparation of highly functionalized pyridines from hetare-
nium salts by results describing scope and limitations of
the application of nitrogen nucleophiles.
4
-yl-pyridin-4-ylamine 10a (Table 2, entry 1), the regio-
chemistry of which was elucidated by HMBC measurements
as described above. The morpholine-substituted trichloro-
pyridine with N ,Cl ,N ,Cl ,Cl substitution pattern is avail-
2
3
4
5
6
3
. Experimental
able by substitution of secondary aliphatic amines on
2
8
(
Z)-perchloro-1,3-butadiene-1-carbonitrile.
pyridine reacts with morpholine at the 2-position. Twofold
Pentachloro-
3
.1. General
2
3
4
5
6
substitution results in the formation of N ,Cl ,Cl ,Cl ,N -
morpholino-substituted pyridine. Some earlier published
structures had to be revised.
1
13
The H and C NMR spectra were recorded on a Bruker
Avance 400 and DPX 200 at 400 and 200 MHz, respectively.
The chemical shifts are reported in parts per million relative
to internal tetramethylsilane (d¼0.00 ppm). FTIR spectra
were obtained on a Bruker Vector 22 in the range of 400–
4000 cm (2.5% pellets in KBr). The GC–MS spectra
were recorded on a GC Hewlett–Packard 5980, Series II in
combination with a MS Hewlett–Packard 5989 B, and on
a Varian GC3900 with SAT2100T mass spectrometer.
Melting points are uncorrected.
2
8
Table 2. Morpholine and piperidine as N-nucleophiles
ꢁ
1
Z
NH2
NH2
N
N
H
Cl
Cl
N
Cl
Cl
Cl
N
+
1
N
N
base
Z
Z
Z
9a,b
10a,b
0 0 0 0
.2. General procedure for the reaction of 2 ,3 ,5 ,6 -
3
tetrachloro-4-dimethylamino-[1,4]bipyridinyl-1-ylium
chloride 1 with amines
Entry Amine
Temp/time Base
Product
Z
Yield %
ꢀ
1
2
Morpholine 90 C, 3 h
NaH
9a
O
10
18
59
0
1
0a
9a
0a
A suspension of 1 (10 mmol, 3.74 g) in 100 mL of the amine
was treated with sodium hydride (50 mmol, 1.25 g) or so-
dium amide (50 mmol, 1.96 g) and heated at reflux temper-
ature over a period of 5 h. Then, the amine was distilled off
in vacuo and the residue was chromatographed (silica gel 60,
EtOAc/petroleum ether¼1:3).
NaNH
100 C, 3 h NaH
NaNH
2
1
ꢀ
3
4
Piperidine
9b
0b
9b
0b
CH
2
54
18
37
25
1
1
2
3
yellow solid, mp 210 C (C H Cl N requires C, 25.90; H,
.2.1. 2,3,5,6-Tetrachloro-pyridin-4-ylamine (2). Pale
ꢀ
On reaction of hetarenium salt 1 with piperidine, 9b and 10b
were obtained under the conditions presented in Table 2
5
2
4 2
0.87; N, 12.08. Found: C, 25.87; H, 0.86; N, 12.18); dH
(DMSO-d ) 7.38 (s, 2H; NH ); d (DMSO-d ) 150.8,
(
entries 3 and 4).
6
2
C
6

A. Schmidt et al. / Tetrahedron 62 (2006) 6893–6898
6897
ꢁ
1
ꢀ
1
1
44.1, 111.6; nmax (KBr) (cm ): 3494, 3390, 1583, 1535,
373, 1250, 1109, 1061, 973; m/z¼233 (MH , 100), 195
mp 41 C (C H Cl N requires C, 54.72; H, 6.73; N,
15
22
2 4
þ
17.02. Found: C, 54.28; H, 7.06; N, 16.81); dH (CDCl3)
4.78 (s, 2H; NH ), 3.10–3.30 (m, 8H; CH ), 1.50–1.75 (m,
12H; CH ); d (CDCl ) 155.3, 148.2, 99.7, 50.4, 26.0,
24.7; nmax (KBr) (cm ): 3480, 3380, 2935, 2918, 2847,
(
MꢁCl, 11).
2
2
2 C 3
ꢁ
1
3.2.2. 3,5,6-Trichloro-pyridine-2,4-diylamine (3). Paleyel-
low solid, mp 168 C (C H Cl N requires C, 28.27; H, 1.90;
ꢀ
N, 19.78. Found: C, 29.06; H, 2.11; N, 19.05); d (DMSO-d )
2827, 1611, 1598, 1553, 1541, 1422, 1373, 1283, 1258,
1217, 1117, 1076, 1007, 866; m/z¼330 (MH , 100); 294
5
4
3 3
þ
H
6
6
1
3
.41 (s, 2H; a-NH ), 6.31 (s, 2H; g-NH ); d (DMSO-d )
6
(MꢁCl, 45); 244 (MꢁC H N, 24).
5 10
2
2
C
ꢁ
1
53.1, 148.7, 143.5, 100.8, 94.3; nmax (KBr) (cm ) 3453,
369, 1612, 1573, 1439; m/z¼213 (M, 100), 176 (MꢁCl, 28).
3.2.9. 2,3,5-Trichloro-6-(morpholin-4-yl)-4-amino-pyri-
dine (10a). Colorless solid, mp 144 C (C H Cl N O
ꢀ
requires C, 38.26; H, 3.57; N, 14.87. Found: C, 38.23; H,
9
10
3 3
3
(
.2.3. Isopropyl-(2,3,5,6-tetrachloro-pyridin-4-yl)-amine
ꢀ
5.07; H, 2.94; N, 10.22. Found: C, 36.06; H, 2.97; N,
4b). Brownish solid, mp 74 C (C H Cl N requires C,
8
8
4
2
3.12; N, 14.34); d (CDCl ) 5.11 (s, 2H; 10H), 3.77–3.90
H
m, 4H; 9H), 3.25–3.40 (m, 4H; 8H); d (CDCl ) 155.6,
C 3
148.9, 144.2, 108.2, 104.3, 66.8, 49.5; nmax (KBr) (cm ):
3445, 3334, 1622, 1559, 1525, 1417, 1367, 1254, 1112;
m/z¼283 (M, 100).
3
3
1
1
1
1
2
(
3
ꢁ1
0.23); d (CDCl ) 4.85 (s, 1H; NH), 4.61 (h, J¼6.4 Hz,
H
3
3
H; NCH), 1.27 (d, J¼6.4 Hz, 6H; CH ); d (CDCl )
3
C
3
ꢁ
1
50.0, 146.4, 115.4, 47.2, 24.4; n
(KBr) (cm ) 1556,
max
539, 1413, 1353, 1259, 1236, 1140, 1021, 912, 708; m/z¼
75 (M, 100), 260 (MꢁCH ).
0
pyridinyl-4 -ylamine (10b). Yellow oil. dH (CDCl ) 5.04
0
0
0
0
3
3
.2.10. 3 ,5 ,6 -Trichloro-3,4,5,6-tetrahydro-2H-[1,2 ]bi-
3
2
3
(
3
1
.2.4. 3,5,6-Trichloro-N -propyl-pyridine-2,4-diamine
ꢀ
7.75; H, 3.96; N, 16.51. Found: C, 37.56; H, 3.87; N,
(s, 2H; NH ), 3.13–3.30 (m, 4H; CH ), 1.50–1.77 (m, 6H;
CH ); d (CDCl ) 156.7, 148.7, 144.0, 107.3, 104.4, 50.4,
2 2
5a). Yellow solid, mp 76 C (C H N Cl requires C,
8
10
3
3
2
C
3
2
5.8, 24.4; m/z¼281 (M, 100), 245 (MꢁCl, 25); 86
6.49); d (CDCl ) 4.85 (br s, 2H; NH ), 4.78 (br s, 1H;
2
H
3
3
(
C H N, 31).
5
10
NH), 3.38 (dt, J¼7.3, 1.5 Hz, 2H; NCH ), 1.62 (sx,
2
3
3
J¼7.3 Hz, 2H; CH CH ), 0.97 (t, J¼7.3 Hz, 3H; CH );
2
3
3
0 0 0 0
.3. General procedure for the reaction of 2 ,3 ,5 ,6 -
tetrachloro-4-dimethylamino-[1,4]bipyridinyl-1-ylium
chloride (1) with glycine
3
d
(CDCl ) 151.5, 146.9, 144.6, 103.1, 96.1, 43.3, 22.8,
3
C
ꢁ1
1
1
2
1.4; nmax (KBr) (cm ) 3511, 3405, 2969, 2929, 2864,
614, 1583, 1507, 1447, 1298, 1165; m/z¼255 (M, 43);
25 (MꢁC H , 100).
3
7
A suspension of pyridinium salt 1 (3.74 g, 10 mmol) in
100 mL of DMF was treated with sodium amide (1.96 g,
50 mmol) and glycine (1.5 g, 20 mmol) and heated for 5 h
2
3
(
3
1
4
.2.5. 3,5,6-Trichloro-N -isopropyl-pyridine-2,4-diamine
ꢀ
7.75; H, 3.96; N, 16.51. Found: C, 37.34; H, 3.75; N,
5b). Brownish solid, mp 26 C (C H Cl N requires C,
8
8
3
3
ꢀ
at 120 C. After cooling, the reaction mixture was poured
in water, and pH was adjusted to 5 with hydrochloric acid.
The mixture was then evaporated to dryness, and the residue
was chromatographed (silica gel, ethyl acetate/petroleum
ether¼1:4).
6.26); d (CDCl ) 4.85 (s, 2H; NH ), 4.60 (s, 1H; NH),
H
3
2
3
3
.19 (h, J¼6.4 Hz, 1H; NCH), 1.22 (d, J¼6.4 Hz, 6H;
CH ); d (CDCl ) 150.9, 147.0, 144.7, 103.0, 96.1, 42.9,
3
C
3
ꢁ
1
2
1
1
3.1, 11.2; nmax (KBr) (cm ) 3498, 3400, 2972, 1610,
578, 1504, 1437, 1311, 1182, 1126, 1055; m/z¼254 (M,
3
.3.1. 2,3,5,6-Tetrachloro-4-(N-methylamino)-pyridine
7). Oil, d (CDCl ) 4.82 (s, 1H; 5H), 2.91 (s, 3H; 6H); d
(CDCl ) 155.0, 148.5, 97.7, 41.5; n
3
00), 238 (MꢁCH ).
3
(
H
3
C
ꢁ
(KBr) (cm ):
max
1
2
4
3
.2.6. 3,5,6-Trichloro-N ,N -dipropyl-pyridine-2,4-
diamine (6a). Yellow liquid (C H Cl N requires C,
3
8
498, 3397, 3945, 1601, 1553, 1484, 1396, 1325, 1045,
43, 705; m/z¼247 (MH , 100), 214 (MꢁCH N, 75). No
1
1
16
3 3
þ
4
1
3
4.54; H, 5.44; N, 14.17. Found: C, 43.67; H, 4.95; N,
4.18); d (CDCl ) 4.86 (s, 1H; NH), 4.78 (br s, 1H; NH),
4
satisfactory elemental analysis achieved.
H
3
3
3
.39 (t, J¼7.3 Hz, 2H; NCH ), 3.36 (t, J¼7.3 Hz, 2H;
2
3
3
NCH ), 1.61 (h, J¼7.3 Hz, 4H; CH ), 0.96 (t, J¼7.3 Hz,
3.3.2. 2,3,5-Trichloro-4,6-di-(N-methylamino)-pyridine
ꢀ
2
2
6
4
1
1
H; CH ); d (CDCl ) 151.5, 146.9, 144.7, 103.2, 96.1,
3
(8). Colorless solid, 69 C (C
7
H
8
N
3
Cl
3
requires C, 34.96;
C
3
ꢁ
1
3.3, 22.9, 11.4; nmax (NaCl) (cm ) 3398, 2963, 2875,
582, 1356, 1233, 1070; m/z¼296 (M, 4), 260 (MꢁCl,
00), 225 (Mꢁ2Cl, 27), 184 (Mꢁ2ClꢁC H , 22).
H, 3.35; N, 17.47. Found: C, 35.22; H, 2.90; N, 17.55); d
H
(CDCl
(CDCl
) 5.07 (br s, 2H; 7H, 9H), 2.94 (s, 6H; 8H, 10H); d
) 156.3, 148.8, 143.6, 106.5, 102.4, 41.4 (overlapped);
nmax (KBr) (cm ) 3502, 3402, 1601, 1563, 1525, 1397,
1327, 1043, 938; m/z¼241 (MH , 100), 210 (MꢁCH
3
C
3
7
3
ꢁ1
þ
3.2.7. 3,5-Dichloro-(2,6-dimorpholin-4-yl)-pyridin-4-yl-
ꢀ
amine (9a). Colorless solid, mp 64 C (C H Cl N O
N, 15).
4
1
3
18
2
4
2
requires C, 46.86; H, 5.44; N, 16.81. Found: C, 46.50; H,
.70; N, 16.80); d (CDCl ) 4.93 (br s, 2H; NH ), 3.80–3.85
3.3.3. 2,3,5,6-Tetrachloropyridine (11). A suspension of
salt 1 (3.74 g, 10 mmol) in 100 mL of anhydrous 2-propanol
was treated with sodium borohydride (0.57 g, 15 mmol) at rt
and stirred for 6 h. Then, the solution was poured in diluted
hydrochloric acid and extracted twice with diethyl ether. The
organic layer was separated, evaporated, and chromato-
graphed (silica gel, ethyl acetate/petroleum ether¼1/1).
All spectroscopic data are in agreement to an authentic
sample.
5
H
3
2
(
m, 8H), 3.26–3.31 (m, 8H); d (CDCl ): 154.3, 148.7, 100.1,
C
3
ꢁ
1
6
1
1
6.9, 49.5; nmax (KBr) (cm ) 3473, 3321, 2969, 2855,
621, 1554, 1420, 1392, 1365, 1283, 1257, 1154, 1110,
067, 1030, 1019, 1007; m/z¼333 (M, 100); 296 (MꢁCl, 31).
0 0 00 00 00 00
3
2
.2.8. 3 ,5 -Dichloro-3,4,5,6,3 ,4 ,5 ,6 -octahydro-2H,
0
0
0
0
00
0
H-[1,2 ,6 ,1 ]terpyridin-4 -ylamine (9b). Yellow solid,

6898
A. Schmidt et al. / Tetrahedron 62 (2006) 6893–6898
Yoshinori, Y. Synthesis 1992, 8, 746; Ji, J.; Li, T.; Brunelle,
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