Synthesis and conformational properties of 2,6-bis-anilino-3-nitropyridines

Article abstract of DOI:10.1039/b508819b

The synthesis of 2,6-bis-anilino-3-nitropyridines that are alkylated or acylated at the anilino nitrogen atoms is described. These derivatives show characteristic differences in the ¹H-NMR spectra compared with the unsubstituted parent compound

Full text of DOI:10.1039/b508819b

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A R T I C L E
Synthesis and conformational properties of
2,6-bis-anilino-3-nitropyridines†
Sylvia Schmid,a Martin Ro¨ttgen,a Ulf Thewaltb and Volkhard Austel*a
a Universita¨t Ulm, Abteilung Organische Chemie II, Albert-Einstein-Allee 11, 89081, Ulm,
Germany. E-mail: volkhard.austel@chemie.uni-ulm.de
b Universita¨t Ulm, Sektion Ro¨ntgen- und Elektronenbeugung, Albert-Einstein-Allee 11, 89081,
Ulm, Germany
Received 21st June 2005, Accepted 22nd July 2005
First published as an Advance Article on the web 17th August 2005
The synthesis of 2,6-bis-anilino-3-nitropyridines that are alkylated or acylated at the anilino nitrogen atoms is
described. These derivatives show characteristic differences in the 1H-NMR spectra compared with the unsubstituted
parent compound. These differences are used to determine structure–conformation relationships of this type of
compounds. The conclusions drawn from the 1H-NMR spectra in this respect are supported by X-ray
crystallographic data and by 1H-NMR data of conformationally restricted analogues. Preliminary investigations
indicate that these relationships can in principle be extended to other diarylamines.
as the dependence of the conformational preferences on the
Introduction
substituents R and Rꢀ have to be known. Both aspects are
Molecular scaffolds from which molecules of diverse physical-
discussed in this paper.
chemical and conformational properties can be derived via
convenient synthetic procedures are interesting for material
science as well as for medicinal chemistry. In the former case
they can serve as building blocks for oligomers with specific
Results and discussion
Synthesis
molecular architecture which, depending on the type and posi-
tion of functional groups, allows them either to recognize guest
molecules or to undergo self-assembly to form supramolecular
structures. In medicinal chemistry, such molecular scaffolds are
useful for creating spatial arrangements of structural moieties
that are specifically recognized by biological targets.
Under these considerations we became interested in com-
pounds of type 1 that are derived from 2,6-bis-anilino-3-
nitropyridine as the basic scaffold.
To our knowledge, only the parent 2,6-dianilino-3-nitropyridine
(2) (along with the corresponding bis-(2-pyridyl)amino deriva-
tive) has so far been reported in the literature.1 It was obtained as
a side product from the reaction of 2,6-dichloro-3-nitropyridine
(3) with aniline.
In principle, all compounds of type 1 in which R and Rꢀ
represent either H or alkyl substituents should be accessible
from 3 following this procedure by using an excess of the
corresponding aniline (for R = Rꢀ) or by introducing the
corresponding N-substituted anilino groups in two consecutive
steps (Scheme 1). The latter procedure should be viable without
difficulty since a great preference for exchange of Cl-2 over Cl-
6 was observed not only for primary1 but also for secondary
anilines.2
The first step of this sequence occurs readily and gives pure
compounds in good yields.1,2 The same does not apply to the
second step except for Rꢀ = H. In all cases which we have
investigated harsh conditions such as using aniline as a solvent in
addition to high temperatures were needed. The products were
difficult to purify and were obtained at best in low yields. The
Functional groups that are needed for intermolecular interac-
tions can be connected to this scaffold as part of the residues R
and Rꢀ or of substituents on the phenyl rings. Oligomers can be
formed via diamino derivatives of 1 that carry one amino group
in each of the phenyl rings.
As a basic requirement for applying this scaffold to the
purposes mentioned above, suitable synthetic routes as well
† Part of the PhD thesis of Sylvia Schmid, University of Ulm, 2005.
Scheme 1 Conceivable synthesis strategy for compounds of type 1.
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 4 0 8 – 3 4 2 1 T h i s j o u r n a l i s T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 5
3 4 0 8
©

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procedure failed completely if secondary anilines were used in
the second step (even in the case of Rꢀ = H).
Since this acylation is probably a thermodynamically con-
trolled process the selectivity has to be attributed to the higher
stability of the N-6 acyl isomers which retain the hydrogen bond.
In an AM1 calculation the N-6 acyl derivative 5a is favoured over
its N-2 isomer by 4 kcal mol−1.
Therefore, alternative syntheses had to be searched for. We
found that 2 can be selectively alkylated at the nitrogen of the
6-anilino group (Scheme 2).
N-2 Mono alkylated derivatives can be prepared in two ways
depending on whether the corresponding alkyl halide is stable
towards strongly alkaline conditions or not. In the former case
one starts from 2 which is selectively protected at N-6 by a
tert-butoxycarbonyl group (5b) and subsequently alkylated at
N-2 in the presence of strong base followed by deprotection
(Scheme 4).
Compounds of type 1 in which N-2 and N-6 carry the same
alkyl group can be synthesized directly from 2 using a stronger
base. Thus the bis-methyl derivative 8 was prepared from 2 and
methyl iodide in DMF with KOtBu as an auxiliary base.
Scheme 2 Mono-alkylation of 2.
Using DMSO as a solvent in this reaction sometimes turned
out to be problematic when alkyl bromides were used. For ex-
ample, in experiments with tert-butyl bromoacetate we observed
formation of significant amounts of products that were bromi-
nated in 5-position of the pyridine or in the anilino groups.3
The observed selectivity of the alkylation is explicable if one
assumes the reactive species to be the anion derived from 2 by
deprotonation of the 6-anilino nitrogen (N-6). This anion should
be more favourable than the one formed on deprotonation of the
2-anilino nitrogen (N-2) because it does not require breaking of a
hydrogen bond. Semi-empirical calculations (AM1, convergence
limit = 0.01) support this view by showing that the N-6-derived
anion is more favourable by 8 kcal mol−1.
If the alkyl halide is unstable under such conditions (e.g.
benzyl bromide) the 2-alkyl derivatives may be accessible from
9 and the corresponding N-alkyl aniline (Scheme 5).
However, due to the selectivity of the chlorine exchange
mentioned above, 9 cannot be prepared directly from 3 and
aniline. The selectivity may, however, be reversed if the attacking
nucleophile is an anion.4 Therefore, the sodium salt of N-
tert-butoxycarbonyl-aniline (11) was reacted with 3. An NMR
spectrum of the crude product revealed that a 7 : 3 mixture
of the 6-(12) and the 2-(13) substitution products was formed.
After deprotection, we were able to separate the two isomeric
anilino-3-nitropyridines (9, 14) by column chromatography
(Scheme 6).
Acylation shows the same selectivity as alkylation: treating 2
with acetic anhydride or with di-tert-butyl dicarbonate and 4-
N,N-dimethylaminopyridine (DMAP) yielded the correspond-
ing N-6-acyl derivatives 5 (Scheme 3).
Interestingly, under the conditions used for the nucleophilic
replacement of the chlorine of 9, compound 12 reacted consid-
erably more slowly.
Conformational properties
On alkylation as well as on acylation of 2, characteristic changes
in the 1H-NMR spectra were observed that differ for N-2
Scheme 3 Mono-acylation of 2.
Scheme 4 Synthesis strategy for N-2 mono-alkylation products of 2.
Scheme 5 Alternative synthesis strategy for N-2 mono-alkylation products of 2.
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 4 0 8 – 3 4 2 1
3 4 0 9

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Scheme 6 Synthesis strategy for 6-anilino-2-chloro-3-nitropyridine.
alkylation, N-6 alkylation, and N-6 acylation. These changes
can be appreciated by inspection of the chemical shifts compiled
in Table 1 for N-6 derivatives (general structure 15) and in Table 2
for N-2 derivatives (general structure 16).
Therefore, the up-field shift of H5ꢀꢀ must be caused by a
shielding effect from phenyl A. This would imply that in the
parent compound 2 conformation 2A (Scheme 7) in which
phenyl A faces the ring nitrogen is preferred over 2B.
Alkylation
Alkylation of the parent 2,6-bis-anilino-3-nitropyridine (2) at N-
6 shifts the signal of H5ꢀꢀ consistently up-field by approximately
0.4 ppm (compare 4a, 4c, 4d with 2, in Table 1). Concomitantly,
the signals of H3 and H4 are shifted downfield by about 0.3 ppm
and 0.4 ppm respectively whereas the ortho hydrogens (H2)
experience a moderate up-field shift (around 0.15 ppm). These
changes seem to be independent of the particular substituent Rꢀꢀ
(compare 7 with 8 and 9 with 15a in Table 1).
Scheme 7 Conformational states of 2 with respect to the 6-anilino
group.
The pattern of changes of the phenyl signals are explicable if
the conformational states that prevail in 2 are those in which the
angle between the planes of the pyridine and the phenyl deviate at
most moderately from co-planarity. In these conformations the
H2 are shifted down-field by the anisotropy effect of the pyridine.
Moreover, there is considerable conjugation of the N-6 lone
electron pair with both the pyridine and phenyl A. On alkylation,
phenyl A twists out of conjugation with the N-6 lone pair. The
associated decrease in electron density is reflected in the observed
down-field shift of the H3 and H4 signals. Since the pyridine
ring remains in conjugation with the lone pair of N-6, the
planes of the two rings prefer an approximately perpendicular
orientation with respect to each other. Consequently, the H2
become shielded by the pyridine. Apparently, this latter effect
more than compensates for the electronic effect and hence a
moderate net up-field shift of these hydrogens remains.
Regarding the discussed conformational change, the up-field
shift of H5ꢀꢀ can have two conceivable causes:
This conclusion is supported by a comparison of the chemical
shifts of H5ꢀꢀ and H2 of 9 (Scheme 8). If the preferred
conformation were to correspond to 9B both protons would
be subject to similar shielding effects and H5ꢀꢀ being bound to a
more electronegative aromatic system ought to appear at lower
field than H2. In reality the opposite is observed (H5ꢀꢀ: 6.88 ppm;
H2: 7.63 ppm).
Scheme 8 Conformational states of 9 with respect to the anilino group.
1. an increase in conjugative electron release from N-6 to the
pyridine,
Therefore, the predominant conformation must be the one
represented by 9A. As discussed before, in this conformation H2
experiences a strong deshielding effect from the pyridine ring
which is responsible for the considerable difference in chemical
shift with respect to H5ꢀꢀ. According to the observation that the
changes in the pattern of chemical shifts and therefore in the
conformational properties around position 6 do not depend on
2. a shielding by the phenyl, or combinations of these effects.
A major contribution from the first effect can be ruled out
since exchanging the 6-anilino group of 2 for the much more
electron releasing cyclohexylamino group (17) causes an up-
field shift of H5ꢀꢀ of only 0.25 ppm (as compared to 0.39 ppm on
N-6 methylation of 2).
3 4 1 0
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 4 0 8 – 3 4 2 1

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Table 1 Chemical shifts in ppm of the pyridine and anilino hydrogens of compounds of type 15
No.
Rꢀꢀ
R
H2
H3
H4
H4ꢀꢀ
H5ꢀꢀ
2
H
7.51
7.18
7.02
8.23
6.35
5.96
5.90
5.88
4a
4b
4c
CH3
7.36
7.33
7.39
7.52
7.50
7.53
7.41
7.40
7.42
8.15
8.15
8.18
7
8
H
7.64
7.40
7.29
7.51
7.00
7.36
8.06
7.93
6.40
5.94
CH3
9
15a
5a
Cl
Cl
H
CH3
7.63
7.40
7.39
7.37
7.54
7.56
7.10
7.40
7.53
8.31
8.18
8.58
6.88
6.36
7.61
5b
6
7.25
7.25
7.01
7.23
7.49
7.42
7.28
7.43
7.45
7.32
7.28
7.34
8.56
8.20
8.52
8.58
7.51
7.40
7.85
7.92
15b
12
Cl
the substituent in position 2, structure 2A in Scheme 7 must
represent the preferred conformation of 2.
Table 1 shows that the NMR effects of N-6-alkylation hardly
vary with the nature of the alkyl group (this even holds for aryl
groups; unpublished results).
On methylation of N-6, phenyl A is repositioned in such a
way that H5ꢀꢀ becomes located directly above phenyl A and is
therefore shifted to considerably higher field. Concomitantly,
H2 moves from the deshielding zone into the shielding cone of
the pyridine. However, because of the loss of electron density in
phenyl A the observed net up-field shift is less than that for H5ꢀꢀ.
In summary, alkylation of N-6 shifts the equilibrium between
conformations of types A and B in the direction of the latter
and thereby also changes the relative orientation of the pyridine
and the phenyl rings from an approximately co-planar to a more
perpendicular one (Scheme 9).
Alkylation of N-2 has quite different consequences. In this
case the most significant change is an up-field shift of 0.45–
0.58 ppm of the ortho hydrogens of phenyl B (H2ꢀ) (see
Table 2). Significant up-field shifts are also observed for H4ꢀꢀ.
The remaining hydrogen atoms undergo smaller up-field shifts.
In the N-unsubstituted state, the 2-anilino group is hydrogen
bonded to the nitro group as is demonstrated by a shift
of d = 10.59 ppm (in DMSO) for the 2-NH-hydrogen of
2. Therefore, the phenyl ring must point towards the ring
nitrogen. In addition, from the position of the H2ꢀ signals (d =
7.57 ppm in DMSO) it can be concluded that the phenyl and
the pyridine rings are approximately co-planar (conformation
A in Scheme 10). On alkylation, such a conformation is no
longer possible because of repulsive forces between the alkyl
and the nitro groups. The same would apply to a conformation
analogous to B in Scheme 9 which is prevented by a repulsion
between the nitro and the phenyl groups. Therefore, phenyl
B must be located above (or below) the pyridine ring. As a
consequence, the H2ꢀ hydrogens could now be shielded instead of
deshielded by the pyridine and therefore their signals are shifted
up-field. But this shift is larger than that of the H2 hydrogens
Scheme 9 Conformational changes on N-6 alkylation.
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 4 0 8 – 3 4 2 1
3 4 1 1

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Table 2 Chemical shifts in ppm of the pyridine and anilino hydrogens of compounds of type 16
No.
Rꢀꢀꢀ
Rꢀ
H2ꢀ
H3ꢀ
H4ꢀ
H4ꢀꢀ
H5ꢀꢀ
14
16a
16b
Cl
Cl
Cl
H
CH3
7.59
7.14
7.14
7.40
7.30
7.31
7.18
7.14
7.16
8.53
8.16
8.20
7.00
7.06
7.11
16c
Cl
7.13
7.25
7.08
8.18
7.10
2
H
7.57
7.08
7.01
7.37
7.29
7.23
7.22
7.08
7.06
8.23
8.06
8.06
6.35
6.40
6.40
7
CH3
10
4a
8
H
7.63
7.05
7.00
6.97
6.97
7.29
7.26
6.96
7.23
7.20
7.09
7.05
6.91
7.05
7.20
8.15
7.93
8.56
8.20
8.52
5.96
5.94
7.51
7.40
7.85
CH3
H
5b
6
CH3
15b
13
Cl
7.31
7.42
7.31
8.59
7.69
This effect reduces the electron withdrawing character of the
pyridine ring and therefore its competition for the lone electron
pair on N-2 which therefore becomes more available for phenyl
B. The resulting increase in electron donation by N-2 apparently
compensates for the effects of the reduced conjugation. A similar
compensation seems to hold for the pyridine ring and would
explain why the signal of H5ꢀꢀ is not shifted down-field. The twist
of the nitro group makes itself also noticed by the significant up-
field shift of H4ꢀꢀ.
Taken together, the NMR data indicate that N-2 alkyl
derivatives of 2 favour conformational states in which the plane
of the phenyl group is positioned above the plane of the pyridine
ring and in which both planes are twisted considerably with
respect to each other (B in Scheme 10).
Scheme 10 Conformational changes on N-2 alkylation.
on N-6 alkylation. Also unlike hydrogen atoms H3 and H4,
H3ꢀ and H4ꢀ are not shifted down-field, indicating that the
electron density in the phenyl ring does not change significantly.
Apparently, the electron release from the N-2 lone pair remains
more or less unaffected. This is probably a result of two opposing
effects: in order to adopt the new spatial arrangement, both
the pyridine and phenyl B rotate so that the overlap of their
p-systems with the nitrogen lone pair decreases which would
reduce the electron density in both rings. On the other hand the
steric repulsion discussed above also twists the nitro group to
a certain extent out of conjugation with the pyridine p-system.
Acylation
The effect of N-6 acylation (entries 5a and 5b in Table 1) on the
hydrogen signals of phenyl A resembles that of N-6 alkylation.
There is, however, a significant difference in the effects on the
pyridine hydrogens. These are both shifted down-field, H5ꢀꢀ by
as much as 1.2 ppm. Contrary to N-6 alkylation which leaves the
signals of the hydrogen atoms of phenyl B virtually unaffected,
3 4 1 2
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 4 0 8 – 3 4 2 1

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N-6 acylation leads to remarkable up-field shifts of these signals
(0.57, 0.41, and 0.31 ppm for H2ꢀ, H3ꢀ, and H4ꢀ respectively;
compare entry 5b in Table 2 with entries 2 and 4a).
the H2ꢀ signals are shifted moderately up-field and the H3ꢀ and
H4ꢀ signals slightly down-field (compare 14 and 13 in Table 2).
With the N-6 tert-butoxycarbonylanilino derivative 15b, the
H2ꢀ signal is virtually unaffected whereas the three remaining
protons appear at somewhat lower field (compare 5b and 15b in
Table 2). By analogy with the N-6 acyl derivatives, phenyl B is
probably oriented perpendicular to the carbonyl group but the
available data do not allow any significant further conclusions.
The structure–conformation relationships discussed so far
were based only on solutions in DMSO. In order to test a possible
dependence of these relationships on the solvent, a number of
the DMSO spectra were compared with their counterparts in
CDCl3 solution. Tables 3 and 4 list the changes in chemical
shifts in DMSO (upper entries) and in CDCl3 (lower entries)
observed on replacing a proton on one of the anilino nitrogens
by an alkyl or an acyl group. A comparison shows that these
changes go in the same direction in both solvents which suggests
that the conformational properties are to a first approximation
independent of the solvent.
The down-field shift of H5ꢀꢀ may be attributed to an anisotropy
effect of the newly introduced carbonyl group which therefore
must be positioned in the plane of the pyridine ring and point
towards H5ꢀꢀ. This would place the phenyl ring next to the
pyridine nitrogen. For steric reasons and because of the stronger
conjugational interaction of the carbonyl and of the pyridine
with the N-6 lone pair, phenyl A ought to adopt a more or less
perpendicular position with respect to these two groups. The
down-field shift of hydrogens H3 and H4 is a consequence of
the corresponding loss of conjugation with the N-6 lone pair
and the electronegative effect of the carbonyl group whereas the
up-field shift of the H2 signal is due to an overcompensation of
these effects by the loss of deshielding from the pyridine and a
shielding from both the pyridine and the carbonyl group.
The spatial arrangement of the 6-N-acylanilino group also
makes the unusual changes in the shift of the hydrogens of phenyl
B understandable. As mentioned earlier, the conformational
situation in position 2 of the 2-anilino-3-nitropyridines is largely
independent of the substituents in position 6. Therefore, it can
be safely assumed that phenyl B is approximately co-planar with
the pyridine ring. Consequently, the H2ꢀ and H3ꢀ hydrogens lie
in the shielding zone above the N-6 phenyl group. H4ꢀ may still
experience some of this shielding effect resulting in the observed
up-field shift.
X-Ray crystallography‡
The explanations given above for the changes in chemical
shifts caused by substitution at the anilino-nitrogens of 2- and
6-anilino-3-nitropyridines are quite consistent. Nevertheless,
additional support from independent experiments would be
desirable. Therefore, we investigated the conformation of three
representatives of general structure 19 by X-ray crystallography.
In conclusion, N-6-acylation of 6-anilino-3-nitropyridines
affects almost exclusively the torsion around the bond from
the nitrogen to phenyl A favouring a class of conformations in
which the plane of this ring is approximately perpendicular to
the plane of the pyridine (Scheme 11).
Even though the results may to some extent reflect packing
effects, the observed conformations can at least be considered a
realistic possibility.
Scheme 11 Conformational changes on N-6 acylation.
Fig. 1 which shows a stereo view of compound 4c demon-
strates that the whole 2-anilino group, the pyridine ring, and
the nitro group are virtually co-planar (s1 = 173◦, s2 = 180◦,
s5 = −1◦) and that phenyl B points towards the ring nitrogen
In order to test the validity of these conclusions we compared
the changes in chemical shifts on tert-butoxycarbonylation of the
N-6 cyclohexyl analogue 17 of 2 yielding 18, the corresponding
analogue of 5b (Scheme 12).
˚
˚
(dC1–N1 = 2.95 A, dC1–C3 = 3.79 A).
Phenyl A is oriented away from the ring nitrogen (dC2–C4
=
˚
˚
2.86 A, dC2–N1 = 3.64 A) and its plane is perpendicular to those
of the pyridine ring (s4 = 92◦) and of the three atoms attached
to N-6 whereas the pyridine ring remains in this plane (s3 = −
2◦). The conformation in the crystal is therefore the same as that
inferred from the NMR data.
A similarly good agreement is observed for compound 7
(Fig. 2).
As deduced from the NMR spectra for N-6 unsubstituted
compounds, phenyl A points towards the ring nitrogen and does
not deviate very much from co-planarity with the pyridine ring
Scheme 12 Conformational changes on N-6 acylation of the N-6
cyclohexyl analogue of 2.
and the plane of the three atoms attached to N-6 (dC2–N1
=
The changes in chemical shifts of the H4ꢀꢀ and H5ꢀꢀ sig-
nals of 0.36 ppm and 0.81 ppm respectively are comparable
(0.33 and 1.16 ppm for 2 → 5b) indicating that the N-acyl-
cyclohexylamino group of 18 has the same spatial orientation
as the N-acyl-anilino group of 5b. However, the up-field shift
of the phenyl B hydrogens is absent in 18 which supports the
explanation for the up-field shifts in 5b as being caused by a
shielding effect from phenyl A.
2.93 A, dC2–C4 = 3.74 A, s3 = 174◦, s4 = 157◦). Both rings
˚
˚
are therefore conjugated with the lone electron pair on N-6.
Phenyl B points more to the side of the nitro group (dC1–N1
=
˚
˚
3.57 A, dC1–C3 = 3.03 A) and is positioned above (or below)
the plane of the pyridine ring (s2 = − 148◦). This orientation
places one of the H2ꢀ hydrogens above the pyridine ring and
Acylation of the 2-anilino nitrogen leads to a pronounced
down-field shift of the H5ꢀꢀ signal whereas the H4ꢀꢀ signal is
more or less unaffected. In the case of the 6-chloro derivative 13
‡ CCDC reference numbers 243005 (4c), 243006 (7), and 243007 (5b).
See http://dx.doi.org/10.1039/b508819b for crystallographic data in
CIF or other electronic format.
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 4 0 8 – 3 4 2 1
3 4 1 3

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Table 3 Changes in chemical shifts in DMSO (upper entry) and CDCl3 (lower entry) of the pyridine and anilino hydrogens of compounds of type
15 on replacing H by R
No.
Rꢀꢀ
R
H2
H3
0.34
H4
H4ꢀꢀ
H5ꢀꢀ
4a
CH3
−0.15
0.39
−0.08
−0.39
−0.12
−0.18
0.17
0.33
0.20
0.39
−0.20
−0.06
−0.32
−0.44
4d
8
−0.13
−0.24
0.15
0.22
0.20
0.36
−0.19
−0.13
−0.37
−0.46
CH3
CH3
−0.10
−0.23
−0.09
−0.26
0.11
0.17
0.06
0.31
0.16
0.31
0.13
0.43
−0.16
−0.13
−0.21
0.33
−0.34
−0.52
−0.46
1.16
15a
5b
Cl
−0.19
−0.39
0.16
0.13
0.26
0.32
0.17
0.14
1.43
1.00
6
−0.26
−0.40
0.04
0.06
0.16
0.24
0.02
0.27
1.26
1.04
12
Cl
−0.20
−0.02
0.10
0.04
1.21
Table 4 Changes in chemical shifts in DMSO (upper entry) and CDCl3 (lower entry) of the pyridine and anilino hydrogens of compounds of type
16 on replacing H by Rꢀ
No.
16a
16b
Rꢀꢀꢀ
Cl
Cl
Rꢀ
H2ꢀ
H3ꢀ
H4ꢀ
H4ꢀꢀ
H5ꢀꢀ
CH3
−0.45
−0.60
−0.45
−0.10
−0.09
−0.09
−0.04
−0.05
−0.02
−0.37
−0.54
−0.33
0.06
0.01
0.11
−0.53
−0.46
−0.08
−0.15
−0.02
−0.10
−0.55
−0.35
0.02
0.10
16c
Cl
−0.62
−0.47
−0.13
−0.07
−0.07
−0.13
−0.54
−0.17
0.01
0.05
7
CH3
CH3
CH3
−0.49
−0.58
−0.05
−0.03
−0.07
−0.04
−0.29
−0.22
0.04
−0.02
8
−0.57
−0.03
−0.05
−0.05
−0.25
−0.36
0.02
−0.11
6
0.27
0.14
0.02
−0.03
0.26
0.24
0.14
0.29
−0.44
−0.04
−0.13
15b
0.34
0.09
≈0.20
≈0.20
−0.22
0.35
3 4 1 4
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 4 0 8 – 3 4 2 1

View Article Online
Fig. 1 ORTEP stereo view of compound 4c.
Fig. 2 ORTEP stereo view of compound 7.
therefore supports the assumption of a shielding effect from
this ring made above in the discussion of the NMR spectra.
Phenyl B is moderately twisted out of the plane of the atoms
attached to N-2 (s1 = 29◦), i.e. there is still significant resonance
with the lone pair on N-2. The twists of the pyridine ring (s2 =
32◦) and the nitro group (s5 = 32◦) are both in accord with
the conclusions drawn from the NMR spectra. Similarly, the
mutual orientation of the planes of the pyridine and of phenyl
B as discussed previously is corroborated (angle approximately
70◦). It should be mentioned that one half of the molecules in the
B remains co-planar with the pyridine ring and therefore one of
each of the H2ꢀ and H3ꢀ hydrogens is held above phenyl A.
Similarly, the other conformational features suggested by
the NMR data are corroborated by the crystal structure:
approximate co-planarity of the pyridine ring with both the
amide bond (torsion angle C7–N4–C12–N1 = 153◦) and phenyl
B (s1 = 167◦, s2 = 175◦).
Rigid analogues
˚
crystal adopt a slightly different conformation (dC1–N1 = 3.56 A,
In order to obtain further independent support for the con-
clusions drawn from the NMR spectra, the energy difference
between conformations 2A and 2B as well as for the analogous
conformations of 4a were calculated. According to AM1
calculations 2A is 0.5 kcal mol−1 more stable than 2B whereas a
difference of 0.7 kcal mol−1 in the opposite direction was found
for 4a, but both values are within the error limits of the method.
Similarly, DFT calculations (B3LYPfunctional, 6–31Gbasisset)
gave a non significant difference of 0.7 kcal mol−1, this time in
favour of 2B. For the analogous conformation of 4a, a significant
preference of 2.1 kcal mol−1 was found in qualitative accord
with the conclusions drawn above. Altogether, these results may
not be very conclusive since they do not take the solvent into
account. This is particularly relevant for 2 where the 6-NH group
◦
◦
◦
˚
˚
dC1–C3 = 2.96 A, s1 = 44.5 , s2 = 33 , s5 = 22 , dC2–N1 = 2.99 A,
◦
◦
˚
dC2–C4 = 3.73 A, s3 = 174 , s4 = 180 ) in which phenyl B is
twisted more significantly out of the plane of the atoms attached
to N-2 and where the nitro group is twisted slightly less out of
the plane of the pyridine ring. The 6-anilino group is almost
perfectly co-planar with the pyridine ring. The overall shape of
both conformations is, however, still quite similar. Nevertheless,
the NMR data, particularly with respect to the shifts of H3ꢀ, H4ꢀ,
and H4ꢀꢀ seem to be more in accord with the first conformation
The X-ray structure of the N-6 acylated compound 5b (Fig. 3)
clearly confirms the conclusions drawn from the NMR data:
the planes of the pyridine and phenyl A are more or less
perpendicular to one another (s3 = 156◦, s4 = 101◦). Phenyl
Fig. 3 ORTEP stereo view of compound 5b.
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 4 0 8 – 3 4 2 1
3 4 1 5

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serves as a hydrogen bond donor for the solvent DMSO. This
hydrogen bond can be efficiently formed only in conformation
2A which would explain its preference in DMSO as deduced
from the NMR spectra.
Since these calculations were not suitable as an argument for
or against our conclusions from the NMR spectra we tried to
obtain more experimental evidence via rigid analogues of 2,6-
bis-anilino-3-nitropyridines. For this purpose, we synthesized
compounds 20 and 215 which may be considered rigid analogues
of 4a and 7 respectively. These structures were selected because
they were also interesting to us for a project in the field of new
non-planar scaffolds for combinatorial chemistry.
of its p-system with the lone pair on N1. Both effects increase
the electron density in the pyridine and could translate into the
observed additional up-field shift of H5ꢀꢀ.
The unusually high up-field shift of the H4ꢀꢀ signal of 21
(compare the value for 20 in Table 5) is most likely caused by a
more or less total twist of the nitro group out of the plane of the
pyridine ring. All these differences between the 1H-NMR spectra
of 21 and of N-2 alkylated derivatives of 2 indicate clearly that in
the preferred conformations of the latter the phenyl ring adopts
a different position to that of 21 which may be viewed as indirect
support for the conformational properties of 7 as derived from
the 1H-NMR spectra.
It should be pointed out that the present interpretation of
these data assumes that possible effects from conformational
distortions due to the steric strain of the tricyclic scaffold of 20
and 21 can be neglected to a first approximation.
Related N-aryl anilines
It is conceivable that the structure–conformation relationships
derived above for 2,6-bis-anilino-3-nitropyridines could have a
more general significance. In order to test this possibility we
examined a few representative 2-nitro-diphenylamines 22 and
2-anilino-pyridines 23 that lack the nitro group. The chemical
shifts (DMSO) of the aromatic hydrogens of these compounds
are listed in Tables 7 and 8 respectively.
The spatial position and orientation of the phenyl group
in compound 20 should be comparable to the one in the
supposedly preferred conformation of 4a and therefore the
chemical shifts of hydrogens H2, H3, and H4, should also be
similar. Table 5 demonstrates the close correspondence between
the two compounds with respect to these chemical shifts.
The considerable extra up-field shift of H5ꢀꢀ in 20 is most
likely due to the lack of an equivalent of phenyl B of 2 and
4a. A reasonable estimate for the actual shielding effect from
the phenyl group in 20 may be obtained from the difference in
chemical shifts of H5ꢀꢀ between 20 (d = 5.54 ppm) and 21 (d =
5.88 ppm). This difference (−0.34 ppm) is reasonably close to
the shift change on N-6 methylation of 2 (−0.39 ppm).
Contrary to the close relation between 20 and 4a, the preferred
1
conformation of compound 7 as derived from the H-NMR
data does not greatly resemble its rigid analogue 21. Therefore,
considerable differences in the 1H-NMR spectra are to be
expected. The most striking deviation refers to H4ꢀꢀ and H5ꢀꢀ
which both appear at much higher field in 21 (see Table 6). This
shift cannot be attributed solely to the absence of an equivalent
of phenyl A as becomes clear from a comparison with the
corresponding chemical shifts of the 6-cylohexylamino analogue
17 of 2 (see Table 6). In case of H5ꢀꢀ about half of the total shift
difference must be caused by an additional effect, which resides
most likely in the stronger electron donating ability of N1 of 21,
the equivalent of N-2 of 7. As pointed out earlier, in 7 phenyl
B must still be significantly conjugated with the lone pair on
the nitrogen. With compound 21, steric repulsion with the nitro
group should force the phenyl group into an orientation which
at best allows a significantly reduced conjugation. The down-
field shift of the phenyl hydrogens of 21 in relation to those of
7 indicates that this is indeed the case. On the other hand the
pyridine ring of 21 is fixed in the ideal orientation for overlap
From Table 7 it becomes evident that the changes in chemical
shifts on N alkylation of 22a follow qualitatively the pattern
observed on N-2 alkylation of the 2-anilino-3-nitropyridines
except that the H3ꢀ and H4ꢀ hydrogens experience a significantly
larger up-field shift. In addition, an inspection of the X-ray
structure of 22a6 suggests that in this case shielding may not
be a sufficient explanation for the up-field shift of H2ꢀ because
Table 7 Shifts in ppm of the aromatic hydrogens of compounds of type
22
No.
Rꢀ
H2ꢀ
H3ꢀ
H4ꢀ
H4ꢀꢀ
H5ꢀꢀ
H1ꢀꢀ
22a
22b
22c
H
CH3
7.31 7.40 7.19 8.10 6.86 7.18
6.64 7.15 6.77 7.91 7.41 7.50
6.69 7.12 6.78 7.88 7.36 7.53
Table 5 Comparison of the chemical shifts of the phenyl hydrogens of
2, 4a, and 20 in DMSO
H4ꢀꢀ
H5ꢀꢀ
Table 8 Shifts in ppm of the aromatic hydrogens of compounds of type
23
No.
H2
H3
H4
2
4a
20
7.51
7.36
7.32
7.18
7.52
7.48
7.02
7.41
7.28
8.23
8.15
8.08
6.35
5.96
5.54
No.
R
H2
H3
H4
H4ꢀꢀ H5ꢀꢀ
23a
23b
23c
H
CH3
7.66
7.27
7.23–7.27
7.24 6.86 7.53 6.81
7.41 7.21 7.40 6.50
7.36 7.17 7.43 6.52
Table 6 Comparison of the chemical shifts of the phenyl and the
pyridine-5 protons of 2, 7, 17, and 21
No.
H2ꢀ
H3ꢀ
H4ꢀ
H4ꢀꢀ
H5ꢀꢀ
23d
7.15
7.33 7.21 7.83 7.51
2a
17
7
7.51
7.73
7.08
7.22
7.18
7.35
7.29
7.35
7.02
7.12
7.08
7.25
8.32
8.06
8.06
7.74
6.35
6.10
6.40
5.88
21
3 4 1 6
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 4 0 8 – 3 4 2 1

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the planes of the two rings form a rather large angle of 44◦. A
possible alternative reason is indicated by the torsion angles
s1 = − 32.9◦, and s2 = − 19.5◦. The difference in the two
torsion angles is largely due to the hydrogen bond between
the nitro group and the amino group and indicates that the
resonance between the nitrogen lone pair and the nitrophenyl
group is considerably stronger than with the unsubstituted
phenyl. Consequently, the electron density in the unsubstituted
phenyl ring is lower as compared with its counterpart in the
parent diphenylamine. The difference is reflected in the NMR
chemical shifts (in DMSO): d = 7.06, 7.22, and 6.81 ppm for the
ortho, meta, and para hydrogens respectively of diphenylamine
vs. d = 7.31, 7.40, and 7.19 ppm for H2ꢀ, H3ꢀ, and H4ꢀ of
22a. N Alkylation not only abolishes the hydrogen bond but
also introduces an additional steric repulsion which largely
affects the nitrophenyl group. This becomes evident from an
X-ray analysis of the dinitro analogue 24 of 22b7 in which
s1 becomes 143.4◦ (in terms of conjugation, equivalent to
−36.6◦) and s2 143.8◦ (in terms of conjugation, equivalent to
−36.2◦) resulting in a considerable decrease in resonance and
consequently electron withdrawal by the nitrophenyl group.
Since s1 changes only slightly a redistribution of electron density
into the unsubstituted phenyl ring is to be expected and could
cause the up-field shift of protons H3ꢀ and H4ꢀ but seems
insufficient as an explanation for the particularly large effect
on H2ꢀ.
The same authors10 have also investigated a number of com-
pounds of general structure 28.
For X = S the benzene rings are on the side of the ring
nitrogens whereas in the diphenylmethane derivative (X = CH2)
they are oriented towards the ring carbons. The same is true
for the 3,3ꢀ-diamino-diphenylmethane analogue, but in a crystal
which also contains ethanol the opposite orientation occurs.
A similar situation is found with the 2-anilino-5-nitro-
pyridines 29.11
With X = H or N(CH3)2 the phenyl ring is oriented towards
the CH in 3-position whereas in the corresponding chlorine
derivative the phenyl faces the ring nitrogen.
The new values of s1 and s2 reveal an interesting change in the
orientation of the unsubstituted phenyl ring which moves from
a position next to H1ꢀꢀ to one facing the nitro group. This new
orientation places one of the ortho hydrogens above an edge of
the nitrophenyl ring.
Conclusions
The conformational properties of 2,6-bis-anilino-3-nitropyri-
dines depend specifically on the nature of the substituents on
the anilino nitrogens. The structure–conformation relationships
are different for the 2- and the 6-anilino group but, to a first
approximation, independent of the particular substituent in 6-
or 2-position of the pyridine respectively. Even though alkylation
and acylation of the anilino nitrogens give rise to different
conformational preferences, the nature of the individual alkyl
or acyl group does not seem to play a major role [prelimi-
nary experiments with meta-substituted anilines (unpublished
results) indicate that at least m- (or p-)substituted anilino-
nitropyridines behave like their unsubstituted counterparts]. For
the compounds which we have investigated, these relationships
were also invariant with respect to the environment of the
compounds (DMSO, CDCl3, crystal). Moreover, an exploratory
investigation suggests that these structure–conformation rela-
tionships may have a more general significance even though
the susceptibility to influences from the environment may differ
depending on the specific type of structures.
The conclusions drawn from differences in chemical shifts
in the 1H-NMR spectra with respect to the conformational
properties are not only consistent but are also corroborated by
X-ray crystallography and by investigations on rigid analogues.
Based on the synthetic routes and the structure–conformation
relationships which are reported here, it is possible to design
2,6-bis-anilino-3-nitropyridines with a preference for a specific
shape. This makes them useful as scaffolds for biologically
active compounds be it as potential drug molecules or as tools
for biochemical investigations, e.g., as specific conformational
mimetics of small peptide sequences. In addition, the present
compounds can serve as building blocks for oligomers with
preferred conformational properties. Depending on the substi-
tution of the individual monomers these oligomers can be used
A similar repositioning in solution would expose the H2ꢀ
hydrogens of 22b to a shielding effect from the nitrophenyl
ring. This effect together with the increased electron density
could cause the observed large up-field shift of the H2ꢀ signals.
It should be mentioned that this shielding effect corresponds
to the one discussed above for the related nitropyridine deri-
vative 7.
The changes in shifts induced by N alkylation or N acylation
of 23a (Table 8) resemble those observed for 6-anilino-3-
nitropyridines. This means that on alkylation the phenyl ring
becomes twisted out of the conjugation with the anilino nitrogen
and moves from a position pointing towards the pyridine
nitrogen to one neighbouring H5ꢀꢀ. Similarly, on acylation, the
phenyl ring remains on the side of the ring nitrogen whilst the
planes of the two ring systems adopt a mutually perpendicular
position.
Altogether, these examples suggest that the structure–
conformation relationships derived for 2,6-bis-anilino-3-
nitropyridines are also valid for the closely related compounds of
type 22 and 23. It is therefore possible that similar relationships
exist for diarylamines in general.
However, examination of X-ray analyses from the literature
suggest that these relationships may depend on the specific
environment of the molecules more significantly than observed
for the examples investigated here. Thus, 2-anilinopyridine8 and
2,6-bis-anilinopyridine (25)9 adopt a conformation in which the
phenyl rings are oriented away from the ring nitrogen. However,
in N,Nꢀ-bis-2-pyridyl-meta-phenylenediamine (26) and the cor-
responding para-phenylenediamine (27) analogue the benzene
ring faces the pyridine nitrogen on either side10 but the latter
also forms crystals with the opposite orientation.10
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 4 0 8 – 3 4 2 1
3 4 1 7

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to form specifically shaped supramolecular arrangements with
predefined physical and chemical properties.
EtOAc = 4 : 1, ref. 1: 175–177 ◦C); dH 10.59 (1 H, br s, NH(2)),
10.04 (1 H, vbr s, NH(6)), 8.23 (1 H, d, J 9.35, H4ꢀꢀ), 7.55 (2 H,
m, H2ꢀ), 7.51 (2 H, m, H2), 7.36 (2 H, m, H3ꢀ), 7.21 (1 H, m,
H4ꢀ), 7.18 (2 H, m, H3), 7.02 (1 H, m, H4), 6.35 (1 H, d, J 9.35,
H5ꢀꢀ); dC 157.8, 151.9, 139.1, 138.0, 135.5, 128.6, 128.5, 124.8,
124.3, 123.3, 120.7, 119.3, 104.0.
Experimental
General
For chromatography, silica gel 60 (230–400 mesh) from Fluka
was used. Melting points were taken on a Bu¨chi B-545 melting
point apparatus and are uncorrected. 1H and 13C-NMR spectra
were recorded on a Bruker Avance 400 spectrometer in d6-
DMSO. Chemical shifts are expressed in ppm with d6-DMSO =
General procedure for 2-anilino-6-(N-alkylanilino)-3-
nitropyridines
To a solution of 153 mg (0.5 mmol) of 2 in 13 mL of DMF the
appropriate amount of an auxiliary base and of the alkyl halide
were added. The mixture was stirred at room temperature for
10 h. 40 mL of water were added and the mixture extracted
twice with 50 mL of EtOAc. The organic layer was evaporated
to dryness and the remaining product purified by column
chromatography (silica gel, n-hexane : EtOAc = 4 : 1).
1
2.49 ppm for H and 39.5 ppm for 13C as internal standards;
coupling constants are in Hz. Mass spectra were recorded on a
Finnigan SSQ7000 mass spectrometer. Elemental analyses were
done with an Elementar Analysensysteme Vario EL analyser.
2,6-Dichloro-3-nitropyridine (3) and purified Marathon-C
resin were a gift from Boehringer Ingelheim Pharma GmbH &
Co KG, 22a was purchased from Merck, Darmstadt (now VWR
International), NaH and 23a from Aldrich.
2-Anilino-6-(N-methylanilino)-3-nitropyridine
(4a). MeI
16a2 was prepared as described in ref. 2 by refluxing 3 with
N-methylaniline in EtOH in the presence of NaHCO3 (mp 76–
77 ◦C, ref. 2: 75–77 ◦C).
(142 mg or 0.063 mL; 1 mmol), K2CO3 (138 mg,1.0 mmol)
(72 mg, 45%). Yellow crystals, mp 115–117 ◦C (from n-hexane :
EtOAc = 4 : 1). Found: C 67.6, H 5.0, N 17.4. Calc. for
C18H16N4O2: C 67.5, H 5.0, N 17.5%. dH 10.66 (1 H, s, NH),
8.15 (1 H, d, J 9.5, H4ꢀꢀ), 7.63 (2 H, m, H2ꢀ), 7.52 (2 H, m, H3),
7.41 (1 H, m, H4), 7.36 (2 H, m, H2), 7.29 (2 H, m, H3ꢀ), 7.09
(1 H, m, H4ꢀ), 5.96 (1 H, br d, J 9.5, H5ꢀꢀ), 3.44 (3 H, s, Me);
dC 159.6, 150.3, 144.1, 138.1,136.0, 130.0, 128.6, 127.6, 127.1,
123.8, 121.9, 119.0, 100.9, 39.3; m/z (EI) 320 (M+).
X-Ray crystallography
The crystals used in this study were mounted onto the end of
glass fibers. X-Ray data were collected on a STOE IPDS unit
(Imaging Plate Diffraction System). Graphite monochromatized
˚
Mo–Ka radiation (k = 0.71073 A) was used. Crystal data are
listed in Table 9 together with refinement details. Absorption
corrections were not applied. The structures were solved by the
direct Method with the SHELXS-86 program.12 The atomic
coordinates and anisotropic thermal parameters of the non-
hydrogen atoms were refined using the SHELXL-97 program;13
full matrix method, F2 data. Hydrogen atoms were included in
the final refinement cycles in a riding mode.‡
6-(N-Allylanilino)-2-anilino-3-nitropyridine (4b). Allyl bro-
mide (121 mg or 0.084 mL; 1 mmol), K2CO3 (138 mg, 1.0 mmol).
After evaporation of the organic layer the residue was dissolved
in 6 mL of DMF and again treated with the same amounts
of base and allyl bromide (174 mg, 100%). Yellow crystals, mp
104–105 ◦C (triturated with refluxing isopropanol). Found: C
69.3, H 5.3, N 16.05. Calc. for C20H18N4O2: C 69.35, H 5.2,
N 16.2%. dH 10.60 (1 H, s, NH), 8.17 (1 H, d, J 9.5, H4ꢀꢀ),
7.59 (2 H, m, H2ꢀ), 7.51 (2 H, m, H3), 7.41 (1 H, m, H4), 7.35
(2 H, m, H2), 7.28 (2 H, m, H3ꢀ), 7.09 (1 H, m, H4ꢀ), 5.91
(1 H, ddt, J1 16.4, J2 10.6, J3 5.3, H2-allyl) 5.90 (1 H, br, H5ꢀꢀ),
5.12 (1 H, dq, J1 10.6, J2 1.4, H3-trans-allyl), 5.11 (1 H, dq, J1
16.4, J2 1.4, H3-cis-allyl), 4.51 (1 H, dt, J1 5.3, J2 1.4, H1-allyl);
2,6-Bis-anilino-3-nitropyridine (2)1
3.86 g (20 mmol) of 3, 5.60 g (5.47 mL, 60 mmol) of aniline and
5.04 g (60 mmol) of NaHCO3 were heated in 40 mL of EtOH
at 40 ◦C for 4 h. After cooling, the precipitated 2 was collected
by filtration (5.51 g, 90%). Mp 190–191 ◦C (2× from n-hexane :
Table 9 Crystallographic data
4c
7
5b
Empirical formula
Mr
C23 H24 N4 O4
420.46
Monoclinic
C18 H16 N4 O3
320.35
C22 H22 N4 O4
406.44
Crystal system
Triclinic
Triclinic
¯
¯
Space group
P21/c
P1
P1
˚
a/A
7.607(2)
24.695(4)
11.851(3)
90
10.113(3)
12.417(3)
14.105(3)
107.48(3)
95.21(3)
102.18(3)
1628.5(7)
293(2)
8.595(2)
9.790(2)
13.308(2)
75.57(2)
83.91(2)
75.36(2)
1033.1(3)
173(2)
˚
b/A
˚
c/A
a/◦
b/◦
c /◦
108.06(3)
90
2116.7(8)
173(2)
3
˚
V/A
Temperature/K
Z
4
4
2
D(calculated)/g cm−3
l/mm−1
1.319
0.092
0.40 × 0.20 × 0.20
2.45 to 25.97
16630
4066
0.0499
2797
0.996
1.307
0.089
0.40 × 0.30 × 0.20
2.38 to 26.08
14892
5971
0.0460
3473
0.985
1.307
0.092
0.40 × 0.30 × 0.30
2.24 to 26.01
11455
3763
0.0519
3720
1.014
Crystal size/mm3
H range/◦
Refl. collected
Independent refl.
Rint
Observed Refl. [I > 2r(I)]
Goodness-of-fit on F2
R1, wR2 [I > 2r(I)]
R1, wR2 (all data)
0.0370, 0.0800
0.0595, 0.0849
0.174 and −0.149
0.0415, 0.0870
0.0774, 0.0966
0.141 and −0.131
0.0401, 0.1023
0.0588, 0.1090
0.365 and −0.243
Max./min. in DF(e−3
)
3 4 1 8
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 4 0 8 – 3 4 2 1

View Article Online
dC 159.3, 150.4, 142.7, 138.1, 136.3, 132.9, 130.0, 128.5, 127.8,
124.0, 122.2, 119.3, 117.3, 101.0, 53.6; m/z (EI) 346 (M+).
6-Anilino-2-(N-methylanilino)-3-nitropyridine (7). A sus-
pension of 6 (300 mg, 0.71 mmol) in conc. HCl (6 mL) was stirred
at room temperature. Immediately after complete dissolution
the product precipitated. Water was added and the mixture
extracted with DCM. The organic layer was washed with
aqueous NaHCO3 and concentrated in vacuum (216 mg, 95%).
Orange crystals, mp 123–125 ◦C (from n-pentane : EtOAc =
3.2 : 1). Found: C 67.3, H 5.0, N 17.25. Calc. for C18H16N4O2:
C 67.5, H 5.0, N 17.5%. dH 9.87 (1 H, s, NH), 8.06 (1 H, d, J
9.0, H4ꢀꢀ), 7.64 (2 H, m, H2), 7.29 (4 H, m, H3ꢀ, H3), 7.08 (1 H,
m, H4ꢀ), 7.08 (2 H, m, H2ꢀ), 7.00 (1 H, m, H4), 6.40 (1 H, d, J
9.0, H5ꢀꢀ), 3.48 (3 H, s, Me); dC 156.0, 152.5, 147.2, 139.7, 136.8,
129.3, 128.7, 125.0, 124.5, 122.5, 122.3, 119.5, 102.9, 40.9; m/z
(EI) 320 (M+).
2-Anilino-6-(N -tert-butoxycarbonylmethylanilino)-3-nitro-
pyridine (4c). tert-Butyl bromoacetate (195 mg or 0.15 mL;
1 mmol), K2CO3 (138 mg, 1.0 mmol) (110 mg, 52%). Yellow
crystals, mp 118–120 ◦C (from n-hexane : EtOAc = 4 : 1).
Found: C 65.65, H 5.8, N 13.3. Calc. for C23H24N4O4: C 65.7, H
5.75, N 13.3%. dH 10.58 (1 H, s, NH), 8.18 (1 H, d, J 9.4, H4ꢀꢀ),
7.64 (2 H, m, H2ꢀ), 7.53 (2 H, m, H3), 7.42 (1 H, m, H4), 7.39
(2 H, m, H2), 7.35 (2 H, m, H3ꢀ), 7.16 (1 H, m, H4ꢀ), 5.88 (1 H,
br d, J 9.4, H5ꢀꢀ), 4.55 (2 H, s, CH2) 1.22 (9 H, s, tBu); dC 168.0,
150.1, 146.9, 141.9, 137.9, 136.5, 130.1, 128.6, 128.0, 127.5,
124.6, 122.4, 119.7, 100.8, 81.2, 53.5, 27.4; m/z (EI) 420 (M+).
2,6-Bis-(N-methylanilino)-3-nitropyridine (8). MeI (284 mg
or 0.124 mL; 2.0 mmol), KOtBu (224 mg, 2.0 mmol), after
evaporation of the solvent the residue was triturated with
boiling petroleum ether (139 mg, 83%). Yellow crystals, mp 138–
140 ◦C. Found: C 68.1, H 5.5, N 16.6. Calc. for C19H18N4O2: C
68.25, H 5.4, N 16.8%. dH 7.93 (1 H, d, J 9.1, H4ꢀꢀ), 7.51 (2 H, m,
H3), 7.40 (2 H, m, H2), 7.36 (1 H, m, H4), 7.26 (2 H, m, H3ꢀ),
7.05 (1 H, m, H4ꢀ), 7.05 (2 H, m, H2ꢀ), 5.94 (1 H, d, J 9.1, H5ꢀꢀ),
3.50 (3 H, s, Me(2)), 3.48 (3 H, s, Me(6)); dC 158.0, 151.7, 147.2,
144.3, 136.9, 129.9, 129.3, 127.1, 126.8, 124.5, 124.3, 121.7, 99.8,
40.2, 38.6; m/z (EI) 334 (M+).
6-Anilino-2-chloro-3-nitropyridine (9). NaH (120 mg,
5 mmol) was added to a solution of N-tert-butoxycarbonyl-
aniline (931 mg, 5 mmol) in DMF (20 mL) and stirred at room
temperature for 10 min. This solution was added dropwise
without cooling within 1 h to a solution of 3 (1447 mg,
7.5 mmol) in DMF (8 mL) and stirred for 12 h. This solution
was added to 50 mL of 0.2 M aqueous citric acid, extracted
with EtOAc and the organic layer washed with aqueous
NaHCO3 and water and evaporated (an NMR spectrum
of a sample in DMSO showed that a 70 : 30 mixture of
6-(N-tert-butoxycarbonylanilino)-2-chloro-3-nitropyridine and
2-(N-tert-butoxycarbonylanilino)-6-chloro-3-nitropyridine had
formed and that about 60% of the N-tert-butoxycarbonylaniline
had reacted). The residue was stirred overnight at room
temperature with 20 mL of conc. HCl. The mixture was diluted
with 20 mL of water, brought to pH 6 with NaHCO3, and
extracted with EtOAc. The organic phase was dried with
Na2SO4 and evaporated and the residue chromatographed on
silica gradient from pure n-hexane to n-hexane : EtOAc = 1 :
1 (468 mg, 27% based on N-tert-butoxycarbonylaniline). Pale
yellow crystals, mp 169–171 ◦C. Found: C 52.8, H 3.3, N 16.
9. Calc. for C11H8ClN3O2: C 52.9, H 3.2, N 16.8%. dH 10.34
(1 H, s, NH), 8.31 (1 H, d, J 9.0, H4ꢀꢀ), 7.63 (2 H, m, H2), 7.37
(2 H, m, H3), 7.10 (1 H, m, H4), 6.88 (1 H, d, J 9.0, H5ꢀꢀ); dC
156.5, 143.1, 138.8, 136.6, 133.9, 129.0, 123.7, 120.2, 109.2; m/z
(CI) 250, 252 ([M + H]+).
6-(N-Acetylanilino)-2-anilino-3-nitropyridine (5a). 2 (92 mg,
◦
0.3 mmol) and acetic anhydride (3 mL) were heated at 123 C
for 4.5 h. The reaction mixture was stirred for 30 min with
120 mL of aqueous NaHCO3. After extraction with 150 mL of
dichloromethane (DCM), the organic phase was concentrated
◦
in vacuo (62 mg, 59%). Orange crystals, mp 180–181 C (from
acetone). Found: C 65.5, H 4.65, N 16.1. Calc. for C19H16N4O3:
C 65.5, H 4.6, N 16.1%. dH 10.15 (1 H, s, NH), 8.58 (1 H, d, J 9.1,
H4ꢀꢀ), 7.61 (1 H, d, J 9.1, H5ꢀꢀ), 7.56 (2 H, m, H3), 7.53 (1 H, m,
H4), 7.39 (2 H, m, H2), 6.99–7.03 (4 H, m, H2ꢀ, H3ꢀ), 6.95 (1 H,
m, H4ꢀ), 1.96 (3 H, s, Me); dC 167.0, 152.0, 150.5, 147.6, 141.5,
137.6, 133.6, 130.0, 129.4, 128.5, 128.4, 123.3, 120.6, 109.0, 26.0;
m/z (CI) 349 ([M + H]+).
2-Anilino-6-(N -tert-butoxycarbonylanilino)-3-nitropyridine
(5b). A solution of 2 (1.48 g, 4.83 mmol), di-tert-butyl
dicarbonate (1.20 g, 5.5 mmol) and a catalytic amount of
DMAP in 30 mL of DCM was warmed at 27 ◦C for 3 h.
The mixture was washed with 30 mL of 0.1 M citric acid
and aqueous NaHCO3 and the organic solvent evaporated
(1.49 g, 75%). Orange crystals, mp 155–156 ◦C (from n-hexane :
EtOAc = 4 : 1). Found: C 65.0, H 5.5, N 13.8. Calc. for
C22H22N4O4: C 65.0, H 5.5, N 13.8%. dH 10.18 (1 H, s, NH),
8.56 (1 H, d, J 9.4 H4ꢀꢀ), 7.51 (1 H, d, J 9.4, H5ꢀꢀ), 7.49 (2 H,
m, H3), 7.45 (1 H, m, H4), 7.25 (2 H, m, H2), 7.00 (2 H, m,
H2ꢀ), 6.96 (2 H, m, H3ꢀ), 6.91 (1 H, m, H4ꢀ), 1.36 (9 H, s, tBu);
dC 159.4, 153.7, 152.3, 149.3, 142.2, 139.2, 138.9, 130.6, 130.0,
129.7, 128.8, 125.0, 121.6, 108.6, 83.9, 28.9; m/z (CI) 407 ([M +
H]+).
6-Anilino-2-(N-benzylanilino)-3-nitropyridine (10). A solu-
tion of 9 (125 mg, 0.5 mmol), N-benzylaniline (128 mg,
0.7 mmol), and DIPEA (90 mg, 0.11 mL, 0.7 mmol) in 3 mL
of EtOH was heated at 70 ◦C for 4 d. The solvent was removed
under vacuum, the residue dissolved in 1 mL of a 1 : 1 mixture
of n-hexane and EtOAc and chromatographed on silica gel (n-
hexane : EtOAc = 4 : 1) (85 mg, 42%). Orange crystals, mp
◦
95 C. Found: C 72.7, H 5.1, N 14.1. Calc. for C24H20N4O2: C
72.7, H 5.1, N 14.1%. dH 9.83 (1 H, s, NH), 8.06 (1 H, d, J 8.8,
H4ꢀꢀ), 7.42 (2 H, m, H2ꢀꢀꢀ), 7.41 (2 H, m, H2), 7.30 (2 H, m, H3ꢀꢀꢀ),
7.23 (2 H, m, H3ꢀ), 7.20 (1 H, m, H4ꢀꢀꢀ), 7.15 (2 H, m, H3), 7.06
(1 H, m, H4ꢀ), 7.01 (2 H, m, H2ꢀ), 6.96 (1 H, m, H4), 6.40 (1 H,
d, J 8.8, H5ꢀꢀ), 5.36 (2 H, s, CH2) (ꢀꢀꢀ refers to benzylic phenyl);
dC 156.0, 151.3, 146.5, 139.4, 138.7, 136.8, 129.3, 128.5, 128.3,
126.7, 126.4, 125.4, 124.2, 122.6, 121.1, 119.5, 103.4, 55.2; m/z
(CI), 397 ([M + H]+).
6-(N -tert-Butoxycarbonylanilino)-2-(N -methylanilino)-3-
nitropyridine (6). To a solution of 5b (899 mg, 2.2 mmol) in
DMF (22 mL) were added KOtBu (494 mg, 4.4 mmol) and MeI
(625 mg, 0.28 mL, 4 mmol). The mixture was stirred at room
temperature for 45 min. After addition of water the product
was extracted with EtOAc, the organic layer evaporated and
the residue purified by crystallization (650 mg, 77%). Yellow
crystals, mp 164–165 ◦C (from n-hexane : EtOAc = 6 : 1).
Found: C 65.5, H 5.7, N 13.2. Calc. for C23H24N4O4: C 65.7, H
5.75, N 13.3%. dH 8.20 (1 H, d, J 8.9, H4ꢀꢀ), 7.42 (2 H, m, H3),
7.40 (1 H, d, J 8.9, H5ꢀꢀ), 7.32 (1 H, m, H4), 7.25 (2 H, m, H2),
7.23 (2 H, m, H3ꢀ), 7.05 (1 H, m, H4ꢀ), 6.97 (2 H, m, H2ꢀ), 2.95
(3 H, s, Me), 1.39 (9 H, s, tBu); dC 155.3, 152.5, 149.0, 146.2,
140.7, 137.6, 129.5, 128.8, 128.5, 127.1, 124.9, 121.8, 107.8,
82.1, 27.7; m/z (CI) 423 ([M + H]+).
6-(N -tert-Butoxycarbonylanilino)-2-chloro-3-nitropyridine
(12). DMAP (62 mg, 0.5 mmol) was added to a solution of
100 mg (0.4 mmol) of 9 and 110 mg (0.5 mmol) of di-tert-butyl
dicarbonate in 3.5 mL of DCM. The reaction mixture was
stirred at room temperature for 4 h. After removal of the solvent
the residue was purified by column chromatography (silica gel,
n-hexane : EtOAc = 4 : 1) (100 mg, 71%). Colourless crystals,
mp 101–103 ◦C (from n-hexane). Found: C 55.0, H 4.7, N 12.0.
Calc. for C16H16ClN3O4: C 54.9, H 4.6, N 12.0%. dH 8.58 (1 H,
d, J 8.8, H4ꢀꢀ), 7.92 (1 H, d, J 8.8, H5ꢀꢀ), 7.43 (2 H, m, H3), 7.34
(1 H, m, H4), 7.23 (2 H, m, H2), 1.38 (9 H, s, tBu); dC 156.2,
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 4 0 8 – 3 4 2 1
3 4 1 9

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152.2, 140.3, 140.1, 139.5, 137.4, 129.1, 128.3, 127.5, 117.4,
dissolved in 10 mL of EtOAc, washed with saturated aqueous
NaHCO3 and the solvent evaporated. The residue was taken
up in 20 mL of DCM and treated with 2 g of Marathon-C
resin. After evaporation the residue was purified by column
chromatography on silica gel (n-hexane : EtOAc = 4 : 1) (475 mg,
58%). Mp 108 ◦C. Found: C 63.8, H 4.2, N 12.3. Calc. for
C18H14ClN3O2: C 63.6, H 4.15, N 12.4%. dH 8.18 (1 H, d, J 8.3,
H4ꢀꢀ), 7.35 (2 H, m, H2ꢀꢀꢀ), 7.28 (2 H, m, H3ꢀꢀꢀ) 7.25 (2 H, m,
H3ꢀ), 7.20 (1 H, m, H4ꢀꢀꢀ), 7.13 (2 H, m, H2ꢀ), 7.10 (1 H, d, J 8.3,
H5ꢀꢀ) 7.08 (1 H, m, H4ꢀ), 5.31 (2 H, s, CH2) (ꢀꢀꢀ refers to benzylic
phenyl); dC 150.9, 149.7, 144.3, 138.8, 137.6, 133.7, 129.6, 128.3,
127.4, 127.1, 122.3, 115.2, 55.0; m/z (CI) 340 ([M + H]+).
2-Anilino-6-cyclohexylamino-3-nitropyridine (17). 14 (499 mg,
2 mmol), cyclohexylamine (238 mg = 0.274 mL, 2.4 mmol), and
K2CO3 (332 mg, 2.4 mmol) in DMF (3 mL) were stirred at 50 ◦C
for 1 d. Water was added, the precipitate collected by filtration,
washed several times with water and dried (590 mg, 94%). Mp
170–181 ◦C. Found: C 65.3, H 6.5, N 17.8. Calc. for C17H20N4O2:
C 65.4, H 6.45, N 17.9%. dH 10.86 (1 H, s, NH(2)), 8.24 (1 H, d,
J 7.3, NH (6)), 8.06 (1 H, d, J 9.4, H4ꢀꢀ), 7.73 (2 H, m, H2ꢀ), 7.35
(2 H, m, H3ꢀ), 7.12 (1 H, m, H4ꢀ), 6.10 (1 H, d, J 9.3, H5ꢀꢀ), 3.75
(1 H, m, H1ꢀꢀꢀ), 1.92 (2 H, m, H2ꢀꢀꢀe), 1.74 (2 H, m, H3ꢀꢀꢀe), 1.61
(1 H, m, H4ꢀꢀꢀe), 1.10–1.35 (5 H, m, H2ꢀꢀꢀa, H3ꢀꢀꢀa, H4ꢀꢀꢀa) (ꢀꢀꢀ refers
to cyclohexyl); dC 159.3, 151.6, 138.3, 134.8, 128.5, 123.9, 121.9,
117.7, 103.4, 50.4, 32.0, 24.7, 25.2; m/z (CI) 313 ([M + H]+).
2-Anilino-6-(N -tert-butoxycarbonyl-cyclohexylamino)-3-
nitropyridine (18). A solution of 17 (93 mg, 0.3 mmol), di-
tert-butyl dicarbonate (66 mg, 0.3 mmol), and DMAP (37 mg,
0.3 mmol) in DCM (3 mL) was stirred at room temperature
for 1 d. The reaction mixture was fractionated as a whole on
silica (n-hexane: EtOAc = 4 : 1). The fraction that contained
the◦pure product was evaporated to dryness (27 mg, 22%). Mp
96 C. Found: C 64.4, H 6.9, N 13.4. Calc. for C22H28N4O4: C
64.1, H 6.8, N 13.6%. dH 10.12 (1 H, s, NH), 8.42 (1 H, d, J 9.1,
H4ꢀꢀ), 7.54 (2 H, m, H2ꢀ), 7.37 (2 H, m, H3ꢀ), 7.18 (1 H, m, H4ꢀ),
6.91 (1 H, d, J 9.1, H5ꢀꢀ), 4.19 (1 H, tt, J1 12.1, J2 3.5, H1ꢀꢀꢀ), 1.79
(2 H, qd, J1 12.4, J2 3.3, H2ꢀꢀꢀa), 1.65 (2 H, m, H3ꢀꢀꢀe), 1.57 (2 H,
m, H2ꢀꢀꢀe), 1.52 (1 H, m, H4ꢀꢀꢀe), 1.43 (9 H, s, tBu), 1.12 (2 H,
m, H3ꢀꢀꢀa), 0.92 (1 H, m, H4ꢀꢀꢀ) (ꢀꢀꢀ refers to cyclohexyl); dC 158.2,
155.3, 152.7, 143.4, 138.0, 136.3, 128.6, 124.8, 124.1, 123.9,
81.7, 57.8, 30.1, 27.7, 25.9, 25.0; m/z (CI) 413 ([M + H]+).
82.8, 27.5 m/z (CI) 350, 352 ([M + H]+).
2-(N -tert-Butoxycarbonylanilino)-6-chloro-3-nitropyridine
(13). A solution of 14 (250 mg, 1.0 mmol), di-tert-butyl
dicarbonate (364 mg, 1.6 mmol), and DMAP (7 mg) in 2 mL of
DCM was warmed at 38 ◦C for 15 h. The mixture was purified
twice by column chromatography on silica gel (1. n-hexane, 2.
n-hexane : EtOAc = 4 : 1) (245 mg, 70%, honey-coloured resin).
Found: C 55.2, H 4.7, N 11.9. Calc. for C16H16ClN3O4: C 54.9,
H 4.6, N 12.0%. dH 8.59 (1 H, d, J 8.6, H4ꢀꢀ), 7.69 (1 H, d, J 8.6,
H5ꢀꢀ), 7.42 (2 H, m, H3ꢀ), 7.31 (1 H, m, H4ꢀ), 7.31 (2 H, m, H2ꢀ),
1.32 (9 H, s, tBu); dC 151.8, 146.8, 140.9, 140.0, 138.0, 129.0,
127.5, 127.1, 123.5, 83.1, 27.3; m/z (CI) 350, 352 ([M + H]+),
+
=
294, 296 ([(M + H)–Me2C CH2] ).
2-Anilino-6-chloro-3-nitropyridine (14)1. A mixture of 3
(2.50 g, 13 mmol), NaHCO3 (1.18 g, 14 mmol), aniline (1.21 g =
1.18 mL, 13 mmol), and EtOH (30 mL) was stirred at room
temperature for 1 d. The precipitate was collected, washed with
EtOH and water and purified by column chromatography on
silica gel (n-hexane : EtOAc = 4 : 1) (1.71 g, 53%). Mp 104 ◦C
(ref. 1: 102–104 ◦C).
2-Chloro-6-(N-methylanilino)-3-nitropyridine (15a). To a so-
lution of 9 (100 mg, 0.4 mmol) in DMF (2 mL) was added K2CO3
(70 mg, 0.5 mmol) and MeI (71 mg or 0.03 mL, 0.5 mmol) and
the mixture stirred at 45 ◦C for 2 h. 10 mL of water was added
and the mixture extracted with EtOAc. The organic phase was
evaporated and the residue purified by column chromatography
on silica gel (n-hexane : EtOAc = 4 : 1). (86 mg, 81%). Colourless
crystals, mp 107 ◦C. Found: C 54.7, H 3.9, N 15.7. Calc. for
C12H10ClN3O2: C 54.7, H 3.8, N 15.9%. dH 8.18 (1 H, d, J 9.1,
H4ꢀꢀ), 7.54 (2 H, m, H3), 7.41 (1 H, m, H4), 7.40 (2 H, m, H2),
6.36 (1 H, d, J 9.1, H5ꢀꢀ), 3.47 (3 H, s, Me); dC 158.4, 143.6, 143.2,
136.6, 133.0, 130.3, 127.8, 126.7, 106.6, 39.2; m/z (CI) 264, 266
([M + H]+).
2,6-Bis-(N-tert-butoxycarbonylanilino)-3-nitropyridine (15b).
A solution of 2 (140 mg, 0.45 mmol), di-tert-butyl dicarbonate
(240 mg, 1.1 mmol), and DMAP (10 mg) in DCM (15 mL) was
stirred at room temperature for 2 h. The solvent was removed
and the residue purified by column chromatography on silica gel
(n-hexane : EtOAc = 4 : 1) (114 mg, 50%). Mp 137 ◦C. Found:
C 63.7, H 6.0, N 10.7. Calc. for C27H30N4O6: C 64.0, H 6.0, N
11.1%. dH 8.52 (1 H, d, J 9.1, H4ꢀꢀ), 7.85 (1 H, d, J 9.1, H5ꢀꢀ),
7.28 (3 H, m, H3, H4), 7.20 (3 H, m, H3ꢀ, H4ꢀ), 7.01 (2 H, m,
H2), 6.97 (2 H, m, H2ꢀ), 1.33 (9 H, s, tBu) 1.26 (9 H, s, tBu);
dC 161.4, 155.8, 151.8, 145.2, 140.0, 139.7, 136.5, 133.6, 128.8,
128.5, 128.2, 127.6, 127.0, 126.8, 115.7, 82.4, 82.3, 27.5, 27.4;
m/z (CI) 507 ([M + H]+).
2-(N-tert-Butoxycarbonylmethylanilino)-6-chloro-3-nitropyri-
dine (16b). To a solution of 14 (225 mg, 0.9 mmol) in
DMF (15 mL) were added K2CO3 (207 mg, 1.5 mmol) and
subsequently tert-butyl bromoacetate (293 mg = 0.22 mL,
1.5 mmol). After stirring at rt for 16 h water was added and
the mixture extracted with EtOAc. The organic layer was
evaporated and the residue purified by column chromatography
on silica gel (n-hexane : EtOAc = 4 : 1) (198 mg, 60%). Mp
163–165 ◦C (from n-hexane : EtOAc = 4 : 1). Found: C 56.1, H
5.1, N 11.4. Calc. for C17H18ClN3O4: C 56.1, H 5.0, N 11.55%.
dH 8.20 (1 H, d, J 8.2, H4ꢀꢀ), 7.31 (2 H, m, H3ꢀ), 7.16 (1 H, m,
H4ꢀ), 7.14 (2 H, m, H2ꢀ), 7.11 (1 H, d, J 8.3, H5ꢀꢀ), 4.54 (2 H, s,
CH2), 1.37 (9 H, s, tBu); dC 168.0, 150.6, 149.1, 144.4, 138.6,
130.1, 129.5, 126.1, 123.5, 114.9, 81.0, 55.0, 27.7; m/z (EI) 363,
365 (M+).
N-Methyl-2-nitrodiphenylamine (22b)14. To a solution of
624 mg (3 mmol) of 22a in 6 mL of DMF was added K2CO3
(552 mg, 4 mmol) followed by 0.25 mL (548 mg, 4 mmol) of
MeI. The mixture was stirred at room temperature for 2 h,
poured onto water and extracted with EtOAc. The organic
phase was evaporated and the remaining oily product purified
by column chromatography on silica gel (n-hexane : EtOAc =
4 : 1) (380 mg, 64%; oily product). Found: C 68.5, H 5.3, N 12.3.
Calc. for C13H12N2O2: C 68.4, H 5.3, N 12.3%. dH 7.91 (1 H, dd,
J1 8.1, J2 1.5, H4ꢀꢀ), 7.73 (1 H, ddd, J1 8.1, J2 7.3, J3 1.5, H6ꢀꢀ),
7.50 (1 H, dd, J1 8.1, J2 1.3, H1ꢀꢀ), 7.41 (1 H, ddd, J1 8.1, J2 7.3,
J3 1.3, H5ꢀꢀ), 7.15 (2 H, dd, J1 8.8, J2 7.3, H3ꢀ), 6.77 (1 H, tt, J1
7.3, J2 1.0, H4ꢀ), 6.64 (2 H, m, H2ꢀ), 3.24 (3 H, s, CH3); dC 147.7,
146.3, 141.0, 134.6, 129.3, 129.0, 125.9, 125.3, 119.3, 114.9, 40.1;
m/z (CI) 229 ([M + H]+).
N-Benzyl-2-nitrodiphenylamine (22c). To a solution of 22a
(570 mg, 2.7 mmol) in DMF (6 mL) was added KOtBu (350 mg,
3.6 mmol) and subsequently benzyl bromide (616 mg, 0.43 mL,
3.6 mmol). The mixture was stirred at room temperature
for 2 h. The solvent was removed under vacuum and the
residue crystallized from EtOH under addition of enough 1,4-
diazabicyclo[2,2,2]octane (DABCO) to remove unreacted benzyl
bromide (as determined by an NMR spectrum of the crude
2-(N-Benzylanilino)-6-chloro-3-nitropyridine (16c). A solu-
tion of 3 (460 mg, 2.4 mmol), N-benzylaniline (457 mg,
2.5 mmol), and DIPEA (322 mg, 2.5 mmol) in 3 mL of toluene
was heated at 80 ◦C for 4 d. The mixture was washed with 3 mL
of 0.1 M citric acid and the solvent evaporated. The residue was
◦
reaction product) (560 mg, 69%). Mp 110 C. Found: C 75.0,
H 5.4, N 9.2. Calc. for C19H16N2O2: C 75.0, H 5.3, N 9.2%. dH
7.88 (1 H, dd, J1 8.1, J2 1.5, H4ꢀꢀ), 7.68 (1 H, ddd, J1 8.1, J2 7.3,
J3 1.5, H6ꢀꢀ), 7.53 (1 H, dd, J1 8.1, J2 1.0, H1ꢀꢀ), 7.38 (2 H, m,
3 4 2 0
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 4 0 8 – 3 4 2 1

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H2ꢀꢀꢀ), 7.36 (1 H, ddd, J1 8, J2 7, J3 1.3, H5ꢀꢀ), 7.29 (2 H, m, H3ꢀꢀꢀ),
7.21 (1 H, m, H4ꢀꢀꢀ), 7.12 (2 H, m, H3ꢀ), 6.78 (1 H, m, H4ꢀ), 6.69
(2 H, m, H2ꢀ), 4.69 (2 H, s, CH2) (ꢀꢀꢀ refers to benzylic phenyl); dC
147.2, 145.6, 140.2, 138.1, 134.5, 129.1, 128.7, 128.5, 127.0 (3C),
125.7, 125.5, 120.1, 116.6, 56.1; m/z (EI) 304 (M+).
Acknowledgements
We would like to thank Dr Thomas Fox, Department of
Lead Finding, Boehringer Ingelheim Pharma GmbH & Co.
KG at Biberach for the DFT calculation and discussions of
the results, Dr Elena Mena-Osteritz, Department of Organic
Chemistry II, University of Ulm for very helpful discussions
of the theoretical aspects, Dr G. Schmidtberg and Dr Markus
Wunderlin, Section Mass Spectrometry University of Ulm for
recording the mass spectra, and Margit Lang, Department
of Analytical Chemistry, University of Ulm for the elemental
analyses. Technical assistance by Dieter Meinhard during his
advanced practical training is gratefully acknowledged.
V. A. would like to thank Boehringer Ingelheim Pharma
GmbH & Co. KG for sponsoring his guest professorship
at the University of Ulm and for generous gifts of starting
materials. V. A. and S. S. are grateful to Prof. Ba¨uerle, head
of the Department of Organic Chemistry II, University of Ulm
for his generous support with departmental means.
2-(N-Methylanilino)pyridine (23b)15. To a solution of 510 mg
(3 mmol) of 23a in 6 mL of DMF was added KOtBu (369 mg,
3.3 mmol) followed by 0.21 mL (468 mg, 3.3 mmol) of MeI. The
mixture was stirred at room temperature for 1.5 h, poured
onto water and extracted with EtOAc. The organic phase was
collected, evaporated and the remaining oily product purified by
column chromatography on silica gel (n-hexane : EtOAc = 4 :
1) (525 mg, 95%, colourless oil). Found: C 78.2, H 6.6, N 15.3.
Calc. for C12H12N2: C 78.2, H 6.6, N 15.2%. dH 8.14 (1 H, ddd, J1
5.1, J2 2.0, J3 1.0, H2ꢀꢀ), 7.41 (2 H, m, H3), 7.40 (1 H, ddd, J1 8.6,
J2 7.1, J3 2.0, H4ꢀꢀ), 7.27 (2 H, m, H2), 7.21 (1 H, m, H4), 6.65
(1 H, ddd, J1 7.1, J2 5.1, J3 0.8, H3ꢀꢀ), 6.50 (1 H, ddd, J1 8.6, J2
1.0, J3 0.8, H5ꢀꢀ), 3.37 (3 H, s, CH3); dC 157.8, 147.2, 146.0, 136.7,
129.4, 125.6, 125.0, 113.0, 108.2, 37.8; m/z (CI) 185 ([M + H]+).
References
2-(N-Benzylanilino)pyridine (23c). To a solution of 230 mg
(1.35 mmol) of 23a in 2 mL of DMF were added under argon
179 mg (1.5 mmol) of KOtBu. After stirring for 10 min and
cooling in an ice bath 230 mg (1.35 mmol) of benzyl bromide
were added. The cooling was removed and the mixture stirred
at room temperature for 1 d, poured onto 20 mL of water
and extracted with EtOAc (25 mL). The organic phase was
evaporated and the residue crystallized from 34 mL of EtOH
under addition of 30 mg of DABCO. The product was then
purified by column chromatography on silica gel (n-hexane :
EtOAc = 4 : 1) (300 mg, 85%). Mp 71 ◦C. Found: C 83.0, H
6.3, N 10.7. Calc. for C18H16N2: C 83.0, H 6.2, N 10.8%. dH 8.13
(1 H, ddd, J1 5.1, J2 2.0, J3 0.8, H2ꢀꢀ), 7.43 (1 H, ddd, J1 8.8, J2
7.1, J3 2.0, H4ꢀꢀ), 7.36 (2 H, m, H3), 7.23–7.27 (6 H, m, H2, H2ꢀꢀꢀ,
H3ꢀꢀꢀ), 7.17 (2 H, m, H4, H4ꢀꢀꢀ), 6.68 (1 H, ddd, J1 7.1, J2 5.1, J3
0.8, H3ꢀꢀ), 6.52 (1 H, dt, J1 8.6, J2 0.8, H5ꢀꢀ), 5.22 (2 H, s, CH2) (ꢀꢀꢀ
refers to benzylic phenyl); dC 157.8, 147.7, 144.8, 139.3, 137.3,
129.7, 128.2, 127.1, 126.6, 126.2, 125.3, 113.8, 108.6, 52.5; m/z
(CI) 261 ([M + H]+).
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2-(N-tert-Butyloxycarbonylanilino)pyridine (23d). A solu-
tion of 23a (87 mg, 0.51 mmol), di-tert-butyl dicarbonate
(141 mg, 0.65 mmol), and a catalytic amount of DMAP in
DCM (2 mL) was stirred at room temperature for 5 h. The
solvent was removed under vacuum and the residue purified by
column chromatography on silica gel (n-hexane : EtOAc = 4 : 1)
(115 mg, 84%). Mp 86 ◦C. Found: C 71.0, H 6.7, N 10.3. Calc.
for C16H18N2O2: C 71.1, H 6.7, N 10.4%. dH 8.31 (1 H, ddd, J1
4.8, J2 2.0, J3 0.8, H2ꢀꢀ), 7.83 (1 H, ddd, J1 8.1, J2 7.3, J3 2.0,
H4ꢀꢀ), 7.51 (1 H, dt, J1 8.1, J2 0.9, H5ꢀꢀ), 7.33 (2 H, m, H3), 7.21
(2 H, m, H3ꢀꢀ, H4), 7.15 (2 H, m, H2), 1.37 (9 H, s, tBu); dC 154.8,
152.9, 148.2, 141.7, 138.0, 128.6, 127.4, 125.9, 121.3, 121.2, 80.8,
27.7; m/z (EI) 270 (M+).
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¨
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O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 4 0 8 – 3 4 2 1
3 4 2 1