Effects of the pyridine 3-substituent on regioselectivity in the nucleophilic aromatic substitution reaction of 3-substituted 2,6-dichloropyridines with 1-methylpiperazine studied by a chemical design strategy

Article abstract of DOI:10.1002/ejoc.201200978

A chemical design strategy has been used to select 3-substituted 2,6-dichloropyridines for the nucleophilic aromatic substitution reaction with 1-methylpiperazine. The aim was to study the dependency of the regioselectivity in these reactions on the character of the pyridine 3-substituent expressed by their lipophilicity (PI), size (MR), and inductive effect (I_p). Interestingly, the regioselectivity did not correlate with any of these parameters, but in a statistically significant manner with the Verloop steric parameter B1, as indicated by the p value of 0.006 (R² = 0.45). This implies that bulky 3-substituents close to the pyridine ring induce regioselectivity towards the 6-position. Useful in practical synthesis is the different regioselectivity obtained with a carboxylic acid 3-substituent and precursors or derivatives thereof. Thus, in acetonitrile as solvent, 3-carboxylate and 3-amide substituents were preferred to obtain the 2-isomer (9:1 ratio of the 6-isomer), whereas the 3-cyano and 3-trifluoromethyl substitutents were preferred to obtain the 6-isomer (9:1 ratio of the 2-isomer). Analysis of the regioselectivity R_sel for the pyridine 2-position in the reaction of 2,6-dichloro-3-(methoxycarbonyl)pyridine with 1-methylpiperazine in 21 different solvents showed that R_sel could be predicted by the Kamlet-Taft equation: R_sel = 1.28990 + 0.03992α - 0.59417β - 0.46169π* (R² = 0.95, p = 1.9 × 10^-10). R_sel is thus mainly correlated with the ability of the solvent to function as a hydrogen-bond acceptor, as expressed by the solvatochromic β parameter. Thus, the 16:1 regioselectivity for the 2-isomer in DCM (β = 0.10) could be switched to a 2:1 selectivity for the 6-isomer in DMSO (β = 0.76). Copyright

Full text of DOI:10.1002/ejoc.201200978

FULL PAPER
DOI: 10.1002/ejoc.201200978
Effects of the Pyridine 3-Substituent on Regioselectivity in the Nucleophilic
Aromatic Substitution Reaction of 3-Substituted 2,6-Dichloropyridines with
1-Methylpiperazine Studied by a Chemical Design Strategy
Peter Bach,*[a] Michaela Marczynke,[a] and Fabrizio Giordanetto[a]
Keywords: Substituent effects / Regioselectivity / Chemical design / Solvent effects / Nucleophilic substitution
A chemical design strategy has been used to select 3-substi-
ferred to obtain the 2-isomer (9:1 ratio of the 6-isomer),
tuted 2,6-dichloropyridines for the nucleophilic aromatic sub- whereas the 3-cyano and 3-trifluoromethyl substitutents
stitution reaction with 1-methylpiperazine. The aim was to
study the dependency of the regioselectivity in these reac-
tions on the character of the pyridine 3-substituent expressed
by their lipophilicity (PI), size (MR), and inductive effect (σp).
Interestingly, the regioselectivity did not correlate with any
of these parameters, but in a statistically significant manner
with the Verloop steric parameter B1, as indicated by the p
were preferred to obtain the 6-isomer (9:1 ratio of the 2-iso-
mer). Analysis of the regioselectivity Rsel for the pyridine 2-
position in the reaction of 2,6-dichloro-3-(methoxycarbonyl)-
pyridine with 1-methylpiperazine in 21 different solvents
showed that Rsel could be predicted by the Kamlet–Taft equa-
tion: Rsel = 1.28990 + 0.03992α – 0.59417β – 0.46169π* (R2
0.95, p = 1.9ϫ10–10). Rsel is thus mainly correlated with the
=
value of 0.006 (R2 = 0.45). This implies that bulky 3-substitu- ability of the solvent to function as a hydrogen-bond ac-
ents close to the pyridine ring induce regioselectivity towards
the 6-position. Useful in practical synthesis is the different
regioselectivity obtained with a carboxylic acid 3-substituent
and precursors or derivatives thereof. Thus, in acetonitrile as
solvent, 3-carboxylate and 3-amide substituents were pre-
ceptor, as expressed by the solvatochromic β parameter.
Thus, the 16:1 regioselectivity for the 2-isomer in DCM (β =
0.10) could be switched to a 2:1 selectivity for the 6-isomer
in DMSO (β = 0.76).
Of particular relevance for this study are reactions that
employ amines as the nucleophile. The regioselectivity out-
come of this SNAr reaction has been reported in the litera-
ture for different combinations of 3-substituted 2,6-dichlo-
ropyridine, amine nucleophiles, and reaction conditions.
However, no systematic approach to study how the regiose-
lectivity in this reaction depends on the 3-substituent has
previously been reported. Examples of reactions that are
selective at the 2-position include the treatment of 2,6-di-
bromo-3-(trifluoroacetylamino)pyridine with benzylamine
in the presence of 0.1 equiv. of CuI and 0.2 equiv. of l-pro-
line in DMSO, which solely gave the 2-regioisomer.[3] Like-
wise, the 2-isomers were isolated as the sole products from
the reaction of ammonia with 2,6-dichloro-3-(hy-
droxymethyl)pyridine[4,5] (in EtOH) and 2,6-dichloronico-
tinic acid[6,7] (in water); however, no further analysis of re-
gioselectivity outcomes was provided. Also, the treatment
of 2,6-dichloronicotinamides with amines has been reported
to selectively give the 2-isomer, as exemplified by the reac-
tion of phenethylamine with 2,6-dichloro-N-(2-phenoxye-
thyl)nicotinamide in THF.[8] The reactions of 2,6-dichloro-
3-nitropyridine with ammonia in iPrOH,[9,10] methylamine
in EtOH,[11] allylamine in DCM,[12] diethylamine in
MeCN,[13] iBuNH2, tBuCH2NH2, or iPrSO2NH2 in
Introduction
Understanding the underlying factors that govern reac-
tion selectivity in organic synthesis is key to controlling re-
action outcome. This enables improvements to reaction effi-
ciency by minimizing side-reactions. One type of selectivity
in organic reactions is regioselectivity. In a regioselective
reaction, one direction of bond making or breaking occurs
preferentially over all other possible directions.[1]
In 3-substituted 2,6-dichloropyridines, which are useful
starting materials in organic synthesis,[2] the two carbon
atoms neighboring the pyridine nitrogen atom are electro-
philic. 2,6-Dichloropyridine derivatives that are monosub-
stituted at the 3-position are nonsymmetric and can thus
form two different products when treated with a nucleophile
(Nu) in a nucleophilic aromatic substitution (SNAr) reac-
tion (Scheme 1).
[a] Department of Medicinal Chemistry, AstraZeneca R&D
Mölndal,
43183 Mölndal, Sweden
Fax: +46-317-72-13-94
E-mail: bach@chalmers.se
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200978.
6940
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 6940–6952

Regioselectivity in Nucleophilic Aromatic Substitution Reactions
Scheme 1. Reaction of a 3-substituted 2,6-dichloropyridine with a nucleophile.
EtOH,[14] 4-(ethoxycarbonyl)-1-piperazine in CHCl3,[15] or
Each value of PI, MR, and σp were categorized as low
N-(tert-butoxycarbonyl)aniline in DMF[16] gave primarily (L), medium (M), or high (H). This gave a three-letter code
or solely the 2-isomer. Hirokawa et al.[17] reported that the to each starting material, for example, LLH. The starting
reaction of methyl 2,6-dichloronicotinate with methylamine materials 1–8 (Table 1) included the eight possible combina-
gave moderate selectivity for the 2-isomer (49:12 in THF at tions of the extreme (either low or high) values of the three
5 °C), whereas the reaction with benzylamine increased the variables. Seven other starting materials 9–14 included at
selectivity for the 2-isomer (86:14 in THF at –20 °C).
least one medium value, and secondary amine 15 was in-
With 2,6-dichloro-3-(trifluoromethyl)pyridine, the re- cluded to facilitate comparison with primary amine 1 and
gioselectivity was biased towards the 6-isomer; thus, treat- tertiary amine 4. The 15 starting materials were selected
ment with methylamine in EtOH gave the 2- and 6-isomers with consideration given to synthetic feasibility and the
in a 1:4 ratio, whereas treatment with the sterically more chemical stability of the starting materials.
demanding dibenzylamine in N-methyl-2-pyrrolidone gave
solely the 6-isomer.[18] DABCO reacted selectively at the 6-
Table 1. Chemical design of the starting materials with variation of
lipophilicity (PI), size (MR), and inductive effect (σp).
position of methyl 2,6-dichloronicotinate in [D7]DMF or
THF to form a reactive intermediate that was subsequently
treated with phenols.[19] A number of other reports[20–22]
have described the reaction of N-nucleophiles with 3-substi-
tuted 2,6-dichloropyridine derivatives without mentioning
the regiochemical outcome.
Given the differences in nucleophiles and reaction condi-
tions, including solvents, it was difficult to draw general
conclusions from these literature reports about the factors
that control the regioselectivity.
In this paper, the factors that govern the regioselectivity
in the SNAr reactions of 3-substituted 2,6-dichloropyridines
with 1-methylpiperazine have been studied by a chemical
design strategy. To make this type of comparative study it
was necessary to apply the general assumption for SNAr
reactions,[23] that is, that the rate-determining step in all re-
actions is the initial attack of the nucleophile at the 2- or
6-position of the electrophile. Three parameters that express
[a] The letter code represents the combination PI, MR, and σp,
with each value being L = low, M = medium, or H = high.
different aspects of the character of the pyridine 3-substitu-
ent (R3) were varied systematically: lipophilicity (PI), size
(MR = molar refraction), and inductive effect (σp).[24] Al-
Reactions of the starting materials 1–15 (Scheme 2) with
though the size and inductive effects are usual in this con- 1-methylpiperazine (MP) produced the 2-MP regioisomers
text, it was decided also to include the lipophilicity as a way 16a–30a and the 6-MP regioisomers 16b–30b, such that
to represent and study the effect of the polar character of compound 1 gave 16a and 16b, compound 2 gave 17a and
the 3-substituent. Values for the molar refraction (MR) 17b etc.
were available for more relevant substituents than were, for
The regioselectivity Rsel was determined by 1H NMR
example, Taft’s steric constants (Es)[25] or Charton’s steric spectroscopy as the ratio between the integral of the two
constants (ν),[26] and MR was thus used as the size/steric aromatic pyridine hydrogen atoms in the 2-isomer and the
parameter of the 3-substituent. Although MR values do not total integral of the four aromatic pyridine hydrogen atoms
distinguish between substituents that have steric bulk close in the 2- and 6-isomers. Thus, Rsel = 0.5 signifies a reaction
to or remote from the pyridine ring, the substituents se- with no regioselectivity. To determine Rsel reliably, it was
lected are comparatively small and for these reasons MR important that no byproducts were formed in the reactions.
was considered a reasonable size parameter for this study. In particular, in reactions of some of the reactive starting
The inductive effect is represented by the σp parameter. Al- materials it was difficult to completely avoid the formation
though σp does not take into consideration the resonance of the 2,6-bis-MP addition product. This could form from
effects, which are possible for some 3-substituents, these either the 2-MP- or 6-MP-monosubstituted product; how-
were assumed to be similar for reactions at the 2- (ortho to ever, the reaction of 1-methylpiperazine with either of these
the 3-substituent) and 6-positions (para to the 3-substitu- compounds might have different rate constants. Thus, to
ent).
ensure that Rsel was determined correctly, reaction condi-
Eur. J. Org. Chem. 2012, 6940–6952
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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6941

P. Bach, M. Marczynke, F. Giordanetto
FULL PAPER
Scheme 2. Reactions of 3-substituted 2,6-dichloropyridines 1–15 with 1-methylpiperazine (MP) to give 2-MP-pyridines 16a–30a and 6-
MP-pyridines 16b–30b.
tions were chosen such that the formation of the 2,6-bis-
We hypothesized that a hydrogen-bond-accepting 3-sub-
MP addition product was kept below 4% of the total prod- stituent could form hydrogen bonds with 1-methylpipera-
uct. In general, the pyridine hydrogen atoms in the 1H zine and thus direct the addition of 1-methylpiperazine to
NMR spectra of the reaction mixtures appeared as two sets the 2-position. The bias for the formation of a hydrogen
of signals (three if starting material remained), as confirmed bond to 1-methylpiperazine would depend on the type of
1
by H COSY. In most cases, both regioisomers could be solvent, because a hydrogen-bond-accepting solvent could
isolated by chromatography and characterized. Only in the compete with the 3-substituent for hydrogen bonding to 1-
6-MP regioisomers (Scheme 2) could the NOE between the methylpiperazine. In the starting materials 1–15, a number
pyridine 5-hydrogen and hydrogen atoms in MP be ob- of the 3-substituents were hydrogen-bonding acceptors. For
served, and this was used as a diagnostic tool to identify example, the 3-methoxycarbonyl substituent in compound
the 6-MP regioisomers.
9 has this ability. To study any such effect of the solvent,
The spectra of the pure regioisomers were compared with compound 9 was treated with 1-methylpiperazine in 21 dif-
the spectra of the reaction mixtures, and thus Rsel could be ferent and separate solvents. These were selected based on
determined. In some cases, regioisomers were formed in differences in, for example, polarity, hydrogen-bond-donat-
very uneven ratios, and only one regioisomer could be iso- ing and -accepting ability, molecular dipolar momentum μ,
lated. In these cases, LC–MS of the reaction mixtures was and relative static permittivity (dielectric constant) ε.
used to establish that a pair of isomers with identical masses
had formed (and not one isomer and one byproduct), and
Results and Discussion
1
the H NMR spectrum of the minor product was deter-
mined from the 1H NMR spectrum of the product mixture.
Oxidation of 2-chloro-3-methylpyridine (31; Scheme 3)
The two 3-carboxy regioisomers formed from the reac- to N-oxide 32 followed by chlorination provided a 6:1 mix-
tion of 3-carboxy-2,6-dichloropyridine (11) with 1-methyl- ture of 3-methyl-2,6-dichloropyridine (2) and byproduct
piperazine could not be separated by chromatography. In- 2,4-dichloro-3-methylpyridine (33); however, separation of
stead, reference samples for these two products were ob- the products by chromatography was not possible.[27] Treat-
tained by hydrolysis of the separated 3-methoxycarbonyl re- ment of the mixture with Zn selectively reduced the 4-
gioisomers obtained from the reaction of 9 with 1-methylpi- chlorine atom of byproduct 33 to give 31, and compound 2
perazine.
could be separated from 31 by chromatography.
Scheme 3. Synthesis of an inseparable mixture of 2,6- and 2,4-dichloro-3-methylpyridine isomers 2 and 33 followed by selective reduction
of 4-Cl of byproduct 33.
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Regioselectivity in Nucleophilic Aromatic Substitution Reactions
Scheme 4. Derivatization of 3-iodo compound 34 to provide 3 and 13 and conversion of the 3-amino compound 1 to provide 4.
Scheme 5. Derivatization of 2,6-dichloronicotinic acid (11) to give primary amide 12, nitrile 5, phenyl ester 7, and methyl ester 9.
3-Iodo-2,6-dichloropyridine (34; Scheme 4) was em- vide compound 10. Deprotonation of 2,6-dichloropyridine
ployed in Suzuki[28] and Buchwald–Hartwig[29] reactions to (38) with LDA[33] followed by reaction with elemental sul-
produce 3 and 15, respectively. 2,6-Dichloro-3-morpholino- fur gave a mixture of thiols that was ethylated swiftly to
pyridine (4) was synthesized by a three-step procedure from avoid disulfide formation and provided 14.
1.
The results of the reactions, in relation to the regioselec-
The conversion of 2,6-dichloronicotinic acid (11; tivity, of the starting materials 1–15 with 1-methylpipera-
Scheme 5) into acyl chloride 35[30] followed by treatment zine are shown in Table 2. Single variable data analysis of
with aqueous ammonia produced primary amide 12. Subse- this set of data did not reveal any significant correlations
quent dehydration provided 2,6-dichloronicotinonitrile (5). (as defined by the statistical standard of the p value Ͻ 0.05)
Reaction of 35 with phenol or methanol gave esters 7 and between the regioselectivity Rsel and each of the parameters
9,[31] respectively.
PI, MR, and σp used in the chemical design strategy, as
Compounds 8, 10, and 14 were prepared as outlined in shown in Figure 1. Despite the paucity of observations (N
Scheme 6. N,N-Dimethylsulfonamide 8 was prepared by = 15), an attempt was made to combine the different de-
treatment of commercial sulfonyl chloride 36 with dimeth- scriptors (PI, MR, and σp) in a multiple linear regression
ylamine. 3-Hydroxy compound 37, prepared by the method model as a way to predict Rsel and explain its variance in
of Voisin et al.,[32] was O-ethylated with ethyl bromide to pro- more detail. Here, all the possible combinations up to two
Eur. J. Org. Chem. 2012, 6940–6952
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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6943

P. Bach, M. Marczynke, F. Giordanetto
FULL PAPER
Scheme 6. Synthesis of sulfonamide 8, ethyl ether 10, and ethyl
thioether 14.
molecular descriptors were evaluated by using least-squares
fitting to Rsel. Unfortunately, no linear combination of de-
scriptors yielded a significant correlation with the regiose-
lectivity Rsel.
Figure 1. Relationship between the regioselectivity Rsel for the 2-
position and selected parameters describing (a) lipophilicity (PI, R2
= 0.24, p = 0.06), (b) size (MR, R2 = 0.06, p = 0.37), and (c) induc-
tive effect (σp, R2 = 0.13, p = 0.18), and (d) steric bulk in proximity
to the pyridine 3-substituent (Verloop parameter B1, R2 = 0.45, p
= 0.006). Labels indicate compound numbers of the starting mate-
rials.
Table 2. Verloop steric parameters B1 for the 3-substituents and
regioselectivity Rsel for the 2-isomer in the reaction of 3-substituted
2,6-dichloropyridines with 1-methylpiperazine.
3-Substituent
B1 2-isomer 6-isomer Reaction conditions[a]
(a)
(b)
(c)
Rsel Rsel
Rsel
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
NH2
CH3
p-(H3C)2NC6H4
morpholino
CN
1.65
1.7
1.65
1.76
1.7
16a
17a
18a
19a
20a
21a
22a
23a
24a
25a
26a
27a
28a
29a
30a
16b
17b
18b
19b
20b
21b
22b
23b
24b
25b
26b
27b
28b
29b
30b
–
0.96
–
–
–
ingly, this effect was not captured by other steric descriptors
normally employed, such as Taft’s or Charton’s steric con-
stants. The regioselectivity is thus governed by a steric fac-
tor, and no statistically significant effects from the lipophil-
icity or the inductive effect of the 3-substituent was iden-
tified by this chemical design strategy with the present set
of compounds.
Group and pairwise comparisons led to some interesting
observations that could be useful in the planning of syn-
thetic strategies. Particularly interesting in synthesis would
be a carboxylic acid or derivative thereof as substituent at
the pyridine 3-position due to their possible interconversion
and synthetic versatility. Thus, to obtain the 2-isomer (9:1
ratio with the 6-isomer), 3-carboxylate (11) and 3-amide
(12) substituents were preferred, whereas to obtain the 6-
isomer (9:1 ratio with the 2-isomer) the 3-cyano (5) and 3-
trifluoromethyl (6) substituents were preferred. To obtain
high regioselectivity, these substituents were preferred to 3-
methyl (2), 3-phenoxycarbonyl (7), and 3-methoxycarbonyl
0.52 0.26
–
–
0.17
0.43
–
0.11
0.09
0.67
0.37
0.75
–
0.95 0.93
0.91 0.94
0.75 0.66
0.42 0.26
0.15
0.02
0.40
0.20
0.56
–
–
–
–
–
CF3
2.1
COOPh
SO2N(CH3)2
COOCH3
OCH2CH3
COO–
CONH2
Br
SCH2CH3
NHPh
2.03
1.95
1.74
1.42
1.7
0.96
1.7
1.82
1.85
1.85
–
0.71
–
[a] Reaction conditions (a)–(c): (a) 0.1 m in MeCN, 1.0 equiv. of 1-
methylpiperazine, 3.0 equiv. of DIPEA, stirring at room temp. or
heating in a microwave oven; (b) 0.1 m in neat 1-methylpiperazine
(54 equiv.), heating in a microwave oven; (c) 0.1 m in neat 1-methyl-
piperazine (54 equiv.), 0 °C, 20–30 s, then quench with excess
HCOOH.
However, further investigations employing a variety of (9) substituents, of which the 3-methoxycarbonyl gave the
2D- and 3D-based descriptors[34] highlighted the fact that highest (3:1) selectivity for the 2-isomer. The 3-amino (1)
the regioselectivity Rsel is correlated with the Verloop steric substituent gave a high (Rsel = 0.96) selectivity for the 2-
parameter B1 (R2 = 0.45).[35] Because B1 describes the isomer; however, to avoid prolonged heating at high tem-
smallest width of the 3-substituent, as measured perpendic- peratures, an electron-withdrawing 3-substituent is usually
ular to the axis of the bond between the first atom of the preferred in synthesis. With substituted 3-amines the selec-
substituent and the parent molecule, this implies that 3-sub- tivity for the 2-position decreased significantly, as observed
stituents with steric bulk in proximity to the pyridine ring with 3-phenylamino (15, Rsel = 0.71) and 3-morpholino (4,
would steer regioselectivity towards the 6-position. Interest- Rsel = 0.43). Although this comparison indicates a steric
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Regioselectivity in Nucleophilic Aromatic Substitution Reactions
Table 3.[37] Solvent effect on the regioselectivity Rsel for the 2-position in the reaction of methyl 2,6-dichloronicotinate (9) with 1-methylpi-
perazine.[a]
Solvent
Rsel
Unreacted 9 [%][b]
Reaction time [h]
β
α
π*
B.p. [°C]
DN
S1
S2
S3
S4
S5
S6
S7
S8
S9
S10
S11
S12
S13
S14
S15
S16
S17
S18
S19
S20
S21
DMSO
DMF
MeCN
0.34
0.47
0.74
0.72
0.40
0.91
0.82
0.93
0.78
0.44
0.32
0.82
0.57
0.39
0.48
0.81
0.80
0.43
0.73
0.94
0.62
0
0
Ͻ 1
Ͻ 1
Ͻ 1
Ͻ 1
1
20
20
20
20
20
20
20
20
20
4
0.76
0.69
0.40
0.43
0.77
0
0.06
0.10
0.55
0.77
0.82
0.71
0.64
0.76
0.80
0.45
0.37
0.80
0.41
0.11
0.66
0
0
0.19
0.08
0
1
189
153
81
56
203
84
101
40
66
215
198
89
115
165
199
77
29.8
26.6
14.1
17.0
27.3
0
2.7
1.0
20.0
26.0
–
61.0
33.1
27.8
27.0
17.1
14.3
29.6
20.0
1
0.88
0.75
0.71
0.92
0.81
0.85
0.82
0.58
0.72
–
0.14
0.87
0.88
0.90
0.55
0.55
0.83
0.53
0.54
0.60
acetone
N-methylpyrrolidone
1,2-DCE
0
CH3NO2
DCM
THF
0.22
0.13
0
0
0
0
0
0
0.62
0
0
0
0
0
6
21
14
5
0
3
5
7
11
5
5
O=P(OEt)3
N-methylimidazole
triethylamine
pyridine
DMA
N-methylformamide
EtOAc
1,4-dioxane
tetramethylurea
1,2-DME
toluene
4
20
20
4
4
20
20
4
20
20
20
101
177
84
111
65
10
30
13
MeOH
0.98
30.0
[a] Reaction conditions: 0.1 m solution of 9, 1.0 equiv. of 1-methylpiperazine, and 3.0 equiv. of DIPEA, room temp., 4 or 20 h. [b]
1
Determined as percentage of the total H NMR intensity of 9, 2-isomer 24a, and 6-isomer 24b in the aromatic region.
effect of the 3-substituent, the Verloop B1 values would
suggest the steric effect of 3-phenylamino (B1 = 1.85) to be
higher than that of 3-morpholino (B1 = 1.76). The high
selectivity for the 2-isomer (Rsel = 0.96) of the 3-ethoxy
compound (10) compared with the moderate selectivity for
the 6-isomer (Rsel = 0.26) of the analogous 3-ethylthio com-
pound (14) is in line with their values of B1 (1.42 for ethoxy
vs. 1.85 for ethylthio).
For a given starting material, it appears that the regiose-
lectivity for the pyridine 2-position was slightly higher in
acetonitrile than in 1-methylpiperazine [Table 2, compare
conditions (a) with (b) or (c)] as the reaction medium. Con-
sequently, it was decided to investigate whether this appar-
ent solvent effect could be utilized to increase the regiose-
lectivity for either the 2- or 6-isomer. 3-Methoxycarbonyl
compound 9, which had shown only a moderate 3:1 selec-
tivity for the 2-isomer when allowed to react in acetonitrile,
was selected for this study. Thus, 9 was treated with 1-meth-
ylpiperazine in 21 different solvents; the results are listed in
Figure 2. Regioselectivity Rsel for the pyridine 2-position as a func-
tion of the solvatochromic β parameter in the reaction of methyl
2,6-dichloronicotinate (9) with 1-methylpiperazine in 21 different
Table 3.[36]
Data analysis based on the parameters in Table 3 showed
that the regioselectivity Rsel is linearly correlated with the
solvatochromic parameter β (R2 = 0.75, p = 4.6ϫ10–7; see
Figure 2).[38] Rsel is also linearly correlated with the boiling
point b.p. (R2 = 0.72) and Gutmann’s donor number DN
(R2 = 0.68); however, both b.p. and DN are cross-correlated
solvents (S1–S21). Labels indicate solvent numbers. Selected sol-
vents frequently used in synthesis are highlighted.
For the planning of syntheses it is noteworthy that the
with β (R2 = 0.46 and R2 = 0.68, respectively). A combina- regioselectivity could be controlled by choosing a solvent
tion of α, β, and π* in a linear free-energy relationship, as with a high or low β parameter. Thus, the highest selectivity
originally described by Kamlet and Taft,[37c] yielded accu- (16:1) for the 2-isomer (Rsel = 0.93–0.94) was obtained in
rate predictions of Rsel (RMSE = 0.047, R2 = 0.95, p = solvents such as 1,2-DCE and DCM with low β parameters.
1.9ϫ10–10), in line with the added mathematical complex- By the same reasoning, the highest selectivity (2:1) for the
ity, as summarized in Figure 3.
6-isomer (Rsel = 0.32–0.34) was obtained in solvents such
Eur. J. Org. Chem. 2012, 6940–6952
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6945

P. Bach, M. Marczynke, F. Giordanetto
FULL PAPER
that are bulky close to the pyridine ring directed the reac-
tion towards the 6-position.
Particularly useful in synthesis is the different regioselec-
tivity observed when the 3-substituent was carboxylic acid
or its precursors/derivatives, because these substituents are
interconvertible. Thus, to obtain the 2-isomer (9:1 ratio with
the 6-isomer), the 3-carboxylate and 3-amide substituents
would be preferred, whereas to obtain the 6-isomer (9:1 ra-
tio with the 2-isomer) the 3-cyano and 3-trifluoromethyl
substituents would be preferred. To gain a high regioselec-
tivity, these substituents would be preferred to 3-methyl, 3-
methoxycarbonyl, and 3-phenoxycarbonyl substituents.
The effect of solvent on the regioselectivity was also
studied in the reaction of methyl 2,6-dichloronicotinate
with 1-methylpiperazine. It was found that the regioselectiv-
ity is correlated with the ability of the solvent to function
as a hydrogen-bond acceptor, as expressed by the solvato-
chromic β parameter. Thus, the modest 3:1 regioselectivity
for the 2-isomer in acetonitrile (β = 0.40) could be increased
to 16:1 in DCM (β = 0.10) and switched to a selectivity of
2:1 for the 6-isomer in DMSO (β = 0.76) as the reaction
medium.
Figure 3. Prediction of the regioselectivity Rsel for the pyridine 2-
position based on the Kamlet–Taft equation: Rsel = 1.28990 +
0.03992α – 0.59417β – 0.46169π* (R2 = 0.95, p = 1.9ϫ10–10).
as N-methylimidazole and DMSO with high β parameters.
On this basis it seems that selectivity for nucleophilic attack
at the 2-position is most easily attained.[39] It is notable that
Experimental Section
General Methods: Commercial materials were used as provided by
common solvents frequently employed in synthesis, such as the commercial supplier without further purification. Reaction
glassware was oven-dried and purged with anhydrous nitrogen
prior to use. All reactions were performed under dry nitrogen.
Heating was performed in sealed vials in a microwave reactor
(Biotage Initiator, single node heating), and the reaction tempera-
ture was measured inside the vial. Solutions were concentrated in
vacuo with a rotary evaporator at temperatures Ͻ 50 °C. 1H NMR
spectra were recorded at 400, 500, or 600 MHz and 13C NMR spec-
tra at 101, 126, and 151 MHz with Varian UNITY plus 400, 500,
and 600 spectrometers. TMS was used as internal standard for
spectra recorded in CDCl3. Sodium 3-(trimethylsilyl)tetradeuter-
MeCN, EtOAc, acetone, and ethers (1,4-dioxane, 1,2-DME,
THF) gave only moderate regioselectivity.
The β parameter is a measure of a solvent’s hydrogen-
bond acceptor basicity, and solvents that are the weakest
hydrogen-bond acceptors have the lowest β values. The re-
gioselectivity for the 2-position in solvents with a low β pa-
rameter, that is, solvents that are weak hydrogen-bond ac-
ceptors (like DCM), can be tentatively explained by the for-
mation of a hydrogen bond between the 3-methoxycarbonyl
substituent on pyridine and the hydrogen atom of the sec- iopropionate was used as the internal standard for spectra recorded
in D2O. Otherwise, the NMR solvent was used as internal stan-
dard. Isolute phase separators from Biotage were used for extrac-
tions. Analytical TLC was performed on silica gel 60 F254 (Merck
KGaA, Darmstadt). Flash column chromatography was performed
on silica gel Merck grade 9385, 60 Å, from Sigma–Aldrich. Oasis
solid-phase extraction resins from Waters were used. Preparative
reversed-phase HPLC was performed at either acidic or basic pH.
HPLC at acidic pH was performed with a Kromasil C8 column
(10 μm; 250ϫ20 mm, i.d.) or a Kromasil C8 column (10 μm,
250ϫ50 mm i.d.) using linear gradients by increasing the ratio be-
tween mixtures of CH3CN in H2O/CH3CN/HCOOH (95:5:0.2) or
H2O/CH3CN/CH3COOH (95:5:0.2). HPLC at basic pH was car-
ried out with XBridge C18 columns (10 μm, 250ϫ19 mm i.d. or
10 μm, 250ϫ50 mm i.d.) using linear gradients by increasing the
ondary amine of 1-methylpiperazine. This could guide the
nucleophile to reaction at the 2-position. A similar effect
would be less effective in solvents with a high β parameter,
that is, solvents that are strong hydrogen-bond acceptors
(like DMSO), in which hydrogen bonds between the hydro-
gen atom of the secondary amine of 1-methylpiperazine and
the solvent could compete with a hydrogen bond to the 3-
methoxycarbonyl substituent.
Conclusions
A chemical design strategy has been used to study the
effect of the 3-substituent on the regioselectivity in the reac-
tions of 3-substituted 2,6-dichloropyridines with 1-methyl-
piperazine. Interestingly, the regioselectivity in this reaction
is not correlated with the lipophilicity (PI), size (MR), or
inductive effect (σp) of the 3-substituent, but is correlated
in a statistically significant manner with the Verloop steric
parameter B1, as indicated by the p value (0.006) for their
ratio between CH3CN and
a mixture of H2O/CH3CN/NH3
(95:5:0.2). HRMS was determined using an Agilent 6530 Accurate
Mass Q-TOF LC/MS spectrometer equipped with a Waters Acqu-
ity UPLC BEH C18 column (2.1 mmϫ50 mm, 1.7 μm particles) at
50 °C with a gradient of 4–95% MeCN in aqueous 40 mm NH3/
6 mm (NH4)2CO3 at pH = 10 over 6 min with a flow of 0.8 mL/
min. UV detection was carried out at 210 nm and mass detection
in the positive ionization mode (ESI+). Alternatively, HRMS was
relationship (R2 = 0.45). This implies that 3-substituents determined by GC–MS using an Agilent 6890N capillary gas chro-
6946
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© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 6940–6952

Regioselectivity in Nucleophilic Aromatic Substitution Reactions
matograph (15 m OB5-column, 0.25 mm i.d.ϫ0.25 μm film) cou-
pled to a GCT (Waters) mass spectrometer with electron-impact
ionization (70 eV) and lock mass [tris(trifluoromethyl)-s-triazine]
for internal mass calibration.
30 mL) was added, and the mixture was washed with DCM
(3ϫ20 mL). The organic phases were discarded, and the aq. phase
was acidified with HCl (1 m, 6 mL) and extracted with DCM
(3ϫ20 mL) and EtOAc (3ϫ20 mL). The combined organic phases
were dried (Na2SO4) and concentrated to give 2-{2-[(2,6-dichlo-
ropyridin-3-yl)amino]-2-oxoethoxy}acetic acid. Yield: 780 mg
2,6-Dichloro-3-methylpyridine (2): 2-Chloro-3-methylpyridine (31;
1.02 g, 8.00 mmol) was dissolved in chloroform (11.4 mL), and m-
CPBA (3.94 g, 16.0 mmol) was added at 0 °C. The reaction mixture
was stirred at room temp. for 18 h. Sodium pyrosulfite (4.56 g,
24.0 mmol) was added at 0 °C, and the mixture was stirred at room
temp. for 15 min. A saturated aq. solution of NaHCO3 was added
carefully (gas evolution) and the mixture extracted with DCM. The
combined organic phases were washed with a saturated aq. solution
of Na2CO3, and the combined aq. phases were extracted with
DCM. The combined organic phases were dried (Na2SO4) and con-
centrated. Yield: 0.991 g (86%) of 2-chloro-3-methylpyridine 1-ox-
ide (32). 1H and 13C NMR spectroscopic data were found to match
those cited in the literature.[40] Purity analysis: 99%. HRMS: calcd.
for C6H7ClNO 144.0216; found 144.0217. Compound 32 (0.991 g,
6.90 mmol) and TEA (1.44 mL, 10.35 mmol) were dissolved in
DCM (6.30 mL), and POCl3 (0.965 mL, 10.35 mmol) was added
dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 2 h
and then at room temp. for 3 h. Water (3 mL) and NaOH (6 m,
2.76 mL, 16.57 mmol) were added at 0 °C. The organic phase was
separated, and the aq. phase was extracted with DCM. The com-
bined organic phases were concentrated. The crude material was
purified by flash chromatography (5–40% EtOAc in heptane).
Yield: 0.201 g (18%). The product was formed as a mixture of 2,6-
dichloro-3-methylpyridine (2) and 2,4-dichloro-3-methylpyridine
(33) in a 6:1 ratio (by 1H NMR). The 6:1 mixture of 2 and 33
(145 mg, 0.89 mmol) in THF/MeOH (1:1, 6 mL) was added to Zn
powder (0.117 g, 1.79 mmol) in a microwave vial. A saturated aq.
solution of NH4Cl (3 mL) was added, and the reaction mixture was
stirred at room temp. for 45 min and then heated in a microwave
oven at 120 °C for 1 h. The material was extracted with DCM
(3ϫ8 mL), and the combined organic fractions were concentrated.
The crude material was purified by flash chromatography (EtOAc/
heptane gradient). Yield: 74 mg (62%, considering a purity of 83%
of the starting material). 1H NMR (400 MHz, CDCl3): δ = 7.52 (d,
J = 7.85 Hz, 1 H), 7.18 (d, J = 7.85 Hz, 1 H), 2.36 (s, 3 H) ppm.
13C NMR (101 MHz, CDCl3): δ = 150.4, 147.5, 141.5, 131.3, 122.9,
18.9 ppm. Purity analysis: Ͼ 99%. GC–HRMS (EI): calcd. for
C6H5Cl2N [M]+· 160.9799; found 160.9799.
1
(56%). H NMR (400 MHz, CDCl3): δ = 9.09 (s, 1 H), 8.74 (d, J
= 8.5 Hz, 1 H), 8.54 (br. s, 1 H), 7.29 (d, J = 8.5 Hz, 1 H), 4.34 (s,
2 H), 4.28 (s, 2 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 173.7,
168.2, 144.0, 138.9, 131.4, 130.2, 123.7, 70.8, 68.1 ppm. Purity
analysis: 99%. HRMS: calcd. for C9H9Cl2N2O4 [M
+
H]+
278.9939; found 278.9940. 2-{2-[(2,6-Dichloropyridin-3-yl)amino]-
2-oxoethoxy}acetic acid (698 mg, 2.50 mmol) was dissolved in
EtOAc (20.6 mL), and TEA (1.4 mL, 10.0 mmol) was added. 1-
Propanephosphonic acid cyclic anhydride (T3P; 3.0 mL, 5.0 mmol,
50% in EtOAc) was added at 0 °C. After 30 min, the reaction mix-
ture was stirred at room temp. for 16 h, and the mixture was
washed with water (3ϫ20 mL), dried (Na2SO4), and concentrated
to give 4-(2,6-dichloropyridin-3-yl)morpholine-3,5-dione. Yield:
507 mg (78%). 1H NMR (400 MHz, CDCl3): δ = 7.54 (d, J =
8.2 Hz, 1 H), 7.40 (d, J = 8.2 Hz, 1 H), 4.53 (s, 4 H) ppm. 13C
NMR (101 MHz, CDCl3): δ = 167.8, 151.0, 149.1, 141.2, 126.5,
124.0, 67.9 ppm. Purity analysis: 98%. HRMS: calcd. for
C9H7Cl2N2O3 [M
4-(2,6-Dichloropyridin-3-yl)morpholine-3,5-dione
+
H]+ 260.9834; found 260.9829.
(104 mg,
0.40 mmol) was dissolved in THF (0.80 mL) in a microwave vial,
and borane–THF (1 m, 1.2 mL, 1.20 mmol) was added. The vial
was sealed, and the reaction mixture was heated at 60 °C for 4 h.
The mixture was quenched with water (5 mL), and the aq. phase
was extracted with DCM (3ϫ5 mL). The combined organic phases
were concentrated, and the crude product was purified by flash
chromatography on silica gel (gradient: 8–50% EtOAc in heptane)
to yield compound 4. Yield: 81 mg (87%). 1H NMR (400 MHz,
CDCl3): δ = 7.29 (d, J = 8.30 Hz, 1 H), 7.22 (d, J = 8.30 Hz, 1 H),
3.86 (m, 4 H), 3.04 (m, 4 H) ppm. 13C NMR (151 MHz, CDCl3):
δ = 144.82, 144.75, 142.7, 130.4, 123.4, 66.8, 51.1 ppm. Purity
analysis: 99%. HRMS: calcd. for C9H11Cl2N2O [M
233.0248; found 233.0252.
+
H]+
2,6-Dichloronicotinonitrile (5): 2,6-Dichloronicotinamide (12;
460 mg, 2.41 mmol) was dissolved in THF (10 mL). POCl3
(0.449 mL, 4.82 mmol) was added, and the reaction mixture was
heated at 100 °C for 18 h. The mixture was concentrated and redis-
solved in DCM. The solution was washed with NaHCO3 (10% aq.
solution), water, and brine, dried (Na2SO4), and concentrated. The
crude product was purified by reversed-phase preparative HPLC.
Yield after freeze drying: 125 mg (30%). 1H NMR (400 MHz,
CDCl3): δ = 7.94 (d, J = 8.10 Hz, 1 H), 7.43 (d, J = 8.12 Hz, 1 H)
ppm. 13C NMR (101 MHz, CDCl3): δ = 154.3, 152.2, 144.0, 123.2,
113.7, 109.3 ppm. Purity analysis: 99.6%. HRMS: calcd. for
C6HCl2N2 [M – H]– 170.9522; found 170.952.
4-(2,6-Dichloropyridin-3-yl)-N,N-dimethylaniline (3): 2,6-Dichloro-
3-iodopyridine (34; 1.51 g, 5.50 mmol) was dissolved in water/diox-
ane (1:3, 45 mL). [4-(Dimethylamino)phenyl]boronic acid (910 mg,
5.50 mmol), LiCl (350 mg, 8.25 mmol), Ba(OH)2·8H2O (0.80 mL,
5.50 mmol), and [Pd(Ph3P)4] (640 mg, 0.55 mmol) were added, and
the reaction mixture was stirred at 95 °C for 2 h. The mixture was
quenched with 10% NaCO3 and extracted with DCM. The organic
phase was washed with brine and water, dried with Na2SO4, and
concentrated. The crude product was purified by reversed-phase
preparative HPLC. Yield after freeze drying: 180 mg (12%) as a
Phenyl 2,6-Dichloronicotinate (7): 2,6-Dichloronicotinic acid (11;
2.016 g, 10.5 mmol) was dissolved in DCM (25 mL). (COCl)2
(1.19 mL, 12.60 mmol) and DMF (0.081 mL, 1.05 mmol) were
added, and the reaction mixture was stirred at room temp. for 2 h.
The mixture was concentrated and co-concentrated twice with
DCM. PhOH (0.934 mL, 10.50 mmol), pyridine (1.274 mL,
15.75 mmol), and DMAP (0.128 g, 1.05 mmol) were dissolved in
DCM (5 mL) and stirred at room temp. for 3 min. The crude acyl
chloride dissolved in DCM (20 mL) was added to this solution at
room temp. The reaction mixture was heated at reflux for 16 h and
then cooled to room temp. Water (20 mL) was added, and the or-
ganic phase was separated, washed with water and brine, filtered,
and concentrated. The crude product was purified by reversed-
1
light-brown solid. H NMR (400 MHz, CDCl3): δ = 7.61 (d, J =
7.99 Hz, 1 H), 7.35–7.30 (m, 2 H), 7.28 (d, J = 7.99 Hz, 1 H), 6.79–
6.74 (m, 2 H), 3.01 (s, 6 H) ppm. 13C NMR (101 MHz, CDCl3): δ
= 150.4, 148.5, 147.5, 141.5, 135.9, 130.1, 123.5, 123.0, 111.8,
40.3 ppm. Purity analysis: 92%. HRMS: calcd. for C13H13Cl2N2
[M + H]+ 267.0450; found 267.0458.
4-(2,6-Dichloropyridin-3-yl)morpholine (4): A mixture of 3-amino-
2,6-dichloropyridine (1; 815 mg, 5.0 mmol) and 1,4-dioxane-2,6-di-
one (677 mg, 5.25 mmol) in MeCN (12.5 mL) was heated in a mi-
crowave oven at 100 °C for 2 h. Phosphate buffer (0.2 m, pH = 7,
Eur. J. Org. Chem. 2012, 6940–6952
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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6947

P. Bach, M. Marczynke, F. Giordanetto
FULL PAPER
phase preparative HPLC. Yield after freeze drying: 2.161 g (77%).
1H NMR (400 MHz, CDCl3): δ = 8.32 (d, J = 8.15 Hz, 1 H), 7.41
(d, J = 8.39 Hz, 1 H), 7.47–7.38 (m, 2 H), 7.32–7.25 (m, 1 H), 7.24–
warmed up and allowed to react at room temp. for 1.5 h. The reac-
tion was quenched by the slow addition of water (10 mL). The mix-
ture was cooled to 0 °C, and the aq. layer was acidified to pH = 4
7.19 (m, 2 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 162.0, 153.5, by the dropwise addition of 6 m HCl. The mixture was extracted
150.2, 142.9, 129.6, 126.5, 124.6, 123.0, 121.3 ppm. Purity analysis:
99.9%. HRMS: calcd. for C12H8Cl2NO2 [M + H]+ 267.9927; found
267.9934.
with ethyl acetate (3ϫ10 mL). The combined organic phases were
dried (Na2SO4) and concentrated. This gave 1.419 g of a crude in-
termediate that contained the 3- and 4-SH isomers in a 1:1 ratio
and some disulfides as well. NOTE: This crude intermediate dimer-
ized completely at room temp. within 24 h and should be used di-
rectly in the next step. A solution of the intermediate (0.979 g,
5.44 mmol) in DMF (17.6 mL) at 0 °C was treated with K2CO3
(1.127 g, 8.16 mmol) and EtI (0.526 mL, 6.52 mmol), and the reac-
tion mixture was stirred at room temp. for 16 h. Water (10 mL) was
added, and the mixture was extracted with DCM. The organic
phase was concentrated. The residue was difficult to purify, but was
carried out by preparative HPLC on a Kromasil C8 column (10 μm
250ϫ50 mm i.d.). Gradient: 42–52% MeCN in H2O/MeCN/
2,6-Dichloro-N,N-dimethylpyridine-3-sulfonamide (8): 2,6-Dichloro-
pyridine-3-sulfonyl chloride (36; 493 mg, 2.00 mmol) and TEA
(0.335 mL, 2.40 mmol) were dissolved in THF (20 mL) and the
solution was cooled to 0 °C. HN(CH3)2 (0.078 mL, 2.40 mmol) was
added, and the reaction mixture was stirred at room temp. for 16 h.
The mixture was filtered and the filtrate washed with a saturated
aq. solution of NH4Cl, brine, and water, dried (Na2SO4), and con-
1
centrated. Yield: 343 mg (67%). H NMR (400 MHz, CDCl3): δ =
8.25 (d, J = 8.17 Hz, 1 H), 7.39 (d, J = 8.18 Hz, 1 H), 2.87 (s, 6 H)
ppm. 13C NMR (101 MHz, CDCl3): δ = 153.4, 147.9, 143.2, 132.9,
123.3, 37.6 ppm. Purity analysis: 98.3%. HRMS: calcd. for
C7H9Cl2N2O2S [M + H]+ 254.9756; found 254.9766.
1
HCO2H (95:5:0.2). Yield: 0.160 g (15% over two steps). H NMR
(500 MHz, CDCl3): δ = 7.49 (d, J = 8.20 Hz, 1 H), 7.23 (d, J =
8.20 Hz, 1 H), 2.96 (q, J = 7.40 Hz, 2 H), 1.38 (t, J = 7.40 Hz, 3
H) ppm. 13C NMR (101 MHz, CDCl3): δ = 147.5, 145.7, 137.2,
133.6, 123.0, 26.3, 13.3 ppm. Purity analysis: 96%. HRMS: calcd.
for C7H8Cl2NS [M + H]+ 207.9749; found 207.9740.
Methyl 2,6-Dichloronicotinate (9): 2,6-Dichloronicotinic acid (11;
5.76 g, 30.0 mmol) was dissolved in DCM (80 mL). (COCl)2
(3.15 mL, 36.0 mmol) and then DMF (0.232 mL, 3.00 mmol) were
added at room temp. The reaction mixture was stirred at room
temp. for 2 h. MeOH (36.4 mL, 900 mmol) was added, and stirring
at room temp. was continued for 16 h. The mixture was concen-
trated, and the crude material was purified by flash chromatog-
2,6-Dichloro-N-phenylpyridin-3-amine (15): 2,6-Dichloro-3-iodo-
pyridine (34; 274 mg, 1.0 mmol), aniline (0.48 mL, 5.0 mmol), and
sodium tert-butoxide (144 mg, 1.50 mmol) were mixed. A solution
of BINAP (47 mg, 0.08 mmol) and [Pd2(dba)3] (23 mg, 0.03 mmol)
in 1,4-dioxane (10 mL) was added, and the reaction mixture was
heated at 100 °C for 16 h. The mixture was concentrated, dissolved
in DCM, and filtered through silica. The solution was washed with
NaHCO3 (5% aq. solution), brine, and water, dried with Na2SO4,
and concentrated. The crude product was purified by reversed-
phase preparative HPLC. Yield after freeze-drying: 0.110 g (46%)
as a brown oil. 1H NMR (400 MHz, CDCl3): δ = 7.44 (d, J =
8.54 Hz, 1 H), 7.40–7.32 (m, 2 H), 7.16–7.10 (m, 3 H), 7.08 (d, J
= 8.48 Hz, 1 H), 6.10 (s, 1 H) ppm. 13C NMR (101 MHz, CDCl3):
1
raphy (5–40% EtOAc in heptane). Yield: 5.34 g (86%). H NMR
(400 MHz, CDCl3): δ = 8.20 (d, J = 8.10 Hz, 1 H), 7.42 (d, J =
8.10 Hz, 1 H), 3.97 (s, 3 H) ppm. 13C NMR (101 MHz, CDCl3): δ =
163.5, 152.5, 149.3, 142.3, 124.8, 122.7, 52.7 ppm. Purity analysis:
99.9%. HRMS: calcd. for C7H6Cl2NO2 [M + H]+ 205.977; found
205.9769.
2,6-Dichloro-3-ethoxypyridine (10): 2,6-Dichloropyridin-3-ol (37;
120 mg, 0.73 mmol) was dissolved in DMF (5 mL). K2CO3
(152 mg, 1.10 mmol) and EtBr (0.164 mL, 2.20 mmol) were added,
and the reaction mixture was stirred at room temp. for 16 h. Water
(5 mL) was added, and the organic phase was separated, washed
with water and brine, concentrated, and co-concentrated twice with
DCM. Yield: 141 mg (89%). 1H NMR (400 MHz, CDCl3): δ = 7.21
(d, J = 8.45 Hz, 1 H), 7.18 (d, J = 8.47 Hz, 1 H), 4.11 (q, J =
6.99 Hz, 2 H), 1.49 (t, J = 6.99 Hz, 3 H) ppm. 13C NMR (101 MHz,
CDCl3): δ = 150.5, 139.8, 139.6, 123.3, 122.8, 65.5, 14.5 ppm. Pu-
rity analysis: Ͼ 99%. HRMS: calcd. for C7H8Cl2NO [M + H]+
191.9977; found 191.9977.
δ
= 139.7, 138.2, 137.0, 136.5, 129.8, 124.3, 123.8, 123.4,
121.3 ppm. Purity analysis: 97%. HRMS: calcd. for C11H9Cl2N2
[M + H]+ 239.0137; found 239.0144.
6-Chloro-2-(4-methylpiperazin-1-yl)pyridin-3-amine (16a): Com-
pound 1 (33 mg, 0.20 mmol) was dissolved in 1-methylpiperazine
(1.2 mL, 10.78 mmol). The reaction mixture was heated at 170 °C
for 3 h. The mixture was concentrated, and the compound was
purified by preparative HPLC. The relevant fractions were pooled
and concentrated. A 1 m NaOH solution was added, and the sub-
stance was extracted with DCM. The organic phase was concen-
2,6-Dichloronicotinamide (12): 2,6-Dichloronicotinoyl chloride (35;
4.21 g, 20.0 mmol) was dissolved in 1,4-dioxane (8.0 mL) and
added to NH4OH (100 mL, ca. 25% aq. solution) at 0 °C. The
reaction mixture was stirred at 0 °C for 75 min and then vacuum-
filtered. The solids were washed with water. Yield: 2.054 g (54%).
1H NMR (400 MHz, [D6]DMSO): δ = 8.06 (br. s, 1 H), 7.97 (d, J
= 7.97 Hz, 1 H), 7.83 (br. s, 1 H), 7.63 (d, J = 7.96 Hz, 1 H) ppm.
13C NMR (101 MHz, [D6]DMSO): δ = 166.1, 149.1, 145.8, 141.1,
132.7, 123.7 ppm. Purity analysis: Ͼ 99%. HRMS: calcd. for
C6H5Cl2N2O [M + H]+ 190.9773; found 190.9771.
1
trated. Yield: 5 mg (11%). H NMR (600 MHz, CDCl3): δ = 6.89
(d, J = 8.06 Hz, 1 H), 6.81 (d, J = 8.06 Hz, 1 H), 3.70 (br. s, 2 H),
3.16 (br. s, 4 H), 2.56 (br. s, 4 H), 2.34 (s, 3 H) ppm. 13C NMR
(126 MHz, CDCl3): δ = 150.4, 137.6, 133.9, 124.3, 118.6, 55.3, 48.2,
46.27, 46.23 ppm. Purity analysis: 98%. HRMS: calcd. for
C10H16ClN4 [M + 1]+ 227.1058; found 227.1053.
1-(6-Chloro-3-methylpyridin-2-yl)-4-methylpiperazine (17a): Pre-
pared according to the procedure used for the synthesis of 16a from
2,6-Dichloro-3-(ethylthio)pyridine
(14):
Diisopropylamine
2
(24 mg, 0.15 mmol) and 1-methylpiperazine (0.89 mL,
(1.069 mL, 7.50 mmol) was dissolved in THF (5 mL) and cooled
to –40 °C. nBuLi (3.00 mL, 7.50 mmol) was added dropwise, and
the reaction mixture was stirred at –40 °C for 20 min. Then the
mixture was cooled to –80 °C, and 2,6-dichloropyridine (38;
1.110 g, 7.5 mmol) in THF (3.5 mL) was added dropwise. The reac-
tion mixture was stirred at this temperature for 1 h. Sulfur (0.240 g,
7.50 mmol) was then added in three portions. The mixture was
8.00 mmol) with heating at 150 °C for 1 h. Yield: 5 mg (15%) as a
yellow oil. H NMR (500 MHz, CDCl3): δ = 7.31 (d, J = 8.32 Hz,
1
1 H), 6.81 (d, J = 8.32 Hz, 1 H), 3.22 (m, 4 H), 2.56 (m, 4 H), 2.35
(s, 3 H), 2.23 (s, 3 H) ppm. 13C NMR (151 MHz, CDCl3): δ =
161.2, 146.3, 141.7, 122.3, 116.9, 55.2, 49.1, 46.2, 18.1 ppm. Purity
analysis: 98%. HRMS: calcd. for C11H17ClN3 [M + H]+ 226.1106;
found 226.1095.
6948
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© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 6940–6952

Regioselectivity in Nucleophilic Aromatic Substitution Reactions
1-(6-Chloro-5-methylpyridin-2-yl)-4-methylpiperazine (17b): From
the batch of 17a was isolated the regioisomer 17b. Relevant frac-
tions were pooled and concentrated. A 1 m NaOH solution was
added, and the substance was extracted with DCM. Yield: 10 mg
268.5 Hz), 112.2 (q, JC-C-F = 33 Hz), 103.1, 54.6, 46.1, 44.6 ppm.
Purity analysis: 98.1 %. HRMS: calcd. for C11H14ClF3N3
[M + 1]+ 280.0823; found 280.0834.
Phenyl 2-Chloro-6-(4-methylpiperazin-1-yl)nicotinate (22b): Com-
pound 7 (54 mg, 0.20 mmol) was dissolved in MeCN (2.0 mL), and
DIPEA (0.105 mL, 0.60 mmol) and 1-methylpiperazine (0.022 mL,
0.20 mmol) were added. The reaction mixture was stirred at room
temp. for 24 h. The reaction mixture was concentrated and the
compound purified by preparative HPLC. A 10 % solution of
Na2CO3 was added, and the substance was extracted with DCM.
1
(30%). H NMR (500 MHz, CDCl3): δ = 7.32 (d, J = 7.68 Hz, 1
H), 6.47 (d, J = 7.67 Hz, 1 H), 3.51 (m, 4 H), 2.51 (m, 4 H), 2.35
(s, 3 H), 2.23 (s, 3 H) ppm. 13C NMR (151 MHz, CDCl3): δ =
157.7, 149.0, 140.9, 119.8, 105.2, 54.8, 46.2, 45.3, 18.3 ppm. Purity
analysis: 98%. HRMS: calcd. for C11H17ClN3 [M + H]+ 226.1106;
found 226.1105.
1
4-[2-Chloro-6-(4-methylpiperazin-1-yl)pyridin-3-yl]-N,N-dimethyl-
aniline (18a): Prepared according to the procedure used for the syn-
thesis of 16a from 3 (27 mg, 0.10 mmol) and 1-methylpiperazine
(0.60 mL, 5.40 mmol) with heating at 170 °C for 50 min. Yield:
Yield: 33 mg (42%) as a yellow oil. H NMR (400 MHz, CDCl3):
δ = 8.22 (d, J = 8.90 Hz, 1 H), 7.44–7.38 (m, 2 H), 7.28–7.22 (m,
1 H), 7.22–7.17 (m, 2 H), 6.54 (d, J = 8.90 Hz, 1 H), 3.76 (m, 4
H), 2.56 (m, 4 H), 2.38 (s, 3 H) ppm. 13C NMR (151 MHz, CDCl3):
10 mg (30%). 1H NMR (600 MHz, CDCl3): δ = 7.46 (d, J = δ = 162.9, 159.0, 151.4, 150.8, 142.6, 129.4, 125.8, 121.8, 111.5,
8.40 Hz, 1 H), 7.31 (d, J = 8.60 Hz, 2 H), 6.76 (d, J = 8.72 Hz, 2
H), 6.58 (d, J = 8.40 Hz, 1 H), 3.59 (m, 4 H), 2.99 (s, 6 H), 2.53
(m, 4 H), 2.36 (s, 3 H) ppm. 13C NMR (151 MHz, CDCl3): δ =
157.4, 149.7, 147.3, 141.1, 130.1, 126.0, 125.3, 111.9, 105.2, 54.7,
46.1, 44.9, 40.5 ppm. Purity analysis: 83%. HRMS: calcd. for
C18H24ClN4 [M + 1]+ 331.1684; found 331.1683.
103.5, 54.6, 46.1, 44.6 ppm. Purity: 97 %. HRMS: calcd. for
C17H19ClN3O2 [M + 1]+ 332.1160; found 332.1173.
6-Chloro-N,N-dimethyl-2-(4-methylpiperazin-1-yl)pyridine-3-sulfon-
amide (23a): Compound 8 (51 mg, 0.20 mmol) was dissolved in
MeCN (2.0 mL), and DIPEA (0.105 mL, 0.60 mmol) and 1-meth-
ylpiperazine (0.022 mL, 0.20 mmol) were added. The reaction mix-
4-[6-Chloro-2-(4-methylpiperazin-1-yl)pyridin-3-yl]morpholine (19a): ture was stirred at room temp. for 24 h. The reaction mixture was
Prepared according to the procedure used for the synthesis of 16a
from 4 (35 mg, 0.15 mmol) and 1-methylpiperazine (0.900 mL,
concentrated, and the compound was purified by preparative
HPLC. Relevant fractions were pooled and concentrated. A 1 m
5.4 mmol) with heating at 160 °C for 1 h. Yield: 12 mg (27%) as a
yellow oil. H NMR (400 MHz, CDCl3): δ = 7.04 (d, J = 8.08 Hz, DCM. Yield: 7 mg (11%). H NMR (600 MHz, CDCl3): δ = 8.01
NaOH solution was added, and the substance was extracted with
1
1
1 H), 6.79 (d, J = 8.08 Hz, 1 H), 3.83 (m, 4 H), 3.55 (br. m, 4 H),
3.03 (m, 4 H), 2.52 (br. m, 4 H), 2.34 (s, 3 H) ppm. 13C NMR
(101 MHz, CDCl3): δ = 153.3, 141.6, 136.3, 127.5, 116.0, 67.0, 55.2,
49.0, 46.6, 46.2 ppm. Purity analysis: 95%. HRMS: calcd. for
C14H22ClN4O [M + 1]+ 297.1482; found 297.1477.
(d, J = 8.15 Hz, 1 H), 6.97 (d, J = 8.19 Hz, 1 H), 3.47 (m, 4 H),
2.77 (s, 6 H), 2.56 (m, 4 H), 2.34 (s, 3 H) ppm. 13C NMR
(101 MHz, CDCl3): δ = 160.0, 152.4, 143.1, 122.3, 116.9, 54.8, 51.5,
46.1, 38.1 ppm. Purity analysis: 96.7 %. HRMS: calcd. for
C12H20ClN4O2S [M + 1]+ 319.099; found 319.1004.
4-[2-Chloro-6-(4-methylpiperazin-1-yl)pyridin-3-yl]morpholine (19b): 2-Chloro-N,N-dimethyl-6-(4-methylpiperazin-1-yl)pyridine-3-sulfon-
From the batch of 19a was isolated the regioisomer 19b. Relevant
fractions were pooled and concentrated. A 1 m NaOH solution was
added, and the substance was extracted with DCM. Yield: 8 mg
amide (23b): From the batch of 23a was isolated the regioisomer.
Relevant fractions were pooled and concentrated. A 1 m NaOH
solution was added, and the substance was extracted with DCM.
1
1
(17%) as a yellow oil. H NMR (400 MHz, CDCl3): δ = 7.26 (d, J
Yield: 15 mg (24%). H NMR (500 MHz, CDCl3): δ = 8.02 (d, J
= 8.65 Hz, 1 H), 6.52 (d, J = 8.65 Hz, 1 H), 3.84 (m, 4 H), 3.48 = 8.89 Hz, 1 H), 6.50 (d, J = 8.96 Hz, 1 H), 3.69 (m, 4 H), 2.87 (s,
(m, 4 H), 2.93 (m, 4 H), 2.50 (m, 4 H), 2.33 (s, 3 H) ppm. 13C
NMR (101 MHz, CDCl3): δ = 155.3, 144.5, 135.7, 131.1, 105.5,
67.2, 54.7, 51.9, 46.2, 45.4 ppm. Purity analysis: 99%. HRMS:
calcd. for C14H22ClN4O [M + 1]+ 297.1482; found 297.1492.
6 H), 2.49 (m, 4 H), 2.35 (s, 3 H) ppm. 13C NMR (101 MHz,
CDCl3): δ = 159.0, 147.8, 142.4, 119.2, 103.2, 54.5, 46.1, 44.6,
37.5 ppm. Purity analysis: 97.1%. Contained 1.4% of the isomer.
HRMS: calcd. for C12H20ClN4O2S [M + 1]+ 319.0990; found
319.1000.
2-Chloro-6-(4-methylpiperazin-1-yl)nicotinonitrile (20b): Prepared
according to the procedure used for the synthesis of 16a from 5
(0.017 g, 0.10 mmol) and 1-methylpiperazine (0.011 mL,
Methyl 6-Chloro-2-(4-methylpiperazin-1-yl)nicotinate (24a): Com-
pound 9 (0.206 g, 1.0 mmol) was dissolved in pyridine (9.36 mL),
0.10 mmol) with heating at 120 °C for 20 min. Yield: 6 mg (25%). and 1-methylpiperazine (0.111 mL, 1.0 mmol) and DIPEA
1H NMR (500 MHz, CDCl3): δ = 7.58 (d, J = 8.86 Hz, 1 H), 6.49
(0.524 mL, 3.0 mmol) were added. The reaction mixture was stirred
(d, J = 8.88 Hz, 1 H), 3.70 (m, 4 H), 2.49 (m, 4 H), 2.34 (s, 3 H) at room temp. for 3.5 h. The reaction mixture was concentrated,
ppm. 13C NMR (151 MHz, CDCl3): δ = 158.7, 152.4, 142.3, 116.7,
and the crude material purified by preparative HPLC. Relevant
103.9, 95.7, 54.5, 46.1, 44.6 ppm. Purity analysis: 99.1%. HRMS: fractions were pooled and concentrated. A 10% aq. solution of
calcd. for C11H14ClN4 [M + 1]+ 237.0902; found 237.0907.
Na2CO3 (3 mL) was added, and the material was extracted with
DCM (3ϫ3 mL). Yield: 110 mg (41%) as a yellow oil. H NMR
1
1-[6-Chloro-5-(trifluoromethyl)pyridin-2-yl]-4-methylpiperazine
(21b): Compound 6 (0.022 g, 0.10 mmol) was dissolved in MeCN
(1 mL) and 1-methylpiperazine (0.011 mL, 0.10 mmol) and DIPEA
(0.052 mL, 0.30 mmol) were added. The reaction mixture was
heated at 120 °C for 20 min. The reaction mixture was concen-
trated, and the crude product was purified by preparative HPLC.
Relevant fractions were pooled and concentrated. A 1 m NaOH
solution was added, and the substance was extracted with DCM.
(500 MHz, CDCl3): δ = 7.91 (d, J = 7.98 Hz, 1 H), 6.68 (d, J =
7.99 Hz, 1 H), 3.86 (s, 3 H), 3.48 (m, 4 H), 2.50 (m, 4 H), 2.33 (s,
3 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 167.0, 158.6, 151.9,
143.4, 113.1, 110.9, 54.9, 52.2, 48.9, 46.1 ppm. Purity analysis: Ͼ
99%. HRMS: calcd. for C12H17ClN3O2 [M + 1]+ 270.1009; found
270.1008.
Methyl 2-Chloro-6-(4-methylpiperazin-1-yl)nicotinate (24b): From
the batch of 24a was isolated the regioisomer 24b. Relevant frac-
1
Yield: 7 mg (25%) as a yellow oil. H NMR (600 MHz, CDCl3): δ
= 7.66 (d, J = 8.79 Hz, 1 H), 6.48 (d, J = 8.79 Hz, 1 H) 3.66 (m, 4 tions were pooled and concentrated. A 10% solution of Na2CO3
H), 2.49 (m, 4 H), 2.34 (s, 3 H) ppm. 13C NMR (151 MHz, CDCl3): (3 mL) was added, and the substance was extracted with DCM
δ = 159.2, 147.6, 137.5 (q, JC-C-C-F = 4.5 Hz), 123.3 (q, JC-F
=
(3ϫ3 mL). Yield: 78 mg (29%) as
a
yellow oil. 1H NMR
Eur. J. Org. Chem. 2012, 6940–6952
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org 6949

P. Bach, M. Marczynke, F. Giordanetto
FULL PAPER
(500 MHz, CDCl3): δ = 8.03 (d, J = 8.79 Hz, 1 H), 6.48 (d, J =
8.75 Hz, 1 H), 3.87 (s, 3 H), 3.68 (m, 4 H), 2.48 (m, 4 H), 2.34 (s,
3 H) ppm. 13C NMR (151 MHz, CDCl3): δ = 164.9, 158.9, 150.4,
142.2, 112.4, 103.5, 54.6, 52.0, 46.1, 44.5 ppm. Purity analysis: Ͼ
99%. HRMS: calcd. for C12H17ClN3O2 [M + 1]+ 270.1009; found
270.0995.
added, and the substance was extracted with DCM. Yield: 9 mg
(8%). 1H NMR (500 MHz, CDCl3): δ = 7.58 (d, J = 8.76 Hz, 1 H),
6.41 (d, J = 8.79 Hz, 1 H), 3.54 (m, 4 H), 2.48 (m, 4 H), 2.33 (s, 3
H) ppm. 13C NMR (151 MHz, CDCl3): δ = 157.5, 148.1, 142.8,
106.3, 104.9, 54.6, 46.2, 44.9 ppm. Purity analysis: Ͼ 99%. HRMS:
calcd. for C10H14BrClN3 [M + H]+ 290.0060; found 290.0064.
1-(6-Chloro-3-ethoxypyridin-2-yl)-4-methylpiperazine (25a): Pre-
pared according to the procedure used for the synthesis of 16a from
10 (19 mg, 0.10 mmol) and 1-methylpiperazine (0.6 mL, 5.4 mmol)
with heating at 170 °C for 1 h. Yield: 12 mg (47%) as a yellow oil.
1H NMR (500 MHz, CDCl3): δ = 6.95 (d, J = 8.17 Hz, 1 H), 6.73
(d, J = 8.11 Hz, 1 H), 4.01 (q, J = 6.95 Hz, 2 H), 3.51 (m, 4 H),
2.54 (m, 4 H), 2.34 (s, 3 H), 1.44 (t, J = 6.89 Hz, 3 H) ppm. 13C
NMR (151 MHz, CDCl3): δ = 151.3, 144.5, 139.2, 121.6, 115.1,
64.5, 55.0, 47.7, 46.2, 14.8 ppm. Purity analysis: 96.5%. HRMS:
calcd. for C12H19ClN3O [M + 1]+ 256.1211; found 256.122.
1-[6-Chloro-3-(ethylthio)pyridin-2-yl]-4-methylpiperazine
(29a):
Compound 14 (21 mg, 0.10 mmol) was dissolved in 1-methylpiper-
azine (0.60 mL, 5.40 mmol) in a microwave vial. The reaction mix-
ture was heated in a microwave oven at 80 °C for 2 min, and the
compound was purified by preparative HPLC. Relevant fractions
were pooled and concentrated. A 10% solution of Na2CO3 was
added, and the substance was extracted with DCM. Yield: 2 mg
1
(8%) as a yellow oil. H NMR (500 MHz, CDCl3): δ = 7.40 (d, J
= 7.97 Hz, 1 H), 6.85 (d, J = 7.94 Hz, 1 H), 3.40 (m, 4 H), 2.90 (q,
J = 7.35 Hz, 2 H), 2.57 (m, 4 H), 2.35 (s, 3 H), 1.30 (t, J = 7.35 Hz,
3 H) ppm. 13C NMR (151 MHz, CDCl3): δ = 159.5, 145.9, 139.2,
122.5, 117.1, 55.0, 48.9, 46.2, 26.5, 13.8 ppm. Purity analysis: 92%.
HRMS: calcd. for C12H19ClN3S [M + H]+ 272.0983; found
272.0977.
6-Chloro-2-(4-methylpiperazin-1-yl)nicotinic Acid (26a):[41] Com-
pound 24a (13 mg, 0.05 mmol) was dissolved in MeOH (0.25 mL),
and LiOH·H2O (21 mg, 0.50 mmol) was added. The reaction mix-
ture was heated in a microwave oven at 80 °C for 20 min. The crude
product was purified by solid-phase extraction (Oasis MCX,
500 mg) and eluted with 5% NH4OH. Yield: 7 mg (55%). 1H NMR
[600 MHz, 18% DCl in D2O, (CH3)3Si(CD2)2COONa]: δ = 8.32
(d, J = 8.23 Hz, 1 H), 7.28 (d, J = 8.20 Hz, 1 H), 3.99 (app. d, J =
14.55 Hz, 2 H), 3.72 (app. d, J = 12.59 Hz, 2 H), 3.57 (app. t, J =
12.56 Hz, 2 H), 3.40 (app. t, J = 12.46 Hz, 2 H), 3.04 (s, 3 H) ppm.
Purity analysis: 96%. HRMS: calcd. for C11H15ClN3O2 [M + 1]+
256.0853; found 256.0852.
1-[6-Chloro-5-(ethylthio)pyridin-2-yl]-4-methylpiperazine
(29b):
From the batch of 29a was isolated the regioisomer. Relevant frac-
tions were pooled and concentrated. A 1 m NaOH solution was
added and the substance was extracted with DCM. Yield: 2 mg
1
(8%) as a yellow oil. H NMR (400 MHz, CDCl3): δ = 7.56 (d, J
= 8.55 Hz, 1 H), 6.48 (d, J = 8.57 Hz, 1 H), 3.57 (m, 4 H), 2.82 (q,
J = 7.35 Hz, 3 H) 2.51 (m, 4 H), 2.35 (s, 3 H), 1.23 (t, J = 7.35 Hz,
3 H) ppm. 13C NMR (151 MHz, CDCl3): δ = 157.8, 152.2, 144.4,
116.6, 105.2, 54.6, 46.1, 44.8, 28.9, 14.4 ppm. Purity analysis:
96.5%. HRMS: calcd. for C12H19ClN3S [M + H]+ 272.0983; found
272.0978.
2-Chloro-6-(4-methylpiperazin-1-yl)nicotinic Acid (26b): Prepared
from 24b (10 mg, 0.04 mmol) by the procedure of 26a. Yield: 9 mg
(95%). 1H NMR [500 MHz, 18% DCl in D2O, (CH3)3Si(CD2)2CO-
ONa]: δ = 8.08 (d, J = 8.82 Hz, 1 H), 6.83 (d, J = 8.82 Hz, 1 H),
4.52 (app. d, J = 14.88 Hz, 2 H), 3.65 (app. d, J = 12.41 Hz, 2 H),
3.39 (app. t, J = 13.51 Hz, 2 H), 3.19 (app. t, J = 12.47 Hz, 2
H), 2.97 (s, 3 H) ppm. Purity analysis: 95%. HRMS: calcd. for
C11H15ClN3O2 [M + 1]+ 256.0853; found 256.0859.
6-Chloro-2-(4-methylpiperazin-1-yl)-N-phenylpyridin-3-amine (30a):
Prepared according to the procedure used for the synthesis of 16a
from 15 (24 mg, 0.10 mmol) and 1-methylpiperazine (0.60 mL,
5.4 mmol) with heating at 160 °C for 1 h. Yield: 12 mg (40%) as a
1
yellow oil. H NMR (500 MHz, CDCl3): δ = 7.45 (d, J = 8.20 Hz,
1 H), 7.36–7.28 (m, 2 H), 7.08–6.97 (m, 3 H), 6.86 (d, J = 8.20 Hz,
1 H), 5.80 (s, 1 H), 3.22 (m, 4 H), 2.57 (m, 4 H), 2.36 (s, 3 H) ppm.
13C NMR (125 MHz, CDCl3): δ = 152.5, 141.6, 139.3, 130.9, 129.6,
124.3, 122.0, 118.6, 118.4, 55.2, 48.6, 46.1 ppm. Purity analysis:
98.7%. HRMS: calcd. for C16H20ClN4 [M + 1]+ 303.1371; found
303.1383.
6-Chloro-2-(4-methylpiperazin-1-yl)nicotinamide (27a): A mixture of
compound 12 (57 mg, 0.30 mmol), 1-methylpiperazine (0.033 mL,
0.30 mmol), and DIPEA (0.16 mL, 0.90 mmol) in MeCN (2.8 mL)
was heated at 80 °C for 30 min. The mixture was concentrated and
purified by preparative HPLC. Relevant fractions were pooled and
concentrated. A 10% solution of Na2CO3 was added, and the sub-
stance was extracted with DCM. Yield: 31 mg (41%) as a colorless
2-Chloro-6-(4-methylpiperazin-1-yl)-N-phenylpyridin-3-amine (30b):
From the batch of 30a was isolated the regioisomer. Relevant frac-
tions were pooled and concentrated. A 1 m NaOH solution was
added, and the substance was extracted with DCM. Yield: 10 mg
1
oil. H NMR (400 MHz, MeOD): δ = 7.84 (d, J = 7.88 Hz, 1 H),
6.93 (d, J = 7.88 Hz, 1 H), 4.89 (s, 2 H), 3.45 (m, 4 H), 2.61 (m, 4
H), 2.37 (s, 3 H) ppm. 13C NMR (101 MHz, MeOD): δ = 172.3,
159.8, 151.9, 142.9, 119.8, 116.4, 55.9, 50.1, 46.4 ppm. Purity analy-
sis: Ͼ 99%. HRMS: calcd. for C11H16ClN4O [M + 1]+ 255.1013;
found 255.1008.
1
(33%) as a yellow oil. H NMR (400 MHz, CDCl3): δ = 7.51 (d, J
= 8.63 Hz, 1 H), 7.26–7.21 (m, 2 H), 6.93–6.87 (m, 3 H), 6.55 (d,
J = 8.60 Hz, 1 H), 5.55 (s, 1 H), 3.51 (m, 4 H), 2.53 (m, 4 H), 2.36
(s, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 154.5, 143.7,
140.1, 131.6, 129.4, 126.4, 120.7, 116.5, 106.1, 54.7, 46.2, 45.6 ppm.
Purity analysis: Ͼ 99%. HRMS: calcd. for C16H20ClN4 [M + 1]+
303.1371; found 303.1379.
1-(3-Bromo-6-chloropyridin-2-yl)-4-methylpiperazine (28a): Pre-
pared from 13 (0.091 g, 0.40 mmol) by the procedure used for the
synthesis of 27a with heating at 140 °C for 1 h. Yield: 0.035 g
1
(30%). H NMR (500 MHz, CDCl3): δ = 7.67 (d, J = 8.02 Hz, 1
H), 6.75 (d, J = 8.02 Hz, 1 H), 3.42 (m, 4 H), 2.57 (m, 4 H), 2.35
(s, 3 H) ppm. 13C NMR (151 MHz, CDCl3): δ = 158.9, 147.8,
144.4, 117.7, 109.3, 54.8, 49.1, 46.2 ppm. Purity analysis: Ͼ 99%.
HRMS: calcd. for C10H14BrClN3 [M + H]+ 290.0060; found
290.0056.
2,6-Dichloronicotinoyl Chloride (35): 2,6-Dichloronicotinic acid (11;
3.84 g, 20 mmol) was added to toluene (8 mL) to form a slurry, and
then DMF (0.077 mL, 1.00 mmol) was added. The slurry was co-
oled to 0 °C, and SOCl2 (4.38 mL, 60.00 mmol) was added. The
reaction mixture was stirred at 0 °C for 10 min, at room tempera-
ture for 10 min, and then heated to reflux for 2 h. The mixture was
concentrated and co-concentrated twice with toluene and used in
due course.
1-(5-Bromo-6-chloropyridin-2-yl)-4-methylpiperazine (28b): From
the batch of 28a was isolated the regioisomer. Relevant fractions
were pooled and concentrated. A 10% solution of Na2CO3 was
6950
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© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 6940–6952

Regioselectivity in Nucleophilic Aromatic Substitution Reactions
Jambrina, C. R. Nevill, Jr., P. A. Lee, R. C. Schultz, J. A.
Wolos, L. C. Li, R. M. Campbell, B. D. Anderson, Bioorg.
Med. Chem. Lett. 2008, 18, 179–183.
2,6-Dichloropyridin-3-ol (37): Prepared according to the procedure
by Voisin et al.[32] 1H and 13C NMR spectra are in agreement with
literature values. Purity analysis: 98%. HRMS: calcd. for
C5H4Cl2NO [M + H]+ 163.9664; found 163.9667.
[15] J. Matsumoto, T. Miyamoto, A. Minamida, Y. Nishimura, J.
Heterocycl. Chem. 1984, 21, 673–679.
Compounds 16b, 18b, 20a, 21a, 22a, 25b, and 27b were not isolated,
because the regioselectivities of the reactions were biased towards
the other isomers; thus, their 1H NMR spectroscopic data were
determined from the reaction mixtures.
[16]
S. Schmid, M. Röttgen, U. Thewalt, V. Austel, Org. Biomol.
Chem. 2005, 3, 3408–3421.
[17] Y. Hirokawa, T. Horikawa, S. Kato, Chem. Pharm. Bull. 2000,
48, 1847–1853.
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1
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Eur. J. Org. Chem. 2012, 6940–6952
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6951

P. Bach, M. Marczynke, F. Giordanetto
FULL PAPER
from: Knovel Critical Tables, 2nd ed., Knovel, New York, 2008;
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from: J. G. Speight, Lange’s Handbook of Chemistry, 16th ed.,
McGraw-Hill, New York, 2005.
[39] It would have been interesting to test the reaction in HMPA (β
= 1.05), or in a DMSO/HMPA mixture; however, company
safety regulations prohibit the use of HMPA.
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[38] Rsel showed less or no significant single-variable correlations
with the solvatochromic α parameter (R2 = 0.0003), the refrac-
tive index n (R2 = 0.03), ε (R2 = 0.13), μ (R2 = 0.25), dipolarity/
polarizability expressed by π* (R2 = 0.02), Dimroth’s and
Reichard’s ET(30) (R2 = 0.07), or with the derived functions
f(n) = (n2 – 1)/(n2 + 1) and g(ε) = (ε2 – 1)/(ε2 + 1).
[41] Owing to the strongly acidic solution, it was impossible to lock
1
on the resonance frequency of 13C NMR, thus only H NMR
spectra are provided for this compound and its regioisomer.
Received: July 24, 2012
Published Online: November 2, 2012
6952
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 6940–6952