Reactions of methyl ketones and (hetero)arylcarboxamides with N,N-dimethylacetamide dimethyl acetal. A simple metal-free synthesis of 2,4,6-trisubstituted pyridines

Article abstract of DOI:10.1071/CH14349

Two metal-free syntheses of 2,4,6-trisubstituted pyridines 10a-m and 16a-j are described. N,N,6-Trimethyl-4-(substituted)pyridin-2-amines 10 were prepared from aryl or heteroaryl methyl ketones which were transformed with N,N-dimethylacetamide dimethyl ac

Full text of DOI:10.1071/CH14349

RESEARCH FRONT
CSIRO PUBLISHING
Aust. J. Chem. 2015, 68, 184–195
Full Paper
http://dx.doi.org/10.1071/CH14349
Reactions of Methyl Ketones and (Hetero)
arylcarboxamides with N,N-Dimethylacetamide
Dimethyl Acetal. A Simple Metal-Free Synthesis
of 2,4,6-Trisubstituted Pyridines*
A B
,
A
A
C
Benjamin Prek,
Jurij Svete,
Urosˇ Grosˇelj, Marta Kasunicˇ, Silvo Zupancˇicˇ,
A B
,
A B D
, ,
and Branko Stanovnik
A
Faculty of Chemistry and Chemical Technology, University of Ljubljana,
Asˇkercˇeva 5, PO Box 537, 1000 Ljubljana, Slovenia.
B
EN-FIST Center of Excellence, Trg OF 13, 1000 Ljubljana, Slovenia.
C
FARMA GRS, Seidlova cesta 70, 8000 Novo mesto, Slovenia.
D
Corresponding author. Email: branko.stanovnik@fkkt.uni-lj.si
Two metal-free syntheses of 2,4,6-trisubstituted pyridines 10a–m and 16a–j are described. N,N,6-Trimethyl-4-(substituted)
pyridin-2-amines 10 were prepared from aryl or heteroaryl methyl ketones which were transformed with N,N-
dimethylacetamide dimethyl acetal (DMADMA) into enaminones 4a–m, followed by treatment with ammonium acetate
to give (Z)-3-amino-1-(substituted)but-2-en-1-ones 5a–m. These were treated with DMADMA under microwave
irradiation in a closed vessel at 1308C, to give via intermediates 7–9 the final products 10a–m. N2,N2,N4,N4-
Tetramethyl-6-(substituted) pyridine-2,4-diamines 16a–j were prepared in a one-pot synthesis from the corresponding
carboxamides 11a–j by treatment with an excess of DMADMA in a closed vessel under microwave irradiation to give via
intermediates 12a–j to 15a–j the final products 16a–j. X-Ray single crystal diffractometry studies of the enaminones 5c,
5g, 5i, 5j, and 5m and 2,4,6-trisubstituted pyridines 16a, 16b, 16g, 16i, and 16j were consistent with the expected
structures.
Manuscript received: 30 May 2014.
Manuscript accepted: 19 June 2014.
Published online: 3 September 2014.
salts without the use of transition metal catalysts[15] have
recently been reported.
Introduction
Pyridines and their N-oxides with aromatic or heteroaromatic
substituents constitute an important class of compounds that
have found applications in medicinal chemistry.[1] They are also
convenient synthetic precursors of chiral dihydro- and tetra-
hydropyridines, which are of interest as intermediates in alka-
loid synthesis, agrochemistry, as well as in material sciences.[2,3]
Since the early days of synthetic organic chemistry chemists
have searched for efficient methods to prepare functionalized
pyridine derivatives.[4–6]
Palladium-catalyzed reactions are powerful and useful tools
for the synthesis of heterocycles, especially for the formation of
C–C bonds in aryl and heteroaryl substituted heterocycles.[7–12]
In this context, the Suzuki reaction has a special signifi-
cance.[10–12] An attractive alternative is a mild Negishi cross-
coupling of 2-heterocyclic organozinc reagents with aryl and
heteroaryl chlorides, which complements reactions with other
2-heteroarylorganometallic reagents.[13] Direct arylation and
alkylation of nitropyridine N-oxides with Grignard reagents[14]
and arylation of arenes and N-heteroarenes with diaryliodonium
The negative aspects of using organometallic reagents in
organic synthesis are probably most reflected in the pharmaceu-
tical industry. The ever increasing cost of metals, i.e. the
progressive shortage of lithium, and the strict regulations that
are relevant for pharmaceutical compounds regarding the resid-
ual traces of metals left in the final products, represent a very
big financial investment in purification processes, consequently
leading to more expensive final products. Synthetic paths that
avoid using organometallics and/or metals are becoming
increasingly interesting and represent a very important aspect
in chemical industry.
3-Dimethylaminopropenoates and related enaminones have
been demonstrated to exhibit a broad applicability in heterocy-
clic synthesis,[16–20] including thepreparation of natural products
and their analogues, such as aplysinopsins,[21,22] meridia-
nines,[23,24] and dipodazines.[25–27] Recently, polysubstituted
butadienes have been prepared by microwave-assisted [2þ2]
cycloadditions of enaminones to electron-poor acetylenes.[28,29]
*Dedicated to the memory of the late Dr Desmond Joseph Brown, an eminent organic chemist, John Curtin School of Medical Research, Australian National
University, Canberra, Australia.
Journal compilation Ó CSIRO 2015
www.publish.csiro.au/journals/ajc

Metal-Free Synthesis of Trisubstituted Pyridines
185
O
O
Polysubstituted aminobutadienes prepared by this procedure
are suitable for the preparation of polysubstituted pyridine
derivatives. They also represent a group of isomeric inter-
mediates in regard to the aminobutadienes prepared via the
Michael addition in Bohlmann–Rahtz synthesis of pyridine
derivatives.[30,31] On this basis a simple metal-free synthesis
of 2-alkyl-, 2-cycloalkyl-, 2-aryl-, and 2-heteroaryl-substituted
pyridine-3,4-dicarboxylates and their N-oxides has been
developed.[32]
The electron-poor propyne iminium triflates, prepared from
3-trifloxypropene iminium triflates by elimination of triflic acid,
underwent [2þ2] and [2þ4] cycloadditions with enamines.[33]
Their reactivity towards imines has been also reported.[34,35]
Recently, we reported on a simple one-pot metal-free synthesis
of 2,4,5-trisubstituted pyridine derivatives and their N-oxides by
[2þ2] cycloaddition of propyne iminium salts as electron-poor
acetylenes to enaminones as an extension of the research
recently developed in our laboratory.[36]
We also recently reported on a simple, metal-free synthesis
of polysubstituted benzene derivatives, where N,N-dimethyl-
acetamide dimethyl acetal (DMADMA) served as the reagent
and building block for generating aromatic final products.[37]
In this paper, we report on another application of the
enaminone system in the synthesis of heterocyclic compounds.
We have expanded the DMADMA methodology on aryl- and
heteroaryl-enaminone systems, as well as on aromatic and
heteroaromatic carboxamides, to prepare N,N,6-trimethyl-4-
(substituted)pyridin-2-amines and N2,N2,N4,N4-tetramethyl-6-
(substituted)pyridine-2,4-diamines as the final products.
DMFDMA
R
NMe2
R
Me
Toluene,
reflux
1
2
NH4OAc
MeOH
Toluene,
reflux
DMADMA
Dimerization
O
R
Me
N
R
NMe2
R
4
O
3
NH4OAc
MeOH
r. t.
NH2
Me
O
O
O
NH4OAc
MeOH
R
Me
R
5
6
DMADMA
MW
130ЊC
NMe2
N
NMe2
Me
O
N
Me
O
Me
R
R
Me
Results and Discussions
7Ј
7Љ
It has been reported that enaminones 2, which are easily
prepared from methyl ketones 1 using amide acetals, such
as N,N-dimethylformamide dimethyl acetal (DMFDMA),
undergo self-condensation in the presence of ammonium
acetate affording 2,5-disubstituted pyridine derivatives 3
(Scheme 1).[38,39]
On the other hand, when using DMADMA, the enaminone
products of the condensation reaction do not undergo self-
condensation in acidic media. Therefore, the dimethylamino
group can be readily replaced with the amino group, using
ammonium acetate as an active form of ammonia. It is known
that the methyl group attached to the enaminone system is acidic
and is capable of participating in condensation reactions.[37,40]
NMe2
N
NMe2
N
H2C
O
Ϫ
Ϫ
O
R
Me
R
Me
8
9
a) phenyl
b) 4-methylphenyl
R ϭ
ϪH2O
c) 3-(trifluoromethyl)phenyl
d) 4-nitrophenyl
e) 3-nitrophenyl
f) 4-fluorophenyl
g) 4-chlorophenyl
h) 4-bromophenyl
i) furyl-2-yl
NMe2
N
Synthesis of N,N,6-Trimethyl-4-(substituted)pyridin-
2-amines (2-(Hetero)aryl-4,6-bis(N,N-dimethylamino)
pyridines)
R
Me
j) thienyl-3-yl
k) thienyl-3-yl
10
Ketones 1 were transformed with DMADMA into enaminones
4 as was reported previously.[41,42] These were treated with
ammonium acetate in order to substitute the N,N-dimethylamino
group with an amino group to give (Z)-3-amino-1-(substituted)
but-2-en-1-ones 5, using a modified literature procedure.[43] An
alternative path leading to products 5 from 1,3-dicarbonyl
compounds has also been described.[44] The amino group of
the butenones 5 was then transformed with DMADMA
under microwave irradiation to give N,N-dimethylamino-N0-
enaminone-acetamidine derivative, which can exist as confor-
mational rotamers 70 and 700. From 700 anions 8 are formed in the
presence of a base, which cyclize into 9, followed by elimination
ofwater togive 2-methyl-6-(N,N-dimethylamino)-4-(substituted)
l) pyridin-2-yl
m) pyrazin-2-yl
Scheme 1. DMADMA: N,N-dimethylacetamide dimethylacetal,
DMFDMA: N,N-dimethylformamide dimethyl acetal.
pyridine derivatives 10. In this manner a series of N,N,6-
trimethyl-4-(substituted)pyridin-2-amines 10 were prepared.
The reaction conditions were chosen on the basis of the pressure
thar the microwave vial can withstand (Scheme 1, Table 1).
Because of the harsh reaction conditions, no starting material
was recovered and small amounts of various by-products
formed, which were not identified.

186
B. Prek et al.
Table 1. Yields and melting points of enaminones 5 and pyridines 10
Compound 1
R
Enaminone 5
Yield (1 - 4 - 5)
[%]
Mp
Pyridine 10
Yield 10
Mp
[8C]
[%]
[8C]
N
Me
Me2N
NH2
Me
O
a
phenyl
51
142.3–145.0
35
58.4–61.4
N
Me
Me2N
O
NH2
Me
b
p-tolyl
24
68.8–70.1
43
45.0–47.8
Me
Me
Me2N
N
Me
NH2
O
Me
c
3-(trifluoromethyl)phenyl
36
130.0–131.2
13
55.2–58.0
CF3
CF3
Me
N
Me2N
O
NH2
Me
d
40-nitrophenyl
41
173.5–176.3
18
96.2–100.4
O2N
NO2
Me2N
N
Me
O
NH2
Me
e
30-nitrophenyl
26
159.2–160.5
32
84.2–87.6
NO2
NO2
Me
Me2N
N
NH2
O
Me
f
40-fluorophenyl
61
105.6–108.7
28
48.3–52.4
F
F
Me2N
N
Me
O
NH2
Me
g
40-chlorophenyl
57
129.8–132.2
22
68.8–71.2
Cl
Cl
N
Me2N
Me
NH2
Me
O
h
40-bromophenyl
55
129.1–129.7
13
44.2–48.0
Br
Br
N
Me2N
Me
NH2
Me
O
O
i
furan-2-yl
57
109.8–114.2
33
oil
O
(Continued)

Metal-Free Synthesis of Trisubstituted Pyridines
187
Table 1. (Continued)
Compound 1
R
Enaminone 5
Yield (1 - 4 - 5)
[%]
Mp
Pyridine 10
Yield 10
Mp
[8C]
[%]
[8C]
Me2N
N
Me
O
NH2
Me
j
thiophen-3-yl
45
42
52
174.4–176.0
168.7–171.2
147.2–151.3
42
30
27
oil
S
S
S
N
Me
Me
Me2N
NH2
Me
O
O
O
k
thiophen-2-yl
pyridin-2-yl
63.2–65.2
44.6–48.8
S
Me2N
N
NH2
Me
N
l
N
N
Me
Me2N
NH2
Me
N
N
m
pyrazin-2-yl
52
178.9–180.2
24
68.4–72.5
N
N
Synthesis of N2,N2,N4,N4-Tetramethyl-6-(substituted)
Pyridine-2,4-diamines (2-Methyl-6-(N,N-dimethylamino)-
4-(hetero)aryl pyridines)
The structures of five N2,N2,N4,N4-tetramethyl-6-(substituted)
pyridine-2,4-diamine representatives 16a, 16b, 16g, 16i, and 16j
have also been confirmed by X-ray analysis (Fig. 2).
Aryl and heteroaryl amides 11 were transformed with
DMADMA under microwave irradiation at 1308C into N,N-
dimethyl-N0-(hetero)aroylacetamidines 12. The reaction
conditions were chosen on the basis of pressure which the
microwave vial can withstand. The microwave-assisted reaction
progresses so that the methyl group is transformed by further
reaction with excess of DMADMA into a N,N-dimethylethylidene
group to give 1,3-bis(dimethylamino)but-2-en-1-ylidene deri-
vatives, which can exist as conformational rotamers 130 and 1300.
Under influence of a base the anion 14 was formed, which
attacks the carbonyl group to form 15, followed by elimination
of water affording the final 6-(hetero)aryl-2,4-bis(N,N-
dimethylamino)pyridines 16 (Scheme 2, Table 2). A similar
reaction, using a different, cyclic amide acetal, has also
previously been published.[45]
Experimental
Melting points were determined on a Stanford Research Sys-
tems MPA100 OptiMelt automated melting point system. The
NMR spectra were obtained on a Bruker Avance DPX 300 at
300 MHz for 1H and 75.5 MHz for 13C and on a Bruker Avance
1
III UltraShield 500 plus at 500 MHz for H and 126 MHz for
13C, using CDCl3 and DMSO-d6 as solvents with Me4Si as the
internal standard. Mass spectra were recorded on an Agilent
6224 Accurate Mass TOF LC/MS spectrometer. IR spectra were
recorded on a Perkin Elmer Spectrum BX FTIR spectropho-
tometer. Microanalyses were performed on a Perkin–Elmer
CHN Analyzer 2400 II. Column chromatography (CC) was
performed on silica gel (Fluka, Silica gel 60, particle size
35–70 mm). The commercial availability of the starting com-
pounds is stated in the general procedure section.
Structure Determination
General Procedure for the Preparation of
3-(Dimethylamino)-1-(substituted)but-2-en-1-ones 4a–m
The structures of new compounds were determined on the basis
of high-resolution mass spectrometry (HRMS), IR, 1H and
13C NMR spectra, as well as with 2D NMR experiments. In
some cases we were able to prepare appropriate crystals for
X-ray analysis, allowing us to confirm the structures of the
products unambiguously.
The starting methyl ketones, which are all commercially avail-
able, were transformed to the appropriate 3-(dimethylamino)-1-
(substituted)but-2-en-1-ones following a modified literature
procedure.[41,42]
In the case of (Z)-3-amino-1-(substituted)but-2-en-1-ones 5,
we already saw the evidence of an intramolecular hydrogen
bond in the form of two very different chemical shifts for the
amino protons in the 1H NMR spectra. The crystal structures for
5c, 5g, 5i, 5j, and 5m confirmed the orientation around the
double bond to be (Z) (Fig. 1).
General Procedure for the Preparation of (Z)-3-Amino-1-
(substituted)but-2-en-1-ones 5a–m
The products were prepared following a modified literature
procedure.[43] 3-(Dimethylamino)-1-(substituted)but-2-en-1-
ones (1 mmol) were dissolved in methanol and 8–10 equivalents

188
B. Prek et al.
(Z)-3-Amino-1-(3-nitrophenyl)but-2-en-1-one (5e)
Yield: 71 % (337 mg), yellow amorphous solid; mp 159.2–
160.58C. nmax/cmꢀ1 3283, 3130, 3081, 1608, 1531, 1515, 1380,
1351, 1318, 1264, 1227, 1140, 1096, 1065, 1021, 728, 706. dH
(d6-DMSO, 500 MHz) 10.13 (br s, 1H, NH2), 8.57 (ddd, J1 2.3,
J2 1.7, J3 0.4, 1H, 20-CH), 8.31 (ddd, J1 8.1, J2 2.4, J3 1.0, 1H, 40-
CH), 8.28 (ddd, J1 7.8, J2 1.6, J3 1.1, 1H, 60-CH), 8.20 (br s, 1H,
NH2), 7.73 (ddd, J1 8.1, J2 7.7, J3 0.4, 1H, 50-CH), 5.82 (d, J 1.8,
1H, 2-CH), 2.05 (s, 3H, CH3). dC (d6-DMSO, 125 MHz) 183.1,
166.4, 148.0, 141.5, 132.9, 130.0, 125.0, 121.1, 90.3, 21.8. m/z
(HRMS EI) 207.0767; C10H11N2O3 [M þ H]þ requires
207.0764. Anal. Calc. for C10H10N2O3: C 58.25, H 4.89,
N 13.59. Found: C 58.28, H 4.75, N 13.55 %.
O
O
Me
DMADMA
MW
130ЊC
R
NH2
R
N
NMe2
11
12
DMADMA
NMe2
NMe2
Me
Me
O
O
R
N
NMe2
N
R
NMe2
13Ј
13Љ
(Z)-3-Amino-1-(4-chlorophenyl)but-2-en-1-one (5g)[47]
Yield: 96 % (525 mg), yellowish-brown solid; mp 129.8–
132.28C (Lit.[47] mp 126–1298C). nmax/cmꢀ1 3277, 3135, 1585,
1557, 1521, 1481, 1439, 1398, 1368, 1312, 1289, 1274, 1214,
1170, 1089, 1009, 846, 764. dH (CDCl3, 500 MHz) 10.22 (br s,
1H, NH2), 7.84–7.79 (m, 2H, Ph), 7.39–7.36 (m, 2H, Ph), 5.69
(s, 1H, 2-CH), 5.22 (br s, 1H, NH2), 2.07 (s, 3H, CH3). dC
(CDCl3, 125 MHz) 188.1, 163.4, 138.6, 137.1, 128.7, 128.6,
92.2, 23.1. m/z (HRMS EI) 196.0525; C10H11ClNO [M þ H]þ
requires 196.0524. Anal. Calc. for C10H10ClNO: C 61.39,
H 5.15, N 7.12. Found: C 61.39, 5.12, N 7.16 %. Compound
5g: C10H10ClNO, Mr 195.64, Dx 1.274 Mg mꢀ3, orthorhombic,
NMe2
NMe2
H2C
O
Ϫ
Ϫ
O
R
N
NMe2
NMe2
R
N
14
15
ϪH2O
˚
Pccn, a 8.0757(4), b 26.8322(14), c 9.4110(5) A, V 2039.27
3
R ϭ a) phenyl
3
˚
(18) A , Z 8, platelet, colourless, 0.40 ꢁ 0.15 ꢁ 0.10 mm ,
b) 3-(trifluoromethyl)phenyl
c) 4-nitrophenyl
d) 3-nitrophenyl
e) 4-methoxyphenyl
f) furyl-2-yl
g) pyridin-4-yl
h) pyridin-3-yl
i) pyridin-2-yl
j) pyrazin-2-yl
˚
T 293 K, 6.088ꢀ54.968 2y, MoKa radiation, l 0.7107 A,
SuperNova-Atlas single-crystal diffractometer, 8090 measured,
2342 independent, and 1376 observed reflections, Rint 0.0287, v
scans, refinement on F2, R[F2 . 2s(F2)] 0.0483, wR(F2) 0.1532,
NMe2
S 1.033, 2342 contributing reflections, 127 parameters, Drmax
R
N
NMe2
ꢀ3
0.135 e Aꢀ3, Drmin ꢀ0.268 e A
.
˚
˚
16
(Z)-3-Amino-1-(furan-2-yl)but-2-en-1-one (5i)[47]
Scheme 2. DMADMA: N,N-dimethylacetamide dimethyl acetal, MW:
Yield: 95 % (401 mg), brown crystalline solid; mp 109.9–
114.18C (Lit.[47] mp 128–1308C). nmax/cmꢀ1 3296, 3121, 1643,
1568, 1529, 1470, 1393, 1368, 1300, 1221, 1158, 1124, 1083,
1010, 926, 883, 809, 773, 758, 736, 661. dH (CDCl3, 500 MHz)
9.97 (br s, 1H, NH2), 7.48 (dd, J1 1.7, J2 0.9, 1H, 50-CH), 7.01
(dd, J1 3.4, J2 0.8, 1H, 40-CH), 6.47 (dd, J1 3.4, J2 1.7, 1H, 30-
CH), 5.66 (s, 1H, 2-CH), 5.23 (br s, 1H, NH2), 2.04 (s, 3H, CH3).
dC (CDCl3, 125 MHz) 178.7, 163.1, 154.3, 144.2, 112.9, 111.8,
91.7, 22.8. m/z (HRMS EI) 152.0704; C8H10NO2 [M þ H]þ
requires 152.0706. Anal. Calc. C 63.56, H 6.00, N 9.27. Found:
C 63.80, H 6.09, N 9.17 %. Compound 5i: C8H9NO2, Mr 151.16,
Dx 1.220 Mg mꢀ3, triclinic, Pꢀ1, a 9.2279(6), b 9.3829(9), c
microwave irradiation.
of ammonium acetate were added. The reaction mixture was left
to stir at room temperature for 2–6 h. The volatile components
were removed under vacuum, and the desired product was
obtained from the remaining residue either by column chro-
matography or, if the thin-layer chromatography suggested the
reaction proceeded quantitatively, by extracting the aqueous
solution of the residue with ethyl acetate. In the latter case, the
organic phases were collected, dried over anhydrous sodium
sulfate, filtered, and evaporated under vacuum (see Table 1).
˚
9.5326(5) A, a 94.307(6)8, b 90.066(5)8, g 91.582(7)8, V 822.73
3
3
˚
(10) A , Z 4, platelet, colourless, 0.45 ꢁ 0.30 ꢁ 0.02 mm ,
(Z)-3-Amino-1-(3-(trifluoromethyl)phenyl)but-2-en-1-
one (5c)[46]
˚
T 293 K, 5.888ꢀ54.968 2y, MoKa radiation, l 0.7107 A,
SuperNova-Atlas single-crystal diffractometer, 8730 measured,
3763 independent, and 2691 observed reflections, Rint 0.0207,
v scans, refinement on F2, R[F2 . 2s(F2)] 0.0584, wR(F2)
0.1781, S 1.031, 3763 contributing reflections, 210 parameters,
Yield: 89 % (512 mg), white crystalline solid, mp 130.0–
131.28C. Compound 5c: C11H10F3NO, Mr 229.20, Dx 1.482 Mg
m
ꢀ3, monoclinic, P121/c1, a 12.8117(5), b 10.5100(4), c 7.7540
3
˚
˚
(3) A, b 100.323(3)8, V 1027.18(7) A , Z 4, prism, colourless,
0.40 ꢁ 0.30 ꢁ 0.20 mm3, T 150 K, 6.468ꢀ54.968 2y, MoKa radi-
ꢀ3
Drmax 0.342 e Aꢀ3, Drmin ꢀ0.396 e A
.
˚
˚
˚
ation, l 0.7107 A, SuperNova-Atlas single-crystal diffracto-
(Z)-3-Amino-1-(thiophen-3-yl)but-2-en-1-one (5j)
meter, 5349 measured, 2347 independent, and 1853 observed
reflections, Rint 0.0231, v scans, refinement on F2, R[F2 .
2s(F2)] 0.0751, wR(F2) 0.2198, S 1.070, 2347 contributing refꢀle3c-
Yield: 95 % (367 mg), yellow solid; mp 174.4–176.08C.
max/cmꢀ1 3279, 3137, 3090, 1624, 1578, 1524, 1391, 1360,
1278, 1256, 1235, 1203, 1182, 1115, 1088, 1008, 934, 875, 758.
n
tions, 134 parameters, Drmax 0.938 e Aꢀ3, Drmin ꢀ0.791 e A
.
˚
˚

Metal-Free Synthesis of Trisubstituted Pyridines
189
Table 2. Yields and melting points of pyridines 16
Compound 11
R
Pyridine 16
Yield
[%]
Mp
[8C]
Me2N
N
a
phenyl
20
84–88
NMe2
Me2N
N
CF3
NO2
b
3-(trifluoromethyl)phenyl
31
19
71–77
NMe2
Me2N
N
c
4-nitrophenyl
142–147
NMe2
Me2N
N
NO2
d
3-nitrophenyl
26
19
100–102
100–105
NMe2
OMe
Me2N
N
e
4-methoxyphenyl
NMe2
O
Me2N
N
f
furan-2-yl
29
38
oil
NMe2
N
N
Me2N
g
pyridin-4-yl
183–186
NMe2
N
Me2N
N
h
pyridin-3-yl
24
83–89
NMe2
Me2N
N
N
i
pyridin-2-yl
pyrazin-2-yl
14
36
52–60
NMe2
N
N
Me2N
N
j
110–117
NMe2

190
B. Prek et al.
O1
O1
C7
N1
C7
N1
C4
C5
S1
C3
C2
C8
C6
C4
C6
C5
C9
C10
C8
C1
C1
C3
C2
5i
F2
O2
N1
C11
F3
F1
C3
5c
C4
C6
C5
O1
N1
C7
C5
C2
C4
C8
C6
C8
O1
C7
C9
C1
C10
Cl1
5j
C1
C3
O1
C2
N3
C3
N2
5g
C4
C6
C5
C7
C2
N1
C8
C1
5m
Fig. 1. ORTEP view of compounds 5c, 5g, 5i, 5j, and 5m. The dashed lines illustrate an intramolecular N–HꢂꢂꢂO hydrogen bond.
dH (CDCl3, 500 MHz) 10.06 (br s, 1H, NH2), 7.88 (dd, J1 3.0, J2
1.2, 1H, 20-CH), 7.50 (dd, J1 5.0, J2 1.2, 1H, 50-CH), 7.28 (dd, J1
5.0, J2 3.0, 1H, 40-CH), 5.59 (s, 1H, 2-CH), 5.13 (br s, 1H, NH2),
2.04 (s, 3H, CH3). dC (CDCl3, 125 MHz) 184.2, 162.6, 144.4,
127.9, 126.7, 125.6, 93.2, 22.8. m/z (HRMS EI) 168.0478;
C8H10NOS [M þ H]þ requires 168.0478. Anal. Calc. for
C8H9NOS: C 57.46, H 5.42, N 8.38. Found: C 57.52, H 5.50,
N 8.17 %. Compound 5j: C8H9NOS, Mr 167.22, Dx 1.282 Mg
H 5.56, N 25.75. Found: C 58.84, H 5.45, N 25.59%. Compound
5m: C8H9N3O, Mr 163.18, Dx 1.356 Mgmꢀ3, monoclinic,
˚
P21, a 3.8781(3), b 9.3987(6), c 10.9937(6) A, b 93.937(6)8,
3
3
˚
V 399.76(5) A , Z 2, platelet, colourless, 0.50 ꢁ 0.10 ꢁ 0.05 mm ,
˚
T 293K, 7.438ꢀ60.458 2y, MoKa radiation, l 0.7107A,
SuperNova-Atlas single-crystal diffractometer, 3200 measured,
1986 independent, and 1368 observed reflections, Rint 0.0446,
v scans, refinement on F2, R[F2 . 2s(F2)] 0.0523, wR(F2)
0.1321, S 1.025, 1986 contributing reflections, 118 parameters,
mꢀ3, tetragonal, P41, a 8.2883(3), c 12.6091(6) A, V 866.19
˚
3
3
ꢀ3
˚
.
(8) A , Z 4, platelet, colourless, 0.25 ꢁ 0.20 ꢁ 0.02 mm ,
Drmax 0.155 e Aꢀ3, Drmin ꢀ0.143 e A
˚
˚
˚
T 293 K, 5.888ꢀ54.908 2y, MoKa radiation, l 0.7107 A,
SuperNova-Atlas single-crystal diffractometer, 3966 measured,
1767 independent, and 1414 observed reflections, Rint 0.0206,
v scans, refinement on F2, R[F2 . 2s(F2)] 0.0515, wR(F2)
0.1289, S 1.041, 1767 contributing reflections, 102 parameters,
General Procedure for the Preparation of
N,N,6-Trimethyl-4-(substituted)pyridin-
2-amines 10a–m
Drmax 0.288 e Aꢀ3, Drmin ꢀ0.273 e A
.
ꢀ3
˚
˚
(Z)-3-Amino-1-(substituted)but-2-en-1-ones (1 mmol) and 2
equivalents of DMADMA were mixed in a microwave tube
equipped with a magnetic stirring bar. The reaction mixture was
then heated via microwave irradiation (300 W) in a closed vessel
at an automatically controlled elevated constant temperature
(CEM Corporation discover microwave unit). The reaction
temperatures were between 130 and 1408C, the maximum
allowed pressure was set to 16 bar, the reaction times were
short: between 2 and 10 min. After the completion of the reac-
tion, the volatile components were removed under vacuum and
the N,N,6-trimethyl-4-(substituted)pyridin-2-amine product
was obtained from the crude residue with column chromato-
graphy (see Table 1).
(Z)-3-Amino-1-(pyrazin-2-yl)but-2-en-1-one (5m)
Yield: 95 % (547 mg), yellow solid; mp 178.9–180.28C. nmax
/
cmꢀ1 3299, 3152, 3075, 3002, 1633, 1599, 1566, 1532, 1440,
1395, 1381, 1324, 1280, 1211, 1160, 1120, 1073, 1046, 1004,
923, 777. dH (CDCl3, 500 MHz) 10.35 (br s, 1H, NH2), 9.30 (d, J
1.5, 1H, 30-CH), 8.64 (d, J 2.5, 1H, 60-CH), 8.57 (dd, J1 2.5, J2
1.5, 1H, 50-CH), 6.36 (d, J 1.9, 2-CH), 5.55 (br s, 1H, NH2), 2.13
(s, 3H, CH3). dC (CDCl3, 125 MHz) 185.9, 165.4, 150.5, 146.1,
144.1, 143.1, 91.8, 23.1. m/z (HRMS EI) 164.0818; C8H10N2O
[M þ H]þ requires 164.0818. Anal. Calc. for C8H9N2O: C 58.88,

Metal-Free Synthesis of Trisubstituted Pyridines
191
C30
N5
C17
C16
C12
N3
C23
C13
N4
C18
C19
C22
N6
C29
C24
C25
C21
C9
C15
C20
C3
C8
C4
C5
C26
N4
C11
N1
N3
C10
C14
C2
C6
C7
C14
C13
C28
C7
C1
C27
C12
N2
C6
C9
C8
C5
N2
C11
C10
N1
C4
C3
16a
C14
C15
C1
C2
C11
N1
N2
16i
C10
C16
C12
N3
C13
C11
N9
C9
C8
C8
C7
C6
C10
C7
N6
C5
C6
F1
C2
C1
C5
C4
F3
C3
C4
C3
N3
F2
16b
C2
C7
N2
C1
16j
C6
N3
C5
C8
N2
C2a
C4
C3
C2
C1
N1
16g
Fig. 2. ORTEP view of compounds 16a, 16b, 16g, 16i, and 16j.
N,N,6-Trimethyl-4-phenylpyridin-2-amine (10a)
24.9. m/z (HRMS EI) 213.1389; C14H17N2 [M þ H]þ requires
213.1386.
Yield: 35 % (115 mg), yellow solid; mp 58.4–61.48C. nmax
/
cmꢀ1 3052, 3030, 2980, 2919, 2848, 2795, 1593, 1546, 1493,
1400, 1383, 1274, 1243, 1204, 1182, 1022, 992, 837, 764, 701
dH (CDCl3, 500 MHz) 7.61–7.58 (m, 2H, 20-CH and 60-CH),
7.45–7.41 (m, 2H, 30-CH and 60-CH), 7.39–7.36 (m, 1H, 40-CH),
6.64 (d, J 0.7, 1H, 5-CH), 6.48 (d, J 0.7, 1H, 3-CH), 3.12 (s, 6H,
N(CH3)2), 2.46 (s, 3H, CH3). dC (CDCl3, 125 MHz) 159.8,
157.1, 150.3, 140.3, 128.9, 128.4, 127.2, 109.9, 100.9, 38.3,
N,N,6-Trimethyl-4-(p-tolyl)pyridin-2-amine (10b)
Yield: 43 % (151 mg), yellow solid; mp 45.0–47.88C. nmax
/
cmꢀ1 3024, 2917, 2852, 2800, 1681, 1596, 1547, 1513, 1498,
1417, 1398, 1182, 1114, 1062, 1031, 966, 806. dH (CDCl3,
500 MHz) 7.51–7.48 (m, 2H, 20-CH and 60-CH), 7.26–7.23 (m,
2H, 30-CH and 50-CH), 6.63 (d, J 0.7, 1H, 5-CH),6.48 (d, J 0.7,

192
B. Prek et al.
1H, 3-CH), 3.12 (s, 6H, N(CH3)2), 2.45 (s, 3H, CH3), 2.39 (s, 3H,
Ph-CH3). dC (CDCl3, 125 MHz) 159.9, 157.1, 150.1, 138.4,
137.4, 129.6, 127.0, 109.8, 100.7, 38.3, 24.9, 21.3. m/z (HRMS
EI) 227.1542; C15H19N2 [M þ H]þ requires 227.1543.
1281, 1247, 1185, 1104, 1090, 1064, 1028, 951, 845, 805. dH
(CDCl3, 500 MHz) 7.54–7.51 (m, 2H, 20-CH and 60-CH), 7.42–
7.38 (m, 2H, 30-CH and 50-CH), 6.59 (d, J 0.7, 1H, 5-CH), 6.43
(d, J 0.7, 1H, 3-CH), 3.13 (s, 6H, N(CH3)2), 2.45 (s, 3H, CH3). dC
(CDCl3, 125 MHz) 159.9, 157.4, 149.0, 138.8, 134.5, 129.0,
128.5, 109.6, 100.6, 38.3, 24.9. m/z (HRMS EI) 247.0996;
C14H16ClN2 [M þ H]þ requires 247.0997. Anal. Calc. for
C14H15ClN2: C 68.15, H 6.13, N 11.35. Found: C 68.37,
H 6.46, N 11.35 %.
N,N,6-Trimethyl-4-(3-(trifluoromethyl)phenyl)pyridin-
2-amine (10c)
Yield: 13 % (46 mg), yellow viscous oil that crystallizes after
time; mp 55.2–588C. nmax/cmꢀ1 3051, 2988, 2953, 2915, 2848,
2797, 1594, 1552, 1490, 1433, 1397, 1382, 1322, 1265, 1163,
1108, 1070, 1029, 1001, 969, 835, 794, 669. dH (CDCl3,
500 MHz) 7.84–7.81 (m, 1H, 20-CH), 7.78–7.74 (m, 1H, 60-
CH), 7.65–7.61 (m, 1H, 40-CH), 7.57–7.52 (m, 1H, 50-CH), 6.62
(d, J 0.9, 1H, 5-CH), 6.45 (d, J 0.9, 1H, 3-CH), 3.14 (s, 6H,
N(CH3)2), 2.47 (s, 3H, CH3). dC (CDCl3, 125 MHz) 159.8,
157.6, 148.8, 141.2, 131.3 (q, J 32), 130.5, 129.4, 125.0 (q,
J 3.8), 124.2 (q, J 270), 124.0 (q, J 3.9), 109.6, 100.7, 38.2, 24.9.
m/z (HRMS EI) 281.1261; C15H16F3N2 [M þ H]þ requires
281.1260.
4-(4-Bromophenyl)-N,N,6-trimethylpyridin-
2-amine (10h)
Yield: 13 % (50 mg), yellow oil crystallizes over time to a
brown solid; mp 44.2–48.08C. nmax/cmꢀ1 2915, 2847, 2799,
1597, 1574, 1545, 1488, 1417, 1391, 1380, 1248, 1206, 1186,
1072, 1028, 1003, 899, 808. dH (CDCl3, 500 MHz) 7.60–7.57
(m, 2H, 30-CH and 50-CH), 7.51–7.47 (m, 2H, 20-CH and
60-CH), 6.62 (d, J 0.8, 1H, 5-CH), 6.46 (d, J 0.8, 1H, 3-CH),
3.16 (s, 6H, N(CH3)2), 2.49 (s, 3H, CH3). dC (CDCl3, 125 MHz)
159.8, 157.4, 149.0, 139.2, 131.9, 128.7, 122.6, 109.5, 100.5,
38.2, 24.9. m/z (HRMS EI) 291.0492; C14H16BrN2 [M þ H]þ
requires 291.0491.
N,N,6-Trimethyl-4-(4-nitrophenyl)pyridin-2-amine
(10d)
Yield: 18 % (52 mg), orange solid; mp 96.2–100.48C. nmax
/
4-(Furan-2-yl)-N,N,6-trimethylpyridin-2-amine (10i)
cmꢀ1 3085, 2918, 2849, 1605, 1590, 1555, 1521, 1494, 1421,
1397, 1342, 1251, 1107, 1060, 899, 855, 831, 807, 750. dH
(CDCl3, 300 MHz) 8.35–8.28 (m, 2H, 30-CH and 50-CH), 7.79–
7.72 (m, 2H, 20-CH and 60-CH), 6.64 (d, J 0.7, 1H, 5-CH), 6.48
(d, J 0.7, 1H, 3-CH), 3.17 (s, 6H, N(CH3)2), 2.50 (s, 3H, CH3). dC
(CDCl3, 75.5 MHz) 159.8, 157.9, 147.9, 147.0, 128.1, 124.2,
109.5, 100.8, 38.2, 24.9. m/z (HRMS EI) 258.1237; C14H16N3O2
[M þ H]þ requires 258.1237.
Yield: 33 % (145 mg), yellow oil. nmax/cmꢀ1 2919, 2848,
2798, 1611, 1581, 1554, 1501, 1417, 1395, 1375, 1357, 1301,
1275, 1156, 1076, 1061, 1032, 1015, 740. dH (CDCl3, 500 MHz)
7.48 (dd, J1 1.7, J2 0.8, 1H, 50-CH), 6.75 (dd, J1 3.5, J2 0.8, 1H,
40-CH), 6.68 (d, J 0.5, 1H, 5-CH), 6.61 (d, J 0.5, 1H, 3-CH), 6.47
(dd, J1 3.4, J2 1.8, 1H, 30-CH), 3.11 (s, 6H, N(CH3)2), 2.42
(s, 3H, CH3). dC (CDCl3, 125 MHz) 159.8, 157.2, 153.1, 142.8,
138.9, 111.8, 107.4, 106.1, 96.9, 38.2, 24.9. m/z (HRMS EI)
203.1179; C12H14N2O [M þ H]þ requires 203.1179.
N,N,6-Trimethyl-4-(3-nitrophenyl)pyridin-2-amine (10e)
Yield: 32 % (87 mg), red oil crystallizes that over time; mp
84.0–86.88C. nmax/cmꢀ1 3092, 2956, 2917, 2849, 2805, 1716,
1597, 1550, 1523, 1492, 1398, 1343, 1267, 1189, 1132, 1073,
1030, 925, 834, 805, 737. dH (CDCl3, 500 MHz) 8.42 (ddd, J1
2.2, J2 1.8, J3 0.4, 1H, 20-CH), 8.21 (ddd, J1 8.2, J2 2.3, J3 0.4,
1H, 60-CH), 7.90 (ddd, J1 7.7, J2 1.8, J3 1.1, 1H, 40-CH), 7.59
(ddd, J1 8.2, J2 7.7, J3 0.4, 1H, 50-CH), 6.62 (d, J 1.0, 1H, 5-CH),
6.46 (d, J 1.0, 1H, 3-CH), 3.14 (s, 6H, N(CH3)2), 2.47 (s, 3H,
CH3). dC (CDCl3, 125 MHz) 159.8, 157.8, 148.7, 147.6, 142.0,
133.1, 129.8, 123.0, 122.0, 109.3, 100.5, 38.2, 24.8. m/z (HRMS
EI) 258.1236; C14H16N3O2 [M þ H]þ requires 258.1237.
N,N,6-Trimethyl-4-(thiophen-3-yl)pyridin-
2-amine (10j)
Yield: 42 % (120 mg), brown oil. nmax/cmꢀ1 2916, 2848,
2802, 1599, 1557, 1528, 1495, 1421, 1400, 1251, 1190, 1174,
1134, 1092, 1061, 1031, 993, 870, 834, 782. dH (CDCl3,
500 MHz) 7.56 (dd, J1 2.8, J2 1.6, 1H, 20-CH), 7.41–7.37 (m,
2H, 40-CH and 50-CH), 6.64 (d, J 0.7, 1H, 5-CH), 6.50 (d, J 0.7,
1H, 3-CH), 3.12 (s, 6H, N(CH3)2), 2.44 (s, 3H, CH3). dC NMR
(CDCl3, 125 MHz) 160.0, 157.3, 144.4, 141.5, 126.4, 126.3,
122.1, 109.2, 100.0, 38.3, 24.9. m/z (HRMS EI) 203.0951;
C12H14N2S [M þ H]þ requires 219.0950.
4-(4-Fluorophenyl)-N,N,6-trimethylpyridin-
2-amine (10f)
N,N,6-Trimethyl-4-(thiophen-2-yl)pyridin-
2-amine (10k)
Yield: 28 % (110 mg), yellow oil that crystallizes over time;
mp 48.3–52.48C. nmax/cmꢀ1 2919, 2851, 2799, 1722, 1598,
1552, 1509, 1419, 1396, 1273, 1222, 1184, 1157, 1099, 1029,
899, 818, 787. dH (CDCl3, 500 MHz) 7.57–7.53 (m, 2H, 20-CH
and 60-CH), 7.13–7.08 (m, 2H, 30-CH and 50-CH), 6.58 (d, J 0.7,
1H, 5-CH), 6.42 (d, J 0.7, 1H, 3-CH), 3.12 (s, 6H, N(CH3)2),
2.45 (s, 3H, CH3). dC (CDCl3, 125 MHz) 163.1 (d, J 247.5),
159.8, 157.3, 149.2, 136.4 (d, J 3.2), 128.8 (d, J 8.1), 115.7 (d,
J 21.3), 109.7, 100.6, 38.2, 24.9. m/z (HRMS EI) 231.1292;
C14H16FN2 [M þ H]þ requires 231.1292.
Yield: 30 % (100 mg), white-yellowish solid; mp 63.2–
65.28C. nmax/cmꢀ1 3076, 2920, 2844, 1595, 1551, 1498, 1415,
1398, 1384, 1265, 1245, 1198, 1169, 1013, 990, 856, 807, 734,
695. dH (CDCl3, 500 MHz) 7.41 (dd, J1 3.6, J2 1.2, 1H, 50-CH),
7.32 (dd, J1 5.1, J2 1.2, 1H, 30-CH), 7.08 (dd, J1 5.1, J2 3.6, 1H,
40-CH), 6.66 (d, J 0.7, 1H, 5-CH), 6.50 (d, J 0.7, 1H, 3-CH), 3.12
(s, 6H, N(CH3)2), 2.43 (s, 3H, CH3). dC (CDCl3, 125 MHz)
159.9, 157.4, 143.3, 142.8, 128.1, 125.9, 124.4, 108.4, 99.1,
38.2, 24.8. m/z (HRMS EI) 219.0949; C12H15N2S [M þ H]þ
requires 219.0950. Anal. Calc. for C12H14N2S: C 66.02, H 6.46,
N 12.83. Found: C 66.30, H 6.45, N 12.76 %.
4-(4-Chlorophenyl)-N,N,6-trimethylpyridin-
2-amine (10g)
N,N,60-Trimethyl-[2,40-bipyridin]-20-amine (10l)
Yield: 22 % (104 mg), white solid; mp 68.8–71.28C. nmax
/
Yield: 27 % (144 mg), yellow solid; mp 44.5–48.88C. nmax
/
cmꢀ1 3084, 2918, 2847, 2798, 1597, 1575, 1546, 1491, 1391,
cmꢀ1 2918, 2848, 2805, 1667, 1601, 1581, 1551, 1498, 1472,

Metal-Free Synthesis of Trisubstituted Pyridines
193
1431, 1294, 1246, 1209, 1200, 1181, 1151, 1055, 1031, 989,
965, 848, 778. dH (CDCl3, 500 MHz) 8.70 (ddd, J1 4.9, J2 1.9, J3
1.1, 1H, 6-CH), 7.78–7.69 (m, 2H, 3-CH and 4-CH), 7.28 (ddd,
J1 6.7, J2 4.7, J3 1.7, 1H, 5-CH), 6.95 (br s, 1H, 50-CH), 6.94 (br s,
1H, 30-CH), 3.15 (s, 6H, N(CH3)2), 2.48 (s, 3H, CH3). dC
(CDCl3, 125 MHz) 160.0, 157.4, 156.6, 149.8, 148.2, 136.9,
123.3, 121.2, 108.9, 100.5, 38.3, 24.9. m/z (HRMS EI)
214.1340; C13H16N3 [M þ H]þ requires 214.1339.
60-CH), 7.58 (dt, J1 7.9, J2 1.2, 1H, 40-CH), 7.51 (t, J 7.7, 1H,
50-CH), 6.46 (d, J 1.9, 1H, 5-CH), 5.64 (d, J 1.9, 1H, 3-CH), 3.14
2
4
(s, 6H, NMe2), 3.05 (s, 6H, NMe2). dC (CDCl3, 125 MHz)
160.6, 156.9, 154.0, 142.0, 130.6 (q, J 32), 130.1 (q, J 1.2),
128.6, 124.6 (q, J 3.8), 124.4 (q, J 272), 123.7 (q, J 3.9), 94.9,
86.4, 39.7, 38.2. m/z (HRMS EI)310.1525; C16H19F3N3
[M þ H]þ requires 310.1526. Anal. Calc. for C16H18F3N3:
C 62.13, H 5.87, N 13.58. Found: C 61.94, H 6.11, N 13.32 %.
Compound 16b: C16H18F3N3, Mr 309.33, Dx 1.292 Mg mꢀ3
,
˚
N,N,6-Trimethyl-4-(pyrazin-2-yl)pyridin-2-amine (10m)
Yield: 24 % (104 mg), yellow-orange solid; mp 68.4–72.58C.
triclinic, Pꢀ1, a 5.4406(2), b 12.2175(7), c 12.7096(7) A, a
3
104.016(5)8, b 101.955(4)8, g 94.097(4)8, V 795.27(7) A ,
˚
Z 2, prism, colourless, 0.50 ꢁ 0.40 ꢁ 0.30 mm3, T 293 K,
n
max/cmꢀ1 2919, 2847, 1599, 1553, 1480, 1414, 1394, 1384,
˚
6.768ꢀ52.748 2y, MoKa radiation, l 0.7107 A, SuperNova-Atlas
1308, 1246, 1142, 1054, 1015, 996, 965, 820. dH (CDCl3,
500 MHz) 9.02 (d, J 1.5, 1H, 60-CH), 8.65 (dd, J1 2.5, J2 1.5,
1H, 50-CH), 8.57 (d, J 2.5, 1H, 30-CH), 6.96 (d, J 0.7, 1H, 5-CH),
6.94 (d, J 0.7, 1H, 3-CH), 3.17 (s, 6H, N(CH3)2), 2.50 (s, 3H,
CH3). dC (CDCl3, 125 MHz) 160.0, 157.9, 152.1, 145.1, 144.3,
144.2, 142.7, 108.4, 100.3, 38.2, 25.0. m/z (HRMS EI)
215.1290; C12H15N4 [M þ H]þ requires 214.1291.
single-crystal diffractometer, 6214 measured, 3246 indepen-
dent, and 1912 observed reflections, Rint 0.0177, v scans,
refinement on F2, R[F2 . 2s(F2)] 0.1018, wR(F2) 0.3461,
S 1.111, 3246 contributing reflections, 197 parameters, Drmax
ꢀ3
0.441 e Aꢀ3, Drmin ꢀ0.394 e A
.
˚
˚
N2,N2,N4,N4-Tetramethyl-6-(4-nitrophenyl)
pyridine-2,4-diamine (16c)
General Procedure for the Preparation of N2,N2,N4,N4-
Tetramethyl-6-(substituted) Pyridine-2,4-diamines 16a–j
Yield: 19 % (160 mg), orange solid; mp 142.1–147.08C. nmax
/
cmꢀ1 3085, 2975, 2924, 2893, 2838, 1585, 1539, 1495, 1396,
1331, 1160, 1096, 1027, 977, 826. dH (CDCl3, 500 MHz) 8.27–
8.24 (m, 2H, Ph), 8.20–8.13 (m, 2H, Ph), 6.52 (d, J 1.9, 1H, 5-
CH), 5.67 (d, J 1.9, 1H, 3-CH), 3.15 (s, 6H, 4NMe2), 3.06 (s, 6H,
2NMe2). dC (CDCl3, 125 MHz) 160.6, 156.8, 152.9, 147.5,
147.4, 127.5, 123.6, 95.8, 86.9, 39.7, 38.2. m/z (HRMS EI)
287.1498; C15H19N4O2 [M þ H]þ requires 287.1503. Anal.
Calc. for C15H18N4O2: C 62.92, H 6.34, N 19.57. Found:
C 62.98, H 6.57, N 19.41 %.
A mixture of the starting carboxamide (3.00 mmol) and 2.5
equivalents of DMADMA(7.50 mmol) was heated and stirred
vigorously in a closed vessel in an automatically controlled
constant temperature (300 W) CEM Corporation Discover
microwave unit. The set temperature varied from 100 to 1408C
depending on the reaction progress, and the irradiation times
were short: 10 min.
The starting carboxamides 11 are all commercially available.
The only exception was compound 11f, which was prepared
from the corresponding methyl ketone using a literature proce-
dure[48] (see Table 2).
N2,N2,N4,N4-Tetramethyl-6-(3-nitrophenyl)
pyridine-2,4-diamine (16d)
Yield: 26 % (223 mg), orange solid; mp 100.6–102.58C. nmax
/
N2,N2,N4,N4-Tetramethyl-6-phenylpyridine-2,4-
diamine (16a)
cmꢀ1 3108, 2975, 2925, 2886, 2848, 1601, 1541, 1510, 1398,
1332, 1258, 1200, 1067, 1029, 979, 792. dH (CDCl3, 500 MHz)
8.86 (t, J 2.0, 1H, 20-CH), 8.50 (dt, J1 8.0, J2 1.4, 1H, 60-CH),
8.20 (ddd, J1 8.4, J2 2.4, J3 1.1, 1H, 40-CH), 7.70 (t, J 8.0, 1H, 50-
CH), 6.72 (d, J 1.8, 1H, 5-CH), 5.72 (d, J 1.9, 1H, 3-CH), 3.08 (s,
6H, 4NMe2), 3.03 (s, 6H, 2NMe2). dC (CDCl3, 125 MHz) 160.0,
156.8, 151.2, 148.2, 142.1, 132.7, 129.7, 122.7, 120.7, 94.9,
86.7, 39.3, 37.8. m/z (HRMS EI) 287.1499; C15H19N4O2
[M þ H]þ requires 287.1503. Anal. Calc. for C15H18N4O2:
C 62.92, H 6.34, N 19.57. Found: C 62.79, H 6.34, N 19.57 %.
Yield: 20 % (76 mg), brown solid; mp 84.4–88.28C. nmax
/
cmꢀ1 3048, 2980, 2918, 2885, 2795, 1593, 1573, 1538, 1400,
1324, 1163, 1026, 976, 779. dH (CDCl3, 500 MHz) 8.02–7.99
(m, 2H, Ph), 7.44–7.37 (m, 2H, Ph), 7.35–7.31 (m, 1H, Ph), 6.47
(d, J 1.9, 1H, 5-CH), 5.63 (d, J 1.9, 1H, 3-CH), 3.14 (s, 6H,
2
4NMe2), 3.03 (s, 6H, NMe2). dC (CDCl3, 125 MHz) 160.6,
156.9, 155.6, 128.2, 128.1, 126.9, 94.9, 86.0, 39.7, 38.3. m/z
(HRMS EI)242.1654; C15H20N3 [M þ H]þ requires 242.1652.
Anal. Calc. for C15H19N3ꢂ1/7MeOH: C 73.96, H 8.02, N 17.09.
Found: C 74.37, 8.04, 16.71 %. Compound 16a: C15H19N3, Mr
6-(4-Methoxyphenyl)-N2,N2,N4,N4-
tetramethylpyridine-2,4-diamine (16e)
241.33, Dx 1.212 Mg mꢀ3, monoclinic, P121/c1, a 15.3125(4),
3
b 7.2109(2), c 24.5888(6) A, b 102.956(2)8, V 2645.90(12) A ,
˚
˚
Yield: 19 % (154 mg), white solid; mp 100.8–105.68C. nmax
/
cmꢀ1 3075, 3001, 2923, 2894, 2798, 1593, 1537, 1508, 1426,
1394, 1244, 1164, 1030, 785. dH (CDCl3, 300 MHz) 8.03–7.96
(m, 2H, 20-CH and 60-CH), 7.03–6.92 (m, 2H, 30-CH and
50-CH), 6.45 (d, J 1.9, 1H, 5-CH), 5,64 (d, J 1.9, 1H, 3-CH),
3.16 (s, 6H, 2NMe2), 3.05 (s, 6H, 4NMe2). dC (CDCl3, 75.5 MHz)
160.7, 159.9, 157.1, 155.3, 134.1, 128.2, 113.7, 94.2, 85.8, 55.4,
39.7, 38.3. m/z (HRMS EI) 272.1759; C16H22N3O [M þ H]þ
requires 272.1757. Anal. Calc. for C16H21N3O: C 70.82, H 7.80,
N 15.49. Found: C 70.69, H 8.04, N 15.46 %.
Z
8, prism, brown, 0.45 ꢁ 0.35 ꢁ 0.20 mm3,
T 150 K,
˚
5.748ꢀ54.968 2y, MoKa radiation, l 0.7107 A, SuperNova-Atlas
single-crystal diffractometer, 15 804 measured, 6066 indepen-
dent, and 4781 observed reflections, Rint 0.0237, v scans,
refinement on F2, R[F2 . 2s(F2)] 0.0523, wR(F2) 0.1441,
S 1.020, 6066 contributing reflections, 333 parameters, Drmax
0.235 e Aꢀ3, Drmin ꢀ0.245 e A
.
ꢀ3
˚
˚
N2,N2,N4,N4-Tetramethyl-6-(3-(trifluoromethyl)phenyl)
pyridine-2,4-diamine (16b)
6-(Furan-2-yl)-N2,N2,N4,N4-tetramethylpyridine-2,4-
diamine (16f)
Yield: 29 % (247 mg), yellow oil. nmax/cmꢀ1 3114, 2924,
2883, 2853, 2797, 1743, 1672, 1611, 1541, 1498, 1399, 1324,
Yield: 31 % (193 mg), yellow-brown solid; mp 71.3–77.28C.
max/cmꢀ1 3077, 2929, 2893, 2856, 2802, 1601, 1542, 1494,
1327, 1241, 1197, 1149, 1106, 1068, 1028, 785. dH (CDCl3,
n
500 MHz) 8.26 (t, J 1.8, 1H, 20-CH), 8.18 (dt, J1 7.8, J2 1.5, 1H,

194
B. Prek et al.
1153, 1024, 1004, 798. dH (CDCl3, 500 MHz) 7.44 (dd, J1 1.8, J2
0.9, 1H, 50-CH), 6.95 (dd, J1 3.3, J2 0.9, 1H, 30-CH), 6.50 (d, J
2.0, 1H, 5-CH), 6.47 (dd, J1 3.3, J2 1.8, 1H, 40-CH), 5.56 (d, J
2.0, 1H, 3-CH), 3.10 (s, 6H, NMe2), 3.02 (s, 6H, NMe2). dC
(CDCl3, 125 MHz) 160.6, 156.7, 155.5, 147.5, 142.0, 111.6,
107.3, 93.1, 86.0, 39.6, 38.1. m/z (HRMS EI) 232.1446;
C13H18N3O [M þ H]þ requires 232.1444.
diffractometer, 6959 measured, 2960 independent, and 2355
observed reflections, Rint 0.0182, v scans, refinement on F2,
R[F2 . 2s(F2)] 0.0476, wR(F2) 0.1424, S 1.097, 2960 contrib-
2
4
uting reflecꢀti3ons, 167 parameters, Drmax 0.266 e Aꢀ3, Drmin
˚
˚
ꢀ0.196 e A
.
N2,N2,N4,N4-Tetramethyl-6-(pyrazin-2-yl)pyridine-2,4-
diamine (16j)
N4,N4,N6,N6-Tetramethyl-2,40-bipyridine-4,6-
diamine (16g)
Yield: 36 % (266 mg), yellow-green solid; mp 110.7–117.38C.
max/cmꢀ1 3044, 2972, 2926, 2892, 2851, 1599, 1540, 1426,
n
Yield: 38 % (276 mg), yellow-white solid; mp 183.4–
186.08C. nmax/cmꢀ1 3099, 3070, 2920, 2857, 2801, 1720,
1590, 1536, 1455, 1333, 1251, 1159, 1024, 781. dH (d6-DMSO,
500 MHz) 8.62–8.59 (m, 2H, 20-CH and 60-CH), 8.03–7.98 (m,
2H, 30-CH and 50-CH), 6.73 (d, J 1.8, 1H, 3-CH), 5.73 (d, J 1.8,
1H, 5-CH), 3.06 (s, 6H, NMe2), 3.01 (s, 6H, NMe2). dC (d6-
DMSO, 125 MHz) 160.1, 156.7, 151.1, 149.8, 147.4, 120.8,
95.3, 87.3, 39.2, 37.8. m/z (HRMS EI) 243.1603; C14H19N4
[M þ H]þ requires 243.1603. Anal. Calc. for C14H18N4:
C 69.39, H 7.49, N 23.12. Found: C 69.45, H 7.67, N 23.18 %.
Compound 16g: C14H18N4, Mr 242.32, Dx 1.269 Mg mꢀ3, ortho-
1395, 1234, 1062, 978, 811. dH (CDCl3, 500 MHz) 9.64 (d, J 1.5,
1H, 30-CH), 8.54 (dd, J1 2.6, J2 1.5, 1H, 50-CH), 8.51 (d, J 2.5,
1H, 60-CH), 7.16 (d, J 2.0, 1H, 5-CH), 5.71 (d, J 2.0, 1H, 3-CH),
3.16 (s, 6H, 2NMe2), 3.07 (s, 6H, 4NMe2). dC (CDCl3, 125 MHz)
160.7, 157.1, 152.9, 152.1, 144.1, 143.8, 143.2, 95.9, 87.9, 39.8,
38.5. m/z (HRMS EI) 244.1556; C13H18N5 [M þ H]þ requires
244.1557. Anal. Calc. for C13H17N5: C 64.17, H 7.04, N 28.78.
Found: C 64.09, H 7.20, N 28.51 %. Compound 16j: C13H17N5,
6
4
Mr 243.32, Dx 1.270 Mg mꢀ3, orthorhombic, Cmcm, a 6.7919(4),
3
˚
˚
b 11.1592(4), c 16.7932(8) A, V 1272.79(11) A , Z 4, platelet,
yellow, 0.30 ꢁ 0.20 ꢁ 0.03 mm3, T 293 K, 7.028ꢀ54.968 2y,
˚
˚
rhombic, Fdd2, a 16.4792(10), b 14.0329(7), c 10.9681(6) A,
3
MoKa radiation, l 0.7107 A, SuperNova-Atlas single-crystal
3
˚
V 2536.4(2) A , Z 8, prism, yellow, 0.40 ꢁ 0.30 ꢁ 0.25 mm ,
diffractometer, 6827 measured, 820 independent, and 619
observed reflections, Rint 0.0240, v scans, refinement on F2,
R[F2 . 2s(F2)] 0.0528, wR(F2) 0.1577, S 1.122, 820 contribut-
˚
T 150 K, 7.628ꢀ54.968 2y, MoKa radiation, l 0.7107 A,
SuperNova-Atlas single-crystal diffractometer, 12 835 mea-
sured, 1452 independent, and 1348 observed reflections, Rint
0.0387, v scans, refinement on F2, R[F2 . 2s(F2)] 0.0430,
wR(F2) 0.1228, S 0.975, 1452 contributing refꢀle3ctions, 86
ing reflectiꢀo3ns, 61 parameters, Drmax 0.131 e Aꢀ3, Drmin
˚
˚
ꢀ0.220 e A
.
parameters, Drmax 0.260 e Aꢀ3, Drmin ꢀ0.216 e A
.
˚
˚
X-Ray Structure Analysis for Compounds 5c, 5g, 5i,
5j, 5m, 16a, 16b, 16g, 16i, and 16j
N4,N4,N6,N6-Tetramethyl-2,30-bipyridine-4,6-
diamine (16h)
Crystals appropriate for X-ray analysis were prepared by crys-
tallisation from a mixture of ethyl acetate and petroleum ether.
Diffraction data for the above mentioned compounds were
collected on a SuperNova X-ray single crystal diffractometer
equipped with Atlas detector using monochromated MoKa
radiation at 150 K (for 5c, 16a, 16g, and 16i) or ambient
temperature for the remaining structures. Data reduction and
integration were performed with the software package CrysAlis
PRO.[49] The coordinates of all of the non-hydrogen atoms were
found via direct methods using the SIR97, Supeflip, or Olex2
structure solution programs.[50–52] A full-matrix least-squares
refinement on F2 magnitudes with anisotropic displacement
parameters for all non-hydrogen atoms using SHELXL-97 was
employed.[53] All hydrogen atoms were initially located in
difference Fourier maps. All H atoms attached to carbon were
subsequently treated as riding atoms in geometrically idealized
Yield: 24 % (200 mg), brown solid; mp 83.8–89.48C. nmax
/
cmꢀ1 3053, 2924, 2871, 2838, 2800, 1719, 1594, 1538, 1404,
1324, 1268, 1162, 1022, 790. dH (CDCl3, 500 MHz) 9.20 (d, J
2.2, 1H, 20-CH), 8.57 (dd, J1 4.8, J2 1.7, 1H, 40-CH), 8.30 (dt, J1
7.9, J2 2.0, 1H, 60-CH), 7.33 (ddd, J1 7.9, J2 4.8, J3 0.9, 1H, 50-
CH), 6.46 (d, J 1.9, 1H, 3-CH), 5.65 (d, J 1.9, 1H, 5-CH), 3.14 (s,
6H, 4NMe2), 3.05 (s, 6H, 6NMe2). dC (CDCl3, 125 MHz) 160.7,
156.9, 152.9, 149.1, 148.5, 136.6, 134.3, 123.2, 94.9, 86.3, 39.6,
38.2. m/z (HRMS EI) 243.1606; C14H19N4 [M þ H]þ requires
243.1604. Anal. Calc. for C14H18N4: C 69.39, H 7.49, N 23.12.
Found: C 69.46, H 7.75, N 23.12 %.
N4,N4,N6,N6-Tetramethyl-2,20-bipyridine-4,6-
diamine (16i)
˚
Yield: 14 % (102 mg), oily brown solid; mp 52.3–60.98C.
max/cmꢀ1 3108, 2980, 2918, 2842, 2797, 1705, 1598, 1538,
positions with bond lengths C–H of 0.96/0.98 A for methyl and
˚
0.93/0.95 A for aromatic C–H bonds (the first number refers to
n
1476, 1396, 1325, 1288, 1106, 738. dH (d6-DMSO, 500 MHz)
8.60 (ddd, J1 4.9, J2 1.9, J3 0.9, 1H, 30-CH), 8.33 (dt, J1 8.0, J2
1.1, 1H, 60-CH), 7.86 (td, J1 8.0, J2 1.8, 1H, 40-CH), 7.35 (ddd, J1
7.5, J2 4.7, J3 1.2, 1H, 50-CH), 7.18 (d, J 2.0, 1H, 3-CH), 5.75 (d,
J 2.1, 1H, 5-CH), 3.07 (s, 6H, 6NMe2), 3.00 (s, 6H, 4NMe2). dC
(d6-DMSO, 125 MHz) 159.9, 156.8, 156.6, 152.8, 148.6, 136.7,
123.3, 120.3, 94.6, 87.3, 39.2, 37.8. m/z (HRMS EI) 243.1604;
C14H19N4 [M þ H]þ requires 243.1604. Anal. Calc. for
C14H18N4: C 69.39, H 7.49, N 23.12. Found: C 69.09, H 7.58,
N 23.18 %. Compound 16i: C14H18N4, Mr 242.32, Dx 1.245 Mg
ambient and the second to low temperature). The corresponding
displacement parameters Uiso(H) were 1.5-times higher than
those of the carrier methyl carbons and 1.2-times higher than
aromatic hydrogen bearing carbon atoms. All hydrogen atoms
attached to heteroatoms and possibly taking part in hydrogen
bonding were obtained from the difference electron density map
˚
and refined freely or with bond length restraint N–H 0.87(2) A.
Figures depicting the structures were prepared by ORTEP3.[54]
In 16g and 16j, an asymmetric unit represents half of the
molecule, thus several carbon and nitrogen atoms are symmetry
disordered over two sites with occupancies 0.50. In 5c and 16b,
the CF3 group is also disordered over two sites; only one of them
is represented in the ORTEP molecular scheme. In 5i and 5j,
positional disorder between S1 and C1 or O3 and C11 is present.
m
(3) A, b 107.795(4)8, V 1293.28(8) A , Z 4, prism, brown,
ꢀ3, monoclinic, P121/c1, a 6.1248(2), b 28.0478(11), c 7.9067
3
˚
˚
0.40 ꢁ 0.25 ꢁ 0.20 mm3, T 150 K, 5.608ꢀ54.968 2y, MoKa
˚
0.7107 A, SuperNova-Atlas single-crystal
radiation,
l

Metal-Free Synthesis of Trisubstituted Pyridines
195
CCDC 1004681–1004690 contain the supplementary crys-
tallographic data for this paper. These data can be obtained free
of charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
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formulae and yields, 1H and 13C NMR spectra, and MS spectra
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