Formation of new pyridyl substituted enamines. Observation of a diaza-Cope rearrangement

Article abstract of DOI:10.1016/j.tet.2008.08.065

Some 2-arylthiopyridinium imides when reacted with dimethyl acetylene dicarboxylate exhibited ambident behaviour: either a 1,3-dipolar cyclization occurred followed by a ring transformation to yield pyrrolopyridines or 5-pyridyl substituted enamines were formed in a different route. Mechanistic considerations revealed that this latter unusual transformation is initiated by a Michael addition of the imide nitrogen atom of the starting pyridinium compound on the reagent, which is followed by a [3,3]-sigmatropic ('diaza-Cope') rearrangement. Ring opening of the pyrrolopyridine compounds by a base also yielded pyridylenamines, which proved to be positional isomers of the sigmatropic rearrangement products. The new pyridyl derivatives seem to be valuable compounds for further transformations. Thus, they can undergo thermal electrocyclization to 7-azaindoles.

Full text of DOI:10.1016/j.tet.2008.08.065

Tetrahedron 64 (2008) 10375–10380
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Formation of new pyridyl substituted enamines. Observation of a diaza-Cope
rearrangement
*
´
¨
´
Roberta Palko, Orsolya Egyed, Petra Bombicz, Zsuzsanna Riedl, Gyorgy Hajos
Chemical Research Center, Hungarian Academy of Sciences, H-1025 Budapest, Pusztaszeri u´t 59, Hungary
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 17 June 2008
Received in revised form 1 August 2008
Accepted 21 August 2008
Available online 28 August 2008
Some 2-arylthiopyridinium imides when reacted with dimethyl acetylene dicarboxylate exhibited am-
bident behaviour: either a 1,3-dipolar cyclization occurred followed by a ring transformation to yield
pyrrolopyridines or 5-pyridyl substituted enamines were formed in a different route. Mechanistic con-
siderations revealed that this latter unusual transformation is initiated by a Michael addition of the imide
nitrogen atom of the starting pyridinium compound on the reagent, which is followed by a [3,3]-sig-
matropic (‘diaza-Cope’) rearrangement. Ring opening of the pyrrolopyridine compounds by a base also
yielded pyridylenamines, which proved to be positional isomers of the sigmatropic rearrangement
products. The new pyridyl derivatives seem to be valuable compounds for further transformations. Thus,
they can undergo thermal electrocyclization to 7-azaindoles.
Keywords:
Mesomeric betaine
Cycloadditions
Michael-addition
Diaza-Cope rearrangement
Electrocyclization
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
route besides an alternative one. Thus, careful analysis of the re-
action mixture seemed of high interest.
In our earlier study1,2 we have reported that some sulfur-con-
taining pyridyl mesomeric betaines (2)deasily available from
tetrazolopyridinium salts (1)dreadily undergo cycloadditions as
1,3-dipoles. Thus, reaction of 2 with dimethyl acetylene dicarbox-
ylate (DMAD) yielded the pyrrolopyridine compound 4. Formation
of this product was rationalized by a 1,3-dipolar cycloaddition be-
tween 2 and DMAD to give a cycloadduct (3), which undergoes ring
transformation to the fused pyrrole 4 (Scheme 1).
2. Results and discussion
Thin layerchromatographyof the mixture obtained from the reaction
of 2 and DMAD indicated that besides 4, another well-defined compo-
nent was also present in the mother liquor. Column chromatographic
separation allowed the isolation of a new crystalline product, the spectra
of which seemed to be in accordance with the structure 6 (Scheme 2).
R
S
R
S
R
S
R
S
R
S
N
N
DMAD
rt
Ar
SR
N
R
S
N
N
N
N
Ar
Ar
N
N
E
N
E
MeOOC
N
DMAD
rt
N
Ar
+
Ar
A
N
2
N
Ar
1
E
E
N
MeOOC
NH
Ar
3
4
COOMe
MeOOC
2
Scheme 1.
4
6
Similar transformations were also experienced with other
Ar
R
4 (%) 6 (%)
dipolarophiles, e.g., with N-phenylmaleinimide and fumaronitrile.
The finding that the yield of 4 (17%) was substantially lower than
those of the cycloadducts obtained with other dipolarophiles (50–
70%) indicated that this reaction pathway might be only a minor
a
b
c
d
e
f
4-Cl-C6H4-
4-Cl-C6H4-
4-CH3-C6H4- 4-CH3-C6H4-
4-CH3-C6H4-
4-CH3-C6H4-
4-Cl-C6H4-
4-Cl-C6H4-
4-CH3-C6H4-
27
17
26
21
-
15
36
20
18
24
24
4-Cl-C6H4-
C6H5-CH2-
C6H5-CH2-
-
* Corresponding author. Tel.: þ36 14381110; fax: þ36 14381145.
Scheme 2.
´
E-mail address: ghajos@chemres.hu (G. Hajos).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.08.065

10376
R. Palko´ et al. / Tetrahedron 64 (2008) 10375–10380
This structural assignment was also verified by single crystal X-ray
diffraction.
interactions, but two C–H/p interactions are found to the aromatic
rings: C4–H4A/ringC13–C18 2.74 Å, 150ꢀ [1ꢁX,2ꢁY,1ꢁZ]; C6–H6C/
ringC19–C24 2.54 Å, 155ꢀ [ꢁ1þX,Y,Z]. There is one oxygen (O3) rela-
tively close to the ringC13–C18: 3.869 Å and 94.8ꢀ [1þX,1þY,1þZ].
The fact that the sequence of C and N atoms in the products 4 and
6 is entirely different suggests that these two compounds are
formed via different pathways. Furthermore the structural feature
Thereisonemolecule intheasymmetricunitofcrystalstructureof
(2Z)-2-[6-(benzylsulfanyl)pyridin-3-yl]-3-[(4-methylphenyl)amino]
but-2-enedioate (6e) (Fig. 1).3 It crystallizes in the triclinic crystal
system, space group P-1 (No. 2). The quality of the crystal was good,
the measurement was performed at low temperature (117 K), the
structure is ordered, it was possible to locate all hydrogen atoms in
the difference Fourier maps, and to refine the structure to R¼0.0334
of 6, where the pyridine ring is attached in position 5 to the b-car-
bon atom of an enamine moiety strongly suggests that a pre-
dominant rearrangement has taken place. A likely reaction route
can be defined (Scheme 3) by supposing that the observed 1,3-di-
for I>2
s. The unit cell contains no residual solvent accessible void.
Packing coefficient is 69.7%.
Figure 1. ORTEP diagram4 of (2Z)-2-[6-(benzylsulfanyl)pyridin-3-yl]-3-[(4-methylphenyl)amino]but-2-enedioate (6e) represented at 50% probability level, heteroatoms are shaded.
One strong and one weak intramolecular interaction contributes
to the stability of the molecular conformation, their graph set de-
scriptors5 are S6 and S7, respectively: N1–H1/O3 (D–H¼0.880 Å,
H/A¼1.950 Å, D/A¼2.6323(15) Å, D–H/A¼133ꢀ), C20–H20/O1
polar cycloadditions might proceed, not only in a concerted manner,
but also in two steps, of which the first can be a Michael addition to
a. If the second step is formation of the 4-azaindole derivative 4, the
regular 1,3-cycloaddition product will be formed as shown in
Scheme 2. There is, however, a possibility for a [3,3]-sigmatropic
(D–H¼0.950 Å,
H/A¼2.540 Å,
D/A¼3.3482(17) Å,
D–H/
A¼143ꢀ). With the attractive but weak C–H/O type intermolecular
interaction [2ꢁx,4ꢁy,2ꢁz]C23–H23/O3 (D–H¼0.950 Å, H/
A¼2.400 Å, D/A¼3.2362(16) Å, D–H/A¼147ꢀ) repeated by the
symmetry centre, two molecules form a dimer. The graph set de-
scriptor5 of the ring is R24(14) (Fig. 2).
rearrangement with participation of the C5–C6–N1–Na
–C10–C20
string of atoms having double bonds at each terminal atom pair (see
mesomeric structure b). As a result of this diaza-Cope rearrange-
ment, the N1–Na
bond is broken and the C5–C20 bond is established
(i.e., c is formed, which is also illustrated by its mesomeric structure
d). Finally, the product can be stabilized by tautomerism to the
heteroaromatic 6. An analogous conversion taking place by a dif-
ferent mechanism has been reported by Sasaki et al.6
There are no more strong intermolecular interactions in the
crystal structure owing to the lack of donors, although several
potential acceptors are present. There are no attractive
p/p
Figure 2. The two molecules of 6e forming a dimer around the symmetry centre.

R. Palko´ et al. / Tetrahedron 64 (2008) 10375–10380
10377
R
S
R
S
E
N
N
Ar
N
Ar
N
H
E
2
6
DMAD
Michael addition
S
N
S
S
2
S
R
R
Ar
R
R
3
6
4
1
5
N
E
N
N
α
N
N
N
Ar
H
H
E
H
E
N
1'
E
Ar
Ar
E
2'
E
E
E
(d)
(c)
(b)
(a)
Scheme 3.
In one case, interestingly, the formation of the 4-azaindole (4a)
from (2e) was accompanied by formation of a new type of product
(7), which can be regarded as an addition product of the expected
4e and benzylmercaptan (Scheme 4). Such a product can obviously
be formed by nucleophilic addition of the thiolate on the pyridine
C3–C4 double bond.
The new pyridyleneamines seemed to have structural feature
potentially enabling further cyclization reactions. Recently we have
described that azinylaldehyde hydrazones can undergo electro-
cyclization to yield fused pyrazoloazines.8 Since the difference be-
tween the electronic structures of these reported hydrazones and 6
is only the presence of a N or C atom, a similar thermal cyclization
with 6 is possible. In order to explore this synthetic possibility,
some derivatives of 6 were subjected to heating for prolonged time.
As expected, cyclization to fused pyrroles was found and the 7-
azaindoles 9a–c were obtained in medium yield (Scheme 6). The
cyclization was found to proceed in a regioselective manner, and
the side chain N atom attached to the C6 of the pyridine ring in
every case. In contrast to some 7-azaindole syntheses reported in
the literature,9,10 our finding represents a new compilation mode of
this ring system. The synthesis and reactivity of this important class
of compounds has been recently reviewed.11
S
S
3
4
2
1
Me
N
DMAD
rt
+
6e
N
MeOOC
2e
COOMe
7
Scheme 4.
R
S
R
S
In order to support this mechanism, the isolated 4-azaindole 4a
was reacted with benzylthiolate. Formation of a product related to 7
was, unexpectedly, not observed and, instead, the ring opening of
the pyrrole moiety was found, and 6-pyridylenamine (8) was
obtained in very low yield (Scheme 5). The fact that arylthio struc-
tural moiety was not incorporated in the structure of this compound
revealed that the thiolate anion acted as a base rather than a nucle-
ophile: most probably the C6–H was deprotonated and ring-chain
tautomerism of this intermediate lead to formation of the open
chained enamine. The driving force of this transformation is clearly
formation of the aromatic pyridine moiety. The same conversion can
be more conveniently carried out by using pyrrolidine as a base and,
thus, the 4/8 transformation takes place in acceptable (51%) yield.
Comparison of structures 8 and 6 reveals, interestingly, that in these
transformations two positionally isomeric derivatives were formed
in independent reaction pathways. Our literature search revealed
that very few such pyridinyl enamines have been described.7
MeOOC
N
N
1,2-dichlorobenzene
110 °C
MeOOC
MeOOC
Ar
N
N
COOMe
Ar
H
6a,b,f
9
9
a
Ar
4-Cl-C6H4
R
4-Cl-C6H4
b
c
4-Cl-C6H4 4-Me-C6H4
4-Cl-C6H4
benzyl
Scheme 6.
3. Conclusion
The above findings reveal that recognition of a side-product in
some cycloaddition reactions allowed the discovery of a new
rearrangement pathway yielding new enaminopyridine de-
rivatives. These compounds can serve as valuable starting materials
for novel ring closure reactions.
R
S
R
S
N
H
N
N
H
B
Ar
MeOOC
Ar
COOMe
THF, CH2Cl2
4. Experimental part
4.1. General methods
COOMe
NH
MeOOC
4a
8
Ar, R = 4-Cl-C6H4
B = HSCH2Ph, pyrrolidine
Melting points were determined on a Bu¨chi apparatus and are
uncorrected. The IR spectra were recorded on a Thermo Nicolet
Scheme 5.

10378
R. Palko´ et al. / Tetrahedron 64 (2008) 10375–10380
Avatar 320 FT-IR spectrometer. NMR measurements were per-
formed on Varian INOVA-200 or Varian INOVA-400 spectrometers
equipped with a 5 mm inverse detection z-gradient probe. 1H and
13C NMR spectra were measured at room temperature (25 ꢀC) in an
appropriatesolvent.1Hand 13C chemical shiftsare expressed inparts
J¼9.7þ4.4 Hz, H7), 6.98 (2H, m, H300þH500), 7.14 (2H, m, H200þH600),
7.31 (2H, m, H20þH60), 7.47 (2H, m, H30þH50). 13C NMR (CDCl3)
d
(ppm): 20.9, 51.0, 52.8, 56.9, 61.7, 105.6, 122.8, 124.1, 126.8, 127.7,
128.8, 130.1, 134.8, 135.5, 135.9, 136.6, 157.7, 167.6, 167.7, 170.0. Anal.
Calcd for C24H21ClN2O4S (468.09): C, 61.47; H, 4.51; N, 5.97. Found:
C, 61.33; H, 4.15; N, 5.97.
per million (d) referenced to residual solvent signals. The elemental
analysis has been carried out with an Elementar Vario EL III appa-
ratus (at the Analytical Laboratory for Organic Chemistry, Chemical
Research Center, Hungarian Academy of Sciences, H-1025 Budapest,
4.2.4. Dimethyl (2Z)-2-[(4-chlorophenyl)amino]-3-{6-[(4-
chlorophenyl)sulfanyl]pyridin-3-yl}but-2-enedioate (6a)
´
Pusztaszeri ut 59). Chromatographic separations werecarried outon
Prepared from 2a, colorless crystals (0.076 g, 15%), mp 129–
134 ꢀC. IR (KBr) nmax: 3270, 2950, 1736, 1662, 1583, 1220, 1092, 1014,
aluminium oxide (activated, neutral, Brockmann I, approx. 150
mesh, Sigma–Aldrich). Reactions were monitored with Merck alu-
minium oxide 60 F254, neutral, precoated TLC plates (0.25 mm
thickness). All the chemicals and solvents were used as supplied.
Syntheses of pyridinium arylimides (2a–f)1,2,12 and dimethyl 1-
(4-chlorophenyl)-5-[(4-chlorophenyl)sulfanyl]-1H-pyrrolo[3,2-b]
pyridine-2,3-dicarboxylate (4a)2 have been published earlier.
818, 748 cmꢁ1
. d (ppm): 3.41 (3H, s, O–CH3 (b)),
1H NMR (CDCl3)
3.72 (3H, s, O–CH3
(
a
)), 6.82 (1H, d, J¼8 Hz, H3), 6.95 (2H, m,
H200þH600), 7.20–7.60 (7H, m, H300þH500þH20þH30þH50þH60þH4),
8.26 (1H, d, J¼2 Hz, H6), 10.6 (1H, s, NH). 13C NMR (CDCl3)
d (ppm):
51.7, 52.5, 98.4, 120.4, 122.9, 127.8, 129.5, 129.6, 129.8, 130.7, 135.3,
136.0, 137.8, 139.4, 149.9, 151.3, 159.0, 163.7, 169.5. Anal. Calcd for
C23H18Cl2N2O4S (488.04): C, 56.45; H, 3.71; N, 5.72; S, 6.55. Found:
4.2. General procedure for reaction of aryl- and
benzylsulfanylpyridinium arylimides with DMAD
C, 56.52; H, 3.67; N, 5.66; S, 6.67.
4.2.5. Dimethyl (2Z)-2-[(4-chlorophenyl)amino]-3-{6-[(4-
methylphenyl)sulfanyl]pyridin-3-yl}but-2-enedioate (6b)
Prepared from 2b, colorless crystals (0.170 g, 36%), mp 110–
A solution of the appropriate pyridinium arylimide (1 mmol)
and DMAD (1.35 mmol, 163 mL) in abs dichloromethane (5 mL) was
stirred at room temperature, and the progress of the reaction was
monitored by TLC. After disappearance of the starting material (1–
4 h) the solution was evaporated and treated with diethyl ether to
give white precipitate (4). The filtrate was then evaporated and
subjected to column chromatography on alumina with a mixture of
hexane–ethyl acetate (4:1) as eluent. Separation of the main frac-
tion around Rf¼0.6 gave the appropriate compound (6).
113 ꢀC. IR (KBr) nmax: 2951,1737,1664,1601,1219,1023, 814 cmꢁ1. 1H
0
NMR (CDCl3)
d
(ppm): 2.40 (3H, s, CH3 ), 3.40 (3H, s, O–CH3
(b
)),
3.68 (3H, s, O–CH3
(
a
)), 6.77 (1H, d, J¼8 Hz, H3), 6.92 (2H, m,
H200þH600), 7.18–7.40 (5H, m, H300þH500þH30þH50þH4), 7.50 (2H, m,
H%þH60), 8.25 (1H, d, J¼2 Hz, H6), 10.56 (1H, s, NH). 13C NMR
(CDCl3) d (ppm): 21.2, 51.7, 52.5, 98.6,119.7,122.8,127.0,127.2,129.4,
130.4, 130.5, 135.2, 137.8, 139.2, 139.4, 149.8, 151.0, 160.8, 163.7,
169.6. Anal. Calcd for C24H21ClN2O4S (468.09): C, 61.47; H, 4.51; N,
5.97. Found: C, 61.39; H, 4.68; N, 5.98.
4.2.1. Dimethyl 1-(4-chlorophenyl)-5-[(4-methylphenyl)sulfanyl]-
1H-pyrrolo[3,2-b]pyridine-2,3-dicarboxylate (4b)
Prepared from 2b, colorless crystals (0.080 g, 17%), mp 94–
102 ꢀC. IR (KBr) nmax: 2949, 1733, 1689, 1591, 1495, 1439, 1220, 10605,
4.2.6. Dimethyl (2Z)-2-[(4-methylphenyl)amino]-3-{6-[(4-
methylphenyl)sulfanyl]pyridin-3-yl}but-2-enedioate (6c)
1014, 810 cmꢁ1
.
1H NMR (CDCl3)
d
(ppm): 2.34 (3H, s, CH3 ),
Prepared from 2c, colorless crystals (0.180 g, 20%), mp 128–
129 ꢀC. IR (KBr) nmax: 3267, 2949, 1737, 1664, 1583, 1218, 1044, 809,
3.70þ3.78 (6H, s, 2ꢂOCH3), 4.68 (1H, dd, J¼12.4þ5.3 Hz, H7a), 5.24
(1H, d, J¼12.4 Hz, H3a), 5.82 (1H, d, J¼11.2 Hz, H6), 6.10 (1H, dd,
J¼11.2þ5.3 Hz, H7), 7.02 (2H, m, H200þH600), 7.15 (2H, m, H30þH50),
7.30 (2H, m, H20þH60), 7.40 (2H, m, H300þH500). 13C NMR (CDCl3)
7480cmꢁ1. 1H NMR (CDCl3)
d
(ppm): 2.30 (3H, s, CH300), 2.40 (3H, s,
CH3 ), 3.38 (3H, s,O–CH3 (b)), 3.67 (3H, s, O–CH3 (a)), 6.77 (1H, d,
J¼8.2 Hz, H3), 6.92 (2H, m, H200þH600), 7.09 (2H, m, H300þH500), 7.24
(2H, m, H30þH50), 7.33 (1H, dd, J¼8.2þ2.3 Hz, H4), 7.50 (2H, m,
H20þH60), 8.24 (1H, d, J¼2.3 Hz, H6), 10.58 (1H, s, NH). 13C NMR
d
(ppm): 21.2, 51.2, 55.9, 56.6, 61.6, 114.7, 122.9, 124.4, 125.0, 125.8,
126.3, 129.4, 129.6, 131.0, 134.6, 136.3, 159.4, 163.0, 164.8, 168.8.
Anal. Calcd for C24H21ClN2O4S (468.09): C, 61.47; H, 4.51; N, 5.97; S,
6.83. Found: C, 61.25; H, 4.54; N, 5.83; S, 6.96.
(CDCl3)
d (ppm): 21.1, 21.5, 51.8, 52.6, 97.2, 120.0, 122.1, 127.6, 127.7,
130.2, 130.7, 135.3, 135.4, 136.9, 139.6, 139.7, 151.1, 151.5, 160.7, 164.2,
170.0. Anal. Calcd for C25H24N2O4S (448.15): C, 66.94; H, 5.39; N,
6.25. Found: C, 66.74; H, 5.58; N, 6.21.
4.2.2. Dimethyl 1-(4-methylphenyl)-5-[(4-methylphenyl)sulfanyl]-
1H-pyrrolo[3,2-b]pyridine-2,3-dicarboxylate (4c)
Prepared from 2c, colorless crystals (0.230 g, 26%), mp 145–
149 ꢀC. IR (KBr) nmax: 2951, 2919, 1738, 1698, 1609, 1514, 1438, 1218,
4.2.7. Dimethyl (2Z)-2-{6-[(4-chlorophenyl)sulfanyl]pyridin-3-yl}-
3-[(4-methylphenyl)-amino]but-2-enedioate (6d)
1066, 8021, 810, 769 cmꢁ1. 1H NMR (CDCl3)
d
(ppm): 2.31þ2.36 (6H,
Prepared from 2d, colorless crystals (0.087 g, 18%), mp 140–
142 ꢀC. IR (KBr) nmax: 3267, 2949, 1736, 1665, 1590, 1218, 1015,
s, CH3 þCH300), 3.71þ3.76 (6H, s, 2ꢂOCH3), 4.70 (1H, dd,
J¼12.6þ5.0 Hz, H7a), 5.27 (1H, d, J¼12.6 Hz, H3a), 5.80 (1H, d,
J¼9.1 Hz, H6), 6.10 (1H, dd, J¼9.1þ5.0 Hz, H7), 6.96 (2H, m,
H300þH500), 6.98 (2H, m, H20þH60), 7.0–7.20 (4H, m,
818 cmꢁ1. 1H NMR (CDCl3)
d
(ppm): 2.32 (3H, s, CH300), 3.40 (3H, s,
O–CH3 (
b
)), 3.73 (3H, s, O–CH3 (
a
)), 6.86 (1H, d, J¼8.5 Hz, H3), 6.91
(2H, m, H200þH600), 7.10 (2H, m, H300þH500), 7.38 (1H, dd,
H30þH50þH200þH600). 13C NMR (CDCl3)
d (ppm): 20.8, 21.1, 51.0, 52.8,
J¼8.5þ2 Hz, H4), 7.40 (2H, m, H30þH50), 7.54 (2H, m, H20þH60), 8.26
56.9, 61.7, 105.9, 122.5, 124.1, 125.8, 126.3, 129.6, 130.0, 134.5, 135.9,
136.4, 138.8, 159.1, 163.2, 165.0, 170.2. Anal. Calcd for C25H24N2O4S
(448.15): C, 66.94; H, 5.39; N, 6.25. Found: C, 66.77; H, 5.39; N, 6.24.
(1H, d, J¼2 Hz, H6), 10.58 (1H, s, NH). 13C NMR (CDCl3)
d (ppm):
20.8, 51.5, 52.3, 96.7, 120.4, 121.9, 128.2, 129.7, 129.8, 129.9, 135.2,
135.3, 135.9, 136.5, 139.6, 150.9, 151.5, 151.8, 158.6, 169.5. Anal. Calcd
for C24H21ClN2O4S (468.09): C, 61.47; H, 4.51; N, 5.97; S, 6.84.
Found: C, 61.12; H, 4.50; N, 5.91; S, 6.89.
4.2.3. Dimethyl 5-[(4-chlorophenyl)sulfanyl]-1-(4-methylphenyl)-
1H-pyrrolo[3,2-b]pyridine-2,3-dicarboxylate (4d)
Prepared from 2d, colorless crystals (0.100 g, 21%), mp 144–
4.2.8. Dimethyl (2Z)-2-[6-(benzylsulfanyl)pyridin-3-yl]-3-[(4-
methylphenyl)amino]but-2-enedioate (6e)
Prepared from 2e, yellow crystals (0.110 g, 24%), mp 108–110 ꢀC.
Besides this product, compound 7 was also separated from the
reaction mixture by chromatography as discussed below. IR (KBr)
148 ꢀC. IR (KBr) nmax: 2947, 1738, 1689, 1597, 1516, 1437, 1223, 1068,
1013, 819 cmꢁ1
.
1H NMR (CDCl3)
d
(ppm): 2.32 (3H, s, CH3),
3.70þ3.75 (6H, s, 2ꢂOCH3), 4.71 (1H, dd, J¼11.6þ4.4 Hz, H7a), 5.26
(1H, d, J¼11.6 Hz, H3a), 5.83 (1H, d, J¼9.7 Hz, H6), 6.13 (1H, dd,

R. Palko´ et al. / Tetrahedron 64 (2008) 10375–10380
10379
nmax: 2951, 1744, 1662, 1602, 1215, 1039, 816 cmꢁ1. 1H NMR (CDCl3)
d
4.5. General procedure for ring closure of pyridylenamines
(6) to pyrrolo[2,3-b]pyridines (9)
(ppm): 2.31 (3H, s, CH300), 3.33þ3.69 (6H, s, 2ꢂOCH3), 4.43 (2H, s,
CH2), 6.93 (2H, m, H200þH600), 7.10 (3H, m, H300þH500þH3), 7.20–7.50
(6H, m, H20þH30þH40þH50þH60þH4), 8.27 (1H, d, J¼2.5 Hz, H6),
A solution of the appropriate pyridylenamine 6 (0.6 mmol) in
o-dichlorobenzene (11 mL) was heated at 110 ꢀC until the starting
material disappeared, which was monitored by TLC (typically 168–
264 h). The organic solvent was removed in vacuo and the residue
was separated by column chromatography on alumina by a mixture
of hexane–ethyl acetate (2:1) as eluent.
10.54 (1H, s, NH). 13C NMR (CDCl3)
d (ppm): 20.8, 34.5, 51.5, 52.2,
97.1, 120.9, 121.8, 127.0, 127.4, 128.4, 128.9, 129.9, 135.0, 136.6, 137.9,
138.8, 150.8, 151.0, 157.1, 163.9, 169.7. Anal. Calcd for C25H24N2O4S
(448.15): C, 66.94; H, 5.39; N, 6.25. Found: C, 66.66; H, 5.37; N, 6.21.
4.2.9. Dimethyl (2Z)-2-[6-(benzylsulfanyl)pyridin-3-yl]-3-[(4-
chlorophenyl)amino]but-2-enedioate (6f)
4.5.1. Dimethyl 1-(4-chlorophenyl)-6-[(4-chlorophenyl)sulfanyl]-
1H-pyrrolo[2,3-b]pyridine-2,3-dicarboxylate (9a)
Prepared from 2f, yellow crystals (0.110 g, 24%), mp 126–128 ꢀC.
IR (KBr) nmax: 2955, 1743, 1666, 1593, 1217, 1112, 1037, 824 cmꢁ1. 1H
Prepared from 6a, white crystals (0.180 g, 60%), mp 127–135 ꢀC.
NMR (CDCl3)
d
(ppm): 3.36þ3.70 (6H, s, 2ꢂOCH3), 4.43 (2H, s, CH2),
IR (KBr) nmax: 2953, 1735, 1715, 1496, 1226, 1114, 821 cmꢁ1. 1H NMR
6.95 (2H, m, H200þH600), 7.10 (3H, m, H300þH500þH3), 7.20–7.50 (6H,
(CDCl3)
d
(ppm): 3.83þ3.93 (6H, s, 2ꢂOCH3), 7.06 (1H, d, J¼7.1 Hz,
m, H20þH30þH40þH50þH60þH4), 8.27 (1H, d, J¼2.5 Hz, H6), 10.57
H5), 7.26 (2H, m, H30þH50), 7.32 (2H, m, H300þH500), 7.39 (2H, m,
(1H, s, NH). 13C NMR (CDCl3)
d (ppm): 34.6, 51.8, 52.4, 98.8, 120.9,
H200þH600), 7.45 (2H, m, H20þH60), 8.26 (1H, d, J¼7.1 Hz, H4). 13C
122.8, 127.0, 128.4, 128.9, 129.4, 130.5, 137.8, 137.9, 138.7, 150.8,
151.2, 157.5, 163.7, 167.7, 169.7. Anal. Calcd for C24H21ClN2O4S
(468.09): C, 61.47; H, 4.51; N, 5.97. Found: C, 61.32; H, 4.43; N, 5.93.
NMR (CDCl3) d (ppm): 52.0, 53.5, 107.5, 115.3, 118.1, 128.1, 129.4,
129.6,131.7,133.6, 134.4,134.7, 135.5,136.7, 147.2, 149.8,157.2, 162.5,
163.7. Anal. Calcd for C23H16Cl2N2O4S (486.02): C, 56.68; H, 3.31; N,
5.75; S, 6.58. Found: C, 56.55; H, 3.23; N, 5.70; S, 6.74.
4.3. Dimethyl 5,7-bis(benzylsulfanyl)-1-(4-methylphenyl)-1H-
pyrrolo[3,2-b]pyridine-2,3-dicarboxylate (7)
4.5.2. Dimethyl 1-(4-chlorophenyl)-6-[(4-methylphenyl)sulfanyl]-
1H-pyrrolo[2,3-b]pyridine-2,3-dicarboxylate (9b)
Prepared from 6b, white crystals (0.130 g, 46%), mp 124–127 ꢀC.
The mixture obtained from the reaction of 2e and DMAD when
subjected to chromatography contained two products: the main
product was 6e as described above whereas another component of
Rf¼0.3 was also isolated as colorless crystals (0.025 g, 6%), mp 116–
119 ꢀC. IR (KBr) nmax: 3028, 2950, 1743, 1692, 1604, 1515, 1208, 1123,
IR (KBr) nmax: 2952, 1739, 1711, 1495, 1227, 1111, 814 cmꢁ1. 1H NMR
0
(CDCl3)
d
(ppm): 2.45 (3H, s, CH3 ), 3.83þ3.91 (6H, s, 2ꢂOCH3), 6.97
(1H, d, J¼8.6 Hz, H5), 7.19 (2H, m, H30þH50), 7.30–7.40 (4H, m,
H200þH300þH500þH600), 7.44 (2H, m, H20þH60), 8.21 (1H, d, J¼8.6 Hz,
H4). 13C NMR (CDCl3)
d (ppm): 21.2, 51.7, 53.2, 107.2, 114.6, 117.4,
702 cmꢁ1. 1H NMR (CDCl3)
d
(ppm): 2.15 (1H, ddd, J¼17þ1.5þ1 Hz,
127.0, 128.0, 129.1, 130.1, 131.3, 133.5, 134.1, 135.3, 139.3, 147.0, 149.1,
158.7, 162.3, 163.5. Anal. Calcd for C24H19ClN2O4S (466.08): C, 61.73;
H, 4.10; N, 6.00; S, 6.87. Found: C, 61.41; H, 4.03; N, 5.92; S, 7.01.
H60), 2.30 (3H, s, CH3 ), 2.55 (1H, ddd, J¼17þ5þ1.5 Hz, H600), 3.05
(1H, ddd, J¼5þ3þ1 Hz, H7), 3.70þ3.90 (6H, s, 2ꢂOCH3), 3.72 (2H,
m, S–CH2–Ph%), 4.04þ4.38 (2H, d, J¼12 Hz, S–CH2–Ph00), 4.20 (1H,
ddd, J¼8þ3þ1.5 Hz, H7a), 5.30 (1H, dd, J¼8þ1.5 Hz, H3a), 6.67 (2H,
m, H20þH60), 7.02 (2H, m, H30þH50), 7.20 (2H, m, H2%þH6%), 7.21
(1H, m, H400), 7.25 (3H, m, H3%þH4%þH5%), 7.26 (2H, m,
0
4.5.3. Dimethyl 6-(benzylsulfanyl)-1-(4-chlorophenyl)-1H-
pyrrolo[2,3-b]pyridine-2,3-dicarboxylate (9c)
Prepared from 6c, light yellow crystal (0.140 g, 50%), mp 85–
H300þH500), 7.32 (2H, m, H200þH600). 13C NMR (CDCl3)
d (ppm): 21.2,
93 ꢀC. IR (KBr) nmax: 2952, 1747, 1705, 1496, 1219, 1113, 821 cmꢁ1. 1H
32.0, 33.3, 35.4, 36.5, 51.4, 53.0, 60.2, 64.3, 107.0, 124.1, 127.1, 128.6,
128.9, 129.0, 129.3, 130.4, 135.6, 136.7, 137.8, 138.6, 152.2, 163.2,
165.2. Anal. Calcd for C32H32N2O4S2 (572.18): C, 67.11; H, 5.63; N,
4.89; S, 11.20. Found: C, 67.02; H, 5.93; N, 4.80; S, 11.21.
NMR (CDCl3)
d
(ppm): 3.83þ3.93 (6H, s, 2ꢂOCH3), 4.26 (2H, s, CH2),
7.18 (1H, d, J¼8.3 Hz, H5), 7.20–7.30 (5H, m, Ph), 7.38 (2H, m,
H300þH500), 7.58 (2H, m, H200þH600), 8.22 (1H, d, J¼8.3 Hz, H4). 13C
NMR d (ppm): 34.2, 51.7, 53.1, 107.7, 114.3, 118.4, 126.9, 128.2, 128.5,
128.8, 129.3, 131.0, 133.9, 134.6, 137.9, 138.7, 147.4, 156.3, 162.2,
163.6. Anal. Calcd for C24H19ClN2O4S (466.08): C, 61.73; H, 4.10; N,
6.00; S, 6.87. Found: C, 61.53; H, 4.24; N, 5.90; S, 7.06.
4.4. Dimethyl (2Z)-2-[(4-chlorophenyl)amino]-3-{6-[(4-
chlorophenyl)sulfanyl]-pyridin-2-yl}-but-2-enedioate (8)
Acknowledgements
A 60% suspension of NaH (0.019 g, 0.8 mmol) in THF (1 mL) was
cooled down to 10 ꢀC and a solution of pyrrolidine (0.028 g,
0.4 mmol) in THF (1 mL) was added. The mixture was heated at
reflux for 15 min, cooled to ꢁ40 ꢀC and a solution of 4a (0.1 g
0.2 mmol) in dichloromethane (4 mL) was added. The reaction
mixture was allowed to warm up to room temperature and was
stirred for 2 days. The organic solvent was removed by evaporation
and the residue was separated by column chromatography on
alumina using a mixture of hexane–ethyl acetate (8:2) as eluent.
Yellow crystals (0.050 g, 51%), mp 108–118 ꢀC. IR (KBr) nmax: 2950,
1743, 1568, 1497, 1432, 1213, 1094, 1013, 800 cmꢁ1. 1H NMR (CDCl3)
Financial support of projects GVOP-3.2.1-2004-04-0311/3.0,
GVOP-3.2.1-2004-0210/3.0, COST BM0701 (ATENS) as well as a dif-
fractometer purchase grant from the National Office for Research
and Technology (MU-00338/2003) are gratefully acknowledged.
References and notes
´
´
¨
¨
´
1. Messmer, A.; Ko¨ver, P.; Riedl, Zs.; Gomory, A.; Hajos, G. Tetrahedron 2002, 58,
3613.
´
´
´
´
´
2. Riedl, Zs.; Ko¨ver, P.; Soos, T.; Hajos, G.; Egyed, O.; Fabian, L.; Messmer, A. J. Org.
Chem. 2003, 68, 5652.
d
(ppm): 3.64þ3.75 (6H, s, 2ꢂOCH3), 6.74 (2H, m, H200þH600), 6.98
3. Thecrystalsof(2Z)-2-[6-(benzylsulfanyl)pyridin-3-yl]-3-[(4-methylphenyl)amino]but-
2-enedioate (6e) are yellow prisms. The size of the crystal selected for single crystal
X-ray diffraction measurement is 0.50ꢂ0.35ꢂ0.25 mm. Formula is C25H24N2O4S and
formula weight is 448.52. It crystallizes in the triclinic crystal system, space group P-1.
(1H, dd, J¼8þ2.5 Hz, H5), 7.14 (2H, m, H20þH60), 7.22 (2H, m,
H300þH500), 7.38 (2H, m, H30þH50), 7.50 (1H, dd, J¼8.5þ8 Hz, H4),
7.62 (1H, dd, J¼8.5þ2.5 Hz, H3), 12.2 (1H, s, NH). 13C NMR (CDCl3)
The cell dimensions are a¼9.0469(17) Å, b¼11.532(2) Å, c¼12.298(2) Å,
a
¼111.382(8)ꢀ,
b
¼97.422(9)ꢀ,
g
¼106.297(8)ꢀ, V¼1107.5(4) Å3, Z¼2, F(000)¼472, Dx¼1.345 Mg mꢁ3. A
d
(ppm): 51.8, 52.5, 97.4, 108.7, 118.8, 120.6, 124.6, 129.1, 129.3, 129.7,
crystal was mounted on a loop in oil. The diffraction measurement was performed at
131.2, 134.9, 135.8, 137.1, 146.5, 149.1, 156.3, 161.5, 165.4. Anal. Calcd
for C23H18Cl2N2O4S (488.04): C, 56.45; H, 3.71; N, 5.72. Found: C,
56.49; H, 3.61; N, 5.68.
T¼117(2) K. Intensity data were collected on a Rigaku R-Axis Rapid diffractometer
(graphite monochromator, Mo K
a
radiation,
l
¼0.71073 Å) in the range 3.01ꢃ
q
ꢃ27.48ꢀ.
Cell parameters were determined by least-squares of the setting angles of 48,838

10380
collected reflections in the range 6.03ꢃ
R. Palko´ et al. / Tetrahedron 64 (2008) 10375–10380
q
ꢃ55.03ꢀ. A total of 52,894 reflections
7. Baldwin, J. J.; Mensler, K.; Ponticello, G. S. J. Org. Chem. 1978, 43, 4878.
´
´
´
´
¨
¨
´
were collected of which 5065 were unique [R(int)¼0.021, R(
s
)¼0.0094]; 4704
8. Filak, L.; Rokob, T. A.; Vasko, Gy. A.; Egyed, O.; Gomory, A.; Riedl, Zs.; Hajos, Gy.
reflections were >2
was applied to the data,
s
(I). Completeness to 2
q
¼0.999. An empirical absorption correction
J. Org. Chem. 2008, 73, 3900.
m
¼0.181 mmꢁ1, the minimum and maximum transmission
9. Molina, P.; Aller, E.; Lorenzo, M. A. Synthesis 1993, 1239.
10. Kanth, R. S.; Maitraie, D.; Reddy, V. G.; Narsaiah, B.; Rao, S. P. Heterocycles 2005,
65, 1415.
factors were 0.9148 and 0.9561. The structure was solved by direct methods with
SHELXS-97.13 Anisotropic full-matrix least-squares refinement with SHELXL-9714,15
on F2 for all non-hydrogen atoms yielded R1¼0.0334 and wR2¼0.0932 for 4704
´
11. Popowycz, F.; Routier, S.; Joseph, B.; Merour, J.-Y. Tetrahedron 2007, 63, 1031.
[I>2
s
(I)], R1¼0.0355 and wR2¼0.0932 for all (5065) intensity data (goodness-of-fit¼1.
12. Palko´, R.; Riedl, Zs.; Egyed, O.; Fa´bia´n, L.; Hajo´ s, G. J. Org. Chem. 2006, 71, 7805.
13. Sheldrick, G. M. SHELXS-97 Program for Crystal Structures Solution; University of
Go¨ttingen: Go¨ttingen, 1997.
14. Sheldrick, G. M. SHELXL-97 Program for the Refinement of Crystal Structures;
University of Go¨ttingen: Go¨ttingen, 1997.
061; the maximum and mean shift/esd 0.002 and 0.000). Number of parameters¼292.
The maximum and minimum residual electron density in the final difference map was
0.379 and ꢁ0.261 e Åꢁ3
.
The weighting scheme applied was w¼1/[
s
2(Fo2)þ(0.
0536P)2þ0.3678P], where P¼(Fo2þ2F2c)/3. Hydrogen atomic positions were located
in difference maps. Hydrogen atoms were included in structure factor calculations
but they were not refined. The isotropic displacement parameters of the
hydrogen atoms were approximated from the U(eq) value of the atom they were
bonded.16
15. Barbour, L. J. J. Supramol. Chem. 2001, 1, 189.
16. Crystallographic data (excluding structure factors) for the structure in this
paper have been deposited with the Cambridge Crystallographic Data Centre
as supplementary publication number CCDC 691696. Copies of the data can
be obtained, free of charge, on application to CCCD, 12 Union Road,
Cambridge CB2 1EZ, UK (fax: þ44 (0)1223 336033 or e-mail: deposit@ccdc.
cam.ac.uk).
4. Spek, A. L. J. Appl. Crystallogr. 2003, 36, 7.
5. Grell, J.; Bernstein, J.; Tinhofer, G. Acta Crystallogr. 2000, B56, 166.
6. Sasaki, T.; Kanematsu, K.; Kakehi, A. J. Org. Chem. 1971, 36, 2978.