Application of intramolecular cycloaddition/retro cycloaddition reactions for the synthesis of unsymmetrical 2,2′-bipyridine and 2-benzofuropyrazin-2-ylpyridine analogues

Article abstract of DOI:10.1016/j.tet.2004.05.011

1,2,4-Triazines bearing cycloalkeno[c]pyridine substituents at the 5-position, 2a-d, prepared by an intermolecular Diels-Alder reaction of bi-5,5-triazines with cyclic enamines, were provided with an alkynyloxy or a 2-cyanophenoxy group at the 3-position of the triazinyl unit. A subsequent intramolecular Diels-Alder reaction of the former, followed by loss of N ₂ leads to two new classes of 2,2′-bipyridine analogues containing different heterocyclic units, namely cycloalkeno[c]pyridine and 2,3-dihydrofuro- or 2,3-dihydropyrano[2,3-b]pyridine 8a-h; the intramolecular reaction of the 2-cyanophenoxy compound gives benzo[4,5]furo[2,3-b]pyrazine 10a-c.

Full text of DOI:10.1016/j.tet.2004.05.011

Tetrahedron 60 (2004) 6021–6027
Application of intramolecular cycloaddition/retro cycloaddition
reactions for the synthesis of unsymmetrical 2,20-bipyridine and
2-benzofuropyrazin-2-ylpyridine analoguesq
*
D. Branowska
Organic Chemistry, University of Podlasie, ul.3 Maja 54, 08-110 Siedlce, Poland
Received 17 February 2004; revised 14 April 2004; accepted 6 May 2004
Available online 8 June 2004
Abstract—1,2,4-Triazines bearing cycloalkeno[c]pyridine substituents at the 5-position, 2a–d, prepared by an intermolecular Diels–Alder
reaction of bi-5,5-triazines with cyclic enamines, were provided with an alkynyloxy or a 2-cyanophenoxy group at the 3-position of the
triazinyl unit. A subsequent intramolecular Diels–Alder reaction of the former, followed by loss of N2 leads to two new classes of 2,20-
bipyridine analogues containing different heterocyclic units, namely cycloalkeno[c]pyridine and 2,3-dihydrofuro- or 2,3-dihydropyrano[2,3-
b]pyridine 8a–h; the intramolecular reaction of the 2-cyanophenoxy compound gives benzo[4,5]furo[2,3-b]pyrazine 10a–c.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
reports we demonstrated the use of dimeric 1,2,4-triazines 1
as precursors for the preparation of 0a range of symmetrical 3
and unsymmetrical, annulated 2,2 -bipyridines (4, 5)16–19
(Scheme 1). This approach is based on the regioselective,
intermolecular DA-rDA reaction of 1 with cyclic enamines
to give a common intermediate 2. Subsequent treatment of 2
with an appropriate enamine leads to 3, 4 or 5 depending on
the dienophile used. The presence of alkylsulfanyl sub-
stituent in 2 makes these compounds attractive starting
materials for the synthesis of more elaborated bihetero-
cycles, because this group can be easily converted into an
alkylsulfonyl group, which is more reactive toward
nucleophilic reagents.
Aromatic biheterocycles and their complexes with metal
ions have found extensive use in coordination and
supramolecular chemistry.2 Particularly interesting and
useful are functionalized 2,20-bipyridines which have been
shown to exhibit important applications in the area of
catalysis,3 metal containing polymers,4 molecular elec-
tronics5 and optoelectronic devices6 and as photoactivated
species.7 Also monofunctionalized or unsymmetrical bis-
functionalized 2,20-bipyridines have received considerable
attention. These compounds are frequently used as reactive
intermediates8 or fine products9 and are attractive building
blocks for supramolecular chemistry.10
We now show that intramolecular DA-rDA reactions of 2,
substituted with a dienophilic side chain on the 1,2,4-
triazine ring, provide ready access to unsymmetrical 2,20-
bipyridines 8a–h consisting of two different heterocyclic
units: cycloalkeno[c]pyridines and dihydrofuro[2,3-b]- or
dihydropyrano[2,3-b]pyridines. The furo- and pyrano-
pyridine functionalities have emerged as useful pharmaco-
phores in several therapeutic areas.20 This approach evolved
from the developments in 1,2,4-triazine annulation
chemistry21 and from the high reactivity of this heterocycle
toward nucleophilic displacements.22 The essential features
of the strategy are summarized in the sequence depicted in
Scheme 2, wherein methylsulfonyl derivatives 6a–d were
envisaged as a key intermediates and the primary subgoals
of the project.
Various methods exist for the synthesis of unsymmetrical
bipyridines, of which the transition-metal catalyzed hetero-
aryl cross-coupling reactions of specially prepared
12,13
pyridines11 or Kronke–Potts
and Friedlander
¨
strategies14 are the most often employed. However, recent
efforts have centered around the synthesis of unsymmetrical
2,20-bipyridines by inverse electron demand [4þ2] cyclo-
addition/retro-cycloaddition Diels–Alder (DA-rDA) reac-
tion of suitably substituted 1,2,4-triazines.15 In previous
q See Ref. 1.
Keywords: Dimeric triazines; Intramolecular Diels–Alder reaction; 2,20-
Bipyridine analogues.
*
Tel.: þ48-25-6431106; fax: þ48-25-6431106;
Nucleophilic replacement of methylsufinate from the latter
e-mail address: dankab@ap.siedlce.pl
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.05.011

6022
D. Branowska / Tetrahedron 60 (2004) 6021–6027
Scheme 1.
Scheme 2. (i) KMnO4/H2O/C6H6/t-Bu4NþBr2; (ii) 4-pentyn-1-ol or 3-butyn-1-ol, NaH, DMA; (iii) 2-cyanophenol, THF, 0 8C; (iv) bromobenzene, reflux;
(v) nitrobenzene, reflux.

D. Branowska / Tetrahedron 60 (2004) 6021–6027
Table 1. Yields, melting points of compounds 6a–d, 7a–h and 8a–h
6023
Compound
n
m
Time [h]
Yield [%]
Mp [8C]
Compound
n
m
Time [h]
Yield [%]
Mp [8C]
6a
6b
6c
6d
7a
7b
7c
7d
7e
7f
1
2
3
4
1
2
3
4
1
2
—
—
—
—
1
1
1
1
2
3
3
3
64
79
93
98
38
75
95
80
29
30
242–243
306–307
243–244
258–259
169–170
179–180
161–162
178–179
156–157
153–154
7g
7h
8a
8b
8c
8d
8e
8f
3
4
1
2
3
4
1
2
3
4
2
2
1
1
1
1
2
2
2
2
1.5
2.5
21
12
2
76
81
37
85
80
80
33
55
83
84
101–102
141–142
236–237
216–217
215–216
236–237
263–264
254–255
242–243
253–254
3
0.6
0.3
0.5
0.5
1
3
41
46
103
76
8g
8h
2
1.5
with alkoxides bearing an acetylene unit at the terminus
should provide the desired 1,2,4-triazine derivatives 7a–h
with the appropriate dienophilic side chain, which may be
converted into the target molecules 8a–h via an intra-
molecular DA-rDA reaction (Scheme 2).
tion method described above can easily be extended to the
synthesis of more elaborate heteroaryl-condensed pyridines
10a–c. In this case 2-cyanophenol was selected as potential
dienophile. Nucleophilic displacement of methylsulfinate
from 2a–d with sodium 2-cyanophenoxide (generated in
situ by treatment of 2-cyanophenol with sodium hydride in
anhydrous DMF) afforded the corresponding cyanophenoxy
derivatives 9a–c in good yield. Heating of 9a–c in
nitrobenzene at reflux for 16 h gave the desired pyrazinyl-
pyridine analogues 10a–c (Table 2).
2. Results and discussion
The required 2a–d (X¼SCH3) were obtained via a
regioselective intermolecular DA-rDA reaction of easily
available 3,30-dimethylsulfanyl-5,50-bi-1,2,4-triazine 1 with
cyclic enamines according to our published method.18 The
sulfides 2a–d were efficiently oxidized to the methyl-
sulfones 6a–d. The highest yields of the latter, isolated as
precipitated solids from the reaction mixtures, were
obtained when the oxidation reaction was carried out with
potassium permanganate under phase transfer catalytic
conditions. When the reaction of 2a–d with the oxidizing
agent was followed by TLC, it became evident that the
intermediates were quickly converted into the desired
sulfones 6a–d. Condensation of these compounds in
crude form with the sodium salts of 4-hydroxy-1-butyne
and 5-hydroxy-1-pentyne in DMF at 0 8C led smoothly, in a
chemoselective manner to 3-(3-butynyloxy)- 7a–d and
3-(4-pentynyloxy)-1,2,4-triazin-3-yl-cycloalkeno[c]pyri-
dines 7e–h, respectively. These low temperature conditions
were necessary in order to avoid the nucleophilic replace-
ment of methylsulfinate from the pyridine part of 6a–h,
since electron deficient azines bearing an alkylsulfonyl
substituent easily undergo nucleophilic substitution with a
wide variety of nucleophiles.22 Compounds 7a–d under-
went an intramolecular DA-rDA reaction in refluxing
bromobenzene within 0.5 h to give the desired dihydro-
furo[2,3-b]pyridines 8a–d in moderate to good yield. It
should be noted that methylsulfonyl function in 8a–d may
potentially be utilized as a handle for the introduction of
further functionality through ipso nucleophilic substitution
reactions. Finally, thermolysis of 7e–h in refluxing
bromobenzene afforded the corresponding dihydro-
pyrano[2,3-b]pyridines 8e–h in good yield. The formation
of a 6-membered ring in 8e–h is less favorable, and more
time for completion is required than the reaction which
yields a 5-membered ring. The structures of all products
were confirmed by spectroscopic methods and microana-
lysis. Table 1 shows the reaction conditions, yields and
melting points of compounds 6, 7 and 8.
Table 2. Yields, melting points of compounds 9a–c and 10a–c
Compound
n
Time [h]
Yield [%]
Mp [8C]
9a
9b
9c
10a
10b
10c
1
2
3
1
2
3
3
3
3
4
16
4
53
80
70
52
75
54
220–222
222–223
216–217
250–251
297–298
260–261
In conclusion, we have developed the above-mentione0d
synthetic strategy for the preparation of unsymmetrical 2,2 -
bipyridine analogues consisting of different cycloalkeno-
pyridines and dihydrofuro[2,3-b]- or dihydropyrano[2,3-
b]pyridines and heteroaryl-condensed pyridines. The
synthesized compounds contain a methylsulfonyl group on
the cycloalkeno[c]pyridine ring which opens access to
further substituted molecules.
3. Experimental
Melting points are uncorrected. IR spectra were measured
with a Magna IR-760 spectrophotometer. The 1H NMR
spectra were recorded in deuteriochloroform on a Varian-
Gemini 200 MHz spectrometer. Mass spectra were
measured with an AMD 604 (AMD Intectra GmbH,
Germany) spectrometer [electron impact and liquid
secondary ion mass spectrometry (LSIMS) methods].
Elemental analyses were recorded on Perkin–Elmer 2400-
CHN analyzer. Column chromatography was performed on
silica gel (230–400 mesh, 60 Merck). All solvents used
were dried and distilled before use according to standard
procedures.23 Merck 60F254 plates were used for analytical
(TLC) chromatography.
The intermolecular/intramolecular retro Diels–Alder reac-

6024
D. Branowska / Tetrahedron 60 (2004) 6021–6027
3.1. General procedure for the oxidation of
methylsulfanyl derivatives 2a–d to methylsulfonyl
derivatives 6a–d
temperature (see Table 1). The reaction mixture was poured
into ice/H2O and acidified with AcOH. The precipitate was
filtered off and compounds 7a–h were used to the next step
without purification.
A solution of KMnO4 (12 mmol) in water (32 ml) was
added to a solution of 2a–d (1 mmol) and catalytic amounts
of t-Bu4NþBr2 (0.005 g) in a mixture of AcOH (3 ml) and
benzene (37 ml). The reaction mixture was stirred at room
temperature for 3 h. A saturated solution of Na2S2O5 in
water was added to the mixture until the purple color
disappeared. The organic layer was separated and water
phase was extracted (3£50 ml) with benzene. The organic
layers were combined and dried over MgSO4. After removal
of the solvent the crude compound was used to the next step
without purification.
3.2.1. 3-(3-But-3-ynyloxy-1,2,4-triazin-5-yl)-1-methy-
sulfonyl-6,7-dihydro-5H-cyclopenta[c]pyridine
7a.
Yellow crystals, mp 169–170 8C; IR (KBr) nmax/cm21
1
3293 (–CuCH), 2965, 1349 (SO2), 1140 (SO2); H NMR
(CDCl3): d¼2.08 (t, 1H, J¼2.6 Hz, uCH), 2.20–2.36 (qui,
2H, J¼7.7 Hz, CH2), 2.86 (dt, 2H, J1¼2.6 Hz, J2¼6.9 Hz,
CH2), 3.10 (t, 2H, J¼7.6 Hz, CH2), 3.44 (s, 3H, SO2Me),
3.45 (t, 2H, J¼7.6 Hz, CH2), 4.78 (t, 2H, J¼6.9 Hz, OCH2),
8.60 (s, 1H, pyridine-H), 9.90 (s, 1H, triazine-H); HRMS
(EI): m/z calcd for C16H17O3N4S (MH)þ, 345.1021; found,
345.0992.
3.1.1. 1-Methylsulfonyl-3-(3-methylsulfonyl-1,2,4-tri-
azin-5-yl)-6,7-dihydro-5H-cyclopenta[c]pyridine
6a.
3.2.2. 3-(3-But-3-ynyloxy-1,2,4-triazin-5-yl)-1-methy-
Yellow crystals, mp 242–243 8C; IR (KBr) nmax/cm21
2980, 1339 (SO2), 1150 (SO2); 1H NMR (CDCl3): d¼2.09–
2.35 (m, 2H, CH2), 3.1 (t, 2H, J¼6.4 Hz, CH2), 3.45 (t, 2H,
J¼6.2 Hz, CH2), 3.46 (s, 3H, SO2Me), 3.50 (s, 3H, SO2Me),
8.51 (s, 1H, pyridine-H), 10.21 (s, 1H, triazine-H); HRMS
(EI): m/z calcd for C13H14O4N4S2 (Mþ), 354.0456; found,
354.0446.
sulfonyl-5,6,7,8-tetrahydroisoquinoline
7b.
Yellow
crystals, mp 179–180 8C; IR (KBr) nmax/cm21 3290
(–CuCH), 2965, 1350 (SO2), 1145 (SO2); 1H NMR
(CDCl3): d¼1.70–1.85 (m, 4H, 2£CH2), 2.05 (t, 1H,
J¼2.6 Hz, uCH), 2.45 (dt, 2H, J1¼2.6 Hz, J2¼6.9 Hz,
CH2), 2.80 (t, 2H, J¼7.2 Hz, CH2), 3.30 (t, 2H, J¼6.0 Hz,
CH2), 3.50 (s, 3H, SO2Me), 4.75 (t, 2H, J¼6.9 Hz, OCH2),
8.42 (s, 1H, pyridine-H), 9.85 (s, 1H, triazine-H); HRMS
(LIMS): m/z calcd for C17H19O3N4S (MH)þ, 359.1178;
found, 359.1199.
3.1.2. 1-Methylsulfonyl-3-(3-methylsulfonyl-1,2,4-tri-
azin-5-yl)-5,6,7,8-tetrahydroisoquinoline 6b. Yellow
crystals, mp 306–307 8C; IR (KBr) nmax/cm21 2970, 1340
(SO2), 1150 (SO2); 1H NMR (CDCl3) d¼1.87–1.97 (m, 4H,
2£CH2), 3.2 (t, 2H, J¼6.4 Hz, CH2), 3.38 (t, 2H,
J¼6.19 Hz, CH2), 3.52 (s, 3H, SO2Me), 3.62 (s, 3H,
SO2Me), 8.60 (s, 1H, pyridine-H), 10.25 (s, 1H, triazine-H);
HRMS (EI): m/z calcd for C14H16O4N4S2 (Mþ), 368.0613;
found, 368.0600.
3.2.3. 3-(3-But-3-ynyloxy-1,2,4-triazin-5-yl)-1-methy-
sulfonyl-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridine
7c. Yellow crystals, mp 161–162 8C; IR (KBr) nmax/cm21
1
3290 (–CuCH), 2960, 1359 (SO2), 1135 (SO2); H NMR
(CDCl3): d¼1.62–1.98 (m, 6H, 3£CH2), 2.07 (t, 1H,
J¼2.6 Hz, uCH), 2.45 (dt, 2H, J1¼2.8 Hz, J2¼7.0 Hz,
CH2), 3.02 (t, 2H, J¼5.4 Hz, CH2), 3.38 (t, 2H, J¼5.0 Hz,
CH2), 3.53 (s, 3H, SO2Me), 4.77 (t, 2H, J¼6.8 Hz, OCH2),
8.45 (s, 1H, pyridine-H), 9.80 (s, 1H, triazine-H); HRMS
(EI): m/z calcd for C18H21O3N4S (Mþ), 373.1344; found,
373.1329.
3.1.3. 1-Methylsulfonyl-3-(3-methylsulfonyl-1,2,4-tri-
azin-5-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridine
6c. Yellow crystals, mp 243–244 8C; IR (KBr) nmax/cm21
2923, 1329 (SO2), 1140 (SO2); 1H NMR (CDCl3): d¼1.65–
2.05 (m, 6H, 3£CH2), 3.04 (t, 2H, J¼6.3 Hz, CH2), 3.48 (t,
2H, J¼6.1 Hz, CH2), 3.52 (s, 3H, SO2Me), 3.60 (s, 3H,
SO2Me), 8.70 (s, 1H, pyridine-H), 10.31 (s, 1H, triazine-H);
HRMS (EI): m/z calcd for C15H18O4N4S2 (Mþ), 382.0769;
found, 382.0757.
3.2.4. 3-(3-But-3-ynyloxy-1,2,4-triazin-5-yl)-1-methy-
sulfonyl-5,6,7,8,9,10-hexahydrocycloocta[c]pyridine 7d.
Yellow crystals, mp 178–179 8C; IR (KBr) nmax/cm21 3285
(–CuCH), 2945, 1350 (SO2), 1135 (SO2); 1H NMR
(CDCl3): d¼1.38–1.45 (m, 4H, 2£CH2), 1.70–2.05 (m,
4H, 2£CH2), 2.08 (t, 1H, J¼2.6 Hz, uCH), 2.87 (dt, 2H,
J1¼2.7 Hz, J2¼6.9 Hz, CH2), 2.96 (t, 2H, J¼6.1 Hz, CH2),
3.36 (t, 2H, J¼6.2 Hz, CH2), 3.55 (s, 3H, SO2Me), 4.79 (t,
2H, J¼6.8 Hz, OCH2), 8.50 (s, 1H, pyridine-H), 9.82 (s, 1H,
triazine-H); HRMS (EI): m/z calcd for C19H22O3N4S (Mþ),
386.1413; found, 386.1414.
3.1.4. 1-Methylsulfonyl-3-(3-methylsulfonyl-1,2,4-tri-
azin-5-yl)-5,6,7,8,9,10-hexahydrocycloocta[c]pyridine
6d. Yellow crystals, mp 258–259 8C; IR (KBr) nmax/cm21
2940, 1340 (SO2), 1140 (SO2); 1H NMR (CDCl3): d¼1.58–
1.78–2.15 (m, 8H, 4£CH2), 3.01 (t, 2H, J¼6.3 Hz, CH2),
3.39 (t, 2H, J¼6.1 Hz, CH2), 3.55 (s, 3H, SO2Me), 3.61 (s,
3H, SO2Me), 8.64 (s, 1H, pyridine-H), 10.25 (s,1H, triazine-
H); HRMS (EI): m/z calcd for C16H20O4N4S2 (Mþ),
396.0926; found, 396.0932.
3.2.5. 3-(4-Pent-4-ynyloxy-1,2,4-triazin-5-yl)-1-methy-
sulfonyl-6,7-dihydro-5H-cyclopenta[c]pyridine 7e. Yellow
crystals, mp 156–157 8C; IR (KBr) nmax/cm21 3265
(–CuCH), 2965, 1370 (SO2), 1145 (SO2); 1H NMR
(CDCl3): d¼2.00 (t, 1H, J¼2.6 Hz, uCH), 2.09–2.35 (m,
4H, 2£CH2), 2.49 (dt, 2H, J1¼2.7 Hz, J2¼7.0 Hz, CH2), 3.10
(t, 2H, J¼7.7 Hz, CH2), 3.44 (s, 3H, SO2CH3), 3.46 (t, 2H,
J¼7.6 Hz, CH2), 4.78 (t, 2H, J¼6.8 Hz, OCH2), 8.62 (s, 1H,
pyridine-H), 9.89 (s, 1H, triazine-H); HRMS (LIMS): m/z
calcd for C17H19O3N4S (MH)þ, 359.1178; found, 359.1177.
3.2. General procedure for the nucleophilic substitution
of 6a–d with 3-butyn-1-ol and 4-pentyn-1-ol
To a mixture of 3-butyn-1-ol (1 mmol) or 4-pentyn-1-ol
(1 mmol) and 60% NaH in mineral oil (1.1 mmol) in dry
DMF (5 ml), the substrate 6a–d (1 mmol), was added. The
mixture was stirred at 0 8C for 15 min, then at room

D. Branowska / Tetrahedron 60 (2004) 6021–6027
6025
1
3.2.6. 3-(3-Pent-4-ynyloxy-1,2,4-triazin-5-yl)-1-methy-
sulfonyl-5,6,7,8-tetrahydroquinoline 7f. Yellow crystals,
mp 153–154 8C; IR (KBr) nmax/cm21 3295 (–CuCH), 2960,
1345 (SO2), 1145 (SO2); 1H NMR (CDCl3): d¼1.87–1.84 (m,
4H, 2£CH2), 1.99 (t, 1H, J¼2.6 Hz, uCH), 2.10–2.25 (m,
2H, CH2), 2.49 (dt, 2H, J1¼2.6 Hz, J2¼7.0 Hz, CH2), 2.96 (t,
2H, J¼6.3 Hz, CH2), 3.34 (t, 2H, J¼6.4 Hz, CH2), 3.52 (s, 3H,
SO2Me), 4.78 (t, 2H, J¼6.2 Hz, OCH2), 8.23 (s, 1H, pyridine-
H), 9.45 (s, 1H, triazine-H); HRMS (LIMS): m/z calcd for
C18H21O3N4S (MH)þ, 373.1334; found, 373.1344.
(SO2), 1127 (SO2), 1028 (C–O–C); H NMR (CDCl3):
d¼1.65–1.90 (m, 4H, 2£CH2), 2.95 (t, 2H, J¼6.8 Hz,
CH2), 3.30–3.40 (m, 4H, 2£CH2), 3.50 (s, 3H, SO2Me),
4.70 (t, 2H, J¼7.2 Hz, OCH2), 7.50 (d, 1H, J¼7.6 Hz,
pyridine-H), 7.80 (d, 1H, J¼7.6 Hz, pyridine-H), 8.30 (s,
1H, pyridine-H); HRMS (EI): m/z calcd for C17H18O3N2S
(Mþ), 330.1038; found, 330.1038. Anal. calcd for C17H18-
O3N2S·0.25H2O: C, 60.98; H, 5.38; N, 8.37. Found: C,
60.86; H, 5.51; N, 8.01.
3.3.3. 3-(2,3-Dihydrofuro[2,3-b]pyridin-6-yl)-1-methyl-
sulfonyl-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridine
8c. White crystals, mp 215–216 8C; IR (KBr) nmax/cm21
3.2.7. 3-(4-Pent-4-ynyloxy-1,2,4-triazin-5-yl)-1-methy-
sulfonyl-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridine
7g. Yellow crystals, mp 101–102 8C; IR (KBr) nmax/cm21
1
2929, 1305 (SO2), 1130 (SO2), 1020 (C–O–C); H NMR
1
3280 (–CuCH), 2955, 1349 (SO2), 1135 (SO2); H NMR
(CDCl3): d¼1.60–1.95 (m, 6H, 3£CH2), 2.95 (t, 2H, J¼
6.8 Hz, CH2), 3.28–3.40 (m, 4H, 2£CH2), 3.50 (s, 3H,
SO2Me), 4.71 (t, 2H, J¼7.2 Hz, OCH2), 7.80 (d, 1H, J¼
7.6 Hz, pyridine-H), 7.83 (d, 1H, J¼7.6 Hz, pyridine-H), 8.32
(s, 1H, pyridine-H). Anal. calcd for C18H20O3N2S·0.25H2O:
C, 61.98; H, 5.88; N, 8.03. Found: C, 61.94; H, 5.83; N, 8.06.
(CDCl3): d¼1.68–1.84 (m, 6H, 3£CH2), 1.99 (t, 1H,
J¼2.6 Hz, uCH), 2.17 (qui, 2H, J¼6.3 Hz, CH2), 2.49 (dt,
2H, J1¼2.5 Hz, J2¼6.8 Hz, CH2), 3.00 (t, 2H, J¼6.4 Hz,
CH2), 3.40 (t, 2H, J¼6.4 Hz, CH2), 3.42 (s, 3H, SO2Me),
4.78 (t, 2H, J¼6.2 Hz, OCH2), 8.45 (s, 1H, pyridine-H),
9.80 (s, 1H, triazine-H); HRMS (EI): m/z calcd for
C19H23O3N4S (Mþ), 387.1485; found, 387.1487.
3.3.4. 3-(2,3-Dihydrofuro[2,3-b]pyridin-6-yl)-1-methy-
sulfonyl-5,6,7,8,9,10-hexahydrocycloocta[c]pyridine 8d.
White crystals, mp 236–237 8C; IR (KBr) nmax/cm21 2945,
1315 (SO2), 1135 (SO2), 1015 (C–O–C); 1H NMR
(CDCl3): d¼1.30–1.45 (m, 4H, 2£CH2), 1.69–1.95 (m,
4H, 2£CH2), 2.93 (t, 2H, J¼6.8 Hz, CH2), 3.21–3.40 (m,
4H, 2£CH2), 3.51 (s, 3H, SO2Me), 4.71 (t, 2H, J¼7.2 Hz,
OCH2), 7.81 (d, 1H, J¼7.6 Hz, pyridine-H), 7.84 (d, 1H,
J¼7.6 Hz, pyridine-H), 8.35 (s, 1H, pyridine-H). Anal.
calcd for C19H22O3N2S: C, 63.66; H, 6.19; N, 7.82. Found:
C, 63.65; H, 6.21; N, 7.89.
3.2.8. 3-(4-Pent-4-ynyloxy-1,2,4-triazin-5-yl)-1-methy-
sulfonyl-5,6,7,8,9,10-hexahydrocycloocta[c]pyridine 7h.
Yellow crystals, mp 141–142 8C; IR (KBr) nmax/cm21 3290
(–CuCH), 2965, 1339 (SO2), 1145 (SO2); 1H NMR
(CDCl3): d¼1.35–1.45 (m, 4H, 2£CH2), 1.87–1.94 (m,
4H, 2£CH2), 2.00 (t, 1H, J¼2.6 Hz, uCH), 2.20 (qui, 2H,
J¼6.3 Hz, CH2), 2.50 (dt, 2H, J1¼2.5 Hz, J2¼6.8 Hz, CH2),
2.96 (t, 2H, J¼6.4 Hz, CH2), 3.40 (t, 2H, J¼6.4 Hz, CH2),
3.55 (s, 3H, SO2Me), 4.78 (t, 2H, J¼6.2 Hz, OCH2), 8.48 (s,
1H, pyridine-H), 9.81 (s, 1H, triazine-H); HRMS (EI): m/z
calcd for C20H24N4SO3 (Mþ), 400.1569; found, 400.1559.
3.3.5. 7-(1-Methylsulfonyl-6,7-dihydro-5H-cyclo-
penta[c]-pyridin-3-yl)-3,4-dihydro-2H-pyrano[2,3-
b]pyridine 8e. White crystals, mp 263–264 8C; IR (KBr)
3.3. General procedure for the intramolecular Diels–
Alder reaction of 7a–h. Synthesis of furo- and
pyrano[2,3-b]pyridine derivatives 8a–h
n
max/cm21 2924, 1306 (SO2), 1127 (SO2), 1055 (C–O–C);
1H NMR (CDCl3): d¼2.00–2.15 (m, 2H, CH2), 2.20 (qui,
2H, J¼7.6 Hz, CH2), 2.88 (t, 2H, J¼7.7 Hz, CH2), 3.01 (t,
2H, J¼7.7 Hz, CH2), 3.38 (t, 2H, J¼7.6 Hz, CH2), 3.39 (s,
3H, SO2Me), 4.20 (t, 2H, J¼5.2 Hz, CH2), 7.61 (d, 1H,
J¼7.7 Hz, pyridine-H), 7.94 (d, 1H, J¼7.7 Hz, pyridine-H),
8.49 (s, 1H, pyridine-H); HRMS (EI): m/z calcd for
C17H18N2SO3 (Mþ), 330.1038; found, 330.1033. Anal.
calcd for C17H18O3N2S·0.25H2O: C, 60.98; H, 5.38; N,
8.37. Found: C, 60.70; H, 5.35; N, 7.98.
A stirred solution of the 7a–h in bromobenzene (approx.
0.4 g in 10 ml of solvent) was heated at reflux under
nitrogen (see Table 1). After this time, the reaction mixture
was cooled to room temperature and the solvent was
evaporated under reduced pressure. The crude product was
purified by column chromatography using chloroform as
eluent to give a white solid.
3.3.1. 3-(2,3-Dihydrofuro[2,3-b]pyridin-6-yl)-1-methyl-
sulfonyl-6,7-dihydro-5H-cyclopenta[c]pyridine 8a. White
crystals, mp 236–237 8C; IR (KBr) nmax/cm21 2919, 1351
(SO2), 1140 (SO2), 1078 (C–O–C); 1H NMR (CDCl3):
d¼2.10–2.30 (qui, 2H, J¼7.6 Hz, CH2), 3.01 (t, 2H,
J¼7.7 Hz, CH2), 3.33 (t, 2H, J¼6.4 Hz, CH2), 3.38 (t, 2H,
J¼6.0 Hz, CH2), 3.39 (s, 3H, SO2Me), 4.70 (t, 2H, J¼8.5 Hz,
OCH2),7.55–7.63(d, 1H, J¼7.6 Hz, pyridine-H),7.93(d,1H,
J¼7.6 Hz, pyridine-H), 8.48 (s, 1H, pyridine-H); HRMS (EI):
m/z calcd for C16H16O3N2S (Mþ), 316.0881; found, 316.0881.
The hygroscopic nature of the compound led to variability in
the microanalytical data.
3.3.6. 7-(1-Methylsulfonyl-5,6,7,8-tetrahydroisoquinolin-
3-yl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine 8f. White
crystals, mp 254–255 8C; IR (KBr) nmax/cm21 2929, 1299
(SO2), 1130 (SO2), 1060 (C–O–C); 1H NMR (CDCl3):
d¼1.75–1.92 (m, 4H, 2£CH2), 2.04–2.10 (m, 2H, CH2),
2.80–2.95 (m, 4H, 2£CH2), 3.27 (t, 2H, J¼6.1 Hz, CH2), 3.48
(s, 3H, SO2Me), 4.42 (t, 2H, J¼5.3 Hz, OCH2), 7.50 (d, 1H,
J¼7.6 Hz, pyridine-H), 7.82 (d, 1H, J¼7.6 Hz, pyridine-H),
8.29 (s, 1H, pyridine-H); HRMS (EI): m/z calcd for
C18H20O3N2S (Mþ), 344.1205; found, 344.1194. Anal.
calcd for C18H20O3N2S: C, 62.79; H, 5.81; N, 8.14. Found:
C, 62.65; H, 5.93; N, 7.92.
3.3.2. 3-(2,3-Dihydrofuro[2,3-b]pyridin-6-yl)-1-methyl-
sulfonyl-5,6,7,8-tetrahydroisoquinoline 8b. White crys-
tals, mp 216–217 8C; IR (KBr) nmax/cm21 2919, 1302
3.3.7. 7-(1-Methylsulfonyl-6,7,8,9-tetrahydro-5H-cyclo-
hepta[c]pyridin-3-yl)-3,4-dihydro-2H-pyrano[2,3-b]-
pyridine 8g. White crystals, mp 243–244 8C; IR (KBr)

6026
D. Branowska / Tetrahedron 60 (2004) 6021–6027
n
max/cm21 2949, 1305 (SO2), 1145 (SO2), 1035 (C–O–C);
triazine-H); HRMS (EI): m/z calcd for C21H19O3N5S (Mþ),
421.1209; found, 421.1204.
1H NMR (CDCl3): d¼1.60–1.92 (m, 6H, 3£CH2), 2.05
(qui, 2H, J¼6.4 Hz, CH2), 2.85–3.05 (m, 4H, 2£CH2), 3.35
(t, 2H, J¼6.1 Hz, CH2), 3.50 (s, 3H, SO2Me), 4.42 (t, 2H,
J¼5.3 Hz, OCH2), 7.50 (d, 1H, J¼7.6 Hz, pyridine-H), 7.84
(d, 1H, J¼7.6 Hz, pyridine-H), 8.33 (s, 1H, pyridine-H).
Anal. calcd for C19H22O3N2S: C, 63.69; H, 6.15; N, 7.82.
Found: C, 63.67; H, 6.15; N, 7.75.
3.5. Intramolecular Diels–Alder reaction of 9a–c.
General procedure for the synthesis of benzofuro[2,3-
b]pyrazines derivatives 10a–c
A stirred solution of 9a–c in nitrobenzene (approx. 0.4 g in
10 ml of solvent) was heated at reflux under nitrogen for
16 h. After this time, the reaction mixture was cooled to
room temperature, the solvent was evaporated under
reduced pressure. The crude product was purified by
column chromatography using chloroform as eluent to
give white solid.
3.3.8. 7-(1-Methylsulfonyl-5,6,7,8,9,10-hexahydro-
cycloocta[c]pyridin-3-yl)-3,4-dihydro-2H-pyrano[2,3-
b]pyridine 8h. White crystals, mp 253–254 8C; IR (KBr)
n
max/cm21 2930, 1305 (SO2), 1135 (SO2), 1035 (C–O–C);
1H NMR (CDCl3): d¼1.35–1.41 (m, 4H, 2£CH2), 1.60–
1.92 (m, 4H, 2£CH2), 2.04 (qui, 2H, J¼6.4 Hz, CH2), 2.85–
3.05 (m, 4H, 2£CH2), 3.35 (t, 2H, J¼6.1 Hz, CH2), 3.50 (s,
3H, SO2Me), 4.42 (t, 2H, J¼5.3 Hz, OCH2), 7.53 (d, 1H,
J¼7.6 Hz, pyridine-H), 7.86 (d, 1H, J¼7.6 Hz, pyridine-H),
8.36 (s, 1H, pyridine-H). Anal. calcd for C20H24O3N2S
0.25H2O: C, 63.75; H, 6.50; N, 7.44. Found: C, 63.85; H,
6.40; N, 7.56.
3.5.1. 3-(1-Methylsulfonyl-6,7-dihydro-5H-cyclo-
penta[c]pyridin-3-yl)benzo[4,5]furo[2,3-b]pyrazine 10a.
White crystals, mp 250–251 8C; IR (KBr) nmax/cm21 2927,
1
1299 (SO2), 1126 (SO2); H NMR (CDCl3): d¼2.00–2.28
(m, 2H, CH2), 3.10 (t, 2H, J¼7.7 Hz, CH2), 3.39–3.45 (m,
2H, CH2), 3.47 (s, 3H, SO2Me), 7.48–7.58 (m, 1H, Ar),
7.68–7.74 (m, 2H, Ar), 8.25–8.29 (m, 1H, Ar), 8.57 (s, 1H,
pyridine-H), 9.69 (s, 1H, pyrazine-H); HRMS (EI): m/z
calcd for C19H15N3SO3 (Mþ), 365.0834; found, 365.0802.
3.4. General procedure for the nucleophilic substitution
reaction of 6a–c with 2-cyanophenol
60% NaH in mineral oil (1.1 mmol) was added to a solution
of 2-cyanophenol (1.0 mmol) in dry DMF (5 ml), and the
mixture was stirred at 0 8C for 15 min. The substrate 6a–c
(1 mmol) was added, and the mixture was stirred for 3 h at
room temperature. The reaction mixture was then poured
into ice/H2O and acidified with AcOH. The precipitate was
filtered off and purified by column chromatography using
chloroform as eluent to give light yellow compounds 9a–c.
3.5.2. 3-(1-Methylsulfonyl-5,6,7,8-tetrahydroiso-
quinolin-3-yl)benzo[4,5]furo[2,3-b]pyrazine 10b. White
crystals, mp 297–298 8C; IR (KBr) nmax/cm21 2956, 1300
1
(SO2), 1133 (SO2); H NMR (CDCl3): d¼1.84–1.96 (m,
4H, 2£CH2), 2.98 (t, 2H, J¼6.3 Hz, CH2), 3.32 (t, 2H,
J¼6.1 Hz, CH2), 3.55 (s, 3H, SO2Me), 7.49–7.56 (m, 1H,
Ar), 7.68–7.72 (m, 2H, Ar), 8.21–8.26 (m, 1H, Ar), 8.36 (s,
1H, pyridine-H), 9.58 (s, 1H, pyrazine-H); HRMS (EI): m/z
calcd for C20H17N5SO3 (Mþ), 379.0978; found, 379.0992.
3.4.1. 2-[5-(1-Methylsulfonyl-6,7-dihydro-5H-cyclo-
penta[c]pyridin-3-yl)-1,2,4-triazin-3-yloxybenzonitrile
9a. Yellow crystals, mp 220–222 8C; IR (KBr) nmax/cm21
3.5.3. 3-(1-Methylsulfonyl-6,7,8,9-tetrahydro-5H-cyclo-
hepta[c]pyridin-3-yl)benzo[4,5]furo[2,3-b]pyrazine 10c.
White crystals, mp 260–261 8C; IR (KBr) nmax/cm21 2935,
1
2929, 2234 (–CuN) 1334 (SO2), 1120 (SO2); H NMR
1
(CDCl3): d¼2.24–2.32 (m, 2H, CH2), 3.10 (t, 2H,
J¼7.8 Hz, CH2), 3.42–3.47 (m, 2H, CH2), 3.44 (s, 3H,
SO2Me), 7.41–7.50 (m, 2H, Ar), 7.70–7.82 (m, 2H, Ar),
8.57 (s, 1H, pyridine-H), 9.84 (s, 1H, triazine-H); HRMS
(EI): m/z calcd for C19H15O3N5S (Mþ), 393.0896; found,
393.0889.
1296 (SO2), 1120 (SO2); H NMR (CDCl3): d¼1.67–1.99
(m, 6H, 3£CH2), 3.00–3.09 (m, 2H, CH2), 3.35–3.41 (m,
2H, CH2), 3.57 (s, 3H, SO2Me), 7.48–7.57 (m, 1H, Ar),
7.68–7.73 (m, 2H, Ar), 8.24–8.28 (m, 1H, Ar), 8.41 (s, 1H,
pyridine-H), 9.58 (s, 1H, pyrazine-H); HRMS (EI): m/z
calcd for C21H19N3SO3 (Mþ), 393.1147; found, 393.1166.
3.4.2. 2-[5-(1-Methylsulfonyl-5,6,7,8-tetrahydroiso-
quinolin-3-yl)-1,2,4-triazin-3-yloxybenzonitrile 9b. Yellow
crystals, mp 222–223 8C; IR (KBr) nmax/cm21 2939, 2238
(–CuN) 1348 (SO2), 1127 (SO2); 1H NMR (CDCl3):
d¼1.84–1.97 (m, 4H, 2£CH2), 2.97 (t, 2H, J¼6.0 Hz, CH2),
3.35 (t, 2H, J¼6.1 Hz, CH2), 3.52 (s, 3H, SO2Me), 7.41–7.50
(m, 2H, Ar), 7.70–7.82 (m, 2H, Ar), 8.40 (s, 1H, pyridine-H),
9.94 (s, 1H, triazine-H); HRMS (EI): m/z calcd for
C20H17N5SO3 (Mþ), 407.1044; found, 407.1052.
Acknowledgements
The author is grateful to Prof. Andrzej Rykowski for fruitful
discussions and to Mrs Ewa Olender of the University of
Podlasie for technical assistance.
References and notes
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