Tandem vicarious nucleophilic substitution of hydrogen/intramolecular Diels-Alder reaction of 1,2,4-triazines into functionalized cycloalkenopyridines1

Article abstract of DOI:10.1248/cpb.50.463

Synthesis of 2,3- and 3,4-cyclopentenopyridines, 5,6,7,8- tetrahydroquinolines and 5,6,7,8-tetrahydroisoquinolines from 1,2,4-triazine derivatives is reported. Introduction of an α-functionalized methyl substituent (e.g. arylsulphonyl, sulphonamide, sulphonic acid ester) into position 3- or 6- of triazines by vicarious nucleophilic substitution of hydrogen and subsequent alkylation with alkyl iodides bearing an acetylenic function in terminal position afforded valuable intermediates for intramolecular Diels-Alder reaction with inverse electron demand. When heated at higher temperature, these triazine derivatives gave the Diels-Alder cycloadducts, which, after spontaneous extrusion of nitrogen moiety, led to a variety of functionalized cycloalkenopyridine derivatives.

Full text of DOI:10.1248/cpb.50.463

April 2002
Chem. Pharm. Bull. 50(4) 463—466 (2002)
463
Tandem Vicarious Nucleophilic Substitution of Hydrogen/Intramolecular
Diels–Alder Reaction of 1,2,4-Triazines into Functionalized
Cycloalkenopyridines1)
⁄
Danuta BRANOWSKA, Stanislaw OSTROWSKI, and Andrzej RYKOWSKI*
Institute of Chemistry, University of Podlasie, ul. 3 Maja 54, PL-08-110 Siedlce, Poland.
Received October 9, 2001; accepted December 4, 2001
Synthesis of 2,3- and 3,4-cyclopentenopyridines, 5,6,7,8-tetrahydroquinolines and 5,6,7,8-tetrahydroiso-
quinolines from 1,2,4-triazine derivatives is reported. Introduction of an a-functionalized methyl substituent
(e.g. arylsulphonyl, sulphonamide, sulphonic acid ester) into position 3- or 6- of triazines by vicarious nucle-
ophilic substitution of hydrogen and subsequent alkylation with alkyl iodides bearing an acetylenic function in
terminal position afforded valuable intermediates for intramolecular Diels–Alder reaction with inverse electron
demand. When heated at higher temperature, these triazine derivatives gave the Diels–Alder cycloadducts,
which, after spontaneous extrusion of nitrogen moiety, led to a variety of functionalized cycloalkenopyridine de-
rivatives.
Key words cycloalkenopyridine; 1,2,4-triazine; Diels–Alder reaction; vicarious nucleophilic substitution
Substituted cycloalkenopyridines are found in a variety of dides bearing an acetylenic unit in terminal position, fol-
naturally occuring, biologically active compounds, and a lowed by intramolecular cycloaddition involving the extru-
range of synthetic methods to this class of compounds exist.2) sion of molecular nitrogen, offered the synthesis of the titled
More recent approach employs a two-step intramolecular cycloalkenopyridines possessing a high degree of complexity
Diels–Alder cycloaddition/retro-cycloaddition reaction of (Chart 2). It would be more difficult, or almost impossible, to
1,2,4-triazines with inverse electron demand, involving extru- achieve this by the intermolecular cycloaddition between tri-
sion of nitrogen molecule.3) The approach used is outlined in azine derivative and appropriately substituted enamine or
Chart 1, and is focused on the construction of the key other dienophile.
dienophilic intermediate. The synthesis of the latter is ef-
Continuing with our ongoing interest in the preparation of
fected by nucleophilic displacement of methylsulphinate biologically active fused heterocycles, we present herein an
from 3-(methylsulphonyl)-1,2,4-triazine with active methyl- improved synthesis of the cycloalkenopyridines functional-
ene compounds bearing the dienophilic side-chain on the re- ized in both rings, starting from 1,2,4-triazines, and using as
acting carbon atom. However, in some cases, a serious limi- the key steps: (1) vicarious nucleophilic substitution, and (2)
tation for the above approach is rather difficult access to suit- intramolecular Diels–Alder reaction. The reaction sequence
able substrates.3)
presented above has never been examined. We have started
our investigations with easily available 5-phenyl- and 3-
methylthio-5-phenyl-1,2,4-triazines (1, 2). These highly elec-
trophilic derivatives, when reacted with a-chloromethyl aryl
sulphones (3: RϭPh, 4: RϭTol), a-chloromethyl N,N-dialkyl
sulphonamides (5: Rϭmorpholino, 6: Rϭpyrrolidino, 7:
RϭNMe2), and a-chloromethyl sulfonic acid ester (8:
RϭOCH2-But), in the presence of an excess of potassium hy-
droxide in dimethyl sulfoxide (DMSO) at room temperature,
resulted in formation of VNS products 9a—f and 10a in
good yields (Chart 2, Table 1).
To establish optimal conditions for alkylation, the reaction
of triazine 9a with 5-iodo-1-pentyne (11) was investigated
first. In order to optimize this step a variety of base/solvent
systems were tested (NaH/THF, NaH/DMF, tert-BuOK/THF,
Chart 1
On the other hand, it is well documented that 1,2,4-tri- KOH/DMSO, K2CO3/DMF, etc.) under various conditions:
azines with functionalized alkyl substituents can be achieved temperature (Ϫ40 to 155 °C) and reaction time (2 to 50 h).
in a more direct way by nucleophilic substitution of hydro- The highest yield of 5-phenyl-3-[1-(phenylsulphonyl)-5-
gen.4) Among many variants of this process, the most general hexynyl)-1,2,4-triazine (13a) was obtained in NaH/DMF at
appears to be vicarious nucleophilic substitution (VNS), 0 °C (3 h, 94%), and the conditions found were applied to the
which proceeds when the reacting carbanion contains leaving preparation of the acetylenic key-intermediates 13b—i and
group X at the carbanionic center.5) This reaction enables the 14a, g, respectively. The results of the alkylation of 9a—f
preparation of a wide variety of the desired C-substituted de- and 10a with 4-iodo-1-butyne (11) and 5-iodo-1-pentyne
rivatives via nucleophilic substitution of hydrogen in the 3-, (12) are compiled in Table 1. Isolation of the Diels–Alder
5- or 6-positions of the 1,2,4-triazine nucleus.5a) Subsequent precursors 13g—i after the reaction of 9a—c with 4-iodo-1-
alkylation of such obtained products (9, 10) with alkyl io- butyne (12) was complicated by their propensity to undergo
To whom correspondence should be addressed. e-mail: rykowski@ap.siedlce.pl
© 2002 Pharmaceutical Society of Japan

464
Vol. 50, No. 4
Chart 3
Chart 4
Table 1. Yields of the Products 9, 13, and 14 (Charts 1, 2, 3)
Product (%)
Products (%)
R
n
R
9
13
14
a
b
c
d
e
f
Ph
Tol
74a)
87
70
61
68
77
a
b
c
d
e
f
g
h
i
2
2
2
2
2
2
1
1
1
Ph
Tol
94c) 50
66
83
82
74
—
—
—
—
—
20
—
—
Mrphb)
Pyrlb)
NMe2
OCH2-But
Mrphb)
Pyrlb)
NMe2
OCH2-But
Ph
26
c,d)
d)
d)
Tol
Mrphb)
a) See lit.5a); also, compound 10a (RϭPh) was obtained according to the method de-
scribed earlier in the literature.5a) b) Mrph stands for morpholine, Pyrl-for pyrrolidine.
c) They were also obtained according to the scheme shown in Chart 3 (yields: 13a,
26%; 13g, 8%). d) Crude product was directly used in Diels–Alder cycloaddition.
Chart 2
Table 2. Cycloaddition Reactions and the Yields of Products
Substrate
n
Reaction time (h)
R
Product No Yield (%)
fast [4ϩ2]-cycloaddition. In some cases of formation of 5-
membered rings, the cycloaddition occured spontaneously at
0 °C to 2,3-cyclopentenopyridines. To complete cycloaddi-
tion crude reaction mixtures containing 13g—i were heated
in bromobenzene to reflux for a short period of time to give
the Diels–Alder cycloadducts, which, after spontaneous ex-
trusion of nitrogen moiety, led to the desired products 15g—i
in good yields (Chart 2, Table 2). The bulky substituents
(SO2R) at the a-position of the side chains attached to C-3 or
C-6 in triazine ring probably accelerated this process
(Thorpe-Ingold effect6)).
13a
13b
13c
13d
13e
13f
13g
13h
13i
2
2
2
2
2
2
1
1
1
2
1
2
2
10
5
4
3
0.5
0.5
3
7
3
Ph
Tol
15a
15b
15c
15d
15e
15f
15g
15h
15i
76
58
81
65
55
97
Mrpha)
Pyrla)
NMe2
OCH2-But
Ph
98b)
82b)
59b)
27
Tol
Mrpha)
Ph
14a
14g
16a
16g
Ph
29
a) Mrph stands for morpholine, Pyrl-for pyrrolidine. b) Yields for 2 steps.
The intermediates 13a, 13g could be also obtained in one-
step synthesis from the respective triazine derivative 1 in the
reaction with tertiary carbanions 17 and 18 bearing dienophilic
side-chain. However, attempts to prepare these compounds
by this method, probably due to considerable steric hin-
drance, lead to the desired products (13a, g) only in low yield
(Chart 3, Table 1).
Synthesis of several 5,6,7,8-tetrahydroquinoline deriva-
tives, 15a—f, proceeded analogously to the 2,3-cyclopen-
tenopyridines 15g—i. As expected, the rate of the cycloaddi-
tion reactions was substantially slower due to the longer car-
bon chain linking diene and dienophile. In order to optimize
the yields, different solvents (dioxane, bromobenzene, 1,3,5-
triisopropylbenzene, methylene chloride) were examined, and
the best results were obtained for bromobenzene while the
reaction mixture was heated to reflux. Terminal acetylenes
tethered through a carbon atom at position 6- in compounds
14a, 14g afforded in 1,3,5-triisopropylbenzene 5,6,7,8-tetrahy-
droisoquinoline 16a and 3,4-cyclopentenopyridine 16g, re-
spectively, in moderate yields (Table 2).
The attempts to isolate the cycloadduct 19, which has
never been observed before, failed. Several attempts to real-
ize this on model compound 13b in CH2Cl2 under high pres-
sure (12—16 kbar, 20—60 °C) led directly to the product
15b, or the starting material was recovered.
In conclusion, the tandem VNS and intramolecular in-
verse-electron-demand Diels–Alder reactions on 1,2,4-tri-
azines constitute a versatile method for preparation of a vari-

April 2002
465
5.30. Found: C, 55.39; H, 5.25.
ety of functionalized cycloalkenopyridines. Some of them
are compounds of significant importance. They possess po-
tent antishock,7) tuberculostatic,8,9) and antimalarial10) proper-
ties. The biological tuberculostatic activity of the compounds
described in this paper is now under investigation.11)
N,N-Dimethyl-C-(5-phenyl-1,2,4-triazin-3-yl)-methanesulphonamide
(9e): mp 173—174 °C. 1H-NMR (CDCl3, 200 MHz) d: 2.91 (6H, s), 4.84
(2H, s), 7.54—7.67 (3H, m), 8.21—8.28 (2H, m), 9.68 (1H, s). IR (KBr)
cmϪ1: 1345, 1160. Anal. Calcd for C12H14N4SO2: C, 51.78; H, 5.07; N,
20.13. Found: C, 51.90; H, 5.02; N, 20.01.
(5-Phenyl-1,2,4-triazin-3-yl)-methanesulphonic Acid 2,2-Dimethyl-propyl
Experimental
Ester (9f): mp 159—160 °C. 1H-NMR (CDCl3, 200 MHz) d: 0.96 (9H, s),
1H-NMR spectra were recorded with Varian GEMINI-200 and Varian 360 4.05 (2H, s), 4.95 (2H, s), 7.57—7.66 (3H, m), 8.20—8.26 (2H, m), 9.69
spectrometers operating at 200 and 360 MHz, respectively. Coupling con- (1H, s). IR (KBr) cmϪ1: 1380, 1130. Anal. Calcd for C15H19N3SO3: C, 56.06;
stants J are expressed in hertz [Hz]. IR spectra were measured with a Uni- H, 5.96; N, 13.07. Found: C, 56.29; H, 5.98; N, 12.55.
cam SP-200 spectrometer and mass spectra were measured with an AMD
5-Phenyl-3-(1-phenylsulphonyl-hex-5-ynyl)-1,2,4-triazine (13a): mp 179—
604 (AMD Intectra GmbH, Germany) spectrometer [electron impact and 180 °C. 1H-NMR (CDCl3, 200 MHz) d: 1.37—1.64 (4H, m), 1.90 (1H, t,
liquid secondary ion mass spectrometry (LSIMS) methods]; m/z values are Jϭ2.7 Hz), 2.21 (2H, td, J1ϭ6.9, J2ϭ2.7 Hz), 4.88 (1H, dd, J1ϭ9.7, J2ϭ
given as a % of relative intensity. Melting points are uncorrected. TLC 5.6 Hz), 7.41—7.74 (8H, m), 8.05—8.12 (2H, m), 9.59 (1H, s). IR (KBr)
analysis was performed on aluminum foil plates precoated with silica gel cmϪ1: 3295, 1320, 1160. HR-MS m/z: 376.1135 (Calcd for C21H18N3SO2
60F 254 Merck. Silica gel 200—300 mesh (Merck AG) was used for column
chromatography.
(MϪH): 376.1120). MS m/z: 377 (1, Mϩ), 312 (61), 285 (62), 237 (35), 236
(100), 208 (47), 183 (94), 102 (98), 77 (55). Anal. Calcd for C21H19N3SO2:
C, 66.82; H, 5.07; N, 11.13. Found: C, 67.14; H, 4.82; N, 10.97.
The starting carbanion precursors were obtained according to methods de-
scribed earlier in the literature: a-chloromethyl phenyl sulphone (3),12) a-
5-Phenyl-3-(1-phenylsulphonyl-pent-4-ynyl)-1,2,4-triazine (13g): Unsta-
chloromethyl p-tolyl sulphone (4),13) chloromethanesulphomorpholide ble; spontaneously underwent to 15g, for freshly prepared sample mp, IR,
(5),14) N,N-pyrrolidino(chloromethane) sulphonamide (6),14) N,N-dimethyl- 1H-NMR were measured. Mp 141—142 °C. H-NMR (CDCl3, 200 MHz) d:
1
(chloromethane)sulphonamide (7),15) and neo-pentyl chloromethanesulpho- 1.91 (1H, t, Jϭ2.6 Hz), 2.09—2.28 (1H, m), 2.32—2.49 (1H, m), 2.63—
nate (8).16)
2.85 (2H, m), 5.09 (1H, dd, J1ϭ10.0, J2ϭ5.0 Hz), 7.36—7.73 (8H, m),
Alkylation of a-Chloromethyl Phenyl Sulphone (3). General Proce- 8.04—8.10 (2H, m), 9.57 (1H, s). IR (KBr) cmϪ1: 3290, 1320, 1170.
dure. To NaH (27 mg, 1.1 mmol; washed with Et2O from 60% oil suspen-
Alkylation of VNS Products 9a—f and 10a with Alkyl Iodides. Gen-
sion) in DMF (3 ml) chloromethyl phenyl sulphone (3; 191 mg, 1.0 mmol) in eral Procedure. The suspension of NaH (27 mg, 1.1 mmol; washed with
DMF (3 ml) was added via syringe at 0 °C during 5 min. The mixture was Et2O from 60% oil suspension) in DMF (3 ml), cooled to 0 °C, was stirred
stirred at this temperature under argon for ca 15 min. Then, 5-iodo-1-pen- for 15 min under argon. Then, the triazine derivative (9a—f or 10a) (1.0
tyne (214 mg, 1.1 mmol) in DMF (1 ml) was added, and the reaction mixture
mmol) and 5-iodo-1-pentyne (or 4-iodo-1-butyne) (1.0 mmol) in DMF
was stirred at 0 °C for 2 h. The mixture was poured onto water with ice, (3 ml) was added via syringe at 0 °C during 5 min. The reaction mixture was
acidified with AcOH, and extracted with Et2O (3ϫ30 ml). The combined or- stirred at 0 °C for ca 2—4 h (TLC monitoring). The mixture was poured
ganic layers were dried with MgSO4, and the crude product was purified by
onto water with ice, the precipitate was filtered, and the crude product was
column chromatography using a CHCl3/n-hexane (100 : 1) mixture as eluent purified by column chromatography using a CHCl3/n-hexane mixture
to give 189 mg of the desired product 17; oil, 74% yield. It was identified by (100 : 1) or CHCl3 as eluent. Yields – see Table 1.
IR and 1H-NMR spectra: IR (CHCl3) cmϪ1: 3300, 1320, 1170; 1H-NMR
(CDCl3, 60 MHz) d: 1.53—2.05 (5H, m), 2.10—2.74 (2H, m), 4.48—4.83
(1H, m), 7.40—7.60 (3H, m), 7.80—8.10 (2H, m).
5-Phenyl-3-[1-(toluene-4-sulphonyl)-hex-5-ynyl]-1,2,4-triazine (13b): mp
172—173 °C. 1H-NMR (CDCl3, 200 MHz) d: 1.35—1.65 (2H, m), 1.90
(1H, t, Jϭ2.5 Hz), 2.21 (2H, td, J1ϭ7.0, J2ϭ2.5 Hz), 2.38 (3H, s), 2.55—
Compound 18 was obtained analogously, according to the above proce- 2.70 (2H, m), 4.84 (1H, dd, J1ϭ9.7, J2ϭ5.4 Hz), 7.20—7.30 (2H, m), 7.50—
dure, using 4-iodo-1-butyne as alkylating agent; 73 mg; oil, 30% yield. It
7.65 (5H, m), 8.05—8.12 (2H, m), 9.58 (1H, s). IR (KBr) cmϪ1: 3305, 1320,
1
was identified by IR and H-NMR spectra: IR (CHCl3) cmϪ1: 3300, 1330, 1170. HR-MS m/z: 392.1442 (Calcd for C22H22N3SO2 (MϩH): 392.1433).
1
1170; H-NMR (CDCl3, 60 MHz) d: 1.53—2.57 (5H, m), 4.44—4.76 (1H,
MS m/z: 392 (100, MϩH), 236 (9), 209 (10), 176 (14), 155 (19), 154 (68),
137 (45), 136 (46). Anal. Calcd for C22H21N3SO2: C, 67.50; H, 5.41; N,
m), 7.40—7.72 (3H, m), 7.81—8.12 (2H, m).
Vicarious Nucleophilic Substitution of Hydrogen. General Prcedures 10.74. Found: C, 67.30; H, 5.35; N, 10.52.
Procedure A. KOH/DMSO System: To a stirred suspension of powdered
3-[1-(Morpholine-4-sulphonyl)-hex-5-ynyl]-5-phenyl-1,2,4-triazine (13c):
1
KOH (4.0 g, 71 mmol) in anhydrous DMSO (20 ml) a solution of triazine de- mp 164—165 °C. H-NMR (CDCl3, 200 MHz) d: 1.37—1.70 (2H, m), 1.97
rivative 1—2 (10.0 mmol) and a carbanion precursor (3—8; 11.0 mmol) in (1H, t, Jϭ2.6 Hz), 2.25 (2H, td, J1ϭ7.0, J2ϭ2.6 Hz), 2.45—2.64 (1H, m),
DMSO (5 ml) was added dropwise via syringe at room temp. during ca 2.68—2.92 (1H, m), 3.04—3.18 (2H, m), 3.25—3.38 (2H, m), 3.52—3.72
5 min. After additional 1 h of stirring the mixture was poured onto water (4H, m), 4.85 (1H, dd, J1ϭ11.1, J2ϭ4.1 Hz), 7.59—7.67 (3H, m), 8.23—
with ice and acidified with aqueous 5% HCl. The solid was filtered to give 8.29 (2H, m), 9.69 (1H, s). IR (KBr) cmϪ1: 3295, 1320, 1180. HR-MS m/z:
crude products 9a—f and 10a, which were purified by crystallization from 386.1413 (Calcd for C19H22N4SO3: 386.1413). MS m/z: 387 (54, MϩH),
an EtOH/H2O mixture.
386 (2, Mϩ), 236 (9), 209 (7), 107 (28), 91 (17), 90 (14), 89 (19).
Procedure B. KOH/DMF System: To a stirred suspension of powdered
KOH (600 mg, 10.7 mmol) in anhydrous DMF (6 ml) at 0 °C a solution of
5-Phenyl-3-[1-(pyrrolidine-1-sulphonyl-hexyl)-5-ynyl]-1,2,4-triazine
(13d): mp 153—154 °C. 1H-NMR (CDCl3, 200 MHz) d: 1.41—1.67 (2H,
triazine 1 (158 mg, 1.0 mmol) and a carbanion precursor (17, 18; 1.0 mmol) m), 1.74—1.87 (4H, m), 1.94 (1H, t, Jϭ2.6 Hz), 2.25 (2H, td, J1ϭ7.0,
in DMF (3 ml) was added dropwise via syringe at 0 °C during ca 5 min. J2ϭ2.6 Hz), 2.47—2.65 (1H, m), 2.72—2.93 (1H, m), 2.96—3.09 (2H, m),
After additional 2 h of stirring at this temp., the mixture was poured onto 3.33—3.47 (2H, m), 4.91 (1H, dd, J1ϭ11.0, J2ϭ4.1 Hz), 7.53—7.66 (3H,
water with ice, acidified with AcOH, and worked-up as in Procedure A to m), 8.24—8.31 (2H, m), 9.67 (1H, s). IR (KBr) cmϪ1: 3295, 1330, 1160.
give the desired products: 13a, 98 mg (26%), 13g, 29 mg (8%).
HR-MS m/z: 371.1540 (Calcd for C19H23N4SO2 (MϩH): 371.1542).
LSIMS(ϩ) m/z: 371 (100, MϩH). Anal. Calcd for C19H22N4SO2: C, 61.60;
5-Phenyl-3-phenylsulphonylmethyl-1,2,4-triazine (9a): Data see lit.5a)
5-Phenyl-3-(toluene-4-sulphonylmethyl)-1,2,4-triazine (9b): mp 135— H, 5.99; N, 15.12. Found: C, 61.80; H, 5.89; N, 15.39.
136 °C. 1H-NMR (CDCl3, 200 MHz) d: 2.43 (3H, s), 4.94 (2H, s), 7.27—
1-(5-Phenyl-1,2,4-triazin-3-yl)-hex-5-yne-1-sulphonic Acid Dimethyl-
7.34 (2H, m), 7.49—7.63 (3H, m), 7.65—7.72 (2H, m), 8.01—8.07 (2H, m), amide (13e): mp 149—150 °C. H-NMR (CDCl3, 200 MHz) d: 1.42—1.71
1
9.61 (1H, s). IR (KBr) cmϪ1: 1350, 1160. Anal. Calcd for C17H15N3SO2: C, (2H, m), 1.96 (1H, t, Jϭ2.6 Hz), 2.25 (2H, td, J1ϭ6.9, J2ϭ2.6 Hz), 2.45—
62.75; H, 4.65. Found: C, 62.75; H, 4.68.
2.63 (1H, m), 2.70—2.92 (1H, m), 2.77 (6H, s), 4.89 (1H, dd, J1ϭ11.0,
J2ϭ4.1 Hz), 7.58—7.67 (3H, m), 8.24—8.30 (2H, m), 9.68 (1H, s). IR (KBr)
cmϪ1: 3295, 1320, 1160. HR-LSIMS m/z: 345.1386 (Calcd for C17H21N4SO2
3-(Morpholine-4-sulphonylmethyl)-5-phenyl-1,2,4-triazine (9c): mp 155—
156 °C. 1H-NMR (CDCl3, 200 MHz) d: 3.32—3.38 (4H, m), 3.68—3.74
(4H, m), 4.83 (2H, s), 7.64—7.67 (3H, m), 8.21—8.28 (2H, m), 9.69 (1H, (MϩH): 345.1385. LSIMS(ϩ) m/z: 345 (100, MϩH). Anal. Calcd for
s). IR (KBr) cmϪ1: 1350, 1160. Anal. Calcd for C14H16N4SO3: C, 52.49; H,
5.03; N, 17.49. Found: C, 52.70; H, 4.95; N, 17.61.
C17H20N4SO2: C, 59.28; H, 5.85; N, 16.27. Found: C, 59.01; H, 5.61; N, 15.88.
1-(5-Phenyl-1,2,4-triazin-3-yl)-hex-5-yne-1-sulphonic Acid 2,2-Dimethyl-
propyl Ester (13f): mp 64—65 °C. 1H-NMR (CDCl3, 200 MHz) d: 0.91 (9H,
s), 1.46—1.74 (2H, m), 1.96 (1H, t, Jϭ2.6 Hz), 2.26 (2H, td, J1ϭ6.8,
5-Phenyl-3-(pyrrolidine-1-sulphonylmethyl)-1,2,4-triazine (9d): mp 142—
143 °C. 1H-NMR (CDCl3, 200 MHz) d: 1.89—1.98 (4H, m), 3.29—3.37
(4H, m), 4.86 (2H, s), 7.58—7.66 (3H, m), 8.21—8.27 (2H, m), 9.67 (1H, J2ϭ2.6 Hz), 2.53—2.90 (2H, m), 3.93 & 4.01 (2H, AB system, Jϭ8.9 Hz),
s). IR (KBr) cmϪ1: 1350, 1170. Anal. Calcd for C14H16N4SO2: C, 55.25; H,
4.97 (1H, dd, J1ϭ10.5, J2ϭ4.5 Hz), 7.53—7.69 (3H, m), 8.21—8.29 (2H,

466
Vol. 50, No. 4
m), 9.68 (1H, s). IR (KBr) cmϪ1: 3300, 1320, 1160. HR-MS m/z: 372.1382
(Calcd for C19H22N3SO3 (MϪCH3): 372.1382). MS m/z: 372 (2, MϪCH3),
317 (4), 251 (4), 236 (100), 209 (17), 102 (91). Anal. Calcd for C20H25N3-
SO3: C, 61.99; H, 6.50; N, 10.84. Found: C, 62.20; H, 6.35; N, 10.63.
3-Methylsulphanyl-5-phenyl-6-(1-phenylsulphonyl-hex-5-ynyl)-1,2,4-tri-
7.55 & 7.65 (2H, AB system, Jϭ8.1 Hz), 7.97—8.04 (2H, m). IR (KBr)
cmϪ1
: 1350, 1180. HR-MS m/z: 359.1556 (Calcd for C20H25NSO3:
359.1555). MS m/z: 359 (4, Mϩ), 208 (100), 193 (14). Anal. Calcd for
C20H25NSO3: C, 66.82; H, 7.01; N, 3.90. Found: C, 66.90; H, 6.73; N, 3.80.
2-Phenyl-7-phenylsulphonyl-6,7-dihydro-5H-[1]pyrindine (15g): mp 152—
153 °C. 1H-NMR (CDCl3, 200 MHz) d: 2.53—2.74 (1H, m), 2.88—3.35 (3H,
m), 4.75 (1H, dd, J2ϭ9.8, J1ϭ2.0 Hz), 7.32—7.39 (3H, m), 7.48—7.82 (9H,
m). IR (KBr) cmϪ1: 1320, 1160. HR-MS m/z: 335.0979 (Calcd for C20H17-
NSO2: 335.0980). MS m/z: 335 (1, Mϩ), 271 (8), 194 (100). Anal. Calcd for
C20H17NSO2: C, 71.62; H, 5.11; N, 4.18. Found: C, 71.61; H, 4.81; N, 4.16.
2-Phenyl-7-(toluene-4-sulphonyl)-6,7-dihydro-5H-[1]pyrindine (15h): mp
150—151 °C. 1H-NMR (CDCl3, 200 MHz) d: 2.49 (3H, s), 2.53—2.73 (1H,
m), 2.87—3.33 (3H, m), 4.68—4.73 (1H, m), 7.29—7.38 & 7.54—7.68
(11H, 2ϫm). IR (KBr) cmϪ1: 1310, 1150. HR-MS m/z: 349.1138 (Calcd for
C21H19NSO2: 349.1137). MS m/z: 349 (Ͻ1, Mϩ), 285 (13), 194 (100). Anal.
Calcd for C21H19NSO2: C, 72.18; H, 5.48; N, 4.01. Found: C, 72.21; H, 5.34;
N, 3.99.
1
azine (14a): mp 155—156 °C. H-NMR (CDCl3, 200 MHz) d: 1.93 (1H, t,
Jϭ2.6 Hz), 2.08—2.27 (2H, m), 2.35 (2H, td, J1ϭ5.9, J2ϭ2.6 Hz), 2.52—
2.81 (2H, m), 2.68 (3H, s), 4.99 (1H, dd, J1ϭ10.7, J2ϭ4.4 Hz), 7.43—7.56
(3H, m), 7.57—7.67 (2H, m), 7.70—7.81 (5H, m). IR (KBr) cmϪ1: 3290,
1320, 1170. HR-MS m/z: 423.1077 (Calcd for C22H21N3S2O2: 423.1075. MS
m/z: 423 (6, Mϩ), 390 (1), 376 (2), 358 (14), 312 (28), 209 (52), 133 (61),
125 (24), 104 (37), 89 (40), 77 (37). Anal. Calcd for C22H21N3S2O2: C,
62.39; H, 5.00; N, 9.92. Found: C, 62.56; H, 5.00; N, 9.51.
3-Methylsulphanyl-5-phenyl-6-(1-phenylsulphonyl-pent-4-ynyl)-1,2,4-tri-
1
azine (14g): mp 130—131 °C. H-NMR (CDCl3, 200 MHz) d: 1.92 (1H, t,
Jϭ2.6 Hz), 2.08—2.84 (4H, m), 2.68 (3H, s), 5.00 (1H, dd, J1ϭ10.6,
J2ϭ4.4 Hz), 7.43—7.67 (5H, m), 7.69—7.82 (5H, m). IR (KBr) cmϪ1: 3290,
1320, 1170. HR-LSIMS m/z: 410.0997 (Calcd for C21H20N3S2O2 (MϩH):
410.0997. LSIMS(ϩ) m/z: 410 (100, MϩH). Anal. Calcd for C21H19N3S2O2:
C, 61.59; H, 4.68; N, 10.26. Found: C, 61.77; H, 4.54; N, 10.23.
7-(Morpholine-4-sulphonyl)-2-phenyl-6,7-dihydro-5H-[1]pyrindine (15i):
mp 131—132 °C. 1H-NMR (CDCl3, 200 MHz) d: 2.49—2.72 (1H, m),
2.78—3.03 (2H, m), 3.27—3.48 (5H, m), 3.60—3.77 (4H, m), 4.71 (1H, dd,
J1ϭ9.0, J2ϭ1.8 Hz), 7.42—7.55 (3H, m), 7.67 & 7.69 (2H, AB system,
Crude products 13g—i, due to their instability, were directly used in
Diels–Alder cycloaddition. An analytical sample of compound 13g was pu-
rified by column chromatography for characterization (for data see above).
Cycloaddition Reaction. General Procedure. In a round-bottomed
flask (100 ml) equipped with a reflux condenser, under argon, the triazine
derivative (13a—i, 1.0 mmol) was dissolved in bromobenzene (20 ml; com-
pounds 14a, g in triisopropylbenzene), and the reaction mixture was heated
to reflux. The reaction was monitored by TLC (reaction time–see Table 2).
The solvent was distilled in vacuum and the residue was chromatographed
using CHCl3 as eluent to give the desired products 15a—i and 16a, g.
2-Phenyl-8-phenylsulphonyl-5,6,7,8-tetrahydroquinoline (15a): mp 174—
175 °C. 1H-NMR (CDCl3, 200 MHz) d: 1.83—1.97 (1H, m), 2.12—2.32
(1H, m), 2.35—2.54 (1H, m), 2.72—3.12 (3H, m), 4.68 (1H, dd, J1ϭ6.6,
Jϭ8.9 Hz), 8.02—8.10 (2H, m). IR (KBr) cmϪ1
: 1310, 1150. HR-
LSIMS(ϩ) m/z: 345.1273 (Calcd for C18H21N2SO3 (MϩH): 345.1273).
LSIMS(ϩ) m/z: 345 (85, MϩH), 195 (58), 194 (100). Anal. Calcd for
C18H20N2SO3: C, 62.77; H, 5.86; N, 8.14. Found: C, 62.79; H, 5.79; N, 7.99.
3-Methylsulphanyl-1-phenyl-8-phenylsulphonyl-5,6,7,8-tetrahydroiso-
quinoline (16a): mp 165—166 °C. 1H-NMR (CDCl3, 200 MHz) d: 1.78—
1.96 (1H, m), 2.10—2.30 (1H, m), 2.38 (3H, s), 2.38—2.60 (1H, m), 2.71—
3.11 (3H, m), 4.64 (1H, dd, J1ϭ6.6, J2ϭ3.2 Hz), 7.24—7.60 (9H, m), 7.70—
7.80 (2H, m). IR (KBr) cmϪ1: 1330, 1150. HR-MS m/z: 395.1013 (Calcd for
C22H21NS2O2: 395.1014). MS m/z: 395 (1, Mϩ), 282 (60), 256 (21), 254
(100), 209 (22), 148 (30), 133 (18), 104 (8), 89 (10), 77 (10). Anal. Calcd for
C22H21NS2O2: C, 66.81; H, 5.35; N, 3.54. Found: C, 66.63; H, 5.37; N, 3.80.
3-Methylsulphanyl-1-phenyl-7-phenylsulphonyl-6,7-dihydro-5H-[2]-
pyrindine (16g): mp 201—202 °C. 1H-NMR (CDCl3, 200 MHz) d: 2.39 (3H,
s), 2.50—2.73 (1H, m), 2.88—3.11 (2H, m), 3.20—3.41 (1H, m), 4.71 (1H,
dd, J1ϭ9.0, J2ϭ1.3 Hz), 7.30—7.72 (9H, m), 7.77—7.84 (2H, m). IR (KBr)
cmϪ1: 1320, 1155. HR-MS m/z: 381.0858 (Calcd for C21H19NS2O2: 381.0857).
MS m/z: 381 (1, Mϩ), 240 (100), 225 (9), 224 (27), 223 (11), 193 (36).
J2ϭ3.3 Hz), 7.24—7.66 (10H, m), 7.71—7.78 (2H, m). IR (KBr) cmϪ1
:
1320, 1160. HR-MS m/z: 349.1121 (Calcd for C21H19NSO2: 349.1137). MS
m/z: 349 (Ͻ1, Mϩ), 285 (23), 208 (100), 193 (13). Anal. Calcd for
C21H19NSO2: C, 72.18; H, 5.48; N, 4.01. Found: C, 72.05; H, 5.45; N, 3.99.
2-Phenyl-8-(toluene-4-sulphonyl)-5,6,7,8-tetrahydroquinoline (15b): mp
190—191 °C. 1H-NMR (CDCl3, 200 MHz) d: 1.78—1.96 (1H, m), 2.10—
2.30 (1H, m), 2.42 (3H, s), 2.36—2.60 (1H, m), 2.50—2.88 (1H, m), 2.92—
3.11 (2H, m), 4.63 (1H, dd, J1ϭ6.6, J2ϭ3.0 Hz), 7.21—7.42 (7H, m), 7.49—
7.63 (4H, m). IR (KBr) cmϪ1: 1310, 1150. HR-LSIMS m/z: 364.1373 (Calcd
for C22H22NSO2 (MϩH): 364.1371). LSIMS(ϩ) m/z: 364 (100, MϩH).
Anal. Calcd for C22H21NSO2: C, 72.70; H, 5.82, N, 3.85. Found: C, 72.77; H,
5.82; N, 3.87.
8-(Morpholine-4-sulphonyl)-2-phenyl-5,6,7,8-tetrahydroquinoline (15c):
mp 184—185 °C. 1H-NMR (CDCl3, 200 MHz) d: 1.78—1.94 (1H, m),
2.05—2.24 (1H, m), 2.30—2.54 (1H, m), 2.70—3.10 (3H, m), 3.24—3.44
(4H, m), 3.52—3.74 (4H, m), 4.58 (1H, dd, J1ϭ6.2, J2ϭ2.2 Hz), 7.41—7.58
(3H, m), 7.53 & 7.66 (2H, AB system, Jϭ8.1 Hz), 8.02—8.10 (2H, m). IR
(KBr) cmϪ1: 1335, 1120. HR-LSIMS m/z: 359.1426 (Calcd for C19H23N2SO3
(MϩH): 359.1429). LSIMS(ϩ) m/z: 359 (70, MϩH). Anal. Calcd for
C19H22N2SO3: C, 63.66; H, 6.19; N, 7.82. Found: C, 63.79; H, 6.33; N, 7.70.
2-Phenyl-8-(pyrrolidine-1-sulphonyl)-5,6,7,8-tetrahydroquinoline (15d):
mp 161—162 °C. 1H-NMR (CDCl3, 200 MHz) d: 1.63—1.92 (5H, m),
2.06—2.26 (1H, m), 2.35—2.59 (1H, m), 2.70—2.88 (2H, m), 2.96—3.17
(3H, m), 3.37—3.51 (2H, m), 4.65 (1H, dd, J1ϭ6.4, J2ϭ2.4 Hz), 7.38—7.52
(3H, m), 7.54 & 7.65 (2H, AB system, Jϭ8.1 Hz), 7.95—8.02 (2H, m). IR
(KBr) cmϪ1: 1310, 1155. HR-MS m/z: 343.1476 (Calcd for C19H23N2SO2
(MϩH): 343.1480). MS m/z: 343 (Ͻ1, MϩH), 209 (100), 208 (63), 193
(18), 128 (7), 83 (23). Anal. Calcd for C19H22N2SO2: C, 66.64; H, 6.48; N,
8.19. Found: C, 66.30; H, 6.59; N, 7.82.
References and Notes
1) Part 17 in “1,2,4-Triazines in Organic Synthesis.” For part 16, see
Rykowski A., Wolin´ska E., van der Plas H. C., Khim. Geterotsikl.
Soedin. 2001, 1549—1555.
2) Thummel R. P., “Carbocyclic Annelated Pyridines,” in “Pyridine and
Its Derivatives,” Part 5, ed. by Newkome G. R., Vol. 14 in the series
“The Chemistry of Heterocyclic Compounds,” ed. by Weissberger A.,
Taylor E. C., Wiley-Interscience, New York, 1984, pp. 253—445.
3) Taylor E. C., Macor J. E., French L. G., J. Org. Chem., 56, 1807—
1812 (1991).
4) Charushin V. N., Alexeev S. G., Chupakhin O. N., van der Plas H. C.,
Adv. Heterocycl. Chem., 46, 74—142 (1989).
5) a) Rykowski A., Makosza M., Liebigs Ann. Chem., 1988, 627–631; b)
Makosza M., Wojciechowski K., Heterocycles, 54, 445—474 (2001).
6) Jung M. E., Synlett, 1990, 186—190.
7) Brown R. E., Lustgarten D. M., Stanaback R. J., Osborne M. W.,
Meltzer R. I., J. Med. Chem., 7, 232—235 (1964).
8) Meyers A. I., Schneller J., Ralhan N. K., J. Org. Chem., 28, 2944—
2950 (1963).
9) Neilands L., Khim. Geterotsikl. Soedin., 1970, 647—650; Chem.
Abstr., 73: 77013w (1970).
10) Dewar M. J. S., J. Chem. Soc., 1944, 615—619.
11) The samples are under investigation for tuberculostatic activity at the
Southern Research Institute, Birmingham, U.S.A.
12) Ma˛kosza M., Golin´ski J., Baran J., J. Org. Chem., 49, 1488—1494
(1984).
2-Phenyl-5,6,7,8-tetrahydroquinoline-8-sulphonic Acid Dimethylamide
(15e): mp 116—117 °C. 1H-NMR (CDCl3, 200 MHz) d: 1.77—1.92 (1H,
m), 2.07—2.26 (1H, m), 2.34—2.58 (1H, m), 2.69—3.10 (3H, m), 2.82 (6H,
s), 4.62 (1H, dd, J1ϭ6.3, J2ϭ2.4 Hz), 7.37—7.54 (3H, m), 7.56 & 7.67 (2H,
AB system, Jϭ8.1 Hz), 8.01—8.08 (2H, m). IR (KBr) cmϪ1: 1330, 1150.
HR-LSIMS m/z: 317.1322 (Calcd for C17H21N2SO2 (MϩH): 317.1324).
LSIMS(ϩ) m/z: 317 (100, MϩH). Anal. Calcd for C17H20N2SO2: C, 64.53;
H, 6.38; N, 8.86. Found: C, 64.44; H, 6.34; N, 8.67.
13) Ma˛kosza M., Danikiewicz W., Wojciechowski K., Liebigs Ann. Chem.,
1987, 711—715.
14) Christensen L. W., Seaman J. E., Truce W. E., J. Org. Chem., 38,
2243—2245 (1973).
2-Phenyl-5,6,7,8-tetrahydroquinoline-8-sulphonic Acid 2,2-Dimethyl-
propyl Ester (15f): mp 84—85 °C. 1H-NMR (CDCl3, 200 MHz) d: 0.89 (9H,
s), 1.82—1.97 (1H, m), 2.12—2.45 (2H, m), 2.71—3.07 (3H, m), 3.93 &
3.96 (2H, AB system, Jϭ9.2 Hz), 4.69—4.76 (1H, m), 7.35—7.51 (3H, m),
15) Jacobsen H. J., Senning A., Kaae S., Acta Chem. Scand., 25, 3031—
3035 (1971).
16) Ma˛kosza M., Golin´ski J., Synthesis, 1983, 1023—1025.