Imidazopyridinium and pyridopyrimidium bromides: Synthesis and hydrolysis

Article abstract of DOI:10.1021/jo016387l

The reactions of symmetrical and unsymmetrical 2,2′-dipyridylamines with 1,2-dibromoethane and 1,3-dibromopropane give imidazopyridinium and pyridopyrimidium bromides, respectively. These acetone/CH₂Cl₂ -insoluble, highly fluorescent quaternary ammonium salts undergo addition/ring opening upon treatment with methanolic KOH to give pyridin-2-one derivatives. A sequential N,N-dialkylation/ring-opening hydrolysis/N,N-dialkylation/ring-opening hydrolysis strategy was developed for the construction of unsymmetrical bis(pyridin-2-ones).

Full text of DOI:10.1021/jo016387l

2382
J . Org. Chem. 2002, 67, 2382-2385
Sch em e 1. Aza cya n in es (1) fr om
Im id a zop yr id in iu m a n d P yr id op yr im id iu m
Br om id es: Syn th esis a n d Hyd r olysis
2,2′-Dip yr id yla m in es (2)
Kevin S. Huang,† Makhluf J . Haddadin,‡ and
Mark J . Kurth*,†
Department of Chemistry, University of California, Davis,
One Shields Avenue, Davis, California 95616, and
Department of Chemistry, American University of Beirut,
Beirut, Lebanon
mjkurth@ucdavis.edu
Received December 18, 2001
Sch em e 2. Im id a zo- (m ) 1) a n d
P yr id op yr im id iu m (m ) 2) Br om id es
Abstr a ct: The reactions of symmetrical and unsymmetrical
2,2′-dipyridylamines with 1,2-dibromoethane and 1,3-dibro-
mopropane give imidazopyridinium and pyridopyrimidium
bromides, respectively. These acetone/CH2Cl2-insoluble, highly
fluorescent quaternary ammonium salts undergo addition/
ring opening upon treatment with methanolic KOH to give
pyridin-2-one derivatives. A sequential N,N-dialkylation/
ring-opening hydrolysis/N,N-dialkylation/ring-opening hy-
drolysis strategy was developed for the construction of
unsymmetrical bis(pyridin-2-ones).
As recently reported by us1 and by others,2 various
heterocyclic ammonium salts have been shown to activate
the cystic fibrosis transmembrane conductance regulator
protein CFTR.3 Since it is generally believed that resto-
ration of CFTR chloride permeability will be clinically
beneficial, an important goal in cystic fibrosis research
is the identification of small molecule activators of CFTR.
Azacyanine 1, the parent compound in a novel class
we reported capable of modulating chloride-selective ion
channels, can be constructed4 by either reaction of 2,2′-
dipyridylamine 2 with diiodomethane or, more directly,
by reaction of aminopyridine 3 with diiodomethane
(Scheme 1). As part of an investigation of these and other
transformations,5 we wondered if the seven-membered
analogue of 1 (4) would be available by reaction of 2 with
1,2-dibromoethane in the presence of a base such as
DIEA (N,N-diisopropylethylamine).
a 2-bromopyridine (5) with Pd(II) in the presence of
chelating bis(phosphine) ligand 1,3-bis(diphenylphosphi-
no)propane (dppp) and a 2-aminopyridine to deliver the
targeted 2,2′-dipyridylamine (6) in ca. 70-75% yield.
Proper selection of 2-bromo- and 2-aminopyridine start-
ing materials allows for the preparation of unsymmetrical
2,2′-dipyridylamines. Subsequent treatment of the re-
sulting 2,2′-dipyridylamines 6a -c with 1,2-dibromopro-
pane (used also as solvent) and DIEA (2-3 equiv) at
reflux (ca. 130 °C) under a nitrogen atmosphere for 18 h
did produce a quaternary ammonium heterocycle, but not
4. Rather, this N,N-dialkylation produced imidazopyri-
dinium bromide7 7a -c (m ) 1) as the sole product.
Intrigued by this transformation and the fact that
imidazopyridium salts are reported to have hypoglyce-
mic,8 type I allergy,9 and neuromuscular blocking10
properties, we decided to further investigate the synthe-
sis and hydrolysis reactions of these imidazopyridium
salts.
The starting material for this study, 2,2′-dipyridy-
lamine (6), was prepared by the Buchwald method of
palladium-catalyzed carbon-nitrogen bond formation.6
As outlined in Scheme 2, this method involves treating
† University of California.
‡ American University of Beirut.
(1) Luis J . V.; Galietta, L. J . V.; Springsteel, M. F.; Eda, M.;
Niedzinski, E. J .; By, K.; Haddadin, M. J .; Kurth, M. J .; Nantz, M. H.;
Verkman, A. S. J . Biol. Chem. 2001, 276, 19723-19728.
(2) Becq, F.; Mettey, Y.; Gray, M. A.; Galietta, L. J . V.; Dormer, R.
L.; Merten, M.; Metaye, T.; Chappe, V.; Marvingt-Mounir, C.; Zegarra-
Moran, O.; Tarran, R.; Bulteau, L.; Derand, R.; Pereira, M. M.;
McPherson, M. A.; Rogier, C.; J offre, M.; Argent, B. E.; Sarrouilhe,
D.; Kammouni, W.; Figarella, C.; Verrier, B.; Gola, M.; Vierfond, J . M.
J . Biol. Chem. 1999, 274, 27415-27425.
After cooling to room temperature, the crude acetone-
and CH2Cl2-insoluble solids from the reaction of 6 with
(7) For reviews of imidazopyridiniums, see: (a) Sulojeva, E.; Yure,
M.; Gudriniece, E. Chem. Heterocycl. Compd. 2000, 36, 885-898. (b)
Sulojeva, E.; Yure, M.; Gudriniece, E. Chem. Heterocycl. Compd. 1999,
35, 1121-1142. (c) Munavalli, S.; Hsu, F. L.; Poziomek, E. J . Chem.
Ind. 1987, 7, 243-244.
(3) Pilewski, J . M.; Frizzell, R. A. Physiol. Rev. 1999, 79, S215-
S255.
(4) (a) Munavalli, S.; Poziomek, E. J . Synthesis 1986, 402-403. (b)
Munavalli, S.; Hsu, F. L.; Poziomek, E. J . Heterocycles 1986, 24, 1893-
1898. (c) Munavalli, S.; Hsu, F. L.; Poziomek, E. J . Chem. Ind. (London)
1985, 797-798. (d) Leubner, I. H. J . Org. Chem. 1973, 38, 1098-1102.
(5) (a) Huang, K. S.; Haddadin, M. J .; Olmstead, M. M.; Kurth, M.
J . J . Org. Chem. 2001, 66, 1310-1315. (b) Haddadin, M. J .; Kurth, M.
J .; Olmstead, M. M. Tetrahedron Lett. 2000, 41, 5613-5616.
(6) Wagaw, S.; Buchwald, S. L. J . Org. Chem. 1996, 61, 7240-7241.
(8) Kuhla, D. E. Patent 4044015/19770823, 1977.
(9) Scholz, D.; Schmidt, H.; Prieschl, E. E.; Csonga, R.; Scheirer,
W.; Weber, V.; Lembachner, A.; Seidl, G.; Werner, G.; Mayer, P.;
Baumruker, T. J . Med. Chem. 1998, 41, 1050-1059.
(10) Bellani, P.; Clavenna, G.; Sosio, A. Farmaco, Ed. Sci. 1984, 39,
846-862.
10.1021/jo016387l CCC: $22.00 © 2002 American Chemical Society
Published on Web 03/09/2002

Notes
Sch em e 3. Rin g Op en in g of Im id a zo- a n d
J . Org. Chem., Vol. 67, No. 7, 2002 2383
Sch em e 4. Un sym m etr ica l Dia lk yla m in o
Bis(p yr id in -2-on es)
P yr id op yr im id iu m Br om id es
tively.12 In conclusion, we have demonstrated a viable
synthesis of imidazopyridium and pyridopyrimidium
bromides and have further shown that treatment of these
salts with methanolic KOH leads, by addition/ring open-
ing, to novel pyridin-2-one derivatives.
Exp er im en ta l Section
dibromoethane were washed with additional acetone and
CH2Cl2 to remove the DIEA·HBr salts and then recrys-
tallized from hot methanol to afford imidazopyridium
bromides 7a -c (m ) 1) in excellent yields (80-100%).
All of these quaternary ammonium bromides display
signals for the ethylene group at δ 4.4 and 4.9 (t, J ) 10
Hz) in the 1H NMR and δ 47 and 51 in the 13C NMR
(DMSO-d6). This ethylene nonequivalence provides un-
equivocal evidence that these products are imidazopy-
ridium salts (7) and not azacyanine salts (4).
Gen er a l E xp er im en t a l. Unless otherwise noted, starting
materials were obtained from commercial suppliers and used
as received. Melting points were determined using an Electro-
thermal 9100 apparatus and are uncorrected. Infrared spectra
were taken neat on a refractive spectrophotometer. 1H NMR was
measured in CDCl3, MeOH-d4, DMSO-d6, or CD3CO2D at 400
or 300 MHz and 13C NMR was measured at 100 or 75 MHz.
Elemental analyses were performed by Midwest Microlabs
(Indianapolis, IN). Silica gel chromatography was performed
according to the method of Still.13
Gen er a l Meth od for th e P r ep a r a tion of Un sym m etr ica l
2,2′-Dip yr id yla m in e. A three-necked round-bottom flask
equipped with a magnetic stir bar was charged with the specific
2-bromopyridine, aminopyridine (1.3 equiv), Pd2(dba)3 (0.2 equiv),
dppp (0.5 equiv), sodium tert-butoxide (1.7 equiv), and dry
toluene in this order. Under a nitrogen atmosphere, this solution
was stirred at 80 °C for 1 day. Additional Pd2(dba)3 (0.2 equiv),
dppp (0.5 equiv), and sodium tert-butoxide (1.7 equiv) were
added, and the mixture was stirred under nitrogen atmosphere
at 80 °C for an additional 24 h. After TLC showed complete
consumption of bromopyridine, the mixture was cooled to room
temperature and quenched with water. The aqueous layer was
separated from the organic layer and extracted with diethyl
ether. The combined organic layers were dried with MgSO4,
filtered, concentrated, and purified by column chromatography.
Recrystallization afforded white crystals.
In the light of these results with 1,2-dibromoethane,
we next investigated the reaction of 2,2′-dipyridylamine
6a with 1,3-dibromopropane (again, as solvent) in the
presence of DIEA (2 equiv). As with the imidazopyri-
dinium system, this reaction proceeds cleanly to afford
the pyridopyrimidium bromide (7d , m ) 2) in high yield
(88%). The propyl methylenes in this quaternary am-
1
monium salt appear at δ 2.4, 4.0, and 4.5 in the H NMR
and δ 21, 48, and 52 in the 13C NMR (DMSO-d6).
We are aware of only one report of nucleophilic ring
opening of the imidazopyridinium ring system. In that
case, thiophenolate and selenophenolate nucleophiles
were shown to attack at the C2 position (m ) 1) of the
imidazopyridinium analogue.11 Although we expected an
analogous attack by hydroxide to yield 8, we were not
surprised, in the light of our previous work,5 to find that
the reaction followed an alternative course to produce
pyridin-2-ones in quantitative yield. In this reaction, the
hydroxide ion is presumed to attack position C7a of the
imidazopyridinium 7 to produce, via intermediate 9,
pyridin-2-ones (10). This reaction was easily monitored
both by TLC and loss of fluorescence as 7 f 10.The
success of this 6 f 7 f 10 sequence prompted us to
wonder if a second N,N-dialkylation/hydrolysis cycle,
acting on the remaining 2-aminopyridine moiety, might
be possible. To address this question, pyridones 10a and
10c were first reacted with dibromopropane in the
presence of DIEA to give quaternary ammonium salt 11a
and 11c, respectively, in high yields. Nucleophilic addi-
tion of KOH to these pyrido[1,2-a]pyrimidin-5-ylium salts
led to ring opening and formation of the unsymmetrical
dialkylamino bis(pyridin-2-ones) 12a and 12c, respec-
(5-Ch lor op yr id in -2-yl)p yr id in -2-yla m in e (6b).6 The gen-
eral procedure for the preparation of unsymmetrical 2,2′-
dipyridylamine was employed with the following reagents and
quantities: 2-bromopyridine (1.9 g, 12 mmol), 4-chloro-2-ami-
nopyridine (1.6 g, 12 mmol), Pd2(dba)3 (0.2 g, 0.2 mmol), dppp
(0.2 g, 0.5 mmol), sodium tert-butoxide (2 g, 21 mmol), and dry
toluene (90 mL); additional Pd2(dba)3 (0.2 g, 0.2 mmol), dppp
(0.2 g, 0.5 mmol), and sodium-tert-butoxide (2 g, 21 mmol).
Column chromatography (3:1 hexane/ethyl acetate) followed by
recrystallization from hot methanol produced 6b [1.7 g, 8.4
mmol, 70%; mp 102-3 °C; 1H NMR (300 MHz, CDCl3) δ 6.84
(m, 1H), 7.55 (m, 5H), 8.26 (m, 1H), 9.03 (br s, 1H); 13C NMR
(75 MHz, CDCl3) δ 112.1, 112.9, 116.8, 123.3, 137.7, 138.1, 146.1,
147.7, 152.8, 154.1; IR (neat) 3262, 3025, 1602, 1588, 797 cm-1].
(5-Ch lor op yr id in -2-yl)(4-m eth ylp yr id in -2-yl)a m in e (6c).6
The general procedure for the preparation of unsymmetrical 2,2′-
dipyridylamine was employed with the following reagents and
quantities: 4-methyl-2-bromopyridine (1.6 g, 12 mmol), 4-chloro-
2-aminopyridine (1.6 g, 12 mmol), Pd2(dba)3 (0.2 g, 0.2 mmol),
dppp (0.2 g, 0.5 mmol), sodium tert-butoxide (2 g, 21 mmol), and
dry toluene (90 mL); additional Pd2(dba)3 (0.2 g, 0.2 mmol), dppp
(0.2 g, 0.5 mmol), and sodium tert-butoxide (2 g, 21 mmol).
(12) For a report regarding dye properties of these systems, see:
Grabchev, I.; Petkov, C.; Bojinov, V. Dyes Pigm. 2001, 48, 239-244.
(13) Still, W. C.; Kahn, M.; Mitra, A. J . Org. Chem. 1978, 43, 2923-
2925.
(11) Molina, P.; Alajarin, M.; Vilaplana, M. J . J . Chem. Res., Synop.
1985, 262-263.

2384 J . Org. Chem., Vol. 67, No. 7, 2002
Notes
Column chromatography (3:1 hexane/ethyl acetate) followed by
fluorescent starting material (12-24 h). The mixture was then
poured into a separatory funnel containing a 1:1 water/CH2Cl2
mixture. The organic layer was removed and the aqueous layer
was extracted with CH2Cl2. The combined organic layers were
washed with brine and saturated NaHCO3, dried with MgSO4,
filtered, and concentrated via rotatory evaporation. Column
chromatography (gradient from EtOAc to a MeOH/EtOAc ratio
depending on the compound) afforded the desired pyridin-2-one.
1-[2-(P yr id in -2-yla m in o)eth yl]-1H-p yr id in -2-on e (10a ).
The general procedure for the reaction of quaternary ammonium
salts with methanolic KOH was employed with the following
reagents and quantities: pyridinium bromide 7a (1 g, 3.6 mmol)
and 50 mL of 10% methanolic KOH gave 10a [640 mg, 3 mmol,
recrystallization from hot methanol produced 6c [1.5 g, 6.82
1
mmol, 75%; mp 85-6 °C; H NMR (400 MHz, CDCl3) δ 2.32 (s,
3H), 6.69 (dd, J ) 1, 5 Hz, 1H), 7.25 (d, J ) 1 Hz, 1H), 7.53 (dd,
J ) 3, 9 Hz, 1H), 7.60 (d, J ) 9 Hz, 1H), 8.12 (d, J ) 5 Hz, 1H),
8.20 (d, J ) 3 Hz, 1H), 8.40 (br s, 1H; 13C NMR (100 MHz, CDCl3)
δ_ 21.5, 112.1, 112.7, 118.4, 123.3, 137.7, 141.8, 146.4, 147.6,
149.3, 152.5; IR (neat) 3250, 3023, 1603, 1508, 788 cm-1].
Gen er a l Meth od for th e P r ep a r a tion of Qu a ter n a r y
Am m on iu m Br om id es. The specific 2,2′-dipyridylamine was
dissolved in the appropriate dibromoalkane (as solvent) contain-
ing DIEA (about 2 equiv). The mixture was refluxed for 18 h
and monitored by TLC (disappearance of starting material and
the appearance of a fluorescent product on the baseline). The
product precipitated from the reaction mixture and, upon cooling,
the precipitate was collected and washed with CH2Cl2 and
acetone to remove DIEA·HBr salts. Recrystallization from hot
methanol gave the product.
1
86 %; mp 108-109 °C; H NMR (300 MHz, CDCl3) δ 3.67 (q, J
) 6 Hz, 2H), 4.16 (t, J ) 6 Hz, 2H), 5.22 (t, J ) 6 Hz, 1H), 6.06
(dt, J ) 2, 7 Hz, 1H), 6.39 (d, J ) 8 Hz, 1H), 6.51 (m, 2H), 7.17
(dd, J ) 2, 7 Hz, 1H), 7.29 (m, 2H), 8.02 (dd, J ) 1, 5 Hz, 1H));
13C NMR (75 MHz, CDCl3) δ 41.5, 49.7, 106.2, 108.3, 113.1,
120.9, 137.4, 138.6, 139.9, 148.0. 158.3, 163.2; IR (neat) 3298,
1644, 1589 cm-1. Anal. Calcd for C12H13N3O; C, 66.96; H, 6.09;
N, 19.52. Found: C, 66.93; H, 6.20; N, 19.50].
(1-P yr id in -2-yl)-2,3-d ih yd r o-1H -im id a zo[1,2-a ]p yr id in -
iu m Br om id e (7a ). The general procedure for the preparation
of quaternary ammonium bromide was employed with the
following reagents and quantities: dipyridin-2-ylamine 6a (2.8
g, 16.4 mmol), 1,2-dibromoethane (20 mL, 232 mmol), and DIEA
(6 mL, 34 mmol) gave 7a [4.5 g, 16.4 mmol, 100%; mp 200 °C;
1H NMR (400 MHz, DMSO-d6) δ 4.44 (t J ) 10 Hz, 2H), 4.91 (t
J ) 10 Hz, 2H), 7.42 (m, 2H), 7.33 (m, 1H), 7.96 (m, 1H), 8.26
(m, 1H), 8.46 (m, 1H), 8.63 (m, 2H); 13C NMR (100 MHz, DMSO-
d6) δ 47.1, 50.9, 112.4, 114.0, 117.5, 120.4, 139.8, 140.1, 146.4,
148.5, 150.8, 152.0; IR (neat) IR (neat) 2969, 1638, 1560, 1336,
758 cm-1].
1-[2-(5-Ch lor op yr id in -2-yla m in o)et h yl]-1H -p yr id in -2-
on e (10b). The general procedure for the reaction of quaternary
ammonium salts with methanolic KOH was employed with the
following reagents and quantities: pyridinium bromide 7b (1 g,
3.2 mmol) and 50 mL of 10% methanolic KOH gave 10b [643
mg, 2.6 mmol, 80%; 1H NMR (300 MHz, CDCl3) δ 3.69 (q, J ) 6
Hz, 2H), 4.18 (t, J ) 6 Hz, 2H), 5.29 (br s, 1H), 6.12 (dt, J ) 2,
7 Hz, 1H), 6.38 (d, J ) 9 Hz, 1H), 6.56 (dd, J ) 1, 9 Hz, 1H),
7.20 (dd, J ) 2, 7 Hz, 1H), 7.31 (m, 2H), 7.99 (d, J ) 2 Hz, 1H);
13C NMR (75 MHz, CDCl3) δ 41.9, 49.6, 106.4, 109.3, 121.0,
126.1, 137.3, 138.4, 140.0, 146.2, 156.6, 163.4; IR (neat) 3308,
2996, 1651, 1579, 760 cm-1].
1-[2-(5-Ch lor op yr id in -2-yla m in o)eth yl]-4-m eth yl-1H-p y-
r id in -2-on e (10c). The general procedure for the reaction of
quaternary ammonium salts with methanolic KOH was em-
ployed with the following reagents and quantities: pyridinium
bromide 7c (1 g, 3.06 mmol) and 50 mL of 10% methanolic KOH
gave 10c [660 mg, 2.5 mmol, 82%; mp 129-130 °C; 1H NMR
(300 MHz, CDCl3) δ 2.12 (s, 3H), 3.63 (dt, J ) 6 Hz, 2H), 4.12
(t, J ) 6 Hz, 2H), 5.49 (br s, 1H), 5.95 (dd, J ) 2, 7 Hz, 1H), 6.31
(d, J ) 2 Hz, 1H), 6.37 (d, J ) 9 Hz, 1H), 7.06 (d, J ) 7 Hz, 1H),
7.28 (dd, J ) 3, 9 Hz, 1H), 7.96 (d, J ) 3 Hz, 1H); 13C NMR (75
MHz, CDCl3) δ 21.6, 42.0, 49.1, 109.0, 109.4, 119.3, 119.9, 137.1,
137.3, 146.2, 151.8, 156.8, 163.3; IR (neat) 3308, 3308, 1645,
1530, 720 cm-1. Anal. Calcd for C13H14ClN3O; C, 59.21; H, 5.35;
N, 15.91. Found: C, 59.29; H, 5.41; N, 15.72].
1-[3-(P yr id in -2-yla m in o)p r op yl]-1H-p yr id in -2-on e (10d ).
The general procedure for the reaction of quaternary ammonium
salts with methanolic KOH was employed with the following
reagents and quantities: pyridinium bromide 7d (1 g, 3.4 mmol)
and 50 mL of 10% methanolic KOH gave 10d as a yellow oil
[640 mg, 2.8 mmol, 82%; 1H NMR (300 MHz, CDCl3) δ 1.85
(quintet, J ) 7 Hz, 2H), 3.17 (q, J ) 7 Hz, 2H), 3.86 (t, J ) 7
Hz, 2H), 5.47 (t, J ) 7 Hz, 1H), 5.97 (dt, J ) 1, 7 Hz, 1H), 6.24
(dd, J ) 1, 9 Hz, 1H), 6.34 (m, 2H), 7.13 (m, 3H), 7.87 (dd, J )
1, 5 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 29.4, 38.3, 47.1, 106.5,
108.2, 112.5, 120.7, 137.2, 137.9, 139.7, 147.8, 158.7, 162.9; IR
(neat) 3311, 3001, 1649, 1506 cm-1].
1-(5-Ch lor op yr id in -2-yl)-2,3-d ih yd r o-1H-im id a zo[1,2-a ]-
p yr id in iu m Br om id e (7b). The general procedure for the
preparation of quaternary ammonium bromide was employed
with the following reagents and quantities: (5-chloropyridin-2-
yl)pyridin-2-ylamine 6b (1 g, 4.62 mmol), 1,2-dibromoethane (10
mL, 116 mmol), and DIEA (3 mL, 17 mmol) gave 7b [1.2 g, 3.9
1
mmol, 86%; mp 230-233 °C; H NMR (400 MHz, DMSO-d6) δ
4.43 (t J ) 10 Hz, 2H), 4.91 (t J ) 10 Hz, 2H), 7.29 (d, J ) 9 Hz,
1H), 7.37 (m, 1H), 8.09 (dd, J ) 1, 9 Hz, 1H), 8.29 (m, 1H), 8.52
(d, J ) 1 Hz, 1H), 8.56 (dd, J ) 1, 9 Hz, 1H), 8.63 (d, J ) 6 Hz,
1H); 13C NMR (100 MHz, DMSO-d6) δ 47.3, 51.0, 113.9, 114.0,
118.0, 126.3, 139.8, 140.0, 146.6, 146.8, 150.6; IR (neat) 3006,
1635, 1540, 1315, 760 cm-1. Anal. Calcd for C12H11BrClN3•H2O;
C, 46.11; H, 3.55; N, 13.44. Found: C, 43.94; H, 3.38; N, 13.78].
1-(5-Ch lor op yr id in -2-yl)-7-m et h yl-2,3-d ih yd r o-1H -im i-
d a zo[1,2-a ]p yr id in iu m Br om id e (7c). The general procedure
for the preparation of quaternary ammonium bromide was
employed with the following reagents and quantities: (5-
chloropyridin-2-yl)(4-methylpyridin-2-yl)amine 6c (1.5, 6.96 mmol),
1,2-dibromoethane (22 g, 117.3 mmol), and DIEA (2.5 mL, 14.3
1
mmol) gave 7c [2 g, 6.12 mmol, 88%; mp 320 °C; H NMR (300
MHz, DMSO-d6) δ 2.52 (s, 3H), 4.43 (t J ) 9 Hz, 2H), 4.86 (t J
) 9 Hz, 2H), 7.25 (dd, J ) 1, 7 Hz, 1H), 7.31 (d, J ) 9 Hz, 1H),
8.10 (dd, J ) 2, 9 Hz, 1H), 8.41 (d, J ) 1 Hz, 1H), 8.53 (d, J )
7 Hz, 1H), 8.54 (d, J ) 2 Hz, 1H); 13C NMR (75 MHz, DMSO-d6)
δ 22.9, 47.7, 50.5, 113.0, 114.0, 119.3, 126.5, 138.8, 139.6, 146.8,
150.1, 150.5, 159.4; IR (neat) 2996, 1622, 1539, 1300, 750 cm-1
.
Anal. Calcd for C13H13BrClN3; C, 47.81; H, 4.01; N, 12.86.
Found: C, 47.75; H, 4.19; N, 12.33].
1-(P yr id in -2-yl)-1,2,3,4-t et r a h yd r op yr id o[1,2-a ]p yr im -
id iu m Br om id e (7d ). The general procedure for the preparation
of quaternary ammonium bromide was employed with the
following reagents and quantities: (dipyridin-2-ylamine 6a (1
g, 5.84 mmol), 1,3-dibromopropane (30 mL, 290 mmol), and
DIEA (2.5 mL, 14.3 mmol) gave 7d [1.5 g, 5.12 mmol, 88%; mp
290 °C; 1H NMR (300 MHz, DMSO-d6) δ 2.35 (m, 2H), 3.95 (t, J
) 6 Hz, 2H), 4.52 (t, J ) 6 Hz, 2H), 7.05 (d, J ) 9 Hz, 1H), 7.14
(m, 1H), 7.47 (m, 1H), 7.61 (d, J ) 8 Hz, 1H), 7.89 (m, 1H), 8.05
(dt, J ) 2, 8 Hz, 1H), 8.33 (dd, J ) 1, 6 Hz, 1H), 8.56 (dd, J )
1, 4 Hz, 1H); 13C NMR (75 MHz, DMSO-d6) δ 20.8, 48.2, 52.5,
115.7, 116.4, 120.4, 124.2, 140.8, 141.7, 143.2, 150.2, 151.5, 154.4;
IR (neat) 2981, 1600, 1533, 1322, 720 cm-1].
1-[2-(2-Oxo-2H-p yr id in -1-yl)eth yl]-1,2,3,4-tetr a h yd r op y-
r id o[1,2-a ]p yr im id in -5-yliu m Br om id e (11a ). The general
procedure for the preparation of quaternary ammonium bromide
was employed with the following reagents and quantities:
pyridin-2-one 10a (600 mg, 2.78 mmol), 1,2-dibromopropane (30
mL, 294 mmol), and DIEA (1.5 mL, 8.61 mmol) gave 11a [930
mg, 2.78 mmol, 100%; mp 300 °C; 1H NMR (300 MHz, CD3CO2D)
δ 2.35 (m, 2H), 3.78 (t, J ) 5 Hz, 2H), 4.28 (t, J ) 6 Hz, 2H),
4.45 (t, J ) 5 Hz, 2H), 4.82 (t, J ) 6 Hz, 2H), 6.92 (m, 1H), 7.20
(m, 1H), 7.43 (m, 2H), 7.93 (m, 2H), 8.11 (m, 1H), 8.67 (d, J ) 7
Hz, 1H); 13C NMR (75 MHz, CD3CO2D) δ 48.2, 49.3, 50.1, 52.3,
54.9, 112.8, 113.2, 116.1, 116.4, 141.1, 141.8, 143.2, 146.3, 151.8,
161.54; IR (neat) 2998, 1632, 1555 cm-1].
Gen er a l Meth od for th e Rea ction of Qu a ter n a r y Am -
m on iu m Sa lts w ith Meth a n olic KOH. The quaternary am-
monium salt was mixed with 10% methanolic KOH (and water
to dissolve if necessary) and magnetically stirred at 80 °C. The
reaction was monitored by the disappearance of the highly
5-Ch lor o-1-[2-(4-m et h yl-2-oxo-2H -p yr id in -1-yl)et h yl]-
1,2,3,4-tetr a h yd r op yr id o[1,2-a ]p yr im id in -5-yliu m Br om id e
(11c). The general procedure for the preparation of quaternary
ammonium bromide was employed with the following reagents
and quantities: pyridin-2-one 10c (600 mg, 2.28 mmol), 1,2-

Notes
J . Org. Chem., Vol. 67, No. 7, 2002 2385
dibromopropane (30 mL, 294 mmol), and DIEA (1.5 mL, 8.61
mmol) gave 11c [880 mg, 2.28 mmol, 100%; mp 300 °C; 1H NMR
(300 MHz, MeOH-d4) δ 2.25 (m, 2H), 3.63 (t J ) 6 Hz, 2H), 3.98
(t, J ) 6 Hz, 2H), 4.28 (t, J ) 6 Hz, 2H), 4.32 (t, J ) 6 Hz, 2H),
4.90 (s, 3H), 6.35 (d, J ) 7 Hz, 1H), 6.37 (s, 1H), 7.45 (d, J ) 10
Hz, 1H), 7.64 (d, J ) 7 Hz, 1H), 7.89 (dd, J ) 2, 10 Hz, 1H), 8.17
(d, J ) 2 Hz, 1H); 13C NMR (75 MHz, MeOH-d4) δ 19.0, 20.4,
46.2, 47.0, 50.2, 52.2, 111.7, 114.0, 117.2, 119.3, 138.1, 138.5,
142.6, 150.8, 155.3, 163.2; IR (neat) 2998, 1632, 1555 cm-1. Anal.
Calcd for C16H19BrClN3O·H2O·HBr; C, 39.74; H, 4.59; N, 8.69.
Found: C, 39.74; H, 4.40; N, 8.06].
methanolic KOH gave 12c [420 mg, 1.3 mmol, 100%; mp 300
°C; H NMR (300 MHz, CDCl3) δ 1.81 (br s, 1H), 1.87 (m, 2H),
1
2.15 (s, 3H), 2.60 (t, J ) 7 Hz, 2H), 2.92 (t, J ) 6 Hz, 2H), 3.93
(t, J ) 7 Hz, 2H), 3.98 (t, J ) 6 Hz, 2H), 6.00 (dd, J ) 2, 7 Hz,
1H), 6.35 (d, J ) 2 Hz, 1H), 6.49 (d, J ) 10 Hz, 1H), 7.19 (d, J
) 7 Hz, 1H), 7.24 (dd, J ) 2, 10 Hz, 1H), 7.28 (d, J ) 2 Hz, 1H);
13C NMR (75 MHz, CDCl3) δ 21.6, 29.2, 45.9, 47.9, 48.4, 49.7,
108.6, 112.2, 119.3, 121.8, 135.7, 137.3, 140.4, 151.4, 161.1, 162.8;
IR (neat) 3299, 1630, 1590 cm-1. Anal. Calcd for C16H20ClN3O2;
C, 59.72; H, 6.26; N, 13.43. Found: C, 59.90; H, 6.38; N, 13.18].
1-[3-(1H-P yr idin -2-on e)-2-eth ylam in opr opyl]-1H-pyr idin -
2-on e (12a ). The general procedure for the reaction of quater-
nary ammonium salts with methanolic KOH was employed with
the following reagents and quantities: pyridinium bromide 11a
(500 mg, 1.48 mmol) and 40 mL of 10% methanolic KOH gave
12a [360 mg, 1.3 mmol, 88%; 1H NMR (300 MHz, CDCl3) δ 1.67
(br s, 1H), 1.89 (quintet, J ) 7 Hz, 2H), 2.61 (t, J ) 7 Hz, 2H),
2.96 (t, J ) 6 Hz, 2H), 3.97 (t, J ) 7 Hz, 2H), 4.03 (t, J ) 6 Hz,
2H), 6.14 (m, 2H), 6.55 (m, 2H), 7.29 (m, 4H); 13C NMR (75 MHz,
CDCl3) δ 29.5, 46.1, 47.5, 48.3, 50.4, 105.9, 106.2, 121.0, 121.1,
138.0, 138.5, 139.6, 139.8, 162.8, 162.9; IR (neat) 3258, 1653,
1580 cm-1].
5-Ch lor o-1-[3-(4-m et h yl-1H -p yr id in -2-on e)-2-et h yla m i-
n op r op yl]-1H-p yr id in -2-on e (12c). The general procedure for
the reaction of quaternary ammonium salts with methanolic
KOH was employed with the following reagents and quantities:
pyridium bromide 11c (500 mg, 1.3 mmol) with 40 mL of 10%
Ack n ow led gm en t. We are grateful to the Cystic
Fibrosis Foundation and the National Science Founda-
tion for financial support of this research. The 400 and
300 MHz NMR spectrometers used in this study were
funded in part by a grant from NSF (CHE-9808183).
M.J .H. is grateful to the American University of Beirut
for a sabbatical leave at the University of California,
Davis.
1
Su p p or tin g In for m a tion Ava ila ble: Copies of H NMR
and 13C NMR spectra for 7a , 7d , 10b, 10d , 11a , and 12a . This
material is available free of charge via the Internet at
http://pubs.acs.org.
J O016387L