Synthesis of unsymmetrical 5,5'-disubstituted 2,2'-bipyridines

Full text of DOI:10.1021/jo962398g

J . Org. Chem. 1997, 62, 3013-3014
3013
Sch em e 1a
Syn th esis of Un sym m etr ica l
5,5′-Disu bstitu ted 2,2′-Bip yr id in es1
George R. Newkome,* J ens Gross, and Anil K. Patri
Center for Molecular Design and Recognition,
Department of Chemistry, University of South Florida,
Tampa, Florida 33620
Received December 30, 1996
The preparation of unsymmetrical 6,6′-disubstituted
2,2′-bipyridines has generally occurred by the stepwise
mono-N-oxidation,2 followed by a Boekelheide-type rear-
rangement3 or by a coupling of different pyridine precur-
sors;4 both procedures are plagued with difficulties. It
was, however, demonstrated5 that, in THF at -60 °C
with 1 equiv of butyllithium, 6,6′-bis(hydroxymethyl)-2,2′-
bipyridine2 was transformed to the monoalkoxide, which
was trapped as the monomesylate in an overall 96% yield.
This procedure takes advantage of the different solubility
characteristics of the intermediates vs the starting mate-
rial; this monolithium alkoxide is insoluble under these
specific reaction conditions. Application of this general
procedure was used6 to afford 6-(bromomethyl)-6′-(hy-
droxymethyl)-2,2′-bipyridine, which was subsequently
converted to functionalized oligobipyridines. In that we
needed unsymmetrical 5,5′-disubstituted 2,2′-bipyridines
for the synthesis of specifically located binding loci within
dendrons, we herein describe the use of similar solubility
differences of the intermediate(s) to prepare 5′-amino-
2,2′-bipyridine-5-carboxylic acid in excellent overall yield
from the symmetrical diethyl 2,2′-bipyridine-5,5′-dicar-
boxylate.
a
Key: (a) 10% Pd/C; (b) 1.5 equiv of NH2NH2‚H2O, EtOH,
toluene, 80 °C; (c) 2 equiv of NH2NH2‚H2O, EtOH, toluene, 115
°C; (d) HCl, 0 °C, aqueous NaNO2; (e) EtOH, xylene, reflux; (f)
EtOH, 2.5 N aqueous NaOH, 75 °C; (g) EtOH, concentrated H2SO4,
reflux.
The synthesis of 5,5′-diamino-2,2′-bipyridine from di-
ethyl 2,2′-bipyridine-5,5′-dicarboxylate (2) had been pre-
viously reported by Whittle.7 The desired diester 2 was
prepared by refluxing neat ethyl nicotinate 1 with
palladium on charcoal for 6 days under a partial vacuum;
the catalyst and starting ester were removed and recycled
(Scheme 1). Diester 2 was isolated in ca. 35% yield on
the first cycle, and its simple NMR spectra supported the
structure. By taking advantage of the low solubility of
carbohydrazides, the exclusive formation of the mono-
carbohydrazide 3 was achieved by the use of approxi-
mately 1.5 equiv of hydrazine and by adjusting either
the polarity of the solvent system (ethanol/toluene) or the
reaction temperature (80 °C). The monocarbohydrazide
3 precipitated under these conditions and was obtained
in 85% yield. Although 3 is nearly insoluble in many
Reaction of monocarbohydrazide 3 with NaNO2 in
concentrated HCl gave (ca. 100%) the corresponding
carbazide 5, whose IR spectrum clearly demonstrates the
presence of the characteristic carbazide stretch at 2181
and 2143 cm-1 as well as the shift (13C NMR) from δ 163.8
to 171.0 for the carbonyl groups supporting the conver-
sion. Subsequent Curtius rearrangement of carbazide 5
provided (82%) urethane 6; the 13C NMR for 6 shows the
expected upfield shift from δ 171.0 to 153.3 for the
urethane moiety. Saponification of 6 afforded (89%) the
desired 5′-amino-2,2′-bipyridine-5-carboxylic acid hydro-
chloride 7 supported by the carbonyl absorption at δ
176.0 and the disappearance of the peak for the urethane
carbonyl. The bright yellow salt is soluble in aqueous
base but shows only very low solubility in organic solvent
other than DMSO.
In order to enhance the solubility characteristics, the
amino acid 7 was subjected to Fischer esterification
conditions affording the ethyl ester 8, as a pale yellow
solid. The enhanced organic solubility and the appear-
ance of the typical ethyl absorption in the NMR spectra
support the assigned structure.
Application of the selective reactivity due to solubility
differences has great potential in the preparation of
unsymmetrical heterocycles8 and is being pursued in
other N-heterocyclic functionalizations.
1
organic solvent, its H NMR spectrum in DMSO clearly
showed two doublets (J ) 2 Hz) at δ 9.1 and 9.2 for the
two different 6,6′-pyH, respectively, confirming the un-
symmetrical substitution pattern. Treatment of 2 with
excess hydrazine hydrate under more drastic conditions
afforded (100%) the symmetrical dicarbohydrazide 4,
which is insoluble in most common organic solvents.
(1) Chemistry of Heterocyclic Compounds. Part 157. Previous part
in this series, see: Fronczek, F. R.; Schilling, P. J .; Watkins, S. F.;
Majestic, V. K.; Newkome, G. R. Inorg. Chim. Acta 1996, 246, 119.
(2) Newkome, G. R.; Puckett, W. E.; Kiefer, G. E.; Gupta, V. K.; Xia,
Y.; Coreil, M.; Hackney, M. A. J . Org. Chem. 1982, 47, 4116.
(3) Boekelheide, V.; Linn, W. J . Am. Chem. Soc. 1954, 76, 1286
(4) Haginiwa, J .; Higuchi, Y. Yagugaku Zasshi 1973, 93, 144.
(5) Lee, H.-W. Ph.D. Dissertation LSU, 1983.
Exp er im en ta l Section
Gen er a l Com m en ts. All melting points were taken in
capillary tubes and are uncorrected. The 1H and 13C NMR
(6) Eisenbach, C. D.; Schubert, U. S.; Baker, G. R.; Newkome, G. R.
J . Chem. Soc., Chem. Commun. 1995, 69.
(7) Whittle, C. P. J . Heterocycl. Chem. 1977, 14, 191.
(8) See: Cai, D.; Hughes, D. L.; Verhoeven, T. R. Tetrahedron Lett.
1996, 37, 2537.
S0022-3263(96)02398-5 CCC: $14.00 © 1997 American Chemical Society

3014 J . Org. Chem., Vol. 62, No. 9, 1997
Notes
spectra were obtained in CHCl3, unless otherwise stated. All
reagents were purchased from Aldrich and were used without
further purification.
121.4, 126.7, 126.8, 137.8, 138.1, 150.3, 150.6, 157.8, 159.4, 165.0,
171.0; IR 2181, 2143 (N3), 1721, 1715 (CdO), 1294, 1244 (CO2)
cm-1. Anal. Calcd for C14H11N5O3: C, 56.64; H, 3.72; N, 23.56.
Found: C, 56.50; H, 3.96; N, 23.84.
Dieth yl 2,2′-Bip yr id in e-5,5′-d ica r boxyla te (2). Neat ethyl
nicotinate [1; 82 g, 540 mmol; bp 222-224 °C (lit.9 bp 223-224
°C)] with 10% Pd/C was refluxed under reduced pressure (16
mmHg) for 6 days. The reaction mixture was diluted with
hexane, and then the catalyst was filtered and extracted with
toluene in a soxlet extractor. The combined organic solution was
concentrated affording crude product, which was recrystallized
from EtOH: 28.67 g (35.2%); mp 145-147 °C (lit.10 mp 149 °C);
1H NMR δ 1.41 [t, J ) 7.1 Hz, 6H], 4.42 (q, J ) 7.1 Hz, 4H),
8.41 (dd, 3J ) 8.3 Hz, 4J ) 2.15 Hz, 2H), 8.54 (dd, J ) 8.3, 0.8
Hz, 2H), 9.27 (dd, J ) 2.15, 0.8 Hz, 2H); 13C NMR δ 14.3, 61.5,
121.2, 126.5, 138.1, 150.5, 158.3, 165.1; IR 1721 (CdO), 1269,
1112 (CO2) cm-1. Anal. Calcd for C16H16N2O4: C, 63.97; H, 5.37;
N, 9.32. Found: C, 64.07; H, 5.64; N, 9.42.
Eth yl 5′-[(Eth oxyca r bon yl)a m in o]-2,2′-bip yr id in e-5-ca r -
boxyla te (6). A solution of ethyl 5′-carbazido-2,2′-bipyridine-
5-carboxylate (5.1 g, 19 mmol) in a mixture of EtOH (60 mL)
and xylene (60 mL) was refluxed for 4 h. The solvent was
evaporated in vacuo, and the residue was recrystallized from
1
EtOH to yield (82%) 6 as a colorless solid: mp 208-211 °C; H
NMR δ 1.32 (t, J ) 7.2 Hz, 3H), 1.41 (t, J ) 7.2 Hz, 3H), 4.25 (q,
J ) 7.2 Hz, 2H), 4.41 (q, J ) 7.2Hz, 2H), 6.81 (s, 1H), 8.08 (dd,
3J ) 8 Hz, 4J ) 2 Hz, 1H), 8.35 (dd, 3J ) 8.3 Hz, 4J ) 2 Hz, 1H),
8.40 (dd, 3J ) 8.3Hz, 5J ) 1 Hz, 1H), 8.43 (d, 3J ) 8 Hz, 1H),
4
4
5
8.58 (d, J ) 2 Hz, 1H), 9.22 (d, J ) 2 Hz, J ) 1 Hz, 1H); 13C
NMR δ 14.3, 14.5, 61.4, 61.9, 119.9, 122.2, 125.4, 126.0, 135.7,
137.9, 139.5, 150.01, 150.51, 153.30, 158.97, 165.43; IR 3320
(NH), 1724, 1704 (CdO) cm-1; ESI-MS 317.1 (M+ + 1).
Eth yl 5′-Ca r boh yd r a zid o-2,2′-bip yr id in e-5-ca r boxyla te
(3). A mixture of diethyl 2,2′-bipyridine-5,5′-dicarboxylate (7 g,
23.3 mmol) and hydrazine hydrate (1.75 mL, 35 mmol) in a
solution of EtOH (20 mL) and toluene (60 mL) was heated at 80
°C for 30 h. The precipitate was filtered, washed with CH2Cl2
to remove unreacted starting material, and dried in vacuo to
5′-Am in o-2,2′-bip yr id in e-5-ca r boxylic Acid Hyd r och lo-
r id e (7). A stirred solution of ethyl 5′-[(ethoxycarbonyl)amino]-
2,2′-bipyridine-5-carboxylate (4.85 g, 15.3 mmol) in a mixture
of EtOH (50 mL) and 2.5 N aqueous NaOH (50 mL) was heated
at 75 °C for 14 h. The EtOH was concentrated in vacuo, and
the aqueous solution was acidified with HCl to afford a bright
yellow precipitate, which was filtered, washed with cold water,
and dried in vacuo (89%). The resultant solid was recrystallized
from concentrated HCl to give 7‚HCl as a bright yellow solid:
1
give (85%) the pure monocarbohydrazide: mp 235-238 °C; H
NMR (DMSO-d6) δ 1.35 (t, 3H), 4.37 (q, 2H), 4.63 (br, 2H), 8.35
(dd, 3J ) 8.4 Hz, 4J ) 2 Hz, 1H), 8.45 (dd, 3J ) 8.4 Hz, 4J ) 2
Hz, 1H), 8.52 (d, 3J ) 8.4 Hz, 1H), 8.57 (d, 3J ) 8.4 Hz, 1H), 9.1
(d, 4J ) 2 Hz, 1H), 9.2 (d, 4J ) 2 Hz, 1H), 10.1 (br, 1H); 13C
NMR (DMSO-d6) δ 14.1, 61.3, 120.9, 120.9, 126.1, 129.6, 136.2,
138.2, 148.1, 150.0, 155.8, 157.8, 163.8, 164.5; IR 3325, 3187
(NH), 1721, 1715 (CdO) cm-1. Anal. Calcd for C14H14N4O3: C,
58.72; H, 4.92; N, 19.57. Found: C, 58.59; H, 4.70; N, 19.82.
5,5′-Dica r boh yd r a zid o-2,2′-bip yr id in e (4) was formed un-
der similar conditions except that the temperature was main-
tained at 115 °C for 3 h. The creamy insoluble (acid, base, and
most common organic solvents) solid was washed with boiling
EtOH to give (98%) the pure dicarbohydrazide: mp >300 °C;
1
3
mp 286-290 °C dec; H NMR (D2O/NaOD) δ 7.00 (dd, J ) 8.5
4
3
4
Hz, J ) 2.8 Hz, 1H), 7.55, 7.61 (d, J ) 8.5 Hz, 2H), 7.81 (d, J
3
4
) 2.8 Hz, 1H), 7.98 (dd, J ) 8.5 Hz, J ) 2.8 Hz, 1H), 8.65 (d,
4J ) 2.8 Hz, 1H); 13C NMR (D2O/NaOD) δ 123.15, 125.96, 126.49,
133.69, 139.82, 141.34, 147.39, 147.45, 152.33, 159.57, 176.04;
IR 3356, 3287 (NH), 1721 (CdO), 1225 (CO2) cm-1. Anal. Calcd
for
C11H10N3O2Cl: C, 52.57; H, 4.01; N, 16.72; Cl, 13.92.
Found: C, 51.77; H, 4.27; N, 16.28; Cl, 13.87.
Eth yl 5′-Am in o-2,2′-bip yr id in e-5-ca r boxyla te (8). To a
stirred solution of 7 (200 mg, 900 µmol) in ethanol (25 mL), was
added concentrated H2SO4 (2mL), and then the mixture was
refluxed for 12 h. The solid went into the solution in 1 h. The
reaction mixture was cooled, kept on ice bath, neutralized with
ammonium hydroxide, and concentrated in vacuo. The residue
was extracted with ether (3 × 10 mL); the extract was concen-
trated in vacuo to give the ester as a pale yellow solid: mp 130-
IR 3300, 3262, 3199 (NH), 1677 (CdO) cm-1
.
Eth yl 5′-Ca r ba zid o-2,2′-bip yr id in e-5-ca r boxyla te (5). A
stirred solution of 5-(ethoxycarbonyl)-5′-carbohydrazido-2,2′-
bipyridine (5.7 g, 20 mmol) in concentrated HCl (100 mL) was
cooled to 0 °C, and then an aqueous solution of NaNO2 (1.73 g,
25 mmol; 15 mL) was added dropwise, maintaining the temper-
ature below 5 °C. After 60 min, the yellow solution was diluted
with water (300 mL) to precipitate (95%) the monoester 5 as a
colorless powder (5.1 g), which was filtered, washed with water,
and recrystallized (acetone): mp 134-135 °C; 1H NMR δ 1.44
(t, J ) 7.13 Hz, 3H), 4.45 (q, J ) 7.13 Hz, 2H), 8.41 (dd, 3J ) 5.6
Hz, 4J ) 1.8 Hz, 1H), 8.44 (dd, 3J ) 5.6 Hz, 4J ) 1.8 Hz, 1H),
8.57 (d, J ) 5.6 Hz, 1H), 8.60 (d, J ) 5.6 Hz, 1H), 9.26 (d, J )
1.8 Hz, 1H), 9.29 (d, J ) 1.8 Hz, 1H); 13C NMR δ 14.2, 61.5,
1
132 °C; H NMR δ 1.39 (t, J ) 7, 13 Hz, 3H), 4.38 (q, J ) 7, 13
Hz, 2H), 3.82 (s, 2H), 7.06 (dd, 3J ) 8.5 Hz, 4J ) 2.8 Hz, 1Η),
4
3
3
8.14 (d, J ) 2.8 Hz, 1H), 8.25 (d, J ) 8.5 Hz, 1H), 8.3 (d, J )
1, 5 Hz, 2H), 9.17 (t, 4J ) 1, 5 Hz, 1H); 13C NMR δ 14.2, 61.1,
119.0, 121.5, 122.6, 124.5, 136.4, 137.6, 143.6, 145.3, 150.3, 159.5,
165.5; IR 3426 (NH), 3344 (NH), 1715 (CdO), 1294 (CO2) cm-1
ESI-MS 243.8 (M+ + 1).
;
Ack n ow led gm en t. This work was supported by the
National Science Foundation (DMR-92-17331, 92-08925,
96-22609) and the US Army Office of Research
(DAAH04-93-0048).
(9) Wingfield, H. N., J r.; Harlan, W. R.; Hanmer, H. R. J . Am. Chem.
Soc. 1953, 75, 4364. Galat, A. J . Am. Chem. Soc. 1948, 70, 3945;
Badgett, C. O.; Provost, R. C., J r.; Ogg, C. L.; Woodward, C. F. J . Am.
Chem. Soc. 1945, 67, 1135.
(10) Sasse, W. H. F.; Whittle, C. P. J . Chem. Soc. 1961, 1347.
J O962398G