A. C. Benniston, A. Harriman et al.
in-house facilities. Spectroscopic grade solvents were obtained from Al-
drich Chemical Co. and were redistilled before use.
(1:20) as the eluant to produce a pale yellow solid (1.20 g, 60% yield).
1H NMR (d, 300 MHz, [D8]THF): d=2.53 (quint, J=6.0 Hz, 2H; H of
-CH2-), 4.60 (t, J=6.0 Hz, 4H; H of -OCH2-), 7.87 (d, J=4.9 Hz, 2H; Py-
H5), 7.97 (d, J=4.9 Hz, 2H; Py-H6), 8.38 ppm (s, 2H; Py-H2); EI-MS:
m/z calcd for C13H12I2N2O2: 481.9; found: 482.
Preparation of 3-diethylcarbamic acid (pyridin-4-yl boronic acid) ester
(5): B(OiPr)3 (3.2 mL, 13.6 mmol) was added to a solution of 2 (2.00 g,
A
10.3 mmol) in THF (30 mL) under an N2 atmosphere. The solution was
cooled to ꢀ788C and tBuLi (7.5 mL, 1.7m in pentane) was added by sy-
ringe pump over a period of 1h. The light yellow mixture was held at
ꢀ788C for 1h. The dry ice/acetone bath was removed and the mixture
was allowed to warm to ꢀ208C. Then 2m HCl (10 mL) was added and
the mixture stirred until reaching RT. To this solution was added a mix-
ture of toluene (50 mL) and 2m HCl (10 mL). The aqueous layer was
separated, and the organic layer washed with 2m HCl. The combined
aqueous layers were neutralized with 5m NaOH, to afford a white precip-
itate. The suspension was extracted with EtOAc, dried over MgSO4, fil-
tered, and evaporated on a rotary evaporator. The residual white solid
was washed with diethyl ether and used without further purification in
the following reaction (1.6 g, 65% yield). 1H NMR (300 MHz, CD3OD):
d=1.29 (m, 6H; H of -CH3), 3.46–3.64 (m, 4H; H of -NCH2-), 7.50 (d,
J=4.7 Hz, 1H; Py-H5), 8.37 ppm (m, 2H; Py-H2,6); 11B NMR (CD3OD):
d=19.3 ppm.
Generalprocedure for the synthesis of 1a–1e : NaH (1.1 equiv) was
added to a solution of 7 (400 mg, 2.10 mmol) in DMF (60 mL) under an
N2 atmosphere. The mixture was stirred at RT for 1h. The ditosyloxy
linker (1.2 equiv) or CH2I2 (1.2 equiv) in DMF (20 mL) was added slowly
through a syringe pump to this solution. The mixture was stirred at RT
for ꢂ24 h and the DMF was removed under reduced pressure. The resul-
tant residue was extracted with EtOAc, washed with H2O, and dried over
MgSO4. Removal of the solvent afforded the crude product, which was
purified by column chromatography.
Data for 1a: Compound
7 (0.40 g, 2.10 mmol), CH2I2 (0.25 mL,
3.1mmol); silica gel, petrol/acetone (2:3); yield: 40 mg, 9%, off-white
solid; 1H NMR (300 MHz, CD2Cl2): d=5.55 (s, 2H; H of methylene),
7.78 (d, J=5.4 Hz, 2H; Py-H6), 8.39 (d, J=5.4 Hz, 2H; Py-H5), 8.48 ppm
(s, 2H; Py-H3); EI-MS: m/z calcd for C11H8N2O2: 200.06; found: 200.
Data for 1b: Compound 7 (0.40 g, 2.10 mmol), 1,2-bis(toluene-4-sulfony-
loxy)-ethane (0.94 g, 2.50 mmol); silica gel, petrol/acetone (1:2); yield:
58 mg, 13%, off-white solid; 1H NMR (300 MHz, CD2Cl2): d=4.29
(brs,4H; H of ethylene), 7.26 (d, J=4.9 Hz, 2H; Py-H6), 8.44 (d, J=
4.9 Hz, 2H; Py-H5), 8.47 ppm (s, 2H; Py-H3); EI-MS: m/z calcd for
C12H10N2O2: 214.07; found: 214.
Preparation of diethylcarbamic acid 3’-hydroxy-4,4’-bipyridin-3-ylester
(6)
Method I: [Pd(PPh3)4] (0.22 g, 0.19 mmol) was added to an N2-purged so-
G
lution of 3 (1.0 g, 3.1 mmol) in DME (40 mL). The light yellow solution
was stirred at RT for 10 min. Compound 5 (1.1 g, 4.6 mmol) in deoxygen-
ated ethanol (10 mL) and 1m Na2CO3 (9.4 mL) was added to this solu-
tion. The mixture was refluxed overnight after which time TLC showed
complete consumption of 3. Water (50 mL) and EtOAc (100 mL) were
poured into the solution, which was filtered to remove insoluble material.
The isolated organic layer was washed with 0.2m Na2CO3 (2100 mL).
The combined aqueous layers were washed with EtOAc (30 mL) and
neutralized with 2m HCl. The cloudy suspension which formed was ex-
tracted with EtOAc, dried over MgSO4, and filtered. Removal of the or-
ganic solvents afforded an oily solid (0.76 g, 85% yield). 1H NMR
(300 MHz, CD3OD): d=1.04 (m, 6H; H of -N-CH2-), 3.29 (m, 4H; H of
-CH3), 7.28 (d, J=4.9 Hz, 1H; H of Py), 7.51 (d, J=4.9 Hz, 1H; H of
Py), 8.18 (m, 2H; H of Py), 8.52 ppm (m, 2H; H of Py).
Data for 1c: Compound 7 (0.40 g, 2.10 mmol), 1,3-bis(toluene-4-sulfony-
loxy)propane (0.98 g, 2.50 mmol; silica gel, petrol/acetone (1:3); yield:
89 mg, 18%, off-white solid; 1H NMR (300 MHz, CD2Cl2): d=2.05
(quint, J=5.2 Hz, 2H; H of -CH2-), 4.42 (t, J=5.2 Hz, 4H; H of -OCH2-
), 7.18 (d, J=4.7 Hz, 2H; Py-H6), 8.36 (d, J=4.7 Hz, 2H; Py-H5),
8.47 ppm (s, 2H; Py-H3). EI-MS: m/z calcd for C13H12N2O2: 228.09;
found: 228. A minor byproduct 1 f resulting from the elimination of the
tosylate was isolated in varying yield, depending on the nature and quan-
1
tity of the base applied. H NMR (300 MHz, CD2Cl2): d=4.60 (m, 4H; H
of =CH2), 5.21(m, 4H; H of -OCH -), 5.92 (m, 2H; H of -CH=), 7.20 (d,
2
J=4.6 Hz, 2H; Py-H6), 8.26 (d, J=4.6 Hz, 2H; Py-H5), 8.33 ppm (s, 2H;
Py-H3); EI-MS: m/z calcd for C16H16N2O2: 268.3; found: 268.
Method II: B(OiPr)3 (3.2 mL, 13.6 mmol) was added to a solution of 2
C
(2.00 g, 10.3 mol) in THF (25 mL). The solution was cooled to ꢀ788C
and nBuLi (8.0 mL, 1.6m in hexane) was added by syringe pump over a
period of 1h. The yellow mixture was held at ꢀ788C for 1h. The dry ice/
acetone bath was removed and the mixture was allowed to warm to RT
and stirred for a further 1h. Deoxygenated ethanol (10 mL) was added
to the solution. The mixture was transferred to a pre-mixed solution of 3
Data for 1d: Compound 7 (0.40 g, 2.1mmol), 1,4-bis(toluene-4-sulfony-
loxy)butane (1.02 g, 2.6 mmol); silica gel, petrol/acetone (1:5); yield:
1
168 mg, 33%, off-white solid; H NMR (300 MHz, CD2Cl2): d=1.91 (brs,
4H; H of -CH2CH2-), 4.20 (brs, 2H; H of -OCH2-), 4.62 (brs, 2H; H of
-OCH2-), 7.21(d, J=4.8 Hz, 2H; Py-H6), 8.29 (d, J=4.8 Hz, 2H; Py-H5),
8.42 ppm (s, 2H; Py-H3); EI-MS: m/z calcd for C14H14N2O2: 242.1; found:
242.
(1.5 g, 4.7 mmol) and [Pd(PPh3)4] (0.34 g, 0.29 mmol) in DME (45 mL),
G
followed by the addition of deoxygenated ethanol (20 mL) and 1m
Na2CO3 (14 mL). The mixture was refluxed overnight and TLC con-
firmed completion of the reaction. Workup as described in Method I af-
forded an oily solid. Yield: 1.15 g (84%, based on starting material 3).
Data for 1e: Compound 7 (0.40 g, 2.10 mmol), bis-{2-[2-(toluene-4-sulfo-
nyoxy)-ethoxy]ethyl}ether (1.29 g, 2.60 mmol); silica, petrol/acetone
(1:20); yield: 140 mg, 19%, oily solid; 1H NMR (300 MHz, CD2Cl2): d=
3.53 (m, 8H; H of -OCH2-), 3.74 (m, 4H; H of -OCH2-), 4.07 (m, 2H; H
of -OCH2-), 4.30 (m, 2H; H of -OCH2-), 7.10 (d, J=4.7 Hz, 2H; Py-H6),
8.25 (d, J=4.7 Hz, 2H; Py-H5), 8.37 ppm (s, 2H; Py-H3); EI-MS: m/z
calcd for C18H22N2O5: 346.1; found: 346.
Preparation of 4,4’-bipyridinyl-3,3’-diol(7)
: 2m NaOH (32 mL) was
added to a solution of 6 (4.54 g, 16.0 mmol) in methanol (40 mL). The
mixture was refluxed overnight, cooled to RT and filtered. The filtrate
was reduced in volume to about 5 mL, and water was added to the resi-
due before being filtered. The yellow filtrate was acidified to pH~5 with
6m HCl, to afford a yellow precipitate. Yield 2.23 g, 75%; 1H NMR
(300 MHz, [D6]DMSO): d=7.44 (d, J=4.9 Hz, 2H; Py-H6), 8.15 (d, J=
4.9 Hz, 2H; Py-H5), 8.32 (s, 2H; Py-H3), ꢂ11 ppm (brs, 2H; -OH); EI-
MS: m/z calcd for C10H8N2O2: 188.06; found: 188.
Generalprocedure for the synthesis of C1 –C5: CH3I (5 equiv) was
added to a solution of 1a - 1e (0.19–0.66 mmol) in CH3CN (30 mL). The
mixture was refluxed overnight; it was then cooled to RT and diethyl
ether added to complete precipitation of the product. The resultant
yellow to yellow-orange solid was filtered and washed thoroughly with
diethyl ether. After drying, the solid was dissolved in water (ca. 30 mL)
and aqueous KPF6 solution (8 equiv) was added to precipitate the prod-
uct. The pure product was obtained by recrystallization from acetonitrile
and diethyl ether.
Preparation of 1,2-bis(4-iodo-pyridin-3-yl)propane (8): tBuOK (1.22 g,
10.9 mmol) was added to a solution of 4 (2.0 g, 9.1mmol) in DMF
(30 mL)/THF (10 mL) held under an N2 atmosphere at ꢀ158C; the re-
sulting mixture was stirred at ꢀ158C for 30 min. 1,3-Bis(toluene-4-sulfo-
nyloxy)propane (1.60 g, 4.16 mmol) in DMF (15 mL)/THF (5 mL) was
added over one hour at ꢀ158C. The mixture was stirred at RT overnight.
The resultant brown suspension was isolated and extracted with EtOAc.
The EtOAc layer was washed with aqueous Na2CO3, separated, and
dried over MgSO4. The resultant crude product obtained after solvent re-
moval was purified by silica-gel chromatography with petrol/ethyl acetate
Data for C1: Compound 1a (38 mg, 0.19 mmol), CH3I (0.20 mL,
3.20 mmol); yield: 57 mg, 57%, pale yellow solid; 1H NMR (300 MHz,
CD3CN): d=4.39 (s, 6H; CH3), 5.84 (s, 2H; H of methylene), 8.59 (brs,
4H; H of Py), 8.78 ppm (brs, 2H; H of Py); 13C NMR (CD3CN): d=48.0,
96.3, 127.3, 134.4, 139.2, 140.2, 156.1 ppm; ES-MS: m/z calcd for
[Mꢀ2PF6]+: 230.3; found: 231.0; m/z calcd for [Mꢀ2PF6]2+
: 115.1;
7848
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 7838 – 7851