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S. T. Hobson, J. D. Boecker, J. H. Gifford, T. L. Nohe and C. H. Wierks
Vol. 40
(16.10 g, 0.093 mol, 2.0 eq) and benzene (45 mL) were heated to
reflux. The reaction was stopped when 0.85 mL (~100%) of H2O
was collected in a Dean-Stark apparatus. The orange liquid was
neutralized with NaHCO3(sat, aq) (25 mL) and the aqueous layer
was washed with C6H6 (4 x 50 mL). Organic layers were com-
bined, dried over anhydrous CaCl2 and excess solvent was
removed via rotary evaporation to produce a green oil (9.60 g).
To the green oil was added 10% Na2CO3 (30 mL). After stirring
at 100 °C for 3 hours, the dark brown liquid was washed with
ether (4 x 100 mL). Organic layers were combined, dried over
anhydrous MgSO4, and filtered. Removal of solvent in vacuo
resulted in a clear brown oil as the trans diastereomer (3.8 g,
and removal of solvent in vacuo gave a yellow oil (3.40g, 49%).
1H NMR (perdeuteriobenzene): d 3.37 (m, 2H), 3.51 (m, 2H),
5.50 (s, 1H), 7.12 (A2X2, 2H, J = 4.1, 1.8 Hz), 8.51 (A2X2, 2H,
J = 4.1, 1.8 Hz). 13C NMR (perdeuteriobenzene): d 65.0, 102.1,
121.1, 146.9, 150.4. ESI MS (M=151.16) (CH3CN/H2O 1/1 v/v)
152.1 [(M++H+)].
Anal. Calc'd. for C8H9NO2•0.75H20: C, 58.35; H, 6.43; N,
8.51. Found: C, 58.02; H, 5.77; N, 8.61.
2-[1,3]Dioxolan-2-yl-1-methyl-pyridinium Iodide (7).
In a round bottom flask was added 2-[1,3]dioxolan-2-yl-pyri-
dine 5 (1.51 g, 0.010 mol, 1 eq), 3 mL THF, and methyl iodide
(0.62 mL, 0.010 mol, 1 eq). The reaction was stirred under N2(g)
overnight resulting in a yellow solid. Filtration and removal of
residual solvent in vacuo gave a yellow powder (1.25 g, 43%). 1H
NMR (deuterium oxide): d 4.10 (m, 4H), 4.20 (s, 3H), 6.47 (s,
1
41%). H NMR (perdeuteriobenzene): d 2.95 (dd, 1H, J= 11.1,
7.0 Hz), 3.10 (dd, 1H, J = 11.1, 5.3 Hz), 3.45 (dd, 1H, J = 8.8, 5.9
Hz), 3.92 (dd, 1H, J = 8.8, 6.5 Hz), 4.13 (m, 1H), 6.08 (s, 1H),
6.60 (m, 1H), 7.05 (m, 1H), 7.28 (m, 1H), 8.40 (m, 1H). 13C
NMR (perdeuteriobenzene): d 44.1, 68.9, 75.9, 105.0, 120.8
123.9, 136.2, 149.4, 157.6. ESI MS (M=199.63) (CH3CN/H2O
1/1 v/v) m/z 200.1 [(M++H+)].
1H), 8.15 (m, 1H), 8.20 (m, 1H), 8.64 (m, 1H), 9.08 (m, 1H). 13
C
NMR (deuterium oxide): d 45.8, 65.7, 97.5, 125.2, 128.0, 146.5,
148.2, 152.0. ESI MS (M=309.14) (CH3CN/H2O 1/1 v/v) 166.1
(M+-I-).
Anal. Calc'd. for C10H16INO2•0.5H20: C, 35.78; H, 4.34; I,
42.01; N, 4.64. Found: C, 36.19; H, 4.23; I, 41.04, N, 4.70.
Anal. Calc'd. for C9H10ClNO2: C, 54.15; H, 5.05; Cl, 17.76; N,
7.02. Found: C, 53.87; H, 5.30; Cl, 15.68; N, 7.11.
4-(4-Chloromethyl-[1,3]dioxolan-2-yl)-pyridine (4).
4-[1,3]Dioxolan-2-yl-1-methyl-pyridinium Iodide (8).
In a similar fashion to 3, pyridine-4-aldehyde (4.60 mL, 0.048
mol, 1 eq), 3-chloro-1, 2-propanediol (8.00 mL, 0.096 mol, 2.00
eq), p-toluenesulfonic acid (16.12 g, 0.11 mol, 2.30 eq) and ben-
zene (95 mL) were combined and heated until the reaction was
complete. Workup and removal of solvent in vacuo gave a clear,
yellow oil as a mixture of two diastereomers (10.60g, ~100%).
1H NMR (perdeuteriobenzene): d 2.89 (dd, 1H, J= 11.1, 7.6 Hz),
2.99 (m, 1H), 3.40 (m, 1H), 3.52 (m, 1H), 3.80 (m, 1H), 5.32 (s,
1H), 7.05 (m, 2H), 5.58, 8.55 (m, 2H) ppm. 13C NMR (perdeu-
teriobenzene): d 44.0, 44.2, 68.1, 68.3, 75.5, 76.1, 102.6, 103.0,
120.9, 121.1, 127.9, 128.5, 145.7, 146.3, 150.4, 150.5. ESI MS
(M=199.63) (CH3CN/H2O 1/1 v/v) m/z 200.0 [(M++H+)].
Anal. Calc'd. for C9H10ClNO2•0.5H20: C, 51.81; H, 5.31; Cl,
16.99; N, 6.71. Found: C, 52.04; H, 5.04; Cl, 16.65; N, 6.77
In a similar fashion to 7, 4-[1,3]dioxolan-2-yl-pyridine (2.74 g,
0.018 mol, 1 eq), 10 mL THF, and methyl iodide (1.13 mL, 0.018
mol, 1 eq) were combined. Analogous workup gave a brown
1
solid (4.49 g, 85%). H (deuterium oxide): d 3.96 (m, 4H), 4.23
(s, 3H), 6.00 (s, 1H) , 7.96 (d, 2H, J = 6.4 Hz), 8.66 (d, 2H, J = 6.4
Hz). 13C NMR (deuterium oxide): d 48.5, 65.0, 100.0, 125.9,
145.9, 156.0ppm. ESI MS (M=309.14) (CH3CN/H2O 1/1 v/v)
166.1 (M+).
Anal. Calc'd. for C10H16INO2: C, 36.88; H, 4.13; I, 43.30; N,
4.78. Found: C, 37.27; H, 4.45; I, 43.00; N, 4.85.
Representative Procedures for Attempted Hydrolysis of Acetals.
4-(4-Chloromethyl-[1,3]dioxolan-2-yl)-pyridine (4).
1:1THF/5 % HCl.
2-[1,3]Dioxolan-2-yl-pyridine (5).
Pyridine-2-aldehyde (2.3 mL, 0.024 mol, 1 eq), ethylene gly-
col (2.7 mL, 0.048 mol, 2 eq), p-toluenesulfonic acid (1.2 g,
0.007 mol, 0.29 eq) and benzene (30 mL) were heated to reflux.
The reaction was stopped when 0.43 mL of H2O (100% theoreti-
cal) was collected in a Dean-Stark apparatus. The liquid was neu-
tralized with saturated Na2CO3 (100 mL). The aqueous layer was
washed with benzene (4 x 65 mL) and the organic layers were
combined and dried over anhydrous MgSO4. Filtration and
removal of excess solvent in vacuo gave a clear yellow liquid
In a 25 mL round bottom flask, equipped with stir bar, were
added 4 (1.07 g, 0.005 mol) and 30 mL of a 1:1 THF/5 % HCl
solution. After 5 days stirring at room temperature the yellow
solution was neutralized with saturated Na2HCO3. It was then
extracted 4 x 50 mL CH2Cl2. Organic layers were combined and
dried over anhydrous CaCl2, filtered, and excess solvent was
removed via rotary evaporator to produce a yellow oil with a
mass of (0.98 g). According to NMR data the product contains
0% aldehyde and 100% 4-(4-chloromethyl-[1,3]dioxolan-2-yl)-
pyridine.
1
(3.40 g, 94%). H NMR (perdeuteriobenzene): d 3.49 (m, 2H),
3.68 (m, 2H), 6.04 (s, 1H) , 6.64 (m, 1H), 7.10 (m, 1H), 7.42 (m
1H), 8.43 (m, 1H); 13C NMR (perdeuteriobenzene): d 65.4,
104.8, 120.8, 123.8, 136.2, 149.3, 158.4. ESI MS (CH3CN/H2O
1/1 v/v) (M=151.16) m/z 152.0 [(M++H+)].
Anal. Calc'd. for C8H9NO2•0.33H20: C, 61.14; H, 6.20; N,
8.91. Found: C, 61.36; H, 6.05; N, 8.98.
1 M HCl/THF.
In a 100 mL round bottom flask, equipped with stir bar, were
added 4 (0.82 g, 0.004 mol) and 63 mL THF. This was cooled
using an ice bath after which 10 mL of 1 M HCl was added and
warmed to room temperature. After 5 days stirring at room temper-
ature the yellow solution was neutralized with 2 N NaOH. The
solution was then extracted with 4 x 50 mL ethyl acetate. Organic
layers were combined, dried over anhydrous MgSO4, filtered and
the solvent was removed in vacuo to produce a yellow oil (0.79g).
According to NMR data the product appears to contain 0% alde-
hyde and 100% 4-(4-Chloromethyl- [1,3] dioxolan-2-yl)-pyridine.
4-[1,3]Dioxolan-2-yl-pyridine (6).
In a similar fashion to 5, pyridine-4-aldehyde (4.40 mL, 0.046
mol, 1 eq), ethylene glycol (5.30 mL, 0.095 mol, 2.00 eq), and p-
toluenesulfonic acid (2.34 g, 0.014 mol, 0.30 eq) were combined
with benzene (50 mL). After the reaction was complete, work-up