Organic Syntheses, CV 6, 987
Submitted by B. E. Hoogenboom, O. H. Oldenziel, and A. M. van Leusen
1.
Checked by Teresa Y. L. Chan and S. Masamune.
1. Procedure
Caution! The reaction should be conducted in a well-ventilated fume hood.
Benzene has been identified as a carcinogen; OSHA has issued emergency standards on its use. All procedures involving
benzene should be carried out in a well-ventilated hood, and glove protection is required.
A.
N-(p-Tolylsulfonylmethyl)formamide.2 A
3-l., three-necked, round-bottomed flask equipped with a
mechanical stirrer, a
condenser, and a
thermometer is charged with
267 g. (1.50 moles) of sodium p-toluenesulfinate (Note
1). After addition of 750 ml. of water,
350 ml. (378 g.) of an aqueous 34–37% solution of formaldehyde (ca. 4.4 moles) (Note
2),
680 g. (600 ml., 15.5 moles) of formamide (Note
3), and
244 g. (200 ml., 5.30 moles) of formic acid (Note
4), the stirred reaction mixture is heated at 90°. The
sodium p-toluenesulfinate dissolves during heating, and the clear solution is kept at 90–95° for 2 hours (Note
5). The reaction mixture is cooled to room temperature in an
ice–salt bath with continued stirring, then further cooled overnight in a freezer at −20°. The white solid (Note
6) is collected by suction filtration and washed thoroughly in a
beaker by stirring with three 250-ml. portions of ice water. The product is dried under reduced pressure over
phosphorus pentoxide at 70° (Note
7), yielding
134–150 g. (
42–47%) of crude
N-(p-tolylsulfonylmethyl)formamide, m.p.
106–110° (Note
8), which is sufficiently pure for use in the next step.
B.
p-Tolylsulfonylmethyl isocyanide. A
3-l., four-necked, round-bottomed flask equipped with a mechanical stirrer, a thermometer, a
250-ml. dropping funnel, and a
drying tube is charged with
107 g. (0.502 mole) of crude N-(p-tolylsulfonylmethyl)formamide,
250 ml. of 1,2-dimethoxyethane,
100 ml. of anhydrous diethyl ether, and
255 g. (350 ml., 2.52 moles) of triethylamine (Note
9). The stirred suspension is cooled in an ice–salt bath to −5°. A solution of
84 g. (50 ml., 0.55 mole) of phosphorus oxychloride (Note
10) in
60 ml. of 1,2-dimethoxyethane is added from the dropping funnel at such a rate that the temperature is kept between −5° and 0° (Note
11). During the reaction, the
N-(p-tolylsulfonylmethyl)formamide gradually dissolves and triethylamine salts precipitate. Near the completion of the reaction the white suspension slowly turns brown (Note
12). After stirring for another 30 minutes at 0°, 1.5 l. of ice water is added with continued stirring. The solid material dissolves, giving a clear, dark-brown solution before the product begins to separate as a fine, brown, crystalline solid. After stirring for an additional 30 minutes at 0°, the precipitate is collected by suction filtration and washed with 250 ml. of cold water. The wet product is dissolved in
400 ml. of warm benzene (40–60°), the aqueous layer is removed with a
separatory funnel, and the dark-brown
benzene solution is dried over anhydrous
magnesium sulfate. After removal of the
magnesium sulfate,
2 g. of activated carbon (Note
13) is added, and the mixture is heated at about 60° for 5 minutes and filtered (Note
14).
One liter of petroleum ether (b.p.
40–60°) is added to the filtrate with thorough swirling. After 30 minutes the precipitate is collected by suction filtration and dried in a
vacuum desiccator, yielding
74–82 g. (
76–84%) of crude
p-tolylsulfonylmethyl isocyanide as a light-brown, odorless solid, m.p.
111–114° (dec.) (Note
15), which can be used for synthetic purposes without further purification.
Completely white material is obtained by rapid chromatography through alumina (Note
16). An analytically pure product, m.p.
116–117° (dec.), is obtained after one recrystallization from
methanol.
2. Notes
3. Commercial
formamide (E. Merck, Darmstadt) was used. The use of a large excess of
formamide with respect to the sulfinate is required to obtain the yield specified.
2
4. Commercial
97% formic acid (J. T. Baker Chemical Company) was used.
5. Prolonged heating lowers the yield considerably.
6. When no solid is formed overnight, crystallization may be induced by scratching. In this case the solution should be kept for another 4 hours at −20° before the product is collected.
7. The drying process can be speeded up by dissolving the wet product in
dichloromethane, removing the water layer in a separatory funnel, drying the
dichloromethane solution over anhydrous
magnesium sulfate, and removing the solvent on a
rotary evaporator.
8. Recrystallization from
95% ethanol or benzene raised the m.p. to
108–110°.
11. The addition requires about 1 hour. At the beginning of the reaction much heat is evolved, and, therefore, the
phosphorus oxychloride solution should initially be added very slowly.
13. Activated
carbon was purchased from J. T. Baker Chemical Company.
14. The color of the solution is lightened only slightly by treatment with activated
carbon, but eventually a purer product is obtained.
15. The product has the following spectral properties; IR (Nujol) cm.
−1: 2150 (N=C), 1320 and 1155 (SO
2);
1H NMR (CDCl
3), δ (multiplicity, number of protons, assignment): 2.5 (s, 3H, C
H3), 4.6 (s, 2H C
H2), 7.7 (q, 4H, C
6H4).
3. Discussion
p-Tolylsulfonylmethyl isocyanide is a useful and versatile reagent.
7 It has been used for the synthesis of several azole ring systems by base-induced addition of its C-N=C moiety to various C=O, C=N, C=S, C=C, and N=N containing substrates. Thus, oxazoles,
7,8,9,10 imidazoles,
7,8,11,12 thiazoles,
7,13 pyrroles,
7,8 and 1,2,4-triazoles,
7 have been prepared, respectively. Furthermore,
p-tolylsulfonylmethyl isocyanide has found use in a one-step conversion of ketones and aldehydes to cyanides containing one more
carbon atom.
7,14
Another application is based on the umpolung principle. In this sense
p-tolylsulfonylmethyl isocyanide is a formaldehyde anion or dianion equivalent,
7,10 which has been used in the synthesis of symmetrical and unsymmetrical ketones,
7,15,16 α-diketones,
7,17 α-hydroxy aldehydes,
7 and α-hydroxy ketones.
7 Under reducing reaction conditions amino, methylamino or β-hydroxy methylamino compounds have been prepared from the same intermediates.
7
Finally,
p-tolylsulfonylmethyl isocyanide can be transformed into 1-isocyano-1-tosylalkenes,
7 which are useful synthons in their own right, as appears from their use in the synthesis of imidazoles
12 and pyrroles.
7This preparation is referenced from:
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