Organic Syntheses, Vol. 77, 198
Checked by Yan Dong and Steven Wolff.
1. Procedure
C. α-Tosylbenzyl isocyanide (3) (Note
9). A 1-L, three-necked, round-bottomed flask fitted with an overhead stirrer, a
100-mL addition funnel and a temperature probe is charged with
200 mL of tetrahydrofuran (THF) (Note
10) and
27.6 g (94.8 mmol) of N-(α-tosylbenzyl)formamide (2).
Phosphorus oxychloride (17.7 mL, 190 mmol) (Note
11), (Note
12) is added and the resulting solution is stirred for 5 min at 25°C. After cooling the solution to 0°C,
79.3 mL (569 mmol) of triethylamine (Note
11), (Note
12) is added slowly over 30-45 min while keeping the internal reaction temperature below 10°C. After the
triethylamine addition is complete, the reaction is warmed to 5-10°C and held there for 30-45 min.
Ethyl acetate (140 mL) and water (140 mL) are added sequentially to the reaction, the mixture is stirred for 5 min and, after transferring the mixture to a separatory funnel, the aqueous layer is removed. The organic layer is washed with water (2 × 140 mL), saturated
sodium bicarbonate (NaHCO3) solution (140 mL) and
brine (70 mL). The organic layer is transferred to a
500-mL, round-bottomed flask and concentrated on a rotary evaporator (Note
13). The residue is diluted with
140 mL of 1-propanol (Note
11), (Note
14) and this solution is concentrated on a rotary evaporator to half of its original volume. The residue is cooled to 5-10°C for 30 min and the beige solid that crystallizes is filtered through a Büchner funnel. The filter cake is rinsed twice with
75 mL of 1-propanol. The beige solid is dried under vacuum for 3-4 hr (Note
13) to give
18.1-19.7 g (
70-76%) of
α-tosylbenzyl isocyanide (3) (Note
15).
2. Notes
2. Minor decomposition of
p-toluenesulfinic acid is observed at temperatures above 55°C. For this reason, the water bath of the rotary evaporator and all subsequent heating operations should be kept at temperatures below 35-40°C to obtain best results.
3.
p-Toluenesulfinic acid should be used immediately after its preparation or stored under N
2 and used within 2-3 weeks.
4. The spectra are as follows:
1H NMR (300 MHz, DMSO-d
6) δ: 2.36 (s, 3 H), 7.35 (d, 2 H, J = 8.1), 7.54 (d, 2 H, J = 8.1);
13C NMR (75 MHz, DMSO-d
6) δ: 18.7, 122.9, 127.9, 140.85, 143.6.
5.
Reagent grade toluene and
acetonitrile supplied by J.T. Baker Inc. were used without further purification.
7. The
50 mol % excess of p-toluenesulfinic acid is required to obtain the best results. Using only
10-20 mole % excess of the sulfinic acid typically lowers the yield by 20-30%. This has been attributed to the known propensity of arylsulfinic acids to disproportionate.
3 The checkers noted the presence of insoluble material after the addition of
p-toluenesulfinic acid. This did not effect the yield.
8. Compound
2 exists as a 5:1 mixture of amide rotamers at 25°C in DMSO-d
6. The spectra for the major rotamer are as follows:
1H NMR (300 MHz) δ: 2.40 (s, 3 H ), 6.38 (d, 1 H, J = 10.6), 7.42 (m, 5 H), 7.55 (m, 2 H), 7.70 (d, 2 H, J = 8.1), 7.96 (s, 1 H), 9.75 (d, 1 H, J = 10.6);
13C NMR (75 MHz, DMSO-d
6) δ: 21.0, 70.2, 128.1, 129.0, 129.1, 129.3, 129.45, 130.3, 133.4, 144.7, 160.1; mp
172-173°C (lit.
4 160-162°C); IR (KBr) cm
−1: 3336, 1654, 1320, 1145. Anal. Calcd for C
15H
15NO
3S: C, 62.27; H, 5.23; N, 4.84. Found C, 61.97; H, 5.11; N, 4.71.
9. Step C is a modified literature procedure.
4
10. A new bottle of
reagent grade THF (water content < 0.02%) from J. T. Baker Inc. was used without further purification.
12. The excess amounts of
phosphorus oxychloride and
triethylamine are required to ensure that the reaction goes to completion. Using lesser amounts of these reagents leads to incomplete reactions.
13. Isocyanides similar to
3 have been found to be thermally unstable at temperatures above 80°C. To secure a margin of safety, avoid heating
3 and similar isocyanides at temperatures above 35-40°C.
14. The checkers noted formation of a suspension upon addition of the
1-propanol.
15. The spectra are as follows: mp
145°C dec (lit.
4 128-130°C dec); IR (KBr) cm
−1: 2131, 1331, 1158;
1H NMR (300 MHz, CDCl
3) δ: 2.45 (s, 3 H), 5.61 (s, 1 H), 7.39 (m, 7 H), 7.59 (d, 2 H, J = 8.2);
13C NMR (75 MHz, CDCl
3) δ: 21.75, 76.6, 126.7, 128.4, 128.7, 129.8, 130.3, 130.5, 130.7, 146.6, 166.4. Anal. Calcd for C
15H
13NO
2S: C, 66.40; H, 4.83; N, 5.16. Found C, 66.42; H, 4.88; N, 5.13.
All toxic materials were disposed of in accordance with "Prudent Practices in the Laboratory"; National Academy Press; Washington, DC, 1995.
3. Discussion
The present procedure provides ready access to a variety of substituted TosMIC reagents, exemplified by
α-tosylbenzyl isocyanide (3), by dehydration of the corresponding formamides
(2). While this route has been employed previously, the reported methods of preparation for formamides
2 suffer from low yields
7 and extended reaction times.
4 The present process for preparing these formamides offers high yields, mild conditions and generality, as shown below in the Table.
Appendix
Chemical Abstracts Nomenclature (Collective Index Number);
(Registry Number)
α-Tosylbenzyl isocyanide: Benzene, 1-[(isocyanophenylmethyl)sulfonyl]-4-methyl- (9); (36635-66-2)
p-Toluenesulfinic acid (8); Benzenesulfinic acid, 4-methyl- (9); (536-57-2)
p-Toluenesulfinic acid, sodium salt (8); Benzenesulfinic acid, 4-methyl-,
sodium salt (9); (824-79-3)
tert-Butyl methyl ether: Ether, tert-butyl methyl (8); Propane, 2-methoxy-2-methyl- (9); (1634-04-4)
N-(α-Tosylbenzyl)formamide: Formamide, N-[[(4-methylphenyl)sulfonyl]phenylmethyl]- (9); (37643-54-2)
Benzaldehyde (8,9); (100-52-7)
Formamide (8,9); (75-12-7)
Chlorotrimethylsilane: Silane, chlorotrimethyl- (8,9); (75-77-4)
Phosphorus oxychloride: HIGHLY TOXIC: Phosphoryl chloride (8,9); (10025-87-3)
Triethylamine (8); Ethanamine, N,N-diethyl- (9); (121-44-8)
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