有机合成英语论文原文与翻译

Organic Syntheses, Vol. 82, p. 18-21 (2005); Coll. Vol. 11, p. 778-781 (2009).

2,2-DIETHOXY-1-ISOCYANOETHANE

(2,2-Diethoxyethyl isocyanide, Isocyanoacetaldehyde diethyl acetal)

Submitted by Francesco Amato and Stefano Marcaccini.

Checked by Raghuram S. Tangirala and Dennis P. Curran.

1. Procedure

CAUTION: All the operations must be conducted in an efficient hood

because the isocyanide has an obnoxious odor.

A. N-(2,2-Diethoxy)ethyl formamide.

A 100-mL round-bottomed flask

equipped with a magnetic stir bar and fitted with a reflux condenser is

charged with aminoacetaldehyde diethyl acetal (28.34 g, 213 mmol, Note 1)

and propyl formate (22.48 g, 255 mmol, Note 2). The resulting clear solution

is heated at reflux in an oil bath for 3 h (Note 3). After cooling, the reaction

mixture is transferred to a 250-mL round-bottomed flask and freed from the

1-propanol and the unreacted propyl formate by rotary evaporation. The

residue is transferred to a distillation apparatus equipped with a 10 cm

Vigreux column and a two-necked receiver, and distilled under reduced

pressure. After a short forerun, the fraction boiling at 110-111 °

C (0.5

mmHg) is collected to give 29.3

–

29.5 g (86% yield) of N-(2,2-diethoxy)ethyl

formamide (Notes 4, 5).

B.

2,2-Diethoxy-1-isocyanoethane.

A 500-mL one-necked flask

equipped with a reflux condenser bearing a CaCl2 trap at the upper end is

charged with N-(2,2-diethoxyethyl formamide (24.20 g, 150 mmol),

tetrachloromethane (24.61 g, 160 mmol, Note 6), triphenyl phosphine (44.59

g,170 mmol, Note 7), triethylamine (17.20 g, 150 mmol, Note 8), and 150

mL dichloromethane (Note 9). The clear mixture is heated at reflux in an oil

bath, and a precipitate (triphenyl phosphine oxide) begins to appear after 20-

30 min. After 3.5 h at reflux, the suspension is cooled to 5 °

C and filtered

through a Bü

chner funnel under vacuum from a water aspirator.

The

collected solid is washed with 50 mL diethyl ether. The filtrate and the

washings are combined and evaporated to dryness, and the residue is stirred

with a mixture of 100 mL ethyl ether and 100 mL pentanes (Note 10). The

resulting suspension is allowed to stand overnight in the freezer (Note 11),

and then filtered through a fritted funnel under vacuum with chilling of the

collected filtrate in an ice-sodium chloride bath. The solid residue is washed

with 60 mL of pentanes. The filtrate is concentrated on a rotary evaporator

in a fume hood and the residue is transferred to a flask equipped with a short

path distillation head and a two-necked receiver. Distillation under reduced

pressure gives 13.5

–

13.8 g (63-64%) of 2,2-diethoxy-1-isocyanoethane

(Note 12), bp 60-61 °

C at 1 mm Hg, as a colorless, vile-smelling liquid

(Notes 13, 14).

2. Notes

1. Aminoacetaldehyde diethyl acetal was purchased from Aldrich and

used as supplied.

2. Propyl formate (40 mL, purchased from Aldrich) is stirred with 20

mL aq. 5% NaHCO3 for 2 min. The layers are separated, and the propyl

formate layer is washed with 3 x 20 mL of distilled water then dried over

magnesium sulfate. After filtration, the filtrate is distilled at atmospheric

pressure and the fraction boiling at 80-81 °

C is collected for use in Step A.

3. The submitters used an electric shell for heating.

4. The distillation tends to bump, but the Vigreux column prevents

overflow into the receiver.

5. IR spectrum (neat) 3304, 1666 cm-1; 1H NMR (300 MHz, CDCl3),

the formamide is an 6/1 ratio of amide rotamers in this solvent, major

rotamer resonances:

8.21 (s, 1 H, NCHO), 5.81 (broad s, 1 H, NH), 4.52 (t,

J

= 5.1 Hz, 1 H, O-CH-O), 3.50-3.77 (m, 4 H, CH

2

CH

3

), 3.45 (t,

J

= 5.4 Hz,

2 H, CH

2

N), 1.29 (t,

J

= 7.1 Hz, 3 H, CH

2

< br>CH

3

), minor rotamer resonances:

8.05 (d,

J

= 13.5 Hz, 1 H, NCHO), 4.45 (t,

J

= 6 Hz, 1 H, O-CH-O), 3.31 (t,

J

= 6 Hz, 2 H, CH

2

N);

13

C NMR (75 MHz, CDCl

3

) major rotamer

resonances:

161.3, 100.2, 62.4, 40.1, 14.9, minor rotamer resonances:

165.0, 101.3, 63.0, 44.3; LRMS (EI)

m/z

117 (M

–

CH

3

NO, 10%), 103

(100%), 91 (17%), 84 (55%), 75 (77%); HRMS (EI)

m/z

calcd for C

7

H

16

NO

2

(M + H) 162.1130, found, 162.1126.

6. Tetrachloromethane was purchased from Baker or Fisher and dried

over molecular sieves before use.

7. Triphenyl phosphine (99%) was purchased from Aldrich or Acros

and used as supplied.

8.

Reagent grade triethylamine (Fluka) was dried over calcium

hydride pellets and distilled. The fraction boiling at 89 °

C was employed.

9. Dichloromethane was stored overnight on 4 ? molecular sieves

(submitters) or distilled from calcium hydride (checkers) prior to use.

10. The lumps that formed were carefully broken with a spherical-

ended glass rod.

11. The freezer temperature is about

–

15 °

C. If this operation is

omitted, then additional solid that precipitates during the distillation makes

this process difficult.

12. IR (neat) 2156 cm

-1

;

1

H NMR (300 MHz, CDCl

3

)

4.64 (t,

J

=

5.4 Hz, 1 H, O-CH-O), 3.48-3.71 (m, 2 H, CH

2

CH

3

), 3.43 (d,

J

= 5.4 Hz, 2

H, CH

2

NC), 1.17 (t,

J

= 7.0 Hz, 3 H, CH

2

< br>CH

3

);

13

C NMR (75 MHz, CDCl

3

)

157.8, 99.1, 62.8, 44.3, 14.8.

13. The submitters obtained 71-75% yields. The submitters report

that 2,2-diethoxy-1-isocyanoethane can be stored for at least two years at

–

30 °

C under nitrogen without appreciable decomposition. The checkers

stored a sample at

–

20 °

C for three months, and the resulting liquid was still

clear and exhibited a

1

H NMR spectrum identical to that recorded on the

starting sample.

14. The checkers had the impression that this isonitrile smells fouler

than phenyl isonitrile and related aryl isonitriles. Glassware can be freed

from the isonitrile odor by rinsing with a 1:10 mixture of 37% hydrochloric

acid/ethanol.

Waste Disposal Information

All hazardous materials should be handled and disposed of in

accordance with

Press; Washington, DC, 1995.

3. Discusssion

This synthesis of 2,2-diethoxy-1-isocyanoethane is based on the

dehydration of

N

-substituted formamides, which is the most important route

to

isocyanides.

2

The

combination

of

triphenylphosphine,

carbon

tetrachloride and triethylamine allows a smooth dehydration and a facile

workup. The formylation of aminoacetaldehyde diethyl acetal employs

propyl formate, because of the instability of acetals towards acidic reagents

such as formic acid and formic-acetic anhydride that are usually employed in

N

-formylations.

Hartke

3

reported a synthesis of 2,2-diethoxy-1-isocyanoethane in

which amino acetaldehyde acetal was transformed initially into the

corresponding thioformamide. The thioformamide was then converted into

the isocyanide by treatment with diphenylacetyl chloride/diisopropyl

carbodiimide/triethylamine.

The present method appears to be more

convenient, because the experimental procedures are simpler, the yields are

higher (62-68% overall) and the reagents are easily available and cheap.

This isocyanide has been employed as C< /p>

–

C

–

N

–

C unit in the synthesis

of imidazoles, imidazo-imidazoles and aminoisoxazoles.

4

2,2-Dimethoxy-1-

isocyanoethane can be prepared starting from aminoacetaldehyde dimethyl

acetal following this procedure. The yields are similar and the product

shows the same reactivity of its ethyl analogues. A procedure for the