Chemistry Reference
In-Depth Information
Typical procedure. t-Butyl isocyanide [1165]:
Phosgene (for a safe source and safety
instructions, see Chapter 7) (1.0 kg, 10.1 mol) was delivered through a wide tube
into a stirred solution of N-t-butylformamide (1.01 kg, 10.0 mol) in triethylamine
(1.30 kg) and o-dichlorobenzene (7.0 L) in a flask fitted with a reflux condenser
charged with a freezing mixture of ice and salt (
20
C). Water was added, the
layers were separated, and the non-aqueous layer was dried over anhydrous potas-
sium carbonate or magnesium sulfate and fractionated; bp 90-92
C/750 mmHg;
yield: 681 g (82%).
Isocyanides are very useful tools in the synthesis of N-heterocycles such as in-
doles, imidazoles, tetrazoles, and oxazoles. To form 2,3-disubstituted indoles such
as 3-substituted 2-iodo indoles 1518, o-isocyano cinnamates 1517 are important in-
termediates. They are prepared in high yield (87% for 1517) by dehydration of o-(N-
formylamino)cinnamate 1516 with phosgene [1153, 1166].
CO
2
Me
CO
2
Me
CO
2
Me
COCl
2
I
CH
2
Cl
2
0°C
NH-CHO
N
NC
1516
87 %
1517
1518
Typical procedure. Methyl o-isocyanocinnamate 1517 [1166]:
To a solution of methyl
o-(N-formylamino)cinnamate 1516 (141 mg, 0.68 mmol) and triethylamine (287
m
L, 2.06 mmol) in dichloromethane at 0
C, a solution of phosgene (for a safe
source, see Chapter 7) in dichloromethane was added dropwise. The reaction was
closely monitored by TLC until completion. The mixture was then partitioned be-
tween Et
2
O and satd. aq. NaHCO
3
, and then brine. The combined extracts were
dried (Na
2
SO
4
), filtered, and concentrated to dryness in vacuo. The crude product
was purified by flash column chromatography on silica gel eluting with Et
2
O/hex-
ane (1:4) to give methyl o-isocyanocinnamate (106 mg, 87%) as a white solid; mp
57-59
C.
Various vinyl isocyanides 1521-1525 are prepared from oximes (for example,
1519) by reductive formylation and dehydration of the resulting vinyl formamides
(for example, 1520) with phosgene in 40-97% yield [1167]. For the dehydration
step, DABCO proved to be the most effective base among acid scavengers (Et
3
N,
pyridine, and quinoline were also used).
General procedure. Vinyl isocyanides [1167]: The N-formyl enamine (1 g) and
DABCO (3 equiv.) were dissolved in dry dichloromethane (20 mL) and the solution
was cooled to 0
C. Phosgene (for a safe source, see Chapter 7) (2 equiv., 10% w/v in
dichloromethane) was added dropwise with stirring at 0
C and the resulting solu-
tion was stirred until TLC indicated that no starting material remained. The cold
solution was filtered, and the filtrate was concentrated to a volume of 10 mL, fil-
tered once more, and concentrated to dryness in a flask containing glass wool. The
residue was flash distilled at 8 Torr using a kugelrohr apparatus with a preset oven
temperature of 100
C.
