Facile synthesis of a chiral auxiliary bearing the isocyanide group

Article abstract of DOI:10.1002/hc.1086

A previous study synthesized a chiral auxiliary bearing the isocyanide functionality in six steps and with an oxazoline functionality. This paper discusses the synthesis of a chiral isocyanide possessing the easily cleaved menthoxy group. The synthesis pr

Full text of DOI:10.1002/hc.1086

Heteroatom Chemistry
Volume 12, Number 7, 2001
Rapid Communication
Facile Synthesis of a Chiral Auxiliary Bearing
the Isocyanide Group
Palanichamy Ilankumaran, Philip Kisanga, and John G. Verkade
Department of Chemistry, Iowa State University, Ames, Iowa 50011-3111
Received 28 February 2001; revised 28 April 2001
process in which ClCH2CO2H was reacted with 1-
ABSTRACT: The synthesis of a chiral isocyanide
(R)-menthol in refluxing benzene in the presence
of PTSA [4] was allowed to react with sodium
possessing the easily cleaved menthoxy group is
C
reported.
2001 John Wiley & Sons, Inc. Heteroatom
azide in DMF. Upon work-up and purification, the
azide 4, that was obtained in 81% yield, was con-
verted to the formamide 5 in a one-pot reaction in
which 4 was reduced with hydrogen on Pd/C. The
formamide 5, obtained in 99% yield, was treated
with the phosgene equivalent CCl3COCCl3 to afford
the target isocyanide (L)-2 in 73% yield and with
an overall yield of 59% in three steps. This syn-
thesis offers a more convenient and higher-yield
alternative to procedures reported by previous inves-
tigators [5].
Chem 12:561–562, 2001
INTRODUCTION
Previously we reported the synthesis of (R)-1 [1],
a chiral auxiliary bearing the isocyanide function-
ality. However, the synthesis was achieved in six
steps and it bears an oxazoline functionality that
EXPERIMENTAL SECTION
All reactions were conducted under nitrogen. 1H and
13C NMR spectra were recorded on a Bruker VRX300
or Bruker DRX400 machine and were calibrated us-
ing TMS as an internal standard.
requires a two-step procedure for removal [2]. We
therefore investigated the synthesis of a chiral iso-
cyanoester bearing the menthoxy group, a chiral
auxilliary that has recently emerged [3] as being
easily removable. The incorporation of this group
into the isocyanide (L)-2 is shown in Scheme 1.
The known compound 3 [prepared by a reported
Correspondence to: John G. Verkade; e-mail: jverkade@iastate.
edu.
Present address of Palanichamy Ilankumaran and Philip
Kisanga: University of Medicine and Dentistry of New Jersey,
Piscataway, New Jersey and Aldrich Chemical Co., Dept. 271,
Milwaukee, Wisconsin 53233.
Contract grant sponsor: National Science Foundation.
2001 John Wiley & Sons, Inc.
c
SCHEME 1
561

562 Ilankumaran, Kisanga, and Verkade
Calcd for C13H24NO3 242.34, found m/e (MH+)
242.1.
Preparation of Azide 4
A mixture of 11.6 g (50.0 mmol) of the chloro com-
pound 3, prepared by a reported procedure [4], and
13.0 g (200 mmol) of sodium azide were weighed
under nitrogen into a flask. To this mixture was
added 30 ml of DMF followed by connection of the
flask to a water condenser. The reaction mixture was
then warmed at 50 C for 20 h after which it was
cooled to room temperature. The reaction mixture
was dissolved in 150 ml of diethyl ether and then the
solution was washed with 3 100 ml of water. The
organic layer was washed with brine and dried over
anhydrous sodium sulfate. Removal of the solvent
in vacuo afforded azide 4 which was purified by
flash chromatography on silica gel using 20% ethyl
acetate in hexane to afford 9.70 g (81% yield) of the
Synthesis of Isocyanide (L)-2
A small flask was charged with 1.2 g (5.0 mmol)
of formate 5 (weighed under nitrogen). To this was
added 5 ml of methylene chloride followed by 2.7
ml (20 mmol) of triethylamine. The reaction mix-
ture was cooled to 0 C followed by dropwise addi-
tion of 2.0 ml (590 mmol) of CCl3OCO2CCl3. The
reaction mixture was allowed to warm to room tem-
perature with continuous stirring for 18 h. After the
reaction mixture was filtered to remove triethyl-
amine hydrochloride, solvent was removed under
reduced pressure and then the crude product was
purified by flash chromatography on silica gel using
20% ethyl acetate in hexane to afford 818 mg (73%
yield) of the target isocyanide. 1H NMR (CDCl3):
0.70–0.80 (overlapping area, 3H), 0.82–1.00 (over-
lapping area, 7H), 1.09 (m, 2H), 1.51 (m, 2H), 1.70
(m, 2H), 1.83 (m, 2H), 2.01 (m, 1H), 4.21 (s, 2H), 4.80
(m, 1H). 13C NMR (CDCl3): 163.5, 161.1, 76.7, 46.9,
40.6, 34.0, 31.4, 26.4, 23.4, 22.0, 20.8, 16.3. LRMS:
Calcd for C13H21NO2 223.32, found m/e (M+) 223.5.
1
pure azide. H NMR (CDCl3): 2.10–0.68 (aliphatic
area, 18 H), 3.81 (s, 2H), 4.77 (m, 1H). 13C NMR
(CDCl3): 168.0, 76.3, 50.5, 47.0, 40.8, 34.1, 31.5,
26.3, 23.4, 22.8, 16.3. LRMS: Calcd for C12H21N3O2
239.32, found m/e (M+) 239.9.
Synthesis of Formamide 5
To 2.00 g (8.83 mmol) of azide 4 dissolved in 10 ml of
ethyl formate was added 200 mg of Pd/C. A hydrogen
atmosphere was maintained for 30 h followed by stir-
ring at room temperature for an additional 48 h. The
reaction mixture was then filtered and excess solvent
was removed under reduced pressure to afford 2.00 g
(99% yield) of 5 which was found to be essentially
pure by both 1H and 13C NMR spectroscopic analysis.
1H NMR (CDCl3): 1.98–0.70 (aliphatic area, 18H),
4.05 (d, 2H), 4.76 (m, 1H), 6.09 (bs, 1H), 8.23 (s, 1H).
13C NMR (CDCl3): 169.2, 161.3, 76.0, 46.9, 40.8,
40.1, 34.1, 31.4, 26.3, 23.4, 22.0, 20.7, 16.3. LRMS:
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