Versatile, fragrant, convertible isonitriles

Article abstract of DOI:10.1021/ja0644374

The metalation of oxazoles leads to ring opening to the isocyanoenolate that can be O-acylated to give the unsaturated isonitriles. These substances undergo conventional multicomponent reactions. The products of their reactions are readily converted to acyl substitution products by treatment with acid and a nucleophile. These unsaturated isonitriles are notable by their simple preparations and, unusually, their nonoffensive odors. Copyright

Full text of DOI:10.1021/ja0644374

Published on Web 08/19/2006
Versatile, Fragrant, Convertible Isonitriles
Michael C. Pirrung* and Subir Ghorai
Department of Chemistry, UniVersity of California, RiVerside, California 92521
Received June 22, 2006; E-mail: michael.pirrung@ucr.edu
Scheme 1. Reaction Pathways for Metalated Oxazoles
Isonitriles are versatile functionalities in organic synthesis. They
are active participants in radical reactions, and as such have played
crucial roles in several total and combinatorial syntheses.1 They
can substitute for the gaseous and poisonous carbon monoxide in
organometallic transformations,2 they are polymerized to helical
polymers,3 and they are key to several multicomponent processes,
such as the Passerini and Ugi reactions, of high interest in
combinatorial chemistry.4 Despite these attractions, isonitriles are
relatively unavailable commercially and can be challenging to
prepare. The most common method of isonitrile preparation is by
dehydration of formamides. Reagents often used for this reaction
(e.g., COCl2)5 are hazardous and reactive. Only a few routes to
isonitriles not involving formamide dehydration are known.6
Another hindrance to the use of isonitriles is their piercing odor.
Ugi states5 “The development of the chemistry of isonitriles has
probably suffered ... through the characteristic odor of volatile
isonitriles, which has been described by Hofmann and Gautier as
‘highly specific, almost overpowering’, ‘horrible’, and ‘extremely
distressing’. It is true that many potential workers in this field have
been turned away by the odor.” The potent odor of isonitriles is
the basis of a classic qualitative test for primary amines via
conversion to the “carbylamine” by KOH/CHCl3 (the Hofmann
isonitrile synthesis)7 and makes them useful for the characterization
of odorant receptors.8 They are sufficiently obnoxious to have been
included in nonlethal weapons.9 As a consequence of these
properties, only the simplest, unfunctionalized isonitriles, which
chemists can purchase and which need minimal handling, are used
routinely. We have provided a solution to these problems with the
family of isonitriles described herein.
Oxazoles 1 are readily metalated at the 2-position (Scheme 1).
The resulting anion 2 equilibrates (by R-elimination/ring-opening)
with R-isocyano enolate 3. With benzoxazole and oxazole, the latter
form dominates and has been observed by NMR.10 Reactions of
this equilibrating anion are dependent on the electrophile. Most
carbonyl electrophiles give products such as 5.11 O-Acylation gives
products such as 4.12 O-Silylation can occur, but the enol silane
can close back to the 2-silyloxazole (like 5).11b Iodine is one of the
few electrophiles to react with 3 on carbon. Following C-iodination
to give an intermediate like 6 (R1 ) H), cyclization produces
4-iodooxazole.13
Our initial investigations centered on commercial oxazoles 7 and
9 (Scheme 2). These compounds are readily metalated by treatment
at -78 °C in THF with n-BuLi and allowed to react with an acyl
chloride. Following warming to room temperature and stirring for
2 h, the desired (Z)-isocyanovinyl (8) and 2-isocyanophenyl (10)
esters are obtained in good to excellent yields. Results are
summarized in Table 1. All of these compounds exhibit isonitrile
IR stretches in the normal range of 2124-31 cm-1. That these
derivatives include the ester functionality, widely regarded as giving
pleasant organoleptic properties to organic compounds, stimulated
Scheme 2. Synthesis of Unsaturated Isonitriles from Oxazoles
Table 1. Synthesis of Unsaturated Isonitrile-esters
1
reactant
yield
IR (cm-
)
odor
8a
8b
AcCl
75%
95%
85%
92%
96%
83%
96%
90%
93%
2128
2126
2125
2125
2126
2124
2128
2128
2131
mild isonitrile
soy
malt
natural rubber
creosote
taffy
mild cherry
old wood
mild petroleum
O-formylmandeloyl-Cl
AcCl
PivCl
MeC6H4COCl
BocCl
MeOC6H4COCl
NCC6H4COCl
C6H5COCl
10a
10b
10c
10d
10e
10f
10g
our curiosity concerning their odor. Included in the table is a
subjective assessment of the olfactory properties of isonitriles 8
and 10.
Ugi reactions with isonitriles 8 and 10 should give enamide
products similar to those derived from the “convertible” isonitrile
1-isocyanocyclohexene reported by Armstrong.14 He showed that
isocyanocyclohexene-derived Ugi products 11 could undergo acyl
substitution to yield esters 13. When R1 ) Ph, they may also cyclize
to mu¨nchnones 12 that undergo 1,3-dipolar cycloaddition with
alkynes to give pyrroles. The convertibility of an Ugi reaction
product derived from 8a was first examined (Scheme 3). Treatment
of 14 under Armstrong’s conditions (anhydrous HCl, MeOH, 55
°C, 3 h) provides 15 quantitatively. Two further reactions provide
information concerning the mechanism of this conversion. The
related Ugi product 16 was prepared from 10c so that the portion
of the amide derived from the isonitrile would be nonvolatile and
easily traceable. When treated with HCl/MeOH, 16 is converted
quantitatively to 15 and benzoxazole 17 (Scheme 4). Whether Ugi
reaction products derived from 10 can form a mu¨nchnone was
9
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J. AM. CHEM. SOC. 2006, 128, 11772-11773
10.1021/ja0644374 CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Scheme 3. Convertible Isonitriles
Scheme 6. Other Multicomponent Reactions of Convertible
Isonitriles
Despite the significantly modified odor properties of 8 and 10,
their reactivity does not seem to be compromised; they undergo
the classical multicomponent reactions of isonitriles. As convertible
isonitriles, they are far superior to isocyanocyclohexene, which we
have found difficult to prepare in quantities larger than a few
hundred milligrams, unstable on storage, and of vile odor. Conver-
sion of Ugi products derived from isocyanocyclohexene to esters
also requires more demanding reaction conditions than Ugi products
derived from 10. Studies of 10e have so far shown it stable at room
temperature under nitrogen. We have had no difficulty preparing
10e in batches as large as 5 g.
Scheme 4. A Conversion Reaction and Evidence about Its
Mechanism
Owing to their combination of two different functionalities having
distinctive odors, molecules 8 and 10 may also pose interesting
questions for theories of olfaction.
Supporting Information Available: Experimental descriptions and
characterization for key compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
Scheme 5. Test for Possible Intermediates in the Conversion
Reaction
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