The Journal of Organic Chemistry
JOCSynopsis
Scheme 21. Conjugate Addition of Dianion 41d to Enones
The obtained product 45 contains an acidic hydrogen as
well as electrophilic cyano and carbonyl functionalities. These
structural features allow for a pseudo-intramolecular process,
via which the efficient synthesis of polyfunctionalized hetero-
cycles 46 and 47 can be realized in a single step (Scheme
1
,68
20).
While NAN enacts 1,2-addition to α,β-unsaturated aldehyde
, dianion 41d (N-methylpyrrolidinium salt) effects conjugate
9
addition (1,4-addition) to various α,β-unsaturated ketones 48
69
and esters. This reaction affords distinct products depending
on the level of steric hindrance in 48; that is, only single
addition proceeds in the case of β-substituted enones 48a,
whereas double addition proceeds in the case of enone 48b
without a substituent at the β-position to afford double adduct
5
0 (Scheme 21).
Double adduct 50 can be converted to naphthyridine 52
6
3
1
5). The dianionic cyano-aci-nitroacetate intermediate 41 is
69
stable and can be isolated. Barium salt 41a was first synthesized
by Ulpiani in 1912 via hydrolysis of ester 40 with barium
hydroxide. Due to the negative charge repulsion, it is
considered that dianion 41 is more reactive than monoanionic
reagent 6; however, it has not been employed in organic
synthesis owing to its inadequate solubility in common organic
solvents.
upon heating with ammonium acetate (Scheme 22). In this
reaction, the formation of intermediate bis(enamine) 51 is a
likely first step, whereupon the amino group attacks the cyano
group, followed by aromatization accompanied by elimination
of nitrous acid and ammonia and by air oxidation to afford 52.
When the conjugate addition of 42 is applied to α-chloro-
α,β-unsaturated ketones 53, intramolecular nucleophilic
substitution of the chloro group with the nitronate and
subsequent dehydration proceed to afford polyfunctionalized
isoxazoles 54 (Scheme 23). The vicinal functionalities can be
manipulated for ring construction, as demonstrated by the
synthesis of isoxaloquinoline derivative 55 in 35% overall yield
from 54a via three steps: oxime formation, O-acetylation, and
6
4
Anionic nitroisoxazolone 42 is readily prepared from
commercially available ethyl nitroacetate in two steps.
6
5
28
Although 42 is an anionic species, ring opening reaction
proceeds efficiently at room temperature to afford dianionic
cyano-aci-nitroacetate 41 upon treatment with base, such as a
hydroxide, carbonate, ethoxide, or amines (Scheme 16). The
counter cations of 41 can be modified by altering the base.
While the dimetal salt is insoluble, diammonium salt 41c,
prepared by using pyrrolidine, is soluble in common organic
solvents. Dianion 41 and its precursor 42 are stable even at
65
28
cyclization (Scheme 24).
While the oxygen atom of a nitronate exhibits nucleophil-
icity, the carbon atom of O-acylated nitronates is highly
70
electrophilic toward nucleophilic addition. As glutaronitrile
3 contains two nitronates, one serves as a nucleophile and the
1
40 °C and release considerably less energy (250 and 163 J/g,
respectively) than NAN (874 J/g). These DSC results indicate
that both compounds 41 and 42 are safe to handle in air.
4
O-acetylated nitronate serves as an electrophile to yield
isoxazoline 56. As the formed isoxazoline 56 has an
electrophilic moiety, intramolecular ring transformation
proceeds to afford polyfunctionalized isoxazoline 57 (Scheme
28
As already mentioned, neutral NAN and anionic nitro-
acetonitrile 6 efficiently react with aromatic aldehydes 7 to
form the corresponding electron-deficient alkenes 8 (α-
nitroacrylonitriles). In the case of cyano-aci-nitroacetate 41c,
not only aromatic aldehydes but also aliphatic aldehydes and
ketones can be used as substrates; in this reaction, two
molecules of 41c react with one molecule of aldehyde to give
glutaronitriles 43 with concomitant decarboxylation (Table
71
1
25). In the case of glutaronitriles derived from aldehydes (R
=
H), 3,5-dicyanoisoxazole is obtained as a result of further
aromatization accompanied by elimination of nitrous acid.
CYANONITRILE OXIDE
■
6
6
1
). Alkenes 8 are obtained via C−C bond cleavage initiated
1,3-Dipolar cycloaddition is one of the most powerful synthetic
tools whereby a heterocyclic framework is generated through
66
by acidification of 43 (Scheme 17).
7
2
The condensation is initiated by nucleophilic attack of
dianion 41c onto the carbonyl functionality yielding adduct 44.
Subsequent decarboxylation affords α-nitroacrylonitrile deriv-
atives 8. The high electron-deficiency of 8 allows for a second
addition of 41c, forming glutaronitrile 43 (Scheme 18). When
this reaction is conducted in acetone, intermediate alkene 8
undergoes nucleophilic attack by the enol of acetone instead of
the formation of two new bonds in a single reaction.
Although numerous reports are found in the literature, the
number of reports dealing with functionalized nitrile oxides is
relatively low, despite the high synthetic utility thereof.
Regarding cyano-substituted nitrile oxide (cyanogen N-oxide)
58, only a few generation methods are known. Although
dehydrochlorination of cyanoformhydroximic chloride 59
and flash pyrolysis of furazan derivative 60 are known,
7
3
7
4,75
67
76
4
1c, affording α-nitro-δ-keto nitrile 45 (Scheme 19).
Scheme 22. Synthesis of Naphthyridine 52
E
J. Org. Chem. XXXX, XXX, XXX−XXX