2-(Ethoxycarbonylmethyl)-1H-naphtho[1,8-de]-1,2,3-triazine anion: A new glycine enolate equivalent

Article abstract of DOI:10.1016/S0040-4039(00)01115-1

The titled triazine can be alkylated with LDA and a variety of alkyl halides: Subsequent reduction with aluminium amalgam cleaves the naphthotriazine moiety to afford substituted α amino acids in excellent overall yields; the sequence defines a novel methodology that can be applied under non-acidic and largely non-aqueous conditions. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01115-1

Tetrahedron Letters 41 (2000) 6665±6668
2-(Ethoxycarbonylmethyl)-1H-naphtho[1,8-de]-1,2,3-triazine
anion: a new glycine enolate equivalent
R. Anilkumar, Sosale Chandrasekhar* and Malayalam Sridhar
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, India
Received 25 April 2000; revised 21 June 2000; accepted 29 June 2000
Abstract
The titled triazine can be alkylated with LDA and a variety of alkyl halides: subsequent reduction with
aluminium amalgam cleaves the naphthotriazine moiety to a€ord substituted a amino acids in excellent
overall yields; the sequence de®nes a novel methodology that can be applied under non-acidic and largely
non-aqueous conditions. # 2000 Elsevier Science Ltd. All rights reserved.
Keywords: amino acid; glycine enolate; naphthotriazine.
The synthesis of a amino acids has experienced a remarkable resurgence in recent years,
essentially driven by the increasing need for modi®ed peptides and proteins in biological studies.1
The most general classical methods of amino acid synthesis involve the introduction of the amino
group onto the pre-formed carbon framework, most notably the Strecker and the Perkin±Gabriel
syntheses.2 A few specialised methods involve the condensation of a `glycine enolate equivalent'
with an aldehyde, most notably the Erlenmeyer azlactone and the hydantoin syntheses.2 With the
modern trend towards carbanion-based methodologies, the glycine enolate approach has received
increased attention, e.g. ethyl isocyanoacetate,3 glycine Schi€ bases4 or hippuric acid.5,6 However,
these methods generally involve a ®nal hydrolysis step under strongly acidic conditions, so there
is a need for a glycine equivalent which can be cleaved under non-acidic conditions.
The present study is based on the naphthotriazinylglycinate 1 (Scheme 1), which was ®rst
reported by Tavs and co-workers7 in 1967. It was envisaged that 1 could be deprotonated to the
ylidic species 2, which would be alkylated with the halide 3 to 4; reductive cleavage of the
naphthotriazine moiety would then furnish the alkylated glycinate 5. The strategy relies on
the relatively facile deprotonation of 1 a to the ester moiety, which is expected to be aided by the
positively charged nitrogen atom (the formation of nitrogen ylides from the corresponding
quarternary ammonium derivatives is well known6,8).
In the event, it was found that addition of 1 to lithium diisopropylamide in THF solution
yielded the putative ylidic species 2, which reacted readily with methyl iodide 3a to furnish the
* Corresponding author. Fax: +91-80-3600-529; e-mail: sosale@orgchem.iisc.ernet.in
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01115-1

6666
Scheme 1.
alanyltriazine ester 4a in 85% yield. Apart from traces of the dimethylated product, a minor side-
reaction appeared to be the displacement of the naphthotraizinyl moiety by the LDA in the above
reaction. The above strategy was extended to include a variety of primary alkyl halides 3, the
monoalkylated products 4 being so obtained in excellent yields (Table 1; note that 4g is the
cyclised product obtained with 2 equivalents of the base).
Table 1
Percentage yields for the alkylation of the naphthotriazines 1 with the halides 3 to furnish 4, and their subsequent
reductive cleavage (Al±Hg) to the glycinates 5

6667
The reductive cleavage of the triazine moiety in 4 to the alkylated glycinate 5 and 1,8-diami-
nonaphthalene was then investigated. The cleavage was successfully accomplished with aluminium
amalgam in 10% aqueous THF at 25ꢀC, to a€ord the alkylglycinates 5 in excellent yields, after
chromatographic puri®cation (Table 1; note that the nitro group in 4e is concomitantly reduced
to the amino; also, the 1,8-diaminonaphthalene was recovered in nearly quantitative yields in all
cases).
Thus, a novel glycine equivalent, which furnishes substituted amino acids under non-acidic
(and largely non-aqueous) conditions and in excellent yields, has been introduced. Further work
to extend the above results is planned.
1. Typical procedures
Alkylation of 1: diisopropylamine (1.1 mmol) in THF (1 ml) was treated with n-BuLi (0.68 ml
of 1.6 M solution in hexane) at 0ꢀC for 0.5 h. The resulting LDA solution, at ^78ꢀC, was treated
with a solution of 1 (1.0 mmol) in THF (8 ml) over 0.25 h. After being stirred for 1 h at ^78ꢀC,
the mixture was treated with the alkyl halide (1.1 mmol) in THF (1 ml). After 2 h at ^78ꢀC, the
reaction was continued at 25ꢀC for 4 h. Work-up and chromatography (SiO2) furnished pure 4.
Reductive cleavage of 4: strips of aluminium foil (0.1 g) were treated with 2% mercuric chloride
solution (5 ml), and the resulting amalgam washed with absolute ethanol and ether. THF (5 ml)
and water (0.5 ml) were added, and the mixture treated slowly with a solution of 4 (0.5 mmol) in
THF (2 ml). After being stirred for 12±24 h, the mixture was ®ltered through Celite and the
®ltrate worked-up and chromatographed to obtain the pure glycinate 5 and 1,8-diamino-
naphthalene (>95% yield).
2. Characterisation
1
This was accomplished spectroscopically (IR, H and 13C NMR, and MS), with selected new
compounds furnishing satisfactory elemental analysis. Selected data: Compound 4: IR, 1740 cm^1
1
(ester CO); H NMR (300 MHz, CDCl3), ꢀ 4.48±4.75 (m, 1H, N+-CH(R)-CO2Et); 13C NMR (75
MHz, CDCl3), ꢀ 108.4±109.3 (N+-C-CO2Et); MS, M+ observed almost invariably as the base
peak.
Acknowledgements
The CSIR and UGC (New Delhi) are thanked for generous ®nancial support.
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