N,O-bis-(ethoxycarbonyl)hydroxylamine: A convenient reagent for the Lossen transformation

Article abstract of DOI:10.1016/S0040-4039(00)00808-X

The titled compound effects the Lossen rearrangement on aromatic carboxylic acids, via activation by DCC or formation of the acid chlorides, to furnish the corresponding amines in excellent yields, in an essentially 'one-pot' procedure. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00808-X

Tetrahedron Letters 41 (2000) 5291±5293
N,O-Bis-(ethoxycarbonyl)hydroxylamine: a convenient
reagent for the Lossen transformation
R. Anilkumar, Sosale Chandrasekhar* and Malayalam Sridhar
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, India
Received 10 April 2000; revised 11 May 2000; accepted 16 May 2000
Abstract
The titled compound e€ects the Lossen rearrangement on aromatic carboxylic acids, via activation by
DCC or formation of the acid chlorides, to furnish the corresponding amines in excellent yields, in an
essentially `one-pot' procedure. # 2000 Elsevier Science Ltd. All rights reserved.
Keywords: amines; carbamates; ethoxycarbonyl; hydroxylamine; Lossen.
Among the synthetically important family of reactions involving migration to electron-de®cient
nitrogenÐthe Hofmann, the Curtius and the Lossen reactionsÐthe Lossen reaction has been
relatively neglected, largely because of a complicated experimental procedure.1,2 We report herein
a new Lossen reagent which much simpli®es the reaction.
The Lossen reaction is preceded by the formation of a hydroxamic acid and its subsequent
activation:1,2 the conversion would be much simpli®ed were these steps to collapse into a single
one. This indicates the use of a pre-activated hydroxylamine, e.g. an O-acyl derivative, but these
3
are known to isomerise to N-acylhydroxylamines, as our own attempts con®rmed. Such iso-
merisation could be avoided by blocking the nitrogen centre, so an N,O-bis-acylated hydroxyl-
4
amine was sought. An interesting derivative appeared to be N,O-bis-ethoxycarbonylhydroxylamine
1
(
(Scheme 1). It was envisaged that 1 could be acylated with a carboxylic acid or its chloride 2
R=OH or Cl), to the N-acyl-N,O-bis-ethoxycarbonylhydroxylamine 3, which appeared well-set
to undergo a reaction of the Lossen type on treatment with base. A concerted process in which
the departure of the O-ester group is assisted by the N-ester, via the cyclic intermediate 4 and its
subsequent fragmentation as shown, seems likely; the production of the ®nal amine 6 via the
4,5
isocyanate 5 follows the classical Lossen pathway. (4-Aza analogs of 4 have been prepared from 1.)
4
The bis-ester 1Ðfrom hydroxylamine and ethyl chloroformateÐwas readily acylated by various
aromatic acid chlorides 2 (XˆCl) to give 3 in excellent yields. The subsequent Lossen conversion
of 3 was also e€ected in high yields, via treatment with triethylamine in re¯uxing acetonitrile with
*
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)00808-X

5
292
Scheme 1.
Table 1
One-pot' conversion of carboxylic acids 2 to amines 6 via a Lossen transformationa
`

5
293
a trace of water. Potassium hydroxide led to lower yields, and the substitution of ethanol for
water led to the cleavage of the aroyl group. The trace of water apparently facilitates the formation
of 4. The conversion also occurred in `one pot', i.e. without the isolation of the intermediate 3,
with only a marginal loss of overall yield (Table 1).
The acylated derivatives 3 were also prepared directly from the acids 2 (XˆOH) and 1 in the
ꢀ
presence of dicyclohexylcarbodiimide (DCC; MeCN/25 C/5 h), in high yields. A `one-pot' con-
version of 2 to the amines 6 by the DCC route was also performed, in yields generally comparable
to the acid chloride route (Table 1). Work-up with ethanol a€orded the ethyl carbamates 6h and 6i.
The above Lossen reaction with 1 failed with aliphatic carboxylic acids, the hydrolysis of the
`
introduced' acyl group (RCO) in 3 being observed and the starting acid being recovered. Such
deacylation in the aromatic casesÐalthough occurring marginallyÐis perhaps prevented by
conjugation (sterically in the case of phenylacetic acid, 2f!6f). The above failure in the aliphatic
cases is perhaps a strength in terms of selectivity, as aliphatic amines are approached anyway via
6
2
7
the Gabriel syntheses. A recent methodÐreported after the present studies and promoting N-t-
butyloxycarbonyl-O-methanesulphonylhydroxylamine as a Lossen reagentÐis relatively less
facile.
Acknowledgements
CSIR and UGC (N. Delhi) are thanked for generous ®nancial support.
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