Reaction of α-amidoalkylphenyl sulfones with Reformatsky reagents. A new entry to β-amino esters

Article abstract of DOI:10.1016/S0040-4039(00)00245-8

The reaction of Reformatsky reagents with α-amidoalkylphenyl sulfones proceeds in dichloromethane at room temperature leading to the synthesis of the corresponding β-amino esters in good yields. The procedure presents syn stereoselectivity and can be also

Full text of DOI:10.1016/S0040-4039(00)00245-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 2709–2712
Reaction of α-amidoalkylphenyl sulfones with Reformatsky
reagents. A new entry to β-amino esters
Tiziana Mecozzi and Marino Petrini ∗
Dipartimento di Scienze Chimiche, Università di Camerino, via S. Agostino 1, I-62032 Camerino, Italy
Received 23 November 1999; accepted 9 February 2000
Abstract
The reaction of Reformatsky reagents with α-amidoalkylphenyl sulfones proceeds in dichloromethane at room
temperature leading to the synthesis of the corresponding β-amino esters in good yields. The procedure presents syn
stereoselectivity and can be also extended to Reformatsky reagents based on γ-bromocrotonates. © 2000 Elsevier
Science Ltd. All rights reserved.
Keywords: amino acids and derivatives; N-imides; Reformatsky reagents; sulfones.
The addition of nucleophilic reagents to unsaturated carbon–nitrogen bonds represents a viable and
powerful method to produce an exceptionally wide array of nitrogeneous derivatives.1 The imino
group has gained a particular relevance among these electrophilic substrates as in the case of N-tosyl
imines that exhibit an enhanced reactivity towards nucleophiles.2 The preparation of N-tosyl imines
starting from aromatic aldehydes is rather straightforward, while aliphatic aldehydes are converted to
the corresponding imines using N-sulfonyl sulfonamides at low temperature.3 These N-tosyl imines must
be promptly used since any attempt to isolate them leads to isomerization products.4 This drawback has
stimulated the search for some synthetic analogues of reactive imines that can be easily prepared and
which are sufficiently stable. N-Acyl-α-substituted amines are a valuable source of N-acyl imines since,
as portrayed in Scheme 1, a base-(nucleophile)-induced elimination of HX from the amido derivative I
affords the corresponding imino derivative II.
Scheme 1.
∗
Corresponding author. Fax: +39 0737 637345; e-mail: petrini@camserv.unicam.it (M. Petrini)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00245-8
tetl 16525

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The excess of the nucleophile rapidly attacks the imino derivative II as soon as it is formed thus giving
the corresponding addition product III. Metal ester enolates efficiently add to imino derivatives5 and
amido derivatives of type I6 giving the corresponding β-amino esters and β-lactams.7 Similarly, zinc
enolates generated from the corresponding α-bromo esters8 may react with N-acyl-amines I to afford
β-amino esters.9 α-Amidoalkylphenyl sulfones 1 are easily prepared by reaction of a carbamate with
a suitable aldehyde and sodium benzenesulfinate in the presence of formic acid.10 Because of the well
known proclivity of the phenylsulfonyl group to act as a good leaving group in elimination reactions,11
sulfones 1 can behave as N-acyl imino equivalents in reactions with nucleophiles.12 Thus sulfones 1
react with Reformatsky reagents 2 in dichloromethane at room temperature to afford the corresponding
β-amino esters 3 in good yields (Scheme 2, Table 1).
Scheme 2.
Table 1
Reaction of α-amidoalkylphenyl sulfones with Reformatsky reagents
The organozinc reagent is prepared in situ by reaction of the corresponding α-bromo ester with a
zinc–copper couple13 and two equivalents of the reagent are needed in order to get a complete conversion
of the substrate. The formation of β-amino esters 3 proceeds with modest to good syn selectivity using α-
alkyl substituted bromo esters.14 This trend is opposite to that observed with N-acyl-α-methoxy amines
which show a preference for the anti stereoisomer.9a Neither the size of the alkyl substituent of the
carbamoyl group, nor the size of the alkyl framework on sulfone 1 seems to have any beneficial effect
on the stereoselectivity. The use of t-butyl α-bromo esters does not improve the stereochemical outcome
of the reaction but leads to a consistent increase of the reaction time (4–18 h) that is usually about 1 h
for the entries displayed in Table 1. On the other hand, a satisfactory syn:anti ratio has been observed
using ethyl 2-bromophenyl acetate 2h thus indicating that α-substitution may be advantageous for the
stereoselectivity of the process. Methyl γ-bromocrotonate 4 has been also used for the preparation of the
corresponding Reformatsky reagents and the results of its reaction with some sulfones 1 (Scheme 3) are
displayed in Table 2.

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Scheme 3.
Table 2
Reaction of α-amidoalkylphenyl sulfones with Reformatsky reagent prepared from methyl
γ-bromocrotonate
The opposite selectivity in favour of the γ- over the α-regioisomer has been observed also in this
circumstance using N-acyl-α-methoxy amines.9a For the α-regioisomer 6 a preference for the syn
stereoisomer has been once again observed.
In conclusion, α-amidoalkylphenyl sulfones 1 can be profitably used as precursors of the corres-
ponding N-acyl imines in reactions with Reformatsky reagents. The β-amino esters are obtained in
satisfactory yields with syn stereoselectivity.15 Some extra functional groups such as chlorides, esters
and double bonds can be included in the alkyl framework of the sulfones 1 thus extending the synthetic
significance of the present methodology.
Acknowledgements
Financial support from University of Camerino (National Project Stereoselezione in Sintesi Organica.
Metodologie e Applicazioni) is gratefully acknowledged.
References
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932–982. The chemical shift of the N–H proton for the syn isomer is usually around 5.4 ppm while that for the anti isomer
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15. Typical experimental procedure for preparation of β-amino esters 3. To a stirred solution of sulfone 1 (1 mmol) in dry
dichloromethane (5 mL) α-bromo ester 2 (2.1 mmol) was added at room temperature. The zinc–copper couple (0.2 g)
was then added and the suspension was strirred for 1 h at room temperature. The solid was filtered and washed with
dichloromethane. The combined filtrates were washed with saturated ammonium chloride and then dried over magnesium
sulfate. After evaporation of the solvent the crude β-amino ester was purified by column chromatography. 3f: IR (KBr) ν:
3350, 1716; syn isomer: mp 43°C; 1H NMR (200 MHz, CDCl3) δ: 0.94 (t, 3H, J=7.3 Hz), 1.27 (t, 3H, J=7.1 Hz), 1.46 (s,
9H), 1.55–1.80 (m, 4H), 2.40–2.55 (m, 1H), 2.62–2.75 (m, 2H), 3.80–3.95 (m, 1H), 4.15 (q, 2H, J=7.1 Hz), 5.35 (d, 1H,
1
J=9.9Hz), 7.15–7.31 (m, 5H); anti isomer: mp 61°C; H NMR δ: 0.89 (t, 3H, J=7.3 Hz), 1.24 (t, 3H, J=7.1 Hz), 1.46 (s,
9H), 1.60–1.90 (m, 4H), 2.45–2.50 (m, 1H), 2.60–2.80 (m, 2H), 3.75–3.90 (m, 1H), 4.13 (q, 2H, J=7.1 Hz), 4.64 (d, 1H,
J=9.9 Hz), 7.15–7.35 (m, 5H).