Communication
which the lateral a-substituent is chosen by the selection of
the alkylating agent and also provides the final products as
the N-alkoxycarbonyl-protected form, thus being an advantage
for future synthetic applications.[13] Moreover, this C!N acyl
transfer reaction can also be applied to pyrrolidine- and piperi-
dine-2,2-dicarboxylates, leading to the formation of quaternary
prolines and pipecolinic acid derivatives in a single step.
Scheme 6. Proposed mechanism for the C!N acyl rearrangement.
Experimental Section
molecular addition to one of the two carboxylate groups, lead-
ing to the formation of a key 2-alkoxyaziridine-2-olate inter-
mediate.[12] This strained intermediate would next undergo
a fast and irreversible ring-opening process, generating the in-
termediate enolate species, which is finally quenched by the
addition of a proton source or an alkylating agent. The impor-
tance of kinetic control in the deprotonation of the substrate
is also evidenced by the fact that the use of weak bases, that
would very likely favor an aminomalonate enolate intermedi-
ate, do not provide any rearrangement product. When two dif-
ferent carboxylate groups are incorporated in the starting ma-
terial (for example, 1n), the formation of an equilibrating mix-
ture of both possible aziridine intermediates is proposed, in
which the most strained one should have a more pronounced
tendency to undergo the subsequent irreversible ring-opening
process in order to exclusively form the product 2n.
We have tried to detect or identify these proposed inter-
mediates through NMR experiments though with no success.
However, when the reaction was quenched with trimethylsilyl
triflate (TMSOTf), 2,2-dialkoxyaziridine 10 could be isolated and
fully characterized in a moderate yield (Scheme 7). Importantly,
this compound led to the formation of 2o after reacting with
tetra-n-butylammonium fluoride (TBAF), thus providing addi-
tional support for this mechanistic proposal.
General procedure for the C!N acyl rearrangement:
synthesis of 2a–r
MeLi (2.00 mmol) was added to a solution of the corresponding
amine hydrochloride 1a–r·HCl (1.00 mmol) and LiCl (4.00 mmol) in
THF at ꢀ788C under inert atmosphere and vigorous stirring. The
reaction mixture was stirred at ꢀ788C for 10 min. Then, HCl aq.
(1m) and brine (10 mL) were added and, after separating the
phases, the aqueous layer was extracted with EtOAc (3ꢁ15.0 mL).
The combined organic layers were dried over Na2SO4 and the sol-
vent was removed under reduced pressure. The residue was puri-
fied by flash column chromatography (hexanes/EtOAc 8:2) to
afford pure N-alkoxycarbonyl-a-amino esters 2a–r.
General procedure for the C!N acyl rearrangement/
alkylation: synthesis of 4a-i
MeLi (2.00 mmol) was added to a solution mixture of the corre-
sponding hydrochloride 1a–r·HCl (1.00 mmol) and LiCl (4.00 mmol)
in THF at ꢀ788C under inert atmosphere and vigorous stirring. The
reaction mixture was stirred at ꢀ788C for 10 min, then the corre-
sponding alkylating agent (4.00 mmol) was added and the reaction
mixture was stirred overnight at room temperature. Once the reac-
tion was finished, HCl (1m, 2 mL) and brine (10 mL) were added
and the phases were separated. The aqueous layer was extracted
with EtOAc (3ꢁ15.0 mL), the combined organic layers were dried
over Na2SO4 and the solvent was removed under reduced pressure.
The residue was purified by flash column chromatography (hex-
anes/EtOAc 8:2) to afford pure N-alkoxycarbonyl-a-amino esters
4a–i.
Acknowledgements
The authors thank the Spanish MINECO (CTQ2011–22790 and
Juan de la Cierva contract to U. U.), the Basque Government
(Grupos IT328–10), and UPV/EHU (EHUA12/09, UFI QOSYC 11/
22, and fellowship to I. U.) for financial support. We also ac-
knowledge Petronor S.A. (Muskiz, Bizkaia) for the generous gift
of solvents. Membership in the COST Action CM0905 is also ac-
knowledged.
Scheme 7. Isolation of key intermediate 10.
In conclusion, we have developed a novel unprecedented
C!N acyl rearrangement reaction promoted by a strong base,
a reaction that constitutes a useful approach for the synthesis
of a-amino acid derivatives starting from aminomalonates. De-
spite the presence of abundant references regarding intramo-
lecular acyl transfer processes between heteroatoms, this is the
first case of an anionic rearrangement in which an acyl group
is transferred from a carbon atom to a heteroatom, the process
requiring a CꢀC bond cleavage event. Moreover, the fact that
an enolate intermediate is generated after the acyl transfer
process, allows the formation of an additional CꢀC bond if
a carbon electrophile is subsequently added in a typical
tandem sequence. In this sense, the reaction is a highly effi-
cient and modular approach to a-amino acid derivatives in
Keywords: acyl transfer
·
alkylation
·
amino acids
·
rearrangements · tandem reactions
[1] a) Comprehensive Organic Synthesis, Vol. 3 (Eds.: B. M. Trost, I. Fleming,
G. Pattenden), Pergamon Press, Oxford, 1991, Section 3; b) Comprehen-
sive Organic Synthesis, Vol. 5 (Eds.: B. M. Trost, I. Fleming, G. Pattenden),
Pergamon Press, Oxford, 1991, Section 7.
[2] See for example: a) C. Bengtsson, H. Nelander, F. Almqvist, Chem. Eur. J.
2013, 19, 9916; b) K. Ha, M. Chahar, J.-C. M. Monbaliu, E. Todadze, F. K.
Hansen, A. A. Oliferenko, C. E. Ocampo, D. Leino, A. Lillicotch, C. V. Ste-
Chem. Eur. J. 2014, 20, 11650 – 11654
11653
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