Angewandte
Chemie
Multicomponent Reactions
A Four-Component Reaction for the Synthesis of
Dioxadiazaborocines**
Thomas Flagstad, Mette T. Petersen, and Thomas E. Nielsen*
Abstract: A four-component reaction for the synthesis of
heterocyclic boronates is reported. Readily available hydra-
zides, a-hydroxy aldehydes, and two orthogonally reactive
boronic acids are combined in a single step to give structurally
distinct bicyclic boronates, termed dioxadiazaborocines
(DODA borocines). In this remarkable process, one boronic
acid reacts as a carbon nucleophile and the other as a boron
electrophile to provide enantio- and diastereomerically pure
heterocyclic boronates with multiple stereocenters in high
yields.
which the a-hydrazido alcohol 1 generated in the Petasis 3-
CR subsequently undergoes a double condensation with the
electrophilic boron moiety of an additional boronic acid,
thereby yielding the dihydro-dioxadiazaborocine (DODA
borocine) scaffold
2 in a single synthetic operation
(Scheme 1). Organoboron heterocycles have found broad
M
ulticomponent reactions are powerful tools for the rapid
generation of molecular complexity.[1] In such processes, more
than two components are combined in a single reaction,
thereby providing an operationally effective and highly
modular approach to the synthesis of structurally diverse
molecules. The vast majority of reported multicomponent
reactions are three-component reactions (3-CRs), and the
most well-known examples bear the names of their discov-
erers, including the Mannich,[2] Passerini,[3] Strecker,[4]
Hantzsch,[5] Biginelli,[6] and Petasis[7] reactions. The impor-
tance of these reactions is evident from their numerous
applications in total synthesis and medicinal chemistry.[1a]
The design of multicomponent reactions beyond three
components poses an exceptionally demanding challenge for
organic synthesis,[8] with the Ugi reaction[9] being one of the
only known synthetically useful four-component reactions (4-
CRs). Herein, we report the elaboration of a 3-CR into a 4-
CR when the product of the 3-CR contains latently reactive
functional groups. We envisioned that a hydrazido variant of
the Petasis 3-CR[10] would generate a-hydrazido alcohols
containing strategically positioned nucleophilic moieties,
represented by the two nitrogen atoms, the hydroxy group,
and the carbonyl. Exploration of the pluripotent reactivity of
the hydrazido moiety led to the discovery of a novel 4-CR, in
Scheme 1. Combination of Petasis 3-CR and boronic acid condensation
in a novel 4-CR for the synthesis of DODA borocines.
use as reagents, catalysts, and chiral auxiliaries,[11] and more
recently as chemical biology probes and leads for drug
discovery efforts.[12] We therefore set out to investigate the
chemistry of this new and structurally unique class of boron-
containing heterocycles (2), including their formation and
reactions.
The substrate scope of the condensation reaction was
studied with respect to the boronic acid and it was demon-
strated that heteroaromatic, vinyl, aliphatic, and substituted
phenylboronic acids successfully underwent the condensation
(Table 1). The only limitation was encountered for sterically
hindered boronic acids, such as 2,6-dimethyl-phenylboronic
acid (4i), although both o-tolyl-boronic acid and 1-pyrene
boronic acid were sufficiently reactive for an effective
condensation (4h and 4j). We also demonstrated the con-
densation of a BINOL-derived bis(boronic) acid with an a-
hydrazido alcohol to give the highly sterically encumbered
scaffold 4u, which has potential for application in the field of
chiral catalysis.[13]
Initially, the 4-CR of hydrazide, a-hydroxy aldehyde, and
two boronic acids was investigated by employing an excess of
boronic acid in a hydrazido-Petasis reaction, which satisfy-
ingly furnished the desired DODA borocines (Table 2, 7a–c).
The a-hydroxy aldehyde component of the hydrazido-Petasis
reaction was used as its more stable dioxolanol derivative,
which facilitated convenient handling and preparation (see
the Supporting Information). It was considered plausible that
the DODA borocines could be generated in a more controlled
fashion by employing two differentially reactive boronic
acids. In the 4-CR of hydrazide, a-hydroxy aldehyde, and two
such boronic acids, the hydrazido-Petasis reaction proceeds
significantly more slowly than the subsequent condensation
reaction with any of the two boronic acids. However, the
resulting mixture of DODA borocines equilibrates into the
[*] T. Flagstad,[+] M. T. Petersen,[+] Prof. T. E. Nielsen
Department of Chemistry, Technical University of Denmark
2800 Kgs. Lyngby (Denmark)
E-mail: ten@kemi.dtu.dk
Prof. T. E. Nielsen
Singapore Centre on Environmental Life Sciences Engineering
Nanyang Technological University, Singapore 637551 (Singapore)
[+] These authors contributed equally to this work.
[**] The DSF Center for Antimicrobial Research, Danish Council for
Independent Research (Technology and Production Sciences), and
the Technical University of Denmark are gratefully acknowledged for
financial support.
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2015, 54, 8395 –8397
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
8395