Petasis three-component coupling reactions of hydrazides for the synthesis of oxadiazolones and oxazolidinones

Article abstract of DOI:10.1021/ol203280b

An application of readily available hydrazides in the Petasis 3-component coupling reaction is presented. An investigation of the substrate scope was performed to establish a general, synthetically useful protocol for the formation of hydrazido alcohols, which were selectively converted to oxazolidinone and oxadiazolone ring systems through triphosgene-mediated cyclization reactions.

Full text of DOI:10.1021/ol203280b

ORGANIC
LETTERS
2012
Vol. 14, No. 2
640–643
Petasis Three-Component Coupling
Reactions of Hydrazides for the Synthesis
of Oxadiazolones and Oxazolidinones
Sebastian T. Le Quement,† Thomas Flagstad,† Remi J. T. Mikkelsen,†
Mette R. Hansen,† Michael C. Givskov,‡ and Thomas E. Nielsen*,†
Department of Chemistry, Technical University of Denmark, DK-2800 Kgs. Lyngby,
Denmark, and Department of International Health, Immunology and Microbiology,
University of Copenhagen, DK-2200 Copenhagen, Denmark
ten@kemi.dtu.dk
Received December 8, 2011
ABSTRACT
An application of readily available hydrazides in the Petasis 3-component coupling reaction is presented. An investigation of the substrate scope
was performed to establish a general, synthetically useful protocol for the formation of hydrazido alcohols, which were selectively converted to
oxazolidinone and oxadiazolone ring systems through triphosgene-mediated cyclization reactions.
Considering the huge potential of the three-component
reaction of amines (primary or secondary), R-hydroxy
aldehydes, and substituted vinyl or aryl boronic acids, also
known as the Petasis three-component coupling reaction
(Petasis 3-CCR),1 for the stereoselective synthesis of
amino alcohols,2 there have been surprisingly few reports
onitsapplication insyntheticorganicchemistry.3 Evidence
for the unique reliability of the reaction is illustrated
by applications in the synthesis of natural products,4
carbohydrate derivatives,5 and unnatural amino acids.6
Advantages of the reaction comprise simple and mild
reaction conditions, broad substrate scope, easy access to
building blocks, and amenability to combinatorial synthe-
sis strategies, including those that aim for structurally
diverse molecular libraries.7
As part of ongoing efforts aimed at identifying novel
antibacterial compounds, we became interested in synthetic
methods that allowed the rapid generation of compounds
incorporating heterocyclic motifs analogous to those of
renowned bioactives.
In this context, we have been particularly interested in
the oxazolidinone core which is a key structural element of
several known antibiotics, such as Linezolid8 and N-thio-
lated 2-oxazolidinones.9 This heterocycle could also serve
† Technical University of Denmark.
‡ University of Copenhagen.
(1) For early accounts on the Petasis three-component coupling
reaction, see: (a) Petasis, N. A.; Akritopoulou, I. Tetrahedron Lett.
1993, 34, 586–583. (b) Harwood, L. M.; Currie, G. S.; Drew, M. G. B.;
Luke, R. W. A. Chem. Commun. 1996, 1953–1954. (c) Dyker, G. Angew.
Chem., Int. Ed. 1997, 36, 1700–1702.
(2) Petasis, N. A.; Zavialov, I. A. J. Am. Chem. Soc. 1998, 120, 11798–
11799.
(3) For reviews on the Petasis three-component coupling reaction,
ꢀ
see: (a) Petasis, N. A. In Multicomponent Reactions; Zhu, J., Bienayme,
H., Eds.; Wiley-VCH: Weinheim, Germany, 2005; pp 199ꢀ223. (b) Batey,
R. A. In Boronic Acids; Hall., D. G., Ed.; Wiley-VCH: Weinheim, Germany,
2005; pp 279ꢀ304. (c) Candeias, N. R.; Montalbano, F.; Cal, P. M. S. D.;
Gois, P. M. P. Chem. Rev. 2010, 110, 6169–6193.
(4) For selected examples, see: (a) Batey, R. A.; MacKay, D. B.
Tetrahedron Lett. 2000, 41, 9935–9938. (b) Jiang, B.; Xu, M. Angew.
Chem., Int. Ed. 2004, 43, 2543–2546. (c) Sugiyama, S.; Arai, S.; Ishii, K.
Tetrahedron: Asymmetry 2004, 15, 3149–3153. (d) Furstner, A.; Ackerstaff,
J. Chem. Commun. 2008, 2870–2872.
(5) (a) Davis, A. S.; Pyne, S. G.; Skelton, B. W.; White, A. H.
J. Org. Chem. 2004, 69, 3139–3143. (b) Hong, Z.; Liu, L.; Hsu,
C.-C.; Wong, C.-H. Angew. Chem., Int. Ed. 2006, 45, 7417–7421.
(6) (a) Petasis, N. A.; Zavialov, I. A. J. Am. Chem. Soc. 1997, 119,
445–446. (b) Currie, G. S.; Drew, M. G. B.; Harwood, L. M.; Hughes,
D. J.; Luke, R. W. A.; Vickers, R. J. J. Chem. Soc., Perkin Trans. 1 2000,
2982–2990.
(7) (a) Kumagai, N.; Muncipinto, G.; Schreiber, S. L. Angew. Chem.,
Int. Ed. 2006, 45, 3635–3638. (b) Muncipinto, G.; Kaya, T.; Wilson,
J. A.; Kumagai, N.; Clemons, P. A.; Schreiber, S. L. Org. Lett. 2010, 12,
5230–5233. (d) Nielsen, T. E.; Schreiber, S. L. Angew. Chem., Int. Ed.
2008, 47, 48–56.
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10.1021/ol203280b
Published on Web 01/10/2012
2012 American Chemical Society

as a mimic of the lactone ring of N-acylated homoserine
lactones which are signaling molecules involved in bacte-
rial quorum sensing (Figure 1).10
Table 1. Substrate Scope: Variation of the Hydrazide Compo-
nent
Figure 1. Synthetic strategy for the two-step generation of
hydrazide-derived oxazolidinones (3).
To this end, it was envisioned that a Petasis 3-CCR of
hydrazides 1 followed by subsequent carbonylative stitch-
ing of the resulting 1,2-hydrazido alcohol 2 would provide
an expeditive entry toward such analogs (Figure 1, 3). This
strategy would also allow for systematic appendage varia-
tion of the hydrazide component, which may be function-
alized at multiple positions before or after the Petasis
3-CCR, in the synthesis of combinatorial libraries.
Given their wide availability and synthetic utility, it is
remarkable that hydrazides have not been reported as
amine components in the Petasis 3-CCR. With a few
reports on the use of structurally related carbazates
(alkoxycarbonylated hydrazines) in mind,11 we therefore
set out to investigate this variant of the reaction. Several
conditions (solvent, temperature, and stoichiometry) were
thoroughly studied for the reaction of different hydrazides,
glycolaldehyde, and trans-phenylvinylboronic acid by
LC/MS, culminating in the use of a 1:1 mixture of MeOH
and HFIP as solvent at 65 °C,12 employing a slight excess
ofboronic acid(1.2equiv) overthealdehydeand hydrazide
components.13 The developed protocol proved useful
(Table 1), the desired products being obtained in
yields ranging from 31 to 84%. Notably, N0-alkylated
secondary hydrazides proved most efficient in the reaction
a Isolated yield after flash column chromatography. b Reactions were
generally run until conversion of starting hydrazide had stopped.
(entries 13ꢀ15). Unfortunately, products 4g and 4l, stem-
ming from the reactions of 2-furoic hydrazide and
N-allylbenzoylhydrazide, respectively, were not detected
(entries7 and 12). Variationoftheboronicacidcomponent
clearly illustrates the reactivity profile of boronic acids in
the Petasis 3-CCR (Table 2). Electron-rich 2-furylboronic
acid proved to be highly reactive (5g, entry 7), whereas
electron-neutral phenylboronic acid failed to react (5h,
entry 8). Finally, the application of a range of aldehydes,
previously reported for Petasis 3-CCRs, proved more
difficult (entries 12ꢀ16). Gratifyingly, carbohydrate-
derived 5m was obtained in good yield (81%). Several
attempts to apply glyoxal and salicylaldehyde all proved
unfruitful (entries 15ꢀ16).
€
(8) (a) Muller, M.; Schimz, K.-L. CMLS, Cell. Mol. Life Sci. 1999,
56, 280–285. (b) Bozdogan, B.; Appelbaum, P. C. Int. J. Antimicrob.
Agents 2004, 23, 113–119.
(9) Mishra, R. K.; Revell, K. D.; Coates, C. M.; Turos, E.; Dickey, S.;
Lim, D. V. Bioorg. Med. Chem. Lett. 2006, 16, 2081–2083.
(10) (a) Hentzer, M.; Eberl, L.; Nielsen, J.; Givskov, M. Biodrugs
2003, 17, 241–250. (b) Welch, M.; Mikkelsen, H.; Swatton, J. E.; Smith,
D.; Thomas, G. L.; Glansdorp, F. G.; Spring., D. R. Mol. BioSyst. 2005,
1, 196–202. (c) Galloway, W. R. J. D.; Hodgkinson, J. T.; Bowden, S. D.;
Welch, M.; Spring, D. R. Chem. Rev. 2011, 111, 28–67. (d) Mattmann,
M. E.; Blackwell, H. E. J. Org . Chem. 2010, 75, 6737–6746.
(11) (a) Portlock, D. E.; Naskar, D.; West, L.; Li, M. Tetrahedron
Lett. 2002, 43, 6845–6847. (b) Portlock, D. E.; Osteszewski, R.; Naskar,
D.; West, L. Tetrahedron Lett. 2003, 44, 603–605. (c) Neogi, S.; Roy, A.;
Naskar, D. J. Comb. Chem. 2010, 12, 75–83. (d) Neogi, S.; Roy, A.;
Naskar, D. J. Comb. Chem. 2010, 12, 617–629.
Following our original proposal, we then went on to
subject the Petasis 3-CCR products to carbonylation con-
ditions. Using known procedures,14 we subjected Petasis
(12) Nanda, K. K.; Trotter, B. W. Tetrahedron Lett. 2005, 46, 2025–
2028.
(13) See Supporting Information for a full account of the performed
optimization experiments.
(14) (a) McReynolds, M. D.; Sportt, K. T.; Hanson, P. R. Org. Lett.
2002, 4, 4673–4676. (b) Mishra, R. K.; Coates, C. M.; Revell, K. D.;
Turos, E. Org. Lett. 2007, 9, 575–578.
Org. Lett., Vol. 14, No. 2, 2012
641

Table 2. Substrate Scope: Variation of the Boronic Acid and
Aldehyde Components
Scheme 1. Reaction of Petasis 3-CCR Product 4a with BTC
either of the two main products. We reasoned that forma-
tion of both products would proceed through common
intermediate 9 (Scheme 2). Furthermore we speculated
that oxadiazolone formation could be facilitated by the
addition of excess amounts of BTC tothe reactionmixture.
This would lead to the formation of 10, where the nucleo-
philic hydroxyl group was blocked, thereby enabling nu-
cleophilic attack from the hydrazide carbonyl group to
form the oxadiazolone product. These speculations were
further supported by the isolation of trace amounts of
carbonate dimer 8 (Scheme 1) which, probably, is formed
through the intermediacy of 11 and nucleophilic attack by
7. A mild basic workup of the reaction mixture then
provided the oxadiazolone, by hydrolysis of 11 and any
dimer 8 that was present. Contrarily, we found that the
oxazolidinone 6 could be accessed via slow addition of
stoichiometric amounts of BTC, where advantage was
taken of the higher reactivity of the hydroxyl group.
Scheme 2. Proposed Pathway for the Generation of Oxazolidi-
none 6 and Oxadiazolone 7
a Isolated yield after flash column chromatography. b Reactions were
generally run until conversion of starting hydrazide had stopped. c The
product resulting from a double Petasis 3-CCR was isolated in 39%
yield. d The intermediate imine was isolated in 49% yield.
3-CCR product 4a to the one-pot addition of excess
amounts of bis(trichloromethyl)carbonate (BTC), expect-
ing clean conversion to the oxazolidinone product 6
(Scheme 1). LC/MS and TLC of the reaction showed not
only instantaneous conversion of the starting material but
also a complex reaction mixture containing several pro-
ducts. The two main products were isolated and assigned
as the desired oxazolidin-2-one (oxazolidinone) 6 and the
1,3,4-oxadiazol-2-(3H)-one (oxadiazolone) 7.
In accordance with the work of Milcent et al.,15 we also
speculated whether strong basic workup would convert
any oxadiazolones present in the reaction mixture to the
(15) (a) Milcent, R.; Barbier, G.; Yver, B.; Mahzouz, F. J. Hetero-
cycl. Chem. 1991, 28, 1511–1516. (b) Milcent, R.; Yver, B.; Barbier, G.
J. Heterocycl. Chem. 1992, 29, 959–962. (c) Milcent, R.; Barbier, G.
J. Heterocycl. Chem. 1992, 29, 1081–1084. (d) Milcent, R.; Yver, B.;
Barbier, G. J. Heterocycl. Chem. 1993, 30, 905–908.
Intrigued by these findings, we decided to investigate if
procedures could be developed for the selective synthesis of
642
Org. Lett., Vol. 14, No. 2, 2012

Oxazolidinone 6 was easily synthesized by the slow addi-
tion of 1 equiv of BTC and a strong basic workup (aqueous
NaOH). In accordance with our considerations, subjecting
oxadiazolone 7 to aqueous NaOH in THF provided
oxazolidinone 6 in nearly quantitative yield.
Scheme 3. Selective Conversion of Petasis 3-CCR Product via
BTC-Mediated Carbonylation
We next synthesized two small libraries from structu-
rally diverse Petasis 3-CCR products, which were selec-
tively converted to either oxadiazolones or oxazolidinones
via the developed reaction protocols (Table 3). In all
instances, the desired oxadiazolones were easily accessed
(yields between 75 and 88%). However, in a few cases,
oxazolidinone formation was hampered by low solubility
of the applied hydrazido alcohol (Table 3, entries 2, 3, and
8). For 14b, this issue was circumvented by first forming
the oxadiazolonewitha large excess of BTC, followed byin
situ conversion to the oxazolidinone using NaOH (aq).
Similarly, 14c and 14h were obtained by conversion of the
crude oxadiazolone to the oxazolidinone. We hypothesize
that oxadiazolone formation is facilitated by the presence
of intermediates similar to 11 (Scheme 2) which, generally,
should display greatly enhanced solubilities in dichloro-
methane compared to the starting materials. Unfor-
tunately, several workup strategies and the use of dif-
ferent reagent stoichiometries all failed to provide com-
pound 14g.
Table 3. BTC-Mediated Oxadiazolone and Oxazolidinone
Formation
In summary, the use of hydrazides as amine components
in the Petasis 3-CCR has been investigated. The reaction
conditions were optimized, and the scope of the reaction
with respect to hydrazides, boronic acids, and hydroxyal-
dehydes was examined. The resulting protocol allowed the
routine preparation of synthetically versatile hydrazido
alcohols, which were selectively converted into oxazolidinone
and oxadiazolone ring systems via triphosgene-mediated
cyclization processes. Ongoing work focuses on further
diversification reactions of hydrazide-derived Petasis
3-CCR products for the creation of structurally diverse
compound libraries for biological screening. All synthe-
sizedcompounds are currentlybeing testedfor antibacterial
activity, and results will be reported in due course.
a Isolated yield after flash column chromatography. b No formation
of oxazolidinone was observed. c Minor traces of oxadiazolone (∼5%)
were typically observed before aq. NaOH workup. d The oxadiazolone
reaction mixture was added THF and 2 M NaOH (aq) to enable the in
situ conversion of oxadiazolone to oxazolidinone. e The oxadiazolone
reaction mixture was worked up, and the crude remaining oil was treated
with THF and 2 M NaOH (aq).
Acknowledgment. The Technical University of Denmark,
Danish Council for Independent Research (Natural
Sciences), Danish Council for Strategic Research,
Carlsberg Foundation, and Torkil Holm Foundation are
gratefully acknowledged for financial support.
Supporting Information Available. Description of Pet-
asis 3-CCR protocol optimization, experimental proce-
dures, and compound characterization data. This material
is available free of charge via the Internet at http://pubs.
acs.org.
desired oxazolidinone via in situ formation of oxy-anion
12. Pleasingly, oxadiazolone 7 could be selectively synthe-
sized by the fast addition of a large excess of BTC and a
mild basic workup with sat. aqueous NaHCO3 (Scheme 3).
Org. Lett., Vol. 14, No. 2, 2012
643