Solid Phase Synthesis of (Benzannelated) Six-Membered Heterocycles via Cyclative Cleavage of Resin-Bound Pseudo-Oxazolones

Article abstract of DOI:10.1021/acs.orglett.6b01609

A solid supported procedure for the synthesis of benzoxazinones, dihydropyrazinones, quinoxalinones, and dihydrooxazinones using immobilized oxazolones in combination with difunctional nucleophiles as cleavage agent is presented. The scope of the novel me

Full text of DOI:10.1021/acs.orglett.6b01609

Letter
pubs.acs.org/OrgLett
Solid Phase Synthesis of (Benzannelated) Six-Membered
Heterocycles via Cyclative Cleavage of Resin-Bound Pseudo-
Oxazolones
Simone Graßle,† Sylvia Vanderheiden,‡ Patrick Hodapp,† Bekir Bulat,†,∥ Martin Nieger,§ Nicole Jung,*,†,‡
̈
and Stefan Brase*,†,‡
̈
†Institute of Toxicology and Genetics, Karlsruhe Institute of Technology, Hermann-von-Helmholtz-Platz 1, 76344
Eggenstein-Leopoldshafen, Germany
‡Institute of Organic Chemistry, Karlsruhe Institute of Technology, Fritz-Haber-Weg 6, 76131 Karlsruhe, Germany
§Laboratory of Inorganic Chemistry, Department of Chemistry, University of Helsinki, P.O Box 55, A. I. Virtasen aukio 1, 00014
Helsinki, Finland
S
* Supporting Information
ABSTRACT: A solid supported procedure for the synthesis of benzoxazinones, dihydropyrazinones, quinoxalinones, and
dihydrooxazinones using immobilized oxazolones in combination with difunctional nucleophiles as cleavage agent is presented.
The scope of the novel method has been demonstrated through subsequent modification of the parent oxazolone scaffold on
solid supports using conversions with electrophiles or CuAAC reactions to give functionalized pyrazin-2-ones. The described
method allows the synthesis of the target heterocycles in good yields via three to five steps on solid phases with only one
chromatographic purification step.
xazol-5-ones are well-known heterocycles with manifold
citations in the chemical literature as they occur as parts of
O
natural products, pharmaceuticals, and intermediates in chemical
reactions.1 The conversion of the oxazol-5-one core has been
investigated only in very few studies even though the high
reactivity of the 5-membered heterocycle in the presence of
nucleophiles and the good availability of those compounds
allows diverse transformations. For example, ring opening
reactions to give amino acids,2a N-arylpyruvamides,2b and α-
keto carbonyls2b,c have been published. In addition, it has been
shown for a few examples that the reaction of 2-(trifluor-
omethyl)-5(2H)-oxazolones or 2,2-bis(trifluoromethyl)-5-
(2H)oxazolones as activated starting materials with difunctional
nucleophiles can be used for the synthesis of heterocyclic
compounds.3 The products of such reactions are interesting
targets since quinoxalines and their derivatives the quinoxalin-2-
ones and dihydropyrazin-2-ones are prominent in synthetic
chemistry4,5 and possess a wide range of biological activities
(Figure 1).6 They are known as compounds with antimicrobial,7
anti-inflammatory,8 and antiviral9 effects, they have been shown
to act as enzyme inhibitors10 and are potent candidates for
antitumor therapeutics.11 Until now, the condensation of
oxazolones with 1,2-diaminobenzenes to quinoxalinones remains
the unique application of this strategy as source for chemical
diversity. Other compound classes, like, e.g. benzoxazin-2-ones
or dihydrooxazin-2-ones, have not been gained in a similar
manner although they are well-known as building blocks in
Figure 1. Biologically active molecules containing a dihydropyrazinone
(A), quinoxaline (B), or benzoxazin-2-one moiety (C).
organic chemistry and show potential in affecting biological
model systems.12
Our group has recently identified the oxazolone core as
intermediate for the generation of many interesting heterocycles
including quinoxalinones and benzoxazinones. In contrast to
former well-known approaches toward the synthesis of those
heterocycles,13 we were interested in the potential of oxazolones
as solid supported building blocks that enable the formation of
heterocycles in a combinatorial manner. According to a
previously published protocol,2 a set of five different 4-
substituted 2-trifluoromethyl oxazolones 2a−e was synthesized
in good purity and yield. The attachment of the oxazolones to the
Received: June 3, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01609
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Letter
solid supported material was achieved via installation of an acrylic
acid linker on Merrifield resin and followed by Michael addition
of the oxazolone in 2-position (Scheme 1).2a Independent of the
results, we extended the protocol to a conversion of the resins 3
with aliphatic 1,2-diamines. As far as we know, similar
transformations are not known. Resins 3a−e were reacted with
different aliphatic nucleophiles, namely, the three diamines
(1R,2R)-(−)-1,2-diaminocyclohexane (4d), 1,2-diaminoethane
(4e), and propane-1,2-diamine (4f) for 16 h in methanol at
80 °C. The desired dihydropyrazin-2-ones 5 could be obtained
mostly in good to excellent yields depending on the nature of the
immobilized oxazolone. In only three cases (5ad, 5dd, 5ed)
moderate yields (51−57%) were obtained (Table 1). In contrast
a
Scheme 1. Synthesis of Oxazolone-Modified Resins 3a−e
Table 1. Cleavage of Oxazolones 3a−e with Aliphatic 1,2-
Diamines Giving Dihydropyrazine-2-ones 5
a
Conditions: 2 (3−4 equiv), NEt3, CH2Cl2, rt, 16 h. *Use of DMAP as
base.
calculated loadings of the obtained resins 3a−e, which
correspond to almost quantitative conversion for all of the
immobilization experiments (detailed calculation given in
Supporting Information), we observed that the oxazolone 2e
should be purified via chromatography to reach high purity of the
cleaved compounds in the end (see Tables 1 and 2).
The resins 3a−e were then used for the formation of
quinoxalinones, pyrazin-2-ones, benzoxazoles, and dihydroox-
azinones. We were pleased to observe that the literature
procedure using the activated 2,2-bis- or 2-mono(trifluoro-
methyl)-5-oxazolones as starting material3 could be transferred
successfully to a solid supported procedure. Thus, when the
immobilized oxazoles 3b−d were reacted with aromatic diamines
4a and 4b the desired quinoxalinones 5 could be obtained in 44−
84% overall yield (linker attachment, oxazolone immobilization,
and cyclative cleavage, Scheme 2). Additionally it was shown by
one selected example that the procedure can be adapted
successfully to the formation of pyridopyrazin-2-ones, as, e.g.,
5cc.
These results show that the solid supported procedure
(Scheme 2) is as efficient as the known alternatives in solution
with yields of 66−86% for the reactions of phenyl-, isopropyl,
benzyl-, and methyl-substituted 2,2-bis(trifluoromethyl)-5-ox-
azolidinones with 1,2-diaminobenzene.3 Encouraged by these
Scheme 2. Cleavage of Immobilized Oxazolones 3b−d Giving
a
Quinoxalin-2-ones 5 (Yield Calculated over 3 Steps)
a
Yield calculated over 3 steps. Conditions: 4 (3 equiv), methanol, 80
b
°C, 16 h. Product was obtained as a mixture of isomers.
to the condensations of (het)aromatic 1,2-diamines, which
required up to 20 days to reach full conversion, condensations of
aliphatic 1,2-diamines were completed within 16 h.
A further extension of the scope of the protocol was achieved
by the reaction of resins 3a−e with several 2-amino-phenols. The
average yield of the isolated benzoxazolones were lower in
a
b
Conditions: 4 (3 equiv), methanol, 80 °C. Mixture of isomers.
c
d
e
Reaction for 48 h. Reaction for 20 d. Conditions: 1.2 equiv of 4c
f
and 0.3 equiv NEt3, 13 d. Reaction for 16 h.
B
DOI: 10.1021/acs.orglett.6b01609
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Letter
comparison to the results obtained via cleavage with 1,2-
diaminobenzenes (up to 85% yield calculated for three steps)
(Table 2). The yield of the reaction depends on both, the
Scheme 3. Cleavage of Immobilized Oxazolone 3b Giving
Dihydro-1,4-oxazin-2-one 7bf
Table 2. Cleavage of Immobilized Oxazolones 3a−e Giving
Benzoxazin-2-ones 7
a
Yield calculated over 3 steps.
workup and chromatography after each step), we were interested
in further modifying of the immobilized oxazolone scaffold on
solid supports. The hydroxyphenylglycin-derived oxazolone
resin 3b, offering a hydroxyl functionality suitable for derivation
with alkyl bromides 8, was selected. The reactions with tert-butyl
bromoacetic acid (8a) and propargyl bromide (8b) where
performed using literature known procedures. The obtained
intermediates, resins 9a and 9b, have been cleaved with (1R,2R)-
(−)-1,2-diaminocyclohexane (4d) to give the modified quinox-
alin-2-ones 11a and 11b in 29% and 36% yield calculated over 4
steps. The scope for further derivatization was shown by reacting
the immobilized alkyne derivative 9b with benzylazide as a
common model system for Cu-catalyzed alkyne azide cyclo-
additions (CuAAC). In accordance with the assumed
quantitative conversion of terminal alkynes with benzyl azide
in the so-called Click reaction, the obtained yield of the cleaved
triazole-modified pyrazin-2-one 11c is comparable to the
nonmodified precursor 11b (36% yield calculated over 5 steps,
Scheme 4).
The herein described procedure allows the synthesis of 6-
membered heterocycles via a solid-supported procedure using
immobilized oxazoles in combination with difunctional
Scheme 4. On-Bead Functionalization of Immobilized
a
Oxazolones and Cleavage
a
Yield calculated over 3 steps. Conditions: 6 (3 equiv), methanol, 80
°C, 16 h.
aminophenol and the immobilized oxazolone. Good results have
been obtained for all compounds, which have been cleaved from
the hydroxyphenylglycin-derived oxazolone resin 3b, while
benzoxazolone forming reactions with the phenylglycin-derived
oxazolone resin 3c or alanine-derived oxazolone resin 3a resulted
in general lower yields (entries 1, 2, and 8, Table 2).
To prove the applicability of the method to the preparation of
dihydro-1,4-oxazin-2-ones, we selected the hydroxyphenylgly-
cine-derived oxazolone resin 3b for a conversion with
commercially available 2-amino-3-methylbutan-1-ol (6f). As
shown for the transformations of the parent o-aminophenols in
Table 2, the reaction with an aliphatic N,O-nucleophile was
successful as well. The target compound 3-(4-hydroxyphenyl)-5-
isopropyl-5,6-dihydro-2H-1,4-oxazin-2-one (7bf, Scheme 3) was
obtained in 67% yield (calculated over three steps).
a
t
Reagents: 8a, Bu-bromoacetate; 8b, propargyl bromide. Conditions:
A: 8a, K2CO3, DMF, 60 °C, 18 h. B: 8b, K2CO3, DMF, rt, 15 h. C:
CuI, sodium ascorbate, benzyl azide, CH2Cl2, rt, 2 h. D: (1R,2R)-
(−)-1,2-diaminocyclohexane (4d), methanol, 80 °C, 16 h.
As postcleavage derivatization suffers from the general
disadvantages of combinatorial reactions in solution (e.g.,
C
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b01609.
Experimental procedures and spectra (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: braese@kit.edu.
C.; Cook, A.; Paton, R. S.; Muller, S.; Knapp, S.; Brennan, P. E.; Conway,
̈
S. J. Angew. Chem., Int. Ed. 2014, 53, 6126−6130.
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Med. Chem. 2014, 86, 122−132.
(11) Zykova, S. S.; Karmanova, O. G. Pharm. Chem. J. 2015, 49, 362−
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(12) Sweis, R. F.; Wang, Z.; Algire, M.; Arrowsmith, C. H.; Brown, P. J.;
Chiang, G. G.; Guo, J.; Jakob, C. G.; Kennedy, S.; Li, F. ACS Med. Chem.
Lett. 2015, 6, 695−700.
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*E-mail: nicole.jung@kit.edu.
Present Address
∥(B.B.) Molekulare Physikalische Chemie, Heinrich-Heine-
Universitat Dusseldorf, 40225 Dusseldorf, Germany.
̈
̈
̈
Notes
The authors declare no competing financial interest.
Supplementary crystallographic data for this paper (crystallo-
graphic data for compounds 7ba (CCDC-1442205) and 7be
(CCDC-1442198)) can be obtained from the CCDC via www.
ccdc.cam.ac.uk/data_request/cif.
ACKNOWLEDGMENTS
■
This work was supported by the Helmholtz program
Biointerfaces in Technology and Medicine (BIFTM). Research
data have been stored and registered with support of the DFG-
funded project Chemotion.
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