Oxidative radical skeletal rearrangement induced by molecular oxygen: Synthesis of quinazolinones

Article abstract of DOI:10.1021/ol4011745

Oxidative skeletal rearrangement of 5-aryl-4,5-dihydro-1,2,4-oxadiazoles into quinazolinones is induced by molecular oxygen (under a dry air atmosphere) that likely proceeds via transient iminyl radical species. Concise syntheses of biologically active qu

Full text of DOI:10.1021/ol4011745

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Oxidative Radical Skeletal Rearrangement
Induced by Molecular Oxygen: Synthesis
of Quinazolinones
Yi-Feng Wang,† Feng-Lian Zhang,† and Shunsuke Chiba*
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical
Sciences, Nanyang Technological University, Singapore 637371, Singapore
shunsuke@ntu.edu.sg
Received April 26, 2013
ABSTRACT
Oxidative skeletal rearrangement of 5-aryl-4,5-dihydro-1,2,4-oxadiazoles into quinazolinones is induced by molecular oxygen (under a dry air
atmosphere) that likely proceeds via transient iminyl radical species. Concise syntheses of biologically active quinazolinone derivatives were
demonstrated using the present strategy.
Nitrogen-containing heterocycles (azaheterocycles) are
an omnipresent component of numerous natural alka-
loids and potent pharmaceutical drugs.1 Among various
azaheterocycles, quinazolinone derivatives show a broad
spectrum of potent biological activities.2 Typically, the
quinazolinone structures are constructed using anthra-
nilic acids or their derivatives via the sequence of their
acylation and condensation, which normally require
strong acidic or basic reaction conditions.3 While several
efficient methods have recently been developed to assem-
ble quinazolinone frameworks with Pd or Cu catalysts,4
there remains a demand for robust processes to construct
these azaheterocyclic scaffolds from readily available
building blocks in atom- and step-economical manners.
Free-radical mediated reactions are powerful tools for
construction of various carbonꢀcarbon and carbonꢀ
heteroatom bonds.5 Rational design of substrates and reac-
tion conditions would enable control of the highly reactive
radical species, leading to the formation of desired target
molecules with high efficiency. The group of Malacria,
Fensterbank, Lacote, and Courillon has recently developed
an elegant strategy to assemble quinazolinone structures by a
radical-cascade reaction of N-benzoylcyanamides bearing
iodo-aryl/alkenyl tethers or azido-alkyl tethers (Scheme 1A).6
The reaction mechanism includes generation of cyclic iminyl
radicals A followed by radical addition of A to the intra-
molecular aromatic moiety, while this method requires stoi-
chiometric use of toxic organotin compounds (Bu3SnH).
Herein, we report oxidative radical skeletal rearrangement
of readily available 5-aryl-4,5-dihydro-1,2,4-oxadiazoles 1
into quinazolinones 2 via iminyl radicals A, which is carried
out just by heating 1 under a dry air atmosphere in DMSO
without any other additives (Scheme 1B).
† Y.-F.W. and F.-L.Z. contributed equally.
(1) For recent reviews, see: (a) Thomas, G. L.; Johannes, C. W. Curr.
Opin. Chem. Biol. 2011, 15, 516. (b) Dandapani, S.; Marcaurelle, L. A.
Curr. Opin. Chem. Biol. 2010, 14, 362. (c) Welsch, M. E.; Snyder, S. A.;
Stockwell, B. R. Curr. Opin. Chem. Biol. 2010, 14, 347.
(2) For recent reviews, see: (a) Rashmi, A.; Ashish, K.; Gill, N. S.; Rana,
A. C. Int. Res. J. Pharm. 2011, 12, 22. (b) Mhaske, S. B.; Argade, N. P.
Tetrahedron 2006, 62, 9787. (c) Michael, J. P. Nat. Prod. Rep. 2004, 21, 650.
(3) For reviews, see: (a) Patil, A.; Patil, O.; Patil, B.; Surana J. Mini-
Rev. Med. Chem. 2011, 11, 633. (b) Connolly, D. J.; Cusack, D.;
O’Sullivan, T. P.; Guiry, P. J. Tetrahedron 2005, 61, 10153.
(4) (a) Xu, L.; Jiang, Y.; Ma, D. Org. Lett. 2012, 14, 1150. (b) Ma, B.;
Wang, Y.; Peng, J.; Zhu, Q. J. Org. Chem. 2011, 76, 6362. (c) Giri, R.;
Lam, J. K.; Yu, J.-Q. J. Am. Chem. Soc. 2010, 132, 686. (d) Liu, X.; Fu,
H.; Jiang, Y.; Zhao, Y. Angew. Chem., Int. Ed. 2009, 48, 348. (e) Zheng,
Z.; Alper, H. Org. Lett. 2008, 10, 829.
(5) For reviews, see: (a) Encyclopedia of Radicals in Chemistry,
Biology and Materials; Chatgilialoglu, C., Studer, A., Eds.; Wiley-VCH:
Weinheim, 2012; Vols. 1 and 2. (b) Radicals in Organic Synthesis; Renaud,
P., Sibi, M. P., Eds.; Wiley-VCH: Weinheim, 2001; Vols. 1 and 2.
^
(6) (a) Larraufie, M.-H.; Courillon, C.; Ollivier, C.; Lacote, E.; Malacria,
M.; Fensterbank, L. J. Am. Chem. Soc. 2010, 132, 4381. (b) Larraufie, M.-H.;
Ollivier, C.; Fensterbank, L.; Malacria, M. Angew. Chem., Int. Ed. 2010, 49,
2178. (c) Beaume, A.; Courillon, C.; Derat, E.; Malacria, M. Chem.;Eur. J.
2008, 14, 1238. (d) Servais, A.; Azzouz, M.; Lopes, D.; Courillon, C.;
Malacria, M. Angew. Chem., Int. Ed. 2007, 46, 576.
r
10.1021/ol4011745
XXXX American Chemical Society

aromatization (Table 1, entry 1), while that with 1,4-benzo-
quinone did not provide any product at all (entry 2). It was
found that oxidation of 1a with PhI(OAc)2 provided quina-
zolinone 2a11 in 29% yield in addition to the formation of
1,2,4-oxadiazole 3a (60% yield) (entry 3). Interestingly,
treatment of 1a with TEMPO resulted in selective formation
of quinazolinone 2a without yielding oxadiazole 3a, although
the reaction rate was very slow (entry 4). It is worthy to note
that heating of 1a in DMSO at 100 °C under an O2 atmo-
sphere rendered the process more efficient for the synthesis of
quinazolinone 2a (entry 5). A higher reaction temperature
(120°C) allowed the aerobic reaction to complete to afford 2a
as a sole product in 73% yield (entry 6). The yield of 2a was
further improved to 84% by conducting the reaction under a
dry air atmosphere (0.21 atm of O2) (entry 7). Screening of
the solvents revealed that DMF and DMA also performed
well for this transformation, while nonpolar solvents such as
toluene did not work at all (entries 8ꢀ10). Heating of 1a in
DMSO at 120 °C under an Ar atmosphere gave 2a only in
2% yield with recovery of 1a (entry 11).
Scheme 1. Free-Radical Approaches to Quinazolinones
Scheme 2. Oxidative Generation of Iminyl Radicals A from 1
Table 1. Optimization of Reaction Conditionsa
yield (%)b
Our reaction design was guided by the potential of
tin-free radical-mediated molecular transformation.7
In this context, oxidative radical skeletal rearrangement
of 5-aryl-4,5-dihydro-1,2,4-oxadiazoles 1 into quinazoli-
nones 2 was envisioned via the iminyl radical intermedi-
ates A (Scheme 2). For generation of iminyl radicals A,
two possible scenarios were speculated upon: (path a) via
single-electron oxidation of 1 followed by homolytic
NꢀO bond cleavage of the resulting cation radical and
subsequent deprotonative CdO bond formation to gen-
erate iminyl radical A; (path b) via H radical abstraction
with an external radical source (X•) and subsequent homo-
lytic NꢀO bond cleavage8 to give iminyl radical A. The
resulting iminyl radical A then undergoes radical addition
onto the intramolecular aryl moiety,9 which is followed by
oxidative aromatization to afford quinazolinones 2.10
With our hypothesis depicted in Scheme 2, we commenced
our investigation with the reactions of dihydrooxadiazole 1a
using a series of oxidants. The reaction of 1a with DDQ in
DMSO at 100 °C gave no desired quinazolinone 2a but
oxadiazole 3a exclusively in 82% yield via debenzylation and
oxidant
(equiv)
temp time
entry
solvent
(°C)
(h)
2a
3a
1
DDQ (2)
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
100
100
100
100
100
120
120
120
120
110
120
0.3
24
20
48
47
28
28
32
32
21
24
0
82
0
2
BQ (2)
0 (85)c
29
16 (76)c
47 (41)c
73
3
PhI(OAc)2 (2)
TEMPO (3)
O2 (1 atm)
O2 (1 atm)
60
0
4
5
0
6
0
7
dry air (1 atm) DMSO
84
0
8
dry air (1 atm)
dry air (1 atm)
dry air (1 atm)
ꢀ
DMF
81
0
9
DMA
76
0
10
11d
toluene
DMSO
0 (95)c
2 (83)c
0
0
a The reactions were carried out using 0.3 mmol of 1a in solvents (0.1 M).
b Isolated yields. c Recovery yield of 1a. d The reaction was conducted under
an Ar atmosphere. Bn = benzyl; DDQ = 2,3-dichloro-5,6-dicyano-
p-benzoquinone; BQ = p-benzoquinone; TEMPO = 2,2,6,6-tetra-
methylpiperidine 1-oxyl.
The scope of the quinazolinone synthesis was next
explored with the optimized aerobic reaction conditions
(Scheme 3).12 By varying the substituent R1, both electron-
rich and -deficient benzene rings (2bꢀd) as well as nitrogen-
heteroaromatic (pyridyl and indolyl) motifs (2eꢀf) could be
installed. Moreover, primary and secondary alkyl groups
were tolerated in the present process (2gꢀh). Instead of a
benzyl group as R2, the 4-methoxybenzyl group (2i) and
(7) For reviews on tin-free radical reactions, see: (a) Renaud, P.
Chimia 2012, 66, 361. (b) Kim, S.; Kim, S. Bull. Chem. Soc. Jpn. 2007,
80, 809. (c) Quiclet-Sire, B.; Zard, S. Z. Chem.;Eur. J. 2006, 12, 6002.
(8) (a) Forrester, A. R.; Gill, M.; Meyer, C. J.; Sadd, J. S.; Thomson,
R. H. J. Chem. Soc., Perkin Trans. 1 1979, 606. (b) Perkins, M. J.;
Roberts, B. P. J. Chem. Soc., Perkin Trans. 2 1975, 77.
(9) For reviews on NꢀC bond formation with nitrogen-centered
radicals, see: (a) Zard, S. Z. Chem. Soc. Rev. 2008, 37, 1603. (b) Fallis,
A. G.; Brinza, I. M. Tetrahedron 1997, 53, 17543 and references therein.
(10) Curran, D. P.; Keller, A. I. J. Am. Chem. Soc. 2006, 128, 13706.
(11) For assigments of the structures of 2a, 2s0, 2t, 2u, 2v, 2w, 4w, and
5w by X-ray crystallographic analysis, see the SI.
(12) See the SI for preparation of 1.
B
Org. Lett., Vol. XX, No. XX, XXXX

several benzene rings (2jꢀ2l) could be installed. It is note-
worthy that the reaction of 1m bearing a hydrogen atom as
R2 also proceeded very smoothly to give quinazolinone 2m
in 77% yield without forming 1,2,4-oxadiazole. Facile con-
struction of polycyclic quinazolinone 2n could be achieved
by the present strategy. As the substituents R3 on the
aminated benzene ring, both electron-donating (2o) and
-withdrawing (2p) groups at the para position were tolerated
while the substrate bearing a CꢀBr bond provided a mod-
erate yield (2q, 50%). In the case of substrates 1r and 1s
bearing a meta-substituted benzene ring, regioisomeric mix-
tures were obtained where the sterically hindered CꢀH bond
was preferentially aminated (marked in green) to provide 2r
yield along with the unexpected formation of quinazoli-
none 2r in 18% yield (Scheme 4a). Similarly, 4-pyridyl
substrate 1w led to the formation of not only the desired
quinazolinone 2w but also another regioisomeric quina-
zolinone 4w and 3-(4-pyridiylimino)isoindolinone 5w in
28, 13, and 26% yields, respectively (Scheme 4b). The
unexpected formation of 2r from 1v as well as 4w and 5w
from 1w could be rationalized by the presence of car-
bamoyl radical II that might be generated by aryl group
migration (path b) via attack of putative iminyl radical I to
the ipso-carbon (marked in purple).13,14 The resulting
carbamoyl radical II could add to the migrated aryl
moiety to afford 2r or 4w, while its addition to the phenyl
part could generate iminoisoindolinone 5w.
Scheme 3. Substrate Scopea
Scheme 4. Reactions of 1v and 1w
To further demonstrate the potential utility of this aer-
obic method, concise syntheses of biologically active
compounds bearing the quinazoline core were carried
out from readily available starting materials. An indolo-
quinazoline alkaloid, 2-methoxy-13-methyl-rutaecarpine
(9), was isolated from the stem bark of an African ever-
green tree, Araliopsis tabouensis, and exhibited significant
antimalarial activity.15 Indolyl imino methylthioether16
was converted into amidoxime 7 with hydroxylamine
(Scheme 5). Upon simple filtration and evaporation of
a Unless otherwise noted, the reactions were carried out using
0.3 mmol of 1 in DMSO (0.1 M) at 120 °C under a dry air atmosphere
for 5.5ꢀ48 h. b Isolated yields. c The reaction was conducted at 100 °C for
2 h. d Synthesis of 2n was conducted starting from 3,4-dihydroisoquino-
line-1(2H)-thione via formation of amidoxime, acetal exchange with
benzaldehyde dimethyl acetal, and aerobic quinazolinone formation (see
the Supporting Information (SI) for more details).
(13) Malacria et al. also observed the formation of the regioisomeric
quinazolinone from the substrate bearing a 3-pyridyl group as the iminyl
radical acceptor and investigated the possible reaction pathways by
theoretical studies; see ref 6c and 6d.
(14) The similar aryl group migration by the reaction of the iminyl
moiety was observed; see: (a) Chiba, S.; Zhang, L.; Lee, J.-Y. J. Am.
Chem. Soc. 2010, 132, 7266. (b) McNab, H.; Smith, G. S. J. Chem. Soc.,
Perkin Trans. 1 1984, 381 and references therein.
and 2s, respectively. From the reaction of 1t with a 2-naphthyl
moiety, only quinazolinone 2t formed via amination on the
R-carbon of the naphthyl moiety (marked in green) could be
isolated, although the yield was moderate. Similarly, cycliza-
tion with a 5-indolyl moiety was observed only at its C(4)
(marked in green) to afford 2u in 40% yield.
(15) Christopher, E.; Bedir, E.; Dunbar, C.; Khan, I. A.; Okunji,
C. O.; Schuster, B. M.; Iwu, M. M. Helv. Chim. Acta 2003, 86, 2914.
The reaction of substrate 1v bearing a 2-methylphenyl
moiety provided the desired quinazolinone 2v in 54%
(16) Hamid, A.; Elomri, A.; Daıch, A. Tetrahedron Lett. 2006, 47, 1777.
¨
Org. Lett., Vol. XX, No. XX, XXXX
C

not only serves as an atom- and step-economical alter-
native to existing synthetic methods but also allows facile
construction of quinazolinone cores under tin-free aero-
bic radical conditions. We are currently engaged in
further synthetic applications of this aerobic radical
strategy for other types of molecular transformations.
Scheme 5. A Synthesis of 2-Methoxy-13-methyl-rutaecarpine (9)
Scheme 6. A Synthesis of Ispinesib Precursor 16
the reaction mixture, the residue including 7 was further
treated with 4-anisaldehyde dimethylacetal in the pre-
sence of a catalytic amount of TsOH in DMSO to afford
dihydro-1,2,4-oxadiazole 8. Successive aerobic treatment
of 8 just by changing the reaction atmosphere to dry air
smoothly delivered 2-methoxy-13-methyl-rutaecarpine
(9) in 62% yield from 6 via simple operations without
purification of intermediates 7 and 8.
Ispinesib (17)17 is an inhibitor of kinesin spindle protein
(KSP), which is currently being evaluated under several
phase II and I clinical trials for cancer therapies. Optically
active alcohol 10 prepared from L-valine18 was oxidized to
R-phthalimidyl aldehyde 11 through Swern oxidation
(Scheme 6). Conversion of aldehyde 11 to oxime 12 followed
by treatment of 12 with NCS delivered C-chlorooxime, which
was coupled with aldimine 13 via [3 þ 2]-cycloaddition in the
presence of Et3N to afford 4,5-dihydro-1,2,4-oxadiazole 14 as
a 1:1 diastereomixture. Aerobic treatment of each isomer of
14 afforded quinazolinone 15 in 62% and 50% yields, in
which partial racemization was observed (87% ee each).19
Further deprotection of the phthalimido moiety of 15
with hydrazine delivered amine 16, the key precursor of
Ispinesib (17).
Acknowledgment. This work was supported by fund-
ing from Nanyang Technological University and the
Singapore Ministry of Education (Academic Research
Fund Tier 2: MOE2012-T2-1-014). Y.-F.W. is thankful for
the Lee Kuan Yew postdoctoral fellowship. We thank Dr.
Yongxin Li and Dr. Rakesh Ganguly (Division of Chem-
istry and Biological Chemistry, School of Physical and
Mathematical Sciences, Nanyang Technological University)
for assistance in X-ray crystallographic analysis.
In summary, we have developed an unprecedented
oxidative radical skeletal rearrangement of 5-aryl-4,5-
dihydro-1,2,4-oxadiazoles induced by molecular oxygen
that enables concise assembly of substituted quinazoli-
nones with the simple operation.20 The present strategy
ꢀ
ꢀ
(17) Sorbera, L. A.; Bolos, J.; Serradell, N.; Bayes, M. Drugs of the
Future 2006, 31, 778.
(18) Carocci, A.; Catalano, A.; Corbo, F.; Duranti, A.; Amoroso, R.;
Franchini, C.; Lentini, G.; Tortorella, V. Tetrahedron: Asymmetry 2000,
11, 3619.
(19) The stereochemistry of each diastereomer 14 was not deter-
mined. Interestingly, the aerobic reaction of a mixture of diastereomers
14 was very sluggish, giving 15 in 29% yield (48 h).
(20) A deuterium-labeling experiment suggested that the CꢀH bond
cleavage step is most likely rate-determining for the present quinazoli-
none formation; see the SI for mode details.
Supporting Information Available. Experimental pro-
cedures, characterization of new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX