Transition-metal-catalyzed uninterrupted four-step sequence to access trisubstituted isoxazoles

Article abstract of DOI:10.1021/ol202719n

We describe herein a novel uninterrupted four-step sequence to access trisubstituted isoxazoles from readily available propargylic alcohols using sequentially iron and palladium catalytic systems. The advantages of such a strategy are illustrated by the high overall yields and the time-saving procedure that are reported.

Full text of DOI:10.1021/ol202719n

ORGANIC
LETTERS
2011
Vol. 13, No. 24
6418–6421
Transition-Metal-Catalyzed Uninterrupted
Four-Step Sequence to Access
Trisubstituted Isoxazoles
ꢀ
ꢀ
Eric Gayon, Ophelie Quinonero, Sebastien Lemouzy, Emmanuel Vrancken,* and
Jean-Marc Campagne*
Institut Charles Gerhardt UMR 5253 CNRS-UM2-UM1-ENSCM, 8 rue de l’Ecole
Normale, 34296 Montpellier Cedex 5, France
emmanuel.vrancken@enscm.fr; jean-marc.campagne@enscm.fr
Received October 11, 2011
ABSTRACT
We describe herein a novel uninterrupted four-step sequence to access trisubstituted isoxazoles from readily available propargylic alcohols using
sequentially iron and palladium catalytic systems. The advantages of such a strategy are illustrated by the high overall yields and the time-saving
procedure that are reported.
Increasing research efforts are directed toward the de-
velopment of new methodologies with high synthetic
efficiency and atom economy. To achieve this goal, syn-
thetic chemists have shown great interest for one-pot,
multistep sequences of reactions, due to the inherent effi-
ciency of avoiding operations of isolation and purification
of intermediates generated from traditional iterative syn-
thetic methods.1 Clarke et al. recently disclosed the prin-
ciple of “pot economy”, which is defined as the aim “to
complete an entire multi-step, multi-reaction synthesis in a
single pot”.2 On the basis of this concept, Hayashi et al.
have, for instance, reported the synthesis of several drugs
using an “uninterrupted sequence of reactions” strategy
allowing solely the removal of various volatiles by distilla-
tion: reactive wastes, excess of reagents, solvents, etc.3 In
this communication, we report our efforts to build up an
uninterrupted multistep, one-pot sequence to obtain fully
substituted isoxazoles from readily available propargylic
alcohols using Fe and Pd catalysts.
Isoxazoles exert interesting biological activities and
are core components of many pharmaceutically valuable
compounds.4 Typical regio- and chemoselective syntheses
of 3,4-diarylisoxazoles consist of a stepwise approach
based on a palladium-catalyzed cross-coupling between a
preformed (and purified) 4-iodo-,5 4-silicon-,6 or 4-boron-
isoxazole derivative7 and the appropriate aryl coupling
partner.8 We recently described a Fe(III)-catalyzed one-
pot synthesis of 3,5-disubstituted isoxazolines and isoxa-
zoles from propargylic alcohols 1 via N-protected propar-
gyl hydroxylamines as key intermediates.9 Our next move
(4) (a) Sperry, J.; Wright, B. Curr. Opin. Drug Discovery Dev. 2008, 8,
723. (b) Giomi, D.; Cordero, F.; Machetti, F. In Comprehensive Hetero-
cyclic Chemistry III; Katriski, A. R., Ramsden, C. A., Scriven, E. F. V.,
Taylor, R. J. K., Joule, J., Eds.; Elsevier: Oxford, U.K., 2008; Vol. 4, p 365.
(c) Sutharchanadevi, M. In Comprehensive Heterocyclic Chemistry II;
Katriski, A. R., Rees, A. R., Scriven, E. F. V., Shinkai, I., Eds.; Elsevier:
Oxford, U.K., 1996; Vol. 3, p 221.
(5) (a) Waldo, J. P.; Larock, R. C. Org. Lett. 2005, 7, 5203. (b) Waldo,
J. P.; Larock, R. C. J. Org. Chem. 2007, 72, 9643. (c) Crossley, J. A.;
Browne, D. L. J. Org. Chem. 2010, 75, 5414. (d) Waldo, J. P.; Metha, S.;
Neuenswander, B.; Lushington, G. H.; Larock, R. C. J. Comb. Chem.
2008, 10, 658. (e) Okitsu, T.; Potewar, T. M.; Wada, A. J. Org. Chem.
2011, 76, 3438.
(6) Denmark, S. E.; Kallemeyn, J. M. J. Org. Chem. 2005, 70, 2839.
(7) (a) Davies, M. W.; Wybrow, R. A. J.; Johnson, C. N.; Harrity,
J. P. A. Chem. Commun. 2001, 1558. (b) Kumar, J. S. D.; Ho, M. M.;
Leung, J. M.; Toyokuni, T. Adv. Synth. Catal. 2002, 344, 1146.
(c) Moore, J. E.; Davies, M. W.; Goodenough, K. M.; Wybrow,
R. A. J.; York, M.; Johnson, C. N.; Harrity, J. P. A. Tetrahedron
2005, 61, 6707.
(1) For a recent highlight on this topic, see: Vaxelaire, C.; Winter, P.;
Christmann, M. Angew. Chem., Int. Ed. 2011, 50, 2.
(2) Clarke, P. A.; Santos, S.; Martin, W. H. C. Green Chem. 2007, 9,
438.
(3) (a) Ishikawa, H.; Suzuki, T.; Hayashi, Y. Angew. Chem., Int. Ed.
2009, 48, 1304. (b) Ishikawa, H.; Suzuki, T.; Orita, H.; Uchimaru, T.;
Hayashi, Y. Chem.;Eur. J. 2010, 16, 12616. (c) Ishikawa, H.; Honma,
M.; Hayashi, Y. Angew. Chem., Int. Ed. 2011, 50, 2824.
r
10.1021/ol202719n
Published on Web 11/18/2011
2011 American Chemical Society

was to develop an efficient and selective one-pot strategy to
access trisubstituted 3,4-diarylisoxazoles from 1. We an-
ticipated that the introduction of another aryl group (Ar2)
could be performed through an annulation/cross-coupling
reaction that could ideally be followed, in the same se-
quence, by the removal of the nitrogen protecting group to
lead to trisubstituted isoxazoles 5 (Scheme 1). Whereas the
direct propargylic alcohol substitution by N-protected
hydroxylamine to give 2 is now well-precedented, the cru-
cial step in this sequence appears to be the annulation/
cross-coupling reaction. We envisioned that an in situ
generated electrophilic arylÀpalladium(II) complex would
allow the activation of the triple bond, and the resulting
vinylic organopalladium intermediate would undergo a
reductive elimination to provide the trisubstituted isoxazo-
line 3. In this sequence, the presence of a palladium com-
plex could be advantageously exploited for protecting
group removal (Scheme 1, PG = Cbz), to give isoxazoline
4, which could undergo an aerobic aromatization to yield
isoxazole 5 (Scheme 1).
in situ generated arylÀpalladium complexes for the con-
struction of 2,3-disubstituted benzofuran derivatives, in
moderate yields.11 More recently, Yang et al. revisited this
methodology and use a Pd(0)/bipyridine complex as the
catalytic system, to allow for the efficient preparation of
various 2,3-diarylbenzo[b]furans.12,13
Under Yang conditions [PhI (2 equiv), Pd2(dba)3
(5 mol %), bipyridine (bpy, 10 mol %), and K2CO3 (4 equiv)
in freshly distilled CH3CN under an argon atmosphere], 2a
was converted selectively to isoxazoline 3a in a 85%
isolated yield after 72 h at 50 °C (see Table 1, entry 1).
Heating the reaction mixture to reflux had a detrimental
effect, yielding 3a along with two new products whose
structures have been assigned to the disubstituted isoxazo-
line 6a and the enone 7a (3a/6a/7a: 4/1/1 ratio, entry 2).
Some complementary experiments have been carried out
to better understand the formation of these side products.
When 2a was heated at 50 °C over 20 h in CH3CN with
K2CO3 (4 equiv) in the absence of a palladium catalyst,
enone 7a was cleanly obtained in 89% isolated yield with
no detectable amount of 6a in the crude mixture (entry 3).
Moreover, no reaction occurred when 6a was submitted to
the same reaction conditions [K2CO3 (4 equiv), CH3CN,
50 °C, 20 h], which indicates that (1) 7a is formed through a
palladium-free process, (2) 6a is not an intermediate
product of 7a, and (3) K2CO3 itself is not able to promote
the formation of 6a.14 Intriguingly, when 2a was submitted
to Pd2(dba3)/bpy and K2CO3 at 50 °C without PhI, 6a was
obtained as the main product (73% yield), along with low
traces of enone 7a (7%, entry 4), showing that 6a is
generated through a Pd(0)-catalyzed process. We thus
investigated the influence of the nature of the palladium
ligands (L) on the course of the transformation. Moving to
Pd(PPh3)4 results in the formation of disubstituted isoxa-
zoline 6a as the major compound and enone 7a in the
presence (or not) of PhI in the reaction mixture (entries 5
and 6). We next examined the role of the base and noticed
that no reaction occurred when Pd(PPh3)4 or Pd2dba3/bpy
were used in the absence of K2CO3 or when DMAP,
imidazole (Imd), or propylene oxide15 were used as a base
or scavenger with Pd2(dba3)/bpy (entries 7À11). However,
Et3N can be employed instead of K2CO3 with the Pd2-
(dba3)/bpy catalytic system without significant impact on
the yield of 3a (entry 12). The presence of a base with
pKa > 10 appears to be necessary for the annulation process.
Scheme 1. Annulation/Cross-Coupling and Deprotection
Strategy
First, our objective was to validate the palladium-
catalyzed annulation/cross-coupling key step using 2a
(PG = Cbz, R = nBu, Ar1 = p-tol) as a model com-
pound.10 Arcadi et al. disclosed the first example of an
annulation/cross-coupling cascade reaction promoted by
(8) For selected examples of isoxazole synthesis by other methods,
see: (a) Talley, J. J.; Brown, D. L.; Carter, J. S.; Graneto, M. J.; Koboldt,
C. M.; Masferrer, J. L.; Perkins, W. E.; Rogers, R. S.; Shaffer, A. F.;
Zhang, Y. Y.; Zweifel, B. S.; Seibert, K. J. Med. Chem. 2000, 43, 775.
(b) Di Nunno, L.; Vitale, P.; Scilimati, A.; Tacconelli, S.; Patrignani, P.
J. Med. Chem. 2004, 47, 4881. (c) Ueda, M.; Sato, A.; Ikeda, Y.; Miyoshi,
T.; Naito, T.; Miyata, O. Org. Lett. 2010, 12, 2594. (d) Burhard, J. A.;
Tchitchanov, B. H.; Carreira, E. M. Angew. Chem., Int. Ed. 2011, 50,
5379. (e) Jackowski, O.; Lecourt, T.; Micouin, L. Org. Lett. 2011, 13,
5664.
(11) Arcadi, A.; Cacchi, S.; Del Rosario, M.; Fabrizi, G.; Marinelli,
F. J. Org. Chem. 1996, 61, 9280.
(12) Hu, Y.; Nawoschik, K. J.; Liao, Y.; Ma, J.; Fathi, R.; Yang, Z.
J. Org. Chem. 2004, 69, 2235.
(13) For an application of this strategy to the synthesis of indolizi-
none, see: Kim, I.; Kim, K. Org. Lett. 2010, 12, 2500.
(9) (a) Debleds, O.; dal Zotto, C.; Vrancken, E.; Campagne, J. M.
Adv. Synth. Catal. 2009, 351, 1991. (b) Gayon, E.; Debleds, O.; Nicouleau,
M.; Lamaty, F.; Vand der Lee, A.; Vrancken, E.; Campagne, J. M. J.
Org. Chem. 2010, 75, 6050. (c) Debleds, O.; Gayon, E.; Ostaszuk, E.;
Vrancken, E.; Campagne, J. M. Chem.;Eur. J. 2010, 16, 12207.
(d) Debleds, O.; Gayon, E.; Vrancken, E.; Campagne, J. M. Beilstein
J. Org. Chem. 2011, 7, 866.
(10) 2a is easily obtained in good isolated yield (91%) by refluxing 1a
and CbzNHOH in the presence of FeCl3 (10 mol %) in DCM according
to the Zhan et al procedure: Zhan, Z.-P.; Yu, J.-L.; Liu, H.-J.; Cui,
Y.-Y.; Yang, R.-F.; Yang, W.-Z.; Li, J.-P J. Org. Chem. 2006, 71, 8298–
8301.
(14) The obtention of analogues of 7a through the NÀO bond
cleavage of isoxazolines has already been described: (a) Lopez-Callen,
E.; Keller, M.; Eberbach, W. Eur. J. Org. Chem. 2003, 1438. (b) Lager,
€
M.; Dietrich, D.; Weinrich, D.; Ruck-Braun, K. Heterocycles 2007, 74,
743. To the best of our knowledge, the direct transformation of
propargylic hydroxylamines to enones is unknown.
(15) (a) Moreau, X.; Campagne, J.-M. J. Organomet. Chem. 2003,
687, 322. (b) Moreau, X.; Campagne, J.-M.; Meyer, G.; Jutand, A. Eur.
J. Org. Chem. 2005, 3749. (c) Tong, Z.; Gao, P.; Deng, H.; Zhang, L.;
Xu, P.; Zhai, H. Synlett 2008, 3239.
Org. Lett., Vol. 13, No. 24, 2011
6419

Table 1. Palladium-Catalyzed Annulation/Cross-Coupling Sequence (Product Distribution and Conditions)
entry
catalytic system
ArX (2 equiv)
additive (4 equiv)
temperature and time
3a/6a/7a (yield, %)a
1
2
Pd2dba3 (5 mol %), bpy (10 mol %)
Pd2dba3 (5 mol %), bpy (10 mol %)
none
PhI
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
none
50 °C, 72 h
Reflux, 1 h
50 °C, 20 h
50 °C, 20 h
50 °C, 20 h
50 °C, 20 h
50 °C, 72 h
50 °C, 72 h
50 °C, 72 h
50 °C, 72 h
50 °C, 72 h
50 °C, 40 h
50 °C, 40 h
50 °C, 20 h
1/0/0 (85/-/-)
4/1/1 (33/5/13)
0/0/1 (-/-/89)
0/9/1 (-/73/7)
0/3/1 (-/58/19)
0/1.5/1 (-/41/30)
no reaction
PhI
3
none
none
PhI
4
Pd2dba3 (5 mol %), bpy (10 mol %)
Pd(PPh3)4 (10 mol %)
5
6
Pd(PPh3)4 (10 mol %)
none
PhI
7
Pd(PPh3)4 (10 mol %)
8
Pd2dba3 (5 mol %), bpy (10 mol %)
Pd2dba3 (5 mol %), bpy (10 mol %)
Pd2dba3 (5 mol %), bpy (10 mol %)
Pd2dba3 (5 mol %), bpy (10 mol %)
Pd2dba3 (5 mol %), bpy (10 mol %)
Pd2dba3 (5 mol %), bpy (10 mol %)
Pd2dba3 (10 mol %), bpy (20 mol %)
PhI
none
no reaction
9
PhI
DMAP
Imd
no reaction
10
11
12
13
14
PhI
no reaction
PhI
propylene oxide
Et3N
no reaction
PhI
1/0/0 (75/-/-)
0/4.5/1 (-/50/11)
1/0/0 (86/-/-)
PhBr
PhI
K2CO3
K2CO3
a Isolated yield.
Some observations can be brought forward from this
first study: In this transformation, three different path-
ways, respectively, leading to 3a, 6a, and 7a are in competi-
tion. Among them, the oneleadingtoenone7aispromoted
byK2CO3 and appearstobetheslowestone. Thetwo other
reaction pathways are Pd-catalyzed, and both lead to
annulation products: the disubstituted isoxazoline 6a with
Pd(0) and the trisubstituted 3a with Pd(II). The rate
difference between these two processes strongly depends
on the nature of the ligand. With PPh3, the Pd(0) way is
faster than the Pd(II) one, although the oxidative addition
(OA) step into the ArÀI bond is known to occur easily
under these reaction conditions. In strong contrast, the
Pd(II) way is preferred when using bpy. It is worth noting
that the use of PhBr instead of PhI in the Yang conditions
leads to the exclusive formation of 6a (entry 13). Surpris-
ingly, Pd(0) appears to be able to activate a triple bond
toward an internal nucleophile, whereas Pd(II) sources are
generally used for the π-activation of double/triple CÀC
bonds. In some particular cases during this study, the cata-
lytic cycle using Pd(0) appears to be more efficient than the
corresponding Pd(II) one (compare entries 1, 5, and 6).16
Nevertheless, under Yang conditions, 3a can be selec-
tively obtained and the reaction time can be shortened by
increasing the amount of Pd2dba3 to 10 mol %, leading to
3a in 86% isolated yield (entry 14) over 20 h. For practical
reasons, these conditions were thus chosen as standard
reaction conditions for the rest of this study.
Scheme 2
With these conditions in hand, we next turned our atten-
tion to the development of a one-pot direct propargylic
alcohol substitution/annulation/cross-coupling sequence:
1a f [2a] f 3a. Initial attempts to promote direct forma-
tion of 3a from 1a in the presence of a Pd(II) catalyst were
unsuccessful with full recovery of the starting material.
We then envisoned that the use of FeCl3 would first pro-
mote the propargylic substitution.9,10 1a and CbzNHOH
were thus treated by FeCl3 (5 mol %) in CH3CN at 60 °C.
After complete conversion of 1a to 2a (as judged by
TLC),17 PhI, Pd2(dba)3, K2CO3, and bpy were added
and the reaction was heated at 50 °C over 20 h. Gratify-
ingly, 3a was selectively obtained in a 86% isolated yield,
(16) (a) Pd(II) complexes are generally used for the activation of π
systems; see: Cacchi, S.; Arcadi, A. In Handbook of Organopalladium
Chemistry for Organic Synthesis; Negishi, E. I., Ed.; Wiley-Interscience:
New York, 2002; Vol. 2, p 2193. (b) For a rare study on the possible use of
Pd(0) in this type of reaction, see: Ahlquist, M.; Fabrizi, G.; Cacchi, S.;
Norrby, P.-O. Chem. Commun. 2005, 4196–4198.
(17) For a paper dealing with the association of Pd and Fe in a
catalytic process, see: Terrasson, V.; Michaux, J.; Gaucher, A.; Wehbe,
J.; Marque, S.; Prim, D.; Campagne, J.-M. Eur. J. Org. Chem. 2007,
5332.
6420
Org. Lett., Vol. 13, No. 24, 2011

overall benefits of performing an uninterrupted se-
quence of reactions for the general efficiency of this
transformation.
Scheme 3. a,b,c
We next studied the scope and limitations of this 4-step
sequence, with regard to variously substituted aryl iodides
and propargylic alcohols. Using our optimized conditions
(Scheme 3), the reaction proceeds cleanly and isoxazoles
5bÀ5i were obtained in good-to-excellent yields no matter
the nature of the substituent on the Ar2 group (Scheme 3).
Electron-withdrawing or electron-donating groups are
well-tolerated. Interestingly, the presence of an orthogonal
bromide at the para position of Ar2 is allowed (see
compound 5g), despite the use of the palladium catalyst,
which potentially allows for further functionalization.
Using 2-iodothiophene, isoxazole 5i was obtained in a
modest 40% overall yield (80% per step), which may be
partially explained by the intrinsic instability of 4i. The
main limitation was observed when starting from pro-
pargylic alcohols bearing a phenyl group on the acetylenic
position (R = Ph). Only the corresponding diaryl enone
1
could be observed by H NMR analysis of the crude
reactions mixtures. In this case, these highly conjugated
compounds are formed faster than the usual cyclization
product.
In conclusion, we have developed an access to trisub-
stituted isoxazoles from readily available propargylic
alcohols through a one-pot substitution/annulation/
cross-coupling/hydrogenolysis/oxidation uninterrupted
sequence. This approach is solvent- and time-saving since
no intermediate workups or purification operations are
needed. High overall yields in the formation of various
fully substituted isoxazoles are thus granted by this opera-
tional simplicity and by the high efficiency of each indivi-
dual step (nine examples, up to 84% overall yield).
Interestingly, the palladium source mediates most of the
processes of the synthetic sequence. Finally, we have also
observed an unusual, ligand-controlled Pd(0)/Pd(II) com-
petition in the π-activation of disubstituted triple bonds.
This offers interesting perspectives for the development of
new domino sequences, and applications are currently
underway.
a Isolated yield. b Yields in parentheses are average yields per step.
c p-Bromonitrobenzene was used as aryl halide.
identical to the one observed when starting from 2a
(Scheme 2).
With these encouraging results, we next screenedvarious
conditions to develop a one-pot, four-step sequence to
access the trisubstituted isoxazoles 5 (Scheme 3). The
hydrogenolysis of the Cbz can be performed directly after
the previous sequence by addition of a H2 balloon, pro-
vided that the acetonitrile is removed under vacuum with
no particular precautions and replaced by MeOH.18 After
2 h atroom temperature (TLC monitoring), the H2 balloon
was removed and the reaction mixture was stirred for 6 h at
60 °C under an air atmosphere. Isoxazole 5a was then
obtained in 84% isolated yield from 1a in a one-pot, 4-step
uninterrupted sequence (Scheme 3), which represents an
average yield of 96% per step. This average yield is greater
than the yield observed for the sole Pd-catalyzed annulation/
cross-coupling reaction from 2a to 3a, illustrating the
Acknowledgment. The authors deeply acknowledge
Drs. Eric Leclerc and Benoit Liegault (ENSCM) for their
help in the preparation of this manuscript. We also thank
MESR (E.G. Ph.D. grant) and the Ecole Nationale
ꢀ
Superieure de Chimie de Montpellier.
Supporting Information Available. Experimental pro-
cedure and characterization data for all starting materials
and products. This material is available free of charge via
the Internet at http://pubs.acs.org.
(18) Alternative solvents (AcOEt, MeNO2, DMF...) for the whole
sequence, that is, able to promote the substitution/cyclization and the
hydrogenolysis steps, were also examined but did not lead to any
satisfactory results.
Org. Lett., Vol. 13, No. 24, 2011
6421