Direct synthesis of polysubstituted aluminoisoxazoles and pyrazoles by a metalative cyclization

Article abstract of DOI:10.1021/ol202389u

Alumino-heteroles are obtained from simple precursors in a fully chemo- and regioselective manner by a metalative cyclization. The carbon-aluminum bond is still able to react further with several electrophiles, without the need of transmetalation. This sy

Full text of DOI:10.1021/ol202389u

ORGANIC
LETTERS
2011
Vol. 13, No. 20
5664–5667
Direct Synthesis of Polysubstituted
Aluminoisoxazoles and Pyrazoles by a
Metalative Cyclization
Olivier Jackowski, Thomas Lecourt, and Laurent Micouin*
ꢀ
UMR8638, CNRS-Paris Descartes University, Faculte de Pharmacie,
4 av. de l0Observatoire, 75006 Paris, France
Laurent.micouin@parisdescartes.fr
Received September 4, 2011
ABSTRACT
Alumino-heteroles are obtained from simple precursors in a fully chemo- and regioselective manner by a metalative cyclization. The carbonꢀaluminum
bond is still able to react further with several electrophiles, without the need of transmetalation. This synthetic route provides a novel entry to
heterocyclic organoaluminum reagents as well as a straightforward access to 3,4,5-trisubstituted isoxazoles and 1,3,4,5-tetrasubstituted pyrazoles.
The preparation of main-group aryl and heteroaryl
organometallics is a very active field, as these reagents
are key intermediates in diversity-oriented elaboration of
compounds for pharmaceutical and material science appli-
cations.1 In this context, the preparation of aryl- or hetero-
cyclic organoaluminum reagents has gained a renewed in-
terest, due to their potential broad functional tolerance2
and the low cost and toxicity of alanes.3
various aluminum(III) sources,4 or in some cases trough
aluminumꢀtin or boron exchange reactions.5 However,
the transmetalation pathway, generally conducted at low
temperature from reactive organolithium reagents,6 gen-
erates salts as side products. These salts have been reported
to strongly affect the reactivity7 of the final organoalumi-
num reagent and the enantioselectivity of asymmetric pro-
cesses.8 This procedure is very often conducted in ethereal
solvents, known to strongly decrease the Lewis acidity of
organoaluminum reagents and, therefore, to affect their
reactivity. Finally, the potential functional group tolerance
of the carbonꢀaluminum bond cannot be exploited if
A conventional preparative method for aromatic orga-
noaluminum compounds has been the transmetalation of
the corresponding lithium or magnesium derivatives with
(1) (a) Handbook of Functionnalized Organometallics; Knochel, P.,
Ed.; WILEY-VCH: Weinheim, 2005. (b) Chinchilla, R.; Najera, C.; Yus, M.
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(3) Although organoaluminum reagents are usually regarded as
hazardous reagents, their pyrophoric character is mainly a problem
with low-molecular weight reagents, such as trimethylaluminum, and is
drastically reduced when working with diluted solutions in hydrocar-
bons. The nonpyrophoric limits for trimethylaluminum are 11 wt% in
hexane and 14 wt% in heptane: (a) Suzuki, K.; Nagasawa, T. In
Encyclopaedia of Reagents for Organic Synthesis; Paquette, L. A., Ed.;
John Wiley &Sons Ltd: Chichester, 1995; Vol. 7, p 5186. Thus, a commer-
cially available 2 M solution of trimethylaluminum in heptane can be
handled like a commercially available MeLi or BuLi solution. This is
confirmed by comparable safety data sheet hazards identification
according to EC regulations between these reagents. In this work, we
only used commercially available 2 M solutions of trimethylaluminum.
For a discussion on this problem, see also: Von Zezschwitz, P. Synthesis
2008, 1809.
€
(5) (a) Eisch, J. J.; Mackenzie, K.; Windisch, H.; Kruger, C. Eur. J.
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(8) (a) Muller, D.; Hawner, C.; Tissot, M.; Palais, L.; Alexakis, A.
€
Synlett 2010, 1694. (b) Hawner, C.; Muller, D.; Gremaud, L.; Felouat,
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r
10.1021/ol202389u
Published on Web 09/26/2011
2011 American Chemical Society

organoaluminum reagents are prepared from the corre-
sponding lithiated or magnesiated derivatives.9
natural products, and functional materials.15 Further-
more, access to these structures from alkynyloxime using
catalytic16 or stoichiometric electrophilic activation17 is
well documented.
More recently, several alternative procedures, based on
directed metalation10 or oxidative insertion,2 have been
reported, leading to functionalized aromatic organoalumi-
num compounds. However, in most cases, these organo-
metallic reagents must be transmetalated before further
reaction. New alternative routes to aluminated hetero-
cycles are therefore desirable.
Scheme 1. Metalative Cyclization of Oxime 1
In our ongoing work in the field of organoaluminum
chemistry,11 we have reported the preparation of func-
tional aluminotriazoles by a copper catalyzed cycloaddi-
tion of organic azides and mixed aluminum acetylides.12
Herein, we report that aluminated heteroles can be pre-
pared by a tandem addition/intramolecular 5-endo-dig
metalative cyclization mechanism (Figure 1). This kind
of cyclization is well precedented for transition-metal-
catalyzed synthesis of various heterocycles,13 and it has
been shown that a stoichiometric amount of metalated
precursor can lead to metalated benzoheteroles in an
efficient manner.14 However, despite these examples,
such a pathway has never been used to prepare alumi-
nated heterocycles.
Cyclization product 2a was indeed obtained in 92%
yield, starting from compound 1 in the presence of 2 equiv
of trimethylaluminum (Scheme 1). However, only partial
(60%) deuterium incorporation was observed. This mod-
est deuterium incorporation can be explained by a compe-
titive in situ protonation of the aluminated intermediate.18
In order to avoid this troublesome side reaction, we de-
cided to generate the metalated precursor directly from
nitrile oxide 3. Although nitrile oxides are not considered
as electrophiles, complexation to aluminum reagents could
increase their electrophilicity and decrease their dipole re-
activity,asalreadynoticedbyKanemasaandco-workers.19
To our delight, 93% deuterated isoxazole 2a was obtained
with 2 equiv of dimethyl-phenylalkynylaluminum20 and
mesitylene carbonitrile oxide, after deuterolysis of the re-
action mixture (Table 1, entry 1). The use of only 1 equiv of
aluminum acetylide led tothe formationof alkynyloxime 1
as a major reaction product (entry 2), showing that exter-
nal electrophilic assistance is required to trigger the cyc-
lization. Thus, addition of 1 equiv of AlMe3 after initial
reaction between nitrile oxide and aluminum acetylide re-
sulted in the clean formation of compound 2a in 76% iso-
lated yield (Table 1, entry 3). Interestingly, even a substo-
ichiometric amount of AlMe3 can assist the reaction, although
20% are needed to achieve a correct conversion (entry 4).
All these experiments support a tandem addition/intra-
molecular 5-endo-dig metalative cyclization mechanism
(Scheme 2).21 Although the role of aluminum π-acidity
is well-known in carbo- and hydroalumination reactions,
and several examples have been reported showing that
Figure 1. General principle of metalated heterocycles synthesis
by a metalative cyclization process.
We first turned our attention to aluminated isoxazoles
synthesis. Isoxazole is indeed a privileged structure encoun-
tered in numerous compounds with biological activities,
(9) The good functional group tolerance of trimethylaluminum is for
instance used in many copper-catalyzed asymmetric transformations, or
in a trimethylaluminum-assisted transformations, where AlMe3 acts as a
nonreactive methyl donor and/or Lewis acid.
(10) (a) Naka, H.; Masanobu, M.; Matsumoto, Y.; Wheatley,
A. E. H.; McPartlin, M.; Morey, J. V.; Kondo, Y. J. Am. Chem. Soc.
2007, 129, 1921. (b) Mulvey, R. E.; Mongin, F.; Uchiyama, M.; Kondo,
Y. Angew. Chem., Int. Ed. 2007, 46, 3802. (c) Wunderlich, S. H.;
Knochel, P. Angew. Chem., Int. Ed. 2009, 48, 1501. (d) Kienle, M.;
Unsinn, A.; Knochel, P. Angew. Chem., Int. Ed. 2010, 49, 4751.
(11) (a) Feuvrie, C.; Blanchet, J.; Bonin, M.; Micouin, L. Org. Lett.
2004, 6, 2333. (b) Wang, B.; Bonin, M.; Micouin, L. Org. Lett. 2004, 6,
3481. (c) Wang, B.; Bonin, M.; Micouin, L. J. Org. Chem. 2005, 70, 6126.
(12) Zhou, Y.; Lecourt, T.; Micouin, L. Angew. Chem., Int. Ed. 2010,
49, 2607.
(17) (a) Waldo, J. P.; Larock, R. C. Org. Lett. 2005, 7, 5203. (b) Waldo,
J. P.; Mehta, S.; Neuenswander, B.; Lushington, G. H.; Larock, R. C.
J. Comb. Chem. 2008, 10, 658.
(13) Nakamura, I.; Yamamoto, Y. Chem. Rev. 2004, 104, 2127.
(14) (a) Nakamura, M.; Ilies, L.; Otsubo, S.; Nakamura, E. Angew.
Chem., Int. Ed. 2006, 45, 944. (b) Nakamura, M.; Ilies, L.; Nakamura, E.
Org. Lett. 2006, 8, 2803. (c) Tsuji, H.; Sato, K.; Ilies, L.; Itoh, Y.; Sato,
Y.; Nakamura, E. Org. Lett. 2008, 10, 2263. (d) Ilies, L.; Tsuji, H.;
Nakamura, E. Org. Lett. 2009, 11, 3966. (e) Yin, Y.; Ma, W.; Chai, Z.;
Zhao, G. J. Org. Chem. 2007, 72, 5731. (f) Yin, Y.; Chai, Z.; Ma, W.-Y.;
Zhao, G. Synthesis 2008, 4036.
(15) Sutharchanadevi, M.; Murugan, R. In Comprehensive Heteter-
ocyclic Chemistry; Katritzky, A. R., Ress, C. W., Scriven, E. F. V., Eds.;
Elsevier: 1996; Vol. 3, p 221.
(16) (a) Praveen, C.; Kalyanasundaram, A.; Perumal, P. T. Synlett
2010, 777. (b) Ueda, M.; Sato, A.; Ikeda, Y.; Miyoshi, T.; Naito, T.;
Miyata, O. Org. Lett. 2010, 12, 2594. (c) Murarka, S.; Studer, A. Org.
Lett. 2011, 13, 2746.
(18) A similar competitive protonation has been observed in a related
metalative cyclization: see ref 14b.
(19) Kanemasa, S.; Kobayashi, S.; Nishiuchi, M.; Yamamoto, H.;
Wada, E. Tetrahedron Lett. 1991, 32, 6367.
(20) Zhou, Y.; Lecourt, T.; Micouin, L Adv. Synth. Catal. 2009, 351,
2595.
(21) NMR monitoring of the reaction with mesitylene carbonitrile
oxide clearly demonstrated the absence of any protonated species
before quenching with deuterium chloride. We also have checked that
no alumination of protonated isoxazole can occur under the reaction
conditions. The isolation of intermediate 1 rules out a concerted mech-
anism involvinga transientmetalacycle, as proposedfor copper-catalyzed
synthesis of isoxazoles: Himo, F.; Lovell, T.; Hilgraf, R.; Rostovtsev,
V. V.; Noodleman, L.; Sharpless, K. B.; Fokin, V. V. J. Am. Chem. Soc.
2005, 127, 210.
Org. Lett., Vol. 13, No. 20, 2011
5665

Table 1. Optimization of the Reaction Conditions
Table 2. Scope of the Reaction: Alkyne
alane
additive
(equiv)
t
t
yield
(%)a
entry
(equiv)
(h)
(°C)
2a/1
1
2
3
4
5
2
1
1
1
1
_
_
4
4
1
4
4
20
20
50
50
50
1/0
2/8
1/0
1/0
1/1
63
b
_
AlMe3 (1)
76
68
AlMe3 (0.2)
AlMe3 (0.1)
b
_
a Isolated yield. b >99% conversion. Yield not determined.
a Isolated yield.
aluminum derivatives can trigger a trans addition on a
triple bond,22 this intramolecular trans-hydroxyalumina-
tion is, to the best of our knowledge, unprecedented.
of several metalated isoxazoles. Interestingly, not only
aromatic but also aliphatic substituted isoxazoles can be
obtained in a fully regioselective manner (Table 3, entry 5).
Table 3. Scope of the Reaction: Oxime
Scheme 2. Proposed Mechanistic Pathway
entry
R
R’
compd
yield (%)a
1
2
3
4
5
4-Cl-Ph
4-Cl-Ph
4-MeO-Ph
Ph
Ph
4a
4b
4c
4d
4e
70
68
53
73
74
nPr
nPr
nPr
nPr
Ph(CH2)2
a Isolated yield.
Optimized experimental conditions were then applied to
a variety of dimethylaluminum alkynides bearing aromatic,
alkyl, chloroalkyl, and alkenyl groups (Table 2). In all the
cases, the 3,5-disubstitued 4-metalated isoxazoles were
obtainedasunique regioisomers, withmorethan94% deu-
terium incorporation at the mechanistically expected 4-
position after deuterolysis.
Variation of the nitrile oxide part was then investigated.
As unhindered nitrile oxides are notoriously unstable,23
the formation of aluminated isoxazoles was attempted
starting from aromatic (Table 3, entries 1ꢀ4) or aliphatic
(Table 3, entry 5) hydroximoyl chlorides. Best results were
obtained using 1 equiv of trimethylaluminum, followed by
1 equiv of mixed acetylides, leading to the clean formation
The reactivity of these new aluminated heterocycles
was explored (Scheme 3). Thus, compounds 5a and 5b
could be obtained by reaction with several N-halosucci-
nimides. Once again, mesitylene carbonitrile oxide proved
to be a valuable electrophile, leading to compound 5c in
65% yield. Introduction of a primary amide functional
group could also be realized using a reagent recently
proposed by Knochel for the functionalization of orga-
nozinc halides.24 Although aryl and/or heteroaryl orga-
noaluminum species are generally transmetalated before
further reaction, these last two examples clearly show
that a CꢀC bound formation from aluminated isoxa-
zoles can be performed without the help of any other
metal source.
(22) Intermolecular reactions: (a) Asao, N.; Yoshikawa, E.; Yamamoto,
Y. J. Org. Chem. 1996, 61, 4874. Intramolecular reactions:(b) Asao, N.;
Sudo, T.; Yamamoto, Y. J. Org. Chem. 1996, 61, 7654.
(24) Schade, M. A.; Manolikakes, G.; Knochel, P. Org. Lett. 2010,
12, 3648.
(23) Grundmann, C.; Dean, J. M. J. Org. Chem. 1965, 30, 2809.
5666
Org. Lett., Vol. 13, No. 20, 2011

Table 4. Extension to the Synthesis of Aluminated Pyrazoles
Scheme 3. Reactivity of Aluminated Isoazoles
a Isolated yield.
Thus, this regioselective one-pot three-component reac-
tion is, to our opinion, a valuable alternative to the direct
cycloaddition of nitrile oxides with internal alkynes. This
reaction indeed generally suffers from low yield and regio-
selectivity unless appropriate alkynes, nitrile oxide precur-
sors, and/or subtle kinetically controlled reaction condi-
tions are chosen.25
Finally, extension of this metalative cyclization reaction
tothesynthesis of aluminatedpyrazolesstartingfrom com-
pound 6 was briefly investigated (Table 4). After experi-
mental conditions optimization, we found that an additional
amount of 0.5 equiv of trimethylaluminum was necessary to
achieve good conversion into the metalated pyrazole. Thus,
deuterated pyrazole (91% D) 7a was obtained in 75% yield
as a single regioisomer (Table 4, entry 1) . Chlorination
using N-chlorosuccinimide (NCS) enabled the preparation
of chlorinated compounds 7bꢀe (Table 4, entries 2ꢀ5),
showing that aluminated trisubstituted pyrazoles can also
be prepared using a metalative cyclization reaction.
In conclusion, we have developed an access to poly-
substituted alumino-heteroles, based on a metalative
cyclization. The regioselectivity of this reaction, com-
bined with the reactivity of the final organoaluminum
compounds, enables a rapid and simple access to 3,4,5-
trisubstituted isoxazoles with three points of variation
introduced in the same operation. We have also shown
that this reaction can be extended to the preparation of
the corresponding 1,3,5-trisubstituted 4-aluminopyra-
zoles. More generally, this synthetic pathway provides
an alternative entry to complex heterocyclic organoalu-
minum reagents, with unexplored reactivity. We expect
the present strategy to be applicable to other heterocyclic
systems.
Acknowledgment. Financial support from ANR (ANR
blanc AluMeth) is acknowledged
Supporting Information Available. Experimental pro-
cedures and characterization of compounds 2aꢀd, 4aꢀe,
5aꢀd, 7aꢀe. This material is available free of charge via
the Internet at http://pubs.acs.org.
(25) (a) Grecian, S.; Fokin, V. V. Angew. Chem., Int. Ed. 2008, 47,
8285. (b) 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. (c) Crossley, J. A.; Browne, D. L. J. Org. Chem. 2010, 75, 5414.
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