Palladium-catalyzed aza-wittig-type condensation of isoxazol-5(4H)-ones with aldehydes

Article abstract of DOI:10.1002/chem.201304211

This paper describes the development of a palladium-catalyzed decarboxylative inter- and intramolecular condensation reaction of isoxazol-5(4 H)-ones with carbonyl compounds in the presence of PPh₃, giving various 2-azabuta-1,3-dienes or pyrrol

Full text of DOI:10.1002/chem.201304211

DOI: 10.1002/chem.201304211
Communication
&
Synthetic Methods
Palladium-Catalyzed Aza-Wittig-Type Condensation of Isoxazol-
5(4H)-ones with Aldehydes
Kazuhiro Okamoto,* Takuya Shimbayashi, Eisuke Tamura, and Kouichi Ohe*[a]
Chem. Eur. J. 2014, 20, 1490 – 1494
1490
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication
Table 1. Palladium-catalyzed decarboxylative condensation of isoxazo-
lone 1a with aldehyde 2m.[a]
Abstract: This paper describes the development of a palla-
dium-catalyzed decarboxylative inter- and intramolecular
condensation reaction of isoxazol-5(4H)-ones with carbon-
yl compounds in the presence of PPh3, giving various
2-azabuta-1,3-dienes or pyrroles in moderate to high
yields.
Catalyst precursor
Catalyst precursor
Acid [mol%][b]
Acid [mol%][b]
Yield [%][b]
Yield [%][b]
In 1919, Staudinger and Meyer first reported the reaction of or-
ganic azides with phosphines giving iminophosphoranes.[1]
This is one of the epoch-making discoveries in synthetic organ-
ic chemistry, especially because this study triggered the discov-
ery of the Wittig reaction in 1953.[2] Nowadays, the Staudinger
reaction is widely used as a standard method for the reduction
of azides to amines or the aza-Wittig-type condensation.[3,4]
However, the Staudinger reaction is almost the only method
for the generation of iminophosphoranes. Taking the need for
careful handling of organic azides into consideration, the de-
velopment of an alternative method for the formation of imi-
nophosphoranes from more stable precursors is an important
issue.
1
2
3
4
[Pd(PPh3)4]
[Pd(PPh3)4]
[Pd(PPh3)4]
[Pd(PPh3)4]
[Pd(PPh3)4]
[Pd(PPh3)4]
[Pd(PPh3)4]
[Pd(PPh3)4]
[Pd(PPh3)4]
[Pd(PPh3)4]
[Pd(PPh3)4]
Pd(OAc)2
none
4
34
91 (81)[c]
71
17
15
26
85
0
0
3
91
76
0
PhCO2H (10)
PhCO2H (20)
PhCO2H (30)
PhCO2H (100)
PhCO2H (20)
PhCO2H (20)
Ph2P(O)OH (20)
PPTS (20)
HCl (20)
ZnCl2 (20)
PhCO2H (20)
PhCO2H (20)
PhCO2H (20)
5
6[d]
7[e]
8
9
10
11
12[f]
13[f]
14[f]
[Pd2(dba)3]
PdCl2
[a] Reaction conditions: isoxazolone 1a (0.20 mmol), aldehyde 2m
(0.60 mmol), [Pd] (5 mol% Pd) and acid in toluene (1.3 mL). [b] Deter-
mined by 1H NMR spectroscopy (see the Supporting Information). [c] Iso-
lated yield. [d] Without additional PPh3. [e] The reaction was performed at
608C. [f] 1.2 equivalents of PPh3 was used.
We recently reported a palladium-catalyzed decarboxylative
nitrene-transfer reaction of alkene-tethered isoxazol-5(4H)-ones
affording bicyclic aziridines (Scheme 1a).[5] During the course
of our investigation aimed at the intermolecular nitrene-trans-
fer reactions, we postulated that the N-alkenyliminophosphor-
ane was generated from the decarboxylation of isoxazolone
followed by nitrene transfer from palladium to phosphine.[6,7]
Then the iminophosphorane would react with aldehydes to
PPh3, and 5 mol% of [Pd(PPh3)4] in toluene at 808C for 12 h.
The expected azadiene 3am was observed in the 1H NMR
spectrum of the crude mixture, but the yield was only 4%
(Table 1, entry 1). The use of 10 mol% of benzoic acid
(PhCO2H) as an additive dramatically improved the reactivity,
and the yield of 3am was 34% (entry 2). When the amount of
PhCO2H was varied from 10 to 100 mol% (entries 2–5), the
highest yield was obtained with 20 mol% loading of PhCO2H
(91% yield determined by NMR spectroscopy; entry 3). When
the reaction was performed without additional PPh3, the ob-
served yield (15%) was almost equal to the amount of PPh3
(20%) included in the palladium catalyst. This result indicates
that this reaction requires the stoichiometric amount of phos-
phine in this aza-Wittig-type condensation (entry 6).[10] Lower-
ing the reaction temperature to 608C remarkably decreased
the yield of the product (26%; entry 7). The screening of sever-
al other Brønsted or Lewis acids showed that diphenylphos-
Scheme 1. Palladium-catalyzed decarboxylative transformation via hypothet-
ical palladium-nitrene complexes.
phinic acid (Ph2P(O)OH), possessing
a similar acidity to
afford a 2-aza-1,3-diene as a product (Scheme 1b).[8,9]
PhCO2H, also worked well to give the product in relatively high
yield, whereas other acids were not effective for the current re-
action (entries 8–11). As an alternative precursor, Pd(OAc)2 also
showed the same catalytic activity as [Pd(PPh3)4]; however,
other precursors were less or scarcely reactive (entries 12–14).
Under the optimized reaction conditions, various combina-
tions of isoxazolones and aldehydes could be applied to the
present reaction.[11] Table 2 summarizes the scope of isoxazo-
lones. The reaction of isoxazolones bearing a methoxy- and tri-
fluoromethyl-substituted phenyl group, and a naphthyl group
at the R1 position, gave azadienes 3bm, cm, and dm in good
An initial experiment was performed with isoxazolone 1a,
3.0 equivalents of benzaldehyde 2m, an equimolar amount of
[a] Dr. K. Okamoto, T. Shimbayashi, E. Tamura, Prof. Dr. K. Ohe
Department of Energy and Hydrocarbon Chemistry,
Graduate School of Engineering,
Kyoto University, Katsura, Nishikyo-ku, Kyoto 615-8510 (Japan)
E-mail: kokamoto@scl.kyoto-u.ac.jp
ohe@scl.kyoto-u.ac.jp
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201304211.
Chem. Eur. J. 2014, 20, 1490 – 1494
www.chemeurj.org
1491
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication
Table 2. Palladium-catalyzed decarboxylative condensation of isoxazo-
lone 1 with aldehyde 2m.[a]
Table 3. Palladium-catalyzed decarboxylative condensation of isoxazo-
lone 1a with aldehyde 2.[a]
[a] The reaction was performed with isoxazolone 1a (0.20 mmol), alde-
hyde 2 (0.60 mmol), [Pd(PPh3)4] (5 mol%) and benzoic acid (20 mol%) in
toluene (1.3 mL). Isolated yields are shown. Yields in parentheses were
determined with 1H NMR spectroscopy using nitromethane as an internal
standard.
[a] The reaction was performed with isoxazolone 1 (0.20 mmol), aldehyde
2m (0.60 mmol), [Pd(PPh3)4] (5 mol%) and benzoic acid (20 mol%) in tol-
uene (1.3 mL). Isolated yields are shown. Yields in parentheses were de-
termined with 1H NMR spectroscopy using nitromethane as an internal
standard. The ratios written following the yield mean the stereoisomeric
ratio of E/Z mixtures or the ration of two products. The stereochemistry
around the C=N bond was determined as E form (see the Supporting In-
formation). The stereochemistry around the C=C bond of 3 fm, gm, and
hm was not determined.
were also applicable, attempts to isolate the products failed
because of the very high sensitivity of the products toward hy-
drolysis.
We also attempted to use ketones instead of aldehydes, but
the reaction did not proceed. On the other hand, intramolecu-
lar condensation of substrate 1j successfully proceeded under
the standard conditions to afford the corresponding pyrrole 5j
in 95% isolated yield [Eq. (1)].[13] The alkenylated pyrrole 5k
was also obtained in 79% yield.
yields. Spirocyclic isoxazolone 1e afforded the 2-azadiene 3em
bearing a cyclopentylidene moiety. In the case of different sub-
stituents at the R2 and R3 positions, the products were ob-
tained as a mixture of geometrical isomers (3 fm, gm, and hm).
It is noteworthy that 2-azadiene 3hm was selectively obtained
without the formation of the intramolecular aziridination prod-
uct through the reaction of an alkene moiety.[12] Tetrahydro-
naphthalene-fused isoxazolone 1i afforded the corresponding
2-azadiene 3im together with the aromatized N-naphthylimine
3im’ in 61% total yield.
The present reaction shows tolerance for various functional
groups attached to aldehydes (Table 3). The reaction succeed-
ed with a series of benzaldehyde derivatives bearing para-sub-
stituents, such as methoxy, trifluoromethyl, chloro, methoxycar-
bonyl, cyano, dimethylamino, and nitro groups (3an–at). Aza-
diene 3as was obtained in just moderate yield, probably be-
cause the dimethylamino group offset the effect of the acid by
trapping the proton. The reaction of other aromatic or hetero-
aromatic aldehydes, such as ortho-tolualdehyde, 2-naphthalde-
hyde, and 2-thiophenecarbaldehyde, afforded the correspond-
ing 2-azadienes in high yields (3au–aw). Cinnamaldehyde also
reacted to afford the corresponding azatriene 3ax stereoselec-
tively. Pivalaldehyde 2y could also be applied as an aliphatic
aldehyde. Although other aliphatic aldehydes (R4 =nBu or Cy)
A proposed reaction mechanism is shown in Scheme 2. First,
the oxidative addition of the NÀO bond[14–16] in isoxazolone
1 to a zerovalent palladium species A is assumed to form a six-
membered intermediate B that undergoes decarboxylation
leading to nitrene–palladium complex C.[17] Then, nitrene trans-
fer from palladium to PPh3 followed by the aza-Wittig-type
condensation of iminophosphoranes with aldehydes would
afford the 2-azadiene 3 together with triphenylphosphine
oxide (as described in Scheme 1b).[18] Alternatively, nitrene-pal-
Chem. Eur. J. 2014, 20, 1490 – 1494
www.chemeurj.org
1492
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication
Scheme 4. Transformation reactions of azadiene 3am.
Scheme 2. A proposed catalytic cycle for the palladium-catalyzed aza-Wittig
reaction using isoxazolones.
In summary, we have developed a new method for aza-
Wittig-type condensation using isoxazol-5(4H)-ones as a vinylni-
trene source. 2-Aza-1,3-dienes having various substituents
were obtained from isoxazolones and aldehydes in the pres-
ence of triphenylphosphine and a catalytic amount of benzoic
acid. Much less reactive ketone moieties could also be applied
for the construction of pyrrole rings by intramolecular conden-
sation. We have also opened up the opportunity for the result-
ing 2-azadienes to undergo carbon–carbon bond-forming step-
wise 1,4-addition reactions leading to various nitrogen-contain-
ing organic molecules. Further mechanistic investigations, as
well as the development of other transformation reactions by
the use of iminophosphoranes, are currently under way.
Scheme 3. Another possible pathway for the condensation/catalyst regener-
ation step.
ladium complex C can directly react with an aldehyde to yield
2-azadiene 3 with palladium(II) oxide D, which is followed by
the reduction by PPh3 regenerating the palladium(0) catalyst A
(Scheme 3). We cannot exclude either of the two possible
pathways at the present time. The reason for the low yield of
azadiene 3am in the reaction using the stoichiometric amount
of benzoic acid (Table 1, entry 5) might be deactivation of iso-
xazolone 1a by protonation of its nitrogen atom.
The 2-azadienes obtained in the present reaction could be
used as synthetic intermediates for nitrogen-containing mole-
cules. Because 2-azadienes are polarized molecules, unlike the
simple 1,3-dienes, and have both the imine moiety and the en-
amine moiety, they can undergo the addition of organometal-
lic reagents as nucleophiles to generate enamide anions,
which is followed by the coupling with alkyl halides as electro-
philes.[19] Actually, the addition of MeLi or PhLi followed by
quenching with MeI or allyl bromide (allylBr) efficiently pro-
duced the corresponding 1,4-adducts 6–8 in good yield
(Scheme 4, right equation; 68–84% yields). Moreover, treat-
ment of NaBH3CN in protic media caused double hydride re-
duction of 2-azadiene 3am to afford saturated amine 9 in one
step (Scheme 4, left equation; 92% yield). The transformation
of 2-azadiene 3am was expanded into not only nucleophilic or
reductive reactions, but also N-oxidation giving synthetically
useful nitrone derivatives. Methyltrioxorhenium-catalyzed oxi-
dation with urea-hydrogen peroxide to afford N-alkenylnitrone
10 in 70% yield.[20]
Acknowledgements
This work was financially supported by Grants-in-Aid for Scien-
tific Research from JSPS and MEXT, Japan. Dr. K. Okamoto also
thanks Toray Award in Synthetic Organic Chemistry, Japan.
Keywords: aza-wittig · decarboxylation · nitrene transfer ·
palladium · Staudinger reaction
[1] a) H. Staudinger, J. Meyer, Helv. Chim. Acta 1919, 2, 635; b) Y. G. Gololo-
bov, I. N. Zhmurova, L. F. Kasukhin, Tetrahedron 1981, 37, 437.
[2] a) G. Wittig, G. Geiser, Justus Liebigs Ann. Chem. 1953, 580, 44; b) G.
Wittig, Pure Appl. Chem. 1964, 9, 245.
[3] For reviews, see: a) P. M. Fresneda, P. Molina, Synlett 2004, 1; b) F. Pala-
cios, C. Alonso, D. Aparicio, G. Rubiales, J. M. de Los Santos, Tetrahedron
2007, 63, 523.
[4] Staudinger reaction has also been widely used as a bio-orthogonal syn-
thetic method. See: a) E. Saxon, C. R. Bertozzi, Science 2000, 287, 2007;
b) C. I. Schilling, N. Jung, M. Biskup, U. Schepers, S. Brꢁse, Chem. Soc.
Rev. 2011, 40, 4840.
[5] K. Okamoto, T. Oda, S. Kohigashi, K. Ohe, Angew. Chem. 2011, 123,
11672; Angew. Chem. Int. Ed. 2011, 50, 11470.
[6] Although N-alkenyliminophosphoranes can be synthesized from vinyl
azides, preparation of vinyl azides generally requires the use of explo-
sive iodine azide (IN3). See: a) A. Hassner, F. W. Fowler, Tetrahedron Lett.
1967, 8, 1545; b) F. W. Fowler, A. Hassner, L. A. Levy, J. Am. Chem. Soc.
1967, 89, 2077; c) A. Hassner, F. W. Fowler, J. Org. Chem. 1968, 33, 2686.
[7] As a related chemistry, catalytic carbene transfer reactions via phospho-
rus ylides has been reported by some groups. See: a) G. A. Mirafzal, G.
Cheng, L. K. Woo, J. Am. Chem. Soc. 2002, 124, 176; b) G. Cheng, G. A.
Mirafzal, L. K. Woo, Organometallics 2003, 22, 1468, and references
Chem. Eur. J. 2014, 20, 1490 – 1494
www.chemeurj.org
1493
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication
therein; c) V. K. Aggarwal, J. R. Fulton, C. G. Sheldon, J. de Vicente, J.
Am. Chem. Soc. 2003, 125, 6034; d) K. Miki, Y. Washitake, K. Ohe, S.
Uemura, Angew. Chem. 2004, 116, 1893; Angew. Chem. Int. Ed. 2004, 43,
1857.
[8] For examples of carbene complexes-mediated carbene-transfer into 2H-
azirines giving 2-aza-1,3-dienes, see: a) L. S. Hegedus, A. Kramer, C.
Yijun, Organometallics 1985, 4, 1747; b) A. F. Khlebnikov, M. S. Novikov,
A. A. Amer, Tetrahedron Lett. 2004, 45, 6003; c) A. F. Khlebnikov, N. S.
Novikov, A. A. Amer, R. R. Kostikov, J. Magull, D. Vidovic, Russ. J. Org.
Chem. 2006, 42, 515; d) K. Okamoto, A. Mashida, M. Watanabe, K. Ohe,
Chem. Commun. 2012, 48, 3554; e) K. Okamoto, M. Watanabe, A. Mashi-
da, K. Miki, K. Ohe, Synlett 2013, 1541.
[14] For reviews, see: a) M. Kitamura, K. Narasaka, Chem. Rec. 2002, 2, 268;
b) K. Narasaka, M. Kitamura, Eur. J. Org. Chem. 2005, 4505.
[15] For recent examples, see: a) T. Gerfaud, L. Neuville, J. Zhu, Angew.
Chem. 2009, 121, 580; Angew. Chem. Int. Ed. 2009, 48, 572; b) Y. Tan, J. F.
Hartwig, J. Am. Chem. Soc. 2010, 132, 3676; c) M. Kitamura, Y. Moriyasu,
T. Okauchi, Synlett 2011, 643; d) A. Faulkner, J. F. Bower, Angew. Chem.
2012, 124, 1707; Angew. Chem. Int. Ed. 2012, 51, 1675; e) A. Faulkner,
J. S. Scott, J. F. Bower, Chem. Commun. 2013, 49, 1521.
[16] For recent examples of NÀO bond cleavage of oxime esters or ethers in
catalytic reactions using metals other than palladium, see: a) P. C. Too,
Y. F. Wang, S. Chiba, Org. Lett. 2010, 12, 5688; b) Y. Yoshida, T. Kurahashi,
S. Matsubara, Chem. Lett. 2011, 40, 1140; c) P. C. Too, S. H. Chua, S. H.
Wong, S. Chiba, J. Org. Chem. 2011, 76, 6159; d) Z.-H. Ren, Z.-Y. Zhang,
B.-Q. Yang, Y.-Y. Wang, Z.-H. Guan, Org. Lett. 2011, 13, 5394; e) I. Naka-
mura, T. Iwata, D. Zhang, M. Terada, Org. Lett. 2012, 14, 206; f) Y. Yoshi-
da, T. Kurahashi, S. Matsubara, Chem. Lett. 2012, 41, 1498; g) Y. Wei, N.
Yoshikai, J. Am. Chem. Soc. 2013, 135, 3756; h) Z. Shi, D. C. Koester, M.
Boultadakis-Arapinis, F. Glorius, J. Am. Chem. Soc. 2013, 135, 12204.
[17] H. Xie, F. Lin, L. Yang, X. Chen, X. Ye, X. Tian, Q. Lei, W. Fang, J. Organo-
met. Chem. 2013, 745–746, 417.
[9] For example of another type of synthesis of 2-aza-1,3-dienes, see: F. Pal-
acios, C. Alonso, G. Rubiales, J. Org. Chem. 1997, 62, 1146.
[10] Under the optimized reaction conditions (Table 1, entry 3), triphenyl-
phosphine oxide was quantitatively formed (isolated in 99% yield).
[11] In some cases, the isolated yields were lower than the yields estimated
by 1H NMR spectroscopy because of hydrolytic decomposition of the
products.
[12] As a control experiment, we examined the intramolecular aziridination
reaction of 1h in the absence of PhCHO. As shown in Equation (2), the
intramolecular aziridination (see ref. [5]) was completely inhibited in the
presence of PhCO2H (20 mol%), which is required for the selective con-
version of 1h to azadiene 3hm.
[18] We consider that the additional benzoic acid serves as an acid catalyst
for the activation of aldehyde in the aza-Wittig reaction step. For exam-
ples of Brønsted or Lewis acid promoted Wittig reactions, see: a) C. Rꢂ-
chardt, S. Eichler, P. Panse, Angew. Chem. 1963, 75, 858; Angew. Chem.
Int. Ed. Engl. 1963, 2, 619; b) A. K. Bose, M. S. Manhas, R. M. Ramer, J.
Chem. Soc. C 1969, 2728; c) D. L. Hooper, S. Garagan, M. M. Kayser, J.
Org. Chem. 1994, 59, 1126.
[19] Although some transformation reactions of 2-azadienes has been re-
ported, 1,4-addition to 2-azadienes has not been reported to date. See:
a) A. Dehnel, J. P. Finet, G. Lavielle, Synthesis 1977, 474; b) S. Jayakumar,
M. P. S. Ishar, M. P. Mahajan, Tetrahedron 2002, 58, 379. See also ref. [8e]
and [9].
[13] The reaction of isoxazolone 1j with benzaldehyde (2m) in the standard
reaction conditions gave the corresponding pyrrole 5j in 90% yield to-
gether with a small amount of the corresponding 2-azadiene 3jm [5%
yield; Eq. (3)]. This result indicates that the intramolecular condensation
reaction is much faster than intermolecular condensation with alde-
hyde.
[20] G. Soldaini, F. Cardona, A. Goti, Org. Lett. 2007, 9, 473.
Received: October 29, 2013
Published online on January 17, 2014
Chem. Eur. J. 2014, 20, 1490 – 1494
www.chemeurj.org
1494
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim