Unexpected Truce-Smiles type rearrangement of 2-(2'- pyridyloxy)phenylacetic esters: Synthesis of 3-pyridyl-2-benzofuranones

Article abstract of DOI:10.1016/S0040-4039(00)00701-2

Enolization of 2-(2'-pyridyloxy)phenylacetic acid esters with either potassium or sodium hydride induced a Truce-Smiles rearrangement, producing pyridine substituted 2-benzofuranones. Rearrangement of a 2-(4- nitrophenoxy)phenylacetate and a 2-(2'-pyrimidyloxy)phenylacetate produced similar results. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00701-2

Tetrahedron Letters 41 (2000) 4541±4544
Unexpected Truce±Smiles type rearrangement of
2-(20-pyridyloxy)phenylacetic esters: synthesis of
3-pyridyl-2-benzofuranonesy
W. Randal Erickson* and Marc J. McKennon
Dow AgroSciences, 9330 Zionsville Rd, Indianapolis, IN 46268, USA
Received 30 March 2000; revised 21 April 2000; accepted 24 April 2000
Abstract
Enolization of 2-(20-pyridyloxy)phenylacetic acid esters with either potassium or sodium hydride induced
a Truce±Smiles rearrangement, producing pyridine substituted 2-benzofuranones. Rearrangement of a
2-(4-nitrophenoxy)phenylacetate and a 2-(20-pyrimidyloxy)phenylacetate produced similar results. # 2000
Elsevier Science Ltd. All rights reserved.
As a part of our fungal crop disease management program, we have targeted many structures
belonging to the strobilurin class of compounds for use as oomycete control in vines. One of
them, b-methoxyacrylate 1, is structurally related to the natural product Strobilurin A. Both 1
and Strobilurin A share the b-methoxyacrylate subunit, believed to be the toxiphore responsible
for the observed potent fungicidal activity of this compound class.1
Many procedures exist for the synthesis of this moiety.2 The most straightforward involves
formylation of the corresponding ester enolate, followed by O-methylation of the resultant
aldehyde.3 However, no formylation adducts were produced when compounds 2 were submitted to
these literature conditions (Scheme 1). Rather, enolate attack on the pyridine ring was observed.
* Corresponding author. E-mail: wrerickson@dowagro.com
y
Dedicated to the memory of Professor Arthur G. Schultz.
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00701-2

4542
We now wish to report this Truce±Smiles type rearrangement of 2-(2-pyridyloxy)phenylacetic
acid esters 2 as a method for preparation of 3-pyridyl-2-benzofuranones 3.
Scheme 1.
The requisite esters 2 were prepared by treating the disodium salt of 2-hydroxyphenylacetic
acid with the corresponding halopyridine in DMSO, followed by esteri®cation with MeI/K2CO3
(Scheme 2). The formylation of 2a was attempted by enolization with KH/THF at ^20ꢀC fol-
lowed by treatment with methyl formate. The following empirical observations were noted. (1)
No reaction between the ester enolate and methyl formate was observed at ^20ꢀC. (2) When the
reaction was warmed to 0ꢀC, a deep green color appeared. (3) Aqueous quench of the reaction
produced a bright orange solid after extraction. (4) 1H NMR showed no resonances up®eld of 5.2
ppm, indicating loss of the ester methyl group and a-methylene. (5) Also absent was the diagnostic
signal at ꢁ7.4 ppm indicative of the vinyl proton present in the enol form of a formyl ester. (6)
Mass spectral analysis indicated loss of 32 amu with respect to 2a, indicating a loss of methanol
during the course of the reaction. (7) Exposure of the orange product to weak base (K2CO3)
regenerated the green color seen during the formylation attempt. (8) Similar treatment of 2b
(NaH/THF at 0ꢀC) gave nearly identical spectral results, but surprisingly without any appreciable
color changes during reaction, followed by isolation of a colorless product.
Scheme 2.
All of these seemingly anomalous observations were consistent with the production of a
3-substituted 2-benzofuranone 3 as the product of a Truce±Smiles type rearrangement of 2. For
example, treatment of 2a with either NaH or KH4 produced a colorless ester enolate that was
stable in solution at temperatures below 0ꢀC. Warming above this temperature induced the rear-
rangement, producing an intermediate phenoxide which spontaneously lactonized to the benzo-
furanone 3a.

4543
The observed color changes could arise from overlap of the various p-systems during the
course of the reaction; i.e. the benzofuranones 3a and 3c underwent tautomerism to the orange
colored 2-hydroxybenzofurans 4a and 4c, which are green when deprotonated.5 These tautomers
appear to be stabilized further by intramolecular hydrogen bonding to the pyridine nitrogen. In
the case of 3b and 3d, steric interactions between the 3-substituent of the pyridine moiety and H-5
of the benzofuranone ring prevent co-planarity of the two rings, precluding formation of the
2-hydroxybenzofurans 4b and 4d. Spectral data support this supposition: 3b and 3d exhibit a
carbonyl stretch at 1820±1815 cm^1 whereas 4a and 4c show a strong IR band at 1680±1675 cm^1.
We wished to brie¯y examine the generality of this rearrangement with other activated
aromatic ring systems. Treatment of 5 (prepared from 1-¯uoro-4-nitrobenzene) with NaH in
THF at 0ꢀC resulted in a deep violet solution (Scheme 3). Extractive work-up with ethyl acetate
and dilute HCl followed by chromatography gave the nitrophenol adduct 6, isolated as a pale
straw colored solid. The presence of the keto form is supported by a singlet at 5.3 ppm in the
proton NMR spectrum and an IR resonance at 1792 cm^1.
Scheme 3.
Finally, as anticipated, the rearrangement of 7 (prepared from 2-chloropyrimidine) was facile,
giving the hydroxybenzofuran 8, isolated as a bright orange red solid. Curiously, organic solutions
of 8 did not change color within a pH range of 3 to 10, suggesting an extremely tight intramolecular
hydrogen bond between the enolic hydrogen and a pyrimidine nitrogen. Examination of the proton
NMR spectrum of compound 8 provided further evidence.6 In THF-d8 at ambient temperature,
the benzene protons appear normal, but the pyrimidine protons H-40 and H-60 (adjacent to the
nitrogens) appear as broad singlets (8.8 and 8.2 ppm) while the H-50 proton appears as a triplet
(6.7 ppm). This supports the hypothesis of hydrogen bonding locking the rings in a planar
con®guration (or nearly so), but the pyrimidine ring `snaps' back and forth between its two
nitrogens rapidly on the NMR time scale. Cooling to minus 10ꢀC slows this rotation, allowing the
non-equivalent H-40 and H-60 resonances to be observed as sharp multiplets. A rotational barrier
of 17 kcal/mol was calculated,7 and the observed spectrum agrees with the predicted model.
References
1. (a) Clough, J. M. Nat. Prod. Rep. 1993, 10, 565. (b) Beautement, K.; Clough, J. M.; de Fraine, P. J.; Godfrey,
C. R. A. Pestic. Sci. 1991, 31, 499.
2. (a) Rossi, R.; Bellina, F.; Carpita, A. Synlett 1996, 356. (b) Hodgson, D. M.; Witherington, J.; Moloney, B. A.;
Richards, I. C.; Brayer, J.-L. Synlett 1995, 32. (c) Tanimoto, S.; Kokubo, T.; Oida, T.; Ikehira, H. Synth.
Commun. 1982, 723.

4544
3. (a) Wittman, M. D.; Kallmerten, J. J. Org. Chem. 1987, 52, 4303. (b) Akita, H.; Matsukura, H.; Oishi, T.
Tetrahedron Lett. 1986, 2, 5397. (c) Nakata, T.; Kuwabara, T.; Tani, Y.; Oishi, T. Tetrahedron Lett. 1982, 23,
1015.
4. Lithium salts of 2 do not appear to undergo this rearrangement.
5. For similar observations in 3-phenyl-2-benzofuranones, see: (a) Black, T. H.; Arrivo, S. M.; Schumm, J. S.;
Knobeloch, J. M. J. Org. Chem. 1987, 52, 5425. (b) Black, T. H.; Arrivo, S. M.; Schumm, J. S.; Knobeloch, J. M.
J. Chem. Soc., Chem. Commun. 1986, 1524.
6. The authors wish to thank Dr. Scott Thornburgh for his assistance in acquisition and interpretation of these
spectra.
7. Spectra were calculated with the program DNMRSIM Version 1.0 (1994, Heinrich-Heine-University, Dusseldorf
Germany), a PC version of the Binsch program DNMR3. Input parameters were as follows: oA=2634 Hz (8.78 ppm),
oB=2463 Hz (8.21 ppm), oC=2001 Hz (6.67 ppm), JAB=2.39 Hz, JAC=4.29 Hz, JBC=6.35 Hz.