Baeyer-Villiger rearrangement of a substituted pyrrole by Oxone

Article abstract of DOI:10.1016/j.tetlet.2014.04.004

Pyrroloxyls have been reported to exhibit very narrow EPR spectral lines, essential for in vivo imaging. En route to pyrroloxyls, we observed an unexpected Baeyer-Villiger rearrangement, leading to loss of aromaticity and formation of a 4,5-dihydro-1H-ketopyrrole.

Full text of DOI:10.1016/j.tetlet.2014.04.004

Tetrahedron Letters 55 (2014) 3111–3113
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Baeyer–Villiger rearrangement of a substituted pyrrole by Oxone
Joseph P. Y. Kao a,b,c, , Sukumaran Muralidharan a,b, Peter Y. Zavalij d, Steven Fletcher e,f, Fengtian Xue e,f
,
⇑
Gerald M. Rosen a,c,e
a Center for Biomedical Engineering and Technology, University of Maryland School of Medicine, 20 North Pine Street, Baltimore, MD 21201, USA
b Department of Physiology, University of Maryland School of Medicine, 20 North Pine Street, Baltimore, MD 21201, USA
c Center for Low Frequency EPR Imaging for In Vivo Physiology, University of Maryland, Baltimore, MD 21201, USA
d Department of Chemistry and Biochemistry, University of Maryland, College Park, MD 20742, USA
e Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD 21201, USA
f University of Maryland Marlene and Stewart Greenebaum Cancer Center, Baltimore, MD 21201, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Pyrroloxyls have been reported to exhibit very narrow EPR spectral lines, essential for in vivo imaging. En
route to pyrroloxyls, we observed an unexpected Baeyer–Villiger rearrangement, leading to loss of aro-
maticity and formation of a 4,5-dihydro-1H-ketopyrrole.
Received 24 March 2014
Revised 31 March 2014
Accepted 1 April 2014
Available online 8 April 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Pyrrole
Pyrroloxyl
Vilsmeier–Haack
Baeyer–Villiger
Introduction
neither of which was described by Ramasseul and Rassat: (a) 2,
5-di-tert-butyl-3-ethoxycarbonyl-4-hydroxy-1-pyrroloxyl 5b, which is
The advent of low-frequency electron paramagnetic resonance
(EPR) spectrometers1 that can detect and image paramagnetic spe-
cies in animals in real time creates an urgent need to synthesize
stable free radicals (so-called ‘spin probes’) that can report
in vivo physiology (e.g., O2 concentration in various tissues).2 Ow-
ing to their relative ease of synthetic manipulation, nitroxides are
attractive as spin probes for physiological EPR spectroscopy and
imaging.3
readily oxidized to nonparamagnetic 7 and (b) the biradical 2,20,5,
50-tetra(tert-butyl)-4,40-bis(ethoxycarbonyl)-3,30-bipyrrolyl-1,10-di-
oxyl 6 (Scheme 1).6 Despite the enhanced stability of biradical 6
as compared to pyrroloxyl 5b, its dimeric nature makes it less
The utility of nitroxides as EPR imaging probes has been lim-
ited by their relatively large spectral linewidth (ꢀ1 G), which im-
pacts both imaging sensitivity and spatial resolution. In 1970,
Ramasseul and Rassat4 described the synthesis of pyrroloxyls that
exhibited narrow EPR spectral linewidths in deoxygenated organic
solvents (linewidth of one deuterium-substituted pyrroloxyl was
reported to be ꢀ0.1 G5). In view of their remarkable narrow line-
widths, we wished to investigate the potential of pyrroloxyls as
in vivo EPR imaging agents. For our initial series of studies,6 we
decided to prepare 2,5-di-tert-butyl-3-ethoxycarbonyl-1-pyrrol-
oxyl 5a, using methods described by Ramasseul and Rassat.4 To
our surprise, nickel peroxide oxidation of 4 afforded two products,
⇑
Corresponding author. Tel.: +1 410 706 4167; fax: +1 410 706 8184.
E-mail address: jkao@umaryland.edu (J.P.Y. Kao).
Scheme 1. Reagents and conditions: (a) NaOEt, (b) NH2OH, (c) NiO2, (d) O2.
http://dx.doi.org/10.1016/j.tetlet.2014.04.004
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

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J. P. Y. Kao et al. / Tetrahedron Letters 55 (2014) 3111–3113
than optimal as a contrast agent for in vivo EPR imaging. We
therefore sought alternative nitroxides that might exhibit narrow
EPR spectral lines. We decided to investigate the synthesis of
more water-soluble analogs of the reported pyrroloxyls4 with
the expectation that they would also exhibit narrow linewidths.
Results and discussion
Scheme 3. Reagents and conditions: (a) Bn–Br, K2CO3, DMSO (70% yield); (b)
HCON(CH3)C6H5/POCl3 (47% yield). Bn = benzyl.
Based on our earlier publication,6 it is clear that all positions on
the pyrrole ring must be substituted prior to the one-electron
oxidation of NꢁOH to NꢁO. We considered that preparation of
di-ester 8, followed by cyclization with hydroxylamine would
afford the desired pyrrole 9 (Scheme 2). A careful review of the lit-
erature5 revealed that 9 was indeed accordingly obtained, but only
in about 5% yield. In our hands, however, attempts to prepare 9 in
an identical fashion were unsuccessful.
An alternative approach was sought. We reasoned that since 4
can be readily prepared in reasonable yield,4,6 initial protection
of the NꢁOH followed by the Vilsmeier–Haack reaction might
result in the corresponding formylpyrrole 11. Oxidation of 11, fol-
lowed by removal of the protective group, should lead to 9. How-
ever, after O-benzylation of 4 to yield 10, classic Vilsmeier–Haack
reaction conditions7 did not result in formylation (only 10 was
recovered). By optimizing reaction conditions—1 equiv of 10 in
5 equiv of N-methyl-N-phenylformamide/POCl3 (solvent-free),
50 °C, 3 h, followed by hydrolysis with aqueous sodium
acetate—we obtained 11 in acceptable yield (Scheme 3).
Scheme 4. Reagents and conditions: (a) Oxone/EtOH (48% yield). Bn = benzyl.
While there are various methods for oxidizing aldehydes to
acids and esters, the recent procedure of Travis, et al.,8 wherein
OxoneÒ was used to convert aryl aldehydes to the corresponding
ethyl esters, seemed an attractive approach to pyrrole 12. One
potential problem was that electron-rich molecules, such as
4-hydroxybenzaldehyde, can also undergo the Baeyer–Villiger
reaction, resulting in a formate ester, which upon hydrolysis leads
to the corresponding phenol.8 Because pyrrole 11 is not electron-
rich, we were optimistic that the mild experimental conditions
described in Travis, et al.8 might favor oxidation to the desired
ester and not a Baeyer–Villiger rearrangement.
When 11 and OxoneÒ (2:1 molar ratio of KHSO5 to substrate)
were stirred in absolute ethanol at room temperature for 16 h,
no reaction occurred. When the ratio of KHSO5 to 11 was increased
to 6, and the reaction was vigorously stirred at room temperature
for 3 days, TLC analysis indicated the formation of
a new
compound. The 1H NMR spectrum of the isolated product showed
multiple resonances inconsistent with the highly symmetrical
structure of 12. The X-ray crystallographic structure9 of the iso-
lated product revealed a rearrangement of 11 by OxoneÒ, resulting
in 13 rather than the predicted pyrrole 12 (Scheme 4). The
presence of a chiral center in 13 implies the generation of stereo-
isomers. Indeed, 13 crystallizes as a racemate, with an asymmetric
unit comprising a pair of enantiomers (Fig. 1).
We speculated that 11 could have undergone a Baeyer–Villiger-
type oxidation mediated by OxoneÒ, with subsequent rearrange-
ment to 13. To gain further insight into the mechanism underlying
the formation of 13, we changed experimental conditions to avoid
using a protic solvent that could act as a nucleophile: reaction with
Figure 1. Enantiomers of 13 constituting the asymmetric unit in the X-ray
crystallographic structure.9
3
molar equivalents of OxoneÒ in DMF for 16 h at room
temperature transformed 11 into a new product, 16. The 1H NMR
spectrum of 16 suggested the presence of a formate ester. The
structure of 16 was determined by X-ray crystallography
(Fig. 2),10 and is seen to be the formate ester expected from Bae-
yer–Villiger oxidation of 11 (Scheme 5).
Oxone is an acidic triple salt comprising potassium peroxy-
monosulfate, potassium hydrogen sulfate, and potassium sulfate
(2KHSO5ꢂKHSO4ꢂK2SO4). Therefore, if formate ester 16 did form in
the ethanolic Oxone reaction, acid-catalyzed transesterification
Scheme 2. Reagents and conditions: (a) Na/Et2O, (b) NH2OH.

J. P. Y. Kao et al. / Tetrahedron Letters 55 (2014) 3111–3113
3113
rearranges with loss of aromaticity. Attempts to oxidize 13 to
the corresponding nitroxide using typical oxidants such as
m-chloroperbenzoic acid, hydrogen peroxide/sodium tungstate,
and dimethyldioxirane11,12 all failed, presumably owing to 13
being highly hindered.11
Acknowledgments
This research was supported in part by Grants from the U.S.
National Institutes of Health: GM056481 (J.P.Y.K) and EB 2034
(G.M.R). We thank Drs. Olga A. Mukhina and G. R. Eaton in the
Department of Chemistry at the University of Denver for helpful
suggestions during the writing of this manuscript.
Supplementary data
Figure 2. Formate ester 16 formed from Baeyer–Villiger oxidation of 11.
Supplementary data (detailed experimental procedures and
compound characterization data are available as Supplementary
Information in the online version.) associated with this article
can be found, in the online version, at http://dx.doi.org/10.1016/
j.tetlet. 2014.04.004.
References and notes
1. (a) Halpern, H. J.; Spencer, D. P.; van Polen, J.; Bowman, M. K.; Nelson, A. C.;
Dowey, E. M.; Teicher, B. A. Rev. Sci. Instrum. 1989, 60, 1040; (b) Halpern, H. J.;
Bowman, M. K. In EPR Imaging and In Vivo EPR; Eaton, G. R., Eaton, S. S., Ohno, K.,
Eds.; CRC Press: Boca Raton, FL, 1991; pp 45–63.
Scheme 5. Reagents and conditions: (a) Oxone/DMF (65% yield). Bn = benzyl.
2. (a) Halpern, H. J.; Yu, C.; Peric, M.; Barth, E.; Grdina, D. J.; Teicher, B. A. Proc.
Natl. Acad. Sci. U.S.A. 1994, 91, 13047; (b) Halpern, H. J.; Yu, C.; Peric, M.; Barth,
E. D.; Karczmar, C. S.; River, J. N.; Grdina, D. J.; Teicher, B. A. Radiat. Res. 1996,
145, 610; (c) Elas, M.; Williams, B. B.; Parasca, A.; Mailer, C.; Pelizzari, C. A.;
Lewis, M. A.; River, J. N.; Karczmar, C. S.; Barth, E. D.; Halpern, H. J. Magn. Reson.
Med. 2003, 49, 682.
3. For a review on this topic, the reader should consult: (a) Swartz, H. M.;
Sentjurc, M.; Kocherginsky, N. In Nitroxide Spin Labels: Reactions in Biology and
Chemistry; Swartz, H. M., Kocherginsky, N., Eds.; CRC Press: Boca Raton, FL,
1995; pp 175–198; (b) Smirmov, A. I.; Ruuge, A.; Reznikov, V. A.; Voinov, M. A.;
Grigor’ev, I. A. J. Am. Chem. Soc. 2004, 126, 8872; (c) Gallez, B.; Mäder, K.;
Swartz, H. M. Magn. Reson. Med. 1996, 36, 694.
Scheme 6. Reagents and conditions: KHSO4, Na2SO4, EtOH (62% yield). Bn = benzyl.
4. Ramasseul, A.; Rassat, A. Bull. Soc. Chim. Fr. 1970, 72, 4330.
with ethanol could have removed the formyl group to yield a
hydroxypyrrole which, in turn, could have undergone rearrange-
ment to yield the dearomatized compound 13. To investigate this
possibility, formate ester 16 was vigorously stirred with a mixture
of anhydrous KHSO4 and Na2SO4 in absolute ethanol at room tem-
perature for 40 h. The sole isolated product was hydroxypyrrole 17
(Scheme 6). Thus cleavage of the formyl group did not trigger sub-
sequent rearrangements under acidic, non-oxidizing conditions in
anhydrous ethanol. In view of the last finding, we surmise that in
the presence of Oxone in ethanol, formate ester 16 and/or hydroxy-
pyrrole 17 must undergo further oxidative dearomatization and
addition to generate pyrrolinone 13.
5. Radner, F.; Rassat, A.; Hervsall, C.-J. Acta Chem. Scand. 1996, 50, 146.
6. Riplinger, C.; Kao, J. P. Y.; Rosen, G. M.; Kathirvelu, V.; Eaton, G. R.; Eaton, S. S.;
Kutateladze, A.; Neese, F. J. Am. Chem. Soc. 2009, 131, 10092.
7. White, J.; McGillivray, G. J. Org. Chem. 1977, 42, 4248.
8. Travis, B. R.; Sivakumar, M.; Hollist, G. O.; Borhan, B. Org. Lett. 2003, 5, 1031.
9. Rosen, G. M.; Muralidharan, S.; Zavalij, P. Y.; Fletcher, S.; Kao, J. P. Y. Acta Cryst.
2013, E69, o878.
10. Single-crystal structure of 16: C23H31NO5, Mr = 401.49, T = 150(2) K, triclinic,
ꢀ
space group P1, a = 10.1671(7) Å, b = 11.1975(7) Å, c = 11.4168(7) Å,
a
= 66.6953(9)° b = 65.9741(9)°
qcalcd = 1.236 g cmꢁ3 = 0.086 mmꢁ1, 10680 reflections (4244 independent,
Rint = 0.0146), data/restraints/parameters 4244/0/300, goodness-of-fit on F2
c
= 73.5494(10)°
V
= 1078.68(12) Å3, Z = 2,
,
l
1.000, R[F2 > 2
r
(F2)] = 0.042, wR(F2) = 0.086,
D
q
max = 0.38 e Åꢁ3
,
Dqmin
= ꢁ0.22 e Åꢁ3
. Crystallographic data (excluding structure factors) for this
structure have been deposited with the Cambridge Crystallographic Data
Centre (Deposition number CCDC 993030).
To our knowledge, this is the first time that a hindered and fully
substituted pyrrole has undergone a Baeyer–Villiger reaction to
yield a product which, in the presence of an appropriate solvent,
11. Keana, J. F. W.; Heo, G. S.; Mann, J. S.; Van Nice, F. L.; Lex, L.; Prabhu, V. S.;
Ferguson, G. J. Org. Chem. 1988, 53, 2268.
12. Birk, M. E. Tetrahedron Lett. 1995, 36, 5519.