Decarboxylation and ring fragmentation reactions of sydnone N-oxides

Article abstract of DOI:10.1016/j.tetlet.2008.05.025

4-Carboxylated sydnone N-oxides are readily decarboxylated by benzylation to give 2,4-dibenzylsydnone-N-oxides. Ring cleaveage results from their oxidation with bromine which leads to a nitrile N-oxide which is isolated as its furazan dimer.

Full text of DOI:10.1016/j.tetlet.2008.05.025

Tetrahedron Letters 49 (2008) 4550–4552
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Decarboxylation and ring fragmentation reactions of sydnone N-oxides
*
*
D. Scott Bohle , Yoshihiro Ishihara, Inna Perepichka, Lijuan Zhang
Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montreal, Quebec, Canada H3A 2K6
a r t i c l e i n f o
a b s t r a c t
Article history:
4-Carboxylated sydnone N-oxides are readily decarboxylated by benzylation to give 2,4-dibenzylsyd-
none-N-oxides. Ring cleaveage results from their oxidation with bromine which leads to a nitrile N-oxide
which is isolated as its furazan dimer.
Received 10 April 2008
Revised 5 May 2008
Accepted 6 May 2008
Available online 10 May 2008
Ó 2008 Elsevier Ltd. All rights reserved.
MeO
O
O
The mesoionic, 1,2,3-oxadiazoles, found in the N-substituted
sydnones, 1, remain of considerable interest as new materials1,2
and for their biological properties.3,4 Unfortunately, their singular
synthetic access has limited the number of available derivatives
as well as an understanding of their associated reactivity patterns.5
Recently, a new class of remarkably stable sydnones, the N-oxide,
2, was recognized and are readily prepared by the base-mediated
diazeniumdiolation of either dimethylmalonate6 or terminal
alkynes.7 Unlike other sydnones, the sydnone N-oxides are stable
toward strong acids8 to the extent that, for example, sulfuric acid
catalyzed trans-esterification9 of the 4-carboxylate derivatives
opens a wide range of accessible derivatives. The sydnone N-oxides
thus offer a range of potential new chemistry for this heterocycle,
and in this Letter, we describe a facile electrophile-promoted
decarboxylation of the 4-carboxylate upon benzylation, and the
oxidative cleavage of the sydnone ring with bromine which
results in the dimer of the nitrile N-oxide intermediate to give
the furazan 6.
O
O
N
4
CH2Cl2
25 C, 72 hr
N
CH2Ph
O
MeO
ð1Þ
O
PhCH2Br
O
N
CH2Ph
O
N
O
CH2Cl2
reflux, 28 hr
O
N
N
5
O
2
CH2Ph
We have recently found that the methylation of 2 gives either N–O
methylation as the kinetic product 3a or N-methylation as the ther-
modynamic product 3b.9 Now we find that with benzyl bromide at
room temperature only an N-benzyl monobenzylation analog 4 of
3b product is isolated, Eq. 1. The N-benzylated structure 4 is as-
signed based on the similarity of the spectroscopic properties of
3b and 4, as well as a single crystal X-ray diffraction analysis, not
O
MeO
R
R
O
O
O
N
N
Characteristic data for new compounds: Compound 4 mp 103–105 °C. 1H NMR
(300 MHz, CDCl3): d 3.90 (s, 3H,CH3–O), 4.99 (s, 2H, Ph–CH2–N), 7.28–7.39 (m, 5H).
13C NMR (400 MHz, CDCl3, ppm): d 53.5, 61.9, 109.2, 127.3, 129.3, 130.4, 130.9, 155.6,
159.4. IR (KBr, cmꢀ1): 3089w, 3063w, 3040w, 2962w, 1820s, 1804s, 1725s, 1578s,
1497w, 1449s, 1408m, 1364m, 1248s, 1092m, 1067m, 1044w, 1005m, 937w, 861w,
O
N
O
O
N
1
2
R'O
R'O
O
O
828w, 790w, 778s, 744m, 727m, 710m, 696w, 676w, 645w, 478w. UV (CH3OH kmax
,
nm (e, Mꢀ1 cmꢀ1)): 263 (8900), 300 (sh), 320 (sh). MS (ESI), m/z: calcd for C11H10N2O5
OMe
O
[M] 250; found [(M–NO)+Na]+ 243 (17%), [M+Na]+ 273 (100%). Anal. Calcd for
O
O
N
N
C
11H10N2O5 (250 g/mol), %: C, 52.8; H, 4.03; N, 11.19. Found: C, 52.9; H, 3.88; N, 10.81.
O
N
Compound 5 mp 108.5–110.5 °C. 1H NMR (300 MHz, CDCl3): d 3.67 (s, 2H, Ph–CH2–C),
4.86 (s, 2H, Ph–CH2–N), 6.97–7.00 (m, 5H), 7.17–7.30 (m, 5H). 13C NMR (300 MHz,
CDCl3, ppm): d 27.9, 61.5, 117.8, 127.3, 127.6, 128.8, 128.87, 128.96, 129.85, 131.05,
133.5, 163.9. IR (KBr, cmꢀ1): 3084w, 3062w, 3036w, 3012w, 1809w, 1788s, 1590s,
1494m, 1455m, 1426m, 1394m, 1304w, 1286w, 1286w, 1206w, 1167w, 1085w,
1065w, 1029w, 985w, 956w, 927w, 882w, 842w, 766m, 749m, 725m, 693m, 640m,
488w. UV (CH3OH kmax, nm (e, Mꢀ1 cmꢀ1)): 259 (12400). MS (EI), m/z: calcd for
N
Me
3a
3b
* Corresponding authors. Tel.: +1 514 398 7409; fax: +1 514 398 3797 (D.S.B.).
E-mail address: Scott.Bohle@mcgill.ca (D. S. Bohle).
C
C
16H14N2O3 [M] 282; found [M–NO] 252 (20.3%), [M] 282 (4.0%). Anal. Calcd for
16H14N2O3 (282 g/mol), %: C, 68.1; H, 4.99; N, 9.92. Found: C, 67.9; H, 4.97; N, 9.91.
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.05.025

D. S. Bohle et al. / Tetrahedron Letters 49 (2008) 4550–4552
4551
R'
C
1.448(3)
1.443(2)
1.4465
1.315(3)
1.310(2)
1.3201
O
1.253(2)
1.2384
O
1.238(3)
N
C
1.191(3)
1.199(2)
1.1978
R = Me R'= CO2Me 3b, X-ray
R = R' = Benzyl 5, X-ray
1.431(3)
1.440(2)
1.4414
1.379(3)
1.380(2)
1.3990
R = R' = Me, B3LYP/6-311++G**
N
O
1.423(3)
1.433(2)
1.4182
R
Figure 2. Crystallographic and calculated dimensions. Crystallographic data for 3b
shown on top in black bold, for 5 in the middle in red in bold italics, and the
calculated values for the 1,4-dimethyl oxadiazole shown in bottom red italics.
Figure 1. X-ray single crystal diffraction structure of 5 showing H atoms in calc-
ulated positions and 40% thermal ellipsoids. Key metric parameters include: N(1)–
O(1) = 1.2527(17), N(1)–N(2) = 1.4401(16), N(2)–O(3) = 1.4326(15), C(1)–N(1) =
1.3099(18), C(1)–C(2) = 1.443(2), C(2)–O(3) = 1.3797(17), and C(2)–O(2) =
1.1987(17) Å.
The electrophile-mediated decarboxylation of 2 suggests that
the one electron oxidation of the ring might lead to enhanced reac-
tion and/or ring cleavage. This has been borne out experimentally
by the facile reaction of 2 with bromine Eq. 2, which gives
bis(methylcarboxy)furazan, 6, in 37% yield. Prior electrochemical
studies demonstrated that 2 undergoes an irreversible oxidation
at +1.09 V in acetonitrile even with moderately fast CV scan rates
shown. There is no evidence for the formation of a benzyl analog to
3a or the kinetic product of the methylation of 2 under these condi-
tions. Furthermore, benzylation of 2 at slightly elevated tempera-
tures, methylene chloride at reflux, gives a bis-benzyl product, 5,
in 25% yield, in addition to a minor, 3% yield of 4. The remarkably
of 1000 mV sꢀ1 6
. The formation of a furazan suggests that the oxi-
dation of 2 gives a product which readily looses the nitrile N-oxide,
MeO2CCNO, 7, which then dimerizes to give 6, Eq. 3. Although the
dimerization of nitrile N-oxides is known, and the spectroscopic
features of 6 match those in the literature,10,11 the oxidation of a
sydnone N-oxide represents a new access to nitrile N-oxides,12
and one which compliments the recently reported manganese
dioxide oxidation of aldoximes.13Alternatively, the sydnone N-oxi-
des could be viewed as being a formal 1–3 dipolar addition product
of a nitrile N-oxide to the fragment [NOCO]ꢀ, the one electron oxi-
dation of which leads to a facile retro reaction. Finally, the gaseous
side products from reaction 3, in this case proposed to be NO and
CO, are likely to be physiologically active, and thus these deriva-
tives have potential biomedical applications.
facile uncatalyzed decarboxylation of
2 suggests that other
electrophiles, and perhaps oxidants, might return a range of new
4-substituted 1,2,3-oxadiazoles related to 5. We speculate that bro-
momethane is a side product of this reaction. The structure of 5 has
been confirmed by X-ray diffraction,à Figure 1, and corresponds to
benzylation/decarboxylation of 2. The contrast of the structure of 5
with that of 3b,9 Figure 2, illustrates the effect of the p-conjugated
methylcarboxylate group in 3b upon the core sydnone structure in
that the framework bond lengths for N(1)–C(1), C(1)–C(2), and
C(2)–O(3) are all shorter in 5, while those bond lengths for N(1)–
N(2) and N(2)–O(3) frameworks are all slightly longer in 5. In
addition, both N(1)–O(1) and C(2)–O(2) bonds are longer for the
bisbenzyl derivative 5, all of which suggests that in the absence of
conjugation with the CO2Me in 3b there is a build up of electron
density in non-bonding or antibonding orbitals localized in these
parts of the ring. Finally, there is substantial pyramidilization of
N(2) in 5 with the angles at the nitrogen summing to 321.9°, with
the smallest intraring angle being N(1)–N(2)–O(3), 103.4° at this
nitrogen.
O
O
N
N
2
1/2 Br2
- Br -
MeO2C
CO2Me
6
dimerize
O
O
MeO
O
N
O
MeO2C
C
N
7
MeO
O
-NO, - CO
O
Br2
O
O
O
N
N
N
O
N
CH2Cl2, Δ, 1.5 hr
ð3Þ
O
N
MeO2C
CO2Me
Acknowledgement
6
2
ð2Þ
The generous support from NSERC, CRC, and CIHR for a training
fellowship to IP is gratefully acknowledged.
à
Crystal data for 5: Crystallizes in the orthorhombic space group Pbca. Key
crystallographic parameters: a = 10.868(2) Å b = 8.8483(18) Å; c = 28.561(6) Å;
Supplementary data
a = b = c = 90°; V = 2746. 5(10) Å3
; ; crystal
Z = 4; qc = 1. 365 Mg mꢀ3
size = 0.11ꢁ0.06ꢁ0.05 mm3 Data: 2773 independent data and 190 parameters,
Sgof = 1.045; R1 = 3.82%, wR2 = 9.57%. Further details are available on the CCDC, #
646992.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2008.05.025.

4552
D. S. Bohle et al. / Tetrahedron Letters 49 (2008) 4550–4552
6. Arulsamy, N.; Bohle, D. S. Angew. Chem., Int. Ed. 2002, 41, 2089–2091.
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9. Bohle, D. S.; McQuade, L. E.; Perepichka, I.; Zhang, L. J. Org. Chem. 2007, 72,
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11. Tzeng, D.; Baum, K. J. Org. Chem. 1983, 48, 5384–5385.
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