Unusual ambident behavior and novel ring transformation of oxazolo[3,2-a]pyridinium salts

Article abstract of DOI:10.1002/(SICI)1099-0690(199801)1998:1<193::AID-EJOC193>3.0.CO;2-6

2-Aryloxazolo[3,2-a]pyridinium perchlorate, 1a, and its 5-methyl homologue, 1b, undergo quite different ring transformations when reacting with piperidine. For 1a the opening of the pyridine fragment occurs with formation of the isomeric aminobutadienes 2

Full text of DOI:10.1002/(SICI)1099-0690(199801)1998:1<193::AID-EJOC193>3.0.CO;2-6

FULL PAPER
Unusual Ambident Behavior and Novel Ring Transformation of
Oxazolo[3,2-a]pyridinium Salts
Eugene V. Babaev*a, Andrey V. Efimova, Dmitriy A. Maiborodaa, b, and Karl Jugb
Chemistry Department, Moscow State Universitya,
GSP-3, Moscow 119899, Russia
Fax: (internat.) ϩ7-095 / 932-8846
E-mail: eugene@babaev.chem.msu.su
Theoretische Chemie, Universität Hannoverb,
Am Kleinen Felde 30, Hannover 30167, Germany
Fax:(internat.) ϩ49(0)511/762-5939
E-mail: jug@mbox.theochem.uni-hannover.de
Received February 3, 1997
Keywords: Nitrogen heterocycles / Nucleophilic additions / Novel recyclization / Semiempirical calculations /
5-Aminoindolizine
2-Aryloxazolo[3,2-a]pyridinium perchlorate, 1a, and its 5-
methyl homologue, 1b, undergo quite different ring transfor- and 1b undergo an opening of the 5-membered ring when
mations when reacting with piperidine. For 1a the opening of reacting with alkali. These results are explained by quantum
the pyridine fragment occurs with formation of the isomeric chemical SINDO1 calculations, which give the energies of
ving the methyl group to form the 5-aminoindolizine 4. 1a
aminobutadienes 2 [with (1E,3E)-configuration] or 3 [(1E,3Z)-
isomer], depending on the temperature, whereas 1b under-
goes an unexpected recyclization of the oxazolium ring invol-
the isomeric C-5 and C-8a adducts with NMe2 and HO
groups.
The reactivity of the bicyclic heteroaromatic system ox- Scheme 1. Ring transformations of the fused oxazolopyridinium
perchlorates
azolo[3,2-a]-pyridinium perchlorate 1 with a bridgehead ni-
trogen (first prepared in 1960’s[1]) is still poorly investigated,
and there are only few examples given in the literature of
its reaction with nucleophiles. Such a cation undergoes an
opening of the oxazolium ring in alkaline solution,[2] and
it transforms the same ring in the reaction with primary
aliphatic[3] (but not aromatic[4]) amines, or some other nu-
cleophiles from the 5th main group.[5] Recently it was found
that carbanions can also be used to transform the cations 1
to indolizines.[6] Although the data reviewed indicate that
only the 5-membered ring opens, the closely related het-
eroanalog, the thiazolo[3,2-a]pyridinium cation, undergoes
an opening of the 6-membered ring in reactions with sec-
ondary amines.[7] No data on the reactions of the cation 1
with secondary amines is available.
We report here that 2-aryloxazolo[3,2-a]pyridinium per-
chlorate, 1a, and its 5-methyl homologue, 1b, undergo quite
different ring transformations with piperidine. For 1a the
opening of the six-membered fragment (previously un-
NMR spectra correspond only to the piperidyl group; the
known for this ring system) occurs with formation of the
absence of other aliphatic carbon atom peaks (expected for
isomeric aminobutadienes 2 and 3, whereas the 5-methyl
any of the addition products) is supporting evidence for the
presence of the open-chain structure. The intense bands in
the UV spectra of 2 (λmax ϭ 350 nm and 462 nm), typical
homologue 1b reacts with the same amine to give 5-piper-
idylindolizine 4 (Scheme 1).
Heating of the salt 1a with piperidine results in formation for conjugated dienes with intramolecular charge transfer,
of the 1:1 adduct (2) of the starting materials; the compo- and the diene band ( ν ϭ 1625 cmϪ1) in its IR spectra, also
sition of the product is confirmed by the MS and elemental confirm that the opening occurs at the six-membered ring.
analysis data. The aliphatic carbon atom signals in the 13C- In the MS of 2 the observed peak M ϭ 241 (loss of the
Eur. J. Org. Chem. 1998, 193Ϫ196
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193

E. V. Babaev, A. V. Efimov, D. A. Maiboroda, K. Jug
FULL PAPER
piperidine fragment) may be associated with the probable selectivity of ring opening, we performed quantum chemical
reversed cyclization of 2 to the cation 1a. The coupling con- SINDO1[12] calculations for the adducts formed from cat-
1
stants in the H-NMR spectra of 2 (J23 ϭ 12.9 Hz, J23
ϭ
ions 1a and 1b and hydroxyl and dimethylamino groups.
Since there are a few electron deficient positions in the
bicyclic ring system 1 the isomeric C-5-, C-8a-, C-7-, and
11.3 Hz, J34 ϭ 15.2 Hz) support the all-(E) configuration
of the butadiene structure of 2.
The reaction of the salt 1a with piperidine at room temp. C-2-adducts with nucleophiles are taken for comparison for
leads to the isomeric aminobutadiene 3. The spectral data every homolog. The structures of the adducts were fully op-
(UV, IR, and MS) and chromatographic behavior of the timized by SINDO1. The total energy (see Table 1) was, in
isomers 2 and 3 are quite similar, and the main difference is all cases, lowest for the C-8a-adduct (favorable for 5-mem-
1
manifested in their H-NMR spectra in benzene. The final bered-ring opening). This can explain the observed results
assignment of the (1E,3Z) configuration to isomer 3 and of the reactions of the cations 1a and 1b with alkali, as well
(1E,3E) configuration to isomer 2 was confirmed by as the initial step of the recyclization 1b Ǟ 4 (see Scheme
NOESY (Scheme 2). The ring opening reactions of 1a to 2 1). The question arises of how to explain the reactions 1a
and 3 occur smoothly, and open an easy route to the un- Ǟ 2 (1a Ǟ 3), where the initial step of the pyridine-ring
known α-amino-ω-(oxazolyl-2)-butadienes which have a opening requires the nucleophilic attack of the amine at po-
high asymmetry in their π-electron density.
sition C5. The answer can be found in Table 2, where the
relative energies of the isomeric adducts are given with re-
spect to the most stable case. As one can conclude, just in
the unique case of C-5 and C-8a adducts of cation 1a with
amine the difference in energy between these two adducts
is negligible. Hence, the driving force for the experimentally
observed 6-membered-ring opening may not be the initial
nucleophilic attack, but the next step of ring cleavage (5- or
6-membered). One can assume that formation of the dien-
eamines 2 and 3 (via the 6-membered-ring opening) may be
much more preferable than the formation of the zwit-
terionic adduct that would result in the case of 5-mem-
Scheme 2. NOESY data and configuration of the aminobutadienes
2 and 3
The salt 1b, in the same reaction with piperidine, yields bered-ring cleavage.
the red product 4, with properties quite different from those
Table 1. Total energy (Hartree)[a] of adducts between the cations
expected from either an adduct or a ring-opening product.
Absence of the signal of methyl group in its 1H-NMR spec-
tra, and appearance of two singlets in the aromatic region,
confirm the closure of the new pyrrole ring via transfor-
mation of the oxazolium fragment and involving the methyl
1a,b and nucleophiles
Oxazolopyridine 1
1a (5-H)
1b (5-Me)
Nucleophile/Place
OH
NMe2
OH
NMe2
1
group. Indeed, the H-NMR spectra of 4 is similar to the
of addition
8a
5
7
2
Ϫ86.621 Ϫ95.196 Ϫ93.548 Ϫ102.124
spectra of the reference structure 2-(p-nitrophenyl)indoliz-
ine, and the absence of a downfield signal of 5-H is compen-
sated by appearance of 5-piperidyl group signals. The mul-
tiplet of 7-H (unresolved in CDCl3) can be resolved in
Ϫ86.613 Ϫ95.194
3.527 Ϫ102.099
Ϫ86.601 Ϫ95.184 Ϫ93.530 Ϫ102.113
Ϫ86.604 Ϫ95.183 Ϫ93.534 Ϫ102.115
[a] 1 Hartree ϭ 627.5 kcal/mol.
(CD3)2CO. The doublets for protons 6-H (δ ϭ 6.09, J67
ϭ
7.3 Hz) and 8-H (δ ϭ 7.17, J78 ϭ 8.8 Hz), that are separated
from 7-H by a single and a double CϪC bond, respectively,
have been assigned according to the known trend for J in
2
Table 2. Relative energies (kcal/mol) of isomeric adducts in respect
to the most stable C-5-adduct
the cyclic polyenes.[8] Assignment of the structure 4 to the
still unknown class of 5-aminoindolizine[9] is also supported
by the fact that it forms a deep blue dye with p-dimethylam-
inobenzaldehyde (the classical Ehrlich test), typical for in-
dolizines.[10] In CF3COOH indolizine 4 undergoes pro-
tonation at C-3 (a singlet at δ ϭ 5.62 is usual for CH2 pro-
tons of 3H-indolizinium cations).[11]
Oxazolopyridine 1
1a (5-H)
1b (5-Me)
Nucleophile/Place
OH
NMe2
OH
NMe2
of addition
8a
5
7
2
0
0
0
0
4.46
12.37
10.31
0.82
7.57
8.03
13.13
11.12
8.28
15.80
7.28
5.96
The unusual shift of the ring-opening selectivity from the
cation 1a to 1b may be connected with either the sterical
effect of the 5-methyl group, or its possible deprotonation.
It should be also mentioned that both homologues 1a and
The previously unreported opening of 6-membered ring
1b undergo the expected opening of 5-membered ring when in 1a, is somewhat similar to the behavior of the related
reacting with alkali to form N-(β-oxoalkyl)pyridones-2. In bridgehead nitrogen heterocycles,[7][13][14] and is the first
order to clarify the complex influence of the 5-methyl proof of the ambident properties of the cation 1. The sec-
group, and the nature of the attacking nucleophile on the ond transformation discovered, 1b Ǟ 4, which opens a
194
Eur. J. Org. Chem. 1998, 193Ϫ196

Novel Ring Transformation of Oxazolo[3,2-a]pyridinium Salts
FULL PAPER
2-(p-Nitrophenyl)-5-piperidylindolizine (4): 0.1 g (0.282 mmol) of
the salt 1b in 1 ml of piperidine was refluxed for 15 min. The cooled
mixture was poured into water, and the resulting solid was filtered
and purified by column chromatography (Silpearl, CHCl3), giving
3 (0.06 g, 66%, m.p. 174°C, EtOH). Ϫ C19H19N3O2 (321.2): calcd.
route to unknown 5-aminoindolizines, is quite unusual,
even when one considers the entire family of bridgehead
azoloazines.[14] It should be mentioned that this novel dis-
connection scheme for the construction of the indolizine
ring was recently predicted[15] using the computer pro-
gram GREH.[16]
1
C 71.01, H 5.90, N 13.08; found C 70.87, H 5.98, N 13.17. Ϫ H
NMR (CDCl3, 200 MHz, TMS): δ ϭ 8.23Ϫ7.80 (m, 4 H, p-
NO2Ph), 7.70 (s, 1 H, H-3), 7.17 (d, J ϭ 8.8 Hz, 1 H, H-8), 6.77
(s, 1 H, H-1), 6.77 (dd, J ϭ 8.8/7.3 Hz, 1 H, H-7), 6.09 (d, J ϭ 7.3
Hz, 1 H, H-6), 3.1 (m, 4 H, piperidyl), 1.6 (m, 6 H, piperidyl). Ϫ
1H NMR (CF3COOH, 400 MHz): δ ϭ 8.43 (m, 2 H, p-NO2Ph),
8.29 (m, 1 H, H-7), 7.93 (m, 2 H; p-NO2Ph), 7.58 (d, J ϭ 7.9 Hz,
1 H, H-8), 7.55 (s, 1 H, H-1), 7.32 (d, J ϭ 8.5 Hz, 1 H, H-6), 5.62
(s, 2 H, H-3), 3.53 (s, 4 H, piperidyl), 1.91 (s, 6 H, piperidyl). Ϫ
MS; m/z (%): 321 (100) [Mϩ], 292 (71), 238 (79), 192 (33), 96 (24).
2-(p-Nitrophenyl)indolizine:[18] 1H NMR (CDCl3, 400 MHz,
TMS): δ ϭ 8.25 (m, 2 H, p-NO2Ph), 7.91 (d, J ϭ 7.0 Hz, 1 H, H-
5), 7.77 (m, 2 H, p-NO2Ph), 7.66 (s, 1 H, H-3), 7.38 (d, J ϭ 9.0
Hz, 1 H, H-8), 6.74 (s, 1 H, H-1), 6.7 (dd, J ϭ 6.8 Hz, J ϭ 9.0 Hz,
1 H, H-7), 6.52 (t, J ϭ 7.0/6.8 Hz, 1 H, H-6).
We thank the Russian Foundation of Basic Research (Grant
No.96-03-32953), St. Petersburg Center of Fundamental Natural
Sciences (GRACENAS, Grant No.95-0-9.4-222), and the Volk-
swagen-Stiftung for generous support. We also thank A. Stepanov
for the NMR spectra and the members of the theoretical chemistry
group at Hannover for help with the calculations.
Experimental Section
2-(p-Nitrophenyl)oxazolo[3,2-a]pyridinium Perchlorate (1a): 1.0
g (3.87 mmol) of N-(p-nitrophenacyl)pyridone-2[17] was dissolved
in 2 ml of H2SO4 and kept for about 12 h. The solution was diluted
by 150 ml of water, heated to 90°C, and 70% HClO4 (10 ml) was
then added to the hot filtered solution, giving 1a as a white solid
(0.93 g, 70%, m.p. 190Ϫ191°C, H2O/EtOH, 1:1). Ϫ C13H9ClN2O7
(340.5): calcd C 45.83, H 2.66, N 8.22; found C 45.74, H 2.70, N
8.02. Ϫ 1H NMR (CF3COOH, 400 MHz, TMS): δ ϭ 9.05 (d, 1 H,
H-5), 8.92 (s, 1 H, H-3), 8.5Ϫ8.6 (m, 3 H, H-7, p-NO2Ph), 8.2Ϫ8.3
(m, 3 H, H-8, p-NO2Ph), 8.00 (t, 1 H; H-6).
6-Methyl-N-(p-nitrophenacyl)pyridone-2: A mixture of 6.0 g
(24.6 mmol) of p-nitrophenacyl bromide, and 3.0 g (24.4 mmol) of
2-methoxy-6-methylpyridine in 20 ml of CH3CN, was refluxed for
11 h yielding a solid (2.5 g, 39%, m.p. 186°C, PrOH). Ϫ
C14H12N2O4 (272.3): calcd. C 61.76, H 4.44; found C 61.78, H 4.68.
Ϫ IR (nujol): ν ϭ 1700 cmϪ1(COPh), 1670 (CON). Ϫ 1H NMR
(CDCl3, 200 MHz, TMS): δ ϭ 8.3 (m, 4 H, p-NO2Ph), 7.33 (dd,
J ϭ 6.8/9.2 Hz, 1 H, H-4), 6.5 (d, J ϭ 9.2 Hz, 1 H, H-3), 6.15 (d,
J ϭ 6.8 Hz, 1 H, H-5), 5.49 (s, 2 H, CH2), 2.29 (s, 3 H, CH3). Ϫ
MS; m/z (%): calcd. 272 (97) [Mϩ].
5-Methyl-2-(p-nitrophenyl)oxazolo[3,2-a]pyridinium Perchlorate
(1b) was prepared, by the method described for 1a, from 6-methyl-
N-(p-nitrophenacyl)pyridone-2;
69%,
m.p.
255°C.
Ϫ
C14H11ClN2O7 (354.5): calcd. C 47.41, H 3.13, N 7.90; found C
1
47.14, H 3.09, N 7.89. Ϫ H NMR (CF3COOH, 400 MHz, TMS):
δ ϭ 8.86 (s, 1 H, H-3), 8.53 (m, 2 H, p-NO2Ph), 8.45 (dd, 1 H, H-
7), 8.27 (m, 2 H, p-NO2Ph), 8.10 (d, 1 H, H-8), 7.78 (d, 1 H, H-6),
3.07 (s, 3 H, CH3).
[1]
C. K. Bradsher, M. Zinn, J. Heterocycl. Chem. 1967, 4, 66Ϫ70.
4-[5-(p-Nitrophenyl)oxazolyl-2]-1-piperidylbutadiene-(1E,3E)
(2): To a solution of 0.2 g (0.59 mmol) of the salt 1a in 5 ml of
CH3CN 0.5 ml of piperidine was added, and the mixture was re-
fluxed for 1 h. The cooled solution was poured into 30 ml of water,
yielding a dark-red solid (0.157 g, 88%, m.p. 179Ϫ180°C). Ϫ
C18H19N3O3 (325.1): calcd. C 66.45, H 5.88, N 12.91; found C
66.59, H 5.95, N 12.35. Ϫ 1H NMR ([D6]benzene, 200 MHz,
TMS): δ ϭ 7.93 (m, 2 H, p-NO2Ph), 7.12 (m, 2 H, p-NO2Ph), 7.60
(dd, J ϭ 11.3/15.2 Hz, 1 H, H-3), 7.30 (s, 1 H; H in oxazole), 6.35
(d, J ϭ 15.2 Hz, 1 H; H-4), 6.12 (d, J ϭ 12.9 Hz, 1 H; H-1), 5.23
(dd, J ϭ 11.3/12.9 Hz, 1 H, H-2), 2.7 (m, 4 H, piperidyl), 1.1 (m,
6 H, piperidyl). Ϫ MS; m/z (%): 325 (60) [Mϩ], 241 (100) [C13H9-
N2O3ϩ], 195 (70) [C13H9NOϩ], 122 (10) [p-NO2Ph], 84 (6) [piperi-
dyl]. Ϫ UV/Vis (CHCl3): λmax (lg ε) ϭ 259 nm (3.80), 287 (3.80),
350 (4.32), 462 (4.36).
[2]
H. Pauls, F. Kröhnke, Chem. Ber. 1976, 109, 3646Ϫ3652.
[3]
A. R. Katritzky, A. Zia, J. Chem. Soc. Perkin Trans. 1, 1982,
1, 131Ϫ136.
[4]
C. K. Bradsher, R. D. Brandau, J. E. Boilek, T. L. Hough, J.
Org. Chem. 1969, 34, 2129Ϫ2133.
[5]
G. Markl, S. Pflaum, Tetrahedron Lett. 1988, 28, 1511Ϫ1514.
[6a] E. V. Babaev, S. V. Bozhenko, D. A. Maiboroda, Russ. Chem.
[6]
Bull. (Engl. Ed.) 1995, 44, 2203. Ϫ [6b] E. V. Babaev, S. V. Bozh-
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[7]
Gy. Hajos, A. Messmer, J. Heterocycl. Chem. 1984, 21,
809Ϫ811.
[8]
P. Crews, R. R. Kintner, H. C. Padget, J. Org. Chem. 1973,
38, 4391Ϫ4395.
[9] [9a]
5-aminoindolizines can not be obtained from α-amino-αЈ-
picolines and phenacylhalides by usual Tschitchibabin method,
see F. Mattu, E. Marongiu, Rend. Sem. Fac. Sci. Univ. Calgiari
1964, 34, 190 Ϫ206 [Chem. Abstr. 1965, 63, 18069c]. Ϫ [9b] Only
unique members of 5-NR2-8-NO2-indolizines may be prepared
by SNH reaction of 8-nitroindolizines, see A. N. Kost, R. S.
Sagitullin, S. P. Gromov, Heterocycles 1977, 7, 997Ϫ1001.
4-[5-(p-Nitrophenyl)oxazolyl-2]-1-piperidylbutadiene-(1E,3Z)
(3): A solution of 0.2 g (0.59 mmol) of the salt 1a in 1 ml of piperi-
dine was kept for 2 h at 20°C. The solution was poured into 50 ml
of water, giving a dark-red solid (0.155 g, 81%, m.p. 160Ϫ161°C).
1H NMR ([D6]benzene, 200 MHz, TMS): δ ϭ 7.90 (m, 2 H, p-
NO2Ph), 7.09 (m, 2 H, p-NO2Ph), 7.40 (s, 1 H, H in oxazole), 7.03
(dd, J ϭ 9.0/12.9 Hz, 1 H, H-2), 6.55 (dd, J ϭ 9.0/10.7 Hz, 1 H,
H-3), 6.22 (d, J ϭ 12.9 Hz, 1 H, H-1), 5.97 (d, J ϭ 10.7 Hz,1 H,
H-4), 2.8 (m, 4 H, piperidyl), 1.2 (m, 6 H, piperidyl). Ϫ MS; m/z
(%): 325 (63) [Mϩ], 241 (100) [C13H9N2O3ϩ], 195 (66) [C13H9NOϩ],
122 (15) [p-NO2Ph], 84 (8) [piperidyl]. Ϫ UV/Vis (CHCl3): λmax (lg
ε) ϭ 259 nm (4.46), 287 (4.41), 346 (4.88), 464 (4.88). Whilst in the
NMR tube (solvent C6D6 or CDCl3) 2 slowly isomerized to 3.
[10]
W. Flitsch in Comprehensive Heterocyclic Chemistry, vol. 4 (Eds.:
A. R. Katritzky, C. W. Rees), Pergamon, Oxford, 1984, p.
443Ϫ495.
[11] [11a] Review: E. V. Babaev, V. N. Torocheshnikov, S. I. Bobrovs-
kii, Khim. Geterotsikl. Soedin. (Engl. Transl.) 1995, 9,
[11b]
1079Ϫ1087; [Chem. Abstr. 1996, 124, 342267g]. Ϫ
M.
Fraser, S. McKenzie, D. H. Reid, J. Chem. Soc. (B) 1966, 1,
44Ϫ48.
[12] [12a] D. N. Nanda, K. Jug, Theor. Chim. Acta 1980, 57, 95Ϫ106.
[12b]
Ϫ
K. Jug, D. N. Nanda, Theor. Chim. Acta 57, 107Ϫ130.
[13]
[14]
D. Mörler, F. Kröhnke, Liebigs Ann. Chem. 1971, 744, 65Ϫ80.
Review on the ring-opening reactions of bridgehead azoloaz-
ines, see D. A. Maiboroda, E. V. Babaev, Khim. Geterotsikl.
Soedin. (Engl. Transl) 1995, 11, 1251Ϫ1279; [Chem. Abstr.
1996, 125, 33500r].
Eur. J. Org. Chem. 1998, 193Ϫ196
195

E. V. Babaev, A. V. Efimov, D. A. Maiboroda, K. Jug
FULL PAPER
[15]
[17]
[18]
General methodology of computer generation of recyclizations
Synthesis of N-(p-nitrophenacyl)pyridone-2 see U. M. Teotino,
L. Polo-Friz, A. Gandini, D. Della-Bella, Farmaco Ed. Sci.
(Pavia) 1962, 7, 988Ϫ999 (Chem. Abstr. 1966, 64, 9676h).
Synthesis of indolizine 4 see: E. T. Borrows, D. O. Holland, J.
Kenyon, J. Chem. Soc. 1946, 11, 1077Ϫ1088.
starting on the prototype or target heterocycle with 16 selected
predictions, see: E. V. Babaev, N. S. Zefirov, Khim. Geterotsikl.
Soedin. (in Russian) 1996, 11Ϫ12, 1564Ϫ1580; [Chem. Abstr.
1997, 126, 211728b].
[16]
Computer program GREH (Graphs of Recyclizations of Heter-
[97046]
ocycles), see: E. V. Babaev, D. E. Lushnikov, N. S. Zefirov, J.
Am. Chem. Soc. 1993, 115, 2416Ϫ2427.
196
Eur. J. Org. Chem. 1998, 193Ϫ196