The -NH-(C=)-Br functionality of heteroaromatic compounds as a synthon for fused dihydrooxazoles

Article abstract of DOI:10.1002/jhet.552

Fused dihydrooxazoles are produced by the reaction of 8-bromoteophylline (1), 6-bromo-2-pyridone (7), or 2-bromobenzimidazole (11) with an N-substituted N-(2,3-epoxypropyl)amine. The product derived from 1 undergoes rearrangement to a fused dihydrooxazine

Full text of DOI:10.1002/jhet.552

720
The ANHA(C¼¼)ABr Functionality of Heteroaromatic
Vol 48
Compounds as a Synthon for Fused Dihydrooxazoles
Marek T. Cegla,a* Marzena Baran,a Agnieszka Czarny,b Marek Zylewski,a
Joanna Potaczek,a Jeff Klenc,c and Lucjan Strekowskic
aDepartment of Organic Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College,
PL 30-688 Krakow, Poland
bDepartment of Organic Chemistry, Faculty of Chemistry, Jagiellonian University,
PL 30-060 Krakow, Poland
cDepartment of Chemistry, Georgia State University, Atlanta, Georgia 30302-4098
*E-mail: mfceglam@cyf-kr.edu.pl
Received March 9, 2010
DOI 10.1002/jhet.552
Published online 15 March 2011 in Wiley Online Library (wileyonlinelibrary.com).
Fused dihydrooxazoles are produced by the reaction of 8-bromoteophylline (1), 6-bromo-2-pyridone
(7), or 2-bromobenzimidazole (11) with an N-substituted N-(2,3-epoxypropyl)amine. The product
derived from 1 undergoes rearrangement to a fused dihydrooxazine while the fused dihydrooxazoles
derived from 7 and 11 are stable.
J. Heterocyclic Chem., 48, 720 (2011).
INTRODUCTION
the presence of a catalytic amount of pyridine. We have
shown previously that pyridine accelerates the chemistry
mentioned above. On the other hand, heating of the
mixtures of 1 and 2 resulted in the initial appearance of
several products that were difficult to separate by chro-
matography. Heating under reflux for 6 h resulted in
complete consumption of the substrate 1, as observed by
thin layer chromatography (TLC), and the formation of
a major product 6. After purification, the dihydrooxazine
6 was obtained in 65% yield. The intermediary of
dihydrooxazoles, such as 4 in Scheme 1, has been noted
previously, and these intermediate products have
previously been isolated and characterized. Heating of
pure dihydrooxazoles resulted in rearrangement to
dihydrooxazines.
Recently, we have reported three examples of a syn-
thesis of 7-(substituted aminomethyl)-6,7-dihydrooxa-
zolo[2,3-f]purines by the reaction of 8-bromotheophyl-
line with an N-substituted N-(2,3-epoxypropyl)amine
[1,2]. The dihydrooxazole product can be isolated but
heating of the crude mixture results in a rearrangement
of the dihydrooxazole to a dihydrooxazine. This chemis-
try is exemplified in Scheme 1 by our previously unre-
ported synthesis of the oxazine derivative 6 by treatment
of 8-bromotheophylline (1) with 1-(2,3-epoxypropyl)-4-
phenylpiperazine (2) followed by rearrangement of the
intermediate dihydrooxazole 4. In addition to the dihy-
drooxazole, such as 4, the mechanism suggested previ-
ously postulates the formation of an open-chain interme-
diate 3 and a zwitterionic structure 5. Additional studies
on the formation of fused dihydrooxazoles are reported
in this article.
It was postulated that similar chemistry could be
achieved by treatment with aminomethyloxiranes of other
heterocyclic substrates containing the AHNA(C¼¼)ABr
functionality. Indeed, the reactions of 6-bromo-2-pyridone
(7) with the aminomethyloxirane 2 and N-(2,3-epoxypro-
pyl)morpholine (9) produced the respective dihydrooxa-
zoles 8 and 10 as the major products (Scheme 2). These
products did not show any instability (rearrangement to
dihydrooxazines) on crystallization from heptanes. This
feature is in a sharp contrast to the instability of dihy-
drooxazoles derived from 8-bromotheophylline.
RESULTS AND DISCUSSION
The treatment of substrate 1 with various aminome-
thyloxiranes was conducted previously at room tempera-
ture and gave the corresponding dihydrooxazoles in high
yields [1,2]. By contrast, a solution of the substrates 1
and 2 in ethanol did not show any changes when left at
room temperature for 2 days either in the absence or in
The reaction of 2-bromobenzimidazole (11) with the
aminomethyloxirane 9 is depicted in Scheme 3. Two
C
V
2011 HeteroCorporation

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The ANHA(C¼¼)ABr Functionality of Heteroaromatic
721
Compounds as a Synthon for Fused Dihydrooxazoles
Scheme 1
products were observed by TLC, which were isolated
and shown to be an open-chain product 12 and a dihy-
drooxazole 13. Again, compound 13 is stable and does
not undergo rearrangement upon heating. Compound 12
is a precursor to dihydrooxazole 13 because the intensity
of 13 on TLC was increasing with time at the expense
of the decreasing amount of 12. Under the optimized
conditions for 13, its isolated yield was 85% and the
intermediate product 12 was obtained in a 9% yield.
Previously, we have postulated the intermediary of
the open-chain products in the synthesis of dihydrooxa-
zoles, resulting from opening of the oxirane ring of
the aminomethyloxirane substrates. Compound 12 is
the first example of the isolated and characterized inter-
mediate product in these types of syntheses. This result
is fully consistent with the proposed mechanism (see
Scheme 1).
Scheme 2
The zwitterionic intermediate compound 5 is the
postulated direct precursor to the dihydrooxazine 6. The
Scheme 3
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

722
M. T. Cegla, M. Baran, A. Czarny, M. Zylewski, J. Potaczek, J. Klenc, and L. Strekowski
Vol 48
Table 1
Finally, we wish to comment on the structure determi-
nation that was conducted by using a variety of spectral
Summary of the calculated charges on the oxygen atom of the
1
methods including HR-MS and H-NMR and elemental
zwitterionic intermediate product 5 and similar zwitterions 14–16
derived from 8, 10, and 13, respectively.
analyses. The molecular composition of the synthesized
compound, with the only exception of 12, was supported
by both the HR-MS data and elemental analysis.
Although product 12 was characterized by HR-MS only,
No.
Mulliken Natural Electrostatic
ꢀ0.6051 ꢀ0.7014 ꢀ0.5587
5
1
its H- and 13C-NMR spectra showed high purity. Anal-
ysis of the HR-MS data or elemental analysis results
could not distinguish between dihydrooxazoles and iso-
1
meric dihydrooxazines. On the other hand, the H-NMR
spectra of these isomeric molecules are strikingly
different. Especially diagnostic are chemical shifts for
methine protons at the asymmetric carbons because the
proton is adjacent to the methylene group in a dihy-
drooxazole and to an amino group in a dihydooxazine.
The validation of this approach was obtained by com-
14
ꢀ0.6291 ꢀ0.7109
ꢀ0.5876
1
parison of H-NMR spectra of the isomeric dihydrooxa-
zoles and dihydrooxazines derived from 8-bromotheo-
phylline. The chemical shifts of the previously synthe-
sized isomers were rigorously assigned by using COSY,
NOESY, HSQC, and HMBC techniques [1,2]. Similarly,
these 2D NMR techniques were used to confirm chemi-
cal structure of newly synthesized compounds. Espe-
cially important for that purpose were NOESY and
long-range 1H and 13C correlation spectra (HMBC),
which show correlations signals between proper atoms
of morpholine (compounds 10, 13) or piperazine (com-
pound 8) rings and atoms of oxazole moiety.
15
ꢀ0.6275 ꢀ0.7082
ꢀ0.6011
16
ꢀ0.6577 ꢀ0.7670
ꢀ0.6963
EXPERIMENTAL
Melting points (Pyrex capillary) are not corrected. Mass
spectra and high resolution time-of-flight mass spectra were
recorded using electron-spray ionization with 0.1% formic acid
in methanol. 1H- and 13C-NMR spectra were obtained at 300
and 75 MHz, respectively, in deuteriochloroform solution with
the solvent used as an internal standard. All commercial
reagents were purchased from Aldrich or Fluka. The aminome-
thyloxiranes 2 and 9 were synthesized by the reaction of epi-
chlorohydrin with morpholine and N-phenylpiperazine, respec-
tively, by using a general method [3–5]. TLC analysis was
conducted by using silica gel-coated plates.
For charge calculations, all structures were d0rawn in Hyper-
chem 8.0 (Hypercube) and imported to Spartan 04 (Wavefunc-
tion). For each structure, the lowest energy conformation was
determined with the equilibrium conformer module using a
molecular mechanics force field. The equilibrium geometry of
the lowest energy conformer was then calculated using B3LYP
density functional theory and 6-31G* basis set. The partial
charges were calculated from this geometry as Mulliken, natu-
ral, and electrostatic charges [6].
facile rearrangement of dihydrooxazole 4 to dihydrooxa-
zine 6 through the presumed intermediary of 5 and the
observed stability of other dihydrooxazoles were
approached by calculating charge densities on the oxy-
gen atoms of 5 and analogous hypothetical structures
14–16 derived from stable dihydrooxazoles 8, 10, and
13, respectively. The charges were calculated as Mul-
liken, natural, and electrostatic charges and are shown in
Table 1. As can be seen, regardless of the method used,
the partial charge is less concentrated in 5 than in the
other structures analyzed. This result is consistent with
good stabilization of the negative charge in the zwitter-
ion 5 and, subsequently, facile ring opening of dihy-
drooxazole 4 to stable zwitterion 5. Conversely, the cor-
responding zwitterions 14–16 would be less stable and,
apparently, are not formed.
7-(4-Phenylpiperazino)-7,8-dihydro-6H-[1,3]oxazino[2,3-
f]theophylline (6). A solution of 8-bromotheophylline (1,
0.26 g, 1 mmol), 1-(2,3-epoxypropyl)-4-phenylpiperazine (2,
0.44 g, 2 mmol), and pyridine (0.08 g, 1 mmol) in anhydrous
ethanol (5 mL) was heated under reflux under a nitrogen
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The ANHA(C¼¼)ABr Functionality of Heteroaromatic
723
Compounds as a Synthon for Fused Dihydrooxazoles
atmosphere for 6 h, after which time the TLC analysis (chloro-
form/triethylamine, 3:1) showed the absence of 1. The solution
was concentrated to 3 mL and refrigerated for 24 h. The re-
sultant crystalline precipitate was filtered, washed with diethyl
ether, and crystallized twice from n-butanol; yield 0.26 g
Compounds 12 and 13. A solution of 2-bromobenzimida-
zole (11, 0.10 g, 0.51 mmol), N-(2,3-epoxypropyl)morpholine
(9, 0.16 g, 1.1 mmol), and a few drops of pyridine in isopropa-
nol (5 mL) was heated under reflux for 19 h, after which time
the TLC analysis (chloroform/methanol, 9:1) showed the ab-
sence of 11. After concentration under reduced pressure, the
residue was subjected to silica gel chromatography eluting
with hexanes/ethanol/triethylamine (5:1:1) (compound 13) and
then with dichloromethane/methanol (49:1) (additional purifi-
cation of 12).
1
(66%), mp 236–238ꢁC; H-NMR: d 2.82 (m, 4H), 3.10 (pent,
J ¼ 5 Hz, 1H, C*H), 3.19 (m, 4H), 3.38 (s, 3H), 3.51 (s, 3H),
4.28 (d, J ¼ 5 Hz, 2H), 4.56 (d, J ¼ 5 Hz, 2H), 6.89 (m, 3H),
7.28 (m, 2H); 13C-NMR (deuteriochloroform): d 27.8, 29.8,
44.1, 49.3, 50.2, 54.2, 68.1, 102.9, 116.2, 120.2, 129.2, 147.1,
150.9, 151.7, 153.0, 154.5. High resolution ms. Calcd for
C20H25N6O3 (Mþ þ 1): m/z 397.1988. Found: m/z 397.1987.
Anal. Calcd. For C20H24N6O3: C, 60.59; H, 6.10; N, 21.19.
Found: C, 60.56; H, 6.18; N, 20.91.
General procedure for 8 and 10. A solution of 6-bromo-2-
pyridone (7, 0.17 g, 1 mmol), 1-(2,3-epoxypropyl)-4-phenylpi-
perazine (2, 0.33 g, 1.5 mmol) or N-(2,3-epoxypropyl)morpho-
line (9, 0.22 g, 1.5 mmol), and pyridine (0.08 g, 1 mmol) in
anhydrous ethanol (5 mL) was heated under reflux under a
nitrogen atmosphere for 4 h. After concentration, the oily resi-
due was subjected to silica gel chromatography eluting with
chloroform/methanol (15:1). Product 8 was crystallized from
n-heptane/toluene (3:1) and product 10 was crystallized from
n-heptane.
2-Bromo-1-(2-hydroxy-3-morpholinopropyl)benzimidazole
(12). This compound was obtained as an oil in a 9% yield (16
mg); 1H-NMR: d 2.50 (br s, exchangeable with D2O, 1H),
2.70 (m, 2H), 2.84 (m, 2H), 3.60 (m, 5H), 3.87 (dd, J ¼ 14
Hz, J ¼ 8 Hz, 1H), 4.18 (m, 2H), 4.45 (dd, J ¼ 14 Hz, J ¼ 8
Hz, 1H), 7.27 (m, 3H), 7.69 (d, J ¼ 8 Hz, 1H); 13C-NMR: d
38.1, 43.7, 49.0, 62.1, 67.2, 109.3, 119.6, 122.7, 123.2, 130.2,
135.4, 155.1. High resolution ms. Calcd. for C14H1979BrN3O2
(Mþ þ 1): m/z 340.0662. Found: m/z 340.0658.
2-(Morpholinomethyl)-2,3-dihydro-4H-[1,3]oxazolo[3,2-a]benz-
imidazole (13) This compound was obtained in an 85% yield
1
(113 mg), mp 147–149ꢁC; H-NMR: d 2.61 (m, 4H), 2.85 (m,
2H), 3.68 (m, 4H), 4.07 (dd, J ¼ 9 Hz, J ¼ 7 Hz, 1H), 4.31
(dd, J ¼ 9 Hz, J ¼ 8 Hz, 1H), 5.47 (m, 1H, C*H), 7.15 (m,
3H), 7.50 (m, 1H); 13C-NMR: d 45.2, 54.5, 61.1, 66.8, 85.7,
108.5, 118.8, 121.0, 121.9, 131.0, 146.6, 163.6. High resolu-
tion ms. Calcd. For C14H18N3O2 (Mþ þ 1): m/z 260.1400.
Found: m/z 260.1406. Anal. Calcd. for C14H17N3O2: C, 64.85;
H, 6.61; N, 16.20. Found: C, 64.65; H, 6.67; N, 15.94.
2-[(4-Phenylpiperazino)methyl]-2,3-dihydro-5H-[1,3]oxa-
zolo[3,2-a]pyridin-5-one (8). This compound was obtained in
a 40% yield (0.12 g), mp 135–136ꢁC; 1H-NMR: d 2.80 (m,
6H), 3.20 (m, 4H), 4.08 (m, 1H), 4.38 (dd, J ¼ 12 Hz, J ¼ 8
Hz, 1H, CH), 5.09 (m, 1H, C*H), 5.61 (d, J ¼ 7 Hz, 1H),
6.09 (d, J ¼ 9 Hz, 1H), 6.87 (m, 3H), 7.33 (m, 3H); 13C-
NMR: d 47.2, 49.1, 54.1, 60.6, 78.9, 83.5, 110.2, 116.1, 119.9,
129.1, 142.4, 151.1, 156.8, 161.0. High resolution ms. Calcd.
for C18H22N3O2 (Mþ
312.1707. Anal. Calcd. for C18H21N3O2: C, 69.43; H, 6.79; N,
13.49. Found: C, 69.09; H, 6.81; N, 13.46.
þ
1): m/z 312.1712. Found: m/z
REFERENCES AND NOTES
[1] Cegla, M. T.; Potaczek, J.; Zylewski, M.; Strekowski, L.
J Heterocycl Chem 2009, 46, 191.
2-(Morpholinomethyl)-2,3-dihydro-5H-[1,3]oxazolo[3,2-a]pyr-
idin-5-one (10). This compound was obtained in a 40% yield
(0.09 g), mp 75–76ꢁC; 1H-NMR: d 2.57 (m, 4H), 2.74 (m,
2H), 3.70 (m, 4H), 4.06 (dd, J ¼ 12 Hz, J ¼ 7 Hz, 1H), 4.35
(dd, J ¼ 12 Hz, J ¼ 8 Hz, 1H), 5.08 (m, 1H, C*H), 5.59 (d, J
¼ 7 Hz, 1H), 6.09 (d, J ¼ 9 Hz, 1H), 7.33 (dd, J ¼ 9 Hz, J ¼
7 Hz, 1H); 13C-NMR: d 47.1, 54.4, 61.0, 66.8, 78.7, 83.5,
110.2, 142.3, 156.8, 161.0. High resolution ms. Calcd. for
C12H17N2O3 (Mþ þ 1): m/z 237.1240. Found: m/z 237.1245.
Anal. Calcd. for C12H16N2O3: C, 61.00; H, 6.83; N, 11.86.
Found: C, 60.74; H, 6.82; N, 11.74.
[2] Cegla, M. T.; Potaczek, J.; Zylewski, M.; Strekowski, L.
Tetrahedron Lett 2005, 46, 3561.
[3] Achmatowicz, O.; Malinowska, I, Wisniewski, A. Gladecki,
Z.; Fruzinski, A. Polym J Chem 1996, 70, 891.
[4] Bosc, J. J.; Jarry, C.; Martinez, B.; Molimard, M. J Pharm
Pharmacol 2001, 53, 923.
[5] Heywood, D. L.; Phillips, B. J Am Chem Soc 1958, 80,
1257.
[6] Wavefunction, Inc. Spartan ‘04 Windows Tutorial and
User’s Manual; Wavefunction, Inc.: Irvine, 2004.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet