Synthesis, Characterization, and Structure of Some 1,4-Disubstituted Cyclopenta[d][1,2]oxazines

Article abstract of DOI:10.1002/jhet.2941

Oxazine-based chemistry offers an alternative to thiophene and pyrrole semiconductors and has been largely unexplored for electronics applications. Discrete monomers or oxazine polymers could serve as an efficient hole carrier for novel devices. A series of 1,4-disubstituted cyclopenta[d][1,2]oxazines (R?=?tolyl, p-nitrophenyl, t-buytl, furyl, and 5-methylthienyl) were isolated via ring closure with hydroxylamine from a 1,2-acylcyclopentadiene precursor. The target oxazines were characterized by NMR and IR spectroscopy and direct analysis in real time (DART) MS. Single-crystal x-ray structure determination confirmed the identity of the tolyl oxazine, which shows a face-to-face stacking pattern of the heterocyclic rings.

Full text of DOI:10.1002/jhet.2941

Month 2017
Synthesis, Characterization, and Structure of Some 1,4-Disubstituted
Cyclopenta[d][1,2]oxazines
Eric M. Collins,b Darrin L. Smith,c Chad A. Snyder,d Bangbo Yan,e and Edwin D. Stevense
a
*
Nathan C. Tice,
aDepartment of Physical Sciences, The University of Findlay, Findlay, Ohio, USA
bDepartment of Chemistry and Biochemistry, Ohio Northern University, Ada, Ohio, USA
cDepartment of Chemistry, Eastern Kentucky University, Richmond, Kentucky, USA
dDepartment of Science and Mathematics, Grace College, Winona Lake, Indiana, USA
eDepartment of Chemistry, Western Kentucky University, Bowling Green, Kentucky, USA
*
E-mail: tice@findlay.edu
Received November 10, 2016
DOI 10.1002/jhet.2941
Published online 00 Month 2017 in Wiley Online Library (wileyonlinelibrary.com).
Oxazine-based chemistry offers an alternative to thiophene and pyrrole semiconductors and has been
largely unexplored for electronics applications. Discrete monomers or oxazine polymers could serve as an
efficient hole carrier for novel devices. A series of 1,4-disubstituted cyclopenta[d][1,2]oxazines (R = tolyl,
p-nitrophenyl, t-buytl, furyl, and 5-methylthienyl) were isolated via ring closure with hydroxylamine from
a 1,2-acylcyclopentadiene precursor. The target oxazines were characterized by NMR and IR spectroscopy
and direct analysis in real time (DART) MS. Single-crystal x-ray structure determination confirmed the
identity of the tolyl oxazine, which shows a face-to-face stacking pattern of the heterocyclic rings.
J. Heterocyclic Chem., 00, 00 (2017).
INTRODUCTION
pharmaceutical effects including inhibitory action towards
acetylcholinesterase (anti-Alzheimer) [13], 5-
Heterocycles comprise an important class of organic
compounds and offer a wide range of applications that
include electronic materials, hydrodesulfurization (HDS)
modeling, medicine, and catalysis [1–6]. These
compounds have been incorporated into conducting
polymers, resulting in semiconducting properties when
doped. Of these organic heterocycles, polythiophene and
polypyrrole (Fig. 1A, B) and their derivatives are the
most common. Both of these polymers offer high
synthetic feasibility and processibility [7]. Additionally,
polythiophenes have practical advantages over other
polymers which include environmental stability and
structural versatility [8,9]. Recent applications have
included field-effect transistors (FETs), organic light-
emitting diodes (OLEDS) [10], and organic photovoltaic
(OPV) cells [11].
While thiophenes and pyrroles have been more
thoroughly investigated and utilized as next generation
materials, oxazines are a similar class of heterocycles that
are particularly of interest because of their robust nature
and unique structural and electronic properties. Oxazines
are six-membered rings that contain both a nitrogen and
oxygen atom within the ring itself (Fig. 2). Oxazines that
contain aromatic fragments or a fused cyclopentadienyl
ring are well known and possess a wide variety of novel
medicinal applications [12]. For example, cyclopenta[d]
[1,2] fused-ring oxazines (Fig. 2B) are known for their
lipoxygenase (anti-Alzheimer) [13], cyclooxygenase 2
(pro-inflammatory disease and anti-diabetic) [14], protein
tyrosine phosphatase 1B (insulin resistance) [15],
treatment of drug resistant malaria [16], and also to
combat certain gram positive bacteria [17]. Some
naturally occurring compounds have even been found to
incorporate an oxazine ring, especially in marine fungi
[18]. Cyclopenta[d][1,2]oxazines are also isoelectronic to
azulene [19], a well-known topical cream, affording these
5,6-fused rings potentially therapeutic and other
pharmacological applications. Similar heterocyclic
systems that contain nitrogen and a sulfur heteroatom
have also been utilized as voltage-sensitive dyes [20].
Thus, there is a strong potential with oxazines for
material applications.
Our primary interest is in the utilization of oxazines and
other alternative heterocycles as building blocks for
electronic materials that possess novel conducting or
optical properties. We have previously reported upon the
formation of 5,6-fused pyridazines from a simple 1,2-
diacylcyclopentadiene precursor employing hydrazine
hydrate [21,22] (Scheme 1, bottom route). This route,
initially reported by Linn and Sharkey, also allows for the
formation of 5,6-fused oxazines, with ring closure
accomplished by hydroxylamine [23] (Scheme 1, top
route). Linn and Sharkey only reported oxazines where
phenyl and tolyl were employed as the substituents at the
© 2017 Wiley Periodicals, Inc.

N. C. Tice, E. M. Collins, D. L. Smith, C. A. Snyder, B. Yan, and E. D. Stevens
Vol 000
Figure 3. 1,4-Disubstituted cyclopenta[d][1,2]oxazines.
Figure 1. Polythiophene (A) and polypyrrole (B).
equivalents of lithium cyclopentadianide with
2
equivalents of the appropriate acid chloride. The fulvene
precursor was then ring closed by refluxing with
hydroxylamine hydrochloride in an anhydrous
pyridine/ethanol solution to afford the desired substituted
oxazines 1–5 in modest yields (28.5–45.8%). These
modest yields matched that reported by Linn and
Sharkey (44% for the tolyl oxazine 1). In contrast, the
slightly modified Lloyd and Preston procedure
employing potassium hydroxide (instead of pyridine as
used by Linn and Sharkey) afforded the t-butyl oxazine
3 somewhat higher yield (61%) [19]. Progress of the
reaction was monitored via thin-layer chromatography,
which afforded different reactions times depending upon
the fulvene employed. Increasing reaction time beyond
5 h tended to cause low product yield, presumably due
to thermal decomposition. Longer reaction times may
have also been necessary because the weaker base
pyridine was employed. For each case, upon completion,
the reaction mixture was quenched with water, and the
oxazines 1–5 were isolated as precipitates. Other than
the p-nitrophenyloxazine 2, all the target compounds
displayed good solubility in common organic solvents
(e.g., methylene chloride). Compounds 1–5 also
displayed reasonably good stability both in air and
solution.
Figure 2. 4H-1,2-oxazine (A) and cyclopenta[d][1,2]oxazine.
Scheme 1. Formation of 1,4-disubstituted cyclopentaoxazines and
pyridazines.
1- and 4-position and with limited characterization. Lloyd
and Preston utilized a slightly modified version of Linn
and Sharkey’s route to form the methyl, and t-butyl cases,
again with limited characterization [19]. There are
additional routes towards formation of oxiranes, including
for example via [6 + 4] cycloaddition [24]. However, we
wished to focus upon the Linn and Sharkey pathway and
more fully characterize some of these previously reported
oxazines (tolyl and t-butyl). Furthermore, we wished to
expand this series to other substituent types, including
thienyl and furyl cases, to see how general the reaction
conditions were. In addition, we also wanted to examine
more closely the solid-state nature of these 5,6-fused
oxazines and see if their packing properties would be
amendable towards device applications. Herein, we report
upon the formation, characterization, and solid-state
structure of a series of 1,4-disubstituted cyclopenta[d]
[1,2]oxazines.
1H NMR spectroscopy confirms the structure for the
oxazines 1–5 showing both asymmetric Cp and alkyl or
aryl substituents (Table 1). The range of chemical shifts
(6.5–7.5 ppm) is typical for fused-ring Cp protons [21,22].
Assignment of the of the Cp protons was based upon
either coupling observed (triplet for the middle Cp2 signal)
or matching the chemical shift to the proximity of the more
electronegative oxygen. However, coupling patterns were
complex and difficult to distinguish at times. Even
switching solvents from chloroform-d to DMSO-d6 in
compound 2 did not resolve the usual coupling behavior,
with the Cp signals observed as three doublets. We
attribute this complexity to the high degree of electron
delocalization and resonance within the Cp moiety. We
also observed the disappearance of the characteristic
“enolic” signals in the 18–20 ppm range indicative of the
fulvene starting material. Cyclopentadianide ring carbons
were also observed in 13C NMR spectroscopy, with a
narrow range of 115–120 ppm (Table 1). For each of the
target compounds, three signals were observed, confirming
the asymmetric nature of 1–5. All NMR spectroscopy was
carried out in chloroform-d, except the p-nitrophenyl
RESULTS AND DISCUSSION
A series of 1,4-disubstituted cyclopenta[d][1,2]oxazines
= tolyl, p-nitrophenyl, t-butyl, furyl, and 5-
methylthienyl) were isolated and characterized using the
procedure initially reported by Linn and Sharkey [23]
(Fig. 3).
(R
The 1,2-diacylcyclopentadiene (fulvene) starting
materials were synthesized by the reaction of
3
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2017
Disubstituted Cyclopentaoxazines
Table 1
Selected 1H and 13C NMR spectroscopic data for products 1–5.
1H NMR (ppm)
C NMR (ppm)
Cp1–3
Compound
1
H1
H2
H3
6.98 (m)
7.05 (s)
7.28 (m)
7.39 (m)
115.9
116.7
117.9
116.9
118.9
119.5
114.5
115.8
116.9
116.0
116.2
117.7
115.0
116.2
116.5
2*
3
7.51 (t) J = 1.8 Hz
6.98 (t) J = 1.8 Hz
7.31 (d) J = 4.4 Hz
7.19 (d) J = 2.8 Hz
7.19 (d) J = 2.8 Hz
6.63 (m)
4
6.69 (m)
J = 2.1 Hz
7.23 (d)
J = 3.2 Hz
5
6.90 (d) J = 0.8
6.94 (d) J = 0.8 Hz
7.18 (d) J = 3.2 Hz
*
13C NMR data obtained in DMSO-d6.
oxirane 2. Due to its relatively poor solubility in chloroform,
13C NMR data were obtained in DMSO. Analysis by IR
spectroscopy also showed the disappearance of the enolic
stretch centered around 3300 cmÀ1 and a set of newly
formed N―O stretches at approximately a 1400 and
1600 cmÀ1. DART mass spectrometry also confirms the
molecular mass of oxiranes 1–5, with the expected [M+1]+
ion peak observed for each case. This observance is typical
for positive scan mode in DART [25]. Elemental analysis
was performed for all previously unreported compounds
(oxazines 2, 4, and 5). Both observed hydrogen and
nitrogen values matched well with calculated values for 2,
4, and 5. Observed carbon values were slightly higher than
calculated values, which we attributed to some thermal
sensitivity of these particular oxazines. This correlates well
with the decomposition and lower yields observed with
extended reaction times. Experimental details and
characterization for a representative reaction (Compound 1)
are given in the Experimental section. Full experimental
details for all compounds 1–5 are available in the
“Supplementary Content.”
Figure 4. Molecular structure for oxazine 1. [Color figure can be viewed
at wileyonlinelibrary.com]
nitrogen and oxygen atom within the oxazine ring (N1
and O1) and near symmetry of the molecule, compound
1 crystallized in two orientations, with the nitrogen
oriented viewer-left or viewer-right. This model of the
solid-state packing gives a better fit to the X-ray data as
compared to the refinement for a single molecular
orientation. The major orientation (shown in Fig. 4, with
the nitrogen on viewer-left) has a 0.642(8) fractional
occupancy (R1 = 4.01% and GoF = 1.041). This model
also yields better anisotropic thermal ellipsoids, which
failed the rigid bond test in the previous, single
orientation model. Data containing the atoms labeled
O1B and N1B are the exchanged atom positions in the
molecular orientation with the minor occupancy (not
shown in the figures here). As expected, the analysis of
the structure of 1 shows the presence of a higher degree
of double bond character for the N1―C7 bond as
compared to O1―C1, with lengths observed at 1.308(3)
The identity of the tolyl oxirane 1 was further confirmed
by single-crystal X-ray diffraction methods (Fig. 4).
Suitable crystals were grown by slow evaporation from
methylene chloride in ambient atmosphere and isolated as
light yellow plates. Compound 1 crystallized with a
triclinic lattice (space group P-1), with two molecules in
the unit cell. Due to the relatively similar size of the
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

N. C. Tice, E. M. Collins, D. L. Smith, C. A. Snyder, B. Yan, and E. D. Stevens
Vol 000
and 1.349(2) Å respectively. The carbon–carbon bond
GENERAL EXPERIMENTAL
lengths had some variation for the Cp ring as well,
ranging from 1.3972(10) Å for C3―C4 to 1.4538(9) Å
for C2―C6. Bond lengths again were consistent with the
expected degree of pi-character based upon the
cyclopentadienyl oxazine structure.
All reactions were carried out using standard Schlenk
techniques under a nitrogen atmosphere unless otherwise
noted. NMR solvent chloroform-d (Acros) and DMSO-d6
(Cambridge Isotope Laboratories), hydroxylamine
hydrochloride, magnesium sulfate (Alfa Aesar), anhydrous
pyridine, anhydrous ethanol, diethyl ether, pentane, and
methylene chloride (Aldrich) were all used without further
purification. The 1,2-diacylcyclopentadiene precursors
were all made according to previously reported procedures
The central nine-membered ring (N1, O1, C1―C7) is
nearly planar, with the root-mean squared deviation
observed at 0.034 Å. Likewise, the puckering parameter
(Q) is quite small and correlates with a nearly planar
central ring, with an observed value of 0.0832 Å. In the
crystal packing, this central ring is pi-stacked with the
nine-membered ring of the neighboring molecule related
by an inversion center symmetry element (Fig. 5) The Cp
portion of one molecule is oriented directly over the
oxazine portion of the next molecule. While there are no
short contacts (a distance less than the sum of the Van
der Waals radii) between these neighboring central rings,
there is strong evidence for pi-stacking based upon the
distances formed between planes created by the central
rings. An inter-planar distance is observed to be 3.375 Å
from these adjacent molecules involving the
cyclopentadienyl oxazine moiety. This is well within the
commonly accepted range for evidence of pi-stacking
(3.4–3.6 Å) [26]. In contrast, the tolyl rings are twisted
out of the plane of the central ring, with the
N1―C7―C8―C9 and O1―C1―C14―C15 torsion
angles at 37.8(2)° and 33.3(3)° respectively. The aryl
rings do not display any pi-stacking with adjacent
moieties. Overall, the pi-stacking observed involving the
central ring indicates a strong potential for effective
charge transfer in the solid state and potential for these
molecules to be utilized as a conducting material.
1
[22,23,28]. H and 13C NMR spectra were recorded on a
Bruker 400 MHz NMR spectrometer at ca. 22°C and were
referenced to residual solvent peaks and TMS internal
standard. All 13C NMR spectra were listed as decoupled.
All infrared spectra were recorded on a Perkin Elmer
Spectrum One FT-IR Spectrometer. The mass
spectrometry analysis was performed with a direct analysis
in real-time SVP ion source (IonSense, Saugus, MA,
USA) interfaced with a LTQ XL linear ion trap mass
spectrometer (Thermo Scientific, San Jose, CA, USA).
Specific details for this system and operation have been
previously reported [25]. All data reported here are under
Positive Scan mode. Melting points were taken on a
standard Mel-Temp apparatus.
EXPERIMENTAL
Synthesis of 1,4-di-p-tolylcyclopenta[d][1,2]oxazine (1).
In a 25-mL round bottom flask, a solution of 1,2-
ditoluylcyclopentadiene (249.7 mg, 0.826 mmol) and
hydroxylamine hydrochloride (250.6 mg, 3.606 mmol,
6 mol. eq.) in 5-mL absolute ethanol and 5-mL anhydrous
pyridine was refluxed for 2.5 h. The brown solution was
quenched with 15-mL distilled water, filtered, and then the
precipitate was allowed to dry. The crude product was
recrystallized from ethanol to afford 1 as golden yellow
solid (113 mg, 45.8% yield). Mp: 170–172°C. Reported:
163–165°C.23 1H NMR (400 MHz, CDCl3, ppm): 2.47 (s,
3H, Me), 2.49 (s, 3H, Me), 6.98 (m, 1H, Cp), 7.28 (m, 1H,
Cp), 7.39 (m, 5H, Cp and Ar), 7.82 (d, 2H, J3 = 8.0 Hz,
Ar), 8.03 (d, 2H, J3 = 8.0 Hz, Ar). 13C NMR (100 MHz,
CDCl3, ppm): 21.4, 21.6, 115.5, 115.9, 116.7, 117.9 128.6,
129.0, 129.2, 129.4, 129.7, 130.8, 134.3, 140.2, 142.4,
156.2, 165.9 IR (cmÀ1): 1383, 1612 (strong, N-O), 1800,
1922, 2918. MS(DART-LTQ): m/z 300.33 ([M+1]+).
Reported analysis for C21H17NO; Calc: C, 84.2; H, 5.7; N,
4.7. Found: C, 84.5; H, 5.8; N, 4.2 [23].
Tables of crystallographic details, atomic coordinates
and displacement parameters, bond distances and angles,
intermolecular contact distances, structure factors, and a
crystallographic information file (CIF) for the structure of
1
have been deposited with the Cambridge
Crystallographic Data Centre [27].
The x-ray crystallographic structure of 1 was determined
by single-crystal x-ray structure determination methods.
The crystal selected for data collection was typical of
others in the batch, which had been grown by slow
evaporation from methylene chloride at room temperature.
Figure 5. Pi-stacking observed for tolyl oxazine 1. [Color figure can be
viewed at wileyonlinelibrary.com]
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2017
Disubstituted Cyclopentaoxazines
Table 2
The crystal was mounted on a MiTeGin microloop with
dodecane oil and cooled to 120 K in a stream of cold N2
gas generated using an Oxford Cryosystems 700 low
temperature device. Data were collected at 120 K on a
Bruker APEX II Kappa CCD diffractometer. The APEX II
software package was used for indexing, data collection
and reduction, and for determination of an empirical
absorption correction (Bruker APEX II; Bruker AXS Inc.:
Madison, WI). The SHELXS/L software package was used
for structure solution and refinement [29]. All hydrogen
atoms were located in difference Fourier maps and
included in the least-squares refinement with isotropic
thermal parameters. Refinement with a single orientation
of the oxygen and nitrogen atoms in the oxazine ring gave
unexpectedly high R-factors and goodness of fit
parameters, and unreasonable anisotropic thermal
ellipsoids. To improve the fit to the x-ray data, a disordered
model was employed in which a second orientation for the
oxazine ring was included with the positions of the
nitrogen and oxygen atoms interchanged. Bond distance
similarity restraints were imposed on the C―N, C―O,
and N―O distances in the oxazine rings to ensure a high
degree of structural similarity between the two molecular
orientations. Crystal data and a summary of experimental
details are given in Table 2.
Sample and crystal data for Compound 1.
Chemical formula
Formula weight
Temperature
Wavelength
Crystal size
Crystal habit
Crystal system
Space group
C21H17NO
299.36 g/mol
120(2) K
0.71073 Å
0.050 × 0.300 × 0.320 mm
Light yellow plate
Triclinic
P À 1
Unit cell dimensions
a = 9.1308
(3) Å
α = 105.3736(10)°
b = 9.8513
(3) Å
β = 105.3139(11)°
γ = 109.2532(11)°
c = 9.9497
(3) Å
Volume
Z
751.49(4) Å3
2
Density (calculated)
Absorption coefficient
F(000)
Theta range for data
collection
1.323 g/cm3
0.081 mmÀ1
316
2.30 to 32.00°
Index ranges
À13 < =h < =9, À14 < =k < =14,
À14 < =l < =14
19701
5186 [R(int) = 0.0188]
98.90%
Reflections collected
Independent reflections
Coverage of independent
reflections
Absorption correction
Max. and min.
Multi-scan
0.9960 and 0.9750
Synthesis of 1,4-di(4-nitrophenyl)cyclopenta[d][1,2]oxazine
(2). In a 50-mL round bottom flask, a solution of 1,2-di(4-
nitrobenzoyl)cyclopentadiene (163.4 mg, 0.452 mmol) and
transmission
Refinement method
Refinement program
Function minimized
Data/restraints/parameters
Goodness-of-fit on F2
Δ/σmax
Full matrix least squares on F2
SHELXL-2014/7 (Sheldrick, [29])
Σ w(F2o À F2c)2
hydroxylamine hydrochloride (167.1 mg, 2.405 mmol,
8 mol. eq.) in 5 mL absolute ethanol and 5 mL anhydrous
pyridine was refluxed for 2 h. The brown solution was
quenched with 15-mL distilled water, filtered, and the
precipitate was allowed to dry. Product 2 was isolated
without further purification as an orange powder (134 mg,
37.4% yield). Mp: 219–223°C. 1H NMR (400 MHz, CDCl3,
ppm): 7.05 (s, 1H, Cp), 7.31 (d, 1H, J3 = 4.4 Hz, Cp), 7.51
(t, 1H, J3 = 1.8 Hz, Cp), 8.12 (d, 2H, J3 = 8.8 Hz, Ar), 8.31
(d, 2H, J3 = 8.8 Hz, Ar), 8.46 (d, 2H, J3 = 8.8 Hz, Ar), 8.48
5186/73/295
1.048
0.003
Final R indices
4855 data; I > 2σ(I) R1 = 0.0401,
wR2 = 0.1193
All data; R1 = 0.0419,
wR2 = 0.1213
Weighting scheme
w = 1/
[σ2(F2o) + (0.0783P)2 + 0.1569P]
where P = (F2o + 2Fc2)/3
Largest diff. peak and hole 0.492 and À0.301 eÅÀ3
RMS deviation from mean
0.057 eÅÀ3
1
(d, 2H, J3 = 8.8 Hz, Ar). H NMR (400 MHz, d6-DMSO,
ppm): 7.16 (d, 1H, J3 = 2.4 Hz, Cp), 7.48 (d, 1H,
J3 = 4.4 Hz, Cp), 7.58 (d, 1H, J3 = 3.2 Hz, Cp), 8.22 (d, 2H,
J3 = 8.8 Hz, Ar), 8.51 (m, 6H, Ar). 13C NMR (100 MHz, d6-
DMSO, ppm): 114.9, 116.9, 118.9, 119.5, 124.7, 124.9,
130.5, 130.9, 136.7, 137.7, 139.1, 149.3, 149.9, 154.7,
163.0. IR (cmÀ1): 1348, 1514 (strong, N-O), 1594, 1633
(Ar), 3077. MS(DART-LTQ): m/z 362.17 ([M+1]+).
Analysis for C19H11N3O5; Calc: C, 63.2; H, 3.07; N, 11.63.
Found: C, 63.9; H, 3.05; N, 11.48.
quenched with 15-mL distilled water, filtered, and the
precipitate was allowed to dry. The crude product was
triturated with cold pentane to afford 3 as a light yellow
solid (71.0 mg, 28.5% yield). Mp: 71–73°C. Reported: 80–
81°C [19]. 1H NMR (400 MHz, CDCl3, ppm): 1.55 (s, 9H,
t-Bu), 1.62 (s, 9H, t-Bu), 6.98 (t, 1H, J3 = 1.8 Hz, Cp),
7.19 (d, 2H, J3 = 2.8 Hz, Cp). Reported: (CCl4) 2.96 (9H,
m), 3.18 (9H, m), 8.39 (1H, m), 8.48 (2H, m) [19]. 13C
NMR (100 MHz, CDCl3, ppm): 29.0, 29.7, 38.1, 39.3,
113.9, 114.5, 115.8, 116.9, 131.2, 162.6, 177.4. IR (cmÀ1):
1364, 1600 (N-O). MS(DART-LTQ): m/z 232.17 ([M+1]+).
Reported analysis for C15H21NO; Calc: C, 77.9; H, 9.15;
N, 6.05. Found: C, 78.1; H, 9.4; N, 6.3 [19].
Synthesis of 1,4-di-tert-butylcyclopenta[d][1,2]oxazine
(3). In a 50-mL round bottom flask, a solution of 1,2-
dipivaloylcyclopentadiene (250.2 mg, 1.08 mmol) and
hydroxylamine hydrochloride (675 mg, 9.71 mmol, 9 mol.
eq.) in 5-mL absolute ethanol and 5-mL anhydrous
pyridine was refluxed for 4 h. The yellow solution was
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

N. C. Tice, E. M. Collins, D. L. Smith, C. A. Snyder, B. Yan, and E. D. Stevens
Vol 000
[3] Dallemagne, P.; Khanh, L. P.; Alsaidi, A.; Varlet, I.; Collot,
V. R.; Paillet, M.; Bureau, R.; Rault, S. Bioorg Med Chem 2003, 11,
1161.
[4] Khanh, L. P.; Dallemagne, P.; Landelle, H.; Rault, S. J Enzyme
Inhib Med Chem 2002, 17, 439.
[5] Khanh, L. P.; Dallemagne, P.; Rault, S. Synthesis-Stuttgart
2002, 1091–1095.
[6] Oh, M.; Reingold, J. A.; Carpenter, G. B.; Sweigart, D. A.
Coord Chem Rev 2004, 248, 561.
Synthesis of 1,4-di(furan-2-yl)cyclopenta[d][1,2]oxazine
(4). In a 50-mL round bottom flask, a solution of 1,2-
difuroylcyclopentadiene (249 mg, 0.992 mmol) and
hydroxylamine hydrochloride (253 mg, 3.64 mmol,
3.5 mol. eq.) in 5-mL absolute ethanol and 5-mL
anhydrous pyridine was refluxed for 3 h. The dark orange
solution was quenched with 15-mL distilled water, filtered,
and the precipitate was allowed to dry. The crude product
was washed with diethyl ether and then triturated with cold
pentane to afford 4 as a deep red powder (98 mg, 39.3%
[7] Tolbert, L. M. Acc Chem Res 1992, 25, 561.
[8] Bredas, J. L.; Heeger, A. J.; Wudl, F. Chem Phys 1986, 85,
4673.
[9] Roncali, J. Chem Rev 1997, 97, 173.
1
yield). Mp: 86–88°C. H NMR (400 MHz, CDCl3, ppm):
[10] Tremblay, J. F. Chem Eng News 2016, 94, 30.
[11] Jacoby, M. Chem Eng News 2016, 94(18), 30.
[12] Sheikhshoaie, I.; Belaj, F.; Kamali, A. Bull Chem Soc Ethiop
2010, 24, 283.
[13] Sukhoruko, A. Y.; Nirvanappa, A. C.; Nirvanappa, A. C.;
Swamy, J.; Ioffe, S. L.; Swamy, S. N.; Basappa; Rangappa, K. S. Bioorg
Med Chem Lett 2014, 24, 3618.
[14] Srinivas, V.; Mohan, C. D.; Baburajeev, C. P.; Rangappa, S.;
Jagadish, S.; Fuchs, J. E.; Sukhorukov, A. Y.; Chandra; Mason, D. J.;
Kumar, K. S. S.; Madegowda, M.; Bender, A.; Basappa; Rangappa, K.
S. Bioorg Med Chem Lett 2015, 25, 2931.
[15] Cho, S. Y.; Baek, J. Y.; Han, S. S.; Kang, S. K.; Ha, J. D.;
Ahn, J. H.; Lee, J. D.; Kim, K. R.; Cheon, H. G.; Rhee, S. D.; Yang, S.
D.; Yon, G. H.; Pk, C. S.; Choi, J. Bioorg Med Chem Lett 2006, 16,
499.
[16] Hannus, M.; Martin, C.; Mota, M.; Prudencio, M.; Rodrigues,
C. D. Use of inhibitors of scavenger receptor class proteins for the
treatment of infectious diseases. WO 2007101710 A1 20070913, 2007.
[17] D’Andrea, S. Barbara, Z.; DenBleyker, K.; Fung-Tomc, J. C.;
Yang, H.; Clark, J.; Taylor, D.; Bronson, J. Bioorg Med Chem Lett
2005, 15, 2834.
[18] Lin, Y.; Shao, Z.; Jiang, G.; Zhou, S.; Cai, J.; Vrijmoed, L. L.
P.; Jones, E. B. G. Tetrahedron 2000, 56, 9607.
[19] Lloyd, D.; Preston, N. W. J Chem Soc (C) 1970, 4, 610.
[20] Lebeuf, R.; Ferezou, I.; Rossier, J.; Arseniyadis, S.; Cossy, J.
Org Lett 2009, 11, 4822.
[21] Snyder, C. A.; Tice, N. C.; Maddox, J. B.; Parkin, S.; Daniel,
A. W.; Thomas, J. M. Heterocycles 2011, 83, 1275.
[22] Snyder, C. A.; Tice, N. C.; Sriramula, P. G.; Neathery, J. L.;
Mobley, J. K.; Phillips, C. L.; Preston, A. Z.; Strain, J. M.; Vanover, E.
S.; Starling, M. P.; Sahi, N. V.; Bunnell, K. R. Synth Commun 2011, 41,
1357.
[23] Linn, W. J.; Sharkey, W. H. J Am Chem Soc 1957, 79,
4970.
[24] Cho, S. Y.; Kang, S. K.; Ahn, J. H.; Ha, J. D.; You, G. H.;
Choi, J. Bull Kor Chem Soc 2006, 27, 1481.
[25] Mazzotta, M. G.; Young, J. O. E.; Evans, J. W.; Dopierala, L.
A.; Claytor, Z. A.; Smith, A. C.; Snyder, C.; Tice, N. C.; Smith, D. L. Anal
Methods 2015, 7, 4003.
[26] Curtis, M. D.; Cao, J.; Kampf, J. W. J Am Chem Soc 2004,
126, 4318.
[27] CCDC 1497138 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_
request/cif.
[28] Tice, N. C. The synthesis, structure, and reactivity of some
organometallic –fused heterocycles. Ph.D. Thesis, Department of
Chemistry, University of Kentucky, Lexington, 2006.
[29] Sheldrick, G. M. Acta Crystallogr, Sect C 2015, 71, 3.
6.63 (m, 1H, Cp), 6.69 (m, 1H, Cp), 7.23 (d, 1H,
J3 = 3.2 Hz, Cp), 7.35 (m, 2H, Fur), 7.42 (d, 1H,
J3 = 3.2 Hz, Fur), 7.54 (dd, 1H, J3 = 0.8 Hz, 4.4 Hz, Fur),
7.72 (s, 1H, Fur), 7.80 (s, 1H, Fur). 13C NMR (100 MHz,
CDCl3, ppm): 111.8, 111.9, 112.6, 115.7, 116.0, 116.2,
117.7, 134.8, 144.6, 146.8, 146.8, 146.9, 147.6, 154.4. IR
(cmÀ1): 1400, 1627 (strong, N-O), 2200, 3086, 3122.
MS(DART-LTQ): m/z 252.08 ([M+1]+). Analysis for
C15H9NO3; Calc: C, 71.7; H, 3.61; N, 5.58. Found: C,
72.3; H, 3.42; N, 5.24.
Synthesis of 1,4-di(5-methylthiophen-2-yl)cyclopenta[d]
[1,2]oxazine (5).
In a 50-mL round bottom flask, a
solution of 1,2-di-(5-methylthienoyl)cyclopentadiene
(196.4 mg, 0.632 mmol) and hydroxylamine hydrochloride
(198.7 mg, 2.86 mmol, 4.4 mol. eq.) in 5-mL absolute
ethanol and 5-mL anhydrous pyridine was refluxed for 3 h.
The dark orange solution was quenched with 15-mL
distilled water, filtered, and the precipitate was allowed to
dry. The crude product was washed with diethyl ether and
triturated with cold pentane to afford 5 as an orange
1
powder (63.0 mg, 32.1% yield). Mp: 84–86°C. H NMR
(400 MHz, CDCl3, ppm): 2.59 (s, 3H, Me), 2.63 (s, 3H,
Me) 6.89 (d, 1H, J3 = 0.8 Hz, Cp), 6.94 (d, 1H,
J3 = 0.8 Hz, Cp), 7.18 (d, 1H, J3 = 2.8 Hz, Cp), 7.31 (d,
1H, J3 = 3.2 Hz, Tp), 7.36 (d, 1H, J3 = 4.4 Hz, Tp), 7.69
(d, 1H, J3 = 3.6 Hz, Tp), 7.89 (d, 1H, J3 = 4.0 Hz, Tp). 13
C
NMR (100 MHz, CDCl3, ppm): 115.0, 116.5, 126.1, 127.0,
129.0, 131.8, 133.9, 143.3. IR (cmÀ1): 1452, 1595 (N-O),
2915, 3073. MS(DART-LTQ): m/z 312.17 ([M+1]+).
Analysis for C17H13NOS2; Calc: C, 65.6; H, 4.21; N, 4.50.
Found: C, 66.6; H, 4.34; N, 4.21.
Acknowledgments. We wish to thank the Department of Physical
Sciences at The University of Findlay for continued financial
support on this project.
REFERENCES AND NOTES
[1] Katritzky, A. R.; Rees, C. W. Comprehensive Heterocyclic
Chemistry: Structure, Reactions, Synthesis and Uses of Heterocyclic
Compounds; Pergamon: Oxford, 1984.
[2] Dallemagne, P.; Khanh, L. P.; Alsaidi, A.; Renault, O.; Varlet,
I.; Collot, V. R.; Bureau, R.; Rault, S. Bioorg Med Chem 2002, 10, 2185.
SUPPORTING INFORMATION
Additional Supporting Information may be found online
in the supporting information tab for this article.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet