Synthesis of chiral bis-oxazines: A preliminary assessment of helical conformational framework

Article abstract of DOI:10.1039/c2ob26669e

A series of novel naphthalene attached bis-oxazines were synthesized and characterized. The bis-oxazines were studied by VT-NMR analysis to assess the possibility of conformational twist. The bis-oxazine prepared from (l)-methylvalinate show a helical conformational twist in the single crystal X-ray analysis. Three isomers of bis-oxazines were prepared from chiral α-methylbenzyl amines, the meso isomer showed small optical rotation probably indicating the helical conformational twist in the molecule.

Full text of DOI:10.1039/c2ob26669e

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COMMUNICATION
Synthesis of chiral bis-oxazines: a preliminary assessment of helical
conformational framework†
Harish R. Talele and Ashutosh V. Bedekar*
Received 26th June 2012, Accepted 20th September 2012
DOI: 10.1039/c2ob26669e
this barrier was quite large and the isomers were stable at room
A series of novel naphthalene attached bis-oxazines were syn-
thesized and characterized. The bis-oxazines were studied by
VT-NMR analysis to assess the possibility of conformational
twist. The bis-oxazine prepared from (l)-methylvalinate show
a helical conformational twist in the single crystal X-ray
analysis. Three isomers of bis-oxazines were prepared from
chiral α-methylbenzyl amines, the meso isomer showed small
optical rotation probably indicating the helical conformation-
al twist in the molecule.
temperature. The single enantiomer of 6 was separated and its
absolute configuration was established.8 Several other examples
of distorted structures of 1,8-naphthalene derivatives were also
known.9 Another group of such compounds is 1,8-diamino
naphthalene 7, also known as proton sponge.10
The derivatives of naphthalene with substitutions at 1,8 posi-
tions show twisted, distorted structure giving rise to helical
isomers due to peri interaction. Such compounds, referred to as
[2]helicenes, with sufficiently high barrier of interconversion at
ambient conditions can be resolved.8 In this communication we
present our efforts towards synthesis of naphthalene unit attached
with heterocyclic rings on C1–C2 and C7–C8 bonds. The mo-
lecules were studied to ascertain the presence of isomers caused
by the conformational twist.
The reaction of 2-naphthol with primary amines and an excess
of formaldehyde gives an angularly fused naphthalene derivative
of 1,3-oxazine via an aromatic Mannich reaction.11 Recently we
have prepared heterohelicenes possessing a 1,3-oxazine ring,12a
however not many similar examples12b are available in the litera-
ture, though some biologically and medicinally active derivatives
are known.13 Basically 1,3-oxazines were derived forms of Betti
The “helical” shape has a distinct place in nature and has
inspired man to adopt it for the construction of objects of func-
tional utility and aesthetic value. This shape is the basis for the
design of architectural and artistic objects. Chemists have syn-
thesized molecules which acquire a helical shape, either as
supramolecular assemblies or as a single molecular unit. The
inherent, internal helical shape is a result of distortion caused by
crowding in the structure, benzo[c]phenanthrene or [4]helicene 1
is an example of such phenomena (Fig. 1). The construction of
such distorted aromatic molecules is a topic of continuous devel-
opments.1 The synthesis and separation of π-helical isomers of
[6]helicene by Newman2 has triggered significant growth in this
area.3 The other type is σ-helicenes and [4]triangulane 2, one of
the smallest molecules to show such helical shape.4 Another
small molecule capable of showing helical form is 1,10-phenan-
throline-N,N-dioxide 3, which was synthesized by oxidation of
1,10-phenanthroline with HOF.5 4,5-Dialkyl phenanthrene 4 was
envisaged to show similar helical shape due to the twisting of
two terminal rings arising from internal strain.6 Naphthalene
derivatives with substitutions at C1 and C8 positions show
peculiar peri interactions.7a Such 1,8-disubstituted naphthalene
moieties having chiral distorted forms, such as 1,8-di(tert-butyl)-
naphthalene derivative 5 is known to racemize at ambient con-
ditions due to low enantiomerization barrier.7b–d Recently an
adamantyl derivative of similar compound 6 was reported where
Department of Chemistry, Faculty of Science, M.S. University of
Baroda, Vadodara 390 002, India. E-mail: avbedekar@yahoo.co.in;
Tel: +91 0265 2795552
†Electronic supplementary information (ESI) available: Experimental
procedures, spectroscopic and X-ray data of the reported compounds is
available. CCDC 882285. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/c2ob26669e
Fig. 1 Examples of small helical molecules, besides [4]helicene.
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Scheme 1 Synthesis of bis-oxazines.
bases where the amine and phenol were linked with a methylene
bridge.14
In the initial study 2,7-dihydroxy naphthalene 8 was treated
with primary amines and an excess of aqueous formaldehyde. A
series of primary amines were chosen for this experiment and a
number of bis-oxazine derivatives 9a–9d were synthesized
(Scheme 1).
The derivatives of 9 were purified and characterized by usual
spectral and analytical techniques. The H-NMR showed a sym-
metrical pattern and the two methylene protons appeared as two
sharp singlets. The inside hydrogens of Ar–CH2–N appeared at
the high field region while the ones flanked by two electronega-
tive atoms, O–CH2–N, appeared at down field region. This
clearly establishes the absence of a helical form in the solution
state at ambient conditions, as that would have made the two
hydrogens unequal. This can also be due to rapid flipping of the
two conformations of the flexible oxazine rings. This hypothesis
was examined by performing H-NMR analysis at low tempera-
ture (Fig. 2). The outside protons remained unchanged as sharp
singlet when the H-NMR was run at −58 °C, while the inside
hydrogens appeared as a broad signal. Even though we were
unable to see two separate signals at this condition, there appears
to have a tendency of this conformation to gain slight rigidity.
The low temperature H-NMR study does not indicate the pres-
ence of helical form but definitely hints towards the possibility
of acquiring a rigid conformational deviation or slow rate of iso-
merization. This VT-NMR study was almost similar for all four
samples of 9a–9d, indicating no role of substituent on N.
The next set of naphthalenes attached with bis-oxazine units
were synthesized by choosing chiral primary amines. The
purpose of introducing a chiral centre in the likely cavity of the
helical fold was to introduce a bulk and give it a diastereomeric
character. In the preliminary study two derivatives were syn-
thesized in single step from 8 and (S)-α-methylbenzyl amine for
10a and with (l)-methylvalinate for 11 (Scheme 2).
The H-NMR spectra of both these compounds were different
compared to 9. The inside hydrogens of Ar–CH2–N in 10a
appeared as two signals, one d (δ 4.18; J = 16.4 Hz, 1H) and
other d (δ 4.05; J = 16.4 Hz, 1H). However, it was interesting to
observe a different pattern for the outside hydrogens, O–CH2–N.
These hydrogens showed one d (δ 4.83, J = 10.0 Hz, 1H) and
another dd (δ 5.08, J = 10.0, 1.2 Hz, 1H). This could be attribu-
ted to the diastereotopic nature of the hydrogens or the twisting
of the conformational framework of the oxazine. A similar
H-NMR pattern was observed for compound 11, but one of the
outside hydrogens which showed dd (δ 4.94, J = 9.6, 1.6 Hz,
1H) at room temperature slowly merged to a d at +40 °C. The
Fig. 2 Variable temperature 1H-NMR of compound 9a. [A] = −20 °C;
[B] = −35 °C; [C] = −58 °C. The down field signal is for Hb and Hb′,
remains unchanged at low temperature, while the inside Ha and Ha′
appear at the up field and show broadening of the signal.
Scheme 2 Synthesis of bis-oxazine from (S)-α-methylbenzyl amine
and (l)-methylvalinate.
HPLC analysis of both these compounds on chiral stationary
phase column showed single peak, probably indicating the
absence of two isomers in solution at ambient conditions.
The single crystal X-ray diffraction analysis of compound 11
was carried out in order to ascertain the deviation in the struc-
ture, if any.15 The ORTEP diagram is presented in Fig. 3 where a
slight twist is noticeable between the conformations of two
oxazine rings, although the similar deviation between the two
bonds of naphthalene C8–C14 and C14–C15 is not found, unlike
in the case of recently reported compound 6.8
The other isomers of compound 10 were synthesized with
appropriate amino compounds (Scheme 3). The enantiomer pair,
10a and 10b, was prepared in a single step from 8 and (S)-
α-methylbenzyl amine and (R)-α-methylbenzyl amine, respect-
ively. As per our expectation the optical rotation of 10a and 10b
was found to be almost similar with opposite sign. The third
meso isomer 10c was prepared in stepwise manner from 8, via
mono oxazine 12 by selecting the chiral amine in both optical
8580 | Org. Biomol. Chem., 2012, 10, 8579–8582
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Scheme 4 Stepwise synthesis of 10b.
Fig. 3 ORTEP diagram of compound (l)-11.
That additional chiral element in 10c could be the helical twist
created by the two half chair conformations of 1,3-oxazines
pointing towards the opposite directions. If this hypothesis is
considered then we may have created an asymmetric synthesis of
the helical chiral unit in this molecule. The X-ray crystal analysis
of 11 indicates the configuration of the helical system to be P if
the direction of the two half chair conformations was considered,
in reference with the known configuration of the L-valine ester.
In this communication we have presented the syntheses and
characterization of a few new naphthalene fused bis-oxazines
with the hope of producing twist and deviation in its confor-
mational framework.
Acknowledgements
This work was supported by a generous grant of a SERC project
of the Department of Science and Technology, New Delhi (SR/
SI/OC-42/2006). We thank DST and CSIR (SRF) for the fellow-
ship to HRT, Mr S. Sahoo of Sun Pharma Advance Research
Centre, Vadodara for the NMR analysis and Prof. B.V. Kamath
for the facilities and constant encouragement.
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