Conformational analysis and inversion process in some perhydrodipyrido[1/2- b;1′/2′/-e]-1,4,2,5-dioxadiazines

Article abstract of DOI:10.1002/poc.1627

The stereoselectivity in the cyclodimerization of several six-membered cyclic nitrones has been investigated. The configurational/conformational analysis of the dimers (i.e. perhydrodipyrido[1, 2-b;1, 2, -e]-1, 4, 2, 5-dioxadiazinesj has been carried out by NMR spectroscopy. The NMR spectra of the dimers at lower temperatures indicated the presence of either a single or two invertomer(s). The nitrogen inversion barriers are determined using complete line-shape analysis. The invertomer ratios have been used to estimate the relative energies associated with the cis and trans ring fusion in these tricycles. A mechanistic rationale for the observed stereochemistry of the dimerization process has been presented. Copyright

Full text of DOI:10.1002/poc.1627

Research Article
Received: 5 May 2009,
Revised: 13 August 2009,
Accepted: 15 August 2009,
Published online in Wiley InterScience: 13 November 2009
(www.interscience.wiley.com) DOI 10.1002/poc.1627
Conformational analysis and inversion process
in some perhydrodipyrido[1,2-b;1020-e]-1,4,2,5-
dioxadiazines
a
a
a
*
Shaikh A. Ali , Alaaeddin AlSbaiee and Mohamed I. M. Wazeer
The stereoselectivity in the cyclodimerization of several six-membered cyclic nitrones has been investigated. The
configurational/conformational analysis of the dimers (i.e. perhydrodipyrido[1,2-b;1(2(-e]-1,4,2,5-dioxadiazines) has
been carried out by NMR spectroscopy. The NMR spectra of the dimers at lower temperatures indicated the presence
of either a single or two invertomer(s). The nitrogen inversion barriers are determined using complete line–shape
analysis. The invertomer ratios have been used to estimate the relative energies associated with the cis and trans ring
fusion in these tricycles. A mechanistic rationale for the observed stereochemistry of the dimerization process has
been presented. Copyright ß 2009 John Wiley & Sons, Ltd.
Keywords: conformational analysis; cyclic nitrones; cycloaddition reactions; dioxadiazines; inversion barriers; nitrogen
inversion; nitrone dimerization; stereochemistry
nitrogen invertomer in this class of tricycle has been identified.
INTRODUCTION
This has indeed permitted us to calculate the energetics of the
inversion process (vide infra). While the trans–trans-2:eeee
invertomer (C10H18N2O2), being centrosymmetric, displayed five
carbon signals, the minor invertomer trans–cis-2:eeae revealed
the presence of 10 distinct carbon signals. The conformation of
the minor invertomer as cis–cis-2:aeae is ruled out as it would also
be an centrosymmeric isomer. The large coupling constant for the
bridgehead C(6)Hs at d4.33 (2H, dd, J 3.2, 10.4 Hz) indicated the
axial orientation of the hydrogens in trans–trans-2:eeee, whereas
axial C(6)H and equatorial C(60)H in trans–cis-2:eeae appeared at
d4.59 (1H, dd, J 3.1, 9.8 Hz) and 5.40 (1H, app s), respectively. The
absence of a larger coupling constant for the equatorial C(60)H
and its shift to a higher frequency by almost 1 ppm ascertained
the conformation as depicted in trans–cis-2:eeae. The axial
substituent (i.e. C-20) at N(10) will have g–gauche interactions with
C(6) and as such these carbon signals are expected to be shielded
in comparison to the corresponding signals for the trans–
trans-2:eeee isomer. As evident from Table 1, this is indeed the
case; both C-20 and C(6) are shifted to lower frequency by over
7 ppm.
The mechanism of the formation of perhydrodipyri-
do[1,2-b;10,20-e]-1,4,2,5-dioxadiazine by an apparent (3 þ 3)
cycloaddition of nitrone 1 still remains a matter of speculation
as a result of the forbidden nature of the thermal (4ps þ 4ps)
addition reaction.[1–4] The dimer 2 has been shown to be the
trans-isomer (i.e. trans relationship of the bridgehead Hs), which
exists both in crystal and in solution in the tetraequatorial (eeee)
conformation with a trans–trans ring fusion (Scheme 1).[5]
A
group has studied the symmetric 4,9-dimethoxy-analogue and
assigned the trans-configuration for the bridgehead Hs with a
probable cis–cis ring fusion.[6] The configuration/conformation of
2,7-di-t-butyl and 4,9-dibutyl-analogues has been examined in a
report.[7] However, the presence of equilibrating nitrogen inver-
tomers in these tricyclic compounds has never been reported
before. Here, we report the synthesis of some new dimers with
the aim of determining, for the first time, the energetics
associated with the equilibration of trans Ð cis ring fusion in this
interesting tricycle using NMR spectroscopy. This study would
also focus on the mechanistic aspects to provide rationale for the
observed stereochemistry of the dimerization process.
The configurations of trans–trans-2:eeee and trans–cis-2:eeae
differ in the nature of the ring fusion between the middle ring
and the ring at the right terminal; while the former configuration
is trans-fused, the ring fusion in the latter is cis. The thermo-
dynamic parameters associated with the trans–trans-2 Ð
trans–cis-2 equilibration must then be dictated largely by the
energy difference between the trans- and cis ring fusions. For the
RESULTS AND DISCUSSION
The configuration/conformation of the parent dimer 2 has been
revisited in this report. The dimer 2 has been shown to be the
trans-isomer having trans–trans ring fusion and tetraequatorial
(eeee) conformation around the middle ring (Scheme 1).[5] The
1
previous researchers were unable to detect the presence of H
*
Correspondence to: S. A. Ali, Chemistry Department, King Fahd University of
Petroleum and Minerals, Dhahran 31261, Saudi Arabia.
E-mail: shaikh@kfupm.edu.sa
signals for minor conformations even at ꢀ80 8C using an 100 MHz
spectrometer. However, we were able to identify the presence of
a minor invertomer trans–cis-2:eeae (2%) in the NMR spectra
measured at temperatures below ꢀ40 8C (Figure 1). To the best of
our knowledge, this is the first time that the actual presence of a
a
S. A. Ali, A. AlSbaiee, M. I. M. Wazeer
Chemistry Department, King Fahd University of Petroleum and Minerals,
Dhahran 31261, Saudi Arabia
J. Phys. Org. Chem. 2010, 23 488–496
Copyright ß 2009 John Wiley & Sons, Ltd.

PERHYDRODIPYRIDO-1,4,2,5-DIOXADIAZINES
Scheme 1.
sake of comparison, it is worth mentioning the reported
thermodynamic parameters for the similar trans Ð cis equilibration
in decalins, the carbocyclic counterparts of the equilibrating bicyclic
portions of the current tricycle (Scheme 1). For the decalins, a DH8
value of 2.7 kcal molꢀ1 (11.3 kJ molꢀ1) favours the trans-decalin over
its cis-counterpart (Scheme 1).[8] While both decalins have a
symmetry number of 2, the cis-decalin, by virtue of its dl-pair enjoys
an entropy of mixing of R ln 2 (or 1.38cal molꢀ1 Kꢀ1); however, the
experimental value 0.55–0.60 cal molꢀ1 Kꢀ1 is appreciably less than
that, indicating the presence of additional factors affecting the
entropy difference. The presence of major and minor invertomers
in a ratio of 98:2 translates into a DG8 value of 1.7kcal molꢀ1
Table 1. 13C NMR chemical shifts of the dimers studied in CDCl3
Dimer
Invertomer
C-2
C-3
C-4
C-5
C-6
C-20
C-30
C-40
C-50
C-60
2a
Major
Minor
solo
solo
solo
52.58
53.31
58.43
67.10
51.16
51.15
51.65
24.21
24.79
29.23
28.54
26.81
26.81
27.43
22.09
22.45
18.71
22.32
39.30
39.33
39.64
28.50
29.27
35.25
35.65
30.46
30.50
31.29
96.12
85.94
78.61
86.27
94.56
94.65
84.68
—
44.99
—
—
24.21
—
—
18.11
—
—
28.38
—
—
88.96
—
4b
5b
59.01
29.60
19.03
35.51
90.18
8c,d
9c,d
major
minor
49.49
44.00
25.43
26.63
36.99
35.34
29.46
29.46
93.39
87.95
a NMR recorded at ꢀ60 8C.
b NMR recorded at þ25 8C.
c NMR recorded at ꢀ40 8C.
d Data taken from Reference [10].
J. Phys. Org. Chem. 2010, 23 488–496
Copyright ß 2009 John Wiley & Sons, Ltd.
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S. A. ALI, A. ALSBAIEE AND M. I. M. WAZEER
Figure 1. (a) H and (b) 13C partial NMR spectra of 2 at ꢀ50 8C in CDCl3
(7.1 kJmolꢀ1) at ꢀ50 8C favouring the major invertomer trans–
trans-2:eeee. While the trans–trans-2:eeee is centrosymmetric, the
minor invertomer trans–cis-2:eeae is a dl-pair and as such, the
enthalpy difference, DH8 is calculated to be 1.8kcalmolꢀ1
(7.5 kJmolꢀ1) by adding TDS to the DG8 at ꢀ50 8C. ADS value of
0.60cal molꢀ1 Kꢀ1, the experimental entropy difference in the case
of decalins, is used in the calculation. For the estimation of the DS,
the use of decalins as models is quite a rough approximation, since
the current compounds have three condensed rings and two
oxygen atoms in the central ring. The enthalpy (DH8) preference of
2.7 kcal molꢀ1 for the trans-fusion in decalin is found to be greater
than the 1.8 kcal molꢀ1 determined for the current tricycle. This
difference may be attributed to the presence of stabilizing
anomeric effect in the trans–cis-2 isomer as a result of the
antiperiplanar arrangement of the N(10)-lone pair and C(60)—O
bond (Scheme 1).
4,9-Diphenylperhydrodipyrido[1,2-b:1020-e]-1,4,2,5-dioxadiazi-
-e]-1,4,2,5-dioxadiazine was prepared by Thesing and Meyer[9] by
dimerization of nitrone 3, but the group did not discuss its
configuration or conformation. On revisiting the reaction, it was
found that the dimerization process afforded a mixture of two
compounds, 4 and 5, in a kinetic ratio of 85:15 (Scheme 2). Both
the dimers were found to equilibrate at 20 8C to a mixture of 3:4:5
in a ratio of ꢁ33:2:65, respectively. The major dimer 4 is, thus,
found to be a kinetic product, while the minor 5 is the
thermodynamic product. Note that the dimers 4 and 5 are not in
direct equilibration; rather both 4 and 5 revert back to the
monomeric nitrone 3, which then recombines and partitions in
favour of the more stable dimer 5. The NMR spectra of major
dimer 4 gave sharp signals at þ25 or ꢀ50 8C; the spectral analysis
revealed the absence of any minor invertomer. The spectral
analysis enabled us to identify the conformation as depicted in
cis–cis-4 (Scheme 2). The compound 4 can, in principle, exist in
three different configurations, equilibrating via nitrogen inver-
sion. Note that the trans–trans configuration is conformationally
frozen in the sense that it cannot undergo chair inversion. The
chair inversion, although possible, is ruled out in the cis–cis and
trans–cis isomers as it would place both the phenyl groups in
destabilizing axial orientation. Spectral data revealed the
centrosymmetric nature of the dimer 4 thereby by ruling out
the presence of the trans–cis isomer. The presence of the other
centrosymmetric trans–trans isomer is also ruled out as a result of
diaxial orientation of the phenyl groups. The 13C NMR spectrum
revealed the presence of five aliphatic carbon signals. Both the
C(6)Hs appeared at d5.85 (2H, dd, J 2.0, 3.8 Hz); while the C(2)Hs
were displayed at 4.84 (2H, dd, J 3.2, 10.8 Hz) ppm. The coupling
constant values confirm the equatorial and axial orientations
(with respect to the terminal chairs) of the C(6)Hs and C(2)Hs,
respectively.
The minor dimer 5 was assigned the trans–cis configuration
based on the 1H and 13C NMR spectroscopic analysis. Unlike the
major dimer 4, the minor isomer 5 (C22H26N2O2), in the absence
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Copyright ß 2009 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2010, 23 488–496

PERHYDRODIPYRIDO-1,4,2,5-DIOXADIAZINES
Scheme 2.
of any symmetry, displayed all the 10 possible signals for the
aliphatic carbons. The NMR spectra gave sharp NMR signals at
þ25 or ꢀ50 8C; the spectral analysis revealed the absence of any
minor invertomer. The signals at d3.82 (1H, dd, J 3.2, 11.1 Hz), 4.76
(1H, dd, J 3.0, 11.0 Hz), 4.85 (1H, dd, J 3.8, 9.3 Hz), and 5.57 (1H, dd, J
2.8, 3.4 Hz) were assigned to the axial hydrogens at C(2), C(20) and
C(6), and equatorial proton at C(60), respectively, with respect to
the terminal chairs. As discussed earlier, the axial substituent (i.e.
C-20) at N(10) will have g–gauche interactions with C(6) and as
such these carbon signals are shifted to considerable lower
frequencies (Table 1). Note that the isomer trans–cis-5 having one
cis ring fusion is found to be more stable than cis–cis-4 having two
cis ring fusions as ascertained by the thermal equilibration of
kinetic dimer 4 to thermodynamic dimer 5 (vide supra).
The correctness of the assigned configuration of 4 and 5 is
further ascertained by considering the conformational energies
of the isomers. The presence of two cis-fusions in cis–cis-4 adds a
destabilizing interaction of 3.6 kcal molꢀ1, while its invertomer
J. Phys. Org. Chem. 2010, 23 488–496
Copyright ß 2009 John Wiley & Sons, Ltd.
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S. A. ALI, A. ALSBAIEE AND M. I. M. WAZEER
Scheme 3.
¼
Table 2. Free energy of activation (DG ) for nitrogen inversion, ratio of the invertomers, and standard free energy change (DG8) for
major Ð minor isomerization in CDCl3 and CD3OD
CDCl3
CD3OD
¼
¼
Compound DG (kcal/mol)a Invertomer ratiob DG8 (kcal/mol)b DG (kcal/mol)a Invertomer ratiob DG8 (kcal/mol)b
2
9
16
14
98:2
82:18
þ1.7
15
14
97:3
89:11
þ1.5
þ0.67
þ0.93
a At 0 8C.
b At ꢀ50 8C.
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Copyright ß 2009 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2010, 23 488–496

PERHYDRODIPYRIDO-1,4,2,5-DIOXADIAZINES
Scheme 4.
trans–cis-4 has to bear the destabilizing energies of ꢁ3.2 and
1.8 kcal molꢀ1 (i.e. a total of 5.0 kcal molꢀ1) due to an axial phenyl
group and a cis ring fusion, respectively (Scheme 2). The cis–cis-4
thus enjoys stabilization enthalpy (DH8) of 1.4 kcal molꢀ1 over its
counterpart trans–cis-4. Note that both the isomers have no axis
of rotation, while cis–cis-4 is centrosymmetric and trans–cis-4
remains as a dl-pair; as such the DG8 at ꢀ50 8C for the
cis–cis-4 Ð trans–cis-4 equilibration is calculated to be
1.3 kcal molꢀ1 by subtracting the contribution of TDS from DH8
[an experinmental DS value of 0.60 cal molꢀ1 Kꢀ1, as in the case of
decalins, is used in the calculation]. Likewise, the energy difference
favouring the trans–cis-5 over trans–trans-5 is calculated to be
1.4 kcal molꢀ1, since the former has a destabilizing energy of
1.8 kcal molꢀ1 for the cis ring fusion while the later has the
conformational energy of 3.2 kcal molꢀ1 for the axial phenyl
group. The entropy difference is assumed to be zero since both
the invertomers remain as dl-pairs and have no axis of rotation.
An energy difference of 1.3–1.4 kcal molꢀ1 at ꢀ50 8C would
predict the presence of 4–5% of the minor invertomers. However,
the absence of the minor invertomers indicates the presence of
additional factors that contribute to the stabilization/destabiliza-
tion of the invertomers. The energy difference between the stable
configuration of cis–cis-4 and trans–cis-5 may now be calculated
to be about 1.8 kcal molꢀ1 in favour of the latter; this is in line with
observation of almost complete equilibration of cis–cis-4 to
trans–cis-5 at 20 8C (vide supra).
to the major invertomer. As a result the major invertomer is
expected to be stable by 0.70 kcal molꢀ1, which is similar to the
experimental value of 0.70 kcal molꢀ1 as presented above. Note
that both the isomers 9-trans–trans and 9-trans–cis remain as
dl-pair and have no axis of rotation, and as a result the entropy
difference (DS) is expected to be zero. While the minor dimer 8
remains stable for weeks in solution at ambient temperatures, the
major dimer 9 equilibrates to the nitrone 7 within a week. As
discussed earlier, the axial substituent (i.e. C-20) at N(10) will have
g–gauche interactions with C(6) of the minor invertomer of 9 and
as such these carbon signals are shifted to considerable lower
frequencies (Table 1).
At lower temperature, the 1H NMR spectra of the dimers 2 and
9 show some well-separated signals for the two invertomers in
CDCl3 or CD3OD. Integration of the relevant peaks gives the
population trends in these systems (Table 2). The proton spectra
in CDCl3 and CD3OD were used in the calculation of the nitrogen
inversion barriers. The complete band shape analysis yielded the
rate constants and the free energy of activation was calculated
¼
¼
using Eyring equation. The activation parameters DH and DS
were calculated from plots of ln(k/T) versus 1/T. It is well known[11]
that NMR band shape fitting frequently gives rather large but
mutually compensating errors in DH and DS and as such their
values are not reported here. However, band shape fitting is
¼
¼
¼
viewed as a method of getting rather accurate values of DG
(probably within ꢂ0.1 kcal/mol) in the vicinity of the coalescence
¼
Based on NMR findings, both the minor 8 as well as major
dimer 9 (C20H34N2O6), obtained via nitrone 7, were assigned[10]
the trans configurations of the bridgehead Hs with a trans–trans
ring fusion and ‘eeee’ conformation for 8 as depicted in Scheme 3.
Dimer 8 showed NMR signals characterstic of its centrosymmetric
structure and remained exclusively as a single invertomer. At
ambient temperatures, the NMR spectra revealed that almost half
the ring-protons as well as ring-carbon signals of 9 were sharp
while the other half were broad. Thus, it is logical to assume that
the ring on the right terminal is able to undergo nitrogen
inversion that would place the ester group in an equatorial
orientation. It would also impart stabilization derived from the
anomeric effect of the anti periplanar arrangement between the
N(10) lone pair and C(60)—O bond. The NMR spectra at ꢀ50 8C
revealed the two invertomers of 9 in a ratio of 82:18, which
translate into a DG8 value of 0.70 kcal molꢀ1 (2.92 kJ molꢀ1) at
ꢀ50 8C. Analysis of the conformational energies (DH8) reveals that
while the cis-ring fusion destabilizes the minor invertomer by
1.8 kcal molꢀ1, the axial-oriented ester group adds 1.1 kcal molꢀ1
temperature. The DG values calculated at 0 8C are reported in
Table 2, along with the invertomer ratios and DG8 values at ꢀ50 8C.
The nitrogen inversion barrier is expected to be high when an
oxygen atom is directly attached to the nitrogen as in isoxa-
zolidines.[12,13] The inversion barriers observed in the dimer 2 and
9 in CDCl3 are 16 and 14 kcal molꢀ1, respectively, while the corres-
ponding values in CD3OD are found to be 15 and 14 kcal molꢀ1
.
The mechanism by which the dimers are formed still remains a
matter of speculation. A thermal (4pa þ 4ps) symmetry allowed
addition reaction, as depicted in Scheme 4, would lead to the
formation of the dimer 11 having cis relationship of
the bridgehead Hs. However, in all the dimerization processes,
we were unable to detect the presence of any such cis dimer. A
more likely mechanism should involve the symmetry allowed
(4ps þ 2ps) process to lead to the intermediate 12, which is then
quickly isomerized to the dimer 2 via the backside attack by the
Oꢀ from the a-face (Scheme 4). For such a scenario, there are
three possible steric controlled dimerization processes involving
the chiral nitrones 3 and 7. For instance, the optical antipodes of 3
J. Phys. Org. Chem. 2010, 23 488–496
Copyright ß 2009 John Wiley & Sons, Ltd.
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S. A. ALI, A. ALSBAIEE AND M. I. M. WAZEER
would lead to the dimers 4 and 6 by two different approaches:
either via crowded face of both the antipodes of the nitrones
approaching the destabilized transition states (TS) (refer the TS
leading to dimer 6 in Scheme 2) or the most favourable TS in
which the least crowded faces of the nitrones approaches to give
for the dimer 4. However, identical enantiomers of 3 can undergo
dimerization in a single possible way involving a transition state
whereby the more crowded face of 3 faces the less crowded face
of the other molecule of 3 having same configuration thereby
leading to 5 (Scheme 2). The relative stability of the transition
states are in line with composition of the dimers as displayed in
Scheme 2. The approximate relative configurational free energies
of the different dimers 4, 5 and 6 are given in Scheme 2. The
dimer 6 is not formed, even though it has the most stable
configuration having trans-fused as well as equatorial oriented
substituents (Scheme 2); note that the TS leading to 6 is the most
destabilized since the crowded face of both nitrones approaches
the TS. As expected the least stable dimer cis–cis-4 equilibrates to
more stable 5 (instead of the most stable 6) in about three weeks’
time at 20 8C; the extremely high energetics of the TS leading to 6
precludes its formation. The observations are in line with the
concerted mechanism presented in this paper (vide supra); otherwise
one could have expected the formation 6 via equilibration.
Likewise, the dimerization of the nitrone 7 may lead to three
possible dimers: the identical enantiomers leading to 9 and the
antipodes leading to 8 and 10. The relative configurational
energies and compositions are given in Scheme 3. Unlike the
dimerization of 3, here in the case of 7, surprisingly the formation
of dimer 10 via the most stable TS was not observed. This could
be attributed to its least stable configurations (trans–trans-10 or
cis–cis-10, Scheme 3), which after its formation must be
equilibrating to the more stable isomers via the nitrone 7. It is
worth mentioning that the dimer 8 is formed in appreciable
quantity, even though the TS is least stable as the crowded face of
both the nitrones approaches the TS. However, unlike the dimeri-
zation of 3, the parallel plane approach of the nitrone functionality
in 7 does not exhibit steric encumbrance since the substituents at
C(4) of the nitrone is at the furthest point from the reacting centre.
and CD3OD with TMS as internal standard. Multiplicities of the
carbons were determined using DEPT experiments.
Dimerization of nitrone 1
The dimer 2 was prepared as described in the literature, m.p.
[4]
127–127.5 8C (literature
m.p. 126–127 8C). The 1H NMR
spectrum in CDCl3 at ꢀ50 8C revealed the presence of two
invertomers in a 98:2 ratio as determined by the integration of
1
several nonoverlapping major and minor H NMR signals.
Major invertomer of 2
dH (CDCl3, ꢀ50 8C) 1.42 (2H, tq, J 3.5, 13.4 Hz), 1.53 (2H, dq, J 3.5,
13.5 Hz), 1.67 (2H, tq, J 3.4, 13.1 Hz), 1.79 (4H, app d, J 12.2 Hz), 1.88
(2H, app d, J 12.5 Hz), 2.64 (2H, dt, J 2.5, 10.4 Hz), 3.31 (2H, d, J
9.8 Hz), 4.33 (2H, dd, J 3.2, 10.4 Hz); dC (CDCl3, ꢀ60 8C) 22.09, 24.21,
28.50, 52.58, 96.12.
Minor invertomer of 2
dH (CDCl3, ꢀ50 8C) Nonoverlapping signals at 4.59 (1H, dd, J 3.1,
9.8 Hz), 5.40 (1H, app s); dC (CDCl3, ꢀ60 8C) 18.11, 22.45, 24.21,
24.79, 28.38, 29.27, 44.99, 53.31, 85.94, 88.96.
The 1H NMR spectrum in CD3OD at ꢀ60 8C revealed the presence
of two invertomers in a 97:3 ratio as determined by the integration
1
of several nonoverlapping major and minor H NMR signals.
Major invertomer of 2
dH (CD3OD, ꢀ60 8C) 1.42 (4H, m), 1.57 (2H, m), 1.74 (4H, m), 1.81
(2H, m), 2.59 (2H, dt, J 2.4, 10.3 Hz), 3.18 (2H, d, J 9.8 Hz), 4.28 (2H,
dd, J 2.8, 9.5 Hz).
Minor invertomer of 2
dH (CD3OD, ꢀ60 8C) Nonoverlapping signals at 3.72 (1H, m), 4.68
(1H, dd, J 3.1, 9.8 Hz), 5.25 (1H, m).
Dimerization of nitrone 3
The dimer was prepared as described in the literature.[9]
Thus, 2-phenyl-N-hydroxypiperidine was oxidized with yellow
HgO to obtain a mixture of nitrone 4 and its regioisomeric
ketonitrone as a liquid, which after 6 days at 0 8C triturated with
small amount of ethyl acetate gave the colourless crystal of the
dimer 4. The mother liquor on TLC (silica, 1:1 ether/hexane)
analysis revealed the presence of two spots belonging to the two
dimers Rf (0.84, 0.80). The crystal obtained above represented the
dimer 4 having the lower Rf value of 0.80. While the higher Rf spot
belonging to the dimer 5 was clean and distinct, the crystalline
dimer 4 was found to be unstable on the TLC plate, and gave a
trailing spot. The mother liquor on chromatography over silica
using 90:10 hexane/ether as eluant gave the higher Rf dimer 5,
which was further purified by crystallization from ether/
dichloromethane. The ratio of the major/minor dimer 4 and 5
was approximately 85:15.
Conclusion
The NMR study has successfully identified the configuration of
the invertomers of the tricycles containing the 1,4,2,5-dioxadiazine
moiety. The presence of relatively slowly equilibrating invertomers
has permitted us, for the first time, to determine the energetics of
the nitrogen inversion process as well as the energy difference
between the cis and trans ring fusion in these tricycles.
EXPERIMENTAL
General
All m.p.s are uncorrected. I.r. spectra were recorded on a Perkin
Elmer 16F PC FTi.r spectrometer. Elemental analysis was carried
out on a Perkin Elmer Elemental Analyzer Series 11 Model 2400.
Silica gel chromatographic separations were performed with
Silica gel 100 from Fluka Chemie AG (Buchs, Switzerland). All the
solvents were of reagent grade.
The 13C and variable temperature 1H NMR spectra were recorded
on a JEOL Lambda NMR spectrometer operating at 500.0 MHz. Most
of the compounds were studied as 25 mg/cm3 solutions in CDCl3
*
*
4-R -9-S -Diphenylperhydrodipyrido[1,2-b:1(2(-e]-
*
5a-H-5a-R -10a-H-10a-S -1,4,2,5-dioxadiazine (4)
*
The major dimer 4 gave sharp 1H and 13C signals and almost
identical spectra at þ25 or ꢀ50 8C. The spectral analysis revealed
the absence of any minor invertomer. Mp 200–2018C (dec)
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Copyright ß 2009 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2010, 23 488–496

PERHYDRODIPYRIDO-1,4,2,5-DIOXADIAZINES
(ether-dichloromethane), (Found: C, 75.3; H, 7.4; N, 7.9. C22H26N2O2
requires C, 75.40; H, 7.48; N, 7.99%.) nmax (KBr) 3033, 2942, 2869,
16001, 1493, 1436, 1360, 1310, 1273, 1240, 1188, 1120, 1066, 1036,
1008, 981, 911, 878, 842, 779, 753, and 699 cmꢀ1; dH (CDCl3, þ25 8C)
1.35–1.95 (12H, m), 4.84 (2H, dd, J 3.2, 10.8 Hz), 5.85 (1H, dd, J 2.0,
3.8 Hz), 7.22–7.42 (10H, m); dC (CDCl3, þ258C) 18.71, 29.23, 35.25,
58.43, 78.61, 127.03, 127.24, 128.75, 142.20.
lower temperatures the 1H and 13C NMR spectra of 9 revealed the
presence of two invertomers in a ratio of 82:18.
Major invertomer of 9
dH (CDCl3, ꢀ40 8C) 0.92 (3H, t, J 7.3 Hz), 0.94 (3H, t, J 7.3 Hz), 1.36
(4H, m), 1.55–2.22 (10H, m), 2.28 (1H, J 12.9 Hz), 2.37 (1H, d, J
12.8 Hz), 2.55 (1H, m), 2.68 (1H, app. T, J 11.9 Hz), 2.73 (1H, app t, J
13.4 Hz), 2.83 (1H, app s), 3.22 (1H, td, J 3.0, 10.4 Hz), 3.36 (1H, td, J
3.0, 10.7 Hz), 4.10 (4H, m), 4.33 (1H, dd, J 3.05, 10.7 Hz), 4.42 (1H,
dd, J 3.05, 11.0 Hz); dC (CDCl3, ꢀ40 8C) 13.83, 13.89, 19.04, 19.09,
25.43, 26.81, 29.46, 30.24, 30.28, 30.50, 36.99, 39.33, 49.49, 51.15,
64.79, 65.06, 93.39, 94.65, 173.23, 173.31.
*
*
4-S -9-S -Diphenylperhydrodipyrido[1,2-b:1(2(-e]-
*
*
5a-H-5a-R -10a-H-10a-S -1,4,2,5-dioxadiazine (5)
1
The minor dimer 5 gave sharp H and 13C signals and almost
identical spectra at þ25 or ꢀ50 8C. The spectral analysis revealed
the absence of any minor invertomer. Mp 204–2058C (dec) (ether-
dichloromethane), (Found: C, 75.2; H, 7.4; N, 7.5). C22H26N2O2
requires C, 75.40; H, 7.48; N, 7.99%.); nmax (KBr) 3028, 2924, 2863,
1601, 1491, 1451, 1378, 1349, 1301, 1234, 1182, 1111, 1065, 983,
912, 881, 848, 755, and 699 cmꢀ1; dH (CDCl3, þ25 8C) 1.35–1.90
(12 H, m), 3.78 (1 H, dd, J 3.2, 11.1 Hz), 4.74 (1 H, dd, J 2.9, 11.1 Hz),
4.80 (1H, apparent dd, J 6.4, 7.1 Hz), 5.53 (1H, dd, J 2.8, 3.4 Hz),
7.20–7.45 (10H, m); dH (CDCl3, ꢀ408C) 1.35–1.90 (12H, m), 3.82 (1H,
dd, J 3.2, 11.1 Hz), 4.76 (1H, dd, J 3.0, 11.0 Hz), 4.85 (1H, dd, J 3.8,
9.3 Hz), 5.57 (1H, dd, J 2.8, 3.4 Hz), 7.25–7.50 (10H, m); dC (CDCl3,
þ25 8C) 19.03, 22.32, 28.54, 29.60, 35.51, 35.65, 59.01, 67.10, 86.27,
90.18, 126.70, 126.93, 126.99 (2C), 127.07 (2C), 128.08 (2C), 128.34
(2C), 142.38, 142.71.
Minor invertomer of 9
dH (CDCl3, ꢀ40 8C) non-overlapping signals at d3.04 (1H, td, J 3.0,
10.0 Hz), 3.33 (1H, td, J 3.0, 10.7 Hz), 3.69 (1H, app t, J 11.0 Hz), 4.57
(1H, dd, J 2.5, 11.0 Hz), 5.43 (1H, app s); dC (CDCl3, ꢀ40 8C) 13.83,
13.89, 19.04, 19.09, 26.63, 27.43, 29.46, 30.24, 30.50, 31.29, 35.34,
39.64, 44.00, 51.65, 64.64, 64.79, 84.68, 87.95, 173.37 (2C).
The 1H NMR spectrum in CD3OD at ꢀ40 8C revealed the
presence of nonoverlapping signals at d 4.33 (1H, dd, J 2.2,
10.1 Hz) and 4.41 (1H, dd, J 3.0, 11.3 Hz) attributed to the NCHO
protons of the major invertomer. The corresponding protons of
the minor invertomer appeared at d 4.69 (1H, dd, J 2.5, 9.8 Hz).
Inversion barrier calculations
Thermal equilibration of nitrone 4 and 5
Simulations of exchange-affected proton spectra for all the
compounds were carried out using a computer program AXEX,[14]
corresponding to a two noncoupled sites’ exchange with unequal
populations. Simulations of exchange affected signals were
carried out by modifying the two-site exchange program.[15] The
first order coupling to these protons is simply assumed as giving
two overlapping site exchanges with the same population ratio
and equal rates of exchange. For 2 in CDCl3, signals at d4.33 (2H,
dd, J 3.2, 10.4 Hz) (major) and 5.40 (1H, app s) (minor) were
utilized. While for 2 in CD3OD, signals at d4.28 (2H, dd, J 2.8, 9.5 Hz)
(major) and 4.68 (1H, dd, J 3.1, 9.8 Hz) (minor) ppm were utilized.
The small coupling of the dd is ignored and assumed as a ‘d’ with
a slight broadening of the doublets. For the minor peak of very
low intensity (ꢁ2%), the complete analysis was not possible, so
we used the width at half height of the minor peak to calculate
the approximate rate constant.
A solution of the dimer 5 (10 mg) in CDCl3 (0.7 cm3) was equili-
brated at room temperature for two weeks. H NMR spectrum
1
revealed the presence of 3:4:5 in a ratio of 35:1:64, respectively.
The presence of the nitrone was revealed by nonoverlapping
signals at d 5.10 (1H, m), 2.65 (2H, m), 2.33 (1H, m), 2.1 (1H, m).
Likewise, a solution of the 4 nitrone in CDCl3 was equilibrated
at room temperature for two weeks. 1H NMR spectrum revealed
the presence of 3:4:5 in a ratio of 30:3:67, respectively.
Dimerization of nitrone 7
The dimers 8 and 9 were prepared as described in the literature.[10]
Thus a solution of nitrone 7 (3 mmol) in CH2Cl2 (5 cm3), kept at
room temperature for 3 days, which after chromatography over
silica using 1:4 ether/hexane as eluant afforded the dimers 8
(127 mg) and 9 (240 mg) in a ratio of 1:2.
For 9 in CDCl3, signals at d4.42 (1H, dd, J 3.05, 11.0 Hz) (major)
and d4.57 (1H, dd, J 2.5, 11.0 Hz) (minor) were utilized, while in
CD3OD, signals at d4.41 (1H, dd, J 3.0, 11.3 Hz) (major) and 4.69
(1H, dd, J 2.5, 9.8 Hz) (minor) were utilized.
Minor dimer 8
1H NMR and 13C NMR spectra at ꢀ40 8C remained the same as
that of 258C; no minor invertomer could be seen. The minor dimer
is stable; no appreciable change in the NMR signals happened even
after weeks in CDCl3 solution. The 1H NMR spectrum[10] in CDCl3 at
þ25 or ꢀ50 8C revealed the bridgehead C(6) axial protons at d 4.32
(2H, dd, J 3.3, 10.8 Hz); dC (CDCl3, ꢀ408C) 13.84, 19.05, 26.81, 30.25,
30.46, 39.30, 51.16, 64.81, 94.56, 173.31.
Acknowledgements
The authors gratefully acknowledge the facilities provided by the
King Fahd University of Petroleum and Minerals, Dhahran.
Major dimer 9
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The NMR spectrum in CDCl3 at ꢀ50 8C revealed the presence of
two invertomers in a 82:18 ratio as determined by the integration
of several nonoverlapping major and minor 1H NMR signals. The
major dimer 9 was equilibrated to nitrone 7 in a ratio of 3:1 after
3 weeks at þ20 8C in CDCl3 solution (10 mg in 0.7 cm3 CDCl3). At
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J. Phys. Org. Chem. 2010, 23 488–496
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Copyright ß 2009 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2010, 23 488–496