Unprecedented synthesis, 1D, and 2D NMR spectral studies of 2,4,6,11-tetraaryl-9-oxa-1,5-diazatricyclo[5.3.1.03.8] undecane via a novel rearrangement

Full text of DOI:10.1002/mrc.4893

M Sundaravadivelu (Orcid ID: 0000-0001-5161-7404)
Unprecedented synthesis, 1D and 2D NMR spectral studies of 2,4,6,11-
tetraaryl-9-oxa-1,5-diazatricyclo [5.3.1.03.8] undecane via a novel
rearrangement
G. Vengatesh, M. Sundaravadivelu*
Department of Chemistry, The Gandhigram Rural Institute (Deemed to be University), Gandhigram 624302,
Tamilnadu, India.
Correspondence email: msundargri@gmail.com
Abstract
A novel rearrangement of a methylene group from nitrogen to oxygen has been
observed during sodium borohydride or lithium aluminium hydride reduction of 4,8,9,10-
tetraaryl-1,3-diazaadamantan-6-one. Resulting new compounds, 2,4,6,11-tetraaryl-9-oxa-1,5-
diazatricyclo [5.3.1.03.8] undecane, containing an oxaquinuclidine skeleton, is characterized
along with its stereochemistry by 2D-NMR and single crystal XRD techniques.
Keywords: 1H NMR; 13C NMR; 15N NMR; 2D NMR; reduction; 13C−19F coupling;
diazaadamantanone; bispidine; quinuclidine; conformation
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Introduction
Piperidine ring-containing cyclic compounds are key structural fragments of many
valuable medicinally active compounds. Some of them are well-known pharmacophores,
present in numerous naturally occurring alkaloids and biologically active molecules such as
drugs and pharmaceutical ingredients.[1] Derivatives of bispidines, containing two piperidine
rings are also of great interest in drug synthesis due to their presence in a variety of naturally
occurring lupin alkaloids and various biologically active molecules. [ ] Bispidine with aromatic
2
substituents enhances the biological property of the molecules. [ ] A huge number of these
3
cyclic compounds have been found to possess useful medicinal and biological properties such
as anti-inflammatory, sedative, [ ] cytotoxicity, [ ] and anti-photoaging activity. [ ] Quinuclidine
4
5
6
is an interesting [2.2.2] bridged bicyclic nitrogen heterocycle with a nitrogen atom placed at
[ ]
7
the bridgehead. The natural products quinine and quinidine are without a doubt the most
recognized members of the quinuclidine family, with a long history in traditional medicine and
[ ]
8
in recent decades as privileged chiral organic ligands in catalysis . Synthesis of new bispidine
derivatives and their conformational analysis have provided a valuable interest in the field of
medicinal chemistry because the biological properties are strongly related to the conformation
[ ]
9
of the molecule . Hence, it is imperative to establish the stereochemistry and conformation of
]
the bioactive molecules [10 . The bioactive bicyclic derivatives exist in chair, chair-boat, twin
[
]
11-13
chair or twin boat conformations with interesting stereochemistry.
Hence, this
methodology will be useful for the development of new biologically active molecules. Herein,
we report the synthesis, 1H and 13C NMR spectral assignment of five new 2,4,6,11-tetraaryl-9-
oxa-1,5-diazatricyclo [5.3.1.03.8] undecanes through solution 2D NMR spectral techniques.
Results and discussion
The starting bicyclic compounds (1a-e) exist in chair-boat conformation with all aryl
groups oriented equatorially.[14] Bicyclic compounds 2,4,6,8-tetraaryl-3,7-diazabicyclo [3.3.1]
nonan-9-ones (1a-e) were prepared through one-pot synthesis from ammonium acetate, acetone
]
and aryl aldehydes in ethanol medium.[15 Bicyclic compounds (1a-e) were refluxed with
paraformaldehyde for 3 h in chloroform medium and yielded 4,8,9,10-tetraaryl-1,3-
diazaadamantan-6-ones (2a-e). In these compounds, two aryl groups, in the β-position with
respect to the carbonyl group are in equatorial position in one piperidine ring. Two aryl groups
in the β-positions with respect to the carbonyl group, are in axial positions in other piperidine
]
16
ring. [ Hence, we wanted to study the stereochemistry of the reduction reaction of these
ketones (2a-e) using either NaBH4 or LAH as a reducing agent. It is reported that in 4-
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substituted cyclohexanone, hydride ion transfer will take place from the less hindered side to
]
17
yield an axial alcohol. [
Synthesis of oxa quinuclidine ring-containing compounds is a novel and efficient
synthetic method that has been developed by NaBH4 or LAH reduction of 4,8,9,10-tetraaryl-
1,3-diazaadamantan-6-one (Scheme 1), and the details are presented in this manuscript. This
method has advantages, such as readily available substrates, mild reaction conditions and good
yields. The reduction of a ketone would normally yield on alcohol, and we expected 6-hydroxy-
4,8,9,10-tetraaryl-1,3-diazaadamantane from the above reduction reaction. But, to our surprise,
the product on analysis by FT-IR, 1D and 2D NMR spectral studies was found to be 2,4,6,11-
tetraaryl-9-oxa-1,5-diazatricyclo [5.3.1.03.8] undecane (3) (Scheme 1).
The 1H and 13C NMR chemical shifts of compounds 3a-e are given in Table 1 and 2,
respectively. The NMR spectrum of 3e is used as the representative compound. In a 1H NMR
spectrum, initially, we assigned a singlet at 1.80 ppm to the -OH proton, expected in the
reduction product of a ketone. A singlet at 4.12 ppm, integrated for two protons, confirmed the
presence of a -CH2-group. The 13C and DEPT-135 NMR spectra indicated the absence of the
carbonyl group in 3e and the presence of -CH2-group. The compound is further characterized
by two−dimensional and 15N NMR spectra. The COSY/NOESY and HSQC/HMBC
correlations of compounds 3e are given in Table 3 and 4, respectively. Important 1H-1H COSY,
NOESY and HMBC correlations are shown in Fig. 1. The broad singlet at 1.80 ppm shows a
strong COSY correlation with the broad signal at 4.15 ppm (H-4 and H-6 protons of the newly
assigned structure). It also shows a NOESY correlation with the same signal. If the signal at
1.80 ppm were due to a hydroxy group, then the above correlations could not be possible,
because the -OH and H-4/H-6 protons would be far separated, and hence, it is concluded that
this signal is not due to a hydroxy group. The triplet at 2.76 (2H) ppm shows COSY, NOESY
correlations with four benzylic (H-4,6=4.15 and H-2,11=4.39 ppm) protons and H-8 (4.07
ppm) proton, hence this signal is unambiguously assigned to bridgehead protons (H-3 and H-
7). In the HMBC spectrum, the triplet at 4.07 ppm (H-8; 1H; J = 3.84 Hz) correlates with C-10
at 72.18 ppm. This shows the proximity of C8-H and at C-10. Had it been due to the -CH2-
group bridging the two piperidine nitrogens as in 2e, diazaadamantanone, then the above
correlation would not be possible. Similarly, the -CH2- hydrogens are correlating with only the
two benzylic carbons at C-2 and C-11. This confirms that the -CH2- group is not bridging the
two piperidine nitrogens.
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1
In the H-15N HSQC correlation spectra, the nitrogen signal at 49.79 ppm correlates
with the proton signal at 1.80 ppm, and it confirms that this proton signal is due to the presence
of an NH group, not an OH group. All these facts/results confirm that the -CH2- group is
bridging the nitrogen and oxygen atoms. Besides, the presence of an N-H group is further
confirmed by the 15N NMR spectrum. Finally, the structure of 3e is unambiguously confirmed
by single crystal X-ray analysis (Fig. 2). Recently we have published the crystal structure and
Hirshfeld surface analysis of compound 3e in Acta Cryst E.[18]
The 13C-19F coupling of compound 3e is explained based on XRD numbering pattern (Fig. 2).
F1/F4 couples with C3/C30 appeared as a doublet at 160.6 ppm (1J = 207.0 Hz). A two-bond
coupling with C2,C4/C29,C31 appear as a doublet at 114.6 ppm (2J = 80 Hz). A three-bond
coupling with C1,C5/C28,C32 appear as a doublet at 129.0 ppm (3J = 32 Hz). A four-bond
coupling with C6/C27 appear as a doublet at 135.9 ppm (4J = 16 Hz). In the same way F2/F3
couples with C13/C21 as well as C10/C18 and appear as a doublet at 163.0 ppm (1J = 211 Hz)
and 137.0 ppm (4J = 12 Hz), respectively. F2/F3 also coupled with C11,C15/C19,C23 and
C12,C14/C20,C22 appear as a doublet at 115.6 ppm (2J = 84 Hz) and 127.9 ppm (3J = 32 Hz),
respectively.
Two piperidine rings are in chair-boat conformations, and the four fluorophenyl groups
1
are equatorially oriented based on H NMR, COSY and NOESY spectra. The bridgehead
protons, H-3 & H-7, appeared as a triplet at 2.76 ppm (t, J=5.04 Hz) and they couple with H-8
at 4.07 ppm (t, J= 3.84 Hz). H3e couples with H2e ( 4.40 ppm, d, J= 4.88 Hz) and also with H4a
( 4.15 ppm, t, J= 3.84 Hz). H7e couples with H11e (4.40 ppm, d, J= 4.88 Hz) and also with H6a
(4.15 ppm). It leads to the conclusion that all aryl groups at C-2, 11 and C-4, 6 are equatorially
oriented. The 3 & 7 bridgehead protons have COSY and NOESY correlation with the
neighbouring benzylic protons and also with H-8 at 4.07 ppm. The N-H proton, appearing as a
broad singlet at 1.80 ppm, has strong COSY and NOESY correlation with the benzylic
hydrogens at positions 4 & 6 but not with benzylic hydrogens at positions 2 & 11. It leads to
the conclusion that the piperidine ring, C3-C4-N5-C6-C7-C8, exists in a chair conformation.
Had this ring been in a boat conformation, then we would have expected flag pole-bow spirit
interactions of piperidine-NH with H-8, which is absent in the compounds studied. A sharp
singlet at 4.12 ppm (H-10; CH2) shows NOESY and COSY correlation with benzylic
hydrogens 2 & 11 and also with H-8. It is evidence for a boat conformation of another
piperidine ring (C8-C7-C11-N1-C2-C3) and for an presence of a six-membered ring (N1-C10-
O-C8-C7/C3-C11/C2) which constituted part of a oxaquiniclidine ring system.
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Long-range coupling in the saturated bicyclic and tri-cyclic compounds occur through
a rigid arrangement of the bonds in the form of W (4J), with hydrogen occupying the end
position. [19] This long-range coupling strongly supports the conformation of the ring. The W
arrangements of the studied compounds are shown in Fig. 3. “W” arrangements between H-3,7
and NH (Fig. 3a & 3b) is evidenced from COSY correlation, which proves the chair
conformation of C3-C4-N5-C6-C7-C8 six membered ring in chair conformation. “W”
arrangements also present in H-2,11 and CH2 (Fig. 3c & 3d), which is evidenced for the
formation of oxaquiniclidine ring (CH2 bridging the N1 and O9).
A plausible mechanism for this unusual rearrangement from the 1,3-diazaadamantan-
6-one into a oxaquinuclidine skeleton is presented in Scheme 2. In-line with the
stereochemistry of metal hydride reduction (structure 2−>4), the hydride ion transfer takes
place through the less hindered side of piperidine ring A, where two aryl groups at C-8 & C-9
in structure 2 are equatorially oriented. A hydride ion transfer through piperidine ring B is
prevented by two axially oriented aryl groups at C-4 & C-10 in structure 2. Obviously, the
newly formed -OH group in structure 5 exerts two severe 1,3-diaxial steric interactions with
two diaxially oriented aryl groups at C-4 & C-10 in piperidine ring B. This might be the driving
force for the spontaneous ring opening from the N-CH2-N group to produce iminium ion 6.
Severe 1,3-diaxial interactions are now relieved when the piperidine ring B undergoes
conformational flipping from a chair to a boat conformation in 7. Two aryl groups at C2 & C11
in structure 8 are now oriented equatorially. Cyclisation of 7 to 8 could take place easily due
to the proximity of the hydroxy group and iminium carbon. This nitrogen to oxygen migration
of a methylene group forms a new oxaquinuclidine skeleton. The reaction was carried in a
different sequence as shown in scheme 3. Here, bicyclic ketone 1e was first reduced with
NaBH4 in a chloroform-ethanol medium. Hydroxy compound 4e, thus formed, was heated with
paraformaldehyde in chloroform medium and yielded compound 3e exclusively. This leads to
the conclusion that tetraaryl hydroxy adamantane, once formed, undergoes spontaneous
rearrangement to yield 3e.
Conclusion
A novel rearrangement involving migration of a methylene group from nitrogen to
oxygen to form a stable oxaquinuclidine skeleton is reported. 4,8,9,10-Tetraaryl-1,3-
diazaadamantan-6-one on reduction either with NaBH4 or with LiAlH4 yielded 2,4,6,11-
tetraaryl-9-oxa-1,5-diazatricyclo [5.3.1.03.8] undecane. In the new compounds, containing an
oxaquinuclidine skeleton, two piperidine rings are in chair-boat conformation with all the aryl
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groups oriented equatorially. The reaction condition is mild, and excellent yields are obtained
in short reaction times. A mechanism for the unusual rearrangement is proposed.
Experimental section
General Method
Melting points were determined by the open capillary method. FT-IR spectra were
recorded on a JASCO FT/IR-4700 instrument. All NMR spectra were recorded on a Bruker
AVANCE III HD 400 MHz spectrometer and recorded at 295-297 K in CDCl3 as the solvent
with TMS as an internal standard. Chemical shifts are reported in ppm (δ) and referenced to
TMS (δH = 0 ppm) in 1H NMR spectra, residual CDCl3 (δH = 7.2 ppm, δC = 77 ppm). Three mg
1
of compound dissolved in 0.5 ml of CDCl3 was used for the assignment of H and D2O
exchange chemical shift. Thirty mg of compound dissolved in 0.5 ml of CDCl3 was used for
13C NMR, DEPT-135, 1H - 1H COSY, NOESY, HSQC, HMBC, 1H-15N HSQC and 15N NMR
analysis.
Recording of one-dimensional NMR spectra
The pulse conditions were as follows: 1H NMR spectra: number of data points (TD) 65536,
number of scans (NS) 16, dummy scans (DS) 2, spectra with (SWH) 8012.8 Hz, acquisition
time (AQ) 4 sec, spectrometer operating frequency 400.23 MHz, line broadening (LB) 0.30
Hz, Recycle Delay (D1) 1.0 sec. 13C NMR spectra: TD 65536, NS 1274, DS 4, SWH 24038.4
Hz, AQ 1.3 sec, SF 100.63 MHz, LB 1.00 Hz, D1 2.0 sec. 15N NMR spectra: TD 32768, NS
1528, DS 4, SWH 20380.4 Hz, AQ 0.80 sec, SF 40.554 MHz, LB 0.25 Hz, D1 10.0 sec.
Recording of two-dimensional NMR spectra
H-H COSY: TD 2048 (F2), TD 128 (F1) NS 1, DS 16, SWH 3289 Hz, AQ 0.31 sec, SF 400.23
MHz, LB 0 Hz, D1 1.88 sec. NOESY: TD 2048 (F2), TD 256 (F1) NS 4, DS 32, SWH 3875.9
Hz, AQ 0.26 sec, SF 400.23 MHz, LB 0 Hz, D1 1.99 sec, mixing time 0.30 sec. HSQC: TD
1024 (F2), TD 128 (F1) NS 4, DS 16, SWH 3875.9 Hz, AQ 0.13 sec, SF 400.23 (F2) MHz, SF
100.63 (F1) MHz, LB 0 Hz, D1 1.46 sec, one bond coupling 145.0 Hz. HMBC: The parameters
were very similar to those used in the HSQC experiment only change in TD 2048 (F2), TD 128
(F1), long-range coupling 10.0 Hz. 1H-15N HSQC: TD 2048 (F2), TD 256 (F1) NS 8, DS 16,
SWH 5597 Hz, AQ 0.18 sec, SF 400.23 MHz, LB 0 Hz, D1 2.00 sec, one bond coupling 90.0
Hz.
Typical experimental procedure
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The compound (2e) 4,8,9,10-tetra(4-fluorophenyl)-1,3-diazaadamantan-6-one (2
mmol, 1.05 g) dissolved in chloroform (5 ml) and NaBH4 (4 mmol, 0.15 g) dissolved in ethanol
(5 ml) were mixed and transferred to a closed container and stirred at 10o C. The reaction was
monitored by TLC, and after complete disappearance of the ketone the resulting mixture was
filtered. The solvent was evaporated and washed with cold water and recrystallised from
chloroform: ethanol to obtain the compound 3e.
2.4,6,11-tetra(4-fluorophenyl)-9-oxa-1,5-diazatricyclo [5.3.1.03.8] undecane 3e; Colorless
1
power, 90 % yield (0.95 g); IR (KBr): 3316, 3078, 2987, 2955, 2930, 1508, 1222, 1158; H-
NMR (CDCl3 / TMS, 400.22 MHz) 1.80 (1H, s), 2.76 (2H, t, J=5.04 Hz), 4.07 (1H, t, J=3.84
Hz), 4.12 (2H, s), 4.15 (2H, s) 4.40 (2H, d, J=4.88 Hz), 6.80 (4H, t, J=8.68 Hz), 6.97-7.01 (8H,
m) 7.46-7.50 (4H, s). D2O Exchange (CDCl3 / D2O / TMS, 400.22 MHz) 2.76 (2H, t, J=5.28
Hz), 4.07 (1H, d, J=6.12 Hz), 4.13 (4H, d, J=5.24 Hz), 4.40 (2H, d, J=3.76 Hz), 6.79 (4H, t,
13
J=8.32 Hz), 6.97-7.00 (8H, m), 7.46-7.49 (4H, m). C-NMR (CDCl3 / TMS, 100.63 MHz)
44.1, 58.2, 60.9, 69.4, 72.1, 114.5, 114.7, 115.5, 115.7, 127.8, 127.9, 129.0, 129.1, 135.9,
135.9, 136.9, 137.0, 160.3, 160.8, 162.7, 163.3. DEPT-135 (CDCl3 / TMS, 100.63 MHz) (44.1,
58.2, 60.9, 69.4, 114.5, 114.7, 115.5, 115.7, 127.8, 127.9, 129.0, 129.1 = Upward direction),
15
72.19 (Downward direction) N NMR (CDCl3 / Formamide, 40.55) 49.79, 200.35. HRMS
(TOP MS ES) m/z: [M-12C+3] calcd. for C31H26F4N2O 521.198; found 521.048.
Acknowledgment
The authors thank the UGC, New Delhi for Major Research Project (grant No. 42-358/2013
(SR)) & UGC-Special Assistance Program (SAP). The authors gratefully acknowledge DST-
FIST NMR facility of Department of Chemistry, The Gandhigram Rural Institute (Deemed to
be University) for recording NMR spectra.
Supplementary Material
1
Copies of H NMR, 13C NMR and FT-IR spectra of compounds 3a-e have been
15
1
provided. Copies of 2D NMR (COSY, NOESY, HSQC, HMBC), D2O treated, N, H-15N
HSQC and HRMS spectra for the compound 3e is given. The supplementary material also
contains X-ray data of compound 3e and this data (CCDC 1854381) can be obtained free of
charge
from
the
Cambridge
Crystallographic
Data
Centre
via
www.ccdc.cam.ac.uk/data_request/cif.
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Table 1. 1H NMR chemical shift (δ, ppm) of 3a-3e
Entry
3a
3b
3c
3d
H-10
4.19
4.17
4.08
4.17
4.12
H-4,6
4.17
4.08
4.13
4.09
4.15
H-3,7
H-2,11
H-8
NH
1.85
1.73
1.80
1.76
1.80
Others
2.85 (t, 5.32 Hz)
2.74 (t, 4.40 Hz)
2.76 (t, 5.12 Hz)
2.76 (t, 4.84 Hz)
2.76 (t, 5.04 Hz)
4.51 (d, 4.72 Hz)
4.42 (d, 4.00 Hz)
4.38 (d, 5.12 Hz)
4.47 (d, 4.96 Hz)
4.40 (d, 4.88 Hz)
4.08 (t, 3.54 Hz)
4.01 (t, 3.60 Hz)
4.06 (t, 3.86 Hz)
4.01 (t, 3.82 Hz)
4.07 (t, 3.84 Hz)
–
3.72, 3.75
–
2.28, 2.22
–
3e
Entry
Ortho H at C2 & C11
7.29 (t, 7.42 Hz)
Ortho H at C4 & C6
Meta H
Para H
3a
3b
3c
3d
3e
7.54 (d, 7.56 Hz)
7.41 (d, 8.00 Hz)
7.27 (d, 5.36 Hz)
7.40 (d, 8.00 Hz)
7.46-7.50 (dd)
7.06, 7.08, 7.19 (t, 7.24 Hz)
6.63 (d, 7.60 Hz), 6.82 (d, 8.00 Hz)
6.95 (d, 8.44 Hz), 7.45 (d, 8.44 Hz)
6.87-6.92 (dd)
7.01, 7.02
6.96 (d, 8.00 Hz)
7.10 (d, 8.60 Hz)
7.10 (d, 7.88 Hz)
6.99-7.01 (m)
–
–
–
–
6.80 (t, 8.68 Hz), 6.97-6.99 (m)
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Table 2. 13C NMR chemical shift (δ, ppm) of 3a-3e
Entry C-
10
C-
4,6
C-
C-
C-8 Others
Ipso
Ortho
Meta
Para
3,7 2,11
3a
3b
3c
3d
3e
72.6 61.9 44.5 58.7 69.8
72.3 61.3 44.6 58.2 69.9
72.3 61.0 43.9 58.2 69.3
72.6 61.8 44.8 58.4 70.0
72.1 60.9 44.1 58.2 69.4
–
140.7,
141.6
133.1,
133.9
138.6,
139.6
138.8,
138.0
135.9,
137.0
127.5,
127.4
127.5,
128.7
129.0,
128.8
127.5,
126.5
127.9,
129.0
128.7
113.0,
114.0
128.0,
127.7
129.3,
128.3
114.6,
115.6
126.3,
126.5
157.9,
158.8
132.5,
133.3
136.8,
135.6
160.6,
163.0
55.1,
55.3
20.9,
21.1
–
–
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Table 3. Correlation in the 1H - 1H COSY and NOESY spectra data of compound 3e
Signal (δ in ppm)
COSY Correlation
Correlation in NOESY
1.80 (1H, NH)
2.76 (2H, H-3,7)
2.76 (w), 4.15
4.07, 4.15, 4.40
4.15, 4.40 (w), 7.46-7.50
4.07, 4.15, 4.40, 7.46-7.50,
6.80 (w), 6.99-7.01
2.76
4.07 (1H, H-8)
2.76
4.12 (2H, H-10)
4.40, 4.07
2.76, 4.40
4.15 (2H, H-4,6)
2.76, 1.80, 7.46-7.50 1.80 (w), 7.46-7.50, 6.99-7.01
2.76, 4.12, 6.99-7.01 1.80, 2.76, 7.46-7.50, 6.99-7.01
4.40 (2H, H-2,11)
6.80 (meta proton of the Ph at
C-2/C-11)
6.99-7.01
6.99-7.01
6.97-7.01 (meta proton of the
Ph at C-4/C-6 and ortho proton 6.80, 7.46-7.50
of the Ph at C-2/C-11)
7.46-7.50 (ortho proton of the
2.76, 4.12, 4.40, 6.80
1.80, 2.76, 4.15, 4.30, 6.99-7.01
Ph at C-4/C-6)
6.97-7.01
w: weak correlation
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Table 4. Correlation in the HSQC and MMBC spectra data of compound 3e
Signal (δ in ppm)
HSQC
Correlations
-
HMBC Correlations
1.80 (1H, NH)
44.1 (C-3,7)
2.76 (2H, H-3,7)
4.07 (1H, H-8)
44.1
69.4 (C8), 135.9 (w), 135.9
44.1 (C-3,7), 58.2 (C-2,11), 72.1 (C-10)
58.2, 69.4 (w)
69.4
4.12 (2H, H-10)
4.15 (2H, H-4,6)
4.40 (2H, H-2,11)
72.1
60.9
44.1 (C-3,7), 58.2 (C-2,11), 69.4, 127.8,
127.9, 136.9, 137.0
58.2
44.1 (C-3,7), 58.2 (C-2,11), 60.9 (C-4,6),
72.1 (C-10), 114.5 (w), 129.0, 129.1,
135.9, 135.9
6.80 (meta proton of the Ph
at C-2/C-11)
114.5,
114.7
115.5,
6.97-7.01 (meta proton of
114.5, 114.7, 129.0, 129.1, 135.9,
135.9,160.3-163.3
the Ph at C-4/C-6 6.99-7.01 115.7
ortho proton of the Ph at C- 129.0,
58.2 (C-2,11), 115.5, 115.7, 129.0,
2/C-11)
129.1
127.8,
127.9
129.1, 136.9, 137.0,
160.3-163.3
7.46-7.50 (ortho proton of
the Ph at C-4/C-6)
60.9 (C-4,6), 115.5, 115.7, 127.8, 126.9,
160.3-163.3
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Compounds 3a-e
Melting point oC
Compounds
Ar
% Yield
91
C6H5
232
230
238
244
242
a
b
c
p-OCH3 C6H4
p-Cl C6H4
p-CH3 C6H4
p-F C6H4
94
89
92
d
e
90
Scheme 1. Synthesis of 2,4,6,8-tetraaryl-3,7- diazabicyclo [3.3.1] nonan-9-one (1), 4,8,9,10-
tetraaryl-1,3-diazaadamantan-6-one (2) and 2,4,6,11-tetraaryl-9-oxa-1,5-diazatricyclo
[5.3.1.03.8] undecane (3).
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Scheme 2. Plausible reaction mechanism for the formation of compounds 3a-e.
Scheme 3 Reduction of 1e and cyclization of 4e yielded 3e.
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Figure 1. a) Selected 1H - 1H COSY and NOESY correlation of 3e. b) Selected HMBC correlation of
3e.
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Figure 2. ORTEP diagram of 3e
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Fig. 3. Correlation between the protons that are in “W” arrangements, from the COSY spectrum of 3e.
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