Prins reaction under manganese dioxide control: The synthesis of 6-oxa-2-azabicyclo[3.2.1]octan-4-ones from tetrahydropyridines and formaldehyde

Article abstract of DOI:10.1070/mc2001v011n01abeh001386

The course of the acid-catalysed Prins reaction of tetrahydropyridines 1 with formaldehyde, leading to derivatives of piperidino-dioxane 4 and 3-oxa-7-azabicyclononanes 5 and 6, is dramatically changed in the presence of manganese dioxide to give new products, 6-oxa-2-azabicyclo[3.2.1]octan-4-ones 7 and 8.

Full text of DOI:10.1070/mc2001v011n01abeh001386

, 2001, 11(1), 27–28
Prins reaction under manganese dioxide control: the synthesis of
6-oxa-2-azabicyclo[3.2.1]octan-4-ones from tetrahydropyridines and formaldehyde
Anatoly T. Soldatenkov,* Kyrill B. Polyanskii, Ayalew W. Temesgen, Svetlana A. Soldatova, Nataliya D. Sergeeva,
Nadezhda M. Kolyadina and Nikolai N. Lobanov
Peoples' Friendship University of Russia, 117198 Moscow, Russian Federation. Fax: +7 095 433 1511
10.1070/MC2001v011n01ABEH001386
The course of the acid-catalysed Prins reaction of tetrahydropyridines 1 with formaldehyde, leading to derivatives of piperidino-
dioxane 4 and 3-oxa-7-azabicyclononanes 5 and 6, is dramatically changed in the presence of manganese dioxide to give new
products, 6-oxa-2-azabicyclo[3.2.1]octan-4-ones 7 and 8.
The previous studies of acid-catalysed condensation of 4-aryl-
Ar
Ar
Ar
O
4
substituted terahydropyridines (THPs) 1 with an excess of
formaldehyde and sulfuric acid have shown that this Prins
reaction gave 3-hydroxymethyl THPs 21 or, in the case of a
tenfold molar excess of formaldehyde, corresponding piperidino-
dioxanes 32 (Scheme 1). In repeating an analogous reaction of
THP 1a with a fourfold excess of formaldehyde, we separated
not only known 1,3-dioxane 3a but also three new products:
8-hydroxymethyl derivative of piperidinodioxane 4 and 3-oxa-
7-azabicyclo[3.3.1]nonanes 5 and 6, the last two being isomers
by the position of 9-hydroxyl in respect to the ring nitrogen
atom (cis N/9-OH and trans N/9-OH, respectively). The X-ray
5
6
O
ii
i
3
8
1
7
N
N
N 2
Me
Me
1a,d
9, 10
7, 8
7, 9 Ar = Ph
1d, 8, 10 Ar = p-MeC6H4
Scheme 2 Reagents and conditions: i, 1:CH2O:MnO2:H2SO4 = 1:3:5:6,
boiling in an aqueous solution, 7 h; ii, 1:MnO2 = 1:10, boiling in toluene, 3 h.
The key step in the mechanism of the formation of bicyclo-
octanes 7, 8 may be the oxidative dehyrogenation of the initial
THPs to form intermediate 1,2-dihydropyridines. It is clear that
analogous dihydropyridines should be formed as intermediates
in other experiments (Scheme 2, conditions ii), which demon-
strated the readiness of THPs 1a,d to transformation into
pyridines 9, 10 on boiling in toluene in the presence of MnO2.
The data thus obtained allow us to propose the following
sequence for the synthesis of bicyclooctanones 7, 8 (Scheme 3).
Ph
OH Ph
Ph
O
i
i
N
O
N
R
N
R
R
–
3a c
a R = Me
b R = CH2Ph
c R = But
–
1a c
–
2a c
ii
Ar
Ar
Ar
HO
HO Ph
Ph
N
OH
9
1
O
Ph
8
[O]
5
2
6
1a,d
4
7
3a
2
1
8
N
O3
N
N
N
7 N
6
O 3
O
Me
5
4
OH
OH
Me
Me
Me
Me
Me
4
5
6
I
II
III
Scheme 1 Reagents and conditions: i, CH2O, H+; ii, 1a:CH2O = 1:4,
boiling in aqueous H2SO4, 7 h, then 20 °C, 18 h.
Ar
Ar
O
O
OH
diffraction data suggest that piperidine and tetrahydropyrane
rings in the crystalline form of cis-isomer 5 (Figure 1 shows the
general view and numeration of atoms in a molecule of 5)
exhibit a chair conformation; the hydroxyl group of one mole-
cule forms an intermolecular hydrogen bond with the nitrogen
atom of another molecule. In solution, the piperidine ring of the
same isomer (1H NMR spectra in CDCl3) has a boat conforma-
tion fixed by an intramolecular hydrogen bond.
+ H2O
– H+
[O]
7 8
,
N
N
Me
Me
IV
V
Scheme 3
As a continuation of our work on the new oxidative reactions
of hydropyridines initiated by manganese compounds,3–5 we
report the reaction of THPs 1a,d with an excess of formaldehyde
in the presence of manganese dioxide with an emphasis on the
modification of the Prins method to prepare an oxidatively new
heterocyclic system (Scheme 2, conditions i). A conventional
chromatographic procedure gave product 7 in an isolated yield
of 31% (from THP 1a) and a product 8 in 35% yield (from 1d).
The structures of these compounds were different from those of
compounds obtained by the Prins reaction previously1,2,6 or in
this work (Scheme 1, conditions ii). Compounds 7 and 8 showed
spectroscopic data consistent with the structure of 6-oxa-2-aza-
bicyclo[3.2.1]octan-4-ones, indicating an unexpected addition
of formaldehyde at the α-position of a THP heterocycle and
unusual oxidation of the latter into a β-piperidone fragment.
Dihydropyridines I formed at the initial oxidative step are
then selectively attacked by protonated formaldehyde at the
α-position (C-6) to give carbocations II stabilised by species
III. The intramolecular cycloaddition yields bicyclic cation IV,
which leads to final products 7 and 8 via hydroxylation fol-
lowed by the oxidative dehydrogenation of intermediate alcohol
V. The trasformation of secondary alcohols into ketones under
the action of MnO2 is well documented.7 The 1H and 13C NMR
spectral data together with the Dreiding modelling and mole-
cular mechanic calculations of conformer energies are consis-
tent with a distorted (flatted) boat conformation of a piperidine
ring cis-1,3-diaxially condensed with a tetrahydrofuranic ring,
which has a rigid envelope confomation.
Thus, the series of conversions demonstrates a new useful
method for an effective control of the Prins reaction by man-
– 27 –

, 2001, 11(1), 27–28
This work was supported by the Russian Foundation for Basic
Research (grant no. 99-03-32940a).
C(15)
C(14)
C(13)
References
C(16)
C(17)
1 C. J. Schmidle and R. C. Mansfield, US Patent 2748140, 1956 (Chem.
Abstr., 1957, 51, 2880f).
2 A. F. Casy, A. B. Simmonds and D. Staneforth, J. Org. Chem., 1972, 37,
3189.
3 A. T. Soldatenkov, A. W. Temesgen, L. N. Kuleshova and V. N. Khrustalev,
Mendeleev Commun., 1998, 193.
C(12)
C(5)
O(11)
4 A. T. Soldatenkov, A. W. Temesgen, I. A. Bekro, T. P. Khristoforova,
S. A. Soldatova and B. N. Anissimov, Mendeleev Commun., 1997, 243.
5 A. T. Soldatenkov, A. W. Temesgen, I. A. Bekro, S. A. Soldatova and
B. N. Anissimov, Mendeleev Commun., 1998, 137.
6 A. F. Casy and F. Ogungbamila, Heterocycles, 1981, 16, 1913.
7 S. P. Korshunov and L. I. Vereshchagin, Usp. Khim., 1966, 35, 2255
(Russ. Chem. Rev., 1966, 35, 942).
C(6)
C(4)
C(8)
C(10)
C(7)
C(3)
O(9)
8 A. E. Chichibabin and D. I. Orochko, Zh. Russ. Fiz.-Khim. Obshch.,
1930, 62, 1201 (in Russian).
N(1)
C(2)
Figure 1 General view and numeration of atoms in a molecule of 5 (X-ray
diffraction data).
ganese dioxide, which dramatically changes the course of con-
densation of tetrahydropyridines with formaldehyde leading to
a new group of 6-oxa-2-azabicyclo[3.2.1]octan-4-ones.
The structures of compounds 3a and 4–10 were confirmed
spectroscopically.†
†
NMR spectra were recorded at 300 MHz (1H) and 75.5 MHz (13C),
standard TMS, CDCl3. Compounds 3a and 4–10 gave satisfactory
elemental analyses.
For 3a: yield 15%, mp 60–62 °C (lit.,2 3a·HCl, mp 320 °C). 1H NMR,
d: 1.8 (m, 2H, 8-CH2), 2.37 (s, 3H, Me), 2.5–3.2 (m, 5H, 5-CH2 and
7-CH2 and 4-Ha), 3.6 (d, 1H, 4-CH2, 2J 11.5 Hz), 3.8 (dd, 1H, 4-CH2, 2J
2
11.5 Hz, 3J 2.5 Hz), 4.77 and 4.83 (2d, 1H each, 2-CH2, J 6.5 Hz), 7.3
(m, 5H, Ph). MS (EI, 70 eV), m/z (%): 233 (7) [M+], 174 (38), 128 (5),
105 (11), 77 (12), 57 (13), 44 (100).
Received: 17th October 2000; Com. 00/1712
For 4: yield 6%, mp 88–90 °C. 1H NMR, d: 1.57 (br. s, 1H, 8-H), 2.34
(s, 3H, Me), 2.83–3.05 (m, 6H, 5-CH2 and 7-CH2 and CH2OH), 3.53 (d,
1H, 4-CH2, 2J 11.6 Hz), 3.61 (dd, 1H, 4-CH2, 2J 11.6 Hz, 3J 2.6 Hz), 3.9
For 7: yield 31%, colourless oil (purified by chromatography on a
silica gel column; eluent, acetone; Rf 0.7). 1H NMR, d: 2.51 (s, 3H, Me),
3.0 (t, 1H, 8-Ha, 2J » 3J 12.6 Hz), 3.16 (br. d, 1H, 8-He, 2J 12.6 Hz), 3.73
(t, 1H, 7-Ha, 2J 10.7 Hz), 4.0 (m, 1H, 1-He), 4.12 (d, 1H, 3-Ha, 2J 9.5 Hz),
4.23 (br. d, 1H, 7-He, 2J » 3J 10.7 Hz), 4.42 (br. d, 1H, 3-He, 2J 9.5 Hz),
7.3–7.5 (m, 5H, Ph). MS, m/z (%): 217 (16) [M+], 202 (43), 187 (15),
131 (12), 105 (100), 77 (37). IR (paraffin oil, n/cm–1): 1680 (C=O), 3360
(br. OH). Found (%): C, 71.7; H, 7.03; N, 6.52. Calc. for C13H15NO2
(%): C, 71.89; H, 6.91; N, 6.45.
3
4
2
(dd, 1H, 4-Ha, J 11.7 Hz, J 2.0 Hz), 4.75 and 4.83 (2d, 1H each, J
6.1 Hz), 7.28–7.5 (m, 5H, Ph). 13C NMR, d: 35.1 (8-C), 46.1 (Me), 47.1
(4a-C), 55.2 (5-C), 57.2 (7-C), 65.8 (COH), 66.2 (4-C), 77.7 (Cquat–O),
89.4 (2-C), 126.5, 127.5, 128.4, 129.3 and 140.7 (6C, Ph); MS, m/z: 263
[M+]. IR (KBr, n/cm–1): 3310 (OH). Found (%): C, 68.21; H, 8.16; N,
5.28. Calc. for C15H21NO3 (%): C, 68.44; H, 7.99; N, 5.32.
For 5: yield 14%, mp 176 °C. 1H NMR, d: 2.38 (s, 3H, Me), 2.68 (m,
For 8: yield 35%, colourless oil (purified by chromatography on a
silica gel column; eluent, acetone; Rf 0.7). 1H NMR, d: 2.39 (s, 3H, Me),
2
3
2H, 1-H and 5-H), 2.84 (dd, 2H, 6-H and 8-H, J 11.1 Hz, J 2.5 Hz),
3.25 (dd, 2H, 6-H and 8-H, 2J 11.1 Hz, 3J 7.3 Hz), 3.64 (d, 2H, 2-H and
4-H, 2J 11.4 Hz), 3.75 (d, 2H, 2-H and 4-H, 2J 11.4 Hz), 7.3–7.5 (m, 5H,
Ph). 13C NMR, d: 37.9 (1-C and 5-C), 45.1 (Me), 55.9 (6-C and 8-C),
69.8 (2-C and 4-C), 71.8 (9-C), 126.1, 127.8, 128.9 and 141.6 (6C, Ph).
MS, m/z (%): 233 (100) [M+], 232 (38), 216 (27), 190 (20), 184 (8), 170
(10), 133 (34), 128 (35), 105 (38), 91 (15), 77 (16). IR (KBr, n/cm–1):
3220 and 3410 (br. OH). Found (%): C, 71.92; H, 8.27; N, 5.85. Calc. for
C14H19NO2 (%): C, 72.10; H, 8.27; N, 6.01.
2
2.51 (s, 3H, Me), 2.98 (t, 1H, 8-Ha, J » 3J 12.9 Hz), 3.16 (br. d, 1H,
2
8-Ha, J 12.9 Hz), 3.76 (t, 1H, 7-Ha, 2J 10.9 Hz), 4.07 (m, 1H, 1-He),
2
4.10 (d, 1H, 3-Ha, J 9.4 Hz), 4.20 (br. d, 1H, 7-He, 2J 10.9 Hz), 4.40
(br. d, 1H, 3-He, 2J » 3J 9.4 Hz), 7.27 and 7.86 (AA'BB' system, 4H, Ar,
3J 7.2 Hz, 4J 1.1 Hz). 13C NMR, d: 22.6 (CMe), 40.3 (1-C), 40.8 (NMe),
55.8 (8-C), 70.2 (7-C), 86.7 (3-C), 129.7 (5-C), 129.3, 130.5, 144.3, 145.4
(Carom.), 200.0 (C=C). MS, m/z (%): 231 (7) [M+], 216 (36), 203 (6), 188
(28), 172 (34), 160 (38), 145 (12), 119 (100), 91 (45). IR (paraffin oil,
n/cm–1): 1675 (C=O), 3350 (br. OH). Found (%): C, 73.01; H, 7.49; N,
5.90. Calc. for C14H17NO2 (%): C, 72.72; H, 7.36; N, 6.06.
1
For 6: yield 7%, mp 180 °C. H NMR, d: 2.12 (s, 3H, Me), 2.37 (m,
2H, 1-H and 5-H), 2.42 (d, 2H, 6-H and 8-H, J 11.4 Hz), 3.0 (d, 2H,
2
For 9: yield 45%, mp 76–78 °C (lit.,8 mp 76–78 °C). 1H NMR and
mass spectra are identical to those given in ref. 3.
2
2
3
6-H and 8-H, J 11.4 Hz), 4.02 (dd, 2H, 2-H and 4-H, J 10.9 Hz, J
2.3 Hz), 4.54 (dd, 2H, 2-H and 4-H, 2J 10.9 Hz, 3J 2.3 Hz), 7.3–7.5
(m, 5H, Ph). 13C NMR, d: 38.3 (1-C and 5-C), 46.5 (Me), 58.3 (6-C and
8-C), 67.4 (2-C and 4-C), 71.3 (9-C), 125.4, 128.0, 129.1, 142.4, (6C,
Ph). MS, m/z (%): 233 (100) [M+]. IR (KBr, n/cm–1): 3200 and 3420
(br. OH). Found (%): C, 72.2; H, 8.23; N, 5.91. Calc. for C14H19NO2
(%): C, 72.10; H, 8.27; N, 6.01.
1
For 10: yield 42%, mp 43–45 °C. H NMR, d: 2.4 (s, 3H, Me), 7.25
3
4
and 7.5 (AA'BB' system, 4H, Ar, J 7.1 Hz, J 1.1 Hz), 7.61 and 8.63
(AA'XX' system, 4H, Py, 3J 5.4 Hz, 4J 2.0 Hz). MS, m/z (%): 169 (100)
[M+], 168 (43), 155 (95), 91 (20). Found (%): C, 84.98; H, 6.67; N, 8.01.
Calc. for C12H11N (%): C, 85.21; H, 6.51; N, 8.28.
– 28 –