Oxidative reactions of azines. 11. The influence of manganese dioxide on the reaction of tetrahydropyridines with formaldehyde: Synthesis and molecular structures of 3-oxa-7-azabicyclo[3.3.1]- and 6-oxa-2-azabicyclo[3.2.1]octanes

Article abstract of DOI:10.1023/B:COHC.0000037321.18924.c0

New derivatives of piperidino[4,5-d]dioxane and 3-oxa-7-bicyclo[3.3.1] nonane were obtained by the oxidatively catalysed condensation of 4-aryl-1,2,3,6-tetrahydropyridines with formaldehyde. The direction of this reaction is sharply altered in the presence of manganese dioxide to give 6-oxa-2-azabicylo[3.2.1]octan-4-one - the product of the oxidative condensation of a new type.

Full text of DOI:10.1023/B:COHC.0000037321.18924.c0

Chemistry of Heterocyclic Compounds, Vol. 40, No. 5, 2004
OXIDATIVE REACTIONS OF AZINES.
11*. THE INFLUENCE OF MANGANESE DIOXIDE
ON THE REACTION OF TETRAHYDROPYRIDINES
WITH FORMALDEHYDE: SYNTHESIS AND MOLECULAR
STRUCTURES OF 3-OXA-7-AZABICYCLO[3.3.1]-
AND 6-OXA-2-AZABICYCLO[3.2.1]OCTANES
A. T. Soldatenkov1, K. B. Polyanskii1, A. V. Temesgen1, N. D. Sergeeva1, V. V. Vysotskaya1,
B. B. Averkiev2, M. Yu. Antipin2, and N. N. Lobanov1
New derivatives of piperidino[4,5-d]dioxane and 3-oxa-7-bicyclo[3.3.1]nonane were obtained by the
oxidatively catalysed condensation of 4-aryl-1,2,3,6-tetrahydropyridines with formaldehyde. The
direction of this reaction is sharply altered in the presence of manganese dioxide to give 6-oxa-2-
azabicylo[3.2.1]octan-4-one – the product of the oxidative condensation of a new type.
Keywords: manganese dioxide, oxabicycloalkanes, tetrahydropyridines, formaldehyde, Prins reaction.
As the result of oxidatively catalysed condensation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (1a)
with formaldehyde (the Prins reaction) with a small excess of the latter 3-hydroxymethyl-1-methyl-6-
phenyltetrahydropyridine is formed [2], while with a ten-fold excess the product is a substituted piperidino[4,5-
d]dioxane 2 [3].
There have been no reports so far on the influence of oxidants on the Prins reaction. In a continuation of
our studies to discover new reactions of hydropyridines initiated by manganese compounds with different
oxidation states [4-6] we have studied in this work the condensation of 4-aryl-substituted 1-methyl-1,2,3,6-
tetrahydropyridines 1a,b with formaldehyde under conditions of the modified Prins reaction (in the presence of
manganese dioxide.
In the first place, to study the composition of the reaction mixture formed in the classical Prins reaction
in greater detail, we carried out the condensation of tetrahydropyridine 1 with a four-fold excess of
formaldehyde which has been described previously [3]. By the use of crystallization and chromatography we
succeeded in isolating from the reaction mixture not only the known 1,3-dioxane 3, but also a series of new
condensation products: 8-hydroxymethyl derivatives of the piperidinodioxane 3 and also cis- and
trans-9-hydroxy-7-methyl-9-phenyl-3-oxa-7-azabicyclo[3.3.1]nonanes (4), which are isomers with respect to the
_______
* Paper 10, see [1].
__________________________________________________________________________________________
1 Russian People's Friendship University, Moscow 117198; e-mail: asoldatenkov@sci.pfu.edu.ru. 2 A. N.
Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, Moscow 117813.
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 755-764, May 2004. Original article
submitted April 13, 2001.
0009-3122/04/4005-0641©2004 Plenum Publishing Corporation
641

position of the 9-hydroxy groups relative to the nitrogen atom. In the 1H NMR spectra of compounds 2 and 3 the
protons in position 4 take the form of a broad doublet (at 3.5-3.6 ppm) with geminal coupling of 1.5 Hz and a
doublet of doublets (at 3.6-3.8 ppm) with a vicinal coupling of 2.5-2. Hz which indicates the stereoselectivity of
the cis-coupling of the heterocyclic fragments [3].
HO
Ph
Ph
Ph 1
O
8
O
2
7
CH2O
6N
+
+
3
O
O
N
Me
+
Me
N
4
5
H
2
3
Me
1a
HO
Ph
9
Ph
OH
6
5
4
+
+
2
1
8
O
O
N
3
7
N
Me
Me
trans-4
cis-4
The individual isomers were isolated by crystallization from the mixture of cis- and trans-
1
bicyclononanes 4 (2:1 according to the H NMR spectrum). They were identified on the basis of the magneto-
anisotropic influence of the phenyl substituent on the chemical shifts of the protons of the methylene group.
Thus in the cis isomer of 4 the protons on the C(2) and C(4) atoms of the tetrahydropyran ring fall within the
region of shielding and their signals occur at 3.64 and 2.75 ppm. In the trans isomer of 4 the analogous signals
appear at weaker field – at 4.02 and 4.54 ppm respectively. Similarly the protons in trans-4 at positions 6 and 8
(the piperidine ring) are screened and their signals occur at 2.42 and 3.0 ppm, whereas the analogous signals for
cis-4 occur at 2.84 and 3.25 ppm. In CDCl3 solution, according to the 1H NMR spectrum, the piperidine ring of
cis-4 has the boat conformation, fixed by an intramolecular hydrogen bond. In order to refine the spatial
structure of the isomers under discussion the X-ray structure of the cis isomer of 4 was determined. The overall
structure of the molecule is shown in Fig. 1, the atomic coordinates are given in Tables 1 and 2, and the bond
lengths and bond angles in Table 3.
The basic geometric parameters of the molecule are normal [7]. The piperidine and tetrahydropyran rings
have the chair conformation. The hydroxy group forms an intermolecular hydrogen bond O–H···N with the
nitrogen atom of neighboring molecules, forming a chain along the c axis (Fig. 2). The parameters of the
hydrogen bond are O(11)···N(1) 2.869(1), H(11)···N(1) 2.06(2) A, and the angle O(11)–H(11)–N(1) 150(1)°.
The hydroxy group is positioned axially to the piperidine ring, while the phenyl group is equatorial ( the
deviation of atoms O(11) and C(12) from the mean squared plane of the ring is 1.731(1) and 0.057(1) Å
respectively). The situation is reversed with respect to the tetrahydropyran ring: the OH group takes an
equatorial position , while the phenyl group is axial ( the respective deviations of O(11) and C(12) are -0.221(2)
and 1.830(2) Å). The angle of rotation of the phenyl ring relative to the piperidine ring is 13.55(7)° and relative
to the tetrahydropyran ring is 81.83(5)°, while the torsion angle C(4)–C(5)–C(12)–C(13) is 45.1(1)°.
642

Fig. 1. General view of the molecule of the cis isomer of 4.
Fig. 2. Formation of a chain of molecules of the cis isomer of 4 in the crystal.
643

TABLE 1. Coordinates of the Non-hydrogen Atoms (×104) and Equivalent
Isotropic Thermal Parameters Ueq (×103) in the Structure of the cis Isomer
of 4
Atom
x
y
z
Ueq, Å2
N(1)
C(2)
C(3)
C(4)
C(5)
C(6)
C(7)
C(8)
O(9)
C(10)
6633(1)
6035(1)
7526(1)
8099(1)
7154(1)
6384(1)
5787(1)
7123(1)
8111(1)
8810(1)
6413(1)
7677(1)
8612(1)
9053(1)
8579(2)
7648(2)
7196(1)
3638(1)
4963(1)
3743(1)
2362(1)
1316(1)
1154(1)
2536(1)
621(1)
3753(1)
3499(1)
4861(1)
5277(1)
5478(1)
4220(1)
3833(1)
3333(1)
3255(1)
4401(1)
6227(1)
6068(1)
7049(1)
7674(2)
7335(2)
6383(2)
5753(1)
36(1)
53(1)
41(1)
37(1)
32(1)
35(1)
38(1)
45(1)
48(1)
48(1)
40(1)
39(1)
51(1)
69(1)
76(1)
74(1)
55(1)
1464(1)
1758(2)
1883(1)
-27(1)
O(11)
C(12)
C(13)
C(14)
C(15)
C(16)
C(17)
49(2)
-1129(2)
-2401(2)
-2495(2)
-1317(1)
When the condensation of the tetrahydropyridines 1a,b with formaldehyde analogous to that described
above but in the presence of manganese dioxide was carried out quite different products were obtained the
structures of which did not correspond to any of the possible products of the classical Prins reaction (see [2, 3,
TABLE 2. Coordinates of the Hydrogen Atoms (×104) and Equivalent
Isotropic Thermal Parameters Ueq (×103) in the Structure of the cis Isomer
of 4
Atom
H(2C)
x
y
z
Ueq Å2
5457(14)
6609(16)
5604(14)
8126(13)
7190(11)
8634(11)
5737(11)
5262(11)
5253(12)
7391(12)
6636(12)
9368(14)
9207(12)
6752(13)
8948(13)
9673(18)
8855(17)
7326(16)
6550(15)
4870(17)
5740(20)
5211(17)
4412(16)
4151(15)
2545(14)
499(14)
2706(16)
3424(16)
4155(16)
4702(13)
5562(12)
6038(12)
4234(11)
4389(11)
3022(12)
3560(13)
2492(14)
4280(14)
4741(12)
6988(14)
7287(14)
8329(20)
7729(18)
6128(17)
5071(16)
66(5)
78(5)
72(5)
53(4)
44(3)
44(3)
40(3)
40(3)
44(3)
52(4)
55(4)
60(4)
49(4)
60(4)
62(4)
94(6)
92(6)
91(6)
72(5)
H(2B)
H(2A)
H(3B)
H(3A)
H(4)
H(6)
H(7B)
H(7A)
H(8B)
H(8A)
H(10B)
H(10A)
H(11)
H(13)
H(14)
H(15)
H(16)
H(17)
2780(13)
2484(13)
-292(17)
656(16)
2437(17)
953(16)
1750(17)
928(18)
-988(21)
-3203(22)
-3361(24)
-1450(18)
644

TABLE 3. Bond Lengths (d) in The Compound cis-4
Bond
d, Å
Bond
d, Å
Bond
d, Å
N(1)–C(2)
N(1)–C(7)
N(1)–C(3)
C(3)–C(4)
C(4)–C(10)
C(4)–C(5)
C(5)–O(11)
1.460(2)
1.464(2)
1.468(1)
1.526(2)
1.524(2)
1.542(2)
1.429(1)
C(5)–C(12)
C(5)–C(6)
C(6)–C(8)
C(6)–C(7)
C(8)–O(9)
O(9)–C(10)
C(12)–C(17)
1.532(2)
1.536(1)
1.531(2)
1.531(2)
1.424(2)
1.421(2)
1.387(2)
C(12)–C(13)
C(13)–C(14)
C(14)–C(15)
C(15)–C(16)
C(16)–C(17)
1.397(2)
1.386(2)
1.373(3)
1.374(3)
1.393(2)
8] and this paper). For example, after standard treatment of the reaction mixture by chromatography compounds
5a,b were isolated which, according to 1H and 13C NMR, had the structure of 6-oxa-2-azabicyclo[3.2.1]octan-4-
ones, which indicates the unexpected addition of formaldehyde to one of the α-positions of the piperidine ring
(for a preliminary report see [9]).
Ar
5
Ar
Ar
O
6 O
+
H , CH2O
4
∆
8
7
3
MnO2
MnO2
2
N
N
N
1
Me
Me
5a,b
6a,b
1a,b
a Ar = Ph; b Ar = p- MeC6H4
The structures of compounds 5a and 5b were established on the basis of the complete assignment of the
signals in the 1H and 13C NMR spectra using H,H COSY, C,H COSY and 13C DEPT. In the 1H NMR spectra of
both compounds signals of two methylene groups attached to heteroatoms appear at weak field (protons at
position 3 at 4.10-4.42 ppm and at position 7 at 3.73-4.23 ppm). The signals of protons at C(8), bonded only to
carbon are found at stronger field (2.98-3.16 ppm). The chemical shift of the methyne proton (at 4.00-4.07 ppm)
TABLE 4. Bond Angles (ω) in Compound cis-4
Angle
ω, deg.
110.76(10)
Angle
ω, deg.
110.22(9)
C(2)–N(1)–C(7)
C(2)–N(1)–C(3)
C(7)–N(1)–C(3)
N(1)–C(3)–C(4)
C(10)–C(4)–C(3)
C(10)–C(4)–C(5)
C(3)–C(4)–C(5)
O(11)–C(5)–C(12)
O(11)–C(5)–C(6)
C(12)–C(5)–C(6)
O(11)–C(5)–C(4)
C(12)–C(5)–C(4)
C(6)–C(5)–C(4)
C(8)–C(6)–C(7)
C(8)–C(6)–C(5)
109.65(10)
111.56(8)
113.33(9)
113.16(10)
109.51(10)
109.95(9)
107.47(8)
106.40(8)
115.32(9)
111.24(9)
112.87(9)
103.40(8)
112.70(9)
C(7)–C(6)–C(5)
108.99(9)
112.53(9)
114.06(10)
112.39(9)
112.82(9)
117.64(12)
123.13(11)
118.92(11)
121.05(15)
120.5(2)
N(1)–C(7)–C(6)
O(9)–C(8)–C(6)
C(10)–O(9)–C(8)
O(9)–C(10)–C(4)
C(17)–C(12)–C(13)
C(17)–C(12)–C(5)
C(13)–C(12)–C(5)
C(14)–C(13)–C(12)
C(15)–C(14)–C(13)
C(14)–C(15)–C(16)
C(15)–C(16)–C(17)
C(12)–C(17)–C(16)
119.34(14)
120.6(2)
120.9(2)
645

indicates that the CH group is bonded to a nitrogen atom. The presence of similar groups bonded in the O–CH2–
CH–CH2 system is also confirmed by the 13C NMR spectrum of compound 5b (see experimental section). In this
spectrum there are also signals assigned to the C=O group (at 200.0 ppm) and of a quaternary aliphatic carbon
atom, the chemical shift of which (at 129.7 ppm) confirms the presence of the grouping O–Cquat–C=O. These
results indicate the addition of one molecule of formaldehyde at the α-position of the piperidine ring with
subsequent cyclization of the hydroxymethyl group at the γ-position (with formation of the tetrahydrofuran unit)
and oxidation to structures 5a,b.
1
Analysis of the parameters of the H and 13C NMR spectra, Dreiding models, and calculation of the
energies of the conformers by molecular mechanics methods, showed that there is some preference for a
compressed boat conformation for the piperidine, cis-1,3-diaxially coupled to the tetrahydropyran ring, which
has a firmly fixed envelope conformation.
The key stage in the probable route to the formation of compounds 5a,b is evidently the oxidative
dehydrogenation of the initial tetrahydropyridines, the products of which can then be attacked by formaldehyde.
An indirect confirmation of such a dehydration was obtained by separate experiments on the aromatization of
substrates 1a,b by boiling their solutions in toluene in the presence of manganese dioxide. Evidently the
arylpyridines 6a,b (isolated in 42-45% yield) should be formed via dihydropyridine intermediates. The results
discussed permit the suggestion of the following sequence for the formation of the bicyclooctanes 5a,b in the
oxidative condensation of tetrahydropyridines with formaldehyde:
Ar
Ar
Ar
+
+
[O]
1a,b
HO
HO
N
N
N
Me
Me
III
Me
I
II
Ar
Ar
N
O
O
OH
[O]
+ H2O
+
5a,b
+
–H
N
Me
Me
IV
V
The dihydropyridines I, formed in the initial (oxidative) stage, add a protonated formaldehyde at the
α-position, which leads to the carbocation II, stabilized by form III. An intramolecular cycloaddition then
follows to give the bicyclic cation IV which is hydroxylated to the alcohol V by the addition of a molecule of
water. The final stage is the oxidation of the alcohols V to the ketones 5a,b (the conversion of alcohols to
ketones is well documented [10]).
Thus it is established using piperidines as an example that the direction of the Prins reaction can be
controlled by manganese dioxide to give the unusual oxidative condensation of tetrahydropyridines with
formaldehyde with "one-step" formation of a new group of 6-oxa-2-azabicyclo[3.2.1]octan-4-ones. We note that
the structure of the end products in the method we have developed differs principally from the structure of the
products of the Prins reaction in the formation of a tetrahydrofuan ring and a β-piperidine unit.
646

EXPERIMENTAL
IR spectra were recorded on a UR-20 instrument. Mass spectra were obtained with an MX-1303
machine. NMR spectra of CDCl3 solutions with TMS as internal standard were recorded with Bruker W-80,
Bruker WM-250, and DPX-500 spectrometers (80, 250, and 500 MHz respectively). The course of reactions and
the purity of individual compounds were monitored by TLC on Silufol UV-254 strips with development by
iodine vapor. Separation and purification of compounds was carried out by column chromatography on silicagel
L-60 (40/100).
X-ray Crystallographic Analysis of Compound cis-4. Crystals of the bicyclononane cis-4, with
composition C14H19NO2, grown from ether, were monoclinic and had the following crystallographic parameters:
P21/c, a = 11.599(3), b = 9.681(3), c = 11.324(3) Å; β = 101.18(2)°; V = 1248.4(6) Å3; Z = 4; dcalc = 1.241 g/cm3;
M = 233.3. The parameters of the unit cell and the intensities of 2869 reflexions were measured on a Siemens
P3/PC automatic four-circle diffractometer (T = 20°C, λMoKα radiation, graphite monochromator, θ/2θ
scanning, θmax = 27°). The structure was solved by direct methods and refined by full matrix least squares
analysis in the anisotropic approximation for non-hydrogen atoms. The hydrogen atoms were localized in
difference Fourier maps and refined isotropically. The final residual factors were R1 = 0.0402 from 2217
independent reflexions with I > 2σ and wR2 = 0.1262 with all 2731 reflexions. All calculations were carried out
using the SHELXTL PLUS (PC version 5.0) family of programs [11].The numbering of the atoms is shown in
Fig. 1.
Condensation of 4-Phenyltetrahydropyridine 1a with Formaldehyde (the Prins Peaction). A
mixture of tetrahydropyridine 1a (3 g, 17.3 mmol) and formaldehyde (as paraformaldehyde) (2 g, 67 mmol) in
60% sulfuric acid (10.5 ml) was boiled for 7 h and then stood at room temperature for 18 h. The reaction mixture
was diluted with water (10 ml), 20% potassium hydroxide solution was added to a pH of 10, and the mixture was
then extracted with benzene (3 × 20 ml). The extract was washed with water and dried over magnesium sulfate.
The solvent was removed in vacuum and the reside was dissolved in ether. The precipitate which separated on
cooling the ether solution was washed with ether and dried to give 9-hydroxy-7-methyl-9-phenyl-3-oxa-7-
azabicyclo[3.3.1]nonane (4) (0.85 g, 21%) (as a 2:1 mixture of the cis- and trans-isomers according to the NMR
spectrum) as a coarse white powder (mp ~160°C), containing some clear monocrystals of the cis-isomer, mp
176°C (from crystallographic data and the NMR spectrum). The cis-isomer was also isolated by crystallization
from methylene chloride in a yield of 8% (0.32 g). Rf 0.40 (acetone). IR spectrum (KBr), ν, cm-1: 3220, 3100 br.
(OH). 1H NMR spectrum, δ, ppm (J, Hz): 2.38 (3H, s, CH3); 2.68 (2H, m, H-1 and H-5); 2.84 (2H, dd, 2J = 11.1,
3J = 2.5, H-6 and H-8); 3.25 (2H, dd, 2J = 11.1, 3J =7.3, H-6 and H-8); 3.64 (2H, d, 2J = 11.4, H-2 and H-4); 3.75
2
13
(2H, d, J = 11.4, H-2 and H-4); 7.30-7.50 (5H, m, Ph). C NMR spectrum, δ, ppm: 37.9 (C(1) and C(5)), 45.11
(CH3), 55.9 (C(6) and C(8)), 69.8 (C(2) and C(4)), 71.8 (C(9)), 126.1, 127.8, 128.9, and 141.6 (C(Ph)). Mass spectrum,
m/z (Irel, %): 233 (M+ (100), 232 (38), 216 (27), 190 (20), 184 (8), 170 (10), 133 (34), 128 (35), 105 (38), 91
(15), 77 (16). Found, %: C 72.20; H 8.23; N 5.91. C14H19NO2. Calculated, %: C 72.10; H 8.16; N 6.01.
The mother liquor, after removing the cis isomer of 4, was evaporated, and the residue was crystallized
from ether to give the trans-isomer of 4 (0.12 g, 3%); mp 180°C. Rf 0.42 (acetone). IR spectrum (KBr, ν, cm-1):
3410 and 3220 br. (OH). Mass spectrum, m/z (Irel, %): 233 [M+] (100). 1H NMR spectrum, δ, ppm (J, Hz): 2.12
2
2
(3H, s, CH3); 2.37 (2H, m, H-1 and H-5); 2.42 (2H, d, J =11.4, H-6 and H-8); 3.00 (2H, d, J =11.4, H-6 and
H-8); 4.02 (2H, dd, 2J = 10.9, 3J = 2.3, H-2 and H-4); 4.54 (2H, dd, 2J = 10.9, 3J = 2.3, H-2 and H-4); 7.30-7.50
(5H, m, C6H5). 13C NMR spectrum, δ, ppm: 38.3 (C(1) and C(5)), 46.5 (CH3), 58.3 (C(6) and C(8)), 67.4 (C(2) and
C(4)), 71.3 (C(9)), 125.4, 128.0, 129.1, 142.4 (C(Ph)). Found, %: C 71.92; H 8.27; N 5.85. C14H19NO2.
Calculated, %: C 72.10; H 8.27; N 6.01.
647

The ether mother liquor after separation of the crystalline mixture of the cis- and trans-isomers of 4 was
evaporated to give an amber yellow sticky oil (2.0 g) which was separated by chromatography on a silica gel
column (d = 3, h =17 cm, eluant acetone) to give consecutively product 3 (0.28 g, 6%) and product 2 (0.6 g, 15%).
8-Hydroxymethyl-6-methyl-8a-phenylpiperidino[4,5-d]dioxane (3), colorless crystals; mp 88-90°C,
1
Rf 0.84 (acetone). IR spectrum (KBr, ν, cm-1): 3210 (OH). Mass spectrum, m/z (Irel, %): 263 [M+]. H NMR
spectrum, δ, ppm (J, Hz): 1.57 (1H, br. s, H-8); 2.34 (3H, s, CH3); 2.83-3.05 (6H, m, H2-5,5, H2-7,7, and
CH2OH); 3.53 (1H, br. d, 2J = 11.6, H2-4); 3.61 (1H, dd, 2J = 11.6, 3J = 2.6, H-4); 3.90 (1H, m, H-8a); 4.75 and
4.83 (2H, two d, 2J = 6.1, H2-2,2); 7.28-7.50 (5H, m, C6H5). 13C NMR spectrum, δ, ppm: 35.1 (C(8)), 46.1 (CH3),
47.1 (C(4a)). 55.2 (C(5)), 57.2 (C(7)), 65.8 (C-OH), 66.2 (C(4)), 77.7 (Cquat)-O), 89.4 (C(2)), 126.5, 127.5, 128.4,
129.3, and 140.7 (C(Ph)). Found, %: 68.21; H 8.16; N 5.28. C15H21NO3. Calculated, %: C 68.44; H 7.99; N 5.32.
6-Methyl-8a-phenylpiperidino[4,5-d]dioxane (2); mp 60-62°C (in [3] the mp of the hydrochloride only
is given, 323°C (dec.)), Rf 0.76 (acetone). Mass spectrum, m/z (Irel, %): 233 [M+] (7), 174 (38), 128 (5), 105 (11),
77 (12), 57 (13), 44 (100). 1H NMR spectrum, δ, ppm (J, Hz): 1.80 (2H, m, H2-8,8); 2.37 (3H, s CH3); 2.50-3.20
(5H, m, H2-5,5 and H2-7,7 and H-4a); 3.60 (1H, br. d, 2J = 11.5, H2-4,4); 3.80 (1H, dd, 2J = 11.5, 3J = 2.5, H-4);
4.77 and 4.83 (2H, two d, 2J = 6.5, H2-2,2); 7.30 (5H, m, Ph).
Oxidative Condensation of the Tetrahydropyridines 1a,b with Formaldehyde in the Presence of
MnO2 (Modified Prins Reaction). A mixture of 4-aryltetrahydropyridine 1a,b (10 mmol), manganese dioxide
(5 g, 50 mmol), formaldehyde (as a 37% aqueous solution) (3 ml, 30 mmol), and conc. H2SO4 (3 ml) was boliled
for 7 h. 20% Sodium hydroxide was added to the cold reaction mass to pH 9, and the mixture was extracted with
benzene. The solvent was evaporated in vacuum and the residue was chromatographed on a silica column with
acetone as eluant. Product 5a (0.84 g, 31%) was obtained from phenyltetrahydropyridine and product 5b (1.0 g,
35%) was obtained from 4-tolyltetrahydropyridine.
2-Methyl-5-phenyl-6-oxa-2-azabicyclo[3.2.1]octan-4-one (5a). A thick, colorless oil, Rf 0.7 (acetone).
IR spectrum (nujol mull), ν, cm-1: 1680 (C=O). 1H NMR spectrum, δ, ppm (J, Hz): 2.51 (3H, s, CH3); 3.00 (1H,
t, 2J = 12.6, Ha-8); 3.16 (1H, br. d, 2J = 12.6, He-8); 3.73 (1H, t, 2J = 10.7, Ha-7); 4.00 (1H, m, He-1); 4.12 (1H, d,
2J = 9.5, Ha-3); 4.23 (1H, br. d, 2J = 10.7, He-7); 4.42 (1H, br. d, 2J =9.5, He-3); 7.30-7.50 (5H, m, C6H5). Mass
spectrum, m/z (Irel, %): 217 [M+] (16), 202 (43), 187 (15), 131 (12), 105 (100), 77 (37). Found, %: C 71.7;
H 7.03; N 6.52. C13H15NO2. Calculated, %: C 71.89; H 6.91; N 6.45.
2-Methyl-5-(4-tolyl)-6-oxa-2-azabicyclo[3.2.1]octan-4-one (5b). A thick, colorless oil, Rf 0.7
(acetone). IR spectrum (nujol mull), ν, cm-1: 1675 (C=O). Mass spectrum, m/z (Irel, %): 231 [ M+] (7), 216 (36),
203 (6), 188 (28), 172 (34), 160 (38), 145 (12), 119 (100), 91 (45). 1H NMR spectrum, δ, ppm (J, Hz): 2.39 (3H,
2
2
2
s, CH3); 2.51 (3H, s, CH3); 2.98 (1H, t, J = 12.9, Ha-8); 3.16 (1H, br. d, J =12.9, Ha-8); 3.76 (1H, t, J =10.9,
Ha-7); 4.07 (1H, m, He-1); 4.10 (1H, d, 2J = 9.4, Ha-3); 4.20 (1H, br. d, 2J = 10.9, He-7); 4.40 (1H, br. d, 2J = 9.4,
He-3); 7.27 and 7.86 (4H, AX'BX' system, 3J = 7.2, 4J = 1.1, Ar). 13C NMR spectrum, δ, ppm: 22.6 (CH3 in Ar),
40.3 (C(1)), 40.8 (N-CH3), 55.8 (C(8)), 70.2 (C(7)), 86.7 (C(3)), 129.7 (C(5)), 129.3, 130.5, 144.3, 145.4 (Carom).
Found, %: C 73.01; H 7.49; N 5.90. C14H17NO2. Calculated, %: C 72.72; H 7.36; N 6.06.
Oxidative Aromatization of the Tetrahydropyridines 1a,b. A mixture of 4-phenyltetrahydropyridine
1a (0.5 g, 2.9 mmol) and manganese dioxide (2.5 g, 29 mmol) in toluene (100 ml) was boiled for 3 h. The
manganese dioxide was filtered off and washed on the filter with chloroform (50 ml). The combined filtrates
were evaporated in vacuum and the residue was separated by column chromatography on silicagel with 1:1
ether: hexane as eluant to give 4-phenylpyridine, 6a, (0.2 g, 45%), Rf = 0.5 (ether); mp 76-78°C [12]. The mass
spectrum and 1H NMR spectra were identical to those cited in [5].
Analogously from the tetrahydropyridine 1b (0.5 g, 2.7 mmol) 4-(p-tolyl)pyridine 6b was obtained
(0.19 g, 42%), Rf 0.5 (ether); mp 43-45°C.
3
1H NMR spectrum, δ, ppm, (J, Hz): 2.40 (3H, s, Me); 7.25 and 7.50 (4H, AA'XX' system, J =7.1,
3
4
4J = 1.1, Ar); 7.61 and 8.63 (AA'BB' system, J =7.1, J = 1.1, Hhet). Mass spectrum, m/z (Irel, %): 169 [M+]
(100), 168 (43), 155 (95), 91 (20). Found, %: C 84.98; H 6.67; N 8.01. C12H11N. Calculated, %: 85.21; H 6.51;
N 8.28.
648

We thank the Russian Fund for Fundamental Research for financial support of this work (grants nos. 99-
03-32940a and 00-15-97359).
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