One-pot condensation of 2-arylpropenes with formaldehyde and ammonium chloride: The synthesis of aryl substituted pyridines and 5,7,11-trioxa-1-azatricyclo[7.3.1.03,8]tridecanes

Article abstract of DOI:10.1070/MC2001v011n04ABEH001457

A mixture consisting of 2-arylpropene 1 or 2, formaldehyde and ammonium chloride condenses in a one-pot manner to yield 5,7,11-trioxa-1-azatricyclo [7.3.1.0^3,8]tridecanes 3 or 4. In the presence of manganese dioxide the reaction leads to 4-arylpyridines 5 or 6.

Full text of DOI:10.1070/MC2001v011n04ABEH001457

, 2001, 11(4), 154–155
One-pot condensation of 2-arylpropenes with formaldehyde and
ammonium chloride: the synthesis of aryl substituted pyridines
and 5,7,11-trioxa-1-azatricyclo[7.3.1.03,8]tridecanes
Anatoly T. Soldatenkov,* Kirill 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; e-mail: asoldatenkov@sci.pfu.edu.ru
10.1070/MC2001v011n04ABEH001457
A mixture consisting of 2-arylpropene 1 or 2, formaldehyde and ammonium chloride condenses in a one-pot manner to yield
5,7,11-trioxa-1-azatricyclo [7.3.1.03,8]tridecanes 3 or 4. In the presence of manganese dioxide the reaction leads to 4-arylpyridines
5 or 6.
It is well known1 that the acid-catalysed reaction of 2-aryl-
propenes with formaldehyde and amines or ammonia leads to
O(7)
C(8)
the formation of 4-aryl-4-hydroxypiperidines, which can be
subsequently dehydrated into tetrahydropyridines (THPs). Under
C(6)
C(9)
the Prins reaction conditions, N-alkyl substituted THPs can be
C(16)
C(15)
C(20)
hydroxymethylated at β -carbon atoms2,3 and subsequently con-
verted into piperidinodioxanes4,5 and 3-oxa-7-azabicyclono-
nanes.5,6 In the presence of manganese dioxide, the hydroxy-
methylation of THP proceeds at the α ,β -carbon atoms leading
to 6-oxa-2-azabicyclooctanones.5
C(5)
N(1)
C(17)
C(4)
C(14)
C(2)
C(3)
C(18)
C(19)
O(10)
C(13)
Continuing our work3,5,7,8 towards the search of a new tetra-
hydropyridine reaction, we decided to study the one-pot con-
densation of 2-arylpropenes with ammonium chloride and an
excess of formaldehyde according to the classic Prins reaction or
modified by the presence of manganese dioxide. The expected
novelty of this research is based on the presumption that ini-
tially formed NH-tetrahydropyridines could then be N- and
C-hydroxymethylated and subsequently cyclocondensed or oxi-
dised. Thus, a mixture containing 2-phenylpropene 1 or 2-(p-tolyl)-
propene 2, ammonium chloride and a 4.5-fold molar excess
of formaldehyde was heated at 80 °C for 7 h. After this time,
hydrochloric acid and 2.5 equiv. of formaldehyde were added
and the reaction mixture was then heated at 80 °C for another
10 h (Scheme 1). After work-up of the reaction mixture, com-
pounds 3 or 4 were obtained as oils in 47% and 34% yields,
respectively, which slowly crystallised on standing.
O(12)
C(11)
Figure 1 General view and numbering of atoms of molecule 4 (X-ray
data).
were obtained as the only isolated products in 32% and 27%
yields, respectively.
Although not all the steps involved in the one-pot synthesis
of final products 3–6 are known with certainty (conversions 1 ®
®A ®B are known), a likely sequence of cascade chemical
events (B ® C ® D ® E ® F) can be proposed as shown in
Scheme 2.
Partial support for the proposed reaction sequence of Scheme 2
is to be found in earlier work3,5 that refers to the aromatization
Ar
10
7
O
11
O
Ar
8
Ar
OH
Ar
9
6
13
ii
i
+ CH2O + NH4Cl
12
N
O5
3
1, 2 + CH2O + NH4Cl
1
N
2
4
N
5, 6
1, 2
3, 4
H
1, 3, 5 Ar = Ph
A
2, 4, 6 Ar = -MeC H
p
6
4
Ar
Ar
Ar
Scheme 1 Reagents and conditions: i, 1 (or 2):CH2O:NH4Cl = 1:4.5:1,
80 °C, 7 h; then 0.006 equiv. of HCl (36% aqueous solution) and 2.5 equiv.
of CH2O were added, 80 °C, 10 h; ii, 1 (or 2):CH2O:NH4Cl = 1:4.5:1, 80 °C,
7 h; then 0.006 equiv. of HCl, 2.5 equiv. of CH2O and 10 equiv. of MnO2
were added, 80 °C, 7 h.
HO
N
N
N
H
HO
HO
X-ray analysis of the product derived from styrene 2 (the de-
tailed data will be reported elsewhere) showed (Figure 1) it to
be 8-(p-tolyl)-5,7,11-trioxa-1-azatricyclo[7.3.1.03,8]tridecane 4.
The 1H NMR spectra of compounds 3 and 4 and X-ray analysis
data of compound 4 support that all three six-membered rings
in these compounds adopt a chair conformation. The dioxane
ring is cis-coupled to the piperidine ring (H-3 is in an axial
position in both heterocycles and appears in the 1H NMR spectra
as a narrow unresolved multiplet with ∆ n1/2 = 7.1 Hz). Further-
more, the oxazine ring is 1,3-cis-diaxially coupled to the piperi-
dine ring.
B
C
MnO2
D
5, 6
Ar
O
Ar
O
OH
OH
3, 4
N
N
E
F
When the reaction was repeated in the presence of manga-
nese dioxide (experiment ii, Scheme 1), 4-arylpyridines 5 or 6
Scheme 2
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, 2001, 11(4), 154–155
of N-methylTHP by action of manganese dioxide and manga-
nese permanganate in a manner depicted by steps B–D above.
In conclusion, we observed that: (1) the one-step condensa-
tion of 2-arylpropenes with formaldehyde and ammonium chlo-
ride gives novel heterocyclic tricyclotridecanes in a stereoselec-
tive manner; and (2) in the presence of an oxidant, the Prins
reaction does not take place and instead 4-arylpyridines are the
stable final products.
This work was supported by the Russian Foundation for Basic
Research (grant no. 99-03-32940a).
References
1 C. J. Schmidle and R. C. Mansfield, J. Am. Chem. Soc., 1955, 77, 5698.
2 C. J. Schmidle and R. C. Mansfield, US Patent 2748140, 1956 (Chem.
Abstr., 1957, 51, P 2880f).
3 A. T. Soldatenkov, A. W. Temesgen, L. N. Kuleshova and V. N. Khrustalev,
Mendeleev Commun., 1998, 193.
The structures of compounds 3–6 were confirmed spectrosco-
pically.†
4 A. F. Casy, A. B. Simmonds and D. Staneforth, J. Org. Chem., 1972, 37,
3189.
5 A. T. Soldatenkov, K. B. Polyanskii, A. W. Temesgen, S. A. Soldatova,
N. D. Sergeeva, N. M. Kolyadina and N. N. Lobanov, Mendeleev Commun.,
2001, 27.
6 A. F. Casy and F. Ogungbamila, Heterocycles, 1981, 16, 1913.
7 A. T. Soldatenkov, A. W. Temesgen, I. A. Bekro, T. P. Khristoforova,
S. A. Soldatova and B. N. Anissimov, Mendeleev Commun., 1997, 243.
8 A. T. Soldatenkov, A. W. Temesgen, I. A. Bekro, S. A. Soldatova and
B. N. Anissimov, Mendeleev Commun., 1998, 137.
†
1H NMR spectra were recorded at 400 MHz, standard TMS, CDCl3.
Compounds 3 and 4 gave satisfactory elemental analyses.
8-Phenyl-5,7,11-trioxa-1-azatricyclo[7.3.1.03,8]tridecane 3: yield 47%,
mp 140–142 °C. 1H NMR, d: 1.3 (m, 1H, 3-H, ∆ n1/2 7.1 Hz), 3.05–3.22
2
(m, 3H, 2-CH2 and 13-H), 3.45 (br. d, 1H, 13-H, J 11.8 Hz), 3.54 and
3.67 (br. d and dd, 1H each, 4-CH2, 2J 11.6 Hz, 3J 2.4 Hz), 3.78 and 3.83
(br. d and dd, 2H, 10-CH2, 2J 11.7 Hz, 3J 2.3 Hz), 3.75–3.85 (br. m, 1H,
2
3
9-H), 4.62 and 4.69 (br. d and dd, 2H, 12-CH2, J 10.4 Hz, J 1.5 Hz),
4.71 and 4.87 (d and br. d, 2H, 6-CH2, 2J 6.4 Hz), 7.2–7.4 (m, 5H, Ph).
MS (EI, 70 eV), m/z (%): 261 (28) [M+], 230 (26), 201 (67), 171 (34),
142 (45), 128 (90), 115 (100), 105 (74), 91 (52), 77 (85), 42 (91), 41
(97). Found (%): C, 68.75; H, 7.32; N, 5.28. Calc. for C15H19NO3 (%):
C, 68.96; H, 7.28; N, 5.36.
8-(p-Tolyl)-5,7,11-trioxa-1-azatricyclo[7.3.1.03,8]tridecane 4: yield 34%,
mp 156–158 °C. 1H NMR, d: 1.28 (narrow unresolved m, 1H, 3-H, ∆ n1/2
7.1 Hz), 2.4 (s, 3H, Me), 3.05–3.25 (m, 3H, 2-CH2 and 13-H), 3.47 (br. d,
1H, 13-H, 2J 11.7 Hz), 3.53 and 3.66 (2d, 1H each, 4-CH2, 2J 11.5 Hz),
3.78 (d, 1H, 10-H, 2J 11.6 Hz), 3.84–3.90 (m, 2H, 10-H and 9-H), 4.62
and 4.69 (2d, 1H each, 12-CH2, 2J 10.3 Hz), 4.71 and 4.87 (2d, 1H each,
6-CH2, 2J 6.4 Hz), 7.1–7.4 (AA'XX' system, 4H, Ar). MS, m/z (%): 275
(11) [M+], 244 (7), 215 (23), 198 (10), 142 (14), 128 (17), 119 (32), 99
(38), 91 (39), 71 (39), 42 (100), 41 (61). Found (%): C, 70.01; H, 7.58;
N, 5.10. Calc. for C16H21NO3 (%): C, 69.81; H, 7.64; N, 5.09.
4-Phenylpyridine 5: yield 32%, mp 76–78 °C. 1H NMR and mass spectra
are identical to those given in ref. 3.
4-(p-Tolyl)pyridine 6: yield 27%, mp 43–45 °C. 1H NMR and mass
spectra are identical to those given in ref. 5.
Received: 30th March 2001; Com. 01/1783
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