Synthesis and molecular structure of substituted 2-hydroxyperhydro-[1,3,2] dioxaborinino[5,4-c]pyridines, perhydro[1,3]dioxano[5,4-c]pyridine, and their precursor-4-hydroxy-3-(α-hydroxybenzyl)-1-methyl-4-phenylpiperidine

Article abstract of DOI:10.1007/s10593-009-0185-y

4,8a-Diphenyl-substituted 2-(2-propoxy)perhydro[1,3,2]dioxaborinino[5.4-c] pyridine was obtained by the condensation of 4-hydroxy-3-(α-hydroxybenzyl) -1-methyl-4-phenylpiperidine with triisopropyl borate, and its 2-hydroxysubstituted analog in the presence of water. 1-Methyl-4,8a-diphenyl- perhidro[1,3]dioxano[5,4-c]pyridine was synthesized by the reaction of the same piperidol with formaldehyde. A comparative study of the molecular structures of the three products was carried out by X-ray crystallography.

Full text of DOI:10.1007/s10593-009-0185-y

Chemistry of Heterocyclic Compounds, Vol. 44, No. 11, 2008
SYNTHESIS AND MOLECULAR STRUCTURE
OF SUBSTITUTED 2-HYDROXYPERHYDRO-
[1,3,2]DIOXABORININO[5,4-c]PYRIDINES,
PERHYDRO[1,3]DIOXANO[5,4-c]PYRIDINE,
AND THEIR PRECURSOR – 4-HYDROXY-
3-(α-HYDROXYBENZYL)-1-METHYL-
4-PHENYLPIPERIDINE
Le Tuan Anh1, A. T. Soldatenkov1, Zh. A. Mamyrbekova2, S. A. Soldatova1,
K. B. Polyanskiy3, Tran Thanh Tung1, and V. N. Khrustalev4
4,8a-Diphenyl-substituted 2-(2-propoxy)perhydro[1,3,2]dioxaborinino[5.4-c]pyridine was obtained by
the condensation of 4-hydroxy-3-(α-hydroxybenzyl)-1-methyl-4-phenylpiperidine with triisopropyl
borate, and its 2-hydroxysubstituted analog in the presence of water. 1-Methyl-4,8a-diphenyl-
perhidro[1,3]dioxano[5,4-c]pyridine was synthesized by the reaction of the same piperidol with
formaldehyde. A comparative study of the molecular structures of the three products was carried out by
X-ray crystallography.
Keywords: 4-hydroxy-3-(α-hydroxybenzyl)-1-methyl-4-phenylpiperidine, perhydro[1,3,2]dioxaborinino-
[5,4-c]pyridines, perhydro[1,3]dioxano[5,4-c]pyridine, triisopropyl borate, molecular structures.
The synthesis of 2,4,8a-triarylperhydro[1,3,2]dioxaborinino[5,4-c]pyridines with aryl substituents at the
boron atom has been reported [1-3]. The preparation of indicated derivatives of new heterocyclic systems was
dictated by the observation that many of them when subjected to the PASS program [4] should possess (to a
high degree of probability) effects on the central nervous system. In the same connection the molecular structure
of B-phenyl-substituted perhydrodioxaborininopyridine was studied in detail – a racemic diastereomer for which
cis-fusion of the two heterocyclic units was established, with three chiral atoms, C(4), C(4a), and C(8a) with the
R-, S-, and S-configurations respectively [2]. In the present paper the syntheses of B-(2-propoxy)- (2a) and
B-hydroxyperhydro[1,3,2]dioxaborinino[5,4-c]pyridine (2b) are described, based on the substituted γ-piperidol 1,
and also their structural analog 2c in which the boron atom is replaced by the CH2 group; the
__________________________________________________________________________________________
1People's Friendship University of Russia, Moscow 117198, Russia; e-mail: asoldatenkov@mail.ru.
2Université d'Adobo-Adjamé 02 BP 801, Abidjan 02, Cote d'Ivoire; e-mail: bekro2001@yahoo.com.
3Chem-Bridge Corporation, Moscow 119048, Russia; e-mail: kirill198@post.ru. 4A. N. Nesmeyanov Institute of
Organoelement Compounds, Russian Academy of Sciences, Moscow 119991, Russia; e-mail:
vkh@xrlab.ineos.ac.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, 1726-1735,
November, 2008. Original article submitted October 26, 2007. Revised version submitted March 7, 2008.
1404
0009-3122/08/4411-1404©2008 Springer Science+Business Media, Inc.

structures of compounds 1 and 2b,c, determined by X-ray spectroscopy are discussed. The choice of he was based
not only on the objective of comparing the most important characteristics with those of the
dioxaborininopiperidine 2b and the piperidol 1, but also on the possibility that compound 2c might possess a
definite amount of bioisostery with its boron-containing analogs since computer screening with the PASS
program showed that it was highly likely to affect the central nervous system; the possibility of treatment of
disturbance of the cognitive function of the brain (74% probability) and treatment of Alzheimer's disease (57%),
antagonism of the receptor of the GABA neuromediator (69%).
The dioxaborinine 2a was synthesized in 56% yield by boiling the piperidol 1 with triisopropyl borate in
dry hexane in a nitrogen atmosphere (variant a). Carrying out this reaction in the presence of moisture (variant
b) gave compound 2b, the product of the partial hydrolysis of its predecessor 2a, in 70% yield.
a. B(OCHMe2)3, ∆
b. B(OCHMe2)3 + H2O, ∆
c. CH2O, H+, ∆
OH
OH
1
Ph
8
5
Ph
O
Z
Ph
N
O
N
Me
1
Me
4
Ph
2a–c
2 a Z = BOCHMe2, b Z = BOH, c Z = CH2
The dioxane derivative 2c was obtained in 84.5% yield by condensation of formaldehyde with the diol 1 on
heating in an acid medium (variant c). In order to establish the structures, refining the relative configuration of the
stereogenic centers, and to determine other stereochemical characteristics of compounds 1, 2b, and 2c, they were
examined by X-ray crystallography. The general shape of molecules 1, 2b, and 2c and their packing in the crystal
are shown in Fig. 1-4 (the atoms are given with their crystallographic numbering). Bond lengths, bond and torsional
angles of these substances are given in Tables 1-3 respectively. Lenghts of valence and hydrogen bonds, and also
angles between them in the fragments of compound 1 D–H···A (D – donor atom, A – acceptor atom) are given in
–
Table 4. The structure of compound 1 is shown in Fig. 1. It crystallized in the triclinic space group P1 ,
Table 1. Lengths (l) of Some Bonds in the Molecules 1, 2b, and 2c
l, Å
Bond
1*
2b
2c
N(1)–C(2)
N(1)–C(6)
N(1)–C(7)
C(2)–C(3)
C(3)–C(4)
C(3)–C(8)
C(4)–O(2)
C(4)–C(5)
C(4)–C(15)
C(5)–C(6)
C(8)–O(1)
C(8)–C(9)
B(1)–O(1)
B(1)–O(2)
B(1)–O(3)
C(1)–O(1)
C(1)–O(2)
1.472(3)
1.473(3)
1.465(3)
1.524(3)
1.550(3)
1.540(3)
1.435(3)
1.537(3)
1.525(3)
1.511(3)
1.429(3)
1.515(3)
1.469(2)
1.477(2)
1.462(2)
1.528(2)
1.550(2)
1.544(2)
1.443(2)
1.539(2)
1.532(2)
1.518(2)
1.434(2)
1.517(2)
1.377(2)
1.371(2)
1.355(2)
1.471(2)
1.463(2)
1.468(2)
1.534(2)
1.544(2)
1.541(2)
1.449(2)
1.530(2)
1.535(2)
1.520(2)
1.435(2)
1.511(2)
1.409(2)
1.412(2)
_______
* Average values for the two independent molecules are cited.
1405

with two crystallographically independent molecules in the unit cell. The geometric parameters of these
molecules are very close (average values are cited in Table 1), consequently we have carried out an averaged
description of molecule 1, which is a diastereomer with the asymmetric atoms C(3), C(4), and C(8) in the first
independent molecule, and C(22), C(23), and C(27) in the second molecule. The relative configurations of these
chiral centers are rac-3S*,4S*,8R* and rac-22S*,23S*,27R* respectively.
1
2b
2c
Fig. 1. Molecular structures of compounds 1, 2b, and 2c.
1406

The piperidine ring in the piperidol 1 has an almost ideal chair conformation (the ranges of the moduli
of the torsion angles of the two independent molecules are 53.0(2)-63.2(2) and 55.4(2)-59.0(2)° respectively).
The substituents Me, CH(OH)Ph, and Ph take equatorial positions in these molecules, while the hydroxy group
takes an axial position. The plane of the phenyl substituent in the piperidine ring is essentially perpendicular to
the plane C(2)C(3)C(5)C(6) or C(22)C(23)C25)C(26) (the angles between these rings are 88.2 and 86.1°
respectively). The phenyl rings are placed practically one above the other and in each of the independent
molecules their planes are almost parallel (the angles between them are 16.8 and 17.5° respectively). In
Table 2. Some Valence Angles (ω) in the Molecules of Compounds 1, 2b, and 2c
ω, deg
2b
Angle
1*
2c
C(2)–N(1)–C(6)
C(2)–N(1)–C(7)
C(6)–N(1)–C(7)
N(1)–C(2)–C(3)
C(2)–C(3)–C(4)
C(2)–C(3)–C(8)
C(4)–C(3)–C(8)
O(2)–C(4)–C(3)
O(2)–C(4)–C(5)
O(2)–C(4)–C(15)
C(3)–C(4)–C(5)
C(3)–C(4)–C(15)
C(5)–C(4)–C(15)
C(4)–C(5)–C(6)
N(1)–C(6)–C(5)
O(1)–C(8)–C(3)
O(1)–C(8)–C(9)
C(3)–C(8)–C(9)
O(1)–B(1)–O(2)
O(1)–B(1)–O(3)
O(2)–B(1)–O(3)
B(1)–O(1)–C(8)
B(1)–O(2)–C(4)
C(1)–O(1)–C(8)
C(1)–O(2)–C(4)
O(1)–C(1)–O(2)
109.6(2)
110.4(2)
110.2(2)
112.0(2)
109.3(2)
109.4(2)
116.4(2)
109.9(2)
105.9(2)
110.6(2)
107.7(2)
113.0(2)
109.4(2)
112.8(2)
111.0(2)
109.8(2)
111.6(2)
115.0(2)
109.1(1)
110.5(1)
110.5(1)
111.1(1)
112.1(1)
108.6(1)
112.4(1)
109.6(1)
105.6(1)
110.1(1)
110.8(1)
111.4(1)
109.1(1)
113.6(1)
110.2(1)
112.2(1)
110.3(1)
115.8(1)
122.8(1)
119.5(1)
117.7(1)
122.4(1)
120.2(1)
110.2(1)
108.6(1)
109.0(1)
113.4(1)
111.1(1)
109.8(1)
108.7(1)
107.8(1)
106.3(1)
109.1(1)
109.6(1)
115.1(1)
108.5(1)
112.2(1)
110.5(1)
109.1(1)
108.5(1)
113.8(1)
110.6(1)
111.8(1)
112.4(1)
_______
* Average values for the two independent molecules are cited.
Table 3. Some Torsion Angles (θ) in the Molecules of Compounds 1, 2b, and 2c
θ, deg
2b
Angle
1*
2c
C(8)–C(3)–C(4)–O(2)
C(8)–C(3)–C(4)–C(15)
C(4)–C(3)–C(8)–C(9)
64.3(2)
-59.8(2)
75.5(2)
51.6(1)
-70.5(1)
86.3(1)
54.9(1)
-67.2(1)
-177.5(1)
_______
* Average values for the two independent molecules are cited.
1407

addition, the phenyl rings of one independent molecule are practically perpendicular to the phenyl rings of the
other. This distribution of the substituents is evidently determined by a system of strong intramolecular O-H···H
and intermolecular O-H···N hydrogen bonds (Table 1, Fig. 1 and 2). The molecules are packed in a chain along
the b axis (Fig. 2).
2-Hydroxydioxaborininopiperidine 2b has cis fusion of the heterocycles (Fig.1) which is explained by
the position of the hydroxyl groups in the starting material 1 at which the cyclization occurs. The conformation
of the piperidine ring is a slightly distorted chair [the range of the values of the torsion angles is
45.3(1)-64.1(1)°], the conformation of the borinine ring is a slightly distorted sofa with a deviation of atom C(3)
from the mean square of the remaining atoms by 0.578 Ǻ. The boron atom has a generally planar configuration
(the sum of its valence angles is 360.0°). Just as in the piperidol 1, compound 2b is a diastereomer with three
asymmetric atoms C(3), C(4), and C(8). The relative configuration of these chiral centers is retained on
cyclization – rac-3S*,4S*,8R*.
Fig. 2. Packing of the molecules in the crystal of compound 1 along the a axis.
The general structure of the molecule of 2b is identical to that of the molecule of piperidol 1 starting
material. The phenyl substituent in the piperidine ring is effectively perpendicular to the C(2)C(3)C(5)C(6) (the
angle between these planes is 84.0°). The two phenyl groups are distributed cis-perpendicularly relative to the
borininine ring, however as a result of the formation of the latter ring the angle between them is increased to
37.2°. It is interesting that in the crystal of 2b overall chain structural motive along the b axis is also retained
because of the intermolecular O(3)–H···N(1) hydrogen bonds [O(3)···N(1) 2.792(2), H···N 1.89 Ǻ, and O–H···N
171°] (Fig. 3).
In the dioxanopiperidine 2c cis fusion of the heterocycles also occurs (Fig.1) which is determined for the
same reason as for compound 2b. The normal chair conformation is characteristic for the piperidine ring [the
range of the moduli of the torsion angles is 49.4(2)-59.8(2)°]. It should be noted that in the formation of
1,3-dioxane ring, which also has the general chair conformation [range of the values of the moduli of the torsion
angles 54.9(1)-61.9(2)°], an inversion of the asymmetric atom C(8) occurs. As a result the relative
configurations of the chiral centers C(3), C(4), and C(8) in the diastereomer 2c becomes rac-3S*,4S*,8S*. In
1408

consequence the planes of the phenyl substituents are positioned anti-periplanar relatively to the newly formed
dioxane ring, with an angle between them of 44.8°. Moreover, the position of the phenyl substituent in the
piperidine ring is changed – it is considerably tilted from the perpendicular position to the C(2)C(3)(C5)(C6)
plane found in compounds 1 and 2b (the angle between these planes equals 53.2°).
Fig. 3. Packing of the molecules in the crystal of compound 2b along the a axis.
Fig. 4. Packing of the molecules in the crystal of compound 2c along the a axis.
1409

Table 4. Lengths (l) of Valence and Hydrogen Bond in the Units D–H···A
in Compound 1, Distance (d) between Atoms D and A, Angles (θ) D–H···A
Unit
l, Å
d, Å
θ, deg
...
...
D–H
A
D–H
0.86
H
A
...
1.94
2.714(2)
149
O(2)–H O(1)
...
0.88
0.91
0.92
1.93
1.82
1.80
2.716(2)
2.727(3)
2.722(3)
148
178
173
O(4)–H O(3)
...
O(1)–H N(2)*
...
O(3)–H N(1)
_______
* The symmetry operation x, y + 1, z was used to generate equivalent atoms.
Table 5. Basic Crystallographic Data and Parameters for the Refinement of
Compounds 1, 2b, and 2c
1
2b
2c
Empirical formula
Molecular mass
T, K
C19H23NO2
297.38
120
C19H22BNO3
323.19
C20H23NO2
309.39
115
120
Crystal system
Space group
Triclinic
–
Monoclinic
P21/c
Monoclinic
P21/c
P
1
a, Å
10.426(3)
11.190(3)
14.416(5)
89.556(8)
71.331(7)
88.007(10)
1592.4(8)
4
11.1303(11)
12.8639(16)
12.5271(16)
90
10.796(2)
14.304(3)
10.6135(19)
90
b, Å
c, Å
α, deg
β, deg
107.045(5)
90
102.105(6)
90
γ, deg
V, Å3
1714.8(4)
4
1602.6(5)
4
Z
dc, g cm–3
F(000)
1.240
1.252
1.282
640
688
664
µ, mm1
0.080
0.083
0.082
2θmax, deg.
No. of reflexions
measured
independent
observed with I > 2σ(I)
No. of parameters refined
R1 (I > 2σ(I))
wR2 (all data)
GooF
54
56
56
14760
6823
17682
4133
11032
3768
4119
3342
3110
399
218
209
0.0645
0.1553
1.007
0.0494
0.1305
1.028
0.0521
0.1243
1.008
The packing of molecules 2c in the crystal is stacked along the a axis. The molecules are distributed at
van der Waals distances, there are no short contacts in the structure.
Comparison of the X-ray crystallographic data for compounds 2b and 2c shows that both have isosteric
cis fusion of the heterocycles. The single structural difference is the cis-1,3-diaxial relative position of the
phenyl substituents in the borinine nucleus of molecules 2b and their trans position in the dioxane ring of
molecules 2c.
1410

EXPERIMENTAL
IR spectra of KBr disks were recorded with an IR-75 instrument. Mass spectra were recorded with a
Finnigan MAT Incos 50 instrument with direct introduction of the sample into the ion source with an ionizing
current of 70 eV. 1H and 13C NMR spectra in CDCl3 solution with TMS as internal standard were recorded with
a Bruker WM-400 instrument (400 and 100 MHz respectively).
X-ray structural analysis of compounds 1, 2b, and 2c. Monocrystals of compounds 1 and 2b were
grown from acetone, of compound 2c were measured from diethyl ether. Unit cell parameters and the intensities
of reflexions for compounds 1, 2b, and 2c were measured on a Bruker SMART 1000 CCD automatic three-
circle diffractometer (λMoKα-radiation, graphite monochromator, φ- and ω-scanning). The basic
crystallographic data are presented in Table 5. The structures of all compounds were solved by direct methods
and refined by full matrix least squares method in the anisotropic approximation for non-hydrogen atoms. The
hydrogen atoms of the hydroxyl groups in compounds 1 and 2b were localized objectively in difference Fourier
syntheses and refined in the isotropic approximation with fixed positions and thermal parameters. The positions
of the remaining hydrogen atoms in the compounds 1, 2b, and 2c were calculated geometrically and refined in
the isotropic aproximation with fixed positions (the "riding" model) and thermal parameters [Uiso(H) = 1.5Ueq(C)
for CH3 groups and Uiso(H) = 1.2Ueq(C) for all other groups]. All calculations were carried out with SHELXTL
PLUS (version 5.10) suite of programs [5]. Tables of atomic coordinates, bond lengths, valence and torsional
angles, and anisotropic thermal parameters for compounds 1, 2b, and 2c have been deposited in the Cambridge
Structural Data Bank (deposit CCDC 693537-693539).
6-Methyl-4,8a-diphenyl-2-(2-propoxy)perhydro[1,3,2]dioxaborinino[5,4-c]pyridine (2a). A mixture
of piperidol 1 (1 g, 3.37 mmol) and triisopropyl borate (2.07 g, 11.0 mmol) in dry hexane (50 ml) was boiled for
2 h under a nitrogen atmosphere in a Dean-Stark apparatus with a calcium chloride tube. The hexane was
evaporated off and the residue was crystallized from acetone to give 0.69 g (56%) of product, mp 185-186°C
(colorless crystals). 1H NMR spectrum, δ, ppm (J, Hz): 1.22 and 1.33 (6H, two d, J1 = J2 = 6.1, CH(CH3)2); 1.79
and 2.01 (2H, two m, H-8); 2.38 (3H, s, NCH3); 2.46 (1H, t, 2J = 10.8, H-4a); 2.63-2.95 (4H, m, NCH2); 4.03 (1H,
m, CHCH3); 4.95 (1H, br. s, H-4); 6.75-6.99 (10H, m, H Ph). Mass spectrum, m/z (Irel, %): 365 [M]+ (2), 323
[M-C(CH3)2]+ (29), 322 (5), 251 (7), 191 (11), 172 (38), 159 (26), 105 (20), 77 (26), 71 (35), 70 (52), 57 (67), 44
(100), 43 (72), 42 (65). Found, %: C 72.41; H 7.55; N 3.62. C22H28BNO3. Calculated, %: C 72.34; H 7.73; N 3.83.
2-Hydroxy-6-methyl-4,8a-diphenylperhydro[1,3,2]dioxaborinino[5,4-c]pyridine (2b). A mixture of
piperidol 1 (4 g, 13.4 mmol), triisopropyl borate (2.6 g, 13.83 mmol, and hexane (50 ml) was boiled in a
Dean Stark apparatus for 8 h in moist air. The reaction mixture was treated as described above for compound 2a
1
to give product 2b (3.04 g, 70%, colorless crystals), mp > 230°C. H NMR spectrum, δ, ppm (J, Hz): 1.78 and
2.06 (2H, two m, H-8); 2.40 (3H, s, NCH3); 2.43 and 2.70 (2H, two m, NCH2); 2.46 and 2.53 (1H, t, 3J = 11.0,
13
H-4a); 2.90-3.10 (2H, m, NCH2); 4.90 (1H, m, H-4); 6.70-7.05 (10H, m, H Ph). C NMR spectrum, δ, ppm:
25.3 (C-8); 40.7 (NCH3); 45.2 (C-5); 45.9 (C-7); 56.9 (C-4a); 65.7 (C-4); 74.0 (C-8a quat), 124.5-128.8 (10C,
C6H5); 141.6 (C Ph quat); 141.4 (C quat arom). Mass spectrum, m/z (Irel, %): 323 [M]+. Found, %: C 70.37;
H 7.05; N 4.20. C19H22BNO3. Calculated, %: C 70.61; H 6.86; N 4.33.
6-Methyl-4,8a-diphenylperhydro[1,3]dioxano[5,4-c]pyridine (2c). A mixture of piperidol 1 (2.0 g,
6.7 mmol), formaldehyde (0.31 g, 10.1 mmol), water (14 ml), and conc. H2SO4 (7 ml) was boiled for 5.5 h, then
cooled and extracted with ethyl acetate (2×20 ml, extract 1). The aqueous layer was basified with 20% NaOH
solution to pH 10, and extracted with ethyl acetate (3×10ml, extract 2). Extract 2 was dried over MgSO4. The
residue after evaporating extract 2 was crystallized from ether to give compound 2c (1.75 g, 84.5%, white
1
crystals), mp 133-135°C. H NMR spectrum, δ, ppm (J, Hz): 1.80 (2H, m, H-8); 2.17 (3H, s, CH3); 2.22-2.60
(4H, m, H-5,7); 2.81 (1H, m, H-4a); 4.83 (1H, d, 3J = 2.5, H-4); 5.01 and 5.10 (2H, two, d, J1 = J2 = 6.4, H-2);
7.21-7.50 (10H, m, H Ph). Mass spectrum, m/z (Irel, %): 309 [M]+. Found, %: C 77.82; H 7.55; N 4.32.
C20H23NO2. Calculated, %: C 77.64; H 7.49; N 4.53.
1411

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1412