Diastereoselective syntheses via Prins cyclization, crystal structures determination and theoretical studies of cis-2,6-diphenyl-4- hydroxytetrahydropyran and analogues

Article abstract of DOI:10.1016/j.molstruc.2012.11.044

We report in this article the diastereoselective syntheses of tetrahydropyranyl derivatives 1-5, its cis configurational ascertainment by spectroscopy and finally the crystal structures determination that unequivocally shows the 1-5 configurations and its

Full text of DOI:10.1016/j.molstruc.2012.11.044

Journal of Molecular Structure 1036 (2013) 478–487
Contents lists available at SciVerse ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstruc
Diastereoselective syntheses via Prins cyclization, crystal structures determination
and theoretical studies of cis-2,6-diphenyl-4-hydroxytetrahydropyran
and analogues
F.P.L. Silva a, J.R. Sabino b, F.T. Martins c, M.L.A.A. Vasconcellos a,
⇑
a Laboratório de Síntese Orgânica Medicinal da Paraíba (LASOM-PB), Departamento de Química, Universidade Federal da Paraíba, Campus I, João Pessoa PB 58059-900, Brazil
b Instituto de Física, Universidade Federal de Goiás, Campus Samambaia, CP 131, 74001-970 Goiânia, GO, Brazil
c Instituto de Química, Universidade Federal de Goiás, Campus Samambaia, CP 131, 74001-970 Goiânia, GO, Brazil
h i g h l i g h t s
"
"
"
Diastereoselective syntheses of tetrahydropyran derivatives via Prins cyclization.
Determination of crystal structures and its crystals packing features.
Theoretical study using density functional theory (M06-2X/6-311++GÃÃ).
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 6 October 2012
Received in revised form 20 November 2012
Accepted 20 November 2012
Available online 19 December 2012
We report in this article the diastereoselective syntheses of tetrahydropyranyl derivatives 1–5, its cis con-
figurational ascertainment by spectroscopy and finally the crystal structures determination that unequiv-
ocally shows the 1–5 configurations and its crystals packing features. Besides that, we have developed a
theoretical study using density functional theory (M06-2X/6-311++GÃÃ) to obtain the 1–5 optimized
molecular geometries in gas phase.
Ó 2012 Elsevier B.V. All rights reserved.
Keywords:
Diastereoselective synthesis
Prins cyclization reaction
Tetrahydropyranyl derivatives
Crystal structures determination
DFT
1. Introduction
Tetrahydropyran analogues of the alcohol 2,6-diphenyl-tetrahy-
dro-2H-pyran-4-ol (1, Fig. 1) are part of a compounds isolated ser-
Six-membered ring saturated oxygen heterocycles are an inte-
gral part of many biologically active compounds [1]. The Prins
cyclization of homoallylic alcohols with aldehydes under strongly
protic acidic conditions is an old reaction [2] that is now emerging
as an efficient methodology for the substituted tetrahydropyrans
preparation [3,4]. In general, 2,4,6-cis all equatorial substituted
are obtained in high diastereoselectivity [4]. Rychnovsky et al.
developed the first axial-selective Prins cyclization methodology
to the heteroatom at the 4-position, expanding the synthetic scope
of this reaction [5]. In fact, selective methods for the equatorial/ax-
ial 4-position synthesis substituent via Prins cyclization are depen-
dent on the reactants, Lewis acids and experimental conditions [2].
ies from Plectranthus sylvestris (labiatae) extracts which present
potent antioxidant and anti-inflammatory properties [6]. In addi-
tion, searching online protein database (PDB) [7] revealed that
the alcohol 1 presents 100% of structural similarity with a drug
crystallized in estrogen receptor. Estrogen receptors
a (ERa) and
b (ERb) are ligand-inducible transcription factors that are involved
in regulating cell growth, proliferation, and differentiation in vari-
ous normal and cancerous tissues [8].
In connection to our interest in the biological activities com-
pounds via Prins cyclization reaction synthesis [9,10] and struc-
tural properties by theoretical knowledge [11], and
crystallographic methodologies [12,13], we report in this article
diastereoselective syntheses of five tetrahydropyran derivatives
compounds 1–5 (Fig. 1), their configurational determinations by
spectroscopy and crystallographic studies that unambiguously
determinate their preferential conformations and crystals packing
⇑
Corresponding author. Tel.: +55 83 3216 7589; fax: +55 3216 7433.
E-mail address: mlaav@quimica.ufpb.br (M.L.A.A. Vasconcellos).
0022-2860/$ - see front matter Ó 2012 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.molstruc.2012.11.044

F.P.L. Silva et al. / Journal of Molecular Structure 1036 (2013) 478–487
479
OH
O
Br
O
O
O
2
1
3
O
O
S
Cl
O
O
O
4
5
Fig. 1. Tetraydropirans derivatives 1–5, synthesized, crystallographically determined and theoretically investigated in this article.
features. Besides that, we have developed a theoretical study using
density functional theory [14,15] to obtain the optimized molecu-
lar geometries in gas phase of 1–5.
doublet of doublets; t = triplet; dt = double triplet; q = quartet;
m = multiplet. The chemical shifts (d, ppm) were reported in values
relative to tetramethylsilane (0 ppm) for 1H NMR and were re-
ported in the relative scale to CDCl3 (77.00 ppm) for 13C NMR
and coupling constants (J) were expressed in Hz. The Fourier Trans-
form Infrared Spectroscopy spectra were obtained using a spectro-
photometer IR-Prestige-21 (Shimadzu). MS data were measured
with a Shimadzu GCMS – QP2010 mass spectrometer.
2. Experimental
2.1. Chemistry
2.1.1. General methods
Commercially available reagents were purchased from Aldrich
and used without further purification. Reactions were monitored
by thin-layer chromatography (TLC) using Silica gel 60 UV254
Macherey–Nagel pre-coated silica gel plates; detection was by
means of a UV lamp and revelation to vanillin. Flash column chro-
matography was performed on 300–400 mesh silica gel. Organic
layers were dried over anhydrous MgSO4 or Na2SO4 prior to evap-
oration on a rotary evaporator. 1H and 13C NMR spectra were ob-
tained by using a Varian Mercury Spectra AC 200 (200 MHz for
1H and 50 MHz for 13C) or Varian Inova (500 MHz for 1H and
125 MHz for 13C) in CDCl3. Spectral patterns are designated as
s = singlet; d = doublet; dd = doublet of doublets; ddd = double
2.1.1.1. 1-Phenylbut-3-en-1-ol synthesis. The ( )-homoallylic alco-
hol 1-phenylbut-3-en-1-ol synthesis (Scheme 1), was performed
through a Barbier reaction. The benzaldehyde (8 mmol) was added
to water (40 mL) containing potassium iodide (24 mmol), stannous
chloride dehydrate (12 mmol) and allyl bromide (1 mL). The or-
ange solution turns white by saturated ammonium chloride addi-
tion (20 mL). The stirring was performed for 2 h at room
temperature. After the end of reaction, the reaction mixture was
extracted with CH2Cl2 (2 Â 50 mL) gave an organic phase, washed
with water, dried with sodium sulfate anhydrous, concentrated un-
der reduced pressure and purified by flash chromatography on sil-
ica gel (AcOEt:Hexane (1:9) as eluent). The product was
Scheme 1. Synthetic rotes for diastereoselective syntheses of 1–5.

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F.P.L. Silva et al. / Journal of Molecular Structure 1036 (2013) 478–487
concentrated under reduced pressure yielding 1-phenylbut-3-en-
1-ol in 97% yield. IR (KBr, cmÀ1): 3371, 3070, 3028, 2904, 1639 e
1492, 1049, 995, 914, 756, 702; 1H NMR (200 MHz, CDCl3):
d = 7.33 (m, 5H), 5.83 (m, 1H), 5.18 (m, 2H), 4.74 (t, J = 6.0 Hz,
1H), 2.53 (m, 3H); 13C NMR (50 MHz, CDCl3): d = 144.57, 135.18,
129.09, 128.22, 126.54, 119.02, 74.03, 44.49;
2.1.1.2. 2,6-Diphenyl-tetrahydro-2H-pyran-4-ol (1) synthesis. A
round bottom flash equipped with a magnetic stir bar was charged
with 0.81 mL of acetic acid, 7 mL of benzene, 4.5 mmol of 1-phe-
nylbut-3-en-1-ol and 9 mmol of benzaldehyde. The mixture was
cooled to 0 °C and after slow addition of 1.2 mL of boron trifluoride
etherate was stirred in this temperature for 3 h. Saturated NaHCO3
(10 mL) was added to the reaction media, followed by extraction
with EtOAc (3 Â 10 mL). The combined organic phase was washed
with brine (3 Â 10 mL), dried over Na2SO4, filtered and concen-
trated under vacuum. The acetylated intermediate obtained in this
reaction was dissolved in methanol (10 mL) and stirred over potas-
sium carbonate (500 mg) for 0.5 h. Then methanol was removed
under reduced pressure and water (20 mL) was added. The mixture
was extracted with AcOEt (2 Â 20 mL) and the combined organic
layers were dried over anhydrous Na2SO4 and the solvent was re-
moved under reduced pressure. The resulting crude product was
purified by column chromatography on silica gel to give compound
4-hydroxy-2,6-disubstituted tetrahydropyran in 60% yield (two
steps). IR (KBr, cmÀ1): 3263, 3032, 2947, 2858,1604, 1496, 1319,
1060,752, 694; 1H NMR (200 MHz, CDCl3): d = 7.37 (m, 10H), 4.57
(d, J = 12 Hz, 2H), 4.10 (m, 1H), 2.27 (dd, J = 12.0, 4.0 Hz, 2H), 2.12
(m, 1H), 1.60 (q, J = 12.0 Hz, 2H); 13C NMR (50 MHz, CDCl3):
d = 142.49, 128.85, 128.02, 126.39, 78.32, 69.03, 43.51.
Scheme 2. A general mechanism to obtain 1–5 cis stereoselectivity compounds
from the cyclization reactions.
O
O
X
Hb
Hb
Hc
Ha
Hc
Ha
X
2.1.1.3. 2,6-Diphenyl-tetrahydropyran-4-one (2) synthesis. 1 mmol
of 2,6-diphenyl-tetrahydro-2H-pyran-4-ol (1) was dissolved in
6 ml of dry CH2Cl2 in one round bottom flash and treated with
1 mmol of Pyridinium Chlorochromate (PCC). The stirring was
not formed
NOESY-2D
Fig. 2. General field correlation by NOESY-2D 1H NMR experiments. X = Br, Cl, OH,
C@O.
Table 1
Crystal data and structure refinement for compounds 1–5.
1
C
2
3
4
5
Molecular formula
Formula weight (g molÀ1
Temperature (K)
Wavelength (Å)
Crystal system
17H18O2
C17H16O2
252.30
298(2)
0.71073
Monoclinic
P21/n
C17H17BrO
317.21
298(2)
0.71073
Orthorhombic
Cmc21
C17H17ClO
272.76
298(2)
0.71073
Orthorhombic
Cmc21
C24H24O4S
408.50
298(2)
0.71073
Monoclinic
P21
)
254.31
298(2)
0.71073
Monoclinic
Cm
Space group
a = 17.744(1) Å
b = 21.357(1) Å
c = 5.5453(5) Å
b = 100.850(4)°
2063.9(2)
6
a = 10.5120(5) Å
b = 5.5021(2) Å
c = 23.8465(10) Å
b = 93.000(3)°
1377.35(10)
4
a = 20.748(1) Å
b = 8.4374(4) Å
c = 8.7905(5) Å
a = 21.439(1) Å
b = 8.2861(6) Å
c = 8.5582(6) Å
a = 15.0148(7) Å
b = 14.3377(6) Å
c = 20.0934(9) Å
b = 95.0294(24)°
4309.0(3)
8
Unit cell parameters
Volume (Å3)
1538.86(14)
4
1.369
1520.33(17)
4
1.192
Z
Density calculated (Mg/m3)
Absorption coefficient
1.228
0.079
1.217
0.079
1.259
0.177
2.661
0.241
(mmÀ1
)
Crystal size (mm3)
0.32 Â 0.21 Â 0.09
0.25 Â 0.20 Â 0.12
2.08–25.05
536
0.19 Â 0.10 Â 0.09
2.61–25.68
648
0.14 Â 0.11 Â 0.08
1.90–25.33
576
0.33 Â 0.13 Â 0.11
1.36–25.71
1728
h-range for data collection (°) 1.91–26.33
F(000)
816
Index ranges
À21 6 h 6 22
À26 6 k 6 26
À6 6 l 6 6
9574
À12 6 h 6 11
À6 6 k 6 6
À28 6 l 6 28
7154
À25 6 h 6 17
À10 6 k 6 9
À4 6 l 6 10
2378
À25 6 h 6 25
À9 6 k 6 9
À7 6 l 6 10
5111
À18 6 h 6 18
À17 6 k 6 17
À22 6 l 6 24
42506
Reflections collected
Independent reflections
2120
2429
1029
1209
15770
[R(int) = 0.0530]
99.7
271
[R(int) = 0.0272]
99.2
299
[R(int) = 0.0307]
94.0
91
[R(int) = 0.0393]
100.0
91
[R(int) = 0.0374]
97.8
1045
Completeness to h = 25° (%)
Parameters refined
Goodness-of-fit on F2
1.051
1.038
1.076
1.090
1.037
R1 for I > 2r(I)
0.0481
0.0546
0.0280
0.0446
0.0542
wR2 for all data
0.1184
0.1946
0.0806
0.1113
0.1629
Largest diff. peak/hole (eÅÀ3) 0.064/À0.175
0.224/À0.204
0.135/À0.182
0.194/À0.298
0.205/À0.269

F.P.L. Silva et al. / Journal of Molecular Structure 1036 (2013) 478–487
481
performed for 2.5 h at room temperature where the reaction com-
pletion was monitored by thin-layer chromatography (TLC). The
mixture was extracted with CH2Cl2 and filtered through a short
pad of silica gel with hexane and the solvent was afterwards evap-
orated, resulting in 2,6-disubstituted-tetrahydropyran-4-one (2) in
98% yield. IR (KBr, cmÀ1): 3032, 2970, 2858,1720, 1604, 1496,
1056, 1060,752, 698; 1H NMR (500 MHz, CDCl3): d = 7.40 (m,
10H), 4.85 (dd, J = 10.0, 5.0 Hz, 2H), 2.73 (m, 4H); 13C NMR
(125 MHz, CDCl3): d = 206.39, 141.10, 128.99, 128.43, 126.01,
79.31, 50.06.
2.1.1.4. 4-Bromo-2,6-diphenyl-tetrahydro-2H-pyra (3) synthesis. 1-
Phenylbut-3-en-1-ol (1 mmol) was added in a dried flask under
magnetic stirrer followed by 2 mL dichloromethane addition (dried
under calcium hydride) and benzaldehyde (1 mmol). This reaction
mixture was kept at 0 °C and then a solution of tin (IV) bromide
(SnBr4, 0.13 mL) in 1 mL dichloromethane dried was added in the
first flask. The stirring was continued for 2 h at room temperature.
After the end of reaction, 5 mL of a saturated NaHCO3 solution to
0 °C was added and agitated for 40 min. The organic phase was
separated and the aqueous phase was extracted with more AcOEt
(3 Â 5 mL). The organic phases were combined, dried with MgSO4,
and filtered. The filtrate was evaporated in vacuum. This crude
product was then submitted to flash column chromatography,
yielding
a
solid in 72% yield. IR (KBr, cmÀ1): 3035, 2947,
2858,1604, 1492,1288,756, 702, 559; 1H NMR (200 MHz,CDCl3):
d = 7.37 (m, 10H), 4.59 (dd, J = 12.0, 2.0 Hz, 2H), 4.45 (m, 1H),
2.57 (m, 2H), 2.18 (s, 2H); 13C NMR (50 MHz, CDCl3): d = 141.96,
129.19, 128.52, 126.54, 80.45, 46.95, 45.86.
2.1.1.5. 4-Chloro-2,6-diphenyltetrahydro-2H-pyran (4) synthe-
sis. Aluminum chloride (AlCl3, 1.1 mmol, 0.145 g) was added in a
dried flask under magnetic stirrer followed by 2 mL dichlorometh-
ane addition (dried under calcium hydride). After, a 1-phenylbut-
3-en-1-ol solution (1 mmol), benzaldehyde (1 mmol), in 3 mL of
dichloromethane was slowly added in the first flask at 0 °C. The
Fig. 4. An ORTEP view of two possible molecular units of 2. The labels of the
tetrahydropyran atomic fractions ending in ‘‘A’’ and in ‘‘B’’ are in 60% and 40%
occupancy sites, respectively, while C1, O1 and O2 lie in full occupancy sites. The
phenyl fractions have equal distribution over the crystal and their atoms were
refined with site occupancy factors of 50%, regardless if its label ends in ‘‘A’’ or in
‘‘B’’. For more drawing details, please see Fig. 4 caption.
Fig. 3. The ORTEP drawing of the three crystallographically independent molecules
of 1. Ellipsoids are at 50% probability level and an arbitrary labeling of atoms is
displayed. The hydrogen atoms are shown as spheres of arbitrary radii. Symme-
trycodes: (i) x; Ày; z; (ii) x; 1Ày; z.

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F.P.L. Silva et al. / Journal of Molecular Structure 1036 (2013) 478–487
mixture reaction was stirred at this temperature for 2.5 h. After the
end of reaction, 5 mL of a saturated NaHCO3 solution at 0 °C was
added. The organic phase was separated and washed with brine,
dried with Na2SO4 and evaporated under reduced pressure. This
crude product was then submitted to flash column chromatogra-
phy, yielding a solid in 70% yield. IR (KBr, cmÀ1): 3035, 2947,
2854,1604, 1492,1307,756, 690, 567; 1H NMR (200 MHz, CDCl3):
d = 7.38 (m, 10H), 4.60 (dd, J = 10.0, 2.0 Hz, 2H), 4.35 (m, 1H),
2.49 (ddd, J = 6.0, 4.0, 2.0 Hz, 2H), 2.19 (s, 1H), 1.98 (dd, J = 12.0,
2H); 13C NMR (50 MHz, CDCl3): d = 142.04, 129.17, 128.50,
126.57, 79.63, 56.37, 45.01.
monitored by thin-layer chromatography (TLC). The reaction mix-
ture was diluted with HCl-1N (25 mL) and extracted with chloro-
form (30 mL). The organic phase was separated and washed with
25 mL of saturated NaHCO3 and 25 mL of water, dried with Na2SO4
and evaporated under reduced pressure to be purified by flash
chromatography on silica gel (AcOEt:Hexane (1.5:8.5) as eluent),
resulting in 82% yield. IR (KBr, cmÀ1): 3032, 2927, 2854, 1600,
1496, 1361, 1176, 813, 756, 698; 1H NMR (500 MHz, CDCl3):
d = 7.84 (d, J = 10.0 Hz, 2H), 7.36 (m, 10H), 7.28 (d, J = 10.0 Hz,
2H), 4.99 (m, 1H), 4.56 (d, J = 10.0 Hz, 2H), 2.45 (s, 3H), 2.32 (dd,
J = 15.0, 5.0 Hz, 2H), 1.86 (dd, J = 25.0, 15.0 Hz, 2H); 13C NMR
(125 MHz, CDCl3): d = 145.15, 141.38, 134.78, 130.27, 128.78,
128.19, 127.95, 126.22, 78.64, 77.91, 40.43, 21.99;
2.1.1.6. 2,6-Diphenyl-tetrahydro-2H-pyran-4-yl 4-methylbenzenesulf-
onate (5) synthesis. A 2,6-diphenyl-tetrahydro-2H-pyran-4-ol (1)
solution (1 mmol) was prepared in dry CH2Cl2 (1.4 mL). Triethyl-
amine (Et3N, 0.3 mL) was added to this solution so that the
medium reaction was kept under magnetic stirring at 0 °C after
p-toluenesulfonyl chloride (2 mmol) was added. The solution was
stirred at room temperature and the reaction progress was
2.2. Crystallography details
Well-shaped single crystals of 1–5 were selected for the X-ray
diffraction experiment. Room temperature diffraction intensities
were measured employing Mo K
a radiation from an IlS micro-
Fig. 5. T-shaped p–p configurations and hydrogen bonding patterns in the packed crystals of compounds 1 and 2. In 1, a view of the two-dimensional layer grown onto the
(001) plane is shown. CgA, CgB and CgC denote the centroids calculated through the phenyl rings of the crystallographically independent molecules A, B and C, respectively. A
projection onto the (010) plane of 2 is shown, where Cg(C12/C13A-B) denotes the centroid calculated through the phenyl rings enclosed by either the C12A, C13A, C14A,
C15A, C16A, C17A atoms or the C12B, C13B, C14B, C15B, C16B, C17B ones. The atom labels ending in ‘‘A–B’’ means that both atomic fractions in the occupancy sites labeled as
A or B are involved in the depicted contacts.

F.P.L. Silva et al. / Journal of Molecular Structure 1036 (2013) 478–487
483
Fig. 7. T-shaped p–p configurations in the crystals packed of 3 and 4 compounds. A
view of the one-dimensional ribbons running along the [001] direction in the
isostructures of 3 and 4 is shown. Cg denotes the centroids calculated through the
phenyl ring.
Fig. 6. The ORTEP drawing of compounds 3 and 4. For more drawing details, please
see Fig. 4 caption. Symmetrycodes: (iii) 1Àx; y; z; (iv) Àx; y; z.
The crystallographic information files (abbreviated CIF) loading
the data sets (excluding the structure factors) for tetrahydropyrans
1–5 have been deposited with the Cambridge Structural Data Base
under deposit codes CCDC 902232–902236.
source with multilayer optics, using a Bruker-AXS Kappa Duo dif-
fractometer with an APEX II CCD detector. The diffraction frames
were recorded by
u and x scans using APEX2 [23], and raw dataset
treatment was performed using the SAINT and SADABS programs
[16].
2.3. Computational details
The structure was solved by direct methods with SHELXS-97
[17], wherein C, O, S, Br and Cl were readily assigned from the Fou-
rier map. The initial model was refined by the full-matrix least
squares method on F2 with SHELXL-97 [17], adopting anisotropic
thermal parameters for non-hydrogen atoms. Hydrogens were
positioned stereochemically and refined with fixed individual iso-
tropic displacement parameters [Uiso(H) = 1.2Ueq (C in methine,
methylene or aromatic groups) or 1.5Ueq (C in methyl or O in hy-
droxyl groups)] using a riding model with CAH bond lengths of
either 0.93 Å (aromatic), 0.96 Å (methyl), 0.97 Å (methylene) or
0.98 Å (methine). Hydroxyl hydrogen atoms were located in the
Fourier map and their fractional coordinates were fixed during
refinements.
Initially, Relaxed Potential Energy Surface Scan (RPESS) was
performed using GAUSSIAN 09W package [21], at semi-empirical
PM6 level, considering important rotational degrees of freedoms
for sigma bonds. For this purpose, dihedral angles were frozen in
steps of 10 and the remainder portion of molecule was optimized.
From potential energy curves for each molecule, the lowest energy
conformation was selected and submitted to a full optimization at
density functional theory (DFT) using new hybrid meta exchange–
correlation Truhlar’s functional M06-2X [22] with the complete
Pople’s 6-311++G(d,p) basis set. No imaginary frequency was
observed. Visualizations were obtained from DFT calculations in
GaussView 5 [23] through .chk file.
Compound 2 showed disordered sites for most of its atoms. It
was refined by splitting the carbon and hydrogen atoms of the pyr-
anone ring groups over two positions, the atomic fractions with
suffix A has been fixed to 60% of site occupancy, whereas the atom-
ic fractions with suffix B filled the remaining 40% occupancy. Con-
cerning the aromatic rings, two conformations with same
populations were found and their CAH atoms were refined in
50% occupancy sites. The programs MERCURY [18] and ORTEP-3
[19] were used within the WinGX [20] software package to prepare
artwork representations.
3. Results and discussion
We showed in Scheme 1 the synthetic routes used for the dia-
stereoselective preparation of 1–5 compounds. Initially the ( )-
alcohol 1-phenylbut-3-en-1-ol was prepared in high yields in an
aqueous medium from the Barbier reaction between benzaldehyde
and allyl bromide promoted by tin (II) chloride (97%). Compounds
1, 3 and 4 were prepared on total 2,4,6-axial diastereoselectivity
from Prins cyclization reaction between 1-phenylbut-3-en-1-ol

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F.P.L. Silva et al. / Journal of Molecular Structure 1036 (2013) 478–487
Fig. 8. The ORTEP drawing of the four conformers of 5. For more drawing details, please see Fig. 4 caption.
and benzaldehyde only by Lewis acid changing, in moderate to
good yields and on mild conditions (0 °C).
The 2,4,6-cis geometry determination in the compounds 1, 3
and 4 were made based on the NMR spectra of NOESY-2D (avail-
able on Supplementary information). In these spectra there is a
strong spatial coupling between the hydrogens Ha, Hb and Hc
(Fig. 2). Such coupling would not be observed if the geometry were
not on the all 2,4,6 cis. Ketone 2 shows a strong correlation be-
tween the hydrogens Ha and Hc, confirming the cis geometry on
carbons attached to aromatic rings.
Even though the spectroscopic analysis has defined the cis con-
figuration of compounds 1, 3, 4 and 5 by 2D-NOESY, the crystallo-
graphic study was essential to conformational preferences
determinations of these compounds. Crystal data of compounds
1–5 and structure refinement statistics are shown in Table 1.
Compound 1 crystallizes in the monoclinic space group Cm with
half of three molecules in the asymmetric unit (Fig. 3). These mol-
ecules also reside on mirror planes at either (x, 0, z) (molecules A
and B) or (x, 1/2, z) (molecule C), with the hydroxyl atoms, the
neighboring methine group and the endocyclic oxygen staying on
Some mechanistic proposals have been described to explain the
high selectivity of 2,4,6-cis in the Prins reaction . Based on the most
commonly accepted reaction mechanism explaining the 2,4,6-cis
preferential geometry for this reaction, proposed by Li and Yang
et al. [24], we propose a general mechanism in Scheme 2. The
mechanism begins with the nucleophilic attack of alcohol a on
the complexed aldehyde-Lewis acid (LA) (step 1) leading to inter-
mediate b formation. Step 2 is a proton exchange followed by elim-
ination (step 3) with intermediate d formation. The step 4 (slow
step) subsequently occurs by synchronously nucleophilic attack
through the transition state e, which produce f. It should be noted
that the nucleophilic attack on step d occurs preferentially on
equatorial position which is a more stable transition state. Another
proposal explaining the equatorial stereoselectivity on C4 of tetra-
hydropyran derivatives was based on the theoretical studies by Al-
der et al. [25].

F.P.L. Silva et al. / Journal of Molecular Structure 1036 (2013) 478–487
485
the symmetry element. The tetrahydropyran ring of the three mol-
ecules assumes a chair conformation, with C1 and O1 atoms far
away from the least-squares planes through the other four copla-
nar atoms, but the benzene conformation differs for the conform-
ers A–C. The least-squares planes through the phenyl rings form
angles of 64.5 (1)°, 64.9 (1)° and 48.7 (1)° in molecules A, B and
C, respectively.
Likewise, the torsions on the bridge bond between the tetrahy-
dropyran and phenyl rings describe the conformational difference
for molecules A and B, since the bends between their phenyl moi-
eties were similar. For instance, the C2AC3AC4AC5 dihedral angle
measures 177.9 (3)° and 114.9 (3)° in the conformers A and B,
respectively. In its crystal assembly, the three molecules are in-
volved in classical O2AH2Á Á ÁO1 hydrogen bonds, all of the three
acting as hydrogen bonding acceptor and donor. In addition to
atom residing on the symmetry element. These two compounds
are isostructural, with similar conformations and crystal packing
features. The six-membered tetrahydropyran ring adopts a chair
conformation in both halogenated analogues, as those of com-
pounds 1 and 2 (major tetrahydropyran conformation). The ben-
zene conformation is also resembled in both compounds, with
the least-squares planes through the phenyl rings forming angles
of 33.5 (2)° and 34.2 (2)° in 3 and 4, respectively. Moreover, their
crystal packing is stabilized by the non-classical hydrogen bonding
through the C1AH1Á Á ÁO1 atoms and by the face-to-edge
C5AH5Á Á Áp interaction involving the phenyl rings of neighboring
molecules on a T-shaped phenyl rings interaction (Fig. 7).
Compound 5 is the most conformationally flexible compound
among all tetrahydropyran derivatives studied here. There are four
conformers (labeled A–D) in the asymmetric unit (Fig. 8), all of
them with R and S absolute configurations in their C3 and C11
asymmetry centers and chair conformation of the heterocycle as
described for the other analogues. The phenyl ring adopts different
conformations in the crystallographically independent molecules,
with the least-squares planes through the aromatic ring varying
from 6.4 (2)° in conformer A to 51.9 (2)° in conformer C. However,
an interesting conformational feature of the conformers resides in
a rotation on the S1AO2 bond axis that sets the para-tosyl moiety
in different conformations (Fig. 8). Concerning this moiety geome-
try, conformers A and C are resembled, with, for instance, the dihe-
dral angle C1AO2AS1AC18 measuring 68.8 (3)° and 69.7 (3)°,
respectively. Meanwhile, conformers B and D are present with sim-
ilar para-tosyl conformations (the corresponding torsion angles are
À70.8 (3)° and À69.6 (3)° in molecules B and D) that differ almost
specularly from those of the conformers A and B. Its crystal packing
the classical hydrogen bonds, face-to-edge CAHÁ Á Á
also occur in this structure. In 1, C7AH7 moieties of molecules A,
B and C interact with the phenyl -systems of the conformers C,
p interactions
p
A and B, respectively. Compound 2 exhibited a classical orienta-
tional disorder with different conformer populations. The major
enantiomer in the chosen asymmetric unit, which is present with
R and S relative configurations of their C3A and C11A asymmetry
centers, had a 60% population and the labels of its tetrahydropyran
atomic fractions end in ‘‘A’’, except the C1, O1, and O2 atoms that
had 100% occupancy in their only corresponding sites belonging to
both major and minor enantiomers (Fig. 4). In other words, the tet-
rahydropyran rings of the two enantiomers were superimposed
through the carbonyl moiety and the heteroatom. Concerning the
minor enantiomer, its C3B and C11B carbons are present with S
and R relative stereochemistry, respectively, and its tetrahydropy-
ran atom fractions are in 40% occupancy sites labeled as ‘‘B’’. Differ-
ent tetrahydropyran conformations were observed for compound
2. A slightly distorted chair conformation similar to that of com-
pound 1 is observed for the major enantiomer in the chosen asym-
metric unit, being therefore the preferred tetrahydropyran
conformation through the crystal lattice of 2. On the other hand,
tetrahydropyran moiety of the minor enantiomer adopts a twist
conformation with the C2BAC1AC10BAC11B forming a plane from
which C3B and O1 deviate to the opposite sites at distances of
À0.643(6) Å and 0.140(1) Å, respectively. Both phenyl moieties
also showed disordered sites for their CAH groups. For each phenyl
moiety, two conformations of equal population were superim-
posed through the carbon bonded to tetrahydropyran heterocycle.
These carbons, namely, C4 and C12 lie in 100% occupancy sites,
while the other phenyl carbon and hydrogen fractions had a site
occupancy factor of 50%. Therefore, four phenyl conformations
are identically distributed over the crystal lattice of compound 2.
In that, the least-squares planes through the phenyl fractions hav-
ing as the common atom either C4 or C12 form similar angles of
28.5 (3)° and 27.8 (3)°, while this measurement is 65.4 (3)°, 86.8
(2)°, 82.9 (3)° and 72.3 (3)° between the phenyl rings enclosed
by C4/C5A and C12/C13A, C4/C5A and C12/C13B, C4/C5B and
C12/C13A, C4/C5B and C12/C13B, respectively. Several non-classi-
cal hydrogen bonding contacts of the type CAHÁ Á ÁO having the car-
bonyl O2 oxygen and CH2 moieties of tetrahydropyran from both
enantiomers as acceptor and donor groups, respectively, stabilize
the crystal packing of this compound together with face-to-edge
is stabilized by many contacts of the types CAHÁ Á ÁO and CAHÁ Á Á
p.
Methyl moieties of para-tosyl are involved only in the last contacts.
The geometric parameters of the intermolecular contacts support-
ing the crystal packing description for compounds 1–5 are pre-
sented in Table 2.
Table 2
Geometry (Å, °) of the main intermolecular contacts present in the structures of 1–5.
Compound DAHÁ Á ÁAa
1
DAH HÁ Á ÁA DÁ Á ÁA
DAHÁ Á ÁA
O2AAH2AÁ Á ÁO1Cb
1.05
0.90
0.95
0.93
0.93
0.93
2.22
2.28
2.14
3.37
3.10
3.01
2.980(6) 128
O2BAH2BÁ Á ÁO1A
O2CAH2CÁ Á ÁO1Bc
C7AAH7AÁ Á ÁCgC
C7BAH7BÁ Á ÁCgAd
C7CAH7CÁ Á ÁCgB
2.954(5) 131
2.788(4) 125
4.057(4) 133
3.892(4) 145
3.909(4) 164
2
3
C15AAH15AÁ Á ÁO2e
0.93
0.93
0.93
0.93
2.61
2.92
3.16
3.24
3.52(2)
3.64(2)
3.82(2)
3.99(2)
167
135
129
139
C15BAH15BÁ Á ÁO2e
C7AAH7AÁ Á ÁCg12/13Af
C7BAH7BÁ Á ÁCg12/13Bf
C1AH1Á Á ÁO1g
C5AH5Á Á ÁCgg
0.98
0.93
2.51
3.11
3.470(6) 168
4.027(6) 168
4
5
C1AH1Á Á ÁO1h
C5AH5Á Á ÁCgh
C23AAH23AÁ Á ÁO2B
C23BAH23BÁ Á ÁO2A
C24AAH24CÁ Á ÁCg18/
19D
0.98
0.93
2.51
2.82
3.476(3) 171
3.721(4) 163
0.93
0.93
0.96
2.57
2.64
2.89
3.301(8) 136
3.384(6) 138
3.826(6) 167
CAHÁ Á Á
C5A-B (CAH) and C12/C13A-B (
configurations in the crystals packing of 1 and 2 compounds
were presented in Fig. 5.
Compounds 3 and 4 have crystallized in the orthorhombic space
group Cmc21 with half molecule in their asymmetric units. In the
chosen asymmetric units, the molecules of 3 and 4 (Fig. 6) sits on a
mirror plane at (1/2, y, z), with the halogen, the carbon bonded to
it, the methine hydrogen bonded to that carbon, and the oxygen
p
interactions between the phenyl rings enclosed by C4/
C24CAH24FÁ Á ÁCg18/19B
0.96
0.96
2.88
3.07
3.776(6) 155
3.924(9) 149
C24CAH24DÁ Á ÁCg4/5A
p-system). The several T-shaped
a
b
c
p-p
D – hydrogen donor; A – hydrogen acceptor. Symmetry operators.
0.5+x, À0.5+y, z.
0.5+x, 0.5+y, 1+z.
À0.5+x, 0.5Ày, z.
0.5+x, 0.5Ày, 0.5+z.
1.5Àx, 0.5+y, 0.5Àz.
x, 1Ày, 0.5+z.
d
e
f
g
h
x, 1Ày, À0.5+z.

486
F.P.L. Silva et al. / Journal of Molecular Structure 1036 (2013) 478–487
Fig. 9. Conformational minima geometries calculated by 1–5 using M06-2X/6-311++G(d,p) as calculation level.
Based on what was reported in this article, we conclude the
Appendix A. Supplementary material
great importance of the relative T-shaped geometries between
the aromatic rings for the stability of these crystals packing fea-
tures in 1–5 studied compounds (e.g. see Figs. 6 and 8).
Furthermore, the theoretical conformational studies were per-
formed by M06-2X hybrid functional [22], which is described to
be efficient to accurately measure of London dispersion interaction.
After complete 1–5 structures optimization, the geometries of min-
ima are obtained and it was detached in Fig. 9.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.molstruc.2012.11.
044.
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