Solvent-free catalysed synthesis of tetrahydropyran odorants: The role of SiO2·p-TSA catalyst on the Prins-cyclization reaction

Article abstract of DOI:10.1590/S0103-50532010000800023

An efficient, green and solvent-free catalysed Prins-cyclization reaction based on the simple grinding of an aldehyde and a homoallylic alcohol in the presence of catalytic amount of p-TSA on silica gel is reported. By this protocol were synthesized tetrahydropyran odorants including commercial Florol^? and Clarycet^?, in one and two steps respectively.

Full text of DOI:10.1590/S0103-50532010000800023

J. Braz. Chem. Soc., Vol. 21, No. 8, 1563-1571, 2010.
Printed in Brazil - ©2010 Sociedade Brasileira de Química
0103 - 5053 $6.00+0.00
Solvent-free Catalysed Synthesis of Tetrahydropyran Odorants: the Role of
•
SiO2 p-TSA Catalyst on the Prins-Cyclization Reaction
Alexandra Macedo,a Edison P. Wendler,a Alcindo A. Dos Santos,*,b
c
,a
Julio Zukerman-Schpector* and Edward R. T. Tiekink
aDepartamento de Química, Universidade Federal de São Carlos, Rod. Washington Luís km 235,
13565-905 São Carlos-SP, Brazil
bInstituto de Química, Universidade de São Paulo, Av. Prof. Lineu Prestes 748,
05508-000 São Paulo-SP, Brazil
cDepartment of Chemistry, University of Malaya, 50603
Kuala Lumpur, Malaysia
Foi desenvolvido um procedimento eficiente e ecologicamente amigável para a promoção da
ciclização de Prins em ausência de solventes orgânicos baseado na maceração de um aldeído e
um álcool alílico em presença de quantidade catalítica de p-TSA disperso em sílica gel. Por esse
procedimento foram sintetizadas as fragrâncias comerciais Florol® e Clarycet®, em uma e duas
etapas sintéticas respectivamente.
An efficient, green and solvent-free catalysed Prins-cyclization reaction based on the simple
grinding of an aldehyde and a homoallylic alcohol in the presence of catalytic amount of p-TSA
on silica gel is reported. By this protocol were synthesized tetrahydropyran odorants including
commercial Florol® and Clarycet®, in one and two steps respectively.
Keywords: Prins-cyclisation, solvent-free catalysis, green chemistry, tetrahydropyrans,
fragrances
Introduction
both odorants were prepared by an enzymatic approach in
6 sequential steps in very low yields.4
The Prins-cyclization reaction is one of the most efficient
strategies to construct the tetrahydropyran core,1 which
is present in several natural products.2 Some non-natural
compounds possessing this functionality were found to be
of commercial interest by the perfume industry. Clarycet®
(commercialized by IFF) and Florol® (commercialized by
Firmenich) are floral odorants handled in the industry as a
racemic diastereoisomeric mixture which can be used in
a large number of fragrances and formulations conferring
floral scents without changing the olfactory character of the
perfume.3,4 So far as we know, there are only two works in
the literature describing the synthesis of both, Clarycet®4
and Florol®. In one of these works, racemic Florol® was
synthesized in 44% overall yield from geraniol/nerol mixture
in 5 sequential steps. All enantioenriched stereoisomers of
With the recent increase of environmental awareness
and subsequent development of “green-chemistry”
principles, several guidelines for the production of
chemicals by cleaner and benign procedures are being
established as crucial for the modern chemical industry
processes. One of the most important requirements in this
context is the development of alternative synthetic routes
aimed at minimizing or substituting mineral solvents by
more benign solvents such as water, acetone, ethanol, ethyl
acetate, etc.5 Further, emerging solvent-free processes and
the utilization of solid matrices that can act as dispersing
agents or as catalysts that is attracting attention.6
In this work, a one-pot procedure for the construction of
the tetrahydropyran core of the floral odorants, Clarycet®,
Florol® and other two not yet commercially utilized
octahydro-2H-chromen-4-ols7 using a solvent-free solid
phase catalysed Prins-cyclization reaction is presented.
*e-mail: alcindo@iq.usp.br

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Solvent-free Catalysed Synthesis of Tetrahydropyran Odorants
J. Braz. Chem. Soc.
Results and Discussion
by the formation of a black colour and the title compound
was produced in low yield among many other by-products.
Other solid matrices (neutral, acid and basic aluminium
oxide, Celite® as well Montmorillonite K10) were also
investigated as partners of p-TSA in the reaction of 3 with 4
and failed to produce 5 in good yields and synthetic useful
reaction time in comparison with SiO2. These experiments
allow us to conclude that SiO2 in association with p-TSA
acts as catalyst and not only as a dispersant agent. In this
way, were adopted the reaction conditions presented in
Scheme 2, as the ideal system for the preparation of the
Prins adducts by a solvent-free protocol in the reaction of
the alcohol 3 with other aldehydes as presented in Scheme
3 and summarized in Table 1.
In all cases the tetrahydropyran derivatives were
formed, as a diastereoisomeric mixture, in reasonable to
good yields by the simple grinding of the reagents in a
mixture of silica gel and catalytic amount of p-TSA. While
aldehydes 6a, 6c and 6g, as well as benzaldehyde 4, were
converted to the corresponding products in good yields in
only 5 min of reaction (entries 1, 3, 7 and Scheme 2), the
aromatic 6b, 6d, cycloalkyl 6f and alkenyl 6h aldehydes
required a longer reaction time for conversion to the
corresponding products (entries 2, 4, 6 and 8). Aldehyde
6e required 25 min to be converted into the product 7e in
69% yield (entry 5).
This proposition was based on previous work related to
thesolvent-freesolidphasecatalysedtetrahydropyranylation
of alcohols and thiols.8 Earlier, it was observed that
citronellal can be converted, in 91% isolated yield, into
iso-pulegol within 2 min by an intramolecular ene-type
reaction. The reaction proceeds by grinding it in a mixture
of silica gel with catalytic amount of p-toluenosulfonic acid
(p-TSA) according to Scheme 1.
.
SiO2 p-TSA
CHO
grinding
2 min
OH
1: (+)-citronellal
2: iso-pulegol (91%)
Scheme 1. Synthesis of iso-pulegol by catalytic system.
This result stimulated the application of similar reaction
conditions in the preparation of tetrahydropyran derivatives
by the intermolecular version of the Prins-cyclization
reaction and studies related of conformational features of
three tetrahydropyrans.9 A detailed stoichiometric screen
showed that a physical mixture of p-TSA (0.29 mmol) in
silica gel (0.5 g) was the best dispersant/catalyst system in
the conversion of 3-methyl-but-3-en-1-ol (3, 1 mmol) and
benzaldehyde (4, 1.1 mmol) in the corresponding Prins
adduct 5, (syn:anti, 63:37) in 88% isolated yield, after
5 min grinding as presented in Scheme 2.
The structure of the tetrahydropyran derivative 7f
(major diastereoisomer) was subsequently confirmed to
have the syn relation, by a single-crystal X-ray structure
determination, as shown in Figure 1.10
OH
PhCHO (4)
.
OH
SiO2 p-TSA
3
5 min
O
Ph
5: 88% (63:37)
syn : anti
Scheme 2. Synthesis of model compound 5.
Figure 1. Molecular structure of 7f determined by X-ray crystallography.
In order to investigate the role of the SiO2/p-TSA
mixture, both components of this catalytic system, SiO2
and p-TSA, were investigated separately in the reaction of
3 with 4. SiO2 only did not display any catalytic behaviour
even at long reaction times. On the other hand when
sub-stoichiometric amount of p-TSA was put together
with 3 and 4 in absence of solvents, a very vigorous and
exothermic reaction took place accompanied by partial
carbonization of the components of the mixture, evidenced
The major diastereoisomer of 7h was submitted to nOe
experiment and the syn relation was confirmed, as show
in Figure 2.
The strong 1D nOe for methyl group and carbinolic
hydrogen provided unquestionable proof for the assigned
syn relation. On the basis of nOe experiment acquired for
compound 7h, the relation of the others tetrahydropyrans
5, 7a-g was similarly assigned.

Vol. 21, No. 8, 2010
Macedo et al.
1565
With the reaction conditions established, this method
procedure 87%, 15 min) and Clarycet® (12) by reacting
alcohol 3 with the appropriate aldehydes (8 and 9,
respectively), and two other odorants of commercial
interest5 (15 and 16) by reacting iso-pulegol 2 with
aldehydes 13 and 14, respectively (Scheme 4).
was applied to the synthesis of Florol® (11, in a one-pot
OH
OH
O
3
Despite the low yield of 15 (49%), due the high
volatility of aldehyde 13, since the reactions were conduced
by grinding the reagents in an open mortar, the synthesis
can be considered attractive since it can be performed in a
single step and by a solvent-free procedure.
.
SiO2 p-TSA
R
H
O
R
6a-h
7a-h
Scheme 3. Reaction of different aldehydes with compound 3.
Table 1. Prins-cyclization reaction of 3 with aldehydes 6a-h
Entry
1
Aldehyde Structure
Compounds
Productsa
time (min)b
5
Yield %c (syn:anti)d
6a
7a
91 (64:36)
2
3
4
6b
6c
6d
7b
7c
7d
10
5
67 (20:80)
89 (30:70)
70 (55:45)
40
5
6
6e
6f
7e
7f
25
60
69 (60:40)
71 (62:38)
7
8
6g
6h
7g
7h
5
62 (40:60)
58 (71:29)
10
aCompounds 7a-h as well a 5, were formed as a diastereisomeric mixture; btotal grinding time; cisolated yields; dGC-FID and nOe experiments were used
to determine the syn:anti ratio.
irradiation
nOe
Me
OH
HO
H
H
O
HO
7h
O
O
H
H
syn diastereoisomer
nOe
(2S,4R) + (2R, 4S) - 7h
Figure 2. Relative stereochemistry of 7h determined by nOe experiments.

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Solvent-free Catalysed Synthesis of Tetrahydropyran Odorants
J. Braz. Chem. Soc.
OH
OAc
OH
H
3
.
SiO2 p-TSA
Ac2O/Py
R
R
+
grinding
R
O
O
O
12, R = H: Clarycet
10, R = H (35 min, 61%)
11, R = Me: Florol
(90%)
8, R = H
9, R = Me
(15 min, 87%)
O
15, R = H (49%)
16, R = Me (66%)
.
SiO2 p-TSA
H
+
O
grinding
R
OH
13, R = H
14, R = Me
2
HO
R
Scheme 4. Application of SiO2.p-TSA system on synthesis of odorants with commercial interest.
Conclusion
were visualized by exposure to ultraviolet light (254 nm)
and/or by immersion in an acidic staining solution of
p-anisaldehyde followed by heating on a hot plate. Organic
solutions were concentrated by rotary evaporation at ca. 30-
100 mmHg. Flash column chromatography was performed
on Fluka silica gel 60 (220-440 mesh).10 Solvents used were
of commercial grade and were previously treated according
to the literature.11
In conclusion, a one-pot strategy has been developed
and applied to the synthesis of three important odorants:
Florol® and compounds 15 and 16. The synthesis of
Clarycet® was accomplished by a usual acetylation of the
Prins adduct 10, with 55% overall yield. The great appeal
of this procedure is found in its operational practicality,
since the simple mixture of the reagents in a mortar
allows the preparation of the target compounds in a few
minutes. Currently, some variants of this protocol are
under investigation aimed towards the total synthesis of
industrially important compounds.
General Procedure
In a mortar containg silica gel (200-400 mesh) (0.5 g,
8.33 mmol) and p-toluenesulfonic acid (0.05 g, 0.29 mmol)
was added the aldehyde (1 mmol) and homoallylic alcohol
(1.1 mmol). The resulting mixture was ground for the
appropriate time and the reaction was monitored by thin
layer chromatography. The reaction media was directly
purified by column chromatography by elution with
appropriate mixture of solvents.
Experimental
General
Thefollowingincludesgeneralexperimentalprocedures,
specific details for representative reaction, and isolation
and spectroscopic information for the new compounds
(5R)-5-Methyl-2-(prop-1-en-2-yl)cyclohexanol (2)
The product was analysed by CG-FID and compared
with commercial standard of iso-pulegol purchased from
Aldrich Chemical Company (Milwaukee,Wisconsin, USA)
(CAS 628693-74-3).
1
prepared. H and 13C NMR spectra were recorded on
a Bruker DRX-400 400 MHz. Infrared spectra were
recorded on a FT-IR Bomem-Hartman & Braun MB-102.
Low resolution mass spectra were obtained on a GC-17A
Shimadzu, equipped with HP-5MS column (5% phenyl /
95% dimethyl polysiloxane, 30 m × 0.25 mm × 0.25 mm),
coupled with a GCMS-QP5000 Shimadzu (70 eV).
High resolution mass spectra were obtained on a
LC-MS Bruker Daltonics MicroTOF Ic by direct infusion.
Analyticalthin-layerchromatography(TLC)wasperformed
on glass plates coated with 0.50 mm 230-400 mesh silica
gel containing a fluorescent indicator (Merck). TLC plates
4-Methyl-2-phenyltetrahydro-2H-pyran-4-ol (5)
Syn diastereoisomer: Eluent: hexane/ethyl acetate (1:1),
1
Rf 0.66; colorless oil, yield 55%; H NMR (400 MHz,
CDCl3) d 1.45 (s, 3H), 1.66 (s, OH), 1.68 (dq, J1 12.94 Hz,
J2 2.39 Hz, 1H), 1.72-1.86 (m, 2H), 1.89 (dt, J1 12.94 Hz,
J2 2.39 Hz, 1H), 3.62 (td, J1 12.48 Hz, J2 2.31 Hz, 1H), 4.13
(ddd, J1 11.86 Hz, J2 5.24 Hz, J3 1.69 Hz, 1H), 4.36 (dd,

Vol. 21, No. 8, 2010
Macedo et al.
1567
J1 11.86 Hz, J2 2.31 Hz, 1H), 7.23-7.37 (m, 5H);13C NMR
(100 MHz, CDCl3) d 25.3, 40.1, 48.4, 66.0, 69.2, 77.7,
125.9, 127.6, 128.5, 142.1. (CAS 63500-72-1).
Anti diastereoisomer: Eluent: hexane/ethyl acetate (1:1),
Rf0.81;colorlessoil,yield33%;1HNMR(400MHz,CDCl3)
d 1.29 (s, 3H), 1.49-1.56 (m, 2H), 1.64 (dd, J1 13.71 Hz,
J2 11.71 Hz, 1H), 1.73-1.83 (m, 2H), 3.90-4.03 (m, 2H),
4.70 (dd, J1 11.71 Hz, J2 2.31 Hz, 1H), 7.21-7.43 (m, 5H);
13C NMR (100 MHz, CDCl3) d 31.8, 38.5, 46.6, 64.1, 68.1,
75.2, 125.9, 127.4, 128.4, 142.8. (CAS 63500-72-1).
1080, 1047, 1013, 939, 899, 506 (film);1H NMR (400 MHz,
CDCl3) d 1.39 (s, 3H), 1.56-1.86 (m, 4H), 3.63 (td, J1 12.07
Hz, J2 2.25 Hz, 1H), 4.01 (ddd, J1 12.07 Hz, J2 5.30 Hz,
J3 2.25 Hz, 1H), 4.31 (dd, J1 12.07 Hz, J2 2.25 Hz, 1H),
6.74 (dt, J1 8.59 Hz, J2 1.95 Hz, 2H), 7.16 (dt, J1 8.59 Hz,
J2 1.95 Hz, 2H);13C NMR (100 MHz, CDCl3) d 25.2, 41.1,
49.1, 66.8, 69.5, 78.8, 116.1, 128.5, 134.6, 158.0; MS:
m/z 208 (M+, 2%), 190 (8), 175 (29), 161 (1), 137 (3), 121
(70), 119 (28), 91 (32), 77 (38), 71 (75), 58 (100); HRMS
[M-Na+] Found: 231.0992. Calc. for C12H16O3: 231.0997.
Anti diastereoisomer: Eluent: hexane/ethyl acetate (1:1),
Rf 0.49; white solid, yield 54%, m.p. 194 °C; IR nmax/cm-1
3467, 2920, 2899, 2855, 1671, 1615, 1518, 1466, 1373,
(E)-4-Methyl-2-styryltetrahydro-2H-pyran-4-ol (7a)
Syn diastereoisomer: Eluent: hexane/ethyl acetate (1:1),
Rf 0.56; colorless oil, yield 58%; IR nmax/cm-1 3431, 2969,
2935, 2851, 1713, 1599, 1494, 1449, 1377, 1250, 1174,
1104, 965, 935, 880, 818, 753, 738, 693 (film); 1H NMR
(400 MHz, CDCl3) d 1.39 (s, 3H), 1.60 (t, J 12.87 Hz, 1H),
1.64 (dq, J1 12.87 Hz, J2 2.22 Hz, 1H), 1.77 (td, J1 12.87 Hz,
J2 5.08 Hz, 1H), 1.81 (dt, J1 12.87 Hz, J2 2.22 Hz, 1H), 2.05
(s, OH), 3.55 (td, J1 12.23 Hz, J2 2.38 Hz, 1H), 4.02 (ddq,
J1 12.23 Hz, J2 5.88 Hz, J3 1.43 Hz, 1H), 4.06 (ddd,
J1 12.23 Hz, J2 5.08 Hz, J3 2.22 Hz, 1H), 6.19 (dd, J1
16.05 Hz, J2 5.88 Hz, 1H), 6.61 (dd, J1 16.05 Hz, J2 1.43 Hz,
1H), 7.20-7.39 (m, 5H); 13C NMR (100 MHz, CDCl3)
d 25.4, 40.3, 46.5, 65.3, 68.8, 75.8, 126.5, 127.7, 128.6,
129.7, 130.5, 136.7; MS: m/z 218 (M+, 34%), 204 (2), 200
(38), 185 (57), 171 (2), 148 (19), 147 (100), 129 (65), 115
(57), 104 (44), 91 (57), 71 (72), 55 (27); HRMS [M-Na+]
Found: 241.1199. Calc. for C14H18O2: 241.1204.
Anti diastereoisomer: Eluent: hexane/ethyl acetate
(1:1), Rf 0.73; colorless oil, yield 33%; IR nmax/cm-1 3430,
2943, 2919, 2855, 1674, 1603, 1518, 1458, 1381, 1281,
1124, 1088, 1035, 935, 886, 818, 741, 637 (film); 1H NMR
(400 MHz, CDCl3) d 1.29 (s, 3H), 1.49 (dq, J1 12.94 Hz,
J2 2.31 Hz, 1H), 1.51 (dd, J1 13.56 Hz, J2 11.51 Hz, 1H),
1.66-1.76 (m, 2H), 1.89 (s, OH), 3.89 (td, J1 11.40 Hz,
J2 2.15 Hz, 1H), 3.90 (dd, J1 7.24 Hz, J2 1.85 Hz, 1H), 4.35
(ddq, J1 11.40 Hz, J2 6.01 Hz, J3 1.54 Hz, 1H), 6.17 (dd,
J1 16.02 Hz, J2 6.01 Hz, 1H), 6.61 (dd, J1 16.02 Hz,
J2 1.54 Hz, 1H), 7.18-7.40 (m, 5H); 13C NMR (100 MHz,
CDCl3) d 31.7, 38.3, 44.7, 63.5, 67.7, 73.4, 126.3, 127.4,
128.4, 130.1, 130.2, 136.9; MS: m/z 218 (M+, 20%), 207
(3), 200 (24), 185 (42), 171 (3), 148 (19), 147 (100), 129
(85), 115 (60), 104 (43), 91 (63), 71 (82), 55 (49); HRMS
[M-Na+] Found: 241.1200. Calc. for C14H18O2: 241.1204.
1
1261, 1084, 1039, 1007, 902, 830, 737 (KBr); H NMR
(400 MHz, CDCl3) d 1.25 (s, 3H), 1.52 (dq, J1 13.84 Hz,
J2 1.69 Hz, 1H), 1.62 (dd, J1 13.70 Hz, J2 11.30 Hz, 1H),
1.65-1.74 (m, 3H), 3.86 (ddd, J1 11.30 Hz, J2 5.22 Hz,
J3 1.13 Hz, 1H), 3.94 (td, J1 11.30 Hz, J2 2.40 Hz, 1H), 4.61
(dd, J1 11.30 Hz, J2 2.40 Hz, 1H), 4.86 (s, OH), 6.74 (dt, J1
8.61 Hz, J2 1.97 Hz, 2H), 7.16 (dt, J1 8.61 Hz, J2 1.97 Hz,
2H); 13C NMR (100 MHz, CDCl3) d 31.6, 39.1, 47.1, 65.2,
68.5, 76.6, 116.1, 128.6, 134.8, 157.9; MS: m/z 208 (M+,
11%), 190 (36), 176 (12), 175 (100), 161 (2), 137 (5), 121
(81), 119 (22), 91 (19), 71 (37), 58 (43); HRMS [M-Na+]
Found: 231.0991. Calc. for C12H16O3: 231.0997.
2-(4-Methoxyphenyl)-4-methyltetrahydro-2H-pyran-4-ol
(7c)
Syn diastereoisomer: Eluent: hexane/ethyl acetate (2:1),
Rf 0.31; colorless oil, yield 27%; IR nmax/cm-1 3426, 2948,
2915, 2847, 1614, 1587, 1518, 1470, 1377, 1249, 1176,
1080, 1031, 942, 898, 830, 770, 737, 605 (film); 1H NMR
(400 MHz, CDCl3) d 1.43 (s, 3H), 1.66 (qd, J1 12.87 Hz,
J2 2.38 Hz, 1H), 1.70-1.88 (m, 4H), 1.95 (s, OH), 3.61
(td, J1 12.87 Hz, J2 1.74 Hz, 1H), 3.79 (s, 3H), 4.10 (ddd,
J112.08Hz, J2 5.24Hz, J3 1.74Hz, 1H), 4.30(dd, J1 12.08Hz,
J2 1.74 Hz, 1H), 6.87 (dt, J1 8.74 Hz, J2 2.06 Hz, 2H), 7.27
(dt, J1 8.74 Hz, J2 2.06 Hz, 2H);13C NMR (100 MHz, CDCl3)
d 25.2, 40.3, 48.1, 55.2, 65.8, 69.1, 77.2, 113.7, 127.2, 134.2,
159.0;MS:m/z222(M+, 16%), 204(30), 190(13), 189(100),
173 (5), 151 (6), 135 (95), 133 (23), 119 (18), 92 (10), 91
(26), 71 (46), 58 (31); HRMS [M-Na+] Found: 245.1152.
Calc. for C13H18O3: 245.1154.
Anti diastereoisomer: Eluent: hexane/ethyl acetate (2:1),
Rf 0.46; white solid, yield 62%, m.p. 82 °C; IR nmax/cm-1
3422, 2947, 2919, 2843, 1611, 1518, 1462, 1377, 1249,
1176, 1144, 1084, 1035, 943, 898, 830, 766, 605 (film);
1H NMR (400 MHz, CDCl3) d 1.27 (s, 3H), 1.50 (dq,
J1 13.82 Hz, J2 2.22 Hz, 1H), 1.59-1.81 (m, 4H), 3.78 (s,
3H), 3.92-3.98 (m, 2H), 4.64 (dd, J1 11.44 Hz, J2 2.54 Hz,
1H), 6.86 (dt, J1 8.74 Hz, J2 2.06 Hz, 2H), 7.26 (dt,
2-(4-Hydroxyphenyl)-4-methyltetrahydro-2H-pyran-4-ol
(7b)
Syn diastereoisomer: Eluent: hexane/ethyl acetate (1:1),
Rf 0.22; colorless oil, yield 13%; IR nmax/cm-1 3363, 2940,
2861, 1614, 1518, 1443, 1377, 1250, 1225, 1170, 1143,

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Solvent-free Catalysed Synthesis of Tetrahydropyran Odorants
J. Braz. Chem. Soc.
J1 8.74 Hz, J2 2.06 Hz, 2H); 13C NMR (100 MHz, CDCl3)
d 31.8, 38.4, 46.4, 55.3, 64.1, 68.1, 74.9, 113.9, 127.5,
135.0, 159.1; MS: m/z 222 (M+, 15%), 204 (29), 190 (13),
189 (100), 173 (4), 151 (5), 135 (86), 133 (23), 109 (15),
92 (9), 91 (21), 71 (37), 58 (27); HRMS [M-Na+] Found:
245.1156. Calc. for C13H18O3: 245.1154.
12.02 Hz, J2 5.24 Hz, J3 1.54 Hz, 1H), 4.31 (dd, J1 12.02 Hz,
J2 1.54 Hz, 1H), 7.18 (t, J1 7.70 Hz, 1H), 7.24 (dt, J1 7.70 Hz,
J2 1.54 Hz, 1H), 7.38 (dt, J1 7.70 Hz, J2 1.54 Hz, 1H), 7.50
(t, J1 1.54 Hz, 1H); 13C NMR (100 MHz, CDCl3) d 25.2,
40.1, 48.3, 65.8, 69.0, 76.8, 122.5, 124.4, 129.0, 129.9,
130.6, 144.4; MS: m/z 272 (M++2, 2%), 254 (22), 237 (49),
227 (2), 209 (1), 199 (1), 185 (35), 173 (6), 157 (13), 145
(6), 128 (7), 115 (5), 103 (37), 78 (16), 71 (90), 58 (100);
HRMS [M-Na+] Found: 293.0146. Calc. for C12H15BrO2:
293.0153.
Anti diastereoisomer: Eluent: hexane/ethyl acetate (3:1),
Rf 0.28; colorless oil, yield 28%; IR nmax/cm-1 3467, 3067,
2969, 2919, 2873, 1713, 1596, 1568, 1477, 1361, 1261,
1044, 984, 925, 864, 816, 783, 739, 692 (film); 1H NMR
(400 MHz, CDCl3) d 1.26 (s, 3H), 1.49 (dq, J1 13.84 Hz,
J2 1.29 Hz, 1H), 1.55 (dd, J1 13.84 Hz, J2 11.80 Hz, 1H),
1.68-1.78 (m, 2H), 1.84 (s, OH), 3.58 (td, J1 11.53 Hz,
J2 2.14 Hz, 1H), 4.66 (ddd, J1 11.53 Hz, J2 6.24 Hz,
J3 1.29 Hz, 1H), 4.31 (dd, J1 11.53 Hz, J2 2.14 Hz, 1H),
7.16 (t, J1 7.76 Hz, 1H), 7.23 (d, J1 7.76 Hz, 1H), 7.36 (dt,
J1 7.76Hz, J2 1.54Hz, 1H), 7.51(t, J1 1.54Hz, 1H);13CNMR
(100 MHz, CDCl3) d 31.6, 38.3, 46.4, 64.0, 67.8, 74.4,
122.4, 124.5, 128.9, 129.8, 130.3, 145.0; MS: m/z 272
(M++2, 2%), 237 (66), 209 (1), 200 (3), 185 (41), 173(7),
157 (15), 145 (6), 128 (6), 115 (5), 103 (31), 78 (16),
71 (82), 58 (100); HRMS [M-Na+] Found: 293.0152. Calc.
for C12H15BrO2: 293.0153.
4-Methyl-2-(4-nitrophenyl)tetrahydro-2H-pyran-4-ol (7d)
Syn diastereoisomer: Eluent: hexane/ethyl acetate
(1:1), Rf 0.42; colorless oil, yield 38%; IR nmax/cm-1 3418,
2972, 2939, 2859, 1604, 1519, 1347, 1252, 1093, 1045,
1014, 940, 809, 738, 697, 595 (film);1H NMR (400 MHz,
CDCl3) d 1.47 (s, 3H), 1.63 (t, J1 12.23 Hz, 1H), 1.71
(dq, J1 12.87 Hz, J2 2.22 Hz, 1H), 1.82 (s, OH), 1.85
(td, J1 12.39 Hz, J2 5.24 Hz, 1H), 1.91 (dt, J1 12.87 Hz,
J2 2.22 Hz, 1H), 3.64 (td, J1 12.87 Hz, J2 2.22 Hz, 1H),
4.17 (ddd, J1 12.39 Hz, J2 5.24 Hz, J3 2.22 Hz, 1H), 4.47
(dd, J1 12.23 Hz, J2 2.22 Hz, 1H), 7.51 (dt, J1 8.90 Hz,
J2 2.22 Hz, 2H), 8.19 (dt, J1 8.90 Hz, J2 2.22 Hz, 2H);
13C NMR (100 MHz, CDCl3) d 25.3, 40.1, 48.4, 65.9,
68.9, 76.5, 123.7, 126.5, 147.3, 149.6; MS: m/z 219 (M+-18,
30%), 204 (82), 188 (4), 174 (15), 152 (34), 135 (3), 120
(21), 107 (35), 103 (16), 91 (22), 71 (55), 58 (100); HRMS
[M-Na+] Found: 260.0894. Calc. for C12H15NO4: 260.0899.
Anti diastereoisomer: Eluent: hexane/ethyl acetate
(1:1), Rf 0.60; colorless oil, yield 32%; IR nmax/cm-1 3474,
2968, 2923, 2875, 1605, 1530, 1349, 1257, 1144, 1013,
985, 906, 803, 749, 697, 596 (film); 1H NMR (400 MHz,
CDCl3) d 1.32 (s, 3H), 1.54 (dd, J1 13.51 Hz, J2 11.76 Hz,
1H), 1.58 (dq, J1 13.51 Hz, J2 2.22 Hz, 1H), 1.74 (s, OH),
1.80 (td, J1 13.66 Hz, J2 6.51 Hz, 1H), 1.83 (dt, J1 13.66 Hz,
J2 2.22 Hz, 1H), 3.99 (td, J1 11.76 Hz, J2 2.22 Hz, 1H),
4.03 (ddd, J1 11.76 Hz, J2 6.51 Hz, J3 2.22 Hz, 1H), 4.84
(dd, J1 11.76 Hz, J2 2.22 Hz, 1H), 7.52 (dt, J1 8.90 Hz,
J2 2.22 Hz, 2H), 8.18 (dt, J1 8.90 Hz, J2 2.22 Hz, 2H); 13C
NMR (100 MHz, CDCl3) d 31.7, 38.2, 46.7, 64.0, 67.9,
74.2, 123.5, 126.4, 147.0, 150.5; MS: m/z 219 (M+–18,
36%), 204 (100), 202 (3), 188 (2), 174 (3), 152 (30), 144
(1), 120 (4), 103 (8), 91 (8), 71 (29), 58 (51); HRMS
[M-Na+] Found: 260.0901. Calc. for C12H15NO4: 260.0899.
2-Cyclohexyl-4-methyltetrahydro-2H-pyran-4-ol (7f)
Syn diastereoisomer: Eluent: hexane/ethyl acetate (3:1),
Rf 0.62; white solid, yield 44%, m.p. 90 °C; IR nmax/cm-1
3414, 2920, 2855, 1708, 1450, 1381, 1333, 1216, 1172,
1146, 939, 862, 826, 741, 649 (KBr);1H NMR (400 MHz,
CDCl3) d 0.72-2.04 (m, 15H), 1.31 (s, 3H), 2.47 (s, OH),
3.03 (ddd, J1 11.27 Hz, J2 6.18 Hz, J3 2.09 Hz, 1H), 3.40
(td, J1 11.86 Hz, J2 2.89 Hz, 1H), 3.96 (ddd, J1 11.86 Hz,
J2 6.18 Hz, J3 2.09 Hz, 1H);13C NMR (100 MHz, CDCl3)
d 25.5, 26.2, 26.6, 28.7, 28.9, 29.0, 40.8, 43.0, 43.5, 65.5,
69.3, 79.8; MS: m/z 180 (M+-18, 2%), 135 (1), 115 (46),
95 (10), 81 (7), 71 (100), 55 (22); HRMS [M-Na+] Found:
221.1519. Calc. for C12H22O2: 221.1517.
2-(3-Bromophenyl)-tetrahydro-4-methyl-2H-pyran-4-ol
(7e)
Anti diastereoisomer: Eluent: hexane/ethyl acetate
(3:1), Rf 0.40; colorless oil, yield 27%; IR nmax/cm-1 3402,
2919, 2843, 1703, 1478, 1450, 1398, 1096, 1007, 863, 826,
733, 645 (film); 1H NMR (400 MHz, CDCl3) d 0.91-1.98
(m, 15H), 1.26 (s, 3H), 3.12 (s, OH), 3.36 (ddd, J1 11.40 Hz,
J2 6.31 Hz, J3 1.54 Hz, 1H), 3.73 (td, J1 11.40 Hz, J2 1.54 Hz,
1H), 3.84 (dd, J1 11.40 Hz, J2 6.31 Hz, 1H); 13C NMR
(100 MHz, CDCl3) d 26.1, 26.2, 26.5, 28.5, 28.9, 31.9,
38.8, 41.4, 42.4, 63.7, 67.9, 77.1; MS: m/z 180 (M+-18,
11%), 165 (3), 135 (2), 125 (6), 115 (78), 95 (28), 83 (17),
Syn diastereoisomer: Eluent: hexane/ethyl acetate (3:1),
Rf 0.22; colorless oil, yield 41%; IR nmax/cm-1 3422, 2964,
2939, 2855, 1716, 1595, 1569, 1474, 1337, 1252, 1092,
1045, 996, 942, 868, 822, 784, 747, 693, 598; 1H NMR
(400 MHz, CDCl3) d 1.41 (s, 3H), 1.62 (d, J1 12.33 Hz, 1H),
1.65 (dq, J1 12.79 Hz, J2 2.46 Hz, 1H), 1.80 (td, J1 12.79 Hz,
J2 5.24 Hz, 1H), 1.84 (dt, J1 12.79, J2 2.46 Hz, 1H), 1.23 (s,
OH), 3.58 (td, J1 12.33 Hz, J2 2.31 Hz, 1H), 4.10 (ddd, J1

Vol. 21, No. 8, 2010
Macedo et al.
1569
69 (100), 55 (41); HRMS [M-Na+] Found: 221.1513. Calc.
for C12H22O2: 221.1517.
(ddd, J1 10.48 Hz, J2 6.62 Hz, J3 1.38 Hz, 1H), 5.44 (ddt,
J1 15.41 Hz, J2 6.47 Hz, J3 1.54 Hz, 1H), 5.76 (dtd,
J1 15.56Hz, J2 6.31Hz, J3 1.07Hz, 1H);13CNMR(100MHz,
CDCl3) d 13.3, 25.3, 31.8, 38.4, 44.8, 63.5, 67.9, 73.6, 129.6,
134.1; MS: m/z 170 (M+, 2%), 152 (3), 141 (22), 123 (6),
113 (2), 99 (3), 83 (13), 71 (100), 55 (21); HRMS [M-Na+]
Found: 193.1202. Calc. for C10H18O2: 193.1204.
(E)-4-Methyl-2-(prop-1-enyl)tetrahydro-2H-pyran-4-ol
(7g)
Syn diastereoisomer: Eluent: hexane/ethyl acetate (2:1),
1
Rf 0.60; colorless oil, yield 25%; H NMR (400 MHz,
CDCl3) d 1.34 (s, 3H), 1.43-1.62 (m, 5H), 1.70 (dq,
J1 6.55 Hz, J2 0.80 Hz, 3H), 3.48 (td, J1 12.19 Hz, J2 2.46 Hz,
1H), 3.78 (ddq, J1 11.33 Hz, J2 6.38 Hz, J3 1.06 Hz, 1H),
3.99 (ddd, J1 11.95 Hz, J2 5.11 Hz, J3 1.99 Hz, 1H), 5.49
(ddq, J1 15.38 Hz, J2 6.43 Hz, J3 1.63 Hz, 1H), 5.72 (ddq,
J1 15.38 Hz, J2 6.49 Hz, J3 1.05 Hz, 1H); 13C NMR
(100 MHz, CDCl3) d 17.9, 27.7, 39.7, 46.4, 58.4, 73.2,
75.1, 128.0, 133.9; (CAS 69359-03-1).
4-Methyl-2-propyltetrahydro-2H-pyran-4-ol (10)
Syn diastereoisomer: Eluent: hexane/ethyl acetate (3:1),
1
Rf 0.28; colorless oil, yield 21%; H NMR (400 MHz,
CDCl3) d 0.91 (t, J1 6.88 Hz, 3H), 1.32 (s, 3H), 1.34-1.88 (m,
9H), 3.21-3.34 (m, 1H), 3.42 (td, J1 11.96 Hz, J2 2.99 Hz,
1H), 3.96 (ddd, J1 11.96 Hz, J2 4.98 Hz, J3 2.99 Hz, 1H);
13C NMR (100 MHz, CDCl3) d 14.0, 18.7, 25.4, 38.4, 40.7,
46.6, 65.4, 68.9, 75.2; (CAS 723340-91-8).
Anti diastereoisomer: Eluent: hexane/ethyl acetate
(3:1), Rf 0.46; colorless oil, yield 40%; 1H NMR (400 MHz,
CDCl3) d 0.91 (t, J1 6.98 Hz, 3H), 1.25 (s, 3H), 1.27-1.76
(m, 8H), 1.95 (s, OH), 3.53-3.89 (m, 3H); 13C NMR
(100 MHz, CDCl3) d 14.0, 18.5, 31.7, 38.2, 38.6, 44.6,
63.5, 67.7, 72.6; (CAS 723340-91-8).
Anti diastereoisomer: Eluent: hexane/ethyl acetate
1
(2:1), Rf 0.73; colorless oil, yield 37%; H NMR
(400 MHz, CDCl3) d 1.27 (s, 3H), 1.40-1.60 (m, 5H),
1.69 (dq, J1 6.46 Hz, J2 0.84 Hz, 3H), 3.82 (td, J1 11.50 Hz,
J2 2.28 Hz, 1H), 3.85 (dd, J1 6.35 Hz, J2 1.46 Hz, 1H), 4.10
(ddq, J1 11.50 Hz, J2 6.46 Hz, J3 0.84 Hz, 1H), 5.46 (ddq,
J1 15.35 Hz, J2 6.56 Hz, J3 1.46 Hz, 1H), 5.72 (ddq,
J1 15.35 Hz, J2 6.48 Hz, J3 1.09 Hz, 1H); 13C NMR
(100 MHz, CDCl3) d 17.8, 31.8, 38.4, 44.7, 63.5, 67.8,
73.5, 127.2, 131.9; (CAS 69359-03-1).
2-Isobutyl-4-methyltetrahydro-2H-pyran-4-ol (11)-Florol®
Syn diastereoisomer: Eluent: hexane/ethyl acetate (3:1),
1
Rf 0.48; colorless oil, yield 35%; H NMR (400 MHz,
(E)-2-(But-1-enyl)-4-methyltetrahydro-2H-pyran-4-ol (7h)
Syn diastereoisomer: Eluent: hexane/ethyl acetate
(3:1), Rf 0.28; colorless oil, yield 41%; IR nmax/cm-1 3418,
2964, 2931, 2859, 1675, 1462, 1381, 1337, 1253, 1081,
971, 830 (film); 1H NMR (400 MHz, CDCl3) d 1.00 (t,
J1 7.49 Hz, 3H), 1.35 (s, 3H), 1.51 (t, J1 11.83 Hz, 1H), 1.60
(dq, J1 12.89 Hz, J2 2.23 Hz, 1H), 1.70 (dt, J1 12.76 Hz,
J2 2.36 Hz, 2H), 2.05 (qt, J1 7.36 Hz, 2H), 3.49 (td,
J1 12.10 Hz, J2 2.49 Hz, 1H), 3.80 (ddq, J1 11.18 Hz,
J2 6.31 Hz, J3 1.18 Hz, 1H), 4.00 (ddd, J1 11.83 Hz,
J2 5.13 Hz, J3 1.84 Hz, 1H), 5.46 (ddt, J1 15.52 Hz,
J2 6.31 Hz, J3 1.57 Hz, 1H), 5.75 (dtd, J1 15.52 Hz,
J2 6.18 Hz, J3 1.05 Hz, 1H);13C NMR (100 MHz, CDCl3)
d 13.3, 25.3, 25.4, 40.4, 46.6, 65.3, 68.9, 76.0, 129.3, 134.4;
MS: m/z 170 (M+, 1%), 155 (4), 141 (25), 123 (3), 107 (2),
99 (4), 83 (10), 71 (100), 55 (18); HRMS [M-Na+] Found:
193.1204. Calc. for C10H18O2: 193.1204.
CDCl3) d 0.90 (d, J1 6.54 Hz, 6H), 1.12 (ddd, J1 13.66 Hz,
J2 8.39 Hz, J3 4.55, 1H), 1.25 (s, 3H), 1.28 (dd, J1 13.66 Hz,
J2 11.52 Hz, 1H), 1.40-1.50 (m, 3H), 1.53 (dtl, J1 13.66 Hz,
J2 2.13 Hz, 1H), 1.63 (td, J1 13.66 Hz, J2 5.83, 1H), 1.78
(hept, J1 6.54 Hz, 1H), 3.19 (sl, OH), 3.65-3.84 (m, 2H),
3.76 (td, J1 12.09 Hz, J2 2.13 Hz, 1H);13C NMR (100 MHz,
CDCl3) d 22.4, 23.3, 24.3, 31.7, 38.7, 45.1, 45.4, 63.6, 67.8,
71.2; (CAS 723440-93-0).
Anti diastereoisomer: Eluent: hexane/ethyl acetate (3:1),
1
Rf 0.22; colorless oil, yield 52%; H NMR (400 MHz,
CDCl3) d 0.90 (d, J1 6.54 Hz, 6H), 1.17 (ddd, J1 12.66 Hz,
J2 8.25 Hz, J3 4.55 Hz, 1H), 1.32 (s, 3H), 1.37 (t, J1 12.24 Hz,
1H), 1.49 (ddd, J1 12.66 Hz, J2 8.25 Hz, J3 5.97 Hz, 1H),
1.58 (dq, J1 12.66 Hz, J2 2.13 Hz, 1H), 1.63 (dt, J1 12.66 Hz,
J2 2.13 Hz, 1H), 1.71 (td, J1 12.66 Hz, J2 5.12 Hz, 1H), 1.77
(hept, J1 6.54 Hz, J2 1.56 Hz, 1H), 2.96 (s, OH), 3.32-3.37
(m, 1H), 3.41 (td, J1 12.24 Hz, J2 2.13 Hz, 1H), 3.95 (ddd,
J1 12.66Hz, J2 5.12Hz, J3 1.56Hz, 1H);13CNMR(100MHz,
CDCl3) d 22.3, 23.1, 24.3, 25.3, 40.5, 45.4, 46.9, 65.3, 68.8,
73.6; (CAS 723440-93-0).
Anti diastereoisomer: Eluent: hexane/ethyl acetate
(3:1), Rf 0.20; colorless oil, yield 17%; IR nmax/cm-1 3434,
2964, 2927, 2875, 1623, 1466, 1381, 1264, 1080, 971, 908,
1
735, 650 (film); H NMR (400 MHz, CDCl3) d 0.99 (t,
J1 7.39 Hz, 3H), 1.27 (s, 3H), 1.45 (dd, J1 13.71 Hz,
J2 11.40 Hz, 1H), 1.59 (dt, J1 13.71 Hz, J2 2.46 Hz, 2H), 1.68
(dq, J1 13.87 Hz, J2 6.16 Hz, 1H), 2.05 (qt, J1 7.24 Hz, 2H),
3.83 (td, J1 11.56 Hz, J2 2.31, 1H), 3.84-3.90 (m, 1H), 4.12
4-Methyl-2-propyltetrahydro-2H-pyran-4-yl acetate
(12)-Clarycet®
To a stirred solution of 4-methyl-2-propyltetrahydro-
2H-pyran-4-ol (10) (500 mg, 3.16 mmol) in pyridine (3 mL)

1570
Solvent-free Catalysed Synthesis of Tetrahydropyran Odorants
J. Braz. Chem. Soc.
are added acetic anhydride (322 mg, 3.16 mmol, 1.0 equiv).
The mixture is magnetically stirred at room temperature
for 7 h. After completion of acetylation, the solution
is neutralized with solid NaHCO3, filtered and solvent
evaporated. Purification by flash column chromatography
on silica gel, using a mixture of hexane/ethyl acetate (10:1)
as eluent, afforded 180 mg (90%) of the title compound
as colourless oil.
Acknowledgments
Fapesp (05/59572-7), CNPq, CAPES for financial
support and LucianaVizotto (LNMR/Universidade Federal
de São Carlos) to perform the NMR and nOe experiments.
References
Syn diastereoisomer: Colorless oil, yield 90%; 1H NMR
(400 MHz, CDCl3) d 0.91 (t, J1 7.20 Hz, 3H), 1.54 (ddq,
J1 12.60 Hz, J2 11.50 Hz, J3 0.90 Hz, 1H), 1.30-1.55 (m,
4H), 1.62 (t, J1 0.90 Hz, 3H), 1.86 (dddq, J1 12.80 Hz,
J2 12.60 Hz, J3 5.30 Hz, J4 0.90 Hz, 1H), 1.97 (s, 3H), 2.03
(dddd, J1 12.80 Hz, J2 2.30 Hz, J3 2.20 Hz, J4 1.90 Hz,
1H), 2.10 (dt, J1 12.60 Hz, J2 2.20 Hz, 1H), 3.33 (m, 1H),
3.46 (ddd, J1 12.60 Hz, J2 12.10 Hz, J3 2.30 Hz, 1H), 3.93
(ddd, J1 12.10 Hz, J2 5.30 Hz, J3 1.90 Hz, 1H); 13C NMR
(100 MHz, CDCl3) d 14.4, 19.1, 21.4, 24.4, 36.3, 37.8, 42.1,
58.5, 66.7, 73.9, 170.2; (CAS 723340-91-8).
Anti diastereoisomer: Colorless oil, yield 90%;
1H NMR (400 MHz, CDCl3) d 0.89 (t, J1 7.20 Hz, 3H),
1.02 (dd, J1 13.80 Hz, J2 11.30 Hz, 1H), 1.28 (ddd,
J1 14.10 Hz, J2 12.60 Hz, J3 5.30 Hz, 1H), 1.25-1.60 (m,
4H), 1.68 (s, 3H), 2.05 (dddd, J1 14.10 Hz, J2 2.30 Hz,
J3 2.10 Hz, J4 1.60 Hz, 1H), 2.20 (dt, J1 13.80 Hz,
J2 2.30 Hz, 1H), 3.52 (dddd, J1 11.40 Hz, J2 7.40 Hz,
J3 4.60 Hz, J4 2.30 Hz, 1H), 3.57 (ddd, J1 12.60 Hz,
J2 11.60 Hz, J3 2.10 Hz, 1H), 3.71 (ddd, J1 11.60 Hz,
J2 5.30 Hz, J3 1.60 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 14.1, 18.7, 21.7, 22.5, 30.4, 37.8, 38.4, 43.5, 64.6, 74.3,
80.1, 170.3; (CAS 723340-91-8).
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2-Ethyl-4,7-dimethyloctahydro-2H-chromen-4-ol (15)
Diastereoisomeric mixture: Eluent: hexane/ethyl
1
acetate (4:1); colorless oil, yield 49%; H NMR
(400 MHz, CDCl3) d 0.85-1.25 (m, 15H), 1.35-1.50 (m,
3H), 1.51-1.63 (m, 2H), 1.68-1.82 (m, 5H), 1.87-1.99 (m,
3H), 3.07 (td, J1 10.44 Hz, J2 4.24 Hz, 1H), 3.24-3.30 (m,
1H);13C NMR (100 MHz, CDCl3) d 9.9, 21.4, 22.2, 23.1,
29.1, 31.5, 34.5, 41.6, 48.0, 52.4, 70.8, 75.9, 76.9. (CAS
134869-45-7).
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2-Isopropyl-4,7-dimethyloctahydro-2H-chromen-4-ol (16)
Diastereoisomeric mixture: Eluent: hexane/ethyl acetate
(7:1); colorless oil, yield 66%; 1H NMR (400 MHz, CDCl3)
d 0.84-1.09 (m, 14H), 1.12-1.21 (m, 4H), 1.35-1.50 (m,
2H), 1.61-1.75 (m, 5H), 1.85-1.99 (m, 3H), 3.00-3.10 (m,
2H);13C NMR (100 MHz, CDCl3) d 18.3 (2C), 21.0, 25.8,
26.2, 31.5, 32.5, 34.6, 36.5, 40.7, 42.3, 76.0, 78.3, 80.9.
(CAS 134869-70-8)

Vol. 21, No. 8, 2010
Macedo et al.
1571
6. Reddy, B. M.; Sreekanth, P. M.; Lakshmanan, P.; J. Molec.
Catal. A: Chem. 2006, 237, 93; Bartoli, G.; Bartolacci, M.;
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Bartolacci, M.; Giuliani, A.; Marcantoni, E.; Massaccesi, M.;
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10. The crystals of 7f are orthorhombic, space group P212121,
with a = 5.5714(10) Å, b = 11.0182(12) Å, c = 18.753(3) Å,
V = 1151.2(3) Å3, Dx = 1.144 g cm-3, and Z = 4. The structure
was solved by direct-methods and refined by full-matrix least-
squares to final R = 0.050. Tiekink, E. R. T.; Macedo, A.;
Wendler, E. P.; Dos Santos, A. A.; Zukerman-Schpector, J.;
Acta Cryst. 2010, E66, o1233.
Received: January 22, 2010
7. Sprecker, M. A.; Belko, R. P.; Hanna, M. R.; Beck, C. E. J.;
Brucato, S. M.; US pat. 4,999,439 1991. (pp. 48).
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