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Tetrahedron 68 (2012) 7414e7421

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Tetrahedron
journal homepage: www.elsevier.com/locate/tet

Amberlyst-15: a reusable heterogeneous catalyst for the dehydration of tertiary


alcohols
Lus M.T. Frija a, b, *, Carlos A.M. Afonso b, *
a
CQFM and Institute of Nanoscience and Nanotechnology (IN), Dep. Eng. Qumica e Biologica, Instituto Superior T
ecnico, Av. Rovisco Pais 1, 1049-001 Lisboa, Portugal
b cia da Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal
iMed.UL, Faculdade de Farma

a r t i c l e i n f o a b s t r a c t

Article history: Tertiary alcohols react under mild conditions in the presence of Amberlyst-15 (dry) (solid-supported
Received 13 April 2012 sulfonic acid) to give predominantly the most stable alkene in very good yield. The dehydration of ter-
Received in revised form 18 June 2012 tiary alcohol functionality occurs without observation of rearrangement and polymerization products,
Accepted 19 June 2012
and with outstanding substrate tolerance, which include the NHCBz, NHBoc, OSEM, OTBDMS, OBOM and
Available online 28 June 2012
ethylene ketal functional groups. Amberlyst-15 (dry) can be easily recovered from the reaction medium
and reused for ve cycles, maintaining the catalytic efciency. In addition, the dehydration can occur
Keywords:
under continuous operation.
Dehydration
Tertiary alcohols
2012 Elsevier Ltd. All rights reserved.
Olens
Amberlyst-15
Heterogeneous catalysis
Catalyst recycling

1. Introduction conditions, increased yields and greater selectivity. Moreover, the


regioselective dehydration of tertiary alcohols by treatment with
The hydroxyl functionality in alcohols is often instrumental in triphenylphosphineeiodine has been described recently.3 Besides,
functional group interconversions. Conversion of hydroxyl into new particularly relevant work in dehydration of alcohols has been done
functional groups, such as carbonyl, carboxyl, ether, epoxide, amine using Martins sulfurane reagent (Ph2S[OC(CF3)2Ph]2),4 DCC/CuCl,5
or alkene, has been the subject of a large number of studies for Grieco reaction6 or Burgess reagent (methyl N-(triethylammo-
decades, leading to a plethora of synthetic methods. Particularly, niumsulfonyl)carbamate).7 However the standing need of a milder
selective dehydration of tertiary alcohols emerges as a signicant and more efcient method prompted us to further investigate this
synthetic tool. Several studies have been performed towards transformation.
optimization of the dehydration procedures available or the de- In the course of our investigation, substrate 1a (trans-terpin),
velopment of new methodologies.1 However, the generality of containing two tertiary alcohols, was used as a model molecule in
methods described so far for tertiary alcohol dehydration involve dehydration reactions. Among the 11 dehydrating agents tested
heterogeneous (for instance, Al2O3, FeCl3eSiO2, CuSO4eSiO2, with 1a, Amberlyst-15 resin (dry)8a was identied as the more
Fe2(SO4)3eSiO2, NaHSO4eSiO2, NH4SO4eSiO2) or homogeneous efcient promoter. To our delight the dehydration of trans-terpin
(such as, TsOHePhH, BF3eOEt2, Ph3BiBr2eI2, I2 or CF3COCCl3) acid occurs in a substrate/Amberlyst-15 (dry) ratio of 1:1 (w/w) (cor-
catalysts in a stoichiometric amount, or the use of strong mineral responding to a substrate/Amberlyst-15 (dry) ratio of 1.2:1 (mol/
acids, high temperatures or transformation to their ester de- mol)) at room temperature, exclusively at the cyclic tertiary alcohol
rivatives, which, in some cases, preclude their use with substrates leaving the acyclic tertiary alcohol unreacted to form the endo-al-
bearing other sensitive functional groups.2 Such heterogeneous kene 2a (alfa-terpineol).
reactions compared with their homogeneous counterparts, often Amberlyst-15 (dry) is a strong cation exchange resin in the H
have the advantage of ease of set-up and work-up, mild reaction form, developed particularly for heterogeneous acid catalysis of
a wide variety of organic reactions (such as alkylation, esterica-
tion, etherication or condensation hydrolysis), was used as a cat-
* Corresponding authors. iMed. UL, Faculdade de Farma cia da Universidade de
alyst. This is a sulfonated styrene divinyl benzene copolymer with
Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal. Fax: 351 21 7946476;
e-mail addresses: lfrija@ff.ul.pt (L.M.T. Frija), carlosafonso@ist.utl.pt, carlosafonso@ a macroreticular structure. The macroreticular pore structure of
ff.ul.pt (C.A.M. Afonso). Amberlyst-15 permits ready access of liquid or gaseous reactants

0040-4020/$ e see front matter 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.06.083
L.M.T. Frija, C.A.M. Afonso / Tetrahedron 68 (2012) 7414e7421 7415

to the hydrogen ion sites located throughout the bead, thus en- Table 2
suring successful performance even in non-swelling organic media. Dehydration of trans-terpin in different solventsa

In fact, this resin was used before in the dehydration of tert-


l
butyl-alcohol in a semi-batch reactor and in a continuous stirred
tank reactor with wet or dry resins.8b,c Very recently, Amberlyst-
15 was successfully applied in the dehydration of phenyl ethanol to
produce styrene.8d So far, to the best of our knowledge and Entry Solvent Time (h) Yield (%)
excluding tert-butyl-alcohol, there has been no reports to use
1 CH2Cl2 3.5 85
a resin catalyst like Amberlyst-15 in the dehydration of tertiary 2 EtOAc 8 74
alcohols even though diverse resins have been used widely in acid 3 Diethyl ether 18 68
catalysis.8eei 4 n-Hexane 18 46
Based on the preliminary results achieved with compound 1a, 5 EtOH 18 0

we decided to extend the dehydration study using Amberlyst-15 a


All reactions were carried out in 15 mL of solvent, by using a substrate/
(dry) as catalyst, to a series of tertiary alcohols. In this paper, we Amberlyst-15 ratio of 1.2:1 (0.435 mmol/0.355 mmol); corresponding to a sub-
strate/Amberlyst-15 ratio of 1:1 (w/w). Mass of substrate used in every
present and discuss the results of our research in this topic.
reaction75 mg.

2. Results and discussion


After selection of the best solvent an additional study was
Alcohol 1a (trans-terpin) was used, in a rst approach, as conducted using alcohol 1a with the aim of optimizing the sub-
a model molecule for the study of dehydration reactions of tertiary strate/Amberlyst-15 (w/w) ratio to be used. From this study we
alcohols. A series of 11 acid promoters (heterogeneous and homo- observed that the best yield for the selective dehydration of 1a
geneous) were tested in the dehydration of 1a using equivalent occurs when a 1:1.2 ratio of substrate/Amberlyst-15 (w/w) is used
reaction conditions (see Table 1). Among the different promoters (Fig. 1). In fact, the change of yield when going from an Amberlyst-

Table 1
Dehydration of trans-terpin using different acid promotersa

OH Promoter
HO HO + +
rt, 3.5h, CH2Cl2
1a 2a 2a' 2a''

Entry Promoter 2a Yieldb (%) 2a0 Yieldb (%) 2a00 Yieldb (%)

1 Amberlyst -15 (dry) 85 0 0
2 Amberlyst-15 (wet) 39 0 0
3 Molecular sieve 4 
A n.r. n.r. n.r.
4 FeCl3eSiO2 25 30 23
5 CF3COOH 26 0 23
6 CF3SO3H 24 21 31
7 Phosphomolybdic acid 21 23 0
8 I2 33 0 0
9 p-Toluenesulfonic acid 10 32 25
10 H2SO4 0 0 21
11 BF3eOEt2 13 27 32
a
All reactions were carried out in 15 mL of solvent, by using a substrate/promoter ratio of 1.2:1 (0.435 mmol/0.355 mmol).
b
Isolated yield. n.r.no reaction. Mass of substrate used in every reaction75 mg.

used, Amberlyst-15 (dry) is the one that clearly leads to better 15/alcohol mass ratio of 0.7:4 is not signicant. Besides, we decided
results. This is true both in terms of yield and selectivity. Thus, if we to use a mass ratio of 1.2 (catalyst/substrate) to prevent a possible
consider the 11 examined promoters presented in Table 1, only 4 of faster deactivation of Amberlyst-15.
these lead to the formation of an exclusive product of reaction Accordingly, all further dehydration reactions of tertiary alco-
(entries 1, 2, 8 and 10). In most cases, we observed the formation of hols tested were carried out in CH2Cl2, using 1:1.2 substrate/
two (entries 5 and 7) or three (entries 4, 6, 9 and 11) products of Amberlyst-15 (w/w). Next, we examined the possibility of recy-
dehydration (i.e., monoterpenes 2a (alfa-terpineol), 2a0 (limonene) cling the Amberlyst-15 resin. As can be seen from Fig. 2 the resin
or 2a00 (terpinolene)). The use of molecular sieve 4  A (entry 3) was can be efciently reused during ve cycles. The recovery of
not effective in dehydration of alcohol 1a. Based on the results Amberlyst-15 from the reaction medium is made simply by l-
obtained with compound 1a, shown in Table 1, it was decided to tration and washing with CH2Cl2. The easy recovery of the de-
extend the study of dehydration at different tertiary alcohols using hydration agent and the possibility of reuse in six cycles are the
Amberlyst-15 (dry) as catalyst. From this point on whenever we major advantages of this new dehydration methodology.
refer Amberlyst, will always mean Amberlyst-15 (dry). Table 3 summarizes the results of dehydration for the range of
Table 2 summarizes results obtained for the dehydration of 1a in alcohols 1aen, tested under optimized conditions. Testosterone
different solvents at room temperature. We observed selective derivative 1b was effectively dehydrated at room temperature to
dehydration in all tested solvents, except ethanol. The best yield for give adduct 2b, possessing a new endocyclic double bond, in 86%
dehydration was achieved in dichloromethane (CH2Cl2) for yield (entry 2). As previously noted for 1a, also for 1c a sole
a shorter reaction time (entry 1). In view of these results hydroxyl group suffered elimination. However, while in 1a selec-
dichloromethane was used as solvent in the dehydration of a range tivity between the two tertiary alcohol functions favours the
of tertiary alcohols (1aen; Table 3). elimination that leads to formation of the endocyclic double bond,
7416 L.M.T. Frija, C.A.M. Afonso / Tetrahedron 68 (2012) 7414e7421

Table 3 100
Dehydration of tertiary alcohols with Amberlyst-15a
90

Olefin isolated yield (%)


Entry Substrate Temp. Time Olen Yieldb (%)
80
(h)
70
60
1 rt 3.5 90 50
1a 2a 40
OH
30
H H
2 rt 6 86
20
H H H H
O O 10
1b 2b 0
0.1 0.2 0.5 0.7 1 1.1 1.2 1.5 2 3 4
OH
HC
HC OH
3 OH rt 8 CH
73 Amberlyst/Alcohol ratio (w/w)
CH

1c 2c Fig. 1. Dehydration yield optimization by variation of Amberlyst-15/alcohol 1a


(75 mg) ratio (w/w). All reactions were carried out in 15 mL of CH2Cl2.
HO
4 reux 1.5 85
1d 2d
R

5 1e: R Me 4 2e: R Me 85
6 1f: R Et rt 3.5 2f: R Et 88
7 1g: R Bu 3.5 2g: R Bu 78
HO R R
H C (CH ) CH
HC CH(CH ) CH
1h: R Me 2h: R Me
8 3 87
1i: R Et 2i: R Et
9 rt 3.5 85
1j: R Bu 2j: R Bu
10 2.5 88
HO R R
MeO MeO

11 1k: R Me 1 2k: R Me 89
1l: R Bu reux 2l: R Bu
12 1.5 79
HO Et
MeO
MeO
13 reux 1.5 90c Fig. 2. Amberlyst-15 recycle study; (formation of olen 2a from alcohol 1a; reactions
in CH2Cl2 (15 mL) and substrate/Amberlyst-15 ratio of 1:1.2 (75 mg/90 mg) and 1:0.7
1m 2m
(75 mg/52.5 mg)).

2 91d
14 reux
HO 2.5 85d,e formation of a mixture of two styrene isomers was conrmed by
1n 2n
NMR spectroscopy (entry 13).
a
All reactions were carried out in CH2Cl2 (15 mL) using a substrate/Amberlyst-15 Afterwards, we decided to scale up our dehydration system in
ratio of 1:1.2 (75 mg/90 mg).
b order to produce higher amounts of olens from tertiary alcohols,
Isolated yield.
c
Mixture of two isomers. attesting the practicability of the method. In the rst instance, we
d
Mixture of three isomers. applied the methodology in aliphatic alcohol 1n using a 5 g scale
e
Reaction performed in a 5 g scale (5 g of 1n; 6 g of Amberlyst-15). (entry 14). The reason for choosing 1n for studies in larger scale and
not any of the other tertiary alcohols presented in this study is due
for diol 1c the dehydration occurs at room temperature with re- to the fact that this molecule is relatively cheap and easily acces-
markable selectivity only on the tertiary alcohol, keeping un- sible. Alcohol 1n is very similar to the acyclic aliphatic alcohols
changed the secondary alcohol function leading to the endocyclic 1hej tested previously. However, and surprisingly, dehydration of
allylic alcohol carveol 2c in 73% yield (entry 3). 1n does not occur at room temperature as noticed for 1hej. Re-
As expected, in agreement with the result obtained for alcohol action of 1n with Amberlyst in reuxing dichloromethane pro-
1a, the dehydration of alcohol 1d at room temperature was not duced a mixture of alkene isomers (entry 14).
effective. In contrast, when the reaction was conducted in reuxing This last result prompted us to perform new tests in order to
dichloromethane, olen 2d was produced in 85% yield (entry 4). understand if our system would be able to isomerize olens
Alcohols 1eem were synthesized in high yields from the respective (Table 4). The submission of an exo-olen to the same conditions
ketones following the Ishihara methodology.9 used in the dehydration of tertiary alcohols with Amberlyst-15
Dehydration of cyclic tertiary alcohols 1eeg occurred at room could give us the answer. Accordingly, the next step consisted in the
temperature, furnishing endo-olens 2eeg in very good yields dehydration of alcohol 1n using a synthetic approach, which might
(entries 5e7). Under similar conditions, acyclic aliphatic alcohols lead predominantly to the formation of the corresponding exo-
1hej were rapidly dehydrated to give 2hej in similar yields olen. In this method, dehydration of 1n occurred in presence of
85e88% (entries 8e10). In contrast, dehydration of tertiary benzylic a mixture of SOCl2 and pyridine in dichloromethane at 78  C.
alcohols 1kem to form adducts 2kem only occurred under Table 4 (entries 1 and 2) shows the percentage of olen isomers
reuxing dichloromethane (entries 11e13). For alcohol 1m, (2n0 , 2n00 and 2n000 ) obtained by dehydration of 1n for the two
L.M.T. Frija, C.A.M. Afonso / Tetrahedron 68 (2012) 7414e7421 7417

Table 4 Table 5
Inuence of Amberlyst-15 on the possible occurrence of isomerization of olens Dehydration of 1n under continuous operation in different conditionsa

l
l
l
Entry Reagent Reaction conditions Productsa (%)

2n0 2n00 2n000 Entry Concn Flow Volume of Amount of Mass of product
of 1n (mL/min) 1n solution 1n passed in 2nf,g (g) [yield, %]
1 1n Amberlyst-15 10 49 41
(M) passed in the the column
CH2Cl2, reux
column (mL) (g) [mmol]
2.5 h
2 1n SOCl2, Py 82 10 8 1 0.1 0.1b 25 0.40 [2.5] 0.294 [84]
CH2Cl2, 78  C 2 25 (50)e 0.40 [2.5] 0.130 [38]
30 min {61}h
3 2n0 2n00 2n000 (mixture, entry 1) Amberlyst-15 9 47 44 3 0.1 0.5b 25 0.40 [2.5] 0.158 [45]
CH2Cl2, reux 4 0.3c 25 0.40 [2.5] 0.151 [43]
overnight, 17 h 5 0.1d 25 0.40 [2.5] 0.301 [87]
4 2n0 2n00 2n000 (mixture, entry 2) Amberlyst-15 78 9 9 6 25 (50)e 0.40 [2.5] 0.147 [42]
CH2Cl2, reux {65}h
2.5 h 7 0.2 0.5b 25 0.80 [5.0] 0.112 [16]
5 2n0 2n00 2n000 (mixture, entry 2) Amberlyst-15 80 8 12 8 0.3c 25 0.80 [5.0] 0.154 [22]
CH2Cl2, reux 9 0.1d 25 0.80 [5.0] 0.315 [45]
overnight, 17 h 10 25 (50)e 0.80 [5.0] 0.049 [7]
a
{26}h
Percentage calculated by integration of olenic proton signals from 1H NMR.
a
All tests were conducted at 50  C except those listed in entries 1 and 2, which
were carried out at 45  C.
systems. Afterwards, the two olen mixtures (from dehydration of
b
Test done with fresh Amberlyst-15 resin (1.986 g).
c
Test done with resin reused.
1n with Amberlyst and SOCl2) were submitted to identical reaction d
Test done with resin reused a second time.
conditions used for tertiary alcohol dehydration with Amberlyst, e
Total volume of 1n solution passed in the column at xed ow.
f
with an increase in reaction times (Table 4, entries 3e5). None of Isolated yield.
g
these reactions revealed the isomerization of the olens remaining Mixture of three isomers (see structure 2n).
h
Overall yield based on total volume of 1n solution passed in the column at xed
unchanged the initial ratio of 2n isomers.
ow.
Besides, dehydration of 1n was performed in a continuous
process using a CH2Cl2 solution of alcohol of known concentration. of 1k with Amberlyst-15 in the presence of compounds 3aef
The solution was passed through an HPLC column packed with proceeded in reuxed dichloromethane affecting the protecting
Amberlyst-15 resin, using a xed ow that allows full conversion groups in small extend. These results further demonstrate the
of 1n at the end of the column (see page S4, Supplementary data). selectivity of the dehydration process developed.
In order to further investigate the reaction, diverse tests were
conducted for dehydration of 1n under continuous operation using
3. Conclusion
different concentrations of alcohol (see Table 1S, Supplementary
data). The solutions were passed in the column packed with
In summary, we have developed a highly efcient and in-
Amberlyst-15 varying the ow and temperature of operation.
expensive system for transformation of tertiary alcohols into the
Table 5 shows the results obtained for dehydration of 1n using
most stable alkene under very mild conditions, using Amberlyst-
0.1 and 0.2 M solutions at 45  C (entries 1 and 2) and 50  C (entries
15 as a heterogeneous catalyst. Rearranged products and poly-
3e10). In fact, good yields were achieved for dehydration of 1n by
merization have not been observed. Some functional groups, gen-
using a 0.1 M solution and a xed ow of 0.1 mL/min, either at
erally affected under acidic conditions, such as acetal, Boc and
45  C (entries 1 and 2) or at 50  C (entries 5 and 6). However, the
TBDMS, remain practically unaltered under conditions of alcohol
use of a 0.2 M solution of 1n at 50  C and an equivalent ow
dehydration. The catalyst may be reused for ve cycles. Further
(0.1 mL/min), led to a considerable decrease in the yield of con-
studies on selective dehydration of the tertiary alcohol function-
version of tertiary alcohol in product 2n (entries 9 and 10). In-
ality in several natural products are in progress.
creasing the ow values for transportation of alcohol through the
column, clearly affects the efciency of dehydration process
(entries 3, 4, 7 and 8). Even, taking into account that the developed 4. Experimental
system for dehydration has used a small column, packed with ap-
proximately 2 g of resin, we are certain that this system can be 4.1. General methods
improved by using larger columns, permitting to obtain higher
amounts of olens in continuous ow. Additionally, given that this All solvents were freshly distilled from commercial grade. Com-
system is characterized as a method in which the catalyst remains mercially available reagents were used as received without further
static inside the column, contrary to what happens when the re- purication, such as MeMgCl (3.0 M in THF), EtMgCl (2.0 M in THF)
action occurs in a ask under stirring, the yields for dehydration of and BuMgCl (2.0 M in THF). Amberlyst-15 was purchased to Sig-
alcohol 1n appear to be attractive. maeAldrich (Amberlyst-15 hydrogen form, dry, moisture <2%).
Encouraged by the results obtained for the series of tertiary al- Column chromatography was performed using Silica gel 60 MN and
cohols, we also tested the new methodology of dehydration in the aluminium-backed silica gel Merck 60 F254 plates were used for
presence of molecules bearing other sensitive functionalities. Six analytical thin layer chromatography (TLC). Mass spectra (MS) and
compounds (3aef) possessing different protecting groups (NHCBz, accurate masses (HRMS) were obtained from the Mass Spectrometry
OBOM, OSEM, OTBDMS, NHBoc and ethylene ketal) were tested in Services of University of Santiago de Compostela (Spain). Infrared
a competitive process with tertiary alcohol 1k (see entries 1e6, spectra (IR) were recorded on a Jasco FT/IR-430 spectrophotometer.
1
Table 6). Based on the results of isolated yields for 3aef after pre- H and 13C NMR spectra were recorded on a Bruker ARX 400 spec-
parative column chromatography, it was veried that dehydration trometer. Chemical shifts are reported as d values relative to
7418 L.M.T. Frija, C.A.M. Afonso / Tetrahedron 68 (2012) 7414e7421

Table 6 4.3. Procedure for the catalyst reuse


Dehydration of 1k by using Amberlyst-15 in the presence of substrates with dif-
ferent functional groupsa,b
Amberlyst-15 (dry) (90 mg) was added to a dichloromethane
solution (15 mL) of 4-(2-hydroxypropan-2-yl)-1-methylcyclohexanol
(1a, trans-terpin) (75 mg; 0.43 mmol). The reaction was stirred at rt
l and monitored by TLC [Et2O/hexane (3:1) as eluent] until verication
l
of the disappearance of the reagent (3.5 h). The Amberlyst-15 was
l ltered from the solvent, which was evaporated under reduced
l l l l
pressure at rt to give a residue (crude of 2-(4-methylcyclohex-3-enyl)
Entry Protected Yield of 2kc (%) Yield of recovered 3d propan-2-ol (2a)). The Amberlyst-15 was washed with dichloro-
molecule (%) methane (50 mL) and dried at rt. The same catalyst was used in the
H dehydration of 1a in 10 cycles.
This procedure was repeated for a trans-terpin/Amberlyst-15
N O Ph
1 O 86 81
ratio of 1:0.7 (75 mg/52.5 mg) (see Fig. 2).
OH
3a
4.4. General procedure for the preparation of alcohols 1eem
2 76 73 (ZnCl2-catalysed alkylation of ketones with Grignard
OBOM 3b reagents)9

To a solution of MeMgCl (3.0 M in THF, 4 mL, 12 mmol) was


added ZnCl2 (95.2 mg; 0.70 mmol) at rt under nitrogen atmo-
3 68 70
sphere. This solution was stirred at that temperature for 1 h. Then,
SEMO the solution was cooled to 0  C, and 4-tert-butylcyclohexanone
H 3c
(1.08 g, 7.00 mmol) was added at 0  C. The mixture was stirred for
2 h at 0  C, and the reaction was monitored by TLC. The resulting
4 OTBDMS 81 86 mixture was quenched by saturated aqueous NH4Cl (15 mL),
3d extracted with EtOAc (350 mL) and washed with brine (30 mL).
The combined extracts were dried over Na2SO4. The organic phase
5 80 78
was concentrated under reduced pressure and the resultant residue
3e
was puried by neutral silica gel column chromatography (eluent:
hexane/EtOAc (1:1)), to give alcohol 1e (0.95 g, 80% yield). Alcohols
1fem were prepared from the correspondent ketones and RMgBr
(RMe, Et or Bu) following this procedure.
6 73 64
O
4.5. General procedure for the dehydration of tertiary
O H 3f
a
alcohols 1aen
Protected molecule/2k ratio (1:1) equiv mol.
b
All reactions were carried out in 25 mL of CH2Cl2, in the presence of a protected
molecule (0.3 mmol)1k (0.3 mmol)/Amberlyst-15 ratio of (1:1.2) (w/w). Amberlyst-15 (dry) (90 mg) was added to a CH2Cl2 solution
c
Isolated yield. (15 mL) of tertiary alcohol 1aen (75 mg) [corresponding to a sub-
d
Isolated yield, relative to the recovered protected molecule by preparative strate/Amberlyst-15 ratio of 1:1.2 (w/w)]. The reaction was stirred
chromatography. at rt and monitored by TLC until the verication of the disappearance
of the reagent. The Amberlyst-15 was ltered and the solvent was
tetramethylsilane (dH0 ppm), CDCl3 (dC77.0 ppm). GCeMS anal- removed under reduced pressure at rt to give a residue. To this
yses were performed on a Gas Chromatograph Mass Spec- residue was added additional 30 mL of CH2Cl2. The organic phase
trometerdQP2010S, Shimadzu by using the column TRB- was dried (Na2SO4), ltered and evaporated to dryness at rt to give
5MSdTeknokroma (30 m0.25 mm0.25 mm) (conditions: solvent: olen 2aen. Olens 2c, 2eeg and 2kem were submitted to
CH2Cl2; Tinitial50  C, Tnal250  C, slope5  C/min, hold additional purication by conventional column chromatography
time5 min). (eluent: from hexane to hexane/EtOAc (3:6)). Dehydration of alco-
hols 1d and 1ken occurred under CH2Cl2 reux. See 1H and 13C NMR
4.2. General procedure for the dehydration of trans-terpin (1a) spectra of olens 2aen in Supplementary data. 1H and 13C NMR
spectra of compounds 2a and 2c are identical to the ones reported.
Amberlyst-15 (dry) (75 mg) was added to a dichloromethane
solution (15 mL) of 4-(2-hydroxypropan-2-yl)-1-methylcyclohexanol 4.6. Procedure for the dehydration of alcohol 1n in
(1a, trans-terpin) (75 mg; 0.43 mmol). The reaction was stirred at a 0.032 mol scale (5g)
room temperature (rt) and monitored by TLC [diethyl ether/hexane
(3:1) as eluent] until the verication of the disappearance of the re- Amberlyst-15 (dry) (6 g) was added to a CH2Cl2 solution (200 mL)
agent (3.5 h). The Amberlyst-15 was removed by ltration and the of tertiary alcohol 1n (5 g) [corresponding to a substrate/Amberlyst-
solvent was evaporated under reduced pressure at rt to give a residue. 15 ratio of 1:1.2 (w/w)]. The reaction was stirred under CH2Cl2 reux
Dichloromethane (30 mL) was added to re-dissolve this residue. The and monitored by TLC (eluent: diethyl ether/hexane (4:1)) until the
organic phase was dried (Na2SO4), ltered and evaporated to dryness verication of the disappearance of the reagent (2.5 h). The
at rt to give 2-(4-methylcyclohex-3-enyl)propan-2-ol (2a) as a pale Amberlyst-15 was ltered and the solvent was removed under re-
yellow oil (56.5 g; 85% yield). MS (EI), m/z 153 [M]. 1H and 13C NMR duced pressure at rt to give a residue. CH2Cl2 (100 mL) was added to
spectra of 2a are identical to the described.10 This procedure was re- re-dissolve this residue. The organic phase was dried (Na2SO4), l-
peated for the ve solvents tested (Table 2) and during dehydration tered and evaporated to dryness at rt to give olen 2n (85% yield) as
yield optimization by variation of Amberlyst-15/alcohol 1a ratio a pale yellow oil (mixture of three isomers 2n0 (15%), 2n00 (33%) and
(Fig. 1). 2n000 (52%); see NMR data in Supplementary data).
L.M.T. Frija, C.A.M. Afonso / Tetrahedron 68 (2012) 7414e7421 7419

4.7. General procedure for the dehydration of 1k in the 4.10. Characterization data for compounds 1e3
presence of additional substrate (3aef)
4.10.1. 4-tert-Butyl-1-methylcyclohexanol (1e).12 Compound 1e was
7-Methoxy-1-methyl-1,2,3,4-tetrahydronaphthalen-1-ol (1k, obtained as pale yellow thick syrup. 1H NMR (400 MHz, CDCl3):
57.5 mg; 0.30 mmol) and (((octan-2-yloxy)methoxy)methyl)ben- d 5.21 (s, 1H, eOH), 1.50e1.67 (m, 4H), 1.181.34 (m, 5H), 1.13 (s, 3H),
zene (3b, 76.5 mg; 0.30 mmol) were dissolved in 25 mL of CH2Cl2. 0.80 (s, 9H); 13C NMR (125 MHz, CDCl3): d 68.9, 47.7, 40.9, 39.3, 31.4,
Amberlyst-15 (dry) (160 mg) was added and the mixture was 27.7, 25.0, 22.7. MS (EI): m/z 170 [M].
stirred under reux until the verication of total transformation of
alcohol 1k (TLC; eluent CH2Cl2/hexane (3:1)). The Amberlyst-15 4.10.2. 4-tert-Butyl-1-ethylcyclohexanol (1f).13 Compound 1f was
was ltered and the solvent was removed under reduced pressure at obtained as colourless oil. 1H NMR (400 MHz, CDCl3): d 5.29 (s, 1H,
rt to give a residue. To this residue was added additional 50 mL of eOH), 1.81e1.78 (m, 2H), 1.66e1.52 (m, 4H), 1.46e1.40 (m, 1H),
CH2Cl2. The organic phase was dried (Na2SO4), ltered and evapo- 1.34e1.27 (m, 4H), 0.91e0.88 (t, 3H), 0.86 (s, 9H); 13C NMR
rated to dryness at rt to give a mixture of olen 2k and substrate 3b (125 MHz, CDCl3): d 70.7, 48.1, 38.4, 36.9, 36.6, 27.6, 24.4, 22.5, 7.5.
(yellow oil). This mixture suffered additional purication by con- MS (EI): m/z 184 [M].
ventional column chromatography (eluent: from H to H/EtOAc
(3:6)). Isolated yields after chromatography: 2k: 76%; 3b: 73%. This 4.10.3. 4-tert-Butyl-1-butylcyclohexanol (1g).14 Compound 1g was
procedure was repeated with the six different substrates possessing obtained as colourless oil. 1H NMR (400 MHz, CDCl3): d 5.24 (s,1H, OH),
various protecting groups (3aef; Table 3). 13C NMR spectra of de- 1.61e1.58 (m, 2H),1.54e1.41 (m, 3H),1.34e1.23 (m, 9H), 0.87e0.84 (m,
rivatives 3aef recovered after dehydration process and 1H NMR 4H), 0.80 (s, 9H); 13C NMR (125 MHz, CDCl3): d 70.7, 48.0, 44.1, 38.9,
spectra of 2k3c and 2k3d reaction mixtures before chromato- 37.4, 27.6, 25.4, 24.5, 23.4, 22.5, 14.2. MS (EI): m/z 212 [M].
graphic separation (Supplementary data).
4.10.4. 2-Methyldodecan-2-ol (1h).15 Compound 1h was obtained
as colourless thick syrup. 13C NMR (125 MHz, CDCl3): d 70.9, 44.0,
31.9, 30.2, 29.6, 29.4, 29.2, 24.4, 22.7, 14.1. MS (EI): m/z 200 [M].
4.8. Preparation of major olen 2n0 by dehydration of alcohol 1n
4.10.5. 3-Methyltridecan-3-ol (1i).16 Compound 1i was obtained as
This experiment was performed under modied condition in
colourless oil. 13C NMR (125 MHz, CDCl3): d 72.9, 41.3, 34.2, 31.9,
the literature;11 to a stirred solution of alcohol 1n (1.0 g;
30.3, 29.7, 29.6, 29.4, 26.4, 23.9, 22.7, 14.1, 8.2. MS (EI): m/z 214 [M].
6.30 mmol; 1.0 equiv) in dry dichloromethane (20 mL) at rt was
added dry pyridine (1.02 mL; 12.60 mmol; 2.0 equiv). After cooling
4.10.6. 5-Methylpentadecan-5-ol (1j).17 Compound 1j was obtained
to 78  C a solution of thionyl chloride (2.2 mL; 31.50 mmol;
as colourless oil. 13C NMR (125 MHz, CDCl3): d 72.7, 41.9, 41.6, 31.9,
5.0 equiv) in dry dichloromethane (10 mL) and dry pyridine (4 mL;
30.3, 29.7, 29.4, 26.9, 26.1, 23.9, 23.3, 22.7, 14.1. MS (EI): m/z 242 [M].
50.40 mmol; 8.0 equiv) was added dropwise. The reaction mixture
was stirred for 30 min at the same temperature before quenching
4.10.7. 7-Methoxy-1-methyl-1,2,3,4-tetrahydronaphthalen-1-ol
with saturated aqueous NaHCO3 (30 mL). The reaction mixture was
(1k).18 Compound 1k was obtained as pale yellow thick syrup. 1H
allowed to warm to rt and the organic layer was separated. The
NMR (400 MHz, CDCl3): d 7.13e7.14 (d, 1H), 6.99e7.01 (d, 1H),
aqueous phase was extracted with dichloromethane (550 mL).
6.75e6.78 (q, 1H), 5.53 (s, 1H), 3.81 (s, 3H), 2.68e2.79 (m, 2H),
The combined organic layers were dried over MgSO4 by ltration to
1.88e1.97 (m, 4H), 1.56 (s, 3H); 13C NMR (125 MHz, CDCl3): d 158.1,
give a crude (pale yellow) oil. This residue was further puried by
144.0, 129.8, 128.4, 113.8, 110.8, 70.9, 55.4, 39.8, 30.8, 29.1, 20.1. MS
conventional column chromatography (eluent: from hexane to
(EI): m/z 192 [M].
hexane/EtOAc (3:6)) to give (0.70 g; 79% overall yield) of a mixture
of olens 2n0 (82%), 2n00 (7%) and 2n000 (11%), ratio determined by
4.10.8. 1-Butyl-7-methoxy-1,2,3,4-tetrahydronaphthalen-1-ol (1l).
NMR; see NMR data of mixture in Supplementary data.
Compound 1l was obtained as pale yellow thick syrup. 13C NMR
(125 MHz, CDCl3): d 158.1, 144.1, 129.7, 128.4, 113.7, 110.8, 70.8, 55.3,
53.5, 39.8, 30.8, 29.1, 20.7. MS (EI): m/z 234 [M]. HRMS (EI (DE))
4.9. Procedure for the dehydration of alcohol 1n under calcd for C15H22O2, 234.16198; found, 234.16213.
continuous operation
4.10.9. 1-Ethyl-7-methoxy-1,2,3,4-tetrahydronaphthalen-1-ol (1m).
Initially, an empty HPLC column was packed with 1.986 g of Compound 1m was obtained as pale yellow thick syrup. 1H NMR
Amberlyst-15 (dry) resin (Fig. 2S, Supplementary data). The col- (400 MHz, CDCl3): d 7.03e7.02, (d, 1H), 6.96 (s, 1H), 6.72e6.71 (d, 1H),
umn was connected to a simple piston pump (Fig. 3S, Supplementary 5.48 (s, 1H), 3.76 (s, 3H), 2.73e2.60 (m, 2H), 2.01e1.69 (m, 6H),
data) and immersed in water at 45  C (see column in a thermostatic 0.89e0.85 (t, 3H); 13C NMR (125 MHz, CDCl3): d 158.0, 143.5, 129.8,
water bath in Fig. 3S). A CH2Cl2 solution of alcohol 1n of known 129.0,113.5,110.8, 72.8, 55.3, 53.5, 35.3, 29.1, 19.9, 8.6. MS (EI): m/z 206
concentration was passed through the column using a constant ow. [M]. HRMS (EI (DE)) calcd for C13H18O2, 206.13068; found, 206.13051.
The mixture passed through the column was collected in a container
and analysed by TLC (eluent: Et2O/hexane (4:1); TLC analysis 4.10.10. 2-(4-Methylcyclohex-3-enyl)propan-2-ol (2a).19 Compound
allowed determination of when total dehydration of alcohol oc- 2a was obtained as colourless oil. 13C NMR (125 MHz, CDCl3):
curred). Different ows and volumes of the reaction mixture col- d 133.9, 120.6, 72.7, 45.0, 31.0, 27.4, 26.9, 26.2, 24.0, 23.3. MS (EI): m/
lected (dichloromethane alcoholic solution) were tested (at 45  C z 154 [M].
and 50  C) in order to reach the optimal conditions, that is, the total
conversion of alcohol 1n into olen 2n (Table 1S, Supplementary 4.10.11. ()-Limonene (2a0 ).20 Compound 2a0 was obtained as col-
data). The CH2Cl2 solution was dried (Na2SO4), ltered and evapo- ourless oil. 13C NMR (125 MHz, CDCl3): d 149.5, 133.1, 120.9, 108.4,
rated to dryness at rt to give a crude (pale yellow) oil. This residue 41.1, 30.8, 30.6, 28.0, 23.6, 20.5. MS (EI): m/z 136 [M].
was further puried by conventional column chromatography (el-
uent: from hexane to hexane/EtOAc (3:6) to give olen 2n (as 4.10.12. Terpinolene (2a00 ). Compound 2a0 was obtained as pale
a mixture of three isomers, 2n0 , 2n00 and 2n000 )). yellow oil. 13C NMR (125 MHz, CDCl3): d 133.1, 126.2, 125.1, 120.1,
7420 L.M.T. Frija, C.A.M. Afonso / Tetrahedron 68 (2012) 7414e7421

31.6, 30.1, 28.1, 23.5, 19.1. MS (EI): m/z 136 [M]. Spectral data CDCl3): d 7.06e7.03 (d, 1H), 6.83e6.82 (d, 1H), 6.76e6.73 (dd, 1H),
identical to an authentic sample. 5.62e5.60 (t, 1H), 3.84 (s, 3H), 2.96e2.93 (t, 2H), 2.78e2.74 (q, 2H),
1.37 (s, 3H); 13C NMR (125 MHz, CDCl3): d 157.6, 143.4, 130.1, 127.1,
4.10.13. (8S,9S,10R,13S,14S)-10,13,17-Trimethyl-7,8,9,11,12,13,14,15- 123.3, 118.0, 111.4, 102.8, 55.3, 31.5, 22.9, 20.7. MS (EI): m/z 174 [M].
octa-hydro6H-cyclopenta[a]phenanthren-3(10H)-one (2b). Compound
2b was obtained as pale yellow thick syrup. 1H NMR (400 MHz, 4.10.23. 4-Butyl-6-methoxy-1,2-dihydronaphthalene (2l). Compound
CDCl3): d 7.13e7.16 (d, 1H), 6.21e6.25 (dd, 1H), 6.06e6.07 (t, 1H), 2l was obtained as a pale yellow oil. 1H NMR (400 MHz, CDCl3):
2.47e2.53 (dd, 1H), 2.33e2.40 (m, 2H), 2.14e2.19 (m, 3H), 2.01e2.07 d 7.10e7.08 (d, 1H), 6.89 (s, 1H), 6.73e6.72 (d, 1H), 5.92e5.90 (t, 1H),
(m, 2H), 1.83e1.92 (m, 2H), 1.61 (s, 3H), 1.23e1.24 (d, 1H), 1.20 (s, 3H), 3.85 (s, 3H), 2.73e2.69 (t, 2H), 2.47e2.44 (t, 2H), 2.29e2.24 (q, 2H),
1.18 (s, 1H), 1.02 (s, 1H), 0.95 (s, 3H), 0.91 (s, 3H); 13C NMR (125 MHz, 1.60e1.40 (m, 4H), 1.00e0.98 (t, 3H); 13C NMR (125 MHz, CDCl3):
CDCl3): d 186.4, 169.0, 155.7, 141.9, 134.2, 127.6, 124.3, 60.8, 49.5, 45.4, d 158.3, 136.5, 129.1, 128.1, 125.4, 121.8, 110.6, 109.7, 55.4, 32.5, 30.7,
43.4, 39.4, 36.6, 33.3, 32.6, 30.0, 26.7, 26.5, 24.1, 22.1, 18.6. HRMS 27.6, 23.5, 22.7, 14.1. MS (EI): m/z 216 [M]. HRMS (EI (DE)) calcd for
(ESI) calcd for C20H26O, 282.19837; found, 282.19821. C15H20O, 216.15141; found, 216.15125.

4.10.14. (1S)-2-Methyl-5-(prop-1-en-2-yl)cyclohex-2-enol (2c).21 4.10.24. 4-Ethyl-6-methoxy-1,2-dihydronaphthalene (2m). Comp-


13
Compound 2c was obtained as colourless oil. C NMR (125 MHz, ound 2m was obtained as pale yellow oil (mixture of two styrene
CDCl3): d 148.6, 135.0, 124.8, 111.4, 68.3, 36.5, 35.4, 30.3, 20.9, 20.3. isomers). NMR data for 2m containing endo and exo isomers: 13C
MS (EI): m/z 152 [M]. NMR (125 MHz, CDCl3): d 157.6, 157.5, 138.8, 130.3, 129.8, 128.1,
126.2, 125.3, 124.3, 123.4, 117.8, 113.6, 111.5, 110.7, 109.5, 102.5, 55.3,
4.10.15. 1-Methyl-4-(prop-1-en-2-yl)cyclohexane (2d).22 Compound 39.5, 29.4, 29.1, 27.0, 23.5, 20.2, 14.6, 12.0. MS (EI): m/z 188 [M].
2d was obtained as colourless oil. 1H NMR (400 MHz, CDCl3): d 5.23 HRMS (EI(DE)) calcd for C13H16O, 188.12011; found, 188.12004.
(s, 2H), 2.17e1.97 (m, 3H), 1.20e1.17 (m, 5H), 1.09 (s, 1H), 0.93e0.92
(d, 3H), 0.81e0.69 (m, 4H); 13C NMR (125 MHz, CDCl3): d 148.1, 4.10.25. cis-Benzyl N-(1-hydroxyindan-2-yl)carbamate () (3a).27
111.7, 44.0, 36.0, 35.6, 33.1, 22.8, 20.0. MS (EI): m/z 138 [M]. White solid. Mp 139e141  C. 1H NMR (400 MHz, CDCl3): d 2.06 (br s,
1H, OH), 2.90 (d, 1H, CH2), 3.12 (dd, 1H, CH2), 4.58 (br s, 1H, CH),
4.10.16. 4-tert-Butyl-1-methylcyclohex-1-ene (2e).23 Compound 2e 5.08e5.20 (m, 3H, OCH2Ph, CH), 5.48 (d,1H, NH), 7.24e7.39 (m, 9H, Ar);
was obtained as colourless thick syrup. 1H NMR (400 MHz, CDCl3): 13
C NMR (125 MHz, CDCl3): d 156.8, 140.9, 139.8, 136.5, 128.4, 128.1,
d 5.33e5.30 (t, 1H), 1.36e1.29 (m, 1H), 1.25e1.18 (m, 3H), 1.16e1.11 128.0, 126.9, 125.2, 124.4, 73.0,66.9, 59.1, 39.6. MS (EI): m/z 297 [M].
(m, 3H), 0.79 (s, 3H), 0.78 (s, 9H); 13C NMR (125 MHz, CDCl3):
d 137.9, 122.0, 45.0, 30.8, 30.2, 27.6, 25.6, 24.5. MS (EI): m/z 152 [M]. 4.10.26. (((Octan-2-yloxy)methoxy)methyl)benzene (3b). Compound
1m was obtained as pale yellow thick syrup. 13C NMR (125 MHz,
4.10.17. 4-tert-Butyl-1-ethylcyclohex-1-ene (2f).24 Compound 2f CDCl3): d 137.9, 128.5, 128.4, 128.0, 127.9, 127.8, 127.7, 93.9, 92.9, 73.3,
was obtained as colourless oil. 1H NMR (400 MHz, CDCl3): 69.6, 69.4, 37.1, 32.0, 29.5, 25.7, 22.7, 20.3, 14.2. MS (EI): m/z 250 [M].
d 5.32e5.30 (t,1H), 1.29e1.19 (m, 5H), 0.93e0.89 (m, 4H), 0.85 (s, 3H), HRMS (ESI) calcd for C16H26O2Na, 273.18249; found, 273.18234.
0.78 (s, 3H), 0.79 (br s, 9H); 13C NMR (125 MHz, CDCl3): d 139.4, 119.5,
44.3, 32.2, 30.2, 29.8, 27.3, 26.8, 24.3, 12.4. MS (EI): m/z 166 [M]. 4.10.27. 5a-Cholestan-3-one ((methoxy)ethyl)trimethylsilane (3c).
13
C NMR (125 MHz, CDCl3): d 92.9, 76.2, 64.9, 56.6, 56.4, 54.5, 45.0,
4.10.18. 4-tert-Butyl-1-butylcyclohex-1-ene (2g).25 Compound 2g 42.7, 40.2, 39.7, 37.2, 36.3, 35.9, 35.8, 35.6, 35.4, 32.3, 29.0, 28.8,
was obtained as pale yellow oil. 1H NMR (400 MHz, CDCl3): 28.4, 28.2, 24.4, 24.0, 23.0, 22.7, 21.4, 18.8, 18.2, 12.4, 12.2. MS (EI):
d 5.30e5.32 (br s, 1H), 1.91e1.40 (m, 7H), 1.26e1.19 (m, 5H), m/z 518 [M]. HRMS (ESI) calcd for C33H62O2NaSi, 541.44113; found,
0.85e0.82 (m, 4H), 0.79 (s, 9H); 13C NMR (125 MHz, CDCl3): d 138.1, 541.44157.
121.1, 53.7, 48.3, 44.4, 39.6, 37.7, 27.9, 22.8,14.4. MS (EI): m/z 194 [M].
4.10.28. tert-Butyldimethyl(1-phenylethoxy)silane (3d).28 13C NMR
4.10.19. 2-Methyldodec-2-ene (2h).26 Compound 2h was obtained (125 MHz, CDCl3): d 147.0, 128.2, 126.7, 125.2, 70.9, 27.4, 26.0, 18.3.
as colourless oil. 1H NMR (400 MHz, CDCl3): d 5.06e5.02 (t, 1H), MS (EI): m/z 236 [M].
1.94e1.86 (m, 2H), 1.61 (s, 3H), 1.52 (s, 3H), 1.19 (br s, 14H), 0.82e0.79
(t, 3H); 13C NMR (125 MHz, CDCl3): d 131.4, 125.4, 32.4, 30.4, 30.1, 4.10.29. tert-Butyl 1-phenylethylcarbamate (3e).29 White solid. Mp
30.0, 29.8, 28.5, 26.1, 23.1, 18.0, 14.5. MS (EI): m/z 182 [M]. 78e79  C. 13C NMR (125 MHz, CDCl3): d 155.2, 145.1, 128.7, 127.2,
126.0, 79.6, 50.3, 28.6, 22.8. MS (EI): m/z 221 [M].
4.10.20. 3-Methyltridec-3-ene (2i). Compound 2i was obtained as
a pale yellow oil. 1H NMR (100 MHz, CDCl3): d 5.10e5.07 (t, 1H), 4.10.30. 5a-Cholestan-3-one ethylene ketal (3f).30 13C NMR
1.99e1.90 (m, 4H), 1.64e1.55 (m, 3H) 1.23 (br s, 14H), 0.97e0.93 (t, (125 MHz, CDCl3): d 109.5, 64.2, 56.2, 54.1, 43.7, 42.6, 40.1, 39.6,
3H), 0.87e0.83 (t, 3H); 13C NMR (125 MHz, CDCl3): d 136.5, 123.7, 38.0, 35.8, 35.5, 35.4, 31.9, 31.2, 28.6, 28.3, 28.0, 24.2, 23.8, 22.9,
32.3, 30.1, 30.04, 30.03, 30.0, 29.8, 28.4, 28.3, 23.7, 23.1, 14.5, 13.2. MS 22.6, 21.2, 18.7, 12.1, 11.4. MS (EI): m/z 430 [M].
(EI): m/z 196 [M]. HRMS (EI (DE)) calcd for C14H28,196.21910; found,
196.21921. Acknowledgements

4.10.21. 5-Methylpentadec-5-ene (2j). Compound 2j was obtained ~o para a Ciencia e Tecnologia
The authors acknowledge Fundaca
as a pale yellow oil. 1H NMR (400 MHz, CDCl3): d 5.03 (t, 1H), (FCT-Portugal) and FEDER (PTDC/QUI/73061/2006, PTDC/QUI-QUI/
2.35e2.28 (m, 2H), 1.94e1.87 (m, 6H), 1.50 (s, 3H), 1.18 (br s, 14H), 102460/2008 and SFRH/BPD/43853/2008) for nancial support.
0.83e0.78 (m, 6H); 13C NMR (125 MHz, CDCl3): d 135.7, 124.9, 32.3,
30.3, 30.0, 29.7, 28.4, 24.2, 23.0, 14.4. MS (EI): m/z 224 [M]. HRMS Supplementary data
(EI (DE)) calcd for C16H32, 224.25040; found, 224.25057.
Copies of 1H and 13C NMR spectra of compounds 1eem, 2aen and
4.10.22. 6-Methoxy-4-methyl-1,2-dihydronaphthalene (2k).18 Com- 3aef and 1H NMR spectra of reaction mixtures resulting from de-
pound 2k was obtained as colourless thick syrup. 1H NMR (400 MHz, hydration of 1k in the presence of substrates 3c and 3d.
L.M.T. Frija, C.A.M. Afonso / Tetrahedron 68 (2012) 7414e7421 7421

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