Efficient,highly diastereoselective MS 4 A-promoted one-pot,three-component synthesis of 2,6-disubstituted-4- tosyloxytetrahydropyrans via Prins cyclization

Article abstract of DOI:10.3762/bjoc.8.19

A simple,efficient and highly diastereoselective one-pot three-component synthesis of functionalized 2,6-disubstituted-4-tosyloxytetrahydropyrans was performed. The synthesis features an optimized Prins cyclization in which an aromatic homoallylic alcohol

Full text of DOI:10.3762/bjoc.8.19

Efficient, highly diastereoselective MS 4 Å-promoted
one-pot, three-component synthesis of
2,6-disubstituted-4-tosyloxytetrahydropyrans
via Prins cyclization
Naseem Ahmed* and Naveen Kumar Konduru
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2012, 8, 177–185.
Department of Chemistry, Indian Institute of Technology Roorkee,
Roorkee- 247 667, Uttarakhand, India
doi:10.3762/bjoc.8.19
Received: 10 October 2011
Accepted: 23 December 2011
Published: 01 February 2012
Email:
Naseem Ahmed* - nasemfcy@iitr.ernet.in
* Corresponding author
Associate Editor: J. N. Johnston
Keywords:
© 2012 Ahmed and Konduru; licensee Beilstein-Institut.
License and terms: see end of document.
aromatic homoallylic alcohols;
2,6-disubstituted-4-tosyloxytetrahydropyrans; MS 4 Å; Prins
cyclization; PTSA
Abstract
A simple, efficient and highly diastereoselective one-pot three-component synthesis of functionalized 2,6-disubstituted-4-tosyloxy-
tetrahydropyrans was performed. The synthesis features an optimized Prins cyclization in which an aromatic homoallylic alcohol,
an aromatic/aliphatic aldehyde, and p-toluenesulfonic acid (catalyst and reagent) are reacted in the presence of molecular sieves
(MS) 4 Å at reflux in dichloromethane to afford excellent yields (72–96%) within short reaction times (20–90 min). The
MS 4 Å-promoted synthesis proved to be versatile enough to provide an array of symmetrical and unsymmetrical tetrahydropyran
derivatives in economical manner. Furthermore, cleavage of the 4-tosyl group under mild conditions afforded 4-hydroxytetrahydro-
pyran in excellent yields (95–96%).
Introduction
Substituted tetrahydropyrans are common structural motifs in biologically active core structures such as 4-oxygenated, 4-halo-
numerous biological molecules and natural products that genated, 4-sulfonyl- and 4-azido/amidotetrahydropyrans [8-11].
include phorboxazoles (A and B) [1], (−)-centrolobine [2], Various applications of tetrahydropyran derivatives have
GEX1A/herboxidiene [3], bryostatins [4], and pheromones [5] inspired organic chemists to develop their efficient, economical
(Figure 1). Tetrahydropyran derivatives are also used as ma- and stereoselective synthesis.
terials in photographic films [6] and host–guest chemistry [7].
In particular, 2,4,6-trisubstituted tetrahydropyrans have tremen- To introduce the desired substituents and stereochemistry at the
dous applications in pharmaceuticals and are widely present in 2, 4 and 6-positions of the tetrahydropyran ring, Prins cycliza-
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Beilstein J. Org. Chem. 2012, 8, 177–185.
Figure 1: Tetrahydropyran ring containing natural products.
tion has been considered to be the best approach. The reaction In continuation of our interest in acid catalysis [35-39], we
can be conducted either with Brønsted acid catalysts – namely report herein an efficient, economical and highly diastereoselec-
TFA [12], AcOH, MeSO3H [13], Sc(OTf)3 [14], O3ReOSiPh3 tive one-pot three-component synthesis for both symmetrical
[15], TMSBr [16] – or with Lewis acid catalysts such as AlCl3 and unsymmetrical 2,4,6-trisubstituted tetrahydropyrans using
[17], InCl3 [18,19], TiCl4, HBF4·OEt2 [20], InBr3 [21], TiBr4 aromatic homoallyl alcohols, aromatic/aliphatic aldehydes and
[22], Fe(III) compounds [23], BF3·OEt2 [24], polymer p-toluenesulfonic acid (both as reagent and catalyst) in the pres-
supported [25], microwave accelerated with BiCl3 [26], and ence of molecular sieves (MS 4 Å) in dichloromethane at
Pd0/SnII mediated by a three component cascade coupling reflux. The molecular sieves (MS 4 Å) had a significant effect
(3-C3) [27]. However, these procedures suffer from drawbacks on improving product yields (72–96%) under short reaction
like moderate yields, high/low reaction temperatures, extended times (20–90 min). Further, cleavage of the 4-tosyl group under
reaction times, and/or strong acid conditions [28,29]. Therefore, mild conditions afforded 4-hydroxytetrahydropyran in excel-
Wills et al. reported an efficient synthetic route for 2,4,6-trisub- lent yields (95–96%).
stituted tetrahydropyrans [30]; however, this method is
restricted to electron withdrawing groups containing aromatic Results and Discussion
homoallylic alcohols. Similarly, She et al. recently have The starting materials, aromatic homoallylic alcohols, were
reported a new approach for the synthesis of 2,4,6-trisubsti- readily prepared by treatment of aromatic aldehydes with allylic
tuted tetrahydropyrans via a Prins cyclization [31]. With this Grignard reagents under a nitrogen atmosphere at −78 °C for
method, both symmetrical and unsymmetrical tetrahydropyrans 2 h [40]. Their structures were assigned by 1H, 13C NMR, IR,
can be synthesized.
and GC–MS data and compared with reported values in the
literature.
p-Toluenesulfonic acid (PTSA) is reported as a versatile
Brønsted acid catalyst in various organic transformations [32- Initially, we carried out the reaction with homoallylic alcohols,
34]. Previously, PTSA has been used as a catalyst in Prins aromatic aldehydes and PTSA at room temperature to afford
cyclizations but the product yields were low even under 2,4,6-trisubstituted tetrahydropyrans. After 22 h stirring more
extended reaction times [10].
side-products than the desired product were observed. This
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Beilstein J. Org. Chem. 2012, 8, 177–185.
might be due to the formation of an oxo-carbenium intermedi- of homoallylic alcohol and benzaldehyde in dichloromethane
ate, which further reacted in a [3,3]sigmatropic rearrangement (DCM) at room temperature gave the product in 35% yield
to give another oxo-carbenium ion (Scheme 1).
(Table 1, entry 6). Compared to that, the addition of homoal-
lylic alcohol to a stirred mixture of PTSA (1.4 equiv) and
To optimize the reaction yield, we varied the reaction condi- aromatic aldehyde in DCM improved the yield (45%) at the
tions such as enhancing the catalytic loading (1.2 equiv to same temperature (Table 1, entry 8). Following the later
1.4 equiv), varying solvents and temperature, rearranging the addition order at reflux (40 °C) in DCM (Table 1, entry 9), the
order of reagent addition and adding MS 4 Å as drying agent yield was enhanced up to 75% within 20 min. Furthermore, the
(Table 1).
addition of molecular sieves (MS 4 Å) to the above mentioned
reaction mixture within 20 min resulted in an essential improve-
ment of the yield (94%, Table 1, entry 10). In the presence of
MS 4 Å, the yield was unexpectedly enhanced from 75% to
94% under the same reaction conditions (Table 1, entry 9 vs
entry 10). The significant improvements in product yields, reac-
tion time and/or diastereoselectivity might be due to the preven-
tion of the [3,3]sigmatropic rearrangement along with the dehy-
drating activity of MS 4 Å. In addition, we studied the stoichio-
metric ratio of MS 4 Å with respect to the substrate and found
that 30 mg/mmol of MS 4 Å are necessary to receive optimal
yields.
Table 1: Optimization of reaction yields.
Entrya
Brønsted acid
Solvent Temp Time Yield
(°C)
(%)b
1
2
PTSA (1.2 equiv) Toluene
PTSA (1.2 equiv) EtOAc
rt
rt
20 h
20 h
28 h
18 h
22 h
20 h
22 h
25
22
26
25
30
35
28
3
PTSA (1.2 equiv)
PTSA (1.2 equiv)
PTSA (1.2 equiv)
PTSA (1.4 equiv)
PTSA (1.4 equiv)
PTSA (1.4 equiv)
PTSA (1.4 equiv)
PTSA (1.4 equiv)
THF
DCE
DCM
DCM
THF
rt
4
rt
5
rt
6
rt
7
66
rt
8
DCM
DCM
DCM
40 min 45
20 min 75
20 min 94
Under optimal reaction conditions we reacted a wide selection
of aromatic homoallylic alcohols and aldehydes. The experi-
mental results are summarized in Table 2. In all cases, the
corresponding tetrahydropyrans were obtained in high dia-
stereoselectivity and excellent yields without side products
(Table 2). A high degree of diastereoselectivity was determined
from the 1H NMR spectra without purification (crude product).
9
40
40
10c
aAll reactions were carried out with homoallylic alcohol (1 equiv), alde-
hyde (1 equiv) and PTSA (1.2–1.4 equiv). bIsolated yield. cMS 4 Å
(30 mg/equiv) was used.
Among different solvents (toluene, THF, DCM, DCE and We observed that substituents on the aromatic rings influenced
diethyl ether) that were used, DCM was found as the solvent of the reaction rates and yields. For example, strong electron-
choice at reflux temperature (Table 1, entries 5, 6, 8–10). Simi- donating groups such as methoxy or trimethoxy at homoallylic
larly, various acids like trifluoroacetic acid (TFA), benzoic acid, alcohols afforded the corresponding tetrahydropyrans in lower
acetic acid, benzylphosphonic acid, and O,O’-diethyl dithio- yields (72–75%) but in a faster rate (Table 2, entries 7 and 9).
phosphate were tried as catalysts but all of them failed to give Similarly, the presence of electron-withdrawing substituents –
the desired product. We expected that the order of reagent such as chlorine or bromine atoms at homoallylic alcohols –
addition would have significant influence on the yield. For gave the corresponding tetrahydropyrans in high yields
example, the addition of PTSA (1.4 equiv) to a stirred solution (85–96%) but the reaction times were longer (Table 2,
Scheme 1: Plausible side products mechanism.
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Beilstein J. Org. Chem. 2012, 8, 177–185.
Table 2: Preparation of tetrahydropyrans from aromatic homoallylic alcohols, aldehydes and PTSA·H2O.
Entry
Homoallylic alcohol
Aldehyde
Product
Reaction time
(min)
Yield
(%)
1
90
94
1a
4a
2a
1b
2
20
82
2b
3b
4b
5b
6b
3
4
5
6
90
25
90
35
92
88
90
85
4a
1a
4a
7
23
72
5a
7b
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Beilstein J. Org. Chem. 2012, 8, 177–185.
Table 2: Preparation of tetrahydropyrans from aromatic homoallylic alcohols, aldehydes and PTSA·H2O. (continued)
8
90
25
90
90
95
75
95
96
4a
8b
9
3a
9b
10
2a
10b
11
2a
11b
12
20
83
1a
2a
1a
12b
13b
14b
13
30
88
14
90
95
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Beilstein J. Org. Chem. 2012, 8, 177–185.
Table 2: Preparation of tetrahydropyrans from aromatic homoallylic alcohols, aldehydes and PTSA·H2O. (continued)
15
60
93
2a
15b
16b
17b
18b
16
17
18
50
50
75
83
86
89
1a
1a
1a
entries 2–4, 6, 8, 10). However, substituents on aldehydes have All structures of the 2,6-disubstituted-4-tosyloxytetrahydro-
no significant effect on the reaction time or yields (Table 2, pyrans were established by 1H, 13C NMR, IR, and GC–MS
entries 2, 4, 6, 12–15). We further extended our method to ali- spectral data and elemental analysis. NOE studies of compound
phatic aldehydes (e.g., acetaldehyde) and hetero aromatic alde- 3b (Table 2, entry 3) confirmed that all three substituents
hydes (e.g., pyrrole aldehyde, furfural). Under optimal reaction occupy equatorial positions on the tetrahydropyran ring. The
conditions they reacted smoothly with homoallylic alcohols to NOE cross peaks H1/H3, H5/H3 reveal that H1, H5 and H3 are
afford the corresponding tetrahydropyran derivatives which on the same side of the ring and take a diaxial orientation
show almost the same distereoselectivity and product yields (Figure 2). 1H NMR experiments were performed at 500 MHz
(83–89%, Table 2, entries 16–18).
in CDCl3. The proposed structure of 3b (Table 1, entry 3) is
further supported by the coupling constants JH1/H2b = 1.5 Hz,
From a mechanistical point of view, these reactions are similar JH1/H2a = 11.5 Hz, JH2b/H3 = 4.5 Hz and JH2a/H3 = 11.5 Hz.
to the Prins cyclization [41]. First, the aldehyde got activated by Thus, H2a and H4a are antiperiplanar to H1, H3 and H5. All
PTSA protonation followed by a nucleophilic attack of the these findings confirm that the pyran ring takes a chair con-
homoallylic alcohol and proton transfer to the hydroxy group. formation, where the substituents at C1, C3 and C5 are present
Then, a nucleophilic attack of PTSA resulted in α-tosyloxy- in equatorial position.
ether formation after losing a water molecule. In the α-tosyloxy-
ether, the delocalization of lone-pair electrons on the oxygen The tosyl group at C4 got easily deprotected at room tempera-
atom led to the removal of the tosylate group and oxo-car- ture with Mg–MeOH (Scheme 3) [42] to afford 2,6-disubstited-
benium ion intermediate formation. Then, an intramolecular 4-hydroxytetrahydropyrans with retention of the stereochem-
nucleophilic attack of the double bond in the oxo-carbenium ion istry in quantitative yield (Table 3). The structures of
led to cyclization and charge transfer complex formation with 2,6-disubstituted-4-hydroxytetrahydropyrans were established
the tosylate group to afford the 2,6-disubstituted-4-tosyloxy- by 1H, 13C NMR, IR, and GC–MS and elemental analysis and
tetrahydropyran (Scheme 2).
were compared with reported data [43].
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Beilstein J. Org. Chem. 2012, 8, 177–185.
Scheme 2: Plausible reaction mechanism via Prins cyclization.
via Prins cyclization. An aromatic homoallylic alcohol, an
aromatic/aliphatic aldehyde, and p-toluenesulfonic acid (cata-
lyst and reagent) are reacted in the presence of MS 4 Å in
dichloromethane at reflux to afford 2,6-disubstituted-4-tosyl-
oxytetrahydropyrans in excellent yields (72–96%) within short
reaction times (20–90 min). The MS 4 Å promoted synthesis
proved to be versatile enough to provide an array of symmet-
rical and unsymmetrical tetrahydropyran derivatives in an
economical manner. Moreover, it was observed that MS 4 Å
might have a vital part in controlling the reversibility of the
[3,3]sigmatropic rearrangement. Furthermore, cleavage of the
Figure 2: Schematic NOE diagram of compound 3b.
Conclusion
In conclusion, we have reported a simple and efficient one-pot 4-tosyl group under mild conditions afforded 4-hydroxytetrahy-
three-component synthesis of highly diastereoselective and dropyrans in high diastereoselectivity and excellent yields
functionalized 2,6-disubstituted-4-tosyloxytetrahydropyrans (95–96%).
Scheme 3: Deprotection of the hydroxy group.
Table 3: Preparation of 2,6-disubstituted-4-hydroxytetrahydropyrans.
Entry
4-Tosyloxytetrahydropyran (R1, R2)
4-Hydroxytetrahydropyran (R1, R2)
Yield (%)
1
2
3
Cl, Cl
H, H
Cl, Cl
H, H
1c (96)
2c (95)
3c (95)
Br, Br
Br, Br
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Beilstein J. Org. Chem. 2012, 8, 177–185.
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Supporting Information File 1
Experimental details and characterization data of
synthesized compounds, 1H and 13C NMR spectra.
[http://www.beilstein-journals.org/bjoc/content/
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The authors thank the Council of Scientific and Industrial
Research and MHRD, India, New Delhi for financial support.
The valuable comments and suggestions from reviewers are
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