Montmorillonite K10 clay catalyzed synthesis of 4-aryltetrahydropyrans: A one-pot, multicomponent, environmentally friendly prins-friedel-crafts-type reaction

Article abstract of DOI:10.1055/s-0033-1338448

The Montmorillonite K10 clay catalyzed synthesis of 4-aryltetrahydropyrans is presented as a one-pot, multicomponent, environmentally friendly Prins-Friedel-Crafts-type reaction. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1338448

LETTER
▌1091
lMetteor ntmorillonite K10 Clay Catalyzed Synthesis of 4-Aryltetrahydropyrans: A
One-Pot, Multicomponent, Environmentally Friendly Prins–Friedel–Crafts-
Type Reaction
Montmorillonite K10 Clay Catalyzed Synthesis of 4-Aryltetrahydropyrans
Matthew R. Dintzner*
Department of Pharmaceutical and Administrative Sciences, Western New England University, College of Pharmacy, Springfield, MA 01119,
USA
Fax +1(413)7962437; E-mail: matthew.dintzner@wne.edu
Received: 18.02.2013; Accepted after revision: 04.04.2013
HO
Abstract: The Montmorillonite K10 clay catalyzed synthesis of
4-aryltetrahydropyrans is presented as a one-pot, multicomponent,
environmentally friendly Prins–Friedel–Crafts-type reaction.
O
Mont-K10
R1
+
O
R2
Key words: aldehydes, cyclization, green chemistry, hetero-
geneous catalysis, multicomponent reaction
R1
R2
Scheme 1 Retrosynthesis
Advances in high throughput screening (HTS) technology
for identification of new potential drugs has prompted re-
searchers to develop more efficient synthetic routes to li-
braries of small organic molecules. Multicomponent
reactions (MCR), which result in the breaking and form-
ing of multiple bonds in a single step or in a single reac-
tion flask, are considered ideal for the generation of new
compound libraries for HTS.1 The tetrahydropyran (THP)
moiety is a naturally occurring and abundant heterocyclic
motif that has been implicated in the physiological activi-
ty of a broad array of natural and synthetic products.2 A
host of synthetic approaches to THP compounds has been
reported, including the one-pot MCR of carbonyls (1)
with 3-buten-1-ol and arenes catalyzed by BF3·OEt2.3
Herein we report our investigation of a more environmen-
tally friendly approach to the synthesis of THPs using
Montmorillonite K10 clay (Mont-K10, Scheme 1) as a
catalyst. In addition to being considerably less expensive
than BF3·OEt2, Mont-K10 clay is also nontoxic, noncorro-
sive, and much simpler to handle. Reactions catalyzed by
BF3·OEt2 must be conducted in rigorously dried glass-
ware, under an inert environment, and they require aque-
ous workup steps, which invariably lead to the generation
of waste products. Mont-K10 catalyzed reactions, on the
other hand, can be conducted open to the air and workup
typically involves only a filtration step; often, both the
clay and the solvent can be recycled and reused.4,5
clay as a catalyst for carbon–carbon bond-forming and
other reactions.6–12
We chose to begin our investigation with p-nitrobenzalde-
hyde (1a) as the carbonyl substrate. We found that reflux-
ing p-nitrobenzaldehyde with excess 3-buten-1-ol in
dichloromethane in the presence of Mont-K10 clay gave
the corresponding acetal 3. When 3 was subsequently tak-
en up in excess benzene and refluxed in the presence of
additional Mont-K10, the corresponding tetrahydropyran
product 2a was generated in good yield (Scheme 2).
O
HO
O
O
H
H
Mont-K10
CH2Cl2
Δ
O2N
O2N
1a
3
O
Mont-K10
benzene
Δ
O2N
2a (racemic)
Scheme 2 Initial experiment
In an effort to simplify the procedure and avoid wasting a
full equivalent of the 3-buten-1-ol, we next refluxed p-
nitrobenzaldehyde with Mont-K10, 3-buten-1-ol (1.1
equiv), and methanol (5 equiv) in benzene for two hours.
This modified procedure successfully resulted in the gen-
eration of 2a in good yield, presumably via dimethyl ace-
tal (or mixed acetal) intermediate 4. We propose a
mechanism in which 4 reacts subsequently with 3-buten-
1-ol to give oxonium ion intermediate 5, which in turn un-
dergoes Prins cyclization to give carbocation 6. Benzene
then reacts with 6 via Friedel–Crafts alkylation to give 2a
(Scheme 3). This initial reaction was robust enough to be
As concern for the environment continues to shape the
way chemists think about the construction of physiologi-
cally active compounds, the development of synthetic
methodologies that promote greener reactions is essential.
Environmentally benign clays are ideally suited for the
‘greening’ of modern synthetic chemistry, and we have
reported the effective application of Montmorillonite K10
SYNLETT 2013, 24, 1091–1092
Advanced online publication: 18.04.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1338448; Art ID: ST-2013-S0154-L
© Georg Thieme Verlag Stuttgart · New York

1092
M. R. Dintzner
LETTER
developed into an undergraduate organic chemistry labo-
ratory discovery/research project, the details of which
have been reported.13
References and Notes
(1) Khan, A. T.; Choudhury, L. H.; Parvin, T.; Ali, M. A.
Tetrahedron Lett. 2006, 47, 8137.
(2) Tian, X. T.; Jaber, J. J.; Rychnovsky, S. D. J. Org. Chem.
2006, 71, 3176.
(3) Reddy, U. C.; Bondalapati, S.; Saikia, A. K. J. Org. Chem.
2009, 74, 2605.
(4) Lasszlo, P. Science 1987, 235, 1473; and references cited
therein.
(5) Nagendrappa, G. Resonance 2002, 64.
O
MeO OMe
MeOH
H
H
Mont-K10
benzene
Δ
O2N
O2N
HO
1a
4
(6) Dintzner, M. R.; Mondjinou, Y.; Pileggi, D. J. Tetrahedron
Lett. 2010, 51, 826.
(7) Dintzner, M. R.; Mondjinou, Y.; Unger, B. Tetrahedron
Lett. 2009, 50, 6639.
(8) Dintzner, M. R.; Little, A. J.; Pacilli, M.; Pileggi, D. J.;
Osner, Z. R.; Lyons, T. W. Tetrahedron Lett. 2007, 48, 1577.
(9) Dintzner, M. R.; Wucka, P.; Lyons, T. W. J. Chem. Educ.
2006, 83, 270.
+
O
O
+
H
(10) Dintzner, M. R.; Lyons, T. W.; Akroush, M. H.; Wucka, P.;
Rzepka, A. T. Synlett 2005, 785.
O2N
O2N
5
(11) Dintzner, M. R.; McClelland, K. M.; Morse, K. M.;
Akroush, M. H. Synlett 2004, 2028.
6
(12) Dintzner, M. R.; Morse, K. M.; McClelland, K. M.;
Coligado, D. M. Tetrahedron Lett. 2004, 45, 79.
(13) Dintzner, M. R.; Maresh, J. J.; Kinzie, C. R.; Arena, A. F.;
Speltz, T. J. Chem. Educ. 2012, 89, 265.
(14) Typical Procedure for the Mont-K10-Catalyzed Prins–
Friedel–Crafts Reaction for the Synthesis of 2a: In a 5-mL
round-bottomed flask, equipped with a magnetic stir bar, the
Mont-K10 clay (200 mg) and p-nitrobenzaldehyde (151 mg,
1 mmol) were combined with benzene (2 mL). Methanol
(202 μL, 5 mmol) was added, followed by 3-buten-1-ol (94
μL, 1.1 mmol) and the reaction mixture was refluxed with
vigorous stirring. Reaction progress was monitored by TLC
(in 1:1 hexanes–EtOAc). When the reaction was complete,
the mixture was allowed to cool to r.t. Then, the product
mixture was vacuum filtered, washing with acetone, to
separate the clay. The filtrate was concentrated under
vacuum to give a pale yellow solid (255 mg, 90%). See ref.
15 for the experimental details and characteristic data.
(15) Analytical Data for Compound 2a: 1H NMR and 13C NMR
spectra were recorded at 300 MHz and 100 MHz,
respectively. The proton signal of residual, non-deuterated
solvent (δ = 7.26 ppm for CHCl3) was used as an internal
reference for 1H NMR spectra. 13C NMR chemical shifts are
reported relative to the δ = 77.23 ppm resonance of CDCl3.
Coupling constants are reported in Hz. IR spectra were
recorded as thin films on a Nicolet Avatar 360 instrument.
GC analysis was performed on a Hewlett Packard 5890
Series II gas chromatograph with a 5971 Series mass
selective detector. Tetrahydro-2-(4-nitrophenyl)-4-
phenyl-2H-pyran (2a): IR (CDCl3): 3029, 2942, 1849,
1602, 1517, 1345, 1130, 1106, 1085, 850, 744 cm–1. 1H
NMR (300 MHz, CDCl3): δ = 8.20 (d, J = 8.8 Hz, 2 H), 7.57
(d, J = 8.8 Hz, 2 H), 7.23–7.33 (m, 5 H), 4.60 (dd, J = 11.2,
2.0 Hz, 1 H), 4.30–4.36 (m, 1 H), 2.75–3.83 (m, 1 H), 2.95–
3.05 (m, 1 H), 2.10 (dq, J = 13.2, 2.0 Hz, 1 H), 1.85–1.90 (m,
2 H), 1.70 (q, J = 12.4 Hz, 1 H). 13C NMR (75 MHz, CDCl3):
δ = 150.0, 145.5, 142.9, 128.3, 127.4, 126.7, 126.4, 125.7,
79.8, 68.5, 42.0, 41.5, 33.3. GC–MS (70 eV; tR = 13.174
min): m/z (%) = 283 (28) [M+], 205 (88) [M – 78]+, 104 (100)
[M – 179]+, 91 (68) [M – 192]+.
O
O
H
+
– H+
Ph
O2N
O2N
2a
Scheme 3 Proposed mechanism
We next set out to probe the scope of the reaction with a
sample of readily available carbonyl compounds (Table
1). Our results, though far from exhaustive, are consistent
with those reported by Reddy et al. using BF3·OEt2.3 Of
particular note are the observed yields for the reactions
with acetone and cyclohexanone (Table 1, entries 5 and 6,
respectively), which are superior to previously reported
values. Our methodology represents a much more envi-
ronmentally and logistically friendly route to the target
compounds, and further expands the repertoire of reac-
tions successfully catalyzed by Montmorillonite K10
clay.14
Table 1 Reaction Scope
Entry Carbonyl R1
R2
Product
Yield (%)
1
2
3
4
5
6
1a
1b
1c
1d
1e
1f
p-O2NC6H4
m-O2NC6H4
o-O2NC6H4
m-BrC6H4
Me
H
2a[3,15]
2b[3]
2c[3]
2d[3]
2e[3]
2f[3]
90
88
99
91
75
90
H
H
H
Me
–(H2C)5–
Synlett 2013, 24, 1091–1092
© Georg Thieme Verlag Stuttgart · New York

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