An iodine catalyzed metal free domino process for the stereoselective synthesis of oxygen bridged bicyclic ethers

Article abstract of DOI:10.1039/c5ob00518c

A domino reaction has been developed for the synthesis of oxygen bridged bicyclic ethers through the coupling of 4-(2-hydroxyethyl)cyclohex-3-enols with aldehydes in the presence of 10 mol% of molecular iodine in dichloromethane at 25 °C. This method is h

Full text of DOI:10.1039/c5ob00518c

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An iodine catalyzed metal free domino process for
the stereoselective synthesis of oxygen bridged
bicyclic ethers†
Cite this: DOI: 10.1039/c5ob00518c
B. V. Subba Reddy,*a B. Someswarao,a,b N. Prudhviraju,a,b B. Jagan Mohan Reddy,b
B. Sridharc and S. Kiran Kumard
A domino reaction has been developed for the synthesis of oxygen bridged bicyclic ethers through
the coupling of 4-(2-hydroxyethyl)cyclohex-3-enols with aldehydes in the presence of 10 mol% of
molecular iodine in dichloromethane at 25 °C. This method is highly diastereoselective affording the
corresponding bicyclic ethers, i.e. octahydro-4a,7-epoxyisochromenes in good yields with high
selectivity. It is the first report on the synthesis of oxygen bridged bicyclic ethers using a domino Prins
strategy.
Received 16th March 2015,
Accepted 11th May 2015
DOI: 10.1039/c5ob00518c
www.rsc.org/obc
They are known to exhibit promising cytotoxicity against
renal cancer cell lines.2 Of various oxygenated heterocycles,
Introduction
An oxygen bridged bicyclic core (englerin) is frequently found the tetrahydropyran ring is often present as a core structure of
in various natural products such as englerin, orientalol, oxy- many biologically active natural products.3 Therefore, several
phyllol, saniculamoid A etc. (Fig. 1).1
efforts have been made to develop efficient synthetic
approaches for the synthesis of these heterocycles.4
Among them, Prins cyclization is one of the most reliable
strategies for the construction of the tetrahydropyran ring
system.5,6 In particular, the Prins cascade is a highly conver-
gent approach for the stereoselective synthesis of fused/
bridged tetrahydropyran derivatives.7,8 Besides its potential
use in natural product synthesis,9,10 the scope of this cascade
process has not yet been explored for the synthesis of
oxygen bridged oxabicycles from readily accessible aldehydes
and 4-(2-hydroxyethyl)-1-methylcyclohex-3-enols. However, the
development of a simple and metal-free approach for the
construction of oxygen bridged oxabicycles using inexpensive
and readily available reagents is well appreciated. Recently,
molecular iodine has received considerable attention in
organic synthesis because of its low cost and ready avail-
ability.11 The mild Lewis acidity associated with iodine has
enhanced its use in organic synthesis to perform several
organic transformations using stoichiometric levels to catalytic
amounts.12
Fig. 1 Representative examples for oxygen bridged oxabicycles.
aNatural Product Chemistry, CSIR-Indian Institute of Chemical Technology, Tarnaka,
500 007 Hyderabad, India. E-mail: basireddy@iict.res.in; http://www.iictindia.org;
Fax: +91-40-27160512
bDepartment of Organic Chemistry, Adikavi Nannaya University, Rajahmundry,
533105, India
Following our interest in the catalytic application of mole-
cular iodine,13 we herein report a metal-free approach for the
synthesis of oxygen bridged oxabicycles from 4-(2-hydroxy-
cLaboratory of X-ray Crystallography, CSIR-Indian Institute of Chemical Technology,
Tarnaka, 500 007 Hyderabad, India
dCentre for Nuclear Magnetic Resonance, CSIR-Indian Institute of Chemical
ethyl)-1-methylcyclohex-3-en-1-ol and aldehydes through
a
Technology, Tarnaka, 500 007 Hyderabad, India
†Electronic supplementary information (ESI) available: Detailed procedures and
spectroscopic data for novel compounds, and copies of 1H NMR and 13C NMR
spectra of novel compounds prepared. CCDC 1048635. For ESI and crystallo-
graphic data in CIF or other electronic format see DOI: 10.1039/c5ob00518c
cascade of Prins cyclization. In a preliminary experiment, 4-(2-
hydroxyethyl)-1-methylcyclohex-3-en-1-ol (1) was treated with
2,4,5-trifluorobenzaldehyde (2) in the presence of 10 mol%
iodine in dichloromethane. To our delight, the reaction pro-
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Table 1 Synthesis of oxygen bridged oxabicycles
Table 1 (Contd.)
Yieldb
(%)
Time
(h)
Yieldb
(%)
Time
(h)
Producta (3)
Entry Aldehyde (2)
Producta (3)
Entry Aldehyde (2)
n
4
72
a
4
4
4
4
3
3
4
82
80
79
82
80
69
80
o
5
80c
b
c
d
e
f
a All products were characterized by NMR, IR and mass spectroscopy.
b Yield refers to pure products after chromatography. c 9 : 1 ratio of
diastereomers.
Scheme 1 Cascade cyclization of endiol (1) with 2,4,5-trifluorobenz-
aldehyde (2).
ceeded smoothly at room temperature to afford the corres-
ponding oxygen bridged bicyclic ether 3a in 82% yield (entry a,
Table 1) (Scheme 1).
g
The relative stereochemistry of compound 3a has been
derived by using 1D and 2D NMR experiments. The major nOe
cross peaks are depicted in Fig. 2. The large scalar coupling
constant between H1 and H2 (3JH1–H2 = 10.5 Hz) and the pres-
ence of the nOe cross peak between H1 and H5′ indicate that
H1, H2 and H5′ protons are in the axial positions in the chair
conformation as indicated in Fig. 2. The stereochemistry at C2,
C3 and C7 was derived by the observation of nOe cross peaks
between H1/H6′, H4′/H9, and H6′/H8 implying that the fused
h
i
2
4
78
70
j
3
4
80
78
k
l
5
3
76
73
m
Fig. 2 Characteristic nOe cross peaks of 3a.
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Table 1). For instance, treatment of the chiral aldehyde 2o
afforded the desired product as a mixture of two diastereomers
3o and 3o′ in 9 : 1 ratio. These diastereomers were purified by
column chromatography and characterized by NMR, IR and
mass spectroscopy. To know the efficiency, the reaction was
carried out using different catalysts such as trifluoroacetic
acid (TFA), p-toluenesulfonic acid (p-TSA), BF3·OEt2 and
TMSOTf.
Among them, molecular iodine was found to be the best
catalyst in terms of conversion. Next, we examined the effect of
solvents such as dichloromethane, acetonitrile, toluene and di-
methoxyethane. Among them, dichloromethane gave the best
results. No improvement in the conversion was observed either
by increasing the reaction time or catalyst loading. In the
absence of iodine, no cyclization was observed even after a
long reaction time (24 h). The reactions proceeded smoothly at
room temperature under mild and neutral conditions. No side
products were detected under these conditions. No additives
or stringent reaction conditions are required to facilitate the
reaction. The scope and generality of this process is illustrated
with respect to aldehydes and the results are presented in
Table 1.
Mechanistically, the reaction was assumed to proceed via
the formation of oxo-carbenium ions from 4-(2-hydroxyethyl)-
cyclohex-3-en-1-ol and aldehydes after activation with mole-
cular iodine. A subsequent attack of the olefin on the oxo-
carbenium ion led to the formation of the carbocation, which
is simultaneously trapped by a tertiary hydroxyl group to
furnish the desired bicyclic ether (Scheme 2). Alternatively,
iodine may react initially with the alcohol to generate HI,
which may be responsible for the activation of the aldehyde to
facilitate the reaction.
In this cascade process, the tertiary alcohol attacks prefer-
entially from the less hindered side to produce the oxygen
bridged oxabicycle 3 with high stereoselectivity. Recently,
Barbero et al. showed the preferential equatorial attack of the
internal nucleophile when termination of Prins cyclization
occurs intramolecularly.15
In conclusion, we have demonstrated a novel metal-free
approach for the synthesis of octahydro-4a,7-epoxyisochro-
mene derivatives through a domino Prins cyclization between
4-(2-hydroxyethyl)cyclohex-3-en-1-ols and aldehydes. The use
Fig. 3 ORTEP diagram of 3j.
“O” is in the axial position whereas C6 in the equatorial posi-
tion as indicated in Fig. 2.
The relative stereochemistry of 3j was established by X-ray
crystallography (Fig. 3).14
Inspired by the above results, we extended this method to
various aldehydes like aromatic, heterocyclic and aliphatic
aldehydes. Interestingly, several aromatic aldehydes such as
p-nitro-, p-isopropyl-, m-bromo-, and p-hydroxy-derivatives par-
ticipated well in this reaction (entries b, c, e and f, Table 1).
Notably, electron-deficient substrates such as p-nitrobenzalde-
hyde also gave the desired product in good yield (entry b,
Table 1). Furthermore, the reaction proceeded quite effectively
with p-hydroxybenzaldehyde without the protection of the
hydroxyl group (entry f, Table 1). In the case of aromatic alde-
hydes, the corresponding aryl substituted oxabicycles were
obtained in good yields. In addition, a heteroaromatic sub-
strate, i.e. 4-bromothiophene-2-carboxaldehyde, was also
effective for this conversion (entry d, Table 1). In addition, the
reaction was quite successful even with α,β-unsaturated alde-
hydes such as 2-nitrocinnamaldehyde and cinnamaldehyde
(entries g and l, Table 1). The scope of this cascade reaction
was further exemplified by the coupling of 4-(2-hydroxyethyl)-
cyclohex-3-en-1-ol with different aldehydes (entries h–n,
Table 1). In all cases, the corresponding products were
obtained in good yields. This method works well with both
aromatic and aliphatic aldehydes. In the case of aliphatic alde-
hydes, the corresponding alkyl substituted bicyclic ethers were
obtained in relatively lower yield (entry h, Table 1). Remark-
ably, sterically hindered substrates such as 2,4,5-trifluorobenz-
aldehyde, 1-naphthaldehyde and 2-bromobenzaldehyde also
gave the products in good yields (entries a, j, and m, Table 1).
As expected, electron rich substrates such as p-hydroxy- and
p-methoxybenzaldehydes gave the products comparatively in
lower yields (entries f and i, Table 1). Finally, we attempted the
coupling of 4-(2-hydroxyethyl)cyclohex-3-en-1-ol with styrene
oxide under the influence of a catalytic amount of molecular
iodine in dichloromethane at 25 °C. Interestingly, the desired
product was obtained in 72% yield (entry n, Table 1). There-
fore, this method was successful not only with aldehydes but
also with epoxides. The reaction was further performed with
chiral aldehydes to study the diastereoselectivity (entry o,
Scheme 2 A plausible reaction pathway.
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of readily accessible precursors and inexpensive molecular
iodine makes it quite simple and more attractive. This method
offers notable advantages such as mild/neutral conditions,
good conversions and excellent selectivity.
J. A. Beutler, W. M. Linehan and L. Neckers, Cancer Cell,
2013, 23, 228; (b) F. J. Sulzmaier, Z. Li, M. L. Nakashige,
D. M. Fash, W. J. Chain and J. W. Ramos, PLoS One, 2012,
7, e48032.
3 (a) N. M. Nasir, K. Ermanis and P. A. Clarke, Org. Biomol.
Chem., 2014, 12, 3323; (b) M. S. Kwon, S. K. Woo, S. W. Na
and E. Lee, Angew. Chem., Int. Ed., 2008, 47, 1733;
(c) S. K. Woo, M. S. Kwon and E. Lee, Angew. Chem., Int.
Ed., 2008, 47, 3242; (d) E. A. Crane and K. A. Scheidt,
Angew. Chem., Int. Ed., 2010, 49, 8316; (e) P. A. Wender and
A. J. Schrier, J. Am. Chem. Soc., 2011, 133, 9228;
(f) M. R. Gesinski and S. D. Rychnovsky, J. Am. Chem. Soc.,
2011, 133, 9727.
4 (a) H. Qian, X. Han and R. A. Widenhoefer, J. Am. Chem.
Soc., 2004, 126, 9536; (b) A. Guérinot, A. Serra-Muns,
C. Gnamm, C. Bensoussan, S. Reymond and J. Cossy, Org.
Lett., 2010, 12, 1808; (c) A. Aponick and B. Biannic, Org.
Lett., 2011, 13, 1330; (d) K. Tadpetch and S. D. Rychnovsky,
Org. Lett., 2008, 10, 4839; (e) D. Strand, P.-O. Norrby and
T. Rein, J. Org. Chem., 2006, 71, 1879; (f) H. Fuwa,
N. Ichinokawa, K. Noto and M. Sasak, J. Org. Chem.,
2012, 77, 2588; (g) J. S. Yadav, V. K. Singh and
P. Srihari, Org. Lett., 2014, 16, 836; (h) N. A. Petasis and
S.-P. Lu, Tetrahedron Lett., 1996, 37, 141; (i) E. O’Neil,
S. V. Kingree and K. P. C. Minbiole, Org. Lett., 2005, 7,
515; ( j) L. Liu and P. E. Floreancig, Angew. Chem., Int.
Ed., 2010, 49, 3069.
5 (a) H. Prins, J. Chem. Weekbl., 1919, 16, 1072;
(b) D. R. Adams and S. P. Bhatnagar, Synthesis, 1977, 661;
(c) B. B. Snider, in The Prins Reaction and Carbonyl Ene Reac-
tions, ed. B. M. Trost, I. Fleming and C. H. Heathcock, Per-
gamon Press, New York, 1991, 2, p. 527.
6 For recent reviews on the Prins reaction see: (a) C. Olier,
M. Kaafarani, S. S. Gastaldi and M. P. Bertrand, Tetra-
hedron, 2010, 66, 413; (b) I. M. Pastor and M. Yus, Curr.
Org. Chem., 2012, 16, 1277; (c) X. Han, G. R. Peh and
P. E. Floreancig, Eur. J. Org. Chem., 2013, 1193.
Experimental
IR spectra were recorded on a FT-IR spectrometer (KBr) and
reported in reciprocal centimetres (cm−1). 1H NMR spectra
were recorded at 600 MHz, 500 MHz, and 300 MHz and 13C
NMR spectra were recorded at 150, 125 MHz, and 75 MHz. For
1H NMR, tetramethylsilane (TMS) was used as the internal
standard (δ = 0) and the values are reported as follows: chemi-
cal shift, integration, multiplicity (s = singlet, d = doublet, t =
triplet, q = quartet, m = multiplet, br = broad), and the coup-
ling constants in Hz. For 13C NMR, CDCl3 (δ = 77.27) was used
as the internal standard and spectra were obtained with com-
plete proton decoupling. Low-resolution MS and HRMS data
were obtained using EI ionization. Reaction progress was
monitored by thin layer chromatography (TLC) on precoated
silica gel GF254 plates and the spots were detected under UV
light (254 nm).
General procedure
To a stirred solution of aldehyde (1.1 mmol) and 1a or 1b
(1.0 mmol) in dichloromethane (5.0 mL) was added 10 mol%
of molecular iodine at 0 °C. The resulting mixture was stirred
at 25 °C for the specified time. The progress of the reaction
was monitored by TLC using ethyl acetate and hexane as the
eluent. After completion, the mixture was quenched with water
and the product was extracted with ethyl acetate. The organic
layers were washed with aqueous sodium thiosulfate followed
by a brine solution and dried over anhydrous sodium sulfate.
Removal of the solvent followed by purification on silica gel
(Merck 100–200 mesh) using ethyl acetate/hexane (2 : 8) as the
eluent gave the pure tetrahydropyran.
7 (a) J. D. Elsworth and C. L. Willis, Chem. Commun., 2008,
1587; (b) S. N. Chavre, P. R. Ullapu, S. J. Min, J. K. Lee,
A. N. Pae, Y. Kim and Y. S. Cho, Org. Lett., 2009, 11, 3834;
(c) A. Barbero, A. Diez-Varga and F. J. Pulido, Org. Lett.,
2013, 15, 5234.
8 (a) Y. S. Cho, H. Y. Kim, J. H. Cha, A. N. Pae, H. Y. Koh,
J. H. Choi and M. H. Chang, Org. Lett., 2002, 4, 2025;
(b) Z.-H. Chen, Y.-Q. Tu, S.-Y. Zhang and F. M. Zhang, Org.
Lett., 2011, 13, 724; (c) E. Fenster, C. Fehl and J. Aube, Org.
Lett., 2011, 13, 2614.
Acknowledgements
B. V. S thanks CSIR, New Delhi for the financial support as a
part of the XII five year plan program under the title ORIGIN
(CSC-0108).
Notes and references
1 (a) M. Zahel and P. Metz, Beilstein J. Org. Chem., 2013, 9,
2028; (b) B. M. Fraga, Nat. Prod. Rep., 2012, 29, 1334;
(c) D. A. Foley and A. R. Maguire, Tetrahedron, 2010, 66,
1131; (d) R. Ratnayake, D. Covell, T. T. Ransom,
9 (a) A. J. Bunt, C. D. Bailey, B. D. Cons, S. J. Edwards,
J. D. Elsworth, T. Pheko and C. L. Willis, Angew. Chem., Int.
Ed., 2012, 51, 3901; (b) B. D. Cons, A. J. Bunt, C. D. Bailey
and C. L. Willis, Org. Lett., 2013, 15, 2046.
K. R. Gustafson and J. A. Beutler, Org. Lett., 2009, 11, 57; 10 (a) X. F. Yang, M. Wang, Y. Zhang and C. J. Li, Synlett, 2005,
(e) M. Zahel, A. Keßberg and P. Metz, Angew. Chem., Int.
Ed., 2013, 52, 5390.
1912; (b) H. M. Lee, C. N. Oberhuber and M. D. Shair,
J. Am. Chem. Soc., 2008, 130, 16864.
2 (a) C. Sourbier, B. T. Scroggins, R. Ratnayake, T. L. Prince, 11 Y. M. Ren, C. Cai and R. C. Yang, RSC Adv., 2013, 3,
S. Lee, M.-J. Lee, P. L. Nagy, Y. H. Lee, J. B. Trepel,
7182.
Org. Biomol. Chem.
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12 (a) H. Togo and S. Iida, Synlett, 2006, 2159; (b) V. Hojat,
Curr. Org. Chem., 2011, 15, 2438; (c) K. R. K. K. Reddy,
(b) J. S. Yadav, G. Narasimhulu, N. Umadevi, Y. V. Reddy
and B. V. S. Reddy, Tetrahedron Lett., 2013, 54, 871.
I. M. L. Rosa, A. C. Doriguetto, E. L. Bastos and L. F. Silva 14 CCDC 1048635 contains supplementary crystallographic
Jr., Molecules, 2013, 18, 11100. data for product 3j.
13 (a) N. P. Raju, B. J. M. Reddy, R. Anjibabu and 15 A. Diez-Varga, H. Barbero, F. J. Pulido, A. Gonzalez-Ortega
B. V. S. Reddy, Tetrahedron Lett., 2013, 54, 3639;
and A. Barbero, Chem. – Eur. J., 2014, 20, 14112.
This journal is © The Royal Society of Chemistry 2015
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