Synthesis of substituted dihydrobenzothiopyrans and dihydrobenzopyrans by cation-mediated cyclisation reactions

Article abstract of DOI:10.1016/j.tetlet.2005.03.161

Treatment with acid of thiosalicylaldehyde- and salicylaldehyde-derived phenyl 3-phenyl-2-propenyl thioethers and ethers possessing latent oxonium ion functionality triggers simple or tandem cyclisation to give substituted dihydrobenzothiopyrans and dihyd

Full text of DOI:10.1016/j.tetlet.2005.03.161

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 3719–3723
Synthesis of substituted dihydrobenzothiopyrans and
dihydrobenzopyrans by cation-mediated cyclisation reactions
Jean-Franc¸ois Bonfanti and Donald Craig*
Department of Chemistry, Imperial College London, South Kensington Campus, London SW7 2AZ, UK
Received 24 February 2005; accepted 21 March 2005
Available online 8 April 2005
Abstract—Treatment with acid of thiosalicylaldehyde- and salicylaldehyde-derived phenyl 3-phenyl-2-propenyl thioethers and
ethers possessing latent oxonium ion functionality triggers simple or tandem cyclisation to give substituted dihydrobenzothiopyrans
and dihydrobenzopyrans. Some derivatisation reactions of the products are described.
Ó 2005 Elsevier Ltd. All rights reserved.
The synthesis of heterocycles by cyclisation through car-
bon–carbon bond formation is a strategy complemen-
tary to the more classical approach involving reaction
of carbon-based electrophilic functional groups with
nucleophilic heteroatoms. In this context, cycloaddi-
tion,1 radical cyclisation,2 ring-closing olefin metathesis3
and anion-4 and carbocation-assisted5 cyclisation
reactions all have recently been deployed. We have
investigated the formation of oxygen- and nitrogen-con-
taining heterocycles through the intramolecular combi-
nation of electron-rich olefins with, respectively,
acetal-derived oxocarbenium ions6 and thionium species
derived either by Pummerer reactions of sulfoxides7 or
by ionisation of a-arylsulfonyl thioethers.8 Some of this
work6b,8 showed that 3-phenyl-2-propenyl groups are
effective intramolecular nucleophiles for oxonium and
thionium ion electrophiles, with the intermediate benz-
ylic cations resulting from the heterocyclisation process
undergoing addition or elimination according to the
reaction conditions (Scheme 1).
using this approach, in which the requisite benzylic cat-
ionic intermediates generated from substrates 1 and 2
would be stabilised additionally by the sulfur or oxygen
atom through which the nucleophilic 3-aryl-2-propenyl
group was appended (Scheme 2). This letter reports
the results of these investigations.
Substrate 1 was studied first. It was assembled using a
simple, four-step sequence beginning from commercially
available methyl thiosalicylate.11 Sulfur alkylation with
E-1-bromo-3-phenyl-2-propene using guanidinium
carbonate in acetone,12 followed by low-temperature
DIBAL-H-mediated ester reduction in CH2Cl2 and oxi-
dation of the resulting primary alcohol with PCC13 gave
an intermediate aldehyde. Finally, acid-catalysed acetali-
sation with trimethyl orthoformate provided 1 in 87%
overall yield from methyl thiosalicylate.
A number of reagents and reaction conditions were evalu-
ated for the cyclisation of 1 before tin(II)chloride–chlo-
rotrimethylsilane was identified as the best combination.
Thus, treatment of 1 with 2 equiv of TMSCl and sub-
stoichiometric SnCl2 in CH2Cl2 at 0 °C14 resulted in
We became interested in the possibility of synthesising
dihydrobenzothiopyrans9 and dihydrobenzopyrans10
PhSO2
PhSO2
Ts
N
Ts
N
O
AgOTf, DBU
ref. 6ii
TiCl4
ref. 8
O
H
Ph
O
S
O
major (4:1)
products
SMe Cl
Ts
Py
OTBDPS
Ph
OTBDPS
SMe Ph
Ph
Scheme 1.
Keywords: Dihydrobenzopyran; Dihydrobenzothiopyran; Cationic cyclisation; Tandem process; Thioether.
*
Corresponding author. Tel.: +44 020 7594 5771; fax: +44 020 7594 5868; e-mail: d.craig@imperial.ac.uk
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.03.161

3720
J.-F. Bonfanti, D. Craig / Tetrahedron Letters 46 (2005) 3719–3723
X
Ph
X
X
X
OMe Nu
X
or
Ph
X = S, O
Ph
MeO
Ph
MeO
Ph
OMe
MeO
1 (X = S)
2 (X = O)
OMe
Scheme 2.
S
1. guanidinium carbonate,
Cl
TMSCl (2 equiv),
SnCl2 (0.1 equiv),
E-PhCH=CHCH2Br, Me2CO
SH
S
H
H
H
2. DIBAL-H, CH2Cl2
3
4
MeO
S
Ph
CH2Cl2 (0.2 M)
0 ºC, 2 h
3. PCC, CH2Cl2
4. (MeO)3CH, CSA
CO2Me
MeO
OMe Ph
Cl
H
1
82%
(3 : 4 = 3:2)
87% overall
MeO
Ph
Scheme 3.
the formation of two diastereoisomeric dihydrobenzo-
thiopyrans in a 3:2 ratio and 82% combined yield. Struc-
ture 3 was assigned to the major isomeric product by
X-ray crystallographic analysis of a single crystal. The
minor product was assigned as 4 by X-ray crystallogra-
phy following oxidation to the corresponding sulfone in
quantitative yield using m-CPBA in CH2Cl2.15 The syn-
thesis and cyclisation reaction of 1 are shown in Scheme
3.
of salicylaldehyde dimethyl acetal16 with E-1-bromo-3-
phenyl-2-propene using the same conditions as in the
synthesis of substrate 1, providing 2 in 82% yield from
salicylaldehyde. Exposure of 2 to the conditions used
successfully for substrate 1 resulted in the formation in
85% yield of a 7.4:1 separable mixture of diastereomers
6. The 3,4-cis substitution of the C3 chlorobenzyl and
C4 methoxy substituents in 6 followed from the rela-
tively small (4 Hz) vicinal J3,4 values (4 and 2 Hz) for
1
the C3 methine signals in the H NMR spectra. Treat-
Inspection of structures 3 and 4 reveals that both are
products of stereospecific anti-addition of the internal
oxonium ion and chloride to the E-double bond in 1.
That 3 and 4 differed with respect to the newly formed
methoxy-bearing stereocentre was further confirmed by
the formation of two diastereomers of 1-methoxy-2-
methyl-1,3-diphenylpropane on separate treatment with
Raney nickel. The lack of stereoselectivity is perhaps
indicative of competing interactions of similar magni-
tude involving the oxonium ion and the ortho-hydrogen
atom in the reactive conformation leading to 3, and a
pseudoaxial methylene hydrogen atom in that leading
to 4 (Scheme 4).
ment of the diastereomeric mixture with Raney nickel
gave a single dihydrobenzopyran 7, in contrast to sul-
fur-containing products 3 and 4, which had given
isomeric products upon desulfurisation–dechlorination.
The synthesis of 2 and its cyclisation and derivatisation
reactions are depicted in Scheme 5.
The results depicted in Scheme 5 show that in contrast
with the cyclisation of 1, that of 2 exhibited complete
selectivity with respect to the stereocentres on the newly
formed oxygen heterocycle. This may arise by a lessen-
ing of the oxonium–pseudoaxial hydrogen interaction
similar to that postulated in the reactive conformation
leading to 4 because of the greater C–O–C bond angle.
The lack of anti-specificity of addition to the double
bond may be a consequence of the greater rate of intra-
Attention was next turned to the oxygenated analogue 2.
This substrate was readily synthesised by O-alkylation
S
S
Ni(R)
Ni(R)
Ph
MeO
Ph
Ph
MeO
Ph
Cl
H
Cl
H
EtOH
reflux
EtOH
reflux
H
H
3
5
6
4
MeO
Ph
MeO
Ph
S
H
δ+
S
S
Cl
O
δ-
δ-
Me
H
Cl
OMe Ph
H
O
δ+
Me
Scheme 4.

J.-F. Bonfanti, D. Craig / Tetrahedron Letters 46 (2005) 3719–3723
3721
1. (MeO)3CH, CSA,
CH2Cl2, MeOH
OH
O
TMSCl (2 equiv),
SnCl2 (0.1 equiv),
O
Cl
CHO
CH2Cl2 (0.2 M)
0 ºC, 2 h
2. guanidinium carbonate,
E-PhCH=CHCH2Br,
Me2CO
MeO
H
MeO
MeO
85%
2
6 (7.4:1 mixture)
82% overall
O
Ni(R), EtOH, reflux
H
7
MeO
Scheme 5.
molecular interception of the oxonium ion on account of
the shorter C–O bonds appending the 3-phenyl-2-propen-
yl internal nucleophile.
Head unit 10 (R = Bn) was readily prepared in 62%
overall yield by benzylation of methyl thiosalicylate fol-
lowed by two-step conversion into the aldehyde; Wittig
homologation and DIBAL-H reduction completed the
synthesis. Compounds 8 and 9 (P = TBDPS) were made
from common intermediates again derived from methyl
thiosalicylate. Reduction was followed by oxidation to
the aldehyde, which simultaneously effected thiol protec-
tion through formation of the symmetrical disulfide–
aldehyde 12.17 This was processed in two separate
routes; simple aldehyde protection gave disulfide–acetal
14 in quantitative yield, whilst Wittig homologation18
followed by ester reduction and allylic alcohol protec-
tion gave disulfide–silyl ether 13. Substrate 11 (n = 1,
R = Bn) was then easily assembled using disulfide reduc-
tion-Mitsunobu chemistry. Treatment of 13 with Bu3P–
H2O in THF gave thiol 9 (P = TBDPS), and the crude
product was coupled with 10 (R = Bn) in the presence
of diisopropyl azodicarboxylate (DIAD) to give 15.
Desilylation of 15 under standard conditions and com-
bination with thiol 8, which had been freshly prepared
from 14 using the conditions employed for the gener-
ation of 9, gave 11 (n = 1, R = Bn) in good overall yield
(Scheme 8).
The final part of our study looked at the possibility of
achieving cation-mediated cascade cyclisations using
oligomeric substrates related to 1. Our idea was that a
substrate comprising a latent oxonium ion trigger and
repeat units of the E-3-phenyl-2-propenylthio Ômono-
merÕ present in 1 might undergo ionisation followed by
a cascade of cyclisation reactions in an anti-specific
manner as depicted in Scheme 6.
An attractive aspect of this plan was the anticipated ease
with which the required substrates 11 would be accessi-
ble synthetically, using inherently reactive arenethiol–
allylic alcohol combinations. We envisaged initial com-
bination of a head unit 10 with ÔmonomerÕ 9 followed
by iterative attachment of further units of 9, and finally
a capping fragment 8 possessing the latent cationic cen-
tre (Scheme 7).
In order both to assess the chemical feasibility of both
the cyclisation reaction and to evaluate the chemistry
planned for the assembly of precursors, we elected to
synthesise a cyclisation substrate 11 (n = 1, R = Bn) cor-
responding to a simple one-monomer extension of 1.
With a robust synthesis of 11 (n = 1, R = Bn) in hand, its
cyclisation behaviour was studied. Disappointingly, the
S
S
H
H
S
S
H
H
H
S
S
H
H
S
S
MeO
MeO
Scheme 6.
SR
SR
S
SH
CH(OMe)2
PO
n
+
+
MeO
MeO
11
S
SH
OH
8
9
10
n
Scheme 7.

3722
J.-F. Bonfanti, D. Craig / Tetrahedron Letters 46 (2005) 3719–3723
1. BnBr,
guanidinium carbonate,
Me2CO, reflux
OHC
S
S
SBn
2. DIBAL-H, CH2Cl2
SH
1. LiAlH4, Et2O-THF
2. PCC, CH2Cl2
57%
3. PCC, CH2Cl2
4. MeO2CCHPPh3, CH2Cl2
5. DIBAL-H, CH2Cl2
12
CHO
CO2Me
10
(R = Bn)
OH
(MeO)3CH,
CSA
100%
62% overall
1. MeO2CCHPPh3, CH2Cl2
2. DIBAL-H, CH2Cl2
3. TBDPSCl, Et3N, DMAP
SH
10 + crude 9
59%
OTBDPS
9 (P = TBDPS)
DIAD, Bu3P
THF
(MeO)2CH
13
14
TBDPSO
S
S
87%
S
S
Bu3P, H2O, THF
SH
CH(OMe)2
OTBDPS
CH(OMe)2
Bu3P, H2O, THF
SBn
8
SBn
S
TBDPSO
S
1. TBAF, THF
11 (n = 1, R = Bn)
2.
add alcohol and crude 8 to
DIAD, Bu3P, THF
MeO
MeO
15
S
77%
Scheme 8.
SnCl2–TMSCl conditions used previously for the cyclisa-
tions of 1 and 2 failed to yield significant amounts of
ring-closure products, as did a range of other Lewis acid
reagent systems. After extensive experimentation it was
found that 11 (n = 1, R = Bn) underwent cyclisation
on treatment with K10 Montmorillonite clay, giving a
new product in 33% yield. However, oxidation (m-
CPBA) to the corresponding sulfone and X-ray crystal-
lographic analysis15 revealed the structure of the cyclised
product to be 16. Presumably, this unexpected tetracy-
clic substance is formed by internal trapping of the
oxonium ion formed initially, followed by interception
of the resulting benzylic cation with a methoxy nucleo-
phile in a fashion similar to the cyclisation of 1.
Subsequently, the product of this mono-cyclisation
undergoes a second ionisation followed by intramolecu-
lar trapping by the thioether sulfur atom and allylic
carbon–sulfur bond scission from the resultant labile
sulfonium ion intermediate (Scheme 9).
In conclusion, we have shown that a simple 3-phenyl-2-
propenyl thioether derivative of thiosalicylaldehyde di-
methyl acetal undergoes efficient, stereospecific—with
respect to the nucleophilic double bond—but non-stereo-
selective cyclisation on treatment with a Lewis acid. A
structurally similar ether-containing substrate under-
goes completely stereoselective cyclisation, but in a
non-stereospecific manner with respect to the substrate
double bond. A higher-order cyclisation substrate was
synthesised using an iterative strategy, which should
prove amenable to the synthesis of higher oligomeric
substrates. Attempted cascade cyclisation resulted in
carbon–carbon and carbon–sulfur bond formation. Fu-
ture investigations will focus on the development of
modified substrates possessing alternative, less highly
oxidised latent cationic functionality, which prohibits
the second, unwanted ionisation process, which triggers
substrate breakdown by nucleophilic attack through
sulfur.
S
H
S
H
K-10 clay
11 (n = 1, R = Bn)
OMe
OMe
OMe
CH2Cl2, rt 24 h
H
H
H
H
16
S
S
33%
R'
S
S
S
H
OMe
OMe
MeO
SR'
MeO
SR'
R'S
R' = 2-BnSC6H4CH:CHCH2
Scheme 9.

J.-F. Bonfanti, D. Craig / Tetrahedron Letters 46 (2005) 3719–3723
3723
7. Craig, D.; Daniels, K.; MacKenzie, A. R. Tetrahedron
1992, 48, 7803.
Acknowledgements
´
8. Craig, D.; Meadows, J. D.; Pecheux, M. Tetrahedron Lett.
1998, 39, 141.
9. Crow, W. D.; Pang, Y. T. Aust. J. Chem. 1984, 37, 1903;
Ishino, Y.; Masaoka, T.; Hirashima, T. Chem. Lett. 1990,
1185.
10. For leading references, see: Nguyen, M. P.; Arnold, J. N.;
Peterson, K. E.; Mohan, R. S. Tetrahedron Lett. 2004, 45,
9369.
11. All commercially available starting materials were pur-
chased from Aldrich Chemical Co.
We thank F. Hoffmann-La Roche Ltd, Basel (postdoc-
toral fellowship to J.-F.B.) for support.
Supplementary data
Supplementary data associated with this article can be
found in the online version, at doi:10.1016/j.tetlet.
2005.03.161.
12. Marciano, D.; Ben Baruch, G.; Maron, M.; Egozi, Y.;
Haklai, R.; Kloog, Y. J. Med. Chem. 1995, 38,
1267.
References and notes
13. Anthony, J.; Boldi, A. M.; Rubin, Y.; Holbi, M.;
Gramlich, V.; Knobler, C. B.; Seiler, P.; Diederich, F.
Helv. Chim. Acta 1995, 78, 13.
´ ´
´
1. Davion, Y.; Joseph, B.; Beneteau, V.; Leger, J.-M.; Jarry,
´
C.; Merour, J.-Y. Helv. Chim. Acta 2003, 86, 2687.
2. For a recent review, see: Majumdar, K. C.; Basu, P. K.;
Mukhopadhyay, P. P. Tetrahedron 2004, 60, 6239.
3. For a recent review, see: Deiters, A.; Martin, S. F. Chem.
Rev. 2004, 104, 2199.
4. For a recent example, involving an intramolecular Stetter
reaction, see: Kerr, M. S.; de Alaniz, J. R.; Rovis, T.
J. Am. Chem. Soc. 2002, 124, 10298.
5. Overman, L. E. Aldrichim. Acta 1995, 28, 107; See also:
Padwa, A.; Heidelbaugh, T. M.; Kuethe, J. T.; McClure,
M. S. J. Org. Chem. 1998, 63, 6778, and references cited
therein.
6. (a) Craig, D.; King, N. P.; Shaw, A. N. Tetrahedron Lett.
1997, 38, 8599; (b) Craig, D.; Pennington, M. W.; Warner,
P. Tetrahedron 1999, 55, 13495; (c) Craig, D.; Munasin-
ghe, V. R. N.; Tierney, J. P.; White, A. J. P.; Williams,
D. J.; Williamson, C. Tetrahedron 1999, 55, 15025.
14. Mukaiyama, T.; Wariichi, K.; Saito, Y.; Hayashi, M.;
Kobayashi, S. Chem. Lett. 1988, 1101.
15. We thank Dr. Andrew J. P. White (Department of
Chemistry, Imperial College London) for the X-ray
structure determinations. Full details will be published
elsewhere.
16. Inoue, S.; Asami, M.; Honda, K.; Miyazaki, H. Chem.
Lett. 1996, 889.
17. Kasmai, H. S.; Mischke, S. G. Synthesis 1989,
763.
18. The Wittig reaction of 12 with MeO2CCHPPh3 gave
significant amounts (ca. 20%) of methyl benzothiophene-
2-carboxylate as a by-product; this was the sole product
formed (47% yield) when 12 was subjected to Wadsworth–
Horner–Emmons reaction with the sodium salt of tri-
methyl phosphonoacetate.