Sequential oxidation-prins reaction processes induced by the same iron salt: Direct access to 2-aryl-4-chloro-tetrahydropyrans from benzyl alcohols

Article abstract of DOI:10.1055/s-0033-1339306

A clay-supported iron(III) nitrate (Clayfen) was used as a stoichiometric reagent to first oxidize benzylic alcohols. The aldehydes thus obtained were converted in situ into tetrahydropyrans by way of a Prins cyclization induced by iron species already present in the media. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0033-1339306

LETTER
▌1781
lSeteterquential Oxidation–Prins Reaction Processes Induced by the Same Iron
Salt: Direct Access to 2-Aryl-4-Chloro-Tetrahydropyrans from Benzyl
Alcohols
Synthesis of 2-Aryl-4-Chloro-Tetrahydropyrans
Fabienne Fache,* Mickaël Muselli, Olivier Piva*
Université de Lyon, Université Lyon 1, Institut de Chimie et de Biochimie Moléculaire et Supramoléculaire (ICBMS), UMR 5246 CNRS,
Bat Raulin, 43, Bd du 11 Novembre 1918, 69622 Villeurbanne Cedex, France
Fax +33(4)72448136; E-mail: piva@univ-lyon1.fr
Received: 03.05.2013; Accepted after revision: 03.06.2013
reaction to the desymmetrization of 1,6-heptadien-4-ol16b
Abstract: A clay-supported iron(III) nitrate (Clayfen) was used as
but also developed a solvent-free and metal-free pro-
a stoichiometric reagent to first oxidize benzylic alcohols. The alde-
cess.18 Moreover, the same process was successfully
hydes thus obtained were converted in situ into tetrahydropyrans by
way of a Prins cyclization induced by iron species already present
applied to the synthesis of sultams.19
in the media.
OH
O
HO
Key words: oxidation, benzyl alcohols, Prins cyclization, sequen-
tial reactions, iron catalysis
O
( )2
O
7
1
OMe
centrolobine
Sequential and tandem reactions are very attractive pro-
cesses to prepare, by way of one-pot procedures, more
complex structures.1 They avoid painstaking isolations of
presumably volatile compounds and generally give better
chemical yields than the processes with multiple purifica-
tions. In this promising and extremely competitive area,
tandem oxidation processes (TOP) which associate a se-
lective oxidation reaction with further functionalization,
have been investigated by a large number of groups.2–4
Taylor et al. demonstrated the usefulness of manganese
dioxide as the oxidant to generate in situ aryl aldehydes
from benzyl alcohols. The thus-obtained structures were
directly implicated in different new C–C bond formations
to deliver more elaborate structures.2 Performed in the
diospongine A
HO
OH
H
H
O
O
H
OH
OH
blepharocalyxin D
presence of stabilized phosphoranes, a straightforward ac- Figure 1 Some tetrahydropyran natural products
cess to α,β-unsaturated esters was achieved,5 while the
synthesis of cyclopropanes was also reported when op-
It is noteworthy that aldehydes are highly sensitive to ox-
idative conditions leading to carboxylic acids.20 In order
to find an alternative procedure, epoxides have been al-
ready considered as surrogates of aldehydes for the Prins
reaction when submitted in the presence of strong Lewis
acids.21 Herein, we have investigated the conversion of
the more readily available benzylic alcohols into alde-
hydes under mild conditions which could be combined
with a further cyclization step. To minimize the amounts
of metal salts during the first step, we discarded MnO2
which required usually a large number of equivalents.22
Furthermore, we were interested to develop a one-pot re-
action in which the same metal salt could induce not only
the oxidative step but also the formation of the tetrahydro-
pyran ring. Such a process, obeying to the green chemistry
principles,23 could be also highly attractive in terms of
cost. While iron salts have been widely used for the Prins
reaction15 and are also commonly associated with numer-
ous processes,24 we have focused our investigations with
iron(III) nitrate supported on bentonite K10, a reagent
posed with sulfur ylides.6
Tetrahydropyran is an important subunit found in a large
number of biological active compounds such as 1,7-di-
arylheptanoides.7 Some are dispatched on Figure 1. For ex-
ample, diospongine A,8–10 exhibits antiosteoporosis
activities, while centrolobine is a compound of interest for
the treatment of leishmaniose.11 More complex structures
as blepharocalyxin D with antiproliferative activities
against human HT-1080 fibrasarcoma cells have been
more recently isolated and synthesized.12 Among the dif-
ferent methods to prepare these heterocycles, two process-
es have emerged: oxa-Michael reactions from ε-hydroxy
α,β-unsaturated ketones or esters13,14 and the Prins reac-
tion generally conducted between an aldehyde and a
homoallylic alcohol.15–17 We recently applied the latter
SYNLETT 2013, 24, 1781–1784
Advanced online publication: 18.07.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1339306; Art ID: ST-2013-B0414-L
© Georg Thieme Verlag Stuttgart · New York

1782
F. Fache et al.
LETTER
first reported in the 1980s by Laszlo et al. for the oxidation OMe or NO2 substituents, some byproducts were detect-
of alcohols.25
ed, which could explain these low overall yields. Finally,
halogenated substrates gave access very efficiently to tetra-
hydropyran derivatives of potential high synthetic inter-
est. Having in hand a one-pot sequential method to
convert benzyl alcohols into tetrahydropyran derivatives,
we investigated a more appealing tandem procedure. It
was anticipated that benzyl alcohols could be selectively
oxidized in the presence of homoallylic alcohols. When a
solution of both benzyl alcohol 1a and 3 in dichlorometh-
ane was submitted to the action of iron(III) nitrate, fol-
lowed by addition of TMSCl at room temperature, the
reaction was stopped after four hours, and the Prins prod-
uct 4a was isolated in only 52% yield (Table 1). This low-
er value was attributed to a competitive oxidation of 3
before the sequential addition of TMSCl. No improve-
ment was noticed when all the reactants were placed
together in the same vessel.
The sequential process was first tested with benzyl alco-
hol in the presence of stoichiometric amounts of oxidizing
reagent, in pentane and at 35 °C (Scheme 1).26 After four
hours, a total conversion was noticed (TLC control). 3-
Buten-1-ol (3) and trimethylsilyl chloride were then di-
rectly added, and the resulting heterogeneous mixture was
stirred for two additional hours at room temperature. To
our delight, 4-chloro-2-phenyl-tetrahydropyran (4a) was
isolated in 62% yield, and NMR analysis revealed the ex-
clusive formation of the cis stereomer. In order to improve
the efficiency of this process, we first decided to change
the nature of the solvent, while the Prins reactions are usu-
ally conducted in dichloromethane instead of alkanes. Un-
der these new conditions,27 after the same time of reaction,
the chemical yield of 4a was noticeably improved to 75%.
CHO
Fe(NO3)3•9H2O
bentonite K10
Cl
OH
1) Fe(NO3)3•9H2O
bentonite K10
CH2Cl2, 35 °C
solvent, 35 °C, 4 h
OH
1a
2a
O
Cl
O
2) 3 + TMSCl, r.t.
R
OH
1
R
3
4 (31–82%)
TMSCl
Scheme 2 Generalization of the sequential process
solvent, r.t., 2 h
4a (62% in pentane)
(75% in CH2Cl2)
Table 1 Scope of Fe(NO3)3–Bentonite-Induced Benzyl Alcohols
Oxidation–Prins Cyclization Sequence Using 3-Buten-1-ol
Scheme 1 Sequential alcohol oxidation–Prins cyclization
Entry
Alcohol 1
R
Yield of 4 (%)a cis/trans
It is noteworthy that the second transformation was per-
formed without new additions of iron species. As we al-
ready demonstrated in a recent report, TMSCl can
promote the Prins cyclization between an aldehyde and 3
without any metal catalyst present in the media. However,
this process was successful only under neat conditions.18
While the present process was carried out at 0.5 M con-
centration, a plausible synergistic effect between iron salts
and TMSCl was suspected. The importance of the pres-
ence of iron salts was clearly demonstrated by placing
benzaldehyde and 3, only in the presence of trimethylsilyl
chloride in dichloromethane. Formation of 4a was noticed
but after four hours, conversion was only 60%. Of inter-
est, the beneficial role of the clay for the Prins reaction
could not be totally excluded as demonstrated by two re-
cent reports, which appeared during our investigations.28
This sequential procedure29 was then applied to different
benzylic alcohols leading to different 2-aryl-4-chloro-
tetrahydropyrans in moderate to high yields (31–82%,
Scheme 2). All the results are collected in Table 1. What-
ever the nature of the substituents present on the aryl
group, cis adducts were predominant, as usually noticed in
Prins cyclizations. Substitution of the phenyl ring with
electron-donating groups led to lower isolated yields.
With electron-withdrawing groups such as NO2, the yields
were also lower whereas with CF3 comparable good
yields were measured. During the oxidation step, with
1
1ab
1ac
1b
1c
1d
1e
1f
H
4a 75
4a 52
4b 55
4c 40
4d 31
4e 42
4f 58
4g 72
4h 66
4i 75
4j 82
100:0
100:0
100:0
5:1
2
H
3
4-Me
4-MeO
2-MeO
2-O2N
4-O2N
4-F3C
3-F3C
2-I
4
5
100:0
100:0
100:0
10:1
6
7
8
1g
1h
1i
9
7:1
10
11
100:0
100:0
1j
4-Br
a Isolated yield of pure product.
b Reaction performed at r.t.
c First step performed in the presence of 3.
In order to extend the scope of this reaction, the procedure
was also applied to substituted homoallylic alcohols 5a–c,
readily available by standard procedures. Reaction be-
tween benzyl alcohol (1a) and substituted homoallylic
alcohols 5 led to the formation of 2,6-disubstituted
4-chloro-tetrahydropyrans 6 (Scheme 3, Table 2). Unfor-
Synlett 2013, 24, 1781–1784
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of 2-Aryl-4-Chloro-Tetrahydropyrans
1783
tunately, the sequence proceeded with lower yields and studies are in progress to expand the scope of this method
selectivities, while compounds 7 resulting from the oxo- and find application in natural product synthesis.
nia-Cope rearrangement30 were also isolated as side prod-
ucts. Considering the difficulty to oxidize primary
Acknowledgment
aliphatic alcohols with the Lazslo’s reagent,25 attempts to
Financial support from Université de Lyon and CNRS are warmly
acknowledged.
carry out this sequential process to these reluctant starting
materials was not achieved.
Supporting Information for this article is available online at
H
Fe(NO3)3•9H2O
bentonite K10
http://www.thieme-connect.com/ejournals/toc/synlett.SnuIpofoiprmntgirStanoIuifpog
r
t
iornat
Ph
O
Ph
OH
CH2Cl2, 35 °C
Cl
1a
2
References and Notes
R
TMSCl
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Cl
OH
5
+
CH2Cl2, r.t.
Ph
O
6
R
R
O
7
R
Scheme 3 Access to 2,6-disubstituted 4-chlorotetrahydropyrans 6
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Entry
5
R
Yield of 6 (%)
Yield of 7 (%)
1
2
3
5a
Ph
6a 40
6b 15
6c 45
–
5ba
5cb
CH2CH=CH2
C6H13
7b 15
7c 25
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1) Fe(NO3)3•9H2O
bentonite K10
H
Ph
OH
Ph
O
CH2Cl2, 35 °C
1a
2) TMSCl
Cl
N
Cl
N
NHTs
Ph
8
Ph
r.t.
Ts
9a
Ts
9b
60% (1:9)
Scheme 4 Sequential alcohol oxidation–aza-Prins cyclization
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In conclusion, iron nitrate supported on bentonite is a re-
agent of choice to perform, in a one-pot manner, the oxi-
dation of benzyl alcohols into aldehydes which can then
be involved in a Prins cyclization with homoallylic alco-
hols and trimethylsilyl chloride. This sequence provides a
direct access to 2-aryl-4-chloro-tetrahydropyrans from
readily available and less sensitive substrates. Further
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 1781–1784

1784
F. Fache et al.
LETTER
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(27) Whereas these procedures worked out very safely in our
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appropriate caution has to be applied for both steps. In
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(29) Typical Procedure
For stability reasons, the catalyst was prepared just before
use: Fe(NO3)3·9H2O (112.5 mg, 0.27 mmol) was diluted in
acetone (2 mL), and the resulting mixture was stirred for 5
min. Then, bentonite K10 (150 mg) was added, and the
mixture was stirred for additional 5 min. After careful
concentration until dryness, under vacuum at 50 °C (and
strictly not at higher temperature), the resulting powder was
immediately implicated in the oxidation procedure. Benzyl
alcohol (0.5 mmol) in CH2Cl2 (1.5 mL) was added to the just
prepared catalyst, and the resulting heterogeneous mixture
was stirred at 35 °C until complete conversion (around 4 h,
TLC monitoring). After cooling to r.t., homoallylic alcohol
3 (0.5 mmol) and trimethylsilylchloride (80 μL, 0.6 mmol)
were added at once, and the reaction mixture was stirred for
two additional hours at r.t. The crude mixture was then
directly chromatographied to deliver the expected
tetrahydropyran. All data were in agreement with the
literature.
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Synlett 2013, 24, 1781–1784
© Georg Thieme Verlag Stuttgart · New York