Axial-selectivity in prins cyclization reaction: Synthesis of 4-iodotetrahydropyrans

Article abstract of DOI:10.1246/cl.2011.1176

Trimethylsily1 triflate and tetrabutylammonium iodide (TBAI) effectively mediate the Prins cyclization of homoallylic alcohols and aldehydes to give 4-iodotetrahydropyrans with axial selectivity and good yields.

Full text of DOI:10.1246/cl.2011.1176

doi:10.1246/cl.2011.1176
1176
Published on the web October 1, 2011
Axial-selectivity in Prins Cyclization Reaction: Synthesis of 4-Iodotetrahydropyrans
Anil K. Saikia,* Somasekhar Bondalapati, Kiran Indukuri, and Paramartha Gogoi
Department of Chemistry, Indian Institute of Technology Guwahati, Guwahati 781039, India
(Received June 13, 2011; CL-110491; E-mail: asaikia@iitg.ernet.in)
Trimethylsilyl triflate and tetrabutylammonium iodide
With the result in hand, the reaction was investigated using
different Lewis acids and is summarized in Table 1. Reaction of
4-bromobenzaldehyde and homoallylic alcohol with BF3¢OEt2/
NaI and TMSCl/NaI gave a 1:1 mixture of axial and equatorial
isomers with 46% and 91% yield, respectively (Entries 1 and 4).
The reaction with TMSI along with catalytic amount of 2,6-
lutidine gave a 3:2 mixture of equatorial and axial products
(Entry 3) which was in contrast to the results reported by
Rychnovsky.19 On the other hand, BF3¢OEt2/TBAI and
TMSCl/TBAI gave mixtures with ratios 1:2.5 and 1:2 in 78%
and 62% yield, respectively (Entries 2 and 5). It was observed
that systems like InCl3/TBAI, Sc(OTf)3/TBAI, and In(OTf)3/
TBAI were not suitable for this reaction (Entries 6-8). The
reaction with one equivalent of TMSOTf produced a single
diastereomer 2b with 76% yield, which was confirmed by
1H NMR of crude product (Entry 10). The same reaction with
catalytic amount of TMSOTf gave only 18% yield (Entry 9).
Replacement of TBAI with iodine (Entry 11) also gave a
mixture (1:1) of products. The scope of the reaction was further
studied with varieties of aldehydes and homoallylic alcohols
under the same reaction conditions (Table 2). Both aliphatic and
aromatic aldehydes gave axial selective products with high
yields and diastereoselectivity. Simple aromatic aldehydes,
benzaldehyde and aldehydes having electron-donating substitu-
ents on an aromatic ring, such as 4-methoxybenzaldehyde, gave
equatorial and axial diastereomers 5 and 6 with a ratio of 1:1 and
1:2, respectively (Figure 1). This is due to the stabilization of
oxocarbenium ion by phenyl and methoxy groups, which leads
to oxina-Cope rearrangement. Similarly, reaction with bro-
(TBAI) effectively mediate the Prins cyclization of homoallylic
alcohols and aldehydes to give 4-iodotetrahydropyrans with
axial selectivity and good yields.
The Prins cyclization is an important reaction for carbon-
carbon and carbon-heteroatom bond formation and it has long
been used for the synthesis of highly substituted tetrahydropyrans
with high stereoselectivity.1 The main advantage of Prins
cyclization is its all-cis selectivity. The tetrahydropyran unit is
found in many natural and biologically active compounds.2
Therefore, efficient and selective synthesis of tetrahydropyran
is of great importance in organic synthesis. Recently, several
groups have reported the highly selective synthesis of all-cis
4-substituted tetrahydropyrans with good yields.2 Among these,
4-halotetrahydropyrans are important in organic synthesis be-
cause they can be transformed into other substituted tetrahydro-
pyrans.2g,3 Generally, 4-halotetrahydropyrans are prepared using
Lewis acids such as SnCl4,4 SnBr4,5 TMSBr,2a-2c TiCl4,6 TiBr4,7
TiF4,8 InCl3,9 AlCl3,10 FeCl3,3b ZrCl4,11 BF3¢OEt2,12 NbCl4,13
BiCl3,14 TMSI,15 CeCl3,16 and others.17 The halo function in all
these reactions is placed in equatorial position. This is in
accordance to the Alder model.18 There are limited methods for
the synthesis of 4-axial halotetrahydropyrans. There are a few
methods where axial-4-halo-substituted tetrahydropyrans are
side products or 1:1 mixture with equatorial products.12,17b
Rychnovsky and co-workers have reported an axial-selective
Prins cyclization reaction by solvolysis of ¡-bromo ethers
promoted by TMSBr in high diastereoselectivity and very good
yields.19 Here, we now report an axial selective Prins cyclization
reaction for the synthesis of 4-iodotetrahydropyran from homo-
allylic alcohols and aldehydes promoted by TMSOTf and tetra-
butylammonium iodide (TBAI). In continuation of our interest
in BF3¢OEt2-mediated tetrahydropyran synthesis,20 we were in
search of a halogenating agent, other than Lewis acid, for the
synthesis of 4-halotetrahydropyrans. Considering tetrabutylam-
monium iodide as such type of iodinating agent, 4-bromobenz-
aldehyde and homoallylic alcohol were treated with tetrabutyl-
ammonium iodide under Prins cyclization conditions. To our
surprise, a diastereomeric mixture 1b and 2b with an equatorial to
axial ratio 1:2.5 was obtained in 78% yield (Scheme 1). The
result is in contrast to the usual Prins cyclization reaction.
Table 1. Prins cyclization in different conditions
Br
Br
OH
O
O
Lewis acid, DCM
O
H
+
Halide ion source
Br
1b
2b
0 °C
I
I
Iodide ion Ratio of
Entry Lewis acid (equiv)
Yielda/%
source
(1b:2b)
1
2
3
4
5
6
7
8
9
BF3¢OEt2 (1)
BF3¢OEt2 (1)
TMSI (1)/2,6-Lutidine ®
TMSCl (1)
TMSCl (1)
NaI
TBAI
1:1
1:2.5
3:2
1:1
1:2
NR
NR
NR
0:1
0:1
1:1
46
78
82
91
62
®
®
®
18
76
50
NaI
TBAI
TBAI
TBAI
TBAI
TBAI
TBAI
I2
InCl3 (1.0)
Br
Br
O
Sc(OTf)3 (1.0)
In(OTf)3 (1.0)
TMSOTf (0.1)
OH
BF3.OEt2
O
I
O
I
H
+
TBAI
DCM / 0 °C
Br
10 TMSOTf (1)
11 TMSOTf (1)
1b
2b
1b:2b = 1:2.5; 78%
aYields refer to isolated yield. The compounds are charac-
1
terized by IR, H and 13C NMR, and mass spectrometry.
Scheme 1. Synthesis of 4-iodotetrahydropyran.
Chem. Lett. 2011, 40, 1176-1178
© 2011 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

1177
R
O
R
Table 2. Synthesis of axial-4-bromo- and iodotetrahydropyran
O
OH
R
O
R'
O
I
R'
O
H
TMSOTf
TMSOTf / TBAI
+
+
TBAI / TBAB
DCM / 0 °C
OH
R
R
H
DCM / 0 °C
3
4
3
5
6
2
R"
I
when R = H; 5a:6a = 1:1; 74%
when R = OMe; 5b:6b =1:2; 80%
where R = alkyl, aryl, R' = H, alkyl
where R" = I, Br
Aldehyde 3
R =
Alcohol 4
R′ =
TBAI/
TBAB
Product
2
Yielda
/%
Entry
1
Time/h
Figure 1. Prins cyclization with benzaldehyde and 4-methoxy-
benzaldehyde.
NO2
O
4-NO2–C6H4
4-Br–C6H4
H
H
TBAI
TBAI
0.5
2a
78
76
I
Br
O
2
3
0.5
0.5
2b
I
O
3-NO2–C6H4
H
TBAI
NO2
76
2c
I
CO2Me
O
4
5
6
4-MeO2C–C6H4
C6H5–CH2
n-C6H13
H
H
H
TBAI
TBAI
TBAI
0.5
0.5
0.5
2d
85
78
83
I
Figure 2. ORTEP diagram of 4-bromo-2,6-dicyclohexyltetra-
hydro-2H-pyran (2n).
O
2e
I
Br
Br
O
C6H13
2f
O
O
I
O
7
c-C6H11
H
TBAI
TBAI
0.5
2g
82
H
I
H
I
I
4.38 ppm
1b
2b
4.91 ppm
C3H7
O
C3H7
8
9
n-C3H7
n-C2H5
n-C3H7
0.5
0.5
2h
2i
80
74
Figure 3. Chemical shift values (ppm) of axial and equatorial
protons of 1b and 2b.
I
Bn
Bn
O
C6H5–CH2 TBAI
C6H5–CH2 TBAI
determined from crude 1H NMR and single-crystal X-ray
crystallographic analysis (Figure 2).21 The axial position of the
halide group at the 4-position was determined by comparison
with equatorial products. It is known that reaction of aldehydes
with homoallylic alcohols in the presence of iodine gives
equatorial iodinated products.17c
It was observed that the equatorial proton of 2b attached to
the axial iodide resonates at 4.91 ppm and in the case of axial
proton of equatorially substituted iodide resonates at 4.38 ppm
(Figure 3). This is in agreement with the fact that the equatorial
proton resonates at lower field than the axial proton.17c,22
The mechanism of formation of axial-selective Prins cy-
clization is proposed as shown in Scheme 2. The reaction of
aldehyde 3 with alcohol 4 in the presence of TMSOTf gives
acetal 7, which after reaction with TBAI gives species 8. The
species 8 decomposes to provide oxocarbenium ion 10, which
then forms an intimate ion pair 11 with iodide ion. The Prins
cyclization of favored chair intermediate 11 and simultaneous
addition of proximate iodide ion produces the desired axial
product 2.
I
Cl
O
10
11
12
4-Cl–C6H4
c-C6H11
2
2
2
2j
86
65
70
I
O
H
H
TBAB
TBAB
2k
2l
Br
O
(CH3)2CHCH2
Br
O
Bn
13
14
n-C2H5
C6H5–CH2 TBAB
cyclo-C6H11 TBAB
2
2
2m
2n
58
60
Br
O
c-C6H11
Br
aYields refer to isolated yield. Compounds are characterized by
IR, H and 13C NMR, and mass spectrometry.23
1
In conclusion, we have developed an axial selective Prins
cyclization reaction with high diastereoselectivity and good
yields. The 4-axial halo-substituted products would be an
important synthetic intermediate for the synthesis of 4-equato-
rial-substituted tetrahydropyrans by substitution reaction.
minating agent, tetrabutylammonium bromide (TBAB) also
yielded axial-4-bromotetrahydropyrans. The TBAB was found
to be less reactive than the TBAI and gave low yields. The
stereoselectivity and stereochemistry of the compounds were
Chem. Lett. 2011, 40, 1176-1178
© 2011 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

1178
6
7
8
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Chem. Lett. 2011, 40, 1176-1178
© 2011 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/