TMSI mediated Prins-type cyclization of ketones with homoallylic and homopropargylic alcohol: Synthesis of 2,2-disubstituted-, spirocyclic-4-iodo- tetrahydropyrans and 5,6-dihydro-2H-pyrans

Article abstract of DOI:10.1016/j.tetlet.2006.02.094

The Prins-type cyclization of ketones with homoallylic and homopropargylic alcohols in the presence of TMSI generated in situ from TMSCl and NaI produced 2,2-disubstituted- or spirocyclic-4-iodo-tetrahydropyrans and spirocyclic-4-iodo-5,6-dihydro-2H-pyran

Full text of DOI:10.1016/j.tetlet.2006.02.094

Tetrahedron Letters 47 (2006) 2807–2810
TMSI mediated Prins-type cyclization of ketones with
homoallylic and homopropargylic alcohol: synthesis of
,2-disubstituted-, spirocyclic-4-iodo-tetrahydropyrans and
2
q
5
,6-dihydro-2H-pyrans
*
Gowravaram Sabitha, K. Bhaskar Reddy, M. Bhikshapathi and J. S. Yadav
Organic Division I, Indian Institute of Chemical Technology, Hyderabad 500007, India
Received 8 December 2005; revised 31 January 2006; accepted 9 February 2006
Abstract—The Prins-type cyclization of ketones with homoallylic and homopropargylic alcohols in the presence of TMSI generated
in situ from TMSCl and NaI produced 2,2-disubstituted- or spirocyclic-4-iodo-tetrahydropyrans and spirocyclic-4-iodo-5,6-dihy-
dro-2H-pyrans in good yields. These iodopyrans are reported for the first time.
Ó 2006 Elsevier Ltd. All rights reserved.
The Prins cyclization reaction has been shown to be a
very useful reaction for the construction of oxygen-con-
taining heterocyclic units that appear in many natural
onic acid. A method for the synthesis of 2-alkyl-4-
chloro-5,6-dihydro-2H-pyrans has been reported by
8
Martin et al. using an iron(III)-catalyzed Prins-type
1
products. This reaction typically involves a reaction be-
cyclization. These reported procedures require more
than stoichiometric amounts of Lewis acids, long reac-
tion times and afford low yields of products. Hence,
there is still a need to develop a new Prins-type cycliza-
tion of ketones. Herein, we report a Prins-type cycliza-
tion reaction of various acyclic and cyclic ketones with
homoallylic and homopropargylic alcohols in the pres-
ence of TMSI. The reaction is fast and proceeds at room
temperature to afford the corresponding 2,2-disubsti-
tuted-, spirocyclic-4-iodotetrahydropyrans and spirocy-
clic-4-iodo-5,6-dihydro-2H-pyrans in good yields
(Schemes 1–3).
tween an aldehyde and a homoallylic alcohol promoted
2
by acid. The relevance of this reaction as a carbon–car-
bon bond forming reaction has led to the study and
application of many variations. Recently, we reported
our results on the Prins cyclization of homoallylic alco-
3
hols and aldehydes. Even though the Prins cyclization
has been subject of much attention in recent years, the
Prins-type cyclization of ketones with homoallylic and
homopropargylic alcohols has received far less atten-
4
tion. Hanschke reported the synthesis of 4-halotetra-
hydropyran derivatives using HCl or HBr and various
5
ketones in 36–50% yield while Li has developed the
Prins-type cross-coupling reaction with allylic alcohols
and various ketones in the presence of InCl /SnCl .
Thompson et al. have also reported an approach to a
We initially tested the reaction of acetone 1a with 3-but-
ene-1-ol 2a in the presence of TMSI (generated in situ
from TMSCl and NaI) in acetonitrile, which resulted
in 2,2-dimethyl-4-iodotetrahydropyran 3a as a single
isomer in 98% yield. The reaction proceeds smoothly
at room temperature and complete conversion was ob-
served in 15 min (Scheme 1).
3
4
6
spirocyclic ether by TiCl -mediated transacetalization-
4
7
cationic cyclization. Recently, Ghosh et al. reported
the synthesis of spirocyclic tetrahydropyranyl mesylates
and tosylates using methanesulfonic or p-toluenesulf-
To test the generality of the reaction, various acyclic ke-
tones (Table 1, entries b–d) reacted with homoallylic
alcohol 2a to afford the corresponding 2,2-disubsti-
tuted-4-iodotetrahydropyrans in good yields. Similarly,
cyclic ketones such as cyclopentanone, cyclohexanone,
cyclododecanone (Table 1, entries e–g) also reacted
Keywords: Prins reaction; Ketones; Tetrahydropyrans; 5,6-Dihydro-
2
H-pyrans; Homoallylic alcohols; Homopropargylic alcohols; TMSI.
q
IICT Communication No.: 050505.
*
Corresponding author. Tel./fax: +91 40 27160512; e-mail:
sabitha@iictnet.org
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.02.094

2808
G. Sabitha et al. / Tetrahedron Letters 47 (2006) 2807–2810
I
O
TMSCl/NaI
+
OH
R'
R
R'
CH CN, r.t.
3
O
R
1
a, R, R' = CH3
b-d, R, R' = alkyl,
2
a
3a-d,
1
1
3
i, j
i, j, R = methyl, R' = aryl
Scheme 1.
I
ketones was attributed to the generation of an oxonium
ion, which was intramolecularly trapped by the triple
bond with concomitant attack of the iodide.
O
TMSCl/NaI
8a
+
OH
(
)n
CH CN, r.t.
3
O
In conclusion, we have accomplished the synthesis of
(
)n
2
,2-disubstituted-, spirocyclic-4-iodo-tetrahydropyrans
1
e-h
2a
3e-h
and 4-iodo-5,6-dihydro-2H-pyrans from various ketones
with homoallylic and homopropargylic alcohols using
TMSI as a halide source. The advantages of the protocol
are mild reaction conditions at room temperature, high
yields of products and moreover these iodides can be
converted into other functionalities and removal of io-
dide may result in the formation of tetrahydropyrans
as reported in our earlier letter. The vinyl iodides may
also find value for C–C bond formation because of their
high reactivity.
Scheme 2.
successfully with homoallylic alcohol 2a to produce the
corresponding spirocyclic-4-iodo-tetrahydropyrans in
high yields (Scheme 2). Indan-2-one smoothly reacted
under similar conditions, whereas, chromanone and 4-
tetralone failed to give cyclization products. Moderate
yields were obtained when acetophenones were reacted
with homoallylic alcohol 2a.
Typical procedure: 9-Iodo-6-oxaspiro[4,5]decane 3e: To
With these results in hand, we elaborated our studies
using homopropargylic alcohol. Iodotrimethylsilane
was also shown to be an excellent catalyst for the
Prins-type cyclization between homopropargylic alcohol
and ketones. Thus, treating cyclohexanone (Table 2, en-
try d) with homopropargylic alcohol 2b in the presence
of TMSI (generated in situ from TMSCl and NaI) in
acetonitrile afforded a mixture of two compounds. The
a
mixture of homoallylic alcohol (2a, 0.300 g,
4.16 mmol), cyclopentanone (1e, 0.350 g, 4.16 mmol)
and NaI (1 equiv, 0.624 g, 4.16 mmol) in dry acetonitrile
(5 mL) was added anhydrous TMSCl (1 equiv, 0.54 mL)
dropwise and the resulting mixture stirred at rt. After
15 min (TLC), the reaction mixture was taken up into
ethyl acetate and the organic layer was washed with so-
dium thiosulfate solution, water and dried over Na SO .
The solvent was removed under reduced pressure and
the crude material was purified by silica gel column
chromatography (n-hexane/EtOAc, 95:5) to afford
the corresponding spirocyclic-4-iodo-tetrahydropyran
2
4
1
H NMR spectrum of the crude product showed the
presence of a major compound, spirocyclic-4-iodo-5,6-
dihydro-2H-pyran 4d contaminated with the corre-
sponding iodovinyl derivative (tetrahydrofuran) 5d as
a minor compound in a ratio of 80:20 (Scheme 3). We
could not isolate the pure tetrahydrofuran derivative
as it always eluted with a small amount of the tetrahy-
dropyran. Similarly, several cyclic ketones reacted suc-
cessfully with homopropargylic alcohol 2b to give the
corresponding spirocyclic dihydropyrans in good yields.
In the case of cycloheptanone and indan-2-one (Table 2,
entries e–f), only tetrahydropyran derivatives (4e–f)
were isolated and no trace of the tetrahydrofurans could
be detected. The formation of two products, 4 and 5 in
the case of the reaction of homopropargylic alcohol with
derivative 3e in 96% yield. Spectroscopic data for 3e:
1
H NMR (CDCl , 200 MHz): d 4.17–4.44 (m, 1H),
3
3.30–3.67 (m, 2H), 2.38–2.04 (m, 4H), 1.20–1.98 (m,
8H); C NMR (CDCl , 75 MHz): d 86.0, 63.8, 49.3,
41.5, 40.0, 32.1, 24.0, 22.9, 22.0; IR (neat) m
2957, 1219, 772 cm ; LCMS: 305 (M +K). Anal.
Calcd for C H OI: C, 40.62; H, 5.68%. Found: C,
40.59; H, 5.50%.
1
3
3
3415,
Max
À1
+
9
15
4-Iodo-1-oxaspiro[5,6]dodec-3-ene 4e (Table 2): To a
mixture of homopropargylic alcohol (2b, 0.300 g,
I
I
O
TMSCl/NaI
H
OH
+
+
(
)n
CH CN, r.t.
3
O
O
(
)n
( )n
1
a-f
2b
4a-f
5a-d
Scheme 3.

G. Sabitha et al. / Tetrahedron Letters 47 (2006) 2807–2810
Table 1. Prins reaction of ketones with homoallylic alcohol 2a
2809
Table 2. Prins reaction of ketones with homopropargylic alcohol 2b
a
b
b
Entry Ketone 1
Product 3
Time Yield
min) (%)
Entry
Ketone 1
Product
ratio 4:5
Time
(min)
Yield
(%)
a
(
O
I
O
a
70:30
70:30
25
30
85
a
15
98
O
O
b
82
92
O
I
O
c
85:15
80:20
20
20
b
15
15
15
15
97
95
95
96
O
I
O
O
O
d
90
c
O
I
e
f
100:0
100:0
20
30
90
55
O
d
O
I
O
O
e
a
All new products were characterized from spectral data.
Isolated yields after column chromatography.
b
O
I
O
and dried over Na SO . The solvent was removed under
2
4
f
15
96
reduced pressure and the crude material was purified by
silica gel column chromatography (n-hexane/EtOAc,
95:5) to afford the corresponding spirocyclic-4-iodo-
O
I
O
5
,6-dihydro-2H-pyran derivative 4e in 90% yield. Spec-
1
troscopic data for 4e: H NMR (CDCl , 300 MHz): d
3
g
15
30
88
58
6.32–6.39 (d, 1H, J = 2.32 Hz), 4.08–4.15 (dd, 1H,
J = 2.32, 5.41 Hz), 3.72–3.81 (t, 1H, J = 5.41 Hz),
O
I
2
1
.48–2.56 (dt, 1H, J = 1.55, 5.41 Hz), 2.39–2.45 (dd,
H, J = 2.32, 4.64 Hz,), 1.18–1.97 (m, 12H); C NMR
13
(
CDCl , 75 MHz): d 144.5, 134.9, 63.1, 60.3, 49.3,
3
h
O
3
2
8.8, 38.2, 38.0, 29.7, 21.9, 21.7; IR (neat) m
2929,
Max
À1
O
I
857, 2360, 911, 794, 735 cm ; LCMS: 291 (MÀ1).
Anal. Calcd for C H OI: C, 45.22; H, 5.86%. Found:
1
1
17
C, 45.59; H, 5.79%.
O
i
O
I
30
30
52
54
Acknowledgements
Cl
K.B.R. thanks UGC, and B.P. thanks CSIR, New
Delhi, for the award of fellowships.
Cl
O
j
O
References and notes
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1
2
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a
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4
4
.2 mmol), cycloheptanone (Table 2, entry 1e, 0.480 g,
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