Lewis acid-catalyzed one-pot crossed Prins cyclizations using allylchlorosilane as allylating agent

Article abstract of DOI:10.1016/j.tetlet.2004.09.049

A one-pot multi-component Lewis acid-catalyzed Prins cyclization was developed with high yield and selectivity. The crossed 2,4,6-trisubstituted tetrahydropyran products were formed with high stereoselectivity. This catalytic method could also be used with α,β-unsaturated aldehydes affording moderate yields of products. A one-pot multi-component Lewis acid-catalyzed Prins cyclization was developed with high yield and selectivity. The crossed 2,4,6-trisubstituted tetrahydropyran products were formed with high stereoselectivity. This catalytic method could also be used with α,β-unsaturated aldehydes affording moderate yields of products.

Full text of DOI:10.1016/j.tetlet.2004.09.049

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 8387–8390
Lewis acid-catalyzed one-pot crossed Prins cyclizations using
allylchlorosilane as allylating agent
Kok-Ping Chan and Teck-Peng Loh*
Department of Chemistry, National University of Singapore, 3 Science Drive 3, Singapore 117543, Singapore
Received 29 June 2004; revised 30 August 2004; accepted 7 September 2004
Available online 23 September 2004
Abstract—A one-pot multi-component Lewis acid-catalyzed Prins cyclization was developed with high yield and selectivity. The
crossed 2,4,6-trisubstituted tetrahydropyran products were formed with high stereoselectivity. This catalytic method could also
be used with a,b-unsaturated aldehydes affording moderate yields of products.
ꢀ 2004 Elsevier Ltd. All rights reserved.
Tetrahydropyran rings are part of the backbones of
many complex natural products.1 Prins cyclization offers
a diverse olefin–aldehyde condensation method for the
formation of pyran rings.2 The use of strong mineral
acids (e.g., sulfuric acid) or Lewis acids (e.g., AlCl3) in
such reactions has previously been reported. Such harsh
conditions often result in unwanted polymerized prod-
ucts, and are also not applicable to aromatic or conju-
gated aldehydes. The development of various Lewis
acid-promoted condensations3 offers elegant and effi-
cient methods for the synthesis of both meso and unsym-
metrical 2,4,6-trisubstituted tetrahydropyrans. One very
good example was described by Li and co-workers3c
using InCl3 to achieve high-yielding Prins cyclization
products. However, the Lewis acids were used in stoichi-
ometric amounts, and hence did not play a catalytic role
in the reaction. Despite many applications of Prins cycl-
izations, interest in achieving stereoselective crossed
Prins cyclizations and to reduce its substrate limitations
remains unabated. Our group has developed a simple,
one-pot Prins cyclization catalyzed by mild indium-
based Lewis acids in allylsilane (Scheme 1).
The product formed is highly dependent on three fac-
tors: (i) the type of acid catalyst used; (ii) the type and
amount of silicon-based reagent; (iii) the sequence of
aldehyde addition. When we introduced an aldehyde
and a derivatized silane into a Lewis acid system, we
obtained primarily the meso products shown in Table
1. The homoallylic alcohol 2 was obtained as the major
product when excess allylsilane was employed (Table 1,
entry 3).4 Slow addition of the aldehyde to a solution
of allylsilane and Lewis acid is also critical in obtain-
ing the homoallylic alcohol. Addition of a mixture of
allylsilane and aldehyde into a dilute solution of the
Lewis acid yielded the 2,4,6-trisubstituted tetrahydropy-
ran instantaneously.
When allylsilanol was used with InCl3, the 4-chloro
tetrahydropyran was obtained in moderate yield,
Y
O
X
OH
+
InY3 (0.2 equiv)
CH2Cl2, 25 oC
Si
+
R
H
R
R
O
R
1a Y = Cl
1b Y = OH
1c Y = Br
2
Scheme 1.
Keywords: Tetrahydropyran; Prins cyclization; In(OTf)3; InCl3.
*
Corresponding author. Tel.: +65 6874 1781; fax: +65 6779 1691; e-mail: chmlohtp@nus.edu.sg
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.09.049

8388
K.-P. Chan, T.-P. Loh / Tetrahedron Letters 45 (2004) 8387–8390
Table 1. Direct Prins cyclization with allylchlorosilane or allylsilanol (R = PhCH2CH2–)
Entry
X
Y
Allylsilane (equiv)a
Yield (%)
1a
1b
1c
2
1
2
3
4
5
6
7
8
Cl
Cl
Cl
Cl
1.2
2.0
3.0
1.2
1.2
1.2
1.2
1.2
67
10
6
—
—
—
23
48
5
—
—
—
36
—
—
—
—
14
76
83
—
—
—
4
Cl
Cl
Br
OH
OH
Cl
—
—
90
53
—
F
OTf
Cl
OH
OH
3
68
OTf
23
a Amount of allylsilane with respect to aldehyde.
whereas only the 4-hydroxy product was observed when
In(OTf)3 was employed. Unexpectedly, the 4-hydroxy
product was also observed using InF3, possibly due to
the high affinity of fluoride to silicon.
The optimized method6 (Scheme 2) produced the Prins
cyclized products in moderate to high yields for aliphatic
aldehydes (Table 2), but no desired product was
obtained with conjugated systems such as cinnamalde-
hyde or trans-2-pentenal.
The chloride at the 4-position of the 2,4,6-trisubstituted
tetrahydropyran must come from the allylchlorosilane
when we used a catalytic amount of In(OTf)3. Hence
the use of excess Lewis acid is avoided compared to
the recently reported methods. The reaction also pro-
duced equivalent yields and selectivity in a 1% water–
CH2Cl2 mixture, showing excellent tolerance of the
catalytic species to the presence of a controlled amount
of moisture.5
Cl
O
Cl
InCl3 (0.2 equiv)
CH2Cl2, 25 oC
Si
+
R
H
R
O
R
Scheme 2.
Table 2. meso-4-Halo-tetrahydropyrans prepared via one-pot indium-silyl Prins cyclization
Entry
R
Time (h)
Product
Yield
90
Cl
O
1
PhCH2CH2–9
2
1a
Cl
2
3
4
5
6
Ph–
4
2
1
1
4
3
4
5
45
65
94
65
45
O
Cl
Cy–
O
Cl
(C2H5)2CH–
CH3(CH2)7–
BnO(CH2)2–
O
Cl
6
O
7
7
Cl
O
7
BnO
OBn

K.-P. Chan, T.-P. Loh / Tetrahedron Letters 45 (2004) 8387–8390
8389
By increasing the amount of allylchlorosilane, the
homoallylic alcohol was formed predominantly. Addi-
tion of more aldehyde promoted in situ Prins cycliza-
tion. Hence we developed a one-pot crossed Prins
cyclization (Scheme 3)7 with high yields and selectivity
(Table 3).
As we expected, the use of mild Lewis acid conditions
and the step-wise formation of homoallylic alcohol ena-
bled the coupling of an a,b-unsaturated aldehyde to
form 12, a structure, which has potentially high syn-
thetic value (Table 3, entry 5).
Furthermore, the X-ray crystal structure of 4-chloro-
2,6-dicyclohexyltetrahydro-2H-pyran 4 revealed that
only the syn product was observed in both the meso
and the crossed 2,4,6-trisubstituted tetrahydropyran
product (Fig. 1).8 This is consistent with the results
established by Li and co-workers.3c
Figure 1. Crystal structure of 4-chloro-2,6-dicyclohexyltetrahydro-2H-
pyran, showing the all-cis configuration at the 2, 4, and 6 positions.
In summary, we have successfully demonstrated that a
catalytic amount of an indium Lewis acid can catalyze
a one-pot crossed Prins cyclization with high yield and
stereoselectivity. Further investigations on the mecha-
nism and applications are in progress.
1. InCl3, CH2Cl2, 25 oC
Cl
O
Cl
Si
+
R2
2.
O
In(OTf)3
R1
H
Acknowledgements
CH2Cl2, 0 oC
R1
O
R2
This work was generously supported by grants from the
National University of Singapore and the Medicinal
Chemistry Programme (Research Grant No. R-143-
000-600-712). K.-P.C. thanks the Agency for Science,
Technology and Research for a graduate scholarship.
Scheme 3.
Table 3. Crossed Prins cyclization (R1 = PhCH2CH2)
Entry R2
Product
Yield
(%)
References and notes
Cl
1. Nicolaou, K. C.; Sorensen, E. J. Classics in Total Synthesis;
VCH: Weinham, 1996.
2. (a) Adams, D. R.; Bhatnagar, S. P. Synthesis 1977, 661–
672; (b) Arundale, E.; Mikeska, L. A. Chem. Rev. 1952, 51,
505–555.
–CH2CH3
8
83
85
1
2
O
Cl
3. (a) Coppi, L.; Ricci, A.; Taddei, M. J. Org. Chem. 1988, 53,
913–915; (b) Wei, Z. Y.; Li, S. J.; Wang, D.; Chan, T. H.
Tetrahedron Lett. 1987, 28, 3441–3444; (c) Yang, J.;
Viswanathan, G. S.; Li, C. J. Tetrahedron Lett. 1999, 40,
1627–1630; (d) Patterson, B.; Marumoto, S.; Rychnovsky,
S. D. Org. Lett. 2003, 5, 3163–3166; (e) Wei, Z. Y.; Li, S. J.;
Wang, D.; Chan, T. H. J. Org. Chem. 1989, 54, 5768–5774;
(f) Coppi, L.; Ricci, A.; Taddei, M. Tetrahedron Lett. 1987,
28, 973–976; (g) Perron, F.; Albizati, K. F. J. Org. Chem.
1987, 52, 4128–4130; (h) Rychnovsky, S. D.; Hu, Y.;
Ellsworth, B. Tetrahedron Lett. 1998, 39, 7271–7274.
4. For mechanistic studies on allylsilane and allyllation
reactions, see: (a) Hayashi, T.; Konishi, M.; Kumada, M.
J. Am. Chem. Soc. 1982, 104, 4963–4965; (b) Fleming, I.;
Terrett, N. K. Tetrahedron Lett. 1983, 24, 4153–4156; (c)
Denmark, S. E.; Fu, J. Chem. Rev. 2003, 103, 2763–2793;
(d) Hosomi, A.; Sakurai, H. Tetrahedron Lett. 1976, 1295–
1298; (e) Hosomi, A.; Sakurai, H. J. Am. Chem. Soc. 1977,
99, 1673–1675.
–Ph
9
10
11
O
Cl
3
4
–CH(CH3CH2)2
89
68
O
Cl
–Cy
O
Cl
5
6
–CH@CHCH2CH3
12 70
O
5. For more information, see: Li, C. J.; Chan, T. H. Organic
Reactions in Aqueous Media; John Wiley & Sons: New-
York, 1997.
6. General procedure for the synthesis of meso-4-halo-tetra-
hydropyrans: In(OTf)3 (0.225g, 0.4mmol) was stirred in
CH2Cl2 (18mL) to form a suspension. A mixture of
Cl
–(CH2)2OBn
13 65
O
OBn

8390
K.-P. Chan, T.-P. Loh / Tetrahedron Letters 45 (2004) 8387–8390
allylchlorodimethylsilane (0.323g, 2.4mmol) and aldehyde
solution. After stirring for 15min, the mixture was
extracted with ether (3 · 20mL). The combined organic
phase was successively washed with water (2 · 15mL),
saturated brine (2 · 10mL), and dried over anhydrous
MgSO4. The solvent was removed under reduced pressure
to give the crude product, which was purified by flash
column chromatography.
(2mmol) in CH2Cl2 (2mL) was added to the suspension at
room temperature. The mixture was stirred for at least 1h,
then quenched with saturated NaHCO3 solution. After
stirring for 15min, the mixture was extracted with ether
(3 · 20mL). The combined organic phase was successively
washed with water (2 · 15mL), saturated brine (2 · 10mL),
and dried over anhydrous MgSO4. The solvent was
removed under reduced pressure to give the crude product,
which was purified by flash column chromatography.
7. General procedure for the synthesis of crossed 4-chloro-
tetrahydropyrans: allylchlorodimethylsilane (0.336g, 2.5
mmol) and InCl3 (0.044g, 0.2mmol) were stirred in CH2Cl2
(4mL) to form a suspension. A solution of hydrocinna-
maldehyde (1mmol) in CH2Cl2 (1mL) was added to the
suspension at room temperature. The mixture was stirred
for at least 1h, and then cooled to 0ꢁC. The mixture was
diluted with CH2Cl2 (4mL), and then a solution of
aldehyde in CH2Cl2 (1mL) was added over a period of
5min. The mixture was allowed to stir at 0ꢁC for at
least 0.5h, then quenched with saturated NaHCO3
8. CCDC 246493 contains the supplementary crystallographic
data for this paper. The data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, by e-mailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12, Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
9. Characterization of product 1a: white solid after purifica-
tion on silica gel (ether–hexane = 1:99): IR (neat, NaCl)
3025, 2914, 2838, 1494, 1319, 1082cmÀ1
;
1H NMR
(300MHz, CDCl3): d 7.32–7.19 (m, 10H), d 3.96 (tt,
J = 4.53, 11.85Hz, 1H) 3.26 (m, 2H), 2.86 (m, 2H), 2.76
(m, 2H), 2.11 (dd, J = 4.18, 12.2Hz, 2H), 1.92 (m, 2H), 1.78
(m, 2H), 1.57 (m, 2H); 13C NMR (50MHz, CDCl3): d
141.8, 128.5, 128.4, 125.9, 75.4, 55.8, 42.6, 37.4, 31.7.