270

Chemistry Letters Vol.37, No.3 (2008)

Platinum(II)-catalyzed Annulation of 5-Methyl-5-hexen-1-ols with Aldehydes
Katsukiyo Miura, Makoto Horiike, Gen Inoue, Junji Ichikawa, and Akira Hosomi
Department of Chemistry, Graduate School of Pure and Applied Sciences, University of Tsukuba, Tsukuba 305-8571(Received December 3, 2007; CL-071331; E-mail: miura@chem.tsukuba.ac.jp, hosomi@chem.tsukuba.ac.jp)
In the presence of catalytic amounts of PtCl2 and AgOTf,
5-methyl-5-hexen-1-ol reacted with aldehydes to give 2,3-disubstituted tetrahydropyrans in moderate to high yields with transstereoselectivity. Use of 5-methyl-5-hexen-1-ols bearing amethyl group at the C1-, C2-, or C3-position led to highly
stereoselective synthesis of trisubstituted tetrahydropyrans.

Table 1. PtII -catalyzed annulation of 1 with aldehydes
OHPtCl2 (0.5 mol %)AgOTf (1 mol %)O+
R

1PhMe, 100 °C, 1–3 hH2O

R

O

R+

Stereoselective construction of substituted cyclic ethers is
an important subject in organic synthesis since these frameworks
frequently appear in biologically active organic molecules.1 The
Brønsted or Lewis acid-promoted reaction of alkenols with aldehydes and acetals provides a convenient route to cyclic ethers.2–4
The key step of this annulation is intramolecular addition ofan alkene to an oxocarbenium ion intermediate. In general, thecyclization step is accompanied with deprotonation leading toene products or with carbon–heteroatom bond formation bynucleophilic addition.
We have previously reported that the PtII -catalyzed reactionof (Z)-6-trimethylsilyl-5-hexen-1-ol with aldehydes gives trans2,3-disubstituted tetrahydropyrans (THPs) with high stereoselectivity (Scheme 1).5 The reaction mechanism involves alkene migration of the vinylsilane and subsequent annulation of the resultant allylsilane with an aldehyde via an oxocarbenium ion intermediate. In view of the reactivity of oxocarbenium ions toward the ene-type cyclization, we anticipated that a similar
annulation would occur with simple alkenes. Our initial trial
with 5-hexen-1-ol resulted in failure; however, use of 5-methyl-5-hexen-1-ol (1) was found to enable a successful annulationunder catalysis by PtCl2 –AgOTf. We herein report the PtII catalyzed annulation of alkenol 1 and the related alkenols withaldehydes.
In the presence of PtCl2 (0.5 mol %) and AgOTf (1 mol %), 1
reacted with benzaldehyde (2a) to give trans-2,3-disubstituted
THP 3a in 77% yield (Entry 1 in Table 1).6,7 The cis isomerand 3-methylene-THP 4a were also obtained as by-products.
The formation of 4a is attributable to alkene migration of 3afollowed by 1,3-allylic transposition.5 The annulation hardly
proceeded without AgOTf or PtCl2 . Other aldehydes also underwent the PtII -catalyzed annulation. Aromatic aldehydes 2b–2d,
bearing an electron-withdrawing group, achieved good to highOH

SiRCHO, cat. PtCl2–AgOTfORPhMe, rt or 45 °C
Si = SiMe3

Si

12
3
4
5
6
7ORSiR

Isolated yield/%
2Ph
4-F–C6 H4
4-O2 N–C6 H4
4-NC–C6 H4
4-MeO–C6 H4
n-C7 H15c-C6 H112a2b2c2d2e2f2gtrans-377757785<37b6559

cis-34b7700098<9<17b78000aAll reactions were carried out with 1 (2.00 mmol), 2 (1.00mmol), PtCl2 (0.005 mmol), and AgOTf (0.010 mmol) in toluene (3 mL). b The product was contaminated with unidentiﬁed
impurities.

yields of 3 (Entries 2–4). 4-Methoxybenzaldehyde (2e) caused
a complex reaction (Entry 5). The annulation with aliphatic
aldehydes 2f–2g showed high trans-selectivity (Entries 6 and 7).
The PtII -catalyzed annulation is applicable to the stereoselective synthesis of 2,3,n-trisubstituted THPs in which all substituents occupy the equatorial positions (Scheme 2).6 The reactions of alkenols 5a and 5b aﬀorded r-2,t-3,c-6-, and r-2,t-3,t-5trisubstituted THPs (6a and 6b), respectively, in high yield withgood to high diastereoselectivity. In contrast, the annulation of
5c leading to r-2,t-3,c-4-trisubstituted THPs 6c was relatively
slow and less eﬃcient although high levels of diastereoselectivity were achieved.
To gain a mechanistic insight, we carried out the reaction ofalkenol 10 with 2a. As a result, it was completed within 15 min togive 3a and 4a in high total yield (eq 1). Thus, both reactions
using 1 and 10 gave similar results. The annulation of 10 proceeds
most probably by the ene-type reaction of oxocarbenium
ion 7a;3c therefore, the annulation of 1 would also involve an
oxocarbenium ion intermediate such as 7a.

Intramolecularallylation
RCHOR

4cis-3

Aldehyde

Entry

PtCl2 (0.5 mol %)AgOTf (1 mol %)OH

AlkenemigrationOH

trans-3O++2aOPhPhMe, 100 °C, 15 min7a1'trans-3aScheme 1. Previous work on PtII -catalyzed annulation.

Copyright Ó 2008 The Chemical Society of Japan79%+

cis-3a12%+

4a2%(1)

Chemistry Letters Vol.37, No.3 (2008)
OH271

PtCl2 (0.5 mol %)AgOTf (1 mol %)

OO

R

1+2+
R
5aPhMe, 100 °C
1hH
26a

R = PhR = 4-F–C6H4
R = 4-O2N–C6H4
R = 4-NC–C6H4
R = n-C7H15OHO

R

H

R

0.5 or 1 h6b2

R = PhR = 4-NC–C6H4
R = n-C7H15
OH

82% (81:19)*
84% (>99:1)
80% (79:21)
Oas aboveOR+RH2h25c6c

R = PhR = 4-NC–C6H4
R = n-C8H17O

cat. Pt

OR3( )47

Scheme 3. A plausible mechanism for annulation of 1 with 2.

+5bOR1

R12, R 1 = (CH2)4CMe=CH213, R 1 = H

85% (95:5)*
82% (98:2)
86% (93:7)
90% (94:6)
84% (96:4)

as aboveO

cat. Pt

56% (>99:1)*
68% (>99:1)
65% (95:5)*Isolated yield (major isomer : minor isomers).

A plausible mechanism for the annulation of 1 is as follows(Scheme 3). The initial step is the reaction of an aldehyde withthe hydroxy group. The resulting intermediate, an acetal 12 ora hemiacetal 13, undergoes alkene migration and eliminationof the alkoxy or hydroxy group to give an oxocarbenium ion
7. The ene-type reaction of 7 aﬀords the annulation product 3.
The PtII -catalysis would serve for all steps except the last
cyclization step.
In conclusion, we have developed a novel type of annulationof alkenols with aldehydes, which proceeds by a PtII -catalyzed
tandem process including alkene migration and the ene-type
reaction of an oxocarbenium ion intermediate. The present
annulation is quite valuable for the stereoselective synthesis ofsubstituted THPs.
This work was partly supported by Grants-in-Aid for Scientiﬁc Research from the Ministry of Education, Culture, Sports,
Science and Technology, Government of Japan.

Scheme 2. PtII -catalyzed annulation of alkenols 5a–5c.
To ascertain the isomerization of 1 to 10 , the reaction of 1
without aldehydes was performed under the same conditions.
However, 10 was not obtained at all, and the formation ofTHP 8a, a volatile compound, was observed. A similar reactionof alkenol 9 gave THP 8b in quantitative yield (eq 2). On theother hand, TIPS-protected alkenol 10 underwent alkene
migration to give trisubstituted alkene 11 (eq 3).8
RPtCl2 (0.25 mol %)AgOTf (0.5 mol %)

OHR

O
(2)

PhMe, 100 °C, 1 h
1 (R = H)
9 (R = n-C8H17)OSii -Pr3

8a (R = H)
8b (R = n-C8H17), 97%
OSii -Pr3

as above(3)
1011, 68%

The PtII -catalyzed reaction of 1 with 2a at room temperatureaﬀorded acetal 12a without 3a (eq 4). The isolated acetal wasconverted into 3a (ca. 60% yield) under catalysis by PtCl2 –AgOTf at 60  C. These results indicate that addition of thehydroxy group to the carbonyl group precedes alkene migrationin the present annulation.
PtCl2 (0.5 mol %)AgOTf (1 mol %)1+2aPhMe, rt, 18 hPhO
(4)O
12a, 14%

References and Notes
1 T. L. B. Boivin, Tetrahedron 1987, 43, 3309; H. Kotsuki,Synlett 1992, 97; U. Koert, Synthesis 1995, 115.
2 B. B. Snider, in Comprehensive Organic Synthesis, ed. byB. M. Trost, I. Fleming, Pergamon Press, Oxford, 1991,Vol. 2, p. 527.
3 a) P. R. Stapp, J. Org. Chem. 1969, 34, 479. b) N. A. Nikolic,E. Gonda, C. P. D. Longford, N. T. Lane, D. W. Thompson,J. Org. Chem. 1989, 54, 2748. c) T.-P. Loh, Q.-Y. Hu, K.-T.
Tan, H.-S. Cheng, Org. Lett. 2001, 3, 2669.
4 Similar annulations of allylsilanes bearing a hydroxy group:a) P. Mohr, Tetrahedron Lett. 1993, 34, 6251. b) P. Mohr,Tetrahedron Lett. 1995, 36, 2453. c) M. Suginome, T.
Iwanami, Y. Ito, J. Org. Chem. 1998, 63, 6096.
5 K. Miura, R. Itaya, M. Horiike, H. Izumi, A. Hosomi, Synlett
2005, 3148.
6 The stereochemical outcomes can be rationalized by thecyclization of the intermediate 7 and its analogues via achair-like cyclic transition structure in which all substituentson the ring occupy the equatorial positions. See Refs. 3cand 4b.
7 Synthetic use of PtCl2 (L)–AgOTf catalyst system: Y.
Kataoka, O. Matsumoto, K. Tani, Organometallics 1996,15, 5246; C. Liu, X. Han, X. Wang, R. A. Widenhoefer,J. Am. Chem. Soc. 2004, 126, 3700; J. Oyamada, T.
Kitamura, Tetrahedron Lett. 2005, 46, 3823.
8 PtII -catalyzed alkene migration: J. F. Harrod, A. J. Chalk,J. Am. Chem. Soc. 1964, 86, 1776; R. Cramer, R. V. Lindsey,Jr., J. Am. Chem. Soc. 1966, 88, 3534.

Published on the web (Advance View) February 2, 2008; doi:10.1246/cl.2008.270