Acid-promoted prins cyclizations of enol ethers to form tetrahydropyrans

Article abstract of DOI:10.1021/ol0342756

(Matrix presented) Trifluoroacetic acid efficiently catalyzes Prins cyclizations of enol ethers 8 to provide tetrahydropyrans 9 and 10. These tetrahydropyrans are isolated with combined yields of 42-85% and stereoselectivities at C₄ ranging fro

Full text of DOI:10.1021/ol0342756

ORGANIC
LETTERS
2003
Vol. 5, No. 9
1499-1502
Acid-Promoted Prins Cyclizations of
Enol Ethers To Form Tetrahydropyrans
David J. Hart* and Chad E. Bennett
Department of Chemistry, The Ohio State UniVersity, 100 West 18th AVenue,
Columbus, Ohio 43210
hart@chemistry.ohio-state.edu
Received February 17, 2003
ABSTRACT
Trifluoroacetic acid efficiently catalyzes Prins cyclizations of enol ethers 8 to provide tetrahydropyrans 9 and 10. These tetrahydropyrans are
isolated with combined yields of 42−85% and stereoselectivities at C ranging from 95:5 to 50:50 depending on the nature of the substituent
4
R. Unique byproducts of these cyclizations that reveal the presence of underlying equilibria have been isolated and identified.
Prins cyclizations of oxocarbenium ions bearing an appended
olefin represent a versatile method for the preparation of
tetrahydropyrans.1 These reactive oxocarbenium ions have
been generated in a variety of ways. The best studied method
involves acid-promoted reaction of homoallylic alcohols with
aldehydes.2 Ionization of acetals3 and R-acetoxy ethers4,5 and
other related methods have also been studied.6,7 Less studied
is the generation of such oxocarbenium ions simply by
protonation of enol ethers derived from homoallylic alco-
hols.8 This paper describes observations that extend the scope
and limitations of this route to tetrahydropyrans and reveal
reaction pathways heretofore not reported for Prins cycliza-
tion reactions.
As a prelude to a target-oriented synthesis, we had reason
to examine the reaction of acetal 1 with trifluoroacetic acid.
This reaction gave tetrahydropyrans 2 (31-44%) and 3
(40-47%) after basic hydrolysis of presumed intermediate
trifluoroacetates (Scheme 1). Whereas tetrahydropyran 2 had
(1) Arundale, E.; Mikeska, L. A. Chem. ReV. 1952, 51, 505. Adams, D.
R.; Bhatnagar, S. P. Synthesis 1977, 661. Blumenkopf, T. A.; Overman, L.
E. Chem. ReV. 1986, 86, 857. Snider, B. B. In ComprehensiVe Organic
Synthesis; Trost, B. M., Ed.; Pergamon Press: New York, 1991; Vol. 2, p
527. Langkppf, E.; Schinzer, D. Chem. ReV. 1995, 95, 1375.
Lett. 2001, 3, 1693. Yadav, J. S.; Subba Reddy, B. V. Mahesh Kumar, G.;
Murthy, Ch. V. S. R. Tetrahedron Lett. 2001, 42, 89. Yang, X.-F.; Mague,
J. T.; Li, C.-J. J. Org. Chem. 2001, 66, 739. Keck, G. E.; Covel, M. A.;
Schiff, T.; Yu, T. Org. Lett. 2002, 4, 1189.
(3) Nishiyama, H.; Itoh, K. J. Org. Chem. 1982, 47, 2496. Kay, I. T.;
Bartholomew, D. Tetrahedron Lett. 1984, 25, 2035. Melany, M. L.; Lock,
G. A.; Thompson, D. W. J. Org. Chem. 1985, 50, 3925. Castenada, A.;
Kucera, D.; Overman. L. E. J. Org. Chem. 1989, 54, 5695. Hu, Y.; Skalitzky,
D. J.; Rychnovsky, S. D. Tetrahedron Lett. 1996, 37, 8679. Al-Mutairi, E.
H.; Crosby, S. R.; Darzi, J.; Harding, J. R.; Hughes, R. A.; King, C. D.;
Simpson, T. J.; Smith, R. W.; Willis, C. L. J. Chem. Soc., Chem. Commun.
2001, 835.
(4) Lolkema, L. D. M.; Semeyn, C.; Ashek, L.; Hiemstra, H.; Speckamp,
W. N. Tetrahedron 1994, 50, 7129.
(5) Rychnovsky, S. D.; Thomas, C. R. Org. Lett. 2000, 2, 1217.
(6) Perron, F.; Albizati, K. F J. Org. Chem. 1987, 52, 4128. Mekhalfia,
A.; Marko, I. E.; Adams, H. Tetrahedron Lett. 1991, 32, 4783. Petasis, N.
A.; Lu, S.-P. Tetrahedron Lett. 1996, 37, 141.
(2) Williams, P. H.; Ballend, S. H. (Shell Oil Co.) US Patent 2,452,977;
Chem. Abstr. 1949, 43, 3042. Olsen, S. Acta Chem. Scand. 1951, 5, 1168.
Colonge, J.; Boisde, P. Bull. Soc. Chim. Fr. 1956, 23, 824. Stapp, P. R. J.
Org. Chem. 1970, 35, 2419. Nishiyama, H.; Narimatsu, S.; Itoh, K. J. Chem.
Soc., Chem. Commun. 1982, 459. Kay, I. T.; Williams, E. G. Tetrahedron
Lett. 1983, 24, 5915. Bunnelle, W. H. Seamon, D. W.; Mohler, D. L.; Ball,
T. F.; Thompson, D. W. Tetrahedron Lett. 1984, 25, 2653. Coppi, L.; Ricci,
A.; Taddei, M. J. Org. Chem. 1988, 53, 911. Wei, Z. Y.; Li, J. S.; Chan,
T.-H. J. Org. Chem. 1989, 54, 5768. Yamada, J.; Asano, T.; Kadota, I.;
Yamamoto, Y. J. Org. Chem. 1990, 55, 6066. Hoffmann, R. W.; Giesen,
V.; Fuest, M. Liebigs Ann Chem. 1993, 629. Metzger, J. O.; Biermann, U.
Bull. Soc. Chim. Belg. 1994, 103, 393. Masuyama, Y.; Gotoh, S.; Kurusu,
Y. Synth. Commun. 1995, 25, 1989. Marko, E. E.; Chelle, F. Tetrahedron
Lett. 1997, 38, 2895, 2899. Suginome, M.; Iwanami, T.; Ito, I. J. Org. Chem.
1998, 63, 6096. Cloninger, M. J.; Overman, L. E. J. Am. Chem. Soc. 1999,
121, 1092. Nishizawa, M.; Shigaraki, T.; Takao, H.; Imagawa, H.; Sugihara,
T. Tetrahedron Lett. 1999, 40, 1153. Samoshin, V. V.; Gremyachinski, Y.;
Gross, P. H. MendeleeV Commun. 1999, 53. Huang, H.; Panek, J. S. Org.
(7) For a unique entry to ions of type 1 from homoallylic alcohols and
epoxides, see: Li, J.; Li, C.-J. Tetrahedron Lett. 2001, 42, 793.
(8) Nussbaumer, C.; Frater, G. HelV. Chim. Acta 1987, 70, 396.
Nussbaumer, C.; Frater, G. J. Org. Chem. 1987, 52, 2096. Kozmin, S. A.
Org. Lett. 2001, 3, 755.
10.1021/ol0342756 CCC: $25.00 © 2003 American Chemical Society
Published on Web 04/05/2003

Scheme 1. Influence of Acid Promoter on Prins Cyclizations
Table 1. Acid-Promoted Cyclization of Enol Ethers
yield of
time 9 + 10
entry substrate
R
acida
TFA
(h)
(%)
9/10
1
2
3
4
5
6
7
8
8a
8a
8b
8c
8d
8e
8f
n-C6H13
n-C6H13
Ph
CH2OBn
CH2OTBDPS TFA
CH2CH2Bn
CHdCH2
-TMS
0.75
85b
12b
77
91:9
HCO2Hc 2.25
TFA
TFA
2.0
95:5
5.25
3.5
1.75
1.0
58b
66b
78
72b
42b
50:50
57:43
91:9
91:9
80:20
been expected, the appearance of 3 was a small surprise.
We imagine that this product was derived from 1-decen-4-
ol (from ionization of 1) and heptanal or an appropriate
derivative thereof (for example 5), as illustrated in Scheme
1. This exchange process has been observed in several
laboratories, and it is clear that the sigmatropic rearrangement
(4 f 5) underlies several cyclization reactions of this type.9,10
Nonetheless, this result underscores a limitation of the acetal
route to 4-hydroxytetrahydropyran-1-ols. We also note that
treatment of 1 with titanium tetrachloride in dichloromethane
gave 7 along with its C4 epimer in a 10:1 ratio (67-85%) in
accord with literature precedent.11 This indicates that the
cyclization promoter also effects whether exchange reactions
complicate this process.
TFA
TFAc
TFA
8g
-
t
5.0
a Unless otherwise noted, reactions were conducted as described in text
for entry 1. b See text and Figure 1 for other products. c Acid was the solvent
(0.25 M).
Based on the results shown in Scheme 1, we decided to
investigate a process that would lead to site selective
generation of an oxocarbenium ion. It was reasoned that an
enol ether might serve as an oxocarbenium ion precursor,
and indeed, we were able to find precedence for this idea in
the work of Nussbaumer and Frater.8 Thus, we set out to
investigate the scope of this little explored variation of the
Prins cyclization route to tetrahydropyrans.
Some results are documented in Table 1 and Figure 1.
Enol ethers of type 8 were prepared in 53-97% yield by
treating the corresponding homoallylic alcohols with ethyl
propiolate and triethylamine in Et2O.12 Exposure of these
cyclization substrates to acid promoters gave results docu-
mented in Table 1 and Figure 1.
The results shown in entry 1 are similar to those reported
by Nussbaumer and Frater. Thus, treatment of a 0.1 M
dichloromethane solution of 8a with 10 equiv of trifluoro-
acetic acid (TFA) at room temperature for 40 min gave a
76% isolated yield of pure 9a, after ester ethanolysis under
basic conditions. The epimeric alcohol 10a was also isolated
Figure 1. Byproducts of acid-promoted Prins cyclizations described
in Table 1.
from this mixture, and it was determined that the ratio of
9a:10a was approximately 10:1.13 A mixture of dihydropy-
rans 11 was also isolated in 10-12% yield.13,14
The results shown in entry 2 underscore the influence of
the cyclization promoter on the course of the reaction. Thus,
treatment of 8a with formic acid gave 9a in only 12% yield
along with starting material (15%), homoallylic alcohols 12
(10%) and 13 (17%), and crossover product 3 (24%). This
illustrates that formal hydrolysis (3 and 12) and sigmatropic
rearrangements (13) can complicate cyclization reactions with
enol ether substrates of type 8.
(9) Roush, W. R.; Dilley, G. J. Synlett 2001, 955.
(10) Semeyn, C.; Blaauw, R. H.; Hiemstra, H.; Speckamp, W. N. J. Org.
Chem. 1997, 62, 3426. Nokami, J.; Yoshizane, K.; Matsuura, H.; Sumida,
S. J. Am. Chem. Soc. 1998, 120, 6609. Gasparski, C. M.; Herrinton, P. M.;
Overman, L. E.; Wolfe, J. P. Tetrahedron Lett. 2000, 41, 9431. Cohen, F.;
MacMillan, D. W. C.; Overman, L. E.; Romero, A. Org. Lett. 2001, 3,
1225. Loh, T.-P.; Tan. K.-T.; Hu. Q.-Y. Angew. Chem., Int. Engl. 2001,
40, 2921. Rychnovsky, S. D.; Marumoto, S.; Jaber, J. J. Org. Lett. 2001, 3,
3815. Nokami, J.; Ohga, M.; Nakamoto, H.; Matsubara, T.; Hussain, I.;
Kataoka, K. J. Am. Chem. Soc. 2001, 123, 9168. Crosby, S. R.; Harding J.
R.; King, C. D.; Parker, G. D.; Willis, C. L. Org. Lett. 2002, 4, 577.
(11) Winstead, B. C.; Simpson, T. H.; Lock, G. A.; Schiavelli, M. D.;
Thompson, D. W. J. Org. Chem. 1986, 51, 275.
(12) Ireland, R. E.; Wipf, P.; Xiang, J.-N. J. Org. Chem. 1991, 56, 3572.
(13) Relative stereochemistry of products was assigned based on 1D-
and 2D-1H NMR experiments, described in the Supporting Information.
(14) The isomeric relationships of dihydropyrans 11, 14, and 17 were
established by catalytic hydrogenation of the mixtures to corresponding
single tetrahydropyrans. Hydrogenation of 24 gave two tetrahydropyrans.
1500
Org. Lett., Vol. 5, No. 9, 2003

The behavior of 8b with trifluoroacetic acid (entry 3)
reveals that this process can be extended to the synthesis of
2-aryltetrahydropyrans. The behavior of 8c upon reaction
with TFA was more interesting (entry 4). This reaction gave
a 1:1 mixture of tetrahydropyrans 9c and 10c (55-58%),
dihydropyrans 14 (10-13%), alcohols 13 (trace) and 15
(11%), 2,6-dioxabicyclo[3.2.1]octane 16 (12%), and benzyl
alcohol (trace).13,14 Two aspects of this reaction are interest-
ing. First, stereochemical control at C4 of the tetrahydropyran
undergoes considerable erosion relative to entries 1 and 3.
Second, bicyclic ether 16 appears as a heretofore unobserved
Prins cyclization product. This product is notable because
of the trans relationship between the C2 and C6 substituents
of the pyran substructure.15
a mixture of cis-2,6- and trans-2,6-disubstituted dihydropy-
rans 24 in 9% combined yield (cis/trans ) 2:1).13,14 The
reduced 2,6-selectivity with 8g, relative to all other substrates
in Table 1, can be attributed to reduced steric requirements
for an alkynyl group in the presumed chairlike transition state
believed to dominate the Prins cyclization route to tetrahy-
dropyrans.9
We have also extended the Nussbaumer-Frater version
of the Prins cyclization to other acid promoters. Treatment
of 8a with titanium tetrachloride in dichloromethane gave
25 and 26 (X ) Cl) in 63% yield as a 20:1 mixture,
respectively (Table 2).13 Similar treatment of 8a with titanium
Whereas the exact sequence of events leading to 16 has
not yet been determined, it was hoped that replacement of
the benzyl group with a protecting group less prone to acid-
promoted cleavage would eliminate this competing process.
Thus, substrate 8d was prepared and treated with TFA (entry
5). This reaction provided a 4:3 mixture of tetrahydropyrans
9d and 10d (66%), dihydropyrans 17 (13%), and bicyclic
ether 16 (trace).13,14 Thus, changing the protecting group
impeded dioxabicyclo[3.2.1]octane formation but did not
correct the stereochemical erosion at C4.
Table 2. TiCl4-, TiBr4-, and SnBr4-Promoted Prins
Cyclizations
yield of
entry
acid
T (°C)
time
X
25 + 26 (%)
25/26
Enol ether 8e (entry 6), the methylene homologue of 8c,
gave only the expected cyclization products 9e and 10e in
91:9 ratio (80%).13 This result confirms that the side chain
oxygens in 8c and 8d play a role in the stereochemical
erosion at C4 observed with these substrates.
1
2
3
TiCl4
TiBr4
SnBr4
rt
0
rt
3 d
2 h
2.5 d
Cl
Br
Br
63
64
69
20:1
6:1
5:1
We next examined hybridization changes in the incipient
C2 side chain. Substrate 8f (sp2-hybridized side chain)
behaved normally when the reaction was run in neat
trifluoroacetic acid (entry 7) to give a separable mixture of
9f and 10f in a 91:9 ratio and greater than 70% yield.13 When
the concentration of trifluoroacetic acid was reduced, how-
ever, diols 18 and 19 (2:1, respectively) appeared as
interesting minor products in up to 13% yield at the expense
of 9f and 10f.16 We suggest that these compounds are formed
as illustrated in Scheme 2.
tetrabromide or tin tetrabromide gave 25 and 26 (X ) Br)
with slightly lower diastrereoselectivity at C4.13 The slow
reaction rates (2-3 days) for titanium tetrachloride and tin
tetrabromide mediated reactions suggest that an alternative
mode of activation, such as Lewis acid complexation of the
vinylogous carbonate carbonyl group, may be operating.
Finally, we have observed that a simple methyl substituent
at C3 in substrates related to 8c can have a dramatic effect
on the course of the reaction (Scheme 3). For example,
treatment of 27 with TFA in dichloromethane provided the
expected tetrahydropyran 28 in only 7% yield.13 The major
product was dioxabicyclo[3.2.1]octane 29 (50%) accompa-
nied by its C3 epimer 30 (16%).13 Reaction of the C3 epimeric
substrate 31 with TFA gave a largely different set of
products. The expected tetrahydropyran 32 was once again
a minor product isolated in 11% yield along with 4% of the
corresponding C4 epimer.13,17 The major product was now
dioxabicyclo[3.3.0]octane 33 (41%).13 Bicyclic diethers 29
(6%) and 30 (4%) were also obtained. We suspect that 30
was the major bicyclo[3.2.1]octane produced from 31, while
most of 29 produced in this reaction arises from the 10%
contamination of 31 with 27.18
Scheme 2. Formation of Diols 18 and 19 during
TFA-Promoted Prins Cyclization of Enol Ether 8f
(15) For closest analogy to this, see Speckamp and Hiemstra. For cases
with CH2OBn where no participation was observed, see: Semeyn, C.;
Blaauw, R. H.; Hiemstra, H.; Speckamp, W. N. J. Org. Chem. 1997, 62,
3426.
(16) The structure of 18 was correlated with that of 9f by hydroboration
(9-BBN)/oxidation of the latter.
(17) We note that only a trace of 32 (less than 1%) was detected in the
cyclization of 27.
Substrate 8g (sp-hybridized side chain) gave the expected
products 9g (33%) and 10g (9%) along with homoallylic
alcohol 13 (4%), trans-2,6-disubstituted pyran 23 (27%) and
Org. Lett., Vol. 5, No. 9, 2003
1501

etry via addition-elimination of nucleophiles present in the
reaction mixture would provide oxocarbenium ions 36a and
36b, respectively. Cyclization of 36a and 36b via a chairlike
transition states would ultimately provide dioxabicyclo[3.2.1]-
octanes 29 and 30, respectively, as the major stereoisomers.
We note that this hypothesis explains the apparent switch in
the diastereomeric C2-C3 relationship observed in this pair
of products. Furthermore, sigmatropic rearrangement of 34a
through a boatlike conformation would afford 35b, providing
a path from 34a to the minor product 30.9 On the other hand,
cyclization of 35b to secondary carbocation 37b followed
by trapping of the cation by the benzylic oxygen would
provide 33. It is possible that the cyclization rate of 37a is
slower than the cyclization rate of 37b because of an
unfavorable steric interaction resulting from endo placement
of the C6-methyl group in the cyclization of 37a. This could
explain why 27 provides dioxabicyclo[3.2.1]octane 29 as the
major product, while 31 provides largely dioxabicyclo[3.3.0]-
octane 33. Although further studies are needed to see which
aspects of Scheme 4 have merit, this hypothesis provides a
mechanistic framework for thinking about these reactions
and designing mechanistic experiments.
Scheme 3. Prins Cyclizations of C3-Methyl-Substituted Enol
Ethers 27 and 31
Although we can only speculate about the divergent
behavior of 27 and 31, a working hypothesis is presented in
Scheme 4. We imagine that 27 and 31 are protonated to
Scheme 4. Possible Mechanistic Pathway for the Formation of
Bicycles 29, 30, and 33
In summary, this research further defines the scope and
limitations of the Nussbaumer-Frater version of the Prins
cyclization route to tetrahydropyrans. Several major reactions
that have not been reported by groups that have studied
variations of the Prins cyclization are also described.
Acknowledgment. C.E.B. thanks the NIH for postdoc-
toral fellowship support.
Supporting Information Available: Representative ex-
perimental procedures for Prins cyclizations of enol ethers
and spectroscopic data for the resulting products are provided.
This material is available free of charge via the Internet at
http://pubs.acs.org.
afford oxocarbenium ions 34a and 34b, respectively. Cy-
clization of these compounds to the observed tetrahydropy-
rans appears to take place via the expected chairlike con-
formation without erosion of stereochemistry across C2 and
C3. Sigmatropic rearrangement of 34a and 34b via a chairlike
conformation would provide oxocarbenium ions 35a and
35b, respectively. Isomerization of oxocarbenium ion geom-
OL0342756
(18) Vinylogous carbonate was prepared as described above from the
appropriate homoallylic alcohol, which was prepared by crotylation of
2-benzyloxyacetaldehyde by the CrCl2-NiCl2 method: Hiyama, T.; Kimura,
K.; Nozaki, H. Tetrahedron Lett. 1981, 22, 1037. 31 prepared in this manner
1
was contaminated with 10% of 27 (by H NMR).
1502
Org. Lett., Vol. 5, No. 9, 2003