The use of nafion-h to promote epoxide cyclizations

Article abstract of DOI:10.1055/s-1998-4495

Nafion-H is shown to be an effective promoter of epoxide cyclizations to aromatic positions. The reactions can be done by passing a solution of the epoxide through a column packed with Nafion-H, or by stirring a mixture of the compound with the acidic pro

Full text of DOI:10.1055/s-1998-4495

SYNTHESIS
August 1998
1133
The Use of Nafion®-H To Promote Epoxide Cyclizations
Stephen K. Taylor,* Michael G. Dickinson, Scott A. May, Dacia A. Pickering, Paul C. Sadek
Department of Chemistry, Hope College, Holland, MI 49422-9000, USA
Fax: 001 616 395 7118
Received 4 June 1997; revised 10 November 1997
Abstract: Nafion®-H is shown to be an effective promoter of
Table. Epoxide Cyclization Products
epoxide cyclizations to aromatic positions. The reactions can be
done by passing a solution of the epoxide through a column packed
with Nafion®-H, or by stirring a mixture of the compound with the
acidic promoter and then filtering off the solid and washing it with
the appropriate solvent. The solvent mixture that gave the highest
yields had a fluorine-containing solvent, and trifluoroethanol in 3–
10% amounts seems to be particularly good at maximizing yields.
In general, yields are comparable to the same reactions that have
been promoted by Lewis acids such as SnCl4 and BF3•OEt2, but the
workup is significantly easier. Because of the convenience of
workup and the fast rates of reaction with this super-acid catalyst,
many reactions can be done in a short time period. The reaction
mixtures show almost no side products. A biomimetic cyclization
was also investigated using the described protocol.
Entry Epoxide R1
R2
Yield of 2 (%)a Yield of 3 (%)a
1
2
3
4
5
6
7
1a
1b
1c
1d
1e
1f
H
H
H
H
H
H
88
77
72b
58
42
–
–
–
–
OMe
Me
F
Cl
H
–
OMe 31
Me
43
Key words: Nafion®-H, super-acid catalyst, epoxy-arene cycliza-
tion
1g
H
35b
43b
a GC yield unless otherwise specified.
b Distilled yield.
In previous reports, we determined the relative facility of
Lewis acid promoted epoxide cyclizations to aromatic po-
sitions (epoxy-arene cyclizations; see eq 1 for an exam-
ple).1, 2
done by passing a solution of approximately 20 mg of ep-
oxide (diluted to 10% by volume with solvent) through an
8 mm i.d. × 10 cm column packed with 100 mesh
Nafion®-H powder. The product was collected in a 20–
50 mL beaker, the solvent was allowed to evaporate, and
the product was analyzed by GC, GCMS and NMR. The
solvent mixtures that gave the highest yields had 3–10%
2,2,2-trifluoroethanol (TFE) in them. Typical solvent
mixtures were CH2Cl2/FCCl3/TFE 62:28:10 for 1b and f
and a 69:28:3 mixture for 1a and g. The fluorinated sol-
vents were necessary to elute the maximum amount of
product possible, as discussed earlier for 1a (the only ep-
oxide cyclization reaction reported earlier).6
Although investigations of such epoxy-arene cyclizations
are newer than the well-studied epoxy-ene cyclizations,2
these reactions have already been used as key steps in the
syntheses of important natural products such as
pseudopterosin A3 and edulone A.4 In very recent studies,
we compared the relative facility of epoxy-arene and ep-
oxy-ene cyclizations in compounds which could compet-
itively cyclize to either a double bond or aromatic position
(eq 2).5
An optimized procedure is as follows. When a 22.5 mg
sample of 1a was passed through the column (with
CH2Cl2/FCCl3/TFE, 25 mL, 50:47:3), an 88% GC yield of
2a resulted. This procedure worked well with ~20 mg
quantities of epoxide. We also stirred 150 mg of epoxide
1a in 113 mg of Nafion®-H and 14 mL of the same sol-
vent. After 1 hour, the mixture was filtered and the prod-
uct was purified by column chromatography (CH2Cl2/
hexane 1:1) giving 89 mg (78% isolated yield, ≥92%
pure). When 1g was treated similarly (using CH2Cl2 with
3% TFE) the two desired products (arising from cycliza-
tion ortho and para to the methyl group) were isolated in
78% distilled yield, and they were the only products de-
tectable by capillary GC. The volatile crude products of
reactions done on epoxides 1a,b,f and g were at least 95%
pure by capillary GC. This is a notable advantage to this
method compared to using Lewis acids, where small
amounts of halohydrin and other side products are more
In a preliminary communication emphasizing the analyti-
cal chemistry of a related approach, we reported that
Nafion®-H, a polymeric super acid,6 promoted a single
epoxy-arene cyclization that was previously done with a
Lewis acid.1a (Table, 1a → 2a) We herein report a series
of epoxides that have been cyclized by a modified proto-
col using Nafion®-H.7 The reactions with the polymeric
acid require essentially no workup or sophisticated glass-
ware, are done quickly, and often have simpler product
mixtures than the Lewis acid promoted reactions. The
yields for the two processes are comparable.
The Table shows the results of epoxy-arene cyclizations prominent.1b,c Also, the use of Lewis acids requires a
promoted by Nafion®-H. In most cases, the reactions were complex workup, usually including a mineral acid wash

SYNTHESIS
Papers
1134
1,2-Epoxy-5-phenylpentane (1a):1a
(to dissolve the Lewis acid), a basic wash (to remove ac-
id), a neutral wash, and drying. With this polymeric acid
promoter, these operations are circumvented. Also, no ef-
fort was made to dry the solvents such as is necessary
when using Lewis acids.1b,c
13C NMR (CDCl3): δ = 27.5, 31.8, 35.4, 46.7, 51.9, 125.7, 128.1,
128.2, 141.8.
MS: m/z (%) = 162 (3), 128 (27), 104 (100), 91 (58).
1,2-Epoxy-5-(p-methoxyphenyl)pentane (1b):1b
13C NMR (CDCl3): δ = 27.0, 31.9, 34.6, 46.9, 52.1, 55.2, 113.7,
129.2, 134.0, 157.7.
The cyclization of 4 (eq 3) was probably the first biomi-
metic epoxide cyclization prepared in the literature.8 We
treated this epoxide with Nafion®-H and compared the
MS: m/z (%) = 192 (19), 134 (89), 121 (100), 91 (26).
1,2-Epoxy-5-(p-tolyl)pentane (1c):1b
•
products (5/6/7 1:0.16:1.4) to those formed by BF3 OEt2
initiated cyclization. Using Nafion®-H, more ketone 7
13C NMR (CDCl3): δ = 20.9, 27.7, 31.9, 35.0, 46.9, 52.1, 128.2,
128.9, 135.2, 138.8.
•
formed than with the BF3 OEt2 promoted reaction 5/6/7
(1.3:1:1.2).8 However, Nafion®-H still promoted the de-
sired reaction.
MS: m/z (%) = 176 (9), 145 (45), 118 (100), 105 (53), 91 (28).
1,2-Epoxy-5-(p-fluorophenyl)pentane (1d):1b
This was characterized earlier, including combustion analysis, and
was consumed and not available for 13C NMR spectroscopy. 13C
NMR data of the cyclization product 2d is given below.
1,2-Epoxy-5-(p-chlorophenyl)pentane (1e):1b
13C NMR (CDCl3): δ = 27.5, 31.7, 34.7, 46.8, 52.0, 128.2, 128.5,
131.3, 140.3.
In earlier work utilizing Lewis acid promoters, 1,2-epoxy-
6-phenylhexane (8) cyclized to produce a seven-mem-
bered ring.1a We could not produce any cyclization prod-
uct using our Nafion®-H procedures. In this case, the
product was a highly viscous oil, and only a small percent-
age of the material could be distilled, even at high vacu-
um. We thus suspect that dimerization, trimerization, etc.
were faster than cyclization under our Nafion®-H condi-
tions.
MS: m/z (%) = 198 (1.5), 196 (5), 140 (33), 138 (100), 125 (46), 103
(26).
1,2-Epoxy-5-(m-methoxyphenyl)pentane (1f):1c
13C NMR (CDCl3): δ = 27.6, 32.0, 35.6, 47.0, 52.2, 55.1, 111.1,
114.2, 120.8, 129.3, 143.6, 159.6.
MS: m/z (%) = 192 (25), 161 (32), 134 (100), 121 (28), 115 (41), 91
(46).
1,2-Epoxy-5-(m-tolyl)pentane (1g):1c
13C NMR (CDCl3): δ = 21.2, 27.6, 31.8, 35.3, 46.7, 51.9, 125.2,
126.4, 128.1, 129.1, 137.6, 141.8.
MS: m/z (%) = 176 (5), 145 (29), 118 (100), 117 (34), 105 (35).
Epoxide Cyclizations:
The reaction of 1a was optimized with respect to residence time (on
a packed column) and solvent composition on a 22.5 mg-scale
(3.6 mmol) reaction using a 8 mm i.d. × 10 cm column packed with
Nafion®-H, and collecting 25 mL of effluent. The solvent had 3%
TFE (CH2Cl2/FCCl3/TFE 50:47:3), the residence time on the column
was 7 min, and the yield was 19.8 mg (88%, GC yield with 6-meth-
oxy-1-tetralone as the internal standard). When the residence time
was 30, 15, and 6 min, 76, 82, and 63% yields resulted respectively.
With 5% TFE, the yield was 80% and with no TFE (CH2Cl2/FCCl3
50:50) it was 69%. Thus the best yield we could obtain was 88% com-
pared to 91% using SnCl4 as the cyclization promoter in anhyd
CH2Cl2.1c
In summary, we demonstrated that the use of Nafion®-H
offers some significant advantages over the use of stan-
dard Lewis acids for some epoxide cyclization reactions.
Specifically, the minimum of side products and ease of
use and workup are attractive features of this chemistry.
The equipment used has been described elsewhere.5a All compounds
in the Table have been characterized and reported by us before.1a–c
However, the work was done before we had access to 13C NMR spec-
troscopy. Therefore, we have included 13C NMR data on all of these
compounds except for 1d and 3g (reasons for these exceptions are
included in the experimental data). 13C NMR spectra are referenced
to the center peak of CDCl3 set at δ = 77.0. Reagent TFE, CH2Cl2 and
FCCl3 were used as provided from the suppliers without drying or
purification. Nafion®-H (100 mesh) was purchased by C.G. Process-
ing, Inc. Compound purities are >95% unless specified otherwise.
A 150-mg scale reaction was performed as described in the text. In a
large scale reaction, 1a (1.46 g, 90 mmol) was stirred for 3.5 h in a
mixture of CH2Cl2 (289 mL), TFE (11 mL), and Nafion®-H (0.980 g).
The Nafion®-H was filtered off through very fine filter paper and the
filtrate was washed with 5% NaHCO3 and concentrated. The desired
product was distilled at 82–84 °C/0.02 Torr using a short-path still,
giving 0.813 g of >95% pure 2a (56%).
13C NMR (CDCl3): δ = 19.5, 24.9, 29.6, 40.1, 66.9, 125.5, 126.0,
128.6, 129.2, 136.6, 138.0.
MS: m/z (%) = 162 (14), 131 (100), 129 (31), 128 (59), 127 (31), 115
(26), 91 (31).
General Synthesis of Epoxides:
The epoxides 1a–g were made by treating the Grignard of (2-bromo-
ethyl)benzene (or substituted analogs) with allyl bromide and then
treating the aryl-ene product with MCPBA as described previous-
ly.1a–c When the alkyl bromide was not available, it was synthesized
from the phenethyl alcohol by making the tosylate and treating the
tosylate with LiBr. Most spectral data for the compounds are included
in cited articles, but 13C NMR and mass spectral data are included
below.
7-Methoxy-1,2,3,4-tetrahydronaphthalene-1-methanol (2b):1b
Prepared by eluting 1b (41 mg, 7.5 mmol) in solvent (1 mL, CH2Cl2/
FCCl3/TFE 50:40:10) through Nafion®-H (2.0 g) packed in a giant
pipet. The volatile crude product distribution was >97% 2b, and the
GC yield was 77%.

SYNTHESIS
August 1998
1135
13C NMR (CDCl3): δ = 20.0, 25.1, 28.8, 40.5, 55.2, 67.1, 112.1,
113.6, 129.2, 130.1, 137.7, 157.5.
MS: m/z (%) = 192 (23), 161 (100), 158 (30), 115 (75).
HPLC.1c It was isolated as a 72:28 2g/3g mixture, and its 13C NMR
peaks were assigned from NMR of this mixture by subtracting the
peaks from the 6-methyl isomer.
13C NMR (CDCl3): δ = 17.8, 19.0, 23.9, 29.5, 37.6, 64.3, 126.0,
127.1, 127.9, 135.0, 136.6, 137.8.
7-Methyl-1,2,3,4-tetrahydronaphthalene-1-methanol (2c):1b
Prepared by stirring 1c (306 mg, 1.7 mmol) in a mixture of CH2Cl2
(72 mL), TFE (3 mL), and Nafion®-H (292 mg). After 2.5 h, the
Nafion®-H was removed by filtration through very fine filter paper,
and the filtrate was rotary evaporated. Kugelrohr distillation (78–
100°C/0.025 Torr gave 0.219 g (72%) of 2c, which contained no im-
purities, according to capillary GC and 13C NMR.
MS: m/z (%) = 176 (10), 145 (100), 129 (34), 128 (31), 115 (35).
6-Methyl-1,2,3,4-tetrahydronaphthalene-1-methanol (3g):1c
Isolated by HPLC.
13C NMR (CDCl3): δ = 19.8, 20.9, 25.3, 29.7, 39.9, 67.1, 126.6,
128.6, 130.0, 133.5, 135.6, 137.8.
13C NMR (CDCl3): δ = 19.8, 21.0, 25.2, 29.2, 40.2, 67.1, 127.0,
129.2, 135.0, 136.4.
MS: m/z (%) = 176 (16), 145 (100), 129 (27), 128 (29), 115 (35).
MS: m/z (%) = 176 (7), 145 (100), 129 (27), 128 (31), 115 (32).
Geraniolene Epoxide (4): 8
Synthesized as described by Goldsmith.8
7-Fluoro-1,2,3,4-tetrahydronaphthalene-1-methanol (2d):1b
Prepared from 1d by the HPLC column cyclization method6 using
CH2Cl2/FCCl3/TFE (62:28:10) (58% GC yield). The major impurities
identified by GCMS were a 2:1 mixture of unreacted epoxide and the
aldehyde1b resulting from epoxide rearrangement.
13C NMR (CDCl3): δ = 19.4, 23.1, 25.5, 27.8, 35.2, 58.9, 64.7, 111.0,
145.5 (94% pure).
8
•
The epoxide was cyclized with BF3 OEt2 as previously reported , and
the products were isolated by preparative GC.8 The isolated products
were identified using the reported H NMR and IR data8 and they
1
13C NMR (CDCl3): δ = 19.9, 25.0, 29.0, 40.4, 66.9, 113.1 (d, J =
22 Hz), 114. 8 (d, J = 20 Hz), 130.5 (d, J = 27 Hz), 133.5, 138.7 (d, J
= 7 Hz), 160.9 (d, J = 242 Hz).
were compared by GCMS to the products formed from Nafion®-H
promoted cyclizations performed on a 2 mg scale by the column
method using CH2Cl2/FCCl3/TFE (77.5:22.5:0.5). This solvent sys-
tem gave the fewest side products.
MS: m/z (%) = 180 (17), 149 (100), 147 (35), 146 (37), 133 (30), 109
(47).
1,2-Epoxy-6-phenylhexane (8):1a
7-Chloro-1,2,3,4-tetrahydronaphthalene-1-methanol (2e):1b
Prepared by cyclizing 1e (2 mg) by the HPLC method6 in CH2Cl2/
FCCl3/TFE (69:28:3) (42% GC yield). Major impurities were unre-
acted 2e and the aldehyde reported earlier.1b
Prepared as reported earlier.1a
13C NMR (CDCl3): δ = 25.5, 31.1, 32.2, 35.7, 46.9, 52.1, 125.6,
128.1, 128.2, 142.2.
The compound (223 mg, 1.27 mmol) was stirred in CH2Cl2/ClCF3/
TFE (50 mL, 5:4.5:5) and Nafion®-H (343 mg). The reaction was fol-
lowed by GC, but few new volatile products appeared, and the peaks
grew smaller. When 157 mg of 8 was treated similarly, the viscous
product was Kugelrohr distilled (up to 130°C/0.08 Torr), yielding
only 39 mg of distillate, which did not show the 1H NMR (or GCMS)
peaks expected of the desired cyclization product (at δ = 3.6–4.0).1a
13C NMR (CDCl3): δ = 19.7, 24.9, 29.1, 40.2, 66.9, 126.2, 128.5,
130.6, 131.1, 136.5, 138.7.
MS: m/z (%) = 198 (7), 196 (21), 165 (100), 130 (47), 129 (58), 128
(44), 127 (36), 115 (25).
8-Methoxy-1,2,3,4-tetrahydronaphthalene-1-methanol (2f):1c
Formed in 31% GC yield during the reaction of 1f with Nafion®-H,
along with a 43% yield of 3f. The products were separated by HPLC
using a 10 mm i.d. × 25 cm column packed with 10 µm silica gel using
hexane/EtOAc (80:20), 2f eluted first (mp 72–73°C)1c (followed by
3f).
Acknowledgment is made to the donors of the Petroleum Research
Fund, administered by the American Chemical Society, for partial
support of this work and to the National Science Foundation (CHE-
8804803 and 8807450) for the purchase of an NMR spectrometer
and for student support. This article is dedicated to William S.
Johnson, whose work in part inspired our own, and who gave per-
sonal and professional encouragement to me (S.K.T.) in his latter
days.
2f:
13C NMR (CDCl3): δ = 18.2, 24.5, 29.4, 35.2, 55.3, 65.7, 107.3,
121.8, 125.7, 126.6, 139.2, 157.4.
MS: m/z (%) = 192 (14), 161 (100), 115 (41).
6-Methoxy-1,2,3,4-tetrahydronaphthalene-1-methanol (3f):1c
Purified by HPLC of the above cyclization mixture was characterized
earlier (and made independently), including derivative mp1c.
13C NMR (CDCl3): δ = 19.7, 25.3, 30.0, 39.5, 55.2, 67.1, 112.0,
113.8, 128.7, 129.6, 139.4, 157.7.
(1) (a) Taylor, S. K.; Hockerman, G. H.; Karrick, G. L.; Lyle, S. B.;
Schramm, S. B. J. Org. Chem. 1983, 48, 2449.
(b) Taylor, S. K.; Davisson, M. E.; Hissom, B. R., Jr.; Brown, S.
L.; Pristach, H. A.; Schramm, S. B.; Harvey, S. M. J. Org. Chem.
1987, 52, 425.
MS: m/z (%) = 192 (11), 161 (100), 115 (66).
(c) Taylor, S. K.; Blankespoor, C. L.; Harvey, S. M.; Richardson,
L. J. J. Org. Chem. 1988, 53, 3309.
(2) For a recent review see (a) Taylor, S. K. Org. Prep. Proc. Int.
1992, 24, 245.
8-Methyl-1,2,3,4-tetrahydronaphthalene-1-methanol (2g):1c
Prepared in a 35% distilled yield along with a 43% distilled yield of
3g as follows. 1g (0.3511 g, 1.9 mmol) was stirred along with CH2Cl2
(79 mL), TFE (4 mL), and Nafion®-H (325 mg). The Nafion®-H was
removed by filtration through very fine filter paper and the filtrate
was concentrated by rotary evaporation. The volatile crude product
mixture was 98% 2g and 3g by capillary GC. The product was puri-
fied by Kugelrohr distillation (90–100°C/ 0.025–0.04 Torr) to give
0.275 g (78%) of distillate which was exclusively 2g and 3g by capil-
lary GC. HPLC (as described above) using trace hexane in EtOAc/
EtOH (85:15) did not cleanly separate the 6- and 8-isomers but 3g
eluted first in an unsymmetrical peak and we did isolate pure 3g by
peak shaving (see below). 2g could not be isolated pure even by
For earlier reviews see (b) van Tamelen, E. E. Acc. Chem. Res.
1968, 1, 111.
(c) Sutherland, J. K. Chem. Soc. Rev. 1980, 9, 265.
(d) Johnson, W. S. Bioorg. Chem. 1976, 5, 51.
(e) Goldsmith, D. Fortsch. Chem. Org. Naturst. 1971, 29, 363.
(3) Broka, C. A.; Chan, S.; Peterson, B. J. Org. Chem. 1988, 53,
1584.
(4) Burnell, R. H.; Dufour, J. M. Can. J. Chem. 1987, 65, 21.
(5) (a) Taylor, S. K.; Bischoff, D. S.; Blankespoor, C. L.; Deck, P. A.;
Harvey, S. M.; Johnson, P. L.; Marolewski, A. E.; Mork, S. W.;

SYNTHESIS
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1136
Motry, D. G.; Van Eenenaam, R. J. Org. Chem. 1990, 55, 4202.
See correction, J. Org. Chem. 1991, 56, 5736.
(b) Taylor, S. K.; May, S. M.; Stansby, E. S. J. Org. Chem. 1996,
61, 2075.
se the powdered Nafion®-H HPLC column packing material
eventually swells and plugs the column when using the solvent
mixture that gives the highest yields. We now prefer the non-
HPLC method described herein.
(6) Sadek, P. C.; Taylor, S. K.; Dick, M. G. Anal. Lett. 1987, 20, 169.
(7) In the preliminary report,6 an HPLC column was packed with Na-
fion®-H powder and the epoxide was passed through the HPLC
column. An analytical column was attached directly after the re-
actor column, and the reactant and product were separated and
analyzed using the tandem analytical column. Although this two-
column approach was very efficient, we have abandoned it becau-
(8) Goldsmith, D. J. J. Am. Chem. Soc. 1962, 84, 3913.
A regioisomer of 5 (2,2,4-trimethylcyclohex-3-en-1-ol) was treat-
ed as though it was 5 in Goldsmith's calculation of the ratio of
products. We did not detect this isomer in our Nafion®-H reaction
•
products by capillary GC. We did detect it in the BF3 OEt2 cycli-
zation products.