Preparation of 2-Ethoxy-3-hydroxy-4-(perfluoroalkyl)tetrahydropyran Derivatives from Substituted 4-Ethoxybut-3-en-1-ols

FULL PAPER

DOI: 10.1002/ejoc.200900687

Preparation of 2-Ethoxy-3-hydroxy-4-(perfluoroalkyl)tetrahydropyran

Derivatives from Substituted 4-Ethoxybut-3-en-1-ols

Stig Valdersnes^[a]and Leiv K. Sydnes*^[a]

Keywords: Perfluoroalkylation / Carbohydrates / Enols

A number of 1-substituted and 1,1-disubstituted (E)-4,5,5-tri-

(perfluoroalkyl)tetrahydropyran-3-ones in 77–100% yield as

ethoxypent-3-en-1-ols (1) have been converted to perfluoro- stereoisomeric mixtures. Subsequent reduction of the keto

alkylated tetrahydrofurans and tetrahydropyrans in a selec-

tive fashion by 1-iodoperfluoroalkane addition under radical

conditions using sodium dithionite (Na₂S₂O₄) as radical initi-

ator. Direct perfluoroalkylation of 1 gave the former products

only, and the yields were moderate (50–75%), but when 1

was converted to corresponding 6-substituted and 6,6-disub-

stituted 2,3-diethoxy-5,6-dihydro-2H-pyrans before per-

fluoroalkylation was carried out, the transformation turned

out to be significantly more successful and afforded, as the

only product, 6-substituted and 6,6-disubstituted 2-ethoxy-4-

group with sodium borohydride in ethanol was uneventful

and completed the syntheses of a range of 4-perfluorobutyl-

ated tetrahydropyran derivatives; the yields in this step were

in the 81–94% range. The best result was obtained with (E)-

2-methyl-5,6,6-triethoxyhex-4-en-2-ol which was converted

to a diastereoisomeric mixture of 2-ethoxy-6,6-dimethyl-4-

(perfluorobutyl)tetrahydropyran-3-ol in 85% yield in three

steps.

Germany, 2009)

one or two additional substituents attached to the ring. The

synthetic approach involves perfluoroalkylation by addition

of a perfluoroalkyl iodide (R_FI) to an alkene promoted by

a radical initiator. Such reactions can be performed under

a variety of conditions,^[5–7]but we settled for a protocol

applied successfully by Zhu and Li.^[7]When their methodol-

ogy was adopted we were able to develop reaction condi-

tions that allowed selective conversion of 1-substituted (E)-

4,5,5-triethoxypent-3-en-1-ol derivatives (1, Figure 1),^[8]

easily available from 3,3,4,4-tetraethoxybut-1-yne (TEB) as

described in the literature,^[9]to perfluoroalkylated deriva-

tives of both tetrahydrofuran and tetrahydropyran.

Introduction

Replacement of a hydrogen atom by a fluorine atom or

a perfluoroalkyl group (R_F) in organic molecules may have

a profound influence on their physical^[1]and biological

properties.^[2]This is intimately related to the fact that fluor-

ine is significantly more electronegative than hydrogen, has

a mass which is 19 times that of hydrogen, and is about

30% larger.^[3]In recent years these facts have triggered an

increasing interest in the making of R_F-substituted organic

molecules, including R_F-substituted carbohydrate deriva-

tives,^[3,4]which are expected to possess quite interesting

properties with many potentially useful applications. Long

hydrophobic and lipophobic perfluoroalkyl groups should

make these derivatives useful as emulsifiers,^[1]and the high

gas-solvating ability of a number of perfluoroalkyl groups

could make such R_F-substituted molecules important com-

ponents in artificial blood.^[2]The possibility of applying

bioactive perfluoroalkylated molecules for in vivo ¹⁹F-

NMR spectroscopy and as liquid crystals is also an attract-

ive idea.^[1]

Figure 1. The hydroxylated vinyl ethers investigated.

On this basis, we became interested in making modified

carbohydrates with perfluoroalkyl substituents in various

positions. In this paper, we present a novel strategy for the

preparation of perfluoroalkylated tetrahydropyrans with

Results and Discussion

Exploratory Experiments Based on 1a

In order to get an impression of the reactivity exhibited

by vinyl ethers 1 under the reaction conditions employed

by Zhu and Li,^[7]various exploratory experiments were per-

formed with the simplest representative of 1, namely (E)-

4,5,5-triethoxypent-3-en-1-ol (1a). Three interesting sets of

[a] Department of Chemistry, University of Bergen,

Allégt. 41, 5007 Bergen, Norway

Fax: +47-55-58-94-90

E-mail: leiv.sydnes@kj.uib.no

Supporting information for this article is available on the

WWW under http://dx.doi.org/10.1002/ejoc.200900687.

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4-Perfluoroalkylated Tetrahydropyran Derivatives

results emerged. First and foremost, irrespective of the 1- group is removed. This approach worked well when 4a-II

iodoperfluoroalkane used, the final product was not any of was reacted first with sodium borohydride [to give 5,5-di-

the corresponding conceivable perfluoroalkylated iodides; ethoxy-4-hydroxy-3-(perfluorohexyl)pentyl acetate (5a-II)]

instead a derivative of 2-(diethoxymethyl)-2-ethoxy-3-(per- and then with sodium methoxide in methanol; in this way

fluoroalkyl)tetrahydrofuran (2a) was obtained (Scheme 1). 5,5-diethoxy-3-(perfluorohexyl)pentane-1,4-diol (6a-II) was

Secondly, the yield of 2a appeared to vary with the length obtained in quite respectable yield (Scheme 3). However,

of the perfluoroalkyl chain; the longer the chain the lower attempts to perform chiral reduction, with mixtures of the

the yield (which dropped from 75% to 51% when the borane–dimethyl sulfide complex and (S)-oxazaborolid-

number of carbon atoms increased from 4 to 8). And fi- ine,^[10]were far less successful; for instance, when 4a-I was

nally, irrespective of the size of R_fgroup the tetra- reduced with this reagent 5,5-diethoxy-3-(perfluorobutyl)-

hydrofurans were formed as 1.0:1.0 mixtures of the cis and pentane-1,4-diol (6a-I) was formed directly, but the yield

trans isomers, which indicates that the product formed is was low (20%) and the main product was the undesired

kinetically controlled.

tetrahydrofuran-2-ol 7a-I, which was obtained in 51% yield

(Scheme 3).

Scheme 1. Addition of 1-iodoperfluoroalkanes to alcohol 1a; 2a-I

(R_F= n-C₄F₉), 2a-II (R_F= n-C₆F₁₃), and 2a-III (R_F= n-C₈F₁₇)

were obtained in 75, 59 and 51% yield, respectively.

Scheme 3. Reduction of 4a-I and 4a-II under different conditions.

As indicated in Scheme 1 the primary products were con-

ceivably the expected iodides (formed via the most stable

radical),^[5,6]which suffered intramolecular substitution and

gave tetrahydrofuran 2a. In order to prevent this from hap-

pening protection of the hydroxy group was apparently re-

quired. Treatment of 1a with acetyl chloride, triethylamine,

and DMAP gave the corresponding acetate, (E)-4,5,5-tri-

ethoxypent-3-enyl acetate (3a), in 86% yield, and when this

ester was exposed to 1-iodoperfluorobutane and 1-iodoper-

fluorohexane in the presence of sodium dithionite, the ex-

pected acyclic 3-perfluoroalkyl-substituted 5,5-diethoxy-4-

oxopentyl acetates, 4a-I and 4a-II, respectively, were iso-

lated (Scheme 2). Again the yield depends on the length of

the carbon chain of R_FI, but in this case the addition reac-

tion was most successful when the iodoperfluoroalkane

with the higher number of carbon atoms was used.

Diols 6a were expected to form tetrahydropyran deriva-

tives under acidic conditions, and that appeared indeed to

be the case, albeit the yields were moderate to low due to

formation of undesired products or unidentified by-prod-

ucts under all the reaction conditions applied. The results

from treatment of 6a-II with 80% aqueous formic acid in

pentane are representative; tetrahydropyran 8a-II was iso-

lated in 40% yield as an isomeric mixture, along with the

predominant product, formate 9, which was isolated in 52%

yield (Scheme 4).

Scheme 4. Attempted synthesis of the corresponding tetrahydro-

pyran from diol 6a-II.

The results presented above show that 4-perfluoroalk-

ylated deoxygenated tetrahydropyran derivatives of type 8a

can be obtained from vinyl ether 1a, but the number of

steps is high (six) and the overall yield is low (in the case of

8a-I only 15%). Since two of the steps are associated with

Scheme 2. Addition of 1-iodoperfluoroalkanes to acetate 3a; 4a-I

(R_F= n-C₄F₉) and 4a-II (R_F= n-C₆F₁₃) were obtained in 61 and

76% yield, respectively.

Deprotection of the hydroxy group is necessary to protection/deprotection to avoid tetrahydrofuran forma-

achieve cyclization and when this transformation was car- tion, it is apparent that it would be attractive if the hydroxy

ried out under neutral or acidic aqueous conditions several group in 1 could be protected through a cyclization reaction

products, including tetrahydrofuran 2a, were formed. In or- analogous to the transformation, which ultimately is re-

der to prevent formation of the latter, the keto moiety of 4a quired in any case to achieve ring formation. Such an alter-

has to be reduced before the ester protection of the OH native approach would amount to converting 1 into the cor-

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5817

S. Valdersnes, L. K. Sydnes

FULL PAPER

responding dihydropyran derivative before perfluoroalk- analyzed by TLC (to work out the flash-chromatographic

ylation was carried out, and this ring formation did indeed conditions) and only one spot was observed regardless of

occur with 1a under acidic conditions. However, the effi- the eluent used. And indeed, when each mixture of the iso-

ciency of the reaction and the product yield were sensitive meric tetrahydropyranones was flashed on a silica-gel col-

to the reagent used (see Scheme 5); thus, when sulfuric acid umn with a gradient going from a 5:95 to a 10:90 mixture

or an ion-exchange resin (Dowex 50W) was used as catalyst, of ethyl acetate and hexanes as eluent, decomposition oc-

the desired reaction did not occur, instead 2-ethoxy-2-(di- curred and gave in each case one isolable product, which,

ethoxymethyl)tetrahydrofuran (10a) was obtained in good on the basis of spectroscopic and spectrometric analyses,

yield. Switching to silica-gel catalysis in ethanol or ethyl was the 4-perfluoroalkylidene analogue of 12a, namely 13a

acetate, however, gave 2,3-diethoxy-5,6-dihydro-2H-pyran (Scheme 6). Spectroscopic data indicated that 13a in each

(11a), but the reaction was very sluggish and stirring at case was obtained as an approximate 4:1 mixture of the E

80 °C for more than 100 h was required to obtain the com- and the Z isomers, but the configuration of the predomi-

pound in better than 60% yield. Finally, a two-phase sys- nant isomer has still not been settled. However, according

tem, with formic acid as catalyst, was tried, and these con- to Huang et al. hydrogen bonding between the fluorine

ditions appeared overall to be the best, giving 11a in 57% atoms of the CF₂group attached to the ring and the neigh-

isolated yield after a reaction time of only 30 min.

bouring hydroxy group generated by enolization is a stabi-

lizing interaction,^[11]which should favour subsequent hy-

drogen fluoride elimination as depicted in Scheme 6. This

line of reasoning is supported by the fact that a similar eli-

mination reaction was observed by Miura et al. when they

carried out perfluoroalkylation of a number of trimethyl-

silyl vinyl ethers, e.g., 1-trimethylsiloxy-1-cyclohexene.^[6]

Scheme 5. Acid-catalyzed intramolecular cyclization of 1a.

With dihydropyranyl vinyl ether 11a at hand 1-iodoper-

fluoroalkane addition was performed.^[7]All three iodides

used gave the corresponding addition product, 2-ethoxy-4-

(perfluoroalkyl)tetrahydropyran-3-one (12a), as a pure sam-

ple of an approximately 1:1 mixture of the cis and trans

isomers in good to excellent yield. Just like perfluoroalk-

ylation of 1a, vinyl ether 11a appeared to afford the corre-

sponding addition product 12a in yields decreasing with in-

creasing length of the perfluoroalkyl chain (see Figure 2).

The isomer composition of the compounds was clearly re-

flected in their proton and carbon NMR spectra, which ex-

hibited both separate and overlapping peaks for the iso-

mers. By NOESY experiments some of the separate peaks

due to the individual isomers could be used to determine

the configuration of the perfluoroalkyl groups relative to

the ethoxy group, and from the integrals in the proton spec-

tra, the cis/trans composition was determined to be 44:56

for 12a-I, 52:48 for 12a-II, and 38:62 for 12a-III.

Scheme 6. HF elimination from 12a, facilitated by enolization and

hydrogen bonding.

Reduction of 12a with sodium borohydride constitutes

the last step in the alternative synthesis of 8a, and when this

reaction was performed with a cis/trans isomeric mixture of

2-ethoxy-4-(perfluorobutyl)tetrahydropyran-3-one (12a-I)

(ratio 44:56), alcohol 8a-I was obtained in 94% yield (as a

mixture of diastereoisomers, vide infra) (Scheme 7). Conse-

quently, the alternative strategy is significantly more attract-

ive than the first stepwise synthesis investigated; not only is

Figure 2. The 2-ethoxy-4-(perfluoroalkyl)tetrahydropyran-3-ones

(12a) prepared from 11a.

Several attempts were made to separate the cis and trans

isomers of 12a-I, 12a-II, and 12a-III by flash chromatog-

raphy, but all efforts failed irrespective of the conditions

applied. An indication that such a failure was about to oc-

Scheme 7. Completion of the synthesis of 2-ethoxy-4-(perfluoro-

cur was indeed observed when the product mixtures were butyl)tetrahydropyran-3-ol (8a-I).

5818 Eur. J. Org. Chem. 2009, 5816–5831

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4-Perfluoroalkylated Tetrahydropyran Derivatives

the number of steps reduced from six to three, the overall

yield for the conversion of 1a to 8a has also more than

tripled (from 15–50%).

carried out. This measure improved the yield in some cases,

and as the results compiled in Table 1 show, the pyrans were

obtained in respectable to excellent yields. Since alcohols

1b–1d are chiral it was expected that 11b–11d would be

formed as mixtures of cis and trans isomers, and that was

indeed observed. Pure samples of all the isomers were ob-

tained by flash chromatography and that paved the way for

unambiguous determination of their structures and thus the

cis/trans ratios. As the results in Table 1 show the ratio is

quite sensitive to the nature of the substituent attached to

the chiral centre of 1, but no general conclusion can be

drawn regarding this sensitivity on the basis of this limited

body of data.

Synthesis of Analogues to 8a from 1b–1f

The latter synthetic route to 8a (Scheme 8) was then ap-

plied to make 4-perfluoroalkylated tetrahydropyrans from

vinyl ethers 1b – 1f, which in fact are available from TEB

in better yields than 1a.^[8]Since perfluoroalkylation of 11a

was most successful when 1-iodoperfluorobutane was used,

this was the only iodide employed in the investigation of

perfluoroalkylation of 11b–11f.

With pure samples of the racemates of pyrans 11e and

11f as well as the cis and trans isomers of 11b–11d available,

1-iodoperfluorobutylation was carried out according to the

procedure for 1-iodoperfluoroalkylation of 11a (see Experi-

mental Section). All the reactions turned out to be very

efficient, and the corresponding 6-substituted 2-ethoxy-4-

(perfluorobutyl)tetrahydropyran-3-ones (12-I) were in most

cases obtained in excellent yield (Table 2). All the 3-pyr-

anones were obtained essentially pure as isomeric mixtures

without performing any special purification step(s). How-

ever, the isomer composition of the compounds could be

worked out by using their ¹H- and ¹³C-NMR spectra,

which contained both separate and overlapping peaks for

the different isomers. By using the signals due to the indi-

vidual isomers in the proton spectra of 12b-I–12f-I,

NOESY experiments and other 2D techniques were used

Scheme 8. The synthesis of 4-perfluoroalkyl-substituted deoxycar-

bohydrate analogues 8 from homoallylic alcohols 1. Position 2 in to determine the configuration of the perfluorobutyl group

the ring is arbitrarily shown with R configuration as a point of

reference.

relative to the ethoxy group for every 3-tetrahydropyranone.

The integrals of the separate signals were subsequently uti-

lized to determine the isomer composition.

The results incorporated in Table 2 show that the stereo-

selectivity of the perfluorobutylation was insignificant,

which is not surprising when molecular models of 11 are

inspected and reveal that it is unlikely that any conforma-

tion should be particularly stable and therefore predomi-

Treatment of a pentane solution of alcohols 1b–1f with

formic acid in water or ethanol afforded the corresponding

6-substituted 2,3-diethoxy-5,6-dihydro-2H-pyrans 11b–11f

in variable yields. In order to obtain as good yields as pos-

sible the alcohols (prepared from the corresponding 1-sub-

stituted 4,4,5,5-tetraethoxy-2-pentyn-1-ols as described in nate. However, it is interesting to note that the highest selec-

the literature^[8]) were not purified before cyclization was tivity is observed when 11e and 11f are reacted; both of

Table 1. Formation of 2,3-diethoxy-5,6-dihydro-2H-pyrans substituted in position 6 (11a–11f) from allylic alcohols 1a–1f as outlined in

Scheme 7.

Alcohol cyclized^[a]

R¹, R²

Product/overall yield^[b]

Yield cyclization^[c]

cis/trans ratio^[d]

1a

1b

1c

1d

1e

1f

H, H

H, Me

H, n-Hex

H, Ph

Me, Me

–(CH₂)₅–

11a/40%

11b/52%

11c/49%

11d/61%

11e/55%

11f/76%

57%

70%

53%

85%

100%

–

n.r.^[e]

27:73

38:62

68:32

n.r.^[e]

[a] The alcohols, prepared from the corresponding 1-substituted 4,4,5,5-tetraethoxy-2-pentyn-1-ols as described in the literature,^[8]were

not purified before cyclization was carried out. [b] The yield of 11 from the corresponding 1-substituted 4,4,5,5-tetraethoxy-2-pentyn-1-

ol. [c] The yield for the cyclization reaction, calculated from the overall yield and the yield published for formation of 1 from the

corresponding 1-substituted 4,4,5,5-tetraethoxy-2-pentyn-1-ols.^[8]The yield of 1f from 1-(3,3,4,4-tetraethoxybut-1-ynyl)cyclohexanol is

not available. [d] With reference to Scheme 8, where the configuration of position 2 has arbitrarily been chosen to be R, the cis isomers

of 11b and 11c have the 2R*,6R* configuration, whereas the cis isomer of 11d has the 2R*,6S* configuration. Consequently, the trans

isomers of 11b and 11c have the 2R*,6S* configuration, whereas the trans isomer of 11d has the 2R*,6R* configuration. [e] n.r.: not

relevant.

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5819

S. Valdersnes, L. K. Sydnes

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Table 2. Formation of 6-substituted 2-ethoxy-4-(perfluorobutyl)- moiety influences the borohydride attack quite considerably

tetrahydropyran-3-ones (12-I) by 1-iodoperfluorobutylation of 6-

so that the hydride approach from the Re face is rendered

substituted 2,3-diethoxy-5,6-dihydro-2H-pyrans (11a–11f) under

more favourable than that from the Si face.

the conditions shown in Scheme 7.

[b]

Substrate^[a]

Product

Yield 4R*/4S*^[c]

(2R*)-11a

(2R*,4R*/4S*)-12a-I

89%

78%

99%

77%

86%

95%

93%

96%

91%

56:44

42:58

60:40

55:45

65:35

50:50

70:30

84:16

80:20

Conclusions

(2R*,6R*)-11b (2R*,4R*/4S*,6R*)-12b-I

(2R*,6S*)-11b (2R*,4R*/4S*,6S*)-12b-I

(2R*,6R*)-11c (2R*,4R*/4S*,6R*)-12c-I

(2R*,6S*)-11c (2R*,4R*/4S*,6S*)-12c-I

(2R*,6S*)-11d (2R*,4R*/4S*,6S*)-12d-I

(2R*,6R*)-11d (2R*,4R*/4S*,6R*)-12d-I

A high-yield synthesis of 2-ethoxy-4-(perfluorobutyl)-

tetrahydropyran-3-ols substituted at position 6 from simple

starting materials has been developed. Overall the best re-

sult was obtained with (E)-2-methyl-5,6,6-triethoxyhex-4-

en-2-ol which was obtained from acetone and 3,3,4,4-tetra-

ethoxybutyne (TEB) and then converted to a diastereoiso-

meric mixture of 2-ethoxy-6,6-dimethyl-4-(perfluorobutyl)-

tetrahydropyran-3-ol in 85% yield in three steps. Thus, a

new group of modified carbohydrates has become easily

(2R*)-11e

(2R*)-11f

(2R*,4R*/4S*)-12e-I

(2R*,4R*/4S*)-12f-I

[a] With reference to Scheme 7 and Scheme 8, where position 2 ar-

bitrarily has been given the R configuration, the configuration of

11a, 11e and 11f becomes 2R* whereas the cis isomers of 11b and

11c have the 2R*,6R* configuration and the cis isomer of 11d has

the 2R*,6S* configuration. Similarly, the trans isomers of 11b and available, and studies of their chemical potential as well as

11c have the 2R*,6S* configuration whereas the trans isomer of

physical and biological properties are about to begin.

11d has the 2R*,6R* configuration. [b] The 4S* configuration cor-

responds to a cis relationship between the ethoxy and the perfluo-

robutyl groups, the 4R* to a trans relationship. [c] The isomeric

composition was determined by means of the integrals in the ¹H

Experimental Section

NMR spectra of the crude products, recorded before the final

work-up was carried out.

General: Diethyl ether and THF were distilled from sodium/benzo-

phenone prior to use in reactions under an inert atmosphere. All

other solvents used in reactions were anhydrous grade and used as

received. Solvents used for extractions and flash chromatography

were technical grade. All reagents were used as received. Reactions

carried out under an inert atmosphere were performed under N₂.

Flash column chromatography was carried out using Merck 60

Kieselgel (230–400 mesh) with mixtures of hexane/ethyl acetate as

the mobile phase. Analytical thin-layer chromatography (TLC) was

performed on plates precoated with Merck Kieselgel 60 F254, and

these substrates have a symmetrically disubstituted carbon

atom in position 6, a consequence of which may be that the

reaction is influenced by conformational effects caused by

some sort of gem-dimethyl or Thorpe–Ingold effect.^[12]

In order to complete the syntheses of the 6-substituted

4-(perfluorobutyl)carbohydrate analogues to 8a-I, the iso-

meric mixtures of 2-ethoxy-4-(perfluorobutyl)tetrahydro- visualized by ultraviolet irradiation (254 nm) or by staining with

aqueous acidic ammonium hexamolybdate, aqueous acidic potas-

sium permanganate or ethanolic acidic phosphomolybdic acid

solutions as appropriate. Boiling points and melting points are un-

corrected. Melting points were performed on a Reichert hot-stage

or a Gallenkamp apparatus. Infrared spectra were obtained with a

Nicolet impact 410 spectrometer with the samples either as a film

between two NaCl plates or as a solid in KBr discs. Absorptions

are given in wavenumbers (cm^–1) and intensities are given as strong

(s), medium (m), weak (w), and broad (br). Mass spectra and accu-

rate mass data were obtained with a VG 7070 Micromass spectrom-

pyran-3-ones 12b-I to 12f-I were treated with sodium

borohydride in aqueous ethanol as described for 12a-I. Re-

duction under these conditions appeared to give the corre-

sponding 4-tetrahydropyranols in very good to excellent

yields (Table 3). Unlike the perfluoroalkylation, the re-

duction occurs with significant stereoselectivity and give

mainly, in two cases (6R*)-8d-I and 6S*)-8d-I) even exclu-

sively, 3-tetrahydropyranols with a cis relationship between

the hydroxy and ethoxy groups, which corresponds to a

2R*,3S* configuration (see Table 3). Apparently the ethoxy eter and an Autospec Ultima GC-MS from Micromass Ltd., both

Table 3. Formation of 6-substituted 2-ethoxy-4-(perfluorobutyl)tetrahydropyran-3-ols (8-I) by treating 6-substituted 2-ethoxy-4-(perfluo-

robutyl)tetrahydropyran-3-ones 12a-I to 12f-I with NaBH₄in aqueous ethanol.

Substrate^[a]

Product

Yield

3S*/4R*:3S*/4S*:3R*/4R*,3R*/4S*^[b](cis-OH):(trans-OH)^[c]

(2R*,4R*/4S*)-12a-I

(2R*,3R*/3S*,4R*/4S*)-8a-I

94%

81%

93%

86%

92%

87%

84%

89%

88%

34:33:22:11

42:48:0:10

76:12:8:4

50:27:5:18

55:35:10:0

22:78:0:0

78:22:0:0

73:12:11:4

80:17:0:3

67:33

90:10

88:12

77:23

90:10

100:0

85:15

97:3

(2R*,4R*/4S*,6R*)-12b-I (2R*,3R*/3S*,4R*/4S*,6R*)-8b-I

(2R*,4R*/4S*,6S*)-12b-I (2R*,3R*/3S*,4R*/4S*,6S*)-8b-I

(2R*,4R*/4S*,6R*)-12c-I (2R*,3R*/3S*,4R*/4S*,6R*)-8c-I

(2R*,4R*/4S*,6S*)-12c-I (2R*,3R*/3S*,4R*/4S*,6S*)-8c-I

(2R*,4R*/4S*,6S*)-12d-I (2R*,3R*/3S*,4R*/4S*,6S*)-8d-I

(2R*,4R*/4S*,6R*)-12d-I (2R*,3R*/3S*,4R*/4S*,6R*)-8d-I

(2R*,4R*/4S*)-12e-I

(2R*,4R*/4S*)-12f-I

(2R*,3R*/3S*,4R*/4S*)-8e-I

(2R*,3R*/3S*,4R*/4S*)-8f-I

[a] For each substrate the 4R*/4S* ratio was that given in Table 2. [b] The ratios were determined by ¹H NMR spectroscopy. [c] The

terms cis-OH and trans-OH are used to indicate the position of the OH group relative to ethoxy substituents. The cis relationship

corresponds to a 2R*,3S* configuration whereas a trans relationship corresponds to a 2R*,3R* configuration.

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Eur. J. Org. Chem. 2009, 5816–5831

4-Perfluoroalkylated Tetrahydropyran Derivatives

operated in the EI mode at 70 eV. The spectra are reported as m/z

(% relative intensity). H NMR spectra were recorded at ambient

Investigations Based on 1a

1

General Procedure for Perfluoroalkylation of 1a; Formation of 2a:

The procedure is based on a protocol published by Zhu and Li.^[7]

To a solution of vinyl ether 1a (0.22 g, 1.0 mmol), CH₃CN

(1.2 mL), water (1.0 mL) and 1-iodoperfluoroalkane (1.3 mmol) at

0 °C (for perfluorooctyl iodide a 20 °C water bath was used) under

N₂were added NaHCO₃(0.11 g, 1.3 mmol) and sodium dithionite

(Na₂S₂O₄) (0.23 g, 1.3 mmol). The resulting solution was stirred

overnight; H₂O was then added, and the hydrolysate was extracted

with DCM. The combined organic extracts were dried with

MgSO₄, filtered, and evaporated on a rotary evaporator until the

solvents were removed and a pure residue was left behind.

temperature either with a Bruker Spectrospin AC 200 F instrument

at 200 MHz or a Bruker Spectrospin DMX 400 spectrometer at

400 MHz with residual protic solvent CHCl₃(δ_H= 7.25 ppm) or

TMS (δ_H= 0.00 ppm) as the internal reference. ¹⁹F NMR spectra

were recorded at ambient temperature with the DMX 400 at

373 MHz. Chemical shifts in fluorine spectra are reported relative

to CFCl₃(δ_F= 0.00 ppm). Chemical shifts are reported downfield

from the reference standard and coupling constants are given in

Hz. Multiplicity is given as singlet (s), doublet (d), triplet (t), quar-

tet (q), double doublet (dd), double triplet (dt), and multiplet (m),

and wide signals are denoted broad (br). The proton and fluorine

spectra are reported as follows: δ/ppm (number of protons/fluorine,

multiplicity, coupling constant J/Hz). ¹³C NMR spectra were re-

corded at ambient temperatures on the same spectrometers at

50 MHz or 100 MHz, with the central peak of CHCl₃as the in-

ternal reference (δ_C= 77.0 ppm). DEPT-135 were used where ap-

propriate, to aid the assignment of signals in the ¹³C NMR spectra.

Where coincident coupling constants have been observed in the ¹H

NMR spectrum, the apparent multiplicity of the proton resonance

concerned has been reported. COSY, HSQC and HMBC was used

to aid the structural assignment of the products and NOESY was

used to decide the relative stereochemistry in the products.

2-(Diethoxymethyl)-2-ethoxy-3-(perfluorobutyl)tetrahydrofuran (2a-

I): The product, 0.33 g (75% yield), was obtained as a clear liquid.

IR (film): ν

= 2980 (s), 2898 (s), 1452 (m), 1382 (m), 1352 (s),

˜

max

1227 (s), 1133 (s), 1072 (s), 940 (m), 907 (m), 800 (m), 727 (m)

1

cm^–1. H NMR (200 MHz, CDCl₃, Me₄Si): δ = 4.63 and 4.62 [2s

in a 1.0:1.0 ratio, 1 H, CH(OEt)₂], 4.16–3.97 (m, 2 H, 5-H), 3.92–

3.51 (m, 6 H, 3 CH₂of 3 OEt), 3.39–3.16 (m, 1 H, 3-H), 2.37–2.15

(m, 2 H, 4-H), 1.29–1.12 (m, 9 H, 3 CH₃of 3 OEt) ppm. ¹³C NMR

(50 MHz, CDCl₃, Me₄Si): δ = 107.5 (C), 103.4 and 103.3 (CH),

67.3 (CH₂), 65.7 (CH₂), 63.7 (CH₂), 58.1 (CH₂), 44.3 (t, J =

20.5 Hz, CH), 25.0 (CH₂), 15.7 (CH₃), 15.4 (CH₃), 15.0 (CH₃) ppm.

MS (EI): m/z (%) = 391 (10), 333 (68), 305 (100), 289 (25), 195 (8),

103 (92), 91 (11), 75 (46). HRMS: m/z calcd. for C₁₃H₁₆F₉O₃([M –

OEt]⁺) 391.0956; found 391.0962.

Synthesis of Vinyl Ethers 1: The syntheses of 1a–1e have been de-

scribed in the literature.^[8]The same procedure was employed to

prepare 1-[(E)-4,5,5-triethoxybut-2-enyl]cyclohexanol (1f) from 1-

(3,3,4,4-tetraethoxybut-1-ynyl)cyclohexanol which was prepared

from TEB (23.0 g, 0.10 mmol) and cyclohexanone (10.8 g,

0.11 mmol). When EtMgBr was used to generate the acetylide,^[8]1-

(3,3,4,4-tetraethoxybut-1-ynyl)cyclohexanol was obtained as a yel-

lowish liquid in 79% yield (24.9 g) after isolation by flash

chromatography (hexane/ethyl acetate in a 80:20 ratio). IR (film):

2-(Diethoxymethyl)-2-ethoxy-3-(perfluorohexyl)tetrahydrofuran (2a-

II): The compound, 0.33 g (59% yield), was obtained as a clear

liquid. IR (film): ν_max= 2981 (s), 2934 (s), 2900 (S), 1453 (w), 1362

˜

(m), 1239 (s), 1202 (s), 1146 (s), 1073 (s), 967 (w), 892 (w), 797 (w),

737 (m), 711 (m), 655 (m) cm^–1. ¹H NMR (200 MHz, CDCl₃,

Me₄Si): δ = 4.63 and 4.62 [2s in a 1.0:1.0 ratio, 1 H, CH(OEt)₂],

4.15–3.96 (m, 2 H, 5-H), 3.91–3.51 (m, 6 H, 3 CH₂of 3 OEt), 3.39–

3.16 (m, 1 H, 3-H), 2.37–2.14 (m, 2 H, 4-H), 1.29–1.12 (m, 9 H, 3

CH₃of 3 OEt) ppm. ¹³C NMR (50 MHz, CDCl₃, Me₄Si): δ = 107.6

(C), 103.4 and 103.3 (CH), 67.3 (CH₂), 65.7 (CH₂), 63.8 (CH₂),

58.2 (CH₂), 44.4 (t, J = 20.3 Hz, CH), 25.1 (CH₂), 15.8 (CH₃), 15.4

(CH₃), 15.0 (CH₃) ppm. MS (EI): m/z (%) = 491 (10), 433 (66), 405

(92), 389 (24), 369 (6), 341 (11), 121 (7), 103 (100), 91 (17), 75 (52).

HRMS: m/z calcd. for C₁₅H₁₆F₁₃O₃, ([M – OEt]⁺) 491.0892; found

491.0893.

ν

= 3418 (m), 2975 (s), 2933 (s), 2237 (w), 1447 (m), 1387 (m),

˜

max

1335 (m), 1260 (m), 1235 (m), 1079 (s), 968 (m), 901 (w), 790 (w),

1

736 (w) cm^–1. H NMR (200 MHz, CDCl₃, Me₄Si): δ = 4.38 [s, 1

H, CH(OEt)₂], 3.88–3.65 (m, 8 H, 4 CH₂of 4 OEt), 3.32 (br. s, 1

H, OH), 1.99–1.94 (m, 2 H, 2 cyclohexyl H), 1.74–1.55 (m, 8 H, 8

cyclohexyl H), 1.23 (t, ³J_H,H= 7.0 Hz, 6 H, 2 CH₃groups of 2 OEt

3

groups), 1.21 (t, J_H,H= 7.0 Hz, 6 H, 2 CH₃groups of 2 OEt

groups) ppm. ¹³C NMR (50 MHz, CDCl₃, Me₄Si): δ = 103.8 (CH),

98.5 (C), 90.9 (C), 78.6 (C), 68.1 (C), 64.0 (2ϫCH₂), 59.5

(2ϫCH₂), 39.5 (2ϫCH₂), 24.9 (CH₂), 23.0 (2ϫCH₂), 15.1

(2ϫCH₃), 15.0 (2ϫCH₃) ppm. MS (EI): m/z (%) = 327 (1), 311

(12), 299 (15), 282 (81), 253 (49), 238 (73), 227 (62), 208 (71), 181

(72), 164 (78), 151 (85), 133 (72), 111 (86), 97 (100), 82 (92), 57

(86). HRMS: m/z calcd. for C₁₈H₃₂O₅[M⁺] 328.2250; found

328.2247. Vinyl ether 1f was prepared from 1-(3,3,4,4-tetraethoxy-

but-1-ynyl)cyclohexanol following a literature procedure, but the

sample was used in 1-iodo-perfluorobutylation without being prop-

2-(Diethoxymethyl)-2-ethoxy-3-(perfluorooctyl)tetrahydrofuran (2a-

III): The compound, 0.32 g (51% yield), was obtained as a clear

liquid. IR (film): ν_max= 2982 (s), 2901 (s), 2934 (s), 1453 (w), 1368

˜

(m), 1323 (m), 1211 (s), 1149 (s), 1073 (s), 897 (w), 807 (w), 778

1

(w), 724 (m), 712 (m), 657 (m) cm^–1. H NMR (200 MHz, CDCl₃,

Me₄Si): δ = 4.62 and 4.63 [2s in a 1.0:1.0 ratio, 1 H, CH(OEt)₂],

4.15–3.96 (m, 2 H, 5-H), 3.91–3.51 (m, 6 H, 3 CH₂of 3 OEt), 3.39–

3.16 (m, 1 H, 3-H), 2.37–2.13 (m, 2 H, 4-H), 1.29–1.11 (m, 9 H, 3

CH₃of 3 OEt) ppm. ¹³C NMR (50 MHz, CDCl₃, Me₄Si): δ = 107.6

(C), 103.5 and 103.4 (CH), 67.3 (CH₂), 65.7 (CH₂); 63.8 (CH₂),

58.2 (CH₂), 44.5 (t, J = 20.6 Hz, CH), 24.1 (CH₂), 15.8 (CH₃), 15.4

(CH₃), 15.0 (CH₃) ppm. MS (EI): m/z (%) = 591 (14), 533 (78), 505

(100), 389 (28), 441 (10), 135 (7), 103 (77), 91 (9), 75 (42). HRMS:

m/z calcd. for C₁₇H₁₆F₁₇O₃([M – OEt]⁺) 591.0839; found 591.0828.

erly purified. IR (film): ν

= 3451 (s), 2973 (s), 2929 (s), 1661

˜

max

(m), 1447 (m), 1386 (m), 1343 (m), 1297 (m), 1263 (m), 1071 (s),

988 (m), 885 (m), 853 (m), 731 (w), 688 (w) cm^–1. ¹H NMR

(200 MHz, CDCl₃, Me₄Si): δ = 5.02 [s, 1 H, CH(OEt)₂], 4.67 (t,

³J_H,H= 8.5 Hz, 1 H, HC=), 3.79–2.43 (m, 6 H, 3 CH₂from 3 OEt),

2.44 (br. s, 1 H, O-H), 2.33 (d, ³J_H,H= 8.5 Hz, 2 H, CH₂C=), 1.70–

1.40 (m, 10 H, 10 cyclohexyl H), 1.35–1.23 (m, 9 H, 3 CH₃of 3

OEt) ppm. ¹³C NMR (50 MHz, CDCl₃): δ = 149.3 (C), 93.4 (CH),

92.0 (CH), 71.9 (C), 62.6 (CH₂), 61.6 (2ϫCH₂), 37.2 (2ϫCH₂),

34.6 (CH₂), 25.2 (CH₂), 21.6 (CH₂), 21.5 (CH₂), 14.2 (2ϫCH₃),

13.6 (CH₃) ppm. MS (EI): m/z (%) = 240 (30), 195 (93), 167 (41),

149 (72), 137 (68), 121 (62), 113 (100), 95 (57), 81 (73). HRMS:

m/z calcd. for C₁₄H₂₅O₃, [M – OEt]⁺241.1804; found 241.1804.

Acetate Protection of 1a; Formation of (E)-4,5,5-Triethoxypent-3-

enyl Acetate (3a): To a solution of 2a (2.45 g, 11.24 mmol), triethyl-

amine (2 mL, 14.46 mmol), and 4-DMAP (0.05 g, 0.41 mmol) at

0 °C under N₂atmosphere was added acetic anhydride (2 mL,

21.18 mmol). After 40 min water was added and the mixture was

extracted with DCM. The combined organic extracts were dried

(MgSO₄) and filtered. Evaporation of the solvent gave 2.95 g of a

Eur. J. Org. Chem. 2009, 5816–5831

www.eurjoc.org

5821

S. Valdersnes, L. K. Sydnes

FULL PAPER

yellowish liquid. The crude product was purified by flash

chromatography (hexane/ethyl acetate in a 85:15 ratio) to give

(2.51 g, 86%) of the title compound as a clear liquid. IR (film):

solution, 2.0 mmol) was added after 4 h. After stirring for another

5 h the reaction was quenched by adding MeOH and the mixture

was extracted with DCM. The combined organic extracts were

ν

= 2975 (s), 2898 (s), 2931 (s), 1740 (s), 1664 (m), 1446 (m), dried (MgSO₄) and filtered. Evaporation of the solvent gave 2.32 g

˜

max

1381 (m), 1239 (s), 1178 (s), 1118 (s), 1061 (s), 926 (m), 898 (m), of a slightly yellow liquid. The crude product was purified by flash

842 (w), 812 (m), 691 (w), 673 (w), 630 (m), 604 (m) cm^–1. ¹H NMR chromatography (hexane/ethyl acetate gradient changing gradually

3

(200 MHz, CDCl₃, Me₄Si): δ = 5.00 (s, 1 H, 5-H), 4.54 (t, J_H,H

=

from a 70:30 to a 50:50 ratio) to give 0.45 g (20%) of 6a-I and

3

7.8 Hz, 1-H, 3-H), 4.06 (t, J_H,H= 6.9 Hz, 1-H), 3.76–3.46 (m, 6 1.14 g (51%) of 7a-I.

H, 3 CH₂of 3 OEt), 2.42 (m, 2 H, 2-H), 2.05 [s, 3 H, CH₃C(O)],

6a-I: IR (film): ν_max= 3420 (br. s), 2980 (s), 2935 (s), 2898 (s), 1449

˜

1.35–1.20 (m, 9 H, 3 CH₃of 3 OEt) ppm. ¹³C NMR (50 MHz,

CDCl₃, Me₄Si): δ = 170.9 (C), 153.4 (C), 99.1 (CH), 96.3 (CH),

64.6 (CH₂), 62.5 (CH₂), 62.3 (2ϫCH₂), 24.8 (CH₂), 20.8 (CH₃),

15.0 (2ϫCH₃), 14.2 (CH₃) ppm. MS (EI): m/z (%) = 214 (7), 200

(67), 171 (8), 155 (87), 143 (6), 127 (15), 103 (100), 85 (43), 75 (85),

69 (27), 57 (15), 43 (91). HRMS: m/z calcd. for C₁₁H₁₉O₄([M –

OEt]⁺) 215.1283; found 215.1282.

(m), 1380 (m), 1349 (m), 1234 (s), 1131 (s), 1061 (s), 960 (m), 888

(m), 825 (m), 740 (m), 687 (m) cm^–1. ¹H NMR (200 MHz, CDCl₃,

3

Me₄Si): δ = 4.66 and 4.65 (2d in a 1.0:1.0 ratio, J_H,H= 6.7 Hz, 1

H, 5-H), 3.92–3.49 (m, 8 H, 2 CH₂of 2 OEt, 2 OH and 1-H), 3.26

(br. s, 1 H, 4-H), 2.87 (m, 1 H, 3-H), 2.08–1.98 (m, 2 H, 2-H), 1.25

(t, ³J_H,H= 7.0 Hz, 3 H, CH₃of OEt), 1.21 (t, ³J_H,H= 7.0 Hz, 3 H,

CH₃of OEt) ppm. ¹³C NMR (50 MHz, CDCl₃, Me₄Si): δ = 103.6

and 103.4 (CH), 71.8 and 71.7 (CH), 64.3 (CH₂), 64.1 (CH₂), 59.4

(CH₂), 39.1 (t, J = 19.0 Hz, CH), 28.1 (CH₂), 15.2 (CH₃), 14.9

(CH₃) ppm. MS (EI): m/z (%) = 365 (12), 347 (58), 319 (32), 241

(6), 103 (100), 93 (7), 75 (67), 60 (10), 47 (100). HRMS: m/z calcd.

for C₁₁H₁₃O₃F₉([M – OEt]⁺) 364.0799; found 364.0793.

General Procedure for Perfluoroalkylation of Ester 3a: To a solution

of 3a (2.6 g, 10 mmol), CH₃CN (10.7 mL), H₂O (8.9 mL) and R_FI

(11 mmol) at 0 °C under N₂was added NaHCO₃(0.93 g, 11 mmol)

and sodium dithionite (Na₂S₂O₄) (1.90 g, 11 mmol). The solution

was stirred overnight followed by addition of H₂O and extraction

with DCM. The combined organic extracts were dried with MgSO₄

and filtered to remove the drying agent. Evaporation of the solvent

gave a clear residue, which was purified by flash chromatography

(hexane/ethyl acetate in a 85:15 ratio) to give the corresponding

5,5-diethoxy-4-oxo-3-(perfluoroalkyl)pentyl acetate (4a).

7a-I: IR (film): ν

= 3471 (m, br), 2979 (s), 2933 (s), 2903 (s),

˜

max

1455 (m), 1350 (s), 1220 (s), 1134 (s), 1073 (s), 982 (s), 937 (m), 897

(m), 797 (m), 740 (m), 719 (m), 688 (m) cm^–1. ¹H NMR (200 MHz,

CDCl₃, Me₄Si): δ = 4.68 and 4.67 [2s in a 1.0:1.0 ratio, 1 H,

CH(OEt)₂], 4.26–4.15 (m, 1 H, 5-H), 4.05–3.82 (m, 3 H, CH₂of

OEt and 5-H), 3.76–3.58 (m, 2 H, CH₂of OEt), 3.43 (s, 1 H, OH),

3.26–3.03 (m, 1 H, 3-H), 2.46–2.18 (m, 2 H, 4-H), 1.32–1.22 (m, 6

5,5-Diethoxy-4-oxo-3-(perfluorobutyl)pentyl Acetate (4a-I): The

compound, 2.75 g (61% yield), was obtained as a clear liquid. IR

(film): ν_max= 2980 (s), 2933 (s), 1747 (s), 1448 (m), 1369 (m), 1233 H, 2 CH₃of 2 OEt) ppm. ¹³C NMR (50 MHz, CDCl₃, Me₄Si): δ

˜

(s), 1134 (s), 1061 (s), 914 (m), 885 (m), 811 (w), 743 (w), 695 (w) = 104.4 (C), 103.1 and 103.0 (CH), 66.3 (CH₂), 65.7 (CH₂), 65.3

1

cm^–1. H NMR (200 MHz, CDCl₃, Me₄Si): δ = 4.61 (s, 1 H, 5-H),

(CH₂), 42.8 (t, J = 20.4 Hz, CH), 24.6 (CH₂), 15.1 (CH₃), 14.9

4.26–3.92 (m, 3 H, 1-H and 3-H), 3.85–3.52 (m, 4 H, 2 CH₂of 2 (CH₃) ppm. MS (EI): m/z (%) = 391 (2), 361 (2), 247 (1), 333 (2),

OEt), 2.34–2.11 (m, 2 H, 2-H), 2.04 [s, 3 H, CH₃C(O)], 1.25 (t, 317 (22), 305 (28), 289 (10), 241 (16), 195 (7), 103 (100), 91 (10),

³J_H,H= 7.0 Hz, 6 H, 2 CH₃of 2 OEt) ppm. ¹³C NMR (50 MHz,

CDCl₃, Me₄Si): δ = 198.9 (C), 170.6 (C), 102.2 (CH), 64.4 (CH₂),

63.9 (CH₂), 61.1 (CH₂), 40.0 (t, J = 20.5 Hz, CH), 25.5 (CH₂), 20.7

(CH₃), 14.9 (CH₃), 14.8 (CH₃) ppm. MS (EI): m/z (%) = 449 (1),

405 (1), 362 (1), 235 (1), 318 (3), 289 (3), 241 (3), 195 (2), 103 (100),

75 (55), 61 (5), 47 (77). HRMS: m/z calcd. for C₁₅H₁₉O₅F₉[M⁺]

450.1089; found 450.1068.

75 (74), 47 (74). HRMS: m/z calcd. for C₁₃H₁₆O₃F₉([M – OH]⁺)

391.0956; found 391.0963.

Reduction of 4a-II; Formation of 5,5-Diethoxy-4-hydroxy-3-(per-

fluorohexyl)pentyl Acetate (5a-II): To

a solution of NaBH₄

(0.020 g, 0.53 mmol) in EtOH (5 mL) was added 4a-II (0.28 g,

0.51 mmol) in 75% aqueous EtOH (5 mL) during 5 min at 0 °C.

After 40 min H₂O was added and the mixture was extracted with

DCM. The combined organic extracts were dried (MgSO₄) and

filtered. Evaporation of the solvent gave 0.19 g (68%) of 5a-II as a

5,5-Diethoxy-4-oxo-3-(perfluorohexyl)pentyl Acetate (4a-II): The

compound, 4.16 g (76% yield), was obtained as a clear liquid. IR

(film): ν

= 2983 (s), 2939 (s), 2899 (s), 1748 (s), 1447 (m), 1366 clear liquid. IR (film): ν_max= 3491 (m), 2980 (s), 2932 (s), 1742 (s),

˜

max

(m), 1316 (m), 1231 (s), 1146 (s), 1063 (s), 939 (w), 910 (w), 859

1450 (m), 1367 (s), 1233 (s), 1142 (s), 1060 (s), 966 (w), 907 (w),

1

(w), 806 (w), 736 (m), 705 (m), 635 (m), 599 (m) cm^–1. H NMR

882 (w), 837 (w), 806 (m), 773 (w), 737 (m), 707 (m), 661 (m) cm^–1.

(200 MHz, CDCl₃, Me₄Si): δ = 4.62 (s, 1 H, 5-H), 4.27–3.93 (m, 3

¹H NMR (200 MHz, CDCl₃, Me₄Si): δ = 4.67 and 4.66 (2d in a

3

H, 1-H and 3-H), 3.86–3.53 (m, 4 H, 2 CH₂of 2 OEt), 2.35–2.13 1.0:1.0 ratio, J_H,H= 6.9 Hz, 1 H, 5-H), 4.31–4.05 (m, 2 H, 1-H),

3

(m, 2 H, 2-H), 2.04 [s, 3 H, CH₃C(O)], 1.25 (t, J_H,H= 7.0 Hz, 6 3.92–3.48 (m, 5 H, 2 CH₂of 2 OEt and 4-H), 2.89–2.76 (m, 1 H,

H, 2 CH₃of 2 OEt) ppm. ¹³C NMR (50 MHz, CDCl₃, Me₄Si): δ

3-H), 2.53–2.51 (m, 1 H, OH), 2.17–2.03 (m, 2 H, 2-H), 2.05 [s, 3

3

= 198.8 (C), 170.5 (C), 102.2 (CH), 64.3 (CH₂), 63.9 (CH₂), 61.1 H, CH₃C(O)], 1.26 (t, J_H,H= 7.0 Hz, 3 H, CH₃of OEt), 1.21 (t,

(CH₂), 43.1 (t, J = 20.3 Hz, CH), 25.5 (CH₂), 20.5 (CH₃), 14.8 ³J_H,H= 7.0 Hz, 3 H, CH₃of OEt) ppm. ¹³C NMR (50 MHz,

(CH₃), 14.6 (CH₃) ppm. MS (EI): m/z (%) = 505 (10), 517 (22), 491 CDCl₃, Me₄Si): δ = 170.8 (C), 103.3 and 103.1 (CH), 71.9 (CH),

(1), 462 (2), 389 (7), 103 (94), 75 (50), 61 (7). HRMS: m/z calcd.

64.3 (CH₂), 64.2 (CH₂), 61.6 (CH₂), 38.2 (t, J = 19.3 Hz, CH), 24.7

(CH₂), 20.7 (CH₃), 15.4 (CH₃), 15.1 (CH₃) ppm. MS (EI): m/z (%)

= 507 (1), 461 (1), 447 (11), 419 (10), 103 (100), 87 (7), 75 (55), 59

(16), 47 (77). HRMS: m/z calcd. for C₁₅H₁₆O₄F₁₃([M – OEt]⁺)

507.0841; found 507.0823.

for C₁₅H₁₄O₄F₁₃(M – OEt)⁺505.0685; found 505.0666.

Reduction of 4a-I; Formation of 5,5-Diethoxy-3-(perfluorobutyl)-

pentane-1,4-diol (6a-I) and 2-(Diethoxymethyl)-3-(perfluorobutyl)-

tetrahydrofuran-2-ol (7a-I): The procedure is based on a protocol

published by Corey and co-workers.^[10]To a stirred solution of (S)-

oxazaborolidine (0.3 mmol) in BH₃·Me₂S in dry THF (3.0 mL of

a 2.0  solution, 6.0 mmol) and dry THF (5 mL) kept at room

temperature was added 4a-I (2.47 g, 5.49 mmol) in dry THF (5 mL)

during 5 min. Additional BH₃·Me₂S in dry THF (1.0 mL of a 2.0 

Deprotection of 5a-II; Formation of 5,5-Diethoxy-3-(perfluorohexyl)-

pentane-1,4-diol (6a-II): To a solution of 5a-II (0.36 g, 0.65 mmol)

in moist MeOH (12.5 mL) was added NaOMe (0.1 g, 1.85 mmol)

at room temperature. After 30 min the reaction was quenched by

the addition of aqueous NH₄Cl and the mixture was extracted with

5822

www.eurjoc.org

Eur. J. Org. Chem. 2009, 5816–5831

4-Perfluoroalkylated Tetrahydropyran Derivatives

DCM. The combined organic extracts were dried (MgSO₄) and

filtered. Evaporation of the solvent gave 0.30 g (89%) of 6a-II as a

ring the reaction was quenched by adding aq. NaHCO₃followed

by extraction with DCM. The combined organic extracts were

dried with MgSO₄, filtered, and the solvent evaporated to give es-

clear liquid. IR (film): ν

= 3418 (s), 2979 (s), 2937 (s), 2901 (s),

˜

max

1449 (m), 1355 (m), 1203 (s), 1141 (s), 1061 (s), 907 (m), 882 (m), sentially pure 10a (0.10 g, 83%). IR (film): ν

= 3251 (m), 2966

˜

max

804 (m), 738 (m), 705 (m), 660 (m) cm^–1. ¹H NMR (200 MHz, (s), 2739 (m), 1738 (m), 1675 (m), 1446 (s), 1385 (m), 1341 (m),

3

CDCl₃, Me₄Si): δ = 4.67 and 4.66 (2d in a 1.0:1.0 ratio, J_H,H

=

1268 (m), 1199 (s), 1065 (s), 980 (s), 927 (m), 875 (m) 806 (m), 732

3

1

6.6 Hz, 1 H, 5-H), 3.92 (d, J_H,H= 6.0 Hz, 2 H, 1-H), 3.87–3.53

(w), 697 (w), 645 (m) cm^–1. H NMR (200 MHz, CDCl₃, Me₄Si):

(m, 7 H, 2 CH₂of 2 OEt, 2 OH and 4-H), 2.87 (m, 1 H, 3-H), δ = 4.60 [s, 1 H, CH(OEt)₂], 3.89–3.38 (m, 8 H, 3 CH₂of 3 OEt

2.13–1.92 (m, 2 H, 2-H), 1.26 (t, ³J_H,H= 7.0 Hz, 3 H, CH₃of OEt),

and 5-H), 1.94–1.66 (m, 4 H, 3-H and 4-H), 1.29–1.15 (m, 9 H, 3

3

1.21 (t, J_H,H= 7.0 Hz, 3 H, CH₃of OEt) ppm. ¹³C NMR CH₃of 3 OEt) ppm. ¹³C NMR (50 MHz, CDCl₃, Me₄Si): δ = 103.7

(50 MHz, CDCl₃, Me₄Si): δ = 103.5 and 103.4 (CH), 72.9 (CH), (C), 97.4 (CH), 62.5 (CH₂), 58.9 (CH₂), 55.2 (CH₂), 55.1 (CH₂),

64.1 (CH₂), 64.0 (CH₂), 60.1 (CH₂), 39.6 (t, J = 19.0 Hz, CH), 28.2

(CH₂), 15.2 (CH₃), 14.8 (CH₃) ppm. MS (EI): m/z (%) = 509 (1),

464 (10), 447 (65), 420 (78), 403 (58), 389 (70), 341 (78), 294 (52),

168 (18), 145 (19), 131 (32), 119 (53), 104 (94), 87 (90), 69 (91), 60

(100). HRMS: m/z calcd. for C₁₃H₁₄O₃F₁₃([M – OEt]⁺) 465.0735;

found 465.0739.

26.3 (CH₂), 22.8 (CH₂), 15.4 (CH₃), 15.3 (CH₃), 14.9 (CH₃) ppm.

MS (EI): m/z (%) = 217 (1), 189 (96), 173 (94), 144 (83), 127 (75),

117 (83), 103 (73), 99 (100), 89 (87), 72 (98). HRMS: m/z calcd. for

C₉H₁₇O₃([M – OEt]⁺) 173.1178; found 173.1174.

Formic Acid Catalyzed Ring Closure of 1a; Formation of 2,3-Di-

ethoxy-5,6-dihydro-2H-pyran (11a): To a stirred solution of 1a

(0.11 g, 0.50 mmol) in pentane (5 mL) was added 80% aq.

HCOOH (10 drops) at room temp. After stirring the reaction mix-

ture for 30 min at this temperature H₂O was added and the mixture

extracted with DCM. The combined extracts were dried with

MgSO₄, filtered and the solvent was evaporated to give a greenish

crude product, from which 11a (0.049 g, 57%) was isolated by flash

chromatography (hexane/ethyl acetate in a 92.5:7.5 ratio). IR (film):

Cyclization of 6a-II; Formation of 2-Ethoxy-4-(perfluorohexyl)tetra-

hydro-3H-pyran-3-ol (8a-II) and 5,5-Diethoxy-4-hydroxy-3-(perfluo-

rohexyl)pentyl Formate (9): To a solution of diol 6a-II (0.11 g,

0.22 mmol) in pentane (5 mL) was added 80% aqueous HCOOH

(10 drops) at room temperature. After stirring for 23 h H₂O was

added and the mixture extracted with DCM. The combined or-

ganic extracts were dried with MgSO₄and filtered. Evaporation of

the solvent gave 0.11 g of a yellow liquid, from which tetra-

hydrofuranol 8a-II (0.040 g, 40%) was isolated as a clear liquid and

ester 9 (0.060 g, 52%) as a yellowish liquid by flash chromatog-

raphy (hexane/ethyl acetate in a 80:20 ratio).

ν

= 3064 (w), 2974 (s), 2898 (s), 2743 (w), 1721 (w), 1673 (s),

˜

max

1443 (m), 1384 (s), 1337 (m), 1310 (m), 1228 (s), 1194 (s), 1066 (s),

945 (m), 891 (w), 836 (m), 790 (m), 701 (w), 657 (w) cm^–1. ¹H

3

NMR (200 MHz, CDCl₃, Me₄Si): δ = 4.80 (dd, J_H,H= 2.2, J_H,H

= 5.8 Hz, 1 H, 4-H), 4.76 (s, 1 H, 2-H), 3.99–3.50 (m, 6 H, 2 CH₂

of 2 OEt and 6-H), 2.47–2.29 (m, 1 H, 5-H), 2.00–1.87 (m, 1 H, 5-

8a-II: IR (film): ν

= 3475 (m), 2978 (m), 2933 (m), 1450 (m),

˜

max

1357 (m), 1237 (s), 1202 (s), 1145 (s), 1087 (m), 1006 (m), 942 (w),

3

H), 1.30 [t, J_H,H= 7.1 Hz, 3 H, CH₃of OEt], 1.26 (t, J_H,H

=

896 (w), 843 (w), 810 (w), 734 (m), 702 (m), 655 (m) cm^–1. ¹H NMR

7.1 Hz, 3 H, CH₃of OEt) ppm. ¹³C NMR (50 MHz, CDCl₃,

Me₄Si): δ = 151.3 (C), 94.2 (CH), 93.7 (CH), 63.1 (CH₂), 61.9

(CH₂), 57.1 (CH₂), 23.2 (CH₂), 15.0 (CH₃), 14.1 (CH₃) ppm. MS

(EI): m/z (%) = 172 (32), 143 (18), 127 (100), 115 (15), 99 (54), 81

(20), 69 (83), 53 (27). HRMS: m/z calcd. for C₇H₁₁O₂[M⁺]

127.0759; found 127.0763.

3

(200 MHz, CDCl₃, Me₄Si): δ = 4.21 (d, J_H,H= 7.3 Hz, 1 H, 5-H),

3

2

4.03 (dd, J_H,H= 4.6, J_H,H= 12.0 Hz, 1 H, 6-H), 4.00–3.92 (m, 1

H, 1 H of CH₂of OEt), 3.87–3.71 (m, 1 H, 3-H), 3.67–3.60 (m, 1

3

2

H, 1 H of CH₂of OEt), 3.49 (dt, J_H,H= 3.0, J_H,H= 12.0 Hz, 1

H, 6-H), 2.62–2.49 (m, 1 H, 4-H), 2.18 (br. s, 1 H, OH), 1.90–1.72

3

(m, 2 H, 5-H), 1.27 (t, J_H,H= 7.0 Hz, 3 H, CH₃of OEt) ppm. ¹³

C

NMR (50 MHz, CDCl₃, Me₄Si): δ = 104.1 (CH), 67.9 (CH), 66.3

(CH₂), 63.3 (CH₂), 43.9 (t, J = 20.5 Hz, CH), 24.2 (CH₂), 15.2

(CH₃) ppm. MS (EI): m/z (%) = 463 (3), 435 (4), 419 (60), 389 (8),

341 (35), 295 (22), 245 (3), 169 (8), 119 (38), 93 (100), 75 (78), 71

(58), 59 (49). HRMS: m/z calcd. for C₁₃H₁₃O₃F₁₃[M⁺] 464.0657;

found 464.0649.

1-Iodoperfluoroalkylation of 11a; General Procedure: To a stirred

solution of 11a (0.172 g, 1.0 mmol), CH₃CN (1.1 mL), H₂O

(0.9 mL) and perfluoroalkyl iodide (1.10 mmol) kept at 0 °C under

N₂atmosphere were added NaHCO₃(0.090 g, 1.07 mmol) and so-

dium dithionite (Na₂S₂O₄) (0.19 g, 1.09 mmol). The solution in-

stantly turned milky white. After stirring for 15–19 h H₂O was

added and the mixture extracted with DCM. The combined or-

ganic extracts were dried (MgSO₄) and then filtered before the sol-

vent was evaporated. An essentially pure sample of the correspond-

ing 2-ethoxy-4-(perfluoroalkyl)tetrahydropyran-3-one (12a) was

left behind.

9: IR (film): ν_max= 3463 (m), 2974 (s), 2931 (s), 1728 (s), 1451 (m),

˜

1356 (m), 1241 (s), 1141 (s), 890 (m), 806 (m), 736 (m), 704 (m)

cm^–1. ¹H NMR (200 MHz, CDCl₃, Me₄Si): δ = 8.06 [s, 1 H,

3

HC(O)], 4.66–4.65 (2d in a 1.0:1.0 ratio, J_H,H= 6.8 Hz, 1 H, 5-

H), 4.38–4.32 (m, 1 H, 1-H), 4.27–4.21 (m, 1 H, 1-H), 3.89–3.50

(m, 6 H, 2 CH₂of 2 OEt, 4-H and OH), 2.86–2.80 (m, 1 H, 3-H),

2.24–2.06 (m, 2 H, 2-H), 1.26 (t, ³J_H,H= 7.0 Hz, 3 H, CH₃of OEt),

2-Ethoxy-4-(perfluorobutyl)tetrahydropyran-3-one (12a-I): The

compound was obtained as a slightly yellow liquid (0.32 g, 89%).

3

1.21 (t, J_H,H= 7.0 Hz, 3 H, CH₃of OEt) ppm. ¹³C NMR

IR (film): ν

= 2982 (s), 2937 (s), 2900 (s), 1755 (s), 1674 (w),

˜

max

(50 MHz, CDCl₃, Me₄Si): δ = 160.6 (CH), 103.2 and 103.1 (CH),

71.8 (CH), 64.3 (CH₂), 64.2 (CH₂), 61.3 (CH₂), 38.6 (t, J = 20.0 Hz,

CH), 24.7 (CH₂), 15.5 (CH₃), 15.1 (CH₃) ppm. MS (EI): m/z (%)

= 503 (2), 493 (1), 463 (1), 447 (90), 419 (95), 403 (28), 389 (31),

341 (48), 295 (22), 245 (3), 169 (4), 119 (28), 104 (73), 87 (79), 75

(100), 60 (80). HRMS: m/z calcd. for C₁₁H₈O₂F₁₃([M – CHO – 2

OEt]⁺) 419.0317; found 419.0339.

1451 (m), 1379 (m), 1349 (s), 1306 (s), 1210 (s), 1132 (s), 1058 (s),

946 (s), 888 (s), 812 (m), 736 (m), 696 (m), 654 (m), 561 (s) cm^–1.

¹H NMR (200 MHz, CDCl₃, Me₄Si): δ = 4.78 and 4.71 (2s in a

44:56 ratio, 1 H, 2-H), 4.30–4.14 (m, 1 H, 1 H of CH₂of OEt),

4.00–3.74 (m, 3 H, 1 H of CH₂of OEt and 6-H), 3.70–3.50 (m, 1

H, 4-H), 2.46–2.23 (m, 2 H, 5-H), 1.28 and 1.27 (2 partly overlap-

ping t, ³J_H,H= 7.1 Hz, 3 H, CH₃of OEt) ppm. ¹³C NMR (50 MHz,

Sulfuric Acid-Catalyzed Ring Closure of 1a; Formation of (Di- CDCl₃, Me₄Si): δ = 194.9 and 194.1 (C), 99.8 and 98.8 (CH), 64.5

ethoxymethyl)-2-ethoxy-2-tetrahydrofuran (10a): To a stirred solu-

tion of 1a (0.12 g, 0.55 mmol) in dry EtOH (5 mL) kept at room

temperature was added concd. H₂SO₄(3 drops). After 2 h of stir-

and 64.0 (CH₂), 58.4 and 57.9 (CH₂), 46.6 (CH, both isomers), 28.9

and 23.8 (CH₂), 14.7 and 14.6 (CH₃) ppm. MS (EI): m/z (%) = 362

(2), 334 (18), 317 (10), 289 (10), 241 (8), 121 (6), 91 (67), 75 (35), 47

Eur. J. Org. Chem. 2009, 5816–5831

www.eurjoc.org

5823

S. Valdersnes, L. K. Sydnes

FULL PAPER

(100). HRMS: m/z calcd. for C₁₁H₁₁O₃F₉[M⁺] 362.056449; found

362.054550.

103 (55), 93 (52), 75 (57). HRMS: m/z calcd. for C₉H₅O₂F₈, ([M –

OEt]⁺) 297.0162; found 297.0143.

2-Ethoxy-4-(perfluorohexyl)tetrahydropyran-3-one (12a-II): The

compound was obtained as a clear liquid (0.32 g, 70%). IR (film):

(Z/E)-2-Ethoxy-4-(perfluorohexylidene)tetrahydropyran-3-one (13a-

II): Elution of 12a-II (0.32 g) gave 0.27 g (62%) of the title com-

ν

= 2982 (s), 2937 (s), 2899 (s), 1752 (s), 1674 (w), 1623 (w),

pound. IR (film): ν_max= 2983 (s), 2936 (s), 2901 (s), 1739 (s), 1673

˜

max

1449 (m), 1362 (s), 1312 (s), 1204 (s), 1146 (s), 1119 (s), 1059 (s), (m), 1444 (m), 1358 (s), 1313 (s), 1172 (s), 1055 (s), 1019 (s), 949

885 (m), 852 (m), 805 (m), 735 (m), 703 (m), 641 (m) cm^–1. ¹H

NMR (200 MHz, CDCl₃, Me₄Si): δ = 4.78 and 4.71 (2s in a 52:48

ratio, 1 H, 2-H), 4.26–4.17 (m, 1 H, 1 H of CH₂of OEt), 3.90–3.77

(s), 895 (m), 874 (m), 848 (m), 813 (m), 728 (s), 663 (m), 632 (m),

537 (s), 449 (s) cm^–1. ¹H NMR (200 MHz, CDCl₃, Me₄Si): δ = 4.82

and 4.81 (2s in a 1:4 ratio, 1 H, 2-H), 4.23–4.10 (m, 1 H, 6-H),

(m, 3 H, 1 H of CH₂of OEt and 6-H), 3.68–3.47 (m, 1 H, 4-H), 3.88–3.76 (m, 2 H, 1 H of CH₂of OEt and 6-H), 3.66–3.55 (m, 1

2.46–2.26 (m, 2 H, 5-H), 1.28 and 1.27 (2 partly overlapping t,

³J_H,H= 7.0 Hz, 3 H, CH₃of OEt) ppm. ¹³C NMR (50 MHz,

CDCl₃, Me₄Si): δ = 195.0 and 194.2 (C), 99.7 and 98.8 (CH), 64.5

and 64.0 (CH₂), 58.4 and 57.9 (CH₂), 46.7 (CH, both isomers), 28.9

and 23.9 (CH₂), 14.9 and 14.8 (CH₃) ppm. MS (EI): m/z (%) = 462

H, 1 H of CH₂of OEt), 2.92–2.81 (m, 2 H, 5-H), 1.27 and 1.26 (2

3

partly overlapping t, J_H,H= 7.1 Hz, 3 H, CH₃of OEt) ppm. ¹³C

NMR (50 MHz, CDCl₃, Me₄Si): δ = 188.9 (C), 122.4 (C), 100.0

(minor) and 99.3 (major) (CH), 64.3 (major) and 64.1 (minor)

(CH₂), 58.1 (minor) and 57.9 (major) (CH₂), 30.3 (minor) and 27.4

(3) [M⁺], 417 (4), 397 (50), 369 (91), 349 (44), 321 (38), 321 (24), (major) (CH₂), 14.7 (minor), 14.6 (major) (CH₃) ppm. MS (EI):

295 (23), 171 (100), 153 (73), 121 (71), 101 (89), 69 (88). HRMS: m/z (%) = 414 (6), 297 (90), 369 (100), 349 (8), 171 (25), 153 (10),

m/z calcd. for C₁₃H₁₁O₃F₁₃[M⁺] 462.0501; found 462.0512.

121 (30), 101 (15), 69 (7). HRMS: m/z calcd. for C₁₃H₁₀O₃F₁₂[M⁺]

442.0438; found 442.0442.

2-Ethoxy-4-(perfluorooctyl)tetrahydropyran-3-one (12a-III): The

compound was obtained as a slightly yellow liquid (0.38 g, 68%).

(Z/E)-2-Ethoxy-4-(perfluorooctylidene)tetrahydropyran-3-one (13a-

III): Elution of 12a-III (0.44 g) gave 0.18 g (34%) of the title com-

IR (film): ν

= 2982 (s), 2938 (s), 2898 (s), 1756 (s), 1675 (m),

˜

max

1450 (m), 1368 (s), 1207 (s), 887 (m), 808 (m), 781 (m), 726 (s), 711 pound. IR (film): ν

= 2983 (m), 2935 (m), 2902 (m), 1740 (m),

˜

max

(s), 656 (s) cm^–1. ¹H NMR (200 MHz, CDCl₃, Me₄Si): δ = 4.78 1673 (w), 1445 (w), 1364 (m), 1317 (m), 1207 (s), 1148 (s), 1052 (s),

and 4.71 (2s in a 38:62 ratio, 1 H, 2-H), 4.30–4.17 (m, 1 H, 1 H of

CH₂of OEt), 3.94–3.76 (m, 3 H, 1 H of CH₂of OEt and 6-H),

3.66–3.56 (m, 1 H, 4-H), 2.42–2.30 (m, 2 H, 5-H), 1.28 and 1.27 (2

983 (m), 897 (m), 865 (w), 805 (w), 780 (w), 713 (m), 661 (m) cm^–1.

¹H NMR (200 MHz, CDCl₃, Me₄Si): δ = 4.82 and 4.81 (2s in a 1:4

ratio, 1 H, 2-H), 4.23–4.10 (m, 1 H, 6-H), 3.89–3.77 (m, 2 H, 1 H

of CH₂of OEt and 1 H, 6-H), 3.70–3.55 (m, 1 H, 1 H of CH₂of

OEt), 3.07–2.79 (m, 2 H, 5-H), 1.26 (major isomer) and 1.25 (minor

3

partly overlapping t, J_H,H= 7.0 Hz, 3 H, CH₃of OEt) ppm. ¹³C

NMR (50 MHz, CDCl₃, Me₄Si): δ = 195.0 (minor) and 194.1

(major) (C), 99.9 (major) and 98.8 (minor) (CH), 64.5 (minor) and

64.0 (major) (CH₂), 58.4 (minor) and 57.9 (major) (CH₂), 46.5

(CH, both isomers), 28.9 (major) and 23.9 (minor) (CH₂), 14.8

(major) and 14.7 (minor) (CH₃) ppm. MS (EI): m/z (%) = 534 (11),

517 (14), 489 (7), 469 (5), 441 (4), 121 (11), 103 (7), 91 (72), 75

(26), 46 (100).

3

isomer) (t, J_H,H= 7.1 Hz, 3 H, CH₃of OEt) ppm. ¹³C NMR

(50 MHz, CDCl₃, Me₄Si): δ = 188.9 (C), 122.4 (C), 100.0 (minor)

and 99.4 (major) (CH), 64.2 (major) and 64.1 (minor) (CH₂), 58.1

(minor) and 58.0 (minor) (CH₂), 30.3 (minor) and 27.5 (major)

(CH₂), 14.7 (major) and 14.6 (major) (CH₃) ppm. MS (EI): m/z

(%) = 514 (6), 497 (65), 469 (100), 449 (15), 171 (47), 153 (18), 133

(12), 121 (73), 101 (34), 69 (39).

Decomposition of 12a on a Silica-Gel Column; General Procedure:

4-(Perfluoroalkyl)tetrahydropyran-3-ones 12a-I, 12a-II, and 12a-III

were eluted on a flash-chromatography column using Merck 60

Kieselgel (230–400 mesh) as stationary phase and a gradient going

from hexane/ethyl acetate mixture (95:5 to 90:10) as the mobile

phase. The fractions collected contained either no product(s) or

one product (mixture) which gave a single spot when analyzed by

TLC. The product-containing fractions were combined, the sol-

vents were evaporated, and the residue was thoroughly analyzed

chromatographically and spectroscopically and by mass spectrome-

try. The residues turned out to be essentially pure Z/E mixtures of

the corresponding 2-ethoxy-4-(perfluoroalkylidene)tetrahydro-

pyan-3-ones 13a.

Reduction of 2-Ethoxy-4-(perfluorobutyl)tetrahydropyran-3-one

[(2R*,4R*/4S*)-12a-I]; Formation of (2R*,3R*/3S*,4R*/4S*)-8a-I:

To a stirred solution of NaBH₄(0.020 g, 0.53 mmol) in 75% EtOH/

H₂O (5 mL) kept at room temperature was added dropwise a solu-

tion of 12a-I (0.18 g, 0.50 mmol) in 75% EtOH/H₂O (5 mL) during

5 min. After stirring for 4 h H₂O was added and the hydrolysate

was extracted with DCM. The combined organic extracts were

dried (MgSO₄) and filtered. Evaporation of the solvent gave 0.18 g

(94%) of (2R*,3R*/3S*,4R*/4S*)-8a-I as a yellowish liquid. Its iso-

meric composition was determined by ¹H NMR investigations of

the product mixture before isolation of the major isomers started,

using the integrals of the anomeric protons to determine the iso-

meric composition. The anomeric protons showed the following

chemical shifts and relative intensities: 4.70 ppm, 22% (3R*,4R*);

4.43 ppm, 11% (3R*,4S*); 4.83 ppm, 34% (3S*,4R*); 4.35 ppm,

33% (3S*,4S*). Separation and purification were carried out by

flash chromatography (hexane/ethyl acetate in a 80:20 ratio), and

the two most abundant isomers were isolated pure.

(Z/E)-2-Ethoxy-4-(perfluorobutylidene)tetrahydropyran-3-one (13a-

I): Elution of 12a-I (0.32 g) gave 0.21 g (62%) of the title com-

pound. IR (film): ν_max= 2983 (s), 2935 (s), 2900 (s), 1739 (s), 1673

˜

(m), 1445 (m), 1354 (s), 1307 (s), 1218 (s), 1124 (s), 1053 (s), 995

(s), 930 (s), 913 (s), 860 (m), 807 (m), 746 (m) cm^–1. ¹H NMR

(200 MHz, CDCl₃, Me₄Si): δ = 4.82 and 4.81 (2s in a 1:4 ratio, 1

H, 2-H), 4.22–4.10 (m, 1 H, 6-H), 3.88–3.76 (m, 2 H, 1 H of CH₂(2R*,3S*,4S*)-8a-I: IR (film): ν

= 3447 (br. s), 2983 (s), 2936

˜

max

of OEt and 1 H, 6-H), 3.70–3.58 (m, 1 H, 1 H of CH₂of OEt), (s), 2885 (s), 1451 (m), 1381 (m), 1354 (m), 1296 (m), 1218 (s), 1132

2.92–2.80 (m, 2 H, 5-H), 1.27 and 1.26 (2 partly overlapping t,

³J_H,H= 7.1 Hz, 3 H, CH₃of OEt) ppm. ¹³C NMR (50 MHz,

CDCl₃, Me₄Si): δ = 188.9 (C), 122.3 (C), 99.9 (minor) and 99.4

(major) (CH), 64.3 (major) and 64.1 (minor) (CH₂), 58.1 (minor)

and 58.0 (major) (CH₂), 30.3 (minor) and 27.4 (major) (CH₂), 14.8 of OEt), 3.67–3.57 (m, J_H,H= 7.0, J_H,H= 9.5 Hz, 1 H, 1 H of

(minor) and 14.7 (major) (CH₃) ppm. MS (EI): m/z (%) = 289 (25),

(s), 1081 (s), 1010 (m), 965 (m), 896 (m), 815 (m), 729 (m), 695 (m)

1

cm^–1. H NMR (200 MHz, CDCl₃, Me₄Si): δ = 4.35 (br. s, 1 H, 2-

H), 4.12 (dd, ³J_H,H= 4.7, ²J_H,H= 12.1 Hz, 1 H, 6-H), 4.09 (s, 1 H,

3

2

3-H), 4.00–3.92 (m, J_H,H= 7.0, J_H,H= 9.5 Hz, 1 H, 1 H of CH₂

3

2

3

2

CH₂of OEt), 3.52 (dt, J_H,H= 2.3, J_H,H= 12.1 Hz, 1 H, 6-H),

3

269 (72), 240 (24), 221 (10), 195 (13), 171 (26), 149 (15), 121 (78),

2.45–2.34 (m, 1 H, 4-H), 2.30 (br. s, 1 H, OH), 2.19 (dq, J_H,H=

5824

www.eurjoc.org

Eur. J. Org. Chem. 2009, 5816–5831

4-Perfluoroalkylated Tetrahydropyran Derivatives

2

4.7, J_H,H= 13.1 Hz, 1 H, 5-H), 1.62 (br. d, J_H,H= 13.1 Hz, 1 H, 2,3-Diethoxy-6-hexyl-5,6-dihydro-2H-pyran [(2R*,6R*/6S*)-11c]:

5-H), 1.25 (t, J_H,H= 7.0 Hz, 3 H, CH₃of OEt) ppm. ¹³C NMR The compound, 0.063 g (49% yield), was obtained as a colourless

(50 MHz, CDCl₃, Me₄Si): δ = 100.3 (CH), 64.9 (CH), 64.5 (CH₂),

53.9 (CH₂), 41.8 (t, J = 21.3 Hz, CH), 19.1 (CH₂), 15.0 (CH₃) ppm. Pure samples of the cis (2R*,6R*)-11c and trans (2R*,6S*)-11c iso-

3

liquid over two steps from 1,1,2,2-tetraethoxy-3-undecyn-5-ol.^[8]

MS (EI): m/z (%) = 363 (3), 336 (8), 319 (53), 301 (7), 289 (10),

241 (48), 195 (38), 177 (8), 145 (12), 121 (20), 102 (22), 93 (92), 75

(100). HRMS: m/z calcd. for C₉H₈O₂F₉([M – OEt]⁺) 319.0381;

found 319.0376.

mers were isolated by flash chromatography (hexane/ethyl acetate

in a 92.5:7.5 ratio). From the ¹H NMR spectrum of the crude prod-

uct mixture the cis/trans ratio was determined to be 38:62.

(2R*,6R*)-11c: IR (film): ν

= 2975 (s), 2957 (s), 2859 (s), 1682

˜

max

(2R*,3S*,4R*)-8a-I: IR (film): ν

= 3475 (m), 2978 (s), 2938 (s),

˜

max

(m), 1517 (w), 1458 (m), 1443 (m), 1378 (m), 1327 (w), 1298 (w),

1259 (w), 1206 (s), 1152 (m), 1118 (s), 1072 (s), 939 (w), 788 (m)

2896 (s), 1450 (m), 1382 (m), 1349 (s), 1309 (s), 1225 (s), 1134 (s),

1078 (s), 1009 (s), 944 (m), 904 (m), 876 (m), 788 (m), 732 (m), 694

1

cm^–1. H NMR (200 MHz, CDCl₃, Me₄Si): δ = 5.08 (br. s, 1 H, 2-

1

3

(m) cm^–1. H NMR (200 MHz, CDCl₃, Me₄Si): δ = 4.83 (d, J_H,H

H), 4.80 (dd, ³J_H,H= 2.8, ³J_H,H= 5.6 Hz, 1 H, 4-H), 3.82–3.60 (m,

5 H, 2 CH₂of 2 OEt and 6-H), 2.14–2.00 (m, 2 H, 5-H), 1.71–1.62

(m, 2 H, hexyl), 1.52–1.40 (m, 2 H, hexyl), 1.32–1.26 (m, 9 H, CH₃

= 3.7 Hz, 1 H, 2-H), 3.87–3.79 (m, 2 H, 1 H of CH₂of OEt and

3

2

3-H), 3.74 (dt, J_H,H= 2.5, J_H,H= 12.0 Hz, 1 H, 6-H), 3.64–3.51

3

(m, 2 H, 1 H of CH₂of OEt and 4-H), 2.78–2.65 (m, J_H,H= 4.0,

of OEt and 3 CH₂of hexyl), 1.24 (t, J_H,H= 7.1 Hz, 3 H, CH₃of

²J_H,H= 12.0 Hz, 1 H, 6-H), 2.03 (br. s, 1 H, OH), 1.86 (br. d, ²J_H,H

OEt), 0.88 (m, 3 H, CH₃of hexyl) ppm. ¹³C NMR (50 MHz,

CDCl₃): δ = 151.3 (C), 96.3 (CH), 95.0 (CH), 72.6 (CH), 62.4

(CH₂), 62.3 (CH₂), 35.4 (CH₂), 31.7 (CH₂), 29.1 (2 CH₂), 25.6

(CH₂), 22.4 (CH₂), 15.1 (CH₃), 14.2 (CH₃), 13.9 (CH₃) ppm. MS

(EI): m/z (%) = 256 (8), 211 (48), 183 (8), 165 (9), 153 (18), 143

(52), 139 (88), 125 (30), 113 (77), 103 (70), 97 (76), 85 (100), 73

(51), 70 (82), 57 (98). HRMS: m/z calcd. for C₁₅H₂₈O₃[M⁺]

256.2038; found 256.2028.

3

2

= 13.1 Hz, 1 H, 5-H), 1.74 (dq, J_H,H= 5.0, J_H,H= 13.1 Hz, 1 H,

5-H), 1.27 (t, J_H,H= 7.0 Hz, 3 H, CH₃of OEt) ppm. ¹³C NMR

3

(50 MHz, CDCl₃, Me₄Si): δ = 97.5 (CH), 66.5 (CH), 63.6 (CH₂),

57.6 (CH₂), 41.5 (t, J = 20.5 Hz, CH), 23.9 (CH₂), 15.0 (CH₃) ppm.

MS (EI): m/z (%) = 364 (3), 336 (34), 319 (65), 301 (38), 289 (37),

241 (60), 195 (83), 177 (41), 145 (38), 119 (65), 102 (71), 91 (79),

71 (100). HRMS: m/z calcd. for C₉H₈O₂F₉([M – OEt]⁺) 319.0381;

found 319.0399.

(2R*,6S*)-11c: IR (film): ν

= 2957 (s), 2929 (s), 2872 (s), 2859

˜

max

Investigations Based on 1b–1f

(s), 1729 (w), 1674 (m), 1459 (m), 1380 (m), 1335 (w), 1308 (w),

1290 (w), 1269 (w), 1201 (s), 1121 (s), 1105 (s), 1064 (s), 1041 (s),

Ring Closure of 1b–1f Catalyzed by Formic Acid: The reactions

were performed following the procedure used to synthesize 2,3-di-

ethoxy-5,6-dihydro-2H-pyran (11a) from 1a (vide supra). The fol-

lowing products were obtained.

960 (m), 949 (m), 817 (w), 786 (m), 734 (w), 722 (w) cm^–1. ¹H NMR

3

(200 MHz, CDCl₃, Me₄Si): δ = 4.81 (s, 1 H, 2-H), 4.73 (t, J_H,H

=

3.6 Hz, 1 H, 4-H), 3.96–3.90 (m, 1 H, 6-H), 3.88–3.80 (m, 1 H, 1

H of CH₂of OEt), 3.79–3.67 (m, 2 H, CH₂of OEt), 3.62–3.54 (m,

1 H, 1 H of CH₂of OEt), 2.01–1.99 (m, 2 H, 5-H), 1.48–1.45 (m,

2 H, CH₂of hexyl), 1.29 (m, 11 H, CH₃of OEt and 4 CH₂of

2,3-Diethoxy-6-methyl-5,6-dihydro-2H-pyran [(2R*,6R*/6S*)-11b]:

The compound, 0.048 g (52% yield), was obtained as a yellowish

liquid over two steps from 5,5,6,6-tetraethoxy-3-hexyn-2-ol.^[8]Pure

samples of the cis (2R*,6R*)-11b and trans (2R*,6S*)-11b isomers

were isolated by flash chromatography (hexane/ethyl acetate in a

3

hexyl), 1.26 (t, J_H,H= 7.1 Hz, 3 H, CH₃of OEt), 0.89 (m, 3 H,

CH₃of hexyl) ppm. ¹³C NMR (50 MHz, CDCl₃): δ = 151.5 (C),

95.0 (CH), 94.1 (CH), 66.8 (CH), 63.0 (CH₂), 62.2 (CH₂), 35.1

(CH₂), 31.7 (CH₂), 29.5 (CH₂), 29.1 (CH₂), 25.6 (CH₂), 22.5 (CH₂),

15.1 (CH₃), 14.3 (CH₃), 13.9 (CH₃) ppm. MS (EI): m/z (%) = 256

(10), 225 (12), 211 (63), 199 (52), 180 (70), 165 (18), 151 (51), 143

(62), 133 (43), 123 (85), 110 (86), 97 (98), 85 (100), 70 (91), 53 (72).

HRMS: m/z calcd. for C₁₅H₂₈O₃[M⁺] 256.2038; found 256.2017.

1

92.5:7.5 ratio). From the H NMR spectrum of the crude product

mixture the cis/trans ratio was determined to be 27:73.

(2R*,6R*)-11b: IR (film): ν

= 3063 (w), 2974 (s), 2894 (s), 1670

˜

max

(s), 1445 (m), 1379 (s), 1328 (m), 1294 (m), 1203 (s), 1156 (s), 1070

1

(s), 938 (m), 917 (m), 791 (m), 729 (w) cm^–1. H NMR (400 MHz,

5

CDCl₃, Me₄Si): δ = 5.10 (t, J_H,H= 1.9 Hz, 1 H, 2-H), 4.81 (t,

³J_H,H= 4.2 Hz, 1 H, 4-H), 3.86 (q, ³J_H,H= 6.3 Hz, 1 H, 6-H), 3.81–

3.61 (m, 4 H, 2 CH₂of 2 OEt), 2.10–2.07 (m, 2 H, 5-H), 1.31 (t,

2,3-Diethoxy-6-phenyl-5,6-dihydro-2H-pyran [(2R*,6R*/6S*)-11d]:

The compound, 0.076 g (61% yield), was obtained as a yellowish

liquid over two steps from 4,4,5,5-tetraethoxy-1-phenyl-2-pentyn-

1-ol.^[8]Pure samples of the cis (2R*,6S*)-11d and trans (2R*,6R*)-

11d isomers were isolated by flash chromatography (hexane/ethyl

acetate in a 92.5:7.5 ratio). From the ¹H NMR spectrum of the

crude product mixture the cis/trans ratio was determined to be

68:32.

3

³J_H,H= 7.0 Hz, 3 H, CH₃of OEt), 1.28 (d, J_H,H= 6.3 Hz, 3 H,

3

6-Me), 1.25 (t, J_H,H= 7.0 Hz, 3 H, CH₃of OEt) ppm. ¹³C NMR

(100 MHz, CDCl₃): δ = 150.9 (C), 95.9 (CH), 94.7 (CH), 68.4 (CH),

62.3 (CH₂), 62.0 (CH₂), 30.6 (CH₂), 20.8 (CH₃), 15.0 (CH₃), 14.2

(CH₃) ppm. MS (EI): m/z (%) = 186 (67), 157 (38), 141 (100), 129

(65), 113 (80), 95 (97), 86 (98), 67 (88), 57 (73). HRMS: m/z calcd.

for C₁₀H₁₈O₃[M⁺] 186.1256; found 186.1258.

(2R*,6S*)-11d: IR (film): ν_max= 3062 (m), 3031 (m), 2977 (s), 2922

˜

(2R*,6S*)-11b: IR (film): ν

= 3060 (w), 2974 (s), 2900 (s), 2841 (s), 2895 (s), 1669 (s), 1482 (m), 1449 (m), 1378 (m), 1330 (m), 1280

˜

max

(m), 1674 (m), 1445 (m), 1381 (s), 1337 (m), 1299 (m), 1199 (s), (m), 1214 (s), 1181 (s), 1121 (s), 1070 (s), 942 (m), 896 (w), 790 (w),

1

1106 (s), 1062 (s), 966 (m), 909 (m), 874 (w), 795 (m), 736 (w), 663

755 (m), 700 (m) cm^–1. H NMR (200 MHz, CDCl₃, Me₄Si): δ =

(w) cm^–1. ¹H NMR (400 MHz, CDCl₃, Me₄Si): δ = 4.81 (s, 1 H, 2-

7.41–7.23 (m, 5 H, phenyl), 5.32 (t, ³J_H,H= 2.0 Hz, 1 H, 2-H), 4.92

3

H), 4.74 (t, J_H,H= 4.0 Hz, 1 H, 4-H), 4.14–4.06 (m, 1 H, 6-H), (dd, J_H,H= 2.0, J_H,H= 6.6 Hz, 1 H, 4-H), 4.71 (dd, J_H,H= 3.4,

3.87–3.57 (m, 4 H, 2 CH₂of 2 OEt), 2.04–2.01 (m, 2 H, 5-H), 1.30 ³J_H,H= 10.5 Hz, 1 H, 6-H), 3.86–3.67 (m, 4 H, 2 CH₂of 2 OEt),

3

2

(t, ³J_H,H= 7.0 Hz, 3 H, CH₃of OEt), 1.26 (t, ³J_H,H= 7.0 Hz, 3 H,

2.43 (ddd, J_H,H= 2.0, J_H,H= 10.5, J_H,H= 16.0 Hz, 1 H, 5-H),

3

2

CH₃of OEt), 1.23 (d, J_H,H= 6.3 Hz, 3 H, 6-Me) ppm. ¹³C NMR

2.27 (ddd, J_H,H= 3.4, J_H,H= 6.6, J_H,H= 16.0 Hz, 1 H, 5-H),

3

(100 MHz, CDCl₃): δ = 151.3 (C), 95.2 (CH), 93.9 (CH), 63.2

1.33 (t, J_H,H= 7.0 Hz, 3 H, CH₃of OEt), 1.26 (t, J_H,H= 7.0 Hz,

(CH₂), 62.9 (CH), 62.2 (CH₂), 30.9 (CH₂), 20.5 (CH₃), 15.2 (CH₃), 3 H, CH₃of OEt) ppm. ¹³C NMR (50 MHz, CDCl₃): δ = 151.4

14.2 (CH₃) ppm. MS (EI): m/z (%) = 186 (85), 157 (38), 141 (81),

129 (68), 113 (96), 95 (100), 86 (93), 67 (93), 57 (94). HRMS: m/z 95.3 (CH), 74.3 (CH), 62.5 (CH₂), 62.1 (CH₂), 31.3 (CH₂), 15.2

calcd. for C₈H₁₃O₂([M – OEt]⁺) 141.0916; found 141.0910.

(CH₃), 14.2 (CH₃) ppm. MS (EI): m/z (%) = 248 (1), 203 (38), 173

(C), 141.5 (C), 128.0 (2 CH), 127.2 (CH), 125.5 (2 CH), 96.9 (CH),

Eur. J. Org. Chem. 2009, 5816–5831

www.eurjoc.org

5825

S. Valdersnes, L. K. Sydnes

FULL PAPER

(18), 157 (73), 143 (81), 127 (78), 113 (93), 104 (84), 91 (100), 86

(98), 77 (83), 70 (77), 55, (68). HRMS: m/z calcd. for C₁₃H₁₅O₂

([M – OEt]⁺) 203.1072, 203.1066.

perfluoroalkylation of 11a (vide supra). The following products

were obtained.

2-Ethoxy-6-methyl-4-(perfluorobutyl)tetrahydropyran-3-one

[(2R*,4R*/4S*,6R*)-12b-I]: The compound was prepared from

(2R*,6R*)-11b (0.19 g, 1.0 mmol). Evaporation of the solvent gave

0.30 g (78%) of (2R*,4R*/4S*,6R*)-12b-I as a yellowish liquid. The

compound was obtained as a 42:58 mixture of the (4R*/4S*) dia-

stereomers according to ¹H NMR spectra of the crude product. IR

(2R*,6R*)-11d: IR (film): ν_max= 3061 (m), 3033 (m), 2975 (s), 2901

˜

(s), 1726 (w), 1673 (s), 1605 (w), 1493 (m), 1449 (m), 1383 (m),

1335 (m), 1282 (m), 1209 (m), 1103 (s), 1061 (m), 975 (m), 912 (m),

888 (m), 812 (m), 789 (m), 754 (s), 700 (s), 674 (w), 639 (w), 576

1

(m) cm^–1. H NMR (200 MHz, CDCl₃, Me₄Si): δ = 7.41–7.25 (m,

3

5 H), 5.02 (dd, J_H,H= 4.3, J_H,H= 10.7 Hz, 1 H, 6-H), 5.00 (s, 1

(film): ν

= 3498 (w), 2981 (s), 2936 (s), 2908 (s), 1755 (s), 1675

˜

max

3

H, 2-H), 4.85 (dd, J_H,H= 2.5, J_H,H= 5.6 Hz, 1 H, 4-H), 3.89–

3.72 (m, 3 H, 3 H of CH₂of 2 OEt), 3.67–3.59 (m, 1 H, 1 H of

CH₂of OEt), 2.38 (m, J_H,H= 10.7, J_H,H= 16.6 Hz, 1 H, 5-H),

(w), 1451 (m), 1381 (m), 1350 (m), 1294 (m), 1210 (s), 1133 (s),

1065 (s), 947 (m), 906 (m), 881 (m), 841 (m), 739 (m) cm^–1. ¹H

NMR (200 MHz, CDCl₃, Me₄Si): δ = 4.81 and 4.79 (2s in a 58:42

ratio, 1 H, 2-H), 4.28–4.22 (major) and 4.22–4.15 (minor) (m, 1 H,

6-H), 3.96–3.87 (m, 1 H, 1 H of CH₂of OEt), 3.77–3.71 and 3.44–

3

2

3

2

3

2.31 (m, J_H,H= 5.6, J_H,H= 16.6 Hz, 1 H, 5-H), 1.33 (t, J_H,H

=

3

7.0 Hz, 3 H, CH₃of OEt), 1.25 (t, J_H,H= 7.0 Hz, 3 H, CH₃of

OEt) ppm. ¹³C NMR (50 MHz, CDCl₃): δ = 151.6 (C), 141.7 (C),

128.2 (2 CH), 127.3 (CH), 125.9 (2 CH), 95.5 (CH), 94.3 (CH),

68.9 (CH), 63.5 (CH₂), 62.5 (CH₂), 31.1 (CH₂), 15.3 (CH₃), 14.3

(CH₃) ppm. MS (EI): m/z (%) = 248 (2), 203 (78), 175 (30), 157

(92), 143 (88), 129 (81), 113 (100), 104 (86), 86 (95), 77 (83), 70

(77), 55 (68). HRMS: m/z calcd. for C₁₃H₁₅O₂([M – OEt]⁺)

203.1072; found 203.1078.

3.32 (m, 1 H, 4-H), 3.68–3.59 (m, 1 H, 1 H of CH₂of OEt), 2.47–

3

2.40 (m, 1 H, 5-H), 2.35–2.20 (m, 1 H, 5-H), 1.42 (major, J_H,H

=

3

6.5 Hz) and 1.39 (minor, J_H,H= 6.2 Hz) (d, 3 H, 6-Me), 1.27

(major) and 1.26 (minor) (2 overlapping t, J_H,H= 7.0 Hz, 3 H,

3

CH₃of OEt) ppm. ¹³C NMR (50 MHz, CDCl₃): δ = 195.2 (major)

and 193.6 (minor) (C), 99.9 (major) and 99.3 (minor) (CH), 69.8

(minor) and 67.8 (major) (CH), 64.7 (major) and 64.6 (minor)

(CH₂), 48.0 (minor, t, J = 21.3 Hz), 45.2 (major, t, J = 21.3 Hz)

(CH), 32.2 (major) and 30.7 (minor) (CH₂), 22.0 (minor) and 21.3

(major) (CH₃), 14.8 (minor) and 14.7 (major) (CH₃) ppm. MS (EI):

m/z (%) = 376 (18), 330 (10), 301 (22), 157 (13), 133 (19), 103 (100),

75 (65). HRMS: m/z calcd. for C₁₂H₁₃O₃F₉[M⁺] 376.0721,

376.0705.

2,3-Diethoxy-6,6-dimethyl-3,6-dihydro-2H-pyran (11e): The com-

pound, 0.055 g (55% yield), was obtained as a yellowish liquid over

two steps from 5,5,6,6-tetraethoxy-2-methyl-3-hexyn-2-ol.^[8]Purifi-

cation was performed by flash chromatography (hexane/ethyl ace-

tate in a 90:10 ratio). IR (film): ν

= 2975 (s), 2928 (s), 2891 (s),

˜

max

1678 (s), 1446 (m), 1378 (s), 1336 (m), 1311 (m), 1271 (m), 1217

(m), 1112 (s), 1065 (s), 1034 (s), 963 (m), 901 (w), 874 (w), 790 (w),

2-Ethoxy-6-methyl-4-(perfluorobutyl)tetrahydropyran-3-one [(2R*,

4R*/4S*,6S*)-12b-I]: The compound was prepared from

(2R*,6S*)-11b (0.19 g, 1.0 mmol). Evaporation of the solvent gave

0.38 g (99%) of (2R*,4R*/4S*,6S*)-12b-I as a yellow liquid. The

compound was obtained as a 60:40 mixture of the (4R*/4S*) dia-

stereoisomers according to ¹H NMR spectra of the crude product.

1

750 (w) cm^–1. H NMR (200 MHz, CDCl₃, Me₄Si): δ = 4.89 (s, 1

3

H, 2-H), 4.72 (dd, J_H,H= 3.1, J_H,H= 5.6 Hz, 1 H, 4-H), 3.90–

3.69 (m, 3 H, 3 H of CH₂of 2 OEt), 3.61–3.53 (m, 1 H, 1 H of

2

CH₂of OEt), 2.22 (br. d, J_H,H= 16.4 Hz, 1 H, 5-H), 2.06 (dd,

2

³J_H,H= 5.6, J_H,H= 16.4 Hz, 1 H, 5-H), 1.37 (s, 3 H, 6-Me), 1.32

3

(t, J_H,H= 7.0 Hz, 3 H, CH₃of OEt), 1.27 (s, 3 H, 2-Me), 1.24 (t,

IR (film): ν

= 2982 (s), 2936 (s), 1756 (s), 1674 (w), 1452 (m),

˜

max

³J_H,H= 7.0 Hz, 3 H, CH₃of OEt) ppm. ¹³C NMR (50 MHz,

CDCl₃): δ = 150.2 (C), 94.3 (CH), 92.9 (CH), 71.0 (C), 62.6 (CH₂),

62.2 (CH₂), 35.3 (CH₂), 29.5 (CH₃), 26.9 (CH₃), 15.0 (CH₃), 14.2

(CH₃) ppm. MS (EI): m/z (%) = 200 (75), 185 (45), 155 (83), 143

(68), 139 (72), 124 (65), 115 (78), 110 (75), 103 (98), 95 (78), 83

(87), 79 (84), 75 (63), 67 (100), 59 (83), 53 (86). HRMS: m/z calcd.

for C₉H₁₅O₂([M – OEt]⁺) 155.1072; found 155.1074.

1384 (m), 1351 (s), 1209 (s), 1133 (s), 1053 (s), 958 (m), 904 (m),

811 (m), 734 (m), 696 (m), 652 (m) cm^–1. ¹H NMR (400 MHz,

CDCl₃, Me₄Si): δ = 4.77 and 4.67 (2s in a 40:60 ratio, 1 H, 2-H),

4.51–4.44 (major) and 4.44–4.35 (minor) (2m, 1 H, 6-H), 3.93–3.85

(major) and 3.52–3.41 (minor) (2m, 1 H, 4-H), 3.88–3.78 (m, 1 H,

1 H of CH₂of OEt), 3.65–3.56 (m, 1 H, 1 H of CH₂of OEt), 2.39–

2.30 (m, 1 H, 5-H), 2.18–2.10 (minor) and 2.04–1.94 (major) (2m,

1 H, 5-H), 1.31 (minor) and 1.29 (major) (2d, ³J_H,H= 6.3 Hz, 3 H,

6-Me), 1.27 (major) and 1.26 (minor) (2t, ³J_H,H= 7.0 Hz, 3 H, CH₃

of OEt) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 195.8 (minor) and

194.4 (major) (C), 99.7 (major) and 98.6 (minor) (CH), 64.4

(major) and 63.1 (minor), (CH), 64.3 (minor) and 64.0 (major)

(CH₂), 46.0 (major, t, J = 21.3 Hz) and 45.8 (minor, t, J = 21.3 Hz)

(CH), 35.6 (major) and 30.9 (minor) (CH₂), 20.8 (minor) and 20.2

(major) (CH₃), 14.9 (major) and 14.7 (minor) (CH₃) ppm. MS (EI):

m/z (%) = 375 (4), 359 (22), 348 (48), 331 (38), 311 (81), 301 (32),

283 (91), 265 (72), 254 (76), 240 (88), 215 (62), 163 (83), 145 (82),

107 (88), 69 (100). HRMS: m/z calcd. for C₁₂H₁₃O₃F₉[M⁺]

376.0721; found 376.0696.

2,3-Diethoxy-1-oxaspiro[5.5]undec-3-ene (11f): The compound,

0.091 g (76% yield), was obtained as a colourless liquid over two

steps from 1-(3,3,4,4-tetraethoxybut-1-ynyl)cyclohexanol (1f) (vide

supra). Purification was carried out by flash chromatography (hex-

ane/ethyl acetate in a 90:10 ratio). IR (film): ν_max= 3057 (w), 2930

˜

(s), 1679 (m), 1446 (m), 1381 (m), 1340 (m), 1249 (m), 1208 (m),

1151 (m), 1105 (s), 1067 (s), 847 (s), 892 (m), 867 (m), 790 (m), 742

1

(m), 655 (w) cm^–1. H NMR (200 MHz, CDCl₃, Me₄Si): δ = 4.90

3

(s, 1 H, 2-H), 4.70 (dd, J_H,H= 3.6, J_H,H= 5.0 Hz, 1 H, 4-H),

4.04–3.50 (m, 4 H, 2 CH₂of 2 OEt), 2.25–2.04 (m, 2 H, 5-H), 2.03–

1.94 (m, 4 H, 2 CH₂of cyclohexyl), 1.70–1.37 (m, 6 H, 3 CH₂of

3

cyclohexyl), 1.31 (t, J_H,H= 7.0 Hz, 3 H, CH₃of OEt), 1.25 (t,

³J_H,H= 7.0 Hz, 3 H, CH₃of OEt) ppm. ¹³C NMR (50 MHz,

CDCl₃): δ = 150.1 (C), 94.1 (CH), 92.7 (CH), 72.6 (C), 63.3 (CH₂),

62.3 (CH₂), 38.0 (CH₂), 35.3 (CH₂), 33.9 (CH₂), 25.9 (CH₂), 22.3

(CH₂), 22.2 (CH₂), 15.0 (CH₃), 14.3 (CH₃) ppm. MS (EI): m/z (%)

= 240 (4), 239 (30), 181 (100), 153 (33), 135 (97), 117 (38), 103 (94),

89 (75), 75 (82), 67 (40), 59 (62). HRMS: m/z calcd. for C₁₄H₂₄O₃

[M⁺] 240.1725; found 240.1717.

2-Ethoxy-6-hexyl-4-(perfluorobutyl)tetrahydropyran-3-one

[(2R*,

4R*/4S*,6R*)-12c-I]: The compound was prepared from

(2R*,6R*)-11c (0.13 g, 0.51 mmol). Evaporation of the solvent gave

0.18 g (77%) of (2R*,4R*/4S*,6R*)-12c-I as a yellowish liquid. The

compound was obtained as a 55:45 mixture of the (4R*/4S*) dia-

stereoisomers according to ¹H NMR spectra of the crude product.

IR (film): ν

= 2931 (s), 2958 (s), 2860 (m), 1755 (m), 1681 (m),

˜

max

1-Iodoperfluorobutylation of 11b–11f: All the reactions were per-

formed following the general procedure used to carry out 1-iodo-

1651 (w), 1644 (w), 1519 (w), 1467 (m), 1460 (m), 1379 (m), 1353

(m), 1296 (w), 1236 (s), 1221 (s), 1136 (s), 1119 (s), 1056 (s), 878

5826

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Eur. J. Org. Chem. 2009, 5816–5831

4-Perfluoroalkylated Tetrahydropyran Derivatives

(w), 842 (w), 792 (w), 739 (w), 695 (w), 665 (w) cm^–1. ¹H NMR 2-Ethoxy-4-(perfluorobutyl)-6-phenyltetrahydropyran-3-one [(2R*,

(400 MHz, CDCl₃, Me₄Si): δ = 4.80 and 4.76 (2s in a 55:45 ratio,

4R*/4S*,6R*)-12d-I]: The compound was prepared from

1 H, 2-H), 4.00–3.28 (m, 4 H, CH₂of OEt, 6-H and 4-H), 2.37– (2R*,6R*)-11d (0.26 g, 1.0 mmol). Evaporation of the solvent gave

2.22 (m, 1 H, 5-H), 2.13–2.00 (m, 1 H, 5-H), 1.71–1.27 (m, 10 H,

0.42 g (93%) of (2R*,4R*/4S*,6R*)-12d-I as a yellowish liquid. The

compound was obtained as a 70:30 mixture of the (4R*/4S*) dia-

stereoisomers according to ¹H NMR spectra of the crude product.

3

5 CH₂of hexyl), 1.26 and 1.25 (2t, J_H,H= 7.1 Hz, 3 H, CH₃of

OEt), 0.89–0.87 (m, 3 H, CH₃of hexyl) ppm. ¹³C NMR (100 MHz,

CDCl₃): δ = 195.4 and 193.7 (C), 99.8 and 99.3 (CH), 73.6 and

IR (film): ν_max= 3092 (w), 3066 (w), 3035 (w), 2981 (m), 2932 (m),

˜

72.7 (CH), 65.0 and, 64.7 (CH₂), 48.0 and 45.6 (t, J = 21.6 Hz, 2903 (m), 1755 (m), 1497 (w), 1455 (w), 1353 (m), 1295 (m), 1236

CH), 35.6 and 35.2 (CH₂), 31.8 and 31.7 (CH₂), 29.2 and 29.0 (s), 1171 (m), 1135 (s), 1109 (m), 1047 (s), 1028 (m), 030 (w), 912

(CH₂), 25.8 and 25.7 (CH₂), 25.5 (CH₂), 22.6 and 22.5 (CH₂), 15.2

and 14.9 (CH₃), 13.9 (CH₃) ppm. MS (EI): m/z (%) = 446 (72), 430

(21), 417 (81), 402 (30), 389 (64), 371 (100). HRMS: m/z calcd. for

C₁₇H₂₃O₃F₉[M⁺] 446.1503; found 446.1495.

(w), 892 (w), 880 (w), 867 (w), 844 (w), 802 (w), 791 (w), 759 (m),

745 (m), 731 (m), 699 (m) cm^–1. ¹H NMR (200 MHz, CDCl₃,

Me₄Si): δ = 7.40–7.31 (m, 5 H, phenyl), 5.39–5.26 (m, 1 H, 6-H),

4.96 and 4.86 (2s in a 30:70 ratio, 1 H, 2-H), 4.13–3.50 (m, 3 H,

CH₂of OEt and 4-H), 2.66–2.28 (m, 2 H, 5-H), 1.28 (major) and

3

2-Ethoxy-6-hexyl-4-(perfluorobutyl)tetrahydropyran-3-one

[(2R*,

1.27 (minor) (2 partly overlapping t, J_H,H= 7.1 Hz, 3 H, CH₃of

OEt) ppm. ¹³C NMR (50 MHz, CDCl₃): δ = 195.2 (minor) and

194.0 (major) (C), 139.0 (C), 128.7 (2 CH), 128.4 (CH), 126.1 (2

CH), 100.0 (major) and 99.9 (minor) (CH), 70.3 (minor) and 70.2

(major) (CH), 64.3 (major) and 64.0 (minor) (CH₂), 46.2 (2t, J =

21.3 Hz, CH), 36.2 (CH₂), 14.9 (CH₃) ppm. MS (EI): m/z (%) =

437 (2), 373 (60), 344 (93), 324 (81), 283 (72), 264 (54), 205 (63),

175 (82), 146 (92), 115 (100), 77 (92).

4R*/4S*,6S*)-12c-I]: The compound was prepared from

(2R*,6S*)-11c (0.26 g, 1.01 mmol). Evaporation of the solvent gave

0.39 g (86%) of (2R*,4R*/4S*,6S*)-12c-I as a yellowish liquid. The

compound was obtained as a 65:35 mixture of the (4R*/4S*) dia-

stereoisomers according to ¹H NMR spectra of the crude product.

IR (film): ν

= 2933 (s), 2958 (s), 2861 (m), 1759 (m), 1685 (w),

˜

max

1467 (m), 1460 (m), 1353 (m), 1292 (m), 1236 (s), 1171 (m), 1135

(s), 1111 (m), 1048 (m), 923 (w), 881 (w), 816 (w), 744 (w), 729 (w),

696 (w), 665 (w) cm^–1. ¹H NMR (400 MHz, CDCl₃, Me₄Si): δ =

4.79 and 4.68 (2s in a 35:65 ratio, 1 H, 2-H), 4.29–4.22 (major) and

4.22–4.14 (minor) (2m, 1 H, 6-H), 4.01–3.95 and 3.54–3.42 (2m, 1

H, 4-H), 3.93–3.76 (m, 1 H, 1 H of CH₂of OEt), 3.67–3.54 (m, 1

H, 1 H of CH₂of OEt), 2.35–2.13 (m, 2 H, 5-H), 1.64–1.18 (m, 10

H, 5 CH₂of hexyl), 1.26 (major) and 1.25 (minor) (2 partly overlap-

2-Ethoxy-6,6-dimethyl-4-(perfluorobutyl)tetrahydropyran-3-one

[(2R*,4R*/4S*)-12e-I]: The compound was prepared from (2R*)-

11e (2.00 g, 10 mmol). Evaporation of the solvent gave 3.74 g

(96%) of (2R*,4R*/4S*)-12e-I as a yellowish liquid. The compound

was obtained as a 84:16 mixture of the (4R*/4S*) diastereoisomers

according to ¹H NMR spectra of the crude product. IR (film): ν

˜

max

= 3500 (m) 2981 (s), 2935 (s), 1757 (s), 1453 (m), 1375 (m), 1350

(m), 1319 (m), 1232 (s), 1133 (s), 1055 (s), 938 (w), 880 (m), 813

3

ping t, J_H,H= 7.1 Hz, 3 H, CH₃of OEt), 0.89 (m, 3 H, CH₃of

hexyl) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 196.6 (minor) and

194.6 (major) (C), 99.6 (major) and, 98.5 (minor) (CH), 67.9

(major) and 66.8 (minor) (CH), 64.1 (minor) and 63.8 (major)

(CH₂), 46.0 (major, t, J = 20.1 Hz) and 45.8 (minor, t, J = 20.1 Hz)

(CH), 35.3 (minor) and 34.6 (major) (CH₂), 34.0 (CH₂), 31.7

(CH₂), 29.1 (major) and 29.0 (minor) (CH₂), 25.5 (major) and 25.4

(minor) (CH₂), 22.5 (CH₂), 14.9 (major) and 14.7 (minor) (CH₃),

13.9 (CH₃) ppm. MS (EI): m/z (%) = 445 (3), 405 (6), 381 (8), 352

(58), 310 (69), 296 (78), 281 (72), 262 (67), 254 (35), 226 (36), 207

(18), 183 (71), 163 (65), 143 (74), 113 (68), 107 (76), 95 (83), 69

(84), 57 (100). HRMS: m/z calcd. for C₁₇H₂₂O₃F₉([M – H]⁺)

445.1425; found 445.1414.

1

(w), 742 (m), 717 (m) cm^–1. H NMR (400 MHz, CDCl₃, Me₄Si):

δ = 4.71 and 4.68 (2s in a 16:84 ratio, 1 H, 2-H), 4.07–3.95 (major)

and 3.61–3.56 (2m, 1 H, 4-H), 3.93–3.86 (m, 1 H, 1 H of CH₂of

3

OEt), 3.60–3.52 (m, 1 H, 1 H of CH₂of OEt), 2.32 (dd, J_H,H

=

2

3

4.6, J_H,H= 13.5 Hz, 1 H, 5-H), 2.22 (t, J_H,H= J_H,H= 13.5 Hz,

1 H, 5-H), 1.62 (s, 3 H, 6-Me), 1.34 (s, 3 H, 6-Me), 1.25 (t, J_H,H

3

= 7.0 Hz, 3 H, CH₃of OEt) ppm. ¹³C NMR (100 MHz, CDCl₃):

δ = 195.1 (major) and 194.8 (minor) (C), 99.6 (major) and 98.6

(minor) (CH), 73.0 (minor) and 72.8 (major) (C), 64.6 (minor) and

64.1 (major) (CH₂), 44.7 (minor, t, J = 21.3 Hz) and 43.0 (major,

t, J = 21.3 Hz) (CH), 38.6 (CH₂), 30.8 (CH₃), 27.3 (minor) and

26.3 (major) (CH₃), 14.5 (minor) and 14.6 (major) (CH₃) ppm. MS

(EI): m/z (%) = 390 (60) [M⁺], 371 (33), 361 (48), 343 (41), 329

(100), 315 (54), 299 (50), 287 (44), 149 (42), 103 (38). HRMS: m/z

calcd. for C₁₃H₁₅O₃F₉[M⁺] 390.0877; found 390.0864.

2-Ethoxy-4-(perfluorobutyl)-6-phenyltetrahydropyran-3-one [(2R*,

4R*/4S*,6S*)-12d-I]: The compound was prepared from

(2R*,6S*)-11d (0.26 g, 1.0 mmol). Evaporation of the solvent gave

0.43 g (95%) of (2R*,4R*/4S*,6S*)-12d-I as a yellowish liquid. The

compound was obtained as a 50:50 mixture of the (4R*/4S*) dia-

stereoisomers according to ¹H NMR spectra of the crude product.

2-Ethoxy-4-(perfluorobutyl)-1-oxaspiro[5.5]undec-3-one [(2R*,4R*/

4S*)-12f-I]: The compound was prepared from (2R*)-11f (2.80 g,

11.7 mmol). Evaporation of the solvent gave 4.54 g (91%) of

IR (film): ν

= 3067 (w), 3035 (w), 2981 (s), 2933 (s), 2902 (m), (2R*,4R*/4S*)-12f-I as a yellowish liquid. The compound was ob-

˜

max

1755 (s), 1677 (m), 1497 (w), 1453 (m), 1376 (m), 1352 (m), 1294 tained as a 80:20 mixture of the (4R*/4S*) diastereoisomers accord-

(m), 1240 (s), 1135 (s), 1055 (s), 949 (w), 911 (w), 883 (w), 845 (w),

ing to ¹H NMR spectra of the crude product. IR (film): ν

3529 (m), 2936 (s), 2975 (s), 1755 (m), 1450 (m), 1349 (m), 1306

=

˜

max

827 (w), 761 (m), 738 (m), 700 (m) cm^–1. ¹H NMR (400 MHz,

CDCl₃, Me₄Si): δ = 7.44–7.30 (m, 5 H, phenyl), 5.14 (³J_H,H= 4.6, (m), 1217 (s), 1131 (s), 1069 (s), 974 (m), 916 (m), 857 (m), 810

3

1

³J_H,H= 9.6 Hz) and 5.04 (³J_H,H= 2.9, J_H,H= 11.7 Hz) (2dd in a

(m), 740 (m), 701 (m) cm^–1. H NMR (200 MHz, CDCl₃, Me₄Si):

1.0:1.0 ratio, 1 H, 6-H), 5.04 and 4.94 (2s in a 1.0:1.0 ratio, 1 H,

δ = 4.74 and 4.72 (2s in a 1.0:4.0 ratio, 1 H, 2-H), 4.00–3.94 and

2-H), 4.01–3.50 (m, 3 H, CH₂of OEt and 4-H), 2.73–2.46 (m, 2 H, 3.42–3.31 (2m, 1 H, 4-H), 3.97–3.88 (m, 1 H, 1 H of CH₂of OEt),

3

5-H), 1.25 and 1.24 (2t in a 1.0:1.0 ratio, ³J_H,H= 7.2 Hz, 3 H, CH₃3.64–3.54 (m, 1 H, 1 H of CH₂of OEt), 2.43 (dd, J_H,H= 4.3,

2

3

of OEt) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 194.7 and 193.0

²J_H,H= 13.6 Hz, 1 H, 5-H), 2.04 (t, J_H,H= J_H,H= 13.6 Hz, 1 H,

3

(C), 139.9 (C), 128.6 (2 CH), 128.3 (CH), 126.1 (2 CH), 99.9 and 5-H), 1.96–1.32 (m, 10 H, 5 CH₂of cyclohexyl), 1.25 (t, J_H,H

=

99.5 (CH), 75.4 and 73.1 (CH), 65.3 and 65.1 (CH₂), 48.3 and 46.8

(2t, J = 21.4 Hz, CH), 32.5 and 31.5 (CH₂), 14.7 (CH₃) ppm. MS

7.0 Hz, 3 H, CH₃of OEt) ppm. ¹³C NMR (50 MHz, CDCl₃): δ =

195.6 (major) and 195.2 (minor) (C), 99.6 (major) and 99.1 (minor)

(EI): m/z (%) = 438 (2), 360 (73), 323 (5), 253 (100), 225 (75), 207 (CH), 74.0 (major) and 73.4 (minor) (C), 65.1 (major) and 64.8

(36), 177 (22), 157 (44), 146 (36), 105 (93), 77 (52). (minor) (CH₂), 58.3 (major) and 55.7 (minor) (CH₂), 44.5 (minor,

Eur. J. Org. Chem. 2009, 5816–5831

www.eurjoc.org

5827

S. Valdersnes, L. K. Sydnes

FULL PAPER

t, J = 21.5 Hz) and 42.8 (major, t, J = 21.5 Hz) (CH), 39.8 (minor) (CH₃) ppm. MS (EI): m/z (%) = 377 (3), 363 (10), 345 (18), 333

and 39.4 (major) (CH₂), 36.0 (minor) and 35.4 (major) (CH₂), 25.6 (78), 317 (72), 303 (45), 287 (62), 267 (68), 255 (71), 226 (62), 206

(major) and 25.4 (minor) (CH₂), 22.4 (minor) and, 22.3 (major)

(CH₂), 22.2 (major), 22.0 (minor) (CH₂), 14.9 (minor) and 14.8

(major) (CH₃) ppm. MS (EI): m/z (%) = 430 (100) [M⁺], 385 (27),

367 (31), 339 (21), 327 (7), 239 (83), 158 (63), 129 (43), 103 (62),

81 (63). HRMS: m/z calcd. for C₁₆H₁₉O₃F₉[M⁺] 430.1190; found

430.1185.

(53), 145 (53), 88 (78), 69 (100), 57 (98). HRMS: m/z calcd. for

C₁₂H₁₅O₃F₉[M⁺] 378.0877; found 378.0850.

2-Ethoxy-6-methyl-4-(perfluorobutyl)tetrahydropyran-3-ol

[(2R*,

3R*/3S*,4R*/4S*,6S*)-8b-I]: The compound was prepared from

0.30 g (0.80 mmol) of (2R*,4R*/4S*,6S*)-12b-I with a 4R*/4S* ra-

tio of 40:60. Solvent evaporation gave 0.28 g (93%) of (2R*,3R*/

Synthesis of 2-Ethoxy-4-(perfluorobutyl)tetrahydropyran-3-ols 8b-I– 3S*,4R*/4S*,6S*)-8b-I as a yellowish liquid consisting of a mixture

8f-I: The reactions were carried out by reduction of 2-ethoxy-4-

(perfluorobutyl)tetrahydropyran-3-ones 12b-I–12f-I as described

for the conversion of 12a-I to 8a-I (vide supra). The products were

obtained as isomer mixtures, and flash chromatography, using hex-

ane/ethyl acetate mixtures as eluents, was used in attempts to iso-

late pure samples of all the isomers. This was not always successful

due to the very similar R_fvalues for some of the isomers. The

solvent ratio used is given below for each of the compounds.

of four pairs of diastereomers. The isomeric composition was deter-

mined by ¹H NMR investigations of the product mixture before

isolation of the major isomers started, using the integrals of the

anomeric protons to determine the isomeric composition. The an-

omeric protons showed the following chemical shifts and relative

intensities: 4.82 ppm, 76% (3S*,4R*); 4.72 ppm, 8% (3R*,4R*);

4.68 ppm, 12% (3S*,4S*); 4.35 ppm, 4% (3R*,4S*). Separation

and purification were carried out by flash chromatography (hexane/

ethyl acetate in a 90:10 ratio), and the two diastereomeric pairs

with a trans relationship between the perfluorobutyl and OEt

groups were isolated pure.

2-Ethoxy-6-methyl-4-(perfluorobutyl)tetrahydropyran-3-ol

[(2R*,

3R*/3S*,4R*/4S*,6R*)-8b-I]: The compound was prepared from

0.25 g (0.66 mmol) of (2R*,4R*/4S*,6R*)-12b-I with a 4R*/4S* ra-

tio of 58:42. Solvent evaporation gave 0.20 g (81%) of (2R*,3R*/

3S*,4R*/4S*,6R*)-8b-I as a yellowish liquid consisting of a mixture

of three pairs of diastereomers. The isomeric composition was de-

(2R*,3S*,4R*,6S*)-8b-I: IR (film): ν_max= 3566 (m), 3491 (m), 2980

˜

(s), 2937 (m), 2907 (m), 1450 (m), 1388 (m), 1353 (s), 1291 (m),

1236 (s), 1135 (s), 1039 (s), 1058 (s), 1000 (m), 956 (m), 919 (m),

881 (m), 785 (w), 747 (m), 732 (m), 710 (w), 699 (w), 642 (w) cm^–1.

1

termined by H NMR investigations of the product mixture before

3

isolation of the major isomers started, using the integrals of the

anomeric protons to determine the isomeric composition. The an-

omeric protons showed the following chemical shifts and relative

intensities: 4.82 ppm, 10% (3R*,4S*); 4.70 ppm, 42% (3S*,4R*);

¹H NMR (400 MHz, CDCl₃, Me₄Si): δ = 4.82 (d, J_H,H= 3.6 Hz,

1 H, 2-H), 3.96–3.88 (m, 1 H, 6-H), 3.87–3.78 (m, 2 H, 1 H of CH₂

of OEt and 3-H), 3.62–3.52 (m, 1 H, 1 H of CH₂of OEt), 2.83–

3

2.66 (m, 1 H, 4-H), 2.23 (d, J_H,H= 11.2 Hz, 1 H, OH), 1.87 (br.

2

3

4.39 ppm, 48% (3S*,4S*); no signal due to the (3R*,4R*) isomer d, J_H,H= 14.2 Hz, 1 H, 5-H), 1.41 (q, J_H,H= J_H,H= 12.6 Hz, 1

3

was observed. Separation and purification were carried out by flash

chromatography (hexane/ethyl acetate in a 90:10 ratio), and the two

diastereomeric pairs with a cis relationship between the OH and

OEt groups were isolated pure.

H, 5-H), 1.26 (t, J_H,H= 7.1 Hz, 3 H, CH₃of OEt), 1.19 (d, J_H,H

= 6.2 Hz, 3 H, 6-Me) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 97.7

(CH), 66.3 (CH), 63.4 (CH₂), 63.3 (CH), 41.3 (t, J = 20.3 Hz, CH),

30.9 (CH₂), 20.6 (CH₃), 14.8 (CH₃) ppm. MS (EI): m/z (%) = 367

(62), 355 (87), 333 (60), 327 (61), 255 (64), 93 (58), 88 (58), 59 (100).

HRMS: m/z calcd. for C₁₀H₁₀O₂F₉([M – OEt]⁺) 333.0537; found

333.0550.

(2R*,3S*,4S*,6R*)-8b-I: IR (film): ν_max= 3499 (m), 2981 (s), 2937

˜

(s), 2877 (s), 1449 (m), 1378 (m), 1351 (m), 1328 (m), 1285 (m),

1236 (s), 1134 (s), 1098 (m), 1066 (m), 1041 (m), 966 (m), 940 (m),

910 (m), 893 (m), 880 (m), 857 (m), 804 (m), 734 (m), 717 (m), 698 (2R*,3R*,4R*,6S*)-8b-I: IR (film): ν_max= 3451 (m), 2980 (s), 2937

˜

1

(w), 673 (w) 619 (m) cm^–1. H NMR (200 MHz, CDCl₃, Me₄Si): δ

(m), 1450 (m), 1388 (m), 1354 (m), 1327 (m), 1286 (m), 1236 (s),

= 4.39 (d, J_H,H= 0.8 Hz, 1 H, 2-H), 4.04 (br. s, 1 H, 3-H), 4.01– 1167 (m), 1134 (s), 1079 (m), 1066 (m), 1021 (m), 985 (m), 952 (w),

3

3.94 (m, 1 H, 1 H of CH₂of OEt), 3.65–3.52 (m, 2 H, 1 H of CH₂917 (w), 895 (m), 857 (w), 788 (m), 748 (w), 733 (m), 716 (w), 696

1

of OEt and 6-H), 2.46–2.32 (m, 1 H, 4-H), 2.37 (d, ³J_H,H= 2.7 Hz,

(w), 690 (w) cm^–1. H NMR (200 MHz, CDCl₃, Me₄Si): δ = 4.72

2

3

1 H, OH), 1.86 (m, 1 H, 5-H), 1.63 (br. d, J_H,H= 13.2 Hz, 1 H,

(d, J_H,H= 1.2 Hz, 1 H, 2-H), 3.98–3.90 (m, 2 H, 3-H and 6-H),

3

5-H), 1.32 (d, J_H,H= 6.2 Hz, 3 H, 6-Me), 1.25 (t, J_H,H= 7.1 Hz,

3.79–3.72 (m, 1 H, 1 H of CH₂of OEt), 3.57–3.49 (m, 1 H, 1 H of

3 H, CH₃of OEt) ppm. ¹³C NMR (50 MHz, CDCl₃): δ = 100.2 CH₂of OEt), 2.93–2.81 (m, 1 H, 4-H), 2.04 (d, J_H,H= 8.3 Hz, 1

3

(CH), 70.3 (CH), 64.5 (CH₂), 63.5 (CH), 41.5 (t, J = 20.8 Hz, CH), H, 5-H), 1.82–1.63 (m, 2 H, 1 H of 5-H and OH), 1.24 (d, J_H,H

=

25.8 (CH₂), 21.0 (CH₃), 15.0 (CH₃) ppm. MS (EI): m/z (%) = 378

6.3 Hz, 3 H, 6-Me), 1.22 (t, ³J_H,H= 7.1 Hz, 3 H, CH₃of OEt) ppm.

(2), 359 (4), 333 (68), 317 (30), 303 (47), 286 (34), 274 (52), 255 (69), ¹³C NMR (50 MHz, CDCl₃): δ = 99.0 (CH), 64.0 (CH), 63.8 (CH),

226 (54), 206 (52), 145 (42), 103 (77), 69 (98), 57 (100). HRMS: m/z 63.0 (CH₂), 37.3 (t, J = 20.2 Hz, CH), 26.0 (CH₂), 21.2 (CH₃), 15.0

calcd. for C₁₀H₁₀O₂F₉, ([M – OEt]⁺) 333.0537; found 333.0545.

(CH₃) ppm. MS (EI): m/z (%) = 389 (100), 380 (35), 375 (51), 371

(28), 354 (19), 342 (33). HRMS: m/z calcd. for C₁₂H₁₅O₃F₉[M⁺]

378.0877; found 378.0890.

(2R*,3S*,4R*,6R*)-8b-I: IR (film): ν_max= 3445 (m), 2979 (s), 2934

˜

(s), 1448 (m), 1381 (m), 1354 (m), 1326 (m), 1303 (m), 1233 (s),

1168 (s), 1135 (s), 1108 (s), 1070 (s), 1025 (s), 975 (s), 951 (m), 892

(s), 951 (m), 892 (s), 866 (m), 840 (w), 821 (w), 799 (w), 766 (m),

2-Ethoxy-6-hexyl-4-(perfluorobutyl)tetrahydropyran-3-ol (2R*,3R*/

3S*,4R*/4S*,6R*)-8c-I): The compound was prepared from 0.16 g

748 (m), 728 (m), 701 (m), 689 (w), 663 (w), 650 (w) cm^–1. ¹H NMR (0.37 mmol) of (2R*,4R*/4S*,6R*)-12c-I with a 4R*/4S* ratio of

3

(200 MHz, CDCl₃, Me₄Si): δ = 4.70 (d, J_H,H= 2.3 Hz, 1 H, 2-H),

45:55. Solvent evaporation gave 0.14 g (86%) of (2R*,3R*/3S*,4R*/

4.23–4.19 (m, 1 H, 6-H), 4.02 (br. s, 1 H, 3-H), 3.92–3.84 (m, 1 H, 4S*,6R*)-8c-I as a yellowish liquid consisting of a mixture of four

1 H H of CH₂of OEt), 3.55–3.48 (m, 1 H, 1 H of CH₂of OEt), pairs of diastereomers. The isomeric composition was determined

1

3.08–2.96 (m, 1 H, 4-H), 2.41–2.33 (m, 1 H, 5-H), 2.29–2.19 (m, 1 by H NMR investigations of the product mixture before isolation

3

H, 5-H), 1.57 (br. d, J_H,H= 13.7 Hz, 1 H, OH), 1.38 (d, J_H,H

=

of the major isomers started, using the integrals of the anomeric

protons to determine the isomeric composition. The anomeric pro-

6.9 Hz, 3 H, 6-Me), 1.20 (t, ³J_H,H= 7.1 Hz, 3 H, CH₃of OEt) ppm.

¹³C NMR (50 MHz, CDCl₃): δ = 99.8 (CH), 67.4 (CH), 65.5 (CH), tons showed the following chemical shifts and relative intensities:

63.6 (CH₂), 33.4 (t, J = 20.2 Hz, CH), 23.7 (CH₂), 21.6 (CH₃), 14.8

4.83 ppm, 27% (3S*,4S*); 4.64 ppm, 5% (3R*,4R*); 4.69 ppm,

5828

www.eurjoc.org

Eur. J. Org. Chem. 2009, 5816–5831

4-Perfluoroalkylated Tetrahydropyran Derivatives

50% (3S*,4R*); 4.54 ppm, 18% (3R*,4S*). Separation and purifi-

cation were carried out by flash chromatography (hexane/ethyl ace-

tate in a 95:5 ratio), and the two diastereomeric pairs with a cis

relationship between the OH and OEt groups were isolated pure.

H, 4-H), 2.15–2.07 (m, 1 H, 5-H), 1.62–1.54 (m, 1 H, 5-H), 1.45–

1.25 (m, 10 H, 5 CH₂of hexyl), 1.25 (t, ³J_H,H= 7.0 Hz, 3 H, CH₃of

OEt), 0.93–0.87 (m, 3 H, CH₃of hexyl) ppm. ¹³C NMR (50 MHz,

CDCl₃): δ = 95.4 (CH), 68.2 (CH), 64.2 (CH), 63.4 (CH₂), 37.3 (t,

J = 20.6 Hz, CH), 31.8 (CH₂), 29.7 (CH₂), 29.1 (CH₂), 25.6 (CH₂),

25.0 (CH₂), 22.6 (CH₂), 15.0 (CH₃), 14.0 (CH₃) ppm. MS (EI): m/z

(%) = 447 (3) [M – 1], 403 (27), 382 (66), 367 (58), 363 (32), 345

(47), 336 (38), 317 (82), 313 (61), 289 (73), 167 (53), 241 (28), 207

(25), 195 (22), 128 (67), 110 (63), 95 (73), 85 (100). HRMS: m/z

calcd. for C₁₅H₂₀O₂F₉([M – OEt]⁺) 403.1320; found 403.1328.

(2R*,3S*,4R*,6R*)-8c-I: IR (film): ν_max= 3424 (br), 2959 (s), 2931

˜

(s), 2874 (s), 2860 (s), 1460 (m), 1380 (m), 1354 (m), 1304 (m), 1236

(s), 1221 (s), 1167 (m), 1135 (s), 1111 (s), 1067 (s), 1019 (s), 977

(w), 916 (w), 842 (w), 817 (w), 796 (w), 789 (w), 748 (m), 730 (m),

704 (w), 688 (w), 650 (w) cm^–1. ¹H NMR (200 MHz, CDCl₃,

3

Me₄Si): δ = 4.69 (d, J_H,H= 2.8 Hz, 1 H, 2-H), 4.00 (m, 1 H, 3-

H), 3.94–3.84 (m, 2 H, 1 H of CH₂of OEt and 6-H), 3.59–3.50 (m,

1 H, 1 H of CH₂of OEt), 3.00–2.88 (m, 1 H, 4-H), 2.32–2.20 (m,

(2R*,3S*,4R*,6S*)-8c-I: IR (film): ν_max= 3573 (m), 3491 (m), 2958

(s), 2932 (s), 2875 (s), 2860 (s), 1468 (m), 1459 (m), 1378 (m), 1353

˜

2 H, 1 H of 5-H and OH), 1.82–1.57 (m, 1 H, 5-H), 1.36–1.24 (m, (s), 1287 (m), 1236 (s), 1135 (s), 1060 (s), 928 (m), 879 (m), 785

3

10 H, 5 CH₂of hexyl), 1.20 (t, J_H,H= 7.1 Hz, 3 H, CH₃of OEt), (w), 745 (m), 732 (m), 707 (w), 665 (w), 642 (w) cm^–1. ¹H NMR

3

0.91–0.87 (m, 3 H, CH₃of hexyl) ppm. ¹³C NMR (50 MHz,

CDCl₃): δ = 100.5 (CH), 71.6 (CH), 66.5 (CH), 64.2 (CH₂), 57.7

(200 MHz, CDCl₃, Me₄Si): δ = 4.83 (d, J_H,H= 3.8 Hz, 1 H, 2-H),

3.87–3.76 (m, 2 H, 1 H of CH₂of OEt and 6-H), 3.76–3.70 (m, 1

(CH₂), 35.5 (CH₂), 34.4 (t, J = 20.0 Hz, CH), 31.8 (CH₂), 29.2 H, 3-H), 3.60–3.50 (m, 1 H, 1 H of CH₂of OEt), 2.83–2.64 (m, 1

3

(CH₂) 26.5 (CH₂), 22.5 (CH₂) 15.0 (CH₃), 13.9 (CH₃) ppm. MS

H, 4-H), 2.15 (d, J_H,H= 11.2 Hz, 1 H, 5-H), 1.86 (m, 1 H, 5-H),

(EI): m/z (%) = 447 (2) [M – 1], 429 (3), 410 (2), 403 (4), 374 (5), 1.51–1.39 (m, 3 H, OH and 1 CH₂of hexyl), 1.35–1.23 (m, 8 H, 4

3

367 (10), 363 (22), 345 (18), 336 (8), 217 (91), 299 (18), 289 (31),

267 (19), 128 (20), 112 (82), 88 (69), 83 (84), 70 (97), 55 (100).

HRMS: m/z calcd. for C₁₅H₂₀O₂F₉([M – OEt]⁺) 403.1320; found

403.1320.

CH₂of hexyl), 1.25 (t, J_H,H= 7.1 Hz, 3 H, CH₃of OEt), 0.90–

0.87 (m, 3 H, CH₃of hexyl) ppm. ¹³C NMR (50 MHz, CDCl₃): δ

= 97.5 (CH), 67.1 (CH), 66.5 (CH), 63.3 (CH₂), 41.5 (t, J =

20.1 Hz, CH), 35.2 (CH₂), 31.8 (CH₂), 29.4 (CH₂), 29.2 (CH₂), 25.5

(CH₂), 22.6 (CH₂), 14.9 (CH₃), 14.0 (CH₃) ppm. MS (EI): m/z (%)

= 447 (M-1, 3), 417 (30), 387 (53), 353 (58), 317 (78), 289 (63), 241

(68), 207 (23), 147 (63), 133 (82), 113 (85), 85 (100). HRMS: m/z

calcd. for C₁₇H₂₄O₃F₉([M – H]⁺) 447.1582; found 447.1568.

(2R*,3S*,4S*,6R*)-8c-I: IR (film): ν_max= 3499 (br), 2957 (s), 2930

˜

(s), 2859 (s), 1732 (w), 1672 (m), 1480 (m), 1467 (m), 1445 (m),

1379 (m), 1351 (m), 1293 (m), 1234 (s), 1134 (s), 1119 (s), 1067 (s),

965 (w), 941 (m), 902 (w), 883 (w), 858 (w), 804 (w), 789 (m), 734

(m), 720 (m), 698 (w), 589 (w), 665 (w) cm^–1. ¹H NMR (200 MHz, (2R*,3R*,4R*,6S*)-8c-I: IR (film): ν_max= 3447 (br), 2931 (s), 2859

˜

CDCl₃, Me₄Si): δ = 4.83 (s, 1 H, 2-H), 4.05 (m, 1 H, 3-H), 4.02–

(m), 1459 (m), 1379 (m), 1354 (m), 1235 (s), 1219 (s), 1167 (m),

3.93 (m, 1 H, 1 H of CH₂of OEt), 3.85–3.55 (m, 2 H, 1 H of CH₂1135 (s), 1063 (m), 1020 (m), 976 (w), 928 (w), 917 8 (w), 884 (w),

of OEt and 6-H), 2.47–2.00 (m, 3 H, 5-H and 4-H), 1.67–1.45 (m,

1 H, OH), 1.37–1.22 (m, 13 H, 5 CH₂of hexyl and CH₃of OEt),

0.90–0.87 (m, 3 H, CH₃of hexyl) ppm. ¹³C NMR (50 MHz,

CDCl₃): δ = 95.2 (CH), 72.8 (CH), 67.0 (CH), 64.5 (CH₂), 62.6

796 (w), 748 (w), 733 (m), 697 (w), 690 (w), 665 (w) cm^–1. ¹H NMR

3

(200 MHz, CDCl₃, Me₄Si): δ = 4.73 (d, J_H,H= 1.7 Hz, 1 H, 2-H),

3

3.98 (br. d, J_H,H= 8.3 Hz, 1 H, 3-H), 3.86–3.70 (m, 2 H, 1 H of

CH₂of OEt and 6-H), 3.62–3.48 (m, 1 H, 1 H of CH₂of OEt),

(CH₂), 41.6 (t, J = 21.6 Hz, CH), 35.4 (CH₂), 31.8 (CH₂), 29.3 2.91 (m, 1 H, 4-H), 2.29–1.60 (m, 3 H, 5-H and OH), 1.48–1.21

(CH₂), 25.7 (CH₂), 22.6 (CH₂), 15.3 (CH₃), 14.0 (CH₃) ppm. MS (m, 13 H, 5 CH₂of hexyl and CH₃of OEt), 0.91–0.87 (m, 3 H,

(EI): m/z (%) = 447 (3), 429 (4), 403 (22), 374 (28), 356 (30), CH₃of hexyl) ppm. ¹³C NMR (50 MHz, CDCl₃): δ = 98.9 (CH),

336 (62), 317 (88), 299 (72), 289 (82), 267 (40), 241 (28), 207 (30),

137 (60), 128 (66), 116 (88), 84 (100). HRMS: m/z calcd. for

C₁₅H₂₀O₂F₉([M – OEt]⁺) 403.1320; found 403.1317.

67.6 (CH), 64.4 (CH), 62.9 (CH₂), 37.5 (t, J = 21.1 Hz, CH), 35.7

(CH₂), 31.8 (CH₂), 29.7 (CH₂), 29.2 (CH₂), 25.4 (CH₂), 22.6 (CH₂),

14.9 (CH₃), 14.0 (CH₃) ppm. MS (EI): m/z (%) = 448 (22), 447

(100), 442 (25), 431 (22). HRMS: m/z calcd. for C₁₇H₂₅O₃F₉[M⁺]

448.1660; found 448.1630.

2-Ethoxy-6-hexyl-4-(perfluorobutyl)tetrahydropyran-3-ol [(2R*,3R*/

3S*,4R*/4S*,6S*)-8c-I]: The compound was prepared from 0.36 g

(0.81 mmol) of (2R*,4R*/4S*,6S*)-12c-I with a 4R*/4S* ratio of

35:65. Solvent evaporation gave 0.34 g (92%) of (2R*,3R*/3S*,4R*/

2-Ethoxy-4-perfluorobutyl-6-phenyltetrahydropyran-3-ol [(2R*,3R*/

3S*,4R*/4S*,6S*)-8d-I]: The compound was prepared from 0.24 g

4S*,6S*)-8c-I as a yellowish liquid consisting of a mixture of three (0.55 mmol) of (2R*,4R*/4S*,6S*)-12d-I with a 4R*/4S* ratio of

pairs of diastereomers. The isomeric composition was determined

by H NMR investigations of the product mixture before isolation

of the major isomers started, using the integrals of the anomeric

protons to determine the isomeric composition. The anomeric pro-

tons showed the following chemical shifts and relative intensities:

50:50. Solvent evaporation gave 0.21 g (87%) of (2R*,3R*/3S*,4R*/

4S*,6S*)-8d-I as a yellowish liquid consisting of a mixture of two

pairs of diastereomers. The isomeric composition was determined

by H NMR investigations of the product mixture before isolation

of the major isomers started, using the integrals of the anomeric

1

4.83 ppm, 55% (3S*,4R*); 4.73 ppm, 10% (3R*,4R*); 4.67 ppm, protons to determine the isomeric composition. The anomeric pro-

35% (3S*,4S*); no signal due to the (3R*,4S*) isomer was ob-

served. Separation and purification were carried out by flash

chromatography (hexane/ethyl acetate in a 95:5 ratio), and all the

three diastereomeric pairs were isolated pure.

tons showed the following chemical shifts and relative intensities:

5.01 ppm, 22% (3S*,4R*); 4.58 ppm, 78% (3S*,4S*); no signals

due to the (3R*,4R*) and (3R*,4S*) diastereomeric pairs were ob-

served. Separation and purification were carried out by flash

chromatography (hexane/ethyl acetate in a 90:10 ratio), and both

diastereomeric pairs, with a cis relationship between the OH and

EtO groups, were isolated pure.

(2R*,3S*,4S*,6S*)-8c-I: IR (film): ν_max= 3608 (m), 4583 (m), 3564

˜

(m), 2959 (s), 2931 (s), 2960 (s), 1462 (m), 1379 (m), 1351 (m), 1290

(m), 1235 (s), 1168 (m), 1134 (s), 1061 (m), 1031 (m), 805 (w), 728

(w), 711 (w), 665 (w) cm^–1. ¹H NMR (200 MHz, CDCl₃, Me₄Si): δ (2R*,3S*,4S*,6S*)-8d-I: IR (film): ν_max= 3500 (m), 2093 (w), 3066

˜

3

= 4.67 (d, J_H,H= 3.7 Hz, 1 H, 2-H), 4.26 (m, 1 H, 3-H), 4.08 (m,

1 H, 1 H of CH₂of OEt), 3.95–3.84 (m, 1 H, 6-H), 3.65–3.57 (m,

1 H, 1 H of CH₂of OEt), 2.81 (br. s, 1 H, OH), 2.54–2.40 (m, 1

(w), 3034 (w), 2980 (m), 2932 (m), 2874 (m), 1497 (m), 1455 (m),

1351 (m), 1308 (m), 1295 (m), 1236 (s), 1268 (m), 1134 (s), 1061

(s), 1013 (s), 970 (w), 940 (m), 911 (m), 884 (m), 829 (w), 818 (w),

Eur. J. Org. Chem. 2009, 5816–5831

www.eurjoc.org

5829

S. Valdersnes, L. K. Sydnes

FULL PAPER

800 (w), 788 (w), 749 (m), 735 (m), 720 (m), 700 (s), 677 (w), 634 (52), 59 (75). HRMS: m/z calcd. for C₁₇H₁₇O₃F₉[M⁺] 440.1034;

1

(w) cm^–1. H NMR (200 MHz, CDCl₃, Me₄Si): δ = 7.42–7.28 (m, found 440.1053.

3

5 H, phenyl), 4.58 (s, 1 H, 2-H), 4.51 (br. d, J_H,H= 11.4 Hz, 1 H,

(2R*,3S*,4S*,6R*)-8d-I: IR (film): ν_max= 3582 (m), 3444 (m), 3089

˜

6-H), 4.14 (br. s, 1 H, 3-H), 4.04–3.96 (m, 1 H, 1 H of CH₂of

OEt), 3.69–3.60 (m, 1 H, 1 H of CH₂of OEt), 2.68–2.52 (m, 1 H,

4-H), 2.52 (br. s, 1 H, OH), 2.32–2.13 (m, 1 H, 5-H), 1.89 (br. d,

(w), 3064 (w), 3031 (w), 2928 (s), 2873 (m), 2856 (m), 1496 (m),

1453 (m), 1403 (m), 1375 (m), 1343 (m), 1235 (s), 1219 (m), 1185

(m), 1163 (m), 1135 (s), 1112 (m), 1050 (s), 1028 (s), 1003 (m), 944

(w), 910 (w), 893 (w), 845 (w), 798 (w), 756 (m), 699 (s), 636 (m)

cm^–1. ¹H NMR (200 MHz, CDCl₃, Me₄Si): δ = 7.40–7.30 (m, 5 H,

3

²J_H,H= 13.2 Hz, 1 H, 5-H), 1.25 (t, J_H,H= 7.0 Hz, 3 H, CH₃of

OEt) ppm. ¹³C NMR (50 MHz, CDCl₃): δ = 140.4 (C), 128.5 (2

CH), 128.0 (CH), 125.9 (2 CH), 100.7 (CH), 76.0 (CH), 64.6 (CH₂),

64.2 (CH), 41.9 (t, J = 21.1 Hz, CH), 26.3 (CH₂), 15.0 (CH₃) ppm.

MS (EI): m/z (%) = 439 (2), 395 (18), 366 (73), 348 (87), 335 (90),

317 (100), 287 (48), 272 (38), 116 (39), 105 (92), 89 (46), 59 (30).

HRMS: m/z calcd. for C₁₅H₁₂O₂F₉([M – OEt]⁺) 395.0694; found

395.0706.

3

phenyl), 4.94 (d, J_H,H= 3.6 Hz, 1 H, 2-H), 4.72 (dd, J_H,H= 1.8,

³J_H,H= 11.0 Hz, 1 H, 6-H), 3.90–3.83 (m, 1 H, 1 H of CH₂of

OEt), 3.80–3.71 (m, 1 H, 3-H), 3.59–3.51 (m, 1 H, 1 H of CH₂of

OEt), 2.67–2.52 (m, 1 H, 4-H), 2.33–2.18 (m, 3 H, 5-H and OH),

3

1.27 (t, J_H,H= 7.0 Hz, 3 H, CH₃of OEt) ppm. ¹³C NMR

(50 MHz, CDCl₃): δ = 141.6 (C), 128.4 (2 CH), 127.6 (CH), 126.1

(2 CH), 98.4 (CH), 70.3 (CH), 67.8 (CH), 63.3 (CH₂), 29.7 (CH),

28.0 (CH₂), 15.2 (CH₃) ppm. MS (EI): m/z (%) = 440 (2), 392 (3),

375 (3), 177 (12), 133 (42), 103 (34), 89 (100), 73 (78), 59 (93).

HRMS: m/z calcd. for C₁₅H₁₂O₂F₉([M⁺– OEt]) 395.0694; found

395.0691.

(2R*,3S*,4R*,6S*)-8d-I: IR (film): ν_max= 3444 (m), 3066 (w), 3034

˜

(w), 2979 (m), 2929 (m), 1497 (w), 1455 (m), 1377 (m), 1354 (m),

1322 (m), 1295 (m), 1234 (s), 1166 (m), 1134 (s), 1068 (m), 1049

(m), 1029 (m), 980 (w), 961 (w), 906 (w), 848 (w), 816 (w), 795 (w),

748 (m), 735 (w), 721 (m), 699 (m) cm^–1. ¹H NMR (200 MHz,

CDCl₃, Me₄Si): δ = 7.40–7.29 (m, 5 H, phenyl), 5.01 (m, 1 H, 6-

H), 4.83 (m, 1 H, 2-H), 4.06 (br. s, 1 H, 3-H), 3.63–3.55 (m, 1 H,

1 H of CH₂of OEt), 3.45–3.67 (m, 1 H, 1 H of CH₂of OEt), 3.22–

3.10 (m, 1 H, OH), 2.50–2.43 (m, 1 H, 4-H), 2.33–2.17 (m, 2 H, 5-

2-Ethoxy-6,6-dimethyl-4-(perfluorobutyl)tetrahydropyran-3-ol

[(2R*,3R*/3S*,4R*/4S*)-8e-I]: The compound was prepared from

0.39 g (1.00 mmol) of (2R*,4R*/4S*)-12e-I with a 4R*/4S* ratio of

15:85. Solvent evaporation gave 0.35 g (89%) of (2R*,3R*/3S*,4R*/

4S*)-8e-I as a yellowish liquid consisting of a mixture of four pairs

of diastereomers. The isomeric composition was determined by ¹H

NMR investigations of the product mixture before isolation of the

major isomers started, using the integrals of the anomeric protons

to determine the isomeric composition. The anomeric protons

showed the following chemical shifts and relative intensities:

4.80 ppm, 73% (3S*,4R*); 4.73 ppm, 11% (3R*,4R*); 4.57 ppm,

12% (3S*,4S*); 4.65 ppm, 4% (3R*,4S*). Separation and purifica-

tion were carried out by flash chromatography (hexane/ethyl ace-

tate in a 85:15 ratio), and the two diastereomeric pairs with a trans

relationship between the perfluorobutyl and OEt groups were iso-

lated pure.

3

H), 0.87 (t, J_H,H= 7.0 Hz, 3 H, CH₃of OEt) ppm. ¹³C NMR

(50 MHz, CDCl₃): δ = 165.3 (C), 128.4 (2 CH), 127.4 (CH), 126.1

(2 CH), 100.7 (CH), 71.0 (CH), 67.4 (CH), 64.2 (CH₂), 35.8 (CH),

24.7 (CH₂), 14.6 (CH₃) ppm. MS (EI): m/z (%) = 440 (2), 402 (12),

395 (8), 349 (22), 335 (36), 317 (23), 177 (14), 146 (47), 128 (49),

116 (93), 103 (95), 88 (100), 60 (94). HRMS: m/z calcd. for

C₁₇H₁₇O₃F₉[M⁺] 440.1034; found 440.1036.

2-Ethoxy-4-(perfluorobutyl)-6-phenyltetrahydropyran-3-ol

[(2R*,

3R*/3S*,4R*/4S*,6R*)-8d-I]: The compound was prepared from

0.25 g (0.56 mmol) of (2R*,4R*/4S*,6R*)-12d-I with a 4R*/4S* ra-

tio of 30:70. Solvent evaporation gave 0.21 g (84%) of (2R*,3R*/

3S*,4R*/4S*,6R*)-8d-I as a yellowish liquid consisting of a mixture

of two pairs of diastereomers. The isomeric composition was deter-

mined by ¹H NMR investigations of the product mixture before

isolation of the major isomers started, using the integrals of the

anomeric protons to determine the isomeric composition. The an-

omeric protons showed the following chemical shifts and relative

intensities: 5.00 ppm, 78% (3S*,4R*); 4.94 ppm, 22% (3S*,4S*);

no signals due to the (3R*,4R*) and (3R*,4S*) diastereomeric pairs

were observed. Separation and purification were carried out by

flash chromatography (hexane/ethyl acetate in a 90:10 ratio), and

both diastereomeric pairs, with a cis relationship between the OH

and EtO groups, were isolated pure.

(2R*,3S*,4R*)-8e-I: IR (film): ν_max= 3564 (m), 3495 (m), 2980 (s),

˜

2935 (s), 2909 (s), 1454 (m), 1372 (m), 1351 (m), 1315 (m), 1215

(s), 1132 (s), 1070 (s), 983 (m), 942 (m), 885 (m), 808 (w), 798 (w),

1

736 (m), 703 (m) cm^–1. H NMR (200 MHz, CDCl₃, Me₄Si): δ =

4.80 (d, ³J_H,H= 4.0 Hz, 1 H, 2-H), 3.95–3.87 (m, 1 H, 1 H of CH₂

3

of OEt), 3.83 (dd, J_H,H= 4.0, J_H,H= 10.5 Hz, 1 H, 3-H), 3.55–

3.48 (m, 1 H, 1 H of CH₂of OEt), 2.91–2.78 (m, 1 H, 4-H), 2.32

(br. s, 1 H, OH), 1.85 (m, ²J_H,H= 13.5 Hz, 1 H, 5-H), 1.62 (t, ²J_H,H

= 13.5 Hz, 1 H, 5-H), 1.38 (s, 3 H, 6-Me), 1.25 (s, 3 H, 6-Me), 1.24

3

(t, J_H,H= 7.0 Hz, 3 H, CH₃of OEt) ppm. ¹³C NMR (50 MHz,

CDCl₃): δ = 98.0 (CH), 71.8 (C), 67.0 (CH), 63.7 (CH₂), 38.5 (t, J

= 20.5 Hz, CH), 34.7 (CH₂), 31.5 (CH₃), 26.4 (CH₃), 14.7 (CH₃)

ppm. MS (EI): m/z (%) = 391 (1), 377 (53), 359 (58), 348 (72), 336

(71), 309 (55), 301 (80), 281 (84), 241 (84), 227 (72), 195 (56), 145

(58), 131 (77), 93 (94), 71 (100). HRMS: m/z calcd. for C₁₁H₁₂O₂F₉

([M – OEt]⁺) 347.0694; found 347.0688.

(2R*,3S*,4R*,6R*)-8d-I: IR (film): ν

= 3565 (m), 2388 (m),

˜

max

3092 (w), 3067 (w), 3035 (w), 2979 (m), 2931 (m), 1498 (m), 1454

(m), 1403 (m), 1352 (m), 1236 (s), 1135 (s), 1057 (s), 1030 (w), 982

(w), 956 (w), 937 (m), 912 (w), 884 (w), 867 (w), 854 (w), 841 (w),

782 (w), 760 (m), 747 (m), 730 (m), 665 (w), 649 (w) cm^–1. ¹H NMR

(200 MHz, CDCl₃, Me₄Si): δ = 7.42–7.29 (m, 5 H, phenyl), 5.00

(d, ³J_H,H= 3.6 Hz, 1 H, 2-H), 4.83 (br. d, ³J_H,H= 11.4 Hz, 1 H, 6- (2R*,3R*,4R*)-8e-I: IR (film): ν

= 3423 (s), 2973 (s), 2924 (m),

˜

max

3

H), 3.99 (dt, J_H,H= 3.6, J_H,H= 10.8 Hz, 1 H, 3-H), 3.90–3.80

1483 (m), 1376 (m), 1322 (m), 1234 (s), 1137 (s), 1073 (m), 1054

(m, 1 H, 1 H of CH₂of OEt), 3.65–3.55 (m, 1 H, 1 H of CH₂of (m), 1029 (m), 976 (m), 937 (m), 885 (m), 851 (w), 800 (m) cm^–1.

3

OEt), 3.00–2.83 (m, 1 H, 4-H), 2.22 (d, ³J_H,H= 11.4 Hz, 1 H, OH), ¹H NMR (200 MHz, CDCl₃, Me₄Si): δ = 4.73 (d, J_H,H= 1.9 Hz,

3

2.11 (m, 1 H, 5-H), 1.76 (m, 1 H, 5-H), 1.28 (t, J_H,H= 7.0 Hz, 3 1 H, 2-H), 4.03 (s, 1 H, 3-H), 3.89–2.81 (m, 1 H, 1 H of CH₂of

H, CH₃of OEt) ppm. ¹³C NMR (50 MHz, CDCl₃): δ = 140.3 (C),

128.6 (2 CH), 128.1 (CH), 126.1 (2 CH), 98.0 (CH), 69.4 (CH),

OEt), 3.53–3.45 (m, 1 H, 1 H of CH₂of OEt), 3.06–2.93 (m, 1 H,

2

3

4-H), 2.09 (t, J_H,H= J_H,H= 13.5 Hz, 1 H, 5-H), 1.83 (br. s, 1 H,

3

2

66.3 (CH), 63.8 (CH₂), 41.7 (t, J = 20.5 Hz, CH), 31.5 (CH₂), 15.0 OH), 1.62 (dd, J_H,H= 2.7, J_H,H= 13.5 Hz, 1 H, 5-H), 1.39 (s, 3

3

(CH₃) ppm. MS (EI): m/z (%) = 440 (4), 421 (10), 393 (38), 375

(32), 365 (27), 347 (24), 161 (22), 133 (30), 104 (100), 91 (81), 73

H, 6-Me), 1.31 (s, 3 H, 6-Me), 1.19 (t, J_H,H= 7.0 Hz, 3 H, CH₃

of OEt) ppm. ¹³C NMR (50 MHz, CDCl₃): δ = 100.0 (CH), 72.2

5830

www.eurjoc.org

Eur. J. Org. Chem. 2009, 5816–5831

4-Perfluoroalkylated Tetrahydropyran Derivatives

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(C), 64.3 (CH), 63.2 (CH₂), 34.5 (t, J = 19.8 Hz, CH), 32.2 (CH₃),

29.1 (CH₂), 26.8 (CH₃), 14.7 (CH₃) ppm.

2-Ethoxy-4-(perfluorobutyl)-1-oxaspiro[5.5]undec-3-ol [(2R*,3R*/

3S*,4R*/4S*)-8f-I]: The compound was prepared from 0.43 g

(1.00 mmol) of (2R*,4R*/4S*)-12f-I with a 4R*/4S* ratio of 20:80.

Solvent evaporation gave 0.38 g (88%) of (2R*,3R*/3S*,4R*/4S*)-

8f-I as a yellowish liquid consisting of a mixture of three pairs of

diastereomers. The isomeric composition was determined by ¹H

NMR investigations of the product mixture before isolation of the

major isomers started, using the integrals of the anomeric protons

to determine the isomeric composition. The anomeric protons

showed the following chemical shifts and relative intensities:

4.81 ppm, 80% (3S*,4R*); 4.61 ppm, 3% (3R*,4S*); 4.56 ppm,

17% (3S*,4S*); no signal due to the (3R*,4R*) isomer was ob-

served. Separation and purification were carried out by flash

chromatography (hexane/ethyl acetate in a 90:10 ratio), and the

most abundant diastereomeric pair, with a cis relationship between

the OH and OEt groups, was isolated pure.

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˜

1484 (w), 1450 (m), 1404 (m), 1374 (m), 1352 (m), 1317 (m), 1293

(m), 1236 (s), 1134 (s), 1063 (s), 998 (m), 964 (m), 918 (m), 880

(m), 745 (m), 737 (m), 696 (m) cm^–1. ¹H NMR (200 MHz, CDCl₃,

[5]

3

Me₄Si): δ = 4.81 (d, J_H,H= 4.0 Hz, 1 H, 2-H), 4.01–3.93 (m, 1 H,

3

1 H of CH₂of OEt), 3.84 (dd, J_H,H= 4.0, J_H,H= 10.3 Hz, 1 H,

3-H), 3.63–3.53 (m, 1 H, 1 H of CH₂of OEt), 2.87–2.73 (m, 1 H,

4-H), 2.41 (br. s, 1 H, OH), 2.05–1.96 (m, 2 H, 5-H), 1.79–1.34 (m,

3

10 H, 5 CH₂of cyclohexyl), 1.23 (t, J_H,H= 7.0 Hz, 3 H, CH₃of

OEt) ppm. ¹³C NMR (50 MHz, CDCl₃): δ = 98.1 (CH), 73.2 (C),

67.3 (CH), 64.6 (CH₂), 40.1 (CH₂), 38.3 (t, J = 20.1 Hz, CH), 35.4

(CH₂), 32.7 (CH₂), 25.8 (CH₂), 22.5 (CH₂), 22.2 (CH₂), 14.7 (CH₃)

ppm. MS (EI): m/z (%) = 432 (18) [M⁺], 387 (8), 369 (10), 358 (15),

343 (22), 167 (46), 141 (72), 138 (91), 109 (85), 97 (95), 69 (100).

HRMS: m/z calcd. for C₁₆H₂₁O₃F₉[M⁺] 432.1347; found 432.1351.

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Acknowledgments

Financial support (to L. K. S.) from the Research Council of Nor-

way is highly appreciated. Recording of mass spectra by Dr. Dag

Egeberg at Norwegian University of Environmental and Biological

Sciences is highly appreciated. Institut für Organische Chemie, Uni-

versität Wien, Austria and Professor Udo H. Brinker are gratefully

acknowledged for excellent working conditions during a recent sab-

batical stay.

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Received: June 20, 2009

Published Online: September 30, 2009

Eur. J. Org. Chem. 2009, 5816–5831

www.eurjoc.org

5831

Article Doi

Preparation of 2-Ethoxy-3-hydroxy-4-(perfluoroalkyl)tetrahydropyran Derivatives from Substituted 4-Ethoxybut-3-en-1-ols

DOI: 10.1002/ejoc.200900687

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