Isomerization of cyclic ethers having a carbonyl functional group: New entries into different heterocyclic compounds

Tetrahedron 58 (2002) 7049–7064

Isomerization of cyclic ethers having a carbonyl functional group:

new entries into different heterocyclic compounds

*

Shigeyoshi Kanoh, Masashi Naka, Tomonari Nishimura and Masatoshi Motoi

Department of Industrial Chemistry, Faculty of Engineering, Kanazawa University, Kodatsuno, Kanazawa 920-8667, Japan

Received 19 March 2002; accepted 23 May 2002

Abstract—Oxiranes (epoxides) and oxetanes having a carbonyl functional group are chemoselectively isomerized to different heterocyclic

compounds via Lewis acid-promoted 1,6- and 1,7-intramolecular nucleophilic attacks of the carbonyl oxygen on the electron-deﬁcient

carbon neighboring the oxonium oxygen: for example, cyclic imides to bicyclic acetals, esters to bicyclic orthoesters, sec-amides to 4,5-

dihydrooxazole or 5,6-dihydro-4H-1,3-oxazines, and tert-amides to bicyclic acetals or azetidines. The intramolecular attack of a 1,5-

positioned carbonyl oxygen predominantly results in a propagating-end isomerization polymerization. On the other hand, cyclic ethers

having a 1,8- or farther positioned carbonyl group undergo conventional ring-opening polymerization. A tetrahydrofuran (oxolane) ring does

1. Introduction

polymerization involves the isomerization of the starting

oxetanes to bicyclic compounds as the real monomers. We

have intended to develop this isomerization process to a new

synthetic method for preparing various heterocyclic com-

pounds from oxetanes by suppressing the polymerization.

Strained cyclic ethers are especially useful intermediates in

synthetic organic chemistry, because of their high reactivity

and the variety of their reactions.¹Moreover, epoxide/

oxirane, oxetane, and tetrahydrofuran/oxolane are of major

interest in the ﬁeld of polymer chemistry.²The cationic

ring-opening polymerization of these cyclic ethers has been

examined at a level of detail comparable to the polymeriz-

ation of familiar vinyl monomers such as styrene and

(meth)acrylates. As shown in Scheme 1, it is generally

known that the cationic ring-opening polymerization

proceeds in two modes: the active chain end mechanism

in usual cases, or the activated monomer mechanism in

elaborated cases.³

This paper describes the Lewis acid-promoted isomerization

of oxiranes and oxetanes having a carbonyl functional group

to different heterocyclic compounds, as outlined in

Scheme 2. The chemoselective isomerization affords

bicyclic acetals, bicyclic orthoesters, 4,5-dihydrooxazole,

5,6-dihydro-4H-1,3-oxazines, and azetidines, depending on

the nature of the starting carbonyl functional groups. The

formation of azetidines appears as if the endocyclic oxygen

is exchanged with the exocyclic nitrogen, but the rearrange-

ment proceeds by an interesting double isomerization

involving ring expansion to bicyclic acetals and subsequent

ring contraction to different four-membered azetidines. In

addition, these results present a new elementary reaction

process in the cationic ring-opening polymerization of

cyclic ethers.

Among cationically polymerizable cyclic ethers, oxetanes

have an advantage in that various chemical modiﬁcations

are permitted under neutral or basic conditions and the

introduction of bulky substituents causes little or no

decrease of polymerizability. We have previously reported

the preparation and application of various functionalized

poly(oxetane)s.⁴Because of the high nucleophilicity of

oxetanyl oxygen,²the ring-opening polymerization of

substituted oxetanes by the active chain end mechanism

proceeds readily in the presence of common functional

groups including vinyl, halo, ether, acetal, ketone, ester,

amide, imide, azo, nitro, nitrile, sulfonate, etc. Notably, we

found that the polymerization of oxetanes having a carbonyl

functional group at the 3-position gives unusual polymers

with cyclic structures in the main chain.^5–7This new type of

Keywords: oxetanes; epoxides; carbonyl compounds; isomerization.

*

Corresponding author. Fax: þ81-76-234-4800;

e-mail: kanoh@t.kanazawa-u.ac.jp

Scheme 1. Cationic ring-opening polymerization of cyclic ethers.

PII: S0040-4020(02)00701-9

7050

S. Kanoh et al. / Tetrahedron 58 (2002) 7049–7064

prior to polymerization, and the resulting bicyclic acetals

polymerize cationically in situ by single ring opening at low

temperature (usually at room temperature and below) or by

double ring opening at high temperature (usually above

808C). This new mode of polymerization involving such an

isomerization has been termed ‘monomer-isomerization

polymerization’.⁵

The above isomerization of oxetanes can provide a new

entry into bicyclic acetals and a useful method for breaking

the symmetry of cyclic imides. However, the yields of

isomerization products were more or less compensated by

the subsequent polymerization of these as the real

monomers. Fortunately, it was found that the single ring-

opening polymerization is an equilibrium process, although

double ring-opening polymerizations are virtually

irreversible. The equilibrium constant (K ) of the single

ring-opening polymerization of a bicyclic acetal can be

deﬁned as follows:

½polyacetal

Scheme 2. Lewis acid-promoted isomerization of small cyclic ethers

having a carbonyl functional group.

e

21

e

K ¼

¼ ½bicyclic acetal

e

½bicyclic acetal ½polyacetal

e

ð1Þ

If no side reaction occurs, the following mass balance can be

established:

2. Results and discussion

2.1. Isomerization of oxetanes having a carbonyl

functional group

½bicyclic acetal ¼ ½oxetane₀2 ½polyacetal

ð2Þ

K is dependent on temperature, and hence ln K can be

e

2.1.1. Oxetane imides. Recently we have reported the

cationic polymerization of oxetanes having a cyclic imide

group at the 3-position (Scheme 3).^5,6The polymerization

gave two kinds of polymers with different structures

depending on the temperature: one is a polyacetal contain-

ing tetrahydro-1,3-oxazine rings in the main chain, and the

other is a polyether carrying pendant imide groups. The

latter appears as if it is formed via a straightforward ring

opening. However, both polymerizations can be distin-

guished from conventional cationic ring-opening

polymerization. The oxetane imides undergo isomerization

expressed as Dainton’s equation:⁸

ln K ¼ 2ln½bicyclic acetal ¼ DS8=R 2 DH8=RT

ð3Þ

e

where T, DH8, and DS8 are the polymerization temperature

in degrees Kelvin, and the standard enthalpy and entropy

changes of polymerization, respectively. As already

reported,^5,6the plots of ln[bicyclic acetal] vs T ²¹showed

good linear correlations in low-temperature polymeriz-

ations. This clearly indicated that equilibrium exists

between bicyclic acetals and polyacetals via ring-opening

polymerization and ring-closure depolymerization. The

maximum yield of an isomerization product will be

achieved when the equilibrium is completely shifted to the

monomer state. Eqs. (1) and (2) imply that K is equal to

[oxetane]²₀¹in such an equilibrium, and thus Eq. (3) gives a

certain equilibrium temperature, which is called the ceiling

temperature (T_c) in the ﬁeld of polymer chemistry.

We examined the Lewis acid-promoted isomerization of

some oxetane imides (1a–h) (Scheme 4) and the results are

shown in Table 1. Lewis acids and Brønsted acids, such as

CF₃SO₃H and d-camphorsulphonic acid, were effective

catalysts. The isomerization took place above 2108C and,

of course, proceeded more rapidly at higher temperature.

However, isomerization at room temperature and below was

sometimes accompanied by the single ring-opening

polymerization, and above 808C the double-ring opening

polymerization of 2 took place. To obtain 2 in high yields, it

was necessary to use weak Lewis acids, such as trimethyl-

aluminium (Me₃Al) and methylaluminium bis(2,6-di-tert-

butyl-4-methylphenoxide) (MAD), which initiated neither

polymerization.⁹The nature of the cyclic imide (R²) and the

steric demand of the 3-R¹substituent exerted little or no

effect on the isomerization yield. The choice of catalyst was

Scheme 3. Monomer-isomerization polymerization of oxetane imides (1).

S. Kanoh et al. / Tetrahedron 58 (2002) 7049–7064

7051

Scheme 4. Isomerization of oxetane imides (1).

Table 1. Isomerization of oxetane imides (1) to bicyclic acetals (2) under the optimized conditions

Entry

Substrate

R¹

Lewis acid^a

Conditions^b(solvent, 8C, h)

Yield^c(%)

R²

1

2

3

4

5

6

7

8

9

1a

1b

1c

1d

1e

1f

Me

Phthalimide

Maleimide

Succinimide

Glutarimide

Phthalimide

Me₃Al

MAD^d

PhCl, 120, 12

PhCl, 120, 24

PhCl, 120, 3

PhCl, 120, 12

PhCl, 120, 3

CH₂Cl₂,^g35, 72

PhCl,^h80, 10 min

PhCl, 120, 12

96

91

73

74

84

77

74

82

Me

Et

CH₂Ph

Ph

i Pr

BnTA^e

TMSOTf^f

Me₃Al

BF₃·Et₂O

CF₃SO₃H

Me₃Al

1g

1h

a

5 mol%.

b

c

d

e

f

1 (0.5 g) in 2.0 mL of the solvent.

Isolated yield of 2.

Methylaluminium bis(2,6-di-tert-butyl-4-methylphenoxide).

1-Benzyltetrahydrothiophenium hexaﬂuoroantimonate.

Trimethylsilyl triﬂuoromethanesulfonate.

g

h

7.5 mL.

3.5 mL.

not so crucial since the single ring-opening polymerization

is an equilibrium phenomenon. If the polyacetals are

formed, dilution of the reaction mixture allows regeneration

of 2 through depolymerization.^5,6Selecting the appropriate

concentration of 1 was rather critical for avoiding

polymerization, namely, the isomerization temperature

ought to be higher than the T_cunder the experimental

conditions. The concentration can be predicted from the T_c,

which has been estimated to be 214 to 958C under the

standard conditions (1.0 mol L²¹in CH₂Cl₂).^5,6For

example, the reaction of 1f with BF₃·Et₂O at 358C (entry

7) proceeded without polymerization in a relatively dilute

solution of CH₂Cl₂(0.2 mol L²¹). For the most part 2a–h

showed sufﬁcient stability for chromatographic manipu-

lation and recrystallization, except that 2d was relatively

sensitive toward moisture. On the other hand, 2a–h were

readily hydrolyzed in aqueous THF containing a small

amount of ca. 1 M HCl at room temperature, to give

2-(imidomethyl-substituted)propane-1,3-diols 3a–h almost

quantitatively.

carbonyl.⁶The intramolecular nucleophilic attack of the

carbonyl oxygen on the a-carbon of the oxetane oxonium

cation is entropically preferred over the intermolecular

attack of the other oxetane molecule. Ring closure of the

resulting 1,3-oxazin-2-ylium cation then affords 2 (oxonium

form). Oxetanes having a phthalimide group separated by

longer spacers such as CH₂O(CH₂)_n(n¼4 and 6) did not

isomerize under the inﬂuence of BF₃·Et₂O, but polymerized

in the conventional ring-opening manner¹⁰to give the

corresponding polyether. Detailed X-ray crystallographic

1

and H NMR spectroscopic analyses of 2a–d revealed an

interesting difference between the bicyclic structures, as

The isomerization likely involves coordination of Lewis

acid (LA) to the oxetanyl oxygen rather than the imide-

Figure 1. Molecular modes of 2a and 2d based on X-ray crystallographic

data.

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S. Kanoh et al. / Tetrahedron 58 (2002) 7049–7064

Scheme 5. Isomerization of oxetane esters (4).

can occur in a limited temperature range between T_cof the

equilibrium single-ring opening polymerization and the

lowest temperature needed for the double-ring opening

polymerization. Pseudo ﬁrst-order rate constants (k_i) of the

isomerizations of 1 and 4 were determined by NMR analysis

using 5 mol% of BF₃·Et₂O in CDCl₃at 258C.^6,7The k_i

values showed that 4 isomerized more slowly than 1 did.

However, 4 was sufﬁciently reactive to permit the slow

isomerization even at 2788C, while 1 did not isomerize

below 2108C. It is most likely that the isomerization of 4

also proceeds by 1,6-intramolecular nucleophilic attack of

the ester-carbonyl oxygen. The similarity between the yields

of 5c and 5f (91% for X in R²¼NO₂, and 78% for X in

R²¼OCH₃) suggests that the stability of a 1,3-dioxolan-2-

ylium cation intermediate can overcome the strong electron-

withdrawing nature of the 4-nitrophenyl group. Moisture-

sensitive 5a–h were hydrolyzed under neutral conditions in

aqueous THF at 358C, to give 2-(ester-substituted)propane-

1,3-diols (6a–h) almost quantitatively. In addition, lower

aliphatic acid orthoesters, such as 5a and 5b, underwent

rapid hydrolysis even in air at room temperature.⁷

Scheme 6. Isomerization of other oxetane esters (4).

shown in Fig. 1.^5,6In the cases of 2a–c, the bicycles

attached to a ﬁve-membered ring are highly symmetrical. In

contrast, the bicycle of 2d is considerably twisted both in the

solid state and in CDCl₃solution, probably due to an

additional six-membered lactam ring.⁶

Orthoesters (OBO esters)^11,12are useful groups for protect-

ing carboxylic esters from nucleophilic attack. The oxetane

esters of 4-vinylbenzoic acid and methacrylic acid (4g and

4h) were readily converted into the bicyclic orthoesters (5g

and 5h) without affecting the vinyl groups.¹³Compounds 4i

and 4j (Scheme 6) possess two oxetane rings bound through

ether and ester linkages. When the isomerizations were

conducted in dilute CH₂Cl₂solutions (ca. 0.5 mol L²¹),

only oxetanes proximal to the esters were converted into

bicyclic orthoesters. Notably, BF₃·Et₂O had no inﬂuence on

the other ether-linked oxetanes. This isomerization was also

applicable to oxetanes linked with an ester moiety in the

reverse direction. Thus, 4k and 4l were rearranged to the

orthoesters (5k and 5l) of an exocyclic type.

2.1.2. Oxetane esters. Similarly, oxetanes having an ester

substituent (4) also brought about a monomer-isomerization

polymerization to give poly(orthoester)s and polyethers

(Scheme 5).⁷In contrast to the cases of 1a–h, the

isomerization of 4 was not accompanied by polymerization

even in ca. 1.0 M CH₂Cl₂solution at room temperature, due

to the relatively low T_cof bicyclic orthoesters (5). For

example, the T_ctemperatures of 5b and 5d under the

standard conditions in CH₂Cl₂are 27.5 and 222.58C,

respectively.⁷Thus, the isomerization of 4a–h with

BF₃·Et₂O in CH₂Cl₂at 358C gave 5a–h in good yields, as

shown in Scheme 5. These results mirror Corey’s orthoester

synthesis,¹¹which is regarded as a special phenomenon that

2.1.3. Oxetane sec-amides. Oxetanes having an amide

group are also candidates for the present isomerization. In a

Scheme 7. Isomerization of oxetane sec-amides (7).

S. Kanoh et al. / Tetrahedron 58 (2002) 7049–7064

7053

graphy on alumina with AcOEt. When 8e was exposed to

in THF containing a small amount of 0.5 M H₂SO₄at room

temperature, the benzoate of 8e was obtained in 24%

yield.¹⁴

Like the formation of 2, the mechanism for the reaction

giving 8 can also be explained by a 1,6-intramolecular

nucleophilic attack of the amide-carbonyl oxygen. In this

case, cation intermediates have a nitrogen atom with amine

character, unlike the amide nitrogen in the cations formed

from 1. Therefore, the oxazinium cations are interconvert-

ible to the stable iminium cations without cyclization. This

isomerization mode supports the intervention of the cation

intermediates presumed in the isomerizations of 1 and 4, i.e.

a 1,3-oxazin-2-ylium cation for 1 and a 1,3-dioxolan-2-

ylium cation for 4.

Figure 2. Time-conversion curves in the isomerization of 7e (0.5 g) with

BF₃·Et₂O in CH₂Cl₂(2.4 mL). Conditions (BF₃·Et₂O in mol%, temperature

in 8C); B (10, 25), O (25, 25), † (25, 35).

2.1.4. Oxetane tert-amides. In contrast to the sec-amides

(7), isomerization of oxetane tert-amides (10a–u) gave

bicyclic acetals (11a–u).^14,16This reaction mode (Scheme

8) apparently resembles that of the cyclic imides 1.

However, the reactions are self-quenching, because 11 can

function as an amine base to trap the acid catalyst.

Therefore, the isomerization of 10 with BF₃·Et₂O required

a high temperature (120–1308C) for completion. To

suppress polymerization, the reactions were quenched by

the addition of Et₃N immediately after disappearance of the

starting materials (1–1.5 h). Although oligomeric products

had formed, highly moisture-sensitive 11a–u were obtained

in moderate yields by direct distillation of the reaction

mixture from CaH₂under nitrogen. Analogous bicyclo-

[n.3.0] amino-acetals (n¼3 and 4) have previously been

obtained by intermolecular cycloaddition or transacetaliza-

tion, and the high susceptibility of these compounds to

nucleophiles has been reported.¹⁷Similarly, 11a–u were

immediately hydrolyzed in air to give 12a–u as a result of

C–N bond ﬁssion. The hydrolysis products having less

bulky R¹or R²group, such as 12a–c, e, f, n, and r, on

standing, were spontaneously converted into 13 via acyl

exchange.¹⁸

preliminary experiment, the isomerization of oxetane

benzamide (7e) was examined using 10 mol% of

BF₃·Et₂O in CH₂Cl₂at 258C (Scheme 7). The result sharply

differed from the isomerization of 1 and 4. First, the product

was the monocyclic 1,3-oxazine (8e), instead of a bicyclic

compound. Also, as can be seen from the time-conversion

curve shown in Fig. 2, the rapid reaction in the initial stage

slowed down remarkably halfway, with unreacted 7e

remaining. In contrast, both 1 and 4 isomerized according

to good pseudo ﬁrst-order kinetics up to high conversions.

This self-quenching phenomenon suggested that the

catalytic cycle of BF₃·Et₂O was disturbed owing to

the basicity of the product 8e. As shown in Fig. 2, the

isomerization was virtually complete after four days by

increasing both the amount of BF₃·Et₂O and the reaction

temperature (25 mol%, 358C).

Additional examples are also given in Scheme 7. The

isomerization of these oxetane sec-amides (7a–d) required

higher temperatures and, therefore, the competing

polymerization by BF₃·Et₂O occurred to a greater extent.

The use of Me₃Al suppressed oligomer formation, and the

corresponding 1,3-oxazine derivatives (8a–d) were

obtained in satisfactory yields even at 1208C.¹⁴This method

allows the preparation of 5,6-dihydro-4H-1,3-oxazines with

various 2-R substituents including hydrogen.¹⁵The

products were sufﬁciently stable to distillation and

recrystallization. However, 8a–d hydrolyzed to (2-amide-

substituted)propane-1,3-diols (9a–d) during chromato-

When the above isomerization was continued for a further

24 h, the initially formed 11 disappeared and oligomeric

products with a polyether backbone were formed, along

with a small amount of the azetidine having an ester group at

the 3-position (14). The more forcing conditions of methyl

triﬂuoromethanesulfonate (TfOMe, 2 mol%) in nitro-

benzene at 1508C improved the yield of 14 in some

Scheme 8. Isomerization of oxetane tert-amides (10) with ring expansion and contraction: substituents R¹and R²refer to Table 2.

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S. Kanoh et al. / Tetrahedron 58 (2002) 7049–7064

Table 2. Double isomerization of oxetane tert-amides (10) to azetidine

ester (14)

Scheme 9. Double isomerization of oxetane benzimidate (15).

mechanism proposed in Scheme 8. The double isomeriza-

tion involves two key steps: a four-membered oxetane ring

in 10 is ﬁrst expanded to a [2.2.2]-bicycle in 11, which is in

turn contracted to a different four-membered azetidine ring

in 14. The ammonium ion of 11 suffers steric repulsion

between the adjacent R¹and R²groups, making the C–N^þ

bond scission feasible. The resulting 1,3-dioxan-2-ylium

cation closes to form an azetidine ring. Stabilization of the

1.3-dioxan-2-ylium cation does not seem to be important,

because the double isomerization of N-ethylbenzamides

(10h–k) results in similar yields of 14h–k regardless of the

nature of the p-X-substituent. It is likely that 14 are ring-

opening monomers, and hence 14 would be consumed by

oligomerization in the latter half of reaction, as shown in

Fig. 3. In our examination, TfOMe is the preferred catalyst.

The very reactive methylating reagent is likely to be

extremely short-lived, and may simply serve to generate in

situ the true catalytic species, presumably TfOH, following

methylation or hydrolysis with water impurity. However,

TfOH itself was less suitable as the catalyst in that the

oligomerization of 14 was accelerated to a greater extent

(48% yield of 14j in 68 h).

NMR conversion of 14. The reaction of 10 (0.9 mmol) in anhydrous

nitrobenzene (1.0 mL) was carried out using TfOMe (2 mol%) at 1508C for

48–96 h.

cases.¹⁶The results are summarized in Table 2, where the

R¹and R²groups are arranged according to the bulkiness.

Apparently, the product yields are governed by the

bulkiness of both substituents. The scope of the reaction

for constructing azetidine rings may be limited by the

vigorous reaction conditions and the steric requirements for

a bulky R¹or R²group. However, this method offers an

alternative to the general syntheses, including the cycliza-

tion of a,g-difunctionalized alkanes or the reduction of

b-lactams and malonimides.¹⁹

The unusual, counter-intuitive isomerization of 10 to 14 was

of primary interest from a mechanistic point of view. The

fate of 10j was examined by NMR analysis of the

isomerization accelerated with 2.5 times the usual amount

of TfOMe in nitrobenzene-d₅(Fig. 3). The product

distribution suggests that 14j could be formed via 11j.

This possibility was substantiated from the fact that the

isomerization starting from 11j in place of 10j also yielded

14j. We refer to this reaction sequence as ‘double

isomerization’ distinguishing it from the ‘single’ isomeriza-

tions of carbonyl-functionalized oxetanes. The potential

intervention of 11 as the intermediate is shown in the

Oxetane benzimidate (15) is a functional-group isomer of

10, and the unsaturated nitrogen can also act as an

intramolecular nucleophile (Scheme 9). Thus, a bicyclic

acetal (11v) and an azetidine benzoate (14v) were

alternatively obtained by choosing different reaction

conditions. The mode of isomerization is fundamentally

similar to that of the double isomerization of 10. On the

other hand, oxetane tosylate (16: 3-methyloxetan-3-

ylmethyl toluene-4-sulfonate) underwent an ordinary ring-

opening polymerization.²⁰This indicates that the unsatu-

rated oxygen attached to a sulfur lacks nucleophilicity.

2.1.5. Effect of the carbonyl position in the 3-substituent

of oxetane. As mentioned above, we have demonstrated the

isomerization of oxetanes having varied carbonyl function-

ality, such as cyclic imides, esters, and amides. It has been

shown that the isomerization modes of these oxetanes are

extremely chemoselective toward the nature of carbonyl

functional group and all of the isomerizations are preferred

over the conventional cationic ring-opening polymerization

of the oxetane moiety. Irrespective of the variety of the

isomerization modes, there is a common step passing

through an intramolecular nucleophilic attack of the 1,6-

positioned carbonyl oxygen on the a-carbon of the oxetane

oxonium cation. Our next focus was on the importance of

the positional relationship between the nucleophilic oxygen

and the electrophilic carbon. The ﬁrst example is the

reaction of 1,5-positioned oxetane benzoate 4m, as shown in

Figure 3. Time-conversion curves in the double isomerization of 10j with

TfOMe (5 mol%) in nitrobenzene-d₅at 1508C: (†) 10j, (O) 11j, (W) 14j,

(A) oligomeric products.

S. Kanoh et al. / Tetrahedron 58 (2002) 7049–7064

7055

Scheme 10. Effect of the carbonyl position in the 3-substituent of oxetane.

Scheme 10.²¹If the isomerization takes place in the same

mode as that of 1,6-positioned oxetane benzoate 4e,

bicyclo[2.2.1]-orthoester 5m could be formed. Contrary to

this expectation, the acid-promoted reaction of 4m pre-

dominately resulted in polymerization to give a poly-

(orthoester) composed of ﬁve-membered dioxolane rings.

When the poly(orthoester) was subjected to degradation

under depolymerization conditions, no formation of 5m was

detected. The cyclic orthoester structure provided a piece of

evidence for the occurrence of a 1,5-intramolecular attack of

the carbonyl oxygen. Presumably, the subsequent ring

closure would suffer from a higher ring strain to form 5m,

and hence the cation intermediate would preferentially

undergo the intermolecular attack of 4m (propagating-end

isomerization polymerization).

was not formed, because an isomerization to a possibly

more strained bicyclo[4.2.1]-acetal (23b) was realized, as

mentioned later.

2.2. Isomerization of other cyclic ethers having a

carbonyl functional group

2.2.1. Oxirane sec-amide. A series of isomerizations of

oxetanes strongly suggests that similar isomerizations

should be possible for smaller three-membered cyclic

ethers, as long as the carbonyl group is properly positioned.

Thus, we examined the acid-promoted isomerization of

oxirane benzamide 19. The amide-carbonyl oxygen can

attack on either the electrophilic a- or b-carbon in the

oxirane ring or both. mCPBA oxidation of N-allyl-

benzamide for preparing 19 directly gave ﬁve-membered

2-phenyl-5-hydroxymethyl-4,5-dihydrooxazole (20) in a

quantitative NMR conversion, instead of six-membered

2-phenyl-5,6-dihydro-4H-1,3-oxazin-5-ol (21), as outlined

in Scheme 11. The rather low isolated yield of 20 arises

from hydrolytic ring opening and benzoyl transfer during

chromatographic work-up (see Section 2.1.3). Apparently,

the epoxidation was followed by the isomerization of

intermediate 19, probably catalyzed by m-chlorobenzoic

acid that was produced in situ from mCPBA. Consequently,

the formation of a ﬁve-membered ring reveals that the attack

of the 1,5-positioned carbonyl oxygen leads to a-exo

cyclization, in accord with Baldwin’s rules.²²

A keto-carbonyl oxygen is also expected to possess good

nucleophilicity. Oxetane ketone (17a) has the carbonyl

oxygen at the 1,7-position. The BF₃·Et₂O-promoted iso-

merization to a bicyclo[3.2.2]-acetal (18a) indicated that the

1,7-intramolecular attack took place as readily as the 1,6-

intramolecular attack did. On the other hand, farther 1,8-

positioned oxetane ketone (17b) predominately brought

about the ordinary ring-opening polymerization to give a

polyether alone. The observation deserves the following

comments: the intramolecular attack of the 1,8-positioned

carbonyl oxygen becomes less favorable than the inter-

molecular attack of 17b (polymerization), as rationally

predicted from common organic chemistry. In addition, the

potential ring strain of a hypothetical product bicyclo-

[4.2.2]-acetal 18b would be ruled out as the reason why it

2.2.2. Oxirane imides. The isomerization of homologous

oxirane phthalimides (22a–c) was investigated to elucidate

Scheme 11. Isomerization of oxirane benzamide (19).

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S. Kanoh et al. / Tetrahedron 58 (2002) 7049–7064

esters and oxirane carbonates having the 1,5-positioned

carbonyl groups.²⁵Also therein, poly(orthoester)s and

poly(carbonate)s of cyclic structures were obtained instead

of polyethers. Based on the present outcomes, we consider it

reasonable that the polymerization of these oxiranes can be

categorized as a propagating-end isomerization polymeriz-

ation involving the same 1,5-intramolecular nucleophilic

attack as those of 4m and 22a.

3. Conclusion

In this study we investigated the Lewis acid-promoted

isomerization of small cyclic ethers having a carbonyl

functional group. The oxiranes (epoxides) and oxetanes

were chemoselectively isomerized to different heterocyclic

compounds via 1,6- and 1,7-intramolecular nucleophilic

attacks of the carbonyl oxygen (neighboring carbonyl-group

assistance in an expanded meaning): for example, cyclic

imides to bicyclic acetals, esters to bicyclic orthoesters, sec-

amides to 4,5-dihydrooxazole or 5,6-dihydro-4H-1,3-oxa-

zines, and tert-amides to bicyclic acetals or azetidines.

Interestingly, the rearrangement to azetidines proceeded

through a double isomerization mechanism involving ring

expansion of four-membered oxetanes to bicyclo[2.2.2]-

acetals and subsequent ring contraction to different four-

membered azetidines. The intramolecular attack of a 1,5-

positioned carbonyl oxygen predominantly resulted in a

propagating-end isomerization polymerization. On the other

hand, cyclic ethers having a 1,8- and farther positioned

carbonyl group underwent the conventional ring-opening

polymerization. A tetrahydrofuran (oxolane) ring did not

open, even with a 1,6-positioned carbonyl group. The above

isomerizations of small-membered oxiranes and oxetanes

can be extended to other carbonyl precursors, except for the

carbonates, which failed in the tandem cyclization under the

conditions examined. In addition, some of the above

bicyclic acetals and orthoesters further underwent compli-

cated cyclodimerization to afford unexpected products

having a dioxane or dioxolane ring, which will be reported

in the following paper in this journal issue.

Scheme 12. Isomerization of oxirane phthalimides (22).

the effect of the relative position of the carbonyl oxygen

(Scheme 12). In the reaction of 1,5-positioned 22a, an

isomerization polymerization occurred predominately to

give only polyacetal with ﬁve-membered 4,5-dihydro-

oxazole rings in the main chain.²³This result was similar

to the isomerization polymerization of 1,5-positioned

oxetane benzoate 4m. In contrast, the isomerization of

1,6-positioned 22b and 1,7-positioned 22c gave the

expected bicyclic acetals (23b, c). All of the cyclic

structures of these products including the polyacetal are

apparently formed as a result of the a-exo attack. The

hydrolysis of 23b and 23c as well as the polyacetal of 22a

gave phthalimido-substituted ethylene glycols 24a–c under

the same conditions as those for 2.

Similar neighboring assistance was previously observed by

Chamberlin et al.²⁴in the preparation of stereochemically

controlled tetrahydrofurans, tetrahydropyrans, and oxepans

from ester- and ketone-substituted oxiranes in cooperation

with nucleophiles and Lewis acids. They postulated or

isolated the ﬁve-membered monocyclic cations and the six-

and seven-membered bicyclic acetals as key intermediates.

This agrees with our observations, which complements

Chamberlin’s method mechanistically.

4. Experimental

4.1. General

2.2.3. Other cyclic ethers having a carbonyl functional

group. As an example of a ﬁve-membered cyclic ether,

oxolane phthalimide (25: 2-(tetrahydrofuran-3-ylmethyl)-

isoindole-1,3-dione) was prepared. Although the imide-

carbonyl oxygen is placed at the 1,6-position, neither

isomerization nor polymerization took place, unlike 1,6-

positioned analogues of oxetane and oxirane (1a and 22b). It

is not surprising because the less strained ﬁve-membered

cyclic oxonium cation is expected to be an insufﬁcient

electron acceptor. For the same reason, substituted tetra-

hydrofuran, except when the substituents form additional

rings, cannot polymerize cationically.^2b

All of melting points are uncorrected, and all boiling ranges

denote bath temperatures. NMR spectra were measured on

JEOL JNM GSX-500, LA-400, EX-270, and FX-100S

NMR spectrometers using CDCl₃as the solvent. The

chemical shifts were determined with respect to TMS (d

1

0.00 ppm) for H nuclei and CDCl₃(d 77.00 ppm) for ¹³C

nuclei as internal standards. Spectral data were reported at

1

270 MHz for H nuclei unless otherwise noted. In NMR

measurement of moisture-sensitive compounds, they were

taken into NMR tubes ﬁlled with dry nitrogen by

evacuation, and dissolved in anhydrous CDCl₃that was

freshly distilled from powdered CaH₂. IR spectra were

recorded on JASCO FT/IR-3 and JASCO A-202 infrared

spectrometers. High resolution mass spectroscopic analyses

(HRMS) and microanalyses were accomplished at the

Center for Instrumental Analysis, Kanazawa University,

Since our ﬁnding of the monomer-isomerization

polymerization, similar ring-opening polymerizations

involving neighboring carbonyl-group assistance have

been reported by other polymer chemists.^25,26Miyamoto

et al. have reported the cationic polymerization of oxirane

S. Kanoh et al. / Tetrahedron 58 (2002) 7049–7064

7057

using a JEOL JMS-SX102 A mass spectrometer (ionization

potential, 70 eV for EIMS) and a YANAKO CHN Corder

MT-5, respectively. GPC was performed on a Shimadzu

LC-10A high-speed liquid chromatography system

equipped with a differential refractometer, using THF as

the eluent with a ﬂow rate of 1.0 mL min²¹at room

isoindole-1,3-dione (8.44 g, 82%) as colorless crystals: mp

48–498C. mCPBA (9.19 g, 37.3 mmol) was added by

portions to a solution of the above imide (7.50 g,

37.3 mmol) in AcOEt (30 mL). After stirring at 808C for

1 h, the mixture was successively washed with sat. aq

NaHCO₃and brine. The organic layer was dried over

Na₂SO₄, and evaporated in vacuo. The crude product was

recrystallized from AcOEt–hexane to give 22b (6.46 g,

80%). Colorless crystals; mp 83–858C; IR (KBr) 1770,

temperature. Number-average molecular weights (M_{n GPC}

)

were determined on the basis of the molecular weight

calibration curve obtained using polystyrene standards. All

heterocyclic compounds obtained by the isomerization in

this study were hydrolyzed to ring-opened diols, amino-

alcohols, or the related compounds, which were character-

ized by IR, NMR, and MS analyses. These spectroscopic

data are omitted for simplicity.

1

1710, 1400, 915, 803 cm²¹; H NMR d 1.84 (dq, J¼14.1,

7.1 Hz, 1H, NCH₂CH₂), 2.10 (ddt, J¼14.2, 6.6, 4.6 Hz, 1H,

NCH₂CH₂), 2.45 (dd, J¼5.0, 2.6 Hz, 1H, OCH₂cis to

2-ethyl), 2.72 (dd, J¼4.8, 4.1 Hz, 1H, OCH₂trans to

2-ethyl), 2.97–3.03 (m, 1H, OCH ), 3.86, 3.93 (both dt,

J¼13.7, 6.8 Hz, 1H, NCH₂CH₂), 7.72, 7.85 (both dd, J¼5.5,

3.1 Hz, 2H, m- and o-ArH ); ¹³C NMR d 31.6, 35.1, 46.4,

50.2, 123.3, 132.1, 134.0, 168.3; EI HRMS Calcd for

C₁₂H₁₁NO₃: 217.0739. Found: 217.0742.

In experiments requiring anhydrous solvents, dichloro-

methane (CH₂Cl₂), chloroform (CHCl₃), and chlorobenzene

(PhCl) were freshly distilled from powdered CaH₂under

nitrogen, and toluene and nitrobenzene were freshly

distilled from butyllithium and phosphorus pentoxide,

respectively. Triethylamine (Et₃N) used as a quencher was

freshly distilled from powdered CaH₂. 1-Benzyltetra-

hydrothiophenium hexaﬂuoroantimonate (BnTA)²⁷as a

thermally latent Lewis acid was prepared by Endo’s

method: 60% yield, mp 112–1138C (lit.²⁷mp 121.5–

1228C). Methylaluminium bis(2,6-di-tert-butyl-4-methyl-

phenoxide) (MAD) was prepared by Aida’s method²⁸and

recrystallized from toluene–hexane under a nitrogen

atmosphere: 60% yield. 3-Methyloxetanylmethanol (26)¹¹

and its tosylate (16),²⁹which were used as the principal

precursors of oxetane derivatives reported here, were

prepared from 2-hydroxymethyl-2-methylpropane-1,3-diol

according to literature methods. For puriﬁcation of products

by preparative column chromatography, alumina (Merck

Art. 101097, aluminium oxide 90, 70–230 mesh ASTM)

was used throughout this work.

4.2.2. 2-(3-Oxiranylpropyl)isoindole-1,3-dione (22c).

Pent-4-enol (18.8 g, 219 mmol), which was prepared from

tetrahydrofuran-2-ylmethanol according to the Organic

Syntheses method,³¹was added to a solution of NaOH

(35.0 g, 874 mmol) in H₂O (150 mL). To the aqueous

solution cooled to 08C, a solution of p-toluenesulfonyl

chloride (47.9 g, 251 mmol) in THF (150 mL) was added

dropwise for 1.5 h, and then the mixture was stirred at room

temperature for 24 h. The THF was removed in vacuo and

the remaining mixture was extracted with Et₂O. The organic

layer was washed with brine, dried over Na₂SO₄, and

evaporated in vacuo to give pent-4-enyl p-toluenesulfonate

(40.3 g, 77%) as an oil. The crude product was used in the

next step without further puriﬁcation. In the same procedure

for 22b, 2-(pent-4-enyl)isoindole-1,3-dione (1.35 g, 86%)

was obtained from the above tosylate (1.72 g, 7.26 mmol),

potassium phthalimide (2.02 g, 10.9 mmol), and DMF

(5 mL). The crude product was puriﬁed by vacuum

distillation: colorless oil; bp 80–908C (1 mmHg). Then,

2-(3-oxyranylpropyl)isoindole-1,3-dione was obtained from

the above oleﬁn (1.35 g, 6.27 mmol), mCPBA (1.55 g,

6.27 mmol), and AcOEt (10 mL). The crude product was

puriﬁed by alumina column chromatography using toluene

as the eluent, followed by vacuum distillation to give pure

22c (0.79 g, 55%). Colorless oil; bp 130–1408C (1 mmHg);

IR (liquid ﬁlm) 1770, 1710, 1395, 915, 795 cm²¹; ¹H NMR

d 1.56 (ddt, J¼14.0, 8.4, 6.8 Hz, 1H, NCH₂CH₂CH₂), 1.67

(ddt, J¼14.0, 6.1, 4.5 Hz, 1H, CH₂CH₂CH₂N), 1.75–1.95

(m, 2H, NCH₂CH₂CH₂), 2.50 (dd, J¼4.9, 2.6 Hz, 1H, OCH₂

cis to propyl), 2.75 (t, J¼4.5 Hz, 1H, OCH₂trans to propyl),

2.93–3.00 (m, 1H, OCH ), 3.72 (dt, J¼13.5, 6.9 Hz, 1H,

NCH₂CH₂CH₂), 3.78 (dt, J¼13.5, 7.3 Hz, 1H, NCH₂CH_2-

CH₂), 7.72, 7.85 (both dd, J¼5.6, 3.0 Hz, 2H, m- and

o-ArH ); ¹³C NMR d 25.1, 29.8, 37.6, 46.9, 56.6, 123.2,

132.1, 134.0, 168.4; EI HRMS Calcd for C₁₃H₁₃NO₃:

231.0896. Found: 231.0896.

4.2. Preparation of cyclic ethers having a cyclic imide

substituent

Oxetane imides 1a–h^5,6,9and oxirane phthalimide 22a^23,30

were prepared as described in our previous reports, and the

spectroscopic properties and analytical data were reported

therein.

4.2.1. 2-(2-Oxiranylethyl)isoindole-1,3-dione (22b).

p-Toluenesulfonyl chloride (14.5 g, 76.3 mmol) was added

by portions to a solution of but-3-enol (5.00 g, 69.3 mmol)

in pyridine (50 mL) at 08C. After stirring at room

temperature for 1 h, the mixture was acidiﬁed with 1 M

HCl, and extracted with Et₂O. The organic layer was

successively washed with 5% aq NaOH and brine, dried

over Na₂SO₄, and evaporated in vacuo. The residue was

distilled in vacuo to give but-3-enyl p-toluenesulfonate

(12.2 g, 78%) as a colorless oil: bp 90–1008C (1 mmHg).

The above tosylate (11.6 g, 51.4 mmol) and potassium

phthalimide (10.9 g, 59.1 mmol) were dissolved in DMF

(30 mL), and the solution was stirred at 808C for 2 h. After

addition of a large amount of H₂O (300 mL), the mixture

was extracted with Et₂O. The organic layer was succes-

sively washed with 5% aq NaOH and brine, dried over

Na₂SO₄, and evaporated in vacuo. The residue was

recrystallized from Et₂O–hexane to give 2-(but-3-enyl)-

4.2.3. 2-(Tetrahydrofuran-3-ylmethyl)isoindole-1,3-

dione (25). p-Toluenesulfonyl chloride (10.3 g,

53.5 mmol) was added by portions to a solution of

tetrahydrofuran-3-ylmethanol (5.00 g, 49.0 mmol) in

pyridine (16 mL) at 08C, and stirring was continued at

room temperature for 3 h. The solution was acidiﬁed with

1 M HCl and extracted with Et₂O. The organic layer was

7058

S. Kanoh et al. / Tetrahedron 58 (2002) 7049–7064

successively washed with 5% aq NaOH and brine, dried

over Na₂SO₄, and evaporated in vacuo. The resulting crude

tosylate (11.1 g, 88%) was used in the next step without

further puriﬁcation. Potassium phthalimide (9.22 g,

49.8 mmol) was suspended in a solution of the above

tosylate (11.1 g, 43.3 mmol) in DMF (45 mL), and the

mixture was stirred at 808C for 4 h. A large amount of water

(450 mL) was added to deposit white precipitates, which

were collected by ﬁltration and dissolved in CHCl₃. The

organic layer was washed with water, dried over Na₂SO₄,

and evaporated in vacuo. The residue was puriﬁed by

recrystallization from CH₂Cl₂–hexane to give 25 (7.18 g,

72%). Colorless crystals; mp 121–1228C; IR (KBr) 1770,

o-ArH to 4-NO₂); ¹³C NMR d 21.2, 39.3, 69.8, 79.4, 123.5,

130.6, 135.1, 150.5, 164.5; FAB HRMS Calcd for

C₁₂H₁₄NO₅(M^þþH): 252.0872. Found: 252.0867.

4.3.3. 3-Methyloxetan-3-ylmethyl 4-methoxybenzoate

(4f). In the same procedure for 4c, 4f was obtained from

26 (0.267 g, 2.62 mmol), 4-methoxybenzoic acid (0.648 g,

4.26 mmol), diethyl azodicarboxylate (40% toluene sol-

ution, 1.90 mL, 4.36 mmol), and Ph₃P (1.12 g, 4.26 mmol)

in toluene (10 mL). The crude product was puriﬁed by

alumina column chromatography using AcOEt–

hexane¼1:9 as the eluent, followed by vacuum distillation,

to give pure 4f (0.553 g, 89%). Colorless liquid; bp 122–

1258C (1 mmHg); IR (liquid ﬁlm) 1710, 1255, 1100, 980,

1

1706, 1399, 912, 720 cm²¹; H NMR (400 MHz) d 1.71,

1

2.00 (both dq, J¼13.2, 6.7 Hz, 1H, C4H₂), 2.72 (septet,

J¼6.8 Hz, 1H, C3H ), 3.59 (dd, J¼8.8, 5.9 Hz, 1H, OC2H₂),

3.68 (dd, J¼13.7, 7.8 Hz, 1H, NCH₂), 3.73 (dd, J¼13.7,

7.3 Hz, 1H, NCH₂), 3.75 (q, J¼7.6 Hz, 1H, OC5H₂), 3.81

(dd, J¼8.8, 6.8 Hz, 1H, OC2H₂), 3.92 (q, J¼7.3 Hz, 1H,

OC5H₂), 7.72, 7.84 (both dd, J¼5.4, 2.9 Hz, 2H, m- and

o-ArH ); ¹³C NMR (100 MHz) d 30.0, 38.9, 40.4, 67.6, 71.1,

123.3, 131.9, 134.0, 168.4; EI HRMS Calcd for C₁₃H₁₃NO₃:

231.0896. Found: 231.0886. Anal. Calcd for C₁₃H₁₃NO₃: C,

67.52; H, 5.67; N, 6.06. Found: C, 67.60; H, 5.68; N, 5.96.

845 cm²¹; H NMR d 1.42 (s, 3H, 3-CH₃), 3.87 (s, 3H,

ArOCH₃), 4.37 (s, 2H, 3-CH₂O), 4.46, 4.65 (both d,

J¼5.9 Hz, 2H, OCH₂trans and cis to 3-CH₂O), 6.94, 8.02

(both d, J¼7.8 Hz, 2H, m- and o-ArH to 4-OCH₃); ¹³C

NMR d 21.4, 39.4, 55.4, 68.7, 79.6, 113.6, 122.2, 131.5,

163.3, 166.1; EI HRMS Calcd for C₁₃H₁₆O₄: 236.1049.

Found: 236.1050.

4.3.4. 3-Methyloxetan-3-ylmethyl 4-vinylbenzoate (4g).

N,N⁰-Dicyclohexylcarbodiimide (1.39 g, 6.76 mmol) was

added by portions to a THF (30 mL) solution of 26 (0.690 g,

6.76 mmol), 4-vinylbenzoic acid (1.00 g, 6.76 mmol), and

4-dimethylaminopyridine (cat. amount) at 08C. After the

mixture was stirred at 08C for 2 h and then at room

temperature for 3 h, the urea precipitated was ﬁltered off.

The ﬁltrate was evaporated in vacuo, and the residue was

dissolved in Et₂O. The organic layer was successively

washed 5% aq NaOH and brine, dried over Na₂SO₄, and

evaporated in vacuo. The residue was distilled from CuCl in

vacuo to give 4g (0.911 g, 53%). Yellowish oil; bp 100–

1058C (1 mmHg); IR (liquid ﬁlm) 1720, 1630, 1280, 1100,

980, 830 cm²¹; ¹H NMR d 1.43 (s, 3H, 3-CH₃), 4.39 (s, 2H,

3-CH₂O), 4.46, 4.65 (both d, J¼5.9 Hz, 2H, OCH₂trans and

cis to 3-CH₂O), 5.40 (d, J¼10.9 Hz, 1H, trans-CH₂vCH),

5.87 (d, J¼17.6 Hz, 1H, cis-CH₂vCH), 6.76 (dd, J¼17.6,

10.8 Hz, 1H, CH₂vCH ), 7.47, 8.01 (both d, J¼8.4 Hz, 2H,

o- and m-ArH to 4-vinyl); ¹³C NMR d 21.4, 39.4, 69.0, 79.6,

116.6, 126.1, 128.9, 129.8, 135.8, 142.1, 166.1; FAB HRMS

Calcd for C₁₄H₁₇O₃(M^þþH): 233.1178. Found: 233.1176.

4.3. Preparation of oxetanes having an ester group

Oxetane esters 4b, d, and e were prepared as described in

our previous report,⁷and the spectroscopic properties and

analytical data were reported therein.

4.3.1. 3-Methyloxetan-3-ylmethyl propionate (4a). Pro-

pionyl chloride (2.20 g, 23.8 mmol) was added dropwise to

a solution of 26 (2.00 g, 19.6 mmol) and Et₃N (13.9 mL,

100 mmol) in CH₂Cl₂(10 mL) at 0–68C. After stirring at

58C for 5 h, the mixture was successively washed with 1 M

HCl, 10% aq NaOH, and brine, dried over Na₂SO₄, and

distilled in vacuo to give 4a (1.14 g, 37%). Colorless oil; bp

94–988C (10 mmHg); IR (liquid ﬁlm) 1740, 1180, 1080,

980, 830 cm²¹

;

¹H NMR d 1.17 (t, J¼7.6 Hz, 3H,

CH₂CH₃), 1.34 (s, 3H, 3-CH₃), 2.39 (q, J¼7.6 Hz, 2H,

CH₂CH₃), 4.17 (s, 2H, 3-CH₂O), 4.38, 4.52 (both d,

J¼5.9 Hz, 2H, OCH₂trans and cis to 3-CH₂O); ¹³C NMR

d 9.13, 21.2, 27.5, 39.1, 68.4, 79.5, 174.2; FAB HRMS

Calcd for C₈H₁₅O₃(M^þþH): 159.1022. Found: 159.1015.

4.3.5. 3-Methyloxetan-3-ylmethyl methacrylate (4h). In

the same procedure for 4c, 4h was obtained from 26 (1.52 g,

14.9 mmol), methacrylic acid (2.57 g, 29.4 mmol), diethyl

azodicarboxylate (40% toluene solution, 8.65 mL,

29.8 mmol), and Ph₃P (7.81 g, 29.8 mmol) in toluene

(10 mL). Extractive work-up with AcOEt gave the crude

product, which was puriﬁed by vacuum distillation to give

pure 4h (1.79 g, 72%).³²Colorless liquid; bp 40–438C

(1 mmHg); IR (liquid ﬁlm) 1720, 1640, 1160, 980,

4.3.2. 3-Methyloxetan-3-ylmethyl 4-nitrobenzoate (4c).

Diethyl azodicarboxylate (40% toluene solution, 1.90 mL,

4.36 mmol) was added dropwise to a toluene (10 mL)

solution of 26 (0.217 g, 2.13 mmol), 4-nitrobenzoic acid

(0.735 g, 4.40 mmol), and Ph₃P (1.12 g, 4.26 mmol) at 08C

under nitrogen. The mixture was stirred overnight, treated

with aq NaHCO₃, and then extracted with AcOEt. The

organic layer was washed with brine, dried over Na₂SO₄,

and evaporated in vacuo. The residue was puriﬁed by

alumina column chromatography using AcOEt–

hexane¼1:1 as the eluent, followed by vacuum distillation,

to give pure 4c (0.400 g, 75%) as a yellow liquid, which

solidiﬁed at room temperature. Bp 125–1308C (1 mmHg);

mp 62–648C; IR (liquid ﬁlm) 1730, 1530, 1350, 1280, 1100,

980, 845 cm²¹; ¹H NMR d 1.45 (s, 3H, 3-CH₃), 4.47 (s, 2H,

3-CH₂O), 4.50, 4.65 (both d, J¼6.1 Hz, 2H, OCH₂trans and

cis to 3-CH₂O), 8.24, 8.31 (both d, J¼8.8 Hz, 2H, m- and

1

835 cm²¹; H NMR d 1.37 (s, 3H, 3-CH₃), 1.97 (pseudo

d, J¼1.0 Hz, 3H, CH₂vC–CH₃), 4.23 (s, 2H, 3-CH₂O),

4.40, 4.56 (both d, J¼5.9 Hz, 2H, OCH₂trans and cis to 3-

CH₂O), 5.60 (pseudo qui, J¼1.6 Hz, 1H, cis-CH₂vCMe),

6.14 (pseudo s, 1H, trans-CH₂vCMe); ¹³C NMR d 18.4,

21.3, 39.3, 68.8, 79.6, 125.8, 135.9, 167.2; FAB HRMS

Calcd for C₉H₁₅O₃(M^þþH): 171.1022. Found: 171.1034.

4.3.6. 3-Methyloxetan-3-ylmethyl 4-(3-methyloxetan-3-

ylmethoxy)benzoate (4i). A solution of 16 (10.0 g,

S. Kanoh et al. / Tetrahedron 58 (2002) 7049–7064

7059

39.06 mmol) and sodium bromide (8.04 g, 78.13 mmol) in

DMF (25 mL) was stirred at 408C for 3 h. The solvent was

removed in vacuo and the residue was dissolved in Et₂O and

water. The organic layer was washed with brine, dried over

Na₂SO₄, and distilled in vacuo to give 3-bromomethyl-3-

methyloxetane (4.79 g, 74%) as a colorless oil; bp 35–408C

(1 mmHg).

(16 mL) below 58C, and then diethyl malonate (0.905 g,

5.65 mmol) and the above iodide (1.00 g, 4.72 mmol) were

added successively. The resulting solution was reﬂuxed for

1.5 h, cooled, and quenched by adding MeOH (1 mL) and

then water (6 mL). Keeping the mixture at pH¼6 with acetic

acid, it was concentrated halfway in vacuo and extracted

with Et₂O. The organic layer was washed with brine, dried

over Na₂SO₄, and evaporated in vacuo. The residue was

separated into unreacted diethyl malonate and 4k (0.53 g,

50%) by fractional distillation in vacuo. Colorless oil; bp

80–858C (1 mmHg); IR (liquid ﬁlm) 1725, 1150, 1090,

A solution of 4-hydroxybenzoic acid (0.310 g, 2.24 mmol)

and KOH (0.264 g, 4.71 mmol) in EtOH (10 mL) was

stirred at room temperature for 1 h, and evaporated in vacuo.

The above bromide (0.741 g, 4.49 mmol) and DMF (10 mL)

were added to the residue. The solution was stirred at 1008C

for 3 h, and then the solvent was evaporated in vacuo. After

dilution with water, the mixture was extracted with

Et₂O. The organic layer was successively washed with

1 M HCl, 5% aq NaOH, and brine, dried over Na₂SO₄, and

evaporated in vacuo. The residue was distilled in vacuo and

recrystallized from CH₂Cl₂–hexane to give 4i (0.489 g,

65%). The residue was ‘ester’ and ‘ether’ in ¹H NMR

assignment denote the ester- and ether-linked oxetanyl

groups, respectively. Colorless plates; bp 150–1608C

(1 mmHg); mp 68–708C; IR (KBr) 1710, 1250, 1100,

1

1025, 1090, 980, 825 cm²¹; H NMR d 1.27 (t, J¼7.2 Hz,

6H, OCH₂CH₃), 1.34 (s, 3H, 3-CH₃), 2.30 (d, J¼7.1 Hz, 2H,

3-CH₂CH), 3.35 (t, J¼7.1 Hz, 1H, 3-CH₂CH ), 4.19 (q,

J¼7.1 Hz, 4H, OCH₂CH₃), 4.29, 4.45 (both d, J¼5.9 Hz,

2H, oxetane OCH₂trans and cis to 3-CH₂CH); ¹³C NMR d

14.1, 22.9, 37.2, 38.5, 48.5, 61.7, 82.4, 169.2; EI HRMS

Calcd for C₁₂H₂₀O₅: 244.1311. Found: 244.1319.

4.3.9. Ethyl 3-(3-methyloxetan-3-yl)propionate (4l).

According to Krapcho’s method,³³the decaroboethoxyl-

ation of 4k (5.04 g, 20.6 mmol) was carried out in DMSO

(30 mL) containing H₂O (0.74 mL, 41 mmol) and NaCl

(1.21 g, 20.6 mmol) with stirring at 1108C for 5 h. The

reaction mixture was diluted with H₂O (30 mL), and

extracted with Et₂O. The organic layer was washed with

brine, dried over Na₂SO₄, and distilled in vacuo to give pure

4l (2.53 g, 71%). Colorless oil; bp 40–458C (1 mmHg); IR

(liquid ﬁlm) 1740, 1175, 980, 830 cm²¹; ¹H NMR d 1.27 (t,

J¼7.1 Hz, 3H, OCH₂CH₃), 1.30 (s, 3H, 3-CH₃), 1.99

(pseudo t, J¼8.0 Hz, 2H, 3-CH₂CH₂), 2.29 (pseudo t,

J¼8.0 Hz, 2H, 3-CH₂CH₂), 4.14 (q, J¼7.1 Hz, 2H,

OCH₂CH₃), 4.34, 4.42 (both d, J¼5.7 Hz, 2H, oxetane

OCH₂trans and cis to 3-CH₂CH₂); ¹³C NMR d 14.2, 23.0,

29.8, 33.8, 38.8, 60.5, 82.2, 173.1; EI HRMS Calcd for

C₉H₁₆O₃: 172.1100. Found: 172.1105.

1

1050, 975, 850 cm²¹; H NMR (500 MHz) d 1.43, 1.45

(both s, 3H, ester- and ether-CH₃), 4.09 (s, 2H, CH₂OAr),

4.37 (s, 2H, CH₂OCOAr), 4.46, 4.48 (both d, J¼5.9 Hz, 2H,

ester- and ether-OCH₂trans to 3-CH₂O), 4.63, 4.65 (both d,

J¼5.9 Hz, 2H, ester- and ether-OCH₂cis to 3-CH₂O), 6.97,

8.03 (both d, J¼8.3 Hz, 2H, o- and m-ArH to ether); ¹³C

NMR (100 MHz) d 21.2, 21.3, 39.3, 39.6, 68.7, 72.9, 79.6,

114.2, 122.6, 131.7, 162.9, 166.2; EI HRMS Calcd for

C₁₇H₂₂O₅: 306.1468. Found: 306.1465. Anal. Calcd for

C₁₇H₂₂O₅: C, 66.65; H, 7.24. Found: C, 66.36; H, 7.20.

4.3.7. 3-Methyloxetan-3-ylmethyl [4-(3-methyloxetan-3-

ylmethoxy)phenyl]acetate (4j). In the same procedure for

4i, j was obtained from the above bromide (0.432 g,

2.62 mmol), 4-hydroxylphenylacetic acid (0.203 g,

1.31 mmol), KOH (0.226 g, 4.03 mmol), and DMF

(10 mL) at 1008C for 4 h. The crude product was distilled

in vacuo from CaH₂to give pure 4j (0.323 g, 70%). Ester

4.3.10. Oxetan-3-yl benzoate (4m). Oxetan-3-ol was

prepared from epichlorohydrin according to Baum’s

method,³⁴except using 3,4-dihydro-2H-pyran in place of

ethyl vinyl ether as an OH-protecting reagent. 1,3-

Dicyclohexylcarbodiimide (1.72 g, 8.31 mmol) was added

to a solution of the alcohol (0.615 g, 8.31 mmol), benzoic

acid (1.02 g, 8.31 mmol), and 4-(dimethylamino)pyridine

(0.10 g, 0.83 mmol) in THF (50 mL) at 08C. The mixture

was stirred at 08C for 1 h and then at room temperature for

3 h, and the resulting precipitates were ﬁltered off. The

solvent was removed in vacuo from the ﬁltrate, and the

residue was extracted with Et₂O. The organic layer was

successively washed with 1 M HCl, 10% aq NaOH, and

brine, dried over Na₂SO₄, and distilled in vacuo to give 4m

(0.355 g, 24%). Colorless oil; bp 55–608C (1 mmHg); IR

1

and ether in H NMR assignment denote the ester- and

ether-linked oxetanyl groups, respectively. Colorless oil; bp

160–1708C (1 mmHg); IR (KBr) 1730, 1240, 1140, 975,

1

830 cm²¹; H NMR d 1.29, 1.43 (both s, 3H ester- and

ether-CH₃), 3.61 (s, 2H, ArCH₂CO₂), 4.00 (s, 2H, CH₂OAr),

4.16 (s, 2H, CH₂OCO), 4.35, 4.45 (both d, J¼5.9 Hz, 2H,

ester- and ether-OCH₂trans to 3-CH₂O), 4.48, 4.62 (both d,

J¼5.9 Hz, 2H, ester- and ether-OCH₂cis to 3-CH₂O), 6.89,

7.21 (both d, J¼8.5 Hz, 2H, o- and m-ArH to ether); ¹³C

NMR d 21.2, 21.3, 39.1, 39.7, 40.4, 68.9, 72.8, 79.4, 79.7,

114.6, 126.2, 130.2, 158.1, 171.7; EI HRMS Calcd for

C₁₈H₂₄O₅: 320.1624. Found: 320.1623.

1

(liquid ﬁlm) 1720, 1275, 1115, 975, 840 cm²¹; H NMR d

4.79 (dd, J¼7.8, 5.4 Hz, 2H, OCH₂cis to 3-benzoate), 5.00

(t, J¼7.1 Hz, 2H, OCH₂trans to 3-benzoate), 5.67 (qui,

J¼5.9 Hz, 1H, C3H ), 7.46 (t, J¼7.8 Hz, 2H, m-ArH ), 7.60

(t, J¼7.4 Hz, 1H, p-ArH ), 8.09 (d, J¼8.3 Hz, 2H, o-ArH );

¹³C NMR d 68.4, 77.6, 128.5, 129.3, 129.7, 133.5, 165.8; EI

HRMS Calcd for C₁₀H₁₀O₃: 178.0632. Found: 178.0630.

4.3.8. Diethyl 2-(3-methyloxetan-3-ylmethyl)malonate

(4k). A solution of 16 (15.0 g, 55.2 mmol) and sodium

iodide (18.0 g, 120 mmol) in acetone (40 mL) was reﬂuxed

for 3 h. The solvent was removed in vacuo, and the residue

was dissolved in Et₂O and water. The organic layer was

washed with brine, dried over Na₂SO₄, and distilled in

vacuo to give 3-iodomethyl-3-methyloxetane (8.88 g, 76%)

as a yellowish oil; bp 90–958C (20 mmHg). Small pieces of

Na metal (0.223 g, 9.70 mmol) were slowly added to EtOH

4.4. Preparation of cyclic ethers having an amide group

Oxetane sec-amides (7a–e)¹⁴and oxirane benzamide (19)²³

7060

S. Kanoh et al. / Tetrahedron 58 (2002) 7049–7064

were prepared as described in our previous reports. Oxetane

tert-amides (10a–u) were prepared by N-alkylation³⁵of 7

as described in our previous reports,^14,16and obtained as a

mixture of s-cis and s-trans isomers at room temperature,

except for stereochemically pure pivalamides (Z)-10d and

(Z )-10m. The spectroscopic properties and analytical data

of these oxetane amides were reported therein.

4.5.2. 3-(3-Methyloxetan-3-ylmethoxy)-1-phenylpropan-

1-one (17b). According to the procedure for 17a, the phase-

transfer-catalysis reaction of 3-iodomethyl-3-methyloxe-

tane (0.335 g, 1.58 mmol, see Section 4.3.8), 2-(1,3-

dioxolan-2-yl)-2-phenylethanol³⁸(0.307 g, 1.58 mmol),

solid NaOH (0.60 g, 15 mmol), and tetrabutylammonium

hydrogensulfate (cat. amount) in benzene (15 mL),

followed by chromatographic puriﬁcation of the crude

product using AcOEt–hexane¼1:9 as the eluent, gave 2-[2-

(3-methyloxetan-3-ylmethoxy)ethyl]-2-phenyl-1,3-dioxo-

lane (0.221 g, 50%) as a colorless oil. The above oxolane

(0.300 g, 1.08 mmol) was dissolved in a mixture of acetone

(15 mL)–H₂O (7.5 mL) containing p-toluenesulfonic acid

(cat. amount), and the solution was reﬂuxed for 10 h. The

acetone was removed in vacuo, and then the remaining

mixture was extracted with Et₂O. The organic layer was

dried over Na₂SO₄, and distilled in vacuo to give 17b

(0.202 g, 80%). Pale yellowish oil; bp 115–1208C

4.4.1. Preparation of 3-methyloxetan-3-ylmethyl

N-phenylbenzimidate (15). Small pieces of Na metal

(0.105 g, 4.58 mmol) and 26 (0.539 g, 5.28 mmol) were

reﬂuxed in benzene (10 mL) for 6 h, and then N-phenyl-

benzimidoyl chloride³⁶(0.759 g, 3.52 mmol) was added to

the mixture, which was reﬂuxed for a further 2 h. The

benzene layer was washed with brine, dried over Na₂SO₄,

and evaporated in vacuo. The residue was repeatedly

washed with hexane, and puriﬁed by alumina column

chromatography using AcOEt–hexane¼1:3 as the eluent, to

give pure 15 (0.375 g, 35%). Colorless solid; mp 75–768C;

(1 mmHg); IR (liquid ﬁlm) 1680, 1120, 980, 835 cm²¹

;

IR (KBr) 1650, 1150, 730, 980, 845 cm²¹

;

¹H NMR

¹H NMR d 1.27 (s, 3H, CH₃), 3.27 (t, J¼6.4 Hz, 2H,

OCH₂CH₂), 3.53 (s, 2H, 3-CH₂O), 3.92 (t, J¼6.4 Hz, 2H,

OCH₂CH₂), 4.43, 4.48 (both d, J¼5.7 Hz, 2H, CH₂O trans

and cis to 3-CH₂O), 7.45 (pseudo t, J¼7.4 Hz, 2H, m-ArH ),

7.56 (pseudo t, J¼7.3 Hz, 1H, p-ArH ), 7.97 (pseudo d,

J¼7.1 Hz, 2H, o-ArH ); ¹³C NMR d 21.4, 38.8, 39.9, 66.8,

76.4, 80.0, 128.0, 128.5, 133.0, 136.9, 198.3; EI HRMS

Calcd for C₁₄H₁₈O₃: 234.1256. Found: 234.1255.

(400 MHz) d 1.44 (s, 3H, 3-CH₃), 4.42 (s, 2H, 3-CH₂O),

4.44, 4.69 (both d, J¼5.9 Hz, 2H, OCH₂trans and cis to

3-CH₂O), 6.73 (d, J¼8.1 Hz, 2H, o-ArH to NvC), 6.64 (t,

J¼7.3 Hz, 1H, p-ArH to NvC), 7.16, 7.19 (both t,

J¼7.6 Hz, 2H, m-ArH to NvC and 3-ArH-m ), 7.27 (t,

J¼7.3 Hz, 1H, 3-ArH-p), 7.32 (d, J¼8.0 Hz, 2H, 3-ArH-o );

¹³C NMR (100 MHz) d 21.4, 39.3, 70.6, 79.8, 121.3, 122.6,

127.8 (overlapped), 128.8, 129.2, 129.9, 130.8, 148.0,

158.3; EI HRMS Calcd for C₁₈H₁₉NO₂: 281.1417. Found:

281.1415.

4.5.3. Isomerization of imide-substituted cyclic ethers.

Typically,

a hexane solution of Me₃Al (1.70 mL,

1.0 mol L²¹, 1.70 mmol) was added to a solution of 1a

(8.02 g, 34.7 mmol) in anhydrous PhCl (32 mL) under dry

nitrogen. The resulting solution was allowed to stand at

1208C for 12 h, and the reaction was quenched by adding

anhydrous Et₃N (1.6 mL). The mixture was diluted with

CH₂Cl₂(50 mL) to deposit insoluble materials, which were

removed by ﬁltration. After decolorization of the ﬁltrate

with charcoal followed by evaporation, the residue was

recrystallized from CH₂Cl₂–hexane to give 2,3-benzo-7-

methyl-9,10-dioxa-5-azatricyclo[5.2.2.0^1,5]undeca-2-en-4-

one (2a; 7.28 g, 91%). Colorless needles; mp 172–1748C;

4.5. Preparation of oxetanes having a ketone substituent

4.5.1. 2-(3-Methyloxetan-3-ylmethoxy)-1-phenyletha-

none (17a). A solution of 3-iodomethyl-3-methyloxetane

(1.26 g, 5.90 mmol, see Section 4.3.8) and (2-phenyl-1,3-

dioxolan-2-yl)methanol³⁷(1.00 g, 5.54 mmol) in benzene–

hexane¼1:1 (15 mL) was reﬂuxed over solid NaOH (3.01 g,

75.3 mmol) with stirring for 12 h, while tetrabutylammo-

nium bromide (0.895 g, 2.78 mmol) was added by 90 mg

portions every 1 h. After water (25 mL) was added to the

mixture, the organic layer was separated, washed with brine,

dried over Na₂SO₄, and evaporated in vacuo. The residue

was puriﬁed by alumina column chromatography using

AcOEt–hexane¼1:3 as the eluent, to give 2-(3-methyl-

oxetan-3-ylmethoxymethyl)-2-phenyl-1,3-dioxolane (0.220 g,

58%) as a colorless oil. The ketal (0.475 g, 1.80 mmol) was

stirred in 0.5 M aq H₂SO₄(23 mL) at room temperature for

10 h. The reaction mixture was neutralized with sat. aq

NaHCO₃and extracted with Et₂O. The organic layer was

washed with brine, dried over Na₂SO₄, and evaporated in

vacuo. The residue was puriﬁed by alumina column

chromatography using AcOEt–hexane¼2:3 as the eluent,

followed by vacuum distillation, to give 17a (0.249 g, 63%).

Colorless oil; bp 100–1058C (1 mmHg); IR (liquid ﬁlm)

IR (KBr) 1721, 1711, 1132, 1055–968 cm²^{1 1}H NMR

;

(400 MHz) d 0.95 (s, 3H, 7-CH₃), 3.63 (s, 2H, NCH₂), 3.94,

4.07 (both d, J¼8.3 Hz, 2H, equatorial and axial OCH₂with

respect to a boat-type 1,3-dioxane ring), 7.44–7.53 (m, 3H,

carbonyl m- and p-ArH ), 7.72 (d, J¼7.3 Hz, 1H, carbonyl

o-ArH ); ¹³C NMR (100 MHz) d 15.6, 31.2, 49.3, 74.0,

101.2, 121.8, 123.2, 130.5, 132.0, 132.9, 139.6, 163.9; EI

HRMS Calcd for C₁₃H₁₃NO₃: 231.0896. Found: 231.0885.

Anal. Calcd for C₁₃H₁₃NO₃: C, 67.52; H, 5.67; N, 6.06.

Found: C, 67.29; H, 5.73; N, 5.98.

The preparation, spectroscopic properties, and analytical

data of bicyclic acetals 2b–h were described in our previous

reports.^5,6,9

1

1700, 1135, 975, 830 cm²¹; H NMR d 1.35 (s, 3H, CH₃),

3.64 (s, 2H, 3-CH₂O), 4.38, 4.58 (both d, J¼5.7 Hz, 2H,

CH₂O trans and cis to 3-CH₂O), 4.79 (s, 2H, OCH₂CO),

7.47 (pseudo t, J¼7.4 Hz, 2H, m-ArH ), 7.59 (pseudo t,

J¼7.3 Hz, 1H, p-ArH ), 7.94 (pseudo d, J¼7.0 Hz, 2H,

o-ArH ); ¹³C NMR d 21.3, 40.0, 65.3, 74.2, 79.9, 126.0,

127.9, 133.5, 134.8, 196.5; EI HRMS Calcd for C₁₃H₁₆O₃:

220.1100. Found: 220.1104.

4.5.4. 2,3-Benzo-10,11-dioxa-5-azatricyclo[6.2.1.0^1,5]un-

dec-2-en-4-one (23b). Reaction conditions: 22b (0.205 g,

0.943 mmol), MAD (5 mol%), toluene (2.1 mL), 258C,

72 h. 23b (0.172 g, 84%); colorless crystals; mp 105–1078C

(Et₂O–hexane); IR (KBr) 1700, 1145, 1040–935 cm²¹; ¹H

NMR d 1.71 (ddd, J¼13.9, 5.4, 1.8 Hz, 1H, C7H₂), 2.21

(dddd, J¼13.9, 11.9, 7.3, 3.3 Hz, 1H, C7H₂), 3.45 (ddd,

S. Kanoh et al. / Tetrahedron 58 (2002) 7049–7064

7061

J¼13.5, 11.9, 5.6 Hz, 1H, NC6H₂), 4.18 (dd, J¼13.5,

7.3 Hz, 1H, NC6H₂), 4.23 (d, J¼2.6 Hz, 2H, OC9H₂), 4.96

(m, 1H, OC8H ), 7.52–7.61 (m, 3H, ArH other than

carbonyl o-ArH), 7.77–7.81 (m, 1H, carbonyl o-ArH );

¹³C NMR d 26.1, 32.8, 68.0, 74.2, 111.3, 122.5, 123.3,

131.2, 132.1, 133.6, 137.6, 163.2; EI HRMS Calcd for

C₁₂H₁₁NO₃: 217.0739. Found: 217.0738.

0.398 mmol), BF₃·Et₂O (5 mol%), CH₂Cl₂(1.2 mL), 358C,

48 h. 5c (90.5 mg, 91%); pale yellowish crystals; mp 160–

1628C; IR (KBr) 1520, 1340, 1100, 1010, 980, 850 cm²¹

;

¹H NMR (CDCl₃) d 0.91 (s, 3H, 4-CH₃), 4.10 (s, 6H,

OCH₂), 7.78, 8.19 (both d, J¼8.8 Hz, 2H, m- and o-ArH to

4-NO₂); ¹³C NMR (CDCl₃) d 14.5, 30.7, 73.3, 106.6, 123.1,

127.1, 143.6, 148.2; EI HRMS Calcd for C₁₂H₁₃NO₅:

251.0794. Found: 251.0800.

4.5.5. 2,3-Benzo-11,12-dioxa-5-azatricyclo[7.2.1.0^1,5]do-

dec-2-en-4-one (23c). Reaction conditions: 22c (0.500 g,

2.16 mmol), BF₃·Et₂O (250 mol%), CH₂Cl₂(14.5 mL),

258C, 72 h. 23c (0.452 g, 90%); the large amount of

BF₃·Et₂O was required to suppress polymerization. Color-

less oil; bp 140–1508C (1 mmHg); IR (KBr) 1700, 1140,

4.5.9. 1-(4-Methoxyphenyl)-4-methyl-2,6,7-trioxabi-

cyclo[2.2.2]octane (5f). Reaction conditions: 4f (0.306 g,

1.30 mmol), BF₃·Et₂O (5 mol%), CH₂Cl₂(1.4 mL), 358C,

48 h. 5f (0.240 g, 78%); colorless crystals; mp 82–848C; IR

(KBr) 1250, 1095, 1050–985 cm²¹; ¹H NMR d 0.87 (s, 3H,

4-CH₃), 3.79 (s, 3H, OCH₃), 4.07 (s, 6H, OCH₂), 6.85 (d,

J¼8.7 Hz, 2H, o-ArH to 4-OCH₃), 7.54 (d, J¼8.6 Hz, 2H,

m-ArH to 4-OCH₃); ¹³C NMR d 14.6, 30.5, 55.3, 73.2,

107.4, 113.2, 126.9, 129.9, 160.0; EI HRMS Calcd for

C₁₃H₁₆O₄: 236.1049. Found: 236.1041.

1060–940 cm²¹

;

¹H NMR

d

1.87–2.16 (m, 4H,

C7H₂C8H₂), 3.26 (ddd, J¼13.7, 11.5, 2.1 Hz, 1H,

NC6H₂), 3.94 (ddd, J¼13.9, 5.4, 2.5 Hz, 1H, NC6H₂),

4.19 (dd, J¼7.4, 0.8 Hz, 1H, OC10H₂), 4.21 (t, J¼6.6 Hz,

1H, OC10H₂), 4.86 (m, 1H, OC9H), 7.44–7.58 (m, 3H,

ArH other than carbonyl o-ArH), 7.73 (d, J¼7.1 Hz, 1H,

carbonyl o-ArH); ¹³C NMR d 20.6, 34.8, 41.1, 69.4, 76.1,

116.7, 121.7, 122.8, 130.6, 132.0, 132.4, 141.9, 166.5;

EI HRMS Calcd for C₁₃H₁₃NO₃: 231.0896. Found:

231.0896.

4.5.10. 4-Methyl-1-(4-vinylphenyl)-2,6,7-trioxabi-

cyclo[2.2.2]octane (5g). Reaction conditions: 4g (100 mg,

0.431 mmol), BF₃·Et₂O (10 mol%), CH₂Cl₂(0.4 mL), 258C,

24 h. 5g (79 mg, 79%); colorless plates; mp 107–1098C

(CH₂Cl₂–hexane); IR (KBr) 1630, 1100–950 cm²^{1 1}H

;

4.5.6. Isomerization of ester-substituted cyclic ethers.

Typically, BF₃·Et₂O (1.80 mL, 0.432 mol L²¹in CH₂Cl₂,

0.778 mmol) was added to an CH₂Cl₂(12 mL) of 4d

(3.00 g, 15.6 mmol) under dry nitrogen. The resulting

solution was allowed to stand at 258C for 24 h, and

quenched by adding anhydrous Et₃N (1.6 mL). The volatile

materials were evaporated to dryness, and then the crude

product was puriﬁed by alumina column chromatography

using toluene as the eluent, followed by recrystallization

from CH₂Cl₂–hexane, to give 4-methyl-1-phenyl-2,6,7-

trioxabicyclo[2.2.2]octane (5d; 2.37 g, 74%). Colorless

NMR d 0.87 (s, 3H, orthoester 4-CH₃), 4.08 (s, 6H, OCH₂),

5.24 (dd, J¼10.9, 0.8 Hz, 1H, trans-CH₂vCH), 5.74 (dd,

J¼17.6, 0.8 Hz, 1H, cis-CH₂vCH), 6.70 (dd, J¼17.6,

10.9 Hz, 1H, CH₂vCH ), 7.38, 7.57 (both d, J¼8.2 Hz, 2H,

o- and m-ArH to 4-vinyl); ¹³C NMR d 14.5, 30.5, 73.2,

107.3, 114.3, 125.5, 125.7, 136.4, 136.7, 138.1; EI HRMS

Calcd for Calcd for C₁₄H₁₆O₃: 232.1100. Found:

232.1103.

4.5.11. 1-Isopropenyl-4-methyl-2,6,7-trioxabicyclo-

[2.2.2]octane (5h). Reaction conditions: 4h (0.206 g,

1.21 mmol), BF₃·Et₂O (5 mol%), CH₂Cl₂(2.0 mL), 258C,

24 h. 5h (0.156 g, 76%); colorless plates; mp 56–588C; IR

(KBr) 1625, 1170, 1040, 980 cm²¹; ¹H NMR d 0.83 (s, 3H,

4-CH₃), 1.81 (pseudo t, J¼1.2 Hz, 3H, CH₂vC–CH₃), 3.97

(s, 6H, CH₂O), 5.00 (pseudo qui, J¼1.6 Hz, cis-CH₂

vCMe), 5.37 (pseudo q, 1H, trans-CH₂vCMe); ¹³C

NMR d 14.6, 17.8, 30.3, 72.9, 107.0, 114.0, 140.6; EI

HRMS Calcd for C₉H₁₄O₃: 170.0943. Found: 170.0941.

1

needles; mp 128–1298C; IR (KBr) 1105–990 cm²¹; H

NMR (500 MHz) d 0.87 (s, 3H, 4-CH₃), 4.08 (s, 6H, OCH₂),

7.33–7.36 (m, 3H, m- and p-ArH ), 7.62 (dd, J¼6.6, 3.2 Hz,

2H, o-ArH ); ¹³C NMR (126 MHz) d 14.5, 30.5, 73.3, 107.4,

125.6, 128.0, 129.1, 135.7; EI HRMS Calcd for C₁₂H₁₄O₃:

206.0943. Found: 206.0949.

Moisture-sensitive 5 was isolated by direct distillation of the

reaction mixture from CaH₂, and stored under nitrogen. The

preparation, spectroscopic properties, and analytical data of

bicyclic orthoesters 5b and 5e were described in our

previous report.⁷

4.5.12. 4-Methyl-1-[4-(3-methyloxetan-3-ylmethoxy)-

phenyl]-2,6,7-trioxabicyclo[2.2.2]octane (5i). Reaction

conditions: 4i (0.200 g, 0.653 mmol), BF₃·Et₂O (5 mol%),

CH₂Cl₂(3.1 mL), 258C, 24 h. 5i (0.122 g, 61%); colorless

plates; mp 160–1628C (CH₂Cl₂–hexane); IR (KBr) 1240,

4.5.7. 1-Ethyl-4-methyl-2,6,7-trioxabicyclo[2.2.2]octane

(5a). Reaction conditions: 4a (0.315 g, 1.99 mmol),

BF₃·Et₂O (5 mol%), CH₂Cl₂(6.2 mL), 358C, 24 h. 5a

(0.283 g, 90%); colorless oil, which was rapidly hydrolyzed

with moisture in air; bp 30–358C (1 mmHg); IR (liquid

ﬁlm) 1065, 1050, 990 cm²¹; ¹H NMR (anhydrous CDCl₃) d

0.73 (s, 3H, 4-CH₃), 0.87 (t, J¼7.5 Hz, 3H, 1-CH₂CH₃),

1

1090, 1030, 1000, 960, 830 cm²¹; H NMR (500 MHz) d

0.87 (s, 3H, orthoester 4-CH₃), 1.42 (s, 3H, oxetane 3-CH₃),

4.00 (s, 2H, CH₂OAr), 4.07 (s, 6H, orthoester OCH₂), 4.43,

4.61 (both d, J¼6.2 Hz, 2H, oxetane OCH₂trans and cis to

3-CH₂O), 6.89, 7.55 (both d, J¼8.8 Hz, 2H, o- and m-ArH

to 4-OCH₂); ¹³C NMR (125 MHz) d 14.5, 21.3, 30.4, 39.7,

72.8, 73.2, 79.8, 107.1, 113.9, 127.1, 130.4, 159.6; EI

HRMS Calcd for C₁₇H₂₂O₅: 306.1468. Found: 306.1467.

Anal. Calcd for C₁₇H₂₂O₅: C, 66.65; H, 7.24. Found: C,

66.72; H, 7.35.

1.62 (q, J¼7.5 Hz, 2H, 1-CH₂CH₃), 3.82 (s, 6H, CH₂O); ¹³

C

NMR (anhydrous CDCl₃) d 7.57, 14.6, 29.9, 30.3, 72.6,

109.2; FAB HRMS Calcd for C₈H₁₅O₃(M^þþH): 159.1022.

Found: 159.1025.

4.5.8. 4-Methyl-1-(4-nitrophenyl)-2,6,7-trioxabi-

cyclo[2.2.2]octane (5c). Reaction conditions: 4c (101 mg,

4.5.13. 4-Methyl-1-[4-(3-methyloxetan-3-ylmethoxy)-

benzyl]-2,6,7-trioxabicyclo[2.2.2]octane (5j). Reaction

7062

S. Kanoh et al. / Tetrahedron 58 (2002) 7049–7064

conditions: 4j (0.103 g, 0.322 mmol), BF₃·Et₂O (5 mol%),

CH₂Cl₂(6.1 mL), 258C, 24 h. 5j (79 mg, 79%); colorless

oil, which solidiﬁed gradually at room temperature; bp

160–1708C (1 mmHg); mp 67–688C; IR (KBr) 1250, 1040,

PhCl (1.0 mL) solution of 7b (150 mg, 1.05 mmol). The

resulting solution was allowed to react at 1208C for 24 h,

and quenched by adding Et₃N (0.1 mL) followed by MeOH

(3.0 mL). The solvents were replaced by CH₂Cl₂(1.0 mL),

and then vacuum distillation of the soluble part afforded 5-

hydroxymethyl-2,5-dimethyl-5,6-dihydro-4H-1,3-oxazine

(8b; 139 mg, 93%). Colorless oil; bp 110–1208C

1010, 990, 970, 830 cm²^{1 1}H NMR d 0.70 (s, 3H,

;

orthoester 4-CH₃), 1.34 (s, 3H, oxetane 3-CH₃), 2.86 (s,

2H, CH₂Ar), 3.80 (s, 6H, orthoester OCH₂), 3.91 (s, 2H,

CH₂OAr), 4.36, 4.54 (both d, J¼5.8 Hz, 2H, oxetane OCH₂

trans and cis to 3-CH₂O), 6.77, 7.14 (both d, J¼8.5 Hz, 2H,

o- and m-ArH to 4-OCH₂); ¹³C NMR d 14.6, 21.4, 30.5,

39.7, 42.0, 72.6, 79.8, 108.5, 113.8, 127.4, 131.4, 157.6;

FAB HRMS Calcd for C₁₈H₂₅O₅(M^þþH): 321.1703.

Found: 321.1706.

1

(1 mmHg); IR (liquid ﬁlm) 3300, 1670 cm²¹; H NMR d

0.94 (s, 3H, 5-CH₃), 1.90 (s, 3H, 2-CH₃), 2.96, 3.24 (both d,

J¼16.1 Hz, 1H, NCH₂), 3.41 (s, 2H, CH₂OH), 3.74, 3.98

(both dd, J¼10.9, 1.0 Hz, 1H, OCH₂); ¹³C NMR d 19.0,

20.9, 32.2, 50.4, 65.1, 70.3, 157.8. EI HRMS Calcd for

C₇H₁₃NO₂: 143.0948. Found: 143.0948.

4.5.14. Ethyl 1-ethoxy-4-methyl-2,6-dioxabicyclo-

[2.2.2]octane-7-carboxylate (5k). Reaction conditions: 4k

(195 mg, 0.789 mmol), BF₃·Et₂O (5 mol%), CH₂Cl₂

(2.0 mL), 258C, 6 h. 5k (125 mg, 64%); colorless oil; bp

80–908C (1 mmHg); IR (liquid ﬁlm) 1720, 1150, 1050,

4.5.18. 5-Hydroxymethyl-5-methyl-5,6-dihydro-4H-1,3-

oxazine (8a). Reaction conditions: Me₃Al (50 mol%),

PhCl, 1208C, 24 h. The reaction was quenched with Et₃N

followed by MeOH containing a small amount of aq NaOH.

8a (50%); colorless oil; bp 50–708C (1 mmHg); IR (liquid

ﬁlm) 3300, 1650 cm²¹; ¹H NMR d 0.98 (s, 3H, 5-CH₃), 2.30

(br s, 1H, OH), 3.00, 3.27 (both d, J¼14.9 Hz, 1H, NCH₂),

3.48 (s, 2H, CH₂OH), 3.64 (d, J¼10.7 Hz, 1H, OCH₂,), 4.03

(dd, J¼10.7, 2.0 Hz, 1H, OCH₂,), 7.01 ppm (br s, 1H,

C2H ).

990 cm²^{1 1}H NMR d 0.84 (s, 3H, 4-CH₃), 1.16 (t,

;

J¼7.1 Hz, 3H, 1-OCH₂CH₃), 1.27 (t, J¼7.1 Hz, 3H,

7-CO₂CH₂CH₃), 1.90 (ddd, J¼13.2, 11.0, 3.3 Hz, 1H,

C8H₂trans to 7-CO₂CH₂CH₃), 2.17 (ddd, J¼13.1, 4.9,

3.1 Hz, 1H, C8H₂cis to 7-CO₂CH₂CH₃), 3.15 (dd, J¼11.0,

4.9 Hz, 1H, C7H ), 3.74–3.97 (m, 5H of 1-OCH₂CH₃, endo-

C3H, and C5H₂), 4.06–4.33 (m, 3H of exo-C3H and

7-CO₂CH₂CH₃): the carbons of syn- and anti-OCH₂to

7-CO₂Et in an enantiomer of 5k are deﬁned as the 3- and

5-positions, respectively; ¹³C NMR d 14.3, 15.4, 17.8, 28.9,

34.2, 47.2, 58.2, 60.8, 75.6, 108.8, 171.8; EI HRMS Calcd

for C₁₂H₂₀O₅: 244.1311. Found: 244.1309.

4.5.19. 5-Hydroxymethyl-5-methyl-2-propyl-5,6-dihy-

dro-4H-1,3-oxazine (8c). Reaction conditions: Me₃Al

(5 mol%), PhCl, 1208C, 24 h. 8c (89%); colorless oil; bp

100–1208C (1 mmHg); IR (liquid ﬁlm) 3300, 1670 cm²¹

;

¹H NMR d 0.93 (t, J¼7.2 Hz, 3H, CH₂CH₂CH₃), 0.95 (s,

3H, 5-CH₃), 1.59 (sex, J¼7.4 Hz, 2H, CH₂CH₂CH₃), 2.14

(t, J¼7.8 Hz, 2H, CH₂CH₂CH₃), 2.7 (br s, 1H, OH ), 2.98,

3.28 (both d, J¼15.4 Hz, 1H, NCH₂), 3.44 (s, 2H, CH₂OH),

3.72 (d, J¼10.8 Hz, 1H, OCH₂), 3.99 (dd, J¼10.7, 2.2 Hz,

1H, OCH₂).

4.5.15. 1-Ethoxy-4-methyl-2,6-dioxabicyclo[2.2.2]octane

(5l). Reaction conditions: 4l (200 mg, 1.16 mmol), MAD

(15 mol%), toluene (1.2 mL), 08C, 96 h. 5l (168 mg, 82%);

colorless oil, which was rapidly hydrolyzed with moisture

under air; bp 30–358C (1 mmHg); IR (liquid ﬁlm) 1000–

4.5.20. 2-Benzyl-5-hydroxymethyl-5-methyl-5,6-dihy-

dro-4H-1,3-oxazine (8d). Reaction conditions: Me₃Al

(5 mol%), PhCl, 1208C, 24 h. 8d (71%); colorless oil; bp

;

140–1608C (1 mmHg); IR (neat) 3300, 1670 cm²^{1 1}H

NMR d 0.91 (s, 3H, 5-CH₃), 3.07 (br s, 1H, OH ), 3.30, 3.53

(both d, J¼17.1 Hz, 1H, NCH₂), 3.38 (s, 2H, PhCH₂), 3.45

(s, 2H, CH₂OH), 3.70 (d, J¼10.7 Hz, 1H, OCH₂), 3.97

(dd, J¼10.6, 2.1 Hz, 1H, OCH₂), 7.23–7.35 ppm (m, 5H,

ArH ).

1

1100 cm²¹; H NMR (anhydrous CDCl₃) d 0.81 (s, 3H,

4-CH₃), 1.20 (t, J¼7.1 Hz, 3H, 1-OCH₂CH₃), 1.76–1.82

(m, 2H, C8H₂), 2.06–2.12 (m, 2H, C7H₂), 3.80 (q,

J¼7.2 Hz, 2H, 1-OCH₂CH₃), 3.88–3.96 (m, 4H, C3H₂

and C5H₂); ¹³C NMR (anhydrous CDCl₃) d 15.7, 18.3, 29.8,

31.0₇, 31.1₃, 58.0, 76.1, 110.3; FAB HRMS Calcd for

C₉H₁₇O₃(M^þþH): 173.1178. Found: 173.1181.

4.5.16. Poly(orthoester) from 4m: poly{oxy(2-phenyl-

1,3-dioxolane-2,5-diyl)methylene}. Reaction conditions:

4m (0.209 g, 1.17 mmol), MAD (5 mol%), CH₂Cl₂

(1.2 mL), 08C, 72 h. The poly(orthoester) obtained in 95%

NMR conversion was puriﬁed by precipitation from a

CH₂Cl₂solution with MeOH. IR (cast ﬁlm) 1720 (vw),

1310–1280, 1110–980 cm²¹; ¹H NMR (500 MHz) d 3.76–

3.44 (m, 2H, OCH₂), 4.05–3.76 (m, 2H, CH₂in ring), 4.28–

4.05 (m, 1H, CH in acetal ring), 7.40–7.10 (br s, 3H, m- and

p-ArH ), 7.72–7.40 (br s, 2H, o-ArH ), 8.07–7.91 (br s,

o-ArH of the benzoate pendant group in the ether-type units

contained in 7%); ¹³C NMR (125 MHz) d 63.0, 67.3, 75.2,

121.3, 125.9, 126.0, 128.1, 129.1, 137.9–137.8.

M_{n GPC}¼8160.

4.5.21. 5-Hydroxymethyl-5-methyl-2-phenyl-5,6-dihy-

dro-4H-1,3-oxazine (8e). Reaction conditions: BF₃·Et₂O

(25 mol%), CH₂Cl₂, 358C, 96 h. 8e (89%); colorless oil; mp

135–1378C (CH₂Cl₂–hexane); IR (KBr) 3200, 1645 cm²¹

;

¹H NMR d 1.02 (s, 3H, 5-CH₃), 2.02 (br s, 1H, OH ), 3.27 (d,

J¼16.6 Hz, 1H, NCH₂), 3.48 (dd, J¼16.9, 2.2 Hz, 1H,

NCH₂), 3.47, 3.57 (both d, J¼10.7 Hz, 1H, CH₂OH), 3.92

(d, J¼10.7 Hz, 1H, OCH₂), 4.23 (dd, J¼10.7, 2.4 Hz, 1H,

OCH₂), 7.33–7.44 (m, 3H, m- and p-ArH ), 7.89 ppm (dd,

J¼6.9, 1.5 Hz, 2H, o-ArH ); ¹³C NMR d 19.0, 32.7, 51.1,

65.8, 127.0, 128.0, 130.5, 133.3, 155.0; EI HRMS Calcd for

C₁₂H₁₅NO₂: 205.1104. Found: 205.1115. Anal. Calcd for

C₁₂H₁₅NO₂: C, 70.22; H, 7.37; N, 6.82. Found: C, 69.96; H,

7.33; N, 6.76.

4.5.17. Isomerization of sec-amide-substituted cyclic

ethers. Typically, a hexane solution of Me₃Al (0.054 mL,

0.98 mol L²¹, 0.052 mmol) was added to an anhydrous

4.5.22. Isomerization of tert-amide-substituted oxetanes.

Typically, BF₃·Et₂O (0.112 mL, 0.43 mol L²¹in PhCl,

S. Kanoh et al. / Tetrahedron 58 (2002) 7049–7064

7063

0.048 mmol) was added to a PhCl (1.0 mL) solution of 10j

4.6. Isomerization of ketone-substituted oxetanes

(0.224 g, 0.961 mmol). The resulting solution was allowed

to stand at 1308C for 1.5 h, and quenched by adding

anhydrous Et₃N (1.0 mL) and a small amount of CaH₂.

Moisture-sensitive isomerization product, 7-ethyl-4-

methyl-1-phenyl-2,6-dioxa-7-azabicyclo[2.2.2]octane (11j;

0.121 g, 54%), was isolated by direct distillation of the

reaction mixture from CaH₂, and stored under nitrogen.

Colorless liquid; bp 100–1208C (1 mmHg); ¹H NMR

(100 MHz, anhydrous CDCl₃) d 0.88 (s, 3H, 4-CH₃), 0.94

(t, J¼7.3 Hz, 3H, CH₂CH₃), 2.36 (q, J¼7.2 Hz, 2H,

CH₂CH₃), 2.99 (s, 2H, NCH₂), 3.98 (s, 4H, OCH₂), 7.29–

7.38 (m, 3H, m- and p-ArH ), 7.60 (dd, J¼6.8, 3.2 Hz, 2H,

o-ArH ); EI HRMS Calcd for C₁₄H₁₉NO₂: 233.1417. Found:

233.1439.

4.6.1. 1-Methyl-5-phenyl-3,6,9-trioxabicyclo[3.2.2]no-

nane (18a). Reaction conditions: 17a (200 mg,

0.909 mmol), BF₃·Et₂O (5 mol%), CH₂Cl₂(1.1 mL), 258C,

72 h. 18a (164 mg, 82%); pale yellowish liquid, which

solidiﬁed at room temperature; bp 100–1058C (1 mmHg);

mp 98–1008C (CHCl₃–hexane); IR (KBr) 1120–

975 cm²^{1 1}H NMR d 0.80 (s, 3H, CH₃), 3.78 (s, 2H,

;

C2H₂), 3.85 (s, 2H, C4H₂), 3.79, 4.19 (both d, J¼9.4 Hz,

2H, equatorial and axial C7H₂and C8H₂with respect to a

boat-type 1,3-dioxane ring), 7.21–7.28 (m, 3H, ArH-m- and

-p), 7.41–7.49 (m, 2H, ArH-o ); ¹³C NMR d 18.9, 37.0,

65.7, 71.9, 79.6, 105.0, 125.7, 128.0, 128.1, 138.2; FAB

HRMS Calcd for C₁₃H₁₇O₃(M^þþH): 221.1178. Found:

221.1185.

On the other hand, TfOMe (0.05 mL, 0.43 mol L²¹in

nitrobenzene, 0.022 mmol) was added to a nitrobenzene

(1.0 mL) solution of 10j (0.224 g, 0.961 mmol). The

resulting solution was allowed to stand at 1508C for 96 h,

quenched with anhydrous Et₃N (0.1 mL), and then evapor-

ated. The residue was puriﬁed by column chromatography

on alumina with AcOEt–hexane¼2:3 as the eluent,

followed by distillation in vacuo, to give 1-ethyl-3-

methyl-azetidin-3-ylmethyl benzoate (14j; 0.141 g, 63%).

Pale yellow liquid; bp 130–1408C (1 mmHg); IR (liquid

ﬁlm) 1720, 1270, 1110 cm²¹; ¹H NMR (400 MHz) d 0.97 (t,

J¼7.3 Hz, 3H, 1-CH₂CH₃), 1.38 (s, 3H, 3-CH₃), 2.51 (q,

J¼7.2 Hz, 2H, 1-CH₂CH₃), 3.03, 3.21 (both d, J¼7.3 Hz,

2H, cis- and trans-NCH₂to 3-CH₃), 4.33 (s, 2H, 3-CH₂O),

7.45 (t, J¼7.6 Hz, 2H, m-ArH ), 7.57 (t, J¼7.3 Hz, 1H, p-

ArH ), 8.05 (d, J¼7.8 Hz, 2H, o-ArH ); ¹³C NMR

(100 MHz) d 12.2, 22.7, 34.5, 53.4, 62.0, 70.4, 128.3,

129.5, 130.2, 132.9, 166.5; EI HRMS Calcd for C₁₄H₁₉NO₂:

233.1417. Found: 233.1427.

4.6.2. Polyether from 17b: poly{oxy[2-(3-oxo-3-phenyl-

propoxymethyl)-2-methyltrimethylene]}. Reaction con-

ditions: BF₃·Et₂O (5 mol%), CH₂Cl₂, 258C, 48 h. The

poly(orthoester) obtained in 100% NMR conversion was

puriﬁed by precipitation from a THF solution with hexane.

1

IR (cast ﬁlm) 1680, 1100 cm²¹; H NMR d 0.84 (s, 3H,

CH₃), 3.09–3.50 (m, 8H, CH₂except for OCH₂CH₂CO),

3.78 (br s, 2H, OCH₂CH₂CO), 7.41–7.51 (m, 3H, m- and

p-ArH), 7.94 (br s, 2H, o-ArH); ¹³C NMR d 17.5, 38.9, 41.1,

67.1, 73.9, 74.1, 74.4, 128.2, 128.5, 133.0, 137.2, 198.8.

M_{n GPC}¼4530.

Acknowledgments

The authors would like to thank Professor Amy Howell,

University of Connecticut, for carefully proofreading the

manuscript and also for her many valuable suggestions that

were important to clarifying the presentation.

The preparation, spectroscopic properties, and analytical

data of other bicyclic acetals 11^14,16and azetidines 14¹⁶

were described in our previous reports.

References

4.5.23. 4-Methyl-1,7-diphenyl-2,6-dioxa-7-azabicyclo-

[2.2.2]octane (11v). Reaction conditions: BF₃·Et₂O

(5 mol%), CH₂Cl₂, 358C, 100 h. 11v (50%); colorless oil;

1. (a) Haines, A. H. Cyclic Ethers. Comprehensive Organic

Chemistry; Stoddart, J. F., Ed.; Pergamon: Oxford, 1979; Vol.

1, pp 853–896. (b) Smith, J. G. Synthesis 1984, 629–656.

2. Penczek, S.; Kubisa, P. Cationic Ring-opening Polymeriz-

ation. Comprehensive Polymer Science; Allen, G., Bevington,

J. C., Eastmond, G. C., Ledwith, A., Russo, S., Sigwalt, P.,

Eds.; Pergamon: Oxford, 1989; Vol. 3, pp 751–786.

1

bp 120–1258C (1 mmHg); H NMR (100 MHz, anhydrous

CDCl₃) d 0.91 (s, 3H, 4-CH₃), 3.69 (s, 2H, NCH₂), 3.88–

4.09 (m, 4H, OCH₂), 6.80–7.15 (m, 3H, o- and p-ArH to

NvC), 7.19–7.41 (m, 5H, 4-ArH-m and -p), 7.53–7.63 (m,

2H, 4-ArH-o).

´

3. (a) Penczek, S.; Kubisa, P.; Szymanski, R. Makromol. Chem.:

4.5.24. 3-Methyl-1-phenylazetidin-3-ylmethyl benzoate

(14v). Reaction conditions: TfOMe (35 mol%), nitro-

benzene, 1508C, 4.5 h. 14v (74%); colorless oil, which

solidiﬁed at room temperature; bp 120–1258C (1 mmHg);

Macromol. Symp. 1986, 3, 203–220. (b) Wojtania, M.;

Kubisa, P.; Penczek, S. Makromol. Chem.: Macromol. Symp.

1986, 6, 201–206. (c) Biedron, T.; Kubisa, P.; Penczek, S.

J. Polym. Sci., Part A: Polym. Chem. 1991, 29, 619–628.

4. (a) Kanoh, S.; Motoi, M. Bull. Chem. Soc. Jpn 1997, 70,

1649–1657. (b) Hiruma, T.; Kanoh, K.; Yamamoto, T.;

Kanoh, S.; Motoi, M. Polym. J. 1995, 27, 78–89. (c) Motoi,

M.; Saito, E.; Kyoda, S.; Takahata, N.; Nagai, S.; Arano, A.

Polym. J. 1991, 23, 1225–1241. (d) Motoi, M.; Nagahara, S.;

Akiyama, H.; Horiuchi, M.; Kanoh, S. Polym. J. 1989, 21,

987–1001, and other references cited therein.

mp 48–498C; IR (KBr) 1720, 1120 cm²^{1 1}H NMR

;

(400 MHz) d 1.44 (s, 3H, 3-CH₃), 3.64, 3.86 (both d, 2H,

J¼6.9 Hz, NCH₂trans and cis to 3-CH₂O), 4.41 (s, 2H,

3-CH₂O), 6.46 (d, J¼7.6 Hz, 2H, o-ArH to NvC), 6.75 (t,

J¼7.3 Hz, 1H, p-ArH to NvC), 7.22 (t, J¼8.1 Hz, 2H,

m-ArH to NvC), 7.40 (t, J¼7.4 Hz, 2H, 1-ArH-m ), 7.54 (t,

J¼7.3 Hz, 1H, 1-ArH-p ), 7.98 (d, J¼7.3 Hz, 2H, 1-ArH-o);

¹³C NMR (100 MHz) d 22.5, 35.0, 60.3, 70.2, 111.3, 117.4,

128.4, 129.0, 129.6, 130.0, 133.0, 151.2, 166.5; EI HRMS

Calcd for C₁₈H₁₉NO₂: 281.1417. Found: 281.1412.

5. Kanoh, S.; Nishimura, T.; Senda, H.; Motoi, M.; Tanaka, T.;

Kano, K. Macromolecules 1999, 32, 2438–2448.

6. Kanoh, S.; Nishimura, T.; Tsuchida, T.; Senda, H.; Motoi, M.;

7064

S. Kanoh et al. / Tetrahedron 58 (2002) 7049–7064

Takani, M.; Matsuura, N. Macromol. Chem. Phys. 2001, 202,

2489–2503.

22. Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 734–736.

23. Kanoh, S.; Nishimura, T.; Mitta, Y.; Ueyama, A.; Motoi, M.;

Tanaka, T.; Kano, K. Macromolecules 2002, 35, 651–657.

24. Fotsch, C. H.; Chamberlin, A. R. J. Org. Chem. 1991, 56,

4141–4147.

7. Kanoh, S.; Naka, M.; Yokozuka, T.; Itoh, S.; Nishimura, T.;

Honda, M.; Motoi, M.; Matsuura, N. Macromol. Chem. Phys.

2002, 203, 511–521.

8. Dainton, F. S.; Ivin, K. Q. Rev. 1958, 12, 61–92.

9. Kanoh, S.; Hashiba, T.; Ando, K.; Motoi, M. Synthesis 1997,

1077–1080.

25. (a) Miyamoto, M.; Saeki, Y.; Lee, C.-W.; Kimura, Y.; Maeda,

H.; Tsutsui, K. Macromolecules 1997, 30, 6067–6073.

(b) Miyamoto, M.; Saeki, Y.; Maeda, H.; Kimura, Y.

J. Polym. Sci., Part A: Polym. Chem. 1999, 37, 435–444.

(c) Miyamoto, M.; Tsutsui, K.; Kimura, Y. J. Polym. Sci., Part

A: Polym. Chem. 1999, 37, 445–453.

10. Motoi, M.; Sekizawa, S.; Asakura, K.; Kanoh, S. Polym. J.

1993, 25, 1283–1294.

11. Corey, E. J.; Raju, N. Tetrahedron Lett. 1983, 24, 5571–5574.

12. Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic

Synthesis. 3rd ed.; Wiley: New York, 1999; pp 437–440.

13. (a) Richardson, S. K.; Jeganathan, A.; Watt, D. S. Tetrahedron

Lett. 1987, 28, 2335–2338. (b) Mori, H.; Hirao, A.;

Nakahama, S. Macromolecules 1994, 27, 35–39. (c) Ishizone,

T.; Okamoto, K.; Hirao, A.; Nakahama, S. Macromolecules

1999, 32, 1453–1462. (d) Ducray, P.; Lamotte, H.; Rousseau,

B. Synthesis 1997, 404–406.

26. (a) Choi, W.; Sanda, F.; Endo, T. Macromolecules 1998, 31,

9093–9095. (b) Nemoto, N.; Xu, X.; Sanda, F.; Endo, T.

Macromolecules 2001, 34, 7642–7647.

27. Endo, T.; Uno, H. J. Polym. Sci., Polym. Lett. Ed. 1985, 23,

359–363.

28. Adachi, T.; Sugimoto, H.; Aida, T.; Inoue, S. Macromolecules

1993, 26, 1238–1243.

29. Kawakami, Y.; Takahashi, K.; Hibino, H. Macromolecules

1991, 24, 4531–4537.

14. Nishimura, T.; Kanoh, S.; Senda, H.; Tanaka, T.; Ando, K.;

Motoi, M. J. Chem. Soc., Chem. Commun. 1998, 43–44.

15. (a) Seeliger, W.; Aufderhaar, E.; Diepers, W.; Feinauer, R.;

Nehring, R.; Their, W.; Hellmann, H. Angew. Chem., Int. Ed.

Engl. 1966, 5, 875–888. (b) Ito, Y.; Inubushi, Y.; Zenbayashi,

M.; Tomita, S.; Saegusa, T. J. Am. Chem. Soc. 1973, 95,

4447–4448, and references cited therein.

30. Hayashi, Y.; Kayatani, T.; Sugimoto, H.; Suzuki, M.; Inomata,

K.; Uehara, A.; Mizutani, Y.; Kitagawa, T.; Maeda, Y. J. Am.

Chem. Soc. 1995, 117, 11220–11229.

31. Brooks, L. A.; Synder, H. R. Organic Syntheses; Horning,

E. C., Allen, C. F. H., Shriner, R. L., Drake, N. L., Smith, L. I.,

Hamilton, C. S., Snyder, H. R., Eds.; Wiley: New York, 1955;

Collect. Vol. 3, pp 698–700.

16. Kanoh, S.; Nishimura, T.; Kita, Y.; Motoi, M.; Takani, M.;

Tanaka, T. J. Org. Chem. 2000, 65, 2253–2256.

32. Sato, K.; Kameyama, A.; Nishikubo, T. Macromolecules

1992, 25, 1198–1199.

17. (a) Feinauer, R. Synthesis 1971, 16–26. (b) Lu, C.; Odian, G.

J. Polym. Sci., Part A: Polym. Chem. 1994, 32, 2283–2290.

18. Porter, G. R.; Rydon, H. N.; Schoﬁeld, J. A. J. Chem. Soc.

1960, 2686–2690.

33. Krapcho, A. P.; Lovey, A. J. Tetrahedron Lett. 1973, 14,

957–960.

34. Baum, K.; Berkowitz, P. T.; Grakauskas, V.; Archibald, T. G.

J. Org. Chem. 1983, 48, 2953–2956.

19. (a) Cromwell, N. H.; Phillips, B. Chem. Rev. 1979, 79,

331–358. (b) Moore, J. A.; Ayers, R. S. In Chemistry of

Heterocyclic Compounds. Hassner, A., Ed.; Wiley: New York,

1983; pp 1–127 Part 2. (c) Davies, D. E.; Starr, R. C.

Comprehensive Heterocyclic Chemistry, Lwowski, W., Ed.;

Pergamon: Oxford, 1984; Vol. 7, pp 237–284 Part 5.

20. Unpublished data.

35. Gajda, T.; Zwierzak, A. Synthesis 1981, 1005–1008.

36. Schulenberg, J. W.; Archer, S. J. Am. Chem. Soc. 1960, 82,

2035–2038.

37. Mayﬁeld, R. J.; Yates, P. Org. Prep. Proced. Int. 1971, 3,

201–204.

38. Johnson, C. R.; Dutra, G. A. J. Am. Chem. Soc. 1973, 95,

7777–7782.

21. Itoh, S.; Kanoh, S.; Motoi, M. Polym. Preprints Jpn 1998, 47,

302.

Article Doi

Isomerization of cyclic ethers having a carbonyl functional group: New entries into different heterocyclic compounds

DOI: 10.1016/S0040-4020(02)00701-9

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Full text of DOI:10.1016/S0040-4020(02)00701-9

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