Controlled release of perfumery alcohols by neighboring-group participation. Comparison of the rate constants for the alkaline hydrolysis of 2-acyl-, 2-(hydroxymethyl)-, and 2-carbamoylbenzoates

Helvetica Chimica Acta Vol. 86 (2003)

2871

Controlled Release of Perfumery Alcohols by Neighboring-Group

Participation. Comparison of the Rate Constants for the Alkaline Hydrolysis

of 2-Acyl-, 2-(Hydroxymethyl)-, and 2-Carbamoylbenzoates

by Jean-Yves de Saint Laumer, Eric Fre¬rot*, and Andreas Herrmann*

¬

¡

Firmenich SA, Division Recherche et Developpement, B. P. 239, CH-1211 Geneve 8

Dedicated to our colleague Dr. Sina Escher on the occasion of her retirement

A series of 2-acylbenzoates 1 and 2, 2-(hydroxymethyl)benzoates 3, 2-carbamoylbenzoates 4 6, as well as

the carbamoyl esters 7 or 8 of maleate or succinate, respectively (see Fig. 2), were prepared in a few reaction

steps, and the potential use of these compounds as chemical delivery systems for the controlled release of

primary, secondary, and tertiary fragrance alcohols was investigated. The rate constants for the neighboring-

group-assisted alkaline ester hydrolysis were determined by anal. HPLC in buffered H₂O/MeCN solution at

different pH (Table 1). The rates of hydrolysis were found to depend on the structure of the alcohol, together

with the precursor skeleton and the structure of the neighboring nucleophile that attacks the ester function.

Primary alcohols were released more rapidly than secondary and tertiary alcohols, and benzoates of allylic

primary alcohols (e.g., geraniol) were hydrolyzed 2 4 times faster than their homologous saturated alcohols

(e.g., citronellol). For the same leaving alcohol, 2-[(ethylamino)carbonyl]benzoates cyclized faster than the

corresponding 2-(hydroxymethyl)benzoates, and much faster than their 2-formyl and 2-acetyl analogues (see,

e.g., Fig. 4). Within the carbamoyl ester series, 2-[(ethylamino)carbonyl]benzoates were found to have the

highest rate constants for the alkaline ester hydrolysis, followed by unsubstituted 2-(aminocarbonyl)benzoates,

or the corresponding isopropyl derivatives. To rationalize the influence of the different structural changes on the

hydrolysis kinetics, the experimental data obtained for the 2-[(alkylamino)carbonyl]benzoates were compared

with the results of density-functional computer simulations (Table 2 and Scheme 4). Based on a preliminary

semi-empirical conformation analysis, density-functional calculations at the B3LYP/6-31G** level were carried

out for the starting precursor molecules, several reaction intermediates, and the cyclized phthalimides. For the

same precursor skeleton, these simple calculations were found to model the experimental data correctly. With

an understanding of the influence of structural parameters on the rate constants obtained in this work, it is now

possible to influence the rates of hydrolysis over several orders of magnitude, to design tailor-made precursors

for a large variety of fragrance alcohols, and to predict their efficiency as controlled-release systems in practical

applications.

1. Introduction. Many perfumes contain intense-smelling primary, secondary, or

tertiary alcohols such as geraniol ((2E)-3,7-dimethylocta-2,6-dien-1-ol), citronellol

( 3,7-dimethyloct-6-en-1-ol), or menthol ( p-menthan-3-ol) (Fig. 1), which give rise

to rosy-floral and fresh notes in the final composition [1]. However, due to their high

volatility, many of these fragrance molecules can be perceived only over a relatively

short period of time in classical applications of functional perfumery. To increase the

performance of these compounds in a broad variety of consumer products, the design of

specific delivery systems for the controlled release of odorants has become an

important research area in the flavor and fragrance industry [2][3]. Until now, the

inclusion of active compounds into a matrix is the most widely used technique to

prolong the long-lasting effect of volatile compounds and, as an additional benefit, to

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Helvetica Chimica Acta Vol. 86 (2003)

increase their stability in aggressive media [3]. Chemical delivery systems which are

based on the release of active molecules by cleavage of a chemical bond of a precursor

molecule are an interesting alternative to encapsulation [4]. Reaction conditions, such

as the action of O₂, light [5 7] or enzymes, hydrolysis [8], change in pH [9][10], or

temperature, may be used to chemically transform suitable precursors to the desired

flavors or fragrances. Ideally, due to their high molecular masses, the precursor

compounds are odorless, increase the substantivity of the flavor or fragrance

compounds to be released, and may also serve as protection for chemically unstable

functionalities. Following our investigations on the controlled light-induced release of

fragrance aldehydes and ketones [5], we now report the design of delivery systems for

the release of perfumery alcohols by alkaline ester hydrolysis [9 11]¹).

Fig. 1. Structures and trivial names of primary, secondary, and tertiary fragrance alcohols giving rise to floral and

fresh notes [1]

The release of fragrance alcohols by lipase-triggered ester cleavage has already

been described for use in laundry applications [12]. However, enzymes are not present

in all washing powders and, furthermore, due to enzyme selectivity, these precursors

are mainly restricted to the release of primary alcohols. In general, the efficiency of

enzymatic reactions is based on the principle that specific functional groups that are

held in close proximity to the substrate to be cleaved in the reactive center of the

enzyme dramatically increase the reaction rates. Transferring this phenomenon to

intramolecular reactions by placing a substituent that influences the rate of the targeted

reaction close to the desired reaction center is known as neighboring-group

participation [13] or, if this participation leads to an enhancement of the reaction

rate, as intramolecular catalysis [14]. The general release principle of the precursors

described in this work is based on the presence of an intermediate nucleophilic species

that then intramolecularly attacks the carbonyl group of an ester function and releases

the desired alcohol upon cyclization (Scheme 1) [15]. This effect is well-known in

organic chemistry and has already been applied to the design of intramolecularly

activated pro-drugs [16].

1

)

Parts of the present publication are the subject of patent applications [11].

Helvetica Chimica Acta Vol. 86 (2003)

2873

Scheme 1. Concept of Neighboring-Group Participation for the Controlled Release of Fragrance Alcohols

The kinetics of alkaline ester hydrolysis of alkyl or aryl 2-acyl- or 2-benzoylben-

zoates [9][17 22] and their pseudoesters (phthalides isobenzofuran-1(3H)-ones)

[9][18][22][23], as well as of ethyl 2-(hydroxymethyl)benzoate [24], aryl 4-hydrox-

ybutanoates and (2-hydroxyphenyl)acetates [25], alkyl and aryl 2-(aminomethyl)ben-

zoates [26], or different carbamoyl ester derivatives [10][27 29] by neighboring-group

participation has been investigated separately by different research groups in a large

variety of solvents. In most of these studies, the dependence of the rate of hydrolysis

with respect to substitution at either the neighboring nucleophile or the backbone of

the substrate as well as the influence of buffer catalysis was analyzed in detail.

However, the influence of the leaving alcohol on the rate constants for hydrolysis,

which is crucial for the targeted application in functional perfumery, has been studied in

only a few cases. Phenyl 2-carbamoylbenzoates, e.g., were reported to hydrolyze 30 70

times faster than their corresponding butyl esters [28], in analogy to phenyl 2-acetyl-

[20] or 2-benzoylbenzoates [18], which hydrolyze 1.3 and 4.1 times faster, respectively,

than their corresponding methyl esters. However, the influence of the alcohol released

in the hydrolysis of the pseudoester analogues was found to be unremarkable [9] [18].

Apart from the neighboring-group participation of carbonyl groups for the hydrolysis

of a series of methyl esters [30], until now, no systematic study comparing the rate

constants for the alkaline hydrolysis of the same alcohols from systems with different

nucleophiles acting as neighboring groups has been reported.

The goal of this work is to develop tailor-made fragrance precursors that could

release different perfumery alcohols by neighboring-group-assisted alkaline ester

hydrolysis at desired rate constants in typical bodycare and household applications of

functional perfumery [11]. To achieve this goal, we studied the influence of the alcohol,

the structure of the precursor skeleton, and the nature of the neighboring group on the

rate of ester hydrolysis for a series of 2-acylbenzoates 1 and 2, 2-(hydroxymethyl)-

benzoates 3, and carbamoyl esters 4 8 (Fig. 2) in buffered solution, and tried to

rationalize our experimental data with the aid of computational calculations.

2. Results and Discussion.

2.1. 2-Acylbenzoates and Their Corresponding

Pseudoesters. The preparation of a series of methyl and ethyl 2-acylbenzoates via the

corresponding acid chloride [31], by esterification of 2-acylbenzoic acids in the

presence of HCl or H₂SO₄[32], or alternatively, by reaction of the carboxylic acid with

alkyl halides [33][34] has already been reported. Whereas in the former two cases, the

formation of the open ester form and/or the cyclic pseudoester was observed [33], the

reaction with the alkyl halides generally afforded exclusively the open ester form.

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Helvetica Chimica Acta Vol. 86 (2003)

Fig. 2. Structures of 2-acylbenzoates 1 and 2, 2-(hydroxymethyl)benzoates 3, and carbamoyl esters (4 8)

investigated as precursors for the controlled release of fragrance alcohols by alkaline hydrolysis

Several attempts to synthesize 2-acylbenzoates from their acid chlorides and the

corresponding perfumery alcohol failed, presumably due to the ring chain tautomer-

ism of the benzoic acid and the corresponding phthalide [35] during the formation of

the acid chloride. For example, in the reaction of 2-formylbenzoic acid with oxalyl

chloride, 3-hydroxyphthalide 9 was the only compound isolated (Scheme 2). Methyl 2-

acetylbenzoate (10; see below, Table 1) was successfully obtained by reaction of the

corresponding acid with diazomethane [21][36]; however, the attempted transester-

ification with geraniol and NaOMe in cyclohexane resulted in a ca. 1:1 mixture of the

desired benzoate 2b and phthalide derivative 11b. Reaction of 2-formylbenzoic acid

with 2-(bromoethyl)benzene and potassium carbonate in acetone according to the

literature procedure of Gautier and Dodd [37] gave benzoate 1e in 14% yield, without

formation of the corresponding phthalide 12e. The 2-formyl and 2-acetylbenzoates

1a,b,e and 2a c as well as geranyl 4-formylbenzoate (13; i.e., 1b with CHO at C(4))

were finally prepared in higher yields by using dicyclohexylcarbodiimide (DCC) with

N,N-dimethylpyridine-4-amine (DMAP) in CH₂Cl₂[9][20][38] (Scheme 2). Whereas

phthalides 12 were obtained as by-products in the DCC coupling reaction of 2-

Helvetica Chimica Acta Vol. 86 (2003)

2875

formylbenzoic acid, the formation of 3-methylphthalides 11 in the reaction with 2-

acetylbenzoic acid was not observed. All compounds were stable and could be isolated

in their pure state. No evidence for equilibration between the corresponding ring

chain tautomers of the final products was obtained under the conditions described in

this study [39]. Interestingly, the acidic esterification of 2-acetylbenzoic acid and

menthol in the presence of HCl, as reported in the literature for the synthesis of 2c [40],

could not be reproduced in this work. Following the published conditions, we only

obtained diastereoisomeric phthalide derivatives 11c (Scheme 2).

Scheme 2. Preparation of 2-Acylbenzoates (1 and 2) and of their Corresponding Phthalides 11 and 12. For R¹,

see Fig. 2.

2.2. 2-(Hydroxymethyl)benzoates. A few procedures for the preparation of 2-

(hydroxymethyl)benzoates such as transesterification of the corresponding lactones

[41], reaction of 2-(hydroxymethyl)benzoic acid with alkyloxonium fluoroborates [24],

or reduction of the corresponding alkyl hydrogen phthalates or their mixed anhydrides

either with H₂on Pd/C [42] or various borohydrides [43] have been reported in the

literature. We prepared 2-(hydroxymethyl)benzoates 3a c from their corresponding

alkyl hydrogen phthalates 14a c, the latter being obtained in almost quantitative yield

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Helvetica Chimica Acta Vol. 86 (2003)

by reaction of a perfumery alcohol with phthalic anhydride [44] in the presence of base

(Scheme 3). Reduction of the intermediate acyl chlorides or mixed anhydrides with

sodium borohydride afforded 2-(hydroxymethyl)benzoates 3a c in 30 55% yield.

Scheme 3. Preparation of 2-(Hydroxymethyl)benzoates 3 and 2-Carbamoylbenzoates 4 6. For R¹, see Fig. 2.

2.3 Carbamoyl Esters. Ring opening of N-alkylphthalimides with alkyl bromides

under alkaline reaction conditions, or of phthalic anhydride with alkylamines, followed

by esterification of the remaining free acid function, afforded 2-carbamoylbenzoates in

low to moderate yields, respectively [45]. Higher amounts of 2-(aminocarbonyl)- as

well as of 2-[(alkylamino)carbonyl]benzoates have been obtained from alkyl hydrogen

phthalates, either via their acyl chlorides and reaction with hexamethyldisilazane

[28] [46] or alkylamines [47], respectively, or by using peptide coupling reagents [48].

The synthesis of carbamoyl esters 4 8 was achieved in three consecutive reaction

steps starting from commercially available acid anhydrides. In the first step, diacid

monoesters (such as 14) were obtained by reaction of the desired fragrance alcohol

with the corresponding anhydride as described above for the synthesis of 2-

(hydroxymethyl)benzoates. The intermediate alkyl hydrogen phthalates (see 14),

maleates, or succinates were then converted to mixed anhydrides with pivaloyl chloride

or ethyl carbonochloridate, and, finally, reacted with ammonium acetate or alkyl amines

to give the target compounds 4 8 (Scheme 3 and Fig. 2). Although all three steps may

be carried out in a one-pot reaction sequence, we isolated and characterized some of

the intermediates common to the preparation of differently substituted products.

Compounds 6a and 6e were obtained by a consecutive one-pot reaction of phthaloyl

dichloride with the corresponding perfumery alcohols followed by addition of ⁱPrNH₂.

Helvetica Chimica Acta Vol. 86 (2003)

2877

2.4. Rate Constants for the Alkaline Hydrolysis by Neighboring-Group Participation.

To compare the rate constants for the alkaline hydrolysis of 2-formyl- or 2-

acetylbenzoates 1 and 2, 2-(hydroxymethyl)benzoates 3, and carbamoylesters 4 8

(Fig. 2), and to study the influence of the leaving alcohol, the nature of the nucleophile,

or the structure of the precursor skeleton, all kinetics measurements were carried out

under the same conditions in buffered solutions at pH 7.62 (phosphate), 10.47 (borate),

or 11.54 (phosphate/hydrogencarbonate) in H₂O/MeCN 2 :1 (v/v) at 208. The

comparison of the rate constants obtained for the hydrolysis of 2-formyl- and 2-

acetylbenzoates 1 and 2 with those of their corresponding phthalides (pseudoesters) 12

and 11, respectively, has already been reported elsewhere [9].

In most of the cases described in the literature, rate constants for the alkaline

hydrolysis of ester derivatives have been determined spectrophotometrically [20 27],

but also acid-base titrimetric methods [18], conductivity measurements [19], or NMR

spectroscopy [28] have been used. The rate constants can be determined graphically by

plotting the logarithm of the difference of the end absorption (A_i) and the absorption at

time t (A_t) against time (infinity-time method), by plotting the logarithm of the

difference of absorption at time t Dt and time t against time (Guggenheim method)

[49], or by plotting the absorption at time t against the absorption at time t Dt

(Kezdy Mangelsdorf Swinbourne method) [50]. Whereas the first procedure is the

one most often currently used [21][24 27][51], the latter methods have the advantage

that the end absorption A_i, which is often difficult to be determined accurately, is not

taken into account for the calculation of the rate constants (the reaction does not have

to go to completion) [52]. Recording the UV/VIS spectra of a buffered solution of 2-

acylbenzoates in H₂O/MeCN 2 :1 at constant time intervals between 260 and 360 nm at

208, as shown for citronellyl 2-formylbenzoate (1a) as an example, gave the plot

illustrated in Fig. 3. Comparison of these UV/VIS spectra with those of 3-hydroxy-

phthalide (9) and 2-formylbenzoic acid suggests that, at least in the case of the formyl

and acetylbenzoates, the reaction proceeds completely to the acid in the open form.

Exploitation of the same experimental data obtained for the hydrolysis of 1a

(Fig. 3) by all three graphical methods gave rate constants varying between 1.13 ¥ 10^À4

and 2.35 ¥ 10^À4s^À1(at l 280 nm) and between 1.37 ¥ 10^À4and 2.48 ¥ 10^À4s^À1(at l 285 nm).

Based on these large variations obtained by UV/VIS spectroscopy, and, especially

because possible consecutive reactions cannot be distinguished [52], we decided to

investigate the kinetics of hydrolysis by high-performance liquid chromatography

(HPLC) [9] [10]. Following the decrease in peak area of the precursors obtained by

reinjection of the reaction solution at constant time intervals allows an accurate

determination of rate constants with good reproducibility. Besides the advantage that

the reaction does not have to be driven to completion, the HPLC analysis can also be

carried out on considerably smaller amounts of compound and, because all the peaks

are base-line-separated, several compounds may be analyzed at the same time.

Furthermore, the development of new monolithic ultrafast HPLC columns allowed us

to follow the kinetics of fast reactions with half-life times of only a few minutes by

reinjecting the reaction samples at very short time intervals.

Since the hydroxide concentration was held constant by the buffer, the second-

order rate expression r k₂¥ [OH^À] ¥ [precursor] can be reduced to the first-order

expression r k₀¥ [precursor] [9][10][21][24 28]. Plotting the logarithm of the peak-

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Helvetica Chimica Acta Vol. 86 (2003)

Fig. 3. Determination of the rate constant for the alkaline hydrolysis of 1a by UV/VIS spectroscopy. k₀was

determined at l 285 nm by the Guggenheim method (see text).

area quotients (A_t/A₀) of the precursors against time gave a straight line with good

correlation coefficients (r²> 0.99) for all the measurements, thus justifying the general

assumption of first-order kinetics. The concentrations of the precursor compounds

were chosen to avoid the use of any solubilizer which, due to micelle formation in

solution, may influence the reaction kinetics. Generally 0.7-1.2 ¥ 10^À3m solutions of the

compound in MeCN were prepared and added to a buffer solution in H₂O/MeCN to

give the final reaction mixtures at pH 7.62, 10.47, or 11.54 in H₂O/MeCN 2 :1 (v/v). In a

typical experiment, the reaction solutions were injected at constant time intervals into a

HPLC apparatus and eluted on a reversed-phase column with H₂O/MeCN. The elution

conditions as well as the choice of the reversed-phase column were adapted to the

speed of hydrolysis to get a minimum of eight points; in most of the analyses, 20 points

were recorded. All experiments were repeated two to four times, and, in the case of

precursor 4b, the measured rate constants k₀varied between 1.05 ¥ 10^À4and 1.10 ¥ 10^À4

s^À1(at l 254 nm), thus showing that good reproducibility was obtained for the data.

Most of the compounds were detected at l 254 and 280 nm simultaneously, and, as

expected, the rate constants were found to be independent of the wavelength of the

analysis in all cases [21]. The results obtained for the alkaline hydrolysis of esters 1 8

are summarized in Table 1.

To be able to compare the rate constants obtained in this work with other values

reported in the literature and to be able to compare rate constants over a wide pH

range, we calculated the second-order rate constant k₂(obtained for constant hydroxide

concentration) by dividing the measured k₀values by 10^(pHÀpK⁾[21][24 26] using the

w

Table 1. Rate Constants k₀and k₂and Half-Life Times t_1/2for the Alkaline Hydrolysis of Precursors 1 8 in H₂O/MeCN 2 : 1 (v/v) at 208 (determined by HPLC analysis

)

w

at l 254 nm). The rate constants k₂were obtained by dividing the measured k₀values by 10^(pHÀpK(constant hydroxide concentration) by using the autoprotolysis

constant pK_w 14.83 obtained for H₂O/MeCN 2 : 1 [53]. All numbers are average values of at least two experiments (r²> 0.99).

No. pH

k₀¥ 10⁵[s^À1

]

k₂[l mol^À1s^À1

]

t_1/2[h]

No. pH

7.62

10.47 12.7

k₀¥ 10⁵[s^À1

]

k₂[l mol^À1s^À1

]

t_1/2[h]

4b

5b

3b

7b

7.62 10.7

10.47

11.54

1735.34

1.8

10

5a

3a

8b

2.90

1.5

11.54

7.62

10.47

11.54

5.49

5.50

1.36

889.56

892.00

219.76

3.5

7.62

10.47

11.54

2.13

345.45

9.0

7.62

10.47

11.54

3.5

7.62

10.47

11.54

1.37

222.19

14.1

7.62

10.47

11.54

14.2

7.62

10.47

11.54

3.88^a)

0.88

5.0

Table 1 (cont.)

No. pH

k₀¥ 10⁵[s^À1

]

k₂[l mol^À1s^À1

]

t_1/2[h]

No. pH

k₀¥ 10⁵[s^À1

]

k₂[l mol^À1s^À1

]

t_1/2[h]

6b

7.62

10.47

11.54

1.11

180.02

17.4

6a

7.62

10.47 347

11.54

0.606

98.28

79.38

31.9

0.06

1b

2b

6e

7.62

10.47 108

11.54

1a

2a

4c

7.62

10.47

11.54

24.6

0.2

30.0

6.85

0.6

7.62

10.47

11.54

7.62

10.47

11.54

3.98

38.2

0.91

0.75

4.8

0.5

2.50

25.6

0.57

0.50

7.7

0.8

7.62

10.47

11.54

2.04

330.85

9.4

7.62

10.47

11.54

1.64

265.17

11.8

Table 1 (cont.)

No. pH

7e 7.62

k₀¥ 10⁵[s^À1

]

k₂[l mol^À1s^À1

]

t_1/2[h]

No. pH

3c 7.62

10.47 4.93

k₀¥ 10⁵[s^À1

]

k₂[l mol^À1s^À1

]

t_1/2[h]

1.57

253.81

12.3

10.47

11.54

1.13

0.25

3.9

1.7

11.54 12.8

1e

7.62

10.47 315

11.54

0.258

41.9

72.0

74.8

0.1

2c

7.62

10.47

11.54 2.89

0.06

6.7

4d

7.62

5d

7.62

10.47 31.6

11.54

7.25

0.6

10.47 16.1

11.54

3.69

1.2

^a) Detection at l 220 nm.

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Helvetica Chimica Acta Vol. 86 (2003)

autoprotolysis constant pK_w 14.83 obtained for H₂O/MeCN 2 :1 (v/v) [53]²). Direct

comparison of the rate constants k₂measured for methyl 2-acetylbenzoate (10) in this

study with those reported in dioxane/H₂O [19][21] shows that our reaction rates are ca.

twice as slow as these literature values³). The rates of hydrolysis were found to deviate

only slightly from proportionality to the hydroxide concentration. A large deviation

was only measured in the case of 2-(hydroxymethyl)benzoate 3c at pH 10 11, where

the k₂values vary by a factor of 4.5, with the reaction being faster at pH 10 than at

pH 11. Doubling the borate buffer concentration (pH 10.52) did not generally

influence the rate of hydrolysis of the systems within the experimental error.

2.5. Influence of the Leaving Alcohol on the Rate of Hydrolysis. As expected,

primary alcohols were found to be released more rapidly than secondary and tertiary

alcohols. This is best demonstrated by comparing the rate constants k₂for the

hydrolysis of 2-(hydroxymethyl)benzoates 3b and 3c or 2-[(ethylamino)carbonyl]ben-

zoates 4b and 4c (Table 1). In the latter case, geraniol (primary) was released 6 7

times faster from 4b than menthol (secondary) from 4c, and 240 times faster than

benzyldimethyl alcohol (tertiary) from 4d. Comparison of the hydrolysis of menthyl 2-

acetylbenzoate (2c) with primary alcohol derivatives 2a or 2b shows that the rate

constants increase even more, namely by a factor of 10 and 15, respectively. Moreover,

benzoates of allylic primary alcohols (geraniol) are hydrolyzed between two to four

times faster than their homologous saturated alcohols (citronellol) as shown by

comparing 1b with 1a, 2b with 2a, or 3b with 3a.

2.6. Influence of the Neighboring Group on the Rate of Hydrolysis. Besides the

structure of the leaving alcohol, the nature of the neighboring group is an important

parameter that has a strong influence on the rate constants as shown in Fig. 4 for the

series of geranyl esters 1b 8b. The rate constants k₂were found to cover several orders

of magnitude between 0.75 for 2b and 1735 for 4b. Carbamoylbenzoate 4b cyclizes

twice as fast as 2-(hydroxymethyl)benzoate 3b, ca. 70 times faster than 2-formylben-

zoate 1b and almost 2000 faster than its 2-acetyl analogue 2b. The hydrolysis of geranyl

2-formylbenzoate (1b) is ca. 25 times faster than that of its 2-acetyl analogue 2b,

whereas citronellyl 2-formylbenzoate (1a) hydrolyzes ca. ten times faster than the

corresponding 2-acetyl derivative 2a. The release mechanism of alcohols from 2-

acylbenzoates such as 1 and 2 in basic solution has been described to proceed via

hydration of the carbonyl group followed by intramolecular nucleophilic attack to form

a lactone and an alcohol [30]. For 2-acylbenzoates, the OH^Àaddition [19] or the

cyclization [21] has been found to be the rate-determining step. Rapid ring opening

gives then the anion of the corresponding carboxylic acid together with the alcohol. The

mechanisms for the intramolecular cyclization of 2-(hydroxymethyl)benzoates [24], 2-

carbamoylbenzoates [27][28][55], or other related systems [25][26][29][51] are very

similar. However, in contrast to the 2-acylbenzoates, the internal nucleophile does not

2

)

Note that the literature values have been reported for reaction at 258, whereas our experiments were

carried out at 208. As compared to the pk_Wvalues of pure H₂O (14.16 at 208), the influence of the

temperature on the absolute values is expected to be relatively small as compared to the difference in

solvent. Since we are not interested in absolute rate constants but only in an estimation of the correct

order of magnitude, we consider this difference to be not very important since it affects all values equally.

The pK_wvalue of 15.05 used in our previous report to calculate k₂of compound 10 [9] corresponds to a

solvent mixture H₂O/MeCN ca. 1.2:1 (v/v) and 3:2 (w/w) at 258 [54].

3

)

Helvetica Chimica Acta Vol. 86 (2003)

2883

have to be generated by hydration. Within the carbamoylbenzoate series, 2-[(ethyl-

amino)carbonyl]benzoates such as 4b were found to have the highest rate constants for

the alkaline ester hydrolysis, followed by unsubstituted 2-(aminocarbonyl)benzoates

(see 5b) or the corresponding isopropyl derivatives (see 6b). The great diversity of

available neighboring groups corresponding to various kinetics of alcohol release is

presumably the most-important factor that can efficiently be varied for the tailor-made

design of optimized perfume precursors. Carbamoylbenzoates have the added

advantage that they are easily synthesized and, by structural modification of the

amide part, can be designed to attain the optimum rate of alcohol release for the

targeted application.

Fig. 4. Graphical representation of the different rate constants k₂[l mol^À1s^À1] (see Table 1) obtained for the

alkaline hydrolysis of geranyl esters 1b 8b

2.7. Influence of the Precursor Skeleton on the Rate of Hydrolysis. Another factor

that strongly influences the rate of ester hydrolysis is the structure of the precursor

substrate itself (Table 1, Fig. 4). First of all, the importance of the presence of a

neighboring group in the 2-position is illustrated by comparing the absolute rate

constants k₂of 2-formylbenzoate 1b (k₂ 24.6 l mol^À1s^À1) and the corresponding 4-

formylbenzoate 13 (k₂ 8.93 ¥ 10^À3l mol^À1s^À1, obtained from k₀ 4.58 ¥ 10^À6s^À1

measured at pH 11.54), which results in a rate enhancement for 1b by a factor of

2800. Generally, the rigidity of the substrate favors the cyclization of the precursor, and

an increase of the rate of hydrolysis by a factor of ca. 250 was, thus, observed for

maleate derivative 7b as compared to succinate derivative 8b, where free rotation

between the ester group and the attacking nucleophile is possible. Surprisingly, the rate

of hydrolysis increases by a factor of eight when comparing maleate derivative 7b with

benzoate 4b (Table 1, Fig. 4).

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Helvetica Chimica Acta Vol. 86 (2003)

2.8. Calculations. To have a general tool to predict the order of magnitude of the

structural changes on the release kinetics without preparing all the compounds in

question, we tried to rationalize our experimental data based on density-functional

computer simulations. Since the direct comparison of the different types of

nucleophiles used as the attacking neighboring groups in this work is very complicated

and time-consuming, we decided to investigate only the influence of the leaving

alcohols and the substitution effects on the nucleophiles in the case of the 2-

carbamoylbenzoates. For simplicity, and to save computation time, the leaving

fragrance alcohols citronellol, menthol, and geraniol used in the kinetics measurements

were replaced by EtOH, ⁱPrOH and 3-methylbut-2-en-1-ol, respectively. The different

reaction steps that are expected to be involved in the fragrance release of compounds

15 21 are illustrated in Scheme 4 as a simple model. In the first step, the OH^Àion of the

buffer solution abstracts a proton from the carbamoyl moiety to form the anionic

species A. After adopting the ideal conformation for the neighboring-group attack, A

cyclizes to intermediate B, which then yields phthalimide 22 together with the

corresponding alcoholate. The latter is protonated in the last step to form the final

products. Based on the fact that both the leaving alcohol R¹OH and the substituent R²

at the attacking nucleophile influence the rate constants considerably, we assume that

the first and the last steps of the reaction sequence in Scheme 4 are not rate-

determining. For example, if the deprotonation of the precursor were the rate-

determining step, the strong reactivity differences which were observed on varying the

structure of the leaving alcohol could not be explained. Therefore, as shown for

comparable cases, either the adoption of the ideal conformation for nucleophilic attack

(near-attack conformation) [56] or the breakdown of the tetrahedral intermediate [57]

were considered to be the rate-determining steps.

To simplify our calculations, the energies of the starting structures 15 18 were first

minimized by systematic conformer analyses at the semi-empirical PM3 level [58] with

the −Spartan× program. Based on these minima, all reactants, products, and inter-

mediates were then further optimized by density-functional calculations [59] in H₂O at

the B3LYP/6-31G** level within the −Jaguar× program. H₂O solvation energies were

computed by using the self-consistent reaction field as implemented in −Jaguar×. The

results obtained by these methods are summarized in Table 2. In the first series of

compounds, 15 18, we investigated the influence of the leaving alcohol R¹OH (allylic,

primary, and secondary) by keeping the substitution at the carbamoyl moiety the same;

in the second series, 19 21, we modified the substituent R²at the carbamoyl moiety

while keeping the same leaving alcohol. The energy differences DE₃and DE_totalin

Table 2 are obtained by subtracting either the sum of the energies of intermediate B

and H₂O or the sum of the energies of starting compounds 15 21 and the OH^Àion

from the sum of energies of phthalimides 22, the leaving alcoholate R¹O^Àand H₂O.

In the case of precursor 16, the B3LYP calculations showed that the anionic

intermediate A is ca. 4.5 kcal/mol higher in energy than species B, thus favoring the

cyclization. The reaction coordinate for the intramolecular nucleophile was explored at

the semi-empirical level PM3 in the gas phase and was found to contain a very low

energy barrier (0.5 kcal/mol) for the formation of B. We can, thus, suppose that the

activation energy for the second step is probably very low and will not greatly influence

the kinetics of the reaction. This, in return, suggests the third step to control the kinetics

Helvetica Chimica Acta Vol. 86 (2003)

2885

Scheme 4. Reaction Sequence for the Alkaline Hydrolysis of 2-[(Alkylamino)carbonyl]benzoates 15 21 Used

for the Density-Functional Calculations in H₂O. For R¹and R², see Table 2.

of the reaction. It is out of the scope of this publication to calculate the exact transition

state of this reaction, however, it can be assumed that the energy maximum of the

reaction pathway is very close to the end of the third step. When comparing the

different leaving alcoholates R¹O^À, the calculation of the energy difference DE₃for this

reaction step reflects correctly the order of the experimentally measured rate constants.

However, in the case that the leaving alcoholate is kept constant and the substituent R²

at the carbamoyl moiety varies, the experimental order of rate constants is not correctly

reflected by this reaction step. We, therefore, decided to compute the total energy

difference (DE_total) between the starting molecules 15 21 and their corresponding

phthalimides 22 together with the released alcoholate (Scheme 4). In this case, the

influence of both R¹and R²should be taken into account. Again, to save computing

time, the substituents R¹were reduced to between one and five C-atoms. The

significance of the absolute energy difference is probably low if we consider that it

includes anionic species, which may require explicit H₂O molecules for the calculation.

By taking into account relative energy differences for the entire reaction pathway,

errors are probably cancelled out since for all compounds, similar intermediates are

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Helvetica Chimica Acta Vol. 86 (2003)

Table 2. Energy Differences [kcal/mol] Obtained by Density-Functional Calculations (B3LYP/6-31G**) in H₂O.

The relative energies DE₃and DE_totalwere obtained by subtraction of the sum of energies of intermediate B and

H₂O (DE₃) or the sum of energies of compounds 15 21 and OH^À(DE_total) from the sum of energies of

compounds 22, the leaving alcoholate R¹O^À, and H₂O, respectively, according to the reaction pathway illustrated

in Scheme 4.

Starting

compound

R¹

R²

DE₃

[kcal mol^À1

DE_total

[kcal mol^À1

]

Order of exper.

rate constants^a)

]

15

16

17

18

19

20

21

23

24

Me₂CCHCH₂

Me

Et

13.26

12.13

15.37

16.80

11.64

13.53

12.73

14.90

10.44

À 2.55

À 2.50

0.78

a

Me

Et

Me₂CH

Me

b

c

1

2

3

2.94

À 2.44

À 2.06

À 0.27

2.94

H

Me₂CH

Me

I

II

À 0.54

^a) See Table 1: e.g., a (4b) > b > c (4c); 1 (4b) > 2 (5b) > 3 (6b); I (7b) > II (8b).

involved in the different reaction steps. The order of the DE_totalvalues calculated for

compounds 15 21 are consistent with the experimentally determined rate constants of

the corresponding fragrance precursors, thus confirming our hypothesis.

The structure of the alcohol influences the reaction rate for the breakdown of the

tetrahedral intermediate B with its ability to form an alcoholate R¹O^À(being related to

the acidity of the alcohol), whereas the substituent R²at the carbamoyl moiety appears

to influence the energy of the cyclization step. For the same precursor skeleton, these

simple calculations nicely reflect the experimental reactivity of the precursors.

However, the comparison of DE_totalfor the corresponding maleate derivative 23 and

succinate derivative 24 (R¹ R² Me) suggests that the saturated compound would

react faster than the unsaturated one, which is not in accordance with the experimental

values and, thus, illustrates the limitations of our model. The loss of entropic energy in

the cyclization of saturated 24 is not taken into account in our calculations, and the

computed DE_totalfor 24 is, thus, presumably too low⁴). Furthermore, the use of a

continuum model for the solvation treatment probably overestimates the strength of

the intramolecular H-bond in 23 giving rise to a higher value for DE_totalin this case.

3. Conclusions. A series of 2-acylbenzoates 1 and 2, 2-(hydroxymethyl)benzoates

3, and carbamoyl esters 4 8 were prepared in a few reaction steps as chemical delivery

systems for the controlled release of primary, secondary, and tertiary fragrance

alcohols. The perfumery alcohols were found to be efficiently released by neighboring-

group-assisted alkaline hydrolysis of suitably designed fragrance precursors in aqueous

4

)

The calculated zero-point vibrational-energy corrections and thermodynamic properties of molecules 23

and 24, as well as of their corresponding cyclization products, showed that the difference between the two

resulting energies is not significant when compared to the computed energy differences (DE_total) given in

Table 2. The quantification of the entropic contribution to the cyclization would, therefore, require a much

more-specific evaluation (based on molecular-dynamics studies) beyond the scope of this publication.

Helvetica Chimica Acta Vol. 86 (2003)

2887

solution. The general release principle of the precursors described in this work is based

on the formation of an intermediate nucleophilic species, which then intramolecularly

attacks the carbonyl group of an ester function and, upon cyclization, releases the

desired alcohol. The kinetics measurements were carried out at 208 in buffered

solutions in H₂O/MeCN by HPLC analysis.

The rates of hydrolysis depend on the structure of the leaving alcohol, together with

the precursor skeleton and structure of the neighboring nucleophile that attacks the

ester function. As a general trend, the experimental data showed that the fragrance

alcohols are released more rapidly from 2-carbamoylbenzoates or 2-(hydroxymethyl)-

benzoates than from 2-formyl- or 2-acetylbenzoates. The geometrically favored

structure of the 2-carbamoylbenzoates cyclizes more rapidly than the corresponding

conformationally mobile structure of a carbamoyl derivative of succinate. The 2-

[(ethylamino)carbonyl]benzoates react faster than the corresponding 2-(aminocar-

bonyl)- or the bulkier 2-[(isopropylamino)carbonyl]benzoates; and allylic primary

alcohols are more readily released than secondary or tertiary alcohols. A suitable

choice of these different structural parameters allows one to influence the rates of

hydrolysis over several orders of magnitude.

To understand and predict the order of magnitude of the structural changes on the

release kinetics, the experimental data were compared to the results of density-

functional computer simulations in the case of the 2-[(alkylamino)carbonyl]benzoates

as an example. Based on a preliminary semi-empirical conformation analysis, density-

functional calculations at the B3LYP/6-31G** level were carried out for the starting

precursor molecules, several reaction intermediates, and the cyclized phthalimides. The

total-energy difference (DE_total) between the starting molecules and the OH^Àion of the

buffer solution, and the corresponding phthalimides together with the released

alcoholate and H₂O, corresponds to the experimental reactivity of the precursors by

taking into account the structural variety of the leaving alcohol and the different

substitution at the attacking nucleophile. For the same precursor skeleton, these simple

calculations were found to model the experimental data correctly.

Based on the solid understanding of the influence of structural parameters on the

kinetic rate constants obtained in this work, it is now possible to design tailor-made

precursors for a large variety of fragrance alcohols and to predict their efficiency as

controlled-release systems in practical applications of functional perfumery. Further-

more, the chain length of the N-substituent of the 2-carbamoylbenzoates allows control

of hydrophobicity (log P) and, thus, the retention of the precursors on different

surfaces such as fabric or hair during washing [11]. The neighboring-group-assisted

release of alcohols from 2-acyl-, 2-(hydroxymethyl)-, or 2-carbamoylbenzoates

investigated in this work is very generally applicable and may, therefore, be extended

to the delivery of biologically active material in pharmaceutical or agrochemical

research.

Experimental Part

General. Commercially available reagents and solvents were used without further purification if not stated

otherwise. Reactions were carried out in standard glassware under N₂or Ar, and yields are not optimized.

Demineralized water was obtained from a Millipore Synergy-185 water purifier. Column chromatography (CC):

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Helvetica Chimica Acta Vol. 86 (2003)

silica gel 60 (35 70 mm from SDS). Anal. HPLC: Thermo Separation Products apparatus composed of an

online vacuum degasser, a SpectraSystem P4000 quaternary pump, a SpectraSystem AS3000 autosampler

thermostatted at 208, and a SpectraSystem UV6000LP diode array detector. UV/VIS Spectra: Perkin-Elmer

1

Lambda-14 spectrometer; l in nm (e). IR Spectra: Perkin-Elmer 1600-FTIR spectrometer; nÄ in cm^À1. H- and

¹³C-NMR Spectra: Bruker AMX-360 spectrometer; d in ppm downfield from Me₄Si as internal standard, J in

Hz; the NMR data of 1a, 3b, 4d, 7e, 8b, and (3R)-11c are assigned as examples in Table 3; the signals of other

structures may be attributed in analogy. GC/MS: Hewlett-Packard 5890 or 6890-GC system equipped with a

Supelco SPB-1 capillary column (30 m, 0.25 mm i.d.) at 708 for 10 min then to 2608 (108/min), He flow ca. 1 ml/

min, coupled with a Hewlett-Packard MSD-5972 or -5973 quadrupole mass spectrometer, electron energy ca.

70 eV, fragment ions m/z (rel. int. in % of the base peak).

1

Table 3. Assignment of ¹³C-NMR (90.6 MHz) and H-NMR (360 MHz) Data for Precursors 1a, 3b, 4d, 7e, 8b,

and (3R)-11c in CDCl₃Based on 1D and 2D NMR Measurements. d in ppm. Arbitrary numbering.

1a^a)

3b

d (C) d (H) d (C) d (H) d (C) d (H) d (C) d (H) d (C) d (H)

4d^a)

7e

8b^a)

(3R)-11c^a)

d (C) d (H)

C(1)

C(2)

132.45

137.10

129.29

143.13

130.98

138.07

125.03 6.07

138.41 6.30

31.07 2.47

29.72 2.67

168.01

C(3)

128.35 7.93

130.35 7.44

127.71 7.42

109.24

C(3a)

C(4)

C(5)

C(6)

C(7)

148.18

132.26 7.64

132.89 7.64

130.31 7.96

166.33

132.91 7.51

127.83 7.37

131.21 8.01

168.06

131.37 7.46

129.38 7.40

129.84 7.73

166.27

122.83 7.50

134.35 7.71

130.35 7.58

125.28 7.88

127.50

26.47 1.84

31.47 1.19

43.83 2.11, 1.09

75.47 3.04

48.40 1.20

22.80 1.55, 0.77

34.10 1.55, 0.77

22.21 0.86

24.90 2.09

16.08 0.37

21.46 0.87

166.16

173.12

C(7a)

C(8)

192.06 10.63

64.49 4.42

35.44 1.83, 1.63 117.94 5.48

29.53 1.63 142.87

36.94 1.40, 1.26 39.55 2.05

25.37 2.01

124.45 5.09

131.46

25.70 1.67

19.46 0.98

17.66 1.60

64.84 4.77

62.33 4.86

169.18

84.05

46.16 3.21

137.17

130.66 7.20

128.00 7.25

126.50 7.21

128.00 7.25

130.66 7.20

25.88 1.56

163.92

171.34

C(1')

C(2')

C(3')

C(4')

C(5')

C(6')

C(7')

C(8')

C(9')

C(10')

C(1'')

C(2'')

OH / NH

65.87 4.38

34.84 2.98

137.31

128.89 7.21

128.58 7.30

126.73 7.22

128.58 7.30

128.89 7.21

61.63 4.60

118.18 5.33

142.30

39.53 2.05

26.30 2.09

123.73 5.08

131.82

25.68 1.68

16.47 1.69

17.69 1.60

34.43 3.27

14.79 1.13

6.08

26.27 2.09

123.65 5.09

131.92

25.68 1.68

16.58 1.78

17.71 1.61

34.91 3.40

14.65 1.19

5.84

34.52 3.33

14.37 1.17

8.09

3.93

a

)

Kinetic Measurements [9]. Buffer solns. were prepared by dissolving (upon sonication) two buffer tablets

pH 7.0 (phosphate) or 9.0 (borate) (Fluka) in a mixture of 160 ml of demineralized H₂O and 40 ml MeCN, or, by

dissolving one envelope of buffer pH 11.0 (phosphate/hydrogencarbonate) (Aldrich) in 400 ml of demineralized

Helvetica Chimica Acta Vol. 86 (2003)

2889

H₂O and 100 ml of MeCN. To determine the pH values of the reaction solns., 10 ml of the buffer solns. were

diluted with 2 ml of MeCN (to give a mixture of H₂O/MeCN 2 :1 (v/v)) and the pH values measured to be 7.62 Æ

0.01, 10.47 Æ 0.02 and 11.54 Æ 0.02, respectively (Mettler-Toledo MP220 apparatus with an InLab 410-Ag/AgCl

glass electrode). For the soln. with double borate-buffer concentration, a pH value of 10.52 Æ 0.01 was

determined. All samples were thermostatted at 208.

For the measurement of the rate constants, the ester (35 to 45 mg) was dissolved in MeCN (25 ml), and this

soln. (0.2 ml) was added to a buffer soln. (1.0 ml) to give pH 7.62, 10.47, 10.52, or 11.54 in H₂O/MeCN 2 :1. The

mixture was immediately injected in a HPLC apparatus (t 0), eluted on a reversed-phase column with H₂O/

MeCN containing 0.1% of CF₃COOH, and analyzed at l 254 nm. Most of the chromatograms were recorded on

a Macherey-Nagel Nucleosil-100-5-C18 column (250 Â 4 mm i.d.) with H₂O/MeCN 7:3 ! 2 :8 during 20 min at

1 ml/min, and the reaction soln. (20 ml) was reinjected every 35 or 70 min (8 20 times). The kinetics of the fast

hydrolysis reactions were measured on a Merck Chromolith-SpeedROD-RP-C18e column (50 Â 4.6 mm i.d.) by

isocratic elution with H₂O/MeCN 3 :7 or 4 :6 at 1 or 3 ml/min, or by using H₂O/MeCN 7 :3 ! 4 :6 during 3 min at

3 ml/min; the reaction soln. (10 ml) was reinjected at constant time intervals varying between 3 and 6 min (8

20 times).

Computational Methods. All calculations were carried out on a Silicon-Graphics SGI-R10000 computer.

Since it is hardly possible to minimize all possible conformers at high computation levels, the starting precursor

structures were obtained from systematic conformer analyses by using the −Spartan× program (Version 02, edn.

2001; Wavefunction Inc., Irvine, CA, USA) at the semi-empirical PM3 level [58]. All reactants, products, and

intermediates were then further optimized by density-functional calculations [59] at the B3LYP/6-31G** level

within the −Jaguar× program (Version 4.0, edn. 2000; Schrˆdinger Inc., Portland, OR, USA) with the previously

calculated PM3 minima as the starting structures. H₂O solvation energies were computed with the self-

consistent reaction field as implemented in −Jaguar×.

Methyl 2-Acetylbenzoate (10) was prepared from 2-acetylbenzoic acid with diazomethane as described in

[21][36].

(Æ)-3,7-Dimethyloct-6-enyl 2-Formylbenzoate (1a) and (Æ)-3-(3,7-dimethyloct-6-enyloxy)isobenzofuran-

1(3H)-one (12a) [20][38]. A soln. of 2-formylbenzoic acid (7.50 g, 50.0 mmol), N,N-dimethylpyridin-4-amine

(DMAP; 4.88 g, 40.0 mmol) and citronellol (15.60 g, 100.0 mmol) in CH₂Cl₂(75 ml) was cooled in an ice-bath

before a soln. of dicyclohexylcarbodiimide (DCC; 11.35 g, 55.0 mmol) in CH₂Cl₂(25 ml) was added during 10

15 min. The mixture was stirred for 15 min at 08, then at 208 for 48 h. The formed precipitate was filtered off and

the filtrate washed with 10% HCl soln. (2Â), sat. Na₂CO₃soln. (2Â), and H₂O, dried (Na₂SO₄), and

evaporated. Repetitive CC (SiO₂, toluene/AcOEt 19 :1 and toluene) gave 2.45 g (17%) of 12a and 2.25 g (16%)

of 1a as colorless oils.

Data of 1a: UV/VIS (hexane): 288 (1400), 241 (8500). IR (neat): 2960m, 2924m, 2854m, 2117m, 1774w,

1713s, 1697s, 1594m, 1577w, 1449m, 1379m, 1359w, 1346w, 1302w, 1264s, 1192m, 1162w, 1131m, 1077s, 1043w,

985w, 947w, 890w, 821m, 800w. ¹H-NMR (360 MHz, CDCl₃; Table 3): 10.63 (s, 1 H); 8.00 7.90 (m, 2 H); 7.70

7.60 (m, 2 H); 5.15 5.05 (m, 1 H); 4.50 4.36 (m, 2 H); 2.12 1.92 (m, 2 H); 1.92 1.78 (m, 1 H); 1.78 1.52 (m,

2 H); 1.67 (s, 3 H); 1.60 (s, 3 H); 1.48 1.34 (m, 1 H); 1.34 1.17 (m, 1 H); 0.98 (d, J 6.3, 3 H). ¹³C-NMR

(90.6 MHz, CDCl₃; Table 3): 192.06 (d); 166.33 (s); 137.10 (s); 132.89 (d); 132.45 (s); 132.26 (d); 131.46 (s);

130.31 (d); 128.35 (d); 124.45 (d); 64.49 (t); 36.94 (t); 35.44 (t); 29.53 (d); 25.70 (q); 25.37 (t); 19.46 (q); 17.66

(q). EI-MS: 151 (20), 150 (15), 149 (89), 140 (3), 139 (4), 138 (41), 137 (21), 134 (17), 133 (100), 132 (12), 124

(5), 123 (53), 122 (5), 121 (7), 111 (6), 110 (6), 109 (24), 106 (4), 105 (37), 104 (32), 97 (4), 96 (15), 95 (73), 94

(7), 93 (10), 84 (7), 83 (17), 82 (58), 81 (93), 80 (9), 79 (5), 78 (3), 77 (36), 76 (17), 75 (3), 71 (5), 70 (26), 69

(91), 68 (27), 67 (49), 65 (12), 57 (12), 56 (15), 55 (46), 54 (4), 53 (12), 51 (17), 50 (7), 43 (12), 42 (10), 41 (98),

40 (3), 39 (17), 29 (14), 27 (11).

Data of 12a (mixture of stereoisomers): UV/VIS (hexane): 295 (sh, 100), 288 (sh, 100), 278 (700), 270

(700), 264 (sh, 600), 231 (sh, 3400), 224 (4300). IR (neat): 2957m, 2914m, 2863w, 1770s, 1614w, 1604w, 1466m,

1410w, 1363m, 1311m, 1284m, 1213m, 1152w, 1131m, 1089m, 1056s, 1011m, 924s, 896s, 832w, 800w. ¹H-NMR

(360 MHz, CDCl₃): 7.88 (dt, J 7.5, 0.8, 1 H); 7.70 (ddd, J 7.5, 7.5, 1.2, 1 H); 7.62 7.54 (m, 2 H); 6.36 (s, 1 H);

5.13 5.05 (m, 1 H); 4.42 3.90 (m, 1 H); 3.88 3.76 (m, 1 H); 2.09 1.88 (m, 2 H); 1.82 1.65 (m, 1 H); 1.68, 1.67

(2 s, 3 H); 1.65 1.55 (m, 1 H); 1.59 (s, 3 H); 1.55 1.44 (m, 1 H); 1.43 1.29 (m, 1 H); 1.28 1.11 (m, 1 H); 0.92,

0.92 (2 d, J 6.7, 3 H). ¹³C-NMR (90.6 MHz, CDCl₃): 168.72 (s); 145.10 (s); 134.33 (d); 131.30 (s); 130.74 (d);

129.03 (d); 128.22 (d); 127.27 (s); 125.42 (d); 124.61 (d); 123.40 (d); 102.57 (d); 102.45 (d); 68.69 (t); 68.62 (t);

37.06 (t); 36.39 (t); 36.33 (t); 29.40 (d); 29.34 (d); 25.71 (q); 25.40 (t); 19.46 (q); 17.65 (q). EI-MS: 151 (4), 149

(6), 138 (10), 137 (11), 136 (27), 135 (4), 134 (20), 133 (100), 123 (18), 122 (4), 121 (23), 109 (12), 105 (23), 104

(4), 96 (8), 95 (42), 94 (3), 93 (3), 83 (7), 82 (24), 81 (63), 80 (4), 79 (4), 77 (24), 76 (8), 71 (3), 70 (7), 69 (56),

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Helvetica Chimica Acta Vol. 86 (2003)

68 (25), 67 (25), 65 (3), 57 (6), 56 (5), 55 (24), 54 (3), 53 (7), 51 (10), 50 (4), 43 (9), 42 (6), 41 (53), 39 (10), 29

(7), 27 (6).

(2E)-3,7-Dimethylocta-2,6-dienyl 2-Formylbenzoate (1b) and (Æ)-3-[(2E)-3,7-Dimethylocta-2,6-dienylox-

y]isobenzofuran-1(3H)-one (12b) [9]. As described for 1a and 12a, with geraniol (15.42 g, 100.0 mmol). CC

(SiO₂, heptane/Et₂O 8 :2) gave 2.55 g (22%) of 1b and 4.36 g (38%) of 12b.

Data of 1b: UV/VIS (hexane): 288 (1400), 241 (9000), 209 (36800). IR (neat): 2967w, 2914m, 2853w,

1777w, 1711s, 1695s, 1594m, 1577m, 1484w, 1446m, 1376m, 1340w, 1303w, 1253s, 1191m, 1162w, 1128m, 1071s,

1040w, 963w, 924m, 890w, 819m, 799w, 748s, 699m, 639m. ¹H-NMR (360 MHz, CDCl₃): 10.63 (s, 1 H); 8.01 7.90

(m, 2 H); 7.68 7.60 (m, 2 H); 5.52 5.45 (m, 1 H); 5.13 5.05 (m, 1 H); 4.90 (d, J 7.5, 2 H); 2.18 2.03 (m,

4 H); 1.78 (s, 3 H); 1.67 (s, 3 H); 1.61 (s, 3 H). ¹³C-NMR (90.6 MHz, CDCl₃): 192.14 (d); 166.34 (s); 143.48 (s);

136.99 (s); 132.91 (d); 132.57 (s); 132.23 (d); 131.95 (s); 130.41 (d); 128.31 (d); 123.63 (d); 117.73 (d); 62.75 (t);

39.55 (t); 26.26 (t); 25.68 (q); 17.71 (q); 16.59 (q). EI-MS: 151 (8), 150 (3), 149 (29), 137 (3), 136 (20), 135 (3),

134 (12), 133 (51), 123 (4), 122 (5), 121 (20), 107 (7), 106 (4), 105 (18), 104 (4), 95 (8), 94 (9), 93 (40), 92 (11),

91 (5), 81 (10), 80 (19), 79 (7), 78 (3), 77 (20), 76 (6), 70 (7), 69 (100), 68 (60), 67 (24), 65 (8), 55 (7), 53 (12), 51

(11), 50 (5), 43 (5), 42 (4), 41 (80), 39 (14), 29 (7), 27 (9).

Data of 12b (off-white crystals): UV/VIS (hexane): 300 (sh, 9), 287 (sh, 42), 278 (800), 271 (800), 265 (sh,

610), 231 (sh, 7900), 223 (11100). IR (neat): 2967w, 2900m, 2870m, 2819w, 1804w, 1753s, 1714w, 1677w, 1604w,

1465m, 1436w, 1415m, 1376m, 1354m, 1311m, 1287m, 1239w, 1214m, 1207m, 1180w, 1139m, 1108w, 1089m,

1

1067m, 1011w, 992m, 963w, 913m, 893m, 885m, 801m, 786m, 778m, 752m, 713m, 690m, 639m, 617w. H-NMR

(360 MHz, CDCl₃): 7.88 (dt, J 7.5, 1.2, 1 H); 7.70 (ddd, J 7.5, 7.5, 1.2, 1 H); 7.58 (t, J 7.5, 2 H); 6.41 (s, 1 H);

5.48 5.39 (m, 1 H); 5.13 5.05 (m, 1 H); 4.41 (d, J 7.1, 2 H); 2.18 2.04 (m, 4 H); 1.73 (s, 3 H); 1.65 (s, 3 H);

1.60 (s, 3 H). ¹³C-NMR (90.6 MHz, CDCl₃): 168.82 (s); 145.35 (s); 143.33 (s); 134.31 (d); 131.88 (s); 130.71 (d);

127.25 (s); 125.40 (d); 123.75 (d); 123.45 (d); 118.74 (d); 101.06 (t); 66.21 (t); 39.63 (t); 26.26 (t); 25.68 (q); 17.70

(q); 16.55 (q). EI-MS: 151 (15), 150 (3), 149 (28), 137 (3), 136 (15), 135 (3), 134 (14), 133 (70), 123 (8), 122 (6),

121 (19), 108 (5), 107 (12), 106 (4), 105 (22), 104 (4), 95 (7), 94 (15), 93 (45), 92 (14), 91 (7), 85 (4), 81 (15), 80

(17), 79 (8), 78 (3), 77 (23), 76 (7), 70 (8), 69 (86), 68 (100), 67 (31), 65 (4), 55 (7), 53 (12), 51 (11), 50 (6), 43

(7), 42 (4), 41 (72), 39 (14), 29 (8), 27 (10).

2-Phenylethyl 2-Formylbenzoate (1e) and (Æ)-3-(2-Phenylethoxy)isobenzofuran-1(3H)-one (12e). As

described for 1a and 12a, with 2-formylbenzoic acid (12.72 g, 84.8 mmol), DMAP (8.27g, 67.8 mmol), 2-phenyl-

ethanol (20.69 g, 169.6 mmol), CH₂Cl₂(130 ml), DCC (19.25 g, 93.3 mmol), and CH₂Cl₂(40 ml). CC (SiO₂,

heptane/Et₂O 8 :2) yielded 2.38 g (11%) of 1e and 8.25 g (38%) of 12e, containing unreacted 2-phenylethanol.

Data of 1e: UV/VIS (hexane): 336 (28), 288 (1400), 241 (8400), 209 (37700). IR (neat): 3064w, 3026w,

2953w, 2893w, 1712s, 1692s, 1593m, 1577m, 1496m, 1483w, 1465w, 1452m, 1382m, 1264s, 1253s, 1191m, 1163w,

1126s, 1075s, 1040m, 1030m, 989m, 961m, 908w, 891w, 863w, 818m, 799m, 746s, 698s. ¹H-NMR (360 MHz,

CDCl₃): 10.50 (s, 1 H); 7.95 7.86 (m, 2 H); 7.66 7.57 (m, 2 H); 7.37 7.30 (m, 2 H); 7.30 7.22 (m, 3 H); 4.60 (t,

J 6.9, 2 H); 3.10 (t, J 6.9, 2 H). ¹³C-NMR (90.6 MHz, CDCl₃): 192.06 (d); 166.17 (s); 137.44 (s); 137.04 (s);

132.91 (d); 132.35 (d); 132.18 (s); 130.34 (d); 128.92 (d); 128.65 (d); 128.35 (d); 126.79 (d); 66.36 (t); 35.08 (t).

EI-MS: 150 (3), 149 (27), 134 (3), 133 (23), 121 (3), 106 (5), 105 (35), 104 (100), 91 (8), 79 (6), 78 (7), 77 (18),

76 (5), 65 (5), 51 (7), 50 (3).

Data of 12e: ¹H-NMR (360 MHz, CDCl₃): 7.86 (d, J 7.5, 1 H); 7.67 (ddd, J 7.5, 7.5, 1.2, 1 H); 7.57 (ddd,

J 7.5, 7.5, 0.8, 1 H); 7.44 (d, J 7.5, 1 H); 7.35 7.26 (m, 2 H); 7.26 7.18 (m, 3 H); 6.31 (s, 1 H); 4.12 (dt, J 9.5,

6.7, 1 H); 3.97 (dt, J 9.5, 7.3, 1 H); 2.98 (t, J 6.9, 2 H). ¹³C-NMR (90.6 MHz, CDCl₃): 168.69 (s); 144.86 (s);

137.98 (s); 134.38 (d); 130.80 (d); 128.98 (d); 128.48 (d); 127.16 (s); 126.53 (d); 125.41 (d); 123.44 (d); 102.48 (d);

70.67 (t); 36.07 (t). EI-MS: 254 (1, M ), 236 (3), 149 (11), 134 (9), 133 (100), 106 (14), 105 (18), 104 (28), 91

(11), 79 (4), 78 (7), 77 (14), 76 (3), 65 (3), 51 (5), 50 (2).

(Æ)-3,7-Dimethyloct-6-enyl 2-Acetylbenzoate (2a) [20][38]. A soln. of 2-acetylbenzoic acid (6.49 g,

39.0 mmol), DMAP (3.81 g, 31.2 mmol), and citronellol (12.48 g, 80.0 mmol) in CH₂Cl₂(60 ml) was cooled in an

ice-bath before a soln. of DCC (8.84 g, 42.9 mmol) in CH₂Cl₂(40 ml) was added during 5 min. The mixture was

stirred at 408 for 75 h. The formed precipitate was filtered off and the filtrate washed with 10% HCl soln. (2Â)

and sat. Na₂CO₃soln. (2Â). The org. layer was dried (Na₂SO₄) and evaporated, the excess citronellol distilled

off, the residue chromatographed (SiO₂, toluene/AcOEt 9 :1), and the crude product distilled at 150 1558/0.6

Torr: 7.43 g (63%) of 2a. Colorless oil. UV/VIS (hexane): 313 (sh, 100), 281 (sh, 1000), 276 (1000), 229 (9000).

IR (neat): 2961m, 2913m, 2872w, 2855w, 1717s, 1704s, 1597w, 1574w, 1446m (br), 1378w, 1354m, 1264s, 1248m,

1129m, 1100m, 1064m, 1038w, 1007w, 956m, 884w, 835w, 801w. ¹H-NMR (360 MHz, CDCl₃): 7.86 (dd, J 7.5, 1.2,

1 H); 7.56 (ddd, J 7.5, 7.5, 1.2, 1 H); 7.49 (ddd, J 7.5, 7.5, 1.6, 1 H); 7.40 (dd, J 7.5, 1.2, 1 H); 5.14 5.05 (m,

1 H); 4.42 4.27 (m, 2 H); 2.54 (s, 3 H); 2.12 2.18 (m, 2 H); 1.87 1.72 (m, 1 H); 1.72 1.48 (m, 2 H); 1.67 (s,

Helvetica Chimica Acta Vol. 86 (2003)

2891

3 H); 1.60 (s, 3 H); 1.46 1.32 (m, 1 H); 1.29 1.15 (m, 1 H); 0.95 (d, J 6.3, 3 H). ¹³C-NMR (90.6 MHz,

CDCl₃): 202.93 (s); 166.97 (s); 142.92 (s); 131.95 (d); 131.35 (s); 129.92 (d); 129.70 (d); 129.09 (s); 126.36 (d);

124.54 (d); 64.25 (t); 36.97 (t); 35.29 (t); 30.13 (q); 29.49 (d); 25.70 (q), 25.38 (t); 19.40 (q); 17.65 (q). EI-MS: 165

(23), 149 (12), 148 (19), 147 (100), 146 (41), 138 (18), 137 (3), 124 (3), 123 (28), 118 (6), 110 (3), 109 (13), 105

(7), 104 (18), 96 (6), 95 (30), 91 (13), 90 (9), 89 (5), 83 (5), 82 (21), 81 (33), 80 (3), 77 (5), 76 (14), 75 (3), 74

(3), 71 (4), 70 (4), 69 (26), 68 (8), 67 (16), 56 (4), 55 (11), 53 (3), 50 (4), 43 (5), 41 (15), 39 (3).

(2E)-3,7-Dimethylocta-2,6-dienyl 2-Acetylbenzoate (2b). As described for 2a, with geraniol (12.32 g,

80.0 mmol). The excess geraniol was distilled off and the residue chromatographed (SiO₂, toluene/AcOEt 9 :1):

9.08 g (78%) of 2b. Slightly yellow oil. UV/VIS (hexane): 313 (sh, 200), 300 (sh, 200), 282 (sh, 900), 276 (900),

268 (1000), 228 (9200). IR (neat): 2966w, 2920m, 2856w, 1784w, 1715s, 1704s, 1673w, 1597w, 1574w, 1494w,

1484w, 1445m, 1376m, 1354m, 1263s, 1205w, 1163w, 1137m, 1126m, 1100m, 1062m, 1038w, 1006w, 955m, 931m,

886w, 834w, 799w, 761m, 731m, 708m, 696m, 661w. ¹H-NMR (360 MHz, CDCl₃): 7.90 7.84 (m, 1 H); 7.55 (ddd,

J 7.5, 7.5, 1.2, 1 H); 7.48 (ddd, J 7.5, 7.5, 1.2, 1 H); 7.39 (dd, J 7.5, 1.6, 1 H); 5.49 5.41 (m, 1 H); 5.13 5.05

(m, 1 H); 4.83 (d, J 7.5, 2 H); 2.53 (s, 3 H); 2.20 1.95 (m, 4 H); 1.75 (s, 3 H); 1.67 (s, 3 H); 1.60 (s, 3 H).

¹³C-NMR (90.6 MHz, CDCl₃): 203.01 (s); 166.92 (s); 143.12 (s); 142.94 (s); 131.95 (d); 131.85 (s); 129.91 (d);

129.78 (d); 129.09 (s); 128.23 (s); 126.36 (d); 123.73 (d); 117.75 (d); 62.51 (t); 39.55 (t); 30.17 (q); 26.31 (t); 25.66

(q); 17.69 (q); 16.54 (q). EI-MS: 165 (23), 149 (6), 148 (28), 147 (100), 146 (8), 137 (3), 136 (26), 123 (3), 121

(19), 107 (6), 105 (11), 104 (6), 95 (4), 94 (11), 93 (33), 92 (10), 91 (20), 81 (5), 80 (13), 79 (6), 77 (8), 76 (7), 70

(3), 69 (46), 68 (42), 67 (15), 65 (4), 55 (3), 53 (6), 43 (6), 42 (2), 41 (22), 39 (4).

(1R,2S,5R)-5-Methyl-2-(1-methylethyl)cyclohexyl 2-Acetylbenzoate (2c). As described for 2a, with 2-

acetylbenzoic acid (11.36 g, 50.0 mmol), DMAP (4.88 g, 40.0 mmol), (À)-menthol (23.40 g, 150.0 mmol),

CH₂Cl₂(80 ml), DCC (11.36 g, 55.0 mmol), and CH₂Cl₂(40 ml). CC (SiO₂, toluene) and recrystallization from

hexane gave 1.96 g (13%) of 2c. White crystals. M.p. 89 918. UV/VIS (hexane): 315 (sh, 100), 281 (sh, 900), 275

(1000), 229 (9700). IR (neat): 3068w, 2962m, 2951m, 2924m, 2914m, 2865m, 2847m, 1716s, 1686s, 1593w, 1576w,

1488w, 1455m, 1417w, 1385w, 1360m, 1335w, 1284m, 1272s, 1259s, 1183w, 1154w, 1139m, 1106m, 1095m, 1080w,

1

1064m, 1035m, 1016w, 980m, 954s, 914m, 884w, 838w. H-NMR (360 MHz, CDCl₃): 7.87 (dd, J 7.7, 1.4, 1 H);

7.55 (ddd, J 7.5, 7.5, 1.6, 1 H); 7.48 (ddd, J 7.5, 7.5, 1.6, 1 H); 7.38 (dd, J 7.5, 1.2, 1 H); 4.93 (ddd, J 11.0,

11.0, 4.3, 1 H); 2.54 (s, 3 H); 2.21 2.12 (m, 1 H); 2.02 1.88 (m, 1 H); 1.78 1.67 (m, 2 H); 1.63 1.44 (m, 2 H);

1.20 1.03 (m, 2 H); 1.00 0.85 (m, 1 H); 0.94 (d, J 6.7, 3 H); 0.92 (d, J 7.1, 3 H); 0.80 (d, J 6.7, 3 H).

¹³C-NMR (90.6 MHz, CDCl₃): 203.20 (s); 143.20 (s); 131.92 (d); 129.76 (d); 129.64 (d); 129.26 (s); 126.23 (d);

75.84 (d); 47.16 (d); 40.59 (t); 34.25 (t); 31.49 (d); 30.35 (q); 26.30 (d); 23.42 (t); 22.02 (q); 20.81 (q); 16.26 (q).

EI-MS: 303 (1, [M 1] ), 166 (4), 165 (37), 149 (9), 148 (32), 147 (100), 146 (3), 139 (6), 138 (23), 123 (10),

105 (6), 104(4), 96 (5), 95 (20), 91 (13), 83 (9), 82 (5), 81 (13), 77 (3), 76 (4), 69 (4), 67 (3), 55 (6), 43 (4), 41

(3).

(Æ)-3-[(2E)-3,7-Dimethylocta-2,6-dienyl]-3-methylisobenzofuran-1(3H)-one (11b). Two drops (ca. 0.05 g)

of 30% NaOMe in MeOH were added to a soln. of 10 (0.5 g, 2.81 mmol) and geraniol (0.43 g, 2.79 mmol) in

cyclohexane (7 ml). The mixture was heated to reflux for 24h before another two drops of 30% NaOMe soln.

were added. The mixture turned red. After refluxing overnight, the mixture was cooled to r.t., neutralized with 2

drops of AcOH, extracted with Et₂O (2Â), washed with H₂O (2Â), filtered through Celite, and evaporated. CC

(SiO₂, heptane/Et₂O 7:3) afforded 0.09 g (10%) of pure 11b as a colorless oil, besides 0.20 g of 11b/2b ca. 1:1.

11b: ¹H-NMR (360 MHz, CDCl₃): 7.89 (dt, J 7.9, 1.0, 1 H); 7.73 (ddd, J 7.4, 7.4, 1.2, 1 H); 7.59 (ddd, J 7.5, 7.5,

0.8, 1 H); 7.53 (dt, J 7.5, 0.8, 1 H); 5.30 5.21 (m, 1 H); 5.09 5.01 (m, 1 H); 3.95 3.86 (m, 1 H); 3.61 3.53 (m,

1 H); 2.10 1.94 (m, 4 H); 1.86 (s, 3 H); 1.66 (s, 3 H); 1.56 (s, 3 H); 1.49 (s, 3 H). ¹³C-NMR (90.6 MHz, CDCl₃):

168.08 (s); 148.11 (s); 141.30 (s); 134.51 (d); 131.69 (s); 130.51 (d); 127.42 (s); 125.52 (d); 123.85 (d); 122.28 (d);

119.33 (d); 108.64 (s); 60.95 (t); 39.53 (t); 25.26 (t); 25.85 (q); 25.65 (q); 17.66 (q); 16.33 (q). EI-MS: 165 (29),

149 (8), 148 (25), 147 (100), 136 (11), 123 (4), 121 (10), 107 (6), 105 (7), 104 (3), 95 (3), 94 (6), 93 (26), 92 (9),

91 (20), 81 (8), 80 (11), 79 (4), 77 (8), 76 (7), 69 (36), 68 (42), 67 (13), 65 (4), 55 (3), 53 (7), 51 (3), 50 (3), 43

(11), 41 (30), 39 (7), 27 (3).

(3S)-and (3 R)-3-Methyl-3-{[1R,2S,5R)-5-methyl-2-(1-methylethyl)cyclohexyl]oxy}isobenzofuran-1(3H)-

one ((3S)- and (3R)-11c) [40][60]. HCl was bubbled through an ice-cold soln. of 2-acetylbenzoic acid (4.10 g,

25.0 mmol) and (À)-menthol (7.80 g, 50.0 mmol) in Et₂O (75 ml). After 30 min, the exothermic reaction slowed

down (T ca. 15 208). The mixture was stirred at 58 for 5 min and at 208 for 1 h under a weak current of HCl gas.

The soln. was slowly poured into a stirred sat. Na₂CO₃soln. and extracted with Et₂O (2Â), the extract washed

with sat. Na₂CO₃soln. and H₂O, dried (Na₂SO₄), and evaporated, and the residue submitted to CC (SiO₂,

toluene): 5.45 g (72%) of a partially crystallized product. Pentane was added and the crystals were filtered off.

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Helvetica Chimica Acta Vol. 86 (2003)

Washing with pentane (3Â) yielded 0.55 g of pure (3R)-11c⁵). White crystals. M.p. 1268. UV/VIS (hexane): 279

(700), 271 (700), 264 (sh, 500), 231 (sh, 7200), 225 (9000). IR (neat): 2989w, 2960m, 2948m, 2924m, 2884w,

2862w, 1762s, 1722w, 1612w, 1602w, 1466m, 1451m, 1384w, 1377m, 1368w, 1339m, 1308w, 1284s, 1242w, 1230w,

1218w, 1183s, 1172s, 1127m, 1096w, 1074m, 1043m, 1036m, 1013s, 997m, 970w, 897s, 888m, 848w, 805w. ¹H-NMR

(360 MHz, CDCl₃; Table 3): 7.88 (d, J 7.5, 1 H); 7.71 (ddd, J 7.5, 7.5, 1.2, 1 H); 7.58 (ddd, J 7.5, 7.5, 1.2, 1 H);

7.50 (d, J 7.5, 1 H); 3.10 2.98 (m, 1 H); 2.17 2.00 (m, 2 H); 1.84 (s, 3 H); 1.64 1.47 (m, 2 H); 1.28 1.01 (m,

3 H); 0.87 (d, J 7.1, 3 H); 0.86 (d, J 6.3, 3 H); 0.85 0.65 (m, 2 H); 0.37 (d, J 6.7, 3 H). ¹³C-NMR

(90.6 MHz, CDCl₃, Table 3): 168.01 (s); 148.18 (s); 134.35 (d); 130.35 (d); 127.50 (s); 125.28 (d); 122.83 (d);

109.24 (s); 75.47 (d); 48.40 (d); 43.83 (t); 34.10 (t); 31.47 (d); 26.47 (q); 24.90 (d); 22.80 (t); 22.21 (q); 21.46 (q);

16.08 (q). EI-MS: 302 (2, M ), 155 (3), 149 (10), 148 (73), 147 (100), 138 (3), 137 (8), 105 (4), 104 (3), 95 (4),

91 (10), 83 (3), 81 (5), 69 (3), 55 (4), 43 (4).

Crystallization of the concentrated mother liquor at À308 yielded (3S)-11c/(3R)-11c ꢀ 44 :55 (1.85 g).

White crystals. M.p. 92 1038. IR (neat): 2990w, 2961m, 2950m, 2925m, 2884w, 2864w, 1763s, 1722w, 1613w,

1602w, 1466m, 1452m, 1384w, 1378m, 1368w, 1339m, 1308w, 1284s, 1243w, 1230w, 1219w, 1183s, 1173s, 1127m,

1

1097w, 1075m, 1043m, 1036m, 1012s, 998m, 971w, 896s, 888m, 848w, 806w. H-NMR (360 MHz, CDCl₃): 7.91

7.84 (m, 2 H); 7.75 7.66 (m, 2 H); 7.63 7.47 (m, 4 H); 3.24 (ddd, J 10.5, 10.5, 4.4, 1 H); 3.04 (ddd, J 10.2,

10.2, 4.4, 1 H); 2.41 2.26 (m, 1 H); 2.18 2.00 (m, 2 H); 1.84 (s, 3 H); 1.83 (s, 3 H); 1.68 1.49 (m, 5 H); 1.30

1.00 (m, 5 H); 0.99 0.68 (m, 5 H); 0.93 (d, J 7.1, 3 H); 0.87 (d, J 7.1, 3 H); 0.86 (d, J 6.3, 3 H); 0.81 (d, J

6.7, 3 H); 0.76 (d, J 6.7, 3 H); 0.37 (d, J 7.1, 3 H ) . ¹³C-NMR (90.6 MHz, CDCl₃): 168.20 (s); 168.00 (s); 149.31

(s); 148.16 (s); 134.36 (d); 134.11 (d); 130.35 (2 d); 127.49 (s); 127.02 (s); 135.31 (d); 125.26 (d); 122.85 (d);

109.24 (s); 108.24 (s); 75.46 (d); 74.46 (d); 48.58 (d); 48.39 (d); 43.83 (t); 42.91 (t); 34.15 (t); 34.10 (t); 31.51 (d);

31.46 (d); 26.47 (q); 25.61 (q); 25.05 (d); 24.89 (d); 23.02 (t); 22.79 (t); 22.21 (q); 22.18 (q); 21.45 (q); 21.42 (q),

16.07 (q); 16.01 (q). EI-MS: 302 (1, M ), 149 (9), 148 (71), 147 (100), 137 (6), 105 (3), 95 (3), 91 (8), 81 (4), 55

(3), 43 (3).

(2E)-3,7-Dimethylocta-2,6-dienyl 4-Formylbenzoate (13). A soln. of 4-formylbenzoic acid (5.00 g,

33.3 mmol), DMAP (3.3 g, 26.6 mmol), and geraniol (10.3 g, 66.6 mmol) in CH₂Cl₂(40 ml) was cooled in an

ice-bath before a soln. of DCC (7.6 g, 36.6 mmol) in CH₂Cl₂(10 ml) was added dropwise. After the addition of

more CH₂Cl₂(50 ml), the mixture was left warming up to r.t. and stirred overnight. The formed precipitate was

filtered off, the filtrate washed with 10% HCl soln. (2Â), a sat. soln. of Na₂CO₃(2Â), and H₂O (pH ꢀ 7), dried

(Na₂SO₄), and evaporated, and 5 g of the crude mixture (14.9 g) were submitted to CC (SiO₂, heptane/Et₂O

4 :1): 2.7 g (84%) of 13. Slightly yellow oil. R_f(heptane/Et₂O 4 :1): 0.34. UV/VIS (MeCN): 302 (sh, 1400), 291

(2000), 261 (sh, 16800), 251 (21100). IR (neat): 2964m, 2914m, 2850m, 2729w, 1703s, 1673w, 1609w, 1577m,

1502m, 1443m, 1418m, 1381m, 1376m, 1338w, 1297w, 1265s, 1199s, 1166w, 1100s, 1090s, 1046w, 1015m, 981w,

926m, 854m, 807m, 757s, 687m, 681m. ¹H-NMR (360 MHz, CDCl₃): 10.10 (s, 1 H); 8.20 (d, J 8.3, 2 H); 7.95 (d,

J 8.3, 2 H); 5.53 5.45 (m, 1 H); 5.13 5.06 (m, 1 H); 4.88 (d, J 7.1, 2 H); 2.19 2.04 (m, 4 H); 1.78 (s, 3 H);

1.67 (s, 3 H); 1.61 (s, 3 H). ¹³C-NMR (90.6 MHz, CDCl₃): 191.64 (d); 165.57 (s); 143.01 (s); 139.08 (s); 135.53 (s);

131.89 (s); 130.20 (d); 129.46 (d); 123.67 (d); 117.98 (d); 62.45 (t); 39.55 (t); 26.27 (t); 25.68 (q); 17.70 (q); 16.58

(q). EI-MS: 286 (0.3, M ), 150 (6), 149 (11), 137 (3), 136 (22), 134 (11), 133 (64), 123 (4), 122 (3), 121 (29), 107

(8), 106 (3), 105 (18), 104 (4), 95 (4), 94 (12), 93 (70), 92 (16), 91 (15), 81 (6), 80 (21), 79 (14), 78 (3), 77 (20),

76 (4), 70 (5), 69 (100), 68 (27), 67 (15), 65 (5), 55 (5), 53 (9), 51 (7), 50 (3), 43 (4), 41 (39), 40 (3), 39 (9), 29

(3), 27 (4).

(3R)-3,7-Dimethyloct-6-enyl Hydrogen Benzene-1,2-dicarboxylate (14a) [44]. A soln. of citronellol (10.1 g,

64.6 mmol), phthalic anhydride ( isobenzofuran-1,3-dione; 9.6 g, 64.8 mmol), DMAP (0.8 g, 6.5 mmol), and

ⁱPr₂EtN (8.4 g, 64.8 mmol) in CH₂Cl₂(130 ml) was left stirring at r.t. for 5 h ( ! slightly yellow soln. which

decolored within 15 min). The mixture was extracted with 5% KHSO₄soln. (3Â) and sat. NaCl soln. (3Â) and

the org. phase dried (Na₂SO₄) and evaporated: 15.7 g (80%) of 14a. Slightly yellow oil that was used as such for

further transformations. ¹H-NMR (360 MHz, CDCl₃): 9.63 (br. s, 1 H); 7.95 7.88 (m, 1 H); 7.73 7.66 (m, 1 H);

1

5

)

The configuration was elucidated by H-NMR spectroscopy in combination with computer modelling of

the energy-minimized structures of the two diastereoisomers. The downfield shift of one of the Me d to

d0.37 ppm could be explained if the corresponding Me group lies close above the benzene ring system.

This was confirmed by computer simulation of the two diastereoisomers by using the −Monte Carlo×

procedure with the MM2 molecular force field as implemented in −MacroModel× [61]. Only in the

minimized structure of (3R)-11c, a Me group of the menthol-derived moiety was found to be in proximity

to the aromatic ring system.

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7.64 7.52 (m, 2 H); 5.12 5.03 (m, 1 H); 4.45 4.31 (m, 2 H); 2.08 1.88 (m, 2 H); 1.87 1.73 (m, 1 H); 1.71

1.49 (m, 2 H); 1.65 (s, 3 H); 1.56 (s, 3 H); 1.46 1.29 (m, 1 H); 1.28 1.13 (m, 1 H); 0.94 (d, J 6.7, 3 H).

¹³C-NMR (90.6 MHz, CDCl₃): 172.24 (s); 168.20 (s); 133.54 (s); 132.12 (d); 131.33 (s); 130.77 (d); 130.12 (s);

129.86 (d); 128.77 (d); 124.59 (d); 64.57 (t); 36.99 (t); 35.22 (t); 29.49 (d); 25.68 (q); 25.36 (t); 19.36 (q); 17.63

(q). CI-MS (NH₃): 306 (5), 305 (25, [M H] ), 184 (17), 174 (12), 173 (5), 171 (3), 168 (9), 167 (100), 166 (21),

158 (3), 157 (31), 155 (5), 153 (3), 149 (11), 139 (10), 138 (18), 137 (8), 124 (3), 123 (26), 121 (4), 110 (6), 109

(14), 105 (17), 104 (24), 96 (6), 95 (27), 94 (5), 93 (24), 83 (7), 82 (17), 81 (22).

(2E)-3,7-Dimethylocta-2,6-dienyl Hydrogen Benzene-1,2-dicarboxylate (14b). As described for 14a, with

geraniol (10.0 g, 64.9 mmol): 17.5 g (89%) of 14b. Slightly yellow oil. IR (neat): 2965m, 2914m, 2854m, 2663w,

2541w, 1724s, 1696s, 1599m, 1578m, 1491m, 1447m, 1410m, 1376m, 1339w, 1281s, 1256s, 1164w, 1120s, 1069s,

1037m, 978w, 959w, 924m, 888w, 831w, 797m, 790m, 772m, 740s, 703m, 685m. ¹H-NMR (360 MHz, CDCl₃):

7.95 7.90 (m, 1 H); 7.72 7.67 (m, 1 H); 7.63 7.52 (m, 2 H); 5.49 5.42 (m, 1 H); 5.09 5.02 (m, 1 H); 4.86 (d,

J 7.1, 2 H); 2.20 2.00 (m, 4 H); 1.75 (s, 3 H); 1.65 (s, 3 H); 1.57 (s, 3 H). ¹³C-NMR (90.6 MHz, CDCl₃): 172.33

(s); 168.26 (s); 143.17 (s); 133.76 (s); 132.21 (d); 131.77 (s); 130.66 (d); 129.91 (d); 129.85 (s); 128.71 (d); 123.78

(d); 117.61 (d); 62.82 (t); 39.55 (t); 26.29 (t); 25.66 (q); 17.66 (q); 16.50 (q). CI-MS (NH₃): 320 (2, [M NH₄] ),

185 (16), 184 (100), 167 (14), 154 (10), 138 (6), 137 (49), 81 (3).

(1,1-Dimethyl-2-phenylethyl) Hydrogen Benzene-1,2-dicarboxylate (14d). A 20% KH dispersion in oil (8 g,

39.9 mmol) was washed with pentane (5 Â 10 ml) and THF (2 Â 10 ml). Then THF (10 ml) and 2-methyl-1-

phenylpropan-2-ol (5 g, 33.3 mmol) in THF (10 ml) were added dropwise during 15 min. The mixture was

stirred for 1 h at r.t. and then added dropwise during 15 min to a mechanically stirred soln. of phthalic anhydride

(4.93 g, 33.3 mmol), ⁱPr₂EtN (4.30 g, 33.3 mmol) and DMAP (0.40g, 3.3 mmol) in THF (200 ml). At the end of

the introduction, more THF (50 ml) was added, and the mixture was heated to 508 and left cooling to r.t. during

1 h. The reaction mixture was poured on a stirred mixture of ice (300 ml) and 5% KHSO₄soln. (200 ml). Et₂O

(200 ml) was added and the org. phase extracted with 5% KHSO₄soln. (2 Â 100 ml) and sat. NaCl soln. (3Â).

Extraction with sat. NaHCO₃soln. (2 Â 100 ml), treatment of the aq. phase with KHSO₄(25 g), re-extraction

with Et₂O (2 Â 100 ml), washing with 5% KHSO₄soln. (2 Â 50 ml), drying, and evaporation gave 7.42 g (75%)

of 14d. Off-white crystals. IR (neat): 2973w, 2919w, 2866w, 2661w, 2556w, 1716m, 1689s, 1596m, 1578m, 1490m,

1467w, 1452m, 1415m, 1383m, 1370m, 1310m, 1285s, 1268s, 1237m, 1207w, 1186w, 1140m, 1114s, 1068s, 1031w,

1009w, 968w, 938m, 910w, 866w, 844m, 833m, 806w, 792m, 772m, 737s, 724m, 699s, 684m, 670w. ¹H-NMR

(360 MHz, CDCl₃): 11.55 (br. s, 1 H); 7.91 7.85 (m, 1 H); 7.62 7.47 (m, 3 H); 7.29 7.15 (m, 5 H); 3.17 (s, 2 H);

1.58 (s, 6 H). ¹³C-NMR (90.6 MHz, CDCl₃): 172.85 (s); 167.26 (s); 136.99 (s); 135.02 (s); 132.14 (d); 130.66 (d);

130.31 (d); 129.74 (d); 129.61 (s); 128.62 (d); 127.95 (d); 126.50 (d); 84.49 (s); 46.67 (t); 25.54 (q). EI-MS: 167

(3), 150 (9), 149 (100), 147 (3), 146 (21), 133 (5), 132 (37), 122 (3), 121 (9), 118 (3), 117 (25), 115 (9), 105 (8),

104 (15), 93 (10), 92 (12), 91 (27), 77 (6), 76 (8), 73 (3), 70 (4), 65 (18), 61 (5), 59 (10), 57 (3), 55 (4), 51 (4), 50

(5), 45 (5), 44 (3), 43 (19), 41 (4), 39 (6).

2-Phenylethyl Hydrogen Benzene-1,2-dicarboxylate (14e). As described for 14a, with 2-phenylethanol

(4.00 g, 32.7 mmol), phthalic anhydride (4.85 g, 32.7 mmol), DMAP (0.40 g, 3.3 mmol), ⁱPr₂EtN (4.23 g,

32.7 mmol) and CH₂Cl₂(80 ml): 8.60 g (97%) of 14e. Slightly yellow oil, which slowly crystallized. ¹H-NMR

(360 MHz, CDCl₃): 11.27 (br. s, 1 H); 7.92 7.86 (m, 1 H); 7.65 7.50 (m, 3 H); 7.32 7.16 (m, 5 H); 4.52 (t, J 7.1,

2 H); 3.04 (t, J 7.1, 2 H ) . ¹³C-NMR (90.6 MHz, CDCl₃): 172.41 (s); 168.02 (s); 137.57 (s); 133.37 (s); 132.20 (d);

130.83 (d); 129.97 (s); 129.87 (d); 128.94 (d); 128.75 (d); 128.51 (d); 126.58 (d); 66.32 (t); 34.77 (t). CI-MS

(NH₃): 290 (6), 289 (21), 288 (100, [M NH₄] ), 272 (3), 271 (3), 261 (4), 246 (4), 245 (13), 244 (84), 242 (6),

229 (3), 228 (5), 227 (45).

3,7-Dimethyloct-6-enyl 2-(Hydroxymethyl)benzoate (3a). A soln. of 14a (5.0 g, 16.4 mmol) in oxalyl

chloride (25 ml, 18 equiv.) was heated under reflux for 3 h. The excess oxalyl chloride was distilled off under

vacuum, and the crude acid chloride (5.3 g) was diluted in THF (40 ml). The soln. was cooled to À88 under Ar,

and NaBH₄(1.87 g, 3 equiv.) were added. The mixture was stirred at 08 for 4 h and at r.t. for another 16 h. The

mixture was then cooled again to 08, and MeOH (10 ml) was added dropwise. After 15 min, the mixture was

poured into cold 5% KHSO₄soln. and extracted with cold AcOEt. CC (SiO₂, toluene/Et₂O 9 :1) yielded 1.41 g

(31%) of 3a. Colorless oil. UV/VIS (hexane): 287 (sh, 930), 279 (1300), 270 (sh, 1000), 231 (10400). IR (neat):

3416m (br.), 3067w, 2958m, 2913m, 2872m, 2854m, 1709s, 1698s, 1601w, 1576w, 1450m, 1380m, 1289m, 1255s,

1195m, 1133s, 1082s, 1029s, 982w, 949m, 879w, 832w, 803w, 737s, 709m 669m. ¹H-NMR (360 MHz, CDCl₃): 7.99

(dd, J 7.8, 1.2, 1 H); 7.52 (ddd, J 7.5, 7.2, 1.2, 1 H); 7.45 (dd, J 7.5, 1.2, 1 H); 7.37 (ddd, J 7.8, 7.5, 1.2, 1 H);

5.10 (m, 1 H); 4.78 (d, J 7.2, 2 H); 4.38 (m, 2 H); 3.96 (t, J 7.2, 1 H); 2.02 (m, 2 H); 1.81 (m, 2 H); 1.68 (s,

3 H); 1.63 (m, 1 H); 1.61 (s, 3 H); 1.41 (m, 1 H); 1.25 (m, 1 H); 0.98 (d, J 6.5, 3 H). ¹³C-NMR (90.6 MHz,

CDCl₃): 168.08 (s); 143.04 (s); 132.93 (d); 131.46 (s); 131.08 (d); 130.34 (d); 129.22 (s); 127.81 (d); 124.49 (d);

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Helvetica Chimica Acta Vol. 86 (2003)

64.81 (t); 64.03 (t); 36.97 (t); 35.45 (t); 29.55 (d); 25.71 (q); 25.39 (t); 19.53 (q); 17.67 (q). CI-MS (NH₃): 308 (l,

[M NH₄] ), 291 (0.5, [M H] ), 174 (8), 169 (15), 152 (100), 135 (5), 105 (3).

(2E)-3,7-Dimethylocta-2,6-dienyl 2-(Hydroxymethyl)benzoate (3b). To a soln. of 14b (5.0 g, 16.6 mmol) in

CH₂Cl₂(50 ml) ⁱPr₂EtN (2.35 g, 1.1 equiv.) and, at 58, isobutyl carbonochloridate (2.26 g, 1 equiv.) were added

dropwise. The mixture was stirred at r.t. for 3 h, before CH₂Cl₂(200 ml) was added. The org. phase was washed

with H₂O, dried (Na₂SO₄), and evaporated to afford 6.34 g of a slightly yellow oil. At À208, this product (1.0 g,

2.49 mmol) was then added dropwise to a soln. of NaBH₄(0.38 g, 4 equiv.) in EtOH (10 ml). After reacting for

30 min, the mixture was poured into a cold mixture of AcOEt and 5% KHSO₄soln.. The org. phase was washed

with H₂O, dried (Na₂SO₄), and evaporated. CC (SiO₂, cyclohexane/AcOEt 4 :1) yielded 0.36 g (50%) of 3b.

Colorless oil. UV/VIS (hexane): 287 (sh, 860), 278 (1200), 270 (sh, 990), 231 (11000). IR (neat): 3422m (br.),

3068w, 2964m, 2917m, 2852m, 1765w, 1709s, 1698s, 1601w, 1576w, 1483w, 1445m, 1378m, 1339w, 1286m, 1252s,

1196m, 1167w, 1132s, 1076s, 1030s, 985w, 941m, 880w, 831w, 803w, 737s, 709m, 670w. ¹H-NMR (360 MHz, CDCl₃;

Table 3): 8.01 (dd, J 7.5, 1.1, 1 H); 7.51 (ddd, J 7.5, 7.5, 1.1, 1 H); 7.44 (dd, J 7.5, 1.1, 1 H); 7.37 (ddd, J 7.5,

7.5, 1.1, 1 H); 5.51 5.44 (m, 1 H); 5.13 5.06 (m, 1 H); 4.86 (d, J 7.0, 2 H); 4.77 (d, J 6.6, 2 H); 3.93 (t, J

7.0, 1 H); 2.18 2.04 (m, 4 H); 1.78 (s, 3 H); 1.68 (s, 3 H); 1.61 (s, 3 H). ¹³C-NMR (90.6 MHz, CDCl₃; Table 3):

168.06 (s); 143.13 (s); 142.87 (s); 132.91 (d); 131.92 (s); 131.21 (d); 130.35 (d); 129.29 (s); 127.83 (d); 123.65 (d);

117.94 (d); 64.84 (t); 62.33 (t); 39.55 (t); 26.27 (t); 25.68 (q); 17.71 (q); 16.58 (q). CI-MS (NH₃): 306 (3, [M

NH₄] ), 289 (1, [M H] ), 107 (100), 152 (35), 137 (45).

(1R,2S,5R)-5-Methyl-2-(1-methylethyl)cyclohexyl 2-(Hydroxymethyl)benzoate (3c). A soln. of commer-

cially available (1R,3R,4S)-p-menthan-3-yl hydrogen phthalate ((1R,2S,5R)-5-methyl-2-(1-methylethyl)cy-

clohexylhydrogen benzene-1,2-dicarboxylate; 14c; 3.78 g, 12.4 mmol) in oxalyl chloride (19 ml, 18 equiv.) was

heated under reflux for 1.5 h. The excess of oxalyl chloride was distilled off under vacuum and the crude acid

chloride (2.75 g) was diluted in THF (5 ml). The soln. was cooled to À88 under Ar, and NaBH₄(0.97 g, 3 equiv.)

was added. The mixture was stirred at 08 for 10 min and at r.t. for another 30 min. The mixture was then poured

into cold 5% KHSO₄soln. and extracted with Et₂O. CC (SiO₂, toluene/Et₂O 93 :7) yielded 1.85 g (55%) of 3c.

Colorless oil. UV/VIS (hexane): 287 (sh, 850), 278 (1300), 271 (sh, 1000), 231 (10700). IR (neat): 3426m (br.),

3068w, 2951m, 2923m, 2866m, 1767w, 1691s, 1601w, 1577w, 1451m, 1408w, 1385w, 1366m, 1288m, 1254s, 1184m,

1

1132s, 1080s, 1032s, 980m, 956s, 915m, 886w, 844w, 802w, 736s, 709m, 670m. H-NMR (360 MHz, CDCl₃): 7.99

(dd, J 7.5, 1.2, 1 H); 7.52 (ddd, J 7.5, 7.5, 1.6, 1 H); 7.45 (dd, J 7.5, 1.2, 1 H); 7.38 (ddd, J 7.5, 7.5, 1.6, 1 H);

4.97 (ddd, J 11.0, 11.0, 4.3, 1 H); 4.81, 4.73 (AB of ABX, J 12.6, 7.1, 2 H); 4.00 (t, J 7.1, 1 H, exchange with

D₂O); 2.13 (m, 1 H); 1.97 (m, 1 H); 1.75 (m, 2 H); 1.56 (m, 2 H); 1.14 (m, 1 H); 0.95 (d, J 6.7, 3 H); 0.93 (d,

J 7.1, 3 H); 0.81 (d, J 7.1, 3 H ) . ¹³C-NMR (90.6 MHz, CDCl₃): 167.64 (s); 142.92 (s); 132.81 (d); 130.94 (d);

130.44 (d); 129.71 (s); 127.84 (d); 75.55 (d); 64.92 (t); 47.25 (d); 40.93 (t); 34.26 (t); 31.51 (d); 26.46 (d); 23.46 (t);

22.04 (q); 20.83 (q); 16.32 (q). CI-MS (NH₃): 291 (1), 152 (100), 135 (52), 123 (5), 105 (10), 95 (2).

(2E)-3,7-Dimethylocta-2,6-dienyl 2-[(Ethylamino)carbonyl]benzoate (4b). Et₃N (12 ml, ca. 2 equiv.) was

added to a soln. of geraniol (6.16 g, 39.9 mmol) and phthalic anhydride (5.92 g, 40.0 mmol) in CH₂Cl₂(80 ml),

and the mixture was stirred under Ar at r.t. for 2 d. After the addition of more Et₃N (6 ml) and cooling to À208,

ethyl carbonochloridate (4.84 g, 44.6 mmol) in CH₂Cl₂(10 ml) was added dropwise during 8 min. The mixture

was left warming to r.t. and stirred for 4 h before 1 ml of ethyl carbonochloridate was added, and 10 min later,

EtNH₂¥ HCl (3.26 g, 40.0 mmol) was introduced. After stirring for 1 h, the mixture was acidified with 5%

KHSO₄soln., and the org. phase was washed with H₂O (2Â), dried (Na₂SO₄), and evaporated. CC (SiO₂,

cyclohexane/AcOEt 3 :1) yielded 8.33 g (63%) of 4b. Brownish yellow oil. UV/VIS (hexane): 283 (sh, 990), 276

(1200), 227 (sh, 10500). IR (neat): 3272m, 3065w, 2967m, 2915m, 2877m, 2853m, 1718s, 1639s, 1598m, 1577m,

1536s, 1483m, 1444m, 1376m, 1357w, 1336w, 1306m, 1283s, 1254s, 1163w, 1148w, 1123s, 1098w, 1073s, 1042m,

980w, 937m, 873m, 827w, 772w, 742m, 705m, 690m. ¹H-NMR (360 MHz, CDCl₃): 7.88 7.81 (m, 1 H); 7.52 7.39

(m, 3 H); 6.09 6.01 (m, 1 H); 5.42 (dt, J 7.1, 1.2, 1 H); 5.13 5.04 (m, 1 H); 4.80 (d, J 7.1, 2 H); 3.50 3.39

(m, 2 H); 2.17 2.00 (m, 4 H); 1.73 (s, 3 H); 1.68 (s, 3 H); 1.60 (s, 3 H); 1.22 (t, J 7.3, 3 H). ¹³C-NMR

(90.6 MHz, CDCl₃): 169.29 (s); 166.83 (s); 142.49 (s); 138.37 (s); 131.84 (s); 131.75 (d); 130.02 (d); 129.43 (s);

129.39 (d); 127.64 (d); 123.73 (d); 118.04 (d); 62.45 (t); 39.58 (t); 34.96 (t); 26.30 (t); 25.68 (q); 17.69 (q); 16.53

(q); 14.63 (q). CI-MS (NH₃): 347 (50, [M NH₄] ), 330 (68, [M H] , 68), 211 (100), 194 (42), 172 (21), 154

(21), 137 (6).

(1R,2S,5R)-5-Methyl-2-(1-methylethyl)cyclohexyl 2-[(Ethylamino)carbonyl]benzoate (4c). A soln. of

commercial 14c (15.22 g, 49.9 mmol) and Et₃N (6.95 ml, 1 equiv.) in CH₂Cl₂(40 ml) was cooled to À28 before

ethyl carbonochloridate (5.26 ml, 1.1 equiv.) in CH₂Cl₂(5 ml) was added during 10 min to generate the

corresponding mixed carbonic anhydride. After warming to r.t. and stirring for 2 h, the formation of a white

precipitate was observed. More Et₃N (6.95 ml), EtNH₂¥ HCl (4.07 g, 1 equiv.), and 30 min later, Et₃N (2 ml)

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were added. After 2 h, the mixture was diluted with AcOEt and extracted with 5% aq. KHSO₄soln. (5Â) and

washed with sat. NaCl soln. (2 Â 100 ml). Drying (Na₂SO₄), evaporation, and recrystallization from CH₂Cl₂

gave 5.44 g (32%) of 4c. White crystals. M.p. 177.8 178.28. UV/VIS (MeCN): 283 (sh, 750), 271 (1100), 222 (sh,

10900). IR (neat): 3298m, 3081w, 3060w, 2958m, 2944m, 2920m, 2864m, 1711s, 1671w, 1634s, 1597m, 1575m,

1546s, 1487w, 1463w, 1445m, 1382w, 1359m, 1347w, 1312m, 1290s, 1284s, 1181m, 1166m, 1147m, 1127s, 1096m,

1082m, 1046m, 1036m, 1007m, 982m, 959m, 916m, 891w, 870m, 846m, 799m, 782m, 748m, 688m. ¹H-NMR

(360 MHz, CDCl₃): 7.88 7.82 (m, 1 H); 7.53 7.40 (m, 3 H); 5.94 (m, 1 H); 4.92 (dt, J 10.9, 4.4, 1 H); 3.52

3.42 (m, 2 H); 2.19 2.10 (m, 1 H); 1.96 (dquint., J 6.9, 2.8, 1 H); 1.77 1.67 (m, 2 H); 1.59 1.44 (m, 2 H); 1.24

(t, J 7.1, 3 H); 1.17 1.02 (m, 2 H); 0.98 0.83 (m, 1 H); 0.92 (t, J 6.5, 6 H); 0.79 (d, J 7.1, 3 H ) . ¹³C-NMR

(90.6 MHz, CDCl₃): 169.21 (s); 166.26 (s); 138.40 (s); 131.67 (d); 129.86 (d); 129.71 (s); 129.36 (d); 127.84 (d);

75.56 (d); 47.14 (d); 40.62 (t); 34.98 (t); 34.26 (t); 31.46 (d); 26.20 (d); 23.31 (t); 22.02 (q); 20.89 (q); 16.21 (q);

14.65 (q). CI-MS (NH₃): 349 (100, [M NH₄] ), 332 (22, [M H] ), 326 (15), 300 (100), 254 (5).

1,1-Dimethyl-2-phenylethyl 2-[(Ethylamino)carbonyl]benzoate (4d). As described for 4c, with 14d (1.00 g,

3.4 mmol), Et₃N (0.68 g, 6.7 mmol) in ^tBuOMe (50 ml), ethyl carbonochloridate (0.36 g, 3.4 mmol), and

t

EtNH₂¥ HCl (1.10 g, 13.4 mmol) in BuOMe (50 ml): 1.07 g (98%) of 4d. Yellow solid. UV/VIS (MeCN): 278

(sh, 1000), 268 (sh, 1200), 263 (sh, 1400), 258 (sh, 1600), 228 (sh, 9000), 218 (sh, 15100). IR (neat): 3302m,

3062w, 3032w, 2977w, 2916w, 2877w, 2850w, 1712s, 1636s, 1595m, 1575w, 1538s, 1492m, 1454m, 1444w, 1382m,

1366m, 1356w, 1295s, 1255m, 1215m, 1179m, 1163m, 1145w, 1129m, 1117s, 1088m, 1041m, 1032m, 978m, 957w,

939w, 917w, 904w, 890w, 874m, 846m, 798m, 764m, 751m, 738m, 715m, 699s. ¹H-NMR (360 MHz, CDCl₃;

Table 3): 7.76 7.70 (m, 1 H); 7.50 7.37 (m, 3 H); 7.29 7.17 (m, 5 H); 5.84 (m, 1 H); 3.40 (dq, J 7.1, 1.6, 2 H);

3.21 (s, 2 H); 1.56 (s, 6 H); 1.19 (t, J 7.1, 3 H ) . ¹³C-NMR (90.6 MHz, CDCl₃; Table 3): 169.18 (s); 166.27 (s);

138.07 (s); 137.17 (s); 131.37 (d); 130.98 (s); 130.66 (d); 129.84 (d); 129.38 (d); 128.00 (d); 127.71 (d); 126.50 (d);

84.05 (s); 46.16 (t); 34.91 (t); 25.88 (q); 14.65 (q). EI-MS: 194 (19), 177 (8), 176 (74), 175 (11), 161 (3), 160 (23),

149 (11), 148 (13), 133 (15), 132 (90), 131 (20), 130 (16), 129 (5), 128 (4), 118 (11), 117 (100), 116 (11), 115 (37),

105 (13), 104 (21), 103 (6), 102 (4), 92 (8), 91 (50), 89 (5), 78 (5), 77 (11), 76 (16), 75 (4), 74 (4), 66 (3), 65 (13),

64 (3), 63 (5), 52 (3), 51 (7), 50 (8), 44 (4), 41 (3), 39 (7), 30 (3).

(3R)-3,7-Dimethyloct-6-enyl 2-(Aminocarbonyl)benzoate (5a). As described for 4c with 14a (2.00 g,

6.6 mmol), Et₃N (1.3 g, 13.1 mmol) in ^tBuOMe (100 ml), ethyl carbonochloridate (0.7 g, 6.6 mmol), and

NH₄OAc (2.00 g, 25.9 mmol). CC (SiO₂, heptane/AcOEt 1:1) gave 0.8 g (40%) of 5a. Slightly yellow oil. UV/

VIS (hexane): 283 (sh, 850), 275 (1000), 223 (sh, 8500). IR (neat): 3410m, 3338m, 3182m, 3072w, 2956m, 2915m,

2851m, 1718s, 1659s, 1601m, 1576m, 1492w, 1448m, 1379s, 1282s, 1261s, 1128s, 1073s, 1042m, 950m, 886w, 834w,

742m, 706m, 665m. ¹H-NMR (360 MHz, CDCl₃): 7.85 (d, J 7.5, 1 H); 7.55 7.45 (m, 3 H); 6.16 (br. d, 2 H); 5.09

(m, 1 H); 4.34 (m, 2 H); 2.00 (m, 2 H); 1.79 (m, 1 H); 1.67 (s, 3 H); 1.65 1.50 (m, 1 H); 1.60 (s, 3 H); 1.39 (m,

1 H); 1.23 (m, 2 H); 0.95 (t, J 6.3, 3 H). ¹³C-NMR (90.6 MHz, CDCl₃): 171.50 (s); 166.94 (s); 137.28 (s); 131.77

(d); 131.38 (s); 129.92 (d); 129.85 (d); 129.63 (s); 127.59 (d); 124.57 (d); 64.28 (t); 36.99 (t); 35.27 (t); 29.49 (d);

25.71 (q); 19.40 (q); 17.66 (q). CI-MS (NH₃): 304 (100, [M H] ), 183 (10), 166 (18), 148 (20).

(2E)-3,7-Dimethylocta-2,6-dienyl 2-(Aminocarbonyl)benzoate (5b). As described for 4c, with 14b (2.00 g,

6.6 mmol), Et₃N (1.33 g, 13.2 mmol) in ^tBuOMe (100 ml), ethyl carbonochloridate (0.7 g, 6.6 mmol), and

t

NH₄OAc (2.00 g, 25.9 mmol), and more Et₃N (4.0 g) and BuOMe (100 ml). CC (SiO₂, heptane/AcOEt 1 :1)

gave 1.54 g (77%) of 5b. Slightly yellow oil. UV/VIS (hexane): 283 (sh, 900), 275 (1100), 225 (sh, 9700). IR

(neat): 3415m, 3345m, 3182m, 3067w, 2964m, 2915m, 2851m, 1716m, 1658s, 1601m, 1576m, 1490w, 1444m,

1378m, 1340w, 1282m, 1257s, 1125s, 1069s, 1037m, 933m, 874w, 832w, 743m, 706m, 666m. ¹H-NMR (360 MHz,

CDCl₃): 7.83 (d, J 7.1, 1 H); 7.54 7.42 (m, 3 H); 6.42 (br. d, J 88.8, 2 H); 5.44 (m, 1 H); 5.08 (m, 1 H); 4.81

(d, J 7.1, 2 H); 2.17 2.01 (m, 4 H); 1.74 (s, 3 H); 1.67 (s, 3 H); 1.60 (s, 3 H). ¹³C-NMR (90.6 MHz, CDCl₃):

171.95 (s); 166.93 (s); 142.87 (s); 137.03 (s); 131.85 (s); 131.74 (d); 129.93 (d); 129.90 (d); 129.71 (s); 127.63 (d);

123.75 (d); 117.86 (d); 62.57 (t); 39.55 (t); 26.31 (t); 25.68 (q); 17.71 (q); 16.53 (q). CI-MS (NH₃): 319 (6, [M

NH4] ), 302 (5, [M H] ), 183 (100), 166 (57).

1,1-Dimethyl-2-phenylethyl 2-(Aminocarbonyl)benzoate (5d). As described for 4c, with 14d (1.00 g,

3.4 mmol), Et₃N (0.68 g, 6.7 mmol) in BuOMe (50 ml), ethyl carbonochloridate (0.36 g, 3.4 mmol), NH₄OAc

(1.03 g, 13.4 mmol) in BuOMe (50 ml), and more Et₃N (2.00 g): 0.97 g (97%) of 5d. Yellow oil. UV/VIS

t

(MeCN): 279 (sh, 830), 267 (1000), 263 (1100), 258 (sh, 1300), 252 (sh, 1500), 228 (sh, 7500), 218 (sh, 13000). IR

(neat): 3367m, 3195m, 3175m, 3062w, 3024w, 2997w, 2968w, 2920m, 2849w, 1721m, 1708s, 1639s, 1616m, 1599m,

1573m, 1491m, 1465w, 1450m, 1397m, 1379m, 1363m, 1335w, 1301s, 1280s, 1262w, 1212s, 1175m, 1153w, 1131s,

1116s, 1068m, 1039w, 1028w, 987w, 972m, 934w, 916w, 892m, 868m, 845m, 827w, 798m, 785m, 768m, 752m, 731m,

712m, 697s, 669m. ¹H-NMR (360 MHz, CDCl₃): 7.76 (d, J 7.5, 1 H); 7.52 7.40 (m, 3 H); 7.29 7.17 (m, 5 H);

5.96 (d, J 76.5, 2 H); 3.23 (s, 2 H); 1.58 (s, 6 H). ¹³C-NMR (90.6 MHz, CDCl₃): 171.54 (s); 166.24 (s); 137.19

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Helvetica Chimica Acta Vol. 86 (2003)

(s); 137.04 (s); 131.45 (d); 130.99 (s); 130.71 (d); 129.90 (d); 129.76 (d); 128.02 (d); 127.51 (d); 126.54 (d); 84.45

(s); 46.13 (t); 25.85 (q). EI-MS: 166 (6), 149 (13), 148 (100), 147 (34), 135 (3), 133 (11), 132 (95), 131 (16), 130

(17), 129 (5), 128 (4), 121 (6), 118 (9), 117 (94), 116 (10), 115 (35), 105 (12), 104 (33), 103 (11), 102 (6), 93 (4),

92 (32), 91 (56), 89 (5), 78 (5), 77 (10), 76 (28), 75 (6), 74 (6), 66 (3), 65 (17), 64 (4), 63 (5), 59 (11), 52 (3), 51

(8), 50 (11), 43 (3), 41 (3), 39 (7).

(3R)-3,7-Dimethyloct-6-enyl 2-{[(1-Methylethyl)amino]carbonyl}benzoate (6a). A soln. of citronellol

(5.0 g, 32.1 mmol) and Et₃N (4.5 ml) in CH₂Cl₂(40 ml) was added dropwise (during 3 h) under Ar at 08 to a soln.

of phthaloyl dichloride ( benzene-1,2-dicarbonyl dichloride; 6.51 g, 32.1 mmol) in CH₂Cl₂(40 ml). After

stirring for 3 h, a soln. of ⁱPrNH₂(1.89 g, 32.0 mmol) and Et₃N (4.5 ml) in CH₂Cl₂(20 ml) was added dropwise

during 9 min, and the mixture was left stirring overnight. Extraction with H₂O (3Â), drying (Na₂SO₄), and

evaporation gave 10.5 g of crude product. CC (SiO₂, cyclohexane/AcOEt 3 :1) yielded 5.66 g (51%) of 6a.

Yellow oil. UV/VIS (hexane): 283 (sh, 970), 276 (1100), 223 (sh, 10100). IR (neat): 3269m, 3064w, 2962m,

2916m, 2869m, 1721s, 1635s, 1597m, 1576w, 1536s, 1451m, 1380m, 1354w, 1327w, 1286s, 1256s, 1172m, 1125s,

1

1076s, 1042m, 951m, 883m, 829m, 780w, 740m, 707m, 687w. H-NMR (360 MHz, CDCl₃): 7.82 (m, 1 H); 7.51

7.40 (m, 3 H); 5.84 (br. d, J 7.8, 1 H); 5.09 (m, 1 H); 4.38 4.18 (m, 3 H); 2.08 1.90 (m, 3 H); 1.83 1.73 (m,

1 H); 1.67 (s, 3 H); 1.65 1.44 (m, 1 H); 1.59 (s, 3 H); 1.44 1.33 (m, 1 H); 1.25 (d, J 6.7, 6 H); 1.25 1.17 (m,

1 H); 0.95 (d, J 6.4, 3 H). ¹³C-NMR (90.6 MHz, CDCl₃): 168.45 (s); 166.83 (s); 138.53 (s); 131.67 (d); 131.33

(s); 129.86 (d); 129.57 (s); 129.36 (d); 127.66 (d); 124.56 (d); 64.13 (t); 41.96 (d); 36.99 (t); 35.34 (t); 29.52 (d);

25.71 (q); 25.36 (t); 22.63 (q); 19.45 (q); 17.66 (q). EI-MS: 346 (5, [M H] ), 208 (100), 190 (95), 148 (75), 130

(25), 123 (20), 95 (25), 81 (30), 69 (40), 60 (25), 41 (40).

(2E)-3,7-Dimethylocta-2,6-dienyl 2-{[(1-Methylethyl)amino]carbonyl}benzoate (6b). A soln. of geranyl

hydrogen phthalate anhydride with ethyl hydrogen carbonate (2 g, 5.34 mmol; prepared as described for 4b and

stored in the freezer) was reacted with ⁱPrNH₂(0.43 g, 1.1 equiv.) in CH₂Cl₂(20 ml) for 4 h at r.t. The mixture

was extracted with demineralized H₂O (2Â) and 5% KHSO₄soln. (2Â) and washed with demineralized H₂O.

The org. phase was dried (Na₂SO₄) and evaporated. CC (SiO₂, cyclohexane/AcOEt 7:3) gave 1.17 g (64%) of

6b. Colorless oil. UV/VIS (hexane): 283 (sh, 990), 275 (1200), 225 (sh, 11200). IR (neat): 3270m, 3064w, 2967m,

2922m, 2874m, 1719s, 1635s, 1597m, 1579w, 1536s, 1482w, 1447m, 1379m, 1329m, 1283s, 1254s, 1172m, 1123s,

1072s, 1038m, 981w, 939m, 882m, 829m, 777w, 741m, 708m, 688w. ¹H-NMR (360 MHz, CDCl₃): 7.86 (m, 1 H);

7.53 7.42 (m, 3 H); 5.72 (d, J 7.5, 1 H); 5.43 (m, 1 H); 5.09 (m, 1 H); 4.82 (d, J 7.1, 2 H); 4.26 (m, 1 H);

2.14 2.01 (m, 4 H); 1.74 (s, 3 H); 1.68 (s, 3 H); 1.60 (s, 3 H); 1.26 (d, J 6.7, 6 H). ¹³C-NMR (90.6 MHz, CDCl₃):

168.48 (s); 166.83 (s); 142.41 (s); 138.52 (s); 131.85 (s); 131.71 (d); 130.05 (d); 129.51 (s); 129.39 (d); 127.64 (d);

123.74 (d); 118.08 (d); 62.49 (t); 41.99 (d); 39.58 (t); 26.30 (t); 25.69 (q); 22.66 (q); 17.71 (q); 16.56 (q). CI-MS

(NH₃): 344 (35, [M H] ), 225 (80), 208 (100), 154 (10).

2-Phenylethyl 2-{[(1-Methylethlyl)amino]carbonyl}benzoate (6e). A soln. of 2-phenylethanol (5.0 g,

41.0 mmol) and Et₃N (6 ml) in CH₂Cl₂(40 ml) was added dropwise (during 45 min) under Ar at 08 to a soln.

i

of phthaloyl dichloride (8.32 g, 41.0 mmol) in CH₂Cl₂(40 ml). After stirring for 2 h, a soln. of PrNH₂(2.42 g,

40.9 mmol) and Et₃N (6 ml) in CH₂Cl₂(20 ml) was added dropwise during 45 min, and the mixture was stirred

for 2 h. Extraction with H₂O (3Â), drying (Na₂SO₄), evaporation, and recrystallization of the crude product

(12.3 g) from Et₂O gave 6.46 g (51%) of 6e. White solid. UV/VIS (hexane): 275 (1100), 267 (1100), 264 (1200),

257 (sh, 1400), 225 (sh, 10500). IR (neat): 3274m, 3062w, 3030w, 2972m, 2952w, 2034w, 2889w, 2874w, 1716s,

1682w, 1632s, 1598m, 1579m, 1537s, 1498m, 1470m, 1455m, 1446m, 1380m, 1368m, 1348m, 1327w, 1292s, 1281s,

1251s, 1174m, 1167m, 1149m, 1127s, 1085m, 1038m, 1031m, 998w, 976m, 949m, 910w, 890m, 880w, 866w, 845w,

837m, 806w, 787m, 752s, 715s, 698s. ¹H-NMR (360 MHz, CDCl₃): 7.75 (m, 1 H); 7.48 7.36 (m, 3 H); 7.32 7.18

(m, 5 H); 5.87 (br. d, J 7.9, 1 H); 4.47 (t, J 7.3, 2 H); 4.22 (sept.d, J 7.9, 6.7, 1 H); 3.02 (t, J 7.3, 2 H); 1.22

(d, J 6.7, 6 H). ¹³C-NMR (90.6 MHz, CDCl₃): 168.38 (s); 166.60 (s); 138.57 (s); 137.61 (s); 131.73 (d); 129.86

(d); 129.34 (d); 128.94 (d); 128.51 (d); 127.62 (d); 126.59 (d); 65.87 (t); 41.92 (d); 35.00 (t); 22.56 (q). CI-MS

(NH₃): 329 (100, [M NH₄] ), 312 (95, [M H] ), 244 (12), 207 (20), 140 (55), 117 (35).

(2E)-3,7-Dimethylocta-2,6-dienyl Hydrogen (2Z)-But-2-enedioate. Et₃N (50 ml, ca. 2 equiv.) was added to a

soln. of geraniol (24.6 g, 159.5 mmol) and maleic anhydride ( furan-2,5-dione; 15.7 g, 159.9 mmol) in CH₂Cl₂

(400 ml), and the mixture was stirred under Ar at r.t. overnight. Acidification with KHSO₄, washing of the org.

phase with H₂O, drying (Na₂SO₄), and evaporation gave 40.2 g (99%) of the hydrogen butenedioate. ¹H-NMR

(360 MHz, CDCl₃): 11.78 (br. s, 1 H); 6.42 (AB, J 12.7, 1 H); 6.35 (AB, J 12.7, 1 H); 5.47 5.35 (m, 1 H);

5.11 5.04 (m, 1 H); 4.78 (d, J 7.1, 2 H); 2.15 2.03 (m, 4 H); 1.74 (s, 3 H); 1.68 (s, 3 H); 1.60 (s, 3 H). ¹³C-NMR

(90.6 MHz, CDCl₃): 167.31 (s); 165.73 (s); 144.50 (s); 134.74 (d); 131.99 (s); 129.90 (d); 123.53 (d); 116.70 (d);

63.53 (t); 39.52 (t); 26.19 (t); 25.67 (q); 17.69 (q); 16.55 (q).

Helvetica Chimica Acta Vol. 86 (2003)

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(2E)-3,7-Dimethylocta-2,6-dienyl (2Z)-4-(Ethylamino)-4-oxo-but-2-enoate (7b). A soln. of (2E)-3,7-

dimethylocta-2,6-dienyl hydrogen (2Z)-but-2-enedioate (5.0 g, 19.8 mmol; see above) and Et₃N (3 ml) in

CH₂Cl₂(50 ml) was cooled to À208 before pivaloyl chloride (2,2-dimethylpropanoyl chloride; 2.6 g,

21.7 mmol) in CH₂Cl₂(50 ml) was added dropwise during 2 min. The mixture was stirred at À208 for 3.5 h and

then left warming to r.t. Then Et₃N (3 ml) and EtNH₂¥ HCl (1.7 g, 20.2 mmol) were introduced. After stirring

for 1 h, the mixture was acidified with KHSO₄and the org. phase washed with H₂O (2Â), dried (Na₂SO₄), and

evaporated. CC (SiO₂, cyclohexane/AcOEt 7:3) yielded 3.5 g (97%) of 7b. Brownish oil. UV/VIS (hexane):

283 (sh, 1100). IR (neat): 3286m, 3073w, 2967m, 2926m, 2874m, 2855w, 1725s, 1654m, 1625s, 1538s, 1441m,

1403m, 1376m, 1352w, 1268m, 1205s, 1168s, 1105m, 1059w, 1047w, 980m, 940m, 834m, 805m, 777w, 740w.

¹H-NMR (360 MHz, CDCl₃): 8.29 (s, 1 H); 6.31 (d, J 13.1, 1 H); 6.12 (d, J 12.3, 1 H); 5.37(t, J 7.1, 1 H ) ;

5.08 (t, J 6.7, 1 H); 4.70 (d, J 7.1, 2 H); 3.36 (dq, J 7.1, 2.0, 2 H); 2.15 2.03 (m, 4 H); 1.72 (s, 3 H); 1.68 (s,

3 H); 1.60 (s, 3 H); 1.20 (t, J 7.1, 3 H ) . ¹³C-NMR (90.6 MHz, CDCl₃): 166.31 (s); 163.95 (s); 143.36 (s); 138.49

(d); 131.92 (d); 125.16 (d); 123.61 (d); 117.43 (d); 62.36 (t); 39.53 (t); 34.53 (t); 26.24 (t); 25.68 (q); 17.69 (q);

16.53 (q); 14.39 (q). CI-MS (NH₃): 297 (26, [M NH₄] ), 280 (47, [M H] ), 178 (7), 161 (100), 144 (20).

2-Phenylethyl (2Z)-4-(ethylamino)-4-oxo-but-2-enoate (7e). A soln. of 2-phenylethyl hydrogen maleate

(5.0 g, 22.7 mmol; synthesized as described for 7b) and Et₃N (6 ml) in CH₂Cl₂(30 ml) was cooled to À208 before

ethyl carbonochloridate (2 ml, 20.9 mmol) and CH₂Cl₂(40 ml) were added. The mixture was stirred at À208 for

10 min before Et₃N (6 ml) and EtNH₂¥ HCl (1.7 g, 20.2 mmol) were introduced. After stirring for 75 min, the

mixture was acidified with KHSO₄and the org. phase washed with H₂O (2Â), dried (Na₂SO₄), and evaporated.

CC (SiO₂, cyclohexane/AcOEt 3 :2) yielded 1.2 (24%) of 7e. Yellow oil. IR (neat): 3286m, 3062w, 3027w,

2970m, 2932m, 2874w, 1724s, 1656m, 1621s, 1542s, 1495m, 1452m, 1403m, 1376m, 1352m, 1265m, 1212s, 1169s,

1

1108w, 1086m, 1048m, 1030w, 1007w, 994m, 964w, 909m, 846m, 828m, 799m, 748m, 697s. H-NMR (360 MHz,

CDCl₃; Table 3): 8.09 (s, 1 H); 7.38 7.16 (m, 5 H); 6.30 (d, J 13.1, 1 H); 6.07 (d, J 13.1, 1 H); 4.38 (t, J 6.9,

2 H); 3.33 (dq, J 7.1, 1.6, 2 H); 2.98 (t, J 7.1, 2 H); 1.17 (t, J 7.3, 3 H). ¹³C-NMR (90.6 MHz, CDCl₃;

Table 3): 166.16 (s); 163.92 (s); 138.41 (d); 137.31 (s); 128.89 (d); 128.58 (d); 126.73 (d); 125.03 (d); 65.87 (t);

34.84 (t); 34.52 (t); 14.37 (q). CI-MS (NH₃): 265 (17, [M NH₄] ), 248 (100, [M H] ), 140 (7).

(2E)-3,7-Dimethylocta-2,6-dienyl 4-(Ethylamino)-4-oxobutanoate (8b). Et₃N (20 ml, ca. 2 equiv.) was

added to a soln. of geraniol (10.0 g, 64.9 mmol) and succinic anhydride ( 3,4-dihydrofuran-2,5-dione; 6.49 g,

64.9 mmol) in CH₂Cl₂(100 ml), and the mixture was stirred under Ar at r.t. for 3 h. After cooling to À208 and

adding more Et₃N (10 ml), pivaloyl chloride (8.6 g, 71.3 mmol) in CH₂Cl₂(5 ml) was introduced dropwise

during 15 min. The mixture was stirred at À208 for 1 h and then left warming to r.t. before Et₃N (10 ml) and

EtNH₂¥ HCl (5.3 g, 64.9 mmol) were introduced. After stirring for 30 min, the mixture was acidified with

KHSO₄and the org. phase washed with H₂O (2Â), dried (Na₂SO₄), and evaporated. CC (SiO₂, cyclohexane/

AcOEt 3 :2) yielded 14.6 g (80%) of 8b. Slightly yellow oil. IR (neat): 3302m, 3080w, 2969m, 2926m, 2875m,

2857w, 1732s, 1644s, 1540s, 1478w, 1440m, 1374m, 1358w, 1317w, 1267m, 1230m, 1205m, 1159s, 1107m, 1074w,

1046m, 1013w, 982m, 957m, 889m, 831w, 800w, 778w, 741w. ¹H-NMR (360 MHz, CDCl₃; Table 3): 6.08 (s, 1 H);

5.33 (t, J 7.1, 1 H); 5.08 (t, J 5.9, 1 H); 4.60 (d, J 6.7, 2 H); 3.27 (dq, J 7.1, 1.6, 2 H); 2.67 (t, J 6.9, 2 H);

2.47 (t, J 6.9, 2 H); 2.15 1.99 (m, 4 H); 1.69 (s, 3 H); 1.68 (s, 3 H); 1.60 (s, 3 H); 1.13 (t, J 7.1, 3 H ) . ¹³C-NMR

(90.6 MHz, CDCl₃; Table 3): 173.12 (s); 171.34 (s); 142.30 (s); 131.82 (s); 123.73 (d); 118.18 (d); 61.63 (t); 39.53

(t); 34.43 (t); 31.07 (t); 29.72 (t); 26.30 (t); 25.68 (q); 17.69 (q); 16.47 (q); 14.79 (q). CI-MS (NH₃): 299 (10, [M

NH₄] ), 282 (21, [M H] ), 163 (100), 153 (10), 146 (100).

We thank Erik Decorzant, Paul Enggist, and Sabine Rochat for their contributions to this project as well as

Prof. Nigel Richards for helpful discussions on computational aspects and Dr. Roger Snowden for constructive

comments on the manuscript. We are grateful to Alain Trachsel for kinetic measurements, Alain Bagnoud and

Laurence Frascotti for the preparation of some of the compounds, and Walter Thommen and Robert Brauchli for

NMR measurements.

REFERENCES

[1] S. Arctander, −Perfume and Flavor Chemicals×, published by the author, Montclair, 1969.

[2] Chimia 2001, 55, 378 453 (Special Edition on Flavours and Fragrances).

¬

[3] D. Benczedi, in −Food Flavour Technology×, Ed. A. J. Taylor, Sheffield Academic Press, Sheffield, 2002,

p. 153; C. Quellet, M. Schudel, R. Ringgenberg, Chimia 2001, 55, 421; B. F. Gibbs, S. Kermasha, I. Alli,

C. N. Mulligan, Int. J. Food Sci. Nutr. 1999, 50, 213; K. Rogers, Cosmet. Toiletries 1999, 114, 53; L. Brannon-

Peppas, ACS Symp. Ser. 1993, 520, 42; ref. cit. therein.

2898

Helvetica Chimica Acta Vol. 86 (2003)

[4] M. Gautschi, J. A. Bajgrowicz, P. Kraft, Chimia 2001, 55, 379.

[5] S. Rochat, C. Minardi, J.-Y. de Saint Laumer, A. Herrmann, Helv. Chim. Acta 2000, 83, 1645; A. Herrmann,

C. Debonneville, V. Laubscher, L. Aymard, Flavour Fragr. J. 2000, 15, 415.

[6] C. Plessis, S. Derrer, Tetrahedron Lett. 2001, 42, 6519.

[7] B. Levrand, A. Herrmann, Photochem. Photobiol. Sci. 2002, 1, 907.

[8] H. Kamogawa, S. Okabe, M. Nanasawa, Bull. Chem. Soc. Jpn. 1976, 49, 1917; H. Kamogawa, H. Mukai, Y.

Nakajima, M. Nanasawa, J. Polym. Sci., Polym. Chem. Ed. 1982, 20, 3121.

[9] P. Enggist, S. Rochat, A. Herrmann, J. Chem. Soc., Perkin Trans. 2 2001, 438.

¬

[10] E. Frerot, K. Herbal, A. Herrmann, Eur. J. Org. Chem. 2003, 967.

¬

[11] E. Frerot, A. Herrmann, J.-Y. Billard de Saint Laumer, O. Gr‰ther, to Firmenich SA, PCT Int. Patent Appl.

¬

WO 00/58260, 2000 (Chem. Abstr. 2000, 133, 266604); E. Frerot, to Firmenich SA, PCT Int. Patent Appl.

¬

WO 01/28980, 2001 (Chem. Abstr. 2001, 134, 328230); A. Herrmann, E. Frerot, to Firmenich SA, PCT Int.

Patent Appl. WO 02/077074, 2002 (Chem. Abstr. 2002, 137, 284012).

[12] W. Paget, D. Reichlin, R. L. Snowden, E. C. Walborsky, C. Vial, to Firmenich SA, US Patent 5,649,979, 1997

and 5,726,345, 1998 (Chem. Abstr. 1995, 123, 116298).

[13] B. Capon, Q. Rev., Chem. Soc. 1964, 18, 45; M. I. Page, Chem. Soc. Rev. 1973, 2, 295; B. Capon, S. P.

McManus, −Neighboring Group Participation×, Plenum Press, New York, 1976.

[14] A. J. Kirby, A. R. Fersht, Prog. Bioorg. Chem. 1971, 1, 1; A. J. Kirby, Adv. Phys. Org. Chem. 1980, 17, 183; L.

Mandolini, Adv. Phys. Org. Chem. 1986, 22, 1.

[15] M. Balakrishnan, G. V. Rao, N. Venkatasubramanian, J. Sci. Ind. Res. 1974, 33, 641.

[16] D. Shan, M. G. Nicolaou, R. T. Borchardt, B. Wang,J. Pharm. Sci. 1997, 86, 765; B. Testa, J. M. Mayer, Drug

Metab. Rev. 1998, 30, 787; ref. cit. therein.

[17] M. S. Newman, C. Courduvelis, J. Org. Chem. 1965, 30, 1795.

[18] M. V. Bhatt, K. S. Rao, G. V. Rao, J. Org. Chem. 1977, 42, 2697; M. V. Bhatt, G. V. Rao, K. S. Rao, J. Org.

Chem. 1979, 44, 984.

[19] K. Bowden, G. R. Taylor, J. Chem. Soc. (B) 1971, 149.

[20] F. Anvia, K. Bowden, J. Chem. Soc., Perkin Trans. 2 1990, 1805.

[21] M. S. Newman, A. L. Leegwater, J. Am. Chem. Soc. 1968, 90, 4410.

[22] M. L. Bender, J. A. Reinstein, M. S. Silver, R. Mikulak, J. Am. Chem. Soc. 1965, 87, 4545.

[23] F. Anvia, K. Bowden, F. A. El Kaissi, V. Saez, J. Chem. Soc., Perkin Trans. 2 1990, 1809.

[24] T. H. Fife, B. M. Benjamin, J. Am. Chem. Soc. 1973, 95, 2059; T. H. Fife, B. M. Benjamin, Bioorg. Chem.

1976, 5, 37.

[25] B. Capon, S. T. McDowell, W. V. Raferty, J. Chem. Soc., Perkin Trans. 2 1973, 1118.

[26] T. H. Fife, B. R. DeMark, J. Am. Chem. Soc. 1976, 98, 6978; T. H. Fife, L. Chauffe, J. Org. Chem. 2000, 65,

3579.

[27] J. A. Schafer, H. Morawetz, J. Org. Chem. 1963, 28, 1899.

¬

[28] M. Leung, J. M. J. Frechet, J. Chem. Soc., Perkin Trans. 2 1993, 2329.

[29] J. E. H. Hancock, R. P. Linstead, J. Chem. Soc. 1953, 3490; E. Sondheimer, R. W. Holley, J. Am. Chem. Soc.

1954, 76, 2467.

[30] K. Bowden, Adv. Phys. Org. Chem. 1993, 28, 171; K. Bowden, Chem. Soc. Rev. 1995, 24, 431.

[31] G. Egerer, H. Meyer, Monatsh. Chem. 1913, 34, 69; J. O. Halford, B. Weissmann, J. Org. Chem. 1952, 17,

1646; R. Riemschneider, H. G. Kassahn, Monatsh. Chem. 1959, 90, 575; M. Renson, Bull. Soc. Chim. Belg.

1961, 70, 77.

[32] S. Gabriel, G. Giebe, Ber. Dtsch. Chem. Ges. 1896, 29, 2518; R. Riemschneider, H. G. Kaahn, L. Hˆrner,

Monatsh. Chem. 1960, 91, 1034.

[33] K. von Auwers, A. Heinze, Ber. Dtsch. Chem. Ges. 1919, 52, 584; A. Kirpal, K. Zieger, Ber. Dtsch. Chem.

Ges. 1929, 62, 2106; I. M. Heilbron, D. G. Wilkinson, J. Chem. Soc. 1932, 2809; H. de Diesbach, O. Klement,

Helv. Chim. Acta 1941, 24, 158.

[34] M. S. Newman, K. Naiki, J. Org. Chem. 1962, 27, 863; J. Barry, G. Bram, G. Decodts, A. Loupy, C. Orange,

A. Petit, J. Sansoulet, Synthesis 1985, 40.

[35] R. E. Valters, W. Flitsch, −Ring-Chain Tautomerism×, Plenum Press, New York, 1985, and ref. cit. therein.

[36] E. E. Smissman, J. P. Li, Z. H. Israili, J. Org. Chem. 1968, 33, 4231; P. M. Pojer, E. Ritchie, W. C. Taylor,

Austr. J. Chem. 1968, 21, 1375.

[37] N. Gautier, R. H. Dodd, Synth. Commun. 1998, 28, 3769.

[38] B. Neises, W. Steglich, Org. Synth. 1990, Coll. Vol. VII, 93.

[39] K. Bowden, G. R. Taylor, J. Chem. Soc. (B) 1971, 1395.

Helvetica Chimica Acta Vol. 86 (2003)

[40] H. G. Rule, J. Smith, J. Chem. Soc. 1926, 553.

2899

[41] R. C. Anand, N. Selvapalam, Synth. Commun. 1994, 24, 2743.

[42] M. Falorni, G. Giacomelli, A. Porcheddu, M. Taddei, J. Org. Chem. 1999, 64, 8962.

[43] J. V. B. Kanth, M. Periasamy, J. Org. Chem. 1991, 56, 5964; B. P. Bandgar, R. K. Modhave, P. P.

Wadgaonkar, A. R. Sande, J. Chem. Soc., Perkin Trans. 1 1996, 1993; S. Narasimhan, S. Swarnalakshmi, R.

Balakumar, S. Velmathi, Synlett 1998, 1321; S. Narasimhan, S. Swarnalakshmi, R. Balakumar, Synth.

Commun. 2000, 30, 941.

¬

[44] H. Erdmann, P. Huth, J. Prakt. Chem. 1897, 56, 6; J. Flatau, H. Labbe, M. Friedel, C. R. Hebd. Seances Acad.

Sci. 1898, 126, 1725; E. H. Rennie, W. T. Cooke, H. H. Finlayson, J. Chem. Soc. 1920, 117, 338; H. von

Soden, W. Rojahn, Ber. Dtsch. Chem. Ges. 1900, 33, 1720.

[45] T. N. Vasilevskaya, N. I. Grineva, G. A. Chernousova, Z. A. Grankina, V. N. Andrievskii, J. Appl. Chem.

(Leningrad) 1987, 60, 220; N. Yasuda, A. Nakamura, M. Tsuboi, J. Heterocycl. Chem. 1987, 24, 303.

[46] R. Pellegata, A. Italia, M. Villa, G. Palmisano, G. Lesma, Synthesis 1985, 517.

[47] J. P. E. Human, J. A. Mills, J. Chem. Soc. 1949, S77.

¡

[48] N. Aguilar, A. Moyano, M. A. Pericas, A. Riera, Synthesis 1998, 313; J. R. Casimir, G. Guichard, P.-P.

¬

Briand, Synthesis 2001, 75; J. R. Casimir, G. Guichard, D. Tourwe, P.-P. Briand, Synthesis 2001, 1985.

[49] E. A. Guggenheim, Phil. Mag. 1926, 2, 538.

[50] F. J. Kezdy, J. Jaz, A. Bruylants, Bull. Soc. Chim. Belg. 1958, 67, 687; P. C. Mangelsdorf Jr., J. Appl. Phys.

1959, 30, 442; E. S. Swinbourne, J. Chem. Soc. 1960, 2371.

[51] K. Bowden, A. M. Last, J. Chem. Soc., Perkin Trans. 2 1973, 345.

[52] K. A. Connors, −Chemical Kinetics The Study of Reaction Rates in Solution×, VCH, New York, 1990,

p. 17.

¡

¬

[53] J. Barbosa, V. Sanz-Nebot, Anal. Chim. Acta 1991, 244, 183; E. Bosch, G. Fonrodona, C. Rafols, M. Roses,

Anal. Chim. Acta 1997, 349, 367.

[54] U. Mandal, S. Bhattacharya, K. K. Kundu, Indian J. Chem., Sect A 1985, 24, 191.

[55] A. B. Onofrio, J. C. Gesser, A. C. Joussef, F. Nome, J. Chem. Soc., Perkin Trans. 2 2001, 1863.

[56] F. C. Lightstone, T. C. Bruice, J. Am. Chem. Soc. 1996, 118, 2595; T. C. Bruice, F. C. Lightstone, Acc. Chem.

Res. 1999, 32, 127.

[57] A. E. Dorigo, K. N. Houk, J. Am. Chem. Soc. 1987, 109, 3698; K. N. Houk, J. A. Tucker, A. E. Dorigo, Acc.

Chem. Res. 1990, 23, 107.

[58] J. J. P. Stewart, J. Comput. Chem. 1989, 10, 209.

[59] R. G. Parr, W. Yang, −Density Functional Methods in Atoms and Molecules×, Oxford University Press, New

York, 1989; J. W. Labanowski, J. Andzelm, −Density Functional Methods in Chemistry×, Springer Verlag,

New York, 1991.

[60] L. Horner, J. Klaus, Liebigs Ann. Chem. 1979, 1232.

[61] F. Mohamadi, N. G. J. Richards, W. C. Guida, R. Liskamp, M. Lipton, C. Caufield, G. Chang, T. Henrickson,

W. C. Still, −MacroModel V6.0×, J. Comput. Chem. 1990, 11, 440.

Received February 19, 2003

Article Doi

Controlled release of perfumery alcohols by neighboring-group participation. Comparison of the rate constants for the alkaline hydrolysis of 2-acyl-, 2-(hydroxymethyl)-, and 2-carbamoylbenzoates

DOI: 10.1002/hlca.200390236

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