Preparation of imidazolidin-4-ones and their evaluation as hydrolytically cleavable precursors for the slow release of bioactive volatile carbonyl derivatives

FULL PAPER

DOI: 10.1002/ejoc.201200081

Preparation of Imidazolidin-4-ones and Their Evaluation as Hydrolytically

Cleavable Precursors for the Slow Release of Bioactive Volatile Carbonyl

Derivatives

Alain Trachsel,^[a]Barbara Buchs,^[a]Guillaume Godin,^[a]Aurélien Crochet,^[b]

Katharina M. Fromm,*^[b]and Andreas Herrmann*^[a]

Keywords: Fragrances / Nitrogen heterocycles / Aldehydes / Ketones / Hydrolysis

Imidazolidin-4-ones are suitable in practical applications as

hydrolytically cleavable precursors for the controlled release

of fragrant aldehydes and ketones. The corresponding pro-

fragrances were prepared by treating aliphatic carbonyl

compounds with commercially available amino acid amines

in the presence of a base to yield mixtures of diastereomers.

The two diastereomers isolated from the reaction of glycin-

amide hydrochloride with (–)-menthone were separated by

column chromatography. The absolute stereochemistry of the

isomers was determined by NMR spectroscopy and con-

firmed by X-ray single crystal structure analysis. Under

acidic conditions and in protic solvents, the two dia-

stereomers slowly isomerized without releasing the ketone.

The hydrolysis of the precursors was investigated by solvent

extraction from buffered aqueous solutions and a cationic

surfactant emulsion, as well as by dynamic headspace analy-

sis after deposition onto a cotton surface. Generally, ketones

were shown to be more readily released than aldehydes. In-

creasing the size of the substituents at C-5 decreased the rate

of hydrolysis in solution and on the cotton surface. Glycin-

amide-based imidazolidin-4-ones were more efficient than

the corresponding oxazolidin-4-ones or oxazolidines. Neither

the release rates in solution, nor the hydrophobicity of the

precursor structure (which influences deposition), nor the

combination of these two parameters allowed easily predic-

ting the performance of the delivery systems in application.

labile profragrances depends on the behavior of the precur-

sors at different pH levels and, in particular, in the presence

of surfactants. However, fragrance delivery systems usually

must be stored in an aqueous environment. An ideal com-

promise between high precursor stability (during product

storage) and efficient hydrolysis to release the volatile (in

use) is often difficult to achieve.^[2]

1,3-Heterocycles have been repeatedly considered as hy-

drolytically cleavable precursors for the release of fragrant

aldehydes or ketones (see Figure 1).^[2]Although successfully

applied under certain conditions, cyclic acetals or ketals^[4]

are generally too stable to efficiently release the correspond-

Introduction

Bioactive volatile compounds, so-called semiochemicals

or signalling compounds, serve in nature as a means for the

communication between species. As a consequence of their

pleasant smell or taste to humans, some of these com-

pounds are also used as flavors or fragrances in our every-

day life.^[1]To be perceived, these compounds must evapo-

rate from a surface and move through the air to reach their

target. As a result, they have high volatilities (vapor pres-

sures) and, thus, a limited duration of smell. To increase

the duration in the perception of fragrances in functional

perfumery, so-called profragrances or properfumes have

been developed as nonvolatile precursors, which slowly re-

lease volatile compounds by covalent bond cleavage under

mild environmental conditions.^[2,3]

Water is presumably the most commonly used solvent for

applications in functional perfumery, and therefore, hydro-

lytically labile precursors are particularly interesting as pro-

fragrances.^[2]The successful development of hydrolytically

[a] Firmenich SA, Division Recherche et Développement,

Route des Jeunes 1, B. P. 239, 1211 Genève 8, Switzerland

E-mail: andreas.herrmann@firmenich.com

[b] Université de Fribourg, Département de Chimie,

Chemin du Musée 9, 1700 Fribourg, Switzerland

E-mail: katharina.fromm@unifr.ch

Figure 1. 1,3-Heterocyclic structures investigated for the controlled

release of bioactive volatiles.

Supporting information for this article is available on the

WWW under http://dx.doi.org/10.1002/ejoc.201200081.

Eur. J. Org. Chem. 2012, 2837–2854

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K. M. Fromm, A. Herrmann et al.

FULL PAPER

ing aldehydes or ketones under mild reaction conditions at and by testing their performance in different applications

neutral pH. Efforts have been made to prepare less stable of functional perfumery in more detail.^[38]In this work, we

heterocycles and, thus, to increase the rates of hydrolysis by focused our interest on the use of aliphatic aldehydes and

introducing various substituents onto the heterocycle. The ketones.

rate of aldehyde release from dicarboxyldioxolanes, for ex-

ample, was expected to be influenced by varying the bulki-

ness of the carboxylate ester groups,^[5]and other structures

Results and Discussion

obtained by modifying the substitution on the heterocycle

include dioxolanones^[6]or aldoxanes.^[7]

Synthesis and Isomerization of Imidazolidinones

In addition, less stable heterocycles such as oxazolid-

ines^[8]or imidazolidines (aminals)^[9,10]have been explored

to control the release of fragrances. While oxazolidines have

been reported to rapidly hydrolyze in aqueous media under

acidic or neutral conditions,^[11]aminals form an equilibrium

with the corresponding diamine and aldehyde (see

Scheme 1).^[12]Aminals, presumably the least stable com-

pounds in the series, have been explored as “classical” pro-

fragrances to be hydrolyzed^[9]or, by profiting from the re-

versibility of the system, as dynamic mixtures obtained by

reacting a diamine with several aldehydes or ketones.^[10]In

search of easily accessible and biocompatible precursor sys-

tems, we investigated the use of amino acid amides in the

formation of imidazolidin-4-ones (imidazolidinones).

Imidazolidinones 1–9 (see Figure 2) were prepared by

treating commercially available 2-aminoacetamide (hydro-

chloride) derivatives with typical fragrant aldehydes or

ketones. Profragrances 1a–1d were obtained starting from

(Ϯ)-3-phenylbutanal (Trifernal^®) in ethanol with solid

K₂CO₃to trap the water formed during the reaction. As

glycinamide, l-alaninamide, and l-phenylalaninamide were

available as hydrochlorides, 1 equiv. of triethylamine (TEA)

was added to neutralize the hydrochloride salt, whereas d-

prolinamide [(S)-pyrrolidine-2-carboxamide] was not

treated with TEA. Compounds 1a–1d were obtained in rea-

sonable to good yields by simply heating at 60 °C for 1 d.

Although this method worked well for the preparation of a

series of Trifernal^®derivatives, it turned out not to be gen-

erally applicable to the preparation of imidazolidinones

from other carbonyl compounds. To extend our delivery

systems to the release of ketones, we investigated the forma-

tion and purification of imidazolidinones in more detail. A

series of methods allowing the preparation of imidazolid-

Scheme 1. Controlled release of volatile aldehydes by reversible for-

mation and hydrolysis of aminals (top) and imidazolidin-4-ones

(bottom).

Aldehydes or ketones react with amino acid amides and

(di)peptides to form imidazolidinones,^[13–37]which have pre-

viously been investigated as prodrugs by several research

groups.^[25–29]In particular, the formation of hetacillin from

6-(d-α-aminophenylacetamido)penicillanic acid (ampicillin)

with acetone^[29]and the preparation of the imidazolidinone

derivatives of primaquine as peptidomimetic antimalarial

drugs^[25]have been studied in some detail. Despite the re-

versibility of the reaction,^[21,29]imidazolidinones have been

described to be relatively stable at neutral pH and to hy-

drolyze under acidic conditions.^[25–31]Hydrolysis in a buff-

ered solution was found to be of pseudo-first order (with

half-life times of several hours or days at physiological pH)

and neither acid- nor base-catalyzed. Both the substituents

at the C-2 and C-5 imidazolidin-4-one moiety influenced

the reactivity.^[21,25,27]

From these findings and in view of our recent studies

using dynamic mixtures obtained by the reversible forma-

tion and hydrolysis of aminals with fragrant aldehydes and

ketones,^[10]we investigated the potential of imidazolid-

inones as precursors in the controlled release of fragrant

aldehydes and ketones by optimizing their synthesis and pu-

Figure 2. Structures of imidazolidin-4-ones 1–9 prepared and inves-

rification, by studying their hydrolysis in aqueous media, tigated as fragrance delivery systems.

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Precursors for Slow Release of Fragrant Aldehydes or Ketones

inones from amino acid amides with aldehydes or ketones confirmed by X-ray single crystal structure analysis. Some

have been described.^{[13–26,30–37]}

single crystal structures of different imidazolidin-4-one de-

According to the literature, imidazolidinones from ali- rivatives have already been reported in the literature.^[16–19,36]

phatic aldehydes or ketones were prepared in polar solvents Compound (5S,6S,9R)-4a (200 mg, isolated from a pure

such as dimethylformamide,^[14]methanol, or ethanol^[18–22]chromatography fraction) was dissolved in a mixture of

and, in particular, if the hydrochloride of the amino acid 0.5 mL of ethyl acetate and 2.5 mL of heptane and left to

amide was used, they were prepared in the presence of a crystallize overnight. X-ray crystal structure analysis

base (TEA or NaOH).^[23–26]Pure products were obtained showed the presence of multiple twinned crystals, which

by acidic workup and column chromatography^{[14,19–21,25,26]}were not suitable for single crystal X-ray diffraction.

or by extraction and recrystallization.^[24]Alternatively, reac- Recrystallization from pure heptane finally afforded color-

tions were carried out in methanol or isopropanol by using less single crystals, allowing for precise X-ray crystal struc-

zeolites, para-toluenesulfonic acid, acetic acid, or trifluoro- ture determination (see Figures 3 and 4).

acetic acid (TFA) as catalysts.^[15–17]Imidazolidinones of ste-

rically demanding pivalaldehyde were prepared under acidic

conditions (in the presence of TFA) in dichloromethane or

toluene^[13,39]followed by basic workup and crystallization

or chromatography to afford pure imidazolidinones in mod-

erate to good yields. Other methods describe the reaction

in benzene or toluene with the azeotropic removal of water,

typically in the presence of an acidic catalyst.^{[18,30,33,34]}

A

series of imidazolidinones of aromatic aldehydes or ali-

phatic ketones was also obtained without the addition of

solvent.^[31,32]

To have a universally applicable method for the synthesis

of imidazolidinones, we optimized the preparation of imid-

azolidinones 3a, 4a, 5a, and 6a (see Figure 2) by treating

glycinamide hydrochloride with (R)-3,7-dimethyl-6-octenal

[(R)-citronellal], (2S,5R)-2-isopropyl-5-methylcyclohexan-

one [(–)-menthone], 2-heptanone, and (Ϯ)-5-methyl-3-hept-

anone, respectively, on the basis of some of the above-men-

tioned literature procedures.^{[13,20,24,25,39]}

Figure 3. View of the molecular structure of (5S,6S,9R)-4a (30%

probability).

Compound (5S,6S,9R)-4a crystallized in the trigonal

Treatment of glycinamide hydrochloride with (R)-citro- space group P3₁21 (No. 152) in two crystallographic posi-

nellal in dichloromethane or toluene in the presence of tions with an occupancy of 70% (Figure 3, Position A) and

TFA^[13,39]entirely consumed the aldehyde, but did not af- 30% (see Supporting Information, Figure S1, Position B).

ford target compound 3a. 2-Heptanone, (Ϯ)-5-methyl-3- The two positions differ by the angle between the imidazole

heptanone, and (–)-menthone did not react under these and the cyclohexane moieties [N-1–C-3–C-4 of 111.8(4)° for

conditions, and the unreacted ketones were the only prod- part A and 102.0(6)° for part B]. The two molecules have

ucts isolated. The reaction of glycinamide hydrochloride in the same shape in which the cyclohexane ring takes a chair

ethanol, in the absence of TEA,^[20]afforded imidazolidin- conformation with a torsion angle for C-3–C-4A–C-5A–C-

one 3a in low purity, but no reaction occurred in the case 6A of 58.2(8)° [48(2)° for C-3–C-4B–C-5B–C-6B]. The

of the ketones.

imidazole ring has a torsion angle of 17.4(4)° (for C-2–N-

In the presence of TEA,^[24,25]imidazolidinones 4a–6a 2–C-3–N-1). The two nitrogen atoms N-1 and N-2 [C-1–N-

were finally isolated in reasonable purity after bulb-to-bulb 1–H-1, 124(3)° and C-2–N-2–H-2, 109(2)°] form intermo-

distillation (to remove the remaining unreacted ketones), lecular bonds with the neighboring molecules (see Fig-

and pure 3a and 3b were obtained after plug filtration ure 4). Indeed, H-1 forms a hydrogen bond with O-1 of the

through silica gel using ethyl acetate as the eluent. Imid- next molecule [H-1···O-1, 2.10(6) Å and N-1–H-1···O-1,

azolidinones of (Ϯ)-3,5,5-trimethylhexanal (i.e., 2a–d), (Ϯ)- 172(4)°, see Supporting Information, Figure S3) to yield an

2-methylundecanal (i.e., 7a and 7b), hexanal (i.e., 8a), and eight-membered hydrogen-bonded ring system with H-1–N-

(Ϯ)-2,4-dimethyl-3-cyclohexene-1-carbaldehyde (Triplal^®, 1–C-1–O-1 and the symmetry equivalents of a neighboring

i.e., 9a) were prepared accordingly. With the exception of molecule, whereas H-2 forms a short contact with O-1 of

5a and 8a, the imidazolidinones were isolated as mixtures yet another neighbor, with the angle of N-2–H-2···O-1 be-

of diastereomers.

ing 156(3)° [H-2···O-1, 2.28(5) Å].

Column chromatography of 4a allowed separating the

When left on silica gel, compound (5S,6S,9R)-4a par-

two diastereomers (5R,6S,9R)-4a (eluting first) and tially equilibrated to the (5R,6S,9R)-4a isomer, presumably

(5S,6S,9R)-4a (eluting second), both of which were fully according to the mechanism illustrated in Scheme 2.

characterized. The absolute stereochemistry of the two iso-

The isomerization of (5R,6S,9R)- and (5S,6S,9R)-4a un-

mers was determined by 1D and 2D homonuclear and het- der acidic conditions was investigated in more detail by

1

eronuclear H and ¹³C NMR experiments in CDCl₃and mixing small amounts of the pure diastereomers with silica

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K. M. Fromm, A. Herrmann et al.

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Figure 4. View of the crystal packing of (5S,6S,9R)-4a (30% probability). Some hydrogen atoms are omitted for clarity. Hydrogen bonds

are represented by dashed lines.

structure of the starting isomer as shown by ¹³C NMR

spectroscopic data recorded at different time intervals (see

Figure 5). The formation of (–)-menthone was not observed

under these conditions. Solutions of the isomer (5S,6S,9R)-

4a in CDCl₃or C₆D₆, for example, did not isomerize even

after standing for 400 h.

Scheme 2. Hypothetical mechanism for the isomerization of imid-

azolidinones (5R,6S,9R)- and (5S,6S,9R)-4a under acidic condi-

tions.

gel or TFA (at a final concentration of 0.1%) in ethyl acet-

ate or chloroform. The product mixtures were stirred over-

night (approximately 15 h) and analyzed by NMR spec-

troscopy. Table 1 illustrates the product distributions ob-

tained under the different conditions. Isomerization was rel-

atively slow, as stable equilibrium conditions [equal to con-

stant amounts of (5R,6S,9R)- and (5S,6S,9R)-4a] were not

reached after approximately 15 h. Isomerization only oc-

curred in protic solvents or in the presence of a proton

source such as acidic silica gel or TFA.

Leaving a solution of the pure isomers (5R,6S,9R)-4a or

(5S,6S,9R)-4a in methanol for several days showed that an

Figure 5. Amount of imidazolidinones (5R,6S,9R)-4a (solid lines)

and (5S,6S,9R)-4a (dotted lines) during equilibration in CD₃OD as

equilibrium between the two isomers was in fact reached,

resulting in final composition of (5R,6S,9R)-4a/

determined by ¹³C NMR spectroscopy, starting from pure

(5R,6S,9R)-4a (᭹) or pure (5S,6S,9R)-4a (᭿). For numerical data,

a

(5S,6S,9R)-4a of approximately 2:3, independent of the see Exp. Section.

Table 1. Composition of ethyl acetate and chloroform solutions obtained after 15 h for the isomerization of imidazolidinones (5R,6S,9R)-

4a and (5S,6S,9R)-4a in the presence of SiO₂or TFA.

Final composition

[%]

Starting isomer

[SiO₂, ethyl acetate]

Starting isomer

[TFA, ethyl acetate]

Starting isomer

[SiO₂, chloroform]

Starting isomer

[TFA, chloroform]

(5R)-4a

(5S)-4a

(5R)-4a

(5S)-4a

(5R)-4a

(5S)-4a

(5R)-4a

(5S)-4a

(5R,6S,9R)-4a

(5S,6S,9R)-4a

80

20

9

91

80

20

6

94

89

11

28

72

79

21

8

92

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Precursors for Slow Release of Fragrant Aldehydes or Ketones

Synthesis of Structurally Related Oxazolidinones and

Oxazolidines

typically consist of approximately 15% (w/w) of the es-

terquat (mixture of mono-, di-, and triesters) in water, up

to 1% perfume, small amounts of CaCl₂, and, optionally, a

dye. In use, this concentrated formulation is diluted by a

factor of about 300–400 before coming into contact with

the fabric, onto which the surfactant, the perfume, and the

profragrances are then deposited.^[43]Aggregation of the

surfactant to form micelles enables the precursor (as well as

the carbonyl compounds released from them) to partition

between the inside and outside of the surfactant aggregates.

The hydrophilicity or hydrophobicity of the different com-

pounds, expressed by their logarithmic octanol/water par-

tition coefficients (logP_o/w),^[44]might influence the partition

and could therefore have an influence on the hydrolysis of

the compounds. Table S1 (see Supporting Information)

summarizes the calculated logP_o/wof the precursors pre-

pared as described above.^[45]

To compare the performance of fragrance release from

the imidazolidinones with that of other hydrolytically cleav-

able 1,3-heterocycles, we prepared oxazolidin-4-one 10 and

oxazolidine 11 (see Figure 6) as additional reference com-

pounds, both of which were expected to release 3,5,5-tri-

methylhexanal.

Figure 6. Structures of oxazolidin-4-one 10 and oxazolidine 11,

serving as reference compounds with a different 1,3-heterocyclic

moiety.

Release measurements were carried out in duplicate in a

glass flask by adding an ethanolic solutions of imidazolid-

inones 1–9 to either one of the buffer solutions or the cat-

ionic surfactant emulsion to give a final concentration of

approximately 1.5ϫ10^–4molL^–1. The samples were shaken

vigorously and left at room temperature (21.7 °CϮ1.7 °C)

for two weeks. At different time intervals, an aliquot of the

solutions or the emulsion was removed by pipette and ex-

tracted with heptane. The amount of volatiles released from

the precursor was then determined by analyzing the hept-

ane extract by gas chromatography (GC). Removing ali-

quots of the reaction medium at regular time intervals con-

tinuously decreased the total volume of the solution or

emulsion in the closed flask and increased the headspace

above it. We observed that the increasing headspace volume

above the sample had almost no influence on the recovery

of the volatiles by solvent extraction (see Supporting Infor-

mation).

A few literature methods describe the synthesis of oxaz-

olidin-4-ones by reaction of an α-hydroxyamide with the

corresponding carbonyl compound in toluene or benzene

and in the presence of para-toluenesulfonic acid.^[40,41]Al-

though reasonable yields have been reported in the litera-

ture, the reaction of 2-hydroxyacetamide with different al-

dehydes under these conditions gave only small amounts

(5–10%) of the desired oxazolidin-4-ones. We finally pre-

pared oxazolidin-4-one 10 by reaction in tetrahydrofuran

(THF) in the presence of boron trifluoride etherate.^[41]

Again, the desired product was obtained in only modest

yield (11%).

Nevertheless, with sufficient amounts of product in hand

to serve as a reference for the release studies, we did not

further optimize the preparation of the oxazolidin-4-ones.

Oxazolidine 11 was prepared without any difficulty by reac-

tion of 2-(methylamino)ethanol with the corresponding

carbonyl compound under para-toluenesulfonic acid-cata-

lyzed cyclization along with the azeotropic removal of

water.

The efficiency of the extraction from the different media

used in this work was verified with 3,5,5-trimethylhexanal

as an example. Known quantities of the aldehyde (corre-

sponding to 1, 5, 10, 50, and 100 mol-% of the total amount

to be theoretically released from the precursors) were added

to the buffer solutions and the cationic surfactant emulsion.

The samples were then extracted with heptane after stand-

Hydrolysis of Imidazolidinones in Aqueous Media

The hydrolysis of imidazolidinones was investigated in ing for 1 h and 240 h and analyzed by GC. Figure 7 summa-

buffered aqueous solutions at pH = 4.6 (potassium hydro- rizes the data obtained from the extraction of the cationic

gen phthalate) and 7.3 (sodium/potassium phosphate), thus surfactant emulsion. Under the present conditions, one can

covering a slightly acidic or neutral pH range, typically see that the recovery of 3,5,5-trimethylhexanal is not quan-

found in various perfumed consumer articles. For solubility titative, as both curves (corresponding to the extraction af-

reasons, the buffers were prepared in a mixture of water/ ter 1 h and after 240 h) are lying below the diagonal line

acetonitrile (4:1). Furthermore, because most formulations of the graph, which would correspond to 100% extraction.

of applied perfumery contain surfactants, we also analyzed Nevertheless, the linearity of the lines indicates that con-

the hydrolysis of the imidazolidinones in an emulsion of a stant amounts of aldehyde were extracted within the con-

cationic surfactant in water at pH = 4.4. As a surfactant centration range investigated in the present work. The fact

helps to solubilize hydrophobic compounds in an aqueous that higher amounts of 3,5,5-trimethylhexanal were ex-

environment, the emulsion was prepared in pure water.

tracted after 1 h than after 240 h suggests that the aldehyde

For our studies, we chose a quaternized triethanolamine was not stable under the given conditions. A controlled re-

ester of fatty acids (TEA-esterquat) as the cationic surfac- lease of the compound from a profragrance might therefore

tant, which is commonly used as a rinse-added fabric soft- have a beneficial stabilizing effect. In the case of the cationic

ening agent.^[42]Concentrated fabric softener formulations surfactant emulsion, about 40% of the aldehyde was lost

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K. M. Fromm, A. Herrmann et al.

FULL PAPER

(Figure 7), however, its degradation in the water/acetonitrile mation, Table S3). Although similar quantities were typi-

buffer solutions was considerably less pronounced (see Sup- cally recovered from the buffer solutions at pH = 4.6 and

porting Information, Figure S5 and Table S2).

7.3, the extraction from the cationic surfactant emulsion

was generally less efficient. The absolute values of aldehydes

and ketones extracted from the different media were thus

corrected according to this data. The incomplete recovery

of the carbonyl compounds was expected to increase the

standard deviations in the measurements. In particular, the

extraction of only 7% of (Ϯ)-2-methylundecanal from the

emulsion was expected to result in a larger error in the abso-

lute value than would occur with the other compounds.

Figure 8 shows the amounts of carbonyl compounds (in

mol-%) released at different time intervals from imidazol-

idinones 1a–9a with respect to the total amount of precur-

sor present at the beginning of the measurements (see Sup-

porting Information, the corresponding numerical data are

listed in Table S4). In all cases, the volatile carbonyl com-

pounds were released from their precursors, although in

some cases at only very low concentrations.

Figure 7. Efficiency of the heptane extraction of (Ϯ)-3,5,5-trimeth-

ylhexanal (corresponding to 1, 5, 10, 50, and 100 mol-% of the

theoretical amount to be released from 2) from a cationic surfac-

tant emulsion after standing for 1 h (Ϫ᭿Ϫ) and 240 h (---᭿---).

For numerical data, see Supporting Information.

Although the amount of aldehydes recovered from the

buffer solutions continuously increased with increasing re-

action time, the aldehyde concentrations released from

imidazolidinones 1, 2, 8, and 9 into the cationic surfactant

From these findings, we also determined the efficiency of emulsion reached a maximum after approximately 50 h and

extraction for the other fragrances at different concentra- then rapidly dropped to values of almost zero. This strong

tions with respect to the total amount to be released from decrease in concentrations was attributed to the degrada-

the corresponding precursor. All compounds were only par- tion of the aldehydes as a result of their inherent instability

tially extracted after standing for 1 h (see Supporting Infor- in the surfactant emulsion.

Figure 8. Comparison of the hydrolysis of imidazolidinones 1a–9a releasing different fragrant aldehydes and ketones in buffered solutions

of water/acetonitrile (4:1) at pH = 4.6 (Ϫ᭹Ϫ) and 7.3 (Ϫ᭺Ϫ) or in a diluted aqueous TEA-esterquat emulsion at pH = 4.4 (Ϫ᭿Ϫ). For

numerical data, see Supporting Information.

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Eur. J. Org. Chem. 2012, 2837–2854

Precursors for Slow Release of Fragrant Aldehydes or Ketones

For imidazolidinones derived from the same amino acid Release and Evaporation of Volatiles after Deposition on a

amine, for example, glycinamide-based imidazolidinones Cotton Surface

1a–9a, the ketones were generally more readily released

than the aldehydes. At pH = 7.3, 15–40% of (–)-menthone,

In practical applications, volatile compounds must be de-

2-heptanone, or 5-methyl-3-heptanone were released from posited and evaporated from a surface before being per-

4a, 5a, and 6a, respectively, after 1 h. After 240 h, these ceived as a fragrance. Typical surfaces, which are important

values increased to 40% for 4a, 50% for 5a, and even above for perfumery, are skin, hair, and fabric, especially cotton.

90% for 6a. (R)-Citronellal derivative 3a was found to be Whereas the deposition of fragrances on skin is generally

the most efficient aldehyde precursor. Its release profile achieved by directly spraying ethanolic solutions onto the

was relatively flat, forming 10–20% of the aldehyde over surface, the deposition onto other substrates, such as hair

the entire period of the measurement, independent of the or cotton, is more complicated, as it has to occur during a

reaction medium. Hydrophobic imidazolidinone 7a re- washing (and rinsing) process.

leased less than 2% of the corresponding 2-methylundec-

anal and, therefore, was quite stable under the conditions known to be efficiently deposited onto cotton^[42]by trans-

tested. porting apolar compounds from an aqueous environment

Besides having a softening effect, cationic surfactants are

Keeping the same aldehyde structure yet varying the onto the surface of the fabric.^[43]Typically, the higher the

structure of the imidazolidinone showed that the substitu- logP_o/wof a given compound, the better it is expected to

tion at C-5 strongly influenced the rate of hydrolysis for the be deposited from an aqueous environment onto the fabric.

corresponding heterocycle, which decreased with increasing To assess the performance of the profragrances under more

size (or hydrophilicity) of the substituent.^[25]From the series realistic application conditions, we added a cotton sheet to

of 3,5,5-trimethylhexanal-releasing precursors 2a–2d (see the diluted TEA-esterquat emulsion described above con-

Figure 8 and Supporting Information, Figure S6), glycin- taining the heterocyclic profragrance (or an equimolar

amide-based imidazolidinone 2a hydrolyzed more readily amount of the corresponding reference fragrance to be re-

than its alanine analogue 2b and phenylalanine derivative leased) and investigated the release of the volatile carbonyl

2c. However, the structurally more rigid prolinamide ana- compound by following its evaporation from dry cotton by

logue 2d released higher amounts of 3,5,5-trimethylhexanal employing dynamic headspace analysis. Dynamic head-

than alanine derivative 2b. The same trend was observed for space analysis^[47]has the advantage of directly quantifying

Trifernal^®-releasing precursors 1a–1d, (R)-citronellal-releas- the evaporated fragrance from the targeted surface without

ing precursors 3a and 3b, and (–)-menthone-releasing pre- complicated sample preparation. The desired longevity of

cursors 4a and 4b (see Figure 8 and Supporting Infor- perception in the application is achieved if, after a certain

mation, Figure S6).

time, higher headspace concentrations of the fragrances are

The hydrolysis of imidazolidinones in the buffered solu- measured above the samples with the profragrance than

tions showed that, in general, slightly higher amounts of above the reference sample containing an equimolar

volatiles were released in the samples kept at pH = 7.3 com- amount of the corresponding unmodified fragrance.^[10,48]

pared with those at pH = 4.6. The observation that higher

One of the imidazolidinone, oxazolidinone, or oxazolid-

amounts of aldehydes or ketones were usually extracted ine profragrances, prepared as described above, was added

from the aqueous buffer solutions with respect to the cat- to a concentrated TEA-esterquat fabric softening formula-

ionic surfactant emulsion indicated that the presence of the tion, which was then diluted with water. The diluted formu-

surfactant had a stabilizing effect on the precursors by lation corresponded to the emulsion that was used for the

slowing down the rate of hydrolysis. This is also in line with hydrolysis experiments described in the previous section.

previous observations made in a slightly different con- One small cotton square (approximately 12ϫ12 cm) was

text.^[46]

added to the diluted surfactant emulsion for 5 min to allow

Despite the high standard deviations observed at the be- the deposition of the cationic surfactant together with the

ginning of the experiment, oxazolidine 11 released the profragrance (or the corresponding reference fragrance)

corresponding aldehyde almost quantitatively, both in the onto the cotton surface. The cotton sheets were wrung out

buffered solutions and in the cationic surfactant emulsion and air-dried for three days. For each measurement, one

(see Supporting Information, Figure S8 and Table S6). cotton square was placed inside a closed headspace-sam-

Under the experimental conditions described, the oxazolid- pling cell and then exposed to a constant flow of air. The

ine hydrolyzes faster than the corresponding imidazolid- airflow was passed through an activated charcoal filter and

inones.

a saturated sodium chloride solution to maintain constant

The release kinetics recorded in the buffered solutions humidity in the sampling cell. The fragrance evaporating

might help us to understand the general behavior of the from the cotton surface was trapped at constant time inter-

precursors in an aqueous environment and to study the in- vals onto a cartridge containing a polymeric adsorbent

fluence of the structural variations on the rate of hydrolysis. (Tenax^®). After thermal desorption, the quantities of the

As a next step, we investigated the release of the volatile volatiles trapped were determined by GC analysis. All

aldehydes and ketones from the corresponding imidazolid- analyses were compared with a reference sample composed

inones under more realistic application conditions by fol- of the unmodified fragrance, which was prepared and ana-

lowing their evaporation from a cotton surface.

lyzed under the same conditions as the corresponding pro-

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2843

K. M. Fromm, A. Herrmann et al.

FULL PAPER

Figure 9. Dynamic headspace concentrations of different fragrant aldehydes and ketones (---᭺---) and the corresponding fragrant alde-

hydes and ketones released from glycinamide-derived imidazolidinones 1a–9a (Ϫ᭹Ϫ) measured on dry cotton after drying for three days.

In the case of (–)-menthone derivative 4a, both isomers were analyzed separately, (5R,6S,9R)-4a (Ϫ᭡Ϫ) and (5S,6S,9R)-4a (Ϫ᭿Ϫ). For

numerical data, see Supporting Information.

fragrance. Average values result from at least two measure- of 2-heptanone by a factor of 30 with respect to the refer-

ments.^[10,48]

ence. 3,5,5-Trimethylhexanal was the most efficiently re-

Figure 9 shows the headspace concentrations of the alde- leased aldehyde, with an increase in headspace concentra-

hydes and ketones released from glycinamide derivatives tion by a factor of about 8. The release of 2-methylundeca-

1a–9a compared to an equimolar amount of the corre- nal from 7a and hexanal from 8a resulted in almost the

sponding unmodified reference (see Supporting Infor- same headspace concentrations as those measured for the

mation, the corresponding numerical data are listed in unmodified reference. The strong dependence on the struc-

Table S7).

ture of the leaving carbonyl compound could be illustrated

In all cases, our data show that the carbonyl compounds by the release of (–)-menthone from (5R,6S,9R)- and

were successfully released from the different imidazolid- (5S,6S,9R)-4a. The two isomers were measured separately

inones. As previously seen in the hydrolysis experiments, the and, under the present reaction conditions, the (5S)-isomer

release efficiency was influenced by the structure of the leav- released about 1.5 times more (–)-menthone than its (5R)-

ing carbonyl compounds. It is interesting to note that the analogue.

headspace concentrations of the ketones evaporated from

Absolute headspace concentrations measured by the

the reference samples were close to zero, whereas the head- present method show large variations, which presumably re-

space concentrations of the aldehydes varied between about sult from the lack of control of various parameters during

2 and 15 ngL^–1. However, much higher headspace concen- the line drying of the cotton sheets. Nevertheless, relative

trations were measured for the ketones released from 4a–6a values (obtained by comparison to the reference) were

(approximately 10–125 ngL^–1) than for the aldehydes gener- found to be quite reproducible. Typically, the headspace

ated from 1a–3a and 7a–9a (approximately 2–50 ngL^–1). concentrations increased at the beginning of the measure-

This difference is even more pronounced when comparing ment and reached a maximum before decreasing again. This

the ratios between the concentrations of the released com- effect was generally observed for different types of precur-

pounds and the corresponding reference at a given time. sors and has been attributed to the equilibration of the

After 150 min of sampling, approximately 210 times more headspace cells.^[10,48]

5-methyl-3-heptanone was found in the headspace above

Figure 10 shows the headspace concentrations of a given

the sample treated with 6a than above the reference sample aldehyde or ketone released from imidazolidinones with dif-

(see Figure 9). The presence of 5a increased the headspace ferent substituents at C-5. With respect to the glycinamide-

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Precursors for Slow Release of Fragrant Aldehydes or Ketones

Figure 10. Dynamic headspace concentrations of different fragrant aldehydes and ketones (---᭺---) and the corresponding fragrant alde-

hydes or ketones released from imidazolidinones 2b–2d, 4b; from oxazolidin-4-one 10; and from oxazolidine 11 (Ϫ᭹Ϫ) measured on dry

cotton after drying for three days. For numerical data, see Supporting Information.

based imidazolidinones (see Figure 9) and as seen in the with respect to the reference sample, despite its almost

hydrolysis experiments, the substitution at C-5 generally re- quantitative hydrolysis in solution (see Figure 10). In this

sulted in lower headspace concentrations of the correspond- case, the hydrolysis in solution is probably so fast^[11]that

ing carbonyl compounds released from the precursors.

the compound behaves almost like the unmodified reference

Changing the substituent at C-5 from hydrogen (1a, 2a) sample. Similarly, although not tested in solution, oxazol-

to methyl (1b, 2b) and to benzyl (1c, 2c) decreased the hy- idin-4-one 10 did not efficiently release 3,5,5-trimethylhex-

drophilicity of the precursor (see Supporting Information, anal on the cotton and, thus, was not a suitable precursor

Table S1) and thus its water solubility. On the other hand, for this type of application. Imidazolidinones were more

more hydrophobic molecules are expected to be more pref- efficient precursors for the targeted application than the

erably deposited onto a cotton surface than more hydro- corresponding oxazolidinones or oxazolidines.

philic ones.^[43,46]Therefore, with an equally efficient hydro-

lysis reaction, one could expect the more hydrophobic pre-

cursor to give rise to the highest headspace concentrations

in application. However, as stated above, hydrolysis effi-

Conclusions

ciency works in the opposite direction with the more polar

The development of hydrolytically cleavable precursors

glycinamide-based imidazolidinones 1a–9a being more for the controlled release of fragrances is particularly chal-

readily hydrolyzed than their C-5-substituted analogues. lenging, as these compounds are often stored in aqueous

Overall, the efficiency of hydrolysis seems to be more im- media and, thus, in the presence of the release trigger. Find-

portant than the amount of precursor deposition.

ing the ideal compromise between precursor stability and

Comparison of the data obtained for the release of the release efficiency is typically not easily achieved, especially

carbonyl compounds from imidazolidinones 1a–9a by hy- as there are a considerable number of different physico-

drolysis (Figure 8) and headspace analysis (Figures 9 and chemical parameters to take into account. Subtle modifica-

10) shows a correlation only within a homologous series of tions of the precursor structure have an important influence

compounds with a different substituent at C-5 (e.g., imid- on the interplay of these parameters and can, therefore,

azolidinones 2a–2d) or with the ketone-releasing precursors strongly impact the performance of these products in appli-

4a–6a. It is not possible to predict the efficiency of release cation.

of the different aldehydes in practical application from the

Imidazolidin-4-ones are efficient precursors for the slow

hydrolysis data. For example, precursor 7a was relatively release of bioactive volatile compounds and prolong the

stable in a solution releasing less than 2 mol-% of the alde- longevity of fragrance evaporation in practical applications.

hyde after two weeks. Nevertheless, dynamic headspace Hydrolysis experiments carried out in buffered solutions of

analysis on cotton revealed a slight slow-release effect, when water/acetonitrile (4:1) at different pH levels or in a cationic

compared with the free aldehyde as the reference (see Fig- surfactant containing aqueous emulsion showed that

ure 9). This effect might be due to a favorable deposition of ketones were generally more readily released than alde-

the precursor as a result of its high logP_o/w. On the other hydes. Increasing the size of the substituents at C-5 in-

hand, oxazolidine 11 did not give rise to higher headspace creased the hydrophobicity of the precursors, but decreased

concentrations of 3,5,5-trimethylhexanal on the dry cotton the rate of hydrolysis in solution as well as on the target

Eur. J. Org. Chem. 2012, 2837–2854

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2845

K. M. Fromm, A. Herrmann et al.

FULL PAPER

(neat): ν = 3432 (w), 3291 (w), 3196 (m, br.), 3083 (w), 3060 (w),

˜

surface. Dynamic headspace analysis above a cotton surface

showed that glycinamide-based imidazolidinones repre-

sented the ideal compromise between precursor stability

and release efficiency for the applications tested.

Hydrolysis rates determined in solution might be useful

for predicting the efficiency of a controlled release under

physiological conditions for drug delivery, but these data

are only partially relevant for evaluating the release of fra-

grances from different surfaces. Although the combination

of release efficiency in solution and the amount of surface

deposition were occasionally used to estimate the efficiency

of fragrance-delivery systems, our data show that neither

the release rates in solution, nor the hydrophobicity of the

3026 (w), 2960 (m), 2927 (w), 2871 (w), 1689 (s), 1602 (m), 1582

(w), 1493 (m), 1451 (m), 1376 (m), 1331 (w), 1304 (m), 1273 (m),

1203 (w), 1169 (w), 1154 (w), 1113 (w), 1081 (w), 1072 (w), 1054

(w), 1026 (w), 997 (w), 984 (w), 952 (w), 909 (w), 884 (w), 863 (w),

796 (m), 762 (s), 699 (s), 644 (m) cm^–1. HRMS: calcd. for

C₁₂H₁₇N₂O [M + H]⁺205.1340; found 205.1333.

(؎)-(5S)-5-Methyl-2-(2-phenylpropyl)imidazolidin-4-one (1b): This

compound was prepared as described above from Trifernal^®

(1.18 g, 5.0 mmol), l-alaninamide hydrochloride (1.00 g,

8.0 mmol), TEA (0.81 g, 1.1 mL, 8.0 mmol), K₂CO₃(0.98 g), and

ethanol (8 mL). The residue was dissolved in ether, and the mixture

was filtered. The filtrate was concentrated, and the residue was

dried under vacuum to give a colorless oil (1.87 g, quantitative) as

precursor structure, nor the combination of both was suf- a mixture of diastereomers. ¹H NMR (400 MHz, CDCl₃): δ = 7.90,

7.71, 7.06, and 6.81 (br. s, 1 H, NHC=O), 7.34–7.26 (m, 2 H, Ph),

7.26–7.17 (m, 3 H, Ph), 4.38–4.25 [m, 1 H, C(2)H], 3.57–3.35 [m, 1 H,

C(5)H], 3.00–2.83 (m, 1 H, PhCHCH₃), 2.05–1.75 [m, 3 H,

C(2)HCH₂and C(5)NH], 1.37–1.18 [m, 6 H, PhCHCH₃and

C(5)CH₃] ppm. ¹³C NMR (100.6 MHz, CDCl₃): δ = 179.65,

179.57, 179.30, and 179.05 [s, C(4)=O], 145.78, 145.73, 145.61, and

145.58 [s, PhC(1Ј)], 128.88, 128.79, 128.71, and 128.70 [d, PhC(3Ј)],

126.97, 126.92 (2 C), and 126.87 [d, PhC(2Ј)], 126.76, 126.59,

126.53, and 126.45 [d, PhC(4Ј)], 68.32, 68.17, 67.86, and 67.85 [d,

C(2)], 55.17, 54.90, 53.80, and 53.54 [d, C(5)], 45.52, 45.48, 45.32,

ficient to predict the performance of the precursor-based

fragrance-delivery systems in application. To control the re-

lease of volatiles, additional parameters such as equilibria

resulting from the presence of surfactants, surface deposi-

tion, volatility of the released compounds, and evaporation

rates will have to be considered to understand and improve

fragrance delivery in future work.

Nevertheless, hydrolytically cleavable 1,3-heterocycles are

important and efficient delivery systems within different

areas of the life sciences, and our work will not only con- and 45.22 [t, C(2)CH₂], 36.68, 36.65, 36.33, and 36.31 [d,

PhCHCH₃], 23.09, 22.94, 22.85, and 22.80 (q, PhCHCH₃), 17.25,

tribute to the future development of precursor-based release

systems for fragrances, but also to the development of deliv-

ery systems for drugs, agrochemicals, and other bioactive

compounds. More research efforts are required to better

understand the interplay of the different parameters in-

volved to predict and achieve an optimum performance of

hydrolytically cleavable 1,3-heterocycles.

17.21, 17.20, and 17.12 [q, C(5)CH ] ppm. IR (neat): ν = 3202 (m,

˜

3

br.), 3105 (w), 3084 (w), 3061 (w), 3027 (w), 2964 (m), 2928 (m),

2870 (m), 1694 (s), 1602 (m), 1582 (w), 1493 (m), 1451 (m), 1371

(m), 1338 (w), 1321 (w), 1294 (m), 1260 (w), 1198 (w), 1182 (w),

1134 (m), 1059 (m), 1025 (m), 999 (w), 973 (w), 932 (w), 911 (w),

880 (w), 843 (w), 762 (s), 699 (s), 619 (w), 606 (w) cm^–1. HRMS:

calcd. for C₁₃H₁₉N₂O [M + H]⁺219.1497; found 219.1488.

(؎)-(5S)-5-Benzyl-2-(2-phenylpropyl)imidazolidin-4-one (1c): This

compound was prepared as described above from Trifernal^®

(0.74 g, 5.0 mmol), l-phenylalaninamide hydrochloride (1.00 g,

5.0 mmol), TEA (0.505 g, 0.7 mL, 5.0 mmol), K₂CO₃(0.98 g), and

ethanol (8 mL). Removing the solvent and drying under vacuum

gave a highly viscous, slightly yellow oil (1.41 g, 96%) as a mixture

of diastereomers. ¹H NMR (400 MHz, CDCl₃): δ = 7.67, 7.63, 6.77,

and 6.69 (s, 1 H, NHC=O), 7.36–7.11 (m, 10 H, Ph), 4.35–4.25 and

4.14–4.06 [m, 1 H, C(2)H], 3.78–3.67 and 3.67–3.58 [m, 1 H, C(5)

H], 3.16–3.08, 3.07–3.02, and 2.93–2.77 [m, 2 H, C(5)CH₂], 2.93–

2.77 [m, 1 H, PhCHCH₃], 2.04 [br. s, 1 H, C(5)NH], 1.92–1.65 and

1.62–1.52 [m, 2 H, C(2)CH₂], 1.28–1.20 [m, 3 H, PhCHCH₃] ppm.

¹³C NMR (100.6 MHz, CDCl₃): δ = 177.85, 177.71, 177.54, and

177.18 [s, C(1)=O], 145.63 [s, PhC(1Ј)], 137.57, 137.40, 137.32, and

137.29 [s, PhC(1ЈЈ)], 129.49 (2 C), 129.42, and 129.41 [d, PhC(2ЈЈ)],

128.85, 128.77, 128.69, and 128.67 [d, PhC(3Ј)], 128.59 and 128.53

(3 C) [d, PhC(3ЈЈ)], 126.92, 126.90, and 126.87 (2 C) [d, PhC(2Ј)],

126.72 (3 C), 126.70 (2 C), 126.62, 126.47, and 126.46 [d, PhC(4Ј)

and PhC(4ЈЈ)], 68.35, 68.31, 68.12, and 67.97 [d, C(2)], 60.32, 60.70,

59.28, and 59.20 [d, C(5)], 45.68, 45.58, 45.48, and 45.46 [t,

Experimental Section

General Comments: Commercially available reagents and solvents

were used without further purification if not stated otherwise. Re-

actions were carried out in standard glassware under N₂.

General Method for the Preparation of Imidazolidin-4-ones 1a–1d:

A mixture of (Ϯ)-3-phenylbutanal (Trifernal^®), amino acid amide

hydrochloride, TEA, and K₂CO₃in ethanol was heated to 60 °C

for 24 h. After cooling to room temperature, the solvent was re-

moved, and the residue was dissolved in ether. The solvent was

evaporated to yield the imidazolidin-4-one, usually as a mixture of

diastereomers.

(؎)-2-(2-Phenylpropyl)imidazolidin-4-one (1a): This compound was

prepared as described above from Trifernal^®(0.67 g, 4.5 mmol),

glycinamide hydrochloride (0.50 g, 4.5 mmol), TEA (0.46 g,

4.5 mmol), K₂CO₃, and ethanol (4 mL) to yield a highly viscous,

yellow oil (0.52 g, 57%) as a mixture of diastereomers still contain-

1

ing ethyl acetate. H NMR (400 MHz, CDCl₃): δ = 8.06 (br. s, 1

H, NHC=O), 7.34–7.26 (m, 2 H, Ph), 7.25–7.15 (m, 4 H, Ph), 4.44– C(2)CH₂], 37.59, 37.37, 37.20, and 37.12 [t, C(5)CH₂], 36.55, 36.54,

4.34 [m, 1 H, C(2)H], 3.45–3.28 [m, 2 H, C(5)H₂], 2.99–2.84 (m, 1 and 36.33 (2 C) [d, PhCHCH₃], 22.99, 22.92, 22.84, and 22.80 (q,

H, PhCHCH₃), 2.05 [br. s, C(5)NH], 1.99–1.78 [m, 2 H, C(2)- PhCHCH ) ppm. IR (neat): ν = 3660 (w), 3194 (m, br.), 3084 (w),

˜

3

HCH₂], 1.29 (d,

J

=

6.9 Hz,

3

H, CH₃) ppm. ¹³C NMR

3061 (w), 3026 (m), 3001 (w), 2958 (m), 2924 (m), 2870 (w), 1947

(w), 1879 (w), 1810 (w), 1695 (s), 1602 (m), 1582 (w), 1494 (m),

1452 (m), 1374 (m), 1342 (m), 1281 (m), 1202 (w), 1182 (w), 1155

(w), 1117 (m), 1077 (m), 1066 (w), 1057 (w), 1027 (m), 1000 (w),

(100.6 MHz, CDCl₃): δ = 177.71 and 177.23 [s, C(4)=O], 145.68

and 145.64 [s, PhC(1Ј)], 128.82 and 128.71 [d, PhC(3Ј)], 126.91 and

126.90 [d, PhC(2Ј)], 126.65 and 126.49 [d, PhC(4Ј)], 70.57 and 70.37

[d, C(2)], 49.07 and 48.79 [t, C(5)], 45.34 and 45.08 [t, C(2)CH₂], 970 (w), 911 (w), 877 (w), 762 (m), 752 (m), 697 (s), 620 (w) cm^–1.

36.55 and 36.36 [d, PhCHCH₃], 22.91 and 22.87 (q, CH₃) ppm. IR HRMS: calcd. for C₁₉H₂₃N₂O [M + H]⁺295.1810; found 295.1804.

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Precursors for Slow Release of Fragrant Aldehydes or Ketones

(؎)-(7aS)-3-(2-Phenylpropyl)hexahydro-1H-pyrrolo[1,2-c]imidazol-

1-one (1d): This compound was prepared as described above (with-

out TEA) from Trifernal^®(0.65 g, 4.4 mmol), d-prolinamide

(0.50 g, 4.4 mmol), K₂CO₃, and ethanol (4.48 g) to yield a colorless

oil (1.03 g, 97 %) as a mixture of diastereomers. ¹H NMR

(400 MHz, [D₆]DMSO): δ = 8.23 (br. s, 1 H, NHC=O), 7.35–7.14

due under high vacuum (0.2 mbar, 1 h) gave a white solid (1.26 g,

74%). H NMR (400 MHz, CDCl₃): δ = 7.64, 7.58, 7.35, and 7.23

(br. s, 1 H, NHC=O), 4.64–4.53 [m, 1 H, C(2)H], 3.59–3.42 [m, 1

H, C(5)H], 1.96 [br. s, 1 H, C(5)NH], 1.78–1.61 [m, 1 H, C(2Ј)H],

1.61–1.37 [m, 2 H, C(1Ј)H₂], 1.35, 1.34, 1.32, and 1.32 [d, J = 6.7–

6.9 Hz, 3 H, C(5)CH₃], 1.27–1.04 [m, 2 H, C(3Ј)H₂], 0.99, 0.99,

1

(m,5H,Ph),3.81(t,J=6.1 Hz)and3.68[dd,J=8.7,4.1 Hz,1H,C(3)- 0.98, and 0.97 [d, J = 6.4–6.7 Hz, 3 H, C(2Ј)CH₃], 0.91, 0.91, 0.91,

H], 3.52 [ddd, J = 14.6, 10.3, 4.1 Hz, 1 H, C(7a)H], 3.04–2.85 [m,

and 0.90 [s, 9 H, C(4Ј)CH₃] ppm. ¹³C NMR (100.6 MHz, CDCl₃):

2 H, C(5)H and CHCH₃], 2.53–2.37 [m, 1 H, C(5)H], 1.96–1.81 [m, δ = 179.66 and 179.50 [s, C(4)=O], 67.96, 67.94, and 67.91 [d, C(2)],

1 H, C(7)H], 1.81–1.49 [m, 5 H, C(7)H, C(6)H₂, and C(3)HCH₂],

55.39, 53.86, and 53.77 [d, C(5)], 51.63, 51.37, and 51.33 [t, C(3Ј)],

46.99, 46.74, 46.70, and 46.58 [t, C(1Ј)], 31.18 and 31.16 [s, C(4Ј)],

1.21 and 1.20 (d, J = 7.2 Hz, 3 H, CH₃) ppm. ¹³C NMR

(100.6 MHz, [D₆]DMSO): δ = 176.25 and 176.09 [s, C(1)=O], 29.99, 29.98, and 29.95 [q, C(4Ј)CH₃], 26.08, 25.94, and 25.88 [d,

146.74 and 146.51 [s, PhC(1Ј)], 128.39 and 128.28 [d, PhC(3Ј)],

126.86 and 126.76 [d, PhC(2Ј)], 125.97 and 125.84 [d, PhC(4Ј)],

75.14 and 75.12 [d, C(3)], 62.61 and 62.45 [d, C(7a)], 55.59 and

55.24 [t, C(5)], 46.64 and 46.12 [t, C(3)CH₂], 35.54 and 34.88 [d,

PhCHCH₃], 27.19 and 27.14 [t, C(7)], 24.60 and 24.48 [t, C(6)],

C(2Ј)], 22.82, 22.64, 22.63, and 22.57 [q, C(2Ј)CH₃], 17.14, 17.11,

and 17.03 [q, C(5)CH ] ppm. IR (neat): ν = 3676 (w, br.), 3251 (w),

˜

3

3187 (w, br.), 3094 (w), 2951 (m), 2903 (m), 2867 (m), 1701 (s),

1475 (w), 1452 (m), 1388 (w), 1376 (w), 1365 (m), 1327 (w), 1294

(m), 1247 (w), 1198 (w), 1180 (w), 1135 (m), 1091 (w), 1077 (w),

22.77 and 22.17 (q, CH ) ppm. IR (neat): ν = 3675 (w), 3184 (w, 1060 (w), 1037 (w), 981 (w), 966 (w), 930 (w), 900 (w), 878 (w), 849

˜

3

br.), 3083 (w), 3061 (w), 3026 (w), 2960 (m), 2927 (w), 2870 (w),

2818 (w), 1994 (s), 1602 (w), 1582 (w), 1494 (m), 1451 (m), 1375

(w), 835 (w), 797 (w), 767 (m), 720 (w), 689 (w), 656 (w), 614

(w) cm^–1. HRMS: calcd. for C₁₂H₂₅N₂O [M + H]⁺213.1967; found

(m), 1329 (m), 1305 (w), 1274 (m), 1249 (m), 1186 (w), 1164 (w), 213.1981.

1115 (m), 1099 (m), 1074 (w), 1049 (w), 1026 (m), 1000 (w), 987

(؎)-(5S)-5-Benzyl-2-(2,4,4-trimethylpentyl)imidazolidin-4-one (2c):

(w), 907 (w), 878 (w), 762 (s), 699 (s) cm^–1. HRMS: calcd. for

C₁₅H₂₁N₂O [M + H]⁺245.1658; found 245.1653.

This compound was prepared as described above from (Ϯ)-3,5,5-

trimethylhexanal (0.64 g, 4.5 mmol), TEA (0.50 g, 5.0 mmol), l-

phenylalaninamide hydrochloride (0.74 g, 4.5 mmol), and dry

methanol (6 mL) to give a highly viscous, yellow oil (1.23 g, 95%).

¹H NMR (400 MHz, CDCl₃): δ = 7.66, 7.51, and 7.34–7.20 (br. s,

1 H, NHC=O), 7.34–7.20 (m, 5 H, Ph), 4.56–4.50, 4.45–4.39, 4.36–

4.31, and 4.30–4.24 [m, 1 H, C(2)H], 3.80–3.69 [m, 1 H, C(5)H],

3.19–2.89 [m, 2 H, C(5)CH₂], 2.55 [br. s, 1 H, C(5)NH], 1.68–1.54

[m, 1 H, C(2Ј)H], 1.54–1.20 [m, 2 H, C(1Ј)H₂], 1.20–0.99 [m, 2 H,

C(3Ј)H₂], 0.95–0.84 [m, 12 H, C(2Ј)CH₃and C(4Ј)CH₃] ppm. ¹³C

NMR (100.6 MHz, CDCl₃): δ = 178.03, 177.97, 177.93, and 177.69

[s, C(4)=O], 137.51, 137.47, 137.34, and 137.15 [s, PhC(1Ј)], 129.60,

129.56, 129.55, and 129.44 [d, PhC(2Ј)], 128.65, 128.61, 128.53, and

128.49 [d, PhC(3Ј)], 126.80, 126.78, and 126.73 [d, PhC(4Ј)], 68.26,

68.11, 68.01, and 67.88 [d, C(2)], 60.40, 60.30, 59.57, and 59.43 [d,

C(5)], 51.63, 51.39, 51.25, and 51.17 [t, C(3Ј)], 47.04, 46.85 (2 C),

and 46.72 [t, C(1Ј)], 37.31, 37.28, 37.18, and 36.94 [t, C(5)CH₂],

31.15, 31.14, and 31.09 [s, C(4Ј)], 29.99 and 29.96 [q, C(4Ј)CH₃],

25.96, 25.82, 25.81, and 25.58 [d, C(2Ј)], 22.76, 22.67 (2 C), and

General Method for the Preparation of Imidazolidin-4-ones 2–9: The

carbonyl compound and TEA were added to a suspension of the

amino acid amide hydrochloride in dry methanol. The mixture was

heated at reflux for 18 h. After cooling to room temp. and, in some

cases, stirring for 24 h, the solvent was removed under reduced

pressure. Then, demineralized water (20–25 mL) was added to the

residue, and the mixture extracted with ethyl acetate (3 ϫ 20–

25 mL). The combined organic phases were dried with Na₂SO₄and

concentrated, and the residue was dried under high vacuum

(0.2 mbar, 1 h at room temperature) to give the imidazolidin-4-one,

usually as a mixture of diastereomers.

(؎)-2-(2,4,4-Trimethylpentyl)imidazolidin-4-one (2a): This com-

pound was prepared as described above from (Ϯ)-3,5,5-trimeth-

ylhexanal (2.58 g, 18.1 mmol), TEA (2.00 g, 19.8 mmol, 2.7 mL),

glycinamide hydrochloride (2.00 g, 18.1 mmol), and dry methanol

(20 mL) to give, after additional drying (0.5 h at 60 °C), a yellow

paste (3.44 g, 96%). ¹H NMR (400 MHz, CDCl₃): δ = 7.90 and

7.62 (br. s, 1 H, NHC=O), 4.70–4.61 [m, 1 H, C(2)H], 3.50–3.33

[m, 2 H, C(5)H₂], 2.58 [br. s, 1 H, C(5)NH], 1.78–1.63 [m, 1 H,

C(2Ј)H], 1.63–1.41 [m, 2 H, C(1Ј)H₂], 1.31–1.05 [m, 2 H, C(3Ј)H₂],

0.99 and 0.98 [d, J = 6.7 Hz, 3 H, C(2Ј)CH₃], 0.91 and 0.90 [s, 9

H, C(4Ј)CH₃] ppm. ¹³C NMR (100.6 MHz, CDCl₃): δ = 177.74 and

177.69 [s, C(4)=O], 70.42 and 70.39 [d, C(2)], 51.44 and 51.35 [t,

C(3Ј)], 49.16 and 49.08 [t, C(5)], 46.62 and 46.35 [t, C(1Ј)], 31.15

[s, C(4Ј)], 29.98 and 29.96 [q, C(4Ј)CH₃], 25.95 and 25.82 [d, C(2Ј)],

22.57 [q, C(2Ј)CH ] ppm. IR (neat): ν = 3726 (w), 3627 (w), 3200

˜

3

(w, br.), 3086 (w), 3063 (w), 3029 (w), 2951 (m), 2905 (m), 2867

(m), 1944 (w), 1699 (s), 1603 (w), 1584 (w), 1541 (w), 1496 (m),

1475 (w), 1464 (w), 1454 (m), 1438 (w), 1393 (w), 1364 (m), 1265

(w), 1244 (m), 1201 (w), 1120 (m), 1078 (w), 1047 (w), 1030 (w),

973 (w), 916 (w), 775 (m), 749 (m), 728 (w), 697 (s), 663 (m), 648

(w), 621 (w), 611 (w) cm^–1. HRMS: calcd. for C₁₈H₂₉N₂O

[M + H]⁺289.2274; found 289.2244.

(؎)-(7aS)-3-(2,4,4-Trimethylpentyl)hexahydro-1H-pyrrolo[1,2-c]-

imidazol-1-one (2d): This compound was prepared as described

above from (Ϯ)-3,5,5-trimethylhexanal (0.99 g, 7.0 mmol), TEA

(1.07 g, 10.6 mmol), d-prolinamide (0.80 g, 7.0 mmol), and dry

methanol (10 mL) to give a viscous, slightly yellow oil (1.63 g,

22.70 and 22.62 [q, C(2Ј)CH ] ppm. IR (neat): ν = 3198 (m, br.),

˜

3

2951 (s), 2904 (m), 2867 (m), 1692 (s), 1538 (w), 1475 (w), 1466

(m), 1392 (m), 1377 (w), 1364 (s), 1315 (m), 1299 (m), 1280 (m),

1247 (m), 1200 (m), 1136 (w), 1113 (w), 1096 (w), 1054 (w), 1017

(w), 973 (m), 947 (w), 927 (w), 911 (w), 865 (m), 746 (m), 695 (m),

654 (m), 615 (w) cm^–1. HRMS: calcd. for C₁₁H₂₃N₂O [M + H]⁺

199.1805; found 199.1854.

1

98%). H NMR (400 MHz, CDCl₃): δ = 8.01 and 7.64 (br. s, 1 H,

NHC=O), 4.22–4.13 [m, 1 H, C(3)H], 3.79–3.68 [m, 1 H, C(7a)H],

3.22–3.12 [m, 1 H, C(5)H], 2.74–2.63 [m, 1 H, C(5)H], 2.16–2.02

[m, 1 H, C(7)H], 2.03–1.89 [m, 1 H, C(7)H], 1.86–1.70 [m, 2 H,

C(6)H₂], 1.86–1.70 and 1.70–1.62 [m, 1 H, C(2Ј)H], 1.62–1.28 [3 m,

2 H, C(1Ј)H₂], 1.24 [dt, J = 14.1, 4.0 Hz, 1 H, C(3Ј)H], 1.09 [ddd,

J = 13.9, 6.4, 2.4 Hz, 1 H, C(3Ј)H], 0.98 and 0.96 [d, J = 6.7 Hz, 3

H, C(2Ј)CH₃], 0.91 and 0.90 [s, 9 H, C(4Ј)CH₃] ppm. ¹³C NMR

(100.6 MHz, CDCl₃): δ = 178.72 and 178.68 [s, C(1)=O], 76.48 and

(؎)-(5S)-5-Methyl-2-(2,4,4-trimethylpentyl)imidazolidin-4-one (2b):

This compound was prepared as described above from (Ϯ)-3,5,5-

trimethylhexanal (1.16 g, 8.1 mmol), TEA (0.89 g, 8.8 mmol), l-al-

aninamide hydrochloride (1.00 g, 8.0 mmol), and dry methanol

(10 mL). Plug filtration (SiO₂, ethyl acetate) of the crude com-

pound followed by concentrating the mixture and drying the resi-

Eur. J. Org. Chem. 2012, 2837–2854

www.eurjoc.org

2847

K. M. Fromm, A. Herrmann et al.

FULL PAPER

76.36 [d, C(3)], 63.36 and 63.24 [d, C(7a)], 56.31 and 56.09 [t, C(5)],

51.35 and 51.20 [t, C(3Ј)], 47.94 and 47.81 [t, C(1Ј)], 31.16 [s, C(4Ј)],

30.09 and 30.07 [q, C(4Ј)CH₃], 27.67 and 27.42 [t, C(7)], 25.70 and

25.58 [d, C(2Ј)], 25.13 and 25.04 [t, C(6)], 22.90 and 22.52 [q,

(w), 1293 (m), 1261 (w), 1177 (w), 1134 (m), 1059 (w), 1031 (w),

983 (w), 939 (w), 825 (w), 788 (m, br.), 738 (m), 692 (m), 647 (w),

632 (w), 604 (m) cm^–1. HRMS: calcd. for C₁₃H₂₅N₂O [M + H]⁺

225.1961; found 225.2004.

C(2Ј)CH ] ppm. IR (neat): ν = 3187 (m, br.), 3090 (w, br.), 2950

˜

3

(5R,6S,9R)-6-Isopropyl-9-methyl-1,4-diazaspiro[4.5]decan-2-one

[(5R,6S,9R)-4a] and (5S,6S,9R)-6-isopropyl-9-methyl-1,4-diaza-

spiro[4.5]decan-2-one [(5S,6S,9R)-4a]: These compounds were pre-

pared as described above from (2S,5R)-2-isopropyl-5-methylcy-

clohexanone [(–)-menthone, 5.58 g, 36.2 mmol], TEA (5.40 g,

53.5 mmol), glycinamide hydrochloride (4.00 g, 36.2 mmol), and

dry methanol (30 mL). Extraction with ethyl acetate (3ϫ40 mL)

gave a yellow oil (5.60 g). Column chromatography (SiO₂, ethyl

acetate) yielded (5R,6S,9R)-4a (0.79 g, 10%) as a slightly yellow

paste and (5S,6S,9R)-4a (1.11 g, 15%) as colorless crystals. Data

(m), 2908 (w), 2868 (m), 1698 (s), 1476 (w), 1465 (m), 1447 (m),

1392 (w), 1375 (w), 1364 (m), 1326 (m), 1305 (w), 1275 (w), 1246

(m), 1188 (m), 1164 (w), 1141 (m), 1114 (m), 1084 (m), 1029 (w),

988 (w), 972 (w), 928 (w), 906 (w), 877 (w), 781 (m), 752 (m), 698

(m), 621 (w), 616 (w) cm^–1. HRMS: calcd. for C₁₄H₂₇N₂O

[M + H]⁺239.2118; found 239.1970 and 239.2039.

(؎)-2-[(R)-2,6-Dimethyl-5-heptenyl]imidazolidin-4-one (3a): This

compound was prepared as described above from (R)-3,7-dimethyl-

6-octenal [(R)-citronellal, 2.10 g, 13.6 mmol], TEA (1.48 g,

14.6 mmol, 2.0 mL), glycinamide hydrochloride (1.50 g,

1

for (5R,6S,9R)-4a: H NMR (400 MHz, CDCl₃): δ = 7.02 (br. s, 1

13.6 mmol), and dry methanol (15 mL) to give a brown paste H, NHC=O), 3.48 [dd, J = 47.1, 16.4 Hz, 2 H, C(3)H₂], 2.03–1.94

(2.22 g). Plug filtration (SiO₂, ethyl acetate) yielded a viscous, yel-

low oil (0.38 g, 13%; approximate ratio of diastereomers, 1.5:1). ¹H

NMR (400 MHz, CDCl₃): δ = 7.65 (minor isomer) and 7.58 (major

[m, 1 H, C(6)CH], 1.87 [br. s, 1 H, C(3)NH], 1.82–1.70 [m, 2 H,

C(8)H and C(10)H], 1.70–1.57 [m, 2 H, C(7)H and C(9)H], 1.44–

1.31 [m, 1 H, C(7)H], 1.31–1.18 [m, 2 H, C(6)H and C(10)H], 0.97–

isomer, br. s, 1 H, NHC=O), 5.15–5.01 [m, 1 H, C(5Ј)H], 4.74–4.65 0.81 [m, 1 H, C(8)H], 0.92 [d, J = 7.2 Hz, 3 H, C(6)CHCH₃], 0.91

[m, 1 H, C(2)H], 3.43 (minor isomer) and 3.42 [major isomer, q, J

= 15.5, 15.2 Hz, 2 H, C(5)H₂], 3.29 [br. s, 1 H, C(5)NH], 2.08–1.87

[m, 2 H, C(4Ј)H₂], 1.68 [s, 3 H, C(6Ј)CH₃(trans)], 1.68–1.55 [m, 2

H, C(1Ј)H and C(2Ј)H], 1.60 [s, 3 H, C(6Ј)CH₃(cis)], 1.52–1.41 [m,

[d, J = 6.6 Hz, 3 H, C(6)CHCH₃], 0.90 [d, J = 7.2 Hz, 3 H,

C(9)CH₃] ppm. ¹³C NMR (100.6 MHz, CDCl₃): δ = 176.07 [s,

C(2)=O], 79.49 [s, C(5)], 50.52 [d, C(6)], 49.78 [t, C(10)], 49.37 [t,

C(3)], 34.52 [t, C(8)], 29.52 [d, C(9)], 25.09 [d, C(6)CH], 24.19 [q,

1 H, C(1Ј)H], 1.41–1.30 [m, 1 H, C(3Ј)H], 1.28–1.14 [m, 1 H, C(3Ј) C(6)CHCH₃], 22.68 [t, C(7)], 22.01 [q, C(9)CH₃], 18.64 [q, C(6)-

H], 0.96 (minor isomer) and 0.95 [major isomer, d, J = 6.1, 6.7 Hz,

3 H, C(2Ј)CH₃] ppm. ¹³C NMR (100.6 MHz, CDCl₃, major iso-

mer): δ = 177.69 [s, C(4)=O], 131.61 [s, C(6Ј)], 124.29 [d, C(5Ј)],

70.34 [d, C(2)], 49.08 [t, C(5)], 44.00 [t, C(1Ј)], 37.10 [t, C(3Ј)], 28.95

CHCH ] ppm. IR (neat): ν = 3322 (w), 3189 (w, br.), 3081 (w),

˜

3

2950 (m), 2924 (m), 2867 (m), 1688 (s), 1454 (m), 1441 (w), 1383

(w), 1360 (m), 1348 (m), 1333 (w), 1311 (m), 1297 (w), 1260 (w),

1241 (w), 1197 (w), 1178 (w), 1159 (w), 1139 (w), 1100 (w), 1085

[d, C(2Ј)], 25.72 [q, C(6Ј)CH₃(trans)], 25.25 [t, C(4Ј)], 19.61 [q, (w), 1056 (w), 1026 (w), 1005 (w), 984 (w), 945 (w), 919 (w), 894

C(2Ј)CH₃], 17.69 [q, C(6Ј)CH₃(cis)] ppm. ¹³C NMR (100.6 MHz,

CDCl₃, minor isomer): δ = 177.72 [s, C(4)=O], 131.61 [s, C(6Ј)],

124.26 [d, C(5Ј)], 70.40 [d, C(2)], 49.10 [t, C(5)], 44.03 [t, C(1Ј)],

(w), 854 (w), 792 (w), 729 (m, br.), 681 (m), 661 (w), 639 (m), 615

(w) cm^–1. HRMS: calcd. for C₁₂H₂₃N₂O [M + H]⁺211.1805; found

1

211.1817. Data for (5S,6S,9R)-4a: H NMR (400 MHz, CDCl₃): δ

37.33 [t, C(3Ј)], 29.20 [d, C(2Ј)], 25.72 [q, C(6Ј)CH₃(trans)], 25.21 = 8.86 (br. s, 1 H, NHC=O), 3.57 [dd, J = 45.1, 16.4 Hz, 2 H, C(3)-

[t, C(4Ј)], 19.61 [q, C(2Ј)CH₃], 17.69 [q, C(6Ј)CH₃(cis)] ppm. IR

H₂], 2.16–2.03 [m, 1 H, C(6)CH], 1.92 [s, 1 H, C(3)NH], 1.89–1.76

[m, 2 H, C(8)H and C(10)H], 1.70–1.56 [m, 2 H, C(7)H and

C(9)H], 1.35–1.17 [m, 3 H, C(6)H, C(7)H, and C(10)H], 0.95–0.82

(neat): ν = 3283 (m, br.), 3210 (m, br.), 2961 (m), 2918 (m), 2870

˜

(w), 2854 (m), 2730 (w), 1671 (s, br.), 1533 (m, br.), 1443 (s), 1376

(s), 1334 (w), 1310 (w), 1265 (m), 1179 (w), 1140 (w), 1114 (m), [m, 1 H, C(8)H], 0.94 [d, J = 7.2 Hz, 3 H, C(6)CHCH₃], 0.91 [d, J

1087 (w), 1009 (w), 983 (m), 936 (w), 824 (m), 737 (m), 641 (m), = 6.6 Hz, 3 H, C(9)CH₃], 0.80 [d, J = 6.7 Hz, 3 H, C(6)-

623 (w), 615 (w), 608 (m) cm^–1. HRMS: calcd. for C₁₂H₂₃N₂O [M

+ H]⁺211.1805; found 211.1772.

CHCH₃] ppm. ¹³C NMR (100.6 MHz, CDCl₃): δ = 176.45 [s,

C(2)=O], 79.92 [s, C(5)], 51.99 [d, C(6)], 50.62 [t, C(10)], 49.63 [t,

C(3)], 34.51 [t, C(8)], 30.14 [d, C(9)], 25.41 [d, C(6)CH], 23.97 [q,

C(6)CHCH₃], 22.70 [t, C(7)], 22.17 [q, C(9)CH₃], 17.94 [q,

(؎)-(S)-2-[(R)-2,6-Dimethylhept-5-enyl]-5-methylimidazolidin-4-one

(3b): This compound was prepared as described above from (R)-

citronellal (0.69 g, 4.5 mmol), TEA (0.50 g, 5.0 mmol), l-alanin-

amide hydrochloride (0.56 g, 4.5 mmol), and dry methanol (6 mL)

to give a viscous, orange oil (0.67 g). Plug filtration (SiO₂, ethyl

acetate) followed by concentrating the mixture yielded a yellow oil

(0.25 g, 24%) which still contained small amounts of ethyl acetate.

¹H NMR (400 MHz, CDCl₃): δ = 7.47 and 7.35 (br. s, 1 H,

NHC=O), 5.13–5.04 [m, 1 H, C(5Ј)H], 4.69–4.63 and 4.63–4.57 [m,

1 H, C(2)H], 3.60–3.51 and 3.51–3.43 [m, 1 H, C(5)H], 2.18 [br. s,

1 H, C(5)NH], 2.10–1.89 [m, 2 H, C(4Ј)H₂], 1.68 [s, 3 H, C(6Ј)CH₃

(trans)], 1.67–1.51 [m, 2 H, C(1Ј)H and C(2Ј)H], 1.60 [s, 3 H, C(6Ј)-

CH₃(cis)], 1.51–1.14 [m, 3 H, C(1Ј)H, C(3Ј)H₂], 1.35 and 1.32 [d,

J = 6.7, 7.2 Hz, 3 H, C(5)CH₃], 0.96 and 0.94 [d, J = 6.4 Hz, 3 H,

C(2Ј)CH₃] ppm. ¹³C NMR (100.6 MHz, CDCl₃): δ = 179.64 and

179.53 [s, C(4)=O], 131.61 and 131.52 [s, C(6Ј)], 124.38 and 124.26

[d, C(5Ј)], 67.96 and 67.89 [d, C(2)], 55.40 and 53.87 [d, C(5)], 44.37

and 44.28 [t, C(1Ј)], 37.31 and 37.17 [t, C(3Ј)], 29.29 and 29.03 [d,

C(6)CHCH ] ppm. IR (neat): ν = 3331 (w), 3166 (m, br.), 3066 (w),

˜

3

2947 (m), 2918 (m), 2869 (m), 2842 (w), 1674 (s), 1447 (m), 1430

(m), 1366 (m), 1344 (m), 1334 (m), 1305 (m), 1255 (w), 1242 (w),

1197 (w), 1179 (w), 1155 (m), 1137 (w), 1124 (w), 1096 (w), 1064

(w), 1024 (w), 996 (w), 974 (w), 952 (w), 929 (w), 917 (w), 897 (w),

860 (w), 801 (m), 765 (m), 671 (m), 664 (m), 630 (m) cm^–1. HRMS:

calcd. for C₁₂H₂₃N₂O [M + H]⁺211.1805; found 211.1849. A pure

fraction of (5S,6S,9R)-4a (200 mg) was dissolved in ethyl acetate

(1 mL) and heptane (5 mL), and the solution was refrigerated over-

night to give small crystals. Removing the solvent and dissolving

the residue again in a mixture of ethyl acetate (0.5 mL) and heptane

(2.5 mL) at 50 °C gave, after the mixture was refrigerated, crystals

suitable for X-ray crystal analysis. Recrystallization from pure hept-

ane afforded the crystals used for the single crystal X-ray structure

analysis.

Single-Crystal X-ray Structure Analysis: Crystals of (5S,6S,9R)-4a

C(2Ј)], 25.72 [q, C(6Ј)CH₃(trans)], 25.28 and 25.27 [t, C(4Ј)], 19.76 were mounted on loops, and all geometric and intensity data were

and 19.54 [q, C(2Ј)CH₃], 17.70 and 17.69 [q, C(6Ј)CH₃(cis)], 17.20

and 17.08 [q, C(5)CH ] ppm. IR (neat): ν = 3205 (w, br.), 2964 (m),

taken from a single crystal. Data collection using Mo-K_αradiation

(λ = 0.71073 Å) was performed at 120 K with a STOE IPDS II-

˜

3

2922 (m), 2871 (m), 2853 (m), 1699 (s), 1450 (m), 1376 (m), 1324 T diffractometer equipped with an Oxford Cryosystem open flow

2848

www.eurjoc.org

Eur. J. Org. Chem. 2012, 2837–2854

Precursors for Slow Release of Fragrant Aldehydes or Ketones

cryostat.^[49]The structure was solved and refined using full-matrix

least-squares on F²with the SHELX-97 package.^[50]All heavy

atoms were refined anisotropically. Hydrogen atoms were intro-

duced as fixed contributors, when a residual electronic density was

observed near their expected positions. Table 2 shows the crystallo-

graphic data and details of the structure analysis.

Table 3. Kinetics for the equilibration of imidazolidinones

(5R,6S,9R)-4a and (5S,6S,9R)-4a in CD₃OD.

Starting

compd.

4 h

18 h

42 h

66 h

90 h

(5R,6S,9R)-4a

(5S,6S,9R)-4a

n.d.

91.0%

56.6%

75.3%

45.1%

67.0%

41.1%

63.0%

40.1%

61.8%

Table 2. Crystal data and structure refinement for compound

(5S,6S,9R)-4a.

(؎)-(3S,6S,9R)-6-Isopropyl-3,9-dimethyl-1,4-diazaspiro[4.5]decan-2-

one (4b): This compound was prepared as described above from

(–)-menthone (1.25 g, 8.1 mmol), TEA (0.89 g, 8.8 mmol), l-alanin-

amide hydrochloride (1.00 g, 8.0 mmol), and dry methanol (10 mL)

to give a yellow oil (1.02 g). Plug filtration (SiO₂, ethyl acetate)

followed by concentrating the mixture and drying the residue under

high vacuum (0.2 mbar, 1 h) gave a white solid (0.54 g, 30%). ¹H

NMR (400 MHz, CDCl₃, isomer I): δ = 7.60 (br. s, 1 H, NHC=O),

3.53 [q, J = 6.9 Hz, 1 H, C(3)H], 1.99–1.87 [m, 1 H, C(6)CH], 1.79–

1.65 [m, 2 H, C(8)H and C(3)NH], 1.65–1.56 [m, 3 H, C(7)H, C(9)

H , a n d C ( 1 0 ) H ] , 1 . 4 4 [ t , J = 1 3 . 3 H z , 1 H , C ( 1 0 ) -

H], 1.42–1.35 [m, 1 H, C(7)H], 1.34 [d, J = 7.2 Hz, 3 H, C(3)CH₃],

1.21–1.14 [m, 1 H, C(6)H], 1.01–0.84 [m, 1 H, C(8)H], 0.91 [d, J =

7.0 Hz, C(6)CHCH₃], 0.90 [d, J = 6.2, 3 H, C(9)CH₃], 0.88 [d, J =

6.2 Hz, 3 H, C(6)CHCH₃] ppm. ¹³C NMR (100.6 MHz, CDCl₃,

isomer I): δ = 178.42 [s, C(2)=O], 77.28 [s, C(5)], 55.53 [d, C(3)],

52.10 [t, C(10)], 50.91 [d, C(6)], 34.53 [t, C(8)], 29.28 [d, C(9)], 25.10

[d, C(6)CH], 24.02 [q, C(6)CHCH₃], 22.62 [t, C(7)], 22.12 [q,

C(9)CH₃], 19.64 [q, C(3)CH₃], 18.38 [q, C(6)CHCH₃] ppm. ¹H

NMR (400 MHz, CDCl₃, isomer II): δ = 8.26 (br. s, 1 H, NHC=O),

3.75 [q, J = 6.8 Hz, 1 H, C(3)H], 2.23–2.10 [m, 1 H, C(6)CH], 1.99–

1.87 [m, 1 H, C(10)H], 1.87–1.79 [m, 1 H, C(8)H], 1.79–1.65 [m, 2

H, C(7)H and C(3)NH], 1.57–1.48 [m, 1 H, C(9)H], 1.36–1.25 [m,

1 H, C(7)H], 1.32 [d, J = 7.2 Hz, 3 H, C(3)CH₃], 1.21–1.14 [m, 1

H, C(6)H], 1.14 [t, J = 12.7 Hz, 1 H, C(10)H], 1.01–0.84 [m, 1 H,

C(8)H], 0.94 [d, J = 6.9, 3 H, C(6)CHCH₃], 0.90 [d, J = 6.2, 3

H, C(9)CH₃], 0.78 [d, J = 6.9 Hz, C(6)CHCH₃] ppm. ¹³C NMR

(100.6 MHz, CDCl₃, isomer II): δ = 177.96 [s, C(2)=O], 77.16 [s,

C(5)], 53.30 [d, C(3)], 50.51 [t, C(10)], 49.10 [d, C(6)], 34.49 [t,

C(8)], 29.94 [d, C(9)], 24.75 [d, C(6)CH], 23.94 [q, C(6)CHCH₃],

22.93 [t, C(7)], 22.07 [q, C(9)CH₃], 18.02 [q, C(3)CH₃], 17.81 [q,

(5S,6S,9R)-4a

Formula

C₁₂H₂₂N₂O

210.32

trigonal

P3₁21

a = 13.3874(5)

c = 12.8293(5)

1991.25(13)

6

M [gmol^–1]

Crystal system

Space group

Unit cell [Å]

V [Å³]

Z

T [K]

120

ρ calcd. [Mgm^–3]

Absorption coefficient

F(000)

1.052

0.067 mm^–1

696

1.76, 24.66°

4449

1274 [R(int) = 0.0707]

1274/9/173

0.961

R₁= 0.0535, wR₂= 0.1085

R₁= 0.0803, wR₂= 0.1192

Min. Ͻ θ Ͻ max.

Reflections collected

Independent reflections

Data/restraints/parameters

GOOF

R indices [I Ͼ 2σ(I)]

R indices (all data)

CCDC-813985 [for [(5S,6S,9R)-4a] contains the supplementary

crystallographic data for this paper. These data can be obtained

free of charge from The Cambridge Crystallographic Data Centre

via www.ccdc.cam.ac.uk/data_request/cif.

Isomerization of (5R and 5S)-(6S,9R)-6-Isopropyl-9-methyl-1,4-diaza-

spiro[4.5]decan-2-one (4a): Pure (5R,6S,9R)-4a or (5S,6S,9R)-4a

(approximately 30 mg) was stirred overnight in ethyl acetate (1 mL)

with silica gel (50 mg). The mixture was filtered, and the filtrate

was concentrated. NMR spectroscopic analysis in CDCl₃showed

that the sample of (5R)-4a isomerized to a mixture containing 25%

of (5S)-4a, whereas the sample of pure (5S)-4a remained un-

changed. No release of (–)-menthone was observed under these

conditions. In a further test, the pure isomers (20 mg) were mixed

with flash silica gel (50 mg) and either ethyl acetate or chloroform

(CDCl₃, 1 mL), or alternatively, the pure isomers were mixed with

TFA (to give a final concentration of 0.1%) and either ethyl acetate

or chloroform. The mixtures were stirred overnight and filtered

(using a 0.45 μm membrane filter). The ethyl acetate solutions were

concentrated, and the residue was then dissolved in CDCl₃,

whereas the CDCl₃solutions were directly analyzed by NMR spec-

troscopy. The compositions indicated in Table 1 were obtained.

Equilibration kinetics were measured for solutions of pure

(5R,6S,9R)-4a or (5S,6S,9R)-4a (30 mg) in CD₃OD (0.7 mL) by

NMR spectroscopy at different time intervals. To determine the

composition of the samples at a given time, we used average peak

integrals corresponding to three pairs of ¹³C NMR signals, that is,

the peak pairs at 35.83 [(5S)-4a] and 35.65 [(5R)-4a] ppm, 30.97

[(5R)-4a] and 30.41 [(5S)-4a] ppm, and 19.10 [(5S)-4a] and 18.17

[(5R)-4a] ppm. The data obtained at a given time are listed in

Table 3 and illustrated in Figure 5. The sum of the two peak areas

of a given pair corresponded to 100%. The standard deviations

calculated from the percentages of the three different peak pairs

were found to be below 0.009.

C(6)CHCH ] ppm. IR (neat): ν = 3676 (w), 3331 (w), 3162 (w),

˜

3

3074 (w), 2947 (m), 2926 (m), 2868 (m), 1697 (s), 1671 (m), 1451

(m), 1439 (w), 1381 (w), 1376 (w), 1362 (m), 1349 (m), 1329 (w),

1308 (w), 1294 (w), 1277 (w), 1266 (w), 1241 (w), 1206 (w), 1180

(w), 1152 (w), 1129 (m), 1114 (w), 1058 (w), 1027 (w), 990 (w), 979

(w), 953 (w), 932 (w), 905 (w), 870 (w), 858 (w), 803 (m), 779 (m),

738 (m), 717 (w), 699 (w), 650 (w), 617 (m), 607 (m) cm^–1. HRMS:

calcd. for C₁₃H₂₅N₂O [M + H]⁺225.1967; found 225.1960.

(؎)-2-Methyl-2-pentylimidazolidin-4-one (5a): This compound was

prepared as described above from 2-heptanone (1.03 g, 9.1 mmol),

TEA (1.00 g, 9.9 mmol, 1.35 mL), glycinamide hydrochloride

(1.00 g, 9.1 mmol), and dry methanol (10 mL). Bulb-to-bulb distil-

lation (0.5 mbar, 100 °C) to remove the remaining volatile com-

pounds followed by drying under high vacuum yielded a yellow

paste (0.77 g, 50%). ¹H NMR (400 MHz, CDCl₃): δ = 8.11 (s, 1

H, NHC=O), 3.49 [d, J = 4.9 Hz, 2 H, C(5)H₂], 2.05 [s, 1 H, C(5)-

NH], 1.66–1.57 [m, 2 H, C(1Ј)H₂], 1.47–1.22 [m, 6 H, C(2Ј)H₂–

C(4Ј)H₂], 1.39 [s, 3 H, C(2)CH₃], 0.89 [t, J = 6.9 Hz, 3 H,

C(5Ј)H₃] ppm. ¹³C NMR (100.6 MHz, CDCl₃): δ = 176.94 [s,

C(4)=O], 77.01 [s, C(2)], 49.40 [t, C(5)], 41.89 [t, C(1Ј)], 31.95 [t,

C(3Ј)], 27.07 [q, C(2)CH₃], 23.73 [t, C(2Ј)], 22.52 [t, C(4Ј)], 13.99

[q, C(5Ј)] ppm. IR (neat): ν = 3199 (m, br.), 3072 (w), 2955 (m),

˜

2932 (m), 2859 (m), 1688 (s), 1458 (m), 1416 (m), 1377 (m), 1348

(m), 1314 (m), 1240 (w), 1211 (w), 1165 (m), 1143 (m), 1097 (w),

Eur. J. Org. Chem. 2012, 2837–2854

www.eurjoc.org

2849

K. M. Fromm, A. Herrmann et al.

FULL PAPER

1076 (w), 1058 (w), 1015 (w), 951 (w), 844 (w), 767 (w), 727 (m), 31.90 [t, C(8Ј)], 31.77 and 31.68 [t, C(2Ј)], 29.81, 29.60 (2 C), and

670 (w), 633 (m) cm^–1. HRMS: calcd. for C₉H₁₉N₂O [M + H]⁺

171.1493; found 171.1521.

29.33 [t, C(4Ј)–C(7Ј)], 26.95 [t, C(3Ј)], 22.69 [t, C(9Ј)], 14.20 and

13.75 [q, C(1Ј)CH ], 14.11 [t, C(9Ј)CH ] ppm. IR (neat): ν = 3675

˜

3

(w), 3338 (w), 3189 (w, br.), 3079 (w), 2956 (m), 2917 (s), 2852 (s),

1682 (s), 1540 (w), 1456 (m), 1440 (m), 1378 (m), 1357 (w), 1322

(m), 1311 (m), 1291 (w), 1262 (m), 1235 (w), 1220 (w), 1208 (w),

1162 (w), 1139 (w), 1124 (w), 1111 (w), 1091 (w), 1075 (w), 1066

(w), 1056 (w), 1027 (w), 1018 (w), 970 (w), 892 (w), 878 (w), 864

(w), 777 (m, br.), 714 (m), 659 (m) cm^–1. HRMS: calcd. for

C₁₄H₂₉N₂O [M + H]⁺241.2273; found 241.2244.

(؎)-(5S)-5-Benzyl-2-methyl-2-pentylimidazolidin-4-one (5c): This

compound was prepared as described above from 2-heptanone

(0.51 g, 4.5 mmol), TEA (0.50 g, 5.0 mmol), l-phenylalaninamide

hydrochloride (0.74 g, 4.5 mmol), and dry methanol (6 mL) to give

a viscous, colorless oil (0.86 g, 73%). ¹H NMR (400 MHz, CDCl₃):

δ = 7.56 and 7.55 (s, 1 H, NHC=O), 7.35–7.20 (m, 5 H, Ph), 3.86

and 3.84 [t, J = 5.4 Hz and dd, J = 4.8, 1.3 Hz, 1 H, C(5)H], 3.12–

3.00 [m, 2 H, C(5)CH₂], 1.80 [br. s, 1 H, C(5)NH], 1.62–0.82 [m, 8

H, C(1Ј)H₂–C(4Ј)H₂], 1.33 and 1.11 [s, 3 H, C(2)CH₃], 0.87 and

0.85 [t, J = 6.9, 7.1 Hz, 3 H, C(5Ј)H₃] ppm. ¹³C NMR (100.6 MHz,

CDCl₃): δ = 176.97 and 176.95 [s, C(4)=O], 137.08 and 137.06 [s,

PhC(1Ј)], 129.70 and 129.62 [d, PhC(2Ј)], 128.66 and 128.63 [d,

PhC(3Ј)], 126.89 and 126.84 [d, PhC(4Ј)], 74.62 and 74.52 [s, C(2)],

60.41 and 59.60 [d, C(5)], 42.80 and 41.62 [t, C(1Ј)], 37.43 and 36.77

[t, C(5)CH₂], 31.95 and 31.80 [t, C(3Ј)], 28.22 and 28.04 [q,

C(2)CH₃], 23.85 and 22.88 [t, C(2Ј)], 22.56 and 22.43 [t, C(4Ј)],

(؎)-(5S)-5-Methyl-2-(undecan-2-yl)imidazolidin-4-one (7b): This

compound was prepared as described above from (Ϯ)-2-methylun-

decanal (1.48 g, 8.0 mmol), TEA (0.89 g, 8.8 mmol), l-alaninamide

hydrochloride (1.00 g, 8.0 mmol), and dry methanol (10 mL). Plug

filtration (SiO₂, ethyl acetate) followed by concentrating the mix-

ture and drying the residue under high vacuum (0.2 mbar, 1 h) gave

a viscous, colorless oil (1.52 g, 74%). ¹H NMR (400 MHz, CDCl₃):

δ = 7.78 and 7.66 (br. s, 1 H, NHC=O), 4.48–4.36 [m, 1 H, C(2)

H], 3.59–3.49 [m, 1 H, C(5)H], 2.33 [br. s, 1 H, C(5)NH], 1.66–1.52

[m, 1 H, C(1Ј)H], 1.52–1.05 [m, 19 H, C(2Ј)–C(9Ј)H₂and C(5)CH₃],

14.00 and 13.95 [q, C(5Ј)] ppm. IR (neat): ν = 3199 (m, br.), 3107

˜

(w), 3085 (w), 3063 (w), 3029 (w), 2955 (m), 2930 (m), 2859 (m), 0.97–0.90 [m, 3 H, C(1Ј)HCH₃], 0.87 [t, J = 6.8 Hz, 3 H, C(9Ј)

2309 (w), 1947 (w), 1694 (s), 1603 (w), 1583 (w), 1496 (m), 1454 CH₃] ppm. ¹³C NMR (100.6 MHz, CDCl₃): δ = 179.70, 179.58,

(m), 1435 (m), 1420 (m), 1376 (m), 1341 (m), 1243 (w), 1202 (w),

179.54, and 179.40 [s, C(4)=O], 73.94, 73.89, 73.66, and 73.53 [d,

1180 (w), 1149 (m), 1109 (m), 1078 (w), 1062 (w), 1030 (w), 1002 C(2)], 55.15, 55.10, 54.56, and 54.37 [d, C(5)], 39.45, 39.23, 38.37,

(w), 973 (w), 935 (w), 917 (w), 749 (m), 725 (m), 698 (s), 664 (w), and 37.99 [d, C(1Ј)], 31.96, 31.86, and 31.74 (2 C) [t, C(2Ј)], 31.90

647 (w), 610 (m) cm^–1. HRMS: calcd. for C₁₆H₂₅N₂O [M + H]⁺[t, C(8Ј)], 29.85, 29.82, 29.80, 29.60 (2 C), 29.58, and 29.33 [t,

261.1961; found 261.1960.

C(4Ј)–C(7Ј)], 27.02, 26.99, 26.93, and 26.91 [t, C(3Ј)], 22.68 [t,

C(9Ј)], 17.94, 17.82, and 17.36 (2 C) [q, C(5)CH₃], 14.39, 14.32,

13.78, and 13.69 [q, C(1Ј)CH₃], 14.11 [t, C(9Ј)CH₃] ppm. IR (neat):

(؎)-2-Ethyl-2-(2-methylbutyl)imidazolidin-4-one (6a): This com-

pound was prepared as described above from (Ϯ)-5-methyl-3-hept-

anone (1.74 g, 13.6 mmol), TEA (1.48 g, 14.7 mmol, 2 mL), glycin-

amide hydrochloride (1.50 g, 13.6 mmol), and dry methanol

(15 mL). Bulb-to-bulb distillation to remove the remaining volatile

compounds followed by drying under high vacuum yielded a yel-

ν = 3674 (w), 3198 (w, br.), 3099 (w), 2957 (m), 2922 (s), 2853 (m),

˜

1699 (s), 1456 (m), 1377 (m), 1324 (m), 1295 (m), 1261 (w), 1133

(m), 1058 (m), 996 (w), 944 (w), 776 (w), 721 (m), 686 (w), 617

(w) cm^–1. HRMS: calcd. for C₁₅H₃₁N₂O [M + H]⁺255.2402; found

255.2414.

1

low-orange paste (0.26 g, 10%). H NMR (400 MHz, CDCl₃): δ =

7.77 and 7.62 (s, 1 H, NHC=O), 3.49 and 3.48 [d, J = 1.4, 2.0 Hz,

(؎)-2-Pentylimidazolidin-4-one (8a): This compound was prepared

2 H, C(5)H₂], 1.97 [br. s, 1 H, C(5)NH], 1.74–1.57 [m, 3 H,

as described above from hexanal (1.00 g, 10.0 mmol), TEA (1.01 g,

C(2)CH₂CH₃and C(2)CH₂CHCH₃], 1.56–1.29 [m, 3 H, C(2)- 10.0 mmol), glycinamide hydrochloride (1.11 g, 10.0 mmol), and

CH₂CHCH₃, CH(CH₃)CH₂CH₃, and CH(CH₃)CH₂CH₃], 1.29– dry methanol (10 mL) to give a yellow paste (1.03 g) that slowly

1.14 [m, 1 H, CH(CH₃)CH₂CH₃], 0.98 and 0.96 (d, 3 H, J = 3.2, crystallized. Column chromatography (SiO₂, ethyl acetate/meth-

3.8 Hz, CHCH₃), 0.94 [t, J = 7.6 Hz, 3 H, C(2)CH₂CH₃], 0.88 and anol, 95:5) followed by concentrating the resulting mixture gave

0.87 [t, J = 7.4, 7.6 Hz, 3 H, CH(CH₃)CH₂CH₃] ppm. ¹³C NMR

(100.6 MHz, CDCl₃): δ = 176.90 and 176.86 [s, C(4)=O], 79.80 and

79.73 [s, C(2)], 49.67 and 49.41 [t, C(5)], 46.04 and 45.87 [t, C(2)-

CH₂CHCH₃], 33.41 and 33.19 [t, C(2)CH₂CH₃], 31.24 and 30.87

[t, CH(CH₃)CH₂CH₃], 30.27 and 30.13 (d, CHCH₃), 21.11 and

21.05 (q, CHCH₃), 11.35 and 11.26 [q, CH(CH₃)CH₂CH₃], 7.98 [q,

slightly yellow crystals (0.26 g, 16%). ¹H NMR (400 MHz, CDCl₃):

δ = 7.75 (s, 1 H, NHC=O), 4.64–4.58 [m, 1 H, C(2)H], 3.43 [ddd,

J = 16.2, 9.5, 0.8 Hz, 2 H, C(5)H₂], 2.32–2.23 [m, 1 H, C(5)NH],

1.65–1.56 [m, 2 H, C(1Ј)H₂], 1.47–1.24 [m, 6 H, C(2Ј)–C(4Ј)H₂],

0.89 [t, J = 7.1 Hz, 3 H, C(4Ј)CH₃] ppm. ¹³C NMR (100.6 MHz,

CDCl₃): δ = 177.64 [s, C(4)=O], 72.08 [d, C(2)], 49.22 [t, C(5)],

C(2)CH CH ] ppm. IR (neat): ν = 3200 (w, br.), 2962 (m), 2926 36.77 [t, C(1Ј)], 31.57 [t, C(3Ј)], 24.36 [t, C(2Ј)], 22.47 [t, C(4Ј)],

˜

2

3

(m), 2875 (w), 2856 (w), 1687 (s), 1460 (m), 1423 (m), 1378 (m),

1359 (m), 1316 (m), 1161 (w), 1083 (w), 1043 (w), 969 (w), 909 (w),

794 (m), 737 (m, br.), 633 (m) cm^–1. HRMS: calcd. for C₁₀H₂₁N₂O

[M + H]⁺185.1649; found 185.1674.

13.95 [q, C(4Ј)CH ] ppm. IR (neat): ν = 3181 (m, br.), 3087 (w),

˜

3

3029 (w), 2962 (w), 2949 (w), 2927 (m), 2911 (w), 2870 (w), 2862

(w), 2847 (w), 2738 (w), 1696 (s), 1492 (w), 1468 (m), 1460 (w),

1437 (m), 1383 (m), 1365 (m), 1351 (m), 1307 (m), 1289 (w), 1275

(m), 1264 (m), 1249 (w), 1221 (w), 1198 (w), 1139 (w), 1127 (w),

1101 (m), 1076 (m), 1059 (w), 1042 (w), 1011 (m), 982 (w), 952 (m),

920 (m), 896 (w), 880 (m), 838 (w), 769 (m), 757 (w), 725 (m), 696

(m), 659 (m), 609 (w) cm^–1. HRMS: calcd. for C₈H₁₇N₂O

[M + H]⁺157.1335; found 157.1324.

(؎)-2-(Undecan-2-yl)imidazolidin-4-one (7a): This compound was

prepared as described above from (Ϯ)-2-methylundecanal (1.50 g,

8.1 mmol), TEA (0.91 g, 9.0 mmol), glycinamide hydrochloride

(0.90 g, 8.1 mmol), and dry methanol (10 mL) to give a yellow solid

1

(1.85 g, 94%). H NMR (400 MHz, CDCl₃): δ = 7.85 and 7.79 (s,

1 H, NHC=O), 4.53–4.45 [m, 1 H, C(2)H], 3.45 [s, 2 H, C(5)H₂],

2.60 [br. s, 1 H, C(5)NH], 1.66–1.52 [m, 1 H, C(1Ј)H], 1.52–1.05

[m, 16 H, C(2Ј)–C(9Ј)H₂], 0.94 and 0.93 [d, J = 6.7 Hz, 3 H, C(1Ј)-

HCH₃], 0.88 [t, J = 6.8 Hz, 3 H, C(9Ј)CH₃] ppm. ¹³C NMR

(100.6 MHz, CDCl₃): δ = 177.62 and 177.47 [s, C(4)=O], 76.25 and

2-(2,4-Dimethylcyclohex-3-en-1-yl)imidazolidin-4-one (9a): This

compound was prepared as described above from (Ϯ)-2,4-dimethyl-

3-cyclohexene-1-carbaldehyde (Triplal^®, trans/cis, approximately

3:1; 1.00 g, 7.2 mmol), TEA (1.10 g, 11.0 mmol), glycinamide hy-

drochloride (0.80 g, 7.2 mmol), and dry methanol (10 mL) to give

75.94 [d, C(2)], 49.36 and 49.29 [t, C(5)], 39.05 and 38.74 [d, C(1Ј)], a yellow oil (1.37 g). Bulb-to-bulb distillation to remove the re-

2850 Eur. J. Org. Chem. 2012, 2837–2854

www.eurjoc.org

Precursors for Slow Release of Fragrant Aldehydes or Ketones

maining aldehyde gave a highly viscous, orange-yellow oil [1.10 g,

(m), 608 (w) cm^–1. HRMS: calcd. for C₁₁H₂₂NO₂[M + H]⁺

78 %, (1RS,2SR)-9a and (1RS,2RS)-9a, trans/cis, approximately 200.1645; found 200.1613.

3:1]. ¹H NMR (400 MHz, CDCl₃, major isomers): δ = 8.26 and

3-Methyl-2-(2,4,4-trimethylpentyl)oxazolidine (11): (Ϯ)-3,5,5-Tri-

7.83 (s, 1 H, NHC=O), 5.26–5.18 [m, 1 H, C(3Ј)H], 4.80 and 4.74

[d, J = 4.6, 5.4 Hz, 1 H, C(2)H], 3.51–3.37 [m, 2 H, C(5)H₂], 2.27–

2.09 [m, 1 H, C(2Ј)H], 2.22 [br. s, 1 H, C(5)NH], 2.07–1.88 [m, 2

H, C(5Ј)H₂], 1.85–1.72 [m, 1 H, C(6Ј)H], 1.64 [s, 3 H, C(4Ј)CH₃],

1.57–1.43 [m, 1 H, C(6Ј)H], 1.43–1.32 [m, 1 H, C(1Ј)H], 1.04 and

1.02 [d, J = 7.0, 6.9 Hz, 3 H, C(2Ј)CH₃] ppm. ¹³C NMR

(100.6 MHz, CDCl₃, major isomers): δ = 177.90 and 177.74 [s,

C(4)=O], 133.24 and 133.21 [s, C(4Ј)], 126.67 and 126.47 [d, C(3Ј)],

72.91 and 72.40 [d, C(2)], 49.46 and 49.29 [t, C(5)], 45.48 [d, C(1Ј)],

31.16 [d, C(2Ј)], 28.55 and 28.21 [t, C(5Ј)], 23.48 and 23.44 [q,

C(4Ј)CH₃], 21.03 and 20.76 [q, C(2Ј)CH₃], 20.66 and 20.17 [t,

methylhexanal (1.89 g, 13.1 mmol) in toluene (2.5 mL) was added

to an ice-cold solution of 2-(methylamino)ethanol (1.01 g, 13.

5 mmol) in toluene (17.5 mL). The mixture was heated to reflux

for 4 h along with the azeotropic removal of water. The reaction

mixture was then cooled to room temperature and concentrated

under vacuum to give the crude compound (2.02 g). Bulb-to-bulb

distillation (50 °C, 0.2 mbar) yielded a colorless oil (1.33 g, 49%,

approximate ratio of diastereomers, 1.2:1). ¹H NMR (400 MHz,

CDCl₃, major isomer): δ = 3.92–3.80 [m, 3 H, C(2)H and C(5)H₂],

3.24–3.15 [m, 1 H, C(4)H], 2.66–2.57 [m, 1 H, C(4)H], 2.35 [s, 3 H,

NCH₃], 1.81–1.72 [m, 1 H, C(2Ј)H], 1.59–1.45 [m, 1 H, C(1Ј)H],

1.42–1.30 [m, 1 H, C(1Ј)H], 1.24 [dd, J = 13.9, 4.3 Hz, 1 H,

C(3Ј)H], 1.10 [dd, J = 14.0, 5.9 Hz, 1 H, C(3Ј)H], 0.97 [d, J =

6.7 Hz, 3 H, C(2Ј)CH₃], 0.91 [s, 9 H, C(4Ј)CH₃] ppm. ¹³C NMR

(100.6 MHz, CDCl₃, major isomer): δ = 95.80 [d, C(2)], 63.85 [t,

C(5)], 54.53 [t, C(4)], 51.91 [t, C(3Ј)], 42.94 [t, C(1Ј)], 39.04 (q,

NCH₃), 31.20 [s, C(4Ј)], 30.00 [q, C(4Ј)CH₃], 26.05 [d, C(2Ј)], 22.36

1

C(6Ј)] ppm. H NMR (400 MHz, CDCl₃, minor isomers): δ = 8.28

and 8.21 (s, 1 H, NHC=O), 5.40–5.32 [m, 1 H, C(3Ј)H], 4.46 and

4.44 [d, J = 5.9, 6.2 Hz, 1 H, C(2)H], 3.51–3.37 [m, 2 H, C(5)H₂],

2.45–2.28 [m, 1 H, C(2Ј)H], 2.22 [br. s, 1 H, C(5)NH], 2.07–1.88

[m, 2 H, C(5Ј)H₂], 1.85–1.72 [m, 1 H, C(6Ј)H], 1.66 and 1.64 [s, 3

H, C(4Ј)CH₃], 1.65–1.58 [m, 1.5 H, C(1Ј)H and C(6Ј)H], 1.43–1.32

[m, 0.5 H, C(6Ј)H], 0.93 and 0.93 [d, J = 7.0, 6.9 Hz, 3 H,

C(2Ј)CH₃] ppm. ¹³C NMR (100.6 MHz, CDCl₃, minor isomers): δ

= 178.10 and 177.95 [s, C(4)=O], 133.09 and 133.02 [s, C(4Ј)],

126.70 and 126.63 [d, C(3Ј)], 74.13 and 74.00 [d, C(2)], 49.10 and

49.08 [t, C(5)], 44.17 and 43.80 [d, C(1Ј)], 30.22 and 30.21 [t, C(5Ј)],

30.12 and 30.01 [d, C(2Ј)], 23.40 and 23.39 [q, C(4Ј)CH₃], 20.02

and 19.14 [t, C(6Ј)], 15.43 and 15.35 [q, C(2Ј)CH₃] ppm. IR (neat):

1

[q, C(2Ј)CH₃] ppm. H NMR (400 MHz, CDCl₃, minor isomer): δ

= 3.92–3.80 [m, 3 H, C(2)H and C(5)H₂], 3.24–3.15 [m, 1 H,

C(4)H], 2.66–2.57 [m, 1 H, C(4)H], 2.35 [s, 3 H, NCH₃], 1.72–1.64

[m, 1 H, C(2Ј)H], 1.59–1.45 [m, 1 H, C(1Ј)H], 1.42–1.30 [m, 2 H,

C(1Ј)H], 1.27 [dd, J = 14.1, 3.2 Hz, 1 H, C(3Ј)H], 1.06 [dd, J =

13.8, 6.8 Hz, 1 H, C(3Ј)H], 1.00 [d, J = 6.7 Hz, 3 H, C(2Ј)CH₃],

0.91 [s, 9 H, C(4Ј)CH₃] ppm. ¹³C NMR (100.6 MHz, CDCl₃, minor

isomer): δ = 96.20 [d, C(2)], 63.73 [t, C(5)], 54.53 [t, C(4)], 51.06 [t,

C(3Ј)], 42.75 [t, C(1Ј)], 38.85 (q, NCH₃), 31.06 [s, C(4Ј)], 30.00 [q,

ν = 3196 (m, br.), 3093 (w), 3004 (w), 2957 (m), 2924 (m), 2911

˜

(m), 2870 (m), 2834 (w), 2730 (w), 1693 (s), 1580 (w), 1506 (w),

1435 (m), 1373 (m), 1357 (w), 1310 (m), 1270 (m), 1251 (m), 1197

(w), 1161 (w), 1143 (w), 1119 (m), 1088 (w), 1039 (m), 1001 (m),

966 (m), 933 (w), 906 (w), 841 (m), 799 (m), 762 (w), 746 (w), 725

(m), 682 (m), 648 (m), 607 (w) cm^–1. HRMS: calcd. for C₁₁H₁₉N₂O

[M + H]⁺195.1492; found 195.1439.

C(4Ј)CH ], 26.42 [d, C(2Ј)], 23.70 [q, C(2Ј)CH ] ppm. IR (neat): ν

˜

3

= 2950 (s), 2892 (m), 2868 (m), 2847 (w), 2799 (m), 2702 (w), 2659

(w), 2594 (w), 1683 (w), 1651 (w), 1467 (m), 1456 (m), 1421 (w),

1392 (m), 1376 (m), 1364 (s), 1293 (w), 1247 (m), 1207 (m), 1161

(m), 1143 (m), 1116 (m), 1087 (s), 1024 (s), 953 (m), 920 (m), 863

(w), 852 (w), 809 (w), 780 (w), 743 (w), 703 (w), 673 (w), 665 (w),

647 (w), 639 (w), 620 (w) cm^–1. HRMS: calcd. for C₁₂H₂₆NO [M

+ H]⁺200.2009; found 200.2003.

2-(2,4,4-Trimethylpentyl)oxazolidin-4-one (10): Boron trifluoride

etherate (3.8 mL) was added to a mixture of 2-hydroxyacetamide

(1.00 g, 13.3 mmol) and (Ϯ)-3,5,5-trimethylhexanal (1.87 g,

13.2 mmol) in THF (5 mL) and ether (7.5 mL). After stirring at

room temperature for 24 h, the reaction mixture was washed with

sodium acetate (10%, 5 mL), dried with Na₂SO₄, and concentrated

to give a brownish-orange paste (2.86 g). Column chromatography

(SiO₂, ethyl acetate/heptane, 4:1) gave a yellow oil (0.28 g. 11%,

approximate ratio of diastereomers, 2:1). ¹H NMR (400 MHz,

CDCl₃, major isomer): δ = 8.29 (br. s, 1 H, NHC=O), 5.33–5.27

Procedure for the Hydrolysis in Aqueous Media (with Increasing

Headspace Volume): Buffer stock solutions were prepared by dis-

solving (upon sonication) eight buffer tablets (Fluka), pH = 4.0

(potassium hydrogen phthalate) or 7.0 (sodium/potassium phos-

phate), in demineralized water (640 mL). Then, acetonitrile

(160 mL) was added to give a mixture of water/acetonitrile (4:1,

v/v). The pH values of the final buffer solutions were measured

[m, 1 H, C(2)H], 4.27–4.14 [m, 2 H, C(5)H₂], 1.83–1.42 [m, 3 H, (with a Mettler Toledo MP220 apparatus with an InLab 410 Ag/

C(1Ј)H₂and C(2Ј)H], 1.29–1.20 [m, 1 H, C(3Ј)H], 1.16–1.05 [m, 1 AgCl glass electrode) as 4.6 (for the potassium hydrogen phthalate

H, C(3Ј)H], 0.98 [d, J = 6.7 Hz, 3 H, C(2Ј)CH₃], 0.90 [s, 9 H, buffer solution) and 7.3 (for the sodium/potassium phosphate

C(4Ј)CH₃] ppm. ¹³C NMR (100.6 MHz, CDCl₃, major isomer): δ

= 174.28 [s, C(4)=O], 87.66 [d, C(2)], 67.14 [t, C(5)], 51.46 [t, C(3Ј)],

buffer solution). A concentrated cationic surfactant formulation of

a TEA-esterquat (Stepantex VL 90A, 16.5%, w/w), 10% calcium

45.86 [t, C(1Ј)], 31.17 [s, C(4Ј)], 29.93 [q, C(4Ј)CH₃], 24.99 [d, chloride (0.6%, w/w), and water (82.9%, w/w) was prepared. This

C(2Ј)], 22.57 [q, C(2Ј)CH₃] ppm. ¹H NMR (400 MHz, CDCl₃,

minor isomer): δ = 8.50 (br. s, 1 H, NHC=O), 5.33–5.27 [m, 1 H,

formulation (1.8 g) was then dispersed with demineralized, cold tap

water (600 mL) to give a diluted TEA-esterquat emulsion, and the

C(2)H], 4.27–4.14 [m, 2 H, C(5)H₂], 1.83–1.42 [m, 3 H, C(1Ј)H₂pH was measured as 4.4. Imidazolidinones 1–9 and oxazolidine 11

and C(2Ј)H], 1.29–1.20 [m, 1 H, C(3Ј)H], 1.16–1.05 [m, 1 H,

C(3Ј)H], 0.99 [d, J = 6.4 Hz, 3 H, C(2Ј)CH₃], 0.90 [s, 9 H,

were weighted into ethanol (2 mL) to obtain concentrations as

closely as possible to 7.5ϫ10^–2molL^–1(1a, 31.4 mg; 1b, 33.1 mg;

C(4Ј)CH₃] ppm. ¹³C NMR (100.6 MHz, CDCl₃, minor isomer): δ 1c, 44.7 mg; 1d, 37.2 mg; 2a, 29.9 mg; 2b, 32.1 mg; 2c, 43.8 mg; 2d,

= 174.38 [s, C(4)=O], 87.87 [d, C(2)], 67.18 [t, C(5)], 51.31 [t, C(3Ј)],

45.84 [t, C(1Ј)], 31.13 [s, C(4Ј)], 29.93 [q, C(4Ј)CH₃], 25.26 [d, 25.6 mg; 6a, 28.2 mg; 7a, 36.6 mg; 7b, 38.4 mg; 8a, 23.5 mg; 9a,

C(2Ј)], 22.99 [q, C(2Ј)CH ] ppm. IR (neat): ν = 3206 (m, br.), 3106 29.9 mg; 11, 32.5 mg). All measurements were carried out in dupli-

36.6 mg; 3a, 31.6 mg; 3b, 34.0 mg; 4a, 32.0 mg; 4b, 33.7 mg; 5a,

˜

3

(w), 2952 (m), 2903 (m), 2867 (m), 1712 (s), 1529 (w), 1476 (w), cate. In a 50-mL glass flask, the imidazolidinone or oxazolidine

1465 (w), 1439 (m, br.), 1394 (m), 1378 (w), 1364 (m), 1330 (m), solution (0.1 mL) was added to either one of the buffer solutions

1279 (m), 1247 (w), 1201 (w), 1139 (w), 1087 (m), 1036 (w), 993 or the cationic surfactant emulsion (50 mL, to give a final concen-

(w), 974 (w), 941 (w), 929 (w), 821 (m), 750 (m), 722 (m, br.), 655 tration of approximately 1.5ϫ10^–4molL^–1). The flask was closed

Eur. J. Org. Chem. 2012, 2837–2854

www.eurjoc.org

2851

K. M. Fromm, A. Herrmann et al.

FULL PAPER

and shaken vigorously (10ϫ). After 1 h, the flask was shaken again

(10ϫ), and then an aliquot (5 mL) was removed by pipette and

extracted with heptane (0.3 mL). The heptane phase (0.10 to

0.15 mL) was decanted and analyzed by GC. The samples (5 μL)

were injected into an Agilent Technologies 7890A GC system

equipped with a HP-5 capillary column (30 m, 0.32 mm ID, film

0.25 μm) and eluted with a constant flow of He (3 mLmin^–1) using

a temperature gradient starting from 60 °C during 1 min, then heat-

ing to 260 °C at 20 °Cmin^–1. The injector temperature was kept at

250 °C with the FID-detector temperature at 280 °C. The samples

were left at room temperature (21.7 °CϮ1.7 °C). Additional ali-

quots (5 mL) were removed by pipette and extracted after 24, 48,

72, 96, 168, 192, 216, and 240 h. During the measurement, the total

volume of the sample in the flask continuously decreased, as the

headspace above it increased. The amount of aldehydes and

ketones released from the precursors was quantified by external

standard calibration using a mixture of the freshly distilled carb-

onyl compounds at five different concentrations. Calibrations were

carried out in triplicate by linear regression (forced through the

origin of the coordinate system).

charcoal and aspirated through a saturated solution of NaCl. The

headspace system was allowed to equilibrate (15 min), and then the

volatiles were adsorbed onto a clean Tenax^®cartridge (15 min) and

a waste Tenax^®cartridge (45 min), the latter of which was dis-

carded. The sampling was repeated (7ϫ). The cartridges were de-

sorbed with a Perkin–Elmer TurboMatrix ATD 350 desorber cou-

pled to a Perkin–Elmer Autosystem XL gas chromatograph

equipped with a J&W Scientific DB1 capillary column (30 m,

0.25 mm ID, film 0.25 μm) and a Perkin–Elmer Turbomass Up-

grade mass spectrometer. The volatiles were analyzed by GC using

a two-step temperature gradient starting from 60 °C during 5 min,

then heating to 120 °C at 15 °Cmin^–1, and then heating to 230 °C

at 45 °Cmin^–1. The injection temperature was 240 °C with the de-

tector temperature at 260 °C. Headspace concentrations (in ngL^–1

of air) were obtained by an external standard calibration of the

corresponding fragrant aldehydes and ketones using ethanol solu-

tions at a minimum of five different concentrations. The calibrated

solutions (0.2 μL) were injected onto Tenax^®cartridges, which were

then immediately desorbed under the same conditions as those re-

sulting from the headspace sampling. Calibrations were carried out

by linear regression (forced through the origin of the coordinate

system).

Verification of the Extraction Efficiency: A stock solution of (Ϯ)-

3,5,5-trimethylhexanal (215.1 mg) in ethanol (20 mL) was pre-

pared. The solution was then diluted by a factor of 2 and 10, and

each of these solutions was further diluted by a factor of 10 to give

solutions at five different concentrations (1, 5, 10, 50, and 100 mol-

% of the total amount of aldehyde to be theoretically released from

the respective precursor). The different solutions (0.14 mL) were

then added to the buffer solutions or the cationic surfactant emul-

sion (7 mL) in a small glass flask. Two flasks were prepared for

each solution or emulsion. The flasks were closed and shaken vig-

orously (10ϫ). After 1 h, the content of one of the flasks was ex-

tracted with heptane (0.3 mL). The heptane phase (0.10 to

0.15 mL) was decanted and analyzed by GC as described above.

The content of the second flask was extracted after 240 h. All mea-

surements were carried out in triplicate. The average amount of

aldehyde extracted was plotted against the total amount originally

added to the sample. Similarly, the efficiency of the extraction for

the other fragrances was determined using concentrations corre-

sponding to 1 [(Ϯ)-2-methylundecanal], 3 (Trifernal^®, hexanal, and

Triplal^®), 10 [(R)-citronellal], 15 (2-heptanone), 20 [(–)-menthone],

and 35 mol-% [(Ϯ)-5-methyl-3-heptanone] with respect to the total

amount to be released from the corresponding precursor. Extrac-

tions with heptane were carried out 1 h after the preparation of

the samples. In all cases, average values were obtained from three

measurements (see Supporting Information).

Note: Trifernal^®is a registered trademark of Firmenich SA, Tri-

plal^®is a registered trademark of Int. Flavors and Fragrances Inc.

Supporting Information (see footnote on the first page of this arti-

cle): Instrumentation used in this work, additional figures of the

crystal structure, the hydrolysis experiments and the headspace

measurements, the calculated logP_o/wvalues of the precursors, the

data for the efficiency of the aldehyde and ketone extractions, the

procedure for the hydrolysis experiments in aqueous media with a

constant headspace volume, the numerical data for Figures 7, 8, 9,

1

and 10, and the figures of the H and ¹³C NMR spectra for com-

pounds 1–11.

Acknowledgments

We thank Sandy Frank and Dr. Wolfgang Fieber for the NMR

measurements, Daniel Grenno for recording the high resolution

mass spectra, Sophie Cottier for her assistance in the synthesis and

headspace sampling, and Dr. Alexandre Huboux and Dr. Maurus

Marty for the fruitful discussions.

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Procedure for the Dynamic Headspace Measurements on Cot-

ton:^[10,48]For the measurements, a solution of imidazolidinone

(1 mL, conc. = 7.5ϫ10^–2molL^–1) was added to a concentrated

TEA-esterquat fabric softener formulation (1.80 g, see above).

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flow (about 200 mLmin^–1). The air was filtered through activated

2852

www.eurjoc.org

Eur. J. Org. Chem. 2012, 2837–2854

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Preparation of imidazolidin-4-ones and their evaluation as hydrolytically cleavable precursors for the slow release of bioactive volatile carbonyl derivatives

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