A new class of enehydroxylamino ketones - (R)-2-(1-hydroxy-4,4,5,5- tetraalkylimidazolidin-2-ylidene)ethanones: Synthesis and reactions

FULL PAPER

A New Class of Enehydroxylamino Ketones ؊ (R)-2-(1-Hydroxy-4,4,5,5-

tetraalkylimidazolidin-2-ylidene)ethanones: Synthesis and Reactions

Vladimir A. Reznikov,*^[a]Galina I. Roshchupkina,^[b]Dmitrii G. Mazhukin,^[a]

Pavel A. Petrov,^[c]Sergei A. Popov,^[c]Sergey V. Fokin,^[c]Galina V. Romanenko,^[c]

Tatjana V. Rybalova,^[a]Yuri V. Gatilov,^[a]Yuri G. Shvedenkov,^[c]Irina G. Irtegova,^[a]

Leonid A. Shundrin,^[d]and Victor I. Ovcharenko^[c]

Keywords: Enaminones / EPR spectroscopy / Imidazolidines / Ketones / Nitroxides / Nucleophilic substitution

Three approaches to the synthesis of (R)-2-(1-hydroxy-

amine) carbon atom is shown to be the major site of elec-

4,4,5,5-tetraalkylimidazolidin-2-ylidene)ethanones 1 are de- trophilic attack. Synthesized chloro-substituted 1-hydroxy-2-

scribed: (a) condensation of 1,2-bishydroxylamines with β-

ketoaldehyde synthons, (b) treatment of metallated 1-hy-

droxy-2-methyl-4,5-dihydroimidazoles with esters, and (c)

acetylideneimidazolidines react with sodium cyanide to form

the corresponding nitriles. Oxidation of these nitriles occurs

with formation of persistent vinyl nitroxides, which are of in-

1,3-dipolar cycloaddition between 1-hydroxy-4,5-dihydroim- terest as potential paramagnetic ligands.

idazole-3-oxide and DMAD. The reactivity of 1 with elec- ( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,

trophiles has been studied. The exocyclic methylene (en-

Germany, 2004)

Introduction

nitroxides, generated by oxidation of enehydroxylamino ke-

tones B, results in CϪC- (C) or CϪO-type (D) dimer for-

mation. The reason for this regiochemistry of nitroxides A

is highly efficient spin delocalization in the conjugate π-sys-

tem (Scheme 1).^[4,15]At the same time, we have previously

shown that oxidation of similar structures with endocyclic

localization of the enehydroxylamino ketone group and

with a cyano group as a strong electron acceptor at the

enamine carbon atom produces persistent vinyl nitroxides,

stable enough to be isolated as individual compounds.^[7,12]

It is noteworthy that ketene aminals, including cyclic im-

idazolidines, which are analogues of 1, are known to be

highly reactive compounds, attracting the attention of in-

vestigators as convenient precursors for syntheses of fused

heterocyclic systems. Syntheses and reactions of these com-

pounds are discussed in detail in reviews,^[16,17]and in more

recent works by Huang’s group. In contrast, no data on

the reactivity of N-hydroxyketene aminals are available in

the literature.

This paper presents a study of methods for the synthesis

of cyclic ketene N-hydroxyaminals [derivatives of (R)-2-(1-

hydroxy-4,4,5,5-tetraalkylimidazolidin-2-ylidene)ethanones,

1] and their properties. The distinctive feature of the struc-

ture of compound 1 is the presence of reactive enaminone

and enehydroxylamino ketone groups in one molecule.

While the reactivity of enaminones is well known,^[1,2]data

on the reactivity of enehydroxylamino ketones with hetero-

lytic reagents Ϫ electrophiles and nucleophiles Ϫ are rela-

tively scarce and mainly limited to our previous works.^[3Ϫ14]

More is known about the oxidative transformations of en-

ehydroxylamino ketones, with intermediate formation of ex-

tremely unstable vinyl nitroxides capable of further trans-

formations. In particular, recombination of type A vinyl-

[a]

N. N. Vorozhtsov Institute of Organic Chemistry, Siberian

Branch, Russian Academy of Sciences,

630090 Novosibirsk, Russian Federation

On the other hand, the synthesis of transition metal com-

plexes with paramagnetic ligands, mainly complexes with

stable nitroxides bearing functional groups suitable for co-

ordination with the metal ion, is one of the more challeng-

ing fields in coordination chemistry.^[18,19]Compounds with

structure 1 seem to be promising precursors for syntheses

of new magnetoactive heterospin complexes (cf. ref.^[20]).

[b]

Novosibirsk State University

630090 Novosibirsk, Russian Federation

[c]

International Tomography Center, Siberian Branch, Russian

Academy of Sciences,

630090 Novosibirsk, Russian Federation

[d]

Novosibirsk Institute of Bioorganic Chemistry, Siberian

Branch, Russian Academy of Sciences,

630090 Novosibirsk, Russian Federation

Eur. J. Org. Chem. 2004, 749Ϫ765

DOI: 10.1002/ejoc.200300536

 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

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V. A. Reznikov et al.

FULL PAPER

Scheme 1

and subsequent Claisen reaction with esters failed because

of unfavorable steric and electronic effects (cf. ref.^[23]).

Results and Discussion

Synthesis of (R)-2-(1-Hydroxy-4,4,5,5-tetraalkylimidazolidin-

2-ylidene)ethanones

b. Condensation of 1,2-Bishydroxyamines with Synthetic

Equivalents of 1,3-Keto Aldehydes

a. Treatment of Metallated 2,4,4,5,5-Pentamethyl-4,5-di-

hydro-1H-imidazol-1-ol with Esters

Aliphatic 1,2-diamines (1,2-DAs) are known to react with

1,3-dicarbonyl compounds (1,3-DCCs) in acidic media to

The first example of a synthesis of a type 1 compound form 2,3-dihydro-1,4-diazepinium salts.^[24]The reactions of

was the reaction between a 2-imidazoline of type 2 and another type of N-binucleophile, aliphatic 1,2-bishydroxyla-

ethyl benzoate in the presence of LDA.^[21]Recently, we have mines (1,2-BHAs),^[25,26]had not been studied previously,

found that imidazoline 2a can also be involved in this reac- and it was considered that reactions between 1,3-ketoal-

tion, and a convenient method for the synthesis of 2a based dehydes (1,3-KAs) and 1,2-BHA 4 should result in the for-

on thermal oxidative dehydration of dihydroxyimidazolid- mation of N-oxide or N-hydroxy derivatives of 1,4-diazep-

ines 3 has been worked out (preliminary communication: ine (preliminary communication: ref.^[26]).

ref.^[21]). This method for the synthesis of 1 is shown here to

Since 1,3-KAs are unstable in the free state, protected

be sufficiently general, and affording a series of enaminones forms of 1,3-KAs Ϫ namely, 1,3-keto acetal 5a, salts 5b and

1 (Scheme 2). It is only viable, though, for compounds with 5c, and enol ether 5d Ϫ were used in reactions with 1,2-

a substituent the size of a methyl group at the 2-position of BHAs 4aϪc (Scheme 3). The free form of the 1,3-KA was

heterocycle 2. Metallation of compound 2b with R ϭ Et generated in situ by acid-catalyzed hydrolysis in acidic me-

Scheme 2

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Eur. J. Org. Chem. 2004, 749Ϫ765

A New Class of Enehydroxylamino Ketones

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Scheme 3

dia at pH ഠ 2Ϫ5. The reaction between 1,2-BHA 4a and

Treatment of the 1,2-BHAs 4a or 4c with trans-β-ethoxy-

sodium 3-oxo-3-phenylpropenoxide (5b) proceeds in glacial vinyl trifluoromethyl ketone 5c^[29]in a water/methanol solu-

acetic acid at 20 °C in 30 h, giving, according to element tion of HCl also gave the enaminones 1m and 1c, respec-

analysis data, a product of addition of the 1,2-BHA at two tively. In the case of 4c, an approximately equal amount

carbonyl groups of the 1,3-KA with elimination of two of enaminone 10c was formed together with 1c. Moreover,

water molecules. The compound obtained was neither 1,4- according to the NMR spectroscopic data, a crude sample

diazepine-1,4-dioxide 6 nor 7; according to its spectroscopic of 1m contains enaminone 10m as an impurity. This result

data it has the structure of the cyclic N-hydroxyketene ami- cannot be attributed to insufficient purity of starting 4c;

nal 2-(1-hydroxyimidazolidin-2-ylidene)-1-phenylethanone most probably it is the result of some redox processes of

1h (see Exp. Sect. for spectroscopic data).

unknown nature.

A similar reaction between the sterically hindered 1,2-

BHA 4c and the 1,3-KA 5b gives the corresponding 1-

hydroxy-2-phenacetylideneimidazolidine (1a). In the reac-

tion between the asymmetric 1,2-BHA 4b and 5b, two iso-

mers were obtained: 1iA and 1iB. Enaminones 1 are obvi-

ously formed by dehydration of the intermediate imidazoli-

dines 8 (cf. ref.^[28]) to enaminones 1A and 1B. Introduction

of a methyl group at the C-2 atom of the 1,3-KA molecule

Treatment of 4c with ethyl 2-cyano-3-ethoxyacrylate pro-

ceeds in a similar way, but is accompanied by hydrolysis of

the nitrile group, giving rise to amide 11, the crystal struc-

ture of which is shown in Figure 4.

c. Cycloaddition Reaction

Finally, the third approach to the synthesis of structures

does not influence the reaction pathway; condensation of of type 1 is the 1,3-dipolar cycloaddition reactions between

the 1,2-BHA 4c with the sodium salt of 3-hydroxy-2- 4,4,5,5-tetramethyl-4,5-dihydro-1H-imidazol-1-ol 3-oxide

methyl-1-phenylprop-2-en-1-one (5c) occurs similarly and (12) and activated alkynes (Scheme 4, cf. ref.^[31]). While

yields the corresponding imidazolidine 1k. Treatment of the cycloadditions between 2,5-dihydroimidazole nitrones and

1,2-BHA 4a with acetoacetaldehyde diethyl acetal 5a in different dipolarophiles, including activated alkynes, are

methanol saturated with HCl gives the dihydrochloride 9l well known (for recent papers, see ref.^[32Ϫ35]), there is only

in a good yield; subsequent neutralization of the solution one example of 1,3-dipolar cycloadditions of 4,5-dihydro-

results in the isolation of enaminone 1l (Scheme 3).

imidazole nitrones as dipoles described in the literature.^[35]

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Scheme 4

Strictly speaking, compound 12 is an N-hydroxyamidoxime of intramolecular proton transfer from N to O. It seems

rather than a nitrone, and one cannot exclude the possibil- unlikely that compounds 1 should exist in bicyclic tautom-

ity of a nucleophilic addition of the hydroxy group to the eric forms EB or IB (Scheme 5).

activated CC multiple bond of the addend along with, or

instead of, cycloaddition.

In contrast to other imidazolidines 1, existing in conju-

gated form both in the solid state and in DMSO and CDCl₃

solutions, compound 1k is found to exist in chloroform

solution in the non-conjugated tautomeric form. Thus, the

¹H NMR spectrum of 1k contains a doublet for a methyl

group at δ ϭ 1.48 ppm and a quadruplet for the proton at

the exocyclic carbon atom at δ ϭ 4.81 ppm. The tautomeric

form KA seems to be more probable than KN because the

signal of the C-2 atom in the ¹³C NMR spectrum lies at

δ ϭ 162.0 ppm.

Nevertheless, treatment of 12 with dimethyl acetylened-

icarboxylate (DMAD) gives the corresponding cycloadduct

13 as the sole product, and this is spontaneously trans-

formed into the imidazolidine 14, differing from the pre-

viously synthesized 1 in the presence of a methoxycarbonyl

group at the enamine carbon atom. This reaction is charac-

terized by the relatively high stability of cycloadduct 13,

1

which can readily be isolated; according to H NMR spec-

troscopic data, its subsequent transformation into the imid-

azolidine 14 is much slower than its formation (cf.

refs.^[36Ϫ39]).

Since rotation around the exocyclic carbonϪcarbon

double bond is hindered, one can imagine that the conju-

gate tautomeric forms EK and (or) EA may exist as E and

Z (cf. ref.^[30]) isomers (or conformers) and that the geometry

of the exocyclic double bond cannot easily be determined

from NMR spectroscopic data. The equilibrium may be

Structures of the (R)-2-(1-Hydroxyimidazolidin-2-ylidene)-

ethanones 1

¹³C NMR spectroscopic data have demonstrated that the slow or fast on the NMR timescale, so determination of the

(R)-2-(1-hydroxyimidazolidin-2-ylidene)ethanones 1, 11, true geometry of 1 or of the isomer ratio and quantity is

1

and 14 exist in the conjugated enaminone tautomeric form not an easy task. For instance, the H NMR spectrum of

EK; no signals of the ketone-amidine form KA have been 1e contains low-field signals at δ ϭ 8.8 and 9.7 ppm (NH

observed. The signals may be assigned both to the enami- and OH protons), but nothing can be said about the geo-

none form EK and to the enol-amidine form EA, existing metry of the exocyclic double bond in 1e. X-ray analysis

in a fast (NMR timescale) equilibrium EK ^Ǟ_ǟEA as a result data show that crystalline enaminone 1a exists in the conju-

Scheme 5

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A New Class of Enehydroxylamino Ketones

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Figure 1. Atomic numbering scheme and structure of the (R)-2-

(1-hydroxy-4,4,5,5-tetramethylimidazolidin-2-ylidene)-1-phenyl-

ethanone molecule (1a); average bond lengths (in two crystallo-

˚

Figure 2. Atomic numbering scheme and molecular structure of

dimethyl 2-(1-hydroxy-4,4,5,5-tetramethylimidazolidin-2-ylidene)-

graphically independent molecules, A): N(1)ϪC(2) 1.362(4);

C(2)ϪN(3) 1.337(4); N(3)ϪC(4) 1.376(4); C(4)ϪC(5) 1.554(4);

C(5)ϪN(1) 1.488(4); N(1)ϪO(1) 1.405(3); C(2)ϪC(6) 1.388(4);

C(6)ϪC(7) 1.381(4); C(7)ϪC(8) 1.505(4); C(7)ϪO(7) 1.270(4); the

O(7)ϪC(7)ϪC(8)ϪC(13) torsion angles are 14.6 and Ϫ14.5°; hy-

3-oxosuccinate

(14);

selected

bond

lengths:

CϪC_Me

1.504(4)Ϫ1.542(3), O(1)ϪN(1) 1.399(3), N(1)ϪC(2) 1.339(3),

N(1)ϪC(5) 1.476(3), C(2)ϪN(3) 1.324(3), C(2)ϪC(6) 1.437(3),

N(3)ϪC(4) 1.481(3), C(4)ϪC(5) 1.549(4), C(6)ϪC(10) 1.461(3),

C(10)ϪO(5) 1.203(2), C(6)ϪC(7) 1.399(3), C(7)ϪO(2) 1.260(3),

C(7)ϪC(8) 1.515(3), C(8)ϪO(3) 1.202(3); H-bond parameters:

˚

drogen bond parameters (A, deg, head-to-tail chains along the a

axis): O(1)ϪH(1)···O(7)¹1.09(6), 1.53(6), 2.580(4), 158(5);

O(1A)ϪH(1A)···O(7A)¹0.98(4), 1.67(4), 2.639(3), 174(5); sym-

˚

1

O(1)ϪH(1) 1.37(5), H(1)···O(2) 1.16(5), O(1)···O(2) 2.490(3) A,

metry operations: x Ϫ 1, y, z (CCDC-214520)

O(1)ϪH(1)···O(2) 160(5)°, N(3)ϪH(3) 0.83(3), H(3)···O(3)¹2.21(3),

1

˚

N(3)···O(3) 2.984(3) A, N(3)ϪH(3)···O(3) 155(2)°; symmetry op-

1

gated enaminone form EK as the E isomer (Figure 1). Ac-

cording to X-ray analysis data, diester 14 possesses the E

erations: Ϫx, Ϫy ϩ 1, Ϫz (CCDC-214521)

configuration of the exocyclic carbon-carbon double bond ing the hydroxy group and the amide carbonyl atom, but

in the crystalline state (Figure 2), with the carbonyl oxygen also by intermolecular hydrogen bonding of the amide

hydrogen-bonded to the endocyclic hydroxyamino group. group (Figure 3).

As to the structure of compound 14 in solution, the prob-

It thus seems virtually impossible to predict the configu-

lem is more complex Ϫ the spectra of different samples con- ration of the exocyclic carbonϪcarbon double bond for

tain double sets of proton signals for NH, OH, and meth- solid (R)-2-(1-hydroxyimidazolidin-2-ylidene)ethanone (1)

oxy groups (see Exp. Sect.) and the comparative intensities and to determine the geometry of 1 in solutions unambigu-

of the signals in pairs differ from sample to sample. This ously because of possible E/Z isomerization.

obviously means that two forms (E and Z) are present in

This investigation coincided with the publication of an-

a solution of 14, but we did not determine whether they other synthetic procedure for compounds of type 1. The

equilibrate or not. The configuration of the exocyclic CϭC method is based on reactions between 1,2-BHA 4c and an-

bond in the crystalline state of amide 11 seems to be dic- other masked form of 1,3-ketoaldehydes Ϫ substituted phe-

tated not only by intramolecular hydrogen bonding involv- nylpropargyl aldehydes (Scheme 6).^[43]Contrary to the

˚

Figure 3. Molecular structure of 11 and atomic numbering scheme (a); projection of packing onto the (100) plane; (b) bond lengths (A):

N(1)ϪC(7) 1.343(4), N(1)ϪC(1) 1.471(4), C(1)ϪC(3) 1.517(5), C(1)ϪC(2) 1.518(4), C(1)ϪC(4) 1.563(4), C(4)ϪN(2) 1.484(4), C(4)ϪC(6)

1.510(4), C(4)ϪC(5) 1.529(5), N(2)ϪC(7) 1.341(4), N(2)ϪO(1) 1.396(3), C(7)ϪC(8) 1.431(4), C(8)ϪC(9) 1.440(4), C(8)ϪC(12) 1.453(4),

C(9)ϪO(2) 1.226(4), C(9)ϪO(3) 1.345(4), O(3)ϪC(10) 1.441(4), C(10)ϪC(11) 1.486(6), C(12)ϪO(5) 1.257(4), C(12)ϪN(3) 1.343(4); hydro-

1

˚

gen bond parameters (A, deg): N(1)ϪH(1)···O(2) 0.80(4), 2.28(4), 3.038(4), 157(3); O(1)ϪH(11)···O(5) 1.02(4), 1.52(4), 2.493(3), 158(4);

N(3)ϪH(41)···O(2) 0.87(4), 1.94(4), 2.665(4), 140(4); N(3)ϪH(42)···O(5)²0.92(5), 2.03(5), 2.950(4), 177(4); symmetry operations: Ϫx,

Ϫy ϩ 2, Ϫz ϩ 1; Ϫx, Ϫy ϩ 2, Ϫz ϩ 2 (CCDC-215674)

1

2

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statement of the authors, this seems to be a less general product Ϫ enaminone 17, the crystal structure of which is

procedure than the first two methods described above, only shown in Figure 4. The way in which 1a undergoes re-

suitable for syntheses of aryl-substituted derivatives.

duction in the presence of methyl nitrate as an oxidant re-

mains unknown.

Scheme 6

Reactions between (R)-2-(1-Hydroxyimidazolidin-2-ylidene)-

ethanones and Some Electrophiles

Methods have thus been worked out for the synthesis of

cyclic (R)-2-(1-hydroxy-4,4,5,5-tetraalkylimidazolidin-2-yli-

dene)ethanones 1, thanks to which these compounds are

available for further reactivity studies. There are five pos-

sible sites of electrophilic attack in molecule 1 (Scheme 7).

Nitrosation of 1a with amyl nitrite in the presence of so-

dium methoxide occurs at the enamine carbon atom and is

accompanied by oxidation, giving an imino nitroxide Ϫ ox-

Figure 4. Atomic numbering scheme and molecular structure of 17;

bond lengths: N(1)ϪC(2) 1.332(5), C(2)ϪN(3) 1.332(5), N(3)ϪC(4)

1.454(6), C(4)ϪC(5) 1.565(7), C(5)ϪN(1) 1.458(7), C(2)ϪC(6)

1.393(6), C(6)ϪC(7) 1.376(6), C(7)ϪC(12) 1.510(6), C(7)ϪO(1)

˚

1.272(5) A; the O(1)ϪC(7)ϪC(12)ϪC(17) torsion angle is Ϫ45.6°;

˚

hydrogen bond parameters (A, deg, head-to-tail chains along the a

1

˚

axis): N(1)ϪH(1)···O(1) 0.76(5), 2.11(5), 2.865(5) A, 169(6); sym-

metry operations: x Ϫ 1/2, 1/2 Ϫ y, 1 Ϫ z (CCDC-214521)

1

Alkylation of 1a with methyl iodide occurs mainly at the

ime 15. In contrast, the reaction between 1a and methyl oxygen atom of the hydroxyamino group, forming the meth-

nitrate under the same conditions results in the formation oxy derivative 16a. C-Methylated product 1k was also iso-

of O-methylation product 16a together with the reduction lated from the reaction mixture, in a low yield, along with

Scheme 7

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A New Class of Enehydroxylamino Ketones

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16a. Treatment of imidazolidine 1c with CH₃I yields the

The substitution reaction proceeds smoothly at room

methoxy derivative 16c as the sole product. It is important temperature in DMSO, forming nitriles 24 in moderate

to note that, according to literature data, an enehydroxyla- yields. Treatment of methoxy derivative 22a and acetoxy de-

mino ketone with a similar structure reacts with CH₃I un- rivative 22b with cyanide gives nitriles 25 and 26, respec-

der similar conditions at the enamine carbon atom, forming tively; the latter hydrolyzes during isolation, forming nitrile

a C-alkylated product.^[8]Acylation of 1a by acetic anhy- 24a in a high yield, which seems to be a convenient alterna-

dride proceeds at the hydroxylamino oxygen atom and tive method for the synthesis of 24a. We failed to obtain

forms acetate 18. The reaction of 1a with methylamine and nitriles 24 by chlorination of enaminones 1d or 1n (amide

formaldehyde involves both the enamine carbon atom and 1n was obtained by ammonolysis of ester 1d) and sub-

the endocyclic nitrogen atom of the enamino ketone group sequent treatment with NaCN, probably because of the hy-

and gives rise to 2,3,5,6,7-hexahydroimidazo[1,2-c]pyrimid- drolysis of the ester or amide groups during the isolation of

ine derivative 19 (cf. ref.^[40], Scheme 7).

the desirable nitriles.

We had previously found that both enaminones and en-

According to their NMR spectroscopic data, each of the

ehydroxylamino ketones react with N-chloro- and N- nitriles 24Ϫ26 exists in the conjugated enehydroxylamino

bromosuccinimides to form mono- or dihalo derivatives de- ketone form in solution. For example, the ¹³C NMR spec-

pending on the substrate/reagent ratio.^[7,30,41]Treatment of trum of nitrile 24c contain the signals for the nitrile carbon

1 with an equimolar amount of N-chlorosuccinimide (NCS) at δ ϭ 115.8 ppm, the signals for the enamine carbon atoms

gives moderate yields of monochloro derivatives 20, of low at 63.6 [C(CN)ϭ] and 162.8 ppm (C-2), and the signal for

stability and not isolable in pure form (cf. ref.^[22]). The reac- the carbonyl carbon at δ ϭ 173.8 ppm (q, J ϭ 32 Hz).

tion is hindered by easy oxidation of the starting enehydrox-

It is interesting to note that treatment of 22a with NaN₃

ylamino ketones (cf. Scheme 1) and by low selectivity. Thus, occurs as observed earlier for chlorosubstituted enaminones

chlorination of 1a gives a noticeable amount of dichloro (cf. ref.^[42]), forming α-diketone monoimine 27.

derivative 21 along with monochloro derivative 20a; the for-

As mentioned above, sterically hindered 2-acylmethylene-

mer is easily separated thanks to its low solubility in chloro- 1-hydroxyimidazolidines 1 (R^1Ϫ4ϭ CH₃) are of interest as

form. In contrast, methoxy (16a) and acetoxy (18) deriva- precursors of paramagnetic ligands for the synthesis of

tives give stable monochlorides 22a and 22b in high yields transition metal complexes with potentially unusual mag-

under the same conditions.

netic properties.^[20]However, because of the strong tendency

toward recombination of most radicals generated by oxi-

dation of the corresponding enehydroxylamino ketones

(Scheme 1), isolation of nitroxides 28 that could be gener-

ated by oxidation of 1 seems to be improbable (Scheme 9).

Synthesis of Persistent Vinyl Nitroxides ؊ 2-(1-Oxyl-

4,4,5,5-tetramethylimidazolidin-2-ylidene)-3-oxopropionitrile

In view of the potential easy substitution of chlorine at

the enamine carbon in the enaminone molecule (cf.

refs.^[22,30]) and also of the synthesis of persistent vinyl nitro-

xides of type 23^[7,12]through introduction of a cyano group

at a similar position in the endocyclic β-oxonitrone mol-

ecule, we studied the reaction between 20 and sodium cyan-

ide (Scheme 8).

Scheme 9

Scheme 8

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Imidazolidine 1a is oxidized by PbO₂into the unstable

radical 28, the EPR spectrum of which demonstrates split-

ting on two nonequivalent nitrogen atoms. The values of

the hfs constants (a_N1ϭ 9.2 G, a_N2ϭ 4.6 G) are similar to

those of iminonitroxides. These data, along with the ab-

sence of splitting on hydrogen atoms, indicate that nitroxide

28 exists in the iminonitroxide tautomeric form (INR).

Nitroxide 28 forms in very low concentrations not increas-

ing with time; after a few minutes the solution becomes

entirely diamagnetic and a complex mixture of compounds

forms according to TLC. It might be thought that de-

composition of this type of radical is the result of dimer-

forming recombination (cf. Scheme 1). As a matter of fact,

the reaction is a rather complex process producing a large

variety of products depending strongly on the character of

the oxidant and solvent. The only product isolated in the

oxidation reaction of 1a was enaminone 17; formally, this

is the product of the reduction of starting 1a, which demon-

strates that the oxidation is a complex process. At the same

time, oxidation of Ni^2ϩ, Co^2ϩ, Cu^2ϩ, and Pd^2ϩcoordi-

nation compounds of 1c by PbO₂results in the formation

of complexes containing the deprotonated nitroxide of type

28 as a ligand (cf. ref.^[20]).

The introduction of the cyano group at the enamine car-

bon atom in molecule 24 obviously hinders recombination

(cf. refs.^[7,12,22]), and the oxidation of these compounds ac-

tually leads to the formation of persistent vinyl nitroxides

29. These radicals could not be isolated in analytically pure

form, but they exist in the crystalline state at about 0 °C

for prolonged periods (months). The main decomposition

route of these radicals is reduction to the corresponding

hydroxylamines 24 on storage in ethanol solutions and even

as crystals at room temperature. The EPR spectroscopic

data (Figure 5) are summarized in Table 1. The dis-

tinguishing feature of these spectra is coupling on three

nonequivalent nitrogen atoms, including the nitrogen atom

of the cyano group, evidently the result of very efficient spin

density delocalization over the conjugated π-system, and

the high splitting constant on a hydrogen atom (ഠ 2 G),

apparently on the one lying at the N-3 atom. This could be

explained by the existence of nitroxides 29 in imidazolidine

rather than the INR tautomeric forms.

Figure 5. EPR spectra and simulations for nitroxides 29: a: 29b, b:

29g, c: 29e, d: 28c, e: 29a

It is important to note that the magnetic susceptibility

curve of nitroxide 29c (Figure 6, d) shows the presence of a

strong intermolecular exchange interaction in the solid

sample, which hinders evaluation of the paramagnetic mol-

ecule content (cf. ref.^[12]). Nevertheless, the structure of

nitroxide 29c was determined precisely, thanks to X-ray

analysis data for its potassium salt, the structure of which

is shown in Figure 7.

In an attempt to obtain nitroxide 28g in crystalline form

suitable for an X-ray analysis, we found that the sample

contains an impurity of compound 30, which was separated

manually and its structure determined (Figures 8 and 9).

Table 1. EPR spectral data for radicals 29

g factor

Hfs constants, G

28a 2.0044 8.03 (¹⁴N₁), 1.80 (¹⁴N₃), 0.27 (¹⁴N_CN), 1.95 (¹H_NH

29b 2.0040 8.13 (¹⁴N₁), 1.72 (¹⁴N₃), 0.41 (¹⁴N_CN), 1.85 (¹H_NH

28c 2.0043 7.37 (¹⁴N₁), 2.19 (¹⁴N₃), 0.30 (¹⁴N_CN), 2.39 (¹H_NH

28e 2.0051 7.86 (¹⁴N₁), 1.82 (¹⁴N₃), 0.40 (¹⁴N_CN), 2.00 (¹H_NH

28g 2.00451 8.29 (¹⁴N₁), 1.67 (¹⁴N₃), 0.30 (¹⁴N_CN), 1.87 (¹H_NH

)

quite similar to the mechanisms postulated earlier for the

A possible scheme showing the formation of compound reactions of chlorosubstituted enaminones of imidazolidine

30 in the course of the reaction between chloride 20g and nitroxide; the first stage is the nucleophilic attack of the

sodium cyanide and subsequent oxidation is given below cyanide anion at the carbonyl carbon, forming cyanohydrin

(Scheme 10). It is believed that the reaction mechanism is anion 31.

756

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A New Class of Enehydroxylamino Ketones

FULL PAPER

Figure 8. Atomic numbering scheme and structure of molecule 30;

average bond lengths (on two crystallographically independent

molecules): CϪC_Me1.501(4)Ϫ1.541(3), O(1)ϪN(1) 1.260(3),

N(1)ϪC(7) 1.383(3), N(1)ϪC(1) 1.485(3), C(1)ϪC(4) 1.555(4),

C(4)ϪN(2) 1.493(3), N(2)ϪC(7) 1.267(3), C(7)ϪC(8) 1.498(3),

C(8)ϪO(3) 1.437(2), C(8)ϪC(9) 1.547(3), C(9)ϪO(2) 1.403(3),

C(9)ϪC(10) 1.473(4), C(9)ϪC(11) 1.568(4), C(10)ϪN(3) 1.140(4),

O(3)ϪN(4) 1.433(2), N(4)ϪC(21) 1.396(3), N(4)ϪC(15) 1.495(3),

C(15)ϪC(18) 1.564(4), C(18)ϪN(5) 1.500(3), N(5)ϪC(21) 1.273(3),

C(21)ϪC(22) 1.475(3), C(22)ϪO(4) 1.427(3), C(22)ϪC(23)

Figure 6. Effective magnetic moment curves (aϪc) for nitroxides

29 (radical content, %): a: 29a (93), b: 29e (63), c: 29g (85) and

magnetic susceptibility for 29c (d)

1.477(3),

O(4)ϪC(23)

1.429(3),

C(23)ϪC(24)

1.462(4),

˚

C(23)ϪC(25) 1.515(3), C(24)ϪN(6) 1.135(3) A

Subsequent migration of the multiple bond inside the

heterocycle and intramolecular nucleophilic substitution

give epoxide 32. An epoxide with a similar structure has

previously been isolated and characterized similar to the

case of the reaction of enaminone of imidazolidin-4-ylidene

with a tert-butyl group at the carbonyl function, which is

one of the products of the reaction with sodium cyanide.^[30]

The relatively high kinetic stability of the epoxide with a

tert-butyl group substituent in relation to the kinetic sta-

bility of other substituents, probably due to steric hindrance

to subsequent nucleophilic cleavage of the epoxide hetero-

cycle, permits an alternative to the normal route Ϫ epoxide

cleavage in molecule 32 as a result of a nucleophilic attack

Figure 7. Crystal structure of the potassium salt of nitroxide 29c^[22]

1

˚

Figure 9. Chain in the structure of 30; H-bond parameters: O(2)ϪH(2E) 0.82(3) A, H(2E)···N(5) 2.03(3) A, O(2)···N(5) 2.837(3) A,

O(2)ϪH(2E)ϪN(5)¹166(3)°, O(2A)ϪH(2AE)···N(5A)², 0.91(3) A, H(2AE)···N(5A)²1.93(3) A, O(2A)···N(5A)²2.828(3) A,

˚

O(2A)H(2AE)N(5A)²169(3)°; symmetry operations: Ϫx, y ϩ 1/2, Ϫz ϩ 1/2; Ϫ x Ϫ 1, y ϩ 1/2, Ϫz ϩ 1/2 (CCDC-215673)

1

2

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757

V. A. Reznikov et al.

FULL PAPER

Scheme 10

of the hydroxy group of another molecule 32 instead of the ease of substitution of chlorine at the enamine carbon atom

cyanide anion. Subsequent oxidation of the resulting hy- by the cyano group and subsequent oxidation provide

droxylamine 33 gives the nitroxide 30. Compound 30 was syntheses of a series of new persistent vinyl nitroxides,

formed as a minor by-product along with nitroxide 29g, but which are prospective paramagnetic ligands.

its formation is good evidence in favor of the previously

postulated mechanism for the reactions of halo-substituted

enaminones and enehydroxylamino ketones with nucleo-

Experimental Section

philes (cf. ref.^[42]

)

IR spectra were recorded on a Bruker IFS 66 spectrometer as KBr

pellets (concentration 0.25%, pellet thickness 1 mm). UV spectra

were measured on a Specord M-40 spectrophotometer in EtOH.

NMR spectra were recorded on Bruker WP 200 SY and Bruker

AC 200 spectrometers with 5Ϫ10% solutions in CDCl₃, or

[D₆]DMSO and HMDS or solvent as the internal standard. High-

resolution mass spectra were recorded on a Finnigan MAT 8200

Conclusions

Three approaches to the synthesis of a new class of com-

pounds Ϫ (R)-2-(1-hydroxy-4,4,5,5-tetraalkylimidazolidin-

2-ylidene)ethanones 1 Ϫ have been worked out:

(a) Claisen condensations between metallated 2,4,4,5,5- mass spectrometer with direct sample injection at a resolution of

10000. X-ray data were measured on a Bruker P4 diffractometer

with graphite monochromated Mo-K_αradiation. CCDC-214520,

-214521, -215674, and -215673 contain the supplementary crystal-

lographic data for this paper. These data can be obtained free of

charge at www.ccdc.cam.ac.uk/conts/retrieving.html [or from the

Cambridge Crystallographic Data Centre, 12 Union Road, Cam-

bridge CB2 1EZ, UK; Fax: (internat.) ϩ 44-1223/336-033; E-mail:

deposit@ccdc.cam.ac.uk]. ESR spectra were registered for 5·10^Ϫ4

 solutions of radicals 29 in chloroform on a Bruker ESP-300 spec-

trometer with a double resonator. The g-factors were calculated

pentamethyl-4,5-dihydro-1H-imidazol-1-ol and esters,

(b) condensation of 1,2-bishydroxyamines with 1,3-keto

aldehyde precursors, and

(c) cycloaddition between 4,4,5,5-tetramethyl-4,5-di-

hydro-1H-imidazol-1-ol 3-oxide and DMAD.

Route (a) permits variation of a substituent at carbonyl

group and seems to be most versatile thanks to the avail-

ability of starting esters, but limited by the availability of

the only known suitable precursor Ϫ imidazoline 2a. The

advantage of route (b) is its potential for the synthesis of a relative to the standard (MnO) positioned on the back shoulder of

the resonator. ESR spectra were simulated by use of the WINSYM

program with an LMB1 optimization algorithm. Melting points

were measured on a ‘‘Boetius’’ plate and are uncorrected. Thin

layer chromatography monitoring was carried out on Silufol UV-

254 plates with chloroform and chloroform/MeOH (30:1 or 20:1)

as eluents. Diethyl ether was dried with CaCl₂and then over so-

dium wire; DMSO was dried with NaOH and distilled in vacuo

over BaO. Alumina neutral (degree of activity II) and silica gel

(Merck, 0.063Ϫ0.200 mm) were used for chromatographic purifi-

cation of the synthesized compounds. The solutions were evapo-

wide scope of starting 1,2-bishydroxyamines of type 4. The

third approach (c) is at the very beginning of its explo-

ration, and further studies to investigate this reaction are

underway.

The reactivity of (R)-2-(1-hydroxy-4,4,5,5-tetraalkylimid-

azolidin-2-ylidene)ethanones 1 with electrophiles mainly de-

pends on the presence of an enaminone function in the mol-

ecule. The site of the electrophilic attack is the enamine car-

bon atom, but in some cases the reactions proceed at the

oxygen atom of the endocyclic hydroxyamino group. The rated in vacuo in all cases.

758  2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.eurjoc.org

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A New Class of Enehydroxylamino Ketones

FULL PAPER

Reactions between 2,4,4,5,5-Pentamethyl-4,5-dihydroimidazol-1-ol

(2a) and Esters (General Procedure): The reaction was carried out

under argon. Diisopropylamine (2.7 mL, 19.5 mmol) was added

dropwise with stirring over 10 min to a solution of phenyllithium

prepared from bromobenzene (3 g, 19.2 mmol) and lithium (0.27 g,

38.4 mmol) in anhydrous diethyl ether (30 mL). The stirring was

continued for 30 min at room temperature, and finely powdered

imidazoline 2a (1 g, 6.4 mmol) was then added portionwise to the

resulting solution of LDA. The stirring was continued for another

Compound 1d: Yield 40%, m.p. 153Ϫ156 °C (decomp., from etha-

nol). ¹H NMR ([D₆]DMSO, 200.13 MHz, δ, ppm): 1.06 (s, 6 H),

1.17 [s, 6 H, 4,5-(CH₃)₂], 1.21 (t, 3 H, CH₃, J ϭ 7 Hz), 4.12 (q, J

0 7 Hz, 2 H, CH₂), 5.39 (s, 1 H, ϭCH-), 8.8 (s, 1 H, NH), 9.7 (s, 1

H, OH). ¹³C NMR ([D₆]DMSO, 50.32 MHz, δ, ppm): 14.0

(OCH₂CH₃), 17.9, 22.5 [4,5-(CH₃)₂], 60.4 (OCH₂CH₃), 60.9 (C-4),

68.5 (C-5), 76.3 (ϭCH-), 163.7 (C-2), 164.9 (CO₂Et), 173.5 (CϭO).

IR (ν˜, cm^Ϫ1): 3320, 3140, 3000Ϫ2600 (NH, OH), 1730 (CO₂Et),

1600Ϫ1464 (NϪCϭCHϪCϭO). UV [λ_max(ethanol), nm (log ε)]:

30 min at room temperature, and the reaction mixture was then 329 (4.29). C₁₂H₂₀N₂O₄: calcd. C 56.2, H 7.9, N 10.9; found C

cooled to 0 °C and an ester (ethyl benzoate, ethyl acetate, ethyl

trifluoroacetate, ethyl pivalate, diethyl oxalate, or ethyl picolinate)

solution (12 mmol) in diethyl ether was added rapidly. The reaction

mixture was stirred for 2 h at 20 °C, cooled to 0 °C, and then

quenched by slow addition of water (20 mL). The aqueous solution

was separated, and the diethyl ether solution was extracted with

water (5 mL) and discarded. The combined aqueous solution was

washed with diethyl ether (2 ϫ 20 mL) and neutralized with 5%

HCl. After that, either the precipitate of enaminone 1 was filtered

off, or the solution was extracted with CHCl₃(5 ϫ 30 mL). The

combined extract was evaporated, and the residue was recrys-

tallized.

56.5, H 8.3, N 11.0%.

Compound 1e: Yield 55%, m.p. 192Ϫ196 °C (decomp., from ethyl

acetate/hexane mixture). ¹H NMR ([D₆]DMSO, 200.13 MHz, δ,

ppm): 1.09 (s, 6 H), 1.21 [s, 6 H, 4,5-(CH₃)₂], 6.17 (s, 1 H, ϭCH-),

7.30 (m, 1 H), 7.86 (m, 1 H, 3,5-pyridyl), 7.94 (m, 1 H, 4-pyridyl),

8.55 (m, 1 H, 6-pyridyl), 9.0 (s, 1 H, NH), 9.35 (s, 1 H, OH). ¹³C

NMR ([D₆]DMSO, 50.32 MHz, δ, ppm): 17.7, 22.8 [4,5-(CH₃)₂],

60.1 (C-4), 68.0 (C-5), 74.0 (ϭCH-), 120.2, 124.6, 136.6, 148.1,

156.6 (pyridyl), 163.8 (C-2), 182.3 (CϭO). IR (ν˜, cm^Ϫ1): 3285,

3121, 2976, 2873, 3200Ϫ2600 (NH, OH), 1600, 1570, 1532, 1504,

1463 (NϪCϭCHϪCϭO, CϭC). UV [λ_max(ethanol), nm (log ε)]:

250 (3.91), 342 (4.22). C₁₄H₁₉N₃O₂: calcd. C 64.35, H 7.33, N

16.08; found C 64.09, H 7.46, N 15.87%.

1

Compound 1a: Yield 60%. H NMR ([D₆]DMSO, 200.13 MHz, δ,

ppm): 1.08 (s, 6 H), 1.19 [s, 6 H, 4,5-(CH₃)₂], 5.49 (s, 1 H, CHϭ),

7.33Ϫ7.44 (m, 3 H), 7.70Ϫ7.82 (m, 2 H, Ph), 8.80Ϫ9.20 (broad s,

1 H), 9.38 (s, 1 H, NH, OH). ¹³C NMR ([D₆]DMSO, 50.32 MHz,

δ, ppm): 18.0 [5,5-(CH₃)₂], 23.0, [4,4-(CH₃)₂], 60.2 (C-4), 68.2 (C-

5), 74.2 (CHϭ), 126.4, 128.2, 130.0, 141.0 (Ph), 163.7 (C-2), 183.9

(CϭO). IR (ν˜, cm^Ϫ1): 3300, 3110 (OH, NH), 1600, 1575, 1525,

1485 (HNϪCϭCϪCϭO). UV [λ_max(ethanol), nm (log ε)]: 242

(4.13), 330 (4.41). m.p. 185Ϫ188 °C (from ethanol).

C₁₅H₂₀N₂O₂·H₂O: calcd. C 66.9, H 7.9, N 10.4; found C 66.9, H

7.9, N 10.0.

Compound 1f: Yield 35%, m.p. 238Ϫ241 °C (from an ethyl acetate/

hexane mixture). ¹H NMR ([D₆]DMSO, 200.13 MHz, δ, ppm):

1.08 (s, 6 H), 1.20 [s, 6 H, 4,5-(CH₃)₂], 5.49 (s, 1 H, CHϭ), 7.64 (d,

J ϭ 3 Hz, 2 H, β-pyridyl), 8.62 (d, J 3 Hz, 2 H, α-pyridyl), 9.08

(broad s, 1 H, NH), 9.53 (broad s, 1 H, OH). IR (ν˜, cm^Ϫ1): 3270,

2600Ϫ3000 (OH, NH), 1599, 1561, 1535 (NϪCϭCϪCϭO, CϭC).

UV [λ_max(ethanol), nm (log ε)]: 240 (3.96), 343 (4.23).

C₁₄H₁₈N₃O₂: calcd. C 64.60, H 6.97, N 16.14; found C 64.36, H

7.18, N 15.96%.

C₁₅H₂₀N₂O₂, FW ϭ 260.33, monoclinic, P2₁/n, a ϭ 6.979(1), b ϭ

Compound 1g: Yield 60%. m.p. 215Ϫ219 °C (from an ethyl acetate/

hexane mixture in a sealed capillary). ¹H NMR ([D₆]DMSO,

200.13 MHz, δ, ppm): 1.02 [s, 6 H, 5-(CH₃)₂], 1.03 (s, 9 H, tert-

Bu), 1.18 [s, 6 H, 5-(CH₃)₂], 4.91 (s, 1 H, CHϭ), 8.72 (broad s, 1

H, NH), 9.11 (broad s, 1 H, OH). ¹³C NMR ([D₆]DMSO,

50.32 MHz, δ, ppm): 17.5, 22.7 [4,5-(CH₃)₂], 27.7 [C(CH₃)₃], 59.3

[C(CH₃)₃], 67.3 (C-4), 71.8 (ϭCH-), 78.8 (C-5), 163.0 (C-2), 198.8

(CϭO). IR (ν˜, cm^Ϫ1): 3424, 3325, 3115, 3009, 2971, 2898, 2864,

3200Ϫ2600 (NH, OH), 1606, 1521, 1504, 1483, 1455, 1434 (NϪCϭ

CHϪCϭO). UV [λ_max(ethanol), nm (log ε)]: 238 (3.42), 299 (4.35).

C₁₃H₂₄N₂O₂: calcd. C 64.97, H 10.06, N 11.66; found C 64.96, H

10.24, N 11.61%.

3

˚

13.429(2), c ϭ 31.532(5) A, β ϭ 94.31(1)°, V ϭ 2946.9(8) A , Z ϭ

8, D_Cϭ 1.174 g/cm³, µ(Mo-K_α) ϭ 0.079 mm, 1.99 Ͻ θ Ͻ 22.50°,

4234 reflections collected, 3860 unique, R_intϭ 0.0290, data/param-

eters ϭ 3860/504, Goof ϭ 1.006, R indices (2293, I Ͼ 2σ_I): R₁ϭ

0.0512, wR₂ϭ 0.1050; R indices (all data): R₁ϭ 0.1040, wR₂

ϭ

0.1269. (For the crystal structure of ethyl acetate crystal solvate 1b,

see ref.^[43]).

1

Compound 1b: Yield 40%. H NMR ([D₆]DMSO, 200.13 MHz, δ,

ppm): 1.02 (s, 6 H), 1.13 [s, 6 H, 4,5-(CH₃)₂], 1.82 (s, 3 H, CH₃CO),

4.75 (s, 1 H, CHϭ), 8.40Ϫ8.75 (broad s, 1 H), 9.00Ϫ9.35 (broad s,

1 H, NH, OH). ¹³C NMR ([D₆]DMSO, 50.32 MHz, δ, ppm): 17.7

[4,4-(CH₃)₂], 22.9 [5,5-(CH₃)₂], 28.6 (CH₃), 59.7 (C-4), 67.6 (C-5),

77.2 (CHϭ), 162.2 (C-2), 190.1 (CϭO). IR (ν˜, cm^Ϫ1): 3335, 3135

(OH, NH), 1610, 1545Ϫ1430 (HNϪCϭCϪCϭO). UV [λ_max(etha-

nol), nm (log ε)]: 242 (3.40), 297 (4.48). m.p. 141Ϫ143 °C (from

ether). C₁₀H₁₈N₂O₂: calcd. C 60.6, H 9.2, N 14.1; found C 60.5, H

9.3, N 13.9%.

2-(1-Hydroxyoctahydrobenzoimidazol-2-ylidene)-1-phenylethanone

(1h): A solution of the sodium salt of benzoyl acetaldehyde 5b

(2.55 g, 15 mmol) in water (25 mL) was carefully acidified to pH 3

with 5% HCl and stirring. The resulting solution was extracted with

diethyl ether (3 ϫ 15 mL). The combined extract was washed with

water (10 mL) and dried with MgSO₄, and the solution was evapo-

rated to dryness. The residue was dissolved in ethanol (15 mL) and

1

Compound 1c: Yield 80%. H NMR ([D₆]DMSO, 200.13 MHz, δ,

ppm): 1.09 (s, 6 H), 1.20 [s, 6 H, 4,5-(CH₃)₂], 5.07 (s, 1 H, CHϭ), finely powdered 1,2-BHA 4a (1.46 g, 10 mmol) was added to this

8.68Ϫ8.86 (broad s, 1 H), 9.70 (broad s, 1 H, NH, OH). ¹³C NMR

solution portionwise over 20 min with stirring; the resulting mix-

([D₆]DMSO, 50.32 MHz, δ, ppm): 17.8 [5,5-(CH₃)₂], 22.2 [4,4- ture was stirred for 3 h at 20 °C and then kept for 30 h at that

(CH₃)₂], 61.2 (C-4), 68.7 (C-5), 71.5 (CHϭ), 118.2 (q, J_C,Fϭ 280, temperature. The light precipitate was filtered off, and the solution

CF₃), 163.8 (C-2), 171.0 (q, J_C,Fϭ 30, CϭO). IR (ν˜, cm^Ϫ1): 3325, was evaporated. The residue was dissolved in diethyl ether (40 mL).

3150 (OH, NH), 1615, 1575, 1520 (HNϪCϭCϪCϭO), 1270, 1195,

The resulting solution was kept at Ϫ12 °C for 1 h, and the precipi-

1145 (CF₃). UV [λ_max(ethanol), nm (log ε)]: 302 (4.32). m.p. tated imidazolidine 1h was filtered off; yield 1.13 g. Additional im-

208Ϫ211 °C (from an ethyl acetate/hexane mixture).

C₁₀H₁₅F₃N₂O₂: calcd. C 47.6, H 6.0, F 22.6, N 11.1; found C 47.6,

H 6.1, F 22.7, N 11.1%.

idazolidine 1i could be obtained after keeping the mother liquor at

Ϫ12 °C for 3 days (0.50 g). The total yield was 63%. ¹H NMR

([D₆]DMSO, 200.13 MHz, δ, ppm): 1.15Ϫ1.98 [m, 8 H, (CH₂)₄],

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3.71 (q, J ϭ 6.5 Hz, 1 H, C-4), 3.35Ϫ3.50 (m, 1 H, C-5), 5.62 (s, 1 dryness. The oily residue was mixed with water (150 mL), and the

H, CHϭ), 7.35Ϫ7.45 (m, 3 H), 7.72Ϫ7.85 (m, 2 H, Ph), 9.05Ϫ9.40 mixture was made basic (pH 8) by shaking with a saturated solu-

(broad s, 1 H), 9.52 (s, 1 H, OH, NH). ¹³C NMR ([D₆]DMSO, tion of sodium carbonate. The resulting mixture was extracted with

50.32 MHz, δ, ppm): 20.2, 21.3, 23.5, 28.9 [(CH₂)₄], 51.6 (C-4) 61.7 chloroform (1 ϫ 300 mL and 2 ϫ 100 mL) and ethyl acetate (100

(C-5), 75.4 (CHϭ), 126.4, 128.1, 129.9, 140.9 (Ph), 166.9 (C-2), mL). The combined extract was dried with MgSO₄, the solution

184.2 (CϭO). IR (ν˜, cm^Ϫ1): 3315, 3100 (OH, NH), 1615, 1580, was evaporated, and the residue was chromatographed on a silica

1525 (HNϪCϭCϪCϭO). UV [λ_max(ethanol), nm (log ε)]: 243 gel column (h ϭ 35 cm, d ϭ 7 cm) with chloroform as eluent. After

(4.13),333 (4.44). m.p. 196Ϫ201 °C (from ethanol). C₁₅H₁₈N₂O₂: elution of all benzoyl acetaldehyde (R_fഠ 0.80), the elution was

calcd. C 69.8, H 7.0, N 10.9; found C 69.7, H 7.2, N 10.8%.

continued with a chloroform/MeOH (40:1) mixture, and the frac-

tion containing imidazolidine 1b was collected (R_fഠ 0.15). The

residue obtained after evaporation of the eluate was suspended with

hexane (100 mL), and the precipitate was filtered off to give imida-

zolidine 1b (15.81 g, 68%).

2-(1-Hydroxy-4,5,5-trimethylimidazolidin-2-ylidene)-1-phenyl-

ethanone (1iA) and 2-(1-Hydroxy-4,4,5-trimethylimidazolidin-2-ylid-

ene)-1-phenylethanone (1iB): A solution of 1,2-BHA 4b (1.34 g,

10 mmol) in glacial acetic acid (10 mL) was added dropwise with

stirring over 15 min to a solution of the sodium salt of benzoyl 1-(1-Hydroxyoctahydrobenzoimidazol-2-ylidene)propan-2-one Dihy-

acetaldehyde 5b (2.55 g, 15 mmol) in glacial acetic acid (20 mL). drochloride (9l) and the Free Base (1l): A solution of freshly distilled

The reaction mixture was kept for 48 h at 20 °C, and the solution acetoacetaldehyde dimethyl acetal 5a (0.76 g, 5.75 mmol) in MeOH

was evaporated. The residue was diluted with water (40 mL) and (3 mL) was added dropwise over 15 min at 20 °C to a solution of

CHCl₃(50 mL), and sodium carbonate was added slowly with 1,2-BHA 4a (0.73 g, 5 mmol) in MeOH (15 mL) saturated with

shaking until carbon dioxide ceased to evolve. The chloroform hydrogen chloride. The reaction mixture was kept for 1 h at 20 °C,

solution was separated, and the aqueous solution was extracted and the residue was filtered off and washed with a saturated solu-

with chloroform (3 ϫ 10 mL). The combined extract was kept for tion of hydrogen chloride in MeOH (2 ϫ 6 mL). The yield of 9l

1 h at 5 °C, and the resulting precipitate was filtered off and washed was 0.91 g. To prepare free base 1l, compound 10m (0.40 g) was

with cold chloroform (10 mL) to give imidazolidine 1kA (0.40 g). dissolved in water (10 mL) and the resulting solution was neu-

The filtrate was evaporated, and the solid residue was dissolved in tralized with sodium carbonate and then extracted with CHCl₃(5

hot MeOH (10 mL) and mixed with silica gel to give a thick sus- ϫ 10 mL). The combined extract was dried with MgSO₄, the solu-

pension. The resulting mixture was dried and placed on a chroma- tion was evaporated to dryness, the residue was suspended with

tographic column; subsequent elution with an (1:1) ethyl acetate/ anhydrous diethyl ether, and the precipitate was filtered off to give

hexane mixture gave two fractions with R_fഠ 0.20 and 0.15. Evap- 0.12 g of imidazolidine 1l.

oration of eluates and treatment of the residues with hexane gave

1iB (0.45 g) and isomer 1iA (0.35 g), respectively.

Compound 9l: Yield 60%. IR (ν˜, cm^Ϫ1): 2800Ϫ2600, 1635, 1590.

UV [λ_max(ethanol), nm (log ε)]: 296 (4.25). m.p. 156Ϫ159 °C (from

Compound 1iA: Yield 30%. ¹H NMR ([D₆]DMSO, 200.13 MHz, δ, an ethyl acetate/MeOH mixture). C₁₀H₁₆N₂O₂·2HCl·CH₃OH:

ppm): 0.98 (s, 3 H), 1.21 [s, 3 H, 5,5-(CH₃)₂], 1.17 (d, J ϭ 6.5 Hz, calcd. C 43.9, H 7.4, Cl 23.5, N 9.3; found C 43.7, H 7.4, Cl 23.6,

4-CH₃), 3.49 (q, J ϭ 6.5 Hz, 1 H, 4-H), 5.50 (s, 1 H, CHϭ), N 9.3%.

8.90Ϫ9.15 (broad s, 1 H), 9.36 (s, 1 H, OH, NH). ¹³C NMR

Compound 1l: Yield 46%. ¹H NMR ([D₆]DMSO, 200.13 MHz, δ,

([D₆]DMSO, 50.32 MHz, δ, ppm): 14.2 (4-CH₃), 15.1, 22.4 [5,5-

ppm): 1.06Ϫ2.04 [m, 8 H, (CH₂)₄], 1.84 (s, 3 H, CH₃CO), 3.59 (q,

(CH₃)₂], 57.4 (C-4), 66.4 (C-5), 74.0 (CHϭ), 126.2, 128.0, 129.8,

J ϭ 6.5 Hz, 1 H, 4-H), 3.22Ϫ3.50 (m, 1 H, 5 H), 4.85 (s, 1 H,

CHϭ), 8.64Ϫ8.88 (broad s, 1 H), 9.34 (s, 1 H, NH, OH). ¹³C NMR

([D₆]DMSO, 50.32 MHz, δ, ppm): 20.2, 21.4, 23.5, 28.9 [(CH₂)₄],

28.8 (CH₃), 51.3 (C-4), 61.4 (C-5), 78.6 (CHϭ), 165.3 (C-2), 190.5

(CϭO). IR (ν˜, cm^Ϫ1): 3335, 3160 (OH, NH), 1610, 1550Ϫ1490

(HNϪCϭCϪCϭO). UV [λ_max(ethanol), nm (log ε)]: 238 (3.62),

140.9 (Ph), 164.6 (C-2), 183.8 (CϭO). IR (ν˜, cm^Ϫ1): 3360, 3130

(OH, NH), 1600, 1575, 1520, 1485 (HNϪCϭCϪCϭO). UV [λ_max

(ethanol), nm (log ε)]: 242 (4.13), 332 (4.40). m.p. 202Ϫ203 °C

(from ethanol). C₁₄H₁₈N₂O₂: calcd. C 68.3, H 7.4, N 11.4; found

C 67.8, H 7.3, N 11.0%.

1

Compound 1iB: Yield 19%. H NMR ([D₆]DMSO, 200.13 MHz, δ, 298 (4.49). m.p. 182Ϫ185 °C (from an ethyl acetate/MeOH mix-

ppm): 1.11 (s, 3 H), 1.31 [s, 3 H, 4,4-(CH₃)₂], 1.15 (d, J ϭ 6.5 Hz, ture). C₁₀H₁₆N₂O₂: calcd. C 61.2, H 8.2, N 14.3; found C 60.8, H

5-CH₃), 3.18 (q, J ϭ 6.5 Hz, 1 H, 5-H), 5.56 (s, 1 H, CHϭ), 8.1, N 14.0%.

9.10Ϫ9.32 (broad s, 1 H), 9.59 (s, 1 H, OH, NH). ¹³C NMR

([D₆]DMSO, 50.32 MHz, δ, ppm): 11.3 (5-CH₃), 21.6, 26.5 [4-

(CH₃)₂], 58.1 (C-4), 67.5 (C-5), 74.3 (CHϭ), 126.3, 128.0, 129.9,

1-(1-Hydroxy-4,4,5,5-tetramethylimidazolidin-2-ylidene)propan-2-

one (1b): This compound was synthesized as described above for

imidazolidine 1l from 1,2-BHA 4c (0.74 g, 5 mmol, synthesized ac-

140.8 (Ph), 165.3 (C-2), 184.0 (CϭO). IR (ν˜, cm^Ϫ1): 3310, 3100

(OH, NH), 1600, 1575, 1520, 1485 (HNϪCϭCϪCϭO). UV [λ_max

(ethanol), nm (log ε)]: 242 (4.12), 334 (4.40). m.p. 198Ϫ199 °C

(from ethyl acetate). C₁₄H₁₈N₂O₂: calcd. C 68.3, H 7.4, N 11.4;

found C 68.5, H 7.4, N 11.0%.

cording to ref.^[44]

) and 1,3-ketoaldehyde acetal 5a (0.76 g,

5.75 mmol). The reaction mixture was kept for 15 h at 20 °C, and

the solvent was evaporated. The residue was treated with diethyl

ether, and the semisolid mass was separated from diethyl ether by

decantation and dissolved in water (15 mL). The aqueous solution

2-(1-Hydroxy-4,4,5,5-tetramethylimidazolidin-2-ylidene)-1-phenyl- was neutralized with sodium carbonate and extracted with chloro-

ethanone (1a): A solution of 3-hydroxy-1-phenylprop-2-en-1-one form (4 ϫ 15 mL). The combined extract was dried with MgSO₄,

sodium salt 5b (18.35 g, 108 mmol) in MeOH (200 mL) was added the solution was removed, and crude enaminone 1b was purified

dropwise over 35 min to a stirred solution of 1,2-BHA 4c hydro- by silica gel chromatography and sequentially eluted with chloro-

chloride (16.56 g, 90 mmol) in MeOH (100 mL). The reaction mix- form and a chloroform/MeOH (20:1) mixture; a fraction with R_fഠ

ture was kept for 48 h at 20 °C. The NaCl residue was filtered off, 0.5 was collected. The residue obtained after eluate evaporation

and concentrated HCl (5 mL) was added to the filtrate. The re- was dissolved in anhydrous diethyl ether (10 mL). After the solu-

sulting solution was boiled for 7 h and then cooled. The inorganic tion has been cooled to Ϫ12 °C and kept for 24 h, the imidazolidine

salt precipitate was filtered off, and the filtrate was evaporated to 1b precipitate was filtered off; the yield of 1b was 0.22 g (22%).

760

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Eur. J. Org. Chem. 2004, 749Ϫ765

A New Class of Enehydroxylamino Ketones

FULL PAPER

1,1,1-Trifluoro-3-(1-hydroxyoctahydrobenzoimidazol-2-ylidene)- 2-(1-Hydroxy-4,4,5,5-tetramethylimidazolidin-2-ylidene)-1-phenyl-

propan-2-one (1m): A suspension of 1,2-BHA 4a (2.19 g, 15 mmol) propan-1-one (1k): A suspension of 1,2-BHA 4c sulfate (5 g,

in MeOH (20 mL) was acidified with a mixture of concentrated 18.9 mmol) and the sodium salt of 2-methyl-1-phenylpropane-1,3-

HCl and MeOH (1:1, 6 mL), and a solution of trans-4-ethoxy- dione 5c (3.5 g, 18.9 mmol) in a water/MeOH mixture (1:2, 75 mL)

1,1,1-trifluorobut-3-en-2-one (5d) (3.02 g, 8 mmol, synthesized ac- was stirred for 48 h at 50 °C. MeOH was removed, and the aqueous

cording to ref.^[29]) in MeOH (3 mL) was then added dropwise with

stirring over 8 min. The reaction mixture was kept for 0.5 h at 20

°C and then boiled for 3 h. The solvent was removed, the residue

was dissolved in water (20 mL), and the solution was alkalized to

pH 8 with a saturated solution of sodium carbonate. The precipi-

tate of imidazolidine 1m was filtered off and washed with water (2

solution was washed with diethyl ether (30 mL) and extracted with

chloroform (2 ϫ 50 mL). The combined extract was dried with

MgSO₄, and the solution was evaporated. Imidazolidine 1k was

purified chromatographically on silica gel with a (20:1) chloroform/

MeOH mixture as eluent. Yield 2.1 g (40%), oil. ¹H NMR (CDCl₃,

200.13 MHz, δ, ppm): 0.98 (s, 3 H), 1.06 (s, 3 H), 1.15 [s, 6 H, 4,5-

ϫ 10 mL); yield 33%. ¹H NMR ([D₆]DMSO, 200.13 MHz, δ, ppm): (CH₃)₂], 1.48 (d, J ϭ 6.9 Hz, 3 H, -CH-CH₃), 4.81 (q, J ϭ 6.9 Hz,

1.10Ϫ1.94 [m, 8 H, (CH₂)₄], 3.74 (q, J ϭ 6.5 Hz, 1 H, 4-H), 3.55 1 H, CH-CH₃), 7.84 (m), 7.35 (m, 5 H, Ph), 10.05 (broad s, 1 H,

(dq, 1 H, J₁ϭ 7.0, J₂ϭ 4.5 Hz, 5-H), 5.15 (s, 1 H, CHϭ), 8.99

(broad s, 1 H), (s, 1 H, NH, OH). ¹³C NMR ([D₆]DMSO, 18.3, 22.3 [4,5-(CH₃)₂], 39.4 (-CHCH₃), 64.1 (C-4), 71.9 (C-5),

50.32 MHz, δ, ppm): 19.9, 20.9, 23.1, 28.1 [(CH₂)₄], 52.1 (C-4), 61.6

128.5, 133.4, 134.9 (Ph), 162.0 (C-2), 194.6 (CϭO). IR (ν˜, cm^Ϫ1):

OH). ¹³C NMR (CDCl₃, 50.32 MHz, δ, ppm): 13.5 (-CHCH₃),

(C-5), 72.5 (CHϭ), 118.1 (q, J_C,Fϭ 290 Hz, CF₃), 167.3 (C-2), 1691 (CϭO), 1596, 1579 (CϭN). UV [λ_max(ethanol), nm (log ε)]:

171.2 (q, J_C,Fϭ 30 Hz, CϭO). IR (ν˜, cm^Ϫ1): 3345, 3190 (OH, NH), 246 (4.09). Found, m/z: 274.16797; calculated for C₁₆H₂₂N₂O₂

1610, 1570 (HNϪCϭCϪCϭO), 1255, 1190, 1135 (CF₃). UV [λ_maxm/z: 274.16812.

(ethanol), nm (log ε)]: 253 (3.44), 300 (4.35). m.p. 195Ϫ199 °C

(from CHCl₃). C₁₀H₁₃F₃N₂O₂: calcd. C 48.0, H 5.2, N 11.2, F 22.8;

found C 47.8, H 5.2, N 10.9, F 22.8%.

Ethyl 2-(1-Hydroxy-4,4,5,5-tetramethylimidazolidin-2-ylidene)ma-

lonamic Acid Ester (11): A solution of 1,2-BHA 4c (1.0 g,

6.75 mmol) and ethyl 2-cyano-3-ethoxyacrylic ester (1.14 g,

6.74 mmol) in MeOH (25 mL) was kept for 24 h at 20 °C, the sol-

1,1,1-Trifluoro-3-(1-hydroxy-4,4,5,5-tetramethylimidazolidin-2-yli-

dene)propan-2-one (1c) and 1,1,1-Trifluoro-3-(4,4,5,5-tetramethylim-

idazolidin-2-ylidene)propan-2-one (10c): Enol ether 5d (18.9 g,

112.5 mmol) was added dropwise with stirring to a solution of 1,2-

BHA hydrochloride 4c (13.8 g, 75 mmol) in MeOH (150 mL) over

15 min. The reaction mixture was kept for 5 days at 20 °C and was

then boiled for 7 h; the light precipitate was filtered off, and the

solution was evaporated to a volume of ca. 20 mL. The residue was

dissolved in water (50 mL), and the resulting solution was carefully

alkalized with shaking with a concentrated solution of sodium car-

bonate. The precipitate formed was triturated, and the suspension

was cooled to 5 °C for 15 h. [If crystallization did not occur, the

mixture was extracted with ethyl acetate (4 ϫ 100 mL), the com-

bined extract was dried with MgSO₄, the solution was evaporated,

and the residue was dissolved in methanol and chromatographed

as described in the given procedure.] After that, the precipitate, a

mixture consisting mainly of 1c and 10c, was filtered off, washed

three times with water (15 mL), and dried. The mixture of 1c and

10c was dissolved in MeOH (100 mL) with heating, the resulting

solution was mixed with silica gel, and the solvent was removed.

The obtained mixture was suspended with chloroform (200 mL)

and placed on a chromatographic silica gel column (h ϭ 50 cm,

d ϭ 7 cm). Elution with chloroform gave a fraction with R_fഠ 0.1

(Silufol TL plate, CHCl₃/MeOH mixture, 50:1). Elution was con-

tinued with a chloroform/MeOH mixture (30:1), and a fraction

with R_fഠ 0.07 (Silufol TL plate, CHCl₃/MeOH mixture, 50:1) was

collected. The residues obtained after eluate evaporation were

treated with a pentane/CH₂Cl₂mixture, and the precipitates of im-

idazolidines 10c (5.94 g) and 1c (5.20 g, 33%), respectively, were

filtered off.

vent was removed, and the solid residue of imidazolidine 11 was

recrystallized from diethyl ether. Yield 60%, m.p. 125Ϫ128 °C

(from ether).

¯

C₁₂H₂₁N₃O₄, FW 271.32, space group P1, unit cell dimensions a ϭ

˚

7.633(2), b ϭ 9.993(2), c ϭ 10.691(2) A, α ϭ 65.52(3), β ϭ 79.86(3),

3

γ ϭ 81.18(3)°, V ϭ 727.6(2) A , Z ϭ 2, D_Cϭ 1.238 g/cm³, µ(Mo-

˚

K_α) ϭ 0.093 mm, 2.11 Ͻ θ Ͻ 24.99°, 2675 reflections collected/

2470 unique (R_intϭ 0.0339), data/parameters ϭ 2470/257, Goof ϭ

0.870, R indices (I Ͼ 2σ_I): R₁ϭ 0.0508, wR₂ϭ 0.1272, R indices

(all data): R₁ϭ 0.1154, wR₂ϭ 0.1683.

¹H NMR ([D₆]DMSO, 200.13 MHz, δ, ppm): 1.13 (s, 6 H), 1.18 [s,

6 H, 4,5-(CH₃)₂], 1.19 (t, J ϭ 7.00 Hz, 3 H, CH₃), 4.03 (q, J ϭ

7 Hz, 2 H, CH₂), 6.83 (s, 1 H), 7.72 (s, 1 H), 8.25 (s, 1 H), 13.02

(s, 1 H, OH, NH). ¹³C NMR ([D₆]DMSO, 50.32 MHz, δ, ppm):

14.2 (-OCH₂CH₃), 18.4, 22.3 [4,5-(CH₃)₂], 58.6 (OCH₂CH₃), 60.8

(C-4), 68.5 (C-5), 72.1 (ϭC), 160.6 (C-2), 167.9, 171.5 (CϭO). IR

(ν˜, cm^Ϫ1): 3378, 3309, 2980, 2937, 2901, 3500Ϫ2800 (NH, OH),

1618, 1527, 1504, 1476, 1441 (NϪCϭCHϪCϭO). UV [λ_max(etha-

nol), nm (log ε)]: 239 (4.21), 274 (4.17), 350 (2.03). C₁₂H₂₁N₃O₄: C

53.12, H 7.80, N 15.49; found C 53.22, H 7.89, N 15.42%.

Dimethyl 2-(1-Hydroxy-4,4,5,5-tetramethylimidazolidin-2-ylidene)-

3-oxosuccinate (14): Imidazoline 12 was synthesized by hydrogen-

ation of 4,4,5,5-tetramethyl-4,5-dihydro-1H-imidazole 3-oxide 1-

oxyl with Pd/C as a catalyst in tetrahydrofuran as a solvent. After

the catalyst had been filtered off and the solvent had been evapo-

rated, crude imidazoline 12 was obtained, and was used without

further purification.

A solution of imidazoline 12 (0.135 g, 0.87 mmol) in CHCl₃(3 mL)

was cooled to freezing point, and a solution of DMAD (0.12 mL,

0.96 mmol) in CHCl₃(1 mL) was added. The resulting mixture was

1

Compound 10c: Yield 34%. H NMR ([D₆]DMSO, 200.13 MHz, δ,

ppm): 1.15 [s, 12 H, 4,5-(CH₃)₂], 4.78 (s, 1 H, CHϭ), 8.25Ϫ8.43 heated to 20 °C. The solution was placed on a silica gel column

(broad s, 2 H, NH). ¹³C NMR ([D₆]DMSO, 50.32 MHz, δ, ppm):

cooled to about 10 °C. Flash chromatography with ethyl acetate

22.4 [4,5-(CH₃)₄], 62.3 (C-4,5), 71.5 (CHϭ), 117.5 (q, J_C,Fϭ 280, gave an eluate containing a cycloadduct Ϫ dimethyl 1-hydroxy-

CF₃), 161.9 (C-2), 169.4 (q, J_C,Fϭ 30). IR (ν˜, cm^Ϫ1): 3160 (NH),

2,2,3,3-tetramethyl-1,2,3,7a-tetrahydroimidazo[1,2-b]isoxazole-6,7-

1605, 1570, (HNϪCϭCϪCϭO), 1265, 1175, 1135 (CF₃). UV [λ_maxdicarboxylate (13) in a yield of 0.06 g. Cycloadduct 13 is stable as

(ethanol), nm (log ε)]: 290 (4.39). m.p. 193Ϫ194 °C (from CHCl₃).

C₁₀H₁₅F₃N₂O: calcd. C 50.8, H 6.4, F 24.1, N 11.9; found C 50.9,

H 6.5, F 24.3, N 11.8%.

a solid at 0 °C for prolonged periods, but in solution at 20 °C it

quantitatively transforms into imidazolidine 14. Evaporation of a

solution gave imidazolidine 14 as the sole product. After recrystalli-

Eur. J. Org. Chem. 2004, 749Ϫ765

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761

V. A. Reznikov et al.

FULL PAPER

zation, the yield of 14 was 0.05 g (85%), m.p. 125Ϫ126 °C (from 2-(1-Methoxy-4,4,5,5-tetramethylimidazolidin-2-ylidene)-1-phenyl-

1

an ethyl acetate/hexane mixture). H NMR (CDCl₃, 200.13 MHz, ethanone (16a): A solution of imidazolidine 1a (0.26 g, 1 mmol),

δ, ppm): 1.14 (s, 6 H), 1.17 [s, 6 H, 4,5-(CH₃)₂], 3.57(s, 3 H), 3.58

sodium methoxide (0.11 g, 2 mmol), and methyl iodide (0.21 g, 0.1

(s, 3 H, -CO₂CH₃), 3.70 (s, 3 H), 3.71 (s, 3 H, -COCO₂CH₃), 7.73, mL, 1.5 mmol) in MeOH (25 mL) was kept for 10 h at 20 °C. The

7.89 (broad s, NH), 9.07, 10.89 (broad s, OH), the ratio of forms

solvent was removed, and the residue was chromatographed on sil-

was 1:2. IR (ν˜, cm^Ϫ1): 3500Ϫ2500 (OH, NH), 1737, 1666, 1596 ica gel. The first fraction, containing methoxy derivative 16a, was

(CϭO), 1557 (CϭC). UV [λ_max(ethanol), nm (log ε)]: 234 (4.18), eluted with a chloroform/MeOH (30:1) mixture; yield 0.15 g (55%).

273 (4.16).

Subsequent elution with a chloroform/MeOH (10:1) mixture re-

sulted in collection of the second fraction, containing imidazolidine

1k; yield 0.04 g (15%).

C₁₃H₂₀N₂O₆, FW ϭ 300.31, orthorhombic, Pbca, a ϭ 14.7171(12),

3

˚

b ϭ 12.6034(5), c ϭ 16.2410(7) A, V ϭ 3012.5(3) A , Z ϭ 8, D_Cϭ

1.324 g/cm³, µ (Mo-K_α) ϭ 0.105 mm, 2.47 Ͻ θ Ͻ 25.01°, absorp-

tion correction by integration, max. and min. transmission 0.966

and 0.934, 2589 reflections collected, 2589 unique, data/param-

eters ϭ 2589/271, Goof ϭ 1.025, R indices 1962 (I Ͼ 2σ_I): R₁

0.0456, wR₂ϭ 0.1221; R indices (all data): R₁ϭ 0.0637, wR₂

0.1358.

Similarly, treatment of 1c with CH₃I gave 1,1,1-trifluoro-3-(1-meth-

oxy-4,4,5,5-tetramethylimidazolidin-2-ylidene)propan-2-one (16c) in

1

a yield of 60%. H NMR ([D₆]DMSO, 200.13 MHz, δ, ppm): 1.37

ϭ

(s, 6 H), 1.20 [s, 6 H, 4,5-(CH₃)₂], 3.77 (s, 3 H, OCH₃), 5.03 (s, 1

H, ϭCH-), 9.04 (broad s, NH). ¹³C NMR ([D₆]DMSO,

50.32 MHz, δ, ppm): 18.1, 21.9 [4,5-(CH₃)₂], 61.6 (C-4), 65.2

(OCH₃), 68.5 (C-5), 71.1 (ϭCH-), 117.9 (q, J_C,Fϭ 290 Hz, CF₃),

163.5 (C-2), 171.8 (q, J_C,Fϭ 31 Hz, CϭO). IR (ν˜, cm^Ϫ1)): 3305

(NH), 2813 (OCH₃), 1628, 1590 (NϪCϭCϪCϭO). UV [λ_max

(ethanol), nm (log ε)]: 250 (3.60), 301 (4.43). m.p. 142Ϫ143 °C

(from an ethyl acetate/hexane mixture). C₁₁H₁₇F₃N₂O₂: C 49.6, H

6.5, F 21.4, N 10.5; found C 50.8, H 7.2, N 10.7, F 21.2%.

ϭ

1-(1-Oxyl-4,4,5,5-tetramethyl-4,5-dihydro-1H-imidazol-2-yl)-2-

phenylethane-1,2-dione 1-Oxime (15): A solution of enaminone 1a

(1.04 g, 4 mmol), sodium methoxide (0.87 g, 16 mmol), and amyl

nitrite (1.2 mL, 8 mmol) in MeOH (40 mL) was kept for 2 h at 20

°C and then evaporated. The residue was dissolved in water (30

mL), and the solution was washed with diethyl ether (2 ϫ 20 mL),

neutralized with 5% HCl, and extracted with chloroform (4 ϫ 30

mL). The combined extract was dried with MgSO₄, and the solu-

tion was evaporated to give crude oxime 15, which was purified

chromatographically on alumina with a chloroform/MeOH (30:1)

mixture as eluent. Yield 0.63 g (55%). IR (ν˜, cm^Ϫ1): 3500Ϫ2500

(OH), 1659 (CϭO), 1600, 1580 (CϭN). UV [λ_max(ethanol), nm

(log ε)]: 265 (4.22). m.p. 142Ϫ143 °C (from an ethyl acetate/hexane

mixture). C₁₅H₁₈N₃O₃: C 62.5, H 6.3, N 14.6; found C 63.1, H 6.6,

N 14.6%.

2-[4,4,5,5-Tetramethyl-2-(2-oxo-2-phenylethylidene)imidazolidin-1-yl

Acetate (18): A solution of imidazolidine 1a (0.26 g, 1 mmol) and

acetic anhydride (0.11 mL, 1.2 mmol) in chloroform (10 mL) was

kept for 1 h at 20 °C, washed with aqueous sodium hydrogencar-

bonate, and dried with MgSO₄. The residue obtained after solvent

removal crystallized after addition of hexane, and the precipitate

of acetoxy derivative 18 was filtered off; yield 0.22 g (75%), m.p.

141Ϫ142 °C (from hexane). ¹H NMR (CCl₄, 200.13 MHz, δ, ppm):

1.16 (s, 6 H), 1.35 [s, 6 H, (4,5-(CH₃)₂], 2.21 (s, 3 H, CH₃CO), 5.14

(s, 1 H, ϭCH-), 7.30 (m, 3 H), 7.72 (m, 2 H, C₆H₅), 9.43 (broad s,

1 H, NH). IR (ν˜, cm^Ϫ1): 3428, 3301 (NH), 1800 (CϭO), 1621, 1581,

1522 (NϪCϭCϪCϭO, CϭC). UV [λ_max(ethanol), nm (log ε)]: 239

(4.10), 326 (4.37). C₁₇H₂₂N₂O₂: C 67.53, H 7.33, N 9.26; found C

67.42, H 7.33, N 9.26%.

Treatment of 1a with methyl nitrate was carried out in the same

manner. A mixture of unchanged 1a (yield 40%), methoxy deriva-

tive 16a (yield 10%), and enaminone 17 (yield 15%) was separated

chromatographically on alumina by elution of (in sequence) 16a

(chloroform as eluent), 1a, and 1-phenyl-2-(4,4,5,5-tetramethylimid-

azolidin-2-ylidene)ethanone (17) (50:1 chloroform/MeOH mixture

as eluent).

(1-Hydroxy-2,2,3,3,6-pentamethyl-1,2,3,5,6,7-hexahydroimidazo-

[1,2-c]pyrimidin-8-yl)phenylmethanone (19): A solution of imidazol-

idine 1a (0.3 g, 1.1 mmol), a formaldehyde solution (30%, 0.5 mL),

and aqueous ammonia (20%, 0.6 mL) in MeOH (5 mL) was kept

for 15 min at 20 °C, and the MeOH was evaporated. The precipitate

of 19 was filtered off and washed with water. Yield 0.2 g (55%). ¹H

NMR ([D₆]DMSO, 200.13 MHz, δ, ppm): 1.17 (s, 6 H), 1.20 [s, 6

H, 4,5-(CH₃)₂], 2.14 (s, 3 H, N-CH₃), 3.31 (s, 2 H, 1-CH₂), 4.03 (s,

2 H, 3-CH₂), 7.3 (m, 5 H, Ph). ¹³C NMR ([D₆]DMSO, 50.32 MHz,

δ, ppm): 18.6, 19.4 [4,5-(CH₃)₂], 39.1 (N-CH₃), 52.6 (C-3), 62.5 (C-

1), 64.3 (C-7), 69.4 (C-6), 83.3 (C-4), 127.2, 127.9, 128.7, 141.0

(Ph), 156.9 (C-4a), 181.8 (CϭO). IR (ν˜, cm^Ϫ1): 2787 (NϪCH₃),

1525 (NϪCϭCϪCϭO). UV [λ_max(ethanol), nm (log ε)]: 235

(3.90), 334 (4.11). m.p. 153Ϫ154 °C (from a hexane/ethyl acetate

mixture). C₁₈H₂₅F₃N₃O₂: C 68.5, H 8.0, N 13.3; found C 69.1, H

8.0, N 13.1%.

1

Compound 16a: H NMR (CDCl₃, 200.13 MHz, δ, ppm): 1.17 (s,

6 H), 1.20 [s, 6 H, (4,5-(CH₃)₂], 3.80 (s, 3 H, -OCH₃), 5.54 (s, ϭ

CH-), 7.35 (m, 2 H), 7.85 (m, 3 H, Ph), 9.1 (broad s, NH). ¹³C

NMR (CDCl₃, 50.32 MHz, δ, ppm): 18.2, 23.2 (4,5-(CH₃)₂], 60.4

(C-4), 65.0 (-OCH₃), 69.5 (C-5), 74.5 (ϭCH-), 126.7, 127.8, 130.0,

140.6 (Ph), 163.3 (C-2), 186.8 (CϭO). IR (ν˜, cm^Ϫ1): 3303, 3270

(NH), 2816 (OCH₃), 1614, 1579, 1540 (NϪCϭCϪCϭO). UV [λ_max

(ethanol), nm (log ε)]: 241 (4.14), 328 (4.38). m.p. 128Ϫ129 °C

(from an ethyl acetate/hexane mixture). C₁₆H₂₂N₂O₂: calcd. C 70.0,

H 8.1, N 10.2; found C 70.4, H 8.4, N 10.3%.

Compound 17: C₁₅H₂₀N₂O, FW ϭ 244.33, orthorhombic, P2₁2₁2₁,

3

˚

a ϭ 10.850(2), b ϭ 11.043(3), c ϭ 11.797(2) A, V ϭ 1413.5(5) A ,

Z ϭ 4, D_Cϭ 1.148 g/cm³, µ (Mo-K_α) ϭ 0.073 mm, 2.53 Ͻ θ Ͻ

24.99°, 1436 unique reflections collected, data/parameters ϭ 1436/

244, Goof ϭ 1.048, R indices (965 I Ͼ 2σ_I): R₁ϭ 0.0607, wR₂ϭ 2-Chloro-2-(1-methoxy-4,4,5,5-tetramethylimidazolidin-2-ylidene)-1-

0.1421; R indices (all data): R₁ϭ 0.0997, wR₂ϭ 0.1669. ¹H NMR

(CDCl₃, 200.13 MHz, δ, ppm): 1.20 (s, 12 H), 5.27 (s, 1 H,

ϭCH-), 7.32, 7.78 (m, 5 H, Ph), 8.65 (broad s, 1 H, NH), 9.30

(broad s, 1 H, NH). IR (ν˜, cm^Ϫ1): 3430Ϫ3127 (NH), 1610, 1582,

phenylethanone (22a): NCS (0.21 g, 1.54 mmol) was added to a

solution of enaminone 16a (0.4 g, 1.47 mmol) in CCl₄(20 mL), and

the resulting mixture was stirred for 40 min at 20 °C. The succinim-

ide precipitate was filtered off, and the solution was evaporated to

1547 (NϪCϭCϪCϭO). UV [λ_max(ethanol), nm (log ε)]: 236 dryness. The residue was treated with hexane, and the precipitate of

(4.03), 319 (4.11), m.p. 236Ϫ238 °C (from an ethyl acetate/hexane 22a was filtered off and recrystallized from a hexane/ethyl acetate

mixture). C₁₅H₂₀N₂O: C 73.74, H 8.25, N 11.47; found C 73.35, H

8.39, N 11.46%.

mixture to give 0.32 g (70%) of monochloro derivative 22a. ¹H

NMR (CDCl₃, 200.13 MHz, δ, ppm): 0.88 (s, 3 H), 1.27 [s, 9 H,

762

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A New Class of Enehydroxylamino Ketones

FULL PAPER

4,5-(CH₃)₂], 3.82 (s, 3 H, OCH₃), 7.29 (m, 3 H), 7.48 (m, 2 H, Ph), C₁₁H₁₇N₃O₂: C 59.2, H 7.7, N 18.8; found C 59.1, H 7.6, N 18.8%.

10.11 (broad s, NH). IR (ν˜, cm^Ϫ1): 3235 (NH), 1590, 1524 (NϪCϭ

CϪCϭO). UV [λ_max(ethanol), nm (log ε)]: 243 (3.99), 336 (3.86).

Found, m/z: 223.13261; calculated for C₁₁H₁₇N₃O₂m/z: 223.13208.

Compound 24c was purified by reprecipitation by water from pyri-

dine and subsequent recrystallization from ethyl acetate; yield 50%.

¹H NMR ([D₆]DMSO, 200.13 MHz, δ, ppm): 1.11 (s, 6 H), 1.21 [s,

m.p. 125Ϫ127 °C (from

a hexane/ethyl acetate mixture).

C₁₆H₂₁ClN₂O₂: calcd. C 62.23, H 6.85, N 9.07; found C 61.84, H

6.60, N 9.19%.

6

H, 4,5-(CH₃)₂], 9.30 (s, NH), 10.4 (s, OH). ¹³C NMR

([D₆]DMSO, δ, ppm): 18.3, 22.2 [4,5-(CH₃)₂], 61.9 (C-4), 63.6 (ϭ

C-CN), 70.3 (C-5), 115.8 (CϵN), 117.2 (q, J_C,Fϭ 291 Hz, CF₃),

162.8 (C-2), 173.8 (q, J_C,Fϭ 32 Hz, CϭO). IR (ν˜, cm^Ϫ1):

3400Ϫ3200 (NH, OH), 2218 (CϵN), 1620, 1547 (NϪCϭCϪCϭ

O). UV [λ_max(ethanol), nm (log ε)]: 241 (4.25), 294 (4.21). m.p.

189Ϫ191 °C (from ethanol). C₁₁H₁₄F₃N₃O₂: C 47.7, H 5.1, N 15.2;

found C 47.6, H 4.8, N 14.4%.

2-(1-Chloro-2-oxo-2-phenylethylidene)-4,4,5,5-tetramethyl-

imidazolidin-1-yl Acetate (22b): NCS (0.29 g, 2.1 mmol) was added

portionwise with stirring to a solution of enaminone 18 (0.62 g,

2 mmol) in chloroform over 10 min. The stirring was continued for

4 h at 20 °C, and the reaction mixture was evaporated to dryness.

The residue was dissolved in a minimum amount of DMSO, and

the solution was cooled to 0 °C and poured into ice-cold brine (15

mL). The precipitate of 22b was filtered off and washed with brine

and water. Yield 0.63 g (95%); m.p. 165Ϫ167 °C (from a hexane/

ethyl acetate mixture). ¹H NMR (CDCl₃, 200.13 MHz, δ, ppm):

1.22 (s, 6 H), 1.34 [s, 6 H, 4,5-(CH₃)₂], 2.15 (s, 3 H, CH₃CO), 7.3

(m, 3 H), 7.5 (m, 2 H, C₆H₅), 10.1 (broad s, 1 H, NH). IR (ν˜,

cm^Ϫ1): 3245 (NH), 1803 (CϭO), 1592, 1576, 1523 (NϪCϭCϪCϭ

O, CϭC). UV [λ_max(ethanol), nm (log ε)]: 244 (3.98), 337 (3.98).

C₁₇H₂₁ClN₂O₂: calcd. C 60.62, H 6.28, N 8.32; found C 60.80, H

6.46, N 8.41%.

Compound 24e: Yield 50%, m.p. 196Ϫ200 °C (decomp., from ethyl

acetate/hexane). ¹H NMR ([D₆]DMSO, 200.13 MHz, δ, ppm): 1.13

(s, 6 H), 1.24 [s, 6 H, 4,5-(CH₃)₂], 7.45 (m, 1 H), 7.54 (m, 1 H, 3,5-

H, pyridyl), 7.69 (m, 1 H, 4-H, pyridyl), 8.56 (m, 1 H, 6-H, pyridyl),

9.54 (s, 1 H, NH), 10.11 (s, 1 H, OH). ¹³C NMR ([D₆]DMSO,

50.32 MHz, δ, ppm): 18.0, 22.3 [4,5-(CH₃)₂], 60.1 (C-4), 67.0 [Cϭ

C(CN)], 69.6 (C-5), 119.1 (CϵN), 121.6, 124.6, 136.6, 148.0, 157.4,

(pyridyl), 163.8 (C-2), 188.6 (CϭO). IR (ν˜, cm^Ϫ1): 3259, 3145,

2981, 2882, 3200Ϫ2600 (NH, OH), 2111 (CϵN), 1602, 1566, 1537

(NϪCϭCHϪCϭO, CϭC). UV [λ_max(ethanol), nm (log ε)]: 241

(3.90), 305 (4.09). C₁₅H₁₈N₄O₂: C 62.92, H 6.34, N 19.57; found C

62.69, H 6.39, N 19.31%.

2-(1-Hydroxy-4,4,5,5-tetramethylimidazolidin-2-ylidene)-3-oxo-3-

phenylpropionitrile (24a): NCS (0.56 g, 4.23 mmol) was added por-

tionwise over 10 min to a stirred solution of imidazolidine 1a (1 g,

3.85 mmol) in chloroform (10 mL) dried with CaCl₂. The stirring

was continued for 10 min, and the residue of dichloride 21 was

filtered off. The solvent was removed at a temperature below 30

°C. The residue was dissolved in a solution of NaCN (0.38 g,

0.77 mmol) in DMSO (5 mL) and the resulting mixture was stirred

for 2 h at 20 °C. The mixture was then cooled to 0 °C and diluted

with ice-cold brine (20 mL), and the precipitate of nitrile 24a was

filtered off, washed with water, and recrystallized from ethyl acet-

ate. Yield 0.38 g (35%). ¹H NMR ([D₆]DMSO/[D₆]acetone,

200.13 MHz, δ, ppm): 1.18 (s, 6 H), 1.29 [s, 6 H, (4,5-(CH₃)₂], 7.5

(m, 5 H, Ph), 9.6 (broad s, 1 H, NH), 10.1 (s, 1 H, OH). ¹³C NMR

(CD₃OD, 50.32 MHz, δ, ppm): 18.5, 23.1 (4,5-(CH₃)₂], 62.6 (C-4),

71.6 (C-5), 72.4 (ϭC-CN), 121.7 (CϵN), 128.7, 128.9, 131.6, 141.5

1

Compound 24f: Yield 40%. H NMR ([D₆]DMSO, 200.13 MHz, δ,

ppm): 1.12 (s, 6 H), 1.18 (t, 3 H, OCH₂CH₃, ethyl acetate), 1.23 [s,

6 H, 4,5-(CH₃)₂], 1.98 (3 H, CH₃CO, ethyl acetate), 4.02 (q, 3 H,

OCH₂CH₃, ethyl acetate), 7.49 (d, J ϭ 6 Hz, 2 H, β-H, pyridyl),

8.65 (d, J ϭ 6 Hz, 2 H, α-H, pyridyl), 9.57 (1 H, broad s, NH),

10.22 (1 H, broad s, NH). IR (ν˜, cm^Ϫ1): 3275, 2600Ϫ3000 (NH,

OH), 2201 (CϵN), 1600, 1554, 1532 (NϪCϭCϪCϭO). UV [λ_max

(ethanol), nm (log ε)]: 247 (3.95), 307 (4.03). m.p. 231Ϫ235 °C

(from an ethyl acetate/MeOH mixture). C₁₅H₁₈N₄O₂·1/2 C₄H₈O₂:

C 61.80, H 6.71, N 16.96; found C 61.45, H 6.60, N 17.11%.

Compound 24g: Yield 30%. ¹H NMR ([D₆]DMSO, 200.13 MHz, δ,

ppm): 1.07 (s, 6 H), 1.17 [s, 6 H, 4,5-(CH₃)₂], 1.25 [s, 9 H, C(CH₃)₃],

(Ph), 166.3 (C-2), 194.0 (CϭO). IR (ν˜, cm^Ϫ1): 3200Ϫ2800 (NH, 9.57 (broad s, 1 H), 9.81 (broad s, 1 H, NH, OH). ¹³C NMR

OH), 2209 (CϵN), 1600, 1577, 1534 (NϪCϭCϪCϭO). UV [λ_max([D₆]DMSO, 50.32 MHz, δ, ppm): 17.6, 22.1 [4,5-(CH₃)₂], 26.5

(ethanol), nm (log ε)]: 235 (4.01), 304 (4.06). m.p. 213Ϫ214 °C (de-

comp. from ethyl acetate). C₁₆H₁₉N₃O₂: calcd. C 67.3, H 6.7, N

14.7; found C 65.9, H 6.6, N 14.6%.

[C(CH₃)₃], 42.4 [C(CH₃)₃], 60.0 (C-4), 64.0 [CϭC(CN)], 68.9 (C-5)

120.6 (CϵN), 164.7 (C-2), 200.0 (CϭO). IR (ν˜, cm^Ϫ1): 3362, 3247

(NH, OH), 2203 (CϵN), 1606, 1549, 1539 (NϪCϭCϪCϭO). UV

[λ_max(ethanol), nm (log ε)]: 223 (4.02), 287 (4.18) m.p. 225Ϫ229

°C (from ethyl acetate). C₁₄H₂₃N₃O₂: C 63.37, H 8.74, N 15.84;

found C 63.37, H 8.92, N 15.76%.

The yield of 2,2-dichloro-2-(1-hydroxy-4,4,5,5-tetramethyl-4,5-di-

1

hydro-1H-imidazol-2-yl)-1-phenylethanone (21) was 15%. H NMR

([D₆]DMSO, 200.13 MHz, δ, ppm): 0.80 (s, 6 H), 1.09 [s, 6 H, (4,5-

(CH₃)₂], 7.55 (m, 3 H), 7.96 (m, 2 H, Ph). IR (ν˜, cm^Ϫ1): 1716 (Cϭ

O), 1608 (CϭN). UV [λ_max(ethanol), nm (log ε)]: 229 (4.17). m.p.

134Ϫ136 °C (from chloroform). Found, m/z: 328.07529; calculated

for C₁₅H₁₈N₂O₂Cl₂m/z: 328.07452.

Treatment of 22a and 22b with NaCN was carried out in the same

way. To isolate nitrile 24a, the resulting solution was extracted with

chloroform (4 ϫ 20 mL) after pouring into brine. The combined

extract was washed with brine (2 ϫ 10 mL) and with water and

dried with MgSO₄. The residue obtained after solvent removal was

dissolved in MeOH (20 mL) and the solution was boiled for 1 h

and then evaporated. The residue was treated with hexane, and the

precipitate of nitrile 24a was filtered off and washed with a small

amount of ethyl acetate; yield 60%.

Enaminones 1b, 1c, 1e, 1f, and 1g were converted into nitriles 24b,

24c, 24e, 24f, and 24g in a similar manner.

Compound 24b: Yield 35%, m.p. 193Ϫ195 °C (from ethyl acetate).

¹H NMR ([D₆]DMSO, 200.13 MHz, δ, ppm): 1.06 (s, 6 H), 1.26 [s,

6 H, (4,5-(CH₃)₂], 2.13 (s, 3 H, CH₃), 9.31 (s, 1 H), 9.99 (s, 1 H, 2-(1-Methoxy-4,4,5,5-tetramethylimidazolidin-2-ylidene)-3-oxo-3-

OH, NH). ¹³C NMR ([D₆]DMSO, 50.32 MHz, δ, ppm): 22.9, 27.3

[4,5-(CH₃)₂], 32.4 (CH₃CO), 65.8 (C-4), 72.3 (ϭC-CN), 74.3 (C-5),

phenylpropanenitrile (25): Yield 60%, m.p. 180Ϫ183 °C (from a hex-

ane/ethyl acetate mixture). ¹H NMR (CDCl₃, 200.13 MHz, δ,

125.5 (CϵN), 168.0 (C-2), 197.2 (CϭO). IR (ν˜, cm^Ϫ1): 3424, 3252, ppm): 1.29 [s, 12 H, 4,5-(CH₃)₂], 3.90 (s, 3 H, OCH₃), 7.38 (m, 3

3119, 2985, 2871 (NH, OH), 2194 (CϵN), 1598, 1543 (NϪCϭ

CHϪCϭO). UV [λ_max(ethanol), nm (log ε)]: 220 (3.99), 285 (4.12). 3252 (NH), 2203 (CϵN), 1604, 1550 (NϪCϭCϪCϭO, CϭC). UV

H), 7.72 (m, 2 H, C₆H₅), 10.10 (broad s, 1 H, NH). IR (ν˜, cm^Ϫ1):

Eur. J. Org. Chem. 2004, 749Ϫ765

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V. A. Reznikov et al.

FULL PAPER

[λ_max(ethanol), nm (log ε)]: 234 (4.13), 305 (4.25). C₁₇H₂₁N₃O₂,%:

calcd. C 68.20, H 7.07, N 14.04; found C 67.97, H 7.21, N 14.23%.

Compound 29f: Yield 30%, IR (ν˜, cm^Ϫ1): 3426, 3243 (NH), 2204

(CϵN), 1629, 1609, 1563 (NϪCϭCϪCϭO). λ_max, (chloroform),

nm (log ε): 242 (3.47), 302 (3.61), 592 (2.70), m.p. 203Ϫ211 °C

(decomp. from an ethyl acetate/hexane mixture).

3-(1-Hydroxy-4,4,5,5-tetramethylimidazolidin-2-ylidene)-2-oxopro-

pionamide (1n): A solution of ester 1d (0.5 g, 1.95 mmol) in a satu-

rated MeOH solution of ammonia (10 mL) and aqueous ammonia

(20%, 3 mL) was kept for 8 h at 20 °C. The MeOH was evaporated

from the mixture, and the precipitate was filtered off and washed

with water to give 0.39 g (90%) of amide 1n. ¹H NMR ([D₆]DMSO,

200.13 MHz, δ, ppm): 1.06 (s, 6 H), 1.17 [s, 6 H, 4,5-(CH₃)₂], 1.18

(t, J ϭ 7 Hz, 3 H, CH₃CH₂ethyl acetate), 1.98 (s, 3 H, CH₃CO

ethyl acetate), 4.02 (q, J ϭ 7 Hz, 2 H, CH₃CH₂O ethyl acetate),

5.62 (s, 1 H, ϭCH-), 7.20 (broad s, 2 H, NH₂), 9.48 (s, 2 H, OH).

¹³C NMR ([D₆]DMSO, 50.32 MHz, δ, ppm): 14.0 (-OCH₂CH₃

ethyl acetate), 20.7 (CH₃CO ethyl acetate), 17.8, 22.6 (4,5-(CH₃)₂],

59.7 (OCH₂CH₃ethyl acetate), 60.6 (C-4), 68.3 (C-5), 73.4

(ϭCH-), 164.0 (C-2), 166.7 (CONH₂), 177.7 (CϭO). IR (ν˜, cm^Ϫ1):

3500Ϫ2500 (OH), 1690 (CONH₂), 1584, 1539 (NϪCϭCϪCϭO).

UV [λ_max(ethanol), nm (log ε)]: 327 (4.31). m.p. 226Ϫ228 °C (from

an ethyl acetate-ethanol mixture) C₁₀H₁₇N₃O₃·1/2C₄H₈O₂: calcd.

C 53.1, H 7.8, N 15.5; found C 52.5, H 7.7, N 15.3%.

Compound 29g: Yield 40%, m.p. 73 °C (decomp. from hexane), IR

(ν˜, cm^Ϫ1): 3440Ϫ3241 (NH), 2198 (CϵN), 1631, 1562 (NϪCϭ

CϪCϭO). UV [λ_max(ethanol), nm (log ε)]: 270 (3.91), 322 (3.53),

593 (3.10). C₁₄H₂₂N₃O₂: calcd. C 63.61, H 8.39, N 15.90; found C

63.23, H 8.45, N 15.73%.

Oxidation of imidazolidine 1a afforded a complex mixture of prod-

ucts. Enaminone 17 was isolated chromatographically on alumina

with a chloroform/MeOH (50:1) mixture in a yield of about 10%.

Potassium Salt of Deprotonated 4,4,4-Trifluoro-2-(1-oxyl-4,4,5,5-

tetramethyl-imidazolidin-2-ylidene)-3-oxobutyronitrile (29c): Lead

dioxide (3 g, 12.5 mmol) was added to a solution of imidazolidine

24c (1 g, 3.6 mmol) in ethyl acetate (100 mL), and the resulting

mixture was stirred for 20 min at 20 °C. The lead oxides were fil-

tered off, a solution of KOH (4.0 mmol) in MeOH (5 mL) was

added to the filtrate, and the solution was stirred for 20 min. The

precipitate of inorganic salts was filtered off, and the filtrate was

evaporated at a temperature below 20 °C. The residue was diluted

with toluene (50 mL), and the precipitate of the potassium salt of

29c was filtered off and dried in vacuo. Yield 0.57 g (50%). Crystals

of the potassium salt of 29c suitable for an X-ray analysis were

obtained by slow diffusion of benzene into an ethyl acetate solution

of this salt. IR (ν˜, cm^Ϫ1): 2190 (CϵN), 1603, 1553 (NϭCϪCϭ

CϪO). UV [λ_max(ethanol), nm (log ε)]: 280 (4.22), 518 (2.65). m.p.

257Ϫ262 °C (from an ethyl acetate/benzene mixture).

C₁₁H₁₂F₃N₃O₂K: C 42.0, H 3.9, F 18.1, N 13.3; found C 41.8, H

3.9, F 18.5, N 13.1%.

2-Imino-2-(1-methoxy-4,4,5,5-tetramethyl-4,5-dihydro-1H-imidazol-

2-yl)-1-phenylethanone (27): Crude monochloro derivative 20a

(0.16 g, 0.52 mmol) was added portionwise to a stirred solution of

NaN₃(0.07 g, 1 mmol) in DMSO (5 mL), and the resulting mixture

was stirred for 2 h at 20 °C. The solution was cooled to 0 °C and

diluted with cold brine (20 mL). The precipitate of imine 27 was

filtered off and washed with water. Yield 0.10 g (65%), m.p. 88Ϫ91

1

°C (from hexane). H NMR (CCl₄, 200.13 MHz, δ, ppm): 1.12 (s,

6 H), 1.14 [s, 6 H, 4,5-(CH₃)₂], 3.26 (s, 3 H, OCH₃), 7.41 (m, 3 H),

8.0 (m, 3 H, C₆H₅), 11.49 (s, 1 H, NH). IR (ν˜, cm^Ϫ1): 3216 (NH),

1666 (CϭO), 1625, 1595, 1578 (CϭN, CϭC). ν˜_max(ethanol), nm

(log ε): 255 (4.12). C₁₆H₂₁N₃O₂: calcd. C 66.88, H 7.20, N 14.62;

found C 66.78, H 7.20, N 14.34%.

Crystals of 2-tert-butyl-3-{1-[2-cyano-2-hydroxy-1-(1-oxyl-4,4,5,5-

tetramethyl-4,5-dihydro-1H-imidazol-2-yl)-3,3-dimethylbutoxy]-

4,4,5,5-tetramethyl-4,5-dihydro-1H-imidazol-2-yl}oxirane-2-carbo-

nitrile (30) suitable for an X-ray analysis were obtained in an at-

tempt to grow crystals from crude radical 29g from an ethyl acetate/

heptane mixture. Two types of crystal formed: dark-blue crystals

of nitroxide 29g, unsuitable for an X-ray analysis, and dark-red

crystals of nitroxide 30, which were separated manually.

2-(1-Oxyl-4,4,5,5-tetramethylimidazolidin-2-ylidene)-3-oxo-3-

phenylpropionitrile (29a): Lead dioxide (3 g, 12.5 mmol) was added

to a solution of 24a (1 g, 3.5 mmol) in chloroform (100 mL), and

the resulting mixture was stirred for 20 min at 20 °C. The lead

oxides were filtered off, and the filtrate was evaporated at a tem-

perature below 20 °C to half the original amount. The residue was

diluted with hexane (50 mL), and the precipitate was filtered off to

give 0.68 g (70%) of nitroxide 29a. IR (ν˜, cm^Ϫ1): 3300Ϫ3200 (NH),

2201 (CϵN), 1608, 1578, 1550 (NϪCϭCϪCϭO). UV [λ_max(etha-

nol), nm (log ε)]: 303 (4.09), 602 (2.60). m.p. Ն 200 °C (decomp.,

from ethyl acetate/hexane). Found, m/z: 284.14052; calculated for

C₁₆H₁₈N₃O₂m/z: 284.13989.

Compound 30: C₂₈H₄₅N₆O₄, FW ϭ 529.70, monoclinic, P2₁/c, a ϭ

˚

19.549(1), b ϭ 18.259(1), c ϭ 20.335(1) A, β ϭ 117.655(1)°, V ϭ

3

6428.9(6) A , Z ϭ 8, D_Cϭ 1.095 g/cm³, µ(Mo-K_α) ϭ 0.074 mm,

˚

1.18 Ͻ θ Ͻ 23.31°, 27676 reflections collected, 9255 unique, R_intϭ

0.0916, data/parameters ϭ 9255/1046, Goof ϭ 0.931, R indices (I

Ͼ 2σ_I): R₁ϭ 0.0484, wR₂ϭ 0.1097; R indices (all data): R₁

0.0854, wR₂ϭ 0.1241.

ϭ

Nitroxides 29b, 29c, 29e, 29f, and 29g were synthesized similarly

by oxidation of the corresponding hydroxylamines 24b, 24c, 24e,

24f, 24g.

Compound 29b: Yield 40%, m.p. 130Ϫ133 °C, IR (ν˜, cm^Ϫ1): 3239

(NH), 2197 (CϵN), 1642, 1576 (NϪCϭCϪCϭO). UV [λ_max(etha-

nol), nm (log ε)]: 265 (3.60), 294 (3.51), 324 (3.35), 600 (2.88).

C₁₁H₁₆N₃O₂: calcd. C 59.4, H 7.3, N 18.9; found C 59.0, H 7.1, N

18.6%. Found, m/z ϭ 222.12434, calculated for C₁₁H₁₆N₃O₂,

m/z: 222.12424.

Acknowledgments

The work was supported by RFBR (03-03-32518), Minobr (E02-

5.0-188), and BRHE (NO-008-X1) grants and RAS and SB RAS

integration programs.

Compound 29c: Yield 90%. IR (ν˜, cm^Ϫ1): 3260 (NH), 2216 (CϵN),

1650, 1576 (NϪCϭCϪCϭO). UV [λ_max(ethanol), nm (log ε)]: 280

(4.02), 355 (3.56), 573 (3.22). m.p. Ն 150 °C. Found, m/z:

276.09553; calculated for C₁₁H₁₃F₃N₃O₂m/z: 276.09598.

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Received August 28, 2003

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A new class of enehydroxylamino ketones - (R)-2-(1-hydroxy-4,4,5,5- tetraalkylimidazolidin-2-ylidene)ethanones: Synthesis and reactions

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