Lithiated oxazolinyloxiranes and oxazolinylaziridines: key players in organic synthesis

α-Lithiated oxazolinyloxiranes

Within the large family of α-lithiated oxiranes, for long time considered only fleeting intermediates in reactions of epoxides with strong bases and successively estimated useful synthons in synthetic organic chemistry because of their chamaleon-like character which gives them the ability to react either with electrophiles and with nucleophiles [6], α-lithiated oxazolinyloxiranes occupy a special place because of the their viable synthetic elaboration.

Subjected to lithiation (s-BuLi/TMEDA, THF, –100 °C) diphenyloxirane 1 generates lithiated species 1-Li which is stable at low temperature and could be successfully trapped with electrophiles to give functionalized oxazolinyloxiranes 2, elaborable to formyl epoxides 3 by using a known protocol [7].

Configurationally stable lithiated oxazolinyloxirane 4-Li, generated from the trans precursor 4, reacted regio- and stereospecifically with electrophiles, with complete retention of configuration to give 5 (Scheme 1) [8], while the lithiation-trapping sequence of the corresponding cis oxazolinyloxirane occurred with poor diastereoselectivity for steric reasons.

Scheme 1

Synthesis of functionalized oxazolinyloxiranes 2 and formyl epoxides 3.

The α-lithiated oxazolinyloxiranes 6-Li, generated from the optically active oxazolinyloxiranes 6 proved to be configurationally unstable; indeed, they tend to epimerize and the addition of electrophiles ends up with the formation of diastereomeric mixtures of 7 (Scheme 2) [9].

Scheme 2

Configurational instability of α-lithiated oxazolinyloxiranes 6-Li.

In the absence of epoxide-ring hydrogens, as in the case of the diphenyl epoxide 8, a remote lithiation occurs at the aryl group cis to the oxazolinyl group to give the arylalkanones 9 (Scheme 3) [10].

Scheme 3

ortho-Lithiation of aryl oxazolinyloxiranes 8: synthesis of arylalkanones 9.

Interestingly, ortho-lithiated aryloxirane 10-Li, generated by lithium-bromine exchange performed on the corresponding ortho-bromo aryloxirane 10, gives the isoquinolines 11 (Scheme 4) [11].

Scheme 4

ortho-Lithiated aryloxiranes 10-Li: preparation of isoquinolines 11.

An interesting aspect of the reactivity of α-lithiated oxiranes resides in the stereochemical outcome of their reactions with electrophiles which in principle can take place with retention or inversion of configuration or racemization.

A detailed multinuclear magnetic resonance investigation, jointly with an in situ IR study [12], demonstrated that α-lithiated oxazolinyloxiranes are thermally stable at low temperature but generally configurationally unstable. An indirect dynamic interconversion between two lithiated η³-aza-allyl enantiomeric monomers, namely (R)-η³-12-Li and (S)-η³-12-Li, mediated by a complex mixture of diastereomeric oxazoline-bridged dimeric species variously intra-aggregated, has been proposed as a possible mechanism responsible for the racemization 12-Li undergoes (Scheme 5).

Scheme 5

Racemization of α-lithiated oxazolinyloxirane 12-Li.

Lithiation of racemic 2-oxazolinyl-3,3-diphenyloxirane 13 afforded interchangeable enantiomeric anions 13-Li and ent-13-Li [13], which reacted with (S)-2-p-tolylsulfinylbenzaldehyde 15 to give a 50:44:6 mixture of diastereoisomeric sulfinyl hydroxybenzyl oxazolinylepoxides 14a–c (65 % combined yield) (Scheme 6).

Scheme 6

Reaction of α-lithiated 2-oxazolinyl-3,3-diphenyloxirane 13-Li with (S)-2-p-tolylsulfinylbenzaldehyde 15.

The absolute configuration of (1S,2S,S_S)-14b, (1R,2S,S_S)-14c and (1S,2R,S_S)-14a was unequivocally determined by X-ray diffraction studies jointly with chemical correlations [13]. On the basis of these studies it was concluded that the sulfinyl group plays a significant role in the control of the configuration at the carbinolic carbon, determining a completely stereoselective evolution of 13-Li, yielding only 14a, and a highly stereoselective transformation of ent-13-Li to give an 88:12 mixture of 14b and 14c. It was also established that the influence of an additional stereogenic center in the nucleophile on the stereoselectivity of the process is very low.

As expected on the basis of the configurational stability of α-lithiated aryloxiranes, which proved to be dependent upon the substitution on the aryl group (Scheme 7) [1]c-d.

Scheme 7

Configurational stability of α-lithiated aryloxiranes.

cis and trans Lithiated aryl oxazolinyloxiranes 16-Li and 19-Li are configurationally stable and, once generated, can be trapped with a series of electrophiles with complete retention of configuration [14, 15]. In particular, the trapping reaction of 16-Li with carbonyl compounds has been exploited for the preparation of α,β-epoxy-γ-butyrolactones 18 (Scheme 8).

Scheme 8

Preparation of α,β-epoxy-γ-butyrolactones 18.

The capture of 19-Li by electrophiles furnished epoxides of the kind of 20 and 21 (Scheme 9).

Scheme 9

Reaction of oxazolinyloxiranes 19-Li with electrophiles.

Almost optically pure α,β-epoxy-γ-butyrolactones 24 and 28 could be obtained starting from the chiral nonracemic oxazolinyloxirane 22 (dr trans/cis 90:10, er trans > 99:1) [16] (Scheme 10). The reaction of oxirane 23-Li with PhCHO takes place with a poor diastereoselective giving the easily separable epoxylactones 27 and 28, almost optically pure.

Scheme 10

Synthesis of optically pure epoxylactones 27.

Synthesis of α,β-epoxy-γ-amino acids and α,β-epoxy-γ-butyrolactams

When lithiated (1R*,2S*)-1-methyl-1-oxazolinyloxirane 29-Li was reacted with (Z)-N-t-butyl- and N-cumylnitrones, diazaspiro[4.5]decanes diast-30 formed in good yields (42–71 %) and diastereoselectively (dr > 98/2) (Scheme 11). In CDCl₃ as well as in THF-d₈ spirocyclic compounds 30 equilibrate with the hydroxylamino forms 32 and diast-31. Trifluoroacetic acid (TFA)-catalyzed hydrolysis, carried out in dioxane/H₂ O, afforded in good yields (40–94 %) and diastereoselectivity (dr > 98/2) 4,5-epoxy-1,2-oxazin-6-ones 33 (R¹ = t-Bu) (Scheme 11) [16].

Scheme 11

Synthesis of epoxy-1,2-oxazin-6-ones 33.

Lithiation of the optically active oxazolinyloxirane 34 (er = 98/2) [14], followed by the coupling of the corresponding lithiated intermediate 34-Li with N-tert-butyl- and N-cumylnitrones, gave spirocyclic compounds (-)-35 with complete diastereoselectivity. Hydrolysis (TFA) of (-)-35 furnished highly enantioenriched N-t-butyl- and N-cumyl-epoxy-1,2-oxazinones (-)-36, which could be converted to the corresponding α,β-epoxy-γ-amino acids (-)-37 (Scheme 12).

Scheme 12

Synthesis of optically active α,β-epoxy-γ-amino acids (-)- 37.

Synthesis of polysubstituted oxazolinylcyclopropanes

The addition of lithiated aryl oxazolinyloxiranes 38-Li and 39-Li to tungsten Fischer carbene complexes 40 produced cyclopropanes 41 and 42, respectively (Scheme 13), which are likely the result of a Michael initiated ring closure (MIRC reaction) [17]. Oxidation of 41 furnished the ester 43.

Scheme 13

Synthesis of polysubstituted oxazolinylcyclopropanes.

Lithiation of terminal oxazolinyloxirane: synthesis of trisubstituted oxazolinyloxiranes and (E)-dioxazolinyl-diphenylbut-2-ene-1,4-diol

A simple method of synthesis of trisubstituted oxazolinyloxiranes based on the stereospecific lithiation-trapping of a terminal α-substituted oxazolinyloxirane, good precursor to α-hydroxy-β-aminoalkanamides 50 of potential antifungal activity, was developed in our lab [18]. The required starting oxirane 46 was synthesized from 2-benzoyl-2-oxazoline 44 (Scheme 14). The trapping of the lithiated intermediate worked reasonably well with several electrophiles to give 47 and 49. It is interesting that in the absence of an external electrophile 44-Li undergoes an “eliminative dimerization” (the typical carbene-like reactivity often associate to α-lithiated ethers) [19] with a very high E diastereoselectivity to give the 1,4-dioxazolinylbutenediol 51.

Scheme 14

Stereospecific lithiation-trapping of terminal α-substituted oxazolinyloxirane 46.

α-Lithiated oxazolinylaziridines

Aziridines are valuable and widely used intermediates in synthetic chemistry [20, 21]. Numerous methods of synthesis of aziridines have been developed. A conceptually appealing strategy is the transformation of an already constructed aziridine scaffold through the generation of aziridinyl anions, followed by the reaction with electrophiles [22–25]. When treated with strong bases such as lithium amides or organolithiums, aziridines may undergo deprotonation at the aziridine ring carbons ending up with the formation of α-lithiated derivatives which can be captured with an electrophile to give a more substituted aziridine. Such a useful lithiation-electrophile trapping sequence, named aziridinyl anion methodology parallels the known oxiranyl anion methodology. The α-lithiated heterocycle-substituted aziridines, on their side, have an added value as the heterocyclic moiety can be synthetically elaborated.

α-Lithiated N-alkyl (aryl) oxazolinylaziridines: synthesis of aziridinolactones

Treatment of readily available N-phenyl oxazolinylaziridines 52 with n-BuLi at low temperature generates aziridinyllithiums 52-Li that react with electrophiles giving functionalized aziridines 53 and 54 of potential utility as ligands for asymmetric syntheses (Scheme 15) [26].

Scheme 15

Synthesis of functionalized N-phenyl oxazolinylaziridines 53 and 54.

Considering the stereochemistry, lithiation of 55 by using s-BuLi/TMEDA at –98 °C resulted in the formation of aziridinyllithiums 55-Li: deuteration occurred with retention of configuration to give aziridine 56 and the reaction with aldehydes provided spirocyclic compounds 57 and then aziridinolactones 58 [27]. It is worthy pointing out that the oxazolinyl ring plays a role in the deprotonation process exalting the acidity of the proton to be removed and providing stabilization to the resulting lithiated intermediate by chelation (Scheme 16) [14].

Scheme 16

Regioselective lithiation of aziridine 55.

Lithiation of N-alkyl terminal aziridines

The role of the oxazolinyl ring as lithiation promoter was highlighted also with the chiral terminal N-trityl aziridine (S)-59 [28]. Subjected to deprotonation (s-BuLi/TMEDA at –70 °C), aziridine (S)-59 underwent surprisingly regioselective lithiation at the cis-β-position (Scheme 16) instead of at the more acidic α-position. The highly sterically demanding N-trityl group which, on the basis of NOESY experiments carried out on (S)-59, sets in a trans relationship with respect to the oxazoline ring, likely prevents lithiation at the α-position for steric reasons. The configurationally stable aziridinyllithium (S,S)-59-Li has been successfully used in the preparation of highly enantioenriched cis functionalized aziridines 60 and 61, which could be stereoselectively converted into the corresponding aziridino-γ-butyrolactones 62 (Scheme 17).

Scheme 17

The sterically demanding of N-trityl group: asymmetric synthesis of aziridines 60.

In contrast, lithiation of the less hindered N-benzyl oxazolinylaziridine 63 occurred at the more acidic α-position producing almost exclusively α-functionalized aziridines 64, upon electrophilic trapping (Scheme 17). Not unespectedly, N-cumyl substituted oxazolinylaziridine 65 underwent lithiation with s-BuLi at both the α and β positions to give 66 and 67 in a 1:2 ratio (Scheme 18).

Scheme 18

The effect of the N-substituent on the lithiation of aziridines 63 and 65.

Enantioenriched diastereomeric aziridines (R,R)-68 and (R,S)-70 have been regioselectively lithiated with n-BuLi in THF to give the α-lithiated aziridines (R,R)-68-Li and (R,S)-70-Li, which proved to be configurationally stable as testified by trapping them with a deuterium source (Schemes 19 and 20) [29]. This is in sharp contrast with the reported configurational instability of the corresponding α-lithiated oxazolinyloxiranes [12]. Such a peculiar behavior of the nitrogen bearing heterocycle has been rationalized on the basis of the investigated aziridine nitrogen dynamics and DFT calculations. A dynamically controlled lithiation has been proposed as a model supported by the estimation of the nitrogen inversion barrier by dynamic NMR experiments [29].

Scheme 19

Configurational stability of (R,R)-68-Li.

Scheme 20

Configurational stability of (R,S)-70-Li.

Lithiation of heterosubstituted oxazolinylaziridines

The ability of the oxazolinyl group as a promoter of α-lithiation of aziridines is stronger than that of other heterocycles [30]. Indeed, diastereomeric aziridines (R*,R*)-72 and (R*,S*)-74 are regioselectively lithiated only at the oxazoline-bearing carbon atom giving aziridinyllithiums (R*,R*)-72-Li and (R*,S*)-74-Li which can be trapped with a variable degree of retention of configuration to give 73 and 75 (Scheme 21) [30].

Scheme 21

Regioselective lithiation of heterosubstituted oxazolinylaziridines (R*,R*)-72 and (R*,R*)-74.

Lithiation occurs at the other heterocycle-substituted carbon atom only in the absence of protons at the oxazoline-bearing carbon atom. In fact, aziridines (R*,S*)-76 were lithiated with n-BuLi in THF at –78 °C, producing aziridinyllithiums (R*,S*)-76-Li which could be trapped with a deuterium source again with a variable degree of stereoselectivity leading to the oxazolinyl aziridines 77 (Scheme 22).

Scheme 22

Synthesis of heterosubstituted oxazolinylaziridines 77.

Lithiation of N-sulfonyl- and phosphinylaziridines

The N-substitution may control the lithiation-trapping sequence of aziridines. Indeed, the lithiation of diastereomeric N-sulfonyl oxazolinylaziridines (R*,R*)-78 and (R*,S*)-83 takes place at the benzylic position and the resulting aziridinyllithiums (R*,R*)-78-Li and (R*,S*)-83-Li are both configurationally stable although differing in their reactivity. Aziridinyllithium (R*,R*)-78-Li could be trapped with electrophiles giving aziridines 79 only with low yield because of side reactions such as dearomatization, affording tricyclic aziridine 80, and ortho-lithiation furnishing aziridine 81 upon quenching with electrophiles (Scheme 23) [27]. Variable amounts of azirine 82 could also be observed.

Scheme 23

Lithiation of N-sulfonylaziridine (R*,R*)-76.

In its turn, diastereomeric aziridinyllithium (R*,S*)-83-Li did not undergo dearomatization reaction likely because of the trans arrangement of the sulfinyl group and the C-Li bond, and could be trapped with ketones to furnish spirocyclic derivatives 84 which could be elaborated to aziridino-γ-lactones 85 (Scheme 24).

Scheme 24

Lithiation of N-sulfonylaziridine (R*,S*)-83.

Moreover, the trans arrangement between the sulfonyl group and the C-Li bond in lithiated aziridine (R*,S*)-83-Li causes a fast trans β-elimination of lithium phenylsulfinate with formation of azirine 86 almost quantitatively.

The N-phosphinyl group cooperates with the oxazolinyl group in promoting deprotonation of diastereomeric aziridines (R*,S*)-87 and (R*,R*)-90 [27]. Diastereoisomer (R*,S*)-87 could be smoothly lithiated providing configurationally stable (R*,S*)-87-Li, which, upon trapping with acetone, gave first spirocyclic derivative 88 and aziridino-γ-lactone 89 after acidic hydrolysis. The lithiation-deuteration of diastereomer (R*,R*)-90 showed a different reactivity depending on the base used for the deprotonation: the use of s-BuLi gave a certain degree of epimerization furnishing, upon quenching with D₂ O, a mixture of the epimers (R*R*)-91 and (R*S*)-92; the use of LDA gave a more pronounced epimerization and favored the N- to C-migration of the phosphinyl group leading to aziridine 93 (Scheme 25).

Scheme 25

Lithiation of N-phosphinylaziridines (R*,S*)-87 and (R*,R*)-90.

Concluding remarks

In conclusion, the chemistry and synthetic utility of α-lithiated oxazolinyl epoxides and aziridines have been highlighted in this paper. It has been shown that such lithiated species can be easily generated and captured with electrophiles leading to more functionalized derivatives. Spectroscopic and computational studies have proved their utility not only for the comprehension of the chemistry of aziridine and epoxides in general but also for the elucidation of the mechanisms of their lithiation and the stereochemistry of their reactions. Combining bench experiments with spectroscopic investigations and DFT calculations has contributed to enormously increase the synthetic potential of the lithiated oxazolines described in this manuscript.