Asymmetric 1,3-dipolar reactions of cyclic vinyl p -tolyl sulfilimines with diazoalkanes

1,3-Dipolar reactions of vinyl p -tolyl sulfilimines 1 and 2 with diazoethane afforded mixtures of adducts with almost complete π -facial- selectivity and a high exo/endo-selectivity, under smooth conditions. The anti-approach with respect to the tolyl group, and the exo-arrangement of the dipole are clearly favored on steric grounds. Reactions with diazomethane are slower and less stereoselective.


Introduction
Vinyl sulfoxides have been shown to be efficient chiral dienophiles 1 owing to the ability of the sulfinyl group to differentiate the diastereotopic faces of the double bond.In order to increase the reactivity as well as the π−facial-and endoselectivities, the presence is required at the double bond of other electron-withdrawing groups restricting the conformational equilibrium around the C─S bond.In the course of our studies on the behavior of differently substituted activated vinyl sulfoxides as chiral dienophiles in asymmetric Diels-Alder reactions, 1a,2 we have demonstrated that (Z)-3-p-tolylsulfinylacrylonitriles exhibit high reactivity, a complete π-facial selectivity and a very high endo-selectivity 3,4 (Scheme 1).These features transform 3-sulfinylacrylonitriles into some of the most efficient sulfinyl-dienophiles so far reported.We found that the transformation of (Z)-3-p-tolylsulfinylacrylonitriles into the cyclic vinyl-p-tolylsulfilimines (1 and 2) allowed us to invert the π−facial selectivity of the Diels-Alder reactions with cyclopentadienes 5 and others dienes 6 (Scheme 1).
We have recently demonstrated that (Z)-3-p-tolylsulfinylacrylonitriles are also excellent dipolarophiles in their asymmetric reactions with diazoalkanes, 7 and their adducts can easily be converted into cyclopropanes. 8On this basis, we decided to study the dipolarophilic behavior of cyclic vinyl p-tolyl sulfilimines to check whether they are also complementary to sulfinylacrylonitriles when they are confronted with diazoalkanes.The results obtained in the reactions of the sulfilimines 1 and 2 (Scheme 1) with diazoethane and diazomethane are presented in this paper.

Results and Discussion
Compounds 1 and 2 were prepared according to the previously reported procedure. 5The reaction of (R)-1-p-tolyl-1λ 4 -isothiazol-3-one (1) with diazoethane proceeded under quite smooth conditions (<20 ºC) in short or moderate reaction times (<90 min).The results are collected in Table 1.The reaction afforded mixtures of three cycloadducts, 3-5, two of them (3 and 4) obtained as the major products regardless the used conditions.The use of CH 2 Cl 2 as the solvent (entries 2-5) meant an improvement in the endo/exo and π-facial selectivities, which were not substantially modified by any change in the temperature.Compounds 3-5 could not be isolated diastereomerically pure, either by crystallization or by chromatography.Therefore, they were characterized from the spectroscopic data of diastereomeric mixtures of the cycloadducts. 9eactions of (R)-4-n-butyl-1-p-tolyl-1λ 4 -isothiazol-3-one (2) 5 with diazoethane, performed under similar experimental conditions, gave the results collected in Table 2.
Table 1.Results of the reaction of (R)-1-p-tolyl-1λ Results of the 1,3-dipolar cycloadditions of (R)-4-n-butyl-1-p-tolyl-1λ As expected, reactions of 2 with diazoethane required longer reaction times to reach completion than those needed for the sulfilimine 1.The process afforded only two adducts, anti-6-exo-and anti-7-endo-, with complete control of the π-facial selectivity and a high exoselectivity.The latter was improved when CH 2 Cl 2 was used as the solvent for the reaction (compare entries 1 and 3).Additionally, a slight increase in the proportion of exoadduct was detected when the temperature was lower (entries 2-5).
The thermal instability of the adducts hindered their isolation; hence, these compounds were also characterized from diastereomeric mixtures of 6 and 7.As in the case of compounds 3-5, the stereochemical assignment was made by spectroscopic methods. 1 H-NMR and HMQC experiments proved the complete control of the regioselectivity of the cycloaddition of 1 with diazoethane.The relative configuration of the chiral centers in cycloadducts 3-5 was established by NOESY experiments, and also from the values of their coupling constants (Figure 1).

Figure 1
Bearing in mind the fact that the Sconfiguration at sulfur must not be affected during the cycloaddition, the NOESY effect observed between hydrogen atoms at the orthoposition at the aromatic ring (H-4 and H-4') and the hydrogen H-2, for adducts 3 and 4, evidence a synarrangement of both substituents, which accounts for the Rabsolute configuration at the chiral carbon bonded to H-2.
The values of J 1,2 (7.3 Hz for 3, and 8.0 Hz for 4) show a synarrangement of H-1 and H-2, both for 3 and for 4, in agreement with the concerted mechanism of these cycloadditions.The absolute configurations at the chiral centers derived from diazoethane (R-for 3 and Sfor 4) were initially established from the coupling constant values J 2,3 for each adduct.The value of 1.9 Hz observed for 3 is evidence of an antiarrangement for H-2 and H-3 in adduct 3, whereas the value of 7.5 Hz for 4 indicates that both hydrogen atoms adopt a synarrangement.The NOESY effect detected between H-2 and CH 3 for adduct 3, and between H-2 and H-3 for 4, lead to the same conclusion.From all these data, the anti-exo stereochemistry for the major adduct 3 and the anti-endo stereochemistry for adduct 4 could be established. 10he configurational assignment of the minor adduct, 5, was only tentative.The only available data are related to the coupling constants J 1,2 (8.1 Hz) and J 2,3 (4.0 Hz).The former value, indicative of a cisarrangement of the hydrogen atoms, is a consequence of the cyclic structure of the dipolarophile and of the concerted character of the reaction.The latter value suggests a trans arrangement of H-2 and H-3.As the two major cycloadducts 3 and 4 exhibit an antistereochemistry, compound 5 must be syn-.The observed value for J 2,3 (4.0 Hz) suggests its exo nature.Unfortunately, the small proportion of 5 in the obtained diastereomeric mixtures did not allow a NOESY experiment, which would have confirmed this tentative assignment unequivocally.
As we have already seen (see Table 2), the 1,3-dipolar cycloaddition reaction of vinyl sulfilimine 2 with diazoethane afforded a mixture of only two adducts 6 and 7, with 6 being clearly predominant in the reaction mixtures under all the conditions tested.The regioselectivity (confirmed by 1 H-NMR and HMQC experiments) and the relative configuration in the stereogenic carbon atoms in the adducts (deduced from NOESY experiments, Figure 2) was determined as in the previous case.This relative configuration becomes the absolute configuration if we admit that the Rconfiguration at the chiral sulfur does nor change during the reaction.

Figure 2
As was the case for 3 and 4, the value of the coupling constants for H-1 and H-2 allowed us to determine the configuration at the chiral center derived from diazoethane.In the major cycloadduct 6, the constant J 1,2 is 3.6 Hz, which indicates a transarrangement and, therefore, an exostereochemistry.Similarly, the endostereochemistry for the minor adduct 7 was deduced from the value of 8.3 Hz for the coupling constant J 1,2 , indicative of a cisarrangement of H-1 and H-2.
The absolute configuration of 6 was finally corroborated by chemical correlation with compound 11 (obtained by reaction of (Z)-3-p-tolylsulfinyl-2-n-butylacrylonitrile with diazoethane), 7 whose configuration was already known by X-ray diffraction.Thus, reduction of the sulfilimine functionality by treatment of a mixture of 6 and 7 with LiAlH 4 afforded an epimeric mixture of sulfenylcarboxamides, 8 and 8'.Only diastereomerically pure 8 could be isolated by chromatography of the crude reaction mixture (Scheme 2).It was oxidized into sulfone 9 and then dehydrated to the sulfonylcyanopyrazoline 10.The spectroscopic properties ( 1 H-and 13 C-NMR) of 10 were coincident with those of the compound prepared by oxidation of 11 (Scheme 2), but the values of the specific optical rotation for both compounds 10 derived from anti-6-exo and 11, respectively, exhibited the opposite sign, (+)-10 and (-)-10.This led to the conclusion that they are enantiomers and, therefore, resulting from the approach of the diazoethane to the dipolarophile with opposite π-facial selectivities, in agreement with the results from Diels-Alder cycloadditions for both types of substrates.

Scheme 2
In Table 3 are collected the most relevant results obtained in the 1,3-dipolar cycloaddition reactions of (R)-1-p-tolyl-1λ 4 -isothiazol-3-one (1) with diazomethane under different experimental conditions.Under similar, and even stronger, conditions compound 2 does not react with diazomethane.The reactions of 1 with this dipole were complete under mild conditions in short or moderate reaction times to yield two diastereomeric cycloadducts, anti-12 and syn-13, resulting from both π-facial approaches of diazomethane to the dipolarophile.As was the case for the reactions with diazoethane (Table 1), the best stereoselectivity was observed using CH 2 Cl 2 as the solvent (entries 2-5).As expected, the reactivity of 1 decreased as the temperature was lower.Surprisingly, the π-facial selectivity also decreased with the reaction temperature (compare entries 2-5).
All attempts failed to isolate diastereomerically pure 12 and 13, either by crystallization or by chromatography, possibly owing to the instability of these compounds.Therefore, their characterization was made from the spectroscopic parameters of freshly prepared cycloadduct mixtures.Once again, NMR experiments (COSY and HMQC) allowed us to determine that 1,3dipolar cycloadditions of vinyl sulfilimine 1 proceed with complete control of the regioselectivity.The configuration of the major adduct, anti-12, resulting from the diazomethane's approach to the less hindered face of the dipolarophile, was determined unequivocally by 1 H-NMR (n.O.e.).Thus, in a way quite similar to that described above for cycloadducts derived from diazoethane, the n.O.e.value of 2.7 between the orthohydrogen atoms of the aromatic ring and the hydrogen atom on C-α to the sulfur function, gives evidence of the synarrangement of both substituents (proton and p-tolyl group) in compound 12 (Figure 3).Therefore, in adduct 13, where the corresponding n.O.e.value was not detected, both groups must exhibit an antiarrangement.If we consider that the configuration at sulfur must not be altered during the reaction, this analysis allowed us to determine the absolute configuration at all the chiral centers existing at the reaction products.anti-12 syn-13

Figure 3
As we have seen, 1,3-dipolar cycloaddition reactions of (R)-1-p-tolyl-1λ 4 -isothiazol-3-ones 1 and 2 with diazoalkanes proceed in a completely regioselective way, usually with a high or complete π-facial selectivity and a good exoselectivity (for diazoethane).In order to account for the observed π-facial diastereoselectivity, we assume that the favored approach of the dipole is to the less hindered face of the molecule, which is the one bearing the sulfur lone electron pair (Scheme 3), to afford the antiadducts.

Scheme 3
This behavior had also been observed in the Diels-Alder reactions of 1 and 2. 5,6 However, in the latter case, the π-facial selectivity was always complete, whereas in reactions with diazoalkanes it depended on the experimental conditions and the dipoles used.The lower steric restrictions of the diazoalkanes with linear structures, with respect to that of the dienes can account for these differences.
As this selectivity has been explained on steric grounds, the relevance of these factors must be smaller in 1,3-dipolar reactions.This can easily be understood for diazoalkanes, owing to the linear structure of these dipoles.Otherwise, the evident larger size of diazoethane than that of diazomethane, would account for the smaller selectivity in Et 2 O/MeOH (entry 1, Table 3).This would also explain the complete facial selectivity observed in the reaction of 2 with diazoethane, which decreases for compound 1 (compare Tables 1 and 2, respectively).
In cycloadditions with diazoethane, an additional fact must be considered: the dipole approach to both faces of the sulfilimine may take place in two different ways, affording the endoand exoadducts.These two possible approaches to the face opposite to that bearing the ptolyl group (anti-adducts) are depicted in Scheme 4. In the exoapproach, the methyl group of the dipole faces the hydrogen atom of the sulfilimine, whereas the hydrogen atom of the dipole faces the C─S bond of the dipolarophile.In the endo approach, the methyl group faces the C─S bond and the hydrogen atom of the dipole faces the hydrogen atom of the dipolarophile.The steric interactions existing in the endoapproach (Me/S and H/H) are more restrictive than those in the exoone (Me/H and H/S).This explains why the approach of the sulfilimines to the pro-S face of diazoethane will be the favored one, yielding the exoadducts as the major ones (Scheme 4).The fact that the exoselectivity of these reactions is lower than that observed in the Diels-Alder reactions, where it is complete, 5,6 can also be explained on the basis of the lower steric restrictions existing with diazoalkanes.

ISSN 1424-6376
Page 154 From all the results presented herein we can conclude that cyclic vinyl sulfilimines are interesting dipolarophiles in their reactions with diazoalkanes, producing ∆ 1 -pyrazolines in a highly stereoselective manner.Concerning the π-facial selectivity, their behavior as dipolarophiles is complementary to that observed for (Z)-3-sulfinylacrylonitriles, but both the reactivity and stereoselectivity are higher than that reported for the corresponding nitriles.The search for conditions improving the reactivity and stereoselectivity of our sulfilimines, as well as the transformation of their adducts into cyclopropanes, are in progress and will be reported in due course.

Experimental Section
General Procedures.All moisture-sensitive reactions were performed in flame-dried glassware equipped with rubber septa under positive pressure of argon.Silica gel 60 (230-400 mesh ASTM) and DC-Alufolien 60 F 254 were used for flash column chromatography and analytical TLC, respectively.Melting points were determined on a Gallenkamp apparatus in open capillary tubes and are uncorrected.Microanalyses were performed with a Perkin Elmer 2400 CHN and Perkin Elmer 2400 C-10II CHNS/O analyzers.NMR spectra were determined in CDCl 3 solutions, unless otherwise indicated, at 300-and 75 MHz for 1 H-and 13 C-NMR respectively; chemical shifts (δ) are reported in ppm and J values in Hertz.IR spectra frequencies are given in cm -1 .Compounds 1 and 2 were synthesized and purified according to procedures described in ref. 5.