Isoquinoline-and piperazinedione-derived α -acylamino peroxide moieties in asymmetric oxidation of sulphides and epoxidation of naphthoquinones

The application of chiral α -acylamino hydroperoxide moieties in asymmetric sulphoxidation and epoxidations was pursued. In order to synthesize new isoquinoline-derived α -acylamino hydroperoxides isoquinolines were treated with ( R )-menthyl chloroformate and hydrogen peroxide. Instead of the expected hydroperoxides novel bis(2-menthyloxycarbonyl-1,2-dihydroisoquinolin-1-yl) peroxides were obtained as 1:1 epimeric mixtures by a subsequent reaction. 1:1 mixtures of t-butyl (2-menthyloxycarbonyl-1,2-dihydroisoquinolin-1-yl) peroxides were formed from t-butyl hydroperoxide, isoquinoline and (R)-menthyl chloroformate. For eventual in situ preparation of chiral ( R )-menthyloxycarbonyl-1,2-dihydroisoquinolin-1-yl) hydroperoxides and their application in stereoselective O-transfer reactions, isoquinolines were combined with ( R )-menthyl chloroformate, hydrogen peroxide and metal alkoxides. These mixtures allowed a stereoselective synthesis of aryl methyl sulphoxides from corresponding sulphides. The stereoselectivity results from a kinetic resolution of racemic sulphoxides formed in the first step wherein the (S)-enantiomer was faster oxidized to the corresponding sulphone. As another type of chiral α -acylamino hydroperoxide moiety piperazinedione hydroperoxide was applied in the transformation of aryl methyl sulphides into sulphoxides. Low enantioselectivities were achieved. The same reagent allowed a high yielding epoxidation of naphthoquinones, but again in modest stereoselectivities.


Introduction
Chiral sulphoxides have gained wide interest in asymmetric C-C and C-X bond formation reactions. 1,2To obtain them in optically active form either resolution of racemic sulphoxides or asymmetric oxidation of sulphides has been used. 35][6] As an alternative, chiral catalysts or chiral reagents in the presence of non-chiral oxidizing reagents (t-butyl hydroperoxide, cumene hydroperoxide, oxone or hydrogen peroxide) have been used. 7Selective oxidations of sulphides 1 to sulphoxides 2 is challenging due to the sensibility to overoxidation to achiral sulphones 3. When optically active hydroperoxides were used in asymmetric oxidation of sulphides 1 enantioselectivity was achieved mostly in the consecutive step, i. e. by kinetic resolution during the oxidation of the racemic sulphoxides 2(S) and 2(R) obtained in the first step.In general, enantioselectivities obtained with chiral hydroperoxides were not satisfactory so far.
We report here attempts to synthesize new chiral α-N-acylamino hydroperoxides derived from isoquinolines, (R)-menthyl chloroformate and hydrogen peroxide and the use of the combinations of these reagents in enantioselective oxidation of aryl methyl sulphides 1. 8 Furthermore the application of a chiral piperazinedione hydroperoxide bearing a chiral Nacylamino hydroperoxide moiety in this reaction as well as in the epoxidation of naphthoquinones is included.

Results and Discussion
8][29][30] However, the original assumption of complete diastereoselective formation of the 1,2-adducts was erroneous, as found out by two independent groups. 28,29Instead, 1:1 mixtures of epimers were formed.As an alternative to those nucleophiles used before, it would be interesting to investigate how hydrogen peroxide behaves when used in such additions to isoquinolines.Thus we combined isoquinolines 7 with (R)-menthyl chloroformate 8 in dichloromethane at -40°C and added a 3 M solution of hydrogen peroxide in diethyl ether after the formation of intermediate N-acyliminium salts 9. Peroxidic products were isolated by quenching with water and column chromatography.All products turned out to be unstable, but NMR-spectra and in part HRMS could be obtained.The latter revealed that the products were not hydroperoxides 10 but peroxides 11 which were formed by a subsequent reaction of the expected 10 with further N-acyliminium salt 9.When t-butyl hydroperoxide was used as a nucleophile the expected t-butyl peroxides 12 were obtained.

Scheme 2. Formation of chiral isoquinoline-derived peroxides 11and 12.
Elucidating the configuration of peroxides 11 and 12 turned out to be difficult.For instance, the H-NMR spectrum of 11d in CDCl 3 at room temperature showed two signals for each proton at position 1, 3 and 4 coalescing at 50°C (see supplementary material).This phenomenon is presumably caused by rotamers derived from hindered rotation around the C-N-bond of the carbamate moiety.Evidence for the formation of diastereomers and rotamers was revealed by the NMR spectra of the t-butyl peroxide 12a.This product is more stable and thus reliable integrations of signals could be obtained.By rising the measuring temperature from 25 °C to 50 °C splitting of the signals of H-8 at about 7.5 ppm into two doublets of J = 3.8 Hz was observed, which is in agreement with the existence of a 1:1 mixture of diastereomers.This fact could also be seen at room temperature when the spectrum was recorded in DMSO-d 6 , however the compound decomposes relatively fast in this solvent.Attempts to shed light on the configuration of the peroxides 11 and 12 by matrix isolation and vibrational dichroism undertaken by Tarczay et al. 31 were unsuccessful due to the instability of the material and the complexity of the structures.
At this stage it could be presumed that the reaction of isoquinolines 7 with (R)-menthyl chloroformate 8 and hydrogen peroxide or t-butyl peroxides give rise to new α-N-acylamino peroxides 11 and 12, respectively.However, stereoselectivity could not be achieved, as it was also missing before in analogous reactions with cyanide as nucleophile. 27,29Thus all these products 11 and 12 were not useful in asymmetric oxidations of sulphides 1.As a consequence and having in mind the in situ formation of α-aminohydroperoxide moieties from flavine-derived cyclophanes and hydrogen peroxide in the stereoselective sulphoxidations, 21 our strategy was turned to the combination of hydrogen peroxide, isoquinolines 7 and (R)-menthyl chloroformate 8 and metal compounds as additives (Scheme 3).Scheme 3. Asymmetric sulphoxidation of methyl phenyl sulphide with H 2 O 2 .
Since VO(OiPr) 3 had turned out to be very useful in oxygen transfer reactions from hydrogen peroxide, [32][33][34] this compound was applied in the in situ procedure according to Scheme 3 giving rise to an enantioselective formation of the sulphoxides 2. The effect of several parameters on the enantioselectivity was screened (see table in supporting information).Hydrogen peroxide as oxygen donor turned out to be more effective than t-butyl peroxide.Lowering the temperature from 0 °C to -40 °C did not improve the enantioselectivity.Sometimes higher ee were obtained which, however, could not be reproduced.A molar excess of (R)-menthyl chloroformate 8 seems to be advantageous.
A time resolved record of the enantiomeric ratio of the reaction of methyl phenyl sulphide 1a with hydrogen peroxide in the presence of VO(OiPr) 3 revealed that an increase of the enantiomeric ratio of 2(R):2(S) occurred with increasing time reaching 60:40 after 45 min.This indicates a kinetic resolution of primarily formed racemic methyl phenyl sulphoxides 2(R) and 2(S), where the S-enantiomer was faster oxidized to the sulphone 3.Under slightly changed reaction conditions (mixing of isoquinoline 7 with (R)-menthyl chloroformate 8 and addition of VO(OEt) 3 , PhSMe and H 2 O 2 , waiting after each addition for 30 min) an ee of 32% was achieved.
In order to prove the assumption of a kinetic resolution being responsible for the stereoselective outcome of this reaction, racemic methyl phenyl sulphoxide 2(R/S)a was treated with hydrogen peroxide under the same conditions as methyl phenyl sulphide 1a before.An ee of 36% was obtained thus proving a kinetic resolution.Hence, two oxidation steps are necessary to achieve stereoselective access to sulphoxide 2(R)a starting from the sulphide 1a, namely formation of racemic sulphoxide 2(R/S)a in the first step and further preferential oxidation of the enantiomer 2(S)a to the sulphone 3a in a second step.As a consequence, a higher ratio than 1:1 of hydrogen peroxide had to be used for an effective stereoselective synthesis of 2(R)a.By varying the H 2 O 2 ratio (see Table 1) we found an optimum at 1.7 equivalents of this oxidizing reagent.a HPLC peak areas obtained by integration, the assignment to the enantiomers 2(R)a and 2(S)a is based on the sign of optical rotation and their comparison with reported data.
We further tried to apply Ti(OiPr) 4 instead of VO(OEt) 3 and to use 4-bromoisoquinoline.The latter formed more stable peroxidic structures 11 and 12 (vide supra) and thus was expected to perform better than unsubstituted isoquinoline in the 4-component oxidation system according to Scheme 3. As can be seen in Fig. 2, the overoxidation of the sulphoxide 2a to sulphone 3a is severe.We therefore reduced the reaction time to 10 min, and removed 4-bromoisoquinoline in the work up by 20% hydrochloric acid for effective quenching.As an optimal result we achieved 73% ee at an overoxidation of 49%, when 2.2 equivalents of H 2 O 2 were used (see Table 2).The ee could even be further increased to values higher than 99% with 3.3 equivalents of H 2 O 2 , however overoxidation of 84% occurred.Further variation of reaction conditions revealed that Ti(OiPr) 4 is essential as shown by re-isolation of more than 95% of starting material 1 when Ti(OiPr) 4 was left out.Slower addition of H 2 O 2 over a period of 2 h resulted in low yield while much overoxidation occurred.Increasing the amount of (R)-menthyl chloroformate 8 did not show an advantageous effect.
The application of 5-bromoisoquinoline 7a instead of 4-bromoisoquinoline 7b in the Ti(OiPr) 4 -assisted oxidation of methyl phenyl sulphide was possible but gave unsatisfactory results (28% ee with 50% overoxidation).Advantageous effects of adding small amounts of methanol in sulphoxidations of sulphides were reported. 35But the addition of 1.2 equivalents methanol to our system resulted in unsatisfactory enantioselectivities (2-6% ee) using several ratios of hydrogen peroxide.Surprisingly, an advantageous effect was observed, when the same amount of methanol was added to the oxidizing system with 4-bromoisoquinoline 7b (17% ee at 54% overoxidation in the absence of methanol versus 23% ee at 69% overoxidation with methanol).
When unsubstituted isoquinoline 7d was used, a highly chemoselective oxidation of methyl phenyl sulphide 1a to methyl phenyl sulphoxide 2a could be achieved with 1.1 equivalents of H 2 O 2 .However, stereoselectivity was missing as it was also in cases of higher amounts of H 2 O 2 where overoxidation occurred.Thus the stereoselectivity increased in the sequence of isoquinoline, 5-bromoisoquinoline and 4-bromoisoquinoline.Obviously, substituents influence the performance of isoquinolines 7 in the oxidation of methyl phenyl sulphide 1a considerably.a determined by integration of HPLC peaks 7][38][39] Adopting a proposal made by Adam et al. a Ti-complex 13, could be assumed formed from 9, hydrogen peroxide and Ti(OiPr) 4 .13 binds the sulphoxide via the O-atom (transition state 14) and transfers oxygen from the peroxide moiety affording the sulphone 3a and the complex 15. 40The transition state of the (S)enantiomer must be lower in energy to lead to the observed kinetic resolution.Scheme 4. Mechanistic proposal for the transformation of methyl phenyl sulphoxide 2a into methyl phenyl sulphone 3a during the kinetic resolution.The transformation of 14 into 3b is faster for the (S)-enantiomer of 2a.
We further thought there might be an opportunity to regenerate the Ti-complex 13 from 15 via N-acyliminium salt 9 and further hydrogen peroxide while water is eliminated.Thus we checked if the oxidation system of isoquinolines 7, (R)-menthyl chloroformate 8, Ti(OiPr) 4 can act in catalytic quantities when molecular sieve was added to trap the water, which would be formed by the transformation of 15 into 13.Two equivalents of hydrogen peroxide, t-butyl hydroperoxide or oxone were used as oxygen-donor with or without additional bases, such as DABCO or sodium bicarbonate in the presence of molecular sieve.However, all attempts resulted in unsatisfactory enantioselectivities. Thus the system according to Scheme 3 could not be used in a catalytic fashion.
Independently of the investigations of Laschat et al. who failed to achieve enantioselectivity in sulphoxidation reactions we also sought to apply the piperazinedione hydroperoxide 4a as potential stereoselective oxygen-transfer reagent. 26Unlike Laschat et al. we added Ti(OiPr) 4 and succeeded in enantioselective transformations of aryl methyl sulphides into aryl methyl sulphoxides 2. Wide variations of reaction conditions (see supporting information) lead to a maximal ee of 33% while 17% of sulphone 3 was isolated as overoxidation product.Remarkably, two equivalents of the piperazinedione hydroperoxide 4a were necessary for an enantioselective reaction although only one equivalent was consumed.The application of just one equivalent of 4a led to a lower extent of overoxidation while the sulphoxides were formed in similar yields, however almost racemic.Treatment of racemic methyl phenyl sulphoxide 2a under the same conditions did not give any ee´s of 2a but an almost complete transformation into the sulphone 3 under the same conditions.a determined by integration of HPLC peaks b piperazinedione hydroperoxide 4a : Ti(OiPr) 4 : methyl phenyl sulphide 1 While the 4-component oxygen transfer system consisting of isoquinolines 7, (R)-menthyl chloroformate, Ti(OiPr) 4 and hydrogen peroxide successfully used in the stereoselective synthesis of sulphoxides 2 turned out to fail in epoxidation reactions the piperazinedione hydroperoxide, 4a could successfully be employed in certain epoxidations.Laschat et al. used 4a in a Weitz-Scheffer epoxidation of cyclic enones and chalcones and could achieve full conversion with a maximal ee of 37 %.Our investigations with 2-alkylnaphthoquinones as another interesting target revealed that 4a can also epoxidize 2-alkylnaphthoquinones 16 in the presence of DBU in excellent yields, but with unsatisfactory enantioselectivities. Extensive variation of temperatures and reaction times (see Table 5) led to 14 % ee at best.If the reaction temperature was lowered too much the reaction stopped.Other bases such as KOH or LiH gave worse results.Thus the piperazinedione hydroperoxide 4a performed less satisfactory in the epoxidation of 2-alkylnaphthoquinones than known cases using sugar-derived hydroperoxides.

Conclusions
Novel isoquinoline-derived peroxides could be synthesized from isoquinolines, (R)-menthyl chloroformate and ethereal hydrogen peroxide or t-butylhydroperoxide.This synthesis lacks stereoselectivity, i. e. 1:1 epimeric mixtures were obtained.The same components were used in an in situ method in the presence of Ti(OiPr) 4 or other metal compounds for a novel stereoselective oxidation of methyl phenyl sulphide.As a best result 73% ee with 49% overoxidation to the sulphone was achieved.This is a much better result as obtained with isolated chiral N-acylamino hydroperoxides so far.Unlike other findings reported in the literature, the application of optically active piperazinedione hydroperoxide 4a gave also a stereoselective access to aryl methyl sulphoxides, but in a less efficient way than in the first method.4a is an effective epoxidizing reagent for 2-alkylnaphthoquinones, however in unsatisfactory stereoselectivities.

Experimental Section
General Procedures. 1 H NMR and 13 C NMR spectra were recorded at 300 and 75 MHz, respectively, with a Bruker AC 300 in CDCl 3 with TMS as internal standard.Silica gel (0.04-0.063 mm, Merck) was used for preparative column chromatography.7][48][49][50] All the other materials were purchased from commercial suppliers.
General procedure for the synthesis of peroxides 11 and 12 (-)-(R)-Menthyl chloroformate (105 mg, 0.48 mmol) was added to a solution of an isoquinoline 4 (0.48 mmol) in dry dichloromethane (15 mL) at -40°C under argon.After 60 min while the solution turned slightly yellow, it was cooled to -78°C and a 3 M solution of t-butyl hydroperoxide (0.16 mL, 0.48 mmol) or 3 M ethereal hydrogen peroxide (0.16 mL, 0.48 mmol) was added by a syringe.The mixture was kept at this temperature for 60 min and was then quenched by pouring into water (30 mL).The organic phase was separated and the aqueous layer extracted with dichloromethane (20 mL).The combined organic phases were dried (Na 2 SO 4 ) and the solvent stripped off under vacuum.The remainder was purified by column chromatography (80 g of silica, cyclohexane/AcOEt 7:3).R f of the products around 0.9.
Oxygen transfer to aryl methyl sulphides 1 and naphthoquinones 16 by the piperazinedione hydroperoxide 4a (Tables 4, 5) Ti(OiPr) 4 (0,01 mL, 0.04 mmol) and sulphide 1 or DBU (0.006 mL, 0.04 mmol) and the 2methylnaphthoquinone 16 (0.04 mmol) were added to a solution of the piperazinedione hydroperoxide 4a (0.08 mmol respectively 0.04 mmol) in dry dichloromethane under argon at the reported temperature (see Tables 4, 5).The mixture was kept at this temperature overnight and was then poured into water (30 mL) containing a few drops of concentrated aqueous Na 2 SO 3 .The mixture was extracted with dichloromethane (2 x 30 mL).The combined organic layers were dried (Na 2 SO 4 ) and the solvent was stripped off.The remaining oil was investigated by chiral HPLC (see also supporting information).

Supporting Information Available
NMR-spectra of selected peroxides 12, Table with results of oxidation of methyl phenyl sulphide in the presence of VO(OiPr) 3 , parameters of analyses or reaction mixtures.

Figure 1 .
Figure 1.Dependence of enantiomeric ratios on reaction time in the oxidation of methyl phenyl sulphide 1a with hydrogen peroxide in the presence of isoquinoline 7d, 8 and VO(OiPr) 3 on reaction time.

Figure 2 .
Figure 2. Dependence of enantiomeric ratios on the amount of H 2 O 2 used in the oxidation of methyl phenyl sulphide 1a in the presence of 4-bromoisoquinoline 7b, 8 and Ti(OiPr) 4 .

Table 1 .
Effect of H 2 O 2 ratio on enantiomeric ratios in formation of sulphoxides 2(R)a and 2(S)a in oxidation of methyl phenyl sulphide 1a with hydrogen peroxide in the presence of isoquinoline 7d, 8 and VO(OiPr) 3