Highly efficient stereoconservative syntheses of new, bifunctional atropisomeric organocatalysts

The first synthesis of new organocatalysts with 1-phenylpyrrole atropisomeric skeleton containing a thiourea group is reported. A possible structural reason for the stereochemical lability of an atropisomeric intermediate is described together with a way to preserve the isomeric purity during the synthesis. The catalytic activities of the new atropisomeric organocatalysts have been tested in Michael addition reactions.


Introduction
The application of chiral bifunctional urea and thiourea derivatives as enantioselective organocatalysts to the synthesis of optically active compounds has recently appeared as a new and exciting area of contemporary synthetic organic chemistry. 1,2The observed good stereocontrol achieved by the chiral bifunctional catalysts is due to concomitant and synergistic activation of both reacting partners during C-C bond formation.
][16][17][18] Furthermore, only few examples are known in which the thiourea and the amino groups are connected to an atropisomeric skeleton within the organocatalyst molecule.The 1,1′-binaphthyl-2,2′-diamine scaffold was applied first by Wang 19 in enantioselective Baylis-Hillman reactions and later on by Melchiorre and co-workers 20 for the enantioselective addition of 3methyloxindole to cinnamaldehyde.The same atropisomeric skeleton was used by Barbas and co-workers, 21 who connected an additional chiral alkaloid moiety to the other side of the thiourea and applied this novel multifunctional organocatalyst for enantioselective cascade reactions.The binaphthalene based organocatalysts contain quite rigid structures and similar rigidity can be recognized in many alkaloid-based thiourea catalysts.However, other authors have demonstrated the advantage of conformational flexibility of guanidine/bisthiourea organocatalysts in substrate activation and chiral induction during phase transfer catalytic processes. 22ifunctional organocatalysts are frequently tested in enantioselective Michael addition of nitrostyrene to 1,3-dialkyl-and 1,3-diaryl-1,3-propanediones.Dibenzoylmethane is normally not considered as a good Michael donor due to the steric hindrance of the two aryl groups and usually requires harsh reaction conditions and long reaction times.In previous reports several new bifunctional organocatalysts were described which efficiently accelerated the Michael reaction of dibenzoylmethane.Structures and efficiencies of those organocatalysts are depicted in Scheme 1. [23][24][25][26][27] Wang et al. applied a trans-1,2-diaminocyclohexane based thiourea as the organocatalyst with good selectivities. 23Malerich et al. combined first a chincona alkaloid moiety with a squaramide derivative. 24They took advantages of the higher diastance between the two H-bridge forming NH groups in the squaramide compared to the same distance in thiourea.The above mentioned Michael reaction was accomplished in the presence of 0.5 mol % catalyst with excellent yield and good selectivity.In the same reaction Tan et al. applied 9-aminoquinine as organocatalyst with higher selectivity, however complete conversion required as much as 15 mol % catalyst loading. 25Liu et al. synthesized the chiral cinchona alkaloid connected squaramide instead of thiourea and the axially chiral 2,2'-dihydroxy-1,1'-binaphtalene moiety was coupled to the second amino group of the squaramide.This modification resulted in a highly efficient organocatalyst, but reaction of dibenzoylmethane with -nitrostyrene was much slower (36 h). 26Isik et al. published a new squaramide type organocatalyst with a more simple structure than the previously mentioned one. 27The authors coupled the strongly basic 4dimethylaminopyridine moiety to the first amino group of trans-1,2-diaminocyclohexane, while the other amino group was connected to the adamantyl group containing squaramide.Addition of -nitrostyrene to dibenzoylmethane was complete within 5 hours in the presence of 1 mol% of that catalyst and the product was isolated with high yield and ee.

Scheme 1. Examples of reported chiral bifunctional organocatalysts of Michael addition.
9][30] We envisaged the combination of the atropisomeric 1-phenylpyrrole structure with thiourea and tertiary amine functions in one molecule to provide a new class of bifunctional organocatalyst having the potential to produce a synergistic effect in asymmetric transformations.Two types of organocatalyst were designed: a series with a direct connection between the thiourea moiety and the benzene ring of the biaryl skeleton (type 1, Scheme 2) to produce a relatively rigid structure, and another in which a methylene group is inserted between the thiourea function and the atropisomeric aromatic skeleton (type 2).The latter compounds are conformationally more flexible than those of type 1, and so we could compare the effect of this structural difference on the catalytic activity and asymmetric induction ability of these new organocatalysts.
We now report an efficient synthesis of these new atropisomeric bifunctional thiourea type organocatalysts, and their performance in two model reactions: the Michael additions of acetylacetone and dibenzoylmethane to (E)-β-nitrostyrene.

Results and Discussion
Modification of the pyrrole-and the benzene-ring-connected α-and/or ortho-substituents is always challenging because the rotational barrier around the C-N bond strongly depends on the structure and possible chemical interactions of these "percussive" groups.2][33][34] Therefore careful selection of the applied reactions and stepwise control of the ee values of each intermediates were important during the development of the stereoconservative syntheses of the designed new bifunctional atropisomeric 1-phenylpyrrole derivatives ((R a )-1a-f and (S a )-2a,b, Scheme 2).Both types of target compounds were prepared from the optically active 1-(2-carboxy-6trifluoromethylphenyl)pyrrole-2-carboxylic acid ((S a )-3, Scheme 3) as starting material.
The synthesis and optical resolution of (±)-3 with methyl phenylglycinate (PhGMe) and selective monoesterification of (S a )-3 were accomplished according to literature procedures (Scheme 2). 31,32Chemoselectivity of the (S a )-4 ester-forming reaction is due to the significant difference between the reactivity of the two carboxylic groups in (S a )-3.Then, preparation of (R a )-8a-e was continued by analogy to our previously developed series of reactions. 33Thus the carboxylic function connected to the pyrrole ring was transformed into different acid amides ((S a )-5a-e) in two steps.Even when the acid chloride formation was carried out at 80 o C for 2 hours in toluene followed by the addition of the different amines at 0 o C, no racemization was observed.Each amide ((S a )-5a-e) was isolated in enantiopure form (ee >99%).Then the ester function connected to the benzene ring was hydrolysed using sodium hydroxide at ambient temperature.This hydrolysis is quite slow (1-7 days) but the chemo-and stereo-selectivities were perfect in each case.Transformation of the free carboxylic function in (S a )-6a-e into a primary amine group was accomplished using diphenylphosphoryl azide (DPPA).This method provided the atropisomeric aniline derivatives ((R a )-7a-e) without any racemization.The intermediates containing tertiary amine functions ((R a )-8a-e) were obtained using the borane-dimethyl sulfide complex because application of a more reactive reducing agent like lithium aluminium hydride could partially defluorinate the trifluoromethyl groups of the molecules.Reduction of the deactivated pyrrole carbonyl group required prolonged reaction time (2 days) at 60 o C but each acid amide could be transformed into the tertiary amine derivative without any racemization.Finally the thiourea function was constructed using the corresponding aryl isothiocyanates.The products ((R a )-1a-f) were purified by flash chromatography.Each compound was obtained in enantiomerically pure form (ee >99%, HPLC).Scheme 3. Synthesis of compounds (S a )-1a-f (a: R 1 =R 2 =Me, Ar=3,5-bis(trifluoromethyl)phenyl; b: R 1 =R 2 =Et, Ar=3,5-bis(trifluoromethyl)phenyl; c: R 1 =R 2 =Bu, Ar=3,5-bis(trifluoromethyl) phenyl; d: NR 1 R 2 =pyrrolidin-1-yl, Ar=3,5-bis(trifluoromethyl)phenyl; e: R 1 =Me, R 2 =(S)-1methylbenzyl, Ar=3,5-bis(trifluoromethyl)phenyl; f: R 1 =R 2 =Et, Ar=phenyl).
The same dicarboxylic acid ((±)-3) was used as starting material for the preparation of compounds (S a )-2a,b, and (S a )-4, (S a )-5b and (S a )-6b were also the isolated intermediates of this synthesis (Scheme 3).
In order to find a shorter route to compounds (S a )-2a and (S a )-2b, transformation of the carboxylic group of (S a )-6b into the primary amide function in compound (10) was also accomplished in two steps (Scheme 3) via the corresponding acid chloride.The two amide functions in compound 10 could be reduced in one pot with the borane complex and one could avoid the use of hydrazine hydrate as well.However, starting from optically pure (S a )-6b we obtained a practically racemic diamide (10, Scheme 4).It may be recalled that racemization was also observed during esterification of (S a )-6b in methanol with thionyl chloride. 33On the other hand we have described high conformational stabilities of numerous α,o,o′-trisubstituted 1-phenylpyrrole type atropisomers, [28][29][30][31][32][33][34] and stereochemical lability was observed only in the cases where a tricyclic intermediate with a low rotational barrier (such as 9, Scheme 4) could be formed during the modification of the substituents.Therefore we suppose that during the formation of the diamide 10, the activated acyl group of compound (S a )-6b may react with the electron-rich amide function situated in the pyrrole α-position, providing an isoimidium salt (9) which is quite similar to several known compounds, 35,36 and the formation of this stereochemically labile tricyclic intermediate might be responsible for the racemization.The molecular structure of (S a )-6b (Figure 1) based on single crystal X-ray diffraction measurements confirms the possibility of the steric arrangement of 9; the proximity of the benzene-connected carboxylic group and the carbonyl oxygen atom of the pyrrole-connected diethylamido group can be seen in this structure.
In order to avoid racemization, another strategy was applied for the preparation of enantiomerically pure (S a )-2a and (S a )-2b (Scheme 5).First, selective reduction of the methoxycarbonyl group of (S a )-5b was carried out with an excess of sodium borohydride while the less reactive diethylamide group remained intact.The primary hydroxyl group of (S a )-11 was transformed into a primary amine function in three steps using the well-known Gabriel synthesis protocol (intermediate (S a )-12).Then the amide group of compound (S a )-13 was reduced with borane-dimethyl sulfide complex.Finally the products (S a )-2a,b were obtained by the addition of the corresponding aryl isothiocyanate to the amine (S a )-14.This procedure provided compounds (S a )-2a and (S a )-2b in enantiomerically pure form (ee >99%, HPLC).The catalytic activities of the new bifunctional atropisomeric compounds ((R a )-1a-f and (S a )-2a,b) were tested in two Michael addition reactions.In the first run β-nitrostyrene (15) was reacted with dibenzoylmethane ( 16) in the presence of 5 mol % of (R a )-1b.The reactions were carried out in different solvents at different temperatures and the yield and ee of product 17 were determined by HPLC measurements (Scheme 6, Table 1).The best ee values were achieved in toluene at about 10-15 o C, and therefore the activities of the other organocatalysts ((R a )-1a-f and (S a )-2a) were tested under these conditions (Table 2).Although it was found that (S a )-2a is the most efficient catalyst for the addition (97 % yield), no asymmetric induction was observed in its use.Compound (S a )-2b was less effective as a catalyst than (S a )-2a, therefore it is not mentioned in Table 2.In the presence of the more rigid (R a )-1 type catalysts each reaction proceeded slower than in the presence of (S a )-2a and a small to medium level of asymmetric inductions were observed.In this respect (R a )-1b seems to be the best among the investigated compounds.Therefore this compound was used to investigate the effect of catalyst concentration.Experimental data showed (Table 2) significant increase of the yield when the amount of (R a )-1b was set up from 1 mol% to 5 and 10 mol%, respectively.In the same time the ee of the product slightly decreased.These observations indicate self association of (R a )-1b in higher concentrations in toluene.
The catalyst associations may serve as more active species in the reactions, but at the same time the greater freedom of connections among the catalyst associations and the two reactants may cause a decrease in the asymmetric induction effect of the catalyst.This phenomenon is known among other thiourea-type organocatalysts too. 37,38The experimental results are collected in Table 3. Regarding the product formation (yields of 19 within the same reaction time), (R a )-1 type catalysts worked slower than the more flexible (S a )-2a which showed the same high activity (95% yield) as in the previous test reaction.Catalyst (R a )-1b provided much lower yields and ee in this case, and the best asymmetric inductions were observed using (R a )-1d and (S a )-2a.

Conclusions
Efficient syntheses of new 1-phenylpyrrole type organocatalysts containing thiourea and tertiary amino groups have been developed.Compounds (R a )-1a-f could be prepared without any racemization.Loss of the conformational stability towards certain chemical transformations of the percussive groups was observed during preparation of (S a )-2a and (S a )-2b, which could be explained by the formation of a tricyclic intermediate ( 9) because of the presence of an activated acyl group which is able to attack the pyrrole-connected amido group.This observation led us to find another stereoconservative route to the target compounds (S a )-2a,b.The synthesized new atropisomeric compounds were successfully tested as organocatalysts.The experimental results of the Michael addition reactions served as proof of concept: compounds (R a )-1b,d and (S a )-2a can be treated as a new class of atropisomeric bifunctional organocatalysts.The more flexible (S a )-2a efficiently catalysed both investigated reactions, the products being formed in 95-97% yields.Reactions were slower with the more rigid (R a )-1b and (R a )-1d catalysts, but they gave higher asymmetric inductions.

Experimental Section
General.All commercial starting materials were purchased from Sigma-Aldrich Kft.Hungary and Merck Kft.Hungary and were used without further purification.The organometallic reactions and the reductions were carried out in Schlenk flasks under dry nitrogen atmosphere.Solvent were typically freshly distilled or dried over molecular sieves.All reactions were monitored by thin-layer chromatography.TLC was carried out on Kieselgel 60 F 254 (Merck) aluminium sheets (visualization of the products was effected by exposing the plate to UV radiation or by staining it with an aqueous solution of (NH 4 ) 6 Mo 7 O 24 , Ce(SO 4 ) 2 and sulfuric acid).Flash column chromatography was performed using a CombiFlash ® (Teledyne ISCO).
Routine 1 H, 13 C and 19 F NMR spectra were obtained on a Bruker AV 300 or DRX 500 spectrometer.The chemical shifts () are reported in parts per million (ppm) and the coupling constants (J) in Hz.Usually deuterated chloroform (CDCl 3 ) was used as the solvent, with chemical shifts measured relative to the signal for TMS ( TMS = 0 ppm for 1 H NMR) and for CDCl 3 ( CDCl3 = 77.0ppm for 13 C NMR).Infrared (IR) spectra were recorded on a Perkin Elmer 1600 appliance with a Fourier Transformer.Data are given in cm -1 .Melting points were determined in capillary tubes, using a Gallenkamp melting point apparatus.The enantiomeric ratios of the optically active samples were determined by high-performance liquid chromatography (HPLC) measurement and by gas chromatography (GC) analysis.HPLC was performed on a Perkin Elmer Series 200 system using a Phenomonex Lux Cellolose-1 or Amylose-2 columns (d 5 m, 250 × 4.6 mm).Specific rotation of the optically active samples were determined on a Perkin Elmer 245 MC polarimeter using sodium lamp (589 nm).Highresolution mass spectra (HRMS) were recorded on Waters LCT Premier XE spectrometer in electrospray ionization (ESI, 2.5 kV) mode, using water (0.035% trifluoroacetic acid)/acetonitrile (0.035% trifluoroacetic acid) as eluent in gradient elution (5%-95% acetonitrile); samples were made up in acetonitrile.Preparation and resolution 31 of dicarboxylic acid (R a ,S a )-3 followed by selective monoesterification 32 of (S a )-3 and multistep transformation of (S a )-4 into the optically active aniline derivatives ((S a )-8a-f) were carried out analogously to the processes developed by our laboratory. 33

Single crystal X-ray measurements (S a )-2-(2-(Diethylcarbamoyl)-1H-pyrrol-1-yl)-3-(trifluoromethyl)benzoic acid ((S a )-6b)
Compound 6b was prepared for single crystal X-ray measurements by hydrolysis of 5b 33 as follows: amido ester (S a )-5b (7.00 mmol, 2.58 g) was dissolved in methanol (25 mL).Sodium hydroxide (21.0 mmol, 0.84 g) was added and the mixture was stirred at room temperature for one day.The reaction was monitored by TLC (in hexane/ethyl acetate = 1/1 (R f,6b = 0.4)).The solvent was evaporated in vacuo.Then water (20 mL) and diethyl ether (15 mL) were added.The phases were separated, the aqueous phase was washed with diethyl ether (2 × 10 mL).A solution of hydrogen chloride (5 M, 10 mL) was added, the precipitate was filtered off and washed with water (20 mL).Cell parameters were determined by least-squares using 20299 (6.86    71.86) reflections. 40 numerical absorption correction 41 was applied to the data (the minimum and maximum transmission factors were 0.628 and 0.759).The structure was solved by direct methods 42 (and subsequent difference syntheses).Anisotropic full-matrix least-squares refinement 42 on F 2 for all non-hydrogen atoms yielded R 1 = 0.0327 and wR 2 = 0.0821 for 1332 [I>2(I)] and R 1 = 0.0343 and wR 2 = 0.0836 for all (3365) intensity data, (number of parameters = 232, goodness-of-fit = 1.096, the maximum and mean shift/esd is 0.000 and 0.000).The absolute structure parameters are: Flack (x) 0.08(3), Hooft (y) 0.08(3), Parsons (z) 43 0.08(3) (Friedel coverage: 0.725, Friedel fraction max.: 0.967, Friedel fraction full: 0.993).The maximum and minimum residual electron density in the final difference map was 0.51 and -0.24e.Å -3 .The weighting scheme applied was 2 )/3.Hydrogen atomic positions were calculated from assumed geometries except H 3 O that was located in difference maps.Hydrogen atoms were included in structure factor calculations but they were not refined.The isotropic displacement parameters of the hydrogen atoms were approximated from the U(eq) value of the atom they were bonded to.ORTEP style molecular structure diagram can be found in Figure 1.
Crystallographic data (including structure factors) for structure 6b have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication no.CCDC 1434065.Copies of the data can be obtained free of charge on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK, (fax: ţ44-(0)1223 336033 or e-mail: deposit@ccdc.cam.ac.uk).Synthesis of thioureas (R a )-1a-f, general procedure.A sample among compounds (S a )-8a-f (0.5 mmol) was dissolved in dry dichloromethane (2 mL) and phenyl isothiocyanate (0.5 mmol, 59.6 μL) or 3,5-bis(trifluoromethyl)phenyl isothiocyanate (0.5 mmol, 91.3 μL) was added.The reaction mixture was stirred for 30 min.The organic solvent was evaporated in vacuo and the residue was purified by flash chromatography.Enantiomeric purities of 1a-f products were checked by HPLC and each samples were pure enantiomers (ee >99%).
The phases was separated, the aqueous phase was washed with dichloromethane (2 × 3 ml), then the collected organic phase was washed with water (2 × 30 ml), dried over sodium sulfate and concentrated under reduce pressure to get the product as a solid.
The residue was dissolved in dry toluene (3 mL) under nitrogen atmosphere and borane dimethylsulfide complex (2.8 mmol, 0.27 mL) was added dropwise.The mixture was stirred for 2 days at 60 ºC.The formation of the product was monitored by TLC (hexane/ethyl acetate = 1/1).Methanol (2 mL) was added dropwise to decompose the excess of borane at room temperature.After the reaction was completed the solvent was evaporated in vacuo and the residue was dissolved in methanol (3 mL).Sodium hydroxide (8.4 mmol, 0.34 g) was added into it, and the mixture was stirred for 5 days at 50 °C.The solvent was evaporated in vacuo, then solution of hydrogen chloride (5 M, 3.5 mL) and diethyl ether (4 mL) was added.After stirring 15 min the aqueous phase was separated.The collected organic phase was washed with water (2 × 3 mL).Sodium hydroxide (30,0 mmol, 1.20 g) and diethyl ether (5 mL) was added to the collected aqueous phase and was extracted with diethyl ether (3 × 5 ml).The collected organic phase was dried over sodium sulfate an concentrated under reduced pressure.The residue (crude (S a )-14) was dissolved in dry dichloromethane (3 mL) and 3,5-bis(trifluoromethyl)phenyl isothiocyanate (0.7 mmol, 128 μL) was added.The reaction mixture was stirred for 30 min.The organic solvent was evaporated in vacuo.General procedure for the addition of 1,3-dicarbonyl-compounds to β-nitrostyrene.β-Nitrostyrene (0.4 mmol, 59.6 mg) was dissolved in the corresponding solvent (60 μL), the chiral catalyst was added at the corresponding temperature.After stirring 10 min dibenzoylmethane (1.0 mmol, 224.2 mg) or acetylacetone (1.0 mmol, 102:7 μl) was added.The mixture was stirred for a week.The solvent was evaporated in vacuo, and the residue was purified by flash chromatography.

Scheme 4 .
Scheme 4. Proposed mechanism of the racemization during acid amide formation.

Figure 1 .Scheme 5 .
Figure 1.The crystallographically independent molecule in the asymmetric unit of the crystal (S a )-6b with the atomic labelling.Displacement ellipsoids are drawn at the 30% probability level (C -black, N -blue, O -red, F -green and H -white).

Scheme 6 .
Scheme 6. Addition of 16 to 15 in the presence of catalysts (R a )-1a-f and (S a )-2a,b.

a
Scheme 7. Addition of 18 to 15 in the presence of catalysts (R a )-1a-f and (S a )-2a,b.

Table 1 .
Solvent and temperature effects on the formation of 17 in the presence of (R a )-1b a Reactions were accomplished in the presence of 5 mol% of 1b catalyst, 7 days reaction time.b Yields and ee values were determined from the crude reaction mixture by HPLC measurements using Phenomenex Lux Cellulose-1 column.

Table 2 .
Effects of structure and amounts of catalyst on the formation of compound 17

Table 3 .
Effect of the catalyst structure on the enantioselective formation of 19 a Each reaction was carried out in toluene over 7 days, in the presence of 5 mol% catalyst, at 10 o C. bYields and ee values were determined from the crude reaction mixture by HPLC measurements using Phenomenex Lux Cellulose-1 column.c Reactions were conducted at 24 o C.