Chlorinated Aldimines As Versatile Polyfunctional Substrates in the Lewis Acid Mediated

Sara Stas

Engelse abstract doctoraatsthesis

Chlorinated aldimines as versatile polyfunctional substrates in the Lewis acid mediated borono Mannich reaction

The nucleophilic 1,2-addition to imines is an important and established reaction in organic synthesis to obtain amines. In the same step a new C-C bond is formed and a stereogenic centre is created. Allylic amines, propargylic amines and homoallylic amines are fundamental building blocks in organic chemistry and their synthesis is an important industrial and synthetic goal. However, in comparison to carbonyl compounds, nucleophilic additions to the C=N bonds encounter much more problems and consequently are rather limited described in the literature, both by the poor electrophilicity of the azo-methine carbon and by the tendency of enolizable imines to undergo deprotonation rather than addition. To overcome these problems and hence perform an 1,2-addition to imines, it is necessary to activate the C=N bond by increasing the electrophilicity of the imino carbon atom. Classical methodologies for the preparation of propargylic amines have usually exploited the high acidity of a terminal acetylenic C-H bond to form the metal acetylide by reaction with strong bases. Zinc and copper mediated alkyne additions occur under milder conditions but external promoters (base, cocatalyst, ligand) are usually necessary before addition to C=N can take place; moreover, addition very often only takes place with activated N-substituted imines (iminium salts, nitrones, acylimines, sulfonimines) or N-coordinated imines (coordination of the nitrogen lone pair with a Lewis acid). Similarly, allyl metal complexes (AllylMgX or AllylX/M) add to imines and provide an entry to homoallylic amines. However, the basic reagents employed in such reactions are very often incompatible with sensitive substrates like functionalized imines.

The boronic acid Mannich reaction (BAM-reaction, also referred to as Petasis reaction, named after its inventor) is a powerful and mild one-pot, three-component condensation reaction between aldehydes, amines and boronic acids. Applying vinyl boronic acids in the Petasis reaction lead to the formation of allylamines. However, up till now this method remained limited to a brief number of aldehydes, mostly non-enolizable, all containing a functional group or a heteroatom in a- or ortho-position which serves as an anchor for the boron compound. Because of this limitation it is regarded highly interesting to extend the boronic acid Mannich reaction to the use of other carbonyl compounds. Therefore, in this PhD thesis the possibility is investigated to use functionalized, non-enolizable a-chlorinated carbonyl compounds in a borono Mannich reaction, in order to obtain a new class of halogenated amines, which are of great importance in the organic chemistry and find mostly applications in agrochemistry and pharmaceutical industry.

First, 2,2-dichloroalkanals 1 were reacted with morpholine and aryl boronic acids 2 under classical Petasis reaction conditions (equimolar, one-pot reaction in refluxing toluene). Instead of the expected b,b-dichlorinated Mannich bases, 1-aryl-1-morpholinopropan-2-ones 4 were obtained (18-63%). In this conversion, the dichloromethylene group of the 2,2-dichloroalkanals is formally converted into a ketone functionality, and thus acts as a masked carbonyl group. This conversion probably occurs through intermediate amino epoxide 3 (Scheme 1). The reaction, however, was limited to the use of morpholine as amine component and the yields of the obtained products were relatively low (18-63%). In an attempt to extend the Petasis reaction of 2,2-dichloropropanal (1, R1 = Me) with morpholine to the use of the more reactive styryl boronic acid, it was noticed that the corresponding 3-morpholino-5-phenylpent-4-en-2-one (5) was only formed in CH2Cl2 or CHCl3 and that the yields were also low (23-31%). Purification of the a-morpholinoketones by flash chromatography on silica gel had a deleterious effect on the yields (2-24%).

Scheme 1: Boronic acid Mannich reaction of 2,2-dichloroalkanals, morpholine and organo boronic acids

Because of the diverging results, disappointing yields, limitation in possible reagents and problems with purification encountered in this reaction of boronic acids with 2,2-dichloroalkanals, it was tried to extend the borono Mannich reaction to the use of the corresponding imines of the a,a-dichloroaldehydes as carbonyl equivalents. Different N-(2,2-dichloro-1-propylidene)amines 6 were evaluated as substrates in a reaction with potassium arylethynyltrifluoroborates 7 and potassium (2-aryl)vinyltrifluoroborates 8 in the presence of BF3·OEt2. It was gratifying to observe that this reaction did lead to the envisaged new class of dichlorinated secondary propargylic 11 and allylic 12 amines. The reaction mechanism of this Lewis acid promoted Petasis type reaction of a,a-dichloroaldimines with organotrifluoroborates was unravelled by identifying the intermediate compounds of this reaction by means of 11B and 19F NMR. The reaction starts with the formation of the very electrophilic difluoroborane 9, generated in situ from the corresponding potassium organotrifluoroborate and BF3·OEt2, which coordinates with the imine. Then, the organic part of the difluoroborane 9 is transferred to the activated imino carbon atom to give aminodifluoroborane 10 which upon alkaline aqueous workup is converted into the desired b,b-dichloroamine. In case of reactions with potassium (2-aryl)vinyltrifluoroborates 8 a remarkable solvent effect was observed. When the reaction was performed in dichloromethane with HFIP as cosolvent (CH2Cl2/HFIP (9/1)) the yields of Mannich products 12 were situated in the range 62-74%. The same borono Mannich reactions in pure CH2Cl2 furnished b,b-dichloro-a-(2-arylvinyl)amines 12 in only 9-46% yield. By using the more reactive potassium arylethynyltrifluoroborates 7 the same good yields (72-90%) of Mannich products 11 were obtained in the reactions with HFIP as cosolvent as when no HFIP was added. b,b-Dichloroamines 11 (obtained in reaction without HFIP) and 12 (obtained in reaction with HFIP) were isolated in very high purity (>95%) so that no extra purification was required. Scheme 2 gives an overview of the functionalized dichlorinated propargyl- and allylamines obtained in the Lewis acid promoted Petasis type reaction of N-(2,2-dichloro-1-propylidene)amines 6 with respectively arylethynyltrifluoroborates 7 and (2-aryl)vinyltrifluoroborates 8.

The (E)-geometry of the (2-aryl)vinyltrifluoroborates did not change during the reaction. Aliphatic alkenyl- and alkynyltrifluoroborates did not always react with a,a-dichloroaldimines in the presence of BF3·OEt2 and yields of the few obtained aliphatic Mannich products were rather low (17-44%), probably due to a combination of the low reactivity of the trifluoroborate in the Petasis reaction and the volatility of the Mannich product. Aryltrifluoroborates turned out not to be reactive in the Lewis acid mediated Petasis type reaction with a,a-dichloroaldimines.

Upon addition of the vinyl or ethynyl group to the imino carbon atom, a new chiral centre was created. Reactions with enantiomerically pure N-(2,2-dichloro-1-propylidene)-(R or S)-a-methylbenzylamines resulted in 50/50 mixtures of the two possible diastereomers, indicating that this particular Lewis acid promoted Petasis type reaction is not stereoselective.

Scheme 2: Lewis acid promoted Petasis type reaction of N-(2,2-dichloro-1-propylidene)amines with potassium organotrifluoroborates

Extension of this Petasis reaction to other N-(2,2-dichloro-1-alkylidene)amines did not occur smoothly and refluxing of the reaction mixture was necessary to induce any reaction, but the yields remained low (9-24%) and more side products were formed.

Because complexation of the difluoroborane with the imino nitrogen atom facilitates the transfer of the alkenyl or alkynyl group to the imino carbon atom, it was expected that the same Lewis acid promoted borono Mannich reaction with a,a,a-trichloroaldimines 13 would proceed as well, if not better, because of the even more electron-withdrawing capacity of the trichloromethyl group. N-Alkyl-(4,4,4-trichloro-1-phenylbut-1-yn-3-yl)amines 14 and N-alkyl-(4,4,4-trichloro-1-phenylbut-1-en-3-yl)amines 15 were obtained in good yields (55-69%), but yields of the corresponding b,b-dichloroamines were slightly better (Scheme 3).

Scheme 3: Lewis acid promoted Petasis type reaction of N-(2,2,2-trichloro-1-ethylidene)amines with potassium organotrifluoroborates

The behaviour of a-monochloroaldimines in the Lewis acid promoted borono Mannich reaction with potassium organotrifluoroborates was also evaluated (Scheme 4). When N-(2-chloro-1-alkylidene)amines 16 were used in the Petasis reaction with phenylethynyltrifluoroborate, b-monochloro-a-phenylethynylamines 17 were obtained in moderate yields (21-54%) and without any trace of the corresponding aziridines. Petasis reactions of a-monochloroaldimines 16 with (2-phenyl)vinyltrifluoroborate and BF3·OEt2, resulted in complex reaction mixtures. When no HFIP was used as additive, indications were present in the 1H NMR spectra that besides the expected b-chloroamines 18 also the corresponding vinylaziridines 19 were formed. Purification of these two compounds remains a challenge: flash chromatography (SiO2) and high vacuum distillation were too drastic methods to separate both Mannich products and led to degradation of the reaction products.

Scheme 4: Lewis acid promoted Petasis type reaction of N-(2-chloro-1-alkylidene)amines with potassium organotrifluoroborates

When N-3-butenyl-(2,2-dichloro-1-propylidene)amine (20) was subjected to the optimal conditions of the newly developed Lewis acid mediated borono Mannich reaction, the rearranged Mannich products 23 and 24 were obtained by a tandem cationic 2-aza-Cope rearrangement - Lewis acid promoted Petasis type reaction (Scheme 5). After all, due to the presence of the homoallyl moiety, iminium salt 21, formed by complexation of imine 20 with the in situ generated organodifluoroborane, can participate in a cationic 2-aza-Cope rearrangement. The obtained rearranged formaldiminium ion 22 is more prone for nucleophilic attack by the organic moiety of the difluoroborane, than the sigmatropic isomer 21. The Lewis acid promoted borono Mannich reaction thus takes place on the rearranged imine, resulting in Mannich products 23 and 24.

Scheme 5: Tandem cationic 2-aza-Cope rearrangement - Lewis acid promoted Petasis type reaction

Extension of the Lewis acid mediated Petasis reaction to a,a,w-trichloroaldimines 25, bearing an extra chloro atom in w-position, resulted in reaction products, b,b,w-trichloroamines 26 and 27, which have a huge potential to form aza-heterocycles. It was indeed proved that during the Petasis reaction the non-ring closed intermediate aminodifluoroboranes are formed which upon aqueous workup turn into the corresponding secondary amines 26 and 27. Subsequently, intramolecular nucleophilic substitution of the w-chloro atom by the amine moiety immediately takes place and aza-heterocyclic compounds become available. The presence of the remaining halogens on the ring and the unsaturation (double or triple bond) would then allow further transformations towards potential physiologically active compounds.

Reaction of N-(2,2,4-trichloro-1-butylidene)amines 25a with potassium phenylethynyl- and (2-phenyl)vinyltrifluoroborates in the presence of BF3·OEt2 resulted exclusively in the corresponding pyrrolidines 28 and 29 in moderate to good yields (Scheme 6). In both cases yields of pyrrolidines with less sterically hindered N-atoms (R = Allyl, Et, Me) were higher than yields of pyrrolidines with bulkier N-substituents (R = tBu, iPr). Purification by flash chromatography (SiO2) led to a decrease in yield.

Scheme 6: Synthesis of substituted 3,3-dichloropyrrolidines

Petasis reactions of N-(2,2,5-trichloro-1-pentylidene)amines 25b with trifluoroborates gave mixtures of non-ring closed b,b,w-trichlorinated amines 26b and 27b and the corresponding piperidines 30 and 31, the latter product being the main compound only in case of imines with a less sterically hindered nitrogen atom (R = Allyl, Et) (Scheme 7). When the reaction mixtures, obtained after the Petasis reaction, were additionally refluxed in iPrOH (5-18 h), the reaction was forced completely towards the envisaged piperidines in good yields, except for the amines with bulky nitrogen substituents (R = tBu, iPr) which remained present as open Mannich products alone or as mixtures of open Mannich product and piperidine.

Scheme 7: Synthesis of substituted 3,3-dichloropiperidines

The Lewis acid promoted Petasis type reactions of N-(2,2,6-trichloro-1-hexylidene)amines 25c with potassium organotrifluoroborates resulted exclusively in the non-ring closed Mannich products 26c and 27c (Scheme 8). Attempts to obtain the corresponding 3,3-dichloroazepanes failed.

Scheme 8: Synthesis of N-alkyl-(4,4,8-trichloro-1-phenyloct-1-en/yn-3-yl)amines

The tandem cationic 2-aza-Cope rearrangement - Lewis acid promoted Petasis type reaction with N-3-butenyl-(2,2,w-trichloro-1-alkylidene)amines 32 was also explored (Scheme 9). During these reactions three mechanisms are combined: aza-Cope rearrangement of the N-homoallylimine, borono Mannich reaction on the obtained formaldimine and finally, intramolecular ring closure by nucleophilic substitution of the w-chloro atom. The latter step only occured for the synthesis of pyrrolidines and piperidines. Substituted 3,3-dichloro-2-(2-propenyl)pyrrolidines 33 were obtained in moderate yields (27-32%, prep RP-HPLC), just like the non-ring closed N-(5,5,9-trichloronon-1-en-4-yl)amines 34 (29-39%, prep RP-HPLC). 3,3-Dichloropiperidines 35 were formed in very complex reaction mixtures in the presence of the rearranged trichlorinated Mannich products 36. The yields of the purified (prep RP-HPLC) rearranged Mannich products 35 and 36 were very low, especially for the reactions with (2-phenyl)vinyltrifluoroborate. Attempts to force the reaction towards piperidine as single product by additionally refluxing of the mixture in iPrOH, led only to more complex mixtures.

Scheme 9: Cationic 2-aza-Cope rearrangement - Lewis acid promoted Petasis type reaction - ring closure tandem process

In a next stage the reactivity and possible applications of the Mannich products formed during the Lewis acid promoted Petasis type reaction of a-chlorinated aldimines with potassium organotrifluoroborates were investigated. The stability of the acyclic chlorinated amines towards a range of bases and acids was examined. When b,b-dichloroamines 11 and 12 and b,b,b-trichloroamines 14 and 15 were treated with KOtBu, dehydrochlorinations occurred, resulting in a-chloroketimines 39 with a purity of more than 85% (Scheme 10). Two possible reaction mechanisms were proposed to execute HCl elimination: 1,2-dehydrochlorination to the b-chloroenamine 37 which is in tautomeric equilibrium with ketimine 39; or deprotonation of NH and subsequent formation of the intermediate azirinium chloride 38 which upon rearrangement and consecutive attack of the chloride anion results in ketimine 39. NaOR (R = Me, Et) turned out to be less suitable to induce dehydrochlorinations within b,b-dichloro- and b,b,b-trichloroamines in view of the lower yields and purities of the corresponding ketimines. NaH, MeMgCl, Et3N and propylamine were not reactive towards the b-chlorinated amines and the strong bases BuLi and LDA led to degradation of the product. Hydrolysis of the a-chloroketimines to the corresponding a-chloroketones 40 occurred smoothly in the biphase system CH2Cl2/4 N HCl or with (COOH)2 in CH2Cl2/H2O. When N-(4-chloro-1-phenylpent-1-yn-3-ylidene)amines 39a were treated with HCl (4 N), the corresponding a-chloroketones 40a were formed as intermediate compounds which after addition of HCl to the alkynyl moiety were turned into 1,4-dichloro-1-phenylpent-1-en-3-on (41). As well the a-chloroimines 39 as the a-chloroketones 40 were instable compounds and could not be stored (-20 °C, under argon) for long time. Moreover, the purification of both compounds remains a drawback: purification of a-chloroketimines 39 by distillation resulted in degradation of the product while purification of a-chloroketones 40 by flash chromatography on silica gel decreased the yield.