Organocatalytic Asymmetric Α-chlorination of 1,3-dicarbonyl Compounds Catalyzed by 2-aminobenzimidazole Derivatives

Bifunctional chiral 2-aminobenzimidazole derivatives 1 and 2 catalyze the enantioselective stereodivergent α-chlorination of β-ketoesters and 1,3-diketone derivatives with up to 50% ee using N-chlorosuccinimide (NCS) or 2,3,4,4,5,6-hexachloro-2,5-cyclohexadien-1-one as electrophilic chlorine sources.


Results and Discussion
To identify the best organocatalyst (0.01 mmol, 10 mol%) and reaction conditions, the chlorination of ethyl 2-oxocyclopentanecarboxylate (0.125 mmol) in toluene with N-chlorosuccinimide (NCS, 0.1 mmol) was chosen as the model reaction (Table 1).Besides chiral benzimidazoles 1 and 2, we also studied catalyst 3, easily prepared from 2-chlorobenzimidazole and (R)-1-phenylethan-1-amine. Catalyst 1 afforded the desired compound 5a in excellent conversion but nearly no enantioselectivity when working at room temperature (Table 1, entry 1).Examination of the effect of temperature revealed that lowering of the temperature to −50 °C significantly improved the enantioselectivity, being 5a obtained with a promising 95% isolated yield and a 40% ee when C2-symmetric chiral benzimidazole 2 was used as catalyst (entry 3).No further improvement was detected at lower temperatures (−78 °C) (Table 1, entry 4).

Results and Discussion
To identify the best organocatalyst (0.01 mmol, 10 mol%) and reaction conditions, the chlorination of ethyl 2-oxocyclopentanecarboxylate (0.125 mmol) in toluene with N-chlorosuccinimide (NCS, 0.1 mmol) was chosen as the model reaction (Table 1).Besides chiral benzimidazoles 1 and 2, we also studied catalyst 3, easily prepared from 2-chlorobenzimidazole and (R)-1-phenylethan-1-amine. Catalyst 1 afforded the desired compound 5a in excellent conversion but nearly no enantioselectivity when working at room temperature (Table 1, entry 1).Examination of the effect of temperature revealed that lowering of the temperature to ´50 ˝C significantly improved the enantioselectivity, being 5a obtained with a promising 95% isolated yield and a 40% ee when C 2 -symmetric chiral benzimidazole 2 was used as catalyst (entry 3).No further improvement was detected at lower temperatures (´78 ˝C) (Table 1, entry 4).very active and selective organocatalysts for the asymmetric functionalization of 1,3-dicarbonyl compounds (Figure 1).Through a bifunctional Brønsted base/hydrogen bonding activation, these catalysts have afforded excellent enantioselectivities in the conjugate addition of malonates, 1,3-diketones, and β-ketoesters to nitroolefins [31] and maleimides [32,33].Also, catalyst 1 has shown enantioselectivities of up to 92% in the α-amination of cyclic β-ketoesters with azodicarboxylates [34].Based on the good selectivities obtained so far with our 2-aminobenzimidazole-derived catalysts, in this work we describe an enantioselective procedure for the α-chlorination of cyclic 1,3-dicarbonyl compounds (Figure 1).
After the exhaustive search for the optimal reaction conditions, and in view of the results, two procedures for the asymmetric chlorination of 1,3-dicarbonyl compounds were established, namely methods A and B [36].The first one (Method A) implies the use of 10 mol% of catalyst 1 and 2,3,4,5,6,6-hexachlorocyclohexa-2,4-dienone as an electrophilic chlorine source, while Method B involves a 10 mol% of catalyst 2 in combination with NCS as a chlorinating agent [37].In both methods the reaction was performed in toluene at −50 °C.Next, with these optimal conditions in place, the scope of the reaction was evaluated (Table 3).
As previously described, ketoester 4a was effectively chlorinated under both methods although with moderate enantioselectivities (Table 3, entries 1 and 2).The influence of a bulkier substituent in the ester moiety was next evaluated.Thus, the tert-butyl derivative 4b was submitted to the optimized reaction conditions achieving high yields in both cases although with an opposite behavior in the enantioselectivity.Thus, whereas the use of this substrate produced a drop in the ee compared to the less sterically crowded analogue 4a when Method A conditions were applied, a small enhancement of the optical purity was observed for the case of Method B (Table 3, entries 3 and 4).By the contrary, six-membered ketoester 4c only rendered the corresponding chlorinated product 5c with some enantioselectivity (39% ee) when Method A conditions were employed (Table 3, entries 5 and 6).Benzocondensed β-ketoesters were next taken into account.When compound 4d was submitted to chlorination, high yields and poor to moderate enantioselectivities were obtained in both cases, being slightly better the results obtained under Method A conditions (Table 3, entries 7 and 8).Next, methyl ester 4e was tested obtaining high yield and moderate enantioselectivity (40% ee) using Method A (Table 3, entry 9).A parallel behavior to that observed with the non-benzocondensed analogue was obtained with Method B, namely excellent yield and poor enantioselectivity (Table 3, entry 10).The replacement of methyl by an ethyl group in the ester moiety produced an enhancement in the enantioselectivity in both methods (Table 3, entries 11 and 12), reaching up to 50% ee when Method A was used.Next, the more reactive 1,3-diketones were essayed.As somewhat expected due to the high reactivity of this type of nucleophiles, almost no enantioselection was observed when compounds 4g and 4h were tested regardless of the method employed (Table 3, entries 13-16).Obtaining the best enantioselectivities when ketoester 4f was employed as a nucleophile led us to test 2-acetyl-1-tetralone 4i as a substrate.Unfortunately, only poor enantioselectivities at best were also obtained (Table 3, entries 17 and 18).The results obtained so far demonstrate that the studied catalytic chlorination reaction is quite sensitive to the catalyst/electrophile combination, obtaining the best results when combining catalyst 1 with 2,3,4,5,6,6-hexachlorocyclohexa-2,4-dien-1-one and catalyst 2 with NCS or N-chlorophthalimide.With these two catalytic systems in our hands, we continued the optimization of the reaction conditions which led to the best enantioselectivity (47% ee) using a 20 mol% of catalyst 2 at −50 °C and using NCS as chlorinating reagent (entry 14).Unfortunately, this result could not be improved any further by using other different solvents, such as methylene chloride, hexane, diethyl ether, and methanol, acid additives such as TFA (Table 2, entry 15), or other basic additives such as, NaHCO3 and TEA which have been previously demonstrated to accelerate the turnover of the catalyst [21].
After the exhaustive search for the optimal reaction conditions, and in view of the results, two procedures for the asymmetric chlorination of 1,3-dicarbonyl compounds were established, namely methods A and B [36].The first one (Method A) implies the use of 10 mol% of catalyst 1 and 2,3,4,5,6,6-hexachlorocyclohexa-2,4-dienone as an electrophilic chlorine source, while Method B involves a 10 mol% of catalyst 2 in combination with NCS as a chlorinating agent [37].In both methods the reaction was performed in toluene at −50 °C.Next, with these optimal conditions in place, the scope of the reaction was evaluated (Table 3).
As previously described, ketoester 4a was effectively chlorinated under both methods although with moderate enantioselectivities (Table 3, entries 1 and 2).The influence of a bulkier substituent in the ester moiety was next evaluated.Thus, the tert-butyl derivative 4b was submitted to the optimized reaction conditions achieving high yields in both cases although with an opposite behavior in the enantioselectivity.Thus, whereas the use of this substrate produced a drop in the ee compared to the less sterically crowded analogue 4a when Method A conditions were applied, a small enhancement of the optical purity was observed for the case of Method B (Table 3, entries 3 and 4).By the contrary, six-membered ketoester 4c only rendered the corresponding chlorinated product 5c with some enantioselectivity (39% ee) when Method A conditions were employed (Table 3, entries 5 and 6).Benzocondensed β-ketoesters were next taken into account.When compound 4d was submitted to chlorination, high yields and poor to moderate enantioselectivities were obtained in both cases, being slightly better the results obtained under Method A conditions (Table 3, entries 7 and 8).Next, methyl ester 4e was tested obtaining high yield and moderate enantioselectivity (40% ee) using Method A (Table 3, entry 9).A parallel behavior to that observed with the non-benzocondensed analogue was obtained with Method B, namely excellent yield and poor enantioselectivity (Table 3, entry 10).The replacement of methyl by an ethyl group in the ester moiety produced an enhancement in the enantioselectivity in both methods (Table 3, entries 11 and 12), reaching up to 50% ee when Method A was used.Next, the more reactive 1,3-diketones were essayed.As somewhat expected due to the high reactivity of this type of nucleophiles, almost no enantioselection was observed when compounds 4g and 4h were tested regardless of the method employed (Table 3, entries [13][14][15][16].Obtaining the best enantioselectivities when ketoester 4f was employed as a nucleophile led us to test 2-acetyl-1-tetralone 4i as a substrate.Unfortunately, only poor enantioselectivities at best were also obtained (Table 3, entries 17 and 18).The results obtained so far demonstrate that the studied catalytic chlorination reaction is quite sensitive to the catalyst/electrophile combination, obtaining the best results when combining catalyst 1 with 2,3,4,5,6,6-hexachlorocyclohexa-2,4-dien-1-one and catalyst 2 with NCS or N-chlorophthalimide.With these two catalytic systems in our hands, we continued the optimization of the reaction conditions which led to the best enantioselectivity (47% ee) using a 20 mol% of catalyst 2 at ´50 ˝C and using NCS as chlorinating reagent (entry 14).Unfortunately, this result could not be improved any further by using other different solvents, such as methylene chloride, hexane, diethyl ether, and methanol, acid additives such as TFA (Table 2, entry 15), or other basic additives such as, NaHCO 3 and TEA which have been previously demonstrated to accelerate the turnover of the catalyst [21].
After the exhaustive search for the optimal reaction conditions, and in view of the results, two procedures for the asymmetric chlorination of 1,3-dicarbonyl compounds were established, namely methods A and B [36].The first one (Method A) implies the use of 10 mol% of catalyst 1 and 2,3,4,5,6,6-hexachlorocyclohexa-2,4-dienone as an electrophilic chlorine source, while Method B involves a 10 mol% of catalyst 2 in combination with NCS as a chlorinating agent [37].In both methods the reaction was performed in toluene at ´50 ˝C.Next, with these optimal conditions in place, the scope of the reaction was evaluated (Table 3).
As previously described, ketoester 4a was effectively chlorinated under both methods although with moderate enantioselectivities (Table 3, entries 1 and 2).The influence of a bulkier substituent in the ester moiety was next evaluated.Thus, the tert-butyl derivative 4b was submitted to the optimized reaction conditions achieving high yields in both cases although with an opposite behavior in the enantioselectivity.Thus, whereas the use of this substrate produced a drop in the ee compared to the less sterically crowded analogue 4a when Method A conditions were applied, a small enhancement of the optical purity was observed for the case of Method B (Table 3, entries 3 and 4).By the contrary, six-membered ketoester 4c only rendered the corresponding chlorinated product 5c with some enantioselectivity (39% ee) when Method A conditions were employed (Table 3, entries 5 and 6).Benzocondensed β-ketoesters were next taken into account.When compound 4d was submitted to chlorination, high yields and poor to moderate enantioselectivities were obtained in both cases, being slightly better the results obtained under Method A conditions (Table 3, entries 7 and 8).Next, methyl ester 4e was tested obtaining high yield and moderate enantioselectivity (40% ee) using Method A (Table 3, entry 9).A parallel behavior to that observed with the non-benzocondensed analogue was obtained with Method B, namely excellent yield and poor enantioselectivity (Table 3, entry 10).The replacement of methyl by an ethyl group in the ester moiety produced an enhancement in the enantioselectivity in both methods (Table 3, entries 11 and 12), reaching up to 50% ee when Method A was used.Next, the more reactive 1,3-diketones were essayed.As somewhat expected due to the high reactivity of this type of nucleophiles, almost no enantioselection was observed when compounds 4g and 4h were tested regardless of the method employed (Table 3, entries [13][14][15][16].Obtaining the best enantioselectivities when ketoester 4f was employed as a nucleophile led us to test 2-acetyl-1-tetralone 4i as a substrate.Unfortunately, only poor enantioselectivities at best were also obtained (Table 3, entries 17 and 18).Remarkably, from experimental evidence it was observed that the opposite configuration in the chlorinated product was obtained when using method A and B, despite both catalysts 1 and 2 being derived from the same (1R,2R)-cyclohexane-1,2-diamine.Thus, Method A rendered the (S)-configured product, whereas Method B gave rise to the chlorinated (R)-product.However, this switch in the final configuration does not seem to be a consequence of the catalysts configuration but of the nature of the chlorinating agent which would produce a different arrangement of the rather participating species in the transition state.This assumption was based on the fact that the reaction using catalyst 1 with NCS and 2,3,4,5,6,6-hexachlorocyclohexa-2,4-dienone as chlorine source rendered   Remarkably, from experimental evidence it was observed that the opposite configuration in the chlorinated product was obtained when using method A and B, despite both catalysts 1 and 2 being derived from the same (1R,2R)-cyclohexane-1,2-diamine.Thus, Method A rendered the (S)-configured product, whereas Method B gave rise to the chlorinated (R)-product.However, this switch in the final configuration does not seem to be a consequence of the catalysts configuration but of the nature of the chlorinating agent which would produce a different arrangement of the rather participating species in the transition state.This assumption was based on the fact that the reaction using catalyst 1 with NCS and 2,3,4,5,6,6-hexachlorocyclohexa-2,4-dienone as chlorine source rendered   Remarkably, from experimental evidence it was observed that the opposite configuration in the chlorinated product was obtained when using method A and B, despite both catalysts 1 and 2 being derived from the same (1R,2R)-cyclohexane-1,2-diamine.Thus, Method A rendered the (S)-configured product, whereas Method B gave rise to the chlorinated (R)-product.However, this switch in the final configuration does not seem to be a consequence of the catalysts configuration but of the nature of the chlorinating agent which would produce a different arrangement of the rather participating species in the transition state.This assumption was based on the fact that the reaction using catalyst 1 with NCS and 2,3,4,5,6,6-hexachlorocyclohexa-2,4-dienone as chlorine source rendered   Remarkably, from experimental evidence it was observed that the opposite configuration in the chlorinated product was obtained when using method A and B, despite both catalysts 1 and 2 being derived from the same (1R,2R)-cyclohexane-1,2-diamine.Thus, Method A rendered the (S)-configured product, whereas Method B gave rise to the chlorinated (R)-product.However, this switch in the final configuration does not seem to be a consequence of the catalysts configuration but of the nature of the chlorinating agent which would produce a different arrangement of the rather participating species in the transition state.This assumption was based on the fact that the reaction using catalyst 1 with NCS and 2,3,4,5,6,6-hexachlorocyclohexa-2,4-dienone as chlorine source rendered   Remarkably, from experimental evidence it was observed that the opposite configuration in the chlorinated product was obtained when using method A and B, despite both catalysts 1 and 2 being derived from the same (1R,2R)-cyclohexane-1,2-diamine.Thus, Method A rendered the (S)-configured product, whereas Method B gave rise to the chlorinated (R)-product.However, this switch in the final configuration does not seem to be a consequence of the catalysts configuration but of the nature of the chlorinating agent which would produce a different arrangement of the rather participating species in the transition state.This assumption was based on the fact that the reaction using catalyst 1 with NCS and 2,3,4,5,6,6-hexachlorocyclohexa-2,4-dienone as chlorine source rendered   Remarkably, from experimental evidence it was observed that the opposite configuration in the chlorinated product was obtained when using method A and B, despite both catalysts 1 and 2 being derived from the same (1R,2R)-cyclohexane-1,2-diamine.Thus, Method A rendered the (S)-configured product, whereas Method B gave rise to the chlorinated (R)-product.However, this switch in the final configuration does not seem to be a consequence of the catalysts configuration but of the nature of the chlorinating agent which would produce a different arrangement of the rather participating species in the transition state.This assumption was based on the fact that the reaction using catalyst 1 with NCS and 2,3,4,5,6,6-hexachlorocyclohexa-2,4-dienone as chlorine source rendered   Remarkably, from experimental evidence it was observed that the opposite configuration in the chlorinated product was obtained when using method A and B, despite both catalysts 1 and 2 being derived from the same (1R,2R)-cyclohexane-1,2-diamine.Thus, Method A rendered the (S)-configured product, whereas Method B gave rise to the chlorinated (R)-product.However, this switch in the final configuration does not seem to be a consequence of the catalysts configuration but of the nature of the chlorinating agent which would produce a different arrangement of the rather participating species in the transition state.This assumption was based on the fact that the reaction using catalyst 1 with NCS and 2,3,4,5,6,6-hexachlorocyclohexa-2,4-dienone as chlorine source rendered   Remarkably, from experimental evidence it was observed that the opposite configuration in the chlorinated product was obtained when using method A and B, despite both catalysts 1 and 2 being derived from the same (1R,2R)-cyclohexane-1,2-diamine.Thus, Method A rendered the (S)-configured product, whereas Method B gave rise to the chlorinated (R)-product.However, this switch in the final configuration does not seem to be a consequence of the catalysts configuration but of the nature of the chlorinating agent which would produce a different arrangement of the rather participating species in the transition state.This assumption was based on the fact that the reaction using catalyst 1 with NCS and 2,3,4,5,6,6-hexachlorocyclohexa-2,4-dienone as chlorine source rendered   Remarkably, from experimental evidence it was observed that the opposite configuration in the chlorinated product was obtained when using method A and B, despite both catalysts 1 and 2 being derived from the same (1R,2R)-cyclohexane-1,2-diamine.Thus, Method A rendered the (S)-configured product, whereas Method B gave rise to the chlorinated (R)-product.However, this switch in the final configuration does not seem to be a consequence of the catalysts configuration but of the nature of the chlorinating agent which would produce a different arrangement of the rather participating species in the transition state.This assumption was based on the fact that the reaction using catalyst 1 with NCS and 2,3,4,5,6,6-hexachlorocyclohexa-2,4-dienone as chlorine source rendered   Remarkably, from experimental evidence it was observed that the opposite configuration in the chlorinated product was obtained when using method A and B, despite both catalysts 1 and 2 being derived from the same (1R,2R)-cyclohexane-1,2-diamine.Thus, Method A rendered the (S)-configured product, whereas Method B gave rise to the chlorinated (R)-product.However, this switch in the final configuration does not seem to be a consequence of the catalysts configuration but of the nature of the chlorinating agent which would produce a different arrangement of the rather participating species in the transition state.This assumption was based on the fact that the reaction using catalyst 1 with NCS and 2,3,4,5,6,6-hexachlorocyclohexa-2,4-dienone as chlorine source rendered   Remarkably, from experimental evidence it was observed that the opposite configuration in the chlorinated product was obtained when using method A and B, despite both catalysts 1 and 2 being derived from the same (1R,2R)-cyclohexane-1,2-diamine.Thus, Method A rendered the (S)-configured product, whereas Method B gave rise to the chlorinated (R)-product.However, this switch in the final configuration does not seem to be a consequence of the catalysts configuration but of the nature of the chlorinating agent which would produce a different arrangement of the rather participating species in the transition state.This assumption was based on the fact that the reaction using catalyst 1 with NCS and 2,3,4,5,6,6-hexachlorocyclohexa-2,4-dienone as chlorine source rendered   Remarkably, from experimental evidence it was observed that the opposite configuration in the chlorinated product was obtained when using method A and B, despite both catalysts 1 and 2 being derived from the same (1R,2R)-cyclohexane-1,2-diamine.Thus, Method A rendered the (S)-configured product, whereas Method B gave rise to the chlorinated (R)-product.However, this switch in the final configuration does not seem to be a consequence of the catalysts configuration but of the nature of the chlorinating agent which would produce a different arrangement of the rather participating species in the transition state.This assumption was based on the fact that the reaction using catalyst 1 with NCS and 2,3,4,5,6,6-hexachlorocyclohexa-2,4-dienone as chlorine source rendered   Remarkably, from experimental evidence it was observed that the opposite configuration in the chlorinated product was obtained when using method A and B, despite both catalysts 1 and 2 being derived from the same (1R,2R)-cyclohexane-1,2-diamine.Thus, Method A rendered the (S)-configured product, whereas Method B gave rise to the chlorinated (R)-product.However, this switch in the final configuration does not seem to be a consequence of the catalysts configuration but of the nature of the chlorinating agent which would produce a different arrangement of the rather participating species in the transition state.This assumption was based on the fact that the reaction using catalyst 1 with NCS and 2,3,4,5,6,6-hexachlorocyclohexa-2,4-dienone as chlorine source rendered   Remarkably, from experimental evidence it was observed that the opposite configuration in the chlorinated product was obtained when using method A and B, despite both catalysts 1 and 2 being derived from the same (1R,2R)-cyclohexane-1,2-diamine.Thus, Method A rendered the (S)-configured product, whereas Method B gave rise to the chlorinated (R)-product.However, this switch in the final configuration does not seem to be a consequence of the catalysts configuration but of the nature of the chlorinating agent which would produce a different arrangement of the rather participating species in the transition state.This assumption was based on the fact that the reaction using catalyst 1 with NCS and 2,3,4,5,6,6-hexachlorocyclohexa-2,4-dienone as chlorine source rendered   Remarkably, from experimental evidence it was observed that the opposite configuration in the chlorinated product was obtained when using method A and B, despite both catalysts 1 and 2 being derived from the same (1R,2R)-cyclohexane-1,2-diamine.Thus, Method A rendered the (S)-configured product, whereas Method B gave rise to the chlorinated (R)-product.However, this switch in the final configuration does not seem to be a consequence of the catalysts configuration but of the nature of the chlorinating agent which would produce a different arrangement of the rather participating species in the transition state.This assumption was based on the fact that the reaction using catalyst 1 with NCS and 2,3,4,5,6,6-hexachlorocyclohexa-2,4-dienone as chlorine source rendered   Remarkably, from experimental evidence it was observed that the opposite configuration in the chlorinated product was obtained when using method A and B, despite both catalysts 1 and 2 being derived from the same (1R,2R)-cyclohexane-1,2-diamine.Thus, Method A rendered the (S)-configured product, whereas Method B gave rise to the chlorinated (R)-product.However, this switch in the final configuration does not seem to be a consequence of the catalysts configuration but of the nature of the chlorinating agent which would produce a different arrangement of the rather participating species in the transition state.This assumption was based on the fact that the reaction using catalyst 1 with NCS and 2,3,4,5,6,6-hexachlorocyclohexa-2,4-dienone as chlorine source rendered   Remarkably, from experimental evidence it was observed that the opposite configuration in the chlorinated product was obtained when using method A and B, despite both catalysts 1 and 2 being derived from the same (1R,2R)-cyclohexane-1,2-diamine.Thus, Method A rendered the (S)-configured product, whereas Method B gave rise to the chlorinated (R)-product.However, this switch in the final configuration does not seem to be a consequence of the catalysts configuration but of the nature of the chlorinating agent which would produce a different arrangement of the rather participating species in the transition state.This assumption was based on the fact that the reaction using catalyst 1 with NCS and 2,3,4,5,6,6-hexachlorocyclohexa-2,4-dienone as chlorine source rendered   Remarkably, from experimental evidence it was observed that the opposite configuration in the chlorinated product was obtained when using method A and B, despite both catalysts 1 and 2 being derived from the same (1R,2R)-cyclohexane-1,2-diamine.Thus, Method A rendered the (S)-configured product, whereas Method B gave rise to the chlorinated (R)-product.However, this switch in the final configuration does not seem to be a consequence of the catalysts configuration but of the nature of the chlorinating agent which would produce a different arrangement of the rather participating species in the transition state.This assumption was based on the fact that the reaction using catalyst 1 with NCS and 2,3,4,5,6,6-hexachlorocyclohexa-2,4-dienone as chlorine source rendered   Remarkably, from experimental evidence it was observed that the opposite configuration in the chlorinated product was obtained when using method A and B, despite both catalysts 1 and 2 being derived from the same (1R,2R)-cyclohexane-1,2-diamine.Thus, Method A rendered the (S)-configured product, whereas Method B gave rise to the chlorinated (R)-product.However, this switch in the final configuration does not seem to be a consequence of the catalysts configuration but of the nature of the chlorinating agent which would produce a different arrangement of the rather participating species in the transition state.This assumption was based on the fact that the reaction using catalyst 1 with NCS and 2,3,4,5,6,6-hexachlorocyclohexa-2,4-dienone as chlorine source rendered Remarkably, from experimental evidence it was observed that the opposite configuration in the chlorinated product was obtained when using method A and B, despite both catalysts 1 and 2 being derived from the same (1R,2R)-cyclohexane-1,2-diamine.Thus, Method A rendered the (S)-configured product, whereas Method B gave rise to the chlorinated (R)-product.However, this switch in the final configuration does not seem to be a consequence of the catalysts configuration but of the nature of the chlorinating agent which would produce a different arrangement of the rather participating species in the transition state.This assumption was based on the fact that the reaction using catalyst 1 with NCS and 2,3,4,5,6,6-hexachlorocyclohexa-2,4-dienone as chlorine source rendered the corresponding product 5a with opposite configurations.The same stereodivergent [38][39][40][41][42] behavior was observed with catalyst 2.
Finally, and based on previous studies from our group on which chiral 2-aminobenzimidazole-derived organocatalysts were employed in different reactions, tentative mechanisms can be proposed for methods A and B (Figures 2 and 3).In both cases the organocatalysts have a bifunctional role.Firstly, the benzimidazole derivatives would act as a Brønsted base deprotonating the 1,3-dicarbonyl compound generating the corresponding enolate which could be coordinated through a dual hydrogen bond as shown in intermediates I and III.Next, the chlorinating agent would be activated by hydrogen bond either with the ammonium moiety (II, Figure 2) or with the second benzimidazol moiety (IV, Figure 3) favoring a tight transition state which would render the final product, regenerating the catalyst.On the other hand, an alternative and previously suggested [35,43,44] initial N-chlorination of the catalysts and subsequent chlorine inner transfer to the coordinated dicarbonyl compound seems to be discarded, since no chlorine incorporation to the organocatalysts was detected by ESI-MS after mixing them with the chlorinating reagents.the corresponding product 5a with opposite configurations.The same stereodivergent [38][39][40][41][42] behavior was observed with catalyst 2.
Finally, and based on previous studies from our group on which chiral 2-aminobenzimidazolederived organocatalysts were employed in different reactions, tentative mechanisms can be proposed for methods A and B (Figures 2 and 3).In both cases the organocatalysts have a bifunctional role.Firstly, the benzimidazole derivatives would act as a Brønsted base deprotonating the 1,3-dicarbonyl compound generating the corresponding enolate which could be coordinated through a dual hydrogen bond as shown in intermediates I and III.Next, the chlorinating agent would be activated by hydrogen bond either with the ammonium moiety (II, Figure 2) or with the second benzimidazol moiety (IV, Figure 3) favoring a tight transition state which would render the final product, regenerating the catalyst.On the other hand, an alternative and previously suggested [35,43,44] initial N-chlorination of the catalysts and subsequent chlorine inner transfer to the coordinated dicarbonyl compound seems to be discarded, since no chlorine incorporation to the organocatalysts was detected by ESI-MS after mixing them with the chlorinating reagents.the corresponding product 5a with opposite configurations.The same stereodivergent [38][39][40][41][42] behavior was observed with catalyst 2.
Finally, and based on previous studies from our group on which chiral 2-aminobenzimidazolederived organocatalysts were employed in different reactions, tentative mechanisms can be proposed for methods A and B (Figures 2 and 3).In both cases the organocatalysts have a bifunctional role.Firstly, the benzimidazole derivatives would act as a Brønsted base deprotonating the 1,3-dicarbonyl compound generating the corresponding enolate which could be coordinated through a dual hydrogen bond as shown in intermediates I and III.Next, the chlorinating agent would be activated by hydrogen bond either with the ammonium moiety (II, Figure 2) or with the second benzimidazol moiety (IV, Figure 3) favoring a tight transition state which would render the final product, regenerating the catalyst.On the other hand, an alternative and previously suggested [35,43,44] initial N-chlorination of the catalysts and subsequent chlorine inner transfer to the coordinated dicarbonyl compound seems to be discarded, since no chlorine incorporation to the organocatalysts was detected by ESI-MS after mixing them with the chlorinating reagents.

General Remarks
All reagents were purchased from commercial sources and used without further purification.Substrates which were not commercially available were synthesized according to known procedures from the literature.Catalysts 1 and 2 were synthesized as described in the literature and the spectroscopical data fully agreed with the reported values [31][32][33][34].Conversions were measured by GC chromatography employing a HP-6890 equipped with a WCOT HP-5 silica column (30 m ˆ0.25 mm ˆ0.25 µm) with 5% PHME siloxane as stationary phase.IR spectra were recorded on a Jasco FT-IR 4100 LE (Pike Miracle ATR) (Jasco Analitica Spain S.L., Madrid, Spain) and only the structurally most relevant peaks are listed.NMR spectra were performed on a Bruker AC-300 or Bruker Avance-400 (Bruker Corporation, Billerica, MA, USA) using CDCl 3 as solvent and TMS as internal standard unless otherwise stated.Low-resolution electron impact (EI) mass spectra were obtained at 70 eV on Agilent GC/MS-5973N apparatus equipped with a HP-5MS column (Agilent technologies, 30 m ˆ0.25 mm).Optical rotations were measured on a Jasco P-1030 Polarimeter (Jasco Analitica Spain S.L., Madrid, Spain) with a 5 cm cell (c given in g/100 mL).Enantioselectivities were determined by HPLC analysis (Agilent 1100 Series HPLC) (Agilent Technologies, Santa Clara, CA, USA) equipped with a G1315B diode array detector and a Quat Pump G1311A equipped with the corresponding Daicel chiral column or by Chiral GC employing an Agilent GC Series 7820A chromatograph (Agilent Technologies, Santa Clara, CA, USA) equipped with Chirasil-Dex CB (25 m ˆ0.25 mm ˆ0.25 µm) or Cyclosil-B (30 m ˆ0.25 mm ˆ0.25 µm) columns.The retention time of the major enantiomer is highlighted in bold.Analytical TLC was performed on Merck silica gel plates (Merck Millipore, Darmstadt, Germany) and the spots visualized with UV light at 254 nm.Flash chromatography was performed using Merck silica gel 60 (0.040-0.063 mm) using hexanes and ethyl acetate as eluents.

General Procedure for the Asymmetric Chlorination of 1,3-Dicarbonyl Compounds
Catalysts 1 or 2 and 1.5 mL of toluene were added to an open air round bottom tube (15 µmol, 10 mol%).The solution was stirred for 5 min in a thermostatized bath at ´50 ˝C and then the corresponding 1,3-dicarbonyl compound (0.18 mmol, 1.25 equiv.) was added.After stirring for 5 additional minutes, the chlorinating agent was added in a single portion (0.15 mmol).The mixture was allowed to react for 12 h.After this time water (5 mL) and ethyl acetate (5 mL) were added and the organic phase was separated.The aqueous layer was re-extracted twice with ethyl acetate (2 ˆ5 mL).The organic phases were dried (MgSO 4 ), filtered and evaporated under vacuum.The crude compound was then purified by flash chromatography using hexanes and ethyl acetate mixtures.
In the case of using co-catalysts, those were added together with the catalysts.The analytical data shown below corresponds to those enantioenriched products as representative compounds.All the compounds are described in the literature.Therefore, only 1 H NMR, MS (EI) and enantiomeric excess determination conditions are listed.

Conclusions
In conclusion, in this work the asymmetric chlorination of cyclic 1,3-dicarbonyl compounds has been disclosed using benzimidazole-derived organocatalysts.In this sense, catalysts 1 and 2 have been proven to be very efficient for such a purpose, rendering the corresponding chlorinated compounds in high yields and producing enantioselectivites ranging from poor to moderate.The organocatalysts seems to play a bifunctional role in activating both the dicarbonyl compound and the chlorinating agent.Interestingly, this process turned out to be stereodiveregent, since the opposite configuration can be obtained in the final product using the same catalyst and simply varying the electrophilic chlorine source.

a
Reaction conversion and ee determined by chiral GC (CP-Chirasil-Dex CB); b Isolated yield after flash chromatography.

a
Reaction conversion and ee determined by chiral GC (CP-Chirasil-Dex CB); b Isolated yield after flash chromatography.

a
Reaction conversion and ee determined by chiral GC (CP-Chirasil-Dex CB).

a
Reaction conversion and ee determined by chiral GC (CP-Chirasil-Dex CB).

Figure 2 .
Figure 2. Plausible mechanism for the asymmetric chlorination using Method A.

Figure 3 .
Figure 3. Plausible mechanism for the asymmetric chlorination using Method B.

Figure 2 .
Figure 2. Plausible mechanism for the asymmetric chlorination using Method A.

Figure 2 .
Figure 2. Plausible mechanism for the asymmetric chlorination using Method A.

Figure 3 .
Figure 3. Plausible mechanism for the asymmetric chlorination using Method B.

Figure 3 .
Figure 3. Plausible mechanism for the asymmetric chlorination using Method B.