Final Report Summary - ENAFUNTRAMECAT (Remote Enantioselective Functionalization of C–H bonds in Saturated Nitrogen Heterocycles)
Introduction
Transition-metal-catalysed cross-coupling reactions[1,2] are indispensible tools for the targeted or parallel synthesis of heterocyclic compounds. In particular, C–H bond functionalisation[3] has become an attractive and synthetically powerful alternative to traditional C–C cross-coupling; the starting materials are considerably less expensive and more abundant than their halogenated derivatives and the formation of stoichiometric metallic waste is minimized. In contrast, there are only a handful of reports in the literature where C(sp3)–H bond functionalisation[4] is efficiently achieved.
However, very recent developments in the field that exploit normally “unreactive” C(sp3)–H bonds for functionalisation, via transition metal catalysis, have opened opportunities regarding the development of new and efficient methodologies for arylation, alkenylation, alkylation for the synthetic community.
Amino acid derivatives are common motifs found in many biologically relevant molecules (Figure 1). As such they are important in drug design and for medicinal chemistry programs and, accordingly, new methods for their direct construction, and that of their analogues, are of significant value.
Based on the literature precedent,[5] we started our investigation via use of nitrile group as directing group for the remote Csp3-H functionalisation of cyclic amine. A series of diversely functionalised derivatives were synthesized and tested for the arylation. Figure 2 summarizes the overall class of substrates used for the initial screening of conditions.
To achieve the efficient transformation, several reaction conditions were tested with change of reaction parameters. Conditions ranging from diverse metal-catalysts known to perform arylation were used like metal salts of [Pd], [Ni] and [Ru]. An extensive screening in terms of base, oxidants, solvents and reaction temperature were also carried out. To our surprise, all reactions led to unsatisfactory results leading to either fully unreacted starting materials or in some cases <2% conversion to the desired product. Next, we focused our attention on achieving alkenylation using electron-rich or electron-deficient alkenes under Pd(II)-catalysis with these substrates. Based on the prior literature conditions, no desired product was obtained with several combination of reaction conditions. Use of highly acidic protic solvents and several silver salts as oxidants with Pd(OAc)2 as catalyst led to inefficient conversion, giving unreacted starting material at the end of the reaction. Optimization in terms of use of mono-protected amino acids (MPAA), which are known to promote C-H activation were also tested with disappointing outcome.
We next decided for an alternative route to functionalise via use of bidentate directing group. It was envisioned that use of a bidentate directing group, installed via amidation of the corresponding acid, would facilitate efficient arylation under optimized reaction conditions. The use of protected amino acids as model system for the arylation and alkylation at β−, γ- and δ – positions via these methods have recently been reported (Scheme 1). However, the scope was limited with respect to use of acyclic α-amino acids, encouraging us to develop and expand scope. Based on these hypothesis, we set out to explore the arylation of derivatives.
Table 1 shows extensive set of reaction conditions screened to obtain optimized conditions for corresponding transformation. After brief screening of reaction parameters (catalyst, oxidant, solvent and temperature), we found best condition affording desired mixture of mono-substituted major and minor diastereomer along with small amount of disubstituted products.
With optimized condition in hand, we next studied the substrate scope of the newly developed protocol. Several substituted aryl iodides containing electron withdrawing and electron donating groups are shown to react under optimized reaction conditions to afford corresponding mixture of mono-substituted major and minor diastereomer in 2:1 to 4:1 selectivity (Scheme 2, 3d - 3m). When arylations were carried out using derivatives the corresponding products were obtained in good yields (Scheme 2, 3n and 3o). It is worth mentioning that the use of enantiomerically pure starting material afforded two mono-arylated diastereomers possessing same enantiomeric excess. This demonstrates the versatility of this newly developed mild reaction conditions to afford enantioselective transformation. When α-amino acid derivatives were used under optimized conditions, the products were obtained in good isolated yield and excellent enantioselectivity (Scheme 2, 3r - 3s). The methodology is also compatible with the use of heteroaryl iodides to afford the products in good yields (Scheme 2, 3t - 3y). Finally, single crystal X-ray study confirmed unambiguously the structures of the newly synthesized compounds (Figure 2).
Having obtained the success with the efficient mono arylation, we next continued our efforts towards improving the diastereoselectivity for the said transformation. Moreover, the removal of directing group from the product proved to be difficult and could only be cleaved under relatively harsh conditions. To address these difficulties, we decided to explore alternative directing group for efficient arylation in diastereoselective and preferably in enantioselective manner. Scheme 3 demonstrates synthesis of several of such directing groups coupled with amino acid.
Based on our previously optimised conditions, the newly synthesised derivatives were subjected for the arylation. Interestingly, the reaction performed well with 4a, affording desired mono arylated product in 74% isolated yield. Similar results were obtained when the protecting group was changed from Boc- to Ts-group affording the desired product in 83% isolated yield. Interestingly, when the newly synthesised products were analysed via 1HNMR and 2D-NMR experiments, it was revealed that the products were obtain in highly diastereoselective fashion (dr, 12:1 - 15:1). Having successfully obtained the desired compound in diastereoselective fashion, we next embarked on to the evaluation of several substitution and different chain length. A range of substrates were evaluated for its efficacy, however, to our surprise, the group demonstrated higher reactivity in comparison to other similar analogues. The strategy could also be amenable to different ring size yielding highly regioselective and diastereoselective mono arylated product in >80% conversion and 67% isolated yield. Extension of the protocol to the use of chiral starting materials derived from amino acids gave regioselective and diastereoselective mono arylated product possessing the same enantiomeric excess as of starting material. Finally, single crystal X-ray study revealed the structure of the final product, showing "cis" relationship.
In conclusion, we have demonstrated that a range of derivatives possessing a directing group can be directly and stereoselectively arylated in a mild Pd(II) catalysed process using aryl iodide electrophiles. The same auxilliary was shown to serve as an efficient directing group for the installation of a second aryl group under similar reaction conditions. The reaction was tolerant of a range of functional groups on the arylating agent as well as a variety of heteroaryl iodides. The reaction could be performed on a 3 mmol scale without significant loss of yield. This is the first account of use of such derivatives in such a direct C-H functionalisation reaction. The strategy was also extended to use of alternative directing groups to achieve the same transformation in mild and diastereoselective fashion.
Transition-metal-catalysed cross-coupling reactions[1,2] are indispensible tools for the targeted or parallel synthesis of heterocyclic compounds. In particular, C–H bond functionalisation[3] has become an attractive and synthetically powerful alternative to traditional C–C cross-coupling; the starting materials are considerably less expensive and more abundant than their halogenated derivatives and the formation of stoichiometric metallic waste is minimized. In contrast, there are only a handful of reports in the literature where C(sp3)–H bond functionalisation[4] is efficiently achieved.
However, very recent developments in the field that exploit normally “unreactive” C(sp3)–H bonds for functionalisation, via transition metal catalysis, have opened opportunities regarding the development of new and efficient methodologies for arylation, alkenylation, alkylation for the synthetic community.
Amino acid derivatives are common motifs found in many biologically relevant molecules (Figure 1). As such they are important in drug design and for medicinal chemistry programs and, accordingly, new methods for their direct construction, and that of their analogues, are of significant value.
Based on the literature precedent,[5] we started our investigation via use of nitrile group as directing group for the remote Csp3-H functionalisation of cyclic amine. A series of diversely functionalised derivatives were synthesized and tested for the arylation. Figure 2 summarizes the overall class of substrates used for the initial screening of conditions.
To achieve the efficient transformation, several reaction conditions were tested with change of reaction parameters. Conditions ranging from diverse metal-catalysts known to perform arylation were used like metal salts of [Pd], [Ni] and [Ru]. An extensive screening in terms of base, oxidants, solvents and reaction temperature were also carried out. To our surprise, all reactions led to unsatisfactory results leading to either fully unreacted starting materials or in some cases <2% conversion to the desired product. Next, we focused our attention on achieving alkenylation using electron-rich or electron-deficient alkenes under Pd(II)-catalysis with these substrates. Based on the prior literature conditions, no desired product was obtained with several combination of reaction conditions. Use of highly acidic protic solvents and several silver salts as oxidants with Pd(OAc)2 as catalyst led to inefficient conversion, giving unreacted starting material at the end of the reaction. Optimization in terms of use of mono-protected amino acids (MPAA), which are known to promote C-H activation were also tested with disappointing outcome.
We next decided for an alternative route to functionalise via use of bidentate directing group. It was envisioned that use of a bidentate directing group, installed via amidation of the corresponding acid, would facilitate efficient arylation under optimized reaction conditions. The use of protected amino acids as model system for the arylation and alkylation at β−, γ- and δ – positions via these methods have recently been reported (Scheme 1). However, the scope was limited with respect to use of acyclic α-amino acids, encouraging us to develop and expand scope. Based on these hypothesis, we set out to explore the arylation of derivatives.
Table 1 shows extensive set of reaction conditions screened to obtain optimized conditions for corresponding transformation. After brief screening of reaction parameters (catalyst, oxidant, solvent and temperature), we found best condition affording desired mixture of mono-substituted major and minor diastereomer along with small amount of disubstituted products.
With optimized condition in hand, we next studied the substrate scope of the newly developed protocol. Several substituted aryl iodides containing electron withdrawing and electron donating groups are shown to react under optimized reaction conditions to afford corresponding mixture of mono-substituted major and minor diastereomer in 2:1 to 4:1 selectivity (Scheme 2, 3d - 3m). When arylations were carried out using derivatives the corresponding products were obtained in good yields (Scheme 2, 3n and 3o). It is worth mentioning that the use of enantiomerically pure starting material afforded two mono-arylated diastereomers possessing same enantiomeric excess. This demonstrates the versatility of this newly developed mild reaction conditions to afford enantioselective transformation. When α-amino acid derivatives were used under optimized conditions, the products were obtained in good isolated yield and excellent enantioselectivity (Scheme 2, 3r - 3s). The methodology is also compatible with the use of heteroaryl iodides to afford the products in good yields (Scheme 2, 3t - 3y). Finally, single crystal X-ray study confirmed unambiguously the structures of the newly synthesized compounds (Figure 2).
Having obtained the success with the efficient mono arylation, we next continued our efforts towards improving the diastereoselectivity for the said transformation. Moreover, the removal of directing group from the product proved to be difficult and could only be cleaved under relatively harsh conditions. To address these difficulties, we decided to explore alternative directing group for efficient arylation in diastereoselective and preferably in enantioselective manner. Scheme 3 demonstrates synthesis of several of such directing groups coupled with amino acid.
Based on our previously optimised conditions, the newly synthesised derivatives were subjected for the arylation. Interestingly, the reaction performed well with 4a, affording desired mono arylated product in 74% isolated yield. Similar results were obtained when the protecting group was changed from Boc- to Ts-group affording the desired product in 83% isolated yield. Interestingly, when the newly synthesised products were analysed via 1HNMR and 2D-NMR experiments, it was revealed that the products were obtain in highly diastereoselective fashion (dr, 12:1 - 15:1). Having successfully obtained the desired compound in diastereoselective fashion, we next embarked on to the evaluation of several substitution and different chain length. A range of substrates were evaluated for its efficacy, however, to our surprise, the group demonstrated higher reactivity in comparison to other similar analogues. The strategy could also be amenable to different ring size yielding highly regioselective and diastereoselective mono arylated product in >80% conversion and 67% isolated yield. Extension of the protocol to the use of chiral starting materials derived from amino acids gave regioselective and diastereoselective mono arylated product possessing the same enantiomeric excess as of starting material. Finally, single crystal X-ray study revealed the structure of the final product, showing "cis" relationship.
In conclusion, we have demonstrated that a range of derivatives possessing a directing group can be directly and stereoselectively arylated in a mild Pd(II) catalysed process using aryl iodide electrophiles. The same auxilliary was shown to serve as an efficient directing group for the installation of a second aryl group under similar reaction conditions. The reaction was tolerant of a range of functional groups on the arylating agent as well as a variety of heteroaryl iodides. The reaction could be performed on a 3 mmol scale without significant loss of yield. This is the first account of use of such derivatives in such a direct C-H functionalisation reaction. The strategy was also extended to use of alternative directing groups to achieve the same transformation in mild and diastereoselective fashion.