Synthesis of CF3-Containing Spiro-[Indene-Proline] Derivatives via Rh(III)-Catalyzed C-H Activation/Annulation

An efficient method of accessing new CF3-containing spiro-[indene-proline] derivatives has been developed based on a Cp*Rh(III)-catalyzed tandem C-H activation/[3+2]–annulation reaction of 5-aryl-2-(trifluoromethyl)-3,4-dihydro-2H-pyrrole-2-carboxylates with alkynes. An important feature of this spiro annulation process is the feasibility of dehydroproline moiety to act as a directing group in the selective activation of the aromatic C-H bond.


Introduction
Nitrogen spirocyclic compounds constitute an important class of heterocycles with unique characteristics.The introduction of spiro moieties can profoundly alter the physicochemical and biological profiles of the parent compounds due to their high rigidity and unique three-dimensional geometries.In addition, spiralization has often been used as a reliable methodology to create more privileged structures in the drug discovery process [1,2].Such heterocyclic spiro systems, in particular nitrogen spiro [4.4]nonanes, are widely represented in natural and synthetic biologically relevant molecules exhibiting important pharmacological and pesticidal properties [3,4].They are able to function as β-secretase inhibitors [5], AMPA antagonists [6], aldose reductase inhibitors [7,8], herbicides [9], anticancer agents [10] (Figure 1), etc.

Introduction
Nitrogen spirocyclic compounds constitute an important class of heterocycles with unique characteristics.The introduction of spiro moieties can profoundly alter the physicochemical and biological profiles of the parent compounds due to their high rigidity and unique three-dimensional geometries.In addition, spiralization has often been used as a reliable methodology to create more privileged structures in the drug discovery process [1,2].Such heterocyclic spiro systems, in particular nitrogen spiro [4.4]nonanes, are widely represented in natural and synthetic biologically relevant molecules exhibiting important pharmacological and pesticidal properties [3,4].They are able to function as β-secretase inhibitors [5], AMPA antagonists [6], aldose reductase inhibitors [7,8], herbicides [9], anticancer agents [10] (Figure 1), etc.  Selected examples of bioactive azaspiro [4,4]nonanes.
In the past decade, transition-metal-catalyzed, directing group (DG)-assisted C-H functionalization has emerged as one of the most efficient and straightforward strategies for the assembly of many valuable molecules in an atom-efficient and step-economical manner [11][12][13][14].Following this methodology, the synthesis of various heterocyclic compounds can be readily achieved via a tandem CH-activation-annulation process from DG-equipped aromatic compounds using different alkynes as coupling partners.Herewith, Cp*Rh(III)systems have been shown the most competent catalysts for these transformations [15][16][17][18][19][20][21][22].However, the outcome of annulation rigorously depends on directing group architecture as well as the nature and location functional groups presented in the acetylene component.With the recent expansion of the directing group to the cyclic architecture, the synthesis of spiro compounds, including heterocyclic spiro [4,4]nonanes, has become possible [23].
On the top of this, fluorinated compounds have found widespread applications in life and material sciences.The incorporation of fluorine-containing functionalities into potential pharmaceuticals is a well-recognized synthetic tool used to adjust their steric, electronic, and biological properties [24].In the field of amino acids and peptides, special attention is focused on α-amino acids with fluoromethyl groups in the α-position, owing to their ability to act as selective enzyme inhibitors, while exhibiting a range of interesting biological activities [25][26][27][28].For these and the above reasons, the development of efficient synthetic approaches to new functionalized azaspiro- [4,4]nonane, in particular α-CF 3 -substituted spiroproline derivatives, is highly desirable.
Molecules 2023, 28, x FOR PEER REVIEW 2 of 14 In the past decade, transition-metal-catalyzed, directing group (DG)-assisted C-H functionalization has emerged as one of the most efficient and straightforward strategies for the assembly of many valuable molecules in an atom-efficient and step-economical manner [11][12][13][14].Following this methodology, the synthesis of various heterocyclic compounds can be readily achieved via a tandem CH-activation-annulation process from DGequipped aromatic compounds using different alkynes as coupling partners.Herewith, Cp*Rh(III)-systems have been shown the most competent catalysts for these transformations [15][16][17][18][19][20][21][22].However, the outcome of annulation rigorously depends on directing group architecture as well as the nature and location functional groups presented in the acetylene component.With the recent expansion of the directing group to the cyclic architecture, the synthesis of spiro compounds, including heterocyclic spiro [4,4]nonanes, has become possible [23].
On the top of this, fluorinated compounds have found widespread applications in life and material sciences.The incorporation of fluorine-containing functionalities into potential pharmaceuticals is a well-recognized synthetic tool used to adjust their steric, electronic, and biological properties [24].In the field of amino acids and peptides, special attention is focused on α-amino acids with fluoromethyl groups in the α-position, owing to their ability to act as selective enzyme inhibitors, while exhibiting a range of interesting biological activities [25][26][27][28].For these and the above reasons, the development of efficient synthetic approaches to new functionalized azaspiro- [4,4]nonane, in particular α-CF3-substituted spiroproline derivatives, is highly desirable.

Results and Discussion
The synthesis of starting dehydroprolines 2a-d was accomplished using a two-step procedure previously developed by us [35] from available arylpropargyl amino esters 1a-d [36], including acid-mediated Boc-group deprotection followed by the silver(I)-catalyzed intramolecular hydroamination to afford the corresponding dehydroproline derivatives 2a-d in high yields (Scheme 2).
Molecules 2023, 28, x FOR PEER REVIEW 3 of 14 catalyzed C-H activation/[3+2]annulation with internal alkynes (Scheme 1c).The latter reaction, to the best of our knowledge, demonstrates the first example of aromatic C-H bond activation with the assistance of a dehydroproline directing group.

Results and Discussion
The synthesis of starting dehydroprolines 2a-d was accomplished using a two-step procedure previously developed by us [35] from available arylpropargyl amino esters 1ad [36], including acid-mediated Boc-group deprotection followed by the silver(I)-catalyzed intramolecular hydroamination to afford the corresponding dehydroproline derivatives 2a-d in high yields (Scheme 2).In order to check the feasibility of the proline moiety of 2 to act as directing group in theortho-metalation of the adjacent phenyl ring, we examined a model reaction between dehydroproline 2a and tolane 3a (Table 1).

Entry
Catalyst (mol%) Ag Additive (Equiv.) Other Additive (Equiv.)Yield 2 (%) In order to check the feasibility of the proline moiety of 2 to act as directing group in theortho-metalation of the adjacent phenyl ring, we examined a model reaction between dehydroproline 2a and tolane 3a (Table 1).

Table 1. Optimization of [3+2]-annulation of 5-phenyl dehydroproline 2a with acetylene 3a 1 .
Molecules 2023, 28, x FOR PEER REVIEW 3 of 14 catalyzed C-H activation/[3+2]annulation with internal alkynes (Scheme 1c).The latter reaction, to the best of our knowledge, demonstrates the first example of aromatic C-H bond activation with the assistance of a dehydroproline directing group.

Results and Discussion
The synthesis of starting dehydroprolines 2a-d was accomplished using a two-step procedure previously developed by us [35] from available arylpropargyl amino esters 1ad [36], including acid-mediated Boc-group deprotection followed by the silver(I)-catalyzed intramolecular hydroamination to afford the corresponding dehydroproline derivatives 2a-d in high yields (Scheme 2).In order to check the feasibility of the proline moiety of 2 to act as directing group in theortho-metalation of the adjacent phenyl ring, we examined a model reaction between dehydroproline 2a and tolane 3a (Table 1).First, we tested a [Cp*RhCl 2 ] 2 /Ag(I) catalytic system that has demonstrated the best activity in many C-H activation reactions of (hetero)arenes with different coupling partners including acetylenes.When 5 mol% of the dimeric rhodium complex was combined with 30 mol % of chloride scavenger AgBF 4 , the desired spiro ring product, the corresponding 2,3-diphenyl-5 -(trifluoromethyl)spiro[indene-1,2 -pyrrolidine]-5 -carboxylate (4a), was obtained in moderate yields (entry 1) after reaction at 80 • C in DCE, along with significant amounts of starting materials.The increase in the amount of silver additive to one equivalent did not improve the conversion of 2a and the yield of 4a (entries 2,3).However, the use of copper acetate as the second additive led to a better result (entry 4).The decrease in catalyst loading essentially diminished the yield of 4a (entry 5).The further variation of additives, solvents (toluene, methanol), reaction temperature, and time revealed the follow-ing optimal conditions: the heating of 5-phenyl dehydroproline 2 with 1.1 equiv. of alkyne 3 at 80 • C in DCE in the presence of [Cp*RhCl 2 ] 2 (5 mol%), AgOTf (0.3 eqiuv.),Cu(OAc) 2 (0.5 equiv.)for 16 h (entry 11).The reaction does not take place in the absence of silver additive (entry 14).Iridium-and cobalt-based complexes have proved to be absolutely inactive in the process (entries 15-16).
In the identified conditions, 5-aryl dehydroprolinates 2a-d bearing different substituents in the phenyl ring were involved in C-H activation/[3+2]annulation with tolane derivatives 3.As a result, a series of the corresponding CF 3 -containing spiro-[indene-prolinates] 4a-p were synthesized in acceptable yields (Scheme 3).The nature of the substituents in both coupling components did not significantly affect the outcome of the reaction in most investigated cases.The exception was found only for the compounds 4n and 4o; thus, two-fold excess of alkyne component 3 and higher temperature (100 • C) were required to achieve the full conversion of starting dehydroproline 2a for the same period of time.
First, we tested a [Cp*RhCl2]2/Ag(I) catalytic system that has demonstrated the best activity in many C-H activation reactions of (hetero)arenes with different coupling partners including acetylenes.When 5 mol% of the dimeric rhodium complex was combined with 30 mol % of chloride scavenger AgBF4, the desired spiro ring product, the corresponding 2,3-diphenyl-5′-(trifluoromethyl)spiro[indene-1,2′-pyrrolidine]-5′ -carboxylate (4a), was obtained in moderate yields (entry 1) after reaction at 80 °C in DCE, along with significant amounts of starting materials.The increase in the amount of silver additive to one equivalent did not improve the conversion of 2a and the yield of 4a (entries 2,3).However, the use of copper acetate as the second additive led to a better result (entry 4).The decrease in catalyst loading essentially diminished the yield of 4a (entry 5).The further variation of additives, solvents (toluene, methanol), reaction temperature, and time revealed the following optimal conditions: the heating of 5-phenyl dehydroproline 2 with 1.1 equiv. of alkyne 3 at 80 °C in DCE in the presence of [Cp*RhCl2]2 (5 mol%), AgOTf (0.3 eqiuv.),Cu(OAc)2 (0.5 equiv.)for 16 h (entry 11).The reaction does not take place in the absence of silver additive (entry 14).Iridium-and cobalt-based complexes have proved to be absolutely inactive in the process (entries 15-16).
In the identified conditions, 5-aryl dehydroprolinates 2a-d bearing different substituents in the phenyl ring were involved in C-H activation/[3+2]annulation with tolane derivatives 3.As a result, a series of the corresponding CF3-containing spiro-[indene-prolinates] 4a-p were synthesized in acceptable yields (Scheme 3).The nature of the substituents in both coupling components did not significantly affect the outcome of the reaction in most investigated cases.The exception was found only for the compounds 4n and 4o; thus, two-fold excess of alkyne component 3 and higher temperature (100 °C) were required to achieve the full conversion of starting dehydroproline 2a for the same period of time.All synthesized compounds isolated in analytically pure form via flash chromatography were fully characterized by means of standard physicochemical methods (see Supplementary Materials).In addition, a single crystal of good quality was obtained from 4a for X-ray analysis (Figure 2).All synthesized compounds isolated in analytically pure form via flash chromatography were fully characterized by means of standard physicochemical methods (see Supplementary Materials).In addition, a single crystal of good quality was obtained from 4a for X-ray analysis (Figure 2).Based on the literature precedents [23,[37][38][39] and the results obtained above, the mechanism of the transformation outlined in Scheme 4 is proposed.Initially, the rhodium dimer complex [Cp*RhCl2]2 is easily converted into the catalytically active Cp*Rh III (OAc) species via dissociation and consecutive ligand exchange.Precomplexation to the directing dehydropirrolidine moiety is followed by the cleavage of ortho-C-H bond of phenyl Based on the literature precedents [23,[37][38][39] and the results obtained above, the mechanism of the transformation outlined in Scheme 4 is proposed.Initially, the rhodium dimer complex [Cp*RhCl 2 ] 2 is easily converted into the catalytically active Cp*Rh III   Based on the literature precedents [23,[37][38][39] and the results obtained above, the mechanism of the transformation outlined in Scheme 4 is proposed.Initially, the rhodium dimer complex [Cp*RhCl2]2 is easily converted into the catalytically active Cp*Rh III (OAc) species via dissociation and consecutive ligand exchange.Precomplexation to the directing dehydropirrolidine moiety is followed by the cleavage of ortho-C-H bond of phenyl ring to form rhodacyle A. Then

General Information
All solvents used in reactions were freshly distilled from appropriate drying agents before use.All other reagents were distilled as necessary.The corresponding starting dehydroprolines were easily synthesized via the previously described protocol [35,36].Analytical TLC was performed with Merck silica gel 60 F 254 plates; visualization was accomplished with UV light or spraying with Ce(SO 4 ) 2 solution in 5% H 2 SO 4 .Chromatography was carried out using Merck silica gel (Kieselgel 60, 0.063-0.200mm) and petroleum ether/ethyl acetate and petroleum ether/dichloromethane as an eluent.The NMR spectra were obtained with Bruker AV-300, AV-400, AV-500 and Inova-400 spectrometers operating at 300, 400, and 500 MHz, respectively, for 1 H (TMS reference), at 101 and 126 for 13 C { 1 H}, and at 282 and 376 MHz for 19 F (CCl 3 F reference).Analytical data (C, H, N content) were obtained with a Carlo Erba model 1106 microanalyzer.High-resolution mass spectra were recorded on a Bruker Daltonics micrOTOF-Q II device (electrospray ionization).

General Procedure for the Synthesis of 5-Aryl Dehydroprolines 2a-d
To a solution of compound 1 [36] (0.3 g, 0.81 mmol, 1 equiv.) in dry CH 2 Cl 2 (5 mL), TFA (2 mL) was added.The resulting mixture was stirred for 3-4 h at room temperature.The solvent and the excess of acid were removed under reduced pressure and the residue was dissolved in water (5 mL) and neutralized with sodium hydrogen carbonate until the pH reached 7. The product was extracted with ethyl acetate (2 × 10 mL), and the organic layer was dried over MgSO 4 .After removal of the solvent, the residue was dissolved in dry acetonitrile (3 mL), AgOTf (0.01 g, 0.04 mmol, 0.05 equiv.) was added, and the mixture was stirred for 4-5 h at room temperature.The solvent was removed under reduced pressure, and the corresponding product 2 was isolated via column chromatography on silica gel (eluent petroleum ether/ethyl acetate = 15:1).The spectral characteristics of the obtained compounds correspond to the literature data [35].
Molecules 2023, 28, x FOR PEER REVIEW 7 of 14 1.0 equiv.)under air.The reaction mixture was stirred at 80 °C for 16 h until the completion of the reaction, as monitored via TLC and 19 F NMR.The heterogeneous mixture was passed through a short layer of celite, which was additionally washed with a CH2Cl2.After removal of the solvent, the residue was purified via column chromatography on silica gel (gradient elution petroleum ether/dichloromethane = 5:1, eluent petroleum ether/ethyl acetate = 10:1) to give the desired product.

Conclusions
In summary, we have presented a convenient and highly efficient method of accessing CF 3 -containing spiro-[indene-proline] derivatives from readily available precursors under mild catalytic conditions.An important feature of the Cp*Rh(III)-catalyzed tandem C-H activation/[3+2]-annulation of 5-aryl-2-(trifluoromethyl)-3,4-dihydro-2H-pyrrole-2carboxylates with acetylenes is the feasibility of the dehydroproline moiety to function as a directing group in this spiro annulation process.As a result, the developed strategy opens the door to a novel series of α-trifluoromethyl-substituted spiro-proline derivatives in good yields.
(OAc) species via dissociation and consecutive ligand exchange.Precomplexation to the directing dehydropirrolidine moiety is followed by the cleavage of ortho-C-H bond of phenyl ring to form rhodacyle A. Then, the selective insertion of the alkyne triple bond into the C-Rh bond provides a seven-membered rhodacycle intermediate B. Within intermediate B, the addition of the vinyl C-Rh bond to the C=C double bond of the pyrrolidine ring leads to the intermediate C. Finally, the cleavage of the N-Rh bond of C through protonolysis produces 4, and regenerates the active species for new catalytic cycle.
, the selective insertion of the alkyne triple bond into the C-Rh bond provides a seven-membered rhodacycle intermediate B. Within intermediate B, the addition of the vinyl C-Rh bond to the C=C double bond of the pyrrolidine ring leads to the intermediate C. Finally, the cleavage of the N-Rh bond of C through protonolysis produces 4, and regenerates the active species for new catalytic cycle.