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Article

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

by
Alexandra S. Bubnova
,
Daria V. Vorobyeva
,
Ivan A. Godovikov
,
Alexander F. Smol’yakov
and
Sergey N. Osipov
*
A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, 28/1 Vavilova Str., 119334 Moscow, Russia
*
Author to whom correspondence should be addressed.
Molecules 2023, 28(23), 7809; https://doi.org/10.3390/molecules28237809
Submission received: 26 October 2023 / Revised: 17 November 2023 / Accepted: 24 November 2023 / Published: 27 November 2023
(This article belongs to the Special Issue Fluorine Chemistry 2.0)
Browse Figures
Versions Notes

Abstract

:
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.

Graphical Abstract

1. 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.
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-CF3-substituted spiroproline derivatives, is highly desirable.
Recently, we have elaborated upon a convenient method for the preparation of novel α-CF3-substituted α-amino acid derivatives decorated with the pharmacophore isoquinolone [29,30] (Scheme 1a) and pirimidoindolone [31] (Scheme 1b) cores via Rh(III)-catalyzed C-H activation/(4+2)-annulation of the aryl hydroxamates and indole carboxamides with orthogonally protected propargyl-containing α-amino acid derivatives.
Now, in accordance with our current investigations focused on the development of efficient routes to new representatives of fluorinated α-amino acids and their multifunctional derivatives under metal catalysis [32,33,34], we want to report on a convenient region-selective approach to new CF3-containing spiro[indene-prolines]. The method involves the initial transformation of α-arylpropargyl-α-amino esters into corresponding 5-aryl-2-(trifluoromethyl)-3,4-dihydro-2H-pyrrole-2-carboxylates [35] followed by rhodium(III)-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.

2. 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).
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*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).
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*RhIII(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.

3. Materials and Methods

3.1. 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(SO4)2 solution in 5% H2SO4. Chromatography was carried out using Merck silica gel (Kieselgel 60, 0.063–0.200 mm) 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 1H (TMS reference), at 101 and 126 for 13C {1H}, and at 282 and 376 MHz for 19F (CCl3F 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).

3.2. 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 CH2Cl2 (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 MgSO4. 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].
Methyl 5-phenyl-2-(trifluoromethyl)-3,4-dihydro-2H-pyrrole-2-carboxylate 2a.
Yield 85% as a white solid. 1H NMR (300 MHz, CDCl3): δ 7.98 (d, J = 7.1 Hz, 2H, Ar), 7.60–7.48 (m, 3H, Ar), 3.89 (s, 3H, OCH3), 3.29 (t, J = 7.9 Hz, 2H, CH2), 2.72–2.62 (m, 1H, CH2), 2.58–2.48 (m, 1H, CH2). 19F NMR (282 MHz, CDCl3): δ −74.76 (s, 3F, CF3).
Methyl 5-p-tolyl-2-(trifluoromethyl)-3,4-dihydro-2H-pyrrole-2-carboxylate 2b.
Yield 78% as a white solid. 1H NMR (300 MHz, CDCl3): δ 7.84 (d, J = 8.1 Hz, 2H, Ar), 7.26 (d, J = 8.1 Hz, 2H, Ar), 3.85 (s, 3H, OCH3), 3.22 (t, J = 7.9 Hz, 2H, CH2), 2.66–2.56 (m, 1H, CH2), 2.52–2.46 (m, 1H, CH2), 2.42 (s, 3H, CH3). 19F NMR (282 MHz, CDCl3): δ −74.79 (s, 3F, CF3).
Methyl 5-(4-methoxyphenyl)-2-(trifluoromethyl)-3,4-dihydro-2H-pyrrole-2-carboxylate 2c.
Yield 80% as a white solid. 1H NMR (300 MHz, CDCl3): δ 7.90 (d, J = 8.8 Hz, 2H, Ar), 6.95 (d, J = 8.8 Hz, 2H, Ar), 3.88 (s, 3H, OCH3), 3.85 (s, 3H, OCH3), 3.20 (t, J = 7.9 Hz, 2H, CH2), 2.65–2.55 (m, 1H, CH2), 2.51–2.41 (m, 1H, CH2). 19F NMR (282 MHz, CDCl3): δ −74.82 (s, 3F, CF3).
Methyl 5-(4-nitrophenyl)-2-(trifluoromethyl)-3,4-dihydro-2H-pyrrole-2-carboxylate (2d).
Yield 90% as a yellow solid. 1H NMR (300 MHz, CDCl3): δ 8.32 (d, J = 8.8 Hz, 2H, Ar), 8.12 (d, J = 8.8 Hz, 2H, Ar), 3.88 (s, 3H, OCH3), 3.28 (t, J = 7.8 Hz, 2H, CH2), 2.74–2.64 (m, 1H, CH2), 2.60–2.50 (m, 1H, CH2). 19F NMR (282 MHz, CDCl3): δ −74.60 (s, 3F, CF3).

3.3. General Procedure for the C-H Activation/Annulation of 5-Aryl Dehydroprolines with Tolane Derivatives. Synthesis of the Compounds 4a-m

A 10 mL Schlenk tube equipped with a magnetic stirring bar was charged with a corresponding 5-aryl dehydroproline (0.1 g, 0.37 mmol, 1.0 equiv.), DCE (3 mL), a corresponding tolane derivative (0.07 g, 0.41 mmol, 1.1 equiv.), [Cp*RhCl2]2 (11.4 mg, 18 µmol, 5 mol%), AgOTf (28.4 mg, 0.11 mmol, 30 mol%), and Cu(OAc)2∙H2O (0.07 g, 0.37 mmol, 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 19F 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.
Methyl 2,3-diphenyl-5′-(trifluoromethyl)spiro[indene-1,2′-pyrrolidine]-5′-carboxylate 4a.
Molecules 28 07809 i002
Yield: 75% as a white solid. M.p. 168 °C. 1H NMR (500 MHz, CDCl3): δ 7.61 (d, J = 7.05 Hz, 1H, Ar), 7.35–7.21 (m, 11H, Ar), 7.17–7.15 (m, 2H, Ar), 3.58 (s, 3H, OCH3), 3.10 (s, 1H, NH), 2.62–2.56 (m, 1H, CH2), 2.41–2.34 (m, 2H, CH2), 2.00–1.93 (m, 1H, CH2). 13C{1H} NMR (126 MHz, CDCl3): δ 169.6, 150.6, 148.4, 142.0, 139.3, 135.7, 134.1, 130.2, 129.2, 128.1, 128.0, 127.8, 127.4, 127.3, 126.8, 125.3 (q, J = 285.8 Hz, CF3), 122.5, 120.7, 77.6, 72.1 (q, J = 28.2 Hz, >C<), 53.0, 35.3, 30.5. 19F NMR (376 MHz, CDCl3): δ −77.33 (s, 3F, CF3). Elemental analysis calcd (%) for C27H22F3NO2: C, 72.15; H, 4.93; N, 3.12; found: C, 72.11; H, 5.04; N, 3.11. HRMS (ESI): calcd for C27H23F3NO2 [M+H]+: 450.1680; found: 477.1676.
Methyl 5-methyl-2,3-diphenyl-5′-(trifluoromethyl)spiro[indene-1,2′-pyrrolidine]-5′-carboxylate 4b.
Molecules 28 07809 i003
Yield: 70% as a white solid. M.p. 169–171 °C. 1H NMR (500 MHz, CDCl3): δ 7.52 (d, J = 7.5 Hz, 1H, Ar), 7.33–7.23 (m, 8H, Ar), 7.19–7.16 (m, 3H, Ar), 7.10 (s, 1H, Ar), 3.59 (s, 3H, OCH3), 3.11 (s, 1H, NH), 2.62–2.56 (m, 1H, CH2), 2.42–2.35 (m, 2H, CH2, 3H, CH3,), 2.02–1.95 (m, 1H, CH2). 13C{1H} NMR (126 MHz, CDCl3): δ 169.7, 148.7, 147.7, 142.3, 139.3, 137.7, 135.8, 134.3, 130.2, 129.2, 128.1, 127.4, 127.3, 127.2, 125.4 (q, J = 285.8 Hz, CF3), 122.3, 121.5, 77.4, 72.1 (q, J = 28.2 Hz, >C<), 53.0, 35.4, 30.6, 21.5. 19F NMR (376 MHz, CDCl3): δ −77.29 (s, 3F, CF3). Elemental analysis calcd (%) for C28H24F3NO2: C, 72.56; H, 5.22; N, 3.02; found: C, 72.67; H, 5.34; N, 2.91.
Methyl 5-methoxy-2,3-diphenyl-5′-(trifluoromethyl)spiro[indene-1,2′-pyrrolidine]-5′-carboxylate 4c.
Molecules 28 07809 i004
Yield: 65% as a white solid. M.p. 143–145 °C. 1H NMR (500 MHz, CDCl3): δ 7.52 (d, J = 8.1 Hz, 1H, Ar), 7.30–7.23 (m, 8H, Ar), 7.18–7.17 (m, 2H, Ar), 6.88–6.85 (m, 2H, Ar), 3.83 (s, 3H, OCH3), 3.59 (s, 3H, OCH3), 3.10 (s, 1H, NH), 2.60–2.56 (m, 1H, CH2), 2.40–2.34 (m, 2H, CH2), 2.00–1.93 (m, 1H, CH2). 13C{1H} NMR (126 MHz, CDCl3): δ 169.6, 160.0, 149.7, 143.6, 142.5, 138.9, 135.7, 134.0, 130.2, 129.2, 128.1, 127.4, 127.3, 125.4 (q, J = 286.0 Hz, CF3), 123.1, 111.5, 107.3, 77.1, 72.0 (q, J = 28.2 Hz, >C<), 55.6, 53.0, 35.4, 30.5. 19F NMR (282 MHz, CDCl3): δ −77.29 (s, 3F, CF3). Elemental analysis calcd (%) for C28H24F3NO3: C, 70.14; H, 5.05; N, 2.92; found: C, 70.07; H, 5.29; N, 2.84.
Methyl 5-nitro-2,3-diphenyl-5′-(trifluoromethyl)spiro[indene-1,2′-pyrrolidine]-5′-carboxylate 4d.
Molecules 28 07809 i005
Yield: 60% as a yellow solid. M.p. 188 °C. 1H NMR (500 MHz, CDCl3): δ 8.21 (dd, J = 8.2, 2.05 Hz, 1H, Ar), 8.06 (d, J = 2.0 Hz, 1H, Ar), 7.71 (d, J = 8.2 Hz, 1H, Ar), 7.32–7.28 (m, 6H, Ar), 7.25–7.23 (m, 2H, Ar), 7.17–7.15 (m, 2H, Ar), 3.59 (s, 3H, OCH3), 3.16 (s, 1H, NH), 2.63–2.57 (m, 1H, CH2), 2.41–2.36 (m, 2H, CH2), 1.98–1.91 (m, 1H, CH2). 13C{1H} NMR (126 MHz, CDCl3): δ 169.2, 157.7, 150.8, 148.5, 143.6, 137.9, 134.6, 132.7, 129.9, 128.9, 128.5, 128.4, 128.0, 127.9, 125.2 (q, J = 285.6 Hz, CF3), 123.0, 122.6, 115.5, 77.4, 72.1 (q, J = 28.4 Hz, >C<), 53.2, 35.4, 30.3. 19F NMR (282 MHz, CDCl3): δ −77.38 (s, 3F, CF3). Elemental analysis calcd (%) for C27H21F3N2O4: C, 65.58; H, 4.28; N, 5.67; found: C, 65.74; H, 4.29; N, 5.41.
Methyl 2,3-bis(4-methoxyphenyl)-5′-(trifluoromethyl)spiro[indene-1,2′-pyrrolidine]-5′-carboxylate 4e.
Molecules 28 07809 i006
Yield: 57% as a yellow solid. M.p. 146–148 °C. 1H NMR (500 MHz, CDCl3): δ 7.60 (d, J = 6.5 Hz, 1H Ar,), 7.33–7.27 (m, 3H, Ar), 7.21–7.18 (m, 2H, Ar), 7.09–7.06 (m, 2H, Ar), 6.85–6.80 (m, 4H, Ar), 3.81 (s, 3H, OCH3), 3.79 (s, 3H, OCH3), 3.61 (s, 3H, OCH3), 3.07 (s, 1H, NH), 2.60–2.53 (m, 1H, CH2), 2.42–2.37 (m, 1H, CH2), 2.35–2.30 (m, 1H, CH2), 2.06–2.00 (m, 1H, CH2). 13C{1H} NMR (126 MHz, CDCl3): δ 169.7, 158.8, 158.6, 150.7, 147.3, 142.2, 138.8, 131.4, 130.4, 127.9, 127.7, 126.6, 126.5, 125.4 (q, J = 285.7 Hz, CF3), 122.5, 120.6, 113.7, 113.6, 77.4, 72.1 (q, J = 28.3 Hz, >C<), 55.2, 55.1, 53.0, 35.3, 30.5. 19F NMR (282 MHz, CDCl3): δ −77.20 (s, 3F, CF3). Elemental analysis calcd (%) for C29H26F3NO4: C, 68.36; H, 5.14; N, 2.75; found: C, 68.51; H, 5.24; N, 2.91.
Methyl 2,3-bis(4-methoxyphenyl)-5-methyl-5′-(trifluoromethyl)spiro[indene-1,2′-pyrrolidine]-5′-carboxylate 4f.
Molecules 28 07809 i007
Yield: 52% as a yellow solid. M.p. 180–182 °C. 1H NMR (400 MHz, CDCl3): δ 7.42 (d, J = 7.7 Hz, 1H, Ar), 7.14 (d, J = 8.6 Hz, 2H, Ar), 7.08 (d, J = 7.4 Hz, 1H, Ar), 7.03 (s, 2H, Ar), 7.00 (s, 1H, Ar), 6.78 (d, J = 8.6 Hz, 4H, Ar), 3.76 (s, 3H, OCH3), 3.75 (s, 3H, OCH3), 3.56 (s, 3H, OCH3), 2.99 (s, 1H, NH), 2.52–2.44 (m, 1H, CH2), 2.36–2.23 (m, 5H, CH3, CH2), 2.00–1.92 (m, 1H, CH2). 13C{1H} NMR (101 MHz, CDCl3): δ 169.7, 158.8, 158.5, 147.8, 147.6, 142.4, 138.8, 137.5, 131.3, 130.3, 127.9, 127.1, 126.6, 125.3 (q, J = 286.7 Hz, CF3), 122.1, 121.3, 113.6, 113.5, 77.1, 72.0 (q, J = 28.3 Hz, >C<), 55.1, 55.0, 52.9, 35.3, 30.5, 21.5. 19F NMR (282 MHz, CDCl3): δ −77.17 (s, 3F, CF3). Elemental analysis calcd (%) for C30H28F3NO4: C, 68.82; H, 5.39; N, 2.68; found: C, 68.69; H, 5.64; N, 2.54.
Methyl 5-methoxy-2,3-bis(4-methoxyphenyl)-5′-(trifluoromethyl)spiro[indene-1,2′-pyrrolidine]-5′-carboxylate 4g.
Molecules 28 07809 i008
Yield: 43% as a yellow solid. M.p. 154–156 °C. 1H NMR (400 MHz, CDCl3): δ 7.43 (d, J = 8.9 Hz, 1H, Ar), 7.13 (d, J = 8.8 Hz, 2H, Ar), 7.02 (d, J = 8.6 Hz, 2H, Ar), 6.79–6.75 (m, 6H, Ar), 3.78 (s, 3H, OCH3), 3.76 (s, 3H, OCH3), 3.75 (s, 3H, OCH3), 3.56 (s, 3H, OCH3), 2.99 (s, 1H, NH), 2.51–2.43 (m, 1H, CH2), 2.35–2.22 (m, 2H, CH2), 1.99–1.91 (m, 1H, CH2). 13C{1H} NMR (101 MHz, CDCl3): δ 169.6, 159.9, 158.8, 158.6, 148.6, 143.8, 142.6, 138.5, 132.8, 131.3, 130.3, 130.0, 127.9, 126.4, 125.3 (q, J = 286.5 Hz, CF3), 122.9, 113.6, 113.5, 111.2, 107.2, 76.8, 71.9 (q, J = 28.3 Hz, >C<), 55.6, 55.1, 55.0, 52.9, 35.3, 30.5. 19F NMR (282 MHz, CDCl3): δ −77.19 (s, 3F, CF3). Elemental analysis calcd (%) for C30H28F3NO5: C, 66.78; H, 5.23; N, 2.60; found: C, 66.48; H, 5.41; N, 2.63.
Methyl 2,3-bis(4-methoxyphenyl)-5-nitro-5′-(trifluoromethyl)spiro[indene-1,2′-pyrrolidine]-5′-carboxylate 4h.
Molecules 28 07809 i009
Yield: 59% as a yellow solid. M.p.118–120 °C. 1H NMR (400 MHz, CDCl3): δ 8.15 (dd, J = 8.2, 2.1 Hz, 1H, Ar), 8.02 (d, J = 2.0 Hz, 1H, Ar), 7.65 (d, J = 8.2 Hz, 1H, Ar), 7.13 (d, J = 8.8 Hz, 2H, Ar), 7.02 (d, J = 8.7 Hz, 2H, Ar), 6.81 (d, J = 8.8 Hz, 4H, Ar), 3.77 (s, 3H, OCH3), 3.77 (s, 3H, OCH3), 3.59 (s, 1H, OCH3), 3.07 (s, 1H, NH), 2.56–2.48 (m, 1H, CH2), 2.38–2.26 (m, 2H, CH2), 2.00–1.91 (m, 1H, CH2). 13C{1H} NMR (101 MHz, CDCl3): δ 169.3, 159.2, 159.1, 157.8, 149.7, 148.4, 143.8, 137.5, 131.0, 130.1, 126.7, 125.2 (q, J = 286.3 Hz, CF3), 125.1, 122.9, 122.3, 115.3, 113.9, 113.8, 77.1, 72.1 (q, J = 28.3 Hz, >C<), 55.2, 53.1, 35.3, 30.3. 19F NMR (282 MHz, CDCl3): δ −77.29 (s, 3F, CF3). Elemental analysis calcd (%) for C29H25F3N2O6: C, 62.81; H, 4.54; N, 5.05; found: C, 63.11; H, 4.86; N, 4.97.
Methyl 2,3-di-p-tolyl-5′-(trifluoromethyl)spiro[indene-1,2′-pyrrolidine]-5′-carboxylate 4i.
Molecules 28 07809 i010
Yield: 65% as a white solid. M.p. 159–160 °C. 1H NMR (500 MHz, CDCl3): δ 7.60 (d, J = 6.8 Hz, 1H, Ar), 7.33–7.26 (m, 3H, Ar), 7.16 (d, J = 8.0 Hz, 2H, Ar), 7.11–7.07 (m, 4H, Ar), 7.04 (d, J = 8.0 Hz, 2H, Ar), 3.58 (s, 3H, OCH3), 3.07 (s, 1H, NH), 2.59–2.53 (m, 1H, CH2), 2.40–2.36 (m, 2H, CH2), 2.35 (s, 3H, CH3), 2.32 (s, 3H, CH3), 2.03–1.97 (m, 1H, CH2). 13C{1H} NMR (126 MHz, CDCl3): δ 169.6, 150.7, 147.9, 142.2, 138.9, 136.8, 132.6, 131.2, 130.0, 129.0, 128.9, 128.8, 127.7, 126.6, 125.4 (q, J = 285.4 Hz, CF3), 122.4, 120.6, 77.5, 72.1 (q, J = 28.1 Hz, >C<), 52.9, 35.3, 30.5, 21.3, 21.2. 19F NMR (282 MHz, CDCl3): δ -77.30 (s, 3F, CF3). Elemental analysis calcd (%) for C29H26F3NO2: C, 72.94; H, 5.49; N, 2.93; found: C, 72.74; H, 5.65; N, 2.88.
Methyl 5-methyl-2,3-di-p-tolyl-5′-(trifluoromethyl)spiro[indene-1,2′-pyrrolidine]-5′-carboxylate 4j.
Molecules 28 07809 i011
Yield: 56% as a white solid. M.p. 189–190 °C. 1H NMR (500 MHz, CDCl3): δ 7.47 (d, J = 7.5 Hz, 1H, Ar), 7.15 (d, J = 8.1 Hz, 2H, Ar), 7.12 (d, J = 7.6 Hz, 1H, Ar), 7.10–7.07 (m, 5H, Ar), 7.03 (d, J = 8.0 Hz, 2H, Ar), 3.57 (s, 3H, OCH3), 3.04 (s, 1H, NH), 2.56–2.47 (m, 1H, CH2), 2.39–2.36 (m, 1H, CH2), 2.37 (s, 3H, CH3), 2.34 (s, 3H, CH3), 2.33 (s, 3H, CH3), 2.33–2.29 (m, 1H, CH2), 2.02–1.95 (m, 1H, CH2). 13C{1H} NMR (126 MHz, CDCl3): δ 169.6, 148.2, 147.7, 142.4, 138.9, 137.5, 136.7, 132.7, 131.3, 130.0, 129.0, 128.8, 127.1, 125.4 (q, J = 285.4 Hz, CF3), 122.1, 121.4, 77.2, 72.1 (q, J = 28.1 Hz, >C<), 52.8, 35.3, 30.5, 21.5, 21.3, 21.2. 19F NMR (282 MHz, CDCl3): δ −77.28 (s, 3F, CF3). Elemental analysis calcd (%) for C30H28F3NO2: C, 73.30; H, 5.74; N, 2.85; found: C, 73.33; H, 5.93; N, 2.88.
Methyl 5-metoxy-2,3-di-p-tolyl-5′-(trifluoromethyl)spiro[indene-1,2′-pyrrolidine]-5′-carboxylate 4k.
Molecules 28 07809 i012
Yield: 58% as a white solid. M.p. 183–184 °C. 1H NMR (500 MHz, CDCl3): δ 7.48 (d, J = 8.2 Hz, 1H, Ar), 7.15 (d, J = 8.1 Hz, 2H, Ar), 7.10–7.07 (m, 4H, Ar), 7.03 (d, J = 8.0 Hz, 2H, Ar), 6.85–6.83 (m, 2H, Ar), 3.81 (s, 3H, OCH3), 3.57 (s, 3H, OCH3), 3.04 (s, 1H, NH), 2.55–2.47 (m, 1H, CH2), 2.38–2.33 (m, 1H, CH2, 3H, CH3), 2.32–2.29 (m, 3H, CH3, 1H, CH2), 2.02–1.95 (m, 1H, CH2). 13C{1H} NMR (126 MHz, CDCl3): δ 169.6, 159.9, 149.2, 143.7, 142.6, 138.6, 136.8, 132.6, 131.1, 129.9, 129.0, 128.8, 128.8, 125.4 (q, J = 285.3 Hz, CF3), 122.9, 111.3, 107.2, 77.0, 71.9 (q, J = 28.1 Hz, >C<), 55.6, 52.8, 35.2, 30.5, 21.3, 21.2. 19F NMR (282 MHz, CDCl3): δ −77.31 (s, 3F, CF3). Elemental analysis calcd (%) for C30H28F3NO3: C, 70.99; H, 5.56; N, 2.76; found: C, 70.74; H, 5.62; N, 2.81.
Methyl 5-nitro-2,3-di-p-tolyl-5′-(trifluoromethyl)spiro[indene-1,2′-pyrrolidine]-5′-carboxylate 4l.
Molecules 28 07809 i013
Yield: 68% as a yellow solid. M.p. 171–172 °C. 1H NMR (500 MHz, CDCl3): δ 8.19 (dd, J = 8.2, 2.1 Hz, 1H, Ar), 8.05 (d, J = 2.1 Hz, 1H, Ar), 7.69 (d, J = 8.5 Hz, 1H, Ar), 7.15–7.11 (m, 6H, Ar), 7.03 (d, J = 8.0 Hz, 2H, Ar), 3.59 (s, 3H, OCH3), 3.12 (s, 1H, NH), 2.60–2.54 (m, 1H, CH2), 2.40–2.35 (m, 2H, CH2), 2.35 (s, 3H, CH3), 2.34 (s, 3H, CH3), 2.01–1.95 (m, 1H, CH2). 13C{1H} NMR (126 MHz, CDCl3): δ 169.2, 157.8, 150.3, 148.4, 143.8, 137.6, 137.5, 131.5, 129.8, 129.7, 129.2, 129.0, 128.8, 125.2 (q, J = 285.2 Hz, CF3), 122.9, 122.3, 115.4, 77.3, 72.1 (q, J = 28.6 Hz, >C<), 53.0, 35.3, 30.3, 21.3, 21.2. 19F NMR (282 MHz, CDCl3): δ −77.40 (s, 3F, CF3). Elemental analysis calcd (%) for C29H25F3N2O4: C, 66.66; H, 4.82; N, 5.36; found: C, 66.51; H, 4.94; N, 5.41.
Methyl 2,3-di(naphthalen-2-yl)-5′-(trifluoromethyl)spiro[indene-1,2′-pyrrolidine]-5′-carboxylate 4m.
Molecules 28 07809 i014
Yield: 65% as a white solid. M.p. 184 °C. 1H NMR (500 MHz, CDCl3): δ 7.88 (s, 1H, Ar), 7.83–7.79 (m, 2H, Ar), 7.77–7.72 (m, 4H, Ar), 7.69–7.65 (m, 2H, Ar), 7.50–7.46 (m, 2H, Ar), 7.45–7.42 (m, 2H, Ar), 7.40–7.32 (m, 4H, Ar), 7.31–7.29 (m, 1H, Ar), 3.24 (s, 1H, NH), 3.15 (s, 3H, OCH3), 2.71–2.65 (m, 1H, CH2), 2.50–2.46 (m, 1H, CH2), 2.38–2.33 (m, 1H, CH2), 1.95–1.88 (m, 1H, CH2). 13C{1H} NMR (126 MHz, CDCl3): δ 169.6, 150.7, 148.8, 142.1, 139.4, 133.2, 133.1, 133.0, 132.5, 132.4, 131.7, 129.4, 128.2, 128.1, 128.1, 128.0, 127.9, 127.8, 127.7, 127.6, 127.6, 127.3, 126.9, 126.2, 126.1, 126.0, 125.4 (q, J = 286.0 Hz, CF3), 122.7, 120.8, 78.0, 72.1 (q, J = 28.0 Hz, >C<), 52.7, 35.7, 30.5. 19F NMR (282 MHz, CDCl3): δ −77.31 (s, 3F, CF3). Elemental analysis calcd (%) for C35H26F3NO2: C, 76.49; H, 4.77; N, 2.55; found: C, 76.41; H, 5.17; N, 2.50.
Methyl 2,3-bis(4-nitrophenyl)-5′-(trifluoromethyl)spiro[indene-1,2′-pyrrolidine]-5′-carboxylate 4n.
Molecules 28 07809 i015
Yield: 63% as a yellow solid. M.p. 223–224 °C. 1H NMR (500 MHz, CDCl3): δ 8.16 (dd, J = 8.7, 3.2 Hz, 4H, Ar), 7.64 (d, J = 7.4 Hz, 1H, Ar), 7.41–7.33 (m, 6H, Ar), 7.19 (d, J = 7.4 Hz, 1H, Ar), 3.65 (s, 3H, OCH3), 3.08 (s, 1H, NH), 2.68–2.62 (m, 1H, CH2), 2.45–2.40 (m, 1H, CH2), 2.31–2.29 (m, 1H, CH2), 1.87–1.81 (m, 1H, CH2). 13C{1H} NMR (126 MHz, CDCl3): δ 169.6, 149.9, 148.6, 147.5, 147.2, 142.3, 140.3, 140.2, 138.9, 131.1, 129.9, 128.4, 128.0, 125.1 (q, J = 285.4 Hz, CF3), 123.8, 123.5, 122.9, 120.7, 78.0, 71.9 (q, J = 28.4 Hz, >C<), 53.3, 35.5, 30.4. 19F NMR (282 MHz, CDCl3): δ −76.89 (s, 3F, CF3). Elemental analysis calcd (%) for C27H20F3N3O6: C, 60.11; H, 3.74; N, 7.79; found: C, 60.24; H, 3.77; N, 7.72.
Methyl 5′-(trifluoromethyl)-2,3-bis(4-(trifluoromethyl)phenyl)spiro[indene-1,2′-pyrrolidine]-5′-carboxylate 4o.
Molecules 28 07809 i016
Yield: 51% as a yellow solid. M.p. 144–146 °C. 1H NMR (300 MHz, CDCl3): δ 7.63–7.54 (m, 5H, Ar), 7.40–7.28 (m, 6H, Ar), 7.20 (d, J = 6.8 Hz, 1H, Ar), 3.56 (s, 3H, OCH3), 3.07 (s, 1H, NH), 2.66–2.58 (m, 1H, CH2), 2.44–2.30 (m, 2H, CH2), 1.88–1.84 (m, 1H, CH2). 13C{1H} NMR (126 MHz, CDCl3): δ 169.7, 150.2, 148.3, 140.9, 139.2, 138.9, 137.4, 130.6, 129.7 (q, J = 32.8 Hz), 129.4, 128.2, 127.6, 125.4 (q, J = 3.7 Hz, >C<), 125.2 (q, J = 3.7 Hz, >C<), 125.2 (q, J = 285.9 Hz, CF3), 124.0 (q, J = 272.8 Hz, CF3), 123.9 (q, J = 272.4 Hz, CF3), 122.8, 120.7, 77.9, 71.9 (q, J = 28.4 Hz, >C<), 53.0, 35.5, 30.4. 19F NMR (282 MHz, CDCl3): δ −62.61 (s, 3F, CF3), -62.62 (s, 3F, CF3), −77.27 (s, 3F, CF3). Elemental analysis calcd (%) for C29H20F9NO2: C, 59.49; H, 3.44; N, 2.39; found: C, 59.35; H, 3.58; N, 2.55.
Methyl 2,3-bis(4-fluorophenyl)-5′-(trifluoromethyl)spiro[indene-1,2′-pyrrolidine]-5′-carboxylate 4p.
Molecules 28 07809 i017
Yield: 73% as a yellow solid. M.p. 155–157 °C. 1H NMR (300 MHz, CDCl3): δ 7.60 (d, J = 6.6 Hz, 1H, Ar), 7.34–7.28 (m, 2H, Ar), 7.22–7.17 (m, 3H, Ar), 7.15–7.10 (m, 2H, Ar), 7.03–6.94 (m, 4H, Ar), 3.62 (s, 3H, OCH3), 3.05 (s, 1H, NH), 2.64–2.53 (m, 1H, CH2), 2.44–2.27 (m, 2H, CH2), 2.00–1.89 (m, 1H, CH2). 13C{1H} NMR (126 MHz, CDCl3): δ 169.7, 162.2 (d, J = 248.2 Hz), 161.9 (d, J = 246.9), 150.4, 147.5, 141.6, 138.9, 131.9 (d, J = 7.6 Hz), 131.4 (d, J = 3.8 Hz), 130.8 (d, J = 7.6 Hz), 129.8 (d, J = 3.8 Hz), 127.9, 127.1, 125.3 (q, J = 285.9 Hz, CF3), 122.6, 120.5, 115.4 (d, J = 3.7 Hz), 115.2 (d, J = 5.0 Hz), 77.4, 72.0 (q, J = 28.3 Hz, >C<), 53.1, 35.3, 30.5. 19F NMR (282 MHz, CDCl3): δ −77.16 (s, 3F, CF3), −113.98 (s, 1F, F), −114.08 (s, 1F, F). Elemental analysis calcd (%) for C27H20F5NO2: C, 66.80; H, 4.15; N, 2.89; found: C, 67.03; H, 4.23; N, 3.01.

4. Conclusions

In summary, we have presented a convenient and highly efficient method of accessing CF3-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- 2-carboxylates 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.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules28237809/s1. The following are available online: copies of 1H and 13C NMR spectra for all novel compounds.

Author Contributions

Conceptualization, S.N.O.; methodology, S.N.O.; investigation, D.V.V., A.S.B. and I.A.G. (synthesis, NMR spectra registry and characterization); synthesis, D.V.V. and A.S.B., X-ray investigation, A.F.S.; writing—original draft preparation, S.N.O. and D.V.V.; writing—review and editing, D.V.V. and S.N.O.; supervision, S.N.O.; project administration, S.N.O.; funding acquisition, S.N.O. All authors have read and agreed to the published version of the manuscript.

Funding

This work was financially supported by the Russian Science Foundation (grant RSF No. 21-13-00328).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Data are contained within the article and Supplementary Materials.

Acknowledgments

NMR studies and spectral characterization were performed with financial support from the Ministry of Science and Higher Education of the Russian Federation using the equipment of the Center for Molecular Composition Studies of INEOS RAS.

Conflicts of Interest

The authors declare no conflict of interest.

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Molecules 28 07809 g001
Figure 1. Selected examples of bioactive azaspiro[4,4]nonanes.
Figure 1. Selected examples of bioactive azaspiro[4,4]nonanes.
Molecules 28 07809 g001
Molecules 28 07809 sch001
Scheme 1. Previous and present work: (a) preparation of isoquinolones; (b) preparation of pirimidoindolones; (c) synthesis of dehydroprolines.
Scheme 1. Previous and present work: (a) preparation of isoquinolones; (b) preparation of pirimidoindolones; (c) synthesis of dehydroprolines.
Molecules 28 07809 sch001
Molecules 28 07809 sch002
Scheme 2. Synthesis of starting dehydroprolines 2.
Scheme 2. Synthesis of starting dehydroprolines 2.
Molecules 28 07809 sch002
Molecules 28 07809 sch003
Scheme 3. Synthesis of spiro prolines 4a–p.
Scheme 3. Synthesis of spiro prolines 4a–p.
Molecules 28 07809 sch003
Molecules 28 07809 g002
Figure 2. X-ray structure of 4a (CCDC 2301938).
Figure 2. X-ray structure of 4a (CCDC 2301938).
Molecules 28 07809 g002
Molecules 28 07809 sch004
Scheme 4. Proposed pathway of spiro cyclization.
Scheme 4. Proposed pathway of spiro cyclization.
Molecules 28 07809 sch004
Table 1. Optimization of [3+2]-annulation of 5-phenyl dehydroproline 2a with acetylene 3a 1.
Table 1. Optimization of [3+2]-annulation of 5-phenyl dehydroproline 2a with acetylene 3a 1.
Molecules 28 07809 i001
EntryCatalyst (mol%)Ag Additive (Equiv.)Other Additive (Equiv.)Yield 2 (%)
1[Cp*RhCl2]2 (5)AgBF4 (0.3)-41(28 3)
2[Cp*RhCl2]2 (5)AgBF4 (1)-39
3[Cp*RhCl2]2 (5)AgOTf (1)-43
4[Cp*RhCl2]2 (5)AgOTf (1)Cu(OAc)2∙H2O (1)71
5[Cp*RhCl2]2 (2)AgOTf (1)Cu(OAc)2∙H2O (1)42
6[Cp*RhCl2]2 (5)AgOTf (1)Cu(OAc)2∙H2O (2)63
7[Cp*RhCl2]2 (5)AgOAc (0.3)Cu(OAc)2∙H2O (1)NR
8[Cp*RhCl2]2 (5)AgOTf (0.3)Cu(OAc)2∙H2O (1)80
9[Cp*RhCl2]2 (5)AgBF4 (0.3)Cu(OAc)2∙H2O (1)77
10[Cp*RhCl2]2 (5)AgSbF6 (0.3)Cu(OAc)2∙H2O (1)79
11[Cp*RhCl2]2 (5)AgOTf (0.3)Cu(OAc)2∙H2O (0.5)88(75 3)
12[Cp*RhCl2]2 (5)AgOTf (0.3)CsOAc (2)19
13[Cp*RhCl2]2 (5)AgOTf (0.3)Zn(OAc)2∙H2O (2)56
14[Cp*RhCl2]2 (5)-Cu(OAc)2∙H2O (1)NR
15[Cp*IrCl2]2 (7)AgOTf (1)Cu(OAc)2∙H2O (1)NR
16[Cp*CoI2]2 (10)AgOTf (1)Cu(OAc)2∙H2O (1)NR
1 Reagents and conditions: dehydroproline 2a (0.2 mmol), acetylene 3a (0.22 mmol), DCE (2 mL), 80 °C, 16 h; 2 Determined via 19F NMR spectroscopy; 3 Isolated yield.
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MDPI and ACS Style

Bubnova, A.S.; Vorobyeva, D.V.; Godovikov, I.A.; Smol’yakov, A.F.; Osipov, S.N. Synthesis of CF3-Containing Spiro-[Indene-Proline] Derivatives via Rh(III)-Catalyzed C-H Activation/Annulation. Molecules 2023, 28, 7809. https://doi.org/10.3390/molecules28237809

AMA Style

Bubnova AS, Vorobyeva DV, Godovikov IA, Smol’yakov AF, Osipov SN. Synthesis of CF3-Containing Spiro-[Indene-Proline] Derivatives via Rh(III)-Catalyzed C-H Activation/Annulation. Molecules. 2023; 28(23):7809. https://doi.org/10.3390/molecules28237809

Chicago/Turabian Style

Bubnova, Alexandra S., Daria V. Vorobyeva, Ivan A. Godovikov, Alexander F. Smol’yakov, and Sergey N. Osipov. 2023. "Synthesis of CF3-Containing Spiro-[Indene-Proline] Derivatives via Rh(III)-Catalyzed C-H Activation/Annulation" Molecules 28, no. 23: 7809. https://doi.org/10.3390/molecules28237809

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