Practical Synthesis of α-Perfluoroalkyl Cyclic Imines and Amines

Abstract

A convenient and simple approach for the preparation of α-CF₃ and α-C₂F₅ substituted pyrrolines, tetrahydropyridines, tetrahydroazepine is described. Claisen condensation of N-protected cyclic amides with esters of perfluorocarboxylic acids followed by deprotection and decarboxylation in acidic media leads to the desired products. Reduction of these imines permits to obtain 5-, 6-, and 7-membered cyclic amines with α-CF₃ or α-C₂F₅ group in good to moderate overall yields.

From different viewpoints, the α-substituted cyclic imines are of important class of nitrogen heterocycles. Besides the fact that some of them are present in natural products, [¹] they are also very versatile and useful building blocks to construct a large variety of biologically interesting heterocyclic compounds, especially pyrrolidine, piperidine, or azepane cycles. [²] Since these azacycles are the structural feature of many alkaloids, the α-substituted cyclic imines can be also a starting point in alkaloid synthesis. [³] As an evidence of their outstanding importance it may be noted that by the end of the year 2000 there were over 12 000 compounds with piperidine and pyrrolidine entities mentioned in clinical or preclinical studies. [4]

Despite the possible interest in fluorinated analogues of these imines, the preparation of cyclic imines bearing an α-fluoroalkyl group has almost not been studied so far. [5] In this paper, we have focused our interest on an easy access to α-trifluoromethylated and α-pentafluoroethylated pyrrolines, tetrahydropyridines, and tetrahydroazepines not only for potential bioactivity of their derivatives but also as prospective valuable fluorinated building blocks that can be converted into a variety of nitrogen heterocycles and other functionalized acyclic compounds.

Among the known syntheses of the nonfluorinated α-substituted cyclic imines, [6] the most common and useful is the Claisen condensation of N-protected lactams with esters followed by simultaneous deprotection and decarboxylation in acidic media (Scheme  [¹] ) [7] or the reaction of N-protected amides with organolithium reagents. [8] It seems to be a challenging synthetic task to extend the field of application of these two methods to the organofluorine chemistry. Much attention has been devoted to the development of synthetic routes to various classes of fluorinated compounds. Very often fluorinated compounds demonstrate unusual, unpredictable chemical properties due to the influence of perfluorinated fragment.

Concerning the organometallic approach, we have recently been able to demonstrate that α-pentafluoroethylpyrroline and -tetrahydropyridine are accessible by the reaction of pentafluoroethyllithium with lactim esters in the presence of boron trifluoride. [9] Unfortunately, on account of the instability of trifluoromethyllithium and low reactivity of other nucleophilic trifluoromethylating reagents [¹0] this method does not permit the synthesis of the α-CF₃ heterocycles. This restriction promoted us to study Claisen strategy­, especially because the starting fluorinated compounds (esters of perfluorinated carboxylic acids) in this approach are readily available.

Our attempt to synthesize the α-CF₃ pyrroline starting from N-vinylpyrrolidinone and ethyl trifluoroacetate (model substrates) under literature conditions for non­fluorinated aromatic and aliphatic esters [7] was unsuccessful. Therefore, we decided to study each steps separately and more carefully. [¹¹]

At first, we carried out the condensation of N-protected cyclic amides with esters of aliphatic perfluorinated acids (Scheme  [²] ). As one would expect, the polyfluorinated esters­ easily react with amides in Claisen condensation manner and after deprotection, the corresponding per­fluorinated acyllactams 2 were synthesized in very good yields. It is not unusual that initially these substances were isolated from aqueous media as hydrate as the corresponding 1,1-diols 1; the ability of electron-withdrawing CF₃ and C₂F₅ group to stabilize the tetrahedral adducts of such type are well documented. [¹²]

After elimination of water from the gem-diols 1a-f by azeotropic drying with toluene, the corresponding per­fluoroacyllactams 2a-f were isolated in quantitative yields. Like the nonfluorinated derivatives, [¹³] the acyl­caprolactams 2e and 2f exist exclusively in the keto form, whereas the perfluoroacycllactams 2a-d with five- and six-membered rings were isolated as enols (accordingly to the NMR data, the content of keto form in chloroform solution of 2a-d is less than 2%). Earlier, [¹³] it has been shown that 2-acyl derivatives of piperidin-2-one are amidoketones, but in the corresponding pyrrolidin-2-ones, the keto form is the major tautomer. As an example, N-methyl-3-trifluoroacylpyrrolidin-2-one consists of 20% of enol form. [¹4]

We have then investigated the hydrolysis and decarboxylation of perfluoroacyllactams 1a-f under aqueous acidic condition. In a typical experiment, trifluoroacylated amide 1a was dissolved in aqueous 6 M HCl and heated under reflux and the reaction was monitored by spectra. After one hour, besides the signal at -83.9 ppm, the singlet at -87.7 ppm appeared, which corresponds to the structure 3a and no other signals were detected in ^¹9F NMR spectra during the progress of hydrolysis. Consequently, decarboxylation of α-trifluoroacylated γ-amino acid A - intermediate that initially formed in the course of hydrolysis of amide bond of 1a - proceeds very fast and the rate-determining step seems to be the hydrolysis (Scheme  [³] ). Progress of the reaction is shown in Table  [¹] . Quite a prolonged time (60 h) is necessary to complete the reaction. It dramatically differs from the reaction time necessary for decarboxylation of the nonfluorinated acyllactams for which four hours are quite enough to finish the transformation. [7]

Unfortunately, the water-stable salt 3a easily loses a molecule of water when we attempted to isolate it in pure form. Nevertheless, more stable pentafluoroethyl derivative 3b was isolated successfully and fully characterized by NMR data and chemical analysis.

When decarboxylation was completed, the reaction mixture was carefully made alkaline with potassium hydroxide under cooling, and the hemiaminal formed was extracted with diethyl ether. Removal of solvent under atmospheric pressure yields aminal 4a admixed with imine 5a. To prepare pure imine 5a, this mixture was dissolved in chloroform and refluxed using a Dean-Stark adapter and after careful removal of solvents, the residue was distilled under atmospheric pressure. Alternately, the crude cyclic hemiaminals can be distilled at atmospheric pressure to the receiving flask charged with anhydrous sodium sulfate. Removal of the drying agent afforded the imine 5a in pure form.

With an aim to determine the scope and limitations of this procedure, we carried out decarboxylation under analogous conditions with substrates 1b-f. In all instances, the α-pentafluoroethyl- or α-trifluoromethylimines 5b-d with five- and six-membered rings were obtained in excellent to good yields (Table  [²] ) after a reaction time of 60 hours. Hemiaminals 4b and 4d were found to be stable so that they could be isolated and characterized in pure form.

Notable results were obtained when we studied the hydrolysis and decarboxylation of perfluoroacylcaprolactams 1e,f. Accord to ^¹9F NMR spectra, starting acyllactams were consumed in 40 hours and the main fluoro­-containing products were the corresponding tri­fluoroacetic and pentafluoropropionic acids. Therefore, we were unable to prepare imine 5f, which was only detected by ^¹9F NMR spectroscopy. Another tetrahydro­azepine product 5e was isolated in low yield. Although some details of the reaction deserve further study, we suggest that retro-Claisen reaction takes place in these cases. Reasonable explanation of dramatic difference between five- and six-membered acyllactams 1a-d contrary to seven­-membered acyllactams 1e,f seems to be connected with the fact that 1a-d can exist in water as a mixture of gem-diols and enols whereas 1e,f as a mixture of gem-diols­ and ketones (Scheme  [²] ).

We have simplified further the preparation of imines 5a-e by carrying out the acylation of N-protected amides followed by deprotection and simultaneous decarboxylation without isolation of 1a-e (one-pot). In all cases for one-pot procedure yields are better than the corresponding overall yields obtained in two-step approach (Table  [²] ). Therefore, starting from cheap and available starting materials the cyclic amines bearing α-CF₃ or α-C₂F₅ group can be easily synthesized in a two-step one-pot procedure. This sequence can be easily scaled up to produce these imines in large quantities. For instance, 100 g of 5a have been produced in one batch.

Having in our hands a number of cyclic imines bearing CF₃ and C₂F₅ group, we decided to investigate the reduction of them. This reaction opens a general and practical way to a new synthesis of simplest trifluoro and penta­fluoro analogues of monosubstituted pyrrolidine, piperidine, and azepane alkaloids. As far as we know, the syntheses of only α-trifluromethyl pyrrolidine and piperidine have been reported in literature. [¹5]

We chose zinc in acetic acid, NaBH₄/AcOH system in methanol, and catalytic hydrogenation using Pd/C as a catalyst as reducing agents. The isolated yields and reaction times for reduction are summarized in Table  [³] . The best yields were achieved in the reduction of 5a,b with hydrogen and palladium under atmospheric pressure. Unfortunately, this method does not work in the case of six- and seven-membered imines 5c-e due to very low rate of the reactions. Probably, hydrogenation under higher pressure permits to overcome this problem. Zinc in acetic acid gave low yield and the problem of separation of reaction mixture from inorganic materials. The most convenient and practical reduction of imines 5a-e for laboratory use was found to be with the in situ generated sodium triacetoxyborohydride in methanol. It is applicable for all substrate 5a-e under investigation; the reaction proceeds in reasonable time and leads to good yields of the desired products 6a-e (Scheme  [4] ).

In conclusion, we have shown that syntheses of the α-CF₃ and α-C₂F₅ substituted pyrrolines, tetrahydropyridines, and tetrahydroazepine can be achieved through classic Claisen condensation of N-protected cyclic amides with esters of perfluorocarboxylic acids followed by deprotection and decarboxylation. This practical and easily scalable method utilizes available and cheap fluorinated starting materials and can be realized in two-step one-pot technique. Together with subsequent reduction this opens a general and practical way to new synthesis of simplest trifluoro and pentafluoro analogues of monosubstituted pyrrolidine, piperidine, and azepane alkaloids. The reducing reagent of choice was found to be the sodium triacet­oxyborohydride.

NMR spectra were obtained on a Bruker DPX-200 (200.1 MHz for ^¹H; 188.3 MHz for ^¹9F; 50.32 MHz for ^¹³C) or a Bruker AM-360 (360.1 MHz for ^¹H; 90.5 MHz for ^¹³C) spectrometer. Chemical shifts for ^¹H NMR data are referenced internally to TMS (0.0); chemical shifts for ^¹³C NMR data are referenced to corresponding CDCl₃ (77.2), DMSO-d ₆ (39.5); and chemical shifts for ^¹9F NMR data are referenced to CFCl₃ (0.0) or PhCF₃ (-63.90). High-resolution mass spectra (HRMS) were recorded using a Varian MAT CH7A instrument at 70 eV. Melting points are uncorrected. TLC was carried out on precoated silica gel plates (Merck 60F₂₅₄) with UV light visualization. Flash chromatography was performed using MP Silica 60 (320-630 mesh) with the indicated solvents. All reactions were conducted under N₂. THF was distilled from sodium/benzophenone prior to use. All reagents were purchased from Aldrich­, unless otherwise stated. The starting N-(diethoxymethyl)piperidin-2-one was prepared by the reaction of piperidin-2-one with triethyl orthoformate according to the described procedure. [¹6] N-Vinylpyrrolidin-2-one and N-vinylcaprolactams were distilled prior to use.

Trifluoroacetyl and Pentafluoropropanoyl Lactams 2a-f and Their Hydrated Forms ( gem -Diols) 1a-c; General Procedure

To a stirred and heated at reflux suspension of NaH (60% in mineral oil, 10.4 g, 0.26 mol) in anhyd THF (300 mL) was added a mixture of the N-protected lactam [0.20 mol, N-vinylpyrrolidin-2-one (22 g), N-(diethoxymethyl)piperidin-2-one (40 g), or N-vinylcaprolactam (28 g)] and the ester of the corresponding perfluorocarboxylic acid [0.21 mol, ethyl trifluoroacetate (30 g) or ethyl pentafluoropropionate (40 g)] at a such rate that the evolution of H₂ and boiling of the mixture was not very intensive. After heating for an additional hour, the reaction mixture was cooled down to r.t. and the resultant clear solution was carefully diluted with a mixture of H₂O (50 mL) and AcOH (15.6 g). The layers were separated and the aqueous layer was extracted again with THF (100 mL). The combined organic extracts (solution of the crude N-protected ketolactam in THF) were slowly added (over 1 h) to aq 3 M HCl (400 mL) under stirring and heating at reflux. THF was collected during the addition by use of a short-path distilling head. After heating for an additional 0.5 h, the mixture was cooled to r.t., filtered through a Celite plug, extracted with cold pentane (2 × 100 mL) and the aqueous solution was evaporated carefully under reduced pressure at r.t. To obtain the pure gem-diols 1a-c, the residues were crystallized from H₂O with a drop of concd HCl. To isolate the pure acyllactams 2a-f, the residues were dissolved in CHCl₃ (250 mL), and the solutions were dried under Dean-Stark condition; the CHCl₃ was removed in vacuo and residues were crystallized from hexane-CH₂Cl₂ mixture.

3-(2,2,2-Trifluoro-1,1-dihydroxyethyl)pyrrolidin-2-one (1a)

Yield: 33.4 g (84%); white crystals; mp 91-92 ˚C (dec.).

^¹H NMR (200 MHz, DMSO-d ₆): δ = 2.01-2.14 (m, 2 H), 2.73 (dd, J = 9.7, 9.9 Hz, 1 H), 3.14-3.22 (m, 2 H), 7.22 (s, 1 H, NH), 8.14 (s, 1 H, OH), 8.45 (s, 1 H, OH).

^¹³C NMR (50 MHz, DMSO-d ₆): δ = 22.51, 39.54, 93.11 [q, J = 31.3 Hz, C(OH)₂], 122.95 (q, J = 288.2 Hz, CF₃), 177.53 (CONH).

^¹9F NMR (188 MHz, DMSO-d ₆): δ = -83.87.

HRMS (EI): m/z calcd for C₆H₆F₃NO₂ (M - H₂O): 181.0351; found: 181.0351.

3-(2,2,3,3,3-Pentafluoro-1,1-dihydroxypropyl)pyrrolidin-2-one (1b)

Yield: 41.8 g (81%); white crystals; mp 82-84 ˚C (dec.).

^¹H NMR (200 MHz, DMSO-d ₆): δ = 2.04-2.13 (m, 2 H), 2.81 (dd, J = 9.8, 9.3 Hz, 1 H), 3.16-3.23 (m, 2 H), 7.19 (s, 1 H, NH), 8.39 (s, 1 H, OH), 8.51 (s, 1 H, OH).

^¹³C NMR (50 MHz, DMSO-d ₆): δ = 22.71, 39.85, 42.43, 94.15 [t, J = 25.4 Hz, C(OH)₂], 111.20 (tq, J = 260.7, 34.1 Hz, CF₂CF₃), 118.39 (qt, J = 287.7, 36.0 Hz, CF₂CF₃), 177.27 (CONH).

^¹9F NMR (188 MHz, DMSO-d ₆): δ = -127.89, -126.43, -123.60, -122.14 (2 F, AB system, J _AB = 275.9 Hz, CF₂), -78.70 (3 F, CF₃).

HRMS (EI): m/z calcd for C₇H₆F₅NO₂ (M - H₂O): 231.0319; found: 231.0317.

3-(2,2,2-Trifluoro-1,1-dihydroxyethyl)piperidin-2-one (1c)

Yield: 35.4 g (83%); white crystals; mp 95-96 ˚C (dec.).

^¹H NMR (200 MHz, DMSO-d ₆): δ = 1.55-1.90 (m, 4 H), 2.60-2.68 (m, 1 H), 3.08-3.22 (m, 2 H), 7.34 (s, 1 H, NH), 8.39 (s, 1 H, OH), 9.02 (s, 1 H, OH).

^¹³C NMR (50 MHz, DMSO-d ₆): δ = 21.00, 21.94, 40.91, 43.70, 94.30 [t, J = 30.4 Hz, C(OH)₂], 123.29 (t, J = 289.7 Hz, CF₃), 172.42 (CONH).

^¹9F NMR (188 MHz, DMSO-d ₆): δ = -80.74.

HRMS (EI): m/z calcd for C₇H₈F₃NO₂ (M - H₂O): 195.0507; found: 195.0509.

(3 Z )-3-(2,2,2-Trifluoro-1-hydroxyethylidene)pyrrolidin-2-one (2a)

Yield: 30.4 g (84%); white crystals; mp 117-121 ˚C.

^¹H NMR (200 MHz, CDCl₃): δ = 2.90-3.02 (m, 2 H), 3.49-3.56 (m, 2 H), 6.80 (br s, 1 H, NH), 11.88 (br s, 1 H, OH).

^¹³C NMR (50 MHz, DMSO-d ₆): δ = 22.12, 40.70, 104.65, 119.50 (q, J = 274.6 Hz, CF₃), 148.66 [q, J = 37.2 Hz, C(OH)CF₃], 175.60 (CONH).

^¹9F NMR (188 MHz, DMSO-d ₆): δ = -71.60.

HRMS (EI): m/z calcd for C₆H₆F₃NO₂: 181.0351; found: 181.0351.

(3 Z )-3-(2,2,3,3,3-Pentafluoro-1-hydroxypropylidene)pyrrolidin-2-one (2b)

Yield: 37.4 g (81%), white crystals; mp 110-114 ˚C.

^¹H NMR (200 MHz, CDCl₃): δ = 2.81-2.87 (m, 2 H), 3.35-3.42 (m, 2 H), 6.80 (br s, 1 H, NH).

^¹³C NMR (50 MHz, CDCl₃): δ = 22.32, 41.09, 110.03, 110.71 (tq, J = 254.8, 38.8 Hz, CF₂CF₃), 119.21 (qt, J = 287.4, 37.1 Hz, CF₂CF₃), 146.84 [t, J = 27.3 Hz, C(OH)CF₃], 175.34 (CONH).

^¹9F NMR (188 MHz, CDCl₃): δ = -121.58 (2 F, CF₂CF₃), -83.70 (3 F, CF₂CF₃).

HRMS (EI): m/z calcd for C₇H₆F₅NO₂: 231.0315; found: 231.0319.

(3 Z )-3-(2,2,2-Trifluoro-1-hydroxyethylidene)piperidin-2-one (2c)

Yield: 32.3 g (83%); white crystals; mp 88-90 ˚C.

^¹H NMR (200 MHz, CDCl₃): δ = 1.78-1.91 (m, 2 H), 2.49-2.63 (m, 2 H), 3.27-3.41 (m, 2 H), 6.84 (br s, 1 H, NH), 15.26 (s, 1 H, OH).

^¹³C NMR (50 MHz, CDCl₃): δ = 21.55, 21.66, 41.43, 99.85, 119.75 (q, J = 277.4 Hz, CF₃), 155.77 [q, J = 34.4 Hz, C(OH)CF₃], 171.64 (CONH).

^¹9F NMR (188 MHz, CDCl₃): δ = -68.35.

HRMS (EI): m/z calcd for C₇H₈F₃NO₂: 195.0507; found: 195.0510.

(3 Z )-3-(2,2,3,3,3-Pentafluoro-1-hydroxypropylidene)piperidin-2-one (2d)

Yield: 38.7 g (79%); white crystals; mp 117-118 ˚C.

^¹H NMR (200 MHz, DMSO-d ₆): δ = 1.63-1.75 (m, 2 H), 2.43-2.49 (m, 2 H), 3.15-3.22 (m, 2 H), 3.52 (br s, 1 H, OH), 8.80 (br s, 1 H, NH).

^¹³C NMR (50 MHz, DMSO-d ₆): δ = 20.97, 21.18, 40.14, 101.61, 109.84 (tq, J = 257.3, 38.3 Hz, CF₂CF₃), 118.39 (qt, J = 287.3, 36.6 Hz, CF₂CF₃), 154.93 [t, J = 24.2 Hz, C(OH)C₂F₅], 170.87 (CONH).

^¹9F NMR (188 MHz, DMSO-d ₆): δ = -116.64 (2 F, CF₂CF₃), -83.10 (3 F, CF₂CF₃).

HRMS (EI): m/z calcd for C₈H₈F₅NO₂: 245.0479; found: 245.0475.

3-(Trifluoroacetyl)azepan-2-one (2e)

Yield: 29.7 g (71%); white crystals; mp 78-80 ˚C.

^¹H NMR (200 MHz, CDCl₃): δ = 1.43-1.61 (m, 2 H), 1.80-1.94 (m, 2 H), 2.08-2.16 (m, 2 H), 3.22-3.38 (m, 2 H), 3.95 (d, J = 11.3 Hz, 1 H), 6.57 (br s, 1 H, NH).

^¹³C NMR (50 MHz, CDCl₃): δ = 21.55, 21.66, 41.43, 99.85, 119.75 (q, J = 277.4 Hz, CF₃), 171.64 (CONH), 190.7 [q, J = 34.4 Hz, C(O)CF₃].

^¹9F NMR (188 MHz, CDCl₃): δ = -78.13.

HRMS (EI): m/z calcd for C₈H₁₀F₃NO₂: 209.0662; found: 209.0664.

3-(2,2,3,3,3-Pentafluoropropanoyl)azepan-2-one (2f)

Yield: 34.7 g (67%); white crystals; mp 75-77 ˚C.

^¹H NMR (200 MHz, CDCl₃): δ = 1.40-1.57 (m, 2 H), 1.75-1.87 (m, 2 H), 2.01-2.15 (m, 2 H), 3.22-3.32 (m, 2 H), 3.97 (d, J = 10.7 Hz, 1 H), 7.18 (br s, 1 H, NH).

^¹³C NMR (50 MHz, CDCl₃): δ = 24.32, 28.68, 28.79, 42.52, 53.27, 106.60 (tq, J = 265.7, 61.8 Hz, CF₂CF₃), 117.93 (qt, J = 286.8, 64.7 Hz, CF₂CF₃), 173.93 (CONH), 191.20 [dd, J = 25.4, 29.7 Hz, C(O)C₂F₅].

^¹9F NMR (188 MHz, CDCl₃): δ = -125.67, -124.15, -122.52, -121.00 (2 F, AB system, J _AB = 287.9 Hz, CF₂), -82.22 (3 F, CF₂CF₃).

HRMS (EI): m/z calcd for C₉H₁₀F₅NO₂: 259.0643; found: 259.0632.

6-Amino-1,1,1,2,2-pentafluorohexane-3,3-diol Hydrochloride (3b)

The gem-diol 1b (2.5 g, 10 mmol) was dissolved under heating in aq 6 M HCl (50 mL) and the clear solution was heated at reflux for 60 h. After cooling, the solvent was carefully removed in vacuo at r.t. and the residue was triturated with cold hexane, filtered, and dried in vacuo to give the hydrochloride 3b as a brownish solid; yield: 1.9 g (87%); mp 127-129 ˚C (H₂O).

^¹H NMR (200 MHz, D₂O): δ = 1.85-1.94 (m, 4 H), 3.03 (t, J = 6.0 Hz, 2 H), 3.16-3.23 (m, 2 H), 4.75 (br s, 3 H, NH₃), 8.55 (br s, 2 H, OH).

^¹³C NMR (50 MHz, D₂O): δ = 19.91, 31.64, 39.65, 94.60 [t, J = 25.4 Hz, C(OH)₂], 112.90 (tq, J = 262.8, 33.9 Hz, CF₂CF₃), 119.18 (qt, J = 286.9, 35.3 Hz, CF₂CF₃).

^¹9F NMR (188 MHz, D₂O): δ = -127.34 (2 F, CF₂), -79.84 (3 F, CF₃).

Anal. Calcd for C₆H₁₃ClF₅NO₂˙H₂O: C, 26.0; H, 4.7. Found: C, 26.4; H, 4.8.

Trifluoromethyl- and Pentafluoroethylimines 5a-e and Hemiaminals 4a-c; General Procedure

Method A (Stepwise): The cyclic acyllactams 2a-e (0.10 mol) or gem-diols 1a-c (0.10 mol) were dissolved under heating in aq 6 M HCl (200 mL) and the clear solutions were heated at reflux for 60 h. After that, the reaction mixture was cooled to r.t., filtered through a Celite plug, extracted with cold pentane (2 × 100 mL), carefully made alkaline with aq 50% KOH to pH 12-13 under cooling (ice-bath) and then extracted with Et₂O (4 × 75 mL). The combined organic layers were dried (K₂CO₃) and concentrated under atmospheric pressure to give a liquid residue consisting of a mixture of crude cyclic hemiaminal and the corresponding imine. The hemiaminal products usually are unstable at r.t., but in several cases (4b, c, and d) they can be isolated in pure form as a solid. To remove the H₂O, the crude cyclic hemiaminals were distilled at atmospheric pressure to the receiving flask charged with anhyd Na₂SO₄ (20 g). The drying agent was removed by filtration to afford the imine as a clear, colorless liquid with characteristic odor.

Method B (Without Isolation of Acyllactams): To a stirred and heated at reflux suspension of NaH (60% in mineral oil, 10.4 g, 0.26 mol) in anhyd THF (300 mL) was added a mixture of the N-protected lactam [0.20 mol, N-vinylpyrrolidin-2-one (22 g), N-(diethoxymethyl)piperidin-2-one (40 g) or N-vinylcaprolactam (28 g)] and the ester of the corresponding perfluorocarbonic acid [0.21 mol, ethyl trifluoroacetate (30 g) or ethyl pentafluoropropionate (40 g)] at such rate that the evolution of H₂ and boiling of the mixture was not very intensive. After heating for an additional hour, the reaction mixture was cooled to r.t. and the resultant clear solution was carefully diluted with a mixture of H₂O (50 mL) and AcOH (15.6 g). The layers were separated and the aqueous layer was extracted with THF (100 mL). The combined organic extracts (solution of the crude N-protected ketolactam in THF) was slowly added (over 1 h) to aq 6 M HCl (400 mL) under stirring and heating at reflux. THF was collected during the addition using a short-path distilling head. After heating for an additional 60 h, the mixture was cooled to r.t., and the product was isolated as described above in Method A.

2-(Pentafluoroethyl)pyrrolidin-2-ol (4b)

Yield: 82% (Method A); colorless crystals; mp 52-54 ˚C (dec.).

^¹H NMR (200 MHz, CDCl₃): δ = 1.88-2.16 (m, 4 H), 2.67 (br s, 2 H, NH and OH), 3.09-3.16 (m, 2 H).

^¹9F NMR (188 MHz, CDCl₃): δ = -128.55, -127.11, -123.77, -122.34 (2 F, AB system, J _AB = 269.0 Hz, CF₂), -79.78 (3 F, CF₃).

HRMS (EI): m/z calcd for C₆H₆F₅N (M - H₂O): 187.0420; found: 187.0420.

2-(Trifluoromethyl)piperidin-2-ol (4c)

Yield: 89% (Method A); colorless crystals; mp 91-92 ˚C (dec.).

^¹H NMR (200 MHz, DMSO-d ₆): δ = 1.39-1.66 (m, 6 H), 1.67 (br s, 1 H, NH or OH), 2.67-3.13 (m, 2 H), 5.80 (br s, 1 H, NH or OH).

^¹³C NMR (50 MHz, DMSO-d ₆): δ = 18.64, 24.36, 28.49, 39.16, 81.37 [t, J = 28.5 Hz, C(OH)NH], 125.16 (q, J = 286.1 Hz, CF₃).

^¹9F NMR (188 MHz, DMSO-d ₆): δ = -78.65.

Anal. Calcd for C₆H₁₃ClF₃NO₂: C, 42.6; H, 6.0. Found: C, 42.1; H, 6.1.

2-(Pentafluoroethyl)piperidin-2-ol (4d)

Yield: 83% (Method A); colorless crystals; mp 59-61 ˚C (dec.).

^¹H NMR (200 MHz, CDCl₃): δ = 1.53-1.75 (m, 6 H), 2.04 (br s, 1 H, NH or OH), 2.58 (br s, 1 H, NH or OH), 2.86-3.13 (m, 2 H).

^¹³C NMR (50 MHz, CDCl₃): δ = 18.79, 24.55, 29.04, 39.85, 82.36 [t, J = 29.7 Hz, C(OH)NH], 110.24 (tq, J = 258.1, 35.6 Hz, CF₂CF₃), 118.12 (qt, J = 287.4, 36.2 Hz, CF₂CF₃).

^¹9F NMR (188 MHz, CDCl₃): δ = -128.65, -127.21, -123.87, -122.44 (2 F, AB system, J _AB = 269.0 Hz, CF₂), -80.88 (3 F, CF₃).

HRMS (EI): m/z calcd for C₇H₈F₅N (M - H₂O): 201.0571; found: 201.0579.

5-(Trifluoromethyl)-3,4-dihydro-2 H -pyrrole (5a)

Yield: 83% (Method A); colorless liquid; bp 78-81 ˚C/760 Torr.

^¹H NMR (200 MHz, CDCl₃): δ = 2.01-2.12 (m, 2 H), 2.70-2.78 (m, 2 H), 3.98-4.08 (m, 2 H).

^¹³C NMR (50 MHz, CDCl₃): δ = 22.60, 33.67, 62.19, 120.15 (q, J = 274.5 Hz, CF₃), 165.17 (q, J = 35.4 Hz, C=N).

^¹9F NMR (188 MHz, CDCl₃): δ = -71.14.

HRMS (EI): m/z calcd for C₅H₆F₃N: 137.0452; found: 137.0456.

5-(Pentafluoroethyl)-3,4-dihydro-2 H -pyrrole (5b)

Yield: 79% (Method A); colorless liquid; bp 99-102 ˚C/760 Torr.

^¹H NMR (200 MHz, CDCl₃): δ = 1.94-2.10 (m, 2 H), 2.72-2.80 (m, 2 H), 4.03-4.14 (m, 2 H).

^¹³C NMR (50 MHz, CDCl₃): δ = 21.81, 34.01, 62.42, 110.78 (tq, J = 252.6, 38.4 Hz, CF₂CF₃), 118.91 (qt, J = 286.2, 35.7 Hz, CF₂CF₃), 165.90 (t, J = 27.4 Hz, C=N).

^¹9F NMR (188 MHz, CDCl₃): δ = -118.15 (2 F, CF₂), -83.43 (3 F, CF₃).

HRMS (EI): m/z calcd for C₆H₆F₅N: 187.0420; found: 187.0416.

6-(Trifluoromethyl)-2,3,4,5-tetrahydropyridine (5c)

Yield: 86% (Method A); colorless liquid; bp 100-103 ˚C/760 Torr.

^¹H NMR (200 MHz, CDCl₃): δ = 1.55-1.79 (m, 4 H), 2.23-2.31 (m, 2 H), 3.71-3.77 (m, 2 H).

^¹³C NMR (50 MHz, CDCl₃): δ = 18.47, 21.48, 23.95, 49.61, 120.05 (q, J = 278.4 Hz, CF₃), 159.21 (q, J = 32.5 Hz, C=N).

^¹9F NMR (188 MHz, CDCl₃): δ = -75.64.

HRMS (EI): m/z calcd for C₆H₈F₃N: 151.0609; found: 151.0610.

6-(Pentafluoroethyl)-2,3,4,5-tetrahydropyridine (5d)

Yield: 79% (Method A); colorless liquid; bp 125-128 ˚C/760 Torr.

^¹H NMR (200 MHz, CDCl₃): δ = 1.62-1.68 (m, 2 H), 1.73-1.80 (m, 2 H), 2.30-2.33 (m, 2 H), 3.78-3.83 (m, 2 H).

^¹³C NMR (50 MHz, CDCl₃): δ = 18.23, 21.08, 24.06, 49.69, 110.64 (tq, J = 255.1, 36.6 Hz, CF₂CF₃), 119.12 (qt, J = 286.4, 36.4 Hz, CF₂CF₃), 159.75 (t, J = 25.9 Hz, C=N).

^¹9F NMR (188 MHz, CDCl₃): δ = -120.51 (2 F, CF₂), -82.68 (3 F, CF₃).

HRMS (EI): m/z calcd for C₇H₈F₅N: 201.0571; found: 201.0579.

7-(Trifluoromethyl)-3,4,5,6-tetrahydro-2 H -azepine (5e)

Yield: 21% (Method A); colorless liquid; bp 148-151 ˚C/760 Torr.

^¹H NMR (200 MHz, CDCl₃): δ = 1.44-1.62 (m, 4 H), 1.77-1.85 (m, 2 H), 2.48-2.54 (m, 2 H), 3.74-3.78 (m, 2 H).

^¹³C NMR (50 MHz, CDCl₃): δ = 23.04, 25.14, 28.40, 31.12, 52.26, 120.23 (q, J = 278.4 Hz, CF₃), 163.64 (q, J = 32.5 Hz, C=N).

^¹9F NMR (188 MHz, CDCl₃): δ = -76.08.

HRMS (EI): m/z calcd for C₇H₁₀F₃N: 165.0765; found: 165.0760.

Reduction of Imines 5 to 6

Method A: To a solution of imine 5 (50 mmol) in MeOH (100 mL) was added AcOH (12 mL) dropwise at 0 ˚C. The reaction mixture was cooled to -20 ˚C and kept at this temperature while NaBH₄ (4 g, 0.1 mol) was added portionwise over a period of 1 h. After stirring at r.t. for 12 h, the mixture was quenched with aq 6 M HCl (15 mL). The solvent was evaporated under reduced pressure and the residue was dissolved in H₂O (50 mL), made alkaline with aq ammonia (10 mL) and extracted with Et₂O (3 × 20 mL). The combined organic extracts were dried (K₂CO₃), concentrated under atmospheric pressure, and the residue was distilled to yield the desired amine as a colorless liquid.

Method B: To a stirred suspension of Zn powder (13 g, 0.2 mol) in AcOH (50 mL) with an additive ZnCl₂ (0.5 g) as an activator was added a solution of cyclic imine 5 (70 mmol) in AcOH (20 mL) dropwise at such a rate that the temperature of the reaction mixture did not exceed 40 ˚C. After stirring for 12 h, the mixture was filtered, quenched with aq 6 M HCl (15 mL) and the solvents were removed in vacuo. The residue was made alkaline with aq ammonia (50 mL), extracted with Et₂O (3 × 20 mL), and the combined organic extracts were dried (K₂CO₃). Evaporation of the solvent under atmospheric pressure followed by distillation of the residue gave the target amine as a colorless liquid.

Method C: To neat 5a or 5b (0.2 mol) was added 10% Pd/C (500 mg) and H₂ was purged through the reaction mixture with simultaneous stirring for 15 h at r.t. The mixture was thoroughly filtered through a Celite plug to afford the corresponding amines in almost quantitative yields as a colorless liquid.

2-(Trifluoromethyl)pyrrolidine (6a)

Prepared by Method A (67%), Method B (42%), and Method C (99%); colorless liquid; bp 89-90 ˚C/760 Torr.

^¹H and ^¹9F NMR data were identical with the reported data. [¹7]

^¹³C NMR (50 MHz, CDCl₃): δ = 25.53, 25.76, 47.07, 58.54 [q, J = 29.7 Hz, C(CF₃)NH], 126.90 (q, J = 279.8 Hz, CF₃).

2-(Pentafluoroethyl)pyrrolidine (6b)

Prepared by Method A (73%), Method B (40%), and Method C (94%); colorless liquid; bp 109-111 ˚C/760 Torr.

^¹H NMR (200 MHz, CDCl₃): δ = 1.69-2.03 [m, 5 H, incl. 1.94 (br s, 1 H, NH)], 2.96-3.02 (m, 2 H), 3.57-3.75 (m, 1 H).

^¹³C NMR (50 MHz, CDCl₃): δ = 25.33, 25.61, 47.10, 57.15 [dd, J = 24.0, 21.2 Hz, C(C₂F₅)NH], 109.57-127.91 (m, 2 C, CF₂CF₃).

^¹9F NMR (188 MHz, CDCl₃): δ = -128.23, -128.15, -126.80, -126.72, -125.67, -125.61, -124.24, -124.18 (2 F, AB part of ABX system, J _AB = 268.9 Hz, J _AX = 12.1 Hz, J _BX = 15.5 Hz, CF₂), -82.87 (3 F, CF₃).

HRMS (EI): m/z calcd for C₆H₇F₅N: 188.0500; found: 188.0492.

2-(Trifluoromethyl)piperidine (6c)

Yield: 71% (Method A); colorless liquid; bp 118-120 ˚C/760 Torr.

^¹H and ^¹9F NMR data were identical with the reported data. [¹8]

^¹³C NMR (50 MHz, CDCl₃): δ = 23.09, 24.88, 25.42, 45.94, 57.96 [q, J = 28.2 Hz, C(CF₃)NH], 125.78 (q, J = 279.8 Hz, CF₃).

2-(Pentafluoroethyl)piperidine (6d)

Yield: 75% (Method A); colorless liquid; bp 136-138 ˚C/760 Torr.

^¹H NMR: δ = 1.34-1.62 [m, 5 H, incl. 1.38 (br s, 1 H, NH)], 1.80-1.92 (m, 2 H), 2.56-2.69 (m, 1 H), 3.07-3.23 (m, 2 H).

^¹³C NMR (50 MHz, CDCl₃): δ = 23.57, 24.69, 25.87, 46.45, 57.07 [dd, J = 22.6, 21.2 Hz, C(C₂F₅)NH], 109.15-127.79 (m, 2 C, CF₂CF₃).

^¹9F NMR (188 MHz, CDCl₃): δ = -128.01, -127.93, -126.54, -126.48, -125.53, -125.47, -124.07, -124.01 (2 F, AB part of ABX system, J _AB = 274.1 Hz, J _AX = 12.1 Hz, J _BX = 13.8 Hz, CF₂), -81.97 (3 F, CF₃).

HRMS (EI): m/z calcd for C₇H₁₀F₅N: 203.0733; found: 203.0730.

2-(Trifluoromethyl)azepane (6e)

Prepared by Method A and was isolated as the hydrochloride; yield: 82%; white solid; mp 163-164 ˚C.

^¹H NMR (400 MHz, DMSO-d ₆): δ = 1.61-2.20 (m, 8 H), 3.32-3.36 and 3.51-3.54 (m, 2 H, CH₂N), 3.92-3.96 [m, 1 H, CH(CF₃)N], 10.35 (br s, 1 H, NH₂ ⁺).

^¹³C NMR (50 MHz, DMSO-d ₆): δ = 24.15, 24.81, 25.19, 27.32, 46.13, 57.95 [q, J = 30.7 Hz, C(CF₃)NH], 123.70 (q, J = 281.7 Hz, CF₃).

^¹9F NMR (188 MHz, DMSO-d ₆): δ = -77.80 (d, J = 8.7 Hz), 2.65 (m, 1 H), 2.99-3.13 (m, 2 H).

Anal. Calcd for C₇H₁₃ClF₃N: C, 41.3; H, 6.4. Found: C, 41.4; H, 6.5.

Acknowledgment

The authors thank the Deutsche Forschungsgemeinschaft (436 RUS 113/812/0-1) and Grant P1471 Federal Special Program for finan­cial support of this work.

References

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  Search in Google Scholar
• 1b Shvekhgeimer M.-GA. Chem. Heterocycl. Compd.  2003,  39:  405 
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• 2a Nenajdenko VG. Zakurdaev EP. Balenkova ES. Tetrahedron Lett.  2002,  43:  8449 
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• 2c Mariano PS. Tetrahedron  1983,  39:  3845 
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• 2d Mariano PS. Acc. Chem. Res.  1983,  16:  130 
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• 2e Nenajdenko VG. Zakurdaev EP. Balenkova ES. Russ. Chem. Rev.  2009,  78:  431 
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• For reviews, see:
• 3a Ikeda M. Sato T. Ishibashi H. Heterocycles  1988,  27:  1465 
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• 3b Zakurdaev EP. Balenkova ES. Nenajdenko VG. Mendeleev Commun.  2006,  213 
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• 6b Cheng S.-S. Piantadosi C. Irvin JL. J. Pharm. Sci.  1968,  57:  1910 
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• 6c For aza-Wittig reactions, see: Lambert PH. Vaultier M. Carrie R. J. Chem. Soc., Chem. Commun.  1982,  1224 
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• 6e For rearrangement of tertiary azides, see: Astier A. Plat MM. Tetrahedron Lett.  1978,  2051 
• 6f For use of aroyl chlorides, see: Mundy BP. Larsen BR. McKenzie LF. Braden G. J. Org. Chem.  1972,  37:  1635 
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• 7a Nenajdenko VG. Zakurdaev EP. Prusov EV. Balenkova ES. Tetrahedron  2004,  60:  11719 
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• 7b Sorgi KL. Maryanoff CA. McComsey DF. Maryanoff BE. Org. Synth.  1998,  75:  215 
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• 8a Feringa BL. Jansen FGA. Tetrahedron Lett.  1986,  27:  507 
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• 8b Koldobskij AB. Vakhmistrov VE. Solodova EV. Sholova OS. Kalinin VN. Dokl. Acad. Nauk  2002,  387:  61 ; Dokl. Chem. (Engl. Transl.) 2002, 387, 289
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• 9 Shevchenko NE. Nenajdenko VG. Röschenthaler G.-V. J. Fluorine Chem.  2008,  129:  390 
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• See, for example:
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• 12b Druzhinin SV. Balenkova ES. Nenajdenko VG. Tetrahedron  2007,  63:  7753 
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• 13 Plater MJ. Rees CW. Roe DG. Torroba T. J. Chem. Soc., Perkin Trans. 1  1993,  769 
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  CrossrefSearch in Google Scholar
• 15a For conversion of proline or pipecolic acid, see: Raash MS. J. Org. Chem.  1962,  46:  423 
  Search in Google Scholar
• 15b For approach via ring-closing metathesis, see: Gille S. Ferry A. Billard T. Langlois BR. J. Org. Chem.  2003,  68:  8932 
  Search in Google Scholar
• 15c For approach via intramolecular Mannich reaction, see: Bariau A. Jatoi WB. Calinaud P. Troin Y. Canet J.-L. Eur. J. Org. Chem.  2006,  3421 
• 16 Koldobsky AB. Vakhmistrov VE. Solodova EV. Sholova OS. Kalinin VN. Dokl. Akad. Nauk  2002,  387:  61 ; Dokl. Chem. 2002, 387, 289
  Search in Google Scholar
• 17 Shustov GV. Denisenko SN. Chervin II. Kostyanovskii RG. Izv. Akad. Nauk SSSR, Ser. Khim.  1988,  37:  1606 ; Russ. Chem. Bull. 1988, 37, 1665
  Search in Google Scholar
• 18 Raasch MS. J. Org. Chem.  1962,  27:  1406 
  CrossrefSearch in Google Scholar

A mixture of Claisen products 1a and 2a was isolated in this reaction.

References

• 1a Marayanoff BE. McComsey DF. Gardocki JF. Shank RP. Costanzo MJ. Nortey SO. Schneider CR. Setler PE. J. Med. Chem.  1987,  30:  1433 
  Search in Google Scholar
• 1b Shvekhgeimer M.-GA. Chem. Heterocycl. Compd.  2003,  39:  405 
  Search in Google Scholar
• 1c Singh PND. Klima RF. Muthukrishnan S. Murthy RS. Sankaranarayanan J. Stahlecker HM. Patel B. Gudmundsdottir AD. Tetrahedron Lett.  2005,  46:  4213 
  Search in Google Scholar
• 2a Nenajdenko VG. Zakurdaev EP. Balenkova ES. Tetrahedron Lett.  2002,  43:  8449 
  Search in Google Scholar
• 2b Willoughby CA. Buchwald SL. J. Am. Chem. Soc.  1994,  116:  8952 
  Search in Google Scholar
• 2c Mariano PS. Tetrahedron  1983,  39:  3845 
  Search in Google Scholar
• 2d Mariano PS. Acc. Chem. Res.  1983,  16:  130 
  Search in Google Scholar
• 2e Nenajdenko VG. Zakurdaev EP. Balenkova ES. Russ. Chem. Rev.  2009,  78:  431 
  Search in Google Scholar
• For reviews, see:
• 3a Ikeda M. Sato T. Ishibashi H. Heterocycles  1988,  27:  1465 
  Search in Google Scholar
• 3b Zakurdaev EP. Balenkova ES. Nenajdenko VG. Mendeleev Commun.  2006,  213 
• 4 Watson PS. Jiang B. Scott B. Org. Lett.  2000,  2:  3679 
  CrossrefPubMedSearch in Google Scholar
• 5 The solution 2-trifluoromethylpyrroline without any characterizations was obtained by oxidation of 2-trifluoro-methylpyrrolidine: Shustov GV. Denisenko SN. Kostyanovskii RG. Russ. Chem. Bull.  1986,  35:  1662 
  CrossrefSearch in Google Scholar
• 6a For Friedel-Crafts methods, see: Koller W. Schlack P. Chem. Ber.  1963,  96:  93 
  Search in Google Scholar
• 6b Cheng S.-S. Piantadosi C. Irvin JL. J. Pharm. Sci.  1968,  57:  1910 
  Search in Google Scholar
• 6c For aza-Wittig reactions, see: Lambert PH. Vaultier M. Carrie R. J. Chem. Soc., Chem. Commun.  1982,  1224 
• 6d For radical cyclization sulfenyl imines, see: Boivin J. Fouquet E. Zard SZ. Tetrahedron Lett.  1990,  31:  85 
  Search in Google Scholar
• 6e For rearrangement of tertiary azides, see: Astier A. Plat MM. Tetrahedron Lett.  1978,  2051 
• 6f For use of aroyl chlorides, see: Mundy BP. Larsen BR. McKenzie LF. Braden G. J. Org. Chem.  1972,  37:  1635 
  Search in Google Scholar
• 7a Nenajdenko VG. Zakurdaev EP. Prusov EV. Balenkova ES. Tetrahedron  2004,  60:  11719 
  Search in Google Scholar
• 7b Sorgi KL. Maryanoff CA. McComsey DF. Maryanoff BE. Org. Synth.  1998,  75:  215 
  Search in Google Scholar
• 8a Feringa BL. Jansen FGA. Tetrahedron Lett.  1986,  27:  507 
  Search in Google Scholar
• 8b Koldobskij AB. Vakhmistrov VE. Solodova EV. Sholova OS. Kalinin VN. Dokl. Acad. Nauk  2002,  387:  61 ; Dokl. Chem. (Engl. Transl.) 2002, 387, 289
  Search in Google Scholar
• 9 Shevchenko NE. Nenajdenko VG. Röschenthaler G.-V. J. Fluorine Chem.  2008,  129:  390 
  CrossrefSearch in Google Scholar
• 10 For new advantages on nucleophilic trifluoromethylation, see: Prakash GKS. Hu J. In Fluorine-Containing Synthons   Soloshonok VA. American Chemical Society; Washington DC: 2005.  p.17-56  
• See, for example:
• 12a Creary X. J. Org. Chem.  1987,  52:  5026 
  Search in Google Scholar
• 12b Druzhinin SV. Balenkova ES. Nenajdenko VG. Tetrahedron  2007,  63:  7753 
  Search in Google Scholar
• 13 Plater MJ. Rees CW. Roe DG. Torroba T. J. Chem. Soc., Perkin Trans. 1  1993,  769 
  Crossref
• 14 Folmer JJ. Weinreb SM. Tetrahedron Lett.  1993,  34:  2737 
  CrossrefSearch in Google Scholar
• 15a For conversion of proline or pipecolic acid, see: Raash MS. J. Org. Chem.  1962,  46:  423 
  Search in Google Scholar
• 15b For approach via ring-closing metathesis, see: Gille S. Ferry A. Billard T. Langlois BR. J. Org. Chem.  2003,  68:  8932 
  Search in Google Scholar
• 15c For approach via intramolecular Mannich reaction, see: Bariau A. Jatoi WB. Calinaud P. Troin Y. Canet J.-L. Eur. J. Org. Chem.  2006,  3421 
• 16 Koldobsky AB. Vakhmistrov VE. Solodova EV. Sholova OS. Kalinin VN. Dokl. Akad. Nauk  2002,  387:  61 ; Dokl. Chem. 2002, 387, 289
  Search in Google Scholar
• 17 Shustov GV. Denisenko SN. Chervin II. Kostyanovskii RG. Izv. Akad. Nauk SSSR, Ser. Khim.  1988,  37:  1606 ; Russ. Chem. Bull. 1988, 37, 1665
  Search in Google Scholar
• 18 Raasch MS. J. Org. Chem.  1962,  27:  1406 
  CrossrefSearch in Google Scholar

A mixture of Claisen products 1a and 2a was isolated in this reaction.