Intramolecular carbolithiation of <i>N</i>-allyl-<i>N</i>-2-lithioallylamines: effect of the allyl moiety

José Barluenga; Francisco J. Fañanás; Roberto Sanz; Yolanda Fernández

doi:10.1016/j.crci.2004.02.015

Intramolecular carbolithiation of N-allyl-N-2-lithioallylamines: effect of the allyl moiety

José Barluenga ¹ ; Francisco J. Fañanás ¹ ; Roberto Sanz ² ; Yolanda Fernández ²

¹ Instituto Universitario de Química Organometálica ‘Enrique Moles’, Unidad Asociada al C.S.I.C. Julián Clavería, 8, Universidad de Oviedo, 33071 Oviedo, Spain
² Departamento de Química, Área de Química Orgánica, Facultad de Ciencias, Pza. Missael Bañuelos s/n, Universidad de Burgos, 09001 Burgos, Spain

Comptes Rendus. Chimie, Volume 7 (2004) no. 8-9, pp. 855-864.

Résumés

Anglais
Français

The preparation of new N-2-bromoallyl-N-(3-functionalized)allylamines and the intramolecular carbolithiation reactions of the corresponding organolithiums generated by bromine–lithium exchange are reported. The effect of the substituent at the terminal position of the allyl moiety is studied. This methodology allows the efficient synthesis of a variety of interesting functionalized pyrrolidine and hexahydroindole derivatives from simple starting materials. .

La préparation de nouvelles N-2-bromoallyl-N-(3-functionalized)allylamines ainsi que la carbolithiation intramoléculaire des organolithiens correspondants générés par échange bromine–lithium est présentée. L'effet du substituant en position terminale du fragment allyle est étudié. Cette méthodologie permet la synthèse efficace d'une variété intéressante de pyrrolidine fonctionnalisées et d'hexahydroindoles provenant de produits de départ simples. .

Métadonnées

Reçu le : 2003-11-17
Accepté le : 2004-02-03
Publié le : 2004-07-30

DOI : 10.1016/j.crci.2004.02.015

Keywords: Organolithium compounds, Carbolithiation, Pyrrolidines, Hexahydroindoles
Mots clés : Composés organolithiens, Carbolithiation, Pyrrolidines, Hexahydroindoles

Affiliations des auteurs :

José Barluenga ¹ ; Francisco J. Fañanás ¹ ; Roberto Sanz ² ; Yolanda Fernández ²

¹ Instituto Universitario de Química Organometálica ‘Enrique Moles’, Unidad Asociada al C.S.I.C. Julián Clavería, 8, Universidad de Oviedo, 33071 Oviedo, Spain
² Departamento de Química, Área de Química Orgánica, Facultad de Ciencias, Pza. Missael Bañuelos s/n, Universidad de Burgos, 09001 Burgos, Spain

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     author = {Jos\'e Barluenga and Francisco J. Fa\~nan\'as and Roberto Sanz and Yolanda Fern\'andez},
     title = {Intramolecular carbolithiation of {\protect\emph{N}-allyl-\protect\emph{N}-2-lithioallylamines:} effect of the allyl moiety},
     journal = {Comptes Rendus. Chimie},
     pages = {855--864},
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     volume = {7},
     number = {8-9},
     year = {2004},
     doi = {10.1016/j.crci.2004.02.015},
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José Barluenga; Francisco J. Fañanás; Roberto Sanz; Yolanda Fernández. Intramolecular carbolithiation of N-allyl-N-2-lithioallylamines: effect of the allyl moiety. Comptes Rendus. Chimie, Volume 7 (2004) no. 8-9, pp. 855-864. doi : 10.1016/j.crci.2004.02.015. https://comptes-rendus.academie-sciences.fr/chimie/articles/10.1016/j.crci.2004.02.015/

Version originale du texte intégral

1 Introduction

Although simple alkenes are not generally thought of as sites of nucleophilic attack, the formation of ring systems by the anionic cyclisation of olefinic alkyl, aryl and vinyllithiums is an interesting synthetic transformation and provides a regiospecific and highly stereoselective route to five-membered carbocycles [1,2] and heterocycles [3]. Most importantly, it should be possible to functionalize the initially formed cyclisation product by reaction with electrophiles, a reaction that is not generally possible in the case of radical cyclisations. A major drawback of this kind of carbocyclisations is that they are limited to terminal double bonds; however, it has been possible to obtain cyclised products for 1,2-disubstituted olefins in which the initially formed alkyllithium product is substituted with a moderately activating group [4] or with a leaving group in a β-position [5]. Although the development of this methodology for the preparation of heterocyclic systems has received less attention, several oxygen and nitrogen heterocycles, such as tetrahydrofurans [5,6], pyrrolidines [7], indolines [8,9] or indoles [10], have been synthesized via intramolecular carbolithiation reactions. Moreover, the fact that the ring closure of achiral olefinic organolithiums could proceed enantioselectively in the presence of (–)-sparteine dramatically increases the potential of this kind of processes [11,12]. In this area, we have studied in the last years the behaviour of 2-lithioallyl and 2-lithioaryl amines [13,14], as well as of 2-lithioaryl ethers [15], in their anionic cyclisations onto unactivated double bonds. Here we report our studies about the effect of different substituents at the terminal position of the allyl moiety in the intramolecular carbolithiation reaction of N-allyl-N-2-lithioallylamine derivatives.

2 Results and discussion

Sometime ago, we reported that N-allyl-N-(2-lithioallyl)amines 2, generated by bromine-lithium exchange from the corresponding N-allyl-N-(2-bromoallyl)amines 1, undergo a 5-exo intramolecular carbolithiation in the presence of N,N,N´,N´-tetramethylethylenediamine (TMEDA) to afford 3-lithiomethyl-4-methylenepyrrolidines 3 when the starting amine is aliphatic (R = alkyl) [13]. However, if the 2-bromoallylamine 1 is aromatic (R = aryl), the secondary amide 4 is generated (Fig. 1). In this case, we initially proposed a 6-endo cyclisation followed by an irreversible β-elimination (for an alternative mechanism involving an exo cyclisation of organolithium 3, γ-elimination, and a rapid and irreversible fragmentation of the corresponding cyclopropyl intermediate, see [3]). Aside from the mechanistic pathways, these cyclisations provide an efficient method for the preparation of methylenepyrrolidine derivatives.

Fig. 1
Intramolecular carbolithiation of N-allyl-N-(2-lithioallyl)amines 2.

In order to investigate the effect of the substituents of the allyl moiety of the starting amine in the outcome of the intramolecular cyclisation, we decided to prepare several allyl amines substituted at the terminal position. The syntheses of these compounds 6 were carried out according to Fig. 2. The commercially available N-allyl-N-cyclohexylamine or N-allylaniline was selectively functionalized by successive treatment with n-BuLi and t-BuLi and further reaction with electrophiles (chlorotrimethylsilane, diphenyldisulfide or tributyltin chloride), affording secondary amines 5a-d as the Z-isomers [16]. On the other hand, the aromatic amines 5e–f were easily obtained by alkylation of aniline with cinnamyl and crotyl bromide, respectively. Finally, tertiary amines 6 were prepared by alkylation of the corresponding amine 5 with 2,3-dibromopropene using potassium carbonate as base (Table 1).

Fig. 2
Synthesis of N-(3-substituted-2-propenyl)-N-(2-bromoallyl)amines 6.

Starting amine	R	G	Product	Yield (%)^a
5a	c-C₆H₁₁	(Z)-SPh	6a	72
5b	c-C₆H₁₁	(Z)-SiMe₃	6b	71
5c	c-C₆H₁₁	(Z)-SnBu₃	6c	79
5d	Ph	(Z)-SiMe₃	6d	83
5e	Ph	(E)-Ph	6e	81
5f	Ph	Me^b	6f	75

^a Isolated yields based on starting amines 5.

^b Mixture of E:Z-diastereoisomers (6:1).

Treatment of N-(2-bromoallyl) amines 6 with 2 equiv. of t-BuLi at –78 °C in diethyl ether afforded the vinyllithium derivatives 7. Addition of TMEDA (2.2 equiv) at low temperature, warming up of the mixture until 0 °C and further reaction with different electrophiles allowed the isolation, after hydrolysis and purification by column chromatography, of 3-substituted-4-methylenepyrrolidines 8 in good yields (Fig. 3 and Table 2). The formation of these pyrrolidine derivatives can be understood by assuming a 5-exo intramolecular carbolithiation process that would give rise to the organolithium intermediates 9, which are finally functionalized by treatment with electrophiles.

Fig. 3
Intramolecular carbolithiation of N-(2-lithioallyl)amines 7.

Starting amine	Organolithium compound	R	G	E	Product	Yield (%)^a
6a	7a	c-C₆H₁₁	SPh	D	8a	92
6a	7a	c-C₆H₁₁	SPh	SPh	8b	90
6a	7a	c-C₆H₁₁	SPh	SnBu₃	8c	83^b
6a	7a	c-C₆H₁₁	SPh	C(OH)Ph₂	8d	84^b
6b	7b	c-C₆H₁₁	SiMe₃	D	8e	90
6b	7b	c-C₆H₁₁	SiMe₃	SiMe₃	8f	80
6b	7b	c-C₆H₁₁	SiMe₃	SPh	8g	85^b
6b	7b	c-C₆H₁₁	SiMe₃	SnBu₃	8h	73^b
6c	7c	c-C₆H₁₁	SnBu₃	D	8i	94
6d	7d	Ph	SiMe₃	D	8j	53^c
6d	7d	Ph	SiMe₃	SPh	8k	50^b,c
6d	7d	Ph	SiMe₃	SnBu₃	8l	55^b,c
6e	7e	Ph	Ph	D	8m	61

^a Isolated yields based on starting amines 6.

^b Yields referred to the mixture of diastereoisomers.

^c Low yields obtained due to a partial decomposition of the product on the purification by silica gel chromatography.

In those cases in which the E and G groups are different, pyrrolidine derivatives 8 were obtained as an approximately 2:1 mixture of diastereoisomers. This fact seems to indicate that if we assume that carbolithiation reactions are stereospecific syn-addition processes, organolithiums 9 must be configurationally labile at the temperature required to achieve the cyclisation [17,18].

The lack of formation of pyrrolidine derivatives starting from amine 6f, with a methyl group at the terminal position of the double bond, could be attributed to the fact that in the carbolithiation step a non-stabilized secondary carbanion would be generated.

It is interesting to note the effect that the trimethylsilyl and phenyl groups at the terminal position of the allyl moiety exert on the regioselectivity of the process when the starting amine is aromatic (R = Ph). Organolithium compounds 7d and 7e undergo regioselectively 5-exo cyclisations giving rise to pyrrolidine derivatives 8j-m. These results contrast with our previous report where aromatic N-allyl-N-(2-lithioallyl)amines undergo a 6-endo cyclisation processes [13] (see Fig. 1). So, the presence of the trimethylsilyl or phenyl groups at the terminal position of the double bond not only favours the carbolithiation of 1,2-disubstituted alkenes but also directs it to a 5-exo closure. So, the observed regioselectivity of the cyclisation of aromatic amines is inverted when the double bond is substituted at the terminal position with a moderately activating group such as phenyl or trimethylsilyl.

Moreover, although carbolithiation reactions of phenyl, trimethylsilyl or phenylthio-substituted double bonds are known [4,19], in this paper we present the first example of this kind of carbocyclisations in which the alkene moiety to be carbolithiated is functionalized with a tributyltin group (see organolithium 7c). Surprisingly, this reaction takes place almost quantitatively though it is well known the easy tin-lithium transmetalation reaction.

In order to know the temperature at which the carbolithiation processes take place for each of the N-2-(lithioallyl)amines 7, the cyclisations were monitored by GC–MS analysis of aliquots quenched with MeOD at different temperature intervals. After this study, we can conclude that in all the cases the temperature at which the cyclisation reaction takes place is lower than the temperature at which the unsubstituted parent N-allyl-N-(2-lithioallyl)amines 2 cyclises (see Fig. 1). In addition, some interesting differences were found depending on the G group and on the nitrogen electron density. So, organolithium compound 7a, with a phenylthio substituent at the allyl moiety, cyclises at –78 °C, whereas 7b, substituted with a trimethylsilyl group, cyclises at –20 °C. On the other hand, the exact temperature at which the cyclisation of tributyltin-substituted 7c occurs could not be determined with accuracy. However, we could estimate that, in this, case the cyclisation step proceeds at temperature lower than –50 °C. In the case of the organolithium compound 7d, derived from an aromatic amine and activated with a trimethylsilyl group, the cyclisation takes place at –50 °C and so, by comparing with 7b, we can conclude that the carbolithiation reactions are faster with aromatic amines than with aliphatic ones. This result could be interpreted taking into account that aliphatic amines could coordinate better with the lithium atom in the organolithium compounds 7, decreasing the reactivity of these intermediates.

Taking into account the activation effect of a phenylthio group on the double bond and with the aim of extending this reactivity to other starting amines, N-(2-bromo-2-cyclohexenyl)-N-[(Z)-3-phenylthio-2-propenyl]cyclohexylamine 10 was synthesized by alkylation of secondary amine 5a with 1,6-dibromocyclohexene [20] in the usual way (Fig. 4). Treatment of 10 with t-BuLi at –78 ºC rendered organolithium derivative 11 by a bromine-lithium exchange. Addition of TMEDA (2.2 equiv) at the same temperature and warming to –60 °C followed by reaction with MeOH or Ph₂S₂ from –78 to 20 °C afforded hexahydroindole derivatives 12a,b in excellent yields and as single diastereoisomers. The structure of compounds 12 and the anti relationship of H¹ and H² were unequivocally ascertained by 2D-NMR experiments (COSY, HMQC, HMBC, and NOESY). Again, the formation of the bicyclic compounds 12 can be explained by assuming a 5-exo intramolecular carbolithiation process that gives rise to the organolithium intermediate 13. Further reaction with the corresponding electrophile produces the final products 12 (Fig. 4).

Fig. 4
Diastereoselective intramolecular carbolithiation of organolithium compound 11.

The observed diastereoselectivity of this cyclisation is consistent with a four-centre transition state similar to the one proposed by Chamberlin for the synthesis of related methylenecyclopentane derivatives [21]. A preferred coplanar approach of the C–Li bond to the double bond would give the observed product (Fig. 5).

Fig. 5
Proposed transition state for the cyclisation of organolithium 11.

In conclusion, we have described the intramolecular carbolithiation of N-allyl-N-2-lithioallylamines that present a moderately activating group at the terminal position of the double bond. These groups favour the cyclisation and the 5-exo regioselectivity. The first example of this kind of reactions with a tributyltin-substituted olefin has also been presented. Following this strategy, interesting functionalized pyrrolidine and hexahydroindole derivatives have been synthesized.

3 Experimental part

3.1 General remarks

Experiments involving organometallics were carried out in dried glassware under an atmosphere of dry nitrogen using standard Schlenk techniques. Liquid nitrogen was used as a cryoscopic fluid. All common reagents and solvents were obtained from commercial suppliers and used without further purification, unless otherwise indicated. n-BuLi was used as a 2.5-M solution in hexane. t-BuLi was used as a 1.5-M solution in pentane. THF and Et₂O were freshly distilled from sodium-benzophenone ketyl prior to use. TLC was performed on Al-backed plates coated with silica gel 60 with F₂₅₄ indicator (Merck). Flash column chromatography was carried out over Merck silica gel 60. ¹H NMR and ¹³C NMR spectra were recorded on a Varian Inova 400 (400 and 100.6 MHz, respectively), Varian Gemini VXR-200 (200 and 50.3 MHz, respectively) and Bruker AC-300 (300 and 75.5 MHz, respectively). Chemical shifts are reported in δ relative to an internal standard of residual chloroform (δ = 7.27 for ¹H NMR and δ = 76.95 for ¹³C NMR). Low-resolution electron impact mass spectra (EI–LRMS) were obtained at 70 eV on a HP 5971 A instrument, and the intensity of the molecular peak is reported as a percentage relative to the base peak after the corresponding m/z value. Elemental analyses were performed with a LECO CHNS-932.

3.2 General preparation of compounds 6 and 10

The corresponding secondary amine 5 (10 mmol), K₂CO₃ (10 mmol), 2,3-dibromopropene or 1,6-dibromocyclohexene (10 mmol), and acetonitrile (20 ml) were placed in a flask. The mixture was heated at reflux overnight. The solvent was removed (15 mm Hg), the residue was extracted with Et₂O (3 × 10 ml), dried over Na₂SO₄ and the residue purified by column chromatography to afford amines 6 and 10.

3.2.1 N-(2-Bromoallyl)-N-[(Z)-3-phenylthioallyl]cyclohexylamine 6a

From amine 5a (2.64 g, 72%). R_f = 0.28 (hexane/AcOEt, 30:1). ¹H NMR (400 MHz, CDCl₃): δ 7.36–7.18 (m, 5H, ArH), 6.31–6.26 (m, 1H, CH=CHS), 6.01–5.99 (m, 1H, C(Br)=CHH), 5.97–5.85 (m, 1H, CH=CHS), 5.54–5.52 (m, 1H, C(Br)=CHH), 3.36 (dd, J = 6.4 and 1.2 Hz, 2H, NCH₂CH=), 3.30 (s, 2H, NCH₂C(Br)=), 2.60–2.49 (m, 1H, NCH), 1.90–1.10 (m, 10H, 5 × CH₂ cyclohexyl). ¹³C NMR (50.3 MHz, CDCl₃): δ 134.1, 131.4, 129.0, 128.9, 126.3, 124.6, 123.5, 116.7, 59.8, 58.6, 48.5, 29.2, 26.2, 26.1. EI-LRMS, m/z (%): 367 (5) [M⁺+2], 365 (5) [M⁺], 149 (100). Elemental analysis calcd (%) for C₁₈H₂₄BrNS (366.4): C 59.01, H 6.60, N 3.82; found C 59.08, H 6.53, N 3.92.

3.2.2 N-(2-Bromoallyl)-N-[(Z)-3-trimethylsilylallyl]cyclohexylamine 6b

From amine 5b (2.34 g, 71%). R_f = 0.3 (hexane). ¹H NMR (400 MHz, CDCl₃): δ 6.32 (dt, J = 14.4 and 6.8 Hz, 1H, CH=CHSi), 5.98–5.96 (m, 1H, C(Br)=CHH), 5.58 (dt, J = 14.4 and 1.6 Hz, 1H, CH=CHSi), 5.51–5.49 (m, 1H, C(Br)=CHH), 3.25 (s, 2H, NCH₂C(Br)=), 3.22 (dd, J = 6.8 and 1.6 Hz, 2H, NCH₂CH=), 2.54–2.44 (m, 1H, NCH), 1.81–1.73 (m, 4H, cyclohexyl), 1.64–1.57 (m, 1H, cyclohexyl), 1.28–0.98 (m, 5H, cyclohexyl), 0.11 (s, 9H, 3 × CH₃ SiMe₃). ¹³C NMR (100.6 MHz, CDCl₃): δ 148.0, 134.2, 130.4, 116.4, 59.4, 58.1, 52.3, 29.3, 26.2, 26.0, 0.20. EI-LRMS, m/z (%): 331 (8) [M⁺+2], 329 (8) [M⁺], 250 (100), 73 (98). Elemental analysis calcd (%) for C₁₅H₂₈BrNSi (330.4): C 54.53, H 8.54, N 4.24; found C 54.65, H 8.48, N 4.31.

3.2.3 N-(2-Bromoallyl)-N-[(Z)-3-tributyltinallyl]cyclohexylamine 6c

From amine 5c (4.32 g, 79%). R_f = 0.4 (hexane). ¹H NMR (400 MHz, CDCl₃): δ 6.51 (dt, J = 12.4 and 6.4 Hz, 1H, CH=CHSn), 5.99–5.97 (m, 1H, C(Br)=CHH), 5.95 (dt, J = 12.4 and 1.6 Hz, 1H, CH=CHSn), 5.51–5.49 (m, 1H, C(Br)=CHH), 3.25 (s, 2H, NCH₂C(Br)=), 3.15 (dd, J = 6.4 and 1.6 Hz, 2H, NCH₂CH=), 2.53–2.48 (m, 1H, NCH), 1.78–0.80 (m, 37H, 5 × CH₂ cyclohexyl and 3 × (CH₂)₃CH₃ SnBu₃). ¹³C NMR (100.6 MHz, CDCl₃): δ 148.1, 134.3, 129.8, 116.3, 59.4, 58.0, 56.0, 29.2, 29.1, 27.3, 26.3, 26.1, 13.7, 10.3. EI-LRMS, m/z (%): 490 (7) [M⁺-C₄H₉], 313 (29), 256 (30), 176 (100). Elemental analysis calcd (%) for C₂₄H₄₆BrNSn (547.2): C 52.67, H 8.47, N 2.56; found C 52.81, H 8.60, N 2.51.

3.2.4 N-(2-Bromoallyl)-N-[(Z)-3-trimethylsilylallyl]aniline 6d

From amine 5d (2.69 g, 83%). R_f = 0.38 (hexane). ¹H NMR (400 MHz, CDCl₃): δ 7.40–7.30 (m, 2H, ArH), 6.91–6.81 (m, 3H, ArH), 6.49 (dt, J = 14.6 and 6.2 Hz, 1H, CH=CHSi), 5.97–5.87 (m, 2H, CH=CHSi and C(Br)=CHH), 5.69–5.67 (m, 1H, C(Br)=CHH), 4.22–4.13 (m, 4H, 2 × NCH₂), 0.34 (s, 9H, 3 × CH₃ SiMe₃). ¹³C NMR (50.3 MHz, CDCl₃): δ 147.6, 144.6, 132.5, 129.6, 129.2, 117.3, 115.8, 112.2, 58.5, 52.0, 0.1. EI-LRMS, m/z (%): 325 (40) [M⁺+2], 323 (40) [M⁺], 244 (52), 224 (64), 73 (100). Elemental analysis calcd (%) for C₁₅H₂₂BrNSi (324.3): C 55.55, H 6.84, N 4.32; found C 55.48, H 6.75, N 4.39.

3.2.5 N-(2-Bromoallyl)-N-[(E)-cinnamyl]aniline 6e

From amine 5e (2.66 g, 81%). R_f = 0.33 (hexane:AcOEt, 40:1). ¹H NMR (300 MHz, CDCl₃): δ 7.40–6.80 (m, 10H, ArH), 6.60 (d, J = 15.9 Hz, 1H, PhCH=), 6.35–6.25 (m, 1H, CH₂CH=), 5.80 (t, J = 1.7 Hz, 1H, C(Br)=CHH), 5.60 (t, J = 1.7 Hz, 1H, C(Br)=CHH), 4.20–4.15 (m, 4H, 2 × NCH₂). ¹³C NMR (75.5 MHz, CDCl₃): δ 147.5, 136.5, 131.4, 129.4, 129.2, 128.4, 127.4, 126.2, 124.8, 117.2, 115.8, 112.1, 58.3, 52.2. Elemental analysis calcd (%) for C₁₈H₁₈BrN (328.2): C 65.86, H 5.53, N 4.27; found C 65.58, H 5.71, N 4.29.

3.2.6 N-(2-Bromoallyl)-N-(2-butenyl)aniline 6f

From amine 5f (1.99 g, 75%, mixture of Z,E-diastereoisomers). R_f = 0.43 (hexane:AcOEt, 25:1). Data from the (E) diastereoisomer: ¹H NMR (300 MHz, CDCl₃): δ 7.30–6.70 (m, 5H, ArH), 5.80–5.50 (m, 4H, CH=CH and C(Br)=CH₂), 4.10 (s, 2H, NCH₂C(Br)), 3.90 (d, J = 5.2 Hz, 2H, NCH₂CH=), 1.70 (d, J = 6.0 Hz, 3H, CH₃). ¹³C NMR (50.3 MHz, CDCl₃): δ 147.6, 129.6, 129.0, 127.7, 125.8, 116.9, 115.6, 112.0, 58.2, 47.1, 17.6. EI-LRMS, m/z (%): 267 (43) [M⁺+2], 265 (46) [M⁺], 186 (100). Elemental analysis calcd (%) for C₁₃H₁₆BrN (266.2): C 58.66, H 6.06, N 5.26; found C 58.50, H 6.01, N 5.09.

3.2.7 N-(2-Bromo-2-cyclohexenyl)-N-[(Z)-3-phenylthioallyl]aniline 10

From amine 5a (2.76 g, 68%). R_f = 0.26 (hexane). ¹H NMR (400 MHz, CDCl₃): δ 7.36–6.95 (m, 5H, ArH), 6.30–6.26 (m, 1H, C(Br)=CH), 6.21 (dt, J = 9.2 and 1.6 Hz, 1H, CH=CHS), 6.02–5.95 (m, 1H, CH=CHS), 3.59–3.49 (m, 2H, NCH₂CH=), 3.31 (ddd, J = 15.6, 4.8 and 2.0 Hz, 1H, NCHC(Br)=), 2.63–2.54 (m, 1H, NCH), 2.14–1.00 (m, 16H, 5 x CH₂ cyclohexyl and 3 × CH₂ cyclohexenyl). ¹³C NMR (100.6 MHz, CDCl₃): δ 136.4, 134.7, 133.2, 129.1, 128.9, 128.6, 126.1, 122.5, 59.5, 58.4, 44.2, 32.6, 31.7, 28.8, 27.6, 26.4, 26.3, 26.2, 20.9. EI-LRMS, m/z (%): 407 (2.3) [M⁺+2], 405 (1.3) [M⁺], 149 (100). Elemental analysis calcd (%) for C₂₁H₂₈BrNS (406.4): C 62.06, H 6.94, N 3.45; found C 61.95, H 6.98, N 3.37.

3.3 General preparation of compounds 8 and 12

A solution of the corresponding 2-bromoallylamine 6 or 10 (2 mmol) in Et₂O (15 ml) was treated with 2 equiv of t-BuLi (4 mmol, 2.67 ml of a 1.5 M solution in pentane) at –78 ºC. The mixture was stirred for 20 min at this temperature, and then TMEDA (4.4 mmol, 0.66 ml) was added. The resulting mixture was stirred for 2 h at –78 ºC in the case of amine 6a, for 2 h at –20 °C in the case of amine 6b, for 30 min at 0 °C in the case of amine 6c and for 1 h at –50 ºC in the case of aromatic amine 6d. In all the cases, the ethereal solution of the cyclised anions 9 and 13 was cooled to –78 °C and 1.1 equiv (2.2 mmol) of the corresponding electrophile (deuterium oxide, chlorotrimethylsilane, tributyltin chloride, diphenyl disulfide, benzophenone) was added. Then, the mixture was allowed to reach room temperature, and the reaction was further stirred for 3 h. The mixture was hydrolysed with water and extracted with Et₂O (3 × 10 ml). The combined organic layers were dried over anhydrous Na₂SO₄ and the resulting residue was purified by column chromatography yielding compounds 8 and 12.

3.3.1 1-Cyclohexyl-3-(1-deuterio-1-phenylthiomethyl)-4-methylenepyrrolidine 8a

From amine 6a (0.53 g, 92%). R_f = 0.28 (hexane/AcOEt, 1:1). ¹H NMR (400 MHz, CDCl₃): δ 7.35–7.31 (m, 2H, ArH), 7.28–7.22 (m, 2H, ArH), 7.17–7.12 (m, 1H, ArH), 4.97–4.95 (m, 1H, =CHH), 4.93–4.90 (m, 1H, =CHH), 3.38 (d, J = 13.6 Hz, 1H, NCHHC=), 3.19 (d, J = 4.8 Hz, 1H, CHCHDS), 3.14 (ddd, J = 13.6, 4.4 and 2.0 Hz, 1H, NCHHC=), 3.04 (dd, J = 9.2 and 7.2 Hz, 1H, NCHHCH), 2.88–2.80 (m, 1H, CHCHDS), 2.43 (dd, J = 9.2 and 6.8 Hz, 1H, NCHHCH), 2.00–1.50 (m, 6H, cyclohexyl and NCH), 1.29–1.11 (m, 5H, cyclohexyl). ¹³C NMR (100.6 MHz, CDCl₃): δ 150.9, 136.3, 129.0, 128.7, 125.8, 105.5, 63.3, 57.5, 57.1, 41.6, 37.5 (t, J = 21.3 Hz), 31.4, 25.9, 24.8. EI-LRMS, m/z (%): 288 (1) [M⁺], 165 (100). Elemental analysis calcd (%) for C₁₈H₂₄DNS (288.5): C 74.94, H/D 9.08, N 4.86; found C 74.88, H/D 9.01, N 4.93.

3.3.2 3-[1,1Bis(phenylthio)methyl]-1-cyclohexyl-4-methylenepyrrolidine 8b

From amine 6a (0.71 g, 90%). R_f = 0.2 (hexane/AcOEt, 2:1). ¹H NMR (400 MHz, CDCl₃): δ 7.47–7.42 (m, 2H, ArH), 7.42–7.37 (m, 2H, ArH), 7.31–7.20 (m, 6H, ArH), 5.10–5.07 (m, 1H, =CHH), 5.07–5.04 (m, 1H, =CHH), 4.59 (d, J = 3.6 Hz, 1H, CHS₂), 3.58 (d, J = 12.8 Hz, 1H, NCHHC=), 3.34–3.22 (m, 2H, NCHHCH), 3.10 (dd, J = 12.8 and 2.4 Hz, 1H, NCHHC=), 2.58 (t, J = 8.0 Hz, 1H, NCHHCH), 2.12–2.05 (m, 1H, NCH), 2.00–1.55 (m, 5H, cyclohexyl), 1.32–1.14 (m, 5H, cyclohexyl). ¹³C NMR (100.6 MHz, CDCl₃): δ 148.3, 134.8, 134.6, 132.3, 132.2, 128.8, 128.7, 127.5, 127.4, 106.5, 63.0, 62.4, 58.1, 54.2, 46.2, 31.2, 31.1, 25.8, 24.6, 24.5. EI-LRMS, m/z (%): 395 (0.05) [M⁺], 164 (100). Elemental analysis calcd (%) for C₂₄H₂₉NS₂ (395.6): C 72.86, H 7.39, N 3.54; found C 72.78, H 7.31, N 3.64.

3.3.3 1-Cyclohexyl-3-(1-phenylthio-1-tributyltinmethyl)-4-methylenepyrrolidine 8c

From amine 6a (0.96 g, 83%). R_f = 0.2 (hexane/AcOEt, 10:1). Data from major diastereoisomer: ¹H NMR (400 MHz, CDCl₃): δ 7.36–7.32 (m, 2H, ArH), 7.29–7.23 (m, 2H, ArH), 7.16–7.10 (m, 1H, ArH), 4.94–4.91 (m, 1H, =CHH), 4.88–4.84 (m, 1H, =CHH), 3.31–3.08 (m, 4H, NCHHC=, CHCHSSn), 2.92 (dd, J = 8.8 and 7.2 Hz, 1H, NCHHCH), 2.55 (dd, J = 8.8 and 5.6 Hz, 1H, NCHHCH), 2.00–1.42 (m, 12H, NCH, SnBu₃ and cyclohexyl), 1.39–1.28 (m, 6H, SnBu₃), 1.28–1.10 (m, 5H, cyclohexyl), 1.09–0.85 (m, 15H, SnBu₃). ¹³C NMR (100.6 MHz, CDCl₃): δ 152.3, 138.2, 128.8, 128.4, 125.5, 104.9, 63.7, 58.2, 57.6, 44.8, 33.6, 31.7, 31.2, 29.2, 27.5, 26.1, 25.2, 25.1, 13.7, 11.0. EI-LRMS, m/z (%): 520 (0.2) [M⁺–C₄H₉], 518 (0.19), 176 (100), 164 (82). Elemental analysis calcd (%) for C₃₀H₅₁NSSn (576.5): C 62.50, H 8.92, N 2.43; found C 62.56, H 8.86, N 2.48.

3.3.4 1-Cyclohexyl-3-(2,2-diphenyl-1-phenylthio-2-hydroxyethyl)-4-methylenepyrrolidine 8d

From amine 6a (0.79 g, 84%). Mp = 151–153 °C. Data from major diastereoisomer: ¹H NMR (400 MHz, CDCl₃): δ 8.45 (s broad, 1H, OH), 7.67 (d, J = 7.2 Hz, 4H, ArH), 7.40–7.06 (m, 11H, ArH), 4.81–4.77 (m, 1H, =CHH), 4.72 (d, J = 4.8 Hz, 1H, CHCHS), 4.55–4.51 (m, 1H, =CHH), 3.83 (d, J = 9.2 Hz, 1H, NCHHCH), 3.24–3.17 (m, 1H, CHCHS), 2.82 (d, J = 14.0 Hz, 1H, NCHHC=), 2.63 (d, J = 14.0 Hz, 1H, NCHHC=), 2.30 (dd, J = 9.2 and 7.2 Hz, 1H, NCHHCH), 2.16–1.22 (m, 11H, CHN and 5 × CH₂ cyclohexyl). ¹³C NMR (100.6 MHz, CDCl₃): δ 147.8, 147.7, 146.5, 136.4, 131.6, 128.8, 127.6, 127.0, 126.7, 126.6, 126.2, 125.8, 125.2, 108.6, 79.5, 62.6, 62.2, 56.7, 53.6, 47.6, 31.2, 31.0, 25.7, 24.9, 24.8. EI–LRMS, m/z (%): 359 (9) [M⁺–PhSH], 163 (100). Elemental analysis calcd (%) for C₃₁H₃₅NOS (469.7): C 79.27, H 7.51, N 2.98; found C 79.21, H 7.43, N 2.90.

3.3.5 1-Cyclohexyl-3-(1-deuterio-1-trimethylsilylmethyl)-4-methylenepyrrolidine 8e

From amine 6b (0.45 g, 90%). R_f = 0.19 (hexane/AcOEt, 5:1). ¹H NMR (400 MHz, CDCl₃): δ 4.87–4.84 (m, 1H, =CHH), 4.80–4.77 (m, 1H, =CHH), 3.64 (d, J = 14.0 Hz, 1H, NCHHC=), 3.21 (t, J = 8.0 Hz, 1H, NCHHCH), 2.90 (ddd, J = 14.0, 4.8 and 2.4, 1H, NCHHC=), 2.68–2.57 (m, 1H, CHCHD), 1.97–1.83 (m, 4H, NCHHCH, NCH and cyclohexyl), 1.77–1.54 (m, 3H, cyclohexyl), 1.28–1.05 (m, 5H, cyclohexyl), 0.96–0.92 (m, 1H, CHD), –0.01 (s, 9H, 3 × CH₃ SiMe₃). ¹³C NMR (100.6 MHz, CDCl₃): δ 155.2, 103.1, 63.8, 59.6, 57.1, 38.9, 31.7, 31.6, 26.0, 25.0, 24.9, 19.7 (t, J = 18.4 Hz), –0.9. EI–LRMS, m/z (%): 252 (14) [M⁺], 209 (100), 73 (57). Elemental analysis calcd (%) for C₁₅H₂₈DNSi (252.5): C 71.35, H/D 11.98, N 5.55; found C 71.27, H/D 12.05, N 5.63.

3.3.6 3-[1,1Bis(trimethylsilyl)methyl]-1-cyclohexyl-4-methylenepyrrolidine 8f

From amine 6b (0.52 g, 80%). R_f = 0.33 (hexane/AcOEt, 4:1). ¹H NMR (400 MHz, CDCl₃): δ 4.86–4.82 (m, 1H, =CHH), 4.76–4.72 (m, 1H, =CHH), 3.67 (d, J = 14.8 Hz, 1H, NCHHC=), 3.16 (t, J = 8.0 Hz, 1H, NCHHCH), 2.99–2.90 (m, 2H, NCHHC= and CHCHSi₂), 2.15 (dd, J = 10.4 and 8.0 Hz, 1H, NCHHCH), 2.02–1.53 (m, 6H, NCH and cyclohexyl), 1.30–1.05 (m, 5H, cyclohexyl), 0.39 (d, J = 1.2 Hz, 1H, CHSi₂), 0.01 (s, 9H, 3 × CH₃ SiMe₃), 0.00 (s, 9H, 3 × CH₃ SiMe₃). ¹³C NMR (100.6 MHz, CDCl₃): δ 154.3, 103.2, 63.7, 57.6, 57.2, 41.4, 31.6, 31.5, 26.0, 25.1, 25.0, 16.6, 2.5, 0.7. EI–LRMS, m/z (%): 323 (5) [M⁺], 322 (8), 151 (100), 73 (90). Elemental analysis calcd (%) for C₁₈H₃₇NSi₂ (323.7): C 66.80, H 11.52, N 4.33; found C 66.71, H 11.47, N 4.39.

3.3.7 1-Cyclohexyl-3-(1-phenylthio-1-trimethylsilylmethyl)-4-methylenepyrrolidine 8g

From amine 6b (0.61 g, 85%). Data from minor diastereoisomer: R_f = 0.5 (hexane/AcOEt, 4:1). ¹H NMR (400 MHz, CDCl₃): δ 7.37–7.32 (m, 2H, ArH), 7.28–7.23 (m, 2H, ArH), 7.16–7.11 (m, 1H, ArH), 4.94–4.91 (m, 1H, =CHH), 4.86–4.83 (m, 1H, =CHH), 3.32 (d, J = 13.6 Hz, 1H, NCHHC=), 3.27–3.20 (m, 1H, NCHHC=), 3.11–3.03 (m, 1H, CHCHSSi), 2.95 (dd, J = 8.8 and 7.2 Hz, 1H, NCHHCH), 2.80 (d, J = 3.6 Hz, 1H, CHCHSSi), 2.62 (dd, J = 8.8 and 6.4 Hz, 1H, NCHHCH), 2.02–1.85 (m, 3H, NCH and cyclohexyl), 1.77–1.55 (m, 3H, cyclohexyl), 1.30–1.10 (m, 5H, cyclohexyl), 0.19 (s, 9H, 3 × CH₃ SiMe₃). ¹³C NMR (100.6 MHz, CDCl₃): δ 151.5, 137.3, 129.0, 128.9, 125.8, 105.0, 63.6, 58.3, 55.6, 45.2, 37.8, 31.6, 31.4, 26.0, 25.0, 24.9, –0.2. EI-LRMS, m/z (%): 359 (0.16) [M⁺], 164 (100). Elemental analysis calcd (%) for C₂₁H₃₃NSSi (359.6): C 70.13, H 9.25, N 3.89; found C 70.19, H 9.18, N 3.98. Data from major diastereoisomer: R_f = 0.35 (hexane/AcOEt, 1:1). ¹H NMR (400 MHz, CDCl₃): δ 7.38–7.34 (m, 2H, ArH), 7.20–7.14 (m, 2H, ArH), 7.12–7.07 (m, 1H, ArH), 4.82–4.79 (m, 1H, =CHH), 4.66–4.63 (m, 1H, =CHH), 3.62 (d, J = 13.2 Hz, 1H, NCHHC=), 3.23–3.10 (m, 2H, NCHHCH and CHCHSSi), 2.88 (ddd, J = 13.2, 4.8 and 2.8 Hz, 1H, NCHHC=), 2.82 (d, J = 2.8 Hz, 1H, CHCHSSi), 2.37 (dd, J = 9.2 and 8.4 Hz, 1H, NCHHCH), 2.10–2.00 (m, 1H, NCH), 1.98–1.55 (m, 5H, cyclohexyl), 1.32–1.07 (m, 5H, cyclohexyl), 0.12 (s, 9H, 3 × CH₃ SiMe₃). ¹³C NMR (100.6 MHz, CDCl₃): δ 150.3, 139.0, 130.3, 128.4, 125.8, 105.4, 63.6, 58.3, 55.3, 43.9, 37.9, 31.6, 31.5, 26.0, 25.0, 24.9, -1.7. EI-LRMS, m/z (%): 359 (0.16) [M⁺], 164 (100). Elemental analysis calcd (%) for C₂₁H₃₃NSSi (359.6): C 70.13, H 9.25, N 3.89; found C 70.18, H 9.35, N 3.80.

3.3.8 1-Cyclohexyl-3-methylene-4-(1-tributyltin-1-trimethylsilylmethyl)pyrrolidine 8h

From amine 6b (0.79 g, 73%). Data from minor diastereoisomer: R_f = 0.22 (hexane/AcOEt, 10:1). ¹H NMR (400 MHz, CDCl₃): δ 4.91–4.87 (m, 1H, =CHH), 4.81–4.78 (m, 1H, =CHH), 3.70 (d, J = 13.2 Hz, 1H, NCHHC=), 3.21–2.95 (m, 3H, NCHHC=, CHCHSiSn and NCHHCH), 2.20–0.68 (m, 40H, CHCHSiSn, NCH, NCHHCH, 5 × CH₂ cyclohexyl and 3 × (CH₂)₃CH₃ SnBu₃), 0.02 (s, 9H, 3 × CH₃ SiMe₃). ¹³C NMR (100.6 MHz, CDCl₃): δ 155.0, 104.5, 63.9, 59.5, 57.8, 43.0, 31.6, 31.5, 29.2, 27.6, 26.0, 25.1, 25.0, 13.8, 13.7, 10.9, 2.1. EI–LRMS, m/z (%): 485 (1), 483 [M⁺–C₄H₉] (0.6), 250 (100). Elemental analysis calcd (%) for C₂₇H₅₅NSiSn (540.5): C 59.99, H 10.26, N 2.59; found C 60.10, H 10.31, N 2.51. Data from major diastereoisomer: R_f = 0.21 (hexane/AcOEt, 10:1). ¹H NMR (400 MHz, CDCl₃): δ 4.90–4.85 (m, 1H, =CHH), 4.80–4.76 (m, 1H, =CHH), 3.72 (d, J = 14.4 Hz, 1H, NCHHC=), 3.27 (t, J = 8.0 Hz, 1H, NCHHCH), 3.20–3.10 (m, 1H, CHCHSiSn), 3.00–2.93 (m, 1H, NCHHC=), 2.00–0.68 (m, 40H, CHCHSiSn, NCH, NCHHCH, 5 × CH₂ cyclohexyl and 3 × (CH₂)₃CH₃ SnBu₃), 0.03 (s, 9H, 3 × CH₃ SiMe₃). ¹³C NMR (100.6 MHz, CDCl₃): δ 155.1, 103.5, 63.8, 60.3, 57.0, 42.5, 31.6, 31.5, 29.2, 27.6, 26.0, 25.1, 25.0, 15.3, 13.6, 11.6, 0.5. EI-LRMS, m/z (%): 483 (5) [M⁺–C₄H₉], 248 (100). Elemental analysis calcd (%) for C₂₇H₅₅NSiSn (540.5): C 59.99, H 10.26, N 2.59; found C 60.12, H 10.33, N 2.50.

3.3.9 1-Cyclohexyl-3-(1-deuterio-1-tributyltinmethyl)-4-methylenepyrrolidine 8i

From amine 6c (0.88 g, 94%). R_f = 0.32 (hexane/AcOEt, 5:1). ¹H NMR (400 MHz, CDCl₃): δ 4.89–4.87 (m, 1H, =CHH), 4.82–4.80 (m, 1H, =CHH), 3.62 (d, J = 14.0 Hz, 1H, NCHHC=), 3.14 (t, J = 8.0 Hz, 1H, NCHHCH), 2.98 (ddd, J = 14.0, 4.8 and 2.0 Hz, 1H, NCHHC=), 2.86–2.77 (m, 1H, CHCHDSn), 1.97–1.83 (m, 40H, 5 × CH₂ cyclohexyl, NCH, 3 × (CH₂)₃CH₃ SnBu₃, NCHHCH and CHCHDSn). ¹³C NMR (100.6 MHz, CDCl₃): δ 155.6, 103.5, 63.8, 60.9, 57.6, 40.9, 31.7, 31.6, 29.2, 27.4, 26.0, 25.0, 24.9, 13.7, 12.0 (t, J = 19.8 Hz), 9.4. Elemental analysis calcd (%) for C₂₄H₄₆DNSn (469.4): C 61.42, H/D 10.31, N 2.98; found C 61.91, H/D 10.39, N 2.91.

3.3.10 3-(1-Deuterio-1-trimethylsilylmethyl)-4-methylene-1-phenylpyrrolidine 8j

From amine 6d (0.26 g, 53%). Mp = 43–45 °C. ¹H NMR (400 MHz, CDCl₃): δ 7.33 (dd, J = 8.4 and 7.6 Hz, 2H, ArH), 6.80 (t, J = 7.6 Hz, 1H, ArH), 6.66 (d, J = 8.4, 2H, ArH), 5.06–5.03 (m, 1H, =CHH), 5.02–4.99 (m, 1H, =CHH), 4.15 (d, J = 13.6 Hz, 1H, NCHHC=), 3.92 (dd, J = 13.6 and 1.6 Hz, 1H, NCHHC=), 3.75 (t, J = 6.8 Hz, 1H, NCHHCH), 3.00–2.88 (m, 2H, NCHHCH and CHCHDSi), 1.07 (s, 1H, CHD), 0.72 (d, J = 10.4 Hz, 1H, CDH), 0.18 (s, 9H, 3 × CH₃ SiMe₃). ¹³C NMR (100.6 MHz, CDCl₃): δ 152.7, 147.7, 129.1, 116.1, 111.8, 104.3, 55.1, 52.8, 39.0, 18.6 (t, J = 18.7 Hz), –0.9. EI–LRMS, m/z (%): 246 (75) [M⁺], 173 (56), 158 (100), 73 (84). Elemental analysis calcd (%) for C₁₅H₂₂DNSi (246.4): C 73.10, H/D 9.82, N 5.68; found C 73.15, H/D 9.75, N 5.74.

3.3.11 3-Methylene-1-phenyl-4-(1-phenylthio-1-trimethylsilylmethyl)pyrrolidine 8k

From amine 6d (0.35 g, 50%). Data from minor diastereoisomer: R_f = 0.16 (hexane/AcOEt, 25:1). ¹H NMR (400 MHz, CDCl₃): δ 7.45–7.41 (m, 2H, ArH), 7.36–7.19 (m, 5H, ArH), 6.79 (t, J = 7.4 Hz, 1H, ArH), 6.67 (d, J = 8.8 Hz, 2H, ArH), 5.15–5.12 (m, 1H, =CHH), 5.07–5.03 (m, 1H, =CHH), 4.07 (dd, J = 14.0 and 2.0 Hz, 1H, NCHHC=), 3.87 (d, J = 14.0 Hz, 1H, NCHHC=), 3.55–3.47 (m, 2H, NCHHCH), 3.31 (m, 1H, CHCHSSi), 2.91 (d, J = 4.0 Hz, 1H, CHCHSSi), 0.20 (s, 9H, 3 × CH₃ SiMe₃). ¹³C NMR (100.6 MHz, CDCl₃): δ 149.0, 147.7, 138.5, 130.2, 129.1, 128.5, 126.0, 116.5, 112.3, 107.0, 53.6, 51.8, 44.2, 38.2, -1.5. EI–LRMS, m/z (%): 353 (0.15) [M⁺], 158 (100). Elemental analysis calcd (%) for C₂₁H₂₇NSSi (353.6): C 71.33, H 7.70, N 3.96; found C 71.25, H 7.80, N 3.85. Data from major diastereoisomer: R_f = 0.13 (hexane/AcOEt, 25:1). ¹H NMR (400 MHz, CDCl₃): δ 7.42–7.38 (m, 2H, ArH), 7.33–7.15 (m, 5H, ArH), 6.78 (t, J = 7.4 Hz, 1H, ArH), 6.63 (d, J = 8.8 Hz, 2H, ArH), 5.00–4.97 (m, 1H, =CHH), 4.93–4.90 (m, 1H, =CHH), 4.02 (d, J = 14.0 Hz, 1H, NCHHC=), 3.85 (dd, J = 14.0 and 2.0 Hz, 1H, NCHHC=), 3.70–3.60 (m, 1H, NCHHCH), 3.46–3.36 (m, 2H, NCHHCH and CHCHSSi), 2.94 (d, J = 2.8 Hz, 1H, CHCHSSi), 0.25 (s, 9H, 3 × CH₃ SiMe₃). ¹³C NMR (100.6 MHz, CDCl₃): δ 149.0, 147.7, 138.5, 130.2, 129.1, 128.5, 126.0, 116.5, 112.3, 107.0, 53.6, 51.8, 44.2, 38.2, –1.5. EI–LRMS, m/z (%): 353 (0.15) [M⁺], 158 (100). Elemental analysis calcd (%) for C₂₁H₂₇NSSi (353.6): C 71.33, H 7.70, N 3.96; found C 71.24, H 7.82, N 3.90.

3.3.12 3-Methylene-1-phenyl-4-(1-tributyltin-1-trimethylsilylmethyl)pyrrolidine 8l

From amine 6d (0.59 g, 55%). Mixture of diastereoisomers: R_f = 0.24 (hexane). ¹H NMR (400 MHz, CDCl₃): δ 7.37–7.31 (m, 2H, ArH), 6.85–6.79 (m, 1H, ArH), 6.70–6.65 (m, 2H, ArH), 5.20–5.15 (m, 1H, =CHH), 5.08–5.04 (m, 1H, =CHH), 4.26–4.16 (m, 2H, NCHHC=, major diast.), 4.05–3.93 (m, 2H, NCHHC=, minor diast.), 3.87 (t, J = 8.8 Hz, 1H, NCHHCH, major diast.), 3.71 (t, J = 8.8 Hz, 1H, NCHHCH, minor diast.), 3.56–3.47 (m, 1H, CHCHSiSn, major diast.), 4.47–3.38 (m, 1H, CHCHSiSn, minor diast.), 3.13 (t, J = 8.8 Hz, 1H, NCHHCH, minor diast.), 2.86 (t, J = 8.8 Hz, 1H, NCHHCH, major diast.), 1.70–1.30 (m, 13H, CHCHSiSn and SnBu₃), 1.12–0.80 (m, 15H, SnBu₃), 0.22 (s, 9H, 3 × CH₃ SiMe₃, major diast.), 0.15 (s, 9H, 3 × CH₃ SiMe_3, minor diast.). ¹³C NMR (100.6 MHz, CDCl₃): δ 153.4, 153.2, 147.7, 147.4, 129.1, 116.4, 116.3, 112.1, 111.9, 105.5, 104.4, 56.4, 55.7, 53.6, 52.9, 43.0, 41.9, 29.3, 29.2, 27.6, 27.5, 15.7, 14.4, 13.7, 13.6, 11.4, 11.0, 2.0, 0.4. EI–LRMS, m/z (%): major diast.: 477 (5) [M⁺-C₄H₉], 242 (100); minor diast.: 477 (1.8) [M⁺-C₄H₉], 242 (100). Elemental analysis calcd (%) for C₂₇H₄₉NSiSn (534.5): C 60.67, H 9.24, N 2.62; found C 60.78, H 9.29, N 2.57.

3.3.13 3-(1-Deuterio-1-phenylmethyl)-4-methylene-1-phenylpyrrolidine 8m

From amine 6e (0.31 g, 61%). R_f = 0.38 (hexane/AcOEt, 10:1). ¹H NMR (200 MHz, CDCl₃): δ 7.53–6.73 (m, 10H, ArH), 5.24 and 5.13 (2s, 2H, =CHH and =CHH), 4.15 (s, 2H, NCH₂C=), 3.55 (dd, J = 7.0 and 6.7 Hz, 1H, NCHHCH), 3.32–3.08 (m, 3H, NCHHCH, CH and CHD). ¹³C NMR (50.5 MHz, CDCl₃): δ 149.5, 147.7, 139.9, 129.0, 128.7, 128.3, 126.1, 116.3, 112.0, 105.8, 53.1, 52.9, 44.2, 38.8 (t, J = 20.3 Hz). EI-LRMS, m/z (%): 250 (20) [M⁺], 249 (18), 158 (100), 156 (37).

3.3.14 (2R,7aR)-1-Cyclohexyl-3-phenylthio-2,3,5,6,7,7a-hexahydro-1H-indole 12a

From amine 10 (0.60 g, 92%). R_f = 0.32 (hexane/AcOEt, 5:1). ¹H NMR (400 MHz, CDCl₃): δ 7.35–7.30 (m, 2H, ArH), 7.28–7.22 (m, 2H, ArH), 7.18–7.12 (m, 1H, ArH), 5.54–5.50 (m, 1H, =CH), 3.22 (dd, J = 8.8 and 7.2 Hz, 1H, NCHHCH), 3.16–3.11 (m, 1H, CHCHHS), 3.08–3.00 (m, 1H, NCHC=), 2.89–2.77 (m, 2H, CHCHHS), 2.71–2.61 (m, 1H, NCH), 2.32 (dd, J = 8.8 and 8.0 Hz, 1H, NCHHCH), 1.85–0.99 (m, 16H, 5 × CH₂ cyclohexyl and =CHCH₂CH₂CH₂). ¹³C NMR (100.6 MHz, CDCl₃): δ 143.2, 136.4, 129.1, 128.7, 125.8, 119.9, 58.3, 56.6, 51.9, 39.2, 39.1, 32.1, 28.1, 26.4, 25.7, 25.1, 24.1, 20.3. EI–LRMS, m/z (%): 327 (3) [M⁺], 204 (100), 176 (78). Elemental analysis calcd (%) for C₂₁H₂₉NS (327.5): C 77.01, H 8.92, N 4.28; found C 77.10, H 9.04, N 4.21.

3.3.15 (2R,7aR)-3-[1,1-Bis(phenylthio)methyl]-1-cyclohexyl-2,3,5,6,7,7a-hexahydro-1H-indole 12b

From amine 10 (0.78 g, 90%). R_f = 0.32 (hexane/AcOEt, 5:1). ¹H NMR (400 MHz, CDCl₃): δ 7.44–7.36 (m, 4H, ArH), 7.29–7.18 (m, 6H, ArH), 5.63–5.59 (m, 1H, =CH), 4.55 (d, J = 4.0 Hz, 1H, CHCHS₂), 3.31–3.20 (m, 2H, NCHHCH, NCHC=), 3.18 (t, J = 8.4 Hz, 1H, NCHHCH), 2.77 (dd, J = 8.4 and 7.6 Hz, 1H, NCHHCH), 2.73–2.67 (m, 1H, NCH), 2.15–0.81 (m, 16H, 5 × CH₂ cyclohexyl and =CHCH₂CH₂CH₂). ¹³C NMR (100.6 MHz, CDCl₃): δ 141.2, 135.1, 134.7, 132.6, 132.3, 128.9, 128.8, 127.6, 127.4, 121.4, 63.8, 59.3, 56.8, 48.6, 44.4, 32.0, 28.3, 26.4, 25.8, 25.2, 24.3, 20.2. Elemental analysis calcd (%) for C₂₇H₃₃NS₂ (435.7): C 74.43, H 7.63, N 3.21; found C 74.48, H 7.55, N 3.25.

Acknowledgements

Financial support from the Ministerio de Ciencia y Tecnología (MCYT, BQU2001–1079) and Junta de Castilla y León (BU24/02) is gratefully acknowledged. Y.F. thanks Junta de Castilla y León for a fellowship.

Bibliographie

[1] W.F. Bailey; J.J. Patricia; V.C. Del Globo; R.M. Jarret; P.J. Okarma J. Org. Chem., 50 (1985), p. 1999

[2] W.F. Bailey; T.V. Ovaska Advances in Detailed Reaction Mechanisms (J.M. Coxon, ed.), Mechanisms of Importance in Synthesis, 3, JAI Press, Greenwich, CT, 1994, p. 251

[3] M.J. Mealy; W.F. Bailey J. Organomet. Chem., 646 (2002), p. 59

[4] W.F. Bailey; K.V. Gavaskar Tetrahedron, 50 (1994), p. 5957

[5] C.A. Broka; W.J. Lee; T. Shen J. Org. Chem., 53 (1988), p. 1338

[6] C.A. Broka; T. Shen J. Am. Chem. Soc., 111 (1989), p. 2981

[7] I. Coldham; R. Hufton Tetrahedron Lett., 36 (1995), p. 2157

[8] D. Zhang; L.S. Liebeskind J. Org. Chem., 61 (1996), p. 2594

[9] W.F. Bailey; X.-L. Jiang J. Org. Chem., 61 (1996), p. 2596

[10] J. Barluenga; R. Sanz; A. Granados; F.J. Fañanás J. Am. Chem. Soc., 120 (1998), p. 4865

[11] W.F. Bailey; M.J. Mealy J. Am. Chem. Soc., 122 (2000), p. 6787

[12] G. Sanz Gil; U.M. Groth J. Am. Chem. Soc., 122 (2000), p. 6789

[13] J. Barluenga; R. Sanz; F.J. Fañanás Tetrahedron Lett., 38 (1997), p. 2763

[14] F.J. Fañanás; A. Granados; R. Sanz; J.M. Ignacio; J. Barluenga Chem. Eur. J., 7 (2001), p. 2896

[15] J. Barluenga; F.J. Fañanás; R. Sanz; C. Marcos Org. Lett., 4 (2002), p. 2225

[16] J. Barluenga; F.J. Fañanás; F. Foubelo; M. Yus J. Chem. Soc., Chem. Commun. (1988), p. 1135

[17] M.J. Woltering; R. Fröhlich; D. Hoppe Angew. Chem. Int. Ed. Engl., 36 (1997), p. 1764

[18] R.W. Hoffmann; R. Koberstein; B. Remacle; A. Krief Chem. Commun. (1997), p. 2189

[19] R.W. Hoffmann; R. Koberstein; K. Harms J. Chem. Soc., Perkin. Trans., 2 (1999), p. 183

[20] J. Org. Chem, 27 (1962), p. 748

[21] A.R. Chamberlin; S.H. Bloom; L.A. Cervini; C.H. Fotsch J. Am. Chem. Soc., 110 (1988), p. 4788

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