Synthesis of spirocyclic β- and γ-sultams by one-pot reductive cyclization of cyanoalkylsulfonyl fluorides

Abstract

One-pot intramolecular cyclization of novel sp³-enriched cyanoalkylsulfonyl fluorides into spirocyclic β- or γ-sultams is disclosed. The method relies on nitrile group reduction followed by sulfonylation of amino group thus formed upon mild conditions (NaBH₄, NiCl₂·6H₂O in MeOH). Cyclization proceeds smoothly with considerable efficiency (48–84%, 10 examples) on up to 30 g scale. The cyanoalkylsulfonyl fluoride intermediates can be obtained via S-nucleophilic substitution in β-functionalized alkanenitriles or double alkylation of α-alkylthioacetonitrile, followed by oxidative chlorination with Cl₂ and further reaction with KHF₂. The title mono- and bifunctional sultams are advanced sp³-enriched building blocks for drug discovery and organic synthesis providing novel substitution patterns and frameworks mimicking saturated nitrogen heterocycles such as pyrrolidine/pyrrolidone.

Graphical Abstract

Multigram synthesis of spirocyclic γ- and β-sultams – advanced building blocks for organic synthesis and drug discovery – via one-pot reductive cyclization of cyclic cyano sulfonyl fluorides is developed.

Introduction

Since discovery of the first SO₂NH₂-containing antibacterial drug Prontosil in the 1932, sulfonamides have become indispensable in drug discovery with about a hundred of FDA-approved drugs present on the market to date.^[1,2] Those include sulfanilamide antibiotics, also known as “sulfa drugs” (Sulfanilamide, Sulfamethoxazole), several important diuretics (i.e. Furosemide, Hydrochlorothiazide) etc.^[3,4] In turn, cyclic sulfonamides (sultams) provide an example of promising scaffolds with manifold applications in modern drug discovery, i.e. anti-inflammatory drug piroxicam, its prodrug ampiroxicam,^[5,6] or anticonvulsant sultiame.^[7] γ-Sultam-based scaffolds provide important physico-chemical properties to as compared to other five-membered molecular frameworks (Scheme 1). In particular, unlike saturated nitrogen heterocycles (i.e. pyrrolidines), γ-sultams possess very low basicity, which is accompanied by increased acidity and enhanced aqueous solubility. On the other hand, γ-sultams are 3D-shaped, stable towards protease-catalyzed degradation^[8] and can be easily modified by N-alkylation, which brings them closer to pyrrolidines as compared to isosteric γ-lactams (pyrrolidones) with planar amide moiety.

Scheme 1.

Comparison of γ-sultams, pyrrolidines and pyrrolidones

Therefore γ-sultams can be considered as prominent building blocks for lead-oriented synthesis^[9] – analogs of saturated nitrogen heterocycles^[8] – which allow “escaping from flatland”^[10,11] without considerable efforts.

A number of approaches to γ-sultams has been described in recent years (Scheme 2),^[12–21] including intramolecular cyclization of 3-aminopropane-1-sulfonyl chlorides (A),^[22–26] or aryl propane-1-sulfonates (B),^[27,28] intramolecular N-alkylation of propane-1-sulfonamides (C),^[29–37] double alkylation of alkanesulfonamides (D),^[38,39] intramolecular C-alkylation of N-substituted methanesulfonamides (E),^[40–43] cyclizations of N-allyl-1-halomethanesulfonamides (F),^[44] and intramolecular aliphatic C–H sulfonamidations (G).^[45]

Scheme 2.

Approaches to mono- and disubstituted γ-sultams

Most of these methods have been used for the synthesis of monocyclic and fused bicyclic γ-sultams. While preparation of γ-sultams bearing a spirocyclic fragment at the C-5 position have been also presented in the literature,^[46–50] their C-4-substituted counterparts are underrepresented to date, being limited by several 4,4′-spirobi(γ-sultam) derivatives.^[51] Keeping in mind further possible applications in lead discovery projects, herein we have aimed at preparation of spirocyclic building blocks 1a–h (Figure 1) with high sp³-atom fraction bearing alicyclic or saturated heterocyclic moieties at the C-4 position of the sultam ring.

Figure 1.

C-4-spirocyclic sultams 1a–h – targets molecules of this study

A proposed strategy to construct the spirocyclic scaffolds of 1 relied on reductive cyclization of previously unknown cyclic 2,2-disubstituted 2-cyanoethane-sulfonyl fluorides 2 derived from monocyclic ring systems (Scheme 2). Utility of the title methodology for the preparation of other spirocyclic derivatives (e.g. β-sultams) was also to be validated.

Results and Discussion

The study commenced with preparation of 2,2-disubstituted 2-cyanoethanesulfonyl fluorides 2a–h. The first step of the reaction sequence included reduction of homologous cyanoacetates 3a–d and tetrahydropyran derivative 3e with NaBH₄ in DME – MeOH, which resulted in the corresponding β-cyanoalcohols 4a–e in 79–90% yield (Table 1). Mesylation of 4a–e in the presence of Et₃N in CH₂Cl₂ led to corresponding mesylates 5a–e (89–95% yield).

Table 1.

Synthesis of intermediates 4 and 5

#		Starting material	Alcohol (yield, %)	Mesylate (yield, %)
1	(CH2)2	3a	4a (90)	5a (91)
2	(CH2)3	3b	4b (86)	5b (93)
3	(CH2)4	3c	4c (79)	5c (95)
4	(CH2)5	3d	4d (85)	5d (94)
5	(CH2)2O(CH2)2	3e	4e (81)	5e (89)

Subsequent incorporation of the sulfur atom was performed via nucleophilic substitution in mesylates 5a–e with t-BuSH (Table 2). While most tert-butyl sulfides 6a–c and 6e were obtained in good yields (Table 2, Entries 1–3 and 5), cyclohexane derivative 6d was formed in moderate yield (ca. 60%). Instead, when reaction was performed with KSAc, thioacetate 7d was obtained in 87% yield (Entry 4).

Table 2.

Preparation of sulfonyl chlorides 8a–e

#		Mesylate	Sulfide or thioacetate (%)[a]	Sulfonyl chloride (%)[a]
1	(CH2)2	5a	6a (79)[b]	8a (61)
2	(CH2)3	5b	6b (83)[b]	8b (67)
3	(CH2)4	5c	6c (77)[b,c]	8c (71)
4	(CH2)5	5d	7d (87)[d]	8d (82)
5	(CH2)2O(CH2)2	5e	6e (85)[b]	8e (71)

^[a]Isolated yields

^[b]Method A: t-BuSH, K₂CO₃, DMF, 70 °C (completion of the reaction was monitored by ¹H NMR)

^[c]Reaction was performed at 90 °C

^[d]Method B: KSAc, DMF, 70 °C, (completion of the reaction was monitored by ¹H NMR)

tert-Butyl sulfides 6a–c and 6e and thioacetate 7d smoothly underwent the oxidative chlorination with Cl₂ and the corresponding β-cyano sulfonyl chlorides 8a–e were obtained in 61–82% yield.

Synthesis of heterocyclic nitriles 5f–h relied on chloromethylation of N-Boc protected 3-cyanoazetidine (3f), 3-cyanopyrrolidine (3g) and 4-cyanopiperidine (3h). The reaction was performed via metallation with LDA at −78 °C followed by reaction with ClCH₂I, which gave β-chloropropanenitriles 5f–h in 90–95% yield (Scheme 3).

Scheme 3.

Synthesis of β-chloropropanenitriles 5f–h

Reactions of heterocyclic derivatives 5f–h with S-nucleophiles proceeded analogously to synthesis of 5a–e (Table 3). As it was found, synthesis of thioacetates 7f and 7h was more efficient as compared to corresponding tert-butyl sulfides 6f and 6h. Moreover, the chlorination step proceeded with better outcome for thioacetates 7f and 7h than for sulfides 6f and 6h.

Table 3.

Preparation of sulfonyl chlorides 8f–h

#	Cyclic substituent	Chloride	Sulfide or thioacetate (%)[a]	Sulfonyl chloride (%)[a]
1		5f	6f (73)[b]	8f (60)
2			7f (80)[c]	8f (63)[c]
3		5g	7g (97)[c]	8g (71)[c]
4		5h	6h (71)[b]	8h (73)
5			7h (93)[c]	8h (84)[c]

^[a]Isolated yields

^[b]Method A: t-BuSH, K₂CO₃, DMF, 60 °C (for 6f) or 70 °C (for 6h), (completion of the reaction was monitored by ¹H NMR)

^[c]Method B: KSAc, DMF, 85 °C, 12 h

Due to limited stability of the SO₂Cl derivatives 8 under reductive conditions, they were transformed into the target sulfonyl fluorides 2 by reaction of 8a–h with KHF₂ in MeOH – H₂O (1:1, v/v) (Table 4). The reaction proceeded smoothly at rt and gave exclusively 2a–h in good to excellent yields (72–94%, 85% average yield).

Table 4.

Intramolecular reductive cyclization of 2a–h

#		Sulfonyl chloride	Sulfonyl fluoride (%)[a]	Sultam (%)[a]
1	(CH2)2	8a	2a (87)	1a (61)
2	(CH2)3	8b	2b (89)	1b (71)
3	(CH2)4	8c	2c (94)	1c (82)
4	(CH2)5	8d	2d (94)	1d (78)
5	(CH2)2O(CH2)2	8e	2e (90)	1e (84)
6		8f	2f (77)	1f (74)
7		8g	2g (72)	1g (75)
8		8h	2h (80)	1h (78)

^[a]Isolated yields

The key intramolecular reductive cyclization of SO₂F-derivatives 2a–h was performed with NaBH₄ in the presence of NiCl₂·6H₂O, and the spirocyclic sultams 1a–h were obtained exclusively in the one-pot reaction in 61–84% yield (Table 4).

Moreover, N-Boc-protecting group cleavage was successfully performed for the case of monoprotected bifunctional sultams 1g and 1h. Deprotection proceeded smoothly with 4 M HCl – 1,4-dioxane at rt and gave corresponding hydrochlorides 9g and 9h, both in quantitative yield (Scheme 4).

Scheme 4.

N-Deprotection of sultams 1g and 1h

Being inspired by aforementioned results, we have evaluated the developed approach for synthesis of analogous spirocyclic β-sultams. It should be noted that known approaches to β-sultams (Scheme 5) relied on intermolecular reactions of α-bromomethyl sulfonamides with α-halocarbonyl compounds (A),^[52] [2 + 2] cycloadditions of sulfonyl chlorides with imines (B),^[53–55] intramolecular alkylation of sulfonamides bearing a leaving group at the β-position (C),^[56,57] and intramolecular cyclization of β-amino sulfonyl chlorides (D).^[44,58–66] As in the case of γ-sultams, the intramolecular reductive cyclization of substituted α-cyano sulfonyl fluorides has never been reported to date. To demonstrate possibility of such cyclyzations, spirocyclic β-sultams 10a and 10b were selected as the synthetic targets.

Scheme 5.

Approaches to β-sultams

Synthesis of corresponding cyanomethanesulfonyl fluorides 11a and 11b relied on the double alkylation of easily accessible 2-(tert-butylthio)acetonitrile 12 (Scheme 6). The NaH-mediated reaction of 12 with 1,3-dibromopropane 13a in DMF gave cyclobutane derivative 14a in 62% yield, while 1-bromo-2-(2-bromoethoxy)ethane 13b was used for preparation of tetrahydropyrane-derived sulfide 14b (68% yield). The oxidative chlorination proceeded smoothly for sulfides 14a and 14b, and correspondding sulfonyl chlorides 15a and 15b were isolated in 80% and 87% yield, respectively.

Scheme 6.

Synthesis of cyanomethanesulfonyl chlorides 15a and 15b

Finally, sulfonyl chlorides 15a and 15b were successfully transformed into corresponding fluorides 11a and 11b in 77% and 66% yield, respectively (Scheme 7). To our delight, intramolecular cyclizations of 11a and 11b into β-sultams proceeded smoothly upon the common conditions, despite the fact that 10a and 10b were obtained in slightly lower yields (58% and 63% yield, respectively) as compared to γ-counterparts 1a–h, that were synthesized with 75% average yield. This might be contributed to the general fact that the four-membered rings are formed less efficiently than the five-membered ones.

Scheme 7.

Synthesis of β-sultams 10a and 10b

Molecular structure of sultam 1h was obtained by X-Ray diffraction studies of single crystals (Figure 2). It was shown that the γ-sultam ring in the molecule of 1h adopts envelope conformation in the solid state, with the nitrogen atom outstanding of the mean plane formed by other ring atoms by 0.604 Å. This is somewhat different from the case of the corresponding spirocyclic derivative 16 (Figure 3): although the pyrrolidine ring also adopts the envelope conformation, it is the spirocyclic carbon atom which outstands from the mean plane formed by other five-membered ring atoms by 0.575 Å. Exit vector plot (EVP) analysis^[67–70] of the corresponding bifunctional scaffolds shows that despite some differences, their overall geometry is similar and corresponds to truly three-dimensional relative disposition of the corresponding groups attached to the variation points (Table 5).

Figure 2.

ORTEP diagram of sultam 1h (thermal ellipsoids are shown at 50% probability level)

Figure 3.

ORTEP diagram of spirocyclic pyrrolidine 16 (thermal ellipsoids are shown at 30% probability level)

Table 5.

EVP analysis of the spirocyclic scaffods of 1h and 16

#	X	r, Å	φ1, deg	φ2, deg	|θ|, deg
1	CH2	4.96	43.8	11.4	71.0
2	SO2	5.39	37.4	24.0	48.4

Conclusions

Intramolecular reductive cyclization of alicyclic and saturated heterocyclic cyanoalkylsulfonyl fluorides is an efficient approach for the preparation of spirocyclic β- and γ-sultams. The protocol includes using NaBH₄ in presence of NiCl₂·6H₂O in MeOH for nitrile group reduction, that is accompanied with intramolecular sulfonylation of amino group with the side chain SO₂F-functional group. The method is scalable (up to 30 g), equally suitable for both α- and β-cyano-substituted sulfonyl fluorides, and leads exclusively to β-(48–53% yield, 2 examples) and γ-sultams (61–84% yield, 8 examples), respectively.

Preparation of the previously unknown β-cyano sulfonyl fluorides was performed via mesylation of β-hydroxy nitriles or chloromethylation of heterocyclic nitriles, followed by incorporation of the sulfur atom via nucleophilic substitutions with t-BuSH or KSAc. Subsequent oxidative chlorination with Cl₂ and reaction with KHF₂ gave SO₂F-derivatives. To obtain α-cyano sulfonyl fluorides, double alkylation of 2-(tert-butylthio)acetonitrile was used, which was followed by the transformations mentioned above for the homologous counterparts.

The title mono- and bifunctional sultams can be considered as analogs of common saturated nitrogen heterocycles – advanced building blocks for modern organic chemistry and lead-oriented synthesis. In particular, replacement of spirocyclic pyrrolidine derivatives with the corresponding three-dimensional sulfonamide analogues can be envisaged, which is confirmed by crystallographic studies and exit vector plot (EVP) analysis of the corresponding bifunctional scaffods.

Experimental Section

The solvents were purified according to the standard procedures.^[71] Compounds 3a–h, 12, 13a, 13b and 16 were available from Enamine Ltd. All other starting materials were purchased from commercial sources. Melting points were measured on MPA100 OptiMelt automated melting point system. Column chromatography was performed using Kieselgel Merck 60 (230–400 mesh) as the stationary phase. ¹H, ¹³C and ¹⁹F NMR spectra were recorded on a Bruker 170 Avance 500 spectrometer (at 500 MHz for ¹H NMR, 126 MHz for ¹³C NMR and 470 MHz for ¹⁹F NMR) and Varian Unity Plus 400 spectrometer (at 400 MHz for ¹H NMR, 101 MHz for ¹³C NMR and 376 MHz for ¹⁹F NMR). NMR chemical shifts are reported in ppm (δ scale) downfield from TMS as an internal standard and are referenced using residual NMR solvent peaks at 7.26 and 77.16 ppm for ¹H and ¹³C in CDCl₃, 2.50 and 39.52 ppm for ¹H and ¹³C in DMSO-d₆. Coupling constants (J) are shown in Hz. Spectra are reported as follows: chemical shift (δ, ppm), multiplicity, integration, coupling constants (Hz). Elemental analyses were performed at the Laboratory of Organic Analysis, Department of Chemistry, Taras Shevchenko National University of Kyiv. Mass spectra were recorded on an Agilent 1100 LCMSD SL instrument (chemical ionization (CI)) and Agilent 5890 Series II 5972 GCMS instrument (electron impact ionization (EI)). Single crystals of 1h and 16·(16·CO₂)·H₂O were obtained by slow evaporation of their solutions in hexanes – THF (1:1, v/v) and MeCN, respectively. CCDC 1990716 (1h) and CCDC 1990717 (16) contain the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.

General procedure for the preparation of 4a–e

To a solution of ester 3a–e (0.360 mol) in dimethoxyethane - MeOH (600 mL, 5:1, v/v), NaBH₄ (27.2 g, 0.720 mol) was added in portions at 0 °C over 3 h. The reaction mixture was warmed up to rt and stirred for 24 h. The resulting solution was diluted with H₂O (700 mL), and extracted with CH₂Cl₂ (3×400 mL). Combined organic layers were dried over Na₂SO₄ and evaporated in vacuo.

1-(Hydroxymethyl)cyclopropanecarbonitrile (4a)

^[72,73] The crude compound was purified by distillation in vacuo. Yield 31.5 g (90%); colorless liquid; bp 60–63 °C / 0.2 mmHg. ¹H NMR (400 MHz, CDCl₃) δ 3.57 (s, 2H), 2.99 (s, 1H), 1.28 – 1.17 (m, 2H), 1.01 – 0.89 (m, 2H). ¹³C NMR (126 MHz, CDCl₃) δ 122.5, 65.5, 12.7, 12.0. GC/MS (EI): m/z = 66 [M-CH₂OH]⁺, 97 [M]⁺. Anal. Cald. for C₅H₇NO: C 61.84; H 7.27; N 14.42. Found: C 62.19; H 7.62; N 14.36.

1-(Hydroxymethyl)cyclobutanecarbonitrile (4b)

The crude compound was purified by distillation in vacuo. Yield 34.4 g (86%); colorless liquid; bp 67–70 °C / 0.2 mmHg). ¹H NMR (400 MHz, CDCl₃) δ 3.75 (s, 2H), 2.79 (s, 1H), 2.49 – 2.41 (m, 2H), 2.19 – 2.09 (m, 3H), 2.04 – 1.97 (m, 1H). ¹³C NMR (126 MHz, CDCl₃) δ 123.6, 65.8, 37.3, 28.4, 16.7. GC/MS (EI): m/z = 111 [M]⁺. Anal. Cald. for C₆H₉NO: C 64.84; H 8.16; N 12.60. Found: C 65.11; H 8.55; N 12.44.

1-(Hydroxymethyl)cyclopentanecarbonitrile (4c)

The crude compound was purified by distillation in vacuo. Yield 35.6 g (79%); colorless liquid; bp 82–84 °C / 0.2 mmHg). ¹H NMR (400 MHz, CDCl₃) δ 3.58 (s, 2H), 2.75 (s, 1H), 2.12 – 1.97 (m, 2H), 1.89 – 1.62 (m, 6H). ¹³C NMR (126 MHz, CDCl₃) δ 124.8, 66.7, 45.2, 34.7, 24.8. GC/MS (EI): m/z = 125 [M]⁺. Anal. Cald. for C₇H₁₁NO: C 67.17; H 8.86; N 11.19. Found: C 67.26; H 8.88; N 11.41.

1-(Hydroxymethyl)cyclohexanecarbonitrile (4d)

^[74,75] Yield 42.6 g (85%); colorless liquid. ¹H NMR (400 MHz, CDCl₃) δ 3.60 (s, 2H), 2.57 (s, 1H), 2.01 (d, J = 13.3 Hz, 2H), 1.82 – 1.71 (m, 3H), 1.61 (td, J = 13.3, 3.4 Hz, 2H), 1.27 (td, J = 13.3, 3.4 Hz, 2H), 1.23 – 1.07 (m, 1H). ¹³C NMR (126 MHz, CDCl₃) δ 122.9, 68.8, 42.2, 31.9, 25.4, 22.6. GC/MS (EI): m/z = 122 [M–CN]⁺, 139 [M]⁺. Anal. Cald. for C₈H₁₃NO: C 69.03; H 9.41; N 10.06. Found: C 68.73; H 9.32; N 9.98.

4-(Hydroxymethyl)tetrahydro-2H-pyran-4-carbonitrile (4e)

The crude compound was purified by distillation in vacuo. Yield 41.2 g (81%); colorless oil; bp 108–111 °C (0.2 mmHg). ¹H NMR (400 MHz, CDCl₃) δ 3.96 (dq, J = 12.2, 1.9 Hz, 2H), 3.67 (td, J = 12.2, 1.9 Hz, 2H), 3.61 (s, 2H), 2.79 (s, 1H), 1.87 (dd, J = 13.7, 1.9 Hz, 2H), 1.60 (ddd, J = 13.7, 12.2, 4.6 Hz, 2H). ¹³C NMR (126 MHz, CDCl₃) δ 121.9, 68.4, 64.5, 40.0, 31.7. GC/MS (EI): m/z = 141 [M]⁺. Anal. Cald. for C₇H₁₁NO₂: C 59.56; H 7.85; N 9.92. Found: C 59.19; H 8.1; N 10.29.

General procedure for the preparation of 5a–e

Et₃N (34.1 mL, 24.8 g, 0.245 mol) was added to the corresponding alcohol 4a–e (0.204 mol) in CH₂Cl₂ (200 mL), and the resulting solution was cooled to 0 °C. Then, MsCl (17.4 mL, 25.7 g, 0.224 mol) was added dropwise at 0 °C, the reaction mixture was stirred at rt for 12 h, and washed with H₂O (200 mL). The organic layer was separated, dried over Na₂SO₄ and evaporated in vacuo. Unless other is specified, the crude compound was purified by column chromatography on silica gel using 40 g RediSep column (flow rate: 40 mL / min, rack: 16 mm × 150 mm tubes) and gradient hexanes – t-BuOMe as eluent.

(1-Cyanocyclopropyl)methyl methanesulfonate (5a)

Yield 32.5 g (91%); yellowish oil. ¹H NMR (400 MHz, CDCl₃) δ 4.11 (s, 2H), 3.05 (s, 3H), 1.42 – 1.33 (m, 2H), 1.17 – 1.08 (m, 2H). ¹³C NMR (101 MHz, CDCl₃) δ 120.8, 71.7, 38.1, 13.5, 10.2. LC/MS (CI): m/z = 176 [M+H]⁺. Anal. Cald. for C₆H₉NO₃S: C 41.13; H 5.18; N 7.99; S 18.3. Found: C 41.08; H 4.83; N 7.84; S 18.40.

(1-Cyanocyclobutyl)methyl methanesulfonate (5b)

Yield 35.9 g (93%); yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 4.33 (s, 2H), 3.09 (s, 3H), 2.60 – 2.52 (m, 2H), 2.28 – 2.17 (m, 3H), 2.13 – 2.05 (m, 1H). ¹³C NMR (126 MHz, CDCl₃) δ 121.6, 70.1, 37.9, 34.9, 28.8, 16.6. GC/MS (EI): m/z = 95 [M-OSO₂CH₃]⁺, 189 [M]⁺. Anal. Cald. for C₇H₁₁NO₃S: C 44.43; H 5.86; N 7.40; S 16.94. Found: C 44.14; H 5.88; N 7.35; S 16.55.

(1-Cyanocyclopentyl)methyl methanesulfonate (5c)

Yield 39.4 g (95%); colorless liquid. ¹H NMR (400 MHz, CDCl₃) δ 4.16 (s, 2H), 3.09 (s, 3H), 2.22 – 2.08 (m, 2H), 1.96 – 1.82 (m, 2H), 1.82 – 1.69 (m, 4H). ¹³C NMR (126 MHz, CDCl₃) δ 122.6, 70.9, 42.7, 37.9, 35.2, 24.5. GC/MS (EI): m/z = 108 [M-OMs]⁺, 203 [M]⁺. Anal. Cald. for C₈H₁₃NO₃S: C 47.27; H 6.45; N 6.89; S 15.77. Found: C 47.66; H 6.53; N 6.94; S 16.09.

(1-Cyanocyclohexyl)methyl methanesulfonate (5d)

Yield 41.7 g (94%); colorless liquid. ¹H NMR (500 MHz, CDCl₃) δ 4.12 (s, 2H), 3.07 (s, 3H), 2.00 (d, J = 12.9 Hz, 2H), 1.81 – 1.74 (m, 3H), 1.60 (qt, J = 12.9, 3.4 Hz, 2H), 1.32 (td, J = 12.9, 3.4 Hz, 2H), 1.19 (qt, J = 12.2, 4.4 Hz, 1H). ¹³C NMR (126 MHz, CDCl₃) δ 120.8, 72.8, 39.7, 37.7, 31.9, 25.0, 22.2. GC/MS (EI): m/z = 122 [M-OMs]⁺, 217 [M]⁺. Anal. Cald. for C₉H₁₅NO₃S: C 49.75; H 6.96; N 6.45; S 14.76. Found: C 49.86; H 7.17; N 6.28; S 15.09.

(4-Cyanotetrahydro-2H-pyran-4-yl)methyl methanesulfonate (5e)

The crude compound was purified by flash chromatography (5 bar) on silica gel using 40 g column gradient hexanes – t-BuOMe as eluent. Yield 39.8 g (89%); colorless oil. ¹H NMR (500 MHz, CDCl₃) δ 4.18 (s, 2H), 3.99 (dd, J = 12.3, 4.5 Hz, 2H), 3.69 (t, J = 12.3 Hz, 2H), 3.11 (s, 3H), 1.91 (d, J = 13.2 Hz, 2H), 1.69 (td, J = 13.2, 4.5 Hz, 2H). ¹³C NMR (126 MHz, CDCl₃) δ 119.9, 72.0, 63.9, 37.8, 37.7, 31.6. GC/MS (EI): m/z = 124 [M-OMs]⁺, 141 [M–H₂C=SO₂]⁺, 219 [M]⁺. Anal. Cald. for C₈H₁₃NO₄S: C 43.82; H 5.98; N 6.39; S 14.62. Found: C 44.00; H 6.35; N 6.43; S 14.68.

General procedure for the preparation of chloromethyl derivatives 5f–h

2.1 M LDA (31.4 mL, 65.9 mmol) in THF was added dropwise to a solution of corresponding nitrile 3f–h (54.9 mmol) in THF (100 mL) at −78 °C under argon atmosphere. The reaction mixture was stirred at −78 °C for 1 h, and a solution of СlСH₂I (14.9 g, 82.3 mmol) in THF (30 мл) was added dropwise at −78 °C. The resulting mixture was warmed up to rt, stirred for 1 h, and H₂O (100 mL) was added. The misture was extracted with EtOAс (2×100 mL), combined organic layers were dried over Na₂SO₄, and evaporated in vacuo.

tert-Butyl 3-(chloromethyl)-3-cyanoazetidine-1-carboxylate (5f)

The crude compound was purified by column chromatography on silica gel using 80 g RediSep column (flow rate: 60 mL / min, rack: 16 mm × 150 mm tubes) and gradient hexanes – t-BuOMe as eluent. Yield 11.4 g (90%); yellowish solid; mp 81–83 °C. ¹H NMR (400 MHz, CDCl₃) δ 4.27 (d, J = 9.1 Hz, 2H), 3.96 (d, J = 9.1 Hz, 2H), 3.84 (s, 2H), 1.44 (s, 9H). ¹³C NMR (126 MHz, CDCl₃) δ 155.5, 119.1, 81.3, 56.3, 46.2, 33.0, 28.4. LC/MS (CI): m/z = 131 [M–CO₂–(H₃C)₂C=CH₂+H]⁺. Anal. Calcd. for C₁₀H₁₅ClN₂O₂: C 52.07; H 6.55; N 12.14; Cl 15.37. Found: C 52.17; H 6.19; N 12.39; Cl 15.17.

tert-Butyl 3-(chloromethyl)-3-cyanopyrrolidine-1-carboxylate (5g)

The crude compound was purified by column chromatography on silica gel using 80 g RediSep column (flow rate: 60 mL / min, rack: 16 mm × 150 mm tubes) and gradient hexanes – t-BuOMe as eluent. The compound was obtained as ca. 1:1 mixture of rotamers. Yield 12.8 g (95%); yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 3.92 – 3.76 (m, 1H), 3.71 – 3.62 (m, 2H), 3.58 (s, 2H), 3.49 (d, J = 11.6 Hz, 1H), 2.47 – 2.33 (m, 1H), 2.23 – 2.08 (m, 1H), 1.46 (s, 9H) ppm. ¹³C NMR (126 MHz, CDCl₃) δ 153.8, 120.2, 80.7, 53.5 and 53.4, 46.0, 45.0, 44.3 and 44.1, 34.7 and 33.9, 28.5 ppm. GC/MS (EI): m/z = 144/146 [M–CO₂–H₂C=C(CH₃)₂]⁺, 171/173 [M–Ot-Bu]⁺, 188/190 [M–H₂C=C(CH₃)₂]⁺, 209 [M–Cl]⁺, 244/246 [M]⁺. Anal. Calcd. for C₁₁H₁₇ClN₂O₂: C 53.99; H 7.00; N 11.45; Cl 14.49. Found: C 54.07; H 7.33; N 11.50; Cl 14.79.

tert-Butyl 4-(chloromethyl)-4-cyanopiperidine-1-carboxylate (5h)

The crude compound was purified by column chromatography on silica gel using 80 g RediSep column (flow rate: 60 mL / min, rack: 16 mm × 150 mm tubes) and gradient CHCl₃ – MeCN as eluent. Yield 12.8 g (90%); colorless solid; mp 113–115 °C. ¹H NMR (400 MHz, CDCl₃) δ 4.33 – 4.07 (m, 2H), 3.56 (s, 2H), 3.13 – 2.93 (m, 2H), 2.04 (d, J = 12.9 Hz, 2H), 1.49 (td, J = 12.9, 4.4 Hz, 2H), 1.45 (s, 9H). ¹³C NMR (126 MHz, CDCl₃) δ 154.4, 119.9, 80.4, 49.6, 41.0, 40.7, 32.9, 28.5. GC/MS (EI): m/z = 185/187 [M–Ot-Bu]⁺, 258/260 [M]⁺. Anal. Calcd. for C₁₂H₁₉ClN₂O₂: C 55.70; H 7.40; N 10.83; Cl 13.70. Found: C 55.67; H 7.36; N 11.07; Cl 13.85.

General procedure for the preparation of tert-butyl sulfides 6a–h

A mixture of the corresponding mesylate or chloride (0.124 mol), t-BuSH (16.8 mL, 13.4 g, 0.149 mol) and K₂CO₃ (20.6 g, 0.149 mol) in DMF (200 mL) was heated at 70 °C. Completion of the reaction was monitored by ¹H NMR. Then, the reaction mixture was diluted with H₂O (400 mL) and extracted with EtOAc (3×200 mL). Combined organic layers were washed with H₂O (2×200 mL), dried over Na₂SO₄ and evaporated in vacuo. Unless other is specified, the crude compound was purified by column chromatography on silica gel using 40 g RediSep column (flow rate: 40 mL / min, rack: 16 mm × 150 mm tubes) and gradient hexanes – t-BuOMe as eluent.

1-((tert-Butylthio)methyl)cyclopropanecarbonitrile (6a)

Yield 16.6 g (79%); colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 2.66 (s, 2H), 1.30 (s, 9H), 1.29 – 1.25 (m, 2H), 0.96 – 0.91 (m, 2H). ¹³C NMR (126 MHz, CDCl₃) δ 122.7, 42.6, 33.5, 30.9, 14.5, 10.2. GC/MS (EI): m/z = 169 [M]⁺. Anal. Cald. for C₉H₁₅NS: C 63.85; H 8.93; N 8.27; S 18.94. Found: C 63.79; H 8.9; N 8.41; S 18.97.

1-((tert-Butylthio)methyl)cyclobutanecarbonitrile (6b)

The crude compound was purified by flash chromatography (5 bar) on silica gel using 80 g column gradient hexanes – t-BuOMe as eluent. Yield 18.9 g (83%); yellowish oil. ¹H NMR (500 MHz, CDCl₃) δ 2.85 (s, 2H), 2.54 – 2.48 (m, 2H), 2.21 – 2.13 (m, 3H), 2.06 – 1.98 (m, 1H), 1.33 (d, J = 1.1 Hz, 9H). ¹³C NMR (126 MHz, CDCl₃) δ 123.8, 42.5, 36.0, 35.5, 31.9, 30.9, 16.5. GC/MS (EI): m/z = 183 [M]⁺. Anal. Cald. for C₁₀H₁₇NS: C 65.52; H 9.35; N 7.64; S 17.49. Found: C 65.53; H 9.24; N 7.49; S 17.47.

1-((tert-Butylthio)methyl)cyclopentanecarbonitrile (6c)

The reaction was performed at 90 °C. The crude compound was purified by flash chromatography (5 bar) on silica gel using 40 g column gradient hexanes – t-BuOMe as eluent. Yield 18.8 g (77%); yellowish oil. ¹H NMR (400 MHz, CDCl₃) δ 2.72 (s, 2H), 2.17 – 2.06 (m, 2H), 1.87 – 1.76 (m, 2H), 1.75 – 1.65 (m, 4H), 1.29 (s, 9H). ¹³C NMR (126 MHz, CDCl₃) δ 124.5, 43.5, 42.6, 37.9, 35.9, 30.8, 24.4. GC/MS (EI): m/z = 197 [M]⁺. Anal. Cald. for C₁₁H₁₉NS: C 66.95; H 9.71; N 7.1; S 16.25. Found: C 67.18; H 9.35; N 7.05; S 16.49.

4-((tert-Butylthio)methyl)tetrahydro-2H-pyran-4-carbonitrile (6e)

Yield 22.5 g (85%); colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 3.89 (ddd, J = 12.2, 4.6, 1.9 Hz, 2H), 3.62 (td, J = 12.2, 1.9 Hz, 2H), 2.66 (s, 2H), 1.87 (dd, J = 13.4, 1.9 Hz, 2H), 1.62 (ddd, J = 13.4, 12.2, 4.6 Hz, 2H), 1.28 (s, 9H). ¹³C NMR (126 MHz, CDCl₃) δ 121.6, 64.6, 42.8, 37.9, 37.6, 35.0, 30.8. GC/MS (EI): m/z = 157 [M–H₂C=C(CH₃)₃]⁺, 198 [M–Me]⁺, 213 [M]⁺. Anal. Cald. for C₁₁H₁₉NOS: C 61.93; H 8.98; N 6.57; S 15.03. Found: C 61.84; H 9.13; N 6.89; S 15.02.

tert-Butyl 3-((tert-butylthio)methyl)-3-cyanoazetidine-1-carboxylate (6f)

The reaction was performed at 60 °C. The crude compound was purified by flash chromatography (5 bar) on silica gel using 40 g column gradient hexanes – t-BuOMe as eluent. Yield 25.7 g (73%); colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 4.19 (d, J = 8.8 Hz, 2H), 3.87 (d, J = 8.8 Hz, 2H), 2.94 (s, 2H), 1.39 (s, 9H), 1.31 (s, 9H). ¹³C NMR (126 MHz, CDCl₃) δ 155.5, 120.6, 80.7, 57.6, 43.2, 34.2, 31.0, 30.8, 28.3. GC/MS (EI): m/z = 229 [M–H₂C=C(CH₃)₃]⁺, 284 [M]⁺. Anal. Cald. for C₁₄H₂₄N₂O₂S: C 59.12; H 8.51; N 9.85; S 11.27. Found: C 58.73; H 8.18; N 9.48; S 11.35.

tert-Butyl 4-((tert-Butylthio)methyl)-4-cyanopiperidine-1-carboxylate (6h)

The compound existed as a mixture of ca. 1:1 rotamers. Yield 27.5 g (71%); colorless crystals; mp 82–83 °C. ¹H NMR (400 MHz, CDCl₃) δ 4.27 – 4.02 (m, 2H), 3.01 (t, J = 10.9 Hz, 2H), 2.70 (s, 1H) and 2.69 (s, 1H), 1.96 (d, J = 13.4 Hz, 2H), 1.60 – 1.49 (m, 2H), 1.44 (s, 4.5H) and 1.43 (s, 4.5H), 1.32 (s, 4.5H) and 1.32 (s, 4.5H). ¹³C NMR (101 MHz, CDCl₃) δ 154.4, 121.4, 80.1, 42.9, 40.7, 39.0, 37.3, 34.4, 30.8, 28.4. GC/MS (EI): m/z = 212 [M–CO₂–H₂C=C(CH₃)₂]⁺, 239 [M–Ot-Bu]⁺, 256 [M–H₂C=C(CH₃)₂]⁺. Anal. Cald. for C₁₆H₂₈N₂O₂S: C 61.5; H 9.03; N 8.97; S 10.26. Found: C 61.23; H 8.63; N 9.20; S 10.56.

General procedure for the preparation of thioacetates 7d and 7f–h

KSAc (19.8 g, 0.174 mol) was added to a solution of the corresponding mesylate or chloride (0.124 mol) in DMF (625 mL). The reaction mixture was stirred at 85 °C for 12 h, then cooled to rt and evaporated in vacuo at 85 °C to ca. 150 mL volume. The residue was diluted with H₂O (1000 mL) and extracted with EtOAc (4×125 mL). Combined organic layers was washed with brine (4×125 mL), dried over Na₂SO₄ and evaporated in vacuo.

S-((1-Cyanocyclohexyl)methyl) ethanethioate (7d)

The crude compound was purified by column chromatography on silica gel using 40 g RediSep column (flow rate: 40 mL / min, rack: 16 mm × 150 mm tubes) and gradient hexanes – t-BuOMe as eluent. Yield 21.3 g (87%); yellowish liquid. ¹H NMR (500 MHz, CDCl₃) δ 3.12 (s, 2H), 2.39 (s, 3H), 1.98 (d, J = 13.2 Hz, 2H), 1.80 – 1.69 (m, 3H), 1.59 (q, J = 13.2 Hz, 2H), 1.36 – 1.26 (m, 2H), 1.21 – 1.12 (m, 1H). ¹³C NMR (126 MHz, CDCl₃) δ 193.9, 122.0, 40.3, 37.6, 34.8, 30.5, 25.0, 22.9. GC/MS (EI): m/z = 122 [M–SAc]⁺, 155 [M–H₂CCC(O)]⁺, 182 [M–Me]⁺, 197 [M]⁺. Anal. Cald. for C₁₀H₁₅NOS: C 60.88; H 7.66; N 7.10; S 16.25. Found: C 61.08; H 8.01; N 7.23; S 16.35.

tert-Butyl 3-((acetylthio)methyl)-3-cyanoazetidine-1-carboxylate (7f)

The crude compound was purified by column chromatography on silica gel using 80 g RediSep column (flow rate: 60 mL / min, rack: 16 mm × 150 mm tubes) and gradient CHCl₃ – MeCN as eluent. Yield 26.8 g (80 %); yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 4.22 (d, J = 8.9 Hz, 2H), 3.85 (d, J = 8.9 Hz, 2H), 3.43 (s, 2H), 2.42 (s, 3H), 1.43 (s, 9H) ppm. ¹³C NMR (126 MHz, CDCl₃) δ 193.3, 155.5, 120.2, 81.0, 57.5, 34.0, 31.6, 30.7, 28.4. GC/MS (EI): m/z = 228 [M–CH₂CC(O)]⁺, 197 [M–Ot-Bu]⁺. Anal. Calcd. for C₁₂H₁₈N₂O₃S: C 53.31; H 6.71; N 10.36; S 11.86. Found: C 53.29; H 6.92; N 10.18; S 11.75.

tert-Butyl 3-((acetylthio)methyl)-3-cyanopyrrolidine-1-carboxylate (7g)

The crude compound was purified by flash chromatography (5 bar) on silica gel using 80 g column gradient hexanes – t-BuOMe as eluent. Yield 34.2 g (97%); yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 4.25 (d, J = 8.7 Hz, 2H), 3.92 (d, J = 8.7 Hz, 2H), 2.95 (t, J = 9.3, 6.5 Hz, 2H), 2.35 (s, 3H), 2.15 (dd, J = 9.3, 6.5 Hz, 2H), 1.43 (s, 9H). ¹³C NMR (151 MHz, CDCl₃) δ 195.1, 155.5, 120.7, 80.9, 57.9 (2C), 36.4, 30.7, 30.5, 28.4, 24.7. LC/MS (CI): m/z = 185 [M–CO₂–H₂C=C(CH₃)₂+H]⁺, 229 [M– H₂C=C(CH₃)₂+H]⁺, 307 [M+Na]⁺. Anal. Calcd. for C₁₃H₂₀N₂O₃S: C 54.91; H 7.09; N 9.85; S 11.27. Found: C 54.88; H 7.44; N 9.97; S 11.52.

tert-Butyl 4-((acetylthio)methyl)-4-cyanopiperidine-1-carboxylate (7h)

The crude compound was purified by flash chromatography (5 bar) on silica gel using 80 g column gradient hexanes – t-BuOMe as eluent. Yield 34.4 g (93%); beige powder; mp 94–95 °C. ¹H NMR (500 MHz, CDCl₃) δ 4.24 – 4.10 (m, 2H), 3.20 (s, 2H), 3.07 – 2.98 (m, 2H), 2.44 (s, 3H), 1.95 (d, J = 12.8 Hz, 2H), 1.56 – 1.51 (m, 2H), 1.48 (s, 9H). ¹³C NMR (126 MHz, CDCl₃) δ 193.5, 154.2, 120.7, 80.2, 40.7, 39.3, 36.9, 33.8, 30.5, 28.4. GC/MS (EI): m/z = 198 [M–CO₂–H₂C=C(CH₃)₂]⁺, 225 [M–Ot-Bu]⁺, 242 [M–H₂C=C(CH₃)₂]⁺, 298 [M]⁺. Anal. Cald. for C₁₄H₂₂N₂O₃S: C 56.35; H 7.43; N 9.39; S 10.74. Found: C 56.32; H 7.43; N 9.27; S 11.13.

Preparation of tert-butyl sulfides 14a and 14b

2-(tert-Butylthio)aceto-nitrile (12, 20.0 g, 0.155 mol) was added dropwise to a suspension of NaH (60%, 13.0 g, 0.325 mol) in DMF (100 mL) at 0 °C under argon atmosphere. The resulting mixture was stirred at rt for 2 h, then cooled to −10 °C, and 1,3-dibromopropane (13a, 31.3 g, 0.155 mol) or 1-bromo-2-(2-bromoethoxy)ethane (13b, 35.9 g, 0.155 mol) was added dropwise at −10 °C. The reaction mixture was stirred at rt for 12 h, then diluted with H₂O (200 mL) and extracted with EtOAс (3×100 mL). Combined organic layers were washed with H₂O (2×70 mL), dried over Na2SO4, and evaporated in vacuo.

1-(tert-Butylthio)cyclobutanecarbonitrile (14a)

The crude compound was purified by flash chromatography (5 bar) on silica gel using 80 g column gradient hexanes – CHCl₃ as eluent. Yield 16.3 g (62%); colorless oil. ¹H NMR (500 MHz, CDCl₃) δ 2.75 (ddt, J = 15.0, 8.7, 3.5 Hz, 2H), 2.47 – 2.40 (m, 2H), 2.35 – 2.25 (m, 1H), 2.21 – 2.11 (m, 1H), 1.44 (s, 9H). ¹³C NMR (126 MHz, CDCl₃) δ 123.4, 47.0, 37.4, 36.4, 31.5, 18.1. GC/MS (EI): m/z = 169 [M]⁺. Anal. Calcd. for C₉H₁₅NS: C 63.85; H 8.93; N 8.27; S 18.94. Found: C 64.14; H 9.26; N 7.91; S 19.14.

4-(tert-Butylthio)tetrahydro-2H-pyran-4-carbonitrile (14b)

The crude compound was purified by column chromatography on silica gel using 40g RediSep column (flow rate: 40 mL / min, rack: 16 mm × 150 mm tubes) and gradient t-BuOMe – MeOH as eluent. Yield 21.0 g (68%); colorless oil. ¹H NMR (500 MHz, CDCl₃) δ 3.92 (dt, J = 11.7, 3.8 Hz, 2H), 3.71 (dd, J = 11.7, 2.3 Hz, 2H), 2.15 (dq, J = 13.6, 2.3 Hz, 2H), 1.95 (ddd, J = 13.6, 11.7, 3.8 Hz, 2H), 1.51 (s, 9H). ¹³C NMR (126 MHz, CDCl₃) δ 121.3, 64.2, 48.1, 39.2, 38.0, 32.3. GC/MS (EI): m/z = 199 [M]⁺. Anal. Calcd. for C₁₀H₁₇NOS: C 60.26; H 8.60; N 7.03; S 16.09. Found: C 60.01; H 8.88; N 7.03; S 16.19.

General procedure for the preparation of sulfonyl chlorides 8a–h, 15a and 15b

A solution of the corresponding tert-butyl sulfide 6 or thioacetate 7 (0.180 mmol) in CH₂Cl₂ – H₂O (450 mL, 2:1, v/v) was cooled to 0 °C, and Cl₂ was bubbled through the reaction mixture at 0 °C for 1 h (CAUTION! Gaseous Cl₂ is toxic, has irritating odor, strong oxidizing agent. The experiments with gaseous Cl₂ must be performed carefully and accurately, while the temperature of the reaction mixture should not exceed 5 °C). The organic phase was separated, and the aqueous phase was washed with CH₂Cl₂ (300 mL). Combined organic phases were washed with H₂O (300 mL), dried over Na₂SO₄ and evaporated in vacuo. Unless other is specified, the crude compound was purified by column chromatography on silica gel using 80 g or 330 g RediSep column (flow rate: 60 mL / min or 100 mL / min, respectively, rack: 16 mm × 150 mm tubes) and hexanes – t-BuOMe followed by gradient hexanes – EtOAc as eluents.

(1-Cyanocyclopropyl)methanesulfonyl chloride (8a)

Yield 19.7 g (61% from 6a); colorless crystals; mp 71–72 °C. ¹H NMR (400 MHz, CDCl₃) δ 3.81 (s, 2H), 1.69 – 1.61 (m, 2H), 1.44 – 1.37 (m, 2H). ¹³C NMR (126 MHz, CDCl₃) δ 119.9, 69.1, 15.8, 5.9. GC/MS (EI): m/z = 80 [M– SO₂Cl]⁺. Anal. Cald. for C₅H₆ClNO₂S: C 33.43; H 3.37; N 7.8; S 17.85; Cl 19.74. Found: C 33.15; H 3.52; N 7.65; S 18.17; Cl 19.70.

(1-Cyanocyclobutyl)methanesulfonyl chloride (8b)

Yield 23.3 g (67% from 6b); colorless liquid. ¹H NMR (400 MHz, CDCl₃) δ 4.09 (s, 2H), 2.76 – 2.66 (m, 2H), 2.53 – 2.45 (m, 2H), 2.44 – 2.33 (m, 1H), 2.17 – 2.08 (m, 1H). ¹³C NMR (126 MHz, CDCl₃) δ 120.8, 70.1, 32.9, 32.8, 17.4. LC/MS (CI): m/z = 194/196 [M+H]⁺. Anal. Cald. for C₆H₈ClNO₂S: C 37.21; H 4.16; N 7.23; S 16.56; Cl 18.31. Found: C 37.11; H 4.11; N 7.12; S 16.32; Cl 18.12.

(1-Cyanocyclopentyl)methanesulfonyl chloride (8c)

The crude compound was purified by flash chromatography (5 bar) on silica gel using 80 g column gradient hexanes – t-BuOMe as eluent. Yield 26.5 g (71% from 6c); yellowish oil. ¹H NMR (500 MHz, CDCl₃) δ 4.06 (s, 2H), 2.47 – 2.37 (m, 2H), 2.07 – 1.96 (m, 2H), 1.95 – 1.86 (m, 4H). ¹³C NMR (126 MHz, CDCl₃) δ 120.8, 71.0, 40.6, 38.5, 23.5. GC/MS (EI): m/z = 108 [M–SO₂Cl]⁺, 207/209 [M]⁺. Anal. Cald. for C₇H₁₀ClNO₂S: C 40.49; H 4.85; N 6.74; S 15.44; Cl 17.07. Found: C 40.45; H 4.6; N 6.48; S 15.36; Cl 16.97.

(1-Cyanocyclohexyl)methanesulfonyl chloride (8d)

Yield 32.7 g (82% from 7d); colorless solid; mp 55–56 °C. ¹H NMR (400 MHz, CDCl₃) δ 3.97 (s, 2H), 2.25 (d, J = 13.0 Hz, 2H), 1.87 – 1.67 (m, 5H), 1.57 (td, J = 13.0, 3.7 Hz, 2H), 1.29 – 1.18 (m, 1H). ¹³C NMR (126 MHz, CDCl₃) δ 119.4, 72.7, 37.9, 35.1, 24.4, 22.4. GC/MS (EI): m/z = 122 [M–SO₂Cl]⁺, 221/223 [M]⁺. Anal. Cald. for C₈H₁₂ClNO₂S: C 43.34; H 5.46; N 6.32; S 14.46; Cl 15.99. Found: C 43.59; H 5.18; N 5.98; S 14.07; Cl 15.70.

(4-Cyanotetrahydro-2H-pyran-4-yl)methanesulfonyl chloride (8e)

Yield 28.6 g (71% from 6e); colorless powder; mp 160–162 °C. ¹H NMR (400 MHz, CDCl₃) δ 4.05 – 4.00 (m, 1H), 4.00 – 3.96 (m, 3H), 3.76 (td, J = 12.1, 1.8 Hz, 2H), 2.13 (dd, J = 13.2, 1.9 Hz, 2H), 1.87 (ddd, J = 13.2, 12.1, 4.7 Hz, 2H). ¹³C NMR (126 MHz, CDCl₃) δ 118.4, 72.0, 63.8, 35.6, 34.6. GC/MS (EI): m/z = 124 [M-SO₂Cl]⁺, 223/225 [M]⁺. Anal. Cald. for C₇H₁₀ClNO₃S: C 37.59; H 4.51; N 6.26; S 14.33; Cl 15.85. Found: C 37.94; H 4.48; N 6.64; S 14.39; Cl 15.63.

tert-Butyl 3-((chlorosulfonyl)methyl)-3-cyanoazetidine-1-carboxylate (8f)

Yield 31.8 g (60% from 6f) and 33.4 g (63% from 7f); beige powder; mp 132–134 °C. ¹H NMR (400 MHz, CDCl₃) δ 4.42 (d, J = 9.3 Hz, 2H), 4.28 (s, 2H), 4.17 (d, J = 9.3 Hz, 2H), 1.45 (s, 9H) ppm. ¹³C NMR (126 MHz, CDCl₃) δ 155.2, 117.8, 81.8, 68.1, 57.8, 28.3, 27.7 ppm. LC/MS (CI): m/z = 195/197 [M–CO₂–(H₃C)₂C=CH₂+H]⁺. Anal. Calcd. for C10H15ClN2O4S: C 40.75; H 5.13; N 9.50; S 10.88; Cl 12.03. Found: C 40.44; H 5.25; N 9.21; S 10.93; Cl 12.15.

tert-Butyl 3-((chlorosulfonyl)methyl)-3-cyanopyrrolidine-1-carboxy-late (8g)

Yield 39.5 g (71% from 7g); yellow solid, mp 102–105 °C. The compound existed as ca. 1:1 mixture of rotamers. ¹H NMR (400 MHz, CDCl₃) δ 4.21 – 3.97 (m, 3H), 3.71 – 3.48 (m, 3H), 2.67 – 2.52 (m, 1H), 2.36 – 2.18 (m, 1H), 1.47 (s, 9H) ppm. ¹³C NMR (126 MHz, CDCl₃) δ 153.6, 118.4, 81.2, 68.2, 54.8, 43.9 and 43.5, 39.6 and 38.9, 36.3 and 35.8, 28.5. LC/MS (CI): m/z = 209/211 [M–CO₂–H₂C=C(CH₃)₂+H]⁺, 253/255 [M–H₂C=C(CH₃)₂+H]⁺. Anal. Calcd. for C₁₁H₁₇ClN₂O₄S: C 42.79; H 5.55; N 9.07; S 10.38; Cl 11.48. Found: C 42.75; H 5.73; N 9.28; S 10.23; Cl 11.21.

tert-Butyl 4-((chlorosulfonyl)methyl)-4-cyanopiperidine-1-carboxy-late (8h)

The crude compound was purified by column chromatography on silica gel using 80 g RediSep column (flow rate: 60 mL / min, rack: 16 mm × 150 mm tubes) and gradient CHCl₃ – MeCN as eluent. Yield 42.4 g (73% from 6h) and 48.8 g (84% from 7h); yellow solid, mp 113–115 °C. ¹H NMR (400 MHz, CDCl₃) δ 4.40 – 4.00 (m, 2H), 3.97 (s, 2H), 3.17 – 3.01 (m, 2H), 2.17 (dd, J = 12.9, 2.2 Hz, 2H), 1.69 (td, J = 12.9, 4.4 Hz, 2H), 1.43 (s, 9H). ¹³C NMR (126 MHz, CDCl₃) δ 154.2, 118.2, 80.8, 71.9, 40.2, 36.8, 34.2, 28.5. Anal. Calcd. for C₁₂H₁₉ClN₂O₄S: C 44.65; H 5.93; N 8.68; S 9.93; Cl 10.98. Found: C 44.52; H 5.55; N 8.54; S 10.10; Cl 10.72.

1-Cyanocyclobutane-1-sulfonyl chloride (15a)

Yield 25.9 g (80%); yellow liquid. ¹H NMR (400 MHz, CDCl₃) δ 3.12 – 3.00 (m, 2H), 2.93 – 2.81 (m, 2H), 2.42 – 2.25 (m, 2H). ¹³C NMR (126 MHz, CDCl₃) δ 115.1, 66.9, 30.9, 15.6. GC/MS (EI): m/z = 179/181 [M]⁺. Anal. Cald. for C₅H₆ClNO₂S: C 33.43; H 3.37; N 7.80; S 17.85; Cl 19.74. Found: C 33.48; H 3.33; N 7.74; S 17.59; Cl 19.38.

4-Cyanotetrahydro-2H-pyran-4-sulfonyl chloride (15b)

Yield 32.8 g (87%); yellowish crystals; mp 93–95 °C. ¹H NMR (400 MHz, CDCl₃) δ 4.26 – 4.17 (m, 2H), 3.75 – 3.66 (m, 2H), 2.45 – 2.33 (m, 4H). ¹³C NMR (126 MHz, CDCl₃) δ 113.4, 71.5, 63.5, 30.2. LC/MS (CI): m/z = 111 [M–SO₂Cl]⁺, 210/212 [M+H]⁺. Anal. Cald. for C₆H₈ClNO₃S: C 34.38; H 3.85; N 6.68; S 15.29; Cl 16.91. Found: C 34.39; H 4.11; N 6.80; S 15.00; Cl 16.92.

General procedure for the preparation of sulfonyl fluorides 2a–h, 11a and 11b

KHF₂ (0.900 mol) was added at rt to the corresponding sulfonyl chloride 8 or 15 (90.0 mmol) in MeOH–H₂O (240 mL, 1:1, v/v). The resulting mixture was stirred at rt for 12 h, then diluted with H₂O (240 mL) and extracted with CH₂Cl₂ (3×200 mL). Combined organic layers were dried over Na₂SO₄ and evaporated in vacuo. Unless other is specified, the crude compound was purified by column chromatography on silica gel using 40 g, 80 g or 330 g RediSep column (flow rate: 40 mL / min, 60 mL / min, or 100 mL / min, respectively, rack: 16 mm × 150 mm tubes) and gradient hexanes – t-BuOMe as eluent.

(1-Cyanocyclopropyl)methanesulfonyl fluoride (2a)

The crude compound was purified by flash chromatography (5 bar) on silica gel using 40 g column gradient hexanes – t-BuOMe as eluent. Yield 12.8 g (87%); colorless crystals; mp 56–58 °C. ¹H NMR (500 MHz, CDCl₃) δ 3.55 (d, J = 4.1 Hz, 1H), 1.64 – 1.58 (m, 1H), 1.34 – 1.29 (m, 1H). ¹³C NMR (126 MHz, CDCl₃) δ 119.9, 55.5 (d, J = 17.9 Hz), 15.4, 5.1. ¹⁹F{H} NMR (376 MHz, CDCl₃) δ 57.0. GC/MS (EI): m/z = 163 [M]⁺. Anal. Cald. for C₅H₆FNO₂S: C 36.81; H 3.71; N 8.58; S 19.65. Found: C 36.61; H 4.08; N 8.23; S 19.54.

(1-Cyanocyclobutyl)methanesulfonyl fluoride (2b)

Yield 14.2 g (89%); colorless crystals; mp 43–44 °C. ¹H NMR (400 MHz, CDCl₃) δ 3.80 (d, J = 4.2 Hz, 2H), 2.73 – 2.59 (m, 2H), 2.50 – 2.37 (m, 2H), 2.37 – 2.26 (m, 1H), 2.17 – 2.02 (m, 1H). ¹³C NMR (126 MHz, CDCl₃) δ 121.1, 56.37 (d, J = 16.1 Hz), 32.4, 32.1, 17.1. ¹⁹F{H} NMR (376 MHz, CDCl₃) δ 61.3. GC/MS (EI): m/z = 177 [M]⁺. Anal. Cald. for C₆H₈FNO₂S: C 40.67; H 4.55; N 7.91; S 18.09. Found: C 40.37; H 4.79; N 7.63; S 17.89.

(1-Cyanocyclopentyl)methanesulfonyl fluoride (2c)

The crude compound was purified by flash chromatography (5 bar) on silica gel using 40 g column gradient hexanes – t-BuOMe as eluent. Yield 16.2 g (94%); colorless oil. ¹H NMR (500 MHz, CDCl₃) δ 3.72 (s, 2H), 2.47 – 2.32 (m, 2H), 2.03 – 1.91 (m, 2H), 1.92 – 1.81 (m, 4H). ¹³C NMR (126 MHz, CDCl₃) δ 121.1, 56.9 (d, J = 16.5 Hz), 39.7, 38.3, 23.5. ¹⁹F{H} NMR (470 MHz, CDCl₃) δ 62.1. GC/MS (EI): m/z = 108 [M–SO₂F]⁺, 191 [M]⁺. Anal. Cald. for C₇H₁₀FNO₂S: C 43.97; H 5.27; N 7.33; S 16.77. Found: C 43.8; H 5.39; N 7.36; S 16.75.

(1-Cyanocyclohexyl)methanesulfonyl fluoride (2d)

Yield 17.4 g (94%); colorless liquid. ¹H NMR (400 MHz, CDCl₃) δ 3.63 (d, J = 3.2 Hz, 2H), 2.25 (d, J = 12.9 Hz, 2H), 1.86 – 1.68 (m, 5H), 1.54 (td, J = 12.9, 3.6 Hz, 2H), 1.32 – 1.18 (m, 1H). ¹³C NMR (126 MHz, CDCl₃) δ 119.4, 58.7 (d, J = 16.3 Hz), 36.7, 35.0, 24.4, 22.4. ¹⁹F NMR (470 MHz, CDCl₃) δ 65.4. GC/MS (EI): m/z = 122 [M–SO₂Cl]⁺, 205 [M]⁺. Anal. Cald. for C₈H₁₂FNO₂S: C 46.82; H 5.89; N 6.82; S 15.62. Found: C 46.67; H 6.22; N 6.98; S 15.56.

(4-Cyanotetrahydro-2H-pyran-4-yl)methanesulfonyl fluoride (2e)

Yield 16.8 g (90%); colorless crystals; mp 143–144 °C. ¹H NMR (500 MHz, CDCl₃) δ 4.04 (dd, J = 12.2, 4.3 Hz, 2H), 3.78 (t, J = 12.2 Hz, 2H), 3.67 (s, 2H), 2.14 (d, J = 13.2 Hz, 2H), 1.86 (td, J = 13.2, 4.3 Hz, 2H). ¹³C NMR (126 MHz, CDCl₃) δ 118.5, 63.8, 58.4, 58.2, 34.6, 34.5. ¹⁹F{H} NMR (470 MHz, CDCl₃) δ 65.5. GC/MS (EI): m/z = 124 [M-SO₂F]⁺, 207 [M]⁺. Anal. Cald. for C₇H₁₀FNO₃S: C 40.57; H 4.86; N 6.76; S 15.47. Found: C 40.44; H 4.94; N 6.58; S 15.37.

tert-Butyl 3-cyano-3-((fluorosulfonyl)methyl)azetidine-1-carboxylate (2f)

The crude compound was purified by flash chromatography (5 bar) on silica gel using 80 g column gradient hexanes – t-BuOMe – MeCN as eluent. Yield 19.3 g (77%); yellowish powder; mp 112–114 °C. ¹H NMR (400 MHz, CDCl₃) δ 4.41 (d, J = 9.3 Hz, 2H), 4.12 (d, J = 9.3 Hz, 2H), 3.99 (d, J = 4.1 Hz, 2H), 1.45 (s, 9H). ¹³C NMR (126 MHz, CDCl₃) δ 155.2, 117.8, 81.8, 57.6, 55.0 (d, J = 18.3 Hz), 28.3, 27.1. ¹⁹F{H} NMR (376 MHz, CDCl₃) δ 62.3. LC/MS (CI): m/z = 277 [M-H]_-. Anal. Calcd. for C₁₀H₁₅FN₂O₄S: C 43.16; H 5.43; N 10.07; S 11.52. Found: C 42.99; H 5.75; N 10.24; S 11.82.

tert-Butyl 3-cyano-3-((fluorosulfonyl)methyl)pyrrolidine-1-carboxy-late (2g)

Yield 18.9 g (72%); yellow solid, mp 134–136 °C. The compound existed as ca. 1:1 mixture of rotamers. ¹H NMR (400 MHz, DMSO-d₆) δ 4.85 – 4.68 (m, 2H), 3.86 (dd, J = 11.9, 4.8 Hz, 1H), 3.53 (t, J = 9.8 Hz, 1H), 3.47 – 3.37 (m, 2H), 2.49 – 2.41 (m, 1H), 2.28 – 2.13 (m, 1H), 1.41 (s, 9H). ¹³C NMR (101 MHz, DMSO-d₆) δ 153.2 and 152.9, 119.6, 79.5, 54.1, 52.8 (d, J = 15.0 Hz), 43.7 and 43.5, 38.6 and 37.8, 35.2 and 34.4, 28.0. ¹⁹F NMR (376 MHz, DMSO-d₆) δ 60.9 and 60.8. LC/MS (CI): m/z = 193 [M–CO₂–H₂C=C(CH₃)₂+H]⁺, 237 [M– H₂C=C(CH₃)₂+H]⁺. Anal. Calcd. for C₁₁H₁₇FN₂O₄S: C 45.20; H 5.86; N 9.58; S 10.97. Found: C 45.23; H 5.85; N 9.83; S 10.82.

tert-Butyl 4-cyano-4-((fluorosulfonyl)methyl)piperidine-1-carboxy-late (2h)

The crude compound was purified by column chromatography on silica gel using 330 g RediSep column (flow rate: 100 mL / min, rack: 16 mm × 150 mm tubes) and gradient CHCl₃ – MeCN as eluent. Yield 22.1 g (80%); yellow solid, mp 134–136 °C. ¹H NMR (400 MHz, CDCl₃) δ 4.21 (s, 2H), 3.65 (d, J = 3.5 Hz, 2H), 3.18 – 3.01 (m, 2H), 2.17 (dd, J = 13.1, 2.7 Hz, 2H), 1.67 (td, J = 13.1, 4.3 Hz, 2H), 1.45 (s, 9H) ppm. ¹³C NMR (126 MHz, CDCl₃) δ 154.2, 118.3, 80.8, 58.2 (d, J = 17.0 Hz), 40.1, 35.7, 34.2, 28.4 ppm. ¹⁹F NMR (376 MHz, CDCl₃) δ 65.0 ppm. GC/MS (EI): m/z = 206 [M-CO₂-(H₃C)₂C=CH₂]⁺, 233 [M –Ot-Bu]⁺. Anal. Calcd. for C₁₂H₁₉FN₂O₄S: C 47.05; H 6.25; N 9.14; S 10.47. Found: C 47.16; H 6.35; N 8.95; S 10.56.

1-Cyanocyclobutane-1-sulfonyl fluoride (11a)

The crude compound was purified by flash chromatography (5 bar) on silica gel using 120 g column gradient hexanes – CHCl₃ as eluent. Yield 11.3 g (77%); colorless liquid. ¹H NMR (400 MHz, CDCl₃) δ 3.12 – 3.01 (m, 2H), 2.99 – 2.88 (m, 2H), 2.50 – 2.33 (m, 2H). ¹³C NMR (126 MHz, CDCl₃) δ 114.4 (d, J = 1.8 Hz), 54.9 (d, J = 19.2 Hz), 30.5, 16.5. ¹⁹F{H} NMR (470 MHz, CDCl₃) δ 41.8. GC/MS (EI): m/z = 163 [M]⁺. Anal. Calcd. for C₅H₆FNO₂S: C 36.81; H 3.71; N 8.58; S 19.65. Found: C 36.98; H 3.56; N 8.46; S 19.43.

4-Cyanotetrahydro-2H-pyran-4-sulfonyl fluoride (11b)

The crude compound was purified by HPLC using gradient H₂O – MeCN as eluent. Yield 11.5 g (66%); yellowish crystals; mp 57–59 °C. ¹H NMR (400 MHz, CDCl₃) δ 4.16 (ddd, J = 12.4, 4.2, 1.9 Hz, 2H), 3.71 (td, J = 12.4, 2.4 Hz, 2H), 2.40 – 2.26 (m, 4H). ¹³C NMR (126 MHz, CDCl₃) δ 113.0, 63.4, 60.6 (d, J = 18.2 Hz), 30.4. ¹⁹F{H} NMR (376 MHz, CDCl₃) δ 39.4. GC/MS (EI): m/z = 193 [M]⁺. Anal. Cald. for C₆H₈FNO₃S: C 37.3; H 4.17; N 7.25; S 16.6. Found: C 37.41; H 4.31; N 7.56; S 16.97

General procedure for the preparation of sultams 1a–h, 10a and 10b

A mixture of the corresponding sulfonyl fluoride 2 or 11 (0.140 mol) and NiCl₂*6H₂O (36.6 g, 0.154 mol) in MeOH (300 mL) was cooled to −20 °C. Then, NaBH₄ (18.5 g, 0.490 mol) was added in portions at −20 °C (NOTE: the temperature should not exceed −10 °C). The resulting mixture was warmed up to rt and stirred for 12 h. The precipitate was filtered off and washed with MeOH (3×500 mL), and the filtrate was evaporated in vacuo. The residue was dissolved in EtOAc - H₂O (1000 mL, 1:1, v/v), the organic phase was separated, and the aqueous phase was extracted with EtOAc (500 mL). Combined organic phases were dried over Na₂SO₄ and evaporated in vacuo. Unless other is specified, the crude compound was purified by column chromatography on silica gel using 40 g, 80 g or 330 g RediSep column (flow rate: 40 mL / min, 60 mL / min or 100 mL / min, respectively, rack: 16 mm × 150 mm tubes) and gradient t-BuOMe – MeOH as eluent.

5-Thia-6-azaspiro[2.4]heptane 5,5-dioxide (1a)

The crude compound was purified by flash chromatography (5 bar) on silica gel using 330 g column gradient t-BuOMe – MeOH as eluent. Yield 12.6 g (61%); colorless crystals; mp 72–74 °C. ¹H NMR (400 MHz, CDCl₃) δ 4.60 (s, 1H), 3.21 (s, 2H), 3.07 (s, 2H), 0.97 – 0.81 (m, 2H), 0.81 – 0.63 (m, 2H). ¹³C NMR (126 MHz, CDCl₃) δ 55.4, 51.4, 20.3, 11.8. LC/MS (CI): m/z = 148 [M+H]⁺. Anal. Cald. for C₅H₉NO₂S: C 40.80; H 6.16; N 9.52; S 21.78. Found: C 40.52; H 5.84; N 9.89; S 21.58.

6-Thia-7-azaspiro[3.4]octane 6,6-dioxide (1b)

Yield 16.0 g (71%); colorless liquid. ¹H NMR (400 MHz, CDCl₃) δ 4.53 (s, 1H), 3.36 (d, J = 5.7 Hz, 2H), 3.17 (s, 2H), 2.25 – 2.18 (m, 2H), 2.13 – 2.06 (m, 2H), 1.99 – 1.91 (m, 2H). ¹³C NMR (126 MHz, CDCl₃) δ 58.7, 54.6, 44.6, 32.3, 16.0. GC/MS (EI): m/z = 161 [M]⁺. Anal. Cald. for C₆H₁₁NO₂S: C 44.7; H 6.88; N 8.69; S 19.89. Found: C 45.02; H 6.89; N 8.51; S 19.72.

2-Thia-3-azaspiro[4.4]nonane 2,2-dioxide (1c)

Yield 20.1 g (82%); colorless powder; mp 61–64 °C. ¹H NMR (400 MHz, CDCl₃) δ 4.63 (s, 1H), 3.20 (d, J = 6.3 Hz, 2H), 3.06 (s, 2H), 1.83 – 1.76 (m, 2H), 1.75 – 1.70 (m, 2H), 1.69 (s, 4H). ¹³C NMR (126 MHz, CDCl₃) δ 59.0, 54.1, 50.8, 37.8, 23.9. LC/MS (CI): m/z = 176 [M+H]⁺. Anal. Cald. for C₇H₁₃NO₂S: C 47.98; H 7.48; N 7.99; S 18.29. Found: C 47.92; H 7.81; N 7.95; S 18.67.

2-Thia-3-azaspiro[4.5]decane 2,2-dioxide (1d)

Yield 20.7 g (78%); Colorless liquid. ¹H NMR (500 MHz, CDCl₃) δ 4.94 (t, J = 6.8 Hz, 1H), 3.11 (dd, J = 6.5, 1.7 Hz, 2H), 2.97 (d, J = 1.7 Hz, 2H), 1.69 (dd, J = 14.0, 6.5 Hz, 2H), 1.60 – 1.53 (m, 2H), 1.52 – 1.44 (m, 3H), 1.39 – 1.31 (m, 3H). ¹³C NMR (126 MHz, CDCl₃) δ 57.9, 53.7, 44.3, 36.3, 25.3, 22.7. GC/MS (EI): m/z = 189 [M]⁺. Anal. Cald. for C₈H₁₅NO₂S: C 50.77; H 7.99; N 7.4; S 16.94. Found: C 50.99; H 8.34; N 7.41; S 17.07.

8-Oxa-2-thia-3-azaspiro[4.5]decane 2,2-dioxide (1e)

Yield 22.5 g (84%); colorless powder; mp 85–86 °C. ¹H NMR (500 MHz, CDCl₃) δ 4.85 (s, 1H), 3.88 – 3.74 (m, 2H), 3.61 – 3.48 (m, 2H), 3.22 (d, J = 6.1 Hz, 2H), 3.10 (s, 2H), 1.87 – 1.71 (m, 4H). ¹³C NMR (126 MHz, CDCl₃) δ 64.4, 57.2, 53.5, 41.7, 36.2. GC/MS (EI): m/z = 191 [M]⁺. Anal. Cald. for C₇H₁₃NO₃S: C 43.96; H 6.85; N 7.32; S 16.76. Found: C 43.61; H 6.91; N 7.71; S 16.70.

tert-Butyl 6-thia-2,7-diazaspiro[3.4]octane-2-carboxylate 6,6-dioxide (1f)

Yield 27.2 g (74%); colorless powder; mp 146–147 °C.¹H NMR (500 MHz, CDCl₃) δ 5.10 (s, 1H), 4.04 (d, J = 9.1 Hz, 2H), 3.92 (d, J = 9.2 Hz, 2H), 3.54 (s, 2H), 3.32 (s, 2H), 1.42 (s, 9H). ¹³C NMR (126 MHz, CDCl₃) δ 156.0, 80.4, 59.2, 56.2, 52.8, 38.5, 28.3. LC/MS (CI): m/z = 163 [M– CO₂–(H₃C)₂C=CH₂+H]⁺. Anal. Cald. for C₁₀H₁₈N₂O₄S: C 45.79; H 6.92; N 10.68; S 12.22. Found: C 46.19; H 6.55; N 10.92; S 12.22.

tert-Butyl 2-thia-3,7-diazaspiro[4.4]nonane-7-carboxylate 2,2-dioxide (1g)

The compound existed as ca. 1:1 mixture of rotamers. Yield 29.0 g (75%); colorless oil. ¹H NMR (500 MHz, CDCl₃) δ 5.13 (s, 0.5H) and 4.96 (s, 0.5H), 3.61 – 3.38 (m, 4H), 3.37 – 3.23 (m, 2H), 3.15 (q, J = 13.3 Hz, 2H), 2.11 (s, 1H) and 2.04 (s, 1H), 1.46 (s, 9H). ¹³C NMR (126 MHz, cdcl₃) δ 154.4 and 154.3, 80.1, 56.3 and 56.2, 55.9 and 55.4, 51.4, 48.8 and 48.6, 44.6 and 44.2, 36.1 and 35.6, 28.4. LC/MS (CI): m/z = 177 [M– CO₂–(H₃C)₂C=CH₂+H]⁺. Anal. Cald. for C₁₁H₂₀N₂O₄S: C 47.81; H 7.30; N 10.14; S 11.60. Found: C 48.04; H 7.67; N 10.35; S 11.74.

tert-Butyl 2-thia-3,8-diazaspiro[4.5]decane-8-carboxylate 2,2-dioxide (1h)

Yield 31.7 g (78%); colorless powder; mp 173–174. ¹H NMR (500 MHz, CDCl₃) δ 4.76 (s, 1H), 3.69 (d, J = 13.7 Hz, 2H), 3.21 (s, 2H), 3.18 – 3.10 (m, 2H), 3.06 (s, 2H), 1.79 (dt, J = 8.7, 4.2 Hz, 2H), 1.66 (ddd, J = 13.7, 9.4, 4.2 Hz, 2H), 1.45 (s, 9H). ¹³C NMR (126 MHz, CDCl₃) δ 154.6, 80.1, 56.7, 53.0, 42.5, 40.5, 35.5, 28.4. LC/MS (CI): m/z = 235 [M– H₂C=C(CH₃)₃+H]⁺, 291 [M+H]⁺. Anal. Cald. for C₁₂H₂₂N₂O₄S: C 49.64; H 7.64; N 9.65; S 11.04. Found: C 49.49; H 7.67; N 9.65; S 11.21.

1-Thia-2-azaspiro[3.3]heptane 1,1-dioxide (10a)

Yield 9.89 g (48%); colorless crystals; mp 167–169 °C. ¹H NMR (400 MHz, CDCl₃) δ 5.51 (s, 1H), 3.24 (s, 2H), 2.78 (ddt, J = 14.3, 8.9, 5.4 Hz, 2H), 2.42 – 2.32 (m, 2H), 2.00 – 1.84 (m, 2H). ¹³C NMR (101 MHz, CDCl₃) δ 80.0, 43.1, 28.5, 15.6. GC/MS (EI): m/z = 147 [M]⁺. Anal. Cald. for C₅H₉NO₂S: C 40.8; H 6.16; N 9.52; S 21.78. Found: C 40.88; H 6.52; N 9.81; S 21.98.

7-Oxa-1-thia-2-azaspiro[3.5]nonane 1,1-dioxide (10b)

The crude compound was purified by flash chromatography (5 bar) on silica gel using 220 g column gradient t-BuOMe – MeOH as eluent. Yield 13.1 g (53%); colorless crystals; mp 129–131 °C. ¹H NMR (400 MHz, DMSO-d₆) δ 7.77 (s, 1H), 3.67 (ddd, J = 11.8, 6.1, 4.0 Hz, 2H), 3.57 (ddd, J = 11.8, 8.0, 3.4 Hz, 2H), 3.04 (d, J = 3.4 Hz, 2H), 2.13 (ddd, J = 13.9, 6.1, 3.4 Hz, 2H), 1.98 (ddd, J = 13.9, 8.0, 4.0 Hz, 2H). ¹³C NMR (126 MHz, DMSO-d₆) δ 78.0, 64.9, 42.1, 31.7. GC/MS (EI): m/z = 177 [M]⁺. LC/MS (CI): m/z = 178 [M+H]⁺. Anal. Cald. for C₆H₁₁NO₃S: C 40.66; H 6.26; N 7.9; S 18.09. Found: C 40.65; H 6.19; N 8.03; S 17.79.

Genreal procedure for preparation of hydrochlorides 9g and 9h

The corresponding N-Boc amine 1g (950 mg, 3.44 mmol) or 1h (1.00 g, 3.44 mmol) was added to 4 M HCl – 1,4-dioxane (10 mL) at rt. The reaction mixture was stirred at rt for 12 h, then evaporated in vacuo to dryness. The precipitate thus obtained was dried in vacuo.

2-Thia-3,7-diazaspiro[4.4]nonane 2,2-dioxide hydrochloride (9g)

Yield 732 mg (100%); yellowish solid; mp 187–189 °C. ¹H NMR (500 MHz, DMSO-d₆) δ 9.66 (s, 2H), 7.27 (t, J = 6.5 Hz, 1H), 3.29 – 3.15 (m, 8H), 2.05 (qt, J = 13.7, 7.1 Hz, 2H). ¹³C NMR (126 MHz, DMSO-d₆) δ 55.9, 53.1, 51.0, 49.7, 43.9, 35.3. LC/MS (CI): m/z = 177 [M–HCl+H]⁺. Anal. Cald. for C₆H₁₃ClN₂O₂S: C 33.88; H 6.16; N 13.17; S 15.07; Cl 16.67. Found: C 33.53; H 6.52; N 13.46; S 15.45; Cl 16.39.

2-Thia-3,8-diazaspiro[4.5]decane 2,2-dioxide hydrochloride (9h)

Yield 780 mg (100%); colorless crystals; mp 241–244 °C. ¹H NMR (500 MHz, DMSO-d₆) δ 9.19 (s, 2H), 7.27 (t, J = 6.9 Hz, 1H), 3.16 – 3.10 (m, 4H), 3.02 (d, J = 6.9 Hz, 2H), 2.96 (t, J = 11.0 Hz, 2H), 1.90 – 1.85 (m, 2H), 1.80 (dt, J = 11.9, 5.7 Hz, 2H). ¹³C NMR (126 MHz, DMSO-d₆) δ 56.5, 52.5, 41.9, 40.6, 32.0. LC/MS (CI): m/z = 191 [M–HCl+H]⁺. Anal. Calcd. for C₇H₁₅ClN₂O₂S: C 37.08; H 6.67; N 12.36; S 14.14; Cl 15.64. Found: C 37.10; H 6.96; N 12.66; S 14.26; Cl 15.83.