Scalable Synthesis of Biologically Relevant Spirocyclic Pyrrolidines.

Synthetic approaches toward multigram preparation of spirocyclic α,α-disubstituted pyrrolidines from readily available starting materials are discussed. It was shown that although a number of synthetic methodologies have been known to date, many of the title compounds remain hardly accessible. The most appropriate literature method (which relied on reaction of imines and allyl magnesium halide, followed by bromocyclization) was identified and optimized. It was found that the method is most fruitful for simple non-functionalized substrates. Two novel approaches based on the Sakurai or Petasis reactions of cyclic ketones, followed by hydroboration-oxidation at the allyl moiety thus introduced, were elaborated. The latter method had the largest scope and was beneficial for the substrates containing organosulfur or protected amino functions. For the synthesis of 4-azaspiro[2.4]heptane, an alternative synthetic scheme commencing from tert-butyl cyclopropanecarboxylate (instead of the corresponding ketone) was developed. It was shown that the whole set of the methodologies developed can be used for the synthesis of various spirocyclic α,α-disubstituted pyrrolidines-advanced building blocks of potential importance to medicinal and agrochemistry-at up to a 100 g scale.

Introduction

For nearly two decades, the concepts like “escape the flatland”, “conformational restriction”, and “scaffold hopping” have remained the major hallmarks of medicinal chemistry.[1−3] The resulting shift from “traditional” drug design based mainly on (hetero)aromatic cores toward sp3-enriched, 3D-shaped templates prompted more sophisticated methodologies to produce medicinally relevant molecules. Nevertheless, as shown by a number of recent analyses, the majority of medicinal chemists do not easily accept novel synthetic methods and still prefer to use well-known, robust procedures in their synthetic planning.[4] Possible (and somewhat overlooked) design strategies to address this issue rely on the use of advanced building blocks, in many cases available from commercial sources. It is not surprising therefore that synthesis of three-dimensional building blocks with a high fraction of sp3-hybridized carbon atoms (Fsp3) has become a part of the industry.[5] The criteria for these compounds were recently reviewed by Goldberg et al. from AstraZeneca.[6] Low-molecular-weight spirocyclic motifs can be examples of such building blocks; in 2010, they were outlined as a class of compounds highly relevant to drug discovery by Carreira and co-workers.[7,8] As part of our ongoing efforts on design and synthesis of advanced building blocks for medicinal chemistry,[9] we turned our attention to pyrrolidines with a spirocyclic moiety attached at the α carbon atom of the heteroaliphatic ring (i.e., 1-azaspiro[4.n]alkanes and their hetera-substituted analogues). Derivatives of these building blocks are presented with highly potent compounds demonstrating a wide range of biological effects (Figure ).[10] Furthermore, over 5,000 1-azaspiro[4.n]alkane derivatives or their hetera-analogues with annotated biological activity were retrieved by a quick substructure search in the Reaxys database.[11]

Figure 1

Representative examples of biologically active 1-azaspiro[4.n]alkanes.

In this work, we describe our synthetic efforts toward multigram preparation of the smallest spirocyclic α,α-disubstituted pyrrolidines 1a–1r for our in-house medchem project as well as building block collection enhancement shown in Figure . Over the last 10 years, derivatives of the compounds 1a–1e, 1i, 1p, and 1r were broadly represented in patents, while other members of the series remained unknown to date (Table ).

Figure 2

The target spirocyclic pyrrolidines 1a–1r.

Table 1

Reaxys Data for the Known Compounds of Type 1

entry	compound	no. of biologically active derivatives	no. of patents/papers	no. of syntheses described	known N-protected derivative(s)
1	1a	11	14/0	0	Bn[12]
2	1b	15	7/0	0	Boc[13]
3	1c	7	4/1	0	Boc,[13] Ts[14]
4	1d	23	7/7	2[15]	Boc,[13] Ts,[16] CO2Et[17]
5	1e	2	3/0	1[13]	Boc,[13] CO2Et[17]
6	1i	5	12/0	0
7	1p	839	770/70	1[18]
8	1r	81	69/11	0	Bn[19]

Despite their well-documented biological activity, synthesis of these compounds is not described properly in the literature. In particular, only three spirocyclic pyrrolidines (i.e., 1d, 1e, and 1p) were described as the free amines, and four more (1a–1c and 1r) as the corresponding N-protected derivatives (Table ). The known approaches to assemble the spirocyclic core of 1-azaspiro[4.n]alkanes and their hetera-analogues are summarized in Figure . The historically first and very straightforward approach was described for the preparation of the compound 1d in 1957 (method A); it was based on the three-step synthetic sequence commencing from cyclic nitro compounds.[15] Since then, a number of alternative synthetic schemes were elaborated. In 2013, Perry and co-workers described a reductive cyclization of α-amino nitrile derivatives mediated by lithium di-tert-butyl biphenylide (LiDBB), which were made by double alkylation of aminoacetonitrile derivatives (method B).[13] In 2016, Um et al. developed an intermolecular Cu-catalyzed carboamination of cyclic vinylarenes with potassium N-carbamoyl-β-aminoethyltrifluoroborate (method C).[20] At the same time, Yu et al. applied the gold-catalyzed tandem reductive cycloisomerization of cyclic homopropargyl sulfonamides for the synthesis of N-tosyl-protected compound 1c (method D).[14] In 2017, Skvorcova and co-workers studied a rearrangement of N-protected spirocyclic (cyclopropylmethyl)amines promoted with trifluoroacetic acid (method E).[17] A related approach was described by Shi et al.; it relied on the Au(I)-catalyzed reaction of methylenecyclopropanes with sulfonamides via a domino ring-opening–ring-closing–hydroamination sequence (method F).[16] The approach was illustrated by the synthesis of two examples of Ts-protected spiropyrrolidines.

Figure 3

Known approaches A–G for the synthesis of spirocyclic α,α-disubstituted pyrrolidines.

However, the aforementioned methods have their own drawbacks when their application for multigram (at least ∼20 g6) and cost-effective synthesis of building blocks is considered. These drawbacks include the use of uncommon, hazardous, or toxic reagents and/or catalysts, multistep reaction sequences, and/or limited substrate scope (Table ). Herein, we have turned our attention to the method described by chemists from AstraZeneca (Scheme , G),[18] which relied on bromine-mediated cyclization of a cyclic homoallylamine derivative with subsequent catalytic debromination. In our hands, this synthetic sequence was reproduced at a 30 g scale with 27% overall yield (36% at the last step). Therefore, we considered this strategy as a starting point for further optimization.

Table 2

Drawbacks of Existing Approaches to α,α-Disubstituted Spirocyclic Pyrrolidines

entry	approach	major drawbacks
1	A	Lack of commercially available aliphatic low-molecular-weight nitro compounds. The in-house multigram synthesis of such compounds is not safe due to potential explosion hazard.
2	B	The synthetic scheme is too long. The scale-up of LiDBB-promoted step is problematic. Toxic cyanide wastes are side products of the reaction.
3	C	N-Carbamoyl-β-aminoethyl trifluoroborate is not available on multigram scale. The synthesis is limited only to aryl-fused systems.
4	D	An expensive and hardly accessible Au (I) catalyst is used at high loading. Removal of the tosyl protective group is not convenient at a large scale.
5	E	Harsh reaction conditions of the key step complicate scale-up and limit the substrate scope.
6	F	Expensive and hardly accessible Ag (I) and Au (I) catalysts are used at high loading. Removal of the tosyl protective group is not convenient at a large scale.
7	G	Moderate yield of the last step.

Scheme 3

Synthesis of Spirocyclic Pyrrolidine 1n (Approach II)

Results and Discussion

The initial optimization of the literature method started with minor modifications of the reaction conditions. At the first step, simple refluxing of ketones 2b–2d and benzylamine in toluene with a Dean–Stark trap for 1 h was used (Scheme ). This resulted in the formation of imines 3b–3d in nearly quantitative yields, which could be used in the next step after removal of the solvent without any additional purification. For the second step, allylmagnesium bromide was replaced with more accessible allylmagnesium chloride (commercially available, 2 M in THF); thus, the solvent was also changed to THF. These minor modifications did not affect the yield of the products 4b–4d, which exceeded 90% in all cases studied. Further steps of the reaction sequence (4b–4d → 6b–6d) were performed in a one-pot manner, including subsequent addition of 40% aq HBr, Br2, and Et3N to a solution of 4b–4d in CH2Cl2. We found this modification of the protocol to be more robust and convenient for scale-up as compared to the literature method (i.e., addition of in situ generated methanolic HBr, Br2, and aq K2CO3 to a solution of the substrate in MeOH–CH2Cl2). The crude products 6b–6d were obtained in nearly quantitative yield with at least 90% purity.

Scheme 1

Synthesis of Spirocyclic Pyrrolidines (Approach I)

The final transformations of the reaction sequence, that is, removal of the bromine atom and catalytic debenzylation, were performed as two separate steps. In particular, the products 6b–6d were reduced with LiAlH4 to give 7b–7d, which in turn were subjected to catalytic hydrogenolysis leading to the formation of the target spirocyclic pyrrolidines 1b–1d. The desired products were isolated as hydrochlorides in 71–74% yields (over two steps). Therefore, all the minor improvements of the procedures allowed increasing the overall yield of the target products to 62–67%. Moreover, spirocyclic pyrrolidines 1e, 1h, 1i, and 1j bearing a seven-membered ring or cyclic ether moiety could be also obtained as hydrochlorides in 66–74% overall yields (Table ).

Table 3

Overall Yields of Spirocyclic Pyrrolidines 1a–1r Obtained in This Work

		overall yield (%)
entry	product no.	approach I	approach II	approach III	approach IV
1	1a				24
2	1b	62	56
3	1c	65
4	1d	67	43
5	1e	69	43
6	1f		22	39
7	1g	42
8	1h	66
9	1i	74
10	1j	67
11	1k			49
12	1l			46
13	1m		25
14	1n		31
15	1o		47
16	1p	27		43
17	1r			31

Unfortunately, the synthetic scheme (i.e., approach I) was not fruitful with the compounds 1f, 1k, and 1m bearing the thioether moieties due to their partial oxidation at the bromination step, as well as issues with catalytic debenzylation. Compound 1g bearing a sulfone group could be obtained in moderate overall yield (42%); in this case, the reductive debromination step was problematic (48% yield). Similar issues were observed with the products 1p and 1r. Unfortunately, no further improvement of the overall yields could be achieved for these compounds.

Therefore, alternative synthetic schemes to avoid the problematic steps mentioned above had been considered (approach II, Scheme ). For starters, we decided to use the Cbz protective group instead of the benzyl moiety. To this end, the Sakurai reaction of ketones 2 with readily available allyltrimethylsilane and O-benzyl carbamate[21] was selected. The HBF4·Et2O catalyst, which was used in the previous publication referenced above was replaced with more common BF3·Et2O, which is also more convenient for the scale-up. This replacement, as well decreasing the reaction temperature from rt to 0 °C and changing the solvent from CH3CN to CH2Cl2, resulted in an increase of the yield of the intermediate 8d from 56 to 74% (as compared to the literature procedure). Moreover, this yield was maintained when the reaction was performed at up to a 100 g scale.

Scheme 2

Synthesis of Spirocyclic Pyrrolidines (Approach II)

Further, part of the synthetic sequence was also altered significantly. In particular, cyclization of mesylates 10 was considered as the key step for the construction of the pyrrolidine ring. The compounds 10 were obtained via hydroboration–oxidation of the product 8, followed by mesylation of the resulting alcohol 9. In this part of the synthetic scheme, the hydroboration–oxidation step seemed to be the most problematic for the scale-up. Nevertheless, 71–83% yields could still be achieved. It should be noted that the use of freshly prepared borane (by reaction of NaBH4 and I2) was critical at this step. All the experiments with common commercial sources of BH3 led to the diminished yields of alcohol 9.

The final step of the synthetic sequence (approach II) included Pd-catalyzed hydrogenolysis of the Cbz moiety. The products 1b, 1d, 1e, and 1o (whose synthesis was not tested via approach I) were obtained as hydrochlorides in 43–56% overall yields (Table ).

All our attempts to adjust the aforementioned reaction sequence for the preparation of the compounds 1f and 1m bearing the thioether moiety were not fruitful. The presence of the sulfur (II) atom made the catalytic hydrogenolysis (General Procedure xi) impossible. Other methods of the Cbz group cleavage (i.e., refluxing with concd aq HBr or Me3SiI) led to partial decomposition of the thioether ring so that the products were obtained in low yield and with modest purity. Nevertheless, approach II was efficient for the preparation of the Cbz-protected derivative 11m, which could be easily converted to SO2-containg product 11n via oxidation with the RuCl3–NaIO4 system. Deprotection of 11n by catalytic hydrogenolysis (General Procedure xi) led to the target product 1n in 31% overall yield (Scheme ).

To obtain the target products 1f and 1m using approach II, the Cbz protective group had to be replaced with carboxyethyl (Scheme ). To achieve this, ethyl carbamate was used in the Sakurai reaction, which led to the corresponding products 12f and 12m. Further transformations of 12f and 12m followed General Procedures viii–x described above for the Cbz counterparts and led to the spirocyclic compounds 15f and 15m. Finally, the target products 1f and 1m were obtained as hydrochlorides in 22 and 25% overall yield, respectively, by reaction of 15f and 15m with hydrazine hydrate and KOH in ethylene glycol at 155 °C.

Scheme 4

Synthesis of Sulfur-Containing Spirocyclic Pyrrolidines 1f and 1m (Approach II)

Despite many derivatives of general formula 1 could be obtained using approach II, for some of them (e.g., sulfur-containing compounds), the overall yields remained far from being excellent. Therefore, one more synthetic sequence was elaborated (approach III), which started with preparation of compounds 16 by the Petasis reaction of ketones 2, pinacol allylboronate, and NH3 in methanol (Scheme ). The main advantage of this method is formation of product 16 as a free amine so that any protective group can be installed at the nitrogen atom in further transformations. In particular, Boc protection was used to obtain the sulfur-containing spirocyclic pyrrolidines 1f, 1k, and 1l via the typical reaction sequence discussed above (General Procedures viii–x); the target products were obtained as hydrochlorides in 39–49% overall yield. It should be outlined that approach III appeared to be more fruitful as compared to approach II in terms of the overall yield (39 vs 22%, respectively, in the case of 1f; Table ).

Scheme 5

Synthesis of Sulfur-Containing Spiropyrrolidines 1f, 1k, and 1l (Approach III)

Another variation of this approach relied on the use of trifluoroacetyl as the protecting group. In this case, the method could be extended to Boc-protected piperidones 2p and 2r (Scheme ). The corresponding products of the Petasis reaction 16p and 16r were trifluoroacetylated, and the resulting orthogonally protected diamines 17p and 17r were introduced into the typical reaction sequence discussed above (General Procedures viii–x). Removal of the trifluoroacetyl group in the products 20p and 20r thus obtained accomplished the synthesis of N-Boc-monoprotected diamines 1p and 1r (43 and 31% overall yield, respectively).

Scheme 6

Synthesis of N-Boc-Monoprotected Diamines 1p and 1r (Approach III)

In our opinion, approach III can be considered as the most convenient of the methods discussed herein for “challenging” spirocyclic pyrrolidines bearing an additional functional group. Nevertheless, none of the approaches I–III can be applied for those synthetic targets where the corresponding cyclic ketone 2 is not accessible or even unstable. This was the case with 4-azaspiro[2.4]heptane (1a) bearing the cyclopropyl moiety. We assumed that an alternative approach to the key intermediate 17a, which would not require formation of unstable cyclopropanone (2a), should be elaborated to accomplish synthesis of 1a (Scheme ). To this end, it turned out that tert-butyl cyclopropylcarboxylate (21a) can be an appropriate starting compound. Compound 17a was obtained from 21a in 50% yield over three steps including allylation,[22] acidic hydrolysis, and modified Curtius rearrangement. Further transformations of 17a followed the typical synthetic sequence used in this work (General Procedures viii–x and xiv) and led to the target compound 1a as hydrochloride (24% overall yield).

Scheme 7

Synthesis of 4-Azaspiro[2.4]heptane (1a) (Approach IV)

It should be noted that several spirocyclic pyrrolidines obtained in this work (compounds 1i–1n and 1r) contained an asymmetric carbon atom. We have demonstrated that they can be obtained as pure enantiomers via preparative chiral stationary phase chromatography for the case of the compound 1n. Separation was achieved for the Cbz derivative 11n using a Chiralcel OD-H column (hexane–i-PrOH–MeOH (60:20:20) as eluent). Both enantiomers (R)-1n and (S)-1n were obtained after deprotection of (R)-11n and (S)-11n (General Procedure xi). Absolute configuration of these compounds was determined by X-ray diffraction studies for the hydrochloride (R)-1n·HCl (Figure ).

Figure 4

Molecular structure of (R)-1n·HCl.

Conclusions

It is a common situation in organic chemistry and drug discovery that some compounds, although appearing to be described in the literature via a number of published synthetic methodologies, become challenging targets when their preparation for industrial use or even late-stage R&D is necessary. It often happens when multigram scale-up (to ∼100 g, in some cases – even ∼10 g) and extension of the scope toward “inconvenient” functionalized substrates are required – a problem highlighted by Churcher and co-workers in their recent perspective.[23] As part of our ongoing research on medicinally relevant building blocks, we faced such a problem in the case of spirocyclic pyrrolidines. This resulted in development of four synthetic approaches (one being an optimization of the literature method), which were used for the preparation of 17 building blocks at the multigram scale. It was found that approach I (based on the method of Jenkins et al.[18]) was optimal for the simplest non-functionalized substrates, which were obtained from common cyclic ketones in 62–74% overall yield. Approach II, which was based on the Sakurai reaction, partially solved the problems with sulfur-containing substrates; however, the overall yields of the target products diminished (43–56% for the simplest representatives and 22–31% for the organosulfur derivatives). Approach III, which relied on the Petasis reaction, appeared to be the most general since it allowed for the largest variation of the protective groups for the key intermediates. In particular, it was efficient in the case of either sulfur-containing products (39–49% overall yield) or monoprotected spirocyclic diamines (31–43% overall yield). Finally, approach IV was developed for those substrates where the corresponding cyclic ketone is not available. Its utility was demonstrated for the smallest representative of the series studied—4-azaspiro[2.4]heptane, which was obtained in 24% total yield. The developed synthetic schemes included 5–7 steps, commenced from readily available starting materials, were scalable up to 100 g, and led to biologically relevant spirocyclic pyrrolidines—advanced building blocks for drug discovery, which can be now considered as readily available to the chemical community.

Experimental Section

General Information

The solvents were purified according to the standard procedures. All starting materials were purchased from commercial sources. Melting points were measured on an automated melting point system. Column chromatography was performed using a silica gel (230–400 mesh) as the stationary phase. 1H, and 13C, and 19F NMR spectra were recorded at 499.9 or 400.4, 124.9 or 100.7, and 376 MHz, respectively. Chemical shifts are reported in ppm downfield from TMS as an internal standard. Elemental analyses were performed at the Laboratory of Organic Analysis, Department of Chemistry, National Taras Shevchenko University of Kyiv, and their results were found to be in good agreement (±0.4%) with the calculated values. Mass spectra were recorded on an 1100 LCMSD SL instrument (chemical ionization (APCI), electrospray ionization (ESI)) and GCMS instrument (electron impact ionization (EI)). Chiral chromatography was performed on a Chiralcel OD-H (250 20 mm 5 μm) column, mobile phase: hexane–IPA–MeOH 60/20/20, flow rate: 25 mL/min, column temperature: 24 °C, and wavelength: 205 nm. The optical rotation was determined using an MCP 300 modular circular polarimeter.

X-Ray diffraction studies were performed on CCDC-1896555, which contains the supplementary crystallographic data for this paper (compound (R)-1n·HCl). These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.

General Procedures i and ii

Ketone 2 (1.0 mol) was dissolved in dry toluene (1500 mL), and benzylamine (1.0 mol, 105 mL) was added. The reaction mixture was refluxed for 1 h with a Dean–Stark trap and an effective condenser until complete water separation (18 mL). Toluene was evaporated, and the obtained product was used in the next step without further purification.

The obtained crude compound 3 (1.0 mol) was dissolved in THF (2000 mL) and cooled to −20 °C. A solution of allylmagnesium chloride in THF (2 M, 500 mL) was added dropwise to the obtained solution for 30 min keeping the reaction mixture temperature below −15 °C. The reaction mixture was allowed to warm to rt and left overnight. A saturated solution of NH4Cl (∼500 mL) was added for complete precipitation of magnesium salts. The organic layer was separated, and the THF layer was dried under Na2SO4 and was evaporated under reduced pressure. The residue was distilled in vacuum (0.2 mmHg).

1-Allyl-N-benzylcyclobutanamine (4b)

Yield = 185.2 g, 92%, colorless liquid (bp = 74–75 °C, 0.2 mmHg). 1H NMR (400 MHz, DMSO-d6) δ 7.35–7.25 (m, 4H), 7.23–7.17 (m, 1H), 5.86 (m, 1H), 5.14–5.00 (m, 2H), 3.59 (s, 2H), 2.33 (d, J = 7.1 Hz, 2H), 1.90 (td, J = 9.4, 2.4 Hz, 2H), 1.79 (m, 2H), 1.67 (m, 2H); the proton of the NH group is not observed due to the exchange. 13C{1H} NMR (126 MHz, DMSO-d6) δ 142.2, 135.9, 128.5, 128.4, 126.8, 117.3, 59.4, 46.4, 41.4, 32.2, 13.5. LCMS, positive mode, m/z: 202.2 [M + H]+. Anal calcd for C14H19N: C, 83.53; H, 9.51; N, 6.96. Found: C, 83.40; H, 9.84; N, 6.87.

1-Allyl-N-benzylcyclopentanamine (4c)

Yield = 198.1 g, 92%, colorless liquid (bp = 88–89 °C, 0.2 mmHg). 1H NMR (400 MHz, DMSO-d6) δ 7.34–7.25 (m, 4H), 7.19 (t, J = 6.8 Hz, 1H), 5.89 (m, 1H), 5.16–5.00 (m, 2H), 3.62 (s, 2H), 2.28 (d, J = 7.2 Hz, 2H), 1.68 (m, 2H), 1.62–1.48 (m, 4H), 1.43 (dd, J = 12.3, 5.8 Hz, 2H), the proton of the NH group is not observed due to the exchange. 13C{1H} NMR (126 MHz, chloroform-d) δ 142.4, 136.4, 128.5, 126.8, 117.3, 64.7, 46.8, 42.0, 37.1, 24.2. LCMS, positive mode, m/z: 216.2 [M + H]+. Anal calcd for C15H21N: C, 83.67; H, 9.83; N, 6.50. Found: C, 83.55; H, 9.78; N, 6.77.

1-Allyl-N-benzylcyclohexanamine (4d)

Yield = 220.2 g, 96%, colorless liquid (bp = 106–107 °C, 0.2 mmHg). 1H NMR (400 MHz, DMSO-d6) δ 7.34 (d, J = 7.6 Hz, 2H), 7.29 (t, J = 7.4 Hz, 2H), 7.20 (t, J = 7.2 Hz, 1H), 5.88 (m, 1H), 5.13–4.99 (m, 2H), 3.59 (d, J = 5.9 Hz, 2H), 2.19 (d, J = 7.3 Hz, 2H), 1.64–1.41 (m, 5H), 1.31 (m, 5H); the proton of the NH group is not observed due to the exchange. 13C{1H} NMR (126 MHz, chloroform-d) δ 142.5, 135.5, 128.5, 126.8, 117.5, 53.9, 45.1, 42.3, 35.4, 26.3, 21.7. LCMS, positive mode, m/z: 230 [M + H]+. Anal calcd for C16H23N: C, 83.79; H, 10.11; N, 6.11. Found: C, 83.58; H, 10.02; N, 5.92.

4-Allyl-N-benzyltetrahydro-2H-pyran-4-amine (4e)

yield = 208.2 g, 90%, colorless liquid (bp = 117–118 °C, 0.2 mmHg). 1H NMR (400 MHz, DMSO-d6) δ 7.37 (d, J = 7.3 Hz, 2H), 7.30 (t, J = 7.5 Hz, 2H), 7.21 (t, J = 7.2 Hz, 1H), 5.88 (m, 1H), 5.18–5.04 (m, 2H), 3.72 (ddd, J = 12.3, 9.3, 3.6 Hz, 2H), 3.61 (s, 2H), 3.51 (dt, J = 11.3, 4.2 Hz, 2H), 2.25 (d, J = 7.3 Hz, 2H), 1.60–1.39 (m, 4H); the proton of the NH group is not observed due to the exchange. 13C{1H} NMR (126 MHz, DMSO-d6) δ 142.3, 134.8, 128.53, 128.50, 126.9, 118.1, 63.2, 52.0, 45.1, 42.5, 35.7. LCMS, positive mode, m/z: 232.2 [M + H]+. Anal calcd for C15H21NO: C, 77.88; H, 9.15; N, 6.05. Found: C, 77.81; H, 9.3; N, 5.92.

4-Allyl-4-(benzylamino)tetrahydro-2H-thiopyran 1,1-dioxide (4g)

Yield = 134.1 g, 96%, colorless liquid (compound was purified by flash column chromatography). 1H NMR (400 MHz, DMSO-d6) δ 7.37 (d, J = 7.6 Hz, 2H), 7.32 (t, J = 7.5 Hz, 2H), 7.23 (t, J = 7.2 Hz, 1H), 5.85 (m, 1H), 5.21–5.07 (m, 2H), 3.61 (s, 2H), 3.26 (td, J = 13.5, 3.4 Hz, 2H), 2.82 (d, J = 11.6 Hz, 2H), 2.28 (d, J = 7.4 Hz, 2H), 2.12–1.97 (m, 2H), 1.91–1.77 (m, 2H); the proton of the NH group is not observed due to the exchange. 13C{1H} NMR (126 MHz, chloroform-d) δ 141.7, 134.4, 128.62, 128.55, 127.1, 118.8, 52.1, 47.0, 45.1, 42.3, 32.6. LCMS, positive mode, m/z: 280 [M + H]+. Anal calcd for C15H21NO2S: C, 64.48; H, 7.58; N, 5.01; S, 11.47. Found: C, 64.84; H, 7.59; N, 4.61; S, 11.66.

1-Allyl-N-benzylcycloheptanamine (4h)

Yield = 231.2 g, 95%, colorless liquid (bp = 120–121 °C, 0.2 mmHg). 1H NMR (400 MHz, DMSO-d6) δ 7.37–7.26 (m, 4H), 7.21 (t, J = 7.2 Hz, 1H), 5.87 (m, 1H), 5.16–5.01 (m, 2H), 3.63 (s, 2H), 2.21 (d, J = 7.3 Hz, 2H), 1.54 (m, 10H), 1.37 (t, J = 10.2 Hz, 2H); the proton of the NH group is not observed due to the exchange. 13C{1H} NMR (126 MHz, DMSO-d6) δ 141.4, 135.6, 128.7, 128.5, 127.1, 117.9, 58.6, 45.5, 43.3, 38.2, 30.1, 22.3. LCMS, positive mode, m/z: 244 [M + H]+. Anal calcd for C17H25N: C, 83.89; H, 10.35; N, 5.75. Found: C, 83.49; H, 10.42; N, 5.80.

3-Allyl-N-benzyltetrahydrofuran-3-amine (4i)

Yield = 206.4 g, 95%, dark yellow liquid (compound was obtained with 85% purity and used in the next step without additional purification). LCMS, positive mode, m/z: 218.2 [M + H]+.

4-Allyl-N-benzyltetrahydro-2H-pyran-4-amine (4j)

Yield = 208.2 g, 90%, colorless liquid (bp = 114–115 °C, 0.2 mmHg). 1H NMR (400 MHz, DMSO-d6) δ 7.38–7.25 (m, 4H), 7.20 (t, J = 7.2 Hz, 1H), 5.88 (m, 1H), 5.12–5.00 (m, 2H), 3.62 (s, 2H), 3.57–3.41 (m, 4H), 2.29–2.13 (m, 2H), 1.74–1.42 (m, 4H); the proton of the NH group is not observed due to the exchange. 13C{1H} NMR (126 MHz, DMSO-d6) δ 142.2, 135.0, 128.53, 128.50, 126.9, 117.5, 74.8, 67.9, 52.9, 45.1, 38.6, 31.9, 22.3. LCMS, positive mode, m/z: 232.2 [M + H]+. Anal calcd for C15H21NO: C, 77.88; H, 9.15; N, 6.05. Found: C, 78.11; H, 8.82; N, 5.93.

General Procedures iii and iv

Compound 4 (0.95 mol) was dissolved in CH2Cl2 (2000 mL) and was added to the 48% aqueous solution of HBr (0.95 mol, 240 mL). Then, Br2 (1 mol, 500 mL) was slowly added dropwise to the obtained mixture for 1 h keeping the temperature below 25 °C. The resulting mixture was cooled to rt and left for 1 h resulting in formation of 5.

Triethylamine (1.5 mol, 110 mL) was added dropwise at rt to the obtained solution of 5 in General Procedure iii for 25–30 min keeping the temperature below 25 °C (Caution: exothermic process). The resulting solution was left at rt for 1 h. Distilled water (500 mL) was added to the solution to extract all water-soluble impurities and triethylammonium bromide. The organic layer was separated and dried over Na2SO4, and the solvent was evaporated under reduced pressure. The obtained product 6 with a purity of approximately 90% was used in the next step without further purification. The analytical samples were additionally purified by flash column chromatography.

5-Benzyl-7-bromo-5-azaspiro[3.4]octane (6b)

Yield = 266.2 g, 100%, brown oil. 1H NMR (400 MHz, DMSO-d6) δ 7.38–7.27 (m, 4H), 7.23 (m, 1H), 4.50 (m, 1H), 3.87–3.60 (m, 2H), 3.08–2.96 (m, 1H), 2.82 (dd, J = 11.2, 4.3 Hz, 1H), 2.69 (dd, J = 13.7, 7.9 Hz, 1H), 2.44–2.21 (m, 3H), 1.92 (m, 1H), 1.66 (m, 3H). 13C{1H} NMR (126 MHz, DMSO-d6) δ 140.2, 128.6, 128.5, 127.2, 66.6, 61.4, 52.3, 50.0, 45.2, 30.6, 29.9, 13.8. LCMS, positive mode, m/z: 280.0 [M + H]+. Anal calcd for C14H18BrN: C, 60.01; H, 6.48; N, 5.00; Br, 28.52. Found: C, 60.34; H, 6.77; N, 4.86; Br, 28.22.

1-Benzyl-3-bromo-1-azaspiro[4.4]nonane (6c)

Yield = 279.5 g, 100%, brown oil. 1H NMR (400 MHz, DMSO-d6) δ 7.31 (m, 4H), 7.22 (m, 1H), 4.51 (m, 1H), 3.72–3.42 (m, 2H), 3.09–2.79 (m, 2H), 2.48–2.42 (m, 1H), 2.15 (dd, J = 13.7, 5.1 Hz, 1H), 1.88–1.77 (m, 1H), 1.76–1.46 (m, 6H), 1.36 (dd, J = 12.4, 7.0 Hz, 1H). 13C{1H} NMR (126 MHz, chloroform-d) δ 140.4, 128.6, 128.5, 127.2, 72.5, 61.8, 51.8, 51.5, 45.5, 33.5, 31.9, 24.1, 23.9. LCMS, positive mode, m/z: 294 [M + H]+. Anal calcd for C15H20BrN: C, 61.23; H, 6.85; N, 4.76; Br, 27.16. Found: C, 60.86; H, 7.09; N, 5.11; Br, 27.37.

1-Benzyl-3-bromo-1-azaspiro[4.5]decane (6d)

Yield = 293.0 g, 100%, brown oil. 1H NMR (400 MHz, DMSO-d6) δ 7.31 (m, 4H), 7.22 (m, 1H), 4.51 (m, 1H), 3.77–3.49 (dd, J = 71.3, 11.6 Hz, 2H), 2.97 (ddd, J = 71.3, 12.8, 5.1 Hz, 2H), 2.49 (m, 1H), 2.10 (dd, J = 12.8, 5.1 Hz, 1H), 1.78–1.49 (m, 5H), 1.46–1.35 (m, 2H), 1.29 (m, 2H), 1.10 (m, 1H). 13C{1H} NMR (126 MHz, DMSO-d6) δ 140.3, 128.8, 128.4, 127.4, 59.7, 51.4, 45.9, 33.6, 32.3, 25.7, 24.1, 23.7. LCMS, positive mode, m/z: 308 [M + H]+. Anal calcd for C16H22BrN: C, 62.34; H, 7.19; N, 4.54; Br, 25.92. Found: C, 62.12; H, 7.30; N, 4.94; Br, 25.75.

1-Benzyl-3-bromo-8-oxa-1-azaspiro[4.5]decane (6e)

Yield = 294.7 g, 100%, brown oil. 1H NMR (400 MHz, DMSO-d6) δ 7.31 (m, 4H), 7.26–7.18 (m, 1H), 4.53 (q, J = 5.9, 5.2 Hz, 1H), 3.87 (td, J = 12.7, 4.6 Hz, 2H), 3.74 (d, J = 13.7 Hz, 1H), 3.56 (d, J = 13.5 Hz, 1H), 3.43–3.34 (m, 2H), 3.07 (t, J = 8.6 Hz, 1H), 2.89 (m, 1H), 2.63 (dd, J = 14.4, 8.1 Hz, 1H), 2.21 (dd, J = 14.4, 4.8 Hz, 1H), 1.87 (q, J = 10.9 Hz, 1H), 1.72 (q, J = 10.0, 8.2 Hz, 1H), 1.50 (d, J = 12.9 Hz, 1H), 1.30 (d, J = 12.9 Hz, 1H). 13C{1H} NMR (126 MHz, DMSO-d6) δ 140.6, 128.6, 128.5, 127.1, 65.7, 65.4, 61.6, 60.0, 51.0, 46.3, 45.9, 34.7, 32.8. LCMS, positive mode, m/z: 310 [M + H]+. Anal calcd for C15H20BrNO: C, 58.07; H, 6.50; N, 4.51; Br, 25.76. Found: C, 58.00; H, 6.33; N, 4.15; Br, 25.37.

1-Benzyl-3-bromo-8-thia-1-azaspiro[4.5]decane 8,8-dioxide (6g)

Yield = 170.2 g, 100%, dark brown oil. 1H NMR (400 MHz, DMSO-d6) δ 7.39–7.18 (m, 5H), 4.56 (tt, J = 8.1, 4.6 Hz, 1H), 3.75 (d, J = 13.5 Hz, 1H), 3.54 (d, J = 13.5 Hz, 1H), 3.37–2.03 (m, 10H), 2.03–1.73 (m, 2H). 13C{1H} NMR (126 MHz, chloroform-d) δ 140.0, 128.7, 128.5, 127.3, 61.7, 60.2, 50.9, 49.0, 48.6, 45.6, 45.3, 32.4, 29.6. EIMS, 70 eV, m/z (rel. int.): 359 [M + H]+ (2); 267 (44); 266 (12); 265 (44); 132 (11); 131 (100); 91 (88); 65 (19); 41 (19); 39 (13). Anal calcd for C15H20BrNO2S: C, 50.28; H, 5.63; N, 3.91; S, 8.95; Br, 22.30. Found: C, 50.46; H, 5.81; N, 4.22; S, 9.31; Br, 22.03.

1-Benzyl-3-bromo-1-azaspiro[4.6]undecane (6h)

Yield = 306.2 g, 100%, brown oil. 1H NMR (400 MHz, DMSO-d6) δ 7.55–7.17 (m, 5H), 4.48 (s, 1H), 3.62 (dd, J = 73.2, 13.4 Hz, 2H), 3.06–2.75 (m, 2H), 2.10 (d, J = 13.2 Hz, 1H), 1.85 (d, J = 11.9 Hz, 1H), 1.79–1.28 (m, 12H). 13C{1H} NMR (126 MHz, DMSO-d6) δ 143.3, 131.6, 130.0, 129.3, 59.0, 51.4, 46.7, 36.8, 29.0, 28.7, 23.6, 22.4; LCMS, positive mode, m/z: 323 [M + H]+. Anal calcd for C17H24BrN: C, 63.36; H, 7.51; N, 4.35; Br, 24.79. Found: C, 63.18; H, 7.32; N, 4.53; Br, 24.51.

1-Benzyl-3-bromo-7-oxa-1-azaspiro[4.4]nonane (6i)

Yield = 281.4 g, 100%, dark brown oil (compound was obtained with 85% purity and used in the next step without additional purification). LCMS, positive mode, m/z: 296.2 [M + H]+.

1-Benzyl-3-bromo-7-oxa-1-azaspiro[4.5]decane (6j)

Yield = 294.7 g, 100%, dark brown oil (compound was obtained with 85% purity and used in the next step without additional purification). LCMS, positive mode, m/z: 310.2 [M + H]+.

General Procedure v

The crude compound 6 (0.95 mol) was dissolved in THF (1000 mL), and the obtained solution was added dropwise at rt to a solution of LiAlH4 (2 mol, 76 g) in THF (2000 mL) under stirring for 2 h keeping the reaction temperature at 0 °C. The reaction mixture was allowed to warm to rt and stirred for 72 h. A mixture of water with THF (1:4, ∼500 mL) was carefully added to the reaction mixture until the excess of LiAlH4 was completely neutralized. The organic layer was separated and dried over Na2SO4, and the solvent was evaporated under reduced pressure. The residue was distilled in vacuum (0.2 mmHg).

5-Benzyl-5-azaspiro[3.4]octane (7b)

Yield = 141.5 g, 74%, colorless liquid (bp = 83–84 °C, 0.2 mmHg). 1H NMR (400 MHz, DMSO-d6) δ 7.29 (d, J = 4.4 Hz, 4H), 7.20 (h, J = 4.1 Hz, 1H), 3.65 (s, 2H), 2.43 (t, J = 7.3 Hz, 2H), 2.32–2.18 (m, 2H), 1.97–1.86 (m, 2H), 1.64 (m, 6H). 13C{1H} NMR (126 MHz, DMSO-d6) δ 141.0, 128.6, 128.5, 126.9, 66.4, 53.4, 51.1, 38.4, 29.6, 20.4, 13.9. LCMS, positive mode, m/z: 202.2 [M + H]+. Anal calcd for C14H19N: C, 83.53; H, 9.51; N, 6.96. Found: C, 83.35; H, 9.79; N, 7.28.

1-Benzyl-1-azaspiro[4.4]nonane (7c)

Yield = 147.3 g, 72%, colorless liquid (bp = 97–98 °C, 0.2 mmHg). 1H NMR (400 MHz, DMSO-d6) δ 7.28 (d, J = 4.3 Hz, 4H), 7.20 (h, J = 4.2 Hz, 1H), 3.51 (s, 2H), 2.48–2.43 (m, 2H) 1.80–1.46 (m, 10H), 1.36 (m, 2H). 13C{1H} NMR (126 MHz, chloroform-d) δ 141.2, 128.6, 128.5, 126.9, 72.1, 52.9, 51.6, 39.8, 32.0, 24.3, 20.9. LCMS, positive mode, m/z: 216.2 [M + H]+. Anal calcd for C15H21N: C, 83.67; H, 9.83; N, 6.50. Found: C, 83.99; H, 9.64; N, 6.21.

1-Benzyl-1-azaspiro[4.5]decane (7d)

Yield = 155.0 g, 71%, colorless liquid (bp = 110–111 °C, 0.2 mmHg). 1H NMR (400 MHz, DMSO-d6) δ 7.37–7.14 (m, 5H), 3.56 (s, 2H), 2.54 (s, 2H), 1.64 (m, 7H), 1.40 (m, 6H), 1.10 (t, J = 13.1 Hz, 1H). 13C{1H} NMR (126 MHz, DMSO-d6) δ 141.6*, 140.8, 128.6*, 128.5, 128.4, 127.0*, 126.8, 63.7*, 62.9, 60.2, 52.2, 51.0*, 50.6, 46.7*, 46.2, 34.5, 34.1*, 32.6, 32.3*, 26.3, 25.9*, 24.4, 24.2*, 24.0*, 21.1 (*due to hindered rotation). LCMS, positive mode, m/z: 230.2 [M + H]+. Anal calcd for C16H23N: C, 83.79; H, 10.11; N, 6.11. Found: C, 83.73; H, 10.06; N, 6.27.

1-Benzyl-8-oxa-1-azaspiro[4.5]decane (7e)

Yield = 171.4 g, 78%, colorless liquid (bp = 127–128 °C, 0.2 mmHg). 1H NMR (400 MHz, DMSO-d6) δ 7.28 (d, J = 4.4 Hz, 4H), 7.23–7.17 (m, 1H), 3.86 (dd, J = 11.4, 4.9 Hz, 2H), 3.57 (s, 2H), 3.38 (td, J = 12.1, 2.0 Hz, 2H), 2.54 (t, J = 7.0 Hz, 2H), 1.81–1.70 (m, 4H), 1.66 (m, 2H), 1.25 (dd, J = 12.7, 2.0 Hz, 2H). 13C{1H} NMR (126 MHz, DMSO-d6) δ 141.3, 128.6, 128.5, 126.9, 65.9, 60.8, 52.1, 50.4, 34.0, 33.2, 21.0. LCMS, positive mode, m/z: 232.2 [M + H]+. Anal calcd for C15H21NO: C, 77.88; H, 9.15; N, 6.05. Found: C, 78.15; H, 9.50; N, 6.36.

1-Benzyl-8-thia-1-azaspiro[4.5]decane 8,8-dioxide (7g)

Yield = 64.4 g, 48%, colorless liquid (compound was purified by flash column chromatography). 1H NMR (400 MHz, DMSO-d6) δ 7.29 (m, 4H), 7.21 (m, 1H), 3.56 (s, 2H), 3.22 (td, J = 13.9, 3.4 Hz, 2H), 3.07 (d, J = 11.8 Hz, 2H), 2.55 (t, J = 7.1 Hz, 2H), 2.14 (t, J = 12.7 Hz, 2H), 1.87 (m, 2H), 1.80–1.61 (m, 4H). 13C{1H} NMR (126 MHz, DMSO-d6) δ 140.7, 128.6, 127.1, 61.2, 52.0, 50.6, 49.2, 33.3, 30.1, 20.7. LCMS, positive mode, m/z: 280 [M + H]+. Anal calcd for C15H21NO2S: C, 64.48; H, 7.58; N, 5.01; S, 11.47. Found: C, 64.69; H, 7.96; N, 4.86; S, 11.20.

1-Benzyl-1-azaspiro[4.6]undecane (7h)

Yield = 166.5 g, 72%, colorless liquid (bp = 121–122 °C, 0.2 mmHg). 1H NMR (400 MHz, DMSO-d6) δ 1H NMR (400 MHz, DMSO-d6) δ 7.28 (d, J = 4.4 Hz, 4H), 7.19 (p, J = 4.4 Hz, 1H), 3.58 (s, 2H), 2.46 (d, J = 7.3 Hz, 2H), 1.79–1.69 (m, 2H), 1.63 (m, 6H), 1.51 (m, 6H), 1.41 (m, 2H). 13C{1H} NMR (126 MHz, DMSO-d6) δ 141.4, 128.6, 128.5, 126.9, 65.8, 52.6, 50.7, 37.8, 35.6, 29.3, 24.0, 20.9. LCMS, positive mode, m/z: 244.2 [M + H]+. Anal calcd for C17H25N: C, 83.89; H, 10.35; N, 5.75. Found: C, 83.72; H, 10.23; N, 5.38.

1-Benzyl-7-oxa-1-azaspiro[4.4]nonane (7i)

Yield = 169.3 g, 82%, colorless liquid (bp = 109–110, 0.2 mmHg). 1H NMR (400 MHz, DMSO-d6) δ 7.28 (d, J = 4.4 Hz, 4H), 7.20 (m, 1H), 3.90 (td, J = 8.6, 4.3 Hz, 1H), 3.79 (d, J = 9.0 Hz, 1H), 3.73–3.61 (m, 2H), 3.51 (d, J = 13.4 Hz, 1H), 3.39 (d, J = 9.0 Hz, 1H), 2.60–2.51 (m, 1H), 2.40 (td, J = 8.9, 6.3 Hz, 1H), 2.09 (dt, J = 12.6, 8.5 Hz, 1H), 1.82 (ddd, J = 8.3, 6.8, 3.0 Hz, 2H), 1.73–1.60 (m, 3H). 13C{1H} NMR (126 MHz, DMSO-d6) δ 140.3, 128.4, 128.2, 126.7, 73.9, 71.6, 68.2, 53.4, 51.5, 37.6, 32.7, 21.2; LCMS, positive mode, m/z: 218.2 [M + H]+. Anal calcd for C14H19NO: C, 77.38; H, 8.81; N, 6.45. Found: C, 77.00; H, 8.77; N, 6.83.

1-Benzyl-7-oxa-1-azaspiro[4.5]decane (7j)

Yield = 173.6 g, 79%, colorless liquid (bp = 126–127, 0.2 mmHg). 1H NMR (400 MHz, DMSO-d6) δ 7.31–7.24 (m, 4H), 7.20 (td, J = 6.0, 2.6 Hz, 1H), 3.74 (m, 1H), 3.69 (s, 2H), 3.38 (dd, J = 10.7, 2.3 Hz, 1H), 3.27 (d, J = 10.7 Hz, 1H), 3.20 (m, 1H), 2.63–2.51 (m, 2H), 1.93 (dd, J = 12.1, 4.5 Hz, 1H), 1.74 (m, 1H), 1.69–1.49 (m, 6H). 13C{1H} NMR (126 MHz, DMSO-d6) δ 141.4, 128.5, 128.4, 126.9, 72.7, 67.6, 60.6, 52.8, 51.4, 35.0, 31.0, 24.7, 21.6. LCMS, positive mode, m/z: 232.2 [M + H]+. Anal calcd for C15H21NO: C, 77.88; H, 9.15; N, 6.05. Found: C, 78.09; H, 8.94; N, 6.14.

General Procedure vi

Wet Pd/C (10%, 15 g) was added to the solution of 7 (0.68 mol) in 1500 mL of MeOH in an autoclave. The mixture was heated at 50 °C in an atmosphere of H2 (20 atm) for 6 h. Then, the catalyst was filtered off and washed with MeOH (2 × 200 mL), and the solution obtained was purified by flash column chromatography (SiO2). The saturated HCl/MeOH solution (500 mL) was added to the obtained solution. The solvent was removed in vacuo. The desired product as HCl salt was dried in vacuo.

5-Azaspiro[3.4]octane hydrochloride (1b·HCl)

Yield = 91.4 g, 91%, white solid (mp = 131–133 °C, dec.). 1H NMR (400 MHz, chloroform-d) δ 9.77 (br s, 2H), 3.25 (dt, J = 12.4, 6.0 Hz, 2H), 2.73 (dt, J = 11.0, 8.7 Hz, 2H), 2.11–1.99 (m, 5H), 1.93 (p, J = 7.0 Hz, 2H), 1.88–1.74 (m, 1H). 13C{1H} NMR (126 MHz, chloroform-d) δ 65.9, 43.1, 35.4, 31.2, 21.9, 14.9. LCMS, positive mode, m/z: 112.2 [M–Cl]+. Anal calcd for C7H14ClN: C, 56.94; H, 9.56; N, 9.49; Cl, 24.01. Found: C, 57.30; H, 9.87; N, 9.18; Cl, 24.36.

1-Azaspiro[4.4]nonane hydrochloride (1c·HCl)

Yield = 107.7 g, 98%, white solid (mp = 103–105 °C, dec.). 1H NMR (400 MHz, chloroform-d) δ 9.45 (br s, 2H), 3.31 (t, J = 7.5 Hz, 2H), 2.21 (m, 2H), 2.05–1.93 (m, 2H), 1.89 (t, J = 6.6 Hz, 4H), 1.68 (m, 4H). 13C{1H} NMR (126 MHz, chloroform-d) δ 74.0, 43.5, 36.3, 36.0, 24.2, 22.8. LCMS, positive mode, m/z: 126.2 [M–Cl + H]+. Anal calcd for C8H16ClN: C, 59.43; H, 9.98; N, 8.66; Cl, 21.93. Found: C, 59.20; H, 10.27; N, 8.30; Cl, 22.31.

1-Azaspiro[4.5]decane hydrochloride (1d·HCl)

Yield = 93.0 g, 98%, white solid (mp = 113–115 °C, dec). 1H NMR (400 MHz, chloroform-d) δ 9.36 (br s, 2H), 3.33 (quint, J = 6.6 Hz, 2H), 2.01 (quint, J = 7.4 Hz, 2H), 1.87 (dt, J = 14.8, 8.5 Hz, 4H), 1.81–1.69 (m, 4H), 1.53–1.30 (m, 4H). 13C{1H} NMR (126 MHz, chloroform-d) δ 67.6, 43.4, 34.6, 34.4, 24.8, 23.0, 22.4. LCMS, positive mode, m/z: 140.1 [M–Cl + H]+. Anal calcd for C9H18ClN: C, 61.52; H, 10.33; N, 7.97; Cl, 20.18. Found: C, 61.29; H, 10.49; N, 7.57; Cl, 19.78.

8-Oxa-1-azaspiro[4.5]decane hydrochloride (1e·HCl)

Yield = 118.4 g, 98%, white solid (mp = 181–184 °C, dec.). 1H NMR (400 MHz, chloroform-d) δ 9.62 (br s, 2H), 3.95 (m, 2H), 3.60 (m, 2H), 3.41 (t, J = 7.3 Hz, 2H), 2.17 (ddd, J = 12.6, 8.0, 3.9 Hz, 2H), 2.08 (p, J = 7.2 Hz, 2H), 1.97 (t, J = 7.2 Hz, 2H), 1.82 (m, 2H). 13C{1H} NMR (126 MHz, chloroform-d) δ 65.0, 64.6, 43.7, 35.1, 34.4, 22.4; LCMS, positive mode, m/z: 142.2 [M–Cl + H]+. Anal calcd for C8H16ClNO: C, 54.08; H, 9.08; N, 7.88; Cl, 19.95. Found: C, 53.78; H, 9.16; N, 7.49; Cl, 20.16.

8-Thia-1-azaspiro[4.5]decane 8,8-dioxide hydrochloride (1g·HCl)

Yield = 84.5 g, 92%, white solid (mp = 188–191 °C, with decomposition). 1H NMR (400 MHz, DMSO-d6) δ 8.98 (s, 2H), 3.25 (m, 6H), 2.33 (m, 2H), 2.26–2.15 (m, 2H), 1.98 (dd, J = 10.9, 5.2 Hz, 4H). 13C{1H} NMR (126 MHz, DMSO-d6) δ 64.7, 47.6, 44.1, 33.7, 31.9, 22.3. LCMS, negative mode, m/z: 190.2 [M–Cl + H]+. Anal calcd for C8H16ClNO2S: C, 42.57; H, 7.14; N, 6.20; S, 14.20; Cl, 15.71. Found: C, 42.59; H, 7.28; N, 6.02; S, 14.07; Cl, 15.87.

1-Azaspiro[4.6]undecane hydrochloride (1h·HCl)

Yield = 125.2 g, 97%, white solid (mp = 127–130 °C, dec.). 1H NMR (400 MHz, chloroform-d) δ 9.33 (s, 2H), 3.32 (p, J = 6.6 Hz, 2H), 2.11 (dd, J = 14.5, 10.0 Hz, 2H), 1.99 (p, J = 7.4 Hz, 2H), 1.83 (q, J = 8.7, 8.0 Hz, 4H), 1.74 (dd, J = 14.9, 7.6 Hz, 2H), 1.59 (m, 2H), 1.50 (m, 2H), 1.42 (m, 2H). 13C{1H} NMR (126 MHz, chloroform-d) δ 71.3, 43.4, 37.3, 36.6, 29.2, 23.1, 22.2. LCMS, positive mode, m/z: 190 [M]+. Anal calcd for C10H20ClN: C, 63.31; H, 10.63; N, 7.38; Cl, 18.68. Found: C, 63.56; H, 10.48; N, 7.40; Cl, 18.47.

7-Oxa-1-azaspiro[4.4]nonane hydrochloride (1i·HCl)

Yield = 105.7 g, 95%, white solid (mp = 125–127 °C, dec.). 1H NMR (400 MHz, chloroform-d) δ 9.83 (s, 2H), 4.39 (d, J = 10.2 Hz, 1H), 4.20 (q, J = 8.0 Hz, 1H), 3.90 (td, J = 8.9, 4.9 Hz, 1H), 3.63 (d, J = 10.2 Hz, 1H), 3.48–3.36 (m, 2H), 2.66 (ddd, J = 13.1, 7.8, 4.9 Hz, 1H), 2.14–1.90 (m, 5H). 13C{1H} NMR (126 MHz, chloroform-d) δ 73.9, 72.9, 67.5, 44.3, 36.1, 33.4, 23.1. LCMS, positive mode, m/z: 128.4 [M–Cl + H]+. Anal calcd for C7H14ClNO: C, 51.38; H, 8.62; N, 8.56; Cl, 21.66. Found: C, 51.14; H, 8.87; N, 8.95; Cl, 22.01.

7-Oxa-1-azaspiro[4.5]decane (1j)

Yield = 91.2 g, 95%, white vitreous solid. 1H NMR (400 MHz, chloroform-d) δ 3.63–3.49 (m, 2H), 3.32–3.22 (m, 2H), 2.95 (dt, J = 10.2, 6.3 Hz, 1H), 2.86 (dt, J = 10.2, 7.0 Hz, 1H), 1.84 (s, 1H), 1.78–1.49 (m, 7H), 1.47–1.35 (m, 1H). 13C{1H} NMR (126 MHz, chloroform-d) δ 75.3, 68.0, 59.4, 45.6, 36.3, 34.3, 25.0, 24.1. EIMS, 70 eV, m/z (rel. int.): 141 [M]+ (11); 96 (52); 83 (100); 82 (34); 41 (10). Anal calcd for C8H15NO: C, 68.04; H, 10.71; N, 9.92. Found: C, 68.37; H, 10.70; N, 10.14.

General Procedure vii

Benzylcarbamate (0.6 or 0.5 mol in the case of 8m) and trimethyl allyl silane (0.7 mol, 57.5 mL) were added to a solution of ketone 2 (0.5 mol) in dry CH2Cl2 (700 mL). The reaction mixture was cooled to 0 °C, and BF3·Et2O (0.6 mol, 98 mL or 0.5 mol, 82 mL in the case of 8m) was added dropwise for 30 min. The mixture was stirred at 0 °C for additional 1 h and overnight at rt. The saturated aqueous solution of NaHCO3 (700 or 380 mL in the case of 8 m) was added. The layers were separated; the organic layer was washed with distilled water (350 mL), dried over Na2SO4, filtered, and evaporated. The residue was purified by flash column chromatography to give the desired product.

Benzyl (1-allylcyclobutyl)carbamate (8b)

Yield = 112.9 g, 94%, colorless oil. 1H NMR (400 MHz, chloroform-d) δ 7.43–7.30 (m, 5H), 5.77 (m, 1H), 5.16–5.01 (m, 4H), 4.88 (s, 1H), 2.53 (d, J = 7.2 Hz, 2H), 2.34 (m, 2H), 2.09–2.00 (m, 2H), 1.96–1.70 (m, 2H). 13C{1H} NMR (101 MHz, chloroform-d) δ 154.2, 136.2, 133.1, 128.1, 127.63, 127.60, 118.1, 65.8, 55.6, 41.8, 31.8, 14.0. EIMS, 70 eV, m/z (rel. int.): 245 [M]+ (2); 126 (12); 92 (10); 91 (100); 65 (11); 41 (10). Anal calcd for C15H19NO2: C, 73.44; H, 7.81; N, 5.71. Found: C, 73.72; H, 7.44; N, 5.97.

Benzyl (1-allylcyclohexyl)carbamate (8d)

Yield = 101.1 g, 74%, yellow oil. 1H NMR (400 MHz, chloroform-d) δ 7.36 (m, 5H), 5.85–5.69 (m, 1H), 5.12–4.99 (m, 4H), 4.56 (s, 1H), 2.49 (d, J = 7.5 Hz, 2H), 1.97 (d, J = 12.5 Hz, 2H), 1.62–1.22 (m, 8H). 13C{1H} NMR (101 MHz, chloroform-d) δ 154.0, 136.4, 133.2, 128.1, 127.58, 127.55, 117.7, 65.7, 54.5, 42.3, 34.5, 25.5, 21.4. EIMS, 70 eV, m/z (rel. int.): 273 [M]+ (2); 232.1 (20); 188.1 (30); 124.1 (20); 91.1 (100); 81.1 (24); 79 (15). Anal calcd for C17H23NO2: C, 74.69; H, 8.48; N, 5.12. Found: C; 74.58; H; 8.41; N; 5.36.

Benzyl (4-allyltetrahydro-2H-pyran-4-yl)carbamate (8e)

Yield = 115.64 g, 84%, white solid (mp = 49–51 °C). 1H NMR (400 MHz, chloroform-d) δ 7.32 (s, 5H), 5.71 (m, 1H), 5.10–4.97 (m, 4H), 4.66 (s, 1H), 3.78–3.52 (m, 4H), 2.48 (d, J = 7.5 Hz, 2H), 1.93 (d, J = 13.9 Hz, 2H), 1.69–1.59 (m, 2H). 13C{1H} NMR (101 MHz, chloroform-d) δ 154.7, 136.6, 132.6, 128.5, 128.1, 128.0, 118.9, 66.2, 63.4, 52.5, 42.7, 35.0. LCMS, positive mode, m/z: 276 [M + H]+. Anal calcd for C16H21NO3: C, 69.79; H, 7.69; N, 5.09. Found: C, 69.69; H, 7.78; N, 5.39.

Benzyl (1-allyl-4,4-difluorocyclohexyl)carbamate (8o)

Yield = 114.46 g, 74%, white solid (mp = 64–66 °C). 1H NMR (400 MHz, chloroform-d) δ 7.41–7.27 (m, 5H), 5.71 (m, 1H), 5.15–4.96 (m, 4H), 4.46 (s, 1H), 2.45 (d, J = 7.5 Hz, 2H), 2.14 (d, J = 14.0 Hz, 2H), 1.87 (m, 4H), 1.62 (m, 2H). 13C{1H} NMR (126 MHz, chloroform-d) δ 154.3, 135.9, 132.2, 128.1, 127.7, 127.6, 122.3 (t, J = 240.7 Hz), 118.2, 65.9, 53.2, 41.6, 30.6 (d, J = 7.4 Hz), 29.1 (t, J = 24.6 Hz). 19F NMR (470 MHz, chloroform-d) δ −93.4 (d, J = 236.7 Hz), −102.0 (d, J = 239.3 Hz). LCMS, positive mode, m/z: 310 [M + H]+. Anal calcd for C17H21F2NO2: C, 66.00; H, 6.84; N, 4.53. Found: C, 66.00; H, 7.23; N, 4.33.

Benzyl (3-allyltetrahydro-2H-thiopyran-3-yl)carbamate (8m)

Yield = 100.54 g, 69%, colorless oil. 1H NMR (500 MHz, chloroform-d) δ 7.43–7.29 (m, 5H), 5.75 (m, 1H), 5.25 (s, 1H), 5.16–5.03 (m, 4H), 2.91 (s, 1H), 2.67 (q, J = 13.9 Hz, 2H), 2.51 (m, 1H), 2.45 (m, 1H), 2.38 (s, 1H), 2.25 (d, J = 13.8 Hz, 1H), 1.82 (s, 2H), 1.29 (dt, J = 14.8, 7.4 Hz, 1H). 13C{1H} NMR (101 MHz, chloroform-d) δ 154.6, 136.8, 132.8, 128.5, 128.0, 127.9, 118.8, 66.2, 51.2, 42.4, 37.3, 33.5, 28.0, 23.2. EIMS, 70 eV, m/z (rel. int.): 291 [M]+ (2); 184 (24); 142 (77); 141 (11); 140 (55); 114 (11); 108 (45); 107 (30); 99 (32); 91 (100); 80 (15); 79 (54); 77 (36); 65 (19); 61 (11); 51 (14); 47 (10); 45 (11); 41 (22); 39 (22). Anal calcd for C16H21NO2S: C, 65.95; H, 7.26; N, 4.81; S, 11.00. Found: C ,65.93; H, 7.39; N, 4.59; S, 10.90.

General Procedure viii

A solution of I2 (0.5 mol, 127 g) in THF (1900 mL) was added to a suspension of crushed NaBH4 (1 mol, 38 g) in THF (1100 mL). The reaction mixture was stirred for 30 min accompanied by decoloring of the solution. The solution of alkene 8, 12, or 17 (0.42 mol) in THF (450 mL) was added dropwise for 30 min and stirred for 90 min. The complete conversion was confirmed by TLC. A 3 M solution of NaOH (2 mol, 740 mL) was added dropwise during 2-3 h (Caution: exothermic process) with further dropwise addition of 30% solution of H2O2 (2 mol, 230 mL) for 1 h. The reaction mixture was stirred at rt for 1 h, diluted with brine (4400 mL), and extracted with EtOAc (3 × 1900 mL). The organic layer was evaporated with further re-dissolution of the residue in CH2Cl2 (500 mL). The organic layer was separated, dried over Na2SO4, and evaporated. The residue was purified by flash column chromatography to give the desired product.

Benzyl (1-(3-hydroxypropyl)cyclobutyl)carbamate (9b)

Yield = 90.9 g, 75%, yellow oil. 1H NMR (400 MHz, chloroform-d) δ 7.36 (d, J = 4.2 Hz, 5H), 5.06 (s, 3H), 3.64 (t, J = 6.5 Hz, 2H), 2.23 (m, 2H), 2.01 (m, 2H), 1.81 (m, 5H), 1.53 (m, 2H). 13C{1H} NMR (101 MHz, chloroform-d) δ 154.1, 136.2, 128.1, 127.6, 65.9, 62.6, 56.3, 33.4, 32.4, 26.9, 14.3. EIMS, 70 eV, m/z (rel. int.): 245 [M–H2O]+ (2); 232 (2); 100 (15); 91 (100); 65 (10). Anal calcd for C15H21NO3: C, 68.42; H, 8.04; N, 5.32. Found: C, 68.66; H, 8.02; N, 5.72.

Benzyl (1-(3-hydroxypropyl)cyclohexyl)carbamate (9d)

Yield = 89.5 g, 83%, white solid (mp = 89–91 °C). 1H NMR (400 MHz, chloroform-d) δ 7.42–7.29 (m, 5H), 5.04 (s, 2H), 4.63 (s, 2H), 3.60 (t, J = 6.5 Hz, 2H), 1.95 (m, 2H), 1.77 (m, 2H), 1.51 (s, 6H), 1.46–1.39 (m, 2H), 1.36 (m, 2H). 13C{1H} NMR (101 MHz, chloroform-d) δ 154.1, 136.3, 128.1, 127.61, 127,59, 65.8, 62.9, 54.4, 34.8, 34.1, 26.2, 25.5, 21.5. LCMS, positive mode, m/z: 314 [M + Na]+. Anal calcd for C17H25NO3: C, 70.07; H, 8.65; N, 4.81. Found: C, 69.83; H, 8.73; N, 4.62.

Benzyl (4-(3-hydroxypropyl)tetrahydro-2H-pyran-4-yl)carbamate (9e)

Yield = 87.48 g, 71%, white solid (mp = 89–90 °C). 1H NMR (500 MHz, chloroform-d) δ 7.42–7.29 (m, 5H), 5.05 (s, 2H), 4.72 (s, 1H), 3.74 (d, J = 12.2 Hz, 2H), 3.64–3.56 (m, 4H) 1.96 (d, J = 13.9 Hz, 2H), 1.81 (m, 3H), 1.64 (m, 2H), 1.51 (m, 2H). 13C{1H} NMR (126 MHz, chloroform-d) δ 154.6, 136.5, 128.6, 128.2, 128.0, 66.3, 63.4, 62.9, 52.5, 35.3, 34.7, 26.1. LCMS, positive mode, m/z: 294 [M + H]+. Anal calcd for C16H23NO4: C, 65.51; H, 7.90; N, 4.77. Found: C, 65.64; H, 8.11; N, 5.16.

Benzyl (4,4-difluoro-1-(3-hydroxypropyl)cyclohexyl)carbamate (9o)

Yield = 93.27 g, 77%, white solid (mp = 97–98 °C). 1H NMR (400 MHz, chloroform-d) δ 7.35 (m, 5H), 5.05 (s, 2H), 4.58 (s, 1H), 3.61 (t, J = 6.5 Hz, 2H), 2.16 (d, J = 14.1 Hz, 2H), 1.93 (m, 3H), 1.77 (m, 2H), 1.64 (m, 2H), 1.51 (m, 3H). 13C{1H} NMR (126 MHz, chloroform-d) δ 154.8, 136.3, 128.6, 128.3, 128.1, 122.9 (t, J = 241.9 Hz), 66.5, 62.8, 53.6, 34.0, 31.3 (d, J = 6.3 Hz), 29.6 (t, J = 24.6 Hz), 26.7. 19F NMR (470 MHz, chloroform-d) δ −93.4 (d, J = 234.3 Hz), −102.1 (d, J = 240.1 Hz). LCMS, positive mode, m/z: 350 [M + Na]+. Anal calcd for C17H23F2NO3: C, 62.37; H, 7.08; N, 4.28. Found: C, 62.61; H, 7.08; N, 4.05.

Benzyl (3-(3-hydroxypropyl)tetrahydro-2H-thiopyran-3-yl)carbamate (9m)

Yield = 81.13 g, 76%, white solid (mp = 80–81 °C). 1H NMR (500 MHz, chloroform-d) δ 7.40–7.28 (m, 5H), 5.33 (s, 1H), 5.06 (s, 2H), 3.61 (t, J = 6.4 Hz, 2H), 2.64 (q, J = 13.8 Hz, 2H), 2.52 (m, 1H), 2.45 (dt, J = 13.6, 4.2 Hz, 1H), 2.25–2.15 (m, 2H), 1.80 (m, 3H), 1.62 (m, 1H), 1.52 (dq, J = 14.9, 6.7 Hz, 2H), 1.26 (m, 1H). 13C{1H} NMR (126 MHz, chloroform-d) δ 154.7, 136.7, 128.5, 128.0, 128.0, 66.2, 62.8, 51.9, 37.5, 34.4, 34.0, 28.1, 26.0, 23.2. LCMS, positive mode, m/z: 310 [M + H]+. Anal calcd for C16H23NO3S: C, 62.11; H, 7.49; N, 4.53; S, 10.36. Found: C, 61.73; H, 7.66; N, 4.22; S, 10.17.

Ethyl (4-(3-hydroxypropyl)tetrahydro-2H-thiopyran-4-yl)carbamate (13f)

Yield = 60.55 g, 72%, white solid (mp = 82–83 °C). 1H NMR (500 MHz, DMSO-d6) δ 4.40 (s, 1H), 4.06 (t, J = 7.3 Hz, 2H), 3.63 (t, J = 6.5 Hz, 2H), 2.78 (ddd, J = 14.0, 11.1, 2.8 Hz, 2H), 2.47 (dt, J = 14.3, 4.3 Hz, 2H), 2.29 (d, J = 13.9 Hz, 2H), 1.84–1.68 (m, 4H), 1.59–1.47 (m, 2H), 1.24 (dt, J = 14.1, 7.0 Hz, 3H); the proton of the OH group is not observed due to the exchange. 13C{1H} NMR (126 MHz, chloroform-d) δ 154.3, 62.4, 59.9, 52.9, 35.4, 34.4, 25.5, 23.1, 14.1. LCMS, positive mode, m/z: 159.2 [M–NCOOEt]+. Anal calcd. for C11H21NO3S: C, 53.41; H, 8.56; N, 5.66; S, 12. 96. Found: C, 53.50; H, 8.43; N, 5.47; S, 13.36.

Ethyl (3-(3-hydroxypropyl)tetrahydro-2H-thiopyran-3-yl)carbamate (13m)

Yield = 71.43 g, 76%, yellow oil. 1H NMR (500 MHz, chloroform-d) δ 5.21 (s, 1H), 4.06 (q, J = 7.3 Hz, 2H), 3.63 (t, J = 6.3 Hz, 2H), 2.64 (q, J = 13.7 Hz, 2H), 2.56–2.42 (m, 2H), 2.18 (s, 2H), 1.81 (s, 3H), 1.57 (d, J = 27.4 Hz, 3H), 1.26–1.20 (m, 3H); the proton of the OH group is not observed due to the exchange. 13C{1H} NMR (126 MHz, chloroform-d) δ 154.6, 62.4, 59.9, 51.2, 37.1, 33.9, 33.6, 27.6, 25.5, 22.7, 14.1. EIMS, 70 eV, m/z (rel. int.): 247 [M]+ (5); 159 (15); 158 (100); 140 (11); 129 (29); 127 (13); 122 (15); 113 (35); 101 (13); 100 (11); 99 (18); 97 (63); 96 (10); 84 (10); 82 (18); 79 (12); 74 (20); 61 (17); 57 (17); 55 (13); 54 (10); 47 (10); 46 (13); 45 (24); 43 (10); 42 (18); 41 (31); 39 (12). Anal calcd for C11H21NO3S: C, 53.41; H, 8.56; N, 5.66; S, 12.96. Found: C, 53.45; H, 8.44; N, 6.02; S, 12.84.

tert-Butyl (4-(3-hydroxypropyl)tetrahydro-2H-thiopyran-4-yl)carbamate (18f)

Yield = 75.40 g, 74%, white solid (mp = 147–148 °C). 1H NMR (500 MHz, chloroform-d) δ 4.26 (s, 1H), 3.64 (t, J = 6.5 Hz, 2H), 2.80 (ddd, J = 14.1, 11.4, 2.6 Hz, 2H), 2.47 (dt, J = 14.4, 4.1 Hz, 2H), 2.28 (dd, J = 13.7, 4.2 Hz, 2H), 1.82–1.65 (m, 4H), 1.60–1.49 (m, 3H), 1.43 (s, 9H). 13C{1H} NMR (126 MHz, chloroform-d) δ 154.3, 79.2, 63.0, 53.2, 36.0, 34.9, 28.4, 26.0, 23.6. EIMS, 70 eV, m/z (rel. Int.): 275 [M]+ (2); 207 (11); 201 (15); 173 (10); 160 (20); 159 (11); 158 (24); 157 (15); 140 (27); 130 (24); 114 (13); 112 (31); 99 (61); 97 (28); 83 (10); 82 (14); 79 (12); 59 (39); 57 (44); 56 (50); 55 (24); 54 (10); 53 (12); 45 (10); 44 (70); 43 (13); 42 (11); 41 (100); 40 (19); 39 (47). Anal calcd for C13H25NO3S: C, 56.69; H, 9.15; N, 5.09; S, 11.64. Found: C, 56.68; H, 9.33; N, 4.79; S, 11.60.

tert-Butyl (3-(3-hydroxypropyl)tetrahydrothiophen-3-yl)carbamate (18k)

Yield = 82.60 g, 79%, white powder, (mp = 101–102 °C). 1H NMR (400 MHz, chloroform-d) δ 4.65 (s, 1H), 3.63 (t, J = 6.4 Hz, 2H), 2.84 (m, 3H), 2.75 (d, J = 11.4 Hz, 1H), 2.60–2.49 (m, 1H), 2.22 (t, J = 11.3 Hz, 1H), 1.81–1.51 (m, 5H), 1.40 (s, 9H). 13C{1H} NMR (126 MHz, chloroform-d) δ 154.7, 79.4, 66.0, 62.9, 41.5, 39.6, 31.6, 28.7, 28.4, 28.4. LCMS, positive mode, m/z: 284 [M + Na]+. Anal calcd for C12H23NO3S: C, 55.14; H, 8.87; N, 5.36; S, 12.27. Found: C, 55.51; H, 9.20; N, 5.01; S, 12.07.

tert-Butyl 4-(3-hydroxypropyl)-4-(2,2,2-trifluoroacetamido)piperidine-1-carboxylate (18p)

Yield = 100.66 g, 65%, white solid (mp = 86–87 °C). 1H NMR (500 MHz, chloroform-d) δ 6.47 (m, 1H), 3.81–3.68 (s, 2H), 3.63 (q, J = 6.3, 5.9 Hz, 2H), 3.09 (t, J = 12.9 Hz, 2H), 2.18 (s, 2H), 1.88 (s, 2H), 1.67–1.48 (m, 4H), 1.48–1.39 (m, 9H); the proton of the OH group is not observed due to the exchange. 13C{1H} NMR (126 MHz, chloroform-d) δ 157.2–156.3 (m), 154.7, 115.5 (q, J = 289.8 Hz), 80.0, 62.4 (q, J = 4.2, 3.7 Hz), 56.0, 39.4, 33.5, 33.4, 28.4, 25.9. 19F NMR (470 MHz, chloroform-d) δ −75.8 (m). EIMS, 70 eV, m/z (rel. int.): 377 [M + Na]+ (2); 279 (52); 263 (42); 262 (25); 236 (12); 235 (59); 192 (13); 139 (34); 126 (11); 108 (15); 96 (27); 95 (16); 83 (14); 82 (98); 69 (15); 57 (100); 55 (15); 44 (23); 41 (64); 39 (31). Anal calcd for C15H25F3N2O4: C, 50.84; H, 7.11; N, 7.91. Found: C, 50.60; H, 6.89; N, 7.93.

tert-Butyl 3-(3-hydroxypropyl)-3-(2,2,2-trifluoroacetamido)piperidine-1-carboxylate (18r)

Yield = 90.96 g, 62%, white solid (mp = 127–128 °C). 1H NMR (500 MHz, chloroform-d) δ 6.51 (s, 1H), 4.20 (d, J = 13.5 Hz, 1H), 3.97 (dt, J = 13.7, 3.9 Hz, 1H), 3.63 (m, 2H), 2.90–2.37 (m, 3H), 2.06 (d, J = 75.3 Hz, 3H), 1.53 (s, 5H), 1.46 (s, 9H); the proton of the OH group is not observed due to the exchange. 13C{1H} NMR (126 MHz, chloroform-d) δ 156.8 (m), 154.4, 115.5 (q, J = 289.3 Hz), 80.9, 62.4, 57.9, 51.6, 45.6, 32.2, 31.5, 28.2, 26.0, 21.7. 19F NMR (470 MHz, chloroform-d) δ −75.9, −76.2 LCMS, negative mode, m/z: 353.2 [M–H]−. Anal calcd for C15H25F3N2O4: C, 50.84; H, 7.11; N, 7.91. Found: C, 50.52; H, 7.10; N, 7.88.

tert-Butyl (1-(3-hydroxypropyl)cyclopropyl)carbamate (18a)

Yield = 127.0 g, 59%, white solid (mp = 55–57 °C). 1H NMR (400 MHz, chloroform-d) δ 4.93 (s, 1H), 3.62 (t, J = 6.3 Hz, 2H), 1.70–1.60 (m, 2H), 1.55 (s, 2H), 1.39 (s, 9H), 0.70 (m, 2H), 0.57 (m, 2H), the proton of the OH group is not observed due to the exchange. 13C{1H} NMR (101 MHz, chloroform-d) δ 155.5, 79.2, 62.7, 33.2, 32.8, 29.5, 28.4, 14.0. EIMS, 70 eV, m/z (rel. int.): 159 [M-C(CH3)3 + H]+ (4); 98 (41); 84 (25); 71 (37); 59 (25); 57 (100); 56 (21); 55 (11); 54 (12); 44 (10); 42 (10); 41 (45); 39 (17). Anal calcd for C11H21NO3: C, 61.37; H, 9.83; N, 6.51. Found: C, 61.37; H, 10.14; N, 6.74.

General Procedure ix

i-Pr2NEt (0.35 mol, 34 mL) (triethylamine (0.35 mol, 26 mL) in the case of 19k) was added to a solution of alcohol 9, 13, or 18 (0.30 mmol) in CH2Cl2 (1400 mL). The reaction mixture was cooled to 0 °C, and a solution of methanesulfonyl chloride (0.31 mol, 53 mL) in CH2Cl2 (140 mL) was added dropwise for 45 min. The mixture was further stirred at 0 °C for 30 min and overnight at rt. In the case of 19a, the solution was stirred for 3 h at ambient temperature, and complete conversion was confirmed by NMR spectroscopy. An aqueous solution of citric acid (10%, 1000 mL) was added and stirred for 10 min. Layers were separated; the organic layer was washed with a saturated aqueous solution of NaHCO3 (560 mL) and brine (560 mL) (only a solution of NaHCO3 was used in the case of 19a). The organic layer was dried over Na2SO4 and evaporated. The residue was used in the next step without further purification.

In the case of 19r and 19p, the alcohol (0.257 mol) was dissolved in dry CH2Cl2 (1250 mL), and then DIPEA (0.308 mol, 30 mL) and mesyl chloride (0.27 mol, 46 mL) were added. The reaction mixture was stirred overnight, washed with 10% citric acid solution (200 mL), dried over Na2SO4, and evaporated.

The analytical samples were additionally purified by flash column chromatography.

3-(1-(((Benzyloxy)carbonyl)amino)cyclobutyl)propyl methanesulfonate (10b)

Yield = 108.7 g, 91%, light yellow viscous oil. 1H NMR (400 MHz, chloroform-d) δ 7.40–7.28 (m, 5H), 5.05 (s, 2H), 4.96 (s, 1H), 4.21 (t, J = 6.6 Hz, 2H), 2.96 (s, 3H), 2.14 (m, 2H), 2.08–1.99 (m, 2H), 1.97–1.75 (m, 4H), 1.75–1.66 (m, 2H). 13C{1H} NMR (126 MHz, chloroform-d) δ 153.9, 136.0, 128.1, 127.63, 127.57, 69.7, 65.8, 55.8, 36.9, 32.6, 32.3, 23.5, 14.1. LCMS, positive mode, m/z: 342 [M + H]+. Anal calcd for C16H23NO5S: C, 56.29; H, 6.79; N, 4.10; S, 9.39. Found: C, 55.96; H, 6.39; N, 4.37; S, 9.18.

3-(1-(((Benzyloxy)carbonyl)amino)cyclohexyl)propyl methanesulfonate (10d)

Yield = 100.5 g, 85%, white solid (mp = 65–67 °C). 1H NMR (500 MHz, chloroform-d) δ 7.40–7.28 (m, 5H), 5.04 (s, 2H), 4.56 (s, 1H), 4.18 (d, J = 6.8 Hz, 2H), 2.96 (d, J = 2.9 Hz, 3H), 1.93 (d, J = 12.9 Hz, 2H), 1.80 (d, J = 9.2 Hz, 2H), 1.71 (d, J = 3.5 Hz, 2H), 1.61–1.20 (m, 8H). 13C{1H} NMR (126 MHz, chloroform-d) δ 154.4, 136.7, 128.5, 128.1, 128.0, 70.5, 66.1, 54.3, 37.4, 34.9, 34.1, 25.6, 23.3, 21.5. LCMS, positive mode, m/z: 370 [M + H]+. Anal calcd for C18H27NO5S: C, 58.51; H, 7.37; N, 3.79; S, 8.68. Found: C, 58.32; H, 7.77; N, 3.89; S, 8.37.

3-(4-(((Benzyloxy)carbonyl)amino)tetrahydro-2H-pyran-4-yl)propyl methanesulfonate (10e)

yield = 105.86 g, 95%, white solid (mp = 76–77 °C). 1H NMR (500 MHz, chloroform-d) δ 7.42–7.28 (m, 5H), 5.05 (s, 2H), 4.73 (s, 1H), 4.19 (t, J = 6.1 Hz, 2H), 3.74 (d, J = 8.4 Hz, 2H), 3.59 (t, J = 10.5 Hz, 2H), 2.96 (s, 3H), 1.95 (d, J = 13.9 Hz, 2H), 1.85 (m, 2H), 1.71 (m, 2H), 1.63 (m, 2H). 13C{1H} NMR (126 MHz, chloroform-d) δ 154.5, 136.4, 128.6, 128.2, 128.0, 70.0, 66.4, 63.3, 52.3, 37.4, 35.1, 34.5, 23.0. LCMS, positive mode, m/z: 372 [M + H]+. Anal calcd for C17H25NO6S: C, 54.97; H, 6.78; N, 3.77; S, 8.63. Found: C, 54.57; H, 7.10; N, 3.54; S, 8.69.

3-(1-(((Benzyloxy)carbonyl)amino)-4,4-difluorocyclohexyl)propyl methanesulfonate (10o)

Yield = 112.09 g, 97%, white solid (mp = 73–75 °C). 1H NMR (400 MHz, chloroform-d) δ 7.34 (dt, J = 9.2, 4.3 Hz, 5H), 5.03 (s, 2H), 4.60 (s, 1H), 4.16 (t, J = 6.2 Hz, 2H), 2.94 (s, 3H), 2.13 (d, J = 12.4 Hz, 2H), 1.98–1.76 (m, 6H), 1.69 (m, 2H), 1.59 (m, 2H). 13C{1H} NMR (101 MHz, chloroform-d) δ 154.7, 136.3, 128.6, 128.3, 128.1, 121.9 (t, J = 241.9 Hz), 69.9, 66.5, 53.3, 37.4, 33.8, 31.2 (d, J = 7.1 Hz), 29.5 (t, J = 24.6 Hz), 23.6. 19F NMR (470 MHz, chloroform-d) δ −93.4 (d, J = 237.1 Hz), −102.4 (d, J = 240.5 Hz). LCMS, positive mode, m/z: 406 [M + H]+. Anal calcd for C18H25F2NO5S: C, 53.32; H, 6.21; N, 3.45; S, 7.91. Found: C, 53.56; H, 5.85; N, 3.43; S, 7.97.

3-(3-(((Benzyloxy)carbonyl)amino)tetrahydro-2H-thiopyran-3-yl)propyl methanesulfonate (10m)

Yield = 98.74 g, 98%, yellow oil. 1H NMR (500 MHz, chloroform-d) δ 7.41–7.29 (m, 5H), 5.30 (s, 1H), 5.11–5.04 (m, 2H), 4.27–4.14 (m, 2H), 2.97 (d, J = 3.3 Hz, 3H), 2.64 (s, 2H), 2.58–2.42 (m, 2H), 2.30–2.14 (m, 2H), 1.86–1.61 (m, 5H), 1.31–1.22 (m, 1H). 13C{1H} NMR (126 MHz, chloroform-d) δ 154.2, 136.1, 128.1, 127.6, 127.4, 69.7, 65.8, 51.2, 37.0, 36.9, 33.6, 33.5, 27.6, 22.6, 22.4. LCMS, positive mode, m/z: 389 [M + H]+; 388 [M]+. Anal calcd for C17H25NO5S2: C, 52.69; H, 6.50; N, 3.61; S, 16.55. Found: C, 52.54; H, 6.72; N, 3.61; S, 16.86.

3-(4-((Ethoxycarbonyl)amino)tetrahydro-2H-thiopyran-4-yl)propyl methanesulfonate (14f)

Yield = 67.17 g, 86%, brown oil. 1H NMR (400 MHz, chloroform-d) δ 5.27 (d, J = 2.9 Hz, 1H), 4.18 (m, 2H), 4.01 (m, 2H), 2.97 (d, J = 2.8 Hz, 3H), 2.85–2.65 (m, 2H), 2.43 (dd, J = 14.4, 4.0 Hz, 2H), 2.26 (d, J = 13.9 Hz, 2H), 1.78 (m, 2H), 1.69 (tt, J = 11.4, 3.3 Hz, 4H), 1.20 (td, J = 7.1, 2.9 Hz, 3H). 13C{1H} NMR (126 MHz, chloroform-d) δ 154.1, 69.6, 60.0, 52.7, 44.7, 38.9, 36.9, 35.3, 34.2, 23.0, 22.4, 14.1. LCMS, positive mode, m/z: 237.2 [M–NCOOEt]+. Anal calcd for C12H23NO5S2: C, 44.29; H, 7.12; N, 4.30; S, 19.70. Found: C, 44.13; H, 7.31; N, 4.68; S, 19.87.

3-(3-((Ethoxycarbonyl)amino)tetrahydro-2H-thiopyran-3-yl)propyl methanesulfonate (14m)

Yield = 83.05 g, 88%, brown oil. 1H NMR (500 MHz, chloroform-d) δ 5.29 (s, 1H), 4.20 (m, 2H), 4.06 (q, J = 7.1 Hz, 2H), 2.99 (s, 3H), 2.62 (s, 2H), 2.57–2.42 (m, 2H), 2.27–2.13 (m, 2H), 1.80 (m, 2H), 1.73 (m, 2H), 1.68–1.60 (m, 2H), 1.23 (t, J = 7.0 Hz, 3H). 13C{1H} NMR (101 MHz, chloroform-d) δ 154.9, 70.3, 60.3, 53.6, 51.4, 37.3, 34.0, 33.9, 28.0, 23.1, 22.9, 14.6. EIMS, 70 eV, m/z (rel. int.): 229 (27); 169 (10); 168 (100); 155 (52); 140 (14); 127 (10); 113 (13); 83 (67); 83 (28); 80 (10); 67 (10); 55 (18); 54 (11); 45 (12); 42 (11); 41 (26); 39 (12). Anal calcd for C12H23NO5S2: C, 44.29; H, 7.12; N, 4.30; S, 19.70. Found: C, 44.25; H, 7.37; N, 4.26; S, 19.74.

3-(4-((tert-Butoxycarbonyl)amino)tetrahydro-2H-thiopyran-4-yl)propyl methanesulfonate (19f)

Yield = 93.54 g, 98%, yellow solid (mp = 88–89 °C). 1H NMR (500 MHz, chloroform-d) δ 4.29 (s, 1H), 4.17 (t, J = 6.2 Hz, 2H), 2.96 (s, 3H), 2.75 (t, J = 11.6 Hz, 2H), 2.41 (d, J = 14.5 Hz, 2H), 2.24 (d, J = 14.0 Hz, 2H), 1.68 (m, 6H), 1.38 (s, 9H). 13C{1H} NMR (126 MHz, chloroform-d) δ 154.1, 79.3, 70.2, 53.0, 37.4, 35.9, 34.7, 28.4, 23.5, 23.0. EIMS, 70 eV, m/z (rel. int.): 377 [M + Na]+ (1); 363 (1); 257 (12); 201 (42); 184 (13); 173 (29); 140 (28); 129 (31); 128 (11); 97 (12); 96 (100); 83 (35); 82 (12); 57 (46); 56 (16); 44 (12); 41 (39); 39 (17). Anal calcd for C14H27NO5S2: C, 47.57; H, 7.70; N, 3.96; S, 18.14. Found: C, 47.61; H, 7.71; N, 4.04; S, 17.74.

3-(3-((tert-Butoxycarbonyl)amino)tetrahydrothiophen-3-yl)propyl methanesulfonate (19k)

Yield = 108.63 g, 100%, brown powder (mp = 84–85 °C). 1H NMR (500 MHz, chloroform-d) δ 4.65 (s, 1H), 4.23 (dq, J = 6.9, 4.8, 4.2 Hz, 2H), 2.99 (s, 3H), 2.89–2.82 (m, 3H), 2.76 (d, J = 11.2 Hz, 1H), 2.55 (d, J = 11.6 Hz, 1H), 2.29 (d, J = 13.3 Hz, 1H), 1.88–1.67 (m, 4H), 1.42 (s, 9H). 13C{1H} NMR (126 MHz, chloroform-d) δ 154.6, 79.6, 70.0, 65.7, 41.4, 39.6, 37.5, 31.4, 28.6, 28.4, 25.2. LCMS, positive mode, m/z: [M + Na]+. Anal Calcd for C13H25NO5S2: C, 46.00; H, 7.42; N, 4.13; S, 18.89. Found: C, 46.17; H, 7.04; N, 4.16; S, 19.2.

tert-Butyl-4-(3-((methylsulfonyl)oxy)propyl)-4-(2,2,2-trifluoroacetamido)piperidine-1-carboxylate (19p)

Yield = 113.0 g, 92%, beige solid (mp = 121–122 °C). 1H NMR (500 MHz, chloroform-d) δ 6.16 (s, 1H), 4.22 (t, J = 5.9 Hz, 2H), 3.83 (s, 2H), 3.08–2.94 (m, 5H), 2.14 (s, 2H), 2.01–1.90 (s, 2H), 1.73 (m, 2H), 1.60 (ddd, J = 14.5, 11.3, 4.2 Hz, 2H), 1.45 (s, 9H). 13C{1H} NMR (126 MHz, chloroform-d) δ 156.6 (q, J = 36.2 Hz), 154.6, 115.5 (q, J = 289.4 Hz), 80.1, 69.4, 55.7, 39.3, 37.5, 33.7, 33.3, 28.4, 23.2. 19F NMR (470 MHz, chloroform-d) δ −75.7. LCMS, positive mode, m/z: 333 [M–Boc + 1]. Anal calcd for C16H27F3N2O6S: C, 44.44; H, 6.29; N, 6.48; S, 7.41. Found: C, 44.66; H, 6.30; N, 6.18; S, 7.06.

tert-Butyl 3-(3-((methylsulfonyl)oxy)propyl)-3-(2,2,2-trifluoroacetamido)piperidine-1-carboxylate (19r)

Yield = 100.0 g, 90%, yellow solid (mp = 93–94 °C). 1H NMR (500 MHz, chloroform-d) δ 6.27 (s, 1H), 4.22 (m, 3H), 4.02 (d, J = 13.4 Hz, 1H), 3.00 (s, 3H), 2.78 (m, 2H), 2.40 (br m, 1H), 1.86–1.63 (m, 2H), 1.56 (s, 3H), 1.45 (s, 11H). 13C{1H} NMR (126 MHz, chloroform-d) δ 156.7 (q, J = 37.2 Hz), 154.0, 115.4 (q, J = 289.1 Hz), 81.1, 69.4, 57.6, 51.7, 45.7, 37.4, 31.8, 31.5, 28.2, 23.1, 21.7. 19F NMR (470 MHz, chloroform-d) δ −75.9, −76.2. LCMS, positive mode, m/z: 377.0 [M–C(CH3)3]+; 333.2 [M–Boc]+. Anal calcd for C16H27F3N2O6S: C, 44.44; H, 6.29; N, 6.48; S, 7.41. Found: C, 44.31; H, 5.97; N, 6.24; S, 7.63.

3-(1-((tert-Butoxycarbonyl)amino)cyclopropyl)propyl methanesulfonate (19a)

Yield = 164.4 g, 95%, beige solid (mp = 52–53 °C). 1H NMR (400 MHz, chloroform-d) δ 4.85 (s, 1H), 4.24 (t, J = 6.5 Hz, 2H), 2.96 (s, 3H), 1.86 (dt, J = 14.6, 6.6 Hz, 2H), 1.60 (m, 2H), 1.38 (s, 9H), 0.73 (m, 2H), 0.59 (q, J = 5.0 Hz, 2H). 13C{1H} NMR (101 MHz, chloroform-d) δ 155.5, 79.3, 70.0, 37.3, 32.8, 32.3, 28.4, 26.3, 14.0. EIMS, 70 eV, m/z (rel. int.): 141 (48); 140 (13); 97 (28); 96 (86); 69 (10); 57 (100); 56 (10); 41 (48); 39 (15). Anal calcd for C12H23NO5S: C, 49.13; H, 7.90; N, 4.77; S, 10.93. Found: C, 49.42; H, 8.05; N, 4.57; S, 10.71.

General Procedure x

NaH (60% in mineral oil, 0.48 mol, 11.5 g) was added in portions of solutions of mesylate 10, 14, or 19 (0.32 mol) in THF (3200 mL) over 30 min. The reaction mixture was heated to 60 °C and was stirred overnight at this temperature. Then, THF was evaporated and a saturated aqueous solution of NH4Cl (1600 mL) was carefully added. In the case of 20a, 20r, and 20p, distilled water (1420 mL) instead of an aqueous solution of NH4Cl was used. The product was extracted with CH2Cl2 (3 × 600 mL). The organic layer was dried over Na2SO4 and evaporated. The residue was purified by flash column chromatography to give the desired product.

Benzyl 5-azaspiro[3.4]octane-5-carboxylate (11b)

Yield = 72.2 g, 92%, yellow oil. 1H NMR (400 MHz, chloroform-d) δ 7.49–7.28 (m, 5H), 5.23–5.13 (m, 2H), 3.42 (m, 2H), 3.14–2.86 (m, 2H), 2.04 (m, 2H), 1.86–1.57 (m, 6H). 13C{1H} NMR (101 MHz, chloroform-d) δ 154.4, 137.3, 128.4, 127.9, 127.8, 66.0, 63.5, 48.0, 40.1, 32.6, 22.1, 13.6. EIMS, 70 eV, m/z (rel. int.): 245 [M]+ 217 (11); 172 (18); 92 (11); 91 (100); 65 (14). Anal calcd for C15H19NO2: C, 73.44; H, 7.81; N, 5.71. Found: C, 73.69; H, 7.57; N, 5.86.

Benzyl 1-azaspiro[4.5]decane-1-carboxylate (11d)

Yield = 63.5 g, 86%, white solid (mp = 55–56 °C). 1H NMR (500 MHz, chloroform-d) δ 7.45–7.29 (m, 5H), 5.18–5.09 (m, 2H), 3.51 (dt, J = 21.3, 6.7 Hz, 2H), 2.56–2.19 (m, 2H), 1.88 (m, 2H), 1.67 (m, 6H), 1.37 (m, 2H), 1.28 (m, 2H). 13C{1H} NMR (126 MHz, chloroform-d) δ 153.1, 136.9, 127.9, 127.22, 127.16, 65.3, 64.1, 47.2, 35.4, 32.9, 24.7, 23.8, 21.9. LCMS, positive mode, m/z: 274 [M + H]+. Anal calcd for C17H23NO2: C, 74.69; H, 8.48; N, 5.12. Found: C, 74.52; H, 8.24; N, 5.36.

Benzyl 8-oxa-1-azaspiro[4.5]decane-1-carboxylate (11e)

Yield = 51.84 g, 82%, white solid (mp = 94–95 °C). 1H NMR (500 MHz, chloroform-d) δ 7.42–7.33 (m, 4H), 7.30 (t, J = 6.8 Hz, 1H), 5.16 (m, 2H), 3.94 (m, 2H), 3.52 (m, 2H), 3.44 (t, J = 12.4 Hz, 2H), 2.98–2.60 (m, 2H), 1.98 (m, 2H), 1.79 (p, J = 6.6 Hz, 2H), 1.24 (m, 2H). 13C{1H} NMR (126 MHz, chloroform-d) δ 153.6, 137.2, 128.4, 127.9, 127.8, 66.0, 61.9, 47.6, 35.4, 35.3, 34.1, 22.2. LCMS, positive mode, m/z: 276 [M + H]+. Anal calcd for C16H21NO3: C, 69.79; H, 7.69; N, 5.09. Found: C, 69.47; H, 7.37; N, 4.99.

Benzyl 8,8-difluoro-1-azaspiro[4.5]decane-1-carboxylate (11o)

Yield = 75.71 g, 89%, white solid (mp = 128–130 °C). 1H NMR (500 MHz, chloroform-d) δ 7.36 (s, 4H), 7.30 (s, 1H), 5.14 (m, 2H), 3.54 (s, 2H), 2.97–2.60 (m, 2H), 2.09 (s, 2H), 1.93 (m, 2H), 1.89–1.70 (m, 4H), 1.41 (m, 2H). 13C{1H} NMR (126 MHz, chloroform-d) δ 153.0, 136.6, 127.9, 127.32, 127.26, 122.0 (t, J = 241.6 Hz), 65.6, 62.4, 47.2, 34.8, 31.3 (t, J = 24.7 Hz), 28.8 (d, J = 10.0 Hz), 21.8. 19F NMR (470 MHz, chloroform-d) δ −93.3 (d, J = 235.5 Hz), −102.8 (m). EIMS, 70 eV, m/z (rel. int.): 309 [M]+ (20); 186 (45); 91 (100). Anal calcd for C17H21F2NO2: C, 66.00; H, 6.84; N, 4.53. Found: C, 65.72; H, 6.44; N, 4.31.

Benzyl 7-thia-1-azaspiro[4.5]decane-1-carboxylate (11m)

Yield = 54.25 g, 73%, yellowish solid (mp = 61–63 °C). 1H NMR (500 MHz, chloroform-d) δ 7.36 (t, J = 7.2 Hz, 5H), 5.13 (d, J = 46.6 Hz, 2H), 3.78–3.40 (m, 2H), 2.71–2.55 (m, 2H), 2.47 (m, 1H), 2.38 (d, J = 12.9 Hz, 2H), 2.12 (d, J = 12.8 Hz, 1H), 2.05 (dt, J = 13.5, 3.5 Hz, 1H), 1.92 (dt, J = 13.4, 7.8 Hz, 1H), 1.78 (m, 3H), 1.49 (m, 1H). 13C{1H} NMR (126 MHz, chloroform-d) δ 153.3, 136.6, 127.9, 127.3, 127.2, 65.7, 62.9, 47.7, 35.2, 33.40, 33.35, 27.1, 26.5, 21.7. LCMS, positive mode, m/z: 292 [M + H]+. Anal calcd for C16H21NO2S: C, 65.95; H, 7.26; N, 4.81; S, 11.00. Found: C, 66.13; H, 7.60; N, 5.13; S, 10.69.

Ethyl 8-thia-1-azaspiro[4.5]decane-1-carboxylate (15f)

Yield = 34.86 g, 76%, white solid, (mp = 67–68 °C). 1H NMR (500 MHz, chloroform-d) δ 4.19 (q, J = 7.2 Hz, 1H), 4.07 (q, J = 7.2 Hz, 1H), 3.50 (t, J = 6.9 Hz, 1H), 3.43 (t, J = 6.7 Hz, 1H), 2.86 (dt, J = 13.2, 8.1 Hz, 1H), 2.76 (t, J = 13.1 Hz, 2H), 2.68–2.58 (m, 1H), 2.54 (d, J = 13.4 Hz, 2H), 1.86 (dt, J = 23.1, 6.9 Hz, 2H), 1.74 (p, J = 6.9 Hz, 2H), 1.65 (t, J = 15.6 Hz, 2H), 1.30 (t, J = 7.4 Hz, 1H), 1.23 (t, J = 7.0 Hz, 2H). 13C{1H} NMR (126 MHz, DMSO-d6) δ 149.2, 58.3, 55.4, 42.7, 31.0, 29.9, 22.1, 17.4, 10.1. LCMS, positive mode, m/z: 230.0 [M + H]+. Anal calcd for C11H19NO2S: C, 57.61; H, 8.35; N, 6.11; S, 13.98. Found: C, 57.71; H, 8.22; N, 6.07; S, 14.16.

Ethyl 7-thia-1-azaspiro[4.5]decane-1-carboxylate (15m)

Yield = 40.94 g, 70%, yellow oil. 1H NMR (400 MHz, chloroform-d) δ 4.04 (m, 2H), 3.68 (d, J = 13.0 Hz, 1H), 3.47 (m, 2H), 2.58 (m, 2H), 2.35 (m, 2H), 2.15–1.94 (m, 2H), 1.94–1.63 (m, 4H), 1.44 (m, 1H), 1.22 (m, 3H). 13C{1H} NMR (126 MHz, chloroform-d) δ 153.6, 62.6, 59.8, 47.6, 35.2, 33.4, 33.3, 27.1, 26.5, 21.7, 14.2. EIMS, 70 eV, m/z (rel. int.): 231 (2); 230 [M + H]+ (5); 229 [M]+ (41); 168 (100); 155 (48); 140 (10); 96 (15); 83 (29); 82 (13). Anal calcd for C11H19NO2S: C, 57.61; H, 8.35; N, 6.11; S, 13.98. Found: C, 57.77; H, 8.25; N, 6.09; S, 14.29.

tert-Butyl 8-thia-1-azaspiro[4.5]decane-1-carboxylate (20f)

Yield = 50.86 g, 76%, white solid (mp = 89–90 °C). 1H NMR (500 MHz, chloroform-d) δ 3.43 (d, J = 36.8 Hz, 2H), 2.89 (m, 1H), 2.76 (t, J = 13.2 Hz, 2H), 2.63 (m, 1H), 2.55 (d, J = 13.2 Hz, 2H), 1.85 (m, 2H), 1.72 (p, J = 7.0 Hz, 2H), 1.65 (s, 2H), 1.49 (d, J = 34.4 Hz, 9H). 13C{1H} NMR (126 MHz, chloroform-d) δ 154.3, 153.3*, 79.8, 78.7*, 62.7*, 62.3, 47.9, 36.1*, 35.8, 35.1*, 34.7, 28.6, 27.0, 26.9*, 22.0*, 21.5 (*due to hindered rotation). EIMS, 70 eV, m/z (rel. int.): 259 (1); 258 [M + H]+ (2); 257 [M]+ (13); 201 (46); 184 (14); 173 (33); 140 (33); 129 (28); 128 (12); 97 (13); 96 (100); 83 (34); 82 (12); 57 (55); 44 (12); 41 (42); 39 (18). Anal calcd for C13H23NO2S: C, 60.66; H, 9.01; N, 5.44. Found: C, 60.36; H, 9.10; N, 5.82; S, 12.34.

tert-Butyl 7-thia-1-azaspiro[4.4]nonane-1-carboxylate (20k)

Yield = 60.75 g, 78%, white powder (mp = 69–70 °C). 1H NMR (400 MHz, chloroform-d) δ 3.60–3.27 (m, 3H), 3.03–2.65 (m, 3H), 2.40–2.05 (m, 2H), 1.82–1.59 (m, 4H), 1.44 (d, J = 11.9 Hz, 9H). 13C{1H} NMR (126 MHz, chloroform-d) δ 153.8*, 153.1, 80.1*, 79.2, 72.2, 71.6*, 48.5, 40.1*, 38.9, 38.0*, 36.8*, 36.5, 36.0, 28.6, 27.8, 22.3, 21.8* (*due to hindered rotation). EIMS, 70 eV, m/z (rel. int.): 245 (2); 244 [M + H]+ (3); 243 [M]+ (20); 188 (10); 187 (96); 170 (25); 142 (12); 140 (15); 128 (18); 126 (72); 125 (10); 115 (10); 99 (22); 97 (48); 96 (90); 86 (15); 82 (13); 57 (100); 56 (20); 55 (12); 45 (12); 41 (70); 39 (29). Anal calcd for C12H21NO2S: C, 59.22; H, 8.70; N, 5.76; S, 13.17. Found: C, 59.19; H, 8.66; N, 6.10; S, 12.83.

tert-Butyl-1-(2,2,2-trifluoroacetyl)-1,8-diazaspiro[4.5]decane-8-carboxylate (20p)

Yield = 76.96 g, 88%, white vitreous solid. 1H NMR (400 MHz, chloroform-d) δ 4.14 (s, 2H), 3.67 (t, J = 6.4 Hz, 2H), 2.90–2.67 (m, 4H), 2.03–1.85 (m, 4H), 1.43 (s, 9H), 1.29 (d, J = 12.3 Hz, 2H). 13C{1H} NMR (126 MHz, chloroform-d) δ 155.0 (q, J = 36.0 Hz), 154.5, 116.1 (q, J = 289.0 Hz), 79.7, 67.1, 48.0 (q, J = 4.0 Hz), 41.5 (d, J = 98.9 Hz), 34.5, 31.6, 28.4, 23.2. 19F NMR (470 MHz, chloroform-d) δ −72.8. LCMS, positive mode, m/z: 359 [M + Na]+. Anal calcd for C15H23F3N2O3: C, 53.56; H, 6.89; N, 8.33. Found: C, 53.24; H, 6.91; N, 8.57.

tert-Butyl 1-(2,2,2-trifluoroacetyl)-1,7-diazaspiro[4.5]decane-7-carboxylate (20r)

Yield = 53.38 g, 69%, colorless oil. 1H NMR (500 MHz, chloroform-d) δ 4.24–3.56 (m, 4H), 2.88 (td, J = 13.0, 4.5 Hz, 1H), 2.71 (br m, 1H), 2.03 (br m, 3H), 1.59 (br m, 5H), 1.45 (s, 9H). 13C{1H} NMR (126 MHz, chloroform-d) δ 155.5 (q, J = 36.0 Hz), 154.6, 116.1 (q, J = 289.0 Hz), 79.7, 67.3, 48.7 (q, J = 4.1 Hz), 47.1, 42.9, 34.3, 31.2, 28.4, 23.7, 23.1. 19F NMR (470 MHz, chloroform-d) δ −72.8. EIMS, 70 eV, m/z (rel. int.): 336 [M]+ (1); 280 (14); 263 (16); 236 (11); 235 (19); 140 (11); 110 (15); 96 (100); 57 (43); 41 (25); 39 (10). Anal calcd for C15H23F3N2O3: C, 53.56; H, 6.89; N, 8.33. Found: C, 53.42; H, 7.13; N, 8.62.

tert-Butyl 4-azaspiro[2.4]heptane-4-carboxylate (20a)

Yield = 105.0 g, 95%, colorless oil. 1H NMR (500 MHz, chloroform-d) δ 3.49 (t, J = 6.2 Hz, 2H), 1.84 (m, 4H), 1.54 (br m, 2H), 1.41 (s, 9H), 0.41 (m, 2H). 13C{1H} NMR (126 MHz, chloroform-d) δ 153.1, 79.0, 48.5, 42.6, 36.9, 28.5, 22.6, 9.1. EIMS, 70 eV, m/z (rel. int.): 197 [M]+ (1); 141 (52); 140 (13); 124 (14); 97 (30); 96 (91); 69 (12); 68 (11); 57 (100); 56 (10); 41 (49); 39 (16). Anal calcd for C11H19NO2: C, 66.97; H, 9.71; N, 7.10. Found: C, 67.36; H, 9.86; N, 6.82.

General Procedure xi

Pd/C (10%, 7.25 g) was added to solution of Cbz-protected amine 11 (0.3 mol) in MeOH (1000 mL). The reaction mixture was hydrogenated at 1 atm of H2 until the disappearance of the starting material. The catalyst was filtered and washed with MeOH (2 × 100 mL), and saturated HCl/MeOH solution (400 mL) was added. The solvent was removed in vacuo. The desired product was dried in vacuo.

In the case of 1n, starting Cbz-amine 11n (0.166 mol) was dissolved in MeOH (800 mL), and Pd/C (5.35 g) was added. The reaction mixture was stirred overnight in an atmosphere of H2 (1 atm). The catalyst was filtered and washed with MeOH (268 mL), and the solution was evaporated. The obtained residue was dissolved in diethyl ether (535 mL) and treated with dioxane/HCl (270 mL). The white solid was filtered and dried in vacuo.

Yield = 54.8 g, 95%, white solid (mp = 131–133 °C, dec.).

1-Azaspiro[4.5]decane hydrochloride (1d·HCl)

Yield = 38.4 g, 95%, white solid (mp = 113–115 °C, dec.).

8-Oxa-1-azaspiro[4.5]decane hydrochloride (1e·HCl)

Yield = 31.39 g, 93%, white solid (mp = 181–184 °C, dec.).

8,8-Difluoro-1-azaspiro[4.5]decane hydrochloride (1o·HCl)

Yield = 49.79 g, 96%, white solid (mp = 134–136 °C, dec.).

1H NMR (500 MHz, DMSO-d6) δ 9.55 (s, 2H), 3.22 (m, 2H), 2.16 (m, 2H), 2.02–1.90 (m, 6H), 1.90–1.80 (m, 4H). 13C{1H} NMR (126 MHz, DMSO-d6) δ 123.1 (t, J = 240.6 Hz), 64.4, 43.0, 33.8, 29.9 (t, J = 24.5 Hz), 29.6 (t, J = 5.1 Hz), 21.8. 19F NMR (470 MHz, DMSO-d6) δ −96.4. EIMS, 70 eV, m/z (rel. int.): 175 [M–Cl]+ (17); 96 (100); 83 (26); 82 (18). Anal calcd for C9H16ClF2N: C, 51.07; H, 7.62; N, 6.62; Cl, 16.75. Found: C, 51.41; H, 7.52; N, 6.82; Cl, 16.72.

7-Thia-1-azaspiro[4.5]decane 7,7-dioxide hydrochloride (1n·HCl)

Yield = 34.48 g, 92%, white solid (mp = 260–261 °C, dec.).

1H NMR (400 MHz, deuterium oxide) δ 4.66 (s, 2H), 3.63–3.60 (m, 1H), 3.50–3.45 (m, 1H), 3.36 (m, 2H), 3.20 (t, J = 6.6 Hz, 2H), 2.23–2.10 (m, 2H), 2.09–1.97 (m, 5H), 1.87 (m, 1H). 13C{1H} NMR (126 MHz, chloroform-d) δ 66.9, 54.2, 49.1, 44.9, 36.4, 30.2, 21.1, 19.0. LCMS, positive mode, m/z: 190.2 [M–Cl]+. Anal calcd for C8H16ClNO2S: C, 42.57; H, 7.14; N, 6.21; S, 14.20; Cl, 15.70. Found: C, 42.47; H, 7.12; N, 6.41; S, 14.07; Cl, 15.89.

(R)-7-Thia-1-azaspiro[4.5]decane 7,7-dioxide hydrochloride (1n(R)·HCl)

[α]D21 = −0.84° (c = 0.5, H2O).

(S)-7-Thia-1-azaspiro[4.5]decane 7,7-dioxide hydrochloride (1n(S)·HCl)

[α]D21 = 0.84° (c = 0.5, H2O).

General Procedure xii

Compound 11m or 20k (0.5 mol) was dissolved in acetonitrile (1800 mL). Sodium periodate (1.0 mol, 214 g) in water (3300 mL) was added. A catalytic amount (0.1–0.2 mol %) of RuCl3 was added. The reaction mixture was stirred for 1 h at rt. The reaction mixture was filtered through a layer of SiO2, and acetonitrile was evaporated. The aqueous layer was extracted with ethyl acetate (5 × 430 mL). The organic layer was dried over Na2SO4 and evaporated. The product was used in the next step without additional purification. The analytical sample was purified by flash column chromatography.

tert-Butyl 7-thia-1-azaspiro[4.4]nonane-1-carboxylate 7,7-dioxide (20l)

Yield = 129.40 g, 94%, white powder (mp = 76–77 °C). 1H NMR (500 MHz, chloroform-d) δ 3.84 (d, J = 13.0 Hz, 1H), 3.73–3.54 (m, 1H), 3.51–3.31 (m, 2H), 3.06 (dt, J = 13.2, 6.9 Hz, 1H), 2.93 (td, J = 18.0, 16.1, 9.3 Hz, 1H), 2.77 (d, J = 13.0 Hz, 1H), 2.40–2.26 (m, 1H), 2.12 (dt, J = 14.0, 7.4 Hz, 1H), 1.96 (m, 1H), 1.91–1.84 (m, 1H), 1.77 (q, J = 9.3 Hz, 1H), 1.48 (d, J = 39.1 Hz, 9H). 13C{1H} NMR (126 MHz, chloroform-d) δ 153.4, 152.9*, 81.7*, 80.2, 64.4, 64.3*, 58.0*, 56.3, 52.1*, 51.7, 48.1*, 47.7, 41.7*, 41.2, 34.1*, 33.6, 28.6*, 28.4, 22.6, 21.8* (*due to hindered rotation). LCMS, positive mode, m/z: 298.2 [M + Na]+. Anal calcd for C12H21NO4S: C, 52.34; H, 7.69; N, 5.09; S, 11.64. Found: C, 51.96; H, 7.40; N, 5.30; S, 11.62.

Benzyl 7-thia-1-azaspiro[4.5]decane-1-carboxylate 7,7-dioxide (11n)

Yield = 53.54 g, 89%, white solid (mp = 101–102 °C). 1H NMR (500 MHz, chloroform-d) δ 7.35 (s, 5H), 5.10 (s, 2H), 3.60–3.44 (m, 2H), 3.06–2.88 (m, 3H), 2.80 (d, J = 14.1 Hz, 1H), 2.72–2.61 (m, 1H), 2.53 (m, 1H), 2.14–1.93 (m, 3H), 1.83 (q, J = 7.0 Hz, 2H), 1.59 (m, 1H). 13C{1H} NMR (126 MHz, chloroform-d) δ 153.9, 136.5, 128.5, 128.1, 127.8, 66.6, 63.9, 56.4, 50.7, 47.6, 35.6, 31.8, 22.3, 19.9. LCMS, positive mode, m/z: 324 [M + H]+. Anal calcd for C16H21NO4S: C, 59.42; H, 6.54; N, 4.33; S, 9.91. Found: C, 59.63; H, 6.29; N, 4.01; S, 9.82.

General Procedure xiii

Ethylcarbamate (0.50 mol, 47 mL) and trimethyl allyl silane (0.58 mol, 48 mL) were added to a solution of ketone 2 (0.50 mol) in dry CH2Cl2 (1000 mL). The reaction mixture was cooled to 0 °C, and BF3·Et2O (0.5 mol, 82 mL) was added dropwise for 30 min. The mixture was further stirred at 0 °C for 1 h and overnight at rt. A saturated aqueous solution of NaHCO3 (1000 mL) was added carefully. The layers were separated; the organic layer was washed with water (250 mL), dried over Na2SO4, filtered, and evaporated. The residue was purified by column chromatography (H/EA = 9:1) to give the desired product.

Ethyl (4-allyltetrahydro-2H-thiopyran-4-yl)carbamate (12f)

Yield = 77.98 g, 68%, colorless oil. 1H NMR (500 MHz, chloroform-d) δ 5.72 (m, 1H), 5.16–5.01 (m, 2H), 4.36 (s, 1H), 4.05 (m, 2H), 2.78 (m, 2H), 2.45 (q, J = 5.5 Hz, 4H), 2.30 (d, J = 12.3 Hz, 2H), 1.71 (m, 2H), 1.23 (dt, J = 14.0, 6.6 Hz, 3H). 13C{1H} NMR (126 MHz, chloroform-d) δ 154.2, 132.2, 118.4, 59.9, 53.0, 42.6, 35.3, 23.1, 14.1. EIMS, 70 eV, m/z (rel. int.): 229 [M]+ (2); 189 (10); 188 (100); 154 (12); 142 (10); 116 (14); 99 (26); 82 (15); 41 (11). Anal calcd for C11H19NO2S: C, 57.61; H, 8.35; N, 6.11; S, 13.98. Found: C, 57.97; H, 8.64; N, 6.23; S, 13.84.

Ethyl (3-allyltetrahydro-2H-thiopyran-3-yl)carbamate (12m)

Yield = 87.15 g, 76%, yellow oil. 1H NMR (400 MHz, chloroform-d) δ 5.69 (m, 1H), 5.11–4.97 (m, 3H), 4.01 (q, J = 7.1 Hz, 2H), 2.87–2.78 (m, 1H), 2.66–2.54 (m, 2H), 2.42 (m, 2H), 2.33–2.24 (m, 1H), 2.16 (d, J = 14.1 Hz, 1H), 1.75 (m, 2H), 1.23 (m, 1H), 1.18 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (101 MHz, chloroform-d) δ 154.9, 132.9, 118.6, 60.2, 51.7, 42.4, 37.3, 33.5, 28.0, 23.1, 14.6. EIMS, 70 eV, m/z (rel. int.): 229 [M]+ (5); 188 (74); 142 (37); 141 (17); 140 (100); 116 (10); 112 (10); 99 (46); 96 (11); 82 (16); 80 (14); 79 (11); 45 (10); 41 (22); 39 (13). Anal calcd for C11H19NO2S: C, 57.61; H, 8.35; N, 6.11; S, 13.98. Found: C, 57.36; H, 8.71; N, 6.42; S, 14.24.

General Procedure xiv

KOH (2.1 mol, 118 g) and hydrazine monohydrate (1.2 mol, 62 mL) were added to a solution of protected amine 15 (0.15 mol) in ethyleneglycol (510 mL). The reaction mixture was heated to 155 °C and stirred for 72 h. Then reaction mixture was cooled to rt, diluted with water (720 mL), and extracted with CH2Cl2 (4 × 320 mL). The organic layer was dried over Na2SO4 and evaporated. The residue was dissolved in ethylacetate (100 mL) with further slow addition of saturated HCl solution in ethylacetate (80 mL). The mixture was cooled to 0 °C and stirred for 30 min. The white solid was filtered, washed with ethylacetate, and dried in vacuo.

8-Thia-1-azaspiro[4.5]decane hydrochloride (1f·HCl)

Yield = 20.34 g, 70%, white solid (mp = 179–181 °C, dec.). 1H NMR (400 MHz, DMSO-d6) δ 9.31 (s, 2H), 3.18 (s, 2H), 2.80–2.56 (m, 4H), 2.06–1.87 (m, 6H), 1.86–1.76 (m, 2H). 13C{1H} NMR (126 MHz, deuterium oxide) δ 66.5, 43.6, 34.4, 32.6, 24.1, 21.8. EIMS, 70 eV, m/z (rel. int.): 157 [M–Cl]+ (4); 129 (50); 96 (100); 84 ( 43); 83 (17); 41 (10). Anal calcd for C8H16NSCl: C, 49.60; H, 8.32; N, 7.23. Found: C, 49.79; H, 8.61; N, 7.63; S, 16.68; Cl, 18.41.

7-Thia-1-azaspiro[4.5]decane hydrochloride (1m·HCl):

Yield = 24.76 g, 71%, white solid (mp = 160–163 °C, dec.). 1H NMR (400 MHz, deuterium oxide) δ H4.66 (s, 1H), 3.26 (t, J = 6.9 Hz, 2H), 2.85–2.60 (m, 2H), 2.60–2.40 (m, 1H), 2.07–1.78 (m, 6H), 1.74 (s, 2H); the protons of the NH group are not observed due to the exchange. 13C{1H} NMR (126 MHz, chloroform-d) δ 65.3, 44.2, 35.7, 34.0, 33.2, 26.4, 23.8, 21.7. LCMS, positive mode, m/z: 158.2 [M–Cl]+. Anal calcd for C8H16ClNS: C, 49.60; H, 8.32; N, 7.23; S, 16.55; Cl, 18.30. Found: C, 49.52; H, 8.26; N, 7.23; S, 16.32; Cl, 17.95.

General Procedure xv

Ketone 2 (0.50 mol) was dissolved in a saturated solution of ammonia in MeOH (870 mL) and stirred for 20 min. Allyl pinacol boronate (0.80 mol, 120 mL) was added dropwise for 15 min. The reaction mixture was stirred at rt overnight. Then, MeOH was evaporated, and 1 M solution of HCl (300 mL) was added carefully. The solution was extracted with CH2Cl2 (300 mL). The water layer was basified with NaOH solution (until pH = 10) and extracted with CH2Cl2 (3 × 200 mL). The organic layer obtained was washed with brine (200 mL), dried over Na2SO4, and evaporated.

In the case of compounds 16p and 16r, ketone 2 (0.50 mol) was added into methanolic ammonia (1500 mL, w = 20%) and stirred for 20 min at rt. Allyl pinacol boronate (0.625 mol, 94 mL) was added, and the solution was stirred overnight. The solvent was evaporated under reduced pressure, and 10% citric acid solution (1500 mL) was added and washed with CH2Cl2 (3 × 375 mL). A solution of NaOH (20%) was added until the water layer became alkaline (pH = 10). The water solution was extracted with CH2Cl2 (3 × 375 mL). The combined organic layer was washed with water (4 × 375 mL), dried over Na2SO4, and evaporated.

4-Allyltetrahydro-2H-thiopyran-4-amine (16f)

Yield = 61.34 g, 78%, yellow oil. 1H NMR (500 MHz, chloroform-d) δ 5.77 (m, 1H), 5.12–4.99 (m, 2H), 2.79 (m, 2H), 2.43 (m, 2H), 2.05 (d, J = 7.4 Hz, 2H), 1.70 (m, 2H), 1.60 (m, 2H), 1.01 (s, 2H). 13C{1H} NMR (126 MHz, chloroform-d) δ 133.0, 118.9, 49.5, 48.1, 39.1, 24.1. LCMS, positive mode, m/z: 158 [M + H]+. Anal calcd for C8H15NS: C, 61.09; H, 9.61; N, 8.91; S, 20.38. Found: C, 61.08; H, 9.76; N, 9.25; S, 20.70.

3-Allyltetrahydrothiophen-3-amine (16k)

Yield = 58.02 g, 81%, light yellow oil. 1H NMR (400 MHz, chloroform-d) δ 5.88–5.72 (m, 1H), 5.21–5.00 (m, 2H), 2.95–2.70 (m, 3H), 2.48 (d, J = 10.6 Hz, 1H), 2.29 (d, J = 6.9 Hz, 2H), 1.86–1.68 (m, 2H), 1.49 (s, 2H). 13C{1H} NMR (126 MHz, chloroform-d) δ 134.0, 118.0, 63.4, 44.4, 43.6, 42.6, 28.8. EIMS, 70 eV, m/z (rel. int.): 145 (2); 144 [M + H]+ (4); 143 [M]+ (36); 102 (100); 100 (13); 96 (73); 85 (32); 82 (50); 69 (30); 68 (13); 57 (11); 56 (17); 54 (13); 42 (22); 41 (23); 39 (19). Anal calcd for C7H13NS: C, 58.69; H, 9.15; N, 9.78; S, 22.38. Found: C, 58.30; H, 8.94; N, 9.83; S, 22.41.

tert-Butyl 4-allyl-4-aminopiperidine-1-carboxylate (16p)

Yield = 110.56 g, 92%, yellow oil. 1H NMR (500 MHz, chloroform-d) δ 5.82 (m, 1H), 5.17–5.05 (m, 2H), 3.68–3.58 (m, 2H), 3.25 (m, 2H), 2.12 (d, J = 7.5 Hz, 2H), 1.50 (m, 3H), 1.44 (s, 9H), 1.33 (dt, J = 13.6, 3.9 Hz, 2H), 1.25–1.21 (m, 1H). 13C{1H} NMR (126 MHz, chloroform-d) δ 154.8, 133.1, 119.0, 79.3, 49.3, 48.0, 39.7, 37.5, 28.4. EIMS, 70 eV, m/z (rel. int.): 199 [M–(CH2—CH=CH2)]+ (50); 167 (17); 143 (100); 126 (20); 82 (73); 70 (50); 57 (85); 57 (25); 45 (16); 43 (30); 41 (50); 40 (22). Anal calcd for C13H24N2O2: C, 64.97; H, 10.07; N, 11.66. Found: C, 65.34; H, 10.19; N, 11.47.

tert-Butyl 3-allyl-3-aminopiperidine-1-carboxylate (16r)

Yield = 110.56 g, 92%, yellow oil. 1H NMR (400 MHz, chloroform-d) δ 5.89–5.74 (m, 1H), 5.14–5.03 (m, 2H), 3.26 (d, J = 71.9 Hz, 4H), 2.09 (qd, J = 13.5, 7.2 Hz, 2H), 1.63–1.45 (m, 4H), 1.41 (d, J = 2.3 Hz, 9H), 1.25–1.14 (m, 2H). 13C{1H} NMR (101 MHz, chloroform-d) δ 155.1, 133.1, 119.0, 79.5, 50.2, 43.5, 36.7, 28.4, 24.7, 24.6, 21.6. LCMS, positive mode, m/z: 241.2 [M + H]+. Anal calcd for C13H24N2O2: C, 64.97; H, 10.07; N, 11.66. Found: C, 65.14; H, 10.27; N, 11.82.

General Procedure xvi

Amine 16 (0.39 mol) was dissolved in CH2Cl2 (930 mL) under an argon atmosphere, triethylamine (0.47 mol, 35 mL) was added, and the reaction mixture was cooled to 0 °C. A solution of Boc2O (0.39 mmol, 81 mL) in CH2Cl2 (150 mL) was added dropwise for 15 min. The mixture was stirred at rt overnight, washed with 10% aq citric acid (2 × 300 mL) and brine (300 mL), dried over Na2SO4, and evaporated.

tert-Butyl (4-allyltetrahydro-2H-thiopyran-4-yl)carbamate (17f)

Yield = 95.36 g, 95%, colorless oil. 1H NMR (500 MHz, chloroform-d) δ 5.80–5.69 (m, 1H), 5.09 (m, 2H), 4.20 (s, 1H), 2.87–2.75 (m, 2H), 2.45 (d, J = 8.5 Hz, 4H), 2.29 (d, J = 13.8 Hz, 2H), 1.75–1.64 (m, 2H), 1.43 (s, 9H). 13C{1H} NMR (126 MHz, chloroform-d) δ 154.3, 132.8, 118.8, 53.3, 43.1, 35.8, 28.4, 27.4, 23.5. EIMS, 70 eV, m/z (rel. int.): 377 (2); 333 (2); 301 (1); 283 (1); 269 (1); 257 [M]+ (92); 239 (2); 230 (1); 216 (23); 160 (62); 116 (100); 96 (10); 82 (15); 58 (67); 57 (12); 44 (10); 41 (35); 39 (16). Anal calcd for C13H23NO2S: C, 60.66; H, 9.01; N, 5.44; S, 12.46. Found: C, 60.41; H, 8.95; N, 5.80; S, 12.74.

tert-Butyl (3-allyltetrahydrothiophen-3-yl)carbamate (17k)

Yield = 97.35 g, 100%, white powder (mp = 51–52 °C). 1H NMR (40 0 MHz, chloroform-d) δ 5.84–5.69 (m, 1H), 5.11–5.02 (m, 2H), 4.58 (s, 1H), 2.89–2.74 (m, 5H), 2.50 (dd, J = 14.1, 7.7 Hz, 2H), 1.74 (m, 1H), 1.39 (s, 9H). 13C{1H} NMR (126 MHz, chloroform-d) δ 154.5, 133.8, 118.5, 79.3, 65.6, 40.9, 39.5, 39.1, 28.6, 28.4. EIMS, 70 eV, m/z (rel. int.): 250 (2); 243 [M]+ (2); 235 (2); 227 (2); 128 (10); 127 (15); 126 (100); 102 (26); 96 (15); 85 (14); 57 (62); 56 (10); 41 (37); 39 (18). Anal calcd for C12H21NO2S: C, 59.22; H, 8.70; N, 5.76; S, 13.17. Found: C, 58.94; H, 8.33; N, 5.58; S, 13.57.

General Procedure xvii

Boc-protected amine 20 (0.20 mol) was dissolved in MeOH/HCl (245 mL) or dioxane/HCl (1300 mL) for 1f, 1k, or 1l, respectively, and stirred overnight at rt. Then, the reaction mixture was evaporated and treated with Et2O, and the solid was filtered and washed with Et2O to give the desired product as a hydrochloride salt.

8-Thia-1-azaspiro[4.5]decane hydrochloride (1f·HCl)

Yield = 36.81 g, 95%, white solid (mp = 179–181 °C, dec.).

7-Thia-1-azaspiro[4.4]nonane hydrochloride (1k·HCl)

Yield =44.48 g, 99%, white powder (mp = 127–129 °C, dec.). 1H NMR (400 MHz, deuterium oxide) δ 4.66 (d, J = 2.3 Hz, 2H), 3.30 (t, J = 6.3 Hz, 2H), 3.00–2.88 (m, 3H), 2.84 (m, 1H), 2.36–2.22 (m, 1H), 2.12 (m, 1H), 2.04 (m, 4H). 13C{1H} NMR (126 MHz, deuterium oxide) δ 76.5, 45.1, 38.5, 37.9, 32.9, 27.6, 23.1. LCMS, positive mode, m/z: 144 [M–Cl]+. Anal calcd for C7H14ClNS: C, 46.78; H, 7.85; N, 7.79; S, 17.84; Cl, 19.73. Found: C, 46.87; H, 7.58; N, 7.84; S, 18.19; Cl, 19.5.

7-Thia-1-azaspiro[4.4]nonane 7,7-dioxide hydrochloride (1l·HCl)

Yield = 97.51 g, 98%, white powder (mp = 204–205 °C, dec.). 1H NMR (400 MHz, DMSO-d6) δ 10.06 (s, 2H), 3.74 (d, J = 14.2 Hz, 1H), 3.59–3.46 (m, 2H), 3.39–3.16 (m, 3H), 2.64 (dt, J = 14.4, 7.3 Hz, 1H), 2.38 (dt, J = 14.8, 7.9 Hz, 1H), 2.15–1.89 (m, 4H). 13C{1H} NMR (126 MHz, DMSO-d6) δ 67.8, 57.2, 50.8, 44.0, 36.3, 31.5, 22.1. LCMS, positive mode, m/z: 176.0 [M–Cl + H]+. Anal calcd for C7H14ClNO2S: C, 39.72; H, 6.67; N, 6.62; S, 15.14; Cl, 16.75. Found: C, 39.37; H, 6.90; N, 6.58; S, 15.45; Cl, 17.12.

4-Azaspiro[2.4]heptane hydrochloride (1a·HCl)

Yield = 61.5 g, 92%, beige solid (mp = 80–81 °C, dec.). 1H NMR (400 MHz, DMSO-d6) δ 9.53 (s, 2H), 3.23 (p, J = 6.4 Hz, 2H), 2.06–1.93 (m, 2H), 1.89 (t, J = 7.1 Hz, 2H), 1.17 (t, J = 6.4 Hz, 2H), 0.82–0.73 (m, 2H). 13C{1H} NMR (126 MHz, deuterium oxide) δ 46.4, 42.6, 30.8, 23.5, 9.4. LCMS, positive mode, m/z: 98 [M–Cl]+. Anal calcd for C6H12ClN: C, 53.93; H, 9.05; N, 10.48; Cl, 26.53. Found: C, 53.76; H, 9.16; N, 10.57; Cl, 26.66.

General Procedure xviii

In the case of compounds 17p and 17r, starting amine 16 (0.46 mol) and triethylamine (0.69 mol, 51 mL) were added to 1660 mL of CH2Cl2, and the mixture was cooled to −15 °C. Trifluoroacetic acid anhydride (0.55 mol, 175 mL) was added dropwise over 1 h. Then, the reaction mixture was stirred overnight at rt. The reaction mixture was washed with 10% solution of citric acid (400 mL), dried over Na2SO4, and evaporated. The residue was purified by flash column chromatography to give targeted product 17.

tert-Butyl 4-allyl-4-(2,2,2-trifluoroacetamido)piperidine-1-carboxylate (17p)

Yield =146.98 g, 95%, yellow oil. 1H NMR (500 MHz, chloroform-d) δ 5.93 (s, 1H), 5.70 (m, 1H), 5.21–5.07 (m, 2H), 3.76 (m, J = 21.8 Hz, 2H), 3.06 (t, J = 11.3 Hz, 2H), 2.57 (s, 2H), 2.13 (s, 2H), 1.64 (m, 2H), 1.45 (s, 9H). 13C{1H} NMR (126 MHz, chloroform-d) δ 156.5 (q, J = 36.3 Hz), 154.6, 131.3, 120.1, 115.47 (q, J = 289.5 Hz), 79.9, 55.9, 41.1, 39.3, 33.6, 28.4. 19F NMR (470 MHz, chloroform-d) δ −76.0. LCMS, positive mode, m/z: 359 [M + Na]+. LCMS, negative mode, m/z (rel. int.): 336 [M]− (15); 335 [M–H]− (100). Anal calcd for C15H23F3N2O3: C, 53.56; H, 6.89; N, 8.33. Found: C, 53.62; H, 6.93; N, 8.09.

tert-Butyl 3-allyl-3-(2,2,2-trifluoroacetamido)piperidine-1-carboxylate (17r)

Yield = 139.25 g, 90%, yellow solid (mp =94–95 °C). 1H NMR (500 MHz, chloroform-d) δ 6.20 (s, 1H), 5.72 (m, 1H), 5.15 (dd, J = 24.1, 13.5 Hz, 2H), 4.21 (s, 1H), 4.02 (d, J = 13.6 Hz, 1H), 2.92–2.73 (m, 3H), 2.63 (s, 1H), 2.23 (s, 1H), 1.57 (d, J = 11.7 Hz, 3H), 1.47 (d, J = 1.6 Hz, 9H). 13C{1H} NMR (126 MHz, chloroform-d) δ 156.6 (q, J = 35.8 Hz), 154.3, 131.1, 119.9, 115.5 (q, J = 289.2 Hz), 80.9, 57.7, 51.6, 45.6, 39.9, 31.0, 28.1, 21.8. 19F NMR (470 MHz, chloroform-d) δ −76.1, −76.3. LCMS, positive mode, m/z: 359.2 [M + Na]+. LCMS, negative mode, m/z: 335.2 [M–H]−. Anal calcd for C15H23F3N2O3: C, 53.56; H, 6.89; N, 8.33. Found: C, 53.54; H, 6.50; N, 8.40.

General Procedure xix

N-Trifluoroacetyl-protected amine 20 (0.23 mol) was dissolved in dry MeOH (1160 mL). NaOH (0.46 mol, 18.4 g) was added by portions. The reaction mixture was stirred overnight, washed with water, dried over Na2SO4, and evaporated.

tert-Butyl 1,8-diazaspiro[4.5]decane-8-carboxylate (1p)

Yield = 51.96 g, 94%, yellow oil. 1H NMR (400 MHz, chloroform-d) δ 3.50 (m, 2H), 3.36–3.27 (m, 2H), 2.96 (t, J = 6.9 Hz, 2H), 1.91 (s, 1H), 1.78 (p, J = 7.1 Hz, 2H), 1.56 (t, J = 7.6 Hz, 2H), 1.53–1.46 (m, 4H), 1.43 (s, 9H). 13C{1H} NMR (126 MHz, chloroform-d) δ 154.8, 79.4, 60.3, 45.4, 41.5, 37.2, 36.5, 28.5, 25.2. EIMS, 70 eV, m/z (rel. int.): 240 [M]+; 184 (10); 183 (59); 167 (14); 139 (41); 97 (16); 96 (79); 95 (15); 84 (24); 83 (49); 82 (30); 57 (43); 56 (62); 55 (24); 50 (10); 44 (50); 42 (11); 41 (100); 40 (17); 39 (64); 38 (10). Anal calcd for C13H24N2O2: C, 64.97; H, 10.07; N, 11.66. Found: C, 65.31; H, 10.30; N, 11.57.

tert-Butyl 1,7-diazaspiro[4.5]decane-7-carboxylate (1r)

Yield = 36.92 g, 96%, yellow oil. 1H NMR (400 MHz, chloroform-d) δ 3.60–2.85 (m, 6H), 1.83–1.73 (m, 4H), 1.62 (tt, J = 12.2, 6.8 Hz, 2H), 1.53 (m, 3H), 1.41 (s, 9H). 13C{1H} NMR (126 MHz, chloroform-d) δ 155.2, 79.4, 60.6, 52.9, 45.6, 43.4, 37.3, 34.1, 28.5, 25.1, 23.3. LCMS, positive mode, m/z: 241.2 [M + H]+. Anal calcd for C13H24N2O2: C, 64.97; H, 10.07; N, 11.66. Found: C, 64.80; H, 10.08; N, 11.79.

General Procedure xx

A freshly prepared solution of lithium diisopropylamide (2.4 mol) in THF (2800 mL) was cooled to −80 °C. A solution of tert-butyl cyclopropanecarboxylate 21a (2 mol) in THF (100 mL) was slowly added dropwise for 10 min. The resulting solution was stirred at −80 °C for 5.5 h. A solution of allyl bromide (4 mol) in THF (1400 mL) was slowly added dropwise for 10 min. The solution was allowed to warm slowly from −80 to 0 °C for 4.5 h, and the obtained solution was removed from the cooling bath and quenched by addition of a saturated aqueous solution of NH4Cl (1700 mL). The aqueous phase was extracted with diethyl ether (2 × 1400 mL). The combined organic phases were washed with brine (1400 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was distilled in vacuo (bp = 25 °C, 0.75 mmHg).

tert-Butyl 1-allylcyclopropanecarboxylate (22a)

Yield = 295.3 g, 81%, colorless oil. 1H NMR (400 MHz, chloroform-d) δ 5.85 (m, 1H), 5.06–4.96 (m, 2H), 2.27 (d, J = 6.7 Hz, 2H), 1.42 (s, 9H), 1.12 (q, J = 4.0 Hz, 2H), 0.64 (q, J = 4.0 Hz, 2H). 13C{1H} NMR (101 MHz, chloroform-d) δ 174.1, 136.0, 115.9, 80.0, 37.5, 28.0, 23.4, 14.6. EIMS, 70 eV, m/z (rel. int.): 126 [M–(C(CH3)3) + H]+ (55); 111 (17); 109 (20); 83 (10); 81 (60); 80 (40); 77 (11); 67 (13); 57 (100); 53 (24); 43 (20); 41 (84); 40 (12); 39 (53). Anal calcd for C11H18O2: C, 72.49; H, 9.95. Found: C, 72.30; H, 9.69.

General Procedure xxi

A mixture of compound 22a (1.62 mol) with trifluoroacetic acid (1.94 mol, 330 mL) was refluxed for 2 h. The complete conversion was confirmed by NMR spectroscopy. The reaction mixture was cooled to 5 °C and poured to a diluted (15%) aqueous solution of NaOH to pH = 10. Byproducts were extracted with MTBE (2 × 600 mL), and the aqueous layer was acidified with diluted HCl to pH = 1–2. The target compound was extracted with MTBE (2 × 1800 mL), separated, dried, and evaporated to give the desired product.

1-Allylcyclopropanecarboxylic Acid (23a)

Yield = 163.49 g, 80%, colorless oil. 1H NMR (400 MHz, chloroform-d) δ 12.03 (s, 1H), 5.84 (m, 1H), 5.12–4.89 (m, 2H), 2.30 (d, J = 6.7 Hz, 2H), 1.27 (q, J = 4.1 Hz, 2H), 0.79 (q, J = 4.1 Hz, 2H). 13C{1H} NMR (101 MHz, chloroform-d) δ 182.3, 135.3, 116.5, 36.7, 22.6, 15.9. EIMS, 70 eV, m/z (rel. int.): 126 [M]+ (4); 125 (8); 124 (1); 122 (1); 11 (53); 108 (35); 98 (14); 97 (42); 83 (30); 81 (84); 80 (64); 79 (100); 77 (33); 70 (23); 68 (10); 67 (42); 66 (13); 65 (22); 55 (30); 54 (22); 53 (75); 52 (24); 51 (36); 50 (24); 45 (39); 43 (15); 42 (25); 41 (62); 40 (16); 39 (99); 38 (15). Anal calcd for C7H10O2: C, 66.65; H, 7.99. Found: C, 66.26; H, 7.93.

General Procedure xxii

A mixture of 23a (1.30 mol), DPPA (1.55 mol, 545 mL), and Et3N (1.55 mol, 115 mL) in tert-butyl alcohol (1400 mL) was heated to 80 °C and stirred overnight. The reaction mixture was evaporated, redissolved in EtOAc (1600 mL), and washed with a saturated solution of Na2CO3 (2 × 600 mL). The organic layer was separated, dried over Na2SO4, and concentrated. The product after work-up was used in the next step without further purification. The analytical sample was purified by column chromatography.

tert-Butyl(1-allylcyclopropyl)carbamate (17a)

Yield = 197.47 g, 77%, white solid (mp = 41–43 °C). 1H NMR (400 MHz, chloroform-d) δ 5.84–5.70 (m, 1H), 5.07–4.96 (m, 2H), 4.86 (br s, 1H), 2.25 (d, J = 7.2 Hz, 2H), 1.38 (s, 9H), 0.69 (s, 2H), 0.59 (s, 2H). 13C{1H} NMR (101 MHz, chloroform-d) δ 155.5, 135.0, 117.2, 79.1, 40.5, 32.7, 28.3, 12.9. EIMS, 70 eV, m/z (rel. int.): 141 [M–(C(CH3)3) + H]+ (3); 126 (20); 96 [M–Boc]+ (27); 82 (26); 69 (10); 59 (14); 57 (100); 56 (11); 41 (39); 39 (15). Anal calcd for C11H19NO2: C, 66.97; H, 9.71; N, 7.10. Found: C, 66.72; H, 10.00; N, 7.12.