Synthesis of Spirocyclic β- and γ-Sultams by One-Pot Reductive Cyclization of Cyanoalkylsulfonyl Fluorides

Article abstract of DOI:10.1002/ejoc.202000351

One-pot intramolecular cyclization of novel sp³-enriched cyanoalkylsulfonyl fluorides into spirocyclic β- or γ-sultams is disclosed. The method relies on nitrile group reduction followed by sulfonylation of amino group thus formed upon mild con

Full text of DOI:10.1002/ejoc.202000351

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: Synthesis of spirocyclic β- and γ-sultams by one-pot reductive
cyclization of cyanoalkylsulfonyl fluorides
Authors: Kateryna O. Stepannikova, Bohdan V. Vashchenko,
Oleksandr O. Grygorenko, Marian V. Gorichko, Artem Yu.
Cherepakha, Yurii S. Moroz, Yulian M. Volovenko, and Serhii
Zhersh
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202000351
Link to VoR: https://doi.org/10.1002/ejoc.202000351
0
1/2020

European Journal of Organic Chemistry
10.1002/ejoc.202000351
FULL PAPER
Synthesis of spirocyclic β- and γ-sultams by one-pot reductive
cyclization of cyanoalkylsulfonyl fluorides
[
a]
[a,b]
[a,b]
Kateryna O. Stepannikova, Bohdan V. Vashchenko,
Dr. Oleksandr O. Grygorenko,
[
b]
[a]
[b,c]
Dr. Marian V. Gorichko, Artem Yu. Cherepakha, Dr. Yurii S. Moroz,
[b]
[a,b]
Prof. Dr. Yulian M. Volovenko, Dr. Serhii Zhersh*
Dedicated to Prof. Andrey A. Tolmachev’s 63th anniversary
3
catalyzed degradation[8] and can be easily modified by N-
alkylation, which brings them closer to pyrrolidines as compared
to isosteric -lactams (pyrrolidones) with planar amide moiety.
Abstract: One-pot intramolecular cyclization of novel sp -enriched
cyanoalkylsulfonyl fluorides into spirocyclic β- or γ-sultams is
disclosed. The method relies on nitrile group reduction followed by
sulfonylation of amino group thus formed upon mild conditions
(NaBH
4
, NiCl
2
2
6H O in MeOH). Cyclization proceeds smoothly with
considerable efficiency (48–84%, 10 examples) on up to 30 g
scale. The cyanoalkylsulfonyl fluoride intermediates can be
obtained via S-nucleophilic substitution in β-functionalized
alkanenitriles or double alkylation of -alkylthioacetonitrile,
followed by oxidative chlorination with Cl
2
and further reaction with
3
KHF
2
. The title mono- and bifunctional sultams are advanced sp -
enriched building blocks for drug discovery and organic synthesis
providing novel substitution patterns and frameworks mimicking
saturated nitrogen heterocycles such as pyrrolidine/pyrrolidone.
Introduction
2 2
Since discovery of the first SO NH -containing antibacterial drug
Scheme 1. Comparison of -sultams, pyrrolidines and pyrrolidones
Prontosil in the 1932, sulfonamides have become indispensable
in drug discovery with about a hundred of FDA-approved drugs
present on the market to date.[1,2] Those include sulfanilamide
antibiotics, also known as “sulfa drugs" (Sulfanilamide,
Sulfamethoxazole), several important diuretics (i.e. Furosemide,
Hydrochlorothiazide) etc.[3,4] In turn, cyclic sulfonamides
Therefore -sultams can be considered as prominent building
[9]
blocks for lead-oriented synthesis – analogs of saturated
nitrogen heterocycles[8]
–
which allow “escaping from
flatland”[10,11] without considerable efforts.
(
sultams) provide an example of promising scaffolds with
A number of approaches to -sultams has been described in
manifold applications in modern drug discovery, i.e. anti-
inflammatory drug piroxicam, its prodrug ampiroxicam,[5,6] or
anticonvulsant sultiame.[7] -Sultam-based scaffolds provide
important physico-chemical properties to as compared to other
five-membered molecular frameworks (Scheme 1). In particular,
unlike saturated nitrogen heterocycles (i.e. pyrrolidines), -
sultams possess very low basicity, which is accompanied by
increased acidity and enhanced aqueous solubility. On the other
hand, -sultams are 3D-shaped, stable towards protease-
[12–21]
recent years (Scheme 2),
including intramolecular cycli-
[22–26]
zation of 3-aminopropane-1-sulfonyl chlorides (A),
or aryl
[27,28]
propane-1-sulfonates (B),
intramolecular N-alkylation of
(C),[29–37]
propane-1-sulfonamides
alkanesulfonamides (D),
double
alkylation
of
[38,39]
intramolecular C-alkylation of N-
[40–43]
substituted methanesulfonamides (E),
cyclizations of N-
allyl-1-halomethanesulfonamides (F),[44] and intramolecular
aliphatic C–H sulfonamidations (G).[45]
Most of these methods have been used for the synthesis of
monocyclic and fused bicyclic γ-sultams. While preparation of γ-
sultams bearing a spirocyclic fragment at the C-5 position have
been also presented in the literature,[46–50] their C-4-substituted
[
a]
K. O. Stepannikova, B. V. Vashchenko, Dr. O. O. Grygorenko,
A. Yu. Cherepakha, Dr. Yu. S. Moroz, Dr. S. Zhersh
Enamine Ltd. (www.enamine.net),
counterparts are underrepresented to date, being limited by
Chervonotkatska Street 78, Kyiv 02094, Ukraine
E-mail: zhersh@ukr.net
[51]
several 4,4-spirobi(-sultam) derivatives.
Keeping in mind
further possible applications in lead discovery projects, herein
[
b]
c]
B. V. Vashchenko, Dr. O. O. Grygorenko, Dr. M. V. Gorichko, Dr.
Yu. S. Moroz, Prof. Dr. Yu. M. Volovenko, Dr. S. Zhersh
Taras Shevchenko National University of Kyiv
Volodymyrska Street 60, Kyiv 01601, Ukraine
Dr. Yu. S. Moroz
we have aimed at preparation of spirocyclic building blocks 1a–h
3
(Figure 1) with high sp -atom fraction bearing alicyclic or
saturated heterocyclic moieties at the C-4 position of the sultam
ring.
[
Chemspace, Ilukstes iela 38-5, Riga LV-1082, Latvia
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.202000351
FULL PAPER
Table 1. Synthesis of intermediates 4 and 5
#
Starting
material
3a
3b
3c
Alcohol
Mesylate
(yield, %)
5a (91)
5b (93)
5c (95)
5d (94)
5e (89)
(yield, %)
4a (90)
4b (86)
4c (79)
4d (85)
4e (81)
1
2
3
4
5
(CH
(CH
(CH
(CH
(CH
2
2
2
2
2
)
)
)
)
)
2
3
4
5
2
3d
3e
O(CH
2
)
2
Subsequent incorporation of the sulfur atom was performed via
nucleophilic substitution in mesylates 5a–e with t-BuSH (Table
2
). While most tert-butyl sulfides 6a–c and 6e were obtained in
good yields (Table 2, Entries 1–3 and 5), cyclohexane derivative
d was formed in moderate yield (ca. 60%). Instead, when
Scheme 2. Approaches to mono- and disubstituted γ-sultams
6
reaction was performed with KSAc, thioacetate 7d was obtained
in 87% yield (Entry 4).
tert-Butyl sulfides 6a–c and 6e and thioacetate 7d smoothly
A proposed strategy to construct the spirocyclic scaffolds of 1
relied on reductive cyclization of previously unknown cyclic 2,2-
disubstituted 2-cyanoethane-sulfonyl fluorides 2 derived from
monocyclic ring systems (Scheme 2). Utility of the title
methodology for the preparation of other spirocyclic derivatives
underwent the oxidative chlorination with Cl
corresponding β-cyano sulfonyl chlorides 8a–e were obtained in
1–82% yield.
2
and the
6
Table 2. Preparation of sulfonyl chlorides 8a–e
(
e.g. β-sultams) was also to be validated.
#
Mesylate Sulfide or thio- Sulfonyl chlo-
acetate (%)[
a]
ride (%)[a]
8a (61)
8b (67)
8c (71)
8d (82)
8e (71)
6a (79)[
b]
1
2
3
4
5
(CH
(CH
(CH2)4
2
)
)
2
3
5a
5b
5c
5d
5e
6b (83)[
b]
2
6c (77)[b,c]
7d (87)[d]
6e (85)[b]
(CH
(CH
2
)
)
5
Figure 1. C-4-spirocyclic sultams 1a–h – targets molecules of this study
2
2
2 2
O(CH )
[
a]
Isolated yields [b] Method A: t-BuSH, K
2
3
CO , DMF, 70 °C (completion of the
reaction was monitored by 1H NMR) [c] Reaction was performed at 90 °C
Results and Discussion
[d]
Method B: KSAc, DMF, 70 °C, (completion of the reaction was monitored by
1H NMR)
The study commenced with preparation of 2,2-disubstituted 2-
cyanoethanesulfonyl fluorides 2a–h. The first step of the
reaction sequence included reduction of homologous
cyanoacetates 3a–d and tetrahydropyran derivative 3e with
Synthesis of heterocyclic nitriles 5f–h relied on chloromethyla-
tion of N-Boc protected 3-cyanoazetidine (3f), 3-cyanopyrrolidine
(3g) and 4-cyanopiperidine (3h). The reaction was performed via
NaBH
cyanoalcohols 4a–e in 79–90% yield (Table 1). Mesylation of
a–e in the presence of Et N in CH Cl led to corresponding
mesylates 5a–e (89–95% yield).
4
in DME – MeOH, which resulted in the corresponding β-
2
metallation with LDA at –78 °C followed by reaction with ClCH I,
which gave β-chloropropanenitriles 5f–h in 90–95% yield
(Scheme 3).
4
3
2
2
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.202000351
FULL PAPER
Table 4. Intramolecular reductive cyclization of 2a–h
Scheme 3. Synthesis of β-chloropropanenitriles 5f–h
#
Sulfonyl
chloride
8a
8b
8c
8d
8e
8f
Sulfonyl
fluoride (%)[
2a (87)
2b (89)
2c (94)
2d (94)
2e (90)
2f (77)
Sultam
(%)[a]
Reactions of heterocyclic derivatives 5f–h with S-nucleophiles
proceeded analogously to synthesis of 5a–e (Table 3). As it was
found, synthesis of thioacetates 7f and 7h was more efficient as
compared to corresponding tert-butyl sulfides 6f and 6h.
Moreover, the chlorination step proceeded with better outcome
for thioacetates 7f and 7h than for sulfides 6f and 6h.
a]
1
2
3
4
5
6
(CH
(CH
(CH
(CH
(CH
2
2
2
2
2
)
)
)
)
)
2
3
4
5
2
1a (61)
1b (71)
1c (82)
1d (78)
1e (84)
1f (74)
O(CH
2
)
2
Table 3. Preparation of sulfonyl chlorides 8f–h
7
8
8g
8h
2g (72)
2h (80)
1g (75)
1h (78)
[a]
Isolated yields
#
Cyclic
substituent
Chloride Sulfide or thio-
acetate (%)[
Sulfonyl chlo-
ride (%)
a]
[a]
1
2
3
6f (73)[b]
8f (60)
8f (63)
5
5
5
f
7f (80)[c]
[c]
Scheme 4. N-Deprotection of sultams 1g and 1h
g
h
7g (97)[c]
8g (71)[c]
4
5
6h (71)[b]
7h (93)[c]
8h (73)
8h (84)
Being inspired by aforementioned results, we have evaluated
the developed approach for synthesis of analogous spirocyclic
β-sultams. It should be noted that known approaches to β-
sultams (Scheme 5) relied on intermolecular reactions of α-
bromomethyl sulfonamides with α-halocarbonyl compounds
[c]
[
a]
Isolated yields [b] Method A: t-BuSH, K
2
3
CO , DMF, 60 °C (for 6f) or 70 °C (for
6
h), (completion of the reaction was monitored by 1H NMR) [c] Method B:
KSAc, DMF, 85 °C, 12 h
(
(
A),[52] [2 + 2] cycloadditions of sulfonyl chlorides with imines
B),[53–55] intramolecular alkylation of sulfonamides bearing a
Due to limited stability of the SO
conditions, they were transformed into the target sulfonyl
fluorides 2 by reaction of 8a–h with KHF in MeOH – H O (1:1,
v/v) (Table 4). The reaction proceeded smoothly at rt and gave
exclusively 2a–h in good to excellent yields (72–94%, 85%
average yield).
The key intramolecular reductive cyclization of SO
2
and the spirocyclic sultams 1a–h were obtained exclusively in
the one-pot reaction in 61–84% yield (Table 4).
Moreover, N-Boc-protecting group cleavage was successfully
performed for the case of monoprotected bifunctional sultams 1g
and 1h. Deprotection proceeded smoothly with 4 M HCl – 1,4-
dioxane at rt and gave corresponding hydrochlorides 9g and 9h,
both in quantitative yield (Scheme 4).
2
Cl derivatives 8 under reductive
[56,57]
leaving group at the β-position (C),
cyclization of β-amino sulfonyl chlorides (D).[
and intramolecular
44,58–66]
As in the
2
2
case of γ-sultams, the intramolecular reductive cyclization of
substituted α-cyano sulfonyl fluorides has never been reported
to date. To demonstrate possibility of such cyclyzations,
spirocyclic β-sultams 10a and 10b were selected as the
synthetic targets.
Synthesis of corresponding cyanomethanesulfonyl fluorides 11a
and 11b relied on the double alkylation of easily accessible 2-
(tert-butylthio)acetonitrile 12 (Scheme 6). The NaH-mediated
reaction of 12 with 1,3-dibromopropane 13a in DMF gave
cyclobutane derivative 14a in 62% yield, while 1-bromo-2-(2-
bromoethoxy)ethane 13b was used for preparation of
tetrahydropyrane-derived sulfide 14b (68% yield). The oxidative
chlorination proceeded smoothly for sulfides 14a and 14b, and
2
F-derivatives
6H O,
a–h was performed with NaBH in the presence of NiCl
4
2
2
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.202000351
FULL PAPER
the -sultam ring in the molecule of 1h adopts envelope
conformation in the solid state, with the nitrogen atom
outstanding of the mean plane formed by other ring atoms by
0.604 Å. This is somewhat different from the case of the
corresponding spirocyclic derivative 16 (Figure 3): although the
pyrrolidine ring also adopts the envelope conformation, it is the
spirocyclic carbon atom which outstands from the mean plane
formed by other five-membered ring atoms by 0.575 Å. Exit
vector plot (EVP) analysis[
67–70]
of the corresponding bifunctional
scaffolds shows that despite some differences, their overall
geometry is similar and corresponds to truly three-dimensional
relative disposition of the corresponding groups attached to the
variation points (Table 5).
Scheme 5. Approaches to β-sultams
Figure 2. ORTEP diagram of sultam 1h (thermal ellipsoids are shown at 50%
probability level)
Scheme 6. Synthesis of cyanomethanesulfonyl chlorides 15a and 15b
correspondding sulfonyl chlorides 15a and 15b were isolated in
80% and 87% yield, respectively.
Figure 3. ORTEP diagram of spirocyclic pyrrolidine 16 (thermal ellipsoids are
Finally, sulfonyl chlorides 15a and 15b were successfully
transformed into corresponding fluorides 11a and 11b in 77%
and 66% yield, respectively (Scheme 7). To our delight,
intramolecular cyclizations of 11a and 11b into β-sultams
proceeded smoothly upon the common conditions, despite the
fact that 10a and 10b were obtained in slightly lower yields (58%
and 63% yield, respectively) as compared to γ-counterparts 1a–
h, that were synthesized with 75% average yield. This might be
contributed to the general fact that the four-membered rings are
formed less efficiently than the five-membered ones.
shown at 30% probability level)
Table 5. EVP analysis of the spirocyclic scaffods of 1h and 16
#
1
2
X
r, Å

43.8
37.4
1
, deg

11.4
24.0
2
, deg
, deg
71.0
48.4
CH
SO
2
4.96
5.39
2
Conclusions
Intramolecular reductive cyclization of alicyclic and saturated
heterocyclic cyanoalkylsulfonyl fluorides is an efficient approach
for the preparation of spirocyclic β- and γ-sultams. The protocol
Scheme 7. Synthesis of β-sultams 10a and 10b
includes using NaBH
nitrile group reduction, that is accompanied with intramolecular
sulfonylation of amino group with the side chain SO F-functional
4
in presence of NiCl
2
6H
2
O in MeOH for
Molecular structure of sultam 1h was obtained by X-Ray
diffraction studies of single crystals (Figure 2). It was shown that
2
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.202000351
FULL PAPER
3
.57 (s, 2H), 2.99 (s, 1H), 1.28 – 1.17 (m, 2H), 1.01 – 0.89 (m, 2H). 13C
group. The method is scalable (up to 30 g), equally suitable for
both α- and β-cyano-substituted sulfonyl fluorides, and leads
exclusively to β-(48–53% yield, 2 examples) and γ-sultams (61–
NMR (126 MHz, CDCl3) δ 122.5, 65.5, 12.7, 12.0. GC/MS (EI): m/z = 66
+
+
[
M-CH2OH] , 97 [M] . Anal. Cald. for C5H7NO: C 61.84; H 7.27; N 14.42.
Found: C 62.19; H 7.62; N 14.36.
84% yield, 8 examples), respectively.
1-(Hydroxymethyl)cyclobutanecarbonitrile (4b). The crude compound
Preparation of the previously unknown β-cyano sulfonyl fluorides
was performed via mesylation of β-hydroxy nitriles or chloro-
methylation of heterocyclic nitriles, followed by incorporation of
the sulfur atom via nucleophilic substitutions with t-BuSH or
was purified by distillation in vacuo. Yield 34.4 g (86%); colorless liquid;
bp 67–70 °C / 0.2 mmHg). 1H NMR (400 MHz, CDCl3) δ 3.75 (s, 2H),
2
.79 (s, 1H), 2.49 – 2.41 (m, 2H), 2.19 – 2.09 (m, 3H), 2.04 – 1.97 (m,
H). 13C NMR (126 MHz, CDCl3) δ 123.6, 65.8, 37.3, 28.4, 16.7. GC/MS
1
KSAc. Subsequent oxidative chlorination with Cl
2
and reaction
(EI): m/z = 111 [M]+. Anal. Cald. for C H NO: C 64.84; H 8.16; N 12.60.
6 9
with KHF gave SO F-derivatives. To obtain α-cyano sulfonyl
2
2
Found: C 65.11; H 8.55; N 12.44.
-(Hydroxymethyl)cyclopentanecarbonitrile
fluorides, double alkylation of 2-(tert-butylthio)acetonitrile was
used, which was followed by the transformations mentioned
above for the homologous counterparts.
1
(4c).
The
crude
compound was purified by distillation in vacuo. Yield 35.6 g (79%);
colorless liquid; bp 82–84 °C / 0.2 mmHg). 1H NMR (400 MHz, CDCl3) δ
3
.58 (s, 2H), 2.75 (s, 1H), 2.12 – 1.97 (m, 2H), 1.89 – 1.62 (m, 6H). 13C
The title mono- and bifunctional sultams can be considered as
analogs of common saturated nitrogen heterocycles – advanced
building blocks for modern organic chemistry and lead-oriented
synthesis. In particular, replacement of spirocyclic pyrrolidine
derivatives with the corresponding three-dimensional sulfon-
amide analogues can be envisaged, which is confirmed by
crystallographic studies and exit vector plot (EVP) analysis of
the corresponding bifunctional scaffods.
NMR (126 MHz, CDCl3) δ 124.8, 66.7, 45.2, 34.7, 24.8. GC/MS (EI): m/z
+
=
125 [M] . Anal. Cald. for C7H11NO: C 67.17; H 8.86; N 11.19. Found: C
67.26; H 8.88; N 11.41.
1
-(Hydroxymethyl)cyclohexanecarbonitrile (4d).[74,75] Yield 42.6
g
1
(85%); colorless liquid. H NMR (400 MHz, CDCl3) δ 3.60 (s, 2H), 2.57 (s,
1
H), 2.01 (d, J = 13.3 Hz, 2H), 1.82 – 1.71 (m, 3H), 1.61 (td, J = 13.3, 3.4
Hz, 2H), 1.27 (td, J = 13.3, 3.4 Hz, 2H), 1.23 – 1.07 (m, 1H). 13C NMR
(
=
126 MHz, CDCl3) δ 122.9, 68.8, 42.2, 31.9, 25.4, 22.6. GC/MS (EI): m/z
122 [M–CN] , 139 [M] . Anal. Cald. for C8H13NO: C 69.03; H 9.41; N
+
+
10.06. Found: C 68.73; H 9.32; N 9.98.
Experimental Section
4-(Hydroxymethyl)tetrahydro-2H-pyran-4-carbonitrile (4e). The crude
compound was purified by distillation in vacuo. Yield 41.2 g (81%);
colorless oil; bp 108–111 °C (0.2 mmHg). 1H NMR (400 MHz, CDCl3) δ
3.96 (dq, J = 12.2, 1.9 Hz, 2H), 3.67 (td, J = 12.2, 1.9 Hz, 2H), 3.61 (s,
2H), 2.79 (s, 1H), 1.87 (dd, J = 13.7, 1.9 Hz, 2H), 1.60 (ddd, J = 13.7,
12.2, 4.6 Hz, 2H). 13C NMR (126 MHz, CDCl3) δ 121.9, 68.4, 64.5, 40.0,
The solvents were purified according to the standard procedures.[71]
Compounds 3a–h, 12, 13a, 13b and 16 were available from Enamine
Ltd. All other starting materials were purchased from commercial
sources. Melting points were measured on MPA100 OptiMelt automated
melting point system. Column chromatography was performed using
Kieselgel Merck 60 (230–400 mesh) as the stationary phase. 1H, 13C and
+
31.7. GC/MS (EI): m/z = 141 [M] . Anal. Cald. for C7H11NO2: C 59.56; H
7.85; N 9.92. Found: C 59.19; H 8.1; N 10.29.
19F
NMR spectra were recorded on
a
Bruker 170 Avance 500
General procedure for the preparation of 5a–e. Et3N (34.1 mL, 24.8 g,
1
13
spectrometer (at 500 MHz for H NMR, 126 MHz for C NMR and 470
MHz for 19F NMR) and Varian Unity Plus 400 spectrometer (at 400 MHz
for 1H NMR, 101 MHz for 13C NMR and 376 MHz for 19F NMR). NMR
chemical shifts are reported in ppm (δ scale) downfield from TMS as an
internal standard and are referenced using residual NMR solvent peaks
at 7.26 and 77.16 ppm for 1H and 13C in CDCl3, 2.50 and 39.52 ppm for
1H and 13C in DMSO-d6. Coupling constants (J) are shown in Hz. Spectra
are reported as follows: chemical shift (δ, ppm), multiplicity, integration,
coupling constants (Hz). Elemental analyses were performed at the
Laboratory of Organic Analysis, Department of Chemistry, Taras
Shevchenko National University of Kyiv. Mass spectra were recorded on
an Agilent 1100 LCMSD SL instrument (chemical ionization (CI)) and
Agilent 5890 Series II 5972 GCMS instrument (electron impact ionization
0
.245 mol) was added to the corresponding alcohol 4a–e (0.204 mol) in
CH2Cl2 (200 mL), and the resulting solution was cooled to 0 °C. Then,
MsCl (17.4 mL, 25.7 g, 0.224 mol) was added dropwise at 0 °C, the
reaction mixture was stirred at rt for 12 h, and washed with H2O (200
mL). The organic layer was separated, dried over Na2SO4 and
evaporated in vacuo. Unless other is specified, the crude compound was
purified by column chromatography on silica gel using 40 g RediSep
column (flow rate: 40 mL / min, rack: 16 mm  150 mm tubes) and
gradient hexanes – t-BuOMe as eluent.
(1-Cyanocyclopropyl)methyl methanesulfonate (5a). Yield 32.5
g
(91%); yellowish oil. 1H NMR (400 MHz, CDCl3) δ 4.11 (s, 2H), 3.05 (s,
3H), 1.42 – 1.33 (m, 2H), 1.17 – 1.08 (m, 2H). 13C NMR (101 MHz,
CDCl3) δ 120.8, 71.7, 38.1, 13.5, 10.2. LC/MS (CI): m/z = 176 [M+H]+.
Anal. Cald. for C6H9NO3S: C 41.13; H 5.18; N 7.99; S 18.3. Found: C
41.08; H 4.83; N 7.84; S 18.40.
(EI)). Single crystals of 1h and 16(16CO2)H2O were obtained by slow
evaporation of their solutions in hexanes – THF (1:1, v/v) and MeCN,
respectively. CCDC 1990716 (1h) and CCDC 1990717 (16) contain the
supplementary crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
(
(
2
1-Cyanocyclobutyl)methyl methanesulfonate (5b). Yield 35.9
g
93%); yellow oil. 1H NMR (400 MHz, CDCl3) δ 4.33 (s, 2H), 3.09 (s, 3H),
.60 – 2.52 (m, 2H), 2.28 – 2.17 (m, 3H), 2.13 – 2.05 (m, 1H). 13C NMR
General procedure for the preparation of 4a–e. To a solution of ester
(126 MHz, CDCl3) δ 121.6, 70.1, 37.9, 34.9, 28.8, 16.6. GC/MS (EI): m/z
= 95 [M-OSO2CH3] , 189 [M] . Anal. Cald. for C7H11NO3S: C 44.43; H
5.86; N 7.40; S 16.94. Found: C 44.14; H 5.88; N 7.35; S 16.55.
+
+
3a–e (0.360 mol) in dimethoxyethane - MeOH (600 mL, 5:1, v/v), NaBH4
(27.2 g, 0.720 mol) was added in portions at 0 °C over 3 h. The reaction
mixture was warmed up to rt and stirred for 24 h. The resulting solution
was diluted with H2O (700 mL), and extracted with CH2Cl2 (3400 mL).
Combined organic layers were dried over Na2SO4 and evaporated in
vacuo.
(
(
3
1-Cyanocyclopentyl)methyl methanesulfonate (5c). Yield 39.4 g
95%); colorless liquid. 1H NMR (400 MHz, CDCl3) δ 4.16 (s, 2H), 3.09 (s,
H), 2.22 – 2.08 (m, 2H), 1.96 – 1.82 (m, 2H), 1.82 – 1.69 (m, 4H). 13
C
NMR (126 MHz, CDCl3) δ 122.6, 70.9, 42.7, 37.9, 35.2, 24.5. GC/MS
(EI): m/z = 108 [M-OMs] , 203 [M] . Anal. Cald. for C8H13NO3S: C 47.27;
+
+
-(Hydroxymethyl)cyclopropanecarbonitrile (4a).[72,73] The crude
1
H 6.45; N 6.89; S 15.77. Found: C 47.66; H 6.53; N 6.94; S 16.09.
compound was purified by distillation in vacuo. Yield 31.5 g (90%);
colorless liquid; bp 60–63 °C / 0.2 mmHg. 1H NMR (400 MHz, CDCl3) δ
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.202000351
FULL PAPER
(
(
3
1-Cyanocyclohexyl)methyl methanesulfonate (5d). Yield 41.7
94%); colorless liquid. 1H NMR (500 MHz, CDCl3) δ 4.12 (s, 2H), 3.07 (s,
H), 2.00 (d, J = 12.9 Hz, 2H), 1.81 – 1.74 (m, 3H), 1.60 (qt, J = 12.9, 3.4
Hz, 2H), 1.32 (td, J = 12.9, 3.4 Hz, 2H), 1.19 (qt, J = 12.2, 4.4 Hz, 1H).
g
mL) was heated at 70 °C. Completion of the reaction was monitored by
H NMR. Then, the reaction mixture was diluted with H2O (400 mL) and
1
extracted with EtOAc (3200 mL). Combined organic layers were
washed with H2O (2200 mL), dried over Na2SO4 and evaporated in
vacuo. Unless other is specified, the crude compound was purified by
column chromatography on silica gel using 40 g RediSep column (flow
rate: 40 mL / min, rack: 16 mm  150 mm tubes) and gradient hexanes –
t-BuOMe as eluent.
1
3
C NMR (126 MHz, CDCl3) δ 120.8, 72.8, 39.7, 37.7, 31.9, 25.0, 22.2.
+
+
GC/MS (EI): m/z = 122 [M-OMs] , 217 [M] . Anal. Cald. for C9H15NO3S: C
9.75; H 6.96; N 6.45; S 14.76. Found: C 49.86; H 7.17; N 6.28; S 15.09.
4
(4-Cyanotetrahydro-2H-pyran-4-yl)methyl methanesulfonate (5e).
The crude compound was purified by flash chromatography (5 bar) on
silica gel using 40 g column gradient hexanes – t-BuOMe as eluent. Yield
1
-((tert-Butylthio)methyl)cyclopropanecarbonitrile (6a). Yield 16.6 g
79%); colorless oil. 1H NMR (400 MHz, CDCl3) δ 2.66 (s, 2H), 1.30 (s,
(
9
3
3
1
9.8 g (89%); colorless oil. 1H NMR (500 MHz, CDCl3) δ 4.18 (s, 2H),
.99 (dd, J = 12.3, 4.5 Hz, 2H), 3.69 (t, J = 12.3 Hz, 2H), 3.11 (s, 3H),
.91 (d, J = 13.2 Hz, 2H), 1.69 (td, J = 13.2, 4.5 Hz, 2H). 13C NMR (126
H), 1.29 – 1.25 (m, 2H), 0.96 – 0.91 (m, 2H). 13C NMR (126 MHz,
+
CDCl3) δ 122.7, 42.6, 33.5, 30.9, 14.5, 10.2. GC/MS (EI): m/z = 169 [M] .
Anal. Cald. for C9H15NS: C 63.85; H 8.93; N 8.27; S 18.94. Found: C
MHz, CDCl3) δ 119.9, 72.0, 63.9, 37.8, 37.7, 31.6. GC/MS (EI): m/z =
6
3.79; H 8.9; N 8.41; S 18.97.
+
+
+
1
24 [M-OMs] , 141 [M–H2C=SO2] , 219 [M] . Anal. Cald. for C8H13NO4S:
C 43.82; H 5.98; N 6.39; S 14.62. Found: C 44.00; H 6.35; N 6.43; S
4.68.
1-((tert-Butylthio)methyl)cyclobutanecarbonitrile (6b). The crude
compound was purified by flash chromatography (5 bar) on silica gel
1
using 80 g column gradient hexanes – t-BuOMe as eluent. Yield 18.9 g
General procedure for the preparation of chloromethyl derivatives
f–h. 2.1 M LDA (31.4 mL, 65.9 mmol) in THF was added dropwise to a
solution of corresponding nitrile 3f–h (54.9 mmol) in THF (100 mL) at –
83%); yellowish oil. 1H NMR (500 MHz, CDCl3) δ 2.85 (s, 2H), 2.54 –
(
5
2.48 (m, 2H), 2.21 – 2.13 (m, 3H), 2.06 – 1.98 (m, 1H), 1.33 (d, J = 1.1
13
Hz, 9H). C NMR (126 MHz, CDCl3) δ 123.8, 42.5, 36.0, 35.5, 31.9,
7
7
8 °C under argon atmosphere. The reaction mixture was stirred at –
8 °C for 1 h, and a solution of СlСH2I (14.9 g, 82.3 mmol) in THF (30
+
30.9, 16.5. GC/MS (EI): m/z = 183 [M] . Anal. Cald. for C10H17NS: C
65.52; H 9.35; N 7.64; S 17.49. Found: C 65.53; H 9.24; N 7.49; S 17.47.
мл) was added dropwise at –78 °C. The resulting mixture was warmed
up to rt, stirred for 1 h, and H2O (100 mL) was added. The misture was
extracted with EtOAс (2100 mL), combined organic layers were dried
over Na2SO4, and evaporated in vacuo.
1
-((tert-Butylthio)methyl)cyclopentanecarbonitrile (6c). The reaction
was performed at 90 °C. The crude compound was purified by flash
chromatography (5 bar) on silica gel using 40
hexanes – t-BuOMe as eluent. Yield 18.8 g (77%); yellowish oil. 1H NMR
g column gradient
tert-Butyl 3-(chloromethyl)-3-cyanoazetidine-1-carboxylate (5f). The
crude compound was purified by column chromatography on silica gel
using 80 g RediSep column (flow rate: 60 mL / min, rack: 16 mm  150
mm tubes) and gradient hexanes – t-BuOMe as eluent. Yield 11.4 g
(400 MHz, CDCl ) δ 2.72 (s, 2H), 2.17 – 2.06 (m, 2H), 1.87 – 1.76 (m,
3
2H), 1.75 – 1.65 (m, 4H), 1.29 (s, 9H). 13C NMR (126 MHz, CDCl ) δ
3
124.5, 43.5, 42.6, 37.9, 35.9, 30.8, 24.4. GC/MS (EI): m/z = 197 [M]+.
Anal. Cald. for C11H19NS: C 66.95; H 9.71; N 7.1; S 16.25. Found: C
67.18; H 9.35; N 7.05; S 16.49.
(
(
90%); yellowish solid; mp 81–83 °C. 1H NMR (400 MHz, CDCl3) δ 4.27
d, J = 9.1 Hz, 2H), 3.96 (d, J = 9.1 Hz, 2H), 3.84 (s, 2H), 1.44 (s, 9H).
4
-((tert-Butylthio)methyl)tetrahydro-2H-pyran-4-carbonitrile
(6e).
1
3
C NMR (126 MHz, CDCl3) δ 155.5, 119.1, 81.3, 56.3, 46.2, 33.0, 28.4.
Yield 22.5 g (85%); colorless oil. 1H NMR (400 MHz, CDCl3) δ 3.89 (ddd,
+
LC/MS (CI): m/z = 131 [M–CO2–(H3C)2C=CH2+H] . Anal. Calcd. for
J = 12.2, 4.6, 1.9 Hz, 2H), 3.62 (td, J = 12.2, 1.9 Hz, 2H), 2.66 (s, 2H),
C10H15ClN2O2: C 52.07; H 6.55; N 12.14; Cl 15.37. Found: C 52.17; H
1
1
.87 (dd, J = 13.4, 1.9 Hz, 2H), 1.62 (ddd, J = 13.4, 12.2, 4.6 Hz, 2H),
.28 (s, 9H). 13C NMR (126 MHz, CDCl3) δ 121.6, 64.6, 42.8, 37.9, 37.6,
6.19; N 12.39; Cl 15.17.
+
+
tert-Butyl 3-(chloromethyl)-3-cyanopyrrolidine-1-carboxylate (5g).
The crude compound was purified by column chromatography on silica
gel using 80 g RediSep column (flow rate: 60 mL / min, rack: 16 mm 
35.0, 30.8. GC/MS (EI): m/z = 157 [M–H2C=C(CH3)3] , 198 [M–Me] , 213
[M] . Anal. Cald. for C11H19NOS: C 61.93; H 8.98; N 6.57; S 15.03.
+
Found: C 61.84; H 9.13; N 6.89; S 15.02.
1
50 mm tubes) and gradient hexanes – t-BuOMe as eluent. The
compound was obtained as ca. 1:1 mixture of rotamers. Yield 12.8 g
95%); yellow oil. 1H NMR (400 MHz, CDCl3) δ 3.92 – 3.76 (m, 1H), 3.71
tert-Butyl 3-((tert-butylthio)methyl)-3-cyanoazetidine-1-carboxylate
(6f). The reaction was performed at 60 °C. The crude compound was
(
purified by flash chromatography (5 bar) on silica gel using 40 g column
gradient hexanes – t-BuOMe as eluent. Yield 25.7 g (73%); colorless oil.
–
1
1
3
1
3.62 (m, 2H), 3.58 (s, 2H), 3.49 (d, J = 11.6 Hz, 1H), 2.47 – 2.33 (m,
H), 2.23 – 2.08 (m, 1H), 1.46 (s, 9H) ppm. 13C NMR (126 MHz, CDCl3) δ
53.8, 120.2, 80.7, 53.5 and 53.4, 46.0, 45.0, 44.3 and 44.1, 34.7 and
3.9, 28.5 ppm. GC/MS (EI): m/z = 144/146 [M–CO2–H2C=C(CH3)2] ,
71/173 [M–Ot-Bu] , 188/190 [M–H2C=C(CH3)2] , 209 [M–Cl] , 244/246
1
H NMR (400 MHz, CDCl3) δ 4.19 (d, J = 8.8 Hz, 2H), 3.87 (d, J = 8.8 Hz,
H), 2.94 (s, 2H), 1.39 (s, 9H), 1.31 (s, 9H). 13C NMR (126 MHz, CDCl3)
2
+
δ 155.5, 120.6, 80.7, 57.6, 43.2, 34.2, 31.0, 30.8, 28.3. GC/MS (EI): m/z
+
+
+
+
+
=
229 [M–H2C=C(CH3)3] , 284 [M] . Anal. Cald. for C14H24N2O2S: C
+
[
M] . Anal. Calcd. for C11H17ClN2O2: C 53.99; H 7.00; N 11.45; Cl 14.49.
59.12; H 8.51; N 9.85; S 11.27. Found: C 58.73; H 8.18; N 9.48; S 11.35.
Found: C 54.07; H 7.33; N 11.50; Cl 14.79.
tert-Butyl 4-((tert-Butylthio)methyl)-4-cyanopiperidine-1-carboxylate
6h). The compound existed as a mixture of ca. 1:1 rotamers. Yield 27.5
g (71%); colorless crystals; mp 82–83 °C. 1H NMR (400 MHz, CDCl3) δ
tert-Butyl 4-(chloromethyl)-4-cyanopiperidine-1-carboxylate (5h).
The crude compound was purified by column chromatography on silica
gel using 80 g RediSep column (flow rate: 60 mL / min, rack: 16 mm 
(
4
1
1
.27 – 4.02 (m, 2H), 3.01 (t, J = 10.9 Hz, 2H), 2.70 (s, 1H) and 2.69 (s,
H), 1.96 (d, J = 13.4 Hz, 2H), 1.60 – 1.49 (m, 2H), 1.44 (s, 4.5H) and
.43 (s, 4.5H), 1.32 (s, 4.5H) and 1.32 (s, 4.5H). 13C NMR (101 MHz,
1
(
50 mm tubes) and gradient CHCl3 – MeCN as eluent. Yield 12.8 g
90%); colorless solid; mp 113–115 °C. 1H NMR (400 MHz, CDCl3) δ
.33 – 4.07 (m, 2H), 3.56 (s, 2H), 3.13 – 2.93 (m, 2H), 2.04 (d, J = 12.9
4
CDCl3) δ 154.4, 121.4, 80.1, 42.9, 40.7, 39.0, 37.3, 34.4, 30.8, 28.4.
Hz, 2H), 1.49 (td, J = 12.9, 4.4 Hz, 2H), 1.45 (s, 9H). 13C NMR (126 MHz,
+
+
GC/MS (EI): m/z = 212 [M–CO2–H2C=C(CH3)2] , 239 [M–Ot-Bu] , 256
[
CDCl3) δ 154.4, 119.9, 80.4, 49.6, 41.0, 40.7, 32.9, 28.5. GC/MS (EI):
+
M–H2C=C(CH3)2] . Anal. Cald. for C16H28N2O2S: C 61.5; H 9.03; N 8.97;
+
+
m/z = 185/187 [M–Ot-Bu] , 258/260 [M] . Anal. Calcd. for C12H19ClN2O2:
S 10.26. Found: C 61.23; H 8.63; N 9.20; S 10.56.
C 55.70; H 7.40; N 10.83; Cl 13.70. Found: C 55.67; H 7.36; N 11.07; Cl
General procedure for the preparation of thioacetates 7d and 7f–h.
KSAc (19.8 g, 0.174 mol) was added to a solution of the corresponding
mesylate or chloride (0.124 mol) in DMF (625 mL). The reaction mixture
was stirred at 85 °C for 12 h, then cooled to rt and evaporated in vacuo at
1
3.85.
General procedure for the preparation of tert-butyl sulfides 6a–h. A
mixture of the corresponding mesylate or chloride (0.124 mol), t-BuSH
(16.8 mL, 13.4 g, 0.149 mol) and K2CO3 (20.6 g, 0.149 mol) in DMF (200
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.202000351
FULL PAPER
+
85 °C to ca. 150 mL volume. The residue was diluted with H2O (1000
18.1. GC/MS (EI): m/z = 169 [M] . Anal. Calcd. for C9H15NS: C 63.85; H
mL) and extracted with EtOAc (4125 mL). Combined organic layers was
washed with brine (4125 mL), dried over Na2SO4 and evaporated in
vacuo.
8.93; N 8.27; S 18.94. Found: C 64.14; H 9.26; N 7.91; S 19.14.
4-(tert-Butylthio)tetrahydro-2H-pyran-4-carbonitrile (14b). The crude
compound was purified by column chromatography on silica gel using
40g RediSep column (flow rate: 40 mL / min, rack: 16 mm  150 mm
tubes) and gradient t-BuOMe – MeOH as eluent. Yield 21.0 g (68%);
colorless oil. 1H NMR (500 MHz, CDCl3) δ 3.92 (dt, J = 11.7, 3.8 Hz, 2H),
3.71 (dd, J = 11.7, 2.3 Hz, 2H), 2.15 (dq, J = 13.6, 2.3 Hz, 2H), 1.95 (ddd,
J = 13.6, 11.7, 3.8 Hz, 2H), 1.51 (s, 9H). 13C NMR (126 MHz, CDCl ) δ
121.3, 64.2, 48.1, 39.2, 38.0, 32.3. GC/MS (EI): m/z = 199 [M] . Anal.
S-((1-Cyanocyclohexyl)methyl) ethanethioate (7d). The crude
compound was purified by column chromatography on silica gel using 40
g RediSep column (flow rate: 40 mL / min, rack: 16 mm  150 mm tubes)
and gradient hexanes – t-BuOMe as eluent. Yield 21.3 g (87%); yellowish
liquid. 1H NMR (500 MHz, CDCl3) δ 3.12 (s, 2H), 2.39 (s, 3H), 1.98 (d, J
3
+
=
13.2 Hz, 2H), 1.80 – 1.69 (m, 3H), 1.59 (q, J = 13.2 Hz, 2H), 1.36 –
.26 (m, 2H), 1.21 – 1.12 (m, 1H). 13C NMR (126 MHz, CDCl3) δ 193.9,
Calcd. for C10H17NOS: C 60.26; H 8.60; N 7.03; S 16.09. Found: C 60.01;
H 8.88; N 7.03; S 16.19.
1
1
22.0, 40.3, 37.6, 34.8, 30.5, 25.0, 22.9. GC/MS (EI): m/z = 122 [M–
+
+
+
+
SAc] , 155 [M–H2CCC(O)] , 182 [M–Me] , 197 [M] . Anal. Cald. for
General procedure for the preparation of sulfonyl chlorides 8a–h,
C10H15NOS: C 60.88; H 7.66; N 7.10; S 16.25. Found: C 61.08; H 8.01; N
15a and 15b. A solution of the corresponding tert-butyl sulfide 6 or
7.23; S 16.35.
thioacetate 7 (0.180 mmol) in CH2Cl2 – H2O (450 mL, 2:1, v/v) was
cooled to 0 °C, and Cl2 was bubbled through the reaction mixture at 0 °C
for 1 h (CAUTION! Gaseous Cl₂ is toxic, has irritating odor, strong
oxidizing agent. The experiments with gaseous Cl2 must be performed
carefully and accurately, while the temperature of the reaction mixture
should not exceed 5 °C). The organic phase was separated, and the
aqueous phase was washed with CH2Cl2 (300 mL). Combined organic
phases were washed with H2O (300 mL), dried over Na2SO4 and
evaporated in vacuo. Unless other is specified, the crude compound was
purified by column chromatography on silica gel using 80 g or 330 g
RediSep column (flow rate: 60 mL / min or 100 mL / min, respectively,
rack: 16 mm  150 mm tubes) and hexanes – t-BuOMe followed by
gradient hexanes – EtOAc as eluents.
tert-Butyl 3-((acetylthio)methyl)-3-cyanoazetidine-1-carboxylate (7f).
The crude compound was purified by column chromatography on silica
gel using 80 g RediSep column (flow rate: 60 mL / min, rack: 16 mm 
1
50 mm tubes) and gradient CHCl3 – MeCN as eluent. Yield 26.8 g (80
); yellow oil. 1H NMR (400 MHz, CDCl3) δ 4.22 (d, J = 8.9 Hz, 2H), 3.85
%
d, J = 8.9 Hz, 2H), 3.43 (s, 2H), 2.42 (s, 3H), 1.43 (s, 9H) ppm. 13C NMR
(
(
2
126 MHz, CDCl3) δ 193.3, 155.5, 120.2, 81.0, 57.5, 34.0, 31.6, 30.7,
8.4. GC/MS (EI): m/z = 228 [M–CH2CC(O)] , 197 [M–Ot-Bu] . Anal.
+
+
Calcd. for C12H18N2O3S: C 53.31; H 6.71; N 10.36; S 11.86. Found: C
3.29; H 6.92; N 10.18; S 11.75.
5
tert-Butyl 3-((acetylthio)methyl)-3-cyanopyrrolidine-1-carboxylate
7g). The crude compound was purified by flash chromatography (5 bar)
(
on silica gel using 80 g column gradient hexanes – t-BuOMe as eluent.
Yield 34.2 g (97%); yellow oil. 1H NMR (400 MHz, CDCl3) δ 4.25 (d, J =
(1-Cyanocyclopropyl)methanesulfonyl chloride (8a). Yield 19.7
1H NMR (400 MHz,
(61% from 6a); colorless crystals; mp 71–72 °C.
CDCl3) δ 3.81 (s, 2H), 1.69 – 1.61 (m, 2H), 1.44 – 1.37 (m, 2H). 13C NMR
g
8
3
.7 Hz, 2H), 3.92 (d, J = 8.7 Hz, 2H), 2.95 (t, J = 9.3, 6.5 Hz, 2H), 2.35 (s,
H), 2.15 (dd, J = 9.3, 6.5 Hz, 2H), 1.43 (s, 9H). 13C NMR (151 MHz,
(126 MHz, CDCl ) δ 119.9, 69.1, 15.8, 5.9. GC/MS (EI): m/z = 80 [M–
3
+
CDCl3) δ 195.1, 155.5, 120.7, 80.9, 57.9 (2C), 36.4, 30.7, 30.5, 28.4,
4.7. LC/MS (CI): m/z = 185 [M–CO2–H2C=C(CH3)2+H]+ , 229 [M–
SO2Cl] . Anal. Cald. for C5H6ClNO2S: C 33.43; H 3.37; N 7.8; S 17.85; Cl
2
19.74. Found: C 33.15; H 3.52; N 7.65; S 18.17; Cl 19.70.
+
+
H2C=C(CH3)2+H] , 307 [M+Na] . Anal. Calcd. for C13H20N2O3S: C 54.91;
H 7.09; N 9.85; S 11.27. Found: C 54.88; H 7.44; N 9.97; S 11.52.
(
1-Cyanocyclobutyl)methanesulfonyl chloride (8b). Yield 23.3 g (67%
from 6b); colorless liquid. 1H NMR (400 MHz, CDCl3) δ 4.09 (s, 2H), 2.76
tert-Butyl
4-((acetylthio)methyl)-4-cyanopiperidine-1-carboxylate
– 2.66 (m, 2H), 2.53 – 2.45 (m, 2H), 2.44 – 2.33 (m, 1H), 2.17 – 2.08 (m,
1H). 13C NMR (126 MHz, CDCl3) δ 120.8, 70.1, 32.9, 32.8, 17.4. LC/MS
(CI): m/z = 194/196 [M+H] . Anal. Cald. for C6H8ClNO2S: C 37.21; H
4.16; N 7.23; S 16.56; Cl 18.31. Found: C 37.11; H 4.11; N 7.12; S 16.32;
Cl 18.12.
(7h). The crude compound was purified by flash chromatography (5 bar)
+
on silica gel using 80 g column gradient hexanes – t-BuOMe as eluent.
Yield 34.4 g (93%); beige powder; mp 94–95 °C. 1H NMR (500 MHz,
CDCl3) δ 4.24 – 4.10 (m, 2H), 3.20 (s, 2H), 3.07 – 2.98 (m, 2H), 2.44 (s,
3
H), 1.95 (d, J = 12.8 Hz, 2H), 1.56 – 1.51 (m, 2H), 1.48 (s, 9H). 13C
(1-Cyanocyclopentyl)methanesulfonyl chloride (8c). The crude
NMR (126 MHz, CDCl3) δ 193.5, 154.2, 120.7, 80.2, 40.7, 39.3, 36.9,
compound was purified by flash chromatography (5 bar) on silica gel
using 80 g column gradient hexanes – t-BuOMe as eluent. Yield 26.5 g
+
3
[
3.8, 30.5, 28.4. GC/MS (EI): m/z = 198 [M–CO2–H2C=C(CH3)2] , 225
M–Ot-Bu]+, 242 [M–H2C=C(CH3)2]+, 298 [M]+. Anal. Cald. for
71% from 6c); yellowish oil. 1H NMR (500 MHz, CDCl3) δ 4.06 (s, 2H),
2
(
C14H22N2O3S: C 56.35; H 7.43; N 9.39; S 10.74. Found: C 56.32; H 7.43;
N 9.27; S 11.13.
.47 – 2.37 (m, 2H), 2.07 – 1.96 (m, 2H), 1.95 – 1.86 (m, 4H). 13C NMR
(
126 MHz, CDCl3) δ 120.8, 71.0, 40.6, 38.5, 23.5. GC/MS (EI): m/z = 108
+
+
Preparation of tert-butyl sulfides 14a and 14b. 2-(tert-Butylthio)aceto-
nitrile (12, 20.0 g, 0.155 mol) was added dropwise to a suspension of
NaH (60%, 13.0 g, 0.325 mol) in DMF (100 mL) at 0 °C under argon
atmosphere. The resulting mixture was stirred at rt for 2 h, then cooled to
[M–SO2Cl] , 207/209 [M] . Anal. Cald. for C7H10ClNO2S: C 40.49; H 4.85;
N 6.74; S 15.44; Cl 17.07. Found: C 40.45; H 4.6; N 6.48; S 15.36; Cl
16.97.
(
1-Cyanocyclohexyl)methanesulfonyl chloride (8d). Yield 32.7 g (82%
–
(
–
10 °C, and 1,3-dibromopropane (13a, 31.3 g, 0.155 mol) or 1-bromo-2-
2-bromoethoxy)ethane (13b, 35.9 g, 0.155 mol) was added dropwise at
10 °C. The reaction mixture was stirred at rt for 12 h, then diluted with
from 7d); colorless solid; mp 55–56 °C. 1H NMR (400 MHz, CDCl3) δ
3
1
1
2
1
.97 (s, 2H), 2.25 (d, J = 13.0 Hz, 2H), 1.87 – 1.67 (m, 5H), 1.57 (td, J =
3.0, 3.7 Hz, 2H), 1.29 – 1.18 (m, 1H). 13C NMR (126 MHz, CDCl3) δ
H2O (200 mL) and extracted with EtOAс (3100 mL). Combined organic
layers were washed with H2O (270 mL), dried over Na2SO4, and
evaporated in vacuo.
+
19.4, 72.7, 37.9, 35.1, 24.4, 22.4. GC/MS (EI): m/z = 122 [M–SO2Cl] ,
+
21/223 [M] . Anal. Cald. for C8H12ClNO2S: C 43.34; H 5.46; N 6.32; S
4.46; Cl 15.99. Found: C 43.59; H 5.18; N 5.98; S 14.07; Cl 15.70.
1
-(tert-Butylthio)cyclobutanecarbonitrile (14a). The crude compound
(
4-Cyanotetrahydro-2H-pyran-4-yl)methanesulfonyl chloride (8e).
was purified by flash chromatography (5 bar) on silica gel using 80 g
Yield 28.6 g (71% from 6e); colorless powder; mp 160–162 °C. 1H NMR
column gradient hexanes – CHCl3 as eluent. Yield 16.3
colorless oil. H NMR (500 MHz, CDCl3) δ 2.75 (ddt, J = 15.0, 8.7, 3.5
g
(62%);
(400 MHz, CDCl ) δ 4.05 – 4.00 (m, 1H), 4.00 – 3.96 (m, 3H), 3.76 (td, J
3
1
=
1
12.1, 1.8 Hz, 2H), 2.13 (dd, J = 13.2, 1.9 Hz, 2H), 1.87 (ddd, J = 13.2,
Hz, 2H), 2.47 – 2.40 (m, 2H), 2.35 – 2.25 (m, 1H), 2.21 – 2.11 (m, 1H),
2.1, 4.7 Hz, 2H). 13C NMR (126 MHz, CDCl3) δ 118.4, 72.0, 63.8, 35.6,
1
.44 (s, 9H). 13C NMR (126 MHz, CDCl3) δ 123.4, 47.0, 37.4, 36.4, 31.5,
2
34.6. GC/MS (EI): m/z = 124 [M-SO Cl] , 223/225 [M] . Anal. Cald. for
+
+
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.202000351
FULL PAPER
C7H10ClNO3S: C 37.59; H 4.51; N 6.26; S 14.33; Cl 15.85. Found: C
for C5H6FNO2S: C 36.81; H 3.71; N 8.58; S 19.65. Found: C 36.61; H
4.08; N 8.23; S 19.54.
3
7.94; H 4.48; N 6.64; S 14.39; Cl 15.63.
tert-Butyl 3-((chlorosulfonyl)methyl)-3-cyanoazetidine-1-carboxylate
8f). Yield 31.8 g (60% from 6f) and 33.4 g (63% from 7f); beige powder;
mp 132–134 °C. 1H NMR (400 MHz, CDCl3) δ 4.42 (d, J = 9.3 Hz, 2H),
.28 (s, 2H), 4.17 (d, J = 9.3 Hz, 2H), 1.45 (s, 9H) ppm. 13C NMR (126
MHz, CDCl3) δ 155.2, 117.8, 81.8, 68.1, 57.8, 28.3, 27.7 ppm. LC/MS
CI): m/z
195/197 [M–CO2–(H3C)2C=CH2+H]+. Anal. Calcd. for
C10H15ClN2O4S: C 40.75; H 5.13; N 9.50; S 10.88; Cl 12.03. Found: C
0.44; H 5.25; N 9.21; S 10.93; Cl 12.15.
(1-Cyanocyclobutyl)methanesulfonyl fluoride (2b). Yield 14.2
g
1
(
(89%); colorless crystals; mp 43–44 °C. H NMR (400 MHz, CDCl3) δ
3.80 (d, J = 4.2 Hz, 2H), 2.73 – 2.59 (m, 2H), 2.50 – 2.37 (m, 2H), 2.37 –
2.26 (m, 1H), 2.17 – 2.02 (m, 1H). 13C NMR (126 MHz, CDCl3) δ 121.1,
56.37 (d, J = 16.1 Hz), 32.4, 32.1, 17.1. 19F{H} NMR (376 MHz, CDCl3) δ
4
+
(
=
61.3. GC/MS (EI): m/z = 177 [M] . Anal. Cald. for C6H8FNO2S: C 40.67;
H 4.55; N 7.91; S 18.09. Found: C 40.37; H 4.79; N 7.63; S 17.89.
4
(1-Cyanocyclopentyl)methanesulfonyl fluoride (2c). The crude
tert-Butyl 3-((chlorosulfonyl)methyl)-3-cyanopyrrolidine-1-carboxy-
late (8g). Yield 39.5 g (71% from 7g); yellow solid, mp 102–105 °C. The
compound existed as ca. 1:1 mixture of rotamers. 1H NMR (400 MHz,
CDCl3) δ 4.21 – 3.97 (m, 3H), 3.71 – 3.48 (m, 3H), 2.67 – 2.52 (m, 1H),
compound was purified by flash chromatography (5 bar) on silica gel
using 40 g column gradient hexanes – t-BuOMe as eluent. Yield 16.2 g
(94%); colorless oil. 1H NMR (500 MHz, CDCl3) δ 3.72 (s, 2H), 2.47 –
2.32 (m, 2H), 2.03 – 1.91 (m, 2H), 1.92 – 1.81 (m, 4H). 13C NMR (126
.36 – 2.18 (m, 1H), 1.47 (s, 9H) ppm. 13C NMR (126 MHz, CDCl3) δ
MHz, CDCl3) δ 121.1, 56.9 (d, J = 16.5 Hz), 39.7, 38.3, 23.5. F{H} NMR
19
2
1
3
2
+
+
53.6, 118.4, 81.2, 68.2, 54.8, 43.9 and 43.5, 39.6 and 38.9, 36.3 and
(470 MHz, CDCl3) δ 62.1. GC/MS (EI): m/z = 108 [M–SO2F] , 191 [M] .
Anal. Cald. for C7H10FNO2S: C 43.97; H 5.27; N 7.33; S 16.77. Found: C
43.8; H 5.39; N 7.36; S 16.75.
5.8, 28.5. LC/MS (CI): m/z
=
209/211 [M–CO2–H2C=C(CH3)2+H]+,
+
53/255 [M–H2C=C(CH3)2+H] . Anal. Calcd. for C11H17ClN2O4S: C 42.79;
H 5.55; N 9.07; S 10.38; Cl 11.48. Found: C 42.75; H 5.73; N 9.28; S
0.23; Cl 11.21.
(
(
1-Cyanocyclohexyl)methanesulfonyl fluoride (2d). Yield 17.4
g
1
94%); colorless liquid. 1H NMR (400 MHz, CDCl3) δ 3.63 (d, J = 3.2 Hz,
tert-Butyl 4-((chlorosulfonyl)methyl)-4-cyanopiperidine-1-carboxy-
late (8h). The crude compound was purified by column chromatography
on silica gel using 80 g RediSep column (flow rate: 60 mL / min, rack: 16
mm  150 mm tubes) and gradient CHCl3 – MeCN as eluent. Yield 42.4 g
2H), 2.25 (d, J = 12.9 Hz, 2H), 1.86 – 1.68 (m, 5H), 1.54 (td, J = 12.9, 3.6
Hz, 2H), 1.32 – 1.18 (m, 1H). 13C NMR (126 MHz, CDCl3) δ 119.4, 58.7
(d, J = 16.3 Hz), 36.7, 35.0, 24.4, 22.4. 19F NMR (470 MHz, CDCl3) δ
65.4. GC/MS (EI): m/z = 122 [M–SO2Cl] , 205 [M] . Anal. Cald. for
C8H12FNO2S: C 46.82; H 5.89; N 6.82; S 15.62. Found: C 46.67; H 6.22;
N 6.98; S 15.56.
+
+
(
73% from 6h) and 48.8 g (84% from 7h); yellow solid, mp 113–115 °C.
1
H NMR (400 MHz, CDCl3) δ 4.40 – 4.00 (m, 2H), 3.97 (s, 2H), 3.17 –
3
2
4
.01 (m, 2H), 2.17 (dd, J = 12.9, 2.2 Hz, 2H), 1.69 (td, J = 12.9, 4.4 Hz,
H), 1.43 (s, 9H). 13C NMR (126 MHz, CDCl3) δ 154.2, 118.2, 80.8, 71.9,
0.2, 36.8, 34.2, 28.5. Anal. Calcd. for C12H19ClN2O4S: C 44.65; H 5.93;
(
4-Cyanotetrahydro-2H-pyran-4-yl)methanesulfonyl fluoride (2e)..
Yield 16.8 g (90%); colorless crystals; mp 143–144 °C. 1H NMR (500
MHz, CDCl3) δ 4.04 (dd, J = 12.2, 4.3 Hz, 2H), 3.78 (t, J = 12.2 Hz, 2H),
3
NMR (126 MHz, CDCl3) δ 118.5, 63.8, 58.4, 58.2, 34.6, 34.5. F{H}
NMR (470 MHz, CDCl3) δ 65.5. GC/MS (EI): m/z = 124 [M-SO2F] , 207
[M] . Anal. Cald. for C7H10FNO3S: C 40.57; H 4.86; N 6.76; S 15.47.
Found: C 40.44; H 4.94; N 6.58; S 15.37.
N 8.68; S 9.93; Cl 10.98. Found: C 44.52; H 5.55; N 8.54; S 10.10; Cl
.67 (s, 2H), 2.14 (d, J = 13.2 Hz, 2H), 1.86 (td, J = 13.2, 4.3 Hz, 2H). 13C
10.72.
19
+
1-Cyanocyclobutane-1-sulfonyl chloride (15a). Yield 25.9 g (80%);
1
+
yellow liquid. H NMR (400 MHz, CDCl3) δ 3.12 – 3.00 (m, 2H), 2.93 –
2
6
.81 (m, 2H), 2.42 – 2.25 (m, 2H). 13C NMR (126 MHz, CDCl3) δ 115.1,
6.9, 30.9, 15.6. GC/MS (EI): m/z = 179/181 [M] . Anal. Cald. for
+
tert-Butyl 3-cyano-3-((fluorosulfonyl)methyl)azetidine-1-carboxylate
C5H6ClNO2S: C 33.43; H 3.37; N 7.80; S 17.85; Cl 19.74. Found: C
(2f). The crude compound was purified by flash chromatography (5 bar)
33.48; H 3.33; N 7.74; S 17.59; Cl 19.38.
on silica gel using 80 g column gradient hexanes – t-BuOMe – MeCN as
eluent. Yield 19.3 g (77%); yellowish powder; mp 112–114 °C. 1H NMR
(400 MHz, CDCl3) δ 4.41 (d, J = 9.3 Hz, 2H), 4.12 (d, J = 9.3 Hz, 2H),
3.99 (d, J = 4.1 Hz, 2H), 1.45 (s, 9H). 13C NMR (126 MHz, CDCl3) δ
155.2, 117.8, 81.8, 57.6, 55.0 (d, J = 18.3 Hz), 28.3, 27.1. 19F{H} NMR
(376 MHz, CDCl3) δ 62.3. LC/MS (CI): m/z = 277 [M-H] . Anal. Calcd. for
C10H15FN2O4S: C 43.16; H 5.43; N 10.07; S 11.52. Found: C 42.99; H
5.75; N 10.24; S 11.82.
4
-Cyanotetrahydro-2H-pyran-4-sulfonyl chloride (15b). Yield 32.8 g
(
87%); yellowish crystals; mp 93–95 °C. 1H NMR (400 MHz, CDCl3) δ
4
.26 – 4.17 (m, 2H), 3.75 – 3.66 (m, 2H), 2.45 – 2.33 (m, 4H). 13C NMR
(126 MHz, CDCl3) δ 113.4, 71.5, 63.5, 30.2. LC/MS (CI): m/z = 111 [M–
+
+
-
SO2Cl] , 210/212 [M+H] . Anal. Cald. for C6H8ClNO3S: C 34.38; H 3.85;
N 6.68; S 15.29; Cl 16.91. Found: C 34.39; H 4.11; N 6.80; S 15.00; Cl
1
6.92.
General procedure for the preparation of sulfonyl fluorides 2a–h,
1a and 11b. KHF2 (0.900 mol) was added at rt to the corresponding
tert-Butyl 3-cyano-3-((fluorosulfonyl)methyl)pyrrolidine-1-carboxy-
late (2g). Yield 18.9 g (72%); yellow solid, mp 134–136 °C. The
compound existed as ca. 1:1 mixture of rotamers. 1H NMR (400 MHz,
DMSO-d6) δ 4.85 – 4.68 (m, 2H), 3.86 (dd, J = 11.9, 4.8 Hz, 1H), 3.53 (t,
J = 9.8 Hz, 1H), 3.47 – 3.37 (m, 2H), 2.49 – 2.41 (m, 1H), 2.28 – 2.13 (m,
1H), 1.41 (s, 9H). 13C NMR (101 MHz, DMSO-d6) δ 153.2 and 152.9,
119.6, 79.5, 54.1, 52.8 (d, J = 15.0 Hz), 43.7 and 43.5, 38.6 and 37.8,
35.2 and 34.4, 28.0. 19F NMR (376 MHz, DMSO-d6) δ 60.9 and 60.8.
1
sulfonyl chloride 8 or 15 (90.0 mmol) in MeOH–H2O (240 mL, 1:1, v/v).
The resulting mixture was stirred at rt for 12 h, then diluted with H2O (240
mL) and extracted with CH2Cl2 (3200 mL). Combined organic layers
were dried over Na2SO4 and evaporated in vacuo. Unless other is
specified, the crude compound was purified by column chromatography
on silica gel using 40 g, 80 g or 330 g RediSep column (flow rate: 40
mL / min, 60 mL / min, or 100 mL / min, respectively, rack: 16 mm  150
mm tubes) and gradient hexanes – t-BuOMe as eluent.
LC/MS (CI): m/z
H2C=C(CH3)2+H] . Anal. Calcd. for C11H17FN2O4S: C 45.20; H 5.86; N
=
193 [M–CO2–H2C=C(CH3)2+H]+, 237 [M–
+
9.58; S 10.97. Found: C 45.23; H 5.85; N 9.83; S 10.82.
(1-Cyanocyclopropyl)methanesulfonyl fluoride (2a). The crude
tert-Butyl 4-cyano-4-((fluorosulfonyl)methyl)piperidine-1-carboxy-
compound was purified by flash chromatography (5 bar) on silica gel
late (2h). The crude compound was purified by column chromatography
on silica gel using 330 g RediSep column (flow rate: 100 mL / min, rack:
16 mm  150 mm tubes) and gradient CHCl3 – MeCN as eluent. Yield
using 40 g column gradient hexanes – t-BuOMe as eluent. Yield 12.8 g
87%); colorless crystals; mp 56–58 °C. 1H NMR (500 MHz, CDCl3) δ
(
.55 (d, J = 4.1 Hz, 1H), 1.64 – 1.58 (m, 1H), 1.34 – 1.29 (m, 1H). 3C
1
3
NMR (126 MHz, CDCl3) δ 119.9, 55.5 (d, J = 17.9 Hz), 15.4, 5.1. 19F{H}
22.1 g (80%); yellow solid, mp 134–136 °C. 1H NMR (400 MHz, CDCl ) δ
3
+
4.21 (s, 2H), 3.65 (d, J = 3.5 Hz, 2H), 3.18 – 3.01 (m, 2H), 2.17 (dd, J =
NMR (376 MHz, CDCl3) δ 57.0. GC/MS (EI): m/z = 163 [M] . Anal. Cald.
1
3.1, 2.7 Hz, 2H), 1.67 (td, J = 13.1, 4.3 Hz, 2H), 1.45 (s, 9H) ppm. 13C
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.202000351
FULL PAPER
NMR (126 MHz, CDCl3) δ 154.2, 118.3, 80.8, 58.2 (d, J = 17.0 Hz), 40.1,
3H). 13C NMR (126 MHz, CDCl3) δ 57.9, 53.7, 44.3, 36.3, 25.3, 22.7.
GC/MS (EI): m/z = 189 [M] . Anal. Cald. for C8H15NO2S: C 50.77; H 7.99;
N 7.4; S 16.94. Found: C 50.99; H 8.34; N 7.41; S 17.07.
5.7, 34.2, 28.4 ppm. 19F NMR (376 MHz, CDCl3) δ 65.0 ppm. GC/MS
+
3
+
+
(EI): m/z = 206 [M-CO2-(H3C)2C=CH2] , 233 [M –Ot-Bu] . Anal. Calcd. for
C12H19FN2O4S: C 47.05; H 6.25; N 9.14; S 10.47. Found: C 47.16; H
8
(
-Oxa-2-thia-3-azaspiro[4.5]decane 2,2-dioxide (1e). Yield 22.5
g
6.35; N 8.95; S 10.56.
84%); colorless powder; mp 85–86 °C. 1H NMR (500 MHz, CDCl3) δ
1
-Cyanocyclobutane-1-sulfonyl fluoride (11a). The crude compound
4.85 (s, 1H), 3.88 – 3.74 (m, 2H), 3.61 – 3.48 (m, 2H), 3.22 (d, J = 6.1
Hz, 2H), 3.10 (s, 2H), 1.87 – 1.71 (m, 4H). 13C NMR (126 MHz, CDCl3) δ
64.4, 57.2, 53.5, 41.7, 36.2. GC/MS (EI): m/z = 191 [M] . Anal. Cald. for
C7H13NO3S: C 43.96; H 6.85; N 7.32; S 16.76. Found: C 43.61; H 6.91; N
7.71; S 16.70.
was purified by flash chromatography (5 bar) on silica gel using 120 g
column gradient hexanes – CHCl3 as eluent. Yield 11.3 (77%);
colorless liquid. 1H NMR (400 MHz, CDCl3) δ 3.12 – 3.01 (m, 2H), 2.99 –
+
g
2
(
.88 (m, 2H), 2.50 – 2.33 (m, 2H). 13C NMR (126 MHz, CDCl3) δ 114.4
d, J = 1.8 Hz), 54.9 (d, J = 19.2 Hz), 30.5, 16.5. 19F{H} NMR (470 MHz,
tert-Butyl 6-thia-2,7-diazaspiro[3.4]octane-2-carboxylate 6,6-dioxide
+
CDCl3) δ 41.8. GC/MS (EI): m/z = 163 [M] . Anal. Calcd. for C5H6FNO2S:
C 36.81; H 3.71; N 8.58; S 19.65. Found: C 36.98; H 3.56; N 8.46; S
1
(
1f). Yield 27.2 g (74%); colorless powder; mp 146–147 °C. H NMR (500
MHz, CDCl3) δ 5.10 (s, 1H), 4.04 (d, J = 9.1 Hz, 2H), 3.92 (d, J = 9.2 Hz,
H), 3.54 (s, 2H), 3.32 (s, 2H), 1.42 (s, 9H). 13C NMR (126 MHz, CDCl3)
19.43.
2
4
-Cyanotetrahydro-2H-pyran-4-sulfonyl fluoride (11b). The crude
δ 156.0, 80.4, 59.2, 56.2, 52.8, 38.5, 28.3. LC/MS (CI): m/z = 163 [M–
CO2–(H3C)2C=CH2+H] . Anal. Cald. for C10H18N2O4S: C 45.79; H 6.92; N
10.68; S 12.22. Found: C 46.19; H 6.55; N 10.92; S 12.22.
+
compound was purified by HPLC using gradient H2O – MeCN as eluent.
Yield 11.5 g (66%); yellowish crystals; mp 57–59 °C. 1H NMR (400 MHz,
CDCl3) δ 4.16 (ddd, J = 12.4, 4.2, 1.9 Hz, 2H), 3.71 (td, J = 12.4, 2.4 Hz,
tert-Butyl 2-thia-3,7-diazaspiro[4.4]nonane-7-carboxylate 2,2-dioxide
2
H), 2.40 – 2.26 (m, 4H). 13C NMR (126 MHz, CDCl3) δ 113.0, 63.4, 60.6
(
(
(
1g). The compound existed as ca. 1:1 mixture of rotamers. Yield 29.0 g
75%); colorless oil. 1H NMR (500 MHz, CDCl3) δ 5.13 (s, 0.5H) and 4.96
s, 0.5H), 3.61 – 3.38 (m, 4H), 3.37 – 3.23 (m, 2H), 3.15 (q, J = 13.3 Hz,
(
(
d, J = 18.2 Hz), 30.4. 19F{H} NMR (376 MHz, CDCl3) δ 39.4. GC/MS
+
EI): m/z = 193 [M] . Anal. Cald. for C6H8FNO3S: C 37.3; H 4.17; N 7.25;
S 16.6. Found: C 37.41; H 4.31; N 7.56; S 16.97
H), 2.11 (s, 1H) and 2.04 (s, 1H), 1.46 (s, 9H). 13C NMR (126 MHz,
2
General procedure for the preparation of sultams 1a–h, 10a and 10b.
A mixture of the corresponding sulfonyl fluoride 2 or 11 (0.140 mol) and
NiCl2*6H2O (36.6 g, 0.154 mol) in MeOH (300 mL) was cooled to –20 °C.
Then, NaBH4 (18.5 g, 0.490 mol) was added in portions at –20 °C
cdcl3) δ 154.4 and 154.3, 80.1, 56.3 and 56.2, 55.9 and 55.4, 51.4, 48.8
and 48.6, 44.6 and 44.2, 36.1 and 35.6, 28.4. LC/MS (CI): m/z = 177 [M–
CO2–(H3C)2C=CH2+H] . Anal. Cald. for C11H20N2O4S: C 47.81; H 7.30; N
+
10.14; S 11.60. Found: C 48.04; H 7.67; N 10.35; S 11.74.
(
NOTE: the temperature should not exceed –10 °C). The resulting
tert-Butyl 2-thia-3,8-diazaspiro[4.5]decane-8-carboxylate 2,2-dioxide
(
MHz, CDCl3) δ 4.76 (s, 1H), 3.69 (d, J = 13.7 Hz, 2H), 3.21 (s, 2H), 3.18
mixture was warmed up to rt and stirred for 12 h. The precipitate was
filtered off and washed with MeOH (3500 mL), and the filtrate was
evaporated in vacuo. The residue was dissolved in EtOAc - H2O (1000
mL, 1:1, v/v), the organic phase was separated, and the aqueous phase
was extracted with EtOAc (500 mL). Combined organic phases were
dried over Na2SO4 and evaporated in vacuo. Unless other is specified,
the crude compound was purified by column chromatography on silica
gel using 40 g, 80 g or 330 g RediSep column (flow rate: 40 mL / min, 60
mL / min or 100 mL / min, respectively, rack: 16 mm  150 mm tubes)
and gradient t-BuOMe – MeOH as eluent.
1h). Yield 31.7 g (78%); colorless powder; mp 173–174. 1H NMR (500
–
1
8
3.10 (m, 2H), 3.06 (s, 2H), 1.79 (dt, J = 8.7, 4.2 Hz, 2H), 1.66 (ddd, J =
3.7, 9.4, 4.2 Hz, 2H), 1.45 (s, 9H). 13C NMR (126 MHz, CDCl3) δ 154.6,
0.1, 56.7, 53.0, 42.5, 40.5, 35.5, 28.4. LC/MS (CI): m/z = 235 [M–
+
+
H2C=C(CH3)3+H] , 291 [M+H] . Anal. Cald. for C12H22N2O4S: C 49.64; H
7.64; N 9.65; S 11.04. Found: C 49.49; H 7.67; N 9.65; S 11.21.
1
-Thia-2-azaspiro[3.3]heptane 1,1-dioxide (10a). Yield 9.89 g (48%);
colorless crystals; mp 167–169 °C. 1H NMR (400 MHz, CDCl3) δ 5.51 (s,
1
2
1
6
H), 3.24 (s, 2H), 2.78 (ddt, J = 14.3, 8.9, 5.4 Hz, 2H), 2.42 – 2.32 (m,
5
-Thia-6-azaspiro[2.4]heptane 5,5-dioxide (1a). The crude compound
was purified by flash chromatography (5 bar) on silica gel using 330 g
column gradient t-BuOMe – MeOH as eluent. Yield 12.6 (61%);
colorless crystals; mp 72–74 °C. 1H NMR (400 MHz, CDCl3) δ 4.60 (s,
H), 2.00 – 1.84 (m, 2H). 13C NMR (101 MHz, CDCl3) δ 80.0, 43.1, 28.5,
+
5.6. GC/MS (EI): m/z = 147 [M] . Anal. Cald. for C5H9NO2S: C 40.8; H
g
.16; N 9.52; S 21.78. Found: C 40.88; H 6.52; N 9.81; S 21.98.
7-Oxa-1-thia-2-azaspiro[3.5]nonane 1,1-dioxide (10b). The crude
1
1
H), 3.21 (s, 2H), 3.07 (s, 2H), 0.97 – 0.81 (m, 2H), 0.81 – 0.63 (m, 2H).
3
compound was purified by flash chromatography (5 bar) on silica gel
C NMR (126 MHz, CDCl3) δ 55.4, 51.4, 20.3, 11.8. LC/MS (CI): m/z =
+
using 220 g column gradient t-BuOMe – MeOH as eluent. Yield 13.1 g
1
48 [M+H] . Anal. Cald. for C5H9NO2S: C 40.80; H 6.16; N 9.52; S 21.78.
(
53%); colorless crystals; mp 129–131 °C. 1H NMR (400 MHz, DMSO-d6)
Found: C 40.52; H 5.84; N 9.89; S 21.58.
δ 7.77 (s, 1H), 3.67 (ddd, J = 11.8, 6.1, 4.0 Hz, 2H), 3.57 (ddd, J = 11.8,
6
-Thia-7-azaspiro[3.4]octane 6,6-dioxide (1b). Yield 16.0 g (71%);
8
.0, 3.4 Hz, 2H), 3.04 (d, J = 3.4 Hz, 2H), 2.13 (ddd, J = 13.9, 6.1, 3.4
1
colorless liquid. H NMR (400 MHz, CDCl3) δ 4.53 (s, 1H), 3.36 (d, J =
13
Hz, 2H), 1.98 (ddd, J = 13.9, 8.0, 4.0 Hz, 2H). C NMR (126 MHz,
DMSO-d6) δ 78.0, 64.9, 42.1, 31.7. GC/MS (EI): m/z = 177 [M] . LC/MS
5
–
1
6
.7 Hz, 2H), 3.17 (s, 2H), 2.25 – 2.18 (m, 2H), 2.13 – 2.06 (m, 2H), 1.99
+
1.91 (m, 2H). 13C NMR (126 MHz, CDCl3) δ 58.7, 54.6, 44.6, 32.3,
+
(CI): m/z = 178 [M+H] . Anal. Cald. for C6H11NO3S: C 40.66; H 6.26; N
+
6.0. GC/MS (EI): m/z = 161 [M] . Anal. Cald. for C6H11NO2S: C 44.7; H
7.9; S 18.09. Found: C 40.65; H 6.19; N 8.03; S 17.79.
.88; N 8.69; S 19.89. Found: C 45.02; H 6.89; N 8.51; S 19.72.
Genreal procedure for preparation of hydrochlorides 9g and 9h. The
corresponding N-Boc amine 1g (950 mg, 3.44 mmol) or 1h (1.00 g, 3.44
mmol) was added to 4 M HCl – 1,4-dioxane (10 mL) at rt. The reaction
mixture was stirred at rt for 12 h, then evaporated in vacuo to dryness.
The precipitate thus obtained was dried in vacuo.
2
-Thia-3-azaspiro[4.4]nonane 2,2-dioxide (1c). Yield 20.1 g (82%);
colorless powder; mp 61–64 °C. 1H NMR (400 MHz, CDCl3) δ 4.63 (s,
1
1
5
H), 3.20 (d, J = 6.3 Hz, 2H), 3.06 (s, 2H), 1.83 – 1.76 (m, 2H), 1.75 –
.70 (m, 2H), 1.69 (s, 4H). 13C NMR (126 MHz, CDCl3) δ 59.0, 54.1,
0.8, 37.8, 23.9. LC/MS (CI): m/z
=
176 [M+H]+. Anal. Cald. for
2
-Thia-3,7-diazaspiro[4.4]nonane 2,2-dioxide hydrochloride (9g).
C7H13NO2S: C 47.98; H 7.48; N 7.99; S 18.29. Found: C 47.92; H 7.81; N
Yield 732 mg (100%); yellowish solid; mp 187–189 °C. 1H NMR (500
7.95; S 18.67.
MHz, DMSO-d6) δ 9.66 (s, 2H), 7.27 (t, J = 6.5 Hz, 1H), 3.29 – 3.15 (m,
2
-Thia-3-azaspiro[4.5]decane 2,2-dioxide (1d). Yield 20.7 g (78%);
H), 2.05 (qt, J = 13.7, 7.1 Hz, 2H). 13C NMR (126 MHz, DMSO-d6) δ
5.9, 53.1, 51.0, 49.7, 43.9, 35.3. LC/MS (CI): m/z = 177 [M–HCl+H]+.
8
5
Colorless liquid. 1H NMR (500 MHz, CDCl3) δ 4.94 (t, J = 6.8 Hz, 1H),
3
6
.11 (dd, J = 6.5, 1.7 Hz, 2H), 2.97 (d, J = 1.7 Hz, 2H), 1.69 (dd, J = 14.0,
.5 Hz, 2H), 1.60 – 1.53 (m, 2H), 1.52 – 1.44 (m, 3H), 1.39 – 1.31 (m,
Anal. Cald. for C6H13ClN2O2S: C 33.88; H 6.16; N 13.17; S 15.07; Cl
6.67. Found: C 33.53; H 6.52; N 13.46; S 15.45; Cl 16.39.
1
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.202000351
FULL PAPER
2
-Thia-3,8-diazaspiro[4.5]decane 2,2-dioxide hydrochloride (9h).
R. King, T. C. Wang, A. R. Rendina, J. M. Luettgen, R. M. Knabb, R.
R. Wexler, P. Y. S. Lam, Bioorg. Med. Chem. Lett. 2007, 17, 4419–
Yield 780 mg (100%); colorless crystals; mp 241–244 °C. 1H NMR (500
MHz, DMSO-d6) δ 9.19 (s, 2H), 7.27 (t, J = 6.9 Hz, 1H), 3.16 – 3.10 (m,
4
427.
A. W. M. Lee, W. H. Chan, L. S. Jiang, K. W. Poon, Chem. Commun.
997, 611–612.
[
26]
4
2
5
H), 3.02 (d, J = 6.9 Hz, 2H), 2.96 (t, J = 11.0 Hz, 2H), 1.90 – 1.85 (m,
1
H), 1.80 (dt, J = 11.9, 5.7 Hz, 2H). 13C NMR (126 MHz, DMSO-d6) δ
[27]
É. S. Lipina, R. I. Bodina, T. P. Efimova, T. A. Novikova, V. V.
Perekalin, Pharm. Chem. J. 1999, 33, 598–600.
K. Hanaya, S. Yoshioka, S. Ariyasu, S. Aoki, M. Shoji, T. Sugai,
Bioorg. Med. Chem. Lett. 2016, 26, 545–550.
+
6.5, 52.5, 41.9, 40.6, 32.0. LC/MS (CI): m/z = 191 [M–HCl+H] . Anal.
[
[
[
[
28]
29]
30]
31]
Calcd. for C7H15ClN2O2S: C 37.08; H 6.67; N 12.36; S 14.14; Cl 15.64.
Found: C 37.10; H 6.96; N 12.66; S 14.26; Cl 15.83.
W. F. Erman, H. C. Kretschmar, J. Org. Chem. 1961, 26, 4841–
4
850.
A. J. Preston, J. C. Gallucci, L. A. Paquette, J. Org. Chem. 2006, 71,
573–6578.
6
C. Valente, R. C. Guedes, R. Moreira, J. Iley, J. Gut, P. J. Rosenthal,
Bioorg. Med. Chem. Lett. 2006, 16, 4115–4119.
Acknowledgements
[
[
32]
33]
E. H. White, H. M. Lim, J. Org. Chem. 1987, 52, 2162–2166.
S. Hirashima, T. Oka, K. Ikegashira, S. Noji, H. Yamanaka, Y. Hara,
H. Goto, R. Mizojiri, Y. Niwa, T. Noguchi, I. Ando, S. Ikeda, H.
Hashimoto, Bioorg. Med. Chem. Lett. 2007, 17, 3181–3186.
H. Jin, M. Wright, R. Pastor, M. Mish, S. Metobo, S. Jabri, R.
Lansdown, R. Cai, P. Pyun, M. Tsiang, X. Chen, C. U. Kim, Bioorg.
Med. Chem. Lett. 2008, 18, 1388–1391.
The work was funded by Enamine Ldt. O.O.G. was also funded
by Ministry of Education and Science of Ukraine (Grant No.
19BF037-03). The authors thank Prof. Andrey A. Tolmachev for
[34]
his encouragement and support.
[
35]
K. X. Chen, B. Vibulbhan, W. Yang, L. G. Nair, X. Tong, K. C.
Cheng, F. G. Njoroge, Bioorg. Med. Chem. Lett. 2009, 19, 1105–
Keywords: spirocyclic, sultams, building blocks, reduction,
1109.
sulfonylation
[36]
M. Inagaki, T. Tsuri, H. Jyoyama, T. Ono, K. Yamada, M. Kobayashi,
Y. Hori, A. Arimura, K. Yasui, K. Ohno, S. Kakudo, K. Koizumi, R.
Suzuki, M. Kato, S. Kawai, S. Matsumoto, J. Med. Chem. 2000, 43,
2040–2048.
[
[
37]
38]
D. Freitag, P. Metz, Tetrahedron 2006, 62, 1799–1805.
V. A. Rassadin, D. S. Grosheva, I. A. Arefeva, A. A. Tomashevskiy,
V. V. Sokolov, A. De Meijere, Eur. J. Org. Chem. 2012, 5028–5037.
V. A. Rassadin, A. A. Tomashevskii, V. V. Sokolov, A. A. Potekhin,
Chem. Heterocycl. Compd. 2008, 44, 474–485.
N. Lad, R. Sharma, V. E. Marquez, M. Mascarenhas, Tetrahedron
Lett. 2013, 54, 6307–6309.
E. Cleator, F. J. Sheen, M. M. Bio, K. M. Jos Brands, A. J. Davies, U.
H. Dolling, Tetrahedron Lett. 2006, 47, 4245–4248.
G. F. Cooper, Synthesis 1991, 1991, 859–860.
N. Lad, R. Sharma, V. E. Marquez, M. Mascarenhas, ChemInform
2014, 45, no-no.
S. M. Leit, L. A. Paquette, J. Org. Chem. 1999, 64, 9225–9229.
D. Zhong, D. Wu, Y. Zhang, Z. Lu, M. Usman, W. Liu, X. Lu, W. B.
Liu, Org. Lett. 2019, 21, 5808–5812.
M. V. Popova, A. V. Dobrydnev, V. V. Dyakonenko, I. S. Konovalova,
S. V. Shishkina, Y. M. Volovenko, Tetrahedron 2019, 75, 1231–
1245.
A. V. Dobrydnev, B. V. Vashchenko, I. S. Konovalova, K. O. Bisikalo,
Y. M. Volovenko, Monatsh. Chem. 2018, 149, 1827–1833.
M. S. Dyachenko, A. V. Dobrydnev, Y. M. Volovenko, Mol. Divers.
2018, 22, 919–927.
A. V. Dobrydnev, B. V. Vashchenko, Y. M. Volovenko, Tetrahedron
Lett. 2018, 59, 1581–1582.
M. V. Popova, A. V. Dobrydnev, M. S. Dyachenko, C. Duhayon, D.
Listunov, Y. M. Volovenko, Monatsh. Chem. 2017, 148, 939–946.
E. Goethals, Bull. des Sociétés Chim. Belges 1963, 72, 750–760.
W. R. S. Barton, L. A. Paquette, Can. J. Chem. 2004, 82, 113–119.
M. Zajac, R. Peters, Chem. Eur. J. 2009, 15, 8204–8222.
M. Zajac, R. Peters, Org. Lett. 2007, 9, 2007–2010.
T. Iwama, A. Takagi, T. Kataoka, Chem. Pharm. Bull. 1998, 46,
757–766.
References
[
[
1]
2]
J. Drews, Science 2000, 287, 1960–1964.
A. Scozzafava, T. Owa, A. Mastrolorenzo, C. Supuran, Curr. Med.
[39]
[40]
[41]
Chem. 2005, 10, 925–953.
[
[
[
3]
4]
5]
J. E. Lesch, The First Miracle Drugs: How the Sulfa Drugs
Transformed Medicine, Oxford University Press, 2019.
E. J. Corey, B. Czakó, L. Kürti, Molecules and Medicine, John Wiley
&
Sons, 2007.
[42]
[43]
A. S. De Miranda, W. Bispo, Y. K. C. Da Silva, Magna Suzana
Alexandre-Moreira, R. De Paula Castro, J. R. Sabino, L. M. Lião, L.
M. Lima, E. J. Barreiro, Molecules 2012, 17, 14126–14145.
T. J. Carty, A. Marfat, P. F. Moore, F. C. Falkner, T. M. Twomey, A.
Weissman, Agents Actions 1993, 39, 157–165.
N. Swiderska, D. Hawcutt, V. Eaton, F. Stockton, R. Kumar, R.
Kneen, R. Appleton, Seizure 2011, 20, 805–808.
S. Hanessian, H. Sailes, E. Therrien, Tetrahedron 2003, 59, 7047–
[44]
[45]
[
[
[
[
[
[
6]
7]
[46]
8]
7056.
[47]
[48]
[49]
[50]
9]
O. O. Grygorenko, D. M. Volochnyuk, S. V. Ryabukhin, D. B. Judd,
Chem. – A Eur. J. 2020, 26, 1196–1237.
F. Lovering, J. Bikker, C. Humblet, J. Med. Chem. 2009, 52, 6752–
10]
11]
6756.
M. Aldeghi, S. Malhotra, D. L. Selwood, A. W. E. Chan, Chem. Biol.
Drug Des. 2014, 83, 450–461.
[
[
12]
13]
S. Mondal, S. Debnath, Synthesis 2014, 46, 368–374.
O. O. Grygorenko, A. V. Biitseva, S. Zhersh, Tetrahedron 2018, 74,
[51]
[52]
[53]
[54]
[55]
1
355–1421.
M. V. Popova, A. V. Dobrydnev, Chem. Heterocycl. Compd. 2017,
3, 492–494.
[
14]
5
[
[
15]
16]
S. Debnath, S. Mondal, Eur. J. Org. Chem. 2018, 2018, 933–956.
V. A. Rassadin, D. S. Grosheva, A. A. Tomashevskii, V. V. Sokolov,
Chem. Heterocycl. Compd. 2013, 49, 39–65.
[56]
C. Baldoli, P. Del Buttero, D. Perdicchia, T. Pilati, Tetrahedron 1999,
55, 14089–14096.
M. E. Thompson, J. Org. Chem. 1984, 49, 1700–1703.
H.-H. Otto, P. Schwenkkraus, Tetrahedron Lett. 1982, 23, 5389–
5390.
A. Meinzer, A. Breckel, B. A. Thaher, N. Manicone, H. H. Otto, Helv.
Chim. Acta 2004, 87, 90–105.
P. Schwenkkraus, S. Merkle, H. H. Otto, Liebigs Ann. 1997, 1261–
1266.
[
[
17]
18]
K. C. Majumdar, S. Mondal, Chem. Rev. 2011, 111, 7749–7773.
T. B. Samarakoon, J. K. Loh, A. Rolfe, L. S. Le, S. Y. Yoon, G. H.
Lushington, P. R. Hanson, Org. Lett. 2011, 13, 5148–5151.
A. Zhou, P. R. Hanson, Org. Lett. 2008, 10, 2951–2954.
[57]
[58]
[
[
[
19]
20]
21]
M. Jiménez-Hopkins, P. R. Hanson, Org. Lett. 2008, 10, 2223–2226.
S. A. Zhersh, O. P. Blahun, I. V. Sadkova, A. A. Tolmachev, Y. S.
Moroz, P. K. Mykhailiuk, Chem. Eur. J. 2018, 24, 8343–8349.
R. J. Cherney, R. Mo, D. T. Meyer, K. D. Hardman, R.-Q. Liu, M. B.
Covington, M. Qian, Z. R. Wasserman, D. D. Christ, J. M. Trzaskos,
R. C. Newton, C. P. Decicco, J. Med. Chem. 2004, 47, 2981–2983.
D. Enders, A. Moll, J. W. Bats, Eur. J. Org. Chem. 2006, 1271–1284.
R. Di Fabio, Y. St-Denis, F. M. Sabbatini, D. Andreotti, R. Arban, G.
Bernasconi, S. Braggio, F. E. Blaney, A. M. Capelli, E. Castiglioni, E.
Di Modugno, D. Donati, E. Fazzolari, E. Ratti, A. Feriani, S. Contini,
G. Gentile, D. Ghirlanda, S. Provera, C. Marchioro, K. L. Roberts, A.
Mingardi, M. Mattioli, A. Nalin, F. Pavone, S. Spada, D. G. Trist, A.
Worby, J. Med. Chem. 2008, 51, 7370–7379.
[59]
[60]
[61]
[
22]
P. Schwenkkraus, H. ‐H Otto, Liebigs Ann. der Chemie 1994, 1994,
251–257.
[
[
23]
24]
[62]
[63]
[64]
[65]
P. Schwenkkraus, H. ‐H Otto, Arch. Pharm. 1993, 326, 519–523.
D. Enders, S. Wallert, Tetrahedron Lett. 2002, 43, 5109–5111.
D. Enders, S. Wallert, J. Runsink, Synthesis 2003, 1856–1868.
D. Enders, A. Moll, A. Schaadt, G. Raabe, J. Runsink, Eur. J. Org.
Chem. 2003, 3923–3938.
D. Enders, A. Moll, Synthesis 2005, 1807–1816.
O. O. Grygorenko, P. Babenko, D. M. Volochnyuk, O. Raievskyi, I. V.
Komarov, RSC Adv. 2016, 6, 17595–17605.
[66]
[67]
[
25]
J. X. Qiao, C. H. Chang, D. L. Cheney, P. E. Morin, G. Z. Wang, S.
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.202000351
FULL PAPER
[
[
68]
69]
O. O. O. Grygorenko, D. Demenko, D. M. Volochnyuk, I. V.
Komarov, New J. Chem. 2018, 42, 8355–8365.
V. V. Semeno, V. O. Vasylchenko, B. V. Vashchenko, D. O.
Lutsenko, R. T. Iminov, O. B. Volovenko, O. O. Grygorenko, J. Org.
Chem. 2020, 85, 2321–2337.
Y. M. Sokolenko, Y. Y. Yurov, B. V. Vashchenko, O. V. Hryshchuk,
Y. Filimonova, E. N. Ostapchuk, A. Artemenko, O. V. Zaremba, O.
O. Grygorenko, J. Org. Chem. 2019, 84, 13908–13921.
W. L. F. Armarego, C. Chai, Purification of Laboratory Chemicals,
Elsevier: Oxford, 2003.
H. Tu, J. P. Powers, J. Liu, S. Ursu, A. Sudom, X. Yan, H. Xu, D.
Meininger, M. DeGraffenreid, X. He, J. C. Jaen, D. Sun, M. Labelle,
H. Yamamoto, B. Shan, N. P. C. Walker, Z. Wang, Bioorg. Med.
Chem. 2008, 16, 8922–8931.
Y. Rew, D. L. McMinn, Z. Wang, X. He, R. W. Hungate, J. C. Jaen,
A. Sudom, D. Sun, H. Tu, S. Ursu, E. Villemure, N. P. C. Walker, X.
Yan, Q. Ye, J. P. Powers, Bioorg. Med. Chem. Lett. 2009, 19, 1797–
1801.
Y. Kuroda, S. Harada, A. Oonishi, H. Kiyama, Y. Yamaoka, K. I.
Yamada, K. Takasu, Angew. Chem. Int. Ed. 2016, 55, 13137–13141.
H.-J. Liu, H. Wynn, Tetrahedron Lett. 1982, 23, 3151–3154.
[73]
[
70]
[74]
[75]
[
[
71]
72]
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.202000351
FULL PAPER
Entry for the Table of Contents
FULL PAPER
Spirocyclic sultams
Kateryna O. Stepannikova,
Bohdan V. Vashchenko,
Oleksandr O. Grygorenko,
Marian V. Gorichko,
Artem Yu. Cherepakha, Yurii S. Moroz,
Yulian M. Volovenko, Sergey A. Zhersh
Multigram synthesis of spirocyclic γ- and β-sultams – advanced building blocks for
organic synthesis and drug discovery – via one-pot reductive cyclization of cyclic
cyano sulfonyl fluorides is developed.
Page No. – Page No.
Synthesis of spirocyclic β- and γ-
sultams by one-pot reductive
cyclization of cyanoalkylsulfonyl
fluorides
Twitter: @EnamineLtd @KyivUniversity @Chem_space
This article is protected by copyright. All rights reserved.