[3+2] Cycloaddition of an Azomethyne Ylide and Vinyl Sulfonyl Fluorides ― an Approach to Pyrrolidine-3-sulfonyl Fluorides

Article abstract of DOI:10.1002/ejoc.201800521

[3+2] Cycloaddition reactions of vinyl sulfonyl fluorides with an in-situ generated nonstabilized azomethine ylide is described for the first time. The resulting pyrrolidine-3-sulfonyl fluorides were obtained in 50–83 % yield on a scale of up to 25 g. Their utility as reagents for sulfur(VI)–fluoride exchange (SuFEx) and some other transformations was also demonstrated.

Full text of DOI:10.1002/ejoc.201800521

A Journal of
Accepted Article
Title: [3+2] Cycloaddition of Azomethyne Ylide and Vinyl Sulfonyl
Fluorides - an Approach to Pyrrolidine-3-sulfonyl Fluorides
Authors: Volodymyr L. Mykhalchuk, Vladimir S. Yarmolchuk, Roman
O. Doroschuk, Andrey A. Tolmachev, and Oleksandr O
Grygorenko
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of the final Version of Record (VoR). This work is currently citable by
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201800521
Link to VoR: http://dx.doi.org/10.1002/ejoc.201800521
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10.1002/ejoc.201800521
European Journal of Organic Chemistry
FULL PAPER
[3+2] Cycloaddition of Azomethyne Ylide and Vinyl Sulfonyl
Fluorides – an Approach to Pyrrolidine-3-sulfonyl Fluorides
Volodymyr L. Mykhalchuk,[a,b] Vladimir S. Yarmolchuk,[a,b] Roman O. Doroschuk,[a,b]
Andrey A. Tolmachev,[a,b] Oleksandr O. Grygorenko*[a,b]
Abstract: [3+2] cycloaddition of vinyl sulfonyl fluorides and
generated in situ non-stabilized azomethine ylide is described for the
first time. The resulting pyrrolidine-3-sulfonyl fluorides were obtained
in 50–83% yields on up to 25 g scale. Their utility as reagents for
sulphur (VI) fluoride exchange (SuFEx) and some other
transformations was also demonstrated.
particular type of transformation – vinyl sulfonyl fluorides (1). It
should be noted that sulfonyl fluorides have given rise to
significant interest in recent years; they are widely used in
design of covalent inhibitors,[23] as well as reagents for sulfur (VI)
fluoride exchange (SuFEx), which was proposed by Sharpless
and co-workers as “another good reaction for the click
chemistry”.[24] Moreover, the parent vinyl sulfonyl fluoride (1a)
was referred to as “the most perfect Michael acceptor ever
found”.[24,25] To date, [3+2] cycloaddition with nitrones,[26] as well
as Diels – Alder reactions[27,28] of 1 were reported in the literature.
Introduction
Herein, we describe reactions of
1
with non-stabilized
[3+2] cycloaddition with azomethine ylides (Scheme 1) is an
important synthetic method which have attracted much attention
in the last two decades.[1–11] The main reason behind this is that
the products of this reaction – pyrrolidines – are important class
of compounds widespread among both natural products[12–14]
and synthetic drugs.[15] Typically, cycloaddition with azomethine
ylides requires participation of electron-poor dipolarophile;
various alkenes with electron-withdrawing groups (EWGs) were
studied comprehensively in the reaction including ,β-unsatu-
rated carboxylic acid derivatives, nitro compounds and
sulfones.[5] Vinyl sulfonamides were also introduced in this
transformation.[16–22]
azomethine ylide 2, as well as some further transformations of
the products 3 obtained (Scheme 2). It should be outlined that
pyrrolidines of the type 3 or their analogues have been virtually
unknown to date; only Cbz-protected sulfonyl chloride 4 was
described in the literature previously.[29,30] Meanwhile, these
conformationally restricted derivatives of β-amino sulfonic acids
are of special interest to organic and medicinal chemistry,[31] in
particular as building blocks in synthesis of sulfonopeptides.[32–34]
Scheme 2. Synthesis of sulfonyl fluorides 3 via [3+2] cycloaddition (relative
configuration is shown)
Scheme 1. [3+2] cycloaddition with azomethine ylides
Results and Discussion
First of all, we have checked if the standard protocol for
generation of azomethine ylide 2 (N-benzyl-1-methoxy-N-((trime-
thylsilyl)methyl)methanamine, CH2Cl2, cat. TFA, rt), which was
originally developed by Achiwa and co-workers[35,36] and has
been widely used by us[37–40] and others[41–44] in recent years,
works for the parent commercially available vinyl sulfonyl
fluoride 1a (Scheme 2, R1 = R2 = H). It was found that under
these typical conditions, the target adduct 3a was obtained in
75% yield (Table 1). Notably, the reaction could be scaled up to
25 g without significant change in its outcome.
Being encouraged by this result, we have prepared a series of
β-aryl-substituted vinyl sulfonyl fluorides 1b–j using a variation
of the previously reported method,[45,46] i.e. chlorosulfonation of
the corresponding styrenes 5b–h with varied electronic and
steric properties (42–71% yield), followed by reaction of the
sulfonyl chlorides 6b–h with KHF2 (92–99% yield, Scheme 3). In
In both above-mentioned cases, the resulting sulfur-containing
pyrrolidines
provide
limited
possibilities
for
further
functionalization. In this work, we report [3+2] cycloaddition of
azomethine ylides with novel organosulfur substrates for this
[a]
[b]
V. L. Mykhalchuk, V. S. Yarmolchuk, R. O. Doroschuk,
A. A. Tolmachev, O. O. Grygorenko
Enamine Ltd. (www.enamine.net)
Chervonotkatska Street 78, Kyiv 02094, Ukraine
V. L. Mykhalchuk, V. S. Yarmolchuk, R. O. Doroschuk,
A. A. Tolmachev, O. O. Grygorenko
National Taras Shevchenko University of Kyiv
Volodymyrska Street 60, Kyiv 01601, Ukraine
E-mail: gregor@univ.kiev.ua
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201800521
European Journal of Organic Chemistry
FULL PAPER
addition to that, bicyclic ,β-unsaturated sulfonyl fluorides 1i–k
were also prepared in 26–60% overall yield using the same
reaction sequence. It was found that all the substrates 1b–k
reacted smoothly under the conditions shown in Scheme 2, and
the corresponding adducts 3b–k were obtained in 50–83%
yields.
H
H
H
N
H
H
Strong
correlation
SO2F
H
Bn
Weak
correlation
Ar
Table 1. Reaction of vinyl sulfonyl fluorides
azomethine ylide 2 (according to Scheme 2)
1 and generated in situ
#
Substrate
Product
3a
R1
R2
H
H
H
H
H
H
H
H
Yield, %
80
Figure 1. Significant 1H-1H and 1H-19F NOESY correlations observed for 3e
(Ar = 4-ClC6H4) and/or 3g (Ar = 4-FC6H4)
1
1a
1b
1c
1d
1e
1f
H
2
3b
3c
Ph
82
To demonstrate utility of adducts 3 as (potentially) bifunctional
building blocks for organic synthesis and drug discovery, we
have performed some transformations at both protected amino
and sulfonyl fluoride functions. In particular, the parent
compound 3a smoothly underwent the SuFEx click reaction, so
that sulfonamides 7a–f were obtained (Scheme 4). In turn,
catalytic debenzylation of 7a–f gave free pyrrolidines 8a–f (87–
96% yield for two steps). Direct debenzylation was also possible
with 3a either upon action of chloroethyl formate, followed by
methanolysis, or catalytic hydrogenolysis in the presence of
Boc2O. Thus, sulfonyl fluorides 9 and 10 were obtained in 77%
and 94% yields, respectively. It was also shown that 9 can form
amides (e. g. 11, 72% yield) or carbamates (10 or 12, 90% and
50% yield, respectively) without the sulfonyl fluoride function
being affected.
3
4-MeC6H4
83
4
3d
3e
4-t-BuC6H4
4-ClC6H4
60
5
80
6
3f
4-BrC6H4
87
7
1g
1h
1i
3g
3h
3i
4-FC6H4
80
8
2-ClC6H4
77
9
–o-C6H4CH2CH2–
81
10
11
1j
3j
–o-C6H4CH2CH2CH2–
–o-C6H4CH2O–
50
1k
3k
70
Scheme 3. Synthesis of vinyl sulfonyl fluorides 1 (for R1/R2, see also Table 1)
Scheme 4. Chemical properties of amino sulfonyl fluoride 3a
As it might be expected for the synchronous process, single
diastereomers of the products 3b–n were formed in the reaction,
with trans relative configuration of the R1 and SO2F groups. This
was confirmed using NOESY experiments with adducts 3e and
3g (Figure 1).
Conclusions
[3+2] cycloaddition of vinyl sulfonyl fluorides and generated in
situ non-stabilized azomethine ylide 2 is an efficient method for
the multigram diastereoselective synthesis of 3-substituted, 3,4-
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10.1002/ejoc.201800521
European Journal of Organic Chemistry
FULL PAPER
2H-Chromene-3-sulfonyl chloride (6k). Yield 9.2 g, 26 %. Colorless
solid. Mp 58–59 °C. Anal. calcd. for C9H7ClO3S: C 46.87; H 3.06; S 13.9;
Cl 15.37. Found: C 46.61; H 3.23; S 14.01; Cl 15.62. 1H NMR (400 MHz,
CDCl3) δ = 7.51 (s, 1H), 7.41 – 7.32 (m, 1H), 7.28 – 7.20 (m, 1H), 7.02 (d,
J = 7.5, 1H), 6.93 (d, J = 8.2 Hz, 1H), 5.13 (s, 2H). 13C NMR (101 MHz,
CDCl3) δ = 154.7, 134.9, 134.4, 132.8, 130.4, 122.9, 118.6, 116.8, 62.6.
disubstituted, or 3,3,4-trisubstituted pyrrolidine-derived sulfonyl
fluorides. These adducts can be considered as monoprotected
bifunctional conformationally restricted building blocks, which
have great potential for application in drug discovery and organic
synthesis. This statement was illustrated by some common
chemical transformations, including sulphur (VI) fluoride
exchange (SuFEx) which has been recently referred to as
another click reaction;[24] in all cases, either the (protected)
amino function or the sulfonyl fluoride moiety participated in the
reaction selectively.
General procedure for the preparation of sulfonyl fluorides 1. To a
solution of sulfonyl chloride 6 (0.092 mol) in MeCN (320 mL), 28% aq
KHF2 (0.188 mol, 360 mL) was added, and the mixture was stirred at rt
overnight. After the reaction was completed, the upper layer of the
biphasic mixture was concentrated in vacuo, diluted with H2O (300 mL)
and extracted with EtOAc (3200 mL). The aqueous phase was
extracted with EtOAc (300 mL), and the combined organic extracts were
washed with 10% aq NaCl (2100 mL), brine (250 mL), dried over
Na2SO4, and concentrated under reduced pressure.
Experimental Section
General. The solvents were purified according to the standard
procedures.[47] Sulfonyl halides 1[45,46] and 6[48,49] were obtained using the
reported procedures. All other starting materials were purchased from
commercial sources. Melting points were measured on MPA100 OptiMelt
automated melting point system. Analytical TLC was performed using
Polychrom SI F254 plates. Column chromatography was performed
using Kieselgel Merck 60 (230–400 mesh) as the stationary phase. 1H
and 13C NMR spectra were recorded on a Bruker 170 Avance 500
spectrometer (at 499.9 MHz for Protons and 124.9 MHz for Carbon-13)
and Varian Unity Plus 400 spectrometer (at 400.4 MHz for protons and
100.7 MHz for Carbon-13). Chemical shifts are reported in 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. Mass spectra were recorded on an
Agilent 1100 LCMSD SL instrument (chemical ionization (APCI),
electrospray ionization (EI)) and Agilent 5890 Series II 5972 GCMS
instrument (electron impact ionization (EI)).
(E)-2-(p-Tolyl)ethenesulfonyl fluoride (1c).[45] Yield 17.7 g, 96%.
Colorless solid. Mp 132–133 °C. Anal. calcd. for C9H9FO2S: C 53.99; H
1
4.53; S 16.01. Found: C 54.11; H 4.45; S 16.02. MS (EI): 200 ([M]+). H
NMR (400 MHz, CDCl3): δ 7.76 (d, J = 15.5 Hz, 1H), 7.43 (d, J = 8.0 Hz,
2H), 7.26 (d, J = 8.0 Hz, 2H), 6.79 (d, J = 15.5 Hz, 1H), 2.40 (s, 3H). 13C
NMR (101 MHz, CDCl3): δ 148.9 (d, J = 2.7 Hz), 143.6, 130.1, 129.1,
128.3, 116.6 (d, J = 27.8 Hz), 21.7. 19F NMR (376 MHz, CDCl3): δ = 62.1.
(E)-2-(4-(tert-Butyl)phenyl)ethenesulfonyl fluoride (1d). Yield 21.8 g,
98%. Colorless solid. Mp 54–56 °C. Anal. calcd. for C12H15FO2S: C
59.48; H 6.24; S 13.23. Found: C 59.64; H 6.29; S 13.28. MS (EI): 242
([M]+). 1H NMR (400 MHz, CDCl3): δ 7.79 (d, J = 15.5 Hz, 1H), 7.49 (s,
4H), 6.82 (dd, J = 15.5, 2.6 Hz, 1H), 1.34 (s, 9H). 13C NMR (101 MHz,
CDCl3): δ 156.7, 148.8 (d, J = 2.7 Hz), 129.0, 128.2, 126.4, 116.7 (d, J =
27.8 Hz), 35.2, 31.0. 19F NMR (376 MHz, CDCl3): δ = 62.1.
(E)-2-(4-Chlorophenyl)ethenesulfonyl fluoride (1e).[45] Yield 18.7 g,
93%. Colorless solid. Mp 127–128 °C. Anal. calcd. for C8H6ClFO2S: C
43.55; H 2.74; S 14.53; Cl 16.07. Found: C 43.49; H 2.85; S 14.24; Cl
16.28. MS (EI): 220/222 ([M]+, 3:1). 1H NMR (400 MHz, CDCl3): δ 7.75 (d,
General procedure for the preparation of sulfonyl chlorides 6.
Sulfuryl chloride (41.6 g, 0.308 mol) was added dropwise to anhydrous
DMF (25 mL) at 0 °C with stirring under argon atmosphere. After the
addition was completed, the mixture was warmed to rt and stirred for
additional 0.5 h. Styrene 5 (0.154 mol) was then added in three portions,
and the reaction mixture was heated to 90 C over 3 h. The reaction
mixture was cooled and poured onto the crushed ice, the resulting
precipitate was filtered, washed with cold H2O and dissolved in t-BuOMe
(300 mL). If the precipitate was not formed, the mixture obtained after
pouring on ice was extracted with t-BuOMe (3150 mL). The organic
phase was washed with brine (150 mL), dried over Na2SO4 and
evaporated under reduced pressure. The crude product was
recrystallized from t-BuOMe.
J = 15.5 Hz, 1H), 7.52 – 7.39 (m, 4H), 6.83 (dd, J = 15.5, 2.6 Hz, 1H). 13
C
NMR (101 MHz, CDCl3): δ 147.3 (d, J = 2.6 Hz), 138.9, 130.2, 129.8,
129.4, 118.5 (d, J = 28.6 Hz). 19F NMR (376 MHz, CDCl3): δ = 53.68.
(E)-2-(4-Bromophenyl)ethenesulfonyl fluoride (1f).[50] Yield 22.9 g,
95%. Colorless solid. Mp 143–146 °C. Anal. calcd. for C8H6BrFO2S: C
36.25; H 2.28; S 12.09; Br 30.14. Found: C 36.34; H 2.65; S 11.95; Br
30.28. MS (EI): 264/266 ([M]+, 1:1). 1H NMR (500 MHz, CDCl3): δ 7.76 (d,
J = 15.5 Hz, 1H), 7.62 (d, J = 8.5 Hz, 1H), 7.43 (d, J = 8.5 Hz, 1H), 6.88
(dd, J = 15.5, 2.5 Hz, 1H). 13C NMR (126 MHz, CDCl3): δ 147.5 (d, J =
2.8 Hz), 132.9, 130.4, 130.0, 127.5, 118.8 (d, J = 28.7 Hz). 19F NMR (376
MHz, CDCl3): δ = 61.80.
3,4-Dihydronaphthalene-2-sulfonyl chloride (6i).[48] Yield 22.1 g, 63%.
Colorless solid. Mp 61–62 °C. Anal. сalcd. for C10H9ClO2S: C 52.52; H
3.97; S 14.02; Cl 15.50. Found: C 52.64; H 3.58; S 13.82; Cl 15.63. 1H
NMR (400 MHz, CDCl3): δ 7.55 (s, 1H), 7.41 – 7.32 (m, 1H), 7.32 – 7.18
(m, 3H), 3.07 (t, J = 8.3 Hz, 2H), 2.88 (t, J = 8.3 Hz, 2H). 13C NMR (101
MHz, CDCl3): δ 141.3, 137.4, 135.9, 131.8, 130.2, 129.5, 128.1, 127.5,
27.6, 22.1.
(E)-2-(4-Fluorophenyl)ethenesulfonyl fluoride (1g).[51] Yield 18.2 g,
97%. Colorless solid. Mp 92–94 °C. Anal. calcd. for C8H6F2O2S: C 47.06;
H 2.96; S 15.70. Found: C 46.92; H 3.02; S 16.03. MS (EI): 204 ([M]+). 1H
NMR (400 MHz, CDCl3): δ 7.78 (d, J = 15.5 Hz, 1H), 7.57 (dd, J = 8.5,
5.3 Hz, 2H), 7.17 (t, J = 8.5 Hz, 2H), 6.81 (dd, J = 15.5, 2.5 Hz, 1H). 13
C
NMR (101 MHz, CDCl3): δ 165.2 (d, J = 255.5 Hz), 147.5 (d, J = 2.7 Hz),
131.3 (d, J = 9.7 Hz), 127.3 (d, J = 2.9 Hz), 117.6 (dd, J = 28.3, 2.5 Hz),
116.8 (d, J = 22.3 Hz). 19F NMR (376 MHz, CDCl3): δ = 61.9 (s), –105.56
– –105.48 (m).
6,7-Dihydro-5H-benzo[7]annulene-8-sulfonyl chloride (6j). Yield
19.4 g, 52%. Colorless solid. Mp 63–64 °C. Anal. calcd. for C11H11ClO2S:
C 54.43; H 4.57; S 13.21; Cl 14.61. Found: C 54.09; H 4.23; S 13.08; Cl
14.7. 1H NMR (400 MHz, CDCl3): δ 7.73 (s, 1H), 7.42 – 7.14 (m, 4H),
2.99 (t, J = 6.5 Hz, 2H), 2.96 – 2.90 (m, 2H), 2.21 – 2.10 (m, 2H). 13C
NMR (101 MHz, CDCl3): δ 145.3, 143.4, 140.5, 134.7, 131.1, 130.3,
130.1, 126.9, 35.3, 30.2, 25.1.
(E)-2-(2-Chlorophenyl)ethenesulfonyl fluoride (1h).[52] Yield 18.6 g,
92%. Colorless oil. Anal. calcd. for C8H6ClFO2S: C 43.55; H 2.74; S
14.53; Cl 16.07. Found: C 43.67; H 2.69; S 14.48; Cl 15.94. MS (EI):
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10.1002/ejoc.201800521
European Journal of Organic Chemistry
FULL PAPER
1
220/222 ([M]+, 3:1). H NMR (400 MHz, CDCl3) δ 8.22 (dd, J = 15.7, 2.4
(3R*,4S*)-1-Benzyl-4-(p-tolyl)pyrrolidine-3-sulfonyl
fluoride (3c).
Yield 13.8 g, 83%. Colorless oil. Anal. calcd. for C18H20FNO2S: C 64.84;
H 6.05; N 4.20; S 9.62. Found: C 64.72; H 6.08; N 4.47; S 9.52. MS
Hz, 1H), 7.59 (dt, J = 7.7, 2.0 Hz, 1H), 7.53 – 7.41 (m, 2H), 7.35 (t, J =
7.4 Hz, 1H), 6.92 (dt, J = 15.6, 2.2 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ
144.6, 135.9, 133.3, 130.8, 129.3, 128.6, 127.5, 120.6 (d, J = 28.6 Hz).
19F NMR (376 MHz, CDCl3) δ 61.50.
1
(APCI) m/z: 334 ([M+H]+). H NMR (400 MHz, CDCl3): δ 7.40 – 7.20 (m,
7H), 7.14 (d, J = 7.8 Hz, 2H), 3.99 – 3.88 (m, 1H), 3.85 – 3.77 (m, 1H),
3.74 (d, J = 13.0 Hz, 1H), 3.69 (d, J = 13.0 Hz, 1H), 3.28 – 3.18 (m, 1H),
3.17 – 3.06 (m, 2H), 2.83 (dd, J = 9.5, 5.5 Hz, 1H), 2.32 (s, 3H). 13C NMR
(101 MHz, CDCl3): δ 138.1, 137.7, 137.4, 129.6, 128.5, 127.5, 127.2,
67.5 (d, J = 12.9 Hz), 61.2, 59.1, 54.6, 45.6, 21.0. 19F NMR (376 MHz,
CDCl3): δ 47.80.
3,4-Dihydronaphthalene-2-sulfonyl fluoride (1i). Yield 18.7 g, 96%.
Colorless oil. Anal. calcd. for C10H9FO2S: C 56.59; H 4.27; S 15.11.
Found: C 56.33; H 4.46; S 15.02. MS (EI): 212 ([M]+). 1H NMR (400 MHz,
CDCl3): δ 7.60 (s, 1H), 7.42 – 7.32 (m, 1H), 7.31 – 7.17 (m, 3H), 3.03 (t, J
= 8.3 Hz, 2H), 2.77 (t, J = 8.3 Hz, 2H). 13C NMR (126 MHz, CDCl3): δ
140.3, 136.1, 131.9, 130.4 (d, J = 25.1 Hz), 129.9, 129.8, 128.2, 127.6,
27.3, 22.1. 19F NMR (376 MHz, CDCl3) δ 53.68.
(3R*,4S*)-1-Benzyl-4-(4-(tert-butyl)phenyl)pyrrolidine-3-sulfonyl fluo-
ride (3d). Yield 11.2 g, 60%. Colorless solid. Mp 99–101 °C. Anal. calcd.
for C21H26FNO2S: C 67.17; H 6.98; N 3.73; S 8.54. Found: C 66.85; H
1
6.61; N 3.39; S 8.57. MS (APCI) m/z: 376 ([M+H]+). H NMR (400 MHz,
6,7-Dihydro-5H-benzo[7]annulene-8-sulfonyl fluoride (1j). Yield
20.4 g, 98%. Colorless solid. Mp 61–63 °C. Anal. calcd. for C11H11FO2S:
C 58.39; H 4.90; S 14.17. Found: C 58.17; H 4.84; S 14.45. MS (EI): 226
([M]+). 1H NMR (400 MHz, CDCl3): δ 7.72 (s, 1H), 7.41 – 7.13 (m, 3H),
2.97 – 2.89 (m, 2H), 2.84 (t, J = 6.5 Hz, 2H), 2.18 – 2.07 (m, 2H). 13C
NMR (101 MHz, CDCl3): δ 143.4, 142.6, 134.4, 134.2 (d, J = 20.5 Hz),
131.1, 130.6 (d, J = 1.4 Hz), 130.0, 126.8, 35.3, 30.3, 25.4. 19F NMR
(376 MHz, CDCl3) δ 51.95.
CDCl3): δ 7.39 – 7.21 (m, 9H), 4.00 – 3.89 (m, 1H), 3.85 – 3.79 (m, 1H),
3.74 (d, J = 16.0 Hz, 1H), 3.70 (d, J = 16.0 Hz, 1H), 3.28 – 3.18 (m, 1H),
3.11 (m, 2H), 2.92 – 2.80 (m, 1H), 1.30 (s, 9H). 13C NMR (101 MHz,
CDCl3): δ 150.6, 138.1, 137.7, 128.7 – 128.3 (2C), 127.5, 127.0, 125.9,
67.4 (d, J = 13.0 Hz), 61.1, 59.2, 54.6, 45.4, 34.5, 31.3. 19F NMR (376
MHz, CDCl3): δ = 47.7.
(3R*,4S*)-1-Benzyl-4-(4-chlorophenyl)pyrrolidine-3-sulfonyl fluoride
(3e). Yield 14.1 g, 80%. Colorless solid. Mp 73–74 °C. Anal. calcd. for
2H-Chromene-3-sulfonyl fluoride (1k). Yield 19.5 g, 99%. Colorless oil.
Anal. calcd. for C9H7FO3S: C 50.46; H 3.29; S 14.97. Found: C 50.84;
H 3.69; S 15.14. MS (EI): 214 ([M]+). 1H NMR (400 MHz, CDCl3) δ = 7.57
(s, 1H), 7.36 (d, J = 7.9 Hz, 1H), 7.29 – 7.18 (m, 1H), 7.09 – 6.99 (m, 1H),
6.92 (d, J = 8.2 Hz, 1H), 5.03 (s, 2H). 13C NMR (101 MHz, CDCl3) δ =
154.8, 138.1 (d, J = 2.8 Hz), 134.4, 130.1, 122.8, 122.5, 122.2, 118.8,
116.8, 62.5. 19F NMR (376 MHz, CDCl3) δ 57.45.
C17H17ClFNO2S: C 57.71; H 4.84; N 3.96; S 9.06; Cl 10.02. Found:
C 57.45; H 4.57; N 4.22; S 9.13; Cl 9.72. MS (APCI) m/z: 354/356
([M+H]+, 3:1). 1H NMR (400 MHz, CDCl3): δ 7.43 – 7.18 (m, 9H), 3.89 (dd,
J = 14.0, 7.0 Hz, 1H, 3-CH), 3.81–3.76 (m, 1H, 4-CH), 3.74 (d, J = 13.2
Hz, 1H, CHHPh), 3.70 (d, J = 13.2 Hz, 1H, CHHPh), 3.29 (t, J = 9.5 Hz,
1H, 2-CHH), 3.10 – 3.03 (m, 2H, 2-CHH and 5-CHH), 2.86 (dd, J = 9.5,
4.8 Hz, 1H, 5-CHH). 13C NMR (101 MHz, CDCl3): δ 139.8, 137.5, 133.5,
129.2, 128.8, 128.6, 128.5, 127.6, 67.3 (d, J = 13.2 Hz, 3-CH), 60.8 (5-
CH2), 59.1 (CH2Ph), 54.6 (2-CH2), 45.3 (4-CH). 19F NMR (376 MHz,
CDCl3): δ 47.9.
General procedure for the preparation of sulfonyl fluorides 3. A
solution of the sulfonyl fluoride 1 (50.0 mmol) in CH2Cl2 (75 mL) was
cooled to
0 °C under argon. N-benzyl-1-methoxy-N-((trimethylsilyl)-
methyl)methanamine (12.1 g, 5.5 mmol) was added in one portion, and
then dropwise addition of trifluoroacetic acid (0.38 mL, 5.0 mmol) in
CH2Cl2 (5 mL) followed at 0 °C. After the reaction was complete
(monitored by 1H NMR), the mixture was diluted with H2O (50 mL), the
organic layer was separated, washed with saturated aq NaHCO3 (225
mL) and brine (25 mL), dried over Na2SO4, and evaporated under
reduced pressure. The residue was purified by recrystallization (Hexanes
– t-BuOMe) or column chromatography.
(3R*,4S*)-1-Benzyl-4-(4-bromophenyl)pyrrolidine-3-sulfonyl fluoride
(3f). Yield 17.3 g, 87%. Colorless solid. Mp 61–62 °C. Anal. calcd. for
C17H17BrFNO2S: C 51.27; H 4.30; N 3.52; S 8.05; Br 20.06. Found:
C 51.41; H 4.69; N 3.68; S 7.68; Br 19.67. MS (APCI) m/z: 398/400
1
([M+H]+, 1:1). H NMR (400 MHz, CDCl3): δ 7.50 – 7.42 (m, 2H), 7.39 –
7.21 (m, 7H), 3.89 (q, J = 6.5 Hz, 1H), 3.83 – 3.65 (m, 3H), 3.29 (t, J =
9.4 Hz, 1H), 3.11 – 3.02 (m, 2H), 2.91 – 2.81 (m, 1H). 13C NMR (101
MHz, CDCl3): δ 140.3, 137.5, 132.1, 129.1, 128.6, 128.5, 127.6, 121.6,
67.2 (d, J = 13.3 Hz), 60.8, 59.1, 54.6, 45.3. 19F NMR (376 MHz, CDCl3):
δ 48.0.
1-Benzylpyrrolidine-3-sulfonyl fluoride (3a). Yield 25.1 g, 80%.
Colorless oil. Anal. calcd. for C11H14FNO2S: C 54.30; H 5.80; N 5.76;
S 13.18. Found: C 54.61; H 5.99; N 5.42; S 13.02. MS (APCI) m/z: 244
([M+H]+). 1H NMR (500 MHz, CDCl3): δ 7.38 – 7.25 (m, 5H), 3.98 (p, J =
7.7 Hz, 1H), 3.70 (d, J = 12.9 Hz, 1H), 3.67 (d, J = 12.9 Hz, 1H), 3.16 –
3.08 (m, 1H), 2.95 (dd, J = 10.6, 6.3 Hz, 1H), 2.84 – 2.75 (m, 1H), 2.71 (q,
J = 7.2 Hz, 1H), 2.43 – 2.34 (m, 2H). 13C NMR (126 MHz, CDCl3): δ
137.9, 128.7, 128.6, 127.6, 59.3, 59.0 (d, J = 14.8 Hz), 54.1, 52.9, 26.8.
19F NMR (376 MHz, CDCl3): δ 46.30.
(3R*,4S*)-1-Benzyl-4-(4-fluorophenyl)pyrrolidine-3-sulfonyl fluoride
(3g). Yield 13.5 g, 80%. Colorless solid. Mp 59–60 °C. Anal. calcd. for
C17H17F2NO2S: C 60.52; H 5.08; N 4.15; S 9.50. Found: C 60.18; H 5.43;
N 4.07; S 9.51.MS (APCI): 338 ([M+H]+). 1H NMR (500 MHz, CDCl3): δ
7.39 – 7.26 (m, 7H), 7.04 (t, J = 8.6 Hz, 2H), 3.92 (dd, J = 14.0 and 6.9
Hz, 1H, 3-CH), 3.87 – 3.79 (m, 1H. 4-CH), 3.76 (d, 12.9 Hz, 1H, CHHPh) ,
3.73 (d, 12.9 Hz, 1H, CHHPh), 3.30 (t, J = 9.5 Hz, 1H, 2-CHH), 3.11 –
3.04 (m, 2H, 2-CHH and 5-CHH), 2.88 (dd, J = 9.5, 4.9 Hz, 1H, 5-CHH).
13C NMR (126 MHz, CDCl3): δ 163.2, 161.3, 137.7, 137.2 (d, J = 3.3 Hz),
129.1 (d, J = 8.1 Hz), 128.6 (d, J = 5.9 Hz), 127.7, 116.0 (d, J = 21.4 Hz),
67.6 (d, J = 13.2 Hz), 61.1, 59.2, 54.7, 45.3. 19F NMR (376 MHz, CDCl3):
δ 47.87, –115.14.
(3R*,4S*)-1-Benzyl-4-phenylpyrrolidine-3-sulfonyl fluoride (3b). Yield
13.1 g, 82%. Colorless oil. Anal. calcd. for C17H18FNO2S: C 63.93; H
5.68; N 4.39; S 10.04. Found: C 63.83; H 5.70; N 4.31; S 9.71. MS
1
(APCI) m/z: 320 ([M+H]+). H NMR (500 MHz, CDCl3): δ 7.42 – 7.27 (m,
10H), 4.05 – 3.95 (m, 1H), 3.90 – 3.84 (m, 1H), 3.78 (d, J = 12.8 Hz, 1H),
3.75 (d, J = 12.8 Hz, 1H), 3.30 (t, J = 9.5 Hz, 1H), 3.20 – 3.12 (m, 2H),
2.91 (dd, J = 9.5, 5.4 Hz, 1H). 13C NMR (126 MHz, CDCl3): δ 140.7,
137.3, 128.6, 128.1, 127.3, 127.1, 127.0, 67.0 (d, J = 13.0 Hz), 60.7, 58.7,
54.3, 45.6. 19F NMR (376 MHz, CDCl3): δ 47.9.
(3R*,4S*)-1-Benzyl-4-(2-chlorophenyl)pyrrolidine-3-sulfonyl fluoride
(3h). Yield 13.6 g, 77%. Colorless oil. Anal. calcd. for C17H17ClFNO2S:
C 57.71; H 4.84; N 3.96; S 9.06; Cl 10.02. Found: C 57.70; H 4.67; N
1
4.12; S 9.21; Cl 10.39. MS (APCI): 354/356 ([M+H]+, 3:1). H NMR (400
MHz, CDCl3): δ 7.49 (dd, J = 7.8, 1.7 Hz, 1H), 7.41 – 7.16 (m, 8H), 4.46 –
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800521
European Journal of Organic Chemistry
FULL PAPER
4.36 (m, 1H), 4.16 – 4.06 (m, 1H), 3.76 (d, J = 13.0 Hz, 1H), 3.71 (d, J =
13.0 Hz, 1H), 3.31 (t, J = 9.4 Hz, 1H), 3.24 – 3.12 (m, 2H), 2.82 (dd, J =
9.4, 5.7 Hz, 1H). 13C NMR (101 MHz, CDCl3): δ 138.1, 137.6, 133.5,
130.0, 128.9 (2C), 128.5, 127.6, 127.5, 66.0 (d, J = 13.9 Hz), 60.4, 59.0,
54.4, 42.6. 19F NMR (376 MHz, CDCl3): δ 48.30.
3-(N-Methylsulfamoyl)pyrrolidine hydrochloride (8bHCl). Yield 7.94 g,
86%. Colorless solid. Mp 167–168 °C. Anal. calcd. for C5H13ClN2O2S: C
29.93; H 6.53; N 13.96; S 15.98; Cl 17.66. Found: C 30.11; H 6.67;
N 14.08; S 16.15; Cl 17.76.MS (APCI): 165 ([M+H]+). 1H NMR (400 MHz,
DMSO-d6) δ = 9.75 (s, 2H), 7.48 (q, J = 4.8 Hz, 1H), 4.11 – 3.99 (m, 1H),
3.58 – 3.48 (m, 1H), 3.38 – 3.28 (m, 1H), 3.30 – 3.13 (m, 2H), 2.61 (d,
J=4.8 Hz, 3H), 2.32 – 2.13 (m, 2H). 13C NMR (101 MHz, DMSO-d6) δ =
56.7, 45.1 (2C), 29.1, 26.8.
2-Benzyl-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]isoindole-3a-sulfonyl
fluoride (3i). Yield 13.9 g, 81%. Colorless solid. Mp 77–78 °C. Anal.
calcd. for C19H20FNO2S: C 66.07; H 5.84; N 4.05; S 9.28. Found: C
65.81; H 5.48; N 3.86; S 8.97. MS (APCI) m/z: 345 ([M+H]+). 1H NMR
(500 MHz, CDCl3): δ 7.39 – 7.10 (m, 4H), 4.07 – 4.00 (m, 1H), 3.70 –
3.60 (m, 3H), 3.36 (t, J = 8.5 Hz, 1H), 2.90 – 2.82 (m, 2H), 2.77 (dd, J =
11.4, 2.4 Hz, 1H), 2.38 (t, J = 8.5 Hz, 1H), 2.29 – 2.18 (m, 2H). 13C NMR
(126 MHz, CDCl3): δ 137.8, 136.1, 135.3, 128.8, 128.6, 128.5, 128.3,
127.5, 127.2, 127.1, 70.9 (d, J = 10.5 Hz), 62.9, 60.9, 58.9, 44.0, 29.9,
25.8. 19F NMR (376 MHz, CDCl3): δ 35.99.
N-Ethylpyrrolidine-3-sulfonamide (8c). Yield 22.4 g, 94%. Colorless
solid. Mp 69–70 °C. Anal. calcd. for C6H14N2O2S: C 40.43; H 7.92; N
15.72; S 17.99. Found: C 40.06; H 7.61; N 15.43; S 17.69. MS (APCI):
179 ([M+H]+). 1H NMR (400 MHz, DMSO-d6) δ = 7.01 (s, 1H), 3.63 – 3.53
(m, 1H), 3.20 – 2.80 (br. s, 1H), 3.06 – 2.93 (m, 6H), 2.88 – 2.77 (m, 1H),
2.78 – 2.67 (m, 1H), 2.01 – 1.82 (m, 2H), 1.07 (t, J=7.2 Hz, 3H). 13C NMR
(101 MHz, DMSO-d6) δ = 60.6, 49.1, 47.6, 37.8, 29.0, 16.2.
2-Benzyl-1,2,3,3a,4,5,6,10b-octahydrobenzo[3,4]cyclohepta[1,2-c]-
pyrrole-3a-sulfonyl fluoride (3j). Yield 8.98 g, 50%. Colorless oil. Anal.
calcd. for C20H22FNO2S: C 66.83; H 6.17; N 3.90; S 8.92. Found:
N-Isopropylpyrrolidine-3-sulfonamide (8d). Yield 4.09 g, 96%.
Colorless solid. Mp 105–106 °C. Anal. calcd. for C7H16N2O2S: C 43.73; H
8.39; N 14.57; S 16.67. Found: C 43.36; H 8.65; N 14.67; S 16.49. MS
(APCI): 193 ([M+H]+). 1H NMR (400 MHz, DMSO-d6) δ 7.03 (d, J = 7.8
Hz, 1H), 3.76 – 3.49 (m, 1H), 3.49 – 3.38 (m, 1H), 3.05 – 2.90 (m, 2H),
3.05 – 2.93 (m, 1H), 2.77 – 2.70 (m, 1H), 2.70 – 2.54 (m, 2H), 2.01 –
1.82 (m, 2H), 1.31 – 0.83 (m, 6H). 13C NMR (101 MHz, DMSO-d6) δ
61.46, 49.30, 47.67, 45.59, 29.19, 24.56 (d, J = 3.1 Hz).
1
C 66.86; H 5.98; N 4.29; S 8.74. MS (APCI) m/z: 360 ([M+H]+). H NMR
(500 MHz, CDCl3) δ 7.42 – 7.34 (m, 4H), 7.33 – 7.20 (m, 4H), 7.14 (d, J =
7.2 Hz, 1H), 4.13 (t, J = 6.3 Hz, 1H), 3.78 (s, 2H), 3.35 (d, J = 11.4 Hz,
1H), 3.29 – 3.14 (m, 2H), 3.08 (d, J = 11.4 Hz, 1H), 2.87 – 2.76 (m, 1H),
2.02 - 1.94 (m, 3H), 1.90 – 1.77 (m, 1H). 13C NMR (126 MHz, CDCl3) δ
138.4, 138.2, 135.7, 129.7, 128.5, 128.5, 128.3, 127.4, 126.9, 59.4, 58.7,
57.7, 48.2, 29.7, 28.6, 21.1. 19F NMR (470 MHz, CDCl3) δ 39.42.
3-(N-Cyclopropylsulfamoyl)pyrrolidine hydrochloride (8eHCl). Yield
14.2 g, 87%. Colorless solid. Mp 165–166 °C. Anal. calcd. for
C7H15ClN2O2S: C 37.08; H 6.67; N 12.36; S 14.14; Cl 15.64. Found: C
2-Benzyl-1,2,3,3a,4,9b-hexahydrochromeno[3,4-c]pyrrole-3a-sulfo-
nyl fluoride (3k). Yield 12.1 g, 70%. Colorless solid. Mp 105–108 °C.
Anal. сalcd. for C18H18FNO3S: C 62.23; H 5.22; N 4.03; S 9.23. Found:
C 62.51; H 5.11; N 3.81; S 9.05. MS (APCI): m/z = 348 ([M+H]+). 1H NMR
(400 MHz, CDCl3) δ = 7.41 – 7.25 (m, 5H), 7.25 – 7.16 (m, 1H), 7.17 –
7.08 (m, 1H), 7.07 – 6.93 (m, 1H), 4.64 (d, J = 12.3 Hz, 1H), 4.08 (dd, J =
12.3, 3.8 Hz, 1H), 4.00 (t, J = 7.5 Hz, 1H), 3.82 – 3.63 (m, 2H), 3.52 (d, J
= 11.1 Hz, 1H), 3.46 (t, J = 8.6 Hz, 1H), 2.83 – 2.57 (m, 2H). 13C NMR
(101 MHz, DMSO-d6) δ = 153.3, 136.9, 128.5, 128.1, 127.9, 127.8, 127.1,
122.2, 121.7, 117.2, 68.4 (d, J = 11.0 Hz), 66.3, 60.8, 58.1, 57.5, 39.1.
19F NMR (376 MHz, CDCl3): δ 43.7.
1
36.87; H 7.03; N 12.67; S 13.89; Cl 15.41. MS (APCI): 191 ([M+H]+). H
NMR (400 MHz, DMSO-d6) δ = 10.37 – 9.26 (m, 2H), 7.97 – 7.91 (m, 1H),
4.09 (p, J=6.9 Hz, 1H), 3.62 – 3.51 (m, 1H), 3.41 – 3.31 (m, 1H), 3.28 –
3.13 (m, 2H), 2.55 – 2.44 (m, 1H), 2.35 – 2.16 (m, 2H), 0.66 – 0.51 (m,
4H). 13C NMR (101 MHz, DMSO-d6) δ = 57.4, 45.1, 26.7, 24.4, 6.2, 6.1.
3-(Pyrrolidin-1-ylsulfonyl)pyrrolidine hydrochloride (8fHCl). Yield
5.12 g, 92%. Colorless solid. Mp 178–179 °C. Anal. calcd. for
C8H17ClN2O2S: C 39.91; H 7.12; N 11.64; S 13.32; Cl 14.72. Found: C
1
40.11; H 7.02; N 11.26; S 13.54; Cl 14.52. MS (APCI): 205 ([M+H]+). H
NMR (400 MHz, DMSO-d6) δ = 9.81 (s, 2H), 4.18 (p, J=7.6 Hz, 1H), 3.61
– 3.51 (m, 1H), 3.44 – 3.02 (m, 7H), 2.36 – 2.22 (m, 1H), 2.24 – 2.10 (m,
1H), 1.91 – 1.79 (m, 4H). 13C NMR (101 MHz, DMSO-d6) δ = 57.1, 48.2,
45.1, 45.0, 27.0, 25.8.
General procedure for the preparation of sulfonamides 8. To a
solution of sulfonyl fluoride (3a) (15.0 mmol) in 1,4-dioxane (30 mL), the
corresponding amine (45.0 mol) was added (in the case 8a–c, 25–40%
aqueous amines were used), and the mixture was heated at 50 °C. After
the reaction was complete (monitored by 1H NMR), the solvent was
evaporated in vacuo, the residue was diluted with water (50 mL) and
extracted with EtOAc (350 mL). The combined organic extracts were
washed with brine (25 mL), dried over Na2SO4 and evaporated under
reduced pressure to give sulfonamide 7, which was used in the next step
without purification. The residue was dissolved in anhydrous MeOH (60
mL) and 10% Pd-C (0.3 g) was added. This mixture was hydrogenated
under 300 psi of H2 at rt for ca. 10 h. After the reaction was complete
3-(Fluorosulfonyl)pyrrolidine hydrochloride (9). To a solution of 3a
(45.0 g, 0.185 mol) in CH2Cl2 (500 mL), 1-chloroethyl chloroformate (33.9
g, 0.241 mol) was added dropwise at 0 C. The reaction mixture was
refluxed for 8 h and then evaporated in vacuo. The residue was dissolved
in MeOH (500 mL) heated to reflux for 2 h, and then cooled to rt. The
solvent was evaporated in vacuo and the residue was triturated with
acetone (250 mL). The resulting solid was filtered and dried on air. Yield
26.3 g, 77%. White powder. Mp 140–141 °C. Anal. calcd. for
C4H9ClFNO2S: C 25.34; H 4.78; N 7.39; S 16.91; Cl 18.69. Found: C
25.49; H 4.65; N 7.19; S 17.12; Cl 18.63. MS (APCI): m/z = 154 ([M+H]+).
1H NMR (400 MHz, DMSO-d6): δ 10.15 (s, 2H), 5.07 – 4.94 (m, 1H), 3.79
(dd, J = 13.4, 9.0 Hz, 1H), 3.59 (dd, J = 13.4, 5.6 Hz, 1H), 3.38 – 3.22 (m,
2H), 2.61 – 2.48 (m, 1H), 2.47 – 2.34 (m, 1H). 13C NMR (101 MHz,
DMSO-d6): δ 58.5 (d, J = 15.7 Hz), 45.1, 44.8, 27.1. 19F NMR (376 MHz,
DMSO-d6): δ 48.0.
1
(monitored by H NMR), the catalyst was filtered off, and the filtrate was
evaporated in vacuo. The crude product was triturated with t-BuOMe
(10–20 mL) and filtered.
Pyrrolidine-3-sulfonamide (8a). Yield 20.2 g, 90%. Colorless solid. Mp
124–125 °C. Anal. calcd. for C4H10N2O2S: C 31.99; H 6.71; N 18.65;
S 21.34. Found: C 32.25; H 6.32; N 18.34; S 21.66. MS (APCI): 151
1
([M+H]+). H NMR (400 MHz, DMSO-d6) δ = 6.75 (s, 2H), 3.47 (p, J=7.1
Hz, 1H), 3.10 – 2.40 (br. s, 1H), 3.07 – 2.93 (m, 2H), 2.87 – 2.78 (m, 1H),
2.77 – 2.66 (m, 1H), 1.93 (q, J = 7.1 Hz, 2H). 13C NMR (101 MHz,
DMSO-d6) δ = 63.2, 49.4, 47.6, 29.3.
tert-Butyl 3-(fluorosulfonyl)pyrrolidine-1-carboxylate (10).
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800521
European Journal of Organic Chemistry
FULL PAPER
From 9: To a solution of 9 (14.8 g, 78.1 mmol) and di-tert-butyl
dicarbonate (17.0 g, 78.1 mmol) in THF (250 mL), a solution of Et3N
(11.0 mL, 78.9 mmol) in THF (50 mL) was added dropwise. The resulting
mixture was stirred at rt for 24 h, and the solvent was evaporated under
reduced pressure. The residue was dissolved in t-BuOMe (100 mL),
washed with H2O (250 mL), 10% aq citric acid (250 mL), saturated aq
NaHCO3 (250 mL), and brine (50 mL). The organic layer was dried over
Na2SO4 and evaporated in vacuo. Yield 17.8 g, 90%. Anal. calcd. for
C9H16FNO4S: C 42.68; H 6.37; N 5.53; S 12.66. Found: C 42.61; H 6.59;
N 5.15; S 12.79. MS (EI): m/z = 253 ([M]+).1H NMR (400 MHz, CDCl3): δ
4.07 – 3.97 (m, 1H), 3.97 – 3.70 (m, 3H), 3.68 – 3.53 (m, 1H), 3.53 –
3.39 (m, 1H), 2.55 – 2.33 (m, 2H), 1.42 (s, 9H). 13C NMR (126 MHz,
CDCl3): δ 153.0, 80.0, 58.8 (d, J = 80.6 Hz), 45.6, 43.8, 27.8, 26.8. 19F
NMR (376 MHz, CDCl3): δ 47.3 (d, J = 11.6 Hz).
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From 3a: Compound 3a (3.51 g, 14.4 mmol) was dissolved in anhydrous
MeOH (50 mL), and Pd(OH)2-C (0.710 g) was added, followed by di-tert-
butyl dicarbonate (3.22 g, 15.1 mmol). This mixture was hydrogenated
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1
(monitored by H NMR), the catalyst was filtered off, and the filtrate was
evaporated in vacuo. Yield 3.42 g, 94%.
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1-Benzoylpyrrolidine-3-sulfonyl fluoride (11). To a suspension of 9
(0.381 g, 2.05 mmol) in CH2Cl2 (5 mL), benzoyl chloride (0.23 mL, 2.10
mmol) was added, followed by Et3N (0.61 mL, 4.05 mmol). The resulting
mixture was stirred at rt overnight. The resulting mixture diluted with H2O
(5 mL), the organic layer was washed with saturated aq NaHCO3 (25
mL) and brine (25 mL), dried over Na2SO4, and evaporated under
reduced pressure. Yield 0.379 g, 72%. Anal. calcd. for C11H12FNO3S: C
51.35; H 4.70; N 5.44; S 12.46. Found: C 51.19; H 4.66; N 5.71; S 12.42.
MS (APCI): 258 ([M+H]+). 1H NMR (500 MHz, CDCl3) δ 7.58 – 7.34 (m,
5H), 4.45 – 3.51 (m, 5H), 2.69 – 2.38 (m, 2H). 13C NMR (126 MHz,
CDCl3) δ 169.3, 135.0, 130.2, 128.1, 126.6, 59.2 and 58.1, 48.7 and 47.0,
45.9 and 44.1, 27.4 and 25.5. 19F NMR (376 MHz, CDCl3) δ 48.33 and
47.74.
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Ethyl 3-(fluorosulfonyl)pyrrolidine-1-carboxylate (12). Compound 12
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instead of benzoyl chloride. Yield 0.228 g, 50%. Anal. calcd. for
C7H12FNO4S: C 37.33; H 5.37; N 6.22; S 14.23. Found: C 37.35; H 5.22;
N 6.42; S 14.54. MS (EI): 225 ([M]+). 1H NMR (500 MHz, CDCl3) δ 4.25 –
4.12 (m, 2H), 4.14 – 3.85 (m, 3H), 3.77 – 3.64 (m, 1H), 3.59 (s, 1H), 2.55
(s, 1H), 2.49 (s, 1H), 1.25–1.30 (m, 3H). 13C NMR (126 MHz, CDCl3) δ
154.0 and 153.8, 61.2, 59.2 (d, J = 15.8 Hz) and 58.4 (d, J = 15.2 Hz),
45.9 and 45.5, 44.1 and 43.7, 26.8 and 26.0, 14.14.19F NMR (470 MHz,
CDCl3) δ 48.07 and 48.02.
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Entry for the Table of Contents
FULL PAPER
Sulfonyl Fluorides
Volodymyr L. Mykhalchuk, Vladimir S.
Yarmolchuk, Andrey A. Tolmachev,
Roman O. Doroschuk,
Oleksandr O. Grygorenko*
Page No. – Page No.
[3+2] cycloaddition of various vinyl sulfonyl fluorides and unsubstituted azomethine
ylide results in the formation of pyrrolidine-3-sulfonyl fluorides. The method is
scalable, and the products are suitable building blocks for sulphur (VI) fluoride
exchange (SuFEx), which has been referred to as another click reaction.
[3+2] Cycloaddition of Azomethyne
Ylide and Vinyl Sulfonyl Fluorides –
an Approach to Pyrrolidine-3-sulfonyl
Fluorides
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