Synthesis of 2-carboxylated aza-ring derivatives through α-monohalogenation/ring-contraction of N-sulfonyl lactams

Article abstract of DOI:10.1016/j.tet.2017.06.067

2-Carboxylated aza-rings have been synthesized in two steps through a highly selective monohalogenation of N-sulfonylated lactams of various ring sizes (from 5- to 8-membered rings) followed by a ring contraction reaction. The selective monohalogenation of N-sulfonyl lactams has been achieved in modest to excellent yields (9 examples, 39–96%) using N-halogenosuccinimides via the in situ generation of trimethylsilyl ketene aminal derivatives. The so-obtained α-halogeno N-sulfonyl lactams were engaged in a ring opening/ring closing reaction in the presence of various alcohols or anilines under basic conditions affording 2-carboxylated aza-rings, such as azetidine, pyrrolidine or piperidine derivatives in high yields (24 examples, 61–99%).

Full text of DOI:10.1016/j.tet.2017.06.067

Accepted Manuscript
Synthesis of 2-carboxylated aza-ring derivatives through α-monohalogenation/ring-
contraction of N-Sulfonyl lactams
Fatih Sirindil, Solène Miaskiewicz, Nicolas Kern, Arno Lalaut, Anne-Sophie Felten,
Jean-Marc Weibel, Patrick Pale, Aurélien Blanc
PII:
S0040-4020(17)30710-X
10.1016/j.tet.2017.06.067
TET 28832
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 31 May 2017
Revised Date: 27 June 2017
Accepted Date: 28 June 2017
Please cite this article as: Sirindil F, Miaskiewicz Solè, Kern N, Lalaut A, Felten A-S, Weibel J-M, Pale
P, Blanc Auré, Synthesis of 2-carboxylated aza-ring derivatives through α-monohalogenation/ring-
contraction of N-Sulfonyl lactams, Tetrahedron (2017), doi: 10.1016/j.tet.2017.06.067.
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to
our customers we are providing this early version of the manuscript. The manuscript will undergo
copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please
note that during the production process errors may be discovered which could affect the content, and all
legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT
Graphical Abstract
Synthesis of 2-Carboxylated Aza-Ring
Derivatives through α-Monohalogenation/Ring-
Contraction of N-Sulfonyl Lactams
Leave this area blank for abstract info.
Fatih Sirindil, Solène Miaskiewicz, Nicolas Kern, Arno Lalaut, Anne-Sophie Felten, Jean-Marc Weibel,
Patrick Pale* and Aurélien Blanc*
Laboratoire de Synthèse, Réactivité Organiques et Catalyse, Institut de Chimie, UMR 7177 - CNRS, Université
de Strasbourg, 4 rue Blaise Pascal, 67070 Strasbourg, France.

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Synthesis of 2-Carboxylated Aza-Ring Derivatives through α-
Monohalogenation/Ring-Contraction of N-Sulfonyl Lactams
Fatih Sirindila, Solène Miaskiewicza, Nicolas Kerna, Arno Lalauta, Anne-Sophie Feltena, Jean-Marc
Weibela, Patrick Palea* and Aurélien Blanca*
a Laboratoire de Synthèse, Réactivité Organiques et Catalyse, Institut de Chimie, UMR 7177 - CNRS, Université de Strasbourg, 4 rue Blaise Pascal, 67070
Strasbourg, France.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
2-Carboxylated aza-rings have been synthesized in two steps through a highly selective
monohalogenation of N-sulfonylated lactams of various ring sizes (from 5- to 8-membered
rings). The selective monohalogenation of N-sulfonyl lactams has been achieved in modest to
excellent yields (9 examples, 39-96%) using N-halogenosuccinimides via the in situ generation
of trimethylsilyl ketene aminal derivatives. The so-obtained α-halogeno N-sulfonyl lactams were
engaged in a ring opening/ring closing reaction in the presence of various alcohols or anilines
under basic conditions affording 2-carboxylated aza-rings, such as azetidine, pyrrolidine or
piperidine derivatives in high yields (19 examples, 19-99%).
Available online
Keywords:
Monohalogenation,
Ring-Contraction,
N-Sulfonyl Lactams
2-Carboxylate Aza-Rings
2009 Elsevier Ltd. All rights reserved
.
1. Introduction
lactams 2 with various nucleophiles (Scheme 1). We started from
N-sulfonylated lactams 1 to favor the nucleophilic attack over
proton transfer and to stabilize the intermediate anion.
N-heterocyclic aminoacids are important natural products
found in various organisms, in which they play different roles,
either defensive or vital (Figure 1, top). The latter aspect can be
illustrated by the azetidine-2-carboxylic acid (AZE) or natural
products containing the AZE motif such as mugineic acid
family,1 which exhibits chelating properties for iron and other
metals required for organism growth. The former role can be
represented with the kainic acid family2 with their anthelmintic
and neuroexcitatory activities. These N-heterocyclic aminoacids
thus often act as lead structures towards drug discovery (Figure
1, bottom). Recently, they even raised more interest with the
emergence of conformationally restricted, but non-flattened and
non-aromatic building blocks as alternative scaffolds for drug
candidates.3 However, few routes have been reported to form
these functionalized heterocycles, especially for small rings such
as azetidines.4
Figure 1. Selected Examples of Azetidine, Pyrrolidine and Piperidine
Carboxylic Acids Containing Natural Products and Drugs.
For the investigation of metal-catalyzed rearrangements of
various heterocycles,5 we developed rapid, reliable and scalable
syntheses of N-aryl azetidines6 and substituted N-protected α-
carbonylated azetidines from easily available pyrrolidinones.7 We
now report here the generalization of the latter strategy to the
formation of N-heterocyclic aminoacid derivatives, i.e.
azetidine-, pyrrolidine-, piperidine-2-carboxylates. As in our
preceding communication,7 but in a more general way, we
expected the formation of α-carbonylated aza-cycles 3 by SN2
cyclization of α-halogenocarbonyl amide anion intermediates,
which could be generated by opening α-halogeno-N-sulfonyl
Ring-opening/ Ring-
closing Reaction
Electrophilic
Monohalogenation
O
R1
O
X
R1
R1
R1
Nu
NuH
n
Nu
O
O
N
n
n
N
N
X
n
Base
N
X = Br, I
SO2R
3
2
1
SO2R
SO2R
SO2R
-Carbonylated
Aza-Rings
-Halogeno N-
Sulfonyl Lactams
n = 1-4
Scheme 1. Retrosynthetic Approach towards 2-Carboxylate
Aza-Ring Derivatives from N-sulfonyl Lactams.

2
Tetrahedron
2. Results and discussion
entry 5). Chromatographical separation of both compounds was
ACCEPTED MANUSCRIPT
clearly unconvenient, and this problem led us to investigate a
2.1. α-Monohalogenation of N-Sulfonyl Lactams
different approach where the corresponding silyl ketene aminal
would be formed and directly trapped by a halogenated
electrophile. After a short optimization study, we rewardingly
only obtained the monobrominated product 2a following the
sequential action of trimethylsilyl triflate (TMSOTf) and
triethylamine (Et3N) as a mild base followed by low temperature
quenching with NBS (Table 1, entries 6-11). In this case,
increasing the amount of base while adjusting the amount of
TMSOTf allowed a cleaner one-pot process (Table 1, entry 10 vs
8-9). Interestingly, these conditions proved to be suitable to
brominate 100 mmol of 1a (24.9 g) without any loss in efficiency
(Table 1, entry 11 vs 10).
The first step of this sequence relies on the selective α-
monohalogenation of lactams 1. Although a priori simple, this
step was surprisingly almost unprecedented.8 With the aim of
using common reagents for this transformation, we selected the
readily available N-tosyl pyrrolidin-2-one 1a as model substrate
and N-bromosuccinimide (NBS) as halogen source (Table 1).
Table 1. Screening of Conditions for α-Monobromination of
1-Sulfonylpyrrolidin-2-one 1a using Various Bases.
Br
Br
Br
1) Base
2) NBS
+
O
O
O
N
N
N
We then explored this monobromination reaction with various
lactams (Table 2). The use of other halogenation agents was only
briefly surveyed since NIS instead of NBS gave lower yields of
the corresponding N-tosyl 3-iodopyrrolidin-2-one 2b, but still
with a very high selectivity in favor of the monohalogenated
derivative (Table 2, entry 2 vs 1). The nature of the N-sulfonyl
substituent did not significantly affect the reaction (Table 2, entry
3 vs 1), except for the 2-trimethylsilylethylsulfonyl group (SES),
probably sensitive to the bromination conditions (Table 2, entry 4
vs 1).
1a
2a
2a'
Ts
Ts
Ts
Step 1
Step 2
temp
(°C),
time
Yieldsa
2a/2a’
(%)
Base
(equiv)
Solvent
temp (°C),
NBS
Entry
(concn) time, additive (equiv)
(equiv)
LDA
(1.1)
THF
(0.2M)
1
2
3
4
5
-78, 1 h
-78, 1 h
-78, 1 h
-78, 1 h
-78, 1 h
1.2
1.2
1.2
1.2
1.2
-78, 1 h
60/5b
LiHMDS
(1.1)
THF
(0.2M)
-78, 1 h 55/28c
-78, 1 h 53/23c
-78, 1 h 37/34c
LiHMDS
(1.3)
THF
(0.2M)
Rewardingly, the reaction proved to be as selective and as
efficient with larger ring sized lactams, providing the 6-, 7- and
8-membered α-bromolactams in high yields (Table 2, entries 5-
9). Surprisingly, the sulfonyl group nature had some influence on
the reaction course with 7-membered lactams, as revealed by the
slow reaction rate observed with the N-nosyl caprolactam 1h
(Table 2, entry 8 vs 6-7).
LiHMDS
(2.1)
THF
(0.2M)
LiHMDS
(1.6)
THF
(0.2M)
-78, 1 h
0, 1 h
72/5d
70/-
0, 30 min
TMSOTf (1.5)
then rt, 1 h
Et3N
(2.5)
DCM
(0.25M)
6
7
1.5
1.5
1.5
1.5
1.5
1.5
Table 2. Preparation of α-Halogenated N-Sulfonyl Lactams 2.
0, 30 min
Et3N
(2.5)
DCM
(0.25M)
0, 1 h
53/-e
74/-
80/-
87/-
89/-f
TMSOTf (1.5)
then rt, 1 h
-20, 30 min
TMSOTf (1.5)
then 0, 45 min
-20, 30 min
TMSOTf (1.2)
then 0, 45 min
-20, 30 min
TMSOTf (1.2)
then 0, 45 min
-20, 30 min
TMSOTf (1.2)
then 0, 45 min
-78 to
-40,
1.5 h
-78 to
-40,
1.5 h
-78 to
-40,
1.5 h
-78 to
-40,
Et3N
(2.5)
DCM
(0.25M)
8
Entry
1
α-Halogenated Lactams
Yieldsa (%)
89
Et3N
(2.5)
DCM
(0.25M)
9
2a
2b
2c
DCM
(0.25M)
10
11
Et3N (4)
Et3N (4)
2
3
59
83
DCM
(0.25M)
1.5 h
a Estimated yield relative to 1H NMR spectrum of the crude.
4
5
2d
2e
61
86
b The use of LiHMDS (1.1 equiv) gave a cleaner reaction mixture
than LDA (entry 2 vs 1).
c Along with 15-30% of unreacted starting material.
d Reaction was not scalable.
e Reaction run on 20 mmol scale.
f Reaction run on 100 mmol scale.
6
7
8
9
2f
2g
2h
2i
90
83
Strong bases, such as LDA or LiHMDS, gave a mixture of
mono and dibrominated N-tosyl pyrrolidin-2-ones 2a and 2a',
even at low temperature (Table 1, entries 1-5). Although the
overall yield and ratio of mono and dibrominated product were
promising, the use of LDA induced a messier reaction than the
use of LiHMDS (Table 1, entry 1 vs 2-3). With the latter,
conversion of 1a remained partial, and its use in excess amounts
did not improve this trend while increasing the amount of
dibrominated N-tosyl pyrrolidin-2-one 2a' (Table 1, entry 4 vs 2-
3). The best compromise between selectivity and conversion
could be achieved with 1.6 equiv of LiHMDS, affording a good
yield of the monobrominated product 2a, nevertheless still
contaminated by the dibrominated pyrrolidin-2-one 2a' (Table 1,
39b
96
a C = 0.25 mol/L; isolated yield.
b 41% of starting material was recovered.

3
Having in hand a useful and general method for the
monohalogenation of lactams, we then explored the second step
of the sequence, i.e. the one-pot ring opening–ring closing
reaction.
methoxybenzenesulfonyl (Mbs) group at the N position (see
ACCEPTED MANUSCRIPT
overall yields for 3h vs 3g, respectively 33 vs 42 %).
Interestingly, these results confirmed the proposed mechanism
(see Scheme 1) with first a ring opening and then an
intramolecular SN2 displacement of the bromine.
2.2. Ring Contraction of α-Halogenated N-Sulfonyl Lactams
The contraction of α-bromo N-tosylpyrrolidinone 2a was
easily performed using 3 equivalents of potassium carbonate in
acetonitrile at 60 °C in the presence of various nucleophiles
(Table 3). We have already demonstrated that primary alcohols,
functionalized or not, readily gave the corresponding α-azetidinyl
esters in excellent yields, as for example with methanol (Table 3,
entry 1).7 In contrast, hindered alcohols slowly reacted and the
more hindered, the less reactive was the alcohol. Indeed,
isopropanol mostly gave degradation products, but the expected
ester 3b could nevertheless be isolated in 19% of yield along
with 10% of the corresponding open product (Table 3, entry 2),
while tert-butanol did not react (Table 3, entry 3). Interestingly,
water was able to promote the ring contraction of 2a, directly
affording the corresponding acid derivative 3d (Table 3, entry 4),
but an excess of water was required and the reaction had to be
conducted in a 1:1 mixture of MeCN/H2O to ensure quantitative
conversion.
Scheme 2. Two-Step Sequence using Anionic Weinreb
Amine as Nucleophile.
We also evaluated the more labile Boc protecting group in the
ring-contraction reaction. We first prepared the monobrominated
N-tert-butoxycarbonyl pyrrolidinone 2j in 53% yield from the
commercially available tert-butyl 2-oxopyrrolidine-1-carboxylate
using reaction conditions of Table 2. Although moderate, this
yield is still appreciable given the known lability of Boc groups
towards TMSOTf.9 When submitted to the ring-contraction
conditions at room temperature, 2j quantitatively afforded the
opened product 4j but without any trace of the expected
azetidine. Heating the reaction mixture only led to degradation
products (Scheme 3).
Phenol as well as aniline derivatives could be used as
nucleophiles with 2a, leading to the expected phenyl ester 3e or
amide 3f in excellent yields (Table 3, entries 5 and 6).
Table 3. Ring-Contraction of α-Bromo N-Tosylpyrrolidinone
2a in the Presence of Nucleophiles.
Scheme 3. Attempt to Ring-Contract α-Bromo N-tert-
butoxycarbonyl pyrrolidinone 2j.
The standard ring contraction conditions were then applied to
the above prepared lactams 2b-i, with various nucleophiles
(Table 4).
Nucleophile
(10 equiv)
Entry
1
Azetidine
Yield (%)
96a
Methanol
iso-Propanol
tert-Butanol
H2O
3a
3b
3c
3d
3e
3f
Starting from the N-tosyl 3-iodo-2-pyrrolidinone 2b, these
conditions provided the α-azetidinyl ester 3a in good yield using
methanol as nucleophile, but the reaction was less efficient
compared to the 3-bromo-2-pyrrolidinone analog 2a (Table 4,
entry 1 vs Table 3, entry 1). The compatibility of more easily
removable N-protecting groups than phenylsulfonyl derivatives,
was also evaluated in the ring opening/ring closing reaction with
the p-nosyl (Ns) and 2-trimethylsilylethanesulfonyl (SES),
groups. In a satisfactory way, the N-nosyl γ-lactam 2c and N-SES
2d afforded the desired azetidinyl products 3i and 3j respectively
in excellent yields (Table 4, entries 2-3 vs 1).
2
3
4
5
6
19
b
-
96c
81
90
Phenol
Interestingly, the one-pot ring opening–ring closing reaction
was also operational starting from 6- and 7-membered lactams
2e-h, providing very efficiently the expected proline- or
pipecoline-like esters 5 and 6 in the presence of various alcohols.
Indeed, the contraction of δ-lactam 2e led in almost quantitative
yields within 4-6 hours to a series of proline ester derivatives 5k-
n employing respectively methanol, ethanol, benzyl alcohol and
3-phenylprop-2-yn-1-ol as nucleophiles (Table 4, entries 4-7).
O
pMeO-Aniline
N
HN
OMe
Ts
a Performed on 0.05 mol.
b The expected 3c could not be detected, and degradation slowly
occurred leading to unidentified by-products.
c Reaction run in a mixture of MeCN/H2O (1/1).
Due to the interesting possibilities this reaction could offer for
further transformations, ring contraction with Weinreb amines as
nucleophile were envisaged. Unfortunately, the optimized
conditions did not allow such amine to react with the
bromolactam 2a. Nevertheless, the Weinreb amido magnesium
bromide was nucleophilic enough at low but controlled
temperature to give the open products 4, which could then be
cyclized in the presence of potassium carbonate in acetonitrile
(Scheme 2). This two-step ring opening-ring closure proved
efficient, but overall seemingly less with the p-
In the 7-membered lactam series, the nature of the N-sulfonyl
group exhibits again a clear influence on the reaction efficiency
(Table 4, entries 8-10). If the tosyl group did not really change
the reaction course compared to γ - and δ-lactam series, affording
quantitatively 6o in 6 h (Table 4, entries 8 vs 1 and 4), the p-
methoxybenzensulfonyl (Mbs) clearly facilitated the reaction,
leading to the expected pipecoline derivatives 6p in only 3 h
(Table 4, entries 9). In contrast, the electron-withdrawing p-nosyl
group significantly increased the reaction time from 6 to 14 h,

4
Tetrahedron
ACCEPTED MANUSCRIPT
presumably by slowing-down the ring-closing step,
nevertheless without affecting too much the yield (Table 4,
entries 10).
4w
8w
34
26
16
2i
18
While primary alcohols were perfectly able to promote the
contraction of ε-lactam (Table 4, entries 11-13), the use of phenol
or aniline derivatives in the contraction of 2f was far less efficient
than in the formation of azetidines from γ-lactam 2a (Table 4,
entries 14-15 vs Table 2, entries 5-6). Indeed, a poor yield of 9%
was obtained in the presence of phenol and 48 h of reaction were
necessary to reach a modest yield of 57% with p-methoxyaniline.
The largest lactam evaluated, i.e. the 8-membered ring 2i, also
led to a ring-contracted product 8w, although not the expected
one. The latter was almost equally produced together with the
open product 4w (Table 4, entry 16). The newly formed
compound could be assigned as the methyl (N-tosyl piperidin-2-
yl)acetate. Taken together, these results showed that, if the ring
opening process readily occurred, the ring closure did not on
Table 4. Synthesis of α-Methylester Aza-Rings 3,5 and 6
from Various N-Sulfonyl Lactams 2.
such long distance (Baldwin rules) and
a competitive
elimination-Michael addition took place (Scheme 4).
Time
(h)
Yield
(%)
Entry Lactam
2-Methylester Aza-Rings
1
2
3
2b
2c
2d
3a
3i
6
3
3
61
98
85
Scheme 4. Competitive Pathway for 8-Membered α -
Bromolactam 2i.
3j
After having explored the scope of this new ring contraction
protocol, we then applied it to a short synthesis of (±)-AZE
natural compound (Scheme 5).10 The N-SES protected free acid
AZE derivative 3z was efficiently obtained in 91% yield starting
from the pyrrolidinone 2d (see Table 2, entry 4) in the presence
of water as nucleophile. The SES protecting group was then
removed using CsF in DMF at 95 °C affording the (±)-AZE in a
reasonable yield of 52%.11
4
5
6
2e
2e
2e
5k
5l
4
6
6
98
94
98
5m
7
2e
5n
5
99
8
2f
2g
2h
2f
2f
2f
2f
6o
6p
6q
6r
6s
6
3
99
93
85
86
83
97
9
Scheme 5. Synthesis of Azetidine-2-Carboxylic Acid AZE.
3. Conclusion
9
Through this work, we have developed a two-step, reliable
and scalable synthesis of azetidine-, pyrrolidine- and piperidine-
2-carboxylate derivatives. For the first step, we developed a
highly selective monobromination of N-sulfonylated lactams of
various ring sizes (from 5 to 8 membered rings). In the second
step, a one-pot ring opening–ring closing reaction was set up
starting from the so-formed 5 to 7-membered α-bromolactams,
providing very efficiently, sometimes quantitatively, the N-
sulfonylated heterocyclic esters and amides resulting from a
formal ring contraction. We highlighted this two-step sequence
with a short synthesis of AZE natural product. This strategy
offers an alternative, general and scalable route to various N-
heterocyclic aminoacids.
10
11
12
13
14
14
6
18
6
6t
6u
18
4. Experimental section
General Information. Proton (1H NMR) and Carbon (13C
NMR) nuclear magnetic resonance spectra were recorded on 300,
400 or 500 MHz instruments. The chemical shifts are given in
part per million (ppm) on the delta scale. The solvent peak was
15
2f
6v
48
57
used as reference value: for 1H NMR, CHCl3 = 7.26 ppm; for 13
C

5
NMR, CHCl3= 77.16 ppm. Infrared spectra were recorded neat.
Wavelengths of maximum absorbance (ν max) are quoted in wave
numbers (cm-1). High resolution mass spectra (HRMS) data were
recorded on a microTOF spectrometer equipped with orthogonal
707, 660, 615, 568, 544 cm–1. 1H NMR (CDCl3, 500 MHz): δ =
ACCEPTED MANUSCRIPT
7.92 (d, J = 8.4 Hz, 2 H), 7.36 (d, J = 8.4 Hz, 2 H), 3.85 (t, J =
6.1 Hz, 2 H), 3.00 (t, J = 6.1 Hz, 2 H), 2.45 (s, 3 H). 13C NMR
(CDCl3, 126 MHz): δ = 164.7, 146.2, 133.0, 130.0, 128.4, 53.6,
44.8, 42.8, 21.9. HRMS (HESI): m/z [M + Na]+ calcd for
C11H11Br2NO3S +Na+: 417.8719; found: 417.8727.
electrospray interface (ESI). The parent ions [M]+., [M+H]+.
,
[M+Li]+. or [M+Na]+. are quoted. Analytical thin layer
chromatography (TLC) was carried out on silica gel 60 F254
plates or basic alumina (63−200 µm) with visualization by
ultraviolet light or potassium permanganate dip. Flash column
chromatography was carried out using silica gel 60 (40−63 µm)
or basic Al2O3 (63−200 µm) and the procedure included the
subsequent evaporation of solvents in vacuo. Reagents and
solvents were purified using standard means. Dichloromethane
(CH2Cl2), acetonitrile (CH3CN), tetrahydrofuran (THF) and
diethyl ether (Et2O) were dried over activated alumina column
(DryStation); triethylamine (Et3N), pyridine and 1,8-
diazabicycloundec-7-ene (DBU) were distilled from KOH.
Anhydrous reactions were carried out in flame-dried glassware
and under an argon atmosphere. Na2CO3, K2CO3 and Cs2CO3
were dried overnight in an oven at 110 °C. All other chemicals
were used as received. All extractive procedures were performed
using non-distilled solvents and all aqueous solutions used were
saturated unless details are given.
4.1.3. 3-Iodo-1-tosylpyrrolidin-2-one (2b):
Prepared following the GP1 in 59 % yield (214 mg) from 241 mg
of 1-tosylpyrrolidin-2-one,7 using N-iodosuccinimide (NIS)
instead of NBS, after purification by column chromatography on
SiO2 (Cyclohexane/EtOAc). Yellow solid: mp = 130 °C. TLC Rf
= 0.30 (Cyclohexane/EtOAc 30 %). IR (neat): 2898, 1722, 1592,
1479, 1432, 1342, 1317, 1293, 1221, 1201, 1183, 1162, 1106,
1081, 1032, 1008, 952, 872, 808, 702, 654, 602, 558, 540, 480
cm–1. 1H NMR (CDCl3, 500 MHz): δ = 7.92 (d, J = 8.2 Hz, 2 H),
7.36 (d, J = 8.2 Hz, 2 H), 4.49 (dd, J = 1.6, 6.6 Hz, 1 H), 3.94
(ddd, J = 1.7, 7.7, 10.1 Hz, 1 H), 3.75 (ddd, J = 6.0, 9.4, 10.1 Hz,
1 H), 2.45 (s, 3 H), 2.51−2.42 (m, 1 H), 2.19 (dddd, J = 1.7, 1.7,
6.0, 14.6 Hz, 1 H). 13C NMR (CDCl3, 126 MHz): δ = 170.5,
145.8, 133.4, 129.9, 128.3, 46.1, 31.1, 21.9, 18.5. HRMS (HESI):
m/z [M + K]+ calcd for C11H12INO3S +K+: 403.9214; found:
403.9231.
4.1.4. 3-Bromo-1-((4-
nitrophenyl)sulfonyl)pyrrolidin-2-one (2c):
4.1. General Procedure 1 for α-bromination of 1-
sulfonylpyrrolidin-, piperidin-, azepan- or azocan-2-ones 1
(GP1):
Prepared following the GP1 in 83 % yield (7.03 g) from 6.55 g
of 1-((4-nitrophenyl)sulfonyl)pyrrolidin-2-one,7 after purification
by flash chromatography (Cyclohexane/EtOAc 20 % to 60 %).
Colorless crystals: mp = 194 °C (Et2O). TLC Rf = 0.28
(Cyclohexane/EtOAc 30 %); revelator: UV/KMnO4. IR (neat):
3113, 2985, 2952, 1743, 1524, 1346, 1313, 1220, 1171, 1119,
TMSOTf (2.17 mL, 12 mmol) was added dropwise to a stirred
solution of the appropriate 1-sulfonylpyrrolidin-, piperidin-,
azepan- or azocan-2-one derivative 1 (10 mmol) and Et3N (5.60
mL, 40 mmol) in CH2Cl2 (40 mL) at -20 °C under argon. The
mixture was stirred at -20 °C for 15 min, warmed to 0 °C and
stirred for 45 min before being cooled to -78 °C. N-
Bromosuccinimide (2.67 g, 15 mmol) was added by portions
under argon. The mixture was warmed to -40 °C and stirred until
completion of the reaction (monitored by TLC; typically 1.5–2
h). Saturated aqueous NH4Cl (40 mL) was then added at -40 °C,
and the resulting yellow solution was warmed to room
temperature and stirred for 15 min. Layers were separated, and
the aqueous layer was extracted with CH2Cl2 (40 mL). The
combined organic layers were washed with water (2 x 100 mL),
brine (50 mL), dried over MgSO4, filtered and concentrated. The
product was purified by recrystallization including hot filtration
(solvent indicated for each compound) or flash chromatography
(SiO2, Cyclohexane/EtOAc) to afford the title compound 2.
1019, 963, 853, 740, 700, 603, 555, 499, 460 cm–1. H NMR
1
(CDCl3, 500 MHz): δ = 8.42 (d, J = 9.0 Hz, 2 H), 8.26 (d, J = 9.0
Hz, 2 H), 4.37 (dd, J = 2.4, 6.5 Hz, 1 H), 4.07 (ddd, J = 2.3, 7.8,
10.1 Hz, 1 H), 3.95 (ddd, J = 6.4, 8.9, 10.1 Hz, 1 H), 2.65 (dtd, J
= 6.4, 8.3, 14.6 Hz, 1 H), 2.35 (ddt, J = 2.6, 6.4, 14.6 Hz, 1 H).
13C NMR (CDCl3, 126 MHz): δ = 168.7, 151.2, 142.0, 129.7,
124.4, 45.6, 42.7, 29.9. HRMS (HESI): m/z [M + Na]+ calcd for
C10H9BrN2O6S +Na+: 370.9308; found: 370.9313.
4.1.5. 3-Bromo-1-((2-
(trimethylsilyl)ethyl)sulfonyl)pyrrolidin-2-one (2d):
Prepared following the GP1 in 61 % yield (200 mg) from 250 mg
of 1-((2-(trimethylsilyl)ethyl)sulfonyl)pyrrolidin-2-one (See
supplementary data), after purification by flash chromatography
(Cyclohexane/EtOAc 20 % to 50 %). Colorless oil. TLC Rf =
0.60 (Cyclohexane/EtOAc 50 %), revelator: UV/KMnO4. IR
(neat): 2954, 2900, 1726, 1488, 1459, 1418, 1344, 1247, 1214,
1194, 1170, 1150, 1124, 1106, 1075, 956, 895, 830, 787, 746,
4.1.1. 3-Bromo-1-tosylpyrrolidin-2-one (2a):
Prepared following the GP1 in 89 % yield (2.76 g) from 2.39 g
of 1-tosylpyrrolidin-2-one,7 after recrystallization from
cyclohexane/EtOAc (3:1). Colorless crystals: mp = 118 °C. TLC
Rf = 0.43 (Cyclohexane/EtOAc 40 %), revelator: UV/KMnO4. IR
(neat): 2951, 2886, 1734, 1356, 1223, 1168, 1115, 954, 817, 707,
714, 690, 638, 621, 583, 571, 511 cm–1. H NMR (CDCl3, 500
1
MHz): δ = 4.48 (dd, J = 6.6, 2.4 Hz, 1 H), 4.06–3.84 (m, 2 H),
3.53 (ddd, J = 14.4, 13.0, 5.0 Hz, 1 H), 3.31 (ddd, J = 14.4, 13.0,
5.1 Hz, 1 H), 2.68 (dddd, J = 14.5, 8.6, 7.9, 6.6 Hz, 1 H), 2.38
(ddt, J = 14.6, 6.0, 2.5 Hz, 1 H), 1.16–0.91 (m, 2 H), 0.07 (s, 9
H). 13C NMR (CDCl3, 126 MHz): δ = 170.2, 49.3, 45.9, 43.5,
30.1, 9.9, -1.9. HRMS (HESI): m/z [M + K]+ calcd for
C9H18BrNO3SSi +K+: 365.9592; found: 365.9637.
1
660, 615, 568, 543 cm–1. H NMR (CDCl3, 500 MHz): δ = 7.92
(d, J = 8.3 Hz, 2 H), 7.36 (d, J = 8.3 Hz, 2 H), 4.34 (dd, J = 2.8,
6.7 Hz, 1 H), 4.05−3.84 (m, 2 H), 2.60 (dddd, J = 6.7, 7.8, 8.4,
14.4 Hz, 1 H), 2.45 (s, 3 H), 2.30 (dddd, J = 2.8, 3.0, 6.2, 14.4
Hz, 1 H). 13C NMR (CDCl3, 126 MHz): δ = 168.5, 145.8, 138.9,
129.9, 128.2, 45.4, 43.4, 29.9, 21.9. HRMS (HESI): m/z [M +
Na]+ calcd for C11H12BrNO3S +Na+: 339.9613; found: 339.9579.
4.1.6. 3-Bromo-1-tosylpiperidin-2-one (2e):
Prepared following the GP1 in 86 % yield (621 mg) from 549 mg
of 1-tosylpiperidin-2-one (see supplementary data), after
purification by column chromatography on silica gel
(Cyclohexane/EtOAc 20%). White solid: mp = 130 °C. TLC Rf =
0.39 (Cyclohexane/EtOAc 30 %); revelator: UV/KMnO4. IR
(neat): 2955, 1690, 1595, 1435, 1387, 1351, 1305, 1277, 1209,
1189, 1157, 1115, 1085, 1053, 1042, 1019, 1001, 973, 895, 880,
4.1.2. 3,3-Dibromo-1-tosylpyrrolidin-2-one (2a’):
Compound 2a’ was obtained as by-product during the screening
of conditions for α-monobromination of 1-sulfonylpyrrolidin-2-
one 1a (Table 1). Colorless crystals: mp = 118 °C. TLC Rf = 0.54
(Cyclohexane/EtOAc 40 %), revelator: UV/KMnO4. IR (neat):
2951, 2886, 1734, 1593, 1482, 1356, 1223, 1168, 1115, 955, 818,

6
Tetrahedron
1
ACCEPTED MANUSCRIPT
825, 810, 754, 690, 655, 623, 590, 565, 534, 477, 460 cm–1. H
MHz): δ = 7.92 (d, J = 8.4 Hz, 2 H), 7.31 (d, J = 8.4 Hz, 2 H),
NMR (CDCl3, 500 MHz): δ = 7.91 (d, J = 8.7 Hz, 2 H), 7.32 (d, J
= 8.7 Hz, 2 H), 4.47 (dd, J = 3.3, 4.7 Hz, 1 H), 4.20 (ddd, J = 4.7,
4.7, 12.4 Hz, 1 H), 3.81 (ddd, J = 4.7, 9.4, 12.4 Hz, 1 H), 2.44 (s,
3 H), 2.38−2.18 (m, 3 H), 1.88−2.05 (m, 1 H). 13C NMR (CDCl3,
126 MHz): δ = 166.1, 145.3, 135.1, 129.5, 128.9, 46.5, 45.3,
30.8, 21.8, 19.9. HRMS (HESI): m/z [M + H]+ calcd for
C12H14BrNO3S +H+: 331.9955; found: 331.9966.
4.86 (dd, J = 4.8, 11.6 Hz, 1 H), 4.53 (dt, J = 3.9, 16.3 Hz, 1 H),
3.75 (ddd, J = 2.9, 11.9, 16.3 Hz, 1 H), 2.43 (s, 3 H), 2.31−2.13
(m, 2 H), 2.04−1.93 (m, 1 H), 1.89−1.80 (m, 1 H), 1.67−1.45 (m,
4 H). 13C NMR (CDCl3, 126 MHz): δ = 169.6, 145.2, 135.7,
129.4, 129.3, 46.9, 46.5, 39.9, 31.2, 25.4, 24.1, 21.9. HRMS
(HESI): m/z [M + K]+ calcd for C14H18BrNO3S +K+: 397.9822;
found: 397.9848.
4.1.7. 3-Bromo-1-tosylazepan-2-one (2f):
4.1.11. tert-Butyl 3-bromo-2-oxopyrrolidine-1-
carboxylate (2j):
Prepared following the GP1 in 90% yield (11.66 g) from 1-
(tosyl)azepan-2-one5e (10 g) and used as a crude product in the
following step. White solid: mp = 102 °C. TLC Rf = 0.52
(Cyclohexane/EtOAc 30 %); revelator: UV/KMnO4. IR (neat):
2973, 2934, 2917, 2850, 1703, 1594, 1438, 1351, 1294, 1246,
1162, 1113, 1080, 984, 943, 901, 870, 764, 702, 676, 642, 541
cm–1. 1H NMR (CDCl3, 500 MHz): δ = 7.85 (d, J = 8.2 Hz, 2 H),
7.31 (d, J = 8.2 Hz, 2 H), 4.69 (dd, J = 2.6, 7.3 Hz, 1 H), 4.31
(dd, J = 6.7, 16.3 Hz, 1 H), 4.18 (dd, J = 9.2, 16.3 Hz, 1 H), 2.43
(s, 3 H), 2.16−2.09 (m, 1 H), 2.08−2.02 (m, 1 H), 2.02−1.92 (m,
2 H), 1.85−1.77 (m, 1 H), 1.77−1.67 (m, 1 H). 13C NMR (CDCl3,
126 MHz): δ = 169.0, 145.0, 136.0, 129.5, 128.7, 51.5, 45.4,
31.8, 29.1, 25.5, 21.8. HRMS (HESI): m/z [M + K]+ calcd for
C13H16BrNO3S +K+: 383.9666; found: 383.9682.
Prepared following the GP1 in 53% yield (1.14 g) from 1.50 g of
commercially available tert-butyl 2-oxopyrrolidine-1-carboxylate
(CAS 85909-08-6) after purification by column chromatography
(Cyclohexane/EtOAc 15 %). White solid: mp = 80 °C. TLC Rf =
0.33 (Cyclohexane/EtOAc 30 %); revelator: UV/KMnO4. IR
(neat): 2993, 2976, 1741, 1714, 1367, 1303, 1248, 1139, 942,
880, 845, 777, 613 cm–1. H NMR (CDCl3, 500 MHz): δ = 4.43
1
(dd, J = 3.0, 6.9 Hz, 1 H), 3.87 (ddd, J = 6.6, 8.2, 10.9 Hz, 1 H),
3.84 (ddd, J = 3.0, 8.2, 10.9 Hz, 1 H), 2.54 (ddt, J = 6.6, 8.2, 14.4
Hz, 1 H), 2.27 (ddt, J = 3.0, 6.6, 14.4 Hz, 1 H), 1.54 (s, 9 H). 13
C
NMR (CDCl3, 126 MHz): δ = 169.3, 149.9, 83.9, 44.4, 44.3,
29.3, 28.0. HRMS (HESI): m/z [M + Na]+ calcd for C9H14BrNO3
+Na+: 286.0049; found: 286.0017.
4.2. General Procedure 2 for conversion of 3-bromo-1-
sulfonylpyrrolidin-, piperidin-, azepan- or azocan-2-ones (2)
to 1-sulfonylazetidin-, pyrrolidin-, piperidin-2-carboxylic
esters (3, 5 or 6) (GP2):
4.1.8. 3-Bromo-1-((4-
methoxyphenyl)sulfonyl)azepan-2-one (2g):
Prepared following the GP1 in 83 % yield (2.11 g) from 2.00 g
of 1-((4-methoxyphenyl)sulfonyl)azepan-2-one.5e White solid:
mp = 135 °C. TLC Rf = 0.56 (Cyclohexane/EtOAc 50 %);
revelator: UV/KMnO4. IR (neat): 2943, 1696, 1594, 1496, 1349,
1264, 1161, 1108, 1081, 1017, 904, 832, 803, 756, 715, 679, 648,
589, 547 cm–1. 1H NMR (CDCl3, 500 MHz): δ = 7.91 (d, J = 9.0
Hz, 2 H), 6.97 (d, J = 9.0 Hz, 2 H), 4.70 (dd, J = 2.8, 7.4 Hz, 1
H), 4.32−4.24 (m, 1 H), 4.21−4.14 (m, 1 H), 3.87 (s, 3 H),
2.16−2.08 (m, 1 H), 2.08−2.01 (m, 1 H), 2.00−1.90 (m, 2 H),
1.84−1.76 (m, 1 H), 1.75−1.65 (m, 1 H). 13C NMR (CDCl3, 126
MHz): δ = 168.9, 163.9, 131.0, 130.2, 114.0, 55.8, 51.6, 45.4,
31.9, 29.0, 25.6. HRMS (HESI): m/z [M + Na]+ calcd for
C13H16BrNO4S +Na+: 383.9876; found: 383.9904.
To
a
stirred solution of the appropriate 3-bromo-1-
sulfonylpyrrolidin-, piperidin-, azepan- or azocan-2-one 2 (1
mmol) in MeCN (4.5 mL) were added 10 equivalents of the
appropriate alcohol, phenol or aniline (see information for each
compound) followed by K2CO3 (414 mg, 3 mmol or 207 mg, 1.5
mmol as specified for each compound). The heterogeneous
mixture was stirred at 60 °C until completion of the reaction, as
monitored by TLC. Filtration through a thin pad of silica gel
(eluting with CH2Cl2 or MeCN when necessary) followed by
concentration and drying under high vacuum (with warming at
50 °C if necessary) afforded the pure compound type 3,5 or 6.
4.1.9. 3-Bromo-1-((4-nitrophenyl)sulfonyl)azepan-
2-one (2h):
Prepared following the GP1 in 39 % yield (1.41 g) from 1.52 g
of 1-((4-nitrophenyl)sulfonyl)azepan-2-one (see supplementary
data) after recrystallization from Cyclohexane/EtOAc (3:1).
4.2.1. Methyl 1-tosylazetidine-2-carboxylate (3a):
Prepared following the GP2 in 96 % yield (12.9 g) from 15.9 g
of 2a and 10 equiv of MeOH after 3 h at 60 °C or in 61 % yield
(36.8 mg) from 81.5 mg of 2b and 10 equiv of MeOH after 6 h
stirring at 60 °C. Colorless needles: mp
=
105 °C
Colorless crystals: mp
=
155 °C. TLC Rf
=
0.58
(CH2Cl2/hexanes). TLC Rf = 0.37 (Cyclohexane/EtOAc 50 %);
(Cyclohexane/EtOAc 50 %); revelator: UV/KMnO4. IR (neat):
3108, 2922, 1717, 1606, 1527, 1351, 1314, 1174, 1143, 1104,
1085, 898, 857, 778, 741, 680, 663, 602, 541, 461 cm–1. 1H NMR
(CDCl3, 500 MHz): δ = 8.37 (d, J = 9.0 Hz, 2 H), 8.16 (d, J =
9.0 Hz, 2 H), 4.69 (dd, J = 2.6, 7.1 Hz, 1 H), 4.41−4.31 (m, 1 H),
4.25−4.15 (m, 1 H), 2.18−2.07 (m, 2 H), 2.07−1.95 (m, 2 H),
1.90−1.82 (m, 1 H), 1.79−1.68 (m, 1 H). 13C NMR (CDCl3, 126
MHz): δ = 169.3, 150.7, 144.5, 130.0, 124.1, 51.0, 45.8, 31.5,
revelator: UV/KMnO4. IR (neat): 2953, 1718, 1593, 1432, 1332,
1285, 1202, 1155, 1082, 1047, 847, 680, 585, 548, 497 cm–1. H
1
NMR (CDCl3, 500 MHz): δ = 7.79 (d, J = 8.2 Hz, 2 H), 7.35 (d, J
= 8.2 Hz, 2 H), 4.60 (dd, J = 7.9, 9.2 Hz, 1 H), 3.87 (dt, J = 7.8,
8.7 Hz, 1 H), 3.74 (ddd, J = 4.0, 7.8, 8.7 Hz, 1 H), 3.72 (s, 3 H),
2.45 (s, 3 H), 2.39 (dddd, J = 8.1, 8.2, 8.6, 11.4 Hz, 1 H), 2.28
(dddd, J = 4.0, 9.0, 9.2, 11.4 Hz, 1 H). 13C NMR (CDCl3, 126
MHz): δ = 170.5, 144.3, 133.3, 129.7, 128.3, 60.6, 52.5, 47.8,
21.7, 19.6. HRMS (HESI): m/z [M + Na]+ calcd for C12H15NO4S
+Na+: 292.0614; found: 292.0587.
29.2, 25.4. HRMS (HESI): m/z [M
+
Na]+ calcd for
C12H13BrN2O5S +Na+: 398.9621; found: 398.9663.
4.1.10. 3-Bromo-1-tosylazocan-2-one (2i):
4.2.2. Isopropyl 1-tosylazetidine-2-carboxylate
(3b):
Prepared following the GP2 in 19 % yield (101 mg) from 579 mg
of 2a and 10 equiv of isopropanol, using 3 equiv of K2CO3 at 80
°C for 24 h, after purification by flash chromatography (from
Cyclohexane/EtOAc 5 % to 40 %). White solid: mp = 95 °C.
Prepared following the GP1 in 96 % yield (896 mg) from 730 mg
of 1-tosylazocan-2-one (see supplementary data) after
purification by column chromatography (Cyclohexane/EtOAc 20
%). White solid: mp
=
136 °C. TLC Rf
=
0.32
(Cyclohexane/EtOAc 30 %); revelator: UV/KMnO4. IR (neat):
3032, 2924, 2862, 1686, 1595, 1462, 1440, 1375, 1353, 1294,
1274, 1204, 1183, 1111, 1079, 1033, 1017, 877, 828, 811, 783,
TLC Rf
= 0.39 (Cyclohexane/EtOAc 30 %); revelator:
UV/KMnO4. IR (neat): 2984, 2935, 2895, 1739, 1597, 1524,
1450, 1377, 1344, 1243, 1195, 1159, 1089, 1049, 998, 948, 931,
1
705, 670, 647, 598, 557, 539, 476 cm–1. H NMR (CDCl3, 500

7
1
906, 813, 802, 786, 710, 661, 600, 547, 497 cm–1. H NMR
4.2.6. Methyl 1-((4-nitrophenyl)sulfonyl)azetidine-
2-carboxylate (3i):
ACCEPTED MANUSCRIPT
(CDCl3, 500 MHz): δ = 7.79 (d, J = 8.2 Hz, 2 H), 7.34 (d, J = 8.2
Hz, 2 H), 5.02 (qq, J = 6.3, 6.3 Hz, 1 H), 4.57 (dd, J = 8.2, 8.7
Hz, 1 H), 3.90 (ddd, J = 7.5, 8.7, 8.7 Hz, 1 H), 3.72 (ddd, J = 4.2,
7.5, 8.7 Hz, 1 H), 2.44 (s, 3 H), 2.41−2.32 (m, 1 H), 2.32−2.24
Prepared following the GP2 in 98 % yield (288 mg) from 350 mg
of 2c and 10 equiv of MeOH after 3 h stirring at 60 °C. Colorless
crystals: mp = 129 °C (CH2Cl2/hexanes). TLC Rf = 0.30
(Cyclohexane/EtOAc 30 %); revelator: UV/KMnO4. IR (neat):
3107, 2979, 2958, 1744, 1607, 1542, 1441, 1348, 1303, 1238,
1161, 1092, 1045, 1010, 906, 857, 802, 738, 684, 628, 583, 466
cm–1. 1H NMR (CDCl3, 500 MHz): δ = 8.38 (d, J = 8.9 Hz, 2 H),
8.13 (d, J = 8.9 Hz, 2 H), 4.89 (dd, J = 7.7, 9.4 Hz, 1 H), 4.13
(ddd, J = 7.8, 7.8, 9.0 Hz, 1 H), 3.77 (ddd, J = 4.5, 7.5, 9.0 Hz, 1
H), 3.72 (s, 3 H), 2.48 (dddd, J = 4.5, 9.0, 9.4, 11.3 Hz, 1 H),
2.42 (dddd, J = 7.7, 8.6, 9.0, 11.3 Hz, 1 H). 13C NMR (CDCl3,
126 MHz): δ = 170.4, 150.3, 144.2, 129.2, 124.2, 60.9, 52.6,
48.1, 19.4. HRMS (HESI): m/z [M + Li]+ calcd for C11H12N2O7S
+Li+: 323.0323; found: 323.0323.
(m, 1 H), 1.21 (d, J = 6.3 Hz, 3 H), 1.20 (d, J = 6.3 Hz, 3 H). 13
C
NMR (CDCl3, 126 MHz): δ = 169.6, 144.3, 133.8, 129.8, 128.4,
69.3, 61.0, 47.8, 21.8, 19.6. HRMS (HESI): m/z [M + Na]+ calcd
for C14H19NO4S +Na+: 320.0927; found: 320.0966.
4.2.3. 1-Tosylazetidine-2-carboxylic acid (3d):
Prepared following modified GP2 in 96 % yield (75 mg) from
100 mg of 2a in a mixture of MeCN/H2O after 16 h at 60 °C.12
After completion of reaction, the solvents were removed in
vacuo. The residue was then partitioned between EtOAc and HCl
aqueous solution (1N). After extraction with EtOAc, the
combined organic layers were dried over MgSO4 concentrated
and dried under high vacuum to afford the pure compound 3d.
White solid: mp = 137 °C. TLC Rf = 0.20 (EtOAc); revelator:
4.2.7. Methyl 1-((2-
(trimethylsilyl)ethyl)sulfonyl)azetidine-2-
carboxylate (3j):
1
UV/KMnO4. H NMR (CDCl3, 500 MHz): δ = 8.74 (br, 1 H),
7.74 (d, J = 8.2 Hz, 2 H), 7.39 (d, J = 7.9 Hz, 2 H), 4.53 (dd, J =
7.8, 9.6 Hz, 1 H), 3.73 (dd, J = 6.6, 8.7 Hz, 2 H), 2.53−2.24 (m, 2
H), 2.46 (s, 3 H). 13C NMR (CDCl3, 126 MHz): δ = 173.1, 145.1,
131.2, 130.1, 128.5, 60.6, 47.8, 21.7, 19.8. HRMS (HESI): m/z
[M + Na]+ calcd for C11H13NO4S +Na+: 278.0457; found:
278.0427.
Prepared following the GP2 in 85 % yield (36 mg) from 50 mg
of 2d and 10 equiv of MeOH after 3 h at 60 °C. Colorless oil.
TLC Rf
= 0.51 (Cyclohexane/EtOAc 30 %); revelator:
UV/KMnO4. IR (neat): 2954, 2900, 1746, 1438, 1421, 1326,
1285, 1248, 1212, 1169, 1138, 1074, 1024, 939, 894, 860, 831,
1
800, 746, 700, 639, 544 cm–1. H NMR (CDCl3, 500 MHz): δ =
4.86 (dd, J = 9.5, 8.1 Hz, 1 H), 4.17 (td, J = 8.8, 7.5 Hz, 1 H),
3.73 (s, 3 H), 3.59 (ddd, J = 8.6, 7.4, 4.3 Hz, 1 H), 3.01 (qdd, J =
14.1, 12.0, 5.4 Hz, 2 H), 2.49–2.34 (m, 2 H), 1.10–0.95 (m, 2 H),
0.02 (s, 9 H). 13C NMR (CDCl3, 126 MHz): δ = 171.4, 60.2, 52.5,
49.9, 47.1, 19.5, 9.9, -1.8. HRMS (HESI): m/z [M + Na]+ calcd
for C11H29NO4SSi +Na+: 279.0961; found: 279.0959.
4.2.4. Phenyl 1-tosylazetidine-2-carboxylate (3e):
Prepared following the GP2 in 81 % yield (135 mg) from 156 mg
of 2a and 10 equiv of phenol after 2 h at 60 °C. The crude
product was purified by flash chromatography (from
Cyclohexane/EtOAc 10% to 40%). White solid: mp = 103−104
°C (CH2Cl2/hexanes). TLC Rf = 0.51 (Cyclohexane/EtOAc 30
%); revelator: UV/KMnO4. IR (neat): 3054, 2920, 2868, 1742,
1598, 1586, 1497, 1479, 1451, 1362, 1346, 1291, 1251, 1184,
1161, 1119, 1083, 1007, 887, 808, 748, 691, 662, 616, 580, 541,
431 cm–1. 1H NMR (CDCl3, 500 MHz): δ = 8.27 (d, J = 8.2 Hz, 2
H), 7.65 (d, J = 8.2 Hz, 2 H), 7.60–7.52 (m, 2 H), 7.34–7.19 (m,
3 H), 5.15 (dd, J = 8.2, 8.2 Hz, 1 H), 4.31 (ddd, J = 3.4, 8.2, 10.2
Hz, 1 H), 4.16 (ddd, J = 7.4, 8.2, 10.2 Hz, 1 H), 2.87 (dddd, J =
3.5, 7.4, 7.5, 13.2 Hz, 1 H), 2.75 (s, 3 H), 2.50 (dddd, J = 8.2, 8.2,
8.2, 13.2 Hz, 1 H). 13C NMR (CDCl3, 126 MHz): δ = 169.8,
157.5, 145.7, 134.9, 130.0, 129.7, 128.3, 122.5, 116.2, 75.6, 43.5,
26.7, 21.9. HRMS (HESI): m/z [M + Na]+ calcd for C17H17NO4S
+Na+: 354.0770; found: 354.0776.
4.2.8. Methyl N-tosyl-L-prolinate (5k):
Prepared following the GP2 in 98 % yield (77.8 mg) from 92.7
mg of 2e and 10 equiv of MeOH in 4 h at 60 °C. White solid: mp
= 79 °C. TLC Rf = 0.14 (Cyclohexane/EtOAc 30 %); revelator:
1
UV/KMnO4. H NMR (CDCl3, 500 MHz): δ = 7.75 (d, J = 8.3
Hz, 2 H), 7.30 (d, J = 8.3 Hz, 2 H), 4.30 (dd, J = 4.4, 7.9 Hz, 1
H), 3.71 (s, 3 H), 3.50−3.44 (m, 1 H), 3.35−3.28 (m, 1 H), 2.42
(s, 3 H), 2.08−1.89 (m, 3 H), 1.82−1.70 (m, 1 H); consistent with
literature data.5e 13C NMR (CDCl3, 126 MHz): δ = 172.7, 143.8,
135.4, 129.8, 127.7, 60.5, 52.5, 48.6, 31.0, 24.8, 21.7; consistent
with literature data.5e
4.2.9. Ethyl N-tosylprolinate (5l):
4.2.5. N-(4-Methoxyphenyl)-1-tosylazetidine-2-
carboxamide (3f):
Prepared following the GP2 in 94 % yield (77 mg) from 91 mg
of 2e and 10 equiv of ethanol after 6 h at 60 °C. Pale yellow
solid: mp = 83-85 °C. TLC Rf = 0.19 (Cyclohexane/EtOAc 30
%); revelator: UV/KMnO4. IR (neat): 3283, 2983, 2958, 2904,
2871, 2177, 2075, 1975, 1744, 1596, 1495, 1476, 1454, 1401,
1380, 1338, 1312, 1292, 1239, 1201, 1181, 1154, 1136, 1091,
1066, 1023, 1008, 934, 920, 886, 851, 818, 758, 709, 660, 635,
Prepared following the GP2 in 90 % yield (240 mg) from 156 mg
of 2a and 10 equiv of p-anisidine after 16 h at 60 °C. The crude
product was dissolved in EtOAc, washed with 1N aqueous HCl,
brine and dried over MgSO4. Evaporation of the solvent yielded
the pure product. White solid: mp = 160−162 °C. TLC Rf = 0.30
(Cyclohexane/EtOAc 30 %); revelator: UV/KMnO4. IR (neat):
3355, 2960, 2916, 2839, 1728, 1598, 1514, 1447, 1339, 1275,
1227, 1155, 1119, 1087, 1027, 996, 908, 830, 809, 754, 657, 583,
546, 494 cm–1. 1H NMR (CDCl3, 500 MHz): δ = 7.94 (d, J = 8.2
Hz, 2 H), 7.35 (d, J = 8.2 Hz, 2 H), 6.75 (d, J = 9.0 Hz, 2 H), 6.56
(d, J = 9.0 Hz, 2 H), 4.04−3.97 (m, 1 H), 3.94 (dd, J = 7.9, 11.0
Hz, 1 H), 3.82−3.75 (m, 1 H), 3.72 (s, 3 H), 2.68 (dddd, J = 1.3,
6.3, 7.8, 12.6 Hz, 1 H), 2.44 (s, 3 H), 1.91 (dddd, J = 8.9, 10.8,
10.8, 12.6 Hz, 1 H). 13C NMR (CDCl3, 126 MHz): δ = 172.4,
153.4, 145.8, 140.6, 135.0, 130.0, 128.3, 115.5, 115.0, 57.1, 55.9,
44.0, 29.1, 21.9. HRMS (HESI): m/z [M + Na]+ calcd for
C18H20N2O4S +Na+: 383.1036; found: 383.1026.
1
590, 543, 493, 429 cm-1. H NMR (CDCl3, 500 MHz): δ = 7.78–
7.73 (m, 2 H), 7.30 (d, J = 7.9 Hz, 2 H), 4.30–4.26 (m, 1 H),
4.21–4.10 (m, 2 H), 3.50–3.44 (m, 1 H), 3.31 (dt, J = 9.6, 7.0 Hz,
1 H), 2.42 (s, 3 H), 2.07–1.90 (m, 3 H), 1.79–1.71 (m, 1 H), 1.25
(t, J = 7.2 Hz, 3 H). 13C NMR (CDCl3, 126 MHz): δ = 172.2,
143.6, 135.5, 129.7, 127.6, 61.4, 60.6, 48.5, 31.1, 24.7, 21.7,
14.2. HRMS (HESI): m/z [M + Na]+ calcd for C14H19O4NS +Na+:
320.0927; found 320.0927.
4.2.10. Benzyl N-tosylprolinate (5m):
Prepared following the GP2 in 98 % yield (98 mg) from 92 mg
of 2e and 10 equiv of benzyl alcohol after 6 h at 60 °C and
purification by bulb-to-bulb distillation. Yellow oil. TLC Rf =
0.16 (Cyclohexane/EtOAc 30 %); revelator: UV/KMnO4. IR

8
Tetrahedron
4.2.14. Methyl 1-((4-
(neat): 3033, 2957, 2924, 2086, 2019, 1746, 1597, 1496, 1454,
ACCEPTED MANUSCRIPT
nitrophenyl)sulfonyl)piperidine-2-carboxylate (6q):
1383, 1339, 1304, 1276, 1153, 1091, 1011, 912, 847, 815, 781,
733, 697, 661, 587, 545, 490, 435 cm-1. H NMR (CDCl3, 500
1
Prepared following the GP2 in 85 % yield (547 mg) from 735 mg
of 2h in 2 h at 60 °C. White solid: mp = 126 °C. TLC Rf = 0.60
(Pentane/Et2O 50 %); revelator: UV/KMnO4. IR (neat): 2953,
1737, 1605, 1528, 1443, 1341, 1277, 1241, 1156, 1090, 1056,
MHz): δ = 7.77–7.72 (m, 2 H), 7.39–7.31 (m, 5 H), 7.28 (d, J =
8.1 Hz, 2 H), 5.19–5.11 (m, 2 H), 4.37 (dd, J = 8.4, 3.9 Hz, 1 H),
3.50–3.44 (m, 1 H), 3.33 (dt, J = 9.3, 7.1 Hz, 1 H), 2.41 (s, 3 H),
2.09–1.88 (m, 3 H), 1.76 (dtt, J = 9.7, 7.5, 5.1 Hz, 1 H). 13C
NMR (CDCl3, 126 MHz): δ = 172.1, 143.7, 135.7, 135.5, 129.8 ,
128.7, 128.5, 128.2, 127.7, 67.1, 60.6, 48.5, 31.1, 24.8, 21.7.
HRMS (HESI): m/z [M + Na]+ calcd for C19H21O4NS +Na+:
382.1083; found 382.1064.
990, 943, 841, 742, 684, 609, 577, 462 cm–1. H NMR (CDCl3,
1
500 MHz): δ = 8.33 (d, J = 8.9 Hz, 2 H), 7.96 (d, J = 8.9 Hz, 2
H), 4.80 (dd, J = 1.7, 5.1 Hz, 1 H), 3.82 (ddd, J = 2.3, 3.0, 12.0
Hz, 1 H), 3.56 (s, 3 H), 3.14 (td, J = 3.0, 12.7 Hz, 1 H),
2.24−2.17 (m, 1 H), 1.84−1.76 (m, 1 H), 1.75−1.67 (m, 1 H),
1.61−1.50 (m, 2 H), 1.31−1.19 (m, 1 H). 13C NMR (CDCl3, 126
MHz): δ = 170.8, 150.0, 145.8, 128.5, 124.2, 55.6, 52.4, 43.1,
28.1, 25.0, 20.2. HRMS (HESI): m/z [M + Na]+ calcd for
C13H16N2O6S +Na+: 351.0621; found: 351.0654.
4.2.11. 3-Phenylprop-2-yn-1-yl N-tosylprolinate
(5n):
Prepared following the GP2 in 99 % yield (116 mg) from 101 mg
of 2e and 10 equiv of 3-phenylprop-2-yn-1-ol after 5 h at 60 °C
and purification by bulb-to-bulb distillation. Yellow oil. TLC Rf
= 0.29 (Cyclohexane/EtOAc 30 %); revelator: UV/KMnO4. IR
(neat): 3060, 2954, 2875, 2225, 1752, 1597, 1571, 1443, 1380,
1338, 1305, 1268, 1153, 1092, 1070, 1024, 1005, 991, 954, 918,
4.2.15. Butyl 1-tosylpiperidine-2-carboxylate (6r):
Prepared following the GP2 in 86 % yield (137 mg) from 162 mg
of 2f and 10 equiv of butanol after 6 h at 60 °C and purification
by flash chromatography (from Cyclohexane/EtOAc 10%).
Colorless oil. TLC Rf = 0.36 (Cyclohexane/EtOAc 30 %);
revelator: UV/KMnO4. IR (neat): 3308, 2956, 2868, 2203, 2147,
2019, 1732, 1597, 1495, 1453, 1378, 1337, 1303, 1245, 1175,
1154, 1110, 1092, 1056, 1036, 1018, 959, 932, 919, 885, 870,
848, 815, 757, 734, 706, 691, 662, 590, 545, 525, 426 cm-1. H
1
NMR (CDCl3, 500 MHz): δ = 7.80–7.76 (m, 2 H), 7.48–7.43 (m,
2 H), 7.37–7.28 (m, 5 H), 4.94 (d, J = 1.0 Hz, 2 H), 4.39 (dd, J =
8.0, 4.5 Hz, 1 H), 3.49 (ddd, J = 9.6, 7.4, 4.7 Hz, 1 H), 3.34 (dt, J
= 9.6, 7.2 Hz, 1 H), 2.41 (s, 3 H), 2.12–1.94 (m, 3 H), 1.84–1.75
(m, 1 H). 13C NMR (CDCl3, 126 MHz) δ 171.6, 143.8, 135.4,
132.0, 129.8, 129.0, 128.5, 127.7, 122.2, 87.0, 82.6, 60.4, 53.8,
48.5, 31.0, 24.8, 21.7. HRMS (HESI): m/z [M + K]+ calcd for
C21H21O4NS +K+: 422.0823; found 422.0837.
842, 814, 726, 654, 582, 544, 509, 476, 415, cm-1. H NMR
1
(CDCl3, 500 MHz): δ = 7.69–7.65 (m, 2 H), 7.27 (d, J = 8.0 Hz, 2
H), 4.77–4.71 (m, 1 H), 3.99 (dt, J = 10.8, 6.7 Hz, 1 H), 3.90 (dt,
J = 10.8, 6.7 Hz, 1 H), 3.76 (dddt, J = 12.6, 4.8, 2.4, 1.2 Hz, 1 H),
3.21 (td, J = 12.7, 3.0 Hz, 1 H), 2.41 (s, 3 H), 2.12 (dtt, J = 13.6,
3.5, 1.8 Hz, 1 H), 1.75 (tdd, J = 13.7, 6.0, 3.7 Hz, 1 H), 1.69–1.59
(m, 2 H), 1.54–1.43 (m, 2 H), 1.36–1.22 (m, 4 H), 0.91 (t, J = 7.4
Hz, 3 H). 13C NMR (CDCl3, 126 MHz): δ = 171.0, 143.2, 137.3,
129.5, 127.4, 65.1, 55.2, 42.7, 30.6, 28.1, 24.9, 21.7, 20.2, 19.2,
13.8. HRMS (HESI): m/z [M + Na]+ calcd for C17H25O4NS +Na+:
362.1397; found 362.1419.
4.2.12. Methyl 1-tosylpiperidine-2-carboxylate
(6o):
Prepared following the GP2 in 99 % yield (10.1 g) from 10.6 g
of 2f in 3 h at 60 °C. White solid: mp = 70 °C. TLC Rf = 0.39
(Cyclohexane/EtOAc 30 %); revelator: UV/KMnO4. IR (neat):
3036, 2984, 2947, 2857, 1727, 1595, 1493, 1448, 1431, 1336,
1283, 1243, 1218, 1181, 1152, 1127, 1107, 1092, 1057, 989, 939,
4.2.16. Allyl 1-tosylpiperidine-2-carboxylate (6s):
925, 841, 810, 733, 659, 584, 562, 537, 509 cm–1. H NMR
1
Prepared following the GP2 in 83 % yield (117 mg) from 152 mg
of 2f and 10 equiv of allyl alcohol after 18 h at 60 °C and
purification by flash chromatography (from Cyclohexane/EtOAc
5% to 20%). Colorless oil. TLC Rf = 0.22 (Cyclohexane/EtOAc
30 %); revelator: UV/KMnO4. IR (neat): 2942, 2860, 2069, 1739,
1649, 1597, 1494, 1446, 1380, 1337, 1302, 1242, 1171, 1153,
1130, 1110, 1092, 1055, 1036, 1018, 982, 944, 873, 840, 814,
(CDCl3, 500 MHz): δ = 7.67 (d, J = 8.2 Hz, 2 H), 7.29 (d, J = 8.2
Hz, 2 H), 4.75 (dd, J = 2.3, 6.0 Hz, 1 H), 3.76 (ddd, J = 2.4, 3.0,
12.5 Hz, 1 H), 3.54 (s, 3 H), 3.21 (ddd, J = 3.0, 12.5, 12.5 Hz, 1
H), 2.42 (s, 3 H), 2.11 (ddddd, J = 2.5, 2.5, 2.5, 2.5, 13.6 Hz, 1
H), 1.74 (dddd, J = 3.3, 5.8, 13.3, 13.6 Hz, 1 H), 1.69−1.60 (m, 2
H), 1.45 (ddddd, J = 3.7, 4.7, 13.0, 13.0, 13.5 Hz, 1 H), 1.28
(ddddd, J = 3.7, 3.7, 12.9, 13.7, 13.7 Hz, 1 H). 13C NMR (CDCl3,
126 MHz): δ = 171.3, 143.2, 137.0, 129.5, 127.3, 55.1, 52.1,
42.7, 27.9, 24.7, 21.6, 20.1. HRMS (HESI): m/z [M + Na]+ calcd
for C14H19NO4S +Na+: 320.0927; found: 320.0937.
728, 654, 580, 547, 507, 476, 413 cm-1. H NMR (CDCl3, 500
1
MHz): δ = 7.72–7.61 (m, 2 H), 7.32–7.22 (m, 2 H), 5.85–5.72
(m, 1 H), 5.30–5.16 (m, 2 H), 4.77 (dd, J = 6.1, 2.4 Hz, 1 H),
4.48 (ddt, J = 13.0, 5.7, 1.4 Hz, 1 H), 4.40 (ddt, J = 13.1, 5.8, 1.5
Hz, 1 H), 3.81–3.69 (m, 1 H), 3.22 (td, J = 12.8, 3.0 Hz, 1 H),
2.41 (s, 3 H), 2.16–2.09 (m, 1 H), 1.75 (tdd, J = 13.7, 6.0, 3.6 Hz,
1 H), 1.70–1.59 (m, 2 H), 1.47 (tdd, J = 14.3, 10.9, 7.5 Hz, 1 H),
1.30 (tt, J = 13.6, 3.7 Hz, 1 H). 13C NMR (CDCl3, 126 MHz) δ
170.6, 143.2, 137.2, 131.7, 129.6, 127.4, 118.8, 65.7, 55.1, 42.7,
28.0, 24.8, 21.7, 20.2. HRMS (HESI): m/z [M + H]+ calcd for
C16H21O4NS +H+: 324.1264; found 324.1266.
4.2.13. Methyl 1-((4-
methoxyphenyl)sulfonyl)piperidine-2-carboxylate
(6p):
Prepared following the GP2 in 93 % yield (1.60 g) from 1.99 g
of 2g in 4 h at 60 °C. White solid: mp = 87 °C. TLC Rf = 0.39
(Cyclohexane/EtOAc 40 %); revelator: UV/KMnO4. IR (neat):
2945, 1728, 1594, 1498, 1440, 1338, 1297, 1261, 1155, 1109,
1093, 1053, 1026, 987, 921, 832, 803, 755, 700, 584, 559, 488
cm–1. 1H NMR (CDCl3, 500 MHz): δ = 7.71 (d, J = 8.9 Hz, 2 H),
6.94 (d, J = 8.9 Hz, 2 H), 4.72 (dd, J = 2.0, 5.4 Hz, 1 H), 3.85 (s,
3 H), 3.72 (ddd, J = 2.9, 3.9, 12.7 Hz, 1 H), 3.55 (s, 3 H), 3.19
(ddd, J = 2.9, 12.7, 12.7 Hz, 1 H), 2.14−2.06 (m, 1 H), 1.78−1.68
(m, 1 H), 1.68−1.58 (m, 1 H), 1.52−1.41 (m, 2 H), 1.33−1.21 (m,
1 H). 13C NMR (CDCl3, 126 MHz): δ = 171.4, 162.8, 131.7,
129.4, 114.0, 55.7, 55.1, 52.1, 42.6, 27.9, 24.8, 20.2. HRMS
(HESI): m/z [M + H]+ calcd for C14H19NO5S +H+: 314.1057;
found: 314.1059.
4.2.17. Benzyl 1-tosylpiperidine-2-carboxylate (6t):
Prepared following the GP2 in 97 % yield (106 mg) from 101 mg
of 2f and 10 equiv of benzyl alcohol after 6 h at 60 °C and
purification by bulb-to-bulb distillation. Yellowish oil. TLC Rf =
0.38 (Cyclohexane/EtOAc 30 %); revelator: UV/KMnO4. IR
(neat): 3032, 2944, 2860, 1990, 1739, 1597, 1496, 1454, 1375,
1337, 1302, 1261, 1241, 1184, 1154, 1109, 1091, 1055, 1035,
1018, 965, 943, 919, 862, 813, 726, 696, 654, 578, 543, 507, 475
cm-1. 1H NMR (CDCl3, 500 MHz): δ = 7.67–7.61 (m, 2 H), 7.39–
7.30 (m, 3 H), 7.26–7.23 (m, 2 H), 7.20 (d, J = 8.0 Hz, 2 H), 5.05
(d, J = 12.2 Hz, 1 H), 4.93 (d, J = 12.2 Hz, 1 H), 4.82–4.77 (m, 1

9
4.2.21. Methyl 2-bromo-7-((4-
methylphenyl)sulfonamido)heptanoate (4w):
H), 3.79–3.71 (m, 1 H), 3.21 (td, J = 12.8, 3.0 Hz, 1 H), 2.40 (s, 3
H), 2.17–2.10 (m, 1 H), 1.76 (tdd, J = 13.7, 6.0, 3.6 Hz, 1 H),
1.63 (ddq, J = 16.5, 11.0, 3.5 Hz, 2 H), 1.54–1.42 (m, 1 H), 1.30–
1.18 (m, 1 H). 13C NMR (CDCl3, 126 MHz): δ = 170.8, 143.2,
137.1, 135.6, 129.5, 128.7, 128.5, 128.2, 127.4, 66.9, 55.2, 42.7,
28.0, 24.8, 21.7, 20.2. HRMS (HESI): m/z [M + K]+ calcd for
C20H23O4NS +K+: 412.0943; found 412.0943.
ACCEPTED MANUSCRIPT
Obtained by following the GP2 in 34 % yield (86.2 mg) from
236 mg of 2i in 16 h. Colorless oil. TLC Rf = 0.19
(Cyclohexane/EtOAc 30 %); revelator: UV/KMnO4. IR (neat):
3285, 2938, 2862, 1738, 1598, 1495, 1435, 1323, 1305, 1288,
1152, 1092, 1019, 911, 814, 730, 660, 571, 549 cm–1. H NMR
1
(CDCl3, 500 MHz): δ = 7.74 (d, J = 8.2 Hz, 2 H), 7.31 (d, J = 8.2
Hz, 2 H), 4.59−4.54 (m, 1 H), 4.16 (dd, J = 6.4, 7.9 Hz, 1 H),
3.77 (s, 3 H), 2.92 (ddd, J = 6.8, 6.8, 6.8 Hz, 2 H), 2.43 (s, 3 H),
2.05−1.85 (m, 2 H), 1.49−1.43 (m, 2 H), 1.43−1.35 (m, 1 H),
1.34−1.25 (m, 3 H). 13C NMR (CDCl3, 126 MHz): δ = 170.4,
143.6, 137.0, 129.9, 127.2, 53.1, 45.5, 43.0, 34.7, 29.4, 26.8,
25.8, 21.7. HRMS (HESI): m/z [M + K]+ calcd for C15H22BrNO4S
+K+: 430.0084; found: 430.0032.
4.2.18. Phenyl 1-tosylpiperidine-2-carboxylate
(6u):
Prepared following the GP2 in 9 % yield (14 mg) from 136 mg
of 2f and 10 equiv of phenol after 18 h at 60 °C and purification
by bulb-to-bulb distillation. White solid: mp = 60-62 °C. TLC Rf
= 0.23 (Cyclohexane/EtOAc 30 %); revelator: UV/KMnO4. IR
(neat): 3065, 2944, 2859, 1994, 1955, 1763, 1591, 1491, 1454,
1401, 1379, 1337, 1303, 1261, 1238, 1186, 1153, 1108, 1091,
1070, 1053, 1034, 1018, 955, 930, 919, 873, 846, 814, 783, 745,
4.2.22. Methyl 2-bromo-4-((tert-
butoxycarbonyl)amino)butanoate (4j):
1
724, 688, 654, 589, 575, 543, 512, 494, 476, 414 cm-1. H NMR
(CDCl3, 500 MHz): δ = 7.75–7.70 (m, 2 H), 7.37–7.31 (m, 2 H),
7.25 (d, J = 6.4 Hz, 2 H), 7.23–7.19 (m, 1 H), 6.94–6.90 (m, 2
H), 4.98 (dd, J = 6.0, 2.3 Hz, 1 H), 3.81 (dddt, J = 12.9, 5.1, 2.6,
1.2 Hz, 1 H), 3.32 (td, J = 12.6, 3.1 Hz, 1 H), 2.38 (s, 3 H), 2.35–
2.27 (m, 1 H), 1.89 (tdd, J = 13.6, 6.0, 3.7 Hz, 1 H), 1.80–1.74
(m, 1 H), 1.73–1.67 (m, 1 H), 1.62–1.51 (m, 1 H), 1.44 (qt, J =
13.3, 3.5 Hz, 1 H). 13C NMR (CDCl3, 126 MHz): δ = 169.5,
150.3, 143.4, 137.1, 129.7, 129.5, 127.4, 126.2, 121.3, 55.2, 42.8,
28.1, 24.9, 21.6, 20.3. HRMS (HESI): m/z [M + Na]+ calcd for
C19H21O4NS +Na+: 382.1083; found 382.1090.
Obtained quantitatively by following the GP2 after 3 h at 45 °C
from 2j. Colorless oil. TLC Rf = 0.59 (Cyclohexane/EtOAc 50
%); revelator: UV/KMnO4. H NMR (CDCl3, 300 MHz): δ =
4.64 (br, 1 H), 4.31 (dd, J = 8.3, 6.1 Hz, 1 H), 3.79 (s, 3 H), 3.40–
3.17 (m, 2 H), 2.32 (dq, J = 13.6, 6.7 Hz, 1 H), 2.14 (ddt, J =
14.5, 8.3, 6.0 Hz, 1 H), 1.44 (s, 9 H).
1
4.2.23. 1-((2-
(Trimethylsilyl)ethyl)sulfonyl)azetidine-2-
carboxylic acid (3z):
Prepared following the modified GP2 in 91 % yield (37 mg)
from 50 mg of 2d in a mixture of MeCN/H2O after 16 h at 60
°C.13 After completion of the reaction, the solvents were removed
in vacuo. The residue was then partitioned between EtOAc and
HCl aqueous solution (1N). After extraction with EtOAc, the
combined organic layers were dried over MgSO4, concentrated
and dried under high vacuum to afford the pure compound 3z.
White solid: mp = 76 °C TLC Rf = 0.36 (EtOAc/MeOH 50 %);
revelator: UV/KMnO4. IR (neat): 3544, 3456, 3406, 2953, 2898,
1723, 1634, 1613, 1591, 1551, 1420, 1327, 1247, 1136, 1110,
1092, 944, 895, 859, 831, 755, 738, 701, 671, 630, 591, 549, 521
cm–1. 1H NMR (CDCl3, 500 MHz): δ = 6.85 (br, 1 H), 4.78 (t, J =
8.7 Hz, 1 H), 3.99 (q, J = 8.2 Hz, 1 H), 3.66 (td, J = 7.6, 4.8 Hz, 1
H), 3.00 (qdd, J = 14.0, 10.1, 7.3 Hz, 2 H), 2.49–2.37 (m, 2 H),
1.00 (tt, J = 10.2, 7.6 Hz, 2 H), 0.02 (s, 9 H). 13C NMR (CDCl3,
500 MHz): δ = 178.5, 63.2, 49.6, 49.4, 21.9, 11.4, 0.0. HRMS
(HESI): m/z [M + K]+ calcd for C9H19NO4SSi +K+: 304.0436;
found: 304.0449.
4.2.19. N-(4-Methoxyphenyl)-1-tosylpiperidine-2-
carboxamide (6v):
Prepared following the GP2 in 57 % yield (111 mg) from 176 mg
of 2f and 10 equiv of p-anisidine after 48 h at 60 °C and
purification by flash chromatography (from Cyclohexane/EtOAc
5% to 30%). Brown solid: mp = 57-60 °C. TLC Rf = 0.15
(Cyclohexane/EtOAc 30 %); revelator: UV/KMnO4. IR (neat):
3384, 2932, 2856, 2832, 2257, 2104, 2019, 1925, 1696, 1595,
1510, 1454, 1382, 1344, 1324, 1307, 1293, 1232, 1185, 1161,
1139, 1109, 1076, 1032, 975, 949, 907, 869, 813, 762, 717, 705,
1
691, 665, 621, 593, 574, 542, 438, 413 cm-1. H NMR (CDCl3,
500 MHz): δ = 7.92–7.87 (m, 2 H), 7.34–7.28 (m, 2 H), 6.77–
6.70 (m, 2 H), 6.45–6.39 (m, 2 H), 4.75–4.66 (m, 1 H), 4.55 (s, 1
H), 4.09 (d, J = 10.5 Hz, 1 H), 3.72 (s, 3 H), 3.53 (dd, J = 15.8,
11.4 Hz, 1 H), 2.42 (s, 3 H), 2.11–1.96 (m, 3 H), 1.86–1.75 (m, 1
H), 1.72–1.61 (m, 1 H), 1.52 (dddd, J = 13.2, 12.0, 10.6, 2.6 Hz,
1 H). 13C NMR (CDCl3, 126 MHz): δ = 174.0, 152.4, 145.0,
140.0, 136.3, 129.5, 128.6, 115.2, 114.4, 58.2, 55.9, 45.9, 31.4,
28.8, 27.4, 21.8. HRMS (HESI): m/z [M + H]+ calcd for
C20H24O4N2S +H+: 389.1530; found 389.1488.
4.3. Preparation of 2-carboxylated aza-ring derivatives by
two-step sequence using anionic Weinreb amine.
4.3.1. N-methoxy-N-methyl 2-bromo-4-((4-
methylphenyl)sulfonamido)butanamide (4g):
4.2.20. Methyl 2-(1-tosylpiperidin-2-yl)acetate
(8w):
To
a
stirred solution of N,O-dimethylhydroxylamine
Obtained by following the GP2 in 26 % yield (52.7 mg) from
236 mg of 2i in 16 h. Colorless oil. TLC Rf = 0.23
(Cyclohexane/EtOAc 30 %); revelator: UV/KMnO4. IR (neat):
2945, 2864, 1733, 1598, 1438, 1384, 1354, 1336, 1287, 1264,
1217, 1151, 1092, 928, 814, 732, 710, 694, 650, 589, 548 cm–1.
1H NMR (CDCl3, 500 MHz): δ = 7.70 (d, J = 8.2 Hz, 2 H), 7.27
(d, J = 8.2 Hz, 2 H), 4.52 (dddd, J = 2.5, 2.5, 5.6, 9.3 Hz, 1 H),
3.79 (ddd, J = 2.2, 4.4, 13.8 Hz, 1 H), 3.63 (s, 3 H), 2.93 (ddd, J
= 2.2, 12.9, 13.8 Hz, 1 H), 2.62 (dd, J = 9.3, 14.9 Hz, 1 H), 2.50
(dd, J = 5.6, 14.9 Hz, 1 H), 2.41 (s, 3 H), 1.58−1.45 (m, 5 H),
1.37−1.25 (m, 1 H). 13C NMR (CDCl3, 126 MHz): δ = 171.4,
143.2, 138.2, 129.8, 127.1, 52.0, 49.8, 41.1, 35.0, 27.8, 24.7,
21.6, 18.4. HRMS (HESI): m/z [M + K]+ calcd for C15H21NO4S
+K+: 350.0823; found: 350.0807.
hydrochloride salt (1.4 mmol) in dry THF (2 mL) was added
isopropyl magnesium chloride (2.83 mmol) at -20 °C. After
stirring for 15 min, the mixture was transferred via cannula to a
cold solution (-40 °C) of 2a (300 mg, 0.94 mmol) in dry THF (8
mL). The resulting mixture was then warmed to 0 °C and stirred
for 1.5 h at this temperature. The reaction mixture was quenched
with an aqueous solution of NH4Cl (10 mL) and extracted with
EtOAc (3 x 10 mL). The combined organic layers were washed
with brine (15 mL), dried over MgSO4 and concentrated in
vacuo. The residue was purified by flash chromatography
(Cyclohexane/EtOAc 40%) to afford 4g (290 mg) in 82 % yield.
Colorless oil. TLC Rf = 0.22 (Cyclohexane/EtOAc 50 %);
revelator: UV/KMnO4. IR (neat): 3251, 2939, 2873, 1645, 1422,
1
1324, 1154, 1092, 990, 660, 549 cm–1. H NMR (CDCl3, 500

10
Tetrahedron
ACCEPTED MANUSCRIPT
1
MHz): δ = 7.72 (d, J = 8.2 Hz, 2 H), 7.30 (d, J = 8.2 Hz, 2 H),
997, 837, 803, 674, 606, 559 cm–1. H NMR (CDCl3, 500 MHz):
δ = 7.90 (d, J = 8.9 Hz, 2 H), 6.99 (d, J = 8.9 Hz, 2 H), 5.14 (dd,
J = 8.3, 8.3 Hz, 1 H), 3.98 (ddd, J = 8.0, 8.2, 8.6 Hz, 1 H), 3.86
(s, 3 H), 3.71 (s, 3 H), 3.65 (ddd, J = 4.8, 7.8, 8.0 Hz, 1 H), 3.17
(s, 3 H), 2.26−2.38 (m, 2 H). 13C NMR (CDCl3, 125 MHz): δ =
170.3, 163.3, 130.3, 129.2, 114.1, 61.7, 59.5, 55.6, 47.7, 32.5,
19.8. HRMS (HESI): m/z [M + Na]+ calcd for C13H18N2O5S
+Na+: 337.0829; found: 337.0248.
5.03 (dd, J = 5.8, 5.9 Hz, 1 H), 4.93 (dd, J = 6.8, 6.9 Hz, 1 H),
3.81 (s, 3 H), 3.25−3.20 (bs, 3 H), 3.06 (dt, J = 5.8, 6.9 Hz, 1 H),
2.42 (s, 3 H), 2.31 (ddt, J = 5.9, 7.0, 14.7 Hz, 1 H), 2.15 (ddt, J =
5.8, 6.8, 14.7 Hz, 1 H). 13C NMR (CDCl3, 126 MHz): δ = 169.6,
143.6, 136.5, 129.8, 127.1, 61.8, 41.1, 39.1, 34.1, 32.6, 21.6.
HRMS (HESI): m/z [M + Na]+ calcd for C13H19BrN2O4S +Na+:
401.0141; found: 401.0151.
4.3.2. N-Methoxy-N-methyl 1-tosylazetidine-2-
(±)-Azetidine-2-carboxylic acid ((±)-AZE):1 3
carboxamide (3g):
To a stirred solution of 3z (30 mg, 0.113 mmol) in dry DMF (2
mL) was added cesium fluoride (0.34 mmol). The mixture was
stirred at 95 °C for 48 h. The solvent was removed in vacuo. The
solid residue was extracted with CHCl3 (3 x 1 mL). The
combined organic layers were concentrated in vacuo. The residue
was purified by flash chromatography (MeOH/EtOAc 20 to 50%)
to afford (±)-AZE (6 mg) in 52 % yield. H NMR (CDCl3, 300
MHz): δ = 4.90 (dd, J = 9.3, 5.7 Hz, 1 H), 1.49−1.43 (m, 2 H),
2.60−2.72 (m, 1 H), 2.49−2.33 (m, 1 H).
To a stirred solution of 4g (300 mg, 0.79 mmol) in MeCN (4 mL)
was added K2CO3 (2.37 mmol). The heterogeneous mixture was
refluxed until completion of the reaction, as monitored by TLC.
Filtration through a thin pad of silica gel (eluting with MeCN)
followed by concentration and drying under high vacuum
afforded the pure compound 3g (120 mg) in 60% yield. White
solid: mp = 97 °C. TLC Rf = 0.12 (Cyclohexane/EtOAc 50 %);
revelator: UV/KMnO4. IR (neat): 2992, 2975, 2951, 2885, 1667,
1599, 1434, 1339, 1155, 1093, 1035, 997, 972, 866, 811, 703,
666, 545 cm–1. 1H NMR (CDCl3, 500 MHz): δ = 7.84 (d, J = 8.2
Hz, 2 H), 7.32 (d, J = 8.2 Hz, 2 H), 5.15 (dd, J = 8.0, 9.0 Hz, 1
H), 3.99 (ddd, J = 7.4, 7.4, 8.6 Hz, 1 H), 3.72 (s, 3 H), 3.73−3.65
(m, 1 H), 3.19 (s, 3 H), 2.43 (s, 3 H), 2.40−2.27 (m, 2 H). 13C
NMR (CDCl3, 500 MHz): δ = 170.3, 143.9, 134.6, 129.6, 128.2,
61.4, 59.6, 47.8, 32.5, 21.7, 19.8. HRMS (HESI): m/z [M + Na]+
calcd for C13H18N2O4S +Na+: 321.0879; found: 321.0885.
1
Acknowledgments
We gratefully acknowledge the French Ministry of Research
and the CNRS for financial supports. FS, SM and NK thank the
French Ministry of Research for PhD fellowships.
Supplementary Material
4.3.3. N-methoxy-N-methyl 2-bromo-4-((4-
methoxyphenyl)sulfonamido)butanamide (4h):
Supplementary data associated with this article can be found
in the online version, at …
To
a
stirred solution of N,O-dimethylhydroxylamine
hydrochloride salt (9.28 mmol) in dry THF (10 mL) was added
isopropyl magnesium chloride (17.94 mmol) at -20 °C. After
stirring for 15 min, the mixture was transferred via cannula to a
cold solution (-40 °C) of 2c (2.00 g, 5.98 mmol) in dry THF (20
mL). The resulting mixture was then warmed to 0 °C and stirred
for 2 h at this temperature. The reaction was quenched with
aqueous NH4Cl (30 mL) and extracted with EtOAc (3 x 30 mL).
The combined organic layers were washed with brine (30 mL),
dried over MgSO4 and concentrated in vacuo. The residue was
purified by flash chromatography (Cyclohexane/EtOAc 20 to
50%) to afford 4h (920 mg) in 39 % yield. Colorless oil. TLC Rf
= 0.29 (Cyclohexane/EtOAc 50 %); revelator: UV/KMnO4. IR
(neat): 3570, 3250, 2941, 2842, 1646, 1595, 1578, 1497, 1459,
1440, 1391, 1324, 1302, 1257, 1148, 1111, 1093, 1022, 989, 940,
References and notes
1. (a) Takemoto, T., Nomoto, K., Fushiya, S., Ouchi, R., Kusano, G.,
Hikino, H., Takagi, S., Matsuura, Y.; Kakudo, M. Proc. Jpn.
Acad. 1978, 54B, 469. (b) Nomoto, K., Yoshioka, H., Arima, M.,
Fushiya, S., Takagi, S.; Takemoto, T. Chimia 1981, 35, 249. (c)
For a crystal structure, see: Mino, Y; Ishida, T.; Ota, N.; Inoue,
M.; Nomoto, K.; Takemoto, T.; Tanaka, H.; Sugiura, Y. J. Am.
Chem. Soc. 1983, 105, 4671.
2. (a) Hashimoto, K.; Shirahama, H. J. Syn. Org. Chem. Jpn. 1989,
47, 212. (b) Hashimoto, K.; Shirahama, H. Trends Org. Chem.
1991, 2, 1.
3. Non-aromatic scaffolds drug design: (a) Mann, A. In The Practice
of Medicinal Chemistry, 3rd ed., Wermuth, C. G., Ed.; Elsevier:
Amsterdam, 2008, 363. (b) Marson, C. M. Chem. Soc. Rev. 2011,
40, 5514. (c) Hu, X.-G.; Hunter, L. Beilstein J. Org. Chem. 2013,
9, 2696. (d) Lovering, F. Med. Chem. Commun. 2013, 4, 515.
4. (a) Dejaegher, Y.; Kuz’menok, N. M.; Zvonok, A. M.; De Kimpe,
N. Chem. Rev. 2002, 102, 29. (b) Couty, F.; Evano, G.; Prim, D.
Mini-Rev. Org. Chem. 2004, 1, 133. (c) Brandi, A.; Cicchi, S.;
Cordero, F. M. Chem. Rev. 2008, 108, 3988.
5. (a) Kern, N.; Blanc, A.; Weibel, J.-M.; Pale, P. Chem. Comm.
2011, 47, 6665. (b) Kern, N.; Blanc, A.; Miaskewicz, S.;
Robinette, M.; Weibel, J.-M.; Pale, P. J. Org. Chem. 2012, 77,
4323. (c) Kern, N.; Hoffmann, M.; Blanc, A.; Weibel, J.-M.; Pale,
P. Org. Lett. 2013, 15, 836. (d) Miaskiewicz, S.; Weibel, J.-M.;
Pale, P.; Blanc, A. Org. Lett. 2016, 18, 844. (e) Miaskiewicz, S.;
Gaillard, B.; Kern, N.; Weibel, J.-M.; Pale, P.; Blanc, A. Angew.
Chem. Int. Ed. 2016, 55, 9088.
1
833, 802, 768, 666, 628, 556, 486 cm–1. H NMR (CDCl3, 500
MHz): δ = 7.78 (d, J = 9.0 Hz, 2 H), 6.98 (d, J = 9.0 Hz, 2 H),
4.93 (dd, J = 7.0, 7.0 Hz, 1 H), 4.78 (dd, J = 6.3, 6.3 Hz, 1 H),
3.87 (s, 3 H), 3.82 (s, 3 H), 3.23 (s, 3 H), 3.10−3.03 (m, 2 H),
2.31 (dtd, J = 5.9, 7.4, 14.6 Hz, 1 H), 2.15 (ddt, J = 5.7, 7.1, 14.7
Hz, 1 H). 13C NMR (CDCl3, 500 MHz): δ = 169.6, 163.0, 131.0,
129.3, 114.4, 61.8, 55.7, 41.1, 39.1, 34.0, 32.6. HRMS (HESI):
m/z [M + H]+ calcd for C13H19BrN2O5S +H+: 395.0271; found:
395.0273.
4.3.4. N-Methoxy-N-methyl 1-((4-
methoxyphenyl)sulfonyl)azetidine-2-carboxamide
(3h):
6. Kern, N.; Hoffmann, M.; Weibel, J.-M.; Pale, P.; Blanc, A.
Tetrahedron 2014, 70, 5519.
To a stirred solution of 4h (920 mg, 2.33 mmol) in MeCN (11
mL) was added K2CO3 (6.99 mmol). The heterogeneous mixture
was refluxed until completion of the reaction, as monitored by
TLC. Filtration through a thin pad of silica gel (eluting with
MeCN) followed by concentration and drying under high vacuum
afforded the pure compound 3h (630 mg) in 86% yield. Colorless
crystals: mp = 78 °C. TLC Rf = 0.09 (Cyclohexane/EtOAc 50 %);
revelator: UV/KMnO4. IR (neat): 2972, 2943, 2897, 2842, 1672,
1594, 1497, 1461, 1442, 1341, 1303, 1258, 1151, 1093, 1025,
7. Kern, N.; Felten, A-S.; Weibel, J.-M.; Pale, P.; Blanc, A. Org. Lett
2014, 16, 6104.
8. To the best of our knowledge, a single example has been reported
on acyclic compounds; see: (a) Otaka, A.; Mitsuyama, E.;
Kinoshita, T.; Tamamura, H.; Fujii, N. J. Org. Chem. 2000, 65,
4888. It is noteworthy that monobromination of cyclic ynamide
could not be achieved cleanly using strong bases, see: (b) Tlais, S.
F.; Danheiser, R. L. J. Am. Chem. Soc. 2014, 136, 15489.
9. Bastiaans, H. M. M.; van der Baan, J. L.; Ottenheijm, H. C. J. J.
Org. Chem. 1997, 62, 3880.

11
10. For a review on Aze synthesis, see: Couty, F.; Evano, G. Org.
ACCEPTED MANUSCRIPT
Prep. Proced. Int. 2006, 38, 427.
11. Matzanke, N.; Gregg, R. J; Weinreb, S. M. J. Org. Chem. 1997,
62, 1920.
12. Biswas, T.; Mukherjee, J. P.; Chattopadhyay, S. K. Tetrahedron:
Asymmetry 2012, 23, 1416.
13. Bouazaoui, M.; Martinez, J.; Cavelier, F. Eur. J. Org. Chem.
2009, 2729.