Palladium-catalyzed ortho-olefination of 2-arylpyrrolidines: A tool for increasing structural complexity in nitrogen heterocycles

Article abstract of DOI:10.1016/j.tet.2018.05.076

The dual role of the (2-pyridyl)sulfonyl unit as directing functionality and readily removable N-protecting group has enabled an efficient and practical transformation of 2-arylpyrrolidine derivatives into more complex tricyclic frameworks via palladium-catalyzed ortho-olefination with electron deficient alkenes and subsequent cyclization upon N-deprotection under mild conditions. The key cross coupling step in the presence of N-fluoro-2,4,6-trimethylpyridinium triflate ([F+]) as the terminal oxidant is both highly efficient and tolerant to a variety of steric and electronic changes at both coupling partners. By adequate choice of reductive conditions, the N-sulfonyl deprotection can be directed to the selective formation of benzo-fused pyrrolizidine or fused pyrrolidino-benzazapine frameworks.

Full text of DOI:10.1016/j.tet.2018.05.076

Accepted Manuscript
Palladium-catalyzed ortho-olefination of 2-arylpyrrolidines: A tool for increasing
structural complexity in nitrogen heterocycles
Pablo D. Legarda, Alfonso García-Rubia, Ramón Gómez Arrayás, Juan C. Carretero
PII:
S0040-4020(18)30635-5
10.1016/j.tet.2018.05.076
TET 29583
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 12 April 2018
Revised Date: 23 May 2018
Accepted Date: 26 May 2018
Please cite this article as: Legarda PD, García-Rubia A, Arrayás RG, Carretero JC, Palladium-catalyzed
ortho-olefination of 2-arylpyrrolidines: A tool for increasing structural complexity in nitrogen heterocycles,
Tetrahedron (2018), doi: 10.1016/j.tet.2018.05.076.
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
Palladium-catalyzed ortho-olefination of 2-
arylpyrrolidines: a tool for increasing structural
complexity in nitrogen heterocycles
Leave this area blank for abstract info.
Pablo D. Legarda , Alfonso García-Rubia, Ramón Gómez Arrayás* and Juan C. Carretero*
Departamento de Química Orgánica, Facultad de Ciencias, UAM, Cantoblanco, 28049 Madrid, Spain

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Palladium-catalyzed ortho-olefination of 2-arylpyrrolidines: a tool for increasing
structural complexity in nitrogen heterocycles†
Pablo D. Legarda a, Alfonso García-Rubiab, Ramón Gómez Arrayás a,c* and Juan C. Carretero a,c*
† In honor of Prof. Leon Ghosez for his deep and lifelong commitment with Tetrahedron.
a
Departamento de Química Orgánica, Facultad de Ciencias, Universidad Autónoma de Madrid (UAM), Cantoblanco, 28049 Madrid, Spain.
b Current address: Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas (CSIC), Ramiro de Maeztu 9, 28040, Madrid, Spain.
c Institute for Advanced Research in Chemical Sciences (IAdChem) UAM, Madrid, Spain. E-mail: ramon.gomez@uam.es; juancarlos.carretero@uam.es
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The dual role of the (2-pyridyl)sulfonyl unit as directing functionality and readily removable N-
protecting group has enabled an efficient and practical transformation of 2-arylpyrrolidine
derivatives into more complex tricyclic frameworks via palladium-catalyzed ortho-olefination
with electron deficient alkenes and subsequent cyclization upon N-deprotection under mild
conditions. The key cross coupling step in the presence of N-fluoro-2,4,6-trimethylpyridinium
triflate ([F+]) as the terminal oxidant is both highly efficient and tolerant to a variety of steric
and electronic changes at both coupling partners. By adequate choice of reductive conditions,
the N-sulfonyl deprotection can be directed to the selective formation of benzo-fused
pyrrolizidine or fused pyrrolidino-benzazapine frameworks.
Available online
Keywords:
2-Phenylpyrrolidine
Palladium
Direct C−H alkenylation
2-Pyridylsulfonyl directing group
Benzopyrrolizidine
Benzazepine
2009 Elsevier Ltd. All rights reserved
.
1. Introduction
achieving an efficient and general Pd-catalyzed C2-alkenylation
of indoles and pyrroles with both electron-poor and non-activated
alkenes (Scheme 1a).6a,b This strategy has also been applied to the
Pd-catalyzed ortho-C−H alkenylation of N-alkylated aniline,
benzylamine, phenethylamine and γ-arylpropylamine derivatives
with electron-poor alkenes (Scheme 1b).6c,j More recently, this
concept was extended to the regiocontrolled direct Pd-catalyzed
C1/C8-diolefination of carbazoles (Scheme 1c).6d
Nitrogen-containing heterocyclic compounds are privileged
structures in terms of biological activity and continues to inspire
the development of new methods for their synthesis and
functionalization.1 Introducing complexity and diversity on a
core molecule is crucial for facilitating lead discovery and
optimization in medicinal chemistry. Toward that goal, the metal
catalyzed C−H alkenylation of nitrogen heterocycles has attracted
much current interest as a unique tactic for rapidly increasing
structural complexity due to the synthetic versatility of the newly
incorporated alkenyl group.2,3 Introducing a directing group on a
N atom has become a commonly used strategy to ensure site-
selectivity, thereby leading to great progress in this area.4
However, to take full advantage of the synthetic potential of this
strategy, directing groups must have the ability to be readily
removed under conditions that are compatible with the presence
of sensitive alkenyl groups. This is not always achievable and
often removal of the ortho-directing group from the product
requires prior derivatization of the newly incorporated alkene,
which is a feat that often limits the transformation’s synthetic
utility. Additionally, controlling mono- vs. disubstitution
selectivity is a continuing challenge in this type of processes.5
Our research group has pioneered the use of the (2-
pyridyl)sulfonyl unit (SO2Py) as a weakly coordinating and
readily removable directing group in metal-catalyzed C−H
functionalization reactions.6 The dual protecting and directing
role of SO2Py in C−H functionalization was first demonstrated by

2
Tetrahedron
ACCEPTED MANUSCRIPT
Scheme 1. N-SO2Py directing group in Pd-catalyzed direct
C−H olefination of nitrogen heterocycles
Table 1. Optimization studies in the model olefination of substrate 1a
(2 equiv)
CO2Bu
N
N
N
SO2Py
CO2Bu
SO2Py
CO2Bu
SO2Py
Pd(OAc)2 (10 mol%)
oxidant (2.0 equiv)
BuO2C
solvent, 110 ºC, 14 h
1
3
2
Entry
Oxidant
Solvent
Conversion %b
2 / 3b
1
[F+]c
DCE
DCE
DCE
DCE
DCE
DCE
Toluene
>97
67
92:8
2
PhI(OAc)2
K2S2O8
Oxone
Ce(SO4)2
Cu(OAc)2
[F+] c
[F+] c
[F+] c
[F+] c
[F+] c
>95:<5
>95:<5
>95:<5
>95:<5
−
3
24
4
11
5
9
6
<3
7
45
>95:<5
>95:<5
>95:<5
>95:<5
90:10
8
1,4-Dioxane
DMSO
DMF
35
9
25
10
11
12d
13d,f
14d,g
76
AcOH
DCE
90
>97 (85)e
[F+] c
[F+] c
[F+] c
>95:<5
>95:<5
>95:<5
DCE
70
DCE
40
aReaction conditions: 1 (0.15 mmol), butyl acrylate (0.30 mmol), Pd(OAc)2 (0.015 mmol), oxidant (0.30 mmol), solvent (1.5 mL), 110 ºC, 14 h under N2.
bDetermined by 1HNMR.
c[F+] = N-fluoro-2,4,6-trimethylpyridinium triflate.
dReaction performed in the presence of 1.2 equiv (0.18 mmol) of butyl acrylate.
eIsolated yield of the mono-olefination product after chromatographic purification.
fIn the presence of 5 mol% of Pd(OAc)2.
gIn the presence of 2 mol% of Pd(OAc)2.
Driven by our continued interest in the development of practical
methods based on catalytic C−H functionalization for the
assembly of nitrogen-containing heterocyclic architectures from
simple precursors, we envisioned that the 2-arylpyrrolidine unit7
could provide an ideal platform for iterative ortho-selective C−H
alkenylation and subsequent cyclization leading to more complex
polycyclic ring systems such as benzo-fused pyrrolizidines
(Scheme 1d). It is important to note that the benzopyrrolizidine
motif forms the core of many natural products with
pharmacological relevance.8,9 In this pursuit, we describe herein
an efficient method for the ortho-olefination of 2-aryl-N-(2-
pyridyl)sulfonylpyrrolidines with electron-deficient alkenes and
their derivatization into heterocyclic systems of increased
complexity such as benzo-fused pyrrolizidines or pyrrolidino-
benzazepines by appropriate choice of N-deprotection conditions.
superiority of [F+] as oxidant was demonstrated upon evaluation
of a handful of oxidants of different oxidizing ability. PhI(OAc)2
proved also to be an effective stoichiometric oxidant for this
reaction, although incomplete conversion was observed (67%,
entry 2). Other oxidants used in Pd-catalyzed C−H activation
processes such as K2S2O8, Oxone or Ce(SO4)2 provided
unpractical conversions (9-24%, entries 3-5). No product was
detected when the reaction was performed in the presence of
Cu(OAc)2, a weaker oxidant widely used in Pd-catalyzed C−H
olfefinations that have been proposed to occur through catalytic
cycles based on PdII/Pd0 redox shuttles (entry 6).3 In contrast, the
powerful oxidant [F+] has been used in Pd-catalyzed C−H
transformations such as fluorination, trifluoromethylation, and
aminations, for which a key stage of the proposed cycle is the
oxidation of a PdII intermediate into high-valent PdIII or PdIV
intermediates.10
A solvent screening revealed DCE as the most effective
reaction media. Other aprotic solvents of varied polarity such as
toluene, 1,4-dioxane or DMSO failed to provide a conversion
beyond 45% (entries 7-9), whereas the use of DMF resulted in a
boost in conversion up to 76% (entry 10). In accordance with the
suggested important role of polar acidic solvents in the
acceleration of cyclopalladation processes,11 the model reaction
of 1 with butyl acrylate in AcOH resulted in 90% conversion,
albeit a slightly diminished mono-/di-substitution selectivity was
observed (2/3 = 90:10, entry 11). The higher efficiency observed
in the chlorinated solvent DCE can be plausibly ascribed to the
presence of small amounts of HCl upon partial decomposition.
Finally, we were glad to find that the di-ortho-olefination process
2. Results and discussion
At the outset of our study, we studied the alkenylation of the
N-SO2Py-protected parent 2-phenylpyrrolidine 1 with butyl
acrylate, taking as the basis for reaction optimization the
conditions previously established for the ortho-olefination of
benzylamine derivatives.6c The results of this study are presented
in Table 1. The reaction of 1 with butyl acrylate (2 equiv) in the
presence of Pd(OAc)2 (10 mol%) and N-fluoro-2,4,6-
trimethylpyridinium triflate ([F+], 2 equiv) as oxidant in DCE at
110 ºC for 14 hours led to the clean formation of the expected
olefination product 2 with complete conversion and very good
mono-/disubstitution selectivity (2/3 = 92:8, entry 1). The

3
was almost completely suppressed by reducing the amount of
cReaction performed with 2 equivalents of alkene. [F+] = N-
fluoro-2,4,6-trimethylpyridinium triflate.
ACCEPTED MANUSCRIPT
alkene to 1.2 equiv without any appreciable impact in reactivity,
thereby providing the desired monoalkenylation product 2 in
85% isolated yield (entry 12). In constrast, decreasing the
palladium catalyst loading to 5 mol% and 2 mol% resulted in
incomplete conversions (entries 13 and 14, respectively).
The versatility with regard to the substitution at the 2-
arylpyrrolidine component was also examined using butyl
acrylate as the model alkene (Scheme 4). This scope study
revealed that although both electron-withdrawing and electron-
donating substituents are tolerated at the aromatic ring of the 2-
arylpyrrolidine unit, both electronic and steric effects influenced
the reactivity. For example, although similar good yields could
be attained in the alkenylation of substrates holding either a p-Me
(product 17, 70%) or an electron-withdrawing p-F group (18,
68%), the need for an excess of 2.0 equivalents of alkene
evidenced the lower reactivity of the latter. When a meta-
The unique directing role of the N-SO2Py unit was illustrated
through a control experiment showing that no reaction was
produced when the analogue N-tosylated 2-phenylpyrrolidine 4
was submitted to the reaction with butyl acrylate under otherwise
identical reaction conditions, resulting in the exclusive recovery
of starting material (Scheme 2).
methoxy substituent is present,
a strong preference for
alkenylaton at the more sterically accessible ortho C−H bond was
observed (19, 66%), although traces of the di-olefination product
were also detected in the reaction mixture (mono-/di- = 95:5).
Importantly, this alkenylation method seems to be not very
sensitive to steric hindrance imposed by aryl ortho-substitution,
as illustrated in smooth reaction observed in the case of the
ortho-methoxy derivative, yet 2.0 equivalents of butyl acrylate
were needed for achieving complete conversion (20, 76%). Also,
the reactions did occur at the C−H bond of a heteroaryl
substituent such as the 2-thienyl group (21, 61%), thus showing
the compatibility with potentially coordinating heteroatoms that
could bind the palladium species preventing successive
turnovers. It is also noteworthy the capacity of the N-SO2Py
Scheme 2. Control experiment with N-Ts substrate 4. [F+] =
N-fluoro-2,4,6-trimethylpyridinium triflate.
With an efficient and selective ortho-alkenylation protocol in
hand, we next set out to investigate the scope of alkenylation of
substrate 1 with various electron-deficient alkenes (Scheme 3).
Not only acrylates, but also phenyl vinyl sulfone and dimethyl
vinyl phosphonate, coupled efficiently with 1 to give the
corresponding ortho-alkenylated products with excellent
monosubstitution selectivity, and E-stereocontrol in synthetically
useful yields (products 6-8, 74−81%). Even acrylonitrile, having
a potentially metal-coordinating nitrogen was also compatible
with this catalytic system, providing the alkenylation product 9 as
a 62:38 mixture of E and Z stereoisomers, respectively. Upon
standard chromatographic separation, E-9 and Z-9 were isolated
in 29% and 27% yield, respectively.12 Unfortunately, no reaction
was observed with 1,1- or 1,2-disubstituted alkenes such as α-
ethylacrolein or (E)-methyl crotonate, showing the sensitivity of
the alkenylation reaction to steric effects. Styrene derivatives
bearing electron-withdrawing substituents such as p-NO2 or p-
CF3 were also suitable substrates in this olefination reaction,
although an excess of 2 equivalents of the alkene was required to
afford the desired products 10 and 11 (54% and 48%,
respectively. The increased of reactivity produced by the excess
of alkene came at the cost of lower mono-/disubstitution
selectivity in the case of product 10 (mono-/di- = 90:10).
directing group to promote the C−H alkenylation with complete
site-selectivity control at C3,13 thus overriding the intrinsic
preference of the thiophene ring system for metalation and
subsequent C−H functionalization at the C5 position.14
Scheme 4. Scope with regard to the substitution at the 2-
arylpyrrolidine component. Yields are isolated yields of the
mono-olefination product after chromatographic purification.
aReaction performed with 1.5 equiv of alkene. bMono-/di- = 95:5.
cReaction performed with 2.0 equivalents of alkene. [F+] = N-
fluoro-2,4,6-trimethylpyridinium triflate.
Encouraged by the high reactivity and the good tolerance of
this catalyst system toward the steric demand of ortho-
substituents, we wondered whether it might enable the
installation of two different alkenes at the two ortho positions of
the arene by sequential double C−H alkenylation reactions. It is
important to note that few protocols have demonstrated capability
for efficient twofold C−H activation of this type.15 To test this
hypothesis, we submitted the monoolefination product 2 to the
reaction with phenyl vinyl sulfone under the standard conditions
Scheme 3. Scope with regard to the olefin coupling partner.
Isolated yields of the mono-olefination product after
a
b
chromatographic purification. E/Z = 62:38. Mono-/di- = 90:10.

4
Tetrahedron
ACCEPTED MANUSCRIPT
for the present method. Although the reaction required 3
equivalents of the alkene to reach full conversion,16 the desired
unsymmetrical diolefinated product 22 could be isolated in useful
yield (55%, Scheme 5). However, while feasible, this sequential
bis-olefination approach was not generally applicable as the
reaction of 2 with dimethyl vinyl phosphonate failed (not shown).
Scheme 7. N-Deprotection/cyclization to afford pyrrolidino-
benzazepinones.
In conclusion, we have demonstrated the ability of the N-
SO2Py group to serve as an efficient directing and readily
removable protecting group for the PdII-catalyzed regiocontrolled
ortho-olefination of 2-arylpyrrolidine derivatives with activated
alkenes. This method features high mono-substitution selectivity
and good structural versatility in both alkene and pyrrolidine
components, providing the olefination products in synthetically
useful yields. Two complementary N-deprotection protocols
enables the access to nitrogen heterocyclic systems of increased
structural complexity that are relevant to medicinal chemistry
such as benzopyrrolizidines or fused pyrrolidino-benzazepinone
motifs.
Scheme 5. Synthesis of the unsymmetrical bis-alkenylated
product 22.
To fully realize the synthetic potential of this C–H olefination
method, we took advantage of the easy reductive removal of the
N-SO2Py protecting/directing group under smooth conditions (Zn
powder, AcOH, rt) without affecting the alkene moiety.6 These
conditions enabled the direct access to valuable
benzopyrrolizidine derivatives, as illustrated in Scheme 6. For
example, N-sulfonyl cleavage in compounds 2 and 18, both with
an embedded butyl acrylate moiety, triggered in situ the
cyclization of the resulting free amine via intramolecular aza-
Michael reaction to afford 23 and 24 in 61% and 67% yield,
respectively, and complete diastereocontrol (syn/anti = >98:<2).17
In contrast, when compound 7, holding a vinyl sulfone as the
Michael acceptor, was used as the starting material, the formation
of a second isomer could be detected (syn/anti = 55:45). Despite
the minor isomer was tentatively assigned to anti-25 on the basis
3. Experimental section
3.1. General Methods. All general reagents were obtained from
usual commercial sources and were used, except when noted,
without further purification. All reactions were carried out in
anhydrous solvents and under inert atmosphere, unless otherwise
noted. Column chromatographies were performed on silica gel
(230-400 mesh ASTM). TLC analysis was performed on 0.2 mm
1
1
aluminium based plates (60 230-400 mesh). H, 13C{1H}NMR
of the close similarity of its H NMR spectrum with that of syn-
and bidimensional spectra were recorded in CDCl3 solutions at
25 °C on AV-300, AVII-300 y AVIII-HD-300 (300 and 75 MHz,
respectively) or DRX-500 (500 y 125 MHz, respectively)
spectrometers (δ, ppm; J, Hz), and referenced using the solvent
signal as internal standard. HRMS electron ionization (EI+) and
electrospray ionization (ESI+) mass spectra were recorded using
an MicroToF Q, API-QToF ESI with a mass range from 20 to
3000 m/z and mass resolution 15000 (FWHM). Melting points
were determined in open-end capillary tubes.
25, all attempts at isolating this product were not successful.
Indeed, conventional chromatographic purification allowed the
isolation of only syn-25 in a 35% isolated yield.
3.2. Typical procedure for the synthesis of starting materials:
Synthesis of N-(2-pyridylsulfonyl)-2-phenylpyrrolidine18 (1)
Scheme
6.
N-Deprotection/cyclization
to
afford
benzopyrrolizidines. aDiastereomeric ratio measured by 1H NMR.
bIsolated yields of syn-diastereomer after conventional
chromatography. cOnly syn-25 could be isolated upon
chromatographic purification.
A flask equipped with a frit with Schlenk valves and sealed with
a two-necked dummy flask on the other end was charged with
pyrrolidin-2-one (2.0 g, 24 mmol), diethyl ether (50 ml) and
triethylamine (3.5 mL, 25 mmol, 1.05 equiv). The mixture was
cooled to 0 °C before chlorotrimethylsilane (3.2 mL, 25 mmol,
1.05 equiv) was added slowly. Once the addition was completed,
the mixture was stirred under reflux for 30 min, then cooled to
room temperature and the resulting Et3NHCl filtered off under
argon through the glass frit into the round-bottomed flask. To the
filtrate was slowly added under argon a 3 M solution of
phenylmagnesium bromide in THF (8 mL, 24 mmol, 1.0 equiv)
and the resulting mixture was stirred under reflux for further 3 h.
The mixture was allowed to cool to room temperature before it
was quenched with 1 M HCl aq. solution (10 mL). The aqueous
phase was separated, basified to pH 10 with 2 M NaOH solution
and extracted with EtOAc (3 x 20 mL). The combined organic
phase was washed with brine (10 mL), then dried (Na2SO4), and
concentrated in vacuo to give I as a colorless oil, which was used
without further purification.
Interestingly, when a stronger reducing agent such as sodium
amalgam [Na(Hg)] was used for the N-desulfonylation reaction,
the desired deprotection was accompanied by concomitant
conjugate reduction of the acrylate moiety, which in turn
triggered a spontaneous intramolecular amidation with formation
of a seven-membered lactam. As shown in Scheme 7, the
corresponding fused pyrrolidino-benzazepinone frameworks
were obtained in good yields (products 26 and 27, 74% and 73%,
yield, respectively).

5
To a solution of the crude I in MeOH/H2O (4:1, 25 mL) was
added NaBH4 (980 mg, 26 mmol, 1.1 equiv). The mixture was
stirred at room temperature overnight before it was acidified to
pH 1-3 with a 2 M HCl aq. solution and maintained at this pH for
30 min. Then, the mixture was basified to pH 13-14 with 2 M
NaOH solution and it was extracted with CH2Cl2 (3 x 30 mL).
The combined organic phase was dried (Na2SO4) and
concentrated in vacuo to give II as a colorless oil, which was
used without further purification.
To a solution of the crude 2-phenylpirrolidine and pyridine (2.9
mL, 36 mmol, 1.5 equiv) in THF (50 mL), cooled to 0 ºC and
under Ar, was added slowly 2-pyridylsulfonyl chloride (6.4 g, 36
mmol, 1.5 equiv).19 The resulting solution was allowed to reach
room temperature and stirred at room temperature overnight. The
mixture was quenched with a sat aq. NH4Cl solution (40 mL) and
extracted with EtOAc (3 x 50 mL). The combined organic phase
was dried (MgSO4) and concentrated under reduced pressure.
The residue was purified by flash chromatography (cyclohexane-
EtOAc 4:1) to afford N-(2-pyridylsulfonyl)-2-phenylpyrrolidine
1 as a white solid; yield: 1.44 g (21%); mp: 101-103 ºC. 1H NMR
(300 MHz, CDCl3) δ 8.69 (d, J = 4.6 Hz, 1H), 7.85 – 7.74 (m,
2H), 7.48 – 7.41 (m, 1H), 7.30 – 7.13 (m, 5H), 5.14 (dd, J = 7.8,
3.3 Hz, 1H), 3.83 – 3.64 (m, 2H), 2.31 – 2.15 (m, 1H), 2.00 –
1.74 (m, 3H). 13C NMR (75 MHz, CDCl3) δ 149.9, 143.0, 137.6,
128.2, 126.9, 126.4, 126.3, 126.1, 122.9, 63.9, 50.0, 35.8, 24.2.
ESI+ calcd. for C15H17N2O2S (M+H)+: 289.1005. Found:
289.1011.
2-{[2-(3-Methoxyphenyl)pyrrolidin-1-yl]sulfonyl}pyridine (14)
ACCEPTED MANUSCRIPT
Following the typical procedure, the N-silylation of 2-
pyrrolidinone (2.0 g, 24 mmol) with Et3N (3.5 mL, 25 mmol,
1.05 equiv) and TMSCl (3.2 mL, 25 mmol, 1.05 equiv), followed
by addition of 3-methoxyphenylmagnesium bromide (24 mL, 24
mmol, 1.0 equiv) and reduction with NaBH4 (980 mg, 26 mmol,
1.1 equiv), afforded 2-(3-methoxyphenyl)pyrroline as an orange
oil. Subsequent N-sulfonylation with pyridine (2.9 mL, 36 mmol,
1.5 equiv) and 2-pyridylsulfonyl chloride (6.4 g, 36 mmol, 1.5
equiv) afforded, after column chromatography (cyclohexane-
EtOAc 4:1), the product 14 (1.45 g, 19%); as a white solid; mp:
1
107-110 ºC. H NMR (300 MHz, CDCl3) δ 8.73 (d, J = 4.5 Hz,
1H), 7.95 – 7.79 (m, 2H), 7.53 – 7.44 (m, 1H), 7.39 (d, J = 7.5
Hz, 1H), 7.24 – 7.16 (m, 1H), 6.90 (t, J = 7.5 Hz, 1H), 6.79 (d, J
= 8.1 Hz, 1H), 5.34 (dd, J = 7.9, 2.2 Hz, 1H), 3.78 (s, 3H), 3.86 –
3.62 (m, 2H), 2.26 – 2.06 (m, 1H), 1.93 – 1.73 (m, 3H). 13C NMR
(76 MHz, CDCl3) δ 157.5, 155.7, 149.9, 137.5, 131.2, 127.9,
127.2, 126.3, 123.0, 120.2, 110.1, 59.7, 55.1, 50.0, 33.9, 24.0.
ESI+ cald for C16H19N2O3S (M+H)+: 319.1111. Found: 319.1116.
2-{[2-(2-Methoxyphenyl)pyrrolidin-1-yl]sulfonyl}pyridine (15)
Following the typical procedure, the N-silylation of 2-
pyrrolidinone (2.0 g, 24 mmol) with Et3N (3.5 mL, 25 mmol,
1.05 equiv) and TMSCl (3.2 mL, 25 mmol, 1.05 equiv), followed
by addition of 2-methoxyphenylmagnesium bromide (24 mL, 24
mmol, 1.0 equiv) and reduction with NaBH4 (980 mg, 26 mmol,
1.1 equiv), afforded 2-(2-methoxyphenyl)pyrroline as a yellow
oil. Subsequent N-sulfonylation with pyridine (2.9 mL, 36 mmol,
1.5 equiv) and 2-pyridylsulfonyl chloride (6.4 g, 36 mmol, 1.5
equiv) afforded, after column chromatography (cyclohexane-
EtOAc 4:1), the product 15 (1.3 g, 17%) as a white solid; mp:
2-{[2-(p-Tolyl)pyrrolidin-1-yl]sulfonyl}pyridine (12) Following
the typical procedure, the N-silylation of 2-pyrrolidinone (2.0 g,
24 mmol), with Et3N (3.5 mL, 25 mmol, 1.05 equiv) and TMSCl
(3.2 mL, 25 mmol, 1.05 equiv), followed by addition of p-
tolylmagnesium bromide (24 mL, 24 mmol, 1.0 equiv) and
reduction with NaBH4 (980 mg, 26 mmol, 1.1 equiv), afforded 2-
(p-tolyl)pyrroline as a yellow oil. Subsequent N-sulfonylation
with pyridine (2.9 mL, 36 mmol, 1.5 equiv) and 2-
pyridylsulfonyl chloride (6.4 g, 36 mmol, 1.5 equiv) afforded,
after column chromatography (cyclohexane-EtOAc 4:1), the
product 12 (1.6 g, 22%) as a white solid; mp: 96-99 ºC. 1H NMR
(300 MHz, CDCl3) δ 8.70 (d, J = 4.6 Hz, 1H), 7.88 – 7.76 (m,
2H), 7.51 – 7.39 (m, 1H), 7.17 (d, J = 7.9 Hz, 2H), 7.06 (d, J =
7.9 Hz, 2H), 5.10 (dd, J = 7.6, 3.2 Hz, 1H), 3.85 – 3.64 (m, 2H),
2.30 (s, 3H), 2.26 – 2.10 (m, 1H), 1.97 – 1.71 (m, 3H). 13C NMR
(76 MHz, CDCl3) δ 157.6, 149.9, 140.0, 137.5, 136.5, 128.9,
126.3, 126.1, 123.0, 63.8, 50.0, 35.8, 24.2, 21.0. ESI+ calcd. for
C16H19N2O2S (M+H)+: 303.1162. Found: 303.1168.
1
112-115 ºC. H NMR (300 MHz, CDCl3) δ 8.69 (d, J = 4.4 Hz,
1H), 7.86 – 7.74 (m, 2H), 7.49 – 7.41 (m, 1H), 7.17 (t, J = 7.9
Hz, 1H), 6.84 (dd, J = 10.5, 4.8 Hz, 2H), 6.73 (dd, J = 8.1, 2.3
Hz, 1H), 5.13 (dd, J = 7.8, 3.0 Hz, 1H), 3.76 (s, 3H), 3.84 – 3.60
(m, 2H), 2.29 – 2.11 (m, 1H), 1.97 – 1.73 (m, 3H). 13C NMR (76
MHz, CDCl3) δ 159.5, 157.4, 149.8, 144.7, 137.5, 129.2, 126.3,
122.9, 118.4, 112.2, 111.8, 63.8, 55.1, 49.9, 35.6, 24.1. ESI+
calcd. for C16H19N2O3S (M+H)+: 319.1111. Found: 319.1116.
2-{[2-(Thiophen-2-yl)pyrrolidyn-1-yl]sulfonyl}pyridine (16)
Following the typical procedure, the N-silylation of 2-
pyrrolidinone (2.0 g, 24 mmol) with Et3N (3.5 mL, 25 mmol,
1.05 equiv) and TMSCl (3.2 mL, 25 mmol, 1.05 equiv), followed
by addition of 2-thienylmagnesium bromide (24 mL, 24 mmol,
1.0 equiv) and reduction with NaBH4 (980 mg, 26 mmol, 1.1
equiv), afforded 2-(2-thiophen)pyrroline as
a yellow oil.
2-{[2-(4-Fluorophenyl)pyrrolidin-1-yl]sulfonyl}pyridine
(13)
Subsequent N-sulfonylation with pyridine (2.9 mL, 36 mmol, 1.5
equiv) and 2-pyridylsulfonyl chloride (6.4 g, 36 mmol, 1.5 equiv)
afforded, after column chromatography (cyclohexane-EtOAc
4:1), the product 16 (1.68 g 17%) as a white solid; mp: 83-85 ºC.
1H NMR (300 MHz, CDCl3) δ 8.68 (d, J = 4.5 Hz, 1H), 7.91 –
7.76 (m, 2H), 7.49 – 7.40 (m, 1H), 7.12 (d, J = 4.9 Hz, 1H), 6.97
(d, J = 3.1 Hz, 1H), 6.88 (dd, J = 4.9, 3.8 Hz, 1H), 5.47 (dd, J =
7.4, 1.9 Hz, 1H), 3.81 – 3.67 (m, 1H), 3.66 – 3.51 (m, 1H), 2.29 –
2.12 (m, 1H), 2.12 – 1.97 (m, 2H), 1.97 – 1.83 (m, 1H). 13C NMR
(76 MHz, CDCl3) δ 157.2, 149.8, 146.9, 137.6, 126.5, 126.4,
124.4, 124.2, 122.8, 59.9, 49.1, 35.3, 24.3. ESI+ calcd. for
C13H15N2O2S (M+H)+: 295.0569. Found: 295.0575.
Following the typical procedure, the N-silylation of 2-
pyrrolidinone (2.0 g, 24 mmol) with Et3N (3.5 mL, 25 mmol,
1.05 equiv) and TMSCl (3.2 mL, 25 mmol, 1.05 equiv), followed
by addition of 4-fluorophenylmagnesium bromide (24 mL, 24
mmol, 1.0 equiv) and reduction with NaBH4 (980 mg, 26 mmol,
1.1 equiv), afforded 2-(4-fluorophenyl)pyrroline as a yellow oil.
Subsequent N-sulfonylation with pyridine (2.9 mL, 36 mmol, 1.5
equiv) and 2-pyridylsulfonyl chloride (6.4 g, 36 mmol, 1.5 equiv)
afforded after column chromatography (cyclohexane-EtOAc 4:1)
the product 13 (1.3 g, 18%) as a light pink solid; mp: 91-92 ºC.
1H NMR (300 MHz, CDCl3) δ 8.70 (d, J = 4.6 Hz, 1H), 7.90 –
7.81 (m, 2H), 7.47 (dd, J = 8.6, 4.8 Hz, 1H), 7.26 (t, J = 6.9 Hz,
2H), 6.95 (t, J = 8.7 Hz, 2H), 5.15 (dd, J = 7.9, 3.3 Hz, 1H), 3.80
– 3.62 (m, 2H), 2.30 – 2.16 (m, 1H), 1.98 – 1.78 (m, 3H). 13C
NMR (76 MHz, CDCl3) δ 161.7 (d, JC-F = 244.9 Hz), 157.2,
149.9, 138.8 (d, JC-F = 2.9 Hz), 137.6, 127.6 (d, JC-F = 8.1 Hz),
126.4, 122.9, 114.9 (d, JC-F = 21.5 Hz), 63.3, 49.9, 35.7, 24.0.
ESI+ calcd. for C15H16FN2O2S (M+H)+: 307.0911.Found:
307.0917.
3.3. Typical procedure for the C−H alkenylation reaction:
Synthesis of (E)-butyl 3-{2-[1-(pyridin-2-ylsulfonyl)pyrrolidin-2-
yl]phenyl}acrylate (2) A screw-capped test tube was charged
with 2-arylpyrrolidine 1 (0.15 mmol), Pd(OAc)2 (3.32 mg, 0.015
mmol, 10 mol%) and 1-fluoro-2,4,6-trimethylpyridinium triflate
(87 mg, 0.3 mmol, 2.0 equiv). The mixture was placed under
nitrogen atmosphere before DCE (1.5 mL) and the corresponding

6
Tetrahedron
ACCEPTED MANUSCRIPT
alkene (0.15 to 045 mmol, 1.0 to 3.0 equiv) were successively
added. The mixture was heated to 110 ºC for 16 h, and then it
was allowed to reach room temperature, diluted with CH2Cl2 (10
mL) and filtered through a pad of Celite. The filtrate was
concentrated under reduced pressure and the residue was purified
by flash chromatography (cyclohexane-EtOAc 6:1) to afford 2
(53 mg, 85%) as a yellow oil. 1H NMR (300 MHz, CDCl3) δ 8.75
(d, J = 4.6 Hz, 1H), 8.00 (d, J = 15.7 Hz, 1H), 7.94 – 7.82 (m,
2H), 7.61 – 7.46 (m, 3H), 7.35 (t, J = 7.1 Hz), 7.29 – 7.16 (m,
2H), 6.34 (d, J = 15.7 Hz, 1H), 5.48 (dd, J = 8.0, 3.7 Hz, 1H),
4.21 (t, J = 6.6 Hz, 2H), 3.89 – 3.67 (m, 2H), 2.35 – 2.19 (m,
1H), 1.95 – 1.63 (m, 6H), 1.53 – 1.37 (m, 3H), 0.97 (t, J = 7.3
Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 166.9, 157.2, 150.1,
142.2, 141.5, 137.7, 131.5, 130.0, 127.3, 126.8, 126.7, 126.6,
123.0, 120.3, 64.4, 61.3, 50.2, 35.7, 30.7, 24.0, 19.2, 13.7. ESI+
calcd. for C22H27N2O4S (M+H)+: 415.1686. Found: 415.1689.
(d, JC-P = 1.1 Hz), 126.6, 126.6 (d, JC-P = 1.6 Hz), 123.0, 114.9 (d,
JC-P = 190.7 Hz), 61.1, 52.5 (d, JC-P = 8.3 Hz), 52.4 (d, JC-P = 8.4
Hz)., 35.6, 24.1. ESI+ calcd. for C19H24N2O4PS (M+H)+:
407.1189. Found: 407.1194.
(E)–
and
(Z)-3-{2-[1-(Pyridin-2-ylsulfonyl)pyrrolidin-2-
yl]phenyl}acrylonitrile [(E)-9 and (Z)-9]
Following the typical procedure, the reaction of 1 (43 mg, 0.15
mmol) with acrylonitrile (15 ꢀL, 0.18 mmol, 1.2 equiv),
Pd(OAc)2 (3.32 mg, 0.015 mmol, 10 mol%) and 1-fluoro-2,4,6-
trimethylpyridinium triflate (87 mg, 0.3 mmol, 2.0 equiv)
afforded a mixture of compounds (E)-9 and (Z)-9. The column
chromatography purification (cyclohexane-EtOAc 6:1) afforded
(E)-9 (29%) followed by (Z)-9 (27%). Compound (E)-9: white
solid; mp: 131-132 ºC. 1H NMR (300 MHz, CDCl3) δ 8.84 – 8.74
(m, 1H), 7.97 – 7.86 (m, 2H), 7.80 (d, J = 16.4 Hz, 1H), 7.60 (d,
J = 7.8 Hz, 1H), 7.53 (ddd, J = 6.1, 4.7, 2.9 Hz, 1H), 7.48 – 7.37
(m, 2H), 7.31 – 7.23 (m, 1H), 5.80 (d, J = 16.4 Hz, 1H), 5.48 (dd,
J = 8.0, 4.1 Hz, 1H), 3.87 – 3.70 (m, 1H), 3.63 (dt, J = 10.0, 7.3
Hz, 1H), 2.38 – 2.23 (m, 1H), 1.98 – 1.66 (m, 3H). 13C NMR (76
MHz, CDCl3) δ 157.1, 150.1, 148.0, 142.2, 137.8, 131.0, 130.7,
127.6, 126.9, 126.8, 126.0, 123.1, 118.2, 98.3, 61.1, 50.1, 35.7,
24.1. ESI+: calcd. for C18H18N3O2S (M+H)+: 340.1114. Found:
(E)-Methyl-3-{2-[1-(pyridin-2-ylsulfonyl)pyrrolidin-2-
yl]phenyl}acrylate (6) Following the typical procedure, the
reaction of 1 (43 mg, 0.15 mmol) with methyl acrylate (16 ꢀL,
0.18 mmol, 1.2 equiv), Pd(OAc)2 (3.32 mg, 0.015 mmol, 10
mol%) and 1-fluoro-2,4,6-trimethylpyridinium triflate (87 mg,
0.3 mmol, 2.0 equiv) afforded, after column chromatography
(cyclohexane-EtOAc 4:1), the compound 6 (45 mg, 81 %) as a
1
340.1104. Compound (Z)-9: white solid; mp: 123-124 ºC. H
1
white solid; mp: 129-131 ºC. H NMR (300 MHz, CDCl3) δ 8.70
NMR (500 MHz, CDCl3) δ 8.71 (d, J = 4.7 Hz, 1H), 7.83 (d, J =
3.7 Hz, 2H), 7.75 (dd, J = 7.2, 1.4 Hz, 1H), 7.64 (d, J = 11.8 Hz,
1H), 7.50 – 7.46 (m, 1H), 7.46 – 7.41 (m, 1H), 7.36 – 7.28 (m,
2H), 5.58 (d, J = 11.7 Hz, 1H), 5.40 (dd, J = 8.0, 4.5 Hz, 1H),
3.81 – 3.72 (m, 1H), 3.65 (dt, J = 10.1, 7.1 Hz, 1H), 2.35 – 2.22
(m, 1H), 2.00 – 1.87 (m, 1H), 1.87 – 1.79 (m, 1H), 1.80 – 1.71
(m, 1H). 13C NMR (126 MHz, CDCl3) δ 157.3, 150.0, 147.9,
141.9, 137.7, 131.1, 130.4, 128.3, 127.5, 126.6, 126.6, 123.0,
116.8, 98.5, 61.3, 50.0, 35.6, 24.3. ESI+: calcd. for C18H18N3O2S
(M+H)+: 340.1114. Found: 340.1108.
– 8.65 (m, 1H), 7.94 (d, J = 15.7 Hz, 1H), 7.86 – 7.74 (m, 2H),
7.50 – 7.37 (m, 3H), 7.26 (t, J = 7.4 Hz, 1H), 7.21 – 7.11 (m,
1H), 6.26 (d, J = 15.7 Hz, 1H), 5.39 (dd, J = 7.9, 3.9 Hz, 1H),
3.73 (s, 3H), 3.80 – 3.58 (m, 2H), 2.29 – 2.13 (m, 1H), 1.89 –
1.40 (m, 3H). 13C NMR (76 MHz, CDCl3) δ 167.2, 157.2, 150.1,
142.3, 141.8, 137.74, 131.5, 130.0, 127.3, 126.8, 126.7, 126.6,
123.0, 119.9, 61.2, 51.7, 50.2, 35.7, 24.1. ESI+ calcd. for
C19H21N2O4S (M+H)+: 373.1217. Found: 373.1223.
(E)-2-{[2-(2-(2-(Phenylsulfonyl)vinyl)phenyl)pyrrolidin-1-
yl]sulfonyl}pyridine (7) Following the typical procedure, the
reaction of 1 (43 mg, 0.15 mmol) with phenyl vinyl sulfone (30
mg, 0.18 mmol, 1.2 equiv), Pd(OAc)2 (3.32 mg, 0.015 mmol, 10
mol%) and 1-fluoro-2,4,6-trimethylpyridinium triflate (87 mg,
0.3 mmol, 2.0 equiv) afforded, after column chromatography
(cyclohexane-EtOAc 2:1), the compound 7 (56 mg, 82 %); as a
(E)-2-{[2-(2-(4-Nitrostyryl)phenyl)pyrrolidin-1-
yl]sulfonyl}pyridine (10) Following the typical procedure, the
reaction of 1 (43 mg, 0.15 mmol) with 4-nitrostyrene (45 mg, 0.3
mmol, 2 equiv), Pd(OAc)2 (3.32 mg, 0.015 mmol, 10 mol%) and
1-fluoro-2,4,6-trimethylpyridinium triflate (87 mg, 0.3 mmol, 2.0
equiv) afforded, after column chromatography (cyclohexane-
EtOAc 4:1), the compound 10 (35 mg, 54 %); as a yellow solid;
1
white solid; mp: 149-151 ºC. H NMR (300 MHz, CDCl3) δ 8.82
1
(d, J = 4.3 Hz, 1H), 8.10 (d, J = 15.1 Hz, 1H), 8.05 – 7.87 (m,
4H), 7.67 – 7.50 (m, 5H), 7.43 – 7.35 (m, 2H), 7.31 – 7.20 (m,
1H), 6.77 (d, J = 15.1 Hz, 1H), 5.50 (dd, J = 7.9, 4.2 Hz, 1H),
3.85 – 3.65 (m, 2H), 2.43 – 2.26 (m, 1H), 1.96 – 1.75 (m, 3H).
13C NMR (76 MHz, CDCl3) δ 156.9, 150.3, 142.9, 140.5, 139.7,
137.9, 133.4, 130.9, 129.6, 129.3, 129.1, 127.6, 127.5, 127.2,
127.1, 126.7, 123.1, 61.3, 50.2, 35.9, 24.2. ESI+ calcd. for
C23H23N2O4S2 (M+H)+: 455.1094. Found: 455.1099.
mp: 158-161 ºC. H NMR (300 MHz, CDCl3) δ 8.73 (d, J = 4.5
Hz, 1H), 8.24 (d, J = 8.7 Hz, 2H), 7.94 – 7.79 (m, 2H), 7.71 –
7.59 (m, 3H), 7.59 – 7.41 (m, 3H), 7.33 – 7.19 (m, 3H), 6.99 (d, J
= 16.0 Hz, 1H), 5.61 (dd, J = 7.9, 3.7 Hz, 1H), 3.88 – 3.76 (m,
1H), 3.76 – 3.59 (m, 1H), 2.43 – 2.22 (m, 1H), 2.00 – 1.72 (m,
3H). 13C NMR (76 MHz, CDCl3) δ 157.4, 150.0, 146.8, 143.9,
141.1, 137.7, 133.8, 130.7, 128.7, 127.3, 127.0, 126.6, 126.5,
126.5, 124.1, 123.0, 61.4, 50.0, 35.4, 24.2. ESI+: calcd. for
C23H22N3O4S (M+H)+: 436.1325. Found: 436.1315.
(E)-Dimethyl-{2-[1-(pyridin-2-ylsulfonyl)pyrrolidin-2-
yl]styryl}phosphonate (8) Following the typical procedure, the
reaction of 1 (43 mg, 0.15 mmol) with dimethyl vinylfosfonate
(22 ꢀL, 0.18 mmol, 1.2 equiv), Pd(OAc)2 (3.32 mg, 0.015 mmol,
10 mol%) and 1-fluoro-2,4,6-trimethylpyridinium triflate (87 mg,
0.3 mmol, 2.0 equiv) afforded, after column chromatography
(CH2Cl2-EtOAc 2:1), the compound 8 (47 mg, 74 %) as a light
(E)-2-{[2-(2-(4-(Trifluoromethyl)styryl)phenyl)pyrrolidin-1-
yl]sulfonyl}pyridine (11) Following the typical procedure, the
reaction of 1 (43 mg, 0.15 mmol) with 4-(trrifluromethyl)styrene
(44 µL, 0.3 mmol, 2 equiv), Pd(OAc)2 (3.32 mg, 0.015 mmol, 10
mol%) and 1-fluoro-2,4,6-trimethylpyridinium triflate (87 mg,
0.3 mmol, 2.0 equiv), afforded, after column chromatography
(cyclohexane-EtOAc 6:1) the compound 11 (33 mg, 48 %); as a
1
yellow solid; mp: 149-151 ºC. H NMR (300 MHz, CDCl3) δ
1
8.75 (d, J = 4.7 Hz, 1H), 8.02 – 7.72 (m, 3H), 7.60 – 7.44 (m,
3H), 7.34 (t, J = 7.5 Hz, 1H), 7.29 – 7.19 (m, 1H), 6.14 (dd, JH-P
= 18.8 Hz, J = 17.3 Hz, 1H), 5.47 (dd, J = 8.1, 4.1 Hz, 1H), 3.77
(d, JH-P = 11.1 Hz, 3H), 3.76 (d, JH-P = 11.1 Hz, 3H), 3.81 – 3.65
(m, 2H), 2.37 – 2.22 (m, 1H), 1.94 – 1.68 (m, 3H). 13C NMR (76
MHz, CDCl3) δ 157.0, 150.1, 146.8 (d, JC-P = 7.2 Hz), 141.9,
137.8, 132.3, 132.0, 132.1 (d, JC-P = 22.9 Hz), 130.1, 127.3, 126.7
white solid; mp: 153-154 ºC. H NMR (300 MHz, CDCl3) δ 8.73
(d, J = 3.8 Hz, 1H), 7.82 – 7.69 (m, 2H), 7.67 – 7.55 (m, 3H),
7.57 – 7.39 (m, 4H), 7.31 – 7.16 (m, 3H) 6.96 (d, J = 16.0 Hz,
1H), 5.64 – 5.52 (m, 1H), 3.90 – 3.77 (m, 1H), 3.77 – 3.63 (m,
1H), 2.38 – 2.18 (m, 1H), 2.00 – 1.77 (m, 3H). 13C NMR (76
MHz, CDCl3) δ 157.4, 150.0, 140.9, 140.8, 137.6, 134.2, 129.5,
128.9 (q, JC-F = 34.9 Hz), 127.3, 126.7, 126.5, 126.4, 126.0,

7
125.9, 125.6 (q, JC-F = 3.8 Hz), 124.2 (q, JC-F = 271.8 Hz), 123.0,
118.7, 61.5, 50.1, 35.3, 24.2. ESI+: calcd. for C24H22F3N2O2S
(M+H)+: 459.1348. Found: 459.1331.
mmol, 2.0 equiv) afforded, after column chromatography
ACCEPTED MANUSCRIPT
(cyclohexane-EtOAc 4:1), the compound 20 (51 mg, 76 %) as a
colorless oil. H NMR (300 MHz, CDCl3) δ 8.75 (d, J = 4.6 Hz,
1
1H), 8.04 – 7.80 (m, 3H), 7.64 – 7.41 (m, 2H), 7.10 (d, J = 2.4
Hz, 1H), 6.78 (dd, J = 8.4, 2.5 Hz, 1H), 6.25 (d, J = 15.6 Hz, 1H),
5.48 (dd, J = 8.0, 3.5 Hz, 1H), 4.19 (t, J = 6.6 Hz, 2H), 3.83 (s,
3H), 3.84 – 3.68 (m, 2H), 2.37 – 2.22 (m, 1H), 1.97 – 1.62 (m,
5H), 1.51 – 1.31 (m, 2H), 0.96 (t, J = 7.3 Hz, 3H). 13C NMR (76
MHz, CDCl3) δ 167.27, 161.2, 157.2, 150.1, 144.4, 140.9, 137.8,
128.5, 126.6, 124.0, 123.1, 117.6, 112.8, 112.3, 64.3, 61.3, 55.3,
50.3, 35.7, 30.8, 24.0, 19.2, 13.7. ESI+ calcd. for C23H29N2O5S
(M+H)+: 445.1792. Found: 445.1797.
(E)-Butyl
3-{5-methyl-2-[1-(pyridin-2-ylsulfonyl)pyrrolidin-2-
yl]phenyl}acrylate (17) Following the typical procedure, the
reaction of 12 (46 mg, 0.15 mmol) with butyl acrylate (26 µL,
0.18 mmol, 1.2 equiv), Pd(OAc)2 (3.32 mg, 0.015 mmol, 10
mol%) and 1-fluoro-2,4,6-trimethylpyridinium triflate (87 mg,
0.3 mmol, 2.0 equiv) afforded, after column chromatography
(cyclohexane-EtOAc 4:1), the compound 17 (65 mg, 70 %) as a
1
colorless oil. H NMR (300 MHz, CDCl3) δ 8.75 (d, J = 4.4 Hz,
1H), 7.98 (d, J = 15.7 Hz, 1H), 7.95 – 7.82 (m, 2H), 7.54 – 7.47
(m, 1H), 7.44 (d, J = 7.9 Hz, 1H), 7.34 (s, 1H), 7.17 (d, J = 8.0
Hz, 1H), 6.33 (d, J = 15.7 Hz, 1H), 5.42 (dd, J = 7.8, 3.7 Hz, 1H),
4.20 (t, J = 6.6 Hz, 2H), 3.86 – 3.66 (m, 2H), 2.33 (s, 3H), 2.40 –
2.20 (m, 1H), 1.94 – 1.62 (m, 5H), 1.51 – 1.36 (m, 2H), 0.97 (t, J
= 7.3 Hz, 3H). 13C NMR (76 MHz, CDCl3) δ 167.0, 157.3, 150.1,
141.7, 139.5, 137.7, 136.9, 131.4, 130.9, 127.4, 126.8, 126.5,
123.1, 120.0, 64.4, 61.2, 50.3, 35.8, 30.8, 24.1, 20.9, 19.2, 13.7.
ESI+ calcd. for C23H29N2O4S (M+H)+: 429.1843. Found:
429.1848.
(E)-Butyl 3-{2-[1-(pyridin-2-ylsulfonyl)pyrrolidin-2-yl]thiophen-
3-yl}acrylate (21) Following the typical procedure, the reaction
of 16 (44 mg, 0.15 mmol) with butyl acrylate (26 µL, 0.18 mmol,
1.2 equiv), Pd(OAc)2 (3.32 mg, 0.015 mmol, 10 mol%) and 1-
fluoro-2,4,6-trimethylpyridinium triflate (87 mg, 0.3 mmol, 2.0
equiv) afforded, after column chromatography (cyclohexane-
EtOAc 4:1), the compound 21 (38 mg, 61 %) as a colorless oil.
1H NMR (300 MHz, CDCl3) δ 8.73 (d, J = 4.5 Hz, 1H), 7.95 –
7.80 (m, 2H), 7.71 (d, J = 15.7 Hz, 1H), 7.50 (ddd, J = 6.8, 4.7,
2.0 Hz, 1H), 7.17 (d, J = 5.4 Hz, 1H), 7.12 (d, J = 5.4 Hz, 1H),
6.21 (d, J = 15.7 Hz, 1H), 5.66 (dd, J = 7.9, 3.2 Hz, 1H), 4.19 (t,
J = 6.7 Hz, 2H), 3.84 – 3.71 (m, 1H), 3.67 – 3.48 (m, 1H), 2.42 –
2.22 (m, 1H), 2.14 – 1.98 (m, 1H), 1.98 – 1.79 (m, 2H), 1.77 –
1.63 (m, 2H), 1.51 – 1.32 (m, 2H), 0.96 (t, J = 7.3 Hz, 3H). 13C
NMR (76 MHz, CDCl3) δ 167.5, 157.1, 150.9, 150.0, 137.8,
135.8, 131.5, 126.7, 125.6, 124.1, 123.1, 117.9, 64.4, 58.8, 49.7,
36.3, 30.8, 24.3, 19.2, 13.7. ESI+ calcd. for C20H25N2O4S2
(M+H)+: 421.1250. Found: 421.1254.
(E)-Butyl-3-{5-fluoro-2-[1-(pyridin-2-ylsulfonyl)pyrrolidin-2-
yl]phenyl}acrylate (18) Following the typical procedure, the
reaction of 13 (46 mg, 0.15 mmol) with butyl acrylate (32 µL,
0.225 mmol, 1.5 equiv), Pd(OAc)2 (3.32 mg, 0.015 mmol, 10
mol%) and 1-fluoro-2,4,6-trimethylpyridinium triflate (87 mg,
0.3 mmol, 2.0 equiv) afforded, after column chromatography
(cyclohexane-EtOAc 4:1), the compound 18 (44 mg, 68 %) as a
1
colorless oil. H NMR (300 MHz, CDCl3) δ 8.75 (d, J = 4.3 Hz,
1H), 8.02 – 7.81 (m, 3H), 7.62 – 7.45 (m, 2H), 7.20 (dd, J = 9.6,
2.5 Hz, 1H), 7.09 – 6.90 (m, 1H), 6.32 (d, J = 15.7 Hz, 1H), 5.44
(dd, J = 7.8, 3.9 Hz, 1H), 4.21 (t, J = 6.6 Hz, 2H), 3.85 – 3.60 (m,
2H), 2.35 – 2.17 (m, 1H), 1.95 – 1.63 (m, 5H), 1.51 – 1.33 (m,
2H), 0.97 (t, J = 7.3 Hz, 3H). 13C NMR (76 MHz, CDCl3) δ
166.5, 161.8 (d, JC-F = 246.1 Hz), 157.1, 150.1, 140.2 (d, JC-F
2.1 Hz), 138.2, 137.8, 133.4 (d, JC-F = 7.4 Hz), 128.7 (d, JC-F
8.1 Hz), 126.66, 123.07, 121.46, 116.8 (d, JC-F = 21.3 Hz), 113.2
(d, JC-F = 22.6 Hz), 64.6, 60.9, 50.2, 35.8, 30.7, 24.0, 19.2, 13.7.
ESI+ calcd. for C22H26FN2O4S (M+H)+: 433.1592. Found:
433.1597.
(E)-Methyl 3-{3-[(E)-2-(phenylsulfonyl)vinyl]-2-[1-(pyridin-2-
ylsulfonyl)pyrrolidin-2-yl]phenyl}acrylate (22) Following the
typical procedure, the reaction of the olefinated product 2 (56
mg, 0.15 mmol) with phenyl vinyl sufone (76 mg, 0.45 mmol,
3.0 equiv), Pd(OAc)2 (3.32 mg, 0.015 mmol, 10 mol%) and 1-
fluoro-2,4,6-trimethylpyridinium triflate (130 mg, 0.45 mmol, 3.0
equiv) afforded, after column chromatography (cyclohexane-
EtOAc 3:1), the compound 22 (44 mg, 55 %); as a yellow solid;
mp: 141-144 ºC. 1H NMR (300 MHz, CDCl3) δ 9.02 – 8.83 (m,
1H), 8.51 (d, J = 15.1 Hz, 1H), 8.41 (d, J = 15.8 Hz, 1H), 8.03 –
7.86 (m, 4H), 7.66 – 7.51 (m, 5H), 7.47 (d, J = 7.7 Hz, 1H), 7.42
– 7.33 (m, 1H), 7.33 – 7.15 (m, 2H), 6.69 (d, J = 15.1 Hz, 1H),
6.23 (d, J = 15.7 Hz, 1H), 5.62 – 5.44 (m, 1H), 4.08 – 3.85 (m,
2H), 3.82 (s, 3H), 2.29 – 2.14 (m, 1H), 2.12 – 1.94 (m, 2H), 1.75
– 1.55 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 166.9, 156.4,
150.6, 143.7, 141.8, 140.4, 139.5, 137.9, 133.4, 130.2, 129.4(2C),
128.0, 127.8, 126.8, 123.3, 60.9, 51.7, 50.2, 35.1, 25.4. ESI+:
calcd. for C27H27N2O6S2 (M+H)+: 539.1305. Found: 539.1290.
=
=
(E)-Butyl 3-{4-methoxy-2-[1-(pyridin-2-ylsulfonyl)pyrrolidin-2-
yl]phenyl}acrylate (19) Following the typical procedure, the
reaction of 14 (48 mg, 0.15 mmol) with butyl acrylate (26 µL,
0.18 mmol, 1.2 equiv), Pd(OAc)2 (3.32 mg, 0.015 mmol, 10
mol%) and 1-fluoro-2,4,6-trimethylpyridinium triflate (87 mg,
0.3 mmol, 2.0 equiv) afforded, after column chromatography
(cyclohexane-EtOAc 4:1), the compound 19 (44 mg, 66 %) as a
1
colorless oil. H NMR (300 MHz, CDCl3) δ 8.71 (d, J = 3.9 Hz,
1H), 8.30 (d, J = 15.8 Hz, 1H), 7.75 (t, J = 7.7 Hz, 1H), 7.65 (d, J
= 7.6 Hz, 1H), 7.46 – 7.37 (m, 1H), 7.19 (t, J = 8.0 Hz, 1H), 7.03
(d, J = 7.7 Hz, 1H), 6.78 (d, J = 8.2 Hz, 1H), 6.19 (d, J = 15.7
Hz, 1H), 5.34 (t, J = 8.3 Hz, 1H), 4.21 (t, J = 6.7 Hz, 2H), 4.09 (t,
J = 9.1 Hz, 1H), 3.82 – 3.65 (m, 1H), 3.72 (s, 3H), 2.24 – 2.05
(m, 2H), 2.04 – 1.87 (m, 1H), 1.82 – 1.65 (m, 3H), 1.52 – 1.36
(m, 2H), 0.97 (t, J = 7.3 Hz, 3H). 13C NMR (76 MHz, CDCl3) δ
166.8, 157.5, 157.5, 149.8, 143.6, 137.3, 128.6, 128.4, 126.0,
122.7, 120.1, 112.4, 64.4, 57.5, 55.7, 50.4, 44.0, 30.8, 26.1, 19.2,
13.7. ESI+ calcd. for C23H29N2O5S (M+H)+: 445.1792. Found:
445.1795.
3.4. Typical procedure for acidic condition cyclization reaction:
synthesis of butyl 2-(2,3,5,9b-tetrahydro-1H-pyrrolo[2,1-
a]isoindol-5-yl)acetate (23) To a solution of the olefinated
product 2 (62 mg, 0.15 mmol) in acetic acid (1 mL) under N2
atmosphere, Zn (294 mg, 4.5 mmol, 30 equiv) was added and the
suspension was stirred 48 hours at room temperature. The
mixture was diluted with EtOAc (5 mL) and filtered. Over the
filtrate a solution 2M NaOH was added until slightly basic pH
was reached and the mixture was stirred for 15 min. The aqueous
phase was extracted with EtOAc (3 x 5 mL) and the combined
organic phases were dried (MgSO4) and concentrated under
reduced pressure. The residue was purified by flash
chromatography (CH2Cl2-EtOAc 2:1) to afford 23 (29 mg, 61%)
(E)-Butyl 3-{3-methoxy-2-[1-(pyridin-2-ylsulfonyl)pyrrolidin-2-
yl]phenyl}acrylate (20) Following the typical procedure, the
reaction of 15 (48 mg, 0.15 mmol) with butyl acrylate (44 µL, 0.3
mmol, 2.0 equiv), Pd(OAc)2 (3.32 mg, 0.015 mmol, 10 mol%)
and 1-fluoro-2,4,6-trimethylpyridinium triflate (87 mg, 0.3
1
as a light yellow oil. H NMR (300 MHz, CDCl3) δ 7.33 – 7.23
(m, 2H), 7.19 (d, J = 6.7 Hz, 1H), 7.13 (d, J = 7.0 Hz, 1H), 4.92
(t, J = 7.3 Hz, 1H), 4.74 (d, J = 7.4 Hz, 1H), 4.27 – 4.13 (m, 2H),

8
Tetrahedron
ACCEPTED MANUSCRIPT
3.10 – 2.96 (m, 1H), 2.96 – 2.88 (m, 2H), 2.58 – 2.43 (m, 1H),
2.42 – 2.21 (m, 1H), 2.09 – 1.90 (m, 2H), 1.89 – 1.75 (m, 1H),
1.73 – 1.59 (m, 2H), 1.51 – 1.30 (m, 2H), 0.95 (t, J = 7.3 Hz,
3H). 13C NMR (75 MHz, CDCl3) δ 171.2, 144.3, 140.7, 128.1,
127.5, 122.9, 122.5, 68.6, 65.0, 62.1, 46.9, 35.5, 30.6, 29.7, 25.4,
19.1, 13.7. ESI+: calcd. para C17H24NO2 (M+H)+: 274.1801.
Found: 274.1797.
1H NMR (300 MHz, CDCl3) δ 7.31 – 7.19 (m, 1H), 6.98 – 6.83
(m, 2H), 5.01 (t, J = 7.2 Hz, 1H), 3.88 – 3.73 (m, 1H), 3.55 –
3.44 (m, 1H), 3.30 – 3.15 (m, 1H), 3.04 – 2.88 (m, 1H), 2.87 –
2.72 (m, 1H), 2.60 – 2.29 (m, 3H), 2.06 – 1.82 (m, 2H). 13C NMR
(75 MHz, CDCl3) δ 170.6, 162.3 (d, JC-F= 247.3 Hz), 143.1 (d, JC-
F= 7.6 Hz), 134.0 (d, JC-F= 3.2 Hz), 126.3 (d, JC-F= 8.4 Hz), 115.8
(d, JC-F= 21.3 Hz), 113.0 (d, JC-F= 21.0 Hz), 56.50, 48.12, 35.53,
30.91, 29.0 (d, JC-F = 1.4 Hz). 22.76. ESI+: calcd. for C13H14FNO
(M)+: 219.1059. Found: 219.1052.
Butyl 2-(7-fluoro-2,3,5,9b-tetrahydro-1H-pyrrolo[2,1-a]isoindol-
5-yl)acetate (24) Following the typical procedure, the reaction of
the olefinated product 18 (65 mg, 0.15 mmol) with activated Zn
(294 mg, 4.5 mmol, 30 equiv) afforded, after column
chromatography (CH2Cl2-EtOAc 2:1), the compound 24 (33 mg,
Acknowledgments
We thank the Spanish Ministerio de Economía
y
1
67%) as a light yellow oil. H NMR (300 MHz, CDCl3) δ 7.10
Competitividad (MINECO, Project CTQ2012-35790), and
MINECO/FEDER, UE (Project CTQ2015-66954-P) for financial
support. P.D.L. thanks MECD for a FPU predoctoral fellowship.
(dd, J = 8.1, 4.8 Hz, 1H, Ar), 6.95 (td, J = 8.6, 2.2 Hz, 1H), 6.82
(dd, J = 8.6, 1.8 Hz, 1H), 4.77 (t, J = 7.3 Hz, 1H), 4.57 – 4.50 (m,
1H), 4.31 – 4.13 (m, 2H), 2.87 (d, J = 7.3 Hz, 2H), 2.50 – 2.35
(m, 1H), 2.32 – 2.17 (m, 2H), 1.98 – 1.77 (m, 3H), 1.74 – 1.59
(m, 2H), 1.49 – 1.34 (m, 2H), 0.96 (t, J = 7.3 Hz, 3H). 13C NMR
(75 MHz, CDCl3) δ 171.5, 162.6 (d, JC-F = 244.4 Hz), 144.6 (d,
JC-F = 7.3 Hz), 141.7 (d, JC-F = 2.3 Hz), 123.8 (d, JC-F = 9.1 Hz),
114.5 (d, JC-F = 22.9 Hz), 109.9 (d, JC-F = 23.0 Hz), 67.6, 64.9,
61.9 (d, JC-F = 2.1 Hz), 6.7, 35.6, 30.6, 29.7, 29.7, 25.6, 19.1,
13.7. ESI+: calcd. for C17H23FNO2 (M+H)+: 292.1695. Found:
292.1696.
References and notes
1. For the importance of the N-heterocyclic motif in medicinal
chemistry: a) Welsch, M. E.; Snyder, S. A.; Stockwell, B. R. Curr.
Opin. Chem. Biol. 2010, 14, 347. b) Horton, D. A.; Bourne, G. T.;
Smythe, M. L. Chem. Rev. 2003, 103, 893. (c) Vieth, M.; Siegel,
M. G.; Higgs, R. E.; Watson, I. A.; Robertson, D. H.; Savin, K.
A.; Durst, G. L.; Hipskind, P. A. J. Med. Chem. 2003, 47, 224.
2. For general reviews on C-H functionalization: a) Metal-Catalyzed
Cross-Coupling Reactions and More; de Meijere, A., Bräse, S.,
Oestreich, M., Eds.; VCH: Weinheim, 2014; Vol. 3. b) Wencel-
Delord, J.; Glorius, F. Nat. Chem. 2013, 5, 369. c) Chen, D. Y.-K.;
Youn, S. W. Chem. Eur. J. 2012, 18, 9452. d) Yamaguchi, J.;
Yamaguchi, A. D.; Itami, K. Angew. Chem., Int. Ed. 2012, 51,
8960. e) Yu, D.-G.; Li, B.-J.; Shi, Z.-J. Tetrahedron 2012, 68,
5130.
5-[(Phenylsulfonyl)methyl]-2,3,5,9b-tetrahydro-1H-pyrrolo[2,1-
a]isoindole (25) Following the typical procedure, the reaction of
the olefinated product 7 (68 mg, 0.15 mmol) with activated Zn
(294 mg, 4.5 mmol, 30 equiv) afforded a 55:45 mixture of two
isomers. After column chromatography (CH2Cl2-EtOAc 1:1) the
compound syn-25 was isolated (26 mg, 35%) as a colorless oil.
1H NMR (300 MHz, CDCl3) δ 8.09 (d, J = 7.8 Hz, 2H), 7.73 –
7.65 (m, 1H), 7.64 – 7.56 (m, 2H), 7.35 – 7.23 (m, 3H), 7.23 –
7.14 (m, 1H), 4.88 – 4.78 (m, 1H), 4.68 – 4.53 (m, 1H), 3.70 (d, J
= 6.0 Hz, 2H), 2.96 – 2.80 (m, 1H), 2.51 – 2.35 (m, 1H), 2.18 –
2.07 (m, 1H), 2.02 – 1.70 (m, 3H). 13C NMR (75 MHz, CDCl3) δ
144.8, 139.3, 139.1, 134.0, 129.4, 128.5(2C), 127.7, 123.0(2C),
68.4, 59.9, 57.0, 46.8, 29.5, 25.0. EI+: calcd. for C18H19NO2S
(M)+: 313.1137. Found: 313.1132.
3. For reviews on direct C−H alkenylation reaction: a) Le Bras, J.;
Muzart, J. Chem. Rev. 2011, 111, 1170. b) Yeung, C. S.; Dong, V.
M. Chem. Rev. 2011, 111, 1215. c) Kozhushkov, S. I.;
Ackermann, L. Chem. Sci. 2013, 4, 886. d) Wu, Y.; Wang, J.;
Mao, F.; Kwong, F. Y. Chem. Asian J. 2014, 9, 26. e) Zhou, L.;
Lu, W. Chem. Eur. J. 2014, 20, 634.
4. For reviews on removable directing groups in C−H activation, see:
a) Rousseau, G.; Breit, B. Angew. Chem., Int. Ed. 2011, 50, 2450.
b) Wang, C.; Huang, Y. Synlett 2013, 24, 145. c) Rouquet, G.;
Chatani, N. Angew. Chem., Int. Ed. 2013, 52, 11726.
5. See, for instance: a) Rauf, W.; Thompson, A. L.; Brown, J. M.
Chem. Commun. 2009, 3874. b) Engle, K. M.; Wang, D.-H.; Yu,
J.-Q. Angew. Chem., Int. Ed. 2010, 49, 6169. c) Li, G.; Leow, D.;
Wan, L.; Yu, J.-Q. Angew. Chem., Int. Ed. 2013, 52, 1245. d)
Chan, L. Y.; Kim, S.; Ryu, T.; Lee, P. H. Chem. Commun. 2013,
49, 4682.
3.5. Typical procedure for cyclization with sodium amalgam:
synthesis
of
2,3,6,7-tetrahydro-1H-benzo[c]pyrrolo[1,2-
a]azepin-5(11bH)-one (26) Over a suspension of the olefinated
product 2 (62 mg, 0.15 mmol) and Na2HPO4 (64 mg, 0.45 mmol,
3.0 equiv) in MeOH (1.5 mL) under N2 atmosphere, 10% Na(Hg)
was added (155 mg, 2.5 equiv, w/w). The resulting mixture was
stirred until the starting material was disappeared (liquid Hg was
observed, typically 3 h, TLC), was diluted in EtOAc and filtered.
The filtrate was washed with water, was dried (MgSO4) and
concentrated under reduced pressure. The residue was purified by
flash chromatography (cyclohexane-EtOAc 2:1) to afford 26 (15
mg, 74%) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 7.32 –
7.18 (m, 4H, Ar), 5.07 (t, J = 7.2 Hz, 1H), 3.82 (ddd, J = 12.0,
7.4, 4.7 Hz, 1H), 3.51 (dt, J = 12.0, 7.6 Hz, 1H), 3.32 – 3.18 (m,
1H), 3.02 – 2.90 (m, 1H), 2.88 – 2.78 (m, 1H), 2.61 – 2.45 (m,
2H), 2.43 – 2.31 (m, 1H), 2.09 – 1.84 (m, 2H). 13C NMR (75
MHz, CDCl3) δ 170.6, 140.8, 138.2, 128.9, 128.1, 126.5, 124.4,
56.9, 48.0, 35.9, 30.6, 29.1, 22.8. ESI+: calcd. for C13H15NO
(M)+: 201.1154. Found: 201.1155.
6. For examples on the use of the N-SO2Py directing group in C−H
functionalization, see: (a) García-Rubia, A.; Gómez Arrayás, R.;
Carretero, J. C. Angew. Chem., Int. Ed. 2009, 48, 6511. b) García-
Rubia, A.; Urones, B.; Gómez Arrayás, R.; Carretero, J. C. Chem.
Eur. J. 2010, 16, 9676. c) García-Rubia, A.; Urones, B.; Gómez
Arrayás, R.; Carretero, J. C. Angew. Chem., Int. Ed. 2011, 50,
10927. d) Urones, B.; Gómez Arrayás, R.; Carretero, J. C. Org.
Lett. 2013, 15, 1120. e) Urones, B.; Martínez, A. M.; Rodríguez,
N.; Gómez Arrayás, R.; Carretero, J. C. Chem. Commun. 2013, 49,
11044. f) Mei, T.-S.; Leow, D.; Xiao, H.; Laforteza, B. N.; Yu, J.-
Q. Org. Lett. 2013, 15, 3058. g) Rodríguez, N.; Romero-Revilla, J.
A.; Fernández-Ibáñez, M. A.; Carretero, J. C. Chem. Sci. 2013, 4,
175. h) Yan, Z.-L.; Chen, W.-L.; Gao, Y.-R.; Mao, S.; Zhang, Y.-
L.; Wang, Y.-Q. Adv. Synth. Catal. 2014, 356, 1085. i) Poveda,
A.; Alonso, I.; Fernández-Ibáñez, M. A. Chem. Sci. 2014, 5, 3873.
j) A. García-Rubia, E. Laga, C. Cativiela, E. P. Urriolabeitia, R.
Gómez-Arrayás, J. C. Carretero, J. Org. Chem. 2015, 80, 3321. k)
Hernando, E.; Villalva, J.; Martínez, A. M.; Alonso, I.; Rodríguez,
N.; Gómez Arrayás, R.; Carretero, J. C. ACS Catal. 2016, 6, 6868.
See also: l) Legarda, P. D.; García-Rubia, A.; Gómez Arrayás, R.;
Carretero, J. C. Adv. Synth. Catal. 2016, 358, 1065. m) Guilbaud,
J.; Labonde, M.; Cattey, H.; Contal, S.; Montalbetti, C.; Pirio, N.;
Roger, J.; Hierso, J.-C. Adv. Synth. Catal. 2017, 359, 3792. n)
García-Rubia, A.; Fernández-Ibáñez, M. A.; Gómez Arrayás, R.;
Carretero, J. C.; Chem. Eur. J. 2011, 17, 3567. o) Richter, H.;
9-Fluoro-2,3,6,7-tetrahydro-1H-benzo[c]pyrrolo[1,2-a]azepin-
5(11bH)-one (27) Following the typical procedure, the reaction
of the olefinated product 18 (65 mg, 0.15 mmol) with Na2HPO4
(64 mg, 0.45 mmol, 3.0 equiv) and Na(Hg) (155 mg, 2.5 equiv,
w/w) afforded, after column chromatography (cyclohexane-
EtOAc 2:1), the compound 27 (16 mg, 73%). as a colorless oil.

9
Beckendorf, S.; Mancheño, O. G. Adv. Synth. Catal. 2011, 353,
19. Diltz, S.; Aguirre, G.; Ortega, F.; Walsh, P. J. Tetrahedron:
Asymmetry 1997, 8, 3559. See also ref. 6c.
ACCEPTED MANUSCRIPT
295. p) Romero-Revilla, J. A.; García-Rubia, A.; Gómez Arrayás,
R.; Fernández- Ibáñez, M. A.; Carretero, J. C. J. Org. Chem. 2011,
76, 9525. q) Yu, M.; Liang, Z.; Wang, Y.; Zhang, Y. J. Org.
Chem. 2011, 76, 4987.
Supplementary Material
7. The 2-arylpyrrolidine scaffold can be readily accessed via Pd-
catalyzed direct α-arylation of pyrrolidine derivatives: Jain, P.;
Verma, P.; Xia, G.; Yu, J.-Q. Nat. Chem. 2017, 9, 140. See
references therein for an overview on the relevance and synthesis
of 2-arylpyrrolidines.
Experimental procedures, characterization data, H and 13C
1
NMR spectra for new compounds (PDF).
8. For recent examples of synthesis of benzopyrrolizidines, see: a)
Lu, H.; Lin, J.-B.; Liu, J.-Y.; Xu, P.-F. Chem. Eur. J. 2014, 20,
11659. b) Sirvent, J. A.; Foubelo, F.; Yus, M. J. Org. Chem. 2014,
79, 1356. c) Mahoney, S. J.; Fillion, E. Chem. Eur. J. 2012, 18,
68. d) Lemen, G. S.; Wolfe, J. P. Org. Lett. 2011, 13, 3218. e)
Yip, K.-T.; Yang, D. Org. Lett. 2011, 13, 2134. f) Yip, K.-T.;
Yang, M.; Law, K.-L.; Zhu, N.-Y.; Yang, D. J. Am. Chem. Soc.
2006, 128, 3130. g) Vedejs, E.; Naidu, B. N.; Klapars, A.; Warner,
D. L.; Li, V.-s.; Na, Y.; Kohn, H. J. Am. Chem. Soc. 2003, 125,
15796. h) Kusama, H.; Takaya, J.; Iwasawa, N. J. Am. Chem. Soc.
2002, 124, 11592.
9. For natural products containing benzopyrrolizidine skeleton, see:
a) Wu, W.; Xiao, M.; Wang, J.; Li, Y.; Xie, Z. Org. Lett. 2012, 14,
1624. b) Patel, P.; Ramana, C. V. J. Org. Chem. 2012, 77, 10509.
c) Vallakati, R.; May, J. A. J. Am. Chem. Soc. 2012, 134, 6936. d)
Lee, J.; Panek, J. S. Org. Lett. 2011, 13, 502. d) Zhang, X.; Mu,
T.; Zhan, F.-X.; Ma, L.-J.; Liang, G.-X. Angew. Chem., Int. Ed.
2011, 50, 6164. e) Dethe, D. H.; Erande, R. D.; Ranjan, A. J. Am.
Chem. Soc. 2011, 133, 2864. f) Zeldin, R. M.; Toste, F. D. Chem.
Sci. 2011, 2, 1706. g) Karadeolian, A.; Kerr, M. A. Angew. Chem.,
Int. Ed. 2010, 49, 1133.
10. For early successful examples of [F+] as oxidant, see: a) X. Wang,
T.-S. Mei, J.-Q. Yu, J. Am. Chem. Soc. 2009, 131, 7520. For a
review, see: b) K. M. Engle, T.-S. Mei, X. Wang, J.-Q. Yu,
Angew. Chem. Int. Ed. 2011, 50, 1478. For a recent review on the
oxidizing ability of a number of oxidants used in palladium Pd-
catalyzed aromatic C–H functionalizations, see: Budnikova, Y. H.;
Dudkina, Y. B.; Khrizanforov, M. N. Inorganics 2017, 5, 70. For a
recent example on the use of N-fluoro-2,4,6-trimethylpyridinium
triflate ([F+]) as bystanding oxidant in Pd-catalyzed C-H
functionalization: d) X.-Y. Chen, S. Ozturk, E. J. Sorensen, Org.
Lett. 2017, 19, 6280.
11. a) Granell, J.; Martıń ez, M. Dalton Trans. 2012, 41, 11243. See
also: b) Stephens, D. E.; Lakey-Beitia, J.; Atesin, A. C.; Ateşin, T.
A.; Chavez, G.; Arman, H. D.; Larionov, O. V. ACS Catal. 2015,
5, 167.
12. The coupling constants of the olefinic protons provided a valuable
diagnostic for assignment of the E/Z configurations (16.4 Hz for
E-9 and 11.7 Hz for Z-9).
13. The regioselectivity of the C−H alkenylation in compound 21 was
unambiguously established from 1H−1H NOE NMR experiments.
The figure below shows a diagnostic NOE cross peak.
14. See, for example: a) Yanagisawa, S.; Ueda, K.; Sekizawa, H.;
Itami, K. J. Am. Chem. Soc. 2009, 131, 14622. b) Schipper, D. J.;
Fagnou, K. Chem. Mater. 2011, 23, 1594; and references cited
therein.
15. See, for example: a) García-Rubia, A.; Fernández-Ibáñez, M. A.;
Gómez Arrayás, R.; Carretero, J. C. Chem. Eur. J. 2011, 17, 3567.
b) Deb, A.; Bag, S.; Kancherla, R.; Maiti, D. J. Am. Chem. Soc.
2014, 136, 13602. See also reference 6b.
16. High conversion, yet incomplete (82%), was attained when 2
equivalents of phenyl vinyl sulfone were used. A lower conversion
(41%) was observed in the presence of 1.2 equivalents of alkene.
17. Stereochemical assignment was established by analysis by NOE
difference spectroscopy. The figure below shows some diagnostic
NOE cross peaks.
18. a) Coindet, C.; Comel A.; Kirsch, G. Tetrahedron Lett. 2001, 42,
6101. b) Dunsmore, C. J.; Carr, R.; Fleming, T.; Turner, N. J. J.
Am. Chem. Soc. 2006, 128 , 2224.