Visible light/Ir(III) photocatalytic initiation of xanthate-based radical-chain reactions: Xanthate group transfer and oxidative addition to aromatic systems

Article abstract of DOI:10.1016/j.tet.2018.04.079

A photocatalyzed redox generation of radicals from O-ethyl xanthates to generate electrophilic radicals under photoredox catalysis, using Ir(ppy)₃ and blue LEDs irradiation is described. The protocol can be used in classical xanthate-based inter- and intra-molecular group transfer reactions and oxidative radical addition to several heteroaromatic systems. The process does not require high temperature and reactions are cleaner compared with the traditional peroxide initiation. In the oxidative addition to aromatic systems, the oxidation process is part of the catalytic cycle and does not require a stoichiometric oxidant such as DLP which is particularly difficult to separate from the product.

Full text of DOI:10.1016/j.tet.2018.04.079

Accepted Manuscript
Visible light/Ir(III) photocatalytic initiation of xanthate-based radical-chain reactions:
Xanthate group transfer and oxidative addition to aromatic systems
Pedro López-Mendoza, John E. Díaz, Alix E. Loaiza, Luis D. Miranda
PII:
S0040-4020(18)30484-8
10.1016/j.tet.2018.04.079
TET 29494
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 2 March 2018
Revised Date: 23 April 2018
Accepted Date: 24 April 2018
Please cite this article as: López-Mendoza P, Díaz JE, Loaiza AE, Miranda LD, Visible light/Ir(III)
photocatalytic initiation of xanthate-based radical-chain reactions: Xanthate group transfer and oxidative
addition to aromatic systems, Tetrahedron (2018), doi: 10.1016/j.tet.2018.04.079.
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Visible light/Ir(III) photocatalytic initiation
of xanthate-based radical-chain reactions:
xanthate group transfer and oxidative
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Pedro López-Mendozaa,c, John E. Díazb,c, Alix E. Loaizab and Luis D. Mirandaa*

1
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Tetrahedron
journal homepage: www.elsevier.com
Visible light/Ir(III) photocatalytic initiation of xanthate-based radical-chain reactions:
xanthate group transfer and oxidative addition to aromatic systems
Pedro López-Mendozaa,c, John E. Díazb,c, Alix E. Loaizab and Luis D. Mirandaa*
aInstituto de Química, Universidad Nacional Autónoma de México, Circuito Exterior S. N., Ciudad Universitaria, Coyoacán México, D. F. 04510, México. E-
mail: lmiranda@unam.mx
bDepartamento de Química, Facultad de Ciencias, Pontificia Universidad Javeriana, Cra. 7 No.40-62, Edificio Carlos Ortiz, Bogotá, 110231561, Colombia.
cThese authors contributed equally to this work
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A photocatalyzed redox generation of radicals from O-ethyl xanthates to generate electrophilic
radicals under photoredox catalysis, using Ir(ppy)3 and blue LEDs irradiation is described. The
protocol can be used in classical xanthate-based inter- and intra-molecular group transfer
reactions and oxidative radical addition to several heteroaromatic systems. The process does not
require high temperature and reactions are cleaner compared with the traditional peroxide
initiation. In the oxidative addition to aromatic systems, the oxidation process is part of the
catalytic cycle and does not require a stoichiometric oxidant such as DLP which is particularly
difficult to separate from the product.
Available online
Keywords:
Xanthate
Photoredox Catalysis
Blue LEDs
Xanthate Group Transfer
Oxidavive Addition
2009 Elsevier Ltd. All rights reserved
.
1. Introduction
alkene,
a
polymerization process may (RAFT/MADIX
polymerization process) or may not occur.
Since its inception by Sir Derek Barton1 and further extended
by Zard,2 xanthate-based radical chemistry has become an
important tool in organic synthesis. Because of the ease by which
new carbon-carbon bonds are generated via radical addition to
both activated and simple alkenes3 as well as by oxidative
addition to aromatic systems,3 these protocols have been applied
elegantly in the total synthesis of natural products4 and in the
development of new synthetic methodologies for the construction
of molecules with a vast range of complexity.4 Over the last three
decades, Zard and co-workers have provided many different
functionalized xanthates which, in turn, have generated free
radicals, useful for various synthetic purposes. The main features
of the reaction mechanism in the xanthate transfer process are: 1)
once the radical b is generated from xanthate a, (by the action of
an initiator In•, Scheme 1), the fast and degenerate reversible
addition/fragmentation process between the radical b and its
xanthate precursor (path A), extends the lifetime of radical b,
allowing it to be captured even by unactivated alkenes and homo
and heteroaromatic systems (d) in an inter- and intra-molecular
processes, giving a new radical e (path B). 2) The equilibrium
between the reactive radical species and the xanthates (a and g)
maintains a low concentration of the reactive species (b and e),
allowing the reactions to progress in a quite concentrated
medium (even under solvent-free conditions). Interestingly,
depending on the conditions and combination of xanthate and
R2
Path B
n
R1
[O]
R2
R1
R1
R2
R2
h
i
e
R2
d
S
R1
R1
R1
S
R1
S
OEt
R1
S
S
S
a
R1
S
OEt
R1
In
OEt R2
S
OEt
a
c
b
f
Path A
R2
OEt
R1
S
S
g
Scheme 1. Mechanism for xanthate radical process.
Under standard conditions however, the radical e is trapped by
the xanthate a to finally afford the expected transfer-xanthate g.

2
Tetrahedron
ACCEPTED MANUSCRIPT
3) Product g is itself a new xanthate, which may function as a
catalyst loading to 2 mol% resulted in a slightly higher yield;
substrate in other radical or ionic processes. Thus, several
complex transformations can occur that take advantage of the
rich sulfur-based chemistry. In some specific cases (e. g., in the
addition to an aromatic system), the presence of an oxidant (e. g.,
peroxide itself) in the reaction media might induce the conversion
of the radical e into the corresponding cation h, which might
undergo a proton elimination to regenerate the olefinic system.
however, the use of 5 mol% did not improve the yield (entry 3).
Thus, 2 mol% was selected as the optimum. When the less
reducing Ru(bpy)3 was tested as a photocatalyst, the reaction did
not proceed (entry 4). Substituting DMF for acetonitrile resulted
in an improved yield (entry 5) and this solvent was selected for
subsequent reactions. Under the same conditions, the use of
[Ir(dtbbpy)(ppy)]PF6 gave a slightly lower yield (entry 6). The
use of triethylamine resulted only in decomposition of the
starting material (entry 7). Surprisingly, when the reaction was
performed without lutidine, 3 was isolated in higher yield (entry
8). This result suggested that the base does not play a determinant
role in the xanthate group transfer process. Apparently, the
efficient radical chain process, once initiated, persists long
enough to afford an improved product yield without the need to
regenerate the organometallic initiator by the action of the base.
Another possible explanation for this observation is that the
electron rich radical species c and f (Scheme 1) reduce Ir(IV) via
a SET process to regenerate the initiator7 consuming a portion of
the substrate. Increasing the stoichiometric ratio between
xanthate 1 and vinyl acetate 2 resulted in a better yield (entry 9).
Using vinyl acetate as a solvent favored polymerization of the
alkene. Interestingly, when the reaction was carried out without
Ir(ppy)3, product 3 was obtained in 25% yield (entry 10). This
result clearly indicates that the reaction starts only with the blue
LEDs irradiation, presumably via homolytic C–S scission.8
Nevertheless, under these conditions the chain reaction is only
moderately efficient and therefore catalyst assistance is required.
Finally, the reaction did not proceed in the absence of irradiation
(entry 11).
Scheme 2. Photoredox catalysis generation of radicals from thiocarbamates
The xanthate-based radical chain process is commonly
initiated using organic peroxides such as dilauroyl peroxide
(DLP) and dicumyl peroxide (DCP). However, these peroxides
require high temperatures to be fragmented and byproducts can
be difficult to eliminate from the product, especially when DLP
is used. As an alternative, triethylborane can initiate the radical
chain process at room temperature. Unfortunately, several
equivalents of this reagent are usually required, with poor
reproducibility of results. Photoredox catalysis has re-emerged
as a powerful strategy to construct C-C and/or C-X bonds under
mild conditions by the activation of simple substrates. Several
novel methodologies and applications in total synthesis have
been reported in the last decade, showing the versatility of this
chemistry5.
Table 1. Optimization of the xanthate transfer reaction conditions under
photoredox catalysis.
Recently, several research groups have developed photoredox
catalytic systems to generate radical species from
dithiocarbonates (xanthates) and thiocarbamates. Ollivier and co-
workers
reported
a
photocatalytic Barton–McCombie
deoxygenation process of secondary and tertiary alcohols using
Ir(ppy)3, in the presence of DIPEA as the sacrificial electron
donor, under blue LED irradiation (Scheme 2, a).6a Molander and
co-workers developed a reductive cross-coupling reaction using
Ni/Ir-based photoredox dual catalysis. In this case, the radical
species were generated from the corresponding O-benzyl
xanthates, also under blue LEDs irradiation (Scheme 2, b).6b
[a] Reaction conditions: 1 (0.1 mmol, 1.0 equiv.), 2 (0.3 mmol, 3.0 equiv), catalyst,
base (0.11 mmol, 1.1 equiv.) solvent (0.4 mL, 0.25 M).[b] Isolated yield. [c] These
reactions were performed using 1 (0.2 mmol, 2.0 equiv) and 2 (0.1 mmol, 1.0
equiv.). [d] Reaction performed without blue LEDs irradiation.
Based on these reports, we wondered if the radical initiation
process via reduction of O-ethyl xanthates under photoredox
catalysis would be useful for intra- and intermolecular radical
additions to alkenes and oxidative addition to heteroaromatic
systems.
With the optimal conditions in hand, we proceeded to explore
the scope of the radical initiation protocol (Scheme 3). The
addition of the xanthate derived from ethyl acetate as compared
to allyl acetate, vinyl acetate, or Boc-protected allyl amine was
evaluated. Then, the corresponding xanthate transfer products 6a-
c were obtained in moderate yields. When we tested the xanthate
derived from acetonitrile, the product 6d was obtained in good
yield with vinyl acetate as the radical acceptor and the product 6e
2. Results and discussion
We first investigated the xanthate group transfer reaction
between xanthate 1 and vinyl acetate 2 (Table 1). The reaction
was performed using Ir(ppy)3 (1 mol%) and 2,6-lutidine as a
sacrificial electron donor in acetonitrile, under blue LED light
(entry 1). Gratifyingly, under these conditions, the xanthate
transfer product was obtained in 25 % yield. An increase in the

3
was obtained in moderate yield when the simple alkene 4-allyl-
ACCEPTED MANUSCRIPT
1,2-dimethoxybenzene was utilized. Additionally, xanthates
derived from ketones and amides were tested with various
alkenes, giving rise the corresponding products 6f-j in moderate
yield. Importantly, the synthetized compounds may serve as
substrates for several ionic and radical transformations. For
example, xanthate 6h is a synthetic equivalent of a 1,4-
ketoaldehyde9 useful for the synthesis of several heteroaromatic
systems. On the other hand, substrate 6f may be utilized for the
synthesis of tetralones by ring-closure onto the aromatic ring10 as
well as for the synthesis of thiazolidine 2-ones.11 Vinyl acetate
derivatives have been used in the synthesis of α,β-unsaturated
trifluoromethylketones.12 It should be emphasized that some of
the products were obtained in yields comparable to those
Scheme 4. Xanthate group transfer in intramolecular reaction.
Then, we explored intramolecular reactions using substrates
7a-i (Scheme 4). When n=1 (7a-g), the substrates underwent a 5-
exo radical cyclization, giving rise to pyrrolidones 8a-g. When
n=2 (7h), a 6-exo radical cyclization was observed, affording
piperidone 8h (Scheme 4). In addition, when n=3 (7i), the
reaction provided aza-octanone 9i, via an 8-endo cyclization. The
results obtained in this intramolecular radical addition are
comparable to those reported for analogous substrates using the
DLP initiation methodology.15 It is important to point out that
most of the reactions reach a stage in which the process stops,
thus precluding full consumption of starting material. Thus, the
calculated yields of heterocycles 8b-f (up to 94%) are based on
recovered starting material show the potential of this protocol.
Ir(ppy)3
S
S
(2 mol %)
EtO
S
R1
EtO
R1
S
R
DMF(0.25 M)
24 °C
Blue LED's
R
5
4
6
Ir(ppy)3
(2 mol %)
R1
H
R1
S
Het
+
Het
O
O
O
DMF (0.25 M)
24 °C
Blue LED's
O
EtO
S
EtO
EtO
O
10-12
13-15
4
Xa
O
Xa
6b. 55 %
Xa
6a. 68 %
O
CO2Et
R
R
O
O
R
O
N
CO2Et
EtO
N
OtBu
N
N
NC
O
H
H
H
H
Xa
13a. R = CN (64%)
13b. R = CO2Et (23%)
13c. R = Me (30%)
13d. R = H (65%)
13e. R = CN (0%)
13f. R = CO2Et (0%)
6c. 58 %
6d. 82%
O
O
O
NC
OMe
OMe
CO2Et
R
N
OtBu
Xa
H
N
CO2Et
N
H
N
Xa
6f. 60%
Cl
H
H
6e. 50%
Cl
13g. (0%)
14a. R = CN (63%)
14b. R = CO2Et (52%)
14c. 63%
O
O
Cl
O
N
N
N
Xa
MeO
OMe
Xa
O
N
6g. 54%
6h. 56 %
OMe
O
R
CO2Et
EtO2C
O
O
O
15a. R = CN (90%)
15b. R = CO2Et (56%)
O
15c. 68%
N
N
O
O
Xa
O
Xa
N
N
N
Me
R1
6i. 51 %
6j. 55 %
N
Xa = SC(S)OEt
Me
Cl
reported by Zard13 (67% for compound 6d) and Renaud14 (74%
for compound 6a), using the classical peroxide initiation.
R
R
15f. R = CN; R1 = H (65%)
15g. R = CO2Et; R1 = H (33%)
15h. R = CN; R1 = Cl (66%)
15d. R = CN (61%)
15e. R = CO2Et (66%)
N
N
Scheme 3. Intermolecular additions of electrophilic radicals to alkenes.
N
N
N
N
S
S
EtO
O
R
Ir(ppy)3
(2 mol %)
O
O
R
O
O
S
OEt
O
N
O
OEt
S
N
or
N
N
n
S
S
DMF (0.25 M)
24 °C
Blue LED’s
R
n
9
n
7(a-i)
O
8
15k. 56%
15j. 53% OMe
exo product
endo product
15i. 39%
S
O
O
R
S
S
S
S
O
Scheme 5. Oxidative addition to heterocyclic systems.
OEt
N
N
OEt
N
R
EtO
n = 2
8h. R = Bn, 55%
S
R
n = 3
9i. R = Bn, 65%
n = 1
8a. R = Ph, 80%
To extend the scope of the photoredox initiation protocol, the
more challenging direct intermolecular oxidative alkylation of
heteroaromatic systems, was further explored (Scheme 5). It is
worth mentioning that such a process permits the regioselective
installation of an alkyl group onto heteroaromatic systems
8b. R = 4-(F)Ph, 62%, (80%)a
8c. R = 4-(iPr)Ph, 59%, (94%)
8d. R = 2,6(Me)Ph, 62%, (77%)
8e. R = 3,4(OMe)Ph(CH2)2, 61%, (80%)
8f. R = (C4H4O)CH2, 66%, (80%)
8g. R = Bn 69%

4
Tetrahedron
ACCEPTED MANUSCRIPT
through a direct C-H bond functionalization (Minisci type
adds to the aromatic ring, resulting in a new radical which is
reaction).16 Furthermore, the protocol might be utilized for
construction of synthetically useful intermediates or for late stage
functionalization of pharmaceutically important molecules.17
Indeed, the use of photocatalytic conditions for the
intermolecular alkylation of heteroaromatics has been recently
oxidized by Ir(IV) to regenerate the catalyst. Finally, proton
abstraction regenerates the aromatic system to generate the final
product.
described.18
In those studies, only bromomalonates and
3. Conclusions
bromoacetonitrile were employed for the radical addition onto
selected heteroaromatic systems.18
In conclusion, we have developed a new radical initiation
system from O-ethyl xanthates to generate electrophilic radicals
under photoredox catalysis, using Ir(ppy)3 and blue light. The
protocol can be used in classical xanthate-based radical reactions
such as xanthate group transfer and oxidative radical addition to
aromatic rings. The process does not require high temperature
and reactions are cleaner compared with the traditional peroxide
initiation. In the oxidative addition to aromatic systems, the
oxidation process is part of the catalytic cycle and does not
Satisfactorily, when the radical addition of xanthates derived
from acetonitrile, ethyl acetate and malonate were effected on
indole and pyrrole, products 13a-d and 14a-c were obtained in
moderate yields. However, when indole-3-carboxaldehyde was
used as the radical acceptor, the expected products (13e, f) were
not obtained under apparent inhibition of the process, and most
of the starting materials were recovered. Similarly, the product
13g was not observed when the m-chlorophenacyl xanthate
precursor was employed. Recently, we and others reported the
radical addition to imidazol[1,2-a]pyridine under DLP-initiation
require
a stoichiometric oxidant such as DLP which is
particularly difficult to separate from the product. Furthermore,
the presence of a base is not necessary as in the photocatalytic
processes previously reported.18 We believe that this novel
photocatalytic initiation process offers the opportunity to expand
the applications of the xanthate-based radical chemistry,
especially those cases when the nature of the initiator and the
temperature might cause difficulties.
conditions.19 Likewise, Sun and co-workers18a reported
a
cyanomethylation of this heterocyclic system using
bromoacetonitrile under photoredox catalysis in the presence of
NaHCO3 as a base. Interestingly, when the radical addition to this
aromatic system using xanthates derived from acetonitrile, ethyl
acetate, malonate, even xanthates derived from ketones and
amides was carried out, moderate product yields were obtained in
the absence of a base (15a-k). Most of the experiments were
conducted in 0.1 mmol scale. However, similar yields were
observed when the experiment for the obtantion of the product
15a was scaled up to 1 gram.
4. Experimental section
4.1. General
Solvents (DMF and MeCN) were purchased from Sigma-
Aldrich and were used without further purification.
Triethylamine and 2,6-lutidine were purchased from Sigma-
Aldrich and used without further purification. Catalysts (Ir(ppy)3,
Ru(bpy)3 and [Ir(dtbbpy)(ppy)2]PF6) were purchased from
Sigma-Aldrich and used without further purification. Melting
points were determined on a Fisher apparatus and are not
corrected. All reactions were performed under an argon
atmosphere. Reaction progress was monitored by analytical thin
layer chromatography using GF silicagel plates purchased from
Merck. Visualization was achieved by short-wave UV light (254
nm) and/or staining with vanillin. 1H and 13C NMR spectra were
recorded on a Jeol Eclipse-300 MHz, Bruker Avance III 400MHz
and Bruker Fourier-300 MHz model spectrometers using CDCl3
as solvent. Chemical shifts are reported as parts per million
downfield from an internal tetramethylsilane standard (δ = 0.0 for
1H) or from solvent reference (CDCl3 δ =7.26 for 1H, δ =77.16
for 13C). NMR coupling constants are reported in hertz (Hz).
Low- and high-resolution DART+ mass spectra were obtained on
Jeol JMS-T100LC spectrometer. The reactions were carried out
in a handmade reactor equipped with four 3 W LEDs and a fan.
To gain insight into the reaction mechanism, the reduction
potential of xanthate 1 was determined by cyclic voltammetry20
(see supporting information). The value obtained for this
xanthate was -1.60 V (SCE), which is in principle, suitable to be
reduced to the radical anion A by the action of the Ir(ppy)3* {E1/2
[Ir(ppy)3]+/Ir(ppy)3 ) = -1.73 V (SCE)}5b.
*
4.2. General procedure for the xanthate transfer group reaction
and oxidative addition to aromatic systems.
In a 4.0 mL glass vial equipped with a stirring bar, were added
the corresponding xanthate (0.2 mmol, 2.0 equiv.), the radical
acceptor (0.1 mmol, 1.0 equiv.) (alkene 2 or 5; or heterocycle 10-
12), Ir(ppy)3 (0.002 mmol, 0.02 equiv.) and DMF (0.4 mL, [0.25
M]). Next, the resulting solution was degassed by three
consecutive freeze−pump−thaw cycles and placed under argon
atmosphere. Finally, the reaction mixture was stirred and
irradiated in a Blue LEDs reactor (12 W) at 24 °C during 12-14
h. After that, the mixture was concentrated in vacuo and the
product was purified by flash column chromatography on silica
gel.
Scheme 6. Proposal mechanism for the oxidative addition.
Thus, based on our experimental observations and previous
reports,6,18 we propose that the mechanism of the oxidative
addition starts with a single electron transfer (SET) from the
Ir(III) excited-state to the xanthate, giving rise to a radical-anion
A, which undergoes a cleavage to generate a new radical and a
xanthogenate anion (Scheme 6). The new carbon-centered radical

5
118.2, 79.0, 70.6, 30.4, 20.8, 13.9, 13.7. HRMS (DART+) (m/z)
4.2.1. 1-((ethoxycarbonothioyl)thio)-4-(4-
methoxyphenyl)-4-oxobutyl acetate 3:
ACCEPTED MANUSCRIPT
[M + H]+: calc. for C9H14NO3S2: 248.04151, found: 248.04165.
Following the general procedure, 3 was obtained as a pale
yellow oil (24.9 mg, 70 % yield) after purification via flash
column chromatography using silica gel (Hex:AcOEt; 9:1). H
1
4.2.6. S-(4-cyano-1-(3,4-dimethoxyphenyl)butan-2-
yl) O-ethyl carbonodithioate 6e:
NMR (300 MHz, CDCl3) δ 7.94 (m, 8.8 Hz, 2H), 6.94 (d, J =
8.8, 2H), 6.74 (t, J = 6.4 Hz, 1H), 4.55 – 4.74 (m, 2H), 3.88 (s,
3H), 3.09 (td, J = 7.1 Hz, 2.3 Hz, 2H), 2.43 (m, 2H), 2.34 – 2.43
(m, 2H), 2.07 (s, 3H), 1.41 (t, J = 7.1 Hz, 3H). 13C NMR (75
MHz, CDCl3) δ 210.0, 196.4, 169.4, 163.6, 130.3, 129.6, 113.8,
80.3, 70.3, 55.5, 33.8, 28.7, 20.9, 13.7. HRMS (DART+) (m/z)
[M + H]+: calc. for C16H21O5S2: 357.08304, found: 357.08364.
Following the general procedure, 6e was obtained as a brown
oil (16.9 mg, 50% yield) after purification via flash column
chromatography using silica gel (Hex:AcOEt; 9:1). 1H NMR
(300 MHz, CDCl3) δ 6.87 – 6.70 (m, 3H), 4.65 (q, J = 7.1 Hz,
2H), 4.03 (m, 1H), 3.89 (s, 3H), 3.87 (s, 3H), 3.12 (dd, J = 14.1,
6.2 Hz, 1H), 2.82 (dd, J = 14.1, 8.5 Hz, 1H), 2.62 – 2.30 (m, 2H),
2.25 – 2.02 (m, 1H), 1.88 (m, 1H), 1.43 (t, J = 7.1 Hz, 3H). 13C
NMR (75 MHz, CDCl3) δ 212.9, 149.0, 148.1, 130.0, 121.3,
119.0, 112.2, 111.2, 70.4, 55.9, 51.1, 40.6, 28.9, 15.2, 13.8.
HRMS (DART+) (m/z) [M + H]+: calc. for C16H22NO3S2:
340.10411, found: 340.10400.
4.2.2. ethyl 5-acetoxy-4-
((ethoxycarbonothioyl)thio)pentanoate 6a:
Following the general procedure, 6a was obtained as a yellow
pale oil (20.9 mg, 68% yield) after purification via flash column
chromatography using silica gel (Hex:AcOEt; 9:1). 1H NMR
(300 MHz, CDCl3) δ 4.63 (q, J = 7.1 Hz, 2H), 4.26 (qd, J = 11.4,
5.5 Hz, 2H), 4.12 (q, J = 7.1 Hz, 2H), 4.07 – 3.92 (m, 1H), 2.04 –
2.23(m, 1H), 2.06 (s, 3H), 2.02 – 1.83 (m, 1H), 1.41 (t, J = 7.1
Hz, 3H), 1.24 (t, J = 7.1 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ
212.9, 172.7, 170.8, 70.4, 65.65, 60.73, 48.9, 31.6, 26.0, 20.9,
14.3, 13.8. HRMS (DART+) (m/z) [M + H]+: calc. for
C12H21O5S2: 309.08304, found: 309.08326.
4.2.7. tert-butyl (5-(3-chlorophenyl)-2-
((ethoxycarbonothioyl)thio)-5-oxopentyl)carbamate
6f:
Following the general procedure, 6f was obtained as a yellow
pale oil (25.9 mg, 60% yield) after purification via flash column
chromatography using silica gel (Hex:AcOEt; 9:1). 1H NMR
(400 MHz, CDCl3) δ 7.93 (t, J = 1.9 Hz, 1H). 7.84 (dt, J = 7.8,
1.1 Hz, 1H), 7.55 (ddd, J = 8.0, 2.2, 1.1 Hz, 1H), 7.42 (t, J = 7.8
Hz, 1H), 4.92 (s, 1H), 4.65 (q, J = 7.1 Hz, 2H), 3.88 – 4.02 (m,
1H), 3.55 (dt, J = 12.6, 6.0 Hz, 1H), 3.44 (dt, J = 13.7, 6.4 Hz,
1H), 3.23 – 3.11 (m, 2H), 2.26 (dq, J = 13.7, 7.0 Hz, 1H), 2.09 –
1.94 (m, 1H), 1.45 (s, 9H), 1.45 (t, J = 7.1 Hz, 3H). 13C NMR
(100 MHz, CDCl3) δ 213.2, 197.7, 155.9, 138.2, 135.0, 133.1,
129.9, 128.1, 126.2, 79.6, 70.3, 51.3, 43.8, 35.8, 28.4, 25.5, 13.7.
HRMS (DART+) (m/z) [M + H]+: calc. for C19H27ClNO4S2:
432.10700 , found: 432.10631.
4.2.3. Ethyl 4-acetoxy-4-
((ethoxycarbonothioyl)thio)butanoate 6b:
Following the general procedure, 6b was obtained as a pale
yellow oil (16.18 mg, 55% yield) after purification via flash
column chromatography using silica gel (Hex:AcOEt; 95:5).
1H NMR (300 MHz, CDCl3) δ 6.67 (t, J = 6.4 Hz, 1H), 4.64
(dtt, J = 10.7, 7.0, 3.5 Hz, 2H), 4.15 (q, J =7.1 Hz, 2H), 2.45 (d,
2H), 2.35 – 2.19 (m, 2H), 2.08 (s, 3H), 1.42 (t, J = 6.0 Hz, 3H),
1.27 (t, J = 6.0 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 210.0,
172.1, 169.4, 80.0, 70.4, 60.9, 30.3, 29.5, 21.0, 14.3, 13.8.
HRMS (DART+) (m/z) [M + H]+: calc. for C11H19O5S2:
295.06739, found: 295.06884.
4.2.8. S-(1-(3,4-dimethoxyphenyl)-5-(4-
methoxyphenyl)-5-oxopentan-2-yl) O-ethyl
carbonodithioate 6g:
Following the general procedure, 6g was obtained as a brown
solid (24.19 mg, 54 % yield) after purification via flash column
chromatography using silica gel (Hex:AcOEt; 9:1). m.p.40-42°C
1H NMR (300 MHz, CDCl3) δ 7.89 (d, J = 9.0 Hz, 2H), 6.90 (d, J
= 9.0 Hz, 2H), 6.84 (s, 1H), 6.80 – 6.79 (m, 2H), 4.59 (q, J = 7.1
Hz, 2H), 3.88 (s, 3H), 3.86 (s, 3H), 3.85 (s, 3H), 3.19 – 2.97 (m,
4H), 2.86 (dd, J = 13.9, 8.3 Hz, 1H), 2.19 – 2.17 (m, 1H), 1.99 –
1.86 (m, 1H), 1.39 (t, J = 7.1 Hz, 3H). 13C NMR (75 MHz,
CDCl3) δ 214.2, 197.7, 163.5, 148.8, 147.8, 131.0, 130.3, 129.8,
121.4, 113.7, 112.4, 111.1, 69.9, 55.9, 55.5, 52.3, 41.2, 35.7,
29.7, 27.4, 13.8. HRMS (DART+) (m/z) [M + H]+: calc. for
C23H29O5S2: 449.14564, found: 449.14524.
4.2.4. ethyl 4-((tert-butoxycarbonyl)amino)-4-
((ethoxycarbonothioyl)thio)butanoate 6c:
Following the general procedure, 6c was obtained as a yellow
pale oil (21.1 mg, 58% yield) after purification via flash column
chromatography using silica gel (Hex:AcOEt; 8:2). 1H NMR
(300 MHz, CDCl3) δ 4.85 (br, 1H), 4.65 (q, J = 7.1 Hz, 2H), 4.13
(q, J = 7.1 Hz, 2H), 3.87 (dq, J = 9.1, 5.8 Hz, 1H), 3.58 – 3.28
(m, 2H), 2.63 – 2.34 (m, 2H), 2.23 – 1.80 (m, 2H), 1.51 - 1.37
(m, 12H), 1.25 (t, 7.2 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ
213.4, 172.9, 156.0, 79.7, 70.4, 60.7, 51.4, 43.8, 31.7, 28.5, 26.7,
14.3, 13.9. HRMS (DART+) (m/z) [M + H]+: calc. for
C15H28NO5S2: 366.14089, found: 366.14042.
4.2.9. 5-chloro-1-((ethoxycarbonothioyl)thio)-4-
oxopentyl acetate 6h:
Following the general procedure, 6h was obtained as a yellow
pale oil (16.6 mg, 56% yield) after purification via flash column
chromatography using silica gel (Hex:AcOEt; 8:2). 1H NMR
(300 MHz, CDCl3) δ 6.63 (t, J = 6.4 Hz, 1H), 4.74 – 4.48 (m,
2H), 4.10 (s, 2H), 2.89 – 2.66 (m, 2H), 2.45 – 2.17 (m, 2H), 2.08
(s, 3H), 1.42 (t, J = 7.1 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ
209.8, 201.0, 169.6, 80.0, 70.5, 48.2, 35.4, 28.0, 21.0, 13.8.
HRMS (DART+) (m/z) [M + H]+: calc. for C10H16ClO4S2:
299.01785, found: 299.01866.
4.2.5. 3-cyano-1-((ethoxycarbonothioyl)thio)propyl
acetate 6d:
Following the general procedure, 6d was obtained as a yellow
pale oil (19.95 mg, 82% yield) after purification via flash column
1
chromatography using silica gel (Hex:AcOEt; 95:5). H NMR
(300 MHz, CDCl3) δ 6.67 (t, J = 6.2 Hz, 1H), 4.66 (q, J = 7.2 Hz,
2H), 2.62 – 2.47 (m, 1H), 2.45 – 2.26 (m, 1H), 2.13 (s, 3H), 1.44
(t, J = 7.1 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 208.9, 169.2,

6
Tetrahedron
ACCEPTED MANUSCRIPT
NMR (300 MHz, CDCl3) δ 7.48 (d, J = 8.6 Hz, 2H), 7.22 (d, J =
8.6 Hz, 2H), 4.66 (q, J = 7.2 Hz, 2H), 3.99 (dd, J = 9.9, 7.3 Hz,
1H), 3.63 (dd, J = 9.9, 5.2 Hz, 1H), 3.25 – 3.41 (m, 2H), 2.74 –
2.93 (m, 3H), 2.45 (dd, J = 16.5, 6.3 Hz, 1H), 1.43 (t, J = 7.1 Hz,
3H), 1.24 (s, 3H), 1.22 (s, 3H). 13C NMR (75 MHz, CDCl3) δ
213.8, 172.3, 145.5, 136.7, 126.8, 120.2, 70.5, 53.4, 39.6, 38.5,
33.6, 30.8, 24.0, 23.9, 13.8. HRMS (DART+) (m/z) [M + H]+:
calc. for C17H24NO2S2: 338.12485, found: 338.12516.
4.2.10. 1-((ethoxycarbonothioyl)thio)-4-
morpholino-4-oxobutyl acetate 6i:
Following the general procedure, 6i was obtained as a yellow
pale oil (17.0 mg, 51% yield) after purification via flash column
chromatography using silica gel (Hex:AcOEt; 7:3). 1H NMR
(400 MHz, CDCl3) δ 6.67 (t, J = 6.4 Hz, 1H), 4.70 – 4.59 (m,
2H), 3.70 – 3.65 (m, 4H), 3.44 (t, J = 4.8 Hz, 2H), 2.50 – 2.40
(m, 2H), 2.36 – 2.26 (m, 2H), 2.08 (s, 3H), 1.42 (t, J = 7.1, 3H).
13C NMR (100 MHz, CDCl3) δ 210.2, 169.8, 169.5, 80.5, 70.5,
67.0, 66.7, 46.0, 42.2, 39.2, 28.9, 21.0, 13.8. HRMS (DART+)
(m/z) [M + H]+: calc. for C13H22N16O5S2: 336.09327 , found:
336.09394.
4.2.15. S-((1-(2,6-dimethylphenyl)-5-oxopyrrolidin-
3-yl)methyl) O-ethyl carbonodithioate 8d:
Following the general procedure, 8d was obtained as a pale
yellow oil (18.1 mg, 62% yield) after purification via flash
column chromatography using silica gel (Hex:AcOEt; 9:1). H
1
NMR (300 MHz, CDCl3) δ 7.10 (m, 3H), 4.67 (q, J = 7.1 Hz,
2H), 3.73 (dd, J = 10.3, 7.7 Hz, 1H), 3.30 – 3.52 (m, 3H), 2.99
(hept, J = 7.2, 6.8 Hz, 1H), 2.80 (dd, J = 16.9, 8.7 Hz, 1H), 2.44
(dd, J = 16.9, 6.9 Hz, 1H), 2.22 (s, 3H), 2.20 (s, 3H), 1.44 (t, J =
7.1 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 213.8, 172.6, 135.9,
135.3, 128.7, 128.4, 70.5, 53.4, 39.9, 36.8, 32.0, 18.0, 17.8, 13.8.
HRMS (DART+) (m/z) [M + H]+: calc. for C16H22NO2S2:
324.10920, found: 324.10869.
4.2.11. 2-((ethoxycarbonothioyl)thio)-5-
morpholino-5-oxopentyl acetate 6j:
Following the general procedure, 6j was obtained as a yellow
pale oil (19.1 mg, 55% yield) after purification via flash column
chromatography using silica gel (Hex:AcOEt; 7:3). 1H NMR
(400 MHz, CDCl3) δ 4.65 (q, J = 7.1 H, 2H), 4.37 – 4.23 (m, 2H),
4.07 – 3.97 (m, 1H), 3.69 – 3.64 (m, 4H), 3.64 – 3.59 (m, 1H),
3.45 (t, J = 4.9 Hz, 2H), 2.57 – 2.40 (m, 2H), 2.25 (dddd, J =
14.5, 9.0, 6.6, 4.5 Hz, 1H), 2.07 (s, 3H), 1.92 (dddd, J = 14.4,
10.0, 8.7, 5.8 Hz, 1H), 1.43 (t, J = 7.1 Hz, 3H). 13C NMR (100
MHz, CDCl3) δ 213.2, 170.8, 170.4, 70.5, 67.0, 66.7, 65.8, 49.4,
46.0, 42.2, 30.2, 26.2, 20.9, 13.9. HRMS (DART+) (m/z) [M +
H]+: calc. for C14H24NO5S2: 350.10959, found: 350.10949.
4.2.16. S-((1-(3,4-dimethoxyphenethyl)-5-
oxopyrrolidin-3-yl)methyl) O-ethyl
carbonodithioate 8e:
Following the general procedure, 8e was obtained as a pale
yellow oil (23.4 mg, 61% yield) after purification via flash
1
column chromatography using silica gel (Hex:AcOEt; 7:3). H
4.2.12. O-ethyl S-((5-oxo-1-phenylpyrrolidin-3-
yl)methyl) carbonodithioate 8a:
Following the general procedure, 8a was obtained as a pale
yellow oil (23.6 mg, 80% yield) after purification via flash
NMR (300 MHz, CDCl3) δ 6.70 – 6.83 (m, 3H), 4.65 (q, J = 7.0
Hz, 2H), 3.86 (s, 3H), 3.88 (s, 3H), 3.31 – 3.62 (m, 3H), 3.20 (dd,
J = 13.7, 6.2 Hz, 1H), 2.95 – 3.12 (m, 2H), 2.80 (t, J = 7.3 Hz,
2H), 2.48 – 2.77 (m, 2H), 2.17 (dd, J = 16.3, 5.6 Hz, 1H), 1.42 (t,
J = 7.1, 3H). 13C NMR (75 MHz, CDCl3) δ 213.9, 173.2, 149.0,
147.7, 130.9, 120.6, 111.8, 111.3, 70.4, 55.9, 52.2, 43.7, 39.8,
37.1, 33.2, 30.9, 13.8. HRMS (DART+) (m/z) [M + H]+: calc. for
C18H26NO4S2: 384.13032, found: 384.12926.
1
column chromatography using silica gel (Hex:AcOEt; 9:1). H
NMR (300 MHz, CDCl3) δ 7.58 (d, J = 7.4 Hz, 2H), 7.31 – 7.43
(m, 2H), 7.16 (t, J = 7.4 Hz, 1H), 4.66 (q, J = 7.1 Hz, 2H), 4.01
(dd, J = 9.8, 7.6 Hz, 1H), 3.65 (dd, J = 10.0, 5.6 Hz, 1H), 3.21 –
3.48 (m, 2H), 2.72 – 3.02 (m, 2H), 2.47 (dd, J = 16.3, 6.1- Hz,
1H), 1.43 (t, J = 7.1 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ
213.7, 172.4, 139.0, 128.9, 124.7, 120.0, 70.5, 53.2, 39.5, 38.6,
30.8, 13.8. HRMS (DART+) (m/z) [M + H]+: calc. for
C14H18NO2S2: 296.07790, found: 296.07803.
4.2.17. O-ethyl S-((1-(furan-2-ylmethyl)-5-
oxopyrrolidin-3-yl)methyl) carbonodithioate 8f:
Following the general procedure, 8f was obtained as a pale
yellow oil (19.8 mg, 66% yield) after purification via flash
1
column chromatography using silica gel (Hex:AcOEt; 7:3). H
4.2.13. O-ethyl S-((1-(4-fluorophenyl)-5-
oxopyrrolidin-3-yl)methyl) carbonodithioate 8b:
NMR (400 MHz, CDCl3) δ 7.36 (dd, J = 1.9, 0.9 Hz, 1H), 6.32
(dd, J = 3.2, 1.9 Hz, 1H), 6.26 – 6.23 (m, 1H), 4.65 (q, J = 7.2,
2H), 4.45 (s, 2H), 3.51 (dd, J = 10.0, 7.7 Hz, 1H), 3.32 – 3.14 (m,
2H), 3.11 (dd, J = 10.0, 5.5 Hz, 1H), 2.75 – 2.70 (m, 1H), 2.63
(dd, J = 16.8, 8.7 Hz, 1H), 2.25 (dd, J = 16.8, 6.4 Hz, 1H), 1.42
(t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 213.9, 173.0,
149.8, 142.5, 110.4, 108.5, 70.4, 51.6, 39.8, 39.2, 36.9, 30.8,
13.8. HRMS (DART+) (m/z) [M + H]+: calc. for C13H18NO3S2:
300.07281, found: 300.07276.
Following the general procedure, 8b was obtained as a pale
yellow oil (19.4 mg, 62% yield) after purification via flash
column chromatography using silica gel (Hex:AcOEt; 9:1). H
1
NMR (300 MHz, CDCl3) δ 7.45 – 7.69 (m, 2H), 6.97 – 7.16 (m,
2H), 4.66 (q, J = 7.1 Hz, 1H), 3.97 (dd, J = 9.9, 7.5 Hz, 1H), 3.62
(dd, J = 9.9, 5.7 Hz, 1H), 3.22 – 3.47 (m, 2H), 2.69 – 3.00 (m,
2H), 2.45 (dd, J = 16.5, 6.3 Hz, 1H), 1.43 (t, J = 7.1 Hz, 2H). 13
C
NMR (75 MHz, CDCl3) δ 213.7, 172.4, 159.6 (d, J = 324 Hz),
135.1, 121.8 (d, J = 8.1 Hz), 115.6 (d, J = 22.5) Hz, 70.5, 53.4,
50.9, 39.5, 38.3, 30.8, 13.8. HRMS (DART+) (m/z) [M + H]+:
calc. for C14H17FNO2S2: 314.06847, found: 314.06874.
4.2.18. S-((1-benzyl-5-oxopyrrolidin-3-yl)methyl)
O-ethyl carbonodithioate 8g:
Following the general procedure, 8g was obtained as a pale
yellow oil (21.4 mg, 69% yield) after purification via flash
column chromatography using silica gel (Hex:AcOEt; 8:2). H
NMR (300 MHz, CDCl3) δ 7.16 – 7.37 (m, 5H), 4.61 (q, J = 7.1
Hz, 2H), 4.30 – 4.52 (m, 2H), 3.39 (dd, J = 10.0, 7.8 Hz, 1H),
3.06 – 3.30 (m, 2H), 3.00 (dd, J = 10.0, 5.6 Hz, 1H), 2.54 – 2.82
4.2.14. O-ethyl S-((1-(4-isopropylphenyl)-5-
oxopyrrolidin-3-yl)methyl) carbonodithioate 8c:
Following the general procedure, 8c was obtained as a pale
yellow oil (19.9 mg, 59% yield) after purification via flash
1
1
column chromatography using silica gel (Hex:AcOEt; 9:1). H

7
4.2.23. diethyl 2-(1H-indol-2-yl)-2-
methylmalonate 13c:
(m, 2H), 2.26 (dd, J = 16.8, 6.4 Hz, 1H), 1.38 (t, J = 7.1 Hz, 3H).
13C NMR (75 MHz, CDCl3) δ 213.9, 173.3, 136.3, 128.9, 128.3,
127.8, 70.5, 51.4, 46.7, 39.9, 37.1, 30.8, 13.9. HRMS (DART+)
(m/z) [M + H]+: calc. for C15H20NO2S2: 310.09355, found:
310.09332.
ACCEPTED MANUSCRIPT
Following the general procedure, 13c was obtained as a
yellow pale solid (8.6 mg, 30% yield) after purification via flash
column chromatography using silica gel (Hex:AcOEt; 9:1). H
1
NMR (300 MHz, CDCl3) δ 9.08 (s, 1H), 7.57 (dd, J = 7.8, 1.0,
1H), 7.37 (dd, J = 8.1, 1.0 Hz, 1H), 7.18 (ddd, J = 8.2, 7.0, 1.3 z,
1H), 7.08 (ddd, J = 8.0, 7.1, 1.1 Hz, 1H), 6.47 (dd, J = 2.0, 0.9
Hz, 1H), 4.25 (q, J = 7.1 Hz, 4H), 1.95 (s, 3H), 1.27 (t, J = 7.1
Hz, 6H). 13C NMR (75 MHz, CDCl3) δ 170.5, 136.4, 134.9,
127.7, 122.4, 120.7, 119.9, 111.2, 101.5, 62.4, 54.5, 21.4, 14.1.
HRMS (DART+) (m/z) [M + H]+: calc. for : C16H20NO4:
290.13923, found: 290.13982.
4.2.19. S-((1-benzyl-2-oxopiperidin-4-yl)methyl) O-
ethyl carbonodithioate 8h:
Following the general procedure, 8h was obtained as a pale
yellow oil (17.8 mg, 55% yield) after purification via flash
1
column chromatography using silica gel (Hex:AcOEt; 8:2). H
NMR (300 MHz, CDCl3) δ 7.23 – 7.35 (m, 5H), 4.55 – 4.76 (m,
3H), 4.49 (d, J = 14.7 Hz, 1H), 3.13 – 3.31 (m, 3H), 3.09 (dd, J =
13.8, 6.2 Hz, 1H), 2.67 – 2.81 (m, 1H), 2.07 – 2.32 (m, 2H), 1.97
– 2.06 (m, 1H), 1.47 – 1.65 (m, 1H), 1.44 (t, J = 7.0 Hz, 3H). 13
C
4.2.24. diethyl 2-(1H-indol-2-yl)malonate 13d:
NMR (75 MHz, CDCl3) δ 214.3, 168.5, 137.0, 128.6, 128.1,
127.4, 70.3, 50.0, 46.0, 40.7, 38.0, 32.8, 28.3, 13.8. HRMS
(DART+) (m/z) [M + H]+: C16H22NO2S2: 324.10919, found:
324.10955.
Following the general procedure, 13d was obtained as a
brown oil (17.8 mg, 65% yield) after purification via flash
column chromatography using silica gel (Hex:AcOEt; 95:5). H
1
NMR (300 MHz, CDCl3) δ 9.00 (s, 1H), 7.58 (d, J = 7.9 Hz,
1H), 7.38 (d, J = 8.3 Hz, 1H), 7.19 (t, J = 8.3 Hz, 1H), 7.09 (t, J =
7.5 Hz, 1H), 6.50 (s, 1H), 4.91 (s, 1H), 4.33 – 4.18 (m, 4H), 1.29
(t, J = 7.2 Hz, 6H). 13C NMR (75 MHz, CDCl3) δ 167.3, 136.7,
128.8, 127.8, 122.5, 120.7, 120.1, 111.3, 103.4, 62.5, 51.8, 14.1.
4.2.20. S-(1-benzyl-2-oxoazocan-5-yl) O-ethyl
carbonodithioate 9i:
HRMS (DART+) (m/z) [M + H]+: calc. for C15H18NO4
:
Following the general procedure, 9i was obtained as a pale
yellow oil (21.9 mg, 65% yield) after purification via flash
column chromatography using silica gel (Hex:AcOEt; 8:2). 1H
NMR (300 MHz, CDCl3) δ 7.14 – 7.45 (m, 5H), 4.46 – 4.78 (m,
4H), 3.62 – 3.85 (m, 1H), 3.33 – 3.58 (m, 2H), 2.73 – 2.82 (m,
1H), 2.58 – 2.67 (m, 1H), 2.26 – 2.47 (m, 1H), 1.90 – 2.10 (m,
2H), 1.70 – 1.89 (m, 3H), 1.42 (t, J = 7.1 Hz, 3H). 13C NMR (75
MHz, CDCl3) δ 213.7, 173.7, 137.5, 128.6, 128.3, 127.5, 69.8,
48.4, 48.2, 46.3, 33.8, 32.4, 31.8, 28.0, 13.8. HRMS (DART+)
(m/z) [M + H]+: calc. for C17H24NO2S2: 338.12484, found:
338.12386.
276.12358, found: 276.12307.
4.2.25. 2-(1H-pyrrol-2-yl)acetonitrile 14a:
Following the general procedure, 14a was obtained as a
yellow pale oil (6.3 mg, 63% yield) after purification via flash
1
column chromatography using silica gel (Hex:AcOEt; 7:3). H
NMR (400 MHz, CDCl3) δ 8.26 (br, 1H), 6.78 (td, J = 2.7, 1.5
Hz, 1H), 6.19 – 6.16 (m, 1H), 6.14 (tdt, J = 2.6, 1.6, 0.8 Hz, 1H),
3.77 (d, J = 0.8 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ 118.8,
118.6, 116.9, 109.3, 108.3, 16.9, HRMS (DART+) (m/z) [M +
H]+: calc. for C6H7N2 : 107.06092 , found: 107.06091.
4.2.21. 2-(1H-indol-2-yl)acetonitrile 13a:
Following the general procedure, 13a was obtained as a brown
solid (9.9 mg, 64% yield) after purification via flash column
chromatography using silica gel (Hex:AcOEt; 9:1). m.p. 96-98
4.2.26. ethyl 2-(1H-pyrrol-2-yl)acetate 14b:
Following the general procedure, 14b was obtained as a
yellow pale oil (8.0 mg, 52% yield) after purification via flash
column chromatography using silica gel (Hex:AcOEt; 95:5). 1H
NMR (400 MHz, CDCl3) δ 8.73 (s, 1H), 6.76 (td, J = 2.7, 1.5 Hz,
1H), 6.14 (q, J = 2.9 Hz, 1H), 6.02 (dddt, J = 3.3, 2.4, 1.6, 0.8 Hz,
1H), 4.18 (q, J = 7.2 Hz, 2H), 3.67 (d, J = 0.8, 2H), 1.28 (t, J =
7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 171.4, 123.5, 117.8,
108.4, 107.4, 61.2, 33.4, 14.3. HRMS (DART+) (m/z) [M + H]+:
calc. for C8H12NO2: 154.08680, found: 154.08699.
1
°C. H NMR (400 MHz, CDCl3) δ 7.57 (dd, J = 7.9, 1.0, 1H),
8.17 (s, 1H), 7.35 (dd, J = 8.2, 1.0 Hz, 1H), 7.21 (ddd, J = 8.2,
7.1, 1.3 Hz, 1H), 7.13 (ddd, J = 8.0, 7.1, 1.1 Hz, 1H), 6.48 (dq, J
= 2.1, 1.0 Hz, 1H), 3.92 (d, J = 1.0, 2H). 13C NMR (100 MHz,
CDCl3) δ 136.7, 128.3, 125.9, 122.9, 120.7, 120.7, 116.4, 111.1,
103.0, 17.8. HRMS (DART+) (m/z) [M + H]+: calc. for :
C10H9N2: 157.07657, found: 157.07688.
4.2.22. ethyl 2-(1H-indol-2-yl)acetate 13b:
Following the general procedure, 13b was obtained as a
brown solid (4.7 mg, 23% yield) after purification via flash
column chromatography using silica gel (Hex:AcOEt; 9:1). m.p
28-31 °C. 1H NMR (400 MHz, CDCl3) δ 8.61 (s, 1H), 7.47 (dd,
J = 7.9, 1.0 Hz, 1H), 7.08 (ddd, J = 8.2, 7.1, 1.3 Hz, 1H), 7.01
(ddd, J = 8.1, 7.1, 1.1 Hz, 1H), 6.28 (dd, J = 2.0, 1.0 Hz, 1H),
4.14 (q, J = 7.2 Hz, 2H), 3.76 (d, J = 0.9 Hz, 2H), 1.23 (t, J = 7.1
Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 170.8, 136.6, 130.7,
128.5, 121.9, 120.3, 120.0, 110.9, 102.0, 61.5, 34.1, 14.3. HRMS
(DART+) (m/z) [M + H]+: calc. for : C12H14NO2: 204.10245,
found: 204.10221.
4.2.27. diethyl 2-(1H-pyrrol-2-yl)malonate 14c:
Following the general procedure, 14c was obtained as a
yellow pale oil (14.1 mg, 63% yield) after purification via flash
1
column chromatography using silica gel (Hex:AcOEt; 95:5). H
NMR (300 MHz, CDCl3) δ 9.05 (br, 1H), 6.92 – 6.71 (m, 1H),
6.25 – 5.99 (m, 2H), 4.75 (s, 1H), 4.22 (qd, J = 7.1, 2.1 Hz, 4H),
1.28 (t, J = 7.1 Hz, 6H). 13C NMR (75 MHz, CDCl3) δ 167.8,
121.7, 118.9, 108.7, 108.4, 62.2, 51.2, 14.1. HRMS (DART+)
(m/z) [M + H]+: calc. for C11H16NO4: 226.10793, found:
226.10757.
4.2.28. 2-(2-phenylimidazo[1,2-a]pyridin-3-
yl)acetonitrile 15a:

8
Tetrahedron
Following the general procedure, 15a was obtained as a
128.6, 127.8, 126.1, 122.2, 121.5, 116.9, 112.6, 61.7, 31.0, 21.4,
ACCEPTED MANUSCRIPT
brown oil (20.9 mg, 90% yield) after purification via flash
column chromatography using silica gel (Hex:AcOEt; 7:3). H
18.6, 14.3. HRMS (DART+) (m/z) [M + H]+: calc. for
C19H21N2O2: 309.16030, found: 309.15950.
1
NMR (300 MHz, CDCl3) δ 8.07 (d, J=6.9, 1H), 7.74 – 7.66 (m,
3H), 7.57 – 7.48 (m, 2H), 7.48 – 7.40 (m, 1H), 7.34 (ddd, J = 9.1,
6.8, 1.2 Hz, 1H), 4.17 (s, 2H). 13C NMR (75 MHz, CDCl3) δ
145.5, 145.2, 133.2, 129.1, 128.7, 125.5, 123.0, 118.1, 115.1,
113.5, 107.9, 14.0. HRMS (DART+) (m/z) [M + H]+: calc. for
C15H12N3: 234.10312, found: 234.10395.
4.2.33. 2-(6-chloro-2-phenylimidazo[1,2-a]pyridin-
3-yl)acetonitrile 15f:
Following the general procedure, 15f was obtained as a brown
solid (17.3 mg, 65% yield) after purification via flash column
chromatography using silica gel (Hex:AcOEt; 9:1). m.p. 140-144
°C. 1H NMR (400 MHz, CDCl3) δ 8.10 (dd, J = 2.0, 0.9 Hz, 1H),
7.71 – 7.65 (m, 3H), 7.55 – 7.49 (m, 2H), 7.47 – 7.43 (m, 1H),
7.30 (dd, J = 9.5, 1.9 Hz, 1H), 4.14 (s, 2H). 13C NMR (100 MHz,
CDCl3) δ 146.3, 144.0, 132.8, 129.2, 129.0, 128.7, 127.0, 121.9,
121.0, 118.6, 114.7, 108.6, 14.1. HRMS (DART+) (m/z) [M +
H]+: calc. for: C15H11ClN3 268.06415, found: 268.06472.
4.2.29. ethyl 2-(2-phenylimidazo[1,2-a]pyridin-3-
yl)acetate 15b:
Following the general procedure, 15b was obtained as a
yellow pale oil (15.6 mg, 56% yield) after purification via flash
1
column chromatography using silica gel (Hex:AcOEt; 7:3). H
NMR: (300 MHz, CDCl3) δ 8.06 (d, J = 6.8 Hz, 1H), 7.77 (d, J =
7.7, 2H), 7.62 (d, J = 9.1 Hz, 1H), 7.41 (t, J = 7.4 Hz, 2H), 7.37 –
7.28 (m, 1H), 7.22 – 7.12 (m, 1H), 6.81 (t, J = 6.9 Hz, 1H), 4.16
(q, J = 7.1 Hz, 2H), 3.98 (s, 1H), 1.21 (t, J = 7.1Hz, 3H). 13C
NMR (75 MHz, CDCl3) δ 169.5. 145.1, 144.7, 134.1, 128.8,
128.1, 124.7, 123.9, 117.8, 113.1, 112.6, 61.8, 31.0, 14.3. HRMS
(DART+) (m/z) [M + H]+: calc. for C17H17N2O2: 281.12900,
found: 281.12914.
4.2.34. ethyl 2-(6-chloro-2-phenylimidazo[1,2-
a]pyridin-3-yl)acetate 15g:
Following the general procedure, 15g was obtained as a brown
solid (10.3 mg, 33% yield) after purification via flash column
chromatography using silica gel (Hex:AcOEt; 9:1). m.p. 105-108
°C. 1H NMR (400 MHz, CDCl3) δ 8.20 (dd, J = 1.9, 0.9 Hz, 1H),
7.84 – 7.78 (m, 2H), 7.62 (dd, J = 9.5, 0.9 Hz, 1H), 7.52 – 7.45
(m, 2H), 7.43 – 7.38 (m, 1H), 7.21 (dd, J = 9.5, 2.0 Hz, 1H), 4.25
(q, J = 7.1 Hz, 2H), 4.03 (s, 2H), 1.31 (t, J = 7.1 Hz, 3H). 13C
NMR (100 MHz, CDCl3) δ 169.2, 145.8, 143.6, 133.7, 128.9,
128.7, 128.4, 126.1, 121.9, 120.9, 118.1, 113.8, 62.0, 31.0, 14.3.
HRMS (DART+) (m/z) [M + H]+: calc. for: C17H16ClN3O2
315.09003, found: 315.09028.
4.2.30. diethyl 2-(2-phenylimidazo[1,2-a]pyridin-3-
yl)malonate 15c:
Following the general procedure, 15c was obtained as a brown
solid (23.9 mg, 68 % yield) after purification via flash column
chromatography using silica gel (Hex:AcOEt; 8:2). m.p. 165-
168. °C. 1H NMR (300 MHz, CDCl3) δ 8.37 (d, J = 7.2 Hz, 1H),
7.78 (d, J = 6.8 Hz, 2H), 7.69 (d, J = 9.0 Hz, 1H), 7.52 (t, J = 7.2
Hz, 2H), 7.45 (d, J = 7.1 Hz, 1H), 7.31 – 7.23 (m, 1H), 6.85 (td, J
= 6.9, 1.2 Hz, 1H), 5.42 (s, 1H), 4.26 (qd, J = 7.2, 1.7 Hz, 4H),
1.28 (td, J = 7.2, 1.2 Hz, 6H). 13C NMR (75 MHz, CDCl3) δ
166.8, 146.5, 145.9, 133.9, 129.2, 128.8, 128.4, 126.4, 125.3,
117.7, 112.1, 112.0, 62.6, 49.3, 14.1. HRMS (DART+) (m/z) [M
+ H]+: calc. for C20H21N204: 353.15013, found: 353.14971.
4.2.35. 2-(6-chloro-2-(4-chlorophenyl)imidazo[1,2-
a]pyridin-3-yl)acetonitrile 15h:
Following the general procedure, 15h was obtained as a
brown solid (19.9 mg, 66 % yield) after purification via flash
column chromatography using silica gel (Hex:AcOEt; 7:3). m.p.
165-168. °C. 1H NMR (400 MHz, CDCl3) δ 8.10 (dd, J = 1.9, 0.9
Hz, 1H), 7.66 (dd, J = 9.6, 0.9 Hz, 1H), 7.63 (d, J = 8.7 Hz, 2H),
7.50 (d, J = 8.6 Hz, 2H), 7.31 (dd, J = 9.6, 1.9 Hz, 1H), 4.12 (s,
2H). 13C NMR (100 MHz, CDCl3) δ 145.1, 144.0, 135.1, 131.2,
129.7, 129.3, 127.1, 122.1, 120.8, 118.5, 114.3, 108.5, 13.9.
HRMS (DART+) (m/z) [M + H]+: calc. for C15H10Cl2N3:
302.02518, found: 302.02525.
4.2.31. 2-(6-methyl-2-(p-tolyl)imidazo[1,2-
a]pyridin-3-yl)acetonitrile 15d:
Following the general procedure, 15d was obtained as a
brown solid (15.9 mg, 61% yield) after purification via flash
column chromatography using silica gel (Hex:AcOEt; 7:3). m.p.
160-163 °C. 1H NMR (400 MHz, CDCl3) δ 7.81 (s, 1H), 7.63 (d,
J = 9.2, 1H), 7.58 (d, J = 8.0 Hz, 2H), 7.31 (d, J = 7.8, 2H), 7.17
(dd, J = 9.3, 1.6 Hz, 1H), 4.12 (s, 2H), 2.42 (s, 6H). 13C NMR
(100 MHz, CDCl3) δ 144.9, 144.5, 138.5, 130.3, 129.8, 128.7,
123.4, 120.7, 117.3, 117.3, 115.2, 107.3, 21.4, 18.6, 14.1. HRMS
(DART+) (m/z) [M + H]+: calc. for C17H16N3: 262.13442 ,
found: 262.13377.
4.2.36. 1-morpholino-2-(2-phenylimidazo[1,2-
a]pyridin-3-yl)ethan-1-one 15i:
Following the general procedure, 15i was obtained as a brown
oil (12.5 mg, 39% yield) after purification via flash column
chromatography using silica gel (Hex:AcOEt; 5:5). 1H NMR
(400 MHz, CDCl3) δ 8.27 (dt, J = 6.9, 1.2 Hz, 1H), 7.56 – 7.62
(m, 3H), 7.39 – 7.44 (m, 2H), 7.31 – 7.36 (m, 1H), 7.14 – 7.18
(m, 1H), 6.80 (td, J = 6.8, 1.2 Hz, 1H), 4.08 (s, 2H), 3.49 (s, 4H),
3.21 – 3.27 (m, 2H), 3.15 (dd, J = 5.6, 3.7 Hz, 2H). 13C NMR
(100 MHz, CDCl3) δ 166.73, 145.2, 143.3, 134.3, 128.8, 128.6,
128.1, 124.8, 117.4, 113.8, 112.5, 66.8, 66.4, 46.4, 42.4, 29.9.
HRMS (ESI) (m/z) [M + H]+: calc. for C19H20N3O2: 322.1555,
found: 322.1553.
4.2.32. ethyl 2-(6-methyl-2-(p-tolyl)imidazo[1,2-
a]pyridin-3-yl)acetate 15e:
Following the general procedure, 15e was obtained as a brown
solid (19.9 mg, 66 % yield) after purification via flash column
chromatography using silica gel (Hex:AcOEt; 7:3). m.p. 95-100
°C. 1H NMR (400 MHz, CDCl3) δ 7.89 (dt, J = 2.0, 1.1 Hz, 1H),
7.72 (d, J = 8.1 Hz, 2H), 7.60 (d, J = 9.1 Hz, 1H), 7.28 (d, J = 7.8
Hz, 2H), 7.09 (dd, J = 9.2, 1.7 Hz, 1H), 4.23 (q, J = 7.1 Hz, 2H),
4.01 (s, 2H), 2.41 (s, 3H), 2.37 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H).
13C NMR (100 MHz, CDCl3) δ 169.7, 144.4, 144.1, 137.8, 129.5,
4.2.37. 1-(4-methoxyphenyl)-2-(2-
phenylimidazo[1,2-a]pyridin-3-yl)ethanone 15j:

9
1998, 37, 1128–1131. (c) Miranda L. D.; Zard, S. Z. Org. Lett.,
2002, 4, 1135-1138
Following the general procedure, 15j was obtained as brown
oil (18.2 mg, 53% yield) after purification via flash column
chromatography using silica gel (Hex:AcOEt; 6:4). 1H NMR
(400 MHz, CDCl3) δ 7.99 – 7.91 (m, 3H), 7.68 – 7.64 (m, 3H),
7.45 (t, J = 7.4 Hz, 2H), 7.42 – 7.33 (m, 1H), 7.19 (ddd, J = 9.1,
6.7, 1.3 Hz, 1H), 6.89 (d, J = 8.9 Hz, 2H), 6.80 (td, J = 6.8, 1.0
Hz, 1H), 3.86 (s, 3H), 4.68 (s, 2H). 13C NMR (100 MHz, CDCl3)
δ 193.4, 164.2, 145.3, 144.8, 134.7, 131.0, 128.8, 128.8, 128.0,
124.5, 124.1, 117.7, 114.1, 112.4, 55.7, 34.6. HRMS (DART+)
(m/z) [M + H]+: calc. for C22H19N2O2: 343.14465, found:
343.14429.
ACCEPTED MANUSCRIPT
5.
(a) Narayanam, J. M. R.; Stephenson, C. R. J. Chem. Soc. Rev.,
2011, 40, 102-113. (b) Shaw, M. H.; Twilton, J.; MacMillan, D.
W. C. J. Org. Chem., 2016, 81, 6898-6926.
6. (a) Chenneberg, L.; Baralle, A.; Daniel, M.; Fensterbank, L:
Goddard, J.-P.; Ollivier, C. Adv. Syn. Cat., 2014, 356, 2756-2762.
(b) Vara, B. A; Patel, N. R.; Molander, G. A. ACS Catalysis, 2017,
7, 3955-3959. (c) Chang, Q.; Liu, Z.; Liu, P.; Yu, L.; Sun, P. J.
Org. Chem., 2017, 82, 5391-5397. (d) Furst, L.; Matsuura, B.S.;
Narayanam, J. M. R.; Tucker, J. W.; Stephenson, C. R. J. Org.
Lett., 2010, 12, 3104-3107.
7. Debien, L.; Quiclet-Sire, B.; Zard, S. Z. Acc. Chem. Res. 2015, 48,
1237-1253.
8. Tazhe Veetil, A.; Šolomek, T.; Ngoy, B. P.; Pavlíková, N.; Heger,
D.; Klán, P. J. Org. Chem., 2011, 76, 8232-8242.
9. Quiclet-Sire, B.; Quintero, L.; Sanchez-Jimenez, g.; Zard, S. Z.
Synlett, 2003, 75-78.
4.2.38. (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl
2-(2-phenylimidazo[1,2-a]pyridin-3-yl)acetate 15k:
10. Quiclet-Sire, B.; Sortais, B.; Zard, S. Z. Synlett, 2002, 903-906.
11. Huang, Z.; Xu, J. Tetrahedron, 2013, 69, 10272-10278.
12. Anthore, L.; Zard, S. Z. Org. Lett., 2015, 17, 3058-3061.
13. Debien, L.; Quiclet-Sire, B.; Zard, S. Z. Org. Lett., 2011, 13,
5676-5679.
14. Ollivier, C; Renaud, P. J. Am. Chem. Soc., 2000, 122, 6496-6497.
15. El Kaïm, L.; Grimaud, L; Miranda, L. D.; Vieu, E. Tetrahedron
Lett., 2006, 47, 8259-8261.
Following the general procedure, 15k was obtained as a
yellow pale oil (21.8 mg, 56% yield) after purification via flash
column chromatography using silica gel (Hex:AcOEt; 7:3). H
1
NMR (400 MHz, CDCl3) δ 8.12 (dt, J = 7.2, 1.2 Hz, 1H), 7.86 –
7.81 (m, 2H), 7.68 (dt, J = 9.0, 1.1 Hz, 1H), 7.51 – 7.45 (m, 2H),
7.40 (d, J = 7.4 Hz, 1H), 7.25 – 7.21 (m, 1H), 6.87 (td, J = 6.8,
1.2 Hz, 1H), 4.74 (td, J = 10.9, 4.5 Hz, 1H), 4.11 – 3.98 (m, 2H),
2.00 (dtd, J = 12.0, 3.6, 1.8 Hz, 1H), 1.73 – 1.59 (m, 2H), 1.52 –
1.42 (m, 1H), 1.38 – 1.28 (m, 1H), 1.09 – 0.91 (m, 3H), 0.89 (d, J
= 6.5 Hz, 3H), 0.87 – 0.81 (m, 1H), 0.79 (d, J = 7.0 Hz, 3H), 0.66
(d, J = 7.0 Hz, 3H).
16. For a review see: Rueping, M.; Nachtsheim, B. J. Beilstein J. Org.
Chem. 2010, 6, 1, and references cited therein.
17. (a) O’Brien, A. G.; Maruyama, A.; Inokuma, Y.; Fujita, M.;
Baran, P. S.; Blackmond, D. G. Angew. Chem. Int. Ed. Engl. 2014,
53 (44), 11868. (b) Gui, J.; Zhou, Q.; Pan, C.-M.; Yabe, Y.; Burns,
A. C.; Collins, M. R.; Ornelas, M. A.; Ishihara, Y.; Baran, P. S. J.
Am. Chem. Soc. 2014, 136 (13), 4853.
18. (a) Chang, Q.; Liu, Z.; Liu, P.; Yu, L.; Sun, P. J. Org. Chem.,
2017, 82, 5391-5397. (b) Furst, L.; Matsuura, B.S.; Narayanam, J.
M. R.; Tucker, J. W.; Stephenson, C. R. J. Org. Lett., 2010, 12,
3104-3107. See also: (c) Jin, J.; MacMillan, D. W. C. Angew.
Chem. Int. Ed. 2015, 54, 1565 –1569. (d) Xu, J.; Fu, C.;
Shanmugam, S.; Hawker, C. J.; Moad, G.; Boyer, C. Angew.
Chem. Int. Ed. Engl. 2017, 56, 8376-8383.
13C NMR (100 MHz, CDCl3) δ 169.3, 145.1, 144.7, 134.2,
128.8, 128.0, 126.3, 124.6, 123.8, 117.7, 113.4, 112.5, 76.0, 47.2,
40.9, 34.2, 31.5, 31.3, 26.4, 23.4, 22.1, 20.8, 16.3. HRMS
(DART+) (m/z) [M + H]+: calc. for C25H31N2O2: 391.23855,
found: 391.23825.
19. (a) Pérez, V. M.; Fregoso-López, D.; Miranda L. D. Tetrahedron
Lett., 2017, 58, 1326-1329. (b) Wang, S.; Huang, X.; Ge, Z.;
Wang, X.; Li, R. RSC Adv., 2016, 6, 63532-63535.
Acknowledgments
Financial support from PAPIIT-DGAPA (project IN210516)
is grate-fully acknowledged. P. L.-M. thanks CONACYT for
PhD scholarship (No. 308233). J.E.D thanks to COLCIENCIAS
for the financial support through the project 120365843351. We
also thank R. Patiño, H. García-Ríos, A. Peña, E. Huerta, I.
Chavez, R. Gaviño, Ma. C. García-González, L. Velasco and J.
Pérez for technical support.
20. The redox potentials were determined by cyclic voltammetry
using a glassy-carbon electrode in a 10mM solution of [(n-
Bu)4N]PF6, as supporting electrolyte, in degassed HPLC grade
acetonitrile; using Fc+/Fc as internal standard under nitrogen
atmosphere. Scan rate: 100 mVs-1, saturated calomel electrode
used as reference electrode and platinum as counter electrode.
References and notes
Supplementary Material
1. Barton, D. H. R.; McCombie, S. W. J. Chem. Soc., Perkin Trans.
1 1975, 1574-1585.
2. Delduc, P.; Tailhan, C.; Zard, S. Z. Chem. Commun., 1988, 4,
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3. For recent reviews on xanthate-based radical chemistry, see: a)
Quiclet-Sire, B.; Zard, S. Z. Isr. J. Chem. 2017, 57, 202–217; b)
Quiclet-Sire, B.; Zard, S. Z. Synlett 2016, 27, 680–701; c) Quiclet-
Sire, B.; Zard, S. Z. Beilstein J. Org. Chem. 2013, 9, 557–576; d)
Zard, S. Z. “Xanthates and Related Derivatives as Radical
Precursors” in Encyclopedia of Radicals in Chemistry, Biology
and Materials, Wiley, Chichester, 2012; e) Quiclet-Sire, B.; Zard,
S. Z. Zard, Chem. Eur. J. 2006, 12, 6002–6016.
Supplementary material that may be helpful in the review
process should be prepared and provided as a separate electronic
file. That file can then be transformed into PDF format and
submitted along with the manuscript and graphic files to the
appropriate editorial office.
4. Selected examples: (a) Osornio, Y. M.; Cruz-Almanza, R.;
Jiménez-Montaño, V; Miranda, L. D. Chem. Commun., 2003,
2316-2317. (b) Reyes-Gutierrez, P. E.; Torres-Ochoa, R. O.;
Martinez, R; Miranda, L. D. Miranda, Org. Biomol. Chem., 2009,
7, 1388-1396. (c) Guerrero, M. A.; Miranda, L. D. Tetrahedron
Lett., 2006, 47, 2517-2520. (e) Miranda, L. D.; Icelo-Ávila, E.;
Rentería-Gómez, Á.; Pila, M. ; Marrero, J. G. Eur. J. Org. Chem.,
2015, 4098-4101. Selected examples: (a) Saicic, N. R.; Zard, S.
Z. Chem. Commun., 1996, 14, 1631-1632. (b) Boiteau, L.; Boivin,
J.; Liard, A.; Quiclet-Sire, B.; Zard, S. Z. Angew. Chem. Int. Ed.

10
Tetrahedron
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