Pd/PTABS: An Efficient Catalytic System for the Aminocarbonylation of a Sugar-Protected Nucleoside

Article abstract of DOI:10.1055/s-0039-1690190

A highly efficient and mild protocol for the aminocarbonylation of a nucleoside is developed by employing palladium/(1,3,5-Triaza-7-phosphaadamantan-1-ium-1-yl)butane-1-sulfonate (Pd/PTABS) as the catalytic system. The developed aminocarbonylation methodology employs CO gas at a relatively low temperature of 60? °C and is suitable for a wide range of amines, including (heteroaryl)benzylic, aliphatic acyclic, alicyclic and secondary amines. This protocol is also utilized for the synthesis of a sangivamycin precursor by carrying out the Pd-catalyzed amination and aminocarbonylation simultaneously. The utility of this protocol is further demonstrated by the synthesis of the drugs moclobemide and nikethamide.

Full text of DOI:10.1055/s-0039-1690190

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2019, 51, A–J
paper
A
en
S. Bhilare et al.
Paper
Synthesis
Pd/PTABS: An Efficient Catalytic System for the Aminocarbonylation
of a Sugar-Protected Nucleoside
Shatrughn Bhilarea
Jagrut Shaha
O
O
O
R
I
NH
N
NH
Pd(OAc)2
PTABS
H
Vinayak Gaikwada
Gaurav Guptaa
Yogesh S. Sanghvib
Bhalchandra M. Bhanagea
Anant R. Kapdi*a
NH2
N
O
N
O
+
DMTO
DMTO
CO
base, solvent
temp
R
O
O
OH
OH
Low Temperature
Low CO Pressure
Large Substrate Scope
Regio- & Chemoselective
Drug Synthesis
P
N
N
N
a Department of Chemistry, Institute of Chemical Technology,
Nathalal Parekh Road, Matunga, Mumbai-400019, India
ar.kapdi@ictmumbai.edu.in
b Rasayan Inc., 2802 Crystal Ridge Road, Encinitas, California
92024-6615, USA
SO3
Low Catalyst Loading
PTABS
Received: 01.07.2019
Accepted after revision: 05.08.2019
Published online: 05.09.2019
Aminocarbonylation or amidation, employing an amine
as a nucleophile, is an important variant of the carbonyla-
tion reaction,10,11 although in comparison to alkoxycarbon-
ylation,12 it has received much less attention. This comes in
spite of the fact that aminocarbonylation has been identi-
fied as one of the most sought-after processes in the phar-
maceutical industry,13 proving to be both valuable and sim-
ple in terms of the involved process parameters. A testa-
ment to the growing importance of aminocarbonylation14
can be visualized in the form of the several well-known am-
ide-cored compounds that have been identified in several
commercially important molecules, natural products, and
biologically active motifs in a variety of drug molecules
(Figure 1).15–20
DOI: 10.1055/s-0039-1690190; Art ID: ss-2019-c0370-op
Abstract A highly efficient and mild protocol for the aminocarbonyla-
tion of a nucleoside is developed by employing palladium/(1,3,5-triaza-
7-phosphaadamantan-1-ium-1-yl)butane-1-sulfonate (Pd/PTABS) as
the catalytic system. The developed aminocarbonylation methodology
employs CO gas at a relatively low temperature of 60 °C and is suitable
for a wide range of amines, including (heteroaryl)benzylic, aliphatic
acyclic, alicyclic and secondary amines. This protocol is also utilized for
the synthesis of a sangivamycin precursor by carrying out the Pd-cata-
lyzed amination and aminocarbonylation simultaneously. The utility of
this protocol is further demonstrated by the synthesis of the drugs mo-
clobemide and nikethamide.
Key words palladium, PTABS, aminocarbonylation, nucleoside, sangi-
vamycin
Amongst the molecules of synthetic and biological rele-
vance that have been highlighted above, echiguanine16
A
and sangivamycin15 are particularly important due to the
presence of a privileged nucleoside scaffold. In past de-
cades, significant progress has been made on nucleoside
chemistry,21 ranging from their synthesis, modification and
photophysical examination, leading to their potential ex-
ploration in the field of medicines.22 For the construction of
such macromolecular biologically relevant motifs/devices
and for the installation of important functionalities such as
amides (as seen in Figure 1), the role of smaller building
blocks (such as carbon monoxide) is crucial and signifi-
cant23 as they offer elegant synthetic pathways for mole-
cules24 of high commercial and biological relevance.25,26
The amide functionality in nucleoside chemistry has
proved useful due to the restricted rotation of the amide
bond27,28 and its ability to serve as both a hydrogen bond
acceptor and donor,29 thus providing an attractive prospect
for the assessment of new H-bonding contacts with differ-
ent protein targets and eventually helping in DNA stabiliza-
tion.30,31 Furthermore, keeping in mind the requirement for
the minimization of the number of rotatable bonds be-
The diversity of palladium-catalyzed coupling systems
is exemplified by the many named reactions, viz., Heck–
Mizoroki, Suzuki–Miyaura, Sonogashira, Stille, Kumada,
Negishi, Buchwald–Hartwig, and others that have found
numerous applications in academia and industry in the
past decades.1,2 However, the scope of palladium catalysis is
not limited to these coupling processes but goes well be-
yond, with carbonylation3 offering a range of options for
generating a variety of functional groups capable of further
elaboration.4 The original reaction conditions defined by
Heck over 30 years ago have undergone tremendous change
through the identification of a broader range of catalyst
precursors allowing the reaction to be conducted under
mild reaction conditions.5 On a similar note, the meteoric
rise in reports involving palladium-catalyzed carbonylation
chemistry has allowed the direct synthesis of carbonyl
compounds using readily available feedstocks such as car-
bon monoxide (CO),6 thus enabling atom economic5 as well
as step-economic approaches to synthesis.7–9
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–J
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
S. Bhilare et al.
Paper
Synthesis
O
NH
Me
O
NH2
N
H2N
H2N
Me
O
OH
OEt
O
O
HN
N
N
N
H
HO
N
O
N
N
H
N
H
NH2
OH OH
echiguanine A
sangivamycin
repaglinide
O
Cl
N
O
OMe
O
Br
S
O
H
N
H
N
OH
O
Me
N
N
N
S
Cl
H
H
Me
O
Me
Me
O
vismodegib
bikinin
articaine
Figure 1 Examples of drugs containing an amide linkage
tween the nucleobase and the pendant modification for
precise orientation at the aptamer protein interface also
makes the amide functionality an ideal candidate for instal-
lation onto the nucleoside backbone. Moreover, modified
2′-deoxyuridine nucleotides, exhibiting an N-substituted
carboxamide group at the 5-position, have been demon-
strated as important tools for expanding the in vitro selec-
tion of protein-binding aptamers (SELEX process) and for
post-SELEX optimization of the binding and pharmacoki-
netic properties of the selected aptamers.32,33
For the installation of the amide functionality on the
nucleoside substructure, it is therefore necessary to identify
environmentally benign and sustainable synthetic proto-
cols (such as aminocarbonylation via CO insertion). Eaton et
al.31 were the first to report the palladium-catalyzed ami-
nocarbonylation of 5′-O-(4,4′-dimethoxytrityl)-5-iodo-2′-
deoxyuridine (5′-O-DMT-5-IdU) (1a) (see Scheme 1) by uti-
lizing CO gas as a C1 source (for the installation of a carbon-
yl group) and an aromatic amine hydrochloride as the
amine source. Matsuda and co-workers34 have reported a
useful palladium-catalyzed transamidation protocol for the
aminocarbonylation of various nucleoside analogs. More re-
cently, Fitzwater et al.32 disclosed a carboxyamidation reac-
tion over the nucleosidic backbone.
Although useful, most of these methods have continued
with the classical carbonylative amidation process condi-
tions for nucleosides, which involve high catalyst loadings,
long reaction times, high CO pressures, lower yields and
limited substrate scope.29,31,32,35 To address and overcome
the above described limitations, we describe herein a sus-
tainable catalytic solution that employs a low-temperature,
low-pressure, palladium-catalyzed carbonylative amidation
protocol with nucleoside 1a, utilizing a simple phosphatri-
azene ligand [PTABS: (1,3,5-triaza-7-phosphaadamantan-
1-ium-1-yl)butane-1-sulfonate].36 We also intend to ex-
pand the repertoire of available reagents for in vitro selec-
tion,29 enabling the incorporation of a second modified
base into randomized DNA libraries in the SELEX process.32
The present method exhibits a substantial substrate scope
(22 examples), and utilizes a low CO pressure (<3 bar), a low
temperature (60 °C) and a low palladium loading (2 mol%),
whilst affording high yields of the desired products.
At the outset of our studies, the influence of the reac-
tion parameters including solvent, palladium precursor,
base, temperature, and the pressure of carbon monoxide
was examined, and the results are discussed below (Scheme
1 and Table 1).
O
O
O
I
Pd catalyst
ligand
NH
N
NH
H
CO
NH2
N
O
N
O
+
DMTO
DMTO
OMe
Et3N, solvent
temp, 24 h
O
O
OH
1a
OH
3a
2a
MeO
DMT =
Scheme 1 The aminocarbonylation of 1a
The catalytic aminocarbonylation protocol was tested
with nucleoside 1a and benzylamine (2a) as the model
substrates in the presence of 5 mol% of Pd(PhCN)2Cl2, as re-
ported by Gait et al.,37 providing a 76% yield of the desired
amide (Table 1, entry 1). Likewise, we tried several precata-
lyst systems such as Pd(PhCN)2Br2 and Pd(PPh3)4 (entries 2
and 3), and also Pd(PhCN)2Cl2 with PTABS as the ligand (en-
try 26), albeit without much further improvement in the
yield. Our recent work on the modification of nucleosides
was based on the development of
a water-soluble
Pd(Sacc)2(PTA)2 complex,38 which was used in an attempt to
the improve the of yield of the aminocarbonylation reaction
(entry 4). However, this well-defined catalyst failed to fur-
nish the desired product in a good yield. Therefore, we
turned our attention to our recently developed 1,3,5-triaza-
7-phosphaadamantane (PTA) variant, PTABS, which has al-
lowed the development of highly efficient protocols for the
modification of nucleosides via palladium-catalyzed cross-
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–J

C
S. Bhilare et al.
Paper
Synthesis
Table 1 (continued)
coupling reactions such as Heck, Suzuki–Miyaura and Sono-
gashira reactions,36 as well as room-temperature amina-
tion,39,40 low-temperature etherification41 and C–H bond
functionalization of 1,3,4-oxadiazoles.42
Entry Pd catalyst ,
(mol%)
Ligand
(mol%)
Solvent
Temp CO
(°C)
Yield
(psi) (%)b
25
26
27
28
29
Pd(OAc)2
(2 mol%)
–
DMF
DMF
DMF
DMF
DMF
60
40
40
40
40
40
43
78
55
61
64
Table 1 Optimization Studies of the Aminocarbonylation of 1aa
Pd(PhCN)2Cl2
(2 mol%)
PTABS
(4 mol%)
60
60
60
60
Entry Pd catalyst ,
(mol%)
Ligand
(mol%)
Solvent
Temp CO
(°C)
Yield
Pd(OAc)2
(2 mol%)
XantPhos
(4 mol%)
(psi) (%)b
Pd(OAc)2
(2 mol%)
XPhos
(4 mol%)
1
2
Pd(PhCN)2Cl2
(5 mol%)
–
–
–
–
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
H2O
70
60
60
60
60
60
60
60
60
60
60
60
60
40
20
14
40
40
40
40
40
40
40
40
40
76
75
65
20
80
60
65
58
82
81
85
75
84
70
0
Pd(OAc)2
(2 mol%)
SPhos
(4 mol%)
Pd(PhCN)2Br2
(5 mol%)
70
70
70
70
70
70
a Reaction conditions: 0.5 mmol of 1a, 1.0 mmol of 2a, 5.0 mmol of triethyl-
amine (as the base unless otherwise stated), 10 mL of solvent, reaction
kept in an autoclave for 24 h.
3
Pd(PPh3)4
(5 mol%)
4
Pd(Sacc)2(PTA)2
(5 mol%)
b Yield of isolated product.
c Reaction at 1 atm pressure using a CO balloon.
d DBU was used instead of triethylamine.
e Diisopropylethylamine (DIPEA) was used instead of triethylamine.
f K2CO3 was used instead of triethylamine.
5
Pd(OAc)2
(5 mol%)
PTABS
(10 mol%)
g Cs2CO3 was used instead of triethylamine.
h The reaction was carried out for 12 h.
6
Pd(OAc)2
(5 mol%)
PTAPS
(10 mol%)
i The reaction was carried out for 48 h.
7
Pd(OAc)2
(5 mol%)
PTABS
(10 mol%)
We envisaged the use of Pd(OAc)2 as a catalyst precursor
in combination with PTABS for this current protocol, and to
our delight, obtained an improved yield (80%) of the amide-
derivatized product (Table 1, entry 5). This yield was higher
than those obtained using other commercially available
monodentate and bidentate ligands (entries 27–29). Having
established the catalytic system for the aminocarbonyla-
tion, we further screened the reaction solvent with H2O and
PEG-400 giving lower yields of the desired product (entries
7 and 8) in comparison to MeCN. Lastly, we employed DMF
(entry 9) instead of MeCN and observed a slight improve-
ment in the yield.
Catalyst concentration is an important parameter in de-
termining the feasibility of the developed protocol for
large-scale applications, and in most reports in the litera-
ture this has been a critical point that needs to be ad-
dressed. Accordingly, the catalytic amidation reaction was
performed at different catalyst concentrations (Pd as well
as PTABS), with Pd (2 mol%) and PTABS (4 mol%) providing
the best result in terms of reactivity (Table 1, entry 11). An-
other aspect besides catalyst concentration that needs ur-
gent attention is the pressure of CO gas applied for the cata-
lytic amidation process, as in most cases pressures in excess
of 100 psi have been applied. Initial studies were performed
at 60 psi of CO pressure; however, it was observed that even
a CO pressure of 40 psi (entry 13) provided a similar yield to
that obtained at 60 psi. Any further reduction in pressure of
CO, such as by carrying out the reaction using a CO balloon,
resulted into complete loss of activity (entry 15). Having so
far carried out all the reactions at 70 °C, we decided to ana-
lyze the effect of temperature on the catalytic activity. It
was observed that a comparable product yield could be ob-
8
Pd(OAc)2
(5 mol%)
PTABS
(10 mol%)
PEG-400 70
9
Pd(OAc)2
(5 mol%)
PTABS
(10 mol%)
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
70
70
70
70
70
70
70
60
50
30
60
60
60
60
60
60
10
11
12
13
14
15c
16
17
18
19d
20e
21f
22g
23h
24i
Pd(OAc)2
(3 mol%)
PTABS
(6 mol%)
Pd(OAc)2
(2 mol%)
PTABS
(4 mol%)
Pd(OAc)2
(1 mol%)
PTABS
(2 mol%)
Pd(OAc)2
(2 mol%)
PTABS
(4 mol%)
Pd(OAc)2
(2 mol%)
PTABS
(4 mol%)
Pd(OAc)2
(2 mol%)
PTABS
(4 mol%)
Pd(OAc)2
(2 mol%)
PTABS
(4 mol%)
82
64
0
Pd(OAc)2
(2 mol%)
PTABS
(4 mol%)
Pd(OAc)2
(2 mol%)
PTABS
(4 mol%)
Pd(OAc)2
(2 mol%)
PTABS
(4 mol%)
45
70
40
55
45
75
Pd(OAc)2
(2 mol%)
PTABS
(4 mol%)
Pd(OAc)2
(2 mol%)
PTABS
(4 mol%)
Pd(OAc)2
(2 mol%)
PTABS
(4 mol%)
Pd(OAc)2
(2 mol%)
PTABS
(4 mol%)
Pd(OAc)2
(2 mol%)
PTABS
(4 mol%)
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–J

D
S. Bhilare et al.
Paper
Synthesis
tained at 60 °C (entry 16) and any further reduction had a
detrimental effect on the yield of the amide product (en-
tries17 and 18). Next, we turned our attention towards op-
timization of the base. A series of catalytic reactions with
different bases, namely Et3N, DIPEA and DBU (organic solu-
ble bases), as well as some inorganic bases, viz. K2CO3 and
Cs2CO3were carried out (entries 19–22). In spite of the wide
range of bases analyzed, Et3N provided the optimum result
in terms of yield. It is also worth noting that the addition of
excess of base (10 equiv) is required to keep the reaction
medium basic and avoid deprotection of the DMT group.43
With the reaction parameters having been optimized,
studies on the scope of the process were undertaken for the
synthesis of several nucleoside-based amides by incorpo-
rating a variety of different amines. Various benzyl, het-
eroaryl, acyclic and cyclic alkyl amines were utilized and
were proficiently transformed into the desired products
3a–v in good to excellent yields (Scheme 2). Initially, simple
amines such as benzylamine, 1-naphthylmethylamine,
4-fluorobenzylamine, 4-methoxybenzylamine and phen-
ethylamine were utilized, providing access to a variety of
amino-carbonylated products (3a–e) in excellent yields.
Dopamine dimethoxide (used for the treatment of hypoten-
sion),44 3,3-diphenylpropan-1-amine (used as an internal
standard for simultaneous determination of D- and L-
modafinil in human plasma using stereospecific high-per-
formance liquid chromatography and which has an antiex-
tensor effect and worsens chronic seizure produced by pen-
tylenetetrazole),45 and (R)-1-phenylethan-1-amine (a hu-
man metabolite)46 were also incorporated onto the
nucleoside backbone of 1a using the developed protocol to
afford the corresponding products 3f–h in excellent yields.
The encouraging results obtained with the benzyl-
amines inspired us to employ heteroaryl methyl- and ethyl-
amine(s), which furnished the carboxyamide products 3i–n
in good to excellent yields, especially that of 2-thiophene
ethanamine 3l (82%). Histamine47 (a nitrogenous com-
pound involved in local immune responses, as well as regu-
lating physiological function in the gut and acting as a neu-
rotransmitter for the brain, spinal cord, and uterus) was
also employed and the corresponding product 3m was ob-
tained in a good yield of 78%. The amide of histamine is of
particular importance as of the 2 competitive N–H groups,
only the primary aliphatic amine reacted. Also, the second
N–H group may provide an additional H-bonding site.29
Next, alicyclic amines such as cyclohexyl, cyclopentyl and
adamantyl amines were tested, providing the correspond-
ing products 3o–q in good yields. Aliphatic long-chain
amines such as decylamine and oleylamine (a surfactant;
coordinates with metal ions, changes the form of metal pre-
cursors and affects the formation kinetics of nanoparticles
during synthesis)48 were next to be used as the amine coun-
terparts, providing good yields of the carboamidation prod-
ucts 3r and 3s. Lastly, we employed this protocol for the
O
O
N
Pd(OAc)2 (2 mol%)
PTABS (4 mol%)
O
R
R
I
NH
NH2
N
NH
+
H
Et3N (10 equiv), DMF
CO (40 psi), 60 °C, 24 h
O
N
O
3
dR
2
dR
1
DMTO
O
dR =
OH
A) Benzylic and related amines
O
O
O
O
N
H
NH
O
O
N
NH
H
F
N
O
N
NH
N
O
H
dR
3c (80%)
dR
N
O
OMe
3b (75%)
dR
MeO
O
O
O
3a (82%)
O
N
H
NH
O
O
N
H
NH
N
O
N
H
NH
N
O
dR
dR
3e (86%)
MeO
Ph
N
O
3f (69%)
3d (82%)
dR
O
O
N
O
O
N
H
NH
O
Ph
N
NH
H
N
dR
O
dR
3h (84%)
3g (85%)
B) Heterocycle-containing amines
O
O
N
O
O
O
O
N
N
NH
O
N
NH
N
NH
H
H
H
O
S
N
N
O
O
dR
3j (80%)
dR
3i (80%)
dR
3k (78%)
N
O
O
O
O
O
O
O
N
S
N
NH N
H
O
N
NH
N
NH
H
H
H
N
N
O
N
O
dR
3m (78%)
3l (82%)
dR
3n (78%)
dR
C) Aliphatic alicyclic amines
O
O
O
O
N
O
O
N
NH
N
NH
H
H
N
H
NH
N
O
O
N
O
dR
3p (68%)
dR
dR
3o (69%)
3q (75%)
O
D) Aliphatic acyclic amines
O
N
H
NH
O
O
O
N
3s (82%)
dR
N
H
NH
N
R
O
3r (76%)
E) Secondary amines
O
O
O
O
O
N
O
N
N
NH
O
N
NH
NH
O
N
N
O
O
dR
dR
3t (72%)
dR
3u (75%)
3v (82%)
Scheme 2 Reaction conditions: 1a (1 mmol), amine 2 (2 mmol),
Pd(OAc)2 (2 mol%), PTABS (4 1mol%), Et3N (10 equiv), DMF (10 mL), CO
(40 psi), 60 °C, 24 h.
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–J

E
S. Bhilare et al.
Paper
Synthesis
synthesis of amides using secondary amines, namely piper-
idine, pyrrolidine and morpholine, with the expected prod-
ucts 3t–v being obtained in good to excellent yields.
Moclobemide was obtained via one step in an excellent 94%
yield (Scheme 4). Additionally, the three-component reac-
tion between 3-bromopyridine (6a), N,N′-diethylamine
(6b) and CO was also successful in producing the corre-
sponding amide, commonly known as nikethamide (6c)52 in
92% yield (Scheme 4). Nikethamide is a stimulant which
mainly affects the respiratory cycle and is widely known by
its former trade name, coramine, which was used in the
Encouraged by these results, the utility of the present
chemistry was highlighted by demonstrating the successful
installation of an amide functionality on a purine structural
motif towards the synthesis of the precursor of the bioac-
tive molecule sangivamycin,15 a naturally occurring nucleo-
side analog that inhibits protein kinase C activity. A recent
report also indicated that this compound is currently un-
dergoing third-phase clinical trials.49 The synthesis of the
sangivamycin precursor also exhibits excellent regio- and
mid-twentieth century as
a medical countermeasure
against tranquilizer overdoses.
Pd(OAc)2 (2 mol%)
PTABS (4 mol%)
O
O
I
+
NH2
N
N
N
chemoselectivity between amination of
a chlorohet-
H
O
Et3N (10 equiv), DMF
CO (40 psi)
eroarene41 and carbonylative amidation. The synthesis is
initiated by the iodination of 6-chloro-7-deazapurine (4a)
to yield 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (4b).
This was followed by tosylation of 4b using an N-tosylation
procedure reported in the literature.50 The corresponding
N-tosyl-6-chloro-7-iodo-7-deazapurine (4c) was then used
for the final step. This involved one-pot amination of the 6-
chloro group and amidation of the 7-iodo group using the
Pd(OAc)2/PTABS catalytic system, benzylamine as the nu-
cleophile and CO (40 psi) in an autoclave to yield the pre-
cursor 4d in 80% yield (Scheme 3).
Cl
Cl
60 °C, 24 h
5a
5b
5c (94%)
Pd(OAc)2 (2 mol%)
PTABS (4 mol%)
O
N
Br
H
N
+
Et3N (10 equiv), DMF
CO (40 psi), 60 °C, 24 h
N
N
6a
6b
6c (92%)
Scheme 4 Synthesis of drug molecules: moclobemide and niketh-
amide
Cl
Cl
Cl
I
I
NaH (1.2 equiv)
In conclusion, we have demonstrated that the Pd/PTABS
catalytic system promotes the efficient carbonylative ami-
dation of nucleoside 1a with amines at a relatively low tem-
perature. A wide spectrum of amines can be used, including
heteroaryl benzyl amines, aliphatic acyclic and alicyclic
amines and secondary amines. The synthetic potential of
the catalytic system was further explored for the regiose-
lective and chemoselective palladium-catalyzed amination
and amidation of 4b in order to synthesize the precursor of
sangivamycin. Finally, the catalytic system was also ex-
plored towards the synthesis of two drug molecules, mo-
clobemide and nikethamide. In summary, we have dis-
closed a mild catalytic system with the potential for gener-
ating a library of amide-containing nucleosides, which
could be utilized for in vitro selection of DNA. This work
will be extended to the synthesis of modified oligonucleo-
tides and studies toward this goal are currently in progress.
NIS (1.1 equiv)
N
N
N
TsCl (1.2 equiv)
0 °C, 1 h, 59%
DMF, 0 °C to rt
8 h, 92%
N
Ts
N
N
N
N
N
H
H
4a
4c
4b
Pd(OAc)2 (2 mol%)
PTABS (4 mol%)
Ph
NH2
O
NH2
N
H2N
(3.0 equiv)
Et3N (4.0 equiv), DMF
CO (40 psi), 60 °C, 24 h
Ph
N
N
H
O
HO
NH
N
N
O
Ph
N
OH OH
sangivamycin
N
Ts
4d (80%)
Scheme 3 Synthesis of sangivamycin precursor 4d
Next, to increase the substrate scope, we employed oth-
er sugar-protected and unprotected nucleosides such as 5-
iodo-2′-deoxycytidine (5-IdC), 8-bromo-2′-deoxyadenosine
(8-BrdA), 8-bromo-2′-deoxyguanosine (8-BrdG) and 2′-de-
oxy-5-iodo-3′,5′-O-[1,1,3,3-tetrakis(1-methylethyl)-1,3-
disiloxanediyl]uridine (see the Supporting Information).
However, positive results were not obtained under the opti-
mized conditions.
To showcase the versatility of the developed protocol,
moclobemide51 (5c), a reversible monoamine-oxidase-A
(RIMA) inhibitor and an antidepressant drug having reac-
tive oxygen and tertiary amine functions, was synthesized
by employing the developed aminocarbonylation protocol.
Unless mentioned otherwise, all materials and solvents were ob-
tained commercially and used without further purification. All exper-
iments were performed under a nitrogen atmosphere. The high-pres-
sure reactions were performed using an autoclave (Amar Equipments
made autoclave of 100 mL size) in a fume hood. Column chromatogra-
phy was performed using Merck silica gel (60–120 mesh size). Optical
rotations were measured on a Rudolph AUTOPOL IV polarimeter at
20 °C. 1H NMR and 13C NMR spectra were recorded at 500 MHz and
126 MHz, respectively, on an Agilent 500 MHz instrument. An Ele-
mentar Vario MICRO cube was used for the experimental determina-
tion of elemental compositions of the final pure products. HPLC anal-
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–J

F
S. Bhilare et al.
Paper
Synthesis
yses were obtained using an Agilent 1260 Infinity instrument. Sepa-
ration was achieved using a Daicel CHIRALPAK AD-H column, a flow
rate of 1 mL/min and hexane/IPA (80:20) as the eluent.
4.07 (d, J = 5.3 Hz, 1 H), 3.94–3.89 (m, 1 H), 3.75–3.62 (m, 6 H), 3.14
(dd, J = 9.3, 8.1 Hz, 2 H), 2.27 (dd, J = 15.2, 4.0 Hz, 1 H), 2.23–2.17 (m, 1
H).
13C NMR (126 MHz, DMSO-d6):  = 163.3, 161.7, 161.4 (d, J = 243.1
Hz), 158.2, 149.6, 145.8, 145.0, 135.6, 135.5, 129.9, 129.8, 129.5 (d,
J = 8.1 Hz), 127.9 (d, J = 21.4 Hz), 126.8, 115.3, 115.1, 113.4, 105.3,
86.2, 86.1, 85.9, 70.6, 63.8, 55.1, 41.6.
Carbonylative Amidation; General Procedure
5′-O-(4,4′-Dimethoxytrityl)-5-iodo-2′-deoxyuridine
(5′-O-DMT-5-
IdU) (1a) (1.0 mmol, 656mg), the corresponding amine 2 (2.0 mmol),
Pd(OAc)2 (2 mol%), PTABS ligand (4 mol%), Et3N (10 mmol) and N2-
purged DMF (10 mL) were added to a 100 mL stainless steel autoclave
reaction flask at room temperature. The autoclave was closed and
flushed with nitrogen gas and then pressurized with CO gas (40 psi).
Caution! Carbon monoxide (CO) is an odorless, colorless and highly
toxic gas. The reactions should be carried out in efficient fume hoods
fitted with CO detectors. The reaction mixture was stirred with a me-
chanical stirrer (500 rpm) and heated at 60 °C for 24 h. The mixture
was then allowed to cool to room temperature and the CO was vented
carefully in a fume hood by adding KMnO4 solution. The reaction
mass was diluted in cold water and subsequently extracted with EtO-
Ac (3 × 25 mL). The combined organic layer was dried over Na2SO4 and
concentrated in vacuo. A slurry was prepared from the residue using
silica gel and the product was isolated by column chromatography
(60–120 neutralized silica gel; CHCl3/MeOH/Et3N, 97.5:2.0:0.5).
19F NMR (471 MHz, DMSO-d6):  = –116.0.
Anal. Calcd for C38H36FN3O8: C, 66.95; H, 5.32; N, 6.16. Found: C,
66.75; H, 5.22; N, 6.10.
N-(4-Methoxybenzyl)-5-carboxamide-5′-O-DMT-2′-deoxyuridine
(3d)
Yield: 568 mg (82%); off-white solid.
1H NMR (500 MHz, DMSO-d6):  = 8.99 (d, J = 6.0 Hz, 1 H), 8.47 (s, 1
H), 7.35 (d, J = 7.7 Hz, 2 H), 7.28–7.15 (m, 10 H), 6.85 (t, J = 8.5 Hz, 6
H), 6.06 (t, J = 6.4 Hz, 1 H), 5.35 (d, J = 4.6 Hz, 1 H), 4.41–4.35 (m, 2 H),
4.08 (dt, J = 9.1, 4.5 Hz, 1 H), 3.92 (dd, J = 8.7, 4.4 Hz, 1 H), 3.70 (s, 9 H),
3.17 (d, J = 4.4 Hz, 2 H), 2.28–2.18 (m, 2 H).
13C NMR (126 MHz, DMSO-d6):  = 163.6, 162.7, 161.7, 158.7, 158.4,
149.8, 146.0, 145.3, 135.8, 135.7, 131.5, 130.1, 129.1, 128.2, 127.0,
114.2, 113.6, 105.5, 86.4, 86.3, 86.1, 70.7, 64.0, 55.4, 42.0, 36.2.
N-Benzyl-5-carboxamide-5′-O-DMT-2′-deoxyuridine (3a)
Anal. Calcd for C39H39N3O9: C, 67.52; H, 5.67; N, 6.06. Found: C, 67.41;
H, 5.52; N, 5.98.
Yield: 544 mg (82%); white solid.
1H NMR (500 MHz, DMSO-d6):  = 9.05 (t, J = 6.6 Hz, 1 H), 8.43 (s, 1 H),
7.35–7.09 (m, 15 H), 6.83 (d, J = 8.7 Hz, 4 H), 6.03 (ddd, J = 6.9, 4.0, 1.8
Hz, 1 H), 5.33–5.26 (m, 1 H), 4.46–4.40 (m, 2 H), 4.09–4.02 (m, 1 H),
3.89 (s, 1 H), 3.67 (d, J = 1.7 Hz, 6 H), 3.16–3.12 (m, 2 H), 2.24–2.13 (m,
2 H).
13C NMR (126 MHz, DMSO-d6):  = 163.6, 161.9, 158.4, 149.8, 146.0,
145.2, 139.6, 135.7, 130.1, 130.0, 128.7, 128.2, 127.6, 127.3, 127.0,
113.6, 105.5, 86.4, 86.3, 86.1, 70.7, 64.0, 55.3, 46.1, 42.5.
N-Phenethyl-5-carboxamide-5′-O-DMT-2′-deoxyuridine (3e)
Yield: 582 mg (86%); white solid.
1H NMR (500 MHz, DMSO-d6):  = 11.93 (s, 1 H), 8.72 (t, J = 5.7 Hz, 1
H), 8.44 (s, 1 H), 7.35 (d, J = 7.4 Hz, 2 H), 7.27 (d, J = 7.9 Hz, 3 H), 7.26–
7.16 (m, 9 H), 6.87 (d, J = 8.4 Hz, 4 H), 6.05 (t, J = 6.4 Hz, 1 H), 5.35 (d,
J = 4.6 Hz, 1 H), 4.08 (td, J = 8.9, 4.4 Hz, 1 H), 3.91 (dd, J = 8.8, 4.4 Hz, 1
H), 3.70 (d, J = 1.1 Hz, 6 H), 3.50–3.44 (m, 2 H), 3.20–3.14 (m, 2 H),
2.76 (t, J = 7.2 Hz, 2 H), 2.28–2.24 (m, 1 H), 2.20 (dd, J = 13.4, 6.7 Hz, 1
H).
Anal. Calcd for C38H37N3O8: C, 68.77; H, 5.62; N, 6.33. Found: C, 68.59;
H, 5.52; N, 6.33.
13C NMR (126 MHz, DMSO-d6):  = 163.5, 161.7, 158.4, 149.8, 145.8,
145.3, 139.6, 135.9, 135.7, 130.1, 129.0, 128.8, 128.2, 127.0, 126.6,
113.6, 105.5, 86.3, 86.2, 86.1, 70.7, 63.9, 55.3, 40.6, 35.6.
N-(Naphthalen-1-ylmethyl)-5-carboxamide-5′-O-DMT-2′-deoxy-
uridine (3b)
Yield: 534 mg (75%); off-white solid.
Anal. Calcd for C39H39N3O8: C, 69.11; H, 5.80; N, 6.20. Found: C, 69.19;
H, 5.63; N, 6.03.
1H NMR (500 MHz, DMSO-d6):  = 9.14–9.08 (m, 1 H), 8.50 (dd, J = 4.7,
2.0 Hz, 1 H), 8.11–8.05 (m, 1 H), 7.96–7.90 (m, 1 H), 7.87–7.81 (m, 1
H), 7.56–7.47 (m, 2 H), 7.47–7.41 (m, 2 H), 7.41–7.34 (m, 2 H), 7.34–
7.19 (m, 7 H), 7.19–7.12 (m, 1 H), 6.90–6.81 (m, 4 H), 6.08–6.03 (m, 1
H), 5.40–5.26 (m, 1 H), 4.98–4.90 (m, 2 H), 4.11–4.06 (m, 1 H), 3.95–
3.91 (m, 1 H), 3.69–3.64 (m, 6 H), 3.19–3.16 (m, 2 H), 2.31–2.24 (m, 1
H), 2.23–2.16 (m, 1 H).
13C NMR (126 MHz, DMSO-d6):  = 163.7, 161.7, 158.45, 158.42,
149.8, 146.1, 145.3, 135.8, 135.7, 134.7, 133.7, 131.1, 130.2, 130.1,
129.0, 128.2, 128.1, 128.0, 126.8, 126.3, 125.9, 123.7, 113.6, 105.3,
86.5, 86.3, 86.1, 70.8, 64.0, 55.3, 55.3, 46.1.
N-(3,4-Dimethoxyphenethyl)-5-carboxamide-5′-O-DMT-2′-deoxy-
uridine (3f)
Yield: 589 mg (69%); white solid.
1H NMR (500 MHz, DMSO-d6):  = 8.71 (t, J = 5.6 Hz, 1 H), 8.44 (s, 1 H),
7.35 (d, J = 7.4 Hz, 2 H), 7.29–7.21 (m, 6 H), 7.18 (t, J = 7.3 Hz, 1 H),
6.87 (d, J = 8.1 Hz, 4 H), 6.83 (d, J = 8.2 Hz, 1 H), 6.81 (d, J = 1.8 Hz, 1
H), 6.71 (dd, J = 8.1, 1.8 Hz, 1 H), 6.05 (t, J = 6.4 Hz, 1 H), 5.35 (s, 1 H),
4.08 (s, 1 H), 3.93–3.90 (m, 1 H), 3.71 (t, J = 3.4 Hz, 6 H), 3.69 (d, J = 2.1
Hz, 6 H), 3.18–3.15 (m, 2 H), 2.69 (t, J = 7.0 Hz, 2 H), 2.64 (dd, J = 14.2,
7.1 Hz, 2 H), 2.28–2.24 (m, 1 H), 2.20 (dd, J = 13.3, 6.6 Hz, 1 H).
13C NMR (126 MHz, DMSO-d6):  = 163.5, 161.7, 158.4, 149.8, 149.0,
147.6, 145.8, 145.2, 135.9, 132.1, 130.2, 128.2, 127.0, 120.8, 113.6,
112.9, 112.3, 105.6, 86.3, 86.2, 86.1, 70.7, 63.9, 55.9, 55.7, 55.4, 46.1,
40.8, 35.16, 11.0.
Anal. Calcd for C42H39N3O8: C, 70.67; H, 5.51; N, 5.89. Found: C, 70.67;
H, 5.31; N, 5.63.
N-(4-Fluorobenzyl)-5-carboxamide-5′-O-DMT-2′-deoxyuridine
(3c)
Yield: 544 mg (80%); white solid.
Anal. Calcd for C41H43N3O10: C, 66.75; H, 5.87; N, 5.70. Found: C,
66.63; H, 5.63; N, 5.53.
1H NMR (500 MHz, DMSO-d6):  = 11.97 (s, 1 H), 9.07 (d, J = 5.5 Hz, 1
H), 8.45 (d, J = 2.4 Hz, 1 H), 7.39–7.04 (m, 13 H), 6.90–6.79 (m, 4 H),
6.05 (t, J = 5.9 Hz, 1 H), 5.38–5.34 (m, 1 H), 4.41 (d, J = 13.2 Hz, 2 H),
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–J

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S. Bhilare et al.
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Synthesis
N-(3,3-Diphenylpropyl)-5-carboxamide-5′-O-DMT-2′-deoxyuri-
dine (3g)
13C NMR (126 MHz, DMSO-d6):  = 163.5, 162.1, 158.4, 149.8, 149.2,
148.4, 146.1, 145.2, 135.8, 135.7, 135.6, 135.3, 130.1, 128.2, 127.0,
123.9, 113.6, 105.4, 86.4, 86.3, 86.1, 70.8, 64.0, 55.4, 46.0, 15.6, 9.0.
Yield: 650 mg (85%); white solid.
1H NMR (400 MHz, DMSO-d6):  = 8.69 (s, 1 H), 8.39 (s, 1 H), 7.45–
6.99 (m, 20 H), 6.89–6.78 (m, 4 H), 6.07–6.02 (m, 1 H), 5.39–5.31 (m, 1
H), 4.10–4.05 (m, 1 H), 3.95–3.89 (m, 2 H), 3.64 (s, 6 H), 3.14 (d, J = 3.2
Hz, 2 H), 2.98–2.90 (m, 4 H), 2.24–2.19 (m, 2 H).
Anal. Calcd for C37H36N4O8: C, 66.86; H, 5.46; N, 8.43. Found: C, 66.65;
H, 5.29; N, 8.12.
N-(Thiophen-2-ylmethyl)-5-carboxamide-5′-O-DMT-2′-deoxyuri-
dine (3k)
13C NMR (101 MHz, DMSO-d6):  = 163.6, 161.7, 158.4, 149.8, 145.7,
145.2, 145.2, 144.9, 135.8 (2 C), 130.1 (2 C), 128.8, 128.0 (2 C), 127.0,
126.5, 113.6, 105.6, 86.3, 86.2, 86.1, 70.8, 63.9, 55.3, 48.6, 40.4, 37.8,
34.9.
Yield: 521 mg (78%); off-white solid.
1H NMR (400 MHz, DMSO-d6):  = 9.11–9.04 (m, 1 H), 8.45 (s, 1 H),
7.38–7.31 (m, 3 H), 7.28–7.14 (m, 8 H), 7.00–6.89 (m, 2 H), 6.85 (d,
J = 8.7 Hz, 4 H), 6.04 (t, J = 6.1 Hz, 1 H), 5.35–5.28 (m, 1 H), 4.59 (t,
J = 7.6 Hz, 2 H), 4.12–4.04 (m, 1 H), 3.95–3.86 (m, 1 H), 3.69 (s, 6 H),
3.23–3.10 (m, 2 H), 2.29–2.09 (m, 2 H).
Anal. Calcd for C46H45N3O8: C, 71.95; H, 5.91; N, 5.47. Found: C, 71.73;
H, 5.86; N, 5.37.
N-[(R)-1-Phenylethyl)-5-carboxamide-5′-O-DMT-2′-deoxyuridine
(3h)
Yield: 568 mg (84%); off-white solid; []D20 +8.088 (c 1.0, MeOH).
13C NMR (101 MHz, DMSO-d6):  = 163.5, 161.7, 158.4, 149.7, 146.1,
145.2, 142.3, 135.9, 130.2, 128.2, 128.1, 127.1, 127.0, 126.1, 125.6,
113.6, 105.3, 86.6, 86.3, 85.1, 70.7, 64.0, 55.4, 46.1, 37.5.
1H NMR (500 MHz, DMSO-d6):  = 9.11 (d, J = 7.8 Hz, 1 H), 8.39 (s, 1
H), 7.42–7.27 (m, 7 H), 7.26–7.20 (m, 7 H), 7.15 (dd, J = 10.4, 4.2 Hz, 1
H), 6.87–6.82 (m, 4 H), 6.07 (t, J = 6.4 Hz, 1 H), 5.44–5.30 (m, 1 H), 5.07
(dd, J = 14.4, 7.1 Hz, 1 H), 4.08 (dd, J = 10.6, 4.4 Hz, 1 H), 3.91 (dd,
J = 9.3, 4.3 Hz, 1 H), 3.69 (s, 6 H), 3.18–3.11 (m, 2 H), 2.25 (ddd,
J = 13.5, 6.3, 4.4 Hz, 1 H), 2.18 (dt, J = 13.4, 6.5 Hz, 1 H), 1.43 (d, J = 6.9
Hz, 3 H).
13C NMR (126 MHz, DMSO-d6):  = 163.9, 161.0, 158.4, 149.9, 145.9,
145.3, 144.4, 135.9, 135.7, 130.2, 128.8, 128.2, 127.3, 127.0, 126.2,
113.6, 105.4, 86.3, 86.2, 86.1, 70.7, 64.0, 55.3, 48.4, 22.9.
Anal. Calcd for C36H35N3O8S: C, 64.56; H, 5.27; N, 6.27; S, 4.79. Found:
C, 64.43; H, 5.37; N, 6.17; S, 4.58.
N-[2-(Thiophen-2-yl)ethyl]-5-carboxamide-5′-O-DMT-2′-deoxy-
uridine (3l)
Yield: 560 mg (82%); off-white solid.
1H NMR (500 MHz, DMSO-d6):  = 11.93 (s, 1 H), 8.81 (t, J = 5.9 Hz, 1
H), 8.44 (s, 1 H), 7.36–7.33 (m, 2 H), 7.31 (dd, J = 5.1, 1.2 Hz, 1 H),
7.29–7.21 (m, 6 H), 7.20–7.16 (m, 1 H), 6.92 (dd, J = 5.1, 3.4 Hz, 1 H),
6.86 (dd, J = 6.6, 1.8 Hz, 5 H), 6.05 (t, J = 6.4 Hz, 1 H), 5.34 (d, J = 4.6 Hz,
1 H), 4.07 (dq, J = 6.4, 4.4 Hz, 1 H), 3.91 (q, J = 4.5 Hz, 1 H), 3.70 (s, 6
H), 3.52–3.46 (m, 2 H), 3.16 (d, J = 4.5 Hz, 2 H), 2.98 (t, J = 7.0 Hz, 2 H),
2.28–2.23 (m, 1 H), 2.20 (dd, J = 13.5, 6.7 Hz, 1 H).
13C NMR (126 MHz, DMSO-d6):  = 163.4, 161.8, 158.4, 149.8, 145.9,
145.3, 141.7, 135.9, 130.2, 128.2, 128.0, 127.4,, 127.0, 125.6, 124.5,
113.6, 105.5, 86.4, 86.2, 86.1, 70.7, 64.0, 55.3, 40.7, 36.2, 29.7.
Anal. Calcd for C39H39N3O8: C, 69.11; H, 5.80; N, 6.20. Found: C, 69.01;
H, 5.80; N, 6.10.
Chiral HPLC analysis [CHIRALPAK AD-H, hexane/IPA (80:20), flow rate
1 mL min−1, 250 nm, 25 °C]: tR = 19.68 min; ee 100%.
N-(Furan-2-ylmethyl)-5-carboxamide-5′-O-DMT-2′-deoxyuridine
(3i)
Anal. Calcd for C, 64.99; H, 5.45; N, 6.15; S, 4.69. Found: C, 64.78; H,
5.32; N, 6.10; S, 4.51.
Yield: 522 mg (80%); white solid.
1H NMR (400 MHz, DMSO-d6):  = 11.94 (s, 1 H), 8.98–8.93 (m, 1 H),
8.43 (s, 1 H), 7.54 (s, 1 H), 7.33 (d, J = 7.4 Hz, 2 H), 7.28–7.19 (m, 6 H),
7.18–7.14 (m, 1 H), 6.90–6.80 (m, 4 H), 6.38–6.33 (m, 1 H), 6.22 (t,
J = 4.5 Hz, 1 H), 6.04 (q, J = 5.8 Hz, 1 H), 5.30 (q, J = 6.1 Hz, 1 H), 4.48–
4.41 (m, 2 H), 4.08 (td, J = 6.3, 4.0 Hz, 1 H), 3.93–3.87 (m, 1 H), 3.69 (s,
6 H), 3.20–3.10 (m, 2 H), 2.26–2.14 (m, 2 H).
13C NMR (126 MHz, DMSO-d6):  = 163.6, 161.7, 158.4, 152.3, 149.8,
146.1, 145.3, 142.7, 135.8, 130.2, 128.2, 128.0, 127.0, 113.6, 110.9,
107.4, 105.2, 86.4, 86.2, 86.1, 70.7, 64.0, 55.4, 55.3, 35.8.
N-[2-(1H-Imidazol-5-yl)ethyl]-5-carboxamide-5′-O-DMT-2′-de-
oxyuridine (3m)
Yield: 520 mg (78%); off-white solid.
1H NMR (500 MHz, DMSO-d6):  = 11.60 (d, J = 0.6 Hz, 1 H), 7.74 (s, 1
H), 7.35 (d, J = 7.3 Hz, 2 H), 7.31–7.16 (m, 8 H), 6.86 (d, J = 8.0 Hz, 4 H),
6.12 (t, J = 5.9 Hz, 1 H), 5.36 (s, 1 H), 4.27 (s, 1 H), 3.90 (s, 1 H), 3.71 (s,
6 H), 3.23–3.19 (m, 1 H), 3.06 (d, J = 8.0 Hz, 1 H), 2.73 (d, J = 9.8 Hz, 6
H), 2.22 (s, 2 H).
13C NMR (126 MHz, DMSO-d6):  = 164.0, 160.6, 158.4, 150.2, 145.1,
140.3, 136.0, 135.7, 130.0, 128.3, 128.0, 127.1, 127.0, 113.6, 112.5,
86.2, 86.1, 85.3, 70.9, 64.1, 55.5, 46.1, 38.2, 34.9, 9.0.
Anal. Calcd for C36H35N3O9: C, 66.15; H, 5.40; N, 6.43. Found: C, 65.95;
H, 5.26; N, 6.33.
N-(Pyridin-3-ylmethyl)-5-carboxamide-5′-O-DMT-2′-deoxyuri-
dine (3j)
Anal. Calcd for C36H37N5O8: C, 64.76; H, 5.59; N, 10.49. Found: C,
64.64; H, 5.45; N, 10.52.
Yield: 530 mg (80%); white solid.
N-(2-Morpholinoethyl)-5-carboxamide-5′-O-DMT-2′-deoxyuri-
dine (3n)
1H NMR (500 MHz, DMSO-d6):  = 11.98 (s, 1 H), 9.15 (t, J = 6.1 Hz, 1
H), 8.51 (d, J = 1.7 Hz, 1 H), 8.46 (s, 1 H), 8.43 (dd, J = 4.7, 1.3 Hz, 1 H),
7.65 (d, J = 7.8 Hz, 1 H), 7.34 (d, J = 7.5 Hz, 2 H), 7.29 (dd, J = 7.8, 4.8
Hz, 1 H), 7.27–7.21 (m, 6 H), 7.16 (t, J = 7.3 Hz, 1 H), 6.86 (s, 2 H), 6.84
(s, 2 H), 6.06 (t, J = 6.4 Hz, 1 H), 5.35 (d, J = 4.4 Hz, 1 H), 4.51–4.45 (m,
2 H), 4.08 (dt, J = 8.4, 4.2 Hz, 1 H), 3.92 (q, J = 4.4 Hz, 1 H), 3.69 (d,
J = 2.4 Hz, 6 H), 3.16 (d, J = 4.6 Hz, 2 H), 2.27 (ddd, J = 10.4, 6.3, 4.4 Hz,
1 H), 2.23–2.17 (m, 1 H).
Yield: 535 mg (78%); white solid.
1H NMR (500 MHz, DMSO-d6):  = 11.99–11.88 (m, 1 H), 8.86 (t,
J = 5.3 Hz, 1 H), 8.43 (s, 1 H), 7.34 (dd, J = 8.4, 1.0 Hz, 2 H), 7.24 (ddd,
J = 10.8, 8.7, 4.8 Hz, 6 H), 7.20–7.16 (m, 1 H), 6.86 (dd, J = 8.9, 1.4 Hz, 4
H), 6.06 (t, J = 6.4 Hz, 1 H), 5.36 (d, J = 4.5 Hz, 1 H), 4.08 (dt, J = 8.9, 4.3
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Hz, 1 H), 3.91 (dd, J = 8.6, 4.4 Hz, 1 H), 3.71 (d, J = 1.1 Hz, 6 H), 3.54 (s,
4 H), 3.18–3.13 (m, 2 H), 2.52–2.46 (m, 2 H), 2.46–2.29 (m, 6 H), 2.29–
2.24 (m, 1 H), 2.22–2.16 (m, 1 H).
4.11–4.03 (m, 1 H), 3.89 (d, J = 3.4 Hz, 1 H), 3.67 (s, 6 H), 3.17 (dd,
J = 11.9, 7.2 Hz, 4 H), 2.23 (s, 1 H), 2.16 (d, J = 6.3 Hz, 1 H), 1.40 (d,
J = 3.8 Hz, 2 H), 1.17 (s, 18 H).
13C NMR (126 MHz, DMSO-d6):  = 163.4, 161.7, 158.4, 149.8, 145.7,
145.2, 135.9, 130.0, 128.2, 128.0, 127.0, 113.6, 105.6, 86.3, 86.2, 86.1,
70.7, 66.5, 63.9, 57.1, 55.4, 53.4, 45.9, 35.8.
13C NMR (101 MHz, DMSO-d6):  = 163.6, 161.6, 158.4, 149.8, 145.6,
145.2, 135.9, 135.7, 130.1, 128.2, 126.9, 113.6, 105.7, 86.3, 86.2, 86.1,
70.7, 63.9, 55.3, 38.8, 31.7, 29.5, 29.4, 29.3, 29.1, 26.8, 22.5, 14.3.
Anal. Calcd for C37H42N4O9: C, 64.71; H, 6.16; N, 8.16. Found: C, 64.56;
H, 6.12; N, 8.02.
Anal. Calcd for C41H51N3O8: C, 68.98; H, 7.20; N, 5.89. Found: C, 68.78;
H, 7.01; N, 5.71.
N-Cyclohexyl-5-carboxamide-5′-O-DMT-2′-deoxyuridine (3o)
N-Oleyl-5-carboxamide-5′-O-DMT-2′-deoxyuridine (3s)
Yield: 457 mg (69%); off-white solid.
Yield: 675 mg (82%); off-white solid.
1H NMR (400 MHz, DMSO-d6):  = 11.95–11.88 (m, 1 H), 8.66 (ddd,
J = 5.7, 5.2, 2.1 Hz, 1 H), 8.40 (s, 1 H), 7.38–7.29 (m, 2 H), 7.29–7.14 (m,
7 H), 6.90–6.79 (m, 4 H), 6.07–6.02 (m, 1 H), 5.31 (d, J = 3.6 Hz, 1 H),
4.11–4.04 (m, 1 H), 3.89 (ddd, J = 5.5, 2.9, 2.1 Hz, 1 H), 3.70 (s, 6 H),
3.18–3.10 (m, 2 H), 2.25–2.12 (m, 2 H), 1.81–1.72 (m, 2 H), 1.61 (dd,
J = 12.2, 5.1 Hz, 2 H), 1.52–1.46 (m, 1 H), 1.36–1.12 (m, 6 H).
13C NMR (101 MHz, DMSO-d6):  = 163.8, 160.7, 158.4, 149.8, 145.7,
145.3, 135.9, 135.7, 130.2, 128.2, 127.0, 113.7, 105.7, 86.3, 86.2, 86.1,
70.7, 64.0, 55.4, 47.4, 36.2, 32.7, 25.6, 24.5.
1H NMR (500 MHz, DMSO-d6):  = 11.94 (s, 1 H), 8.66 (t, J = 5.6 Hz, 1
H), 8.43 (s, 1 H), 7.34 (d, J = 7.9 Hz, 2 H), 7.21 (ddd, J = 30.6, 14.0, 7.3
Hz, 7 H), 6.89–6.81 (m, 4 H), 6.06 (t, J = 6.4 Hz, 1 H), 5.35–5.24 (m, 3
H), 4.08 (dt, J = 8.5, 4.2 Hz, 1 H), 3.91 (dd, J = 8.5, 4.3 Hz, 1 H), 3.70 (s, 6
H), 3.21 (dd, J = 12.7, 6.4 Hz, 2 H), 3.16 (d, J = 4.1 Hz, 2 H), 2.29–2.22
(m, 1 H), 2.22–2.14 (m, 1 H), 2.00–1.85 (m, 4 H), 1.42 (d, J = 5.7 Hz, 2
H), 1.20 (s, 22 H), 0.81 (t, J = 5.7 Hz, 3 H).
13C NMR (126 MHz, DMSO-d6):  = 163.6, 161.6, 158.4, 149.8, 145.7,
145.2, 135.9, 135.7, 130.2, 130.0, 128.0, 127.0, 113.6, 105.7, 86.3, 86.2,
86.1, 70.7, 63.9, 55.3, 38.8, 32.3, 31.7, 29.5, 29.2, 29.1, 29.0, 27.0, 26.8,
22.5, 14.3.
Anal. Calcd for C37H41N3O8: C, 68.77; H, 5.62; N, 6.33. Found: C, 68.58;
H, 5.52; N, 6.38.
Anal. Calcd for C49H65N3O8: C, 71.42; H, 7.95; N, 5.10. Found: C, 71.26;
H, 7.79; N, 5.19.
N-Cyclypentyl-5-carboxamide-5′-O-DMT-2′-deoxyuridine (3p)
Yield: 435 mg (68%); off-white solid.
5-(Piperidine)-carboxamide-5′-O-DMT-2′-deoxyuridine (3t)
1H NMR (400 MHz, DMSO-d6):  = 11.98–11.86 (m, 1 H), 8.69–8.62
(m, 1 H), 8.39 (s, 1 H), 7.37–7.30 (m, 2 H), 7.29–7.12 (m, 7 H), 6.90–
6.79 (m, 4 H), 6.08–6.02 (m, 1 H), 5.35–5.29 (m, 1 H), 4.15–4.04 (m, 2
H), 3.93–3.87 (m, 1 H), 3.70 (s, 6 H), 3.19–3.10 (m, 2 H), 2.27–2.15 (m,
2 H), 1.90–1.79 (m, 2 H), 1.58 (ddd, J = 21.2, 13.8, 8.1 Hz, 4 H), 1.43–
1.33 (m, 2 H).
13C NMR (101 MHz, DMSO-d6):  = 163.7, 161.1, 158.4, 149.8, 145.6,
145.2, 135.9, 130.1, 128.2, 127.0, 113.6, 105.6, 86.3, 86.2, 85.1, 70.8,
64.0, 55.4, 50.7, 33.1, 33.0, 23.7.
Yield: 461 mg (72%); white solid.
1H NMR (500 MHz, DMSO-d6):  = 11.58 (s, 1 H), 7.66 (s, 1 H), 7.34 (d,
J = 7.4 Hz, 2 H), 7.28 (t, J = 7.7 Hz, 2 H), 7.24–7.18 (m, 5 H), 6.87 (d,
J = 8.3 Hz, 4 H), 6.11 (t, J = 6.7 Hz, 1 H), 5.33 (t, J = 4.6 Hz, 1 H), 4.22 (dt,
J = 9.1, 4.6 Hz, 1 H), 3.90–3.87 (m, 1 H), 3.72 (d, J = 0.5 Hz, 6 H), 3.49–
3.35 (m, 2 H), 3.28–3.06 (m, 5 H), 1.51–1.24 (m, 7 H).
13C NMR (126 MHz, DMSO-d6):  = 162.3, 160.7, 158.4, 150.2, 145.1,
139.7, 136.0, 130.0, 128.3, 128.0, 127.0, 113.6, 112.4, 86.2, 86.1, 85.3,
79.6, 70.9, 64.1, 55.4, 47.9, 42.4, 26.2, 25.4, 24.2.
Anal. Calcd for C36H39N3O8: C, 67.38; H, 6.13; N, 6.55. Found: C, 67.16;
H, 6.05; N, 6.27.
Anal. Calcd for C36H39N3O8: C, 67.38; H, 6.13; N, 6.55. Found: C, 67.45;
H, 6.20; N, 6.45.
N-Adamantyl-5-carboxamide-5′-O-DMT-2′-deoxyuridine (3q)
5-(Pyrrolidine)-carboxamide-5′-O-DMT-2′-deoxyuridine (3u)
Yield: 530 mg (75%); off-white solid.
Yield: 470 mg (75%); off-white solid.
1H NMR (500 MHz, DMSO-d6):  = 11.91 (s, 1 H), 8.56 (s, 1 H), 8.39 (d,
J = 3.0 Hz, 1 H), 7.35 (d, J = 7.9 Hz, 2 H), 7.31–7.20 (m, 6 H), 7.20–7.16
(m, 1 H), 6.87 (d, J = 8.8 Hz, 4 H), 6.05 (t, J = 6.4 Hz, 1 H), 5.35–5.31 (m,
1 H), 4.11–4.05 (m, 1 H), 3.93–3.88 (m, 1 H), 3.71 (d, J = 2.6 Hz, 6 H),
3.17 (d, J = 4.1 Hz, 2 H), 2.29–2.23 (m, 1 H), 2.21–2.15 (m, 1 H), 1.95
(dd, J = 3.7 Hz, 9 H), 1.65–1.55 (m, 6 H).
13C NMR (126 MHz, DMSO-d6):  = 163.8, 160.4, 158.4, 149.8, 145.5,
145.2, 135.7, 130.1, 128.2, 128.0, 127.0, 113.6, 106.1, 86.26, 86.22,
86.1, 70.7, 64.0, 55.3, 51.1, 42.4, 41.6, 36.5, 36.3, 29.3, 29.2.
1H NMR (500 MHz, DMSO-d6):  = 11.62 (s, 1 H), 7.76 (s, 1 H), 7.34 (d,
J = 7.5 Hz, 2 H), 7.27 (t, J = 7.7 Hz, 2 H), 7.21 (ddd, J = 17.7, 10.7, 6.0 Hz,
5 H), 6.89–6.83 (m, 4 H), 6.11 (t, J = 6.7 Hz, 1 H), 5.34 (d, J = 4.4 Hz, 1
H), 4.24 (dt, J = 9.1, 4.4 Hz, 1 H), 3.91–3.88 (m, 1 H), 3.71 (s, 6 H), 3.25–
3.15 (m, 4 H), 3.09–3.05 (m, 2 H), 2.25–2.19 (m, 2 H), 1.70–1.58 (m, 4
H).
13C NMR (126 MHz, DMSO-d6):  = 162.2, 160.4, 158.4, 150.1, 145.1,
140.5, 135.9, 130.0, 128.3, 128.0, 127.0, 113.6, 113.2, 86.2, 86.1, 85.3,
70.9, 64.1, 55.4, 47.3, 45.9, 36.2, 25.7, 24.2.
Anal. Calcd for C41H45N3O8: C, 69.57; H, 6.41; N, 5.94. Found: C, 69.53;
H, 6.27; N, 5.69.
Anal. Calcd for C35H37N3O8: C, 66.97; H, 5.94; N, 6.69. Found: C, 66.88;
H, 5.87; N, 6.85.
N-n-Decyl-5-carboxamide-5′-O-DMT-2′-deoxyuridine (3r)
5-(Morpholine)-carboxamide-5′-O-DMT-2′-deoxyuridine (3v)
Yield: 541 mg (76%); off-white solid.
Yield: 527 mg (82%); off-white solid.
1H NMR (400 MHz, DMSO-d6):  = 11.89 (ddd, J = 11.4, 8.7, 4.2 Hz, 1
H), 8.63 (s, 1 H), 8.40 (s, 1 H), 7.31 (d, J = 7.1 Hz, 2 H), 7.25–7.13 (m, 6
H), 6.82 (d, J = 8.4 Hz, 4 H), 6.06–6.00 (m, 1 H), 5.32 (d, J = 3.5 Hz, 1 H),
1H NMR (400 MHz, DMSO-d6):  = 11.58 (s, 1 H), 7.77–7.72 (m, 1 H),
7.35–7.16 (m, 9 H), 6.85 (d, J = 8.6 Hz, 4 H), 6.09 (dt, J = 11.2, 5.5 Hz, 1
H), 5.29 (dd, J = 8.3, 4.3 Hz, 1 H), 4.19 (dd, J = 10.9, 7.6 Hz, 1 H), 4.04–
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3.94 (m, 1 H), 3.90–3.84 (m, 1 H), 3.70 (s, 6 H), 3.47–3.40 (m, 2 H),
3.20–3.03 (m, 4 H), 2.24–2.14 (m, 2 H), 1.98–1.93 (m, 1 H), 1.25–1.09
(m, 2 H).
13C NMR (126 MHz, DMSO-d6):  = 162.7, 160.7, 158.4, 150.2, 145.2,
140.9, 135.9, 130.0, 128.3, 128.0, 127.0, 113.6, 113.1, 111.6, 86.1, 85.4,
70.8, 66.6, 64.1, 55.4, 47.5, 42.3, 21.2, 14.5.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0039-1690190.
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References
Anal. Calcd for C35H37N3O9: C, 65.31; H, 5.79; N, 6.53. Found: C, 65.09;
H, 5.53; N, 6.43.
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4-Chloro-5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (4c)
Yield: 255 mg (59%); white solid.
1H NMR (400 MHz, DMSO-d6):  = 8.78 (s, 1 H), 8.32 (s, 1 H), 8.05 (s, 1
H), 8.03 (s, 1 H), 7.46 (s, 1 H), 7.44 (s, 1 H), 2.35 (s, 3 H).
13C NMR (101 MHz, DMSO-d6):  = 152.9, 152.8, 150.4, 147.2, 133.8,
133.0, 130.8, 128.53, 118.8, 59.4, 21.6.
Anal. Calcd for C13H9ClN3O2S: C, 36.01; H, 2.09; N, 9.69; S, 7.39.
Found: C, 36.25; H, 2.22; N, 9.78; S, 7.45.
N-Benzyl-4-(benzylamino)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine-
5-carboxamide (4d)
Yield: 409 mg (80%); white solid.
1H NMR (400 MHz, DMSO-d6):  = 10.00 (dq, J = 5.6, 3.5 Hz, 1 H),
9.42–9.35 (m, 1 H), 8.58 (s, 1 H), 8.22 (s, 1 H), 7.99 (d, J = 7.8 Hz, 2 H),
7.43 (d, J = 7.9 Hz, 2 H), 7.37–7.12 (m, 10 H), 4.69 (d, J = 5.4 Hz, 2 H),
4.45 (d, J = 4.4 Hz, 2 H), 2.33 (s, 3 H).
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13C NMR (101 MHz, DMSO-d6):  = 163.8, 156.9, 154.65, 154.64,
150.3, 146.7, 139.5, 139.1, 134.1, 130.6, 128.86, 128.82, 128.4, 127.9,
127.6–127.1 (m), 124.8, 114.2, 102.9, 43.7, 43.1, 21.5.
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Anal. Calcd for C28H25N5O3S: C, 65.74; H, 4.93; N, 13.69; S, 6.27.
Found: C, 65.72; H, 4.96; N, 13.72; S, 6.32.
4-Chloro-N-(2-morpholinoethyl)benzamide (Moclobemide) (5c)53
The general procedure was followed employing Et3N (2 equiv) and 2-
morpholinoethan-1-amine (2 equiv).
Yield: 190 mg (94%); white solid.
1H NMR (500 MHz, CDCl3):  = 8.35–8.26 (m, 2 H), 7.55 (t, J = 9.7 Hz, 1
H), 7.48–7.41 (m, 2 H), 3.74–3.71 (m, 4 H), 3.50–3.46 (m, 2 H), 2.58
(ddd, J = 5.9, 5.3, 2.2 Hz, 2 H), 2.50 (s, 4 H).
13C NMR (126 MHz, CDCl3):  = 186.4, 161.5, 141.1, 132.6, 128.9, 66.9,
56.7, 53.3, 35.7.
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2018, 167.
N,N-Diethylnicotinamide (Nikethamide) (6c)54
Yield: 163 mg (92%); pale yellow oil.
1H NMR (500 MHz, DMSO-d6):  = 8.61 (dd, J = 4.9, 1.7 Hz, 1 H), 8.56–
8.53 (m, 1 H), 7.79–7.76 (m, 1 H), 7.44 (ddd, J = 7.8, 4.9, 0.8 Hz, 1 H),
3.43 (d, J = 6.6 Hz, 2 H), 3.15 (d, J = 6.7 Hz, 2 H), 1.13 (t, J = 6.3 Hz, 3 H),
1.03 (t, J = 6.3 Hz, 3 H).
13C NMR (126 MHz, DMSO-d6):  = 168.1, 150.5, 147.2, 134.4, 133.4,
124.0, 43.4, 39.3, 14.5, 13.2.
Funding Information
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S.B. is grateful to the University Grants Commission, India for a UGC-
SAP fellowship (SRF).V.G. thanks the Council of Scientific and Indus-
trial Research (CSIR), New Delhi, Government of India, for providing a
Senior Research Fellowship (SRF).()
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