Tris(o-phenylenedioxy)cyclotriphosphazene as a Promoter for the Formation of Amide Bonds between Aromatic Acids and Amines

Article abstract of DOI:10.1055/s-0040-1707174

The atom-efficient formation of amide bonds has emerged as a top-priority research field in organic synthesis, as amide bonds constitute the backbones of proteins and represent an important structural motif in drug molecules. Currently, the increasing demand for novel discoveries in this field has focused substantial attention on this challenging subject. Herein, the degradable 1,3,5-triazo-2,4,6-triphosphorine (TAP) motif is presented as a new condensation system for the dehydrative formation of amide bonds between diverse combinations of aromatic carboxylic acids and amines. The underlying reaction mechanism was investigated, and potential catalyst intermediates were characterized using 31 P NMR spectroscopy and ESI mass spectrometry.

Full text of DOI:10.1055/s-0040-1707174

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2020, 52, A–J
special topic
A
en
F. S. Movahed et al.
Special Topic
Synthesis
Tris(o-phenylenedioxy)cyclotriphosphazene as a Promoter for the
Formation of Amide Bonds Between Aromatic Acids and Amines
Farzaneh Soleymani Movaheda
Dinesh N. Sawantb
Dattatraya B. Bagala
Susumu Saito*a,b
0
0
0
0-0
0
0
3-0
7
4
9-2
0
2
0
a Graduate School of Science, Nagoya University, Chikusa,
Nagoya 464-8602, Japan
b Research Center for Materials Science, Nagoya University,
Chikusa, Nagoya 464-8602, Japan
saito.susumu@f.mbox.nagoya-u.ac.jp
Published as part of the Special Topic Recent Advances in
Amide Bond Formation
Received: 24.04.2020
Accepted after revision: 04.06.2020
Published online: 06.07.2020
with high atom economy at reasonably low temperatures
(<100 °C).6 A very recently published report by Yamamoto
et al. introduced a novel strategy in which a substrate-di-
rected Lewis acid tantalum catalyst and a stoichiometric
amount of trimethylsilylimidazole were used for the activa-
tion of CAs; this method allows the synthesis of peptides at
45 °C without significant racemization.7 Another notewor-
thy report by Arora et al. explored a selenium-based or-
ganocatalyst that demonstrated outstanding performance
for solid-phase synthesis of oligopeptide, albeit on a rela-
tively small scale.8 Due to the paramount importance of de-
veloping catalytic and waste-free approaches, a multitude
of dehydration catalysts has been presented in the litera-
ture as a possible solution for CA activation, most of which
are based on boron.6,9 Since the first report of arylboronic
acid catalysts by Yamamoto et al.,9a many groups have re-
ported boron-based systems for the amidation of CAs.9
However, most of these reports have focused mainly on the
catalytic synthesis of peptides or the amidation of aliphatic
CAs,6–11 with a few exceptions10 that include our recent re-
port of diboron catalysts.12 Many recently developed cata-
lytic amidations require the use of heavy transition metals.
However, these materials are scarce, and often present en-
vironmental hazards and increased toxicity.13 Accordingly,
the use of earth-abundant, environmentally benign organo-
catalysts represents a desirable research target.
DOI: 10.1055/s-0040-1707174; Art ID: ss-2020-c0222-st
Abstract The atom-efficient formation of amide bonds has emerged
as a top-priority research field in organic synthesis, as amide bonds con-
stitute the backbones of proteins and represent an important structural
motif in drug molecules. Currently, the increasing demand for novel dis-
coveries in this field has focused substantial attention on this challeng-
ing subject. Herein, the degradable 1,3,5-triazo-2,4,6-triphosphorine
(TAP) motif is presented as a new condensation system for the dehydra-
tive formation of amide bonds between diverse combinations of aro-
matic carboxylic acids and amines. The underlying reaction mechanism
was investigated, and potential catalyst intermediates were character-
ized using 31P NMR spectroscopy and ESI mass spectrometry.
Key words amide bond formation, organophosphorus catalyst, dehy-
dration, carboxylic acids, amines
Introduction
The amide bond is a key component in many biological-
ly active compounds, natural products, and therapeutics, as
well as in the food and agricultural industries.1 In fact, 25%
of all synthetic drugs contain amide units.2 However, the
condensation of carboxylic acids (CAs) and amines remains
one of the most challenging transformations in organic syn-
thesis, and ‘amide formation avoiding poor atom economy
reagents’ has been selected as a top-priority research area
in organic chemistry.3
In addition to direct amidation reactions between CAs
and amines at high temperatures (e.g., >200 °C),4 numerous
low-temperature amidation strategies have been estab-
lished, among which the application of coupling reagents
[such as O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyl-
uronium hexafluorophosphate (HATU), COMU®, and
Oxyma®] has emerged as one of the most successful ap-
proaches.5 The catalytic activation of CAs is an intriguing
method that generally provides the desired amide bond
In addition to numerous organoboron catalysts, a vari-
ety of organophosphorus compounds have been introduced
as stoichiometric dehydrative coupling reagents14 based on
the characteristic Lewis-acidity of the phosphorus(V) at-
om.15 While these compounds can be considered as effec-
tive promoters of CA–amine condensation, they often suffer
from low tolerance toward hydrolysis, and robust efficient
organophosphorus catalysts that promote the formation of
amide bonds remain elusive. One promising strategy to po-
tentially overcome this drawback is the development of a
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–J
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
F. S. Movahed et al.
Special Topic
Synthesis
dehydrative catalytic cycle based on the simple interconver-
sion of diaryl hydrogen phosphate (ArHP) and aryl dihydro-
gen phosphate (ArDP) by the addition and removal of water
(Scheme 1a). The use of a cyclic phosphate would be ex-
pected to provide a more robust dehydrative cycle for the
catalytic condensation of a CA and an amine (Scheme 1b).
Results and Discussion
The uncatalyzed dehydrative amidation of aliphatic CAs
and amines is well established,11 while that of aromatic CAs
is non-trivial.12 Our initial aim was to find an effective and
simple method to generate ArHP (CCP) or ArDP (PP), whose
structural robustness could potentially be the key to suc-
cessfully induce amide bond formation with aromatic CAs.
According to detailed studies by Allcock, phosphazenes
readily undergo hydrolysis under acidic or basic conditions,
which results in the in situ generation of ArHP (CCP) deriva-
tives.18 Therefore, a series of TAP derivatives were selected
as potential catalyst precursors and synthesized via a
slightly modified literature procedure.19 For instance, cyclic
triphosphazene TAP-1 was obtained as a white solid from
the reaction between catechol and hexachlorophosphazene
(TAP-10) in the presence of K2CO3. The purification was
achieved by simple filtration, and, due to the high stability
of the isolated compound, the white solid could be stored
under ambient conditions for at least 6 months.
a)
ArO
HO
O
O
ArO
ArO
H2O
+ ArOH
P
P
– H2O
OH
OH
ArHP
ArDP
b)
O
O
H
R2
N
H
R2
+
R1
N
H
R1
OH
step 1
O
O
O
O
P
OH
P
X
X
OH
OH
O
CCP
OH
PP
Optimization of the Reaction Conditions
step 2
As a model reaction, we chose the amide bond forma-
tion between benzoic acid (1a) and benzylamine (2a). To
investigate the feasibility of our proposed strategy, a wide
variety of phosphazene derivatives was examined in order
to identify the most promising organophosphorus struc-
ture (Scheme 2). The best results were obtained for TAP-1
(5 mol %) under azeotropic reflux (128 °C) for 16 hours. In
other words, TAPs that provide CCP (PP) promotors (TAP-1
to TAP-6 and TAP-11) perform significantly better than
those that form ArHPs (ArDPs) (TAP-7 to TAP-9).
H2O
Scheme 1 Working hypothesis of this study: (a) Interconversion be-
tween ArHP and ArDP via the addition or removal of water could lead to
a dehydrative catalytic cycle. (b) The ideal catalytic cycle for the forma-
tion of amide bonds between CAs and amines via the catalytic intercon-
version of CCP and PP.
The proposed catalytic cycle (Scheme 1b) involves two
main steps: First, the interaction of the CA with the ArHP
catalyst catechol cyclic phosphate (CCP; in this specific
case) yields the active ester species, which is immediately
attacked by the amine in the reaction mixture (step 1). Sec-
ond, detachment of the desired amide from the cycle and
hydration of CCP leads to the open ArDP structure PP (pyro-
catechol phosphate), which is converted back to the closed
CCP structure upon azeotropic removal of H2O (step 2).
Based on these hypothetical considerations, we undertook
an extensive search to find effective reaction conditions for
the synthesis of CCP; however, several previously published
studies have concluded that the direct isolation of CCP
might be impracticable,16 and accordingly, we targeted the
in situ generation of CCP. As part of our continuous endeav-
or to employ 1,3,5-triazo-2,4,6-triphosphorine (TAP) deriv-
atives as catalysts for dehydration reactions,17 we report
hereinthatTAP(catecholate)3 [tris(o-phenylenedioxy)cyclo-
triphosphazene: TAP-1], which exhibits a high propensity
to undergo hydrolysis under acidic or basic conditions,18
serves as an effective precursor for the CCP/PP catalyst. An
investigation into the underlying reaction mechanism
clearly identified TAP-1 as a practical precursor that both
produces the catalyst and acts as a coupling reagent in the
early stage of amide formation, which is followed by the
CCP–PP catalytic cycle.
O
O
TAP derivative
(5 mol %)
H2N
+
OH
N
H
toluene, N2
128 °C, 16 h
1a
2a
3aa
R4O OR4
P
TAP derivatives
Cl Cl
P
R3
N
P
N
P
N
P
N
R4O
R4O
TAP-7: R4 = Ph (3%)
OR4
Cl
Cl
TAP-10 (64%)
P
Cl
N
N
OR4
Cl
TAP-8: R4 = p-MeO(C6H4) (3%)
TAP-9: R4 = p-NO2(C6H4) (3%)
O
O
N
P
P
N
N
P
O
O
O
O
R3
R3
HN
N
NH
N
TAP-1: R3 = H (81%)
TAP-2: R3 = Me (72%)
TAP-3: R3 = tBu (60%)
P
N
H
H
N
N
P
P
TAP-4: R3 = CH2=CH (32%)
TAP-5: R3 = Cl (22%)
NH HN
TAP-6: R3 = NO2 (5%)
TAP-11 (68%)
Scheme 2 Amide bond formation between 1a and 2a (0.5 mmol each;
[1a]0 = [2a]0 = 71 mM) in the presence of different organophosphorus
derivatives of TAP. Values in parentheses refer to the yield of the crude
product 3aa as determined by 1H NMR analysis using 1,2,2,2-tetrachlo-
roethane as the internal standard.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–J

C
F. S. Movahed et al.
Special Topic
Synthesis
Table 1 Optimization of the Reaction Conditions for the Amide Bond
Formation Between 1a and 2aa
Then, the reaction temperature was varied. As expected,
azeotropic reflux (128 °C, Table 1, entry 1) is crucial for the
removal of water, and the highest yield of 3aa was achieved
under this condition (entries 1 vs 6–10). The maximum
performance of the catalyst was achieved within a reason-
able timeframe (16 h; entries 1 vs 11–13). Next, the TAP-1
loading in toluene ([TAP-1]0 = 3.57 mM) was varied at azeo-
tropic reflux at 128 °C (entries 1 vs 14–18), and 5 mol% of
TAP-1 was found to be sufficient to provide 3aa in more
than 80% yield. Finally, the employment of an inert atmo-
sphere proved to have a significant effect on the amidation
performance. The presence of air had a detrimental effect
on this system (entry 19), decreasing the yield of 3aa from
81% to 60%. This observation is consistent with previously
reported results that described CCP as being highly sensi-
tive to atmospheric conditions.16
Entry Conditions
[1a]0 = [2a] (mM) Temp (°C) Time (h) TAP-1 (mol %)
Yield (%)b
1
2
71
100
50
33
25
71
71
71
71
71
71
71
71
71
71
71
71
71
71
71
71
71
71
71
128
128
128
128
128
144
100
85
16
16
16
16
16
16
16
16
16
16
24
10
5
5
5
5
5
5
5
5
5
5
5
5
5
5
0.5
1
2
81
73
45
43
41
63
30
22
16
0
3
4
5
6
7
8
9c
66
10c
11
12
13
14
15
16
17
18
19d
20e
21f
22c,g
23c,h
24c,i
25
Reaction Scope and Limitations
The substrate generality of this system with respect to
aromatic CAs was investigated using the optimized condi-
tions and TAP-1 (5 mol%) (Scheme 3). The coupling of CAs
1a–p with 2a was successful in all cases. In particular, CAs
that bear electron-withdrawing or electron-donating
groups produced the corresponding amides in consistently
high yields, with negligible differences (3aa–pa). It is worth
noting here that N,N-dimethyl-substituted benzoic acid 1i,
which is scarcely soluble in nonpolar solvents, underwent
the reaction effectively in polar chlorobenzene, albeit that
the temperature had to be elevated slightly. In contrast,
poor reactivity of 1i was observed using our recently devel-
oped diboron catalysts.12 Screening of the amine scope re-
vealed that the secondary amines 2e and 2g also under-
went condensation under these conditions in high yield
(3ae: 87%; 3ag: 70%). In contrast, the reaction of the aro-
matic amine aniline (2i) with 1a afforded 3ai in only 20%
yield. Aromatic amines are relatively poor nucleophiles;
therefore, the nucleophilic attack of 2i on the activated CA
can be expected to be ineffective. Sterically more hindered
amines 2d and 2f are also poor substrates under the applied
conditions, providing 3ad and 3af in low yield. To investi-
gate the possibility of forming amide bonds using C-pro-
tected--amino acids, L-tryptophan derivative 2j was used
as the amine, and the desired amide 3aj was isolated in 32%
yield with a slight loss of optical purity.
128
128
128
128
128
128
128
128
128
144
85
82
60
36
10
19
35
87
84
60
42
12
10
0
16
16
16
16
16
16
16
16
16
16
16
10
15
5
5
5
66
5
40
5
35
5
0
a Unless otherwise specified, the reaction was performed using 1a and 2a
(0.5 mmol each) under N2.
b Crude yield of 3aa determined by 1H NMR spectroscopy using 1,1,2,2-
tetrachloroethane as the internal standard.
c Molecular sieve was used (4 Å, 2.4 g/1 mmol).
d Under air.
e Solvent: o-xylene.
f Solvent: MeCN.
g Solvent: THF.
h Solvent: CH2Cl2.
i Solvent: Et2O.
Mechanistic Study
The mechanism of our system was explored through
constant monitoring using 31P NMR spectroscopy, ESI mass
spectrometry, and the yield curve of the products during
the reaction procedure (Figure 1a). The amidation between
1a and 2a was designated as the model experiment. To ob-
tain the best insights from the 31P and 1H NMR data, 1a and
2a (3 mmol each) were reacted in the presence of 5 mol % of
TAP-1 under azeotropic reflux (128 °C) ([1a]0 = [2a]0 = 300
mM). Every 2 hours, an aliquot was removed from the reac-
tion mixture under an inert atmosphere (flowing N2), and
After identifying TAP-1 as the most appropriate phosph-
azene skeleton, we shifted our attention to optimizing the
reaction conditions (Table 1). To this end, various para-
meters affecting the reaction conditions were assessed.
Among the different solvents explored, toluene exhibited
the best performance (Table 1, entries 1 and 20–24) at the
optimized initial concentration ([1a]0 = [2a]0 = 71 mM), and
provided the desired amide 3aa in 68 ± 13% crude yield (av-
erage of five runs).
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–J

D
F. S. Movahed et al.
Special Topic
Synthesis
Figure 1 (a) Plot of the time-dependent yield of 3aa during the reaction of 1a and 2a with (□) or without (●) TAP-1 (5 mol %) (crude yields were
determined by 1H NMR spectroscopy using 1,3,5-trimethoxybenzene as the internal standard). The sampling times were consistent in a) and b). (b)
Stacked 31P NMR spectra for the reaction between 1a and 2a (2 h intervals).
all the thus obtained samples were analyzed using 31P and
1H NMR spectroscopy as well as ESI mass spectrometry.
ure 1a, the reaction did not provide the desired amide bond
under the standard conditions in the absence of TAP-1,
whereas the addition of 5 mol % of this precursor promoted
the reaction. During the reaction timeframe, the 31P NMR
peaks related to CCP and PP remained intact; moreover, the
existence of these compounds was confirmed by ESI-MS
measurements upon each sampling. Based on these data,
we would like to propose the catalytic cycle as a plausible
mechanism (Scheme 4).
1
Due to the instability of the catalyst CCP, the 31P and H
NMR spectra were measured under N2 gas (using screw-cap
NMR tubes) to ensure the reliability of the data. The 31P
NMR results revealed that the total conversion of TAP-1 oc-
curred within 30 minutes of reaction, with two new signals
appearing at 14.52 ± 0.10 ppm and 1.74 ± 0.12 ppm (Figure
1b).
To further identify these compounds, ESI mass spectra
were recorded. As expected, CCP (ESI-MS [M – H]– calcd:
170.9853; found: 170.9869) was generated during the deg-
radation of TAP-1, along with PP (ESI-MS [M – H]– calcd:
188.9958, found: 188.9974). Apart from a very small signal,
which was tentatively assigned to phosphoric acid (H3PO4)
that was consistently observed after ca. 8 hours of reaction
and suggested the partial decomposition of CCP or PP to H3PO4
as a side reaction, other species were not observed by ei-
ther 31P NMR spectroscopy or ESI-MS, indicating that the
transformation of TAP-1 proceeded rapidly and efficiently.
As shown in Scheme 4, the catalyst precursor TAP-1 acts
as a stoichiometric reagent for the dehydrative coupling be-
tween the CA and the amine, and subsequently degrades
completely into CCP upon reaction with the resulting H2O.
Following the generation of CCP, the catalytic cycle com-
mences with CCP as the catalyst; the reaction of CCP with
CA or an intermediate derived from a CA–amine adduct
(step b) leads to the corresponding activated ester, which
reacts with the amine via TS1 (inner P-sphere mechanism)
or directly forms TS2 (outer P-sphere mechanism). In the
case of TS1, a nucleophilic attack of the amine on the acti-
vated ester yields the desired amide and PP. In the final step,
the concomitant removal of water from the PP structure
1
The H NMR data recorded throughout the reaction were
used to plot the yield curve (Figure 1a). As illustrated in Fig-
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–J

E
F. S. Movahed et al.
Special Topic
Synthesis
O
O
O
O
H
R2
TAP-1 (5 mol%)
R2
R3HN R2
R2
+
N
H
+
R1
1a–p
OH
R1
N
R3
R1
N
toluene, azeotropic reflux
R1
OH
step b
2a–j
H
N2 (1 atm), 16 h
3aa–aj
[1]0 = 71 mM
[2]0 = 71 mM
amide bond
formation
stoichiometric
reaction
O
O
O
O
O
O
P
OH
O
N
H
Ph
N
Ph
N
H
Ph
step a
H
TAP-1
P
OH
OH
O
CCP
OH
O
3aa, (81%)
3ca, 45% (41%)
PP
3ba, 80%
R2
R1
N
H
O
O
O
Ph
dehydration
tBu
N
H
Ph
MeO
N
N
H
Ph
H
H2O
tBu
tBu
‡
OH
P
3ea, 78% (72%)
3fa, 79% (72%)
3da, 75%
O
O
O
O
O
O
H
O
inner P-sphere
R2
NH2
P
O
O
O
Ph
O
O
R1
NH3R2
+
OH
O
MeO
R1
N
N
H
Ph
Me
N
H
Ph
Ph
CCP
TS1
H
S
N
‡
R2
HO
R2
H
OMe
Me
Me
O
O
O
O
O
H
H
O
outer P-sphere
3ga, 77% (72%)
3ha, 94%
N
P
3ia, 81%
+
N
P
H
OH
R1
O
HO
R1
O
O
H
O
O
O
CCP
TS2
N
H
N
H
Ph
N
H
Ph
Scheme 4 Overview of the mechanism of the ‘stoichiometric TAP’-
O2N
Cl
I
promoted amidation reaction (step a), followed by the catalytic CCP–PP
interconversion cycle for the amidation. In step b, at least two transition
states, TS1 and TS2, are possible.
3ja, 86%
3ka, 79%
3la, 98%
O
O
O
N
Ph
N
Ph
N
H
Ph
H
O
H
O
S
regenerates CCP, thereby completing the catalytic cycle. Due
to the instability of CCP, the use of an inert reaction atmo-
sphere, such as N2, is crucial. To demonstrate the conversion
of CCP to PP, a small portion of the reaction mixture was
subjected to 31P NMR analysis, which confirmed the pres-
ence of the CCP signal. This sample was subsequently ex-
posed to air (containing moisture) for 12 hours. The 31P
NMR spectrum of the resulting sample did not contain any
peak related to CCP; instead, PP was the only signal ob-
served.
3ma, 87% (82%)
3na, 79% (67%)
3oa, 98% (91%)
O
O
O
N
N
H
Ph
N
N
H
5
H
3pa, 94% (85%)
3ab, 88% (81%)
3ac, 72% (66%)
O
O
O
N
N
N
3ad, (7%)
3ae, 87% (80%)
3af, (8%)
Conclusion
O
O
O
We have demonstrated a new catalytic system based on
1,3,5-triazo-2,4,6-triphosphorine (TAP) derivatives for the
efficient formation of amide bonds via the dehydrative cou-
pling of aromatic carboxylic acids with amines. The nontox-
ic and metal-free precatalyst TAP(catecholate)3 (TAP-1) was
used to provide a catalyst system based on catechol cyclic
phosphate (CCP) and pyrocatechol phosphate (PP). The
overall reaction seems to involve distinct stoichiometric
and catalytic steps, and the interconversion between CCP
and PP is likely the key to the catalytic process. Since phos-
phorus atoms are abundant in biological organisms and
stored as adenosine triphosphate (ATP) for the activation of
-amino acids,20 the developed method could potentially
represent a promising method for the synthesis of di- and
oligopeptides; such applications are currently under inves-
tigation in our laboratory.
O
N
N
H
N
H
O
3ag, 70% (63%)
3ah, 77% (70%)
3ai, 20% (14%)
H
N
O
O
N
H
Me
O
3aj, (32%)
91:9 er
Scheme 3 Substrate scope. Reagents and conditions: Unless otherwise
specified, the reaction was performed using 1 and 2 (0.5 mmol each)
with TAP-1 (5 mol %) in toluene for 16 h at a heating bath temperature
of 128 °C. 1H NMR yields of the crude mixtures using 1,1,2,2-tetrachlo-
roethane as the internal standard are given (isolated yields in parenthe-
ses). For 3ia and 3la, PhCl was used as the solvent at 133 °C for 16 h.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–J

F
F. S. Movahed et al.
Special Topic
Synthesis
13C NMR (CDCl3, 150 MHz):  = 147.60, 144.18, 142.05, 120.12,
111.53, 110.02, 34.91, 31.45.
31P{H} NMR (CDCl3):  = 34.46.
HRMS (FAB): m/z [M + H]+ calcd for C30H37N3O6P3+: 628.1895; found:
All the commercial reagents and solvents were used as purchased. 1H
NMR spectra were recorded on a JEOL ECA-500 or ECA-600 (500 or
600 MHz) at r.t. Chemical shifts are presented in ppm  relative to
TMS, coupling constants in Hz, and integrations are based on the in-
ternal standard (1,1,2,2- tetrachloroethane). 13C NMR spectra were
recorded on Jeol ECA-500 or ECA-600 (125 or 150 MHz) at r.t. in CDCl3
or DMSO-d6. Chemical shifts were recorded in ppm based on the NMR
solvent (CDCl3 at 77.06 ppm). High-resolution spectra (HRMS) were
obtained from JEOL JMS-700 (FAB) or Bruker compact-TOF. TLC analy-
sis was performed on commercial glass plates bearing 0.25 mm layer
of Merck TLC silica gel 60 GF254. Optical rotation value was recorded
on Polarimeter P-1010-GT (JASCO). HPLC analysis was conducted on
Shimadzu HPLC system. All reactions were performed in oven-dried
glassware. TAPs 1,21 3,22 and 7–923 as well as amides 3aa–aj12 are
known compounds.
628.1876.
Tris(4-vinyl-o-phenylenedioxy)cyclotriphosphazene (TAP-4)
According to the general procedure, the reaction was carried out be-
tween TAP-10 (905 mg, 2.6 mmol, 1.0 equiv), 4-vinylcatechol (1.06 g,
7.8 mmol, 3.0 equiv), and Na2CO3 (7.8 mmol, 3.0 equiv) in THF (30 mL)
at r.t. for 72 h. TAP-4 was obtained as a white solid after column chro-
matography (EtOAc/n-hexane 1/4); yield: 126 mg (0.23 mmol, 9%); Rf
= 0.75 (25% EtOAc in n-hexane).
1H NMR (DMSO-d6, 600 MHz):  = 7.13 (3 H), 6.99 (6 H), 6.56–6.60 (3
H, m), 5.58–5.61 (3 H, d, J = 17.4 Hz), 5.18–5.20 (3 H, d, J = 10.98 Hz).
31P{H} NMR (CDCl3):  = 34.22.
TAP Derivatives; General Procedure
An oven-dried 100 mL two-necked round-bottom flask was equipped
with a Teflon coated magnetic stirring bar. To seal the apparatus, a
balloon was connected to the flask using a three-way stopcock; then,
the atmosphere was replaced by N2 gas. 1,3,5-Triazo-2,4,6-triphos-
phorine-2,2,4,4,6,6-hexachloride (TAP-10), the related catechol deriv-
ative, and the base were placed in the reaction mixture, following an-
hydrous solvent under N2 flow. The reaction was allowed to stir. Upon
completion, the product was purified by filtration or gradient column
chromatography.
TAP-4 seems to be polymerized during an ESI-MS measurement.
Tris(4-chloro-o-phenylenedioxy)cyclotriphosphazene (TAP-5)
According to the general procedure, the reaction was carried out be-
tween TAP-10 (696 mg, 2 mmol, 1.0 equiv), 4-chlorocatechol (867 mg,
6 mmol, 3.0 equiv), and Na2CO3 (6 mmol, 3.0 equiv) in THF (20 mL) at
66 °C for 72 h. TAP-5 was obtained as a beige solid after column chro-
matography (DCM/MeOH 20/1); yield: 573 mg (1.02 mmol, 51%); Rf =
0.56 (5% MeOH in DCM).
1H NMR (DMSO-d6, 600 MHz):  = 6.55–6.62 (9 H, m).
31P{H} NMR (CDCl3):  = –79.28.
Tris(o-phenylenedioxy)cyclotriphosphazene (TAP-1)
According to the general procedure, the reaction was carried out be-
tween TAP-10 (2.008 g, 6 mmol, 1.0 equiv), catechol (1.98 g, 18 mmol,
3.0 equiv), and K2CO3 (18 mmol, 3.0 equiv) in THF (60 mL) at r.t. for 48
h. TAP-1 was obtained as a white solid after filtration and washing
with THF (100 mL), and then H2O (200 mL); yield: 1350 mg [2.94
mmol, 49 ± 5% (avg. of 8 runs)].
1H NMR (DMSO-d6, 600 MHz):  = 7.29 (6 H, m), 7.09 (6 H, m).
13C NMR (CDCl3, 150 MHz):  = 144.46, 123.82, 112.53.
31P{H} NMR (CDCl3):  = 33.76.
Due in part to structural instability of TAP-5, no relevant peaks were
found by ESI-MS measurement.
Tris(4-nitro-o-phenylenedioxy)cyclotriphosphazene (TAP-6)
According to the general procedure, the reaction was carried out be-
tween TAP-10 (174 mg, 0.5 mmol, 1.0 equiv), 4-nitrocatechol (233
mg, 1.5 mmol, 3.0 equiv), and Na2CO3 (3 mmol, 6.0 equiv) in THF (20
mL) at 66 °C for 72 h. TAP-6 was obtained as a bright yellow solid after
column chromatography (DCM/MeOH 20/1); yield: 211 mg (0.36
mmol, 71%); Rf = 0.14 (5% MeOH in DCM).
1H NMR (CDCl3, 600 MHz):  = 7.71–7.72 (3 H, m), 7.53 (3 H, m), 6.88–
6.90 (3 H, m).
31P{H} NMR (CDCl3):  = –77.56.
Tris(4-methyl-o-phenylenedioxy)cyclotriphosphazene (TAP-2)
According to the general procedure, the reaction was carried out be-
tween TAP-10 (696 mg, 2 mmol, 1.0 equiv), 4-methylcatechol (744
mg, 6 mmol, 3.0 equiv), and K2CO3 (6 mmol, 3.0 equiv) in THF (20 mL)
at r.t. for 72 h. TAP-2 was obtained as a white solid after column chro-
matography (EtOAc/n-hexane 1/5); yield: 130 mg (0.26 mmol, 13%);
Rf = 0.52 (20% EtOAc in n-hexane).
Due in part to structural instability of TAP-6, no relevant peaks were
found by ESI-MS measurement.
1H NMR (CDCl3, 600 MHz):  = 6.74–6.90 (9 H, m), 2.24 (9 H, s).
31P{H} NMR (CDCl3):  = 34.24.
HRMS (ESI): m/z [M + Na]+ calcd for C21H18N3O6P3Na+: 524.0306;
Hexakis(phenoxy)cyclotriphosphazene (TAP-7)
According to the general procedure, the reaction was carried out be-
tween TAP-10 (1.044 g, 3 mmol, 1.0 equiv), phenol (1.778 g, 18.92
mmol, 6.3 equiv), and K3PO4 (34.46 mmol, 11.5 equiv) in MeCN (50
mL) at 88 °C (reflux) for 10 h, then the crude was allowed to cool to r.t.
The solid was filtered and washed with EtOAc (2 × 50 mL), the filtrate
and the washings were combined, and the solvent was removed un-
der reduced pressure. TAP-7 was obtained as white solid after column
chromatography (DCM); yield: 1664.57 mg (2.4 mmol, 80%); Rf = 0.94
(DCM).
1H NMR (DMSO-d6, 600 MHz):  = 7.14–7.18 (12 H, m), 7.08–7.12 (6
H, m), 6.91–6.92 (12 H, m).
13C NMR (CDCl3, 150 MHz):  = 150.67, 129.46, 124.90, 121.12.
31P{H} NMR (CDCl3):  = 9.32.
found: 524.0264.
Tris[4-(tert-butyl)-o-phenylenedioxy]cyclotriphosphazene (TAP-
3)
According to the general procedure, the reaction was carried out be-
tween TAP-10 (1.044 g, 3 mmol, 1.0 equiv), 4-tert-butylcatechol
(1.494 g, 9 mmol, 3.0 equiv), and K2CO3 (9 mmol, 3.0 equiv) in THF (30
mL) at r.t. for 48 h. TAP-3 was obtained as a magenta solid after col-
umn chromatography (EtOAc/n-hexane 1/5); yield: 282 mg (0.45
mmol, 15%); Rf = 0.75 (20% EtOAc in n-hexane).
1H NMR (CDCl3, 600 MHz):  = 6.93–7.08 (9 H, m), 1.22 (27 H, s).
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–J

G
F. S. Movahed et al.
Special Topic
Synthesis
HRMS (ESI): m/z [M + H]+ calcd for C36H31N3O6P3+: 694.1426; found:
694.1398.
flask was cooled to r.t., and the solvent was evaporated under reduced
pressure using a rotary evaporator. The purification was performed
by a three-step acid/base extraction. To this end, a separatory funnel
was charged with H2O and a DCM solution of the crude product mix-
ture; after extraction, the organic layers (3 × 25 mL of DCM) were col-
lected and washed with sat. aq Na2CO3 (25 mL). The aqueous layer
was subsequently extracted with DCM (3 × 25 mL), and the organic
phases were combined. The combined organic phases were washed
with aq HCl (1 M, 25 mL). The aqueous phase was extracted with
DCM (3 × 25 mL). The combined organic layers were washed with
brine solution, dried over Na2SO4, and filtered. Finally the solvent of
the filtrate was removed under reduced pressure.
Hexakis(4-methoxyphenoxy)cyclotriphosphazene (TAP-8)
According to the general procedure, the reaction was carried out be-
tween TAP-10 (1.044 g, 3 mmol, 1.0 equiv), p-methoxyphenol (2.327
g, 18.92 mmol, 6.3 equiv), and K3PO4 (34.46 mmol, 11.5 equiv) in
MeCN (50 mL) at 88 °C (reflux) for 6 h, then the crude was allowed to
cool to r.t. The solid was filtered and washed with EtOAc (2 × 50 mL) ,
the filtrate and the washings were combined, and the solvent was re-
moved under reduced pressure. TAP-8 was obtained as a white solid
after column chromatography (EtOAc/n-hexane 1/1); yield: 2505.5
mg (2.9 mmol, 96%); Rf = 0.66 (EtOAc/n-hexane 1/1).
1H NMR (DMSO-d6, 600 MHz):  = 6.81–6.84 (12 H, m), 6.66–6.68 (12
H, m), 3.76 (18 H, s).
13C NMR (CDCl3, 150 MHz):  = 156.54, 144.35, 121.91, 114.31, 55.54.
31P{H} NMR (CDCl3):  = 10.59.
HRMS (ESI): m/z [M + H]+ calcd for C42H43N3O12P3+: 874.2060; found:
N-Benzylbenzamide (3aa)
According to the general procedure 3aa was obtained as a white solid
after extraction; yield: 85.56 mg (0.40 mmol, 81%).
1H NMR (DMSO-d6, 600 MHz):  = 7.78–7.79 (2 H), 7.47–7.50 (1 H, t,
J = 7.8 Hz), 7.39–7.42 (2 H, t, J = 8.4 Hz), 7.33–7.34 (4 H, d, J = 4.8 Hz),
7.28–7.30 (1 H, m), 6.56 (1 H, br), 4.62–4.63 (2 H, d, J = 5.4 Hz).
874.2053.
13C NMR (DMSO-d6, 150 MHz):  = 167.43, 138.27, 134.48, 131.63,
128.89, 128.69, 128.02, 127.72, 127.04, 44.23.
Hexakis(4-nitrophenoxy)cyclotriphosphazene (TAP-9)
According to the general procedure, the reaction was carried out be-
tween TAP-10 (1.044 g, 3 mmol, 1.0 equiv), p-nitrophenol (2.63 g,
18.92 mmol, 6.3 equiv), and K3PO4 (34.46 mmol, 11.5 equiv) in MeCN
(50 mL) at 88 °C (reflux) for 10 h, then the crude was allowed to cool
to r.t. The crude product was washed with acetone then with H2O.
TAP-9 was recrystallized from o-dichlorobenzene; yield: 1734.39 mg
(1.8 mmol, 60%).
1H NMR (DMSO-d6, 600 MHz):  = 8.16 (12 H, m), 7.30–7.32 (12 H, m).
13C NMR (DMSO-d6, 150 MHz):  = 154.15, 145.34, 126.32, 122.02.
31P{H} NMR (CDCl3):  = 7.86.
N-Benzyl-4-methylbenzamide (3ba)
According to the general procedure 3ba was obtained as a white solid
after extraction; yield: 90.12 mg (0.40 mmol, 80%).
1H NMR (CDCl3, 600 MHz):  = 7.68–7.69 (2 H, d, J = 8.4 Hz), 7.33–7.34
(4 H, m), 7.27–7.30 (1 H, m), 7.20–7.21 (2 H, m), 6.48 (1 H, br), 4.61–
4.62 (2 H, d, J = 6 Hz), 2.38 (3 H, s).
13C NMR (CDCl3, 150 MHz):  = 167.35, 142.00, 138.40, 131.58,
129.28, 128.81, 127.95, 127.61, 127.02, 44.11, 21.49.
N-Benzyl-2-methylbenzamide (3ca)
According to the general procedure 3ca was purified by column chro-
matography as a white solid (EtOAc/n-hexane 1/1); yield: 46.15 mg
(0.20 mmol, 41%); Rf = 0.75 (50% EtOAc in n-hexane).
1H NMR (CDCl3, 600 MHz):  = 7.13–7.35 (9 H, m), 6.92 (1 H, br), 4.58–
4.59 (2 H, d, J = 5.4 Hz), 2.42 (3 H, s).
13C NMR (CDCl3, 150 MHz):  = 169.93, 138.23, 136.29, 136.25,
131.12, 130.00, 128.85, 127.90, 127.68, 126.70, 125.79, 43.98, 19.91.
Tris(4-methyl-o-phenylenediamino)cyclotriphosphazene (TAP-
11)
According to the general procedure, the reaction was carried out be-
tween TAP-10 (1.74 g, 5 mmol, 1.0 equiv), 3,4-diaminotoluene (1.83
g, 15 mmol, 3.0 equiv), and Et3N (30 mmol, 6.0 equiv) in THF (50 mL)
at r.t. for 21 h. Upon completion, the precipitate was collected by fil-
tration and then washed with toluene. The material was recrystal-
lized from MeOH/H2O to yield white crystals of TAP-11; yield: 4830
mg (3.25 mmol, 65%).
HRMS (ESI): m/z [M + Na]+ calcd for C15H15NONa+: 248.1051; found:
248.1052.
1H NMR (DMSO-d6, 600 MHz):  = 7.37 (3 H, m), 6.38 (3 H, s), 2.05 (9
H, s).
N-Benzyl-4-(tert-butyl)benzamide (3da)
13C NMR (DMSO-d6, 150 MHz):  = 135.01, 132.31, 125.60, 117.57,
115.32, 114.71, 20.46.
According to the general procedure 3da was obtained as a white solid
after extraction; yield: 100.26 mg (0.38 mmol, 75%).
1H NMR (CDCl3, 600 MHz):  = 7.72–7.74 (2 H, m), 7.42–7.44 (2 H, m),
7.34–7.35 (4 H, m), 7.27–7.30 (1 H, m), 6.47 (1 H, br), 4.63–4.64 (2 H,
d, J = 6.6 Hz), 1.32 (9 H, s).
13C NMR (CDCl3, 150 MHz):  = 167.31, 155.10, 138.42, 131.55,
128.80, 127.91, 127.60, 126.86, 125.57, 44.08, 34.97, 31.20.
31P{H} NMR (CDCl3):  = 19.60.
Amides; General Procedure
An oven-dried 50 mL two-necked round-bottom flask was equipped
with a Teflon coated magnetic stirrer bar and connected to an azeo-
tropic condenser. To seal the apparatus, a balloon was connected to
the azeotropic condenser by a three-way stopcock; then, the atmo-
sphere was replaced by N2 gas. Under a flow of N2, the flask was
charged with the CA (0.5 mmol, 1 equiv) and TAP-1 (11.48 mg, 5
mol%). Then, the amine (0.5 mmol, 1 equiv) was added under N2 flow,
followed by the solvent (dehydrated toluene or chlorobenzene; 7 mL).
The reaction mixture was stirred under azeotropic reflux at 128 °C
(133 °C in the case of chlorobenzene) for 16 h. Thereafter, the reaction
N-Benzyl-3,5-di-tert-butylbenzamide (3ea)
According to the general procedure 3ea was obtained as a white solid
after extraction; yield: 116.44 mg (0.36 mmol, 72%).
1H NMR (CDCl3, 600 MHz):  = 7.62 (2 H, d, J = 1.8 Hz), 7.56–7.57 (1 H,
m), 7.33–7.38 (4 H, m), 7.28–7.30 (1 H, m), 6.50 (1 H, br), 4.65–4.66 (2
H, d, J = 6 Hz), 1.33 (18 H, s).
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–J

H
F. S. Movahed et al.
Special Topic
Synthesis
13C NMR (CDCl3, 150 MHz):  = 168.50, 151.37, 138.59, 134.11,
N-Benzyl-4-nitrobenzamide (3la)
128.82, 128.01, 127.59, 125.82, 121.21, 44.17, 35.07, 31.48.
According to the general procedure [chlorobenzene (7 mL), 133 °C],
3la was obtained as a white solid after extraction; yield: 125.57 mg
(0.49 mmol, 98%).
N-Benzyl-4-methoxybenzamide (3fa)
1H NMR (CDCl3, 600 MHz):  = 8.22–8.24 (2 H, m), 7.92–7.94 (2 H, m),
7.29–7.36 (5 H, m), 6.80 (1 H, br), 4.62–4.63 (2 H, d, J = 6 Hz).
According to the general procedure 3fa was obtained as a white solid
after extraction; yield: 86.86 mg (0.36 mmol, 72%).
1H NMR (CDCl3, 600 MHz):  = 7.74–7.76 (2 H, m), 7.33–7.34 (3 H, m),
7.27–7.29 (1 H, m), 6.88–6.90 (2 H, m), 6.49 (1 H, br), 4.60–4.61 (2 H,
d, J = 5.4 Hz), 3.83 (3 H, s).
13C NMR (CDCl3, 150 MHz):  = 165.47, 149.64, 139.96, 137.53,
128.95, 128.27, 127.96, 123.84, 44.47.
13C NMR (CDCl3, 150 MHz):  = 166.98, 162.29, 138.54, 128.89,
N-Benzylfuran-2-carboxamide (3ma)
128.82, 127.97, 127.60, 126.74, 113.84, 55.49, 44.12.
According to the general procedure 3ma was obtained as a white sol-
id after extraction; yield: 82.50 mg (0.41 mmol, 82%).
N-Benzyl-3,5-dimethoxybenzamide (3ga)
1H NMR (CDCl3, 600 MHz):  = 7.25–7.40 (6 H, m), 7.14 (1 H, d, J = 3
Hz), 6.69 (1 H, br), 6.49 (1 H, m), 4.60–4.61 (2 H, d, J = 5.4 Hz).
According to the general procedure 3ga was obtained as a white solid
after extraction; yield: 97.67 mg (0.36 mmol, 72%).
13C NMR (CDCl3, 150 MHz):  = 158.45, 148.09, 144.05, 138.20,
128.95, 128.09, 127.81, 114.55, 112.34, 43.34.
1H NMR (CDCl3, 600 MHz):  = 7.32–7.34 (4 H, m), 7.28–7.29 (1 H, m),
6.91–6.92 (2 H, d, J = 3 Hz), 6.54–6.56 (2 H, m), 4.59–4.61 (2 H, d, J = 6
Hz), 3.79 (6 H, s).
13C NMR (CDCl3, 150 MHz):  = 167.29, 160.98, 138.22, 136.70,
128.85, 127.96, 127.67, 105.02, 103.70, 55.64, 44.23.
N-Benzylthiophene-2-carboxamide (3na)
According to the general procedure 3na was obtained as a white solid
after extraction; yield: 72.79 mg (0.34 mmol, 67%).
1H NMR (CDCl3, 600 MHz):  = 7.51–7.52 (1 H, dd, J = 4.2, 1.8 Hz),
7.46–7.47 (1 H, dd, J = 4.8, 1.2 Hz), 7.32–7.34 (4 H, m), 7.27–7.30 (1 H,
m), 7.04–7.06 (1 H, m), 6.45 (1 H, br), 4.59–4.60 (2 H, d, J = 6 Hz).
13C NMR (CDCl3, 150 MHz):  = 161.92, 138.86, 138.15, 130.11,
128.86, 128.25, 128.01, 127.72, 44.07.
N-Benzyl-4-(methylthio)benzamide (3ha)
According to the general procedure 3ha was obtained as a white solid
after extraction; yield: 120.95 mg (0.47 mmol, 94%).
1H NMR (CDCl3, 600 MHz):  = 7.65–7.67 (2 H, m), 7.28–7.30 (4 H, m),
7.23–7.25 (1 H, m), 7.17–7.18 (2 H, m), 6.52 (1 H, br), 4.56–4.57 (2 H,
d, J = 6 Hz), 2.44 (3 H, s).
13C NMR (CDCl3, 150 MHz):  = 166.90, 143.54, 138.32, 130.52,
128.81, 127.94, 127.63, 127.45, 125.48, 44.13, 15.09.
N-Benzylbenzofuran-2-carboxamide (3oa)
According to the general procedure 3oa was obtained as a white solid
after extraction; yield: 114.33 mg (0.46 mmol, 91%).
1H NMR (CDCl3, 600 MHz):  = 7.64–7.66 (1 H, d, J = 8.4 Hz), 7.49 (1 H,
s), 7.44–7.45 (1 H, m), 7.34–7.40 (5 H, m), 7.24–7.31 (2 H, m), 7.01 (1
H, br), 4.66–4.67 (2 H, d, J = 6.6 Hz).
13C NMR (CDCl3, 150 MHz):  = 158.86, 154.79, 148.67, 137.85,
128.88, 128.05, 127.79, 127.66, 126.95, 123.77, 112.81, 111.78,
110.70, 43.46.
N-Benzyl-4-(dimethylamino)benzamide (3ia)
According to the general procedure [chlorobenzene (7 mL), 133 °C],
3ia was obtained as a white solid after extraction; yield: 103.00 mg
(0.40 mmol, 81%).
1H NMR (CDCl3, 600 MHz):  = 7.69–7.71 (2 H, m), 7.31–7.34 (4 H, m),
7.25–7.28 (1 H, m), 6.63–6.66 (2 H, m), 6.37 (1 H, m), 4.61–4.62 (2 H,
d, J = 5.4 Hz), 2.99 (6 H, s).
N-Benzylpicolinamide (3pa)
13C NMR (CDCl3, 150 MHz):  = 167.34, 152.55, 138.94, 128.72,
128.53, 127.91, 127.41, 121.16, 111.13, 43.95, 40.16.
According to the general procedure 3pa was obtained as a white solid
after extraction; yield: 90.21 mg (0.42 mmol, 85%).
1H NMR (CDCl3, 600 MHz):  = 8.52 (1 H, d, J = 4.2 Hz), 8.38 (1 H, br),
8.23–8.24 (1 H, d, J = 7.2 Hz), 7.83–7.86 (1 H, m), 7.40–7.42 (1 H, m),
7.33–7.38 (4 H, m), 7.26–7.29 (1 H, m), 4.67–4.68 (2 H, d, J = 6 Hz).
13C NMR (CDCl3, 150 MHz):  = 164.29, 149.91, 148.13, 138.28,
137.41, 128.76, 127.90, 127.52, 126.25, 122.40, 43.55.
N-Benzyl-4-chlorobenzamide (3ja)
According to the general procedure 3ja was obtained as a white solid
after extraction; yield: 105.65 mg (0.43 mmol, 86%).
1H NMR (CDCl3, 600 MHz):  = 7.71–7.75 (2 H, m), 7.28–7.39 (7 H, m),
6.50 (1 H, br), 4.61–4.62 (2 H, d, J = 5.4 Hz).
13C NMR (CDCl3, 150 MHz):  = 166.36, 138.00, 137.85, 132.78,
N-hexylbenzamide (3ab)
128.88, 128.47, 127.98, 127.77, 44.28.
According to the general procedure 3ab was obtained as a white solid
after extraction; yield: 83.15 mg (0.40 mmol, 81%).
N-Benzyl-4-iodobenzamide (3ka)
1H NMR (CDCl3, 600 MHz):  = 7.75–7.77 (2 H, d, J = 6.6 Hz), 7.46–7.49
(1 H, m), 7.40–7.43 (2 H, m), 6.27 (1 H, br), 3.42–3.45 (2 H, m), 1.58–
1.63 (2 H, m), 1.29–1.40 (6 H, overlapping), 0.88–0.90 (3 H, t, J = 6.6
Hz).
According to the general procedure 3ka was obtained as a white solid
after extraction; yield: 133.18 mg (0.40 mmol, 79%).
1H NMR (CDCl3, 600 MHz):  = 7.76–7.77 (2 H, m), 7.50–7.51 (2 H, m),
7.29–7.37 (5 H, m), 6.45 (1 H, br), 4.61–4.62 (2 H, d, J = 5.4 Hz).
13C NMR (CDCl3, 150 MHz):  = 167.61, 134.98, 131.33, 128.58,
13C NMR (CDCl3, 150 MHz):  = 166.60, 137.96, 137.85, 133.82,
126.93, 40.20, 31.59, 29.72, 26.75, 22.64, 14.09.
128.89, 128.62, 127.99, 127.80, 98.55, 44.28.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–J

I
F. S. Movahed et al.
Special Topic
Synthesis
N-Cyclohexylbenzamide (3ac)
13C NMR (CDCl3, 150 MHz):  = 167.29, 151.26, 142.40, 134.26,
131.69, 128.66, 127.08, 110.61, 107.78, 37.09.
According to the general procedure 3ac was obtained as a white solid
after extraction; yield: 67.08 mg (0.33 mmol, 66%).
N-Phenylbenzamide (3ai)
1H NMR (CDCl3, 600 MHz):  = 7.74–7.76 (2 H, d, J = 7.2 Hz), 7.40–7.49
(3 H, m), 6.01 (1 H, br), 3.95–4.00 (1 H, m), 2.02–2.04 (2 H, m), 1.74–
1.77 (2 H, dt, J = 7.8, 3.6 Hz), 1.63–1.67 (1 H, dt, J = 7.8, 3.6 Hz), 1.39–
1.46 (2 H, m), 1.19–1.27 (3 H, m).
13C NMR (CDCl3, 150 MHz):  = 166.70, 135.21, 131.30, 128.58,
126.90, 48.75, 33.32, 25.66, 25.00.
According to the general procedure 3ai was obtained as a white solid
after extraction; yield: 13.81 mg (0.07 mmol, 14%).
1H NMR (CDCl3, 600 MHz):  = 7.86–7.88 (2 H, m), 7.81 (1 H, br), 7.64–
7.65 (2 H, d, J = 7.2 Hz), 7.54–7.56 (1 H, m), 7.48–7.51 (2H, t, J = 7.8
Hz), 7.37–7.39 (2H, m), 7.14–7.17 (1H, m).
13C NMR (CDCl3, 150 MHz):  = 165.78, 137.99, 135.11, 131.95,
(2-Methylpiperidin-1-yl)(phenyl)methanone (3ad)
129.20, 128.91, 127.08, 124.67, 120.24.
According to the general procedure 3ad was purified by column chro-
matography as a white solid (EtOAc/n-hexane 1/1); yield: 7.11 mg
(0.04 mmol, 7%); Rf = 0.55 (50% EtOAc in n-hexane).
1H NMR (CDCl3, 600 MHz):  = 7.35–7.39 (5 H, m), 3.59–5.07 (2 H, br),
(S)-N-[1-(1H-indol-3-yl)-3-methoxybut-3-en-2-yl]benzamide (3aj)
According to the general procedure 3aj was purified by column chro-
matography as a white solid (EtOAc/n-hexane 1/1); yield: 57.77 mg
20
(0.16 mmol, 32%); Rf = 0.57 (50% EtOAc in n-hexane); []D +74.7 (c
2.96 (1 H, br), 1.41–1.64 (6 H, m), 1.21 (3 H, s).
0.40, CHCl3).
13C NMR (CDCl3, 150 MHz):  = 170.53, 137.18, 129.19, 128.50,
126.44, 30.38 (br), 26.14 (br), 18.97, 16.27 (br) (3 C overlapped in
broad peaks).
HRMS (ESI): m/z [M + Na]+ calcd for C13H17NONa+: 226.1208; found:
226.1201.
1H NMR (CDCl3, 600 MHz):  = 8.08 (1 H, s), 7.67–7.69 (2 H, m), 7.54–
7.55 (1 H, d, J = 7.92 Hz), 7.46–7.47 (1 H, m), 7.35–7.39 (3 H, m), 7.17–
7.20 (1 H, m), 7.07–7.09 (1 H, m), 7.01 (1 H, d, J = 2.4 Hz), 6.65–6.66 (1
H, d, J = 7.5 Hz), 5.14–5.16 (1 H, m), 3.72 (3 H, s), 3.42–3.46 (2 H, m).
13C NMR (CDCl3, 150 MHz):  = 172.58, 166.90, 136.13, 133.94,
131.77, 128.61, 127.86, 127.16, 122.86, 122.41, 119.86, 118.80,
111.35, 110.23, 53.53, 52.52, 27.76.
Phenyl(pyrrolidin-1-yl)methanone (3ae)
According to the general procedure 3ae was obtained as a white solid
after extraction; yield: 70.09 mg (0.40 mmol, 80%).
1H NMR (CDCl3, 600 MHz):  = 7.50–7.52 (2 H, m), 7.37–7.41 (3 H, m),
3.64–3.66 (2 H, t, J = 6.6 Hz), 3.41–3.44 (2 H, t, J = 7.2 Hz), 1.94–1.98 (2
H, m), 1.85–1.89 (2 H, m).
HRMS (ESI): m/z [M + Na]+ calcd for C19H18N2O3Na+: 345.1215; found:
345.1213.
Funding Information
13C NMR (CDCl3, 150 MHz):  = 169.80, 137.35, 129.82, 128.31,
127.15, 49.67, 46.23, 26.48, 24.54.
This work was supported by a MEXT Grant-in-aid for Scientific Re-
search on Innovative Areas (18H04247 to SS) and a JSPS Scientific Re-
search (B) (19H02713 to SS); and partially funded by Japan Society for
the Promotion of Science (JSPS) fellowship for foreign researchers
N,N-Dipropylbenzamide (3af)
According to the general procedure 3af was purified by column chro-
matography as a white solid (EtOAc/n-hexane 1/1); yield: 8.21 mg
(0.04 mmol, 8%); Rf = 0.71 (50% EtOAc in n-hexane).
(P18339 to DB).
M
i
n
i
stryof
E
d
u
c
ati
o
n
,
C
u
l
ture
,
S
p
orst,
S
c
i
e
n
c
e
a
n
d
T
e
c
h
n
o
l
o
g
y
(1
8
H
0
4
2
4
7)J
a
p
a
n
S
o
c
i
etyforth
e
Pro
m
oti
o
n
of
S
c
i
e
n
c
e
(1
9
H
0
2
7
1
3)J
a
p
a
n
S
o
c
i
etyforth
e
Pro
m
oti
o
n
of
S
c
i
e
n
c
e
(P
1
8
3
3
9)
1H NMR (CDCl3, 600 MHz):  = 7.29–7.32 (5 H, m), 3.49 (2 H), 3.10 (2
H), 1.63 (2 H), 1.46 (2 H), 0.92 (3 H), 0.68 (3 H).
Acknowledgment
13C NMR (CDCl3, 150 MHz):  = 171.82, 137.46, 129.03, 128.38,
126.49, 50.72, 46.31, 21.95, 20.75, 11.46, 11.05.
We acknowledge Messrs K. Oyama, Y. Maeda, H. Okamoto, and Ms. H.
Natsume for technical support.
HRMS (ESI): m/z [M + Na]+ calcd for C13H19NONa+: 228.1364; found:
228.1357.
Supporting Information
Morpholino(phenyl)methanone (3ag)
Supporting information for this article is available online at
According to the general procedure 3ag was obtained as a white solid
https://doi.org/10.1055/s-0040-1707174.
S
u
p
p
orit
n
gInformati
o
n
S
u
p
p
orit
n
gInformati
o
n
after extraction; yield: 60.24 mg (0.32 mmol, 63%).
1H NMR (CDCl3, 600 MHz):  = 7.39–7.43 (5 H, m), 3.45–3.78 (8 H,
overlapping).
References
13C NMR (CDCl3, 150 MHz):  = 170.51, 135.42, 129.95, 128.64,
127.16, 66.98, 48.32, 43.17.
(1) Vinogradov, A. A.; Yin, Y.; Suga, H. J. Am. Chem. Soc. 2019, 141,
4167.
(2) Ghose, A. K.; Viswanadhan, V. N.; Wendoloski, J. J. J. Comb. Chem.
1999, 1, 55.
N-(Furan-2-ylmethyl)benzamide (3ah)
(3) Constable, D. J. C.; Dunn, P. J.; Hayler, J. D.; Humphrey, G. R.;
Leazer, J. L.; Linderman, R. J.; Lorenz, K.; Manley, J.; Pearlman, B.
A.; Wells, A.; Zaks, A.; Zhang, T. Y. Green Chem. 2007, 9, 411.
(4) Jursic, B. S.; Zdravkovdki, Z. Synth. Commun. 1993, 23, 2761.
According to the general procedure 3ah was obtained as a white solid
after extraction; yield: 70.43 mg (0.35 mmol, 70%).
1H NMR (CDCl3, 600 MHz):  = 7.78–7.79 (2 H, d, J = 7.2 Hz), 7.48–7.51
(1 H, m), 7.41–7.43 (2 H, m), 7.37 (1 H), 6.51 (1 H, br), 6.33–6.34 (1 H,
dd, J = 3, 1.8 Hz), 6.29 (1 H, d, J = 2.4 Hz), 4.63–4.64 (2 H, d, J = 6 Hz).
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–J

J
F. S. Movahed et al.
Special Topic
Synthesis
(5) (a) Carpino, L. A. J. Am. Chem. Soc. 1993, 115, 4397. (b) El-Faham,
A.; Albericio, F. J. Pept. Sci. 2010, 16, 6. (c) Subiros-Funosas, R.;
Prohens, R.; Barbas, R.; El-Faham, A.; Albericio, F. Chem. Eur. J.
2009, 15, 9394. (d) König, W.; Geiger, R. Chem. Ber. 1970, 103,
788. (e) König, W.; Geiger, R. Chem. Ber. 1970, 103, 2034.
(6) (a) de Azambuja, F.; Parac-Vogt, T. N. ACS Catal. 2019, 9, 10245.
(b) Lundberg, H.; Tinnis, F.; Selander, N.; Adolfsson, H. Chem.
Soc. Rev. 2014, 43, 2714. (c) Pattabiraman, V. R.; Bode, J. W.
Nature 2011, 480, 471. (d) de Figueiredo, R. M.; Suppo, J. S.;
Campagne, J. M. Chem. Rev. 2016, 116, 12029. (e) Georgiou, I.;
Ilyashenko, G.; Whiting, A. Acc. Chem. Res. 2009, 42, 756.
(f) Charville, H.; Jackson, D.; Hodges, G.; Whiting, A. Chem.
Commun. 2010, 46, 1813.
(7) (a) Muramatsu, W.; Hattori, T.; Yamamoto, H. J. Am. Chem. Soc.
2019, 141, 12288. (b) Muramatsu, W.; Yamamoto, H. J. Am.
Chem. Soc. 2019, 141, 18926. (c) Tsuji, H.; Yamamoto, H. J. Am.
Chem. Soc. 2016, 138, 14218.
(8) Handoko; Satishkumar, S.; Panigrahi, N. R.; Arora, P. S. J. Am.
Chem. Soc. 2019, 141, 15977.
(9) (a) Ishihara, K.; Ohara, S.; Yamamoto, H. J. Org. Chem. 1996, 61,
4196. (b) Ishihara, K.; Kondo, S.; Yamamoto, H. Synlett 2001,
1371. (c) Ishihara, K.; Ohara, S.; Yamamoto, H. Macromolecules
2000, 33, 3511. (d) Maki, T.; Ishihara, K.; Yamamoto, H. Org. Lett.
2006, 8, 1431. (e) Maki, T.; Ishihara, K.; Yamamoto, H. Tetrahe-
dron 2007, 63, 8645. (f) Al-Zoubi, R. M.; Marion, O.; Hall, D. G.
Angew. Chem. Int. Ed. 2008, 47, 2876. (g) Sakakura, A.; Ohkubo,
T.; Yamashita, R.; Akakura, M.; Ishihara, K. Org. Lett. 2011, 13,
892. (h) Sakakura, A.; Yamashita, R.; Ohkubo, T.; Akakura, M.;
Ishihara, K. Aust. J. Chem. 2011, 64, 1458. (i) Gernigon, N.; Al-
Zoubi, R. M.; Hall, D. G. J. Org. Chem. 2012, 77, 8386.
(j) Yamashita, R.; Sakakura, A.; Ishihara, K. Org. Lett. 2013, 15,
3654. (k) Ishihara, K. Top. Organomet. Chem. 2015, 49, 243.
(l) Mohy El Dine, T.; Erb, W.; Berhault, Y.; Rouden, J.; Blanchet, J.
J. Org. Chem. 2015, 80, 4532. (m) Ishihara, K.; Lu, Y. Chem. Sci.
2016, 7, 1276. (n) Lu, Y.; Wang, K.; Ishihara, K. Asian J. Chem.
2017, 6, 1191. (o) Wang, K.; Lu, Y.; Ishihara, K. Chem. Commun.
2018, 54, 5410. (p) Arkhipenko, S.; Sabatini, M. T.; Batsanov, A.
S.; Karaluka, V.; Sheppard, T. D.; Rzepa, H. S.; Whiting, A. Chem.
Sci. 2018, 9, 1058.
(11) (a) Charville, H.; Jackson, D. A.; Hodges, G.; Whiting, A.; Wilson,
M. R. Eur. J. Org. Chem. 2011, 5981. (b) Montalbetti, C. A. G. N.;
Falque, V. Tetrahedron 2005, 61, 10827. (c) Perreux, L.; Lpoupy,
A.; Volatron, F. Tetrahedron 2002, 58, 2155.
(12) Sawant, D. N.; Bagal, D. B.; Ogawa, S.; Selvam, K.; Saito, S. Org.
Lett. 2018, 20, 4397.
(13) (a) de Oliveira, V. M.; de Jesus, R. S.; Gomes, A. F.; Gozzo, F. C.;
Umpierre, A. P.; Suarez, P. A. Z.; Rubim, J. C.; Neto, B. A. D. Chem-
CatChem 2011, 3, 1911. (b) Allen, C. L.; Chhatwal, A. R.;
Williams, J. M. J. Chem. Commun. 2012, 48, 666. (c) Rahman, M.;
Kundu, D.; Hajra, A.; Majee, A. Tetrahedron Lett. 2010, 51, 2896.
(d) Shekhar, A. C.; Kumar, A. R.; Sathaiah, G.; Paul, V. L.; Sridhar,
M.; Rao, P. S. Tetrahedron Lett. 2009, 50, 7099. (e) Reddy, C. S.;
Nagaraj, A.; Jalapathi, P. Chin. Chem. Lett. 2007, 18, 1213.
(f) Allen, C. L.; Williams, J. M. J. Chem. Soc. Rev. 2011, 40, 3405.
(14) (a) Shioiri, T.; Ninomiya, K.; Yamada, S. J. Am. Chem. Soc. 1972,
94, 6203. (b) Kokare, N. D.; Nagawade, R. R.; Rane, V. P.; Shinde,
D. B. Synthesis 2007, 766. (c) Klose, J.; Bienert, M.; Mollenkopf,
C.; Wehle, D.; Zhang, C. W.; Carpino, L. A.; Henklein, P. Chem.
Commun. 1999, 1847. (d) Brady, S. F.; Freidinger, R. M.;
Paleveda, W. J.; Colton, C. D.; Homnick, C. F.; Whitter, W. L.;
Curley, P.; Nutt, R. F.; Veber, D. F. J. Org. Chem. 1987, 52, 764.
(e) Ying, J.; Lin, R.; Xu, P.; Wu, Y.; Liu, Y.; Zhao, Y. Sci. Rep. 2018,
8, 936.
(15) Bayne, J. M.; Stephan, D. W. Chem. Soc. Rev. 2016, 45, 765.
(16) (a) Sakakura, A.; Sakuma, M.; Katsukawa, M.; Ishihara, K. Het-
erocycles 2008, 76, 657. (b) Yadav, M.; Krishnamurthy, R. Org.
Lett. 2019, 21, 7400.
(17) (a) Du, Y.; Oishi, S.; Saito, S. Chem. Eur. J. 2011, 17, 12262.
(b) Foo, S. W.; Oishi, S.; Saito, S. Tetrahedron Lett. 2012, 53, 5445.
(18) (a) Allcock, H. R.; Walsh, E. J. J. Am. Chem. Soc. 1972, 94, 4538.
(b) Allcock, H. R.; Walsh, E. J. J. Am. Chem. Soc. 1969, 91, 3102.
(c) Allcock, H. R. Chem. Rev. 1972, 72, 315. (d) Allcock, H. R.;
Walsh, E. J. J. Am. Chem. Soc. 1972, 94, 119.
(19) Allcock, H. R.; Sunderland, N. J. Macromolecules 2001, 34, 3069.
(20) (a) Knowles, J. R. Annu. Rev. Biochem. 1980, 49, 877.
(b) Wiegand, T. W.; Janssen, R. C.; Eaton, B. E. Chem. Biol. 1997,
4, 675. (c) Wilcox, M.; Nirenberg, M. Proc. Natl. Acad. Sci. U. S. A.
1968, 61, 229.
(10) (a) Noda, H.; Furutachi, M.; Asada, Y.; Shibasaki, M.; Kumagai, N.
Nat. Chem. 2017, 9, 571. (b) Liu, Z.; Noda, H.; Shibasaki, M.;
Kumagai, N. Org. Lett. 2018, 20, 612. (c) Opie, C. R.; Noda, H.;
Shibasaki, M.; Kumagai, N. Chem. Eur. J. 2019, 25, 4648.
(d) Noda, H.; Asada, Y.; Shibasaki, M.; Kumagai, N. J. Am. Chem.
Soc. 2019, 141, 1546.
(21) (a) Tian, N.-N.; Wang, L.-S.; Jiang, R.-Y. J. Chem. Eng. Data 2011,
56, 3208. (b) Zhou, F.; Gu, K. H.; Zhang, Z. Y.; Zhang, M. Y.; Zhou,
S.; Shen, Z.; Fan, X. H. Angew. Chem. Int. Ed. 2016, 55, 15007.
(c) Comotti, A.; Bracco, S.; Ferretti, L.; Mauri, M.; Simonutti, R.;
Sozzani, P. Chem. Commun. 2007, 350.
(22) Saito, S.; Noyori, R. JP Patent filed: 2013-065083; opened: 2014-
189509, 2014.
(23) Ye, C.; Zhang, Z.; Liu, W. Synth. Commun. 2002, 32, 203.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–J