Heterocyclic thiolates and phosphine ligands in copper-catalyzed synthesis of propargylamines in water

Article abstract of DOI:10.1002/aoc.6180

The product obtained by reaction of deprotonation of 2-mercaptobenzothiazole or methimazole (2-mercapto-1-methylimidazole) with copper iodide in the presence of tertiary phosphines, PR₂R' (R = R' = cyclohexyl; R = R' = phenyl; R = phenyl, R' = methyl) showed high catalytic activity in A³ coupling of a series of aldehydes with phenylacetylene and piperidine, yielding propargylamines. An investigation into the nature of active species carried out mainly by electrospray ionization mass spectrometry (ESI-MS) techniques underscores a crucial role played by organosulfur and organophosphorus compounds in the generation of active species responsible for these reactions. The coupling reactions were successfully carried out at low catalyst loadings in water/THF (20:1) and in relatively short reaction times. The scope of the reaction was also investigated with 20 examples.

Full text of DOI:10.1002/aoc.6180

Received: 6 November 2020
DOI: 10.1002/aoc.6180
Revised: 26 December 2020
Accepted: 17 January 2021
F U L L P A P E R
Heterocyclic thiolates and phosphine ligands in copper-
catalyzed synthesis of propargylamines in water
Abdollah Neshat1
Piero Mastrorilli2
Farzane Osanlou1
| Mohammad Gholinejad1 | Mahmoud Afrasi1
| Stefano Todisco2 | Shirin Gilanchi1
|
|
1Department of Chemistry, Institute for
Advanced Studies in Basic Sciences
(IASBS), Zanjan, Iran
2DICATECh Department Politecnico di
Bari, Bari, Italy
The
product
obtained
by
reaction
of
deprotonation
of
2-mercaptobenzothiazole or methimazole (2-mercapto-1-methylimidazole)
with copper iodide in the presence of tertiary phosphines, PR2R'
(R = R' = cyclohexyl; R = R' = phenyl; R = phenyl, R' = methyl) showed high
catalytic activity in A3 coupling of a series of aldehydes with phenylacetylene
and piperidine, yielding propargylamines. An investigation into the nature of
active species carried out mainly by electrospray ionization mass spectrometry
(ESI-MS) techniques underscores a crucial role played by organosulfur and
organophosphorus compounds in the generation of active species responsible
for these reactions. The coupling reactions were successfully carried out at low
catalyst loadings in water/THF (20:1) and in relatively short reaction times.
The scope of the reaction was also investigated with 20 examples.
Correspondence
Abdollah Neshat, Department of
Chemistry, Institute for Advanced Studies
in Basic Sciences (IASBS), Zanjan
45137-66731, Iran.
Email: a.neshat@iasbs.ac.ir
Funding information
Institute for Advanced Studies in Basic
Sciences (IASBS) Research Council
K E Y W O R D S
2-mercaptobenzothiazole, A3 coupling, catalysis, methimazole, propargylamines
1 | INTRODUCTION
allowed their surface decoration with transitions metal
ions via grafting techniques.[23,24] Transition metal ion-
Propargylamines are important compounds in the
synthesis of pharmaceutical and natural products,
particularly in the treatment of Alzheimer's and
Parkinson's diseases.[1] Classic methods for the synthe-
sis of propargylamines utilized stoichiometric reaction
of lithium acetylides or Grignard reagents with imine
derivatives that required inert atmosphere and dry
solvents.[2] Currently, an atom-economic and efficient
pathway for the preparation of propargylamines is
transition metal catalyzed coupling of aldehydes with
alkynes and amines, which is commonly known as A3
coupling reactions.[3] Silver chloride salt or silver
nanoparticles in combination with tertiary phosphines
is a well-established method to efficiently catalyze A3
coupling reactions in water.[4–22] Progress in the synthe-
sis of highly ordered mesoporous organic polymers has
grafted mesoporous organic polymers were utilized
by various groups as efficient catalysts in the mul-
ticomponent coupling reactions. Grafting techniques in
these systems have allowed efficient recoverability and
reusability of catalysts for several reactions runs.
Besides, the polar nature of these catalysts has also
allowed carrying out catalytic reactions in an aqueous
media.[25–27]
Efficient catalysts based on N-heterocyclic carbene
complexes of coinage metals have been developed during
past few years.[28–37] Copper-based catalysts because of
natural abundance of copper metal and high reactivity
have also attracted great attention.[38]
In our quest to develop a novel and highly efficient
homogeneous catalytic system based on copper, we
observed that mixing copper iodide with deprotonated
Appl Organomet Chem. 2021;35:e6180.
wileyonlinelibrary.com/journal/aoc
© 2021 John Wiley & Sons, Ltd.
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https://doi.org/10.1002/aoc.6180

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NESHAT ET AL.
2-mercaptobenzothiazole or 2-mercapto-1-methylimidazole
(methimazole), in the presence of monodentate tertiary
phosphines, afforded efficient catalyst precursors for the
synthesis of propargylamines via A3-coupling reactions.
Previous reports dealing with complexes of copper
ions with phosphine and neutral heterocyclic thiones
revealed that in the majority of these compounds,
heterocyclic thiones prefer a monodentate binding
mode, coordinating exclusively through exocyclic sulfur
atom.[39–43] Due to soft nature of sulfur atom in hetero-
cyclic thiones, we speculated that copper–phosphine
complexes with thiolates would provide interesting
mixed-ligand coordination complexes, suitable for
certain catalytic reactions. Structural characterization of
a catalytic system is an important step in aiming at
mechanistic understanding of a catalytic process. There-
fore, we set out to explore true nature of main species
under “operando”-conditions, identical to the conditions
of the catalytic application. In our employed synthetic
route, the expected metal complexes comprising
both phosphine and thionate ligands were formed in
small quantity. However, the investigation of true
nature of catalyst revealed that copper (I) phosphine
and Cu (II) thiolates are highly active catalysts in A3
coupling reactions even in water at room temperature
(rt) reactions.
2.2 | Synthesis of 1–3
2-Mercaptobenzothiazol (100 mg, 0.60 mmol) was dis-
solved in 5.0 ml of ethanol. Then, potassium hydroxide
(33 mg, 0.60 mmol) was added to the flask, and the mix-
ture was stirred for 10 min before the addition of CuI
(113 mg, 0.60 mmol). Finally, an appropriate phosphine
(tricyclohexylphosphine [167 mg, 0.60 mmol], or
methyldiphenylphosphine [110 μl, 0.60 mmol] or
triphenylphosphine [156 mg, 0.60 mmol]) was added.
After overnight stirring, the resulting orange powder was
collected by filtration and dried under nitrogen gas.
Yield: 230 mg (mixture 1), 212 mg (mixture 2), and
122 mg (mixture 3).
2.3 | Synthesis of 4–6
Methimazole (100 mg, 0.88 mmol) was dissolved in
5.0-ml ethanol. Then, potassium hydroxide (49 mg,
0.88 mmol) was added to the flask, and the mixture was
stirred for 10 min before the addition of CuI (160 mg,
0.88 mmol). Finally, an appropriate phosphine
(tricyclohexylphosphine [240 mg, 0.88 mmol], or
methyldiphenylphosphine [163 μl, 0.88 mmol] or
triphenylphosphine [220 mg, 0.88 mmol]). After over-
night stirring, the resulting white solid was collected by
filtration and dried under nitrogen gas. Yield: 245 mg
(mixture 4), 232 mg (mixture 5), and 156 mg (mixture 6).
2 | EXPERIMENTAL SECTION
2.1 | General considerations
Reagents and solvents were used as received from
commercial suppliers. Infrared spectra were recorded
on a Bruker Vector 22 Fourier-transform infrared
spectroscopy (FT-IR) spectrometer (ATR in the range
400–4,000 cm−1). NMR spectra in solution were
recorded on a Bruker AV-400 spectrometer with SiMe4
2.4 | Synthesis of 10
2-Mercaptobenzothiazole (50 mg, 0.3 mmol) was
dissolved in 5.0-ml ethanol. Then, potassium hydroxide
(17 mg, 0.3 mmol) was added to the flask, and the
mixture was stirred for 10 min before the addition of CuI
(56 mg, 0.15 mmol). After 12 h stirring, the resulting
yellow solid was collected by filtration and dried under
nitrogen gas. Yield: 70 mg, 59%. The same complex could
be obtained starting from Cu (II) acetate in methanol.
1
for H and 13C as external references. High-resolution
mass spectrometry (HR-MS) analyses were performed in
positive mode using a time-of-flight mass spectrometer
equipped with an electrospray ion source (Bruker
micrOTOF II). The sample solutions were introduced
(as diluted acetonitrile solutions) by continuous infu-
sion with the aid of a syringe pump at a flow rate of
180 μl/h. The instrument was operated at end plate
offset −500 V and capillary −4,500 V. The nebulizer
pressure was 0.3 bar (N2) and the drying gas (N2) flow
4.0 L/min. Capillary exit was 170 V. The drying gas
temperature was set at 180ꢀC. The software used for
the simulations is Bruker Daltonics Data Analysis
(version 4.0). For all described HRMS peaks, the isoto-
pic patterns were superimposable with those calculated
on the basis of the proposed formulae.
2.5 | Catalytic runs
To a 5-ml flask containing aldehyde (0.50 mmol), amine
(0.75 mmol), phenylacetylene (0.75 mmol) and catalysts
(2 mg), and H2O:THF (10:1, 2 ml) was added, and
reaction mixture was stirred for appropriate reaction
times at rt. The progress of the reactions was investigated
by thin-layer chromatography or H-NMR. After comple-
tion of the reaction, the crude product was extracted with
ethyl acetate (3 × 5 ml). Subsequent purification was
1

NESHAT ET AL.
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performed by column or plate chromatography using
hexane and ethyl acetate as eluents. All products were
characterized by 1H-NMR and 13C-NMR.
These data can be obtained free of charge from The Cam-
bridge Crystallographic Data Centre via www.ccdc.cam.
ac.uk/data_request/cif.
2.6 | X-ray crystallography
3 | RESULTS AND DISCUSSIONS
Crystal data and other details of the structure analysis are
compiled in Table 3. Diffraction quality crystals of
[(PPh2Me)3Cu(I)] were obtained by slow evaporation of
the solvent from a concentrated acetonitrile solution.
Structural determination was performed on a crystal of
approximate dimensions 0.3 × 0.3 × 0.2 mm using a
STOE IPDS II automated diffractometer equipped with a
four-circle Kappa goniometer, an image plate detector,
and a monochromatized Mo Kα radiation. The X-ray dif-
fraction (XRD) measurement was carried out on STOE
IPDS 2 T diffractometer with graphite-monochromated
Mo Kα radiation. Cell constants and an orientation
matrix for data collection were obtained by least-square
refinement of the diffraction data for [(PPh2Me)3Cu(I)].
Diffraction data were collected in a series of ω scans in 1ꢀ
oscillations and integrated using the Stoe X-AREA soft-
ware package.[44] Numerical absorption correction was
applied using the X-Red32 software. The structure was
solved by direct methods and subsequent difference
Fourier maps and then refined on F2 by a full-matrix
least-squares procedure using anisotropic displacement
parameters. All nonhydrogen atoms were refined with
anisotropic displacement parameters. All refinements
were performed using the X-STEP32, SHELXL-2014, and
WinGX-2013.3 programs.[45–52] CIF was visualized using
Olex-2-1.2. CCDC-2035215 for [(PPh2Me)3Cu(I)] contain
the supplementary crystallographic data for this paper.
Deprotonation
of
2-mercaptobenzothiazole
or
2-mercapto-1-methylimidazole was carried out in ethanol
by its reaction with potassium hydroxide. Then, equimo-
lar amounts of copper iodide and an appropriate phos-
phine ligand was added consecutively, resulting, after
work-up, in a yellow (mixtures 1–3) and white powder
(mixtures 4–6), respectively, as shown in Scheme 1.
The catalytic activity of the so-prepared mixtures 1–6
was studied in A3 coupling. The reaction of
phenylacetylene (0.75 mmol), piperidine (0.75 mmol),
and benzaldehyde (0.50 mmol) in water/THF (10:1) was
chosen as a model reaction. Using 2.0 mg of Cu-
containing mixture at rt, quantitative yields in
propargylamine were obtained for all of precatalysts 1–3
(entries 1–3 of Table 1). Under the same conditions, but
after 4 h of reactions, the propargylamine product was
produced in 86% yield using 1 (entry 4, Table 1), and in
98% yield using 2 and 3 (entries 5–6, Table 1). Very good
yields (73%–98%, entries 7–9, Table 1) were also obtained
after 24 h using 2.0 mg of mixtures 1–3 but with quadru-
pled amount of reactants. A control experiment involving
2-mercaptobenzothiazole (entry 16, Table 1) in the
absence of metal revealed crucial catalytic role of copper
complexes in these coupling reactions.
Mixture 3 was then studied for the coupling reaction
of structurally different aldehydes with amines and
alkynes under optimized reaction condition (12-h
SCHEME 1 The procedure for the
synthesis of copper complexes (mixture
1–6) bearing thiolate and phosphine
ligands

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NESHAT ET AL.
TABLE 1 Optimization of the
reaction conditions for the reaction of
benzaldehyde, piperidine, and
phenylacetylene using mixtures 1, 2,
and 3a
Entry
Precatalyst
Temp (ꢀC)
Time (h)
Yield (%)b
>99
>99
>99
86
1
1
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
12
"
2
2
3
3
"
4
1
4
5
2
"
98
6
3
"
98
7c
8c
9c
10
11
12
13
14
15
16
1
12
"
83
2
73
3
"
98
[(PPh2Me)3Cu(I)]
12
12
12
12
"
73
Orange residue
56
4
100
75
5
6
80
10
12
12
98
2-Mercaptobenzothiazole
<2
aReaction conditions: benzaldehyde (0.50 mmol), piperidine (0.75 mmol), phenylacetylene (0.75 mmol),
H2O: THF (20:1, 2.0 ml), and 2.0 mg of precatalyst.
bYields were determined by 1HNMR.
cThe amount of reactants was quadrupled compared with entries 1–6.
reaction time, 2.0-mg precatalyst and rt). Results, col-
lected in Table 2, showed excellent yields for various aro-
matic aldehydes having electron-withdrawing groups
(entries 2–5, Table 2) as well as for aldehydes containing
electron-donating groups (entries 6–10, Table 2) in 12 h.
It is worth mentioning that using mixture 3, the reaction
of heterocyclic and challenging aldehydes were carried
out successfully, and the corresponding propargylamines
were obtained in excellent yields (entries 11–14, Table 2).
Reaction of 3-pyridinecarboxaldehyde with piperidine
and pyrrolidine was also investigated and the yields were
98% and 97%, respectively (entries 11 and 12, Table 2).
Furthermore, reactions of 3-thiophenecarbaldehyde with
piperidine and 2-thiophenecarbaldehyde with mor-
pholine gave 92% and 91% yields, respectively (entries
13 and 14, Table 2). In addition, reactions of biphenyl-
4-carboxaldehyde with piperidine and phenylacetylene
gave excellent yield in 24 h (entry 15, Table 2).
aliphatic alkyne with benzaldehyde and piperidine were
studied affording desired products in 89% and 83% yields,
respectively (entries 16 and 17, Table 2). Finally,
reactions of diverse amines such as pyrrolidine, mor-
pholine, and dimethylamine with benzaldehyde and
phenylacetylene
proceeded
smoothly
and
the
corresponding products were obtained in 97% yield
1
(entries 18–20, Table 2). H NMR and 13C NMR spectra
of all products listed in Table 2 (entries 1–20) are pro-
vided in the supporting information.
In order to gain insights into the active species operat-
ing in the in-situ process for catalytic A3 coupling reac-
tions from mixtures 1–3, we carried out a crystallization
in conditions similar to those of the catalytic runs. Thus,
20 mg of each mixture was gently warmed at 50ꢀC–60ꢀC
in acetonitrile for 2 h and let to cool down to
rt. Although only powder precipitated from mixtures
1 and 3, in the case of mixture 2, colorless crystals suit-
able for XRD analysis were obtained, along with a light
orange solid (in the following: orange residue). The
Reactions of heptanal as an aliphatic aldehyde with
piperidine and phenylacetylene and also 1-octyne as an

NESHAT ET AL.
5 of 12
TABLE 2 Products from reactions of various aldehydes, amines, and alkynes obtained in the presence of mixture 3a
(entry 1) 97%
(entry 2) 93%
(entry 3) 89%
(entry 4) 91%
(entry 6) 94%
(entry 5) 90%
(entry 9) 93%
(entry 8) 90%
(entry 7) 91%
(entry 10) 88%
(entry 13) 92%
(entry 12) 97%
(entry 11) 98%
(entry 14) 91%
(entry 15)b
90%
(entry 16)b
(entry 18) 97%
(entry 17)b 82%
89%
(entry 20) 97%
(entry 19) 97%
aReaction conditions: aldehyde (1 mmol), amine (1.5 mmol), alkyne (1.5 mmol), H2O: THF (20:1, 2 ml), and precatalyst 3 (2 mg) at room temperature. Reaction
time: 12 h. Isolated yields.
bReaction time: 24 h.

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NESHAT ET AL.
TABLE 3 Crystallographic data and structural refinement
details for [(PPh2Me)3CuI]
Chemical formula
C39H39CuIP3
791.06
Mr
Crystal system, space
group
Orthorhombic, Pna21
Temperature (K)
298(2) K
a, b, c (Å)
20.258(4), 10.484(2) Å, c = 17.388
(4) Å
V (Å3)
3,693.0(13) Å3
Z
4
Radiation type
Crystal size (mm)
Diffractometer
Mo Kα
0.300 × 0.300 × 0.200
STOE IPDX II diffractometer
R[F2 > 2σ(F2)], wR(F2), S 0.0526, 0.1087, 0.959
No. of reflections
No. of parameters
11,040
400
FIGURE 1 View of the molecular structure of [(PPh2Me)3CuI]
however, signals related to coordinated ligands in the mix-
tures were observed. 1H NMR spectrum of 1 showed
tricyclohexylphosphine and 2-mercaptobenzothiazole sig-
nals as multiplets at 2.21–0.86 ppm and 7.56–7.04 ppm,
molecular structure of the crystals obtained from 2 is
shown in Figure 1 and reveals a monomeric tetrahedral
[(PPh2Me)3Cu(I)] complex in which the P–Cu–P and
P–Cu–I angles lie close to the tetrahedral angle of 109.5ꢀ.
To check whether [(PPh2Me)3Cu(I)] or the orange resi-
due were the active species in the mixture 2, we carried
out coupling reactions at rt for 12 h using 2.0 mg of
[(PPh2Me)3CuI] or 2.0 mg of the orange residue. In the
case of [(PPh2Me)3CuI], the yield dropped to 73% (entry
10, Table 1), whereas a 56% yield was achieved with the
orange residue (entry 11, Table 1). This results seem to
indicate that the thiolate heterocycle and a phosphine
copper(I) complex synergically catalyze the A3 reaction
in our conditions (Table 3).
1
respectively (Figure S1). In the H NMR spectrum of 3,
Figure S2, triphenylphosphine multiplets observed at
7.70–7.01 ppm. These data confirm abovementioned
hypothesis that heteroleptic species 7–9 are formed in the
synthesis of 1–3, described in Scheme 1. A high intensity
13C NMR spectrum for mixture 1 could not be obtained;
however, sharp signals for coordinated triphenylphosphine
ligand were observed in the 13C spectrum of mixture 3. In
the 31P NMR spectrum of 1 (Figure S8), two signals are
observed perhaps related to [Cu (PCy3)(CH3CN)]+,
observed via ESI-MS, and heteroleptic 7. Only one 31P sig-
nal (Figure S9) was observed for mixture 3.
We decided therefore to submit mixtures 1–3 to HR
ESI-MS analysis. The HRMS(+) analysis of 1, 2, and 3 in
acetonitrile gave intense peaks due to [Cu (PCy3)
(CH3CN)]+, [Cu (PPh2Me)2]+, and [Cu (PPh3)2]+ ions,
respectively, as shown in Figures 2–4.
FT-IR and UV data of 1 and 3 are provided in the
supporting information. Both displayed characteristic
sharp bands related to aliphatic and aromatic C–H
stretching vibrations between 2,800 and 3,100 cm−1 as
well as C N and C C stretching vibrations from 1,300
Although signals for the expected heteroleptic copper
complexes 7, 8, and 9, in Figure 5,[53] were not present in
the spectrograms, we propose that in mixtures 1–3 hetero-
leptic species similar to 7–9 (of general formula
to 1,650 cm−1
.
Distinct π–π* transitions from
2-mercaptobenzothiazole aromatic ring were observed in
the UV–Vis. spectra of 1 and 3 at 331 and 326 nm, respec-
tively. An absorption band at 229 nm is indicative of
coordinated triphenylphosphine ligand in mixture
3 (Figures S16 and S17).
As to the nature of the orange residue, it was found
that it contained, together with other minor species, the
homoleptic complex Cu(κ2-S,N)2 (S^N deprotonated
2-mercaptobenzothiazole) (10 in Figure 5), as shown by
comparison of the IR spectrum of the orange residue with
[(PR2R')xCuy(S^N)z],
with
S^N
deprotonated
2-mercaptobenzothiazole) can form and possibly be active
as catalysts. If this hypothesis is correct, the ions detected
by ESI-MS may be formed in the ionization chamber by
loss of deprotonated 2-mercaptobenzothiazole. Due to
mixed nature of metal complexes formed during the syn-
thesis of 1–6, a clear-cut NMR data could not be obtained;

NESHAT ET AL.
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FIGURE 2 HRMS(+) spectrogram of 1 in acetonitrile showing the peak corresponding to [Cu (PCy3)(CH3CN)]+. Top: experimental;
bottom: calculated
FIGURE 3 HRMS(+) spectrogram of 2 in acetonitrile showing the peak corresponding to [Cu (PPh2Me)2]+. Top: experimental; bottom:
calculated

8 of 12
NESHAT ET AL.
FIGURE 4 HRMS(+) spectrogram of 3 in acetonitrile showing the peak corresponding to [Cu (PPh3)2]+. Top: experimental; bottom:
calculated
FIGURE 5 Proposed formulae of thiolate copper complexes. The presence of above copper complexes in 1–6 mixtures was shown by
electrospray ionization mass spectrometry (ESI-MS) analysis
that of an authentic sample of 10 (Figure 6). The forma-
tion of 10 can occur by air oxidation of Cu(I) to Cu
(II) and the fact that it was not detected by ESI-MS(+)
analysis of 1–3 seems to indicate that it forms when mix-
tures 1–3 are heated in acetonitrile. Another possibility is
that complex 10 can be present in mixtures 1–3, but it is
reluctant to be ionized in our experimental conditions
(see below). To further confirm the structure of orange
residue, its UV–Vis. spectra was compared with that of
10, which shows almost complete overlap of their major
peak at 330 and 326 nm (Figures S20 and S21).
catalyst loading (entry 15, Table 1), indicating 10 as one
possible active species for the A3 coupling.
As mentioned above, we prepared mixtures similar
to 1–3 but with deprotonated methimazole in place
of 2-mercaptobenzothiazole. Upon deprotonation,
methimazole can adopt a monodentate coordination
mode, binding through either sulfur or thioamido nitro-
gen atoms. A third mode in which a chelating κ2-S,N
coordination mode is adopted has also been reported.[54]
The chemistry of this molecule with a multitude of tran-
sition metals ions, including copper, has been reported in
the literature. Methimazole is a redox active molecule
and treating copper (II) salts such as copper (II) nitrate in
The catalytic activity of pure 10 was checked in the
A3 model reaction, and it showed excellent activity at low

NESHAT ET AL.
9 of 12
FIGURE 6 Fourier-transform infrared
spectroscopy (FT-IR) spectra of 10 (homoleptic
copper complex with thiolate ligands shown in
Figure 5) (top) and orange residue (bottom),
obtained by hot filtration of mixture 2 as
described in the text
air results in the copper reduction and formation of
methimazole disulfide and extrusion of one sulfur
atom.[53]
yield was obtained using mixture 4, the reaction gave a
75% yield using mixture 5 and 80% yield using mixture 6,
under identical coupling reaction conditions.
The catalytic activity of mixtures 4–6 was investigated
The ESI-MS(+) analysis of the mixtures prepared
with methimazole showed in all cases signals ascribable
in the model A3 coupling reaction. Although quantitative
FIGURE 7 HRMS(+) spectrogram of 4 in acetonitrile showing the peak corresponding to [Cu (PCy3)(CH3CN)]+. Top: experimental;
bottom: calculated

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NESHAT ET AL.
FIGURE 8 HRMS(+) spectrogram of 5 in acetonitrile showing the peak corresponding to [Cu (PPh2Me)(CH3CN)]+. Top: experimental;
bottom: calculated
FIGURE 9 HRMS(+) spectrogram of 6 in acetonitrile showing the peak corresponding to Cu(S^N)2 (S^N = deprotonated methimazole).
Top: experimental; bottom: calculated

NESHAT ET AL.
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to
copper
complexes
containing
deprotonated
in the A3 coupling of aldehyde, alkyne, and amine in
water/THF 20:1 at rt. Very satisfactory results were
obtained after 12 h reactions and the protocol, opti-
mized for the mixture with triphenylphosphine and
2-mercaptobenzothiazole, was applied for the synthesis
of 20 propargylamines with yields higher than 80%.
ESI-MS(+) analyses on mixtures 1–6 revealed the
presence of ions compatible with the formation of
heteroleptic Cu complexes bearing the phosphine and
the heterocyclic thiolate ligand, which are supposed to
play a crucial role in catalysis.
methimazole (S^N) in the coordination sphere. In partic-
ular, mixture 4 gave intense signals due to [Cu (PCy3)
(CH3CN)]+ (Figure 7) plus less intense signal due to
{[Cu (PCy3)(S^N)] + H}+ (found 457.1839 m/z; calculated
457.1868 Da); mixture
5
gave intense signals
corresponding to [Cu (PPh2Me)(CH3CN)]+ (Figure 8)
plus less intense signals due to {[Cu (PPh2Me)
(S^N)]
+
H}+ (found 377.0720 m/z; calculated
377.0303 Da); mixture
6
gave intense signals
corresponding to [Cu(S^N)2]+ (Figure 9) plus less intense
signals due to [Cu (PPh3)(CH3CN)]+ (found 366.0450
m/z; calculated 366.0473 Da). It should be noted that the
cation [Cu(S^N)2]+ presumably derives from mono-
electron oxidation of one S^N anionic ligands from [Cu
(S^N)2] (14 in Figure 5), a process that seems not opera-
tive in the case of analogous species with deprotonated
2-mercaptobenzothiazole. 1H NMR spectrum of 4 showed
signals related to coordained tricyclohexylphosphine
and methimazole as multiplets and a doublet at 1.89–1.26
and 6.66 ppm, respectively (Figure S3). A singlet for
ACKNOWLEDGMENTS
Funding from the Institute for Advanced Studies in Basic
Sciences (IASBS) Research Council is acknowledged.
AUTHOR CONTRIBUTIONS
Abdollah Neshat: Conceptualization; data curation;
formal analysis; project administration. Mohammad
Gholinejad: Data curation; formal analysis; project
administration. Mahmoud Afrasi: Data curation; formal
analysis. Piero Mastrorilli: Data curation; formal
analysis. Stefano Todisco: Data curation; formal analy-
sis. shirin gilanchi: Formal analysis. Farzane Osanlou:
Formal analysis.
1
methyl is also observed at 3.57 ppm. In the H NMR
spectrum of 6, triphenylphosphine multiplets were
observed at 7.35–7.21 ppm, as shown in Figure S2.
Methimazole resonance was observed as a doublet at
6.16 ppm. 13C spectra of 4 and 6 were consistent with
species observed in their ESI-MS spectrograms. Whereas
tricyclohexylphosphine resonances in 4 were observed in
25–35 ppm region, only signals related to methimazole
were observed for 6 at 125–135 ppm region, consistent
with [Cu(S^N)2]+ signals observed in its ESI-MS analysis.
Broad singlets observed at 31P spectra of 4 and 6,
Figures S10 and S11, revealed coordinated phosphine
ligands.
This results substantiate the formation of heteroleptic
thiolate/phosphine Cu complexes during the preparation
of mixtures 1–6 and validate the hypothesis that hetero-
cyclic thiolate copper complexes are the active species in
the A3 coupling reaction. The detection of Cu species
bearing the heterocyclic thiolate in mixtures with
methimazole, but not with 2-mercaptobenzothiazole may
be thus ascribed to different coordinating and redox prop-
erties of the two heterocyclic thiolates, with deprotonated
methimazole more prone to be oxidized and less prone to
dissociate from the metal, with respect to deprotonated
2-mercaptobenzothiazole.
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are avail-
able in the supporting information of this article.
ORCID
Abdollah Neshat https://orcid.org/0000-0002-1424-2292
Mahmoud Afrasi https://orcid.org/0000-0002-5492-
3869
Piero Mastrorilli https://orcid.org/0000-0001-8841-458X
Stefano Todisco https://orcid.org/0000-0001-7863-3105
Shirin Gilanchi https://orcid.org/0000-0002-4281-7997
Farzane Osanlou https://orcid.org/0000-0001-6092-
510X
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