Addition of Thiols to Isocyanates Catalyzed by Simple Rare-Earth-Metal Amides: Synthesis of S-Alkyl Thiocarbamates and Dithiocarbamates

Article abstract of DOI:10.1021/acs.organomet.9b00147

Simple additions of thiols to isocyanates/isothiocyanates under mild conditions led to the efficient preparation of various S-alkyl thiocarbamates and dithiocarbamates, respectively. The lanthanum complex La[N(SiMe₃)₂]₃ wa

Full text of DOI:10.1021/acs.organomet.9b00147

Article
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Cite This: Organometallics XXXX, XXX, XXX−XXX
Addition of Thiols to Isocyanates Catalyzed by Simple Rare-Earth-
Metal Amides: Synthesis of S‑Alkyl Thiocarbamates and
Dithiocarbamates
Chengrong Lu,† Lijuan Hu,† Bei Zhao,*,‡,† and Yingming Yao*,‡,†
†Key Laboratory of Organic Synthesis of Jiangsu Province and ‡College of Chemistry, Chemical Engineering and Materials Science,
Soochow University, Suzhou 215123, People’s Republic of China
S
* Supporting Information
ABSTRACT: Simple additions of thiols to isocyanates/
isothiocyanates under mild conditions led to the efficient
preparation of various S-alkyl thiocarbamates and dithiocar-
bamates, respectively. The lanthanum complex La[N-
(SiMe3)2]3 was found to be active to give thiocarbamates
and dithiocarbamates in medium to excellent yields with a
good group tolerance. A plausible mechanism of the catalytic
transformation was proposed on the basis of both
experimental observations and DFT calculations.
To the best of our knowledge, rare-earth-metal amides have
acted as active catalysts in a wide range of transformations.10
Very recently, the handy rare-earth-metal amides RE[N-
(SiMe3)2]3 were used successfully by our group to catalyze
guanylation/cyclization of carbodiimides and amino acid esters
and intermolecular addition of alcohols to carbodiimides.11 As
a continuation of our research on the rare-earth-metal-
mediated transformation, we herein report the addition of
thiols to phenyl isocyanates catalyzed by rare-earth-metal
amides. Furthermore, to get a deep insight into the plausible
mechanism of the current addition reaction, DFT calculations
were carried out.
INTRODUCTION
■
Thiocarbamates are useful compounds in biological medicine,1
agricultural chemistry,2 and organic sysnthesis.3 Up to now,
several strategies for the preparation of thiocarbamates were
established. First, the intramolecular rearrangement of
thiocarbonyl compounds under illumination was explored,
while the relatively narrow substrate scope limited its
application.4 A few multistep methods of thiocarbamate
formation were developed, mainly using the carbonylation of
amines, elemental sulfur, and carbon monoxide, followed by a
reaction with alkyl halides.5 The requirement of a large amount
of solvents and raw materials was unsatisfactory. A carbon-
ylation of anilines, thiols, and carbon monoxide mediated by
selenium or palladium was developed; the substrate anilines
can also be replaced by nitroarenes.6 The only fly in the
ointment there was that the method was not suitable for thiols
with large steric hindrance. An oxidative coupling of amines,
thiols, and carbon monoxide yielded thiocarbamates success-
fully by Jones’ group.7 However, a side reaction under the same
catalytic circumstances could not be avoided. The search for an
environmentally friendly and atom-economical method to
synthesize thiocarbamates is urgent. Hence, a method of
intermolecular addition of thiols and isocyanates was
established in succession. Though S-aryl-substituted thiocarba-
mates8a and N-alkyl-substituted thiocarbamates8b,c were easily
available, the more challenging preparation of S-alkyl-
substituted thiocarbamates is worthy of attention. Eisen
realized the catalytic addition of thiols to phenyl isocyanates
efficiently using early actinide amides.9 Nevertheless, the
radioactive catalysts they employed are slightly structurally
complicated and must be prepared under harsh conditions in
advance. Therefore, it is still meaningful to develop simple and
efficient catalytic systems to produce thiocarbamates with a
good functional group tolerance.
RESULTS AND DISCUSSION
■
Four complexes RE[N(SiMe3)2]3 (RE = La, Sm, Yb, Y) were
synthesized according to a previous work.10t As expected, the
model addition reaction of phenyl isocyanate (1a) with benzyl
thiol (2a) was catalyzed by 10 mol % La[N(SiMe3)2]3 to
obtain 83% of the desired product 3aa at 30 °C after 24 h
(Table 1, entry 1). A routine screening of the main factors that
may influence the transformation, including center metals of
the catalysts, catalyst loading, reaction time, temperature, and
solvent were conducted in turn. Different rare-earth-metal
amides were investigated, and all of the amides catalyzed the
model reaction smoothly (Table 1, entries 1−4). The
lanthanum amide La[N(SiMe3)2]3 shows the highest activity
among the catalysts. When the temperature decreased from 75
to 10 °C, the yields of the target product 3aa varied from 59%
to 86% (Table 1, entries 1 and 5−8). Some representative
polar and nonpolar solvents were also tested. Toluene was
Received: March 6, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.organomet.9b00147
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Table 1. Screening of the Optimal Conditions of the
Addition of 2a to 1a
Chart 1. Intermolecular Addition of Thiols and Phenyl
a b
a
,
Isocyanates Catalyzed by La[N(SiMe3)2]3
b
entry
cat. (loading/mol %)
T/°C
sol
t/h
yield/%
1
2
3
4
5
6
7
8
La[N(SiMe3)2]3 (10)
Sm[N(SiMe3)2]3 (10)
Yb[N(SiMe3)2]3 (10)
Y[N(SiMe3)2]3 (10)
La[N(SiMe3)2]3 (10)
La[N(SiMe3)2]3 (10)
La[N(SiMe3)2]3 (10)
La[N(SiMe3)2]3 (10)
La[N(SiMe3)2]3 (10)
La[N(SiMe3)2]3 (10)
La[N(SiMe3)2]3 (10)
La[N(SiMe3)2]3 (10)
La[N(SiMe3)2]3 (10)
La[N(SiMe3)2]3 (10)
La[N(SiMe3)2]3 (10)
La[N(SiMe3)2]3 (10)
La[N(SiMe3)2]3 (5)
La[N(SiMe3)2]3 (3)
La[N(SiMe3)2]3 (2)
La[N(SiMe3)2]3 (1)
La[N(SiMe3)2]3 (1)
La[N(SiMe3)2]3 (1)
La[N(SiMe3)2]3 (1)
30
30
30
30
10
40
60
75
40
40
40
40
40
40
40
40
40
40
40
40
40
40
40
40
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
30
36
30
24
83
79
75
79
81
86
67
59
97
92
89
22
58
86
81
52
98
85
81
81
96
97
21
82
9
toluene
PhCl
CHCl3
DMSO
DMF
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
THF
TBME
CH3CN
toluene
toluene
toluene
toluene
toluene
toluene
c
ate form complex (10)
THF
a
Conditions: phenyl isocyanate (1 mmol), benzyl thiol (1 mmol), 1
b
mL of solvent. Determined by 1H NMR of the crude reaction
mixture. The corresponding ate form complex [(Me3Si)2N]3La(μ-
c
a
Conditions unless specified otherwise: 1a−m (1 mmol), 2a−h (1
Cl)Li(THF)3 was used.
b
c
d
e
mmol). Isolated yield. 48 h. 1 (1 mmol), 2 (1.5 mmol). 1 (1
mmol), 2 (2 mmol).
proved to be the optimal solvent, for a 97% yield of 3aa was
obtained at 40 °C (Table 1, entries 9−16 and 24). Even
though the catalyst loading of amide La[N(SiMe3)2]3 was
reduced to 1 mol %, an 81% yield of 3aa was detected (Table
1, entries 17−20). Prolonging the reaction time to 30 and 36 h
leads to increases in the yield of 3aa to 96% and 97%,
respectively (Table 1, entries 21 and 22). Thus, the ideal
reaction time was chosen as 30 h, while the yield of 3aa was
only 21% at 30 h with 1 mol % catalyst loading under solvent-
free conditions (Table 1, entry 23).
The results of the intermolecular addition between various
phenyl isocyanates and benzyl thiols catalyzed by La[N-
(SiMe3)2]3 are presented in Chart 1. Phenyl isocyanates
bearing different substituents were first investigated under the
optimal reaction conditions of 1 mol % catalyst at 40 °C for 30
h. To our delight, most phenyl isocyanates gave high to
excellent yields, varying from 89% to 95%. Whether the groups
directly attached on the phenyl ring are electron donating or
electron withdrawing, the yields are nearly invariable (Chart 1,
3ba−ha). However, the steric hindrance of the substituent on
the ortho position of the phenyl isocyanates has a significant
effect on the outcomes, since the corresponding yields of
products 3ja−ma decreased after 30 h. A better yield can be
obtained by both prolonging the reaction time and increasing
the feed ratio of substrates (Chart 1, 3ja−ma). Several thiols,
including substituted benzyl thiols (2b−e), furan-2-
ylmethanethiol (2f), and cyclohexanethiol (2g), were tested
under the optimal reaction conditions as well. Different thiols
show excellent reactivities in the current catalytic system,
which gives satisfying yields of the corresponding thiocarba-
mates (Chart 1, 3ab−ag). The steric hindrance effect of thiols
also emerges, for the yield of product 3ah starting from bulky
thiols dropped significantly to 58% after 48 h (Chart 1, 3ah).
These results demonstrate an alternative approach to the
preparation of new thiocarbamates but more importantly
presents a novel reactivity for rare-earth-metal-mediated
catalysis.
Phenyl isothiocyanate is a sulfur-substituted analogue of
phenyl isocyanate; it is a valuable biological activated species12
and is vital in polymer chemistry,13 coordinate chemistry,14
and environmental chemistry.15 Naturally, the model addition
of benzyl thiol and phenyl isothiocyanate was studied under
the same conditions as the above transformation. The reaction
went smoothly, as expected; however, the isolated yield of
dithiocarbamate 5aa was only 75%. This revealed that the
reactivity of phenyl isothiocyanate is slightly less than that of
phenyl isocyanate (isolated yield of 90% for 3aa), and so the
reaction conditions for phenyl isothiocyanate required further
optimization. The main influencing factors, such as catalyst
loading and the ratio of the two reactants, were subsequently
modified. The results are given in Table 2.
B
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Table 2. Screening of the Optimal Conditions of the
Addition of 2a to 4a
Scheme 1. Proposed Mechanism for the Intermolecular
Addition of Benzyl thiols to Isocyanates in the Presence of
RE[N(SiMe3)2]3
a
b
entry
x
y
z
yield/%
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1.2
1
1
1
1
1
1
1
1
1
1.2
1.5
2
c
1
2
3
5
1
1
1
1
83 (75 )
82
83
79
73
89
94
96
a
Conditions: benzyl thiol (y mmol), phenyl isothiocyanate (z mmol),
b
1
1 mL of toluene. Determined by H NMR of the crude reaction
mixture. Isolated yield.
c
the protonolysis of a rare-earth-metal amide by a thiol affords
thiolate A. A stoichiometric reaction between the precatalyst
La[N(SiMe3)2]3 and benzyl thiol was detected by H NMR
The yields of product 5aa were almost the same (79−83%)
when the catalyst dosage was increased from 1 to 5 mol %
(Table 2, entries 2−5). Things started to change when the
molar ratio of the substrates changed. Finally, the optimal feed
of benzyl thiol to phenyl isothiocyanate was proved to be 1:2,
and the yield of dithiocarbamate 5aa reached 96% (Table 2,
entries 6−9).
1
analysis, and the results are illustrated in Figure 1. The peak at
Some thiols and phenyl isothiocyanates were detected using
1 mol % of the amide La[N(SiMe3)2]3 at 40 °C for 30 h. When
the phenyl rings in benzyl thiol molecules were substituted by
hydrocarbyl, halogen, and methyloxy groups, high yields of the
desired dithiocarbamates were obtained (Chart 2, 5ab−ae). A
Chart 2. Intermolecular Addition of Thiols and Phenyl
a b
,
Isothiocyanates Catalyzed by La[N(SiMe3)2]3
Figure 1. 1H NMR monitoring of the stoichiometric reaction between
La[N(SiMe3)2]3 and benzyl thiol: (a) spectrum of catalyst La[N-
(SiMe3)2]3; (b) spectrum of −[N(SiMe3)2]3 after the addition of
benzyl thiol for 30 min.
δ 0.2768 ascribed to the coordinated (SiMe3)2N− disappeared
after 30 min; meanwhile the peak ascribed to methyl protons
in HN(SiMe3)2 was observed at δ 0.1025 (Figure 1). The
change of chemical shifts of (SiMe3)2N− groups during the
reaction indicates the metathesis reaction in the first stage. The
powder A isolated from the above reaction mixture was then
used as a catalyst to initiate the model addition reaction. The
isolated yield of thiocarbamate 3aa was 86%, matching the
outcome of the reaction in situ much better.
a
b
Conditions: 2a−g (1 mmol), 4a−d (2 mmol). Isolated yield.
Subsequently, the oxygen atom of an isocyanate molecule
coordinates to the rare-earth metal of catalyst A, which helps
the insertion of the O−C−N moiety of isocyanate to the RE−
S bond in A to produce Int-1. The nitrogen atom of the O−
C−N moiety coordinates to the central metal to fully complete
the insertion of isocyanate into the RE−S bond. Obviously, the
phenyl isocyanates and thiols substituted with larger groups
retard both their coordination to catalyst A and the generation
of the corresponding key intermediates Int-1 and Int-2.
Therefore, steric hindrance effects of isocyanates and thiols
were observed. Then, a second thiol molecule attacks Int-2 to
slightly decreased yield was observed on the addition of phenyl
isothiocyanate and thiols such as furan-2-ylmethanethiol and
cyclohexanethiol, dropping to 82% and 75%, respectively
(Chart 2, 5af,ag). Also, when 2-isothiocyanato-1,3-dimethyl-
benzene (4d) was used as the starting material, the yield
decreased significantly (Chart 2, 5da).
A possible mechanism of the catalytic transformation was
proposed and is shown in Scheme 1. Initially, on the basis of
some cases of rare-earth-metal amide catalytic processes,10f,g,i,q
C
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Article
give complex D, which liberates the desired thiocarbamate 3.
Meanwhile, the rare-earth-metal thiolate A is regenerated and
the catalytic cycle I is complete.
La[N(SiMe3)2]3 in toluene (Figure 2). Initially, the proto-
nolysis energy of precatalyst La[N(SiMe3)2]3 to real active
species A is calculated to be thermodynamically favored
(Figure S1 in the Supporting Information). The coordination
of isocyanate via its oxygen atom to the La center of A forms
complex B with a relative energy of 0.6 kcal mol−1, which
surmounts an energy barrier (TS-1) of 4.0 kcal mol−1 to give
Int-1 with a relative energy of −6.0 kcal mol−1. The full
insertion of isocyanate into the La−S bond is calculated as the
rate-determining step of the addition, overcoming an energy
barrier of 17.1 kcal mol−1 to give Int-2. Then, the relative
energies of complex C and D decrease to −21.6 and −19.9 kcal
mol−1, respectively. Finally, liberating the target molecule 3aa
from complex D overcomes an energy barrier of 16.5 kcal
mol−1.
In comparison, the approximate relative energy decrease
(8.7 and 7.0 kcal mol−1) for isocyanate insertion (Int-2 →
complex F → TS-5 → Int-3) and thiol insertion (Int-2 →
complex C → TS-3 → complex D) suggest that these two
processes are kinetically competitive. The slight thermody-
namic advantage of Int-3 makes the isocyanate insertion
possible. Each energy barrier for the following steps from Int-3
to compound P′ is relatively low. Therefore, the reverse
reaction from compound P′ to Int-3 and further to Int-2 (the
energy barrier for Int-3 to Int-2 is 8.7 kcal mol−1)is feasible.
This theoretical result is in line with the experimental
observation that compound P′ can further undergo a
transformation to the target molecule.
If at this time Int-2 is attacked by a second isocyanate
molecule, the insertion of isocyanate into the RE−N bond of
Int-2 may occur to produce Int-3. An intramolecular
nucleophilic attack happens in Int-3 to give Int-4, which
quickly undergoes protonolysis with thiol to produce the
nitrogen-containing heterocyclic compound P; meanwhile the
rare-earth-metal thiolate A is free. A set of experiments were
designed to prove the transformation from P to thiocarbamate.
Under the optimum conditions, 2 equiv of o-methyl isocyanate
was treated with 1 equiv of thiol to give P with an isolated yield
of 84%. Continuous addition of 1 equiv of thiol to P yields
30% of the target molecule 3ja. When the molar ratio of thiol
to P is increased to 1.2:1, a 63% yield of 3ja is acquired
(Scheme 2, eq 1). Thus, it is believed that the addition of thiol
Scheme 2. Study for the Heterocyclic Compound P
and isocyanate catalyzed by amide RE[N(SiMe3)2]3 adopts the
reversible path II as well. If the initial molar ratio of thiol to o-
methyl isocyanate is 1.5:1, without the separation of
compound P, an excellent yield (96%) of the corresponding
product 3ja is obtained (Scheme 2, eq 2).
In order to further support both the observed reactivity and
the possible mechanism raised, DFT calculations16 were
performed with the Gaussian 16 software package and the
reaction profiles were determined in silico for phenyl
isocyanate and benzyl thiol promoted by precatalyst
Furthermore, the theoretical calculation suggests the
possibility of catalytic cycle III. The competitive step is an
intermolecular attack of another thiol molecule to complex B
to yield complex C with a relative energy of 9.3 kcal mol−1,
instead of the intramolecular migration to Int-1. To overcome
an energy barrier of 12.9 kcal mol−1, complex E transforms to
complex D via TS-4. Thus, an overall step from complex B to
D is exergonic by 20.5 kcal mol−1. Path III is energetically
unfavorable.
Figure 2. Plausible reaction profile of benzyl thiol addition to phenyl isocyanate mediated by catalyst La[N(SiMe3)2]3: path I (black curve), path II
(blue curve), and path III (red curve)
D
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In terms of relative energies, the key step of the addition of
benzyl thiolto phenyl isocyanate is more likely to proceed by
intramolecular migration of the BnS− moiety to the carbon
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CONCLUSION
■
Rare-earth-metal amides RE[N(SiMe3)2]3 are found to be
efficient catalysts for the intermolecular addition of thiols to
phenyl isocyanates and phenyl isothiocyanates. The lanthanum
amide is the optimal choice, and S-alkyl thiocarbamates and
dithiocarbamates bearing different substituents are obtained in
good to excellent yields under moderate conditions. The
unknown N-containing four-membered heterocycle P is found
in the transformation and can further transfer to the
corresponding thiocarbamates. A plausible mechanism of the
reactions catalyzed by rare-earth-metal amide is proposed,
which is confirmed by both experimental observations and
DFT calculations. More importantly, this work presents a
novel reactivity for rare-earth-metal-mediated catalysis.
ASSOCIATED CONTENT
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S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.organo-
met.9b00147.
Additional experimental procedures, full spectroscopy
data for all the products, and computational methods
(PDF)
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Cartesian coordinates and energies (XYZ)
AUTHOR INFORMATION
Corresponding Authors
*B.Z.: fax, +86-512-65880305; tel, +86-512-65880305; e-mail,
zhaobei@suda.edu.cn.
■
*Y.Y.: e-mail, yaoym@suda.edu.cn.
ORCID
Bei Zhao: 0000-0001-8687-2632
Yingming Yao: 0000-0001-9841-3169
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
We gratefully acknowledge financial support from the National
Natural Science Foundation of China (Grant No. 21572151),
the project of scientific and technologic infrastructure of
Suzhou (SZS201708), and the PAPD.
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