Nickle Catalysis Enables Access to Thiazolidines from Thioureas via Oxidative Double Isocyanide Insertion Reactions

Article abstract of DOI:10.1021/acs.orglett.8b03098

An efficient synthesis of thiazolidine-2,4,5-triimine derivatives was developed via Ni-catalyzed oxidative double isocyanide insertion to thioureas under air conditions, in which thioureas play three roles as a substrate, a ligand, and overcoming isocyanide polymerization. The reaction is featured by employing a low-cost and low loading Ni(acac)₂ catalyst, without any additives, and high atom economy. This is the first example to directly apply a Ni(II) catalyst in oxidative double isocyanide insertion reactions.

Full text of DOI:10.1021/acs.orglett.8b03098

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Nickle Catalysis Enables Access to Thiazolidines from Thioureas via
Oxidative Double Isocyanide Insertion Reactions
Wen-Kui Yuan,† Yan Fang Liu,*,‡ Zhenggang Lan,‡ Li-Rong Wen,*,† and Ming Li*,†
†State Key Laboratory Base of Eco-Chemical Engineering, College of Chemistry and Molecular Engineering, Qingdao University of
Science and Technology, Qingdao 266042, P. R. China
‡Shandong Provincial Key Laboratory of Synthetic Biology, Laboratory of Biofuels, Qingdao Institute of Bioenergy and Bioprocess
Technology, Chinese Academy of Sciences, Qingdao, 266061, China
S
* Supporting Information
ABSTRACT: An efficient synthesis of thiazolidine-2,4,5-triimine derivatives was developed via Ni-catalyzed oxidative double
isocyanide insertion to thioureas under air conditions, in which thioureas play three roles as a substrate, a ligand, and
overcoming isocyanide polymerization. The reaction is featured by employing a low-cost and low loading Ni(acac)2 catalyst,
without any additives, and high atom economy. This is the first example to directly apply a Ni(II) catalyst in oxidative double
isocyanide insertion reactions.
he thiazolidine core is a structural motif of particular
interest in the fields of agriculture and industry. For
on the oxidative single isocyanide insertions (Scheme 1, eq 1),7
only a few scattered examples of Pd-catalyzed oxidative double
T
example, flubenzimines as general structures I have been
applied as a mite growth regulating acaricide (Figure 1).1
Scheme 1. Transition Metal Catalyzed Oxidative Isocyanide
Insertion Reactions
Figure 1. Selected thiazolidines with biological activities and
industrial application.
Compounds II can be used as corrosion inhibitors of C-steel,2
and compound III is a dye for hair fibers.3 However, the
methods for obtaining thiazolidine derivatives are still limited
thus far, which may be due to these reported approaches’ lack
of generality and requirement in some cases of inaccessible
substrates.4 Therefore, the development of a novel and general
approach would be desirable and valuable.
Isocyanides are important active reactants containing stable
divalent carbon atoms and have been widely used in the
construction of nitrogen-containing compounds.5 In particular,
transition-metal-catalyzed isocyanide insertion has served as a
powerful tool in the strategy of organic synthesis.6 However,
most oxidative isocyanide insertion reactions mainly focused
isocyanide insertion reactions were reported.8 In sharp
contrast, given Ni’s position directly above palladium, Ni-
enabled oxidative double isocyanide insertion is virtually rare,
which may be due to easy polymerization of isocyanides in the
presence of a transition metal.9 Therefore, the development of
a double isocyanide insertion by the use of Ni catalysts would
be a highly desirable goal of the utmost synthetic importance.
Received: September 27, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03098
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Organic Letters
Letter
In continuation of our research on the development of
isocyanide as a building block,10 herein, we report the first
example of low-cost Ni(acac)2-catalyzed oxidative double
isocyanide insertion to thioureas for the synthesis of
thiazolidine derivatives (Scheme 1, eq 2). Significantly, in
this transformation thioureas served as not only a substrate but
also a ligand that in situ generated an active Ni(II)−thiourea
complex, avoiding polymerization of isocyanides. This trans-
formation represents the first example of applying Ni(II) in
oxidative double isocyanide insertion reactions that resulted in
the formation of thiazolidines.
amount of the catalyst was tested. Gratifyingly, decreasing the
loading of Ni(acac)2 to 0.03 equiv still gave a 91% yield of 3a
after 4 h (entry 17). However, further decreasing the loading of
Ni(acac)2 to 0.01 equiv showed a loss of reaction efficiency
(entry 18). Therefore, the optimal reaction conditions were
determined to include 0.03 equiv of Ni(acac)2 as the catalyst
and acetone as the solvent at 50 °C for 4 h.
With the optimized reaction conditions in hand, the
substrate scope of thioureas (1) and isocyanides (2) was
explored. First, various alkyl and aromatic isocyanides were
used to insert symmetrical dialkylthioureas. As shown in
Scheme 2, in all cases, the reactions took place smoothly and
Our study commenced with the reaction between 1,3-
diphenylthiourea 1a and isocyanocyclohexane 2a in 1,4-
dioxane at 50 °C. A survey of reaction parameters was
shown in Table 1. After unsuccessful trials by using other
a b
,
Scheme 2. Substrate Scope of Symmetric Thioureas
a
Table 1. Optimization of Reaction Conditions for 3a
temp
(°C)
time
(h)
yield
b
entry
catalyst (equiv)
solvent
(%)
1
2
3
4
5
6
7
8
Pd(OAc)2 (0.3)
Co(acac)2 (0.3)
Cu(OTf)2 (0.3)
Ni(acac)2 (0.1)
-
Ni(acac)2 (0.05)
Ni(OAc)2 (0.05)
Ni(PPh3)2Cl2
(0.05)
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
50
50
50
50
50
50
50
50
20
20
20
4
4
4
trace
16
15
83
NR
81
10
4
72
27
a
Reaction conditions: 1 (0.60 mmol), 2 (1.32 mmol), Ni(acac)2
9
NiCl2·6H2O (0.05) 1,4-dioxane
50
50
50
50
50
rt
40
60
50
50
4
23
4
6
4
4
4
4
4
4
20
70
85
79
92
67
81
85
91
85
b
(0.018 mmol), acetone (2.0 mL), 50 °C, 4 h. Isolated yields (the
10
11
12
13
14
15
16
Ni(acac)2 (0.05)
Ni(acac)2 (0.05)
Ni(acac)2 (0.05)
Ni(acac)2 (0.05)
Ni(acac)2 (0.05)
Ni(acac)2 (0.05)
Ni(acac)2 (0.05)
toluene
2-MeTHF
EtOH
acetone
acetone
acetone
acetone
acetone
acetone
residues in mother liquor are not included). Cy = cyclohexyl, nBu = n-
butyl, tBu = tert-butyl, 1-Ad = 1-Adamantane, PMP = para-
methoxyphenyl, 1-Naph = 1-naphthyl, p-Toly = p-methylphenyl.
gave the corresponding thiazolidines in good to excellent
yields. Notably, diarylthioureas with electron-donating sub-
stituents at the para-position achieved good yields of 80−85%
(3k and 3l). However, diarylthioureas with electron-with-
drawing groups such as Br, Cl, F, and CF3 at para-position
showed slightly low reactivity to provide 40−80% yields (3m−
3p).
Next, a series of unsymmetrical thioureas 1 were utilized to
react with isocyanocyclohexane 2a for identifying the
regioselectivity of the double insertion reactions (Scheme 3).
As shown in Scheme 3, the 1,3-unsymmetrical thioureas with
one aromatic and one aliphatic group can be transformed
efficiently affording the desired products as a single isomer in
moderate to excellent yields (4a−4k). Notably, the regiose-
lectivity profile of this method was nicely illustrated in the
functional groups such as alkynyl (4l), OH (4m), and ester
(4n), which allowed further synthetic utilities, while the
substrate with a carboxyl group showed low reactivity (4o).
Additionally, the 1,3-unsymmetrical thioureas with one 2-
pyridine and an aromatic group also worked well (4q and 4r).
However, the unsymmetrical diarylthioureas gave a mixture of
two regioisomers (4s−4y).
17 Ni(acac)2 (0.03)
18 Ni(acac)2 (0.01)
a
Reaction conditions: 1a (0.60 mmol), 2a (1.32 mmol), solvent (2.0
mL). Isolated yield (the residue in mother liquor is not included).
b
transition-metal catalysts (Table 1, entries 1−3), we found that
0.1 equiv of Ni(acac)2 led to the desired transformation,
product 3a was isolated in 83% yield after 4 h (entry 4). A
control experiment revealed that the reaction could not be
initiated in the absence of the catalyst (entry 5). Then 0.05
equiv of Ni(acac)2 was employed, and an 81% yield of 3a was
obtained (entry 6). Encouraged by these results, a screening of
Ni(II) sources such as Ni(OAc)2, Ni(PPh3)2Cl2, and NiCl2·
6H2O was carried out. The results reveal that they were
ineffective for this transformation (entries 7−9). Next, other
solvents such as toluene, 2-MeTHF, EtOH, and acetone were
also screened with 0.05 equiv Ni(acac)2 as the catalyst at 50
°C, and the results indicated acetone was best, as 3a could
precipitate directly to provide an excellent yield of 92%
(entries 10−13). The reaction temperature was also
investigated, and it was found that increasing or decreasing
the temperature was unfavorable (entries 14−16). Finally, the
B
DOI: 10.1021/acs.orglett.8b03098
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Organic Letters
Letter
a b
,
Scheme 3. Substrate Scope of Unsymmetrical Thioureas
Scheme 5. Reactions of KTAs 6 with 2a
Thus, we speculated the above double isocyanide insertion
reactions could be a step-by-step insertion mode.
Scheme 6. Reactions of Diarylthioureas with α-Acidic
Isocyanides
In order to demonstrate the synthetic utility of this method,
the model reaction was performed on 5 mmol scale under the
standard conditions, and the desired product 3a was provided
in 85% yield (Scheme 7).
Scheme 7. Gram-Scale Experiment
a
Reaction conditions: 1 (0.60 mmol), 2a (1.32 mmol), Ni(acac)2
b
(0.018 mmol), acetone (2.0 mL), 50 °C, 4 h. Isolated yields (The
c
residues in mother liquor are not included). Isomer ratio was
d
determined by 1H NMR. Isomer ratio was determined after
separation. PMP = para-methoxyphenyl. 1-Naph = 1-naphthyl. Th
= 2-thienyl.
Notably, when unsubstituted thiourea was employed to react
with 2a, 1H-imidazole-2(5H)-thione (5) in 40% yield rather
than a thiazolidine compound was obtained (Scheme 4).
To understand the reaction mechanism, we carried out the
following control experiments (Scheme 6). The reaction of
1,3-diphenylthiourea (1a) with 2a by 0.10 equiv Ni(acac)2 as
the catalyst in degassed acetone at 50 °C under N2 provided 3a
in 36% yield (Scheme 8, eq 1). The result suggests that O2 was
very important for this oxidative double isocyanide insertion
reaction. To further illustrate the catalytic cycle process, a
complex A was synthesized using 1,3-diphenylthiourea (1a)
and Ni(acac)2 at room temperature (the structure of complex
A was confirmed by the single crystal X-ray diffraction analysis;
see the Supporting Information) (Scheme 8, eq 2).
Significantly, only 1 mol % complex A could catalyze effectively
the model reaction to give 3a in 93% yield within 1 h (Scheme
8, eq 3). These results suggest that complex A was likely
involved in the catalytic cycle as the active catalyst.
On the basis of the above observation, a plausible reaction
mechanism has been depicted in Scheme 9. The catalytic cycle
is initiated by in situ generated thioureas−Ni(II) complex A
from Ni(II) catalyst precursor Ni(acac)2 and thioureas 1. Next,
two molecules of isocyanides 2 participate via coordination to
form a new four coordination complex B, meanwhile releasing
one molecule of thioureas 1. Then isocyanides insert to the
Ni−S bond of B to give six-membered Ni(II) intermediate C.
Scheme 4. Reaction of Thiourea with 2a
β-Ketothioamides (KTAs)11 have proven to be fascinating
and versatile synthons in the construction of heterocyclic
systems. Our protocol could be applied successfully to
synthesize 2-methylenethiazolidine-4,5-diimines (7) from
KTAs (6) and 2a under similar conditions (Scheme 5).
Interestingly, when α-acidic isocyanides such as isocyanoa-
cetate, BnNC (isocyanomethylbenzene), or TosMIC (tosyl-
methyl isocyanide) were applied to this process under the
optimized conditions, the reactions gave the single isocyanide
insertion products 1,3-thiazetidine-2,4-diimines (8) (Scheme
6). These results may be subjected to the steric hindrance.
C
DOI: 10.1021/acs.orglett.8b03098
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Accession Codes
Scheme 8. Control Experiments
CCDC 1441175, 1447519, 1469948, 1490148, 1503923, and
1547710 contain the supplementary crystallographic data for
this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_
request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: liu_yf@qibebt.ac.cn.
*E-mail: wenlirong@qust.edu.cn.
*E-mail: liming928@qust.edu.cn.
ORCID
Yan Fang Liu: 0000-0002-9086-9599
Li-Rong Wen: 0000-0001-7976-0878
Ming Li: 0000-0003-4906-936X
Notes
Scheme 9. Proposed Catalytic Cycle for the Ni(II)-
The authors declare no competing financial interest.
Catalyzed Oxidative Double Isocyanide Insertion Reaction
ACKNOWLEDGMENTS
■
This work was financially supported by the National Natural
Science Foundation of China (21572110, 21372137,
21607164, and 21801152).
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ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b03098.
Experimental procedures, characterization and spectral
data (PDF)
(7) For selected examples of oxidative single isocyanide insertion,
see: Pd catalysis: (a) Jiang, H. F.; Gao, H. L.; Liu, B. F.; Wu, W. Q.
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E
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