Synthesis of carbodiimides by I2/CHP-mediated cross-coupling reaction of isocyanides with amines under metal-free conditions

Article abstract of DOI:10.1021/acs.orglett.5b00722

An I₂/CHP-mediated cross-coupling reaction of isocyanides with readily accessible amines via C-N formation is described for carbodiimide synthesis in moderate to excellent yields. This represents a metal-free strategy for a coupling reaction of isocyanides with amines, and it provides an efficient approach for symmetric and unsymmetric functionalized carbodiimide derivative synthesis under mild conditions.

Full text of DOI:10.1021/acs.orglett.5b00722

Letter
pubs.acs.org/OrgLett
Synthesis of Carbodiimides by I2/CHP-Mediated Cross-Coupling
Reaction of Isocyanides with Amines under Metal-Free Conditions
Tong-Hao Zhu, Shun-Yi Wang,* Yang-Qing Tao, and Shun-Jun Ji*
Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials Science &
Collaborative Innovation Center of Suzhou Nano Science and Technology, Soochow University, Suzhou 215123, P. R. China
S
* Supporting Information
ABSTRACT: An I2/CHP-mediated cross-coupling reaction of isocya-
nides with readily accessible amines via C−N formation is described for
carbodiimide synthesis in moderate to excellent yields. This represents a
metal-free strategy for a coupling reaction of isocyanides with amines, and
it provides an efficient approach for symmetric and unsymmetric
functionalized carbodiimide derivative synthesis under mild conditions.
arbodiimides such as N,N′-dicyclohexylcarbodiimide
(DCC) and N,N′-diisopropylcarbodiimide (DIC) are
Scheme 1. Oxidative Reactions of Amine with Isocyanide
C
some of the most important chemical reagents in organic
chemistry,1 and they have several useful applications including
the synthesis of nucleotides, dehydration agents for peptide
synthesis,2 and intermediates or precursors for heterocycles.3−5
In view of their high synthetic value, various methods have been
developed for their preparation such as thermolysis−decarbox-
ylation of isocyanates, dehydration of ureas, dehydrosulfurization
of thioureas, and rearrangements of amidoximes.6 However,
these methods suffer from longer reaction time, toxic reagents, as
well as poor atom economy. Palladium-catalyzed reactions of
isocyanide insertion with amines provide an alternative strategy
for the construction of N,N′-dialkylcarbodiimides with high atom
economy.7 It is interesting to note that Au particles could also
catalyze similar reactions in micromolar scales.8 However, these
methods have the drawbacks of limited substrates, low reaction
scales, and expensive catalysts, which limit their further
applications. Therefore, the development of an efficient protocol
to construct carbodiimides under metal-free and mild conditions
is more desirable.
More recently, we have reported a Co-catalyzed isocyanide
insertion reaction with 2-arylanilines under O2 atmosphere for
the creation of 6-aminophenanthridine derivatives.9 Inspired by
this previous work and in continuation of our work on
isocyanide-based reactions, we herein report an I2/CHP-
mediated cross-coupling reaction of isocyanides with readily
accessible amines via C−N formation to construct various
carbodiimides in moderate to excellent yields (Scheme 1).
Our investigations began with the reaction of methyl 3-(2-
aminophenyl)acrylate 1a and tert-butyl isocyanide 2a under
different cobalt-catalyzed conditions. However, the reaction was
messy, and no expected product was detected. To our surprise,
carbodiimide 3aa was formed in 12% GC yield instead of indole
derivative product by the reaction 1a and 2a in the presence of 5
mol % of I2 and 1 equiv of TBHP in 1,4-dioxane (Table 1, entry
4). Only trace amounts of 3a were detected in the absence of
catalyst or oxidant (Table 1, entries 1 and 8). Increasing the
amount of I2 to 20 mol % gave 3aa in 42% GC yield (Table 1,
entry 6). Other iodo-source catalysts such as TBAI, and NIS led
to 3aa in poor yields (Table 1, entries 2 and 3). Further screening
of different oxidants, such as TBPB, DTBP, O2, K2S2O8, and
CHP, showed that CHP was the best oxidant (Table 1, entries
9−13). Increasing the amount of CHP to 2 equiv furnished 3aa
in 69% GC yield (Table 1, entry 13). It should be noted that
further reducing or increasing the amount of CHP resulted in a
decrease in the yield of 3aa. When the reaction was carried out in
toluene, DMF, DCE, DME, and THF, respectively, 3aa was
observed in less than 46% GC yield in all cases (Table 1, entries
17−22). To our delight, the reaction in MTBE led to 3aa in 77%
GC yield (Table 1, entry 23). Further examination of the reaction
temperature (Table 1, entries 24 and 25) showed 3aa could be
obtained in 81% GC yield (76% isolated yield) under reflux
conditions (Table 1, entry 25). Therefore, the optimum reaction
conditions feature 20 mol % of I2 and 2 equiv of CHP as the
oxidant in MTBE at 55 °C for 3 h (Table 1, entry 25, 81% for
3aa).
Received: March 12, 2015
Published: March 31, 2015
© 2015 American Chemical Society
1974
DOI: 10.1021/acs.orglett.5b00722
Org. Lett. 2015, 17, 1974−1977

Organic Letters
Letter
ab
,
Table 1. Optimization of Reaction of Methyl 3-(2-
Aminophenyl)acrylate 1a and tert-Butyl Isocyanide 2a
Scheme 2. Scope of Anilines 1a−s
a
b
entry
catalyst (mol %)
oxidant (equiv)
solvent
yield (%)
e
1
TBHP (1)
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
toluene
trace
trace
11
c
2
TBAI (20)
TBHP (1)
TBHP (1)
TBHP (1)
TBHP (1)
TBHP (1)
TBHP (1)
Ar
d
3
NIS (20)
4
I2 (5)
12
5
I2 (10)
I2 (20)
I2 (30)
I2 (20)
I2 (20)
I2 (20)
I2 (20)
I2 (20)
I2 (20)
I2 (20)
I2 (20)
I2 (20)
I2 (20)
I2 (20)
I2 (20)
I2 (20)
I2 (20)
I2 (20)
I2 (20)
I2 (20)
I2 (20)
26
6
42
7
41
8
trace
46
f
9
TBPB (1)
g
10
11
12
13
14
15
16
17
18
19
20
21
22
23
DTBP (1)
trace
trace
trace
53
O2
K2S2O8 (1)
h
CHP (1)
CHP (0.5)
CHP (2)
CHP (3)
CHP (2)
CHP (2)
CHP (2)
CHP (2)
CHP (2)
CHP (2)
CHP (2)
CHP (2)
CHP (2)
18
69
22
trace
trace
20
i
DMF
MeCN
j
DCE
22
k
DME
46
l
THF
26
m
MTBE
77
n
24
MTBE
MTBE
22
o
25
81
a
Reaction conditions: methyl 3-(2-aminophenyl)acrylate 1a (0.5
mmol) tert-butyl isonitrile 2a (1.2 equiv, 0.6 mmol), catalyst, and
b
oxidant in 3 mL of solvent at 110 °C for 3 h. Yields were determined
a
Reaction condition: anilines 1a−r (0.5 mmol), tert-butyl isonitrile 2a
c
by GC analysis with biphenyl as the internal standard. TBAI =
tertabutylammonium iodide. NIS = N-iodosuccinimide. 70% TBHP
solution in water, TBHP = tert-butyl hydroperoxide. TBPB = tert-
butyl peroxybenzoate. DTBP = 2-(tert-butylperoxy)-2-methylpro-
pane. CHP = cumene hydroperoxide. DMF = N,N-dimethylforma-
mide. DCE = 1,2-dichloroethane. DME = ethylene glycol dimethyl
ether. THF = terahydrofuran. MTBE = methyl tert-butyl ether.
The system was carried out at room temperature. The system was
(1.2 equiv, 0.6 mmol), I2 (20 mol %), and CHP (2 equiv) in 3 mL of
d
e
b
MTBE at 55 °C. Isolated yields.
f
g
h
i
3la, and 3oa in 41%, 84%, and 65% yields, respectively.
Unfortunately, the reaction of pyridin-2-amine 1s could only
give the corresponding product 3sa in trace yield.
j
k
l
m
n
o
Next, we investigated the scope of isocyanides (Scheme 3).
The reaction of 4-aminobenzonitrile 1q with adamantanyl
isocyanide 2b performed well under the optimal conditions
and led to the desired product 3qb in 72% yield. When the
functional isocyanide 2c was used, we could also obtain the
carbodiimide 2qc in 53% yield. When more bulky aryl
carried out at 55 °C.
To explore the scope and limitations of this approach, various
anilines 1a−r were applied to the reaction with tert-butyl
isocyanide 2a under the optimized metal-free conditions, and the
results are summarized in Scheme 2. Most of the reactions
proceeded smoothly to afford the desired carbodiimide products
in moderate to excellent yields. The reaction of aniline 1b with 2a
afforded the desired product 3ba in 70% yield. Anilines 1c−e
with an o-, m-, or p-methyl group could be converted to the
corresponding carbodiimides 3ca−ea in moderate yields (41−
49%). Typically, functional groups including electron-donating
tert-butyl, OMe, OEt, OBn (1f−i) and electron-withdrawing
groups such as CN, COOEt, NO2, 1q, 1p, 1r were tolerated
under identical conditions. However, anilines bearing electron-
withdrawing groups showed less reactivity, and the reaction time
should be extended to 24 h. When halogen-substituted anilines
1j−o were subjected to the reactions, the desired carbodiimides
3ja−oa were observed in good yields (65%−84%). It is worth
noting that more bulky substrates 1e, 1l, and 1o could also
undergo the transformation to furnish the desired products 3ea,
Scheme 3. Scope of Isocyanides 2b−d with 4-
Aminobenzonitrile 1q
1975
DOI: 10.1021/acs.orglett.5b00722
Org. Lett. 2015, 17, 1974−1977

Organic Letters
Letter
isocyanides 2d,e were subjected to the reactions, the reactions
could also furnish carbodiimide derivatives 3qc,qd in 21% and
42% yields, respectively.
Scheme 5. Transformations of Carbodiimides and Total
Synthesis of Antifungal Activity Molecule 6
The reaction is extendable to construct some useful
carbodiimides such as DCC and DIC by the reaction of aliphatic
amines with aliphatic isocyanides under the optimal conditions.
The reaction of cyclohexanamine 1t with cyclohexyl isocyanide
2e proceeded well to furnish symmetric carodiimide DCC 3te in
51% GC yield (Scheme 4, eq 1). Similarly, DIC 3uf could also be
Scheme 4. Select Carbodiimides Synthesis by the Reaction of
Isocyanides with Amines
obtained in 55% GC yield by the reaction of propan-2-amine 1u
with isopropyl isocyanide 2f (Scheme 4, eq 2). Carbodiimide 3ra
could also be generated in 90% yield by the reaction of 1v with 2g
(Scheme 4, eq 3). This result indicated that the unsymmetric
carbodiimide could be prepared by two different sets of the
corresponding amine and isocyanide.
Scheme 6. Proposed Mechanism
To further demonstrate the utility of our above reactions, we
applied the carbodiimides in other transformations (Scheme 5).
For example, the reaction of N-((tert-butylimino)methylene)-
aniline 3ba with piperidine in the presence of a catalytic amount
of Yb(OTf)3 easily led to the trisubstituted guanidine 4 in 95%
GC yield (Scheme 5, eq 4).10 When 3ba was treated with water,
urea 5 could be formed in 72% GC yield (Scheme 5, eq 5).11 Our
protocol has also been successfully applied in the total synthesis
of 1-(3-(4-fluorophenyl)-3,4-dihydro-2-(1H-imidazol-1-yl)-qui-
nazolin-4-yl)propan-2-one 6, which shows good to significant
fungicidal activity against Penicillium digitatum and strong
binding interaction with the cytochrome P450-dependent sterol
14α-demethylase (CYP51).12 I2/CHP mediated cross-coupling
reaction of isocyanide 2h insertion reaction with amine 1a′ gave
carbodiimide 3a′n in 70% yield. Following the reaction of 3a′h
with imidazole in the presence of K2CO3 furnished 6 in 61% yield
(Scheme 6). Compound 6 could be easily prepared over two
steps based on our method instead of 5 steps as reported in the
literature.
work not only represents a metal-free strategy for cross-coupling
of isocyanides with amines but also provides an efficient
approach to symmetric and unsymmetric functionalized
carbodiimides under mild conditions. Further studies to
understand this isocyanide insertion mechanism and their
other synthetic applications are ongoing in our laboratory.
ASSOCIATED CONTENT
■
S
* Supporting Information
On the basis of the above results, a plausible reaction
mechanism is proposed in Scheme 6. The reaction of isocyanide
with iodine via 1,1-addition affords intermediate I.13 Compound
I reacts with amine to give intermediate II by dehydrohaloge-
nation. Following the subsequent second time dehydrohaloge-
nation, carbodiimide III is formed. Hydrogen iodide is oxidized
by CHP to furnish iodine and complete the catalytic cycle.
In conclusion, we have developed a novel I2/CHP-mediated
cross-coupling reaction of isocyanides with readily accessible
amines via C−N bond formation, affording carbodiimides in
moderate to excellent yields under metal-free conditions. This
Detailed experimental procedures and characterization data. This
material is available free of charge via the Internet at http://pubs.
acs.org.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: shunyi@suda.edu.cn.
*E-mail: shunjun@suda.edu.cn.
Notes
The authors declare no competing financial interest.
1976
DOI: 10.1021/acs.orglett.5b00722
Org. Lett. 2015, 17, 1974−1977

Organic Letters
Letter
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ACKNOWLEDGMENTS
■
We gratefully acknowledge the Natural Science Foundation of
China (21172162, 21372174), the Young National Natural
Science Foundation of China (No. 21202111), the Ph.D.
Programs Foundation of Ministry of Education of China
(2013201130004), the Young Natural Science Foundation of
Jiangsu Province (BK2012174), PAPD, Key Laboratory of
Organic Synthesis of Jiangsu Province (KJS1211), and Soochow
University for financial support.
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