A General and Mild Copper(I)-Catalyzed Three-Component Reaction of Cyanamides, Amines, and Diaryliodonium Triflates

Article abstract of DOI:10.1002/ejoc.201600332

A highly efficient copper-catalyzed three-component reaction of cyanamides, amines, and diaryliodonium triflates was developed for the synthesis of guanidines. The mild reaction accommodates both aromatic and aliphatic amines and provides the products in good yields with good functional group tolerance. Moreover, it was demonstrated that C-H activation of the arenes could be realized for the direct preparation of guanidines.

Full text of DOI:10.1002/ejoc.201600332

DOI: 10.1002/ejoc.201600332
Communication
Guanidine Synthesis
A General and Mild Copper(I)-Catalyzed Three-Component
Reaction of Cyanamides, Amines, and Diaryliodonium Triflates
Jihui Li,[a] Hongxing Wang,[a] Yifeng Hou,[a] Weiguang Yu,[a] Shuying Xu,[a] and
Yucang Zhang*[a]
Abstract: A highly efficient copper-catalyzed three-component provides the products in good yields with good functional
reaction of cyanamides, amines, and diaryliodonium triflates group tolerance. Moreover, it was demonstrated that C–H acti-
was developed for the synthesis of guanidines. The mild reac- vation of the arenes could be realized for the direct preparation
tion accommodates both aromatic and aliphatic amines and of guanidines.
Introduction
Multicomponent reactions hold a central place in organic syn-
thesis and medical chemistry as a means to introduce structural
diversity and to prepare complex organic molecules from sim-
ple and easily available starting materials.[1] Theses reactions
can deliver good chemoselectivities, regioselectivities, and ster-
eoselectivities. Particularly noteworthy are multicomponent re-
actions with diaryliodoniums, which are highly efficient for the
Scheme 1. Copper-catalyzed three-component synthesis of guanidines.
preparation of a diverse array of compounds.[2] Diaryliodoniums
are mild and versatile arylating agents that can be used for the
creation of C–C and C–X (C = F, N, O, S etc.) bonds in organic
Results and Discussion
synthetic chemistry.[3] Moreover, these reagents are easily avail-
Initially, the reaction of p-tolylcyanamide, piperidine, and di(p-
tolyl)iodonium triflate was performed in the presence of CuCl
(5 mmol-%)/2,2′-bipyridyl (bipy,
able by C–H activation of arenes, and they are air and moisture
stable, thermostable, and nontoxic.[4]
5 mmol-%) and K2CO3
Guanidines are privileged scaffolds in bioactive synthetic
molecules and natural products,[5] and some have been used
as drugs on the market, including relenza (antiviral), famotidine
(antiulcer),[5c] merzelladine (antiinfectivity),[5f] and batzelladine
(anti-HIV-1 and anti-AIDS).[5g] As versatile molecules, they have
also been widely used in synthesis as organic intermediates,[6]
organocatalysts, and ligands with a unique trinitrogen unit.[7] In
the past decades, the organic synthetic community has devoted
great effort to their synthesis.[5a,5b,8] Recently, we developed a
copper-catalyzed three-component reaction involving cyan-
amides and boronic acids for the synthesis of guanidines under
an oxygen atmosphere, but this method was limited to aliphatic
amines and relatively thermostable boronic acids (Scheme 1,
a).[8f] Herein, a more general and efficient method is described
for synthesis of guanidines under gentle reaction conditions
(Scheme 1, b).
(2.25 equiv.) in toluene at 80 °C for 100 min; these conditions
are similar to the optimized conditions employed in the oxid-
ative three-component reaction of cyanamides, aliphatic
amines, and boronic acids.[8f] Desired guanidine 4a was pro-
duced in 91 % yield. Interestingly, the reaction without the cop-
per salt produced desired guanidine 4a in 20 % yield with a
large number of byproducts, including di(p-tolyl)cyanamide,
and the reaction also afforded 4a in 54 % yield without K2CO3
(Scheme 2).
Having identified the reaction conditions, the scope of the
cyanamides was investigated (Table 1). Aromatic cyanamides
with various substituents afforded the corresponding guan-
idines in high yields. For example, both electron-rich p-methoxy-
phenylcyanamide and electron-poor o-fluorophenylcyanamide
produced corresponding guanidines 4e and 4f in yields of 80
and 82 %, respectively, and the p-, m-, and o-methylphenyl-
cyanamides all gave desired guanidines 4a, 4c, and 4d in com-
parably high yields. Aliphatic cyanamides with both chain and
cyclic alkyl groups also afforded the corresponding guanidines
in good yields. Cyanamides with n-butyl, isopropyl, and tert-
butyl groups gave 4g–i in yields of 75, 87, and 91 %, respec-
tively, and cyclohexylcyanamide provided 4j in 87 % yield. In-
[a] College of Materials and Chemical Engineering, Hainan University,
Haikou 570228, P. R. China
E-mail: zhangyucang88@163.com
http://www.hainu.edu.cn/cailiaohuagong/##
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under http://dx.doi.org/10.1002/ejoc.201600332.
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Scheme 2. Brief investigation of the reaction conditions.
Table 1. Reaction scope of the cyanamides.[a]
[a] Reaction conditions: 1 (0.3 mmol, 1.5 equiv.), 2a (0.2 mmol), 3a (1.5 equiv.), CuCl (0.01 mmol, 5 mmol-%), bipy (0.01 mmol, 5 mmol-%), K2CO3 (0.45 mmol,
2.25 equiv.), toluene (1 mL), 80 °C, 100 min, N2, yields of isolated products are given, as determined by preparative TLC.
Table 2. Reaction scope of the amines.[a]
[a] Reaction conditions: 1a (0.3 mmol, 1.5 equiv.), 2 (0.2 mmol), 3a (1.5 equiv.), CuCl (0.01 mmol, 5 mmol-%), bipy (0.01 mmol, 5 mmol-%), K2CO3 (0.45 mmol,
2.25 equiv.), toluene (1 mL), 80 °C, 100 min, N2, yields of isolated products are given, as determined by preparative TLC. [b] n-Butylcyanamide was used
instead of p-tolylcyanamide..
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Scheme 3. Large-scale synthesis of guanidines.
terestingly, cyclopropylcyanamide, which was not compatible preferred transfer groups.[10] Additionally, the reaction of
in the oxidative three-component reaction with aliphatic phenyl(2.5-dimethylphenyl)iodonium with p-tolylcyanamide
amines and boronic acids,[8f] also furnished desired guanidine provided isomers 4b/4x in a ratio of about 1.3:1 (Table 3, en-
4k in good yield.
try 12), and its reaction with o-toylcyanamide also gave almost
the same ratio of isomers (4z/5e = 1.4:1) but in lower yield
(Table 3, entry 13), which implied that the sterically less-hin-
dered phenyl group was the preferred transfer group for the
reaction. Impressively, phenyl(2,4,6-trimethylphenyl)iodonium
mesylate could be generated in situ through the reaction of
[hydroxy(tosyloxy)iodo]benzene (HTIB) with mesitylene in 2,2,2-
trifluoroethanol (TFE), and its one-pot reaction with p-tolyl-
cyanamide and piperidine produced desired guanidines 4b/4y
(4.3:1) in 58 % yield (Figure 1).
Amines including aromatic and aliphatic were then evalu-
ated (Table 2). Gratefully, aromatic amine p-toluidine, which
does not survive well under an oxygen atmosphere,[8f] yielded
the desired guanidines in moderate yields under oxygen-free
conditions, and reactions with both aromatic and aliphatic
cyanamides afforded similar yields (see products 4l and 4m).
Aliphatic amines with alkyl chains all furnished desired products
4m–s in good yields ranging from 67 to 94 %, and both the
benzyl and alkenyl groups survived well under the mild reac-
tion conditions (see products 4p and 4s). Similarly, amines with
cyclic alkyl groups were compatible with the reaction condi-
tions, except for cyclopropylamine. Cyclic amines including pip-
eridine and pyrrolidine also provided the products in high
yields (Table 1, see product 4a; Table 2, see product 4t). A larger
scale reaction showed that guanidine 4n was obtained in a
high yield with liberation of p-tolyl iodide (6a) in good yield
(Scheme 3).
Table 3. Reaction scope of the diaryliodoniums.[a]
The scope of the reaction with various diaryliodonium tri-
flates was finally explored (Table 3). Symmetric diaryliodonium
triflates with both electron-withdrawing and electron-donating
groups furnished the desired guanidines in high yields (Table 3,
entries 1–4), and halogens including chloride and bromide were
well tolerated under the reaction conditions (Table 3, entries 2
and 3). Sterically hindered diaryliodoniums also provided the
products in high yields (Table 3, entries 5 and 6). For unsymmet-
ric diaryliodoniums, the reactions also afforded comparably
high yields with good functional group compatibility. For exam-
ple, arylphenyliodoniums with tert-butyl, amido, iodo, and nitro
groups all generated the corresponding guanidines in yields
of 96, 89, 80, and 88 %, respectively (Table 3, entries 7–10).
Guanidylthiophene 5d, which is unstable relative to 2-amino-
thiophene,[9] could not be obtained in the oxidative three-com-
ponent reaction of cyanamides, amines, and boronic acids;[8f]
however, the reaction of phenyl(thienyl)iodonium triflate pro-
duced desired guanidylthiophene 5d in moderate yield
(Table 3, entry 11). Clearly, the regioselectivities for unsymmet-
ric arylphenyliodoniums with aryl groups with different elec-
tronics were dependent on the substrates without certain regu-
lation (Table 3, entries 7–11); this is somewhat different from
previous transition-metal-catalyzed reactions of diaryliodonium,
for which more electron-rich aryl groups are generally the
Entry
Ar1
Ar2
Ratio (4/5)
Yield
[%][b]
1
2
3
4
5
6
Ph
p-ClC6H4
p-BrC6H4
p-tBuC6H4
2,5-(CH3)2C6H3
2,4,6-(CH3)3C6H2
Ph
Ph
Ph
Ph
Ph
Ph
Ph
p-ClC6H4
p-BrC6H4
–(4b/–)
–(4u/–)
–(4v/–)
–(4w/–)
–(4x/–)
–(4y/–)
1.0/1.2 (4b/4w)
1.6/1.0 (4b/5a)
1.1/1.0 (4b/5b)
1.0/2.4 (4b/5c)
1.0/3.7 (4b/5d)
1.3/1.0 (4b/4x)
1.4/1.0 (4z/5e)
96
86
78
93
90
83
96
89
80
88
89
92
80
p-tBuC6H4
2,5-(CH3)2C6H3
2,4,6-(CH3)3C6H2
p-tBuC6H4
p-AcHNC6H4
p-IC6H4
p-O2NC6H4
thienyl
2,5-(CH3)2C6H3
2,5-(CH3)2C6H3
7[c]
8
9[c]
10
11
12[c]
13[c,d] Ph
[a] Reaction conditions: 1a (0.3 mmol, 1.5 equiv.), 2a (0.2 mmol), 3 (1.5 equiv.),
CuCl (0.01 mmol, 5 mmol-%), bipy (0.01 mmol, 5 mmol-%), K2CO3 (0.45 mmol,
2.25 equiv.), toluene (1 mL), 80 °C, 100 min, N2. [b] Yield of isolated product,
as determined by preparative TLC. [c] Ratio determined by 1H NMR spectro-
scopy. [d] o-Tolylcyanamide was used.
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Figure 1. In situ generation of diaryliodoniums and one-pot reaction with cyanamide and amine.
Figure 2. The three-component reaction with TEMPO.
Figure 3. Possible reaction pathways.
As for the proposed reaction mechanism for the oxidative way A). Notably, possible arylated carbodiimide E was hardly
CuII-catalyzed three-component reaction of cyanamides, detected during the reactions. Additionally, the result of the
amines, and boronic acids,[8f] the CuI-catalyzed three-compo- uncatalyzed reaction suggests that the following process is also
nent reaction of diaryliodoniums with cyanamides and amines involved: isomerization of cyanamide to carbodiimide F and
may take place via CuIII complex intermediates resulting from subsequent reaction with the diaryliodonium triflate promoted
oxidative addition of CuI and λ3-iodane[11] or through a free- by K2CO3 forms intermediate G; then, sequential nucleophilic
radical progress.[12] The addition of the radical trapper 2,2,6,6- addition of the amine and reductive elimination yield the guan-
tetramethyl-piperidin-1-oxyl (TEMPO, 2 equiv.) did not decrease idine with liberation of the aryl iodide (Figure 3, pathway B). As
the yield at all under the standard reaction conditions, and this a result, the random regioselectivities for the arylphenyl-
ruled out a copper-catalyzed radical process for this reaction iodoniums with aryl groups with different electronics may be
(Figure 2). An alternative reaction mechanism with the forma- accounted for by the different regioselectivity tendencies of
tion of CuIII complexes through oxidative addition seems rea- these two pathways.[10,14]
sonable: oxidative addition of the diaryliodonium to CuI occurs,
and this is followed by coordination with cyanamide.[13] Then,
Conclusions
isomerization to carbodiimide complex D results. Nucleophilic
addition of the amine and subsequent reductive elimination In summary, a general and mild route to access guanidines
generate the guanidine and the CuI catalyst (Figure 3, path- through a copper-catalyzed three-component reaction of cyan-
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amides, amines, and diaryliodonium triflates under oxygen-free
conditions was developed. The mild reaction showed a general
reaction scope with broad functional group tolerance, and a
diversity of guanidines were easily prepared in high yields with
the formation of useful aryl iodides in good yields. A prelimi-
nary investigation showed that in situ generation of the diaryl-
iodoniums and their one-pot reaction with cyanamides and
amines could be achieved by C–H activation of the arenes to
afford guanidines. Further studies to extend the reactions are
currently underway in our laboratory.
Experimental Section
General Procedure for the Synthesis of Guanidines through the
Copper-Catalyzed Three-Component Reaction of Cyanamides,
Amines, and Diaryliodonium Triflates: A round-bottomed flask
with a sidearm was charged sequentially with CuCl (0.01 mmol,
5
mmol-%), bipy (0.01 mmol,
5
mmol-%), cyanamide
1
(0.3 mmol,1.5 equiv.), diaryliodonium triflate
3
(0.3 mmol,
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then degassed and backfilled with nitrogen (balloon). Toluene
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Acknowledgments
The authors acknowledge the National Natural Science Founda-
tion of China (NSFC) (grant number 51263006), Natural Science
Foundation of Hainan Province (grant number 20162015), and
Hainan Province International Science and Technology Specific
(KJHZ2014-02) for financial support of this work. The Analytical
and Testing Center of Hainan University is also acknowledged
for excellent technical and analytical support.
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Keywords: Multicomponent reactions · C–H activation ·
Copper · Guanidines
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Received: April 5, 2016
Published Online: April 27, 2016
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