Transition-metal free N-arylation of cyanamides by diaryliodonium triflates in aqueous media

Article abstract of DOI:10.1039/c5nj02153g

An operationally simple protocol is established for the synthesis of disubstituted cyanamides through the transition-metal free N-arylation of cyanamides by diaryliodonium triflates in aqueous media. Both alkyl and aryl cyanamides are well compatible with the mild reaction conditions. The one-pot synthesis of ureas is also possible through sequential arylation and hydrolysis of cyanamides, diaryliodonium triflates and H₂O with good yields.

Full text of DOI:10.1039/c5nj02153g

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DOI: 10.1039/C5NJ02153G
New Journal of Chemistry
COMMUNICATION
Transition-Metal Free N-Arylation of Cyanamides by
Diaryliodonium Triflates in Aqueous Media
Jihui Li, Xinyi Zheng, Wei Li, Wei Zhou, Wen Zhu and Yucang Zhang*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
palladium-catalyzed N-arylation of alkyl cyanamides by arylhalides
with bidentate phosphane as ligand was developed for the
synthesis of disubstituted cyanamides (Figure a).6e Moreover, an N-
An operationally simple protocol is established for the synthesis
of disubstituted cyanamides through the transition-metal free N-
arylation of cyanamides by diaryliodonium triflates in aqueous
media. Both alkyl and aryl cyanamides are well compatible with
the mild reaction conditions. One-pot synthesis of ureas is also
possible through sequential arylation and hydrolysis of
cyanamides, diaryliodonium triflates and H2O with good yields.
arylation
of
aryl
cyanamides
by
diaryliodonium
hexafluorophosphates was also developed more recently, and the
reaction needed to be performed under oxygen free conditions
(Figure b).7
Cyanamides have attracted considerable attentions as a class of
versatile organic molecules. They have a wide range of uses in
organic synthetic chemistry1 and coordination chemistry,2 not only
can be building blocks for the construction of diverse N-containing
compounds but also metal ligands with their unique reactivity and
structure of cyanamide unit. Additionally, it has been found that
some cyanamide-based compounds show a diversity of interesting
bioactivities,3 such as anti-cathepsins K and L,3a inhibition of
spontaneous myogenic,3d and peptide activator acitivities.3e It has
also been proved that cyanamide is a natural product present in
higher plant even though the distribution is limited.4 As a valuable
dinitrogen resource, there have been some synthetic methods
developed for cyanamides, which can be divided into these two
categories: i) Conventional electrophilic substitution and
condensation of cyanamide, or nucleophilic substitution of
cyanogen bromide;5 ii) Transition-metal catalyzed transformations
of various starting materials.6 The latter method is an alternative
approach to making a diversity of complex cyanamides by using
easily available starting materials. For example, palladium-catalyzed
three component reactions of aryl isocyanides, allyl methyl
carbonate, and trimethylsilyl azide were developed for the
synthesis of allyl cyanamides and N-cyanoindoles,6a,b a copper-
catalyzed cascade reaction of 1-(2-iodoaryl)thioureas and aryl
Figure 1. N-Arylation of Cyanamides
Diaryliodonium salts are popular arylating reagents for construction
of C-C, C-O, C-N, C-S, C-Se and C-X (X=halides) bonds with mild
reaction conditions in organic synthesis.8 For instance, the N-
arylations of various N-nucleophiles by diaryliodoniums have been
wildely used for the construction of C-N bonds. In particular, the
transition-metal free transformations which are potentially
environmentally benign synthetic methods, are highly pursued in
iodies was adopted to build 2-arylsulfanylarylcyanamides.6d
A
a.College of Materials and Chemical Engineering, Hainan University, Haikou,
570228, P. R. China
f,
g
the past decades.8c,
Moreover, diaryliodonium salts are easily
† Email: zhangyucang88@163.com
available, air- and moisture-stable, thermostable, nontoxic and
environmentally benign, and the reactions can generate one
Electronic Supplementary Information (ESI) available: Detailed experimental
procedures as well as spectral data of all synthesized compounds. See
DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1

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Journal Name
molecular aryliodide which is also valuable organic intermediate in The optimized conditions were subsequently appliVeiedw AtorticlveaOrniolinues
DOI: 10.1039/C5NJ02153G
arylation reactions.
cyanamides as depicted in scheme 1. p-, m-, o-Tolyl cyanamides all
furnished coupling products with comparable yields (3a, 3b, 3c),
indicating the steric hindrance of the aryl cyanamides was not a
problem for the reactions. The aryl cyanamides with electron-
drawing and -donating groups were both compatible with the
reaction conditions with high yields. For example, p-methoxyphenyl
and p-fluorophenyl cyanamides provided 91% (3e) and 88% (3f)
yields respectively. Gratifyingly, although the aliphatic cyanamides
can be easily hydrolyzed, the reactions of alkyl cyanamides
including linear and cyclic afforded desired products in moderate
yields in water (3h-3j, 3l, 3m); these have not been reported in the
reaction with diaryliodonium hexafluorophosphates.7 Cyclopropyl
cyanamide also produced the corresponding product even only
giving 5% yield (3l), yet t-butyl cyanamide did not produce any
arylation product (3k). The reactions of alkyl cyanamides were also
investigated in toluene for comparison, the results were similar to
that in water but higher yields were obtained, and the cyclopropyl
cyanamide are well compatible with the mild reaction conditions
with moderate yield. It is worth to note that the reaction in a larger
scale also provided the desired coupling product in high yield and
recovered aryliodide with good yield under the same reaction
conditions.10
Recently, we have reported a copper-catalyzed three-component
reaction of cyanamides, boronic acids and amines for the synthesis
of guanidines, where an N-arylation on the terminal nitrogen of
cyanamides by arylboronic acids can be realized, and an N-arylation
on internal nitrogen of cyanamides was found to be a side
reaction.9 As
a part of our ongoing research in exploiting
cyanamides as a dinitrogen resource, here, an N-arylation on the
internal nitrogen of both alkyl and aryl cyanamides by
diaryliodonium triflates in aqueous media is reported for making
disubstituted cyanamides under transition-metal free conditions
(Figure 1, c). The arylation of p-tolylcyanamide (1a) with
diphenyliodonium triflate (2a) was initially screened in DMF with
K2CO3 as base at 80 °C without excluding oxygen, producing the
cross-coupling product in 82% yield within 2 h (Table 1, Entry 1).
Then, higher and lower reaction temperatures were evaluated,
inferior yields were all obtained (Table 1, Entries 2-4). Additionally,
Table 1, Reaction Conditions Optimization:a
Scheme 1. Phenylation of various cyanamides:a
the reaction only produced trace amount of desired product
without base (Table 1, Entry 5). Other solvents including H2O,
toluene, EtOH, and DMSO were further investigated (Table 1,
Entries 6-10). Pleasantly, a superior yield was produced in water
(Table 1, Entry 6), and the reaction in toluene also afforded
comparable yield (Table 1, Entry 7). Different bases such as K3P04,
Cs2CO3, NaOH, CH3COONa and Et3N were finally explored in H2O, all
the reactions provided inferior yields (Table 1, Entries 11-15). Thus,
the best reaction conditions were K2CO3, H2O, 80 °C, 2 h (Table 1,
Entry 6), and exclusion of oxygen was not required comparing with
the reaction between cyanamides and diaryliodonium triflates.7
The reaction scope was finally extended to other diaryliodonium
salts in the aqueous media. It turned out that both symmetric and
unsymmetric diaryliodonium triflates were fully tolerated with the
reaction conditions, providing good yields (Table 2). For the
2 | J. Name., 2012, 00, 1-3
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Journal Name COMMUNICATION
symmetric substrates with electron-rich and -poor aryl groups, the o-tolyl cyanamides produced more 2,5-dimethylphenylation
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DOI: 10.1039/C5NJ02153G
arylation took place smoothly with similar yields (Entries 1-5); and product than phenylation product with goods yields, which shows a
the halogen substituents bromide and chloride which can be further ortho-effect (3d/4g=1/1.5) (Entry 12).8c These results suggest that
functionalized, were survived under the gentle reaction conditions the steric hindrance of cyanamides plays a significant role on the
(Entries 2, 3). The diaryliodonium salts with ortho substituent (2f) chemoselectivities for unsymmetric diaryliodonium salts with steric
also produced the corresponding product without reducing the hindrance aryl group, which may due to the accelerated reductive
c
yield (Entry 4). In accordance with other N-nucleophiles,8b, the elimination between both bulky cyanamide and bulky aryl groups
aryltransfer of unsymmetric diaryliodonium triflates onto via a T-shape intermediate.
cyanamides generally preferred the electron-poor aryl groups to
As ureas are wildly distributed in pharmaceutical candidates 13and
the electron-rich under transition-metal free conditions, and the
pesticides,14 the hydrolysis of cyanamides was explored to make
selectivities are strongly depended on the gap of the electron
ureas. The reaction was briefly investigated as Scheme 2-a, the
treatment of the disubstituted cyanamides by water in toluene,
which promoted by trifluoroacetic acid, delivered the hydrolysis
product ureas with good yields. The phenyl(p-tolyl) cyanamide and
benzyl(phenyl) cyanamide both afforded desired N,N-disubstituted
density between two aryl groups, which should become better as
11
the gap grows.8a,
For instance, the electron-poorer phenyl of
phenyl(p-t-butylphenyl)iodonium
(2g)
and
phenyl(p-
acetylaminophenyl)iodonium (2h) is more easily transferred onto
cyanamide rather than the other aryl groups (Entries 6, 7).
Acetylamino was well compatible with the mild reaction
Scheme 2. The synthesis of ureas.
Table 2. Arylation of p-tolyl cyanamides:a
ureas which can be the precursors of bioactive benzimidazolones
(Scheme 2-a, 5a, 5b). One-pot synthesis of ureas can also be easily
realized by combination of N-arylation and subsequent hydrolysis
with good yield (Scheme 2-b).
In summary, a transition-metal free N-arylation of cyanamides with
diaryliodonium triflates has been developed for the synthesis of
disubstituted cyanamides with good yields. The reaction shows a
general reaction scope, the aromatic and aliphatic cyanamides are
both well compatible with the mild aqueous reaction conditions.
Diaryliodonium triflates including symmetric and unsymmetric are
all working well, and generally the electron-poorer aryl groups are
the preferentially transferred groups for the unsymmetric
diaryliodonium triflates, the steric hindrance of both substrates is
also an important factor for the reaction chemoselectivities. In
addition, the disubstituted cyanamides can be easily hydrolyzed to
valuable N,N-disubstituted ureas, and the N-arylation of
cyanamides and subsequent hydrolysis can be combined into one-
pot procedure with good yields. The mild transition-metal free
conditions,
as
product
4c
and
byproduct
N-(4-
iodophenyl)acetamide were formed. The treatment of p-
tolylcyanamide by phenyl(p-nitrophenyl)iodonium triflate (2i)
mainly produced the p-tolyl(p-nitrophenyl)cyananmide (4d) in high
yield (Entry 8); similarly, phenyl(2-thiophenyl)iodonium triflate (2j)
afforded an excellent selectivity (Entry 9). Unexpectedly, the
electron-poor p-iodophenyl of phenyl(p-iodophenyl)iodonium
triflate (2k) is not a preferable transferred group in the reaction
(Entry 10), the reason for this discrepancy is unclear at this stage.
This indicates that the iodo group is well accommodated with the
reaction conditions. Considering the steric hindrance of substrates
may be a factor affecting the aryltransfer selectivity.8b,
reactions of (2,5-dimethylphenyl)phenyliodonium triflate (2l) with
12
The
both p-tolyl and o-tolyl cyanamides were evaluated. The treatment aqueous conditions and eco-friendly feature of dirayliodonium salts
will make this method attractive. Further exploration of N,N-
disubstituted ureas for the synthesis of bioactive heterocycles is on
progress and will be detailed in the future.
of 2l by p-tolylcyanamides provided mixture products with 1.2/1
ratio of phenyl(p-tolyl)cyanamide/(2,5-dimethylphenyl)p-
tolycyanamides (3a/4a) (Entry 11). However, the reaction of 2l and
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Acknowledgements
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DOI: 10.1039/C5NJ02153G
2010, 352, 2538–2548; e) R. M. Stolley, W. Guo, and J. Louie,
org. Lett., 2012, 14, 322-325; f) P. Kumari, R. Nagpal, P.
Chauhan, V. Yatindranath and Shive M. Chauhan, J. Chem.
Sci., 2015, 127, 13-18; g) S. Cerezo, J. Cortés, M. Moreno-
Mañas, R. Pleixats, A. Roglans, Tetrahedron, 1998, 54, 14869-
14884.
The authors thank Hainan innovation and entrepreneurship
program for high-tech people, and Hainan international
cooperation program (KJHZ 2014-02) for financial support. We also
thank Xiaopeng Wu and Jiuhui Li [from Institute of Tropical
Bioscience and Biotechnology (ITBB), Chinese Academy of Tropical
Agricultural Sciences (CATAS)] for their excellent technical and
analytical support.
7
8
P. Li, G. Cheng, H. Zhang, X. Xu, J. Gao, and X. Cui, J. Org.
Chem., 2014, 79, 8156-8162.
a) E. A. Merritt and B. Olofsson, Angew. Chem. Int. Ed., 2009,
48, 9052–9070; b) M. S. Yusubov, A. V. Maskaev, and V.V.
Zhdankin, ARKIVOC, 2011, 370-409; c) J. Malmgren, S.
Santoro, N. Jalalian, F. Himo, and B. Olofsson Chem. Eur. J.,
2013, 19, 10334–10342; d) M. Bielawski, M. Zhu, and B.
Olofsson Adv. Synth. Catal., 2007, 349, 2610 – 2618; e) b) Y.
Kita, K. Morimoto, M. Ito, C. Ogawa, A. Goto, and T. Dohi, J.
Am. Chem. Soc., 2009, 131, 1668–1669; f) M. A. Carroll, R. A.
Wood, Tetrahedron 2007, 63, 11349-11353; g) F. Tinnis, E.
Stridfeldt, H. Lundberg, H. Adolfsson, and B. Olofsson, Org.
Lett., 2015, 17, 2688–2691. h) I. P. Beletskaya, D. V. Davydov,
M. Moreno-Manas, Tetrahedron Lett. 1998, 39, 5621-5622. i)
J. Yan, M. Zhu, Z. Zhou, Eur. J. Org. Chem. 2006, 2060-2062.
J. Li and L. Neuville, Org. Lett., 2013, 15, 6124-6127.
Notes and references
1
Selected Examples: a) A. Servais, M. Azzouz, D. Lopes, C.
Courillon and M. Malacria, Angew. Chem. Int. Ed., 2007, 46
576–579; b) M.-H. Larraufie, C. Ollivier, L. Fensterbank, M.
Malacria and E. Laocte, Angew. Chem. Int. Ed., 2010, 49
,
,
2178 –2181, c). Z. Pan, S. M. Pound, N. R. Rondla, and C. J.
Douglas, Angew. Chem. Int. Ed., 2014, 53, 5170 –5174. d). H.
Basavaprabhu and V. V. Sureshbabu, Org. Biomol. Chem.,
2012, 10, 2528–2533; e) V. Panduranga, Basavaprabhu, V. V.
Sureshbabu Tetrahedron Lett., 2013, 54, 975–979; f). S.
Kamijo, T. Jin, and Y. Yamamoto Angew. Chem. Int. Ed., 2002,
41, 1780-1782; g) L. V. R. Boñaga, H.-C. Zhang and B. E.
Maryanoff, Chem. Commun., 2 0 0 4 , 2 3 9 4 – 2 3 9 5; h) K.
Fukumoto, T. Oya, M. Itazaki, and H. Nakazawa, J. Am. Chem.
Soc. 2009, 131, 38–39; i). R. L. Giles, J. D. Sullivan, A. M.
9
10 The reaction of phenyl cyanamide with di(p-tolyl)iodonium
triflate in 1.25 mmol produced 223 mg phenyl(p-
tolyl)cyanamide (3a, 86% yield) and 196 mg p-tolyliodide
(72% yield).
11 M. Ochiai, Y. Kitagawa, and M. Toyonari, ARKIVOC, 2003, 43-
48.
12 K. M. Lancer and G. H. Wiegand, J. Org. Chem., 1976, 41
,
Steiner, and R. E. Looper, Angew. Chem. Int. Ed. 2009, 48
,
3360-3364.
3116–3120; j) S. Guin, S. K. Rout, A. Gogoi, W. Ali, and B. K.
Patela, Adv. Synth. Catal., 2014, 356, 2559-2565; k) T. K. Lane,
B. R. D’Souza and J. Louie J. Org. Chem. 2012, 77, 7555−7563;
l) V. Kumar, M. P. Kaushik, and A. Mazumdar, Eur. J. Org.
Chem., 2008, 1910–1916.
Selected Examples: a) C. J. Adams J. Chem. Soc., Dalton
Trans., 1999, 2059–2064; b) A. S. Smirnov, E. S. Butukhanova,
N. A. Bokach, G. L. Starova, V. V. Gurzhiy, M. L. Kuznetsov
and V. Yu. Kukushkin, Dalton Trans., 2014, 43, 15798–15811.
c) M. Yuan, S. Gao, H.-L. Sun, and G, Su Inorg. Chem., 2004,
43, 8221-8223.
13 a) B. A.-K. Wulfrath, S. S. Goch, E. K. Hattingen US
2011/0263657; b) C. P Decicco, J. L. Seng, K. E. Kennedy, M. B.
Covington, P. K. Welch, E. C. Arner, R. L. Magolda, D. J.
Nelson, Bioorg. Med. Chem. Lett., 1997, 7, 2331-2336; c) J. A.
W. Kruijtzer, D. J. Lefeber, R. M. J. Liskamp, Tetrahedron Lett.
1997, 38, 5335-5338; d) A. R. Katritzky, N. Kirichenko, and B.
V. Rogovoy, ARKIVOC, 2003 (VIII), 8-14.
2
3
14 A. Retnakaran, J. E. Wright, Chitin and Phenzoylphenyl Ureas,
1987, 38, 205-282; b). L. Chen, Q. Wand, R. Huang, C. Mao, J.
Shang, and F. Bi, J. Agric. Food Chem. 2005, 53, 38-41.
a). D. G. Barrett,a, D. N. Deaton, A. M. Hassell, R. B.
McFadyen, A. B. Miller, L. R. Miller, J. A. Payne, L. M.
Shewchuk, D. H. Willard, Jr. and L. L. Wright, Bioorg. Med.
Chem. Lett., 2005, 15, 3039–3043; b) H.-W. K. Bischofsheim,
H.-J. L. Hogheim, J.-R. S. Kelkheim, A. W. Egelsbach, S. F.
Idstein, H.-W. J. Niedernhausen, S. P. Frankfurt,
US
6369069B1; c) K. S. Atwal, G. J. Grover, S. Z. Ahmed, P. G.
Sleph, S. Dzwonczyk, A. J. Baird, and D. E. Normandin, J. Med.
Chem., 1995, 38, 3236-3245; d) P. W. Manley and U. Quast, J.
Med. Chem., 1992, 35, 2327-234; e) G. Danger, A. Michaut,
M. Bucchi, L. Boiteau, J. Canal, R. Plasson, and R. Pascal
Angew. Chem. Int. Ed. 2013, 52, 611 –614.
a). T. Kamo, M. Endo, M. Sato, R. Kasahara, H. Yamaya, S.
Hiradate, Y. Fujii, N. Hirai and M. Hirota, Phytochemistry,
2008, 69, 1166–1172.
a) C. Grundmann, In Methoden der Organischen Chemie
(Houben-Weyl); J. Falbe, Ed.; Georg Thieme Verlag: Stuttgart,
1985; Vol. E5, pp 1611-1658. b) S. R. Sandler, W. Karo,
Organic Functional Group Preparations; Academic: New York,
1972; Vol. 3, p 286-287 and Vol. 2, p174-178.
Selected transition-metal catalyzed synthesis of cyanamides:
a) S. Kamijo, T. Jin, and Y. Yamamoto J. Am. Chem. Soc., 2001,
123, 9453-9454; b) S. Kamijo and Y. Yamamoto J. Am. Chem.
Soc. 2002, 124, 11940-11945; c) S. Kamijo, T. Jin, Y.
Yamamoto, Angew. Chem. Int. Ed., 2002, 41, 1780-1782; d) S.
K. Sahoo, L. Jamir, S. Guin, and B. K. Patel Adv. Synth. Catal.
4
5
6
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Various disubstituted cyanamides were made through transition-metal free N-arylation of
cyanamides by diaryliodonium triflates under aqueous conditions with good yields.