Copper-catalyzed oxidative three-component synthesis of N, N′, N′-trisubstituted guanidines

Article abstract of DOI:10.1021/ol4029622

A copper-catalyzed three-component synthesis of trisubstituted N-aryl guanidines involving cyanamides, arylboronic acids, and amines has been developed. This operationally simple oxidative process, which is performed in the presence of K₂CO₃, a catalytic amount of CuCl ₂·2H₂O, bipyridine, and oxygen (1 atm), allows the rapid assembly of N,N′,N″-trisubstituted aryl guanidines.

Full text of DOI:10.1021/ol4029622

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Copper-Catalyzed Oxidative
Three-Component Synthesis of
N, N0,N00‑Trisubstituted Guanidines
Jihui Li and Luc Neuville*
Centre de Recherche de Gif, Institut de Chimie des Substances Naturelles,
ꢀ
Laboratoire International Associe, CNRS, 91198 Gif-sur-Yvette Cedex, France
luc.neuville@cnrs.fr
Received October 14, 2013
ABSTRACT
A copper-catalyzed three-component synthesis of trisubstituted N-aryl guanidines involving cyanamides, arylboronic acids, and amines has been
developed. This operationally simple oxidative process, which is performed in the presence of K2CO3, a catalytic amount of CuCl2 2H2O,
3
bipyridine, and oxygen (1 atm), allows the rapid assembly of N,N0,N00-trisubstituted aryl guanidines.
Guanidines are important units due to their involvement
in essential biological processes through, for example, their
presence in arginine-containing peptides and have been
found in numbers of molecules of natural origin.1 As a
consequence, they have been actively targeted in medicinal
chemistry and therapeutics such as relenza (antiviral),
famotidine (antiulcer), and clonidine (anesthetic R2 adre-
noceptor agonist) are currently used on the market.2 In
addition, guanidines hold a growing place in the synthetic
toolbox, being notably used as organocatalysts or as metal
ligands in a number of transformations.3
provided a useful entry, especially to N-arylated guanidines.5
In addition, such a strategy is also valuable for the
synthesis of heterocyclic structures such as benzimidazoles
or quinazolines.6 While valuable, all these methods leave
room for the development of an alternative process espe-
cially considering the rapid elaboration of libraries of
N,N0,N00-trisubstituted guanidines which requires pre-
paration of a specific reagent/precursor for most cases.7
Cyanamides are valuable targets for various applica-
tions and have been used as versatile building blocks for
further elaboration through nucleophilic addition, cyclo-
condensation, or radical reactions.8 In connection withour
interest in developing metal-catalyzed transformations
for the rapid synthesis of heterocyclic structures9 through
tandem10 or multicomponent reactions,11 our attention
The synthesis of guanidines mostly relies on the con-
densation between amines and electrophilic guanylating
reagents or carbodiimides.4 Metal-catalyzed functionali-
zations of guanidines have also been described and
(1) (a) Guanidino Compounds in Biology and Medicine; De Deyn, P. P.,
Marescau, B., Quereshi, I. A., Mori, A., Eds.; John Libbey and Co.; London,
1997. (b) Berlinck, R. G. S.; Trindade-Silva, A. E.; Santos, M. F. C. Nat.
Prod. Rep. 2012, 29, 1382–1406.
(6) Selected examples: (a) Evindar, G.; Batey, R. A. Org. Lett. 2003,
5, 133–136. (b) Deng, X.; McAllister, H.; Mani, N. J. Org. Chem. 2009,
74, 5742–5745. (c) Zeng, F.; Alper, H. Org. Lett. 2010, 12, 1188–1191. (d)
He, H.-F.; Wang, Z.-J.; Bao, W. Adv. Synth. Catal. 2010, 352, 2905–
2912. See also ref 5a.
(2) Saczewski, F.; Balewski, L. Expert Opin. Ther. Pat. 2013, 23, 965–
)
995.
€
(7) Dahmen, S.; Brase, S. Org. Lett. 2000, 2, 3563–3565.
(8) Larraufie, M.-H.; Maestri, G.; Malacria, M.; Ollivier, C.;
(3) (a) Superbases for Organic Synthesis: Guanidines, Amidines,
Phosphazenes and Related Organocatalysts; Ishikawa, T., Ed.; John Wiley
& Sons: West Sussex, U.K., 2009. (b) Taylor, J. E.; Bull, S. D.; Williams,
J. M. J. Chem. Soc. Rev. 2012, 41, 2109–2121.
(4) Katritzky, A. R.; Rogovoy, B. V. ARKIVOC 2005, iv, 49–87.
(5) N-Arylations: (a) Rauws, T. R. M.; Maes, B. U. W. Chem. Soc.
Rev. 2012, 41, 2463–2497. Selected other reactions: (b) Miyabe, H.;
Yoshida, K.; Reddy, V. K.; Takemoto, Y. J. Org. Chem. 2006, 74, 305–
311. (c) Kim, M.; Mulcahy, J. V.; Espino, C. G.; Du Bois, J. Org. Lett.
^
Fensterbank, L.; Lacote, E. Synthesis 2012, 44, 1279–1292.
(9) Benzodiazepinediones: (a) Salcedo, A.; Neuville, L.; Rondot, C.;
Retailleau, P.; Zhu, J. Org. Lett. 2008, 10, 857–860. Benzoxazoles: (b)
Salcedo, A.; Neuville, L.; Zhu, J. J. Org. Chem. 2008, 73, 3600–3603.
Phenanthridines: (c) Gerfaud, T.; Neuville, L.; Zhu, J. Angew. Chem.,
Int. Ed. 2009, 48, 572–577. Quinoxalinones: (d) Erb, W.; Neuville, L.;
Zhu, J. J. Org. Chem. 2009, 74, 3109–3115. Oxindoles: (e) Jaegli, S.;
Vors, J.-P.; Neuville, L.; Zhu, J. Tetrahedron 2010, 66, 8911–8921.
Dihydroquinolinones: (f) Piou, T.; Neuville, L.; Zhu, J. Org. Lett.
2012, 14, 3760–3763.
€
~
2006, 8, 1073–1076. (d) Hovelmann, C. H.; Streuff, J.; Brelot, L.; Muniz,
K. Chem. Commun. 2008, 28, 2334–2338.
r
10.1021/ol4029622
XXXX American Chemical Society

was drawn to two Pd-catalyzed reactions involving
cyanamides leading to N-arylated cyanamides12 and
benzamidines,13 respectively (Scheme 1a). Taking into
consideration that, besides palladium, copper has been
particularly effective for catalyzing CꢀN bond forma-
tion14 and based on our experience on metal-catalyzed
aerobic oxidative transformations,15 we became interested
in building N-aryl cyanamides with copper.16 Indeed, a
such process could be valuable considering the cost asso-
ciated to the metal/ligand couple or provide alternative
conditions.
Scheme 1. Pd- and Cu-Catalyzed Processes Involving Cyanamides
An initial attempt, reacting N-(tert-butyl)cyanamide
(1a) with potassium p-tolylboronic acid (6a) under condi-
tions found previously to be optimum for the N-arylation
of amidines,15c afforded benzimidamide 7a, albeit in low
yield(<20%) (Scheme1b); interestingly, wealsoidentified
the presence of urea 8a among the side products. Such
a product, showing a different regiochemical arylation
pattern compared to the described Pd-catalyzed reactions,
could result from a three-component reaction17 involving
cyanamide, boronic acid, and H2O (Scheme 1b). From this
observation we reasoned that replacing water with a more
nucleophilic reagent, namely amine, could offer an entry
to guanidines, keeping in mind that N-arylation of the
amine could constitute a serious competitive reaction
(Scheme 1c). From this study, we now report conditions
allowing an easy assembly of multisubstituted guanidines
from cyanamides, arylboronic acids, and amines, through
a three-component process performed under Cu-catalyzed
aerobic conditions.
Table 1. Survey of the Reaction Conditions
time,
yield
(%)b
entry
1
additive/ligand (equiv) temp (°C) solvent
1c
1a NaPiv(0.4)
1a BiPy (0.2)
1a BiPy (0.2)
1a BiPy (0.2)
1a BiPy (0.2)
1a BiPy (0.2)
1b BiPy (0.2)
1b BiPy (0.2)
1b BiPy (0.2)
10 h, 50
10 h, 50
10 h, 50
10 h, 50
10 h, 50
10 h, 50
10 h, 50
DMF
39
87
75
70
52
2c
DMF
3c
toluene
DMSO
dioxane
4c
5c
6c
amlylOH 44
7c
DMF
52
65
71
95
59
91
91
90
93
0
To evaluate the possible three-component reaction,
we chose to react cyanamide 1a, boronic acid 6a, and
8
10 h, 100 toluene
0.5 h, 100 toluene
9d
10d
11d
12d
13d
1b K2CO3 (2.25)/BiPy (0.2) 0.5 h, 100 toluene
1b K2CO3 (2.25) 0.5 h, 100 toluene
(10) (a) Pinto, A.; Jia, Y.; Neuville, L.; Zhu, J. Chem.;Eur J. 2007,
13, 961–967. (b) Jaegli, S.; Erb, W.; Retailleau, P.; Vors, J.-P.; Neuville,
L.; Zhu, J. Chem.;Eur J. 2010, 16, 5863–5867. Involving CH function-
alizations: (c) Pinto, A.; Neuville, L.; Retailleau, P.; Zhu, J. Org. Lett.
2006, 8, 4927–4930. (d) Jaegli, S.; Dufour, J.; Wei, H.-L.; Piou, T.; Duan,
X.-H.; Vors, J.-P.; Neuville, L.; Zhu, J. Org. Lett. 2010, 12, 4498–4501.
(e) Piou, T.; Neuville, L.; Zhu, J. Angew. Chem., Int. Ed. 2012, 51, 11561–
11565.
1b K2CO3 (2.25)/BiPy (0.2) 6 h, rt
1b K2CO3 (2.25)/BiPy (0.2) 3 h, 50
toluene
toluene
toluene
toluene
toluene
14c,d 1b K2CO3 (2.25)/BiPy (0.2) 3 h, 50
15d,e 1b K2CO3 (2.25)/BiPy (0.2) 3 h, 50
16f
1b K2CO3 (2.25)/BiPy (0.2) 3 h, 70
a Conditions: Cu(OAc)2 H2O (0.2 equiv), additive, cyanamide
(1.5 equiv), p-TolB(OH)2 (1.5 equiv), piperidine (1.0 equiv), O2 (1 atm).
(11) (a) Pinto, A.; Neuville, L.; Zhu, J. Angew. Chem., Int. Ed. 2007,
46, 3291–3295. (b) Pinto, A.; Neuville, L.; Zhu, J. Tetrahedron Lett.
2009, 50, 3602–3605.
3
b Isolated yield. c Under air instead of O2. d CuCl2 H2O (0.2 equiv) was
3
used. e CuCl2 H2O (0.1 equiv). f No copper.
(12) Stolley, R. M.; Guo, W.; Louie, J. Org. Lett. 2012, 14, 322–325.
3
€
(13) (a) Savmarker, J.; Rydfjord, J.; Gising, J.; Odell, L. R.; Larhed,
M. Org. Lett. 2012, 14, 2394–2397. (b) Rydfjord, J.; Svensson, F.; Trejos,
€
€
€
A.; Sjoberg, P. J. R.; Skold, C.; Savmarker, J.; Odell, L. R.; Larhed, M.
piperidine (9a) and rapidly found that guanidine 10a
could indeed be obtained under Cu catalysis (table 1).
The reaction occurred at 50 °C under air in the presence
of a catalytic amount of Cu(OAc)2 and was markedly
improved using bipyridine instead of sodium pivalate as
an additive/ligand (Table 1, entry 2 vs 1). Various solvents
such as toluene and DMSO were a good reaction medium
(Table 1, entries 3ꢀ4), but the best yields were obtained
in DMF allowing isolating guanidine 10a in 87% yield
(Table 1, entry 2).
As N-arylated cyanamides were not evaluated under the
Pd-catalyzedconditionsreportedbyLouieandLarhed,12,13
we immediately evaluated the reactivity of p-tolylcyanamide
and were pleased to obtain the corresponding bis-arylated
guanidine 10b in 52% yield (Table 1, entry 7). Further
Chem.;Eur. J. 2013, 19, 13803–13810.
(14) For reviews, see: (a) Ley, S. V.; Thomas, A. W. Angew. Chem.,
Int. Ed. 2003, 42, 5400–5449. (b) Monnier, F.; Taillefer, M. Angew.
Chem., Int. Ed. 2009, 48, 6954–6971. (c) Sadig, J. E. R.; Willis, M. C.
Synthesis 2011, 43, 1–22. (d) Beletskaya, I. P.; Cheprakov, A. V.
Organometallics 2012, 31, 7753–7808.
(15) For reviews, see: (a) Shi, Z.; Zhang, C.; Tang, C.; Jiao, N. Chem.
Soc. Rev. 2012, 41, 3381–3430. (b) Allen, S. E.; Walvoord, R. R.; Padilla-
Salinas, R.; Kozlowski, M. C. Chem. Rev. 2013, 113, 6234–6458. Our
ꢀ
work: (c) Li, J.; Benard, S.; Neuville, L.; Zhu, J. Org. Lett. 2012, 14,
5980–5983. (d) Li, J.; Neuville, L. Org. Lett. 2012, 14, 1752–1755. (e)
Piou, T.; Neuville; Zhu, J. Tetrahedron 2013, 69, 4414–4420.
(16) Nonoxidative Cu-catalyzed construction of aryl cyanamides: (a)
Ramana, T.; Saha, P.; Das, M.; Punniyamurthy, T. Org. Lett. 2010, 12,
84–87. (b) Yang, D.; Wang, Y.; Yang, H.; Liu, T.; Fu, H. Adv. Synth.
Catal. 2012, 354, 477–482.
(17) (a) Multicomponent Reaction; Zhu, J., Bienayme, H., Eds.; Wiley-
VCH: Weinheim, 2005. (b) DSouza, D. M.; M€uller, T. J. J. Chem. Soc. Rev.
2007, 36, 1095–1108. (c) Arndtsen, B. A. Chem.;Eur. J. 2009, 15, 302–
312.
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ꢀ
B
Org. Lett., Vol. XX, No. XX, XXXX

investigation of the conditions revealed the following: (1)
toluene was a better solvent for N-aryl cyanamides (Table 1,
entry 8); (2) the reaction was effectively catalyzed by the
the process (not shown), but the reaction was not limited
to alkyl amines, as benzyl and allyl amine successfully
afforded guanidines 10p and 10q. In the latter case, per-
forming the reaction at rt greatly improved the reaction’s
outcome avoiding oxidative degradation of the amine.
It should be noted that 10p and 10q provide a handle
for further deprotection and access to disubstituted
guanidines.19
combination CuCl2 H2O in the presence of O2 (1 atm)
3
(Table 1, entry 9);18 (3) the reaction was rather fast at
100 °C, reaching completion in 30 min but could be carried
out at rt over 6 h (Table 1, entries 9ꢀ12); (4) importantly
using a combination of K2CO3 (2.25 equiv) and BiPy (0.2
equiv) as the additive/ligand allowed an almost quantitative
guanidine formation (Table 1, entry 10).
With the best conditions [cyanamide/boronic acid/
amine (1.5/1.5/1.0 equiv), K2CO3 (2.25 equiv), O2 (1 atm),
CuCl2 2H2O (0.1 equiv), Bipy (0.1 equiv), toluene, 100 °C,
3
30 min], the generality of the reaction was surveyed.
Figure 2. Scope of the Cu-catalyzed synthesis of guanidines:
amines.a a Conditions: p-tolyl cyanamide/p-tolyl boronic acid/
amine (1.5/1.5/1.0 equiv), K2CO3 (2.25 equiv), O2 (1 atm),
CuCl2 2H2O (0.1 equiv), Bipy (0.1 equiv), toluene, 100 °C, 30 min.
3
b 70 °C, 30 min. c Rt, 24 h.
Figure 1. Scope of the Cu-catalyzed synthesis of guanidines:
boronic acids.a a Conditions: p-tolyl cyanamide/boronic acid/
piperidine (1.5/1.5/1.0 equiv), K2CO3 (2.25 equiv), O2 (1 atm),
Substitution at the cyanamide residue was finally eval-
uated (Figure 3). The presence of a free NH was found to
be necessary, as secondary N-methyl-N-phenylcyanamide
did not participate in the process. We were delighted to
observe that aryl cyanamides bearing an ortho substituent,
electron-withdrawing and -donating groups, all provided
good results (10e, tꢀw, 76ꢀ93% yields). Cyanamides
bearing a primary, secondary, and tertiary alkyl substitu-
ent aswell asbenzylcyanamidealsoshowedgood reactivity
(10wꢀz). For these compounds we found that the reaction
was best accomplished at 50 °C in DMF under base-free
conditions.
While targeted for direct use,1ꢀ3 substituted guanidines
of type 10 can offer opportunities for building heterocyclic
structures by intramolecular cyclization.5,6 In a prelimi-
narywork, we havefound thatbenzimidazoles 11 (Figure3,
box) could be directly assembled through a three-component
reaction/CꢀH functionalization20 sequence using the same
reaction conditions over a prolonged time (100 °C, 24 h), 10b
being an intermediate of the reaction.21
CuCl2 2H2O (0.1 equiv), Bipy (0.1 equiv), toluene, 100 °C,
3
30 min. b CuCl2 2H2O (0.2 equiv), Bipy (0.2 equiv).
3
The tolerance of the reaction toward the aryl boronic
acid component was investigated, and the results are
shown in Figure 1. Yields ranged from 65% to 93%
demonstrating the tolerance of the reaction to functional
groups such as halides including the iodine, ether, ketone,
nitro, or trifluoromethyl group. Both electron-rich and
-poor as well as sterically demanding aryl boronic acids
provided the corresponding guanidines in high yields (10e,
10g, 10h). For 4-acetyl- and 3-nitro-phenyl boronic acids, a
higher catalyst loading of CuCl2 (20 mol %) was required
to furnish good yields of products (10i and 10j).
A set of diverse amines was next investigated (Figure 2).
Secondary amines, whether cyclic or acyclic, afforded the
desired guanidines in high yields uneventfully. Interest-
ingly, the presence of an additional tertiary amine or a free
hydroxyl group was well tolerated, as demonstrated with
the synthesis of compounds 10r and 10s. The process was
also viable using primary amines including the sterically
demandingtert-butyl amine. Anilineswerenoteffectivefor
It seems reasonable to think that the process is the result
of two distinct events, namely a nucleophilic addition of
(19) (a) Groziak, M. P.; Townsend, L. B. J. Org. Chem. 1986, 51,
1277–1282. (b) Hammoud, H.; Schmitt, M.; Bihel, F.; Antheaume, C.;
Bourguignon, J. J. J. Org. Chem. 2012, 77, 417–423.
(20) Seminal work: Brasche, G.; Buchwald, S. L. Angew. Chem., Int.
Ed. 2008, 47, 1932–1934.
(21) Extension of this and related transformations is being pursued.
(18) Cu(CF3COCH2COCH3)2, CuBr2, and Cu(SO2CF3)2 were less
efficient, furnishing 54%, 69%, and 57% respectively.
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 2. Possible Mechanism
Figure 3. Scope of the Cu-catalyzed synthesis of guanidines:
cyanamides.a Conditions: cyanamide/aryl boronic acid/piperidine =
1.5/1.5/1.0 equiv, K2CO3 (2.25 equiv), O2 (1 atm), CuCl2 2H2O
attempting to perform a simple N-arylation of cyanamides
in the absence of amine tend to argue against this pathway,
as, at least to a significant level, no carbodimiide was
observed. Therefore, we propose that a nucleophilic addi-
tion of the amine 9 to the highly electrophilic diimide
complex C (potentially promoted by a second Cu-atom)26
and a reductive elimination would deliver product 10.
Finally, the Cu(I) complex would be oxidized before re-
entering the catalytic cycle.
In conclusion, we have disclosed a novel Cu-catalyzed
three-component reaction of arylboronic acids, cyanamides,
and amines. A broad diversity of symmetrical and unsynme-
trical N,N0,N00-trisubstituted guanidines were easily prepared
from readily available and simple starting materials using
this method. A preliminary mechanistic investigation ruled
out a simple nucleophilic addition of an amine to a cyan-
amide followed by a Cu-catalyzed ChanꢀLamꢀEvans type
N-arylation.
3
(0.1 equiv), Bipy (0.1 equiv), toluene, 100 °C, 30 min. b In DMF,
without K2CO3, at 50 °C, 6 h. c At 100 °C, 24 h.
amine to cyanamide to form guanidine 12,22 followed by
a Cu-catalyzed ChanꢀLamꢀEvans type N-arylation with
boronic acid23 (Scheme 2a). However, control experiments
clearly established that guanidine 12 was not formed and
that N-arylation did not proceed to a significant level
under the present conditions.24
Based on this result, a reasonable mechanism account-
ing for the observed transformation was proposed
(Scheme 2b). Transmetalation of boronic acid 6 with a
Cu(II) complex wouldinitiatethereaction, and subsequent
coordination and deprotonation of the cyanamide 1 would
deliver complex B which would tautomerize to diimide
complex B0.25 Upon oxidation (with a second Cu(II)
species or with oxygen), a higher oxidation state Cu(III)
complex C could next be generated. At this point, a
reductive elimination could take place to form the
carbodiimide 13; however, initial results obtained when
Acknowledgment. Financial support from ICSN, CNRS.
J.L. thanks the Government of China for a National
Graduate Student Program of Building World-Class
Universities.
(22) Snider, B. B.; O‘Hare, S. M. Tetrahedron Lett. 2001, 42, 2455–
2458 and references therein.
(23) (a) Qiao, J. X.; Lam, P. Y. S. Synthesis 2011, 829–856. (b) Rao,
K. S.; Wu, T.-S. Tetrahedon 2012, 68, 7735–7754. Our contribution: (c)
Benard, S.; Neuville, L.; Zhu, J. J. Org. Chem. 2008, 73, 6441–6444. (d)
Benard, S.; Neuville, L.; Zhu, J. Chem. Commun. 2010, 46, 3393–3395.
(24) See Supporting Information.
(25) Crutchley, R. J. Coord. Chem. Rev. 2001, 219ꢀ221, 125–155.
(26) Arylcyanamides can act as bridging ligands in dinuclear copper
complexes; see: Hadadzadeh, H.; Rezvani, A. R.; Esfandiari, H. Poly-
hedron 2008, 27, 1809–1817.
Supporting Information Available. Experimental pro-
cedures, product characterization, and copies of the
1H and 13C NMR spectra of new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
ꢀ
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX