Nanoparticulate copper(II) oxide catalyzed synthesis of guanidine derivatives and their conversion into functionalized iminoguanidines

Article abstract of DOI:10.1055/s-0034-1380349

Abstract A simple synthesis of functionalized iminoguanidines from N-sulfoketenimines and N,N′,N′′-trisubstituted guanidines, generated by nanoparticulate copper(II) oxide-catalyzed hydroamination of di(cyclo)alkylcarbodiimides, is described.

Full text of DOI:10.1055/s-0034-1380349

SYNLETT
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© Georg Thieme Verlag Stuttgart · New York
2015, 26, 1230–1232
letter
1230
I. Yavari et al.
Letter
Synlett
Nanoparticulate Copper(II) Oxide Catalyzed Synthesis of
Guanidine Derivatives and Their Conversion into Functionalized
Iminoguanidines
Issa Yavari*
O
O
R2
S
+
Esmat Sodagar
R3
N3
Manijeh Nematpour
Mohammad Askarian-Amiri
CuI (10 mol%)
Et3N, toluene
r.t.
O
O
Department of Chemistry, University of Tarbiat Modares,
P.O. Box 14115-175, Tehran, Iran
yavarisa@modares.ac.ir
S
N
R3
O
O
Ar
R1
N
C
S
H
N
R3
N
N
ArNH2
+
CuO-NPs (10 mol%)
toluene, 80 °C, 8 h
R1
R1
R2
r.t., 4 h
Ar
N
N
H
N
R1
N
H
R1
C
R1
R2
N
Received: 06.12.2014
Accepted after revision: 16.02.2015
Published online: 01.04.2015
amines and carbodiimides. Only the nanoparticulate cop-
per(II) oxide gave acceptable results. We therefore opti-
mized the reaction conditions for hydroamination of carbo-
diimides by using nanoparticulate copper(II) oxide as a cat-
alyst for the model reaction of aniline (1a) with N,N′-
dicyclohexylcarbodiimide (2a; DCC). A brief screening of
solvents in the presence of 5 mol% of catalyst under reflux
showed that acetonitrile, tetrahydrofuran, dichlorometh-
ane, and hexane were less effective than toluene (Table 1,
entries 2–6). N,N′-Dicyclohexyl-N′′-phenylguanidine (3a)
DOI: 10.1055/s-0034-1380349; Art ID: st-2014-d1007-l
Abstract A simple synthesis of functionalized iminoguanidines from
N-sulfoketenimines and N,N′,N′′-trisubstituted guanidines, generated
by nanoparticulate copper(II) oxide-catalyzed hydroamination of di(cy-
clo)alkylcarbodiimides, is described.
Key words imines, guanidines, ketenes, tandem reactions, azides,
alkynes, carbodiimides
Guanidines have a wide range of applications as thera-
peutic agents in medicine.1,2 Moreover, guanidine deriva-
tives are used as organocatalysts or as ancillary ligands in
many transformations.3 Consequently, there is increasing
interest in the synthesis of guanidines.4–6 Recently, direct
catalytic guanylation of amines with carbodiimides has re-
ceived much interest because it provides a convenient and
atom-economic approach to guanidines.7
Table 1 Optimization of the Conditions for the Hydroamination of
N,N′-Dicyclohexylcarbodiimide with Nanoparticulate Copper(II) Oxide
as Catalysta
Ph
CuO-NPs
solvent
N
N
+
C
PhNH2
N
N
N
H
H
1a
2a
3a
There has also been much recent interest in the synthe-
sis and application of transition-metal oxide nanoparticles,
because of their large specific surface areas and their high
activities in many catalytic processes.8 Among the various
nanoparticulate metal oxides, nanoparticulate copper(II)
oxide is an effective catalyst for many reactions.9–12 In con-
tinuation of our interest in the applications of nanoparticu-
late copper(II) oxide as a catalyst for organic reactions, we
have prepared nanoparticulate copper(II) oxide13 and have
used it as a new, simple, and efficient catalyst for the gua-
nylation of amines with carbodiimides under mild condi-
tions.
Initially, we examined various copper catalysts, includ-
ing copper(I) iodide, copper(I) bromide, copper(II) acetate,
copper(II) chloride, nanoparticulate copper(I) oxide, bulk
copper(II) oxide, and nanoparticulate copper(II) oxide, for
the synthesis of N,N′,N′′-trisubstituted guanidines from
Entry Catalyst (mol%) Solvent
Temp (°C)
Time (h) Yieldb (%)
1
2
–
5
toluene
toluene
CH2Cl2
hexane
MeCN
reflux
reflux
reflux
reflux
reflux
reflux
r.t.
24
24
24
24
24
24
24
24
8
–
80
35
45
75
60
–
3
5
4
5
5
5
6
5
THF
7
10
10
10
10
20
toluene
toluene
toluene
toluene
toluene
8
60
65
94
94
94
9
80
10
11
100
8
80
8
a Reaction conditions: DCC (1 mmol), PhNH2 (1 mmol).
b Isolated yield.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1230–1232

1231
I. Yavari et al.
Letter
Synlett
was obtained efficiently after eight hours in the presence of
10 mol% of nanoparticulate copper(II) oxide at 80 °C. In-
creasing the catalyst loading to 20 mol% did not affect the
yield. Therefore, the use of 10 mol% of nanoparticulate cop-
per(II) oxide (8 mg) in toluene at 80 °C was considered to be
the best choice for hydroamination of DCC (entry 9).
As part of our current studies on the development of
new applications of N-sulfoketenimines in organic synthe-
sis,14–16 we used the optimized conditions to construct
highly functionalized iminoguanidines from N-sulfoketen-
imines and the N,N′,N′′-trisubstituted guanidines prepared
by the nanoparticulate copper(II) oxide catalyzed hydroam-
ination of dialkylcarbodiimides.
To investigate the scope of this transformation, we ex-
amined the reactions of a wide range of anilines containing
various electron-donating and electron-withdrawing
groups to give 1,3-dialkyl-2-arylguanidines 3. Subsequent-
ly, these intermediates were treated with N-sulfoketen-
imines to give the corresponding iminoguanidines 7a–k in
good yields (Table 2).17
These reactions gave good yields regardless of whether
electron-withdrawing or electron-donating substituents
were present on the aromatic ring. The catalytic system
showed good functional-group tolerance. Both N,N′-di(cy-
clo)alkylcarbodiimides 2 reacted with aromatic amines
bearing bulky and electron-withdrawing substituents in
the ortho- or para-position of the phenyl ring to give the
corresponding iminoguanidines in good yields. Aliphatic
alkynes readily participated in the coupling to give the cor-
responding iminoguanidines 7a–j (Table 2). Aromatic and
aliphatic sulfonyl azides reacted efficiently, and the corre-
sponding products were obtained in good yields.
A plausible mechanism for the formation of products 7
is shown in Scheme 1. The copper acetylide 8, formed from
alkyne 4 and copper(I) iodide, undergoes a 1,3-dipolar cyc-
loaddition reaction with sulfonyl azide 5 to give the triazole
derivative 9. This intermediate can undergo a ring-opening
reaction to give the N-sulfonylketenimine 6. Guanidine de-
rivative 3, formed from arylamine 1 and N,N′-di(cyclo)al-
Table 2 Synthesis of Iminoguanidine Derivatives 7a–ka
O
O
R2
+
S
R3
N3
5
4
(i) CuI (10 mol%)
Et3N, toluene
r.t.
O
O
S
N
C
R3
ArNH2
O
O
Ar
S
H
N
R1
N
1
N
R3
N
N
(ii) CuO-NPs (10 mol%)
toluene, 80 °C, 8 h
+
R1
R2
R1
N
6
R1
C
R1
Ar
N
N
H
N
H
r.t., 4 h
R2
R1
7
2
3
Entry
Ar
R1
R2
R3
Product
Yieldb (%)
1
2
Ph
4-Tol
Cy
i-Pr
i-Pr
Cy
Cy
Cy
Cy
Cy
Cy
Cy
i-Pr
Bu
Ph
Ph
Ph
7a
7b
7c
7d
7e
7f
84
80
74
70
81
78
79
80
83
85
70
Bu
Bu
Pr
3
2,4-Cl2C4H6
4-Tol
4
4-Tol
Ph
5
4-ClC6H4
Ph
Pr
6
Pr
4-Tol
4-Tol
Me
7
4-O2NC6H4
4-ClC6H4
4-Tol
Bu
Pr
7g
7h
7i
8
9
Pr
Me
10
11
Ph
Bu
Ph
4-Tol
Ph
7j
4-ClC6H4
7k
a Reaction conditions: (i) 1 (1.0 mmol), 2 (1.0 mmol), nanoparticulate CuO (8 mg, 20 mol%), toluene (2 mL), 80 °C, 8 h; (ii) 5 (1.2 mmol), 4 (1 mmol), CuI (0.019
g, 0.1 mmol), Et3N (101 mg, 1 mmol), toluene (2 mL), r.t, 4 h.
b Isolated yield.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1230–1232

1232
I. Yavari et al.
Letter
Synlett
Ar
N
R1
R1
CuO-NPs
1
2
+
N
N
H
O
O
H
S
H
N
R1
N
3
R3
N
N
O
O
Ar
R1
Cu
S
N
R3
R2
R1
7
H
5
R1
Cu
C
N
N
SO2R3
4 + CuI
N
– N2
R2
9
8
6
Scheme 1 A plausible mechanism for the formation of products 7
kylcarbodiimide 2, undergoes a nucleophilic addition reac-
tion with the N-sulfonylketenimine 6 to give the imi-
noguanidine 7.
In conclusion, we have developed a multicomponent
protocol for the synthesis of a novel class of iminoguanidine
derivatives through a nanoparticulate copper(II) oxide cata-
lyzed tandem reaction of anilines, di(cyclo)alkylcarbodiim-
ides, sulfonyl azides, and terminal alkynes. The advantages
of this catalytic system are its operational simplicity, simple
workup, substrate and catalyst availability, and low cost.
(9) Kantam, M. L.; Yadav, J.; Laha, S.; Sreedhar, B.; Jha, S. Adv. Synth.
Catal. 2007, 349, 1938.
(10) Babu, S. G.; Karvembu, R. Ind. Eng. Chem. Res. 2011, 50, 9594.
(11) Venkanna, A.; Swapna, K.; Rao, P. V. RSC Adv. 2014, 4, 15154.
(12) Santra, S.; Bagdi, A. K.; Majee, A.; Hajra, A. RSC Adv. 2013, 3,
24931.
(13) Yavari, I.; Sodagar, E.; Nematpour, M. Helv. Chim. Acta 2014, 97,
420.
(14) Yavari, I.; Nematpour, M.; Sodagar, E. Synlett 2013, 24, 161.
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809.
(17) N-(Cyclo)alkyl-N-{[(cyclo)alkylamino](arylimino)methyl}-
N′-(arylsulfonyl)hexanimidamides 7; General Procedure
Aniline 1 (1 mmol), carbodiimide 2 (1.2 mmol), and nanopartic-
ulate CuO (10 mol%) were stirred in toluene (2 mL) at 80 °C for 8
h. A mixture of sulfonyl azide 5, (1.2 mmol), alkyne 4 (1 mmol),
CuI (0.019 g, 0.1 mmol), and Et3N (0.101 g, 1 mmol) in toluene
(2 mL) was slowly added, and the mixture was stirred at r.t.
under N2. When the reaction was complete [~4 h; TLC (EtOAc–
hexane, 1:5)], the mixture was diluted with aq NH4Cl (3 mL) and
stirred for 30 min. The layers were separated and the aqueous
layer was extracted with CH2Cl2 (3 × 3 mL). The organic frac-
tions were combined, dried (Na2SO4), filtered, and concentrated
under reduced pressure, and the residue was purified by flash
column chromatography [silica gel (230–400 mesh; Merck),
hexane–EtOAc (5:1)].
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1380349.
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u
p
p
ortiInfogrmoaitn
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References and Notes
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N-Cyclohexyl-N-[(cyclohexylamino)(phenylimino)methyl]-
N′-(phenylsulfonyl)hexanimidamide (7a)
Colorless crystals; yield: 0.45 g (84%); mp 134–137 °C. IR (KBr):
3329, 3053, 2930, 1652, 1590, 1513, 1448, 1343, 1266, 1146,
1
3
1092, 752 cm–1. H NMR (500 MHz, CDCl3): δ = 0.98 (t, J = 6.8
Hz, 3 H), 1.23–2.38 (m, 28 H), 3.27 (quint, 3J = 6.8 Hz, 1 H), 3.62
(quint, 3J = 6.8 Hz, 1 H), 6.73–6.83 (m, 3 H), 6.96 (s, 1 H), 7.18 (d,
3J = 7.9 Hz, 2 H), 7.42–7.61 (m, 3 H), 7.88 (d, 3J = 7.9 Hz, 2 H). 13
C
NMR (125.7 MHz, CDCl3): δ = 13.6 (Me), 21.5 (CH2), 22.3 (2 CH2),
24.9 (CH2), 25.5 (2 CH2), 26.0 (CH2), 29.1 (CH2), 30.4 (CH2), 31.0
(CH2), 31.3 (CH2), 32.6 (CH2), 34.0 (CH2), 43.6 (CH2), 50.8 (CH),
57.8 (CH), 122.0 (3 CH), 125.1 (2 CH), 126.4 (2 CH), 128.5 (2 CH),
132.4 (CH), 143.2 (C), 144.7 (C), 154.8 (C), 155.5 (C). MS: m/z (%)
= 536 (8) [M+], 478 (20), 395 (24), 362 (40), 238 (36), 141 (88),
91 (38), 77 (100). Anal. Calcd for C31H44N4O2S (536.77): C, 69.37;
H, 8.26; N, 10.44. Found: C, 69.81; H, 8.32; N, 10.51.
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