Catalytic guanylation of aliphatic, aromatic, heterocyclic primary and secondary amines using nanocrystalline zinc(II) oxide

Article abstract of DOI:10.1016/j.tet.2012.05.044

Nanocrystalline ZnO was found to be a highly efficient heterogeneous catalyst for the guanylation of amines with various carbodiimides to afford N,N′,N″-trisubstituted guanidines in excellent yields. Structurally divergent aliphatic, aromatic, heterocyclic primary and secondary amines were converted to the corresponding N,N′,N″-trisubstituted guanidines using optimal conditions. The catalyst was easy to handle even under atmospheric conditions and can be easily recovered by centrifugation and reused for five cycles with consistent activity.

Full text of DOI:10.1016/j.tet.2012.05.044

Tetrahedron 68 (2012) 5730e5737
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Catalytic guanylation of aliphatic, aromatic, heterocyclic primary and secondary
amines using nanocrystalline zinc(II) oxide
,
a
a
a
b
c
M. Lakshmi Kantam a , S. Priyadarshini , P.J. Amal Joseph , P. Srinivas , A. Vinu , K.J. Klabunde ,
*
Yuta Nishina d
a Inorganic and Physical Chemistry Division, Indian Institute of Chemical Technology, Hyderabad 500607, India
b International Centre for Materials Nanoarchitectonics, WPI Research Centre, National Institute for Materials Science, 1-1 Namiki, Tsukuba 305-0044, Japan
c NanoScale Corporation, Manhattan, KS, USA
d Research Core for Interdisciplinary Sciences, Okayama University, Tsushima, Kita-ku, Okayama 700-8530, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Nanocrystalline ZnO was found to be a highly efficient heterogeneous catalyst for the guanylation of
amines with various carbodiimides to afford N,N0,N00-trisubstituted guanidines in excellent yields.
Structurally divergent aliphatic, aromatic, heterocyclic primary and secondary amines were converted to
the corresponding N,N0,N00-trisubstituted guanidines using optimal conditions. The catalyst was easy to
handle even under atmospheric conditions and can be easily recovered by centrifugation and reused for
five cycles with consistent activity.
Received 21 December 2011
Received in revised form 9 May 2012
Accepted 11 May 2012
Available online 18 May 2012
Keywords:
Guanylation
Ó 2012 Elsevier Ltd. All rights reserved.
Amines
Carbodiimides
Nanocrystalline zinc oxide
Heterogeneous catalysis
1. Introduction
imido complexes,8b titanacarborane amide8c and zinc complex-
es,7d,8d lanthanide metal complexes9aeg and half-sandwich lan-
Guanylation, addition of amine NeH bond to carbodiimide, is
one of the most important atom economical and straightforward
methods for the construction of CeN bonds in organic synthesis.
Guanidines are important structural units in many biologically
relevant compounds1 and are widely used as base catalysts2 as well
as ancillary ligands for the construction of various metal com-
plexes.3 The synthesis of guanidines was widely investigated by the
direct guanylation of aliphatic primary amines with
carbodiimides.4e6 The uncatalyzed direct guanylation of aromatic
amines and secondary amines with carbodiimides is an unfeasible
process even under harsh reaction conditions.5d Therefore, much
effort has been devoted to the catalytic hydroamination of carbo-
diimides with aromatic, heterocyclic and secondary amines to
synthesize guanidines.7e9
thanide alkyl complexes9h,i have also been utilized for the synthesis
of guanidines. However, most of these catalytic systems were
sensitive to air and these reactions were often carried out in an
inert atmosphere. Hence, there is an increasing demand to develop
simple and efficient methods to synthesize guanidines that will
allow for the further advancement of guanidine chemistry.
In recent years, there has been a significant progress on the use
and design of metal nanoparticles as catalysts due to its unique
attributes that integrate the advantages of both the homogeneous
and heterogeneous catalysts.10 Nanocrystalline metal oxides have
been efficiently used as adsorbents for gases, destruction of haz-
ardous chemicals,10 as catalysts11 and also as supports12 to make
supported metal catalysts by the exchange of different metal/metal
ions for different organic reactions. These high reactivities are due
to high surface areas combined with unusually reactive morphol-
ogies when compared to their bulk counterparts.10,11
Guanylation of aromatic and secondary amines was reported in
literature using a variety of main group metal complexes, such as
7c
LiN(SiMe3)2,7a alkyl aluminium,7b [Al(NMe2)3]2 and magnesium
Zinc oxide is an important semiconductor and has been in-
vestigated widely for its catalytic, electrical, optical and photo-
chemical properties.13 Recently, it has been used as an efficient
catalyst for the synthesis of cyclic ureas from diamines and for
FriedeleCrafts acylation as well as Beckmann rearrangement re-
actions.14 Nanocrystalline ZnO was purchased from NanoScale
metal complexes.7d Transition metal complexes, such as Ti8a and V
* Corresponding author. Fax: þ91 40 27160921; e-mail address: mlakshmi@
iict.res.in (M.L. Kantam).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.05.044

M.L. Kantam et al. / Tetrahedron 68 (2012) 5730e5737
5731
Corporation, U.S.A. It was oven dried at 80 ꢀC prior to use. The BET
(a)
surface area and the average particle size thus obtained was 60 m2/
g and 10e12 nm, respectively. Klabunde reported earlier the syn-
thesis, isolation and the unique chemical reactivity studies of
nanocrystalline zinc oxide.15 We have recently reported the cyclo-
addition of NaN3 with nitriles to afford 5-substituted tetrazoles
under heterogeneous conditions using nanocrystalline zinc(II) ox-
ide catalyst.11c In continuation of our studies, herein, we report an
efficient synthesis of N,N0,N00-trisubstituted guanidines from
amines and carbodiimides using nano ZnO catalyst.
100
90
80
70
60
50
40
30
Toluene
Xylene
Benzene
1,4-dioxane
THF
2. Results and discussion
Initially, aniline and N,N0-dicyclohexylcarbodiimide were se-
lected as model substrates for carrying out the optimization studies
for the guanylation reaction. In a typical experiment, 1 mmol of
aniline, 1.1 mmol of N,N0-dicyclohexylcarbodiimide and 20 mol %
(0.016 g) of nano ZnO were taken in 1 mL of THF and stirred at 80 ꢀC.
Interestingly, the product N,N0,N00-trisubstituted guanidine 1 was
obtained in 54% yield (Table 1, entry 1). Encouraged by this result,
further optimization studies were carried out by altering reaction
parameters, such as solvent, catalyst and temperature (Table 1,
entries 1e13). Among the solvents studied, best result was obtained
in toluene, which afforded excellent yields of guanidine 1 within
8 h at 80 ꢀC (Table 1, entry 6). In addition, the solvent screening
experiments revealed that the reaction yield is dependent on the
polarity and the coordinating ability of the solvents. This aspect is
illustrated graphically in Fig. 1a and b, which proves that nonpolar
and non coordinating solvents are best suited for guanylation.16 In
a similar way, when the catalyst screening was performed with
other nano metal oxides, such as CeO2, TiO2 and NiO, moderate to
good yields were obtained (Table 1, entries 8e10).17 However,
a significant decrease in the product yield was observed for the
reaction carried out with lower catalyst loading (10 mol %; Table 1,
entry 12). Remarkably, only 5% of product was obtained for the
reaction performed using commercial ZnO (Table 1, entry 11),
which clearly shows nano metal oxides contribute significantly for
the reaction to proceed smoothly.18
Acetonitrile
2.0
2.5
3.0
3.5
4.0
4.5
5.0
5.5
6.0
Solvent Polarity Index (P')
(b)
100
90
80
70
60
50
40
30
Toluene
Xylene
1,4-dioxane
THF
Benzene
Acetonitrile
-1.2
-1.0
-0.8
-0.6
-0.4
-0.2
TM
Solvent coordinating ability index (a
)
Table 1
Fig. 1. a). A graph illustrating the reaction yield versus solvent polarity index. (b). A
graph illustrating the reaction yield versus solvent coordinating ability index.
Catalytic addition of aniline to N,N0-dicyclohexylcarbodiimidea
With the optimal reaction conditions in hand (Table 1, entry 6),
the scope of the nano ZnO catalyzed guanylation reaction was ex-
tended to a variety of structurally divergent aromatic amines (Table
2) and further to secondary amines (Table 3). Aromatic amines
having diverse functional groups, such as OMe, COMe, COPh,
CONH2, COOEt, CN, I, Br, NO2 etc. survived the reaction conditions
and afforded excellent yields of the corresponding guanylation
products (Table 2, entries 1e13 & 18e20). In addition to that, the
reaction furnished excellent yields, irrespective of the position
(ortho, meta or para) of these groups on the aromatic ring. Similarly,
heterocyclic aromatic amines, such as 3-picolyl amine and 5-
methyl-2-picolylamine gave quantitative yields of the corre-
sponding guanylation product (Table 2, entries 14e16). Primary
aliphatic amine, such as cyclohexylamine, also reacted with N,N0-
dicyclohexylcarbodiimide at 80 ꢀC for 8 h, to give the corresponding
N,N0,N00-tricyclohexyl guanidine in 95% yield (Table 2, entry 17).
Entry
Catalyst
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
Nano ZnO
Nano ZnO
Nano ZnO
Nano ZnO
Nano ZnO
Nano ZnO
Nano ZnO
Nano CeO2
Nano TiO2
Nano NiO
Commercial ZnO
Nano ZnO
d
THF
Benzene
Xylene
54
60
70
55
31
98
0c
76
78
62
5
1,4-Dioxane
Acetonitrile
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
9
10
11
12
13
65d
Tracee
Notably,
a
variety of carbodiimides like N,N0-dicyclohex-
ylcarbodiimide, N,N0-diisopropylcarbodiimide, N,N0-di-tert-butyl-
carbodiimide, N-(tert-butyl)-N0-ethylcarbodiimide and N,N0-bis(4-
methylphenyl)carbodiimide also underwent the guanylation re-
action under the optimized conditions (Table 2, entries 21e24).
Finally, a study was performed for the guanylation of less re-
active secondary amines with carbodiimides and the results are
a
Reactions (entries 1e6 and 8e10) performed with aniline (1 mmol), N,N0-
dicyclohexylcarbodiimide (1.1 mmol) and catalyst (20 mol %) in 1 mL solvent for 8 h
at 80 ꢀC.
b
Isolated yield.
c
Reaction (entry 6) performed at 25 ꢀC.
d
Reaction (entry 12) performed with 10 mol % nano ZnO.
Reaction (entry 13) performed without catalyst.
e

5732
M.L. Kantam et al. / Tetrahedron 68 (2012) 5730e5737
Table 2 (continued)
Table 2
Reaction of aromatic and aliphatic primary amines with carbodiimides using nano
ZnO catalysta
Entry
18
RNH2
R1eN]C]NeR2
CyeN]C]NeCy
Product Yieldb (%)
18
19
20
94
97
98
Entry
1
RNH2
R1eN]C]NeR2
CyeN]C]NeCy
Product Yieldb (%)
19
20
CyeN]C]NeCy
CyeN]C]NeCy
1
2
3
98
97
95
2
3
i-PreN]C]Nei-Pr
CyeN]C]NeCy
21
22
EteN]C]NetBu
21
94
96
p-tolyleN]C]Nep-tolyl 22
p-tolyleN]C]Nep-tolyl 23
4
5
6
i-PreN]C]Nei-Pr
CyeN]C]NeCy
CyeN]C]NeCy
4
5
6
97
98
96
23
85
86
24
tBueN]C]NetBu
24
a
Reactions (entries 1e24) performed with amine (1 mmol), carbodiimide
(1.1 mmol) and nano ZnO (20 mol %, 16 mg) in 1 mL toluene for 8 h.
b
Isolated yield.
7
CyeN]C]NeCy
7
96
8
9
CyeN]C]NeCy
CyeN]C]NeCy
8
9
97
97
Table 3
Catalytic addition of secondary amines to carbodiimides using nano ZnO catalysta
10
11
CyeN]C]NeCy
10
11
95
94
Entry
R
R1R2NH
Product
Yieldb (%)
i-PreN]C]Nei-Pr
1
2
3
4
5
6
Cy
25
26
27
28
29
30
86
87
96
95
87
88
12
13
CyeN]C]NeCy
12
13
98
98
i-Pr
Cy
i-PreN]C]Nei-Pr
i-Pr
Cy
14
15
CyeN]C]NeCy
CyeN]C]NeCy
14
15
96
97
i-Pr
7
8
9
10
Cy
Cy
Cy
Cy
(n-Bu)2NH
(Et)2NH
(Ph)2NH
PhNHMe
31
32
33
34
95
86
97
92
16
17
i-PreN]C]Nei-Pr
CyeN]C]NeCy
16
17
97
95
a
Reactions (entries 1e10) performed with amine (1 mmol), carbodiimide
(1.1 mmol) and nano ZnO (20 mol %, 16 mg) in 1 mL of toluene for 10 h.
b
Isolated yield.

M.L. Kantam et al. / Tetrahedron 68 (2012) 5730e5737
5733
presented in Table 3. Several cyclic secondary amines were reacted
with carbodiimides to furnish excellent yields of the respective
products (Table 3, entries 1e6). Since, the secondary amines are
known to be less reactive than the primary amines, a marginal
decrease in the yields of the products in comparison with primary
amines was observed. Similarly, secondary amines, such as N,N0-
dialkylamine, N,N0-diarylamine and N,N0-alkylarylamine also un-
derwent guanylation with N,N0-dicyclohexylcarbodiimide to fur-
nish the corresponding products in good yields (Table 3, entries
7e10).
To demonstrate the reusability of nano ZnO catalyst, a series of
guanylation reactions were performed using aniline and N,N0-
dicyclohexylcarbodiimide. After each reaction the spent catalyst
was easily recovered by centrifugation, washed with ethyl acetate
and sonicated in dichloromethane for 10 min to remove any organic
impurities if present. It was then oven dried at 80 ꢀC and reused for
the next cycle without further activation. As exemplified in Table 4,
the catalyst can be reused for five consecutive reaction cycles with
consistent activity under the optimized reaction conditions. Also, it
is noteworthy to point out that the recovered catalyst showed only
a modest change in BET surface area (43 m2/g) after the fifth re-
cycle. The particle size of nano ZnO catalyst did not change before
and after the reaction (Figs. 2 and 3). XRD patterns indicate that the
Fig. 3. XRD patterns of nano ZnO catalyst: (a) as purchased, (b) dried at 80 ꢀC, (c)
recovered and (d) recovered and calcined at 300 ꢀC for 1 h. The markers (C) show the
signals of zincite.
R N C N R
Table 4
Recycling studies for catalytic guanylation of aniline with N,N0-
H2NAr
ZnO
I
dicyclohexylcarbodiimidea
R N C N R
H
H
NAr
Nano-ZnO
R N C N R
ZnO
R
R
Entry
Cycle
Yieldc (%)
II
Ar
HN
N
Ar
N H
1
2
3
4
5
6
1
2
3
4
5
6
98
98
N
N H
1,3-H shift
N H
R
97, 98b
96
R
Scheme 1. Proposed mechanism for nano ZnO catalyzed guanylation of amines.
95
94
a
Reactions (entries 1e5) performed with aniline (1 mmol), N,N0-dicyclohex-
3. Conclusion
ylcarbodiimide (1.1 mmol) and recovered nano ZnO (20 mol %) in 1 mL toluene for
8 h.
b
In conclusion, we have developed a simple and efficient method
for the synthesis of N,N0,N00-trisubstituted guanidines via nucleo-
philic addition of amines to carbodiimides using nano ZnO as
a heterogeneous catalyst. Various structurally divergent aliphatic,
aromatic, heterocyclic primary and secondary amines were reacted
with different carbodiimides to produce the corresponding N,N0,N00-
trisubstituted guanidines in excellent yields. Moreover, the spent
catalyst can be easily recovered and reused for several cycles with
consistent activity. This methodology may find widespread use in
the synthesis of N,N0,N00-trisubstituted guanidines.
Reaction performed with calcined nano ZnO recovered after second cycle.
c
Isolated yield after the respective cycle.
4. Experimental section
4.1. General methods
Fig. 2. TEM image of as purchased (left), dried at 80 ꢀC (middle) and recovered (right)
ZnO catalyst.
crystal structure of nano ZnO is zincite. The recovered catalyst
contains some organic impurities, which are removed after calci-
nation at 300 ꢀC for 1 h.
It was assumed that the mechanism of guanylation reaction
involves the activation of carbodiimides by nano ZnO.19 Nano ZnO
acts as a Lewis acid catalyst in order to generate the intermediate I
(Scheme 1).20 Nucleophilic addition of amine to I results in the
formation of intermediate II, followed by intramolecular proton
transfer to regenerate nano ZnO and release the guanidine, thereby
continuing the catalytic cycle.
Nanocrystalline ZnO, nanocrystalline CeO2 and nano TiO2 were
purchased from NanoScale Corporation, Manhattan, Kansas, U.S.A.
All other chemicals including nano NiO were purchased from
Sigma Aldrich and were used as received. All solvents used were
analytical grade and were used as received from Merck India Pvt.
Ltd. Routine monitoring of the reactions were performed by TLC
studies using Merck silica gel 60 F254 glass plates. Purification of
products was carried out by flash column chromatography using
neutral alumina and a mixture of ethyl acetate and hexanes as
eluting agent. All the products were characterized by Mass, 1H

5734
M.L. Kantam et al. / Tetrahedron 68 (2012) 5730e5737
and 13C NMR spectroscopy. The NMR spectra of samples were
acquired on a Varian Unity Inova 500 MHz, Inova 400 MHz and
Bruker Avance 300 MHz spectrometer using TMS as an internal
standard in CDCl3 or DMSO-d6. Mass spectra were acquired on
a Thermo LCQ fleet ion trap mass spectrometer. High-resolution
mass spectra were acquired on a Q STAR XL Hybrid LC/MS/MS
system, Applied Biosystems or a Exactive Orbitrap LC-MS, Thermo
Scientific. Infrared (IR) absorption data were acquired on
a Thermo Nicolet Nexus 670 FT-IR spectrometer with DTGS KBr
detector. The Specific surface area of the catalyst was estimated
at 77 K by single point BET method using a Micromeritics-2910
(AUTOCHEM) instrument. Before the measurements, the sam-
ples were oven dried at 373 K for 12 h and flushed in situ with
He gas for 2 h. For the transmission electron microscope (TEM)
analysis, samples were dispersed in methanol solution and
dropped on a 200-mesh Cu grid, and images were taken using
JEOL JEM 2100F high-resolution transmission electron microscope
at an acceleration voltage of 200 kV.
J¼6.4 Hz, 12H, CH3); 13C NMR (75 MHz, CDCl3)
d 151.36 (C]N),
146.09, 129.02, 122.72,122.26, 43.62 (CH), 22.76 (Me); MS (ESI): m/z
220 (MþH)þ.
4.3.3. 1,3-Dicyclohexyl-2-(p-tolyl)guanidine (3).9a IR (KBr):
3192, 2931, 2855, 1621, 1515, 1449, 1353, 1324, 1249, 1151, 814; 1H
NMR (300 MHz, CDCl3) 7.28 (br, NH, overlap with solvent),
n
¼3261,
d
7.14e7.00 (m, 4H, ArH), 3.58e3.31 (m, 2H, CH), 2.32 (s, 3H, Me),
1.92e1.80 (m, 4H, CH2), 1.68e1.57 (m, 4H, CH2), 1.54e1.44 (m, 2H,
CH2), 1.31e1.02 (m, 10H, CH2); 13C NMR (75 MHz, CDCl3)
d 153.30
(C]N), 135.28, 134.51, 129.77, 122.73, 51.69 (CH), 32.32 (CH2), 24.73
(CH2), 24.32 (CH2), 20.60 (Me); MS (ESI): m/z 314 (MþH)þ.
4.3.4. 1,3-Diisopropyl-2-(p-tolyl)guanidine (4).9a IR (KBr):
3042, 3017, 2969, 2925, 1606, 1508, 1461, 1263, 1125, 860 cmꢁ1; 1H
NMR (300 MHz, CDCl3)
6.99 (d, J¼7.8 Hz, 2H, ArH), 6.67 (d,
J¼8.1 Hz, 2H, ArH), 3.88e3.61 (m, 2H, CH), 2.29 (s, 3H, Me),
1.18e1.08 (m, 12H, CH3); 13C NMR (75 MHz, CDCl3)
153.76, 152.70,
n
¼3312,
d
d
135.73, 135.44, 134.18, 133.26, 130.08, 129.63, 122.72, 122.53, 45.56,
4.2. General procedure for optimization studies for
guanylation of aniline with N,N0-dicyclohexylcarbodiimide
listed in Table 1 and recycling studies listed in Table 4
45.23, 22.30, 22.19, 20.77, 20.69; MS (ESI): m/z 234 (MþH)þ.
4.3.5. 1,3-Dicyclohexyl-2-(4-methoxyphenyl)guanidine
(KBr):
¼3337, 3259, 3082, 2936, 2856, 1618, 1514, 1455, 1384, 1329,
1024, 825 cmꢁ1; 1H NMR (300 MHz, CDCl3)
8.22 (br, 2H, NH), 7.05
(5).9a IR
n
A mixture of aniline (1 mmol), N,N0-dicyclohexylcarbodiimide
(1.1 mmol) and catalyst (0.2 mmol, 20 mol %) was stirred in 1 mL
solvent at 80 ꢀC for 8 h. The progress of the reaction was monitored
by TLC analysis. At the end of the reaction, the reaction mixture was
allowed to cool to room temperature, centrifuged and filtered the
supernatant through a sintered funnel. The catalyst was then
washed with ethyl acetate, centrifuged and filtered. The combined
filtrate was concentrated under reduced pressure, and further pu-
rified by column chromatography on neutral alumina using ethyl
acetate/hexane as the eluent to afford the desired products in good
yields. For recycling studies, the residue is then sonicated in
dichloromethane, centrifuged and further oven dried at 80 ꢀC to
obtain around w16 mg of nano ZnO catalyst. This catalyst was used
for the next cycle.
d
(d, J¼9.1 Hz, 2H, ArH), 6.83 (d, J¼9.0 Hz, 2H, ArH), 3.79 (s, 3H, OMe),
3.37e3.20 (m, 2H, CH), 1.88e1.77 (m, 4H, CH2), 1.69e1.60 (m, 4H,
CH2), 1.55e1.46 (m, 2H, CH2), 1.32e1.02 (m, 10H, CH2); 13C NMR
(75 MHz, CDCl3)
d 157.81, 153.45 (C]N), 128.86, 125.27, 114.57,
55.27 (OMe), 51.72 (CH), 32.39 (CH2), 24.76 (CH2), 24.34 (CH2); MS
(ESI): m/z 330 (MþH)þ.
4.3.6. 1,3-Dicyclohexyl-2-(3,4-dimethylphenyl)guanidine (6). Rf¼0.39
(1:1 hexane/ethyl acetateþ3% TEA); white solid; mp 142e143 ꢀC; IR
(KBr):
n
¼3377, 3281, 2930, 2855, 1638, 1599, 1449, 1385, 1313,
822 cmꢁ1
;
1H NMR (300 MHz, CDCl3)
d
7.03 (d, J¼7.8 Hz, 1H, ArH),
6.86 (s, 1H, ArH), 6.81 (d, J¼7.8 Hz, 1H, ArH), 3.53e3.33 (m, 2H, CH),
2.21 (s, 6H, Me), 1.93e1.80 (m, 4H, CH2), 1.71e1.56 (m, 4H, CH2),
1.55e1.42 (m, 2H, CH2), 1.30e1.01 (m, 10H, CH2); 13C NMR (75 MHz,
4.3. General procedure for nano ZnO catalyzed guanylation of
amines with carbodiimides listed in Table 2 and Table 3
CDCl3) d 152.46 (C]N), 137.12, 136.82, 132.62, 129.87, 123.73, 119.84,
50.97 (CH), 32.22 (CH2), 24.56 (CH2), 24.10 (CH2), 19.13 (Me), 18.59
(Me); HRMS (ESI): m/z found 328.2754, calcd for C21H34N3 (MþH)þ
requires 328.2747.
A mixture of amine (1 mmol), carbodiimide (1.1 mmol) and
nanocrystalline ZnO (20 mol %, 0.016 g) was stirred in toluene
(1 mL) at 80 ꢀC for 8 h (for aromatic and aliphatic primary amines)
or at 110 ꢀC for 10 h (for secondary amines). The progress of the
reaction was monitored by TLC analysis. At the end of the reaction,
the reaction mixture was allowed to cool to room temperature,
centrifuged and filtered the supernatant through a sintered funnel.
The catalyst was then washed with ethyl acetate, centrifuged and
filtered. The combined filtrate was concentrated under reduced
pressure, and further purified by column chromatography on
neutral alumina using ethyl acetate/hexane as the eluent to afford
the desired product in good yields.
4.3.7. 1,3-Dicyclohexyl-2-(4-nitrophenyl)guanidine (7).9a 1H NMR
(300 MHz, CDCl3)
d
8.11 (d, J¼9.0 Hz, 2H, ArH), 6.89 (d, J¼9.0 Hz, 2H,
ArH), 3.85 (br d, J¼6.6 Hz, 2H, NH), 3.51e3.36 (m, 2H, CH),
2.06e1.94 (m, 4H, CH2), 1.78e1.67 (m, 4H, CH2), 1.66e1.57 (m, 2H,
CH2), 1.43e1.28 (m, 4H, CH2), 1.27e1.06 (m, 6H, CH2); 13C NMR
(75 MHz, DMSO-d6) d 160.26, 153.72 (C]N), 136.56, 125.36, 120.12,
49.66 (CH), 32.49 (CH2), 25.08 (CH2), 24.46 (CH2); MS (ESI): m/z 345
(MþH)þ.
4.3.8. 2-(4-Bromophenyl)-1,3-dicyclohexylguanidine (8).9a 1H NMR
(300 MHz, CDCl3)
d
7.30 (d, J¼8.4 Hz, 2H, ArH), 6.68 (d, J¼8.3 Hz, 2H,
4.3.1. 1,3-Dicyclohexyl-2-phenylguanidine (1).8c 1H NMR (500 MHz,
ArH), 3.75 (br, 2H, NH), 3.47e3.29 (m, 2H, CH), 2.03e1.89 (m, 4H,
CDCl3)
d
7.22e7.16 (m, 2H, ArH), 6.88 (t, J¼7.5 Hz, 1H, ArH), 6.78 (d,
CH2), 1.76e1.55 (m, 6H, CH2), 1.42e1.02 (m, 10H, CH2); 13C NMR
J¼7.5 Hz, 2H, ArH), 3.68 (br, 2H, NH), 3.52e3.33 (m, 2H, CH),
2.05e1.93 (m, 4H, CH2), 1.73e1.64 (m, 4H, CH2), 1.63e1.56 (m, 2H,
CH2), 1.40e1.28 (m, 4H, CH2), 1.18e1.06 (m, 6H, CH2); 13C NMR
(75 MHz, CDCl3) d 150.57 (C]N), 147.87, 132.16, 125.23, 114.43,
50.47 (CH), 49.01 (CH), 33.89 (CH2), 33.62 (CH2), 25.50 (CH2), 24.91
(CH2), 24.81 (CH2); MS (ESI): m/z 378 (MþH)þ.
(75 MHz, CDCl3)
d 154.37 (C]N), 138.61, 129.31, 124.86, 122.08,
52.50 (CH), 32.77 (CH2), 24.86 (CH2), 24.78 (CH2); MS (ESI): m/z 300
4.3.9. 2-(4-Cyanophenyl)-1,3-dicyclohexylguanidine (9).9h 1H NMR
(300 MHz, CDCl3)
(MþH)þ.
d
7.55 (d, J¼8.4 Hz, 2H, ArH), 7.08 (d, J¼8.4 Hz, 2H,
ArH), 6.53 (br, 2H, NH), 3.51e3.34 (m, 2H, CH), 2.00e1.87 (m, 4H,
CH2), 1.78e1.64 (m, 4H, CH2), 1.63e1.52 (m, 2H, CH2), 1.35e1.08 (m,
4.3.2. 1,3-Diisopropyl-2-phenylguanidine (2).8c 1H NMR (300 MHz,
CDCl3)
d
7.30e7.22 (m, 2H, ArH, overlap with solvent), 7.03e6.90
10H, CH2); 13C NMR (75 MHz, CDCl3)
d
152.05 (C]N), 148.57, 133.47,
(m, 3H, ArH), 5.30 (br, 2H, NH), 3.74 (sept, J¼6.3 Hz, 2H, CH), 1.15 (d,
122.28, 119.18 (C^N), 105.47, 51.79 (CH), 49.05 (CH), 33.79 (CH2),

M.L. Kantam et al. / Tetrahedron 68 (2012) 5730e5737
5735
33.07 (CH2), 25.49 (CH2), 25.13 (CH2), 24.88 (CH2), 24.61 (CH2); MS
17.62 (Me); HRMS (ESI): m/z found 315.2550, calcd for C19H31N4
(MþH)þ requires 315.2543.
(ESI): m/z 325 (MþH)þ.
4.3.10. 2-(3-Acetylphenyl)-1,3-dicyclohexylguanidine (10). Rf¼0.43
(1:1 hexane/ethyl acetateþ3% TEA); white solid; mp 101e102 ꢀC; IR
4.3.16. 1,3-Diisopropyl-2-(5-methylpyridin-2-yl)guanidine
(16). Rf¼0.28 (1:4 hexane/ethyl acetateþ3% TEA); reddish sticky
(KBr):
n
¼3570, 3311, 3073, 2925, 2852, 1685, 1582, 1490, 1280, 1078,
semi solid; IR (KBr):
n
¼3213, 3062, 2973, 1639, 1480, 1385, 1237,
891 cmꢁ1; 1H NMR (300 MHz, CDCl3)
d
7.49 (d, J¼7.8 Hz, 1H, ArH),
1165, 833 cmꢁ1; 1H NMR (300 MHz, CDCl3)
d 7.89 (s, 1H, ArH), 7.36
7.39 (s, 1H, ArH), 7.35e7.26 (m, 1H, ArH), 7.02 (d, J¼7.8 Hz, 1H, ArH),
3.78 (br, 2H, NH), 3.49e3.31 (m, 2H, CH), 2.55 (s, 3H, COMe),
2.05e1.91 (m, 4H, CH2), 1.77e1.53 (m, 6H, CH2), 1.43e1.24 (m, 4H,
(d, J¼8.2 Hz, 1H, ArH), 7.20 (d, J¼8.4 Hz, 1H), 4.24e4.04 (m, 2H, CH),
2.19 (s, 3H, Me), 1.22 (d, J¼6.0 Hz, 12H, Me); 13C NMR (75 MHz,
CDCl3)
d 153.04 (C]N), 151.70, 144.36, 139.19, 127.02, 115.70, 43.83
CH2), 1.23e1.03 (m, 6H, CH2); 13C NMR (75 MHz, CDCl3)
d
198.54
(CH), 22.64 (Me), 17.51 (Me); HRMS (ESI): m/z found 235.1911, calcd
(CO), 150.66 (C]N), 149.50, 138.18, 129.39, 128.38, 123.35, 121.54,
50.39 (CH), 33.58 (CH2), 26.72 (CH3CO), 25.44 (CH2), 24.75 (CH2);
HRMS (ESI): m/z found 342.2547, calcd for C21H32ON3 (MþH)þ re-
quires 342.2539.
for C13H23N4 (MþH)þ requires 235.1922.
4.3.17. 1,2,3-Tricyclohexylguanidine (17).2e 1H NMR (300 MHz,
CDCl3)
d 3.20e3.04 (m, 3H, CH), 1.94e1.80 (m, 6H, CH2), 1.79e1.66
(m, 6H, CH2), 1.65e1.55 (m, 3H, CH2), 1.40e1.09 (m, 15H, CH2); 13C
4.3.11. 1,3-Diisopropyl-2-(2-nitrophenyl)guanidine (11).9a 1H NMR
NMR (75 MHz, CDCl3) d 151.14 (C]N), 52.43 (CH), 34.14 (CH2), 25.66
(300 MHz, CDCl3)
d
7.77 (d, J¼8.4 Hz, 1H, ArH), 7.41e7.32 (m, 1H,
(CH2), 25.11 (CH2); MS (ESI): m/z 306 (MþH)þ.
ArH), 6.96e6.84 (m, 2H, ArH), 3.83e3.66 (m, 2H, CH), 3.65e3.28 (m,
2H, NH), 1.18 (d, J¼6.2 Hz, 12H, CH3); 13C NMR (75 MHz, CDCl3)
4.3.18. Ethyl
4-((bis(cyclohexylamino)methylene)amino)benzoate
d
150.05 (C]N), 145.14, 143.54, 133.30, 126.72, 125.06, 120.70, 43.35
(18). Rf¼0.43 (1:1 hexane/ethyl acetateþ3% TEA); white solid; mp
(CH), 23.18 (CH3); MS (ESI): m/z 265 (MþH)þ.
129e130 ꢀC; IR (KBr):
n
¼3291, 2930, 2854, 1711, 1626, 1583, 1506,
1366, 1271, 1165, 1100, 1021, 868 cmꢁ1 1H NMR (300 MHz, CDCl3)
;
4.3.12. 1,3-Dicyclohexyl-2-(2-iodophenyl)guanidine
(12). Rf¼0.64
d
7.94 (d, J¼8.4 Hz, 2H, ArH), 6.95 (d, J¼8.4 Hz, 2H, ArH), 5.17 (br,
(1:1 hexane/ethyl acetateþ3% TEA); white solid; mp 120e121 ꢀC; IR
2H, NH), 4.34 (q, J¼7.1 Hz, 2H, COOCH2), 3.55e3.29 (m, 2H, CH),
2.04e1.87 (m, 4H, CH2), 1.76e1.51 (m, 6H, CH2), 1.38 (t, J¼7.1 Hz,
3H, Me), 1.34e1.05 (m, 10H, CH2); 13C NMR (75 MHz, CDCl3)
(KBr):
n
¼3326, 3050, 2928, 2852, 2122, 1614, 1494, 1260, 1094, 1021,
802 cmꢁ1; 1H NMR (300 MHz, CDCl3)
d
7.77 (d, J¼7.8 Hz, 1H, ArH),
7.19 (t, J¼7.5 Hz, 1H, ArH), 6.83 (d, J¼7.8 Hz, 1H, ArH), 6.62 (t,
J¼7.5 Hz, 1H, ArH), 3.72e3.30 (m, 4H, CH & NH), 2.14e2.00 (m, 4H,
CH2), 1.81e1.54 (m, 6H, CH2), 1.46e1.25 (m, 4H, CH2), 1.24e1.04 (m,
d 166.58 (COOEt), 153.03 (C]N), 150.88, 130.87, 123.21, 122.24,
60.36 (OCH2), 50.63 (CH), 48.54 (CH), 33.76 (CH2), 33.31 (CH2),
25.49 (CH2), 25.29 (CH2), 24.82 (CH2), 24.67 (CH2), 14.23 (Me);
HRMS (ESI): m/z found 372.2646, calcd for C22H34O2N3 (MþH)þ
requires 372.2645.
6H, CH2); 13C NMR (75 MHz, CDCl3)
d 151.30, 149.47 (C]N), 139.12,
129.09, 123.45, 123.11, 97.10, 50.19 (CH), 33.98 (CH2), 25.61 (CH2),
24.86 (CH2); HRMS (ESI): m/z found 426.1404, calcd for C19H29N3I
(MþH)þ requires 426.1400.
4.3.19. 2-(4-Benzoylphenyl)-1,3-dicyclohexylguanidine (19). Rf¼0.41
(1:1 hexane/ethyl acetateþ3% TEA); white solid; mp 145e146 ꢀC; IR
4.3.13. 2-(2-Iodophenyl)-1,3-diisopropylguanidine (13).9h 1H NMR
(KBr):
n
¼3316, 2927, 2852, 1626, 1568, 1447, 1399, 1277, 1150,
(300 MHz, CDCl3)
d
7.83e7.74 (m, 1H, ArH), 7.25e7.14 (m, 1H, ArH),
701 cmꢁ1; 1H NMR (300 MHz, CDCl3)
d 9.73 (br,1H, NH), 8.88 (br,1H,
6.89e6.77 (m, 1H, ArH), 6.72e6.61 (m, 1H, ArH), 3.79 (sept,
NH), 7.79 (d, J¼8.3 Hz, 2H, ArH), 7.73 (d, J¼7.6 Hz, 2H, ArH), 7.59 (t,
J¼7.6 Hz, 1H, ArH), 7.48 (t, J¼7.6 Hz, 2H, ArH), 7.26 (d, J¼8.3 Hz, 2H,
ArH), 3.48e3.30 (m, 2H, CH), 1.95e1.84 (m, 4H, CH2), 1.75e1.63 (m,
4H, CH2), 1.57e1.47 (m, 2H, CH2), 1.45e1.27 (m, 4H, CH2), 1.25e1.03
J¼6.0 Hz, 2H, CH), 3.59 (br, 2H, NH), 1.20 (d, J¼6.8 Hz, 12H, CH3); 13
C
NMR (75 MHz, CDCl3)
d 150.65, 149.80 (C]N), 139.15, 129.12,
123.52, 123.36, 96.84, 43.34 (CH), 23.51 (CH3); MS (ESI): m/z 346
(MþH)þ.
(m, 6H, CH2); 13C NMR (75 MHz, CDCl3)
d 195.32 (CO),153.87 (C]N),
142.93, 137.36, 132.96, 132.32, 131.72, 129.61, 128.22, 119.91, 52.88
(CH), 32.62 (CH2), 24.76 (CH2), 24.64 (CH2); HRMS (ESI): m/z found
404.2689, calcd for C26H34ON3 (MþH)þ requires 404.2696.
4.3.14. 1,3-Dicyclohexyl-2-(pyridin-3-yl)guanidine
(14). Rf¼0.38
(1:4 hexane/ethyl acetateþ3% TEA); brownish solid; mp 79e81 ꢀC;
IR (KBr):
n
¼3257, 2929, 2854, 1633, 1580, 1480, 1450, 1365, 1265,
1150, 1096, 892, 799, 707 cmꢁ1; 1H NMR (300 MHz, CDCl3)
d
8.36 (s,
4.3.20. 4-((Bis(cyclohexylamino)methylene)amino)benzamide
1H, ArH), 8.27 (d, J¼3.9 Hz, 1H, ArH), 7.74 (br, 1H, NH), 7.43 (d,
J¼8.4 Hz, 1H, ArH), 7.25e7.19 (m, 1H, ArH), 5.51 (br, 1H, NH),
3.47e3.24 (m, 2H, CH), 1.95e1.84 (m, 4H, CH2), 1.74e1.63 (m, 4H,
CH2), 1.59e1.47 (m, 2H, CH2), 1.37e1.06 (m, 10H, CH2); 13C NMR
(20). Rf¼0.37 (1:1 hexane/ethyl acetateþ3% TEA); white solid; mp
139e140 ꢀC; IR (KBr):
n
¼3262, 2931, 2855, 1638, 1599, 1450, 1384,
1366, 1252, 1150, 890, 783 cmꢁ1 1H NMR (300 MHz, CDCl3)
; d 8.10
(d, J¼8.5 Hz, 2H, ArH), 7.52 (br, 2H, CONH2), 6.87 (d, J¼8.5 Hz, 2H,
ArH), 3.94 (br, 2H, NH), 3.50e3.33 (m, 2H, CH), 2.09e1.93 (m, 4H,
CH2), 1.85e1.53 (m, 6H, CH2), 1.51e1.02 (m, 10H, CH2); 13C NMR
(75 MHz, CDCl3)
d 153.70 (C]N), 145.14, 143.57, 137.07, 129.27,
123.89, 52.41 (CH), 32.77 (CH2), 24.88 (CH2), 24.64 (CH2); HRMS
(ESI): m/z found 301.2385, calcd for C18H29N4 (MþH)þ requires
301.2386.
(75 MHz, CDCl3)
d 168.12 (CONH2), 153.03 (C]N), 150.14, 133.60,
130.05, 119.98, 50.30 (CH), 33.13 (CH2), 25.72 (CH2), 25.10 (CH2);
HRMS (ESI): m/z found 343.2488, calcd for C20H31ON4 (MþH)þ
requires 343.2492.
4.3.15. 1,3-Dicyclohexyl-2-(5-methylpyridin-2-yl)guanidine
(15). Rf¼0.46 (1:1 hexane/ethyl acetateþ3% TEA); brownish
solid; mp 110e111 ꢀC; IR (KBr):
n
¼3435, 3327, 2928, 2851, 1626,
4.3.21. 1-(tert-Butyl)-3-ethyl-2-(p-tolyl)guanidine
(1:1 hexane/ethyl acetateþ3% TEA); white semi solid; IR (KBr):
¼3255, 2977, 2882, 1634, 1529, 1399, 1208, 1152, 815, 650,
512 cmꢁ1 1H NMR (300 MHz, CDCl3)
6.99e6.89 (m, 2H, ArH),
(21). Rf¼0.41
1589, 1474, 1237, 1150, 834 cmꢁ1 1H NMR (300 MHz, CDCl3)
;
d
7.85 (d, Jmeta¼2.1 Hz, 1H, ArH), 7.22 (dd, J¼8.4 Hz, 2.4 Hz, 1H,
n
ArH), 6.73 (d, J¼8.4 Hz, 1H), 3.68e3.51 (m, 2H, CH), 2.19 (s, 3H,
Me), 2.04e1.95 (m, 4H, CH2), 1.79e1.69 (m, 4H, CH2), 1.66e1.55
(m, 2H, CH2), 1.48e1.19 (m, 10H, CH2); 13C NMR (75 MHz, CDCl3)
;
d
6.77e6.69 (m, 2H, ArH), 3.04e2.84 (m, 2H, CH2), 2.19 (s, 3H, Me),
1.81e1.73 (m, 2H, NH), 1.32e1.23 (m, 9H, Me), 1.05e0.95 (m, 3H,
d
159.38, 153.46 (C]N), 144.79, 138.16, 123.76, 118.57, 50.11 (CH),
Me); 13C NMR (75 MHz, CDCl3)
d
153.02 (C]N), 140.81, 132.39,
33.85 (CH2), 33.44 (CH2), 25.59 (CH2), 24.92 (CH2), 24.59 (CH2),
129.75, 122.07, 51.84 (4 ꢀC), 37.88 (CH2), 29.99 (Me), 20.67 (Me),

5736
M.L. Kantam et al. / Tetrahedron 68 (2012) 5730e5737
14.55 (Me); HRMS (ESI): m/z found 234.1963, calcd for C14H24N3
(MþH)þ requires 234.1964.
(CH2), 33.48 (CH2), 25.62 (CH2), 25.29 (CH2), 25.22 (CH2), 24.94
(CH2), 24.87 (CH2); MS (ESI): m/z 278 (MþH)þ.
4.3.22. 2-(3,4-Dimethylphenyl)-1,3-di-p-tolylguanidine
4.3.30. N,N0-Diisopropylpyrrolidine-1-carboxidamide (30).21 1H NMR
(22). Rf¼0.59 (1:1 hexane/ethyl acetateþ3% TEA); white solid;
(300 MHz, CDCl3) d 7.65 (br,1H, NH), 3.79e3.62 (m, 2H, CH), 3.60e3.51
mp 158e160 ꢀC; IR (KBr):
n
¼3167, 3028, 2923, 2858, 1641, 1606,
(m, 4H, CH2), 1.99e1.94 (m, 4H, CH2), 1.28 (d, J¼6.4 Hz, 12H, Me); 13
C
1582, 1512, 1410, 1385, 1263, 1019, 1037, 812, 700, 652, 507 cmꢁ1
1H NMR (300 MHz, CDCl3)
8.60 (br, 2H, NH), 6.95e6.69 (m, 11H,
ArH), 2.21e1.97 (m, 12H, Me); 13C NMR (75 MHz, CDCl3)
150.79
;
NMR (75 MHz, CDCl3) d 155.18 (C]N), 48.71 (CH2), 46.87 (CH), 24.91
d
(CH2), 22.77 (Me); MS (ESI): m/z 198 (MþH)þ.
d
(C]N), 137.42, 135.09, 133.93, 133.80, 130.08, 129.60, 123.83,
122.28, 119.83, 20.69 (Me), 19.49 (Me), 19.01 (Me); HRMS (ESI):
m/z found 344.2136, calcd for C23H26N3 (MþH)þ requires
344.2121.
4.3.31. 1,1-Dibutyl-2,3-dicyclohexylguanidine (31). Rf¼0.17 (1:4
hexane/ethyl acetateþ3% TEA); white solid; mp 157e158 ꢀC; IR
(KBr):
n
¼3230, 3071, 2856, 2954, 2927, 1615, 1566, 1452, 1383, 1326,
1234, 1077, 888, 827, 503 cmꢁ1; 1H NMR (300 MHz, CDCl3)
d 7.53 (br,
1H, NH), 3.60e3.16 (m, 5H, CH2 & CH), 3.09e2.91 (m, 1H, CH),
1.92e1.67 (m, 8H, CH2), 1.66e1.45 (m, 8H, CH2), 1.44e1.10 (m, 12H,
4.3.23. 2-(4-Nitrophenyl)-1,3-di-p-tolyl-guanidine
(23). Rf¼0.34
(1:1 hexane/ethyl acetateþ3% TEA); white solid; mp 149e150 ꢀC;
CH2), 0.92 (t, J¼7.2 Hz, 6H, Me); 13C NMR (75 MHz, CDCl3)
d 160.37
1H NMR (400 MHz, CDCl3)
d
8.17 (br, 2H, NH), 7.94 (m, 2H, ArH), 7.26
(C]N), 54.94(CH), 48.60(CH2), 48.20(CH2), 33.05(CH2), 29.59(CH2),
29.30 (CH2), 27.96 (CH2), 25.12 (CH2), 24.88 (CH2), 24.73 (CH2), 24.33
(CH2), 19.79 (CH2), 19.68 (CH2), 13.56 (Me), 13.46 (Me); HRMS (ESI):
m/z found 336.3370, calcd for C21H42N3 (MþH)þ requires 336.3373.
(d, J¼8.4 Hz, 2H, ArH, overlap with solvent), 7.13e6.95 (m, 8H, ArH),
2.27 (s, 6H); 13C NMR (75 MHz, CDCl3)
d
152.72, 151.63 (C]N),
149.78, 136.03, 135.22, 130.15, 129.84, 125.07, 122.76, 20.78 (Me),
20.72 (Me); HRMS (ESI): m/z found 361.1652, calcd for C21H21N4O2
(MþH)þ requires 361.1659.
4.3.32. 2,3-Dicyclohexyl-1,1-diethylguanidine
¼3327, 3036, 2927, 2851, 1627, 1576, 1436, 1384, 1311, 1243, 1087,
892, 641 cmꢁ1 1H NMR (300 MHz, CDCl3)
(32).21 IR
(KBr):
n
4.3.24. 1,3-Di-tert-butyl-2-p-tolylguanidine (24).9a IR (KBr):
2923, 2854, 1621, 1601, 1510, 1240, 1116, 989, 816, 503 cmꢁ1
NMR (300 MHz, CDCl3)
7.01 (d, J¼8.1 Hz, 2H, ArH), 6.68 (d,
J¼8.1 Hz, 2H, ArH), 3.55 (br, 2H, NH), 2.28 (s, 3H, Me), 1.35 (s, 18H,
n
¼3291,
;
d
3.10 (q, J¼7.1 Hz, 4H,
;
1H
CH2), 3.04e2.91 (m, 2H, CH), 1.96e1.55 (m, 10H, CH2), 1.38e1.09 (m,
d
10H, CH2), 1.03 (t, J¼7.2 Hz, 6H, Me); 13C NMR (75 MHz, CDCl3)
d
154.58 (C]N), 54.91 (CH), 48.80 (CH2), 42.84 (CH2), 34.39 (CH2),
Me); 13C NMR (75 MHz, CDCl3)
d
153.56 (C]N), 148.29, 134.57,
33.87 (CH2), 25.61 (CH2), 25.50 (CH2), 25.36 (CH2), 24.93 (CH2),
130.16, 122.23, 53.18 (4 ꢀC), 29.82 (Me), 20.64 (Me); MS (ESI): m/z
262 (MþH)þ.
12.82 (Me); MS (ESI): m/z 280 (MþH)þ.
4.3.33. 2,3-Dicylohexyl-1,1-diphenylguanidine (33). Rf¼0.43 (1:1
hexane/ethyl acetateþ3% TEA); white solid; mp 209e210 ꢀC; IR
4.3.25. N,N0-Dicyclohexylpiperidine-1-carboximidamide (25).21 1H
NMR (300 MHz, CDCl3)
CH) 1.89e1.49 (m, 17H, CH2 & NH), 1.39e1.09 (m, 10H, CH2); 13C
NMR (75 MHz, CDCl3) 153.68 (C]N), 54.80, 49.08, 34.41 (CH2),
d
3.16e3.01 (m, 4H, CH2), 3.01e2.87 (m, 2H,
(KBr):
n
¼3262, 2971, 2926, 1636, 1605, 1507, 1404, 1207, 751 cmꢁ1
;
1H NMR (300 MHz, CDCl3)
d
7.26 (t, J¼7.9 Hz, 4H, ArH, overlap with
d
solvent), 7.10 (d, J¼7.6 Hz, 4H, ArH), 6.99 (t, J¼7.2 Hz, 2H, ArH),
26.00 (CH2), 25.51 (CH2), 25.38 (CH2), 24.83 (CH2); MS (ESI): m/z
292 (MþH)þ.
3.63e3.14 (m, 2H, CH), 2.02e1.01 (m, 20H, CH2); 13C NMR (75 MHz,
CDCl3)
d 147.27 (C]N), 144.39, 129.13, 122.54, 121.16, 53.05 (CH),
48.95 (CH), 33.92 (CH2), 33.58 (CH2), 25.77 (CH2), 25.60 (CH2), 25.00
(CH2); HRMS (ESI): m/z found 376.2742, calcd for C25H34N3 (MþH)þ
requires 376.2747.
4.3.26. N,N0-Diisopropylpiperidine-1-carboximidamide
(26).21 1H
NMR (300 MHz, CDCl3)
d 3.61e3.39 (m, 2H, CH), 3.28e3.19 (m, 4H,
CH2), 1.71e1.54 (m, 6H, CH2), 1.19 (d, J¼6.8 Hz, 12H, Me); 13C NMR
(75 MHz, CDCl3)
d
157.40 (C]N), 49.49 (CH2), 47.07 (CH2), 41.60
4.3.34. 2,3-Dicyclohexyl-1-methyl-1-phenylguanidine (34). Rf¼0.31
(1:1 hexane/ethyl acetateþ3% TEA); white solid; mp 159e160 ꢀC; IR
(CH), 25.50 (CH2), 24.78 (CH2), 23.40 (Me), 22.82 (Me); MS (ESI): m/
z 212 (MþH)þ.
(KBr):
NMR (300 MHz, CDCl3)
n
¼3241, 2930, 2856, 1613, 1451, 1382, 892, 756, 523 cmꢁ1; 1H
d
7.23 (t, J¼7.6 Hz, 2H, ArH, overlap with
4.3.27. N,N0-Dicyclohexylmorpholine-4-carboximidamide (27).21 IR
solvent), 7.14e6.69 (m, 3H, ArH), 3.62e2.77 (m, 6H, CH, NH & NMe),
(KBr):
n
¼3378, 3334, 2926, 2853, 1621, 1582, 1456, 1361, 1259, 1112,
1.99e1.47 (m,10H, CH2),1.45e1.01 (m,10H, CH2); 13C NMR (75 MHz,
849 cmꢁ1; 1H NMR (300 MHz, CDCl3)
d
3.62 (t, J¼4.3 Hz, 4H, CH2),
CDCl3) d 149.39 (C]N), 145.95, 128.92, 118.09, 112.84, 53.35 (CH),
3.53e3.17 (m, 1H, CH), 3.05 (t, J¼4.2 Hz, 4H, CH2), 3.01e2.89 (m, 1H,
48.81 (CH), 36.66 (NMe), 34.19 (CH2), 33.90 (CH2), 25.73 (CH2),
25.61 (CH2), 24.97 (CH2); HRMS (ESI): m/z found 314.2584, calcd for
C20H32N3 (MþH)þ requires 314.2590.
CH), 1.90e1.53 (m, 10H, CH2), 1.39e1.08 (m, 10H, CH2); 13C NMR
(75 MHz, DMSO-d6)
d 154.87 (C]N), 66.04 (CH2), 65.92 (CH2),
53.67, 49.09, 48.46, 47.50, 33.90 (CH2), 33.30 (CH2), 33.04 (CH2),
25.25 (CH2), 25.04 (CH2), 24.81 (CH2), 24.44 (CH2); MS (ESI): m/z
294 (MþH)þ.
Acknowledgements
S.P. thanks CSIR New Delhi for the award of fellowship and also
NIMS-IICT research centre for the support. P.J.A.J. thank UGC, India
for the award of fellowship. M.L.K. thanks DST-JSPS for the ex-
ploratory visit to Okayama University, Japan as part of India-Japan
Cooperative Science Program (IJCSP).
4.3.28. N,N0-Diisopropylmorpholine-4-carboximidamide (28).21 1H
NMR (500 MHz, CDCl3)
CH), 3.34e3.30 (m, 2H, CH2), 1.32e1.12 (m, 12H, Me); 13C NMR
(75 MHz, CDCl3) 157.16 (C]N), 66.44 (CH2), 66.26 (CH2), 48.51
d 3.84e3.51 (m, 6H, CH2), 3.49e3.37 (m, 2H,
d
(CH2), 47.50 (CH2), 43.84 (CH), 42.53 (CH), 23.43 (Me), 23.34 (Me),
22.83 (Me); MS (ESI): m/z 214 (MþH)þ.
Supplementary data
4.3.29. N,N0-Dicyclohexylpyrrolidine-1-carboximidamide (29).21 1H
1H, 13C NMR, HRMS spectra of products and TEM images of nano
TiO2 and CeO2 are provided in the electronic Supplementary data.
Supplementary data related to this article can be found online at
doi:10.1016/j.tet.2012.05.044.
NMR (300 MHz, CDCl3)
CH2), 2.07e1.47 (m, 14H, CH2), 1.43e1.05 (m, 10H, CH2); 13C NMR
(75 MHz, CDCl3) 155.35 (C]N), 54.74, 49.46, 48.99, 45.42, 33.91
d 3.53e3.34 (m, 2H, CH), 3.33e3.22 (m, 4H,
d

M.L. Kantam et al. / Tetrahedron 68 (2012) 5730e5737
5737
Shen, Q. J. Org. Chem. 2008, 73, 8966e8972; (d) Zhu, X.; Xu, F.; Shen, Q. Chin. J.
Chem. 2009, 27, 19e22; (e) Zhu, X.; Du, Z.; Xu, F.; Shen, Q. J. Org. Chem. 2009, 74,
6347e6349; (f) Wu, Y.; Wang, S.; Zhang, L.; Yang, G.; Zhu, X.; Liu, C.; Yin, C.;
Rong, J. Inorg. Chim. Acta 2009, 362, 2814e2819; (g) Zhang, X.; Wang, C.; Qian,
C.; Han, F.; Xua, F.; Shen, Q. Tetrahedron 2011, 67, 8790e8799; (h) Zhang, W.;
Nishiura, M.; Hou, Z. Chem.dEur. J. 2007, 13, 4037e4051; (i) Zhang, W.; Nish-
iura, M.; Hou, Z. Synlett 2006, 1213e1216.
References and notes
1. (a) Guanidines: Historical, Biological, Biochemical and Clinical Aspects of the
Naturally Occurring Guanidino Compounds; Mori, A., Cohen, B. D., Lowenthal, A.,
Eds.; Plenum: New York, NY, 1985; (b) Guanidines 2: Further Explorations of the
Biological and Clinical Significance of Guanidino Compounds; Mori, A., Cohen, B.
D., Koide, H., Eds.; Plenum: New York, NY, 1987; (c) The Pharmacological Basis of
Therapeutics, 7th ed.; Gilman, A. G., Goodman, L. S., Rall, T. W., Murad, F., Eds.;
Pergamon: NewYork, NY, 1990; p 899; (d) Berlinck, R. G. S.; Burtoloso, A. C. B.;
Kossuga, M. H. Nat. Prod. Rep. 2008, 25, 919e954; (e) Durant, G. J. Chem. Soc. Rev.
1985, 14, 375e398; (f) Bae, I.; Han, H.; Chang, S. J. Am. Chem. Soc. 2005, 127,
2038e2039.
2. (a) Ishikawa, T.; Isobe, T. Chem.dEur. J. 2002, 8, 552e557; (b) Ishikawa, T.;
Kumamoto, T. Synthesis 2006, 737e752; (c) McManus, J. C.; Genski, T.; Carey, J.
S.; Taylor, R. J. K. Synlett 2003, 369e371; (d) Kovacevic, B.; Maksic, Z. B. Org. Lett.
2001, 3, 1523e1526; (e) Costa, M.; Chiusoli, G. P.; Taffurelli, D.; Dalmonego, G. J.
Chem. Soc., Perkin Trans. 1 1998, 1541e1546; (f) Ma, D.; Cheng, K. Tetrahedron:
Asymmetry 1999, 10, 713e719; (g) Simoni, D.; Rondanin, R.; Morini, M.; Bar-
uchello, R.; Invidiata, F. P. Tetrahedron Lett. 2000, 41, 1607e1610.
3. (a) Barker, J.; Kilner, M. Coord. Chem. Rev. 1994, 133, 219e300; (b) Deng, M.; Yao,
Y.; Zhang, Y.; Shen, Q. Chem. Commun. 2004, 2742e2743; (c) Rowley, C. N.;
DiLabio, G. A.; Barry, S. T. Inorg. Chem. 2005, 44, 1983e1991; (d) Foley, S. R.;
Zhou, Y.; Yap, G. P. A.; Richeson, D. S. Inorg. Chem. 2000, 39, 924e929; (e)
Bambirra, S.; Bouwkamp, M. W.; Meetsma, A.; Hessen, B. J. Am. Chem. Soc. 2004,
126, 9182e9183; (f) Dagorne, S.; Guzei, I. A.; Coles, M. P.; Jordan, R. F. J. Am.
Chem. Soc. 2000, 122, 274e289; (g) Keaton, R. J.; Jayaratne, K. C.; Henningsen,
D. A.; Koterwas, L. A.; Sita, L. R. J. Am. Chem. Soc. 2001, 123, 6197e6198; (h)
Zhang, J.; Ruan, R.; Shao, Z.; Cai, R.; Weng, L.; Zhou, X. Organometallics 2002, 21,
1420e1424; (i) Zheng, P.; Hong, J.; Liu, R.; Zhang, Z.; Pang, Z.; Weng, L.; Zhou, X.
Organometallics 2010, 29, 1284e1289.
4. (a) Ong, T. G.; O’Brien, J. S.; Korobkov, I.; Richeson, D. S. Organometallics 2006,
25, 4728e4730; (b) Shen, H.; Chan, H. S.; Xie, Z. Organometallics 2006, 25,
5515e5517; (c) Li, J.; Zhang, Z.; Fan, E. Tetrahedron Lett. 2004, 45, 1267e1269;
(d) Wu, Y. Q.; Hamilton, S. K.; Wilkinson, D. E.; Hamilton, G. S. J. Org. Chem.
2002, 67, 7553e7556; (e) Evindar, G.; Batey, R. A. Org. Lett. 2003, 5, 133e136; (f)
Powell, D. A.; Ramsden, P. D.; Batey, R. A. J. Org. Chem. 2003, 68, 2300e2309; (g)
Linton, B. R.; Carr, A. J.; Orner, B. P.; Hamilton, A. D. J. Org. Chem. 2000, 65,
1566e1568; (h) Tin, M. K. T.; Thirupathi, N.; Yap, G. P. A.; Richeson, D. S. Dalton
Trans. 1999, 17, 2947e2950; (i) Feichtinger, K.; Zapf, C.; Sings, H. L.; Goodman,
M. J. Org. Chem. 1998, 63, 3804e3805.
10. (a) Klabunde, K. J.; Mulukutla, R. Nanoscale Materials in Chemistry; Wiley In-
terscience: New York, NY, 2001, Chapter 7, p 223; (b) Lucas, E.; Decker, S.;
Khaleel, A.; Seitz, A.; Fultz, S.; Ponce, A.; Li, W.; Carnes, C.; Klabunde, K. J. Chem.
dEur. J. 2001, 7, 2505e2510; (c) Jiang, Y.; Decker, S.; Mohs, C.; Klabunde, K. J. J.
Catal. 1998, 180, 24e25; (d) Astruc, D.; Lu, F.; Aranzaes, J. R. Angew. Chem., Int.
Ed. 2005, 44, 7852e7872.
11. (a) Schlogl, R.; Abd Hamid, S. B. Angew. Chem., Int. Ed. 2004, 43, 1628e1637; (b)
Bell, A. T. Science 2003, 299, 1688e1691; (c) Kantam, M. L.; Shiva Kumar, K. B.;
Sridhar, C. Adv. Synth. Catal. 2005, 347, 1212e1214; (d) Kantam, M. L.; Laha, S.;
Yadav, J.; Choudary, B. M.; Sreedhar, B. Adv. Synth. Catal. 2006, 348, 867e872; (e)
Kantam, M. L.; Laha, S.; Yadav, J.; Sreedhar, B. Tetrahedron Lett. 2006, 47,
6213e6216; (f) Choudary, B. M.; Mahendar, K.; Kantam, M. L.; Ranganath, K. V.
S.; Athar, T. Adv. Synth. Catal. 2006, 348, 1977e1985; (g) Choudary, B. M.;
Kantam, M. L.; Ranganath, K. V. S.; Mahendar, K.; Sreedhar, B. J. Am. Chem. Soc.
2004, 126, 3396e3397; (h) Choudary, B. M.; Ranganath, K. V. S.; Pal, U.; Kantam,
M. L.; Sreedhar, B. J. Am. Chem. Soc. 2005, 127, 13167e13171.
12. (a) Kantam, M. L.; Chakravarti, R.; Chintareddy, V. R.; Sreedhar, B.; Bhargava, S.
Adv. Synth. Catal. 2008, 350, 2544e2550; (b) Kantam, M. L.; Yadav, J.; Laha, S.;
Sreedhar, B.; Bhargava, S. Adv. Synth. Catal. 2008, 350, 2575e2582; (c) Kantam,
M. L.; Pal, U.; Sreedhar, B.; Bhargava, S.; Iwasawa, Y.; Tada, M.; Choudary, B. M.
Adv. Synth. Catal. 2008, 350, 1225e1229.
13. (a) Vayssieres, L.; Keis, K.; Hagfeldt, A.; Lindquist, S. E. Chem. Mater. 2001, 13,
4395e4398; (b) King, D. S.; Nix, R. M. J. Catal. 1996, 160, 76e83; (c) Pan, Z. W.;
Dai, Z. R.; Wang, Z. L. Science 2001, 291, 1947e1949; (d) Li, Q.; Wang, C. R. Chem.
Phys. Lett. 2003, 375, 525e531; (e) Kong, X.; Sun, X.; Li, X.; Li, Y. Mater. Chem.
Phys. 2003, 82, 997e1001; (f) Xu, C. X.; Sun, X. W.; Chen, B. J.; Shum, P.; Li, S.;
Hu, X. J. Appl. Phys. 2004, 95, 661e666; (g) Hara, K.; Horiguchi, T.; Kinoshita, T.;
Sayama, K.; Sugihara, H.; Arakawa, H. Sol. Energy Mater. Sol. Cells 2000, 64,
115e134.
14. (a) Kim, Y. J.; Varma, R. S. Tetrahedron Lett. 2004, 45, 7205e7208; (b) Sarvari, M.
H.; Sharghi, H. J. Org. Chem. 2004, 69, 6953e6956; (c) Sharghi, H.; Sarvari, M. H.
Synthesis 2002, 8, 1057e1060.
15. (a) Carnes, C. L.; Klabunde, K. J. Langmuir 2000, 16, 3764e3772; (b) Carnes, C. L.;
Klabunde, K. J. Chem. Mater. 2002, 14, 1806e1811.
16. Díaz-Torres, R.; Alvarez, S. Dalton Trans. 2011, 40, 10742e10750.
17. The TEM analysis of nano TiO2 and CeO2 were given in the Supplementary data.
18. This observation clearly proves that the particle size and surface area are also
important factors like Lewis acidity for the catalytic guanylation to proceed
smoothly. For details on Lewis acidity of metal oxides, see reference: Jeong, N.
C.; Lee, J. S.; Tae, E. L.; Lee, Y. J.; Yoon, K. B. Angew. Chem., Int. Ed. 2008, 47,
10128e10132.
5. (a) Tin, M. K. T.; Yap, G. P. A.; Richeson, D. S. Inorg. Chem. 1998, 37, 6728e6730;
(b) Molina, P.; Alajarín, M.; Sanchez-Andrada, P.; Sanz-Aparicio, J.; Martínez-
ꢀ
ꢀ
Ripoll, M. J. Org. Chem. 1998, 63, 2922e2927; (c) Chinchilla, R.; Najera, C.;
ꢀ
ꢀ
Sanchez Agullo, P. Tetrahedron: Asymmetry 1994, 5, 1393e1402; (d) Bernato-
wicz, M. S.; Wu, Y.; Matsueda, G. R. J. Org. Chem. 1992, 57, 2497e2502.
6. For general reviews on guanylating agents, see: (a) Katritzky, A. R.; Rogovoy, B.
V. ARKIVOC 2005, iv, 49e87; (b) Suhs, T.; Konig, B. Mini-Rev. Org. Chem. 2006, 3,
315e331.
19. Yamamoto, N.; Isobe, M. Chem. Lett. 1994, 12, 2299e2302.
7. (a) Ong, T.-G.; O’Brien, J. S.; Korobkov, I.; Richeson, D. S. Organometallics
2006, 25, 4728e4730; (b) Zhang, W.-X.; Li, D.; Wang, Z.; Xi, Z. Organome-
tallics 2009, 28, 882e887; (c) Koller, J.; Bergman, R. G. Organometallics 2010,
29, 5946e5952; (d) Alonso-Moreno, C.; Carrillo-Hermosilla, F.; Garces, A.;
Otero, A.; Lopez-Solera, I.; Rodriguez, A. M.; Antinolo, A. Organometallics
2010, 29, 2789e2795.
8. (a) Ong, T.-G.; Yap, G. P. A.; Richeson, D. S. J. Am. Chem. Soc. 2003, 125,
8100e8101; (b) Montilla, F.; Pastor, A.; Galindo, A. J. Organomet. Chem. 2004,
689, 993e996; (c) Shen, H.; Chan, H.-S.; Xie, Z. Organometallics 2006, 25,
5515e5517; (d) Li, D.; Guang, J.; Zhang, W.-X.; Wang, Y.; Xi, Z. Org. Biomol.
Chem. 2010, 8, 1816e1820.
20. According to HSAB concept unlike Zn2þ which is a borderline Lewis acid, both
Ti4þ and Ce4þ are classified as hard Lewis acids. The first step of guanylation; i.
e., the formation of intermediate I by the interaction of Lewis acid catalyst with
rather soft Lewis base carbodiimide was assumed to be efficient for nano ZnO
than nano TiO2 and nano CeO2. This may explain the observed activity differ-
ence of nano ZnO as compared to nano TiO2. In addition, another important
point to be accounted is that aniline nitrogen is considered as a hard Lewis
base. Therefore, hard Lewis acids like Ti4þ will preferentially attack nitrogen of
aniline instead of carbodiimide and may undergo complexation with the for-
mer. For reference, see: (a) Woodward, S. Tetrahedron 2002, 58, 1017e1050; (b)
Mayr, H.; Breugst, M.; Ofial, A. R. Angew. Chem., Int. Ed. 2011, 50, 6470e6505.
21. Thomas, E. W.; Nishizawa, E. E.; Zimmermann, D. C.; Williams, D. J. J. Med. Chem.
1989, 32, 228e236.
9. (a) Li, Q.; Wang, S.; Zhou, S.; Yang, G.; Zhu, X.; Liu, Y. J. Org. Chem. 2007, 72,
6763e6767; (b) Zhou, S.; Wang, S.; Yang, G.; Li, Q.; Zhang, L.; Yao, Z.; Zhou, Z.;
Song, H. Organometallics 2007, 26, 3755e3761; (c) Du, Z.; Li, W.; Zhu, X.; Xu, F.;