First iron-catalyzed guanylation of amines: A simple and highly efficient protocol to guanidines

Article abstract of DOI:10.1016/j.tetlet.2012.07.065

The first iron-catalyzed guanylation of amines is reported. Commercially available Fe(OAc)₂ acts as an excellent catalyst for the addition of amines to carbodiimides. The reaction is broadly applicable to a variety of primary, secondary, and heterocyclic amines, and tolerates a wide range of functionalities allowing the easy preparation of a large family of guanidines. The low price and low toxicity of the commercially available iron catalyst make this methodology highly attractive.

Full text of DOI:10.1016/j.tetlet.2012.07.065

Tetrahedron Letters 53 (2012) 5156–5158
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Tetrahedron Letters
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First iron-catalyzed guanylation of amines: a simple and highly efficient
protocol to guanidines
⇑
⇑
Srinivas Pottabathula , Beatriz Royo
Instituto de Tecnologia Química e Biológica, Universidade Nova de Lisboa, Av. da República, EAN, 2780-157 Oeiras, Portugal
a r t i c l e i n f o
a b s t r a c t
Article history:
The first iron-catalyzed guanylation of amines is reported. Commercially available Fe(OAc)2 acts as an
excellent catalyst for the addition of amines to carbodiimides. The reaction is broadly applicable to a vari-
ety of primary, secondary, and heterocyclic amines, and tolerates a wide range of functionalities allowing
the easy preparation of a large family of guanidines. The low price and low toxicity of the commercially
available iron catalyst make this methodology highly attractive.
Received 24 May 2012
Revised 11 July 2012
Accepted 13 July 2012
Available online 20 July 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Iron catalyzed
Guanylation
Homogeneous catalysis
Amines
Guanidines
Guanidines are important classes of compounds that have
found relevant applications in medicine as therapeutic agents suit-
able for the treatment of a wide spectrum of diseases.1 Moreover,
guanidine is a substructure of many important molecules with bio-
logical activity,2 and also has extensive uses in organic chemistry
as organic bases, and as ancillary ligands to various metals.3 A con-
venient methodology for the preparation of guanidines is the cata-
lytic addition of amine N–H bonds to carbodiimides, also known as
guanylation reaction (Fig. 1). This methodology provides a waste-
free process, being a convenient atom-economical approach to
substituted guanidines.
Since the seminal publication of a titanium imido complex
capable to effect the catalytic addition of primary aromatic amines
to carbodiimides,4 other catalytic systems including a vanadium
imido,5 half-sandwich lanthanide alkyls,6 lanthanide amides and
aryloxides,7 LiN(SiMe3)2,8 titaniocarborane amide,9 and commer-
cially available alkyl metals ZnEt2,10 MgBu2,10 LiBu,10 AlR3,11 and
Zn(OTf)212 have been reported to catalyze the guanylation reaction
extending the applicability of this reaction to secondary amines.
In recent years the search for cheap, readily available catalysts
for efficient chemical transformations has been responsible for
the resurgence of catalytic systems based on iron metal.13 Indeed,
in the last decade iron catalysis has emerged as a challenging area
for the development of alternative more sustainable methods.14
Following our interest in developing new iron-based catalytic
systems,15,16 we decided to explore the catalytic activity of iron
R1
NHR
NR
Catalyst
R1R2NH
N
+
RN=C=NR
R2
R2 = H for primary amines
R = Cy, Isopropyl
Figure 1. Catalytic addition of primary and secondary amines to carbodiimides.
complexes in the guanylation reaction. Herein, we report for the
first time the efficient addition of amines to carbodiimides using
a convenient iron catalyst, Fe(OAc)2, with excellent functional
group tolerance and broad scope. An attractive feature of this Fe-
catalytic system is its operational simplicity, since the reaction
can be performed with analytical grade solvents in air without spe-
cial precautions.
We first investigated the reaction of p-anisidine with N,N0-dicy-
clohexylcarbodiimide as a model system to identify and optimize
potential catalysts and reaction conditions. We found that in the
presence of 5 mol% of iron(II)acetate the reaction took place in
toluene at 120 °C affording quantitative yield (97%) of the corre-
sponding guanidine in 2 h (Table 1, entry 1).
Iron(II)triflate also afforded quantitative conversion under
similar conditions (Table 1, entry 2). We also tested the catalytic
activity of the well-defined cyclopentadienyl-NHC iron complex
(Cp⁄-NHC)Fe(CO)I (Cp⁄ = 5-C5Me4; NHCMe = N-heterocyclic car-
g
bene) recently prepared by us.15,16 This complex displayed good
catalytic activity affording quantitative yield of the corresponding
guanidine derivative, although longer reaction times were needed
⇑
Tel.: +351 214469754; fax: +351 214411277.
E-mail address: broyo@itqb.unl.pt (B. Royo).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.07.065

S. Pottabathula, B. Royo / Tetrahedron Letters 53 (2012) 5156–5158
5157
Table 1
Catalytic addition of p-anisidine to N,N0-dicyclohexylcarbodiimide with iron catalystsa
Table 2
Fe(OAc)2-catalyzed addition of aromatic primary amines to RN = C = NRa
NHCy
NHCy
Cat
Solvent
Entry ArNH2
Carbodiimide
Time
(h)
T
(°C)
Yieldb
(%)
+
MeO
NH2 CyN C NCy
MeO
N
Cy = cyclohexyl
1
2
3
4
5
C6H5NH2
CyN = C = NCy
CyN = C = NCy
iPrN = C = NiPr
CyN = C = NCy
CyN = C = NCy
iPrN = C = NiPr
CyN = C = NCy
iPrN = C = NiPr
CyN = C = NCy
iPrN = C = NiPr
CyN = C = NCy
CyN = C = NCy
iPrN = C = NiPr
CyN = C = NCy
iPrN = C = NiPr
CyN = C = NCy
CyN = C = NCy
CyN = C = 8NCy
CyN = C = NCy
iPrN = C = NiPr
CyN = C = NCy
iPrN = C = NiPr
CyN = C = NCy
CyN = C = NCy
iPrN = C = NiPr
CyN = C = NCy
2
2
1.5
2
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
130
130
130
130
130
130
130
130
130
94
97
97
96
95
93
96
94
94
96
94
93
95
94
93
91
90
92
93
91
91
90
89
91
90
90
Entry
Catalyst (mol %)
Solvent
T (°C)
Yieldb (%)
4-OMe-C6H4NH2
4-OMe-C6H4NH2
4-Me-C6H4NH2
4-NO2-C6H4NH2
4-NO2-C6H4NH2
4-F-C6H4NH2
1
2
3
4
5
6
7
8
9
10
11
12
13
Fe(OAc)2 (5)
Fe(OTf)2 (5)
(Cp⁄–NHC)Fe(CO)I
FeCl2 (5)
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
THF
benzene
DMF
DMSO
120
120
120
120
120
120
80
97
95
96c
24
12
65
0
0
0
0
0
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
2
6
7
FeCl3 (5)
8
4-F-C6H4NH2
Fe3(CO)12 (5)
Fe(OAc)2 (5)
Fe(OAc)2 (5)
Fe(OAc)2 (5)
Fe(OAc)2 (5)
Fe(OAc)2 (5)
Fe(OAc)2 (2)
Without catalyst
9
4-Cl-C6H4NH2
4-Cl-C6H4NH2
4-Br-C6H4NH2
4-I-C6H4NH2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
80
120
120
100
120
120
4-I-C5H4NH2
Toluene
Toluene
Toluene
4-CN-C6H4NH2
4-CN-C6H4NH2
4-COMe-C6H4NH2
4-COOMe-C6H4NH2
2-Me-C6H4NH2
2-OMe-C6H4NH2
2-OMe-C6H4NH2
2-NO2-C6H4NH2
2-NO2-C6H4NH2
2-I-C6H4NH2
97
0
a
Reaction conditions: aniline (1 mmol), N,N0-dicyclohexylcarbodiimide
(1.2 mmol), solvent (2 mL), 2 h.
b
2
2
Yield of isolated product.
c
5 mol % of Catalyst was used, 5 h of reaction.
2.5
2
2.5
2.5
2
3-Me-C6H4NH2
3-Me-C6H4NH2
2,4,6-(Me)3-
to complete the reaction (5 h, Table 1, entry 3). Other iron sources
such as iron(II) and iron(III) chlorides showed some activity but
gave significantly lower yields (24% and 12% yield, respectively;
Table 1, entries 4 and 5). The iron(0) carbonyl Fe3(CO)12 showed
a moderate activity affording 65% of the corresponding guanidine
under similar conditions (Table 1, entry 6). From the above results,
Fe(OAc)2 was selected as the best catalyst choice because of its
high reactivity, availability, and easy handling.
3
C6H4NH2
27
2,4,6-(Me)3-
iPrN = C = NiPr
3
130
88
C6H4NH2
a
Reaction conditions: aromatic amine (1 mmol), carbodiimide (1.2 mmol),
Fe(OAc)2 (2 mol %), and toluene (2 mL).
b
Yield of isolated product.
After screening the reaction conditions, toluene was found to be
the most suitable solvent for this reaction. The appropriate selec-
tion of solvent and temperature was crucial for the reaction to pro-
ceed efficiently. No reaction occurred in the presence of other
solvents such as THF, benzene, DMF, and DMSO (Table 1, entries
7–10, respectively). The reaction temperature revealed to be a
determinant parameter. If the temperature is lowered to 100 °C,
no reaction occurred even after being reacted for several hours (Ta-
ble 1, entry 11). We observed that the amount of catalyst could be
reduced to 2 mol % without noticeable detrimental effects in the
isolated yields (Table 1, entry 12). As expected, the reaction did
not occur in the absence of catalyst (Table 1, entry 13).
With the optimized conditions in hand, Fe(OAc)2 (2 mol %) in
toluene (2 mL) at 120 °C, we explored the scope and limitations
of Fe(OAc)2 in the catalytic addition of a variety of primary aro-
matic amines bearing different functional groups (Tables 2 and
3). As illustrated in Table 2, the Fe-catalyzed guanylation displayed
remarkable functional group tolerance; many functionalities, such
as -halogens (F, Cl, Br, I), –NO2, –CN, –COMe, –COOEt, –OMe, and –
Me, were unaffected under the reaction conditions used (Table 2,
entries 1–17). In all cases excellent yields (>90% isolated yield)
were obtained, and no difference was detected for electron-with-
drawing or electron-donating groups under the described reaction
conditions. For the ortho and meta-substituted anilines a slight in-
crease in the temperature (130 °C) and time (2–2.5 h) were applied
to improve the yields of the corresponding guanidines (Table 2, en-
tries 18–25).
Table 3
Fe(OAc)2-catalyzed guanylation with heteroaryl and secondary aminesa
Entry Amine
Carbodiimide
Product
Yieldb
(%)
N Cy
O
NH
NH
O
O
N
1
CyN = C = NCy
iPrN = C = NiPr
CyN = C = NCy
iPrN = C = NiPr
96
97
HN Cy
N
iPr
O
N
2
HN iPr
N Cy
NH
NH
3
4
78c
82c
N
HN Cy
N
iPr
N
N
HN iPr
N Cy
CH3
NH
H3C
5
6
CyN = C = NCy
iPrN = C = NiPr
CyN = C = NCy
60
68
95
HN Cy
CH3
NH
H3C
N
iPr
N
HN iPr
The reaction also worked well with N,N0-diisopropylcarbodiim-
ide (Table 2, entries 1–27). Different p-, o, m-substituted electron-
rich and electron-deficient anilines were also added conveniently
to N,N0-diisopropylcarbodiimide in excellent yields. The addition
reaction between the sterically hindered 2,4,6-trimethylaniline
and N,N0-dicyclohexylcarbodiimide or N,N0-diisopropylcarbodiim-
ide also afforded high yield of the corresponding guanidines
(Table 2, entries 26 and 27, respectively). We have also explored
HN Cy
HN Cy
NH2
N
N
N
7
(continued on next page)

5158
S. Pottabathula, B. Royo / Tetrahedron Letters 53 (2012) 5156–5158
Table 3 (continued)
Acknowledgments
Entry Amine
Carbodiimide
iPrN = C = NiPr
Product
Yieldb
(%)
The authors thank FCT of Portugal for financial support, POCI
2010, and FEDER through project PTDC/QUI-QUI/110349/2009.
S.P. thanks FCT for grant SFRH/BDP/68720/2010. We thank FCT
for REDE/1504/REM/2005 and REDE/1517/RMN/2005. The authors
thank João M.S. Cardoso (from our group at ITQB) for preparation of
the iron complex (Cp⁄-NHC)Fe(CO)I.
HN iPr
HN iPr
NH2
N
N
N
8
92
95
HN Cy
HN Cy
NH2
Cl
N
N
Supplementary data
9
CyN = C = NCy
N
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.
07.065.
Cl
N
HN Cy
HN Cy
NH2
NH2
N
10
CyN = C = NCy
iPrN = C = NiPr
96
94
N
N
N
References and notes
HN iPr
HN iPr
N
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butyl-3-ethylcarbodiimide. Its reaction with 4-methoxyaniline
gave 55% yield of the corresponding guanidine after 5 h of reaction
at 130 °C.
Notably, the iron catalytic system demonstrated excellent per-
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3. All substrates are fully converted into the corresponding guani-
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yields of the corresponding guianidines (Table 3, entries 5 and 6).
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