Ytterbium triflate: A highly active catalyst for addition of amines to carbodiimides to N,N′,N″-trisubstituted guanidines

Article abstract of DOI:10.1021/jo900903t

(Chemical Equation Presented) Ytterbium triflate was found to be efficient catalyst for addition of amines to carbodiimides to N,N′,N″- trisubstituted guanidines with a wide scope of amines under solvent-free condition.

Full text of DOI:10.1021/jo900903t

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of complexes of main, transition, and lanthanide metals.2
Ytterbium Triflate: A Highly Active Catalyst for
Addition of Amines to Carbodiimides to N,N0,
N00-Trisubstituted Guanidines
Moreover, the guanidines groups are the structural units in
many biologically relevant compounds.3 As a result, the
synthesis of guanidines has attracted much attention in
organic synthesis. Various methods have been explored for
the synthesis of guanidines,4-9 among them, addition of
amines to carbodiimides provides a convenient and atom-
economic approach. However, addition of amines to carbo-
diimides without a catalyst requires harsh conditions.9 So,
development of an efficient catalyst for this transformation
under mild conditions has become one of the active areas
both in organic chemistry and organometallic chemistry of
main,10 transition,11 and lanthanide12 metals.
Xuehua Zhu,† Zhu Du,† Fan Xu,† and Qi Shen*,†,‡
†Key Laboratory of Organic Synthesis of Jiangsu Province,
Department of Chemistry and Chemical Engineering, Dushu
Lake Campus, Suzhou University, Suzhou 215123, People’s
Republic of China, and ‡State Key Laboratory of
Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, Shanghai 200032,
China
Various lanthanide complexes have recently been found to
be efficient catalysts. Hou’s group reported the catalytic
addition of various primary and secondary amines to carbo-
diimides by half-sandwich lanthanide alkyl complexes, espe-
cially the yttrium complex yielding a series of guanidine
derivatives.12a Wang’s group described the guanylation of
both aromatic and secondary amines with carbodiimides
catalyzed by simple lanthanide amides12b and by
[ethylenebis(indenyl)]lanthanide amides, respectively.12c
Very recently we reported the catalytic addition of amines
to carbodiimides by divalent lanthanide complexes.13 It is
worth noting that all of these catalytic systems need to use the
lanthanide complexes which are very sensitive to air and
moisture. Exploring another class of lanthanide catalysts,
which are stable, easy to handle, and readily prepared, is still
in demand.
qshen@suda.edu.cn
Received April 30, 2009
Although lanthanide triflates, as a novel class of
Lewis acid, have been widely used in carbon-carbon and
Ytterbium triflate was found to be efficient catalyst for
addition of amines to carbodiimides to N,N0,N00-trisub-
stituted guanidines with a wide scope of amines under
solvent-free condition.
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DOI: 10.1021/jo900903t
r
Published on Web 07/21/2009
J. Org. Chem. 2009, 74, 6347–6349 6347
2009 American Chemical Society

Zhu et al.
JOCNote
TABLE 1. Lewis Acid Optimizationa
TABLE 2. Catalytic Addition of Amines to Carbodiimidesa
entry catalyst catalyst loading (mol %) temp (°C) time yield (%)
1
2
3
4
5
6
7
8
9
10
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
La(OTf)3
La(OTf)3
Nd(OTf)3
Sm(OTf)3
Eu(OTf)3
Er(OTf)3
0.5
0.5
0.2
0.5
0.5
0.5
0.5
0.5
0.5
60
25
25
60
60
60
60
60
60
60
5 min 90
1 h
4 h
97
80
2.5 h trace
24 h 30
2.5 h 24
2.5 h 76
50 min 84
12 min 86
5 min n.r.
a
The reaction was performed by treating 1 equiv of amines with 1
equiv of carbodiimides.
carbon-heteroatom bond formation,14 further exploring
their application in organic synthesis has still attracted
increasing attention, as they are water-tolerant, reusable,
and environmentally friendly catalysts. Here we wish to
report the addition of amines to carbodiimides catalyzed
by Yb(OTf)3 and the possible mechanism.
The reaction of aniline PhNH2 with N,N0-diisopropylcar-
i
bodiimide Pr2NdCdNiPr2 was first tried with Yb(OTf)3
as a catalyst. The reaction went smoothly at 60 °C even
with 0.5% mol of Yb(OTf)3 under solvent-free condition to
afford the N,N0,N00-trisubstituted guanidine 2a via 1,3-H
shift in 90% yield after 5 min (Table 1 entry 1). How-
ever, the same reaction without a catalyst does not occur
(Table 1 entry 10). The positive results suggest that Ln(OTf)3
may serve as the catalyst. Therefore, we examined several
lanthanide complexes for this reaction to further assess
the effect of lanthanide metals on activity. It was found
that the metals have great influence on the activity and
the active sequence is La < Nd < Sm < Eu < Er < Yb
(Table 1, entries 1 and 4-9), which is consistent with the
trend in a decreasing of Ln3þ ionic radius. The highest
activity for the Yb metal may be attributed to the strongest
Lewis acidity of the Yb metal among these metals.
The reaction can also be carried out at room tempera-
ture and the product 2a in 97% yield was obtained after
1 h (Table 1, entry 2).
With the optimized conditions (Table 1, entry 2) we first
examined the reactions of various primary aromatic amines
with carbodiimides to explore the generality and scope of
Yb(OTf)3-catalyzed addition of amines to carbodiimides. As
shown in Table 2, Yb(OTf)3 is a very robust and efficient
catalyst, which is compatible with a wide range of substituents
at the phenyl ring, regardless of the electron-withdrawing or
electron-donating groups. In most cases the reactions with
a
The reaction was performed by treating 1 equiv of amines with 1
equiv of carbodiimides. bIsolated yields. 0.5 mol % of cat., 25 °C, for 1 h.
c
(14) (a) Li, C.; Chen, L. Chem. Soc. Rev. 2006, 35, 68–82. (b) Li, C. Chem.
Rev. 2005, 105, 3095–3165. (c) Kobayashi, S. Chem. Rev. 2002, 102, 2227–
2302. (d) Kobayashi, S.; Manabe, K. Acc. Chem. Res. 2002, 35, 209–217.
(e) Topics in Organometallic Chemistry. Lanthanides: Chemistry and Use in
Organic Synthesis; Kobayashi, S., Ed.; Springer-Verlag: Berlin, Germany, 1999;
Vol. 2, Chapter 2. (f) Dzudza, A.; Marks, T. J. Org. Lett. 2009, 11, 1523–1526.
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d1 mol % of cat., 80 °C, for 24 h. 2 mol % of cat., 60 °C, for 3 h. 2 mol %
e
f
of cat. 80 °C, for 3 h.
primary aromatic amines completed at room temperature
within 1 h to give the corresponding N,N0,N00-trisubstitu-
ted guanidines in excellent yields (Table 2, entries 1-14).
6348 J. Org. Chem. Vol. 74, No. 16, 2009

Zhu et al.
JOCNote
SCHEME 1. Proposed Mechanism for Addition of Amines to
Carbodiimides
to generate an intermediate A. Nucleophilic addition of an
amine to A would afford B. Intramolecular proton transfer
of B readily led to regenerate Yb(OTf)3 and release the
guanidine.
In conclusion, Yb(OTf)3 has been found to be an
efficient catalyst for addition of amines to carbodiimides
to N,N0,N00-trisubstituted guanidines in good to excellent
yields under solvent-free condition. The system shows a
wide range of scope of substrate including primary aro-
matic amines and secondary cyclic amines. Detailed
study on the reaction mechanism is going on in our
laboratory.
Experimental Section
General Procedure 1: For the Direct Synthesis of Guanidines
from Reaction of Aromatic Amines with Carbodiimides Catalyzed
by Yb(OTf)3 (product 2a as an example). A 10 mL Schlenk tube
under dried argon was charged with Yb(OTf)3 (0.0035 g, 0.0056
mmol). To the flask were added the N,N0-diisopropylcarbodii-
mide (0.18 mL, 1.13 mmol) and aniline (0.10 mL, 1.13 mmol).
The resulting mixture was stirred at room temperature for 1 h.
The reaction mixture was then hydrolyzed with water (0.5 mL),
extracted with dichloromethane (3ꢀ10 mL), dried over anhy-
drous Na2SO4, and filtered. After the solvent was removed
under reduced pressure, the residue was recrystallized in hexane
to provide a white solid 2a (97% yield).
General Procedure 2: For the Direct Synthesis of Guanidines
from Reaction of Secondary Amines with Carbodiimides Cata-
lyzed by Yb(OTf)3 (product 1a as an example). A 10 mL Schlenk
tube under dried argon was charged with Yb(OTf)3 (0.0217 g,
0.035 mmol). To the flask were added the N,N0-diisopropylcar-
bodiimide (0.27 mL, 1.74 mmol) and pyrrolidine (0.15 mL,
1.74 mmol). The resulting mixture was stirred at 60 °C for 3 h.
The reaction mixture was then hydrolyzed with water (0.5 mL),
extracted with hot hexane (3 ꢀ 10 mL), dried over anhydrous
Na2SO4, and filtered. After the solvent was removed under
vacuum, the final product 1a was obtained as a white powder
in 91% yield.
The catalyst system showed good functional group tolerance.
For example, the groups of F and Cl at the phenyl ring
remained unchanged during the reactions (Table 2, entries 2
and 3, and 10, 11, and 13). However, the reaction with a steric
bulky amine, diisopropylaniline, went slowly and gave the
guanidine in 52% yield, even with 1 mol % of catalyst at 80 °C
(entry 15).
The present catalyst can also catalyze the addition of a
primary aliphatic amine, such as n-BuNH2, to a diisopro-
pylcarbodiimide, even the present catalyst is less active than
divalent lanthanide amides reported.13a As shown in Table 2,
the reaction afforded the corresponding N,N0,N00-trisubsti-
tuted guanidine in 79% yield (entry 16).
Secondary cyclic amines are well-known to be less reactive
than primary amines toward carbodiimides. Thus, the reac-
tions with several cyclic secondary and acyclic secondary
amines were then conducted. In the presence of 2 mol % of
Yb(OTf)3 various cyclic amines could react with diisopro-
pylcarbodiimide and dicyclohexylcarbodiimide at 60 °C
affording the guanidines in good to excellent yields
(Table 2, entries 17-24). Although 1-methylpiperazine is
less active, the reactions with it can still afford the desired
products in over 80% yields (Table 2, entries 23 and 24).
The present reactions are scalable. For example, the
reaction of 102 mmol of diisopropylcarbodiimide with 1
equiv of aniline afforded 2a in 98% yield at room tempera-
ture after 30 min (Supporting Information).
Acknowledgment. We are grateful to the National Natur-
al Science Foundation of China (Grant No. 20632040) and
the Department of National Education Ph.D. Foundation
for financial support.
Supporting Information Available: Experimental proce-
dures and full spectroscopic data for all compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
A possible mechanism for Yb(OTf)3-catalyzed addition of
amines to carbodiimides is proposed in Scheme 1. Yb(OTf)3
should react first with a carbodiimide as a Lewis acid catalyst
J. Org. Chem. Vol. 74, No. 16, 2009 6349