Ti-amide catalyzed synthesis of cyclic guanidines from di-/triamines and carbodiimides

Article abstract of DOI:10.1021/ol201752e

A titanacarborane monoamide catalyzed, one-step synthesis of mono/bicyclic guanidines from commercially available di/triamines and carbodiimides is reported. The reaction mechanism is also proposed.

Full text of DOI:10.1021/ol201752e

ORGANIC
LETTERS
2011
Vol. 13, No. 17
4562–4565
Ti-amide Catalyzed Synthesis
of Cyclic Guanidines from
Di-/Triamines and
Carbodiimides
Hao Shen, Yang Wang, and Zuowei Xie*
Department of Chemistry and State Key Laboratory on Synthetic Chemistry,
The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, China
zxie@cuhk.edu.hk
Received June 29, 2011
ABSTRACT
A titanacarborane monoamide catalyzed, one-step synthesis of mono/bicyclic guanidines from commercially available di/triamines and
carbodiimides is reported. The reaction mechanism is also proposed.
A growing number of biologically and pharmaceutically
relevant compounds incorporate the cyclic guanidine
functionality.1 Cyclic guanidines are also capable of
catalyzing organic reactions2 and exhibiting a variety of
coordination modes and a range of donor properties
leading to compatibility with a wide range of metal ions.3
Therefore, their synthesis has been extensively explored.
Generally, the known methods include (1) the reactions4 of
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Chem. 1971, 36, 46. (b) Baltzer, C. M.; McCarty, C. G. J. Org. Chem.
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r
10.1021/ol201752e
Published on Web 08/04/2011
2011 American Chemical Society

amines with S,S-dimethyl-N-tosyliminodithiocarbonimi-
dates,4a dimethyl cyanoimido-dithiocarbonates,4b isothio-
cyanates,4cꢀe or carbon disulfide;4f (2) cyclization of gua-
nidino-alkynes;5 (3) intramolecular alkylation of guanidines;6
(4) reactions of unsaturated molecules with azridines,7 and
so forth.8 Very recently, oxidative amination and radical
cascade cyclization methods were also successfully applied
to the synthesis of cyclic guanidines.9 However, most of
these routes require multistep operations or functionaliza-
tion of precursors. Herein, we report a novel and direct
method for the catalytic synthesisof cyclic guanidinesfrom
commercially available di/triamines and carbodiimides in
one step.
Scheme 1. Construction and Reconstruction of Guanidines
Catalyzed by 1
Recently, we reported a highly reactive titanacarborane
monoamide [σ:η1:η5-(OCH2)(Me2NCH2)C2B9H9]Ti-(NMe2)
(1),10 which can be viewed as an isoelectronic/isostructral
analogue of constrained-geometry lanthanide amide or a
cationic group 4 metal amide.11 This complex efficiently
catalyzes the cascade hydroamination of cyanoalkynes
to give isoindoles and isoquinolines,12 the sequential
CꢀN bond-forming reaction of propargylamines with
nitriles to yield imidazoles,12 and the [3 þ 2] annulation
of propargylamines with carbodiimides to produce 2-ami-
no-imidazoles.5d
In addition, complex 1 acts as an elegant catalyst
in the hydroamination of carbodiimides (Scheme 1,
eq 1),13 and it also shows a very high catalytic activity
toward the transamination reaction of guanidines
(Scheme 1, eq 2).14
These results and the group 4 metallacarborane
mediated CꢀN bond cleavage of guanidinates15 promote
us to further explore the catalytic metathesis of guanidines
with carbodiimides and that of two guanidines. After a
C6D6 solution of guanidine 2a (0.1 mmol), DCC (0.1
mmol), and 1 (0.01 mmol, 10 mol %) was heated at
115 °C for 24 h, the 1H NMR indicated that an equilibrium
between 2a and 2b (in a molar ratio of 49:51) was reached
(Scheme 1, eq3). Similarly, the NMR reaction of 2awith2c
in the presence of 10 mol % of 1 at 115 °C for 24 h resulted
in another equilibrium of 2a:2b (49:51) (Scheme 1, eq 4). In
marked contrast, no metathesis reaction was observed in
the absence of catalyst 1.
that a reaction of di/triamines with carbodiimides in the
presence of 1 would serve as a new approach for the
synthesis of cyclic guanidines (Scheme 1, eq 5), via the
Table 1. Effects of Metal Complexes in Reaction of 3a with 4aa
On the basis of the prevalence of olefin ring-closing
metathesis (RCM) and the fact that 1 catalyzes both the
hydroamination of carbodiimides (Scheme 1, eq 1) and the
intermolecular metathesis of guanidines with amines/car-
bodiimides/guanidines (Scheme 1, eq 2/3/4), we envisaged
entry catalyst loading (mol %) temp (°C) time (h) yield (%)
1
2
3
4
5
6
7
8
9
none
0
5
110
110
110
140
140
110
110
110
110
110
110
196
196
196
32
<10
60
1
~
€
ꢀ~
(9) (a) Muniz, K.; Streuff, J.; Hovelmann, C. H.; Nunez, A. Angew.
Chem., Int. Ed. 2007, 46, 7125. (b) Kim, M.; Mulcahy, J. V.; Espino,
C. G.; Du Bois, J. Org. Lett. 2006, 8, 1073. (c) Larraufie, M.-H.; Ollivier,
1
10
5
>95
63
1
^
C.; Fensterbank, L.; Malacria, M.; Lacote, E. Angew. Chem., Int. Ed.
2010, 122, 2224.
1
10
10
10
10
10
10
10
32
>95
70
Ti(NMe2)4
Zr(NMe2)4
Hf(NMe2)4
Cp2TiMe2
196
196
196
196
196
196
(10) (a) Shen, H.; Chan, H.-S.; Xie, Z. Organometallics 2007, 26,
2694. (b) Shen, H.; Xie, Z. J. Organomet. Chem. 2009, 694, 1652.
(11) (a) Xie, Z. Coord. Chem. Rev. 2006, 250, 259. (b) Braunschweig,
H.; Breitling, F. M. Coord. Chem. Rev. 2006, 250, 2691. (c) Li, X.; Hou,
Z. Coord. Chem. Rev. 2008, 252, 1842.
(12) Shen, H.; Xie, Z. J. Am. Chem. Soc. 2010, 132, 11473.
(13) Shen, H.; Chan, H.-S.; Xie, Z. Organometallics 2006, 25, 5515.
(14) Shen, H.; Xie, Z. Organometallics 2008, 27, 2685.
(15) Shen, H.; Chan, H.-S.; Xie, Z. J. Am. Chem. Soc. 2007, 129,
12934.
20
18
<10
<10
<10
10 Cp2ZrMe2
11 Cp2HfMe2
a NMR yield using ferrocene as the internal standard.
Org. Lett., Vol. 13, No. 17, 2011
4563

intermolecular hydroamination (3þ4 to A) and the intra-
molecular metathesis (A/B to 5, 5 to 6).
Table 2. Screening of Substrate Scope
The model reaction of o-phenylenediamine (3a) with
diisopropylcarbodiimide (4a) was initially examined
(Table 1) in the presence of a catalytic ammount of 1 or
commercially available complexes or commonly used
catalysts.16 In the absence of a catalyst, no expected
product 5aa was observed at 110 °C for 196 h (entry 1).
However, addition of 10 mol % of 1 led to the formation of
5aa in more than 95% NMR yield under the same condi-
tions (entry 3). The reaction could also go to completion in
32h at140 °C (entry 5). A lower catalyst loading resultedin
a lower yield (entries 2 and 4).
It is documented that carbodiimides react readily with
highly nucleophilic cyclic aliphatic amines, in the absence
of a catalyst, to generate the corresponding guanidines at
high temperatures.17 Thus, the substrate scope of this
reaction was examined to see if the catalyst is necessary
for different substrates (Table 2). The reaction of highly
nucleophilic N,N0-dimethylethylenediamine 3j proceeded
very well in the absence of the catalyst (entry 9 vs 10),
whereas reactions of correspondingly less nucleophilic
amines (such as aromatic diamine 3a and primary aliphatic
diamine 3f) do need the catalyst (entries 1ꢀ6). The diaryl-
carbodiimide showed a better reactivity than the dialkyl-
carbodiimide (entries 1/2 vs 3/4, 5/6 vs 7/8).
a Ar = 4-tol. b NMR yield using ferrocene as an internal standard.
c Isolated yield (shown in parentheses).
Scheme 2. Synthesis and Conversion of the Intermediate 7aa
Figure 1. X-ray Structures for 5ac and 5ec.
According to the above observations, more substrates
were included except for the highly nucleophilic amines.
A series of di- and triamines were examined, and the
corresponding results were compiled in Table 3. Reactions
of diamines afforded five- to seven-membered cyclic gua-
nidines (entries 1ꢀ11). The reaction of cis-1,4-cyclohexa-
diamine 3i gave the bridged cyclic guanidine 5ic (entry 12).
Triamines 3k/3l reacted with carbodiimides to produce the
bicyclic guanidines 6k/6l (entries 13ꢀ15). The chiral cyclic
guanidine (S-5ec) was also prepared from the correspond-
ing chiral amine (S-3e) with the retention of the ee value
(entry 7). All of those products were fully characterized.
Compounds 5ac and 5ec were further confirmed by X-ray
analyses (Figure 1).
Although these reactions were developed on the basis of
the well-established construction and reconstruction of
guanidines (Scheme 1), the mechanism was further inves-
tigated. To gain some insight for the pathway, attempts
to separate the intermediate were made. Treatment of
o-phenylenediamine (3a) with 1 equiv of diisopropylcar-
bodiimide (4a) at room temperature for 3 h, in the presence
of 10 mol % of 1, led to the isolation of the intermediate
7aa in 59% yield (Scheme 2). Two parallel reactions (7aa in
C6D6 vs 7aa with 10 mol % of 1 in C6D6) were carried out
1
at 140 °C, which were monitored by H NMR using
ferrocene as the internal standard. The experimental re-
sults showed that no obvious difference was observed and
both of them resulted in the formation of 5aa in more than
95% NMR yield in 30 h. This observation implies that the
catalyst might not be involved in the cyclization step.
Due tothe unique structureof1 (theTi atom isσ-bonded
to only one amido group and strongly supported by the
(16) For examples, see: (a) Kubiak, R.; Prochnow, I.; Doye, S. Angew.
Chem., Int. Ed. 2009, 48, 1153. (b) Lorber, C.; Choukroun, R.; Vendier, L.
Organometallics 2004, 23, 1845. (c) Straub, B. F.; Bergman, R. G. Angew.
Chem., Int. Ed. 2001, 40, 4632. (d) Bexrud, J. A.; Beard, J. D.; Leitch, D. C.;
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4564
Org. Lett., Vol. 13, No. 17, 2011

possible reaction mechanism is proposed in Scheme 3.
Amine exchange reaction between 1 and amine 3
affords C to enter the catalytic cycle.5d,10,12ꢀ14 An
intermolecular insertion of carbodiimide into TiꢀN
bond leads to the formation of D.10,13,14 Acidꢀbase
reaction of D with 3 regenerates C to complete the
catalytic cycle and releases amino-guanidine A.13,14
Intramolecular metathesis of A produces the cyclic
guanidine 5.18 If a triamine is used as the starting
material (X = NH), sequential intramolecular metath-
esis results in the production of bicyclic guanidine 6
from A via E or 5.18
Table 3. Synthesis of Cyclic Guanidines Catalyzed by 1
Scheme 3. Proposed Reaction Mechanism
In summary, we have developed a methodology for the
synthesis of mono/bicyclic guanidines in good to excellent
yields from di/triamines and carbodiimides, which is cat-
alyzed by a titanium monoamide. A chiral guanidine can
also be prepared with the retention of the ee value. The
possible reaction mechanism, involving the Ti-catalyzed
intermolecular hydroamination and intramolecular me-
tathesis, is proposed as well.
Acknowledgment. This work was supported by grants
from the Research Grants Council of the HKSAR (No.
404609), NSFC/RGC Joint Research Scheme (No.
N_CUHK470/10), and CAS-Croucher Funding Scheme
for Joint Laboratories.
a Ar = 4-tol. b Isolated yield. c ee = 99%. d rac = racemic.
trianionic ligand [σ:η1:η5-(OCH2)(Me2NCH2)C2B9H9]3ꢀ),
the involvement of any titanium-imido (TidN) species can
be ruled out.5d,10,12ꢀ14 Given these experimental results
and those of well-established reactions (Scheme 1), a
Supporting Information Available. Experimental pro-
cedures, spectroscopic data, and X-ray data in CIF for-
mat for 5ac and 5ec. This material is available free of
charge via the Internet at http://pubs.acs.org.
(18) The intramolecular metathesis reaction of an amino-guanidine
in the absence of a catalyst is supported by the parallel reactions of 7aa
(Scheme 2).
Org. Lett., Vol. 13, No. 17, 2011
4565