Catalytic construction and reconstruction of guanidines: Ti-mediated guanylation of amines and transamination of guanidines

Article abstract of DOI:10.1021/ja035716j

Bis(guanidinate) titanium imido complexes [{(Me₂N)C(NⁱPr)₂}₂TiNAr-] (Ar- = 2,6-Me₂C₆H₃ (1a); C₆F₅ (1b)) are competent catalysts for the guanylation of a variety of arylamines with carbodiimide. The reversible [2 + 2] addition of ⁱPrN=C=NⁱPr to 1b is demonstrated and is proposed to be part of the catalytic cycle. Compounds 1a and 1b are also effective precatalysts for the transamination of trialkylguanidines with arylamines to yield aryldialkylguanidines. Copyright

Full text of DOI:10.1021/ja035716j

Published on Web 06/12/2003
Catalytic Construction and Reconstruction of Guanidines: Ti-Mediated
Guanylation of Amines and Transamination of Guanidines
Tiow-Gan Ong, Glenn P. A. Yap, and Darrin S. Richeson*
Department of Chemistry and the Center for Catalysis Research and InnoVation, UniVersity of Ottawa,
Ottawa, Ontario, Canada K1N 6N5
Received April 19, 2003; E-mail: darrin@science.uottawa.ca
Table 1. Guanylation of Aromatic Amines According to Eq 2
The catalytic formation and transformation of C-N bonds by
group 4 complexes is an active research area.1-3 We are interested
in contributing to this field by developing new catalysts, reactions,
and targets. We recently reported that imido complex [{(Me2N)C-
(NiPr)2}2TidN(2,6-Me2C6H3)] (1a) is a catalyst for alkyne hy-
droamination and have determined that the imido group of 1a can
undergo a clean exchange with other aromatic amines to afford
new imine complexes (e.g. {(Me2N)C(NiPr)2}2TidNC6F5 (1b)).1o,4
These observations provided an impetus for exploring the ability
of 1a and related compounds to function as competent catalyst
precursors for other C-N bond transformations.
Substituted guanidines are CN rich targets that represent an
essential functionality in many biologically relevant compounds.5
Typical synthetic routes to guanidines employ the reaction of an
amine with an electrophilic guanylating reagent.6 A variety of such
agents have been developed which rely on displacement of a leaving
group, Y, from a protected carbodiimide-equivalent, A, and often
require that the nitrogen substituents be carbamate-protecting groups
which activate the reagent to reaction with amine and allow for
direct synthesis of protected guanidines. These restrictions fre-
quently limit the products to mono- or N,N-disubstituted guanidines.
Consequently, new efficient and catalytic methods for assembling
the guanidines from a diverse set of amines would be valuable.
We report the first examples of transition metal-catalyzed guany-
lation of amines with carbodiimide using complexes 1a and 1b as
precatalysts (eq 2). Significantly, these species are also capable of
catalyzing the first examples of guanidine transamination (eq 3).
entry
RNCNR
Ar′NH
product
yield (%)a
2
1
2
3
4
5
6
7
8
R1 ) R2 ) iPr
R1 ) R2 ) iPr
R1 ) R2 ) iPr
R1 ) R2 ) iPr
R1 ) R2 ) iPr
R1 ) R2 ) iPr
R1 ) R2 ) iPr
R1 ) iPr; R2 )Cy
2,6-Me2C6H3NH2
C6F5NH2
p-MeOC6H4NH2
o-MeOC6H4NH2
p-ClC6H4NH2
p-NCCH2C6H4NH2
p-C6H4(NH2)2
2,6-Me2C6H3NH2
3
5
6
7
8
9
81.5c
92.3c
82.8c
87.2b
96.6b
47.6b
97.2b
92
10d
11
a All reactions were carried to 100% conversion. b Yields determined
by integration of 1H NMR relative to internal standard of either 1,3-
(MeO)2C6H4 or O(SiMe3)2. c Isolated yields. d Product is the biguanidine,
(iPrNH)2CdN-(C6H4)-NdC(iPrNH)2.
Scheme 1
isolated by simple crystallization in good to excellent yield.8
Complex 1b is also an effective precatalyst for this transformation
and exhibited similar conversion rates to 1a.
Complex 1b reacted readily and reversibly with diisopropylcar-
bodiimide at room temperature to afford the diazametallacycle
complex 2. The molecular structure for complex 2 was confirmed
by X-ray crystallographic analysis (Scheme 1). The coordination
sphere of this pseudo-octahedral Ti (IV) species consists of two
bidentate monoanionic guanidinate ligands, that originated from
the starting material, and one bidentate dianionic guanidinate ligand
i
derived from a [2 + 2] addition reaction of PrNdCdNiPr with
the Ti arylimido group of 1b. The bond distances and angles within
the dianionic ligand are consistent with the valence bond picture
shown for 2 and similar to Cp2Zr((tBu)NCdN(SiMe3)N(SiMe3)).2a
For example, the exocyclic C(13)-N(3) distance of 1.268(5) Å
suggests a CdN and the two remaining C-N distances (C(13)-
N(1) ) 1.412(4) Å, C(13)-N(2) ) 1.416(4) Å) are consistent with
single bonds between two sp2 centers.
When 1 equiv of 2,6-dimethylaniline is added to an NMR sample
of 2, compounds 1a and 5 were formed. These observations lead
us to propose a catalytic cycle for the guanidine formation using
1a/1b that is shown in Scheme 1. The cycle begins with [2 + 2]
addition of a carbodiimide to the TidN moiety.1e,2a, A proton-
transfer reaction between aromatic amine and metal-bound dianionic
guanidinate ligand releases guanidine and reforms the Ti imido
Aliphatic amines will undergo direct guanylation with carbodi-
imides to yield N,N′,N′′-triakylguanidines albeit under rather forcing
conditions (e.g. 120-140 °C, 3d).7 However, less nucleophilic
aromatic amines do not react with diisopropylcarbodiimide to any
detectable degree even with prolonged heating at 140 °C. The
addition of 1-5mol % of catalyst precursor 1a led to efficient
guanylation of 2,6-dimethylaniline with diisopropylcarbodiimide
to yield guanidine 3 (eq 2). This result is generalized to other
substituted anilines as summarized in Table 1. The progress of these
1
reactions was monitored by H NMR spectroscopy and GC-MS
and in all cases was quantitative in less than 18 h. For example,
the guanylation of two isomers of MeOC6H4NH2 (entries 4 and 5)
was complete in less than 8 h. The resulting guanidines could be
9
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J. AM. CHEM. SOC. 2003, 125, 8100-8101
10.1021/ja035716j CCC: $25.00 © 2003 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Transamination of Trialkylguanidine with Aromatic
Amines According to Eq 3
Further elucidating the mechanism of these reactions, expanding
the range of substrates, and developing new catalyst precursors are
the focus of our ongoing work. We anticipate that this effort will
lead to new catalysts with improved activity and application.
conversion
(%)
yield
(%)a
time
(h)
entry
Ar′NH
product
2
1
2
3
4
5
6
2,6-Me2C6H3NH2
C6H5NH2
C6F5NH2
p-MeOC6H4NH2
o-MeOC6H4NH2
p-ClC6H4NH2
3
4
5
6
7
8
100
100
100
100
54
100
100
18
18
18
36
66
18
Acknowledgment. This work was supported by NSERC.
100 (70.0)b
Supporting Information Available: Experimental procedures and
characterization of new compounds, structural data for complexes 1b,
2, and 7 (PDF). X-ray crystallographic files (CIF). This material is
available free of charge via the Internet at http://pubs.acs.org.
93
35b
100
100
a Yields determined by integration of 1H NMR relative to internal
standard of either 1,3-(MeO)2C6H4 or O(SiMe3)2. b Isolated yield.
References
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precatalyst for the guanylations summarized in Table 1. Careful
examination of the reaction products from these guanylation
reactions by GC-MS did show the formation of 1-5% of [RN-
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as it enters the cycle in Scheme 1.
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(2,6-Me2C6H3) (11)1o displayed no catalytic activity. The Ti-imido
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1
summarized in Table 2. Reactions were monitored by H NMR
spectroscopy, which further confirmed that no reaction occurred
between the trialkylguanidine and arylamine under these conditions
in the absence of precatalyst. In most cases full conversion of the
starting material was achieved in less than 18 h and led selectively
to the formation of monoarylguanidines even with longer reaction
times.
A comparison of reactions 2 and 3 for the formation of 6 and 7
shows that while both employ similar conditions and form the same
product there is a clear difference in the rates for these processes.
As noted, the guanylation of o- and p-H2NC6H3(OMe) proceeds to
full conversion in less than 8 h. In contrast the conversion to 6
(93% isolated yield) according to eq 3 takes approximately 36 h.
Furthermore, the transamination of the ortho isomer proceeded to
only 54% conversion in 66 h. The lower rate for guanidine
formation via the transamination route compared to that for the
amine guanylation pathway is consistent with relative stability of
aryldialkylguanidine > trialkylguanidine > arylamine/carbodiimide.
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