Titanium(IV)-mediated conversion of carboxamides to amidines and implications for catalytic transamidation

Article abstract of DOI:10.1021/om050768y

Cp*-ligated imidotitanium(IV) complexes, Cp*TiCl(NR)(py)Cl (R = tBu (5a), PhCH₂ (5b), n-C₅H₁₁ (5c), p-MeC ₆H₄ (5d), p-MeOC₆H₄ (5e)), react with tertiary and secondary carboxamides to yield amidines, a result that is in contrast with previously reported titanium-catalyzed transamidation reactions. The tertiary amide dimethylacetamide reacts directly with the imidotitanium(IV) fragment, whereas the secondary amide phenylacetamide forms an amidate adduct, {(η⁵-C₅Me₅)TiCl[OC(Me)NPh]₂} (10), which undergoes subsequent reaction with exogenous amine.

Full text of DOI:10.1021/om050768y

5208
Organometallics 2005, 24, 5208-5210
Communications
Titanium(IV)-Mediated Conversion of Carboxamides to
Amidines and Implications for Catalytic Transamidation
Denis A. Kissounko, Ilia A. Guzei, Samuel H. Gellman,* and Shannon S. Stahl*
Department of Chemistry, University of WisconsinsMadison, 1101 University Avenue,
Madison, Wisconsin 53706
Received September 5, 2005
Scheme 1. Possible Mechanism for
Summary: Cp*-ligated imidotitanium(IV) complexes,
Cp*TiCl(NR)(py)Cl (R ) tBu (5a), PhCH2 (5b), n-C5H11
(5c), p-MeC6H4 (5d), p-MeOC6H4 (5e)), react with ter-
tiary and secondary carboxamides to yield amidines, a
result that is in contrast with previously reported
titanium-catalyzed transamidation reactions. The ter-
tiary amide dimethylacetamide reacts directly with the
imidotitanium(IV) fragment, whereas the secondary
amide phenylacetamide forms an amidate adduct, {(η5-
C5Me5)TiCl[OC(Me)NPh]2} (10), which undergoes sub-
sequent reaction with exogenous amine.
Imidotitanium-Mediated Transamidation
explored.6 Here we report that both types of sub-
strates react with a well-defined imidotitanium(IV)
complex, Cp*Ti(NtBu)(py)Cl (5a), but neither yields
transamidation products. Instead, the substrates un-
dergo facile stepwise conversion to amidine products.
These observations raise important mechanistic ques-
tions regarding Ti-mediated transamidation and have
potential synthetic utility.
The carboxamide group is ubiquitous in chemistry
and biology, and the development of facile amide
exchange reactions will enable the selective manipula-
tion of these molecules.1 We recently reported a unique
transamidation reaction that employs metal-amido
complexes, such as Ti(NMe2)4, as catalysts (eq 1).2 To
The readily accessible imidotitanium complex 5a7 was
selected for study because Cp* serves as a robust and
spectroscopically diagnostic ancillary ligand.8 N,N-
Dimethylacetamide reacts with an equimolar amount
of 5a to displace pyridine and form adduct 6a in 74%
isolated yield (Scheme 2). Crystallographic character-
ization of 6a (Figure 1) reveals that the tertiary car-
boxamide ligand coordinates through the anti carbonyl
lone pair. This orientation is probably sterically pre-
ferred over coordination of the more basic syn lone pair.
Subsequent thermolysis of 6a at 50 °C in toluene results
in nearly quantitative conversion to the tert-butyl-
N,N-dimethylamidine 7a and the oxo-bridged titanium
trimer 8 (Scheme 2). The Cs-symmetric structure of 8
was confirmed by crystallographic analysis.
facilitate the development of improved catalysts for this
reaction, we have begun probing the fundamental
reactivity of amines and carboxamides with catalytically
relevant metal centers. Primary amines react with
Ti(NMe2)4 to form imido adducts,3 and an imido-
titanium-mediated pathway for transamidation can be
envisioned (Scheme 1). Group 4 metal-imido complexes
have received widespread attention in recent years
because of their diverse reactivity with organic sub-
strates and their role in catalysis;4,5 however, reactions
with secondary and tertiary carboxamides have not been
* To whom correspondence should be addressed. E-mail: gellman@
chem.wisc.edu (S.H.G.); stahl@chem.wisc.edu (S.S.S.).
(1) Equilibrium-controlled manipulation of other functional groups
is the subject of significant current interest: Rowan, S. J.; Cantrill, S.
J.; Cousins, G. R. L.; Sanders, J. K. M.; Stoddart, J. F. Angew. Chem.,
Int. Ed. 2002, 41, 898-952.
(5) For additional leading references, see: (a) Schaller, C. P.;
Cummins, C. C.; Wolczanski, P. T. J. Am. Chem. Soc. 1996, 118, 591-
611. (b) Cantrell, G. K.; Meyer, T. Y. J. Am. Chem. Soc. 1998, 120,
8035-8042. (c) Ong, T.-G.; Yap, G. P. A.; Richeson, D. S. J. Am. Chem.
Soc. 2003, 125, 8100-8101. (d) Ong, T.-G.; Yap, G. P. A.; Richeson, D.
S. Chem. Commun. 2003, 2612-2613. (e) Cao, C.; Shi, Y.; Odom, A. L.
J. Am. Chem. Soc. 2003, 125, 2880-2881. (f) Basuli, F.; Clark, R. L.;
Bailey, B. C.; Brown, D.; Huffman, J. C.; Mindiola, D. J. Chem.
Commun. 2005, 2250-2252.
(6) N-Acylimidozirconium intermediates have been proposed in Zr-
mediated conversion of primary carboxamides into nitriles: Ruck, R.
T.; Bergman, R. G. Angew. Chem., Int. Ed. 2004, 43, 5375-5377.
(7) Dunn, S. C. Mountford, P.; Robson, D. A. J. Chem. Soc., Dalton
Trans. 1997, 293-304.
(2) Eldred, S. E.; Stone, D. A.; Gellman, S. H.; Stahl, S. S. J. Am.
Chem. Soc. 2003, 125, 3422-3423.
(3) (a) Bradley, D. C.; Torrible, E. G. Can. J. Chem. 1963, 41, 134-
138. (b) Nugent, W. A.; Harlow, R. L. Inorg. Chem. 1979, 18, 2030-
2032. (c) Thorn, D. L.; Nugent, W. A.; Harlow, R. L. J. Am. Chem.
Soc. 1981, 103, 357-363.
(4) For recent reviews, see: (a) Wigley, D. E. Prog. Inorg. Chem.
1994, 42, 239-482. (b) Mountford, P. Chem. Commun. 1997, 2127-
2134. (c) Duncan, A. P.; Bergman, R. G. Chem. Rec. 2002, 2, 431-445.
(d) Pohlki, F.; Doye, S. Chem. Soc. Rev. 2003, 32, 104-114. (e) Odom,
A. L. Dalton Trans. 2005, 225-233. (f) Bolton, P. D.; Mountford, P.
Adv. Synth. Catal. 2005, 347, 355-366.
(8) Complex 5a does serve as a catalyst for transamidation between
benzylamine and N-phenylheptanamide under our previously reported
conditions,2 but it is less effective than Ti(NMe2)4 (∼6 vs 20 turnovers
after 20 h, respectively).
10.1021/om050768y CCC: $30.25 © 2005 American Chemical Society
Publication on Web 09/23/2005

Communications
Organometallics, Vol. 24, No. 22, 2005 5209
Scheme 2
Scheme 3
The ability of the tert-butyl imido fragment to undergo
exchange with primary amines enables the facile prepa-
ration of variously substituted amidines. Benzylamine
reacts with 5a at ambient temperature to form an imido-
bridged, dimeric titanium complex, 9b, which was char-
acterized by 1H and 13C NMR spectroscopy and elemen-
tal analysis. Exchange between 5a and p-MeC6H4NH2,
p-MeOC6H4NH2, or n-C5H11NH2 led to a mixture of
species in solution; hence, no attempts were made to
isolate the imidotitanium(IV) products. Removal of the
volatiles, including tert-butylamine, from these ex-
change reactions, followed by dissolution in toluene,
addition of N,N-dimethylacetamide, and thermolysis at
50 °C, led to nearly quantitative formation of the
corresponding amidines and the oxotitanium trimer
(Scheme 3).
Kinetic studies of the decomposition of 6a in toluene-
d8 at 50 °C, monitored by 1H NMR spectroscopy,
revealed clean exponential decay of [6a] with a first-
order rate constant of 4 × 10-4 s-1.9 The reaction rate
is unaffected by the presence of free amine (3-5 equiv
of tBuNH2), and no evidence for transamidation is
observed under the reaction conditions.
Scheme 4
the present results are noteworthy because of the
intrinsic differences in substrate reactivity. Aldehydes
and ketones can form imines by simple condensation
with primary amines under metal-free conditions,
whereas carboxamides are kinetically inert under such
conditions. Amidine synthesis from carboxamides gen-
erally requires preactivation with a highly reactive
electrophile, such as triflic anhydride.11,12
Acetanilide reacts differently from N,N-dimethyl-
acetamide. Two equivalents of the secondary amide
react with 5a by displacing pyridine and tBuNH2
to form the bis(κ2-amidate) 10, which was isolated in
62% yield and characterized by X-ray crystallography
(Scheme 4, Figure 2). This rare example of a well-
defined amidate-titanium complex13 exhibits a pseudo-
octahedral geometry with the Cp* ligand and an ami-
date nitrogen occupying apical positions. The two amidate
ligands are distinguished by their relative localization
of π-electron density (Figure 2): the diequatorial ami-
date exhibits greater double-bond character for the C-O
bond, whereas the equatorial/apical amidate exhibits a
shorter C-N bond. Formation of the 2:1 adduct 10
appears to be highly favored over the 1:1 adduct. When
only 1 equiv of acetanilide is added to a solution of 5a,
unreacted 5a and 10 are the only products observed.
κ2-Amidate adducts are reasonable intermediates in
Ti(IV)-catalyzed transamidation reactions between aryl-
These data are consistent with a mechanism involving
intramolecular [2 + 2] cycloaddition of the coordinated-
carbonyl and TidN fragments. Retro [2 + 2] from the
four-membered metallacyclic intermediate (cf. 2; Scheme
1) yields amidine and the oxotitanium product. Group
4 metal-imido complexes undergo similar reactivity
with aldehydes and ketones to yield imines;10 however,
(9) See the Supporting Information for details.
(10) (a) Walsh, P. J.; Hollander, F. J.; Bergman, R. G. Organo-
metallics 1993, 12, 3705-3723. (b) Lee, S. Y.; Bergman, R. G. J. Am.
Chem. Soc. 1996, 118, 6396-6406.
(11) For leading references, see: (a) Sforza, S.; Dossena, A.; Corra-
dini, R.; Virgili, E.; Marchelli, R. Tetrahedron Lett. 1998, 711-714.
(b) Charette, A.; Grenon, M. Tetrahedron Lett. 2000, 1677-1680. (c)
Katritzky, A. R.; Huang, T.-B.; Voronkov, M. V. J. Org. Chem. 2001,
66, 1043-1045.
(12) Ti complexes have been used to promote amidine synthesis from
amides in mechanistically undefined reactions: (a) Fryer, R. I.; Earley,
J. V.; Field, G. F.; Zally, W.; Sternbach, L. H. J. Org. Chem. 1969, 34,
1143-1145. (b) Wilson, J. D.; Wager, J. S.; Weingarten, H. J. Org.
Chem. 1971, 36, 1613-1615.
(13) (a) Geisbrecht, G. R.; Shafir, A.; Arnold, J. Inorg. Chem. 2001,
40, 6069-6072. (b) Li, C.; Thomson, R. K.; Gillon, B.; Patrick, B. O.;
Schafer, L. L. Chem. Commun. 2003, 2462-2463. (c) Zhang, Z.;
Schafer, L. L. Org. Lett. 2003, 5, 4733-47.
Figure 1. Molecular structure (50% thermal ellipsoids)
of 6a in the major conformation. Hydrogen atoms have been
removed for the sake of clarity. Important bond distances
(Å) and angles (deg): Ti-N(1) ) 1.7056(16), Ti-O(1) )
2.004(7), Ti-Cl ) 2.3697(6), N(1)-C(11) ) 1.452(2), O(1)-
C(15) ) 1.268(4), N(2)-C(15) ) 1.310(3); N(1)-Ti-O(1) )
102.2(7), N(1)-Ti-Cl ) 103.76(6), O(1)-Ti-Cl ) 98.8(2).

5210 Organometallics, Vol. 24, No. 22, 2005
Communications
restricts our ability to establish the mechanism. Direct
attack of the amine on a coordinated amidate seems
unlikely on the basis of electrostatic considerations. No
reaction occurs between amine and a neutral carbox-
amide under these conditions, and attack by amine on
a formally anionic amidate fragment seems even less
likely. Two alternatives seem more probable. Reversible
reaction of amine with 10 could form an unobserved,
but reactive, imidotitanium complex, which yields ami-
dine via the [2 + 2] mechanism proposed for tertiary
amides. Alternatively, an amidotitanium fragment could
undergo nucleophilic attack on a coordinated carbox-
amide or amidate-ligated intermediate. These reaction
pathways are the subject of ongoing studies.
This study highlights the ability of Ti(IV) to activate
kinetically robust carboxamides to form amidines. A ter-
tiary amide reacts directly with an imidotitanium(IV)
fragment, whereas a secondary amide forms an amidate
adduct that undergoes subsequent reaction with exog-
enous amine. In light of these observations, the success
of Ti(IV)-catalyzed transamidation (eq 1) is rather
surprising. In ongoing studies, we are investigating the
origin of divergence between amidine formation and
transamidation in Ti-promoted reactions between amines
and carboxamides.
Figure 2. Molecular structure (50% thermal ellipsoids)
of 10 and a line drawing reflecting the preferred resonance
structures for the coordinated κ2-amidates. Hydrogen atoms
have been removed for the sake of clarity. Important bond
distances (Å) and angles (deg): Ti-O(1) ) 2.0232(11), Ti-
O(2) ) 2.1193(11), Ti-N(1) ) 2.2406(14), Ti-N(2) )
2.1541(13), O(1)-C(11) ) 1.317(2), O(2)-C(19) ) 1.2875(19),
N(1)-C(11) ) 1.286(2), N(2)-C(19) ) 1.310(2); O(2)-Ti-
N(2) ) 61.07(5), O(1)-Ti-N(1) ) 61.05(5).
amides and arylamines (eq 1). However, when 10 is
heated with 1 equiv of a para-substituted aniline in
toluene, the secondary amidines 11a and 11b are
formed (72% and 79% yields, respectively). No trans-
amidation products are observed. The process is ac-
companied by the formation of small quantities of
N-phenylacetanilide (<10%) and unidentified organo-
metallic species believed to be aggregated oxotitanium
fragments. The addition of 2 equiv of aniline instead of
1 equiv had no significant impact on the yield of
amidines 11a and 11b. The conversion of 10 into 11b
was monitored by 1H NMR spectroscopy under pseudo-
first-order conditions (10 equiv of p-MeOC6H4NH2). The
formation of 11b proceeds cleanly with a pseudo-first-
order rate constant, kobs, of 1.5 × 10-4 s-1 at 80 °C.9
The lack of an observable intermediate in this process
Acknowledgment. We are grateful to the NSF
Collaborative Research in Chemistry program (Grant
No. CHE-0404704) for financial support of this work.
Supporting Information Available: Text, figures, and
tables providing details of the synthesis and characterization
of compounds 5-11, including crystallographic analysis of 6a,
8, and 10 and kinetic data for the decomposition of 6a and
10; crystallographic data are also given as CIF files. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OM050768Y