A R T I C L E S
Han et al.
benzylamine (δ CH2 ) 4.23 and 4.34) was diagnostic of the
formation of a zirconium benzylamido species,19b,23 no definitive
conclusion was made at this stage.
Interestingly, in contrast to our original hypothesis (vide
supra), formation of an activated 1-oxy-7-azabenzotriazolate
(OAt) ester was not observed after addition of methyl 3-phenyl-
propionate (1.0 equiv) to a 1:1 Zr(Ot-Bu)4-HOAt mixture in
benzene-d6.17 Thus, our initial results indicated that the additive
HOAt facilitates formation of zirconium amido or amine
complexes (vide infra). Preliminary NMR experiments using
HOBt and 2-hydroxypyridine (HYP) as additives were also
performed in a similar manner. Comparable results were
obtained for HOBt; however, neither a significant downfield
shift of the methylene protons of benzylamine nor an active
2-pyridyl ester was observed using HYP as additive. Future
experiments will address detailed mechanistic issues employing
HYP as additive.
Figure 2. Substrate limitations.
To further understand the catalytic system for ester-amide
1
exchange, we performed H NMR experiments in benzene-d6
to monitor the reaction of methyl 3-phenylpropionate and
benzylamine using 10 mol % Zr(Ot-Bu)4-HOAt.17 During the
reaction, signals corresponding to tert-butyl alcohol (δ CH3 )
1.08) appeared, and those corresponding to zirconium tert-
butoxide disappeared. Similar results were also obtained by
deliberate addition of MeOH into a mixture of Zr(Ot-Bu)4,
HOAt, and benzylamine. The above results indicate that ligand
exchange occurs between the byproduct methanol and the tert-
butoxide ligand of the zirconium species during the reaction
reinforcing the dynamic nature of the ester-amide exchange
process.
(b) X-ray Crystallography. During our NMR studies
employing R,R-dideuteriobenzylamine (cf. Figure 3b), we
serendipitously observed formation of crystals in NMR samples
which were subsequently evaluated by single-crystal X-ray
structure analysis. The molecular structure of 8 obtained by
X-ray diffraction of the crystal obtained from a 1:1:1 mixture
of Zr(Ot-Bu)4, HOAt and R,R-dideuteriobenzylamine is shown
in Figure 4. The molecular structure shows a centrosymmetric
dimer with two Zr(Ot-Bu)3(NH2CD2Ph) units bridged by two
oxygen atoms of the OAt ligands. The Zr-N bond distance
(2.41 Å) is also consistent with a Zr-NH2R species24 rather
than a zirconium amido.23 More importantly, a crystal of the
dimeric zirconium complex 8 was found to be catalytically
active in the ester-amide exchange reactions. There is ample
literature precedent for X-ray crystal structures of zirconium
dimer complexes.25
Figure 3. 1H NMR studies in benzene-d6. (a) Zr(Ot-Bu)4 + HOAt +
PhCH2NH2 (1:1:1). (b) Zr(Ot-Bu)4 + HOAt + PhCD2NH2 (1:1:1). (c) Zr-
(Ot-Bu)4 + HOAt + PhCH2ND2 (1:1:1). (d) Zr(Ot-Bu)4 + HOAt +
n-hexylamine (1:1:1).
control due to its poor solubility in benzene-d6. However, when
1.0 equiv of Zr(Ot-Bu)4 was added to HOAt, peaks correspond-
ing to the aromatic protons of HOAt appeared, indicating the
formation of a soluble zirconium oxy-7-azabenzotriazolate (OAt)
species via ligand exchange. Time-dependent experiments using
Zr(Ot-Bu)4-HOAt (1:1) revealed that the two sets of aromatic
protons of HOAt reached equilibrium after approximately 5 h
at room temperature with one dominant set observed shortly
after mixing. Moreover, addition of 1.0 equiv of Zr(Ot-Bu)4 to
benzylamine led to a downfield shift for the methylene protons
of benzylamine from δ 3.48 to 3.83 which may be caused by
coordination of benzylamine to the zirconium metal center.
Further addition of HOAt (1.0 equiv) to the Zr(Ot-Bu)4-
benzylamine (1:1) mixture resulted in formation of a series of
downfield-shifted peaks (δ 4.23-5.14) (Figure 3a). Further
experiments using R,R-dideuteriobenzylamine21 and N,N-di-
deuteriobenzylamine22 facilitated assignment of the N-H (δ
5.14, 5.05, 4.53, 4.44) (Figure 3b) and methylene protons (δ
4.34, 4.23) (Figure 3c). Use of n-hexylamine (Figure 3d)
simplified the aromatic region in the 1H NMR spectrum
indicating an apparent single 7-aza-1-oxybenzotriazolate species.
Although a downfield shift of the methylene protons of
(c) Further NMR Studies. The X-ray crystal structure of 8
1
provides important insight into the H NMR spectrum of the
(23) For spectral characterization of zirconium benzylamido complexes, see:
(a) Fro¨mberg, W.; Erker, G. J. Organomet. Chem. 1985, 280, 355. (b)
Gibson, V. C.; Long, N. J.; Marshall, E. L.; Oxford, P. J.; White, A. J. P.;
Williams, D. J. J. Chem. Soc., Dalton Trans. 2001, 1162. (c) Cortright, S.
B.; Huffman, J. C.; Yoder, R. A.; Coalter, J. N., III; Johnston, J. N.
Organometallics 2004, 23, 2238.
(24) (a) Rogel, F.; Corbett, J. D. J. Am. Chem. Soc. 1990, 112, 8198. (b) Ciruelos,
S.; Cuenca, T.; Go´mez, R.; Go´mez-Sal, P.; Manzanero, A.; Royo, P.
Organometallics 1996, 15, 5577. (c) Chen, L.; Cotton, F. A. J. Cluster
Sci. 1998, 9, 63. (d) Ho¨ltke, C.; Erker, G.; Kehr, G.; Fro¨hlich, R.; Kataeva,
O. Eur. J. Inorg. Chem. 2002, 2789.
(25) (a) Mu, Y.; Piers, W. E.; Macgillivray, L. R.; Zaworotko, M. J. Polyhedron
1995, 14, 1. (b) Evans, W. J.; Ansari, M. A.; Ziller, J. W. Inorg. Chem.
1999, 38, 1160. (c) Fleeting, K. A.; O’Brien, P.; Otway, D. J.; White, A.
J. P.; Williams, D. J.; Jones, A. C. Inorg. Chem. 1999, 38, 1432. (d) Patil,
U.; Winter, M.; Becker, H.-W.; Devi, A. J. Mater. Chem. 2003, 13, 2177.
(e) Utko, J.; Przybylak, S.; Jerzykiewicz, L. B.; Szafert, S.; Sobota, P. Chem.
Eur. J. 2003, 9, 181.
(19) For selected references concerning zirconium-mediated epoxide opening,
see: (a) Chakraborti, A. K.; Kondaskar, A. Tetrahedron Lett. 2003, 44,
8315. (b) Blum, S. A.; Walsh, P. J.; Bergman, R. G. J. Am. Chem. Soc.
2003, 125, 14276. (c) Swamy, R. N.; Goud, V. T.; Reddy, M. S.; Krishnaiah,
P.; Venkateswarlu, Y. Synth. Commun. 2004, 34, 727.
(20) (a) Maguire, A. R.; Plunkett, S. J.; Papot, S.; Clynes, M.; O’Connor, R.;
Touhey, S. Bioorg. Med. Chem. 2001, 9, 745. (b) Yu, Z.; Alesso, S.; Pears,
D.; Worthington, P. A.; Luke, R. W. A.; Bradley, M. J. Chem. Soc., Perkin
Trans. 1 2001, 1947. (c) Agami, C.; Dechoux, L.; Hebbe, S. Synlett 2001,
1440.
(21) Sleath, P. R.; Noar, J. B.; Eberlein, G. A.; Bruice, T. C. J. Am. Chem. Soc.
1985, 107, 3328.
(22) Prepared by hydrogen-deuterium exchange of benzylamine with CD3OD.
9
10042 J. AM. CHEM. SOC. VOL. 127, NO. 28, 2005