Catalytic transamidation reactions compatible with tertiary amide metathesis under ambient conditions

Article abstract of DOI:10.1021/ja8094262

The carbon-nitrogen bond of carboxamides is extremely stable under most conditions. The present study reveals that simple zirconium- and hafnium-amido complexes are highly efficient catalysts for equilibrium-controlled transamidation reactions between sec

Full text of DOI:10.1021/ja8094262

Published on Web 07/06/2009
Catalytic Transamidation Reactions Compatible with Tertiary
Amide Metathesis under Ambient Conditions
Nickeisha A. Stephenson, Jiang Zhu, Samuel H. Gellman,* and Shannon S. Stahl*
Department of Chemistry, UniVersity of WisconsinsMadison, 1101 UniVersity AVenue,
Madison, Wisconsin 53706
Received December 3, 2008; E-mail: gellman@chem.wisc.edu; stahl@chem.wisc.edu
Abstract: The carbon-nitrogen bond of carboxamides is extremely stable under most conditions. The
present study reveals that simple zirconium- and hafnium-amido complexes are highly efficient catalysts
for equilibrium-controlled transamidation reactions between secondary amines and tertiary amides. In a
number of cases, transamidation proceeds rapidly at room temperature. We find that these new catalysts
are sufficiently active to promote the metathesis of tertiary amides, which arises from successive
transamidation cycles. The catalytic activities we observe are unprecedented and represent a substantial
step toward a long-range goal of conducting equilibrium-controlled reactions with carboxamides.
exchange reactivity.5-8 The findings presented below represent
an important step toward the long-range goal of implementing
Introduction
Thermodynamically controlled chemical reactions can provide
expeditious access to molecules that would be cumbersome to
prepare by traditional, kinetically controlled bond-forming
processes.1 Most applications of the thermodynamic approach,
or “dynamic covalent chemistry” (DCC), involve intrinsically
facile reactions, such as thiol-disulfide, alcohol-ester, amine-
imine, or thiol-thioester exchange.1 This work has provided
valuable insights into the capabilities of DCC, but the labile
bonds present in these molecules limit the ultimate uses of the
reaction products. The field of DCC would benefit from the
development of new exchange reactions involving intrinsically
robust bonds. In this regard, amine-carboxamide exchange
reactions, transamidation (eqs 1 and 2) and amide metathesis
(eq 3), represent highly appealing processes. However, the
carboxamide group is notoriously stable under most conditions,
and the development of catalysts that can promote carboxamide
exchange reactions therefore represents a profound challenge
in terms of reactivity. Known methods for amide exchange
typically require very harsh conditions (>250 °C), long reaction
times, or stoichiometric reagents that limit their potential
application to DCC.2-4
carboxamide-based DCC processes.
In previous work we showed that Al2(NMe2)6 is an effective
(pre)catalyst for transamidation reactions between primary
amines and secondary amides.5 These reactions face critical
limitations, however: (1) they require elevated temperature to
(3) For enzymatic approaches to secondary-amide exchange reactions, see:
(a) Gotor, V.; Brieva, R.; González, C.; Rebolledo, F. Tetrahedron
1991, 47, 9207–9214. (b) Swann, P. G.; Casanova, R. A.; Desai, A.;
Frauenhoff, M. M.; Urbancic, M.; Slomczynska, U.; Hopfinger, A. J.;
LeBreton, G. C.; Venton, D. L. Biopolymers 1996, 40, 617–625. (c)
Sergeeva, M. V.; Mozhaev, V. V.; Rich, J. O.; Khmelnitsky, Y. L.
Biotechnol. Lett. 2000, 22, 1419–1422.
Reported here is a significant advance in the catalysis of
transamidation and amide metathesis reactions involving sec-
ondary amines and tertiary amides. These results have emerged
from our ongoing fundamental exploration of carboxamide
(4) Precedents for transamidation under synthetically practical conditions
are typically limited to intramolecular reactions or require a stoichio-
metric reagent: (a) Galat, A.; Elion, G. J. Am. Chem. Soc. 1943, 65,
1566–1567. (b) Martin, R. B.; Parcell, A.; Hedrick, R. I. J. Am. Chem.
Soc. 1964, 86, 2406–2413. (c) Crombie, L.; Jones, R. C. F.; Haigh,
D. Tetrahedron Lett. 1986, 27, 5151–5154. (d) Zaragoza-Do¨rwald,
F.; von Kiedrowski, G. Synthesis 1988, 11, 917–918. (e) Gotor, V.;
Brieva, R.; Gonzalez, C.; Rebolledo, F Tetrahedron 1991, 47, 9207–
9214. (f) Bon, E.; Bigg, D. C. H.; Bertrand, G. J. Org. Chem. 1994,
59, 4035–4036. (g) Suggs, J. W.; Pires, R. M. Tetrahedron Lett. 1997,
38, 2227–2230. (h) Langlois, N. Tetrahedron Lett. 2002, 43, 9531–
9533. (i) Lasri, J.; Gonza´lez-Rosende, M. E.; Sepu´lveda-Arques, J.
Org. Lett. 2003, 5, 3851–3853. (j) Klapars, A.; Parris, S.; Anderson,
K. W.; Buchwald, S. L. J. Am. Chem. Soc. 2004, 126, 3529–3533.
(k) Alajar´ın, M.; Vidal, A.; Tovar, F. Tetrahedron 2005, 61, 1531–
1537, P. (l) Çalimsiz, S.; Lipton, M. A. J. Org. Chem. 2005, 70, 6218–
6221. (m) Dineen, T. A.; Zajac, M. A.; Myers, A. G. J. Am. Chem.
Soc. 2006, 128, 16406–16409.
(1) For recent reviews of dynamic covalent chemistry: (a) Lehn, J.-M.
Chem. Eur. J. 1999, 5, 2455–2463. (b) 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. (c) Ramström, O.; Lehn, J.-M. Nat. ReV.
Drug DiscoVery 2002, 1, 26–36. (d) Corbett, P. T.; Leclaire, J.; Vial,
L.; West, R. K.; Wietor, J.-L.; Sanders, J. K. M.; Otto, S. Chem. ReV.
2006, 106, 3652–3711.
(2) Transamidation at very high temperatures (>250 °C), typically with
polyamides, has been reported: (a) Smith, M. E.; Adkins, H. J. Am.
Chem. Soc. 1938, 60, 657–663. (b) Beste, L. F.; Houtz, R. C. J. Polym.
Sci. 1952, 8, 395–407. (c) Ogata, N. Makromol. Chem. 1959, 30, 212–
224. (d) Miller, I. K. J. Polym. Sci., Part A: Polym. Chem. 1976, 14,
1403–1417. (e) McKinney, R. J. U.S. Patent 5,302,756, 1994. (f)
McKinney, R. J. U.S. Patent 5,395,974, 1995.
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Stephenson et al.
reach equilibrium (90 °C), and (2) the catalyst is insufficiently
active to achieve amide metathesis via successive transamidation
steps. Mechanistic studies revealed that a transamidation-based
approach to secondary amide metathesis is intrinsically con-
strained by the catalytic mechanism.6 Secondary carboxamides
react rapidly with amidoaluminum species such as Al2(NMe2)6
to form tris(κ2-amidate)AlIII species (eq 4), which constitute the
catalyst resting state under the reaction conditions. This reactiv-
ity is problematic with regard to catalysis of transamidation,
because the metal-bound κ2-amidate is a poorer electrophile than
is a neutral metal-coordinated carboxamide, and a non-
coordinated amine is a poorer nucleophile than is a metal-bound
amido group. The rate law for primary amine-secondary amide
transamidation catalyzed by a tris(κ2-amidate)AlIII complex
exhibits a first-order dependence on both [Al] and [amine]. This
situation is not favorable for efficient promotion of secondary
amide metathesis via multiple transamidation steps, since such
a process should ideally require only a low concentration of
the metal-based catalyst and little or no added amine.
Figure 1. Representative catalyst screen. Standard conditions: equimolar
amide and amine (0.33 mmol) with 5% catalyst (0.017 mmol) and
triphenylmethane (0.875 M) (gas chromatography (GC) internal standard)
in 2 mL of toluene. Reactions were carried out for 16 h at 90 °C. Amide
ratios were determined by GC.
Table 1. Evaluation of Transamidation Catalysts at 50 °Ca
The insights obtained from the study of secondary amide
exchange reactions provided the basis for our subsequent
investigation of exchange reactions between secondary amine-
tertiary amide substrate pairs.8 We reasoned that tertiary amides,
which lack an acidic N-H group, would not form the kinetically
problematic κ2-amidate-Al species. This hypothesis proved to
be correct, and Al2(NMe2)6 was shown to be an effective
(pre)catalyst for transamidation reactions between secondary
amines and tertiary amides. Mechanistic studies revealed that
the resting state of the catalyst in these reactions consists of an
Al(NR2)3 species, and the catalytic rate law exhibits a zero-
order dependence on [amine]. The latter observation suggested
that a transamidation-based approach for the metathesis of
tertiary amides might be possible; however, efforts to achieve
this goal with Al-based catalysts were unsuccessful. Elevated
temperatures (90 °C) were required to promote transamidation,
and the Al catalyst did not exhibit sufficient activity and/or
stability to achieve the multiple rounds of transamidation
necessary to accomplish metathesis of tertiary amide substrate
pairs (eqs 1-3).
a See Figure 1 for standard reaction conditions.
transamidation reaction between the tertiary amide 1 and
benzylmethylamine (Figure 1). Under relatively vigorous condi-
tions (16 h; 90 °C; 5 mol % catalyst, calculated on a metal
atom basis), several metal-amido complexes in addition to the
originally reported catalyst, Al2(NMe2)6,8 were able to achieve
complete amine-amide equilibration, as indicated by their
reaching the same ratio of amides 1 and 2 starting from either
amine/amide pair. Successful new catalysts included Li-
N(SiMe3)2, LiNMe2, Sc[N(SiMe3)2]3, Sm[N(SiMe3)2]3, Zr(NMe2)4,
and Hf(NMe2)4.
More active amide exchange catalysts are clearly needed in
order to achieve the long-term goal of carboxamide-based DCC.
The present study reveals new, highly active catalysts for
secondary amine-tertiary amide exchange reactions. With some
simple substrates, the new catalysts promote tertiary amide
metathesis at room temperature.
Results and Discussion
In order to identify the most active among these catalysts,
we re-examined the reaction at 50 °C and determined the time
required to reach equilibrium (Table 1). These results clearly
revealed Zr(NMe2)4 and Hf(NMe2)4 to be the most effective
catalysts; both achieved equilibrium in less than 1 h, whereas
Sm[N(SiMe3)2]3 required 5 h and Sc[N(SiMe3)2]3 10 h. Neither
LiN(SiMe3)2 nor Al2(NMe2)6 achieved equilibrium after 20 h.
Further investigation revealed that Zr(NMe2)4-catalyzed tran-
samidation of 1 and benzylmethylamine reached equilibrium
within 10 h at room temperature. Zr(NMe2)4 and Hf(NMe2)4
displayed indistinguishable reactivity, and subsequent efforts
focused on the former.
Transamidation. A variety of Lewis acids and metal-amido
complexes were screened for their ability to catalyze the
(5) Eldred, S. E.; Stone, D. A.; Gellman, S. H.; Stahl, S. S. J. Am. Chem.
Soc. 2003, 125, 3422–3423.
(6) Hoerter, J. M.; Otte, K. M.; Gellman, S. H.; Stahl, S. S. J. Am. Chem.
Soc. 2006, 128, 5177–5183.
(7) Secondary amide metathesis can achieved by imide-catalyzed transa-
cylation (i.e., without the involvment of amine-amide exchange steps),
but this process requires high temperatures: Bell, C. M.; Kissounko,
D. A.; Gellman, S. H.; Stahl, S. S. Angew. Chem., Int. Ed. 2007, 46,
761–763.
(8) Hoerter, J. M.; Otte, K. M.; Gellman, S. H.; Cui, Q.; Stahl, S. S. J. Am.
Chem. Soc. 2008, 130, 647–654.
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Catalytic Transamidation Reactions under Ambient Conditions
A R T I C L E S
Table 4. Acyl Group Variation in Transamidation Reactionsa
Table 2. Evaluation of Solvents in Transamidation Reactionsa
a See Figure 1 for standard reaction conditions.
Table 3. Amine Variation in Transamidation Reactionsa,b
a See Figure 1 for standard reaction conditions.
at 90 °C (entry 8). Chelation of the Zr atom by the ether oxygen
atoms in this solvent probably hinders coordination of the
substrates, thereby inhibiting the transamidation. No reaction
is observed in DMSO or acetonitrile (entries 9 and 10), solvents
that are coordinating and have relatively acidic C-H bonds.
Both of these properties could lead to catalyst inhibition or
deactivation. Protic solvents such as methanol react rapidly with
Zr-amido ligands to form Zr-alkoxides9 and, therefore, are
incompatible with the reactions.
Analysis of a variety of substrate pairs under a standard set
of conditions illuminated the scope and limitations of the
transamidation reactions (Tables 3 and 4). A number of reactions
were successful under ambient conditions (Table 3, entries 1-5),
while others required heating to 50 °C (entries 6 and 7).
Comparison of entries 3 and 6 suggests that heptanamides are
more reactive toward transamidation than are toluamides; with
diallyl amine, the toluamide substrate required 50 °C to achieve
full equilibration within 10 h, while the heptanamide version
of this reaction reached equilibrium at room temperature during
the same time period. Entry 7 is the only example expected to
display a substantial intrinsic thermodynamic bias, favoring the
aniline-amide pair over the amine-anilide pair, and only the
aniline-amide products are observed from the equilibration
a See Figure 1 for standard reaction conditions. b In addition to amide
products I and II, small quantities of N,N-dimethylcarboxamide (e5%
yield) are observed in these reactions.
Our initial studies were performed in toluene because this
solvent was most effective in some of our previous studies.
Evaluation of other solvents revealed that the reactivity was
not limited to toluene (Table 2). Complete equilibration was
observed within 5 h at room temperature when chlorobenzene
was used as solvent (entry 3), and partial exchange was achieved
within 5 h with dichloromethane. In the coordinating solvents
THF and pyridine, significant transamidation was observed at
room temperature, but it was necessary to increase the temper-
ature to 50 °C to achieve equilibrium within 5 h (entries 4 and
5). In previous work, we found diglyme [bis(2-methoxy)ethyl
ether] to support imide-mediated amide metathesis reactions that
proceed via a transacylation mechanism;7 however, diglyme is
incompatible with Zr-catalyzed transamidation reactivity, even
(9) Bradley, D. C.; Thomas, I. M. J. Chem. Soc. 1960, 3857–3861.
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Table 5. Zr-Catalyzed Metathesis of Tertiary Carboxamidesa
a See Figure 1 for standard reaction conditions.
reaction performed in either direction. When the amine bears
an R-branched alkyl group (entry 8), no reaction was observed
even at 90 °C, suggesting that this catalytic process is very
sensitive to steric factors.
as base, to yield a Zr-enolate species. The amide with a
4-pyridinyl substituent (entry 10) undergoes significant trans-
amidation at room temperature after 10 h but requires 50 °C to
achieve full equilibration during this time period. No exchange
reaction is observed at room temperature with the amide bearing
the 2-pyridinyl substituent, probably reflecting kinetic inhibition
arising from substrate chelation; however, this substrate achieves
nearly complete equilibration within 10 h upon heating to 50
°C (entry 11). No transamidation activity was observed with
amides bearing more reactive carbonyl groups, including those
derived from an aldehyde, ketones, or an ester (entries 12-15).
1H NMR spectroscopy indicated that these substrates undergo
some alternative form of reaction in the presence of the Zr
catalyst. This reactivity was not explored in detail, but it is
probably related to the known irreversible stoichiometric
reactivity of group 4 metal-amido complexes with organic
compounds containing carbonyl groups.11 The limited reactivity
observed with an R-branched amide (entry 16) strengthens the
The examples in Table 4 probe the effect of variations in the
acyl group on the Zr-catalyzed transamidation reactions and
provide some insight into the functional group compatibility of
the reaction. Several examples achieved equilibrium at room
temperature (entries 1-7), while others were more sluggish
(entries 8-11 and 16). In general, substituents with a methylene
group adjacent to the amide carbonyl undergo facile transami-
dation at room temperature (Table 3, entries 1-3; Table 4,
entries 2-4). A wide variety of functional groups can be
tolerated in Zr-catalyzed transamidation. Examples include
terminal alkyne (entry 4) and aryl chloride (entry 5) as well as
furanyl (entry 7) and pyridinyl (entries 10 and 11) groups. The
terminal alkyne (entry 4) is potentially susceptible to hydro-
amination in the presence of group 4 metal-amido complexes;10
however, such reactivity is not observed under the mild
transamidation reaction conditions. The incomplete reactivity
of the acetamide substrate was unexpected (entry 9); we
speculate that this unhindered amide might undergo deproton-
ation of the acetyl methyl group, with an amido ligand serving
(10) (a) Walsh, P. J.; Baranger, A. M.; Bergman, R. G. J. Am. Chem. Soc.
1992, 114, 1708–1719. (b) Odom, A. L. Dalton Trans. 2005, 225–
233. (c) Severin, R.; Doye, S. Chem. Soc. ReV. 2007, 36, 1407–1420.
(d) Lee, A. V.; Schafer, L. L. Eur. J. Inorg. Chem. 2007, 2243–2255.
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Catalytic Transamidation Reactions under Ambient Conditions
A R T I C L E S
Figure 2. Amide metathesis time course at 24 °C. Individual reaction vials were used for each time point. Reaction conditions: equal amounts of amides
(0.33 mmol) in 2 mL of toluene in the presence of Zr(NMe2)4. Color of amides corresponds to color of markers in time course plot.
Scheme 1. Proposed Catalytic Cycle for Zr-Catalyzed
Transamidation Reactions
conclusion that steric bulk near the amide moiety hinders
exchange (see also entry 8 of Table 3).
Amide Metathesis. The unprecedented activity of Zr(NMe2)4
as a transamidation catalyst suggested that amide metathesis
might be possible; indeed, we found that a number of tertiary
amide substrate pairs undergo full equilibration in the presence
of 5 mol % Zr(NMe2)4 in toluene (Table 5, entries 1-7). Some
of the amide exchange processes occurred extremely rapidly.
For example, the metathesis equilibration corresponding to entry
1 of Table 5 was complete within minutes at room temperature.
A time-course plot reflecting this rapid equilibration is shown
in Figure 2. The origins of substrate reactivity differences
evident in Table 5 are not yet clear, but the data once again
reveal that amides with a methylene unit bonded to the carbonyl
carbon are intrinsically more reactive than amides in which an
aromatic ring is bonded to the carbonyl carbon (entries 1 and 4
vs 10; 2 and 5 vs 11; and 6 vs 12).
Mechanistic Considerations. Scheme 1 shows the catalytic
cycle we envision to explain the Zr-based transamidation
reactivity documented above. This mechanistic hypothesis
closely resembles the catalytic cycle we proposed for Al2(NMe2)6-
catalyzed trasamidation of secondary amine/tertiary amide pairs,
enhance the rates of ligand association, dissociation, or substitu-
tion or the rates of reactions within the metal coordination
sphere, thereby contributing to more rapid catalytic turnover.
Further studies will be needed to explore these possibilities.
on the basis of experimental and computational mechanistic
studies.8 A key feature of this hypothesis is the simultaneous
activation of the electrophile (carboxamide) and the nucleophile
(amido) via coordination to a Zr atom (intermediate B).
Intramolecular attack of the amido on the coordinated amide
gives rise to a Zr-stabilized tetrahedral intermediate (C), which
can interconvert with an isomeric intermediate (C′), ultimately
leading to formation of a new amide/amido pair coordinated to
the Zr atom (B′). If the transamidation processes catalyzed by
homoleptic dimethylamido complexes of AlIII, ZrIV, and HfIV
all proceed via this type of mechanism, then it will be intriguing
to determine why the Zr- and Hf-based processes are so much
more facile than that based on Al. The attenuated reactivity of
the Al-amido species might reflect their less hindered coordina-
tion environment, which often results in the formation of
dimeric, possibly less reactive structures. Alternatively, the
participation of d-orbitals in the Zr- and Hf-based catalysts might
Conclusions
This study demonstrates that secondary amine-tertiary amide
transamidations can be catalyzed efficiently by a commercially
available complex, Zr(NMe2)4. The catalytic activity is suf-
ficiently high to enable rapid tertiary amide metathesis, which
presumably involves successive transamidation steps (eqs 1-3).
These results represent a substantial advance in carboxamide
exchange reactivity relative to the precedents in this challenging
reaction manifold, and they strongly suggest that carboxamide-
based DCC will be feasible. Such a process might provide
interesting, perhaps even useful, oligoamides that are extremely
stable under most conditions.
Experimental Section
(11) For leading references, see: (a) Walsh, P. J.; Hollander, F. J.; Bergman,
R. G. Organometallics 1993, 12, 3705–3723. (b) Lee, S. Y.; Bergman,
R. G. J. Am. Chem. Soc. 1996, 118, 6396–6406. (c) Kissounko, D. A.;
Guzei, I. A.; Gellman, S. H.; Stahl, S. S. Organometallics 2005, 24,
5208–5210. (d) Kissounko, D. A.; Hoerter, J. M.; Guzei, I. A.; Cui,
Q.; Gellman, S. H.; Stahl, S. S. J. Am. Chem. Soc. 2007, 129, 1776–
1783.
General Considerations. The handling of air-sensitive materials
was carried out in a nitrogen atmosphere glovebox. Toluene was
dried with an activated alumina purification column. Gas chroma-
tography was performed with a Shimadzu GC-17A gas chromato-
graph equipped with a Restek, 15 m RTX-5 capillary column. Metal
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Stephenson et al.
complexes were purchased from Aldrich and Strem and used as
received. Amines were purchased from Aldrich and distilled from
CaH2 prior to use. Amides were synthesized following standard
procedures, and liquid amides were further purified by vacuum
distillation from CaH2.
Representative Procedure for Transamidation Studies. Under
a nitrogen atmosphere, a toluene solution of amide (0.33 M), amine
(0.33 M), and triphenylmethane (0.09 M) was prepared. A toluene
solution of catalyst (0.017 M for 5 mol % loading and 0.0083 M
for 2.5% catalyst loading) was also prepared. The amide solution
(1 mL) was dispensed into a 4 mL glass vial, and transamidation
was initiated by the addition of 1 mL of catalyst solution. The glass
vials were sealed with a Teflon-lined cap, removed from the
glovebox, placed on a heated 48-well metal block, and agitated for
the allotted reaction time. The reaction was quenched by the addition
of 0.5 mL of methanol to the reaction solutions. The reaction
mixture was then analyzed by gas chromatography using tri-
phenylmethane as an internal standard.
Representative Procedure for Amide Metathesis Studies. The
transamidation protocol was followed using 5 mol % catalyst (0.017
mmol) and equivalent amounts of two different amides (0.33 mmol)
in 2 mL of toluene. The reaction was quenched with methanol and
analyzed by gas chromatography using triphenylmethane as internal
standard.
Acknowledgment. We thank Dr. J. M. Hoerter for many useful
discussions. This work was supported by the NSF Collaborative
Research in Chemistry program (CHE-0404704).
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