Catalytic metathesis of simple secondary amides

Article abstract of DOI:10.1002/anie.200603588

(Chemical Equation Presented) Trading places: The metathesis of secondary amides through a transacylation mechanism has been achieved by employing catalytic quantities of an organic imide and a Bronsted base (see scheme). Equilibrium-controlled exchange between various amide pairs is demonstrated for substrates bearing N-alkyl and N-aryl substituents.

Full text of DOI:10.1002/anie.200603588

Angewandte
Chemie
DOI: 10.1002/anie.200603588
Amide Metathesis
Catalytic Metathesis of Simple Secondary Amides**
Christen M. Bell, Denis A. Kissounko, Samuel H. Gellman,* and Shannon S. Stahl*
Reactions that interconvert strong covalent bonds, generally
known as dynamic covalent chemistry (DCC), offer a power-
ful approach for the thermodynamically controlled synthesis
of organic molecules with interesting structures and/or
properties. DCC involving esters, thioesters, imines, and
disulfides, among other functional groups, has provided
access to interesting new molecules.[1,2] Such efforts to date
have focused on bonds that were previously known to be
readily exchangeable. Extension of the DCC approach to
other types of functional groups will require advances in
organic reactivity and catalysis. It would be valuable, for
example, to implement DCC with carboxamide-containing
molecules,[1c] but the low intrinsic reactivity of the carbox-
amide group has hampered efforts to achieve this goal. A
fundamental challenge is the identification of catalysts that
induce amide metathesis, that is, the interconversion of
carboxamides based on cleavage and formation of the
N-acyl bonds [Eq. (1)]. We recently described metal-cata-
lyzed transamidation reactions [Eq. (2)],[3] which in principle
offer a pathway to amide metathesis. Subsequent studies in
our lab, however, revealed that metathesis of secondary
amides is not successful under the original transamidation
conditions.[4] Herein we describe an alternative and mecha-
nistically novel strategy for catalytic amide metathesis that
involves imide-mediated transacylation. The results provide a
foundation for future efforts to implement amide-based DCC.
The only previous example of amide metathesis, to our
knowledge, involved the use of proteases under conditions
compatible with both peptide hydrolysis and synthesis.[5]
Drawbacks associated with these reactions include the limited
substrate scope and long reaction times, and these prompted
us to pursue the development of small-molecule catalysts for
amide metathesis. As initial efforts using transamidation
catalysts were unsuccessful, we sought an alternative strategy.
We postulated that substoichiometric quantities of an acyclic
imide and a Brønsted base (the latter to generate amidate
species) might promote acyl-group exchange between secon-
dary amides [Eq. (3)]. Successive reactions of this type should
enable equilibrium-controlled metathesis of secondary
amides.[6]
Initial efforts to promote the metathesis of N-benzylhep-
tanamide and acetanilide [Eq. (4); Bn = benzyl] with the
imide N-benzyldiacetamide (5) established the feasibility of
the proposed strategy.[7] The effectiveness of several different
bases was evaluated by comparing the ratio of the amides 3/1
obtained when the reaction was conducted in both the
forward and reverse directions. Reactions that achieve
equilibrium produce a 3/1 ratio that is independent of the
reaction direction. The most effective bases were found to be
NaN(SiMe3)2, KN(SiMe3)2, and KH (Figure 1); equilibrium
was achieved in all three cases. Significant amide exchange
was observed also for MeMgCl, KOtBu, and LiN(SiMe3)2.
Metal complexes previously shown to promote transamida-
tion,[3a] [Al2(NMe2)6] and [Ti(NMe2)4], were found not to
promote amide metathesis. Based on previous observations,
[*] C. M. Bell, D. A. Kissounko, Prof. S. H. Gellman, Prof. S. S. Stahl
Department of Chemistry
University of Wisconsin-Madison
1101 University Avenue, Madison WI 53706 (USA)
Fax: (+1)608-262-6143
E-mail: gellman@chem.wisc.edu
Figure 1. Results from the screening of bases for Equation (4).
Reaction conditions: 1:1 mixture of amides (0.23 mmol; 1 and 2 for
the forward reaction, or 3 and 4 for the reverse reaction), base
(0.046 mmol), 5 (0.046 mmol), diglyme (0.8 mL), 1208C, 18 h. Amide
ratio was determined by GC analysis (Ph3CH internal standard). Each
bar represents the average of five runs.
stahl@chem.wisc.edu
[**] We gratefully acknowledge financial support from the NSF Collab-
orative Research in Chemistry Program (CHE-0404704).
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Table 2: Metathesis of pairs of nonenolizable amides.[a]
we suspect that these complexes form stable Al–amidate or
Ti–amidate adducts,[8] which are insufficiently nucleophilic to
react with the imide.
Several different pairs of secondary amides were evalu-
ated under the metathesis conditions (Table 1). We examined
three classes of amide reactant pairs (N-aryl/N-aryl, N-aryl/
N-alkyl, and N-alkyl/N-alkyl). The reactions were performed
in both forward and reverse directions to determine whether
equilibrium was achieved. The metathesis of the pairs of
N-aryl/N-aryl (Table 1, entries 1–3) and N-aryl/N-alkyl
amides (Table 1, entries 4–9) generally reached completion
within the error limits of the product analysis. The presence of
a bulky branched alkyl substituent on the amide nitrogen does
not appear to hinder the exchange (Table 1, entry 7).
Amide ratio B/A
Entry
1
R
R1
R2
Forward
Reverse
p-tolyl
Bn
0.82 (0.02)
0.58 (0.11)
0.83 (0.04)
2
C6H13
Bn
0.92 (0.05)
[a] See footnote from Table 1 for reaction conditions and analytical
methods.
The metathesis of the N-alkyl/N-alkyl amide pairs proved
to be more challenging. Partial exchange was observed, but
these reactions did not achieve equilibrium after 18 h under
the standard conditions (Table 1, entries 10 and 11). No
further exchange was observed with longer reaction times
(36 h). We speculated that imide decomposition, which
perhaps involved deprotonation at the a position, could
have prematurely terminated the metathesis process. To test
this hypothesis, we examined the exchange between non-
enolizable amide substrates (Table 2). Since the imide ini-
tiator incorporates the acyl fragments of the amide substrates
during the reaction, the use of nonenolizable amide substrates
should minimize imide deprotonation, even if 5 is initially the
imide component. This strategy proved to be successful:
equilibrium was achieved with an N-alkyl/N-alkyl substrate
pair (Table 2, entry 1). When only one of the starting amides
was nonenolizable, however, equilibrium was not achieved
(Table 2, entry 2).
Imide initiator 5, which was employed in each of the
reactions presented in Table 1 and Table 2, is not commer-
cially available.[9] We were therefore encouraged to find that
the commercially available imide N-methyldiacetamide (6) is
equally effective as an initiator of amide metathesis (Table 3,
entry 1). Even more significant is that simple acylating agents,
such as acetyl chloride and acetylimidazole, promote amide
metathesis (Table 3, entries 2 and 3). The latter reagents,
which presumably form imides in situ, are attractive because
they minimize the quantity of initiator-derived acyl and amine
fragments present in the reaction mixture. For example,
N-methylamide side products were observed when 6 was used
as the initiator, but no analogous side products are possible
when either acetyl chloride or acetylimidazole is used.
Furthermore, acid chlorides bearing an acyl fragment that
matches one (or both) of the amide substrates can be readily
obtained from the corresponding carboxylic acids.
Table 1: Metathesis of pairs of secondary amides.[a]
Amide ratio B/A[b]
Entry
R
R1
Forward
Reverse
R=aryl
Ph
Ph
R1 =aryl
p-MeOC6H4
p-tolyl
1
2
3
0.91 (0.07)
1.02 (0.03)
0.77 (0.01)
1.04 (0.08)
1.09 (0.04)
0.83 (0.03)
p-tolyl
p-FC6H4
R=alkyl
Bn
Bn
R1 =aryl
Ph
p-MeOC6H4
p-FC6H4
4
5
6
0.73 (0.05)
0.64 (0.05)
0.66 (0.04)
0.66 (0.07)
0.72 (0.07)
0.69 (0.02)
Table 3: Alternative initiators for amide metathesis [Eq. (4)].[a]
Amide ratio 3/1[b]
Bn
Entry
Initiator
Forward
Reverse
7
8
9
Ph
Ph
Ph
0.69 (0.06)
0.95 (0.06)
0.87 (0.07)
0.61 (0.06)
0.88 (0.05)
0.81 (0.01)
1
0.83 (0.02)
0.73 (0.08)
0.88 (0.03)
0.82 (0.05)
2[c]
3[c]
0.73 (0.05)
0.81 (0.05)
R=alkyl
R1 =alkyl
[a] Reaction conditions: 1:1 mixture of amides (0.23 mmol; 1 and 2 for
the forward reaction, 3 and 4 for the reverse reaction), KH (0.046 mmol),
initiator (0.046 mmol), diglyme (0.8 mL), 1208C, 18 h. [b] Amide ratio
determined by GC analysis (internal standard=Ph3CH). Data represents
the average of five runs; standard deviation in parentheses. [c] KH
(0.092 mmol) The requirement for a two-fold excess of base relative to
the acylating agent presumably reflects the formation of the imide
in situ, that is, one equivalent of base is consumed in the formation of
the imide.
10
11
Bn
0.98 (0.06)
0.73 (0.02)
0.69 (0.02)
0.87 (0.02)
Bn
[a] Reaction conditions: 1:1 mixture of amides (0.23 mmol each); KH
(0.046 mmol); imide 5 (0.046 mmol), 0.8 mL of diglyme, 1208C, 18 h.
[b] Amide ratio determined by GC (internal standard=Ph3CH). Data
represents the average of five runs; standard deviation in parentheses.
762
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The reaction shown in Equation (5) features nonenoliz-
able substrates together with N-benzoylimidazole as the
initiator. As the plots of the forward and reverse reactions
[1] For reviews of DCC, see: a) J. M. Lehn, Chem. Eur. J. 1999, 5,
2455 – 2463; b) S. J. Rowan, S. J. Cantrill, G. R. L. Cousins,
J. K. M. Sanders, J. F. Stoddart, Angew. Chem. 2002, 114, 938 –
993; Angew. Chem. Int. Ed. 2002, 41, 898 – 952; c) P. T. Corbett, J.
Leclaire, L. Vial, K. R. West, J.-L. Wietor, J. K. M. Sanders, S.
Otto, Chem. Rev. 2006, 106, 3652 – 3711.
[2] For selected recent applications of DCC, see: a) P. A. Brady,
R. P. Bonar-Law, S. J. Rowan, C. J. Suckling, J. K. M. Sanders,
Chem. Commun. 1996, 319 – 320; b) K. Oh, K.-S. Jeong, J. S.
Moore, Nature 2001, 414, 889 – 893; c) S. Otto, R. L. E. Furlan,
J. K. M. Sanders, Science 2002, 297, 590 – 593; d) A. F. M.
Kilbinger, S. J. Cantrill, A. W. Waltman, M. W. Day, R. H.
Grubbs, Angew. Chem. 2003, 115, 3403 – 3407; Angew. Chem.
Int. Ed. 2003, 42, 3281 – 3285; ; e) S. A. Vignon, J. Thibaut, T.
Iijima, H.-R. Tseng, J. K. M. Sanders, J. F. Stoddart, J. Am.
Chem. Soc. 2004, 126, 9884 – 9885; f) S. J. Cantrill, R. H. Grubbs,
D. Lanari, K. C. F. Leung, A. Nelson, K. G. Poulin-Kerstien, S. P.
Smidt, J. F. Stoddart, D. A. Tirrell, Org. Lett. 2005, 7, 4213 – 4216;
g) R. Cacciapaglia, S. Di Stefano, L. Mandolini, J. Am. Chem.
Soc. 2005, 127, 13666 – 13671; h) B. Shi, R. Stevenson, D. J.
Campopiano, M. F. Greaney, J. Am. Chem. Soc. 2006, 128, 8459 –
8467; i) L. Vial, R. F. Ludlow, J. Leclaire, R. PØrez-Fernµndez, S.
Otto, J. Am. Chem. Soc. 2006, 128, 10253 – 10257.
against time reveal (Figure 2), equilibrium is reached within
approximately one hour at 908C. The exchange reaction in
Equation (6), which features an N-butylamide, proceeds to
equilibrium with acetyl chloride as the initiator. This result
complements the data in Table 1 and Table 2, which feature
N-benzylic substrates and an N-benzylimide initiator.
[3] a) S. E. Eldred, D. A. Stone, S. H. Gellman, S. S. Stahl, J. Am.
Chem. Soc. 2003, 125, 3422 – 3423; b) J. M. Hoerter, K. M. Otte,
S. H. Gellman S. S. Stahl, J. Am. Chem. Soc. 2006, 128, 5177 –
5183.
[4] Mechanistic studies reveal that the rate of AlIII-catalyzed
transamidation is proportional to the concentrations of the
metal and the amine (see Ref. [3b]). Both of these species are
present at low concentration in amide metathesis. Thus far, we
have not identified practical conditions for amide metathesis
which involves a transamidation mechanism.
Figure 2. Plots of the approach to equilibrium for Equation (5) both in
[5] P. G. Swann, R. A. Casanova, A. Desai, M. M. Frauenhoff, M.
Urbancic, U. Slomczynska, A. J. Hopfinger, G. C. LeBreton,
D. L. Venton, Biopolymers 1996, 40, 617 – 625.
forward and reverse directions (based on GC analysis of carboxamides
&
*
7
and 9 ). Reaction conditions: 7 and 9 (0.23 mmol), KH
(0.092 mmol), 11 (0.046 mmol), diglyme (0.8 mL), 908C.
[6] This strategy finds loose precedent in the anionic, ring-opening
polymerization (ROP) of lactams, which employs imide (N-
acyllactam) and Brønsted base coinitiators. Polymer chain
initiation and propagation are believed to proceed through
attack of a deprotonated lactam on the imide carbonyl of the
initiator or polymer chain end. For a discussion, see: K.
Hashimoto, Prog. Polym. Sci. 2000, 25, 1411 – 1462.
[7] Typical reaction procedure: In a disposable vial (4 mL), a
1:1 mixture of amides (0.23 mmol) and base (20 mol%,
0.046 mmol) were mixed in diglyme (0.8 mL) under nitrogen.
To this mixture, imide initiator (20 mol%, 0.046 mmol) and
triphenylmethane (0.018 mol, 4.4 mg) as an internal standard
were added. The vials were sealed under nitrogen and placed
into a 48-well parallel reactor mounted on a vortexing mixer.
The reactions were heated to 1208C for 18 h and quenched with
water (1 mL). The organics were extracted into diethyl ether,
and product ratios were determined by GC analysis relative to
the triphenylmethane standard.
[8] See, for example: a) ref. [3b]; b) D. A. Kissounko, I. A. Guzei,
S. H. Gellman, S. S. Stahl, Organometallics 2005, 24, 5208 – 5210;
c) B. H. Huang, T. L. Yu, Y. L. Huang, B. T. Ko, C. C. Lin, Inorg.
Chem. 2002, 41, 2987 – 2994; d) Z. Zhang, L. L. Schafer, Org.
Lett. 2003, 5, 4733 – 4736.
In summary, we have shown that the metathesis of simple
secondary amides can be achieved through the combined
action of simple acylating agents and Brønsted bases. These
findings establish a conceptually novel strategy for inducing
carboxamide exchange reactivity. Significant challenges
remain to be overcome in this class of reactions, such as the
avoidance of competing decomposition reactions for amide
substrates bearing protons adjacent to the carbonyl, and the
enhancement of catalytic efficiency. We anticipate that
mechanistic studies will facilitate further advances.[10] The
results presented above provide a basis for implementing
carboxamide-based dynamic covalent chemistry, a prospect
that we are actively exploring.
[9] For imide preparation, see: R. P. Mariella, K. H. Brown, J. Org.
Chem. 1971, 36, 735 – 737.
[10] One reviewer noted that O-acylated intermediates might
participate in these reactions. Understanding the role of such
intermediates, if they indeed exist, and identifying catalyst-
decomposition pathways might reveal ways to achieve improved
catalytic activity at lower temperature.
Received: September 2, 2006
Published online: December 13, 2006
Keywords: amides · dynamic covalent chemistry ·
.
homogeneous catalysis · metathesis · synthetic methods
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