Mild amidation of aldehydes with amines mediated by lanthanide catalysts

Article abstract of DOI:10.1021/ol702788j

(Chemical Equation Presented) Catalytic amidation of aldehydes with amines is efficiently mediated by homoleptic lanthanide amido complexes, Ln[N(SiMe ₃)₂]₃ (Ln = La, Sm, and Y). Amidation reactivity follows the trend: La > Sm ≈ Y. These reactions proceed in high yield without added oxidants, bases, and/or heat or light, which are usually required in other catalytic amidation processes. The reaction is demonstrated with a variety of amines, with yields as high as 98% based on amine.

Full text of DOI:10.1021/ol702788j

ORGANIC
LETTERS
2008
Vol. 10, No. 2
317-319
Mild Amidation of Aldehydes with
Amines Mediated by Lanthanide
Catalysts
SungYong Seo and Tobin J. Marks*
Department of Chemistry, Northwestern UniVersity, EVanston, Illinois 60208-3113
t-marks@northwestern.edu
Received November 17, 2007
ABSTRACT
Catalytic amidation of aldehydes with amines is efficiently mediated by homoleptic lanthanide amido complexes, Ln[N(SiMe3)2]3 (Ln
) La, Sm,
and Y). Amidation reactivity follows the trend: La > Sm Y. These reactions proceed in high yield without added oxidants, bases, and/or heat
≈
or light, which are usually required in other catalytic amidation processes. The reaction is demonstrated with a variety of amines, with yields
as high as 98% based on amine.
Aromatic and aliphatic amides are functional groups of great
importance in polymers, natural products, and pharmaceu-
ticals.1 Generally, amide groups are introduced by reacting
carboxylic acids or their corresponding derivatives with
amines.1,2 Alternative methods such as late transition metal-
catalyzed aminocarbonylation of halides with CO and
amines,3 modified Staudinger reactions,4 and mercury-
catalyzed rearrangements of ketoximes5 have been utilized
due to the lability of activated carboxylic acid derivatives
under appropriate reaction conditions. Another attractive
approach, reflecting the economical and abundant nature of
the starting materials, is direct aldehyde amidation with
amines. To date, only a few examples of this type of
transformation have been reported.6-11 Davidson’s and
Marko’s groups described radical-mediated oxidative ami-
dation using radical initiators6a and light,6b while Wang’s and
Ishihara’s groups recently reported amidation via Cannizzaro
reactions using LDA7 or lanthanide reagents,8 respectively.
Very recently, Rovis’s and Bode’s groups also reported
amidation using N-heterocyclic carbene (NHC) catalysts.9
However, most catalytic amidation processes have utilized
(1) Humphrey, J. M.; Chanberlin, A. R. Chem. ReV. 1997, 97, 2243-
2266.
(2) Bodanszky, M. Peptide Chemistry: A Practical Textbook; Springer-
Verlag: New York, 1993.
(3) Beller, M.; Cornils, B.; Frohning, C. D.; Kohlpaintner, C. W. J. Mol.
Catal. A: Chem. 1995, 104, 17-85.
(4) Saxon, E.; Bertozzi, C. R. Science 2000, 287, 2007-2010.
(5) Ramalingan, C.; Park, Y.-T. J. Org. Chem. 2007, 72, 4536-4538.
(6) (a) Marko, I. E.; Mekhalfia, A. Tetrahedron Lett. 1990, 31, 7237-
7240. (b) Davidson, R. S.; Edwards, J.; Warburton, S. K. J. Chem. Soc.,
Perkin Trans. 1 1976, 1511-1514.
(7) Ishihara, K.; Yano, T. Org. Lett. 2004, 6, 1983-1986.
(8) For recent, related work on amidation processes for primary amides
using lanthanide catalysts generated in situ from LnCl3 and with LiN(TMS)2
as a stoichiometric reagent, see: Zhang, L.; Wang, S.; Zhou, S.; Yang, G.;
Sheng, E. J. Org. Chem. 2006, 71, 3149-3153.
(9) (a) Vora, H. U.; Rovis, T. J. Am. Chem. Soc. 2007, 129, 13796-
13797. (b) Bode, J. W.; Sohn, S. S. J. Am. Chem. Soc. 2007, 129, 13798-
13799.
(10) (a) Yoo, W.; Li, C. J. Am. Chem. Soc. 2006, 128, 13064-13065.
(b) Tillack, A.; Rudloff, I.; Beller, M. Eur. J. Org. Chem. 2001, 523-528.
(c) Naota, T.; Murahashi, S. Synlett 1991, 693-694. (d) Tamaru, Y.;
Yamada, Y.; Yoshida, Z. Synthesis 1983, 474-476. (e) Nakagawa, K;
Onoue, H.; Minami, K. Chem. Commun. 1966, 17-18.
(11) For an example of a metal-free oxidative amidation using TBHP,
see: Ekoue-Kovi, K.; Wolf, C. Org. Lett. 2007, 9, 3429-3432.
(12) (a) From standard tables,12b ∆H for the simple case in eq 1 (R )
Me) is estimated to be +10.1 kcal/mol. (b) David, R. L. Handbook of
Chemistry and Physics, 87th ed.; CRC Press: Boca Raton, FL, 2006.
(13) Gunanathan, C.; Ben-David, Y.; Milstein, D. Science 2007, 790-
792.
(14) (a) Schuetz, S. A.; Day, V. W.; Sommer, R. D.; Rheingold, A. L.;
Belot, J. A. Inorg. Chem. 2001, 40, 5292-5295. (b) Bradely, D. C.; Ghotra,
J. S.; Hart, F. A. J. Chem. Soc., Chem. Commun. 1973, 1021-1023.
(15) Kim, Y. K.; Livinghouse, T.; Bercaw, J. E. Tetrahedron Lett. 2001,
42, 2933-2935.
(16) Horino, Y.; Livinghouse, T. Organometallics 2004, 23, 12-14.
(17) Horino, Y.; Livinghouse, T.; Stan, M. Synlett 2004, 2639-2641.
(18) Kawaoka, A. M.; Douglass, M. R.; Marks, T. J. Organometallics
2003, 22, 4630-4632.
10.1021/ol702788j CCC: $40.75
© 2008 American Chemical Society
Published on Web 12/20/2007

transition metal complexes (e.g., Cu,10a Rh,10b Ru,10c Pd,10d
Ni10e) with an added oxidant.11 Very recently, Milstein et
al. reported direct, endothermic12 amidation from alcohols
and amines via aldehyde intermediates, using Ru PNN pincer
catalysts, and driven by H2 removal (eq 1).13 Note that all
of these catalytic systems require relatively harsh reaction
conditions, such as oxidants, strong bases, and/or heat or
light.
marginally with increased amine (entry 1 vs 5, Table 1) or
catalyst stoichiometries (entries 1, 3 vs 6, 7, Table 1). Several
homoleptic amido complexes were used to assess the effect
of Ln3+ ionic radius on activity (entries 8 and 9, Table 1),
and the trend follows the order La > Sm ≈ Y.
With reaction conditions optimized (entry 4, Table 1), we
then examined the scope of this lanthanide-catalyzed ami-
dation with selected aldehydes and amines (Table 2).
Table 2. Lanthanide-Mediated Amidation of Aldehydes with
Aminesa
Homoleptic Ln[N(SiMe3)2]3 lanthanide amido complexes14
are versatile catalysts for hydroelementation processes, such
as hydroamination,15,20a hydrosilylation,16 hydroboration,17
hydrophosphination,18 and hydroalkoxylation.19 Recently,
Roesky et al. reported homoleptic lanthanide amido catalyst-
mediated Tishchenko aldehyde dimerizations to yield the
corresponding carboxylic esters.20 Inspired by this successful
esterification process, the challenging amidation of simple
aldehydes and amines is explored in the present contribution.
Homoleptic Ln[N(SiMe3)2]3 complexes are found by in situ
1H NMR spectroscopy to undergo instantaneous protonlysis
with primary or secondary amines at room temperature to
yield the corresponding lanthanide amido complexes and free
HN(SiMe3)2. Addition of aldehydes affords the corresponding
amidation products as discussed below. Preliminary studies
with benzaldehyde and N-methylbenzylamine revealed that
the N-benzyl-N-methylbenzamide amidation product is pro-
duced in a moderate yield (37%) after 24 h at 25 °C (entry
1, Table 1).
Table 1. Optimization of the Ln[N(SiMe3)2]3-Catalyzed
Amidation of Aldehydes with Aminesa
molar
ratio (1:2)
mol % of
catalyst
yield
(%)b
entry
metal
1
2
3
4
5
6
7
8
9
1:1
3:2
2:1
3:1
1:2
1:1
2:1
3:1
3:1
La
La
La
La
La
La
La
Sm
Y
5
5
5
5
5
10
10
5
37
61
71
78
48
47
72
54
47
a Starting amine, aldehyde, and catalyst concentrations are identical in
each experiment. b Isolated yields based on amine.
5
a Starting amine, aldehyde, and catalyst concentrations are identical in
each experiment. See Supporting Information for reaction details. b Isolated
yields based on N-methylbenzylamine except entry 5.
In general, amidation proceeds efficiently at room temper-
ature to provide the desired products in high yields. Aldehyde
Optimization studies reveal that increasing the aldehyde
equivalents enhances the yield significantly, up to 78%
(entries 2-4, Table 1). The yield is, however, improved only
(19) Yu, X.; Seo, S.; Marks, T. J. J. Am. Chem. Soc. 2007, 129, 7244-
7245.
318
Org. Lett., Vol. 10, No. 2, 2008

Scheme 1. Proposed Catalytic Cycle for Lanthanide Amido-Mediated Aldehyde + Amine Amidation
electrophilicity likely plays a significant role as shown by
possible cycles and side reactions place this beyond the scope
of a communication. In the tentative catalytic cycle of
Scheme 1, catalyst 6 is active for amidation and 7 for
Tishchenko coupling.20 To probe for the presence of species
6 and 7, a series of NMR-scale experiments were per-
formed: (i) The addition order was varied; that is, aldehyde
was added first to the catalytic solution, then amine. (ii) A
mixture of aldehyde and amine was added to the active
catalyst solution. Both procedures resulted in amide forma-
tion at a similar rate to the original conditions. (iii) Proposed
catalyst 7 was generated in situ from La[N(SiMe3)2]3 +
benzyl alcohol and used to mediate the amidation reaction.
After addition of aldehyde and amine to 7, amide and ester
the higher yields for electron-poor (entries 8 and 9, Table
2) versus electron-rich aryl aldehydes (entries 1, 6, 7, and
10, Table 2). Amine nucleophilicity21 also likely plays a role
as suggested by the moderate yields in the case of secondary
alkyl amines (entries 2 and 3, Table 2). Surprisingly, this
amidation also proceeds in the case of primary amines
(entries 4 and 5, Table 2). The low yield with benzyl amine
(entry 5, Table 2) is found to result from catalyst deactivation
due to water production via imine formation and the inherent
water sensitivity of the catalyst. Taken together, these results
indicate that electronic effects play an important role in the
rates of the present amidation processes.
1
In the present catalytic amidations, two side products are
identified as ester 4 and alcohol 5, produced in the stoichi-
ometry of eq 2.
formation was verified by H NMR spectroscopy. (iv) To
investigate the possibility of direct ester to amide conversion,
La[N(SiMe3)2]3was combined with ester + amine. Here, no
amide formation is observed, consistent with Scheme 1.
In summary, we have developed a mild, room temperature
homoleptic lanthanide amido-catalyzed aldehyde + amine
amidation process that does not involve strong added
oxidants, bases, and/or heat or light and provides yields as
high as 98%. Further investigations regarding mechanism
and synthetic applications are in progress.
Acknowledgment. We thank NSF (Grant CHE-04157407)
for support of this research. We also thank Dr. X. Yu, Dr.
S. B. Amin, and Prof. R. J. Thomson (Northwestern
University) for helpful discussions.
In essence, aldehyde 1 serves as the H2 acceptor. Detailed
kinetic/mechanistic analysis will be required to fully elucidate
the catalytic pathway operative here, and the multiplicity of
Supporting Information Available: Experimental de-
tails. This material is available free of charge via the Internet
at http://pubs.acs.org.
(20) (a) Burgstein, M. R.; Berberich, H.; Roesky, P. W. Chem.sEur. J.
2001, 7, 3078-3085. (b) Berberich, H.; Roesky, P. W. Angew. Chem., Int.
Ed. 1998, 37, 1569-1571.
(21) Bunting, J. W.; Mason, J. M.; Heo, C. K. M. J. Chem. Soc., Perkin
Trans. 1 1994, 2291-2300.
OL702788J
Org. Lett., Vol. 10, No. 2, 2008
319