A Lewis acid palladium(II)-catalyzed three-component synthesis of α-substituted amides

Article abstract of DOI:10.1021/ol402949t

A Lewis acid palladium-catalyzed reaction of amides, aryl aldehydes, and arylboronic acids is described. This new method allows for a practical and general synthesis of α-substituted amides from simple, readily available building blocks.

Full text of DOI:10.1021/ol402949t

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
A Lewis Acid Palladium(II)-Catalyzed
Three-Component Synthesis
of r‑Substituted Amides
Tamara Beisel and Georg Manolikakes*
Department of Organic Chemistry and Chemical Biology, Goethe-University Frankfurt,
Frankfurt am Main, Germany
g.manolikakes@chemie.uni-frankfurt.de
Received October 12, 2013
ABSTRACT
A Lewis acid palladium-catalyzed reaction of amides, aryl aldehydes, and arylboronic acids is described. This new method allows for a practical
and general synthesis of R-substituted amides from simple, readily available building blocks.
The Petasis or Borono-Mannich reaction;a three-
component reaction of an amine, an aldehyde, and a
boronic acid;allows for a straightforward synthesis of
various nitrogen-containing molecules (Scheme 1; classic
Petasis reaction).1,2 Due to the synthetic utility and bio-
logical activity of the resulting products, the accessibility of
the starting materials and the rapid access to structural
diversity, the Petasis reaction has become a powerful tool
in drug discovery.
However, the classical Petasis method has two severe
limitations.2 In general, the reaction is restricted to acti-
vated aldehydes (e.g., glyoxalates) or aldehydes bearing a
suitable boron-activating group, typically a free hydroxy
group (e.g., R-hydroxyaldehydes or salicylaldehyde).
In addition, the reaction usually proceeds well only with
electron-rich vinyl- and (hetero)arylboronic acids. Successful
examples with electron-poor, nonactivated boronic
acids are rare and require special reagents and substrate
combinations.3,4
In recent years, different approaches to overcome these
limitations have been developed. Nucleophilic activation
of the organoboron reagent with transition metal catalysts
leads to a somewhat greater flexibility in the choice of
starting materials, but there are still some limitations
regarding the exact nature of the aldehyde or arylboronic
acid (Scheme 1; transition metal catalyzed three-component
reaction).5,6 An alternative approach would be a similar
electrophilic activation of the in situ formed imine
(Scheme 1; addition of ArB(OH)2 to acyl imines). Several,
(5) (a) Yu, A.; Wu, Y.; Cheng, B.; Wei, K.; Li, J. Adv. Synth. Catal.
2009, 351, 767. (b) Frauenlob, R.; Garcıa, C.; Bradshaw, G. A.; Burke,
H. M.; Bergin, E. J. Org. Chem. 2012, 77, 4445.
(6) For some examples of transition metal catalyzed additions of
arylboronic acids to preformed imines or imine precursors, see: (a)
Tokunaga, N.; Otomaru, Y.; Okamoto, K.; Ueyama, K.; Shintani, R.;
Hayashi, T. J. Am. Chem. Soc. 2004, 126, 13584. (b) Bolshan, Y.; Batey,
R. A. Org. Lett. 2005, 7, 1481. (c) Jagt, R. B. C.; Toullec, P. Y.; Geerdink,
D.; de Vries, J. G.; Feringa, B. L.; Minnaard, A. J. Angew. Chem., Int.
Ed. 2006, 45, 2789. (d) Beenen, M.; Weix, D. J.; Ellman, J. A. J. Am.
Chem. Soc. 2006, 128, 6304. (e) Bakar, A.; Suzuki, Y.; Sato, M. Chem.
Pharm. Bull. 2008, 56, 973. (f) Dai, H.; Lu, X. Org. Lett. 2007, 9, 3077. (g)
Zhang, Q.; Chen, J.; Liu, M.; Wu, H.; Cheng, J.; Qin, C.; Su, W.; Ding, J.
Synlett 2008, 6, 935. (h) Dai, H.; Lu, X. Tetrahedron Lett. 2009, 50, 3478.
(i) Miyaura, N. Synlett 2009, 13, 2039. (j) Ma, G.-N.; Zhang, T.; Shi, M.
Org. Lett. 2009, 11, 875. (k) Chen, J.; Lu, X.; Lou, W.; Ye, Y.; Jiang, H.;
Zeng, W. J. Org. Chem. 2012, 77, 8541. (l) Johnson, T.; Lautens, M. Org.
Lett. 2013, 15, 4043.
(1) (a) Petasis, N. A.; Akritopoulou, I. Tetrahedron Lett. 1993, 34,
583. (b) Petasis, N. A.; Zavialov, I. A. J. Am. Chem. Soc. 1997, 119, 445.
(c) Petasis, N. A.; Zavialov, I. A. J. Am. Chem. Soc. 1998, 120, 11798.
(2) (a) Candeias, N. R.; Montalbano, F.; Cal, P. M. S. D.; Gois,
P. M. P. Chem. Rev. 2010, 110, 6169. (b) Ramadhar, T. R.; Batey, R. A.
Boronic Acids ꢀ Preparation and Applications in Organic Synthesis,
Medicine and Materials, 2nd ed.; Hall, D. G., Ed.; Wiley-VCH: Weinheim,
Germany, 2011; Vol. 2, Chapter 9, p 427.
(3) For rare exceptions with heteroarylaldehydes, see: (a) Schlienger,
N.; Bryce, M. R.; Hansen, T. K. Tetrahedron Lett. 2000, 41, 1303. (b)
Mandai, H.; Murota, K.; Suga, S. Heterocycles 2012, 85, 1655.
(4) For rare exceptions with arylboronic acids, see: Tremblay-Morin,
J.-P.; Raeppel, S.; Gaudette, F. Tetrahedron Lett. 2004, 45, 3471 and
ref 3b.
r
10.1021/ol402949t
XXXX American Chemical Society

suitable transition metal to activate simple commercial
available arylboronic acids for addition to the formed
reactive imine derivative. As a starting point for our
studies, we chose the reaction between benzamide (1a),
benzaldehyde (2a), and phenylboronic acid (3a) (Table 1).
Scheme 1. Classical and Modified Petasis Reactions
Table 1. Cooperative Dual Catalyzed Three-Component
Reaction: Influence of Reaction Parametersa
entry
variation from the “standard” conditions
yield (%)b
1
2
3
4
5
6
none
86
ꢀ
no Yb(OTf)3
no Pd(TFA)2
no 2,20-bipyridine
ꢀ
ꢀ
no H2O
<10
83
no H2O and Yb(OTf)3-hydrate, instead of
Yb(OTf)3
7
no H2O, with 5 mol % TfOH
þ 10 mol % 2,6-di-tert-butylpyridine
TfOH, instead of Yb(OTf)3
DCE, instead of CH3NO2
Pd(OAc)2, instead of Pd(TFA)2
Pd(PPh3)4, instead of Pd(TFA)2
1.2 equiv of PhB(OH)2, instead of 2.3 equiv
86
8
ꢀ
even enantioselective, direct additions of boronates to pre-
formed acyl imines or N,O-aminals have been reported.7
However, there is only one example of a Petasis-type
reaction utilizing such highly electrophilic acyliminium
salts,8 a copper-catalyzed three-component coupling of
imines and acid chlorides with tetraarylboranes.9
Herein we want to report a new, more general “amide”
version of the Petasis reaction using a cooperative dual
catalyst system capable of combining nucleophilic and
electrophilic activation.10 Our initial idea was to generate
the reactive acyl imine in situ via an acid-mediated con-
densation betweenanamide and analdehyde11 andtousea
c
9
ꢀ
10
11
12
13
84
50
ꢀ
55
a Reactions run at 0.5 mmol scale. b Isolated yield of analytical pure
product. c Benzhydrol was isolated in 67% yield. TFA = trifluoroace-
tate. DCE = 1,2-dichloroethane.
From a range of tested transition metal complexes
(based on Cu, Rh and Pd), palladium(II)-salts proved to
be the most active catalysts. While several Lewis acids
could catalyze this reaction, the use of Yb(OTf)3 gave the
highest and most reproducible yields. Best results were
obtained with Yb(OTf)3 in combination with Pd(TFA)2
(TFA = trifluoroacetate) and 2,20-bipyridine, furnishing
the desired product in 86% yield (Table 1, entry 1). In the
absence of the Lewis acid Yb(OTf)3, the transition metal
Pd(TFA)2, or 2,20-bipyridine12 no product is formed
(entries 2ꢀ4). Interestingly, the presence of small amounts
of water (typically 0.4ꢀ2.0 equiv) is crucial for obtaining a
high yield. In the absence of water the yield drops drama-
tically (entry 5). The amount of water present in the
hydrated form of Yb(OTf)3 is usually sufficient for a high
yielding reaction (entry 6).13 Since metal triflates are
known to hydrolyze to TfOH,14a we also investigated the
(7) (a) Wu, T. R.; Chong, J. M. Org. Lett. 2006, 8, 15. (b) Lou, S.;
Moquist, P. N.; Schaus, S. E. J. Am. Chem. Soc. 2007, 129, 15398. (c)
Bishop, J. A.; Lou, S.; Schaus, S. E. Angew. Chem., Int. Ed. 2009, 48,
4337.
(8) For some examples of acyliminium salts as highly electrophilic
intermediates, see: (a) Zaugg, H. Synthesis 1984, 85. (b) Speckamp,
W. N.; Moolenaar, M. J. Tetrahedron 2000, 56, 3817. (c) Maryanoff,
B. E.; Zhang, H.-C.; Cohen, J. H.; Turchi, I. J.; Maryanoff, C. A. Chem.
Rev. 2004, 104, 1431. (d) Petrini, M.; Torregiani, E. Synthesis 2007, 159.
(e) Yazici, A.; Pyne, S. G. Synthesis 2009, 339.
(9) Morin, M. S. T.; Lu, Y.; Black, D. A.; Arndtsen, B. A. J. Org.
Chem. 2012, 77, 2013.
(10) For some examples using two catalysts to separately generate
two or more active intermediates, see: (a) Sawamura, M.; Sudoh, M.;
Ito, Y. J. Am. Chem. Soc. 1996, 118, 3309. (b) Lee, J. M.; Na, Y.; Han,
H.; Chang, S. Chem. Soc. Rev. 2004, 33, 302. (c) Shao, Z.; Zhang, H.
Chem. Soc. Rev. 2009, 38, 2745. (d) Ikeda, M.; Miyake, Y.; Nishibayashi,
Y. Angew. Chem., Int. Ed. 2010, 49, 7289. (e) Raup, D. E. A.; Cardinal-
David, B.; Holte, D.; Scheidt, K. A. Nat. Chem. 2010, 2, 766. (f) Allen,
ꢀ
A. E.; MacMillan, D. W. C. Chem. Sci. 2012, 3, 633. (g) Nahra, F.; Mace,
(12) We assume that 2,20-bipyridine stabilizes the palladium(II)
species. In the absence of ligand, rapid formation of Pd-black occurs.
(13) For the exact water content of Yb(OTf)3 and Yb(OTf)3-hydrate,
see Supporting Information.
(14) (a) Wabnitz, T. C.; Yu, J.-Q.; Spencer, J. B. Chem.;Eur. J. 2004,
10, 484. (b) Dang, T. T.; Boeck, F.; Hintermann, L. J. Org. Chem. 2011,
76, 9353.
Y.; Lambin, D.; Riant, O. Angew. Chem., Int. Ed. 2013, 52, 2308.
(11) For recent examples utilizing an acid-catalyzed in situ genera-
tion of acyl imines, see: (a) Ba, T.; Ollevier, T. Tetrahedron Lett. 2003, 44,
9003. (b) Gandhi, S.; List, B. Angew. Chem., Int. Ed. 2013, 52, 2573. (c)
Schneider, A.; Manolikakes, G. Synlett 2013, 24, 2057. (d) Halli, J.;
Manolikakes, G. Eur. J. Org. Chem. 2013, published online DOI:
10.1002/ejoc.201301349.
B
Org. Lett., Vol. XX, No. XX, XXXX

possibility of catalysis by an in situ formed Brønsted acid.14b
Indeed, performing the reaction in the absence of water
but with 5 mol % TfOH furnished the desired product in
comparable yield (entry 7). Moreover, no product was form-
ed, when 2,6-di-tert-butylpyridine, a proton scavenger,14a
was added to the reaction (entry 8). On the other hand,
performing the reaction with TfOH as the Brønsted acid
catalyst led to the selective formation of benzhydrol, the
direct addition product of phenylboronic acid to benzal-
dehyde (entry 9). These results indicate that both Yb(OTf)3
and an in situ generated Brønsted acid are important for
the catalytic system.15 Comparable results were obtained
with 1,2-dichloroethane as the solvent (entry 10). While
the use of Pd(OAc)2 as the palladium source led to con-
siderable lower yields (entry 11), Pd(0)-species, such as
Pd(PPh3)4, were generally ineffective (entry 12). Perform-
ing the reaction with less than 2.3 equiv of phenylboronic
acid (3a) led to decreased yields of the desired amide 4
(entry 13).
53ꢀ87% yield (4cꢀ4e and 4g). Using our standard condi-
tions, secondary amides did not react with the exception of
the cyclic carbamate 2-oxazolidone (4h). To our delight,
carbamates could be used as an amide component, allow-
ing the efficient preparation of various N-protected amines
(4iꢀ4k). As the deprotection of products from typical
Petasis reactions is sometimes difficult,2 our method could
provide a more efficient approach to the often desired free
amines. In addition, the reaction with N-phthalyl-protected
valinamide furnished the product in 67% yield (4l).
We next examined reactions with various aryl aldehydes
(see Scheme 4). Aryl aldehydes bearing halogen or trifluoro-
methyl substituents in the ortho-, meta-, or para-position
Scheme 3. Variation of Amidesa
Based on the results from Table 1, a plausible mechan-
ism for the three-component reaction is shown in Scheme 2.
Scheme 2. Proposed Mechanism
A reactive acyl imine 5 is formed through a Lewis acid
catalyzed condensation between the amide and the alde-
hyde. An in situ released Brønsted acid could then pro-
tonate the formed acyl imine to give an even more reactive
acyliminium ion 6. We assume that the Lewis acid can
catalyze the acyl imine formation more efficiently.16
Simultaneously, the dicationic palladium(II) complex
reacts with the arylboronic acid to form a more nucleo-
philic arylpalladium(II) complex 7. Those two catalyti-
cally generated active intermediates, acyl imine 5 (or
acyliminium ion 6) and arylpalladium(II) species 7, can
subsequently react with each other to form the desired
product 4. However, further investigations are necessary
to elucidate the reaction mechanism and to confirm the
formation of the reactive acyliminium ion.
a Reactions run at 0.5 mmol scale. Isolated yields of analytical pure
products. b With Yb(OTf)3 þ H2O (2.0 equiv). c With 2.0 equiv of 1 and
1.0 equiv of 2a. TFA = trifluoroacetate. Fmoc = 9-fluorenylmethylox-
ycarbonyl-. Pht = N-phthalyl-.
afforded the desired product in good to excellent yields
(4mꢀ4r). In some cases better yields were obtained with
4,40-dinitro-2,20-bipyridine as the ligand (4q and 4x). Both
electron-poor and -rich aryl aldehydes are compatible
with our method, but electron-rich aldehydes, such as
4-methoxybenzaldehyde, just gave moderate yields (4sꢀ4u).
More importantly, N-heterocyclic aldehydes could be
employed as an aldehyde component, furnishing the
amides 4w and 4x in moderate yields.
With the optimized conditions established, the scope
and limitations of the method were explored. As shown in
Scheme 3, electron-rich and -poor aryl amides afforded the
corresponding R-substituted aryl amides in good yields (4b
and 4f). Moreover, various alkyl amides, such as trifluoro-
acetamide, worked well and gave the desired products in
Finally, an analogous series of reactions were performed
with various arylboronic acids (see Scheme 5). Ortho-
substituted or halogenated arylboronic acids provided
the desired products in good to high yields (4ab, 4p, and
4q). Only in the case of the sterically very hindered di-
ortho-substituted mesitylboronic acid a lower yield was
obtained (4z). Reactions with highly electron-rich or -poor
arylboronic acids, such as (4-methoxyphenyl)boronic
acid and (4-(ethoxycarbonyl)phenyl)boronic acid, were
also possible (4u and 4aa). Although the yields are low,
(15) Additional water might also facilitate the transmetalation of the
boronic acid to palladium.
(16) Control experiments with preformed acyl imines lead to a rapid
hydrolysis of the acyl imine under our standard reaction conditions.
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 4. Variation of Aryl Aldehydesa
Scheme 5. Variation of Arylboronic Acidsa
a Reactions run at 0.5 mmol scale. Isolated yields of analytical pure
products. b With 6 mol % 4,40-dinitro-2,20-bipyridine as ligand. c With
Yb(OTf)3-hydrate, no additional H2O. d With Pd(OAc)2, in 1,2-dichloro-
ethane. TFA = trifluoroacetate.
a Reactions run at 0.5 mmol scale. Isolated yields of analytical pure
products. b With 6 mol % 4,40-dinitro-2,20-bipyridine as ligand. c With
10 mol % Yb(OTf)3-hydrate. d With Yb(OTf)3 þ H2O (2.0 equiv). e In
1,2-dichloroethane. TFA = trifluoroacetate.
a useful extension of the classical Petasis reaction. Further
applications of this concept as well as the development of an
enantioselective reaction are currently being investigated in
our laboratory.
this is, to the best of our knowledge, the first example of
a Petasis-type reaction with an electron-deficient aryl-
boronic acid.17
It has to be emphasized that this reaction is very simple
to perform. It is not necessary to exclude air or moisture.
All shown reactions were performed without an inert
atmosphere in commercial grade solvents.
Acknowledgment. This work was financially supported
by the Fonds der Chemischen Industrie (Liebig Fellowship
to G.M.), the Stiftung Polytechnische Gesellschaft Frankfurt
am Main (PhD-Fellowship to T.B.), and the Goethe-
University (Nachwuchs im Fokus-Programm). We would
€
like to thank Prof. Michael Gobel (Goethe-University
Frankfurt) for his support and Rockwood Lithium
(Frankfurt) as well as Evonik Industries (Darmstadt) for
the generous gift of chemicals.
In summary, we have developed an efficient and prac-
tical three-component synthesis of R-substituted amides
from readily available amides, aryl aldehydes, and aryl-
boronic acids. A dual catalyst system, consisting of a Lewis
acid (Yb(OTf)3) and a palladium(II) salt, and the presence
of water in the reaction are key to a successful transforma-
tion. This new method has a very broad scope and represents
Supporting Information Available. Experimental pro-
cedures and characterization data for all compounds.
This material is available free of charge via the Internet
at http://pubs.acs.org.
(17) Using our standard conditions, alkenylboronic acids, such as
trans-β-styreneboronic acid, did not react.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX