Derailing the Wacker oxidation: Development of a palladium-catalyzed amidation reaction

Article abstract of DOI:10.1021/ol0066882

(equation presented) 96 % isolated yield A conceptually new palladium-catalyzed amidation reaction is described for the synthesis of β-amido ketones based on derailing the Wacker oxidation of enones. This reaction generates a new carbon-nitrogen bond via a palladium-catalyzed conjugate addition of a carbamate nucleophile to an enone. The regiocontrol, mild and neutral conditions, lack of preactivation of the nucleophile, and lack of reoxidation system for the catalyst are attractive features of this transformation.

Full text of DOI:10.1021/ol0066882

ORGANIC
LETTERS
2
001
Vol. 3, No. 1
5-28
Derailing the Wacker Oxidation:
Development of a Palladium-Catalyzed
Amidation Reaction
2
Matthew J. Gaunt and Jonathan B. Spencer*
UniVersity Chemical Laboratory, Lensfield Road, Cambridge CB2 1EW, U.K.
jbs20@hermes.cam.ac.uk
Received October 4, 2000
ABSTRACT
A conceptually new palladium-catalyzed amidation reaction is described for the synthesis of â-amido ketones based on derailing the Wacker
oxidation of enones. This reaction generates a new carbon−nitrogen bond via a palladium-catalyzed conjugate addition of a carbamate nucleophile
to an enone. The regiocontrol, mild and neutral conditions, lack of preactivation of the nucleophile, and lack of reoxidation system for the
catalyst are attractive features of this transformation.
4
Molecules bearing 1,3-amino-oxygenated functional motifs
are ubiquitous to a variety of biologically important natural
oxidation states. It is notable, though, that there are fewer
developments for palladium(II) catalysts than for the corre-
1
5
products. The development of new methods for their
sponding palladium(0) sources.
2
assembly is therefore of considerable synthetic importance.
We have been interested in how the interaction of
electrophilic palladium(II) catalysts with alkenes can activate
the carbon-carbon double bond to attack by heteroatom
nucleophiles. Our interest in the mechanism of such reactions
led us to consider how it may be possible to exploit the
electronic structure of the alkene in order to control the
regioselectivity of such reactions.
Of particular interest would be a facile method for the
construction of â-amino-ketones, as these molecules are
versatile precursors for 1,2 and 1,3 amino alcohols and
â-amino acids (Figure 1).
Previous studies on the Wacker oxidation had led us to
consider whether the use of nitrogen nucleophiles in a similar
type of reaction is possible. Palladium(II)-mediated addition
(2) For representative examples, see: (a) Drury, W. J., III; Ferraris, D.;
Cox, C.; Young, B.; Leckta, T. J. Am. Chem. Soc. 1998, 120, 11006. (b)
Hagiwara, E.; Fujii, A.; Sodeoka, M. J. Am. Chem. Soc. 1998, 120, 2474.
Figure 1. Examples of 1,3-amino-oxygenated molecules.
(c) Hawkins, J. M.; Fu, G. J. Am. Chem. Soc. 1986, 51, 2820. (d) Enders,
D.; Muller, S. F.; Raabe, G. Angew. Chem., Int. Ed. 1999, 38, 195. (e)
Myers, J. K.; Jacobsen, E. N. J. Am. Chem. Soc. 1999, 121, 8959. (f) Evans,
D. A.; Wu, L. D.; Wiener, J. J. M.; Johnson, J. S.; Ripin, D. H. B.; Tedrow,
J. S. J. Org. Chem. 1999, 64, 6411.
The use of transition metal catalysts has influenced the
development of new synthetic technology in recent years.
In particular, palladium catalysts have enjoyed widespread
use in a large number of chemical transformations due to
the versatility displayed by this metal over two stable
3
(3) For highlights, see: (a) Overman, L. E.; Ricca, D. J.; Tran, V. D. J.
Am. Chem. Soc. 1997, 119, 12031. (b) Nicolaou, K. C.; Chakraborty, T.
K.; Piscopio, A. D.; Minowa, N.; Bertinato, P. J. Am. Chem. Soc. 1993,
115, 4419. (c) Takaya, H.; Ohta, T.; Mashima, K.; Noyori, R. Pure Appl.
Chem. 1990, 62, 1135. (d) Trost, B. M.; Van Vranken, D. L. Chem. ReV.
1996, 96, 395.
(
4) Tsuji, J. In Palladium Reagents and Catalysts; John Wiley & Sons
(
1) Seebach, D.; Matthews, J. L. J. Chem. Soc., Chem. Commun. 1997,
015. Juaristi, E. In EnantioselectiVe Synthesis of â-amino acids; John Wiley
Sons: New York, 1997.
Ltd.: Chichester, 1996.
(5) For example, see: Uozumi, Y.; Kat, K.; Hayashi, T J. Am. Chem.
Soc. 1997, 119, 5063 and references therein.
2
&
1
0.1021/ol0066882 CCC: $20.00 © 2001 American Chemical Society
Published on Web 12/15/2000

of nitrogen nucleophiles to alkenes is a common reaction
and is thought to be closely related to the Wacker oxidation.
Our attention was initially focused on the polarized enone
system. The preliminary investigations on this reaction
6
10
Thus, following the addition of the nucleophile to the
palladium-complexed alkene, â-hydride elimination takes
place, resulting in a net vinylic substitution to form enamine,
appeared promising, with amines such as propylamine adding
1
1
to simple enones. However, problems were encountered
with the isolation of these â-amino ketones, presumably due
to facile â-elimination. Furthermore, aliphatic amines are
known to readily displace complexed alkenes from palladium
and it is possible that the formation of the product was the
7
enamide, or allylic amide-type products. Most of these
examples though, involve an intramolecular nitrogen nucleo-
phile. Few examples of the corresponding intermolecular
8
6
reaction have been reported. If the conventional Wacker
result of uncatalyzed Michael addition. Changing the
oxidation could be derailed, by preventing â-hydride elimi-
nation, it may be possible to form an sp hybridized carbon-
nitrogen bond.
nitrogen source to a carbamate overcame these problems.
The carboxy group reduces the binding ability of the nitrogen
atom to the palladium center, thus preventing an undesirable
interaction with the alkene-palladium complex while main-
taining sufficient nucleophilic character to attack the activated
3
In this Letter we wish to report our first results on the
development of a new palladium-catalyzed amidation. This
reaction generates a new carbon-nitrogen bond via a
palladium-catalyzed conjugate addition of a carbamate nu-
cleophile to an enone. The regiocontrol, mild and neutral
conditions, lack of preactivation of the nucleophile, and lack
of reoxidation of the catalyst are attractive features of this
transformation.
7
enone.
Therefore, in the presence of 10 mol % of bis(acetonitrile)
palladium(II) chloride and benzyl carbamate (1.5 equiv) in
anhydrous dichloromethane (0.5 M wrt enone), enone 1a (1
equiv) was converted to the â-amido ketone 2a in 83%
1
2
isolated yield. The reaction was complete after stirring for
24 h at room temperature under an inert atmosphere.
Dichloromethane was determined to be the superior solvent
for the reaction, and raising the temperature made little
difference to the outcome of the reaction. There was no
reaction in the absence of the catalyst, indicating that this
was indeed a palladium-mediated reaction.
The Wacker oxidation of R,â-unsaturated esters leads to
9
the exclusive formation a â-ketoester. Such absolute regio-
selectivity is rare in the oxidation of internal alkenes and is
probably controlled by the electronic nature of the carbon-
carbon double bond. The intermediate in this reaction must
involve the formation of a species such as A (Scheme 1).
To explore the scope of the reaction, a number of simple
enones were tested under the optimized reaction conditions
1
3
(
Table 1). Acyclic enones 1a-c were smoothly converted
Scheme 1. New Strategy for Palladium-Catalyzed Amidation
to the corresponding â-amido ketones 2a-c in good yields
after purification by flash silica gel chromatography. Enone
1
d did not react, possibly because reaction would require
the breaking of the conjugated system between carbonyl and
aryl groups. Cyclic enone 1e was also a good substrate for
the reaction and generated 2e in 65%. Interestingly, changing
the ratio of ketone to carbamate influences the reaction.
When the enone was in excess, the reaction times were found
(10) No reaction was observed with R,â-unsaturated esters under the
conditions described in ref 13. In comparison to the intermediate palladium
enolate A/A-I, Scheme 1, the corresponding intermediate developed from
the R,â-unsaturated ester we believe would be less stable and hence less
likely to form.
(11) Initial experiments were also conducted using benzyl alcohol. Thus,
enone 1b could be converted to the corresponding â-benzyloxy ketone in
good yield. This reaction has been noted previously: Hosokawa, T.;
Sinohara, T.; Ooka, Y.; Murahashi, S.-I. Chem. Lett. 1989, 2001. However,
in our hands their results could not be reproduced and substantial
modifications of the reaction conditions were required in order to produce
a reliable quantity of the desired product. We also note that 1b was the
only enone with which good results could be obtained.
We were intrigued by the possibility that if we could suppress
â-hydride elimination, then A could tautomerize to the
palladium enolate A-I, forming a 1,4-addition product instead
of the following the conventional Wacker mechanism. A
strategy of this nature would be ideal for the assembly of
â-aminocarbonyl derivatives.
1
(
12) Ketones 2a-h were characterized by H and 13C NMR (500 and
6
2.5 MHz, respectively) spectroscopy and high-resolution mass spectrom-
etry.
(13) Representative procedure: A solution of enone (1 equiv) and
(
6) Hegedus, L. In ComprehensiVe Organic Synthesis; Trost. B. M.,
Fleming, I., Eds.; Pergamon Press: New York, 1991; Vol. 4, pp 463-551.
7) (a) Van Benthem, R. A. T. M.; Hiemstra, H.; Longarela, G. R.;
benzyl carbamate (1.5 equiv) in anhydrous dichloromethane (1 mL per mmol
enone) was added to a stirred solution of bis(acetonitrile)palladium(II)
chloride (10 mol %) in anhydrous dichloromethane (1 mL per mmol enone)
under an inert atmosphere. The reaction mixture is stirred at room
temperature until completion, shown by TLC analysis. The reaction mixture
was diluted with diethyl ether and filtered through a pad of silica, and the
filtrate was concentrated and purified by flash chromatography.
(
Speckamp, W. N. Tetrahedron Lett. 1994, 35, 9821. (b) Harayama, H.;
Tamura, Y.; Hojo, M.; Yoshida, Z. J. Org. Chem. 1988, 53, 5741. (c) Jager,
V.; Hummer, W Angew. Chem., Int. Ed. Engl. 1990, 29, 1171.
(
8) For examples, see: Muller, T.; Beller, M. Chem. ReV. 1998, 98, 675.
(9) Tsuji, J.; Nagashima, H.; Hori, K. Chem. Lett. 1980, 257.
26
Org. Lett., Vol. 3, No. 1, 2001

Table 1. Palladium(II)-Catalyzed Amidation on Enones
Table 2. Palladium(II)-Catalyzed Amidation on Trisubstituted
Enones
a
All reactions were carried out on 1 mmol scale under an argon
atmosphere at room temperature with 10 mol % of (MeCN)2PdCl2, Cbz-
NH2 (1.5 equiv) in anhydrous dichloromethane (0.5 M). b After purification
by flash silica gel chromatography.
1
relative stereochemistry of 2h is anti, based on the H NMR
coupling constant (J ) 11.0 Hz).
Other palladium(II) catalysts were also tested in this
1
4
reaction. The results are summarized in Table 3. From the
a
All reactions were carried out on 1 mmol scale under an argon
atmosphere at room temperature with 10 mol % of (MeCN)2PdCl2, Cbz-
b
NH2 (1.5 equiv) in anhydrous dichloromethane (0.5 M). After purification
Table 3. The Effect of Cationic Palladium(II) Catalysts
c
by flash silica gel chromatography. Cyclohexenone: Cbz-NH2 ) 2:1.
d
Cyclohexenone: Cbz-NH2 ) 3:1.
to be significantly reduced and the yields increased to around
80%. Increasing the concentration of the enone may favor
the formation of the alkene-palladium complex in solution
and thus decreases the time required for completion of the
reaction. This observation also suggests that the reaction may
be reversible and that an excess of either reagent can drive
the reaction to completion. Nevertheless, this allows the
development of a second set of reaction conditions where
the ratio of ketone to carbamate is 2-3:1 in a dichloro-
methane solution (0.5 M with respect to carbamate). Hence,
the new reaction offers an unprecedented level of flexibility
with respect to the use of excesses of reagents. It is possible
to perform the reaction either with excess enone or with
excess carbamate.
optimization studies, we had determined that bis(acetonitrile)
palladium(II) chloride was the catalyst of choice from the
range of available neutral palladium(II) salts. However, we
were intrigued by the possibility that cationic palladium salts
may also catalyze the reaction. Indeed, tetrakis(acetonitrile)
palladium(II) tetrafluoroborate promotes the reaction. Using
this catalyst the amount required can be dramatically reduced
to 1 mol % without affecting the yield. This is also important
for any future development of an asymmetric version of this
reaction, as it would reduce the amount of catalyst and ligand
used.
Trisubstituted alkenes are less reactive than their mono-
and disubstituted homologues due to increased steric interac-
7
tion with the palladium center. We were pleased to discover
that trisubstituted enones could be converted to the corre-
sponding â-amido ketones in some cases (Table 2).
For example, mesityl oxide 1f was converted to 2f in good
yield. However, its regioisomer 1g does not react at all.
Cyclic enone 1h, though, can be converted to 2h, albeit in
modest yield after extended reaction time. The reactivity of
Although the mechanism of this reaction is still unclear,
some proposals can be put forward. First, if the reaction were
to follow a Wacker-type mechanism, then the initial step
1h compared to 1g may be due to release of the inherent
ring strain from 1h upon formation of the product. The
(14) There was no reaction using Pd(OAc)2, (PPh3)3PdCl2, or Pd(TFA)2.
Org. Lett., Vol. 3, No. 1, 2001
27

R-position, the reaction is retarded, suggesting that an
unfavorable steric interaction may result from the location
of the palladium at this position.
Scheme 2. Proposed Mechanism for Amidation Reaction
An alternative explanation involves enone activation
through palladium complexation to the carbonyl oxygen atom
(not shown). This will facilitate a conjugate addition of the
nucleophile to the â-carbon atom. Although this pathway
seems unlikely for neutral palladium(II) sources, it may be
1
7
competitive when cationic catalysts are used.
In summary, a new palladium-catalyzed amidation reaction
has been developed that involves the addition of a carbamate
nucleophile to an enone. The reaction is performed under
extremely mild conditions and has been shown to be
amenable to a range of enone substrates. We are currently
investigating the mechanism of the reaction and the scope
of nitrogen nucleophiles that may be utilized. On the basis
of the outcome of these investigations, we will explore an
enantioselective reaction using asymmetric catalysts and/or
chiral nitrogen sources and whether diastereocontrol is
possible with γ-substituted enones. We believe that this
methodology has a great deal of potential and could find
widespread use in organic synthesis.
would be formation of a π-alkene-palladium complex, X-I
1
5
(Scheme 2). This complex would activate the enone by
enhancing the partial positive charge on the â-carbon atom.
Heteroatom nucleophilic addition to alkenes tends to occur
from the opposite face to that occupied by palladium (distall
Acknowledgment. We thank Royal Society for a Uni-
versity Research Fellowship (J.B.S.) and The Wellcome Trust
1
5
addition) and would lead to the formation of X-II. The
palladium bond in X-II is weakened by the presence of the
adjacent ketone group and may tautomerize to enolate X-III.
The palladium is then eliminated from the substrate through
protonolysis, forming the product and regenerating the
(M.J.G).
Supporting Information Available: Spectral data for all
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
16
catalyst. It is not clear whether protonolysis occurs through
X-II or X-III. Evidence for the location of the palladium on
the R-carbon atom is drawn from the relative reactivities of
enones 1f and 1g. When the enone bears a substituent at the
OL0066882
(16) For examples, see: Takaya, Y.; Ogasawara, M.; Hayashi, T. J. Am.
Chem. Soc. 1998, 120, 5579. Hosokawa, T.; Ohta, T.; Kanayama, S.;
Murahashi, S.-I. J. Org. Chem. 1987, 52, 1758. Lei, A.; Lu, X. Org. Lett.
2000, 2, 2699. Wang, Z.; Lu, X. J. Org. Chem. 1996, 61, 2254.
(
15) Tsuji, J. In ComprehensiVe Organic Synthesis; Trost. B. M., Fleming,
I., Eds.; Pergamon Press: New York, 1991; Vol. 3, 449.
(17) Oi, S.; Kashwagi, K.; Inoue, Y. Tetrahedron Lett. 1998, 39, 6253.
28
Org. Lett., Vol. 3, No. 1, 2001