Synthesis of homoallylic amines via the palladium-catalyzed decarboxylative coupling of amino acid derivatives

Article abstract of DOI:10.1021/ja063115x

Protected homoallylic amines are synthesized by the decarboxylative coupling of α-amino acid derivatives. The catalytic C-C bond-forming reaction relies on the bioinspired decarboxylative metalation of α-amino acids to produce α-amino anion equivalents. The α-amino anion equivalents are intercepted by π-allyl palladium electrophiles to produce substituted homoallylic amines. Copyright

Full text of DOI:10.1021/ja063115x

Published on Web 07/15/2006
Synthesis of Homoallylic Amines via the Palladium-Catalyzed Decarboxylative
Coupling of Amino Acid Derivatives
Erin C. Burger and Jon A. Tunge*
UniVersity of Kansas, Department of Chemistry, 2010 Malott Hall, 1251 Wescoe Hall DriVe,
Lawrence, Kansas 66045
Received May 4, 2006; E-mail: tunge@ku.edu
Scheme 1
Due in part to their application in the synthesis of a variety of
heterocycles that are commonly found in biologically active
compounds, the synthesis of homoallylic amines has received much
attention.1 Traditional approaches for the synthesis of homoallylic
amines have focused on the addition of nucleophilic metal allyls
to electrophilic aldimines.2 Herein we report a complementary route
for the synthesis of protected homoallylic amines, which instead
couples an electrophilic allyl moiety with an R-amino anion derived
from an amino acid precursor.3
In nature, the generation of R-imino anions from R-amino acids
is achieved by pyridoxal 5′-phosphate (PLP)-dependent decarbox-
ylases.4 The transformation involves condensation of PLP with an
Scheme 2
amino acid to form an iminium carboxylate intermediate (Scheme
1). Decarboxylation produces the resonance-stabilized R-imino
anion, which is ultimately protonated. We postulated that decar-
boxylation could also be facilitated by stabilization of the incipient
charge with a transition metal rather than a proton, giving rise to
R-imino organometallic intermediates that may be useful in C-C
bond-forming reactions.
Our lab has recently demonstrated the effectiveness of palladium
Table 1. Substrate Scope for Protected Homoallylic Aminea
in promoting the decarboxylation of allylic esters in which the
anionic intermediate is stabilized by a ketone, a nitrogen-containing
heterocycle, or an alkyne.5,6 In an extension of this chemistry, we
now report that decarboxylation also readily occurs from allylic
esters of amino acids in which the amine is protected as a diphenyl
ketimine.
To begin, the allylic ester of phenylglycine was protected as a
ketimine via reaction with benzophenone imine to produce 1a.7
Decarboxylative coupling was facile at 25 °C when 1a was
subjected to the catalytic system of 5 mol % Pd2dba3 and 10 mol
% dppf [1,1′-bis(diphenylphosphino)ferrocene]. The major side
1
product (3a) observed by H and 13C NMR in this reaction arises
from nucleophilic attack of the R′ carbon into the Pd π-allyl,
suggesting the accessibility of a 2-aza-allyl intermediate akin to B
(Scheme 2). Reaction through ion pairs is also possibile. The ratio
of 2a/3a was found to have a moderate solvent dependence. When
the reaction was run in toluene at room temperature, a 2.5:1 ratio
of products was obtained, while in THF, the selectivity improved
a Conditions: A ) 5 mol % Pd2dba3 and 10 mol % dppf; B ) 5 mol %
to 5:1. Protonation of the putative intermediate R-imino anion was
Pd2dba3 and 10 mol % dppb. Substrates 1a-f in 0.1 M THF, 1g, h, and j
in 0.1 M toluene, and 1i in 0.1 M dioxane.
also found to lead to a minor side product with certain substrates;8
in these cases, the use of dppb [1,1′-bis(diphenylphosphino)butane]
as the ligand minimized the amount of protonation.
at or above 100 °C. Presumably, this reflects the higher activation
energy required to form an R-imino anion that is no longer benzylic.
Nevertheless, decarboxylative coupling of phenylalanine-derived
substrates 1g-i occurred smoothly at elevated temperatures (Table
1). The valine-derived substrate 1j also underwent decarboxylative
coupling, albeit in low yield.
Surprisingly, attempted coupling of the phenylalanine-derived
ketimine 1k bearing an unsubstituted allyl ester led to the
predominant formation of N-allyl aziridine 4k (Table 2). N-allyl
aziridines proved to be the major products arising from the
Modification of the allyl group was also found to impact the
regioselectivity of allylation. When the 2-methallyl ester was
utilized, the reaction rate decreased, however, the regioselectivity
and isolated yields of desired products were greatly improved (Table
1). For example, decarboxylation of 1d resulted in a 5:1 mixture
of 2d/3d, while 1e reacted with an improved regioselectivity of
13:1.
The decarboxylation of substrates derived from phenylalanine
(R1dCH2Ph) proved to be more difficult, requiring temperatures
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10.1021/ja063115x CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Substrate Scope for Aziridine Formationa
Scheme 3
a Conditions: A ) 5 mol % Pd2dba3 and 10 mol % dppf; B ) 5 mol %
Pd2dba3 and 10 mol % dppb. Substrates 1k and 1n in 0.1 M toluene and 1l
and 1m in 0.1 M dioxane.
leading to intermediate C. Similar to proton-catalyzed decarbox-
ylation, coordination of nitrogen is expected to facilitate decar-
boxylation to produce intermediate E. Here the reaction can follow
one of two pathways. A 1,2 shift of palladium gives F, which can
form 2 upon reductive elimination. Alternatively, in analogy to
related azomethine ylides,12 E can undergo electrocyclization to
yield aziridine G.13 Reductive elimination would liberate N-allyl
aziridine 4.
In conclusion, we have demonstrated a bioinspired method for
the synthesis of protected homoallylic amines. The key step in the
reaction involves formation of nucleophilic R-imino anion equiva-
lents via decarboxylative metalation of R-amino acid derivatives.
Subsequent addition to electrophilic π-allyl palladium intermediates
allows C-C bond-forming reactions. We have also identified a
unique decarboxylative cyclization that leads to N-allyl aziridine
products and provides interesting mechanistic insights.
decarboxylation of substrates 1k-n in which an unsubstituted Pd
π-allyl intermediate coupled with an alkyl-substituted amino acid
(Table 2).9
Next, preliminary experiments were performed with the goal of
investigating the mechanism of the decarboxylative C-C coupling
reaction. First, the stereochemical course of the reaction was probed
by treatment of allyl ester 1b derived from (R)-phenylglycine (83%
ee) under standard reaction conditions. The resulting product (2b)
was racemic. Importantly, the reactant 1b was still optically active
at 75% conversion (82% ee). Thus, an intermediate is formed that
is achiral or rapidly racemizes under the reaction conditions but is
not in equilibrium with an R-imino ester. This implies that the
stereochemical determining step is after decarboxylation and that
appropriate chiral ligands may promote enantioselective coupling.
Indeed, treatment of 1g with 5 mol % Pd2dba3 and (R)-BINAP
provided optically active 2g, however, the enantioselectivity is not
high (30% ee).8
Acknowledgment. We thank the National Science Foundation
(CHE-0548081) and the Petroleum Research Fund (44453-AC1)
for financial support. E.C.B. is supported as a Madison and Lila
Self fellow.
Further mechanistic insight was obtained from the reaction of
R-disubstituted substrate 1o. Decarboxylative coupling of 1o
occurred under mild conditions to give a 1:1 mixture of R and R′
allylated products (eq 1). Because 1o lacks an R-hydrogen, coupling
can only take place if decarboxylation precedes allylation.
Supporting Information Available: Experimental procedures and
characterization data for all new compounds (PDF). This material is
available free of charge via the Internet at http://pubs.acs.org.
References
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To probe the role of palladium in the decarboxylation process,
sodium carboxylate 5-Na was heated in the absence of palladium
for 12 h at 110 °C in toluene (eq 2). It was found that, in contrast
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Similar treatment of the sodium carboxylate in the presence of
(allyl)Pd(dppf)BF4 resulted in quantitative decarboxylation, how-
ever, the major product resulted from decarboxylative protonation.10
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in activating the substrate for decarboxylation and may facilitate
decarboxylation by a mechanism similar to that for thermal
decarboxylation in the presence of protons. Proton-induced decar-
boxylation of amino acid imines is known to proceed by formation
of stabilized azomethine ylide intermediates.11 Thus, it is possible
that the analogous palladium-stabilized azomethine ylides are
intermediates in the decarboxylative coupling of amino acids.
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(8) See Supporting Information for more details.
(9) For reasons that are not clear, substrate 1i proved to be an exception.
(10) The protons may originate from the ligand, which would be consistent
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performing catalysis in rigorously dried solvents.
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As illustrated in Scheme 3, imine and aziridine formation both
are likely to begin with the oxidative addition of substrate to Pd0,
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