Dual Catalytic Decarboxylative Allylations of α-Amino Acids and Their Divergent Mechanisms

Article abstract of DOI:10.1002/chem.201503644

The room temperature radical decarboxylative allylation of N-protected α-amino acids and esters has been accomplished via a combination of palladium and photoredox catalysis to provide homoallylic amines. Mechanistic investigations revealed that the stability of the α-amino radical, which is formed by decarboxylation, dictates the predominant reaction pathway between competing mechanisms.

Full text of DOI:10.1002/chem.201503644

DOI: 10.1002/chem.201503644
Communication
&
Homogeneous Catalysis
Dual Catalytic Decarboxylative Allylations of a-Amino Acids and
Their Divergent Mechanisms
Simon B. Lang, Kathryn M. O’Nele, Justin T. Douglas, and Jon A. Tunge*[a]
Abstract: The room temperature radical decarboxylative
allylation of N-protected a-amino acids and esters has
been accomplished via a combination of palladium and
photoredox catalysis to provide homoallylic amines. Mech-
anistic investigations revealed that the stability of the a-
amino radical, which is formed by decarboxylation, dic-
tates the predominant reaction pathway between com-
peting mechanisms.
Scheme 1. Anionic versus radical decarboxylation pathways.
Homoallylic amines are robust building blocks used to con-
struct a wide variety of natural products and other bioactive
molecules.[1] Classically, the addition of stoichiometric organo-
tive allylation of aminoalkanoic acids and esters.[11] A similar ap-
metallic nucleophiles to an electrophilic aldimine has furnished
these versatile molecules.[1,2] More recently, catalytic asymmet-
palladium and photoredox catalysis to effect the decarboxyla-
proach for the a-allylation of secondary amines and N-aryl tet-
ric methods including metal-free variants have been described
in the literature.[1,3]
rahydroisoquinolines has also been employed by Lu and
Xiao.[13] Herein we report that a dual catalytic approach allows
the decarboxylative allylation of protected amino acids and
peptides.
Alternatively, the palladium-catalyzed decarboxylative cou-
pling of a-imino esters has provided an umpolung approach
that couples 2-azaallyl anions with allyl electrophiles
(Scheme 1).[4] This method is advantageous because it uses
abundant, inexpensive carboxylic acid derivatives to access re-
active intermediates under neutral conditions via loss of CO2.[5]
One drawback is that the amine must be activated to stabilize
the a-amino anion to facilitate decarboxylation which leads to
regio- and chemoselectivity issues that limit the substrate
scope (Scheme 1).[6] We endeavored to extend this mode of re-
activity towards synthetically useful N-protected amino acids
that do not undergo anionic decarboxylation due to the for-
mation of highly basic alkyl amino anions by utilizing alternate
single electron pathways to facilitate decarboxylation.
One obstacle encountered in our lab during development of
the decarboxylative coupling of p-(aminophenyl)acetic acid
esters was the products were formed in moderate yields due
to the suspected formation of free radicals.[11] DFT calculations
on nickel-catalyzed radical cross-coupling by Molander and Ko-
zlowski indicate that free benzylic radicals and the nickel-
bound benzyl radical are nearly equienergetic[14] and radical
addition to the metal is reversible. Thus, we hypothesized that
accessing higher energy radicals should disfavor free radical
coupling by favoring formation of metal-bound radical inter-
mediates which can undergo reductive elimination. Readily
available amino acid derivatives bearing synthetically useful
electron withdrawing nitrogen protecting groups, which gen-
erate less stable alkyl radicals upon decarboxylation, were
chosen to test this hypothesis.
The radical decarboxylation of carboxylic acids has historical-
ly been accomplished via electrochemical,[7] photochemical,[8]
and reagent-based methods.[9,10] Recently, the combination of
transition metal and photoredox catalysis has also been used
to overcome high-energy two electron processes in catalysis
via single-electron-transfer (SET) events.[11,12] For example, Mac-
Millan[12g,h] and Molander[12i,j] have utilized photoredox events
to facilitate the generation of alkyl radicals which undergo
nickel-catalyzed cross-coupling. In addition, our lab has used
Optimization studies were initiated by combining Boc-pro-
line-allylester with [Pd(PPh3)4] and various visible-light-mediat-
ed photoredox catalysts [Eq. (1)]. Low conversion was ob-
served by GC/MS when the strongly reducing [Ir(dFppy)3][15]
(dFppy=2-(2,4-difluorophenyl)pyridinate) photocatalyst was
employed. Substituting more oxidizing cationic heteroleptic iri-
dium complexes led to an increase in conversion, but numer-
ous byproducts were also detected by GC/MS analysis. A sol-
vent screen revealed that the combination of the highly oxidiz-
ing photocatalyst Ir{dF(CF3)ppy}2(dtbbpy)[PF6] (dF(CF3)ppy=(2-
(2,4-difluorophenyl)-5-(trifluormethyl)pyridine, dtbbpy=4,4’-di-
tert-butyl-2,2’-bipyridine) (Ered1/2[Ir*III/IrII] = +1.21 V vs. SCE)[16]
[a] S. B. Lang, K. M. O’Nele, Dr. J. T. Douglas, Prof. Dr. J. A. Tunge
Department of Chemistry, The University of Kansas
2010 Malott Hall, 1251 Wescoe Hall Drive, Lawrence KS 66045 (USA)
E-mail: tunge@ku.edu
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201503644.
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Communication
line carboxylic acid was prepared. Tetrahydroisoqui-
nolines are widely used in photoredox couplings due
to the ease of access of the benzylically stabilized a-
amino radical; an excellent example involving the al-
lylation of tetrahydroquinoline by Xiao is shown in
Scheme 3.[13] When our tetrahydroquinoline carboxyl-
ic ester was subjected to the standard reaction condi-
tions, site-specific decarboxylative coupling to form
a CÀC bond occurred without isomerization to the
thermodynamically more stable radical occurred
1
(Scheme 3, >95% selectivity by crude H NMR spec-
troscopy).
We also recognized that, in many cases, it would
be beneficial to generate homoallylic amines directly
from carboxylic acids via an intermolecular process. It was ex-
pected that treatment of the free acid with [Pd(PPh3)4] and al-
lylmethyl carbonate would provide the same ionic intermedi-
ates (a carboxylate anion and Pd–p-allyl cation) that were gen-
erated from the amino acid allyl esters. Indeed, the Boc-pro-
with DMSO led to rapid conversion of the starting material
without the previously observed byproduct formation or signif-
icant deactivation of the active catalytic species.[17] Control re-
actions confirmed that no conversion of starting material to
product occurred when the reaction was conducted without
palladium, photocatalyst, or light.
We next evaluated the scope of a-amino allyl-
esters that underwent decarboxylative allylation to
furnish homoallyl amines (Scheme 2). A brief survey
of nitrogen protecting groups revealed that tert-butyl
and benzyl carbamates along with acetamides were
compatible with the reaction conditions (2a–2c). A
variety of phenylalanine derivatives bearing electron-
withdrawing (2d–2 f), halogen (2g, 2h), and elec-
tron-donating (2i), substituents on the aryl ring were
allylated in good yields. The reaction was also per-
formed on gram scale, but it required a longer reac-
tion time when it was performed under more con-
venient concentrated conditions (2h). A phenylala-
nine allyl ester bearing a tertiary amine and an N-Boc
phenylglycine allyl ester were also tolerated (2j, 2k).
Cyclic amino acid allyl esters derived from proline,
4-hydroxy-, thio-, and homoproline (2l–2o) were also
successfully allylated. Other acyclic tertiary homoallyl
amines were constructed from their amino allyl ester
precursors including alanine (2p), methionine (2q),
and aspartic acid (2r). A protected glycine allyl ester
provided a secondary homoallylic amine, albeit in re-
duced yield (2s). Nitrogen- (2u, 2v) and sulfur-con-
taining (2t) heterocycles also tolerated the reaction
conditions, although lower yields were observed
when pyridine (2v) or an unprotected indole (2u)
was present. Lastly, a b-methallyl ester provided the
desired homoallylic amine (2w), although a slightly
higher reaction temperature (458C) was required.
One of the hallmarks of anionic decarboxylative
couplings is that they are typically site-specific, lead-
ing to coupling only at the positon that bears the
carboxylate.[5a] With the goal of demonstrating that
the typical thermodynamic selectivity of a-amino rad-
ical formation can be overridden by the structure of
Scheme 2. Decarboxylative allylation of a-amino esters: [a] Reactions performed on
a 0.25 mmol scale at 0.13M. [b] Isolated yields. [c] Gram scale, 0.37M. [d] 95% pure. [e]
the starting material used in decarboxylative cou-
pling, the allyl ester of N-Boc tetrahydro-3-isoquino- Average yield of two runs.
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Communication
we propose that the amino carboxylate (for example, Boc-Pro-
OCs, E1/2 red = +0.95 V vs SCE)[18] is then oxidized by the photo-
excited iridium complex (kred1/2[Ir*III/IrII] = +1.21 V vs. SCE)[16]
which triggers radical decarboxylation to form an a-amino rad-
ical. If the radical is suitably stabilized then electron transfer
from the reduced iridium catalyst to the the PdII complex (A)
can result in homolysis to provide an allyl radical (path a,
Scheme 5).[19,20] The ensuing free radical coupling can produce
the allylated amine as well as diamine and hexadiene homo-
coupling products. Alternatively, if the a-amino radical is less
stable, it may prefer to coordinate to palladium generating
a PdIII intermediate (B)[12b,g,i,j] that behaves as a persistent radi-
cal.[21] Electron transfer from the reduced iridium complex prior
to or after reductive elimination would form the observed
product and regenerate Pd(0) (path b, Scheme 5).[12b,g,i,j] A simi-
lar possibility was proposed by Molander and Kozlowski on the
basis of DFT calculations of the pathways for nickel-catalyzed
photoredox coupling of borates and aryl halides.[14]
Scheme 3. Site-specific allylation.
tected amino acids phenylalanine and proline provided the
corresponding products 2a and 2l in higher yields than those
generated from their allylic ester counterparts (Scheme 4).
Next, several Boc-protected dipeptides, which contained both
amide and carbamate moieties that could potentially undergo
oxidation by the excited photo-
catalyst, were examined. The al-
lylated peptides were isolated in
moderate to good yields al-
though extended reaction times
were required.
Our initial hypothesis was that
higher yields of radical decarbox-
ylative allylation may be ach-
ieved by favoring metal-mediat-
ed CÀC bond formation while
avoiding free radical coupling.
On the basis of observations by
MacMiillan,[12b,g]
Molander,[12i,j]
and us,[11] two different potential
mechanistic pathways were pro-
posed (Scheme 5). In either case,
the cycle begins with oxidative
addition of the allyl ester to Pd0
Scheme 5. Divergent pathways for photoredox decarboxylative coupling.
which provides the cationic Pd–
p-allyl species and the carboxylate counterion. Since more oxi-
dizing photocatalysts are more effective for the transformation,
The allyl esters of N,N-dibenzyl phenyalanine (4), N-Boc phe-
nylglycine (5), and N-Boc phenylalanine (6) were prepared to
attempt to distinguish if radical stability influenced
whether CÀC bond formation was occurring within
the Pd coordination sphere (path b) or by an unde-
sired free radical (path a) or radical chain process. Ini-
tial evaluation of BDEs revealed that the a-amino rad-
ical species derived from 6 is ~5–6 kcalmolÀ1 higher
in energy than those derived from 4 and 5.[22] More-
over, the single electron oxidation potential of the
radical derived from 6 is expected to be endergonic
whereas oxidations of the radicals formed from 4 and
5 are exergonic.[19] In short, substrates 4 and 5 gener-
ate relatively stable radicals while substrate 6 gener-
ates a less stable radical (Figure 1).
To probe whether CÀC bond formation occurs
within the coordination sphere of the metal, 4–6
were subjected to slightly modified reaction condi-
tions using a chiral non-racemic palladium complex
Scheme 4. Decarboxylative allylation of a-amino acids: [a] Reactions performed on
a 0.25 mmol scale at 0.13M. [b] Isolated Yields. [c] Yields in parentheses refer to entries
in Scheme 2.
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Figure 1. Substrates and radical intermediates.
(Scheme 6). Substrate 6, which produces a more unstable radi-
cal post decarboxylation, provided enantioenriched product
which provides evidence that the CÀC bond is forming within
the coordination sphere of the chiral palladium complex. In
contrast, the reactions of 4 and 5, which generate more stabi-
lized radical intermediates, led to racemic or nearly racemic
products.
Scheme 7. Does Pd concentration affect homodimerization? [a] At a constant
substrate concentration of 0.0125M. [b] Reaction did not reach complete
conversion
In conclusion, we have devel-
oped a direct method for the de-
carboxylative allylation of a-
amino acid derivatives using
dual palladium and photoredox
catalysis to circumvent tradition-
Scheme 6. Stereochemical test for palladium involvement in CÀC formation.
al limitations in decarboxylative
couplings. The coupling is site-
specific for the position that
The results of reaction with a chiral palladium catalyst sug-
gest that substrate 6 reacts through a Pd-bound intermediate
while substrates 4 and 5 react primarily through free radical
coupling. One way to potentially test for free radical coupling
is to measure products of free-radical homocoupling. Toward
this end, 1H NMR spectroscopy was used to monitor the forma-
tion of 1,5-hexadiene via allyl-allyl coupling in reactions of 4–6.
That free radical coupling is the primary mechanism for the re-
action of 4 is supported by the observation of nearly statistical
amounts homodimerization was observed in much lower
quantity when 6, which produces a less stable a-amino radical,
was utilized (product/hexadiene=1.0:0.08). Similar NMR spec-
troscopic studies were used to examine the effect of palladium
of homodimerization products, including 1,5-hexadiene (prod-
uct/hexadiene=1.0:0.50).[23] In contrast, free radical concentra-
tion on the homodimerization of allyl radicals (Scheme 7).
The amount of hexadiene observed did not appreciably
change when the concentration of Pd was varied in the reac-
tion of 5, which indicates a Pd-independent CÀC bond forma-
tion (path a). Conversely, when 6, which forms a less stable
radical, was subjected to similar inquiry, the quantity of hexa-
diene was affected by the concentration of palladium. This ob-
servation suggests pathways a and b are competitive, but
pathway b is favored at higher palladium concentrations. Ulti-
mately, the simplest interpretation of the observations is that,
under our standard reaction conditions, less stable a-amino
radicals react primarily via metal-mediated CÀC bond forma-
tion, while more stabilized benzylic and a-tert-amino radicals
form CÀC bonds via radical coupling.
bears CO2, allowing the kinetic formation of contra-thermody-
namic radical species. Detailed studies of product and byprod-
uct formation implicate competing mechanisms for the cou-
pling, with more stable radicals preferring to react via radical
coupling and less stabilized radicals preferring to react via
metal-mediated coupling.
Acknowledgement
Support for this research was provided by the National Science
Foundation (CHE-1465172). Support for the NMR instrumenta-
tion was provided by NIH Shared Instrumentation Grant
# S10OD016360,
NIH
Shared
Instrumentation
Grant
# S10RR024664, and NSF Major Research Instrumentation
Grant # 0320648.
Keywords: allylation
·
amino acids
·
cross-coupling
·
homogeneous catalysis · photocatalysis
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Received: September 11, 2015
Published online on November 3, 2015
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