Decarboxylative arylation of α-Amino acids via photoredox catalysis: A one-step conversion of biomass to drug pharmacophore

Article abstract of DOI:10.1021/ja501621q

The direct decarboxylative arylation of α-amino acids has been achieved via visible light-mediated photoredox catalysis. This method offers rapid entry to prevalent benzylic amine architectures from an abundant biomass, specifically α-amino acid precursors. Significant substrate scope is observed with respect to both the amino acid and arene components.

Full text of DOI:10.1021/ja501621q

Communication
pubs.acs.org/JACS
Decarboxylative Arylation of α‑Amino Acids via Photoredox
Catalysis: A One-Step Conversion of Biomass to Drug
Pharmacophore
Zhiwei Zuo and David W. C. MacMillan*
Merck Center for Catalysis, Princeton University, Princeton, New Jersey 08544, United States
S
* Supporting Information
ABSTRACT: The direct decarboxylative arylation of
α-amino acids has been achieved via visible light-
mediated photoredox catalysis. This method offers rapid
entry to prevalent benzylic amine architectures from an
abundant biomass, specifically α-amino acid precursors.
Significant substrate scope is observed with respect to
both the amino acid and arene components.
he controlled excision of carbon dioxide from organic
molecules, commonly known as decarboxylation, is a
T
valuable transformation that is fundamental to biochemistry and
broadly utilized in synthetic molecule construction. For example,
in nature, enzymatically controlled regioselective decarboxylation
allows the conversion of the abundant biomonomer glutamic acid
to γ-aminobutyric acid (GABA), an important neurotransmitter
in the mammalian central nervous system (eq 1).1 Synthetic
chemists also rely on decarboxylative technologies as a means to
remove extraneous carboxyl groups2 with protocols such as the
Kolbe,3 Hunsdiecker,4 and Barton decarboxylations5 having long-
proven value.
Given the worldwide abundance of biomass6 that incorporates
carboxylate functionality (e.g., amino acids, α-hydroxy acids, fatty
acids etc), there is a strong impetus to invent or discover
chemical transformations that target carboxylic acids as chemo-
selective leaving groups for new and valuable C−C bond forming
reactions. More specifically, the productive engagement of
decarboxylation mechanisms into fragment-coupling bond
constructions could enable the direct conversion of abundant,
inexpensive substrates to complex, medicinally relevant
pharmacophores. The seminal studies of Myers7 and Gooßen8
have demonstrated that classical organometallic catalytic
coupling pathways (Heck, biaryl couplings) can be accessed via
aryl and alkynyl carboxylic acids.9 Recently, we questioned
whether Csp −Csp -bearing carboxylates (the carboxyl moiety
most commonly found in biomass) might be rendered suitable
for decarboxylative aryl couplings via the use of a novel
photoredox-mediated radical−radical coupling pathway. Herein
we describe the successful execution of these studies and
demonstrate the direct conversion of broadly available α-amino
acids or α-oxy acids with arene substrates to generate high-value
benzylic amine or ether architectures using photoredox catalysis.
The benzylic amine is a central component of a wide range
of medicinally relevant compounds, including pharmaceuticals,
agrochemicals, and bioactive natural products.10 The develop-
ment of improved methods for the synthesis of these important
pharmacophores from readily available starting materials remains
an important challenge in organic synthesis.11 A recent focus
of our laboratory has been the development of visible light-
mediated photoredox catalysis as a general strategy for achieving
challenging bond constructions not readily accessible via classical
two-electron pathways and without the need for harsh conditions
or toxic reagents.12,13 Along these lines, we recently described
a photoredox-catalyzed amine C−H arylation for the synthesis
of benzylic amines via the coupling of tertiary amines with
cyanoarenes.12 With the goal of further expanding the menu
3
2
Received: February 15, 2014
Published: March 12, 2014
© 2014 American Chemical Society
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Scheme 1. Proposed Catalytic Cycle for Decarboxylative
Arylation
Table 1. Optimization of the Decarboxylative Arylation
a
entry
photocatalyst
base
% yield
1
2
3
4
5
6
7
Ir(ppy)3
Ir(p-F-ppy)3
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2HPO4
CsF
12
58
of amine α-functionalization capabilities, we anticipated that
α-amino acid radical decarboxylation, coupled with in situ
arylation, could provide rapid access to a wealth of complex
primary and secondary benzylic amine pharmacophores using
readily available biomass.
Design Plan. As outlined in eq 2, our general strategy
envisioned photoredox-mediated single-electron oxidation of the
carboxylate functionality of an α-amino acid, followed by loss of
CO2, to render an α-carbamoyl radical. Radical−radical coupling
of this species with the radical anion derived from an arene
coupling partner should forge the benzylic C−C bond to provide,
following aromatization via expulsion of cyanide, the high-value
benzylic amine motif.
Ir(dFppy)3
54
Ir[dF(CF3)ppy]2(dtbbpy)
Ir[p-F(t-Bu)-ppy]3
Ir[dF(t-Bu)-ppy]3
Ir[p-F(t-Bu)-ppy]3
Ir[p-F(t-Bu)-ppy]3
none
trace
73
68
83
b
8
CsF
0
9
CsF
0
10
Ir[p-F(t-Bu)-ppy]3
none
trace
a
b
1
Yield determined by H NMR using an internal standard. Reaction
performed in the absence of visible light. A series of Ru-based
catalysts were unsuccessful. High-dielectric solvents are required (e.g.,
entry 7, DMSO = 83% yield, DMA = 74% yield, hexane = NR).
c
d
A detailed mechanism for the proposed photoredox
decarboxylative aryl coupling is shown in Scheme 1. Irradiation
of tris(2-phenylpyridinato-C2,N)iridium(III) [Ir(ppy)3] (1)
with visible light produces a long-lived (1.9 μs) photoexcited
state,14 *Ir(ppy)3 (2), which can be readily oxidized or reduced
by an appropriate substrate quencher. Given that *Ir(ppy)3 (2) is
a strong reductant (E1/2red [IrIV/*IrIII] = −1.73 V vs SCE),14 we
presumed that facile reduction of 1,4-dicyanobenzene 3 (X =
C−CN, E1/2red = −1.61 V vs SCE)15 via single electron transfer
would generate the corresponding aryl radical anion 4.16 At this
stage, oxidation of the α-amino acid substrate by IrIV(ppy)3
to generate the corresponding carboxyl radical species (with
subsequent extrusion of CO2) would yield the requisite α-amino
radical 6. A survey of relevant oxidation potentials reveals that
delighted to find that the proposed decarboxylative arylation
coupling was feasible under these conditions, the observed
reaction efficiency was poor (entry 1, 12% yield). As stated
above, we recognized that electron transfer from Boc-prolinate
14
red
to IrIV(ppy)3 (E1/2 [IrIV/IrIII]= +0.77 V vs SCE) could be
thermodynamically challenging, and as such, we turned our
attention to the identification of more strongly oxidizing photo-
catalysts. As expected, incorporation of a fluorine substituent
onto the pyridine backbone of the photocatalyst provided a
significant increase in efficiency. More specifically the Ir(p-F-
ppy)3 and Ir(dFppy)3 photocatalysts (E1/2 [IrIV/IrIII] =
red
+0.97 V and +1.13 V vs SCE in CH3CN, respectively)18
provided significantly enhanced yields of the desired α-amino
arylation product (entries 2−3). It is important to note that
highly oxidizing photocatalysts, such as Ir[dF(CF3)ppy]2-
(dtbbpy)PF6,19 were largely ineffective in this coupling protocol
(entry 4), presumably due to their inability to participate in the
arene reduction step of the catalytic cycle.
red
this carboxylate oxidation step is endergonic as proposed (E1/2
[IrIV/IrIII] = +0.77 V vs SCE), (Boc-Pro-OCs+, Ered = +0.95 V vs
SCE);17 however, we recognized that electronic adjustment
of the photocatalyst ligands might render this decarboxylation
thermodynamically feasible. At this stage we hoped that
chemoselective heterocoupling of the persistent radical 4 with
the transiently formed α-amino radical 6 would efficiently enable
the requisite C−C fragment coupling, and subsequent loss of
cyanide would deliver the benzylic amine 7.
On the basis of these findings, we sought to design a
photocatalyst system that would be more strongly reducing
than Ir(p-F-ppy)3 (E1/2 [IrIV/*IrIII] = −1.60 V vs SCE) or
red
Our initial investigations focused on the identification of a
suitable photocatalyst capable of facilitating both single-electron
reduction of the arene and single-electron oxidation of the
α-amino acid (Table 1). We first examined the coupling of
Boc-protected proline and 1,4-dicyanobenzene (1,4-DCB) at
room temperature in the presence of K2HPO4, a 26W household
fluorescent light bulb, and 2 mol% of Ir(ppy)3. While we were
Ir(dFppy)3 (E1/2red [IrIV/*IrIII] = −1.44 V vs SCE),18 yet at the
same time could promote facile oxidation of the α-amino
carboxylate moiety. We hypothesized that introduction of
electron-donating tert-butyl groups into the pyridine ring of
the ligand would serve to further enhance the reducing ability of
the photocatalyst excited state while leaving the oxidation
potential of the corresponding IrIV species largely unaffected.
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ab
,
Table 2. Decarboxylative Arylation: α-Amino Acid Scope
a
b
Performed using the optimized conditions from Table 1 (See Supporting Information). Cited yields are of material isolated by column
c
d
1
chromatography. Unprotected indole Boc-Trp-OH resulted in lower efficiency (54% yield). Determined by H NMR analysis to be 1.1:1 d.r.
Indeed, we were pleased to find that two new photocatalysts,
Ir[p-F(tBu)-ppy]3 (E1/2red [IrIV/*IrIII] = −1.67 V vs SCE)20 and
Ir[dF(tBu)-ppy]3, exhibited a significant increase in overall
efficiency to deliver the desired coupling adduct in 73% and 68%
yield, respectively (entries 5 and 6). Further improvement in
reaction yield was achieved through the use of CsF as the
exogenous base, presumably due to increased solubility of the
carboxylate species (entry 7). As expected, control experiments
revealed that the photocatalyst, visible light, and the base were
all essential components for the catalytic operation of this new
coupling reaction (entries 8−10).
We next evaluated the nature of the aryl coupling partner in
this photoredox-mediated decarboxylative coupling. As shown in
Table 3, a range of cyanoaromatics and cyano-heteroaromatics
a b
,
Table 3. Decarboxylative Arylation: Aromatic Scope
With optimal reaction conditions in hand, we next examined
the scope of the amino acid component in this new
decarboxylative arylation protocol. As illustrated in Table 2,
this transformation generically proceeds at room temperature
and in good to high yields with an extensive range of α-amino
acids (products 8−20, 64−89% yield). These mild reaction
conditions readily accommodate an array of useful functional
groups, including esters, amides, carbamates, and ethers
(products 13, 14, 18, 64−78% yield). Moreover, modification
of the α-amino acid protecting group is well-tolerated between
different carbamate systems (products 8 and 9, 75 and 82% yield,
respectively). A wide range of acyclic α-amino acids incorporating
aliphatic and aryl side chains are amenable to this decarboxylative
coupling, furnishing benzylic amines in good to excellent yield
(products 12−20, 64−89% yield). Remarkably, Boc-protected
methionine, which is often prone to sulfide-oxidation, was a viable
substrate, providing the corresponding arylation adduct in high
yield (product 15, 81% yield). In addition, we have also
demonstrated that unnatural α-amino acids, such as piperidine
and morpholine-derived systems, are amenable to this decar-
boxylative arylation (products 10 and 11, 70 and 86% yield,
respectively). Finally, and perhaps most notably, this trans-
formation readily promotes C−C bond formation at sterically
congested positions, an often underappreciated benefit of radical−
radical couplings and their accompanying elongated transition-
state bonds (product 19, 81% yield).21
a
Cited yields are of material isolated by column chromatography. See
b
Supporting Information for experimental details. Regiomeric ratios
(rr) determined by H NMR (major isomer is shown). 1.3:1 rr. 4:1
chemoselectivity for addition to ipso-CN vs SO2Ph position.
c
d
1
are able to participate in the requisite radical−radical coupling
with good to excellent efficiency (entries 1−8, 52−85% yield).
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As detailed earlier, sterically encumbered substrates, such as 2,5-
dimethylterephthalonitrile, are viable coupling partners (entry 1,
85% yield). Moreover, these mild reaction conditions allow
a broad range of functional groups on the aryl ring (e.g., esters,
lactones, phosphonate esters, and sulfones) to be readily
accommodated (entries 3−6, 52−70% yield). With respect to
pharmacophore production, it is important to note that this
decarboxylative arylation is readily translatable to heteroaromatic
group installation. For example, cyanopyridines serve as viable
coupling partners to generate heterobenzylic amines in one step
from amino acids (entries 7 and 8, 73−83% yield).
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3
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ASSOCIATED CONTENT
* Supporting Information
Experimental procedures, structural proofs, and spectral data for
all new compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
dmacmill@princeton.edu
■
(19) Lowry, M. S.; Goldsmith, J. I.; Slinker, J. D.; Rohl, R.; Pascal, R. A.;
Malliaras, G.; Bernhard, S. Chem. Mater. 2005, 17, 5712.
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cyclic voltammetry. Stern−Volmer quenching studies revealed only 1,4-
dicyanobenzene quenches the excited state of Ir[p-F(tBu)-ppy]3,
lending support to our initial hypothesis in Scheme 1. See Supporting
Information for details on luminescence quenching studies.
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support was provided by NIHGMS (R01 01
GM093213-01) and gifts from Merck and Amgen. Z.Z. is
grateful for a postdoctoral fellowship from the Shanghai Institute
of Organic Chemistry. We thank Dr. Yong Yan for his generous
help with cyclic voltammetry experiments.
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