Unprotected Amino Acids as Stable Radical Precursors for Heterocycle C-H Functionalization

Article abstract of DOI:10.1021/acs.orglett.6b01754

An efficient and general method for the C-H alkylation of heteroarenes using unprotected amino acids as stable alkyl radical precursors is reported. This one-pot procedure is performed open to air under aqueous conditions and is effective for several natural and unnatural amino acids. Heterocycles of varying structure are suitably functionalized, and reactivity trends reflect the nucleophilic character of the radical species generated.

Full text of DOI:10.1021/acs.orglett.6b01754

Letter
pubs.acs.org/OrgLett
Unprotected Amino Acids as Stable Radical Precursors for
Heterocycle C−H Functionalization
Duy N. Mai and Ryan D. Baxter*
Department of Chemistry and Chemical Biology, University of California, 5200 North Lake Road, Merced, California 95343, United
States
S
* Supporting Information
ABSTRACT: An efficient and general method for the C−H
alkylation of heteroarenes using unprotected amino acids as stable
alkyl radical precursors is reported. This one-pot procedure is
performed open to air under aqueous conditions and is effective for
several natural and unnatural amino acids. Heterocycles of varying
structure are suitably functionalized, and reactivity trends reflect the
nucleophilic character of the radical species generated.
ubstituted aromatic heterocycles are critically important to
the field of medicinal chemistry, with many small-molecule
Scheme 1. Radical C−H Functionalization Reactions
S
therapeutics containing one or more substituted heteroaromatics
as essential structural motifs.1 Because of this, researchers have
devoted significant effort toward developing robust chemical
methods for heteroaromatic substitution, traditionally via
transition-metal-mediated cross-coupling reactions.2 Recently,
there has been a surge of interest in direct C−H substitution
reactions that avoid prefunctionalized materials,3 and radical-
mediated processes have shown particular promise for early- and
late-stage functionalization of pharmaceutically relevant mole-
cules.4 Pioneering work by Minisci demonstrated a direct
method for C−H alkylation of heteroarenes via silver-catalyzed
radical decarboxylation of carboxylic acids,5 and recent advance-
ments have greatly expanded the scope and efficiency of radical
C−H functionalizations of heteroarenes using alternative radical
precursors such as boronic acids and metal sulfinates (Scheme
1A).6 Despite these achievements, limitations remain. The
traditional Minisci reaction often produces mixtures of mono-
and bis-alkylated products and requires heating at low pH (aq
H2SO4), which is not suitable for acid-sensitive functional
groups. The milder borono-Minisci reaction is restricted to the
C−H arylation of heterocycles using boronic acids.6a Alkyl
trifluoroborates may be employed for heterocycle alkylation, but
require superstoichiometric metal oxidants.6b More recently,
alkyl and fluoroalkyl sulfinates have been shown to be excellent
radical precursors for C−H alkylation of heteroarenes.6c−e
However, these costly reagents often require specifically
optimized reaction conditions depending on the sulfinate and
heterocycle used. With these limitations in mind, we sought to
develop a strategy that utilizes unprotected amino acids as
inexpensive alkyl radical precursors for the C−H alkylation of
aromatic heterocycles (Scheme 1B).7
forming reactions is less common. Few reports have described
the use of N-protected amino acids in radical9 or photocatalyzed
functionalization of heterocycles,10 but to the best of our
knowledge, unprotected amino acids have not been used as a
source of alkyl radicals for C−C bond-forming reactions. Herein
we describe the design and development of a silver-catalyzed C−
H alkylation reaction for the functionalization of heterocycles
using unprotected amino acids as stable radical precursors
(Scheme 1B). This reaction is believed to proceed via in situ
aldehyde formation followed by a Minisci-type decarbonylation/
alkylation radical process to yield substituted heteroarenes. The
multistep oxidative degradation of amino acids to liberate alkyl
radicals mimics a slow-release strategy of reactive intermediates11
Amino acids are readily available, easily handled, and
renewable carbon feedstock, making them ideal source material
for substitution reactions. Although the incorporation of amino
acids into target molecules via peptide coupling has been
extensively developed,8 the use of amino acids in C−C bond-
Received: June 16, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01754
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Organic Letters
Letter
and offers better selectivity and desired reactivity compared to
C−H alkylative Minisci reactions using carboxylic acids,
aldehydes, and zinc sulfinates as radical precursors (vide infra).
The development of a mild radical C−H alkylation reaction
from unprotected amino acids requires a catalyst system capable
of promoting both oxidative Strecker degradation and radical
decarbonylation via formyl hydrogen abstraction. In addition to
seminal contributions by Minisci, several recent reports have
shown that radical decarboxylation under oxidative conditions is
a direct and efficient method for generating alkyl radicals.12
Although several methods for the oxidative degradation of
unprotected amino acids are known,13 Minisci-type radical
alkylations via aldehyde decarbonylation are rare.14 Nevertheless,
employing conditions similar to those used in the traditional
Minisci and borono-Minisci reactions (silver catalyst and
persulfate oxidant) showed that in the presence of 10 mol %
AgNO3, 2.0 equiv of valine, 5.0 equiv of ammonium persulfate,
1.0 equiv of trifluoroacetic acid, and a 1:1 mixture of DCE/H2O
(0.1M) at 80 °C, 4-ethylisonicotinate was monoalkylated in 62%
yield (1a, Table 1, entry 1).
As shown in Scheme 2, Ag(I)-catalyzed degradation of valine
in the presence of ammonium persulfate promoted the addition
i
Scheme 2. C−H Alkylation of Heteroarenes with Valine
Table 1. Comparison of Radical Sources for Minisci-Type
a
Reactions
b
entry
radical source
valine
yield of 1a (%)
ratio (1a:1a′)
1
2
3
62
26
8
4:1
1:1
isobutyraldehyde
isobutyric acid
Zn(SO2i-Pr)2
1:1.7
1.4:1
c
4
27
a
b
21% yield of bis-alkylated 1a′ also isolated. 19% yield of bis-
a
Standard reaction conditions: heterocycle (0.2 mmol), radical source
c
alkylation product 2a′ also isolated. 9% yield of acyl product 3b also
(0.4 mmol), TFA (0.2 mmol), (NH4)2S2O8 (1 mmol) in 2 mL of
d
e
isolated. C6:C5 (3.7:1). 22% yield of acyl product 8b also isolated.
b
DCE/H2O (1:1) at 80 °C for 24 h. Ratios of 1a/1a′ determined by
f
g
20 mol % of AgNO3 used. 18% yield of acyl product 10b was also
1
crude H NMR for entries 1−3 (see the Supporting Information).
h
isolated. 22% yield of acyl product 12b was also isolated. See the
c
Yield and ratio from ref 6e. Reported reaction conditions: heterocycle
Supporting Information for more details on minor acyl products.
(0.25 mmol), Zn(SO2i-Pr)2 (2.00 mmol), t-BuOOH (5.00 mmol), 1.4
mL DCE/H2O (2.5:1) at 50 °C for 48h. For reaction condition
optimization, see the Supporting Information for details.
i
General reaction conditions: heterocycle (0.2 mmol), amino acid (0.4
mmol), TFA (0.2 mmol), (NH4)2S2O8 (1 mmol) in 2 mL of DCE/
H2O (1:1, 0.1M) at 80 °C for 24 h.
of an isopropyl group to a variety of nitrogen-containing
heterocycles. Pyridines (1a−9a), pyrazines (10a−13a), pyr-
imidines (14a−17a), and pyridazines (18a−19a) are all suitably
monoalkylated, and good functional group tolerance was
observed. Most notably, potentially labile functional groups
such as esters (1a, 5a, 7a, 14a), nitriles (2a, 11a, 16a),10a and
halides (7a, 13a, 17a−19a) were tolerant of our reaction
conditions. Interestingly, entries 3, 8, 10, and 12 also yielded
minor amounts of acyl-substituted products, suggesting a
competition between acyl-radical trapping and decarbonylation
to the isopropyl radical. Attempts to minimize the formation of
acyl-substituted products by purging the reaction system of
carbon monoxide had a negligible effect on product distribution.
In addition to valine, several unprotected amino acids bearing
alkyl side chains were explored with a series of aromatic
heterocycles. As shown in Scheme 3, natural (leucine and
isoleucine) and unnatural (norvaline and tert-leucine) amino
acids are suitable radical precursors for a variety of electronically
deficient heterocycles. Amino acids bearing primary carbon
substituents (norvaline and leucine) often led to mixtures of alkyl
and acyl products. Conversely, amino acids bearing secondary or
The use of isobutyraldehyde (entry 2) and isobutyric acid
(entry 3) as radical precursors under our reaction conditions
provided mixtures of mono- and bis-alkylated products in low
yields. In addition, zinc isopropylsulfinate (entry 4) has
previously been reported to provide a mixture of products with
1a present in low yield. Control experiments revealed that silver
catalyst and persulfate are required and reaction efficiency was
reduced significantly without trifluoroacetic acid. Other metal
sources known to promote the Minisci reaction, such as iron(II)
salts, provided trace product.5b Traditional Minsci reaction
conditions (heating under aqueous H2SO4) led to degradation of
the starting material regardless of radical precursor used.5a With
the conditions outlined in Table 1, we explored the scope of
heterocycles capable of accepting an isopropyl radical from
valine. Although formation of the isopropyl radical from valine is
proficient at ambient temperature under purely aqueous
conditions, many heterocycles required an organic cosolvent
and elevated temperatures for suitable conversion. In all cases,
reactions were prepared open to air at ambient temperature using
solvents and reagents without prior purification.
B
DOI: 10.1021/acs.orglett.6b01754
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Letter
conditions, acetaldehyde requires cold storage and special
handling as a flammable liquid with an extremely high vapor
pressure. Significantly, under our optimized reaction conditions,
acetaldehyde produced only trace amounts of the expected
products. Acyl product 40b is also observed from the reaction of
4-cyanopyridine with threonine and represents the oxidized form
of the expected alkylated product; it is unclear whether this
product arises from α-oxidation of the expected alkylated
product or via an acylation pathway. Although addition of
benzyl radicals to heteroarenes is known,15 low yield of 42a was
observed for the reaction of quinoxaline with phenylalanine
under our general conditions, with oxidation of the intermediate
tolyl radical yielding benzaldehyde as an unwanted byproduct.
Reaction of cyclohexylglycine with ethyl 2-methylnicotinate
produced 41a in moderate yield, with unreacted Strecker
aldehyde (cyclohexanecarboxaldehyde) accounting for the
remaining mass balance of reaction material. Currently, the
described method is limited to simple alkyl-bearing amino acids,
as charged or polar side chains were unreactive under our general
reaction conditions with no desired product or unreacted
Strecker aldehydes being observed.
Scheme 3. Scope of Amino Acids for C−H Heteroarene
d
Alkylation
To support the mechanistic hypothesis of in situ aldehyde
formation as a critical step of our reaction, NMR studies were
undertaken for the reaction of ethyl isonicotinate with valine. As
shown in Table 1, entry 1, a 4:1 mixture of monoalkylated and
bis-alkylated products is produced, and unreacted isobutyralde-
hyde is clearly visible via NMR after 24 h. In the absence of a
heterocyclic substrate, we observed full consumption of valine
with concomitant formation of isobutyraldehyde over the course
of 24 h.16 These studies suggest that C−H functionalized
products are likely the result of in situ aldehyde formation
followed by a Minisci-type radical substitution reaction as
hypothesized. Due to the in situ generation of the aldehyde as an
intermediate prior to alkyl-radical formation, this method likely
provides a different rate of alkyl-radical formation compared to
employing either an aldehyde or carboxylic acid directly as radical
precursors. A similar feature has also been observed for Suzuki
reactions using trifluoroborate salts; slow generation of the active
coupling species via hydrolysis prevents unwanted homocou-
pling and increases overall reaction efficiency.17
a
b
c
C6:C5 (2:1). C4:C5:C6 (1:1:1). 13% of a mixed acyl- and alkylated
product was also observed, presumably via sequential radical additions;
see the Supporting Information for details. General reaction
conditions: heterocycle (0.2 mmol), amino acid (0.4 mmol), TFA
(0.2 mmol), (NH4)2S2O8 (1 mmol) in 2 mL of DCE/H2O (1:1) at 80
°C for 24 h.
d
On the basis of our preliminary studies and literature
precedent, a proposed mechanism is shown above in Figure 1.
tertiary substituents (isoleucine, tert-leucine) yielded predom-
inately monoalkylated heteroarenes. These results may be
rationalized by considering the rate of radical decarbonylation
as being mediated by the stability of the alkyl radical species
generated upon decarbonylation.14g Although alkyl substitution
is typically the major product observed, decarbonylation to
produce primary alkyl radicals appears to be less favorable
compared to more substituted side chains, and direct acyl
trapping of the heteroarene becomes kinetically competent. This
effect is also modulated by the reactivity of the heteroarene
substrate, as entries 32a and 33a were formed exclusively as the
monoalkylated products.
Other amino acids such as alanine, threonine, and cyclo-
hexylglycine can also be employed as radical precursors, albeit in
moderate yields. The reaction of 4-cyanopyridine with alanine
produces 40b as the major product, consistent with acyl trapping
being preferred over decarbonylation to the unstable methyl
radical. The formation of 40b via alanine degradation is especially
attractive when compared to Minisci-type chemistry using
acetaldehyde as a radical precursor. Whereas alanine is
indefinitely bench stable and easily handled under ambient
Figure 1. Proposed mechanism.
C
DOI: 10.1021/acs.orglett.6b01754
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Organic Letters
Letter
The Ag(I)/S2O82−-promoted decarboxylation of an unprotected
amino acid is expected to form 1-aminoalkyl radical species
43.9,13b Under the strongly oxidizing reaction conditions,18 we
believe that 43 is rapidly converted to the corresponding
iminium species 44 and hydrolyzed to aldehyde 45.13b Formyl
hydrogen−atom abstraction via persuflate radical anion gen-
erates acyl radical 46 which undergoes radical decarbonylation to
liberate the α-amino acid side-chain as nucleophilic alkyl radical
47. In the case of 1° substituted amino acids, 46 may be trapped
directly by a heterocyclic substrate to form the observed acyl
products. Addition of 47 into a protonated heterocycle followed
by hydrogen atom abstraction and rearomatization provides the
expected alkylated product 48.19
In summary, we have developed a method that utilizes
unprotected amino acids as bench-stable sources of alkyl radicals
for the C−H functionalization of heterocycles. A variety of
electron-deficient heterocycles are functionalized in good yield
and high levels of selectivity. Preliminary mechanistic studies
suggest the in situ formation of an aldehyde intermediate which
undergoes a Minisci-type radical substitution reaction via a
decarbonylative process. This multistep generation of reactive
intermediates displays reactivity differing from using either an
aldehyde or carboxylic acid directly as an alkyl-radical precursor.
A comprehensive mechanistic study is ongoing and will provide
insight into extending the chemistry to other amino acids.
(4) For a review on direct radical additions to pharmaceutically
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(7) Cost comparison based on isopropyl radical sources available from
the Aldrich online catalogue: isobutyric acid (cat. no. 58360; $0.31/
gram), isopropylboronic acid (cat. no. 648787; $36.00/gram), zinc
isopropylsulfinate (cat. no. 745480; $51.90/gram). L-valine (cat. no.
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ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b01754.
Experimental procedures and spectroscopic data for new
compounds (PDF)
(12) (a) Liu, X.; Wang, Z.; Cheng, X.; Li, C. J. Am. Chem. Soc. 2012,
134, 14330−14333. (b) Wang, Z.; Zhu, L.; Yin, F.; Su, Z.; Li, Z.; Li, C. J.
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: rbaxter@ucmerced.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
For assistance with high-resolution mass data we thank Professor
Brandon White, the National Science Foundation (MRI Grant
́
No. 0923573), and San Jose State University for use of mass
spectrometry facilities in the PROTEIN LAB. We gratefully
acknowledge the University of California, Merced, for financial
support.
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D
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Org. Lett. XXXX, XXX, XXX−XXX