Precious-Metal-Free Heteroarylation of Azlactones: Direct Synthesis of α-Pyridyl, α-Substituted Amino Acid Derivatives

Article abstract of DOI:10.1021/acs.orglett.6b02731

A one-pot, three-component synthesis of α-pyridyl, α-substituted amino acid derivatives is described. The key transformation is a direct, precious-metal-free heteroarylation of readily available, amino acid derived azlactones with electrophilically activated pyridine N-oxides. The resulting intermediates can be used directly as efficient acylating agents for a range of nucleophiles, leading to the heteroarylated amino acid derivatives in a single vessel.

Full text of DOI:10.1021/acs.orglett.6b02731

Letter
pubs.acs.org/OrgLett
Precious-Metal-Free Heteroarylation of Azlactones: Direct Synthesis
of α‑Pyridyl, α‑Substituted Amino Acid Derivatives
Tarn C. Johnson and Stephen P. Marsden*
School of Chemistry and Institute of Process Research and Development, University of Leeds, Leeds, LS2 9JT, U.K.
*
S Supporting Information
ABSTRACT: A one-pot, three-component synthesis of α-
pyridyl, α-substituted amino acid derivatives is described. The
key transformation is a direct, precious-metal-free hetero-
arylation of readily available, amino acid derived azlactones
with electrophilically activated pyridine N-oxides. The resulting
intermediates can be used directly as efficient acylating agents
for a range of nucleophiles, leading to the heteroarylated amino acid derivatives in a single vessel.
α,α-Disubstituted amino acids are found in many biologically1
active compounds, both naturally occurring and man-made.
The incorporation of such motifs into peptides and
peptidomimetics confers conformational preferences (fre-
quently inducing β-turns) as well as hydrolytic stability on
Scheme 1. Arylation of Azlactones
2
the resulting peptides. Among these structures, α-pyridyl,α-
substituted amino acid derivatives have attracted interest a3s
potent and selective inhibitors of proteases such as cathepsin
4
and β-secretase, the latter as potential treatments for
Alzheimer’s disease. Additionally, the hydrogen-bond accepting
capability of the pyridine nitrogen atom promotes well-defined
conformational behavior upon short peptides containing α-2-
5
pyridyl,α-substituted amino acids.
6
Building on our interest in quaternary amino acids, we
wished to develop a direct, convergent approach to α-pyridyl,α-
substituted amino acids based upon heteroarylation of readily
available α-amino acids. The intermolecular arylation of amino
acid enolates or their equivalents is nontrivial. There are only
isolated reports of the arylation of nonstabilized amino acid
7
enolates by S Ar reactions or oxidative coupling to nitro-
N
8
arenes. The arylation of stabilized enolates derived from amino
acid aldimines is limited to S Ar substitution of fluoro-
N
9
nitroarenes and (fluoroarene)chromium(0) carbonyl com-
1
0
11
the carbon acids (and other nucleophiles such as phenols)
examined by Londregan, we anticipated that they might act as
competent nucleophiles for the activated pyridine N-oxide,
facilitating the direct, precious-metal-free synthesis of α-pyridyl,
plexes, or to direct coupling with arylbismuth reagents. By
contrast, the use of azlactones as relatively acidic amino acid
enolate equivalents has been exploited in a broader range of
arylation reactions (Scheme 1, panel A), including palladium-
catalyzed cross-coupling to aryl halides, direct condensation
with diaryliodonium salts, and S Ar reactions with nitro-
20
12
α-substituted amino acid derivatives (Scheme 1, Panel B).
13
Moreover, the azlactones can be regarded as activated acylating
agents, the nucleophilic ring opening of which would lead
directly to diverse α-pyridyl, α-substituted amino acid
derivatives. This strategy is particularly significant and advanta-
geous given the documented issues with facile decarboxylation
of α-pyridyl amino acids, compounding the known poor
electrophilicity of activated α,α-disubstituted amino acids. We
report herein the successful demonstration of this strategy,
N
1
4
haloarenes, as well as direct Michael addition/aromatization
reactions with quinones. Among all of these examples, there
15
are only isolated reports of the synthesis of α-pyridyl,α-
substituted amino acids.
8c,12b,14
21
Londregan and colleagues at Pfizer have recently demon-
strated the in situ activation/substitution of pyridine N-oxides
16−18
using PyBroP with a range of nucleophiles,
including
carbon-based nucleophiles such as β-dicarbonyls (malonates,
17
ketoesters, diketones, and cyanoacetate) and silyl ketene
Received: September 11, 2016
1
8
19
acetals. Given the similar pK of azlactones (ca. 9−10) and
a
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02731
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. Screening of Electrophilic Activating Agents
exemplified in the one-pot, three-component synthesis of a
wide range of α-pyridyl quaternary amino acid derivatives.
22
We commenced our study with a screen of electrophilic
activating agents for the direct coupling of 4-methyl-2-
phenyloxazolin-5-one 1a with pyridine N-oxide 2a; for ease
of analysis, after a standard reaction time of 16 h the presumed
intermediate azlactones were subjected to methanolysis to
generate the α-methyl,α-pyridyl amino acid ester 3a as a
mixture of C2- and C4-regioisomers.
entry
reagent
solvent
THF
ratio C2:C4
isolated yield (%)
1
2
3
4
5
6
7
8
9
PyBroP
TsCl
1:0.7
1:2.2
1:1.7
1:3.8
n/a
53
68
11
16
0
THF
A screen of potential activating agents in THF (Table 1,
entries 1−6) revealed that both PyBroP and TsCl were
competent reaction partners, with the former showing modest
C2 selectivity and the latter a higher level of selectivity in favor
of the C4 isomer. Mindful that THF is regarded as problematic
4-NsCl
MsCl
THF
THF
Ac O
2
THF
AcCl
TsCl
TsCl
TsCl
TsCl
TsCl
TsCl
THF
n/a
0
23
2-MeTHF
EtOAc
PhMe
PhOMe
TBME
MeCN
1:1.6
1:1.5
1:1.6
1:1.4
1:1.4
1:1.7
51
in industrially led analyses of solvents, we screened a variety
of more favorable solvents in conjunction with TsCl (entries
7−12). Pleasingly, a comparable yield to that achieved in THF
b
68 (67 )
67
57
47
42
23
1
1
1
0
1
2
was obtained using ethyl acetate (a “recommended” solvent ),
albeit with a slightly reduced regioselectivity (entry 8).
Additionally, the charge of triethylamine base could also be
reduced to 2 equiv versus the N-oxide/activating agent without
detriment. Other bases (KOAc, K PO , K CO ) were
a
Conditions: Azlactone (0.29 mmol), pyridine N-oxide (0.32 mmol),
activating agent (0.32 mmol), NEt (0.86 mmol), and solvent (1.4
mL) at rt for 16 h followed by addition of MeOH (1 mL) and stirring
for a further 3 h. 0.61 mmol of NEt .
3
3
4
2
3
unsuccessful in the reaction.
We next applied these optimized conditions to a substrate
b
3
scoping study, utilizing a matrix combination of azlactones 1a−
Scheme 2. Substrate Scope in the One-Pot, Three-Component Synthesis of α-Pyridyl,α-Substituted Amino Acid Methyl Esters
a
Conditions: azlactone (0.50 mmol), N-oxide (0.55 mmol), TsCl (0.55 mmol), NEt (1.05 mmol), and EtOAc (2.5 mL) at rt for 16 h followed by
3
NaOMe (1.10 mmol) and MeOH (1 mL) and stirring for a further 3 h.
B
DOI: 10.1021/acs.orglett.6b02731
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3. Scope of Nucleophilic Ring Opening
intermediate for acyl substitution. An additional complication
in attempting C-functionalization of α-pyridyl, α-substituted
amino acids is that the free acids undergo facile decarbox-
ylation, accelerated by the potential for charge delocalization
21
into the pyridyl ring; we have already exploited this in a direct
two-component synthesis of 2-(1-amidoalkyl)pyridines by
22
arylation/decarboxylative ring opening of azlactones. Direct
access to a range of C-functionalized α-pyridyl, α-substituted
amino acids by nucleophilic opening of the azlactones would
therefore be synthetically valuable. The results are shown in
Scheme 3.
While methanol had already been used for azlactone opening
Scheme 2), we were pleased to see that a more hindered
(
secondary alcohol (isopropanol) was also a competent
nucleophile. The use of amines was examined: primary and
cyclic secondary aliphatic amines gave good yields of the
diamide products. The use of more hindered, less nucleophilic
acyclic secondary amines gave a lower yield, as might be
expected, though the Weinreb amide 9 was obtained in
reasonable yield.
Treatment with sodium borohydride in methanol/THF led
to reductive ring opening, giving the amino alcohol derivative
1
0, while the use of a Grignard reagent was also successful,
leading to ketone 11. A broad range of nucleophiles is therefore
compatible with the one-pot, three-component coupling.
In summary, we have described a new synthetic approach to
α-pyridyl, α-substituted amino acid derivatives by direct
pyridylation of azlactones with readily available pyridine N-
oxides, followed by ring opening with diverse nucleophiles. The
reaction shows good robustness (average yield 51%, range 25−
a
Conditions: azlactone (0.50 mmol), N-oxide (0.55 mmol), TsCl
(
0.55 mmol), NEt (1.05 mmol), and EtOAc (2.5 mL) at rt for 7 h.
3
b
c
Nucleophile and stirring for 16−24 h. NaBH (0.50 mmol) and 5:1
4
d
THF/MeOH (6 mL) at 0 °C for 1 h. 3 M MeMgBr in Et O (0.51
2
mmol) and THF (5 mL) at −40 °C for 3 h.
8
1% across 28 examples), while the one-pot, three-component
nature of the reaction should be readily applicable to array
synthesis.
d and pyridine N-oxides 2a−e, again with methanolytic ring
opening of the presumed intermediate azlactone. The results
are shown in Scheme 2. Variation of the azlactone C4-
substituent (which becomes the α-alkyl group of the amino acid
products 3) was well tolerated, with little variation in average
ASSOCIATED CONTENT
■
*
S
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b02731.
1
yield across five pyridine N-oxide substrates for R = methyl
(
56%), benzyl (64%), or isobutyl (52%). Changing the
2
azlactone C2-substituent from aromatic (R = Ph) to aliphatic
2
Experimental procedures, analytical data, and crystallo-
graphic information for all compounds (PDF)
(
R = N-acetyl-4-piperidinyl), was less well tolerated: although
each of the reactions was still successful, the average yield
1
dropped from 64% to 31% (with R = Bn). Regarding the
pyridine N-oxide, the reactions of the parent reagent 2a all gave
similar regioselectivities in favor of the C4 isomer (1.6:1 to
AUTHOR INFORMATION
■
Corresponding Author
1.9:1). Reaction of 3-methylpyridine N-oxide 2b gave rise to a
mixture of 2,3-, 3,4-, and 2,5-disubstituted products, but with
the 3,4-disubstitution product dominating in all cases. The
reaction of 4-substituted pyridine N-oxides 2c−e gives rise to
good yields of the 2,4-disubstituted products as expected. Alkyl
or aryl substituents were well tolerated, though the presence of
an electron-donating 4-methoxy group in 2e leads to
systematically lower yields. Overall, though, the reaction
shows excellent robustness, with the full matrix of 20 substrate
pairings giving products in an average yield for the three-
component coupling of >50%.
*E-mail: s.p.marsden@leeds.ac.uk.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The research for this work has received funding from the
Innovative Medicines Institute joint undertaking project
CHEM21 under Grant Agreement No. 115360, the resources
of which are composed of financial contribution from the
European Union’s Seventh Framework Programme (FP7/
2007-2013) and EFPIA companies in kind contribution.
We next turned our attention to the range of nucleophiles
that could be used to open the intermediate arylated azlactones.
The formation of peptides and peptidomimetics from α,α-
24
disubstituted amino acids is not straightforward, with N-
functionalization limited by the poor nucleophilicity of the
hindered amine and C-functionalization slowed by the difficulty
of forming adjacent quaternary centers in the tetrahedral
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