Deaminative Arylation of Amino Acid-derived Pyridinium Salts

Article abstract of DOI:10.1021/acs.orglett.9b02643

A Suzuki-Miyaura cross-coupling of α-pyridinium esters and arylboroxines has been developed. Combined with formation of the pyridinium salts from amino acid derivatives, this method enables amino acid derivatives to be efficiently transformed into α-aryl

Full text of DOI:10.1021/acs.orglett.9b02643

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Deaminative Arylation of Amino Acid-derived Pyridinium Salts
Megan E. Hoerrner, Kristen M. Baker,‡ Corey H. Basch,‡ Earl M. Bampo, and Mary P. Watson*
Department of Chemistry & Biochemistry, University of Delaware, Newark, Delaware 19716, United States
S
* Supporting Information
ABSTRACT: A Suzuki−Miyaura cross-coupling of α-pyridinium
esters and arylboroxines has been developed. Combined with formation
of the pyridinium salts from amino acid derivatives, this method
enables amino acid derivatives to be efficiently transformed into α-aryl
esters and amides. Under the mild conditions, broad functional group
tolerance on both the amino acid derivatives and the arylboroxine are
observed, including protic functional groups. Mechanistic studies
support an alkyl radical intermediate, similar to other cross-couplings of
alkylpyridinium salts.
classic substitutions on the N atom. Deaminative reactions
continue to be underdeveloped, despite the potential to
efficiently access valuable products. In particular, deaminative
arylations of amino acid derivatives would deliver propionic
acids and related compounds, important for their nonsteroidal
anti-inflammatory activity.3,4 An exception is Wang’s efficient
metal-free reaction of α-diazoesters, generated in situ, and
arylboronic acids; however, only a single example of a protic
functional group (indole) was demonstrated, and the yield was
only 36% (Scheme 1B).5 Based on our work in developing cross-
couplings of Katritzky alkylpyridinium salts,6−8 we envisioned
that pyridinium derivatives of amino acids could also be efficient
reagents for deaminative arylation. Indeed, Glorius was the first
to report an arylation of this class of pyridinium salt, a Minisci-
type reaction enabled by photoredox catalysis; however, this
method is limited to the installation of electron-rich heteroaryl
groups (Scheme 1C).9 In addition, Liu has developed a
photoredox-catalyzed reaction of these pyridinium salts with
biphenyl isocyanates to deliver 6-alkyl phenanthridines,10 and
we have reported a single example of a reductive coupling to
install a pyrimidine.11−14 However, beyond these examples of
installation of specific heteroaryl groups, arylation of these
substrates has not been demonstrated. Specifically, current
methods do not allow installation of a broad scope of aryl
groups, including electronically varied and functionalized aryl
and heteroaryl substituents.
mino acids are a privileged class of starting materials for the
Asynthesis of a wide variety of organic molecules, ranging
from ligands and organocatalysts to natural products or
pharmaceuticals, including both peptides and nonpeptides.1 In
addition to classic synthetic manipulations that allow the
carboxy group to undergo esterification, reductions, and
substitutions, nickel-catalyzed decarboxylative cross-couplings
enable amino acids to be transformed into amines with a range of
new groups at the α-carbon (Scheme 1A).2 However, the
chemistry of the amino substituent remains largely limited to
Scheme 1. Deaminative Arylation of Amino Acid Derivatives
To solve this limitation, we envisioned that a Suzuki−Miyaura
cross-coupling of amino acid-derived pyridinium salts with
arylboronic reagents would enable the synthesis of a diverse
range of α-aryl carboxylates. Suzuki−Miyaura cross-coupling is
one of the most well-established methods for the installation of
an aryl group, often boasts exceptional scope, and is one of the
most useful reactions in medicinal chemistry.15 Herein, we
report the development of this deaminative arylation method,
which uses a catalyst from commercially available components,
Received: July 26, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02643
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
employs mild reaction conditions, and offers wide functional
group tolerance (Scheme 1D).
The pyridinium salt substrates were prepared by treating the
amino esters with 2,4,6-triphenylpyrilium tetrafluoroborate (5)
at room temperature in CH2Cl2 in the presence of Et3N and 4 Å
MS, followed by acidification with AcOH (Scheme 2). This
6). Use of the more electron-rich 4,4′-dimethylbipyridine (4,4′-
dmbpy) ligand resulted in quantitative yield (entry 7). We
hypothesized that the 4 Å MS may be absorbing water from the
boronic acid; accordingly, the use of boroxine is also sufficient to
achieve high yield (entry 8). We found the use of boroxine more
convenient for scope studies (see below), but either protocol
can be used (boronic acid and 4 Å MS or boroxine). Control
experiments demonstrated that 71% yield can be obtained when
the catalyst loading is lowered to 2 mol % (entry 9) and that the
reaction requires heating and nickel catalyst (entries 10 and 11).
With these optimized conditions in hand, we examined their
generality against the pyridinium salt derivatives of common
proteinogenic amino acids (Scheme 3). Of the aliphatic amino
acids, pyridinium salts derived from glycine (7), alanine (8−12),
and phenylalanine (15) esters worked well, including a Weinreb
amide (12). On 5 mmol scale, the reaction also worked well (8).
However, more sterically challenging valine (13) and leucine
(14) derivatives reacted in lower yields. Improved yields were
achieved by heating the reactions at 80 °C; however, the
Scheme 2. Optimized Pyridinium Synthesis
method is a modified procedure from that originally reported by
Katritzky,16 and generally gives 20−30% higher yields than
heating the amine and 2,4,6-triphenylpyrylium in refluxing
EtOH, which is the most common method for pyridinium salt
synthesis.17
We selected the cross-coupling of pyridinium salt 3b, derived
from alanine, and p-tolylboronic acid for optimization. Using
Ni(cod)2 and 1,10-phenanthroline as the catalyst system, we
observed a dramatic effect of base; although NaOMe and K3PO4
resulted in ≤10% yield, the milder K2CO3 provided 69% yield of
desired product 6 (Table 1, entries 1−3). Notably, the Suzuki−
a
Scheme 3. Substrate Scope
a
Table 1. Optimization
b
entry
[Ni]
ligand
base
yield (%)
1
Ni(cod)2
Ni(cod)2
Ni(cod)2
Ni(cod)2
NiCl2·DME
NiCl2·DME
NiCl2·DME
NiCl2·DME
NiCl2·DME
NiCl2·DME
none
1,10-phen
1,10-phen
1,10-phen
1,10-phen
1,10-phen
1,10-phen
4,4′-dmbpy
4,4′-dmbpy
4,4′-dmbpy
4,4′-dmbpy
4,4′-dmbpy
NaOMe
K3PO4
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
10
6
2
3
4
5
6
7
8
69
77
75
88
>99
>99
71
c
c
c de
, ,
c de
, ,
df
,
f g
9 ,
10
11
df h
, ,
i
n.d.
n.d.
f
i
a
Conditions: pyridinium salt 3b (0.10 mmol, 1.0 equiv), [Ni] (10 mol
%), ligand (12 mol %), boronic acid (1.5 equiv), base (1.7 equiv),
b
MeCN (0.33 M), 70 °C, 24 h. Determined by 1H NMR using 1,3,5-
c
trimethoxybenzene as internal standard. Boronic acid (2.5 equiv),
d
e
f
base (2.8 equiv). [Ni] (5 mol %), ligand (6 mol %). 4 Å MS. (p-
g
TolBO)3 (0.8 equiv), K2CO3 (2.8 equiv). [Ni] (2 mol %), ligand (3
mol %). Room temperature. n.d. = not detected.
h
i
Miyaura arylation of alkylpyridinium salts with unactivated alkyl
groups required a much stronger base (KOtBu),7a potentially
indicating that the α-carbonyl facilitates the reaction, consistent
with a more stabilized radical intermediate. Increasing the
equivalents of boronic acid and base further raised the yield
(entry 4). Under these conditions, air-sensitive Ni(cod)2 could
be replaced with air-stable NiCl2·DME without a detrimental
loss in yield (entry 5). By adding 4 Å MS, the catalyst loading
could be lowered to 5 mol % while maintaining high yield (entry
a
Conditions: pyridinium salt 3 (1.0 mmol, 1.0 equiv), [Ni] (5 mol
%), ligand (6 mol %), boroxine (0.8 equiv), K2CO3 (2.8 equiv),
MeCN (0.33 M), 70 °C, 24 h. Average isolated yield of duplicate
experiments ( 6%), unless noted otherwise. Single experiment. n-
b
c
d
PrCN, 80 °C. Run on half the normal scale (0.5 mmol 3).
B
DOI: 10.1021/acs.orglett.9b02643
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
decomposition prevented even higher temperatures.17 The
pyridinium salt derived from methionine also worked well,
highlighting that even an often challenging thioether is tolerated
(16, 17). Pyridinium salts derived from cysteine and serine
methyl esters, with leaving groups in the β-position, could not be
formed due to elimination under the pyridinium synthesis
conditions.17 Side chains with protic functional groups were well
tolerated, as shown by 18−21 and 24. Even tyrosine (19) and
levodopa18 (20) derivatives with mildly acidic phenol groups
were successful, highlighting the mildness of the reaction
conditions. For pyridinium salts derived from asparagine (Trt,
21), aspartic acid (ester, 22), glutamic acid (ester, 23), lysine
(Cbz, 24), and arginine (Pbf, 25), protecting groups were
required. Without these protecting groups, pyridinium salts
were formed in low yields and some of the cross-couplings were
also poor. For the pyridinium salts derived from histidine and
glutamine, even with protection of the side chain, the substrate
syntheses were unsuccessful. In total, a wide range of functional
groups were tolerated on the pyridinium salts, including esters
(22, 23), a Weinreb amide (12), thioethers (16, 17), an
unprotected indole (18), free phenols (19, 20), primary amides
(21, 24), and a protected guanidine (25).
With respect to the range of arylboroxines amenable to this
reaction, we again observed broad functional group tolerance,
including ethers (8, 13−15, 18−22, 24−25), ketones (9),
tertiary anilines (10), fluoro (11, 12, 23), trifluoromethyl (16),
and aryl bromide (17). Notably, derivatives of pharmaceuticals,
such as ketoprofen (9) and flurbiprofen (12), can be prepared
efficiently.19 In terms of heteroarylboroxines, quinolinyl (7) and
3-pyridyl worked well (11, 15), enabling installation of this
prominent heteroaryl. However, electron-rich heteroaryls, such
as indole, resulted in low yields, as did arylboroxines with ortho
substituents.17
Scheme 5. Mechanistic Studies
middle). Finally, the cross-coupling of cyclopropane 3q resulted
in formation of ring-opened product 27 (Scheme 5, bottom).
Further studies are needed to elucidate the nickel intermediates
involved.
In summary, we have developed a nickel-catalyzed Suzuki−
Miyaura arylation of amino acid-derived pyridinium salts. This
reaction harnesses a privileged class of substrates (amino acid
derivatives) and delivers α-aryl esters, which can be readily
hydrolyzed to carboxylates well-appreciated for their bioactiv-
ities. The reaction conditions are mild, enabling a broad range of
functional groups to be installed, making this method a useful,
complementary reaction for the arylation of amino acid
derivatives.
We also attempted to conduct the pyridinium formation and
cross-coupling in a single step. Simultaneous addition of the
pyrylium tetrafluoroborate and cross-coupling reagents (nickel
catalyst, arylboroxine, base) was unsuccessful. However, a one-
pot protocol was developed for the transformation of amino
ester 4a to product 8 without isolation of pyridinium 3a
(Scheme 4). Although this protocol resulted in lower yield than
when pyridinium 3a was isolated, such a one-pot protocol may
be advantageous in certain cases, such as parallel synthesis.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.9b02643.
■
S
Experimental details and data (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: mpwatson@udel.edu.
ORCID
Scheme 4. One-Pot Transformation of Alanine Methyl Ester
Mary P. Watson: 0000-0002-1879-5257
Author Contributions
‡These authors contributed equally.
Notes
The authors declare no competing financial interest.
Like previous nickel-catalyzed cross-couplings of alkylpyr-
idinium salts,7a we hypothesize that this reaction proceeds via
single-electron transfer (SET) from a nickel catalyst to the
pyridinium ring to yield a neutral pyridyl radical. C−N bond
fragmentation then gives an alkyl radical, which likely combines
with a nickel arene intermediate before undergoing reductive
elimination to yield the arylated product. In support of an alkyl
radical intermediate, we observed racemization in the cross-
coupling of enantioenriched 3a, prepared from L-alanine
(Scheme 5, top).20 Also, the addition of TEMPO to the cross-
coupling yielded TEMPO-trapped adduct 26 (Scheme 5,
ACKNOWLEDGMENTS
■
We thank NIH (R01 GM111820, R35 GM131816), University
of Delaware (UD) for University Graduate Fellowships
(C.H.B.), and the UD Summer Scholars and Plastino Alumni
Undergraduate Research Fellowship programs (E.M.B.). Data
were acquired at UD on instruments obtained with assistance of
NSF and NIH funding (NSF CHE0421224, CHE1229234,
CHE0840401, and CHE1048367; NIH P20 GM104316, P20
GM103541, and S10 OD016267). We thank Lotus Separations,
LLC, for assistance with SFC.
C
DOI: 10.1021/acs.orglett.9b02643
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Letter
(6) (a) Bapat, J. B.; Blade, R. J.; Boulton, A. J.; Epsztajn, J.; Katrizky, A.
R.; Lewis, J.; Molina-Buendia, P.; Nie, P.-L.; Ramsden, C. A. Pyridines
as Leaving Groups in Synthetic Transformations: Nucleophilic
Displacements of Amino Groups, and Novel Preparations of Nitriles
and Isocyanates. Tetrahedron Lett. 1976, 31, 2691−2694. (b) Katritzky,
A. R.; Marson, C. M. Pyrylium Mediated Transformations of Primary
Amino Groups into Other Functional Groups. Angew. Chem., Int. Ed.
Engl. 1984, 23, 420−429.
(7) (a) Basch, C. H.; Liao, J.; Xu, J.; Piane, J. J.; Watson, M. P.
Harnessing Alkyl Amines as Electrophiles for Nickel-Catalyzed Cross
Couplings via C−N Bond Activation. J. Am. Chem. Soc. 2017, 139 (15),
5313−5316. (b) Liao, J.; Guan, W.; Boscoe, B. P.; Tucker, J. W.;
Tomlin, J. W.; Garnsey, M. R.; Watson, M. P. Transforming Benzylic
Amines into Diarylmethanes: Cross-Couplings of Benzylic Pyridinium
Salts via C−N Bond Activation. Org. Lett. 2018, 20 (10), 3030−3033.
(c) Guan, W.; Liao, J.; Watson, M. P. Vinylation of Benzylic Amines via
C−N Bond Functionalization of Benzylic Pyridinium Salts. Synthesis
2018, 50 (16), 3231−3237. (d) Plunkett, S.; Basch, C. H.; Santana, S.
O.; Watson, M. P. Harnessing Alkyl Pyridinium Salts as Electrophiles in
De-aminative Alkyl-Alkyl Cross-Couplings. J. Am. Chem. Soc. 2019, 141
(6), 2257−2262.
REFERENCES
■
(1) (a) Hanessian, S. Reflections on the total synthesis of natural
products: Art, craft, logic, and the chiron approach. Pure Appl. Chem.
1993, 65, 1189. (b) Blaser, H. U. The chiral pool as a source of
enantioselective catalysts and auxiliaries. Chem. Rev. 1992, 92 (5), 935−
952.
(2) (a) Johnston, C. P.; Smith, R. T.; Allmendinger, S.; MacMillan, D.
W. Metallaphotoredox-catalysed sp(3)-sp(3) cross-coupling of carbox-
ylic acids with alkyl halides. Nature 2016, 536 (7616), 322−325.
(b) Zuo, Z.; Ahneman, D. T.; Chu, L.; Terrett, J. A.; Doyle, A. G.;
MacMillan, D. W. C. Merging photoredox with nickel catalysis:
Coupling of α-carboxyl sp3-carbons with aryl halides. Science 2014, 345
(6195), 437−440. (c) Cornella, J.; Edwards, J. T.; Qin, T.; Kawamura,
S.; Wang, J.; Pan, C. M.; Gianatassio, R.; Schmidt, M.; Eastgate, M. D.;
Baran, P. S. Practical Ni-Catalyzed Aryl-Alkyl Cross-Coupling of
Secondary Redox-Active Esters. J. Am. Chem. Soc. 2016, 138 (7), 2174−
2177. (d) Huihui, K. M.; Caputo, J. A.; Melchor, Z.; Olivares, A. M.;
Spiewak, A. M.; Johnson, K. A.; DiBenedetto, T. A.; Kim, S.; Ackerman,
L. K.; Weix, D. J. Decarboxylative Cross-Electrophile Coupling of N-
Hydroxyphthalimide Esters with Aryl Iodides. J. Am. Chem. Soc. 2016,
138 (15), 5016−5019. (e) Qin, T.; Cornella, J.; Li, C.; Malins, L. R.;
Edwards, J. T.; Kawamura, S.; Maxwell, B. D.; Eastgate, M. D.; Baran, P.
S. A General Alkyl-Alkyl Cross-Coupling Enabled by Redox-Active
Esters and Alkylzinc Reagents. Science 2016, 352 (6287), 801−805.
(f) Toriyama, F.; Cornella, J.; Wimmer, L.; Chen, T. G.; Dixon, D. D.;
Creech, G.; Baran, P. S. Redox-Active Esters in Fe-Catalyzed C-C
Coupling. J. Am. Chem. Soc. 2016, 138 (35), 11132−11135. (g) Wang,
J.; Qin, T.; Chen, T.-G.; Wimmer, L.; Edwards, J. T.; Cornella, J.;
Vokits, B.; Shaw, S. A.; Baran, P. S. Nickel-Catalyzed Cross-Coupling of
Redox-Active Esters with Boronic Acids. Angew. Chem., Int. Ed. 2016,
55, 9676−9679. (h) Li, C.; Wang, J.; Barton, L. M.; Yu, S.; Tian, M.;
Peters, D. S.; Kumar, M.; Yu, A. W.; Johnson, K. A.; Chatterjee, A. K.;
Yan, M.; Baran, P. S. Decarboxylative borylation. Science 2017, 356,
No. eaam7355.
(8) For other recent work with organopyridinium salts, see:
(a) Ociepa, M.; Turkowska, J.; Gryko, D. Redox-Activated Amines in
C(sp3)−C(sp) and C(sp3)−C(sp2) Bond Formation Enabled by
Metal-Free Photoredox Catalysis. ACS Catal. 2018, 8 (12), 11362−
11367. (b) Sowmiah, S.; Esperanca̧ , J. M. S. S.; Rebelo, L. P. N.; Afonso,
C. A. M. Pyridinium salts: from synthesis to reactivity and applications.
Org. Chem. Front. 2018, 5, 453−493. (c) Wu, J.; He, L.; Noble, A.;
Aggarwal, V. K. Photoinduced Deaminative Borylation of Alkylamines.
J. Am. Chem. Soc. 2018, 140 (34), 10700−10704. (d) Hu, J.; Wang, G.;
Li, S.; Shi, Z. Selective C−N Borylation of Alkyl Amines Promoted by
Lewis Base. Angew. Chem., Int. Ed. 2018, 57 (46), 15227−15231.
(e) Moser, D.; Duan, Y.; Wang, F.; Ma, Y.; O'Neill, M. J.; Cornella, J.
Selective Functionalization of Aminoheterocycles by a Pyrylium Salt.
Angew. Chem., Int. Ed. 2018, 57 (34), 11035−11039. (f) Wu, J.; Grant,
P. S.; Li, X.; Noble, A.; Aggarwal, V. K. Catalyst-Free Deaminative
Functionalizations of Primary Amines by Photoinduced Single-
Electron Transfer. Angew. Chem., Int. Ed. 2019, 58 (17), 5697−5701.
(g) Kong, D.; Moon, P. J.; Lundgren, R. J. Radical Coupling from Alkyl
Amines. Nat. Catal. 2019, 2, 473−476.
(3) (a) Harrington, P. J.; Lodewijk, E. Twenty Years of Naproxen
Technology. Org. Process Res. Dev. 1997, 1 (1), 72−76. (b) Landoni, M.
F.; Soraci, A. Pharmacology of Chiral Compounds: 2-Arylpropionic
Acid Derivatives. Curr. Drug Metab. 2001, 2, 37−51. (c) Davies, N. M.
Clinical Pharmacokinetics of Ibuprofen. Clin. Pharmacokinet. 1998, 34
(2), 101−154.
(9) (a) Klauck, F. J. R.; James, M. J.; Glorius, F. Deaminative Strategy
for the Visible-Light-Mediated Generation of Alkyl Radicals. Angew.
Chem., Int. Ed. 2017, 56 (40), 12336−12339. (b) James, M. J.; Strieth-
Kalthoff, F.; Sandfort, F.; Klauck, F. J. R.; Wagener, F.; Glorius, F.
Visible-Light-Mediated Charge Transfer Enables C−C Bond For-
mation with Traceless Acceptor Groups. Chem. - Eur. J. 2019, 25 (35),
8240−8244.
(4) For alternative methods to form α-aryl carbonyl compounds, see:
(a) Fox, J. M.; Huang, X.; Chieffi, A.; Buchwald, S. L. Highly Active and
Selective Catalysts for the Formation of α-Aryl Ketones. J. Am. Chem.
Soc. 2000, 122 (7), 1360−1370. (b) Moradi, W. A.; Buchwald, S. L.
Palladium-Catalyzed alpha-Arylation of Esters. J. Am. Chem. Soc. 2001,
123 (33), 7996−8002. (c) Jørgensen, M.; Lee, S.; Liu, X.; Wolkowski, J.
P.; Hartwig, J. F. Efficient Synthesis of α-Aryl Esters by Room-
Temperature Palladium-Catalyzed Coupling of Aryl Halides with Ester
Enolates. J. Am. Chem. Soc. 2002, 124 (42), 12557−12565.
(d) Gooßen, L. J. Pd-catalyzed synthesis of arylacetic acid derivatives
from boronic acids. Chem. Commun. 2001, 7, 669−670. (e) Dai, X.;
Strotman, N. A.; Fu, G. C. Catalytic Asymmetric Hiyama Cross-
Couplings of Racemic alpha-Bromo Esters. J. Am. Chem. Soc. 2008, 130
(11), 3302−3303. (f) Fischer, C.; Fu, G. Asymmetric nickel-catalyzed
negishi cross-couplings of secondary alpha-bromo amides with
organozinc reagents. J. Am. Chem. Soc. 2005, 127 (13), 4594−4595.
(g) Lee, S.; Beare, N. A.; Hartwig, J. F. Palladium-Catalyzed α-Arylation
of Esters and Protected Amino Acids. J. Am. Chem. Soc. 2001, 123 (34),
8410−8411. (h) Martin, A.; Vors, J.-P.; Baudoin, O. Synthesis of
Conformationally Constrained Esters and Amines by Pd-Catalyzed α-
Arylation of Hindered Substrates. ACS Catal. 2016, 6 (6), 3941−3945.
(5) (a) Wu, G.; Deng, Y.; Wu, C.; Zhang, Y.; Wang, J. Synthesis of
alpha-aryl esters and nitriles: deaminative coupling of alpha-amino-
esters and alpha-aminoacetonitriles with arylboronic acids. Angew.
Chem., Int. Ed. 2014, 53 (39), 10510−10514. (b) See also: Peng, C.;
Wang, Y.; Wang, J. Palladium-Catalyzed Cross-Coupling of alpha-
Diazocarbonyl Compounds with Arylboronic Acids. J. Am. Chem. Soc.
2008, 130, 1566−1567.
(10) (a) Zhu, Z.-F.; Zhang, M.-M.; Liu, F. Radical alkylation of
isocyanides with amino acid-/peptide-derived Katritzky salts via
photoredox catalysis. Org. Biomol. Chem. 2019, 17 (6), 1531−1534.
(b) Zhu, Z.-F.; Zhang, M.-M.; Liu, F. Correction: Radical alkylation of
isocyanides with amino acid-/peptide-derived Katritzky salts via
photoredox catalysis. Org. Biomol. Chem. 2019, 17 (14), 3640−3640.
(11) (a) Liao, J.; Basch, C. H.; Hoerrner, M. E.; Talley, M. R.; Boscoe,
B. P.; Tucker, J. W.; Garnsey, M. R.; Watson, M. P. Deaminative
Reductive Cross-Electrophile Couplings of Alkylpyridinium Salts and
Aryl Bromides. Org. Lett. 2019, 21 (8), 2941−2946. See also:
(b) Martin-Montero, R.; Yatham, V. R.; Yin, H.; Davies, J.; Martin, R.
Ni-catalyzed Reductive Deaminative Arylation at sp(3) Carbon
Centers. Org. Lett. 2019, 21 (8), 2947−2951. (c) Ni, S.; Li, C.-X.;
Mao, Y.; Han, J.; Wang, Y.; Yan, H.; Pan, Y. Ni-catalyzed Deaminative
Cross-electrophile Coupling of Katritzky Salts with Halides via C−N
Bond Activation. Sci. Adv. 2019, 5, No. eaaw9516. (d) Yue, H.; Zhu, C.;
Shen, L.; Geng, Q.; Hock, K. J.; Yuan, T.; Cavallo, L.; Rueping, M.
Nickel-catalyzed C−N bond activation: activated primary amines as
alkylating reagents in reductive cross-coupling. Chem. Sci. 2019, 10,
4430−4435. (e) Yi, J.; Badir, S. O.; Kammer, L. M.; Ribagorda, M.;
Molander, G. A. Deaminative Reductive Arylation Enabled by Nickel/
Photoredox Dual Catalysis. Org. Lett. 2019, 21 (9), 3346−3351.
D
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Letter
(12) For alkylation of amino acid-derived pyridinium salts, see:
Klauck, F. J. R.; Yoon, H.; James, M. J.; Lautens, M.; Glorius, F. Visible-
Light-Mediated Deaminative Three-Component Dicarbofunctionaliza-
tion of Styrenes with Benzylic Radicals. ACS Catal. 2019, 9 (1), 236−
241.
(13) For allylation of amino acid-derived pyridinium salts, see: Zhang,
M.-M.; Liu, F. Visible-light-mediated allylation of alkyl radicals with
allylic sulfones via a deaminative strategy. Org. Chem. Front. 2018, 5
(23), 3443−3446.
(14) For vinylation of amino acid-derived pyridinium salts, see:
(a) Yang, Z.-K.; Xu, N.-X.; Wang, C.; Uchiyama, M. Photoinduced
C(sp 3 )−N Bond Cleavage Leading to the Stereoselective Syntheses of
Alkenes. Chem. - Eur. J. 2019, 25 (21), 5433−5439. (b) Jiang, X.;
Zhang, M. M.; Xiong, W.; Lu, L. Q.; Xiao, W. J. Deaminative
(Carbonylative) Alkyl-Heck-type Reactions Enabled by Photocatalytic
C-N Bond Activation. Angew. Chem., Int. Ed. 2019, 58 (8), 2402−2406.
(15) (a) Maluenda, I.; Navarro, O. Recent developments in the
Suzuki-Miyaura reaction: 2010−2014. Molecules 2015, 20 (5), 7528−
57. (b) Brown, D. G.; Bostrom, J. Analysis of Past and Present Synthetic
Methodologies on Medicinal Chemistry: Where Have All the New
Reactions Gone? J. Med. Chem. 2016, 59 (10), 4443−4458.
(16) (16) Katritzky, A. R.; Manzo, R. H.; Lloyd, J. M.; Patel, R. C.
Mechanism of the Pyrylium/Pyridinium Ring Interconversion. Mild
Preparative Conditions for Conversion of Amines into Pyridinium Ions.
Angew. Chem., Int. Ed. Engl. 1980, 19 (4), 306−306.
(17) See Supporting Information.
(18) Ehringer, H.; Hornykiewicz, O. Verteilung Von Noradrenalin
Und Dopamin (3-Hydroxytyramin) Im Gehirn Des Menschen Und Ihr
Verhalten Bei Erkrankungen Des Extrapyramidalen Systems. Klin.
Wochenschr. 1960, 38 (24), 1236−1239.
(19) (a) Kantor, T. G. Ketoprofen: A Review of Its Pharmacologic and
Clinical Properties. Pharmacotherapy 1986, 6 (3), 93−102. (b) Adams,
S.; Armitage, B.; Nicholson, J.; Blancafort, A. Therapeutically Active
Phenylalkane Derivatives. US 3793457 A, 1964.
(20) Partial epimerization has been observed in the formation of the
pyridinium salt. See: Said, S. A. Preparation and Nucleophilic
Substitution of the 2,4,6-Triphenylpyridinium Salts, Diazonium
Intermediates and N,N-1,2-Benzenedisulfonylimides of Chiral Amino
Acids. Tanz. J. Sci. 2007, 33, 9−18.
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DOI: 10.1021/acs.orglett.9b02643
Org. Lett. XXXX, XXX, XXX−XXX