β-Selective Reductive Coupling of Alkenylpyridines with Aldehydes and Imines via Synergistic Lewis Acid/Photoredox Catalysis

Article abstract of DOI:10.1021/jacs.7b01373

Umpolung (polarity reversal) strategies of aldehydes and imines have dramatically expanded the scope of carbonyl and iminyl chemistry by facilitating reactions with non-nucleophilic reagents. Herein, we report the first visible light photoredox-catalyzed β-selective reductive coupling of alkenylpyridines with carbonyl or iminyl derivatives with the aid of a Lewis acid co-catalyst. Our process tolerates complex molecular scaffolds (e.g., sugar, natural product, and peptide derivatives) and is applicable to the preparation of compounds containing a broad range of heterocyclic moieties. Mechanistic investigations indicate that the key step involves single-electron-transfer reduction of aldehydes or imines followed by the addition of resulting ketyl or α-aminoalkyl radicals to Lewis acid-activated alkenylpyridines.

Full text of DOI:10.1021/jacs.7b01373

Communication
pubs.acs.org/JACS
β‑Selective Reductive Coupling of Alkenylpyridines with Aldehydes
and Imines via Synergistic Lewis Acid/Photoredox Catalysis
Katarzyna N. Lee,‡ Zhen Lei,‡ and Ming-Yu Ngai*
Department of Chemistry and Institute of Chemical Biology and Drug Discovery, Stony Brook University, Stony Brook, New York
11794-3400, United States
S
* Supporting Information
Scheme 1. Catalytic Transformations of Alkenylpyridines
ABSTRACT: Umpolung (polarity reversal) strategies of
aldehydes and imines have dramatically expanded the
scope of carbonyl and iminyl chemistry by facilitating
reactions with non-nucleophilic reagents. Herein, we
report the first visible light photoredox-catalyzed β-
selective reductive coupling of alkenylpyridines with
carbonyl or iminyl derivatives with the aid of a Lewis
acid co-catalyst. Our process tolerates complex molecular
scaffolds (e.g., sugar, natural product, and peptide
derivatives) and is applicable to the preparation of
compounds containing a broad range of heterocyclic
moieties. Mechanistic investigations indicate that the key
step involves single-electron-transfer reduction of alde-
hydes or imines followed by the addition of resulting ketyl
or α-aminoalkyl radicals to Lewis acid-activated alkenyl-
pyridines.
We postulated that intervention of a reductive Umpolung
step involving ketyl/α-aminoalkyl radicals would provide a
powerful strategy to access previously unattainable pyridine-
containing structures and enhanced flexibility to the design of
new synthetic targets. Nevertheless, a widespread application of
yridines are important substructures of natural products,1
2
agrochemicals,3 functional materials,4
Ppharmaceuticals,
and ligands in catalysis.5 They are often recognized as
“privileged” scaffolds in medicinal chemistry for discovery and
optimization of new synthetic drug molecules. Currently, over
100 marketed pharmaceuticals, including drugs such as Nexium
(anti-acid) and Imatinib (anti-cancer), bear at least one
pyridine ring.6 Due to the prevalence of pyridines in medicinal
chemistry, there is a high demand for novel synthetic
methodologies that enable an access to new molecular
architectures containing this important pharmacophore.
ketyl radicals in synthesis has been hindered by the highly
negative reduction potential of aldehydes (E1/2red = −1.93 V vs
SCE for benzaldehyde),9 and the requirement of employing
toxic, air- and moisture-sensitive reducing agents and harsh
reaction conditions to access the ketyl radical intermediate.10
Recently, however, visible light photoredox catalysis has
emerged as an efficient way to generate ketyl11 and α-
aminoalkyl radicals from the corresponding aldehydes and
imines under mild reaction conditions.11k,12 Nonetheless,
photocatalytic intermolecular ketyl-olefin reductive coupling
reactions are very rare.11l Herein we report the first β-selective
intermolecular reductive coupling reaction between alkenyl-
pyridines and carbonyl or iminyl derivatives enabled by a
synergistic Lewis acid/photoredox catalytic system (Scheme
1b).
Our initial investigation focused on the reaction between 4-
fluorobenzaldehyde 1a and 4-vinylpyridine 2a (Table 1). We
observed that Lewis acid plays a critical role in achieving the
desired reactivity. When a solution of 1a and 2a in MeCN was
irradiated with blue LED light employing Ru(bpy)3(PF6)2 as a
photoredox catalyst and Hantzsch ester (HEH) as a stoichio-
metric reductant, no desired product (3a) was formed in the
Alkenylpyridines are versatile synthetic intermediates that
have been used in the synthesis of more complex molecules
with pyridine subunits.7 Due to their electrophilic nature, the
reductive coupling of alkenylpyridines with another electrophile
is rare.8 Pioneering studies by Krische and co-workers in 2008
resulted in the first catalytic reductive coupling of 2-
vinylpyridines to imines (Scheme 1a).8a After that seminal
report, Lam et al. developed an elegant copper-catalyzed
enantioselective reductive coupling of alkenylpyridines with
ketones8b and imines (Scheme 1a).8c These protocols offer a
useful tool for reductive C−C coupling at the α-position of the
vinyl or alkenyl moiety. However, a general reaction for β-
selective reductive coupling of alkenylpyridines with carbonyl/
iminyl derivatives has yet to be achieved. The successful
development of such a reaction would provide access to a
complementary scope of synthetically useful products.
Received: February 8, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.7b01373
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Journal of the American Chemical Society
Communication
Table 1. Selected Optimization Experiments
Table 2. Selected Examples of the Coupling Reaction
a
between Aldehydes and 4-Vinylpyridine
photocatalyst
(1.00 mol%)
Lewis acid
reductant
yield
a
entry
(20.0 mol%)
(2.00 equiv)
[%]
1
Ru(bpy)3(PF6)2
Ru(bpy)3(PF6)2
Ru(bpy)3(PF6)2
Ru(bpy)3(PF6)2
Ir(ppy)3
−
HEH
HEH
HEH
HEH
HEH
HEH
HEH
DIPEA
BNAH
HEH
HEH
HEH
0
18
85
>99
>99
47
16
0
2
Yb(OTf)3
Gd(OTf)3
La(OTf)3
La(OTf)3
La(OTf)3
La(OTf)3
La(OTf)3
La(OTf)3
La(OTf)3
La(OTf)3
La(OTf)3
3
4
5
6
Rho 6G
7
−
8
Ru(bpy)3(PF6)2
Ru(bpy)3(PF6)2
Ru(bpy)3(PF6)2
Ru(bpy)3(PF6)2
Ru(bpy)3(PF6)2
9
0
b
10
11
12
78
c
0
d
0
a
Yields were determined by 19F NMR using 3-fluoronitrobenzene as
b
the internal standard unless otherwise specified. Without bipyridine.
c
d
Without light. Under oxygen atmosphere.
absence of Lewis acid (entry 1).13 With a sub-stoichiometric
amount of Yb(OTf)3 and bipyridine ligand, 3a was formed,
albeit in low yield (entry 2). The yield of 3a was drastically
improved with Gd(OTf)3 (entry 3), while with La(OTf)3, 3a
was generated quantitatively (entry 4). We also observed that
the reaction worked equally well when Ru(bpy)3(PF6)2 was
substituted with Ir(ppy)3 (entry 5), but the yield was
diminished with Rhodamine 6G (entry 6). Interestingly,
without any photoredox catalyst, a small amount of 3a was
still observed (entry 7). Presumably, ketyl radicals were formed
through direct single electron transfer (SET) between photo-
excited Hantzsch ester and aldehydes.14 Yet, such SET is less
efficient than that in the presence of a photoredox catalyst.
Notably, the use of Hantzsch ester as a reductant is crucial.
a
Cited yields are of isolated material following chromatography.
Reactions performed with 2 equiv of aldehyde and 1 equiv of 4-
b
vinylpyridine.
(1h). Given the importance of heterocyclic structures in the
synthesis of biologically important molecules, we were pleased
to find that heteroaryl aldehydes (1l−1o) and aryl aldehydes
bearing heteroarene substituents (1t) readily participated in the
coupling reaction. To further demonstrate the synthetic utility
of the reaction, we tested more complex substrates, including
sugar (diacetone-D-glucose, 1p), natural product (estrone, 1q),
and peptide (1s) derivatives. To our delight, they all afforded
the desired products in synthetically useful yields. Notably, only
one diastereomer was obtained in these cases, which indicates
that existing chiral centers on aldehydes have a strong influence
on the stereochemical outcome of the transformation.
Next, we directed our attention to delineating the scope of
alkenylpyridine coupling partners (Table 3). Gratifyingly, 2-
vinylpyridine (4a), 2-(1-methylalkenyl)pyridine (4b), and a
range of 2-(1-arylalkenyl)pyridines (4c−4j) were converted
into the corresponding products 5 in good to excellent yields
and with modest diastereoselectivities. The reaction tolerated
substrates bearing electron-neutral (4c), electron-rich (4d−4f),
and electron-poor (4g, 4h) arene rings, as well as heterocyclic
structures such as benzofuran (4i) and indole (4j). The
coupling reaction between aldehydes and 2-(1-arylalkenyl)-
pyridines described here provides the first general route to
compounds 5c−5j, which prior to our studies remained
unknown. Our Lewis acid/photoredox catalytic protocol
enables a straightforward synthesis of this novel molecular
scaffold and its exploration in the context of medicinal
chemistry.
When either Hunig’s base (entry 8) or 1-benzyl-1,4-
̈
dihydronicotinamide (BNAH) (entry 9) was employed as a
stoichiometric reductant in place of HEH, no 3a was obtained.
Use of HEH as a reductant is beneficial because the oxidized-
Hantzsch ester (Ox-HE) could be readily recycled and
converted to HEH through hydrogenation.15 In the absence
of bipyridine, the reaction afforded 3a in only 78% yield (entry
10), the drop likely attributed to the poor solubility of unligated
La(OTf)3 in MeCN. In the control experiments, we found that
both light (entry 11) and an oxygen-free atmosphere (entry 12)
were necessary for the reaction to proceed.
With the optimized reaction conditions in hand, we then
examined the generality of this transformation with respect to
the aldehyde component. As shown in Table 2, the coupling
reactions of both electron-deficient and electron-rich benzalde-
hydes proceeded with high efficiency (up to quantitative yield).
It is noteworthy that halogen functionalities (1a−1f, 1h), in
particular Br and I, remain intact after the reaction, providing
easy handles for further synthetic elaborations. In addition, the
ortho-, meta-, and para-substituents show little influence on the
reaction efficiency (1c−1e). Moreover, the mild reaction
conditions are compatible with a wide range of other functional
groups including ester (1p, 1q, 1s), ketone (1q), amide (1r−
1t), nitrile (1g), ether (1i, 1p, 1r, 1t), −OCF3 (1r), and −CF3
Encouraged by the results of the aldehyde-alkenylpyridine
coupling, we tested imines as potential coupling partners in the
B
DOI: 10.1021/jacs.7b01373
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Journal of the American Chemical Society
Communication
Table 3. Selected Examples of the Coupling Reaction
between 2,4-Dimethoxybenzaldehyde and Alkenylpyridines
a
Figure 1. Proposed reaction mechanism.
a
the excited photocatalyst (both in the absence and presence of
Lewis acid). In order to exclude the possibility of excited HEH
(*HEH) (λmax = 362 nm in MeCN) being the quencher of
*Ru(bpy)32+, we ran the reaction using a laser line filter (CWL
= 488 2 nm, fwhm = 10 2 nm) and obtained the desired
product. Based on these observations, we postulated that the
excited photocatalyst is likely quenched by the catalytically
generated intermediate Hantzsch ester radical (HEH•).19 Since
HEH• is absent at the beginning of the reaction, it is initially
generated via an alternative pathway that involves photo-
excitation of HEH (*HEH), followed by a SET from *HEH to
an aldehyde with a concomitant proton transfer. Reduction of
Cited yields are of isolated material following chromatography. NMR
yield in parentheses and d.r. were determined on the crude reaction
1
sample using H NMR.
reaction with 4-vinylpyridine (Table 4). Prior to this report,
intermolecular reductive imine−olefin coupling reactions under
photoredox conditions were rare.11l,12c This is unfortunate,
considering the great importance of amines in drug design and
development. We were pleased to find that α-aminoalkyl
radicals generated from aromatic imines upon a SET can
indeed undergo the coupling reaction with 4-vinylpyridine.
Importantly, the reaction proceeded well regardless of the
electronic state of the iminyl aromatic rings.
*Ru(bpy)3 by HEH• (E1/2 = −0.76 V vs SCE)18 affords a
2+
red
+
strongly reducing ruthenium(I) species, Ru(bpy)3 , and
pyridinium ion PyH+. Ru(bpy)3 (E1/2
= −1.33 V vs
+
red
Table 4. Selected Examples of the Coupling Reaction
between Imines and 4-Vinylpyridine
SCE)17 engages in a SET with aldehydes activated by hydrogen
a
2+
bonding with PyH+ to regenerate the Ru(bpy)3 catalyst and
afford ketyl radical intermediate I. Addition of I to Lewis acid-
activated 4-vinylpyridine (IIa) forms radical IIb, which can
abstract hydrogen atom directly from HEH, thus generating the
Lewis acid-bound product (IIc) and another molecule of a
reductant (HEH•) capable of reducing *Ru(bpy)32+. Complex
IIc undergoes ligand exchange with 4-vinylpyridine to liberate
the desired coupling product and complete the catalytic cycle.
In conclusion, we have developed the first photocatalytic
reaction for the coupling between alkenylpyridines and
carbonyl or iminyl derivatives with a Lewis acid co-catalyst.
The unique features of our synergistic catalytic system include
the following: (i) mild reaction conditions that tolerate a wide
scope of functional groups and complex molecular architectures
such as sugar, natural product, and peptide derivatives; (ii) the
ability to forge alcohols and amines using a catalytic protocol
that couples two bench stable electrophiles, carbonyl/iminyl
derivatives and alkenylpyridines, provides an attractive
alternative to methods that use stoichiometric amounts of
reactive, unstable intermediates; (iii) access to a broad range of
“privileged” and novel heterocyclic structures, which could
provide a powerful new strategy for the synthesis of versatile
small molecules of potential pharmaceutical relevance; (iv) the
exclusive β-selectivity of our protocol offers a complementary
a
Cited yields are of isolated material following chromatography.
The proposed mechanistic details of our transformation are
depicted in Figure 1. Irradiation of Ru(bpy)32+ with visible light
produces a long-lived (1.1 μs)16 photoexcited state, *Ru-
(bpy)32+. A Stern−Volmer experiment showed no measurable
2+
red
luminescence quenching of *Ru(bpy)3 (E1/2 = +0.77 V vs
SCE)17 by HEH (E1/2 = +0.887 V vs SCE)18 in MeCN. In
red
addition, neither benzaldehyde nor 4-vinylpyridine quenches
C
DOI: 10.1021/jacs.7b01373
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Journal of the American Chemical Society
Communication
Li, X. M.; Liu, H. W.; Xu, L.; Zhuang, J. C.; Li, J.; Li, H.; Wang, W. J.
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of alkenylpyridines; (v) mechanistic studies offer valuable
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anticipate that this reaction will serve as the basis for the
development of broadly useful coupling reactions of two
electrophiles. Further efforts will be directed toward the
development of an asymmetric coupling reaction with the aid
of a chiral ligand/Lewis acid system. In addition, we will
continue working on new visible light photoredox-catalyzed
transformations involving ketyl radical intermediates.
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ASSOCIATED CONTENT
* Supporting Information
■
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The Supporting Information is available free of charge on the
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AUTHOR INFORMATION
Corresponding Author
*ming-yu.ngai@stonybrook.edu
ORCID
Katarzyna N. Lee: 0000-0003-4849-3927
Zhen Lei: 0000-0002-6608-7933
Ming-Yu Ngai: 0000-0002-3055-6662
■
Author Contributions
‡K.N.L. and Z.L. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was partially supported by National Institute of
General Medical Sciences (R35GM119652) and start-up funds
from Stony Brook University. K.N.L. received a graduate
fellowship from the NIH Chemical-Biology training grant
(T32GM092714). We thank James Herbort, a NSF REU
student (CHE-1358959), for the synthesis of some alkenyl-
pyridines. This paper is dedicated to Prof. Barry M. Trost on
the occasion of his 75th birthday.
́
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DOI: 10.1021/jacs.7b01373
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