Visible-Light-Induced Carbo-2-pyridylation of Electron-Deficient Alkenes with Pyridinium Salts

Article abstract of DOI:10.1002/anie.201704385

A simple and practical visible-light-induced carbo-2-pyridylation of electron-deficient alkenes with readily available N-benzoylmethylpyridinium bromides is reported. More than 40 examples are presented and proceed in greater than 80 % yield (on average)

Full text of DOI:10.1002/anie.201704385

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Accepted Article
Title: Visible-Light-Induced carbo-2-pyridylation of Electron-Deficient
Alkenes with Pyridinium Salts
Authors: Rong-Bin Hu, Shuai Sun, and Yijin Su
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10.1002/anie.201704385
Angewandte Chemie International Edition
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Visible-Light-Induced carbo-2-pyridylation of Electron-Deficient
Alkenes with Pyridinium Salts
Rong-Bin Hu,‡ Shuai Sun,‡ Yijin Su*
Abstract:
A simple and practical visible-light-induced carbo-2- formation of EDA complexes to mediate similar alkylation
pyridylation of electron-deficient alkenes with readily available N- reactions[2c-d] (Scheme 1A, II).
benzoylmethylpyridinium bromides has been developed in this
manuscript. More than 40 examples are presented in >80% yield (on induced intramolecular SET process[5] in donor-acceptor (D-A)
Inspired by these findings, we envisioned that a visible-light-
average) with excellent regio- and diastereo-selectivity.
molecules would provide an alternative method for the formation
of biradical intermediates[6] (Scheme 1A, III), which were
previously generated via triplet-triplet energy transfer process[7],
1,5-H shift process[8], or radical addition process[9]. To explore
In the past decades, conceptual advances in visible-light-
driven photocatalysis were often widely embraced by synthetic
applications,[1] in which various high-energy reactive species
were generated under mild conditions. Meanwhile, the
development of external photosensitizer-free photoreactions has
been the focus of intensive research due to their convenience
and efficiency[2]. Recently, Melchiorre and co-workers have
developed a robust photo-organocatalytic strategy for organic
synthesis, in which the in situ-formed chiral enamines served as
strong reductants instead of nucleophiles to trigger the formation
such
a
strategy,
we
proposed
that
a
formal
dicarbofunctionalization of electron-deficient alkenes with
pyridinium salts should be achieved. The proposed reaction
pathway is shown in Scheme 1B: i) dearomative 1,3-dipolar
cycloaddition of pyridinium ylides[10] and electron-deficient
alkenes (syn-addition to alkene) to construct the dienamine
moiety 4[11] (previously formed by condensation of amine and α,
β-unsaturated-aldehyde[2a-d]), ii) absorption of visible light and
subsequent intersystem crossing (ISC) process yielding the
triplet excited state of dienamine moiety 5, iii) intramolecular
electron transfer from the triplet dienamine moiety[12] to the
acceptor to generate the triplet zwitterionic biradical intermediate
6, iv) proton transfer[13] to produce the neutral biradical 7, v) ISC
process followed by formal aza-Norrish II cleavage[14] of 1,4-
of radicals through a single electron transfer (SET) process[3]
.
First, they reported that a SET process in the excited state of
electron-donor-acceptor (EDA) complexes[4], which could be
activated by visible light, enabled the enantioselective catalytic
photochemical alkylation of aldehyde[2a-b] (Scheme 1A, I). They
also achieved an intermolecular SET process from visible-light-
active chiral enamines to bromomalonates without relying on the
Table 1. Evaluation of Reaction Conditions[a]
.
Entry
A
X
Solvent
Conversion[b]
Yield[b]
1
(4-NO2)Ph
Br
Cl
Br
Br
Cl
Cl
Br
Br
Br
Br
Br
Br
Br
Br
Toluene-d8
Toluene-d8
Toluene-d8
Toluene-d8
Toluene-d8
Toluene-d8
Toluene-d8
CDCl3
<10%
<10%
64%
N.D.
2
C(O)NH2
C(O)OEt
Ac
N.D.
3
N.D.
4
45%
N.D.
5
CN
53%
N.D.
6
Bz
69%
45%
7
Bz
92%
81%
8
Bz
100%
75%
trace
trace
trace
38%
Scheme 1. Hypothetic Carbo-2-Pyridylation of Olefin with Pyridinium Salt.
9
Bz
MeOH-d4
DMSO-d6
D2O
10
Bz
100%
100%
100%
76%
11
Bz
12[c]
13[c], [e]
14[c], [f]
Bz
Toluene
Toluene
86%[d]
<10%
<10%[g]
[*]
Dr. R.-B. Hu[‡], Mr. S. Sun[‡], Prof. Dr. Y. Su*
State Key Laboratory for Oxo Synthesis and Selective Oxidation
Lanzhou Institute of Chemical Physics (LICP), Chinese Academy of
Sciences
Bz
Bz
Toluene
100%
Lanzhou 730000, P. R. China
E-mail: suyj@licp.cas.cn
[a] 0.1 mmol. [b] Measured by 1H NMR. [c] 0.5 mmol, toluene (0.2 M). [d]
Isolated yield. [e] In dark and at reflux. [f] Addition of TEMPO (5.0 eq.). [g]
Benzyl 3-benzoylindolizine-1-carboxylate (71% isolated yield).
[‡]
These authors contributed equally to this work.
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201704385
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biradical intermediate to open the 5-membered ring, vi)
tautomerization completing the desired carbo-2-pyridylation
reaction. In contrast, with external radical source (such as
TEMPO, oxygen and so on), indolizine 9 was the only product
observed in the previous studies[15] (Scheme 1B, vii). This further
raised our interest in developing the proposed reaction pathway
using visible light to induce the biradical process.
To develop a synthetically useful dicarbofunctionalization, we
chose to study the reaction of 2a and 1 as a model reaction
(Table 1). Initially, we focused on examining different type of
pyridinium salts varying N-alkyl groups and counter anions, in
the presence of DABCO as the base in toluene-d8 with visible
light. We found that the identity of the N-alkyl group has a
dramatic influence on the outcome of the reaction. With
pyridinium salts bearing N-alkyl groups, such as 4-nitrobenzyl,
aminocarbonylmethyl, ethoxycarbonylmethyl, acetylmethyl, and
cyanomethyl (entry 1-5), the desired transformation did not
occur, probably due to the difficulty of the intramolecular SET
process. In the previous studies[16], benzoyl group was utilized
TEMPO (Scheme 1B, vii), indolizine 9aa was obtained in 71%
yield (entry 14 and Part VII, SI)[15a]
.
Table 2 outlined the effect of varying the structure of the
pyridinium salt. First, this transformation could provide all type 2,
n-disubstituted pyridines (n = 3, 4, 5, or 6). The pyridine ring
moiety tolerated significant electronic perturbation at 4-position
(3ba-ea). Isoquinoline 3fa was obtained with complete regio-
selectivity. Pyridinium ring bearing 3-substituent proceeded this
reaction efficiently with excellent yield and delivered both 2,5-
disubstituted pyridine (3ga and 3ha) and 2,3-disubstituted
pyridine (3ga’ and 3ha’). 2,6-Disubstritued pyridines (3ia, 3ja,
3ka) were synthesized effectively using this transformation.
Second, the scope of this transformation with respect to the
acceptor (A) of pyridinium salt was also summarized. A variety
of electronically modified aryl ketones reacted efficiently with
good yields (3la and 3ma). Potentially reactive aryl bromide was
well tolerated, providing a handle for derivatization of 3na.
Notably, ortho-hydroxy group gave 3oa in 65% yield. Heteroaryl
ketones reacted smoothly (3pa and 3qa). Pyridinium salt
as an acceptor (A) to facilitate the intermolecular SET processes. containing tertiary α-carbon was also competent reaction partner,
Similarly in this intramolecular SET process, reaction of N-
benzoylmethylpyridinium chloride underwent the desired
dicarbofunctionalization in 45% yield (entry 6). The identity of the
counter ion also has a substantial influence on the yield of this
transformation. The reaction of the corresponding pyridinium
bromide (2a) occurred with 92% conversion and afforded 3aa in
81% yield (entry 7). An evaluation of solvents showed that
toluene gave the best performance, probably due to the
formation of exciplex with intermediates (entries 8-11). We found
that a concentration at 0.2 M led to the highest yield (86%
affording 3ra in 75 % with 1:1 of d.r. value.
We next studied the scope of the electron-deficient alkenes.
As shown in Table 3, a variety of α, β-unsaturated compounds,
such as acrylate (3ab-c), enone (3ao), enal (3ap), acrylonitrile
(3aq), vinylphosphonate (3ar) and vinylsulfone (3as) underwent
this transformation with 66% to 96% yields. The reactions also
occurred readily with α, β-unsaturated compounds that have
substitution at α-, β-, or both positions (3ad-g, 3ai, 3al), and
cyclic esters with the conjugated alkene (3ah, 3aj, 3ak). The
relative stereochemistry of the product was set by the geometry
of the alkene and the syn-addition depending on 1,3-dipolar
isolated yield) in
a
scale of 0.5 mmol among other
control experiment
concentrations examined (entry 12).
A
Table 3. Electron-Deficient Alkene Substrate Scope[a]
.
performed in dark showed formation of trace amount of the
product even at reflux for 60 hours (entry 13). In the presence of
Table 2. Scope of Pyridinium Salts[a]
.
[a] 0.5 mmol, isolated yield. [b] DBU instead of DABCO. [c] 1a (1.5 equiv),
DABCO (1.5 equiv). [d] DBU (3.0 equiv) instead of DABCO. [e] N-
Methylmorpholine (3.0 equiv) instead of DABCO. [f] DBU (1.2 equiv)
instead of DABCO. [g] concentration = 0.5 M.
[a] 0.5 mmol scale, isolated yield. [b] 2a (1.5 equiv), DABCO (1.5 equiv).
[c] 2a (1.5 equiv), DBU (1.5 equiv) instead of DABCO. [d] 2a (2.0 equiv),
DBU (3.0 equiv), dioxane (0.1 M). [e] Pyridinium salt (1.5 equiv), DABCO
(1.5 equiv).
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10.1002/anie.201704385
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cycloaddition. Good diastereoselectivity (but not single
diastereomer) was observed with reaction of both cis- and trans-
diethyl-2-butenedioate due to epimerization at Ca center of 3am
and 3an under base condition. The connectivity and
stereochemistry of the products (3ab, 3ad, 3aj, 3ao) were
unambiguously confirmed by X-ray diffraction study.
rearrangement reaction to yield the desired product 3fg in 95%
yield under the irradiation of visible light (eq. 4 and Part VI, SI),
which indicated that the tetrahydroindolizine might be the key
intermediate for this carbo-2-pyridylation reaction. Monitoring the
reactions by 1H NMR spectroscopy confirmed this assumption
(Part VIII, SI). Notably, a control experiment performed in dark
showed formation of trace amount of the product 3fg (eq. 4).
The rate of this rearrangement reaction at lower concentration
was faster than that at higher concentration (eq. 4), which
indicated that this rearrangement reaction of tetrahydroindolizine
To demonstrate the broad synthetic utility of our developed
method, we carried out reactions for the late-stage modification
of two selected pharmaceutical molecules. First, the reaction of
a pyridinium salt derived from Bisacodyl, a drug used for
constipation relief, afforded the product 3sa with 85% total yield
(eq. 1). In addition, 16-dehydro-pregnenonlone acetate (16-
DPA), a key intermediate for the synthesis of drugs of steroid
family, underwent carbo-2-pyridylation reaction to afford 3at in
72% yield as a single isomer (eq. 2), which was confirmed by
NMR and X-ray crystallography. These results demonstrated
that this methodology provided an efficient tool for the late-stage
modification of drugs and their synthetic intermediates without
concerning toxic metal residue.
On the other hand, hexafluoroisopropyl methacrylate 2u, a
synthetic equivalent of acyl cation, also underwent this
dicarbofunctionalization to afford 3au (95% yield, determined by
1H NMR), which could be further derivatized without a need for a
separation process (Scheme 2). Compound 3au underwent
hydrolysis and decarboxylation to provide 10, and nucleophilic
substitution using 3-methyl aniline at reflux to afford amide 11. In
addition, deprotonation of 3au and ensuing cyclization afforded
should be
Furthermore,
a
visible-light-induced unimolecular reaction.
both the reaction mixture and the
tetrahydroindolizine intermediate showed an absorption band at
visible spectrum (Part XI, SI). All the above experimental results
supported the proposed reaction pathway in Scheme 1B.
In summary,
a simple and practical visible-light-induced
carbo-2-pyridylation of electron-deficient alkenes with N-
benzoylmethylpyridinium bromides has been developed with a
broad scope of substrates. Our experimental results suggest
that this transformation consists of two individual reactions. The
pyridinium ylides generated by deprotonation of N-
benzoylmethylpyridinium bromides undergo a dearomative 1,3-
dipolar cycloaddition with electron-poor alkenes to afford a
tetrahydroindolizine intermediate. This compound absorbs
visible light to generate
a biradical intermediate via an
intramolecular SET process, which subsequently undergoes a
formal aza-Norrish II cleavage to afford the final product.
Experimental results show that the relative stereochemistry of
the product depends on the double bond geometry and the
dearomative 1,3-dipolar cycloaddition. Studies on the reaction
mechanism and further synthetic application of biradical
photochemistry are currently ongoing in our laboratory.
a
scaffold of 3,4-dihydro-2H-pyran-2-one 12. Finally,
condensation of 3au with benzylamine and subsequent
cyclization constructed a backbone of 3,4-dihydropyridin-2(1H)-
one 13.
Preliminary mechanistic experiments were conducted to gain
insight of this carbo-2-pyridylation reaction. KIE determined from
an intramolecular competition experiment revealed that the
cleavage of the ortho C-H bond in pyridine ring is not involved in
the rate-determining step (eq. 3). A 1,3-dipolar cycloadduct 4fg
was obtained with 88% yield in dark and could further proceed a
Acknowledgements
Financial support from the Hundred Talent Program of Chinese
Academy of Sciences, the National Natural Science Foundation
of China (21602229), the State Key Laboratory for Oxo
Synthesis and Selective Oxidation, and Lanzhou Institute of
Chemical Physics are gratefully acknowledged.
Conflict of interest
The authors declare no conflict of interest.
Keywords: Difunctionalization • Biradical • Visible light • Alkenes
Scheme 2. One-Pot Approaches for the Synthesis/Derivatization of 3au.
• Nitrogen heterocycles
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COMMUNICATION
Rong-Bin Hu,‡ Shuai Sun,‡ Yijin Su*
Page No. – Page No.
Visible-Light-Induced Carbo-2-
Pyridylation of Electron-Deficient
Alkenes with Pyridinium Salts
Generation of biradical via a visible-light-induced intramolecular electron transfer
process allows a carbo-2-pyridylation reaction of electron-deficient alkenes using N-
benzoylmethylpyridinium bromides. More than 40 examples are presented in >80%
yield (on average) with excellent regio- and diastereo-selectivity.
This article is protected by copyright. All rights reserved.