Photoredox-Catalyzed Addition of Carbamoyl Radicals to Olefins: A 1,4-Dihydropyridine Approach

Article abstract of DOI:10.1002/chem.202002410

Functionalization with C1-building blocks are key synthetic methods in organic synthesis. The low reactivity of the most abundant C₁-molecule, carbon dioxide, makes alternative carboxylation reactions with CO₂-surrogates especially important. We report a photoredox-catalyzed protocol for alkene carbamoylations. Readily accessible 4-carboxamido-Hantzsch esters serve as convenient starting materials that generate carbamoyl radicals upon visible light-mediated single-electron transfer. Addition to various alkenes proceeded with high levels of regio- and chemoselectivity.

Full text of DOI:10.1002/chem.202002410

Accepted Article
Accepted Article
Title: Photoredox-Catalyzed Addition of Carbamoyl Radicals to Olefins:
A 1,4-Dihydropyridine Approach
Authors: Axel Jacobi von Wangelin, Mikhail O. Konev, and Luana
Cardinale
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To be cited as: Chem. Eur. J. 10.1002/chem.202002410
Link to VoR: https://doi.org/10.1002/chem.202002410
01/2020

10.1002/chem.202002410
Chemistry - A European Journal
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Photoredox-Catalyzed Addition of Carbamoyl Radicals to Olefins:
A 1,4-Dihydropyridine Approach
Luana Cardinale,[a] Mikhail O. Konev,[a],* and Axel Jacobi von Wangelin[a],*
Abstract: Functionalization with C1-building blocks are key synthetic
methods in organic synthesis. The low reactivity of the most abundant
C1-molecule, carbon dioxide, makes alternative carboxylation
reactions with CO2-surrogates especially important. We report a
photoredox-catalyzed protocol for alkene carbamoylations. Readily
accessible 4-carboxamido-Hantzsch esters serve as convenient
starting materials that generate carbamoyl radicals upon visible light-
mediated single-electron transfer. Addition to various alkenes
proceeded with high levels of regio- and chemoselectivity.
were recently reported by Donald9 via reductive decarboxylation
of N-oxyphthalimido oxamides and by Feng10 via a related
oxidative decarboxylation of oxamic acids (Scheme 1a). Both
protocols involve noble-metal containing photocatalysts and
further reaction of the intermediate alkyl radicals onto arene
substituents leading to dihydroquinolin-2-ones. Hantzsch ester
derivatives have only very recently been discovered as
convenient precursors to alkyl,11 acyl,12 and - during the course of
this study - carbamoyl13 radicals via photoredox-catalysis or direct
photoexcitation. We surmised that the readily accessible 4-
carboxamido-substituted Hantzsch esters (1) could be utilized for
an unprecedented photocatalytic approach to mild carbamoyl-
radical additions to furnish functionalized carboxamides
comprising 1,4-dicarbonyl motifs (Scheme 1b).
C1-building blocks are among the most abundant and available
chemicals (e.g. CO1-2, COCl2, Me-H/OH/Hal, HCN).1 However,
the range of diverse C1-building blocks is rather limited, hence
access to
a wide variety of methods is crucial to their
implementation into various chemical syntheses. The use of
nucleophilic carbamoyl radicals, as a formal amide synthon and
one-electron-reduced CO2 surrogate, can provide one of the most
valuable C1-functional groups and carboxyl derivatives:
carboxamides. Amide-containing molecules are ubiquitous
across every corner of chemical constituents, from proteins and
pharmaceuticals, to polymers and agrochemicals.2 Classical
condensation-based protocols3 are readily contrasted with
modern and non-obvious retrosynthetic approaches, for example,
by less-explored radical strategies (Scheme 1, top). As such, the
addition of organic carbon-centered radicals to electron-deficient
olefins (Giese reaction) has become a versatile tool for the
construction of C–C bonds in organic synthesis.4a-c Since its
discovery, a variety of free radical species (alkyl,5a acyl,5b
carbamoyl5c) have been employed as nucleophiles to furnish their
corresponding homologues (alkanes, ketones, amides,
respectively). While conventional Giese-type protocols rely on
harsh conditions for the initiation of the reaction (incl. toxic tin
reagents, elevated temperatures, or high-energy UV light), the
advent of modern photoredox catalysis has provided milder
routes of radical generation.6 Significant progress has been made
towards photoredox-catalyzed alkylations and acylations,
whereas the convenient formation and wide utilization of free
carbamoyl radicals has remained elusive and rather limited, in
most of the cases, to the addition to (hetero)arenes in a Minisci-
type process.7 The first light-mediated radical carbamoylation of
olefins was reported by Elad and Rokach in 1964 via H-atom
abstraction of formamide to give low yields and low selectivity of
the desired products.8 Photoredox-catalyzed carbamoylations
We commenced our study with the reaction of the 4-substituted
Hantzsch ester derivative 1a with benzylidene malonitrile 2a
under visible light irradiation (Table 1). We chose the organic dye
3DPAFIPN as a photocatalyst based on its oxidation capability
(E1/2(PC*/PC.-) = +1.09 V vs. SCE, CH3CN)14 which may enable
single-electron transfer (SET) from 1a (Epa = +1.17 V vs. SCE,
CH3CN) to deliver the carbamoyl radical upon aromatization-
driven fragmentation. Indeed, irradiation of a solution of 1a and
2a (1.3 equiv.) with 2.5 mol% 3DPAFIPN in CH2Cl2 with blue light
(λmax = 455 nm) resulted in the formation of the desired dicyano-
propionamide 3a in 80% yield (Table 1, entry 1). Alternative
organic photocatalysts such as the more reducing 3DPA2FBN
(E1/2(PC.+/PC*) = –1.60 V vs. SCE, CH3CN)14 and the more
oxidizing Mes-Acr+ (Ered = +1.88 V vs. SCE, CH3CN)15 afforded
lower yields (entries 2 and 3). The choice of solvent was crucial
to the reaction (entry 4, see ESI). Acetonitrile, N,N-dimethyl-
formamide, and other chlorinated solvents gave lower yields. The
influence of electron mediators (e.g. 1,4-dicyanobenzene,
[Ni(bipy)3](BF4)2, methyl viologen) was tested (entry 7, see ESI).
Slightly enhanced reactivity was observed in the presence of 1,4-
dicyanobenzene. Control experiments established the necessity
of photocatalyst and light (entries 8 and 9). With the optimized
conditions, we explored the scope of the photoredox-catalyzed
carbamoyl-Giese reaction (Scheme 2).
A diverse set of
benzylidene malononitriles gave high yields of the adducts (3ba-
3fa) whereas electron-rich aryl substituents lowered the yield
significantly. Heteroaryl motifs, such as pyridine (3ga), thiophene
(3ia), and furan (3ha), and alkylidene malononitriles (3ja, 3ka)
were well-tolerated. The reaction was also applied to alternative
alkenes with good reactivity including Meldrum´s acid, 1,3-
indandione, and 1,3-dimethyl barbiturates (3la-3na). 1,1-Diaryl-
ethylene derivatives were also competent radical acceptors (3sa-
3wa). The scope of 4-carboxamido substituents within the
Hantzsch esters included acyclic and cyclic sec- and tert-amides
(3ab-3af).
[a]
M.Sc. L. Cardinale, Dr. Mikhail O. Konev,* Prof. Dr. A. Jacobi von
Wangelin*
Dept. of Chemistry, University of Hamburg
Martin Luther King Pl 6, 20146 Hamburg (Germany)
E-mail: axel.jacobi@uni-hamburg.de
Supporting information for this article is given via a link at the end of
the document.
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Scheme 1. Carbamoyl radicals as CO2-surrogates in the synthesis of carboxylate derivatives by a metal-free, photocatalytic addition to alkenes.
Table 1. Selected optimization and control experiments.[a]
We performed key experiments in an effort to probe the
mechanism of this photoredox-catalyzed carbamoyl addition
reaction. The UV-Vis spectrum of the 4-carboxamido-Hantzsch
ester 1a (see ESI) exhibited an absorption maximum at 350 nm.
This excludes direct excitation and photolytic reactivity under
irradiation with a blue LED (λmax = 455 nm) where only the
photocatalyst
exhibits
considerable
absorption.
Cyclic
voltammetry (CV) studies supported the thermodynamic
feasibility of the reaction as the oxidation potential of the Hantzsch
ester 1a (Epa = +1.17 V vs. SCE, CH3CN) matches that of the
excited photocatalyst 3DPAFIPN* (E1/2(PC*/PC.-) = +1.09 V vs.
SCE, CH3CN).14 Fluorescence quenching studies and Stern-
Volmer analysis documented that the rate of single-electron
transfer between 1a and the photocatalyst operates at the
diffusion limit (Kq = 9.22 1010 M-1s-1), while the quenching with the
benzylidene malononitrile 2a is by more than a magnitude slower
(Kq = 2.26 109 M-1s-1). The standard reaction was completely
inhibited in the presence of the radical scavenger (2,2,6,6-tetra-
Entry
Deviations from standard conditions
Yield of 3aa [%][b]
1
2
3
4
5
6
7
8
9
none
80
78
65
65
60
67
89
0
3DPA2FBN instead of 3DPAFIPN
Mes-Acr+ instead of 3DPAFIPN
CH3CN instead of CH2Cl2
405 nm, no 3DPAFIPN
1 mol% 3DPAFIPN
methylpiperidin-1-yl)oxyl (TEMPO,
1 equiv., see ESI); the
resultant carbamoyl-TEMPO adduct 4 (Scheme 3) was detected
by GC/MS. Based on our synthetic and spectroscopic
observations and literature data, we propose the following
reaction mechanism: Excitation of the organic dye 3DPAFIPN by
blue light (λmax = 455 nm) affords the strongly oxidizing species
3DPAFIPN* that undergoes single-electron transfer (SET) from
the electron-rich Hantzsch ester derivative 1.
addition of 20 mol% 1,4-dicyanobenzene
in the dark
no 3DPAFIPN
8
[a] 0.1 mmol 1a (0.1 M in DCM), 2a (1.3 equiv.), 16 h, at r.t. under irradiation of
blue LED (455 nm). [b] 1H NMR yields vs. external 1,3,5-trimethoxybenzene.
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Scheme 2. Scope of the photoredox-catalyzed carbamoylation of alkenes. Isolated yields are given (0.3 mmol scales, 0.1 M in DCM).
The resultant radical cation 1.+ eliminates the carbamoyl radical I
upon aromatization-driven fragmentation. Addition of the
nucleophilic radical I to the electron-deficient alkene 2 furnishes
an electrophilic radical II - via a formal Umpolung reaction - which
can engage in a single-electron reduction with the reduced
photocatalyst PC.-(E1/2(PC/PC.-) = –1.59 V vs. SCE, CH3CN).16
The stabilized anion III is protonated to give the formal hydro-
carboxamidation adduct 3. Deuteration experiments in the
presence of D2O supported the formation of the anionic
intermediate III. A hydrogen atom transfer was discarded based
on the absence of deuterium incorporation in reactions performed
in DMF-d7 and CD2Cl2, respectively (see ESI). The operation of
long radical chains was excluded by a light-on/off experiment.
Over a period of 7 h, steady conversion was recorded under
irradiation while no turnover was detected in the dark (Scheme 3,
bottom). Finally, we propose that the light-driven reaction is very
unlikely to proceed via energy transfer (EnT):17 The triplet energy
(ET) of such dihydropyridine derivatives18 is ~60 kcal mol-1 which
is beyond the thermodynamic reach of the active photocatalysts
(e.g. ET = 44.7 kcal mol-1 for Mes-Acr+).19
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Figure 1. a) UV-Vis spectra of 2a (orange line, 0.05 M in DCM), 1a (yellow line,
0.05 M in DCM) and a 1:1 mixture of 1a and 2a (grey line, 0.05 M in DCM). b)
Fluorescence quenching of 1a in the prescence of increasing amounts of 2a.
Scheme 4. Catalyst-free carbamoyl additions. 0.3 mmol 1a; 1H NMR yields vs.
a
external 1,3,5-trimethoxybenzene. Yield obtained under 455 nm irradiation
(Table 1, entry 9).
Scheme 3. Top: Postulated reaction mechanism. Center: Key reaction
intermediates. Bottom: Alternating light/dark experiments.
From the UV/Vis absorption and emission spectra and
electrochemical data (see ESI) we determined the redox potential
Eox(1a.+/1a*) of the excited state 1a* to be –1.9 V vs. SCE
according to the Rehm-Weller approximation.24 This observation
together with the fluorescence quenching experiments
corroborated our hypothesis of effective SET between 1a* and 2a
within the EDA complex (Figure 2b).25a Consequently, reactions
under irradiation at 405 nm (for better match with the absorption
as the 455 nm irradiation led to only 8% of yield) afforded good
reactivity after short reaction times (Table 1, entry 5). A brief
substrate scope evaluation showed that electron-deficient
alkenes fared better and afforded comparable yields to the
photocatalytic conditions above (Scheme 4). However, the more
electron-rich 1,1-diphenylethylene remained unreacted.25b
Hantzsch ester derivatives have been demonstrated to undergo
direct photoexcitation in the absence of photocatalysts. The
resultant highly reducing excited state species20 are capable of
engaging in SET with a variety of π-electrophiles to afford
products of formal hydrogenation,21 alkylation or acylation.22 Such
reactivity may be harnessed in catalyst-free Giese reactions
between suitable Hantzsch esters and alkenes, which was
already observed in Table 1 (entries 5 and 10). We recorded the
UV-Vis spectra of 1a, 2a, and of their equimolar combination
(Figure 2a). The formation of an electron donor-acceptor (EDA)
complex became obvious from the bathochromic shift observed
when combining both reactants23 that exhibits considerable
absorbance at 455 nm.
In conclusion, we have reported a novel photoredox-protocol that
enables the facile generation of carbamoyl radicals from 4-
carboxamido-1,4-dihydropyridines and their rapid addition to
various electron-deficient and 1,1-disubstituted alkenes. Notably,
this synthetic strategy relies on the use of easily accessible and
bench-stable Hantzsch ester derivatives, the use of an
inexpensive organic photocatalyst, and the operation under mild
conditions at room temperature with visible light. Mechanistic
studies supported the notion of a rapid photo-induced SET
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mechanistic studies were conducted to support the proposed
reaction mechanism. Suitable combinations of Hantzsch esters
and alkenes can be reacted via catalyst-free direct excitation.
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Acknowledgements
This work was generously supported by the University of
Hamburg. M.O.K. thanks the Alexander von Humboldt
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Keywords: photoredox catalysis• carbamoyl radical • Giese
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Entry for the Table of Contents
COMMUNICATION
A
photocatalytic carbamoylation of
Luana Cardinale, Mikhail O. Konev, and
Axel Jacobi von Wangelin*
alkenes was developed under mild
conditions with a metal-free catalyst.
The reaction utilizes easily available
Page No. – Page No.
Hantzsch
ester
derivatives
as
Photoredox-Catalyzed Addition of
Carbamoyl Radicals to Olefins: A 1,4-
Dihydropyridine Approach
precursors to carbamoyl radicals which
readily add to electron-deficient
alkenes.
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