Photoredox-Catalyzed Four-Component Reaction for the Synthesis of Complex Secondary Amines

Article abstract of DOI:10.1021/acs.orglett.0c00614

The one-pot sulfonylation/aminoalkylation of styrene derivatives furnishing substituted ?3-sulfonylamines was accomplished through a photoredox-catalyzed four-component reaction. Besides one molecule of water and the sodium counterion of the sulfinate, all atoms of the starting materials are transferred to the final product, rendering this process highly atom-efficient. The operationally simple protocol allows for the simultaneous formation of three new single bonds (C-S, C-N, and C-C) and therefore grants rapid access to structurally diverse products.

Full text of DOI:10.1021/acs.orglett.0c00614

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Letter
Photoredox-Catalyzed Four-Component Reaction for the Synthesis
of Complex Secondary Amines
§
§
̈
Lisa Marie Kammer, Matthias Krumb, Benjamin Spitzbarth, Benjamin Lipp, Jonas Kuhlborn,
Jonas Busold, Olga M. Mulina, Alexander O. Terentev, and Till Opatz*
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ABSTRACT: The one-pot sulfonylation/aminoalkylation of styrene
derivatives furnishing substituted γ-sulfonylamines was accomplished
through a photoredox-catalyzed four-component reaction. Besides
one molecule of water and the sodium counterion of the sulfinate, all
atoms of the starting materials are transferred to the final product,
rendering this process highly atom-efficient. The operationally
simple protocol allows for the simultaneous formation of three
new single bonds (C−S, C−N, and C−C) and therefore grants rapid
access to structurally diverse products.
ulticomponent reactions (MCRs) are one-pot trans-
formations of at least three substrates, in which multiple
(Scheme 1c).19 Whereas the above-mentioned methods rely
on classical ionic transformations, the reaction reported by
Masson combines the advantages of a 4-CR with the
exceptionally mild conditions of photoredox catalysis (Scheme
1d).20 Inspired by this work and by the atom-efficiency of the
Ugi reaction, the 4-CR highlighted in Scheme 1e was devised.
We have previously reported the sulfonylation/arylation of
styrenes21 in a three-component photoredox reaction.22 The
chemoselectivity of this double-radical alkene difunctionaliza-
tion relies on the persistent radical effect resulting from the
stability of cyanopyridine-derived radical anions.23,24
In search of a promising alternative for the cyanoarene
component, benzalanilines were investigated because they are
known to produce stable neutral radicals upon the reduction of
their protonated forms.25,26 Because the latter can be formed in
situ from an aldehyde and an aniline derivative, a 4-CR can be
envisioned that grants fast access to highly substituted γ-
sulfonylamines. Apart from one molecule of water and the
sodium counterion of the sulfinate, all atoms are transferred to
the final product, resulting in an exceptional atom efficiency.27
Initial experiments were carried out using (E)-N-benzylide-
neaniline (1.0 equiv), sodium p-toluenesulfinate (2.0 equiv),
styrene (1.5 equiv), and fac-Ir(ppy)3 (1 mol %) in an
acetonitrile/water (9:1) mixture. After optimization of all
reaction parameters (see the Supporting Information, section
III), the desired product 1 was obtained in 65% yield after 24 h
M
new bonds are formed, furnishing a product that ideally
contains all atoms of the starting materials.1,2 The reduction of
the number of individual synthetic steps, work-ups, and
purifications minimizes the input of resources and the amount
of waste produced.3,4 Additionally, MCRs enable the rapid
construction of compounds of high molecular complexity and
have hence been recognized as powerful tools in synthetic
chemistry. These advantages render MCRs highly attractive for
medicinal chemistry,5,6 natural product synthesis,7 heterocyclic
chemistry,8 and bioconjugation.9
The first MCR was reported in 1850 by Strecker, who
described the synthesis of α-aminonitriles from aldehydes,
ammonia, and cyanide, which allowed the preparation of α-
amino acids through subsequent hydrolysis.10 In the following
decades, numerous MCRs have been developed, some of
which belong to the standard repertoire of synthetic organic
chemistry,11 such as the Mannich,12 Petasis,13 Biginelli,14 and
the Ugi15 reactions. The latter comprises the one-pot synthesis
of α-aminoacyl amide derivatives from a ketone/aldehyde, an
amine, an isocyanide, and a carboxylic acid (Scheme 1b). Most
MCRs comprise three components, whereas those with a
fourth or even more components are quite rare,16 highlighting
the inherent compatibility issues in terms of desired and
undesired reactivity modes.
The Bucherer−Bergs hydantoin and Ugi reactions (Scheme
1a,b) were the first four-component reactions (4-CRs),
producing only one equivalent of water as a coproduct,
which makes these sustainable transformations outstanding in
terms of their atom efficiency.3,17,18
Received: February 16, 2020
Recently, Li et al. developed a one-pot synthesis of
perfluoroalkylated isoxazoles from styrenes, sodium azide,
tert-butyl hydroperoxide, and perfluorinated alkyl iodides
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Scheme 1. Overview of Literature-Reported Four-
Component Reactions
Scheme 2. Mechanistic Proposal for the Developed 4-CR
occupied molecular orbital (SOMO) energy, the latter species
is strongly electrophilic and rapidly attacks the styrene’s double
bond.36,37 The generated benzylic radical IIIa is, in turn,
trapped by an excess of the more persistent radical Ia
(persistent radical effect).23,24,31,32 An extensive mechanistic
investigation including control experiments, calculated Gibbs
free energies for all plausible SET steps, spectroscopic data,
and a light−dark cycle experiment is provided in the
Supporting Information (section IV).
The optimized conditions were then used to extend the
reaction to a 4-CR by adding benzaldehyde and aniline
separately to the reaction mixture instead of a preformed
imine. The desired product was obtained in similar yield
(Scheme 3, 1, 62% 4-CR vs 65% 3-CR), demonstrating that
the iminium ion is a better oxidative quencher for the
photocatalyst than the less electrophilic aldehyde. Further
comparisons between the yields of the 3-CR and 4-CR were
made with different substitution patterns on each of the four
starting materials, which revealed that the transformation could
generally be performed as a 4-CR (e.g., 4-methoxystyrene (5,
44% 4-CR vs 58% 3-CR), thiophene-2-carbaldehyde (39, 47%
4-CR vs 32, 44% 3-CR), sodium methanesulfinate (20, 62% 4-
CR vs 66% 3-CR), and pyridine-2-carbaldehyde (38, 25% 4-
CR vs 32% 3-CR)).
Luminescence quenching studies (see the SI) revealed,
however, that benzaldehyde does quench the excited iridium
catalyst. The formed ketyl radical could possibly undergo the
same radical cascade as described for α-amino radical Ia.
Gratifyingly, depending on the exact substitution patterns,
none or only trace amounts of the corresponding product were
observed. In a control experiment performed without the
addition of aniline, the corresponding alcohol was obtained in
a nitrogen-free 3-CR, albeit in low yield (19%; see the
Supporting Information for more details).
of irradiation with a 23 W household compact fluorescent lamp
(CFL) in the presence of NaHSO4 (3.0 equiv) as an additive.
The iridium catalyst can be substituted by phenanthrene,
which gives only slightly lower yields but requires the use of
UV-B radiation instead of visible light. A small excess of
styrene (1.50 equiv) is preferred in the reaction because of the
possible polymerization of styrene and its derivatives. The
reaction did not proceed without water or an acidic additive
(see the Supporting Information). A certain amount of water is
needed to solubilize the NaHSO4 in addition to the beneficial
effect of ionic additives on photoinduced electron transfer
(PET) reactions, which is well-known and presumably results
from a facilitated separation of the radical (ion) pairs produced
via single electron transfer (SET).28 The yield drops
dramatically under neutral or basic conditions due to the
loss of protonation. In the present case, protonation of the
imine’s nitrogen is decisive for this transformation because it
reduces the reduction potential (see cyclic voltammetry data in
the Supporting Information) of the imine (E1/2((I−H)+/(I−
H)•) = −1.13 V vs FcH/FcH+, E1/2((I)/(I)•−) = −1.91 V vs
SCE,29 −2.52 V vs FcH/FcH+; see the Supporting
Information). Thus it can be assumed that the initial step is
the oxidative quenching of the excited photocatalyst by the
p r o t o n a t e d i m i n e [ I − H ] + ( S c h e m e 2 ,
(E1/2([IrIV(ppy)3]+/3[IrIII(ppy)3]*) = −1.73 V vs SCE,30
−2.11 V vs FcH/FcH+ (see the Supporting Information)).
Benzylic α-amino radical Ia is a long-lived open-shell species
with a low homodimerization rate,31−33 which is crucial to
achieve the desired chemoselectivity.34,35 The catalytic cycle is
closed by oxidation of the sulfinate component to the
corresponding sulfonyl radical IIa. Because of its low singly
B
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a
Scheme 3. Scope of the Developed Photoredox-Catalyzed Sulfonylation/Aminoalkylation
a
All yields are those of the isolated products after chromatographic purification. Yields obtained with preformed imine (3-CR) are highlighted in
blue, whereas those obtained from the 4-CR procedure are shown in black. In the case of homochiral reaction components, no additional splitting
of the NMR signals due to diastereoisomerism was observed.
C
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Authors
With the optimized conditions in hand, the scope of this
atom-efficient four component reaction was investigated
(Scheme 3). A large variety of substituents on the styrene
core are tolerated, including electron-withdrawing (com-
pounds 2−4) and electron-donating groups (compounds 5
and 6). The reaction proceeds equally well with α-
methylstyrene (9, 68%) and indene (10, 71%). β-Substituted
styrenes are suitable coupling partners (11−13), and even the
sterically hindered cyclohexyl-substituted derivative furnishes
the desired product (12, 20%).
For the sulfinate, aromatic residues such as naphthyl (18,
23) and phenyl (1, 17, 18) as well as aliphatic substituents
(20−22) are well tolerated. Products with a bromine (18, 34,
35) or a chlorine substituent on the aniline backbone (27) or
with a boronic ester on the aldehyde core (42) allow for
further modification through classical Pd-catalyzed cross-
coupling or via dual photoredox/nickel catalysis.38,39 Under
the mild reaction conditions, typical protecting groups such as
Fmoc (15, 41), acetate (43, 44), and benzoate esters (45, 46)
and especially acetals (47, 48) and thioketals (31) remain
untouched. The carbonyl group in 2-acetylpyridine, which
could potentially form a ketimine, is well tolerated (28).
Besides functionalized benzaldehyde derivatives, electron-
deficient pyridine-2-carbaldehyde (38) or electron-rich thio-
phene-2-carbaldehyde (39, 32) reacts smoothly in this
sequenced radical cascade.
Finally, the developed 4-CR was applied to the modification
of complex biomolecules. Styrene-functionalized cholic acid
and biotin derivatives furnished the corresponding products in
50% (16) and 56% (14) yield, respectively. An aldehyde-
substituted dipeptide gave 60% yield (41), whereas a styrene-
modified peptide resulted in only 35% yield (15). The 4-CR of
the ibuprofen ester of p-hydroxybenzaldehyde furnished
compound 40 in 46% yield.
Even complex carbohydrates such as di- and trisaccharide
derivatives (45−48), suitable for targeting dendritic cells,40
reacted smoothly and provided synthetically useful yields of
the desired coupling products.
Lisa Marie Kammer − Department of Chemistry, Johannes
Gutenberg-University, 55128 Mainz, Germany
Matthias Krumb − Department of Chemistry, Johannes
Gutenberg-University, 55128 Mainz, Germany
Benjamin Spitzbarth − Department of Chemistry, Johannes
Gutenberg-University, 55128 Mainz, Germany
Benjamin Lipp − Department of Chemistry, Johannes
Gutenberg-University, 55128 Mainz, Germany
Jonas Kuhlborn − Department of Chemistry, Johannes
̈
Gutenberg-University, 55128 Mainz, Germany
Jonas Busold − Department of Chemistry, Johannes Gutenberg-
University, 55128 Mainz, Germany
Olga M. Mulina − Zelinsky Institute of Organic Chemistry,
Russian Academy of Sciences, 119991 Moscow, Russia
Alexander O. Terentev − Zelinsky Institute of Organic
Chemistry, Russian Academy of Sciences, 119991 Moscow,
Russia; orcid.org/0000-0001-8018-031X
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c00614
Author Contributions
§M.K. and B.S. contributed equally.
Funding
This work was supported by the Studienstiftung des deutschen
Volkes (LMK).
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Dr. Johannes C. Liermann (Mainz) for NMR
spectroscopy and Dr. Christopher Kampf (Mainz) for mass
spectrometry. We gratefully acknowledge John Herszman
(Mainz) for CV measurements, Arne Sell (Mainz) for the
preparation of starting materials, and Alexander Lipp (Mainz)
as well as Fabian Fasan (Mainz) for helpful discussions. We are
In conclusion, a highly atom-efficient four-component
sulfonylation/aminoalkylation of styrene derivatives was
developed that enables the one-pot construction of highly
substituted γ-sulfonylamines from readily available feedstocks.
Because of the mild reaction conditions, many functional
groups are tolerated, and the protocol is applicable to
structurally elaborate starting materials, such as carbohydrates,
natural products, and drug-like molecules. With three new
bonds being formed in a single operation, this reaction might
also prove useful in the context of automated drug-discovery
processes.
grateful to the Zentrum fur Datenverarbeitung (ZDV Uni
̈
Mainz) for access to the MOGON supercomputer.
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AUTHOR INFORMATION
Corresponding Author
■
Till Opatz − Department of Chemistry, Johannes Gutenberg-
University, 55128 Mainz, Germany; orcid.org/0000-0002-
3266-4050; Email: opatz@uni-mainz.de
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