Chemo- and Regioselective Organo-Photoredox Catalyzed Hydroformylation of Styrenes via a Radical Pathway

Article abstract of DOI:10.1021/jacs.7b05082

An unprecedented, chemo- and regioselective, organo-photoredox catalyzed hydroformylation reaction of aryl olefins with diethoxyacetic acid as the formylation reagent is described. In contrast to traditional transition metal promoted ionic hydroformylation reactions, the new process follows a unique photoredox promoted, free radical pathway. In this process, a formyl radical equivalent, produced from diethoxacetic acid through a dye (4CzIPN) photocatalyzed, sequential oxidation-decarboxylation route, regio- and chemoselectively adds to a styrene substrate. Importantly, under the optimized reaction conditions the benzylic radical formed in this manner is reduced by SET from the anion radical of 4CzIPN to generate a benzylic anion. Finally, protonation produces the hydroformylation product. By using the new protocol, aldehydes can be generated regioselectively in up to 90% yield. A broad array of functional groups is tolerated in the process, which takes place under mild, metal-free conditions.

Full text of DOI:10.1021/jacs.7b05082

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Communication
Chemo- and Regio-Selective Organo-Photoredox Catalyzed
Hydro-formylation of Styrenes via a Radical Pathway
He Huang, Chenguang Yu, Yueteng Zhang, Yongqiang Zhang, Patrick S Mariano, and Wei Wang
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b05082 • Publication Date (Web): 10 Jul 2017
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Chemo- and Regio-Selective Organo-Photoredox Catalyzed Hydro-
formylation of Styrenes via a Radical Pathway
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He Huang,† Chenguang Yu,† Yueteng Zhang,† Yongqiang Zhang,‡ Patrick S. Mariano,*,† and Wei
Wang*,†,‡
† Department of Chemistry & Chemical Biology, University of New Mexico, Albuquerque, NM 87131‐0001, USA
‡ State Key Laboratory of Bioengineering Reactor, and Shanghai Key Laboratory of New Drug Design, School of Phar‐
macy, East China University of Science & Technology, Shanghai 200237, China
Supporting Information Placeholder
4l
4o, 4r‐t
by Zhang,4h,
Reek4m,
and Shi.7b These approaches
ABSTRACT: An unprecedented, chemo‐ and regio‐
selective, organo‐photoredox catalyzed hydroformylation
reaction of aryl olefins with diethoxyacetic acid as the
formylation reagent is described. In contrast to traditional
transition metal promoted ionic hydroformylation reactions,
the new process follows a unique photoredox promoted, free
radical pathway. In this process, a formyl radical equivalent,
produced from diethoxacetic acid through a dye (4CzIPN)
photocatalyzed, sequential oxidation‐decarboxylation route,
regio‐ and chemo‐selectively adds to a styrene substrate.
Importantly, under the optimized reaction conditions the
benzylic radical formed in this manner is reduced by SET from
the anion radical of 4CzIPN to generate a benzylic anion.
Finally, protonation produces the hydroformylation product.
By using the new protocol, aldehydes can be generated
regioselectively in up to 90% yield. A broad array of functional
groups is tolerated in the process, which takes place under
mild, metal free conditions.
require the use of transition metal complexes containing
highly functionalized ligands,4h,
special substrates.4o Furthermore, an intrinsic limitation of
transition metal catalyzed processes is associated with the
difficulty in controlling chemoselectivity when both alkyl and
aryl substituted C=C bonds are present in the substrate.
4l, 4m, 4o, 4r‐t, 7b
and/or that
Scheme 1. Organo‐Photoredox Catalyzed and Transi‐
tion‐Metal Catalyzed Hydroformylation Reactions
Aldehydes are perhaps the most important class of
compounds used in organic synthesis. Hydroformylation
reactions of alkenes, which are feedstock chemicals, are
among the most cost‐effective methods for synthesis of
aldehydes.1 Hydroformylation, developed by Roelen in the
1930s,2 is currently the most highly productive homogenous
catalyzed process used on an industrial scale to generate more
than 10 million tons of oxo products annually.3 This success is
attributable to significant efforts made to develop efficient
protocols for aldehyde synthesis. Among these protocols are
those that chiefly employ transition metal complexes (e.g.,
Rh,4 Co,1e Ir,5 Ru6 and Pd7) as catalysts (Scheme 1).
Unfortunately these approaches rely on the use of high
pressures of toxic syngas (CO/H2). In addition, other
important issues associated with these protocols include the
control of chemoselectivity and regiochemistry when
unsymmetric olefins are substrates. In particular, while the
regioselectivity of reactions producing linear aldehydes from
alkyl substituted olefins has been addressed,4a, 4b, 4d, 4f, 4g, 4j
methods for regioselective formylation of aryl olefins remain
elusive. In these cases, branched rather than linear
formylation products are formed predominantly because CO
transfer produces more stable benzylic metal‐species as a
result of η2 electron donation from the aromatic ring (Scheme
1). Although limited in number, a few processes, in which
linear formylation of aryl olefins occurs, have been developed
It is clear that a new synthetic paradigm is needed to
address the development of an viable olefin hydroformyation
process that overcomes shortcomings of the current
transition metal catalyzed reactions. We envisioned that a free
radical based approach involving addition of a formyl radical
equivalent to an olefin might be an effective strategy (Scheme
1). However, the most significant challenge of using a free
radical approach is the need to avoid occurrence of
competitive and undesired polymerization reactions. This
may well be the reason why, to the best of our knowledge, a
radical based hydoformylation strategy has not been devised
thus far.
In a recently completed study8 that led to a novel method
for formylation of haloarenes, we developed a free radical
based
protocol
for
regio‐
and
chemo‐selective
hydroformylation of aryl olefins. In the current effort, we
demonstrated that a formyl radical equivalent, produced from
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2,2‐diethoxyacetic acid via a 1,2,3,5‐tetrakis‐(carbazolyl)‐4,6‐
structurally diverse 3‐arylpropanals in 50‐90% yields and
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dicyanobenzene (4CzIPN) visible light photocatalyzed
oxidation‐decarboxylation sequence,9,10 adds in an anti‐
Markovnikov fashion to the C=C bond11 of styrene derivatives
(Scheme 1). In addition, the benzylic radicals generated are
reduced by SET from the anion radical of 4CzIPN to form
corresonding benyl anions which upon protonation generate
hydroformylation products. Significantly, this process occurs
with only minimal contribution from competitive
polymerization.
To gain information about the feasibility of the new free
radical hydroformylation strategy, we explored the effects of
several parameters, including the reactant ratio,
photosensitizer, base and solvent, on this transformation
(Table 1 and Table S1 in SI). The results show that the use of
1a (0.4 mmol), 2 (0.2 mmol), 4CzIPN (0.01 mmol), Cs2CO3 (0.2
mmol), DMF (10 mL) and blue LED irradiation leads to
formation of 3a in a 70% yield with only linear product (entry
1 and Table S1). More importantly, the presence of molecular
oxygen leads to a dramatic decrease in the reaction efficiency
(entry 2). This finding suggests that O2 captures radical
intermediates in the reaction pathway. Moreover, attempts to
eliminate competitive polymerization of styrene by adding the
radical polymerization inhibitors p‐dihydroxybenzene and
FeCl312 were not successful (Table S1).
with high levels of regioselectivity independent of the nature
of the substituent on the styrene phenyl ring. A variety of
functional groups are tolerated under the mild conditions
used. In addition, aldehydes bearing pharmaceutically
relevant groups, such as trifluoromethyl (3a), nitrile (3b‐3d),
ester (3e), methanesulfonyl (3f), chloride (3g), fused aromatic
(3k), pentafluoro‐aromatic ring (3l) and heterocycle (3p‐3s)
can be efficiently prepared using this method. Furthermore,
this procedure can also be applied to 1,1‐disubstituted
styrene to give 75% yield (3t).
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Scheme 2. Scope of the Hydroformylation Reactiona
Table 1. Exploration and Optimization
entry
method
used
deviation from "standard
conditions"a
% conversionb
% yieldc
1
2
Batch
Batch
None
100
90
70
trace
without N2 protection
[1a] of reaction is 0.02
M, Rt = 18 min
none
without adding 3M HCl
3.44g of 1a
4
Flow
25
12
5
6
7
Flow
Flow
Flow
100
100
100
93 (85)d
82e
87d
a
b
Standard conditions: see SI for detail.
% conversions were
determined by using 1H NMR. Yields were determined by using 1H
NMR. Isolated yields. e Isolated yield of 1‐(3,3‐diethoxypropyl)‐4‐
c
d
(trifluoromethyl)benzene.
a
b
c
See SI for detailed procedures. Isolated yields. Yields were
determined by using 1H NMR d 1.2 mL of 3N HCl for 12 h.e 0.8 mmol of
2 and Cs2CO3 was used. f 1N HCl was used.
A
common technique to enhance the efficiency of
photochemical reactions involves the utilization of
a
continuous flow system.8,13 To minimize competitive polymer‐
ization, visible light induced photoreaction of a mixture of 1a
and 2 (2.0 equiv.) in DMF containing Cs2CO3 (2.0 equiv.) and
4CzIPN (5 mol%) was performed using a continuous flow
system with various residence times (Rt) and styrene
In contrast to the results presented above, we observed
that styrenes possessing electron‐neutral and donating (EDG)
arene ring substituents fail to generates aldehyde products in
acceptable yields when subjected to the continuous flow
conditions. For example, aldehyde 3m is not formed when
styrene in high concentrations is subjected to these conditions.
Instead, a large amount of polymers/oligomers are produced
(see below). To minimize polymerization, the batch method,
was employed because it uses a much lower concentration of
styrene (0.04 M, 2.0 equiv). Indeed, under these conditions
3m is generated in 60% yield. However, a notable amount of
polymers/oligomers are also produced in this reaction.
Utilizing the batch method, styrenes that contain electron
neutral or rich arene ring substituents like methoxy (3h), me‐
thyl (3i) and phenyl (3j) undergo formylation smoothly to
form the corresponding aldehydes in moderate to high yields.
Notably, the new process is compatible with formylations of
bromo‐ and iodo‐substituted arene ring styrenes, which are
concentrations (Table
1 and table S1). Extending the
residence time and elevating the concentration of 1a improve
both conversion and yield (Table S1 and entry 4‐5).
Furthermore, no polymerization occurs (by NMR) when the
continuous flow system is employed. Moreover, 1‐(3,3‐
diethoxypropyl)‐4‐(trifluoromethyl)benzene
(3a‐ace)
is
formed in a 82% yield when the product mixture is not treat‐
ed with acid. This highlights an additional advantage of this
method. Finally, a 3.44 g scale reaction, carried out under flow
condition using only 3 mol% of 4CzIPN, forms 3.52 g of 3a
(entry 7).
The generality of the new hydroformylation reaction was
explored (Scheme 2). The results show that the process using
the flow system serves as a general method to prepare
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problematic substrates in metal catalyzed hydroformyla‐
That a radical pathway is followed in this process is
tions.7b Moreover, the mild conditions enable the process to
be applied to late‐stage synthetic elaboration of biologically
relevant complex substances (eg., 3u‐3z).
supported by the observation that 3a is not produced in the
reaction of styrene 1a when the radical quencher TEMPO is
included (Table S1). The proposal that anion 7 is involved as
the ultimate intermediate in this route is supported by the
results of deuterium labeling studies (Scheme S1).
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4
5
6
7
8
One limitation of transition metal promoted hydro‐
formylation reactions arises from the difficulties associated
with differentiation between aliphatic and aryl olefins. To
determine whether the approach developed in this effort dis‐
plays acceptable levels of olefin selectivity, hydroformylation
reactions of substrates 1aa and 1ab, which contain both alkyl
and aryl substituted alkene moieties, were explored (Scheme
3). The exclusive formation (by 1H NMR) of the respective
aldehydes 3aa and 3ab shows that hydroformylation reac‐
tions of these substances take place in a highly selective man‐
ner on the aryl substituted C=C bond. A similar outcome oc‐
curs when a mixture of styrene 1a and the alkyl substituted
olefin, 1‐octene (4), are subjected to the hydroformylation
conditions. In this case, the aldehyde derived from the aryl
substituted alkene 1a is generated exclusively.
Scheme 5. Benzyl Radical Quenching Process
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Scheme 3. Intra‐ and Intermolecular Chemoselectivity
The effects of styrene arene ring substituents on the
relative efficiencies of hydroformylation and polymerization,
noted above, are fully consistent with the mechanistic
pathway outlined in Scheme 4. Specifically, this route suggests
that the aldehyde to polymer product ratio should be
governed by the relative rates of reduction of benzyl radical 6
by SET from the radical anion of 4CzlPN and addition of
radical 6 to the styrene (Scheme 5). It is known14 that the
rates of benzyl radical additions to p‐substituted styrenes are
retarded when the substituents are electron withdrawing.
Consequently, the observation that electron withdrawing p‐
substituents on the styrenes lead to increased aldehyde
formation efficiencies must be a consequence of substituent
effects on the rates of reduction of benzyl radical 6. The rates
of this reduction process should parallel the thermodynamic
driving force for SET, governed by the oxidation potential of
the radical anion of 4CzlPN (‐1.21 V, vs SCE)15 and the
reduction potentials of the substituted benzyl radicals. It is
known16 that benzyl radicals bearing electron withdrawing
arene ring substituents, have lower reduction potentials (eg., ‐
0.71 V vs SCE for p‐C(O)Me and ‐0.77 V vs SCE for p‐CN). In
contrast, neutral and electron donating arene ring substituted
benzyl radicals have higher reduction potentials (eg., ‐1.43 vs
SCE for H and ‐1.62 V vs SCE for p‐methyl).16 Because the
redox potentials of the 4CzlPN anion radical and the benzyl
radicals were determined using completely different methods,
they cannot be employed to calculate free energy changes in
an accurate manner. However, the redox potentials suggest
that SET from the radical anion of 4CzlPN to benzylic radicals
bearing electron withdrawing groups will be exergonic while
SET to benzylic radicals bearing electron donating arene
groups will be endergonic. Thus, it is reasonable to conclude
that the observed substituent effects on the relative
efficiencies of hydroformylation and polymerization are a
result of variations in the rates of conversion of benzyl free
radical 6 to the corresponding anion 7.
A
plausible mechanistic pathway for the organo‐
photocatalyzed, free radical hydroformylation process
(Scheme 4) is initiated by single electron transfer (SET) from
2,2‐diethoxyacetate to the singlet excited state of 4CzlPN
formed by blue LED irradiation. Rapid decarboxylation of the
formed carboxy radical generates the formyl radical
equivalent 5 which undergoes anti‐Markovnikov addition to
the C=C bond of styrene to produce the stable benzylic radical
6. The process is then terminated by SET from the radical
anion of 4‐CzIPN to 6 to form anion 7 and concurrent
generation of the photocatalyst 4CzIPN. Protonation of 7
followed by acid catalyzed hydrolysis of the acetal then yields
the target aldehyde.
Scheme 4. Proposed Catalytic Cycle
In summary, the investigation described above led to the
development of an unprecedented, chemo‐ and regio‐selective,
organo‐photoredox catalyzed hydroformylation reaction of
aryl olefins that utilizes diethoxyacetic acid as the formylation
reagent. This process takes place via a photoredox promoted
free radical pathway, which differs significantly from those
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of the mild conditions employed for the reactions. Further
efforts are underway to gain a more detailed understanding
the mechanism of this process and to develop unique,
preparatively useful photoredox catalyzed reactions.
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ASSOCIATED CONTENT
Experiment details and spectroscopic data. This material is
available free of charge via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
mariano@unm.edu; wwang@unm.edu.
Author Contributions
All authors have given approval to the final version of the
manuscript.
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
Financial support for this work provided by NSF (CHE‐
1565085, W. W.) and the ACS‐PRF (57164‐ND1, W. W.) and
the National Natural Science Foundation of China (21572055
and 21372073, W. W.) is gratefully acknowledged.
(8) Huang, H.; Li, X.; Yu, C.; Zhang, Y.; Mariano, P. S.; Wang, W. Angew.
Chem., Int. Ed. 2017, 56, 1500.
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1997, 119, 5261. (b) Su, Z.; Mariano, P. S.; Falvey, D. E.; Yoon, U. C.; Oh,
S. W. J. Am. Chem. Soc. 1998, 120, 10676.
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