Visible-Light-Promoted Nickel- and Organic-Dye-Cocatalyzed Formylation Reaction of Aryl Halides and Triflates and Vinyl Bromides with Diethoxyacetic Acid as a Formyl Equivalent

Article abstract of DOI:10.1002/anie.201610108

A simple formylation reaction of aryl halides, aryl triflates, and vinyl bromides under synergistic nickel- and organic-dye-mediated photoredox catalysis is reported. Distinct from widely used palladium-catalyzed formylation processes, this reaction proceeds by a two-step mechanistic sequence involving initial in situ generation of the diethoxymethyl radical from diethoxyacetic acid by a 4CzIPN-mediated photoredox reaction. The formyl-radical equivalent then undergoes nickel-catalyzed substitution reactions with aryl halides and triflates and vinyl bromides to form the corresponding aldehyde products. Significantly, besides aryl bromides, less reactive aryl chlorides and triflates and vinyl halides serve as effective substrates for this process. Since the mild conditions involved in this reaction tolerate a plethora of functional groups, the process can be applied to the efficient preparation of diverse aromatic aldehydes.

Full text of DOI:10.1002/anie.201610108

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201610108
German Edition: DOI: 10.1002/ange.201610108
Photoredox Catalysis
Visible-Light-Promoted Nickel- and Organic-Dye-Cocatalyzed
Formylation Reaction of Aryl Halides and Triflates and Vinyl Bromides
with Diethoxyacetic Acid as a Formyl Equivalent
He Huang, Xiangmin Li, Chenguang Yu, Yueteng Zhang, Patrick S. Mariano,* and Wei Wang*
Abstract: A simple formylation reaction of aryl halides, aryl
triflates, and vinyl bromides under synergistic nickel- and
organic-dye-mediated photoredox catalysis is reported. Dis-
tinct from widely used palladium-catalyzed formylation pro-
cesses, this reaction proceeds by a two-step mechanistic
sequence involving initial in situ generation of the diethoxy-
methyl radical from diethoxyacetic acid by a 4CzIPN-medi-
ated photoredox reaction. The formyl-radical equivalent then
undergoes nickel-catalyzed substitution reactions with aryl
halides and triflates and vinyl bromides to form the corre-
sponding aldehyde products. Significantly,
tions, state-of-the-art formylation technologies employing
transition-metal catalysts have been developed. The pioneer-
ing study on the palladium-catalyzed formylation of aryl
[
3]
halides with CO and H by Heck and co-workers triggered
2
significant interest in the development of more efficient
protocols. Impressive results from studies of this topic have
come from the laboratories of Pri-Bar, Stille, Beller, Manabe,
[
4]
Skrydstrup, Kotsuki, and Liu (Scheme 1a). However, the
approaches developed by these groups generally require high
reaction temperatures, aryl bromides or iodides as substrates,
besides aryl bromides, less reactive aryl chlorides
and triflates and vinyl halides serve as effective
substrates for this process. Since the mild con-
ditions involved in this reaction tolerate a ple-
thora of functional groups, the process can be
applied to the efficient preparation of diverse
aromatic aldehydes.
A
rguably, aromatic aldehydes are the most
fundamentally important substances used in
[1]
organic synthesis. Therefore, the availability
of predictable and chemoselective methods for
the formylation of aromatic compounds will
continue to have a profound impact on chem-
ical synthesis. Classical methods for the prepa-
ration of aromatic aldehydes, such as the
Reimer–Tiemann, Vielsmeier–Haack, Gatter-
[2]
mann–Koch, and Duff reactions, are not
atom- and step-economical. Furthermore, the
lack of control of the regiochemical course of
these reactions makes it difficult to employ
them to introduce an aldehyde functionality at
desired positions. As a result of these limita-
Scheme 1. Methods based on palladium and nickel catalysis for the formylation of aryl
halides and triflates. PMHS=poly(methylhydrosiloxane),
TMEDA=tetramethylethylenediamine.
[
*] H. Huang, X.-M. Li, Dr. C.-G. Yu, Y.-T. Zhang, Prof. Dr. P. S. Mariano,
Prof. Dr. W. Wang
Department of Chemistry and Chemical Biology
University of New Mexico
Albuquerque, NM 87131 (USA)
E-mail: mariano@unm.edu
[
5]
and precious palladium complexes as promoters. Moreover,
in some cases, toxic CO gas
[
4a–c,h,i]
[4b]
and tin compounds are
used. These issues highlight the demand for more cost-
effective, environmentally friendly, and mild protocols for
aryl aldehyde synthesis.
Although significant advances have been made in the
development of inexpensive nickel-catalyzed cross-coupling
reactions, nickel-catalyzed formylation reactions have not
been described. This deficiency results from low reactivity in
the reductive elimination of CO, as demonstrated by Heck
wwang@unm.edu
X.-M. Li, Prof. Dr. W. Wang
State Key Laboratory of Bioengineering Reactor and Shanghai Key
Laboratory of New Drug Design, School of Pharmacy, East China
University of Science & Technology
[6]
130 Mei-Long Road, Shanghai 200237 (P.R. China)
[1c,3]
and co-workers (Scheme 1b).
Furthermore, very few
studies have focused on the palladium-catalyzed formylation
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under http://dx.doi.org/10.
[
4,7]
1002/anie.201610108.
of aryl chlorides,
which are more broadly available and
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cheaper. Clearly, a new nickel-promoted formylation strategy,
which would enable aryl chlorides to serve as coupling
partners, would have substantial synthetic utility within both
academic and industrial settings. In this context, we recently
uncovered a formylation process under synergistic photo-
redox catalysis with nickel and organic catalysts. 2,2-Dieth-
oxyacetic acid served as the formylation reagent, thus
avoiding the need for CO. The process combines an
organic-dye-mediated photoredox-catalyzed formyl-radical-
forming reaction with a nickel-promoted radical coupling
process. Moreover, readily available aryl chlorides can serve
as substrates (Scheme 1b). The transformation proceeds
under straightforward and mild conditions that tolerate
a plethora of functional groups, and does not produce
abundant amounts of chemical waste.
Although nickel-catalyzed reactions of aryl halides with
[
3]
CO/H fail to generate formylation products, the capacity of
2
[6]
Ni catalysts to activate CÀCl bonds of aryl chlorides to
produce highly reactive organic radicals in cross-coupling
[8]
reactions is highly attractive. We reasoned that the gener-
ation of a formyl-radical equivalent in the presence of an aryl
chloride and a Ni catalyst might lead to a cross-coupling
process corresponding to the long-sought-after nickel-pro-
moted formylation reaction. Accordingly, the key to the
successful development of this process was the identification
of a new reagent that would efficiently produce a formyl-
radical equivalent under conditions that are compatible with
nickel catalysis. The results of studies of photochemical
decarboxylation reactions of glyoxylic acid and its acetals by
Scheme 2. Proposed nickel–photoredox-catalyzed formylation of aryl
halides and triflates.
harvesters in organic light-emitting diodes, we were attracted
to readily available 1,2,3,5-tetrakis(carbazol-9-yl)-4,6-dicya-
[
14,15]
nobenzene (4CzIPN).
The high reduction potential of the
*
red
photoexcited state of 4CzIPN (E =+ 1.35 V vs. SCE)
augurs well for the use of this substance to promote photo-
oxidative decarboxylation reactions.
[
9]
us, and related recent efforts by the research groups of
In initial studies to probe the feasibility of the new
formylation reaction, we used glyoxylic acid as the formyl-
radical source. Unfortunately, none of the desired aldehyde
product 3a was produced when a mixture of 4-bromobenzo-
[10]
MacMillan, Doyle, and Overman,
indicated that these
inexpensive and abundant substances might be ideal precur-
sors of formyl-radical equivalents. This consideration sug-
gested that the merging of visible-light photoredox catalysis
with nickel catalysis, in a manner earlier demonstrated by the
nitrile (1a), glyoxylic acid monohydrate, NiCl ·glyme
2
(glyme = ethylene glycol dimethyl ether), 4CzIPN, 4,4’-di-
tert-butyl-2,2’-bipyridine (dtbbpy), and Cs CO in N,N-dime-
[
11,12]
research groups of MacMillan, Doyle, and Molander,
2
3
could serve as the foundation for the new transformation.
Specifically, we hypothesized that photoredox-mediated
single-electron-transfer (SET) oxidation of glyoxylic acid or
thylformamide (DMF) at room temperature was irradiated
with blue-light-emitting diodes (LEDs) for 24 h (Table 1,
entry 1). We reasoned that the failure of this reaction might
be associated with the difficulty of promoting SET oxidation
its acetals, followed by the loss of CO , would form a formyl-
2
ox
radical equivalent 4 (Scheme 2, with a diacetal as an
of glyoxylic acid because of its high oxidation potential (E =
0
example). Reaction of the Ni complex with radical 4 would
+ 1.33 V vs. SCE, CH CN; see Figure S1 in the Supporting
3
[12d]
[16]
form the diacetal–nickel(I) intermediate 5.
Oxidative
Information) and lability. A careful search uncovered the
activation of aryl halide 1 to 5 would then generate the
putative Ni complex 6, which should undergo reductive
elimination to produce the desired aryl diacetal 7, a substance
that can be readily converted into aryl aldehyde 3 through
workup with an aqueous acid.
fact that the readily available and inexpensive diethyl acetal
III
derivative of glyoxylic acid 2a, generated by the hydrolysis of
À1 [17]
ethyl diethoxyacetate ($0.56g ), has a much lower oxida-
ox
tion potential [E (2a Cs salt) =+ 0.95 V vs. SCE, CH CN
3
(see Figure S2). Thus, this acetal should be more readily
oxidized by SET to the excited state of 4CzIPN. Significantly,
Thus far, ruthenium and iridium complexes have typically
been used as photocatalysts in photoredox nickel-catalyzed
reactions. It is somewhat surprising that far fewer reports exist
describing reactions of this type in which organic dyes serve as
photocatalysts, despite the lower cost, wider availability,
higher stability, and superior properties of these substances as
compared to those of their inorganic and organometallic
the irradiation of a mixture containing 1a, 2a, NiCl ·glyme,
2
4CzIPN, dtbbpy, and Cs CO in DMF at room temperature
2
3
with blue-light-emitting diodes (LEDs) led to smooth for-
mation of the formylation product 3a in 72% yield (Table 1,
entry 2).
Encouraged by this preliminary result, we evaluated the
effects of several parameters, including the Ni salt, photo-
sensitizer, base, solvent, ligand, and light source on this
transformation (Table 1; see also Table S1 in the Supporting
Information). Slightly higher efficiency was observed when
[
13]
counterparts in many cases. Because of this comparison, we
decided to exploit organic dyes as photoredox catalysts for the
new formylation reaction. Among the family of carbazoyl
dicyanobenzenes reported by Adachi and co-workers as light
2
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Table 1: Exploration and optimization.
[
a]
[b]
Entry Deviation from the standard conditions
Yield [%]
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
CHOCO H·H O instead of 2a
0
72
75 (75)
0
0
0
19
45
25
0
2
2
NiCl ·glyme instead of NiCl ·6H O
2
2
2
[
c]
none
9-mesityl-10-methylacridinium instead of 4CzIPN
Eosin Y instead of 4CzIPN
Na CO instead of Cs CO
3
2
3
2
[1a] was 0.2 m instead of 0.02 m
[1a] was 0.04 m instead of 0.02 m
2b instead of 2a
2c instead of 2a
2d instead of 2a
1
1
1
1
1
1
0
no light
trace
0
trace
30
without NiCl ·6H O
2
2
without 4CzIPN
without N protective atmosphere
2
[a] Standard reaction conditions: A mixture of 1a (0.2 mmol), 2a
(
0.3 mmol), NiCl ·6H O (0.04 mmol), dtbbpy (0.048 mmol), 4CzIPN
2 2
(
0.01 mmol), and Cs CO (0.3 mmol) in DMF (10 mL) was irradiated
2
3
with blue LEDs at rt for 24 h, and then 3n HCl (0.5 mL) was added (see
the Supporting Information for details). [b] The yield was determined by
using H NMR spectroscopy with dimethyl maleate as an internal
standard. [c] Yield of the isolated product.
Scheme 3. Scope of the formylation reaction with aryl bromides.
Standard reaction conditions: A mixture of 1 (0.2 mmol), 2a
1
(0.3 mmol), NiCl ·6H O (0.04 mmol), dtbbpy (0.048 mmol), 4CzIPN
2 2
(
0.01 mmol), and Cs CO (0.3 mmol) in DMF (10 mL) was irradiated
2
3
with blue LEDs at room temperature for 24 h, then 3n HCl (0.5 mL)
was added, and the mixture was stirred for 2 h (see the Supporting
Information for details). Yields are for the isolated product. Boc=tert-
butoxycarbonyl.
NiCl ·glyme was replaced with less expensive NiCl ·6H O
2
2
2
(
entry 3, 75% yield). The photocatalyst 4CzIPN was found to
play a crucial role in the process. Other photocatalysts,
including commonly used dyes, such as 9-mesityl-10-methyl-
acridinium and eosin Y (entries 4 and 5; for the other dyes
screened, see Table S1), failed to promote aldehyde forma-
tion. Other observations showed that Cs CO was the best
(Scheme 3). Although substituents at the meta and para
positions of the aryl ring in these substrates had little effect on
the efficiency of the process (e.g. products 3a and 3b), ortho
substitution resulted in diminished yields (product 3c).
Furthermore, the process tolerated a variety of functional-
ities, including a trifluoromethyl (product 3d), ester (products
3e and 3 f), methanesulfonyl (product 3g), ketone (product
3h), ether (product 3k), and amide group (product 3l).
Polyaromatic bromides also served as effective substrates in
this reaction, with the production of the corresponding
aldehydes 3i and 3j in moderate to good yields. Moreover,
electron-rich aryl bromides reacted under the optimized
conditions to give 3k and 3l, but in only moderate yields.
Significantly, the formylation method could be employed to
transform a broad range of pharmaceutically relevant heter-
oaromatic bromides, including those containing pyridine,
quinoline, pyrimidine, and indole ring systems, into the
corresponding aldehydes 3m–s.
2
3
base for the process (entry 6; see also Table S1) and that the
concentration of aryl bromide 1a strongly influenced the
efficiency of the reaction. Specifically, the irradiation of 0.02,
0
.04, and 0.2m solutions of 1a generated 3a in 75, 45, and 19%
yield, respectively (Table 1; entries 3, 7, and 8). Interestingly,
the cyclic acetal acid 2b participated in this reaction, but the
yield was appreciably lower (entry 9). Furthermore, when the
Cs salts 2c and 2d were utilized, the formylation reaction did
not take place (entries 10 and 11). We observed the facile
generation of the corresponding highly active radicals, which
caused rapid decomposition and other side reactions. As
expected, light irradiation and the nickel and 4CzIPN
catalysts were essential for the success of the process
(
entries 12–14). Finally, the presence of molecular oxygen
led to decreased reaction efficiency (entry 15).
The scope of the transformation with respect to the aryl
bromide was explored under the optimized reaction con-
ditions (Table 1, entry 3). A series of structurally diverse aryl
bromides were found to undergo highly efficient formylation
reactions with diethoxyacetic acid as the formyl equivalent
We next expanded the scope of the process to include
more readily available and less expensive aryl chlorides
(Scheme 4). As mentioned above, the development of
methods to promote the formylation of the chloride sub-
strates with previously developed catalysts has been unsuc-
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9
a–c in moderate to good yields (Scheme 6). Notably, only
the trans products 9a and 9c were formed, even when
a mixture of trans and cis bromides were used. To the best of
our knowledge, these reactions are the first examples of the
use of non-precious-metal catalysts for the formylation of
[
18]
vinyl bromides.
Scheme 5. Formylation reactions of aryl triflates. Standard reaction
conditions: A mixture of aryl chloride (0.2 mmol), 2a (0.3 mmol),
NiCl ·6H O (0.04 mmol), 4,4’-(OMe) -bpy (0.048 mmol), 4CzIPN
2
2
2
(
0.01 mmol), and Cs CO (0.3 mmol) in DMF (10 mL) was irradiated
2 3
Scheme 4. Formylation reactions of aryl chlorides. For the reaction
conditions, see Scheme 3 and the Supporting Information. Yields are
for the isolated product.
with blue LEDs at room temperature for 48 h, then 3n HCl (0.5 mL)
was added, and the mixture was stirred for 2 h (see the Supporting
Information for details). Yields are for the isolated product.
[
1c,3]
cessful.
We observed that under the optimal conditions for
reactions of their bromide counterparts, a broad range of aryl
chlorides underwent formylation to form the corresponding
aldehyde products in similarly high yields. Again, the reaction
can be applied to generate aldehydes from aryl chlorides
containing pharmaceutically relevant functionality, such as
nitrile (products 3a and 3c), ketone (products 3h, 3t, and 3u),
ester (product 3e), and methanesulfonyl groups (product 3g),
as well as fused-aromatic (product 3i) and hetereoaromatic
moieties (products 3m, 3v, and 3o). Finally, we demonstrated
that the mild reaction conditions enable the process to be
employed for late-stage synthetic elaboration of biologically
relevant substances, including fenofibrate (product 3w) and
indomethacin methyl ester (product 3x).
In the final phase of this investigation, we assessed the
practical utility of the new formylation protocol in a potential
industrial-process-scale setting. An attractive approach to
large-scale synthesis involves the use of a continuous-flow
[
19]
procedure. We found that the new formylation method-
ology is compatible with continuous-flow technology (see
Figure S3 and Scheme S2). Thus, the reaction of 2-chloro-
naphthalene (10.6 g) in a flow system with a short residence
time of 36 min produced the corresponding aldehyde 3i in
91% yield [9.2 g; Scheme 7, Eq. (1)]. Furthermore, the
reactant concentration, whose variation had a pronounced
effect on the efficiency of the batch process (see above), did
not affect the reaction in the continuous-flow system.
Specifically, even the reaction of a 0.5m solution (1 mmol
scale) of 2-chloronaphthalene gave 3i in 93% yield. The
Having established an efficient protocol for the synthesis
of aldehydes from aryl halides, we next investigated the use of
aryl triflates as coupling partners. Substrates of
this type have not been used previously for
formylation reactions. Significantly, when the
more electron rich ligand 4,4’-dimethoxy-2,2’-
bipyridine (4,4’-(MeO) -bpy) was used in con-
2
junction with the optimized conditions de-
scribed above, a variety of aryl triflates were
converted into the corresponding aromatic
aldehydes 3a, 3d, 3e, 3i, 3t, and 3u
(
Scheme 5; see Scheme S1 for the results of
optimization studies). Moreover, the new for-
mylation procedure is applicable to late-stage
synthetic elaboration of biologically relevant
substances, such as estrone (product 3y).
Finally, the protocol was used to transform
vinyl bromides into a,b-unsaturated aldehydes
Scheme 6. Formylation reactions of vinyl bromides. For the reaction conditions, see
Scheme 5 and the Supporting Information. Yield of the isolated product.
4
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[
3] A. Schoenberg, I. Bartolet, R. F. Heck, J. Org. Chem. 1974, 39,
318.
3
[
4] a) I. Pri-Bar, O. Buchman, J. Org. Chem. 1984, 49, 4009; b) V. P.
Baillargeon, J. K. Stille, J. Am. Chem. Soc. 1986, 108, 452; c) S.
Klaus, H. Neumann, A. Zapf, D. Strubing, S. Hubner, J. Almena,
T. Riemeier, P. Gross, M. Sarich, W. R. Krahnert, K. Rossen, M.
Beller, Angew. Chem. Int. Ed. 2006, 45, 154; Angew. Chem. 2006,
118, 161; d) S. Korsager, R. H. Taaning, T. Skrydstrup, J. Am.
Chem. Soc. 2013, 135, 2891; e) T. Ueda, H. Konishi, K. Manabe,
Angew. Chem. Int. Ed. 2013, 52, 8611; Angew. Chem. 2013, 125,
8773; f) K. Natte, A. Dumrath, H. Neumann, M. Beller, Angew.
Chem. Int. Ed. 2014, 53, 10090; Angew. Chem. 2014, 126, 10254;
g) B. Yu, Y. F. Zhao, H. Y. Zhang, J. L. Xu, L. D. Hao, X. Gao,
Z. M. Liu, Chem. Commun. 2014, 50, 2330; h) H. Kotsuki, P. K.
Datta, H. Suenaga, Synthesis 1996, 470; i) A. Brennfꢀhrer, H.
Neumann, M. Beller, Synlett 2007, 2537.
Scheme 7. Reactions performed in a flow system. For the reaction
conditions, see Scheme 3 and the Supporting Information. Yields are
for the isolated product.
[
5] An efficient RuCl -catalyzed oxidative coupling reaction
3
between indoles and N-methylanilines resulted in the formation
of 3-formylindoles: W. Wu, W. Su, J. Am. Chem. Soc. 2011, 133,
improved efficiency associated with the continuous-flow
technique was also demonstrated by the efficient formylation
of 4-tert-butoxybromobenzene [product 3k, 45% in batch
versus 78% in flow; Scheme 7, Eq. (2)].
11924.
[
6] For recent reviews, see: a) E. J. Tollefson, L. E. Hanna, E. R.
Jarvo, Acc. Chem. Res. 2015, 48, 2344; b) T. Chen, L. B. Han,
Angew. Chem. Int. Ed. 2015, 54, 8600; Angew. Chem. 2015, 127,
In summary, a novel, cost-effective formylation strategy
has been developed. Distinct from extensively studied
palladium-catalyzed methods, this process takes place
through nickel-promoted coupling between aryl halides, aryl
triflates, or vinyl bromides and a formyl-radical equivalent
derived from readily available diethoxyacetic acid by photo-
redox catalysis. The synergistic metal–organic catalytic pro-
cess occurs at room temperature and tolerates a wide range of
functional groups. The results of this study expand the scope
of nickel and photoredox catalysis by providing a practical
approach to the preparation of members of the fundamentally
important family of aromatic aldehydes.
8
722; c) M. Tobisu, N. Chatani, Acc. Chem. Res. 2015, 48, 1717;
d) E. P. Jackson, H. A. Malik, G. J. Sormunen, R. D. Baxter, P.
Liu, H. Wang, A.-R. Shareef, J. Montgomery, Acc. Chem. Res.
2
015, 48, 1736; e) V. P. Ananikov, ACS Catal. 2015, 5, 1964;
f) S. Z. Tasker, E. A. Standley, T. F. Jamison, Nature 2014, 509,
99; g) B. Su, Z.-C. Cao, Z.-J. Shi, Acc. Chem. Res. 2015, 48, 886;
2
h) F.-S. Han, Chem. Soc. Rev. 2013, 42, 5270; i) T. Mesganaw,
N. K. Garg, Org. Process Res. Dev. 2013, 17, 29; j) J. Yamaguchi,
K. Muto, K. Itami, Eur. J. Org. Chem. 2013, 19; k) R. Jana, T. P.
Pathak, M. S. Sigman, Chem. Rev. 2011, 111, 1417; l) X. Hu,
Chem. Sci. 2011, 2, 1867.
[
[
7] a) Y. Ben-David, M. Portnoy, D. Milstein, J. Chem. Soc. Chem.
Commun. 1989, 1816; b) W. Mꢁgerlein, A. F. Indolese, M. Beller,
Angew. Chem. Int. Ed. 2001, 40, 2856; Angew. Chem. 2001, 113,
2
940; c) Y. Ben-David, M. Portnoy, D. Milstein, J. Am. Chem.
Soc. 1989, 111, 8742; d) J. L. Serrano, J. Pꢂrez, L. Garcꢃa, G.
Sꢄnchez, J. Garcꢃa, K. Tyagi, A. Kapdi, RSC Adv. 2012, 2, 12237.
8] a) S. Biswas, D. J. Weix, J. Am. Chem. Soc. 2013, 135, 16192;
b) N. D. Schley, G. C. Fu, J. Am. Chem. Soc. 2014, 136, 16588.
[9] a) Z. Su, D. E. Falvey, U. C. Yoon, P. S. Mariano, J. Am. Chem.
Soc. 1997, 119, 5261; b) Z. Su, P. S. Mariano, D. E. Falvey, U. C.
Yoon, S. W. Oh, J. Am. Chem. Soc. 1998, 120, 10676.
Acknowledgements
Support of this research by the ACS-PRF (57164-ND1), the
NSF (CHE-1565085), and the National Science Foundation of
China (21372073 and 21572055) is gratefully acknowledged.
[
10] For a review of catalytic decarboxylative cross-coupling reac-
tions, see: M. O. Konev, E. R. Jarvo, Angew. Chem. Int. Ed. 2016,
Conflict of interest
55, 11340; Angew. Chem. 2016, 128, 11510.
[
11] For reviews, see: a) K. L. Skubi, T. R. Blum, T. P. Yoon, Chem.
Rev. 2016, 116, 10035; b) J. C. Tellis, C. B. Kelly, D. N. Primer, M.
Jouffroy, N. R. Patel, G. A. Molander, Acc. Chem. Res. 2016, 49,
The authors declare no conflict of interest.
1
429; c) J.-R. Chen, X.-Q. Hu, L.-Q. Lu, W.-J. Xiao, Chem. Soc.
Keywords: flow chemistry · formylation · nickel catalysis ·
photoredox catalysis · synthetic methods
Rev. 2016, 45, 2044; d) C. K. Prier, D. A. Rankic, D. W. C.
MacMillan, Chem. Rev. 2013, 113, 5322; e) J. M. R. Narayanam,
C. R. J. Stephenson, Chem. Soc. Rev. 2011, 40, 102.
[
12] a) Z. Zuo, D. T. Ahneman, L. Chu, J. A. Terrett, A. G. Doyle,
D. W. C. MacMillan, Science 2014, 345, 437; b) J. C. Tellis, D. N.
Primer, G. A. Molander, Science 2014, 345, 433; c) J. A. Terrett,
J. D. Cuthbertson, V. W. Shurtleff, D. W. C. MacMillan, Nature
2015, 524, 330; d) O. Gutierrez, J. C. Tellis, D. N. Primer, G. A.
Molander, M. C. Kozlowski, J. Am. Chem. Soc. 2015, 137, 4896;
e) Z. Zuo, H. Cong, W. Li, J. Choi, G. C. Fu, D. W. C. MacMillan,
J. Am. Chem. Soc. 2016, 138, 1832; f) M. H. Shaw, V. W.
Shurtleff, J. A. Terrett, J. D. Cuthbertson, D. W. C. MacMillan,
Science 2016, 352, 1304; g) M. Jouffroy, D. N. Primer, G. A.
Molander, J. Am. Chem. Soc. 2016, 138, 475; h) C. L. Joe, A. G.
Doyle, Angew. Chem. Int. Ed. 2016, 55, 4040; Angew. Chem.
[
1] a) RꢀMPP Chemielexikon (Eds.: J. Falbe, M. Regitz), Thieme,
Stuttgart, 1995; b) L. P. Crawford, S. K. Richardson, Gen. Synth.
Method 1994, 16, 37; c) M. Taddei, A. Mann, Hydroformylation
for Organic Synthesis in Topics in Current Chemistry, Vol. 342,
Springer, Berlin Heidelberg 2013.
[
2] a) H. Wynberg, Chem. Rev. 1960, 60, 169; b) G. Jones, S. P.
Stanforth, Org. React. 2004, 56, 355; c) N. N. Crounse, Org.
React. 2011, 5, 290; d) J. C. Duff, E. J. Bills, J. Chem. Soc. 1932,
1987.
Angew. Chem. Int. Ed. 2017, 56, 1 – 7
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

Angewandte
Communications
Chemie
2
016, 128, 4108; i) J. Xuan, T.-T. Zeng, J.-R. Chen, L.-Q. Lu, W.-J.
Almena, M. Beller, Tetrahedron 2007, 63, 6252; b) R. Zemmouri,
M. Kajjout, Y. Castanet, S. Eddarir, C. Rolando, J. Org. Chem.
2011, 76, 7691; c) X. Jiang, J.-M. Wang, Y. Zhang, Z. Chen, Y.-M.
Zhu, S.-J. Ji, Org. Lett. 2014, 16, 3492.
Xiao, Chem. Eur. J. 2015, 21, 4962.
[
[
13] D. A. Nicewicz, T. M. Nguyen, ACS Catal. 2014, 4, 355.
14] H. Uoyama, K. Goushi, K. Shizu, H. Nomura, C. Adachi, Nature
2
012, 492, 234.
[19] For recent reviews of flow chemistry in industrial process
synthesis, see: a) D. Cambiꢂ, C. Bottecchia, N. J. W. Straathof, V.
Hessel, T. Noꢅl, Chem. Rev. 2016, 116, 10276; b) R. Porta, M.
Benaglia, A. Puglisi, Org. Process Res. Dev. 2016, 20, 2; c) B.
Gutmann, D. Cantillo, C. O. Kappe, Angew. Chem. Int. Ed. 2015,
54, 6688; Angew. Chem. 2015, 127, 6788.
[
15] a) J. Luo, J. Zhang, ACS Catal. 2016, 6, 873; b) C. LꢂvÞque, L.
Chenneberg, V. Corcꢂ, C. Ollivier, L. Fensterbank, Chem.
Commun. 2016, 52, 9877.
16] a) J. E. Baggott, H. M. Frey, P. D. Lightfoot, R. Walsh, Chem.
Phys. Lett. 1986, 132, 225; b) J. E. Baggott, H. M. Frey, P. D.
Lightfoot, R. Walsh, J. Phys. Chem. 1987, 91, 3386.
17] 1 kg/$560: supplier: Labnetwork, supplier SKU: 1648-1kg-
LANG.
[
[
[
18] For the palladium-catalyzed formylation of vinyl bromides, see:
a) A. Brennfꢀhrer, H. Neumann, S. Klaus, T. Riermeier, J.
Manuscript received: October 15, 2016
Final Article published: && &&, &&&&
6
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Communications
Chemie
Communications
Photoredox Catalysis
H. Huang, X.-M. Li, C.-G. Yu, Y.-T. Zhang,
P. S. Mariano,* W. Wang*
&&& — &&&
Visible-Light-Promoted Nickel- and
Organic-Dye-Cocatalyzed Formylation
Reaction of Aryl Halides and Triflates and
Vinyl Bromides with Diethoxyacetic Acid
as a Formyl Equivalent
Masked beauty: Whereas palladium-cat-
alyzed formylation reactions require
harsh reaction conditions, aryl halides,
aryl triflates, and vinyl bromides under-
went formylation with diethoxyacetic acid
under mild conditions through synergis-
tic photoredox catalysis in the presence of
a nickel complex and the organic dye
4CzIPN (see scheme). Even aryl chlorides
could be used as substrates, and the
transformation tolerated a wide range of
functional groups.
Angew. Chem. Int. Ed. 2017, 56, 1 – 7
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
7
These are not the final page numbers!