Photoredox-Catalyzed Hydroacylation of Olefins Employing Carboxylic Acids and Hydrosilanes

Article abstract of DOI:10.1021/acs.orglett.7b01391

A hydroacylation reaction of alkenes has been achieved employing readily available carboxylic acids as the acyl source and hydrosilanes as a hydrogen source via photoredox catalysis. The combination of both single electron transfer and hydrogen atom transfer steps has dramatically expanded new applications of carboxylic acids in organic synthesis. The protocol also features extremely mild conditions, broad substrate scope, and good functional group tolerance, affording a novel and convenient approach to hydroacylation of alkenes.

Full text of DOI:10.1021/acs.orglett.7b01391

Letter
pubs.acs.org/OrgLett
Photoredox-Catalyzed Hydroacylation of Olefins Employing
Carboxylic Acids and Hydrosilanes
Muliang Zhang,† Rehanguli Ruzi,† Junwei Xi,† Nan Li,† Zhongkai Wu,† Weipeng Li,† Shouyun Yu,*,†
and Chengjian Zhu*,†,‡
†State Key Laboratory of Coordination Chemistry, Jiangsu Key Laboratory of Advanced Organic Materials, School of Chemistry and
Chemical Engineering, Nanjing University, Nanjing 210093, China
‡State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Shanghai 200032, China
S
* Supporting Information
ABSTRACT: A hydroacylation reaction of alkenes has been
achieved employing readily available carboxylic acids as the acyl
source and hydrosilanes as a hydrogen source via photoredox
catalysis. The combination of both single electron transfer and
hydrogen atom transfer steps has dramatically expanded new applications of carboxylic acids in organic synthesis. The protocol
also features extremely mild conditions, broad substrate scope, and good functional group tolerance, affording a novel and
convenient approach to hydroacylation of alkenes.
he hydroacylation of unsaturated hydrocarbons is a highly
versatile reaction, which provides a direct approach to
insertion of the unsaturated substrate into the M−H bond
and C−C bond-forming reductive elimination processes enable
this transformation deliver branched and linear products.3
Consequently, the availability of a predictable regio- and
chemoselective strategy for olefin hydroacylation will continue
to have a significant impact on chemical synthesis.
T
valuable ketones.1 This transformation is traditionally carried
out with the addition of aldehydes to carbon−carbon multiple
bonds catalyzed by transition metals (Scheme 1A).1a,d
An alternative protocol is to search for a suitable acyl source
in place of an aldehyde for achieving hydroacylation. Carboxylic
acids are versatile synthons for the preparation of numerous
commodity chemicals.4 Carboxylic acids have several advan-
tages for synthetic organic chemistry: (1) most carboxylic acids
are abundant, inexpensive, structurally diverse feedstocks; (2)
compared with aldehydes as an acyl source, carboxylic acids are
more stable. Recently, Shi and co-workers developed Pd-
catalyzed hydroformylation of olefins with formic acid in the
presence of Ac2O (Scheme 1B).5 However, a general reaction
for the intermolecular hydroacylation of olefins with advanced
carboxylic acids has yet to be achieved. The continuing studies
and successful applications of such a reaction would offer a
complement to the conventional aldehyde-based hydroacyla-
tion and access to synthetically useful products.
Scheme 1. Metal-Catalyzed Olefin Hydroacylation
From a synthetic point of view, direct addition of the acyl
radical onto the double bond is very promising for achievement
of olefin hydroacylation. Caddick and co-workers reported
hydroacylation of α,β-unsaturated esters via aerobic C−H
activation, and production of acyl radicals is a key step in this
reaction.6 However, compared with the development of simple
alkyl and even vinyl radicals, the application of acyl radicals in
modern organic synthesis has largely dropped behind.7
Recently, different strategies have been developed for the
formation of acyl radicals by single electron transfer (SET)
oxidation8 or reduction9 processes. Meanwhile, seminal work
Transition-metal-catalyzed hydroacylation of alkenes with
aldehydes often requires high temperature,1a,d which restricts
the regioselectivity and functional group tolerance of this
reaction. Because the acylmetal intermediate tends to undergo
an undesired decarbonylation process, in particular for
rhodium-catalyzed systems, substrates must frequently have
additional coordinating groups.2 In addition, migratory
Received: May 9, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01391
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
on radical-mediated hydrofunctionalization of olefins has also
provided strong evidence that carbon radical intermediates are
quenched well by abstraction of a hydrogen atom.10 Prompted
by the effectiveness of these two types of catalytic modes, we
postulated that the combination of SET and hydrogen atom
transfer (HAT) steps in a single mechanism would be an
attractive protocol for creating more valuable chemical
transformations. To the best of our knowledge, photocatalytic
intermolecular acyl−olefin reductive coupling reactions are
currently unknown. We wondered whether reduction of
carboxylic acids might be used for the generation of acyl
radicals via an SET pathway, followed by regioselective addition
of the acyl radicals to olefin acceptors and a subsequent HAT
process (Scheme 1C). This would undoubtedly be a
particularly powerful approach to achieve the hydroacylation
of diverse olefins. We describe herein the first olefin
hydroacylation reaction employing readily available carboxylic
acids with tris(trimethylsilyl)silane (TTMSS) as the hydrogen
source and reducing agent.
photocatalyst and a light source in this olefin hydroacylation
reaction (entries 12 and 13).
With the optimized reaction conditions in hand, we then
examined the scope of the hydroacylation with respect to the
alkenes. Representative examples are shown in Scheme 2.
a
Scheme 2. Scope of Olefins in the Hydroacylation Reaction
Our initial investigation focused on the reaction between
benzoic acid (1a) and styrene (2a) in the presence of dimethyl
dicarbonate (DMDC), which gives a mixed anhydride serving
as an oxidative quencher of a photocatalyst.9a As shown in
Table 1, different solvents were examined using 2.0 mol % fac-
a
Table 1. Optimization of the Reaction Conditions
b
entry photocatalyst
base
H source
solvent
yield (%)
1
2
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
−
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2HPO4
K3PO4
Cs2CO3
K3PO4
K3PO4
TTMSS
TTMSS
TTMSS
TTMSS
TTMSS
(Ph)3SiH
(Et)3SiH
DMF
0
0
dioxane
DMSO
DCE
3
0
4
0
a
Reaction conditions: 1 (0.1 mmol), 2 (0.2 mmol, 2.0 equiv), DMDC
5
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
38
8
(0.3 mmol, 3.0 equiv), TTMSS (0.2 mmol, 2.0 equiv), fac-Ir(ppy)3
(0.002 mmol, 2 mol %), K3PO4 (0.2 mmol, 2.0 equiv), and CH3CN (2
mL) at room temperature using 5 W blue LEDs for 20−24 h.
6
7
7
d
8
PMHS
12
60
68
14
0
9
TTMSS
TTMSS
TTMSS
TTMSS
TTMSS
10
11
12
13
Various styrenes, including para-substituted (methyl, methoxy,
fluoro, and chloro) styrenes, reacted with good efficiency
(3ab−ae). The substituent position on the aryl group had no
obvious impact on the reactivity, as m- and o-chlorostyrene gave
the targeted ketones in moderate yields (3af, 3ag). Because acyl
radical addition to electron-poor alkenes is usually facile,
Michael acceptors showed better reactivity in this system. A
variety of vinyl esters worked well with good efficiency,
constructing γ-carbonyl compounds possessing valuable elec-
tron-withdrawing functional groups (3ah−aj).Vinyl sulfone was
also suitable (3ak). Substituents on either the α-position (3an)
or the β-position (3al, 3am) of the Michael acceptor were also
well-tolerated in this alkene hydroacylation reaction. A simple
aliphatic olefin was also found to be compatible in this reaction,
although with lower efficiency (3ap). This visible-light
photocatalytic single-electron reduction process with HAT
allows the application of complex molecules under our standard
reaction conditions. Some alkenes derived from biologically
important molecules such as estrone and light ester IB could
undergo this hydroacylation reaction to give the corresponding
products with a γ-carbonyl functional group incorporated (3aq,
3ar).
c
fac-Ir(ppy)3
0
a
The reactions were carried out with 1a (0.1 mmol), 2a (0.2 mmol,
2.0 equiv), DMDC (0.3 mmol, 3.0 equiv), base (0.2 mmol, 2.0 equiv),
photocatalyst (0.002 mmol, 2 mol %), solvent (2 mL), and H source
(0.2 mmol, 2.0 equiv) at room temperature using 5 W blue LEDs for 6
h. Isolated yields. The reaction was performed in the absence of
light. PMHS = polymethylhydrosiloxane.
b
c
d
Ir(ppy)3 as the photoredox catalyst and TTMSS as the
hydrogen source11 in the presence of K2CO3. The desired
product 3aa was isolated in 38% yield in CH3CN (Table 1,
entry 5), showing that this novel olefin hydroacylation
approach is feasible. Other hydrogen sources, such as
(Ph)3SiH, (Et)3SiH, and PMHS could not improve the result
(entries 6−8), which implied that the choice of hydrogen
source is very important in the system. We then screened a
series of bases, such as K2HPO4, K3PO4, and Cs2CO3. A 68%
yield was achieved when K3PO4 was used as the base (entry
10). Control experiments confirmed the requirement of a
B
DOI: 10.1021/acs.orglett.7b01391
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Next, we directed our attention to delineating the scope of
carboxylic acid coupling partners (Scheme 3). A broad range of
Scheme 4. Proposed Mechanism
Scheme 3. Scope of Carboxylic Acids in the Hydroacylation
a
Reaction
product 3aa. Finally, another SET step could occur between 10
and Ir, regenerating the ground-state photocatalyst.
In conclusion, we have developed the first photocatalytic
reaction for the coupling between alkenes and carboxylic acids
with HAT. The disclosed photoredox-catalyzed selective
reduction of carboxylic acids represents a mild and general
olefin hydroacylation pathway, which could offer a powerful
new strategy for the preparation of versatile small molecules of
potential pharmaceutical relevance. The reaction has good
substrate suitability and functional group tolerance, with
alkenes spanning the broad range from styrenes to unactivated
aliphatic alkenes and electron-poor alkene substrates. We will
continue working on new visible-light photoredox-catalyzed
conversions involving carboxylic acids.
a
Reaction conditions: 1 (0.1 mmol), 2 (0.2 mmol, 2.0 equiv), DMDC
(0.3 mmol, 3.0 equiv), TTMSS (0.2 mmol, 2.0 equiv), fac-Ir(ppy)3
(0.002 mmol, 2 mol %), K3PO4 (0.2 mmol, 2.0 equiv), and CH3CN (2
mL) at room temperature using 5 W blue LEDs for 20−24 h. The
reaction was carried out on a 4 mmol scale with a reaction time of 36
h.
b
carboxylic acids bearing either electron-donating (e.g., methyl,
tert-butyl, methoxy, benzyloxy, or phenyl) or electron-with-
drawing (e.g., fluoro or chloro) substituents reacted smoothly
to furnish the desired ketone products in moderate yields
(3ba−ha). In addition, the substituent position (ortho, meta, or
para) showed little influence on the reaction efficiency (3ba,
3ia, 3ja). Moreover, when 2-furanyl-, 3-thienyl-, and 2-
naphthyl-substituted acids were employed, the desired products
were obtained in moderate yields (3ka−ma). In addition, the
intramolecular hydroacylation of 2-vinylbenzoic acid (4) could
also be achieved. Under the standard conditions, 4 underwent
activation and radical cyclization to afford the product, 1-
indone (5), in high yield.
When the radical scavenger TEMPO (2,2,6,6-tetramethylpi-
peridin-1-oxyl) was introduced into the model reaction, the
hydroacylation was completely terminated, which indicated that
a SET radical process is operative. The proposed mechanistic
details of our transformation are depicted in Scheme 4. In the
presence of base, the mixed anhydride intermediate 6 is
generated from carboxylic acid 1a and DMDC.8a The
photocatalyst fac-Ir(ppy)3 leads to the formation of a long-
lived excited state, Ir*III, which undergoes a metal-to-ligand
charge transfer process under visible-light irradiation. Then the
SET process from this strongly reducing excited state species
Ir*III to 6 generates acyl radical precursor 7 and IrIV.
Intermediate 7 delivers acyl radical 8 along with CO2 and
methanoate after fragmentation. This reactive acyl radical adds
to the olefin to deliver the radical intermediate 9, which rapidly
undergoes HAT from TTMSS to give the desired coupling
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b01391.
Experimental procedures and characterization data
(PDF)
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: cjzhu@nju.edu.cn (C.Z.).
*E-mail: yushouyun@nju.edu.cn (S.Y.).
ORCID
Shouyun Yu: 0000-0003-4292-4714
Chengjian Zhu: 0000-0003-4465-9408
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the National Natural Science
Foundation of China (21474048, 21372114, 21672099, and
21472084).
C
DOI: 10.1021/acs.orglett.7b01391
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
REFERENCES
■
(1) For selected reviews and examples, see: (a) Willis, M. C. Chem.
Rev. 2010, 110, 725. (b) Murphy, S. K.; Dong, V. M. Chem. Commun.
2014, 50, 13645. (c) Leung, J. C.; Krische, M. J. Chem. Sci. 2012, 3,
2202. (d) Biju, A.; Kuhl, T. N.; Glorius, F. Acc. Chem. Res. 2011, 44,
1182. (e) Hatanaka, S.; Obora, Y.; Ishii, Y. Chem. - Eur. J. 2010, 16,
1883. (f) Fujihara, T.; Hosomi, T.; Cong, C.; Hosoki, T.; Terao, J.;
Tsuji, Y. Tetrahedron 2015, 71, 4570.
(2) For selected examples, see: (a) Park, Y. J.; Park, J.-W.; Jun, C.-H.
Acc. Chem. Res. 2008, 41, 222. (b) Coulter, M. M.; Kou, K. G. M.;
Galligan, B.; Dong, V. M. J. Am. Chem. Soc. 2010, 132, 16330.
(c) Chaplin, A. B.; Hooper, J. F.; Weller, A. S.; Willis, M. C. J. Am.
Chem. Soc. 2012, 134, 4885. (d) Lee, H.; Jun, C.-H. Bull. Korean Chem.
Soc. 1995, 16, 66. (e) Zhang, T.; Qi, Z.; Zhang, X.; Wu, L.; Li, X.
Chem. - Eur. J. 2014, 20, 3283. (f) Tanaka, K.; Shibata, Y.; Suda, T.;
Hagiwara, Y.; Hirano, M. Org. Lett. 2007, 9, 1215. (g) Shibata, Y.;
Tanaka, K. J. Am. Chem. Soc. 2009, 131, 12552. (h) Murphy, S. K.;
Bruch, A.; Dong, V. M. Angew. Chem., Int. Ed. 2014, 53, 2455.
́
(3) For selected examples, see: (a) Gonzalez-Rodríguez, C.; Pawley,
R. J.; Chaplin, A. B.; Thompson, A. L.; Weller, A. S.; Willis, M. C.
Angew. Chem., Int. Ed. 2011, 50, 5134. (b) Arnold, J. S.; Mwenda, E.
T.; Nguyen, H. M. Angew. Chem., Int. Ed. 2014, 53, 3688. (c) Xiao, L.
J.; Fu, X. N.; Zhou, M. J.; Xie, J. H.; Wang, L. X.; Xu, X. F.; Zhou, Q. L.
J. Am. Chem. Soc. 2016, 138, 2957. (d) Yang, J.; Seto, Y. W.; Yoshikai,
N. ACS Catal. 2015, 5, 3054. (e) Chen, Q.-A.; Kim, D. K.; Dong, V.
M. J. Am. Chem. Soc. 2014, 136, 3772. (f) Poingdestre, S.-J.; Goodacre,
J. D.; Weller, A. S.; Willis, M. C. Chem. Commun. 2012, 48, 6354.
(4) (a) Gallezot, P. Chem. Soc. Rev. 2012, 41, 1538. (b) Straathof, A.
J. J. Chem. Rev. 2014, 114, 1871.
(5) Ren, W. L.; Chang, W.; Dai, J.; Shi, Y.; Li, J.; Shi, Y. J. Am. Chem.
Soc. 2016, 138, 14864.
(6) Chudasama, V.; Fitzmaurice, R. J.; Caddick, S. Nat. Chem. 2010,
2, 592.
(7) Chatgilialoglu, C.; Crich, D.; Komatsu, M.; Ryu, L. Chem. Rev.
1999, 99, 1991.
(8) For selected recent examples of the formation of acyl radicals by
SET oxidation processes, see: (a) Liu, J.; Liu, Q.; Yi, H.; Qin, C.; Bai,
R.; Qi, X.; Lan, Y.; Lei, A. Angew. Chem., Int. Ed. 2014, 53, 502.
(b) Zhou, Q. Q.; Guo, W.; Ding, W.; Wu, X.; Chen, X.; Lu, L. Q.;
Xiao, W. J. Angew. Chem., Int. Ed. 2015, 54, 11196. (c) Chu, L.;
Lipshultz, J. M.; MacMillan, D. W. C. Angew. Chem., Int. Ed. 2015, 54,
7929. (d) Huang, H. C.; Zhang, G. J.; Chen, Y. Y. Angew. Chem., Int.
Ed. 2015, 54, 7872. (e) Tan, H.; Li, H.; Ji, W.; Wang, L. Angew. Chem.,
Int. Ed. 2015, 54, 8374. (f) Wang, G.; Shang, R.; Cheng, W. M.; Fu, Y.
Org. Lett. 2015, 17, 4830.
(9) For selected recent examples of the formation of acyl radicals by
SET reduction processes, see: (a) Bergonzini, G.; Cassani, C.;
Wallentin, C. J. Angew. Chem., Int. Ed. 2015, 54, 14066. (b) Li, C.-
G.; Xu, G.-Q.; Xu, P.-F. Org. Lett. 2017, 19, 512. (c) Pettersson, F.;
Bergonzini, G.; Cassani, C.; Wallentin, C. J. Chem. - Eur. J. 2017, 23,
7444.
(10) For selected recent reviews and examples of radical-mediated
hydrofunctionalization of olefins, see: (a) Nguyen, J. D.; D’ Amato, E.
M.; Narayanam, J. M. R.; Stephenson, C. R. Nat. Chem. 2012, 4, 854.
(b) Margrey, K. A.; Nicewicz, D. A. Acc. Chem. Res. 2016, 49, 1997.
(c) Singh, A.; Kubik, J. J.; Weaver, J. D. Chem. Sci. 2015, 6, 7206.
(d) Singh, A.; Fennell, C. J.; Weaver, J. D. Chem. Sci. 2016, 7, 6796.
(e) Huang, W.; Chen, W.; Wang, G.; Li, J.; Cheng, X.; Li, G. ACS
Catal. 2016, 6, 7471. (f) Lee, K. N.; Lei, Z.; Ngai, M. J. Am. Chem. Soc.
2017, 139, 5003. (g) Aycock, R. A.; Wang, H.; Jui, N. T. Chem. Sci.
2017, 8, 3121. (h) Musacchio, A. J.; Lainhart, B. C.; Zhang, X.;
Naguib, S. G.; Sherwood, T. C.; Knowles, R. R. Science 2017, 355, 727.
(11) (a) Baguley, P. A.; Walton, J. C. Angew. Chem., Int. Ed. 1998, 37,
3072. (b) Chatgilialoglu, C. Acc. Chem. Res. 1992, 25, 188.
(c) Chatgilialoglu, C. Chem. - Eur. J. 2008, 14, 2310.
D
DOI: 10.1021/acs.orglett.7b01391
Org. Lett. XXXX, XXX, XXX−XXX