Rapid Synthesis of ?-Arylated Carbonyls Enabled by the Merge of Copper- and Photocatalytic Radical Relay Alkylarylation of Alkenes

Article abstract of DOI:10.1021/acs.orglett.8b03485

The development of mild and practical methods for the ?-arylation of carbonyl compounds is an ongoing challenge in organic synthesis. The first formal ?-arylation of carbonyl compounds via radical relay cross-coupling of α-bromocarbonyl precursors with bo

Full text of DOI:10.1021/acs.orglett.8b03485

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Rapid Synthesis of γ‑Arylated Carbonyls Enabled by the Merge of
Copper- and Photocatalytic Radical Relay Alkylarylation of Alkenes
Xu-Lu Lv,† Cong Wang,† Qiao-Li Wang,† and Wei Shu*,†,‡
†Department of Chemistry and Shenzhen Grubbs Institute, Southern University of Science and Technology, 518055 Shenzhen,
China
‡State Key Laboratory of Elemento-Organic Chemistry, Nankai University, 300071 Tianjin, China
S
* Supporting Information
ABSTRACT: The development of mild and practical methods for
the γ-arylation of carbonyl compounds is an ongoing challenge in
organic synthesis. The first formal γ-arylation of carbonyl
compounds via radical relay cross-coupling of α-bromocarbonyl
precursors with boronic acids in the presence of alkenes is reported.
This directing-group-free protocol allows for the rapid and
straightforward access to a wide range of γ-arylated esters, ketones,
and amides under ambient conditions with excellent functional
group tolerance.
associated with these methods, such as additional steps required
for the preconstruction of substrates and for the removal of
directing groups, harsh reaction conditions, and the employ-
ment of precious metal, diminish the efficiency and compat-
ibility of the reactions. To date, direct γ-arylation of carbonyl
compounds is still a formidable challenge. However, to develop
strategies that functionalize abundant and easily available
starting materials to construct common and synthetically useful
synthons has been emerging as an attractive goal.8 A promising
approach for γ-arylated carbonyl compounds is to introduce the
aryl substituent along with the assembly of the carbon skeleton.
To this end, we envision to realize the γ-arylation of carbonyl
compounds through a new disconnection strategy by simulta-
neously formation of two C−C bonds, which circumvents the
difficulties associated with the cleavage of C−H bond at γ-
position of carbonyls, and has the potential to be applied to
different types of carbonyl functional groups, such as ketones,
esters, and amides. Herein, we report the copper- and
photocatalytic9,10 sequential alkylarylation of alkenes11 to afford
γ-arylated carbonyl compounds under mild conditions (Scheme
1b). This radical relay coupling reaction of α-halogencarbonyl
precursors, alkenes, and aryl boronic acids represents the first
example of general and practical γ-arylation of broad types of
carbonyl functionalities, such as esters, ketones, and amides.
This operationally simple strategy allows for the rapid synthesis
of a wide range of γ-arylated carbonyl compounds, including
ketones, esters, and amides, from inexpensive, readily available
starting materials at room temperature.
arbonyl derivatives are ubiquitous in pharmaceuticals,
Cbiologically active natural products, and key intermediates
in chemical synthesis.1 Methods for the functionalization at the
ipso- and α-positions of carbonyl groups have been well
established.2 The β-functionalization of aliphatic carbonyl
compounds relying on C−H cleavage has been extensively
developed over the past decade.3,4 In contrast, corresponding γ-
functionalization of aliphatic carbonyl compounds remains
largely underdeveloped.4 A few examples of γ-functionalizations
of carbonyl compounds thus far are limited to Pd-catalyzed
carboxylic acid derivatives containing a quaternary carbon
center facilitated by a directing group (Scheme 1a).5,6 Recently,
Yu developed an elegant Pd-catalyzed γ-arylation of ketones
enabled by a carboxylic directing group.7 Significant limitations
Scheme 1. Strategies and Challenges for the Synthesis of γ-
Arylated Carbonyl Compounds
An extensive literature survey revealed two potential
challenges for this proposal (Scheme 1c). First, α-halogen
carbonyl precursor may undergo direct cross-coupling with aryl
Received: November 1, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03485
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
metallic species to afford α-arylated carbonyl compounds I.12
Second, the resulting radical intermediate from addition of α-
halogen carbonyl precursor with alkene may undergo atom
transfer (halogen or hydrogen)13 or oxidation14 to terminate the
reaction with formation of II or III. With these concerns in
mind, we started the investigation using ethyl bromodifluor-
oacetate, styrene, and phenylboronic acid as the stereotype
substrates. First trials with Cu(I) and ligand (L1−L5) as catalyst
failed to deliver the radical relay cross-coupling product 1a, and
only the byproducts of bromoalkylation (II) or/and Heck-type
reaction (III) were detected. When the reaction was carried out
with Ir(ppy)3 (1 mol %) in the assistance of visible light
irradiation, the desired γ-arylated ester 1a was formed in 20%
yield using Cs2CO3 as base (Table 1, entry 1).15 No desired
product was observed in the absence of light or [Cu(MeCN)4]-
PF6 (Table 1, entry 2). Ligand evaluation revealed that bipyridyl
ligand L5 or tridentate ligand L6 could increase the yield to 39%
and 30%, respectively (Table 1, entries 3−7). The trial of other
solvents did not give better result (Table 1, entries 8−10). The
use of more cost-effective CuI or CuBr·Me2S further improved
the reactivity to afford 1a in 45% yield (Table 1, entries 11−13).
When the reaction was conducted under more dilute
concentration (Table 1, entry 14), 50% of 1a was obtained.
When a combination of L5 and L6 was used, the reaction
delivered the desired product 1a in 86% yield (Table 1, entry
15).
With the optimal conditions in hand, we evaluated the scope
of this copper- and photocatalytic three-component relay
coupling reactions. This strategy proved to be amenable to a
myriad of aryl boronic acids, providing access to a wide range of
γ-arylated esters. As shown in Figure 1, different types of aryl
a
Table 1. Conditions Evaluation for the Reaction
Figure 1. Scope of aryl group at γ-position. For reaction conditions, see
Table 1, entry 15. Ar = 4-methoxylphenyl.
group could be installed at γ-position. Phenyl group with
electron-donating or -withdrawing substituents could be
tolerated, delivering the desired product in good yields (1a−
1m). Aniline with free N−H is compatible in this dual catalytic
process (1l). ortho-Substituted aryl group is also a good
substrate under the reaction conditions (1n and 1o). This
protocol is also applicable to heteroaromatics, such as
thiophene, furan, and pyridine, affording the desired γ-
heteroarylated esters in synthetic useful yields (1p−1r).
Next, we examined the substituents at γ- and β-positions of
the alkyl chain (Figure 2). Different styrene with electron-rich or
-poor substituents could be applied to this reaction, providing
different biaryl substituents at γ-position (2a−2o). Notably,
vinylpyridines could be tolerated in this reaction (2p and 2q). It
is noteworthy to observe the good reactivity of alkyl alkene
under the standard conditions to furnish alkyl substituent at γ-
position (2r and 2s). This reaction provides a complementary γ-
arylation protocol to transition-metal catalyzed γ-C−H
functionalization pathways, which always restrict the reactivity
to the primary methyl group.8 Internal alkene was successfully
applied to the transformation, delivering corresponding β-
substituted γ-arylated esters in good yields with trans-selectivity
(2t and 2u).
Then we tested precursors bearing different carbonyl
functional groups (Figure 3), which led to different types of γ-
arylated carbonyl compounds. This reaction proved to be a
general γ-arylation method, providing rapid access to various
types of γ-arylated carbonyl functionalities, including esters
(3a−3g), alkyl and aryl ketones (3h−3j), and secondary and
tertiary amides (3k and 3l), which are always problematic for
existing γ-arylation protocols of C−H bonds. It is known that α-
a
The reaction was conducted using styrene (0.1 mmol), ethyl
bromodifluoroacetate (0.2 mmol), PhB(OH)2 (0.2 mmol), Cs2CO3
(2 equiv) in solvent (0.2 M) under 30 W blue LED at room
temperature unless otherwise stated. GC yield using dodecane as
internal standard. No light or no [Cu(MeCN)4]PF6. The reaction
was conducted in 0.033 M. 5 mol % of L5 and 5 mol % of L6 were
used. Isolated yield after chromatography.
b
c
d
e
f
B
DOI: 10.1021/acs.orglett.8b03485
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Figure 4. Late-stage functionalization. For reaction conditions, see
Table 1, entry 15.
Scheme 2. Control Experiments and Proposed Mechanism
for the Reaction
Figure 2. Scope for alkenes (β- and γ-position of the alkyl chain). For
reaction conditions, see Table 1, entry 15. Ar = 4-methoxylphenyl. aThe
reaction was run for 24 h.
that radical intermediate may be involved in the reaction. When
TEMPO was added into the reaction in the absence of
phenylboronic acid, no addition product 6 was detected.
Instead, the TEMPO and difluoroacetate adduct 7 was isolated
in 65% yield, proving the presence of ethyl difluoroacetate
radical in the process. Second, when the reaction was carried out
in the absence of phenyl boronic acid under standard conditions,
bromoalkylation product 6 was observed in quantitative yield,
suggesting the presence of benzyl radical intermediate 5 in the
catalytic cycle. Based on the results and the literature,13,16 we
proposed the following mechanism for this reaction (Scheme
2b). The interaction of α-bromocarbonyl precursor with excited
Ir*(III) photocatalyst would furnish a reactive radical
intermediate M1 and the oxidized photocatalyst Ir(IV) by
single electron transfer. M1 would be trapped by alkene to
generate a new alkyl radical intermediate M2. Then, the reaction
of Cu(I) with aryl boronic acid would deliver the arylcopper
intermediate M3 in the presence of base, which could further
recombine with M2 to give M4. M4 would reduce Ir(IV) to form
Ir(III) and undergo reductive elimination to give the final
product and regenerate Cu(I) species.
Figure 3. Scope of different carbonyl-containing functional groups. For
reaction conditions, see Table 1, entry 15. Ar = 4-methoxylphenyl.
substitution is always necessary in metal-catalyzed γ-arylation via
C−H cleavage due to the configuration requirement of
metallacycle intermediate.6,8 This reaction is also applicable to
carbonyl compounds with different substitution patterns at α-
position (Figure 3). Besides α,α-disubstituted carbonyl func-
tional groups (3d−3g), α-monosubstituted (3a and 3c) and α-
nonsubstituted carbonyl functional groups (3b and3i) are also
tolerated, giving the desired γ-arylated product in good yields.
To further demonstrate the potential utility of this reaction,
late-stage functionalization of the complex system and natural
products was examined (Figure 4). Amino acid derivative was
successfully transformed into corresponding γ-arylated ester 4a
in 57% yield. γ-Tocopherol-containing alkene was successfully
incorporated in the reaction to give γ-arylated ester 4b in 75%
yield.
In summary, we have demonstrated the first formal γ-
(hetero)arylation of carbonyl compounds via the radical relay
alkylarylation of alkenes under mild conditions. The employ-
ment of copper and visible-light catalysis is essential for the
success of this transformation, which allows for the sequential
formation of Csp3−Csp3 and Csp3−Csp2 bonds, providing a rapid
and straightforward access to γ-arylated carbonyl compounds.
Control experiments were designed to probe the mechanism
of this reaction (Scheme 2a). First, when 2 equiv of radical
scavenger TEMPO was added into the reaction under standard
conditions, no desired product 1a was detected. This indicates
C
DOI: 10.1021/acs.orglett.8b03485
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
13288−13292. (g) Shu, W.; Merino, E.; Nevado, C. ACS Catal. 2018, 8,
6401−6406.
This relay coupling strategy tolerates a wide variety of functional
groups, furnishing diverse γ-(hetero)arylated esters, ketones,
and amides, in the absence of any directing groups or
preactivation. The investigations on the asymmetric version of
this reaction and application of this strategy are ongoing in our
lab and will be reported in due course.
(5) For Pd-catalyzed γ-functionalizations: (a) Reddy, B. V. S.; Reddy,
L. R.; Corey, E. J. Org. Lett. 2006, 8, 3391−3394. (b) He, G.; Zhang, S.-
Y.; Nack, W. A.; Li, Q.; Chen, G. Angew. Chem., Int. Ed. 2013, 52,
11124−11128. (c) Li, S.; Chen, G.; Feng, C.-G.; Gong, W.; Yu, J.-Q. J.
Am. Chem. Soc. 2014, 136, 5267−5270. (d) Li, S.; Zhu, R.-Y.; Xiao, K.-
J.; Yu, J.-Q. Angew. Chem., Int. Ed. 2016, 55, 4317−4321. (e) Dey, A.;
Pimparkar, S.; Deb, A.; Guin, S.; Maiti, D. Adv. Synth. Catal. 2017, 359,
1301−1307. (f) Thrimurtulu, N.; Khan, S.; Maity, S.; Volla, C. M. R.;
Maiti, D. Chem. Commun. 2017, 53, 12457−12460. (g) Deb, A.; Singh,
S.; Seth, K.; Pimparkar, S.; Bhaskararao, B.; Guin, S.; Sunoj, R. B.; Maiti,
D. ACS Catal. 2017, 7, 8171−8175.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.8b03485.
(6) For radical mediated γ-functionalizations of amide: (a) Liu, T.;
Mei, T.-S.; Yu, J.-Q. J. Am. Chem. Soc. 2015, 137, 5871−5874. (b) Liu,
T.; Myers, M. C.; Yu, J.-Q. Angew. Chem., Int. Ed. 2017, 56, 306−309.
(7) Zhu, R.-Y.; Li, Z.-Q.; Park, H. S.; Senanayake, C. H.; Yu, J.-Q. J.
Am. Chem. Soc. 2018, 140, 3564−3568.
Experimental details for all the reactions and character-
ization of all new compounds (PDF)
Accession Codes
CCDC 1883036 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_
request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: +44 1223 336033.
(8) Engle, K. M.; Yu, J.-Q. J. Org. Chem. 2013, 78, 8927−8955.
(9) (a) Narayanam, J. M. R.; Stephenson, C. R. J. Chem. Soc. Rev. 2011,
40, 102−113. (b) Prier, C. K.; Rankic, D. A.; MacMillan, D. W. C.
Chem. Rev. 2013, 113, 5322−5363. (c) Schultz, D. M.; Yoon, T. P.
Science 2014, 343, 985−993. (d) Shaw, M. H.; Twilton, J.; MacMillan,
D. W. C. J. Org. Chem. 2016, 81, 6898−6926. (e) Chen, J.-R.; Hu, X.-
Q.; Lu, L.-Q.; Xiao, W.-J. Chem. Soc. Rev. 2016, 45, 2044−2056.
(10) Recent examples of dual catalysis of copper and light, see: (a) Do,
H.-Q.; Bachman, S.; Bissember, A. C.; Peters, J. C.; Fu, G. C. J. Am.
Chem. Soc. 2014, 136, 2162−2167. (b) Ratani, T. S.; Bachman, S.; Fu,
G. C.; Peters, J. C. J. Am. Chem. Soc. 2015, 137, 13902−13907.
(c) Kainz, Q. M.; Matier, C. D.; Bartoszewicz, A.; Zultanski, S. L.;
Peters, J. C.; Fu, G. C. Science 2016, 351, 681−684. (d) Zhao, W.; Wurz,
R. P.; Peters, J. C.; Fu, G. C. J. Am. Chem. Soc. 2017, 139, 12153−12156.
(e) Ahn, J. M.; Peters, J. C.; Fu, G. C. J. Am. Chem. Soc. 2017, 139,
18101−18106. (f) Matier, C. D.; Schwaben, J.; Peters, J. C.; Fu, G. C. J.
Am. Chem. Soc. 2017, 139, 17707−17710. (g) Wang, D.; Zhu, N.; Chen,
P.; Lin, Z.; Liu, G. J. Am. Chem. Soc. 2017, 139, 15632−15635.
(h) Liang, Y.; Zhang, X.; MacMillan, D. W. C. Nature 2018, 559, 83−
88. (i) Le, C.; Chen, T. Q.; Liang, T.; Zhang, P.; MacMillan, D. W. C.
Science 2018, 360, 1010−1014.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: shuw@sustc.edu.cn.
ORCID
Wei Shu: 0000-0003-0890-2634
Author Contributions
All authors have given approval to the final version of the
manuscript.
Notes
The authors declare no competing financial interest.
(11) For reviews on Cu- or visible-light catalyzed radical
difunctionalization of alkene: (a) Koike, T.; Akita, M. Org. Chem.
Front. 2016, 3, 1345−1349. (b) Koike, T.; Akita, M. Acc. Chem. Res.
2016, 49, 1937−1945. (c) Wang, X.; Studer, A. Acc. Chem. Res. 2017,
50, 1712−1724. (d) Wang, F.; Chen, P.; Liu, G. Acc. Chem. Res. 2018,
51, 2036−2046.
(12) (a) Liu, X.-X.; Deng, M.-Z. Chem. Commun. 2002, 622−623.
(b) Gooßen, L. J. Chem. Commun. 2001, 669−670. (c) Liu, C.; He, C.;
Shi, W.; Chen, M.; Lei, A. Org. Lett. 2007, 9, 5601−5604. (d) Xiao, Y.-
L.; Guo, W.-H.; He, G.-Z.; Pan, Q.; Zhang, X. Angew. Chem., Int. Ed.
2014, 53, 9909−9913. (e) Su, Y.-M.; Feng, G.-S.; Wang, Z.-Y.; Lan, Q.;
Wang, X.-S. Angew. Chem., Int. Ed. 2015, 54, 6003−6007.
(13) For selected examples, see: (a) Joung, M. J.; Ahn, J. H.; Lee, D.
W.; Yoon, N. M. J. Org. Chem. 1998, 63, 2755−2757. (b) Yorimitsu, H.;
Shinokubo, H.; Matsubara, S.; Oshima, K. J. Org. Chem. 2001, 66,
7776−7785. (c) Sumino, S.; Fusano, A.; Ryu, I. Org. Lett. 2013, 15,
2826−2829.
(14) (a) Liu, Q.; Yi, H.; Liu, J.; Yang, Y.; Zhang, X.; Zeng, Z.; Lei, A.
Chem. - Eur. J. 2013, 19, 5120−5126. (b) Zhang, X.; Yi, H.; Liao, Z.;
Zhang, G.; Fan, C.; Qin, C.; Liu, J.; Lei, A. Org. Biomol. Chem. 2014, 12,
6790−6793. (c) Xie, J.; Li, J.; Weingand, V.; Rudolph, M.; Hashmi, A. S.
K. Chem. - Eur. J. 2016, 22, 12646−12650. (d) Noda, Y.; Nishikata, T.
Chem. Commun. 2017, 53, 5017−5019.
ACKNOWLEDGMENTS
■
Financial support from Thousand Talents Program for Young
Scholars, National Natural Science Foundation of China (No.
21801126), Shenzhen Nobel Prize Scientists Laboratory Project
(C17783101), and Southern University of Science and
Technology is greatly appreciated. We thank Prof. Xumu
Zhang (SUSTech) for inspiration and accessing to a GC
instrument.
REFERENCES
■
(1) For reviews, see: (a) Tatsuta, K. J. Antibiot. 2013, 66, 107−129.
(b) Dyachenko, V. D.; Karpov, E. N. Russ. J. Org. Chem. 2011, 47, 1−29.
(c) Parenty, A.; Moreau, X.; Campagne, J.-M. Chem. Rev. 2006, 106,
911−939.
(2) For a review, see: Allen, A. E.; MacMillan, D. W. C. Chem. Sci.
2012, 3, 633−658.
(3) (a) Daugulis, O.; Do, H.-Q.; Shabashov, D. Acc. Chem. Res. 2009,
42, 1074−1086. (b) Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010, 110,
1147−1169. (c) Rouquet, G.; Chatani, N. Angew. Chem., Int. Ed. 2013,
52, 11726−11743. (d) He, G.; Wang, B.; Nack, W. A.; Chen, G. Acc.
Chem. Res. 2016, 49, 635−645.
(4) (a) For a review, see: He, J.; Wasa, M.; Chan, K. S. L.; Shao, Q.;
Yu, J.-Q. Chem. Rev. 2017, 117, 8754−8786. For selected examples on
radical-mediated remote functionalizations, see: (b) Chu, J. C. K.;
Rovis, T. Nature 2016, 539, 272−275. (c) Chen, D.; Chu, J. C. K.;
Rovis, T. J. Am. Chem. Soc. 2017, 139, 14897−14900. (d) Shu, W.;
Genoux, A.; Li, Z.; Nevado, C. Angew. Chem., Int. Ed. 2017, 56, 10521−
10524. (e) Shu, W.; Nevado, C. Angew. Chem., Int. Ed. 2017, 56, 1881−
1884. (f) Li, Z.; Wang, Q.; Zhu, J. Angew. Chem., Int. Ed. 2018, 57,
(15) For detailed information, see Supporting Information.
(16) (a) Mao, R.; Frey, A.; Balon, J.; Hu, X. Nat. Catal. 2018, 1, 120−
126. (b) Mao, R.; Balon, J.; Hu, X. Angew. Chem., Int. Ed. 2018, 57,
9501−9504. (c) Mao, R.; Balon, J.; Hu, X. Angew. Chem., Int. Ed. 2018,
57, 13624−13628.
D
DOI: 10.1021/acs.orglett.8b03485
Org. Lett. XXXX, XXX, XXX−XXX