Metal-Free Photoinduced Transformation of Aryl Halides and Diketones into Aryl Ketones

Article abstract of DOI:10.1002/ejoc.201801650

The acylation of aryl halides to prepare aryl ketones without metal catalyst represents an important yet challenging topic towards more sustainable ketone synthesis. Herein, we describe a simple and efficient metal-free protocol for the acylation of aryl halides with diketone under the irradiation of light utilizing N-methylpiperidine as base under an air atmosphere. This reaction can tolerate a wide range of functional groups and the corresponding ketones can be obtained in modest to good yields.

Full text of DOI:10.1002/ejoc.201801650

A Journal of
Accepted Article
Title: Metal-Free Photoinduced Transformation of Arylhalides and
Diketones into Aryl Ketones
Authors: Qiuli Yao, Wenbo Liu, Peng Liu, Linling Ren, Xuehong Fang,
and Chao-Jun Li
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201801650
Link to VoR: http://dx.doi.org/10.1002/ejoc.201801650
Supported by

10.1002/ejoc.201801650
European Journal of Organic Chemistry
COMMUNICATION
Metal-Free Photoinduced Transformation of Aryl Halides and
Diketones into Aryl Ketones
Qiuli Yao[a,b], Wenbo Liu[b], Peng Liu[b], Linjing Ren[a], Xuehong Fang[a] and Chao-Jun Li*[b]
Abstract: The acylation of aryl halides to prepare aryl ketones
without metal catalyst represents an important yet challenging topic
towards more sustainable ketone synthesis. Herein, we describe a
simple and efficient metal-free protocol for the acylation of aryl
halides with diketone under the irradiation of light utilizing N-
methylpiperidine base in an air atmosphere. This reaction can
tolerate a wide range of functional groups and the corresponding
ketones can be obtained in modest to good yields.
aryl halide (Scheme 1d). Subsequently, the aryl radical
intermediate can add to the carbonyl group to form aryl ketone
after the elimination of the leaving group.
However, it is challenging for the addition of a radical
intermediate to carbonyl group due to the formation of a
thermodynamically unfavorable alkoxy radical intermediate,7
which would preferentially undergo C-C β-scission to form a
more stable radical.8 In addition, the hydrogen abstraction from
the solvent or other organic substrates by alkoxyl and aryl
radical intermediates are potential side reactions considering the
high reactivity of oxygen radical and aryl radical (Scheme 1c).7a,9
To overcome these challenges, a good leaving group is
beneficial, which will accelerate the desired reaction and
compete with other side reactions. Furthermore, the use of a
reducing base such as amine can promote the formation of aryl
radical through a single electron transfer process.10
Introduction
Photo-induced organic reactions have opened a new era for the
preparation of diverse important organic molecules in novel and
meaningful ways.1 Via light as the energy input, photoreactions
can be carried out without catalysts.2 More significantly,
photoreactions could realize transformations challenging to
achieve by traditional methodologies,3 thus complementing
conventional reactions, especially the metal-catalyzed ones.
The reaction of aryl halides with carbonyl derivatives through
a mediator represents one of the most useful and traditional
reactions to prepare aryl ketones (Eq. 1).4-5 Among these, the
most common reactions are via the preparation of
organometallic species such as the Grignard reagent, which
subsequently reacts with acyl derivatives (Scheme 1a).4 Such
standard approaches require stoichiometric metals (and
generate stoichiometric metal wastes), and are less sustainable.
As an important alternative to the conventional use of
stoichiometric organometallic reagents, MacMillan reported in
2015 the formation of aryl ketones by utilizing a photoredox
system, through a nickel-catalyzed decarboxylative coupling of
α-oxo acids with aryl halide via a radical intermediate (Scheme
1b).5
To the best of our knowledge, however, the metal-free
coupling of aryl halide with carbonyl derivatives has yet to be
developed. Recently, we have uncovered a series of metal-free
light-enabled chemical transformations that traditionally require
transition-metal catalysts or organometallic reagents.2b-2d,3a,3c,6
We thus considered the possibility of directly coupling aryl
halides with carbonyl compounds to obtain aryl ketones
facilitated by light under metal-free conditions (Scheme 1c). Our
hypothesis consists of two steps. First, under light irradiation
with the assistance of a base, aryl radical will be generated from
[a]
[b]
Prof. Q. Yao, L. Ren, X. Fang
School of Pharmacy
Zunyi Medical University
6 Xuefu Road West, Zunyi, 563000, China.
Dr. W. Liu, Dr. P. Liu, Prof. C.-J. Li
Department of Chemistry and FQRNT Centre for Green Chemistry
and Catalysis
McGill University
Scheme 1. Reactions of aryl halide with carbonyl derivatives.
801 Sherbrooke Street West, Montreal, Quebec H3A 0B8, Canada.
E-mail: cj.li@mcgill.ca
Supporting information for this article is given via a link at the end of
the document.
Results and Discussion
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801650
European Journal of Organic Chemistry
COMMUNICATION
To begin the study, the reaction of 4-iodoanisole (1a) and
diacetyl (2a) was chosen as a model reaction (Table 1). To our
delight, under photo-irradiation (254 nm, 2.5 W*20) for 25 h in
acetonitrile with triethylamine as base, the desired product was
obtained in 17% yield (Table 1, entry 1). To minimize the side
reactions of hydrogen abstraction by alkoxyl and aryl radical
intermediates, 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) was
used as the solvent. Gladly, the yield could be increased to 33%
(Table 1, entry 2). Replacing triethylamine with N-
methylpiperidine (MP) is beneficial and the yield could be
improved to 70% (Table 1, entry 3). Attempts to improve the
yield by using other solvents such as carbon disulfide or
dimethylsulfoxide were not successful (Table 1, entries 4 and 5).
Various amounts of HFIP or diacetyl as well as the use of argon
atmosphere were evaluated (Table 1, entries 6-12) and excellent
NMR yield (95%, isolated yield 81%) could be achieved when
0.12 mL of diacetyl and 0.3 mL of HFIP were used (Table 1,
entry 12).11
desired products in good to excellent yields by using this
protocol, although some of the substrates required longer
reaction time (3c, 3e, 3g, 3h, 3m). In addition, fluoride (3q) and
4-OCF2H (3r) substituents could be tolerated as well, giving 36%
and 41% yields, respectively. More significantly, some products
obtained by this method are difficult to prepare by traditional
means. For example, while ketone 3o is difficult to synthesize by
the widely used Friedel–Crafts reaction with acetyl chloride and
o-xylene, it could be readily accessible by this protocol.
Not only the diacetyl can serve as the ketone donor, other
diketones can also participate in this reaction. For example,
when 3,4-hexanedione was employed, the acylation of aryl
iodide proceeded smoothly to give ketone 3s in 39% yield.
When 2,3-pentanedione was used instead, products 3b and 3s
could be obtained in moderate yields with nearly 1:1 ratio
(Scheme 2).
Table 1. Optimization of reaction conditions[a]
Entry
2a/mL
Others
Yield/%
1
0.2
CH3CN(0.3 mL), NEt3 (1 equiv)
HFIP (0.3 mL), NEt3 (1 equiv)
HFIP (0.3 mL), MP (1 equiv)
CS2(0.3 mL), MP (1 equiv)
DMSO (0.3 mL), MP (1 equiv)
HFIP (0.35 mL), MP (1 equiv)
HFIP (0.25 mL), MP (1 equiv)
HFIP (0.3 mL), MP (1 equiv)
HFIP (0.3 mL), MP (1 equiv)
HFIP (0.3 mL), MP (1 equiv)
HFIP (0.3 mL), MP (1 equiv)
HFIP (0.3 mL), MP (1 equiv)
17
2
0.2
33
3
0.2
70
4
0.2
trace
trace
62
5
0.2
6
0.2
7
0.2
67
8
0.15
0.1
60
9
76
10[b]
11
12
0.1
73
0.08
0.12
63
95(81)
Abbreviations: HFIP, 1,1,1,3,3,3-hexafluoro-2-propanol; MP, N-
methylpiperidine. [a] All the reactions were conducted with 1a (0.1
mmol), 2a, solvent, amine (0.1 mmol) at 30 oC under air in a quartz
tube irradiated by light (254 nm) for 25 h unless otherwise specified.
Yields were determined by 1HNMR analysis with 1,3,5-
trimethylbenzene as internal standard. The yield in parentheses
represented isolated one after purified by TLC. [b] The reaction was
carried out in argon.
Scheme 2. Scope of the metal-free acylation reaction.[a]
With the optimized conditions established, the scope of this
reaction was subsequently explored (Scheme 2). Various
substituted aryl iodides including 3-methoxy (3b), 3-methyl-4-
methoxy (3c), −OBn (3d), −OEt (3e), −NHAc (3f, 3g, 3h),
−NHBoc (3i, 3j, 3k), methyl (3l, 3m) and di-methyl (3n, 3o)
substituted, as well as non-substituted (3p) could give the
Other less reactive aryl halides such as aryl bromides and aryl
chlorides were also evaluated (Eq. 2-5). Aryl bromides can
smoothly deliver the corresponding products (3a, 3p, 3t) in
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801650
European Journal of Organic Chemistry
COMMUNICATION
modest to good yields (Eq. 2-4). Product 3p was obtained in 32% bond in the preparation of ketones without the use of any metal.
yield for the less activated substrate chlorobenzene (5a, Eq. 5).
This protocol allows to be expanded to other reaction systems
that involve the formation of aryl radical intermediates. Further
exploration of the methodologies is on the way in our laboratory,
which will be reported in due course.
Experimental Section
All commercially available compounds were used without further
purification. NMR spectra were recorded on Agilent-NMR-VNMRs 400
spectrometer. Chemical shifts are reported in parts per million (ppm) and
referenced to chloroform-d (7.16 ppm) for 1HNMR, chloroform-d (77.16
ppm) for 13CNMR. Thin-layer chromatography (TLC) was performed with
Qing Dao TLC silica gel 60 F254. Photoreactors with household UV lamps
was from Philips Company (TUV, 2.5 W each, 47 V, T5 16 mm).
Procedure for the reaction of arylhalide1, 4 or 5 with diketone 2 in the
synthesis of aryl ketone 3: To a 10 mL quartz flask under air was added
arylhalide1, 4 or 5 (0.1 mmol) and diacetyl (2a, 0.12 mL, 1.38 mmol) for
3a-3r, or 3,4-hexanedione (2b, 0.10 mL, 0.82 mmol) for 3s, or 2,3-
pentanedione (2c, 0.10 mL, 0.96 mmol). Then, (CF3)2CHOH (HFIP, 0.3
mL, dried over 3 Ǻ molecular sieve before using) and 1-methylpiperidine
(12 μL, 0.1 mmol) were added subsequently. The reaction mixture was
irradiated in the photoreactors with household UV lamps (254 nm, 2.5
W*20) at 30 oC. After the time indicated in Scheme 2 and Eq. 2-5, the
reaction mixture was concentrated and purified by TLC on silica gel with
eluent (petroleum ether : EtOAc 50:1 or 3:2) to give aryl ketone 3.
To understand the reaction mechanism, the crude reaction
mixture was analyzed by GC-MS, which showed the side
product of Ar-H via hydrogen abstraction by aryl radical
intermediate derived from aryl halide. This side product is
especially prominent for substrates with 4-hydroxyl or 2-
carboxylic group. For example, 83% of PhCO2H was obtained
for the reaction of 2-iodobenzoic acid (1s) with diacetyl (2a)
under standard conditions with 2 equiv of N-methylpiperidine as
the base (Eq. 6). Without the use of N-methylpiperidine, only 40%
of PhCO2H was obtained (Eq. 7). Thus, the use of amine could
promote the reduction of aryl halides. Moreover, compound 7,
which was derived from the reaction of acetyl radical with
diacetyl (2a), was observed as a byproduct in all these reactions.
This observation is consistent with the mechanism described
above (Scheme 1c).
Acknowledgements
This work is supported by NSERC, FQRNT, CFI, McGill
University and the Canada Research Chair. Q. Yao is grateful
for NSFC (Nos 21462056, 21801261) and China Scholarship
Council (CSC).
Keywords: Photosynthesis • radical reactions • cross-coupling •
metal-free
[1]
(a) K. Teegardin, J. I. Day, J. Chan and J. Weaverr, Org. Process Res.
Dev. 2016, 20, 1156-1163
(b) K. Luo, W.-C. Yang and L. Wu, Asian J. Org. Chem. 2017, 6, 350-
367.
(c)H. Tu, S. Zhu, F.-L. Qing, L. Chu, Tetrahedron Lett. 2018, 59, 173-
179.
(d) M. H. Shaw, J. Twilton, D. W. C. MacMillan, J. Org. Chem. 2016, 81,
6898-6926.
(e) L. N. Cavalcanti, G. A. Molander, Top. Curr. Chem. 2016, 374.
(f) S. Fukuzumi, K. Ohkubo, Chem. Sci. 2013, 4, 561-574.
(g) J. Zhao, W. Wu, J. Sun, S. Guo, Chem. Soc. Rev. 2013, 42, 5323-
5351.
(h) D. M. Arias-Rotondo, J. K. McCusker, Chem. Soc. Rev. 2016, 45,
5803-5820.
(g) C.-L. Sun, Z.-J. Shi, Chem. Rev. 2014, 114, 9219-9280.
(h) N. Corrigan, S. Shanmugam, J. Xu, C. Boyer, Chem. Soc. Rev.
2016,
45,
6165-6212.
Conclusion
(i) X. Lang, X. Chen, J. Zhao, Chem. Soc. Rev. 2014, 43, 473-486.
(j)E. B. McLean, A.-L. Lee, Tetrahedron 2018, 74, 4881-4902.
(j) C.-S. Wang, P. H. Dixneuf, J.-F. Soule, Chem. Rev. 2018, 118,
7532-7585.
In conclusion, we described herein a simple and efficient method
to convert aryl halides into aryl ketones with the irradiation of
light under metal-free conditions. Via this strategy, aryl ketones
can be prepared readily from aryl halides in modest to high
yields at room temperature under air, tolerating various
functional groups. More significantly, this work demonstrates the
successful coupling of radical intermediates with C=O double
(k) H. Zhang, A. Lei, Asian J. Org. Chem. 2018, 7, 1164-1177.
(l) I. Ghosh, L. Marzo, A. Das, R. Shaikh, B. Konig, Acc. Chem. Res.
2016, 49, 1566-1577.
[2]
(a)
C.-J.
Li,
W.
Liu,
Synlett
2017,
28,
2714-2754.
(b) W. Liu, X. Yang, Y. Gao, C.-J. Li, J. Am. Chem. Soc. 2017, 139,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801650
European Journal of Organic Chemistry
COMMUNICATION
8621-8627.
(d) W. Liu, P. Liu, L. Lv, C.-J. Li, Angew. Chem. Int. Ed. 2018, 57,
(c) P. Liu, W. Liu, C.-J. Li, J. Am. Chem. Soc. 2017, 139, 14315-14321.
(d) L. Li, W. Liu, X. Mu, Z. Mi, C.-J. Li, Nat. Protoc. 2016, 11, 1948-
1954.
13499-13503;
Angew.
Chem.
2018,
130,
13687-13691.
(e) J. Li, D. Zhu, L. Lv, C.-J. Li, Chem. Sci. 2018, 9, 5781-5786.
(f) W. Liu, Z. Chen, L. Li, H. Wang, C.-J. Li, Chem. Eur. J. 2016, 22,
5888-5893.
[3]
(a) W. Liu, X. Yang, Z.-Z. Zhou, C.-J. Li, Chem 2017, 2, 688-702.
(b) J. Jin, D. W. C. MacMillan, Nature 2015, 525, 87-90.
(c) L. Li, X. Mu, W. Liu, Y. Wang, Z. Mi, C.-J. Li, J. Am. Chem. Soc.
(g) X. Yang, W. Liu, L. Li, W. Wei, C.-J. Li, Chem. Eur. J. 2016, 22,
15252-15256.
2016,
(d) T. Zhang, Y. Meng, J. Lu, Y. Yang, G.-Q. Li, C. Zhu, Adv. Synth.
Catal. 2018, 360, 3063-3068.
(e) W. Wei, P. Bao, H. Yue, S. Liu, L. Wang, Y. Li, D. Yang, Org. Lett.
2018, 20, 5291-5295.
(f) Y. Li, K. Zhou, Z. Wen, S. Cao, X. Shen, M. Lei, L. Gong, J. Am.
Chem. Soc. 2018, 140, 15850-15858.
(g) J. Wu, L. He, A. Noble, V. K. Aggarwal, J. Am. Chem. Soc. 2018,
140, 10700-10704.
138,
5809-5812.
[7]
(a) A. Clerici, O. Porta, J. Org. Chem. 1989, 54, 3872-3878.
(b) A. Clerici, O. Porta, P. Zago, Tetrahedron 1986, 42, 561-572.
(c) A. Studer, D. P. Curran, Angew. Chem. Int. Ed. 2016, 55, 58-102;
Angew.
Chem.
2015,
128,
58-106.
(d) A. Citterio, M. Serravalle, E. Vismara, Tetrahedron Lett. 1982, 23,
1831-1834.
(e) C. Dell'Erba, F. Sancassan, M. Novi, G. Petrillo, A. Mugnoli, D.
Spinelli, G. Consiglio, P. Gatti, J. Org. Chem. 1988, 53, 3564-3568.
M. Bietti, M. Salamone, Synlett 2014, 25, 1803-1816.
(a) L. Pitzer, F. Sandfort, F. Strieth-Kalthoff, F. Glorius, J. Am. Chem.
[8]
[9]
(h) S. P. Morcillo, E. M. Dauncey, J. H. Kim, J. J. Douglas, N. S. Sheikh,
D. Leonori, Angew. Chem. Int. Ed. 2018, 57, 12945-12949; Angew.
Chem. 2018, 130, 13127- 13131.
Soc.
2017,
139,
13652-13655.
(b) T. Kawamoto, T. Fukuyama, I. Ryu, J. Am. Chem. Soc. 2011, 134,
[4]
(a) S. Ni, W. Zhang, H. Mei, J. Han, Y. Pan, Org. Lett. 2017, 19, 2536-
2539.
875-877.
(c) A. L. Berger, K. Donabauer, B. König, Chem. Sci. 2018, 9, 7230-
(b) L. Huck, A. de la Hoz, A. Díaz-Ortiz, J. Alcázar, Org. Lett. 2017, 19,
3747-3750.
7235.
[10] (a) A. Bahamonde, J. J. Murphy, M. Savarese, É. Brémond, A. Cavalli,
P. Melchiorre, J. Am. Chem. Soc. 2017, 139, 4559-4567.
(b) W. Zhang, K. Feng, X. Wu, D. Martin, D. C. Neckers, J. Org. Chem.
1999, 64, 458-463.
(c) B. Suchand, G. Satyanarayana, J. Org. Chem. 2016, 81, 6409-6423.
L. Chu, J. M. Lipshultz, D. W. C. MacMillan, Angew. Chem. Int. Ed.
2015, 54, 7929-7933; Angew. Chem. 2015, 127, 8040-8044.
(a) L. Li, W. Liu, H. Zeng, X. Mu, G. Cosa, Z. Mi, C.-J. Li, J. Am. Chem.
[5]
[6]
[11] Other conditions were also examined with PhI and diacetyl as model
substrates by using a standard LZC-4V photoreactor from Luzchem
Company (254 nm, 2.5 W*8). Please see the Electronic Supplementary
Information.
Soc.
(b) J. Li, C. A. D. Caiuby, M. W. Paixão, C.-J. Li, Eur. J. Org. Chem.
2017, 2018, 2498-2503.
(c) W. Liu, L. Li, C.-J. Li, Nat. Commun. 2015, 6, 6526-653.
2015,
137,
8328-8331.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801650
European Journal of Organic Chemistry
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
Qiuli Yao, Wenbo Liu, Peng Liu, Linjing
Ren, Xuehong Fang and Chao-Jun Li*
Page No. – Page No.
Metal-Free Photoinduced
Transformation of Aryl Halides and
Diketones into Aryl Ketones
The acylation of aryl halides to prepare aryl ketone without metal catalyst
represents an important yet challenging topic towards more sustainable ketone
synthesis. Herein, we describe a simple and efficient metal-free protocol for the
acylation of aryl halides with diketone under the irradiation of light utilizing N-
methylpiperidine as base under air. This reaction can tolerate a wide range of
functional groups and gives the corresponding ketones in modest to good yields.
This article is protected by copyright. All rights reserved.