A visible-light-induced chemoselective radical/oxidative addition domino process to access α-chloro and α-alkoxy aryl ketones

Article abstract of DOI:10.1039/c6cc07272k

A visible-light-induced radical-triggered chemoselective domino process to access α,α-di-functionalized ketones under mild conditions has been developed. This protocol provides a direct approach to synthesize α-chloro or α-alkoxy aryl ketones based on the electronic properties of the substrates. The reaction can tolerate a variety of functional groups to afford the corresponding products in moderate to good yields.

Full text of DOI:10.1039/c6cc07272k

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Visible-light-induced chemoselective radical/oxidative addition
domino process to access α-chloro and α-alkoxy aryl ketones
Teng-fei Niu,a Ding-yun Jiang,a Si-yuan Li,a Bang-qing Nia* and Liang Wangb*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
A visible-light-induced radical-triggered chemoselective domino current research mainly focused on the 1,2-difunctionalization
process to access α,α-di-functionalized ketones under mild of double bonds via an ATRA (atom-transfer radical addition)-
conditions has been developed. This protocol provides a direct type mechanism.15 We envisioned whether triple bond could
approach to synthesize α-chloro or α-alkoxy aryl ketones based on undergo such ATRA process with oxygen by radical
the electronic properties of the substrates. The reaction can rearrangement. If possible, the α,α-di-functionalized ketones
tolerate a variety of functional groups to afford the corresponding could be delivered. Given the importance of functionalized
products in moderate to good yields.
ketones, and in continuation of our interest in photoredox
catalysis, herein, we report visible-light-induced
a
α-Functionalized ketones such as α-halo,1 α-alkoxy2 and α-
amino3 ketones are versatile building blocks for
pharmaceutical and natural product synthesis. Traditional
approaches to access these compounds are via halogenation
of ketones4 or their alcohol precursors5 followed by attack
chemoselective radical/oxidative addition domino process to
access α-chloro and α-alkoxy aryl ketones (Scheme 1, (d)).
with
different
nucleophiles.5b,6
Alternatively,
hydroxybromination of styrenes7 and hypervalent iodine (III)-
mediated oxidative rearrangement of vinyl halides,8 silyl enol
ethers9 as well as α-diazo ketones10 are also useful routes to α-
functionalized ketones. However, these methods usually
requires the use of toxic reagents, excess of oxidants or metal
catalysts. Thus, a simple and environmentally friendly way to
synthesize these products is still highly desirable.
Recently, visible-light-induced radical oxidation of
vinylarenes or alkynes has received much attention. The König,
cai, Yadav and our group successfully prepared 1,2-diarylated
ethanones,11,12a β-ketophosphine oxides,12b β-keto sulfoxides13
and α-aryl esters14 utilizing this strategy. However, only mono-
functionalized keto-derivatives at α-position have been
achieved (using arylation as example, Scheme 1, (a-c)). The
synthesis of α,α-di-functionalized ketones, however, has not
been reported yet. The challenge for α,α-di-functionalization
process lies in how to generate and trap the radical
intermediate or its corresponding oxidized electrophilic
cations. Nevertheless, this issue has been less studied since
Scheme 1 Photocatalytic approaches for functionalization of alkenes and alkynes.
Our initial efforts focused on using Cl- to trap the ion
intermediate which was generated by the reaction of aryl
diazonium salt (1a) and phenylacetylene (2a) under oxygen
using visible-light catalysis (Table 1). Pleasingly, a 63% yield of
product 3aa was obtained in the presence of Ru(bpy)3Cl2 (3
mol%) and HCl (2.2 equiv) in methanol after irradiation with a
5 W blue LED for 8 h (entry 1). Other photocatalysts such as
Ir(ppy)3 and Rhodamine B showed less catalytic activities
(entries 2 and 3). Switching the catalysts to Eosin Y and Eosin B
provided the comparable yields with Ru(bpy)3Cl2 (entries 4 and
a.School of Chemical and Material Engineering, Jiangnan University, Wuxi 214122,
Jiangsu Province, P. R. China. E-mail: byron_ni@yeah.net
b.School of Petrochemical Engineering, Jiangsu Key Laboratory of Advanced
Catalytic Materials & Technology, Changzhou University, Gehu Raod 1, Wujin,
Changzhou, 213164, P. R. China. E-mail: lwcczu@126.com
†Electronic Supplementary Informaꢀon (ESI) available: Experimental procedures, 5, 64% and 60%, respectively). Thus, the cheap and
NMR spectra. See DOI: 10.1039/x0xx00000x
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nonmetallic Eosin Y was selected as the ideal photocatalyst. the standard conditions, affording the desired products
3 in
Furthermore, increasing the amount of Eosin Y to 6 mol% led moderate yields, except substrate 1b, which gave the
to a decreased yield (entry 6). Other Cl sources such as NaCl corresponding product in only 22% yield owing to the
and NCS (N-chlorosuccinimide) were also checked. Notably, hindrance effect. It was worth noting that substrate 1h with a
when NaCl was used as the Cl source, the reaction proceeded strong electron-donating group (MeO) was unsuitable for the
smoothly to deliver the desired product 3aa in 62% yield (entry present reaction conditions, providing trace amount of desired
7); while no reaction was observed in the presence of NCS product. Surprisingly, a methoxylated product 3ha (38%) was
(entry 8). This indicated that the reaction may proceed obtained by switching the photocatalyst to Ru(bpy)3Cl2. We
through a nucleophilic attack of chloride anion (see the envisioned that it may provide a new direct route to access α-
mechanism). The choice of solvent had a significant impact on alkoxy aryl ketones using electron-rich aryl diazonium salts.
the reaction. Trace amounts of desired products were Different aromatic alkynes were evaluated as well. Most of the
obtained in DMF and DMSO. Reactions in THF, acetonitrile and substrates showed good activities regardless of electron-
1,4-dioxane afforded relatively lower yields (entries 11~13). withdrawing or -donating groups (45~71%). The aliphatic
Other control experiments were also performed. No reaction alkynes such as 2j, 2k, and 2l, however, were inert toward this
took place in the absence of a photocatalyst or visible light transformation.
(entries 14 and 15). Reaction under air provided a lower yield
of 3aa (46%). Slightly increasing the amount of 2a and NaCl did
not affect the reaction (entries 17 and 18). However, changing
the concentration of 1a afforded decreased yields (entries 19
and 20). In addition, trace amount of by-product 1-nitro-4-
(phenylethynyl)benzene was also observed, indicating a cross-
coupling reaction between 1a and 2a occurred in this reaction.
Table 2. Reaction scope.a
Table 1. Optimization of reaction conditions.a
Entry
1
2
3
4
5
6
7
8
Catalyst (mol%)
Ru(bpy)3Cl2 (3)
Ir(ppy)3 (3)
Rhodamine B(3)
Eosin Y (3)
Eosin B(3)
Eosin Y (6)
Eosin Y (3)
Eosin Y (3)
Eosin Y (3)
Eosin Y (3)
Eosin Y (3)
Eosin Y (3)
Eosin Y (3)
Eosin Y (3)
Eosin Y (3)
Eosin Y (3)
Eosin Y (3)
Eosin Y (3)
Eosin Y (3)
Eosin Y (3)
Cl source
HCl
HCl
HCl
HCl
Solvent
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
DMF
Yield (%)b
63
38
42
64
60
45
62
HCl
HCl
NaCl
NCS
NaCl
NaCl
NaCl
NaCl
NaCl
NaCl
NaCl
NaCl
NaCl
NaCl
NaCl
NaCl
NRc
trace
trace
32
9
10
11
12
13
14
15
16
17
18
19
20
DMSO
THF
CH3CN
1,4-dioxane
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
55
40
NRd
NRe
46f
62g
62h
46i
42j
a Reaction conditions: 1 (0.5mmol), 2 (1.1 equiv) and NaCl (2.2 equiv) in MeOH (2
mL) were irradiated with a 5 W blue LED under oxygen at room temperature for 8
h. Isolated yields.
a Reaction conditions: 1a (0.5 mmol), 2a (1.1 equiv), Cl source (2.2 equiv), and
photocatalyst in indicated solvent (2 mL) were irradiated with a 5 W blue LED
b
d
under oxygen at room temperature for 8 h. Isolated yields. c No reaction.
Reaction without photocatalyst. Reaction without light. f Reaction under open
air. 2a (2 equiv) was used. NaCl (4.4 equiv) was used. j 0.5 M of 1a. j 0.1 M of
e
g
h
The above results from table 2 prompted us to optimize the
reaction conditions for preparation of α-alkoxy aryl ketones.
After adjusting the reaction conditions (see ESI), a 48% yield of
product 4a was obtained in the presence of Ru(bpy)3Cl2 (2
mol%) in a mixed solvent system (MeOH/CH3CN, 1:3) after
irradiation with a 5 W blue LED for 8 h. Aryl diazonium salts
containing functional groups such as methoxyl, fluoro, and
1a.
With these results in hand, the scope and generality of the
present method was then examined (Table 2). As shown from
the table, aryl diazonium salts containing functional groups
such as NO2, Ph, CN, ester, and Cl were well tolerated under
2 | J. Name., 2012, 00, 1-3
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methyl were tolerated, affording the corresponding products
Although the detailed mechanism remains unclear at this
in moderate yields. For substrate 1a, no desired α-alkoxylated stage, a plausible mechanism is proposed on the basis of
product was detected but decomposed products and were previous reports and experimental results (Scheme 3). Initially,
5
6
isolated. Aromatic alkynes also showed good compatibilities. the photocatalyst (PC) is excited under irradiation with visible
Again, aliphatic alkynes were still inert toward the present light, which performs a single electron transfer (SET) to
reaction conditions. Reactions of other simple alcohols such as generate aryl radical
ethanol and isopropanol also proceeded smoothly to give the Subsequent addition of
Ⅰ
from aryl diazonium salt 1 16
to aryl alkyne generates the radical
, which reacts with molecular oxygen to give peroxy radical
.
Ⅰ
2
corresponding products in moderate yields (4h, 44%; 4i, 45%).
We also tried other nucleophiles such as H2O, HCOOH or
CH3COOH, however, no desired products were detected.
Ⅱ
Ⅲ
17
.
Then reaction between intermediate
Ⅱ
and
17 which further abstracts a H+ to form olefin radical
18 Then nucleophilic trapping of intermediate by Cl-
. Subsequent
Ⅲ delivers
radical
cation
Ⅳ,
Ⅴ
.
Ⅴ
Table 3. Photocatalyzed the synthesis of α-alkoxy aryl ketones.a
or RO- affords the corresponding intermediate
Ⅵ
SET oxidation of intermediate
furnishes the product
or 4 19
Ⅵ
via 1,2- hydrogen atom shift
3
.
a
Reaction conditions: 1 (0.5mmol), 2 (1.1 equiv), Ru(bpy)3Cl2 (2 mol%), in an
alcohol (0.5 mL) and CH3CN (1.5 mL) were irradiated with a 5 W blue LED under
oxygen at room temperature for 8 h. Isolated yields.
Following control experiment was carried out to gain
some insight into the mechanism (Scheme 2). Initially, it was
observed that the reaction was completely inhibited when
base (such as Na2CO3, Et3N, and DIPEA) was added to the
reaction mixture, which suggested that H+ may play an
important role in this reaction (scheme 2(a)). It was also worth
noting that the reaction solution showed weakly acidic (pH =
Scheme 2 Control experiments.
5~6). No product was obtained when
7 was used as the
substrate under the standard reaction conditions (scheme
2(b)). When the reaction carried out without any nucleophiles,
no desired products were observed. Insteadly, 4-
nitrobenzaldehyde and benzaldehyde was obtained (scheme
2(c)). This C-C bond cleavage process may proceed via the scission
of dioxetane radical intermediate (see mechanism, path c).
Moreover, when
2 equiv of radical scavenger, 2,2,6,6-
tetramethylpiperidine N-oxide (TEMPO), was added to the
reaction mixture under standard conditions, the
transformation was completely inhibited. Meanwhile, an
adduct of 4-nitrophenyl radical with TEMPO 10 was detected
by LC-MS. However, we did not observed the adduct 11 at the
current stage (scheme 2(d)).
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Scheme 3 Proposed mechanism.
Forster, J. Med. Chem., 2009, 52, 6768; (b) B. E. Blough, A.
Landavazo, J. S. Partilla, M. H. Baumann, A. M. Decker, K. M.
The H+ in this process may be generated by cross-coupling
reaction between 1a and 2a as reported by König group
(Scheme 3, path B).20 The high chemoselectivity in such a
radical-triggered domino process may be attributed to the
strong substituent effect. Electron-withdrawing group
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6
7
substituted intermediates
nucleophilic reaction with chloride ion to give products
while electron-donating substituted ones tend to react with
alcohols to give products . It is noticed that, the redox
potential of the photocatalysts also plays an important role in
Ⅴ preferentially undergoes
Q. Jiang, W. Shenga and C. Guo, Green Chem., 2013, 15
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8
9
4
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,
,
photocatalyst with relatively higher oxidation potential is
necessary at the final SET process for the electron-donating
10347.
12 (a) M. J. Bu, T. F. Niu and C. Cai, Catal. Sci. Technol., 2015,
groups substituted intermediates
withdrawing groups substituted intermediates
oxidation potential of Eosin Y is only about 0.78 V (E1/2M+/M = +
0.78 V vs SCE),21 resulting in that
'' cannot be easily oxidized
Ⅵ
'' compared with electron-
5
Ⅵ
'. The
830; (b) M. J. Bu, G. p. Lu and C. Cai, Catal. Sci. Technol.,
2016, , 413.
6
13 T. Keshari, V. K. Yadav, V. P. Srivastava and L. D. S. Yadav,
Green Chem., 2014, 16, 3986.
Ⅵ
by Eosin Y, but can be oxidized by [Ru(bpy)3]2+ (E1/2
= +
M+/M
14 T. F. Niu, L. Li, B. Q. Ni, M. J. Bu, C. Cai and H. L. Jiang, Eur. J.
Org. Chem., 2015, 5775.
15 Recent reviews: (a) Y. Xi, H. Yi and A. Lei, Org. Biomol. Chem.,
1.29 V vs SCE).22 On the other hand, Eosin Y is capable of
oxidizing the electron-withdrawing groups substituted
intermediates
Ⅵ
', leading to the formation of products
3
.
2013, 11, 2387; (b) T. P. Yoon, ACS Catal., 2013,
3, 895; (c) C.
K. Prier, D. A. Rankic and D. W. C. MacMillan, Chem. Rev.,
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5,
6
and 8, 9 may be
generated through path C.23 Due to the high tension of four-
membered ring intermediates, only electron-withdrawing
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groups substituted intermediates
intramolecular nucleophilic reaction to give intermediates
Further hydrogenolysis or alcoholysis of affords and
respectly.23
In summary, we have developed a visible-light-induced
Ⅶ
can undergo
Ⅷ
.
Ⅷ
5,
6
8,
9
Ravelli, S. Protti and M. Fagnoni, Chem. Rev., 2016, 116
,
radical-triggered chemoselective domino process to access
α,α-di-functionalized ketones. This protocol provides a direct
approach to synthesize α-chloro or α-alkoxy aryl ketones
based on the electronic properties of the substrates. A series
of substrates survived the reaction conditions to give the
corresponding products in moderate to good yields. Notably,
the prepared α-chloro aryl ketones can be further modified to
access other useful compounds.
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We gratefully acknowledge financial support from the
National Natural Science Foundation of China (21302014), the
Natural Science Foundation of Jiangsu Province (BK20160164),
the Enterprise university-research prospective program of 19 R. Tomita, Y. Yasu, T. Koike and M. Akita, Angew. Chem. Int.
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Jiangsu Province (BY2013015-29), the Jiangsu Key Laboratory
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and Advanced Catalysis and Green Manufacturing Innovation
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1,
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Notes and references
1
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4 | J. Name., 2012, 00, 1-3
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