Visible-light-enabled aerobic synthesis of benzoin bis-ethers from alkynes and alcohols

Article abstract of DOI:10.1039/c8gc02766h

A new, facile, atom-economical and good regioselective method for the synthesis of benzoin bis-ethers has been developed via directly using readily available alkynes and alcohols as raw materials under visible light irradiation. The protocol utilizes commercial Mes-Acr⁺ClO₄^- as an organophotoredox catalyst and air (O₂) as a green sustainable reagent. A range of benzoin bis-ether derivatives were easily and efficiently obtained in a one-pot procedure at room temperature, and water is the by-product.

Full text of DOI:10.1039/c8gc02766h

Green Chemistry
View Article Online
View Journal | View Issue
COMMUNICATION
Visible-light-enabled aerobic synthesis of benzoin
bis-ethers from alkynes and alcohols†
Cite this: Green Chem., 2018, 20,
5479
Wen-Long Lei, a Biao Yang,a Qing-Bao Zhang,a Pan-Feng Yuan,a Li-Zhu Wu
b
Received 31st August 2018,
Accepted 7th November 2018
a
and Qiang Liu
*
DOI: 10.1039/c8gc02766h
rsc.li/greenchem
A new, facile, atom-economical and good regioselective method preparation.5 In 2002, Yukio group reported that electro-
for the synthesis of benzoin bis-ethers has been developed via lytic oxidation of benzil hydrazones in MeOH could afford
directly using readily available alkynes and alcohols as raw benzil dimethyl ketal smoothly.6 More recently, a new method
materials under visible light irradiation. The protocol utilizes com- was reported using an aldehyde, hypertoxic KCN and tri-
mercial Mes-Acr+ClO4 as an organophotoredox catalyst and air methoxymethane to prepare benzoin bis-ethers in one pot.7
−
(O2) as a green sustainable reagent. A range of benzoin bis-ether Nevertheless, most of these processes still involve the use of
derivatives were easily and efficiently obtained in a one-pot pro- toxic additives, excess byproducts and labile substrates, which
cedure at room temperature, and water is the by-product.
would lead to increased cost and environmental concerns and
limit their practical application (Scheme 1).
Benzoin bis-ethers and their derivatives, especially 2,2-
dimethoxy-2-phenylacetophenone(DMPA), are widely used in
various industries, such as surface coating, photosensitive
polymer materials, additives for plastic, ink, finish paints for
wood products, and other various fields.1 They are also impor-
tant radical-type photoinitiators widely applied to polymeriz-
ation reaction systems, mainly undergoing cleavage to generate
benzoyl and substituted benzyl radicals upon irradiation.2 As
the most representative benzoin derivative, DMPA has become
an important commercial photocuring agent used mainly for
acrylic and unsaturated polyester resins and an effective UV-
curing initiator.3 Moreover, benzoin bis-ethers are significant
synthons as they are widely used in constructing key structural
elements.4,16
Consequently, developing green and straightforward syn-
thetic strategies of benzoin bis-ethers has been highly antici-
pated for decades. Until now, the ketonization reaction is the
leading approach in most methods of synthesizing benzoin
bis-ethers. In 1961, Trischmann and co-workers obtained
benzoin dimethyl ether from benzils with BaO.5a Later, these
protocols have been reported frequently for benzoin bis-ether
Alkynes as important, accessible raw materials are widely
used for the preparation of a variety of valuable versatile
organic compounds.8 However, there are only two unsatisfac-
tory methods to prepare benzoin bis-ethers from alkynes,9 (i)
oxidation of alkynes with excess H5I06 in methanol, and (ii)
using stoichiometric diphenyl diselenide and ammonium per-
oxydisulfate in reflux. Hence, given the importance of benzoin
bis-ethers and the limitations of previous approaches employ-
ing stoichiometric and hazardous oxidants, the development
of a facile, efficient and eco-friendly method directly using
accessible alkynes to synthesize benzoin bis-ethers is still
highly desirable.
Metal-free visible-light mediated aerobic oxidation is an
appealing green method marked by attractive features such as
clear and sustainable reagents, handy conditions and high
relevancy to solar energy, which has offered a technically
aState Key Laboratory of Applied Organic Chemistry College of Chemistry and
Chemical Engineering Lanzhou University, Lanzhou 730000, P. R. China.
E-mail: liuqiang@lzu.edu.cn
bKey Laboratory of Photochemical Conversion and Optoelectronic Materials,
Technical Institute of Physics and Chemistry, the Chinese Academy of Sciences,
Beijing 100190, P. R. China
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c8gc02766h
Scheme 1 Methods of the synthesis of benzoin bis-ethers.
Green Chem., 2018, 20, 5479–5483 | 5479
This journal is © The Royal Society of Chemistry 2018

View Article Online
Communication
Green Chemistry
Table 1 Reaction scope of alkynesa,b
attractive and energy-saving platform in comparison to the tra-
ditional oxidation processes.10 With increasing attention on
photoredox catalysis,11 the intriguing acridinium-based
organic dye (Acr+-Mes,9-mesityl-10-methylacridinium) has
been widely employed in organic synthesis as its mesityl group
on the 9-position dramatically increases the quantum yields
for the formation of the electron-transfer state,12 which can
effectively promote catalytic conversion. Fukuzumi and
Nicewicz have used the strong oxidizing capability of Acr+-Mes
to realize a range of efficient transformations.13 In continu-
ation of our interest on chemoselective transformation via
visible-light-driven aerobic oxidation,14 we became interested
in exploring a metal-free, mild photocatalytic system to con-
struct benzoin bis-ethers from alkynes. We envisioned that
single electron transfer (SET) from alkynes to the excited state
of Mes-Acr+ can occur efficiently and generate the radical
cation of alkynes15 under photocatalytic aerobic conditions.
Subsequent reaction of an alkyne radical cation with MeOH
and molecular oxygen should produce the desired benzoin bis-
ethers.
To validate our idea and optimise the reaction conditions,
the reaction with diphenylacetylene as the model substrate was
−
performed using
a
catalytic amount of Mes-Acr+ ClO4
(1.5 mol%) in MeOH under irradiation with blue LEDs in open
air (see the ESI†). We were delighted to obtain the desired
product of 2-dimethoxy-2-phenylacetophenone (DMPA) in 82%
yield (see the ESI†). Then, the control experiments were estab-
lished, which show that Mes-Acr+ClO4−, air (O2) and visible
light are necessary for an efficient reaction because in the
absence of any of the reagents/reaction parameters the product
was not detected.
Under the established optimal conditions, we sought to
evaluate the scope of the alkyne component, utilizing MeOH as
the nucleophile and solvent. As shown in Table 1, excellent
regioselectivity was observed which was consistent with the
stability of formed radical cations and various substituted
unsymmetrical and symmetrical alkynes worked well to deliver
the corresponding benzoin bis-ether products in good to excel-
lent yields. In the case of aryl-alkyl alkynes as the substrates, we
only detected benzoin bis-ethers under the optimal conditions.
Many versatile functional groups are readily tolerated, such as
ethyl, n-heptyl, alkyl chlorides, esters, ethers, nitriles, and even
steric bulky ones like cyclohexyl and perhaps most notable,
unprotected alcohols (2a–2l, 44%–76%). Next, exploring the
challenging scope of 1,4-diphenylbuta-1,3-diyne, we delightedly
obtained the benzoin bis-ether product containing an acetylenic
bond (2i, 66%). Moreover, intramolecular transformation was
also tolerated under standard conditions. The expected cycliza-
tion product (2l) was obtained in moderate yield. In the scope
of 1,2-diaryl alkynes, we found that the difference in the substi-
tution of the aromatic ring has an obvious influence on the
conversion. When the substituent group is methyl, tert-butyl,
or dimethyl, the transformation proceeded smoothly under
standard conditions (2m–2n). Substitution at the ortho, meta-
position of the phenyl ring was successfully incorporated
as well (2o–2q, 72%–75%). Furthermore, investigating the
a Reaction conditions: 1a (0.1 mmol, 1.0 equiv.) and Mes-Acr+ ClO4
(1.5 mol%) in MeOH (1.0 mL) were irradiated with 5 W blue LEDs for
3 h in air at room temperature. b Isolated yield. c For 10 h. d Only the
major products are shown with the ratio of 2 to its isomer 2′ given in
parentheses through the 1H NMR determination of the crude product.
−
unsymmetrical di-aryl scope, we found that products were
obtained in the ortho, para-position containing a methyl group
(2r, 2s). However, a mixture of products was afforded as methyl
groups in the meta-position (2t). When the para-position of the
phenyl ring has a ring electron-withdrawing group, a mixture of
products was also afforded (2u–2v, 77%–79%). It is worth
noting that certain alkynes are beyond the reach of the present
catalytic systems, as anticipative products of 2w and 2x were not
obtained.
We next turned our attention to the capacity of various alco-
hols in the protocol shown in Table 2. An important commer-
cial radical-type photoinitiator of (DMPA) was provided in
5480 | Green Chem., 2018, 20, 5479–5483
This journal is © The Royal Society of Chemistry 2018

View Article Online
Green Chemistry
Communication
excellent yield with a mild methodology (3a, 82%). Using
CD3OD as a solvent, we also obtained the deuterium product
3b (81%). Subsequently, a range of aliphatic alcohols including
ethanol (3c), 1-propanol (3d), 1-butanol (3e), 1-dexanol (3g)
and 1-octanol (3h) reacted smoothly with diphenylacetylene to
provide the expected product under the optimal conditions in
moderate to good yields. Notably, ethylene glycol could work
well under the current conditions, affording the desired
product 3f in good yield. 2-Ethoxyethanol was also tolerated
(3j, 65%). Moreover, evaluating secondary and tertiary alco-
hols, we found that isopropanol could convert to the expected
benzoin bis-ether (3i) under standard conditions but tert-
butanol failed. Finally, we obtained 3l in 61% yield using H2O
instead of an alcohol.
To demonstrate the potential utility of the mild, operation-
ally simple strategy, a gram-scale reaction of diphenylacetylene
(10 mmol, 1.78 g) was performed in MeOH for 4.0 h delivering
the desired product DMPA in good yield (1.59 g, 62% yield,
Scheme 2). Moreover, we found that benzoin ethers as useful
building blocks could be transformed into a series of valuable
compounds for organic synthesis as shown in Scheme 2.16
Firstly, N-glycolylneuraminic acid (Neu5Gc) plays a significant
role in human pathologies such as cancer and vascular disease.
The intermediate (4d) for its synthesis was obtained from the
reaction of DMPA with glucose and benzyl alcohol by two steps
in excellent yield.16d As there is an orientation effect of the car-
bonyl group, benzoin bis-ethers were used for C–C bond for-
mation via C–H bond activation in 4b and 4f.16b,f Finally, the
ketal structure is contained in DMPA, which is a good reactive
Scheme 2 (a) Larger scale reaction, and (b) further synthetic appli-
cation of the product.
site for further conversion such as forming 4c by a gallium cata-
lyst in excellent yield.16c The benzyl was obtained in 93% yield
by a simple deprotection from DMPA.16a Cyclic ketal 4e was pre-
pared by alcoholysis in the presence of 4-MeC6H4SO3H.16e
To elucidate the possible reaction mechanism, several
control experiments were conducted as shown in Fig. 1. Firstly,
adding 2.0 equiv. TEMPO under optimized conditions, the
model reaction was completely suppressed and the trapped
peak was detected at 404.1986 by HMRS in accordance with
the calculation (in Fig. 1), suggesting that the present trans-
formation might involve
a diarylacetylene radical cation
process. Secondly, we did not detect the desired product when
the model reaction was carried out under an argon atmo-
sphere. Finally, in the case of replacing diphenylacetylene with
benzil, the desired product was not obtained, which indicates
that benzyl is not necessarily an intermediate. Moreover, the
reported literature has proved that the excited acridine photo-
catalyst (Mes-Acr+ ClO4−) was quenched by diphenylacetylene
in fluorescence quenching (Stern–Volmer) experiments.17
Based on the above experimental results and the previous
related literature,15,17,18 a plausible mechanism for the reac-
tion is outlined in Scheme 3. Under visible-light irradiation,
the acridine photocatalyst is converted into the excited species
[Acr+-Mes ClO4−]* (E1/2red [Acr•-Mes•+/Acr•-Mes] = +2.06 V vs.
Table 2 Reaction scope of alcoholsa,b
a Reaction conditions: Diphenylacetylene (0.1 mmol, 1.0 equiv.) and
Mes-Acr+ ClO4 (1.5 mol%) in ROH/CH3CN (1.2 mL, 0.2 mL CH3CN)
−
were irradiated with 5 W blue LEDs for 3 h in air at room temperature.
b Isolated yield. c H2O/CH3CN (1 : 1, 1.0 mL).
Fig. 1 Control experiments for analysis of the reaction pathway.
Green Chem., 2018, 20, 5479–5483 | 5481
This journal is © The Royal Society of Chemistry 2018

View Article Online
Communication
Green Chemistry
Notes and references
1 (a) D. K. Ahn, K. J. Ihn and I. C. Kwon, J. Macromol. Sci.,
Part A, 1986, 23, 355; (b) H. F. Gruber, Prog. Polym. Sci.,
1992, 17, 953; H. Kaczmarek, P. Galka and J. Kowalonek,
J. Appl. Polym. Sci., 2010, 115, 1598; (c) N. Kizilcan, J. Appl.
Polym. Sci., 1999, 72, 927; (d) Y. L. Wang, X. S. Jiang and
J. Yin, J. Appl. Polym. Sci., 2007, 105, 3819; (e) M. Shinpei,
Manufacturing method of photosensitive composition with
excellent thermal conductivity, JP 2016155999, 2016.
2 J. P. Fouassier, Photoinitiation, Photopolymerization and
Photocuring, Fundametals and Application, Hanser:
New York, 1995.
Scheme 3 Proposed mechanism.
3 (a) M. R. Sandner and C. L. Osborn, Tetrahedron Lett., 1974,
415; (b) T. Pilot, Polym. Photochem., 1984, 5, 57;
(c) M. A. Tehfe, F. Dumur, B. Graff, J. L. Clement,
D. Gigmes, F. Morlet-Savary, J.-P. Fouassier and J. Lalevee,
Macromolecules, 2013, 46, 736.
4 (a) M. Studer, S. Burkhardt and H.-U. Blaser, Chem.
Commun., 1999, 1727; (b) R. Michael, F. Sabine, N. Peter
and K. Uwe, Flame retardant composition based on substi-
tuted di-, tri- and tetra arylethane compounds, EP 2927302,
2015; (c) M. Koji, T. Hiroaki, H. Takeshi and Y. Daiki,
Manufacture of fucosyl-α-(1→3)-chitobiose derivatives, JP
5605541, 2014.
5 (a) R. Kuhn and H. Trischmann, Chem. Ber., 1961, 94,
2258; (b) S. Kitamura, M. Tomioka and T. Goto, Preparation
of 2,2-dimethoxy-2-phenylacetophenone as photochemical
polymerization catalyst, JP 03128341, 1991; (c) X. B. Wang
and G. J. Shen and J. A. Shen, Synthesis process for
2,2-dimethoxy-2-phenylacetophenone, CN 104817443,
2015.
6 O. Mitsuhiro and T. Yukio, Bull. Chem. Soc. Jpn., 2002, 75,
2059.
7 I. Masayuki and A. Yoshio, α, α-Dialkoxyketone as photo-
polymerization initiator, and polymerizable liquid crystal
composition, JP 2018052873, 2018.
8 (a) P. J. Stang and F. Diederich, Modern Acetylene Chemistry,
Wiley, New York, 2008; (b) R. Chinchilla and C. Nájera,
Chem. Rev., 2014, 114, 1783; (c) V. P. Boyarskiy,
D. S. Ryabukhin, N. A. Bokach and A. V. Vasilyev, Chem.
Rev., 2016, 116, 5894.
9 (a) G. Gebeyehu and E. McNelis, J. Org. Chem., 1980, 45,
4280–4283; (b) M. Tiecco, L. Testaferri, M. Tingoli,
D. Chianelli and D. Bartoli, J. Org. Chem., 1991, 56, 4529.
10 (a) T. Mallat and A. Baiker, Chem. Rev., 2004, 104, 3037;
(b) R. A. Sheldon, Green Chem., 2007, 9, 1273; (c) Z. Z. Shi,
C. Zhang, C. C. Tang and N. Jiao, Chem. Soc. Rev., 2012, 41,
3381; (d) M. Stratakis and H. Garcia, Chem. Rev., 2012, 112,
4469; (e) A. A. Ghogare and A. Greer, Chem. Rev., 2016, 116,
9994; (f) C. K. Prier, D. C. Fabry, M. A. Ronge, J. Zoller and
M. Rueping, Angew. Chem., Int. Ed., 2015, 54, 2801.
11 (a) D. A. Rankic and D. W. C. MacMillan, Chem. Rev., 2013,
113, 5322; (b) D. Staveness, I. Bosque and
C. R. J. Stephenson, Acc. Chem. Res., 2016, 49, 2295;
(c) J.-R. Chen, X.-Q. Hu, L.-Q. Lu and W.-J. Xiao, Acc. Chem.
SCE), undergoing
a SET process with diphenylacetylene
(E1a•+/1a = +1.86 V vs. SCE) to generate an alkyne radical cation
and an Acr+-Mes ClO4 radical anion. Subsequently, a nucleo-
philic addition of methanol to the alkene radical cation A gen-
−
•−
erates the radical cation B, which could be captured by O2
and populate intermediate C. It is also plausible that the inter-
mediate C is produced by coupling radical cation B with O2
and subsequent single electron transfer. The electron-rich
alkene C is readily oxidized to form radical cation D by the
excited photocatalyst. Finally, nucleophilic attack of another
methanol on the radical cation D occurs and then the elimin-
ation of water affords the desired product 3a. On the other
hand, the photocatalyst could be regenerated by molecular
oxygen (EO2•−/O2 = −0.87 V vs. SCE).12a,19
Conclusions
In conclusion, we have presented an efficient metal-free visible-
light enabled methodology for synthesis of benzoin bis-ethers
using air (O2) as an oxidant and oxygen source. The protocol
with simple alkynes and alcohols as raw material constructs a
range of benzoin bis-ethers in one step, utilizing commercial
Mes-Acr+ ClO4 as an organophotoredox catalyst. This system
−
exhibits good regioselectivity. Mechanistic insights suggested
that the alkyne radical cation is the key intermediate and visible
light plays a vital role in this transformation. The net reaction is
very clean and water is the byproduct. Further transformations
of benzoin bis-ethers indicate that they can be used as direct
precursors to construct an array of important molecules, which
are also widely applied in industrial production.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
We are grateful for financial support from the NSFC (No.
21572090 and 21871123) and the Fundamental Research
Funds for the Central Universities (lzujbky-2017-k05).
5482 | Green Chem., 2018, 20, 5479–5483
This journal is © The Royal Society of Chemistry 2018

View Article Online
Green Chemistry
Communication
Res., 2016, 49, 1911; (d) X.-Q. Hu, J.-R. Chen and W.-J. Xiao,
Angew. Chem., Int. Ed., 2017, 56, 1960.
S.-F. Du, Z.-F. Chen, L.-Z. Wu and Q. Liu, Green Chem.,
2014, 16, 3752; (c) X. J. Wei, L. Wang, W. L. Jia, S. F. Du,
L. Z. Wu and Q. Liu, Chin. J. Chem., 2014, 32, 1245;
(d) Q.-B. Zhang, Y.-L. Ban, D.-G. Zhou, P.-P. Zhou, L.-Z. Wu
and Q. Liu, Org. Lett., 2016, 18, 5256; (e) Q. B. Zhang,
Y. L. Ban, P. F. Yuan, S. J. Peng, J. G. Fang, L. Z. Wu and
Q. Liu, Green Chem., 2017, 19, 5559; (f) M. Xiang,
Z. K. Xin, B. Chen, C. H. Tung and L. Z. Wu, Org. Lett.,
2017, 19, 3009; (g) M. Xiang, Q. Y. Meng, X. W. Gao, T. Lei,
B. Chen, C. H. Tung and L. Z. Wu, Org. Chem. Front.,
2016, 3, 486.
12 (a) D. A. Nicewicz and T. M. Nguyen, ACS Catal., 2014, 4,
355; (b) S. Fukuzumi and K. Ohkubo, Chem. Sci., 2013, 4,
561; (c) N. A. Romero and D. A. Nicewicz, Chem. Rev., 2016,
116, 10075; (d) D. S. Hamilton and D. A. Nicewicz, J. Am.
Chem. Soc., 2012, 134, 18577; (e) J. Xuan, X. D. Xia,
T.-T. Zeng, Z.-J. Feng, J. R. Chen, L. Q. Lu and W.-J. Xiao,
Angew. Chem., Int. Ed., 2014, 53, 5653; (f) G. Zhang, X. Hu,
C. W. Chiang, H. Yi, P. Pei, A. K. Singh and A. W. Lei, J. Am.
Chem. Soc., 2016, 138, 12037; (g) S. Kato, Y. Saga,
M. Kojima, H. Fuse, S. Matsunaga, A. Fukatsu, M. Kondo, 15 (a) H. G. Roth, N. A. Romero and D. A. Nicewicz, Synlett,
S. Masaoka and M. Kanai, J. Am. Chem. Soc., 2017, 139,
2204; (h) H. Yi, L. B. Niu, C. L. Song, Y. Y. Li, B. W. Dou,
2016, 27, 714; (b) D. l. Wei and F. S. Liang, Org. Lett., 2016,
18, 5860.
A. K. Singh and A. W. Lei, Angew. Chem., Int. Ed., 2017, 56, 16 (a) A. D. Bailey, A. R. Baru, K. K. Tasche and R. S. Mohan,
1120; (i) H. Yi, L. B. Niu, S. C. Wang, T. Y. Liu, A. K. Singh
and A. W. Lei, Org. Lett., 2017, 19, 122.
Tetrahedron Lett., 2008, 49, 691; (b) R. Martinez,
M. O. Simon, R. Chevalier, C. Pautigny, J.-P. Genet and
S. Darses, J. Am. Chem. Soc., 2009, 131, 7887; (c) B. Qin
and U. Schneider, J. Am. Chem. Soc., 2016, 138, 13119;
(d) O. M. T. Pearce and A. Varki, Carbohydr. Res., 2010, 345,
1225; (e) V. V. Yshin and F. A. Mikhailenko, Ukr. Khim. Zh.
(Russ. Ed.), 1990, 56, 1116; (f) F. Hua and M. Szostak,
Chem. Commun., 2016, 52, 9715.
13 (a) K. Ohkubo, K. Mizushima, R. Iwata, K. Souma,
N. Suzuki and S. Fukuzumi, Chem. Commun., 2010, 46, 601;
(b) K. Ohkubo, K. Mizushima, R. Iwata and S. Fukuzumi,
Chem. Sci., 2011, 2, 715; (c) N. A. Romero, K. A. Margrey,
N. E. Tay and D. A. Nicewicz, Science, 2015, 349, 1326;
(d) J. D. Griffin, M. A. Zeller and D. A. Nicewicz, J. Am.
Chem. Soc., 2015, 137, 11340; (e) J. B. McManus and 17 W. F. Tian, D. P. Wang, S. F. Wang, K. H. He, X. P. Cao and
D. A. Nicewicz, J. Am. Chem. Soc., 2017, 139, 2880; Y. Li, Org. Lett., 2018, 20, 1421.
(f) J. B. McManus, N. P. R. Onuska and D. A. Nicewicz, 18 (a) K. Tanaka, Y. Shigematsu, M. Sukekawa, Y. Hoshino
J. Am. Chem. Soc., 2018, 140, 9056; (g) F. J. Wu, L. F. Wang,
J. A. Chen, D. A. Nicewicz and Y. Huang, Angew. Chem., Int.
Ed., 2018, 57, 2174.
and K. Honda, Tetrahedron Lett., 2016, 57, 5914;
(b) S. Fukuzumi, K. Ohkubo and T. Suenobu, Acc. Chem.
Res., 2014, 47, 1455; (c) K. A. Margrey and D. A. Nicewicz,
Acc. Chem. Res., 2016, 49, 1997.
14 (a) T. Song, B. Zhou, G.-W. Peng, Q.-B. Zhang, L.-Z. Wu,
Q. Liu and Y. Wang, Chem. – Eur. J., 2014, 20, 678; 19 D. T. Sawyer, T. S. Calderwood, K. Yamaguchi and
(b) L. Wang, Z.-G. Ma, X.-J. Wei, Q.-Y. Meng, D.-T. Yang,
C. T. Angelis, Inorg. Chem., 1983, 22, 2577.
This journal is © The Royal Society of Chemistry 2018
Green Chem., 2018, 20, 5479–5483 | 5483