Copper-Catalyzed Cycloaddition between Secondary Phosphine Oxides and Alkynes: Synthesis of Benzophosphole Oxides

Article abstract of DOI:10.1002/adsc.201500667

Benzophosphole derivatives have attracted significant attention as promising organic optoelectronic materials. We have successfully developed a copper (2mol%)/tert-butyl hydroperoxide (2equiv.) catalyst system for reaction of readily available secondary phosphine oxides and alkynes in acetonitrile at 60 C under air, which provides a rapid access to a structurally diverse array of benzophosphole oxides in moderate to good yields within 30min. The method can be easily used for a large-scale preparation. Preliminary mechanistic studies revealed that the addition of a phosphoryl radical onto a triple bond followed by cyclization on the phenyl moiety of the secondary phosphine oxide might occur to form the benzophosphole oxide.

Full text of DOI:10.1002/adsc.201500667

UPDATES
DOI: 10.1002/adsc.201500667
Copper-Catalyzed Cycloaddition between Secondary Phosphine
Oxides and Alkynes: Synthesis of Benzophosphole Oxides
a
a
a
a
a
Pengbo Zhang, Yuzhen Gao, Liangliang Zhang, Zhiqiang Li, Yan Liu,
a,
a
Guo Tang, * and Yufen Zhao
Department of Chemistry, College of Chemistry and Chemical Engineering, and the Key Laboratory for Chemical
Biology of Fujian Province, Xiamen University, Xiamen, Fujian 361005, Peopleꢀs Republic of China
Fax: (+86)-592-218-5780; e-mail: t12g21@xmu.edu.cn
a
Received: July 11, 2015; Revised: September 16, 2015; Published online: January 5, 2016
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201500667.
[
4]
Abstract: Benzophosphole derivatives have attract-
ed significant attention as promising organic opto-
electronic materials. We have successfully devel-
oped a copper (2 mol%)/tert-butyl hydroperoxide
Montchamp, Kuninobu and Takai. Yoshikai dis-
closed a synthetic method for a functionalized benzo-
phosphole derivative based on the sequential coupling
of an arylzinc reagent, an alkyne, a Grignard reagent,
[5]
(
2 equiv.) catalyst system for reaction of readily
and an oxidant. Recently, our group reported the
synthesis of benzophosphole oxides from alkynyl
acids and diarylphosphine oxides. In 2013, the Duan
group and the Satoh and Miura groups independently
developed the silver- or manganese-mediated dehy-
drogenative coupling of phenylphosphine oxides with
available secondary phosphine oxides and alkynes
in acetonitrile at 608C under air, which provides
a rapid access to a structurally diverse array of ben-
zophosphole oxides in moderate to good yields
within 30 min. The method can be easily used for
a large-scale preparation. Preliminary mechanistic
studies revealed that the addition of a phosphoryl
radical onto a triple bond followed by cyclization
on the phenyl moiety of the secondary phosphine
oxide might occur to form the benzophosphole
oxide.
[6]
[7]
alkynes. In 2014, Ackermann reported on silver-
mediated alkyne annulations by secondary phosphine
oxides or arylphosphinates via CÀH/PÀH functionali-
[8a]
zation.
Montchamp found the Mn(OAc) /MnO
2 2
combination to be an inexpensive replacement of
Mn(III) in an alkyne-arene annulation.
[8b]
These
simple protocols provide general, one-step ap-
proaches to benzophosphole oxide frameworks. In
these processes, silver or manganese is used in excess
Keywords: alkynes; benzophosphole oxides; tert-
butyl hydroperoxide; copper catalysts; secondary
phosphine oxides
(
2–4 equivalents), which is quite wasteful and expen-
sive. For practical reactions, the use of readily avail-
able starting materials, low-cost, catalysts at low load-
ings for this heterocyclization method would be ap-
pealing.
Benzophosphole oxide, an important phosphorus-con-
In the past decades, reactions with phosphoryl radi-
taining heterocyclic scaffold, has recently attracted cals have shown significant utility in the synthesis of
[9]
much attention in the field of materials chemistry be- organophosphorus compounds. Recently, we devel-
cause of its inherent optical and electronic proper- oped a reaction of phosphoryl radicals with alkynyl
[
1]
ties. These compounds are of particular synthetic acids in the presence of CuSO ·5H O and TBHP to
4
2
[10a]
utility and practical use in phosphole-based fluoro- give b-ketophosphine oxides (Scheme 1a).
When
[
2]
phores and semiconductors. They also have a high ethyl 3-phenylpropiolate was used instead of 3-phe-
potential for the chemical modification of the phos- nylpropiolic acid in the above-mentioned conditions,
phorus center. Recently, many efforts have been de- benzophosphole oxide was isolated, and no b-keto-
voted to the synthesis of benzophosphole oxides. Ya- phosphine oxide was obtained (Scheme 1b).
maguchi, Tanaka, Duan, and Mathey separately de-
Herein, we disclose a more convenient and time-
veloped a versatile synthesis for benzophospholes saving approach by which a series of benzophosphole
based on the base-mediated intramolecular cycliza- oxides is readily prepared by the direct reaction of al-
[
3]
tion reaction. Palladium-catalyzed methods for the kynes with arylphosphine oxides in the presence of
synthesis of phospholes were investigated by Chatani, a Cu(II)-TBHP catalyst system under air. Compared
1
38
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Adv. Synth. Catal. 2016, 358, 138 – 142

UPDATES
Copper-Catalyzed Cycloaddition between Secondary Phosphine Oxides and Alkynes
[
a]
Table 1. Optimization of the reaction conditions.
Entry Catalyst
mol%)
Solvent
Oxidant Yield
[b]
(
(equiv.)
[%]
1
2
3
4
5
6
7
8
9
1
1
1
1
1
AgNO (10)
MeCN
HOAc
HOAc
TBHP
MnO2
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
DTBP
H O
0
55
0
81
64
61
26
38
65
0
3
[
[
c]
c]
Mn(OAc) (10)
2
Mn(OAc) (10)
2
CuSO ·5H O (10) MeCN
4
2
Scheme 1. Reaction of Ph P(O)H with alkynyl acid deriva-
tives.
2
Cu(OTf) (10)
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
2
Cu O (10)
2
CuBr (10)
CuCl (10)
Cu powder (10)
–
to the methods of Duan, Miura and Satoh, Acker-
mann, and Montchamp, the most prominent advan-
tages of our method include reaction conditions con-
sisting of a much reduced reaction time (0.5 h), open
air, and low catalyst loading (2 mol%).
0
1
2
3
4
CuSO ·5H O (10) MeCN
9
8
4
2
CuSO ·5H O (10) MeCN
4
2
2
2
CuSO ·5H O (10) MeCN
TBPB
K S O
8
54
47
41
47
49
47
54
70
80
4
2
CuSO ·5H O (10) MeCN
4
2
2
2
Initially, Ph P(O)H (1a) and diphenylacetylene (2a) 15
CuSO ·5H O (10) MeCN
MnO2
2
4
2
were chosen as the model substrates to survey the re- 16
action conditions. It has been found that many salts 17
CuSO ·5H O (10) DMF
TBHP
TBHP
TBHP
4
4
2
2
CuSO
·5H
O (10) DMSO
[
10]
[11]
[12]
1
1
2
2
8
9
0
1
CuSO ·5H O (10) EtOH
such as copper, silver and manganese can work
4 2
CuSO ·5H O (10) 1,4-dioxane TBHP
with R P(O)H to form the corresponding phosphoryl
4
2
2
[
d]
CuSO ·5H O (10) MeCN
TBHP
TBHP
4
2
radical to promote phosphoryl radical addition
chemistry. In the beginning, various silver and manga-
nese catalysts were tested and all performed poorly
CuSO ·5H O (2)
MeCN
4
2
[
a]
Reaction conditions: 1a (0.4 mmol), 2a (0.2 mmol), cata-
lyst, NH ·H O (25%, 0.25 mL), oxidant (0.4 mmol), sol-
(
entries 1–3, Table 1, also see the Supporting Informa-
tion). Gratifyingly, when a mixture of 1a (0.4 mmol),
(0.2 mmol), CuSO ·5H O (0.02 mmol) and
3
2
vent (2.0 mL) in an open flask at 608C for 30 min.
Isolated yield based on 2a.
[
[
b]
c]
2
a
4
2
NH ·H O was not added.
3
2
NH ·H O (25%, 0.25 mL) in MeCN was heated to
3
2
[d]
Under argon (balloon).
6
08C under air for 30 min, the desired product 3a was
obtained in 81% yield (entry 4). Subsequently, various
Cu(II) and Cu(I) salts were further checked and the even when the loading of CuSO ·5H O was reduced
4
2
results showed that Cu(II) salts were more effective to 2 mol%, the reaction also afforded 3a in approxi-
to give the desired product (entries 4–8). Cu powder mately the same yield (entry 21), which demonstrates
could also execute this reaction but with lower effi- the high catalytic efficiency of this CuSO -TBHP
4
ciency (entry 9). No desired product was afforded system for the generation of phosphoryl radical and
without a copper salt (entry 10). Other oxidants, such the alkyne-arene annulation reaction.
as DTBP (di-tert-butyl peroxide), H O , TBPB (tert-
With the optimum conditions in hand, we next ex-
2
2
butyl peroxybenzoate), or MnO , did not improve the plored the scope of arylphosphine oxides and alkynes
2
yield (entries 11–15). A brief survey of bases such as in the presence of CuSO ·5H O (2 mol%), TBHP
4
2
K CO , NaOAc, KOH, NEt , pyridine, and NH ·H O (2 equiv.), and NH ·H O (25%, 0.25 mL) in MeCN at
2
3
3
3
2
3
2
(
25%) led to the observation that NH ·H O (25%) 608C under air for 30 min. The results are summar-
3 2
gave the highest yield of 3a (see the Supporting Infor- ized in Table 2. The diarylacetylenes undewent cou-
mation). Conducting the reaction in EtOH, DMF, pling with diphenylphosphine oxide to produce the
DMSO and 1,4-dioxane gave the product 3a in low corresponding benzophosphole oxides (3a–3g in
yields (entries 16–19), while the reaction conducted in Table 2). Methyl-substituted diphenylacetylenes, such
MeCN gave a high yield (see the Suppoprting Infor- as those with meta-methyl and para-methyl groups on
mation). Moreover, when the reaction was carried out the aryl ring, reacted with 1a efficiently and gave the
under argon, a similar result was obtained (entry 20). desired products 3b and 3c in good yields. In addition,
The yield of product 3a decreased when the tempera- diarylacetylene having a methoxy group furnished the
ture was raised to 808C or decreased to room temper- transformation, producing the desired benzophos-
ature (see the Suppoprting Information). Notably, phole oxide 3d in high efficiency. Diarylacetylenes
Adv. Synth. Catal. 2016, 358, 138 – 142
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asc.wiley-vch.de
139

Pengbo Zhang et al.
UPDATES
[
a]
Table 2. Reaction of arylphosphine oxides with alkynes.
[
a]
1a (0.8 mmol) and 2a (0.2 mmol) were used.
bearing halogen atoms were also examined. The reac-
tion of chloro- or bromo-substituted diarylacetylenes
with 1a gave lower yields under the standard condi-
tions (3f and 3g in Table 2). This is likely due to their
difficult dissolution ability in MeCN-H O. The reac-
2
tion of ethynylbenzene did not proceed at all (3h). Si-
lylethynylbenzene could give a moderate yield (3i).
The asymmetrical phenylacetylenes reacted with 1a in
a regioselective manner to afford 3j–3m in moderate
to good yields. Our continued interest in the reactivity
[13]
of alkynylphosphine oxides prompted us to explore
a more atom-economical and functional group-toler-
ant method for the synthesis of 2-phosphinobenzo-
phosphole oxides. As expected, a series of aryl(diphe-
nylphosphoryl)ethynes could be used as substrates,
generating the corresponding products (3n–3s) in
good yields. Phenyl-, para-methylphenyl-, and para-
methoxyphenyl(diphenylphosphoryl)ethynes were all
converted into the products 3n–3p in 82%, 80% and
6
8% yields, respectively. 4-Fluoro-, 4-chloro-, and 4-
bromophenyl(diphenylphosphoryl)ethynes reacted
with diphenylphosphine oxide to give products 3q–3s
successfully. Good yields were achieved with phenyle-
thynyl dialkoxyphosphonate (3t and 3u). Notably, no
other isomers were detected in these reactions. When
phenyl 3-phenylpropiolate reacted with 1a, we ac-
quired the phosphorylcoumarin derivative 3v (60%),
which was formed by annulation of the alkenyl radical
with the phenol ring. The reaction of bis(4-methylphe-
nyl)phosphine oxide under the standard conditions
gave both the normal coupling product 3w and the
isomer 3w’ as a 1.5:1 mixture. Bis(4-chlorophenyl)-
phosphine oxide and bis(4-bromophenyl)phosphine
oxide also resulted in mixtures.
In order to demonstrate the practical application of
this method, diphenylphosphine oxide (1a, 20 mmol)
and diphenylacetylene (2a, 10 mmol) were employed
in a gram-scale reaction and delivered 3a in 70%
yield (Scheme 2).
1
40
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ꢁ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2016, 358, 138 – 142

UPDATES
Copper-Catalyzed Cycloaddition between Secondary Phosphine Oxides and Alkynes
In conclusion, we have successfully developed
a facile catalytic method for the preparation of benzo-
phosphole oxides via phosphorylation–cyclization of
various alkynes with secondary phosphine oxides.
This method provides a rapid access to a broad spec-
trum of benzophosphole oxides in moderate to good
yields. Moreover, the use of inexpensive CuSO ·5H O
4
2
catalyst, using readily available alkynes and secondary
phosphine oxides means that this facile protocol will
be attractive for academia and industry.
Scheme 2. Gram-scale preparation of 3a.
Experimental Section
No desired product was obtained when 2.0 equiv. of
TEMPO were added in the reaction of 1a with diphe- Procedure for Copper-Catalyzed Cycloaddition
nylacetylene under the optimal conditions. This result between Secondary Phosphine Oxides and Alkynes
indicates that the phosphoryl radicals may be inter-
Ph P(O)H (1a) (0.4 mmol), diphenylacetylene (2a)
2
cepted by TEMPO. According to our previous
Cu(II)-TBHP catalytic reaction mechanism study,
a plausible mechanism is proposed as shown in
(
0.2 mmol), CuSO ·5H O (2 mol%), TBHP (0.4 mmol),
4 2
[10,14]
NH ·H O (25%, 0.25 mL), and MeCN (2.0 mL) were se-
3
2
quentially added to a Schlenk tube with a magnetic stir bar
Scheme 3. Initially, the Cu(II) cation is oxidized to at room temperature. The resulting mixture was stirred at
the Cu(III) cation by TBHP. The reaction of P(O)H 608C for 30 min under aerobic conditions. The reaction solu-
1
with the Cu(III) salt generates phosphoryl radical A tion was allowed to cool to ambient temperature, and then
added silica gel (5.0 g). This powder was then dry-loaded
which then goes through intermolecular addition onto
alkyne 2 to produce alkenyl radical B. Subsequent in-
tramolecular attack of the radical B on the pendant
aromatic ring then provides radical C. Subsequently,
cationic intermediate D is formed through single-elec-
tron oxidation by Cu(III) which ultimately aromatizes
to afford para-substituted product 3. Alternatively, al-
kenyl radical B attacks the aryl ring at the carbon
atom directly attached to the phosphorus atom to
form spirocyclohexadienyl radical E. The radical E
converts into a phosphoryl radical F via the CÀP
onto a silica gel column and purified by flash chromatogra-
phy using a petroleum ether/AcOEt mixture (3:1–1:1, v/v)
as the eluent to give the product 3a. Other benzophosphole
oxides were prepared similarly.
Acknowledgements
We acknowledge financial support from the Chinese National
Natural Science Foundation (21173178, 21232005, 21375113),
the National Basic Research Program of China
[
15]
bond cleavage.
Subsequently, radical phosphoryla-
tion on the aryl group and oxidation process ultimate-
ly affords the meta-substituted phosphorus heterocy- (2012CB821600), the Program for Changjiang Scholars and
cle 3’.
Innovative Research Team in University, and the Fundamen-
Scheme 3. Possible reaction pathways.
Adv. Synth. Catal. 2016, 358, 138 – 142
ꢁ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
141

Pengbo Zhang et al.
UPDATES
tal Research Funds for the Central Universities (No.
0720150049).
2015; b) S. Vander Jeught, C. V. Stevens, Chem. Rev.
2009, 109, 2672; c) M. Mondal, U. Bora, RSC Adv.
2
2
013, 3, 18716; d) W. Wei, J. X. Ji, Angew. Chem. 2011,
123, 9263; Angew. Chem. Int. Ed. 2011, 50, 9097.
[
10] a) P. Zhang, L. Zhang, Y. Gao, J. Xu, H. Fang, G. Tang,
Y. Zhao, Chem. Commun. 2015, 51, 7839; b) B. Xiong,
X. Feng, L. Zhu, T. Chen, Y. Zhou, C. T. Au, S. F. Yin,
ACS Catal. 2015, 5, 537; c) M. Zhou, M. Chen, Y.
Zhou, K. Yang, J. Su, J. Du, Q. Song, Org. Lett. 2015,
References
[1] a) Phosphorus Heterocycles II, (Ed.: R. K. Bansal), in:
Topics in Heterocyclic Chemistry, Springer, Berlin,
2
010; Vol. 21; b) Y. Matano, H. Imahori, Org. Biomol.
Chem. 2009, 7, 1258; c) F. Mathey, Acc. Chem. Res.
004, 37, 954; d) H. Chen, W. Delaunay, J. Li, Z. Wang,
17, 1786; d) N. Liu, L. L. Mao, B. Yang, S. D. Yang,
Chem. Commun. 2014, 50, 10879; e) H. Y. Zhang, L. L.
Mao, B. Yang, S. D. Yang, Chem. Commun. 2015, 51,
2
P. A. Bouit, D. Tondelier, B. Geffroy, F. Mathey, Z.
Duan, R. RØau, M. Hissler, Org. Lett. 2013, 15, 330.
2] a) T. Baumgartner, R. RØau, Chem. Rev. 2006, 106,
4101.
[
11] a) Z. Z. Zhou, D. P. Jin, L. H. Li, Y. T. He, P. X. Zhou,
X. B. Yan, X. Y. Liu, Y. M. Liang, Org. Lett. 2014, 16,
5616; b) B. Zhang, C. G. Daniliuc, A. Studer, Org. Lett.
2014, 16, 250; c) X. Chen, X. Li, X. L. Chen, L. B. Qu,
J. Y. Chen, K. Sun, Z. D. Liu, W. Z. Bi, Y. Y. Xia, H. T.
Wu, Y. F. Zhao, Chem. Commun. 2015, 51, 3846;
d) Y. M. Li, M. Sun, H. L. Wang, Q. P. Tian, S. D. Yang,
Angew. Chem. 2013, 125, 4064; Angew. Chem. Int. Ed.
2013, 52, 3972.
[
4681; b) E. Yamaguchi, C. Wang, A. Fukazawa, M.
Taki, Y. Sato, T. Sasaki, M. Ueda, N. Sasaki, T. Higa-
shiyama, S. Yamaguchi, Angew. Chem. 2015, 127, 4622;
Angew. Chem. Int. Ed. 2015, 54, 4539; c) Y. Matano, Y.
Motegi, S. Kawatsu, Y. Kimura, J. Org. Chem. 2015, 80,
5944; d) W. H. Jeon, J. Y. Son, S. E. Kim, P. H. Lee,
Adv. Synth. Catal. 2015, 357, 4; e) Y. Hayashi, Y.
Matano, K. Suda, Y. Kimura, Y. Nakao, H. Imahori,
Chem. Eur. J. 2012, 18, 15972; f) Z. Hu, Z. Li, K. Zhao,
R. Tian, Z. Duan, F. Mathey, Org. Lett. 2015, 17, 3518.
3] a) A. Fukazawa, Y. Ichihashi, Y. Kosaka, S. Yamaguchi,
Chem. Asian J. 2009, 4, 1729; b) T. Sanji, K. Shiraishi,
T. Kashiwabara, M. Tanaka, Org. Lett. 2008, 10, 2689;
c) Y. Xu, Z. Wang, Z. Gan, Q. Xi, Z. Duan, F. Mathey,
Org. Lett. 2015, 17, 1732.
[12] a) B. B. Snider, Chem. Rev. 1996, 96, 339; b) W. Liu, D.
Zell, M. John, L. Ackermann, Angew. Chem. 2015, 127,
4165; Angew. Chem. Int. Ed. 2015, 54, 4093; c) X. Li, J.
Xu, Y. Gao, H. Fang, G. Tang, Y. Zhao, J. Org. Chem.
2015, 80, 2621; d) Y. Gao, J. Xu, P. Zhang, H. Fang, G.
Tang, Y. Zhao, RSC Adv. 2015, 5, 36167; e) D. P. Li,
X. Q. Pan, L. T. An, J. P. Zou, W. Zhang, J. Org. Chem.
2014, 79, 1850; f) X. H. Cao, X. Pan, P. J. Zhou, J. P.
Zou, O. T. Asekun, Chem. Commun. 2014, 50, 3359;
g) S. F. Zhou, D. P. Li, K. Liu, J. P. Zou, O. T. Asekun,
J. Org. Chem. 2015, 80, 1214; h) Y. Gao, X. Li, J. Xu,
Y. Wu, W. Chen, G. Tang, Y. Zhao, Chem. Commun.
2015, 51, 1605.
[13] a) Y. Gao, G. Wang, L. Chen, P. Xu, Y. Zhao, Y. Zhou,
L. Han, J. Am. Chem. Soc. 2009, 131, 7956; b) X. Li, G.
Hu, P. Luo, G. Tang, Y. Gao, P. Xu, Y. Zhao, Adv.
Synth. Catal. 2012, 354, 2427; c) X. Xu, H. Chen, Y.
Wang, Y. Gao, G. Tang, Y. Zhao, RSC Adv. 2014, 4,
14740.
[
[
4] a) K. Baba, M. Tobisu, N. Chatani, Angew. Chem. 2013,
125, 12108; Angew. Chem. Int. Ed. 2013, 52, 11892;
b) O. Berger, C. Petit, E. L. Deal, J. L. Montchamp,
Adv. Synth. Catal. 2013, 355, 1361; c) Y. Kuninobu, T.
Yoshida, K. Takai, J. Org. Chem. 2011, 76, 7370.
[
[
[
5] B. Wu, M. Santra, N. Yoshikai, Angew. Chem. 2014,
126, 7673; Angew. Chem. Int. Ed. 2014, 53, 7543.
6] G. Hu, Y. Zhang, J. Su, Z. Li, Y. Gao, Y. Zhao, Org.
Biomol. Chem. 2015, 13, 8221.
7] a) Y. R. Chen, W. L. Duan, J. Am. Chem. Soc. 2013,
1
35, 16754; b) Y. Unoh, K. Hirano, T. Satoh, M. Miura,
Angew. Chem. 2013, 125, 13213; Angew. Chem. Int. Ed.
013, 52, 12975.
2
[14] a) Z. Zhao, W. Xue, Y. Gao, G. Tang, Y. Zhao, Chem.
Asian J. 2013, 8, 713; b) J. Xu, P. Zhang, Y. Gao, Y.
Chen, G. Tang, Y. Zhao, J. Org. Chem. 2013, 78, 8176.
[15] a) D. L. J. Clive, S. Kang, Tetrahedron Lett. 2000, 41,
1315; b) D. L. J. Clive, S. Kang, J. Org. Chem. 2001, 66,
6083.
[
[
8] a) W. Ma, L. Ackermann, Synthesis 2014, 46, 2297;
b) H. C. Fisher, O. Berger, F. Gelat, J. L. Montchamp,
Adv. Synth. Catal. 2014, 356, 1199.
9] a) Phosphorus Chemistry II, (Ed.: J. L. Montchamp),
in: Topics in Current Chemistry; Springer, Switzerland,
1
42
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ꢁ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2016, 358, 138 – 142