Copper-catalyzed asymmetric sp3 C-H arylation of tetrahydroisoquinoline mediated by a visible light photoredox catalyst

Article abstract of DOI:10.3762/bjoc.12.260

This report describes a highly enantioselective oxidative sp³ C-H arylation of N-aryltetrahydroisoquinolines (THIQs) through a dual catalysis platform. The combination of the photoredox catalyst, [Ir(ppy)₂(dtbbpy)]PF₆, and chiral copper catalysts provide a mild and highly effective sp³ C-H asymmetric arylation of THIQs.

Full text of DOI:10.3762/bjoc.12.260

Copper-catalyzed asymmetric sp3 C–H arylation of tetrahydro-
isoquinoline mediated by a visible light photoredox catalyst
Pierre Querard1, Inna Perepichka1, Eli Zysman-Colman2 and Chao-Jun Li*1
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2016, 12, 2636–2643.
1Department of Chemistry, FQRNT Center for Green Chemistry and
Catalysis, McGill University, 801 Sherbrooke Street West, Montreal,
Quebec H3A 0B8, Canada and 2Organic Semiconductor Centre,
EaStCHEM School of Chemistry, University of St Andrews, St
Andrews, Fife, KY16 9ST, UK
doi:10.3762/bjoc.12.260
Received: 23 August 2016
Accepted: 17 November 2016
Published: 06 December 2016
Email:
This article is part of the Thematic Series "Strategies in asymmetric
catalysis".
Chao-Jun Li* - cj.li@mcgill.ca
* Corresponding author
Guest Editor: T. P. Yoon
Keywords:
© 2016 Querard et al.; licensee Beilstein-Institut.
License and terms: see end of document.
C–H arylation; copper catalyst; enantioselectivity; visible light
Abstract
This report describes a highly enantioselective oxidative sp3 C–H arylation of N-aryltetrahydroisoquinolines (THIQs) through a
dual catalysis platform. The combination of the photoredox catalyst, [Ir(ppy)2(dtbbpy)]PF6, and chiral copper catalysts provide a
mild and highly effective sp3 C–H asymmetric arylation of THIQs.
Introduction
Functionalization of sp3 C–H bonds is a unique and powerful conception of new synthetic routes [3-12]. Upon exposure to
transformation in modern organic synthesis, which remains a visible light, photoredox catalysts can function as both reduc-
challenging process despite the advances that have been made tant and oxidant, thereby providing extremely important tools
in this field [1]. The directing group strategies are widely used for potential transition-metal-catalyzed enantioselective reac-
and developed to achieve enantioselective metal-catalyzed C–H tions of sp3 C–H bonds, which could be carried out at low tem-
bond functionalizations in recent years. Unactivated alkyl C–H perature and under mild reaction conditions [13,14]. We envi-
bond activation (i.e., without any directing group) is of great sioned that combining photoredox catalysis with typical cross-
interest in terms of atom economy, nevertheless enantioselectiv- coupling methods will allow us to design a visible-light-medi-
ity is difficult to control due to often-required harsh reaction ated photoredox asymmetric arylation of tetrahydroiso-
conditions. Therefore, the development of simple and facile quinolines (THIQs) [15-20].
processes to functionalize sp3 C–H bonds under mild condi-
tions in the absence of directing groups is of great interest [2]. During the last decade, numerous examples of sp3 C–H bond
arylation procedures have been developed [1,21-29]. In 2008,
The emerging and expanding field of visible-light-mediated our group developed the first direct sp3 C–H arylation of THIQ
photoredox catalysis presents unique opportunities for the with arylboronic acids using a copper catalyst (Scheme 1) [30].
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Beilstein J. Org. Chem. 2016, 12, 2636–2643.
Scheme 1: Design light-mediated arylation of THIQs.
Oxygen gas and tert-butyl hydroperoxide (TBHP) were used as mediated photoredox system might help, which indeed has im-
external oxidants, which gave moderate to good isolated yields proved the reaction yield and enantioselectivity. Different
(up to 75%). In addition, we demonstrated the first enantiose- iridium and ruthenium photoredox catalysts were evaluated and
lective arylation of THIQ using phenylboronic acid with 44% [Ir(ppy)2(dtbbpy)]PF6 was found to be the most efficient [32].
enantiomeric excess (ee), but very poor yield of the optically With this iridium photoredox catalyst, TBHP, and copper(I)
active products. Lowering the reaction temperature, in order to bromide co-catalyst in DME as solvent, we observed a trace
increase the corresponding ee, resulted in inhibition of the reac- amount of the desired product at room temperature. When dif-
tion.
ferent copper salts were evaluated, it was found that CuBr was
less active (Table 1, entry 1) and copper(II) bromide provided
More recently, Liu et al. have demonstrated the arylation of the highest yield for the arylation of THIQ with phenylboronic
THIQs with arylboronic esters via asymmetric organocatalysis acid (2, Table 1, entry 2). Other copper salts such as Cu(OTf)2
methodology [25,28]. The use of chiral tartaric acid derivatives, and Cu(OAc)2 were much less effective (Table 1, entries 3 and
2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and high 4). A significant increase of yield was observed when the stoi-
temperature (70 °C) were found to be the optimal conditions to chiometry of the system was changed to a slight excess of aryl-
obtain the desired arylated product with acceptable yield and boronic acid. When more than 1.6 equivalents of 2 were
good enantioselectivity. However, this methodology has shown involved in the reaction, a drastic acceleration of the reaction
limitations in terms of substrate scope: only phenylboronic was observed, leading to up to 85% yield (Table 1, entries 5 and
esters with electron-donating substituents yielded the corre- 6). During the investigation of solvent influence on the forma-
sponding products.
tion of 3a, it was found that polar solvents such as DCE gave
the best yields, compared to less polar solvents such as toluene
We herein report the first visible light-mediated asymmetric and THF (Table 1, entries 7 and 8). On the other hand, highly
cross-coupling arylation of sp3 C–H bonds adjacent to nitrogen, polar solvents such as MeCN and MeOH were not beneficial for
combining photoredox catalysis with metal-catalyzed transfor- the formation of the desired product 3a (Table 1, entries 9 and
mations.
10). Control experiments performed in the absence of
photoredox catalyst and/or transition metal copper(II) salt
(Table 1, entries 11–13) showed very poor reactivity. Moreover,
in the absence of light, an extremely poor yield was obtained
Results and Discussion
Optimisation of reaction conditions
In our previous work on arylation of N-aryltetrahydroisoquino- (Table 1, entry 14).
line [30], we demonstrated that lowering the temperature from
90 °C to room temperature in the reaction with copper(I) bro- General scope of reaction
mide caused a significant drop in yield. During optimisation of With the optimized reaction conditions in hand, the substrate
the reaction system, TBHP was found to be the best external scope was investigated (Figure 1). N-Phenyltetrahydroisoquino-
oxidant for this reaction over many others [31]. To accelerate line (1) combined with phenylboronic acid (2) gave rise to 85%
the reaction at lower temperature, we reasoned that a light- yield of the corresponding arylated product 3a. N-Phenyl-
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Beilstein J. Org. Chem. 2016, 12, 2636–2643.
Table 1: Optimization of reaction conditionsa.
Entry
Catalyst
Solvent
2 (equiv)
Yield of 3a (%)
1
CuBr
DCE
DCE
DCE
DCE
DCE
DCE
THF
1.6
1.6
1.6
1.6
2
19
29
2
2
CuBr2
Cu(OTf)2
Cu(OAc)2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
–
3
4
14
72
85
15
23
11
13
12
0
5
6
3
7
3
8
toluene
MeCN
MeOH
DCE
DCE
DCE
DCE
3
9
3
10
11b
12b
13b,c
14d
3
3
3
CuBr2
CuBr2
3
0
3
12
aReaction conditions: THIQs (0.10 mmol), arylboronic acid (0.30 mmol), TBHP (0.16 mmol), [Ir(ppy)2(dtbbpy)]PF6 (0.001 mmol), CuBr2 (0.02 mmol),
DCE (0.5 mL), under argon atmosphere. NMR yields are reported. bReaction carried out without Ir(III) photoredox catalyst. cReaction carried out with-
out TBHP. dReaction performed in absence of light. All reported yields were determined by 1H NMR spectroscopy using dibromomethane as an
internal standard.
substituted THIQs bearing electron-donating groups (EDG), conditions and all resulted in good yields. While aromatic
such a OMe and Me, were tolerated in our reaction system. We boronic acids substituted with electron-withdrawing groups
were surprised to see that strong electron-donating substituents (e.g., acyl, F or CF3) were likewise tolerated well (3g–j). Aro-
such as OMe gave lower yields (3b, 3c and 3d), which we attri- matic boronic acids substituted with electron-donating groups
bute to the lowered oxidation potentials of the tertiary amine, resulted in the formation of the corresponding arylated prod-
favouring side reactions. It is notable that weaker EDG substitu- ucts with higher yields (3k–n).
ents on the aryl moiety (e.g., Me) resulted in higher yields (3e).
Electron-withdrawing groups (EWG) such as Br were tolerated Enantioselective arylation reaction
and yielded the desired product in 80% yield (3f). Aromatic Subsequently, we explored the asymmetric version of this aryl-
boronic acids possessing both electron-withdrawing and elec- ation reaction with various chiral ligands (see Scheme 2 and
tron-donating substituents were evaluated under our reaction Supporting Information File 1, Table S3, for a detailed
Scheme 2: Evaluation of chiral ligands.
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Beilstein J. Org. Chem. 2016, 12, 2636–2643.
Figure 1: Reaction scope. Reaction conditions: THIQs (0.10 mmol), arylboronic acid (0.30 mmol), TBHP (0.2 mmol), [Ir(ppy)2(dtbbpy)]PF6
(0.001 mmol), CuBr2 (0.02 mmol), DCE (0.5 mL), under argon atmosphere.
screening table). Among them, Box-type ligands have demon- mono-arylated PyBox L2 gave very good er under our reaction
strated a good performance in this reaction, affording low to conditions (Table 2, entry 2). It is noteworthy that the er ob-
good enantioselectivities.
served was higher when copper(I) bromide was used as a
co–catalyst, compared to copper(II) bromide (Table 2, entry 3),
We began our study by evaluating the efficiency of the ligands possibly due to the Lewis acidity difference of Cu(I) and Cu(II).
using the standard arylation of THIQ with phenylboronic acid. However, the yield of the desired optically active product 3a
A modest enantiomeric ratio (er) of the C−H coupling reaction dropped by about half, when CuBr was used as catalyst. Alkyl-
was obtained using L1 ligand (Table 2, entry 1) at low tempera- substituted PyBox such as L3 was not beneficial to the enantio-
ture (4 °C). On the other hand, the commercially available selectivity (Table 2, entry 4). The efficacy of N,N-Box ligand
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Beilstein J. Org. Chem. 2016, 12, 2636–2643.
Table 2: Effect of chiral ligand on the enantioselectivity of coupling of N-phenyltetrahydroisoquinoline with phenylboronic acida.
Entry
L*
er
1
L1
L2
L2
L3
L4
69:31
82:18
68:32
54:46
54:46
2
3b
4
5
aReaction conditions: THIQs (0.10 mmol), arylboronic acid (0.30 mmol), TBHP (0.2 mmol), [Ir(ppy)2(dtbbpy)]PF6 (0.001 mmol), CuBr (0.01 mmol),
L* (0.012 mmol), DCE (0.5 mL), under argon atmosphere. bCuBr2 was used. All reported enantiomeric ratios were determined using a Chiralcel OD-H
column and 96:4 hexane/isopropanol as an eluent (Supporting Information File 1).
(L4) was investigated and it appeared that the pyridine motif other enantiomer of L2, (S,S)-PhPyBox, the reaction afforded
was extremely important to achieve high enantioselectivity good er. When N-(2-methhoxyphenyl)tetrahydroisoquinoline
(Table 2, entry 5).
was used, the corresponding enantiomer was obtained with sim-
ilar enantioselectivity (Table 3, entry 2). N-Aryl-substituted
To evaluate the scope of the enantiomeric selectivity of the aryl- THIQs gave high er, when either EDG or EWG were present
ation reaction, copper(I) bromide together with (R,R)-PhPyBox (Table 3, entries 3–6). High and moderate enantiomeric ratios
L2 at 4 °C was used as the standard conditions. We were were obtained, respectively, when vinyl-substituted arylboronic
pleased to see that our model reaction yielded 3a with good acids and fluoro-substituted arylboronic acids were subjected to
enantiomeric ratio (Table 3, entry 1). In the presence of the the reaction system (Table 3, entries 7 and 8).
Table 3: Enantioselective arylation reactiona.
Entry
Product
R1
R2
er
1
2b
3
4
5
6
7
8
3a
3b
3c
3d
3e
3f
H
H
19:81
84:16
10:90
15:85
24:76
19:81
19:81
37:63
2-OMe
3-OMe
4-OMe
4-Me
4-Br
H
H
H
H
H
H
3m
3j
4-vinyl
2,4-difluoro
H
aReaction conditions: THIQs (0.10 mmol), arylboronic acid (0.30 mmol), TBHP (0.2 mmol), [Ir(ppy)2(dtbbpy)]PF6 (0.001 mmol), CuBr (0.01 mmol),
(R,R)-2,6-Bis(4-phenyl-2-oxazolinyl)pyridine (0.012 mmol), DCE (0.5 mL), under argon atmosphere. b(S,S)-2,6-bis(4-phenyl-2-oxazolinyl)pyridine was
used instead. All reported yields enantiomeric ratios were determined using a Chiralcel OD-H column and 96:4 hexane/isopropanol as an eluent (Sup-
porting Information File 1).
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A tentative reaction mechanism has been proposed in Scheme 3, Biotage reaction vial was charged with [Ir(ppy)2(dtbbpy)]PF6
in order to rationalize this arylation reaction. Upon visible light (1 mol %, 1.0 mg), CuBr2 (10 mol %, 2.23 mg), N-phenyl-tetra-
irradiation, [Ir(ppy)2(dtbbpy)]PF6 I was converted into an hydroisoquinoline (0.1 mmol), and the corresponding phenyl-
excited state II, Ir(III)* [11,33-37]. The THIQ undergoes a boronic acid (0.3 mmol), evacuated and refilled with argon
single electron transfer (SET), reducing the iridium complex to three times. DCE (0.5 mL) was added, followed by subsequent
Ir(II) III and oxidizing the the nitrogen of THIQ IV to its slow addition of TBHP (0.16 mmol). The reaction vessel was
radical cation V, which then undergoes a hydride abstraction to sealed, placed under white light bulbs irradiation with vigorous
form the iminium salt form VI, of the THIQ. The pre-formed stirring (approx. 1000 rpm) and hold for 24 h. The mixture was
chiral PhCu–PyBox complex [38], coordinates to the iminium diluted with ethyl acetate (2 mL), washed with water (2 mL),
cation VI, followed by stereofacial nucleophilic addition of the filtered through a pad of silica, and rinsed with additional ethyl
arylboronic acid to produce the desired enantioenriched arylated acetate. The combined organic phase was concentrated and
product VII. The Ir(III) is regenerated in the presence of the purified by column chromatography or preparative thin-layer
sacrificial external oxidant TBHP.
chromatography on silica gel to yield the corresponding
arylated compound 3. Dibromomethane was used as internal
standard for 1H NMR analysis.
Conclusion
In conclusion, we have successfully developed a highly effi-
cient light-mediated coupling method for the direct asymmetric Variation for enantioselective sp3 C–H arylation of THIQs
arylation of N-arylated tetrahydroisoquinolines (THIQs) with with boronic acid derivatives (Table 3). A V-shaped 10 mL
arylboronic acids. Using [Ir(ppy)2(dtbbpy)]PF6 as photoredox Biotage reaction vial was charged with CuBr (10 mol %,
catalyst provided a novel facile method to build important 1.43 mg) and PhPybox (12 mol %, 4.43 mg), evacuated and
arylated compounds in very high yields under very mild condi- refilled with argon three times, and then 0.1 mL of DCE was
tions. The combination of copper salts and PhPyBox as chiral added. The reaction was stirred for 30 min. N-Phenyltetrahy-
ligand have demonstrated its efficiency producing good enan- droisoquinoline (0.1 mmol), [Ir(ppy)2(dtbbpy)]PF6 (1 mol %,
tioselectivity and tolerated a fairly diverse substrate scope. We 1.0 mg) and the corresponding phenylboronic acid (0.3 mmol)
envisioned that this visible light-mediated asymmetric arylation were added, and then the atmosphere was evacuated and refilled
reaction could be extended to other sp3 C–H bonds. The devel- with argon three times. DCE (0.4 mL) was added followed by
opment of new light-mediated processes for stereoselective subsequent slow addition of TBHP (0.16 mmol). The reaction
functionalization of unactivated C−H bonds is currently under- vessel was sealed, placed under white light bulbs irradiation
going in our laboratory.
with vigorous stirring (approx. 1000 rpm) and held for 48 h in a
cold room (4 °C). The mixture was diluted with ethyl acetate
(2 mL), washed with water (2 mL), filtered through a pad of
Experimental
General procedure for the sp3 C–H arylation of THIQs with silica, and rinsed with additional ethyl acetate. The combined
boronic acid derivatives (Figure 1). A V-shaped 10 mL organic phase was concentrated and purified by column chro-
Scheme 3: Proposed reaction mechanism.
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19.Amador, A. G.; Sherbrook, E. M.; Yoon, T. P. J. Am. Chem. Soc. 2016,
138, 4722–4725. doi:10.1021/jacs.6b01728
matography or preparative thin-layer chromatography on silica
gel to yield the corresponding arylated compound 3. Dibro-
momethane was used as internal standard for 1H NMR analysis.
20.Maturi, M. M.; Bach, T. Angew. Chem., Int. Ed. 2014, 53, 7661–7664.
doi:10.1002/anie.201403885
21.Barham, J. P.; John, M. P.; Murphy, J. A. Beilstein J. Org. Chem. 2014,
10, 2981–2988. doi:10.3762/bjoc.10.316
Supporting Information
22.Cuthbertson, J. D.; MacMillan, D. W. C. Nature 2015, 519, 74–77.
doi:10.1038/nature14255
Supporting Information File 1
Experimental and copies of spectra.
23.Muramatsu, W.; Nakano, K.; Li, C.-J. Org. Biomol. Chem. 2014, 12,
2189–2192. doi:10.1039/c3ob42354a
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-12-260-S1.pdf]
24.Dhineshkumar, J.; Lamani, M.; Alagiri, K.; Prabhu, K. R. Org. Lett.
2013, 15, 1092–1095. doi:10.1021/ol4001153
25.Liu, X.; Sun, S.; Meng, Z.; Lou, H.; Liu, L. Org. Lett. 2015, 17,
2396–2399. doi:10.1021/acs.orglett.5b00909
26.Li, Z.; Bohle, D. S.; Li, C.-J. Proc. Natl. Acad. Sci. U. S. A. 2006, 103,
8928–8933. doi:10.1073/pnas.0601687103
Acknowledgements
We are grateful to the Canada Research Chair (Tier 1) founda-
tion (to C.-J. Li), NSERC, CFI, and FQRNT (CCVC) for their
support of our research.
27.Yan, C.; Li, L.; Liu, Y.; Wang, Q. Org. Lett. 2016, 18, 4686–4689.
doi:10.1021/acs.orglett.6b02326
28.Liu, X.; Meng, Z.; Li, C.; Lou, H.; Liu, L. Angew. Chem., Int. Ed. 2015,
54, 6012–6015. doi:10.1002/anie.201500703
29.Bergonzini, G.; Schindler, C. S.; Wallentin, C.-J.; Jacobsen, E. N.;
Stephenson, C. R. J. Chem. Sci. 2014, 5, 112–116.
doi:10.1039/C3SC52265B
References
1. He, J.; Li, S.; Deng, Y.; Fu, H.; Laforteza, B. N.; Spangler, J. E.;
Homs, A.; Yu, J.-Q. Science 2014, 343, 1216–1220.
doi:10.1126/science.1249198
30.Baslé, O.; Li, C.-J. Org. Lett. 2008, 10, 3661–3663.
doi:10.1021/ol8012588
2. Li, C.-J. From C-H to C-C Bonds: Cross-Dehydrogenative-Coupling;
RSC Green Chemistry, 2015.
31.For more information, see Supporting Information File 1, Table S1.
32.For more information, see Supporting Information File 1, Table S2.
33.Condie, A. G.; González-Gómez, J. C.; Stephenson, C. R. J.
J. Am. Chem. Soc. 2010, 132, 1464–1465. doi:10.1021/ja909145y
34.Rueping, M.; Koenigs, R. M.; Poscharny, K.; Fabry, D. C.; Leonori, D.;
Vila, C. Chem. – Eur. J. 2012, 18, 5170–5174.
3. Prier, C. K.; Rankic, D. A.; MacMillan, D. W. C. Chem. Rev. 2013, 113,
5322–5363. doi:10.1021/cr300503r
4. Cismesia, M. A.; Yoon, T. P. Chem. Sci. 2015, 6, 5426–5434.
doi:10.1039/C5SC02185E
5. Nicewicz, D. A.; MacMillan, D. W. C. Science 2008, 322, 77–80.
doi:10.1126/science.1161976
doi:10.1002/chem.201200050
35.Boess, E.; Schmitz, C.; Klussmann, M. J. Am. Chem. Soc. 2012, 134,
5317–5325. doi:10.1021/ja211697s
6. Nagib, D. A.; Scott, M. E.; MacMillan, D. W. C. J. Am. Chem. Soc.
2009, 131, 10875–10877. doi:10.1021/ja9053338
7. Narayanam, J. M. R.; Stephenson, C. R. J. Chem. Soc. Rev. 2011, 40,
102–113. doi:10.1039/B913880N
36.Lowry, M. S.; Goldsmith, J. I.; Slinker, J. D.; Rohl, R.; Pascal, R. A., Jr.;
Malliaras, G. G.; Bernhard, S. Chem. Mater. 2005, 17, 5712–5719.
doi:10.1021/cm051312+
8. Kalyani, D.; McMurtrey, K. B.; Neufeldt, S. R.; Sanford, M. S.
J. Am. Chem. Soc. 2011, 133, 18566–18569. doi:10.1021/ja208068w
9. Ischay, M. A.; Anzovino, M. E.; Du, J.; Yoon, T. P. J. Am. Chem. Soc.
2008, 130, 12886–12887. doi:10.1021/ja805387f
10.Yoon, T. P.; Ischay, M. A.; Du, J. Nat. Chem. 2010, 2, 527–532.
doi:10.1038/nchem.687
37.Ladouceur, S.; Fortin, D.; Zysman-Colman, E. Inorg. Chem. 2011, 50,
11514–11526. doi:10.1021/ic2014013
38.Panera, M.; Díez, J.; Merino, I.; Rubio, E.; Gamasa, M. P. Inorg. Chem.
2009, 48, 11147–11160. doi:10.1021/ic901527x
11.Du, J.; Skubi, K. L.; Schultz, D. M.; Yoon, T. P. Science 2014, 344,
392–396. doi:10.1126/science.1251511
12.Beatty, J. W.; Stephenson, C. R. J. Acc. Chem. Res. 2015, 48,
1474–1484. doi:10.1021/acs.accounts.5b00068
13.Perepichka, I.; Kundu, S.; Hearne, Z.; Li, C.-J. Org. Biomol. Chem.
2015, 13, 447–451. doi:10.1039/C4OB02138J
14.Buschmann, H.; Scharf, H.-D.; Hoffmann, N.; Esser, P.
Angew. Chem., Int. Ed. 1991, 30, 477–515.
doi:10.1002/anie.199104771
15.Meggers, E. Chem. Commun. 2015, 51, 3290–3301.
doi:10.1039/C4CC09268F
16.Wang, C.; Harms, K.; Meggers, E. Angew. Chem., Int. Ed. 2016, 55,
13495–13498. doi:10.1002/anie.201607305
17.Murphy, J. J.; Bastida, D.; Paria, S.; Fagnoni, M.; Melchiorre, P. Nature
2016, 532, 218–222. doi:10.1038/nature17438
18.Kizu, T.; Uraguchi, D.; Ooi, T. J. Org. Chem. 2016, 81, 6953–6958.
doi:10.1021/acs.joc.6b00445
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Beilstein J. Org. Chem. 2016, 12, 2636–2643.
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