Palladium-Catalyzed Synthesis of 2,3-Diaryl- N-methylindoles from ortho-Alkynylanilines and Aryl Pinacol Boronic Esters

Article abstract of DOI:10.1021/acs.orglett.8b02835

A palladium-catalyzed synthesis of 2,3-diaryl-N-methylindoles from o-alkynylanilines and aryl pinacol boronic esters was developed. The system possesses high functional group tolerance and a broad substrate scope with a variety of aryl pinacol boronic est

Full text of DOI:10.1021/acs.orglett.8b02835

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Palladium-Catalyzed Synthesis of 2,3-Diaryl‑N‑methylindoles from
ortho-Alkynylanilines and Aryl Pinacol Boronic Esters
Yue-Gui Luo,† R. Sidick Basha,† Daggula Mallikarjuna Reddy,† Yong-Jing Xue,† Te-Hsuan Chen,†
and Chin-Fa Lee*,†,‡,§
†Department of Chemistry, National Chung Hsing University, Taichung, Taiwan 402, R.O.C.
‡Research Center for Sustainable Energy and Nanotechnology (RCSEN), National Chung Hsing University, Taichung, Taiwan 402,
R.O.C.
§Innovation and Development Center of Sustainable Agriculture (IDCSA), National Chung Hsing University, Taichung, Taiwan
402, R.O.C.
S
* Supporting Information
ABSTRACT: A palladium-catalyzed synthesis of 2,3-diaryl-N-
methylindoles from o-alkynylanilines and aryl pinacol boronic
esters was developed. The system possesses high functional
group tolerance and a broad substrate scope with a variety of
aryl pinacol boronic esters to provide valuable 2,3-diaryl-N-
methylindoles in moderate to good yields. Remarkably, the
sequential reaction controlled by iridium-catalyzed C−H
borylation or palladium-catalyzed alkynylation followed by the present palladium-catalyzed C3 arylation reaction provided
functionalized 2,3-diaryl-N-methylindoles in good yields.
ransition-metal-catalyzed reactions have a significant
impact in organic synthesis due to their peculiar synthetic
T
transformations that obtain new chemical compounds.1
Nitrogen-containing heterocycles are a privileged core unit
present in immense bioactive scaffolds. In particular, aryl-fused
N-heterocycles are well suited to acting as structurally enriched
drug discovery entities.2 In particular, indole skeletons have
been found to be a ubiquitous prototypical pattern with
widespread applications in natural products,3 drug discovery,4
and pharmaceuticals.5 Unique prevalent molecules containing
the indole motif are currently under clinical study5 and have
motivated an ongoing and increasingly intense research effort
to overcome the remaining synthetic challenges for obtaining
indole patterns. Over the past decades, several classes of
pioneering methods have been reported for the synthesis of
indole patterns.6,1a,c In particular, substituted indoles have
attracted considerable attention due to their outstanding
biosignificant applications. For example, a U.S.-approved
indomethacin drug exhibits anti-inflammatory properties.7a
Arbidol was demonstrated to be an effective antiviral agent.7b
Fluvastatin is used to lower the level of LDL cholesterol.7c,5a
Bazedoxifene is a selective estrogen receptor modulator,7d and
pravadoline is a potent analgesic agent7e (Figure 1).
Figure 1. Representative bioactive molecules containing substituted
indoles.
methylindoles (Scheme 1b).9b Despite the development of
these methods, arylation on intramolecular amination of o-
alkynylanilines is in great demand and remains a challenging
step in the synthesis of the highly valuable densely substituted
indoles.
Meanwhile, organoboron compounds are well-known as a
key component in various chemical transformations10−12 due
to their stability, ease of handling, and ready availability of the
starting precursors.10b,c Their utilization in a broad range of
chemical entities has contributed widely to valuable chemical
syntheses.11 Boron-arylating compounds are highly prominent
in various synthetic methodologies. In particular, aryl boronic
Palladium catalysts have played a vital role in intramolecular
cyclization of o-alkynylanilines for the synthesis of substituted
indoles.8a−g,6a Alkynyl or aryl halides were reacted with o-
alkynyanilines to synthesize 3-substituted indoles.8h,i Zhu’s
research group has demonstrated the synthesis of 3-alkynyl-N-
methylindoles via the reaction between o-alkynylanilines and
alkynes (Scheme 1a).9a Wu’s group has reported a strategy of
using isocyanides by the amidylation of indoles to 3-amidyl-N-
Received: September 19, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02835
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Initial studies were performed between 1a and 2a to
Scheme 1. Different Approaches for the Synthesis of
Substituted Indoles
determine the optimal reaction conditions (Table 1). In the
t
presence of 5 mol % Pd(OAc)2 in BuOH, a trace amount of
product 3a was detected (Table 1, entry 1). Whereas for the
reactions executed in EtOH, IPA, and iAmOH, product 3a was
afforded in 39%, 30%, and 35% yields, respectively (Table 1,
entries 2−4). By raising the temperature to 74 °C in ethanol,
3a was obtained in 43% yield (Table 1, entry 5). Lower yields
i
were observed when the reactions were performed in AmOH
and nBuOH (Table 1, entries 6 and 7). When the reaction was
carried out using silver acetate as the oxidant, 3a was obtained
in 48% yield (Table 1, entry 8). By switching the oxidant to
Cu(OAc)2·H2O, the product yield was increased to 53%
(Table 1, entry 9). No product was observed when K2S2O8 was
used as the oxidant (Table 1, entry 10). When the reactions
were carried out in the presence of peroxide oxidants, the
product was formed in lower yields (Table 1, entries 11 and
12). Further reaction with hydrate-free copper acetate afforded
a 51% yield (Table 1, entry 13). The reaction was completely
ineffective in the absence of a catalyst (Table 1, entry 14). The
reaction was also screened with a variety of palladium sources
such as PdCl2, Pd(TFA)2, and Pd(PPh3)4, and the desired
product 3a was obtained in 18−45% yields (Table 1, entries
15−17). By decreasing or increasing the amount of Pd(OAc)2,
the product 3a was furnished in 29% and 50% yields,
respectively (Table 1, entries 18 and 19). In the presence of
5 mol % Pd(OAc)2, a reaction time of up to 18 h in ethanol
attained a 45% yield, whereas decreasing the reaction time to
12 h significantly increased the yield to 60% (Table 1, entries
esters have been effectively utilized in diverse coupling
reactions.12,10a,c We reasoned that aryl boronic esters may be
suitable for carrying out the peculiar intermolecular coupling
on intramolecular amination of alkynes. Herein we report a
direct synthesis of densely substituted 2,3-diaryl-N-methyl-
indoles by employing N,N-dimethyl-o-alkynylanilines with aryl
pinacol boronic esters via a Pd-catalyzed intramolecular
amination followed by intermolecular C3 arylation (Scheme
1c).
a
Table 1. Optimization of Reaction Conditions
b
c
entry
catalyst
oxidant
Ag2CO3
solvent
time (h)
temp (°C)
yield (%)
1
5 mol % Pd(OAc)2
5 mol % Pd(OAc)2
5 mol % Pd(OAc)2
5 mol % Pd(OAc)2
5 mol % Pd(OAc)2
5 mol % Pd(OAc)2
5 mol % Pd(OAc)2
5 mol % Pd(OAc)2
5 mol % Pd(OAc)2
5 mol % Pd(OAc)2
5 mol % Pd(OAc)2
5 mol % Pd(OAc)2
5 mol % Pd(OAc)2
−
tBuOH
EtOH
IPA
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
18
12
6
73
70
70
74
74
90
94
74
74
74
74
74
74
74
74
74
74
74
74
74
74
74
trace
39
30
2
3
4
Ag2CO3
Ag2CO3
Ag2CO3
iAmOH
EtOH
iAmOH
nBuOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
35
5
6
Ag2CO3
Ag2CO3
43
<10
<10
48
7
Ag2CO3
8
9
AgOAc
Cu(OAc)2·H2O
K2S2O8
DTBP
TBHP
53
10
11
12
13
14
15
16
17
18
19
20
21
22
N.D.
<10
<10
51
N.D.
18
39
45
29
50
Cu(OAc)2
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
5 mol % PdCl2
5 mol % Pd(TFA)2
5 mol % Pd(PPh3)4
2 mol % Pd(OAc)2
10 mol % Pd(OAc)2
5 mol % Pd(OAc)2
5 mol % Pd(OAc)2
5 mol % Pd(OAc)2
45
60
44
a
b
c
Reactions were performed in 0.2 mmol scale. Internal temperature. Isolated yields. N.D. = not detected.
B
DOI: 10.1021/acs.orglett.8b02835
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
20 and 21). By further decreasing the reaction time, the yield
of the product was decreased (Table 1, entry 22). From these
optimization studies, we finally determined that the optimal
reaction conditions are 5 mol % Pd(OAc)2 with Cu(OAc)2·
H2O in ethanol at 74 °C.
With the optimized reaction conditions in hand, the scope of
the reaction with various of N,N-dimethyl-o-alkynylanilines
and aryl pinacol boronic esters was investigated (Scheme 2).
the resultant product 3o in 60% yield. The structure of 3o was
unambiguously confirmed by single crystal X-ray analysis. The
dissimilar disubstituent electronic nature of 2k was also
investigated. It was found that the reaction proceeded well
and the desired product 3p was obtained in 61% yield. It is to
be noted that while on reaction with heteroaromatic boronic
esters such as 2-(2,5-dimethylfuran-3-yl)-4,4,5,5-tetramethyl-
1,3,2-dioxaborolane and 3-(4,4,5,5-tetramethyl-1,3,2-dioxabor-
olan-2-yl)pyridine with 1a, the reactions failed to afford the
desired products.
Scheme 2. Substrate Scope of o-Alkynylanilines and Aryl
a
We have inspected a sequential iridium-catalyzed C−H
borylation13 followed by the present synthetic strategy
(Scheme 3). The initial reaction was performed with
Boronic Esters
Scheme 3. Iridium-Catalyzed C−H Borylation Followed by
a
C3 Arylation Reactions
a
b
Reactions were performed on 0.2 mmol scale. Isolated yields.
dichloroarene 4a by a sequential process, affording the product
5a in 73% yield. Encouraged by this result, we have examined
disubstituted arene 4b by employing the identical sequential
method, and the product 5b was furnished in 40% yield.
Further reaction with ditrifluoromethyl or dimethyl arenes
afforded the arylation products 5c and 3l in 55% and 43%
yields, respectively.
Inspired by the above sequential process, we further
examined a sequential Sonogashira reaction8f followed by the
present synthetic protocol (Scheme 4). The initial Csp2−Csp
Scheme 4. Sequential Coupling Reaction
a
All the reactions were conducted in 0.2 mmol scale in ethanol.
b
c
Isolated yields. 1 mmol scale.
We examined the reaction with different N,N-dimethyl-o-
alkynylanilines (1a−d) under the standard reaction conditions,
and the desired products 3a−3d were isolated in 43−60%
yields. Furthermore, we conducted the reactions with different
para-substituted aryl pinacol boronic esters (2b−g). In all
cases, the reactions proceeded smoothly, showing compati-
bility with methyl (3e), halides (3f and 3g), methoxy (3h),
trifluoromethyl (3i), and ester (3j). 3-Methylphenyl, 3,5- or
3,4-dimethylphenyl boronic esters (2h−j) reacted well with 1a
in ethanol and furnished the products 3k−3m in moderate
yields. Boronic ester containing ester functional group 2g
undergoing reaction with 1c afforded the corresponding
product 3n in 71% yield. A similar reaction with 1b delivered
coupling reaction was performed between 6 and 7 in the
conditions for the Sonogashira reaction and was followed by
the reaction with 1a and 2g in the presence of 5 mol %
Pd(OAc)2 with Cu(OAc)2·H2O, affording the product 3j in
47% yield. A competition experiment was carried out between
o-alkynylaniline (1c and 1d) with 2a to determine the steric
properties of aminoalkynes (Scheme 5a). The sterically
congested ortho methyl group of 1c led to the lower amount
of the C3 arylation product. On the other hand, a boronic ester
competition experiment was undertaken between 1a with 2a
and 2c to determine the electronic impact of the boronic ester.
It was found that the boronic ester containing an electron-
C
DOI: 10.1021/acs.orglett.8b02835
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Based on the above results, we postulated a plausible
mechanism as follows (Scheme 7). First, Pd(OAc)2 reacts with
Scheme 5. Competition Experiments
Scheme 7. Possible Mechanism for the Palladium-Catalyzed
Arylation Reaction
o-alkynylaniline 1, which leads to aminopalladation inter-
mediate I. The aryl pinacol boronic ester 2 interacts with I to
form an intermediate σ-aryl-σ-indolylpalladium II along with
the concurrent removal of BpinOAc. The intermediate II
further undergoes a reductive elimination to afford the desired
C3 arylation product 3, and Pd(0) was oxidized to Pd(II) by
Cu(II) to furnish the catalytic cycle.
In conclusion, an efficient method for the synthesis of
densely substituted 2,3-diaryl-N-methylindoles was achieved
by using o-alkynylanilines with aryl pinacol boronic esters via
palladium-catalyzed arylation on intramolecular amination of
o-alkynylanilines. The present protocol is compatible with
various aryl pinacol boronic esters under mild reaction
conditions. A sequential iridium-catalyzed C−H borylation
or Sonogashira reaction followed by the present method was
used to obtain functionalized 2,3-diaryl-N-methylindoles. The
reaction is simple to carry out in practice and has high
functional group tolerance, and the mechanistic studies implied
that the reaction proceeds through an aminopalladation
intermediate.
withdrawing group is more favorable for C3 arylation than
phenyl boronic ester (Scheme 5b).
Control experiments were also carried out to gain insight
into this reaction mechanism. A preliminary reaction without
an oxidant was carried out, and only a trace amount of product
3a was detected. This result indicated that Cu(OAc)2·H2O is
essential for this transformation in this system (Scheme 6a).
Scheme 6. Control Experiments and Mechanistic Studies
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b02835.
Experimental procedures, spectroscopic data, copies of
NMR and crystallographic data (PDF)
Accession Codes
CCDC 1858837 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
The reaction performed under an open air atmosphere
afforded the product with a lower yield which revealed that
an inert nitrogen atmosphere is necessary to upturn the yield of
the product (Scheme 6b). Intermediate Ia was prepared
according to the literature,9 and the reaction was implemented
with aryl boronic ester 2a in the presence of Cu(OAc)2·H2O in
ethanol. The desired products 3d and 3a were obtained, which
evidenced that the reaction mechanism proceeds through an
intermediate I (Scheme 6c).
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: cfalee@dragon.nchu.edu.tw.
ORCID
Chin-Fa Lee: 0000-0003-0735-5691
D
DOI: 10.1021/acs.orglett.8b02835
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(9) (a) Yao, B.; Wang, Q.; Zhu, J. Angew. Chem., Int. Ed. 2012, 51,
12311−12315. (b) Qiu, G.; Chen, C.; Yao, L.; Wu, J. Adv. Synth.
Catal. 2013, 355, 1579−1584.
Notes
The authors declare no competing financial interest.
(10) (a) Fyfe, J. W. B.; Watson, A. J. B. Chem. 2017, 3, 31−55.
(b) Hall, D. G. Boronic Acids: Preparation and Applications in Organic
Synthesis and Medicine; Wiley-VCH: Weinheim, 2005. (c) Lennox, A.
J. J.; Lloyd-Jones, G. C. Chem. Soc. Rev. 2014, 43, 412−443.
(11) (a) Bootwicha, T.; Feilner, J. M.; Myers, E. L.; Aggarwal, V. K.
Nat. Chem. 2017, 9, 896−902. (b) Varela, A.; Garve, L. K. B.;
Leonori, D.; Aggarwal, V. K. Angew. Chem., Int. Ed. 2017, 56, 2127−
2131. (c) Carboni, B. Angew. Chem., Int. Ed. 2015, 54, 15010−15011.
(d) Burns, M.; Essafi, S.; Bame, J. R.; Bull, S. P.; Webster, M. P.;
Balieu, S.; Dale, J. W.; Butts, C. P.; Harvey, J. N.; Aggarwal, V. K.
Nature 2014, 513, 183−188.
ACKNOWLEDGMENTS
■
This work was financially supported by the Ministry of Science
and Technology, Taiwan (MOST 107-2113-M-005-019-
MY3); National Chung Hsing University; Research Center
for Sustainable Energy and Nanotechnology; and the
“Innovation and Development Center of Sustainable Agricul-
ture” from The Featured Areas Research Center Program
within the framework of the Higher Education Sprout Project
by the Ministry of Education (MOE) in Taiwan.
(12) (a) Xia, Y.; Wang, J.; Dong, G. J. Am. Chem. Soc. 2018, 140,
5347−5351. (b) Reddy, D. M.; Wang, S.-C.; Du, K.; Lee, C.-F. J. Org.
Chem. 2017, 82, 10070−10076. (c) Moon, P. J.; Yin, S.; Lundgren, R.
J. J. Am. Chem. Soc. 2016, 138, 13826−13829. (d) Wan, L.;
Dastbaravardeh, N.; Li, G.; Yu, J.-Q. J. Am. Chem. Soc. 2013, 135,
18056−18059.
(13) (a) Cheng, J.-H.; Yi, C.-L.; Liu, T.-J.; Lee, C.-F. Chem.
Commun. 2012, 48, 8440−8442. (b) Ishiyama, T.; Takagi, J.; Ishida,
K.; Miyaura, N.; Anastasi, N. R.; Hartwig, J. F. J. Am. Chem. Soc. 2002,
124, 390−391. (c) Cho, J. Y.; Tse, M. K.; Holmes, D.; Maleczka, R.
E.; Smith, M. R. Science 2002, 295, 305−308. (d) Litvinas, N. D.; Fier,
P. S.; Hartwig, J. F. Angew. Chem., Int. Ed. 2012, 51, 536−539.
REFERENCES
■
(1) (a) Zeni, G.; Larock, R. C. Chem. Rev. 2004, 104, 2285−2310.
(b) Li, X.; Chianese, A. R.; Vogel, T.; Crabtree, R. H. Org. Lett. 2005,
7, 5437−5440. (c) Zeni, G.; Larock, R. C. Chem. Rev. 2006, 106,
4644−4680. (d) Trost, B. M.; McClory, A. Angew. Chem., Int. Ed.
2007, 46, 2074−2077. (e) Patil, N. T.; Yamamoto, Y. Chem. Rev.
2008, 108, 3395−3442. (f) Cacchi, S.; Fabrizi, G.; Goggiamani, A.
Org. Biomol. Chem. 2011, 9, 641−652. (g) Clarke, A. K.; Lynam, J.
M.; Taylor, R. J. K.; Unsworth, W. P. ACS Catal. 2018, 8, 6844−6850.
(2) Taylor, R. D.; MacCoss, M.; Lawson, A. D. G. J. Med. Chem.
2014, 57, 5845−5859.
(3) (a) Homer, J. A.; Sperry, J. J. Nat. Prod. 2017, 80, 2178−2187.
(b) Ishikura, M.; Abe, T.; Choshi, T.; Hibino, S. Nat. Prod. Rep. 2015,
32, 1389−1471; Nat. Prod. Rep. 2013, 30, 694−752. (c) Kochanow-
ska-Karamyan, A. J.; Hamann, M. T. Chem. Rev. 2010, 110, 4489−
4497. (d) Kawasaki, T.; Higuchi, K. Nat. Prod. Rep. 2005, 22, 761−
793.
́
(4) de Sa Alves, F. R.; Barreiro, E. J.; Fraga, C. A. M. Mini-Rev. Med.
Chem. 2009, 9, 782−793.
(5) (a) Chadha, N.; Silakari, O. Eur. J. Med. Chem. 2017, 134, 159−
184. (b) Kaushik, N. K.; Kaushik, N.; Attri, P.; Kumar, N.; Kim, C.
H.; Verma, A. K.; Choi, E. H. Molecules 2013, 18, 6620−6662.
(c) Zhang, M.-Z.; Chen, Q.; Yang, G.-F. Eur. J. Med. Chem. 2015, 89,
421−441.
(6) (a) Cacchi, S.; Fabrizi, G. Chem. Rev. 2011, 111, PR215−PR283
and references therein . (b) Platon, M.; Amardeil, R.; Djakovitch, L.;
Hierso, J.-C. Chem. Soc. Rev. 2012, 41, 3929−3968. (c) Inman, M.;
Moody, C. J. Chem. Sci. 2013, 4, 29−41. (d) Wu, X. F.; Neumann, H.;
Beller, M. Chem. Rev. 2013, 113, 1−35. (e) Ilies, L.; Isomura, M.;
Yamauchi, S-i.; Nakamura, T.; Nakamura, E. J. Am. Chem. Soc. 2017,
139, 23−26. (f) Watanabe, T.; Mutoh, Y.; Saito, S. J. Am. Chem. Soc.
2017, 139, 7749−7752. (g) Heckman, L. M.; He, Z.; Jamison, T. F.
Org. Lett. 2018, 20, 3263−3267.
(7) (a) Hart, F. D.; Boardman, P. Br. Med. J. 1963, 2, 965−970.
́
(b) Boriskin, Y. S.; Leneva, I. A.; Pecheur, E.-I.; Polyak, S. J. Curr.
Med. Chem. 2008, 15, 997−1005. (c) Fuenfschilling, P. C.; Hoehn, P.;
Mutz, J.-P. Org. Process Res. Dev. 2007, 11, 13−18. (d) Komm, B. S.;
Kharode, Y. P.; Bodine, P. V. N.; Harris, H. A.; Miller, C. P.; Lyttle, C.
R. Endocrinology 2005, 146, 3999−4008. (e) Haubrich, D. R.; Ward,
S. J.; Baizman, E.; Bell, M. R.; Bradford, J.; Ferrari, R.; Miller, M.;
Perrone, M.; Pierson, A. K.; Saelens, J. K. J. Pharmacol. Exp. Ther.
1990, 255, 511−522.
(8) (a) Yuan, K.; Liu, L.; Chen, J.; Guo, S.; Yao, H.; Lin, A. Org. Lett.
2018, 20, 3477−3481. (b) Hu, Z.; Liang, D.; Zhao, J.; Huang, J.; Zhu,
Q. Chem. Commun. 2012, 48, 7371−7373. (c) Yao, B.; Wang, Q.;
Zhu, J. Angew. Chem., Int. Ed. 2012, 51, 5170−5174. (d) Xia, X.-F.;
Wang, N.; Zhang, L.-L.; Song, X.-R.; Liu, X.-Y.; Liang, Y.-M. J. Org.
Chem. 2012, 77, 9163−9170. (e) Vicente, R. Org. Biomol. Chem.
2011, 9, 6469−6480. (f) Yue, D.; Yao, T.; Larock, R. C. J. Org. Chem.
2006, 71, 62−69. (g) Battistuzzi, G.; Cacchi, S.; Fabrizi, G. Eur. J. Org.
Chem. 2002, 2002, 2671−2681. (h) Arcadi, A.; Cacchi, S.; Fabrizi, G.;
Marinelli, F.; Parisi, L. M. J. Org. Chem. 2005, 70, 6213−6217.
(i) Yamauchi, T.; Shibahara, F.; Murai, T. Tetrahedron Lett. 2016, 57,
2945−2948.
E
DOI: 10.1021/acs.orglett.8b02835
Org. Lett. XXXX, XXX, XXX−XXX