Copper-catalyzed synthesis of N-aryl and N-sulfonyl indoles from 2-vinylanilines with O2 as terminal oxidant and TEMPO as cocatalyst

Article abstract of DOI:10.1055/s-0034-1379015

A copper-catalyzed intramolecular alkene oxidative amination that utilizes TEMPO as cocatalyst and O₂ as the terminal oxidant has been developed. The method furnishes N-aryl and N-sulfonyl indoles from N-aryl and N-sulfonyl 2-vinylanilines, res

Full text of DOI:10.1055/s-0034-1379015

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© Georg Thieme Verlag Stuttgart · New York
2015, 26, 335–339
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T. W. Liwosz, S. R. Chemler
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Copper-Catalyzed Synthesis of N-Aryl and N-Sulfonyl Indoles from
2-Vinylanilines with O2 as Terminal Oxidant and TEMPO as Cocata-
lyst
Copper-Catalyzed Indole Synthesis
Timothy W. Liwosz
R1
R1
cat. [Cu]
ArB(OH)2, air
r.t., 24 h
cat. [Cu]
cat. TEMPO
O2 (1 atm)
Sherry R. Chemler*
R2
R2
Department of Chemistry, The State University of
New York at Buffalo, Buffalo, NY, 14620, USA
schemler@buffalo.edu
toluene
120 °C, 24 h
then TEMPO, O2
120 °C, 24 h
+
1
7
(
1
6
6
)
4
5
6
9
6
3
NH
R3
N
R3
NH2
R1 = H, Me, Ph, R2 = H, Me, R3 = Ar, SO2R
R1 = Me, R2 = H, R3 = Ar
Received: 30.06.2014
Accepted after revision: 01.08.2014
Published online: 25.08.2014
ety of 2,3-unsubstituted indoles from N-acetyl- and N-car-
bamoyl-2-vinylanilines using hypervalent iodine reagents
has also appeared.5b
DOI: 10.1055/s-0034-1379015; Art ID: st-2014-r0552-c
Synthetic methods for indole synthesis based on com-
paratively less expensive copper catalysts have also
emerged.6 We recently reported a copper-catalyzed alkene
C–H amination whose scope includes the synthesis of N-
sulfonyl and N-phenyl indoles.6a The reported method uti-
lized a Cu(OTf)2·bis(oxazoline) complex as catalyst and 300
mol% MnO2 as terminal oxidant (Scheme 1).6a In an effort to
reduce reliance on the stoichiometric metal oxidant, we
pursued development of a procedure based on terminal
aerobic oxidation. The ability of O2 to oxidize copper(I) to
copper(II) is dependant on the solvent and copper coordi-
nation sphere.7a Under the reaction conditions generally ef-
fective for copper-catalyzed alkene amination, and with the
copper complexes most effective for this purpose
[Cu(OTf)2·bis(oxazoline) and Cu(2-ethylhexanoate)2], aero-
bic oxidation is minimally effective (e.g., Table 1, entry 1).
We were aware, however, that when 2,2,6,6-tetramethyl-1-
piperidinyloxy (TEMPO) is used as a cocatalyst in conjunc-
tion with an O2 atmosphere, turnover can be achieved in a
variety of transition-metal-catalyzed reactions.7
Abstract A copper-catalyzed intramolecular alkene oxidative amina-
tion that utilizes TEMPO as cocatalyst and O2 as the terminal oxidant
has been developed. The method furnishes N-aryl and N-sulfonyl in-
doles from N-aryl and N-sulfonyl 2-vinylanilines, respectively. Addition-
ally, sequential copper-catalyzed reactions where initial Chan–Lam cou-
pling of 2-vinylanilines with arylboronic acids is followed by oxidative
amination of the alkene can generate N-aryl indoles in one pot.
Key words copper, oxidation, indoles, oxygen, TEMPO
Methods for the synthesis of indoles have been studied
extensively due to their prevalence in natural products and
bioactive compounds.1 While classical reactions such as the
Fischer indole synthesis and the Bartoli indole synthesis
feature prominently in synthetic routes,2 palladium-cata-
lyzed intermolecular coupling methods such as Larock’s in-
dole synthesis using alkynes as well as intramolecular
methods such as Heck reactions of 2-halo-N-allylanilines
have gained considerable usage in modern indole synthe-
sis.1–3 Conversely, palladium-catalyzed routes involving in-
tramolecular oxidative cyclizations of 2-vinylanilines have
been used comparatively less, presumably because they
have not been as general or efficient.4 Along these lines,
Zheng and coworkers recently reported a comparatively
more general method for the synthesis of N-(4-methoxy-
phenyl) indoles using a ruthenium catalyst under photore-
dox conditions.5a A new method for the synthesis of a vari-
When 50 mol% of TEMPO were used in the presence of
O2 (1 atm, via balloon) under Cu(2-ethylhexanoate)2 cataly-
sis (20 mol%), 41% of indole 2a was isolated along with 20%
of a TEMPO-peroxide 2aa. The presence of 2aa is consistent
with the presence of a carbon radical reaction intermediate
(vide infra).6a
O
O
N
N
cat. [Cu(II)]
cat. TEMPO, O2
Cu(OTf)2 (20 mol%)
NHTs
N
toluene, 120 °C
this work
N
MnO2 (300 mol%)
toluene, 120 °C, 4 Å MS
Ts
Ts
1a
90%
previous work
Scheme 1 Previous method (uses 300 mol% MnO2) and present study (uses O2, 1 atm) for the copper-catalyzed indole synthesis
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 335–339

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T. W. Liwosz, S. R. Chemler
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Table 1 Optimization of Reaction Conditions
O
O
[Cu] (mol%)
[O]2
N
TEMPO, O2
N
N
N
+
3
toluene, 120 °C
24 h
N
N
NHTs
Ts
Ts
1a
2a
2aa
N
4
Entry
[Cu] (mol%)a
TEMPO (mol%)
Yield 2a (%)b
1
2
3
4
5
6
7
8
Cu(eh)2 (15)
Cu(eh)2 (20)
–
28
50
50
50
20
20
10
20
41c
65d
65d
73
Cu(OTf)2·3 (20)
Cu(OTf)2·4 (20)
Cu(eh)2 (20)
Cu(eh)2 (15)
Cu(eh)2 (15)
–
71
40d
n.r.e
a Cu(eh)2 = copper(II) 2-ethylhexanoate.
b Isolated yield.
c 20% of 2aa was also isolated.
d Conversion (%) based on crude 1H NMR analysis.
e n.r. = no reaction.
Changing to Cu(OTf)2 and bis(oxazoline) ligand 3, 65%
conversion was achieved with the remainder being starting
2-vinyl aniline (1a, Table 1, entry 3). Use of 1,10-phenanth-
roline (4) as ligand with Cu(OTf)2 gave similar results (Table
1, entry 4). We hypothesized that the presence of side prod-
uct 2aa formed in Table 1, entry 2, could be reduced if the
TEMPO loading were reduced. Gratifyingly, use of 20 mol%
of both copper(II) 2-ethylhexanoate and TEMPO under O2
(1 atm) gave 73% yield of indole 2a with only trace 2aa (Ta-
ble 1, entry 5). Reduction of the copper loading to 15 mol%
provided 2a in comparable yield (71%, Table 1, entry 6). Fur-
ther reduction in TEMPO loading resulted in decreased con-
version to 2a (Table 1, entry 7). In the absence of copper
there is no reaction (Table 1, entry 8).
Using the optimized conditions (Table 1, entry 6) the re-
action scope was explored (Table 2). Various N-sulfonyl 2-
vinylanilines underwent the oxidative cyclization in moder-
ate to good yield (Table 2, entries 1–5). Interestingly, only
the E isomer was reactive when a mixture of internal
alkenes 1f (E/Z ratio = 2:3) was submitted to the reaction,
giving indole 2f in 22% yield along with 22% recovered (Z)-
1f (Table 2, entry 6). Exclusive reaction with (E)-1f gave 43%
of indole 2f (Table 2, entry 7). N-Aryl-2-vinylanilines 1g, 1h,
and 1i were the most reactive substrates, giving 81–85%
yield range (Table 2, entries 8–10). Substrates with less
alkene substitution, for example 1j, gave reduced conver-
sion into the indole (55% isolated 2j, Table 2, entry 10). The
N-tosyl variant of 1j was unreactive.
Table 2 Substrate Scopea
R1
R1
R2
Cu(eh)2 (15 mol%)
TEMPO (20 mol%)
R2
NH
R3
O2, toluene, 120 °C, 24 h
N
R3
Entry
1
Substrate
Product
Yield (%)b
71
N
NHR
R
1a R = Ts
2a R = Ts
2
3
4
1b R = SESc
1c R = Nsd
1d R = Mse
2b R = SESc
2c R = Nsd
2d R = Mse
55
51
50
Ph
Ph
5
73
N
NHTs
Ts
1e
2e
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T. W. Liwosz, S. R. Chemler
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Table 2 (continued)
ed yields of the indoles are comparable in some cases and
somewhat lower in others, and the substrate scope is more
narrow (e.g., intermolecular C–H aminations do not work as
well under the aerobic conditions, not shown).
Entry
Substrate
Product
Yield (%)b
Ph
Ph
A catalytic cycle consistent with the observations in Ta-
bles 1 and 2 is illustrated in Scheme 2.6a Complexation of N-
tosyl-2-vinylaniline (1a) and Cu(2-ethylhexanoate)2 gives
A. Reversible N–Cu(II) homolysis provides A in equilibrium
with nitrogen radical B and [Cu(I)] complex C. Addition of
the amidyl radical to the pendant alkene generates benzylic
carbon radical D, which under oxidizing conditions pro-
ceeds to indole 2a.9 The [Cu(I)] complex C is then oxidized
by TEMPO radical, thereby regenerating the catalyst and
TEMPO anion.7m The latter is oxidized by O2 and re-enters
the cycle. The relatively lower reactivity of the less substi-
tuted vinylarene 1j argues against an alternative mecha-
nism involving outer-sphere electrophilic activation of the
alkene by [Cu(II)] since such C–[Cu] bond formation should
be more favorable on less substituted alkenes (in analogy to
hypervalent iodine promoted reactions).5b
6f
22
N
NHTs
Ts
1f E/Z = 2:3
2f
2f
7
8
(E)-1f
43
83
N
NHAr
1g Ar = Ph
Ar
2g Ar = Ph
9
1h Ar = 4-FC6H4
1i Ar = 4-MeOC6H4
2h Ar = 4-FC6H4
2i Ar = 4-MeOC6H4
81
85
10
N
NH
11
55
OMe
OMe
2j
1j
NHTs
a Reaction conditions: 1a (0.174 mmol, 1 equiv), Cu(eh)2 (0.026 mmol, 15
mol%), TEMPO (0.035 mmol, 20 mol%), toluene (1.74 mL), O2 (1.013 bar,
balloon).
1a
[Cu(II)L2]
b Isolated yield after column chromatography.
c SES = 2-(trimethylsilyl)ethanesulfonyl.
d Ns = 4-nitrophenylsulfonyl.
TEMPO
O2
e Ms = methanesulfonyl.
L = 2-ethylhexanoate
f Z-Isomer of 1f (22%) was recovered.
TEMPO
•
Taken in sum, these results indicate the efficiency of the
reaction is dependent on the electronics and sterics of the
alkene as well as the electronics of the amine. In general
alkenes that accept radicals more readily (e.g., 1,1-disubsti-
tuted alkenes), and N-substituents able to stabilize an N-
radical are more reactive. Primary anilines and N-alkyl ani-
lines failed to react under the optimized conditions.
[Cu(I)]
+
•
N
N
[Cu(II)]
C
Ts
Ts
B
A
This new aerobic copper-catalyzed indole synthesis is
largely complementary in substrate scope to recently re-
ported oxidative amination reactions of 2-vinylanlinines.5
When compared to the ruthenium-catalyzed photocatalytic
oxidative cyclization of N-(4-methoxyphenyl)-2-vinylani-
lines,5a the N-substituent scope of this aerobic copper-cata-
lyzed reaction is much wider, but the alkene substituent
scope is more narrow. When compared to the hypervalent
iodine-mediated oxidative cyclization of 2-vinylaniline de-
rivatives where unsubstituted alkenes such as 1j perform
best,5b this copper-catalyzed reaction performs better with
higher substituted, 1,1-disubstituted alkenes but is less effi-
cient with less substituted alkenes such as 1j. In compari-
son to our previously reported method where 300 mol%
MnO2 was used as the terminal oxidant,6a this new aerobic
method requires less reagents and creates less waste. Isolat-
[O]
•
– H+
N
N
Ts
Ts
2a
D
Scheme 2 Proposed catalytic cycle
A tandem reaction involving two different copper-cata-
lyzed C–N bond formations was next explored. N-Aryl ani-
lines are efficiently synthesized via copper-catalyzed Chan–
Lam coupling8 between the corresponding anilines and bo-
ronic acids. In the event, commercially available 2-isopro-
penylaniline (5) was subjected to Cu(OAc)2-catalyzed cou-
plings with various aryl boronic acids at room temperature
under air (Scheme 3). After 24 hours, TEMPO (20 mol%) and
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 335–339

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T. W. Liwosz, S. R. Chemler
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O2 (1.013 bar, balloon) were introduced and the mixture
heated to 120 °C for 24 hours. This concise process yielded
N-aryl indoles 2g and 2k, 2l and 2m in moderate yields.
(2) For classical indole syntheses, see: (a) Fischer, E.; Jourdan, F. Ber.
Dtsch. Chem. Ges. 1883, 16, 2241. (b) Robinson, B. Chem. Rev.
1963, 63, 373. (c) Bartoli, G.; Palmieri, G.; Bosco, M.; Dalpozzo,
R. Tetrahedron Lett. 1989, 30, 2129. (d) Larock, R. C.; Yum, E. K.
J. Am. Chem. Soc. 1991, 113, 6689.
Cu(OAc)2 (20 mol%)
myristic acid (40 mol%)
2,6-lutidine, ArB(OH)2
toluene, air, r.t., 24 h
(3) For selected recent indole synthesis methods, see: (a) Taddei,
M.; Mura, M. G.; Rajamäki, S.; Luca, L. D.; Porcheddu, A. Adv.
Synth. Catal. 2013, 355, 3002. (b) Muralirajan, K.; Cheng, C.-H.
Adv. Synth. Catal. 2014, 356, 1571. (c) Dawande, S. G.;
Kanchupalli, V.; Kalepu, J.; Chennamsetti, H.; Lad, B. S.;
Katukojvala, S. Angew. Chem. Int. Ed. 2014, 53, 4076. (d) Stokes,
B. J.; Liu, S.; Driver, T. G. J. Am. Chem. Soc. 2011, 133, 4702.
(e) Ackermann, L.; Lygin, A. V. Org. Lett. 2012, 14, 764.
(f) Yamaguchi, M.; Manabe, K. Org. Lett. 2014, 16, 2386. (g) Hao,
W.; Geng, W.; Zhang, W.-X.; Xi, Z. Chem. Eur. J. 2014, 20, 2605.
(h) Cacchi, S.; Fabrizi, G.; Goggiamani, A.; Molinaro, C.;
Verdiglione, R. J. Org. Chem. 2013, 79, 401. (i) Wang, Q.; Huang,
L.; Wu, X.; Jiang, H. Org. Lett. 2013, 15, 5940. (j) Zheng, L.; Hua,
R. Chem. Eur. J. 2014, 20, 2352. (k) Miura, T.; Funakoshi, Y.;
Murakami, M. J. Am. Chem. Soc. 2014, 136, 2272. (l) Liu, B.; Song,
C.; Sun, C.; Zhou, S.; Zhu, J. J. Am. Chem. Soc. 2013, 135, 16625.
(m) Kiruthika, S. E.; Perumal, P. T. Org. Lett. 2013, 16, 484.
(n) Zhu, C.; Ma, S. Org. Lett. 2013, 15, 2782. (o) Jensen, T.;
Petersen, H.; Bang-Andersen, B.; Madsen, R.; Jorgensen, M.
Angew. Chem. Int. Ed. 2008, 47, 888. (p) Pena-Lopez, M.;
Neumann, H.; Beller, M. Chem. Eur. J. 2014, 20, 1818. (q) Zhao,
D.; Shi, Z.; Glorius, F. Angew. Chem. Int. Ed. 2013, 52, 12426.
(r) Shi, Z.; Zhang, C.; Li, S.; Pan, D.; Ding, S.; Cui, Y.; Jiao, N.
Angew. Chem. Int. Ed. 2009, 48, 4572. (s) Wei, Y.; Deb, I.;
Yoshikai, N. J. Am. Chem. Soc. 2012, 51, 9098. (t) Wagaw, S.;
Yang, B. H.; Buchwald, S. L. J. Am. Chem. Soc. 1999, 121, 10251.
(u) Wang, C.; Huang, Y. Org. Lett. 2013, 15, 5294. (v) Varela-Fer-
nandez, A.; Varela, J. A.; Saa, C. Synthesis 2012, 44, 3285.
N
NH2
then TEMPO (20 mol%)
O2, 120 °C, 24 h
Ar
5
2g, k–m
N
N
N
N
N
OCF3
Me
2m, 39%
Scheme 3 One-pot tandem Chan–Lam Coupling8–C–H amination
2g, 53%
2k, 54%
2l, 42%
In conclusion, a new indole synthesis method involving
oxidative cyclization of N-sulfonyl and N-aryl-2-vinylani-
lines catalyzed by copper under aerobic reaction conditions
has been developed. A further illustration of the synthetic
potential was demonstrated by a one-pot Chan–Lam cou-
pling–oxidative amination sequence. The reaction is com-
plementary to existing indole synthesis protocols and is es-
pecially applicable to the synthesis of 3-substituted N-sul-
fonyl and N-aryl indoles starting from 2-vinyl anilines.
Substrate reactivity trends are consistent with amidyl radi-
cal reactivity. A catalytic sequence implicating TEMPO as a
cocatalyst that functions as intermediary between the cop-
per(II) carboxylate and molecular O2 is proposed.
(4) (a) Harrington, P. J.; Hegedus, L. S. J. Org. Chem. 1984, 49, 2657.
(b) Harrington, P. J.; Hegedus, L. S.; McDaniel, K. F. J. Am. Chem.
Soc. 1987, 109, 4335. (c) Larock, R. C.; Hightower, T. R.; Hasvold,
L. A.; Peterson, K. P. J. Org. Chem. 1996, 61, 3584. (d) Izumi, T.;
Nishimoto, Y.; Kohei, K.; Kasahara, A. J. Heterocycl. Chem. 1990,
27, 1419. (e) Tsvelikhovsky, D.; Buchwald, S. L. J. Am. Chem. Soc.
2010, 132, 14048.
(5) (a) Maity, S.; Zheng, N. Angew. Chem. Int. Ed. 2012, 51, 9562.
(b) Fra, L.; Millan, A.; Souto, J. A.; Muniz, K. Angew. Chem. Int. Ed.
2014, 53, 7349.
Acknowledgment
(6) (a) Liwosz, T. W.; Chemler, S. R. Chem. Eur. J. 2013, 19, 12771.
For alternative copper-catalyzed indole syntheses, primarily
using alkynes, see: (b) Ackermann, L. Org. Lett. 2005, 7, 439.
(c) Oda, Y.; Hirano, K.; Satoh, T.; Miura, M. Org. Lett. 2012, 14,
664. (d) Frischmuth, A.; Knochel, P. Angew. Chem. Int. Ed. 2013,
52, 10084. (e) Zhu, Z.; Yuan, J.; Zhou, Y.; Qin, Y.; Xu, J.; Peng, Y.
Eur. J. Org. Chem. 2014, 511.
We thank the National Institutes of Health (RO1 GM078383) for gen-
erous financial support of this research.
Supporting Information
Supporting information for this article is available online at
(7) For selected reviews and examples, see: (a) Allen, S. E.;
Walvoord, R. R.; Padilla-Salinas, R.; Kozlowski, M. C. Chem. Rev.
2013, 113, 6234. (b) Ortgies, D. H.; Chen, F.; Forgione, P. Eur. J.
Org. Chem. 2014, 3917. (c) Steves, J. E.; Stahl, S. S. J. Am. Chem.
Soc. 2013, 135, 15742. (d) Han, B.; Yang, X.-L.; Wang, C.; Bai, Y.-
W.; Pan, T.-C.; Chen, X.; Yu, W. J. Org. Chem. 2011, 77, 1136.
(e) Liu, J.; Ma, S. Org. Lett. 2013, 15, 5150. (f) Yin, W.; Wang, C.;
Huang, Y. Org. Lett. 2013, 15, 1850. (g) Chen, C.; Liu, B.; Chen, W.
Synthesis 2013, 45, 3387. (h) Qifa, L.; Ming, L.; Fei, Y.; Wei, W.;
Feng, S.; Zhenbang, Y.; Sufeng, H. Synth. Commun. 2010, 40,
1106. (i) Liwosz, T. W.; Chemler, S. R. Org. Lett. 2013, 15, 3034.
(j) Paderes, M. C.; Keister, J. B.; Chemler, S. R. J. Org. Chem. 2012,
78, 506. (k) Fuller, P. H.; Kim, J.-W.; Chemler, S. R. J. Am. Chem.
http://dx.doi.org/10.1055/s-0034-1379015.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
ortioInfgrmoaitn
References and Notes
(1) For selected reviews on synthesis and bioactivity of indoles,
see: (a) Cacchi, S.; Fabrizi, G. Chem. Rev. 2011, 111, PR215.
(b) Humphrey, G. R.; Kuethe, J. T. Chem. Rev. 2006, 106, 2875.
(c) Kochanowska-Karamyan, A. J.; Hamann, M. T. Chem. Rev.
2010, 110, 4489. (d) Taber, D. F.; Tirunahari, P. K. Tetrahedron
2011, 67, 7195.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 335–339

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T. W. Liwosz, S. R. Chemler
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Soc. 2008, 130, 17638. (l) Zeng, W.; Chemler, S. R. J. Am. Chem.
Soc. 2007, 129, 12948. (m) Sheldon, R. A.; Arends, I. W. C. E.
J. Mol. Catal. A: Chem. 2006, 251, 200.
and dry toluene (1.74 mL, 0.1 M). The flask was purged with O2,
put under an O2 atmosphere using an O2balloon, and stirred for
24 h at 120 °C. Filtration of the cooled reaction mixture through
a pad of silica gel with EtOAc (100 mL) and subsequent evapora-
tion of the solvent in vacuo afforded the crude mixture. Flash
chromatography of the resulting crude mixture on silica gel (0–
20% EtOAc in hexanes gradient) afforded indole 2a (36 mg, 71%
yield) as an off-white solid.6 1H NMR (400 MHz, CDCl3): δ = 7.99
(d, J = 8.4 Hz, 1 H), 7.74 (d, J = 8.0 Hz, 2 H), 7.45 (d, J = 7.2 Hz, 1
H), 7.34–7.29 (m, 2 H), 7.26–7.22 (m, 1 H), 7.19 (d, J = 8.4 Hz, 2
H), 2.32 (s, 3 H), 2.24 (d, J = 0.8 Hz, 3 H).
(8) Recent example and review: (a) Antilla, J. C.; Buchwald, S. Org.
Lett. 2001, 3, 2077. (b) Qiao, J. X.; Lam, P. Y. S. Synthesis 2011,
829. (c) Qiao, J. X.; Lam, P. Y. S. Boronic Acids; John Wiley and
Sons: New York, 2011, 2nd ed.
(9) Representative Procedure for the Copper-Catalyzed Intra-
molecular Alkene C–H Amination
An oven-dried 100 mL round-bottom flask was charged with 1a
(50 mg, 0.174 mmol, 1 equiv), Cu(2-ethylhexanoate)2 (9 mg,
0.026 mmol, 15 mol%), TEMPO (5 mg, 0.035 mmol, 20 mol%),
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