Iron/TEMPO-catalyzed direct aerobic oxidative coupling of methyl-mubstituted N-heteroazaarenes with alcohols

Article abstract of DOI:10.1016/j.tetlet.2020.151885

A novel direct oxidative coupling of methyl-substituted N-heteroazaarenes with alcohols has been developed to construct olefins under mild condition. The reaction is catalyzed by Fe(NO₃)₃·9H₂O/TEMPO with oxygen as terminal oxidant. A variety of E-disubstituted olefins bearing diverse functional groups could be obtained selectively in moderate to excellent yields. The reaction is environmentally friendly and ligand-free.

Full text of DOI:10.1016/j.tetlet.2020.151885

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Iron/TEMPO-Catalyzed Direct Aerobic Oxidative Coupling of Methyl-Substi‐
tuted N-Heteroazaarenes with Alcohols
Zhiguang Zhang, Yantao Ma, Siwei Dai, Ling Li, Yong Zhang, Hao Li
PII:
S0040-4039(20)30328-2
DOI:
Reference:
https://doi.org/10.1016/j.tetlet.2020.151885
TETL 151885
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Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
2 February 2020
25 March 2020
26 March 2020
Please cite this article as: Zhang, Z., Ma, Y., Dai, S., Li, L., Zhang, Y., Li, H., Iron/TEMPO-Catalyzed Direct
Aerobic Oxidative Coupling of Methyl-Substituted N-Heteroazaarenes with Alcohols, Tetrahedron Letters
(2020), doi: https://doi.org/10.1016/j.tetlet.2020.151885
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Iron/TEMPO-Catalyzed Direct Aerobic
Oxidative Coupling of Methyl-Substituted N-
Heteroazaarenes with Alcohols
Leave this area blank for abstract info.
Zhiguang Zhang, Yantao Ma, Siwei Dai, Ling Li, Yong Zhang, Hao Li
Fe(NO3)3 9H2O (5 mol%)
TEMPO (5 mol%)
t-BuOK (2 equiv)
18-crown-6 (1 equiv)
THF, 50 oC, O2
Het
Het
2 H2O
+
+
HO
Ar
Ar
33 examples
up to 94% yield

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Iron/TEMPO-Catalyzed Direct Aerobic Oxidative Coupling of Methyl-Substituted N-
Heteroazaarenes with Alcohols
Zhiguang Zhanga, Yantao Ma,a Siwei Daia, Ling Lia, Yong Zhanga* and Hao Lib*
a College of Chemical and Pharmaceutical Engineering, Hebei University of Science and Technology, NO. 26 Yuxiang Rd, Shijiazhuang, 050018, PR China
bState Key Laboratory of Bioengineering Reactor, Shanghai Key Laboratory of New Drug Design, and School of Pharmacy, East China University of Science
and Technology, NO.130 Meilong Rd, Shanghai, 200237, PR China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A novel direct oxidative coupling of methyl-substituted N-heteroazaarenes with alcohols has
been developed to construct olefins under mild condition. The reaction is catalyzed by
Fe(NO3)3·9H2O/TEMPO with oxygen as terminal oxidant. A variety of E-disubstituted olefins
bearing diverse functional groups could be obtained selectively in moderate to excellent yields.
The reaction is environmentally friendly and ligand-free.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Olefination
Azaarenes
Alcohols
Aerobic oxidation
Olefins are highly important building blocks in organic
synthesis.1 N-Heteroarene substituted olefins, in particular, find
widespread application in the syntheses of natural products and
pharmaceuticals, demonstrating biological activities such as anti-
cancer and anti-Alzheimer's diseases.2 They have also been
widely used in organic light-emitting diodes.3 Besides, it has
been developed as novel precursor to synthesize N-heteroarene
derivatives by Lam,4 Lauten,5 Wang6 and Jiang.7 In the classical
olefination methods, such as Wittig reaction,8 Peterson
olefination9 and Julia olefination,10 the prefuctionalized
substrates were needed with producing stoichiometric amounts of
waste. Significant efforts have been made to develop more
efficient catalytic olefination processes in the past decades.11 In
2016, Wang developed the lanthanum pentafluorobenzoate
catalyzed aerobic oxidative olefination of benzylamines with
alkyl-substituted N-heteroazaarenes.12 In 2017, Wu reported
iodine-catalyzed direct C−H olefination of N-heterocycle N-
oxides with olefins (Scheme 1, eq. a).13 Direct coupling of alkyl-
substituted N-heteroazaarenes with alcohols would be an ideal
strategy from the view point of atom economy.14 Acceptorless
dehydrogenative couplings (ADCs) of alcohols have been proven
to be a very powerful strategy for the synthesis of unsaturated
compounds.15 In 2018, Maji and Kempe reported a very efficient
manganese-catalyzed dehydrogenative olefination of alkyl-
substituted N-heteroazaarenes with alcohols through ADCs
strategy (Scheme 1, eq. b).16,17 Unfortunately, these reactions
were proceeded at high temperature and with ligands.
Consequently, the exploration of ligand-free olefination of alkyl-
substituted N-heteroazaarenes with alcohols under mild
conditions is urgent.
Scheme 1. Olefination of heteroazaarenes.
a. Wu's work
I
2 (2 mol%), air R1
R1
H
+
Ar
N
O
Ar
N
O
H
DCM, 120 o
C
b. Maji and Kempe's work
Mn(CO)5Br (2.5 mol%)
H
N
N
(2.5 mol%)
R1
N
N
R1
c. This work
+
+
R2 OH
base, 140 o
C
N
N
R2
Ar
N
CH3
Fe(NO3)3 9H2O (5 mol%)
TEMPO (5 mol%)
R1
R1
Ar
OH
t-BuOK (2 equiv)
18-crown-6 (1 equiv)
THF, 50 oC, O2
N
CH3
In the past decades, 2,2,6,6-tetramethylpiperidin-1-oxyl
(TEMPO), a classical nitroxyl radical, has been extensively
studied in polymer chemistry, biochemistry, radical trapping
reaction and aerobic oxidation of alcohols.18 In sharp contrast, the
application of TEMPO in catalyzing other types of reactions
remains largely ignored.19 For example, TEMPO mediated
oxidative C-C coupling reactions have attracted much attention in
the recent past. Meanwhile, Fe(III) nitrate nonahydrate
(Fe(NO3)3·9H2O) has also been utilized widely in aerobic
oxidation of alcohols to carbonyls or further to their derivatives.20
For example, Ma and coworkers reported iron nitrate/TEMPO
catalyzed aerobic oxidation of alcohols in 2011.20b In 2013, they
further developed Fe(NO3)3·9H2O/TEMPO/NaCl catalyst system
for aerobic oxidation for allylic alcohols.20c More recently, they
described Fe(NO3)3·9H2O/4-OH-TEMPO/NaCl catalyst system

2
Tetrahedron
for oxidation of a wide range of alcohols.20f We envisioned that
The key issue in this reaction maybe the rate of oxidation step
should match with the rate of the condensation step, otherwise
the alcohol could be overoxidized to carboxylic acid.21 In order to
improve the reaction yields, typical TEMPO catalysts were used
in the coupling reactions. To our delight, inexpensive
Fe(NO3)3·9H2O/TEMPO could promote this transformation
cooperatively (entries 8). The reaction yield was effectively
improved to 85% when 2.5 equiv 2a was used (entry 9).
Moreover, when the loading of 18-crown-6 was lowered to 0.5
equiv, the yield was decreased to 64% (entry 10). The yield was
decreased dramatically to 41% when air was used instead of
oxygen (entry 11). Finally, when 1 equiv Fe(NO3)3·9H2O was
used as terminal oxidant instead of O2, the product was obtained
in 32% yield (entry 14). Therefore, the optimal reaction
conditions was chosen as following: a solution of 1 (1 equiv), 2
(2.5 equiv), 5 mol% TEMPO with 5 mol% Fe(NO3)3·9H2O, 2
equiv t-BuOK and 1 equiv of 18-crown-6 in THF was stirred for
8 h at 50 oC with an O2 balloon.
nitroxide may be capable of catalyzing oxidative coupling of
alkyl-substituted N-heteroazaarenes with alcohols. Herein, we
wish to report the first direct oxidative olefination of alkyl-
substituted N-heteroazaarenes with alcohols under mild condition
using 1 atm of O2 as terminal oxidant (Scheme 1, eq. c).
Since strong bases can promote the oxidation of alcohol,21 our
investigation began with a reaction of 2-methylquinoline 1a (1
mmol) with benzyl alcohol 2a (1.5 mmol) in the presence of t-
BuOK (2 equiv) and 18-crown-6 (1 equiv) with an O2 balloon in
DMSO for 8 h at 50 oC for initial evaluation (Table 1). We found
that this oxidative olefination reaction proceeded well in
acceptable yield (entry 1). To our delight, the selectivity of this
reaction was excellent. Only E isomers were obtained without
any alkylation byproduct (2-phenethylquinoline, observed in
Maji’s work).16 The solvent screening results showed that THF
gave the best result in different solvents (entries 2 and 4-7). The
reaction could not proceed well in the absence of 18-crown-6,
probably due to the low solubility of t-BuOK in THF (entry 3).
Table 2. Catalytic aerobic olefination of 1a with various
alcohols 2.a
Fe(NO3)3 9H2O (5 mol%)
TEMPO (5 mol%)
Table 1. Optimization of reaction conditions.a
+
Ar
OH
t-BuOK (2 equiv)
18-crown-6 (1 equiv)
THF, 50 oC, O2
N
Ar
N
CH3
catalyst
3
2
1a
t-BuOK, 18-crown-6
+
Ph
OH
2a
solvent, 50 oC, O2
N
CH3
OMe
N
Ph
1a
3a
N
N
N
3c
3a
, 82%
, 85%
3b
, 85%
OMe
entry
catalyst
solvent
yieldb
43
56
45
37
44
29
13
65
85
64
41
52
55
32
Me
1
2
-
-
-
-
-
-
-
DMSO
THF
N
N
N
tBu
Ph
3d
3e
, 63%
, 76%
3f
, 88%
3c
THF
NO2
4
CH3CN
acetone
DCE
N
N
N
CF3
5
Cl
3i
, 93%
3h
3g,
, 85%
77%
6
Br
Cl
7
toluene
THF
N
N
N
8d
Fe(NO3)3·9H2O, TEMPO
Fe(NO3)3·9H2O, TEMPO
Fe(NO3)3·9H2O, TEMPO
Fe(NO3)3·9H2O, TEMPO
Fe(NO3)3·9H2O
Br
3l
, 61%
N
3j
3k
, 75%
, 70%
9d,e
10d,e,f
11d,e,g
12e,h
13e,i
14e,j
a
THF
THF
S
N
N
THF
3m
, 71%
3n
3o, 81%
, 83%
N
THF
TEMPO
THF
N
O
N
Fe(NO3)3·9H2O, TEMPO
THF
N
3p
, 80%
3r
, 0%
3q
, 90%
Unless otherwise noted, all reactions were carried out using 1a (1
mmol), 2a (1.5 mmol), catalyst (quantity noted below), base (2 mmol), 18-
crown-6 (1 mmol) in a solvent (3 mL) at 50 oC for 8 h under O2 balloon.
N
Ph
N
N
b Isolated yield.
3u
, 0%
3t
, 0%
3s
, 0%
a
c In the absence of 18-crown-6.
Reaction conditions: 1a (1 mmol), 2 (2.5 mmol), 5 mol% TEMPO (0.05
mmol), 5 mol% Fe(NO3)3·9H2O (0.05 mmol), t-BuOK (2 mmol), 18-crown-6
(1 mmol) in THF (3 mL) at 50 oC under O2 balloon. Isolated yield.
d Fe(NO3)3·9H2O (0.05 mmol) and TEMPO (0.05 mmol) was used.
e 2a (2.5 mmol) was used.
With the optimal conditions established, the scope of the
olefination reaction between 2-methylquinoline 1a and various
alcohols 2 was probed (Table 2). The experimental results proved
that this protocol was a general method to synthesize structurally
diverse olefins in good yields. Generally, the alcohol substrates
with electron-neutral or electron-rich groups provided olefins 3a-
3f in good to high yields (63-88%). In addition, those alcohol
substrates with electron-withdrawing groups could participate in
f 0.5 mmol 18-crown-6 was used.
g Air was used instead of oxygen.
h Fe(NO3)3·9H2O (0.05 mmol) was used.
i TEMPO (0.05 mmol) was used.
j Fe(NO3)3·9H2O (1 mmol) and TEMPO (0.05 mmol) was used.

3
this reaction successfully to give olefins 3g-3l in good yields (61-
93%). The reaction between 2-naphthalenemethanol 2n and 1a
resulted in better yield than 1-naphthalenemethanol 2m (71%
yield for 3m, 83% yield for 3n). Besides, the mild olefination
method could accomplish the reaction between 2-
thiophenemethanol 2o, furan-3-ylmethanol 2q and 1a in high
yield (81% yield for 3o, 90% for 3q). Furthermore, electron-
deficient heterocyclic alcohol 2-(hydroxymethyl)pyridine 2p was
well tolerated by this catalytic system to afford product in 80%
yield. Finally, the olefination reaction between 1a and aliphatic
alcohols was examined. Unfortunately, the desired product could
not be obtained under the optimal condition (3r, 3s and 3t).
Besides, the olefination reaction between 1a and seconary
alcohol couldn’t afford product either (3u).
3ae). Finally, di-olefination of 2,6-dimethylpyrazine gave the
desired product 3af in 21% yield.
Indicating the synthetic practicality, the reaction could run on
gram scale successfully. The olefination reaction on a 10.0 mmol
scale of 1a with 2a afforded the desired product 3a in 90% yield
(Scheme 2). Besides, the utility of this new methodology is also
demonstrated in the synthesis of biologically active molecule.
(E)-4-(4-Methylpiperazin-1-yl)-2-styrylquinoline 5, which was
potential multifunctional agents for the treatment of Alzheimer's
disease, could be obtained via oxidative olefination of the
corresponding 2-methylquinoline derivative
4
with (4-
chlorophenyl)methanol 2f under the optimal condition in 70%
yield (Scheme 2). However, high temperature (150 oC) and
aldehyde was needed in the previous method.22
Next, the scope of this olefination process was evaluated with
different alkyl-substituted N-heteroazaarenes. As shown in Table
3, heteroazaarenes with different functional groups were
tolerated. The quinolinyl ring structures bearing electron-
withdrawing Br and -donating Me gave the corresponding olefins
3w and 3v in 94% and 81% yields respectively. It appeared that
the substrate with an electron withdrawing group became more
active and gave relatively higher yield. The reaction between
Scheme 2. Synthetic application.
Fe(NO3)3 9H2O (5 mol%)
TEMPO (5 mol%)
+
Ph
OH
t-BuOK (2 equiv)
18-crown-6 (1 equiv)
THF, 50 oC, O2
N
Ph
N
CH3
3a
2a
1a
2.08 g
10 mmol
90%
N
N
N
N
Table 3. Aerobic olefination of alkyl-substituted N-
Fe(NO3)3 9H2O (5 mol%)
TEMPO (5 mol%)
heteroazaarenes with alcohols.a
OH
+
t-BuOK (2 equiv)
18-crown-6 (1 equiv)
THF, 50 oC, O2
N
Fe(NO3)3 9H2O (5 mol%)
TEMPO (5 mol%)
N
CH3
Cl
Cl
5
2f
4
Het
Het
+
Ar
OH
70%
t-BuOK (2 equiv)
18-crown-6 (1 equiv)
THF, 50 oC, O2
CH3
Ar
To understand the mechanism of this direct olefination reaction, a
series of control experiments were conducted. In the absence of t-
1
2
3
H3C
BuOK/18-crown-6, benzyl alcohol
could be oxidized to
Br
Br
benzaldehyde in 51% yield with Fe(NO3)3·9H2O/TEMPO as sole
catalysts. On the other hand, benzoic acid could be over oxidized
from benzyl alcohol in 63% yield without Fe(NO3)3·9H2O
/TEMPO, suggesting that there are two paths for the generation
of benzaldehyde. Next, it was found that benzaldehyde could
react with 1a under the standard condition to give 3a in 56%
yield. Moreover, the olefination reaction between 1a and
benzaldehyde gave 55% yield without Fe(NO3)3·9H2O/TEMPO,
indicating that the catalyst only involved in the catalytic alcohol
oxidation step. The proposed mechanism for this catalytic
N
N
N
N
3v
, 81%
3w
3x
, 94%
, 92%
Br
S
N
Cl
N
N
Ph
3z
3y
, 78%
, 63%
3aa
, 65%
N
N
N
N
-
oxidative olefination was described in Scheme 3. NO3 is
N
Ph
responsible for producing NO2,20a, 20b, 23 which could oxidize Fe2+
to Fe3+. TEMPOH was oxidized to generate TEMPO+, which
oxidize alcohol to aldehyde. O2 acts as the terminal oxidant in the
reaction, prompting conversion of NO into NO2 and oxidizing
alcohol directly with the assistance of t-BuOK.21 Meanwhile, t-
BuOK worked as base to generate the corresponding enamine salt
from 1a.
3ac
, 77%
3ab
, 74%
3ad
, 0%
N
N
Ph
N
Ph
Ph
Ph
3ae,
3af
, 21%
0%
a Reaction conditions: 1 (1 mmol), 2 (2.5 mmol), 5 mol% TEMPO (0.05
mmol), 5 mol% Fe(NO3)3·9H2O (0.05 mmol), t-BuOK (2 mmol), 18-crown-6
(1 mmol) in THF (3 mL) at 50 oC for 8 h under O2 balloon. Isolated yield.
Scheme 3. Proposed mechanism for the reaction.
6-bromo-2-methylquinoline and 2-(hydroxymethyl)pyridine 2p
or 2-thiophenemethanol 2o gave the corresponding products in
moderate to excellent yields (92% yield for 3x, 63% yield for
3y). The reaction of 7-chloro-2-methylquinoline with benzyl
alcohol afforded 3z in 78 % yield, which is the core structures of
the drug Montelukast. In addition, 4-methylquinolin could
participate in this catalytic process giving 3aa in moderate yield.
To our delight, isoquinoline and pyrazine also proceeded well in
the processes resulting in the product 3ab and 3ac in good yields
(74% yield for 3ab and 77% yield for 3ac). Unfortunately,
olefination at the secondary carbon of the heteroaazarenes, such
as 2-ethylpyrazine and 4-benzylpyridine, could not proceed (3ad,
N
O
-
NO3
Fe3+
OH
Fe2+
Fe3+
NO2
NO
N
O
H2O
O2
Ph
Path1
t-BuOK
O2
Path2
H
O
Ph
N
OH
t-BuOK
3a
- H2O
t-BuOK
18-crown-6
N
N
K

4
Tetrahedron
15. (a) C. Gunanathan and D. Milstein, Science, 2013, 341, 249;
(b) S. Chakraborty, U. K. Das, Y. Ben-David and D. Milstein, J.
Am. Chem. Soc., 2017, 139, 11710;
The role of 18-crown-6 in the reaction is increasing the
solubility of t-BuOK in THF. The nucleophilic attack of enamine
to aldehyde resulted in the final olefination product with H2O as
the sole byproduct.
(c) J. A. Luque-Urritia, M. Sola and D. Milstein, A. Poater, J. Am.
Chem. Soc., 2019, 141, 2398;
(d) S. Waiba, M. K. Barman and B. Maji, J. Org. Chem., 2019, 84,
973.
(e) J. Das, M. Vellakkaran, M. Sk and D. Banerjee, Org. Lett.,
2019, 21, 7514.
In conclusion, we have developed a mild and ligand-free
aerobic olefination reaction for the synthesis of olefins from
alcohols and methyl-substituted N-heteroazaarenes. This protocol
is environmentally friendly with water as the sole byproduct. A
variety of both methyl-substituted N-heteroarenes and alcohols
were tolerated in the olefination process to give olefins in good to
excellent yields. The application of this mild protocol has been
demonstrated in the synthesis of valuable molecule. Further
studies on the application of this methodology into synthesizing
biologically relevant molecules are currently being pursed in our
group.
16. M. K. Barman, S. Waiba and B. Maji, Angew. Chem. Int. Ed.,
2018, 57, 9126.
17. G. Zhang, T. Irrgang, T. Dietel, F. Kallmeier and R. Kempe,
Angew. Chem. Int. Ed., 2018, 57, 9131.
18. (a) R. A. Sheldon, Catal. Today., 2015, 247, 4;
(b) H. A. Beejapur, Q. Zhang, K. -C. Hu, L. Zhu, J. -L. Wang and
Z. -B. Ye, ACS Catal., 2019, 9, 2777.
19. (a) X. Xie and S. S. Stahl, J. Am. Chem. Soc., 2015, 137, 3767;
(b) Z. -G. Zhang, Y. Gao, Y. Liu, J. -J. Li, H. -X. Xie, H. Li and
W. Wang, Org. Lett., 2015, 17, 5492;
(c) J. C. Siu, J. B. Parry and S. Lin, J. Am. Chem. Soc., 2019, 141,
2825.
Acknowledgments
20. (a) X. -L. Wang, X. -M. Liang, Chin. J. Catal., 2008, 29, 935;
(b) S. -M. Ma, J. -X. Liu, S. -H. Li, B. Chen, J. -J. Cheng, J. -Q.
Kuang, Y. Liu, B. -Q. Wan, Y.-L Wang, J. -T. Ye, Q. Yu, W. -M.
Yuan, S. -C. Yu, Adv. Synth. Catal., 2011, 353, 1005;
(c) J. -X. Liu, S. -M. Ma, Org. Lett. 2013, 15, 5150;
(d) E. -L. Zhang, H. -W. Tian, S. -D. Xu, X. -C. Yu, Q. Xu, Org.
Lett. 2013, 15, 2704;
We thank the Natural Science Foundation of Hebei Province
(B2019208137) for financial support.
References and notes
(e) S. Kolle, S. U. Dighe, S. Batra, ARKIVOC, 2016, 2016, 82;
(f) X. -G. Jiang, J. -X. Liu and S. -M. Ma, Org. Process Res. Dev.,
2019, 23, 825
1.
2.
3.
S. Matar and L. F. Hatch, Chemistry of Petrochemical Processes,
Gulf Professional Publishing, Houston, 2001.
F. -S. Chang, W. -C. Chen, C. -H. Wang, C. -C. Tzeng and Y. -L.
Chen, Bioorg. Med. Chem., 2010, 18, 124.
J. H. Burroughes, D. D. C. Bradley, A. R. Brown, R. N. Marks,
K.Mackay, R. H. Friend, P. L. Burns and A. B. Holmes, Nature,
1990, 347, 539.
L. Rupnicki, A. Saxena and H. W. Lam, J. Am. Chem. Soc., 2009,
131, 10386.
A. A. Friedman, J. Panteleev, J. Tsoung, V. Huynh and M.
Lautens, Angew. Chem., Int. Ed., 2013, 52, 9755.
(a) S. -N. Wang, X. -M. Li, H. -W. Liu, L. Xu, J. -C. Zhuang, J.
Li, H. Li and W. Wang, J. Am. Chem. Soc., 2015, 137, 2303;
(b) S. -Z. Liu, M. -C. Tong, Y. Yu, H. -X. Xie, H. Li and W.
Wang, Chem. Commun., 2015, 51, 11221;
(c) C. Qin, Y.-H. Liu, Y. Yu, Y.-W. Fu, H. Li and W. Wang, Org.
Lett., 2018, 20, 1304.
(a) Y. -L. Yin, Y. -T. Dai, H. -C. Jia, J. -T. Li, L. -W. Bu, B. -K.
Qiao, X. -W. Zhao and Z. -Y. Jiang, J. Am. Chem. Soc., 2018, 140,
6083;
21. (a) H. -X. Zheng, J. -P. Qu and Y. -B. Kang, Org. Chem. Front.,
2018, 5, 2349;
(b) Q. -Q. Li, Z. Shah, J. -P. Qu, Y. -B. Kang, J. Org. Chem. 2018,
83, 296.
22. X. -Q. Wang, C. -L. Xia, S. -B. Chen, J. -H. Tan, T. -M. Ou, S. -L.
Huang, D. Li, L. -Q. Gu and Z. -S. Huang, Eur. J. Med. Chem.,
2015, 89, 349.
4.
5.
6.
23. L. I. Rossi, S. E. Martin, App. Catal. A. 2003, 250, 271.
Supplementary Material
Supplementary material that may be helpful in the review
process should be prepared and provided as a separate electronic
file.
7.
(b) K. -N. Cao, S. M. Tan, R. Lee, S. -W. Yang, H. -C. Jia, X. -W.
Zhao, B. -K. Qiao and Z. -Y. Jiang, J. Am. Chem. Soc., 2019, 141,
5437.
B. E. Maryanoff and A. B. Reitz, Chem. Rev., 1989, 89, 863.
L. F. van Staden and D. Gravestock, D. J. Ager, Chem. Soc. Rev.,
2002, 31, 195.
An iron/TEMPO catalyzed aerobic oxidative
coupling reaction of methyl-substituted N-
heteroazaarenes with alcohols afforded various E-
disubstituted olefins in good to excellent yields
under mild condition with H2O as sole byproduct.
8.
9.
10. M. Julia and J. -M. Paris, Tetrahedron Lett., 1973, 14, 4833.
11. (a) Z. Jamal and Y. Teo, Synlett., 2014, 25, 2049;
(b) D. Mao, G. Hong, S. Wu, X. Liu, J. Yu and L. Wang, Eur. J.
Org. Chem., 2014, 14, 3009;
Fe(NO3)3 9H2O (5 mol%)
(c) Z. Jamal, Y. Teo and G. S. Lim, Tetrahedron, 2016, 72, 2132;
(d) C. Zhou, Z. Tan, H. Jiang and M. Zhang, ChemCatChem.,
2018, 10, 2887.
TEMPO (5 mol%)
t-BuOK (2 equiv)
18-crown-6 (1 equiv)
THF, 50 oC, O2
Het
Het
+
HO
Ar
A
12. (a) D. Mao, X. Zhu, G. Hong, S. Wu and L. Wang, Synlett., 2016,
27, 2481;
33 examples
up to 94% yield
(b) R. Sharma, M. Abdullaha and S. B. Bharate, J. Org. Chem.,
2017, 82, 9786.
13. (a) J. Wu, X. Cui, L. Chen, G. Jiang and Y. Wu, J. Am. Chem.
Soc., 2009, 131, 13888;
(b) Z. Zhang, C. Pi, H. Tong, X. Cui and Y. Wu, Org. Lett., 2017,
19, 440.
14. (a) B. Blank and R. Kempe, J. Am. Chem. Soc., 2010, 132, 924;
(b) Y. Obora, S. Ogawa and N. Yamamoto, J. Org. Chem., 2012,
77, 9429;
Highlights
1. Water as sole byproduct.
(c) T. -Y. Feng, H. -X. Li, D. J. Young and J. -P. Lang, J. Org.
Chem., 2017, 82, 4113;
(d) M. Vellakkaran, J. Das, S. Bera and D. Banerjee, Chem.
Commun., 2018, 54, 12369;
(e) J. Rana, R. Babu, M. Subaramanian and E. Balaraman, Org.
Chem. Front., 2018, 5, 3250.
2. Mild conditions, without any ligands.
3. Readily available starting materials.

3