Development of one-pot benzylic amination reactions of azine N-oxides

Article abstract of DOI:10.1016/j.tetlet.2018.03.062

An efficient one-pot synthetic methodology has been developed for the benzylic amination reactions of methyl-substituted azine N-oxides that operate under mild conditions. The reaction was found to tolerate quinoline and isoquinoline N-oxides with electron donating and withdrawing substituents as the electrophilic reaction partners as well as a broad range of nucleophilic primary, secondary and aromatic amines, affording the benzylic amination products in up to 82% yield.

Full text of DOI:10.1016/j.tetlet.2018.03.062

Accepted Manuscript
Development of one-pot benzylic amination reactions of azine N-oxides
Menekşe Liman, Yunus Emre Türkmen
PII:
S0040-4039(18)30388-5
https://doi.org/10.1016/j.tetlet.2018.03.062
TETL 49831
DOI:
Reference:
Tetrahedron Letters
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Revised Date:
Accepted Date:
23 February 2018
20 March 2018
21 March 2018
Please cite this article as: Liman, M., Türkmen, Y.E., Development of one-pot benzylic amination reactions of azine
N-oxides, Tetrahedron Letters (2018), doi: https://doi.org/10.1016/j.tetlet.2018.03.062
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Menekşe Liman and Yunus Emre Türkmen

1
Tetrahedron Letters
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Development of one-pot benzylic amination reactions of azine N-oxides
Menekşe Limana and Yunus Emre Türkmena,b,
∗
a Department of Chemistry, Faculty of Science, and bUNAM — National Nanotechnology Research Center and Institute of Materials Science and
Nanotechnology, Bilkent University, Ankara 06800, Turkey
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An efficient one-pot synthetic methodology has been developed for the benzylic amination
reactions of methyl-substituted azine N-oxides that operate under mild conditions. The reaction
was found to tolerate quinoline and isoquinoline N-oxides with electron donating and
withdrawing substituents as the electrophilic reaction partners as well as a broad range of
nucleophilic primary, secondary and aromatic amines, affording the benzylic amination products
in up to 82% yield.
Available online
Keywords:
Azine N-oxides
Benzylic amination
One-pot synthesis
Heteroaromatic compounds
Amines
2009 Elsevier Ltd. All rights reserved.
During the last decade, there has been a renaissance of interest
in the chemistry of azine N-oxides, which enables efficient
rearrangement have to be hydrolyzed to the corresponding
alcohols and further activated with suitable activating agents for
their subsequent reactions with nucleophiles, all of which
increase the overall number of steps.9d-f,13 In addition to acetic
and trifluoroacetic anhydride, acyl chlorides,19 sulfonyl chlorides
functionalization of
a broad range of N-heteroaromatic
compounds.1 In this context, azine N-oxides were shown to react
successfully with a variety of carbon,2 nitrogen,3 oxygen,4
phosphorus5 and sulfur6-based nucleophiles as well as halides,7
generally in the presence of a suitable activating agent or a
catalyst. Among various activating agents, PyBroP proved to be a
particularly effective reagent for the activation of azine N-oxides
in a plethora of applications.8
and
sulfonic
anhydrides20
and
in
situ-generated
dialkylchlorophosphates21 have occasionally been used in
Boekelheide-type rearrangements for the activation of azine N-
oxides.
Whereas most of the recent synthetic efforts focused on the
reactions of azines with nucleophiles at the 2-position, their
functionalization at the benzylic position represents an equally
important reaction class. In this regard, 2-(aminomethyl)azine
derivatives are commonly encountered as ligands used in metal
complexes,9 natural products such as Aplidiopsamine A (1),10 and
many biologically active compounds such as BI 1356 (2),11 VUF-
K-8788 (3),12 and 4 (Figure 1).13 One of the common methods for
the functionalization of 2-methylazine compounds is via their
radical bromination using NBS followed by nucleophilic
substitution.9a,14 However, this reaction sometimes gives multiple
bromination products,14 and may have selectivity issues in the
presence of other functional groups. 2-Methylazines can also be
oxidized to aldehydes at the benzylic position by SeO2 for further
functionalization.15 One of the most widely employed methods
for the derivatization of 2-methylazine N-oxides is the
Boekelheide rearrangement16 using acetic anhydride (Ac2O)17 and
trifluoroacetic anhydride.18 While highly effective, these
reactions may require high reaction temperatures, and more
Figure 1. Examples of biologically active 2-(aminomethyl)azine
derivatives.
In this work, we performed a systematic investigation on the
activation of methyl-substituted azine N-oxides towards their
importantly, the 2-(acetoxymethyl)azine products of the
———
∗ Corresponding author. E-mail address: yeturkmen@bilkent.edu.tr (Y.E. Türkmen).

2
Tetrahedron
ml of MeCN. b Yields were determined by 1H-NMR spectroscopy using 1,3,5-
reactions with amine nucleophiles, and developed an effective
c
trimethoxybenzene as an internal standard. Activated 4Å molecular sieves
protocol for their one-pot benzylic amination reactions under
mild conditions. Development of synthetic methodologies that
operate in a one-pot manner has recently attracted significant
attention from the synthetic community since such protocols
eliminate the need for the purification of reaction intermediates
and thus, lower the cost, reaction time, labour and waste
generation.22,23
were used. Abbreviatons: PyBroP, bromotripyrrolidinophosphonium
hexafluorophosphate; Ms, methanesulfonyl; Ts, p-toluenesulfonyl; Tf,
trifluoromethanesulfonyl.
With the identification of TsCl as the optimal activating agent
for the investigated one-pot benzylic amination reaction, we next
performed a base, solvent and temperature screening (Table 2).
When the reaction was run in acetonitrile at 80 °C, Na2CO3 and
K3PO4 gave inferior results compared to K2CO3 (entries 1-3). To
our delight, switching the solvent to CH2Cl2 not only increased
the yield to 90% but also demonstrated that the reaction operated
well at a much lower temperature, 35 °C (entry 4). In a control
experiment, the yield of the amination product 7 was found to be
74% when the reaction was conducted in MeCN at 35 °C (entry
5). Lower reaction yields were observed when THF and toluene
were tested as solvents (64 and 27%, respectively; entries 6 and
7). Benzotrifluoride (PhCF3) was introduced by Curran and co-
workers in 1997 as an alternative solvent to CH2Cl2 with a
comparable polarity but higher boiling point.25 However,
amination product 7 was obtained in 62 and 53% yields, when
the reaction was run in PhCF3 at 35 and 60 °C, respectively
(entries 8 and 9). The use of 2-MeTHF as a biorenewable, green
solvent26 and TBME did not provide an improvement (entries 10
and 11). Finally, we focused on the effect of using organic amine
bases instead of K2CO3 as an inorganic base. In this respect,
Et3N, Hunig’s base (iPr2NEt) and DBU were tested in CH2Cl2 at
35 °C, but lower reaction yields were observed in each case
(entries 12-14).
We initiated our study by screening a variety of activating
agents for the targeted one-pot benzylic amination reaction
(Table 1). Inspired by the recent successful utilization of PyBroP
in a broad range of reactions as an activating agent for azine N-
oxides,8 we first tested this reagent in the reaction of quinaldine
N-oxide (5) with morpholine (6) in acetonitrile at 80 °C.
Disappointingly, the formation of the desired benzylic amination
product 7 was not observed by the use of PyBroP (entry 1), and
changing reaction parameters (solvent, temperature and base) did
not provide any improvement. The use of another phosphonium
salt, Ph3PBr2,24 which is structurally related to PyBroP, gave a
similar result and did not lead to the formation of 7 (entry 2). It
should be noted that in these experiments, N-oxide 5 was
observed to remain almost completely unreacted at the end of the
reactions. Based on these observations, we turned our attention to
the use of sulfonyl chlorides and sulfonic anhydrides as
activating agents for the desired transformation. Pleasingly,
methanesulfonyl chloride (MsCl) was found to be an effective
promoter of the reaction providing the benzylic amination
product 7 in 71% yield (entry 3). Switching to p-toluenesulfonyl
chloride (TsCl) led to a further increase in reaction yield (81%,
entry 4). Next, we tested sulfonic anhydrides Ms2O and Ts2O in
order to observe the effect of the counter anion (Cl-, MsO- and
TsO-) formed upon the activation of the N-oxide reactant. While
still active, Ms2O and Ts2O gave slightly lower yields (67 and
70% yields, respectively) compared to their Cl-containg
counterparts, MsCl and TsCl (entries 5 and 6). The more reactive
activating agent Tf2O gave rise to a complex mixture of products
and afforded the amination product 7 in only 7% yield (entry 7).
Finally, the addition of 4Å molecular sieves did not provide an
increase in the reaction yield when TsCl was used (80% yield,
entry 8).
Table 2. Optimization of the one-pot benzylic amination
reactiona
Temperature
Yield
Entry
Base
Solvent
(%)b
(°C)
80
80
80
35
35
35
35
35
60
60
35
35
35
35
1
K2CO3
Na2CO3
K3PO4
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Et3N
MeCN
MeCN
MeCN
CH2Cl2
MeCN
THF
81
61
76
90
74
64
27
62
53
34
27
60
<5
13
2
Table 1. Screening of activating agents for the one-pot
3
benzylic amination reactiona
4
5
6
7
Toluene
PhCF3
8
9
PhCF3
Yield
Entry
Activating agent
(%)b
<5
<5
71
81
67
70
7
10
11
12
13
14
2-MeTHF
TBME
CH2Cl2
CH2Cl2
CH2Cl2
1
2
3
4
5
6
7
8c
PyBroP
Ph3PBr2
MsCl
TsCl
iPr2NEt
DBU
aReaction conditions: 0.31 mmol of quinaldine N-oxide (5), 0.37 mmol of
TsCl, 0.68 mmol of base, 0.47 mmol of morpholine (6) and 2.0 ml of solvent.
bYields were determined by 1H-NMR spectroscopy using 1,3,5-
trimethoxybenzene as an internal standard. Abbreviatons: DBU, 1,8-
diazabicyclo[5.4.0]undec-7-ene.
Ms2O
Ts2O
Tf2O
TsCl
80
We next investigated the substrate scope of the developed
benzylic amination reaction using the optimized conditions
(Table 3). Initially, the performance of a variety of amines as the
a
Reaction conditions: 0.31 mmol of quinaldine N-oxide (5), 0.37 mmol of
activating agent, 0.68 mmol of K2CO3, 0.47 mmol of morpholine (6) and 2.0

3
Table 3. Substrate scope of the one-pot benzylic amination reactiona,27
aReactions were carried out using azine N-oxide (1.0 equiv), TsCl (1.4 equiv), K2CO3 (2.5 equiv) and amine base (2.0 equiv) in anhydrous CH2Cl2. Yields refer to
isolated yields after purification by column chromatography.
nucleophilic component of the reaction was tested systematically.
Under the optimized reaction conditions, amination product 7
was obtained in 82% isolated yield after purification by column
chromatography. Other cyclic secondary amines piperidine and
pyrrolidine were found to be competent reaction partners giving
the amination products 8 and 9 in 76% and 62% yields,
respectively. Medicinally important piperazine moiety was
incorporated to the amination reaction via the use of N-Boc-
piperazine, and the amination product 10 was isolated in 72%
yield. The use of diethylamine amine as an acyclic secondary
amine afforded product 11 in good yield (73%).
Cyclohexylamine and α-methylbenzylamine were tested as
primary amine nucleophiles, and were found to be successful
reaction partners (46 and 64% yields, respectively). Finally, we
investigated pyrazole and imidazole as nitrogen-containing
aromatic amine nucleophiles. While benzylic amination product
14 was obtained in 50% yield, the utilization of imidazole
afforded the amination product 15 in a higher yield (61%). These
results demonstrate that a broad range of cyclic and acyclic
secondary, primary and aromatic amines are successful
nucleophilic reaction partners in the developed one-pot benzylic
amination protocol.
possesses the doubly Boc-protected amino substitutent was
prepared successfully, albeit in a lower yield (40%). Finally, 1-
methylisoquinoline N-oxide was found to be a compatible
reaction partner affording the benzylic amination product 20 in
53% yield, which demonstrates that the methodology can be
extended to the synthesis of functionalized isoquinolines as well.
TsCl, K2CO3
CH2Cl2
0 °C to rt;
a.
O
N
then morpholine (6)
35 °C
N
O
CH3
N
7
5
10 mmol scale, 1.59 g
1st trial: 64% yield; 1.46 g
2nd trial: 63% yield; 1.44 g
R1
TsCl, K2CO3
CH2Cl2
R1
b.
OTs
N
N
O
CH3
0 °C to rt
21
R2NHR3
35 °C
R1
Afterwards, we turned our attention to the investigation of
various methyl-substituted azine N-oxides in the amination
reaction (Table 3). All the N-oxide derivatives tested in this study
were pepared from the corresponding azine compounds through
their oxidation by m-CPBA.28 The use of 6-bromoquinaldine N-
oxide gave product 16 in 66% isolated yield. The Ar-Br moiety
in this product has the potential to be utilized as a functional
handle for further functionalization via a variety of cross-
coupling reactions. The reaction tolerates the presence of the
electron-donating -OMe group on the N-oxide component, and
the amination product was obtained in 47% yield. The use of 4-
chloroquinaldine N-oxide substrate afforded product 18 in good
yield (69%). We next opted to test the reactivity of a substrate
containing an amino group at the 4-position because of the
importance of 4-dimethylaminopyridine (DMAP) analogues in
organic chemistry. With this aim, the amination product 19 that
OTs
R2
N
N
N
R3
22
Scheme 1. Gram-scale example and description of the benzylic
amination reaction.
In order to assess the scalability of the one-pot protocol
developed in this study, we next performed the benzylic
amination reaction of quinaldine N-oxide (5) on 10 mmol scale
(1.59 g), and the amination product 7 was isolated in 64 and 63%
yields on two trials (Scheme 1a). Even though there is a slight
decrease in yield, these gram-scale experiments showcase the
scability and reproducibility of this one-pot method. When
treated with TsCl, a methyl-substituted azine N–oxide first

4
Tetrahedron
a Boekelheide-type rearrangement to give a
6. Su Y, Zhou X, He C, Zhang W, Ling X, Xiao X. J Org Chem.
2016;81:4981-4987.
undergoes
(tosyloxymethyl)azine intermediate (21), which, without
isolation, reacts subsequently with the nucleophilic amine
component (Scheme 1b). When the reaction of quinaldine N-
oxide (5) was performed without the addition of an amine, 2-
(tosyloxymethyl)quinoline (22) was isolated in 72% yield.28,29 It
was reported that this reaction gave an imidazoquinoline side
product with the incorporation of acetonitrile which was used as
the reaction solvent.20c During the optimization studies, we also
observed the formation of this side product in 6-25% yield
depending on the activating agent used when MeCN was the
reaction solvent.28 The higher yields that we obtained with
CH2Cl2 may be attributed to the lack of the formation of this side
product. In another control experiment, the reaction between
quinaldine N-oxide and morpholine, performed under the
optimized conditions but without K2CO3, gave product 7 in only
19% yield along with unreacted N-oxide 5.30 Finally, 2-picoline
N-oxide was found to be unreactive towards the Boekelheide-
type rearrangement under the standard reaction conditions and
did not provide the corresponding benzylic amination product.
7. (a) Wengryniuk SE, Weickgenannt A, Reiher C, Strotman NA,
Chen K, Eastgate MD, Baran PS. Org Lett. 2013;15:792-795. (b)
Wang D, Jia H, Wang W, Wang Z. Tetrahedron Lett.
2014;55:7130-7132. (c) Chen Y, Huang J, Hwang T-L, Chen MJ,
Tedrow JS, Farrell RP, Bio MM, Cui S. Org Lett. 2015;17:2948-
2951. (d) Xiong H, Hoye A T, Fan K-H, Li X, Clemens J,
Horchler CL, Lim, NC, Attardo G. Org Lett. 2015;17:3726-3729.
(e) Qiao K, Wan L, Sun X, Zhang K, Zhu N, Li X, Guo K. Eur J
Org Chem. 2016:1606-1611. (f) Wang D, Wang Y, Zhao J, Li L,
Miao L, Wang D, Sun H, Yu P. Tetrahedron. 2016;72:5762-5768.
(g) Hossain M, Pradhan K, Nanda AK. Tetrahedron Lett.
2017;58:3772-3776.
8. (a) Londregan AT, Jennings S, Wei L. Org Lett. 2010;12:5254-
5257. (b) Londregan AT, Jennings S, Wei L. Org Lett.
2011;13:1840-1843. (c) Londregan AT, Farley KA, Limberakis C,
Mullins PB, Piotrowski DW. Org Lett. 2012;14:2890-2893. (d)
Lecointre B, Azzouz R, Bischoff L. Tetrahedron Lett.
2014;55:1913-1915. (e) Londregan AT, Burford K, Conn EL,
Hesp KD. Org Lett. 2014;16:3336-3339. (f) Lian Y, Coffey SB, Li
Q, Londregan AT. Org Lett. 2016;18:1362-1365. (g) Aithagani
SK, Kumar M, Yadav M, Vishwakarma RA, Singh PP. J Org
Chem. 2016;81:5886-5894.
9. (a) Rieger B, Abu-Surrah AS, Fawzi R, Steiman M. J Organomet
Chem. 1995;497:73-79. (b) Wright DW, Mok HJ, Dubé CE,
Armstrong WH. Inorg Chem. 1998;37:3714-3718. (c) Hanaoka K,
Kikuchi K, Kojima H, Urano Y, Nagano Y. J Am Chem Soc.
2004;126:12470-12476. (d) Walton JW, Carr R, Evans NH, Funk
AM, Kenwright AM, Parker D, Yufit DS, Botta M, Pinto SD,
Wong K-L. Inorg Chem. 2012;51:8042-8056. (e) Gempf KL,
Butler SJ, Funk AM, Parker D. Chem Commun. 2013;49:9104-
9106. (f) Neil ER, Funk AM, Yufit DS, Parker D. Dalton Trans.
2014;43:5490-5504.
10. Carroll AR, Duffy S, Avery VM. J Org Chem. 2010;75:8291-
8294.
11. Eckhardt M, Langkopf E, Mark M, Tadayyon M, Thomas L, Nar
H, Pfrengle W, Guth B, Lotz R, Sieger P, Fuchs H, Himmelsbach
F. J Med Chem. 2007;50:6450-6453.
12. (a) Takizawa T, Matsumoto J, Tohma T, Kanke T, Wada Y,
Nagao M, Inagaki N, Nagai H, Zhang M-Q, Timmerman H. Jpn J
Pharmacol. 2001;86:55-64. (b) Takizawa T, Watanabe C, Saiki I,
Wada Y, Tohma T, Nagai H. Biol Pharm Bull. 2001;24:1127-
1132.
In summary, we have developed a one-pot synthetic protocol
that allows efficient benzylic amination reactions of methyl-
substituted azine N-oxides. This method is operationally simple,
proceeds under mild reaction conditions and does not require the
isolation of reaction intermediates. A broad range of cyclic and
acyclic secondary, primary and aromatic amines as well as
electron rich and deficient quinoline and isoquinoline N-oxides
are well tolerated in the reaction affording the benzylic amination
products in up to 82% yield. Scalability of the method has been
demonstrated through
a gram-scale reaction. Given the
importance of 2-(aminomethyl)azine derivatives as ligands and
biologically active molecules, this one-pot protocol is expected to
find widespread use in synthetic applications.
Acknowledgments
Financial support from the Scientific and Technological
Research Council of Turkey (TÜBİTAK; Grant No: 115Z865) is
gratefully acknowledged.
13. Kasibhatla SR, Hong K, Biamonte MA, Busch DJ, Karjian PL,
Sensintaffar JL, Kamal A, Lough RE, Brekken J, Lundgren K,
Grecko R, Timony GA, Ran Y, Mansfield R, Fritz LC, Ulm E,
Burrows FJ, Boehm MF. J Med Chem. 2007;50:2767-2778.
14. (a) Tavares FX, Al-Barazanji KA, Bigham EC, Bishop MJ, Britt
CS, Carlton DL, Feldman PL, Goetz AS, Grizzle MK, Guo YC,
Handlon AL, Hertzog DL, Ignar DM, Lang DG, Ott RJ, Peat AJ,
Zhou H-Q. J Med Chem. 2006;49:7095-7107. (b) Kuang G-C,
Michaels HA, Simmons JT, Clark RJ, Zhu L. J Org Chem.
2010;75:6540-6548.
References and notes
1. (a) Bull JA, Mousseau JJ, Pelletier G, Charette AB. Chem Rev.
2012;112:2642-2713. (b) Heterocyclic N-Oxides; Larionov, O. V.,
Ed.; Springer, 2017.
15. (a) Mathes W, Sauermilch W. Chem Ber. 1957;90:758-761. (b)
Yu X, Feng G, Huang J, Xu H. RSC Adv. 2016;6:30405-30411.
16. Tabolin AA, Ioffe SL. Chem Rev. 2014;114:5426-5476.
17. (a) Boekelheide V, Linn WJ. J Am Chem Soc. 1954;76:1286-1291.
(b) Lee KC, Chi DY. J Org Chem. 1999;64:8576-8581. (c) Rádl S,
Klecán O, Havlíček J. J Heterocyclic Chem. 2006;43:1447-1453.
18. (a) Pocker A. J Org Chem. 1973;38:4295-4299. (b) Korytnyk W,
Srivastava SC, Angelino N, Potti PGG, Paul B. J Med Chem.
1973;16:1096-1101.
2. (a) Andersson H, Banchelin TS-L, Das S, Olsson R, Almqvist F.
Chem Commun. 2010;46:3384-3386. (b) Andersson H, Olsson R,
Almqvist F. Org Biomol Chem. 2011;9:337-346. (c) Bering L,
Antonchick AP. Org Lett. 2015;17:3134-3137. (d) Jo W, Kim J,
Choi S, Cho SH. Angew Chem Int Ed. 2016;55:9690-9694. (e)
Johnson TC, Marsden SP. Beilstein J Org Chem. 2016;12:1-4. (f)
Johnson TC, Marsden SP. Org Lett. 2016;18:5364-5367. (g)
Crisenza GEM, Dauncey EM, Bower JF. Org Biomol Chem.
2016;14:5820-5825. (h) Zhang W-M, Dai J-J, Xu J, Xu H-J. J Org
Chem. 2017;82:2059-2066. (i) Zhang Z, Pi C, Tong H, Cui X, Wu
Y. Org Lett. 2017;19:440-443. (j) Han Y-P, Li X-S, Zhu X-Y, Li
M, Zhou L, Song X-R. J Org Chem. 2017;82:1697-1704.
3. (a) Keith JM. J Org Chem. 2008;73:327-330. (b) Keith JM. J Org
Chem. 2010;75:2722-2725. (c) Keith JM. J Org Chem.
2012;77:11313-11318. (d) Farrell RP, Elipe MVS, Bartberger
MD, Tedrow JS,Vounatsos F. Org Lett. 2013;15:168-171. (e)
Rassadin VA, Zimin DP, Raskil’dina GZ, Ivanov AY, Boyarskiy
VP, Zlotskii SS, Kukushin VY. Green Chem. 2016;18:6630-6636.
(f) Bugaenko DI, Yurovskaya MA, Karchava AV. J Org Chem.
2017;82:2136-2149. (g) Yu X, Yang S, Zhang Y, Guo M,
Yamamoto Y, Bao M. Org Lett. 2017;19:6088-6091.
19. (a) Koenig T, Wieczorek JS. J Org Chem. 1968;33:1530-1532. (b)
Andreotti D, Miserazzi E, Nalin A, Pozzan A, Profeta R, Spada S.
Tetrahedron Lett. 2010;51:6526-6530.
20. (a) Butera JA, Spinelli W, Anantharaman V, Marcopulos N,
Parsons RW, Moubarak IF, Cullinan C, Bagli JF. J Med Chem.
1991;34:3212-3228. (b) White JD, Yager KM, Stappenbeck F. J
Org Chem. 1993;58:3466-3468. (c) Sledeski AW, O’Brien MK,
Truesdale LK. Tetrahedron Lett. 1997;38:1129-1132. (d) Rane
RA, Pathak RK, Kaushik CP, Rao KVVP, Kumar A. Synth
Commun. 2002;32:1211-1217. (e) Mori T, Satouchi Y, Tohmiya
H, Higashibayashi S, Hashimoto K, Nakata M. Tetrahedron Lett.
2005;46:6417-6422. (f) Lee J, Kang S-U, Kil M-J, Shin M, Lim J-
O, Choi H-K, Jin M-K, Kim SY, Kim S-E, Lee Y-S, Min K-H,
Kim Y-H, Ha H-J, Tran R, Welter JD, Wang Y, Szabo T, Pearce
LV, Lundberg DJ, Toth A, Pavlyukovets VA, Morgan MA,
Blumberg PM. Bioorg Med Chem Lett. 2005;15:4136-4142.
4. Jones DH, Kay ST, McLellan JA, Kennedy AR, Tomkinson NCO.
Org Lett. 2017;19:3512-3515.
5. Wang H, Cui X, Pei Y, Zhang Q, Bai J, Wei D, Wu Y. Chem
Commun. 2014;50:14409-14411.

5
21. Yang Y, Qu C, Chen X, Sun K, Qu L, Bi W, Hu H, Li R, Jing C,
Wei D, Wei S, Sun Y, Liu H, Zhao Y. Org Lett. 2017;19:5864-
5867.
22. Review: Hayashi Y. Chem Sci. 2016;7:866-880.
23. Selected examples: (a) Cameron M, Hoermer RS, McNamara JM,
Figus M, Thomas S. Org Process Res Dev. 2006;10:149-152. (b)
Leggio A, Belsito EL, De Luca G, Di Gioia ML, Leotta V, Romio
E, Siciliano C, Liguori A. RSC Adv. 2016;6:34468-34475. (c)
Leggio A, Belsito EL, Gallo S, Liguori A. Tetrahedron Lett.
2017;58:1512-1514.
24. (a) Wagner A, Heitz M-P, Mioskowski C. J Chem Soc Chem
Commun. 1989:1619-1620. (b) Salomé C, Kohn H. Tetrahedron.
2009;65:456-460.
25. Ogawa A, Curran DP. J Org Chem. 1997;62:450-451.
26. Pace V, Hoyos P, Castoldi L, de María PD, Alcántara AR.
ChemSusChem. 2012;5:1369-1379.
27. Representative procedure for the benzylic amination reaction:
Quinaldine N-oxide 5 (200 mg, 1.26 mmol) was dissolved in
anhydrous CH2Cl2 (8.0 mL) at rt under nitrogen. After the addition
of K2CO3 (428 mg, 3.10 mmol), the reaction mixture was cooled
down to 0 °C in an ice-water bath. After five minutes, TsCl (332
mg, 1.74 mmol) was added, and it was stirred for five more
minutes at this temperature. The cooling bath was removed, and
the reaction mixture was stirred at rt for 5 h. Morpholine (224 µL,
2.52 mmol) was then added, and the reaction mixture was stirred
at 35 °C for 18 h. After the mixture was cooled down to rt, water
was added, and the aqueous phase was extracted three times with
CH2Cl2. The combined organic phase was dried over Na2SO4,
filtered and concentrated under reduced pressure. Purification by
flash column chromatography (SiO2, MeOH:EtOAc = 1:19) gave
pure product 7 as a yellow oil (234 mg, 82%). Rf = 0.39 (MeOH:
EtOAc = 1:19); 1H NMR (400 MHz; CDCl3) δ: 8.11 (1H, d, J =
8.5 Hz), 8.07 (1H, d, J = 8.5 Hz), 7.78 (1H, d, J = 8.1 Hz), 7.68
(1H, ddd, J = 8.4, 6.9 and 1.4 Hz), 7.62 (1H, d, J = 8.4 Hz), 7.50
(1H, ddd, J = 8.1, 7.0 and 1.0 Hz), 3.83 (2H, s), 3.73 (4H, t, J =
4.7 Hz), 2.55 (4H, t, J = 4.6 Hz); 13C NMR (100 MHz; CDCl3) δ:
159.2, 147.8, 136.5, 129.5, 129.2, 127.6, 127.5, 126.3, 121.2, 67.1,
-1
65.7, 54.0; IR νmax (ATR, oil)/cm 2957, 2852, 2808, 1618, 1599,
1503, 1453, 1425, 1349, 1327, 1265; HRMS: Calculated for
C14H17N2O [M+H]+ 229.1335, observed 229.1332.
28. Please see the Supplementary Information for details.
29. This observation is in accordance with the result obtained by
Sledeski and coworkers (reference 20c).
30. 4.5 equivalents of morpholine was used in this control experiment
in order to have an equal total amount of base as in the standard
conditions.
Supplementary Material
Supplementary data associated with this article can be found
in the online version.

6
Tetrahedron
Highlights:
• Operationally simple and proceeds under
mild reaction conditions
• Efficient one-pot method for the benzylic
amination reactions of azine N-oxides
• Broad substrate scope with respect to both
amine and azine N-oxide components