Nucleophilic Amination of Methoxy Arenes Promoted by a Sodium Hydride/Iodide Composite

Article abstract of DOI:10.1002/anie.201705916

A method for the nucleophilic amination of methoxy arenes was established by using sodium hydride (NaH) in the presence of lithium iodide (LiI). This method offers an efficient route to benzannulated nitrogen heterocycles. Mechanistic studies showed that the reaction proceeds through an unusual concerted nucleophilic aromatic substitution.

Full text of DOI:10.1002/anie.201705916

A Journal of the Gesellschaft Deutscher Chemiker
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Accepted Article
Title: Nucleophilic Amination of Methoxy Arenes by a Sodium Hydride-
Iodide Composite
Authors: Atsushi Kaga, Hirohito Hayashi, Hiroyuki Hakamata, Miku Oi,
Masanobu Uchiyama, Ryo Takita, and Shunsuke Chiba
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201705916
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10.1002/anie.201705916
Angewandte Chemie International Edition
COMMUNICATION
Nucleophilic Amination of Methoxy Arenes by a Sodium Hydride-
Iodide Composite
Atsushi Kaga,+a Hirohito Hayashi,+a Hiroyuki Hakamata,+a Miku Oi,b,c Masanobu Uchiyama,b,c Ryo
Takita,b* and Shunsuke Chibaa*
Abstract: A new protocol for nucleophilic amination of methoxy
arenes was established using sodium hydride (NaH) in the presence
of lithium iodide (LiI), offering an efficient route to supply
benzannulated nitrogen-heterocycles. Mechanistic studies showed
that unusual concerted nucleophilic aromatic substitution operates in
the present process.
step-wise event, namely, either addition-elimination via a
negatively charged dearomatized intermediate (a Meisenheimer
complex) (Scheme 1a) or elimination-addition via a benzyne
species (Scheme 1b). These stepwise processes required
special settings onto the substrates and reaction conditions (e.g.
installation of electron-withdrawing groups (EWG) to stabilize the
Meisenheimer complex) with several drawbacks (e.g.
regioselective issues in addition to the benzyne intermediate).
Nucleophilic substitution reactions are one of the most
fundamental and practical processes to forge a covalent bond
linkage in organic synthesis.[1] Nucleophilic substitution at an
aromatic sp2 hybridized carbon[2] is generally considered as the
On the other hand,
a
concerted nucleophilic aromatic
substitution analogous to the SN2 reaction at the sp3 hybridized
carbon, where a Nu approaches to a π* obital of the sp2
hybridized carbon having a leaving group to give the transition
state, is hardly accepted due to the spatial requirement of high
energy barrier (Scheme 1c).[3,4]
a) addition-elimination (a typical case)
Nu–
LG
Nu
Meisenheimer
Amination of arenes enables facile construction of
benzannulated saturated nitrogen-heterocycles, which are an
omnipresent component of numerous natural alkaloids and
EWG
LG
EWG
Nu
EWG
–LG–
π*
complex
potent pharmaceutical.[5]
At present, the most common
b) elimination-addition (a typical case)
Nu–
approach of arene amination for the construction of such
scaffolds involves transition-metal catalyzed amination of
(pseudo)haloarenes,[6] that have advanced the state of the art
(Scheme 2a). On the other hand, the demand of transition-
metal-free procedures rises from the standpoints of the rigid
guideline that limits the level of residual transition-metal
contamination in the pharmaceutical ingredients. In this context,
Meyers developed a method for intramolecular amination of
methoxy arenes, that are electrophilically activated by an ortho-
oxazoline moiety (Scheme 2b).[7-9] This amination thus proceeds
through the addition-elimination manner with lithium amide
species. Annulation of benzynes with nitrogen nucleophiles has
been used for construction of several specific nitrogen-
Nu
LG
–LG–
H+
–H+
H
benzyne
c) concerted fashion (a rare case)
Nu–
δ–
Nu
δ–
LG
Nu
LG
–LG–
π*
transition state
Scheme 1. Nucleophilic aromatic substitution reactions. Nu = nucleophile;
EWG = electron withdrawing group; LG = leaving group
heterocycles (Scheme 2c).[10]
Electrophilic amination of
hydroxylamine derivatives was reported for synthesis of
benzannulated saturated nitrogen-heterocycles under basic or
acidic reaction conditions (Scheme 2d).[11,12] However, these
strategies have been of use for construction of limited types of
nitrogen-heterocycles. Herein, we report an unprecedented
example of nucleophilic amination of methoxy arenes by a
tethered amine moiety in the presence of sodium hydride (NaH)
and lithium iodide (LiI) (Scheme 2e). We found that the resulting
sodium amides undergo facile intramolecular substitution of a
rather unusual leaving group, a methoxy group on the arenes, to
afford benzannulated nitrogen-heterocycles having up-to ten
[a]
[b]
A. Kaga, H. Hayashi, H. Hakamata, and Prof. S. Chiba
Division of Chemistry and Biological Chemistry
School of Physical and Mathematical Sciences
Nanyang Technological University, Singapore 637371 (Singapore)
E-mail: shunsuke@ntu.edu.sg
M. Oi, Prof. M. Uchiyama, and Prof. R. Takita
Advanced Elements Chemistry Research Team, RIKEN Center for
Sustainable Resource Science, and Elements Chemistry
Laboratory, RIKEN, 2-1 Hirosawa, Wako-shi, Saitama 351-0198,
Japan
E-mail: ryo.takita@riken.jp
M. Oi and Prof. M. Uchiyama
Graduate School of Pharmaceutical Sciences, The University of
Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
These authors contributed equally.
membered rings.
Mechanistic studies based on both
[c]
[+]
experimental and theoretical approaches gave a critical insight
that the amination process proceeds via concerted fashion
rather than the conventional step-wise manner.
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201705916
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COMMUNICATION
a) transition-metal catalyzed amination
a) hydrodecyanation of 1 with NaH-LiI
R
n
cat. TM
N
NaH (2 equiv)
LiI (1 equiv)
CN
n
R'
R'
H
N
H
TM = Cu, Pd, Ni
X
Ar
Na+
R
Ar
H
–NaCN
THF, 85 °C
(sealed tube)
N
MeO
b) nucleophilic amination via addition-elimination
2 92%
1
24 h
R
(Ar = 4-MeO-C6H4)
n
R
N
n
n
R'
R'
N
R'
H
b) hydrodecyanation of 3 with NaH-LiI:
LDA
OMe
N
OMe
R
–MeO–
O
N
O
N
O
N
NaH (3 equiv)
LiI (2 equiv)
CN
H
H
Na+
A
–NaCN
THF, 90 °C
(sealed tube)
32 h
N
OMe
OMe
c) nucleophilic amination of benzynes
OMe
4 10%
3
TMS
–NaOMe
F–
OTf
[H–]
+
CO2Me
N
CO2Me
N
N
H
6 57%
Boc
HN
Boc
CO2Me
Boc
N
5 10%
d) electrophilic amination
MeLi
c) nucleophilic amination of 7 with NaH
OMe
OMe
t-BuLi
n
N
n
NaH (3 equiv)
N
n
Li
additive (2 equiv)
NHBn
H
N
then
AcCl
additive
LiI
Li
Br
e) this work
Ac
90% (19 h)
N
THF, 90 °C
(sealed tube)
NaI 31% (24 h)
none trace (24 h)
OMe
Bn
8
7
Me
O
R
NaH-LiI
THF
N
n
n
Na
n
Scheme 3. Reactions with the NaH-iodide composite. [a] The reactions were
conducted using 0.3-0.5 mmol of substrates in THF (0.1 M) and isolated yields
of products were noted above. Bn = benzyl.
H
OMe
N
N
R
R'
R'
R'
R
• concerted nucleophilic aromatic substitution
• a methoxy group as the leaving group
• capable in construction of up-to 10 membered ring
We next evaluated the scope of this unprecedented
nucleophilic amination of methoxy arenes using the NaH-LiI
composite and found it to be broad and versatile for synthesis of
benzannulated saturated nitrogen-heterocycles (Scheme 4a).
The method allowed for construction of not only C3-spirocyclic
indoline 9 but also C2-methyl indoline 10 as well as none-
substituted indolines 11 and 12 having cleavable benzyl (Bn)
and p-methoxybenzyl (PMB) protection on the nitrogen.
Especially, use of the PMB protection is advantageous as it
could be removed readily under transition-metal free manners.
It should also be noted that intermolecular amination of the PMB
moieties (cf. Scheme 4b) was not observed in these
Scheme 2. Synthesis of benzannulated saturated nitrogen-heterocycles
In
a recent report, we described use of NaH-iodide
composite[13] for hydrodecyanation of benzyl cyanides.[13c] For
example, hydrodecyanation of para-methoxybenzyl cyanide 1
proceeded smoothly with the NaH-LiI composite to give 2
(Scheme 3a). During the course of studying the substrate scope,
we were surprised to observe that the reaction of ortho-methoxy
substrate 3 with the NaH-LiI composite provided not only an
expected decyanated product 4 (in only 10% yield), but also 3H-
indole 5 and indoline 6 in 10% and 57% yields, respectively
intramolecular processes (for 10,12).
A
range of
(Scheme 3b).
Assuming that this unanticipated nitrogen-
tetrahydroquinolines could also be constructed with this method
(for 13-24). Of worthy to note is that electron-rich and sterically
hindered methoxy arenes were viable substrates (15-17,20,21).
Moreover, cyclization with the primary amine and N-
methylamine was found to be optimal under the present
conditions (for 14,24). Installation of the substituents on C2-C4
positions of tetrahydroquinolines (22-24) was also tolerated.
heterocycles 5 and 6 are formed via nucleophilic substitution
with a transient anionic imine nucleophile A (subsequent hydride
reduction of 5 affords 6), we wondered if this arene amination
via substitution of a methoxy group could be generalized to a
more versatile method for the synthesis of benzannulated N-
heterocycles. Therefore, as the model experiments, we tested
the reactions of readily available N-benzylamine 7 for synthesis
of indoline 8 (Scheme 3c). We found that with NaH (3 equiv) as
a base, addition of LiI or NaI (2 equiv) is crucial to facilitate the
substitution. The reaction with the NaH-LiI composite resulted in
a full conversion to afford 8 in 90% yield at 90 °C (sealed
conditions) for 19 h, whereas NaH only did not work at all,
indicating unique reactivity installed onto the composite.[14]
The present method enabled facile construction of
dihydrophenanthridine core, that was demonstrated by a concise
three-step synthesis of 5,6-dihydrobicolorine (25).[15]
This
a
method was also capable in constructing larger membered
nitrogen-heterocycles. As for the 7-membered ring, tetrahydro-
1H-benzo[b]azepine
26
as
well
as
tetrahydrobenzo[e][1,4]oxazepine and -[1,4]diazepine (27-29)
were afforded despite the moderate yield of 26. We observed
that during the construction of tricyclic 28, the preinstalled
chirality derived from (L)-prolinol is not lost. Tetrahydro-2H-
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10.1002/anie.201705916
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COMMUNICATION
using amines (0.5 mmol) and methoxy arenes (1 mmol) in THF (1 M) for 40 h
and isolated yields of aminated arenes were noted above. PMB = para-
methoxybenzyl.
benzo[c][1,5]oxazocine 30 (8-membered ring) could be
constructed in 51% yield, whereas construction of the 10-
membered ring 31 became sluggish (only 15% yield).
We found that the NaH-iodide composite is also capable of
performing intermolecular amination of methoxy arenes with
cyclic secondary amines (Scheme 4b), affording the
corresponding aromatic amines 32-39 in good to moderate
yields.
With respect to the limitations, the method has thus far not
proven successful with the secondary amines having aryl and
acyl groups on the nitrogen probably due to delocalization the
resulting anionic charge. In the sharp contrast to the formation
of indolines 9-12 (Scheme 4a), the reaction of substrate 40 gave
2-methylanisole (41) and aldimine 42 as the major products
through the retro-Mannich reaction, whereas indoline 43 was
obtained in only 9% yield and formation of tetrahydroquinoline
44 was observed in 21% yield (Scheme 5a). On the other hand,
the reaction of 45, having one-carbon longer tether than 40,
prevented the retro-Mannich reaction (Scheme 5b). In this case,
the process provided expected tetrahydroquinoline 46 in only
4% yield, but affording tetrahydro-1H-benzo[b]azepine 47 in
40% yield along with formation of alkane 48 in 49% yield through
C-N bond cleavage. This outcome is totally distinct from the
formation of N-methyl 24 (Scheme 4a). The proposed reaction
pathways for these unexpected reactions were illustrated in
Scheme 5c. The retro-Mannich process of 40 is likely facilitated
by formation of relatively stabilized benzyl anion (as a precursor
of 2-methylanisole 41) and conjugated benzaldimine 42 from
sodium amide I (n = 1). Nucleophilic aromatic substitution of
sodium amide I affords 43 or 46, which might further undergo
a) intramolecular amination
NaH (3 equiv)
LiI (2 equiv)
R
n
N
H
n
R'
R'
N
R
OMe
THF, 90 °C
(sealed tube)[a]
N Bn
Me
N
PMB
N
Bn
N
PMB
9 76%
10 52%
11 73%
12 84%
15 (R' = MeO) 76%
16 (R' = t-Bu) 87%
17 (R' = Me) 85%
18 (R' = Ph) 82%
19 (R' = CF3) 90%
R'
N
H
N
Bn
13 89%
N
Bn
14 41%
Ph
Me
N
Bn
N
N
Bn
N
Bn
Me Bn
20 74%
21 88%
22 92%
23 64%
H
Ph
a) reaction of 40
Me
O
+
N
O
O
OMe
N
Me
Ph
NaH-LiI
conditions[a,b]
Ph
N
Bn
N
Ph
N
41 56%
42 58%
Bn
27 94%
Me
Ph
HN
OMe
40
24 75%
25 67%
26 30%
Ph
7 h
+
Bn
Ph
Ph
N
H
N
Ph
O
O
N
O
44 21%
(trans:cis = 62:38)
O
H
43 9%
N
N
Bn
N
Bn
29 85%
N
Bn
30 52%[b]
b) reaction of 45
28 80%
31 15%
N
Ph
b) intermolecular amination
Ph
NaH-LiI
46 4%[b]
conditions[a]
NaH (3 equiv)
LiI (2 equiv)
+
Ph
NH
Ph
Ph
R
H N
R'
R'
R
N
R
+
OMe
(2 equiv)
14 h
OMe
45
Ph
R
THF, 90 °C
(sealed tube)[c]
+
N
H
OMe
Ph
47 40%[c]
48 49%[c]
(trans:cis = 77:23)
c) proposed reaction pathways
n
[1,2]-aza
Wittig
Ph
n
N
N
N
N
Ph
N
N
H
Ph
40 or 45
O
Ph
43 or 46
44 or 47
32 81%
33 69%
34 78%
35 83%
–H2
NaH-LiI
–MeONa
(n = 1 or 2)
–MeONa
MeO
[1,2]-aza
Wittig
Ph
Ph
Ph
Ph
Na
N
Ph
N
N
N
Ar
N
NH
n
n
n
36 45%
37 61%
38 41%
39 74%
OMe
OMe
III
NH
48
(n = 2)
Ph
Ph
Na+
I
II
Na
retro-Mannich
(n = 1)
Scheme 4. Substrate scope. [a] The intramolecular reactions were conducted
using 0.3-0.5 mmol of amines in THF (0.1 M) for 4-47 h and isolated yields of
heterocycles were noted above unless otherwise stated. [b] NaH (6 equiv)
and LiI (4 equiv) were used. [c] The intermolecular reactions were conducted
41 and 42
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10.1002/anie.201705916
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COMMUNICATION
Scheme 5. Retro-Mannich reaction and skeletal rearrangement. [a] The
reactions were conducted using 0.5 mmol of amines with NaH (3 equiv) and
LiI (2 equiv) in THF (0.1 M) at 90 °C. [b] 1H NMR yields. [c] Isolated yields.
Figure 1. Reaction pathways of the nucleophilic amination with methoxy
arenes. Energy changes and bond lengths at the B3LYP/6-31+G* level of
theory (SCRF (pcm, solvent = THF)) are shown in kcal/mol and Å, respectively.
aza-[1,2]-Wittig rearrangement[16] via deprotonation of the
benzylic methylene moiety to form ring-expanded 44 or 47,
This work demonstrated a new reactivity of sodium hydride
in nucleophilic amination of methoxy arenes that proceeds via a
concerted nucleophilic aromatic substitution pathway. Given the
respectively.
Alternatively,
another
aza-[1,2]-Wittig
rearrangement could be proposed from benzylsodium II to forge
a new C-C bond to generate sodium amide III, which cyclizes to
give 44 or 47. Meanwhile, alkane 48 might be formed through
fragmentation of benzylsodium II (n = 2).[17,18]
prevalence
of
saturated
nitrogen-heterocycles
in
pharmaceuticals and biologically active natural products, we
anticipate that this method will simplify the route to access to
these classes of targets. We are currently working to explore
other types of molecular transformations with the NaH-iodide
composite.
Several experimental observations provided clues about the
reaction mechanism of the present nucleophilic amination of
methoxy arenes, that is unlikely through addition-elimination via
the Meisenheimer complex (from electron-rich substrates 15-17)
nor through elimination-addition via the benzyne species (from
2,6-disubstituted substrates 20 and 21). We conducted the DFT
calculations[19] to investigate the mechanism of the formation of
N-methyl tetrahydroquinoline as the model reaction (Figure 1).
The bulk solvent effect of THF was described with an implicit
model, and two molecules of THF were included explicitly. An
exothermic pathway with a single transition state (TS) having a
partial negative charge (δ–) for concerted nucleophilic aromatic
substitution was obtained with the transient Na amides, and the
reaction was found to proceed with the reasonable activation
barrier (14.7 kcal/mol).[20] The concerted nucleophilic aromatic
substitution mechanism could also be supported by the
Hammett plot of log(kX/kH) versus σ with the substrates 13, 15-
17 and 19, which provided a linear correlation with a positive ρ
value of 1.99 (See the SI).[21] The calculated energy changes to
see the substituent effects were consistent with the experimental
Acknowledgements
This work was financially supported by Nanyang Technological
University (NTU) and the Singapore Ministry of Education
(Academic Research Fund Tier 1: RG2/15) for S.C. and The
Tokyo Biochemical Research Foundation for R.T. H.H. is
grateful to Tohoku University and Tohoku Kaihatsu Memorial
Foundation for the financial support.
Keywords: sodium hydride • amination • nucleophilic aromatic
substitution • nitrogen-heterocycles • DFT calculations
[1]
R. Brückner, in: Organic Mechanisms: Reactions, Stereochemistry and
Synthesis, (Ed.: M. Harmata), Springer, Berlin, Heidelberg, 2010,
chapter 2 and chapter 5.
[2]
[3]
F. Terrier, Modern Nucleophilic Aromatic Substitution, Wiley-VCH,
Weinheim, 2013, chapter 1.
results (See the SI).
One of the keys to enable this
For reports on intermolecular concerted nucleophilic aromatic
substitution, see: a) L. I. Goryunov, J. Grobe, D. L. Van, V. D.
Shteingarts, R. Mews, E. Lork, E.-U. Würthwein, Eur. J. Org. Chem.
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Renfrew, J. A. Taylor, J. M. J. Whitmore, A. Williams, J. Chem. Soc.
Perkin Trans. 2 1993, 1703; d) S. E. Fry, N. J. Pienta, J. Am. Chem.
Soc. 1985, 107, 6399.
unprecedented nucleophilic amination of methoxy arenes could
probably be an enhanced Lewis acidity[13a,22] installed onto NaH
in the composite.
Nonetheless, further elucidation of the
detailed mechanism is the subject of our ongoing investigations.
∆G (kcal/mol)
[4]
For reports on intramolecular concerted nucleophilic aromatic
substitution, see: a) C. N. Neumann, J. M. Hooker, T. Ritter, Nature
2016, 534, 369; b) F. Nawaz, K. Mohanan, L. Charles, M. Rajzmann, D.
Bonne, O. Chuzel, J. Rodriguez, Y. Coquerel, Chem. Eur. J. 2013, 19,
17578; c) G. C. Lloyd-Jones, J. D. Moseley, J. S. Renny, Synthesis
2008, 661.
Me
30
O
O
Na
O
N
Me
Na
20
10
Me
O
O
[5]
[6]
a) R. D. Taylor, M. MacCoss, A. D. G. Lawson, J. Med. Chem. 2014, 57,
5845; b) C. M. Marson, Chem. Soc. Rev. 2011, 40, 5514.
N
TS
O
Me
(14.7)
For reviews, see: a) P. Ruiz-Castillo, S. L. Buchwald, Chem. Rev. 2016,
116, 12564; b) K. Okano, H. Tokuyama, T. Fukuyama, Chem. Commun.
2014, 50, 13650; c) J. Bariwal, E. Van der Eycken, Chem. Soc. Rev.
2013, 42, 9283; d) D. S. Surry, S. L. Buchwald, Chem. Sci. 2011, 2, 27;
e) J. Magano, J. R. Dunetz, Chem. Rev. 2011, 111, 2177; f) D. S. Surry,
S. L. Buchwald, Angew. Chem. Int. Ed. 2008, 47, 6338; Angew. Chem.
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A. I. Meyers, M. Reuman, R. A. Gabel, J. Org. Chem. 1981, 46, 783.
There are reports on intermolecular nucleophilic amination of aryl
ethers with lithium amides, see: a) W. ten Hoeve, C. G. Kruse, J. M.
Luteyn, J. R. G. Thiecke, H. Wynberg, J. Org. Chem. 1993, 58, 5101; b)
T. Matsumoto, H, Kakigi, K. Suzuki, Tetrahedron Lett. 1991, 32, 4337.
0
–10
–20
–30
INT
(0.0)
O
Me
O
O
1.45
2.30
Na
2.35
[7]
[8]
TS
N
2.37
Me
2.02
2.35
PD
(–30.2)
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10.1002/anie.201705916
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COMMUNICATION
[9]
For a recent report on carbazole synthesis via nucleophilic amination of
arylsulfones with potassium amides, see: M. Bhanuchandra, K.
Murakami, D. Vasu, H. Yorimitsu, A. Osuka, Angew. Chem. Int. Ed.
2015, 54, 10234; Angew. Chem. 2015, 127, 10372.
[14] Our materials characterization (ref. 13d) revealed that solvothermal
treatment of NaH and LiI induces counter ion methathesis to form the
activated NaH with NaI and LiH. No reaction was observed with LiH
and LiH-LiI composite.
[10] For selected recent reports, see: a) T. K. Shah, J. M. Medina, N. K.
Garg, J. Am. Chem. Soc. 2016, 138, 4948; b) A. E. Goetz, T. K. Shah,
N. K. Garg, Chem. Commun. 2015, 51, 34; c) A. E. Goetz, N. K. Garg,
Nat. Chem. 2013, 5, 54; d) T. Noji, H. Fujiwara, K. Okano, H.
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T. Fukuyama, H. Tokuyama, Angew. Chem. Int. Ed. 2010, 49, 5925;
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Shirakawa, Y. Honda, T. Hiyama, Angew. Chem. Int. Ed. 2002, 41,
3247; Angew. Chem. 2002, 114, 3381.
[15] See the SI for the detailed synthetic scheme starting from commercially
available 6-bromopiperonal. For reports on synthesis and isolation,
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[16] C. Vogel, Synthesis 1997, 497.
[17] A similar fragmentation was observed in [1,2]-Wittig rearrangement,
see: C. R. Hauser, S. W. Kantor, J. Am. Chem. Soc. 1951, 73, 1437.
[18] We conducted several control experiments to elucidate the
mechanisms shown in Scheme 5c. See the SI for the details.
[19] Gaussianꢀ09 (RevisionꢀE.01), M. J. Frisch, et al., Gaussian Inc.,
Wallingford CT, 2009.
[11] a) Y. Kikugawa, A. Nagashima, T. Sakamoto, E. Miyazawa, M. Shiiya, J.
Org. Chem. 2003, 68, 6739; b) P. Beak, G. W. Selling, J. Org. Chem.
1989, 54, 5574; c) Y. Kikugawa, M. Kawase, J. Am. Chem. Soc. 1984,
106, 5728.
[12] For
a recent report Rh-catalyzed aromatic C-H amination with
hydroxylamine derivatives for synthesis of benzannulated nitrogen-
heterocycles, see: M. P. Paudyal, A. M. Adebesin, S. R. Burt, D. H. Ess,
Z. Ma, L. Kürti, J. R. Falck, Science 2016, 353, 1144.
[20] Reactions promoted by conceivable interaction with NaI require high
energies (about 33 kcal/mol; for details, see the SI), indicating that
these pathways seem to be unlikely.
[13] a) Y. Huang, G. H. Chan, S. Chiba, Angew. Chem. Int. Ed. 2017, 56,
6544; Angew. Chem. 2017, 129, 6644; b) D. Y. Ong, C. Tejo, K. Xu, H.
Hirao, S. Chiba, Angew. Chem. Int. Ed. 2017, 56, 1840; Angew. Chem.
2017, 129, 1866; c) P. C. Too, G. H. Chan, Y. L. Tnay, H. Hirao, S.
Chiba, Angew. Chem. Int. Ed. 2016, 55, 3719; Angew. Chem. 2016,
128, 3783; d) Z. Hong, D. Y. Ong, S. K. Muduli, P. C. Too, G. H. Chan,
Y. L. Tnay, S. Chiba, Y. Nishiyama, H. Hirao, H. S. Soo, Chem. Eur. J.
2016, 22, 7108.
[21] Nucleophilic aromatic substitution reactions via addition-elimination
mechanism normally show larger ρ values between 3 and 8. For
examples, see: a) V. M. Vlasov, New J. Chem. 2010, 34, 2962. b) R. Y.
Sung, H. Choi, J. P. Lee, J. K. Park, K. Yang, I. S. Koo, Bull. Korean
Chem. Soc. 2009, 30, 1579.
[22] It was observed that the present aromatic substitution was disturbed by
the addition of TMEDA (see the SI).
This article is protected by copyright. All rights reserved.

10.1002/anie.201705916
Angewandte Chemie International Edition
COMMUNICATION
COMMUNICATION
Atsushi Kaga, Hirohito Hayashi, Hiroyuki
Hakamata, Miku Oi, Masanobu
Uchiyama, Ryo Takita,* and Shunsuke
Chiba*
Page No. – Page No.
Nucleophilic Amination of Methoxy
Arenes by a Sodium Hydride-Iodide
Composite
A new protocol for nucleophilic amination of methoxy arenes was established using
sodium hydride (NaH) in the presence of lithium iodide (LiI), offering an efficient
route to supply benzannulated nitrogen-heterocycles. Mechanistic studies showed
that unusual concerted nucleophilic aromatic substitution operates in the present
process.
This article is protected by copyright. All rights reserved.