Copper-catalyzed electrophilic amination using: N -methoxyamines

Article abstract of DOI:10.1039/c5ob02167g

Copper-catalyzed electrophilic amination of a triarylboroxin using an N-methoxyamine to give quick access to a variety of anilines was reported. The reaction was especially useful for syntheses of functionalized anilines when combined with our previously reported nucleophilic addition to N-methoxyamides.

Full text of DOI:10.1039/c5ob02167g

View Article Online
View Journal
Organic &
Biomolecular
Chemistry
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: F. Yutaro, T.
Wada, T. Meguro, N. Chida and T. Sato, Org. Biomol. Chem., 2015, DOI: 10.1039/C5OB02167G.
This is an Accepted Manuscript, which has been through the
Royal Society of Chemistry peer review process and has been
accepted for publication.
Accepted Manuscripts are published online shortly after
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
Information for Authors.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the Ethical guidelines still
apply. In no event shall the Royal Society of Chemistry be held
responsible for any errors or omissions in this Accepted Manuscript
or any consequences arising from the use of any information it
contains.
www.rsc.org/obc

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 1 of 4
View Article Online
DOI: 10.1039/C5OB02167G
Organic & Biomolecular Chemistry
COMMUNICATION
Copper-Catalyzed Electrophilic Amination Using N-
Methoxyamines
Yutaro Fukami, Takamasa Wada, Tatsuhiko Meguro, Noritaka Chida and Takaaki Sato*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
Copper-catalyzed electrophilic amination of a triarylboroxin using
an N-methoxyamine to give quick access to a variety of anilines was
reported. The reaction was especially useful for syntheses of
functionalized anilines when combined with our previously
reported nucleophilic addition to N-methoxyamides.
Our research group has been exploring nucleophilic additions to
N-methoxyamides
alkaloids and pharmaceuticals (Scheme 1,
to the well-known Weinreb ketone synthesis,4 our nucleophilic
addition to N-methoxyamides enabled installation of two
different organometallic reagents in the presence of an acid,
producing multi-substituted N-methoxyamines in high yields.
The developed reaction proceeded under mild reaction
conditions in the presence of a variety of functional groups, and
was applied to the concise total synthesis of gephyrotoxin.2e We
envisioned that, if we could develop new transformations of the
1
as a practical synthetic tool for complex
1→4
).1-3 In contrast
1
4
Scheme 1 Nucleophilic addition to N-methoxyamide 1 and further transformations of N-
methoxyamine 4.
Transition-metal-catalyzed electrophilic amination6 has been
extensively studied as a useful alternative to the Buchwald-
Hartwig coupling7 and the Chan-Lam-Evans coupling8 (Scheme
generated N-methoxyamines
4, those reactions would render
our nucleophilic additions more useful. Indeed, transformations
2A,
8
→
9
). Most of the reported examples employ N-
as an electrophilic aminating reagent due to
of N-methoxyamines
4 are much less explored than their
benzoyloxyamine
8
construction.5 One representative reaction is reductive
cleavage with SmI2 or zinc via single electron transfer to give
the good leaving ability of the benzoyloxy group. The research
group of Johnson opened up the copper-catalyzed electripphilic
amination of diorganozinc reagents or Grignard reagents using
N-benzoyloxyamines.9a,b After their reports, Hirano/Miura9c and
Lalic9d,e independently disclosed landmark reports on the
copper-catalyzed electrophilic amination of organoborane
reagents. Electrophilic amination using N-benzoyloxyamines is
now one of the hot topics in current organic chemistry.9 On the
other hand, N-methoxyamine 10 could be another practical
electrophilic aminating reagent due to the easy availability of
highly functionalized 10 through multi-step synthesis including
our nucleophilic addition. Unfortunately, the poor leaving
ability of the methoxy group has prevented development of this
electrophilic amination.10 To overcome the poor reactivity, we
envisioned copper-catalyzed electrophilic amination under
acidic conditions (Scheme 2B). Both a copper catalyst and an
organoborane reagent show high Lewis acidity by installation of
electron withdrawing groups. The resulting Lewis acidic
secondary amines 5. Oxidation of 4 to nitrone 6 is another
practical transformation. However, to the best of our
knowledge, no direct carbon-nitrogen bond formation has been
reported from N-methoxyamines 4. In this communication, we
disclose a copper-catalyzed electrophilic amination with an N-
methoxyamine and a triarylboroxin under acidic conditions,
giving access to functionalized tertiary anilines 7.
a.Department of Applied Chemistry, Faculty of Science and Technology, Keio
University 3-14-1, Hiyoshi, Kohoku-ku, Yokohama 223-8522, Japan. E-mail:
takaakis@applc.keio.ac.jp
Electronic Supplementary Information (ESI) available. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 2 of 4
COMMUNICATION
Journal Name
reagents could activate the leaving ability of the methoxy group 75% yield, the 3-tolyl and the 2-tolyl derivatives gaVvieew9ArgticalenOdnl9inhe
by formation of cationic intermediate 11 11
,
which would then in 61% and 45% yields, respectively.
undergo the copper-catalyzed electrophilic amination with the
organoborane reagent to give
DOI: 10.1039/C5OB02167G
Table 1 Optimization of electrophilic amination using N-methoxyamine 12 a
9
.
Entry
[B]
[Cu]
additive
yields (%)b
9a
0
13
16
0
12
60
84
91
0
Scheme 2 Working hypothesis: electrophilic amination using N-methoxyamine 10 under
acidic conditions.
1c
2c
3c
4c
5c
6
14
15
16
17
18
18
18
18
18
18
18
18
[Cu(OTf)]2·C6H6
[Cu(OTf)]2·C6H6
[Cu(OTf)]2·C6H6
[Cu(OTf)]2·C6H6
[Cu(OTf)]2·C6H6
none
none
none
0
none
0
0
The present investigation commenced by examining the
reaction of N,N-dibenzyl-N-methoxyamine 12 (Table 1). A
solution of 12 in DME was treated with various organoborane
reagents in the presence of 10 mol % [Cu(OTf)]2·C6H6 at 85 °C.
The reaction with phenylboronic acid 14 resulted in recovery of
the starting material 12, along with N,N-dibenzylamine 13 in
16% yield (entry 1). Use of boron ester 15 or trifluoroborate 1612
did not promote the reaction (entries 2 and 3). Gratifyingly, the
reaction with phenyl difluoroborane 1713 provided
phenylaniline 9a in 42% yield, together with secondary amine
13 in 33% yield (entry 4). The best result was obtained when
using triphenylboroxin 18, to give phenylaniline 9a in 70% yield
(entry 5). The acidity of the reaction media was proved to be
crucial in this electrophilic amination, in contrast to most
electrophilic aminations that are known to take place under
basic conditions. The reaction required assistance of the highly
acidic copper catalyst, [Cu(OTf)]2·C6H6 (entry 5), while the
reaction without the copper catalysts or with other copper
catalysts resulted in recovery of 12 (entries 6-9). Addition of
triethylamine completely inhibited the reaction, probably
because it neutralized the requisite acidic media (entry 10).
Interestingly, extra addition of Lewis or Brønsted acids provided
none of the desired product 9a, but generated reduced
secondary amine 13 exclusively (entries 11 and 12). Although a
detailed mechanism has not yet been elucidated, we succeeded
in the copper-catalyzed electrophilic amination using N-
methoxyamines.
none
42
70
0
33
14
0
none
0
none
87
81
90
88
88
0
7
Cu(OAc)
none
0
0
8
CuCN
none
0
0
9
CuCl
none
0
0
10c
11c
12c
[Cu(OTf)]2·C6H6
[Cu(OTf)]2·C6H6
[Cu(OTf)]2·C6H6
Et3N
0
0
Sc(OTf)3
CSA
0
71
57
0
0
a
Reaction conditions: 5 (1.0 equiv), PhBX2 (1.1 equiv), CuY (20 mol %), additive
(1.1 equiv), DME (0.4 M), 85 °C, 24 h. b Yields of isolated product after purification
by column chromatography are given. c [Cu(OTf)]2·C6H6 (10 mol %) was used.
With the optimized conditions in hand, we surveyed the
scope of the triarylboroxins (Scheme 3). The reaction proceeded
in the presence of electron donating groups such as 4-methyl
and 4-methoxy groups (9b: 75%; 9c: 51%). Substituents
including 4-methyl ester and 4-fluoro groups were well
tolerated (9d: 77%; 9e: 64%). Although the yield was moderate
with tris(4-bromophenyl)boroxin, the resulting 9f with the
arylbromide moiety was synthetically useful upon further
transformation using other transition metal-catalyzed reactions
such as Suzuki-Miyaura coupling (9f: 51%). This electrophilic
amination was sensitive to the steric factors of the boroxins.
While the reaction with the tris(4-tolyl)boroxin provided 9b in
Scheme 3 Scope for triarylboroxins in the electrophilic amination. a (ArBO)3 (1.5 equiv)
was used.
The most conspicuous advantage of our electrophilic
amination is the quick preparation of a variety of N-
methoxyamines via nucleophilic addition to N-methoxyamides
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 3 of 4
Organic & Biomolecular Chemistry
Please do not adjust margins
Journal Name
COMMUNICATION
(Scheme 4A). Previously, we reported amide-selective reductive
allylation of N-methoxyamide 19 using the Schwartz reagent
[Cp2ZrHCl]14,15 to provide N-methoxyamine 20 in 84% yield.2c,e
The resulting N-methoxyamino group is chemically stable, and
enables quick diversification of 20 due to its high compatibility
with various reaction conditions. For example, the terminal
olefin in 20 was selectively functionalized without affecting the
N-methoxyamine in subsequent hydrogenation, hydroboration
and Suzuki-Miyaura coupling reactions.16 These three products
Conclusions
View Article Online
We have demonstrated copper-caDtaOlIy:z1e0d.1039e/Cle5cOtBro0p21h6i7liGc
amination using an N-methoxyamine and a triarylboroxin. The
reaction allows direct carbon-nitrogen bond formation from the
stable N-methoxyamines under acidic conditions to provide
tertiary anilines. Our method proved to be especially powerful
when combinined with our nucleophilic addition to N-
methoxyamides. We believe that the developed electrophilic
amination has broadened the utility of our nucleophilic
addition, and N-methoxyamines will become the new choice as
an electrophilic aminating reagent.
21
amination conditions, affording functionalized aniline
derivatives 24 26 in good yields. Cyclic N-methoxyamines were
-23 were then exposed to the optimized electrophilic
-
also useful electrophilic aminating reagents (Scheme 4B).
Reductive Mukaiyama-Mannich reaction of N-methoxylactam
27 provided N-methoxyamine 28 in 81% yield. The next
electrophilic amination was relatively insensitive to the steric
factors. The reaction smoothly took place in spite of the steric
congestion of 28, giving multi-substituted aniline 29 in 70%
yield.
Acknowledgement
This research was supported by a Grant-in-Aid for Scientific
Research (C) from MEXT (15K05436). Synthetic assistance from
Ms. Minami Nakajima and Mr. Seiya Katahara is gratefully
acknowledged.
Notes and references
1
For reviews and perspectives on nucleophilic addition to
amides, see: (a) D. Seebach, Angew. Chem. Int. Ed. 2011, 50,
96–101; (b) T. Murai, Y. Mutoh, Chem. Lett. 2012, 41, 2–8; (c)
V. Pace, W. Holzer, Aust. J. Chem. 2013, 66, 507–510; (d) T.
Sato, N. Chida, Org. Biomol. Chem. 2014, 12, 3147–3150; (e)
V. Pace, W. Holzer, B. Olofsson, Adv. Synth. Catal. 2014, 356,
3697–3736.
For selected examples on nucleophilic addition to N-
alkoxyamides, see: (a) H. Iida, Y. Watanabe, C. Kibayashi, J.
Am. Chem. Soc. 1985, 107, 5534–5535; (b) K. Shirokane, Y.
Kurosaki, T. Sato, N. Chida, Angew. Chem. Int. Ed. 2010, 49,
6369–6372; (c) G. Vincent, R. Guillot, C. Kouklovsky, Angew.
Chem. Int. Ed. 2011, 50, 1350–1353; (d) M. Jäkel, J. Qu, T.
Schnitzer, G. Helmchen, Chem. Eur. J. 2013, 19, 16746–16755.
(e) K. Shirokane, T. Wada, M. Yoritate, R. Minamikawa, N.
Takayama, T. Sato, N. Chida, Angew. Chem. Int. Ed. 2014, 53,
512–516. For a complete list of references, see the electronic
supplementary information.
For recent selected examples on nucleophilic addition to
amides and their derivatives, see: (a) Q. Xia, B. Ganem, Org.
Lett. 2001, 3, 485–487; (b) T. Murai, Y. Mutoh, Y. Ohta, M.
Murakami, J. Am. Chem. Soc. 2004, 126, 5968–5969; (c) K.-J.
Xiao, J.-M. Luo, K.-Y. Ye, Y. Wang, P.-Q. Huang, Angew. Chem.
Int. Ed. 2010, 49, 3037–3040; (d) G. Bélanger, G. O’Brien, R.
Larouche-Gauthier, Org. Lett. 2011, 13, 4268–4271; (e) W. S.
Bechara, G. Pelletier, A. B. Charette, Nature Chem. 2012, 4,
228–234; (f) Y. Oda, T. Sato, N. Chida, Org. Lett. 2012, 14, 950–
953; (g) K.-J. Xiao, A.-E. Wang, P.-Q. Huang, Angew. Chem. Int.
Ed. 2012, 51, 8314–8317; (h) Y. Inamoto, Y. Kaga, Y.
Nishimoto, M. Yasuda, A. Baba, Org. Lett. 2013, 15, 3452–
3455; (i) A. W. Gregory, A. Chambers, A. Hawkins, P. Jakubec,
D. J. Dixon, Chem. Eur. J. 2015, 21, 111–114; (j) P.-Q. Huang,
Q.-W. Lang, A.-E. Wang, J.-F. Zheng, Chem. Commun. 2015, 51,
1096–1099. For a complete list of references, see the
electronic supplementary information.
2
3
4
5
S. Nahm, S. M. Weinreb, Tetrahedron Lett. 1981, 22, 3815–
3818.
For selected examples on transformations of N-alkoxyamines,
see: (a) J. J. Tufariello, G. B. Mullen, J. J. Tegeler, E. J. Trybulski,
S. C. Wong, S. A. Ali, J. Am. Chem. Soc. 1979, 101, 2435–2442;
(b) K. Nagasawa, A. Georgieva, H. Koshino, T. Nakata, T. Kita,
Y. Hashimoto, Org. Lett. 2002, 4, 177–180; (c) Y. Kurosaki, K.
Scheme 4 Synthesis of functionalized anilines via the electrophilic amination.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 4 of 4
COMMUNICATION
Journal Name
Shirokane, T. Oishi, T. Sato, N. Chida, Org. Lett. 2012, 14, 13 T. A. Mitchell, J. W. Bode, J. Am. Chem. Soc. 2009, 131, 18057–
View Article Online
2098–2101.
18059.
6
7
For selected reviews on electrophilic amination, see: (a) E. 14 (a) P. C. Wailes, H. Weigold, J. Organomet. Chem.
DOI: 10.1039/1C95O70B,022146,7G
Erdik, M. Ay, Chem. Rev. 1989, 89, 1947–1980; (b) P.
Dembech, G. Seconi, A. Ricci, Chem. Eur. J. 2000, 6, 1281–
1286; (c) K. Narasaka, M. Kitamura, Eur. J. Org. Chem. 2005
4505–4519; (d) T. J. Barker, E. R. Jarvo, Synthesis 2011, 3954–
3964; (e) K. Hirano, M. Miura, Pure Appl. Chem. 2014, 86, 291–
297; (f) M. Corpet, C. Gosmini, Synthesis 2014, 2258–2271; (g)
405–411; (b) D. W. Hart, J. Schwartz, J. Am. Chem. Soc. 1974
96, 8115–8116.
,
,
15 (a) J. M. White, A. R. Tunoori, G. I. Georg, J. Am. Chem. Soc.
2000, 122, 11995–11996; (b) J. T. Spletstoser, J. M. White, A.
R. Tunoori, G. I. Georg, J. Am. Chem. Soc. 2007, 129, 3408–
3419.
P. Starkov, T. F. Jamison, I. Marek, Chem. Eur. J. 2015, 21, 16 For selected reviews on B-alkyl Suzuki-Miyaura coupling, see:
5278–5300.
(a) N. Miyaura, A. Suzuki, Chem. Rev. 1995, 95, 2457–2483; (b)
S. R. Chemler, D. Trauner, S. J. Danishefsky, Angew. Chem. Int.
Ed. 2001, 40, 4544–4568.
For recent selected reviews, see: (a) D. Prim, J.-M. Campagne,
D. Joseph, B. Andrioletti, Tetrahedron 2002, 58, 2041–2075;
(b) J. F. Hartwig, Synlett 2006, 1283–1294; (c) J. F. Hartwig,
Acc. Chem. Res. 2008, 41, 1534–1544; (d) D. S. Surry, S. L.
Buchwald, Angew. Chem. Int. Ed. 2008, 47, 6338–6361; (e) D.
S. Surry, S. L. Buchwald, Chem. Sci. 2011, 2, 27–50.
8
9
For selected reviews, see: (a) S. V. Ley, A. W. Thomas, Angew.
Chem. Int. Ed. 2003, 42, 5400–5449; (d) J. X. Qiao, P. Y. S. Lam,
Synthesis 2011, 829–856; (e) K. S. Rao, T.-S. Wu, Tetrahedron
2012, 68, 7735–7754.
For selected examples on copper-catalyzed electrophilic
amination using N-benzoyloxyamines, see: (a) A. M. Berman,
J. S. Johnson, J. Am. Chem. Soc. 2004, 126, 5680–5681; (b) M.
J. Campbell, J. S. Johnson, Org. Lett. 2007, 9, 1521–1524; (c)
N. Matsuda, K. Hirano, T. Satoh, M. Miura, Angew. Chem. Int.
Ed. 2012, 51, 3642–3645; (d) R. P. Rucker, A. M. Whittaker, H.
Dang, G. Lalic, Angew. Chem. Int. Ed. 2012, 51, 3953–3956; (e)
R. P. Rucker, A. M. Whittaker, H. Dang, G. Lalic, J. Am. Chem.
Soc. 2012, 134, 6571–6574; (f) N. Matsuda, K. Hirano, T.
Satoh, M. Miura, Angew. Chem. Int. Ed. 2012, 51, 11827–
11831; (g) M. H. Nguyen, A. B. Smith III, Org. Lett. 2013, 15,
4872–4875; (h) N. Matsuda, K. Hirano, T. Satoh, M. Miura, J.
Am. Chem. Soc. 2013, 135, 4934–4937; (i) Y. Miki, K. Hirano,
T. Satoh, M. Miura, Angew. Chem. Int. Ed. 2013, 52, 10830–
11834; (j) S. Zhu, N. Niljianskul, S. L. Buchwald, J. Am. Chem.
Soc. 2013, 135, 15746–15749; (k) S. L. McDonald, C. E.
Hendrick, Q. Wang, Angew. Chem. Int. Ed. 2014, 53, 4667–
4670; (l) Y. Yang, S.-L. Shi, D. Niu, P. Liu, S. L. Buchwald, Science
2015, 349, 62–66; (m) S.-L. Shi, S. L. Buchwald, Nature Chem.
2015, 7, 38–44; (n) J.-A. García-López, M. Çetin, M. F. Greaney,
Angew. Chem. Int. Ed. 2015, 54, 2156–2159; (o) R. Sakae, K.
Hirano, M. Miura, J. Am. Chem. Soc. 2015, 137, 6460–6463;
(p) K. Shen, Q. Wang, Chem. Sci. 2015, 6, 4279–4283; (q) M.
Mailig, R. P. Rucker, G. Lalic, Chem. Commun, 2015, 51,
11048–11051; (r) D. Niu, S. L. Buchwald, J. Am. Chem. Soc.
2015, 137, 9716–9721. For a complete list of references on
electrophilic amination, see the electronic supplementary
information.
10 For the effects of leaving groups in copper-catalyzed
electrophilic amination, see Ref 8b, 8l and 8r.
11 For selected examples on transition metal/Lewis acid catalysts
to promote cleavage of carbon-hetero atom and carbon-
carbon bonds, see: (a) C. A. Tolman, W. C. Seidel, J. D. Druliner,
P. J. Domaille, Organometallics 1984, 3, 33–38; (b) Y. Tamaru,
Y. Horino, M. Araki, S. Tanaka, M. Kimura, Tetrahedron Lett.
2000, 41, 5705–5709; (c) K. L. Tan, R. G. Bergman, J. A. Ellman,
J. Am. Chem. Soc. 2002, 124, 13964–13965; (d) N. M. Brunkan,
D. M. Brestensky, W. D. Jones, J. Am. Chem. Soc. 2004, 126,
3627–3641; (e) Y. Nakao, A. Yada, S. Ebata, T. Hiyama, J. Am.
Chem. Soc. 2007, 129, 2428–2429; (f) M. P. Watson, E. N.
Jacobsen, J. Am. Chem. Soc. 2008, 130, 12594–12595; (g) Y.
Kajita, T. Kurahashi, S. Matsubara, J. Am. Chem. Soc. 2008
,
130, 17226–17227; (h) Y. Ogiwara, T. Kochi, F. Kakiuchi, Org.
Lett. 2011, 13, 3254–3257; (i) B. L. H. Taylor, M. R. Harris, E. R.
Jarvo, Angew. Chem. Int. Ed. 2012, 51, 7790–7793.
12 For a recent review, see: G. A. Molander, J. Org. Chem. 2015
80, 7837–7848.
,
4 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins