Copper-catalyzed electrophilic amination of arylsilanes with hydroxylamines

Article abstract of DOI:10.1021/ol303222s

A copper-catalyzed electrophilic amination of aryl[(2-hydroxymethyl)phenyl] dimethylsilanes with O-acylated hydroxylamines has been developed to afford the corresponding anilines in good yields. The catalytic reaction proceeds very smoothly under mild conditions and tolerates a wide range of functional groups.

Full text of DOI:10.1021/ol303222s

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Copper-Catalyzed Electrophilic Amination
of Arylsilanes with Hydroxylamines
Yuya Miki, Koji Hirano,* Tetsuya Satoh, and Masahiro Miura*
Department of Applied Chemistry, Faculty of Engineering, Osaka University, Suita,
Osaka 565-0871, Japan
k_hirano@chem.eng.osaka-u.ac.jp; miura@chem.eng.osaka-u.ac.jp
Received November 22, 2012
ABSTRACT
A copper-catalyzed electrophilic amination of aryl[(2-hydroxymethyl)phenyl]dimethylsilanes with O-acylated hydroxylamines has been developed
to afford the corresponding anilines in good yields. The catalytic reaction proceeds very smoothly under mild conditions and tolerates a wide
range of functional groups.
Arylamines are privileged structural motifs in many
biologically active compounds, pharmaceutical targets, and
functional materials.1 Metal-promoted aromatic CꢀN cross-
coupling reactions provide a powerful and convergent
approach to the above amines. Among them, the copper-
mediated oxidative coupling of arylmetals with amines
(ChanꢀLam-type coupling) ranks as one of the most useful
protocols in synthetic chemistry.2 So far, arylboronic acids
and their derivatives have been mainly employed as the aryl
source. On the other hand, there are a few successful reports
of arylsilanes, despite their low toxicity and abundance which
are similar to those of organoboron compounds.3
enabled the effective amination of not only organometallic
reagents based on Mg,6 Zn,7 Ti,8 Zr,9 and B10 but also
(hetero)aromatic CꢀH bonds.11 Our group also focused
on this type of transformation and succeeded in the copper-
catalyzed electrophilic aminations of heteroarenes,12aꢀe
arylboronates,12f and ketene silyl acetals.12g In the course
of this study, we envisioned that the umpolung strategy
could be applied to the amination of arylsilanes. Herein, we
(6) (a) Tsutsui, H.; Hayashi, Y.; Narasaka, K. Chem. Lett. 1997, 26,
317. (b) Campbell, M. J.; Johnson, J. S. Org. Lett. 2007, 9, 1521. (c)
Hatakeyama, T.; Yoshimoto, Y.; Ghorai, S. K.; Nakamura, M. Org.
Lett. 2010, 12, 1516.
(7) (a) Berman, A. M.; Johnson, J. S. J. Am. Chem. Soc. 2004, 126,
5680. (b) Berman, A. M.; Johnson, J. S. Synlett 2005, 1799. (c) Berman,
A. M.; Johnson, J. S. J. Org. Chem. 2006, 71, 219. (d) Barker, T. J.; Jarvo,
E. R. J. Am. Chem. Soc. 2009, 131, 15598.
Meanwhile, an umpolung,4 electrophilic amination5
using a reagent of type R2Nþ such as chloro- and hydro-
xylamines has recently received significant attention and
(8) Barker, T. J.; Jarvo, E. R. Angew. Chem., Int. Ed. 2011, 50, 8325.
(9) Yan, X.; Chen, C.; Zhou, Y.; Xi, C. Org. Lett. 2012, 14, 4750.
(10) (a) Liu, S.; Yu, Y.; Liebeskind, L. S. Org. Lett. 2007, 9, 1947. (b)
Liu, S.; Liebeskind, L. S. J. Am. Chem. Soc. 2008, 130, 6918. (c) Zhang,
Z.; Yu, Y.; Liebeskind, L. S. Org. Lett. 2008, 10, 3005. (d) He, C.; Chen,
C.; Cheng, J.; Liu, C.; Liu, W.; Li, Q.; Lei, A. Angew. Chem., Int. Ed.
2008, 47, 6414. (e) Rucker, R. P.; Whittaker, A. M.; Dang, H.; Lalic, G.
Angew. Chem., Int. Ed. 2012, 51, 3953. (f) Rucker, R. P.; Whittaker,
A. M.; Dang, H.; Lalic, G. J. Am. Chem. Soc. 2012, 134, 6571. (g) Xiao,
Q.; Tian, L.; Tan, R.; Xia, Y.; Qiu, D.; Zhang, Y.; Wang, J. Org. Lett.
2012, 14, 4230. (h) Mlynarski, S. N.; Karns, A. S.; Morken, J. P. J. Am.
Chem. Soc. 2012, 134, 16449. (i) Zhu, C.; Li, G.; Ess, D. H.; Falck, J. R.;
(1) (a) Hili, R.; Yudin, A. K. Nat. Chem. Biol. 2006, 2, 284. (b) Amino
Group Chemistry, From Synthesis to the Life Sciences; Ricci, A., Ed.;
Wiley-VCH: Weinheim, 2007.
(2) Recent reviews: (a) Ley, S. V.; Thomas, A. W. Angew. Chem., Int.
Ed. 2003, 42, 5400. (b) Qiao, J. X.; Lam, P. Y. S. In Boronic Acids, 2nd
ed.; Hall, D. G., Ed.; Wiley-VCH: Weinheim, 2011; Chapter 6, p 315. (c)
Qiao, J. X.; Lam, P. Y. S. Synthesis 2011, 829.
(3) To the best of our knowledge, only four examples are reported;
see: (a) Lam, P. Y. S.; Deudon, S.; Averill, K. M.; Li, R.; He, M. Y.;
DeShong, P.; Clark, C. G. J. Am. Chem. Soc. 2000, 122, 7600. (b) Lam,
P. Y. S.; Deudon, S.; Hauptman, E.; Clark, C. G. Tetrahedron Lett.
2001, 42, 2427. (c) Song, R.-J.; Deng, C.-L.; Xie, Y.-X.; Li, J.-H.
Tetrahedron Lett. 2007, 48, 7845. (d) Lin, B.; Liu, M.; Ye, Z.; Ding, J.;
Wu, H.; Cheng, J. Org. Biomol. Chem. 2009, 7, 869.
(4) For a concept of umpolung, see: Seebach, D.; Enders, D. Angew.
Chem., Int. Ed. Engl. 1975, 14, 15.
(5) (a) Selected reviews: Erdik, E.; Ay, M. Chem. Rev. 1989, 89, 1947.
(b) Narasaka, K.; Kitamura, M. Eur. J. Org. Chem. 2005, 21, 4505. (c)
Ciganek, E. Org. React. 2009, 72, 1. (d) Barker, T. J.; Jarbo, E. R.
Synthesis 2011, 3954.
€
Kurti, L. J. Am. Chem. Soc. 2012, 134, 18253.
(11) (a) Tan, Y.; Hartwig, J. F. J. Am. Chem. Soc. 2010, 132, 3676. (b)
Sun, K.; Li, Y.; Xiong, T.; Zhang, J.; Zhang, Q. J. Am. Chem. Soc. 2011,
133, 1694. (c) Yoo, E. J.; Ma, S.; Mei, T.-S.; Chan, K. S. L.; Yu, J.-Q. J.
Am. Chem. Soc. 2011, 133, 7652. (d) Liu, X.-Y.; Gao, P.; Shen, Y.-W.;
Liang, Y.-M. Org. Lett. 2011, 13, 4196. (e) Ng, K.-H.; Zhou, Z.; Yu, W.-
Y. Org. Lett. 2012, 14, 272. (f) Grohmann, C.; Wang, H.; Glorius, F.
Org. Lett. 2012, 14, 656. (g) John, A.; Nicholas, K. M. Organometallics
2012, 31, 7914.
r
10.1021/ol303222s
XXXX American Chemical Society

describe a copper-catalyzed electrophilic amination of aryl-
[(2-hydroxymethyl)phenyl]dimethylsilanes with O-acylated
hydroxylamines. The copper catalysis tolerates a diverse
set of functional groups and allows various arylsilanes to
be adopted efficiently in the amination reaction for the syn-
thesis of arylamines.
On the basis of our previous work with arylboronates,12f
we initially attempted the amination of trimethoxyphenyl-
silane (1a0) with O-benzoyl-N,N-dibenzylhydroxylamine
(2a) in the presence of a Cu(OAc)2/dppbz (dppbz = 1,2-
bis(diphenylphosphino)benzene) catalyst and LiO-t-Bu
in THF at room temperature (Scheme 1). Unfortunately,
no desired aniline 3aa was formed, and methyl benzoate
(4) was instead detected asa byproduct, the methoxygroup
of which apparently came from 1a0.13 The use of tetra-
butylammonium fluoride (TBAF) as a base also gave a
similar result, while trimethylphenylsilane (1a00) in place of
1a0 showed no conversion.
such an arylsilane is capable of selective aryl group transfer
through facile formation of an intramolecularly penta-
coordinatedarylsilicate, despiteitshigh stabilityassociated
with a tetraorganosilane structure. Additionally, 1a is
readily prepared and now commercially available from
some suppliers. To our delight, 3aa was obtained in 12%
yield under the same catalytic conditions as those for
Scheme 1 (entry 1). With the preliminary but intriguing
results in hand, we screened copper salts (entries 2ꢀ4), and
CuI showed higher catalytic activity (entry 2). Among
various phosphine ligands tested, some Buchwald
biarylphosphines16 improved the yield of 3aa (entries 5ꢀ9),
with 2-(di-tert-butylphosphino)biphenyl (JohnPhos) prov-
ing to be optimal (entry 5). Subsequent investigation of
the solvent system (entry 10ꢀ12) revealed that 1,4-dioxane
furthermore increased the reaction efficiency (entry 10).
Finally, we could isolate 3aa in 77% yield in the presence
of 5 mol % of CuI and 10 mol % of JohnPhos (entry 13). On
the other hand, other bases such as K3PO4, Cs2CO3, and
NaO-t-Bu did not furnish 3aa at all (data not shown).
Notably, the present amination could be carried out on a
5-fold larger scale, indicating the good reproducibility and
Scheme 1. Initial Attempts on Copper-Catalyzed Electrophilic
Amination of Trimethoxyphenylsilane (1a0) or Trimethylphe-
nylsilane (1a00) with O-Benzoyl-N,N-dibenzylhydroxylamine
(2a)
Table 1. Optimization Studies for Copper-Catalyzed
Electrophilic Amination of [(2-Hydroxymethyl)-
phenyl]dimethylphenylsilane (1a) with O-Benzoyl-N,
N-dibenzylhydroxylamine (2a)a
Thus, we turned our attention to [(2-hydroxymethyl)-
phenyl]dimethylphenylsilane (1a, Table 1), which was
originally developed by Nakao and Hiyama,14,15 because
yield of
entry
Cu/ligand
solvent
THF
3aa (%)b
1
Cu(OAc)2/dppbz
CuI/dppbz
12
2
THF
40
(12) (a) Kawano, T.; Hirano, K.; Satoh, T.; Miura, M. J. Am. Chem.
Soc. 2010, 132, 6900. (b) Hirano, K.; Satoh, T.; Miura, M. Org. Lett.
2011, 13, 2395. (c) Matsuda, N.; Hirano, K.; Satoh, T.; Miura, M. Org.
Lett. 2011, 13, 2860. (d) Matsuda, N.; Hirano, K.; Satoh, T.; Miura, M.
J. Org. Chem. 2012, 77, 617. (e) Matsuda, N.; Hirano, K.; Satoh, T.;
Miura, M. Synthesis 2012, 44, 1792. (f) Matsuda, N.; Hirano, K.; Satoh,
T.; Miura, M. Angew. Chem., Int. Ed. 2012, 51, 3642. (g) Matsuda, N.;
Hirano, K.; Satoh, T.; Miura, M. Angew. Chem., Int. Ed. 2012, 51,
11827. Around the same time, Miura and Murakami independently
reported a relevant amination of ketene silyl acetals with chloroamines:
(h) Miura, T.; Morimoto, M.; Murakami, M. Org. Lett. 2012, 14, 5214.
Also see: (i) Cipollone, A.; Loreto, M. A.; Pellacani, L.; Tardella, P. A. J.
Org. Chem. 1987, 52, 2584. (j) Tanaka, M.; Kurosaki, Y.; Washio, T.;
Anada, M.; Hashimoto, S. Tetrahedron Lett. 2007, 48, 8799.
3
CuBr•SMe2/dppbz
CuCl/dppbz
THF
21
4
THF
trace
68
5c
CuI/JohnPhos
CuI/SPhos
THF
6c
THF
37
7c
CuI/RuPhos
THF
50
8c
CuI/XPhos
THF
32
9c
CuI/DavePhos
CuI/JohnPhos
CuI/JohnPhos
CuI/JohnPhos
CuI/JohnPhos
CuI/JohnPhos
THF
47
10c
11c
12c
13d
14d,e
1,4-dioxane
CPME
DME
81
69
43
1,4-dioxane
1,4-dioxane
90 (77)
(71)
(13) For a similar methoxy group transfer from trimethoxyphenylsi-
lane, see: Lerebours, R.; Wolf, C. J. Am. Chem. Soc. 2006, 128, 13052.
(14) (a) Nakao, Y.; Imanaka, H.; Sahoo, A. K.; Yada, A.; Hiyama, T.
J. Am. Chem. Soc. 2005, 127, 6952. (b) Nakao, Y.; Chen, J.; Imanaka,
H.; Hiyama, T.; Ichikawa, Y.; Duan, W.-L.; Shintani, R.; Hayashi, T. J.
Am. Chem. Soc. 2007, 129, 9137. (c) Nakao, Y.; Chen, J.; Tanaka, M.;
Hiyama, T. J. Am. Chem. Soc. 2007, 129, 11694. (d) Nakao, Y.; Ebata,
S.; Chen, J.; Imanaka, H.; Hiyama, T. Chem. Lett. 2007, 36, 606. (e)
Nakao, Y.; Takeda, M.; Chen, J.; Hiyama, T.; Ichikawa, Y.; Shintani,
R.; Hayashi, T. Chem. Lett. 2008, 37, 290. (f) Chen, J.; Tanaka, M.;
Takeda, M.; Sahoo, A. K.; Yada, A.; Nakao, Y.; Hiyama, T. Bull. Chem.
Soc. Jpn. 2010, 83, 554. (g) Nakao, Y.; Takeda, M.; Matsumoto, T.;
Hiyama, T. Angew. Chem., Int. Ed. 2010, 49, 4447. (h) Tang, S.; Takeda,
M.; Nakao, Y.; Hiyama, T. Chem. Commun. 2011, 47, 307.
a Reaction conditions: Cu (0.025 mmol), ligand (0.025 mmol), LiO-t-
Bu (0.50 mmol), 1a (0.25 mmol), 2a (0.30 mmol), solvent (1.5 mL), rt, 4 h,
N2. b The yields are determined by GC method. Yield of isolated product
is in parentheses. c With 0.050 mmol of ligand. d With 0.013 mmol of CuI
and 0.025 mmol of JohnPhos. e On a 1.25 mmol scale.
(15) Recent applications: (a) Saito, N.; Yamazaki, T.; Sato, Y. Chem.
Lett. 2009, 38, 594. (b) Rooke, D. A.; Ferreira, E. M. Org. Lett. 2012, 14,
3328.
B
Org. Lett., Vol. XX, No. XX, XXXX

reliability of the copper catalysis (entry 14). Moreover, in
this case, the resultant oxasilacyclopentane was recovered in
65% yield (98% purity by GC analysis) by Kugelrohr
distillation, which can be recycled for the starting 1a.17
We next performed the electrophilic amination of var-
ious aryl[(2-hydroxymethyl)phenyl]dimethylsilanes 1 with
2a under conditions employed for entry 13 in Table 1
(Table 2). The catalytic reaction was compatible with an
electron-donating methoxy group as well as an electron-
withdrawing chloride function to afford the corresponding
anilines 3ba and 3ca in good yields (entries 1 and 2).
Particularly notable is that the arylꢀBr moiety remained
intact in the amination system, providing an opportunity
for additional transformations by conventional palladium
chemistry (entry 3). The mildness of the reaction condi-
tions accommodated carbonyl groups including ester and
nitrile functions (entries 4 and 5). In addition, ortho- and
meta-substituted 1g and 1h could be employed (entries 6
and 7). Moreover, the bulky 1-naphthylsilane 1i also
coupled with 2a without any difficulties (entry 8). The
current limitation of the present copper catalysis is inac-
cessibility to 2-thienylamine (entry 9).
corresponding 4-bromoanilines 3dbꢀde in synthetically
useful yields (entries 1ꢀ4). The resultant N-allyl and N-
benzyl moieties can work as a useful synthetic handle for
further manipulations.18 These successful examples de-
serve significant attention because such secondary acyclic
alkylamines are an inaccessible substrate class in the con-
ventional ChanꢀLam-type coupling with arylsilanes.3 The
reaction with 2f that contains the pendant olefin gave the
usual aminated product 3df exclusively, and any pyrroli-
dine derivatives were not detected at all (entry 5). Thus, an
aminyl radical-promoted pathway is less likely.19 On the
other hand, cyclic amines showed somewhat lower effi-
ciency: the reaction of six-membered piperidine 2g and
morpholine 2h provided the corresponding anilines 3dg
and 3dh in moderate yields, whereas the seven-membered
azepane 2i was transformed into 3di in 78% yield.20
Table 3. Copper-Catalyzed Electrophilic Amination of Bromo-
substituted Arylsilane 1d with Various O-Benzoyl-hydroxyla-
mines 2a
Table 2. Copper-Catalyzed Electrophilic Amination of Various
Aryl[(2-hydroxymethyl)phenyl]dimethylsilanes 1 with O-Ben-
zoyl-N,N-dibenzylhydroxylamine (2a)a
entry
Ar 1
3, yield (%)b
1
2
3
4
5
6
7
8
9
Ar = 4-MeOC6H4 (1b)
Ar = 4-ClC6H4 (1c)
Ar = 4-BrC6H4 (1d)
Ar = 4-EtO2CC6H4 (1e)
Ar = 4-NCC6H4 (1f)
Ar = 2-MeC6H4 (1g)
Ar = 3-ClC6H4 (1h)
Ar = 1-naphthyl (1i)
Ar = 2-thienyl (1j)
3ba, 73
3ca, 81
3da, 77
3ea, 76
3fa, 88
3ga, 43
3ha, 76
3ia, 79
3ja, 0
a Reaction conditions: CuI (0.013 mmol), JohnPhos (0.025 mmol),
LiO-t-Bu (0.50 mmol), 1 (0.25 mmol), 2a (0.30 mmol), 1,4-dioxane (1.5
mL), rt, 4 h, N2. b Yield of isolated product.
a Reaction conditions: CuI (0.013 mmol), JohnPhos (0.025 mmol), LiO-
t-Bu (0.50 mmol), 1d (0.25 mmol), 2 (0.30 mmol), 1,4-dioxane (1.5 mL), rt,
4 h, N2. b Yield of isolated product.
With the Br-substituted arylsilane 1d as the aryl source,
the scope of hydroxylamines 2 was evaluated (Table 3).
Acyclic amines with N,N-diethyl, N,N-diallyl, N-ally-N-
methyl, and N-benzyl-N-methyl substituents underwent
the coupling with 1d very smoothly to form the
To attain some insight into the mechanism and inter-
mediates of the reaction, we prepared the mesitylcopper
complex 521 and investigated its reactivity (Scheme 2).
Upon treatment with a stoichiometric amount of O-ben-
zoyl-N,N-dibenzylhydroxylamine (2a) and JohnPhos, the
(16) (a) Martin, R.; Buchwald, S. L. Acc. Chem. Res. 2008, 41, 1461.
(b) Surry, D. S.; Buchwald, S. L. Angew. Chem., Int. Ed. 2008, 47, 6338.
(17) See the Supporting Information for more detailed optimization
studies and experimental procedures.
(18) (a) Jaime-Figueroa, S.; Liu, Y.; Muchowski, J. M.; Putman,
D. G. Tetrahedron Lett. 1998, 39, 1313. (b) Cadierno, V.; Garcıa-
Garrido, S. E.; Gimeno, J.; Nebra, N. Chem. Commun. 2005, 4086. (c)
Wang, J.-Y.; Wang, D.-X.; Zheng, Q.-Y.; Huang, Z.-T.; Wang, M.-X. J.
Org. Chem. 2007, 72, 2040.
€
(19) (a) Noack, M.; Gottlich, R. Chem. Commun. 2002, 536. Also see:
(b) Tsuritani, T.; Shinokubo, H.; Oshima, K. Org. Lett. 2001, 3, 2709. (c)
Tsuritani, T.; Shinokubo, H.; Oshima, K. J. Org. Chem. 2003, 68, 3246.
(20) The reaction with O-benzoyl-N-phenylamine was unsuccessful.
Org. Lett., Vol. XX, No. XX, XXXX
C

Based on the above considerations, a plausible mechan-
ism involves (1) base-assisted transmetalation22 of a Cu(I)
complex with the arylsilane 1, generating a JohnPhos-
ligated neutral monoarylcopper species, and (2) electro-
philic amination with the hydroxylamine 2 to form the
observed aniline 3.6b,10e,12c,12e An alternative is the invol-
vement of a Cu(III) intermediate prior to the CꢀN bond
formation.23 Further efforts toclarify the detailedmechan-
ism are ongoing.
Scheme 2. Stoichiometric and Catalytic Reactions with Mesi-
tylcopper Complex 5
In conclusion, we have developed a copper-catalyzed
electrophilic amination of aryl[(2-hydroxymethyl)phenyl]-
dimethylsilanes with O-acylated hydroxylamines. The
umpolung, electrophilic amination strategy allows aryl-
silanes to serve as an efficient aryl source for the synthe-
sis of aniline derivatives. Moreover, the high halogen
compatibility of the process can provide a facile access
to bromide-substituted arylamines and complement the
conventional Pd-based amination chemistry. Further devel-
opments of related electrophilic aminations are currently
underway.
corresponding CꢀN coupling product 6was formed in 82%
yield (GC, eq 1). In addition, 5catalyzed the amination of 1a
with 2a effectively to furnish 3aa in 95% yield (GC, eq 2),
with concomitant formation of 6 (quantitative based on 5
employed). These findings suggest that a monoarylcopper
species such as 5 would be formed in the catalytic cycle
and responsible for the CꢀN bond forming step.10e,12c
However, given that in our previous work12f the mesityl-
copper 5 did not react with 2a at all in the presence of dppbz,
the reactivity profile of the arylcopper toward O-benzoyl-
hydroxylamines would be dramatically influenced by the
ancillary ligand coordinated to the copper center.
Acknowledgment. This work was partly supported by
Grants-in-Aid from MEXT and JSPS, Japan.
Supporting Information Available. Detailed experimen-
tal procedures and characterization data of compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(21) (a) Tsuda, T.; Yazawa, T.; Watanabe, K.; Fujii, T.; Saegusa, T.
J. Org. Chem. 1981, 46, 192. (b) Leoni, P.; Pasquali, M.; Ghilardi, C. A.
J. Chem. Soc., Chem. Commun. 1983, 240. (c) Meyer, E. M.; Gambar-
otta, S.; Floriani, C.; Chiesi-Villa, A.; Guastini, C. Organometallics
1989, 8, 1067.
(22) Some copper salts are often added as a cocatalyst in the palladium-
catalyzed Hiyama cross-coupling with aryl[(2-hydroxymethyl)phenyl]-
dimethylsilanes 1. They can mediate an aryl group transfer from Si to Pd
through formation of an arylcopper intermediate; see ref 14.
(23) (a) Huffman, L. M.; Stahl, S. S. J. Am. Chem. Soc. 2008, 130,
9196. (b) King, A. E.; Brunold, T. C.; Stahl, S. S. J. Am. Chem. Soc. 2009,
131, 5044. (c) King, A. E.; Huffman, L. M.; Casitas, A.; Costas, M.;
Ribas, X.; Stahl, S. S. J. Am. Chem. Soc. 2010, 132, 12068.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX