Copper-catalyzed aerobic oxidative amination of arylboronic acid with aminal under base-free conditions

Article abstract of DOI:10.1016/j.tetlet.2013.03.058

A new process involving copper-catalyzed oxidative amination reaction of various arylboronic acids with aminals under mild conditions has been developed. The key copper-amide species involved in the C-N bond-forming process was generated via C-N bond cleavage of aminal under base-free conditions. Moderate yields of desired amination products can be obtained under mild conditions when air was served as oxidant and PhCO₂H was used as an additive.

Full text of DOI:10.1016/j.tetlet.2013.03.058

Tetrahedron Letters 54 (2013) 2713–2716
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Copper-catalyzed aerobic oxidative amination of arylboronic acid with aminal
under base-free conditions
Yanping Zhou a, Yinjun Xie b, Lei Yang b, Pan Xie b, Hanmin Huang a,b,
⇑
a College of Chemical Engineering and Materials Science, Zhejiang University of Technology, Hangzhou, 310014, PR China
b State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences, Lanzhou, 730000, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A new process involving copper-catalyzed oxidative amination reaction of various arylboronic acids with
aminals under mild conditions has been developed. The key copper-amide species involved in the C–N
bond-forming process was generated via C–N bond cleavage of aminal under base-free conditions. Mod-
erate yields of desired amination products can be obtained under mild conditions when air was served as
oxidant and PhCO2H was used as an additive.
Received 28 December 2012
Revised 7 March 2013
Accepted 15 March 2013
Available online 24 March 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Copper
Oxidative amination
C–N cleavage
Aminal
Base-free
Introduction
bond formation process for this reaction was believed to be gener-
ated by hydrolysis of the iminium-type intermediate, which was
Aromatic amines represent one of the most important and
abundant compounds in chemistry and can be found in bulk chem-
icals, fine chemicals, natural products as well as drugs.1 Therefore,
the development method for the synthesis of aromatic amines
continues to attract interest from both academia and indus-
try.2 Among many types of methods synthesis documented,
copper-mediated Ullmann and Goldberg coupling,2a Pd-catalyzed
Buchwald–Hartwig reaction,3 and copper-catalyzed Chan-Lam
coupling4 have stood out as powerful tools to fulfill these transfor-
mations. Mechanistically, the metal-amide species was generally
required to furnish the corresponding C–N bond-forming process
in almost all of the above-mentioned reactions.5 Generally, to gen-
erate the corresponding metal-amide species, the stoichiometric
amount of base is typically used to promote the aminometallation,
which dramatically decreases the atom economy and functional
group tolerance. To circumvent this problem, new strategy for gen-
eration of metal-amide species in the absence of base would be
highly desirable.
generated in situ via cleavage of sp3 C–H bond of the tertiary
amines. However, a limitation of the established catalyst system
is that the relatively higher reaction temperature (120 °C) is re-
quired for generation of the iminium-type intermediate. Our
continuing efforts in C–N bond-forming process promoted us to ex-
plore new strategy for generating active iminium-type intermedi-
ate under mild reaction conditions. Aminal is recognized as a
surrogate of imine and widely used as electrophile in the metal-
catalyzed nucleophilic addition reactions.7 The C–N bond in those
molecules is easily cleaved under mild conditions for generation
of iminium ion due to the higher leaving ability of the amino group,
and copper-amide species can be formed by hydrolysis of the imin-
ium ion. Intrigued by this unique feature, we reasoned that a new
type of C–N bond formation reaction would be established by using
aminal as a nitrogen source. Herein, we describe a novel copper
catalyzed amination reaction of aminals with arylboronic acids to
access the aromatic amines through C–N cleavage under mild
and base-free conditions (Scheme 1). To the best of our knowledge,
this is the first copper-catalyzed coupling reaction of aminals with
arylboronic acids to give the aromatic amine products.
As part of our program to develop novel synthetic methods to
amines, we recently reported a copper-catalyzed oxidative C–H
amination of azoles using tertiary amines as nitrogen group
sources via cleavage of C–H and C–N bonds under base-free condi-
tions.6 The important copper-amide species involved in the C–N
Results and Discussion
Initially, the copper-catalyzed aerobic oxidative amination
of aminal 2a with phenylboronic acid 1a was selected as a
model reaction and molecular oxygen was utilized as the oxidant
⇑
Corresponding author. Tel.: +86 931 4968326; fax: +86 931 4968129.
E-mail address: hmhuang@licp.cas.cn (H. Huang).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.03.058

2714
Previous work (C-H Amination)
Y. Zhou et al. / Tetrahedron Letters 54 (2013) 2713–2716
With the optimized reaction conditions in hand, we subse-
quently examined the scope of the arylboronic acids and the re-
sults are shown in Table 2.8 This reaction was successfully
performed with different arylboronic acids. The arylboronic acids
containing electron-donating groups at the para or meta position
of the benzene ring could afford the desired products in moderate
yields (Table 2, entries 2, 3, 5–7, and 9). An obvious steric
hindrance effect on the reactivity was observed, which was dem-
onstrated by the reactivities of o-tolylboronic acid 1d and 2-meth-
oxyphenylboronic acid 1h. When both of them were subjected to
the reaction, only trace amounts of corresponding products could
be obtained under the optimized reaction conditions (Table 2,
entries 4 and 8). The arylboronic acids bearing electron-withdraw-
ing groups could also be transformed smoothly to their corre-
sponding amines in moderate yields (Table 2, entries 10-12). To
expand the substrate scope, 1- and 2-naphthalene boronic acids
R1
R2
R1
R2
CuX2, O2
R1
R2
Ar
H
CH2R3
N
CuLn
N
Ar
N
C-H, C-N cleavage
C-H amination
Present work
NR2
CuX2
ArB(OH)2, O2
Oxidative amination
R2N CuX
Ar NR2
NR2
C-N cleavage
Base-free conditions
Scheme 1. New strategy for Cu-catalyzed C–N bond formation reactions.
Table 1
Optimization of reaction conditionsa
[Cu] (10 mol%)
O
O
Acid (20 mol%), Oxidant
N
B(OH)2
O
+
N
N
Solvent, T°C, 12 h
Table 2
Substrate scope of the arylboronic acidsa
1a
2a
3a
Entry
Catalyst
Acid
Solvent
T (°C)
Yieldb (%)
Cu(acac)2 (10 mol%)
PhCO2H (20 mol%), air
O
O
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16c
17d
CuF2
CuCl2
CuBr2
HOAc
HOAc
HOAc
HOAc
HOAc
HCO2H
C2H5CO2H
F3CCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
25
25
25
25
25
25
25
25
25
25
25
25
40
50
60
50
50
9
11
11
20
7
11
21
3
Ar
N
O
Ar B(OH)2
+
N
N
CH3CN, 50°C, 12 h
1
2a
3
Cu(acac)2
Cu(OTf)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Entry Substrate 1
Product 3
Yieldb
(%)
B(OH)2
B(OH)2 1b
1
2
N
O
53
56
1a
3a
DCM
26
7
Toluene
CH3CN
THF
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
H3C
H3C
H3C
H3C
N
O
3b
34
NR
49
57
56
53
53
B(OH)2
N
N
O
O
1c
3c
3e
3
4
56
B(OH)2
CH3
1d
N
O
3d
Trace
CH3
a
Reaction conditions: 1a (0.5 mmol), 2a (0.5 mmol), [Cu] (10 mol %), acid
(20 mol %) in solvent (1 mL) under O2 (1 atm) for 12 h.
H3C
H3C
H3C
H3C
b
1e
B(OH)2
Isolated yield.
Compound 2a (0.3 mmol).
Using 0.3 mmol of 2a, air as oxidant.
5
57
c
d
1f
1i
6
7
H3CO
B(OH)2
43
48
H3CO
N
O
3f
3g
1g
B(OH)2
N
O
(Table 1). First, different copper catalysts were tested in DCM with
HOAc as the additive. Cu(acac)2 showed the best result with 20%
yield of the desired product 3a (Table 1, entry 4), while other cop-
per catalysts gave lower yields. This result indicated that our pro-
posed process was indeed possible, although the amine 3a was
obtained in a relative lower yield. Encouraged by this result, the ef-
fect of other acidic additives was further investigated and the re-
sult demonstrated that this reaction proceeded most efficiently
when PhCO2H served as the additive (Table 1, entry 9). With
Cu(acac)2 as catalyst and PhCO2H as the additive, solvent effect
was also examined and the highest product yield was obtained
in CH3CN (Table 1, entry 11), and other solvents gave inferior
yields. Investigation of temperature revealed that running the
reaction at 50 °C instead of 25 °C, 57% yield of desired product 3a
could be obtained under the other identical reaction conditions
(Table 1, entry 14). Further optimization of the reaction conditions
demonstrated that the aromatic amine compound 3a could be also
obtained in 53% yield even the ratio of 2a/1a was decreased from
1/1 to 0.6/1 (Table 1, entry 16), which means that the two amine
moieties contained in the aminal are participated in the reaction.
Finally, to our delight, the reaction still proceeded well and the
desired product could be yielded in the same level when air instead
of molecular oxygen served as the oxidant (Table 1, entry 17).
H3CO
H3CO
B(OH)2
OCH3
1h
N
O
3h
8
Trace
OCH3
F3CO
F3CO
F
B(OH)2
N
O
48
53
9
3i
1j
3j
10
B(OH)2
F
N
O
1k
B(OH)2
N
3k
O
11
12
57
39
F
F
1l
F3C
B(OH)2
B(OH)2
F3C
N
O
3l
O
N
1m
13
12
3m
B(OH)2
O
1n
N
14
57
3n
a
Reaction conditions: 1 (0.5 mmol), 2a (0.3 mmol), Cu(acac)2 (10 mol %), PhCO2H
(20 mol %) in CH3CN (1 mL) under air at 50 °C for 12 h.
b
Yield of isolated product.

Y. Zhou et al. / Tetrahedron Letters 54 (2013) 2713–2716
2715
Cu(acac)2 (10 mol%)
PhCO2H (20 mol%), air
B(OH)2
B(OH)2
+
N
N
N
N
CH CN, 50°C, 12 h
3
1a
1a
2o
3o:34%
Cu(acac)2 (10 mol%)
PhCO2H (20 mol%), air
N
+
N
CH CN, 50°C, 12 h
3
2p
3p:45%
N
O
O
O
Cu(acac)2 (10 mol%)
PhCO2H (20 mol%), O2 (1 atm)
3a:20%
N
+
B(OH)2
N
O
+
CH3CN, 80°C, 12 h
O
N
2q
1a
O
3q:11%
Scheme 2. Reactivity of various aminals toward cross-coupling with phenylboronic acid.
by transmetalation with the arylboronic acid. The subsequent
reductive elimination provides the corresponding amine products
in the presence of Cu(II). The released Cu(I) species could be oxi-
dated by O2 to regenerate Cu(II) and complete the catalytic cycle.9
B(OH)2
1a
1/2B2O3+HX+1/2H2O
O
N CuX
A
HCHO+HX
O
N Cu
C
Conclusions
CuX2
H2O/H+
In summary, we have developed a novel copper-catalyzed ami-
nation reaction of arylboronic acids with aminals for the synthesis
of aromatic amines. With air as oxidant and PhCO2H as additive,
the copper-catalyzed reaction could proceed smoothly and give
the corresponding amine products in moderate yields under mild
conditions. Further exploration of this powerful strategy in estab-
lishing new C–N bond formation reactions and reaction mecha-
nism are underway in our laboratory.
O
N
X
CH2
B
N
O
CuX
O
3a
CuX2
N
2a
O
N
O2+HX
H2O
Scheme 3. Plausible reaction mechanism.
Acknowledgments
Financial support provided by the National Natural Science
Foundation of China (21172226, 21133011 and 21222203), and
Chinese Academy of Sciences is gratefully acknowledged.
were tested in the oxidative amination reaction. 2-naphthalene
boronic acid 1n could give the desired product 3n in 57% yield
(Table 2, entry 14), but 4-(naphthalen-1-yl)morpholine 3m could
be only obtained in a relatively lower yield in the same reaction
conditions (Table 2, entry 13).
To further investigate the scope of the reaction, several aminals
derived from other secondary amines were also subjected to this
procedure under the optimized reaction conditions. To our delight,
aminals derived from both pyrroline 2o and piperidine 2p could
also prove to be appropriate substrates for this transformation
and the corresponding amine products were obtained in 34% and
45% yield, respectively. Besides, the unsymmetrical aminal 2q
could also undergo the coupling reaction and furnish the desired
product 3a as well as 3q in moderate yield. This result further sug-
gested that the two amine moieties of the aminal could participate
in the coupling reaction and transform to their corresponding
products under the reaction conditions (Scheme 2).
Although the mechanism of this transformation are not clear
yet at the present stage, on the basis of the results we obtained
previously,6 a plausible mechanism for this cross-coupling reaction
can be proposed as shown in Scheme 3. Initially, the aminal 2a
could react with Cu(acac)2 to generate copper amide A and imini-
um B. The iminium B could react with Cu(acac)2 quickly by hydro-
lysis to afford copper-amide intermediate A which could be
promoted by the benzoic acid. Next, complex C could be formed
Supplementary data
Supplementary data (experimental procedures and full charac-
terization of all products including 1H, 13C NMR and HRMS spectra)
associated with this article can be found, in the online version, at
http://dx.doi.org/10.1016/j.tetlet.2013.03.058.
References and notes
1. (a) Lawrence, S. A. Amines: Synthesis, Properties and Application; Cambridge
University Press: Cambridge, 2004; (b) Schlummer, B.; Scholz, U. Adv. Synth.
Catal. 2004, 346, 1599.
2. For reviews: (a) Ley, S. V.; Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42, 5400;
(b) Corbet, J.-P.; Mignani, G. Chem. Rev. 2006, 106, 2651; (c) Ma, D.; Cai, Q. Acc.
Chem. Res. 2008, 41, 1450; (d) Carril, M.; SanMartin, R.; Domínguez, E. Chem. Soc.
Rev. 2008, 37, 639; (e) Aubin, Y.; Fischmeister, C.; Thomas, C. M.; Renaud, J.-L.
Chem. Soc. Rev. 2010, 39, 4130; (f) Leyva-Pérez, A.; Sabater, M. J.; Corma, A. Chem.
Rev. 2011, 111, 1657; (g) Rauws, T. R. M.; Maes, B. U. W. Chem. Soc. Rev. 2012, 41,
2463; (h) Platon, M.; Amardeil, R.; Djakovitch, L.; Hierso, J.-C. Chem. Soc. Rev.
2012, 41, 3929.
3. For reviews, see: (a) Surry, D. S.; Buchwald, S. L. Angew. Chem., Int. Ed. 2008, 47,
6338; (b) Hartwig, J. F. Acc. Chem. Res. 2008, 41, 1534; (c) Surry, D. S.; Buchwald,
S. L. Chem. Sci. 2011, 2, 27; For selected reports on arylamine formation, see: (d)
Paul, F.; Patt, J.; Hartwig, J. F. J. Am. Chem. Soc. 1994, 116, 5969; (e) Guram, A. S.;
Buchwald, S. L. J. Am. Chem. Soc. 1994, 116, 7901; (f) Mann, G.; Driver, M. S.;
Fernández-Rivas, C.; Hartwig, J. F. J. Am. Chem. Soc. 1998, 120, 827; (g) Wolfe, J.
P.; Tomori, H.; Sadighi, J. P.; Yin, J.; Buchwald, S. L. J. Org. Chem. 2000, 65, 1158;

2716
Y. Zhou et al. / Tetrahedron Letters 54 (2013) 2713–2716
(h) Shen, Q.; Hartwig, J. F. J. Am. Chem. Soc. 2008, 128, 10028; (i) Shen, Q.; Ogata,
6. (a) Guo, S.; Qian, B.; Xie, Y.; Xia, C.; Huang, H. Org. Lett. 2011, 13, 522; (b) Xie, Y.;
Hu, J.; Wang, Y.; Xia, C.; Huang, H. J. Am. Chem. Soc. 2012, 134, 20613; (c) Xie, Y.;
Qian, B.; Xie, P.; Huang, H. Adv. Synth. Catal. 2013. http://dx.doi.org/10.1002/
adsc.201200944. Early view.
T.; Hartwig, J. F. J. Am. Chem. Soc. 2008, 130, 6586; (j) Ueda, S.; Su, M.; Buchwald,
S. L. Angew. Chem., Int. Ed. 2011, 50, 8944; (k) Ueda, S.; Buchwald, S. L. Angew.
Chem., Int. Ed. 2012, 51, 10364.
4. For leading references: (a) Chan, D. M. T.; Monaca, K. L.; Wanag, R.-P.; Winters,
M. P. Tetrahedron Lett. 1998, 39, 2933; (b) Lam, P. Y. S.; Clark, C. G.; Saubern, S.;
Adams, J.; Winters, M. P.; Chan, D. M. T.; Combs, A. Tetrahedron Lett. 1998, 39,
2941; (c) Combs, A. P.; Saubern, S.; Rafalski, M.; Lam, P. Y. S. Tetrahedron Lett.
1999, 40, 1623; (d) 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; (e) Lam, P. Y. S.; Clark,
C. G.; Subern, S.; Adams, J.; Averill, K. M.; Chan, D. M. T.; Combs, A. Synlett 2000,
5, 674; (f) Antilla, J. C.; Buchwald, S. L. Org. Lett. 2001, 3, 2077; (g) Quach, T. D.;
Batey, R. A. Org. Lett. 2003, 5, 4397; (h) He, C.; Chen, C.; Cheng, J.; Liu, C.; Liu, W.;
Li, Q.; Lei, A. Angew. Chem., Int. Ed. 2008, 47, 6414; (i) Qiao, J. X.; Lam, P. Y. S.
Synthesis 2011; (j) Matsuda, N.; Hirano, K.; Satoh, T.; Miura, M. Angew. Chem., Int.
Ed. 2012, 51, 3642; (k) Rucker, R. P.; Whittaker, A. M.; Dang, H.; Lalic, G. Angew.
Chem., Int. Ed. 2012, 51, 3953.
5. For studies on the metal-amide species for C–N bond formation reactions, see:
(a) Widenhofer, R. A.; Zhong, H. A.; Buchwald, S. L. Organometallics 1996, 15,
2745; (b) Widenhoefer, R. A.; Buchwald, S. L. Organometallics 1996, 15, 2755; (c)
Widenhoefer, R. A.; Buchwald, S. L. Organometallics 1996, 15, 3534; (d) Tye, J. W.;
Weng, Z.; Johns, A. M.; Incarvito, C. D.; Hartwig, J. F. J. Am. Chem. Soc. 2008, 130,
9971; (e) Giri, R.; Hartwig, J. F. J. Am. Chem. Soc. 2010, 132, 15860.
7. (a) Katritzky, A. R.; Shobana, N.; Harris, P. A. Tetrahedron Lett. 1991, 32, 4247; (b)
Tan, C. Y. K.; Wainman, D.; Weaver, D. F. Bioorg. Med. Chem. 2003, 11, 113; (c)
Wang, X.; Li, J.; Zhang, Y. Synth. Commun. 2003, 33, 3575; (d) Katritzky, A. R.;
Manju, K.; Singh, S. K.; Meher, N. K. Tetrahedron 2005, 61, 2555; (e) Hatano, B.;
Nagahashi, K.; Kijima, T. J. Org. Chem. 2008, 73, 9188.
8. General procedure for cross-coupling of phenylboronic acid with aminal:
Phenylboronic acid 1a (0.5 mmol), aminal 2a (0.3 mmol), Cu(acac)2
(0.05 mmol), PhCO2H (0.1 mmol),and CH3CN (1 mL) were added into a 25 mL
flame-dried Young-type tube under air. The mixture was stirred at 50 °C for
12 h, then the solvent was evaporated under reduced pressure and the residue
was purified by flash column chromatography on silica gel to give the desired
product.
9. For disproportionation of Cu(II)–Cu(III) and Cu(I), see: (a) King, A. E.; Brunold, T.
C.; Stahl, S. S. J. Am. Chem. Soc. 2009, 131, 5044; (b) King, A. E.; Huffman, L. M.;
Casitas, A.; Costas, M.; Ribas, X.; Stahl, S. S. J. Am. Chem. Soc. 2010, 132, 12068; (c)
Dai, C.; Huang, F.; Xu, Z.; Yu, Z.; Gao, Y.-F. J. Org. Chem. 2012, 77, 4414.