C(sp3)-C(sp3) bond formation via copper/ Bronsted acid co-catalyzed C(sp3)-H bond oxidative cross-dehydrogenative-coupling (CDC) of azaarenes

Article abstract of DOI:10.1039/c4gc00038b

A copper/Bronsted acid dual-catalyst promoted oxidative cross-dehydrogenative-coupling of alkylazaarenes and tertiary amines for C(sp³)-C(sp³) bond formation was developed. This method uses dioxygen as the terminal oxidant under mild reaction conditions and would provide a convenient benzylic C-H transformation of alkylazaarenes to biologically active pharmaceutics. the Partner Organisations 2014.

Full text of DOI:10.1039/c4gc00038b

View Article Online
View Journal
Green
Chemistry
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: F. Wang, C. Luo,
G. Deng and L. Yang, Green Chem., 2014, DOI: 10.1039/C4GC00038B.
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/greenchem

Page 1 of 5
Green Chemistry
View Article Online
DOI: 10.1039/C4GC00038B
Abstract for the Contents Pages
C(sp3)-C(sp3) bond formation via
Copper/Brønsted acid Co-catalyzed C(sp3)–H
bond Oxidative
Cross-Dehydrogenative-Coupling (CDC) of
Azaarenes
Graphic:
Fang-Fang Wang, Cui-Ping Luo, Guojun Deng, and Luo Yang*
Text:
A copper/Brønsted acid dual-catalyst promoted oxidative
cross-dehydrogenative-coupling of alkylazaarenes and tertiary
amines for C(sp3)-C(sp3) bond formation was developed by
using dioxygen as the terminal oxidant under mild reaction
conditions.

View Article Online
Dynamic DAOrI:t1i0c.1l0e39L/Ci4nGCk0s00►38B
Green Chemistry
Page 2 of 5
Green Chemistry
Cite this: DOI: 10.1039/c0xx00000x
www.rsc.org/xxxxxx
COMMUNICATION
C(sp3)-C(sp3) bond formation via Copper/Brønsted acid Co-catalyzed
C(sp3)–H bond Oxidative Cross-Dehydrogenative-Coupling (CDC) of
Azaarenes
Fang-Fang Wang, Cui-Ping Luo, Guojun Deng and Luo Yang*
5
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
A copper/Brønsted acid dual-catalyst promoted oxidative
cross-dehydrogenative-coupling of alkylazaarenes and
tertiary amines for C(sp3)-C(sp3) bond formation was
10 developed. This method uses dioxygen as the terminal oxidant
under mild reaction conditions and would provide convenient
benzylic C-H transformation of alkylazaarenes to biological
active pharmaceutics.
Quinoline and isoquinoline derivatives are among the most
15 common skeletons in natural alkaloids and pharmaceutics with
various interesting biological activities. 1 As a result, great effort
has been directed to the functionalization of these azaarenes.
While the traditional benzylic transformation via deprotonation of
the weak acidic benzylic proton and subsequent nucleophic
20 substitution/addition to highly reactive polar electrophiles
requires strong base such as nBuLi or LDA (Scheme 1, route a), 2
the recent research3 revealed this transformation can be
50 Scheme 1. Benzylic C-H nucleophilic functionalization of
azaarenes
accelerated by shifting the alkylazaarene to its enamine
4a-d, 6a-c
counterpart using a suitable Lewis
25 (Scheme 1, route b).
or Brønsted acid
5a-c
However the substrate scope remains
mostly limited to highly reactive polar electrophiles, such as
imines, 4 carbonyl groups, 5 Michael acceptors7 and olfins7. The
benzylic nucleophilic reaction of alkylazaarenes with other
electron-neutral reagents is rare. Recently, the oxidative
30 olefination of 2-methylazaarenes using TBHP, K2S2O8 or DDQ
as oxidant was reported by Wang8a, Xu8b and Tian8c (Scheme 1,
route c). A convenient benzylic C-H cross-dehydrogenative-
coupling of alkylazaarenes with electron-neutral reagents to form
C(sp3)-C(sp3) would be highly expected (Scheme 1, route d).
35
In line with our interests in the C-H activation and nucleophilic
5a, 9
5a
additions,
our previous studies
discovered that Brønsted
acids turned out to be effective catalyst for the benzylic C-H
addition to carbonyl groups. On the other hand, the oxidation of
Scheme 2. Possible catalytic cycle for Dual-catalyst promoted
CDC of azaarenes
40 Key Laboratory for Environmentally Friendly Chemistry and Application
of the Ministry of Education,
Department of Chemistry, Xiangtan University, Hunan, 411105, China
Fax: +86-731-58292251; Tel: +86-731-58298351;
E-mail: yangluo@xtu.edu.cn
55
C-H bonds adjacent to nitrogen10, 11 is one of the most important
and successful strategies for C-H functionalization to form
electrophilic iminium ions in the presence of a copper catalyst. In
this context, we envisioned a C(sp3)-C(sp3) bond forming process
60 of 2-methylazaarenes and tetrahydroisoquinolines promoted by a
dual-catalyst system composed of a Brønsted acid and a copper
catalyst, in which the Brønsted acid can convert the 2-
45 † Electronic Supplementary Information (ESI) available: experimental
details,
synthesis
and
characterisation
of
products.
See
DOI: 10.1039/b000000x/
This journal is © The Royal Society of Chemistry [year]
[journal], [year], [vol], 00–00 | 1

View Article Online
DOI: 10.1039/C4GC00038B
Page 3 of 5
Green Chemistry
methylazaarene to its more nucleophic enamine counterpart
12
13
14
15
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
PivOH (25)
PivOH (25)
PivOH (25)
PivOH (25)
25
40
80
60
DCE
DCE
DCE
66
73
42
69
(Scheme 2, intermediate A) and the copper catalyst can generate
the reactive electrophilic iminium ion (intermediate B) 10k assisted
by oxidant.
1,4-
dioxane
5
Though the most common and widely used combination for the
oxidation of C-H bonds adjacent to nitrogen is copper/TBHP, 10
obviously the copper/dioxygen combination should be much
more attractive considering dioxygen is readily available, cheap
16
17
18
19
20
21
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
--
PivOH (25)
PivOH (25)
PivOH (25)
PivOH (25)
PivOH (25)
--
60
60
60
60
60
60
Toluene
DMF
tBuOH
CH3CN
DCE
54
63
10l
75
and environmentally benign with only water as byproduct.
10 With this in mind, we first examined the reaction of 2-
methylquinoline (1a) and N-phenyltetrahydroisoquinoline (2a)
catalyzed by CuI and pivalic acid (PivOH) under O2 atmosphere
based on our early work (Table 1, entry 1). To our delight, the
desired oxidative cross-dehydrogenative-coupling product 3a was
15 obtained in 32% yield. During the following optimization study,
we first examined the influence of different copper catalysts.
Common copper catalysts such as CuBr, CuCl, Cu(OAc)2 and
Cu(OTf)2 were screened and Cu(OTf)2 turned out to be the most
effective one (entries 2-5). Next, Brønsted acids with varied
20 acidity were tested and the relatively weak pivalic acid was found
to match Cu(OTf)2 best (entries 6-8). The quantity of Brønsted
acids can be decreased to 10 mol% and a comparable yield was
observed (entry 9). Instead of the O2 atmosphere, much lower
yield was obtained when the CDC was conducted in air (entry 11).
25 Gratifyingly, the reaction can proceed at room temperature with
moderate yield (entry 12), but at higher temperature, the desired
product 3a would undergo further oxidation monitored by the
GC-MS (entry 14). Next, the effect of solvent on this reaction
was investigated and the most satisfactory yield was obtained in
30 low polarity dichloroethane (DCE), other polar or even protic
solvents were also applicable (entries 15-19). It is worthy noting
that both the copper catalyst and the Brønsted acid were essential
for the CDC revealed by the control experiments (entries 20 and
21). Without the copper catalyst, no product 3a was detected and
35 without the Brønsted acid the reaction resulted in very low yield.
74
Trace
23
Cu(OTf)2
DCE
a
Conditions: 1a (0.4 mmol), 1b (0.2 mmol), Cu/Brønsted acid (BA),
solvent (0.5 mL), reacted for 36 h under O2 (1 atm) unless
otherwise noted.
b
c
Isolated yields.
Reacted under air (1 atm).
40
Under the optimized conditions (Table 1, entry 5), the substrate
scope and limitation12 of this dual-catalyst promoted CDC was
explored. The effect of substituents on the alkylquinoline moiety
is listed in Table 2. 2-Methylquinoline bearing electron donating
45 or withdrawing substituents were successfully transformed into
the desired products in moderate to high yields, such as methyl
(1b), methoxyl (1c), halo (1d-1g), phenyl (1h), trifluoromethyl
(1i) and nitro (1g). Besides 2-methylquinolines, the optimized
dual-catalyst system can also be applied to the CDC of 2-
50 methylquinoxaline (1k) or 2,3-dimethylquinoxaline (1l) with N-
phenyltetrahydroisoquinoline (2a). However, the reaction of 2-
methylpyridine (or 2,6-lutidine) under the same conditions was
failed for unknown reason. At elevated temperature (80 °C), the
N-phenyltetrahydroisoquinoline (2a) was oxidized to N-phenyl-
55 3,4-dihydroisoquinolin-1-one and with the 2-methylpyridine
remained intact. 13 Next, the effect of substituents on the phenyl
group of tetrahydroisoquinoline moiety was also investigated
(Table 3). We were pleased to observe that the substituents on the
phenyl group such as methyl (2b), methoxyl (2c) and halo (2d-2f)
60 were all tolerated.
Table 1. Optimization of the dual-catalyst promoted benzylic
CDC of azaarenes a
Table 2. The effect of substituents on the 2-methylazaarene
moiety a
Entry
Cu
BA (mol%)
Temp.
[oC]
Solvent
Yield
[%]
b
(5 mol%)
1
2
CuI
CuBr
PivOH (25)
60
60
60
60
60
60
60
60
60
60
60
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
32
50
19
67
90
67
60
64
85
62
49
PivOH (25)
PivOH (25)
AcOH (25)
PivOH (25)
AcOH (25)
PhCO2H (25)
p-TSA (25)
PivOH (10)
PivOH (50)
PivOH (25)
1a
1b
R = 6-CH3, X = CH
R = H,
X = CH
3
CuCl
1c
1e
1g
R = 6-OCH3, X = CH
R = 6-Cl, X = CH
1d
1f
R = 6-F,
X = CH
X = CH
4
Cu(OAc)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
R = 6-Br,
5
1h
6
R = 6-I, X = CH
R = 6-Ph,
X = CH
7
1i
1j
1l
R = 6-CF3, X = CH
R = 6-NO2, X = CH
R = 3-CH3, X = N
8
1k
R = H,
X = N
9
10
c
11
2
| Journal Name, [year], [vol], 00–00
This journal is © The Royal Society of Chemistry [year]

View Article Online
Green Chemistry
DOI: 10.1039/C4GC00P03a8gBe 4 of 5
15 This work was supported by the National Natural Science
Foundation of China (21202138), Xiangtan University
“Academic Leader Program” (11QDZ20), New Teachers' Fund
for Doctor Stations, Ministry of Education (20124301120007),
University Student Innovation Program, Ministry of Education
20 (201210530008) and Project of Hunan Provincial Natural Science
Foundation (13JJ4047, 12JJ7002), Excellent Young Scientist
Foundation of
(13B114).
Hunan Provincial Education Department
The authors declare no competing financial interest.
25 Notes and references
1
(a) L.-C. Campeau, K. Fagnou, Chem. Soc. Rev. 2007, 36, 1058. (b)
M. C. Bagley, C. Glover, E. A. Merritt, Synlett 2007, 2459. (c) G. D.
Henry, Tetrahedron 2004, 60, 6043. (d) B. H. Heasley, R. Jarosz, K.
M. Carter, S. J. Van, K. R. Lynch, T. L. Macdonald, Bioorg. Med.
Chem. Lett. 2004, 14, 4069.
30
35
40
45
2
For traditional benzylic transformation via deprotonation: (a) E.
Klingsberg, The Chemistry of Heterocyclic Compounds, Pyridine and
Its Derivatives, Wiley, Hoboken, 2009. (b) C. A. Ramsden, J. A.
Joule, V. V. Zhdankin, A. R. Katritzky, Handbook of Heterocyclic
Chemistry, 3rd ed., Elsevier Science & Technology Books, San
Diego, 2010. (c) S. Danishefsky, A. Zimmer, J. Org. Chem. 1976, 41,
4059. (d) E. Pasquinet, P. Rocca, F. Marsais, A. Godard, G.
Quéguiner, Tetrahedron 1998, 54, 8771. (e) V. Rabe, W. Frey, A.
Baro, S. Laschat, M. Bauer, H. Bertagnolli, S. Rajagopalan, T.
Asthalter, E. Roduner, H. Dilger, T. Glaser, D. Schnieders, Eur. J.
Inorg. Chem. 2009, 4660. (f) N. N. Goldberg, R. Levine, J. Am.
Chem. Soc. 1952, 74, 5217. (g) D. F. Taber, P. Guo, M. T. Pirnot, J.
Org. Chem. 2010, 75, 5737.
For recent reports on benzylic arylation: (a) M. L. Hlavinka, J. R.
Hagadorn, Organometallics 2007, 26, 4105. (b) J. J. Mousseau, A.
Larivee, A. B. Charette, Org. Lett. 2008, 10, 1641. (c) S. Duez, A. K.
Steib, S. M. Manolikakes, P. Knochel, Angew. Chem., Int. Ed. 2011,
50, 7686. (d) G. Song, Y. Su, X. Gong, K. Han, X. Li, Org. Lett.
2011, 13, 1968.
a
Conditions: 1a-1l (0.4 mmol), 2a (0.2 mmol), Cu(OTf)2 (3.6 mg, 5
mol%, 0.01 mmol), pivalic acid (5.1 mg, 25 mol%, 0.05 mmol), DCE
(0.5 mL), reacted for 24 h at 60 °C under 1 atm O2 unless otherwise
noted. Isolated yields.
Table 3. The effect of substituents on the phenyl group of
tetrahydroisoquinoline moiety a
3
50 4 (a) B. Qian, S. Guo, J. Shao, Q. Zhu, L. Yang, C. Xia, H. Huang, J.
Am. Chem. Soc. 2010, 132, 3650. (b) B. Qian, S. Guo, C. Xia, H.
Huang, Adv. Synth. Catal. 2010, 352, 3195. (c) M. Rueping, N.
Tolstoluzhsky, Org. Lett. 2011, 13, 1095. (d) B. Qian, P. Xie, Y. Xie,
H. Huang, Org. Lett. 2011, 13, 2580. (e) Y. Yan, K. Xu, Y. Fang, Z.
entry
Product 3m-3q Yield (%)[a]
Substrate 2b-2f
55
60
65
70
Wang, J. Org. Chem. 2011, 76, 6849. (f) J.-Y. Liu, H.-Y. Niu, S. Wu,
G.-R. Qu, H.-M. Guo, Chem. Commun. 2012, 48, 9723.
1
2
3
4
2b
2c
2d
2e
1f
3m
3n
3o
3p
3q
74
87
69
78
72
R’ = CH3
5
(a) F.-F. Wang, C.-P. Luo, Y. Wang, G. Deng, L. Yang, Org. Biomol.
Chem. 2012, 10, 8605. (b) R. Niu, J. Xiao, T. Liang, X. Li, Org. Lett.
2012, 14, 676. (c) J.-J Jin, D.-C Wang, H.-Y. Niu, S. Wu, G.-R. Qu,
Z.-B. Zhang, H.-M. Guo, Tetrahedron 2013, 69, 6579. (d) V. B.
Graves, A. Shaikh, Tetrahedron Lett. 2013, 54, 695. (e) N. N. Rao, H.
M. Meshram, Tetrahedron Lett. 2013, 54, 5087.
(a) H. Komai, T. Yoshino, S. Matsunage, M. Knai, Org. Lett. 2011, 13,
1706. (b) Y. Yang, C. Xie, Y. Xie, Y. Zhang, Org. Lett. 2012, 14,
957. (c) H.-Y. Li, L.-J. Xing, T. Xu, P. Wang, R.-H. Liu, B. Wang,
Tetrahedron Lett. 2013, 54, 858. (d) N. N. Rao, H. M. Meshram,
Tetrahedron Lett. 2013, 54, 1315. (e) B. Qian, L. Yang, H. Huang,
Tetrahedron Lett. 2013, 54, 711.
B.-T. Guan, B. Wang, M. Nishiura, Z. Hou, Angew. Chem., Int. Ed.
2013, 52, 4418.
(a) S.-J. Lou, D.-Q. Xu, D.-F. Shen, Y.-F. Wang, Y.-K. Liu, Z.-Y. Xu,
Chem. Commun. 2012, 48, 11993. (b) Y. Li, F. Guo, Z. Zha, Z. Yang,
Chem. Asian. J. 2013, 8, 534. (c) Y.-G. Zhang, J.-K. Xu. X.-M. Li,
S.-K. Tian, Eur. J. Org. Chem. 2013, 3468.
R’ = OCH3
R’ = F
R’ = Cl
R’ = Br
5
6
a
Conditions: 1a (0.4 mmol), 2b-2f (0.2 mmol), Cu(OTf)2 (3.6 mg, 5
mol%, 0.01 mmol), pivalic acid (5.1 mg, 25 mol%, 0.05 mmol),
DCE (0.5 mL), reacted for 24 h at 60 °C under 1 atm O2 unless
otherwise noted. Isolated yields.
5
7
8
In conclusion, we have developed an efficient C(sp3)-C(sp3)
bond forming process by the oxidative-cross-coupling of benzylic
C-H bond of alkylazaarenes and tetrahydroisoquinolines, which
was promoted by the copper/Brønsted acid dual-catalyst system
10 and using dioxygen as the terminal oxidant under mild reaction
conditions. This reaction would provide an efficient method for
the benzylic C-H transformation of 2-alkylazaarenes to biological
active pharmaceutics.
75 9 (a) L. Yang, C. A. Correia, C.-J. Li, Adv. Synth. Catal. 2011, 353,
1269. (b) L. Yang, Q. Shuai, C.-J. Li, Org. Biomol. Chem. 2011, 9,
7176-7179. (c) R.-J. Tang, C.-P. Luo, L. Yang, C.-J. Li, Adv. Synth.
Catal. 2013, 355, 869.
10 (a) C.-J. Li, Acc. Chem. Res. 2009, 42, 335. (b) L. Zhao, O. Basle,
80
C.-J. Li, Proc. Natl. Acad. Sci. U.S.A. 2009, 106, 4106. (c) Z. Li, C.-J.
Li, J. Am. Chem. Soc. 2005, 127, 3672. (d) Z. Li, C.-J. Li, J. Am.
Chem. Soc. 2005, 127, 6968. (e) Y. Zhang, C.-J. Li, Angew. Chem.,
Int. Ed. 2006, 45, 1949. (f) C. J. Scheuermann, Chem. Asian. J. 2010,
Acknowledgements
This journal is © The Royal Society of Chemistry [year]
Journal Name, [year], [vol], 00–00 | 3

View Article Online
DOI: 10.1039/C4GC00038B
Page 5 of 5
Green Chemistry
5, 436. (g) C. A. Correia, C.-J. Li, Adv. Synth. Catal. 2010, 352, 1446.
(h) M.-Z. Wang, C.-Y. Zhou, M.-K. Wong, C.-M. Che, Chem. Eur. J.
2010, 16, 5723. (i) K. Alagiri, G. S. R. Kumara, K. R. Prabhu, Chem.
Commun. 2011, 47, 11787. (j) J. Dhineshkumar, M. Lamani, K.
Alagiri, K. R. Prabhu, Org. Lett. 2013, 15, 1092. (k) E. Boess, C.
Schmitz, M. Klussmann, J. Am. Chem. Soc. 2012, 134, 5317. (l) O.
Basl, C.-J. Li, Green Chem. 2007, 9, 1047. (m) Y. Shen, M. Li, S.
Wang, T. Zhan, Z. Tan, C.-C. Guo, Chem. Commun. 2009, 45, 953.
(n) O. Basl, N. Borduas, P. Dubois, J. M. Chapuzet, T.-H. Chan, J.
Lessard, C.- J. Li, Chem. Eur. J. 2010, 16, 8162. (o) S.-G. Pan, J.-H.
Liu, Y.-M. Li, Z.-P. Li, Chin. Sci. Bull. 2012, 57, 2382. (p) Z.-P. Li,
L. Cao, C.-J. Li, Angew. Chem., Int. Ed. 2007, 46, 650.
5
10
11 For reviews of C-C bond formations involving CDC reactions, see: (a)
C. Zhang, C.-H. Tang, N. Jiao, Chem. Soc. Rev. 2012, 41, 3464. (b)
K. M. Jones, M. Klussmann, Synlett 2012, 23, 159. (c) L. Shi, W. Xia,
Chem. Soc. Rev. 2012, 41, 7687. (d) E. A. Mitchell, A. Peschiulli, N.
Lefevre, L. Meerpoel, B. U. W. Maes, Chem. Eur. J. 2012, 18, 10092.
(e) C. S. Yeung, V. M. Dong, Chem. Rev. 2011, 111, 1215. (f) S.-I.
Murahashi, D. Zhang, Chem. Soc. Rev. 2008, 37, 1490. (g) K. R.
Compos, Chem. Soc. Rev. 2007, 36, 1069. (h) Z. Li, D. S. Bohle, C.-J.
Li, Proc. Natl. Acad. Sci. U.S.A. 2006, 103, 8928.
15
20
12 The optimized reaction conditions can also be applied to 2-
ethylquinoline, but with much lower yield (31%) and moderate
diastereoselectivities (trans/cis = 86 : 14).
25 13 The reaction of 2-methylpyridine with tetrahydroisoquinoline has been
tried both at 60 oC (which is the optimized temperature ) or 80 oC, but
no CDC product was found indicated by GC-MS.
4
| Journal Name, [year], [vol], 00–00
This journal is © The Royal Society of Chemistry [year]