Metal catalyzed C(sp3)-H bond amination of 2-alkyl azaarenes with diethyl azodicarboxylate

Article abstract of DOI:10.1039/c2cc35309a

Metal-catalyzed direct C(sp³)-H bond amination of 2-alkyl azaarenes with NN double bonds has been developed, which expands the scope of C(sp³)-H bond activation reactions and provides a new access to medicinally important azaarene derivatives. The Royal Society of Chemistry 2012.

Full text of DOI:10.1039/c2cc35309a

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COMMUNICATION
Metal catalyzed C(sp3)–H bond amination of 2-alkyl azaarenes with
diethyl azodicarboxylatew
Jin-Ying Liu,a Hong-Ying Niu,b Shan Wu,a Gui-Rong Qu*a and Hai-Ming Guo*a
Received 23rd July 2012, Accepted 14th August 2012
DOI: 10.1039/c2cc35309a
Metal-catalyzed direct C(sp3)–H bond amination of 2-alkyl
Q
azaarenes with N N double bonds has been developed, which
expands the scope of C(sp3)–H bond activation reactions and
provides a new access to medicinally important azaarene
derivatives.
Ubiquity of the nitrogen-containing compounds among biologically
active molecules continues to drive the development of new C–N
bond-forming reactions.1 Transition-metal-catalyzed direct
amination of unactivated C(sp3)–H bonds without prefunction-
alized substrates is a desirable process to construct C–N bonds in
organic synthesis.2,3 Particularly, the addition of 2-alkyl azaarenes
to azodicarboxylates is of great importance due to the usefulness
of benzylic amines via deprotection in pharmaceutical synthesis.4
Azodicarboxylates are mainly used as an amination reagent
for the a-amination of aldehydes or ketones,5 but there is no
report on the metal-catalyzed benzylic C(sp3)–H amination
with azodicarboxylates.
Recently, the direct C(sp3)–H bond functionalization of
2-alkyl-substituted azaarenes catalyzed by palladium or Lewis
acid without an activating group has been developed.6 For
example, Huang and Rueping et al. reported the addition of
2-alkyl azaarenes to the CQN double bond of N-sulfonyl
aldimines7 (eqn 1, Scheme 1). Matsunaga and Kanai et al.
reported the direct addition of alkyl-substituted azaarenes to
the CQC double bond of enones promoted by Lewis acids8
(eqn 2, Scheme 1). Li and Guo et al. developed Brønsted acid
or Lewis acid catalyzed 2-methyl azaarenes addition to the
CQO double bond of isatins or aldehyde-ester9 (eqn 3,
Scheme 1). To the best of our knowledge, the addition of
2-alkyl azaarenes to the NQN double bond has not been
developed. According to the reported results, we postulated that
palladium or copper catalyzed addition of 2-alkyl azaarenes to
diethyl azodicarboxylate via direct C(sp3)–H activation might be
Scheme 1 C(sp3)–H bond functionalization with different double
bonds containing electrophiles.
feasible, which will expand the substrate scope of the direct
C(sp3)–H bond functionalization of 2-alkyl-substituted azaarenes.
Herein, we report the successful addition of 2-alkyl azaarenes to
the NQN double bond of azodicarboxylates via metal-catalyzed
benzylic C–H amination.
In order to test the practicality of our hypothesis, 2-methyl
quinoline 1a and diethyl azodicarboxylate 2a10 were initially
chosen as model substrates (Table 1). When the reaction was
performed in THF at 120 1C under a N2 atmosphere catalyzed
by palladium acetate in the presence of 1,10-phenanthroline in
a sealed reaction vessel according to the reported conditions
by Huang et al.,7a the anticipated hydrazide was not observed.
Considering that diethyl azodicarboxylate would decompose
under high pressure at high temperature with a metal catalyst,
the high boiling solvent DMF was used as the solvent to
reduce the pressure, and the desired product was given in 43%
yield as well as an unexpected diaminated product (entry 1).
To enhance the selectivity of the monoamination product, we
then screened the influence of the reaction temperature. We
were pleased to find that the monoamination product was
obtained in 67% isolated yield when the reaction temperature
was reduced from 120 1C to 90 1C (entry 3). Further decreasing
the reaction temperature to 80 1C led to a lower yield of 53%
(entry 4). Then, the effect of solvents was examined. The reaction
was found to proceed much better in polar solvents than in
nonpolar ones, and DMSO was found to be an optimal selection
(entries 10–15). A screening of potential catalysts, including
Cu(OTf)2, Cu(OAc)2, CuI, PdCl2 and Ni(acac)2ꢀ2H2O, showed
that palladium acetate was still to be the most efficient catalyst
a College of Chemistry and Environmental Science, Key Laboratory of
Green Chemical Media and Reactions of Ministry of Education,
Henan Normal University, Xinxiang 453007, Henan, China.
E-mail: quguir@sina.com, guohm518@hotmail.com;
Fax: +86 373 3329276; Tel: +86 373 3329255
b School of Chemistry and Chemical Engineering, Henan Institute of
Science and Technology, Xinxiang 453003, China
w Electronic supplementary information (ESI) available: Experimental
procedures, compound characterizations, and the copies of H NMR
1
and 13C NMR spectra. See DOI: 10.1039/c2cc35309a
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 9723–9725 9723

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Table 1 Optimization of the reaction conditionsa
Table 2 Substrate scope of 2-alkyl quinolinesa
Entry
1
Substrate
Time/h
18
Product
Yieldb/%
72
Entry Catalyst
Ligand
Solvent T/1C Yieldb/%
1
2
3
4
Pd(OAc)2 1,10-Phenanthroline DMF
Pd(OAc)2 1,10-Phenanthroline DMF
Pd(OAc)2 1,10-Phenanthroline DMF
Pd(OAc)2 1,10-Phenanthroline DMF
120
100
90
80
90
90
90
90
90
43/13c
54/8c
67d
53
61
28
38
30
0
58
5
6
PdCl2
Ni(acac)2 None
1,10-Phenanthroline DMF
DMF
2
3
4
5
6
7
8
12
18
18
18
24
24
84
78
75
73
41
48
7
8
Cu(OTf)2 1,10-Phenanthroline DMF
Cu(OAc)2 1,10-Phenanthroline DMF
9
CuI
1,10-Phenanthroline DMF
10
11
12
13
14
15
16
17
Pd(OAc)2 1,10-Phenanthroline Dioxane 90
Pd(OAc)2 1,10-Phenanthroline Toluene
Pd(OAc)2 1,10-Phenanthroline DCE
Pd(OAc)2 1,10-Phenanthroline THF
Pd(OAc)2 1,10-Phenanthroline i-PrOH
Pd(OAc)2 1,10-Phenanthroline DMSO
90
90
90
90
90
90
90
13
50
17
0
72d
63
Pd(OAc)2 DPPP
Pd(OAc)2 None
DMSO
DMSO
18
a
Unless otherwise stated, all reactions were carried out with 1a
(0.75 mmol), 2a (0.3 mmol), catalyst (5 mol%), ligand (5 mol%),
b
solvent (1.5 mL), 18 h. Yield of 3a was determined by HPLC.
c
d
Monoaminated product/diaminated product. Isolated yield of 3a.
(entries 5–9). And 1,10-phenanthroline was essential to this
transformation (entry 17).
With the optimal conditions in hand, the scope of various
2-alkyl quinolines with electron-neutral, electron-donating or
electron-withdrawing groups, such as OCH3, CH3, NO2, CF3,
Br or Cl, was examined (Table 2). The results revealed that the
reaction was tolerant of a wide variety of functional groups.
Obviously, the reaction was greatly affected by the electronic
nature of the functional groups. When the H atom at the C6 of
quinoline was substituted with electron-withdrawing groups
(such as NO2, CF3, Br, Cl), the reaction proceeded smoothly
and provided the corresponding products in good yields
(73–84%, entries 2–5). However, replacement of H by an
electron-donating group (OCH3) at the C6 made the reaction
sluggish with 41% yield (entry 6). Then, the influence of the
substituents at the C8 position was also investigated. Unfortunately,
when the C8 position of the 2-alkyl quinolines was substituted
with an electron-withdrawing group such as nitro group
(NO2), no expected product was formed, and the substrates
with electron-donating substituents at the C8 gave relatively
lower yields (42–48%, entries 7–8). Generally, the C6-substituted
2-methyl quinolines gave higher yields than C8-substituted
2-methyl quinolines, which might be caused by not only electronic
effect but also steric interference of the C8 substituents which
might affect the coordination of metal catalyst to the nitrogen
atom of quinolines. And 2-ethyl-6-nitroquinoline was also
examined and 54% yield was obtained (entry 9).
24
24
42
54
9
a
Unless otherwise stated, all reactions were carried out with 1a
(0.75 mmol), 2a (0.3 mmol), Pd(OAc)2 (5 mol%), 1,10-phenanthroline
b
(5 mol%), DMSO (1.5 mL), 90 1C. Isolated yield.
Scheme 2 The palladium-catalyzed diamination reaction.
1,10-phenanthroline, the reaction afforded the diamine products
in 48–71% yields (Scheme 2). The successful diamination of
2-methyl quinolines provides a simple access to benzylic diamines
which are difficult to obtain by the conventional methods.
Prompted by the successful C(sp3)–H amination of 2-alkyl-
quinolines, we next investigated the scope of the 2-alkyl pyridines.
The optimal conditions for quinolines were not applicable to
2-alkyl pyridines due to their different properties. Then we made a
modification of the reaction conditions, and relatively satisfactory
yields (45–63%) were obtained at 110 1C within 12 h by
using 10 mol% of Cu(OTf)2 as the catalyst and 10 mol% of
1,10-phenanthroline as the ligand (entries 2–5, Table 3).
In addition, it was found that the reaction of 2-methyl
quinolines (1a–1d) also gave the corresponding diamines
3aa–3dd in moderate to good yields under a relatively simple
modification of the optimal conditions (Scheme 2). When the
amount of diethyl azodicarboxylate was enhanced to 3.0 equivalents
at 110 1C promoted by 10 mol% of Pd(OAc)2 and 10 mol% of
c
9724 Chem. Commun., 2012, 48, 9723–9725
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Table 3 Substrate scope of 2-alkyl pyridinesa
and Innovative Research Team in University (IRT1061), and
the Excellent Youth Program of Henan Normal University.
Notes and references
1 (a) C. Kibayashi, Chem. Pharm. Bull., 2005, 53, 1375;
(b) J. H. Cheng, K. Kamiya and I. Kodama, Cardiovasc. Drug
Rev., 2001, 19, 152; (c) C. Sanchez, C. Mendez and J. A. Salas,
Nat. Prod. Rep., 2006, 23, 1007.
2 For recent reviews on catalytic C–H amination, see: (a) M. Johannsen
and K. A. Jørgensen, Chem. Rev., 1998, 98, 1689; (b) F. Collet,
R. H. Dodd and P. Dauban, Chem. Commun., 2009, 5061;
(c) D. N. Zalatan and J. Du Bois, Top. Curr. Chem., 2010,
292, 347; (d) S. H. Cho, J. Y. Kim, J. Kwak and S. Chang, Chem.
Soc. Rev., 2011, 40, 5068; (e) T. A. Ramirez, B. Zhao and Y. Shi,
Chem. Soc. Rev., 2012, 41, 931.
Entry
1
Substrate
Product
Yieldb (%)
63c
2
3
4
54
58
3 For examples of unactivated C(sp3)–H bonds aminations, see:
(a) H. Y. Thu, W. Y. Yu and C. M. Che, J. Am. Chem. Soc.,
2006, 128, 9048; (b) Y. M. Badiei, T. R. Cundari and T. H. Warren,
Angew. Chem., Int. Ed., 2008, 47, 9961; (c) J. Neumann, S. Rakshit,
T. Droge and F. Glorius, Angew. Chem., Int. Ed., 2009, 48, 6892;
(d) S. Wiese, Y. M. Badiei, R. T. Gephart, S. Mossin,
M. S. Varonka, M. M. Melzer, K. Meyer, T. R. Cundari and
T. H. Warren, Angew. Chem., Int. Ed., 2010, 49, 8850; (e) J. Pan,
M. Su and S. L. Buchwald, Angew. Chem., Int. Ed., 2011, 50, 8647;
(f) Z. Ni, Q. Zhang, T. Xiong, Y. Zheng, Y. Li, H. Zhang, J. Zhang
and Q. Liu, Angew. Chem., Int. Ed., 2012, 51, 1244; (g) A. Iglesias,
R. Alvarez and K. Muniz, Angew. Chem., Int. Ed., 2012, 51, 2225.
4 D. Moffat, S. Patel, F. Day, A. Belfield, A. Donald, M. Rowlands,
J. Wibawa, D. Brotherton, L. Stimson, V. Clark, J. Owen,
L. Bawden, G. Box, E. Bone, P. Mortenson, A. Hardcastle,
S. van Meurs, S. Eccles, F. Raynaud and W. Aherne, J. Med.
Chem., 2010, 53, 8663.
5 For examples of azodicarboxylates as the aminating agent, see:
(a) A. Bøgevig, K. Juhl, N. Kumaragurubaran, W. Zhuang and
K. A. Jørgensen, Angew. Chem., Int. Ed., 2002, 41, 1790;
(b) M. Terada, M. Nakano and H. Ube, J. Am. Chem. Soc.,
2006, 128, 16044; (c) T. Y. Liu, H. L. Cui, Y. Zhang, K. Jiang,
W. Du, Z. Q. He and Y. C. Chen, Org. Lett., 2007, 9, 3671;
(d) H. Konishi, T. Y. Lam, J. P. Malerich and V. H. Rawal, Org.
Lett., 2010, 12, 2028; (e) J. Y. Fu, Q. C. Yang, Q. L. Wang,
J. N. Ming, F. Y. Wang, X. Y. Xu and L. X. Wang, J. Org. Chem.,
2011, 76, 4661.
51
45
5
a
Unless otherwise stated, all reactions were carried out with 4b–f
(0.75 mmol), 2a (0.3 mmol), Cu(OTf)2 (10 mol%), 1,10-phenanthro-
b
c
line (10 mol%), THF (1.5 mL), 110 1C, 12 h. Isolated yield. The
reactions were carried out with 4a (0.75 mmol), 2a (0.3 mmol),
Pd(OAc)2 (5 mol%), 1,10-phenanthroline (5 mol%), DMSO (1.5 mL),
110 1C, 18 h.
2-Methyl pyridine gave the corresponding product in good
yield when the reaction was conducted at 110 1C for 18 h in
DMSO by using Pd(OAc)2 as the catalyst (entry 1).
In conclusion, we have developed a novel metal-catalyzed
benzylic C(sp3)–H amination of 2-alkyl azaarenes with diethyl
dicarboxylates, which expands the substrate scope of the direct
C(sp3)–H bond functionalization of 2-alkyl-substituted azaarenes.
The present work is a highly selective and practical methodology
for the synthesis of amines and alkyl hydrazides. More detailed
mechanistic studies and applications of this method in the synthesis
of heterocyclic compounds are underway.
6 For selected reactions of prefunctional alkyl-azaarenes, see:
(a) L. C. Campeau, D. J. Schipper and K. Fagnou, J. Am. Chem.
Soc., 2008, 130, 3266; (b) J. J. Mousseau, A. Larivee and
A. B. Charette, Org. Lett., 2008, 10, 1641; (c) D. J. Schipper,
L. C. Campeau and K. Fagnou, Tetrahedron, 2009, 65, 3155.
7 (a) B. Qian, S. Guo, J. Shao, Q. Zhu, L. Yang, C. Xia and
H. M. Huang, J. Am. Chem. Soc., 2010, 132, 3650;
(b) M. Rueping and N. Tolstoluzhsky, Org. Lett., 2011, 13, 1095.
8 H. Komai, T. Yoshino, S. Matsunaga and M. Kanai, Org. Lett.,
2011, 13, 1706.
We are grateful for financial support from the National
Natural Science Foundation of China (Grant No. 21072047,
21272059 and 21172059), the Program for New Century
Excellent Talents in University of Ministry of Education
(No. NCET-09-0122), Excellent Youth Foundation of Henan
Scientific Committee (No. 114100510012), the Program for
Innovative Research Team in University of Henan Province
(2012IRTSTHN006), the Program for Changjiang Scholars
9 (a) R. Niu, J. Xiao, T. Liang and X. Li, Org. Lett., 2012, 14, 676;
(b) J. J. Jin, H. Y. Niu, G. R. Qu, H. M. Guo and J. S. Fossey,
RSC Adv., 2012, 2, 5968.
10 The fact is that diisopropyl azodiformate can give similar yield, but
2,20-azobis(2-methylpropionitrile)
azobenzene
PhNQNPh,
NC(CH3)2CNQNC(CH3)2CN are unreactive. So we believed that
the ester group attached to the nitrogen double bond is essential for
this transformation.
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 9723–9725 9725