Copper catalyzed C-H functionalization for direct Mannich reactions

Article abstract of DOI:10.1021/ol103150g

A protocol for a practical and direct addition of α-and γ-alkyl azaarenes to N-sulfonyl aldimines has been developed. Copper salts act as efficient Lewis acid catalysts for direct Mannich-type reactions providing a mild and fast access to various functionalized heterocycles.(Figure Presented)

Full text of DOI:10.1021/ol103150g

ORGANIC
LETTERS
2011
Vol. 13, No. 5
1095–1097
Copper Catalyzed C-H Functionalization
for Direct Mannich Reactions
Magnus Rueping* and Nikita Tolstoluzhsky
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074
Aachen, Germany
Magnus.Rueping@rwth-aachen.de
Received December 27, 2010
ABSTRACT
A protocol for a practical and direct addition of R- and γ-alkyl azaarenes to N-sulfonyl aldimines has been developed. Copper salts act as efficient
Lewis acid catalysts for direct Mannich-type reactions providing a mild and fast access to various functionalized heterocycles.
The concept of atom economy has driven chemists to
develop more efficient and sustainable methodologies for
new bond forming reactions. In this context, the C-H
activation strategy plays a key role. Although the activa-
tion of an aromatic C-H bond is well documented,1 the
activation of a methyl group directly attached to an
aromatic ring remains much less explored. Significant
contributions to this field have been made by Fagnou
and Charette who studied the palladium catalyzed C-H
activation of alkyl-substituted azine N-oxides and N-imi-
nopyridinium ylides.2,3 Withregard tothe use of substrates
that lack a suitably located activating group, Huang and
co-workers recently reported the palladium catalyzed
benzylic addition of 2-methyl azaarenes to N-sulfonyl-
imines.4,5 In their report, the authors proposed a mecha-
nism involving the activation of the 2-methyl group via a
palladium(II) species (Figure 1).
In line with our interest in the development of organo-
catalytic direct Mannich reactions6 and with the knowl-
edge that the equilibrium between 2-methylpyridine A and
its enamine counterpart B bearing an exocyclic double
bond7 can be easily shifted, we recently investigated the
Brønsted acid catalyzed reaction between 2-methyl azaarenes
and N-sulfonylimines. Although Brønsted acid catalysis
could be achieved the reactions turned out to be sluggish.
Therefore, we decided to investigate a different strategy
based on the activation of both nucleophilic and electrophilic
reagents by use of a Lewis acid. This approach would allow
(1) For recent reviews of heteroarenes direct arylation, see: (a)
Alberico, D.; Scott, M. E.; Lautens, M. Chem. Rev. 2007, 107, 174. (b)
Satoh, T.; Miura, M. Chem. Lett. 2007, 36, 200. (c) Seregin, I. V.;
Gevorgyan, V. Chem. Soc. Rev. 2007, 36, 1173. (d) Campeau, L.-C.;
Stuart, D. R.; Fagnou, K. Aldrichimica Acta 2007, 40, 35. (e) Kakiuchi,
F.; Kochi, T. Synthesis 2008, 3013.
(2) (a) Campeau, L.-C.; Schipper, D.; Fagnou, K. J. Am. Chem. Soc.
2008, 130, 3266. (b) Schipper, D. J.; Campeau, L.-C.; Fagnou, K.
Tetrahedron 2009, 65, 3155.
(6) (a) Rueping, M.; Vila, C.; Koenigs, R. M.; Poscharny, K.; Fabry,
D. C. Chem. Commun. 2011, DOI: 10.1039/C0CC04539J. (b) Rueping,
M.; Lin, M.-Y. Chem.;Eur. J. 2010, 16, 4169. (c) Rueping, M.;
Nachtsheim, B. N. Synlett 2010, 119. (d) Rueping, M.; Antonchick,
A. P.; Sugiono, E.; Grenader, K. Angew. Chem., Int. Ed. 2009, 48, 908.
(e) Rueping, M.; Antonchick, A. P. Angew. Chem., Int. Ed. 2008, 47,
10090. (f) Rueping, M.; Antonchick, A. P. Angew. Chem., Int. Ed. 2008,
47, 5836. (g) Rueping, M.; Antonchick, A. Org. Lett. 2008, 10, 1731. (h)
Rueping, M.; Sugiono, E.; Schoepke, F. R. Synlett 2007, 1441. (i)
ꢀ
(3) Mousseau, J. J.; Larivee, A.; Charette, A. B. Org. Lett. 2008, 10,
1641.
€
(4) Qian, B.; Guo, S.; Shao, J.; Zhu, Q.; Yang, L.; Xia, C.; Huang, H.
J. Am. Chem. Soc. 2010, 132, 3650.
(5) For palladium catalyzed acetoxylation of unactivated benzylic
C-H bonds: Jiang, H.; Chen, H.; Wang, A.; Liu, X. Chem. Commun.
2010, 46, 7259.
Rueping, M.; Sugiono, E.; Theissmann, T.; Kuenkel, A.; Kockritz, A.;
Pews Davtyan, A.; Nemati, N.; Beller, M. Org. Lett. 2007, 9, 1065. (j)
Rueping, M.; Azap, C. Angew. Chem., Int. Ed. 2006, 45, 7832.
(7) When lutidine is refluxed in D2O, full incorporation of deuterium
on the methyl substitutent is observed.
r
10.1021/ol103150g
2011 American Chemical Society
Published on Web 02/02/2011

Table 1. Evaluation of Different Lewis Acidsa
entry
catalyst
Yb(OTf)3
ligand
NMR yield (%)b
1
none
10
2
Co(OAc)2
Bi(OTf)3
1,10-phenanthroline
none
22
3
65
4
CuBr Me2S
none
21
3
5
CuBr
CuI
1,10-phenanthroline
1,10-phenanthroline
none
30
6
26
7
CuOAc
57
8
(CuOTf)2 C6H6 1,10-phenanthroline
62
3
9
CuBr2
1,10-phenanthroline
1,10-phenanthroline
1,10-phenanthroline
1,10-phenanthroline
1,10-phenanthroline
none
50
10
11
12
13
14
CuCl2
68
Cu(OAc)2
Cu(OPiv)2
Cu(OTf)2
Cu(OTf)2
70 (61)c
70 (60)c
85 (80)c
77 (70)c
Figure 1. Palladium and Lewis acid catalyzed C-H functiona-
lization.
a Reaction conditions: 1a (0.76 mmol), 2a (0.304 mmol), catalyst
(5 mol %), ligand (5 mol %), THF (0.2 mL), 120 °C, 12 h. b Yield based
on 1H NMR measurement (internal standard 4-MeO-acetophenone).
c Yield after column chromatography.
the application of cheap and readily available metals under
mild reaction conditions (Figure 1, bottom).8 Furthermore, a
suitable Lewis acid could shift the equilibrium to the enamine
through the formation of a metal enamide species. Herein,
we report an efficient and straightforward addition of
alkylazaarenes to N-sulfonylimines.9
Table 2. Substrate Scope of N-Sulfonyl Aldiminesa
In order to validate this concept, 2,6-lutidine 1a was
initially chosen as an alkyl-azaarene model substrate and
N-benzylidene-tosylamide 2a as the imine. Regarding the
influence of the solvent and temperature, a preliminary
study revealed that THF, high temperature (120 °C), and a
closed reaction vessel constituted the best conditions for
this transformation.
Furthermore, we observed that neither external base nor
oxygen is needed for the reaction. Subsequently, an evalua-
tion of various Lewis acids was performed (Table 1).
Ytterbium(III) triflate,10 cobalt(II) acetate, and bismuth(III)
triflate11 gave the amine product 3a in varying yields (Table 1,
entries 1-3). Nevertheless, these results proved that the
aforementioned direct amination reaction can be performed
applying Lewis acid catalysis. Copper(I) salts exhibited only
entry
Ar
C6H5
R
product
yield (%)b
1
Ts
Bs
Bs
Ns
Bos
Ts
Ts
Ts
Ts
Ts
Ts
3a
3b
3c
3d
3e
3f
80
80
60
61
75
80
79
95
88
89
88
2
C6H5
3
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-CF3C6H4
C6F5
4
5
6
7
3g
3h
3i
8
4-NO2C6H4
2-BrC6H4
3-Pyridyl
4-BrC6H4
9
10
11
3j
3k
a Reaction conditions: 1a (0.76 mmol), 2 (0.304 mmol), Cu(OTf)2 (5
mol %), 1,10-phenanthroline (5 mol %), THF (0.2 mL), 120 °C, 12 h.
b Yield after column chromatography.
(8) For Lewis acid activation of pyridines: (a) Nakao, Y.; Kanyiva,
K. S.; Hiyama, T. J. Am. Chem. Soc. 2008, 130, 2448. For Lewis acid
activation of pyridines and quinolines:(b) Deng, G.; Li, C.-J. Org. Lett.
2009, 11, 1171.
(9) During the preparation of this manuscript a protocol involving
rare earth metal salts has been described: Qian, B.; Guo, S.; Xia, C.;
Huang, H. Adv. Synth. Catal. 2010, 352, 3195.
(10) (a) Kobayashi, S.; Sugiura, M.; Kitagawa, H.; Lam, W. W.
Chem. Rev. 2002, 102, 2227. (b) Tolstoluzhsky, N.; Gorobets, N.; Kolos,
N.; Desenko, S. J. Comb. Chem. 2008, 10, 893.
(11) (a) Suzuki, H.; Ikegami, T.; Matano, Y. Synthesis 1997, 249. (b)
Rueping, M.; Nachtsheim, B. J.; Scheidt, T. Org. Lett. 2006, 8, 3717. (c)
Rueping, M.; Nachtsheim, B. J.; Ieawsuwan, W. Adv. Synth. Catal.
2006, 348, 1033. (d) Rueping, M.; Nachtsheim, B. J.; Kuenkel, A. Org.
Lett. 2007, 9, 825. (e) Rueping, M.; Nachtsheim, B. J.; Kuenkel, A.
Synlett 2007, 1391. (f) Rueping, M.; Nachtsheim, B. J.; Sugiono, E.
Synlett 2010, 1549.
poor efficiency in this transformation (Table 1, entries 4-8).
In contrast, very good results were obtained with the more
Lewis acidic copper(II) salts (Table 1, entries 9-14). Among
all the tested Cu(II) salts, copper(II) triflate was found to give
the best results, affording the desired sulfonamide 3a in 70%
yield (Table 1, entry 14).12 Furthermore, in combination with
1,10-phenanthroline, copper(II) triflate showed the highest
(12) (a) Li, Y.; Yu, Z.; Wu, S. J. Org. Chem. 2008, 73, 5647. (b) Remy,
P.; Langer, M.; Bolm, C. Org. Lett. 2006, 8, 1209.
1096
Org. Lett., Vol. 13, No. 5, 2011

reactivity, providing the product in 80% yield after purifica-
tion (Table 1, entry 13).
derivatives (Table 3, entries 1-5) exhibited varying reac-
tivity and provided the products 4a-14a in moderate to
good yields (50-79%).
With the optimized conditions in hand, the scope of the
reaction with regard to the structure of various N-sulfonyl
aldimines was investigated (Table 2). Reaction of 2,6-
lutidine 1a with N-tosyl and N-benzenesulfonyl protected
aldimines 2a-k, bearing electron-neutral and electron-
withdrawing aryl substituents, proceeded smoothly and
provided the desired amino compounds in good to excel-
lent yields (79-95% Table 2, entries 1-2, 6-11). In the
case of imines containing electron-donating substituents
the reactivity of the imine decreased slightly, resulting in
yields ranging from 60% to 75% (Table 2, entries 3-5).
Subsequently the scope of R-alkylazaarenes was exam-
ined, and the results are summarized in Table 3. Pyridine
A shorter reaction time was required for the pyrimidine
11 (14 h, Table 3, entry 8) and pyridazine 10 (4 h, Table 3,
entry 7). Notably, the 6-bromoquinaldine 13 showed good
reactivity and the halogen substituent remained untouched
during the process, allowing further transformations
(Table 3, entry 10). Surprisingly, due to decomposition
of the starting materials, the general procedure was not
applicable to simple quinaldine 14 (Table 3, entry 11). In
thiscase, theexcessofazaarene wasdecreasedto1.05equiv
and an additional base iPr2EtN (1.5 equiv) was employed
to allow the formation of the targeted compound 14a in
55% yield.
The reactivityofγ-methylazaarenes and the competition
between the two reactive centers of R,γ-dimethylazaarenes
were also investigated (Figure 2).
Table 3. Substrate Scope of R-Alkyl Azaarenesa
Figure 2. Regioselectivity in the copper catalyzed C-H func-
tionalizatin. 1,3- vs 1,5- C-H functionalization.
The reaction of the 2,4-lutidine 15 with the imine 2b
yielded the R- and γ-addition products 15a and 15b in 23
and 45% yield, respectively. Interestingly, 4-picoline was
unreactive under the same conditions. However, if an aryl
substituent was introduced at the R-position of 4-picoline,
the reaction proceeded exclusively in the γ-position and
provided, for the first time, the addition product 16a in a
reasonable 58% yield.
In conclusion, we have developed an efficient and atom-
economical protocol for the direct R- and γ-addition of
2- and 4-alkyl azaarenes to aldimines. The reaction pro-
ceeds through a copper catalyzed direct C-H bond func-
tionalization and provides a set of different heterocycle-
containing amines in good yields.
Acknowledgment. The authors acknowledge financial
support by RWTH Aachen University.
a Reaction conditions: 4-14 (2.5 equiv), 2b (1 equiv), Cu(OTf)2
(5 mol %), 1,10-phenanthroline (5 mol %), THF (0.2-0.4 mL), 120 °C.
b Isolated yields after column chromatography. c Reaction performed
at 130 °C. d Reaction conditions: 14 (1.05 equiv), 2b (1 equiv), iPr2EtN
(1.5 equiv).
Supporting Information Available. Experimental pro-
cedures and full characterization (1H and 13C NMR data
and spectra, MS, and IR analyses) for all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 5, 2011
1097