Palladium-catalyzed benzylic addition of 2-methyl azaarenes to N-sulfonyl aldimines via C-H bond activation

Article abstract of DOI:10.1021/ja910104n

Chemical equation presented An efficient protocol for the generation of amines by palladium-catalyzed nucleophilic benzylic addition of 2-methyl-substituted azaarenes to N-sulfonyl aldimines under neutral conditions via C-H bond activation has been developed. This reaction represents a very efficient methodology for the synthesis of heterocycle-containing amines and thus opens a new way to access amines through C-H bond activation.

Full text of DOI:10.1021/ja910104n

Published on Web 03/02/2010
Palladium-Catalyzed Benzylic Addition of 2-Methyl Azaarenes to N-Sulfonyl
Aldimines via C-H Bond Activation
Bo Qian, Shengmei Guo, Jianping Shao, Qiming Zhu, Lei Yang, Chungu Xia,* and Hanmin Huang*
State Key Laboratory for Oxo Synthesis and SelectiVe Oxidation, Lanzhou Institute of Chemical Physics, Chinese
Academy of Sciences, 18 Tianshui Middle Road, Lanzhou 730000, China
Received November 30, 2009; E-mail: hmhuang@licp.cas.cn
Scheme 1. Strategy for Transition-Metal-Catalyzed Addition of
Nucleophiles to Imines
Transition-metal-catalyzed addition of organometallic compounds
to imines is an attractive carbon-carbon bond-forming process for
the synthesis of amines in which transmetalation is involved for the
generation of the R-M (M ) Rh, Pd) intermediate as the key species
in furnishing the subsequent nucleophilic addition.1 Recent studies have
demonstrated that direct C-H activation by transition metals is an
alternative method for generating R-M intermediates, which have been
applied under versatile reaction conditions to achieve new C-X (X
) C, N, O, etc.) bond formation.2 We reasoned that if this R-M
species produced by C-H activation could react with imines, then
transition-metal-catalyzed nucleophilic addition of simple substrates
to imines would be realized.3
As a reactive intermediate, 2 is known to undergo synthetically
useful transformations and has previously been generated by oxidative
addition of corresponding benzyl halides to Pd(0) or by Pd-catalyzed
C-C bond cleavage.4 For example, Oshima and co-workers recently
described an ingenious method for generating such a moiety via Pd-
catalyzed C-C bond cleavage of pyridyl alcohol and its subsequent
use in coupling reactions (Scheme 1).4c Recent elegant studies5 of the
direct C-H functionalization of azaarenes reported by Fagnou,
Hiyama, Yu, Chang, Sames, Sanford, and others have prompted us to
envision that this kind of moiety 2 might also be produced from 1 by
transition-metal-catalyzed C-H bond cleavage. Herein, we report an
efficient and atom-economical protocol for the direct benzylic addition
of 2-methyl azaarenes to imines via sp3 C-H activation by palladium
catalysis under neutral conditions.
To test the viability of our hypothesis, 2,6-lutidine (1a) was chosen
as a model substrate to react with tosylimine 4a derived from
benzaldehyde, and the reaction was performed under an Ar atmosphere
at 120 °C for 24 h. To our delight, the desired nucleophilic addition
reaction proceeded smoothly in the presence of palladium catalyst
(Table 1, entry 1).6 Screening of palladium sources revealed Pd(OAc)2
as the most efficient catalyst, while other palladium precursors gave
lower yields (Table 1, entries 2-7). A control experiment showed that
no reaction occurred in the absence of Pd catalyst. With Pd(OAc)2 as
the catalyst, we went on to screen other reaction parameters. The
reaction was found to proceed more efficiently in polar solvents than
in nonpolar ones, and tetrahydrofuran (THF) was found to be the best
solvent. Ligand screening showed that nitrogen-containing ligands were
promising, and 1,10-phenanthroline (Phen) proved to be the best one,
affording the highest yield (82%).
Table 1. Screening of Reaction Conditionsa
entry
[Pd]
ligand
solvent
yield (%)b
1
2
3
4
5
6
7
8
Pd(OAc)2
PdCl2
none
none
none
none
none
none
none
none
none
none
none
none
none
THF
THF
THF
THF
THF
THF
THF
MTBE
CH2Cl2
CH3CN
toluene
dioxane
2-PrOH
THF
70
34
60
24
55
11
32
68
55
48
41
47
60
62
82
75
Pd(OCOCF3)2
Pd(CH3CN)2Cl2
Pd(PhCN)2Cl2
Pd(PPh3)2Cl2
Pd(DPPE)Cl2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
9
10
11
12
13
14
15
16
bathocuprine
1,10-phenanthroline
2,2-bipyridine
THF
THF
a Reaction conditions: 1a (0.75 mmol), 4a (0.3 mmol), [Pd] (5 mol %),
ligand (5 mol %), solvent (1.5 mL), 120 °C, 24 h. b Isolated yield.
tutents, the desired amines were obtained in less than 50% yield under
the same conditions; the relatively low yields probably reflect the lower
electrophilicity of the imines. The lower reactivity of these substrates
can be addressed by the introduction of electron-withdrawing groups
on the N-protecting group. Thus, when a p-nitrobenzenesulfonyl (Ns)
group instead of a tosyl group was used as the N-protecting group, 1a
was smoothly added to the corresponding imines to afford 5 in high
yield (Table 2, entries 15 and 16). Alkenyl aldimines were compatible,
but aliphatic tosyl imines were unreactive here.
The scope of 2-methyl azaarenes was also examined. Relative to
2,6-lutidine, the reaction of 2-picoline gave 5ba in lower yield, but in
the reactions of other substituted picolines, good to excellent yields
were obtained. The quinolines 1g-j were also compatible with the
reaction, providing the corresponding adducts in 68-84% yield (Table
3, entries 6-9). Finally, the 2-methylquinoxaline 1k proved to be a
good substrate for this transformation, generating the adduct 5ka in 83%
yield.
With the optimized reaction conditions, the scope of this reaction
with various N-sulfonyl aldimines was explored (Table 2). The data
in Table 2 show that the reactions of N-tosyl aldimines 4 bearing an
electron-withdrawing or electron-neutral group at the ortho, meta, or
para position of the phenyl ring proceeded smoothly to provide
corresponding adducts 5aa-5ak in 67-92% yield (Table 2, entries
1-11). It is noteworthy that halide substituents were tolerated, as this
is advantageous for further transformations with transition-metal
catalysis. However, difficulties were encountered when substrates
containing an electron-donating group were employed (Table 2, entries
12-14); in contrast to the imines with electron-withdrawing substi-
9
3650 J. AM. CHEM. SOC. 2010, 132, 3650–3651
10.1021/ja910104n  2010 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Substrate Scope of N-Sulfonyl Aldiminesa
Scheme 2. Proposed Reaction Pathway
entry
Ar
R
product
yield (%)b
1
2
3
4
5
6
7
8
C6H5
4-ClC6H4
2-ClC6H4
3-ClC6H4,
4-BrC6H4
2-BrC6H4,
3-BrC6H4
4-CF3C6H4,
2,4-Cl2C6H3,
2,6-Cl2C6H3
1-naphthyl,
4-MeC6H4,
4-MeOC6H4,
2-MeOC6H4
4-MeC6H4,
2-BrC6H4
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ns
Ns
Ts
5aa
5ab
5ac
5ad
5ae
5af
5ag
5ah
5ai
5aj
5ak
5al
5am
5an
5ao
5ap
5aq
82
92
91
67
85
86
82
91
81
78
68
47
41
42
73
77
57
giving intermediate 10,9 which would undergo nucleophilic addition to
produce addition product 11. Subsequent protolysis would form the desired
product 5 and regenerate the Pd catalyst to complete the catalytic cycle.
In conclusion, we have developed a novel palladium-catalyzed
addition of 2-methyl azaarenes to imines through C-H bond func-
tionalization. This transformation represents a very efficient methodol-
ogy for the synthesis of amines and thus opens a new way to access
amines through C-H bond activation. Further studies to clearly
understand the detailed mechanism as well as extrapolation of the
reaction to the stereoselective synthesis of heterocycle-containing chiral
amines are currently underway.
9
10
11
12
13
14
15
16
17
(E)-PhCHdCH,
a Reaction conditions: 1a (0.75 mmol), 4 (0.3 mmol), Pd(OAc)2 (5 mol
%), Phen (5 mol %), THF (1.5 mL), 120 °C, 24-30 h. b Isolated yield.
Acknowledgment. This work was supported by the Chinese
Academy of Sciences and the NSFC (20802085, 20625308).
Table 3. Substrate Scope of Heterocyclesa
Supporting Information Available: Detailed experimental proce-
dures, analytical data for all new compounds, and crystallographic data
(CIF). This material is available free of charge via the Internet at http://
pubs.acs.org.
References
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a Reaction conditions: 1 (0.75 mmol), 4a (0.3 mmol), Pd(OAc)2 (5 mol
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6979 The shortest Pd-H(CH3) distances in the crystals of Pd(1a)2Cl2 and
Pd(1a)2(OAc)2 are 2.841 and 2.907 Å, respectively, and the shortest (CH3COO)O-
H(CH3) distance is 2.392 Å (see the Supporting Information for details).
(9) The fact that ArCHdNBoc, ArCHdNCbz, ArCHdNP(O)Ph2, and
ArCHdNCH2Ph are unreactive and additives such as t-BuCO2H, AcOH,
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The kinetic isotope effects observed in both intermolecular (kH/kD
) 3.6) and intramolecular (kH/kD ) 4.1) competition experiments (see
Supporting Information) are consistent with C-H cleavage being the
rate-limiting step. On the basis of the experimental results, a plausible
reaction pathway is outlined in Scheme 2. 1 is coordinated to Pd(OAc)2
to form complex 8, after which C-H bond cleavage might proceed
via agostic three-center-two-electron interactions8 to form the inter-
mediate 94 at elevated temperature, in which the acetate (OAc-) serves
as an internal base. Intermediate 9 might be coordinated with imine 4,
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