Highly efficient vinylaromatics generation via iron-catalyzed sp 3 C-H bond functionalization CDC reaction: A novel approach to preparing substituted benzo[α]phenazines

Article abstract of DOI:10.1039/c2cc36708d

An iron-catalyzed benzylic vinylation was developed to transfer the carbon atom in the N,N-dimethyl moiety of N,N-dimethylacetamide (or N,N-dimethylformamide) to 2-methyl azaarenes to generate 2-vinyl azaarenes. The Royal Society of Chemistry.

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Highly Efficient Vinylaromatics Generation via Iron-Catalyzed sp3 C-H
Bond Functionalization CDC Reaction: A Novel Approach to Preparing
Substituted Benzo[α]phenazines
Shao-Jie Lou,a Dan-Qian Xu,*a Dan-Feng Shen, a Yi-Feng Wang, a Yun-Kui Liua and Zhen-Yuan Xu*a
5
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
An iron-catalyzed benzylic vinylation was developed to
transfer the carbon atom in N,N-dimethyl moiety of N,N-
Table 1. Optimization of the Reaction Condition a
dimethylacetamide (or N,N-dimethylformamide) to 2-methyl
10 azaarenes to generate 2-vinyl azaarenes.
N
N
[Fe] (2 mol %)
[O] (2.0 equiv.)
carbon
sources
N
N
Vinylaromatics are important structural motifs for C-C bond
construction via cross-coupling reactions, such as Heck
reaction, and have been widely applied in the synthesis of
natural products. Traditional formation of terminal alkenes
15 were studied extensively including the elimination of
haloalkanes, alcohols, quaternary ammonium salts, carboxylic
esters, epoxyethanes and sulfones, for instance. However,
most of these procedures are impaired by prefunctional
starting materials, which limit their applications. Hence, this
20 study investigated a new concise pathway employing a cross-
dehydrogenative-coupling (CDC) reaction between a 2-methyl
azaarene and an N,N-dimethyl amide with tandem elimination
to generate vinylarene compounds (Scheme 1).
Given their remarkable advance and significance, iron
25 catalysts, especially hydrous iron salts, have been given
significant attention in studies involving direct C-H bond
activation reaction.[1] Although several efforts have been made in
recent years to develop efficient strategies for the transition
metal-catalyzed, selective oxidation of C-H bonds adjacent to
30 heteroatoms,[2] the use of eco-friendly iron as catalyst is still rare
and little attention has been given to employing the more stable
N-substituted amides as CDC partner.[3, 4] Prompted by the results
of our previous work on the sp2 C-H bond nitration of
quinoxalines,[5] we continued our research on the quinoxaline
35 structure, this time focusing on sp3 C-H bond functionalization.[6]
1a
2a
O
O
O
O
O
N
H2N
N
N
N
Ph
CS 5
CS 1
CS 2
CS 4
CS 3
O
O
O
O
N
HN
N
N
Ph
N
Ph
O
CS 10
CS 6
CS 8
CS 9
CS 7
40
Entry
Iron
Carbon sources
Yield (%) b
1 c
2
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
CS 1
CS 1
n.d. d
90 (81e)
94
3
CS 2
4
CS 3
n.d.
n.d.
83
5
CS 4
6
CS 5
7-11f
12
13
14
15
16
17
CS 6-CS10
CS 2
n.d.
94(87 e)
91
FeCl3·6H2O
FeCl2·4H2O
FeSO4·7H2O
CS 2
CS 2
91
>99.99%, FeCl3
CS 2
94
--
CS 2
4
FeCl3·6H2O g
CS 2
n.d.
[a] Reaction condition : 1a (0.2 mmol), [Fe] (0.004 mmol), K2S2O8 (0.4
mmol), solvent / carbon source (1.5 mL), 110 ℃, 3h, under air (unless
otherwise noted). [b] GC-MS yields. [c] 10 mol % FeCl3 were used, r. t.
for 24 h, under argon. [d] n.d. = not detected. [e] Isolated yields. [f] CS6 –
45 CS10 were used respectively. [g] Without oxidants.
No desired product was initially obtained (entry 1) when the
model substrate 1a was treated with FeCl3 as catalyst (10 mol%)
and N,N-dimethylformamide (DMF) using K2S2O8 (2.0 equiv.) as
an oxidant under argon at room temperature for 24 hours, as
50 shown in Table 1. However, the desired vinyl aromatic, 2a, was
isolated at 81% yield within a shorter complete substrate
consumption time of 3 hours (entry 2) when the temperature was
increased to 110 C and the catalyst loading was reduced to 2
mol%. Alternative amides were employed to test this notable
Scheme 1. Synthesis strategies.
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Table 2. Vinylation of benzylic C-H bond a
Table 3. Scope of substituted 2-methyl azaarenes a
Entry
Ar (2)
R1
R2
Yield (%) b
1
2
Phenyl (2a)
H
H
H
H
H
H
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
87
89
86
92
87
86
84
83
81
87
83
75
91
73
60 c
4’-OMe Phenyl (2b)
4’-Me Phenyl (2c)
2’, 4’-DiMe Phenyl (2d)
4’-Ph Phenyl (2e)
4’-F Phenyl (2f)
4’-Cl Phenyl (2g)
4’-Br Phenyl (2h)
4’-I Phenyl (2i)
2’-Br Phenyl (2j)
3’-NO2 Phenyl (2k)
3’-CF3 Phenyl (2l)
Phenyl (2m)
3
4
5
6
35
7
[a] Reaction condition : 3 (0.2 mmol), FeCl3·6H2O (0.004 mmol), K2S2O8
(0.4 mmol), DMA (1.5 mL), 110 ℃, 3h, under air, isolated yields. [b] n.d.
= not detected. [c] 7.5 mol % FeCl3·6H2O was used, 8h.
8
9
10
11
12
13
14
15
2-Thienyl (2n)
Phenyl (2o)
[a] Reaction condition : 1 (0.2 mmol), FeCl3·6H2O (0.004 mmol), K2S2O8
(0.4 mmol), DMA (1.5 mL), 110 ℃, 3h, under air (unless otherwise
5 noted). [b] Isolated yields. [c] 10 mol % FeCl3·6H2O was used, 8h.
transformation. Vinylation was found to occur only in the
presence of N,N-dimethyl amides, particularly N,N-
dimethylacetamide (DMA), suggesting that the extended carbon
atom was donated by the N,N-dimethyl moiety rather than by the
10 carbonyl carbon in the amides (entries 3–5). Although other N-
methyl sources were also investigated, only N,N-dimethyl amides
were found feasible (entries 6–11).[7] Having established the
optimal carbon source for vinylation, various combinations of
iron salts and oxidants were subsequently surveyed. To our
15 delight, FeCl3·6H2O was found as effective as the anhydrous one
and other hydrous iron salts also provided comparable results
(entries 12–14). About 99.99% FeCl3 was used to avoid metal
impurities in the catalyst (entry 15). The reaction failed in the
absence of catalysts or oxidants (entries 16 and 17). Notably,
20 K2S2O8 was the only applicable compound among a series of
oxidants, including organic and inorganic compounds (see
Supporting Information).[7] Thus, this study developed a unique
benzylic vinylation reaction using N,N-dimethyl in amides as a
new one-carbon source.[8]
40 Figure 1. Proposed mechanism
More substituted 2-methyl azaarenes were employed to
investigate the versatility of the present method (Table 3).
Azaarenes without any substituents at the C3-position failed to
generate the terminal olefines (4a, 4f, 4i). However, vinylation
45 was feasible when 2-methyl quinoxalines were substituted with
phenoxylate, methoxylate, or carboxylate (4b–4d). Other
azaarenes, e.g., pyrazine, quinoline, and pyridine, were also
subjected to the same conditions, and no obstacles were
encountered (4e, 4g, 4h, and 4j). Remarkably, only one side of
50 the benzylic C-H bond in diethyl 2,6-dimethylpyridine-3,5-
dicarboxylate (3j) was vinylated, even when 4.0 equiv. oxidant
and 10 mol% catalyst were loaded onto the system. A steric effect
made the secondary vinylation of 3j sluggish.
Preliminary mechanistic investigations were carried out
55 subsequently. The reaction failed when 2.0 equiv. 2,2,6,6-
tetramethylpiperidine-N-oxyl,
employed in the system, suggesting that a radical mechanism may
be involved in this reaction. A series of deuterated experiments
were carried out to get further insight of the transformation, the
60 results indicated that the C-H bond in both coupling partners were
activated, and the terminal vinyl carbon was produced by the
N,N-dimethyl moiety of amides.[7] Furthermore, KIE studies
showed that the cleavage of the C-H bond of N,N-dimethyl
a
radical scavenger,[9] was
25
Under optimal conditions, the scope of the vinylation was
then explored (Table 2). Both electron-donating and electron-
withdrawing aromatic rings afforded vinylation products in good
to excellent yields (entries 1–13). No observable steric effect was
observed for substrates bearing ortho-substituted aryl rings
30 (entries 4 and 10). Heterocyclic rings, e.g., thiophene, were also
tolerated at 73% isolated yield (entry 14). Notably, ethyl-
substituted quinoxaline was still available to produce the desired
vinylaromatic product at 60% yield (entry 15).
amides may be involved in the rate-determining step (kH/kD
≈
2
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Table 4. Synthesis of Substituted Benzo[α]phenazine a
University of Technology, Hangzhou 310014, P. R. China. Fax: +86 571
8832 0066; Tel: +86 571 8832 0066; E-mail: greenchem@zjut.edu.cn
† Electronic Supplementary Information (ESI) available: Experimental
45 procedures and analysis data for new compounds. See
DOI: 10.1039/b000000x/
1
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[a] Reaction condition : 2 (0.2 mmol), Pd(PPh3)4 (0.004 mmol), Ag2SO4
(0.4 mmol), Degassed NEt3 (0.8 mmol), Degassed DMA (2.5 mL), 140 ℃,
5 under argon. [b] Isolated yields.
2.0)[7]. In addition, the formation of the CDC intermediate was
detected by mass spectrometry.[7]
Based on the above information, a proposed mechanism is
depicted in Figure 1. The in-situ generated enamine 6[6] attacked
10 the iminium species 8[4] to form the intermediate 9, which then
underwent elimination to give the product 2a.
Benzo[α]phenazine derivatives have attracted considerable
attention because of their remarkable biological activities.[10] To
our knowledge, previous studies on the synthesis of substituted
15 benzo[α]phenazines are limited,[10] because of the challenges
posed by substituent compatibility and fussy procedures. Based
on the 2-(2-bromophenyl)-3-vinylquinoxaline (2j) obtained, the
Heck reaction may be the ideal method for preparing
benzo[α]phenazines. After using a modified procedure described
20 in a previous report,[11] the Heck closure occurred smoothly
between the terminal vinyl and bromobenzene under the said
conditions using degassed DMA as alternative solvent (Table 4).
The direct C-H bond ortho-bromination of the O-methyl oximes
developed by Sanford[12] provided a general way to the
4
a) T. Tsuchimoto, Y. Ozawa, R. Negoro, E. Shirakawa and Y.
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25 corresponding
2-(2-bromoaromatic)-3-methylquinoxalines.[7]
7
8
For detail information, see the Supporting Information.
After vinylation and Heck cyclization, the desired substituted
benzo[α]phenazines were collected at 77%-86% isolated yields
based on vinylaromatics (2j, 2p–2v).
a) J. Kim and S. Chang, J. Am. Chem. Soc. 2010, 132, 10272; b) J.
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In conclusion, we have developed a novel and facile
30 procedure for synthesizing terminal aromatic alkenes at high
yields through the direct iron-catalyzed vinylation of benzylic C-
H bond using the N-Methyl group in amides as a novel carbon
source. In addition, a general pathway initiated from simple
propiophenone and o-phenylenediamine to the synthesis of
35 substituted benzo[α]phenazines using the proposed vinylation
approach as a key step was presented as a promising synthetic
strategy. As of this writing, further studies on the detailed
mechanism and expanded substrate variations are under way.
100
Milton, S. Sohal, W. Dangerfield, P. Mistry, N. Vicker, P. A.
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Notes and references
40 a Catalytic Hydrogenation Research Center, State Key Laboratory
Breeding Base of Green Chemistry-Synthesis Technology, Zhejiang
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