α-diazo β-keto ester as precursor to aromatic C-H insertion and wolff rearrangement with different directing groups

Article abstract of DOI:10.1002/adsc.201300763

A tunable aromatic C-H insertion and a Wolff rearrangement of α-diazo β-keto esters precursor were developed. Different directing groups on nitrogen led with high selectivity to either dihydroquinoline or 2-carbamoylacrylate motifs, which can be transformed to multiple heterocyclic scaffolds.

Full text of DOI:10.1002/adsc.201300763

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DOI: 10.1002/adsc.201300763
À
a-Diazo b-Keto Ester as Precursor to Aromatic C H Insertion
and Wolff Rearrangement with Different Directing Groups
Biao Ma,a Fang-Lei Chen,a Xing-Yu Xu,a Yi-Nan Zhang,a,* and Li-Hong Hua,*
a
Shanghai Research Center for Modernization of Traditional Chinese Medicine, Shanghai Institute of Materia Medica,
Chinese Academy of Sciences, Shanghai 201203, Peopleꢀs Republic of China
Fax : (+86)-21-2023-1965; phone: (+86)-21-2023-1965; e-mail: ynzhang@sibs.ac.cn or lhhu@simm.ac.cn
Received: August 22, 2013; Revised: November 6, 2013; Published online: January 13, 2014
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300763.
À
Abstract: A tunable aromatic C H insertion and
a Wolff rearrangement of a-diazo b-keto esters pre-
cursor were developed. Different directing groups
on nitrogen led with high selectivity to either dihy-
droquinoline or 2-carbamoylacrylate motifs, which
can be transformed to multiple heterocyclic scaf-
folds.
activation, allowing access to a number of nitrogen-
containing heterocycles, such as dihydropyridones, b-
lactams, pyridines, isoindolones, and bridged polycyc-
lic rings.[4] Due to their prevalence in natural products
and medicinal molecules, increasing the ability to
access nitrogen-containing heterocycles is very impor-
tant in the medicinal research.
Quinoline and quinolone, as valuable scaffolds, are
the core structures of many bioactive molecules, in-
cluding quinine,[5a] primaquine,[5b] cinchocaine,[5c]
camptothecin,[5d] and brequinar.[5e] For example, Feng
reported recently that an intermolecular C C inser-
tion of a a-diazo ester to isatin produced asymmetri-
À
Keywords: C H insertion; diazo compounds; het-
erocycles; rearrangement; synthetic methods
À
cal oxoquinolines. The key step in their transforma-
À
The aromatic C H insertion and rearrangement of tions is a 1,2-aryl migration catalyzed by the scandium
diazo compounds represent simple and powerful ap- N,N’-dioxide complex (Scheme 1, top).[6] Concurrent
proaches for the construction of structurally unique work by Liu took advantage of the Povarov cycload-
frameworks.[1–3] The robust methods have been exten- dition and carbene elimination as well to generate the
À
sively explored in the transition metal-catalyzed C H tetrahydroquinoline ring regioselectively by treatment
Scheme 1. Construction of quinoline ring with carbenoids.
416
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a-Diazo b-Keto Ester as Precursor to Aromatic C H Insertion
Table 1. Condition screening.[a]
Entry
2 (R)
Catalyst
Solvent
Temp. [oC]/Time [h]
Yield [%][b]
3
4
1
2
3
4
5
6
7
8
2a (Ts)
2a (Ts)
2a (Ts)
2a (Ts)
2a (Ts)
2a (Ts)
2a (Ts)
2b (Ms)
2c (Ac)
2d (Me)
2d (Me)
2d (Me)
2d (Me)
2d (Me)
2d (Me)
2d (Me)
2d (Me)
2d (Me)
2d (Me)
Rh
Rh
Rh
Rh
Rh
G
CH2Cl2
CH2Cl2
DCE
25/6
25/6
25/6
25/6
25/6
25/6
25/6
25/6
25/6
25/3
25/3
40/6
40/6
40/6
100/3
100/3
100/3
80/3
100/6
7
75
68
22
0
0
0
0
0
toluene
dioxane
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
toluene
toluene
dioxane
DCE
34
AgOTf
Cu(acac)2
2A(esp)2[e]
2A(esp)2
2A(esp)2
2A(OAc)4
ND[c]
G
NR[d]
Rh
Rh
Rh
Rh
61
<5
0
0
0
84
73
9
10
11
12
13
14
15
16
17
18
19
0
CuI
ND[c]
CuOTf
Ag2O
Ag2O
0
0
0
0
0
0
0
<5
31
92
66
68
71
21
Rh2ACHTNUTRGENNG(U OAc)4
Ag2O
Ag2O
none[f]
toluene
[a]
Reaction conditions: 2 (0.2 mmol) and catalyst (0.5 mol%) in solvent (2 mL).
Yields are given for isolated products after silica gel purification.
Not determined (ND), a mixture of complex products.
No reaction (NR).
Catalyst loading (1.0 mol%).
Without catalyst.
[b]
[c]
[d]
[e]
[f]
with different gold and rhodium catalysts (Scheme 1, esters 1 with TsN3 in a basic medium (see the Sup-
middle).[7] However, elegant examples to construct porting Information).
quinoline heterocycles using diazo precursors are still
An initial survey of diazo esters 2 using Rh2ACHTUNGTRENNUNG(OAc)4
challenging compared to the thermaldynamically fav- in dichloromethane gave trace amounts of the desired
oured benzo five-membered counterparts.[8] In the product, indicating the futility of a metal complex in
À
view of the importance of diverse a-diazo carbonyl the aromatic C H insertion (Table 1, entry 1). Con-
compounds and for expanding the synthetic utility to sidering that two chelating bis-carboxylate ligand pos-
À
quinoline structures, we employed diazo precursors in sesses more favourable kinetic stability in the C H in-
the intramolecular aromatic C H insertion to provide sertion reaction than the tetracarboxylate ligand,[11]
À
functionalized quinoline rings. In the meantime, we we found that Rh
(esp)2 (a,a,a’,a’-tetramethyl-1,3-
found that the a-diazo b-keto ester precursors bearing benzenedipropionic acid) could enhance the yield
different directing groups on nitrogen can also under- dramatically (Table 1, entry 2). The following screen
go an unprecedent Wolff rearrangement (Scheme 1, of solvents and transition metal catalysts revealed
bottom).[9] Here, we wish to describe the development that dichloromethane and Rh
(esp)2 were the best sol-
À
of this tunable aromatic C H insertion and rearrange- vent and catalyst for this catalytic system (Table 1, en-
ment reaction to access multiple heterocyclic building tries 2–7). Further investigation of the N-protecting
blocks, which show a novel divergent-oriented syn- groups showed that the methanesulfonamide 2b
thetic pattern in the chemistry of diazo compounds.[10] slightly decreased the reactivity, while the conversion
We began our investigations from the synthesis of was totally inhibited by acetamide 2c even with in-
a-diazo b-keto esters 2 with different directing groups creasing amount of catalyst (Table 1, entries 8 and 9).
on the g-nitrogen. The corresponding diazo precursers However, methylamine 2d surprisingly delivered
can be obtained in high yields by treating b-keto a predominant rearranged product 4d, which was elu-
cidated as an a,b-unsaturated ester through spectro-
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Biao Ma et al.
scopic analysis (Table 1, entry 10). Several known
transition metals that can promote the Wolff rear-
rangement, such as Rh2A(OAc)4, Cu(I) and Ag(I), were
CTHUNGTRENNUNG
incorporated with diazo precursor 2d (Table 1, en-
tries 10–14). Although Ag(I) is known to be more ef-
fective in facilitating the rearrangement than Cu(I)
and Rh(II),[12] no improvement was observed until
harsh conditions were employed. Treatment with
silver oxide led to high reactivity and full conversion
to the desired product, compared to the moderate
yield with rhodium catalyst under the same conditions
(Table 1, entry 15 and 16). Further screening support-
ed that a less polar solvent was preferred in this reac-
tion (Table 1, entries 17 and 18). It was also worthy of
note that the self-thermal initiation without any cata-
lyst can partially occur at high temperatures (Table 1,
entry 19).
À
We tested the generality of the aromatic C H inser-
tion with different substituted anilines. For the elec-
tronically donating and neutral substrates, the reac-
tion afforded the desired products with comparative
yields and occurred exclusively at the para-position of
the substituent groups, presumably avoiding steric
hindrance (Scheme 2, 3a, 3e–l). Similarly, the elec-
tron-withdrawing group, such as fluorine, was also tol-
erated in this reaction and gave a moderate yield
(Scheme 2, 3k). However, no quinoline or lactam
product was observed under these conditions after
changing the keto ester to a keto amide (Scheme 2,
3aa), although it was previous reported by Afonso
and co-workers that diazoacetamide could be convert-
À
Scheme 2. Reaction scope of the aromatic C H insertion re-
action.
À
ed to the lactam through intramolecular C H inser-
tion in their case.[4a]
Regarding the rearrangement reaction, the explora-
tion of the reaction scope revealed robust reliability. successfully coordinated to the Wolff rearrangement
For a variety of electronic and regional substituents as well (Scheme 3, 4z).
on the phenyl ring, the reaction afforded 2-
Next, we concentrated on the synthetic versatility
carbamoylacrylates in high yields (Scheme 3). For ex- of dihydroquinoline and 2-carbamoylacrylate deriva-
ACHTUNGTRENNUNG
ample, it worked well with electron-neutral tives, especially to build heterocyclic scaffolds
(Scheme 3, 4m–o), electron-donating (Scheme 3, 4p), (Scheme 4). The dihydroquinoline 3a underwent an
and electron-withdrawing (Scheme 3, 4t) substituents elimination of p-toluenesulfonic acid to give quinoline
and good yields were observed with different regional 5. Likewise, the 2-carbamoylacrylate also exhibited
substitutions including bulky ortho-substitution utility in several different reaction types, such as in
(Scheme 3, 4m, 4n and 4q, 4r). A set of alkyl sub- the synthesis of 1-methylquinolin-2(1H)-one 6 and
À
strates also delivered products with satisfactory yields, pyrazolone 7, via C H bond oxidative activation and
such as strained tetrahydroquinoline and bulky naph- hydrazinolysis, respectively. All the transformations
thalene (Scheme 3, 4u and 4w). The reaction also tol- proceeded in good yields under non-optimized condi-
erated a double bond motif, providing the product in- tions. Since these heterocyclic scaffolds are valuable
stead of the formation of cyclopropanation in medicinal and agrochemical applications,[5,13] the a-
(Scheme 3, 4x). However, the dialkyamino-substituted diazo b-keto esters with different directing groups
substrate failed to give the rearranged product (data could serve as versatile and straightforward building
not shown), while the diarylamino-substituted precur- blocks in the future studies.
sor generated the carbamoylacrylate 4y under either
A plausible mechanism is depicted in Figure 1. We
Ag2O or Rh2A(esp)2 catalysis [Rh2A(esp)2 gave a 76% propose that the first step is a metal insertion to form
C
CHTUNGTRENNUNG
À
yield of 4y and no C H insertion product was ob- intermediate A via extrusion of N2 for both processes.
served]. In addition, the keto amide substrate can be When the tosyl and mesyl groups are used as the di-
recting groups, sulfonamides decrease the electron
418
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Adv. Synth. Catal. 2014, 356, 416 – 420

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a-Diazo b-Keto Ester as Precursor to Aromatic C H Insertion
Scheme 3. Reaction scope of the Wolff rearrangement.
Figure 1. A plausible mechanism of the reactions.
In summary, we have found that the chemoselectiv-
ity in aromatic C H insertion and rearrangement of
a-diazo b-keto ester precursors is based on the differ-
Scheme 4. Synthetic transformations of 3a and 4d.
À
ent directing groups substantially. Sulfonamide sub-
density of the nearby methylene group so that C H stituents gave a C H insertion product, while alkyl
activation favored the more acidic C H bond on the substituents underwent a rearrangement reaction.
aromatic ring, which further generated aromatic inser- Considering the subsequent conversions to various
tion product C. Otherwise, in the case of aliphatic heterocyclic structures under mild conditions, this
substituents as the directing groups, the enhanced protocol should be very useful for the rapid synthesis
electronic density of nitrogen allowed the neighbour- of bioactive analogues.
ing methylene group to participate in the formation
À
À
À
of ketene intermediate D according to a concerted
Wolff mechanism.[14] The nitrogen lone pair next at-
tacked the ketene center to form azetidine enolate E.
To this end, a stable carbamoylacrylate motif F was fi-
nally produced after subsequent electrocyclic ring
opening.
Adv. Synth. Catal. 2014, 356, 416 – 420
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Biao Ma et al.
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À
Typical Procedure for the Rh2ACHTNUTRGNEUNG(esp)2-Catalyzed C H
Insertion Reaction of a-Diazo b-Keto Esters
A solution of a-diazo b-keto ester (0.2 mmol) in anhydrous
CH2Cl2 (2 mL) was added via constant pressure funnel to
a stirred solution of Rh2ACTHNUTRGNE(UNG esp)2 (0.5 mol%) in anhydrous
CH2Cl2 (2 mL) at room temperature under a nitrogen at-
mosphere. After the addition was completed, the reaction
mixture was stirred for 6 h at room temperature until com-
plete conversion was observed. The content was transferred
directly onto silica and purified by eluting with petroleum
ether/EtOAc (5:1). Removal of the solvent followed by
drying under vacuum afforded 3 in high purity.
Typical Procedure for the Ag2O-Catalyzed
Rearrangement Reaction of a-Diazo b-Keto Esters
A solution of a-diazo b-keto ester (0.2 mmol) in Toluene
(2 mL) was added Ag2O (0.5 mol%) at room temperature
under a nitrogen atmosphere. After the addition was com-
pleted, the reaction mixture was stirred at 1008C for 3 h
until complete conversion was observed. Then, the solvent
was cooled down to room temperature and concentrated
under reduced pressure. The content was transferred direct-
ly onto silica and purified by eluting with petroleum ether/
EtOAc (5:1). Removal of the solvent followed by drying
under vacuum afforded 4 in high purity.
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Acknowledgements
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Financial support by the National Natural Science Founda-
tion of China (grants 30925040, 81273397) and the Science
Foundation of Shanghai (grant 12XD1405700) is acknowl-
edged.
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