Chromanones constitute a unique class of the core structural motifs in medicinal chemistry and its related 2-functionalized chromanones are widespread throughout bioactive natural products (Fig. 1) [1–8]. Although certain privileged structures display applicability across a range of transformations, the discovery of new methods for the synthesis of these scaffolds is still crucial. Based on the structure-activity relationship (SAR) for chromone, chromone-3-carboxaldehyde was oft-employed synthetic precursors in a panel of high-value transformations, which was proved to be a promising Michael acceptor to rapidly generate diverse chemical libraries with complex form. Thus far, most reports have focused on chromone based-Michael addition by employing strong nucleophiles, such as activated methylenes [9–12], N-nuclephiles [13–18] and isocyanides [19]. Synthesis to valuable 2-pyridone analogues with activated methylenes have been reported by Lee [9], Maiti [10], Ibrahim [11] and Xu [12] through intramolecular- or intermolecular-cascade cyclization of chromones. In an effort to explore the methodologies for pyridine scaffolds, nitroketene-N,S-acetals [13], acetonitriles [14] and amines [15–18] were selected as readily available feedstocks to afford a nitrogen source. Recently, unexpected strategies, employing isocyanides as strong nucleophiles, for 1,4-addition synthesis of chromone analogues were developed by our group, which were controlled by strategically suppressing competing Ugi reaction (Scheme 1A) [20]. To the best of our knowledge, direct chromone-based 1,4-addition of weak nucleophiles has been disclosed but is relatively rare, only water was involved to attack C2 chromones (Scheme 1A) [21]. Despite these important contributions, the implementation of different catalytic transformations of 3-formylchromones to achieve structural diversity in heterocycle synthesis remains an important goal in organic and medicinal chemistry.
Therefore, central to the successful establishment of this chemistry would depend on choosing appropriate nucleophiles. Notably, the addition of aliphatic groups has been reported using basic organometallics [22–23], but these groups do not broadly map onto bioactive compounds [24]. In this regard, the direct addition of alkynes is desirable because they are readily available and diverse synthons. Recently, Aponick and Mattson developed the addition of copper acetylides to benzopyrylium triflates in the presence of ligands (Scheme 1B) [25–28]. So far, many elegant examples demonstrate the applicability of this strategy. However, excess amount of silyl trifluoromethanesulfonate was often employed to generate the key intermediate benzopyrylium triflates in situ. Despite these impressive contributions, more efficient and practical catalytic systems for alkynylation of chromones are still in high demand. Based on our experiences in construction of multicomponent reactions to access biologically active chromanones [20–21], the reactivity at the C2 position is enhanced by the formation of imine. Our group has been interested in learning how to synthesize the C2-selective alkynylation of chromones through an operationally-simplistic. We envisioned that direct 1,4-addition of chromones with alkynes as nucleophiles would be feasible under certain condition, because C2 position of 3-formylchromone was activated by suppressing the A3-coupling reaction [29–30]. Herein, we present a direct copper-catalyzed C2-alkynylation of chromones with N-propargyl carboxamides as nucleophiles through one-pot protocol (Scheme 1C).
We began our investigation for C2-alkynylation with 3-formylchromone 1a, tert-butylamine 2a and N-propargylamides 4a in 2,2,2-trifluoroethanol (TFE) as solvent. As our previous work indicated, Brønsted acids were more capable of generating 1,4-addition adducts under mild conditions. Unfortunately, with these conditions, unsatisfied yield of desired product was observed (Table 1, entry 1 and 2), while the rest was a mixture of the Schiff base 3a and N-propargylamides 4a. Then we turned our attention to Lewis acids, such as ZnCl2, InCl3, FeCl3, CuCl2, Cu(OAc)2, CuSO4 and AgOTf (entries 3–9), CuSO4 led to moderate yield of C2-alkynayl chromanone 5a with dichloroethane (DCE) as solvent. Further screening of various solvents showed that DCE was more suitable for this transformation (entries 10–14). Among the investigation of reaction temperature, acceptable yield of 5a was obtained in 100 ℃ for 3 hours (entries 15–17). Prolonging reaction time to 5 hours produced a dramatic improvement in yield (entries 18–19). So, the optimized reaction conditions were determined to be: “1a (0.3 mmol), 2 (0.3 mmol) and 4a (0.2 mmol) with 0.1 mmol CuSO4 in presence of DCE (2.0 mL) at 100 ℃ for 5 hours.
Table 1. Optimization of reaction conditionsa
Entry
|
Cat.
|
Solvent
|
Temp.
(℃)
|
Time
(h)
|
Yield
(%)
|
1
|
HCOOH
|
TFE
|
60
|
3
|
< 10
|
2
|
HClO4
|
TFE
|
60
|
3
|
< 10
|
3
|
ZnCl2
|
DCE
|
60
|
3
|
16
|
4
|
InCl3
|
DCE
|
60
|
3
|
21
|
5
|
FeCl3
|
DCE
|
60
|
3
|
< 10
|
6
|
CuCl2
|
DCE
|
60
|
3
|
< 10
|
7
|
Cu(OAc)2
|
DCE
|
60
|
3
|
32
|
8
|
CuSO4
|
DCE
|
60
|
3
|
47
|
9
|
AgOTf
|
DCE
|
60
|
3
|
NR
|
10
|
CuSO4
|
MeCN
|
60
|
3
|
34
|
11
|
CuSO4
|
THF
|
60
|
3
|
19
|
12
|
CuSO4
|
Toluene
|
60
|
3
|
NR
|
13
|
CuSO4
|
Dioxane
|
60
|
3
|
40
|
14
|
CuSO4
|
DMF
|
60
|
3
|
< 10
|
15
|
CuSO4
|
DCE
|
80
|
3
|
52
|
16
|
CuSO4
|
DCE
|
100
|
3
|
61
|
17
|
CuSO4
|
DCE
|
120
|
3
|
49
|
18
|
CuSO4
|
DCE
|
100
|
5
|
73
|
19
|
CuSO4
|
DCE
|
100
|
7
|
65
|
aReaction condition: 1a (0.3 mmol), 2 (0.3 mmol), 4a (0.2 mmol), 50 mmol% catalyst, solvent (2.0 mL), in a sealed tube.
|
With the optimized conditions in hand, we sequentially evaluated the substrate scope using various chromone-3-carboxaldehydes and N-propargylamides for the generation of a library of C2-alkynyl chromanones (Scheme 2). It was identified that electron withdrawing chromone-3-carboxaldehydes furnished desired products 5b-5e with good yields. To our delight, chromone-3-carboxaldehyde 1 including electron donating group (-Me) also worked well and efficiently afforded 5f with the yield of 70%. For the electron density effect of chromone-3-carboxaldehyde moiety did not dramatically decrease the yields of final products, it suggested that the reaction was robust enough for product conversion. We further examined the scope of N-propargylamides with 50 mol % CuSO4 as catalyst under 100 ℃ for 5 hours. N-Propargylamides containing various groups (H, 2,4-di-Cl, 2-Br, 4-Br and 4-Cl) on the phenyl ring were successful in producing the desired products in good yields (5g-5u). In case that the N-propargylamides with acetyl group did not furnish the desired product, such as N-(prop-2-yn-1-yl) benzamide.
Furthermore, based on previous results [31–32], a series of control experiments was performed as shown in Scheme 3. The mixture of 3-formylchromone 1a, tert-butylamine 2a and N-propargylamides 4a was carried out under standard conditions, diminished yield of 5a was delivered. However, oxazole 6 was also isolated through 5-exo-dig cyclization and aromatic reaction (Scheme 3, A). This indicated that a competitive reaction was involved in C2-selective alkynylation of chromones process, which led to dramatically decrease the reaction yields. Thus, the Shiff base of 3 generated in situ was important for product conversion. Under otherwise identical conditions in the absence of CuSO4, none 2-alkynyl chromanone 5a was observed (Scheme 3, B).
With the above evidence, the proposed reaction mechanism was elucidated as Scheme 4. C2-selective alkynylation of chromones process initiated from formation of copper acetylide A, which was obtained by treatment of CuSO4 with 4a. Then, acetylide attacked to C2-position of 3a to form a complex 7. Finally, protonation gave the desired product 5a.