Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
[4 + 1 + 1] Annulations of α‑Bromo Carbonyls and 1‑Azadienes toward Fused Benzoazaheterocycles Rong Zeng,† Changyu Shan,† Ming Liu,† Kun Jiang,*,† Ying Ye,† Tian-Yu Liu,† and Ying-Chun Chen*,†,‡ †
College of Pharmacy, Third Military Medical University, Shapingba, Chongqing 400038, China Department of Medicinal Chemistry, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
‡
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ABSTRACT: An unexpected [4 + 1 + 1] annulation between α-bromo carbonyls and 1-azadienes, derived from 2-methylenebenzofuran-3(2H)-ones or 2-methylenebenzo[b]thiophene3(2H)-ones, has been observed in the presence of DABCO and Cs2CO3. These reactions stand in contrast to the common [4 + 1] cyclization reactions of azadienes with the related sulfonium ylides. A range of fused benzofuro[3,2-b]pyridines and benzo[4,5]thieno[3,2-b]pyridines have been efficiently constructed in fair to excellent yields.
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chemists have devoted much effort to construct benzofuro[3,2-b]pyridines and the sulfur-containing analogues,8 whereas the discovery of novel method to furnish more structural versatility from readily available starting materials is still in demand. The ylides represent valuable synthons in organic chemistry and undergo a diversity of cyclization, olefination, and rearrangement reactions. While sulfur and phosphorus ylides derived from the corresponding onium salts have been extensively explored,9 ammonium-based nitrogen ylides have been much less investigated, probably because of the relatively crowded structure and weaker reactivity; nevertheless, these characteristics may generate products different from reactions with other ylides.10 Until recently, such nitrogen ylides have emerged as a useful class of one-carbon synthons, as demonstrated in a number of [2 + 1],11 [3 + 1],12 and [4 + 1]13 annulation reactions. Recently, our group also disclosed the asymmetric synthesis of spiro-azaheterocycles involving the nitrogen ylides with α-substitutions and 1-azadienes,14 which prompted us to explore more reactions with these interesting species. As outlined in Scheme 1a, it was found that an expected [4 + 1] cycloaddition of aurone-derived 1-azadiene15 1a and sulfonium salt 2 occurred to give the fused pyrroline derivative 3 in the presence of Cs2CO3. In sharp contrast, an unexpected [4 + 1 + 1] annulation process16 that assembled 1azadiene 1a and two molecules of ethyl α-bromoacetate 4a was observed in the presence of catalytic amounts of tertiary amine DABCO and excess Cs2CO3, and a polycyclic benzofuro[3,2b]pyridine 5a was obtained albeit in a fair yield (Scheme 1b), whose structure has been unambiguously confirmed by X-ray diffraction analysis (CCDC 1887196; see Table 1). It should be noted that no desired [4 + 1] cycloadduct 3 was detected in
he development of efficient protocols to access polyheterocycles is of significance owing to their ubiquitous occurrence in natural products and pharmacologically active substances.1 Among them, fused cyclic systems containing nitrogen and oxygen atoms are popular structures in pharmacologically active compounds as hydrogen-bond acceptors to modulate the activity of the target enzymes.2 In particular, the compounds containing a benzofuro[3,2-b]pyridine motif have received special attention, as widely exemplified in a natural product sinensine D (A),3 a nonintercalative topoisomerase I and II dual catalytic inhibitor (B),4 a potential telomerase inhibitor (C),5 and a neuroblastoma RAS (NRAS) repressor (D) (Figure 1).6 Moreover, the related benzo[4,5]thieno[3,2-b]pyridine system also represents a valuable pharmacophore; for example, compound (E) possesses significant cytotoxic activity.7 As a result,
Figure 1. Natural and bioactive compounds containing a benzofuran or benzothiophene pyridine motif. © XXXX American Chemical Society
Received: February 17, 2019
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DOI: 10.1021/acs.orglett.9b00598 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
improved by employing higher amounts of Cs2CO3 (entry 8). Comparable yields were gained when other tertiary amines, such as DAMP and bifunctional A3, were used (entries 9 and 10). Note that 5a could not be generated in the absence of DABCO, suggesting that the nitrogen ylide intermediate should be crucial for the current reaction (entry 11). Increasing the reaction temperature afforded slightly higher yields (entries 12 and 13), but a lower yield was obtained at 100 °C (entry 14). The yield of 5a was gradually improved by increasing the loadings of DABCO (entries 15−17), and an excellent isolated yield (95%) was achieved by using 1.0 equiv of DABCO and extending the reaction time (entry 18). Having established the optimal reaction conditions, the scope and limitations with respect to 1-azadienes 1 and αbromo carbonyl compounds 4 were examined. As illustrated in Scheme 2, 1-azadienes 1 bearing both electron-donating and
Scheme 1. Observed Switchable Annulation Pathways Involving Sulfur or Nitrogen Ylide
Table 1. Optimizations of the Reaction of 1a and 4aa
Scheme 2. Substrate Scope and Limitations of 1-Azadienes 1 and α-Bromo Carbonyl Compounds 4a
entry
amine (equiv)
base
solvent
T (°C)
yieldb (%)
1 2 3 4 5 6 7 8c 9c 10c 11c 12c 13c 14c 15c 16c 17c 18c,e
DABCO (0.2) DABCO (0.2) DABCO (0.2) DABCO (0.2) DABCO (0.2) DABCO (0.2) DABCO (0.2) DABCO (0.2) DMAP (0.2) A3 (0.2)
Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 K2CO3 NaOH t-BuOK Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3
DCM MeCN THF toluene MeCN MeCN MeCN MeCN MeCN MeCN MeCN MeCN MeCN MeCN MeCN MeCN MeCN MeCN
rt rt rt rt rt rt rt rt rt rt rt 40 80 100 40 40 40 40
30 47 15 15 0 25
