Letter Cite This: Org. Lett. 2018, 20, 1244−1247
pubs.acs.org/OrgLett
Anion Relay Enabled [3 + 3]-Annulation of Active Methylene Isocyanides and Ene-Yne-Ketones Jinhuan Dong,† Lan Bao,† Zhongyan Hu, Shenghua Ma, Xinyi Zhou, Mengru Hao, Ni Li, and Xianxiu Xu* College of Chemistry, Chemical Engineering and Materials Science, Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Institute of Molecular and Nano Science, Shandong Normal University, Jinan 250014, China S Supporting Information *
ABSTRACT: A new anion relay enabled [3 + 3]-annulation of active methylene isocyanides and conjugated ene-yne-ketones was developed for the efficient and straightforward synthesis of biologically valuable furo[3,2c]pyridine derivatives. In this transformation, a sequential through-bond and through-space anion relay chemistry cascade is involved, which is initiated by an intermolecular Michael addition. Three new bonds and two rings are sequentially constructed from readily available acyclic precursors.
A
Scheme 1. Previous and Present ARC Tactic
nion relay chemistry (ARC) has proven to be an effective and powerful tool for the divergent synthesis of structural complex natural and unnatural molecules with significant biological activities.1 During the past decade, great progress has been made in this research area.2−6 Representative examples were contributed by the groups of Smith,2 Liang,3 Song,4 and others.5 Mechanically, there are two classes of ARC existing in the literature, that is, “through-bond” and “through-space” (Scheme 1, eq 1).1a Recently, Smith and co-workers presented an elegant combination of through-bond and through-space ARC based on Brook rearrangement (Scheme 1, eq 2).6 Despite these intensive research efforts, the development of a new ARC tactic for the efficient construction of biologically valuable heterocycles remains highly desirable. Isocyanides are versatile and powerful synthons in the construction of heterocycles.7 In this context, the active methylene isocyanides are usually viewed as the formal 1,3dipoles to participate in the [3 + 2]-cycloaddition with polar multiple bonds. To date, this reaction has been well-developed, and a wide range of five-membered heterocycles has been prepared by this method.8 In contrast, the higher-order cycloadditions between the 1,3-dipolar isocyanides and other dipoles have been seldom studied.9,10 In 2014, we reported a [3 + 3]-cycloaddition of active methylene isocyanides with azomethine imines for the synthesis of 1,2,4-trizaoles.9 Later, an elegant [3 + 6]-annulation of isocyanoacetates with fulvenes was reported by Wang and co-workers.10 As part of our continuous interest in developing isocyanide-based annulations,11 herein, we report an unprecedented anion relay enabled [3 + 3]-annulation of active methylene isocyanides and conjugated ene-yne-ketones (Scheme 1, eq 3). This domino reaction provides a new and straightforward protocol for the efficient synthesis of biologically valuable furo[3,2-c]pyridines12 from readily available acyclic precursors. Notably, a sequential through-bond and throughspace ARC cascade is involved in this transformation, which is © 2018 American Chemical Society
initiated by an intermolecular Michael addition of the αcarbanion of isocyanides to the β-position of ene-yne-ketones. Received: January 18, 2018 Published: February 7, 2018 1244
DOI: 10.1021/acs.orglett.8b00186 Org. Lett. 2018, 20, 1244−1247
Letter
Organic Letters Scheme 2. Synthesis of Furo[3,2-c]pyridines 3a,b
Recently, ene-yne-ketones, as one of the safe and versatile nondiazocarbene precursors, have drawn much attention in organic synthesis,13 and many carbene transfer reactions using them as substrates have successfully been developed for the synthesis of substituted furans.13,14 To our knowledge, less attention has been paid to the non-carbene transformations of ene-yne-ketones,13,15 especially the annulation reactions for the assembly of fused furan derivatives,16 whereas the [3 + 3]-,17 [3 + 4]-,18 and [3 + 2]19-cycloadditions of 2-(1-alkynyl)-2-alken-1-ones (analogous enynone synthons) have been well-developed. Initially, the [3 + 3]-annulation was investigated to optimize the reaction conditions employing ene-yne-ketone 1a and ethyl isocyanoacetate 2a as model substrates (Table 1). Under Table 1. Optimization of Reaction Conditionsa
entry
catalyst (equiv)
solvent
temp (°C)
time (h)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
Ag2CO3 (0.1) AgF (0.1) AgOAc (0.1) Ag2O (0.1) CuCl (0.1) CuI (0.1) Ag2CO3 (0.1) Ag2CO3 (0.1) Ag2CO3 (0.1) Ag2CO3 (0.1) Ag2CO3 (0.1) Ag2CO3 (0.1) Ag2CO3 (0.1) Ag2CO3 (0.3) Ag2CO3 (0.5) Ag2CO3 (1.0)
1,4-dioxane 1,4-dioxane 1,4-dioxane 1,4-dioxane 1,4-dioxane 1,4-dioxane CH3CN DCE THF toluene DMF 1,4-dioxane 1,4-dioxane 1,4-dioxane 1,4-dioxane 1,4-dioxane
25 25 25 25 25 25 25 25 25 25 25 45 80 25 25 25
3 3 3 3 3 3 3 3 3 3 3 1 1 3 3 3
3a, yield (%)b 46 27 31 44 trace 41 22 43 15 44c 46 51 66 76 90
a
Reaction conditions: 1 (0.2 mmol), 2a (0.24 mmol), and Ag2CO3 (1.0 equiv) in 1,4-dioxane (1.0 mL) at room temperature. bIsolated yields. cAt 80 °C, 1 h.
the reaction of ene-yne-ketone 1 with ethyl isocyanoacetae 2a. A variety of ene-yne-ketones 1 derived from 1,3-diketones (1a−d), ketonitriles (1e and 1f), and ketoesters (1g−i) participated well in this transformation. Furthermore, the reaction proceeded smoothly with ene-yne-ketones 1 bearing various R2 groups on the alkyne terminus, such as para- (1j−m), meta- (1n), or orthosubstituted aryl (1o), 1-naphthyl (1p), and alkyl groups (1r−t). When ene-yne-ketones 1q bearing a TMS group on the alkyne terminus was employed in this reaction, the deprotected furo[3,2-c]pyridine 3q was obtained in 55% yield. The [3 + 3]-annulation of ethyl isocyanoacetate 2a with a wide range of ene-yne-ketones 1 described above represents a simple and efficient protocol for the straightforward synthesis of furo[3,2-c]pyridine derivatives 3 from readily accessible acyclic precursors. Then, the scope of the reaction was evaluated with respect to active methylene isocyanides 2 (Scheme 3). When methyl isocyanoacetate 2b was employed in this transformation under the optimal conditions (Table 1, entry 16), the responding furo[3,2-c]pyridine 3u was obtained in 80% yield. In the case of tert-butyl isocyanoacetate 2c, the temperature needed to increase to 80 °C to give the product 3v in 81% yield. This reaction did not tolerate TosMIC 2d and isocyanoacetamide 2h, whereas benzyl isocyanide 2e and substituted benzyl isocyanides 2f and 2g gave the corresponding furo[3,2-c]pyridines 3x−z in moderate to good yields when the reaction mixture was treated at 80 °C.
a
Reaction conditions: 1a (0.2 mmol), 2a (0.24 mmol), and catalyst, solvent (1.0 mL) in open air. bIsolated yields. c4a was obtained in 30% yield.
catalysis with Ag2CO3 (0.1 equiv), the reaction of 1a (0.2 mmol) and 2a (0.24 mmol) gave furo[3,2-c]pyridine 3a in 46% yield after being stirred for 3 h at room temperature in 1,4dioxane (Table 1, entry 1). Other silver salts such as AgF, AgOAc, and Ag2O gave a lower yield of 3a (Table 1, entry 1 vs entries 2−4), whereas 3a was not detected in the presence of copper salts such as CuCl and CuI (Table 1, entries 5 and 6). Subsequently, solvent screening revealed that CH3CN, THF, and DMF gave the product 3a in a yield comparable to that in 1,4-dioxane (Table 1, entries 7, 9, and 11 vs entry 1), whereas DCE and toluene afforded 3a in low yield (Table 1, entries 8 and 10). Increasing the reaction temperature to 45 and 80 °C resulted a slightly higher yield of 3a (Table 1, entries 12 and 13). Finally, the amount of Ag2CO3 was also tested from 0.3 to 1.0 equiv (Table 1, entries 14−16). Thus, it was found that in the presence of 1.0 equiv of Ag2CO3, the yield of furo[3,2-c]pyridine 3a was improved to 90% (Table 1, entry 16). With the optimal conditions in hand (Table 1, entry 16), the scope of substrate ene-yne-ketone 1 was first explored (Scheme 2). Generally, a series of polysubstituted furo[3,2-c]pyridines (3a−u) (Scheme 2) were obtained in moderate to high yields by 1245
DOI: 10.1021/acs.orglett.8b00186 Org. Lett. 2018, 20, 1244−1247
Letter
Organic Letters Scheme 3. Scope of Active Methylene Isocyanides 2a,b
Scheme 5. Proposed Mechanism
a
Reaction conditions: 1 (0.2 mmol), 2c (0.24 mmol), and Ag2CO3 (1.0 equiv) in 1,4-dioxane (1.0 mL) at room temperature. bIsolated yields. cAt 80 °C, 1 h. dND = not detected.
abstract a proton from active methylene isocyanides as well as a promoter to activate isocyano and alkyne groups. The practicability of the present anion relay enabling [3 + 3]annulation was further evaluated by both 1.0 mmol and gramscale syntheses of furo[3,2-c]pyridine 3a (Scheme 6). When 1
When 2.0 equiv of 2,2,6,6-tetramethyl-1-piperidinyloxy or 2,6di-tert-butyl-4-methylphenol were added to the model reaction under the standard conditions, 3a was obtained in 51 and 80% yields (Scheme 4), respectively. The reason for noticeably lower Scheme 4. Control Experiments
Scheme 6. 1 mmol and Gram-Scale Synthesis of Furo[3,2c]pyridine 3a
mmol scale of ene-yne-ketone 1a was treated with ethyl isocyanoacetate 2a (1.2 mmol), product 3a was obtained in 80% yield, whereas gram-scale synthesis gave 3a in 62% yield. In summary, a new silver-promoted [3 + 3]-annulation between active methylene isocyanides and ene-yne-ketones was developed for the efficient and straightforward synthesis of biologically valuable furo[3,2-c]pyridine derivatives. This reaction exhibits an unprecedented combination of through-bond and through-space anion relay chemistry, which is initiated by an intermolecular Michael addition. Three new bonds and two rings are sequentially constructed from readily available acyclic precursors. Moreover, the present [3 + 3]-annulation is amenable to gram-scale synthesis. Further studies on the domino reactions of isocyanides with ene-yne-ketones are ongoing.
yields of 3a in the radical scavenger experiment is not very clear at present. This result indicated that an ionic pathway may be involved in the double annulation, whereas a nonchain radical pathway could not be excluded in the overall transformation.20 Based on the present observations, a plausible pathway for this [3 + 3]-annulation is shown in Scheme 5 (exemplified by the generation of 3a). First, in the coordination of Ag2CO3 to isocyanoacetate 2a, subsequent proton abstraction forms the silver complex I (generation of carbanion).11a,b,21 Meanwhile, Ag2CO3 coordinates to ene-yne-ketone 1a to form complex II.13 Nucleophilic addition of the anion I to complex II produces intermediate III15 (anion relays from carbon to oxygen through the bonding system).6 Next, intramolecular nucleophilic addition of oxanion to the activated alkyne moiety of III affords disilver complex IV (negative charge migrates from oxygen to sp2-hybridized carbon by the means of “through-space”),6 which undergoes electrophilic cyclization to terminate the ARC process, delivering the bicyclic intermediate V. Then, protonation of V forms dihydrofuro[3,2-c]pyridine VI, followed by oxidative aromatization to result in the final product 3a. In this domino process, Ag2CO3 plays a dual role, serving as a base to
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b00186. Experimental procedures and characterization data for all compounds (PDF) 1246
DOI: 10.1021/acs.orglett.8b00186 Org. Lett. 2018, 20, 1244−1247
Letter
Organic Letters Accession Codes
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CCDC 1816841 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_
[email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Xianxiu Xu: 0000-0001-7435-7449 Author Contributions †
J.D. and L.B. contributed equally to this work.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS Financial support provided by the NSFC (21672034) and the Research Foundation for Undergraduate Students of Shandong Normal University (2017BKSKY47) is gratefully acknowledged.
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DOI: 10.1021/acs.orglett.8b00186 Org. Lett. 2018, 20, 1244−1247
