Letter pubs.acs.org/OrgLett
Cascade Amination/Cyclization/Aromatization Process for the Rapid Construction of [2,3‑c]Dihydrocarbazoles and [2,3‑c]Carbazoles Xing Fan,† Liu-Zhu Yu,‡ Yin Wei,† and Min Shi*,†,‡ †
State Key Laboratory of Organometallic Chemistry, University of Chinese Academy of Sciences, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, People’s Republic of China ‡ Key Laboratory for Advanced Materials and Institute of Fine Chemicals, School of Chemistry & Molecular Engineering, East China University of Science and Technology, 130 Mei Long Road, Shanghai 200237, People’s Republic of China S Supporting Information *
ABSTRACT: An intramolecular cascade amination/cyclization/aromatization reaction of functionalized alkylidenecyclopropanes has been developed in the presence of silver acetate, affording a variety of [2,3-c]dihydrocarbazoles and [2,3-c]carbazoles in moderate to excellent yields. The mechanistic investigations revealed that this cascade reaction proceeds through a radical initiated process. Moreover, further transformations for the synthesis of eustifoline-D and an OLED exhibit a potential synthetic utility of this method.
T
he [2,3-c]carbazole alkaloids are privileged motifs in biologically and pharmacologically active products due to their unique electronic and thermal stability properties (Figure 1).1 For example, eustifoline D, which is the active component
In general, there are two synthetic approaches to the construction of a benzo[2,3-c]carbazole on the basis of different cyclization strategies. As shown in Scheme 1, classic Fisher− Scheme 1. Synthesis of Benzo[2,3-c]carbazole with Different Cyclization Strategies
Figure 1. Selected examples of natural products with [2,3-c]carbazole motifs and OLED(s).
in some folk medicines in China, is the only natural furo[2,3c]carbazole alkaloid.2a−c Arcyriaflavin A, one of the indolo[2,3c]carbazole alkaloids, has attracted significant attraction due to its antibiotic and antifungal activities.2d,e Eustifoline A and glycoborinine, as pyrano[2,3-c]carbazoles, are also active components in some folk medicines in China for the treatment of fever and swollen spleens and as a digestion stimulant.2f−h On the other hand, benzo[2,3-c]carbazoles are commonly applied in novel functional organic light-emitting diodes (OLEDs), and phosphorescent compounds rely on their particular electronic properties (Figure 1).3 © 2017 American Chemical Society
Borsche synthesis,4 photoexcited cycloaromatization,5 Rhcatalyzed cycloaromatization,6 and Ru-visible-light photocatalysis7 have been developed for the construction of ring B, leading to benzo[2,3-c]carbazole (Scheme 1, eq 1). With regard to the construction of ring C, radical cyclization,8 photodechlorination-initiated coupling,9 gas-phase cascade,10 palladium-cataReceived: July 2, 2017 Published: August 22, 2017 4476
DOI: 10.1021/acs.orglett.7b01957 Org. Lett. 2017, 19, 4476−4479
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Organic Letters
°C for 6 h. With these optimized conditions, a large-scale synthesis with 1.2 g of 1a also worked efficiently (Table 1, entry 8). With the optimized reaction conditions in hand, we then turned our attention toward the reaction scope and limitations, and the results are summarized in Scheme 2. All of the reactions
lyzed domino transformation,11 and Diels−Alder reactions12 have been frequently utilized (Scheme 1, eq 2). Over the past decades, chemical transformation of methyleneor alkylidenecyclopropanes (MCPs or ACPs) has received much attention since they are highly strained but readily accessible compounds and can undergo diversified ring-opening reactions.13 In 2005, Yamamoto’s group reported the first Pd0catalyzed aniline-tethered alkylidenecyclopropanes for the rapid construction of six-membered exomethylene nitrogen heterocycles.14 Since then, the use of functionalized alkylidenecyclopropanes (FACPs) as substrates for the synthesis of polycyclic compounds has been well developed. For example, RhIcatalyzed carbocyclizations have been reported by Evans’s15 and Chung’s groups,16 respectively. Gagné’s group disclosed the AuI-catalyzed rearrangement of FACPs.17 Moreover, Wu’s group reported a CuI-catalyzed cascade reaction18a and a CuIIcatalyzed tandem reaction with regard to FACPs.18b Furthermore, Mascareñas’ group reported novel [3 + 2+2] cycloadditions catalyzed by Pd0,19a,b Ni0,19c,d and RhI.19e Some other groups have also given significant achievements on this aspect in different ways.20−22 AgOAc, Ag2CO3, and AgNO3 are excellent and versatile oxidants for the oxidation of C−H, P−H, and N−H bond in organic transformations.23 Intramolecular oxidative N−H amination is one of the straightforward and efficient ways to construct nitrogen-containing heterocycles.24 On the basis of these findings, herein we describe a concise and simple synthetic protocol on the construction of two rings, B and C, in [2,3c]dihydrocarbazoles and [2,3-c]carbazoles in one step through the intramolecular cascade amination/cyclization/aromatization reaction using FACPs as substrates and AgOAc as an oxidant (Scheme 1, eq 3). We initiated the investigation on the reaction of 1a in DMF in the presence of 3.0 equiv of AgOAc at 120 °C. Fortunately, the yield of the desired product 2a is 88% along with 12% of 3a (see Table S1 in the Supporting Information for more details on the screening of oxidant, reaction temperature, and time). Further examination of solvent effect revealed that DMF was the optimal choice (Table 1, entries 1−7). On the basis of these experimental results, the best reaction conditions were identified to carry out the reaction in DMF with AgOAc (3.0 equiv) at 120
Scheme 2. Substrate Scope of the Cascade Reaction for the Synthesis of 2a,b
a
Reaction conditions: 1 (0.3 mmol), AgOAc (0.9 mmol), in 3.0 mL of DMF at 120 °C under Ar atmosphere for 6 h. bIsolated yields of 2. c Isolated yields of 3. dIsolated yield of 3. 2.0 equiv of AgOAc (0 4 mmol) was used.
proceeded smoothly under the optimal conditions, giving the desired products in moderate to excellent yields except for substrates 1u and 1v. Substrate 1b, having a Ts protecting group, yielded the desired product 2b in 72% yield along with byproduct 4b in 11% yield (see the Supporting Information). Substrates 1c−o with different functional groups at the (Het)aryl moiety afforded the corresponding products 2c−o in 37−91% yields. Introducing halogens on the aniline moiety gave the corresponding products 2p-2t in 62% to 79% yields. For substrate 1u bearing a 2-furyl ring, no desired product was obtained, while substrate 1v having a 3-furyl ring could yield the further oxidized product 3v in 52% yield along with product 2v in 12% yield. Reducing AgOAc from 3.0 equiv to 2.0 equiv afforded the desired product 2v in 49% yield along with 3v in 17%. However, 2v could be easily oxidized into 3v in a CDCl3 solution after 24 h (see the Supporting Information for more information), suggesting that a more electron-rich aromatic ring is beneficial to the formation of 3v. Meanwhile, introducing 2thienyl and 3-thienyl rings into substrate 1 produced the desired products 2w and 2x in 18% and 67% yields, respectively. Ns protecting group also works, but the reaction always associated with some byproducts, leading to complicated product mixtures. Optimal conditions for the further transformation of 2a to 3a have been identified: using 1.4 equiv of chloranil and carrying out the reaction at 120 °C under Ar atmosphere for 5 h resulted in 3a in 99% yield (see Table S2 in the Supporting Information for more details). Next, we examined the generality of this transformation, and the results are summarized in Scheme 3. Most of the reactions proceeded smoothly under the optimal conditions, giving the
Table 1. Optimization of Reaction Conditionsa
yield (%) entrya
oxidant
solvent
time (h)
2ab
3ab
1 2 3 4 5 6 7 8c
AgOAc AgOAc AgOAc AgOAc AgOAc AgOAc AgOAc AgOAc
DMF DMSO dioxane PhCl CH3CN DCE toluene DMF
6 6 12 12 12 12 12 6
88 83 62 47 42 38 44 83
12 12 11 9 26 8 13 11
a All reactions were carried out with 1a (0.1 mmol) and AgOAc (0.3 mmol) in solvent (1.0 mL) at 120 °C under Ar atmosphere for 6−12 h. bIsolated yields. c1.2 g of 1a was used.
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DOI: 10.1021/acs.orglett.7b01957 Org. Lett. 2017, 19, 4476−4479
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Organic Letters Scheme 3. Substrate Scope of the Oxidation of 2a,b
lammonium bromide (CTAB) and KOH at 65 °C in THF/ MeOH = 3/1 (v/v),25 the corresponding benzo[2,3-c]carbazole was obtained and was subsequently used to react with 2bromopyridine after treatment with NaH in THF, giving 5a in 84% yield in two steps. Substrate 1y was smoothly transformed to product 2y which was converted to 3y under the standard reaction conditions. After deprotection with CTAB and KOH at 65 °C in THF/MeOH = 3/1 (v/v), the corresponding natural alkaloid eustifoline D could be obtained in 66% yield for three steps (see the Supporting Information for more information). To validate the original design of the radical cascade process involving a silver-initiated SET process, radical trapping experiments were conducted. No desired product was obtained by addition of 2,6-di-tert-butyl-4-methylphenol (BHT) or benzoquinone (BQ) into the reaction system along with the recovery of 1a in 89% and 91% yields, respectively (Scheme 5). Scheme 5. Control Experiments and the Proposed Reaction Mechanism
a
Reaction conditions: 2 (0.1 mmol), chloranil (0.14 mmol), in 1.0 mL of o-xylene at 120 °C under Ar atmosphere for 5 h. bIsolated yields of 3. cThe reaction was carried out for 12 h. dThe reaction was carried out for 24 h.
desired products in moderate to excellent yields. When R2 is a hydrogen atom, for substrates 2a,b,p−s, the reactions proceeded efficiently within 5 h to give the desired products in >99% yields. When R1 is a hydrogen atom, if R2 is an electron-donating substituent such as an alkyl group (substrates 2c and 2i−k) or methoxyl group (substrates 2d,e,l), the reactions proceeded very well within 5 h to give the desired products in 91% to >99% yields. Moreover, introducing halogen atom as substituent (substrates 2f−h) afforded the corresponding products 3f−h in 91−99% yields. When the reaction time was lengthened to 12 h, the substrates having a naphthyl moiety were also suitable for this reaction, affording the desired product 3n and 3o in 94% yield. However, if two chlorine atoms were introduced on the different aromatic rings, the reaction was sluggish, affording the corresponding product 3t in 28% yield after 24 h. For substrate 2m bearing a strongly electron-withdrawing CF3 group, the reaction also worked within a prolonged reaction time (24 h), but only giving the desired product 3m in 42% yield because it is more difficult to be oxidized. Substrates 2w and 2x bearing a thienyl ring produced the desired products 3w and 3x (X = S) in 86% and 98% yields, respectively. Product 3v bearing a 3-furyl ring (X = O) was given in >99% yield under identical conditions. To demonstrate the synthetic utility of the resulting products, we further explored the synthesis of 5a from 3a and a short total synthesis of furo[2,3-c]carbazole alkaloid eustifoline D from 1y (Scheme 4). Upon treatment of 3a with hexadecyl trimethy-
Interestingly, when 2,2,6,6-tetramethylpiperidinooxy (TEMPO) was used in the radical trapping experiment, product 6a derived from the radical intermediate III was formed in the yield of 88%, indicating that a radical pathway is indeed involved in this reaction. On the basis of these control experimental results, a plausible mechanism for this cascade cyclization reaction is outlined in Scheme 5. The reaction is initiated by AgOAc through deprotonation with an OAc anion to give an intermediate I, which undergoes a SET process to give another intermediate II-A along with a ring-opening process to afford the radical intermediate III (path a). Alternatively, the intermediate I first undertakes a ring-opening process to give an intermediate II-B, which undergoes an intramolecular SET process to provide the radical intermediate III (path b). The intermediate III goes through a direct radical cyclization with an aromatic ring to afford an intermediate IV, which was oxidized by AgOAc and subsequently deprotonated to deliver the desired product 2a. For the Ts protected substrate 1b (NR = NTs), another cyclized product 4b can be formed at the same time, resulting in a complex product mixture. In summary, we have disclosed a novel intramolecular cascade amination/cyclization/aromatization reaction of FACP using silver acetate as the oxidant to produce a variety of [2,3c]dihydrocarbazoles in moderate to excellent yields as well as [2,3-c]carbazoles upon further oxidation. The mechanistic investigations suggested that this reaction underwent a radical process because the key intermediate in this reaction was captured by a radical trapping reagent TEMPO. The further transformations for the synthesis of eustifoline D and an OLED exhibited the potential synthetic utility of this method. Further investigations on the application of this methodology to
Scheme 4. Transformation: Synthesis of 5a (Compound B) and Eustifoline D
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DOI: 10.1021/acs.orglett.7b01957 Org. Lett. 2017, 19, 4476−4479
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synthesize more interesting compounds are underway in our laboratory.
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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.7b01957. Experimental procedure and characterization data for all compounds (PDF) X-ray crystallographic data for 2e (CIF) X-ray crystallographic data for 3b (CIF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Yin Wei: 0000-0003-0484-9231 Min Shi: 0000-0003-0016-5211 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We are grateful for financial support from the National Basic Research Program of China [(973)-2015CB856603], the Strategic Priority Research Program of the Chinese Academy of Sciences (Grant No. XDB20000000), and the National Natural Science Foundation of China (Nos. 20472096, 21372241, 21572052, 20672127, 21421091, 21372250, 21121062, 21302203, 21772037, and 20732008).
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REFERENCES
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DOI: 10.1021/acs.orglett.7b01957 Org. Lett. 2017, 19, 4476−4479
