Domino Aryne Annulation via a NucleophilicâEne Process - Journal of

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Cite This: J. Am. Chem. Soc. 2018, 140, 3555−3559

Domino Aryne Annulation via a Nucleophilic−Ene Process Hai Xu,† Jia He,† Jiarong Shi, Liang Tan, Dachuan Qiu, Xiaohua Luo, and Yang Li* School of Chemistry and Chemical Engineering, Chongqing University, 174 Shazheng Street, Chongqing 400030, P. R. China S Supporting Information *

nucleophilic−ene reaction sequence, which could feature benzo-fused rings that cannot be readily accessed through single benzyne intermediate (Scheme 1b). The reasons to choose ene arynophiles reside in its great functional group compatibility, stereospecificity, and uniqueness in incorporating quaternary carbon centers,6 the transformation of which has also been previously reported in single benzyne-ene reactions with in-depth mechanistic understanding.7 When a nitrogen nucleophile is employed, various benzo-fused N-heterocycles can be conceived. For instance, imipramine8 and clomipramine8b are [6,7,6]-tricyclic antidepressants; oxamniquine (brand name Mansil) is used in the treatment of schistosomiasis (Figure 1).9 Moreover, indolines are common structural motifs

ABSTRACT: 1,2-Benzdiyne equivalents possess the unique property that they can react with two arynophiles through iteratively generated 1,2- and 2,3-aryne intermediates. Upon rational modification on the second leaving group of these aryne precursors, a domino aryne annulation approach was developed through a nucleophilic−ene reaction sequence. Various benzo-fused Nheterocyclic frameworks were achievable under transition metal-free conditions with a broad substrate scope.

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resumably one of the most distinct properties of aryne chemistry1 is the ease with which it can be used to assemble benzo-fused frameworks through annulation reactions, which can concomitantly form two chemical bonds on both alkyne carbons, i.e., pericyclic reactions (path a, Scheme 1a).1c,d,g,h,l Along with the application of mild aryne generation Scheme 1. Background and Our Proposal

Figure 1. Selected molecules with benzo-fused N-heterocycles.

in nature and in medicines,10 i.e., natural antiarrhythmic medicine ajmaline10 and spiroindoline Ibutamoren mesylate,11 which is an orphan drug for growth hormone deficiency (GHD) (Figure 1). These examples underline the importance of benzo-fused N-containing heterocycles and motivated us to develop broad-spectrum aryne annulation protocols. However, it remains a challenge to predict the order of reactivity when two different arynophiles are potential competitors in either a 1,2-aryne or 2,3-aryne step of a domino transformation. Herein, we would like to present our discovery on deferred generation of 2,3-aryne intermediate in 1,2-benzdiyne process, enabling a distinct cascade nucleophilic−ene reaction sequence with diverse substrate scope. To better understand the reactivity of the cascade nucleophilic−ene reaction sequence, we prepared compound 2a by linking a nucleophile and an alkene together for our study.12 The initial examination of 2-(trimethylsilyl)-1,3phenylene bis(trifluoromethanesulfonate) (TPBT) (1a)5a

conditions developed by Kobayashi,2 recently alternative aryne annulation approaches have been accomplished with dualfunctional substrates containing a tethered donor (D) and acceptor (A) (path b, Scheme 1a).1a,3,4 The advantage of these protocols is that arene building blocks are embedded directly into benzo-fused ring systems, whereas other preparation methods are normally not straightforward, requiring either multistep manipulation and/or cyclization with tethered chains. In view of the diverse presence of benzo-fused skeletons especially those with heterocyclic ringsin numerous natural products and medicines, more general methods remain highly in demand in order to expand the realm of aryne annulation. We are interested in the application of 1,2-benzdiyne equivalents as domino aryne synthons that can build polysubstituted arenes in highly selective manner by integrating successively generated 1,2-aryne i and 2,3-aryne ii (Scheme 1b).5 We wondered whether it would be possible to utilize 1,2benzdiyne in annulation transformations, such as through © 2018 American Chemical Society

Received: January 25, 2018 Published: February 8, 2018 3555

DOI: 10.1021/jacs.8b01005 J. Am. Chem. Soc. 2018, 140, 3555−3559

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Journal of the American Chemical Society

which is a fluoride-free aryne-generation condition.5d Compound 3a exists as a mixture of conformational isomers in a ratio of 2.5:1. After cleavage of its Ts group, a derivative of 3a was obtained as a single component in 98% yield (see Supporting Information for details). We are pleased to be able to successfully combine two types of arynophiles, namely N-nucleophile and ene arynophile, in a domino aryne process, whereas in our previous work only nucleophiles could be used.5a,c,d In this transformation, the ene arynophile cannot compete with the nucleophilic reaction on 1,2-aryne i in the first place;12 whereas, the rate of intramolecular ene reaction turned out to be higher than that of intermolecular nucleophilic reaction on 2,3-aryne ii (Scheme 1b). The examples in Table 1 suggest that the reaction efficiency is highly dependent on the second LG on aryne i (Scheme 1b), which could be reasoned by the result of a balance between the rate of elimination of LG on aryne i and that of nucleophilic reaction in order to avoid nonproductive side reactions. In this particular nucleophilic−ene reaction process, compound 1b with a OTs group as the second LG becomes an ideal match. Notably, although other 1,2-benzdiyne equivalents do not fit well with the current nucleophilic−ene process, they might become suitable domino aryne precursors in other transformations. After establishing the structure−reactivity relationship for these domino aryne precursors in Table 1, we then explored the reaction scope of this transformation with 1b. As shown in Scheme 2, substrates with different N-protecting groups were examined and it was found that those with benzenesulfonyl and p-chlorobenzenesulfonyl groups could afford 3b and 3c in 72% and 70% yield, respectively. However, substrate containing a methanesulfonyl (Ms) group gave no desired product. Moreover, in the presence of carbonyl-protecting groups, such as acetyl, trifluoroacetyl, and benzoyl groups, no reaction took place with 1b at all, because of the weak acidity of NH on those carbamides. Substrates with substituents on aryl ring were then examined; they could all afford the desired products 3d− 3g in moderate to high yields. Moreover, substrate with naphthalene framework gave 3h in 70% yield. By employing one shorter carbon as the linker, [6,6,6]-tricyclic products 3i and 3j were obtained in 66% and 58% yield, respectively. It is worth mentioning that 3j bears a benzylic quaternary center, generated from tetrasubstituted olefin precursor. Due to the presence of sulfonyl groups, conformational isomers exist on 3b−3j as well (see Supporting Information for derivatization analysis). A more prominent aspect of this annulation approach is its efficiency on substrates containing aliphatic sulfonamides, which could lead to the production of diverse frameworks, such as indoline, tetrahydroquinoline, and more (Scheme 2). Annulation of 1b with 3,3-dimethylallyl sulfonamide afforded indoline 3k in 71% yield. Moreover, indolines 3l and 3m with C3 quaternary carbon centers could be obtained in 70% and 64% yield, respectively. In the presence of two possible ene reaction sites, cyclization gave 3n with preferential formation of five-membered ring, whereas a 5:3 mixture of E/Z-isomers exists on newly formed olefin. Further exploration revealed that substituent, such as phenyl group, on C1-position of 3,3dimethylallyl sulfonamide could significantly influence the diastereoselective outcome in the ene reaction step, resulting in the formation of 3o in 77% yield with a 17:1 cis/trans ratio. Another interesting product structure is 3p with a [6,5,6]tricyclic system in 53% yield and excellent diastereoselectivity.

with 2a, indeed, afforded the desired benzo-fused product 3a, albeit in only 36% yield (entry 1, Table 1). Unfortunately, all Table 1. Optimization of the Reactiona

entry

1

desilylating agents, additive

solvent

temp (°C)

yield (%)

1 2 3 4 5 6 7 8 9 10 11 12 13 14

1a 1b 1c 1d 1e 1f 1g 1h 1b 1b 1b 1b 1b 1b

CsF, 18-c-6 K2CO3, 18-c-6 K2CO3, 18-c-6 K2CO3, 18-c-6 K2CO3, 18-c-6 K2CO3, 18-c-6 K2CO3, 18-c-6 K2CO3, 18-c-6 K2CO3, 18-c-6 K2CO3, 18-c-6 K2CO3, 18-c-6 Cs2CO3,18-c-6 KF, 18-c-6 CsF, 18-c-6

toluene PhCl PhCl PhCl PhCl PhCl PhCl PhCl toluene dioxane MeCN PhCl PhCl PhCl

100 130 130 130 130 130 130 130 100 100 80 130 130 130

36 77 20 69 67 34 63 24 72 53 22 61 54 57

a Conditions: slow addition of 1 (0.6 mmol) in solvent via syringe pump over 8 h to a suspension of 2a (0.3 mmol), base (1.8 mmol), and 18-c-6 (0.6 mmol) in the same solvent.

our effort to further optimize this reaction with 1a failed, suggesting that 1a does not perform well in this given domino aryne process. Inspired by Suzuki’s discovery of a 1,4-benzdiyne equivalent by employing different leaving groups (LGs, i.e., OTf and OTs),13 we postulated that altering the leaving ability of LGs on aryne i (Scheme 1a) would result in deferred generation of 2,3-aryne ii, which could undergo the proposed intramolecular aryne ene reaction. Consequently, 1,2-benzdiyne equivalent 1b with a OTs group was prepared and tested. Gratifyingly, the reaction of 1b with 2a afforded 3a in 77% yield (entry 2). Further examination with compounds 1c−1g containing other sulfonyloxy groups gave lower yields (entries 3−7). Efforts to analyze side-products in the reactions with 1b−1g only observed messy unknown mixtures, which can be reasoned by the competing side reactions from both aryne intermediates. Moreover, compound 1h with bromide as the second LG also afforded product 3a, albeit in only 24% yield (entry 8), despite the fact that 3-haloarynes are usually used in single aryne chemistry.14 After varying the reaction conditions with 1b on both solvents and fluoride sources (entries 9−14), the optimal one for this transformation was found to be K2CO3/18-crown-6 in chlorobenzene at 130 °C (entry 2), 3556


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suggests that other nucleophiles, i.e., oxygen, could be effective in this domino aryne process as well. To further expand the reaction scope on arene rings, domino aryne precursors 1i−1p with various substituents on 1b were prepared and tested (Scheme 3). When compounds 1i-1l with

Scheme 2. Substrate Scope

Scheme 3. Reactions with Various 1,2-Benzdiyne Equivalents

substituents on the para-position of TMS group were utilized to react with aryl sulfonamide substrate, [6,7,6]-tricyclic 4a−4d could be achieved in good yields. Another distinct property of unsymmetrical 1b is its utilization in chemospecific transformation when additional substituents are on the orthoposition of either OTs or OTf group. For instance, when 1m and 1n were employed in the reaction with 3,3-dimethylallyl sulfonamide, 4e and 4f were obtained in 70% and 52% yield, respectively, exclusively from each corresponding 1,2-benzdiyne equivalent. Same phenomenon was observed when 1o and 1p were utilized, and both 4g and 4h were afforded chemospecifically (Scheme 3). This excellent selectivity originates from the preferential leaving ability of OTf group over OTs group on those aryne precursors, resulting in the generation of 1,2-aryne i exclusively from the OTf end of 1b. Therefore, the employment of unsymmetrical 1b as a new generation of domino aryne precursor not only assists us to achieve this annulation transformation but also provides a chemoselective arene platform whenever additional substituents are present. The convenient construction of the above structural motifs, especially indoline scaffolds, with our approach encouraged us to explore its functionalization directly on drug molecules, which is known a practical way to develop new biologically active compounds from current feedstock of medicines and natural products.15 To this end, the Hoye group recently exhibited an unprecedented utilization of hexadehydro-Diels− Alder (HDDA)-generated arynes on selected natural frame-

a

Conditions: slow addition of 1b (0.6 mmol) in PhCl (10 mL) via syringe pump over 8 h to a suspension of 2 (0.3 mmol), K2CO3 (1.8 mmol), and 18-c-6 (0.6 mmol) in PhCl (30 mL) at 130 °C. bCs2CO3 was used instead of K2CO3.

Notably, the structures of 3k−3p represent a broad scope of indoline scaffolds that belongs to the cores of numerous natural products and medicines.10 The employment of homoallyl sulfonamide as the reactant resulted in the formation of tetrahydroquinoline 3q in 60% yield. Effort to expand the ring size gave compound 3r with construction of a [3.2.2]-bicyclic core in 44% yield. Moreover, compound 3s with a [6,7,6]tricyclic system was afforded in 50% yield. Unexpectedly, compound 3s was found to be an exclusive diastereoisomer with only trace amount of unidentified impurity. Analysis of its X-ray crystal structure suggests that, not only the stereogenic centers on cyclohexane ring, but also the confirmation of Ts group determines the facial selectivity in ene reaction step (Scheme 2). At last, 2-allyl-1,3-cyclohexadione substrate was examined, and the reaction gave [6,7,6]-tricyclic 3t in 41% yield. Although the yield of 3t is not satisfactory, this example 3557



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works.16 We envisioned that our approach could be employed to convert a ketone subunit in a molecule to spiroindoline derivative. As depicted in Scheme 4, androstanolone (5) was

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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/jacs.8b01005. Experimental details for all chemical reactions and measurements and characterization data (PDF) X-ray crystallographic data for 3a (CIF) X-ray crystallographic data for 3i (CIF) X-ray crystallographic data for 3s (CIF)

Scheme 4. Modification of Androstanolone

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AUTHOR INFORMATION

Corresponding Author

*[email protected] ORCID

Yang Li: 0000-0002-0090-2894 Author Contributions †

H.X. and J.H. contributed equally to this work.

chosen for our study. Sulfonamide 6 could be readily prepared from compound 5 in three steps. When 6 was treated with 1b, product 7 was obtained in 63% yield with an overall incorporation of a spiroindoline on the ketone position of 5, despite the presence of a free OH group on the five-membered ring end. At last, we applied our approach toward the synthesis of Ibutamoren mesylate (Figure 1).11 As shown in Scheme 5,

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors gratefully acknowledge research support of this work by NSFC (21372268, 21772017) and Fundamental Research Funds for the Central Universities (106112016CDJZR228806).

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Scheme 5. Synthesis of Ibutamoren Mesylate

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when compound 8 with a N-Ms group reacted with 1b under our standard conditions, indoline 9 was obtained after hydrogenation, showing that Ms can act as an effective group on substrates with aliphatic amine, whereas there was no reaction at all when Ms group was employed on aniline-based substrate. Selective amide hydrolysis of compound 9 could be realized using DIBAL-H in DCM at −78 °C, and compound 10 was afforded in 84% yield.17 After connection with side-chain 11 using literature procedure,11a Ibutamoren mesylate could be successfully prepared. In conclusion, an efficient, transition-metal-free, and broadspectrum domino aryne annulation approach through nucleophilic−ene cascade process was successfully developed, which could construct various benzo-fused N-heterocycles and generate substituted arenes in stereospecific manner. An essential factor for the success of this domino transformation is to alter the leaving ability of the second LG on 1,2-benzdiyne equivalents. This study not only broadens the chemistry of 1,2benzdiyne equivalents but also brings a new avenue for aryne annulation. Our ongoing work includes the in-depth mechanistic study of this process as well as the development of more synthetic applications. 3558


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