Aryne Trifunctionalization Enabled by 3-Silylaryne as a 1,2-Benzdiyne

Letter Cite This: Org. Lett. 2018, 20, 1919−1923

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Aryne Trifunctionalization Enabled by 3‑Silylaryne as a 1,2‑Benzdiyne Equivalent Chunjie Lv,† Caiwen Wan,† Song Liu, Yu Lan,* and Yang Li* School of Chemistry and Chemical Engineering, Chongqing University, 174 Shazheng Street, Chongqing, 400030, P. R. China S Supporting Information *

ABSTRACT: An unprecedented aryne 1,2,3-trifunctionalization protocol from 2,6-bis(silyl)aryl triflates was developed under transition-metal-free conditions. The reaction of generated 3-silylaryne with both pyridine Noxide and N-hydroxylamide afforded o-silyl triflate/tosylate in a one-pot transformation, allowing the formation of 2,3-aryne precursors with various vicinal pyridinyl/amido substituents. These pyridinyl-substituted 2,3-aryne intermediates exhibit a broad scope of reactivity with diverse arynophiles in good yields and high selectivity.

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highly desirable in terms of diversifying the constitution of 1,2benzdiyne equivalents as well as developing more arene multifunctionalization means.2 Along with our study on aryne multifunctionalization,5c−f,h we were curious about the possibility of “reprogramming” the structural constitution of 1,2-benzdiyne synthons in order to accommodate broader combinations of functional groups. It is known that all conventional 1,2-benzdiyne building blocks contain two leaving groups (LGs) and one accepting group (AG) on three consecutive positions, the AG of which is either a halogen or silyl group and the LG can be halogen, OTf, or OTs (see examples in Scheme 1a).2 Alternatively, is that plausible to utilize a set of two AGs and one LG to assemble a 1,2-benzdiyne equivalent (Scheme 1b)? After carefully searching for suitable candidates, 3-silylarynes were chosen, the silyl groups of which have shown both steric repulsion character7 and inductive electron-donating ability8 (Scheme 1c). Consequently, we postulated that a trimethylsilyl (TMS) group on intermediate iii (Scheme 1d) would play dual roles: manipulating the regioselectivity in 1,2-aryne reaction step and acting as a new AG in 2,3-aryne precursor.9 Meanwhile, we intended to use substrates with O-nucleophile in the 1,2-aryne step so that the new C−O bond could be converted to C-OTf/ OTs on the ortho-position of the TMS group, constituting a new AG-LG set. Herein, we would like to present an unprecedented approach toward arene trifunctionalization enabled by 2,6-bis(trimethylsilyl)phenyl triflates, which includes an umpolung 1,2-aryne reaction step with either pyridine N-oxide or N-hydroxylamide (Scheme 1d). Our study commenced with the reaction of 2,6-bis(trimethylsilyl)aryl triflate (1) with pyridine N-oxide 2. It has been previously reported that benzyne reacts with 2 to give either 3- or 2-(2-hydroxyphenyl)pyridines through a [3 + 2] cycloaddition−rearrangement cascade.10 As shown in Scheme

s one of the most active organic intermediates, arynes have been employed in numerous chemical transformations, which led to the syntheses of diverse vicinal difunctionalized arenes.1 A step further toward aryne multifunctionalization2 could be realized by 1,4-,3 1,3-,3e,f,4 and 1,2-benzdiyne5 and benztriyne equivalents.6 Among benzdiynes, 1,2-benzdiyne is unique, primarily because of the double utilization of its C2 position on both 1,2-aryne i and 2,3-aryne ii as well as arene trifunctionalization on consecutive positions, making 1,2benzdiyne a “sesquibenzyne” synthon (Scheme 1a). In contrast to the recent advances in single aryne transformations, however, the 1,2-benzdiyne chemistry is still in its infancy. In view of the enormous aromatic compounds bearing multiple substituents in biologically active natural products, medicines, and functional materials, further exploration in this field is Scheme 1. Background and Our Proposal

Received: February 8, 2018 Published: March 23, 2018 © 2018 American Chemical Society

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DOI: 10.1021/acs.orglett.8b00469 Org. Lett. 2018, 20, 1919−1923

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dimethyl group was used, 3m was obtained as a 1.2:1 mixture of regioisomers (Scheme 2). Although the mechanism between benzyne and pyridine Noxide has been previously studied by both the Abramovitch10a and Larock10b groups, it remains ambiguous on the origin of the meta vs ortho selectivity. As depicted in Scheme 3, after [3 +

2, after screening on the reaction conditions (conditions A, see the Supporting Information (SI) for detailed optimization Scheme 2. One-Pot Reaction with Pyridine N-Oxides

Scheme 3. Mechanistic Investigation

2] cycloaddition of iii with 2, intermediate v could be conceived (X = H), which then undergoes rearrangement to generate intermediate vi (path a). Hydrogen abstraction on vi would either produce A (via deprotonation of H3) or B (via deprotonation of H2). Alternatively, direct deprotonation of H2 on intermediate v will result in the formation of B with an aryl group on the ortho-position of the pyridine ring (path b). Our computational study (DFT method M11 with 6-311+G(d) basis set) reveals that the energy of vi (−62.7 kcal/mol) is significantly lower than that of v (−46.2 kcal/mol), suggesting that vi would be readily formed from v irreversibly. Meanwhile, the transition state (TS) energy (−31.6 kcal/mol for TS1) of this process is much lower than that of TS2 (−25.9 kcal/mol) for the formation of B (path b), indicating that path a is preferred over path b. After the formation of vi, the TS energy for the deprotonation of H3 (TS3, −38.0 kcal/mol) is lower than that of H2 (TS4, −32.6 kcal/mol), which is consistent with Larock’s hypothesis on the higher acidity of H3.10b In addition, our deuterium labeling experiment between Kobayashi aryne precursor and pyridine-3,5-d2 N-oxide gave neither meta- nor ortho-arylated pyridine product (see Supporting Information for details), suggesting that compound B could not be formed from intermediate vi via path a. In order to explain the formation of 3g, the reaction pathway was calculated when 4-cyanopyridine N-oxide was employed (with a set of pink energies in Scheme 3, X = CN). Interestingly, in the presence of 4-cyano group, the TS energy of TS2′ (−30.4 kcal/mol) becomes lower than that of TS1′ (−28.5 kcal/mol), making path b a favored means to produce compound B. After harvesting a series of 2,3-aryne precursors 3 with either pyridin-3-yl or pyridin-2-yl substituents on the C3 position of aryne precursors in Scheme 2, compounds 3a and 3e were chosen to examine their reactivity toward various arynophiles (Table 1). Upon activation with fluoride, 3a could generate the corresponding 2,3-aryne intermediates at room temperature; whereas elevated temperature (100 °C in 1,4-dioxane) was necessary in order to activate 3e. This different activation conditions between 3a and 3e can be explained by the weaker leaving ability of OTs group over OTf group, which has also been observed by the Suzuki group in their 1,4-benzdiyne study.3c When morpholine was used, compounds 4 and 6 were

a Conditions A: (i) 1 (1.0 mmol), 2 (0.5 mmol), and CsF (2.0 mmol) in MeCN (25 mL), rt; (ii) NaH (60%, 0.75 mmol) and PhNTf2 (0.75 mmol) in THF (30 mL), rt. bConditions B: (i) 1 (1.0 mmol), 2 (0.5 mmol), and TBAF (1.5 mmol) in MeCN (25 mL), rt; (ii) NaH (60%, 0.75 mmol) and TsCl (0.75 mmol) in DCM (30 mL), rt.

conditions), a one-pot process was accomplished from 1a and pyridine N-oxide to produce 3-arylpyridine 3a with concomitant incorporation of a Tf group on OH in 75% yield. When substrates possess electron-donating groups on the 4-position of pyridine N-oxide, comparable yields of 3b and 3c were obtained as well. The reaction between 1a and 2-methylpyridine N-oxide afforded product 3d in 63% yield, presumably attributed to the steric repulsion of 2-methyl group in the [3 + 2] cycloaddition step. In contrast, the reaction with quinoline N-oxide changed the reaction outcome, affording 2-arylquinoline 3e in 69% yield after one-pot incorporation of a Ts group on OH. Unexpectedly, there were no suitable conditions to introduce a Tf group on the phenoxy intermediate in this step; instead, the incorporation of a Ts group turned out to be highly efficient (conditions B, see the SI for detailed optimization conditions).11 When 3,5-dimethylpyridine N-oxide was utilized, the reaction afforded 3f in 67% yield using conditions B. Interestingly, 4-cyanopyridine N-oxide altered the reaction orientation and afforded 2-arylpyridine 3g in 58% yield under conditions B. The employment of 2,6-dimethylpyridine Noxide could also produce 3h in 70% yield under conditions B. Replacing one of the TMS groups on 1a with tertbutyldimethylsilyl (TBS) group as the substrate gave 3i in 75% yield. Furthermore, substituents, such as chloro, methyl, and methoxy groups, could be introduced onto aryne precursor framework, and their reactions with 2 afforded 3j−l in good to high yields. When unsymmetrical aryne precursor with 4,51920

DOI: 10.1021/acs.orglett.8b00469 Org. Lett. 2018, 20, 1919−1923

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presumably because of the incompatible aryne generation conditions of 3e with this arynophile.16 All of the above examples in Table 1 indicate that both 3a and 3e are efficient aryne precursors with excellent regiocontrol, the products of which are normally not readily accessible through traditional methods. Although aryls, such as a phenyl group, have been studied as the factors to tune the regioselectivity in aryne reactions,17 this is the first time aryne chemistry has been explored in the presence of proximal pyridinyl substituents using Kobayashi aryne generation conditions, the excellent regioselectivity of which is primarily attributed to the inductive electron-withdrawing effect of pyridinyl groups. With our desire to expand the synthetic application of this protocol, we also studied the reaction behavior of 3(trimethylsilyl)benzyne (iii) with N-hydroxylamides. The Wang group has reported that an aryne can insert into their N−O bond.18 As shown in Scheme 4, satisfyingly, the reaction

Table 1. Reactions of 3a and 3e with Arynophiles

Scheme 4. One-Pot Reaction with N-Hydroxylamidesa

a conditions C: (i) 1 (0.8 mmol), 24 (0.4 mmol), and CsF (1.6 mmol) in MeCN (20 mL), 50 °C; (ii) NaH (60%, 0.6 mmol) and Tf2O (0.6 mmol) in DCM (20 mL), 0 °C.

of 1a with N-hydroxylamide 24 is highly regioselective and afforded 25a in 53% overall yield after one-pot protection of the resulting OH group with Tf (conditions C, see the SI for detailed optimization conditions). Altering the N-hydroxylamide structure harvested 25b in 62% overall yield. Moreover, a comparable yield could be achieved on 25c when chlorosubstituted 1 was employed. The examples in Scheme 4 indicate that this 1,2-benzdiyne approach could also lead to the ready preparation of amide-containing aryne precursors. Among aryne generation methods, an iodo group has been used as an effective AG in place of silyl group. In view of the low electron negativity and large atom radius of an iodo group, we wanted to learn if we could replace the silyl group on aryne iii with an iodo group. Consequently, compound 26 was prepared with iodo as one of the AGs (Scheme 5). When 26 was treated with pyridine N-oxide in the presence of CsF, 27a

a

3a (0.3 mmol), arynophile (0.6 mmol), and CsF (0.6 mmol) in MeCN (10 mL), rt. b3e (0.3 mmol), arynophile (0.6 mmol), CsF (0.6 mmol), and 18-c-6 (0.3 mmol) in 1,4-dioxane (10 mL), 100 °C.

obtained in 85% and 67% yields, respectively; whereas Nmethylpiperazine gave 5 and 7 in 68% and 62% yields, respectively (entry 1, Table 1). Benzenethiol could also act as a good nucleophile, generating 8 and 9 in good yields (entry 2). Diels−Alder reactions of both 3a and 3e with furans could produce the corresponding products 10−13 in good to high yields (entry 3). A [3 + 2] cycloaddition of 3a with nitrone afforded cycloadduct 14 in 62% yield as a 5:1 mixture of regioisomers, and the same reaction with 3e gave 15 in 60% yield as a single product (entry 4).12 When benzyl azide was employed, its reactions with 3a and 3e produced 16 and 17 in 65% and 57% yields, respectively, both of which are single isomer (entry 5).13 Next, [2 + 2] cycloaddition with 1,1dimethoxyethene was tested, and both 18 and 19 were obtained in moderate yields with high regioselectivity (entry 6).14 Moreover, σ-bond insertion of both aryne precursors with 1,3dimethyl-2-imidazolidinone (DMI) performed smoothly to afford 20 and 21 as single isomer and in good yield (entry 7).15 At last, the reaction of 3a with in situ generated Nchloromorpholine from morpholine/NCS produced 22 in 56% yield, whereas no desired product 23 was observed with 3e,

Scheme 5. Reactivity of Aryne Precursor 26

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and 27b were obtained in 45% overall yield with a ratio of 1.2:1, significantly different from the high selectivity of 26 with both N-methylaniline and benzyl azide reported by the Garg and Houk groups (Scheme 5, path a).9 The absent selectivity with compound 26 in this reaction can be rationalized by the comparable opposite strength of the iodo group on intermediate vii between its weak inductive electron-withdrawing effect and steric repulsion with pyridine N-oxide in a [3 + 2] cycloaddition step, hence resulting in a mixture of regioisomers. Interestingly, by altering the aryne generation method, compound 26 could also serve as a precursor of aryne iii. As shown in path b of Scheme 5, in the presence of benzylmagnesium bromide, compound 26 could be activated and generate intermediate iii, which was then captured by pyridine N-oxide. After one-pot protection with Tf group, aryne precursor 3a was obtained in 47% yield. These experiments show that two orthogonal activating methods could be applied on 26 in terms of generating different aryne intermediates, either iii or vii. In summary, 2,6-bis(trimethylsilyl)aryl triflate was utilized as an unconventional formal 1,2-benzdiyne equivalent for arene trisubstitution. Its reactions with both pyridine N-oxides and Nhydroxylamides result in the regioselective incorporation of an OH group on its C2 position in 1,2-aryne reaction step, allowing a one-pot preparation of 2,3-aryne precursor. Further investigation on pyridinyl-substituted aryne precursors exhibited broad reaction scope with excellent regioselectivity. This approach not only provides opportunities for the application of pyridinyl/amido-substituted aryne transformations under transition-metal-free conditions but also sets up a new method for further convenient construction of various 1,2,3-trisubstituted arenes using this 1,2-benzdiyne approach. Ongoing work includes the study of this protocol toward other arene multifunctionalizations.

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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.8b00469. Experimental details for all chemical reactions and measurements (PDF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Yu Lan: 0000-0002-2328-0020 Yang Li: 0000-0002-0090-2894 Author Contributions †

C.L. and C.W. contributed equally to this work.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors gratefully acknowledge research support of this work by the NSFC (21372268, 21772017) and Fundamental Research Funds for the Central Universities (106112016CDJZR228806). 1922

DOI: 10.1021/acs.orglett.8b00469 Org. Lett. 2018, 20, 1919−1923

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DOI: 10.1021/acs.orglett.8b00469 Org. Lett. 2018, 20, 1919−1923