Pd/norbornene-catalyzed sequential ortho-C–H alkylation and ipso-alkynylation: a 1,1-dimethyl-2-alkynol strategy

Abstract

A palladium/norbornene-catalyzed ortho-C–H alkylation and ipso-alkynylation reaction for the synthesis of 2-alkyl-1-alkynyl arenes was reported. By the use of 1,1-dimethyl-2-alkynols as alkynyl reagents, the side O-alkylation reaction was mostly inhibited, and the reactivity of the three components matched well. As a result, A- and B-type side-products could be substantially inhibited and good to excellent yields were achieved.

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Zhenhua Gu

Zhenhua Gu studied chemistry at Nanjing University and received his PhD degree at the Shanghai Institute of Organic Chemistry in 2007 with Professor Shengming Ma. He conducted his postdoctoral research with Professor K. Peter C. Vollhardt (UC Berkeley) and Professor Armen Zakarian (UC Santa Barbara). In 2012, he began his independent academic career at the Department of Chemistry, the University of Science and Technology of China with the support from “Thousand Talents Plan”. Research in his group is mainly focused on the development of new methods and strategies for organic synthesis, including asymmetric catalysis, natural and un-natural bioactive molecule synthesis.

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Introduction

Multi-component reactions, including transition metal-catalyzed transformations, are one of the most attractive research areas in view of their step-economy.¹ Among them, palladium/norbornene-catalyzed ortho C–H functionalization and ipso cross-coupling reaction is a unique transformation, which is particularly useful in the synthesis of poly-substituted aromatic compounds.^2,3 Since its development in 1997, various polyfunctionalized arenes have been synthesized, particularly the contributions from the groups of Lautens and Catellani. During the past decade, numerous reagents, such as alkenes,⁴ cynane,⁵ amines/amides/imine,⁶ hydride,⁷ carbenes,⁸ and electron-rich arenes⁹ have been successfully applied to the final step ipso termination reactions and a number of interesting aromatic compounds have been synthesized.¹⁰ Recently Yu¹¹ and Dong¹² have developed Pd(II)-catalyzed efficiently selective meta-C–H functionalization reactions of arenes with ortho-directing groups, where norbornene worked as an efficient shuttle for selective meta-C–H functionalization. The utility of this reaction was further demonstrated by Lautens,¹³ Bach¹⁴ and our groups¹⁵ in the application of natural product synthesis, such as (+)-linoxepin, goniomitine, rhazinal etc. Alkynes are one of the most important functional groups in organic chemistry. They not only occur in many molecules, but are important building blocks or intermediates in organic syntheses.¹⁶ The ortho-substituted 1-alkynyl arenes are useful substrates for the synthesis of axially or helically chiral molecules.¹⁷ However, the Pd/norbornene-catalyzed ortho-C–H functionalization terminated by ipso-Sonogashira coupling has been rarely studied. In 2004 Catellani and co-workers¹⁸ disclosed a primary investigation on the ipso Sonogashira coupling termination, where a very slow addition of both alkyl bromides and terminal alkynes¹⁹ was necessary to avoid side-reactions and as a result a total of six days were required to get a reasonable conversion (80–89%). Recently we,²⁰ later Chen and Wu et al.²¹, realized an efficient ipso-Sonogashira coupling for the synthesis of 2-alkynylanilines via protected alkynes by the release of small molecules, such as CO₂etc., where the reactivity of different substrates matched well and the reaction was completed within 4 h with good yield.

Our continued studies found that the decarboxylative alkynylation strategy²² was only successful for the synthesis of 2-alkynylanilines. However, when alkyl iodide instead of O-benzoyl hydroxylamine was used, 99% of norbornene adduct A was isolated under identical reaction conditions. The use of a polar solvent, such as CH₃CN in the reaction afforded a mixture of products with poor conversion (Scheme 1c). The desired ortho C–H alkylation and ipso-Sonogashira coupling product was curtailed to 10% of the isolated yield, and the major side reaction was the esterification of carboxylic acid with the alkyl iodides, such as the formation of B under basic conditions. We herein report our efforts on palladium/norbornene-catalyzed ortho-alkylation/ipso-Sonogashira coupling by the use of 1,1-dimethyl-2-alkynols²³ as the alkynyl components.

Scheme 1 Sonogashira coupling termination for Catellani reaction.

Results and discussion

As mentioned above, the formation of propiolic esters is the critical problem for this transformation. We reasoned that the use of bulky 1,1-dimethyl-2-alkynols and tertiary alcohols would substantially lower the rate of O-alkylation reaction of alkynylation reagents, where terminal alkynes could be released via the loss of one molecule of acetone. Pleasingly, no O-alkylation product was detected when the reaction of 3a with 1-iodonaphthalene and 1-iodobutane was performed in dioxane, though only 20% of desired product 4a was isolated (Table 1, entry 1). Upon further optimization of the solvent, we found that a “non-polar” solvent, e.g. toluene was not suitable for this reaction (entry 2). The reactions had good performances in “polar” solvents, such as DME, DMF, MeCN etc., where MeCN was superior to others (entries 3–5). The reaction with K₃PO₄ as the base gave 43% yield of the desired product while the one with NaOAc was completely inert (entries 6 and 7). Other palladium sources, such as PdCl₂, Pd(dba)₂ were also screened, and no higher yield was obtained than Pd(OAc)₂ (entries 8 and 9). The reaction proceeded well in the absence of phosphine ligands though a relatively low yield of 4a was achieved (entry 10). It should be noted that the reaction is sensitive to moisture and fresh distilled dry CH₃CN from calcium hydride is necessary for a reproducible yield. The addition of water scavengers also endeavoured: MgSO₄ showed good performance for this transformation and the yields became more reliable than the ones in the absence of MgSO₄ (entries 11 and 12).²⁴

Table 1 Reaction condition optimization^a

Entry	Base	Additive	Solvent	Yield^a/%
a The reaction was conducted on 0.20 mmol of 1a, 0.40 mmol of 2a, 0.30 mmol of 3a, 0.60 mmol of norbornene, 0.60 mmol of Cs2CO3, 5 mol% of Pd(OAc)2, and 12.5 mol% of phosphine. b PdCl2 was used. c Pd(dba)2 was used. d No phosphine was used.
1	Cs2CO3	—	Dioxane	20
2	Cs2CO3	—	Toluene	Trace
3	Cs2CO3	—	DME	67
4	Cs2CO3	—	DMF	50
5	Cs2CO3	—	MeCN	70
6	K3PO4	—	MeCN	43
7	NaOAc	—	MeCN	NR
8^b	Cs2CO3	—	MeCN	64
9^c	Cs2CO3	—	MeCN	48
10^d	Cs2CO3	—	MeCN	58
11	Cs2CO3	4A MS (200 mg)	MeCN	62
12	Cs2CO3	MgSO4 (150 mg)	MeCN	88

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With the optimized reaction conditions in hand, a series of alkyl iodides 2 and 1,1-dimethyl-2-alkynols 3 were tested (Table 2). The reaction proceeded equally efficiently when iodoethane, iodopropane, and (3-iodopropyl)benzene were used as alkylation reagents (4b–d). The O-Bn, O-TBDPS and O-PMB functionalities in alkyl chains could be tolerated, and good to excellent yields were obtained (4e–g). 1-(Chloromethyl)-4-methoxybenzene (PMBCl) was also a compatible substrate, and the reaction afforded 58% yield of 4h in CH₃CN while 80% in 1,2-dimethoxyethane. The electronic effect of 3-phenylprop-2-yn-1-ols was investigated. The reactions with substrates bearing electron-donating groups on the phenyl rings, such as p-methyl, p-(tert-butyl) and p-methoxyl groups gave the corresponding products in good yields (4i–k). In contrast to the decarboxylative synthesis of 2-alkynylanilines, this reaction worked well with the electron-withdrawing (CF₃) or phenyl group on the para-position of phenyl rings, albeit relatively low yields were obtained (4l and 4m). The reaction proceeded uneventfully with other 3-arylprop-2-yn-1-ols (4n–p). Pleasingly it was found that the aliphatic substituted prop-2-yn-1-ols were compatible components, and the corresponding reactions gave decent yields of the desired products (4q and 4r).

Table 2 Substrate scope^a

a The reaction was conducted on 0.20 mmol of 1a, 0.40 mmol of 2, 0.30 mmol of 3, 0.60 mmol of norbornene, 0.60 mmol of Cs₂CO₃, 5 mol% of Pd(OAc)₂, and 12.5 mol% of P(p-MeOC₆H₄)₃. b 1-(Chloromethyl)-4-methoxybenzene was used.

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The generality of this reaction was further explored by studies of various substituted iodoarenes, and a series of poly-substituted phenyl acetylenes could be synthesized easily (Table 3). Generally electron-rich iodoarenes worked better than the ones bearing electron-withdrawing groups. For example, the compounds bearing an ortho-CF₃, chloro, or para-NO₂ group (4s, 4A and 4C) were formed in around 60% yields while 4t–v, 4B, and 4D were isolated in 71–90% yields. The reaction with 2-iodo-(O-TBS)-hydroxymethyl benzene proceeded uneventfully to deliver the product 4w in 61% yield. The meta-chloro or fluoro-substitution has less electronic effect for this transformation, and both 4x and 4y were formed in 81% yields.

Table 3 Substrate scope for iodoarenes^a

a The reaction was conducted on 0.20 mmol of 1a, 0.40 mmol of 2, 0.30 mmol of 3, 0.60 mmol of norbornene, 0.60 mmol of Cs₂CO₃, 5 mol% of Pd(OAc)₂, and 12.5 mol% of P(p-MeOC₆H₄)₃.

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The use of alkyl bromides instead of alkyl iodides dramatically decreased the efficiency of this reaction. However, the yield could be improved by the addition of NaI as the additive (Scheme 2).

Scheme 2 The reactions with 1-bromopropane.

A brief catalytic cycle for this transformation is proposed in Scheme 3 with 1-iodonaphthalene and 1-iodobutane and 3a as typical substrates. The oxidative addition of Pd(0) with 1a, followed by NBE insertion would give I. Due to the lack of cis-β-hydride, I would undergo carbopalladation to release one molecule HX and form II, which gave III after the oxidative addition with n-BuI and reductive elimination. Norbornene extrusion of III delivered the classic steric bulky aryl palladium species IV. Anion exchange of IV with 1,1-dimethyl-2-alkynols form alkoxypalladium V, which in situ generate alkynylpalladium VIvia the release of acetone. Finally, the reaction delivered the product via reductive elimination. The anion exchange of I with 3a would give VII, which was supposed to afford the A-type by-product via decarbonylation and reductive elimination. However, the relatively slow rate of decarbonylation in comparison with the formation of IIvia cyclopalladation led to the reaction disfavouring the formation of the A-type by-product.

Scheme 3 The plausible catalytic cycle.

Conclusions

We have developed a protocol for the efficient synthesis of poly-substituted 2-alkyl-1-alkynyl arenes in moderate to excellent yields via Pd/norbornene co-catalysis. The use of 1,1-dimethyl-2-alkynols as alkynyl reagents not only matched the reactivity with other components, but also substantially inhibited the side-reaction of O-alkylation.

Acknowledgements

This work was supported by the ‘973’ project from the MOST of China (2015CB856600), NSFC (21272221, 21472179), the Recruitment Program of Global Experts, and the Fundamental Research Funds for the Central Universities (WK 2060190028, 2060190026 and 3430000001).

Notes and references

1. (a) R. W. Armstrong, A. P. Combs, P. A. Tempest, S. D. Brown and T. A. Keating, Acc. Chem. Res., 1996, 29, 123; (b) I. Ugi, Pure Appl. Chem., 2001, 73, 187; (c) A. Dömling and I. Ugi, Angew. Chem., Int. Ed., 2000, 39, 3168; (d) Multicomponent Reactions, ed. J. Zhu and H. Bienaryrme, Wiley-VCH, Weinheim, 2005.
2. (a) M. Catellani and L. Ferioli, Synthesis, 1996, 769; (b) M. Catellani, F. Frignani and A. Rangoni, Angew. Chem., Int. Ed. Engl., 1997, 36, 119.
3. (a) M. Catellani, Synlett, 2003, 298; (b) M. Catellani, Top. Organomet. Chem., 2005, 14, 21; (c) M. Lautens, D. Alberico, C. Bressy, Y.-Q. Fang, B. Mariampillai and T. Wilhelm, Pure Appl. Chem., 2006, 78, 351; (d) M. Catellani, E. Motti and N. Della Ca’, Acc. Chem. Res., 2008, 41, 1512; (e) A. Martins, B. Mariampillai and M. Lautens, Top. Curr. Chem., 2010, 292, 1; (f) P. Sehnal, R. J. K. Taylor and L. J. S. Fairlamb, Chem. Rev., 2010, 110, 824; (g) G. P. Chiusoli, M. Catellani, M. Costa, E. Motti, N. Della Ca’ and G. Maestri, Coord. Chem. Rev., 2010, 254, 456; (h) J.-T. Ye and M. Lautens, Nat. Chem., 2015, 7, 863.
4. (a) A. Rudolph, N. Rackelmann, M.-O. Turcotte-Savard and M. Lautens, J. Org. Chem., 2009, 74, 289; (b) Z. Qureshi, W. Schlundt and M. Lautens, Synthesis, 2015, 2446; (c) P.-X. Zhou, Y.-Y. Y. C. Liu, L.-B. Zhao, J.-Y. Hou, D.-Q. Chen, Q. Tang, A.-Q. Wang, J.-Y. Zhang, Q.-X. Huang, P.-F. Xu and Y.-M. Liang, ACS Catal., 2015, 5, 4927; (d) Y. Huang, R. Zhu, K. Zhao and Z. Gu, Angew. Chem., Int. Ed., 2015, 54, 12669; (e) F. Faccini, E. Motti and M. Catellani, J. Am. Chem. Soc., 2004, 126, 78; (f) A. Rudolph, N. Rackelmann and M. Lautens, Angew. Chem., Int. Ed., 2007, 46, 1485; (g) H. Zhang, P. Chen and G. Liu, Angew. Chem., Int. Ed., 2014, 53, 10174; (h) Z.-Y. Chen, C.-Q. Ye, X.-P. Zeng and J.-J. Yuan, Chem. – Eur. J., 2014, 20, 4237.
5. (a) B. Mariampillai, D. Alberico, V. Bidau and M. Lautens, J. Am. Chem. Soc., 2006, 128, 14436; (b) B. Mariampillai, J. Alliot, M. Li and M. Lautens, J. Am. Chem. Soc., 2007, 129, 15372.
6. (a) P. Thansandote, M. Raemy, A. Rudolph and M. Lautens, Org. Lett., 2007, 9, 5255; (b) P. Thansandote, E. Chong, K.-O. Feldmann and M. Lautens, J. Org. Chem., 2010, 75, 3495; (c) D. A. Candito and M. Lautens, Org. Lett., 2010, 12, 3312; (d) D. A. Candito and M. Lautens, Angew. Chem., Int. Ed., 2009, 48, 6713; (e) M. Blanchot, D. A. Candito, F. Larnaud and M. Lautens, Org. Lett., 2011, 13, 1486; (f) V. Narbonne, P. Retailleau, G. Maestri and M. Catellani, Org. Lett., 2014, 16, 628.
7. (a) K. Mitsudo, P. Thansandote, T. Wilhelm, B. Mariampillai and M. Lautens, Org. Lett., 2006, 8, 3939; (b) A. Martins, D. A. Candito and M. Lautens, Org. Lett., 2010, 12, 5186; (c) Z. Dong and G. Dong, J. Am. Chem. Soc., 2013, 135, 18350; (d) Z. Dong, J. Wang, Z. Ren and G. Dong, Angew. Chem., Int. Ed., 2015, 54, 12664.
8. (a) P.-X. Zhou, Y.-Y. Ye, J.-W. Ma, L. Zheng, Q. Tang, Y.-F. Qiu, B. Song, Z.-H. Qiu, P.-F. Xu and Y.-M. Liang, J. Org. Chem., 2014, 79, 6627; (b) P.-X. Zhou, L. Zheng, J.-W. Ma, Y.-Y. Ye, X.-Y. Liu, P.-F. Xu and Y.-M. Liang, Chem. – Eur. J., 2014, 20, 6745.
9. (a) C. Bressy, D. Alberico and M. Lautens, J. Am. Chem. Soc., 2005, 127, 13148; (b) C. Blaszykowski, E. Aktoudianakis, C. Bressy, D. Alberico and M. Lautens, Org. Lett., 2006, 8, 2043; (c) A. Martins, D. Alberico and M. Lautens, Org. Lett., 2006, 8, 4827; (d) C. Blaszykowski, E. Aktoudianakis, D. Alberico, C. Bressy, D. G. Hulcoop, F. Jafarpour, A. Joushaghani, B. Laleu and M. Lautens, J. Org. Chem., 2008, 73, 1888; (e) N. Della Ca’, G. Maestri and M. Catellani, Chem. – Eur. J., 2009, 15, 7850; (f) C. Lei, X. Jin and J. S. Zhou, Angew. Chem., Int. Ed., 2015, 54, 13397.
10. For other related typical examples, see: (a) L. Jiao and T. Bach, J. Am. Chem. Soc., 2011, 133, 12990; (b) M. Cheng, J. Yan, F. Hu, H. Chen and Y. Hu, Chem. Sci., 2013, 4, 526; (c) K. M. Gericke, D. I. Chai, N. Bieler and M. Lautens, Angew. Chem., Int. Ed., 2009, 48, 1447; (d) H. Liu;, M. El-Salfiti and M. Lautens, Angew. Chem., Int. Ed., 2012, 51, 9846.
11. (a) X.-C. Wang, W. Gong, L.-Z. Fang, R.-Y. Zhu, S. Li, K. M. Engle and J.-Q. Yu, Nature, 2015, 519, 334; (b) P.-X. Shen, X.-C. Wang, P. Wang, R.-Y. Zhu and J.-Q. Yu, J. Am. Chem. Soc., 2015, 137, 11574.
12. Z. Dong, J. Wang and G.-B. Dong, J. Am. Chem. Soc., 2015, 137, 5887.
13. H. Weinstabl, M. Suhartono, Z. Qureshi and M. Lautens, Angew. Chem., Int. Ed., 2013, 52, 5305.
14. L. Jiao, E. Herdtweck and T. Bach, J. Am. Chem. Soc., 2012, 134, 14563.
15. X. Sui, R. Zhu;, G. Li, X. Ma and Z. Gu, J. Am. Chem. Soc., 2013, 135, 9318.
16. (a) Modern Acetylene Chemistry, ed. P. J. Stang and F. Diederich, VCH, Weinheim, 1995; (b) Acetylene Chemistry: Chemistry, Biology and Material Science, ed. F. Diederich, P. J. Stang and R. R. Tykwinski, Wiley-VCH, Weinheim, 2005; (c) R. Chinchilla and C. Nájera, Chem. Rev., 2014, 114, 1783; (d) R. K. Kumar and X. Bi, Chem. Commun., 2016, 52, 853.
17. Transition-Metal-Mediated Aromatic Ring Construction, ed. K. Tanaka, John Wiley & Sons, Inc., Hoboken, New Jersey, 2013.
18. E. Motti, M. Rossetti, G. Bocelli and M. Catellani, J. Organomet. Chem., 2004, 689, 3741.
19. The slow addition was necessary for some terminal alkyne-involved reactions to avoid side reactions, see: (a) T. Hamada, X. Ye and S. S. Stahl, J. Am. Chem. Soc., 2008, 130, 833; (b) L. Chu; and F.-L. Qing, J. Am. Chem. Soc., 2010, 132, 7262; (c) X. Jiang, L. Chu and F.-L. Qing, J. Org. Chem., 2012, 77, 1251.
20. F. Sun and Z. Gu, Org. Lett., 2015, 17, 2222.
21. S.-F. Pan, X.-J. Ma, D.-N. Zhong, W.-Z. Chen, M.-C. Liu and H.-Y. Wu, Adv. Synth. Catal., 2015, 357, 3052.
22. (a) A. Fromm, C. Wüllen, D. Hackenberger and L. J. Gooßen, J. Am. Chem. Soc., 2014, 136, 10007; (b) C. K. Haley, C. D. Gilmore and B. M. Stoltz, Tetrahedron, 2013, 69, 5732; (c) P. Hu, M. Zhang, X. Jie and W. Su, Angew. Chem., Int. Ed., 2012, 51, 227; (d) K. Xie, Z. Yang, X. Zhou, X. Li, S. Wang, Z. Tan, X. An and C.-C. Guo, Org. Lett., 2010, 12, 1564; (e) L. J. Goossen, G. Deng and L. M. Levy, Science, 2006, 313, 662; (f) L. J. Goossen, N. Rodríguez, B. Melzer, C. Linder, G. Deng and L. M. Levy, J. Am. Chem. Soc., 2007, 129, 4824; (g) C.-C. Hu and Y.-Y. Chen, Org. Chem. Front., 2015, 2, 1352; (h) J. M. Crawford, K. E. Shelton, E. K. Reeves, B. K. Sadarananda and D. Kalyani, Org. Chem. Front., 2015, 2, 726.
23. (a) A. Dermenci, J. W. Coe and G. Dong, Org. Chem. Front., 2014, 1, 567; (b) P. Nguyen, S. Todd, D. Van den Biggelaar, N. J. Taylor, T. B. Marder, F. Wittmann and R. H. Friend, Synlett, 1994, 299; (c) C. Huynh and G. Linstrumelle, Tetrahedron, 1988, 44, 6337; (d) C.-K. Choi, I. Tomita and T. Endo, Chem. Lett., 1999, 28, 1253; (e) H. F. Chow, C. W. Wan, K. H. Low and Y. Y. Yeung, J. Org. Chem., 2001, 66, 1910; (f) H. Hu, F. Yang and Y.-J. Wu, J. Org. Chem., 2013, 78, 10506; (g) T. Nishimura, H. Araki, Y. Maeda and S. Uemura, Org. Lett., 2003, 5, 2997.
24. The corresponding reactions with other phosphine ligands under the optimized conditions, such as PPh₃, P(2-fury)₃, Xphos, bis-[2-(diphenylphosphino]phenyl]ether, P(2-MeOC₆H₄)₃ gave 4a in 45%, 29%, 21%, 53% and 32% yields, respectively.

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Footnote

† Electronic supplementary information (ESI) available: Experimental procedures, characterization data, ¹H and ¹³C NMR spectra for all new compounds. See DOI: 10.1039/c5qo00391a

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