Hydrogen Bonding-directed Sequential 1,6/1,4-Addition of Heteroatom Nucleophiles onto Electron-deficient 1,3-Diynes

Abstract

A sequential inter- and intramolecular 1,6/1,4-addition on electron-deficient 1,3-diynes conjugated with a ketone, ester, or imide functionality is described. This tandem process is effectively directed by a propargylic –OH or –NH functionality. Alcohols, amines, and thiols show excellent reactivity for the initial 1,6-addition. The addition of amines occurs at ambient temperature, whereas other nucleophiles require high temperatures up to 100 °C and a base additive such as DABCO. Substrates with propargylic hydrogen undergo double bond isomerization at higher temperatures (70–100 °C) to form furan and pyrrole rings. Nonenolizable 1,3-diynones with an electron-withdrawing group provide good yields (72–86%) with most nucleophiles.

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Introduction

Conjugated additions with non-organometallic reagents onto unsaturated carbonyl compounds constitute an important class of synthetic transformations among which 1,4-additions are the most pronounced process.¹ Although less developed, metal-free 1,6-additions onto activated alkenyl π-systems are reported with a limited substrate scope.² While 1,6-addition mainly engages alkenes, the corresponding reactions with alkynes have been sporadically reported.³

In this regard, we envisioned that the reactions of electron-deficient conjugated 1,3-diynes should critically depend not only on the steric and electronic factors of the substituents but also on the nature of the nucleophiles (Scheme 1).⁴ We recently reported on a novel protocol for 4-pyrone synthesis, which involves 1,4-addition of piperidine onto 1,3-diynone A to form intermediate 1N-A followed by 6-endo-dig cyclization and subsequent hydrolysis of an iminium intermediate to generate pyrone B (eqn (1)).⁵ This outcome contrasts the reported preference of the 1,6-addition of secondary amines including piperidine onto diynones.⁶ We speculated that a hydrogen bonding⁷ element at the propargylic position in C will ensure intermolecular 1,6-addition. This in turn would promote a tandem process⁸via intermediate IN-C, which should undergo an intramolecular 1,4-addition to generate product D (eqn (2)).

Scheme 1 Sequential conjugate additions without or with a hydrogen bonding element.

The hydrogen bonding-directed switch from intermolecular 1,4-addition into 1,6-addition would in turn allow for the hydrogen bonding element to participate in an intramolecular 1,4-addition. This tandem sequence of bond-forming events would constitute a versatile approach for the construction of novel molecular scaffolds in step- and atom-economical manners.⁹ Moreover, the envisioned tandem conjugated additions do not require metal catalysts or organometallic reagents, which will provide unique merits to perform these reactions under mild conditions without rigorous exclusion of moisture and oxygen.

Results and discussion

We commenced our exploration of the hydrogen bonding effect on 1,6-addition with tert-hydroxyl-containing 1,3-diynone 1a and its TBS-protected form 1a-TBS (Table 1). Under identical conditions (3 equiv. of piperidine, toluene, rt), TBS-ether 1a-TBS was converted to 4-pyrone 2a-TBS (63%),⁵ whereas tert-hydroxyl-containing 1a provided 1,6-piperidine addition–cyclization product 2aa (78%).¹⁰ With this encouraging result, we continued to treat 1a with various nucleophiles including amines, alcohols, and thiols, which afforded products 2ab–2ai. A slight excess of amine is enough to provide good yields of the products without any external base whereas at least 3 equivalents of alcohols and DABCO (20 mol%)¹¹ at higher temperatures (70–100 °C) are needed for comparable yields. 1,3-Propanediol participated in the reaction as a mono-nucleophile to generate product 2af (78%). Phenol and aniline addition products 2ah and 2ad were isolated in low yields (20% and 40%) due to the low nucleophilicity of both nucleophiles. N,N-Dimethylhydroxylamine generated the adduct 2ae (78%) at ambient temperature.¹² On the other hand, 1a ¹³ reacted with thiophenol¹⁴ only at elevated temperature (100 °C) to provide the corresponding product 2ai (76%). The reaction with carboxylic acids did not afford the expected products; instead, pyrone 2aj′ was obtained¹⁵ and the yield depends on the structure of the carboxylic acid.

Table 1 OH-directed sequential 1,6/1,4-additions

a Condition A: Nu–H (2 equiv.) in toluene at rt. b Condition B: Nu–H (2 equiv.), DABCO (20 mol%) in toluene at 100 °C. c Condition B but at 90 °C. d Condition B but with Nu–H (5 equiv.) at 70 °C. e Condition C: amine salt (2 equiv.) with Et₃N (3 equiv.) in CH₃CN at rt. f Other complexed by-products were formed. All reactions were performed using undistilled solvents and reagents.

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After the initial screening of nucleophiles that readily undergo 1,6-additions with phenyl ketone-conjugated tert-alcohol 1a, we next turned our attention to the structural variation of the substituent on the ketone and at the propargylic carbon center (Table 2). The reactions of aryl ketones with tertiary (1b, 1c, 1d), secondary (1e), and primary (1f, 1g) propargylic hydroxyl groups, and alkyl ketones of ethyl (1h),^13b isopropyl (1i), cyclohexyl (1j), and tert-butyl (1k) groups with a tertiary propargylic hydroxyl moiety revealed a salient reactivity trend. Aryl ketones 1b–f provided higher yields of amine-addition products 2ba–fa (68–81%) than those of alkyl ketone-derived products 2ha–ja (23–34%) with 2ka (76%) as an exception. This is most likely because of enolization when amines are used as a nucleophile, which is evidenced by isolation of 2ia′,¹⁷ which could be converted to 2ia upon heating.¹⁸ Reactions of aryl ketones with tert-propargylic carbon (1c and 1d) also provided higher yields of methanol addition products 2cb and 2db (85% and 77%) than those of alkyl ketones 1h–k (48–70%) indicating that electron withdrawing aryl groups make the substrate more electrophilic for conjugate addition than electron donating alkyl groups. The yields of amine addition products 2da–fa (76–81%) are not affected by the substituent at the propargylic carbon but the yield of methanol adducts 2db–fb (0–77%) drops as the steric bulk of the propargylic carbon decreases. The reaction of 1g with N-boc-protected cysteine methyl ester^14g at high temperature (70–75 °C) gave a sulfide-containing furan 2ga ¹⁶ (50%) along with 1,6-adduct 2ga′ (12%). Also, it is evident that at higher temperatures substrates with propargylic H, 1e and 1g, undergo double bond isomerization to form more stable furan ring containing products 2eb and 2ga. Unlike 1,3-propanediol, 1,3-propanedithiol reacts as a dinucleophile generating a mixture of vinyl sulfide 2hc (10%) and dithioketal 2hc′ (20%) in a 1 : 2 ratio.

Table 2 OH-directed sequential 1,6/1,4-additions with structural variation on 1,3-diynones

a Condition A: Nu–H (2 equiv.) in toluene at rt. b Condition B: Nu–H (2 equiv.), DABCO (20 mol%) in toluene at 100 °C. c Condition B but at 90 °C. d Condition B but with Nu–H (5 equiv.) at 70 °C. e Mixed with a double bond isomerized furan product in a 5 : 1 ratio. f Dimerized compound 2ia′ was isolated in 18% yield. g Polymerized products were observed. h 1f decomposed. All reactions were performed using undistilled solvents and reagents.

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Next, we examined the 1,6-addition directed by hydrogen bonding with –HNBoc and –HNTs moieties (Table 3).¹⁹ When 1l and 1m containing a primary propargylic –HNBoc moiety were reacted with piperidine, the corresponding addition products 2la and 2ma were obtained in slightly higher yields (81% and 86%) than 2oa and 2pa (70% and 71%) containing a propargylic tert-NHTs moiety. But a significant difference was observed with ephedrine, where the product with 1o was obtained in trace amounts. This discrepancy is likely to be the consequence of increased steric hindrance caused by both the gem-dimethyl moiety and the tosyl group when relatively bulky secondary amines approach the reaction center. The reactions of 1l and 1m with benzylamine, methanol, thiophenol, and Boc-protected cysteine methyl ester generated the corresponding products 2mb, 2lb, 2mc, and 2md in 44–72% yields. It is worth noting that 2mc and 2md are obtained exclusively as pyrrole derivatives due to double bond isomerization. Compared to the failed reaction with a primary propargylic alcohol 1f in generating methanol adduct 2fb, the corresponding primary Boc-bearing propargyl amine 1l (R = H) generated 2lb although in a marginal yield (45%). The reaction of 1o and 1p containing a propargylic tert-NHTs moiety with methanol, ethanol and propane-1,3-diol provided 2oc, 2pb, and 2pc (61–80%) in good yields. The reaction of 1p with 1,3-propanedithiol generated a mixture of vinyl sulfides 2pd (23%) and dithioketal 2pd′ (47%) in a 1 : 2 ratio. The reaction of 1,3-diynone with a propargylic tert-NHBoc moiety gave trace amounts of products with piperidine and ephedrine, whereas with methanol, it formed a 4-pyrone product.

Table 3 NH-directed sequential 1,6/1,4-additions

a Condition A: Nu–H (2 equiv.) in toluene at rt. b Condition B: Nu–H (2 equiv.), DABCO (20 mol%) in toluene at 100 °C. c Condition B but at 90 °C. d Condition B but with Nu–H (5 equiv.) at 70 °C. e Mixed with a double bond isomerized furan product in a 5 : 1 ratio. All reactions were performed using undistilled solvents and reagents.

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We further explored the hydrogen bonding effect on the 1,6-addition with tert-hydroxyl-containing 1,3-diynoate 1q and 1,3-diynimide 1r (Table 4). Both 1q and 1r reacted with piperidine and β-alanine ethyl ester salt to generate the corresponding products 2q and 2r (71% and 77%) in good yields. But the reactions with phenylalanine methyl ester salt, phenylglycine methyl ester salt, and N-Boc-protected cysteine methyl ester provided moderate yields (50–62%), whereas the reaction with proline benzyl ester generated 2qd (40%) in a low yield due to the increased steric hindrance. The reaction of 1q and 1r with methanol provided the 1,4-methanol addition product where the imide group of 1r was also replaced by methanol.

Table 4 OH-directed sequential 1,6/1,4-additions of conjugated esters and imides

a Condition A: Nu–H (2 equiv.) in toluene at rt. b Condition B: Nu–H (5 equiv.), DABCO (20 mol%) in toluene at 80 °C. c Condition C: amine salt (2 equiv.) with Et₃N (3 equiv.) in CH₃CN at rt. All reactions were performed using undistilled solvents and reagents.

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The effects of propargylic and homopropargylic hydroxyl groups on the efficiency of 1,6-addition and 1,4-addition are compared with probes 1s–u (Scheme 2). Treating diol 1s with piperidine (2 equiv., toluene, rt) provided only 5-membered ring product 2sa (65%); the corresponding 6-membered ring adduct 2sa′ was not observed.²⁰ Primary and tertiary homopropargylic substrates 1t and 1u were treated with piperidine under forcing conditions. Although the expected product 2ta could not be obtained, 2ua was obtained in a 20% yield. This clearly demonstrates that the hydrogen bonding element at the propargylic position is crucial for the effective 1,6-addition of nucleophiles.

Scheme 2 Probing the effect of a hydrogen bonding element at the homopropargylic position.

Conclusions

We describe sequential inter- and intramolecular 1,6- and 1,4-addition with electron-deficient 1,3-diynes that are conjugated with an electron-withdrawing group such as a ketone, ester, or imide functionality. These addition processes are directed by hydrogen bonding elements such as –OH, –NHTs and –NHBoc moieties at the propargylic position. The initial 1,6-addition renders these hydrogen bonding elements to become an internal nucleophile for the subsequent intramolecular 1,4-addition to generate the final products. Alcohols, amines, and thiols show excellent reactivity for the initial 1,6-addition, among which amines are the most reactive and their addition occurs at ambient temperature. On the other hand, alcohols and thiols require a base additive such as DABCO and higher temperatures (70–100 °C). Tertiary, secondary and primary propargylic –OH and –NHR functional groups are effective promoters for the sequential 1,6/1,4-additions although primary alcohols have a limited scope. 1,3-Diyne substrates conjugated with aromatic ketones display better yields with amines whereas alkyl ketones resulted in relatively lower yields due to enolization. The hydrogen bonding-directed sequential 1,6/1,4-additions developed herein allow for creating unique heterocycles with structural diversity under mild conditions without using metal catalysts or organometallic reagents. Moreover, the hydrogen bonding-based control for reaction pathways allows for the development of many unprecedented tandem reactions which will be reported in due course.

Conflicts of interest

The authors declare no competing financial interests.

Acknowledgements

The authors thank the Donors of the American Chemical Society Petroleum Research Fund for financial support. The Mass Spectrometry Laboratory at UIUC is acknowledged.

References

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14. For selected examples of addition of thiols to alkynes, see: (a) W. E. Truce and G. J. W. Tichenor, Effect of Activating Group on Trans Stereoselectivity of Thiolate Additions to Activated Acetylenes, J. Org. Chem., 1972, 37, 2391; (b) O. De Lucchi, V. Lucchini, C. Marchioro, G. Valle and G. Modena, Self-induced diastereoselective oxidation of vinyl sulfoxides bearing a chiral hydroxy group as a way of preparation of optically active sulfinyl dienophiles and their use in the asymmetric Diels-Alder reactions to cyclopentadiene, J. Org. Chem., 1986, 51, 1457; (c) M. Journet, A. Rouillard, D. Cai and R. D. Larsen, Double Radical Cyclization/β-Fragmentation of Acyclic ω-Yne Vinyl Sulfides. Synthesis of 3-Vinyldihydrothiophene and Dihydrothiopyran Derivatives. A New Example of a 5-endo-trig Radical Cyclization, J. Org. Chem., 1997, 62, 8630; (d) O. Arjona, R. Medel, J. Rojas, A. M. Costa and J. Vilar-rasa, Chemoselective protection of thiols versus alcohols and phenols. The Tosvinyl group, Tetrahedron Lett., 2003, 44, 6369; (e) J. C. Henise and J. Taunton, Irreversible Nek2 Kinase Inhibitors with Cellular Activity, J. Med. Chem., 2011, 54, 4133; (f) R. Ekkebus, S. I. van Kasteren, Y. Kulathu, A. Scholten, I. Berlin, P. P. Geurink, A. de Jong, S. Goerdayal, J. Neefjes, A. J. R. Heck, D. Komander and H. Ovaa, On Terminal Alkynes That Can React with Active-Site Cysteine Nucleophiles in Proteases, J. Am. Chem. Soc., 2013, 135, 2867; (g) P. Fricero, L. Bialy, W. Czechtizky, M. Méndez and J. P. A. Harrity, Org. Lett., 2018, 20, 198; (h) T. Cheng, W. Huang, D. Gao, Z. Yang, C. Zhang, H. Zhang, J. Zhang, H. Li and X.-F. Yang, Michael Addition/S,N-Intramolecular Rearrangement Sequence Enables Selective Fluorescence Detection of Cysteine and Homocysteine, Anal. Chem., 2019, 91, 10894; (i) K. McAulay, E. A. Hoyt, M. Thomas, M. Schimpl, M. S. Bodnarchuk, H. J. Lewis, D. Barratt, D. Bhavsar, D. M. Robinson, M. J. Deery, D. J. Ogg, G. J. L. Bernardes, R. A. Ward, M. J. Waring and J. G. Kettle, Alkynyl Benzoxazines and Dihydroquinazolines as Cysteine Targeting Covalent Warheads and Their Application in Identification of Selective Irreversible Kinase Inhibitors, J. Am. Chem. Soc., 2020, 142, 10358.
15. The identity of pyrone 2al′ was established by comparison with 2a-TBS. For a plausible mechanism, see: M. J. Fan, G. Q. Li and Y. M. Liang, DABCO-catalyzed reaction of various nucleophiles with activated alkynes leading to the formation of alkenoic acid esters, 1,4-dioxane, morpholine, and piperazinone derivatives, Tetrahedron, 2006, 62, 6782 Alternatively, under acidic conditions 1,6/14-adduct 2al rearranges to pyrone 2al′, see: T. H. Nguyen, V. J. T. Anders, Q. Ma, R. Herbs-Irmer and P. Langer, Synthesis of 5-alkylidene-2,5-dihydropyrrol-2-ones and their ring-transformation into 5,6-dihydrobenzo[h]chromones, 5,6,7,8-tetrahydrochromones and pyran-4-ones, Tetrahedron, 2007, 63, 12975.
16. An example of intramolecular nucleophilic addition followed by proton transfer to form an oxazole moiety: P. Wipf, Y. Aoyama and T. E. Benedum, A Practical Method for Oxazole Synthesis by Cycloisomerization of Propargyl Amides, Org. Lett., 2004, 6, 3593.
17. Related dimerization of alkynyl ketones in the presence of DABCO: (a) P. V. Ramachandran, M. T. Rudd and V. R. Reddy, 1,4-diazabicyclo[2.2.2]octane-catalyzed self- and cross-condensation of α-acetylenic ketones, Tetrahedron Lett., 1999, 40, 3819; (b) A. V. Mareev, M. V. Andreev and I. A. Ushakov, Base-Catalyzed Hydration of Silicon-Containing Activated Alkynes: The Effect of Substituents at the Triple Bond, ChemistrySelect, 2020, 5, 10736.
18. The mechanism involves the 1,6-addition of piperidine with 2ja′ followed by elimination of the enolate moiety.
19. Substrates containing a free amino group (–NH₂) could not be prepared because of the instability.
20. The identity of 2sa was established by converting it to its acetate, which shows a chemical shift change of the methylene protons to a lower field (from 3.87 to 4.39 ppm). No sizable chemical shift change is expected by acetylation if it is 2sa′.

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Footnote

† Electronic supplementary information (ESI) available. See DOI: https://doi.org/10.1039/d2qo01730j

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