Iridium-Catalyzed Highly Efficient and Site-Selective Deoxygenation of

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Iridium-catalyzed highly efficient and site-selective deoxygenation of alcohols Shiyi Yang, Weiping Tang, Zhanhui Yang, and Jiaxi Xu ACS Catal., Just Accepted Manuscript • Publication Date (Web): 27 Aug 2018 Downloaded from http://pubs.acs.org on August 27, 2018

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ACS Catalysis

Iridium-catalyzed highly efficient and site-selective deoxygenation of alcohols Shiyi Yang, † Weiping Tang, ‡,§ Zhanhui Yang*,† and Jiaxi Xu*,† † State Key Laboratory of Chemical Resource Engineering, College of Science, Beijing University of Chemical Technology, Beijing 100029, P. R. China ‡ School of Pharmacy, University of Wisconsin-Madison, 777 Highland Avenue, Madison, WI 53705, USA § Department of Chemistry, University of Wisconsin-Madison, Madison, WI, 53706, USA ABSTRACT: An iridium-catalyzed highly efficient and site-selective deoxygenation of primary, secondary, and tertiary alcohols has been realized, under the assistance of an 4-(N-substituted amino)aryl directing group. Only the hydroxyl adjacent to the directing group can be deoxygenated. The deoxygenation is performed in water, with formic acid as both promoter and hydride donor. Excellent yields and functionality tolerance, as well as high efficiency (S/C up to 1,000,000, TOF up to 445,000 h-1), are obtained. The kinetic isotope effect studies show that hydride formation is the rate-determining step, and the deoxygenation follows an SN1-type pathway. The deoxygenation protocol has been demonstrated useful in the structural modification of naturally occurring ketones and steroids. KEYWORDS: iridium catalysis • deoxygenation • directing group • site-selectivity • high efficiency • water solvent

1.

Introduction

Deoxygenation of alcohols to the corresponding alkanes has been credited with high importance and wide applications, especially in the construction and late-stage modification of high-value chemicals, bioactive compounds, and natural products.1 The Barton-McCombie deoxygenation and its various modifications are classical methods to mainly deoxygenate the sterically encumbered secondary alcohols (Scheme 1a, i).1b,e,2 Deoxygenation of primary alcohols always requires conversions of the hydroxyls to good leaving groups (Scheme 1a, ii).3a-h The Ireland protocol (phosphoryl installation followed by lithium-ammine reduction) is versatile to deoxygenate primary, secondary, and tertiary alcohols.3i In light of the low step-efficiency of the above protocols, direct deoxygenation of free alcohols is highly preferred. Reported methods include transitionmetal-catalyzed hydrogenation (Scheme 1b, iii),4 and acidcatalyzed or -mediated reduction with hydride species (Scheme 1b, iv).5 However, the site-selectivity of deoxygenation varies from conditions and reagents. Recently, primary alcohol deoxygenations were selectively realized based on oxidative dehydrogenation and subsequent Wolff-Kishner reduction under the iridium, 6a ruthenium, 6b and manganese 6c catalysis (Scheme 1b, v). Despite of the above advances, challenges still exist, especially in the single-step deoxygenation. The scope of hydroxyl (primary, secondary, or tertiary) and site-selectivity constitute the main issues that are still not fully addressed. In addition, milder reaction conditions and higher efficiency are also highly demanded.

Scheme 1. Previous and our deoxygenation protocols.

Based on our previous success on the highly efficient transfer hydrogenation of a broad range of aldehydes and ketones in water,7 we began to investigate the aforementioned challenging problem with our newly developed iridium catalysts. We envision that a directing group (DG) may

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be necessary to direct good site-selectivity while maintaining a broad scope for the hydroxyl groups.8 If the directing group itself is also an activating group,9 we may be able to achieve high efficiency under mild conditions. Herein, by using 4-(N-substituted amino) aryl as the directing and activating group, a wide scope of alcohols (primary, secondary, and tertiary) are easily deoxygenated in water, with extremely high site-selectivity and efficiency (Scheme 1c). The directing group can either undergo further transformations,9c,d,10 or remain a sub-structure of drug candidates (Scheme 1d).11 2.

Results and Discussion

2.1 Reaction condition optimization Initial directing-group screening revealed that N,Ndimethylaminophenyl could induce the deoxygenation (see Tables S1 and S2 in SI). With this in hand, the condition optimization commenced with the deoxygenation of secondary alcohol 1a (Table 1). Catalyst TC-3 showed excellent catalytic activity (entries 1-4). Even at 100,000 S/C ratio, the deoxygenation was completed within 25 min (TOF = 240,000 h-1), and product 2a was isolated in 92% yield (entry 4). Increasing the S/C ratio to 500,000 led to various byproducts (entry 5). Further screening of our other catalysts (TC-1, TC-2, and TC-3 to TC-10) at 100,000 S/C ratio also gave satisfactory results, with the deoxygenation completed within 25-40 min and TOF values ranging from 150,000 to 240,000 h-1 (entries 614). We also explored related Li’s catalysts (LC-1 to LC-3) and found that they did not give satisfactory results (entries 15-17).12 Reducing the formic acid amount or lowering the temperature decreased the efficiency (entries 18-20). At 100,000 S/C ratio, organic solvents such as acetonitrile, dichloroethane, acetone, and ethanol did not afford any deoxygenated products. Table 1. Optimization of the reaction conditions.

7 8 9 10 11 12 13 14 15 16 17 18[e] 19[e,f] 20[e,g]

Page 2 of 8 TC-2 TC-4 TC-5 TC-6 TC-7 TC-8 TC-9 TC-10 LC-1 LC-2 LC-3 TC-3 TC-3 TC-3

100,000 100,000 100,000 100,000 100,000 100,000 100,000 100,000 100,000 100,000 100,000 100,000 100,000 5,000

25 30 25 30 30 40 40 25 90 90 90 60 >180 120

>99 >99 >99 >99 >99 >99 >99 >99 31[d] 50[d] 41[d] >99 >99 >99

240,000 200,000 240,000 200,000 200,000 150,000 150,000 240,000 20,670 33,330 27,330 100,000 33,000 2,500

[a] Conversions obtained by 1H NMR analysis of the crude reaction mixtures, and deoxygenated product was identified. During this course, dehydration product appeared, but it was quickly converted to 2a completely. [b] Isolated yield after column chromatography. [c] TLC indicated lots of starting material. [d] 1H NMR conversion with 1,3,5-trimethoxybenzene as internal standard, and 1a was observed in considerate amount. [e] HCOOH (2 equiv.). [f] At 60 oC. [g] At room temperature.

2.2 Directing group screening We then examined different related activating groups (Table 2). Surprisingly, 2-(N,N-Dimethylamino)phenyl (G2) or 3-(N,N-dimethylamino)phenyl (G3) could not induce the deoxygenation, even at much lower 1000 S/C ratio. On the other hand, 4-(N,N-diethylamino)phenyl (G4), 4(pyrrolidin-1-yl)phenyl (G5), 4-(piperidin-1-yl)phenyl (G6), and 4-(3,4-dihydroisoquinolin-2(1H)-yl)phenyl (G7) were all effective activating groups. The reaction of (3,4dihydroquinolin-1(2H)-yl)phenyl (G8) derivative 1b-7 gave messy products. 4-(N-Methylamino)phenyl (G9), with a NH bond, also served as good activating group. The deoxygenation of 4-acetamidophenyl (G10) derivative 1b-9 required lower S/C ratio and addition of hexafluoroisopropanol. Table 2. Screening of directing groups.

entry

Cat.

S/C

Time (min)

Conversion (%)[a]

TOF (h-1)

1 2 3 4 5 6

TC-3 TC-3 TC-3 TC-3 TC-3 TC-1

10,000 20,000 50,000 100,000 500,000 100,000

5 10 15 25 30 25

>99 >99 >99 >99 (92)[b] -[c] >99

120,000 120,000 200,000 240,000 240,000

[a] TLC indicated compete conversion. [b] Isolated yields. [c] S/C = 1000. [d] Complex mixture obtained. [e] HFIP-H2O (1:1, v/v) as solvent.

2.3 Further lower S/C ratios, gram-scale reaction, and pHefficiency correlation

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ACS Catalysis Deoxygenation of 1b at much higher 500,000 and 1,000,000 S/C ratios under nitrogen atomsphere in degassed water afforded 89% and 87% yields, respectively (Table 2, 2b). The TOF values were 445,000 h-1 in the former and 435,000 h-1 in the latter. A gram-scale reaction was completed within 1 h at 100,000 S/C ratio, giving 2b in 80% yield. The correlation between initial pH values and yields were studied (Table 3), using the reaction of 2b at 100,000 S/C ratio as a model. The initial pH values were obtained by tuning the molar ratios of HCOOH and HCOONa (see Table S4 in SI). The highest efficiency was obtained under acidic condtions (pH = 1.6), and the efficiency dropped when the initial pH values of the reaction media was increased. This indicates that formic acid served as not only hydride donor but also reaction promotor. Table 3. Correlation between initial pH values and yields

pHa Yield

(%)b

1.6

3.0

3.5

3.9

4.4

7.2

92

70

68

50

32

1

[a] Initial pH values of the reaction media. [b] Determined by 1H NMR of the crude reaction mixture.

2.4 Substrate scope and fuctionality tolerance studies By using 4-N,N-dimethylaminophenyl (G1) as the directing group, a variety of primary and secondary alcohols was submitted to the optimal conditions, and the functionality tolerance was examined (Table 4). Primary alcohols 1c, 1d, 1e, and 1f were readily deoxygenated. Secondary alchohols (1g-k) with different kinds of aliphatic chains were also susceptible to the deoxygenation. In these cases, the addition of trifluoroethanol or hexafluoroisopropanol was essential. It is worth noting that electron-rich alkenyl group in 1k was well compatible. Alcohols with both electron-rich (1l-t) and electrondeficient (1u-1ae) aryls gave yields ranging from 80% to 96%. In these cases, different kinds of funcitonal groups on the aryl rings, for example, alkyl, aryl, halogen, trifluoromethyl, ester, cyano, and nitro, were well tolerated. Fused or heteroaryls (1af, 1ag, 1ah, 1ai, 1aj, 1ak, 1al, 1am), showed almost no inhibitation against the deoxygenation (74-99% yields); they all surrived well from the acidic conditions, even though the azaryls are basic or acidsensitive. Di-deoxygenation of diol 1an also occurred feasibly. Good tolerance of active benzylic heteroatoms (1ao, 1ap, and 1aq) was also observed. Under the deoxygenation conditions, the alkynyl group in 1ar stayed intact. Desired product 2as was isolated in 76% yield, together with undersired hydrogenated product 2j in 19% yield, from the reactions of 3-phenylprop-2-en-1-ol (1as). Table 4. Deoxygenation of primary and secondary alcohols.[a]

[a] Reactions on 0.25-mmol scale. [b] TLC indicated compete conversion. [c].Isolated yields. [d] S/C = 1000 in HFIP-H2O (1:1, v/v). [e] S/C = 20,000 in TFE-H2O (1:1, v/v).

Tertiary alcohols with directing groups were also easily deoxygenated at 1000 S/C ratio in water-fluoro alcohol mixed solvents (Table 5). Structurally diverse alcohols (3a to 3f) all gave rise to excellent yileds (> 94%). The cyclopropyl with high ring-strain did not undergo ring expansion (4c). Exhilaratingly, the 4-(N,Ndimethyl)phenyl directed deoxygenations of cycloalkanols (3g to 3k) occurred exclusively, with the corresponding products isolated in 98-99% yields. The ring strain in different sizes of cycles did not cause ring-opening or dehydration products. Based on these results, the modifications of a series of ketones via Grignard-type arylation and subsequent deoxygenation were performed. The structral modifications of xanthone, 1-tetralone and 2adamantanone with our deoxygenation strategy gave the corresponding products 4l, 4m, and 4n in excellent yields. Naturally occurring camphor, (S)-carvone, and (R)muscone also successfully underwent the modification, generating 4o, 4p, and 4q in 99%, 96%, and 99% yields, respectively. Notably, the endocyclic C=C bond of 3p was hydrogenated, and four stereoisomers were obtained; cisor trans-3q derived from muscone delivered the same

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results. Dipfluzine, a calcium antagonist,13 was modified into 4r in 97% yields within 60 min. Table 5. Deoxygenation of tertiary alcohols.[a]

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intermediates by dehydroxylation of alcohols. However, the in situ 13C NMR did not detect the carbocation signal (see Figures S2 and S3 in SI), while the ESI-HRMS analyses of alcohols 1 and 3 demonstrated their strong proclivity to form carbocations (see Figures S4-S6 and realted HRMS data in Section 9.6 in SI). Deoxygenations with HCO2H in D2O (Conditions A) and with DCO2H in water (Conditions B) showed that the installed hydrogen majorly came from the formyl hydrogen of formic acid.

[a] Reactions on 0.25-mmol scale. [b] TLC indicated compete conversion. [c] Isolated yields. [d] Water as the sole solvent. [e] S/C = 100,000. [f] HFIP-H2O (1:1, v/v) as solvent.

The current deoxygenation protocol is also highly site-selective. As shown in Table 6, only the hydroxyl adjacent to the directing group could be deoxygenated. The phenolic hydroxyls (1at) kept intact. Other alcoholic hydroxyls, no matter primary (1au, 3s), secondary (3t), or tertiary (3u), were not affected. Surprisingly, even exposed to highly reductive species, ketone group (3u) was immune. This is of high importance in the modification of some hydroxyl- or ketone-containing natural products. Table 6. Selective deoxygenation of diols, ketoalcohols, and phenolic alcohols

[a] TLC indicated compete conversion. [b].Isolated yields. [c] Water as solvent, S/C = 100,000. [d] TFE-H2O (1:1, v/v) as solvent, S/C = 20,000. [e] d.r. of 3t is 70:30. [f] Two-step yield.

2.5 Mechanistic studies Mechanistic studies were performed (Scheme 2). In the absence of iridium catalysts, treating alcohol 3i in water with formic acid gave dehydration product 5 via E1 elimination (eqn. 1), while treating 1b in the presence of a thiol delivered sulfide 6 via SN1 substitution (eqn. 2). These two reactions pointed to the formation of carbocation

Scheme 2. Mechanistic studies

The plausible mechanism is shown in Scheme 3. On one hand, iridium chlorides react with formic acid to generate iridium hydrides B through active catalyst iridium formates A.7 The formation of iridium hydrides was spectrally demonstrated in our previous work via 1H NMR.7a One the other hand, in the acidic conditions alcohols 1 or 3 are converted to carbocations C, which are stabilized by the 4-(N,N-dialkyl)phenyl groups or the added fluorous alcohols. 5f,14 Without the fluoroalkanol cosolvents, dehydration products alkenes were observed in the reactions of tertiary alchols 3. The carbocations C are highly stabilized by the strongly electron-donating 4-(N,Ndialkkylamino)aryl group via the resonant iminium cation form D. Under the standard conditions, other less electron-donating groups such as 2,4,6-trimethoxyphenyl, 4-methoxyphenyl, 4-hydroxyphenyl, fur-2-yl, or thiopen2-yl did not work (see Tables S1 and S2 in SI). The masked carbocations D are highly electrophilic, and react fast with iridium hydrides B to give deoxygenated products 2 or 4, and regenerate active catalysts A. In the kinetic isotope effect (KIE) studies (Scheme 2c), primary KIE was observed (kH/kD = 2.63, eqn. 4), implying that the generation of iridium hydrides B (step b, cleavage of C-H/D bond) is probably the rate-determining step. Secondary KIE was also observed (kH/kD = 1.25, eqn. 5), suggesting that the deoxygenation follows a SN1-type pathway. This is in high accordance with the proposal of carbocation intermediates. The H/D ratios in Conditons A and B in Scheme 2 are atributed to the H–D exchanges in [Ir]H–D2O and in [Ir]D– H2O, respectively.7a

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ACS Catalysis Further transformation of the directing group was demonstrated in Scheme 5. Methylation of the N,Ndimethylamino group of 4l yielded aryltrimethylammonium 12. Palladium-catalyzed Kumadatype coupling of 12 gave 14 in 94% yield, while Nickelcatalyzed Suzuki-type coupling produced 16 in 83% yield.

Scheme 3. Proposed Mechanism.

2.6 Structural modifications of steroids and further Transformations of the directing group Structural modifications of steroid compounds often give potential new bioactive compounds.15 We performed the structural modifications of pasterone (7a), estrone (7b), and epiandrosterone (7c), by installment of 4piperidylphenyl and subsequent deoxygenation (Scheme 4). Only one diastereomer was isolated, and the stereochemistry was assigned by NOE studies. The phenolic and secondary alcoholic hydroxyls remained intact through the two-step sequence. Similarly, cholesterol (9) could also be modified into 11 by DessMartin oxidation, directing group installation, and our iridium-catalyzed deoxygenation, through intermediates 10 (dr. > 20:1).16 Again, very good diastereoselectivity (dr. > 20:1) was observed in the deoxygenation. The Grinard reaction favourably took place at the sterically smaller αface opposite to the 10-methyl. We assume that the hydride installation with sterically bulky iridium hydride preferentially occurred at the sterically less convex β-face of the resultant carbocation, to avoid the steric congestion between G1 and 10-methyl. In other words, it was the installed G1 group that reversed the facial selectivity. Smilar stereochemical outcome in the deoxygenation of 3methylcholesterol was also reported by Ireland and coworkers.3i

Scheme 5. Transformations of the directing group

3.

Conclusion

In conclusion, we have developed an iridium-catalyzed highly efficient and site-selective deoxygenation of alcohols, under the assistance of an N-(substituted amino)aryl directing group. A number of structurally diverse primary, secondary, and tertiary alcohols, adjacent to the directing group, can be deoxygenated with excellent functionality tolerance, in excellent yields, and with extremely high efficiency (S/C up to 1,000,000, TOF up to 445,000 h-1). The alcoholic hydroxyls at other positions, no matter primary, secondary, or tertiary, are not affected. The reaction conditions are very mild (in water and open air), and formic acid is used as both promoter and hydride donor. The KIE studies reveal that hydride generation is the rate-determining step, and the deoxygenation follows an SN1-type pathway. The application of the deoxygenation protocol has been demonstrated in the structural modification of complex ketones and steroids.

ASSOCIATED CONTENT Supporting Information. Further directing group screening, detailed experimental procedures, analytic data of prepared alcohols and products, copies of 1H, 13C, and NOE NMR spectra of products, and 1H NMR spectra of the reaction mixtures.

AUTHOR INFORMATION Corresponding Author * [email protected] (Z. Y.)

* [email protected] (J. X.) ORCID Zhanhui Yang: 0000-0001-7050-8780 Jiaxi Xu: 0000-0002-9039-4933 Notes The authors declare no competing financial interest. Scheme 4. Modification of steroid compounds.

ACKNOWLEDGMENT

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We thank the National Natural Science Foundation of China (No. 21602010 to Z. Yang), and the BUCT Fund for Discipline Construction and Development (Project No. XK1533, to Z. Yang) for financial support.

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ACS Catalysis Chemoselective Reduction of Aldehydes in Water Using Formic Acid as the Hydrogen Source. Green Chem. 2017, 19, 3296-3301. (8) For selected reviews on directing groups, see: (a) Hirano, K.; Miura, M. A Lesson for Site-Selective C–H Functionalization on 2Pyridones: Radical, Organometallic, Directing Group and Steric Controls. Chem. Sci. 2018, 9, 22-32. (b) Ping, Y.; Wang, L.; Ding, Q.; Peng, Y. Nitrile as a Versatile Directing Group for C(sp2)–H Functionalizations. Adv. Synth. Catal. 2017, 359, 3274-3291. (c) Font, M.; Quibell, J. M.; Perry, G. J. P.; Larrosa, I. The Use of Carboxylic Acids as Traceless Directing Groups for Regioselective C– H Bond Functionalization. Chem. Commun. 2017, 53, 5584-5597. (d) Zhu, R.-Y.; Farmer, M. E.; Chen, Y.-Q.; Yu, J.-Q. A Simple and Versatile Amide Directing Group for C−H Functionalizations. Angew. Chem., Int. Ed. 2016, 55, 10578-10599. (9) For selected reviews on activating groups, see: (a) Best, D.; Lam, H. W. C═N-Containing Azaarenes as Activating Groups in Enantioselective Catalysis. J. Org. Chem. 2014, 79, 831-845. (b) Schomaker, J. M.; Grigg, R. D. Activating Group Recycling: a Fresh Approach to Arene Functionalization. Synlett 2013, 24, 401-407. For examples with active 4-(N-substituted amino) aryls, see: (c) Paras, N. A.; MacMillan. D. W. C. The Enantioselective Organocatalytic 1,4-Addition of Electron-Rich Benzenes to α,β-Unsaturated Aldehydes. J. Am. Chem. Soc. 2002, 124, 7894-7895. (d) Yang, J.-M.; Cai, Y.; Zhu, S.-F.; Zhou, Q.-L. Iron-Catalyzed Arylation of α-Aryl-α-Diazoesters. Org. Biomol. Chem. 2016,14, 5516-5519. (10) For selected examples, see: (a) Xie, L.-G.; Wang, Z.-X. Nickel‐Catalyzed Cross‐Coupling of Aryltrimethylammonium Iodides with Organozinc Reagents. Angew. Chem. Int. Ed. 2011, 50, 4901–4904. (b) Reeves, J, T.; Fandrick, D. R.; Tan, Z.; Song, J. J.; Lee, H.; Yee, N. K.; Senanayake, C. H. Room Temperature Palladium-Catalyzed Cross Coupling of Aryltrimethylammonium Triflates with Aryl Grignard Reagents. Org. Lett. 2010, 12, 43884391. (c) Blakey, S, B.; MacMillan, D. W. C. The First Suzuki CrossCouplings of Aryltrimethylammonium Salts. J. Am. Chem. Soc. 2003, 125, 6046-6047. (d) Li, Z.; Li, C.-J. CuBr-Catalyzed Efficient Alkynylation of sp3 C−H Bonds Adjacent to a Nitrogen Atom. J. Am. Chem. Soc. 2004, 126, 11810-11811. (11) (a) Dow, R. L.; Li, J.-C.; Pence, M. P.; Gibbs, E. M.; LaPerle, J. L.; Litchfield, J.; Piotrowski, D. W.; Munchhof, M. J.; Manion, T.

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