Transition-Metal-Free Hydrogenation of Aryl Halides: From Alcohol to

Letter pubs.acs.org/OrgLett

Transition-Metal-Free Hydrogenation of Aryl Halides: From Alcohol to Aldehyde Hong-Xing Zheng,†,§ Xiang-Huan Shan,†,§ Jian-Ping Qu,*,‡ and Yan-Biao Kang*,† †

Department of Chemistry, University of Science and Technology of China, Hefei 230026, China Institute of Advanced Synthesis, School of Chemistry and Molecular Engineering, Jiangsu National Synergetic Innovation Center for Advanced Materials, Nanjing Tech University, Nanjing 211816, China

‡

S Supporting Information *

ABSTRACT: A transition-metal- and catalyst-free hydrogenation of aryl halides, promoted by bases with either aldehydes or alcohols, is described. One equivalent of benzaldehyde affords an equal yield as that of 0.5 equiv of benzyl alcohol. The kinetic study reveals that the initial rate of PhCHO is much faster than that of BnOH, in the ratio of nearly 4:1. The radical trapping experiments indicate the radical nature of this reaction. Based on the kinetic study, trapping and KIE experiments, and control experiments, a tentative mechanism is proposed. As a consequence, a wide range of (hetero)aryl iodides and bromides were efficiently reduced to their corresponding (hetero)arenes. Thus, for the first time, aldehydes are directly used as hydrogen source instead of other well-established alcohol−hydrogen sources. Table 1. Reaction Conditionsa

H

ydrodehalogenation is an important organic transformation in synthesis.1 Organic halides such as chlorinated dibenzo-p-dioxins (dioxins) and polyhalogenated biphenyls (PCBs and PBBs) are hazardous to the environment are also health risks. 2 The development of new dehalogenation approaches remains in demand.1 Transition metals have been widely used as catalysts for the cleavage of C−X bonds of aryl halides.3 In organic synthesis, radical processes have been widely applied as an efficient dehalogenation method using stoichiometric reagents such as Bu3SnH and SmI2,4,5 despite the potential health risks. Alcohols have also been used in the dehalogenation of aryl halide, despite the fact that large excess amounts of alcohols and strong bases are necessary.6 Nevertheless, among the numerous dehalogenation approaches, various hydrogen sources have been employed, but aldehydes have been barely reported as a reductant for such reactions. In this work, we report an efficient metal-free radical dehalogenation using aldehydes as a powerful hydrogen source. The reaction conditions were investigated. In the direct alkylation of amines and the direct Julia olefination, alcohols have been used as starting materials via a self-hydrogen transferring process.7 In the dehalogenation reaction herein, both BnOH and PhCHO were found to be efficient reductants. The yield largely depended on the amount of hydrogen sources (Table 1, entries 1−7). Without a hydrogen source, the reactions in either DMF or dioxane gave low yields (entries 3 and 4). The reaction in the presence of BnOH afforded 2% of dimer (entry 1), whereas the reaction in the absence of H source gives rise to the formation of 12% 5-(tert-butoxy)-1-methylindole (entry 3). The formation of dimers suggests the formation of aryl radicals, and the formation of ArOtBu suggests either a radical via © 2017 American Chemical Society

entry

[H]

M

x

solvent

2a (%)b

1 2 3 4 5 6 7 8 9

BnOH BnOH none none PhCHO PhCHO PhCHO PhCHO PhCHO

K K K K K K K Na K

0.5 0.25 0 0 0.5 0.75 1 1 1

DMF DMF DMF dioxane DMF DMF DMF DMF other

90c 61 15 11 60 (55c) 74 86 56 6−21d

a Conditions: 1a (0.5 mmol), tBuOM (1.0 mmol), [H], solvent (1 mL), 90 °C, argon. bBy 1H NMR. cFor 6 h. dDMA, dioxane, toluene, DMSO, and octane.

SET or benzyne intermediates, which has been discussed previously.8 No dimer was observed in other cases. The conditions in entries 1 and 7 were established as the standard conditions for further investigation of the dehalogenation with BnOH and aldehyde, respectively. Under the standard conditions using BnOH as reductant, the scope, including both heteroaryl iodides and aryl bromides, was investigated with a variety of aryl halides, and the corresponding dehalogenation products were obtained in 77−96% of yields Received: August 3, 2017 Published: September 19, 2017 5114

DOI: 10.1021/acs.orglett.7b02399 Org. Lett. 2017, 19, 5114−5117

Letter

Organic Letters Scheme 2. Reaction Scope with PhCHOa

(Scheme 1, 1a−f). The dehalogenation of 1d and 1f could be performed at 30 °C, giving corresponding products 2d and 2f in Scheme 1. Reaction Scope with BnOHa

a

Conditions: 1 (0.5 mmol), tBuOK (1.0 mmol), BnOH (0.25 mmol), DMF (0.5 M), 90 °C, argon, isolated yields. bAt 30 °C. cAt 130 °C. d Determined by 1H NMR.

a

Conditions: 1 (0.5 mmol), tBuOK (1.0 mmol), PhCHO (0.5 mmol), DMF (1 mL), 90 °C, argon, isolated yields. bAt 30 °C. c1.5 mmol of t BuOK. dAt 130 °C. eDetermined by 1H NMR. fDetermined by GC.

77 and 84% yield, respectively. Besides heteroaryl halides, the aryl halides also exhibited high reactivity with 75−99% isolated yields (1g−1q). Moreover, the electron-donating substituents and electron-withdrawing substituents on the aryl groups have shown limited effect on the reaction activity (1i vs 1l). In all cases, no dimers were isolated except 1a (2%), 1j (4%), and 1k (4%). In the cases of 1d and 1h, 5% N,N-dimethylcarboxyamide and 10% 4-dimethylaminostilbene were isolated without dimer, respectively. Next, the scope of this dehalogenation with PhCHO was investigated (Scheme 2). For either heteroaryl halides or aryl halides, the reduction with PhCHO gave results comparable with those with BnOH. For example, the dehalogenation of 4iodophenol was performed without the protection of the hydroxyl group, affording 2s in 70% yield. Despite the fact that comparable results were given in the dehalogenation of aryl halides with BnOH and PhCHO, what should be noted is that most reactions in the presence of PhCHO finished in half an hour (monitored by TLC), which are much faster than those with BnOH. The kinetic study latterly confirms this phenomenon (see Scheme 6). Such dehalogenation could direct the nitration orthospecifically into an aromatic ring (eq 1), whereas the traditional nitration method afforded a mixture of para/ortho in the ratio of 2:1 (eq 2). To explore the mechanism of this dehalogenation reaction, radical trapping experiments were carried out (Scheme 3). The radical clock experiment gave the cyclization product 6 in 23% yield with 5% of dehalogenation product 2x (eq 3). With typical radical scavengers, either TEMPO or N-tert-butylphenyl nitrone could inhibit the dehalogenation reaction (eq 4). In a previous report, Studer et al. proposed a radical model for such a

Scheme 3. Radical Trapping Experiments

reaction.6b In our work, both the radical clock experiment and the radical trapping experiment suggest a possible radical pathway for this dehalogenation reaction. No dimer was observed except 1k, where 6% of dimer was isolated. A special case is 1u, where 20% of 3-tBuO-ether, a cross-coupling product of tBuO and 1u,8 was afforded. Determining the hydrogen source by isotope labeling experiments is not efficient because there is a fast hydrogen exchange between the reagents and the solvent (Scheme 4). When the reaction was treated with deuterated benzaldehyde, despite the deuterium incorporation occurring only to 15%, the reaction in PhCDO was obviously slower than that in PhCHO. To further amplify the role of PhCHO versus DMF as the hydrogen source, 1:1 PhCHO and DMF was employed using 5115

DOI: 10.1021/acs.orglett.7b02399 Org. Lett. 2017, 19, 5114−5117

Letter

Organic Letters Scheme 4. Deuteration Experiments

Scheme 5. Mechanism

dioxane as solvent (Scheme 4, bottom). The reaction in 1 equiv of PhCHO with 1 equiv of DMF-d7 gave only less than 5% of Dincorporation, whereas the reaction in 1 equiv of PhCDO with 1 equiv of DMF-h7 gave 25% of D-incorporation. So far, even if PhCHO is not the sole hydrogen source, it is safe to say that PhCHO is the main hydrogen source. The solvent DMF might also act as H-donor considering the fact that 0.25 equiv of PhCH2OH could give 61% yield of product (see Table 1), whereas 0.5 equiv of PhCHO could give 60% yield of product, in which the maximum yield should be 50%. However, it is obvious that DMF was not the main H source as it could afford only 15% product in the absence of the extra reductant such as benzaldehyde or benzyl alcohol. Therefore, PhCHO or BnOH should act as the mandatory H source because the yield of dehalogenation is dependent on the amount of reductant (Table 1, entries 1−7). This could be further confirmed by the control experiments. The yield of dehalogenation product 2n with PhCHO and DMF as additives in the presence of dioxane is 97%, whereas the removal of PhCHO, DMF, or both of them leads to the significant decrease of yield, especially in case of the removal PhCHO (eq 5). The electron effect on aromatics also supports that benzaldehyde is the major H source (eq 6).

Isolation of amide and ester byproducts (eq 7) also supports this hypothesis.

To determine which mechanism should be more reasonable, a kinetic study was performed. Although Cannizzaro reaction could never be avoided under such strong basic conditions, it does not mean this reaction must pass through a Cannizzaro pathway. The kinetic study demonstrated in Scheme 6 shows

Based on the above experimental evidence as well as the previous report on the generation of aryl radical anions in the presence of BnOH or PhCHO and tBuOK in DMF by Taillefer et al.,9,10 possible radical pathways for this dehalogenation focusing different reductants were proposed (Scheme 5). In the dehalogenation using BnOH as the hydrogen source, a halide fragmentation of the aryl radical anion A forms after a SET reduction of Ar−X leads to an aryl radical B. Alcoholate C then acts as a H source, providing the targeted reduction product Ar− H together with the radical anion D,6a as it was reported that alcoholates are excellent H-donors for the reduction of aryl halides,6a,11 generating aldehydes or ketones as the byproducts. D further reacts with Ar−X to regenerate A with the formation of PhCHO. In another case, when PhCHO was used as a hydrogen source, the in situ generated SET reductant F or G is generated by the reaction of benzoyl radical E and Me2N− from DMF. The radical anion F or H then reacts with Ar−X via a SET process to afford the radical anion A, followed by the formation of B. Benzoyl radical F is regenerated during the hydrogen transferring reduction of B. Such benzoyl radical was previously proposed by Ryu et al. in a transition-metal-free aminocarbonylation of aryl iodides.12a Similar mechanistic suggestions for acyl radical trapping with NMe2 was also reported by Studer et al.12b−d

Scheme 6. Kinetic Study

that the initial rate of PhCHO is 35.59 mM/min, which is much faster than that of PhCH2OH (9.26 mM/min). There is no sigmoidal behavior of the conversion curve or no point of inflection for the reaction in the presence of PhCHO, providing an indication that PhCHO is being involved in the initiation step. The control experiments further confirms this suggestion. In the absence of aryl halide substrates, treatment of PhCHO with t BuOK in DMF gives 22% of PhC(O)NMe2 together with 13% of PhCH2OH, whereas in the presence of substrate 1a, there is no PhCH2OH observed (eqs 7 and 8). Therefore, the kinetic study obviously proves the direct reaction of PhCHO in the 5116

DOI: 10.1021/acs.orglett.7b02399 Org. Lett. 2017, 19, 5114−5117

Organic Letters

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dehalogenation other than an indirect pathway via Cannizzaro reaction. In the kinetic isotope experiments, a KIE of 2.9 for PhCHO and 5.7 for PhCH2OH was observed (eqs 9 and 10). The

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b02399. Experimental details and spectroscopic data for all products (PDF)

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REFERENCES

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reaction in the presence of PhCDO in DMF at 50 °C for 5 min gives 18% of 2n-D, whereas the reaction with PhCD2OH affords only 4.2% of 2n-D. All these KIE experiments indicate that the C−H bond cleavage of PhCHO should be the rate-limiting step. In conclusion, a dehalogenation of aryl halides using benzyl alcohols or aldehydes as hydrogen sources under basic conditions has been developed. A radical pathway via a benzoyl radical has been established based on the experimental evidence including kinetic study, KIE, trapping reactions, and control reactions. The kinetic study clearly distinguishes two possible reaction pathways and thus rules out the Cannizzaro pathway for the dehalogenation in the presence of PhCHO, where a much larger initial rate is established than that of PhCH2OH (Scheme 6). The solvent DMF has also participated the dehalogenation as a radical initiator together with tBuOK.10 Due to the fast hydrogen exchange between hydrogen sources (PhCHO and PhCH2OH) and DMF, the isotope labeling experiments cannot be established as a rational evidence to support the source of hydrogen, whereas other experiments such as the kinetic study and the KIE experiments exhibit a more clear clue. For the first time, aldehydes were directly used as hydrogen source other than the well-established alcohol−hydrogen sources.

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Letter

AUTHOR INFORMATION

Corresponding Authors

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

Jian-Ping Qu: 0000-0002-5002-5594 Yan-Biao Kang: 0000-0002-7537-4627 Author Contributions §

H.-X.Z. and X.-H.S. contributed equally.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank the National Natural Science Foundation of China (21672196, 21404096, 21602001, U1463202) and Anhui Provincial Natural Science Foundation (1608085MB24) for financial support. 5117

DOI: 10.1021/acs.orglett.7b02399 Org. Lett. 2017, 19, 5114−5117