Empowering alcohols as carbonyl surrogates for Grignard-type reactions

The Grignard reaction is a fundamental tool for constructing C-C bonds. Although it is widely used in synthetic chemistry, it is normally applied in early stage functionalizations owing to poor functional group tolerance and less availability of carbonyls at late stages of molecular modifications. Herein, we report a Grignard-type reaction with alcohols as carbonyl surrogates by using a ruthenium(II) PNP-pincer complex as catalyst. This transformation proceeds via a carbonyl intermediate generated in situ from the dehydrogenation of alcohols, which is followed by a Grignard-type reaction with a hydrazone carbanion to form a C-C bond. The reaction conditions are mild and can tolerate a broad range of substrates. Moreover, no oxidant is involved during the entire transformation, with only H2 and N2 being generated as byproducts. This reaction opens up a new avenue for Grignard-type reactions by enabling the use of naturally abundant alcohols as starting materials without the need for pre-synthesizing carbonyls.

The manuscript by Li et al presents a novel catalytic Grignard-type C-C bond formation between a hydrazone, acting as a traceless carbanion synthon, and an in situ generated carbonyl from alcohols. The authors demonstrate a reasonable scope as well as suggesting a mechanism. As such, I find the work impressive and of more general interest. Generally, the manuscript is written in a reasonably scholar manner. However, previous publications by the authors themselves (eg references 27 and 29 in the manuscript) as well as from others (eg reference 37 in the manuscript and Eur. JOC 2007, 5629) already showcase the hydrazone actiong as a traceless carbanion synthon for the catalysed reaction with carbonyls or alcoholic carbonyl precursors. Furthermore, acceptorless alcohol dehydrogenation is a highly developed field. Hence, I cannot recommend publication in such a highly renowned journal as Nature Communications. Furthermore, I have several suggestions to the authors: 1) In my mind, the scope does not really challenge a traditional Grignard reaction, with the exception of the N-Boc protected substrate. I suggest to test eg amides, esters, carbonates, nitrils, etc.
2) The manuscript would benefit greatly from isolating and characterizing the (assumed) catalytically active complex.
3) The optimised conditions seem to be adopted from previously published projects. This work might benefit from a (minor) new optimisation protocol. For example, acceptorless alcohol dehydrogenation is typically greatly improved by intensely refluxing the media. Also, testing other metal precursors is relevant and might aid the mechanistic considerations. 4) The mechanism should be founded as well as argued based on the experimental results in the work. As of now, the proposed mechanism is claimed without any references to their own observations. 5) In my mind, some citations are missing: When mentioning PNP-ligands: One of more of Beller, ACIE 2011, 50, 9593;Gusev, Org. Met. 2011, 30, 3479;Schneider, Inorg. Chem. 2010, 49, 5482. When discussing the reactivity of the cyclobutyl substrate, perhaps add a reference substantiating your arguments. 6) There are several typos. For example, the abbreviations are inconsistent and the references need a revision.
Reviewer #2 (Remarks to the Author): Li and co-workers have reported a sustainable alternative to the Grignard reaction for the construction of secondary and tertiary alcohols. This work is based on their recent discovery that hydrazone can be employed as traceless carbanion equivalent and their couplings with ketones and aldehydes led to the formal Grignard reaction (Nat. Chem. 2017, 9, 374). Here, instead to use ketones or aldehydes, they start from alcohols using an in-situ dehydrogenation process. They are several advantages to use alcohols as starting materials: higher stability, natural feedstocks, and availability. Unlike to previous tandem oxidative processes, this reaction required only one catalyst. The PNP-Ru can achieve both alcohol dehydrogenation and the umpolung addition process. The scope of the reaction has been studied in detail and is very general, including the use of natural olefinic alcohols without isomerization or reductions. Overall, this manuscript deserves to be published after answer these minor concernes: 1. Table 2, in the general equation: Dcypf should be replaced by L 2. Why did the authors not employ a well-defined catalyst (type complex A) rather than in-situ preparation? Is there a reactivity difference?
In this article, Chao-jun Li et al reported a Ru-complex catalyzed dehydrogenative coupling reaction with alcohols as carbonyl surrogates and aldehyde hydrazones as carbanion equivalent. This strategy allows to access Grignard-type products with naturally abundant alcohols and aldehydes as starting materials. In my opinion, this new unique Grignard-type reaction with alcohols as carbonyl surrogates is highly interested to organic researchers. It may deserve publication in Nature Communication, but several points require attention: 1. I have some concerns regarding the scope of the process. From a synthetic point of view, this reaction shows some limitations regarding the scope. Only simple alcohols and benzalde hydehydrazones are compatible with the process. Secondary alcohols and aliphatic aldehyde hydrazones proved to be less active. Although the authors have made an effort to demonstrate the synthetic application of this transformation by applying two naturally occurring complex alcohols (Scheme4), more examples regarding more kind of aldehyde hydrazones and alcohols should be concluded. Table 2, only nine different conditions with three ligands were tested. It's necessary to perform a more detail study on condition-optimization. More ligands and catalytic systems should be tested (For examples, the ligands and catalytic systems reported in Organometallics 2016, 35, 2840='+(,-12;$.977<8$# '%&)# *# *+),-.537$ /<:$ 0$# '%%+# &(# &%'%&-3; 26" ;9 43; 2 79:3 general condition which may be helpful to broaden the reaction scope. 3. In this reaction, 3 equiv. amount of aldehyde hydrazones 1a and its analogues is required due to the instability of this compound. Stable aldehyde hydrazones, for example these derived from aldehydes and aryl hydrazines, maybe helpful to reduce the dosage of the hydrazone substrates. Also, a stable aldehyde hydrazones can tolerate a higher reaction temperature which apparently can accelerate the dehydrogenation process according literature reports, thus leading to a better reaction scope. Therefore, some stable aldehyde hydrazones should be tested. 4. In Table 2 and Scheme 3, the reaction time and the amount of K3PO4 should be noted. In the chemical scheme of Table 2, the term "dcypf" (upon the second arrow) should be deleted. Some of the yields in SI are inconsistent with the yields given in manuscript (3af, 3ag, 3ap). The authors should carefully re-check their manuscript to avoid such kind of mistakes.