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. Author manuscript; available in PMC: 2016 Aug 21.
Published in final edited form as: Org Lett. 2015 Aug 4;17(16):3978–3981. doi: 10.1021/acs.orglett.5b01836

Rh(II)-catalyzed Reactions of Diazoesters with Organozinc Reagents

Robert Panish 1,‡, Ramajeyam Selvaraj 1,‡, Joseph M Fox 1,*
PMCID: PMC4552333  NIHMSID: NIHMS717588  PMID: 26241081

Abstract

graphic file with name nihms717588f8.jpg

Rh(II)-catalyzed reactions of diazoesters with organozinc reagents are described. Diorganozinc reagents participate in reactions with diazo compounds by two distinct, catalyst-dependent mechanisms. With bulky diisopropylethylacetate ligands, the reaction mechanism is proposed to involve initial formation of a Rh-carbene and subsequent carbozincation to give a zinc enolate. With Rh2(OAc)4, it is proposed that initial formation of an azine precedes 1,2-addition by an organozinc reagent. This straightforward route to the hydrazone products provides a useful method for preparing chiral quaternary α-aminoesters or pyrazoles via the Paul-Knorr condensation with 1,3-diketones. Crossover and deuterium labeling experiments provide evidence for the mechanisms proposed.

Rhodium (II) catalyzed reactions of diazo compounds play an important role across a variety of selective synthetic transformations involving Rh-carbene intermediates,1 which subsequently participate in a number of bond-activating reactions. Selected examples include X-H insertion reactions (where X = C, N, O, Si or S),2–9 ylide forming reactions,10,11 and cyclopropanation or cyclopropene reactions of alkenes and alkynes, respectively.11–14 While the scope of catalytic reactions of diazo compounds is extensive, there are relatively few methods for combining diazo compounds with organometallic reagents. The reactivity of carbon-boron compounds with diazocompounds has been studied.15 Wang has described the Pd(0)-catalyzed as well as metal-free methods for the carboboration of diazo compounds.16–21 Schaus has described three-component Mannich-type reaction involving arylboron reagents, diazo compounds, and alkylidene carbamates.22,23 Recently, Rh(I) catalyzed arylation of α-diazoesters with arylboronic acids has been described by Anbarasan,24 and Rh(I) catalyzed arylation of α-diazoesters with arylsiloxanes and arylstannanes have been described by Wang.25 However, we were unaware of reports where transition row organometallic compounds have been used as substrates in Rh-catalyzed reactions of diazocompounds.

Organozinc reagents have been employed in a variety of transition-metal catalyzed coupling reactions, and have been shown to display a wide range of functional group tolerance.26–31 We considered that organozinc reagents may participate in catalytic reactions with diazo compounds (1) by one of two mechanisms (Scheme 1). The diazo compound could initially form carbene A by a Rh-catalyzed process, and carbozincation of this carbene would lead to the enolate C.32 The organozinc C may combine with electrophiles, including a second equivalent of diazo compound 1 to give rise to hydrazone 2. Alternatively, Rh-carboxylates could catalyze the formation of the azine B,33 which is able to participate subsequently in a 1,2-addition reaction with an organozinc reagent. This straightforward route to the hydrazone products 2 was expected to provide a useful method for preparing chiral quaternary α-aminoesters or pyrazoles via the Paul-Knorr condensation with 1,3-diketones.

Scheme 1.

Scheme 1

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Hydrazones via Rh-mediated organozincation

To investigate carbozincation of diazoesters, the coupling of Et2Zn and methyl α-phenyl-α-diazoacetate 1a was chosen for initial study. A number of Rh(II) catalysts were explored in an effort to optimize the yield of 2a. As shown in Scheme 2, simple Rh2(OAc)4 gave 2a in the highest yield. Thus, diazo 1a with catalytic Rh2(OAc)4 (5 mol %) and Et2Zn (2 equiv) gave 2a in 92% yield with only traces of methyl α-phenylbutyrate 3a.

Scheme 2.

Scheme 2

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Optimization of Rh(II)-catalyst

With suitable conditions for hydrazone product formation identified, the substrate scope for the reaction was explored. As shown in Scheme 3, the reaction was also found to proceed efficiently with Me2Zn. Thus, Rh2(OAc)4 (5 mol %) catalyzes the reaction of Me2Zn with a variety of α-aryl-α-diazoacetate derivatives in 65–100% yield. As shown in Scheme 3, our exploration revealed that ortho-substituents are tolerated under the reaction conditions. Additionally, the reaction conditions are compatible with various functional groups including halide, cyano, ester, methoxy, and dioxolane groups. Diethylzinc as well as in situ generated dihexylzinc and dibenzylzinc also add smoothly to α-aryl-α-diazoesters in 83 – 92% yields.34

Scheme 3.

Scheme 3

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Scope of hydrazone formation

Several synthetic applications of the hydrazone products were investigated. The α-quaternary aminoesters 4a and 4k could be formed upon hydrogenation in good yields. Additionally, Paul-Knorr conditions provide access to pyrazole products. Thus, treatment of hydrazone 2a with pentane-2,4-dione under acidic conditions afforded pyrazole 5a in 81% yield.

In contrast to the Rh2(OAc)4 catalyzed reactions which lead to hydrazone products, Rh(II)-carboxylates with sterically demanding ligands displayed a complete reversal of selectivity. In this regard, the most effective catalyst was Rh2(DIEA)4, a Rh-complex with bulky carboxylate ligands first described by our laboratory.35 The Rh2(DIEA)4 (1 mol %) catalyzed reaction of 1a with Et2Zn provided the carbozincation product 3a in 89% yield (Scheme 2). Likewise, Et2Zn and tert-butyl α-diazohydrocinnamate 6 could be combined under Rh-catalyzed conditions to give the protonated product 7 (Scheme 5). This transformation was achieved with Rh2(OPiv)4 (1 mol %) as a catalyst in 78% yield. Rh2(DIEA)4 gave only 50% yield for this substrate, giving β-hydride migration and azine formation as significant byproducts. Unfortunately, our attempts to create fully substituted carbon centers by capturing these putative zinc enolates with a variety of electrophiles36 were unsuccessful. Cook and coworkers have investigated conjugate addition/enolate capture sequences of diorganozinc reagents with cyclic ketones, and were only able to capture the zinc enolate intermediates efficiently using reactive allyl halide electrophiles after extensively screening reaction conditions.37 As the zinc enolates generated in this manner are fully substituted and would lead to quaternary centers upon functionalization, it is not surprising that they are less reactive.

Scheme 5.

Scheme 5

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Organozinc addition to a Rh-carbene bearing β-hydrogens

Several mechanistic studies were performed to support the hypothesis that Rh2(OAc)4 catalyzed reactions proceed through an azine intermediate (B), whereas the Rh2(DIEA)4 and Rh2(OPiv)4 catalyzed reactions proceed via a zinc enolate intermediate (see Scheme 1). As additional evidence for the formation of 8 from 1a, two mass spectrometry experiments were performed by quenching the intermediate zinc enolate with D2O. In the first experiment, the reaction was quenched with D2O to form the deuterated product 3ad (Scheme 6). GC/MS analysis of the deuterium quenched product showed a parent peak (m/z 179) corresponding to the deuterated product 3ad (see Supporting Information). A second MS experiment was performed to confirm that 3ad was formed by quenching the zinc enolate 8, and not by deuterium exchange. In this experiment, the product of the reaction was initially quenched with H2O (10 equiv) and then with D2O (280 equiv). GC/MS analysis showed a major parent peak of m/z 178 (see Supporting Information), for the product 3a. These experiments are consistent with the formation of 3a via protonation of zinc enolate 8.

Scheme 6.

Scheme 6

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Evidence for a Zn-enolate intermediate in Rh2(DIEA)4 catalyzed reaction of diazoesters with Et2Zn

We also considered that a zinc enolate may be an intermediate in the mechanism for hydrazone formation. As depicted in Scheme 1, a rhodium carboxylate would catalyze the tranformation of diazoester 1 to zinc enolate C, which in a catalyst dependent manner may combine with another equivalent of 1 to form the hydrazone product 2. To test this hypothesis, a ‘crossover’ experiment was performed in which Et2Zn was combined with diazoester 1a in the presence of 1 mol % Rh2(DIEA)4— conditions shown above to catalyze the formation of zinc enolate 8. To this enolate was added Rh2(OAc)4 (which catalyzes hydrazone formation) and a different diazo compound 1i (Scheme 7).

Scheme 7.

Scheme 7

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Evidence for an azine intermediate in Rh2(OAc)4 catalyzed reaction of diazoesters with Et2Zn

If a zinc enolate were an intermediate, then the formation of unsymmetrical hydrazone 2o would be expected. In the event, 2o was not formed. Instead proton quenched product 3a was formed, and the hydrazone 2p derived from two equivalents of 1i was obtained in 70% yield (based on 1i) as depicted in Scheme 7. This experiment suggests that enolate 8 is unlikely to be an intermediate in hydrazone formation.

An alternate hypothesis for hydrazone formation is that Rh2(OAc)4 catalyzes the conversion of the diazoester to form an azine intermediate initially, which upon subsequent reaction with Et2Zn provides the hydrazone product. To provide support for this hypothesis, diazoester 1a was allowed to react with catalytic amounts of Rh2(OAc)4 (5 mol %). The azine 9 was isolated in 78% yield. In a separate reaction with Et2Zn (4.0 equiv) in toluene, hydrazone 2a was formed and isolated in 72% yield (Scheme 7). These experiments support the hypothesis that azine formation precedes the addition of the organozinc reagent.

In conclusion, the first Rh(II)-catalyzed reactions of diazoesters with organozinc reagents are described. Diorganozinc reagents participate in reactions with diazo compounds by two distinct, catalyst-dependent mechanisms. With the bulky Rh2(DIEA)4, the reaction mechanism is proposed to involve initial formation of a Rh-carbene and subsequent carbozincation to give a zinc enolate. With Rh2(OAc)4, initial formation of an azine precedes a 1,2-addition reaction with an organozinc reagent. This straightforward route to the hydrazone products provides a useful method for preparing chiral quaternary α-aminoesters or pyrazoles via the Paul-Knorr condensation with 1,3-diketones. Crossover and deuterium labeling experiments provide evidence for the mechanisms proposed.

Supplementary Material

SI A
SI B

Scheme 4.

Scheme 4

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Elaboration of hydrazone products

ACKNOWLEDGMENT

For financial support we thank NSF CHE 1300329. R. A. P. thanks NIH for support through a CBI training grant: 5T32GM008550. For instrumentation support we thank NIH S10RR026962, NIH S10OD016267, NIH P30GM110758, NIH P20GM104316, and NSF CHE-1229234.

Footnotes

ASSOCIATED CONTENT

Supporting Information

Full experimental details, characterization, 1H and 13C NMR spectra are provided. This material is available free of charge via the Internet at http://pubs.acs.org.

The authors declare no competing financial interest.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

SI A
NIHMS717588-supplement-SI_A.pdf (809.9KB, pdf)
SI B
NIHMS717588-supplement-SI_B.pdf (4.9MB, pdf)

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