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

Article abstract of DOI:10.1021/acs.orglett.5b01836

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 diisopropylethyl acetate 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.

Full text of DOI:10.1021/acs.orglett.5b01836

Letter
pubs.acs.org/OrgLett
Rh(II)-Catalyzed Reactions of Diazoesters with Organozinc Reagents
Robert Panish,† Ramajeyam Selvaraj,† and Joseph M. Fox*
Brown Laboratories, Department of Chemistry and Biochemistry, University of Delaware, Newark, Delaware 19716, United States
S
* Supporting Information
ABSTRACT: 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 diisopropylethyl
acetate 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.
Scheme 1. Hydrazones via Rh-Mediated Organozincation
hodium(II) catalyzed reactions of diazo compounds play
Ran 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 cyclopropenation 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 organo-
metallic 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 reactions 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.
quaternary α-aminoesters or pyrazoles via the Paul−Knorr
condensation with 1,3-diketones.
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. Optimization of Rh(II)-Catalyst
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
Received: June 25, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01836
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Letter
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
Scheme 4. Elaboration of Hydrazone Products
Scheme 3. Scope of Hydrazone Formation
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-
diazo-hydrocinnamate 6 could be combined under Rh-catalyzed
conditions to give the protonated product 7 (Scheme 5). This
Scheme 5. Organozinc Addition to a Rh-Carbene Bearing β-
Hydrogens
transformation was achieved with Rh2(OPiv)4 (1 mol %) as a
catalyst in 78% yield. Rh2(DIEA)4 gave only a 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 co-workers 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.
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
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
Several synthetic applications of the hydrazone products
were investigated (Scheme 4). 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.
B
DOI: 10.1021/acs.orglett.5b01836
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Letter
hypothesis that azine formation precedes the addition of the
organozinc reagent.
Scheme 6. Evidence for a Zn-Enolate Intermediate in
Rh2(DIEA)4 Catalyzed Reaction of Diazoesters with Et2Zn
In conclusion, the first Rh(II)-catalyzed reactions of
diazoesters with organozinc reagents are described. Diorgano-
zinc 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 carbozinca-
tion 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.
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.
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 that were 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).
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b01836.
Full experimental details and characterization (PDF)
1H and 13C NMR spectra (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: jmfox@udel.edu.
Author Contributions
†R.A.P. and R.S. contributed equally.
Notes
Scheme 7. | Evidence for an Azine Intermediate in
Rh2(OAc)4 Catalyzed Reaction of Diazoesters with Et2Zn
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
For financial support we are thankful for NSF CHE 1300329.
R.A.P. thanks the NIH for support through a CBI training
grant: 5T32GM008550. For instrumentation support we are
thankful for NIH S10RR026962, NIH S10OD016267, NIH
P30GM110758, NIH P20GM104316, and NSF CHE-1229234.
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D
DOI: 10.1021/acs.orglett.5b01836
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