Donor-Acceptor-Acceptor 1,3-Bisdiazo Compounds: An Exploration of Synthesis and Stepwise Reactivity

Article abstract of DOI:10.1021/acs.orglett.0c00103

Metal carbenes, derived from the decomposition of diazo compounds, are valued for their capacity to perform a variety of transformations. A unique class of acyclic, bis-diazo compounds, the donor-acceptor-acceptor 1,3-bisdiazo compounds, are described her

Full text of DOI:10.1021/acs.orglett.0c00103

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Letter
Donor−Acceptor−Acceptor 1,3-Bisdiazo Compounds: An
Exploration of Synthesis and Stepwise Reactivity
Dylan J. Abrams, Huw M. L. Davies, and Erik J. Sorensen*
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ABSTRACT: Metal carbenes, derived from the decomposition of diazo compounds, are valued for their capacity to perform a
variety of transformations. A unique class of acyclic, bis-diazo compounds, the donor−acceptor−acceptor 1,3-bisdiazo compounds,
are described herein. These compounds are available from acyclic β-keto esters and especially reactive at the donor−acceptor diazo
unit. These bisdiazo compounds react smoothly with rhodium acetate and alcohols to give monodiazo, cyclic orthoesters,
presumably through the capture of a transient oxonium ylide.
−H functionalization is a powerfully enabling technology
potentially more discerning, electrophilic bond-forming step,
both due to influence of the donor group.10,11,13
In our efforts to conceive bold strategies for synthesis that
are reliant on C−H functionalization methods, we were drawn
to the structure of silvestrol (1, Figure 2). Silvestrol is an
C
which has experienced rapid innovation and growth in
recent years.1−4 These advances allow strong, even electroni-
cally unactivated, carbon−hydrogen bonds to be viewed as
direct progenitors to diverse functionalities and new carbon−
carbon bonds, thus enabling the use of simplified starting
materials and more direct transformations requiring minimal
functional group manipulations.5−8 Like many of the strategic
C−H functionalization manifolds, the C−H insertion of metal
carbenes derived from organic diazo compounds has had great
adoption in synthesis.9−12 Typical carbene precursors can be
classified by the electronic environment around the diazo-
bearing carbon; the number of electron-withdrawing groups,
such as a carbonyl, or electron-donating groups, such as an
arene, divide the compound class into acceptor-only, donor−
acceptor, and acceptor−acceptor diazo compounds, which
produce the analogous carbene on decomposition (Figure 1).
Figure 2. Our envisioned retrosynthesis of the natural product
silvestrol.
anticancer flavagline natural product, which together with its
relatives, has been the target of numerous undertakings in
synthesis.14,15 We envisioned that the 8b−3a and 2−3
carbon−carbon bonds (highlighted in red) might be forged
through a cascade of dirhodium-catalyzed carbene C−H
insertions. This rapid construction of the densely function-
Figure 1. Three classes of carbene precursors.
Received: January 8, 2020
Although all varieties have been demonstrated to possess utility
for synthesis and selectivity, donor−acceptor carbenenes have
enjoyed a broader range of reactivity and higher selectivity in
intermolecular reactions. This phenomenon is attributable to a
combination of a more facile nucleophilic “decomposition”
step to form the carbene and a slower, and therefore
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alized C-ring would logically be preceded by monocyclic
intermediate 2, bearing an unusual 1,3-bisdiazo functionality
about a central ketone. Central to the success of this strategy
would be the need for a selective and stepwise pair of diazo
decompositions. Formation of the C8b−C3a bond at the B−C
ring juncture, derived from the donor−acceptor diazo moiety,
would likely need to occur first, so as to capitalize on the high
propensity of dirhodium carbenes to form 5-membered rings.11
Unexpected challenges beset our effort to synthesize a model
system structurally analogous to 2 and thus undermined our
effort to probe the feasibility of the ring annulation concept
outlined in Figure 2. However, we remained intrigued by the
reactivity that a molecule bearing two electronically differ-
entiated bisdiazo functions would display and especially the
possibility that we might achieve predictable and controllable
reactions at each diazo locus. Acyclic bisdiazo compounds of
the donor−acceptor−acceptor type were undescribed at the
outset of this effort; our inquiry into their synthesis and
reactivity is the main subject of this report.
proceeding through either Wolff rearrangements or cyclo-
propenone formation (Figure 3b).16,18,19,24,26 Selective metal-
catalyzed bond forming reactions of 1,3-bisdiazo compounds
are rare in the literature.25,28 With respect to order of reaction,
it was known that tethered bisdiazo compounds react in a
predictable manner, with more rapid decomposition of the
donor−acceptor diazo, for the reasons discussed above.29−31
However, what was known about the order of reactivity in
these 1,3-bidiazo settings was largely limited to a wavelength
dependent product distribution reported by Murata and
Tomioka.26,27
Our first goal was to develop conditions for the synthesis of
these donor−acceptor−acceptor bisdiazo compounds. We
began with the reaction of methyl 4-(4-bromophenyl)-
acetoacetate (8a, Figure 4a), seeking to install each diazo
As early as 1959, Kirmse had reported the first dialkyl
bisdiazo ketone (Figure 3a, 3).16−19 These studies were
Figure 3. Classes (a) and typical reactivity (b) of 1,3-bisdiazo
compounds.
Figure 4. (a) The optimization of the synthesis of 10a; (b) the
optimal, scalable synthesis of 10a and the crystal structure of 10a. p-
ABSA = para-acetamidobenzenesulfonyl azide. DBU = 1,8-
diazabicyclo[5.4.0]undec-7-ene.
subsequently followed by the first syntheses of the analogues
bearing two electron-withdrawing groups on either side (4,
termed herein acceptor−acceptor−acceptor)20−22 and two
electron-donating groups (5, termed herein donor−acceptor−
donor).19,23,24 However, it was not until several decades later
that Murata and Tomioka reported the first, and until now
only, donor−acceptor−acceptor 1,3-bisdiazo compound
6.25−27 Importantly, the cyclic, aromatic nature of the synthetic
precursor of 6 meant it was unclear to us whether either the
synthesis or behavior of the acyclic analogues we sought (e.g.,
7) would bear any resemblance to those studies. Hence, we set
out to determine if it is possible to synthesize and handle
acyclic donor−acceptor−acceptor systems of type 7, establish
which is the more reactive diazo moiety, and determine if this
type of unique compound is capable of two sequential carbene
transformations.
unit in a stepwise manner. To our surprise, conditions typically
employed for the installation of an acceptor−acceptor diazo
provided an inseparable mixture of the mono- and bisdiazo (9a
and 10a) in modest combined yield (Figure 4a, entry 1).
Increasing the quantity of transfer agent and base drove the
reaction to full conversion, but without significant improve-
ment in yield; moreover, changing the base to DBU, more
typically used for the installation of a donor−acceptor diazo,
provided similar results. However, we found that limiting the
quantity of transfer agent to 1 equiv., as well as decreasing the
reaction time, permitted a more efficient synthesis of 9a. This
compound was subsequently converted to bisdiazo 10a in
good yield (Figure 4b). Crystallization of 10a from ethyl
Known reactivity of these early systems is largely limited to
their decomposition by metal salts, heat, or light, often
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acetate (see Supporting Information) yielded crystals suitable
for X-ray crystallographic analysis (Figure 4b). A notable
feature of the solid-state structure of 10a is the twisted
arrangement, as drawn in Figure 4b, with the two carbon−
nitrogen bonds pointing away from each other, rather than
parallel, and the ester carbonyl directed toward the donor−
acceptor diazo.
We then explored the scope of 4-arylacetoacetate derivatives
8b−i, which could be transformed into the donor−acceptor−
acceptor bisdiazo 10b−i through this two-step procedure
(Figure 5). We found that electron-neural and electron-poor
Figure 6. Exploration of the reactivity of donor−acceptor−acceptor
bisdiazo 10a. All yields were determined from NMR integrations
compared to tert-butyl acetate as an internal standard and averaged
over three runs (see Supporting Information).
reaction of the acceptor−acceptor diazo. Therefore, our design
was to employ heating after initial dropwise addition, to
encourage full conversion of both diazo moieties.
The slow addition of a solution of 10a and cinnamyl alcohol
to Rh2OAc4 in chloroform followed by heating to 55 °C for 4 h
provided a crystalline material in 40% yield, which from the IR
analysis indicated that both diazo groups had reacted, and from
the proton NMR indicated that both the bisdiazo skeleton and
the cinnamyl alcohol had been incorporated into the product.
The expected arrangement of aliphatic protons from the
cinnamyl alcohol (methylene-methine-methine) was present,
but the coupling constants were inconsistent with a cyclo-
propane, and the carbon NMR indicated the presence of only a
single carbonyl. Further, the mass spectral data indicated that
two of the original four nitrogens were retained in the
structure, which could be further confirmed by 15N NMR.
Eventually, X-ray crystallographic analysis revealed that the
unexpected product was tricyclic pyrazoline 13 (Figure 6, eq
2). To better understand the origins of 13, the same conditions
were employed, dropwise addition at ambient temperature, but
without subsequent heating (Figure 6, eq 3). Under these
conditions, monodiazo orthoester 12a was the major product
in 57% yield. Furthermore, heating of a purified sample of 12a
in chloroform induced diazo-alkene [3 + 2] dipolar cyclo-
addition, yielding 13 essentially quantitatively (Figure 6, eq
4).32−35 These data suggest that the initial reaction to form
orthoester 12a is rhodium-dependent, but that cycloaddition
to form 13 is a purely thermally driven process.
Figure 5. Scope of two step diazo transfer. Yields of 9b−i from 8b−i
following step 1, yields of 10b−g are from 9b−g following step 2. p-
ABSA = para-acetamidobenzenesulfonyl azide. DBU = 1,8-
diazabicyclo[5.4.0]undec-7-ene. N.D.= not detected. * = 1.2 equiv
p-ABSA, 1.2 equiv NEt3.
substituents in the 3- and 4-position of the donor arene were
tolerated in this process. However, ortho substitution, as in the
case of 10d, and electron-rich substituents like tert-butyl,
methoxy, and dimethoxy (10f, 10h, 10i) provided low or no
yield of bisdiazo.
At this juncture, we turned to a study of the reactivity of
these molecules. Could the reactivity of a single diazo be
harnessed in such a system to perform one reaction specifically,
and then subsequently a second reaction? Our initial instinct
was to explore the reactivity of these donor−acceptor−
acceptor bisdiazo compounds with cinnamyl alcohol (Figure
6, eq 1). We assumed that the first carbene to form would
undergo selective O−H insertion on the alcohol, followed by
an intramolecular cyclopropanation of the second carbene
onto the pendant olefin. 10a was chosen as a representative
bisdiazo compound with which to begin to understand
reactivity, due to a high yielding synthesis and high long-
term stability at low temperatures, allowing for the
accumulation and storage of large quantities. If indeed the
donor−acceptor nucleus selectively underwent the first
decomposition, this would provide oxabicyclo[4.1.0]heptane
11 as the product from 10a. In the tethered bisdiazo examples
reported by Moody,29 Muthusamy,30 and Padwa,31 further
heating, often refluxing in benzene, is employed to affect full
We attribute the product of the rhodium-catalyzed reaction
of 10a to rapid formation of an ylide following carbene
formation (Figure 7). Ylide formation is well-known in
dirhodium carbene chemistry, and the enforced propinquity
of the ester carbonyl likely encourages this mode of
reactivity.36−39 Following ylide formation, the alcohol traps
the oxocarbenium as the orthoester, and the dirhodium enolate
is protonated to restore the catalyst.40,41 Whether the observed
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diazo derivatives flanked by one donor and one acceptor group
are more prone to rhodium-catalyzed nitrogen extrusion than
analogous derivatives flanked by two acceptor groups. The
bisdiazo compounds described undergo an intramolecular
reaction in which the carbene is trapped by the pendant ester
carbonyl to generate an ylide, with one of the diazo
functionalities retained. This ylide can be trapped intermolec-
ularly by various alcohols to form orthoesters adjacent to a
diazo function, and in the case of cinnamyl alcohol, further
reactivity in the form of diazo-alkene [3 + 2] dipolar
cycloaddition is observed. These studies further illustrate the
novel transformations that can be discovered as one challenges
dirhodium carbene chemistry with more elaborate substrates
inspired by potential synthetic applications.
Figure 7. Proposed mechanism for the formation of monodiazo
orthoesters 12a−d from 10a.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c00103.
■
single diastereoisomer is the result of a rapid epimerization and
high thermodynamic preference, or a kinetically controlled
intramolecular protonation step, is unclear. Conversely,
protonation of the dirhodium enolate could occur first, and
the resulting oxocarbenium/alkoxide ion pair could collapse in
a facially selective manner to afford the single diastereoisomer.
With these conditions in hand, we explored a sample of other
alcohols. The isolated yield of 12a well matched the NMR
yields observed above, and ethanol, methanol, and benzyl
alcohol all underwent the same transformation, providing the
isolable monodiazo orthoesters 12b−d in comparable isolated
yields (Figure 8).
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Experimental procedures, spectral data, and crystallo-
graphic data (PDF)
Accession Codes
CCDC 1975497−1975498 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
Erik J. Sorensen − Department of Chemistry, Princeton
University, Princeton, New Jersey 08544, United States;
orcid.org/0000-0002-9967-6347; Email: ejs@
princeton.edu
Authors
Dylan J. Abrams − Department of Chemistry, Princeton
University, Princeton, New Jersey 08544, United States
Huw M. L. Davies − Department of Chemistry, Emory
University, Atlanta, Georgia 30322, United States;
orcid.org/0000-0001-6254-9398
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c00103
Figure 8. Scope of O−H insertion reaction. All yields are isolated. a<1
b
mol % Rh2OAc4. 1.3 mol % Rh2OAc4.
Notes
Interestingly, in none of these cases were products detected
attributable to reaction of the remaining acceptor-only diazo
moiety, or from reaction of the acceptor−acceptor diazo unit
in 10a. Additionally, this is likely not due to catalyst
deactivation, as subjecting a pure sample of 12b to Rh2OAc4
in dichloromethane over several hours affords 12b unchanged
following chromatography. Heating a sample of 12b either to
75 °C in benzene with Rh2OAc4 or at room temperature in
chloroform with Rh2(esp)2 results in slow conversion (over
several hours) to the same unknown major product.
Unfortunately, efforts to isolate and characterize this product
were unsuccessful.
Warning: Although the authors did not experience any adverse
events on handling the mono- and bisdiazo compounds
described herein, they and their relatives are high energy
compounds and potentially explosive. They should be handled
with care and behind a blast shield whenever possible.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support was provided by the NSF under the CCI
Center for Selective C−H Functionalization (CHE-1700982).
We thank Dr. Istvan Pelzcer (Princeton) for his assistance with
analyzing complex NMR spectra and with performing 15N
NMR analysis. We thank Dr. Philip Jeffrey (Princeton) for
assistance with X-ray crystallographic analysis of 10a and 13.
Herein, we demonstrated the synthesis of acyclic 1,3-
bisdiazo compounds bearing one donor and one acceptor on
either side of the central ketone. These studies confirm that
D
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