Programmed Sequential Additions to Halogenated Mucononitriles

Article abstract of DOI:10.1021/acs.orglett.0c03007

Dihalomucononitriles were synthesized and their reactivity evaluated to assess their ability to function as linchpin reagents. Bis(2-chloroacrylonitrile) and bis(2-bromoacrylonitrile) were synthesized from 2,1,3-benzothiadiazole and undergo conjugate addition/elimination reactions with both nitrogen (40-95% yield) and carbon nucleophiles (72-93% yield). Secondary amines undergo monosubstitutions, while carbon nucleophiles are added twice. The sequence of addition of the nucleophiles could be controlled to give mixed addition products. The multicomponent coupling products could then be converted to natural product like motifs using intramolecular cyclization reactions.

Full text of DOI:10.1021/acs.orglett.0c03007

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Programmed Sequential Additions to Halogenated Mucononitriles
Adam J. Zahara,† Elsa M. Hinds,† Andrew L. Nguyen, and Sidney M. Wilkerson-Hill*
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ABSTRACT: Dihalomucononitriles were synthesized and their
reactivity evaluated to assess their ability to function as linchpin
reagents. Bis(2-chloroacrylonitrile) and bis(2-bromoacrylonitrile)
were synthesized from 2,1,3-benzothiadiazole and undergo
conjugate addition/elimination reactions with both nitrogen
(40−95% yield) and carbon nucleophiles (72−93% yield).
Secondary amines undergo monosubstitutions, while carbon
nucleophiles are added twice. The sequence of addition of the nucleophiles could be controlled to give mixed addition products.
The multicomponent coupling products could then be converted to natural product like motifs using intramolecular cyclization
reactions.
he synthesis of dimeric natural products primarily relies
Ton coupling two similarly sized monomers and often
leverages the inherent symmetry of the compound.1,2 These
strategies are efficient but require ready access to the requisite
monomer. Moreover, additional postfunctionalization of the
monomer is often necessary to access heterodimeric (or
unsymmetrical homodimeric) substrates. Thus, linchpin
strategies are valuable because they use two different synthetic
streams and thus are more convergent.3−7 Furthermore, these
multicomponent8 strategies are attractive because they only
necessitate the synthesis of more synthetically tractable
truncated monomeric units. Lastly, these strategies are valuable
because of their modularity and divergent9 nature which lends
access to symmetric and nonsymmetric homodimers and
heterodimers. Thus, identifying suitable linchpin reagents is
desirable and is a contemporary challenge (Figure 1A).
Dienes such as hexa-2,4-dienedinitriles (mucononitriles), 1,
are underexplored motifs that could serve as linchpin reagents
Figure 1. Proposed strategy to use dihalomucononitriles as linchpin
because they contain two electron-withdrawing groups at the
diene termini. We were intrigued by these substrates because
of their bonding and physical organic properties but also
because we viewed these substrates as privileged Michael
acceptors. We surmised that the incorporation of leaving
groups such as halogens at the 1- and 4-position of the
mucononitrile would permit programmed sequential additions
to the reagent because elimination of the leaving group would
regenerate the electron-deficient olefins to be manipulated in a
subsequent step. In doing so, the diene would formally be
electrophilic at every carbon atom. Additionally, the inert
nature of the nitrile group is critical to obtain the desired
reactivity because the corresponding succinates and 1,6-
diketones are known to undergo cycloaddition10 and
condensation reactions,11 respectively. Notably, these com-
pounds could also serve as bisketene equivalents, which are of
contemporary interest.12,13 As a part of a research program
reagents.
directed toward the synthesis of complex dimeric natural
products, we envisioned that halogenated mucononitriles
would be valuable four carbon atom linchpin molecules that
would enable the union of synthetically tractable truncated
monomeric units, provided that programmed sequential
additions of nucleophiles to these reagents could be achieved.
Received: September 8, 2020
https://dx.doi.org/10.1021/acs.orglett.0c03007
© XXXX American Chemical Society
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To our knowledge, functionalized mucononitriles have not
been thoroughly investigated. Mucononitriles are accessed
through the oxidative degradation of o-phenylenediamines
using sodium periodate,14 bis(acetoxy)iodobenzene,15 O2 and
CuCl2,16 or NiO2.17 Mucononitriles containing acetoxy groups
such as bis(1-cyanovinylacetate) (2) can be obtained from the
corresponding succinyl chloride and were reported by Oku18
and co-workers in 1992; however, outside of the reported
photoisomerization and photocycloaddition reactivity, sub-
strates in this class of compounds are only known to undergo
tandem intramolecular cyclization/formal [5 + 2]-cyclo-
addition reactions to give complex [3.2.1]-
oxabicyclooctenones.19 The synthesis of halogenated mucono-
nitriles such as 3a and 3b have been reported, but the reactivity
of these compounds remains unexplored (Figure 1B).20
Central to our goal of developing a reagent-based linchpin
strategy, we needed to demonstrate that mucononitrile
substrates could be synthesized and these dienes could be
appropriately functionalized at both the terminal and internal
positions in a stepwise fashion to afford annulated products.
Furthermore, it was imperative that we were able to select for
mono- versus double additions of various nucleophiles to
afford both the symmetrical dimers and nonsymmetrical adducts
as well. Dimers of chloroacrylonitrile and bromoacrylonitrile
3a and 3b seemed to be attractive starting points, because the
most likely reactivity of these dienes would be conjugate
addition reactions of soft C- and N- nucleophiles, which would
be in accord with the reactivity of muconate ester derivatives.21
This strategy would be distinct from other coupling
approaches because it could permit access to diverse chemical
space surrounding nonsymmetrical homodimers and poten-
tially heterodimers in a convergent fashion. Given the lack of
knowledge surrounding halogenated mucononitriles, we under-
took a study to systematically synthesize and document the
reactivity of this class of substrates.
We first turned our attention to (2E,4E)-2,5-dichlorohexa-
2,4-dienedinitrile (bis(2-chloroacrylonitrile), 3a) and its
bromo congener (bis(2-bromoacrylonitrile), 3b), which are
dimeric versions of commercially available 2-chloroacrylonitrile
and 2-bromoacrylonitrile and arise from diamines 6a and 6b,
respectively. One of the challenges obtaining o-phenylenedi-
amine 6 needed in this study is accessing its 1,2,3,4-
substitution pattern. Direct halogenation of protected 1,2-
phenylenediamines, for instance, results in the undesired
1,2,4,5-dihaloisomers as the major products, which is in line
with the known ortho/para directing ability of the electron-
donating amine substituents.22 Furthermore, these highly
electron-rich arenes are susceptible to oxidation to afford
undesired o-quinone imines.23
the benzothiadiazole unit with NaBH4 in EtOH at 23 °C,
followed by an oxidative degradation of the resulting o-
phenylenediamine 6 with 2.0 equiv of Pb(OAc)4 at 60 °C for 2
h (eq 2). The configurations of the double bonds of 3a were
confirmed in solution using an 1H coupled 13C NMR
spectroscopy experiment and simulating the second order
AA′X coupling pattern of the nitrile resonance (δ (CDCl3) =
112.5 ppm, 3JC−H = 13 Hz) using SpinWorks online software.27
Additionally, the olefin geometry in 3a was determined to be
E,E- by X-ray crystallographic analysis.
With ample quantities of dienes 3a and 3b in hand, we then
began to investigate their reactivity toward nucleophilic
partners and quickly identified that secondary amines were
viable nucleophiles for these dienes, resulting in the stereo-
selective formation (>20:1 in all cases) of E,E-dienamine
products (Figure 2). Cyclic amines such as pyrrolidine,
piperidine, and azepane were tolerated and gave products 7−
9 in excellent yield (92%, 95%, and 92%, respectively, for X =
Cl and 88%, 93%, and 92% for X = Br). Heteroatom-
containing substrates also produced products 10−13 in
excellent yields. Notably, using 1-methylpiperazine produced
12 in 98% yield, demonstrating chemoselectivity for different
amine groups. Reactions with L-proline methyl ester hydro-
chloride produced substrates 15a and 15b (47% and 40%
yield, respectively) bearing introduced chirality when reacted
with 3a and 3b. Acyclic secondary amines were also reactive
producing products 16−19 in excellent yield (86−94% for X =
Cl and 85−89% for X = Br). Sterically demanding amines such
as diisoproylamine failed to react with 3a or 3b. Reactions with
diallylamine and dibenzylamine also did not produce product.
Presumably, the dienamines arise from a 1,6-conjugate
addition reaction into the electron-deficient mucononitrile
motif followed by ejection of the halide leaving group.28 Single
crystal X-ray crystallographic analysis of compound 19a
confirmed that the addition is stereoretentive and produces
the thermodynamically favored E,E isomer.29 Comparison of
3a and 3b showed that they performed similarly in most cases,
so studies with other soft nucleophiles were performed with 3b
due to its accessibility.
To overcome this challenge, we leveraged the ability of
2,1,3-benzothiadiazole to be selectively halogenated at the 4-
and 7-positions of this heterocycle to obtain the desired
1,2,3,4-substitution pattern. Thus, we began our studies by
evaluating the efficacy of various chlorinating reagents to react
with 4.24 Ultimately, we found that 1,3-dichloro-5,5-
dimethylhydantoin (DCDMH) in H2SO4 at 45 °C for 12 h
provided high conversion of heterocycle 4 to the desired
product 5a (eq 1).25
4,7-Dibromobenzothiadiazole (5b) is available through
known procedures and commercially.26 With ample quantities
of heterocycles 5a and 5b in hand, we then obtained dienes 3a
and 3b as bench-stable crystalline solids on a gram scale (up to
7.2 g of 3b) using a two-step procedure involving reduction of
Additionally, 2-substituted malonates were discovered to be
competent carbon-based nucleophiles in the conjugate
addition/elimination reactions with diene 3b. We were able
to react mucononitrile 3b with excess (3.0 equiv) of
monosubstituted malonates to afford products resulting from
double-conjugate addition/elimination (Figure 3). The re-
actions proceeded in THF at 23 °C and were tolerant of para-
substituted aryl groups to give products 20a−20e (84−93%
yield). Aliphatic groups such as diethyl 2-methylmalonate gave
21 in 72% yield. Heteroaromatic malonates containing a 2-
B
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Figure 3. Reaction scope with malonate component aStandard
conditions: 0.10 mmol of 3b with 3.0 M NaH, 3.0 equiv of malonate,
b
0.1 M THF. E = CO2Et.
Figure 2. Reaction scope with amine nucleophiles. Standard
conditions: 0.10 mmol 3a or 3b with 3.5 equiv amine, 0.3 M THF.
b
aReaction conducted with 1.0 mmol compound 3. Amine HCl salt
c
was used with 5.0 equiv of Cs2CO3. 50% probability level shown.
furyl and 3-indolyl group gave products 24 and 25 in 74% and
83% yield, respectively.
We then sought to demonstrate programmed sequential
additions of two different nucleophiles to our linchpin
reagents. Thus, treating 3b with 1.25 equiv of diethyl 2-(3-
methoxybenzyl)malonate and then excess morpholine afforded
diene 26 in 82% yield after the one-pot, two-step operation (eq
3). A malonate containing an N-Boc-indolyl group could be
used as well to give, after quenching with morpholine, adduct
27 in 71% yield (eq 4). Thus, diene 3b serves as a useful
linchpin reagent to bring together both C and N nucleophiles.
The addition reactions serve as a means to desymmetrize these
substrates. Notably, the functionalized dienamines are valuable
cyclization precursors en route to nonsymmetrical dimeric
natural product motifs.
The addition of C-nucleophiles directly to dienamines 7a or
7b was unsuccessful, presumably due to the decreased
electrophilicity of the dienamine compounds relative to 3a
and 3b. However, the programmed additions could also be
carried out in the reverse order (N- then C-addition), using a
different tactic. After addition of the amine to 3a or 3b, the δ-
halo dienamine products 7a and 7b are also amenable to a
variety of cross-coupling reactions, which permits a greater
scope of C-nucleophiles. For example, we found that the vinyl
chloride (or bromide) group served as a handle for Suzuki−
Miyaura and Sonogashira cross-coupling reactions (eqs
5−6).30 Having demonstrated C−C and C−N bond formation
at the terminus of the linchpin reagents to effectively
desymmetrize them, we then turned our attention to strategies
to functionalize the internal positions of the butadiene units.
C
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Authors
Cyclization reactions of compounds 26 and 27 leverage the
nucleophilicity of the embedded dienamines. Reacting anisole
26 with AlCl3 in 1,2-dichloroethane at 25 °C resulted in the
clean formation of tetrahydronaphthalene 30 (88% yield, 3:1
dr) (eq 7). Treating indole compound 27 with trifluoroacetic
Adam J. Zahara − Department of Chemistry, The University of
North Carolina at Chapel Hill, Chapel Hill, North Carolina
27599, United States
Elsa M. Hinds − Department of Chemistry, The University of
North Carolina at Chapel Hill, Chapel Hill, North Carolina
27599, United States
Andrew L. Nguyen − Department of Chemistry, The University
of North Carolina at Chapel Hill, Chapel Hill, North Carolina
27599, United States
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c03007
Author Contributions
†A.J.Z. and E.M.H. contributed equally.
Notes
The authors declare no competing financial interest.
This work appeared on ChemRxiv Sep 7, 2020.33
ACKNOWLEDGMENTS
acid (7.0 equiv) in 1,2-dichloroethane at room temperature for
14 h gave tetrahydrocarbazole 31 (64% yield, 1.6:1 dr) (eq 8).
In each instance, the vestige of the dienamine moiety remains
as an α-aminoacrylonitrile, which could serve as a handle for
further annulation reactions.
In conclusion, we have synthesized and documented the
reactivity of two dihalomucononitriles.30 These compounds
readily engage both carbon and nitrogen nucleophiles through
conjugate addition/elimination reactions or using cross-
coupling strategies. The interrupted addition products can be
further processed to afford highly functionalized annulated
products. The application of these linchpin reagents to the
total synthesis of both symmetrical and nonsymmetrical binary
hydroxycarbazole natural products such as bismahanine31 and
bisisomahanine32 is ongoing in our laboratory and will be
reported in due time.
■
We are grateful for UNC Chapel Hill for funding and the
Alexanian, Crimmins, Johnson, Meek, Nicewicz, and Aube lab
́
for chemicals, equipment, and helpful discussions used for this
study. We thank the University of North Carolina’s Depart-
ment of Chemistry NMR Core Laboratory for the use of their
NMR spectrometers. This material is based upon work
supported by the National Science Foundation under Grant
Nos. CHE-0922858 and CHE-1828183. We thank the
University of North Carolina’s Department of Chemistry
Mass Spectrometry Core Laboratory, for their assistance with
mass spectrometry analysis. This material is based upon work
supported by the National Science Foundation under Grant
No. CHE-1726291. We thank the University of North
Carolina’s Department of Chemistry X-ray Core Laboratory
for the use of their X-ray diffactometer.
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Corresponding Author
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