Unprecedented Mechanism of an Organocatalytic Route to Conjugated Enynes with a Junction to Cyclic Nitronates

Article abstract of DOI:10.1002/ejoc.201801153

Conjugated enynes as well as cyclic nitronates are crucial building blocks for numerous natural products and pharmaceuticals. However, so far, no common and metal-free synthetic route to both conjugated enynes and cyclic nitronates has been reported. Herein, in situ NMR, labelling studies and theoretical calculations were combined to investigate the mechanism of the unusual triple bond formation towards conjugated enynes. Starting from nitroalkene dimers, first an isoxazolidine-2,5-diol derivative is formed as central intermediate. From this, enynes were generated by a combination of oxidation, dehydration, and retro 1,3-dipolar cycloaddition, whereas for nitronates a base induced intramolecular reorganization is proposed. While the product distribution could be controlled and high yields of nitronate were achieved, only medium to good yields for enynes were obtained due to polymerization losses. Nevertheless, we hope that these mechanistic investigations may provide a basis for further developments of organocatalytic or metal-free preparations of conjugated enynes and nitronates.

Full text of DOI:10.1002/ejoc.201801153

DOI: 10.1002/ejoc.201801153
Full Paper
Reaction Mechanism | Very Important Paper |
Unprecedented Mechanism of an Organocatalytic Route to
Conjugated Enynes with a Junction to Cyclic Nitronates
Verena Streitferdt,[a] Michael H. Haindl,[a] Johnny Hioe,[a] Fabio Morana,[a] Polyssena Renzi,[a]
Felicitas von Rekowski,[a] Alexander Zimmermann,[a] Martina Nardi,[a] Kirsten Zeitler,[a,b] and
Ruth M. Gschwind*[a]
Abstract: Conjugated enynes as well as cyclic nitronates are ation, dehydration, and retro 1,3-dipolar cycloaddition, whereas
crucial building blocks for numerous natural products and phar- for nitronates a base induced intramolecular reorganization is
maceuticals. However, so far, no common and metal-free syn- proposed. While the product distribution could be controlled
thetic route to both conjugated enynes and cyclic nitronates and high yields of nitronate were achieved, only medium to
has been reported. Herein, in situ NMR, labelling studies and good yields for enynes were obtained due to polymerization
theoretical calculations were combined to investigate the losses. Nevertheless, we hope that these mechanistic investiga-
mechanism of the unusual triple bond formation towards con- tions may provide a basis for further developments of organo-
jugated enynes. Starting from nitroalkene dimers, first an isox- catalytic or metal-free preparations of conjugated enynes and
azolidine-2,5-diol derivative is formed as central intermediate. nitronates.
From this, enynes were generated by a combination of oxid-
Introduction
also as ambident nucleophiles due to their O- and α-C-nucleo-
philicity.[19] Moreover, nitronates are 1,3-dipoles and thus can
inter alia participate in [3+2]-cycloadditions generating highly
functionalized heterocycles.[19] Similar to nitronates, also conju-
gated enynes can partake in cycloadditions.[20] Furthermore,
they can be subjected to other ring-closing[21,22] and coupling
reactions,[23,24] or they can serve as transition metal ligands.[25]
A few years ago, in our working group Markus Schmid dis-
covered the first organocatalytic route to conjugated enynes, in
which the C–C triple bond is constituted out of a C–C single
In the fields of natural products and drug design, nitronates
and conjugated enynes are valuable building blocks. While the
structural motif of a conjugated enyne occurs in many pharma-
ceuticals and natural compounds [e.g. Dynemicin A,[1] Terbina-
fine[2,3] (Lamisil®), callipeltosides[4] or Neocarzinostatin[5]],
nitronates, especially cyclic nitronates, find application in the
synthesis of biologically active compounds,[6,7] drug candi-
dates[8–10] and natural products.[11] Due to the fundamental
structural dissimilarities between cyclic nitronates and conju-
gated enynes, these compounds are generally accessed by dis-
parate strategies. The most established methods for the forma-
tion of conjugated enynes are metal catalyzed cross-couplings
exploiting the presence of double and triple bonds in the start-
ing materials.[3,12–17] Although metal-free procedures, especially
organocatalytic ones, to conjugated enynes would be very valu-
able, they are rarely found in literature.[18] On the other hand,
numerous metal-free procedures for the synthesis of cyclic
nitronates already exist among which intramolecular cyclization
via substitution and cycloadditions are commonly employed.[19]
Despite their structural divergences, conjugated enynes and
nitronates exhibit common reactivities. The zwitterionic struc-
ture of nitronates allows them to react as α-C-electrophiles, but
[a] Faculty of Chemistry and Pharmacy, University of Regensburg,
Universitätsstr. 31, 93053 Regensburg, Germany
E-mail: Ruth.Gschwind@ur.de
http://www-oc.chemie.uni-regensburg.de/gschwind/
[b] Institute of Organic Chemistry, University of Leipzig,
Johannisallee 29, 04103 Leipzig, Germany
Scheme 1. General reaction scheme to conjugated enyne 5 and cyclic nitron-
ate 6 from nitroalkenes 1 and 2 or dimer 3 via linking intermediate 4. The
mechanism starting from dimer 3, highlighted by a gray frame, is elucidated
in this work: a) cyclization of dimer 3 to intermediate 4; b) fragmentation of
4 to conjugated enyne 5; c) rearrangement of 4 to cyclic nitronates 6.
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under https://doi.org/10.1002/ejoc.201801153.
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bond in a one-pot reaction.[26] Starting from α,ꢀ-unsaturated fore, hereafter exclusively the studies in [D6]DMSO are dis-
nitroalkenes 1 and 2 with proline-based catalysts, first nitroalk- cussed. Consequently, in Figure 1c–d the pKa values are given
ene dimers 3 were generated via a Rauhut-Currier-like reac- in DMSO as far as available. Otherwise, pKa values in water are
tion[27–29] (see Scheme 1 top) followed by the fragmentation to provided.
conjugated enynes.[26] Furthermore, the pronounced formation
of another product was observed, which could be suppressed
upon addition of benzoic acid and was tentatively assigned to
a nitronic acid derivative.[26]
However, the mechanism of this unprecedented fragmenta-
tion as well as the nature of the other product remained un-
clear. The postulated mechanism via fragmentation to enyne
and nitromethane was regarded to be improbable, because
nitromethane did not accumulate during the reaction in the
expected amount.[26]
Herein, we present our profound mechanistic study on the
unusual organocatalytic formation of conjugated enynes by
means of NMR in combination with theoretical calculations. The
product generated alongside the enyne could be identified as
a cyclic nitronate. In addition, an unprecedented cyclic interme-
diate 4 was discovered, which was found to be common to the
mechanistic pathways of both conjugated enyne 5 and cyclic
nitronate 6 (see Scheme 1 bottom). Furthermore, 13C and 15N
labelling studies allowed for the identification of N2 and CO2
as fragmentation byproducts in the enyne formation. Hence, a
comprehensive mechanism for the first combined metal-free
synthesis of conjugated enynes and cyclic nitronates is pro-
posed. A retro-1,3-dipolar cycloaddition as a fragmentation to-
wards the enyne as well as complex intramolecular rearrange-
ments towards the nitronate are postulated. In addition, factors
influencing the product outcome are identified and approaches
to modify this outcome are presented.
Results and Discussion
Figure 1. Model substrates for the mechanistic investigation of the reaction
to conjugated enynes 5a–c and cyclic nitronate 6a; atoms marked in blue
Compound Pool for Mechanistic Studies. While the dimeriza-
tion of nitroalkenes follows the expected Rauhut-Currier-type
mechanism,[26,27] the mechanistic pathway to conjugated
enynes was still unsettled. Therefore, we focused our NMR study
on the mechanism and intermediates downstream to nitroalk-
ene dimers. As starting material for our studies dimer 3a, syn-
thesized from the unsubstituted nitropentene 1a, was selected
to allow investigations on double bond isomerization, while di-
mers 3b–c were chosen to examine electronic effects (see Fig-
ure 1a; for syntheses see SI). 15N labeled dimer 3a15N was used
for structural investigations on intermediate 4 during in situ
NMR reaction monitoring. For the investigation of the fragmen-
tation byproducts by 15N and 13C labeling, one-pot reactions
were applied to avoid compound loss by further conversion to
the dimer (see Figure 1a, 1a15N and 1a13C). Various bases, acids
or their combinations were examined (see Figure 1c–d, for fur-
ther catalyst screening see SI), since the initial studies revealed
that the reaction to both enyne and nitronate requires a
base.[26] Acids as additional additives potentially suppress the
formation of nitronates.[26] An NMR solvent screening including
and red were labelled with 13C and 15N, respectively; pKa values are given at
25 °C: a;[30] b;[31] c;[32] d;[33] e;[34] f;[35] for syntheses see SI.
Overall, no significant mechanistic deviations were found for
one-pot reactions and those starting from dimers regarding in-
termediate species (outcome and product distribution was de-
pendent on solvent and reaction conditions). Therefore, the in-
formation of both reaction types could be combined.
Identification of Cyclic Nitronate as Second Product. Par-
allel to the formation of 5, the generation of a side product was
observed.[26] Characterization of this side product by 2D NMR
spectroscopy and mass spectrometry revealed this compound
not as the originally suspected nitronic acid derivative,[26] but
as the cyclic nitronate 6a. The structure of 6a could be further
[36]
confirmed by removal of the exocyclic oxygen by P(OCH3)3
and thereby reducing 6a to the corresponding cyclic O-alkyl-
oxime (see SI). The highest yield of 6a (84 %) was obtained
with the base triazabicyclodecene (for synthesis and chemical
assignment of 6a see SI).
Common Pathway of Nitronates and Enynes to a Central
DMSO, DMF, methanol, benzene, dioxane, nitromethane, di- Linking Intermediate. Applying nitroalkene dimers as starting
chloromethane and acetonitrile revealed that highest yields material, NMR reaction monitoring revealed the formation of a
were obtained in DMSO (for more information see SI). There- new intermediate 4 (see Scheme 1 bottom) in the initial phase
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of the reaction. The detectable concentration of intermediate 4 situ NMR reaction monitoring, since it was too unstable for
highly depends on the base strength (see Figure 2). This is other methods. Various 2D NMR experiments were used to as-
shown on the reaction profiles of 3a with DBU 7 and sign the proton and carbon spin systems of this quite unusual
quinuclidine 8 (Figure 2b). Applying DBU as base, dimer 3a was intermediate (see Figure 3 and SI for spectra). To identify het-
instantly and nearly completely converted to intermediate 4a eroatoms and their connectivity in 4a theoretical calculations
(10 % E-isomer and 83 % Z-isomer, see Figure 2a). Employing and 15N-isotope labelling were applied. 1D proton decoupled
quinuclidine 8 as base generated significantly smaller amounts 13C spectra of in situ generated 4a15N revealed a single 13C-15N
of 4a (initial 30 %). The application of further bases corro- coupling constant of 6.3 Hz between carbon B and the nitro-
borated the trend, that stronger bases generate higher amounts gen, which excluded a nitrogen directly bound to the quater-
of 4 (see Figure 4 in SI). In addition, the type and strength of nary carbon A (see Figure 3). Theoretical calculations of 1H, and
base affect significantly the product distribution between 13C chemical shifts enabled to differentiate between potential
enynes and nitronates. With DBU about 60 % nitronate 6a and arrangements of oxygen moieties in 4a (for details see SI). The
9 % of enyne 5a was formed, while in presence of the less basic structure of 4a fitting best to both experimental and theoretical
quinuclidine, enyne 5a was the major product with 29 % yield data is displayed in Figure 3 revealing as basic structure an
and only 10 % of nitronate 6a was generated. Furthermore, isoxazolidine-2,5-diol.
mechanistic investigations of the nitronate formation showed a
clear correlation between the basicity, yield and formation rate
of nitronate (see section “Selectivity“ and Figure 7).
Figure 3. Structural assignment of the central linking intermediate 4 shown
on 4a E. Combined NMR and theoretical data reveal as central feature an
isoxazolidine-2,5-diol (for details see text and SI).
Next, the mechanistic pathway towards linking intermediate
4 was investigated (see Scheme 2). The correlation between
formation of 4 and the base strength (see Figure 2 and text
above) indicates a deprotonation as the rate-determining step.
Two different deprotonations of 3a would be conceivable: in α-
position to the secondary nitro group (A) and in α-position to
the primary nitro group (B). Both routes were investigated with
quantum chemical calculations. The energy profiles of route A
with and without DBU or water reveal, after the deprotonation
towards 19a, a concerted cyclization and protonation mecha-
nism towards 20a (see Scheme 2). Calculations showed that
free 20a is 42.8 kJ/mol less stable than 3a. However, coordina-
Figure 2. Base dependent formation of the central linking intermediate 4a as
tion of DBU results in massive stabilization of 20a by 35.3 kJ/
precursor for both enyne and nitronate. Strong bases caused high amounts
mol compared to the base free case. Thus, the base does not
of 4a and nitronate (a), while enynes were the main product with weaker
serve only as de- and reprotonating agent, but also acts as
stabilizer of intermediate 20a via a hydrogen bond. Such stabili-
zation strategy have been also utilized and observed in
bases (b); a) 3a (55 m
M) with DBU (82 m
M) in [D6]DMSO at 298 K; b) 3a
(55 m ) with quinuclidine (82 m
M
M) in [D6]DMSO at 298 K.
Next, the question arose, whether intermediate 4a is part of enamine catalysis.[37] Furthermore, calculations showed that co-
the mechanistic pathway of both main products, enyne and ordination of the conjugated acid to the primary nitro group in
nitronate. Figure 2 reveals that 4a was present in high con- 19a enables a concerted process: the attack of the carbanion
centrations independent of the main product indicating that on the other nitroxylic oxygen of this nitro group and the pro-
4a is a linking element for the formation of both enynes and ton transfer. This indicates that in the formation of intermediate
nitronates. This was further corroborated by a modified experi- 4a protonation of 19a is essential for the reaction to occur.
ment with DBU: Using a starting point with mainly 4a detect- Altogether, the base facilitates the pathway towards 20a and
able and only traces of dimer 3a left, benzoic acid 15 was subsequently 4a. Since [D6]DMSO always contains some
added leading to an increased amount of enyne (for data see amount of water, intermediate 20a is expected to be trans-
SI). The structure of intermediate 4a was investigated during in formed via an SN reaction into 4a upon release of HNO2.
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Scheme 2. Proposed mechanism from dimer 3a to linking intermediate 4a. Theoretical calculations predicted that two pathways may lead towards 4a: A)
deprotonation in α-position to the secondary nitro group is the thermodynamically favored route over 19a via subsequent concerted ring closure to 20a.
Substitution of the nitro group in 20a by water generates intermediate 4a. Our calculations revealed that DBU can stabilize 20a and thus enables the
formation of 4a. B) Deprotonation in α-position to the primary nitro group is the kinetically favored route via nitronate alt-1 followed by an interconversion
to alt-2 and subsequent ring closure by intramolecular substitution of the secondary nitro group to alt-3. Via an ensuing [1,3]-H-shift to alt-4 and addition
of water addition, intermediate 4a may be generated.
A second alternative towards 4a may be the abstraction of towards the energetically lower E-isomer may take place at the
the proton in the α-position next to the primary nitro group stage of the allylic anion 19a or alt-3 in case of deprotonation
(path B in Scheme 2). This leads to the formation of an unstable at position 1. In accordance with that, the NMR reaction profiles
intermediate alt-1. Quantum chemical calculations predicted revealed a faster conversion of 4a Z than 4a E for both bases
that the deprotonation of 3a to alt-1 is by 22.9 kJ/mol more (see Figure 2).
demanding than the deprotonation leading to 19a. On the
other hand, the abstraction of the α-proton of the primary nitro
group is kinetically slightly favored by 8.7 kJ/mol. Hence, the
second pathway might be feasible in case alt-1 is stabilized by
the formation of hydrogen bonds to the conjugated acid
(H-DBU+) as for 20a to the base. Subsequently, the reactive
alt-1 probably rapidly interconverts to alt-2 through an [1,4]-H
shift, which is followed by an intramolecular ring closure to
alt-3 via the attack of the oxygen of the N-hydroxy-hydroxyl-
amine releasing HNO2. Finally, the formation of 4a is suggested
to be concluded via an [1,3]-H shift generating alt-4 and the
subsequent addition of water (for other potential mechanisms
to intermediate 4 and their exclusion see SI).
Mechanism of the Conjugated Enyne Formation. Next, we
investigated the fragmentation mechanism from intermediate
4 towards conjugated enyne 5 (see Scheme 1 bottom). Since
no further intermediates could be detected, the identification
of fragmentation byproducts was of most importance to get
experimental evidence for discriminating other potential mech-
anistic pathways. The most obvious byproduct would be
CH3NO2 via an elimination.[26] However, accumulation of nitro-
methane in parallel to the product formation was never ob-
served. Instead, in situ 13C NMR monitoring of the one-pot reac-
tion of 1a13C revealed the generation of 13CO2 correlating di-
rectly to the formation of 5a13C (see Figure 4; for further experi-
mental confirmation of CO2 as byproduct see SI).
Our calculations of the first reaction barriers (TS-3a→19a
and TS-3a→alt-1) and reaction energies (3a towards 19a and
alt-1) revealed, that the formation of intermediate 4 may pro-
ceed via both pathways A and B. While pathway A is thermo-
dynamically favored, pathway B is kinetically favored.
Base dependent shifts of the protons attached to the double
bond in 4a were observed (see Figure 3 in the SI). Thus, a stabi-
lization of 4a by hydrogen bonding to bases is highly probable
similar to the situation of 20a.
Furthermore, the NMR profiles displayed in Figure 2 indicate
that partial isomerization of the double bond proceeds within
the formation pathway of 4. While the starting material 3a con-
sisted of 95 % Z-isomer and 5 % E-isomer, the amount of the
Figure 4. Correlated formation of 13CO2 and enyne 5a13C indicating CO2 as
fragmentation byproduct of the enyne pathway [13C NMR reaction monitor-
ing of 1a13C (40 m
M) with diphenylprolinol (20 mM) in [D6]DMSO at 300 K].
To elucidate the fate of the nitrogen we applied 15N NMR in
E-isomer in 4a was found to be significantly higher (10 % with situ reaction monitoring to a one-pot reaction of 1a15N. Inter
DBU; 20 % with quinuclidine; see Figure 2). This isomerization alia pronounced signals at δ = 310.8 ppm and 617.7 ppm ap-
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peared. The chemical shift of 310.8 ppm matches well a litera-
ture value of molecular nitrogen (δ =310.1 ppm).[38] In the initial
stage of the reaction, the N2 signal increases together with the
enyne formation. After about 4 h, the signal intensities deviate
most probably due to degassing effects of N2 (for data see SI).
This is, however, not the case for CO2 probably due to its signifi-
cantly higher solubility in DMSO than N2.[39] The 15N signal at
δ = 617.7 ppm is close to the literature value of sodium nitrite
in water (δ =608 ppm).[40] Considering the differences of our
system in terms of solvents (DMSO vs. H2O), counterions (Na+
vs. H-base+) and the potential presence of free HNO2, the signal
at δ = 617.7 ppm can readily be assigned to X+-NO2– generated
in the formation of intermediate 4a (for kinetic profile and the
assignment of the other 15N-signals see SI). Additionally to CO2
and N2, H2O was observed as third byproduct of the fragmenta-
1
tion of 4a into enyne. During H NMR monitoring of reactions
from 3a to enyne 5a, a significant increase of the water signal
could be observed. Similar to CO2 and N2, the water build-up
correlates qualitatively with the enyne formation (for data see
SI). Thus, CO2, N2 and water represent byproducts in the conju-
gated enyne 5 formation.
Based on the experimental detection of CO2, N2 and H2O as
byproducts and supported by quantum chemical calculations
we propose the transformation of intermediate 4 into conju-
gated enyne 5 via a combination of oxidation, dehydration and
retro 1,3-dipolar cycloaddition as depicted in Scheme 3. The
order of oxidation (by HNO2) and dehydration depends most
likely on the experimental condition. Our theoretical calcula-
tions show that both pathways A and B depicted in Scheme 3
between 4a and 23a are strongly exergonic. In case A the oxid-
ation occurs first and 21a together with hydroxylamine H2NOH
are generated in an exergonic fashion (–89.8 to –98.2 kJ/mol
depending on the diastereomeric starting intermediate). This is
followed by the dehydration step to 23a, which is also exer-
gonic [ΔG = –54.6 kJ/mol; dehydration of 21a(R,R)] but mainly
driven by the entropy (T*ΔS = +53.5 kJ/mol). In case B, the
order is reversed. The dehydration step is significantly less exer-
gonic compared to the first step in case A [ΔG = –19.4 kJ/mol;
dehydration of 4a(R,R)]. However the substrate 22a possesses
higher oxidation potential, and therefore the subsequent step
to 23a is even more facilitated (ΔG = –131.0 kJ/mol). Subse-
quently, we propose a fragmentation of 23a via a retro 1,3-
dipolar cycloaddition to the conjugated enyne 5a and com-
pound 24, which could be described as an “oxidized nitrone”
(see Scheme 3). Further, we propose a Nef-type decomposi-
tion[41,42] of the unstable side product 24 to CO2 and HNO.
HNO in turn comproportionates with the oxidation byproduct
H2NOH to N2 and H2O (see Scheme 3). The proposed mecha-
nism in Scheme 3 is in accordance with all three experimentally
detected byproducts CO2, N2 and H2O. Furthermore, we ob-
served the formation of DMS in the reaction to conjugated
enyne 5a implying a reduction of the solvent DMSO (for more
information see SI). This hints at the presence of redox active
species corroborating the proposed redox reaction in the mech-
anism from 3a to 5a (see Scheme 3).
Scheme 3. Proposed mechanism from intermediate 4a to conjugated enyne
5a (NMR detected compounds are bold). The oxidation step is in both path-
ways strongly exergonic/exothermic, while the dehydration is entropically
driven and enthalpically demanding for pathway B (ΔH = +32.4 kJ/mol; ΔG =
–19.4 kJ/mol), respectively weakly exothermic for pathway A (ΔH = –1.1 kJ/
mol; ΔG = –54.6). Depending on the experimental conditions different com-
binations of oxidation and dehydration lead to intermediate 23a. Next a
retro-1,3-dipolar cycloaddition fragments 23a to 5a and 24. Then 24 decom-
poses further to CO2 and HNO with HNO comproportionating with H2NOH
to N2 and water.
with terminal alkynes (see Scheme 3a in SI)[43] via postulated
cyclic five-membered rings resembling 23a.[44] Next, Nef-type
reactions can be assumed for the decomposition of 24, which
are feasible in a wide pH range (see Scheme 3b, c in SI).[41,42]
While the buildup of N2 was detected (see above) as compro-
portionation product of HNO and H2NOH, a degradation of
HNO to N2O[45,46] (see Scheme 3e in SI) was not observed in
the NMR kinetic measurements of 1a15N (15N2O signals should
appear at around 155 ppm and 240 ppm).[49]
Next, the effects of different acids, substituents and bases
were investigated to get further insights into the mechanism of
the conjugated enyne formation. A carboxylic acid as additive
accelerated significantly the formation of enyne and suppressed
the formation of nitronate almost completely (compare a and
b). Acid as additive is considered to have two effects in the
enyne mechanism. The dehydration should be facilitated and
the oxidizing power of HNO2 increased due to a lower pH. Fur-
thermore, with electron poor compound 3b (see Figure 1), we
also observed a faster enyne 5b formation than with the elec-
tron rich 3c into 5c in the presence of benzoic acid 15 as addi-
In agreement with our proposed mechanism, conventional tive. This corroborates the theoretical calculations revealing the
nitrones are well known for forward 1,3-dipolar cycloadditions dehydration as an enthalpically demanding step (for kinetic
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profiles see Figure 7 in SI). Without acidic additives, the enyne used to compare the relative energetics of possible intermedi-
formation is in general by far slower (see Figure 5a).
ate structures. Several possible pathways leading to 6a were
considered including the formation of cyclic intermediates 25a
and 26a and open chain intermediate open-4a. Both cyclic in-
termediates are energetically strongly disfavored compared to
intermediate 4a. Since a significant production of nitronate 6a
in mild basic condition was observed (see a), such uphill ener-
getic profiles to 25a and 26a are hence very unlikely. In con-
trast, the base mediated rearrangement of 4a to the open chain
intermediate open-4a is thermodynamically slightly favored
over 4a by 4.7 kJ/mol. Moreover, our calculations revealed that
the hemiketalic proton is more acidic than the N-hydroxylic one.
Therefore, we propose the formation of nitronate 6a to proceed
via the open chain intermediate open-4a. Further, we suggest
a first change in heteroatom connectivity by a rearrangement
of open-4a to 27a. Next, we propose a reformation of the five-
membered ring together with a second change of heteroatom
connectivity towards intermediate 28a. Finally, a dehydration
of 28a to cyclic nitronate 6a is suggested. Recently, a similar
dehydration step inter alia under basic conditions was reported
(see Scheme 4b).[48]
Selectivity: Conjugated Enyne vs. Cyclic Nitronate. As dis-
cussed above both products share a common mechanistic
pathway to the central linking intermediate 4, which subse-
quently splits towards conjugated enynes 5 and cyclic nitron-
ates 6. Hence, we examined factors influencing the product dis-
tribution, more precisely acidic additives, temperature and ba-
sicity.
The use of sufficient amounts of acids in addition to the base
suppressed the formation of nitronate 6 down to a few percent
and accelerated the generation of conjugated enyne 5 (see pre-
ceding discussion and Figure 5). In a small screening of acids
benzoic acid 15 led to the fastest formation of 5a (see Figure 6).
However, stronger acids were found to be detrimental, because
they in turn decelerated the enyne formation considerably (see
Figure 6). This essential balance between basic and acidic ex-
perimental conditions corroborated the proposed mechanism
(see Scheme 2, Scheme 3a and Scheme 4a).
Figure 5. Acids accelerated the enyne formation and suppress nitronates.
a) slow formation of 5a and 6a in presence of TEA 10 without acid [not
completed after 40 h; 3a (55 mM) with TEA (72 mM) in [D6]DMSO at 298 K];
b) 10-fold faster formation of 5a and suppression of 6a in presence of TEA
with acid 14 [3a (55 mM) with TEA (77 mM) and propionic acid (115 mM) in
[D6]DMSO at 298 K].
Mechanism of the Cyclic Nitronate Formation. Next, by
applying various acidic additives as well as bases the mechanis-
tic pathway towards nitronates 6 was examined and corro-
borated by theoretical calculation. Addition of carboxylic acids
suppressed the nitronate formation significantly (see Figure 5
and chapter above). In accordance with that, the formation rate
and yield of nitronate 6a increased with higher pKa values (see
Figure 7; for pKa see Figure 1). These experimental data suggest
a deprotonation of intermediate 4a as key step towards nitron-
ates (see Scheme 4a).
Scheme 4. a) Proposed mechanism from intermediate 4a to cyclic nitronate
6a based on quantum chemical calculations. Relative intermediate energies
of cyclic intermediates 25a and 26a and open chain intermediate open-4a
indicate that the reaction most likely proceeds via open-4a after hemiketal
opening. Further, a rearrangement of the nitrogen and oxygen atoms towards
27a is proposed. Intramolecular ring closure is suggested to generate 28a
which leads to nitronate 6a after dehydration; b) recently reported dehydra-
tion[48] similar to the postulated step from 28a to 6a.
Figure 6. The stronger the acid, the slower is the enyne formation. With too
strong acids 17 and 18 the reaction velocity towards enyne even falls below
that in absence of acidic additive [3a (55 mM) with TEA (1.3 equiv.) and acid
(1.3 equiv.) in [D6]DMSO at 298 K].
For the generation of the linking intermediate 4 a certain
basicity is indispensable (see Scheme 2), while acids accelerate
Since no further intermediates between 4a and nitronate 6a the enyne and suppress nitronate formation. Surprisingly, ele-
were detected experimentally, theoretical calculations were vated temperatures altered this product distribution in an ex-
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periment of 3a with TEA and benzoic acid. There, at 298 K ni- problems connected with nitroalkenes.[27,49] This polymeriza-
tronate 6a was suppressed below 3 % yield in the presence of tion was evident from mass spectrometry (electrospray ionisa-
benzoic acid. However, applying 320 K, 13 % of nitronate was tion) throughout a one-pot reaction of 1a with DBU reveal-
produced even in presence of benzoic acid. This hints at an ing molecular ion peaks with m/z ratios higher than 800 (see
alternative nitronate pathway potentially involving higher ener- Table 3 in SI). Furthermore, in the NMR spectra, the sum over
1
getic intermediates at elevated temperatures (for more informa- all H- signals belonging to the combined enyne and nitronate
tion see SI).
mechanism decreased in the ongoing reaction. Despite, several
efforts including various bases, acidic additives, concentrations
and temperatures, so far we have not been able to suppress
effectively this detrimental polymerisation process. Neverthe-
less, in other reactions involving nitroalkenes such polymerisa-
tion processes could be successfully controlled.[49] Thus, we are
confident that the broad community of synthetic chemists
working in the field of catalysis will find a way to raise the yields
of this promising organocatalytic method to build up triple
bonds in conjugated enynes.
Based on these results, a synthetic route to 6a (84 %) was
developed combining elevated temperature and a strong base
(3a with triazabicyclododecene at 50 °C; for procedure see SI).
Under purely basic conditions, we also observed a rough cor-
relation between the basicity and product distribution. While,
with strong bases DBU 7 and 1-(2-aminoethyl)-piperazine 10
nitronate 6a was clearly the major product with all other bases
enyne emerged as major product (except for 11 where no
enyne 5a was generated). For the nitronates 6a, the rates and
yields increased with stronger bases (see Figure 7). For the con-
jugated enyne 5 no clear correlation was observed between
basicity, yield and rate most probably due to the complex
mechanism.
Summary of Mechanistic Proposal and
Conclusion
The first comprehensive mechanistic proposal of the combined
metal-free route to conjugated enynes 5 and cyclic nitronates
6 is depicted in Scheme 5. Starting from nitroalkene dimers 3
NMR reaction profiles reveal a base initiated reaction to
an isoxazolidine-2,5-diol derivative as intermediate 4 (see
Scheme 5a). The unusual structure of this intermediate was cor-
roborated by various NMR experiments including 15N labelling
and theoretical calculations. Furthermore, NMR reaction profiles
revealed 4 as central linking intermediate followed by sepa-
rated pathways to enynes 5 (see Scheme 5b) and nitronates 6
(see Scheme 5c). While the enyne formation can proceed at
both medium and high pH values, effective nitronate formation
required basic conditions opening up an effective control of the
product distribution. The unusual buildup of the triple bond
out of a single bond in the enyne pathway is proposed to pro-
ceed via a combination of oxidation, dehydration and retro-1,3-
dipolar cycloaddition. Theoretical calculations suggested the
oxidation of intermediate 4a as first step in the formation of
23a under basic conditions. With acidic additives, both oxid-
ation to 21a and dehydration to 22a may compete as first
steps. The thereby generated unsaturated isoxazolidinone ring
in 23a is proposed to fragment via a retro-1,3-dipolar cycloaddi-
tion into conjugated enyne 5 and an oxidized nitrone 24. This
mechanistic proposal is corroborated by the experimentally
detected byproducts N2, CO2 and H2O. CO2 and HNO may origi-
nate from the decomposition of 24. HNO further compropor-
tionates with H2NOH to the detected N2 and H2O. In the path-
way towards cyclic nitronate 6 (Scheme 5c), theoretical calcula-
tions propose intramolecular rearrangements over open chain
intermediates open-4a and 27a to achieve the required change
in heteroatom connectivity from 4 to 6. The results of various
reaction conditions corroborated the mechanism presented in
Scheme 5. For example the addition of acids accelerated the
formation of enynes 5 and suppressed nitronates nearly com-
pletely. In contrast, strong bases clearly facilitated the formation
of nitronates 6.
Figure 7. Strong bases lead to higher rates and yields in the formation of
nitronate 6a [3a (80 mM) with 1 equiv. of base respectively: DBU 7, 1-(2-
aminoethyl)piperazine 10, N-(3-aminopropyl)morpholine 11 and N-methyl-
pyrrolidine 12].
Yield and scope of the combined route to conjugated
enynes and cyclic nitronates. While for the synthesis of cyclic
nitronates, there already exist several metal-free strategies,[19]
for conjugated enynes they are rare.[18] Hence, we mainly fo-
cused on examining the scope of conjugated enynes 5. We
found that conjugated enynes could be generated starting from
both homo- and heterodimers (derived from the dimerization
of 1 with 1 or 1 with 2) as well as directly from nitroalkenes 1
and 2 within a one-pot reaction. Besides aliphatic enyne 5a,
which was obtained in good to moderate NMR yields up to
57 %, and the aromatic enynes 5b and 5c several other ali-
phatic, heteroaromatic and functionalized/non-functionalized
aromatic conjugated enynes could be generated successfully.
This demonstrates a tolerance of the enyne formation towards
electronically and sterically different substituted dimers 3 and
nitroalkenes 1 and 2 (for scope and procedures see Figure 16
in the SI). To the cyclic nitronate formation, only aliphatic pre-
cursors were applied. Yet, higher yields were achieved up to
84 % (for scope and procedures see Figure 17 in the SI).
While, selectivity issues could be solved successfully (see
above), the yields of both enynes 5 and nitronates 6 have re-
While mechanistic and selectivity issues were solved and
mained limited so far due to the well-known polymerization high yields up to 84 % could be achieved for nitronates, only
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Scheme 5. Overview of the proposed mechanism to conjugated enynes 5 and cyclic nitronates 6 shown for the nitropentene-derived dimer 3a: a) formation
of the central linking intermediate 4a via two possible routes of base induced cyclizations; b) enyne pathway via a combination of oxidation, dehydration
and retro-1,3-dipolar cycloaddition; c) nitronate formation via base mediated intramolecular reorganization of nitrogen and oxygen atoms. Blue boxes highlight
the NMR-detected, gray frames the isolated compounds.
AccuTOF GCX instrument with an EI and a LIFDI source and on an
Agilent Q-TOF 6540 UHD with an ESI source.
medium to good yields (< 57 %) were obtained for enynes, due
to polymerization pathways well known for nitroalkenes. Never-
theless, we are confident that our mechanistic investigations
have laid a groundwork for further improvements of this highly
valuable, combined metal-free route to conjugated enynes and
cyclic nitronates. Further, we hope that our results pave the
way for further developments of organocatalytic or metal-free
formations of conjugated enynes.
Nitroalkenes 1a, 1a13C and 1a15N were synthesized following a
literature procedure.[50]
General Procedure for the Synthesis of Homo-Dimers: Nitroalk-
ene 1 (1 mmol) and L-proline (1 mmol) were mixed in DMSO
(10 mL). The reaction was left whilst stirring at room temperature
overnight. The mixture was dissolved in water and extracted with
dichloromethane. The combined organic phase was washed three
times with a saturated solution of lithium chloride, dried with
MgSO4 and the solvent was evaporated. The product was purified
by column chromatography (PE/DEE, 100:0–6:1).
Experimental Section
NMR spectroscopic experiments were performed on a Bruker
Avance III HD 400 MHz spectrometer, equipped with 5 mm BBO
BB-1H/D probe head with Z-Gradients, a Bruker Avance III HD
600 MHz spectrometer, equipped with a 5 mm TBI 1H/19F and a
5-Nitro-6-(nitromethyl)non-3-ene D1 (D2) (3a): 78 % yield. 3a Z:
1H NMR (600 MHz, [D6]DMSO): δ = 5.91 (5.94) (m, 1 H), 5.56 (5.59)
(m, 1 H), 5.55 (5.59) (m, 1 H), 4.63 (4.60/4.66) (m, 2 H), 2.91 (2.95)
Bruker Avance III 600 MHz equipped with a CryoProbe™ Prodigy. (m, 1 H), 2.16 (2.14) (m, 2 H), 1.31 (1.35/1.26) (m, 2 H), 1.30 (1.39)
Chemical shifts δ in ppm are referenced on residual solvent signals
or on internal standards. For NMR measurements employing stan-
dard NMR solvents 5 mm NMR tubes were used. NMR-reaction ki-
(m, 2 H), 0.95 (0.95) [t, J = 7.6 Hz (7.6 Hz), 3 H], 0.85 (0.85) [t, J =
7.1 Hz (7.1 Hz), 3 H] ppm. 13C NMR (600 MHz, [D6]DMSO): δ = 141.7
(141.4), 120.0 (120.1), 85.0 (84.3), 74.9 (75.2), 39.2 (39.2), 29.4 (30.2),
netics were performed using tetramethylsilane (TMS) or octameth- 20.4 (20.4), 18.6 (18.6), 13.5 (13.5), 13.2 (13.2) ppm. 3a E: 1H NMR
ylcyclotetrasiloxane (OMS) as internal standard. The samples for
(600 MHz, [D6]DMSO): δ = 6.08 (6.03) [dt (dt), J = 15.3 Hz (15.3 Hz),
NMR-reaction monitoring were prepared from stock solutions of the
6.2 Hz (6.2 Hz) 1 H], 5.55 (5.69) [m (ddt) (J = 15.3 Hz, 9.7 Hz, 1.5 Hz),
respective reagents and reactants. For starting points (t = 0) spectra 1 H], 5.22 (5.25) [dd, J = 9.3 Hz, 8.6 Hz (9.3 Hz, 6.9 Hz), 1 H], ≈ 4.62
of the samples lacking the base were recorded. Afterwards, the base
was added, and the reaction was monitored by NMR spectroscopy.
High-resolution mass spectra (HRMS) were obtained on a Jeol
(≈ 4.62) (m, 2 H), 2.92 (2.92) (m, 1 H), 2.04 (2.10) (m, 2 H), 1.60
(≈ 1.35) (m, 2 H), ≈ 1.24 (≈ 1.28) (m, 2 H), 0.94 (1.05) (t, J = 7.6 Hz)
(7.4 Hz, 3 H), 0.85 (0.85) (t, J = 7.1 Hz, 3 H) ppm. 13C NMR (600 MHz,
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[D6]DMSO): δ = 142.4 (142.2), 119.9 (119.8), 90.7 (89.5), 75.0 (75.6),
≈ 39.2 (≈ 39.2), 30.8 (29.8), 24.4 (24.5), ≈ 18.5 (≈ 18.5), ≈ 13.5 (≈ 13.5),
≈ 13.3 (≈ 13.3) ppm. HRMS (ESI): calcd. for C10H18N2O4 [M + H]+
231.1339, found 231.1341.
points, ORCA 4.0.1 was employed.[56] For further details see Sup-
porting Information.
Acknowledgments
General Procedure for the Synthesis of Hetero-Dimers: L-proline
We would like to thank the German Science Foundation (DFG,
GS 13/3-1 and GS 13/4-1) for financial support. We regret that
Dr. Markus Schmid refused to be Co-author of this manuscript
and preferred to be cited in the given way. Nevertheless, we
would like to thank him for the initialization of this project de-
tecting first this unprecedented enyne formation.
(0.2 mmol) and benzoic acid (0.2 mmol) were dissolved in DMSO
(7 mL) at room temperature. Subsequently, the corresponding nitro-
alkenes (0.3 mmol each) were added. The solution was stirred for
24
h under atmospheric conditions. After the reaction was
quenched by adding brine (10 mL) the reaction mixture was ex-
tracted 4 times with diethyl ether (10 mL each). The combined or-
ganic layers were washed 4 times with distilled water (10 mL each)
and dried with magnesium sulfate. After evaporation of the solvent
the raw product was purified by flash column chromatography (PE/
EA = 9:1).
Keywords: NMR spectroscopy · Enynes · Nitronates ·
Reaction mechanisms · Theoretical calculations
1-(5-Methyl-1,3-dinitrohex-4-en-2-yl)-2-nitrobenzene
(3b):
Nitroalkenes (E)-3-methyl-1-nitrobut-1-ene and (E)-1-nitro-2-(2-
nitrovinyl)benzene were applied as starting material. 24 % yield. H
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1
NMR (400 MHz, [D6]DMSO): δ = 8.09 (7.89) [d (d), J = 7.9 Hz (7.9 Hz)],
7.94 (7.94) (dd, J = 8.1 Hz, 1.2 Hz), 7.78 (7.78) (ddd, J = 7.8 Hz,
7.8 Hz, 1.1 Hz), 7.59 (7.59) (ddd, J = 7.8 Hz, 7.8 Hz, 1.2 Hz), 5.90
(6.03) [dd (dd), J = 9.9 Hz, 9.9 Hz (10.1 Hz, 10.1 Hz)], 5.44 (5.29) [dqq
(dqq), J = 9.7 Hz, 1.3 Hz, 1.3 Hz (10·Hz, 1.3 Hz, 1.3 Hz)], 5.08 (5.22)
[dd (dd), J = 13.8 Hz, 8.6 Hz (14.4 Hz, 10.3 Hz)], 4.96 (5.08) [dd (m),
J = 13.8 Hz, 5.5 Hz], 4.79 (4.88) [ddd (ddd), J = 9.8 Hz, 8.7 Hz, 5.4 Hz
(9.9 Hz, 9.9 Hz, 4.4 Hz)], 1.82 (1.59) [d (d), J = 1.1 Hz (1.2 Hz)], 1.79
(1.53) [d (d), J = 1.0 Hz (1.1 Hz)] ppm. 13C NMR (400 MHz, [D6]DMSO):
δ = 149.9 (150.3), 146.3 (146.4), 133.3 (133.3), 129.6 (129.6), 129.4
(129.1), 129.1 (129.0), 124.8 (124.8), 118.5 (116.6), 86.8 (85.3), 75.9
(76.7), 40.5 (39.7), 25.4 (25.1), 18.4 (18.1) ppm. HRMS (ESI): calcd. for
C
13H15N3O6 [M + Na]+ 332.0853, found 332.0855.
1-Methoxy-2-(5-methyl-1,3-dinitrohex-4-en-2-yl)benzene (3c):
Nitroalkenes (E)-3-methyl-1-nitrobut-1-ene and 1-methoxy-2-[(E)-2-
1
nitrovinyl]benzene were applied as starting material. 24 % yield. H
NMR (400 MHz, [D6]DMSO): δ = 7.31 (7.31) (dd, J = 7.5 Hz, 1.7 Hz,
1 H), 7.29 (7.29) (ddd, J = 7.9 Hz, 7.9 Hz, 1.6 Hz, 1 H), 7.03 (7.00) [dd
(dd), J = 8.3 Hz, 0.7 Hz (8.2 Hz, 0.7 Hz), 1 H], 6.91 (6.91) (ddd, J =
7.4 Hz, 7.4 Hz, 1.0 Hz, 1 H), 5.87 (5.82) [dd (dd), J = 10.2 Hz, 10.2 Hz
(9.9 Hz, 9.9 Hz), 1 H], 5.46 (5.19) [dqq (dqq), J = 9.9 Hz, 1.4 Hz, 1.4 Hz
(9.9 Hz, 1.4 Hz, 1.4 Hz), 1 H], 4.89/4.80 (5.11/4.91) [dd/dd (dd), J =
13.4 Hz, 8.8 Hz/13.4 Hz, 5.6 Hz (13.3 Hz, 10.1 Hz), 2 H], 4.40 (4.50)
[ddd (ddd), J = 10.2 Hz, 8.8 Hz, 5.7 Hz (9.9 Hz, 9.9 Hz, 4.7 Hz), 1 H],
3.83 (3.81) [s (s), 3 H] 1.79 (1.55) [d (d), J = 1.4 Hz (1.4 Hz), 3 H], 1.79
(1.53) [d (d), J = 1.4 Hz (1.3 Hz), 3 H] ppm. 13C NMR (400 MHz,
[D6]DMSO): δ = 149.9 (150.3), 145.0 (142.7), 129.6 (129.6), 129.4
(129.4), 122.7 (122.4), 120.6 (120.6), 117.1 (117.3), 111.7 (111.4), 86.0
(85.5), 75.5 (75.8), 55.7 (55.6), 42.2 (41.3), 25.4 (25.1), 18.3 (17.8) ppm.
HRMS (ESI): calcd. for C14H18N2O5 [M + Na]+ 317.1108, found
317.1112.
For scope and syntheses of conjugated enynes and cyclic nitronates
see Supporting Information.
Computational Details: For the calculation, a smaller model of
dimer 3a was employed. The n-propyl group and the terminal ethyl
group connected with the double bond were substituted by a
methyl group. All structures were optimized at M06–2X/def2-SVP
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Full Paper
Reaction Mechanism
V. Streitferdt, M. H. Haindl, J. Hioe,
F. Morana, P. Renzi, F. von Rekowski,
A. Zimmermann, M. Nardi,
K. Zeitler, R. M. G.* ......................... 1–11
Unprecedented Mechanism of an
Organocatalytic Route to Conju-
gated Enynes with a Junction to Cy-
clic Nitronates
In situ NMR, isotope labelling, and the- build-up of the triple bond out of a
oretical calculations revealed an or- single bond and provides a mechanis-
ganocatalytic mechanism to conju- tic junction to cyclic nitronates, which
gated enynes. This mild route to can be selectively switched by certain
enynes proceeds through an unusual basic and acidic additives.
DOI: 10.1002/ejoc.201801153
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
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