Stereoselective Synthesis of Highly Substituted 1,3-Dienes via “à la carte” Multifunctionalization of Borylated Dendralenes

Article abstract of DOI:10.1002/anie.202104741

Despite the high relevance of 1,3-dienes, stereoselective methods to access tetrasubstituted conjugated dienes are still scarce. We here report an efficient and modular approach that provides access to multifunctional tetrasubstituted 1,3-dienes with excellent levels of regio- and stereoselectivity. This methodology is based on a tetracomponent reaction between a borylated dendralene, an organolithium reagent and two different electrophiles. Mechanistic studies reveal that this transformation proceeds through a regio- and stereoselective carbolithiation/electrophilic trapping of an in situ formed dendralenic boron-ate complex, followed by a stereoretentive halodeborylation. The ease in which complex structural dienes can be accessed and their synthetic versatility highlight the importance and utility of this method.

Full text of DOI:10.1002/anie.202104741

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Accepted Article
Title: Stereoselective Synthesis of Highly Substituted 1,3-Dienes via ‘à
la carte’ Multifunctionalization of Borylated Dendralenes
Authors: Eva Rivera-Chao and Martín Fañanás-Mastral
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Stereoselective Synthesis of Highly Substituted 1,3-Dienes via ‘à
la carte’ Multifunctionalization of Borylated Dendralenes
Eva Rivera-Chao and Martín Fañanás-Mastral*[a]
[
a]
E. Rivera-Chao, Prof. M. Fañanás-Mastral
Centro Singular de Investigación en Química Biolóxica e Materiais Moleculares (CiQUS), Departamento de Química Orgánica
Universidade de Santiago de Compostela
15782 Santiago de Compostela (Spain)
E-mail: martin.fananas@usc.es
Supporting information for this article is given via a link at the end of the document.
Abstract: Despite the high relevance of 1,3-dienes, stereoselective
methods to access tetrasubstituted conjugated dienes are still scarce.
We here report an efficient and modular approach that provides
access to multifunctional tetrasubstituted 1,3-dienes with excellent
levels of regio- and stereoselectivity. This methodology is based on a
tetracomponent reaction between
a borylated dendralene, an
organolithium reagent and two different electrophiles. Mechanistic
studies reveal that this transformation proceeds through a regio- and
stereoselective carbolithiation/electrophilic trapping of an in-situ
formed dendralenic boron-ate complex, followed by a stereoretentive
halodeborylation. The ease in which complex structural dienes can be
accessed and their synthetic versatility highlight the importance and
utility of this method.
1
,3-Dienes represent an important class of compounds owing to
their versatile application in chemical synthesis[1] and their
ubiquitous presence in a wide range of biologically active natural
products,[2] and functional materials and devices.[3] Accordingly, a
number of methods for the preparation of conjugated dienes have
been developed.[4-7] Despite the effectiveness of these methods,
the stereoselective construction of tetra- or more highly
substituted 1,3-dienes is still scarce. Recent advances include
[
2+2] cycloaddition–retroelectrocyclization reactions between
Scheme 1. State-of-the-art methods for the stereoselective synthesis of highly
substituted 1,3-dienes.
[
8]
tetracyanoethylene and electron rich alkynes (Scheme 1a), Pd-
catalyzed coupling of propargylic diols with arylboronic acids
(
(
Scheme 1b)[9] or Pd-catalyzed carbonylation of 1,3-diynes
Scheme 1c).[10] Although highly efficient, these methods
We recently reported a catalytic methodology that allows the
synthesis of borylated dendralenes from readily available alkynes,
somewhat lack the possibility to install structurally diverse
substituents at the different positions of the diene core. Moreover,
besides the challenge associated to the substitution pattern, the
synthesis of 1,3-dienes bearing substituents at all four positions
imposes another big selectivity issue since every double bond
must be constructed stereoselectively while substituents being
incorporated in a regioselective manner. Thus, the development
of new methodologies, particularly those that allow
stereoselective synthesis of highly substituted conjugated dienes
with ‘à la carte’ introduction of diverse substituents remains a
challenge.
.[11] As part of our studies on the
1
,4-dibromo-2-butene and B pin
2 2
[11,12]
functionalization of this new type of organoboronates,
we
attempted to transform 1 into methyl-substituted dendralene 2
through a Zweifel coupling which would involve boronate complex
[13]
formation, 1,2-metallate rearrangement and deiodoborylation.
Surprisingly, when 1 was sequentially treated with 1 equiv of MeLi
and iodine, no tractable amount of Zweifel coupling product 2 was
detected. By using 2 equiv of MeLi the reaction led to productive
conversion although the only reaction product was the
unexpected 1,2,3,4-tetrasubstituted E,E-diene 3 where three new
C-C, C-H and C-I bonds were formed (Scheme 2).
1
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Upon addition of 1 equiv of MeLi to 1 we observed quantitative
11
formation of boronate complex 4 ( B NMR; 6.6 ppm) (Figure 1a).
As expected from our preliminary result (Scheme 2), treatment of
this intermediate with iodine did not afford the 1,2-metallate
rearrangement[13] product 2 nor 1-iodo-1,3-diene 3. Addition of 2
equiv of MeLi led to the formation of two different boronate
complexes (6.6 and 4.8 ppm) along with a new boron species
featuring a sharp singlet at -19.0 ppm which is consistent with a
trimethyl boronate complex[14] (Figure 1b). Interestingly, addition
of a solution of iodine in methanol to this mixture provided
iododiene 3 in 40% yield. Two possible mechanistic scenarios for
the C-C bond forming step were initially considered: an iodine-
mediated intramolecular 1,6-migration of the Me group or an
intermolecular regioselective carbolithiation. 1H NMR analysis
Scheme 2. Preliminary results.
Considering the high relevance of this type of structures and the
scarcity of methods to access multisubtituted conjugated dienes,
we decided to study this transformation and we now report a
method that enables the stereoselective construction of
multifunctional tetrasubstituted 1,3-dienes in a single one-pot
operation that entails a tetra-component three bond-forming
reaction (Scheme 1d).
(
see Supporting Information for details) of the mixture generated
In order to optimize and extend the scope of this reaction, we first
decided to get insight on the mechanism of this new
transformation. For this purpose, we analyzed the nature of the
reaction intermediates by NMR spectroscopy (Figure 1 and
Supporting Information).
by addition of 2 equiv of MeLi revealed the presence of
dienylboronate complex 5 as the major component, somewhat
discarding a 1,6-metallate rearrangement pathway. Formation of
5
might arise from nucleophilic attack at the vinyl group of
boronate complex 4 and subsequent stereoselective protonation
of the resulting allylithium intermediate. Considering that the
presence of multiple boron species was probably not the best
situation to achieve an efficient transformation, we decided to use
PhLi instead of MeLi. Addition of 1 equiv of PhLi to 1 quantitatively
provided dendralenic boronate complex 7 (Figure 1c). Gratifyingly,
addition of a second equivalent of PhLi followed by protonation
cleanly generated a single boronate complex (8, 7.2 ppm), which
afforded tetra-substituted diene 9 in 65% yield upon treatment
with of a solution of iodine (1.2 equiv) in methanol (Figure 1d). To
further prove
a direct carbolithiation mechanism, boronate
complex 7 was sequentially treated with 1 equiv of MeLi and
iodine/methanol and the reaction exclusively afforded diene 3 in
an improved 54% yield (vs 40% yield with 2 equiv of MeLi).
Similarly, addition of PhLi to boronate complex 4 followed by
treatment with iodine and methanol led to the selective formation
of diene 9 (Scheme 3).
Scheme 3. Experiments supporting a carbolithiation pathway.
It is important to note that few examples of carbolithiation of
dendralenes have been described. Besides anionic
polymerization[ and a carbolithiation/electrocyclization of cyclic
15]
[
3]dendralenes,[16]
only
one
example
involving
carbolithiation/electrophilic trapping of dendralenes has been
reported to date.[17] Interestingly, in our system carbolithiation
occurs via a regioselective addition of the organolithium reagent
to the vinyl moiety of the borylated dendralene which generates
an allyllithium intermediate. This is in sharp contrast with previous
examples where dendralene carbolithiation generates a stabilized
Figure 1. Mechanism investigation and reaction optimization via 11B NMR
analysis.
2
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pentadienyllithium intermediate.[15-17] We hypothesized that the
presence of the polarized C-B bond in our system might hamper
both the formation of the pentadienyllithium intermediate and the
carbolithiation at the alkenyl boronate moiety, thus providing a
favored scenario for nucleophilic addition at the vinylic terminus.
Another important feature of the carbolithiation step is the high
level of regio- and stereoselectivity achieved after the electrophilic
trapping. Given that allyllitium species tend to rapidly
equilibrate,[ this high selectivity might likely arise from the
formation of the thermodynamically most stable E-isomer after
electrophilic attack at the less hindered allylic terminus.
18]
Scheme 4. Proposed mechanism for the formation of tetra-substituted 1-iodo-
1,3-dienes.
NMR and GC-MS analysis after iodine addition revealed the
formation of PhBpin together with phenyl boronate complexes
which might originate from reaction between in-situ generated
LiOMe and the phenyl boronic ester (Figure 1e). This suggests
that C-B to C-I transformation would occur through a two-step
iodonium formation/elimination sequence (see below for further
details). Overall, on the basis of these experiments, a mechanism
involving 1) dendralenic boronate complex formation, 2) regio-
and stereoselective carbolithiation/electrophilic trapping and 3)
stereoretentive iododeborylation[19] of the resulting dienyl
boronate complex, can be proposed for this novel transformation
Having disclosed the mechanistic intricacies of this tetra-
component reaction, we set out to explore the scope of this
transformation (Scheme 5). We first investigated the behavior of
different organolithium compounds (Scheme 5a). Primary,
secondary, and tertiary alkyllithium reagents all proved to be
efficient for this transformation. With those nucleophiles,
carbolithiation took place at -78 ºC and subsequent quenching
with MeOH and iodine provided the corresponding tetra-
substituted dienes 3, 10-13 in good yield with complete levels of
regio- and stereoselectivity in nearly all cases. Interestingly,
aryllitihium reagents which failed to provide carbometallation with
other dendralenes,[16] worked well in this transformation albeit
warming to 0 ºC was necessary to achieve full carbolithiation.
(
Scheme 4).
Scheme 5. Scope of the reaction. [a] Reaction conditions: dendralene (1.0 equiv, 0.2 mmol) in 1.0 ml of dry THF, PhLi (1.0 equiv), -78 ºC to 0 ºC and stirred for 5
3
2
1
min; then, R Li (1.2 equiv), -78 ºC, then, I
2
(1.2 equiv, E ) 0.5 M in MeOH (E ), -78 ºC to 0 ºC and stirred for 30 min. [b] Obtained as a mixture of regioisomers (see
1
2
1
1
SI for details); [c] PhLi (or ArLi, 2.2 equiv), -78 ºC to 0 ºC, then E and E ; [d] MeI (E , 2 equiv), -78 ºC to 0 ºC; then, I
(1.2 equiv); [f] n-BuBr (E , 2 equiv), -78 ºC to 0 ºC; then, I
equiv), then NIS (E , 1.2 equiv) instead of I
.2 equiv, 0.5 M in THF) instead of I
2
(1.2 equiv); [e] BnBr (E , 2 equiv), 0 ºC; then,
1
1
1
I
4
1
2
2
(1.2 equiv); [g] PhCHO (E , 2 equiv), -78 ºC to 0 ºC; then, I
2
(1.2 equiv) 0.5 M in MeOH; [h] MeOH (E ,
/MeOH; [j] MeOH (E , 4 equiv), then PhSeCl (E ,
2
1
2
1
2
2
/MeOH; [i] MeOH (E , 4 equiv), then NBS (E , 1.2 equiv) instead of I
/MeOH; [k] MeOH (4 equiv, E ), -78 ºC to rt; solvent evaporation, then, MeCN (1.0 ml), Selectfluor (E , 1.5 equiv), rt; [l] Warmed
/MeOH at 0 ºC.
2
1
®
2
2
to 0 ºC after addition of t-BuLi, then I
2
3
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Under these conditions, dienes 9, 14 and 15 were obtained in
good yield and with excellent selectivity.[20] The nucleophilicity of
the allyllithium intermediate also enabled efficient trapping of
different carbon electrophiles thus providing a handle for the
elongation of the 3-substituent of the dienic core through a second
C-C bond formation. Use of iodomethane, benzyl bromide, 1-
bromobutane or benzaldehyde, instead of MeOH, resulted in
efficient two C-C, one C-I forming processes (Scheme 5b, 16-23).
The intermediate dienyl boronate complex generated after the
carbolithiation/electrophilic trapping step could also be exploited
in other electrophilic couplings to incorporate different
functionalization on the diene structure. For this purpose, a series
of electrophiles rather than iodine were investigated in reactions
involving carbolithiation with PhLi or t-BuLi (Scheme 5c). We
found that the use of NIS is equally effective than iodine to afford
iododiene 9. With NBS and PhSeCl the reactions also proceeded
with total regio- and stereoselectivity, producing 1-bromo-1,3-
dienes 24-25 and 1,3- dienyl selenides 26-27, respectively, as
single E,E isomers in very good yields. Interestingly, in sharp
contrast with the conjunctive functionalization of β,β-disubstituted
vinyl boronate complexes with PhSeCl reported by Aggarwal,[21]
no formation of 1,2-migration products was observed in these
cases.
corresponding tetrasubstituted dienes 31 and 32 in good yield
with excellent regio- and stereoselectivity. Noteworthy, reaction
with a borylated [4]dendralane, which adds an extra point of
regioselectivity
in
the
carbolithiation
step,
afforded
iododendralene 33 as a single product in 82% yield. Surprisingly,
when a borylated dendralene bearing a TMS group in the 2
position was used in combination with PhLi and t-BuLi, products
34 and 35 arising from
a
Zweifel-type 1,2-metallate
rearrangement-elimination sequence were obtained instead of
the expected 1-iodo-1,3-dienes. A similar behavior was observed
for a borylated dendralene bearing substituents both at 1 and 2
positions (formation of 36).[24] A plausible mechanistic rationale
accounting for this divergency is outlined in Scheme 7. After the
carbolithiation/protonation step, treatment of the resulting diene
boronate complex with iodine would form a zwitterionic iodonium
intermediate. This species can either eliminate to afford the
iododiene along with PhBpin or undergo a 1,2-rearrangement of
the phenyl group. The commonly observed elimination may arise
from a partial positive charge stabilization at the  carbon, likely
due to the ,-disubstitution,[ which would allow lengthening of
the C()-I bond thus favoring this pathway (Scheme 7a). However,
the presence of a TMS group in the  position may rather stabilize
positive charge at the α carbon,[ facilitating the 1,2-migration of
the phenyl group (Scheme 7b). Similarly, the presence of an extra
substituent at the α position would also provide a good scenario
to build up partial positive charge at that carbon.
21]
25]
We next investigated
a
transformation involving
a
carbolithiation/protonation/fluorination process. Subsequent
treatment of borylated dendralene 1 with PhLi, t-BuLi, MeOH and
Selectfluor®, afforded 1-fluoro-1,3-diene 28 in moderate yield
with excellent regioselectivity although with slightly diminished
stereoselectivity (E,E:E,Z = 4.5:1).[22] These results suggest that
the formation of a closed three-membered intermediate prior to
the elimination step is important to achieve stereochemical
retention.
Interestingly,
when
a
carbolithiation/alkylation/fluorination process was attempted by
using MeI instead of MeOH, 1-iodo-1,3-diene 17 was exclusively
obtained (Scheme 6). In this case, formation of 17 may be
explained by the presence of LiI which is generated in the first
electrophilic trapping and may be oxidized by Selectfluor® to the
iodine cation,[23] which might promote the electrophilic iodination
of the dienylboronate intermediate.
Scheme 7. Mechanistic rationale for the divergent elimination pathways.
An attractive feature of this new tetra-component reaction is the
functional group diversity that can be installed in the diene core
which allows to access more complex dienic structures (Scheme
8
). Formation of PhBpin as side product could be exploited to
perform an in-situ Suzuki-Miyaura coupling with the 1-iodo-1,3-
diene product just by adding a Pd catalyst and aq. K CO to the
2
3
reaction mixture. The synthesis of diene 37 showcases a route to
incorporate the aryl group from the organolithium used to
generate the initial dendralenic boronate complex into the final
product. The obtained 1-iodo-1,3-dienes also served as good
precursors to prepare stereodefined polyconjugated systems as
illustrated with the synthesis of dienyne 38 by Sonogashira
coupling. Moreover, the versatile reactivity of the C-I bond can
also be used to perform lithium/halogen exchange to generate a
dienyllithium reagent which can react with a carbon electrophile
Scheme 6. Effect of first electrophile in the cascade reaction with Selectfluor®.
2
3
(
e.g. MeI) to establish a new C(sp )-C(sp ) bond as shown for the
Finally, we explored the outcome of different borylated
dendralenes in the carbolithiation/protonation/iodination reaction
synthesis of 39.
(
Scheme 5d). Both electron withdrawing (29) and electron
donating groups (30) were tolerated at the aromatic substituent in
the 2 position, although reaction turned out to be more efficient
with the latter. Gratifyingly, substrates bearing heteroaromatic
and aliphatic substituents also worked well and afforded the
4
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In summary, we have developed an efficient tetra-component
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boronate complex, its regioselective carbolithiation and two
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attractive building-blocks for organic synthesis.
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Acknowledgements
Financial support from the AEI (CTQ2017-88451-R), Xunta de
Galicia (ED431C 2018/04; Centro singular de investigación de
Galicia accreditation 2019-2022, ED431G 2019/03) and the
European Union (European Regional Development Fund - ERDF)
is gratefully acknowledged. E. R.-C. thanks Xunta de Galicia for a
predoctoral fellowship.
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Keywords: boron • carbolithiation• dendralenes •
multicomponent reactions • 1,3-dienes
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5
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Entry for the Table of Contents
An unprecedented tetra-component reaction between a borylated dendralene, an organolithium reagent and two different electrophiles
is reported. The method allows for the regio- and stereoselective synthesis of highly substituted 1,3-dienes with ‘à la carte’ introduction
of diverse functionalities which serve as a versatile handle to access complex dienic structures.
Institute and/or researcher Twitter usernames: @ciqususc, @mfananasmastral
6
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