Heterocyclization and Spirocyclization Processes Based on Domino Reactions of N-Tosylhydrazones and Boronic Acids Involving Intramolecular Allylborylations of Nitriles

Article abstract of DOI:10.1002/chem.201803309

Polycyclic molecules featuring all-carbon quaternary bridgehead centers were synthesized through domino cyclizations between N-tosylhydrazones and boronic acids. Variations of the general cascade have been applied for the preparation of 3-quinuclidinones and related alkaloid-like scaffolds through transannular heterocyclizations. Moreover, the employment of 3-cyanopropyl and 4-cyanobutylboronic acids and α,β-unsaturated N-tosylhydrazones led to spirocycles through unprecedented formal [n+1] cyclizations, including the stereoselective spirocyclization of the Hajos–Parrish ketone. The common feature of all the new reactions described is the creation of an all-carbon quaternary center by formation of two Csp³?C bonds on the hydrazonic carbon atom. DFT-based calculations suggested the occurrence of cascade processes, which involve a diazo compound carboborylation followed by a 1,3-borotropic rearrangement on an intermediate allylboronic acid and a novel bora-aza-ene cyclization.

Full text of DOI:10.1002/chem.201803309

A Journal of
Accepted Article
Title: Heterocyclization and spirocyclization processes based on
domino reactions of N-tosylhydrazones and boronic acids
involving intramolecular allylborylations of nitriles
Authors: Manuel Plaza, Stefano Parisotto, and Carlos Valdés
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To be cited as: Chem. Eur. J. 10.1002/chem.201803309
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Heterocyclization and spirocyclization processes based on
domino reactions of N-tosylhydrazones and boronic acids
involving intramolecular allylborylations of nitriles
Manuel Plaza, Stefano Parisotto and Carlos Valdés*[a]
Abstract: Polycyclic molecules featuring all-carbon quaternary
bridgehead centers are synthesized through domino cyclizations
between N-tosylhydrazones and boronic acids. Variations of the
general cascade have been applied for the preparation of 3-
quinuclidinones and related alkaloid-like scaffolds through
transannular heterocyclizations. Moreover, the employment of 3-
cyanopropyl and 4-cyanobutylboronic acids and ,-unsaturated N-
tosylhydrazones led to spirocycles through unprecedented formal
[n+1] cyclizations, including the steroselective spirocyclization of the
Hajos-Parrish ketone. The common feature of all the new reactions
described is the creation of an all-carbon quaternary center by
formation of two Csp3-C bonds on the hydrazonic carbon atom. DFT-
based calculations suggest cascade processes that involve a diazo
all-carbon quaternary center is to be formed. Moreover, these
classes of cyclizations normally require a transition-metal catalyst
that acts as a molecular assembler of the starting materials.[5,6]
compound carboborylation followed
by
a
1,3-borotropic
rearrangement on an intermediate allylboronic acid and a novel bora-
aza-ene cyclization.
Introduction
Figure 1. Molecular scaffolds featuring quaternary centers at bridgehead
positions and the strategies for their synthesis discussed in this paper.
The synthesis of polycyclic molecules with novel “sp3 rich”
three dimensional scaffolds is a subject of great interest in organic
synthesis, as they allow the exploration of unknown areas of the
chemical space in the search of new biologically active molecular
structures.[1,2] In this regard, polycyclic molecules featuring all-
carbon quaternary centers at bridgehead positions are particularly
attractive.[3] The rigidity imposed by the quaternary center
enforces specific three dimensional structures that display the
functional groups of the molecules into particular arrangements
that might be determining for potential interactions with biological
receptors. Examples of these classes of structures are fused
bicyclic structures I, [a.b.c] bicyclic structures II, and spirocyclic
structures[4] III (Figure 1). Therefore, the development of efficient
and flexible methods for the preparation of these types of
molecules is highly demanded.
In the context of our interest on the metal-free reactions
between sulfonylhydrazones and boronic acids,[7] we have
recently reported a transition-metal free cascade carbocyclization
involving - and -cyano-N-tosylhydrazones and alkenylboronic
acids, which led to fused carbocyclic structures of type I featuring
an all-carbon quaternary stereocenter (Scheme 1).[8] In those
reactions, two Csp3-Csp2 bonds are formed on the same carbon,
representing a novel type of cascade carbocyclization with
concomitant incorporation of a side chain.
The mechanism initially proposed for this transformation
(Scheme 1) is based on the reductive couplings of N-
tosylhydrazones with boronic acids,[7] and involves the following
steps: 1) base promoted decomposition of the N-tosylhydrazone
A to generate diazo compound C, 2) reaction of the diazo
compound with the alkenylboronic acid, that forms an
intermediate allylboronic acid D, 3) intramolecular carboborylation
of the cyano group to give intermediate N-boroimine E, 4)
hydrolysis of the imine to give the final ketone B.
Very appealing approaches towards these scaffolds would be
the formation of two C-C bonds on the same carbon atom in a
single step. While these transformations are relatively frequent
when heteroatoms are involved, they are really challenging if an
[a]
M. Plaza, S. Parisotto, Prof. Dr. Carlos Valdés*
Departamento de Química Orgánica e Inorgánica and Instituto
Universitario de Química Organometálica “Enrique Moles”.
Universidad de Oviedo.
c/ Julián Clavería 8. Oviedo 33006. Spain.
E-mail: acvg@uniovi.es
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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Results and Discussion
Transannular cyclizations for the synthesis of 1-aza[a.b.c] bicyclic
structures II
In order to expand the applicability of the domino cyclization into
heterocyclic systems, we chose the N-tosylhydrazone 1a, bearing
a cyanomethyl moiety attached to the nitrogen atom, as the
platform to explore the construction of 1-aza[2.2.2]bicycles of type
II through the transannular cyclization sketched in Figure 1.
The initial reactions between tosylhydrazone 1a and
alkenylboronic acids 2, carried out under the standard conditions
for boronic couplings with tosylhydrazones[7] (K2CO3, 1,4-dioxane,
120 ºC, MW), led to the recovery of the starting tosylhydrazone 1.
However, the addition of a small amount of DMF increased the
solubility of the highly polar N-tosylhydrazone salt allowing the
reaction to proceed (Scheme 2). Under these conditions, the final
quinuclidinones 3 were obtained in yields ranging from moderate
to good through the planned transannular cyclization for a variety
of alkyl substituted alkenylboronic acids (Scheme 2). Particularly
attractive is compound 3a, featuring a methoxy substituent that
might allow for further derivatization of the side chain. From a
synthetic point of view, this cascade reaction represents an
unprecedented method to build the important 3-quinuclidinone
core[10] by formation of two Csp3-Csp2 bonds (ring forming bond
and side chain incorporation) on the hydrazonic carbon atom.
Moreover, cyanomethylated 3-pyrrolidinone 1b and 4-azepanone
1c led also to the 1-aza[2.2.1] and [2.2.3] bicycles 4 and 5
respectively, increasing the versatility of the transformation.
Scheme 1. Synthesis of fused bicyclic structures of type I by reaction of - and
-cyano-N-tosylhydrazones and alkenylboronic acids and mechanism proposed.
In our previous publication, we have already shown the versatility
of the reaction on carbocyclization processes, allowing for the
synthesis of an ample variety of fused bicyclic structures of type I
with very high diastereoselectivity (Figure 2). Importantly, the
reaction could be even applied for the modification of steroids
through a completely new and original approach.
Figure 2. Fused cyclic structures synthesized through the domino cyclization
Based on this work, we considered that this new mode of
reactivity may hold greater synthetic potential, as it could be
applied for the construction of different classes of complex
polycyclic structures featuring bridgehead quaternary centers by
designing appropriate domino cyclizations.[9] Herein we wish to
report our advances in this regard, that have led lead to
development of synthetic methods for the structural motifs II and
III through the innovative retrosynthetic disconnections
represented in Figure 1. Additionally, mechanistic insights on
these domino cyclizations are provided based on DFT-based
calculations, which may help on the design and development of
new cyclizations based on the same principle.
Scheme 2. Synthesis of quinuclidinones and related systems by transannular
domino cyclization of heterocyclic N-tosylhydrazones and alkenylboronic acids.
Reaction conditions for the domino cyclization: Tosylhydrazone 1 (0.3 mMol),
boronic acid 2 (0.6 mMol), K2CO3 (0.6 mMol), 1,4-dioxane (2.4 mL), MW (120
ºC).
The stereoselectivity of the transannular cyclization was explored
in the reaction with the -allyl-N-tosylhydrazone 6. The presence
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of the substituent at the -position was compatible with the
reaction conditions, as the quinuclidinones 7 were isolated with
moderate yields and with high but no total stereoselectivity (7:1 to
4.5:1 mixtures of isomers) (Scheme 3). As expected,[7f] the major
isomer 7 corresponded to the incorporation of the alkenylboronic
acid in a trans arrangement relative to the allyl substituent, which
is determined in the first step of the cascade reaction. Thus, an all
carbon bridgehead quaternary stereocenter is formed
stereoselectively in this domino reaction.
Thus, in both cases, the protodeboronation of the intermediate
boronic acid is favoured towards the transannular cyclization.
Finally, the reaction with iso-butylboronic acid, led to a complex
reaction mixture, with no cyclization product being detected.
The chemoselectivity of the cyclization was explored in the
reaction with N-tosylhydrazone 12, which features two different
electrophilic positions susceptible to the attack of the allylboronic
acid intermediate. Only the benzofused bicycle 13 was isolated,
therefore, the transannular cyclization is outcompeted by the
cyclization over the cyanide in the side chain (Scheme 5, b).[8]
A
justification for the chemoselectivity of this cyclization reaction by
means of DFT computational modeling is discussed below and in
the supporting information.
Scheme 3. Stereoselectivity on the synthesis of quinuclidinones 7. Reaction
conditions as in Scheme 2. Diastereomeric ratios determined by 1H NMR.
Then, we turned our attention to N-cyanomethylated tropinone,
readily available from commercial tropinone, as starting material.
Thus, treatment of tosylhydrazone 8 with the alkenylboronic acids
2 led to the tricyclic aminoketones 9 with moderate yields. It is
noteworthy the high structural complexity achieved from readily
available starting materials and through a very simple reaction,
which only requires the presence of the coupling reagents and
K2CO3 as a base (Scheme 4).
Scheme 5. (a) Limitations of the transannular cyclization. (b) Chemoselectivity
in the cascade cyclization.
Mechanistic considerations: These results show that the domino
cyclization takes place only when alkenylboronic acids are
employed. Considering the mechanism proposed for the
reactions of N-tosylhydrazones with boronic acids,[7] it suggests
that the formation of an intermediate allylboronic acid is a
requirement for the cyclization reaction to occur.[11] To explain the
observed facts and get further understanding on the mechanism
of the reaction, DFT-based computational studies were
conducted.[12,13] We focused on the cyclization to afford the
quinuclidone nucleus. Thus, we considered as the first step the
formation of the allylboronic acid G, by the reaction of the diazo
compound F generated from the N-tosylhydrazone, with the
alkenylboronic acid.[7f,14] Afterwards, two possible cyclization
pathways from G were found: Pathway a: direct cyclization to give
H. Pathway b: stepwise reaction involving a 1,3-borotropic
rearrangement[15] to give the new allylboronic acid J, followed by
cyclization through the allylboration of the cyano group that
furnishes H. A summary of the results of the computational study
is presented in Scheme 6.
Scheme 4. Synthesis of quinuclidinones and related systems by transannular
domino cyclization of heterocyclic N-tosylhydrazones and alkenylboronic acids.
The limitations of the transannular cyclization must be
indicated. When the reaction was attempted with arylboronic
acids, no cyclization was observed, and the piperidine 10 derived
from the reductive alkenylation was obtained (Scheme 5, a).[7a,d]
Similarly, the reaction with styrylboronic acid led to the reductive
alkenylation product 11, with no cyclization product being
detected. This latter result is not surprising, as we have previously
reported the different behavior of alkyl and aryl substituted
alkenylboronic acids in the reactions with N-tosylhydrazones.[7e]
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b)
Scheme 6. a) Calculated pathways for the domino cyclization. b) Three-dimensional models for the different transition states located. The calculations were carried
out at the M06-2X/6-311++G**(PCM, 1,4-dioxane) level. The relative Gibbs free energies are given in kcal·mol-1. The three-dimensional structures of the transition
states have been rendered with Cylview.[16]
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The stationary points for both cyclization pathways were
characterized. Pathway
a
involves i) chair/twist-boat
isomerization (G to G’), ii) the -attack of the alkenylboronic acid
to the nitrile carbon atom through the transition state TS(G’-H).
This step featured an unreachable very high energy barrier of 62.2
kcal·mol-1, and therefore it was discarded.[17] Pathway b consists
on: i) 1,3-borotropic rearrangement to give allylboronic acid J, ii)
chair to twist-boat isomerization to J’ and iii) intramolecular
allylborylation of the cyano group through the six-centered cyclic
transition state TS(J’-H). The transition state for the 1,3-
borotropic rearrangement TS(G-J) featured the highest energy of
this reaction profile, and therefore could be considered the rate
determining step for the cyclization reaction. The activation barrier
for this step (Gact = 37.3 kcal·mol-1) is very high, and this might
explain why these reactions proceed only at 120 ºC and under
microwave irradiation. Then, after the J to J’ interconversion, J’
undergoes cyclization to form H through the concerted transition
state TS(J’-H) that could be seen as a bora-aza-ene reaction. An
activation free energy of 29.0 kcal·mol-1 was obtained for the
intramolecular allylboration step. Thus, the calculations point to
the stepwise pathway b as the more likely reaction mechanism.
Additionally, the requirement of a cyclic six-centered transition
state explains nicely why the cyclization is observed exclusively
with alkenylboronic acids, and not observed for the reactions with
arylboronic acids.
The cyclization through the six-centered transition state was
also studied for the allylboronic acid derived from N-
tosylhydrazone 12 to account for the regioselectivity observed
(Scheme 5, b). Assuming the 1,3-borotropic rearrangement step,
the allylboronic acid intermediate K could evolve through the
carboborylations of either of the cyano groups to boroimines M or
L
through the transition states TS(K’-M) and TS(K’’-L)
respectively (Scheme 7). The calculations are in agreement with
the experimental observations, and indicate that the formation of
the fused bicycle L is clearly favoured over the product of the
transannular cyclization. Thus, the combination of theoretical and
experimental results give further support to the proposed
concerted bora-aza-ene mechanism.
It must be pointed the novelty of this cyclization mode: while
the allylborations of carbonyl compounds and imines are very well
known reactions,[18] there are very few examples of the analogous
reaction with nitriles, and to the best of our knowledge, no
intramolecular process had been previously reported.[19,20]
The reaction mechanism described above prompted us to
consider other possible combinations that would generate an
intermediate allylboronic acid able to participate in a bora-aza-ene
reaction. We envisioned that the coupling of N-tosylhydrazones
derived from -unsaturated ketones with alkylboronic acids
featuring a cyano substituent in the proper position might meet
those requirements (Figure 3). Such a reaction would represent a
conceptually new [n+1] cyclization under extremely simple
reaction conditions.
TS(K’’-L)
Scheme 7. a) Representation of the DFT-calculated pathways that establish the
preference of the fused towards the transannular cyclization in compound 12.
b) Three-dimensional model for the transition state TS(K’’-L). The calculations
were carried out at the M06-2X/6-311++G**(PCM, 1,4-dioxane) level. The
relative Gibbs free energies are given in kcal·mol-1. The three-dimensional
structures of the transition states have been rendered with Cylview.[16]
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These reaction conditions were applied to a set of N-
tosylhydrazones
14
derived
from
4,4,-disubstituted
cyclohexenones (Scheme 9). The cascade processes occurred
successfully for the formation of the spirocyclic ketones 16 upon
construction of a new five-membered ring in the reactions with (3-
cyanopropyl)boronic acid 15a, and to the spirocyclic ketones 18
featuring a new six-membered ring upon the employment of (4-
cyanobutyl)boronic acid 13b. Additionally, the cyclization
proceeded successfully also with the cyclohepten-2-one N-
tosylhydrazone 19, giving rise to spiro[4.6]undec-6-en-1-one 20a
and spiro[5.6]dodec-7-en-1-one 20b respectively (Scheme 9).
These new spirocyclic scaffolds are very promising synthetic
intermediates, as they present two points for orthogonal
diversification, the carbonyl group and the unsaturation.
Figure 3. Proposal for a [n+1] cascade cyclization with -unsaturated N-
tosylhydrazones and cyanoalkylboronic acids.
The initial experiments were conducted with the N-
tosylhydrazone of 4,4,-dimethylcyclohexenone 14a and (3-
cyanopropyl)boronic acid 15a, and led to a mixture of the
expected spirocyclic ketone 16a and the alkene derived from the
protodeboronation of the intermediate allylboronic acid 17
(scheme 8). Then, we tried the introduction of a Lewis acid with
the idea of enhancing the electrophilicity of the nitrile group.
Delightfully, when ZnCl2 (0.1 M in 1,4-dioxane solution) was
introduced, the formation of the protodeboronation product 17
was totally avoided and the spirocyclic ketone 16a was
exclusively obtained (Scheme 8). At this point the role of the ZnCl2
is not clear,[21] but it should be pointed that it enhances the
selectivity of the reaction, but is not essential for the cyclization to
occur. Thus, an unprecedented [4+1] spirocyclization has
occurred by formation of both a Csp3-Csp3 and a Csp3-Csp2
bonds on the hydrazonic carbon atom.
Scheme 9. Synthesis of spirocyclic ketones 16, 18, 20 and 22 through the [4+1]
and [5+1] cyclizations. Reaction conditions for the domino spirocyclization: N-
Tosylhydrazone 14, 19 (0.15 mMol), boronic acid 15 (0.3 mMol), K2CO3 (0.3
mMol), 1,4-dioxane (1.2 mL), ZnCl2 (0.1 M in 1,4-dioxane ,100 L), MW (120 ̊C),
4h.
To test the applicability of the spirocyclization to more
challenging substrates, we focused on trisubstituted -
unsaturated ketones. We found the venerable Hajos-Parrish
ketone[22] a very appealing platform, which might also allow to
study the diastereoselectivity of the reaction. Thus, the N-
tosylhydrazone 21, easily accessible from the Hajos-Parrish
ketone,[23] was examined in the domino spirocyclization.[24] After
some experimentation we found that the reactions with (4-
Scheme 8. Initial experiments on spirocyclization reactions between -
unsaturated N-tosylhydrazone 14a and (3-cyanopropyl)boronic acid 15a .
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cyanoalkyl)boronic acids 15a and 15b proceeded successfully to
give the spirocyclic ketones 22a and 22b respectively, and
importantly, as a single stereoisomers (Scheme 9).[25] These are
remarkable results, as the all-carbon quaternary stereocenters
have been created in a diastereoselective manner on the optically
pure material.
commercial 0.1 M solution of ZnCl2 in dioxane. The vial was
sealed with a septum, placed into the microwave cavity and
irradiated to maintain the reaction at the desired temperature (120
ºC) during the reaction time (4 h) in a Biotage Initiator microwave
apparatus. When the reaction finished, it was allowed to reach
room temperature, solvents were eliminated and a saturated
solution of NaHCO3 (10 mL) and dichloromethane (5 mL) were
added and the layers were separated. The aqueous phase was
extracted three times with dichloromethane. The combined
organic layers were washed with NaHCO3, brine, dried over
Na2SO4 and filtered. Solvent was removed under reduced
pressure. Finally, the products were purified by flash
chromatography on silica gel.
Conclussions
As summary, we have presented herein new heterocyclization
and spirocyclization reactions based on the coupling between N-
tosylhydrazones and boronic acids. The key of the domino
cyclizations, as established by experiments and computational
calculations, is the generation of an allylboronic acid intermediate
that can undergo an intramolecular allylboration with a cyano
group in a proper position through a bora-aza-ene reaction.
Unprecedented functionalized alkaloid-like nitrogenated bicyclic
structures featuring an all-carbon quaternary center can be
constructed through this method. Additionally, a conceptually new
[4+1] cascade spirocyclization reaction has been devised, which
furnishes functionalized spirocycles, and that has been applied to
the modification cyclohexenones, including the stereoselective
spirocyclization of the Hajos-Parrish ketone. Undoubtfully, these
new domino “diazo compound carboborylation / borotropic
rearrangement / intramolecular allylborylation” reactions hold
great potential in synthetic organic chemistry, and new
applications will be reported in due course.
Acknowledgements
Financial support of this work by Ministerio de Economía y
Competitividad (MINECO) of Spain: Grant CTQ2016-76794-P
(AEI/FEDER, UE). A FPU predoctoral fellowship (MECD) to MP
and an Erasmus+ Traineeship (EU) to SP are gratefully
acknowledged. We wish to thank Dr. Isabel Merino for her
assistance on the NMR stereochemical studies.
Keywords: Boronic acids · N-tosylhydrazones · spiro
compounds · domino reactions · diazo compounds.
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General procedure for the reaction of N-tosylhydrazones
with alkenylboronic acids under microwave irradiation to
form compounds 3, 4, 5, 9, 10, 11 and 13
[3]
[4]
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A microwave vial provided with a triangular stir bar was charged
with the corresponding tosylhydrazone (0.15 mmol), the alkenyl
boronic acid (0.30 mmol), K2CO3 (41.4 mg, 0.30 mmol) in 1.2 mL
of dry 1,4-dioxane and 200 µL of dry DMF. The vial was sealed
with a septum, placed into the microwave cavity and irradiated to
maintain the reaction at the desired temperature (120 ºC) during
the reaction time (4 h) in a Biotage Initiator microwave apparatus.
When the reaction finished, it was allowed to reach room
temperature, solvents were eliminated and a saturated solution of
NaHCO3 (10 mL) and dichloromethane (5 mL) were added and
the layers were separated. The aqueous phase was extracted
three times with dichloromethane. The combined organic layers
were washed with NaHCO3, brine, dried over Na2SO4 and filtered.
Solvent was removed under reduced pressure. Finally, the
products were purified by flash chromatography on silica gel.
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General procedure for the spirocyclization reaction of N-
tosylhydrazones with alkylboronic acids under microwave
irradiation to form compounds 16, 18, 20 and 22
[6]
Selected examples of metal catalyzed cascade spirocyclizations by
formation of two bonds on the same C atom: a) R. Barroso, M.-P. Cabal,
R. Badia-Laino, C. Valdés, Chem. - Eur. J. 2015, 21, 16463. b) L. Bai, Y.
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A microwave vial provided with a triangular stir bar was charged
with the corresponding tosylhydrazone (0.15 mmol), the
alkylboronic acid (0.30 mmol), K2CO3 (41.4 mg, 0.30 mmol) in 1.2
mL of dry 1,4-dioxane. To this vial was also added 100 µL of a
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[12] See Suporting Information for computational details and a further
discussion.
[25] The stereochemistry of compounds 22a and 22b was assigned through
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10.1002/chem.201803309
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Two bonds on the same carbon are
formed in transannular cyclizations
and [n+1] spirocyclizations involving
properly designed N-tosylhydrazones
and boronic acids, that lead to
polycyclic structures featuring an all-
carbon quaternary bridgehead center.
The proposed mechanism for the
domino processes involves
Manuel Plaza, Stefano Parisotto and
Carlos Valdés*
Page No. – Page No.
Heterocyclization and
spirocyclization processes based on
domino reactions of N-
tosylhydrazones and boronic acids
involving intramolecular
allylborylations of nitriles
carboborylation of a diazo compound
a 1,3-borotropic rearrangement, and
intramolecular bora-aza-ene reaction.
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