Domino inverse electron-demand Diels-Alder/cyclopropanation reaction of diazines catalyzed by a bidentate lewis acid

Article abstract of DOI:10.1021/ja308858y

A domino inverse electron-demand Diels-Alder (IEDDA)/cyclopropanation reaction of diazines was discovered by applying electron-rich furans in the bidentate Lewis acid catalyzed IEDDA reaction. This process produces benzonorcaradienes in excellent yields with a low loading of a bidentate Lewis acid catalyst of 2 to 5 mol %. We demonstrate the broad applicability by 20 examples with different dienophiles and a variety of dienes. A detailed mechanism is proposed supported by DFT calculations.

Full text of DOI:10.1021/ja308858y

Communication
pubs.acs.org/JACS
Domino Inverse Electron-Demand Diels−Alder/Cyclopropanation
Reaction of Diazines Catalyzed by a Bidentate Lewis Acid
Simon N. Kessler, Markus Neuburger, and Hermann A. Wegner*
Department of Chemistry, University of Basel, St. Johanns-Ring 19, Basel 4056, Switzerland
S
* Supporting Information
Scheme 1. Reaction Path of the Catalyzed Domino IEDDA/
Cyclopropanation Reaction of an Electron-Rich Furan and a
Diazine
ABSTRACT: A domino inverse electron-demand Diels−
Alder (IEDDA)/cyclopropanation reaction of diazines was
discovered by applying electron-rich furans in the
bidentate Lewis acid catalyzed IEDDA reaction. This
process produces benzonorcaradienes in excellent yields
with a low loading of a bidentate Lewis acid catalyst of 2 to
5 mol %. We demonstrate the broad applicability by 20
examples with different dienophiles and a variety of dienes.
A detailed mechanism is proposed supported by DFT
calculations.
Currently, the efficient use of resources, as well as the
minimization of waste and production costs, is more important
than ever. Therefore, an organic synthesis procedure where one
could form several bonds in one sequence would lead to a
tremendous benefit over usual stepwise procedures. Domino
reactions represent a highly potential approach to address the
above-mentioned criteria.1,2 Especially the incorporation of
Diels−Alder reactions into Domino sequencies allows quick
access to molecular complexity.3 The inverse electron-demand
Diels−Alder (IEDDA) reaction emerged in recent decades4,5 as
a powerful synthetic tool featured in the preparation of complex
molecules.6−12 In 2010 we reported the first catalytic activation
of diazines by a bidentate Lewis acid for an IEDDA reaction.13
More recently also a silver catalyzed formal IEDDA reaction of
phthalazine and siloxy alkynes was published by Rawal and co-
workers.14 Furthermore, we showed the broad application
spectrum of the IEDDA reaction of phthalazines with a variety
of dienophiles, such as enamines and dihydrofurans.15,16
During the investigations of electron-rich furans 1a in the
catalytic IEDDA reaction, we discovered a novel bidentate
Lewis acid catalyzed domino IEDDA/cyclopropanation reac-
tion (Scheme 1). The application of these dienophiles did not
yield the anticipated annellated ring system. Instead the
cycloaddition intermediate was further transformed to the
cyclopropane annellated benzonorcaradiene. In Nature the
benzonorcaradiene framework is for instance found in
salvipuberulin.17,18 Additionally, such highly functionalized
compounds containing small rings are useful building blocks
for further transformations to quickly access complex target
structures especially in the context of new drugs. Lately, two
transition metal catalyzed reactions19,20 and a Diels−Alder
reaction21,22 of a tungsten-tetra-ene complex have been
published forming benzonorcaradiene with either no or a
limited range of aromatic substituents.
We started our investigation with the reaction of phthalazine
and differently substituted oxyfurans 1a−e, to display the scope
of dienophiles in the Lewis acid catalyzed domino reaction
(Table 1). Thereby, we found that all substrates did not show
any reaction in the absence of catalyst even if heated to 160 °C
for 1 day. Both steric and electronic factors play an important
role in the reactivity of oxyfurans. The most reactive oxy-
substituent is the trimethylsilyl (TMS) moiety due to polar
effects followed by the methyl substituent, and the least
reactive, the triisopropylsilyl (TIPS) group due to steric reasons
(Table 1, entries 1−3). Oxyfuran 1a directly yielded the free
acid 3a after purification on silica gel (SiO2), while 1b and 1c
gave access to stable esters 3b and 3c.
The methyl substituent on the furan core accounts for
another positive inductive effect while also adding steric bulk,
which counteract depending on the position of the Me group.
A methyl-substituent in the 3-position as in 1d is beneficial for
the reaction allowing the reaction to proceed at lower
temperature in a shorter time compared to the unsubstituted
analog 1a (Table 1, entry 4). If the methyl substituent is placed
in position 5, it seems to sterically interfere with the reactive
site resulting in permitting the reaction with only the more
reactive dichlorophthalazine 2b (Table 1, entry 5). No reaction
was observed with less electron-deficient phthalazine 2a. This
reactivity can be explained by the steric interference of the
methyl residue in furan 1e with the Lewis acid 4 in complex 615
during the IEDDA reaction (Figure 1).
To demonstrate the scope of dienes, a variety of differently
substituted diazines and trimethylsilyloxyfuran 1a have been
employed in the Lewis acid catalyzed domino IEDDA/
Received: September 6, 2012
Published: October 16, 2012
© 2012 American Chemical Society
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Table 1. Scope of Dienophiles in the Domino IEDDA/
Cyclopropanation Reaction
Table 2. Scope of Dienes in the Domino IEDDA/
Cyclopropanation Reaction
Figure 1. Steric interaction of methyl group in 1e with Lewis acid
moiety of complex 6.
cyclopropanation reaction (Table 2). The substituted diazines
can be accessed by a one-pot synthesis from aldehydes
developed in our laboratory.23 Moreover, we used alkyllithium
chemistry to form dichloro- and difluorophthalazine 2b and 2d,
also in one pot in good yields (see Supporting Information).
Since in an IEDDA reaction an electron-deficient diene is
preferred over an electron-rich one, the reactivity of substituted
phthalazines decreases in the following order of substituents: F
> Cl > MeS > Me > MeO (Table 2). Therefore, the reaction
temperature can be lowered to 80 °C in the case of
dichlorophthalazine 2b and has to be increased to 160 °C
with a prolonged duration in the case of dimethoxyphthalazine
2h. Even pyridopyridazine 2k and benzophthalazine 2l were
reactive in this transformation. The complete desilylation of the
labile trimethylsilyl ester was accomplished by slightly acidic
eluation on silica forming the carboxylic acid.
demonstrate not only the high atom economy merely
producing N2 as a side product but also the versatility of the
procedure.
In cases of nonsymmetrical phthalazine substrates the
IEDDA/cyclopropanation reaction produces mostly re-
gioisomers of both Diels−Alder adducts in similar amounts
Furthermore, we were able to synthesize other TIPS-esters
3q−3s showing good applicability of 1c in the reaction of
electron-poor phthalazine 2b, 2c, and 2e (Table 3). The
reaction of methoxyfuran 1b with pyridopyridazine 2k gave the
methylester 3t (Table 3, entry 4). These additional examples
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by 2D-NMR as well as X-ray analysis (see Supporting
Information).
Table 3. Domino IEDDA/Cyclopropanation Reactions
Forming Isolable Esters
The intermediary formed dihydronaphthalene 8 represents
an o-quinodimethane type, which is a well-known highly
reactive intermediate.31−35 Recently, we were also able to trap
such an o-quinodimethane intermediate by an intramolecular
Diels−Alder reaction consecutive to the Lewis acid catalyzed
IEDDA reaction.16 Stable o-quinodimethanes have been
unambiguously characterized and expose a substantial double
bond with some biradical character indicated by calcula-
tions.36,37 Dihydronaphthalene 8 reacting as tetraene species
undergoes the final rearrangement to form the cyclo-
propanaphthalene 3. The same observations were made starting
from a tungsten−tetraene complex.21,22 From dihydronaph-
thalene 8 we propose the occurrence of a sigmatropic
rearrangement according to the Woodward−Hoffmann
rules.38,39 A σ-bond is moved from position 1 to 3 on one
site and from 1′ to 9′ on the other side (Scheme 3). The
Scheme 3. Proposed [3,9] Sigmatropic Rearrangement
(Tables 2 and 3). Substitution in the 5−8-position on the
phthalazine hardly influences the ratio of the regioisomers.
Mechanistic Considerations. The proposed catalytic
cycle13,15 derived from Heuschmann and co-workers24−27 starts
with the complexation of phthalazine 2 by the bidentate Lewis
acid 4 to activate the diazine for the following IEDDA reaction.
The cycloaddition of complex 6 with methoxyfuran 1b gives
intermediary complex 7. The elimination of molecular nitrogen
regenerates the Lewis acid catalyst 4, and the proposed
dihydronaphthalene intermediate 8 is formed. Intermediate 8
rearranges to endo-cyclopropane 3′, and endo-to-exo isomer-
ization28−30 leads to the final product 3b (Scheme 2).13,15 By
the nature of the IEDDA cycloaddition, the domino reaction is
diastereoselective resulting in only the exo-cyclopropane proven
simplified 3-atom and 9-atom fragments can be divided into
their topologies. On the 3-atom fragment the migration of the
σ-bond occurs on the opposite face and on the nine-membered
fragment on the same leading to an ‘allowed’ antara-suprafacial
[3,9]-sigmatropic rearrangement involving 4n (n = 3) electrons.
Alternatively, the transformation can be described by the model
according to Dewar40 and Zimmerman.41 This way one phase
dislocation occurs, representing a Mobius topology which in
̈
the case of 4n electrons describes an ‘allowed’ transition state.
The antarafacial [3,9]-sigmatropic rearrangement of furan 8
to cyclopropane 3′ is supported via DFT calculations on the
B3LYP level with a basis set of 6-31g(d,p) (Figure 2). The
transition state was located in the gas phase resulting in a free
energy of activation as low as Δ‡G°(T=298) = 11.9 kcal/mol and a
Scheme 2. Proposed Catalytic Cycle
Figure 2. Intrinsic reaction coordinates of the sigmatropic rearrange-
ment.
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(13) Kessler, S. N.; Wegner, H. A. Org. Lett. 2010, 12, 4062−4065.
high Gibbs free energy of reaction ΔrG°(T=298) = −30.3 kcal/
mol (Figure 2; −39.1 kcal/mol for the ester in trans-
conformation). The high thermodynamic driving force of the
rearrangement results from the formation of the ester
resonance and the aromatic stabilization which has been lost
in the dihydronaphthalene intermediate 8 by the elimination of
molecular nitrogen springloading the molecule and easily
accounting for the strain energy of the cyclopropane formation.
Despite the evidence for a rearrangement, an ionic mechanism
cannot be ruled out.
In conclusion, we discovered a new method to produce
cyclopropanated naphthalenes in a diastereoselective fashion by
a bidentate Lewis catalyzed domino process starting with an
IEDDA reaction proceeding with elimination of nitrogen and
concluding with an antarafacial [3,9]-sigmatropic rearrange-
ment. A wide variety of substituents are allowed on the diazine
as well as on the oxyfuran providing a very versatile entry to
substituted aromatonorcaradiene in excellent yields with a low
catalyst loading of 2−5 mol %. Further studies will address the
selectivity issue in the reaction with unsymmetrical phthala-
zines, e.g. by using diboron species with different substituents as
catalysts.
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ASSOCIATED CONTENT
* Supporting Information
■
S
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Experimental details and characterization data for 2b, 2d, and
all products 3, as well as X-ray data for 3g, 3l are available. This
material is available free of charge via the Internet at http://
pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
hermann.wegner@unibas.ch
Funding
The authors declare no competing financial interest.
Notes
The authors declare no competing financial interest.
■
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ACKNOWLEDGMENTS
Financial support by the Swiss National Science Foundation is
greatly acknowledged.
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