Palladium Catalyzed Synthetic Transformations of Diazabicyclic olefins
using Catechols
1. Introduction
Palladium has become the most versatile transition metal in metal-catalyzed reactions,
particularly those involving carbon-carbon bond formation.1Their real synthetic utility lies
in the wide range of organic transformations promoted by these catalysts, and in the
specificity and functional group tolerance shown in most of these processes. They permit
unconventional transformations and therefore give a wide range of starting materials for the
synthetic chemist to use.
Palladium has two stable oxidation states, a + 2 and a zerovalent state, each with its
own chemistry. Palladium (II) complexes are electrophilic and tend to react with electron
rich organic molecules, particularly arenes and alkenes. Palladium (II) catalysts are used in
both catalytic and stoichiometric quantities.
Palladium (0) complexes are strong nucleophiles and strong bases. These catalysts are
most commonly used to promote reactions involving acetates, halides and triflates, and
are used only in catalytic quantities.
The diazabicyclic alkene 3 is easily accessible by the Diels-Alder reaction of
cyclopentadiene 1 with dialkyl azodicarboxylate 2 (Scheme 1.1).2 Even though symmetrical,
bi- and polycyclic hydrazines have been known for a long time, there are only few reports on
their desymmetrization as well as ring opening.
Scheme 1.1
These azabicyclic alkenes exhibit diverse reactivity patterns due to the presence of
following characteristics (Figure 1). (1) The strained double bond of this diaza analogue of
norbornene should be very reactive towards electrophiles. (2) Ring fragmentations, via
nitrogen-nitrogen bond reduction, carbon-carbon oxidative cleavage, ring-opening metathesis
or allylic carbon-nitrogen cleavage are also expected to be thermodynamically favourable (3)
Skeletal rearrangements involving carbocationic intermediates, typically observed in the
norbornene series, could also be observed with this cycloadducts.3
Allylic Fragmentation
Electrophilic additions
C-C bond cleavage
N
E
N-N bond cleavage
N
E
C-N bond cleavage
Figure 1 General reactivity pattern of meso bicyclic hydrazines
The combination of all these transformations should provide a useful synthetic arsenal
for
a
large-scale
elaboration
of
various
functionalized
amino-,
diamino-
or
hydrazinocyclopentanes, potentially valuable scaffolds for target- or diversity-oriented
synthesis of biologically active compounds. This report focuses on the palladium and
catalyzed synthetic transformations of bicyclic hydrazines designed for the synthesis of
carbocycles and heterocycles.
Hydroarylation Reactions
The chemistry of bicyclic hydrazines gained much attention after Kaufmann’s report on
the hydroarylation reactions. The reductive arylation of bicyclic alkenes using palladium
catalysts have been well studied, but there were no reports on the hydroarylation of 2,3diazabicyclic alkenes. Kaufmann et al. have carried out coupling reactions on the 2,3diazabicyclo[2.2.1]hept-5-enes 3a with different organic halides. Its reaction with aryl or βstyryl halides in the presence of an in situ generated palladium catalyst afforded exclusively
the exo-configurated hydroarylation and hydrovinylation products in good yields. They
observed the formation of very small amount of a side product, which was formed by the NN bond cleavage (Scheme 1.2).4
Scheme 1.2
The reductive cleavage of N-N bond of the hydroarylated product 7 with lithium in
liquid ammonia afforded the synthetically interesting cis-1,3-diaminocyclopentane derivative
8 (Scheme 1.3).
Scheme 1.3
They also reported the palladium catalyzed domino coupling of aryl halide 4 and
phenylacetylene 9 onto the bicyclic alkene 3a which resulted in the formation of a bis
coupled product 10.5 In this case, they did not observe the formation of the ring opened
product (Scheme 1.4).
Scheme 1.4
Later reports from the same group have shown that sterically more hindered and more
rigid
tri- and tetracyclic substrates affords the hydroarylated products along with 3,4-
disubstituted cyclopentenes as minor product 14, the latter being formed via the C-N bond
cleavage (Scheme 1.5).4
Scheme 1.5
Under the optimized conditions the ring opened product 14 was obtained in 46% yield
(NaF/DMSO/65 0C). It is interesting to note that under the same set of reaction conditions,
the bicyclic substrates 3 afforded 3,5-disubstituted cyclopentenes while the tri- and tetracyclic
substrates gave 3,4-disubstituted cyclopentenes along with the hydroarylated products. This
was the first report on the formation of 3,4-disubstituted cyclopentenes from tri- and
tetracyclic hydrazines. In the case of tricyclic substrate, the low yields of the products were
explained on the basis of the low stability of the starting material under basic conditions.
Attempts to increase the yield of both products by changing the solvent and base used were
not very much successful.
Rearrangements Involving Allylic Cations
The thermal and/or acid catalyzed fragmentation of bicyclic hydrazines has been
intensively investigated.6 A [3,3]-sigmatropic rearrangement has been proposed to explain the
stereoselective formation of compound 17 from the corresponding bicyclic hydrazine
(Scheme 1.6). The bicyclic hydrazine 3 do not rearrange under similar thermal conditions.
This transformation is also dramatically accelerated by acids.6d The preference for a
concerted pathway instead of a two-step process has been assessed by kinetic studies.6a
Scheme 1.6
Micouin et al. explored the acid catalyzed ring opening of N,N-benzyloxy-2,3diazabicyclo[2.2.1]heptanes, as the ring opening of these substrates by cleavage of the C-N
bond has only been scarcely investigated and has not been exploited for synthetic purposes.
To evaluate the fragmentation ability of bicyclic hydrazine 3d, they investigated its acid
catalyzed rearrangement to carbazate 19 (Scheme 1.7).7
Scheme 1.7
The structure of the rearranged product 19 have recently been reassigned by Lautens and
co-workers with the help of X-ray crystallography to be the [5.5]bicyclic systems 20.8 This
correct structural assignment rules out a concerted [3,3]-sigmatropic pathway for this
transformation which can be conducted on a large scale using sulfuric acid in trifluoroethanol
(Scheme 1.8).
Scheme 1.8
Reactions with Organotin Reagents
The pioneering report on the ring opening of bicyclic hydrazines with organotin
reagents, came from our group in 2005.9 The studies commenced with an attempt to carry out
a domino Heck-Stille coupling10 on 2,3-diazabicyclo[2.2.1]hept-5-ene 3a with aryl iodide 21
and organostannanes 22. Contrary to our expectation of a bis-coupled product, the reaction
afforded allylated hydrazinocyclopentene 24 in 48% yields. The reaction is outlined in
scheme 1.9.
Scheme 1.9
The role of iodine as promoter, facilitating the formation of the ring opened product was
proved by carrying out the reaction with catalytic amount of molecular iodine instead of aryl
iodide. Other Lewis acids were also found to promote this transformation, scandium triflate
giving the better results (Scheme 1.10).
Scheme 1.10
Our efforts in this area proved that this methodology can be used for introducing variety
of substituents to the cyclopentenic core. Thus we were successful in the desymmetrization of
meso bicyclic hydrazines using vinyl, phenyl, furyl and thienyl stannanes. It was interesting
to note that both bi and tricyclic hydrazines gave similar type of products under the same
reaction conditions (Scheme 1.11).11
Scheme 1.11
The possibility of introducing heteroatom substituents in the cyclopentenic core
inspired us to evaluate the reactivity of azidostannane 31 with bicyclic hydrazines. As
expected the reaction afforded 3-azido-4-hydrazinocyclopentene 32 in excellent yield
(Scheme 1.12).12 It is noteworthy that these compounds show remarkable similarity towards
vicinal diamines and hence can be used for the synthesis of bisarmed receptors and chiral
auxiliaries.
Scheme 1.12
Palladium mediated synthesis of cyclopenetene annulated benzofuran by the reaction of
azabicyclic olefins with 2-Iodophenol:
There are so many reports on palladium catalyzed annulations of different ofunctionalized aryl halides with unsaturated substrates.13,14 In 1998, Catellani M. reported the
formation of norbornane annulated benzofuran by the palladium catalyzed reaction of
iodophenol with norbornene.15 But the reactivity of these bicentered nucleophiles with
heterobicyclic substrates have not been studied at all. The reactivity of azabicyclic alkenes,
have been extensively investigated with monocentered nucleophiles.16,17 These investigations
resulted in the formation of either 3,4- or 3,5-disubstituted cyclopentenes. The easy
availability and well documented reactivity of various o-functionalized aryl halides prompted
us to investigate the reactivity of these bicentered nucleophiles towards azabicyclic olefins
under palladium catalysis (Scheme 1.13).
Scheme 1.13
Palladium catalyzed annulation of azabicyclic olefin with 2 - iodobenzonitrile:
As a continuation of our interest in the metal catalyzed annulation process, we examined
the reactivity of o- functionalized aryl halides like o-iodobenzonitrile with the diazabicyclic
olefin. This reaction resulted in the formation of highly functionalized indanones (Scheme
1.14).
Scheme 1.14
Rhodium catalyzed reaction of azabicyclic olefin with ortho-functionalized
phenylboronic acid:
Rhodium catalyzed annulations using ortho functionalized phenyl boronic acids and
unsaturated compounds provide a versatile route to the construction of complex cyclic
systems. Murakami and co-workers reported the rhodium catalysed annulation reactions of 2formylphenylboronic acid and 2-cyanophenylboronic acid with alkynes and strained
alkenes.18,19 This prompted us to carry out the reaction of these ortho functionalized boronic
acids with heterobicyclic olefin under rhodium catalysis. These reactions afforded highly
functionalized indanone as the product (Scheme 1.15).
Scheme 1.15
2. Results and Discussion
Synthesis of Azabicyclic Olefins
The azabicyclic olefins required for our investigations were prepared as per the literature
procedures. 2,3-Diazabicyclo[2.2.1]hept-5-enes 3(a-d) required for our studies were
synthesized by the Diels-Alder cycloaddition of cyclopentadiene with azodicarboxylate 2(ad) .
Scheme 2.1
Palladium catalyzed organic transformations of catechol and resorcinol
Substituted cyclopentenes are valuable synthetic intermediates in synthesis of bio
logically interestining molecules.20 Micouin and co-workers reported the stereo selective ring
opening of meso bicyclic hydrazines by phenol.21 The cleavage of fulvene-derived bicyclic
alkenes with phenol was reported from our group.22Apart from the above mentioned reports
there are not much efforts to check the reactivity of catechol and resorcinol with bicyclic
alkenes. Here we describe the ring opening reactions of bicyclic alkenes using catechol and
resorcinol, leading to the formation of substituted cyclopentenes with phenolic hydroxyl
group which will be an intermediate for the synthesis of cyclopentene appended
benzoquinones.
In an initial attempt, the bicyclic alkene, 3a was treated with catechol 38 in the
presence of Pd2(dba)3CHCl3, BINAP and K2CO3 in THF at room temperature. The reaction
afforded the product 39 in 10% yield (Scheme 2.2).
Scheme 2.2
The IR spectrum of the compound 39 showed the characteristic ester carbonyl absorption at
1705 cm-1. In the 1H NMR spectrum, peaks in the region δ 6.88-6.78 ppm were assigned to
the aromatic protons. -NH and –OH protons resonated in the region δ 6.40 and δ 5.88
respectively. The peak at δ 5.32 ppm corresponds to the proton on the carbon attached to the
oxygen. The proton on the carbon bearing the hydrazine moiety resonated in the region δ 5.32
– 5.21 ppm. The methylene protons of the cyclopentene ring appeared as two separate peaks
at δ 2.76-2.70 and 2.17 ppm. In the 13C NMR spectrum ester carbonyl carbons resonated at δ
156.8 and 155.64 ppm. The carbon attached to oxygen resonated at δ 81.44 ppm. All other
signals in
13
C NMR spectra were in agreement with the proposed structure. The structure
assigned was further confirmed by low resolution mass spectral analysis which showed a
molecular ion peak at m/z =373.73.
Fig: 1H NMR of compound 39
Fig: 1H NMR of compound 39 in D2O
Fig: 13C NMR of compound 39
Optimization Studies
Detailed optimization studies were carried out to find out the best condition for this
transformation. Poor result was obtained when THF was used as solvent. The yield of the
reaction was increased when LiCl was used as additive. The reaction did not work in other
catalysts like [Pd(allyl)Cl]2 and PdCl2. Prolonged reaction time decreased the yield. The best
result was obtained with the catalyst system Pd2(dba)3CHCl3, PPh3 and K2CO3 in toluene at
60 0C. The optimization studies are summarized in the following table.
Table 1. Optimization Studies
N CO Et
2
N
CO2Et
Entry
Catalyst
OH
Catalyst
Ligand,Additive
OH
Solvent,600C
Ligand
Additive
O
OH
Base
Solvent
HN CO2Et
N
CO2Et
Yield %
1
Pd2(dba)3CHCl3
BINAP
K2CO3
Toluene
10
2
Pd2(dba)3CHCl3
PPh3
K2CO3
Toluene
66
3
Pd2(dba)3CHCl3
PPh3
K2CO3
Toluene
81
4
Pd2(dba)3CHCl3
dppf
K2CO3
Toluene
43
5
[Pd(allyl)Cl]2
PPh3
LiCl
K2CO3
Toluene
No Reaction
6
PdCl2
PPh3
LiCl
K2CO3
Toluene
No Reaction
7
Pd2(dba)3CHCl3
LiCl
K2CO3
Toluene
No reaction
8
Pd2(dba)3CHCl3
PPh3
LiCl
K2CO3
THF
9
Pd2(dba)3CHCl3
PPh3
LiCl
K2CO3
MeCN
10
Pd2(dba)3CHCl3
Ba2CO3
MeCN
LiCl
Bu4NCl
Trace
71
No reaction
Reaction Conditions: alkene (1.0 equiv.), nucleophile (1.0 equiv.), catalyst
(5 mol %), base (1.0 equiv.), ligand (10 mol%), solvent (2 ml), 60 °C, 24 hr.
Generality of the methodology was proved by carrying out the reactions of different
bicyclic alkenes with resorcinol and substituted catechols under optimized condition. The
results are summarized in Table 2.
Table 2. Palladium catalyzed coupling of catechol and resorcinol with azabicyclic alkene
Reaction Conditions: alkene (1.0 equiv.), nucleophile (1.0 equiv.), catalyst (5 mol %),
base (1.0 equiv.), ligand ( 10 mol%), solvent (2 mL), 60 °C, 24 h.
Mechanistic Rationale
A plausible mechanism is illustrated for the reaction of catechol and resorcinol with bicyclic
alkenes involves two stages, the initial being the ring opening of bicyclic alkene. The first
step of catalytic cycle involves the formation of π–allyl palladium intermediate B by the
attack of Pd(O) the coordination of the phenolic oxygen atom to Pd(0) on the double bond
(allylic species), and subsequent oxidative addition to C-N bond leading to the ring opening.
In the second stage, the nucleophile attacks the π –allylpalladium species B there by forming
the intermediate C.
Proposed mechanism of the reaction
3. Conclusion
In summary, we have unraveled a facile method towards the synthesis of a new class
of disubstituted cyclopentenes with potent phenolic hydroxyl group. The widespread
occurrence and interesting biological activities of substituted cyclopentane derivatives in
nature make them important targets for synthesis.23 The product can also act as useful
intermediates in the modulation of heterocyclic substituents by multicomponent hydrazine–
based chemistry.
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