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Cycloadditions in aqueous mediaWijnen, Jan Willem

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107

Chapter 6

1,3-Dipolar Cycloadditions in Aqueous Solutions1

This chapter reports kinetic results describing 1,3-dipolar cycloadditions in aqueous media. On the

basis of mechanistic considerations it is expected that this type of cycloaddition should benefit from

an aqueous medium, in a manner similar to that observed for Diels-Alder reactions. Three

representatives of this class of reactions have been studied : (inter- and intramolecular) additions to

aromatic azides, nitrile oxides and nitrones. The intrinsic differences of these reactions enables

formulation of a complete description of the influence of water on Diels-Alder and 1,3-dipolar

cycloadditions. FMO theory is used to rationalise the observed solvent effects.

6.1 Introduction

Diels-Alder (DA) reactions have attained a principle position as an example of a water-promoted

organic reaction and the previous chapters have illustrated that a wide variety of these cycloadditions

benefit from an aqueous reaction medium. The aqueous DA reactions are not just a kinetic peculiarity.

Many synthetic applications are known2. Usually yields and selectivities are upgraded and some

reactions are only successful when water is used as solvent. Therefore it is worthwhile exploring the

influence of water on other organic reactions as well, because similar advantageous results may appear.

DA reactions are classified as pericyclic reactions3 and another representative of pericyclic

C

B

AR

C

B

AR2

CB

AR

+_

_+

BAR2

C

Scheme 6.1

Chapter 6

108

reactions, the Claisen rearrangement, also greatly benefits from aqueous reaction media4. Therefore it is

conceivable that a third pericyclic reaction, 1,3-dipolar cycloadditions (DC reactions), would be also

promoted in water. Some examples of DC reactions are given in Scheme 6.1. DC reactions share many

mechanistic features with DA reactions, so water could possibly accelerate these reactions. This

possibility seems even more likely when we take into account the fact that the dienophiles in DA

reactions act as dipolarophiles in 1,3-dipolar cycloadditions. Perhaps in this case water also promotes

the cycloaddition by reducing the energy of the MOs of the dipolarophile.

6.2 1,3-Dipolar Cycloadditions : Mechanism, Solvent Effects and Applications5

Addition of unsaturated compounds to 1,3-dipoles yields a five-membered (hetero) ring and is known as

1,3-dipolar cycloaddition (DC reaction) (Scheme 6.1). These cycloadditions are reversible6. The 2π-

species are known as dipolarophiles and they are the same compounds that act as dienophiles in DA

reactions. Also in the case of DC reactions both electron-rich and -poor dipolarophiles can be employed.

Dipoles are rather unusual compounds, which contain four electrons in three parallel molecular π

orbitals. These dipoles contain formally a positive charge, which is compensated by a negative charge.

However, dipoles bear a small net charge and have a surprisingly small dipole moment. Usually dipoles

are generated in situ. Dipoles are generally divided in two classes : the propargyl-allenyl type and the

allyl type (Scheme 6.2).

A synopsis of the mechanistic characteristics of DC reactions has a strong déjà-vu flavour :

practically all features are analogous to those mentioned in Chapter 1 for DA reactions. Similarly to DA

reactions, little dispute exists about the mechanism of DC reactions and the conclusions have been

reviewed5. Generally, DC reactions are concerted, nearly synchronous processes with an early transition

state. Sometimes radical or stepwise mechanisms are thought to play a role7. A strong argument in

favour of the concerted mechanism is the retention of configuration of the dipolarophile in the product8.

The negative volume of activation9 and strongly negative entropy of activation10,11 are typical for

concerted bimolecular cycloadditions. The modest Hammett ρ-values for DC reactions point to a small

change in polarity of the reacting system during the activation process5.

Many aspects of DC reactions are accounted for by Frontier Molecular Orbital (FMO)

theory12,13. This theory is summarised in Chapter 1. The reactivity of dipoles towards dipolarophiles is

determined by the energy of the MOs of the reactants. The Gibbs energy of activation is determined by

the energy gap between the two dominantly interacting HOMO and LUMO of the reactants. The energy

of the MOs of the reactants can be experimentally assessed (ionisation potentials (HOMO) or electron

affinities (LUMO)) or theoretically estimated. Houk14 has calculated the energy for MOs of a number of

1,3-Dipolar Cycloadditions in Aqueous Media

109

common DC reactants and the outcome is reasonably in accord with experimental studies. Also the

reactivity of the dipolarophiles follows approximately the same order for all DC reactions. For most DC

reactions a good correlation is observed between the ∆≠Gθ and the ionisation potential of the

dipolarophile, signifying the quantitative correlation with the MO energy13. Also the stereoselectivity

and regioselectivity is accounted for by FMO theory : reactions take place in the direction of maximal

HOMO-LUMO overlap15.

The solvent effects on DC reactions are even smaller than those for the DA reaction11,16. A

remarkable difference is the fact that many DC reactions have an inverted solvent effect i.e. the reaction

is (slightly) retarded by polar solvents. Therefore, the activated complex of DC reactions has a smaller

dipole moment than the reactants16. It has been noticed that protic solvents have an unusual effect on

DC reactions (in terms of reaction rate). The small solvent effect has been generally explained as a

logical consequence of the early transition state. Kadaba17reported the beneficial effect of either dipolar

aprotic or protic solvents (including aqueous mixtures) on a number of DC reactions, in particular when

diazo or azide compounds are used.

Similarly to DA reactions, Lewis acids can catalyse DC reactions18. However, several examples

of Lewis-acid inhibition of DC reactions are also known. For example, both yield and reaction rate of

the addition of acrylates to aromatic nitrones18 or aliphatic nitrile oxides19 decrease in the presence of

several Lewis acids. These particular DC reactions are LUMO(dipolarophile)-HOMO(dipole)

controlled and complexation of Lewis acids should promote the cycloaddition. However, dipoles are

better Lewis bases than the dipolarophiles and consequently the catalysts interact with the dipoles which

increases the MO-energy gap. Other methods that promote DC reactions include the use of ultrasound

radiation20 and biocatalysts21.

CB

A A CB

+ +_ _

CB

A CB

A

+ +__

propargyl-allenyl type

allyl type

Scheme 6.2

Chapter 6

110

6.3 Aqueous 1,3-Dipolar Cycloadditions : An Overview

Compared to Diels-Alder reactions, DC reactions in aqueous solutions have been studied far less. Again

the low solubility of the reactants plays a discouraging role, but an additional problem is the instability

of most of the compounds that can participate as a dipole in this reaction and their tendency to dimerise

(also by means of 1,3-dipolar cycloaddition). In fact, even in inert organic solvents it is common

practise to generate the reactive species in situ in the presence of an excess of dipolarophile to ensure an

efficient reaction.

In the literature several examples can be found of 1,3-dipolar cycloadditions in biphasic

aqueous/organic mixtures22. No attempts were made to elucidate in which phase the cycloaddition takes

place. Synthetically, homogeneous aqueous solutions have only been sparsely used as medium for DC

reactions. Mixed aqueous media are advantageous for a number of DC reactions17. Grigg and

coworkers23 generated ylides in the presence of strong dipolarophiles, but the use of an aqueous solution

seems to be inspired by reagent-solubility, rather than reaction rate.

In 1978, Hegarty24 demonstrated that water can play a useful role in the generation of dipoles

and simultaneously serve as reaction medium for a consecutive 1,3-dipolar cycloaddition with numerous

dipolarophiles. Nitrile oxides were generated in situ by dehydrohalogenation of hydroxamoyl chlorides,

in which case water acts as a base. The nitrile oxides readily hydrolyse in alkaline water25, but in neutral

water this hydrolysis is slow enough to enable cycloaddition of the dipole to dipolarophiles. Using ethyl

acrylate and dimethyl maleate as dipolarophiles, Hegarty24 noted no special beneficial effect of pure

water on the rate of the cycloaddition [k2(water)/k2(water-dioxane (1:1)) ≈ 1.8]. In pure water the

Hammett ρ-value of the addition of acrylonitrile to substituted benzonitrile oxides is small (+0.36),

indicating the absence of any significant charge build-up during the activation process24. This particular

study did not divulge anything ‘special’ about the aqueous reaction medium and therefore it took

another thirteen years before the next paper in this subject appeared. Shiraishi and coworkers26

announced an unusual solvent effect on the cycloaddition of 2,6-dichlorobenzonitrile oxide with 2,5-

dimethyl-p-benzoquinone in ethanol-water solutions. In organic solvents this reaction exhibits the

common insensitivity towards a change of solvents, but in an ethanol-water mixture (6:4, v:v) a

fourteen-fold increase of the rate constant relative to the rate of reaction in chloroform was observed.

Although this rate enhancement may seem rather modest, it is rather large compared to the usual solvent

effects observed in DC reactions. The authors applied UV/VIS-spectroscopic methods to gain insight

into the origins of the rate enhancement, but they could not discover a relationship between the

spectroscopic data of all compounds involved and the rate constants. Their conclusion that “other

reasons, such as cage effect of the solvent or solvophobic effect of the substrates may play a role” is

somewhat uninspired. The authors furthermore point out that the aqueous reaction medium has an


111

attractive synthetic application : the product can be easily isolated, because it precipitates during the

reaction. No recrystallisation is required and yields are higher compared to those in organic media.

Rohloff reported another elegant application of water as a medium for DC reactions27. His

method was actually a modified procedure of the previously mentioned two-phase media.

Dibromoformaldoxime is decomposed in alkaline water after which it smoothly and in high yield adds to

dipolarophiles. Again, the ease of this synthetic procedure is emphasised by the authors.

Following Grigg23, Lubineau and coworkers28 generated azomethine ylides in aqueous solutions

and studied their reactivity in detail. These dipoles add to N-ethylmaleimide but a mixture of products

from a Michael addition and DC reaction is obtained. Curiously, water promotes the Michael addition

and organic cosolvents are required to direct the reaction to the desired cycloaddition pathway.

6.4 Results and Discussion

6.4.1 Intermolecular Cycloaddition of Electron-rich Dipolarophiles to Aromatic Azides in Organic

Solvents and in Water

We have undertaken a kinetic study of the addition of phenyl azide (6.1) to norbornene (6.2) in organic

solvents. Azides are versatile and relatively stable 1,3-dipoles29. Addition of dipolarophiles yields 1,2,3-

triazolines or -triazoles, regularly followed by decomposition to aziridines or imines30. DC reactions

with azides proceed via a highly ordered transition state as revealed by a negative and large in

magnitude entropy of activation10. The cycloadditions are stereospecific and concerted, but the extent to

which both bonds are completed is not equal in the transition state as indicated by the Hammett reaction

constant of +0.84 for the addition of 6.2 to substituted phenyl azides10. On the basis of a rather limited

set of solvents, the addition of 6.1 with 6.2 was classified as very solvent insensitive10. Azides add to

both electron-poor and -rich dipolarophiles. The cycloadditions that are discussed in this section are

dominated by HOMO(dipolarophile)-LUMO(azide) interactions (See Chapter 1).

In a study of the cycloaddition in aqueous media, the nature and in particular the hydrophobicity

of the azide moiety needs to be considered carefully. The azide group is an electron-withdrawing

moiety31 with a relatively small dipole moment (dipole moment of phenyl azide = 1.55 D, less than

bromobenzene (µ = 1.70 D) and similar to aniline (µ = 1.53)). A Hansch P-parameter, a conventional

hydrophobicity scale, is not known for the azide functionality, but the limited solubility of 6.1 shows

that this compound is rather hydrophobic.

Chapter 6

112

On a synthetic scale this DC reaction proceeds smoothly in a water-ethanol (1:1 v/v) solution,

which permits the isolation of 6.3 10,32. Reaction in ethanol leads to the same exo adduct. No other

products were detected. Samples of the product were used to determine the extinction coefficient of the

triazoline. The ‘initial-rate-kinetic’ method10,33 was used to determine the second-order rate constants,

compiled in Table 6.1.

As usual for this type of reaction, a moderate response is observed to a change of solvent. This

trend is largely in accord with a previously reported limited data set10. Polar solvents appear to have a

slight rate-enhancing effect, and the observation that aprotic dipolar solvents (DMSO and DMF) are the

best organic solvents suggests that hydrogen bonding by the solvent is not favourable for this addition.

Considering the wide variety of organic solvents, acceleration of the cycloaddition in aqueous media is

spectacular and unprecedented. On going from hexane to water/1-cyclohexyl-2-pyrrolidinone (NCHP)

(99 : 1) the rate constant increases by a factor of 53. The extent of this aqueous rate enhancement is in

the range observed for the aqueous DA reaction. For the aqueous solutions, alkaline water (pH 12) was

used, in order to prevent the rearrangement of the product30, which hampers the kinetic experiments.

Since norbornene is insoluble in pure water the cycloaddition could not be studied in this solvent.

Another analogy with the aqueous DA reactions is the cosolvent effect. Initial addition of water

Table 6.1 Second-order Rate Constants for the Intermolecular 1,3-Dipolar Cycloaddition of 6.1 with6.2 at 40.3°C in Organic Solvents and in Water

Solvent k2 / 10-5 M-1 s-1 Solvent k2 / 10

-5 M-1 s-1

n-Hexane 4.7 EtOH 7.4THF 5.3 2-PrOH 8.2CHCl3 6.8 t-BuOH 8.0CCl4 5.5 H2O/MeOH (XW = 0.75)b 35CH3CN 7.7 H2O/EtOH (XW = 0.75)b 37DMSO 17.5 H2O/2-PrOH (XW = 0.92)b 83DMF 11.3 H2O/t-BuOH (XW = 0.94)b 72MeOH 7.3 H2O/NCHP

a (XW = 0.99)b 250a NCHP : 1-Cyclohexyl-2-pyrrolidinone. b XW = mole fraction of water.

N N N+ _

+ N

NN

6.1 6.2 6.3

Scheme 6.3


113

to hydrophobic cosolvents (e.g. t-BuOH) has no immediate effect on the reaction rate (Figure 6.1).

Large mole fractions of water are necessary to produce significant accelerations. In agreement with

aqueous DA reactions the mole fraction and the extent of the additional accelerations correlate with the

hydrophobicity of the alcohols. Experimentally, measurement of the second-order rate constants in

highly aqueous media is troublesome. The data points in Figure 6.1 are reproducible to within 4 %. In

solutions with still higher water contents, the reaction rate is considerably reduced. However, the exact

second-order rate constants are irreproducible. In line with DA reactions in water, a reduction of the

rate constants in (almost) pure water may be anticipated. The exact extent remains unknown.

A notable experimental difference with the DA reactions described in the previous chapters has

to be mentioned. The reported rate constants have been measured under pseudo-first-order conditions,

with an excess of 6.2. Due to the modest reactivity of 6.1 and 6.2, the kinetic experiments were carried

out at the highest possible concentrations of 6.2. Certainly, the properties of such solutions are no

longer ideal at these concentrations and microheterogeneities possibly promote the intermolecular DC

reaction. So, aggregation of reactants could be excluded for DA reactions in water, but not for the

present DC reaction.

0.0 0.2 0.4 0.6 0.8 1.00

20

40

60

80

k 2 /

10-5 M

-1.s-

1

Mole Fraction of Water

Figure 6.1 Second-order rate constants for the DC reaction of 6.1 with 6.2in water-alcohol mixtures versus the mole fraction of water at 40.3 °C.MeOH (ˇ), EtOH (u), 2-PrOH (O), t-BuOH (t).

Chapter 6

114

Due to the low solubility of norbornene, the DC reaction of 6.1 with 6.2 could not be

investigated in pure water, which seriously hampers the quest for a suitable explanation of the results.

Therefore, the addition of p-nitrophenyl azide (6.4) to 2,3-dihydrofuran (6.5) was examined (Scheme

6.4), because 6.5 is more hydrophilic than 6.2. This reaction has been previously investigated by

Huisgen34. The second-order rate constant of this reaction in organic solvents is 2.2 . 10-5 (CHCl3), 2.6 .

10-5 (toluene) and 2.7 . 10-5 (acetonitrile) M-1 s-1. Similarly to the DC reaction of 6.1 with 6.2, the

second-order rate constant in water-alcohol solutions increases gradually with the water concentration.

Unfortunately, in highly aqueous media a side reaction interferes and the accuracy of the rate constants

diminishes. A 1H NMR-spectrum of the products of this DC reaction in pure water indicated the

presence of a complex reaction mixture in which p-nitroaniline and butyrolactone were identified, the

products of a hydrolysis34. The hydrolysis only occurs in highly aqueous solvents. Still, despite the large

experimental error, we conclude that the DC reaction is not dramatically accelerated in pure water. In

fact, the second-order rate constant is probably slightly reduced for reactions in pure water, similarly to

the pattern for most bimolecular DA cycloadditions.

N NNO2 NO

NN

NNO2

O

+

_

6.4 6.5 6.6

+

Scheme 6.4


115

6.4.2 Intramolecular Cycloaddition of Electron-rich Dipolarophiles to Aromatic Azides in Organic

Solvents and in Water

More information concerning the influence of aqueous solutions on DC reactions comes from a

comparison of intermolecular and intramolecular 1,3-dipolar cycloadditions (IMDC) to aromatic

azides35. The investigation of an IMDC reaction has several advantages. No pseudo-first-order

conditions are required and therefore very low concentrations of the reactant are possible. Most

importantly, aggregation phenomena in the IMDC reaction can be excluded. This approach was proven

to be highly successful in the study of aqueous DA reactions36. Like their intermolecular counterparts,

the ∆≠Gθ of the intramolecular DA reactions is reduced in aqueous solutions, which elegantly hints at

the absence of hydrophobic aggregation as the factor responsible for the aqueous rate effect of the

intermolecular DA reaction.

IMDC reactions have greatly extended the scope of DC methodology, as they enable synthesis

with control over all stereocentres of complicated multi-ring heterocyclic compounds35. In addition,

IMDC reactions proceed more smoothly than their intermolecular counterparts and this allows synthesis

of heterocycles, that are otherwise difficult to prepare (for example, the addition of nitriles to azides37).

0.0 0.2 0.4 0.6 0.8 1.0

3

4

5

6

7

8

9

10

11

12

k 2 /

10-5

M-1

.s-1

Mole Fraction of Water

Figure 6.2 Second-order rate constants for the DC reaction of 6.4 with 6.5 inwater-alcohol mixtures versus the mole fraction of water at 40.0 °C. EtOH(ˇ), t-BuOH (u).

Chapter 6

116

The IMDC reaction of 6.7 (Scheme 6.5) has been previously reported38. The final step in the

synthesis of 6.7 involves diazotation, followed by addition of azide anions at 0 °C. At this low

temperature cyclisation does not take place, allowing preparation and identification of 6.7. Dissolving

6.7 in warm solvent (40 °C) is sufficient to initiate the cycloaddition and the reaction is readily

monitored using UV/VIS-spectroscopy. The first-order rate constants are presented in Table 6.2.

The rate constants for the reaction in pure alcohols (Table 6.2) are in excellent agreement with

results reported by Garanti et al.38. The data reveal a stunning contrast between the kinetics of the intra-

and intermolecular DC reaction. Compared to a pure organic medium, the IMDC reaction is retarded in

aqueous media and in pure water the rate constant is the lowest. Water is a better hydrogen-bond

donating solvent than the alcohols and therefore this observation shows that hydrogen bonding of the

solvent does not play a significant role in determining reaction rates of DC reactions with azides.

Apparently the interaction of the solvent with both reacting parts of 6.7 does not affect their energy,

because in that case a kinetic effect should have been observed. Similarly, rate enhancement of the

intermolecular DC reaction of 6.1 and 6.2 cannot be attributed to hydrogen-bond interactions. This

would leave hydrophobic interactions to be the prime accelerating factor for the rate enhancement of the

addition of 6.1 to 6.2. For this particular reaction the presence of microheterogeneities (due to the high

concentrations of 6.2) surely further promotes the DC reaction.

6.4.3 1,3-Dipolar Cycloadditions of Electron-poor and -rich Dipolarophiles to Aromatic Nitrile

Oxides in Organic Solvents and in Aqueous Media

A second representative of DC reactions involves cycloadditions with nitrile oxides39. These dipoles are

among the most frequently used reagents in DC chemistry, adding readily to many dipolarophiles

yielding isoxazolines or isoxazoles. Nitrile oxides have been successfully utilised in stereoselective

reaction routes. Apart from a rare exception40, rapid dimerisation prevents isolation of nitrile oxides, so

in general, nitrile oxides are generated in situ and many procedures are available39. Basically, two

methods to generate nitrile oxides are used : (i) oxidation of aldoximes (mostly in a halogenation-

N N N

O CH2 C CH

+ _

O

N

NN

6.7 6.8

Scheme 6.5

Table 6.2 First-order Rate Constants for the Intramolecular Cycloadditionof 6.7 at 40.0 °C in Water-Alcohol Mixtures.

Mole Fraction of Water k1 (2-PrOH) / 10-5 s-1 k1 (t-BuOH) / 10

-5 s-1

0 1.69 1.740.75 1.61 1.630.90 1.54 1.610.95 1.32 1.461 1.08 1.08


117

dehydrohalogenation sequence), and (ii) dehydration of nitro compounds. In some cases an aqueous

two-phase system is used22. Nitrile oxides are dipoles of the propargyl- allenyl type and they are better

Lewis bases than azides.

Addition of electron-poor dipolarophiles to nitrile oxides are the only examples of DC reactions

for which detailed kinetic studies in aqueous media have been carried out24,26. Only when very electron-

poor dipolarophiles are used, an aqueous medium appears favourable26. According to one of these

studies nitrile oxides are slowly hydrolysed and this process is catalysed by bases24.

Our initial experiments were carried out on a synthetic scale by adapting a literature procedure

in which benzonitrile oxide was generated in a two-phase system after which it was allowed to react

with styrene22c. We found that the organic phase is not required for a successful synthesis. The reaction

can be simply accomplished by dissolving styrene (6.10a) and benzaldoxime in a bleach solution which

leads to a swift precipitation of the product. Analysis revealed the formation of 6.11a, in agreement with

results obtained by Huisgen41.

Cycloadditions with benzonitrile oxides proceed rapidly, enabling facile determination of rate

Table 6.3 Second-order Rate Constant for the Intermolecular 1,3-Dipolar Cycloaddition of 6.9with 6.10b-f at 25.0 °C in Organic Solvents and in Water

Dipolarophile

Solvent6.10bk2 / 10

-1 M-1 s-16.10ck2 / 10

-2 M-1 s-16.10dk2 / 10

-3 M-1 s-16.10ek2 / 10

-2 M-1 s-16.10fk2 / 10

-3 M-1 s-1

n-Hexane 4.8 1.5 3.6 2.6 2.71,4-Dioxane 1.8 1.3 1.2 1.7 3.7CH2Cl2 0.9 0.6 0.7 1.2 2.9DMSO 2.3 3.1 3.0 2.7 10.9EtOH 3.3 1.4 2.2 2.3 6.3TFE 0.6 0.2 0.6 3.3 8.3Water 3.0 1.1 2.6 8.5 30.0

C ON + ON

A B

+ _

BA

A B

a : -H -C6H5b : -H -COMec : -H -CNd : -CON(Me)CO-e : -CH2CH2CH2-f : -CH2CH2O-

6.9 6.10 6.11

Scheme 6.6

Chapter 6

118

constants for the reactions in Scheme 6.6. Rate constants for DC reactions of five dipolarophiles

(6.10b-f) with benzonitrile oxide (6.9) in organic solvents and in water are given in Table 6.3. Some of

these reactions have been previously investigated and show a high regioselectivity5,39. Interestingly, the

effect of the solvent depends on the nature of the dipolarophile. Cycloadditions of 6.9 with electron-rich

dipolarophiles (cyclopentene (6.10e) and 2,3-dihydrofuran(6.10f)) are promoted in water, whereas water

has no special accelerating effect on the cycloaddition with the three electron-deficient dipolarophiles

(methyl vinyl ketone (6.10b), acrylonitrile (6.10c) and N-methylmaleimide (6.10d)). Clearly water only

promotes the DC reaction of 6.9 with electron-rich dipolarophiles. We have not analysed whether the

regioselectivity of the DC reactions with 6.10b, 6.10c and 6.10f is changed by the solvent. In view of

studies on DA reactions it is not unlikely that also these aspects of the DC reaction are altered.

Qualitatively, the results are consistent with the two previous kinetic studies, in which it was

shown that cycloadditions of 6.9 with ethyl acrylate and dimethyl maleate are almost equally fast in

water and in water-dioxane (1:1)24 and that the DC reaction with a very electron-deficient dipolarophile

(benzoquinone, comparable to 6.10d) is indeed considerably faster in an aqueous medium compared to

chloroform26.

On several occasions we have carried out cycloadditions in 2,2,2-trifluoroethanol (TFE), a

solvent with hydrogen-bond donating properties similar to that of water. Comparison of kinetic data for

DA reactions in this solvent and in water established that hydrogen bonding (of water) is a major

contribution to the rate enhancements in water. Also in this case the kinetic data for reaction in TFE

shed light on the exact influence of water on the DC reaction. For electron-rich dipolarophiles, the

influence of TFE parallels that of water, but is less extreme. This ‘super-protic’ solvent also promotes

these cycloadditions. The DC reaction with electron-poor dipolarophiles is inhibited in TFE. This

pattern demonstrates that hydrogen bonding by the solvent is an important factor for the reactivity of

DC reactions. We contend that part of the influence of water on cycloadditions is governed by its

hydrogen-bond donating capacity.


119

As in the case of the previously described cycloadditions, the results can be partly explained

using FMO-theory12. This approach was used by Desimoni42 for cycloadditions in organic solvents. For

a large number of cycloadditions a good correlation is observed between rate constants and acceptor

numbers (AN) of the solvents. This latter parameter indicates the capacity of a solvent to interact with

electron pairs. This analysis is also based on a relationship between MO energies and ∆≠Gθ. Figure 6.2

schematically illustrates how hydrogen bonding of protic solvents (e.g. water) affects the MOs of the

reactants. Nitrile oxides are good Lewis bases (as indicated by the preferred complexation of Lewis

acids with nitrile oxides18,19) and consequently the MOs of these dipoles are substantially stabilised.

Because 6.10e and 6.10f are weak hydrogen-bond acceptors, their MOs are either not or only slightly

affected by hydrogen-bond interactions. Overall this interaction leads to a smaller difference of energies

between the dominant MOs of the reacting partners and the ∆≠Gθ is reduced in protic solvents, including

water. The electron-deficient dipolarophiles are relatively good hydrogen-bond acceptors and

consequently their MOs are stabilised in protic solvents. However, this interaction is less efficient

(compared to 6.9) and explains why these cycloadditions are retarded in protic solvents.

As explained previously (Chapter 1), this FMO approach only delineates the interaction

between the two reactants. The influence of the solvent is merely limited to the (de)stabilising influence

on the MOs of the reactants. FMO theory analyses the reaction as if only one or two solvent molecules

are present. The results in Table 6.3 clearly demonstrate that the FMO approach cannot completely

explain the effect of water on DC reactions, because in all cases the reaction in water is faster than in

the other protic solvents, despite the fact that water is the superior hydrogen-bond donor. The reason is

MO energy

HOMO

LUMO

HOMO

HOMO

LUMO

LUMO

Figure 6.3 Schematic representation of the MO energies of anelectron-rich dipolarophile (left), 6.9 (middle) and an electron-poor dipolarophile (right). The solid lines represent the MOs inhexane and the dashed lines those in a protic solvent

Chapter 6

120

that FMO theory does not take into account hydrophobic effects. Similarly to DA reactions, the rate

accelerating effect in water is due to the reduction of the water-accessible surface area during the

activation process which is always a favourable process in water, irrespective of the effect of water on

the MOs of the reacting species.

More than our previous results, this system enables separation of the two factors that influence

organic reactions in water : hydrogen bonding by water and hydrophobic interactions. The nature of the

reactants determines whether these two mechanisms operate collaboratively or counteractively.

Roughly, this pattern can be predicted using FMO theory. However, hydrophobic interactions are

always favourable for cycloadditions in water.

6.4.4 1,3-Dipolar Cycloadditions of Electron-poor and -rich Dipolarophiles to Aromatic Nitrones in

Organic Solvents and in Aqueous Media

Addition of dipolarophiles to nitrones yields isoxazolidines and this procedure is especially attractive for

the synthesis of alkaloids and natural products39a. These DC reactions have been extensively studied and

all mechanistic and kinetic data are in accord with common DC characteristics43. This type of DC

reaction has a so-called inverted solvent effect44 (see Section 6.2). Addition of electron-poor

dipolarophiles generally proceeds efficiently, but when electron-rich dipolarophiles are used, more

drastic reaction conditions are required. Often the addition of dipolarophiles to nitrones is reversible45.

Second-order rate constants are presented in Table 6.4 for the DC reaction of 3,4-

dihydroisoquinoline-N-oxide (6.12) with an electron-poor (dimethyl acetylenedicarboxylate, 6.13)46 and

-rich dipolarophile (norbornadiene, 6.15)47 (Scheme 6.7). In aqueous solutions the DC reaction of 6.12

with 6.13 is severely hindered by a side reaction. This reaction was identified as a previously reported

complicated rearrangement of 6.14 which eventually leads to a diketone46. To ascertain that the

spectroscopically observed reaction involves the DC reaction, this cycloaddition was followed in a D2O-

CD3OD mixture. 1H NMR spectra were analysed on the basis of the literature48 and revealed the

presence of 6.14, without significant quantities of side products. Therefore, rearrangement of 6.14 is not

rate determining and the measured rate constants represent the cycloaddition.


121

Both cycloadditions proceed most rapidly in apolar aprotic solvents, whereas protic solvents

such as TFE considerably retard the reaction. The results of the kinetic study with the nitrone are

comparable to those for the DC reaction of electron-poor dipolarophiles with benzonitrile oxide (6.9).

Also the DC reactions with 6.12 can be partly rationalised on the basis of FMO theory (Figure 6.4).

The effect of protic solvents on the MO energies of the reactants is most dramatic for nitrone 6.12,

because this nitrone is a good Lewis base. As a result ∆≠Gθ increases in protic solvents, including water.

The observation that the second-order rate constants of both reactions are still relatively high in water is

a result of enforced hydrophobic interactions. Because norbornadiene is insoluble in pure water, 5 mol%

of t-BuOH was added to water. For DA reactions in aqueous media this concentration of t-BuOH may

induce a modest additional rate acceleration and therefore it seems probable that this second-order rate

constant overestimates the reactivity in pure water.

The previous chapters disclosed that aqueous rate enhancements of DA reactions are the result

of two cooperative mechanisms of water, hydrogen bonding and enforced hydrophobic effects. In many

cases comparison of reaction rates in fluorinated alcohols might prompt the conclusion that water is just

a good protic solvent which is very effective as a result of its small size. However, this chapter

demonstrates unambiguously how the two mechanisms can actually counteract each other and

establishes the operation of hydrophobic effects. Addition of several dipolarophiles to 6.9 and 6.12 is

inhibited in TFE, resulting from strong Lewis acid-Lewis base interactions. If this factor was decisive

for the ∆≠Gθ of cycloadditions, water would be the worst solvent. But in aqueous solutions, part of the

water-accessible surface area of the reacting substrates is reduced by the formation of the activated

complex which promotes the reaction in water. This mechanism does not depend on the effect that

NO

++ _N

O

CO2CH3CH3OCO

CH3O2C CO2CH3

+O

N

6.12 6.13 6.14

6.15 6.16

Scheme 6.7

Chapter 6

122

hydrogen-bond interactions have on the energy of the MOs of the reactants. The two mechanisms may

either operate cooperatively or counteract each other. Due to the large Lewis basicity of some dipoles,

the separate operation of the two mechanisms becomes clearly manifested for DC reactions.

In principle the same effect can be observed for bimolecular DA reactions, but most common

dienes are poor hydrogen-bond acceptors and therefore this pattern is rare. However, there is one

example. The DA reaction of p-nitrostyrene with di-(2-pyridyl)-1,2,4,5-tetrazine (Chapter 2) is slowest

in TFE and this trend points to the unfavourable effect of hydrogen-bonding on the reaction rate. But

also in that case the reaction still proceeds by far the fastest in water, because of enforced hydrophobic

interactions. Also the hetero retro DA reaction (Chapter 4) serves as an example how hydrogen bonding

(of water) can have an unfavourable influence on pericyclic reactions.

At first sight it is surprising that the DC reaction with an electron-rich dipolarophile such as

6.15 is still hindered by hydrogen bonding of the solvent. This pattern seems inconsistent with the

kinetic results with benzonitrile oxide, in which case the addition to electron-rich dipolarophiles is

promoted. However, a careful analysis of Figure 6.4 resolves this apparent anomaly. The numbers in

this figure are rough estimates, based on calculations by Houk14, who estimated the MOs of nitrones

and a number of dipolarophiles. We have adapted these estimates by taking into account the specific

influence of substituents on the MOs of the reactants. For example, the HOMO and LUMO of the

nitrone moiety are close in energy due to the aromatic substitution. When the MO energy of the

dipolarophile is gradually decreased the dominant HOMO(dipolarophile)-LUMO(dipole) interaction is

eventually replaced by the HOMO(dipole)-LUMO(dipolarophile) interaction (Figure 6.3). This shift

explains why hydrogen-bond interactions are sometimes favourable and sometimes unfavourable for the

reaction, as exemplified by DC reactions with benzonitrile oxide. Generally, 6.15 acts as an electron-

Table 6.4 Second-order Rate Constants for the DC reaction of 6.12with 6.13 (at 25.0 °C) or 6.15 (at 40.0 °C) in Organic Solvents and inAqueous Media.

DipolarophileSolvent 6.13

k2 / 10-2 M-1 s-1

6.15k2 / 10

-5 M-1 s-1

n-Hexane 131 53.8Toluene 61.7 --1,4-Dioxane -- 14.4Chloroform 9.22 --Acetonitrile 24.0 3.12EtOH 6.87 2.56TFEa 0.6 0.53Water 8.45 2.77ba TFE : 2,2,2-trifluoroethanol. b Containing 5 mol % t-BuOH.


123

rich species, but due to the relatively high energy of the HOMO of nitrone 6.12, the former HOMO-

LUMO interaction dominates. Consequently, protic solvents have an unfavourable effect on

cycloadditions with both 6.13 and 6.15.

6.5 Conclusions

In this chapter we have seen a dramatic contrast in the effect of water on DC reactions. Some reactions

are accelerated in water, whereas others are retarded or do not experience a special effect of this solvent.

The rate effects in water are related to those in other protic solvents. In all cases combination of FMO

theory and enforced hydrophobic interactions accounts for the kinetic results. Water interacts with good

Lewis bases (in particular nitrile oxides and nitrones) and this affects the MOs of the reactants. The

overall influence of this interaction on the rate of the DC reaction depends on the dipolarophile and may

be either favourable or unfavourable. Irrespective of this mechanism, constant enforced hydrophobic

interactions in water always favours the formation of the activated complex (and product). These

hydrophobic interactions are solely responsible for the acceleration of the DC reaction with aromatic

azides. Microheterogeneities further accelerate these cycloadditions.

6.6 Experimental Section

Intermolecular DC Reactions with Aromatic Azides

MO energy (eV)

HOMO

LUMO

HOMO

HOMO

LUMO

LUMO

-11

0

1

-9

-7.5

0.5

Figure 6.4 Schematic representation of the MOs of 6.13 (left),6.12 (centre) and 6.15 (right).

Chapter 6

124

Synthesis and Product Analysis

Phenyl azide (6.1) and p-nitrophenyl azide (6.4) were prepared according to a literature procedure49.

Norbornene (6.2) was purchased from Aldrich and used as received. 2,3-Dihydrofuran (6.5) was

purchased from Aldrich and distilled before use. All solvents were of the highest purity available or

freshly distilled. Water was distilled twice. The cycloadduct 6.3 was prepared by dissolving 0.1 g of 6.1

and 0.12 g of 6.2 in 10 ml of water-ethanol (1:1 v/v) and stirring the solution for 24 hours at 40-50 °C,

during which time a white solid precipitated. After cooling, the reaction mixture was filtered and the

solid was recrystallised from n-hexane. M.p. 101-102 °C (lit.10 101-102 °C). The cycloadduct 6.6 was

prepared and identified on a synthetic scale as follows : 0.215 g of p-nitrophenyl azide and 0.5 ml of

2,3-dihydrofuran were dissolved in 2.5 ml of water-ethanol (91:9 v/v) and stirred at room temperature.

After 2 hours a solid had formed and the solution was filtered. The white solid was washed with water,

dried and crystallised from CH2Cl2-MeOH (1:1). M.p 157 °C (lit. : 156 °C34). 1H NMR (DMSO) : δ

2.28 (m, 2H), 3.01 (m, 1H), 3.92(t, 1H), 5.37 (t, 1H), 6.14 (d, 1H), 7.54 (d, 2H), 8.27 (d, 2H).

Kinetic Experiments

Second-order rate constant for both reactions were determined at 40.0 °C in a thermostatted cell holder,

using a Perkin-Elmer Lambda 2, 5 or 12. The ‘initial-rate method’10,33 was employed. This method

requires estimation of the extinction coefficient of both reactants and product. The slow reactions

prompted use of high concentrations of 6.2 (0.1-0.01 M) or 6.5 (0.1-0.5 M). The DC reaction of 6.1

with 6.2 was followed at 320 nm, the addition of 6.1 to 6.5 at 350 nm. Following this procedure, the

reproducibility of the rate constants was within 5 %.

Intramolecular DC Reaction with Aromatic Azides


6.7 was synthesised following the method of Garanti and coworkers38. The last step of this synthesis

involves diazotation of a substituted aniline. This reaction was carried out at 0°C and 6.7 was kept as a

solution in ether. A small amount of this solution was evaporated to dryness and the residue was

dissolved in CDCl3. The 1H NMR spectrum was in accord with that reported for 6.738. A second portion

of the ether solution was evaporated to dryness and the residue dissolved in a water-ethanol solution

(2:1 v/v)). This solution was stirred for several days at 40-50 °C after which 1H NMR analysis revealed

the formation of 6. 838.

Kinetic Experiments

First-order rate constants were determined at 40.0 °C by monitoring the reaction at 293 nm.

Reproducibility was within 3 %.


125

DC Reactions with Aromatic Benzonitrile Oxide


All chemicals were purchased from Aldrich. Methyl vinyl ketone (6.10b), acrylonitrile (6.10c),

cyclopentene (6.10e) and 2,3-dihydrofuran (6.10f) were distilled before use. Solvents were either of the

best quality available or distilled before use. One DC reaction was performed on a synthetic scale. 1.6 g

of pure benzaldoxime was added dropwise while stirring vigorously to a solution of 1.6 g of styrene

(6.10a) in a 50 ml household-bleach solution. The reaction mixture became warm and a cream-coloured

solid spontaneously precipitated. M.p. 72-73 °C (lit.22c 73-75°C) 1H NMR (CDCl3) : δ 3.34 (dd, 1H),

3.79 (dd, 1H), 5.75 (dd, 1H), 7.39 (m, 8H), 7.70 (m, 2H)41.

Kinetic Experiments

For kinetic experiments 6.9 was prepared in a test tube by dissolving a small amount of benzaldoxime in

a bleach/dichloromethane two-phase system. Several microliters of the organic phase were transferred to

a UV cuvette which contained the dipolarophile solution (dipolarophile in excess). In all solvents no or a

very slow reaction was observed in the absence of dipolarophile. Pseudo-first-order rate constants for

the DC reactions were monitored at 273 nm and 25.0 °C. Starting concentrations were ~ 0.1 mM of 6.9

and 5-40 mM of dipolarophile. Reproducibility was within 4 %.

DC Reactions with Aromatic Nitrones


6.12 was synthesised following a literature procedure50 and purified by column chromatography (Al2O3

(neutral), CHCl3-Et3N (98:2)). It was not possible to obtain completely anhydrous samples. The 1H

NMR spectrum was in accord with the literature50b. Dimethyl acetylenedicarboxylate (6.13) and

norbornadiene (6.15) were purchased from Aldrich and distilled before use. Adduct 6.14 was identified

through 1H NMR-analysis. 6.16 was prepared by following a procedure of Boyle47.

Kinetic Experiments

Both reactions were monitored at 297 nm. The DC reaction of 6.12 with 6.13 was monitored at 25.0

°C, using conventional pseudo-first-order kinetics and an excess of 6.13. Typical starting concentrations

were [6.12] = 4-8.10-5 M and [6.13] = 5-8.10-3 M. Reproducibility was within 2%. The second-order

rate constants for the addition of 6.12 to 6.15 were determined at 40.0 °C, by means of initial-rate

kinetics10,33. This requires determination of the extinction coefficients of 6.12 in all solvents (typically in

the range 16000-17000). Both 6.15 and 6.16 have a negligible extinction coefficient at 297 nm, thus

facilitating the procedure. Typical starting concentration was [6.15] = 1-4.10-2 M. Reproducibilty was

4%.

Chapter 6

126

1H NMR-experiments

Addition of 6.12 to 6.13 was carried out in a D2O-CD3OD (1:2 v/v) mixture, with [6.13] = 0.02 M and

[6.12]=0.01 M. After 12 minutes, the 1H NMR spectrum showed evidence of the (first) product at 7.38-

7.13 (4H, m), 5.87 (H, s), 3.85 (3H, s), 3.83 (3H, s), 3.35-2.60 (4H, m). Following Scheeren48 these

features were assigned to 6.14. Addition of 6.12 to 6.15 was also carried out in a D2O-CD3OD (1:1 v/v)

mixture. The 1H NMR spectrum was in accord with the literature47.

Acknowledgement

This chapter contains the work of several researchers, who deserve admiration because kinetic

experiments with DC reactions in aqueous media turned out to be experimentally difficult.

Roberto Steiner, Francesca Dal Santo and Simona Barison initiated and carried out most of the work

with the azides. Evert van Rietschoten admirably persevered in investigating the reactions with nitrones

and Dick van Mersbergen superbly controlled the DC reactions with benzonitrile oxide.

6.7 References

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