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2 Epoxides in the Synthesis of 1,2-Amino Alcohols in Water

2 Epoxides in the Synthesis of 1,2-Amino Alcohols in Water

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7 Water as Reaction Medium in the Synthetic Processes Involving Epoxides



211



The beneficial effect of water on this reaction is well represented by the data

reported in 2003 by Hou et al. in their study on the use of tributylphosphine as catalyst for the ring opening of epoxides in water [30]. For example, in the reaction of

cyclohexene oxide (1) with aniline (2a) or benzylamine (2b) besides the catalytic

effect of tributylphosphine (10 mol%) that allowed to obtain most satisfactory yields

of 3, the presence of water is essential for the success of the process. In fact, the

same reactions performed in MeCN gave only traces of products 3 (Scheme 7.1)

[30]. This catalytic system was also found to be efficient in water when phenol was

used as nucleophile, whereas in the case of thiols, the yields were lower compared

to those obtained in organic solvent [30].



OH

PhNH2

2a

O +

1



25-40 °C



or



3a

or



12 h



PhCH2NH2

2b



NHPh



OH

3b



NHCH2Ph



catalyst



medium



yield (%)



nBu3P (10 mol%)



H2O



78 (3a), 64 (3b)



-



H2O



39 (3a), 25 (3b)



nBu3P (10 mol%)



MeCN



traces



Scheme 7.1 nBu3P-catalyzed aminolysis of cyclohexene oxide (1) in water [30]



In 2005, aminolysis of epoxides with arylamines has been efficiently performed

in water in the presence of 1 mol% of the base, 1,4-diazabicycl-[2.2.2]octane

(DABCO), or triethylamine (Scheme 7.2) [31]. With this protocol, also, benzylamine gave satisfactory results, but isopropyl amine gave no reaction at all. In this case,

other nucleophiles were also used, and very good results were obtained with aromatic thiols, while aliphatic thiols were scarcely reactive [31].

For this transformation, the results reported by Azizi et al. in the same years were

different. Aminolysis of aliphatic epoxides with aliphatic amines was performed in

water without any addition of catalyst [32]. In this chapter, it was reported that

aniline and p-isopropylaniline reacted only with styrene oxide, while other aryl

amines and epoxides gave only discouraging results (Scheme 7.2).



212



D. Lanari et al.

R



O



R1R2NH



H2O



ArNH2



R1 = Alkyl, R2 = H or alkyl



base

(1 mol%)



no catalyst



OH



OH

R



R



NR1R2



NHAr



30 examples - 5-24 h, r.t., 84-97% yield



8 examples - r.t. to 40 °C

base: DABCO: 14-98% yield

NEt3: 68-98% yield



Scheme 7.2 Aminolysis of epoxides in water catalyzed [31, 32]



b-Cyclodextrin (b-CD) has proved to be an effective catalyst for the aminolysis

of aromatic amines with glycidol derivatives 4 in water at room temperature. The

presence of b-CD is essential for the efficiency of this process (Scheme 7.3) [33].

Scheme 7.3 b-Cyclodextrinpromoted aminolysis

of glycidols in water [33]



O

OR + ArNH2



R

4



β-CD (1 equiv)

H2O



OR



ArHN

R



2



OH

5



24 examples - r.t., 80-92% yield



We have started our investigation on the aminolysis of epoxides with the intention

of rationalizing these data, believing that the pH of the aqueous medium has a crucial

role in determining the efficiency of the nucleophilic ring-opening process of epoxides in water [34–48]. A study to evaluate the dependence of the reactions of aliphatic

and aromatic amines with several epoxides on the pH of the aqueous medium was

carried out [49]. Initially, it was found that the reaction of cyclohexene oxide (1)

with almost equimolar amount of aniline (2a) was very slow at pH lower than 7.0,

with the competitive formation of the corresponding trans-1,2-cyclohexandiol byproduct (coming from the attack of water to the epoxide). Under basic conditions

(pH 8–10), the reaction was expectedly faster. It was also noticed that the pH resulting from the simple mixing of the reactants was 8.30 at 30°C, sufficiently basic to

warrant a 90% conversion to 3a. The best conversion (95%) was achieved by raising

the temperature to 60°C (pH was 8.0) or at 30°C at pH 10. By extending the study

to other amines, it was generally concluded that aliphatic amines are sufficiently

basic to define an adequate pH condition for a successful uncatalyzed aminolysis.



7 Water as Reaction Medium in the Synthetic Processes Involving Epoxides



213



In the case of substituted poorly nucleophilic anilines, the pH resulting from the

mixing of the reactants was lower than 7.0, and therefore, reactions were slow, and

significant amount of the corresponding diols were formed. By raising the pH of the

reaction mixture to 10 (aq. NaOH addition), satisfactory yields were obtained in

these cases (Scheme 7.4).

Scheme 7.4 pH influence on

the aminolysis of

representative epoxide 1 in

water [13]



Represenative study on aniline (PhNH2,2a)



O



OH



H2O, pH 5.0-10.0

2a



NHPh

3a



1

pH

5.0

7.0

8.30

10.0

8.0*

* 60 °C



t (h)



Conversion to 3a (%)



100

45

25

25

14



90 (20% of diol)

90

90

95

95



Extension of the study to various amines

OH



H2O, pH = 7.8-12

R



R



O

R1R2NH



NR1R2



R1, R2 = Alkyl or aryl or H

17 examples - 2-26 h, 30-60 °C, 70-93% yield



We also highlighted that in some cases, there is the unavoidable formation of a

bis-product, coming from the attack of the ring-opened product to another molecule

of epoxide, which can be reduced only by running the reaction with an excess of

amine.

As expected, the regioselectivity of the ring openings favored the product at the

less hindered carbon (b-attack) except in the case of styrene oxides where a-attack

was preferred.

Several other protocols have been recently proposed [50–54] where the addition

of various amines to epoxides has been promoted by ultrasounds [50], monodispersed silica nanoparticles [51], or catalyzed by erbium(III) triflate [52], zirconium

dodecyl sulfate [53], or aluminum dodecyl sulfate trihydrate [54].

The use of water as reaction medium for the enantioselective ring opening of

meso-epoxides by amines has recently been reported, achieving better results than

those obtained in organic medium by using Lewis acid–surfactant-combined catalysts



214



D. Lanari et al.



(LASCs) [55]. These catalytic systems are able to furnish both the Lewis acidity

needed for the activation of a basic center and the hydrophobic environment that

favors the approaching of the reactants [55]. In 2005, Kobayashi et al. used LASCs

based on Sc(III) [56] and Bi(III) [57] in combination with a chiral bipyridine 7 as

ligand, in the desymmetrization of highly hydrophobic epoxides 6 by aromatic

amines 2 in water (Schemes 7.5 and 7.6) [56, 57].

The best results were obtained by using scandium(III) dodecyl sulfate

(Sc(DS)3) (1 mol-%), (S,S)-6,6¢-bis(1-hydroxy-2,2-dimethylpropyl)-2,2¢-bipyridine

(7) (1.2 mol%), and equimolar amounts of reactants (Scheme 7.5). Although

there are no mechanistic insights on the precise role of water in this process, this reaction

medium provides better results than those obtained by using an organic solvent

[58, 59] in terms of either enantioselectivity and of isolated yields of products.

It should be mentioned that the use of bipyridine (7) for epoxide ring-opening

process was initially developed by Schneider et al. in 2004 [58].

Sc(DS)3 / (S,S)-7

R

O+

R

6



ArNH2

(1.0 equiv)



(1.0/1.2 mol%)



R



OH



H2O, r.t.



R



NHAr



2



(+)-(S,S)-8



9 examples - 30-48 h, 61-89% yield, 60-96% ee



N



N



HO

OH

(S,S)-7



Scheme 7.5 Sc(DS) LASC–catalyzed enantioselective aminolysis of epoxides in water [56]



When Bi(III) was used as Lewis acid, the influence of the surfactant was

considered. The best results were obtained by using Bi(OTf)3 (5 mol%), sodium

dodecylbenzene sulphonate (SDBS) (20 mol%), and bipyridine 7 (6 mol%)

(Scheme 7.6). In this case, the LASC system was generated in situ. Other anionic

surfactants like sodium dodecyl sulfate (SDS) and sodium dioctyl sulfosuccinate

(AOT) gave the desired products 8 in low yields. In this study, only cis-stilbene

oxides were considered [57].

Ar

Ar

6



O + ArNH2

(1.0 equiv)

2



Bi(OTf)3/ SDBS/ (S,S)-7

5.0/20/6.0 mol%



Ar



OH



H2O, r.t., 40 h



Ar



NHPh



(+)-(S,S)-8



7 examples - 68-85% yield, 83-94% ee



Scheme 7.6 Bi(III) LASCs in the desymmetrization of cis-stilbene oxides in water [57]



7 Water as Reaction Medium in the Synthetic Processes Involving Epoxides



215



LASCs based on different Lewis acids have also been used for the same process.

In particular, in 2008, we have reported that transition metal catalysts Zn(II), Cu(II),

Ni(II), and Co(II), combined with SDS, are also able to efficiently promote the

desymmetrization of cis-stilbene oxide (6a) with aniline (2a) (Scheme 7.7, Ar = Ph)

in water by using (R,R)-bipyridine 9 (Scheme 7.7) [60]. Zn(II) and Cu(II) catalysts

gave the best results. It should be highlighted that the use of transition metals as

Lewis acids and (R,R)-bipyridine 9 as ligand produced the same product (+)-(S,S)-8

that is obtained when Sc(DS)3 is used with the ligand enantiomer (S,S)-bipyridine 7

(cf. Schemes 7.5 and 7.7).



Scheme 7.7 Zn(OTf)2/9/

SDS catalytic system for the

enantioselective aminolysis

of epoxides in water [60]



R

O+

R

6



ArNH2

(1.0 equiv)



Zn(OTf)2 / 9 / SDS

(5.0 mol%)

H2O, 4 ˚C



2



R



OH



R



NHAr



(+)-(S,S)-8

N



N



HO

OH

(R,R)-bipyridine 9

13 examples - 79-92% yield, 46-91% ee



This enantioselective outcome was confirmed when Zn(II) and Cu(II) undecane

sulfonates were used in combination with (S,S)-bipyridine 7 in the desymmetrization of epoxides by amines in water [61]. Kobayashi et al. justified the different

enantioselection by accounting some significant differences between the crystal

structures of the two complexes of (S,S)-7 with CuBr2 and with ScBr3. They also

confirmed the importance to have both hydroxyl groups in the structure of 7 for

achieving the best enantioselectivity, in fact their corresponding mono- or bismethyl ether showed low enantioselectivity [58, 59, 61].

In our contribution [60], the influences of other reaction parameters were also

considered. By varying temperature and concentration, it was found that the catalytic system Zn(OTf)2/SDS/9 was most effective at 4°C and 0.5 M concentration

level. This result was extended to a variety of epoxides 6 and anilines 2 including

very small epoxides such as cyclohexene oxide (1), cyclopentene oxide, and 2-butene

oxide, for which rare and generally very poor results have been reported, and none

of them obtained with water as reaction medium. Representatively, the enantiomeric

excess of 85% achieved in the case of cyclohexene oxide (1) with aniline (2a) was

very good (Scheme 7.7).

It has been also reported that Sc(DS)3 is a good catalyst for the enantioselective

ring opening of cis-stilbene oxide (6a) by benzotriazole [62].



216



D. Lanari et al.



The use of catalytic systems formed by the combination of a metal salt with SDS

has been applied to other reactions of epoxides with N− and other nucleophiles. In

particular, the system made by Ce(OTf)4 (10 mol%) and SDS (30 mol%) has been

used [63] for promoting the reactions of a variety of epoxides with nitrite, nitrate,

thiocyanate, azido ions besides cyanide, chloride, and bromide ions (Scheme 7.8).

Other surfactants were also considered, but SDS gave the best results [63].

Scheme 7.8 Ce(OTf)4/SDS

system in the ring opening of

epoxides in water [63]



Ce(OTf)4 /SDS

R



O + NaX



10/30 mol%



OH

R



H2O, r.t.



X



X = CN-, N3-, NO2-, NO3-, Cl-, Br28 examples - 0.08-10 h, 75-91% yield



As a valid alternative route for the preparation of 1,2-amino alcohol, the azidolysis

of epoxides has been extensively studied [13–16, 24–27].

The protocol using NaN3 as reagent and NH4Cl as a coordinating salt in aqueous

methanol at 65–80°C has been commonly considered as the classical protocol for

preparing 1,2-azido alcohols. Azidolysis under these conditions generally requires

long reaction time (12–48 h), and the azidohydrin is often accompanied by isomerization, epimerization, and rearrangement products [13–16, 64]. Unsymmetrical

epoxides generally undergo azido ion attack at the less substituted carbon, except

for the aryl-substituted epoxides. Attempts to reverse the regioselectivity have little

success [24–26], with the exception of the protocol that uses Et3Al/HN3 in dry toluene at −70°C [27].

In 1999 [48], we have reported the first use of sole water as reaction medium for

the reactions of epoxides and sodium azide. Both rate and regioselectivity of the

process have been dramatically affected by varying the pH of the aqueous medium.

Under basic condition (pH 9.5), at 30°C, the azido ion generally attacks the less

substituted b-carbon of 10 through an expected SN2 mechanism. At acidic pH (4.2),

a partial protonation of the oxygen of the epoxide ring promotes a much faster reaction, and under these conditions, an increased preference for the attack on the more

substituted a-carbon of 10 probably takes place through an SN2 borderline mechanism (Scheme 7.9) [48].

αO



NaN3, H2O

β



10



Scheme 7.9 pH-controlled

regioselectivity of the

azidolysis of representative

epoxide 10 in water [48]



N3



OH

OH



N3



30 ˚C

C-α



C-β



pH



t (h)



C-α/C-β



9.5



20



3/97



4.2



1.5



70/30



7 Water as Reaction Medium in the Synthetic Processes Involving Epoxides



217



Recently, polyethylene glycol supported on silica gel [65] or Dowex resin [66]

has been used as solid recoverable catalysts for the reaction of epoxides with sodium

azide in water under reflux.

Azidolysis of a,b-epoxycarboxylic acids 11 and their esters is a well-studied

process that if regio- and stereoselective, opens a direct access route to a-hydroxyb-amino acids (also known as norstatines), a key moiety of several pharmaceutical

target compounds [67–70]. The classical azidolysis protocol that uses NaN3 in alcohol or alcohol/water (8:1) generally furnishes a mixture of products including the

formation of some retention products [71, 72]. To overcome this problem, the use of

large amounts (150–500 mol-%) of various Lewis acids in an organic reaction

medium has been adopted [71–73].

As a more recent alternative, the use of water as reaction medium together with

a careful adjustment of the pH has allowed to define very efficient protocols for the

completely b-regio- and anti-stereoselective azidolysis of a variety of a,b-epoxycarboxylic acids 11 by employing for the first time catalytic amounts (1 or 10 mol–

%) of a metal salt such as InCl3 or AlCl3 at pH 4.0 or Cu(NO3)2 at pH 4.0 or 7.0 [38,

43–47].

b-Azido-a-hydroxycarboxylic acids 12 have been prepared with a complete

stereoselectivity and in high yields by controlling the pH (Scheme 7.10).



R1 β



O



Cu(NO3)2 (10 mol%)

or InCl3, or AlCl3 (1 mol%)



R2



pH 4.0 or 7.0

NaN3, H2O



COOH

α



11



N3

COOH



R1



R2 OH

12

(anti-C−β)



10 examples - 0.25-18 h, 30-65 C, 93-95% yield



Scheme 7.10 Metal-catalyzed regio- and stereoselective azidolysis of a,b-epoxycarboxylic acids

in water [38, 43–47]



These efficient protocols are the result of a study devoted at the comparison of

the efficiency of a metal salt employed as catalyst in water and in organic media. It

has proved that the pH of the aqueous medium is crucial for realizing this process

satisfactorily; in fact, only in water a Lewis acid can be used in a catalytic amount,

while in organic media, large excess is needed. Both the catalyst and water (used as

reaction medium) have been recovered and reused in further runs, without observing any decrease in the efficiency of the process. These results prove the environmental efficiency of these procedures.

By coupling the catalyzed protocols for the preparation of 12 with that for the azido

group reduction catalyzed by the same metal salt [74], it has been possible to define

the first one-pot synthesis of a-hydroxy-b-amino acids (norstatines) starting from the

corresponding a,b-epoxycarboxylic acids avoiding at all the use of organic solvent

[38]. Among all the metal catalysts tested, Cu(II), Co(II), Al(III), and In(III), Cu(II)

salts proved to be the most efficient for this one-pot protocol. In this case also, the

catalyst used could be completely recovered and reused efficiently (Scheme 7.11).



218



D. Lanari et al.

1. oxirane-ring azidolysis

(pH 4.5-5.5)



R1



O



CO2H



2. azido group reduction

(pH ca. 10)



11



CO2H

R3



R2



R3



R2



OH

R1



Cu2+



NH2



Cu(B)(s)



norstatines



H2O/H

pH ca. 2



Scheme 7.11 Cu(II)-based catalytic cycle for the synthesis of norstatines [38]



Similarly, very efficient protocols for the Lewis acid–catalyzed ring opening of

epoxides by thiols and halides have been realized [34, 42, 45]. In all cases, the careful control of the pH has allowed the highest efficiency.

The reaction of sodium azide with epoxides at room temperature has been

recently proposed by using Zr(DS)4 as catalyst [75].

b-CD has been used as promoter for the kinetic resolution of epoxides in water

[76, 77]. Rao et al. reported interesting results in the reactions of glycidols 5 with

trimethylsilyl azide (TMSN3,) and isopropylamine (Scheme 7.12). Enantioselectivity

outcome is strongly influenced by the amount of b-CD used, and the best results

have been obtained by using 1.33 or 2.0 equivalents, while the use of substoichiometric amounts led to very low ees [76].



Scheme 7.12 Kinetic

resolution of glycidols 5 in

water promoted by b-CD [76]



β-CD (1.33 mol equiv)

O

RO



NuH

H2O, 37 ˚C



4



OH

RO



Nu



(S)-enantiomer

16 (Nu = N3)

17 (Nu = PrNH)



12 examples : 38-47 % yield, 64-99% ee for 16

40-56% yield, 56-90% ee for recovered 5

40-48 % yield, 65-90% ee for 17

41-57% yield, 59-89% ee for recovered 5



7.3



Epoxides in the Synthesis 1,2-Diols, 1,2-Alkyloxy,

and -Aryloxy Alcohols in Water



Water, alcohols, and phenols react very poorly as nucleophiles with epoxides

[78–80]. Anyway, this reaction is important because it is the most direct access

route for the preparation of 1,2-diols, 1,2-alkyloxy, and -aryloxy alcohols.



7 Water as Reaction Medium in the Synthetic Processes Involving Epoxides



219



Jafarpour et al. reported the use of Zr(DS)4 (5 mol-%) as a recoverable and

reusable LASC for the ring opening of epoxides with water under reflux. The same

catalyst was effective in the reactions with alcohols, but in these cases, the transformations were conducted in the same alcohol as reaction medium [75].

Weberskirch et al. reported the hydrolytic kinetic resolution (HKR) of epoxides

in water [81]. The authors designed a novel catalytic system with the intention of

creating a localized area where hydrophobic substrates are concentrated in order to

make reactions proceed more efficiently (micellar catalysis). They prepared core–

shell-type nanoreactors (particle radius in the range of 10–12 nm) where a hydrophobic core furnishes the favorable environment for the catalytic center, that is a

Co(III)–(salen) complex (H2 salen = N,N¢-bis(salicylidene)ethylenediamine), and

the substrate epoxide, while a hydrophilic shell warrants the solubility in water of

the whole nanoreactor. Co(III)–(salen) unit was covalently attached to an amphiphilic

polymer and hence capable to create micellar aggregates in water and form complex

18 (Scheme 7.13). The formation of micellar aggregates of 18 in water at a 0.18–

0.39 mmol/L dilution was studied with transmission electron microscopy (TEM)

analysis and dynamic light scattering (DLS).

O

R



H2O, N2, r.t.

4 examples



HO



O



18 (0.02-0.1 mol%)



R



R

95.6-99.9% ee



OH



86.9-95.9% ee



N



N

Co



O



O



O



t-Bu



Amphiphilic Polymer



O

OAc



t-Bu



t-Bu

18



Scheme 7.13 Hydrolytic kinetic resolution (HKR) of epoxides in water [81]



The efficiency of 18 was studied in the case of aromatic terminal epoxides that

usually need large amounts of Jacobsen’s catalyst and long reaction times under

homogenous conditions [18, 81]. The results obtained were comparable to those

reached under homogenous conditions. The authors successfully generated a nanoreactor with high local concentration of the catalyst in the hydrophobic core, while

the amount of water that could penetrate into the micelle was very little, which is

crucial for achieving high yields and stereoselectivity. The catalyst was recovered

and reused in four consecutive runs without decrease in its efficiency.

The use of a polymeric Co(III)–(salen) complex was also reported by Zheng

et al. in organic solvent or under solvent-free conditions. These authors also showed

that better ees were achieved for the preparation of diols when the recovered catalyst was used with water as reaction medium and as reactant [82].



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