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Rearrangement of β-amino alcohols via aziridiniums: a review
Thomas-Xavier Métro, Béranger Duthion, Domingo Gomez Pardo, Janine Cossy
To cite this version:
Thomas-Xavier Métro, Béranger Duthion, Domingo Gomez Pardo, Janine Cossy. Rearrangement of
β-amino alcohols via aziridiniums: a review. Chemical Society Reviews, Royal Society of Chemistry,
2010, 39, pp.89 - 102. �10.1039/b806985a�. �hal-03228884�
Janine Cossy*
Received 6th October 2008
First published as an Advance Article on the web 8th September 2009 DOI: 10.1039/b806985a
Thistutorial reviewfocuses on the rearrangement ofb-amino alcoholsviaaziridinium intermediates. It covers the literature from 1947 to January 2009 (55 references). The rearrangement ofb-amino alcohols can be performed by activation of the hydroxy group followed by the addition of nucleophiles (Nu). In most examples, an aziridinium intermediate is involved in the rearrangement. The ratio of amines resulting from the attack of nucleophiles at either the C-1 or C-2 position of the aziridinium intermediate, depends on the nature of the nucleophiles and the R2substituent. In some cases, solvent as well as temperature can influence the ratio of amines.
Aziridines have been extensively used as useful building blocks.1,2 The control of the regio- and stereoselectivity in the opening of aziridines provides convenient access to chiral nitrogen-containing compounds.3–6 Although N,N-dialkyl aziridiniums are stronger electrophiles than neutral aziridines, their use as key intermediates in organic synthesis is rare.7–9 Aziridiniums, generally obtained through activation ofb-amino alcohols, can be opened by a wide range of nucleophiles with or without rearrangement depending on the regioselectivity of the nucleophilic attack.
This review covers only the rearrangement of b-amino alcohols of type A,B, and C(Fig. 1) as the rearrangement of prolinols of typeDhas been recently covered.10
1. General overview
When b-amino alcohols A are converted into a derivative bearing a good leaving group (LG), the latter can be displaced through an SNi mechanism to generate aziridiniums F (Scheme 1). In a similar fashion,b-amino alcoholsBcan give F. Subsequently, the liberated anion LGcan then attackF either on the less and/or more substituted carbon atom (C-1 and/or C-2) to produce amines Eand/orG. In the case of b-amino alcohols A, a rearrangement will be observed if anion LGattacks aziridiniumsFat C-2. On the other hand,
the rearrangement ofb-amino alcoholsBintoEwill take place if anion LGattacks aziridiniumsFat C-1. However, even if the attack is regioselective, a mixture of E andG could be obtained as these compounds are in a thermodynamic equilibrium withF. The proportion of aminesEandGis the
Scheme 1
Scheme 2 Fig. 1
Laboratoire de Chimie Organique, Ecole Supe´rieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI ParisTech), CNRS, 10 rue Vauquelin, 75231 Paris Cedex 05, France.
E-mail: domingo.gomez-pardo@espci.fr, janine.cossy@espci.fr;
Fax: (+33) (0)1 40 79 46 60; Tel: (+33) (0)1 40 79 44 29
result of thermodynamic control. Complete rearrangement of amino alcoholsA(orB) will be observed only ifG(orE) are the thermodynamically more stable products (Scheme 1).
In some cases, nucleophiles other than LGare present in the reaction medium and this ‘‘external nucleophile’’ (Nu) can compete with LG, attacking aziridiniumsFat C-1 to produce aminesIor at C-2 to produce aminesH(Scheme 2).
The ratio of amines I and H depends mainly on the
‘‘external nucleophile’’ (Nu) present in the reaction medium.
If Nu, present now inI andHis a good leaving group, the reaction is reversible and the proportion of aminesIandHwill correspond to a thermodynamic equilibrium (thermodynamic control). On the other hand if Nu, present inIandHis not a good leaving group, the opening ofF is irreversible and the reaction will be under kinetic control. In this case, the proportions of aminesIandHwill correspond to the regioselectivity of the nucleophilic attack on the aziridinium intermediate F (Scheme 2).
The major factors that determine the proportion of aminesI and H are the nature of the nucleophile as well as the substituents R1, R10, and R2 (as well as R3 for b-amino
alcoholsC). To a lesser extent, the solvent and the temperature may also affect the product distribution.
2. Influence of the R
2substituent on the rearrangement of b-amino alcohols A and B
2.1 R2= Alkyl
When the R2substituent ofb-amino alcoholsAorBis an alkyl group, the obtained ratio of aminesHandIdepends strongly on the nucleophile (LGor Nu) (cf.Schemes 1 and 2).
2.1.1 Nucleophilic attack at C-2 (formation of amines H) 2.1.1.1 By halide (Cl, Bror F).The first rearrangement of b-amino alcohols of type A was described in 1947 by Brode and Hill.11 The authors observed that the treatment ofb-amino alcohols1and2with SOCl2led to the ammonium chlorides3and4, which after treatment with NaOH led to the same b-chloro amine (Scheme 3). Even though the authors were not able to determine if the obtained product wasb-chloro
Thomas-Xavier Me´tro
Thomas-Xavier Me´tro gradu- ated with a Master’s degree in medicinal biochemistry from the Universite´ de Pharmacie de Montpellier in 2004. He achieved his PhD in organic chemistry in 2007 from the Universite´ Pierre et Marie Curie (Paris) under the super- vision of Dr Domingo Gomez Pardo and Professor Janine Cossy. His research work was dedicated to the rearrange- ment of amino alcohols and its application to the synthesis of bioactive molecules. After having spent one year in Process R&D at Sanofi-Aventis Sisteron, he is currently working on a post-doctoral project in medicinal chemistry at Sanofi-Aventis R&D Montpellier.
Be´ranger Duthion
Be´ranger Duthion studied chemistry at the Ecole Supe´r- ieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI ParisTech).
As a graduate student, he joined the Laboratory of Organic Chemistry of the ESPCI ParisTech and obtained a Master’s degree in bioorganic and organic chemistry at the Universite´ Pierre et Marie Curie (Paris) in 2007. He is currently doing his PhD under the supervision of Dr Domingo Gomez Pardo and Professor Janine Cossy at ESPCI ParisTech.
Domingo Gomez Pardo
Domingo Gomez Pardo is currently Maıˆtre de Confe´rences at the ESPCI ParisTech. He received his PhD in organic chemistry in 1992 from the Universite´ Pierre et Marie Curie (Paris) working with Professor J. d’Angelo. He is interested in synthetic methodo- logies (rearrangement of amino alcohols, ring expansion reactions, synthesis of nitrogen heterocycles, stereoselective reactions) and in their applica- tion to the synthesis of natural products and biologically active molecules.
Janine Cossy
Janine Cossy studied at the University of Reims with Professor J. P. Pe`te. After a postdoctoral stay with Barry Trost, at the University of Wisconsin, she returned to Reims to become Director of Research of the CNRS in 1990. She then moved to Paris to become Professor of Organic Chemistry at the ESPCI ParisTech. She is Director of the CNRS Unit UMR 7084.
From 2003 to 2007, she was President of the Organic Division of the French Chemical Society and since 2005, she has been Associate Editor for Organic Letters.
amine6or7, they supposed that 3and4were transformed into6or7viathe aziridinium intermediate5after treatment with NaOH.
This hypothesis was confirmed by Zirkleet al.,12who showed that under similar conditions, the chloro amine7was produced (attack of5at C-2 by the chloride anion). As the chloride atom is a good leaving group, the reaction is reversible, implying that 7is the thermodynamic product (Scheme 3).
The formation of an aziridinium intermediate was also proven by treating amines6and7with an ‘‘external nucleophile’’.
By using the diphenyl acetonitrile anion, 8 and 9 were obtained in a 50/50 ratio, no matter whichb-chloro amine6 or7was reacting (Scheme 4).13
We have to point out that the treatment of10with SOCl2 led to11which was rearranged to 12at 1401C without any base (Scheme 5).12 Another example of b-amino alcohol rearrangement without any base was described by Achini.14
The rearrangement ofb-amino alcohols of typeAinduced by SOCl2can tolerate a diversity of functionalities present on theN-alkyl moiety, such as a nitrile,14an allyl, an imidazole15 or a sulfonyl group.16
However, whenb-amino alcohols13and16, possessing an electron-withdrawing group (CN or CO2t-Bu) in a position ato the nitrogen atom, were treated with SOCl2then with a base, either the expected rearranged product was not observed (Scheme 6, eqn (1)) or a mixture of rearranged and non- rearranged products was obtained (Scheme 6, eqn (2)).17 The formation of the non-rearranged product can be explained by the low nucleophilicity of the nitrogen due to the orbital overlapnN-s*C–EWG which prevents the total or partial formation of the aziridinium intermediate. Thus a direct substitution of the chlorosulfite intermediate by the chloride anion occurred.18
Interestingly, the proportion ofb-chloro amines17and18 could be modified by applying conditions facilitating the formation of an aziridinium intermediate. Thus, after heating 17and18at 651C in DMF, only the secondary chloride17 was isolated. The authors explained this result by postulating that the aziridinium intermediate19is formed faster from18 than from17(Scheme 6, eqn (2)).
Similar to the formation ofb-chloro amines fromb-amino alcohols when treated with SOCl2, b-bromo amines were obtained from N,N-dialkyl b-amino alcohols 20 or from N-alkyl b-amino alcohol 22 when treated with SOBr2
(Scheme 7).19 Scheme 3
Scheme 4
Scheme 6
Reagents other than SOCl2 and SOBr2 can promote the rearrangement of b-amino alcohols of type Ato the corres- ponding b-amino halides of type H. Among those, MsCl/
Et3N, TsCl/Et3N, Ms2O/LiCl, DAST (F3S–NEt2) and Deoxo-Fluors[F3S–N(CH2CH2OCH3)2] are worthy of note.
For example, when b-amino alcohol 24 was treated with MsCl/Et3N, mesylate25was first observed by NMR spectro- scopy, and this compound was rapidly transformed to b-chloro amine27viaaziridinium26(Scheme 8).20
The use of tosyl chloride also allowed the rearrangement of b-amino alcoholsAtob-chloro aminesH. WhenN,N-dibenzyl b-amino alcohols28were activated with TsCl in the presence of pyridine (Py) and DMAP, b-chloro amines 29 were obtained in 38% to 48% yields (Scheme 9).21
The rearrangement of b-amino alcohols Ato products H can also be performed by treatment with Ms2O/Et3N followed by the addition of LiCl. When24was treated with Ms2O in the presence of Et3N, the rearranged mesylate31was formed and corresponded to the nucleophilic attack of a mesylate anion at the C-2 position of the aziridinium30. As the mesylate was a good leaving group, the reaction was reversible implying that 31 was the thermodynamic product. When mesylate 31 was treated with LiCl, b-chloro amine27 was obtained with retention of configuration of the stereogenic center which can be explained by the formation of the aziridinium intermediate
30followed by the attack of Cl(Scheme 10). The replacement of LiCl by LiBr led to the correspondingb-bromo amine.20
Other conditions, such as the combination of CBr4 with PPh3, were able to convert b-amino alcoholsA tob-bromo amines H. Thus, treatment of b-amino alcohol 32 with CBr4/PPh3in CH2Cl2at room temperature furnishedb-bromo amine34in 71% yield. Treatment of this latter with AgOTf led to the formation of aziridinium35which was attacked at C-1 by the pyrrole to produce, after deprotection of the acetal with TFA, the bicyclic compounds36and360(Scheme 11).22 b-Fluoro aminesHcan also be obtained by rearrangement of b-amino alcohols A. When 37 was reacted with Deoxo-Fluors,b-fluoro amines 38 and 39 were isolated in 71% and 15% yield respectively. In a similar manner, (R)-N,N-dibenzyl-2-amino-propan-1-ol 40 was transformed to41and42in 82% and 7% yield respectively (Scheme 12).
The majorb-fluoro amines38and41are the result of the attack of the fluorine anion on the C-2 position of the aziridinium intermediate 44 formed from 43.23 Contrary to bromide and chloride, fluoride is not a good leaving group.
Consequently, the opening of aziridinium 44 by a fluorine anion is irreversible, and the obtainedb-fluoro amines were the result of kinetic control.
2.1.1.2 By nucleophilic sulfur.The use of sulfides as external nucleophiles also leads predominantly to a nucleophilic attack on aziridinium intermediates at C-2. These intermediates were obtained by activation ofb-amino alcoholsA.
Whenb-amino alcohol45was treated with MsCl/Et3N and then with KSCN, thiocyanate47was formed in 81% yieldvia aziridinium intermediate46(Scheme 13).24
Scheme 7
Scheme 8
Scheme 9
Scheme 10
b-Thioamine5025was isolated in 80% yield,viaaziridinium 49 formed from b-amino alcohol 48 when this latter was reacted with MsCl/Et3N followed by the addition of n-propanethiol (Scheme 14).26As the thio group is not a good leaving group, the reaction is under kinetic control.
2.1.1.3 By nucleophilic oxygen. b-Amino formates (compounds of type H) can also be formed from b-amino alcohols A. When51 reacted with SOBr2 in DMF,b-amino formates 53 and 54 were isolated in 92% and 2% yield respectively (Scheme 15).
The rearrangement ofb-amino alcohol51can be explained by the nucleophilic attack of DMF at the more substituted carbon (C-2) of the aziridinium intermediate52, which led to a Vilsmeier-type intermediate that was further hydrolyzed to the corresponding formate esters53and54.27
Recently,b-amino alcoholsAhave been converted tob-amino alcoholsHby treatment with a stoichiometric amount of trifluoro- acetic anhydride (TFAA) and Et3N followed by the addition of NaOH.28Later on, it was demonstrated that a catalytic amount of trifluoroacetic anhydride can be used to induce the rearrangement ofb-amino alcoholsAtob-amino alcoholsH. Under stoichio- metric or catalytic conditions,20 was transformed to55regio- selectivelyvia aziridinium intermediate56. This enantioselective transformation was achieved in good yield (Scheme 16).28
It is worth noting that whenN-benzylamino alcohol22was treated with trifluoroacetic anhydride (1 equiv.) and Et3N (1 equiv.) followed by the addition of NaOH,N-benzylamino alcohol 57 was isolated in 70% yield and with an excellent enantiomeric excess (Scheme 17).29
The rearrangement of b-amino alcohols was also realized using a catalytic amount of H2SO4(5 mol%) in THF at 1801C under microwave irradiation. Under these conditions,20was transformed into55regioselectively in good yield and with an excellent enantiomeric excess (Scheme 18).28
Scheme 11
Scheme 12
Scheme 14
Scheme 15
2.1.2 Nucleophilic attack at C-1 (formation of amines of type I)
2.1.2.1 By nucleophilic oxygen. Depending on the oxygenated nucleophiles used, a predominant attack of the aziridinium at C-1 by the nucleophiles can also be observed.
For example, after treatment of58with DCC andp-nitrophenol at 95–981C for 60 h, compounds60and61were obtained in a ratio of 10/90 in favour of amino ether61(attack of59at C-1 by the phenate ion) (Scheme 19).30
We have to point out that the nucleophilic attack of a diphosphate anion [(n-Bu4N)3HPO7] on an aziridinium inter- mediate is similar to the attack of a phenate ion.31
2.1.2.2 By nucleophilic carbon.When nucleophilic carbons are used to open an aziridinium, the C-1 position of the aziridinium intermediate is the favoured site of attack. In the case ofb-chloro amine27, obtained by treatment ofb-amino alcohol24with MsCl/Et3N, the addition of NaCN led to62a and63ain a 1/10 ratio in favour of63a. It is worth noting that whereas 27 did not react with cuprates, the addition of Me2CuLi tob-mesylamine31, obtained by treatment of 24 with Ms2O, led to63bin moderate yield (46%) (Scheme 20).20
2.1.2.3 By nucleophilic nitrogen. Contrary to nucleophilic sulfur, oxygen and carbon, the regioselectivity of the nucleo- philic nitrogen attack promoting the opening of aziridinium intermediates, derived from amino alcohols A and B, is difficult to rationalize. Treatment of secondary alcohol 64 with Tf2O followed by the addition of theO-silylated hydroxyl- amine led to the rearranged amine66in 56% yield resulting from the attack of the amine on aziridinium 65 at C-1 (Scheme 21).32
Similarly, the treatment of b-bromo amine 68 with the primary amino group present in 69 led to 70 (46% yield) (Scheme 22).19
However, other reactions were not as clean. The regio- selectivity of the nucleophilic attack of the phthalimide (PhtNH) on aziridinium intermediate 71 was moderate, as compounds 72 and 73 were obtained in a 29/71 ratio (Scheme 23).20
Poor regioselectivity is also observed in the opening of aziridinium74with azides, as the treatment ofb-chloro amine 15with NaN3at 1501C in DMSO led to77and78in a 47/53 ratio. These tetrazoles resulted from an intramolecular [2 + 3]-cycloaddition of intermediates75and76issued from the nucleophilic attack on the aziridinium74by azide anions at C-2 or C-1 respectively (Scheme 24). Although the orbital overlapnN-s*C–CN may lower the nucleophilicity of the nitrogen atom in15, conditions facilitating the formation of Scheme 16
Scheme 17
Scheme 18
Scheme 19
Scheme 20
an aziridinium intermediate (DMSO, 150 1C) allowed the rearrangement ofb-chloro amine15.18
The regioselectivity of the nucleophilic attack on an aziridinium intermediate depends on the amino compound as well as on the nature of the substituents present in the aziridinium.26
The influence of theN-alkyl groups (R1) as well as the R2 group on the regioselectivity of the attack of the aziridinium intermediates by amines has been the subject of a few studies.
Thus, whenb-amino alcohol79(R1= allyl) was treated with
Tf2O/Et3N in the presence of morpholine, a mixture of regioisomers 81 and 82 was obtained in a ratio of 12/88 in favour of 82 (attack of the aziridinium 80 at C-1). The selectivity was increased when the twoN,N-allyl substituents were replaced with twoN,N-benzyl groups (Scheme 25).33
In the case of the nucleophilic attack of aziridiniums 84 with bulky R2 groups (Bn 4 Me), by methylamine, a better regioselectivity was observed. The major products were diamines 85, which corresponded to the attack of methylamine at the less sterically hindered position of aziridinium84(position C-1) (Scheme 26).34In this latter case, the mechanism of the rearrangement has been studied and two processes can take place, either the attack of the aziridinium at C-1 by methylamine (predominant process) and a direct substitution of the mesylate83by methylamine (minor process).34
Scheme 22
Scheme 23
Scheme 24
Scheme 25
Furthermore, it has been shown that aziridinium inter- mediates are not always formed, particularly when b-amino alcohols are treated with sulfonyl reagents in a non-polar solvent. A cyclic intermediate 87 can be formed instead of an aziridinium intermediate (Fig. 2).35
2.2 R2= an electron-withdrawing group (EWG): CF3or CO2R
AziridiniumsF0, issued fromb-amino alcoholsA0, where R2is an electron-withdrawing substituent such as CF3or CO2R, are in general, attacked by nucleophiles at C-2 as this carbon atom is more electropositive than C-1. If the Nu group present in aminesH0andI0is not a good leaving group, the reaction will be under kinetic control and compoundsH0will be favoured (attack at C-2) (Scheme 27).
2.2.1 Nucleophilic attack at C-1 (formation of amines of type I0). When b-amino alcohol 88, substituted by a CF3 group, was treated with PPh3Cl2, halide90awas obtained in 91% yield resulting from the attack of the aziridinium89at C-1. Identical regioselectivity was observed with PPh3Br2, giving the corresponding b-bromo amine 90b in 46% yield (Scheme 28).36
The formation of 90a and90b could be explained by the presence of the electron-withdrawing CF3group which could decrease the nucleophilicity of the nitrogen in compound90 enough to prevent reversion to aziridinium 89. In this case, b-amino halide90would be the kinetic product. On the other hand, if the nitrogen atom in90 was nucleophilic enough to form aziridinium 89, anion X would have attacked the aziridinium intermediate89 at C-1 and/or C-2, butb-amino halide90would have been the thermodynamic product.
2.2.2 Nucleophilic attack at C-2 (formation of amines of type H0)
2.2.2.1 By halide. Similar to 88, b-amino alcohol 91, containing an ester group, led to b-mesyl amine 92 when treated with MsCl/Et3N at room temperature (Scheme 29).37 In this case, it was not possible to know if an aziridinium intermediate was formed during the transformation or not.
The mesylate92was described as stable and this stability was assigned to the steric hindrance of the twoN,N-benzyl groups which could prevent92from the formation of an aziridinium intermediate from theb-elimination of the mesylate.
However, it was later proven that when harsher conditions were used, mesylate92could be transformed into an aziridinium species. Thus, when b-amino alcohol 91 was treated with MsCl/Et3N at 1101C in methylisobutylketone, the rearranged Scheme 26
Fig. 2
Scheme 27
Scheme 28
Scheme 29
halide93was obtained in 93% yield. This halide is the result of the nucleophilic attack of the aziridinium 94 at C-2 by the chloride anion (Scheme 29).38
When a fluoride anion was used as the nucleophile, the products obtained were also the result of an attack at the C-2 position of the aziridinium intermediate. b-Fluoro amine 96 was obtained after treatment of b-amino alcohol 95 with DAST (Scheme 30).39–41
The presence of an alkyl group R3 such as in b-amino alcohols 97 can modify the regioselectivity of the attack of the aziridinium intermediate by the fluoride anion. When97a (R3= Me) was treated with DAST, a mixture of regioisomers 99a (attack at C-2) and 100a(attack at C-1) was obtained.
It is worth noting that when R3was an isopropyl group, only b-amino fluoride99bwas isolated (Scheme 31).39
2.2.2.2 By nucleophilic nitrogen and sulfur.In general, the attack of an aziridinium substituted by an ester group at C-2 by nucleophilic nitrogen or nucleophilic sulfur takes place at C-2. When mesylate92was heated at 801C in MeCN in the presence of a nucleophilic nitrogen, the major compound102 generally resulted from the nucleophilic attack of the aziridinium 101at C-2 (Scheme 32). However, the rearranged compounds 102 were obtained with yields strongly depending on the nucleophilic nitrogen. The best yields were obtained with morpholine (92%).37
When thiols were used as nucleophiles, aziridinium101was attacked at C-2 and the rearranged products102were isolated in moderate yields (42–50%) (Scheme 32).37
2.3 R2= Aryl
When R2is an aryl group, the C-2 position of the aziridinium F0 0, being an electrophilic benzylic position, is prone to nucleophilic attack. No matter which nucleophile is used, the attack of the aziridinium always occurs at C-2, thus producing aminesH0 0 (Scheme 33).
2.3.1 Nucleophilic attack at C-2 (formation of amines H0 0) 2.3.1.1 By halide. The first rearrangement of a b-amino alcohol possessing an R2aryl group was realized withb-amino alcohol 104 using SOCl2 in Et2O without any base. Under these conditions, the rearrangedb-chloro ammonium105was obtained in 72% yield (Scheme 34).42 The first explanation for the rearrangement of104to105was the direct transformation of the chlorosulfite intermediate107to the rearrangedb-chloro amine108(Scheme 34, path 1). A second explanation could be the formation of the aziridinium intermediate109issued from an intramolecular nucleophilic attack of the pyrrolidine ring at the carbon bearing the chlorosulfite in107(Scheme 34, path 2).
This aziridinium109could be attacked by the chloride anion at the benzylic position (C-2) to produce the ammonium salt 105via108(Scheme 34).
The rearrangement ofb-amino alcohols induced by SOCl2is general, as compounds110 were respectively transformed to the correspondingb-chloro amines111 in good to excellent yields (58%oyieldo100%) (Scheme 35).14,17
It is worth noting that, b-chloro amine 115 was the only isolated product when a mixture of b-amino alcohols 112 and 113 was treated with MsCl/Et3N in dichloromethane (nucleophilic attack on aziridinium intermediate114 at C-2 by the chloride anion) (Scheme 36).43
2.3.1.2 By nucleophilic nitrogen, oxygen and sulfur. When b-amino alcohol 116 was treated with MsCl/Et3N in the presence ofn-butylamine, diamine11844was the result of the nucleophilic attack on intermediate117(Scheme 37).26 Scheme 31
Scheme 33
Similar results were obtained when amines,45–48 alcohols49 or thiols45,49were used as nucleophiles. Good regioselectivity for the nucleophilic attack on the aziridinium intermediate at C-2 was observed.
Mitsunobu conditions have also been used to induce the rearrangement of b-amino alcohols in which R2 is an
aryl group. Treatment of b-amino alcohol 119 with PPh3/1,10-(azodicarbonyl)dipiperidine (ADDP) in the presence of 2-methoxyphenol led to ethers120and121in a 96/4 ratio in favour of120(92% yield) (nucleophilic attack on the aziridinium intermediate at C-2) (Scheme 38).50
The use of acetyl chloride also promoted the rearrangement ofb-amino alcohol104. Whereas ester123was obtained as the major product (58% yield), the rearranged ester 122 was isolated in moderate yield (15%).42A concerted mechanism was proposed to explain the transformation of104to122via intermediate124(Scheme 39).
b-Amino alcohol 125 has been transformed to b-amino alcohol 126 by treatment with a stoichiometric amount of trifluoroacetic anhydride (TFAA) and Et3N followed by the Scheme 34
Scheme 35
Scheme 36
Scheme 37
Scheme 38
Scheme 39
addition of NaOH or by treatment with a catalytic amount of trifluoroacetic anhydride. Under these conditions b-amino alcohol125was transformed,viaan aziridinium intermediate, to b-amino alcohol 126 in good yield and with excellent enantioselectivity (Scheme 40).28
b-Amino alcohols possessing a quaternary center can also be rearranged under these conditions with almost no loss of chirality. (R)-N,N-Dibenzyl-2-allyl-2-phenylglycinol 127 was transformed to 128 in 63% yield when subjected to TFAA (2.0 equiv.) and Et3N (3.0 equiv.) (Scheme 41).28
It is worth noting that when N-benzylphenylglycinol 129 was treated with TFAA (1.0 equiv.) and Et3N (1.0 equiv.) followed by the addition of NaOH, the rearrangedN-benzyl- amino alcohol130was isolated in 72% yield with an enantiomeric excess of 94% (Scheme 42).29
The rearrangement ofb-amino alcohol125was also induced by a catalytic amount of H2SO4(5 mol%) in THF at 1801C under microwave irradiation (MW) for 2 h. Under these conditions 125 was converted to 126 (65% yield, 95% ee) (Scheme 43).28
the ratio of compounds L andM can be influenced by the presence of the R3substituent (Scheme 44).
3.1 R3= Alkyl
In general, if the R3substituent ofb-amino alcoholsCis an alkyl group, the rearranged products are the result of a nucleophilic attack on the benzylic position of the aziridinium intermediate. Thus, whenb-amino alcohols131were treated with MsCl/Et3N in the presence of potassium thioacetate (AcSK), the only products isolated were compounds 133, which resulted from the attack of the nucleophile on the benzylic position of the aziridinium intermediate 132 (Scheme 45).51
This benzylic attack was also observed when b-amino alcohols134and135were reacted under Mitsunobu conditions (DEAD/PPh3) in the presence of 2-methoxyphenol to furnish 136(Scheme 46).52
Scheme 40
Scheme 41
Scheme 42
Scheme 43
Scheme 44
Scheme 45
However, when N-methylpseudoephedrine ()-137 was treated with MsCl/Et3N, a mixture of regioisomers 139and 140 was obtained.52 b-Amino chloride 140 may not be the result of a kinetic control as after four days in refluxing benzene, conditions that should have brought about a thermo- dynamic equilibrium, a mixture ofb-amino chlorides139and 140 was still observed.26The formation of b-amino chloride 141was probably the result of an epimerisation at the benzylic position (Scheme 47).
Similarly, when N-methylpseudoephedrine (+)-137 was reacted under Mitsunobu conditions in the presence of 4-nitrobenzoic acid, a mixture of regioisomers 142 and 143 was obtained in a 33/67 ratio in favour of nitrobenzoate143, (attack of the nucleophile at the C-2 position of the aziridinium) (Scheme 48).53
When the same conditions were applied to N-methyl- ephedrine 144, this latter was not transformed to the rearranged product 146, but rather to b-amino ester 145, which corresponds to the nucleophilic attack on an aziridinium intermediate at the benzylic position with retention of configuration (Scheme 49).53
The use ofb-amino alcohol147as the starting material for the synthesis of ecopipam is an interesting example where the rearrangement of a b-amino alcohol C was realized on an industrial scale.54The ecopipam precursor150 was obtained by nucleophilic attack of the arylmagnesium bromide149on the benzylic position of the aziridinium148. The rearrangement ofb-amino alcohol147was achieved in a wide range of yields (0–84%) by activation of the hydroxy group with phosphorus- based reagents. A good yield (80–82%) of150 was obtained when pentavalent phosphorus-based reagents were used.
Among them the best reagent to induce the rearrangement was revealed to be ClP(O)(OPh)2with which150was formed in 84% yield (Scheme 50).
3.2 R3= Electron-withdrawing group
Whenb-amino alcoholsC0possess an R2aryl group and an R3 electron-withdrawing group (R3= EWG), both the C-1 and Scheme 46
Scheme 47
Scheme 48
Scheme 49
Scheme 50
C-2 positions of aziridinium K0 are activated, resulting in competitive formation of aminesL0and/orM0(Scheme 51).
When a mixture of b-amino alcohols 152 and 153 was treated with MsCl/Et3N, benzylic chlorides of type155were obtained exclusively (Scheme 52).55,56Even when R3was an ester group, no isomer from the nucleophilic attack on aziridinium154at C-1 was detected.
On the other hand, when thiols were used as nucleophiles, the other regioisomers, compounds158, were formed as the major products (ratio158/1594 82/18) (Scheme 53).55,56The regio- selective attack on aziridinium intermediate157by nucleophiles was probably related to HSAB theory.
Finally, when b-amino hydroxy phosphonate 160 was treated with MsCl/Et3N in the presence of nucleophiles (amines, chloride and H2O), only rearranged products 161, resulting from the attack of nucleophiles at the benzylic position of the aziridinium were observed (Scheme 54).57 The presence of the electron-withdrawing phosphonate group did not affect the regioselectivity of the nucleophilic attack on the aziridinium intermediate.
Conclusion
The rearrangement ofb-amino alcohols of typeA,B, orCcan be performed by activation of the hydroxy group followed by the addition of nucleophiles. In most examples, an aziridinium intermediate is involved in the rearrangement. The ratio of amines H and I (L and M), resulting from the attack on aziridinium intermediates at either C-1 or C-2 by nucleophiles, depends on the nature of the nucleophiles and R2 and R3 substituents. In some cases, the solvent as well as the temperature can influence the ratio of amines H and I (L and M).
A summary of the rearranged products H and/or I issued fromAandB(Scheme 55) is reported in Table 1.
Scheme 51
Scheme 52
Scheme 53 Scheme 55
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Table 1 Final products (Hand/orI) obtained by nucleophilic attack on aziridiniumsF
R2
Nu
Br Cl F Sa Ob CF3CO2 SO42 DMF Nc Cd
Alkyl H H H+I H H+I H H H+I H+I H+I
CF3 I I — — — — — — — —
CO2R — H H H — — — — H+I —
Aryl H H H H H+I H H — H H
aNucleophilic sulfurs.bNucleophilic oxygens.cNucleophilic nitrogens.dNucleophilic carbons.
