chemcomm viewonline dynamic article linksszolcsanyi/education/files... · 3. [3,3]-sigmatropic...

4624 Chem. Commun., 2011, 47, 4624–4639 This journal is c The Royal Society of Chemistry 2011

Cite this: Chem. Commun., 2011, 47, 4624–4639

Quaternary centres bearing nitrogen (a-tertiary amines) as products

of molecular rearrangements

Jonathan Clayden,* Morgan Donnard, Julien Lefranc and Daniel J. Tetlow

Received 4th January 2011, Accepted 1st February 2011

DOI: 10.1039/c1cc00049g

Quaternary centres bearing a nitrogen substituent (a-tertiary amines and their derivatives) are

found in a variety of bioactive molecules but pose a major challenge in synthesis, particularly

when enantiomeric purity is required. Approaches comparable to those used for tertiary alcohols

are typically hampered by the poor electrophilicity of imines, requiring powerful nucleophiles that

may also act as bases. A set of powerful alternative approaches make use of the rearrangement

of readily available precursors, often (but not always) with formation of a new tertiary carbon to

nitrogen bond. In this Feature Article we review the scope, limitations and specificities of some

of these rearrangements in order to illuminate their synthetic potential.

1. Introduction

Among the simple structural classes which form the building

blocks of organic chemistry, a-tertiary amines 1 pose a

surprisingly difficult synthetic challenge—especially when the

quaternary carbon centre has to be synthesised in an enantio-

selective way. Nonetheless, their wide occurrence in naturally

occurring and synthetic bioactive molecules1 (Fig. 1) has

provided an impetus for the development of a number of

synthetic strategies over the last 50 years. The most common

approach has been the addition of a nucleophile to a

ketimine,2 but the lack of reactivity of these species coupled

School of Chemistry, University of Manchester, Oxford Road,Manchester, M13 9PL, United Kingdom.E-mail: [email protected]

Daniel J. Tetlow, Julien Lefranc, Morgan Donnard and

Jonathan Clayden

Jonathan Clayden was born in Uganda in 1968, grew up in Essex,and was an undergraduate at Churchill College, Cambridge. In1992 he completed a PhD at the University of Cambridge withDr Stuart Warren. After postdoctoral work with Prof. Marc Juliaat the Ecole Normale Superieure in Paris, he moved in 1994 toManchester and in 2001 was promoted to a chair in organicchemistry. He has published over 175 papers, and his researchinterests encompass various areas of synthesis and stereochemistry,particularly where conformation has a role to play: asymmetricsynthesis, atropisomerism, organolithium chemistry, dearomatisingreactions and remote stereocontrol. He is co-author of thebest-selling textbook ‘‘Organic Chemistry’’(OUP, 2001), and of‘‘Organolithiums: Selectivity for Synthesis’’ (Pergamon, 2002).He has received the Royal Society of Chemistry’s Meldola (1997)and Corday Morgan (2003) medals, Stereochemistry Prize (2005)and Hickinbottom Fellowship (2006).

Morgan Donnard was born in 1980 in Strasbourg, France. After a stay in Netherlands at DSMPharmaceuticals where he worked withProf. Johannes De Vries, he returned to Strasbourg where he graduated in chemistry and biology in 2005 with Dr Andre Mann. In 2008,he completed his doctoral studies with Prof. Jacques Eustache at the Ecole Nationale Superieure de Chimie in Mulhouse (F). In 2011,after 2 years working as a postdoctoral researcher with Prof. Jonathan Clayden on asymmetric organolithium rearrangements, Morganjoined Dr Nicolas Blanchard in Mulhouse and his research interests are focusing on ynamide reactivity and organo-metallic chemistry.

Julien Lefranc was born in 1984 in Marseille, France. He studied chemistry at the Universite de la Mediterranee, Marseille, and thenmoved to the Ecole Nationale Superieure de Chimie de Montpellier in 2006. In 2008 He joined the group of Prof. Jonathan Claydenwhere he is now completing his PhD working on the applications of new carbolithiation reactions.

Daniel J. Tetlow was born inWarrington, UK, in 1984. He graduated from the University of Leeds in 2007, after which he undertook apostgraduate research project with Prof. Jonathan Clayden at the University of Manchester. His PhD work focuses on the asymmetricsynthesis of hindered amine derivatives.

ChemComm Dynamic Article Links

www.rsc.org/chemcomm FEATURE ARTICLE

Dow

nloa

ded

by U

nive

rsity

of

Oxf

ord

on 0

6 A

pril

2011

Publ

ishe

d on

07

Mar

ch 2

011

on h

ttp://

pubs

.rsc

.org

| do

i:10.

1039

/C1C

C00

049G

View Online

http://dx.doi.org/10.1039/c1cc00049g



This journal is c The Royal Society of Chemistry 2011 Chem. Commun., 2011, 47, 4624–4639 4625

with the difficulty of achieving good stereoselectivity2e has

encouraged the exploration of alternative ways of constructing

of the quaternary centre. Of these, rearrangement of readily

available substrates appears to be one of the most promising,

and has already allowed the development of powerful tools for

the synthesis of compounds that would be far more challenging

to obtain efficiently by other methods. An important feature of

many of these rearrangements is a well-defined cyclic transi-

tion state, allowing a high degree of stereospecificity and/or

stereoselectivity. By their nature, rearrangements are atom-

economic processes, consistent with the requirements of

modern efficient synthetic methods.3

In this article we review the scope, limitations and specificities

of some of these rearrangements, illustrating our discussion

with selected examples from the literature. Most of the major

synthetic advances in this field have been made over the last

fifteen years. For this reason the review focusses principally

on the period 1995–2010. Our own interest in the use of

rearrangements to synthesise hindered amines was spurred

by our discovery, in 2006, of a new rearrangement of lithiated

ureas, and the article concludes with an analysis of these urea

rearrangements as a new means of making a-tertiary amines 1.

2. Curtius rearrangement

In 1890, Curtius observed the decomposition of acyl azide 2

with loss of nitrogen (3) to generate aniline after hydrolysis

of the intermediate isocyanate 4 (Scheme 1).4 The Curtius

rearrangement now provides a valuable and commonly used

way to synthesise amines from the corresponding acid

(Scheme 1).

In 2005, Lebel and coworkers published a one-pot method

for the synthesis of Boc-protected amines from carboxylic

acids using the Curtius rearrangement.5 In this example, the

treatment of the acid 6 with a mixture of Boc2O and sodium

azide in the presence of a phase-transfer catalyst, at room

temperature, produced the acyl azide. The desired carbamate 7

was generated by increasing the temperature to 80 1C (Scheme 2).

When the reaction was carried out at 40 1C, only traces of 7

were observed. This problem was solved using zinc triflate as

an additive (3.3 mol%), which resulted in complete con-

version. Malonate derivatives 8 were also used as substrates

for the rearrangement, with the corresponding amino acid

derivatives 9 being obtained in good yields (Scheme 3).

The Curtius rearrangement can also be performed on

strained substrates such as cyclopropenes6 or cyclobutane

derivates.7 In 2009, Baudoin and coworkers reported a synthesis

of 3,4-dihydroisoquinolines using a Curtius rearrangement of

benzocyclobutenes 10 (Scheme 4).

Sunami and coworkers have reported an efficient method

for solid phase synthesis of amines.8 The carboxylic acid 13

was converted to the corresponding isocyanate 14 which can

be trapped with Wang resin to generate the carbamate 15.

Fig. 1 Bioactive molecules bearing an a-tertiary amine.

Scheme 1 Curtius rearrangement.

Scheme 2 Synthesis of Boc-protected amines using Curtius

rearrangement.

Scheme 3 Curtius rearrangement in the presence of zinc-triflate.

Scheme 4 Synthesis of dihydroisoquinolines.

Scheme 5 Curtius rearrangement and reaction with Wang resin.

Dow

nloa

ded

by U

nive

rsity

of

Oxf

ord

on 0

6 A

pril

2011

Publ

ishe

d on

07

Mar

ch 2

011

on h

ttp://

pubs

.rsc

.org

| do

i:10.

1039

/C1C

C00

049G

View Online



Cleavage of the resin using TFA led to the desired amine 16

(Scheme 5).

3. [3,3]-Sigmatropic rearrangements

[3,3]-Sigmatropic rearrangements have long been used in

organic chemistry, due to the fact that they allow regio and

stereoselective carbon–carbon or carbon–heteroatom bond

formation with relative ease.

3.1 Allylic cyanate to isocyanate rearrangement

3.1.1 Thiocyanate to thioisocyanate (the Billeter–Gerlich

rearrangement). The first [3,3]-sigmatropic rearrangement to

be described—the transposition of allyl thiocyanate to allyl

isothiocyanate (mustard oil)—was discovered independently

in 1875 by Otto Billeter9 and Gustav Gerlich.10 This reaction

has received detailed investigation11 over the last century and

it is now well established that it proceeds via a suprafacial

mechanism.12 Surprisingly few studies involving the construc-

tion of a quaternary centre have been reported: in those

few cases the reaction takes place efficiently. An interesting

example was reported by Gonda et al. during investigation

into the diastereoselective synthesis of 3-(S)-isothiocyanato-

3-deoxy-3-C-vinyl glucose13 18, a compound which can be

easily converted to an advanced precursor of (+)-myriocin14

(Scheme 6). In the course of these studies Gonda demonstrated

that the [3,3]-sigmatropic rearrangement of both geometrical

isomers of the substrate 17 to allylic hexofuranosides 18

(Scheme 6) provides the same diastereoisomerically pure

product. The results, supported by DFT calculations, allowed

the authors to attribute the stereoselectivity of the reaction to

the steric interactions of the 1,2-O-isopropylidene group in the

transition state 19 (Scheme 7). In addition, optimisation of this

thermal rearrangement (usually performed at 90 1C in o-xylene

for 4 h) showed that the time of reaction can be halved with

identical results (i.e. 88% yield, 1 diastereoisomer) by using

microwave irradiation.

3.1.2 Cyanate to isocyanate. The first rearrangement of

this type involving a cyanate instead of a thiocyanate was

reported by Holms et al. in 1970.15 In spite of the fairly mild

conditions, the difficulties encountered in generating the allyl

cyanate discouraged chemists from using this approach until

Ichikawa et al.16 improved Holms’s concept by developing a

more convenient approach from its corresponding carbamate

20. A simple dehydration of this readily-obtained starting

material gives an allyl cyanate 21 as an intermediate which,

under these conditions, spontaneously rearranges to the

desired product 23 in good yields. In addition to its practical

advantages, this modification allowed for the first time the efficient

synthesis (yield Z 90%) of a quaternary carbon atom bearing a

nitrogen substituent using this transformation (Scheme 8). It is

interesting to notice that under normal conditions a 3-substituted

cyclohexenyl group gave rise to a [1,3]-sigmatropic17 product

(16%) in addition to the desired allylic rearrangement (38%).

However, the addition of methoxytributyltin and methanol

allowed this competitive pathway to be avoided by directly

converting the [3,3]-sigmatropic product into its corresponding

methyl carbamate in good overall yield (70%).18

This reaction proceeds with a complete 1,3-transfer of

stereochemistry.19 This stereospecificity can be explained by

the lower energy transition state 25-A which leads to the

isocyanate with a E-double bond. By contrast, the Z-isomer

is never observed, undoubtedly due to the A1,3 strain incurred

in the alternative transition state 25-B20 (Fig. 2). In 2001, the

first direct observation, by NMR, of the [3,3]-sigmatropic

cyanate to isocyanate rearrangement was made by Banert

et al., allowing measurement of its activation parameters.21 The

large negative activation entropy (DSa o �100 J mol�1 K�1) is

characteristic of a cyclic transition state. During this study it was

furthermore demonstrated that this transposition is much more

rapid than the analogous rearrangement of a propargylic cyanate

to an allenyl isocyanate.

Since this reaction proceeds under mild conditions with

complete stereospecificity, it has been used as a key tool forScheme 6 Thiocyanate to thioisocyanate rearrangement.

Scheme 7 Stereoselectivity of the thiocyanate-to-thioisocyanate

rearrangement in the case of Gonda’s (+)-myriocin synthesis.

Scheme 8 Ichikawa’s domino dehydration–[3,3]-sigmatropic rearrange-

ment of carbamates.

Dow

nloa

ded

by U

nive

rsity

of

Oxf

ord

on 0

6 A

pril

2011

Publ

ishe

d on

07

Mar

ch 2

011

on h

ttp://

pubs

.rsc

.org

| do

i:10.

1039

/C1C

C00

049G

View Online



the construction of quaternary centres bearing nitrogen in

several total syntheses. Recent examples feature in the syntheses

of (�)-adaline and (�)-euphococcine reported by Spino

et al.,22 the synthesis of prostaglandin derivatives described

by Florent et al.23 and the (S)-ketamine synthesis by Kiyooka

et al.24 Common to all these studies is the fact that the

[3,3]-sigmatropic rearrangement provides a crucial step for

the efficient and stereoselective syntheses of compounds that

were previously challenging to obtain.

3.2 Allylic imidate rearrangement (the Overman

rearrangement)

The aza-Claisen rearrangement is a [3,3]-sigmatropic rearrange-

ment involving an iminium CQN bond acting as a p component,

and much interest has been invested in the development of this

reaction and its variants. Some of the advances in this area

have been discussed in recent reviews.25

3.2.1 Thermal rearrangement. In 1974, Overman first

reported the conversion of a trichloroacetimidate into a trichloro-

acetamide either by heating or by metal (M = Hg, Pd or Co)

catalysis. More recent work has greatly expanded this field.

This rearrangement offers an elegant route to allylic amines

from their counterpart allylic alcohols. Treating the allylic

alcohol with trichloroacetonitrile in the presence of base

(DBU) gives rise to the allylic trichloroacetimidate esters

29.26 Heating 29 leads to a [3,3]-sigmatropic rearrangement,

and subsequent removal of the trichloroacetamide group under

basic conditions gives the free allylic amine (Scheme 9).

Chirality is retained in the sigmatropic rearrangement by

suprafacial migration through the chair-like transition state

shown for the rearrangement of 31 (Scheme 10).27

More recently Ramachandran et al. have exploited as

starting materials for this reaction the addition products of

unsaturated aldehydes and the a-pinene based allylborating

reagents 35. The resulting homoallylic allylic alcohols, formed

in moderate to good yields with high ees, were subjected to

the Overman rearrangement to give the trichloroacetamides 36

in good yields and retention of configuration (Scheme 11).28

Further chemical transformations allow access to the

a,a-disubstituted amino acid derivatives 38 (Scheme 12).

The thermal [3,3]-sigmatropic rearrangement of imidates

has been utilised in a number of total syntheses, such as the

synthesis of sphingofungins E, F and lactacystin.29 In Isobe’s

synthesis of tetrodotoxin, the potent toxin found in the puffer

fish,30 the acetimidate 39 undergoes rearrangement to acetamide

40 (Scheme 13). The steric constraints of the ring system

favour conformer 41, which in turn dictates the stereochemistry

Fig. 2 Stereoselectivity of the [3,3]-sigmatropic cyanate-to-isocyanate

rearrangement.

Scheme 9 [3,3]-Sigmatropic (Overman) rearrangement of a trichloro-

acetimidate.Scheme 10 Overman-rearrangement chirality transfer.

Scheme 11 Allylborylation and Overman rearrangement sequence.

Scheme 12 Synthesis of unnatural a-amino acid 38.

Scheme 13 Overman rearrangement in the synthesis of tetrodotoxin.

Dow

nloa

ded

by U

nive

rsity

of

Oxf

ord

on 0

6 A

pril

2011

Publ

ishe

d on

07

Mar

ch 2

011

on h

ttp://

pubs

.rsc

.org

| do

i:10.

1039

/C1C

C00

049G

View Online



of the rearrangement. Further chemical transformations yield

tetrodotoxin.

3.2.2 Metal-catalysed rearrangement. The aza-Claisen

rearrangement can be catalysed by transition metals, allowing

the reaction to take place at a lower temperature. Catalysts

tend to be soft metal salts such as those of palladium(II) and

mercury(II).31 It is presumed that this reaction occurs via a

cyclic intermediate (as shown in Scheme 14 for a Pd(II)

catalyst),32 and chiral catalysts have been developed to allow

this reaction to take place enantioselectively.

Overman and coworkers reported the use of cobalt based

palladacycles 49 in 2003.33 These catalysts allow the aza-Claisen

rearrangement of trichloroacetimidates to take place with high

enantioselectivities (Scheme 15).

The COP catalysts 49were an improvement on the previously

reported ferrocene analogue FOP 48 (Scheme 16): they avoid

the need for activation by silver salts and are easier to prepare.

The use of the COP catalysts allows prochiral imidates 46 to

be converted to the chiral allylic acetamides 47. By careful

selection of amine protecting group, the corresponding

enantiomerically enriched amine can also be obtained.34

Application of these catalysts to the synthesis of quaternary

stereocentres has not been straightforward, due to the steric

bulk of C3-disubstituted allylic alcohols. These catalyst systems

also struggle to rearrange trifluoroacetimidates (requiring Pd

loadings of 410%), which are more desirable substrates as a

result of the ease of hydrolysis of the trifluoroacetamide group.

In 2006 Berkowitz et al. reported the synthesis of racemic

amines bearing a quaternary centre using a palladium-catalysed

aza-Claisen reaction of PMP protected trifluoroimidates 52.

Optimal catalysts were found to be Cl2Pd(MeCN)2 or

Cl2Pd(PhCN)2.35 The amines synthesised contain a protected

hydroxyl group which can be further manipulated in order to

access vinyl-substituted a-amino acids 54 (Scheme 17).

Not long after this racemic reaction was reported, the Peters

group reported the development of a group of catalysts that

are effective for the enantioselective generation of quaternary

carbon centres. A series of ferrocenylimidazoline palladacycle

(FIP) catalysts (which require activating silver salts)

induce high levels of enantioselectivity in the rearrangement

(Scheme 17).36

Initially the palladacycle 50 allowed a series of highly

enantioenriched N-aryl/alkyl amidates to be synthesised, but

the catalyst was further improved by creating a hybrid between

50 and COP 49. After optimisation of rearrangement con-

dition, the palladacycle 51 allowed the synthesis of allylic

amines bearing quaternary stereocentres (Table 1).

More hindered substrates are problematic, as the catalyst

begins to struggle when both substituents are bigger than

methyl groups: higher catalyst loadings are required and a

drop off in yield is also observed.

The enantioselectivity of the rearrangement, induced by the

planar chirality of the palladium complex, is independent of

the steric difference between the R and R1 substituents of the

olefin. The reaction is sterospecific, with E and Z olefins giving

opposite enantiomers. The enantiodetermining step is thought

to be the face-selective coordination of the olefin to the

active palladium complex. The olefin is expected to coordinate

trans to the imidazoline nitrogen, allowing the imidate nitrogen

to attack the face of the olefin trans to Pd. The less sterically

demanding olefin coordinates near the ferrocene core reducing

unfavourable interactions, whereas the bulkier imidate is

kept away from the ferrocene (see Scheme 18 for a pictorial

representation). The protected amide products 57 can undergo

further transformations to provide for example synthetically

useful a- and b-amino acids (Scheme 19).

It is important to note that the choice of activating agent

plays a crucial role in the catalytic activity of these systems.

With AgO2CCF3 the hybrid catalyst 51 performs worse than

FIP 50, but with AgNO3 excellent catalytic activity is restored.

Scheme 14 General catalytic cycle for palladium catalysed aza-Claisen

rearrangement of imidates.

Scheme 15 Asymmetric synthesis of chiral amine synthons.

Scheme 16 Catalysts for the asymmetric aza-Claisen rearrangement.

Scheme 17 Racemic synthesis of quaternary stereocentres bearing

nitrogen via palladium-catalysed aza-Claisen rearrangement.

Dow

nloa

ded

by U

nive

rsity

of

Oxf

ord

on 0

6 A

pril

2011

Publ

ishe

d on

07

Mar

ch 2

011

on h

ttp://

pubs

.rsc

.org

| do

i:10.

1039

/C1C

C00

049G

View Online



Despite these developments, access to these highly substituted

amines via the aza-Claisen rearrangement is still challenging.

3.3 Phosphorimidate rearrangements

In 2004 Mapp et al. described for the first time a one-

pot phosphorimidate to phosphoramidate [3,3]-sigmatropic

rearrangement.37 The allylic phosphorimidate 62, being the

reactive intermediate in this transposition, is produced in situ

by a three-component combination of an allylic alcohol, a

chlorophosphite and an organic azide. Crossover experiments

confirm that the rearrangement is intramolecular and that, as

usual, the stereochemistry of the starting material is efficiently

transferred to the transposed product. However, even though

the reaction gives quaternary carbon atoms efficiently (yield up

to 70%) (Scheme 20), the reaction was explored only with

achiral starting materials.38 Nonetheless, this reaction remains

particularly interesting when it is considered that one of the

protecting groups on the nitrogen of the fully protected allylic

amine product 63 is a phosphoramidate.39 Phosphoramidates

are stable under a wide range of reaction conditions but can

nonetheless be easily removed by either treatment with TMSI

or nucleophilic attack by a thiol followed by HCl/MeOH.40

It is interesting to notice as well that the second protecting

group, derived from the azide, can be very easily varied—the

three-component process is particularly tolerant of such

variations. Activation of the allylic system either by incorpora-

tion of electron-deficient functional groups or by using a

transition metal catalyst significantly facilitates the reaction.

4. Steglich–Hofle rearrangement (O to C acyl

transfer)

An interesting and powerful way to make quaternary oxazolones

(precursors of a-alkylated a-aminomalonic acids) is the organo-

catalysed rearrangement of 5-acyloxyoxazoles 64 into the

corresponding C-4 acylated oxazolone 65. First discovered

by Steglich and Hofle in 197041 as a racemic transposi-

tion promoted by 4-(dimethylamino)pyridine (DMAP) or

4-(pyrrolidino)pyridine (PPY), this reaction advanced in utility

in 1998 when Fu et al. developed the first enantioselective

version, introducing new planar-chiral derivatives of the

catalysts42 67 and 68 (Scheme 21). This study demonstrated

that the best enantiodiscrimination is obtained with O-benzyl-

carbamate substrates and that high yields (93–95%) and ee’s

(88–92%) can be reached with a wide range of C4-substituents

R2 (Scheme 21).

Interestingly, Fu’s studies indicated that under typical reac-

tion conditions the rearrangement is zero-order in substrate

Table 1 Enantioselective rearrangement of trifluoroimidates

R1 R2 Mol% 51 T/1C t/h er (%) (Yield (%))

CH3 CH2Ph 2.0 50 24 nd (12)CH3 (CH2)2Ph 2.0 50 24 99 : 1 (71)CH3 (CH2)2Ph 2.0 50 72 499 : 1 (90)CH2OBn CH3 1.0 50 24 99 : 1 (98)CH2OBn CH3 0.5 70 24 98 : 2 (74)CH2OBn (CH2)3OTIPS 4.0 50 48 99 : 1 (95)CH2OBn (CH2)3OTIPS 2.0 50 72 99 : 1 (95)

Scheme 18 Planar chirality and coordination of active palladium

complex.

Scheme 19 Conversion of 57 into a-and b-amino acids.

Scheme 20 Mapp’s phosphorimidate rearrangement.

Dow

nloa

ded

by U

nive

rsity

of

Oxf

ord

on 0

6 A

pril

2011

Publ

ishe

d on

07

Mar

ch 2

011

on h

ttp://

pubs

.rsc

.org

| do

i:10.

1039

/C1C

C00

049G

View Online



and independent of concentration. This observation supports

a mechanism with the tight ion pair 66 as the resting state of

the system (Scheme 21). Fu designed additional experiments

which suggested that reaction of the O-acylated azlactone with

PPY* (Scheme 21, step A) is reversible. The configurational

stability of the product 65 under the reaction conditions

demonstrates without ambiguity that step B is irreversible.43

Subsequently Vedejs et al. described another chiral derivative

of DMAP ((S)-TADMAP 69)44 which gave similar results to

those reported by Fu (Scheme 21) but with best enantio-

selectivities obtained with an O-phenylcarbamate as the

migrating group. In 2009, Groger et al. reported the synthesis

of all the stereoisomers of a-methylthreonine45 using the

Steglich-Hofle rearrangement catalysed by Birman-type

catalyst 70 as a key step. During this investigation the asymmetric

transfer of acyl groups (er up to 93 : 7) to yield a ketone instead

of the usual ester was achieved (Scheme 21). An interesting

extension of this transposition has been the development by

Smith et al. of an N-heterocyclic carbene-promoted tandem

multistep reaction allowing the synthesis of quaternary oxazolones

starting from simple, cheap N-p-anisoyl amino acids 71

(Scheme 22).46

5. [2,3]-Sigmatropic rearrangements

Few [2,3]-sigmatropic rearrangements have been applied to the

synthesis of a-tertiary amines, and stereoselective examples are

rare. This section discusses the scope of these reactions, and

also points out where lack of information concerning stereo-

selective versions of the reactions points to future potential for

new methods for constructing a quaternary nitrogen-bearing

centre.

5.1 [2,3]-Sigmatropic aza-Wittig rearrangement

Despite a few earlier reports,47 the aza-Wittig variant of

[2,3]-Wittig rearrangement (Scheme 23)48 was first studied

thoroughly by Eisch and Kovacs in 1971.49 Since then the

reaction has been shown to be generally slower and less

selective than its oxygen based counterpart.

Relief of steric strain in cyclic systems such as azetidinone

7750 and in vinyl aziridine 7951 promotes the [2,3]-aza-Wittig

rearrangement, forming azepinones and tetrahydropyridines

in high yields and stereoselectivities (Scheme 24).

Prior to 1995 there were few reported examples of this

reaction working well with acyclic compounds, limiting its

potential use in the synthesis of amines bearing quaternary

stereocentres. In 1995 Anderson et al. reported the [2,3]-aza-Wittig

rearrangement of crotyl derived amines (Scheme 25).52 Here

the amine had been specifically designed to favour rearrange-

ment (with an electron withdrawing group on the nitrogen to

stabilise the nitrogen-centred anion formed in the reaction).

The reaction worked well, allowing access to the rearranged

product 82 in good yield but with poor diastereoselectivity.

This work has been further developed to allow the diastereo-

selective synthesis of protected amines and amino acids

bearing an a,a-disubstituted centre using a silylated olefin to

direct the selectivity (Scheme 26).53 The selectivity of the

Scheme 21 Steglich–Hofle rearrangement: mechanism and catalysts.

Scheme 22 One-pot DCC-coupling/NHC-promoted Steglich-Hofle

rearrangement.

Scheme 23 [2,3]-Aza-Wittig rearrangement.

Dow

nloa

ded

by U

nive

rsity

of

Oxf

ord

on 0

6 A

pril

2011

Publ

ishe

d on

07

Mar

ch 2

011

on h

ttp://

pubs

.rsc

.org

| do

i:10.

1039

/C1C

C00

049G

View Online



rearrangement is thought to arise from the transition state

shown (Scheme 27) in which steric interactions between the

R groups and the bulky silyl group lead to the observed

diastereoselectivity (the largest of the R groups having an

anti relationship with the methyl group of the cis olefin in the

favoured diastereomer).

The methyl esters were subsequently studied as well and also

show good stereoselectivities for some of the more hindered

substrates (Scheme 28).

Some work has been carried out on an enantioselective

version of this reaction, starting from enantioenriched amines.

However so far the results reported are ambiguous.54 The use

of chiral bases (i.e. alkyllithium–sparteine complexes) has also

been studied by Anderson, so far without success (due to the

rate of epimerisation of the chiral lithiated intermediate being

faster than that of the [2,3]-rearrangement). Instead, asymmetric

induction with chiral auxilliaries55 and chiral Lewis acids is

being investigated,51b but these have so far not been applied to

the generation of quaternary stereocentres.

Recently the methodology has also been applied to the

diastereoselective synthesis of substituted prolines in which the

[2,3]-sigmatropic rearrangement is followed by a rare 5-endo-trig

cyclisation.56

5.2 Tandem imidation-rearrangement of sulfides or selenides

5.2.1 Sulfide rearrangement. Among the four different

[2,3]-sigmatropic rearrangements involving the transposition

of an allylic sulfur derivative to give an amine as a product,57

only one of those allows the efficient enantioselective synthesis

of a quaternary centre bearing a nitrogen substituent: the

conversion of an S-allylsulfimine 91 (X = S) to an N-allyl-

sulfenamide 93 (X = Se) (Scheme 29). This transposition was

reported in 1951 by Challenger et al., who found that diallyl-

sulfide was converted under the action of chloramine T

(sodiumN-chlorotoluenesulfonamide salt) to the corresponding

N-allyl sulfenamide.58 Evidence for a [2,3]-sigmatropic

rearrangement emerged when Challenger showed that the

migration of a cinnamyl group involves an allylic inversion.59

After these studies, this reaction remained unexploited for two

decades until the development of new imidation reagents

that were more efficient and easier to handle than chloramine

T. The reaction can be promoted with PhI = NTs in the

presence of a Cu(I)-salt,60 with O-mesitylenesulfonylhydroxyl-

amine (MSH),61 with N-aminophthalimide/Pb(OAc)4,62 with

Scheme 24 Aza-Wittig rearrangement in the ring expansion of

azetidiones and aziridines.

Scheme 25 Rearrangement of crotyl amine 81.

Scheme 26 Diastereoselective [2+3] aza-Wittig rearrangement.

Scheme 27 Diasteroselectivity in the aza-Wittig rearrangement of 85.

Scheme 28 Aza-Wittig rearrangement of methyl ester substrates.

Scheme 29 Tandem imidation/[2,3]-sigmatropic rearrangement.

Dow

nloa

ded

by U

nive

rsity

of

Oxf

ord

on 0

6 A

pril

2011

Publ

ishe

d on

07

Mar

ch 2

011

on h

ttp://

pubs

.rsc

.org

| do

i:10.

1039

/C1C

C00

049G

View Online



ethyl N-[(trifluoromethanesulfonyl)oxy]carbamate63 and with

BocN3/FeCl2.64 Many of these transpositions allowed the

synthesis of quaternary carbon atoms, but invariably without

stereoselectivity. Everything changed in 2006 when Armstrong

et al. reported that the use of their previously developed

oxaziridine-based amination reagent 9565 allows the stereo-

selective rearrangement of chiral a-branched allyl-sulfides 94

to 96 a-tertiary amines with an er up to 97 : 3 (Scheme 30).66

Armstrong also demonstrated that the transposition using

these imidation conditions could be performed, for the first

time, on sulfur-containing a,b-unsaturated esters 94 to give

a-amino acids (Scheme 30).

While pushing this investigation further, Armstrong demon-

strated that it is possible to obtain selectively either enantiomer

of the desired amine while keeping the same absolute con-

figuration at the sulfur-bearing stereocentre, providing the

geometry of the carbon–carbon double bond is inverted

instead. The product nonetheless always contains a double

bond of E stereochemistry. By assuming that the rearrange-

ment is suprafacial and concerted, the authors rationalised the

stereoselectivity by comparing the transition states 98-A and

98-B (Scheme 31). It appears that 98-A is significantly lower in

energy than 98-B, probably because of a destabilizing allylic

interaction between R1 and R3 in 98-B. Exchange of R2 and R3

by inverting the geometry of 97 clearly leads to the enantiomer

of the product (Scheme 31). Even though the stereogenic

centre generated on the sulfur atom during the sulfimidation

is not controlled, yields are excellent and E-selectivity in

the final product is complete, suggesting that the sulfimide

configuration does not significantly affect the stereochemical

outcome of the rearrangement.

5.2.2 Selenide rearrangement. In 1975, inspired by the

previously reported and widely used allylic selenoxide to

allylic alcohol transformation, Sharpless et al.67 described

the [2,3]-sigmatropic rearrangement of allylic selenides 91

(X = Se) to the corresponding allylic amines 93 (X = Se)

(Scheme 29). This transposition was promoted by imidation of

the selenide with anhydrous chloramine T and gave the desired

rearranged product in 44% yield. This encouraging but moderate

results stimulated Hopkins et al.68 to investigate this reaction

further, developing alternative imidation methods in order to

avoid the use of chloramine T (essentially because of the

difficulty of removing the p-tolylsulfonyl protecting group

from the final product) and by optimising the overall yield

of the two step sequence. First of all, a new imidation method

was developed to allow the use of an N-chlorocarbamate or,

even more simply, a pair of reagents consisting of a carbamate

and an oxidant such as N-chlorosuccinimide. Indeed, it

appears that the first step of this imidation is the chlorination

of selenium which can then be attacked by the nucleophilic

carbamate (Scheme 32). Using this new imidation, Hopkins

increased the rearrangement yield to up to 95% and demon-

strated the synthesis of a-tertiary amines. Although the stereo-

selectivity of this reaction has been investigated,69 this approach

has thus far only been applied to symmetrical dialkylalkenes from

which the rearrangement generates only an achiral quaternary

carbon atom.

5.3 N–O [2,3]-sigmatropic rearrangement

In 1998, while investigating lithium amide chemistry, Davies’s

group discovered that N-benzyl-O-allylhydroxylamine 105

can give N-allyl-N-benzylhydroxylamine 106 when treated

with n-BuLi.70 This transformation was attributed to a

[2,3]-sigmatropic rearrangement analogous to the Wittig trans-

position described above and its intramolecularity was confirmed

by crossover experiments.71 After rearrangement, a trisubstituted

alkene returned an a-tertiary amine in moderate yield (60%)

(Scheme 33). Interestingly, it appeared that for this particular

transposition the reaction mixture had to be heated, probably

due to the more hindered substrate. So far, only achiral a-tertiaryamines have been synthesised using this methodology, and

no information is yet available on the stereospecificity of the

rearrangement.72

Scheme 30 Armstrong’s sulfide to amine [2,3]-sigmatropic rearrangement.

Scheme 31 Origin of chirality transfer in Armstrong’s sulfide to

amine [2,3]-sigmatropic rearrangement.

Scheme 32 Hopkins’s selenide to amine [2,3]-sigmatropic rearrangement.

Dow

nloa

ded

by U

nive

rsity

of

Oxf

ord

on 0

6 A

pril

2011

Publ

ishe

d on

07

Mar

ch 2

011

on h

ttp://

pubs

.rsc

.org

| do

i:10.

1039

/C1C

C00

049G

View Online



6. Ammonium salt rearrangements

6.1 Stevens rearrangement

In 1928, Stevens and co-workers observed a 1,2-shift of

ammonium ylides during work on quaternary ammonium

salts as protecting groups for amines.73 Treatment of 107

with a solution of sodium hydroxide led to the rearranged

compound 108 in excellent yield. In his early studies, Stevens

demonstrated the intramolecular character of this reaction and

proposed an ionic mechanism involving the formation of a

zwitterionic intermediate 109 which rapidly dissociates to form

the amine 108.73b In 1932, Stevens and Thomson hypothesised

an alternative mechanism involving a radical pathway,73g

evidence for which was found later.74 The mechanism proceeds

via homolytic cleavage of the C–N bond (Scheme 34) to

generate the most stable radical. Rapid recombination forms

the rearranged product. In the same study, Stevens presented

the first example of rearrangement involving an allyl group,

which later came to be referred to as the Stevens [2,3]-shift.73g

In 1952, Stevens provided the first synthesis of an a-tertiaryamine using fluorenyl derivatives (Scheme 35).73 In all previous

examples, the treatment of the quaternary ammonium salt

with a strong base was necessary to form the ylides that

undergo rearrangement. Unfortunately, side reactions, such

as Hofmann degradation, could be observed during these

reactions. In 1952 Stevens presented an alternative method,

generating ylides from carbenes (Scheme 35).75

West and co-workers investigated chirality transfer from

nitrogen to carbon in the Stevens rearrangement using cyclic

ammonium salts (Scheme 36).76 This method uses a temporary

chiral nitrogen atom to transfer selectively only one of the

N-substituents in a suprafacial migration. Ammonium salt 115

was treated with potassium tert-butoxide to generate the

desired ylides which underwent [1,2]- or [2,3]-shift depending

on the R group. The resulting a-tertiary amines were obtained

with good diastereoselectivity. The relative stereochemistry of

the final product was confirmed by X-ray crystallography.

This method can be extended to oxazolidines (Scheme 37). In

this case the compound 121 can be obtained using Me3OBF4.

Coldham et al. developed a simple method for the synthesis

of glycine derivatives based on a [2,3]-Stevens rearrange-

ment (Scheme 38).77 Glycine methyl ester was treated with

allyl bromide to form a quaternary ammonium ylid 124

which rearranged directly to the corresponding a-tertiaryamine 125. Deprotection with palladium(0) gave the amino

acid derivative. Substituted simple a-amino esters were also

investigated.

Based on the work reported by West,76 this method has also

been used for the synthesis of proline derivatives (Scheme 39).

In 2002, Clark showed that a-substituted and a,a-disubstitutedamino acids could be made using the rearrangement of

ammonium ylides.78 In this work, the ylides were generated

from the metal carbenes (Scheme 40) using copper or rhodium

catalysts (Table 2).

The [2,3]-Stevens rearrangement of spiro ylids (Scheme 41)

is also successful.79 Compound 133 was treated with Cu(acac)2in toluene to generate the intermediate ylid 134 which rearranged

to form the desired amine 135 in 54% yield (with a cis : trans

selectivity of 57 : 43).

Rearrangement of a proline-derived ammonium salt is

highly enantioselective.80 In order to perform the Stevens

rearrangement with high stereospecificity, different biphasic

conditions were investigated (Scheme 42). Treatment of

Scheme 33 N–O [2,3]-sigmatropic rearrangement.

Scheme 34 Stevens rearrangement.

Scheme 35 Synthesis of a-tertiary amine using Stevens rearrangement.

Scheme 36 Chirality transfer in Stevens rearrangement.

Dow

nloa

ded

by U

nive

rsity

of

Oxf

ord

on 0

6 A

pril

2011

Publ

ishe

d on

07

Mar

ch 2

011

on h

ttp://

pubs

.rsc

.org

| do

i:10.

1039

/C1C

C00

049G

View Online



t-butyl ester 136 with solid CsOH in dichloroethane formed

the desired amine 137 in 73% yield and 92% ee. Variation of

the aromatic group of the ammonium salt increased the

selectivity up to 99% ee.

An enantioselective [1,2]-Stevens rearrangement was reported

in 2008 by Tomooka and co-workers,81 with sugar-derived

alkoxides as chiral promoters. The treatment of the ammonium

salt 138 in the presence of a chiral alkoxide led to the forma-

tion of the enantiomerically enriched a-tertiary amine 139

(4–61% ee) (Scheme 43).

Metal-containing ammonium ylids undergo tandem [1,2]-

Stevens-1,2 alkyl migration of (Scheme 44).82 In the presence

of a metal, the alkyne p-complex 144 is generated and the corres-

ponding metal-containing ammonium ylid 146 is formed. 146

undergoes a [1,2]-Stevens rearrangement followed by alkyl

migration to generate the N-fused tricyclic indole 148.

Different metallic complexes were also investigated with only

W(CO)6 providing the desired product. Photoirradiation was

crucial for the generation of the unsaturated tungsten species.

The carbene intermediate was trapped using 10% Et3SiH,

allowing the a-tertiary amine 149 to be recovered in 7% yield

(Scheme 44).

Lewis-acids can be used to promote [1,2]-Stevens rearrange-

ment of proline derivatives.83 with complete C to N to C

chirality transfer (Scheme 45). The desired free amine was

obtained in moderate to good yields via a mechanism involving

the formation of 151 with a high degree of stereospecificity.

Addition of triethylamine promotes the formation of 152

which can recombine after homolysis to form the desired

amine 154 (after hydrolysis) (Scheme 45).

6.2 Sommelet–Hauser rearrangement

In 1937, M. Sommelet observed that the decomposition of the

quaternary ammonium salt 155 led to the formation of the

rearranged amine 156 (Scheme 46).84 In 1957, C. Hauser investi-

gated the rearrangement of the benzyltrimethylammonium ion.85

Scheme 37 Synthesis of oxazolidines using Stevens rearrangement.

Scheme 38 Synthesis of glycine derivatives.

Scheme 39 Synthesis of proline-derivatives using [2,3]-Stevens

rearrangement.

Scheme 40 Amino acids synthesis using metal-carbene to initiate

Stevens rearrangement.

Table 2

Entry X Catalyst Yield (%)

1 H Cu(acac)2 592 H Cu(hfacac)2 483 H Rh2(OAc)4 364 COMe Cu(acac)2 545 COMe Cu(hfacac)2 666 COMe Rh2(OAc)4 377 CO2Et Cu(acac)2 598 CO2Et Cu(hfacac)2 819 CO2Et Rh2(OAc)4 42

Scheme 41

Scheme 42 Stevens rearrangement under heterogeneous conditions.Dow

nloa

ded

by U

nive

rsity

of

Oxf

ord

on 0

6 A

pril

2011

Publ

ishe

d on

07

Mar

ch 2

011

on h

ttp://

pubs

.rsc

.org

| do

i:10.

1039

/C1C

C00

049G

View Online



Hauser also proposed a possible mechanism for this rearrange-

ment involving the deprotonation of the quaternary

ammonium salt 157 followed by [2,3]-sigmatropic rearrangement

(Scheme 46).86

Following their work on the Stevens rearrangement, Tayama

and coworkers reported a unique example of Sommelet–Hauser

rearrangement in which no [1,2]-Stevens rearrangement was

detected (Scheme 47).80 The treatment of the ammonium

iodide 161 with solid CsOH in DCE at �10 1C led to

the formation of the rearranged amine 162 (product of

[1,2]-Stevens rearrangement). The treatment of the same amine

with t-BuOK at �40 1C in THF led to the Sommelet–Hauser

product 163.

Tayama also reported an asymmetric version of Sommelet–

Hauser rearrangement (Scheme 48).87 Ammonium salts

164 were treated with t-BuOK to generate the a-tertiary amine

165 with excellent diastereoselectivity. Meta and ortho

substituted compounds also gave a-tertiary amines in good

yields.

7. N to C Migration of a-lithiated ureas and

carbamates

7.1 Nitrogen to carbon aryl migration

Although amides and amide-like functional groups (carabamate,

oxazolines etc.) have long been recognised as powerful directors

of lithiation,88 the use of ureas as lithiation directors had until

recently received little attention,89 despite growing interest in

ureas as a structural class in catalytic, foldamer and supra-

molecular chemistry.90 As part of a study of the conformation

of aromatic ureas,91 we had cause to investigate the lithia-

tion of benzylic ureas such as 166. Remarkably, the expected

Scheme 44 Tandem [1,2]-Stevens-type rearrangement/1,2-alkyl

migration.

Scheme 45 Enantioselective Lewis-Acid mediated Stevens rearrangement.

Scheme 43 Enantioselective Stevens rearrangement using chiral alkoxides.

Scheme 46 Sommelet–Hauser rearrangement.

Scheme 47 Stevens rearrangement vs. Sommelet–Hauser rearrangement.

Dow

nloa

ded

by U

nive

rsity

of

Oxf

ord

on 0

6 A

pril

2011

Publ

ishe

d on

07

Mar

ch 2

011

on h

ttp://

pubs

.rsc

.org

| do

i:10.

1039

/C1C

C00

049G

View Online



deprotonation of the urea in the benzylic position was followed

rapidly by an unexpected migration of the second aryl ring

from nitrogen to carbon, yielding rearranged diarylmethylurea

167.92 Noting the potential of this rearrangement for the

synthesis of a-tertiary amines, we repeated the reaction on the

enantiomerically pure a-methylbenzyl ureas 168. Rearrange-

ment was slower, but could be accelerated by addition of

DMPU as a cosolvent, returning high yields of ureas 169 with

essentially complete retention of configuration (Scheme 49).93

The reaction was surprisingly tolerant of the electronic or

steric nature of the substituents borne by the migrating

ring—even 2,6-dimethyl and 3,4-dimethoxyphenyl rings migrate

successfully. Alkyllithium bases are frequently incompatible

with electron-deficient arenes, but during a screen of bases

suitable for the rearrangement of pyridyl ureas we discovered

that LDA in a mixture of THF and DMPU likewise promotes

lithiation and stereospecific rearrangement of 168.94 Removal

of the carbamoyl group from the rather acid sensitive products

to reveal the a-tertiary amine 170 was initially achieved by

reduction with DIBAL or by hydrolysis of their N-nitroso

derivatives. However, in later work we discovered that simple

solvolysis of 169 on reflux in ethanol, or for faster reaction,

n-butanol (if necessary buffered with sodium carbonate) provides

170 cleanly and efficiently. This new reactivity of lithiated

ureas, featuring an anionic heteroatom-to-carbon aryl migra-

tion reminiscent of the Truce-Smiles rearrangement,95 has

opened up numerous new possibilities for the synthesis of

enantiomerically enriched a-tertiary amines by stereospecific

arylation of their secondary homologues. In particular, it allows

for the first time to the synthesis of enantiopure nitrogen-

bearing quaternary centres carrying two similar aryl rings.

The stereospecificity of the reaction is presumably a con-

sequence of the configurational stability of the intermediate

dipole-stabilised organolithium 171.96 We gained further insight

into the mechanism of the transposition when we discovered

that, in the case of a naphthyl migrating ring, oxidative

conditions return a dearomatised spirocycle 173—evidence

that rearrangement proceeds through a dearomatised inter-

mediate 172 (Scheme 49). X-ray crystallography confirmed the

absolute stereochemistry of 172 and proved the rearrangement

to be stereochemically retentive, rather than invertive.97

The related rearrangement of various cyclic substrates took

place in good yield (up to 89%) but even with enantiomerically

enriched starting material, the rearranged products turned out

to be racemic Presumably racemisation of the intermediate

organolithium competes with slower rearrangement in the

constrained cyclic system.98

Recently, we found that the rearrangement takes place not

only withN-benzyl ureas 166 and 168 but also with theirN-allyl

or N-vinyl analogues 174 or 176. Both can be deprotonated,

respectively a or g to nitrogen, to generate an allyllithium

intermediate susceptible to rearrangement. The most effective

conditions made use of lithium amides as bases and DMPU or

LiCl as promoters of rearrangement. We also found that the

protecting group on the nitrogen atom adjacent to the anionic

centre influences dramatically the efficiency of the rearrangement.

A PMP (p-methoxyphenyl) group promotes a clear increase in

the rate of aryl migration in comparison with the customary

methyl group. Given that the simple unsubstituted allylurea

174 can be deprotonated and rearranged, an alternative

approach to vinylureas 176 is possible: the rearranged product

175 can be coupled, using palladium chemistry, to a second

aryl ring to give a product that can be rearranged a second

time (Scheme 50).99

Because the vinyl urea 176 is achiral, this sequence offers the

opportunity to carry out an asymmetric synthesis of a-tertiaryamines by a stereoselective (rather than a stereospecific, as in

Scheme 49) process. Replacing LDA with a chiral lithium

amide 177 allows the synthesis of enantioenriched rearrange-

ment products in good yields and er’s (yield up to 91%, er up

to 94 : 6) (Scheme 50). Interestingly, the reaction seems to be

sensitive to the geometry of the vinyl group of 176: the Z isomer

Scheme 48 Diastereoselective Sommelet–Hauser rearrangement.

Scheme 49 N-to-C aryl migration in lithiated N-benzyl-N0-aryl

ureas.

Dow

nloa

ded

by U

nive

rsity

of

Oxf

ord

on 0

6 A

pril

2011

Publ

ishe

d on

07

Mar

ch 2

011

on h

ttp://

pubs

.rsc

.org

| do

i:10.

1039

/C1C

C00

049G

View Online



gives better results in terms of yield and er, while the E

isomer reacts poorly to give the desired product in a racemic

mixture.

Attempts to rearrange more hindered analogues of benzylic

substrates 166 give poor yields of the desired product. Alter-

native ways of generating the required benzylic organolithium

were investigated with the aim of circumventing this problem.

The solution emerged during work on the deprotonation

of N-vinyl ureas. While investigating deprotonation with bases

more nucleophilic than LDA and lithium amide derivatives,

we discovered that the attack of an alkyllithium on vinyl urea

179 gave not the expected allyl lithium by deprotonation

but instead a carbolithiated intermediate 180 by nucleophilic

attack on the vinyl group. Addition of DMPU to promote

rearrangement gives the a-tertiary amine derivative 181 in

very good yields (up to 86%) (Scheme 51).100 The carbolithia-

tion is remarkable for its ‘‘umpolung’’ character, with attack

occurring on the more nucleophilic carbon of the enamine

derivative 179. The carbolithiation is also diastereospecific:

substrates 179 with E or Z CQC double bonds101 give

different diastereoisomers of the product 180. X-ray structures

of the products 181 allowed us to conclude (assuming

a retentive rearrangement93) that the carbolithiation is a syn

addition. A wide range of alkyllithiums and aromatic urea

substituents are tolerated, making this approach particularly

versatile for the synthesis of derivatives of branched a-tertiaryamines (Scheme 51). Encouraging preliminary results on an

enantioselective version of this tandem reaction are currently

in progress.

7.2 Nitrogen to carbon carboxyl migration

In 2007, Coudert et al. reported a tandem carbolithiation

and N-to-C acyl migration of vinyl carbamates 182 to give

a-quaternary a-amino esters 184 (Scheme 52).102 The general

behaviour of the carbolithiation step is similar to the one

observed with vinyl ureas (section 7.1).100 However the carbamate

carbolithiation seems more tolerant to different substrates

and was extended to a wider range of organolithium reagents.

Even lithium amides and lithium phosphides added to

the CQC double bond in satisfactory to excellent yields

(up to 95%)102,103 (Scheme 52) allowing the synthesis of

unusual a-amino acid precursors. No details are reported of

an enantioselective version of this reaction.

8. Conclusions

The range of reactivity embodied in rearrangement reactions

means that many classes of a-tertiary amines may be made

using rearrangement strategies. New reactions, such as the

rearrangement of aryl ureas, and those based on carbolithiation

chemistry, are still emerging, and many of the rearrangements

described in this review still do not exist in asymmetric form.

Concepts explored in this field will also be of value in the

synthesis of other challenging targets—quaternary centres adjacent

to sulfur for example.104

Acknowledgements

We are grateful to the EPSRC for research grants, and to

AstraZeneca for support.

Notes and references

1 For selected reviews, see: (a) D. J. Ramon and M. Yus, Curr. Org.Chem., 2004, 8, 149; (b) J. Kobayashi and H. Morita, Alkaloids,2003, 60, 165; (c) I. Moldvai, E. Temesvari-Major, M. Incze,G. Doernyei, E. Szentirmay and C. Szantay, Helv. Chim. Acta,2005, 88, 1344; (d) T. Reynolds, Phytochemistry, 2005, 66, 1399.

2 (a) O. Riant and J. Hannedouche, Org. Biomol. Chem., 2007, 5,873; (b) M. Shibasaki and M. Kanai, Chem. Rev., 2008, 108, 2853;(c) S. Kobayashi and H. Ishitani, Chem. Rev., 1999, 99, 1069;(d) D. A. Cogan and J. A. Ellman, J. Am. Chem. Soc., 1999, 121,268; (e) R. Bloch, Chem. Rev., 1998, 98, 1407; (f) Chiral AmineSynthesis: Methods, Developments and Applications, ed. T. C.Nugent, Wiley-VCH, Weinheim, Germany, 2010.

3 (a) B. M. Trost, Science, 1991, 254, 1471; (b) B. M. Trost, Angew.Chem., Int. Ed. Engl., 1995, 34, 259; (c) Y. Coquerel, T. Boddaert,M. Presset, D. Mailhol and J. Rodriguez, in Ideas in Chemistryand Molecular Sciences: Advances in Synthetic Chemistry,

Scheme 50 Allylic deprotonation followed by N-to-C aryl migration.

Scheme 51 Tandem carbolithiation/ N-to-C rearrangement of

vinyl ureas.

Scheme 52 Tandem carbolithiation/N-to-C carboxyl migration on

vinyl carbamates.

Dow

nloa

ded

by U

nive

rsity

of

Oxf

ord

on 0

6 A

pril

2011

Publ

ishe

d on

07

Mar

ch 2

011

on h

ttp://

pubs

.rsc

.org

| do

i:10.

1039

/C1C

C00

049G

View Online



ed. B. Pignataro, Wiley-VCH, Weinheim, Germany, 2010, ch. 9,pp. 187–202.

4 (a) T. Curtius, Ber. Dtsch. Chem. Ges., 1890, 23, 3023;(b) T. Curtius, J. Prakt. Chem., 1894, 50, 275; (c) P. A. S. Smith,Organic Reactions, vol. III, p. 337.

5 H. Lebel and O. Leogane, Org. Lett., 2005, 7, 4107.6 F. Zhang and J. M. Fox, Org. Lett., 2006, 8, 2965.7 (a) M. Lasa, P. Lopez and C. Cativiela, Tetrahedron: Asymmetry,2005, 16, 4022; (b) M. Chaumontet, R. Piccardi and O. Baudoin,Angew. Chem., Int. Ed., 2009, 48, 179.

8 S. Sunami and M. Ohkubo, Tetrahedron, 2009, 65, 638.9 O. Billeter, Ber. Dtsch. Chem. Ges., 1875, 8, 462.10 G. Gerlich, Justus Liebigs Ann. Chem., 1875, 178, 80.11 (a) O. Billeter, Helv. Chim. Acta, 1925, 8, 337; (b) O. Mumm and

H. Richter, Ber. Dtsch. Chem. Ges., 1940, 73, 84; (c) R. H.DeWolfe and W. G. Young, Chem. Rev., 1956, 56, 753;(d) A. Iliceto, A. Fava and U. Mazzucato, Tetrahedron Lett.,1960, 11, 27; (e) D. W. Emerson and J. Klapprodt Booth, J. Org.Chem., 1965, 30, 2480.

12 P. A. S. Smith and D. W. Emerson, J. Am. Chem. Soc., 1960, 82,3076.

13 J. Gonda and M. Bednarikova, Tetrahedron Lett., 1997, 38, 5569.14 J. Gonda, M. Martinkova, Raschmanova and E. Balentova,

Tetrahedron: Asymmetry, 2006, 17, 1875.15 C. Christophersen and A. Holms, Acta Chem. Scand., 1970, 24,

1512; C. Christophersen and A. Holms, Acta Chem. Scand., 1970,24, 1852.

16 Y. Ichikawa, Synlett, 1991, 238.17 (a) L. A. Clizbe and L. E. Overman, Org. Synth., 1988, Coll. Vol.

6, 507; L. A. Clizbe and L. E. Overman, Org. Synth., 1978, 58, 4;(b) L. E. Overman, J. Am. Chem. Soc., 1976, 98, 2901;(c) L. E. Overman, Tetrahedron Lett., 1975, 16, 1149.

18 Y. Ichikawa, M. Osada, I. I. Ohtani and M. Isobe, J. Chem. Soc.,Perkin Trans. 1, 1997, 1449.

19 Y. Ichikawa, Synlett, 2007, 2927.20 (a) P. Kapferer, F. Sarabia and A. Vasella, Helv. Chim. Acta,

1999, 82, 645; (b) Y. Ichikawa, E. Yamauchi and M. Isobe,Biosci., Biotechnol., Biochem., 2005, 69, 939; (c) Y. Matsukawa,M. Isobe, H. Kotsuki and Y. Ichikawa, J. Org. Chem., 2005, 70,5339; (d) S. Roy and C. Spino, Org. Lett., 2006, 8, 939.

21 K. Banert and A. Melzer, Tetrahedron Lett., 2001, 42, 6133.22 M. Arbour, S. Roy, C. Godbout and C. Spino, J. Org. Chem.,

2009, 74, 3806.23 E. Roulland, C. Monneret and J. C. Florent, J. Org. Chem., 2002,

67, 4399.24 R. Yokoyama, S. Matsumoto, S. Nomura, T. T. Higaki,

T. Yokoyama and S. I. Kiyooka, Tetrahedron, 2009, 65, 5181.25 K. C. Majumdar, T. Bhattacharyya, B. Chattopadhyay and

B. Sinha, Synthesis, 2009, 13, 2117.26 (a) L. E. Overman, J. Am. Chem. Soc., 1974, 96, 597;

(b) L. E. Overman, Acc. Chem. Res., 1980, 13, 218;(c) L. E. Overman and N. E. Carpenter, Organic Reactions,2005, 66, ch. 1. The Allylic Trihaloacetimidate rearrangement.

27 Y. Yamamoto, H. Shimoda, J. Oda and Y. Inouye, Bull. Chem.Soc. Jpn., 1976, 49, 3247.

28 P. V. Ramachandran, T. E. Burghardt and M. V. Reddy, J. Org.Chem., 2005, 70, 2329.

29 (a) N. Chida, J. Takeoka, N. Tsutsumi and S. Ogawa, J. Chem.Soc., Chem. Commun., 1995, 793; (b) S. H. Kang, S. Y. J. Kang,H.-S. Lee and A. J. Buglass, Chem. Rev., 2005, 105, 4357.

30 T. Nishikawa, M. Asai, N. Ohyabu, N. Yamamoto, Y. Fukadaand M. Isobe, Tetrahedron, 2001, 57, 3875; T. Nashikawa,D. Urobe and M. Isobe, Angew. Chem., Int. Ed., 2004, 43, 4782.

31 And are discussed in high detail in L. E. Overman andN. E. Carpenter, Organic Reactions, 2005, ch. 1, and L. E.Overman and K. T. Hollis, J. Organomet. Chem., 1999, 576,290–299.

32 H. Nomura and C. J. Richards, Chem.–Eur. J., 2007, 13, 10216and references therin.

33 L. E. Overman, C. E. Owen andM.M. Pavan,Org. Lett., 2003, 5,1809.

34 C. E. Anderson, Y. Donde, C. J. Donde and L. E. Overman,J. Org. Chem., 2005, 70, 648; C. E. Anderson and L. E. Overman,J. Am. Chem. Soc., 2003, 125, 12412; H. Nomura andC. J. Richards, Chem.–Eur. J., 2007, 13, 10216.

35 D. B. Berkowitz, B. Wu and H. Li, Org. Lett., 2006, 8, 971.36 D. F. Fischer, Z. Xin and P. Peters, Angew. Chem., Int. Ed., 2007,

46, 7704; Z. Xin, D. F. Fischer and R. Peters, Synlett, 2008, 10,1495 and D. F. Fischer, A. Barakat, Z. Xin, M. E. Weiss andR. Peters, Chem.–Eur. J., 2009, 15, 8722.

37 B. Chen and A. K. Mapp, J. Am. Chem. Soc., 2004, 126, 5364.38 B. Chen and A. K. Mapp, J. Am. Chem. Soc., 2005, 127, 6712.39 R. Ramage, D. Hopton, M. J. Parrott, G. W. Kenner and

G. A. Moore, J. Chem. Soc., Perkin Trans. 1, 1984, 1357.40 B. H. Dahl, K. Bjergarde, L. Henriksen and O. Dahl, Acta Chem.

Scand., 1990, 44, 639.41 W. Steglich and G. Hofle, Tetrahedron Lett., 1970, 54, 472.42 J. C. Ruble and G. C. Fu, J. Am. Chem. Soc., 1998, 120, 11532.43 G. C. Fu, Acc. Chem. Res., 2000, 33, 412.44 S. A. Shaw, P. Aleman and E. Vedejs, J. Am. Chem. Soc., 2003,

125, 13368; S. A. Shaw, P. Aleman, J. Christy, J. W. Kampf,P. Va and E. Vedejs, J. Am. Chem. Soc., 2006, 128, 925.

45 (a) F. R. Dietz and H. Groger, Synlett, 2008, 663; (b) F. R. Dietzand H. Groger, Synthesis, 2009, 4208.

46 (a) C. D. Campbell, N. Duguet, K. A. Gallagher, J. E. Thomson,A. G. Lindsay, A. C. O’Donoghue and A. D. Smith, Chem.Commun., 2008, 3528; (b) J. E. Tomson, C. D. Campbell,C. Concellon, N. Duguet, K. Rix, A. M. Z. Slawin andA. D. Smith, J. Org. Chem., 2008, 73, 2784; (c) C. Joanesse,C. Simal, C. Concellon, J. E. Thomson, C. D. Campbell, A. M. Z.Slawin and A. D. Smith, Org. Biomol. Chem., 2008, 6, 2900.

47 (a) H. Dahn and U. Solms, Helv. Chim. Acta, 1951, 34, 907;(b) R. A. W. Johnstone and T. S. Stevens, J. Chem. Soc., 1960,3346.

48 C. Vogel, Synthesis, 1997, 497.49 J. J. Eisch and G. A. Kovacs, J. Organomet. Chem., 1971,

30, C97.50 Durst, J. Am. Chem. Soc., 1972, 94, 9261.51 (a) J. Ahman and P. Somfai, J. Am. Chem. Soc., 1994, 116, 9781;

(b) P. Somfai and O. Panknin, Synlett, 2007, 1190 and referencestherein; (c) I. Coldham, A. J. Collis, R. J. Mould andR. E. Rathmell, J. Chem. Soc., Perkin Trans. 1, 1995, 2739;(d) I. Coldham, A. J. Collis, R. J. Mould and R. E. Rathmell,Tetrahedron Lett., 1995, 36, 3557.

52 J. C. Anderson, D. C. Siddons, S. C. Smith and M. E. Swarbrick,J. Chem. Soc., Chem. Commun., 1995, 1855.

53 J. Anderson and S. Skeratt, J. Chem. Soc., Perkin Trans. 1, 2002,2871.

54 J. C. Anderson, J. M. A. O’Loughlin and J. A. Tornos, Org.Biomol. Chem., 2005, 3, 2741.

55 J. C. Anderson, J. G. Ford and M. Whiting, Org. Biomol. Chem.,2005, 3, 3734.

56 J. C. Anderson and E. A. Davies, Tetrahedron, 2010,66, 6300.

57 The four rearrangements are: sulfoximine to N-allyl-sulfinamide,S-allyl-imidosulfinate to N-allyl-sulfoxylate, S-allyl-sufinamidineto sulfoxylic acid amide and sulfimine to sulfenamide; for acomplete review on these transpositions see: ‘‘Sulfur-MediatedRearrangements II’’M. Reggelin, Top. Curr. Chem., 2007, 275,1–65.

58 A. S. F. Ash, F. Challenger and D. Greenwood, J. Chem. Soc.,1951, 1877.

59 P. A. Briscoe, F. Challenger and P. S. Duckworth, J. Chem. Soc.,1956, 1755.

60 (a) H. Takada, Y. Nishibayashi, K. Ohe and S. Uemura, Chem.Commun., 1996, 931; (b) H. Takada, Y. Nishibayashi, K. Ohe,S. Uemura, S. C. P. Baird, T. J. Sparey and P. C. Taylor, J. Org.Chem., 1997, 62, 6512.

61 Y. Tamura, H. Matsushima, J. Minamikawa, M. Ikeda andK. Sumoto, Tetrahedron, 1975, 31, 3035.

62 R. S. Atkinson and S. B. Awad, J. Chem. Soc., Perkin Trans. 1,1977, 346.

63 Y. Tamura, H. Ikeda, C. Mukai, I. Morita and M. Ikeda, J. Org.Chem., 1981, 46, 1732.

64 T. Bach and C. Korber, J. Org. Chem., 2000, 65, 2358.65 A. Armstrong and R. S. Cooke, Chem. Commun., 2002, 904.66 A. Armstrong, L. Challinor, R. S. Cooke, J. H. Moir and

N. R. Treweeke, J. Org. Chem., 2006, 71, 4028.67 K. B. Sharpless, K. M. Gordon, R. F. Lauer, D. W. Patrick,

S. P. Singer and M. W. Young, Chem. Scr., 1975, 8A, 9.

Dow

nloa

ded

by U

nive

rsity

of

Oxf

ord

on 0

6 A

pril

2011

Publ

ishe

d on

07

Mar

ch 2

011

on h

ttp://

pubs

.rsc

.org

| do

i:10.

1039

/C1C

C00

049G

View Online



68 R. G. Shea, J. N. Fitzner, J. E. Fankhauser, A. Spaltenstein,P. A. Carpino, R. M. Peevey, B. D. V. Pratt, J. Tenge andP. B. Hopkins, J. Org. Chem., 1986, 51, 5243.

69 For recent examples: (a) Y. Nishibayashi, T. Chiba, K. Ohe andS. Uemura, J. Chem. Soc., Chem. Commun., 1995, 1243;(b) N. Kurose, T. Takahashi and T. Koizumi, J. Org. Chem.,1996, 61, 2932; (c) H. Takada, M. Oda, Y. Miyake, K. Ohe andS. Uemura, Chem. Commun., 1998, 1557.

70 (a) S. G. Davies, S. Jones, M. A. Sanz, F. C. Teixeira andJ. F. Fox, Chem. Commun., 1998, 2235; (b) The reaction has beenrediscovered in 2001 before retractation of the novelty claims:T. Ishikawa, M. Kawakami, M. Fukui, A. Yamashita, J. Uranoand S. Saito, J. Am. Chem. Soc., 2001, 123, 7734; T. Ishikawa,M. Kawakami, M. Fukui, A. Yamashita, J. Urano and S. Saito,J. Am. Chem. Soc., 2001, 123, 9724.

71 S. G. Davies, J. F. Fox, S. Jones, A. J. Price, M. A. Sanz, T. G. R.Sellers, A. D. Smith and F. C. Teixeira, J. Chem. Soc., PerkinTrans. 1, 2002, 1757.

72 Reaction diastereoselectivity has been studied and rationalisedfor a-secondary-amine synthesis: S. D. Bull, S. G. Davies,S. Hernandez Domıngez, S. Jones, A. J. Price, T. G. R.Sellers and A. D. Smith, J. Chem. Soc., Perkin Trans. 1, 2002,2141.

73 (a) T. S. Stevens, E. M. Creighton, A. B. Gordon andM. MacNicol, J. Chem. Soc., 1928, 3193; (b) T. S. Stevens,J. Chem. Soc., 1930, 2107; (c) T. S. Stevens, W. W. Snedden,E. T. Stiller and T. Thomson, J. Chem. Soc., 1930, 2119;(d) T. Thomson and T. S. Stevens, J. Chem. Soc., 1932, 55;(e) T. Thomson and T. S. Stevens, J. Chem. Soc., 1932, 69;(f) J. L. Dunn and T. S. Stevens, J. Chem. Soc., 1932, 1926;(g) T. Thomson and T. S. Stevens, J. Chem. Soc., 1932, 1932;(h) J. L. Dunn and T. S. Stevens, J. Chem. Soc., 1934, 279;(i) W. R. Bamford, T. S. Stevens and J. W. Wright, J. Chem. Soc.,1952, 4334; (j) R. A. W. Johnstone and T. S. Stevens, J. Chem.Soc., 1955, 4487.

74 (a) W. D. Ollis, M. Rey, I. O. Sutherland and G. L. Closs,J. Chem. Soc., Chem. Commun., 1975, 543; (b) U. H. Dolling,G. L. Closs, A. H. Cohen and W. D. Ollis, J. Chem. Soc., Chem.Commun., 1975, 545; (c) W. D. Ollis, M. Rey andI. O. Sutherland, J. Chem. Soc., Perkin Trans. 1, 1983, 1009;(d) A. Campbell, H. J. Houston and J. Kenyon, J. Chem. Soc.,1947, 93; (e) J. H. Brewster and M. W. Kline, J. Am. Chem. Soc.,1952, 74, 5179.

75 W. R. Bamford and T. S. Stevens, J. Chem. Soc., 1952, 4675.76 K. W. Glaeske and F. G. West, Org. Lett., 1999, 1, 31.77 A. P. A. Arbore, D. J. Cane-Honeysett, I. Coldham and

M. L. Middleton, Synlett, 2000, 236.78 J. S. Clark and M. D. Middleton, Org. Lett., 2002, 4, 765.79 E. Roberts, J. P. Sancon and J. B. Sweeney, Org. Lett., 2005, 7,

2075.80 E. Tayama, S. Nanbara and T. Nakai, Chem. Lett., 2006, 35, 478.81 K. Tomooka, J. Sakamaki, M. Harada and R. Wada, Synlett,

2008, 683.82 J. Takaya, S. Udagawa, H. Kusama and N. Iwasawa, Angew.

Chem., Int. Ed., 2008, 120, 4984.83 P. Tuzina and P. Somfai, Org. Lett., 2009, 11, 919.84 M. Sommelet, C. R. Chim., 1937, 205, 56.85 S. W. Kantor and C. R. Hauser, J. Am. Chem. Soc., 1951, 73,

4122.86 J. B. Sweeney, Chem. Soc. Rev., 2009, 38, 1027.

87 (a) E. Tayama and H. Kimura, Angew. Chem., 2007, 119, 9025;(b) E. Tayama, K. Orihara and H. Kimura, Org. Biomol. Chem.,2008, 6, 3673.

88 J. Clayden, in Chemistry of Organolithium Compounds, ed.Z. Rappoport and I. Marek, Wiley, Chichester, 2004, vol. 1,pp. 495–646; C. Hartung and V. Snieckus, in Modern AreneChemistry, ed. D. Astruc, Wiley-VCH, Weinheim, Germany,2002, pp. 330–367; J. Clayden, Organolithiums: Selectivity forSynthesis, Pergamon, Oxford, 2002; V. Snieckus, Chem. Rev.,1990, 90, 879.

89 (a) J. Clayden, H. Turner, M. Pickworth and T. Adler, Org. Lett.,2005, 7, 3147; (b) J. Clayden and J. Dufour, Tetrahedron Lett.,2006, 47, 6945.

90 J. Clayden, L. Lemiegre, G. A. Morris, M. Pickworth, T. J. Snapeand L. H. Jones, J. Am. Chem. Soc., 2008, 130, 15193; J. Clayden,H. Turner, M. Helliwell and E. Moir, J. Org. Chem., 2008, 73,4415; J. Clayden, U. Hennecke, M. A. Vincent, I. H. Hillier andM. Helliwell, Phys. Chem. Chem. Phys., in press.

91 J. Clayden, M. Pickworth and L. H. Jones, Chem. Commun.,2009, 547; J. Clayden, L. Lemiegre and M. Helliwell, J. Org.Chem., 2007, 72, 2302.

92 W. Dannecker and M. Fariborz, Z. Naturforsch., 1974, 29b, 578.93 J. Clayden, J. Dufour, D. M. Grainger and M. Helliwell, J. Am.

Chem. Soc., 2007, 129, 7488.94 J. Clayden and U. Hennecke, Org. Lett., 2008, 10, 3567.95 T. J. Snape, Chem. Soc. Rev., 2008, 37, 2452.96 N. C. Faibish, Y. S. Park, S. Lee and P. Beak, J. Am. Chem. Soc.,

1997, 119, 11561.97 Tertiary organolithiums a to nitrogen commonly (but with

exceptions) alkylate with inversion but acylate with retention:(a) N. C. Faibish, Y. S. Park, S. Lee and P. Beak, J. Am. Chem.Soc., 1997, 119, 11561; J. Clayden, Organolithiums: Selectivity forSynthesis, Pergamon, New York, 2002, pp. 252–253. Althoughthe reaction we present here may be formalized as a kind of[1,4]-aza-Wittig rearrangement, we have not pursued thisinterpretation first because of evidence for a dearomatized inter-mediate and second because Wittig rearrangements usuallyproceed with inversion at a chiral organolithium centre:J. Clayden, Organolithiums Selectivity for Synthesis, Pergamon,New York, 2002, pp. 247–249 and 356–360; (b) In comparison,analogous rearrangement with carbamates in order to obtaintertiary alcohols proceeds with inversion of configuration:A. M. Fournier, R. A. Brown, W. Farnaby, H. Miyatake-Ondozabal> and J. Clayden, Org. Lett., 2010, 12, 2222;J. Clayden, W. Farnaby, D. M. Grainger, U. Hennecke,M. Mancinelli, D. J. Tetlow, I. H. Hillier and M. A. Vincent,J. Am. Chem. Soc., 2009, 131, 3410.

98 R. Bach, J. Clayden and U. Hennecke, Synlett, 2009, 421.99 D. J. Tetlow, U. Hennecke, J. Raftery, M. J. Waring, S. C. Clarke

and J. Clayden, Org. Lett., 2010, 12, 5442.100 J. Clayden, M. Donnard, J. Lefranc, A. Minassi and

D. T. Tetlow, J. Am. Chem. Soc., 2010, 132, 6624.101 J. Lefranc, D. J. Tetlow, M. Donnard, A. Minassi, E. Galvez

and J. Clayden, Org. Lett., 2011, 13, 296.102 B. Cottineau, I. Gillaizeau, J. Farad, M. L. Auclair and

G. Coudert, Synlett, 2007, 1925.103 A. Bouet, M. Cieslikiewicz, K. Lewinski, G. Coudert and

I. Gillaizeau, Tetrahedron, 2010, 66, 498.104 P. MacLellan and J. Clayden, Chem. Commun., 2011, 47, DOI:

10.1039/c0cc04912c.

Dow

nloa

ded

by U

nive

rsity

of

Oxf

ord

on 0

6 A

pril

2011

Publ

ishe

d on

07

Mar

ch 2

011

on h

ttp://

pubs

.rsc

.org

| do

i:10.

1039

/C1C

C00

049G

View Online


chemcomm viewonline dynamic article linksszolcsanyi/education/files... · 3. [3,3]-sigmatropic...

Documents