Introduction of Halogen Atoms into Organic Compounds Under Solvent- Free Reaction Conditions

Current Organic Chemistry, 2009, 13, 47-70 47

1385-2728/09 $55.00+.00 © 2009 Bentham Science Publishers Ltd.

Introduction of Halogen Atoms into Organic Compounds Under Solvent-Free Reaction Conditions

Igor Pravst,a Marko Zupan,

a,b and Stojan Stavber

b,*

aFaculty of Chemistry and Chemical Technology, University of Ljubljana, Askerceva 5, Ljubljana, Slovenia

bLaboratory for Organic and Bioorganic Chemistry, “Jozef Stefan” Institute, Jamova 39, Ljubljana, Slovenia

Abstract: Avoiding volatile and toxic organic solvents during each particular phase of synthetic protocols should become

important goal of chemical synthesis designers in academia and particularly in the industrial research community. Sol-

vent-free reaction conditions (SFRC) are becoming a widely used experimental technique for the selective and efficient

introduction of halogen atoms into organic compounds. The different approaches to the preparation of halosubstituted or-

ganic molecules using equimolar amount of the substrate and reagent under SFRC are reviewed and evaluated. Fluorina-

tion of various types of organic compounds under SFRC using fluorine gas, N-F reagents, and hydrogen or metal fluorides

is compiled. Chloro-, bromo- or iodofunctionalisation under SFRC using molecular halogens, N-halosuccinimides, hydro-

gen or others halides is reviewed. Oxidative halogenations of comprehensive types of organic compounds under SFRC are

evaluated.

1. INTRODUCTION

Sustainable development is of crucial importance for the quality of life on our planet. Growing concerns about this fact has had a considerable effect on modern research and scientific trends in chemistry, especially organic chemistry. Green chemistry and its principles [1-3]

are dictating devel-

opment of new, or revisions of already known, protocols for the synthesis of organic compounds. Following this modern approach to transformations of organic compounds, contrary to traditional thinking, the best solvent for organic reactions is regarded to be “no solvent at all”. Thus, performing reac-tions under solvent-free reaction conditions (SFRC) are at-

tracting increased attention in recent years [4-9].

The goal of these efforts is not only in development of new “greener” synthetic protocols, but also in exploring of new chemistry, since the course of organic reactions in sol-vents could be very different from those under SFRC. The type of transformation and its efficiency, as well as regio or stereo control, could be essentially affected, since the reac-tivities of all the components involved could be changed dramatically, undesirable side reactions, like polymerization, enhanced, while energy transport through the reaction sys-

tem is very different for the two reaction conditions.

When investigating organic reactions under SFRC many reaction parameters should be considered; the most impor-tant are shown in Scheme 1. Aggregate state (AS; s- solid, l- liquid, g- gas) and reactivity of the substrate (S) and reagent (R) have to be considered first. Further analysis is connected with the reaction conditions (C). The energy source (thermal or photochemical conditions, high pressure, microwave or

*Address correspondence to this author at the Laboratory for Organic and Bioorganic Chemistry, “Jozef Stefan” Institute, Jamova 39, Ljubljana, Slo-venia, Tel: +386 1 477 3660; Fax: +386 1 2519 385; E-mail: [email protected]

Scheme 1. Reaction scenarios in solvent-free functionalization of

organic molecules.

ultrasound irradiation etc.), catalyst and support are only a

few of them, but usually the most important ones. The first

important stage of a transformation is considered to be ho-

mogenization of the reactants. The method of mixing could

Energy

Support Catalyst

h

kT

P

SS SL

SG

RS RL

RG

C

R

Substrate Reagent

Reaction

Mixture

Progress of

Transformation

Product

Agregate state (A.S.)

Molecular mobility

Change of A.S.

Differences in contacts

P

ConditionsC

S R

S

48 Current Organic Chemistry, 2009, Vol. 13, No. 1 Pravst et al.

have a huge impact on the molecular mobility of the reac-

tants and the first changes in the aggregate states of compo-

nents could be noted in this step. During the progress of a

transformation towards product formations, energy release or

consumption could cause changes in the aggregate state,

reflected in differences in contact between the reactants. A

careful analysis of these observations is even more important

if the transformation is declared to be a solid state one. An

important contribution to this issue and criticism of pub-

lished studies was stressed by Raston et al. [10,11].

In order to get better insight into the transformation, it is advisable to split it into three stages (Scheme 2). Interaction (I) between substrate and reagent, assisted by the reaction conditions, results in the first transition state, enabling ex-change of electrons between the donor and acceptor (EE) and the formation of reactive intermediates (cations, anions, radi-cals). In the further product formation step (PF), the system decides whether substitution, addition or elimination will take place, and finally the corresponding products are formed (P-R). It is very difficult to affirm that in all these three phases the behaviour of the reaction system under SFRC is similar to those in solvents. Due to the very high concentra-tions of reactants, the interactions among them differ consid-erably, affecting their polarisation and the subsequent elec-

tron flow between them.

Scheme 2. Important steps in functionalisations under SFRC.

The primary interaction phase can also be divided into stages (Scheme 3). The first interaction represents the situa-tion achieved immediately after mixing of the reactants. The next process is molecular migration, which is dependent on the aggregate state of the reactants and results in the contact of the active site of the donor molecule and the active site of the acceptor molecule, which is crucial for further progress of the process. This organization is also extremely important for improvements in regioselectivity and stereoselectivity

and could also be modified by preorganisation (PO) of the reactants in various solvents prior to SFRC [12]. The organi-zation of the reactants could also be enhanced with the addi-tion of small amounts of solvent vapours [13], while interest-ing behaviour was observed in high concentration media, when a few equivalents (up to 5 molar equiv.) of solvent were added to the reaction system [14]. In the final step, when the reactants are approached at appropriate distances, electrons exchange takes place, while steric interactions and differences in electronegativity between acceptor and donor

regulate this process.

In this account we will discuss different approaches to the preparation of halosubstituted organic molecules under SFRC. The main classes or reagents used for this purpose are schematically presented in Scheme 4 and their particular representatives in Scheme 5. The reactivity of each reagent depends on its structure, where intramolecular polarization of electron density represents the main regulating factor. Halogens and hydrogen halides are typical reactive sources of halogen atoms. Molecular halogens, with the exception of iodine, are very strong electrons acceptors, while hydrogen halides, with the exception of HF, are very strong proton donors, which have important effects on their reactivity. The next classis represented by the neutral X-L type of reagents with two possible modes of polarization, while the ionic type of reagents L

+X

- is a source of nuclophilic and L

-X

+ a source

of electrophilic halogen atoms. In the case of the L+(XYN)

-

type of reagents, the nature of the halogen species (anion / cation) transferred to the substrate depends on the structure

of the reagent.

Scheme 4. Types of halogenating reagents used in SFRC transfor-

mations.

The primary literature dealing with SFRC halogenations has not yet been reviewed, while some relevant partial data were included in review accounts dealing with solvent-free organic synthesis [4,15-18], gas/solid reactions [17] and re-actions on various supports [8,9,18-21]. In this account we mainly focused on papers published in last two decades, while earlier relevant studies are also included. Except when noted, the studies in which one of the reactants was used in large excess and serves also as a reaction medium are not

included in this review.

2. FLUOROFUNCTIONALISATION

2.1. Reactions with Fluorine and N-F Reagents

Wide use of fluorosubstituted organic substrates in di-verse fields of human activities has induced the development of many solvent-free techniques for the synthesis of per-fluoro substituted organic compounds using metal fluorides

Scheme 3. Details in the interaction phase of functionalisations

under SFRC.

Interaction

Organisation

I1

I3

I2

C

S

R

Transition

State

S R

X X

H X - +

X L

X L

-+

L X L X

L (XYN)

C

S

R

Interactions

Electron

Exchange

S R

Product formation

S R

S R

S R

Introduction of Halogen Atoms into Organic Compounds Current Organic Chemistry, 2009, Vol. 13, No. 1 49

or fluorine during the last century. These topics have been widely covered in monographs [22]. Since molecular fluo-rine is very reactive, dilution with inert gases was used as a regulator of its reactivity. Kobayashi et al. [23] studied the fluorination of 1,3-dioxolane-2-one (F1a) with a 20-30% mixture of fluorine with nitrogen at 50°C and 70% of fluoro substituted product F2a was obtained as the primary product. Further fluorination was found to be less regioselective, but the formation of trans-4,5-difluoro-1,3-dioxolan-2-one (F3b) was established (Scheme F1). Under similar reaction condi-tions -butyrolactone (F1b) gave a mixture of up to 4 prod-ucts, monofunctionalisation was not regioselective and sub-stitution at C2, C3 and C4 took place, but the formation of the 3-fluoro derivate F2b could be enhanced by the addition

of NaF as a HF scavenger [24]. A highly diluted fluorine mixture was used for fluorine addition to propene (F4) at various temperatures [25]. Gas-liquid microreactors were also applied for functionalisation of toluene (F6) resulting in the formation of a mixture of ring substituted products (F7)

in low yield [26].

N-F compounds are an important class of fluorinating reagents, extensively used for the selective and efficient fluorination of a comprehensive range or organic compounds under mild reaction conditions, mainly in MeCN or MeOH as solvents

[27-29]. Recently efficient fluorofunctionalisation

of organic substrates was also reported under SFRC. Enoli-sation of 1,3-diketones and -keto was also obviously suc-cessful in the absence of solvents and their transformation to

Scheme 5. Main classes of halogenating reagents used for SFRC transformations.

F

N+

N+ CH2Cl

F (BF4-)2

F-TEDA

PhS

N

F

SPh

O

OO

ONFSi

F F

H F

K

Na

NBu4

PBu4

L

1 2

0

[F(HF)N]

Cl

NCSCl Cl H Cl

N

O

O

Cl

N

N

R1

R2

Na

Mg

L Cl2+

Cl / Oxid.

Br

NBS

Br Br H Br

N

O

O

Br

N

R

N

N

R

Me

NR1R2R3R4

O O Br2

Br2N

N

N

N

DXB

HMTAB

N

N

R1

R2

K

Mg

L Br2+

Br / Oxid.

Br3-

NIS

I I

H I

N

O

O

I

I Cl

I2 / Oxid.I2 / Supp.

I / Oxid.

I

N

N

R1

R2

KMg 2+

NMe4

N NPh

ICl2L

I

Na


monofluoro derivatives F9a-d either with 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2] octane bis(tetrafluoro-borate) (F-TEDA) or N-fluorobenzenesulfonimide (NFSi) in a 1:1 molar ratio at 85°C was established. Fluorofunctionali-sation performed under SFRC took place in the molten state, while its efficiency depended on the structure of the reagent and the substrate (Scheme F2) [30]. Ketones were found to be less reactive and their activation by prior derivatisation to enole acetates F10 was necessary for successful -fluorination to the corresponding products F11 [30]. A dif-ferent course of this transformation was established when performed in solvents. Prior activation was not necessary in this case, while the regioselectivity of fluorofunctionalisation of aryl-alkyl ketones could be regulated by choice of solvent: in methanol fluorination at the alpha position took place, while in acetonitrile ring functionalization occurred [31,32].

Activated aromatic molecules could also be effectively fluorinated with NFSi or F-TEDA. Hydroxy and ethoxy ben-zene derivatives F12 were functionalised at the ortho posi-tion (F13) with NFSi (Scheme F3). 1,3-Dimethoxy benzene gave the 4-fluoro derivative as the major product, but further fluorination took place and 13-15% of 1,3-dimethoxy-4,6-difluorobenzene was obtained. 2-Alkoxynaphthalene deriva-tives (F14) were functionalised at position 1 with both rea-gents at 85°C [30]. Fluorination of some aromatic substrates (i.e. benzene, chlorobenzene and anisole) used in excess as solvents in fluorination with NFSi [33] and 1-fluoro-2,4,6-trichloro-1,3,5-triazinium tetrafluoroborate was reported

[34].

2.2. Functionalisation with HF and Various Fluorides

The second strategy for preparation of fluoro substituted organic substrates under SFRC is based on the nucleophilic

introduction of fluorine with either HF or various fluorides. Landini and Penso first developed epoxide ring opening with KHF2 at 80-120°C in the presence of Bu4NH2F3 as a phase transfer catalyst [35]. The reactivity of substrate F16 and the regioselectivity of ring opening, transforming to vicinal fluoroalcohols (F17, F18), depends on the substituent, but attack of the fluoride anion at less hindered position in the epoxide prevails in all cases (F17, Scheme F4). This proto-

col has been successfully applied to various epoxides [36].

The stereochemistry of the ring opening of epoxides was studied in detail. As demonstrated in Scheme F5, fluoride entered in an anti manner in all cases, while reactivity and

Scheme F1. Fluorofunctionalisation with fluorine.

Scheme F2. Fluorofunctionalisation of -keto esters, 1,3-diketones

and enolacetate with N-F reagents.

Scheme F3. Fluorination of aromatic compounds with N-F rea-gents.

YO

O

OY

O

20-30% F2/N2

30-50°C

F

FF1% F2/N2

0 to -20°C

gas phase

F2a (Y=O; 70%)

F2b (Y=CH2; 4 products)

F5 (10%)

F1a: Y= O

F1b: Y=CH2Y=O

OO

O

F

OO

O

F

OO

O

FF FF

+ +

F3a (11%) F3b (59%) F3c (5%)

CH3CH3

10% F2/N2

-16°C, FFMR

F7 (3%)

F4

F6

F

O

CH3

O

Ph

F

O

OEt

OF

N-F

NFSi: F11 (92%)

F-TEDA: (95%)

OOAc

F

R3

O

H

R1

R2R3

O

F

R1

R2

N+

N+(BF4

-)2

F-TEDA

PhS

N

F

SPh

O

OO

O

NFSi

F

CH2F

85°CF8 F9

O

OEt

OF

O O

F

NFSi:

F-TEDA:

F9a F9b F9c F9d

89%

71% 82%

dec.

90% (wet)

87% 78%

87%

F10

85°C

OR OR

OR

tBu

OR

tBu

F

NFSi

85°C

F14a (R=Et)

F14b (R=iPr)

F-TEDA:

(61%)

(52%)

(67%)

(55%)

F

F12a: R=H

F12b: R=Et

F13a (55%)

F13b (52%)

NFSi

85°C

NFSi:

F15a

F15b


the amount of phase transfer catalyst varied from case to case. Cyclohexene epoxide (F19c) could be opened in the presence of 10% of the catalyst, while an equimolar amount of Bu4NH2F3 was required for ring opening of trans and cis 1,2-diphenylethyleneoxides (F19a,b). Both substrates we found to be less reactive and functionalisation was achieved after 120 h or 72 h, respectively. Several sugar molecules

were also efficiently transformed to fluoro derivatives using a similar protocol [38], but derivative F19e required higher molar amounts of catalyst and fluoride (3 eq. of catalyst and 6 eq. of KHF2) [39,40], while lower regioselectivity of the transformation was established and two anti products were

formed (F20e1, F20e2).

R Conditions Yield [%] Regioselect.

(F17 : F18) Ref.

Ph F16a 8h, 120°C 74 61 : 39 [37]

C10H21 F16b 48h, 120°C 84 74 : 26 [37]

HOCH2 F16c 30h, 80°C 47 100 : 0 [37]

PhOCH2 F16d 8h, 120°C 90 100 : 0 [37]

O

F16e 6h, 120°C 70 91 : 9 [37]

OO

F16g 39h, 75°C 70 100 : 0 [36]

Scheme F4. The effect of substituent on the regioselectivity of the transformation of epoxides to vicinal fluoro alcohols with KHF2.

Substrate Conditions Product (yield) Ref.

O

Ph

Ph

F19a 120h, 120°C PhPh

OH

F

F20a (72%) [37]

O

Ph Ph

F19b 72h, 120°C PhPh

OH

F

F20b (71%) [37]

O

F19c 7h, 120°C

HO F

F20c (71%) [37]

O

O

AcHN

O

F19d 120°C

O

AcHN

O

HO F

F20d (28%) [38]

O

O

H3CO OH

F19e 12h, 130°C

O

H3CO OH

HO F

F20e1 (70%)

O

H3CO OH

F OH

F20e2 (6%)

[40]

Scheme F5. Stereochemistry of epoxide opening with KHF2.

O

RR

OH

F

RF

OH

+

2KHF2

0.1 Bu4N+H2F3-

F17 F18F16

O

R1R1

R2

OH2KHF2

F20F19

R2

F

Bu4N+H2F3- (cat.)


Bu4NH2F3 as a source of fluoride anion has been success-fully applied for the fluorofunctionalisation of various bioac-tive compounds among the epoxides (F21, Scheme F6) [36,41-43]. Nitrogen atom was replaced by phosphorus in the cationic part of fluorides and the important role of the content of fluoride in the reagent on reactivity and regiose-lectivity was found. Higher reactivity and regioselectivity was established for reagents bearing only one fluoride anion, and epoxide F23 was transformed with Bu4P

+F

- mainly to

F24 [44].

Scheme F6. The effect of reagent on regioselectivity and stereo-

chemistry of epoxide opening to fluorohydrines.

Tetrabutylphosphonium hydrogendifluoride was also ef-fectively used for SFRC functionalisation of various pyri-dine, pyrimidine, pyrazine and pyridazine derivatives in nu-cleophilic substitutions starting from chloro substituted pre-cursors, and the following products were thus prepared: 2-fluoro-3-cyano and 2-fluoro-5-methyl pyridine (88%, 72%), 1,3,5-trifluoropyrimidine (85%), 2-fluoropyrazine (93%) and 6-fluoro-3-phenyl pyridazine (F27, Scheme F7) [45].

The

effect of phase transfer catalyst (PTC: 18-crown-6, NBu4HSO4, NBu4Br, NBu4Cl) on the nucleophilic function-alisation of 3-chloro-6-phenylpyridazine (F26), 2,3-dichloroquinoxaline and 1,4-dichlorophthalazine with KF under SFRC was also investigated under thermal or micro-

wave conditions [46].

Scheme F7. Effect of the structure of the fluorinating reagent on

nucleophilic substitution at the pyridazyne ring.

Tetrabutylammonium and polymer-supported dihydro-gentrifluoride were used as the source of hydrogen fluoride in addition reactions to acetylenes. Markovnikov type of

regioselectivity was observed, while the degree of syn addi-

tion depended on the substituents (F28a-d, Scheme F8) [47].

Scheme F8. Effect of the structure of acetylenes on transformation

to fluoroalkenes.

3. CHLOROFUNCTIONALISATION

3.1. Reactions with Chlorine and N-Chlorosuccinimide

Anthracene was first chlorinated using gaseous chlorine almost 140 years ago [48]. Chlorination of activated benzene derivatives with chlorine gas was reported. The regioselec-tivity of mono chlorofunctionalisation and the share of poly-chloro substituted products formed were found to be depend-ent on substituents and reaction conditions (Scheme C1). Benzene, when exposed to Cl2 at -196°C and irradiated with a mercury vapour lamp, gave very low yield (0.4%) of at least six chloro-substituted products [49]. FRC chlorination of acetanilide (C1c) at -40°C was much more efficient and after 6 hours 4-chloro and 2-chloro products in 7:3 relative ratio were formed in 50% yield. Functionalisation of sodium phenoxide (C1b) was temperature dependent and at -40°C further chlorination increased to 28%, thus giving 2,4-dichlorophenol, while the overall yield of chlorinated prod-ucts reached up to 70% [49]. The effect of the structure of the solid alkyl substituted phenol on the course of SFRC chlorination was further investigated and mono vs. polyfunc-tionalisation was determined [50].

Light-induced chlorination

of alkyl substituted benzene derivatives was studied using SO2Cl2 in the presence of various solid catalysts (neutral Al2O3 and SiO2, K10 montmorillonite, xonotlite, zeolites: FeX, HAB A40, NaX and NaY) and the strong dependence of the degree of side chain functionalisation on the catalyst

used was established [51].

Scheme C1. Functionalisation of aromatic compounds with gase-

ous chlorine.

O

C12H25C12H25

OH

F

C12H25

F

OH

+

O

HO HO

OH F

95°C, 24h

F21 F22 (99%)

F23 F24 F25

Bu4P+ A-

A-Conditions Yield

78 22H2F3-

100°C, 10h 92% :

93 7HF2-

100°C, 4h 94% :

97 3F-20°C, 20h 82% :

Bu4N+ H2F3-

F26 F27

reagent

Reagent Conditions Yield

3Bu4P+ HF2-

100°C, 2h 89%

1.5KF (0.1 PTC) 200°C, 1h 100%

NN

Ph

Cl

NN

Ph

F

time Z : E (yield)

50h 100:0 F29a (53%)

4.5h 91:9 F29b (75%)

R1 R2

2Bu4N+H2F3- R1 R2

F110-120°C

F28a

F28b

R1

Ph

Ph

R2

COPh

CHO

21h 95:5 F29c (75%)

7h 70:30 F29d (95%)

F28c

F28d

Ph

C17H15

COOMe

CN

Y

Y

Cl

Y

Cl

Cl2 Cl2 Cl2

Y

Cl

Y

Cl

Cl

Cl

Cl

C2

C3

C4 C5C1a: Y=OH

b: Y=ONa

c: Y=NHCOMe


Chlorine addition to trans-stilbene (C6a) under SFRC at room temperature was investigated, and similarly as in sol-vents prevailing anti addition was established, with a yield significantly lower than the reaction performed in dichloro-methane (Scheme C2) [52].

The important role of the struc-

ture of cyclodextrin (CD) on chlorine addition to its complex with ethyl trans-cynamate was observed. The complex with

-CD was unreactive, while with -CD (C6b) at -15°C two dichloro derivatives (C7, C8) were formed in 64-77% yield [53].

The stereochemistry of chlorine addition was found to

be temperature dependent; syn addition dominated at -15°C, anti addition was the main process at room temperature and moderate optical activity of the products was also observed [53].

Kaupp et al. extensively studied the addition of chlorine

to various solid alkenes under SFRC [54-56]. Low tempera-

ture (-50°C) anti chlorine addition to cholesterol C9 result-ing in 5- ,6- configuration of di-chloro product C10, with an optical rotation of -32°. An interesting effect of reaction temperature on the course of chlorine addition to C9 was observed. The addition was much slower at -30°C than at -50°C, what was explained by partial melting and prevention

of contact of the crystals with the gas [56].

Scheme C2. Effect of olefine structure and reaction conditions on

the stereochemistry of chlorine adition.

Olah et al. used boron trifluoride monohydrate to activate N-chlorosuccinimide for the chlorination of deactivated aromatics (C11, Scheme C3). Chlorination of halosubsti-tuted benzene derivatives gave para products C12, while meta functionalisation occurred in the case of nitrobenzene (C11e) [57].

NCS chlorination of ketones require an acid catalyst (PTSA), while more enolized 1,3-diketones and -keto am-ides (C15) could be functionalised without catalysts in 67-95% yield at room temperature (Scheme C4) [58].

Stable

hydrates C16c-e were isolated after a water-based work-up following chlorination of various trifluoromethyl substituted

1,3-diketones with NCS at room temperature under SFRC

[58].

Scheme C4. Effect of the structure of carbonyl compounds on chlo-

rination with NCS.

3.2. Functionalisation with HCL and Various Chlorides

The addition of hydrogen chloride to olefins was exten-sively studied (Scheme C5) [52,59-61]. Powdered N-vinylphthalimide and N-vinylsaccharin easily added gaseous HCl almost quantitatively on a gram scale at 1 bar and room

Scheme C3. Chlorination of substituted benzenes with NCS.

Ph

R

Ph H

Cl

Cl

RH

Ph H

Cl

RH

Cl

Cl2

Yield C7

(39%) 39

(91%) 40

C6a

R

Ph

Conditions

SFRC, 20°C

CH2Cl2, 20°C

+

C8

61

60

(64-77%) 34-35C6b COOEt -CD, -15°C 65-66

(63-72%) 65-43-CD, 20°C 35-57

Cl2

-50°C, 5h

R

HO

R

HO

ClCl

C9C10 (34%)

[%] [%]

R=C8H15

:

:

:

:

YieldC13 [%]

(95%)0

(86%)46

a

Y

F

time

1h

24h

C12 [%]

100 :

54 :

(90%)40c Br 24h60 :

3862 :

Y

Y YNO2

NO O

Cl

Cl

b Cl

d I

C14

Y=NO2

C11a: Y=F

b: Y=Cl

c: Y=Br

d: Y=I

e: Y=NO2

100°C, 24h

20°C

BF3-H2O

(60%)8h

Cl

Cl

R1

O O

R2 R1

O

Cl

O

R2

NCS

20°C

O O

Ph

O

Cl

O

NHPh CF3

HO

Cl

O

Ar

ClOH

SO

C15 C16

C16a (95%) C16b (67%)

C16c (71%)

C16e (80%)(74%) C16d


temperature thus forming C18b and C18c after 30 minutes, both very sensitive to hydrolysis [60,61].

On the other hand,

liquid N-vinylpyrrolidinone (C17a) crystallized on freezing below -80°C and compact crystals were formed. Chlorine gas uptake was rather smooth even without powdering and reactive compound C18a was formed [52,60].

Solid chalcone

C19 was much less reactive and the addition of HCl was completed after 5 days at room temperature and the anti-Markovnikoff type 1,4-adduct C20 was isolated in 72% yield [60].

The important role of reaction conditions on the

type of transformation was reported in the case of HCl addi-tion to solid camphene which proceeded without Wagner-Meerwein rearrangement, thus giving a quantitative amount of camphene hydrochloride (C22, Scheme C5). The similar reaction in solution gave isobornyl chloride [59]. Contrary to the addition of HBr, gaseous HCl did not react with choles-

terol and its derivatives [56].

Scheme C5. Addition of hydrogen chloride to olefines.

Transformation of alcohols to chlorides could also be achieved with hydrogen chloride (Scheme C6). Di- and triphenylmethanol was easily converted to chlorinated de-rivatives C24a and C24b in 92% and 97% yield respec-tively, when powdered substrates were exposed to HCl gas in desiccator at room temperature. Similar treatment of t-butyl alcohol for 30 minutes gave the corresponding chloride in 89% yield, while dehydration was observed in the case of powdered substrates bearing a methylene group (C23c-e) and olefines C24c-e in almost quantitative yields were formed [62]. 1-Hydroxy-1-N-phthalimidoethane was also

rapidly converted by HCl gas to the chloro derivative [61].

Immobilisation of HCl with methylimidazole was re-ported and an excess of the thus formed ionic liquid [Hmim] Cl was used for transformations of alcohols C25 to alkyl halides [63]. However if 1-n-butyl-3-methylimidazolium chloride ([bmim]Cl) was used in equimolar amounts for conversion of alcohols at room temperature, external addi-tion of equimolar amounts of a Brønsted acid such as H2SO4

or CH3SO3H was necessary [64].

Solid epoxides reacted with gaseous HCl regioselectively

without melting in the case where the melting points were sufficiently high (Scheme C7) [65]. Preferential syn ring

opening was observed with epoxide C27 at -60°C, which is

more selective than found after the reaction performed in dichloromethane or benzene at 20°C. The reaction pathway

was very dependent on the structure of the substrate. After

20 hours at room temperature the product C28c was quanti-tatively formed following anti addition of HCl to C27c.

Crystalline epoxytosylates (S)-C30 and (R)-C30 could be

regiospecifically and quantitatively transformed at 0°C to (R)-C31 and (S)-C31, respectively. Addition of HCl to ster-

oidic epoxides could also be achieved. After 24 hours treat-

ment of substrate C32 at room temperature, chlorohydrine C33 was selectively formed.

-Chloro substituted ketones were prepared in a two step

transformation under microwave irradiation. Ketones were

first transformed to -tosyloxyketone intermediates C35 with [hydoxy(tosyloxy)iodo]benzene (HTIB, Koser's rea-

gent) and subsequently treated with magnesium dichloride to

give chloro derivatives in good yields (Scheme C8) [66].

3.3. Transformations with the Chloride/Oxidizer System

Direct halogention of carbonyl compounds by 1.2 equivalents of the acetic acid derivative of methylimida-

zolium halides ([Acmim]X) in combination with ceric (IV)

ammonium nitrate (CAN) was reported [67]. Cycloalcanone

derivatives C37, -tetralone derivatives C38 and cyclohex-2-

enone C39 were successfully transformed to -chlorinated

products C40, C41 or C42 in over 82% yield at room tem-perature under a nitrogen atmosphere (Scheme C9). The

reaction was completely quenched in the presence of the

radical scavenger TEMPO and a radical mechanism was suggested.

Ring chlorination of arenes (C43) by the system NaCl

and (diacetoxyiodo)benzene (DIB) as oxidizer in 1 : 1 : 1.1

ratio was performed and after 30 minutes of trituration monochlorosubstituted products C44 were isolated in good

to excellent yields (Scheme C10) [68].

Scheme C6. Conversion of alcohols to chlorides. C17

Ph Ph

Cl

Cl

Y

C18

NN

O

O

ON

S

O

O

O

-80°CC18a

20°C, 30 minC18b

20°C, 30 minC18c

O

Ph

O

Ph

HCl

20°C, 5dC19 C20 (72%)

HCl

25°C

C21 C22

HCl

25°C

Cl

Y

Y:

R OH R Cl

H

N

N

Me

Cl-

C25a: R=C7H15

b: R=Ph

C26

C23a: R=H

b: R=Ph

c: R=Me

d: R=CH2Me

e: R=CH2Ph

Ph R

Cl

Ph

HCl

20°CPh R

OH

Ph

C24a: R=H

b: R=Ph

Ph

Ph

R1

C24c: R1=H

d: R1=Me

e: R1=Ph


The silica supported hydrogen chloride/iodosobenzene

system was also used as a source of the chlorine atom. The

type of transformation strongly depended on the structure of

the substrate. Trans-stilbene (C45a) gave vicinal dichloride

(C46a), while hydroxychlorination took place in the case of

1,1-diphenyl (C45b) and 1,1,2-triphenyl ethene (C45c,

Scheme C11). Chlorination also took place when treating

1,2-diphenylacetilene and anthracene with this reagent and

1,2-diphenyl-1,2-dichloroethene (C48) or 9,10-dichloro an-

thracene (C50) were isolated, respectively [69].

The oxidation chlorination approach under SFRC using the HCl-SiO2/PhIO reaction system [69] was aplied for the chlorination of tetraphenyl ethene (C52) and the correspond-ing epoxide C55 was isolated in high yield (Scheme C12). Oxidative demethylation was observed in the case of 9,10-dimethoxy anthracene (C51), while the type of functionalisa-tions of sulfides and disulfides depended on structure of the substrate. Phenylsulfonychlorides (C57) were formed from

disulfide C53b and phenylbenzyl sulfide (C53c), while the

diphenylsulfide was transformed to sulfone C56.

4. BROMOFUNCTIONALISATION

4.1. Reactions with Bromine

The functionalisation of anthracene with gaseous bro-mine was noted in 1870 [48]. Several inactivated aromatics were also brominated under similar conditions [54,70,71]

and interesting regioselectivity was observed in the case of aromatic compounds bearing a double bond (Scheme B1). Tetraphenylethene B1c was brominated on the aromatic ring, while bromine addition to a double bond was noted when less substituted olefins were exposed to molecular bromine [54,70]. These reactions took place in the adsorbed phase on

Scheme C8. Chlorofunctionalisation of carbonyl compounds with

the tandem HTIB/ MgCl2 system under microwave irradiation.

Scheme C9. Effect of substrate structure on functionalisation with the tandem [Acmim]Cl / cerium ammonium nitrate.

Scheme C7. Stereochemistry of epoxide ring opening with gaseous hydrogen chloride.

Ph H

Cl

OH

CO2MeH

Ph H

OH

CO2MeH

Cl

C28

71%

61%

C27b

Cond.

SFRC

CH2Cl2

+

C29

29%

39%

O

PhH

COOMeH

27%

10%

C27a

CH2Cl2

SFRC

73%

90%

O

HPh

COOMeH

HClC27

O OH H

OTs OTs

OHH

Cl

OHH

Cl

OTs OTs

(S)-C30 (R)-C31 (S)-C31 (R)-C30

HCl

0°C

HCl

0°C

HOO

O

HO

O

HCl

20°C, 24h

C32 C33OH

Cl

R H

Cl

OH

H

O

HR

H HCl

20°C, r.t.

OH OH

C27c (2S,3S) C28c (2S,3R)R: O2N

O

R2R1

O

OTsR1

O

ClR1

(HTIB)

MgCl2R2

R2

MW

MW

S

O

O

I

Ph

OH

C34

C35C36 Yield

(92%)

(86%)

a Me

(90%)OMec

b

d (83%)

R1 R2

H

H H

H

Br H

e (80%)NO2 H

N

N

Me

Cl-

COOH

(CH2)n

O

O

O

R

R

(CH2)n

O

O

O

R

R

Cl

Cl

Cl2CAN

C37a: n=1, R=H

b: n=1, R=COOEt

c: n=2, R=H

d: n=3, R=H

e: n=4, R=H

C38a: R=H

b: R=COOEt

C39

C40 (83-90%)

C41

(82-85%)

C42

(83%)


the surface of the substrate crystals, in a film of solution, formed by the substrate dissolved in liquid bromine, or in a combination of both [70].

Direct bromination of anilines in

solution often requires protection of the amino group, while under SFRC the direct transformation of aromatic amines B1d-g was successfully performed at room temperature. The observed mono / dibromo selectivity (B3 : B5) was similar to those established for reactions in solution, except in the case of aminobenzoic acid B1g, where dibrominated product B5g was formed quantitatively [72]. Functionalisations with neat liquid bromine were less explored, but bromination of thio-phene was effiiciently performed by using the micro reactor technique [73]. A continuous method was also used for bro-mination of toluene B1a, where ring (B2a, B3a) and side chain (B4a) brominated products were formed, while selec-tive benzylic bromination was observed in the case of 3-nitrotoluene (B1b) [74]. The approach of introducing a bro-mine atom under SFRC conditions was reported with the use of molecular bromine adsorbed on neutral alumina and selec-tive bromination of 1,4-quinones and coumarins was

achieved using microwave irradiation [75].

Addition of gaseous bromine to olefines was first per-formed in 1863 [76], and was later studied extensively [52,53,56,60,61,70,77-82]. Like many other olefines, N-vinylphthalimide (B6a) and N-vinylsaccharin (B6b) could be brominated successfully (Scheme B2) [60,61], while treat-ment of dibenzobarrelene (B8) with bromine vapor resulted in rearrangement and formation of optically active B9. Rear-rangement was also observed in solution, but racemic prod-

ucts were formed [81].

The effect of the structure of the olefin on the stereo-chemistry of bromine addition was also studied (Scheme B3). Anti addition prevailed in the case of trans-stilbene (B10a), similarly to the reaction in CH2Cl2, but only 20% yield was observed [52]. Bromine addition under SFRC was also studied with the solid inclusion complex of ethyl trans-cinnamate B10b with cyclodextrin (CD), and an important

Scheme C10. Effect of structure of substituted benzenes on func-tionalisation with the tandem NaCl / PhI(OAc)2.

Scheme C11. Effect of substrate structure on chlorofunctionalisa-

tion with SiO2-HCl / PhIO.

Scheme C12. Effect of structure of substrates on functionalisation with the tandem SiO2-HCl / PhIO.

Yield

74%

71%

a

Y

1-NMe2

84%c 1-OMe

80%2-OMe

Y

b 1-NHCOMe

d 1-OMe

(R)n

Y

(R)n

Cl

NaCl

IPh

OAc

OAc

r.t.,

RC43

H

H

81%

78%

e 1-OMe

69%g 1-Me 2-Me

71%3-Me

f 1-OMe

h 1-Me

3-OMe

4-OMe

C44

4-Cl

4-Cl

H 4-Cl

4-Cl

5-Cl

2-Cl

68%4-Mei 1-Me

4-Cl

4-Cl

2-Cl

SiO2-HCl

IPh O

C45a: R1=H, R2=Ph

b: R1=Ph, R2=H

c: R1=Ph, R2=Ph

R1

Ph

R2

Cl

Ph Ph

Cl

HO

Ph

Ph

R2

Cl

C46a: R2=Ph (65%)

C46b: R2=H (80%)

c: R2=Ph (66%)

Ph Ph

Cl

Cl

Cl

Ph Ph

ClC47

C48 (74%)

C49C50 (31%)

SiO2-HCl

IPh O

SiO2-HCl

IPh O

SiO2-HCl

IPh O

C53a: Y=Ph

b: Y=SPh c: n=CH2Ph

C51

C52

C54 (79%)

C55

(82%)

Ph

Ph Ph

PhPh S Y

OMe

OMe

O

O

Ph

Ph Ph

Ph

O

Ph SO2Cl

Ph SO2Ph

C57

(56% from C53b)

(96% from C53c)

C56

(82% from C53a)


effect of CD structure was observed. The use of -CD re-sulted in the formation of erythro product B12b, while a mixture of B12b and B13b was isolated using -CD [53]. The effect of reaction conditions on the reactions of crystal-line fluoro olefins with bromine vapor was also investigated. E-oriented substrate B10c underwent addition mostly in an syn manner towards threo B13c, while almost no syn / anti preference was observed when treating B10d [82]. Erythro products B12 were mainly formed from Z-isomers of sub-strates B11c and B11d and this reaction was found to be insensitive to reaction conditions (dark, h ) [82].

Bromine

added to cholesterol at room temperature and the thermody-

namically less favoured 5 , 6 -dibromide B15 was formed quantitatively and diastereospecifically in contrast to chlo-rine addition, which had to be performed at low temperature

[56].

Transformations under SFRC were also performed with bromine complexes. Microwave induced synthesis of -bromo B17 and , -dibromoalkanones B18 was performed using dioxane-dibromide / silica gel (Scheme B4) [83]. The use of the hexamethylenetetramine-bromine complex for bromination of ketones by trituration is also reported and

only -monobrominated products were formed [84].

4.2. Bromination with the Tribromide Anion

A variety of tribromide reagents were used for bromina-tion of organic compounds under SFRC (Scheme B5). Pyridinium, imidazolium and tetrasubstituted ammonium tribromides are the most often used representatives, since

they can be regenerated after bromine transfer.

Reactions of activated benzene derivatives B30 with tri-bromide reagents resulted in the formation of para bromi-nated products B31, while 2-bromo B33 and 2,6-dibromo products B34 were isolated from 4-substituted phenols B32a

and anilines B32b (Scheme B6) [72,85-90].

The effect of the cationic part of the tribromide reagent on the regioselectivity of bromination of phenol (B35a), o-cresol (B35b) and m-cresol (B35c), resulting in para bromi-nated B36 and ortho substituted B37 as a by-product

Scheme B1. Functionalisation of aromatic compounds with bromine.

Scheme B2. Functionalisation of olefines with bromine.

Y

Br2

Br

Br

Br

R

Y=Me

Y=NH2

NH2

R

NH2

R

Br Br Br

B1a: Y=Me, R=H

b: Y=Me, R=3-NO2

c: Y=CPhCPh2, R=H

d: Y=NH2, R=4-Cl

e: Y=NH2, R=4-Br

f: Y=NH2, R=4-NO2

g:Y=NH2, R=4-COOH

B2a B3a B4a (R=H)

MR

B5[%]

73

75

d

R

Cl

B3[%]

27 :

25 :

81f NO2 16 :

e Br

100g COOH 0 :

r.t., 12h

BrBr

BrBr

B2cY=CPhCPh2

B4b (R=NO2)

R

Br

Br

N

X

O

N

X

O

Br

Br

Br2

Br2

B6a: X=CO

b: X=SO2

B7

B8 B9


(Scheme B7), was studied. Higher para selectivity was ob-served for both cresols in comparison to phenol, while no important differences were found between tetraethyl (B26, TEATB), tetrabutyl (B27, TBATB), cetyltrimethyl (B23, CTMATB), benzyltrimethyl (B24, BTMATB) ammonium tribromides and 1,2-dipyridiniumditribromide ethane (B29, DPTBE) [90].

Substituted naphthalenes B38 were also brominated with tribromide reagents (Scheme B8). Transformation of naph-thalene (B38a) with 3-methylimidazolium tribromide (B20, [Hmim][Br3]) at 70°C resulted in quantitative and selective formation of 1-bromo product B39a after 23 hours, while only 10% conversion with the same regioselectivity was found when 1-butyl-3-methylimidazolium analogue B21, ([bmim][Br3]) was used as the reagent [89]. The regioselec-tivity of the bromination of 1-substituted naphthalenes de-pended on the nature of the substituent. Ortho functionalised product B39b was formed from hydroxy substituted deriva-tive B38b with DPTBE (B29) at room temperature, while

para bromination was observed when methoxy (B38c) [85] and amino derivative (B38d) [86] were treated with [bmim][Br3] (B21). The same reagent was also used for

Scheme B3. Effect of the structure of the alkene on stereochemistry of bromine addition.

Scheme B4. Microwave induced bromination of substituted ke-

tones with bromine-dioxane-SiO2 system.

Scheme B5. Overview of various tribromide reagents.

Scheme B6. Regioselectivity of bromination of benzene derivatives with tribromide reagents.

Ar X

Br

Br

RX

Ar X

Br

RX

Br

B12Cond.

+

B13

61

100

r.t.

-CD, -5°C

39

0

Br2

Subs.

B10a

B10b

46

50

dark

h , 5°C

54

50

28

21

dark

h , 5°C

72

79

B10d

B10c

75

76

dark

h , 5°C

25

24

80

83

dark

h , 5°C

20

17

B11d

B11c

Br2

25°C, 2h

R1

HO HO

BrBr

B14 B15R1=C8H17

R1

X

XAr

R R

XAr

X

(E) (Z)

E

Z

B10 B11

B12 B13

B10a: Ar=Ph, R=Ph, X=H

B10b: Ar=Ph, R=COOEt, X=H

B10c, B11c: Ar=4-HOOC-C6H4, R=Cl, X=F

B10d, B11d: Ar=4-HOOC-C6H4, R=CF3, X=F

SiO2

R1

O

R2

R1

O

R2

R1

O

R2

B16

BrBr

Br

B17

(72-95%)

B18

O O Br

Br

MW

Br3-

N

H

N

N

H

Me

N

N

Bu

Me

N+N+

+N(Et)4

Me3N+ R B22: R=Me

B23: R=C16H33

B24: R=CH2Ph

B25: R=Ph

B19

B20

B21

+N(Bu)4

B26

B27

B29

N+

B28

Y

B30: Y= OH, OMe, NHMe

B31

Y

Br

Y

R

Y

R

Br

Y

R

BrBr

B32a: Y=OH,

R=H, OMe, Me, Cl;

b: Y=NH2, R=Me, Cl, Br, NO2, COOH

B33 B34

B19, B21, B29

L+Br3-


bromination of various aryl-amines B40 which were trans-

formed to B41 after 5 minutes at -10°C in good yield [86].

Scheme B8. Regioselectivity of bromination of substituted naph-

thalene, 2-aminopyridine and 2-aminopyrimidine derivatives with

tribromide reagents.

Substrates containing the ethylenic functionality were also brominated with tribromide reagents under SFRC

(Scheme B9). DPTBE (B29) was successfully used for selec-tive addition to 1,1-diphenylethene (B42b) and 1,3-diphenylpropenone (B42c), as well as for chemoselective bromination of one double bond in dibenzylidine acetone (B42d), a substrate which contains two symmetrical double bonds [90]. Bromine addition in a trans manner was ob-served when (E)-o-stilbenecarboxylic acid B42e was treated with pyridiniumtribromide (B19, PTB), while bromo cyclisa-tion to B43f mainly occurred from para methoxy derivative

B42f [91].

Scheme B9. Effect of alkene structure on bromination with tribro-

mide reagents.

Stereochemistry of bromine addition to alkenes under SFRC using tribromide reagents was examined (Scheme B10). Treatment of crystalline trans-stilbene (B44a) with bromine vapour gives a mixture of meso and racemic prod-ucts in low yield [52], while selective syn addition was ob-served at room temperature after reaction with solid PTB (B19) and meso derivative (B46a) was isolated in 71% yield after 168 hours, applying a green isolation procedure without the use of organic solvents [92]. In contrast syn addition was reported on the Z-oriented analogue (B45a) with liquid pen-tylpyridinium tribromide (B28, PPTB) and B47a was iso-lated in 80% yield. Bromination of chalcone B44c was per-formed with PTB (B19) [92], phenyltrimethylammonium tribromide (B25, PTMATB) [92], tetrabutylammoninum tribromide (B27, TBATB) [92], PPTB (B28) [88] or DPTBE (B29) [90] and erythro product B46c was exclusively formed in all these cases. The corresponding erythro products B46 were also isolated after transformation of (E)-4-phenylbut-3-en-2-one (B44d) or cinnamaldehyde diacylate (B44e) with DPTBE (B29) [90] and B44b with PTB (B19) [91]. Reaction of PPTB (B28) with cyclohexene at room temperature re-sulted in the formation of trans-1,2-dibromocyclohexane B49 in 84% yield [88], while enantioselectivity was ob-served in the reaction of the inclusion complex B48 with PTB (B19) and product (+)-B49 (12% e.e.) was isolated in

56% yield [92].

Bromine addition to acetylenes with PPTB (B28) and DPTBE (B29) was also studied (Scheme B11). Reaction of

Scheme B7. Effect of the cationic part of the tribromide reagent on para regioselectivity of bromination of phenol derivatives.

OH

OH

OH

B29B26B24B23 B27

89%

96%

96%

86%

95%

95%

87%

96%

96%

85%

93%

93%

87%

94%

94%

a

b

c

ReagentaSubstrate

OH

R

OH

R

OH

R

Br

BrL+Br3-

B35

B36 B37

a Orto and para products were formed. Numbers represent

part of para product (B36).

B35

Y

B38a: Y=H

b: Y=OH

c: OMe

d: NH2

Y

Br

Br

Br

B21

B39b (95%)

B39c (Y=OMe, 92%)

B39d (Y=NH2, 95%)

B39a (100%)B20

B29

Y

N NH2

B40a: Y=CH

b: Y=N

Y

N NH2

Br

B21

B41a (91%)

b (96%)

R1 R2

X

O

OMeBr

H

H

O

B19

B43e

O

Ph

Br

Br

R2

Br

Br

R1

B42B43a (93%)

b (87%)

c (92%)

B29

B29

B43d (87%)

Legend:

a: R1=R2=X=H

b: R1=Ph, R2=X=H

c: R1=X=H, R2=COPh

d: R1=X=H, R2=COCH=CHPh

e: R1=H, R2=4-OMeC6H5,

X=COOH


phenylacetylene (B50a) with B29 resulted in a mixture of trans and cis products in 80:20 relative ratio [90], while ex-clusively trans B51a in 92% yield was formed with PPTB (B28) [88]. E-isomer B51b was preferentially formed in the case of ethylpropiolate (B50b), accompanied by 6% of the Z-

product [88].

For the bromination of acetophenone derivatives (B53, Scheme B12) to the -bromo derivatives B54 PPTB (B28) [88], DPTBE (B29) [90] and [bmim][Br3] (B21) [93,94]

were used under SFRC at room temperature.

4.3. Reactions with N-bromosuccinimide

N-bromosuccinimide (NBS) was seldom used for nuclear bromination of aromatics also under SFRC. Reactions with phenol derivatives are presented in Scheme B13. Polybromi-

nated B56a was isolated after 1 minute of trituration of 2-aminophenol (B55a) at room temperature, while bromination of orcinol (B55b) resulted in disruption of the aromaticity and the formation of B56b, while hydroquinones B57 were

converted into quinones B58 in 45-50% yield [95].

Scheme B13. Bromination of substituted phenols with NBS.

Various other substituted phenols and anilines (B59, Scheme B14) were also brominated with NBS under SFRC, but for enhanced reactivity of substrates, as well as for reac-tion selectivity, the crystallinity of the starting material is important [96]. Substituted benzaldehydes (B61) could be successfully brominated only in the case when the aromatic ring was additionally activated by an electron donor func-tional group [97]. Alumina supported and thus activated NBS was used for efficient bromination of anthracene to 9,10-dibromoantharcene (63%), since neat NBS gave only

20% of desired product [98].

Methoxy substituted acetophenones, possessing two po-tentially electron-rich sites, i.e. the aromatic ring and the -carbonyl position, are very sensitive model compounds and the important role of the solvent on the regioselectivity of electrophilic halofunctionalisations of these compounds was reported [31,32,99]. Reaction of 2,4-dimethoxyacetophenone (B63) with NBS under SFRC at room temperature resulted in ring bromination and the formation of B64 with 88% yield after 24 hours, while the presence of an acid catalyst (10% of

Scheme B10. Stereochemistry of bromine addition to alkenes with

tribromide reagents.

Scheme B11. Stereochemistry of bromine addition to acetylenes

with tribromide reagents.

Scheme B12. Bromofunctionalisation of substituted acetophenones

with tribromide reagents. Ph H

Br

Br

RH

Ph H

Br

RH

Br

B46Reag.

+

B47

1B19 0

L+Br3-

Subs.

B44a

1

1

B29

B29

0

0

B44d

0B28 1B45a

Ph

R R

Ph

(E) (Z)

E

Z

B44 B45

B46 B47

O

OCPh2OH

CPh2OH

B19Br

Br

B48 (+)-B49

(56%, 12% ee)

R

Ph

COMe

CH(OAc)2

Ph

B44e

1B19 0B44b 2-CO2H-C6H5

1BXa0B44c COPh

aBX: B19, B25, B27, B28, B29

R

Br

R

Br

RBr

Br

L+Br3-

Yield B52

(84%) 20

(92%) 0

a

R

Ph

B51

80 :

100 :

(90%) 6b COOEt 94 :

a Ph

B50 Reag.

B29

B28

B28

:

X

O

X

O

Br

B21, B28, B29

B53 X= H, Me, OH, MeO,

NO2, Cl, Br, F

B54 (85-96%)

OH

R2R1

OH

NH2

O

OMe

Br

BrBr

Br

Br

Br

Br

Br

NBS

B55a: R1=H, R2=NH2

b: R1=Me, R2=OH

B56a (45%)

B56b (60%)

OH

R

OH

O

O

Br

R1NBS

B57a: R=OMe

b: R=H

B58a (R1=OMe, 45%)

B58b (R1=Br, 50%)


p-toluenesulfonic acid, PTSA) increased the yield up to 93%

[58,100].

Scheme B14. Bromofunctionalisation of di- and trisubstituted ben-

zene derivatives with NBS.

An interesting effect of the reaction conditions on re-gioselectivity was shown for the benzocycloalkanone deriva-tives (B65, Scheme B15) bearing only one methoxy group. Bromination with NBS and 10% PTSA was successfully performed at 80°C under SFRC giving -bromo products B67, while ring bromination occurred when reaction was

performed in aqueous medium [100].

Scheme B15. Directed Regioselectivity of Bromination of Ketones

with NBS.

Contrary to ketones, where a catalytic amount of acid has to be used for successful transformation with NBS under SFRC, bromination of 1,3-diketones, -keto esters and -keto amides does not require any catalysts and could be per-formed at room temperature even if the reaction mixture

remains solid (Scheme B16) [58,100,101]. In many cases a desirable green approach to synthetic protocols is not fol-lowed by environmentally friendly isolation and purification procedures, whereas in this case organic solvents were not

used even in the isolation procedure.

Scheme B16. Bromination of 1,3-diketones, -keto esters and -

keto amides with NBS.

The effect of the aggregate state and preorganisation (PO) in a solvent [12] was investigated for two structurally similar ketones, solid indanone (B65c) and liquid tetralone (B65d). Under SFRC the liquid substrate was almost twice as reactive as the solid one (Scheme B17), while very low conversion was observed in acetonitrile [58]. Preorganiza-tion was achieved by dissolving the ketone, NBS and PTSA in acetonitrile, which was then immediately evaporated. Both ketones were more reactive in the preorganized state, but the increase in reactivity was much more pronounced for

solid B65c [58].

Scheme B17. Effect of aggregate state of ketones and reaction con-

ditions on bromination with NBS.

The kinetics of acid catalyzed bromination of ketones with NBS under SFRC was studied (Scheme B18) [58]. Dual behaviour of ketones was found when the enolisation con-stants (pKE) of substrates were correlated with their reactiv-ities. In the substituted acetophenone series (B74a-e), less enolized substrates were found to be more reactive. It was established that functionalisation obeys first order kinetics and is probably controlled by the rate of enole formation,

NBS

YH

R

YH

R

Br

B59: YH=OH, R=4-NO2, 4-COMe;

YH=NH2, R=4-NO2, 3-COMe, 2-COOH

OR

OR

O

OR

OR

O

Br

B61: R=H, Me, -CH2-

NBS

B62 (76-79%)

B60 (30-80%)

OMe

O

OMe

O

Br

B63

NBS

B64 (88%)

OMe OMe

B66 (a: 87%, b: 81%)

H2O

(CH2)n

O

MeO

(CH2)n

O

MeO

(CH2)n

O

MeO

Br

Br

NBS

B65a: n=1

b: n=2

B67 (a, b: 97%)

60°C

PTSA

20°C

SFRC

O

R

O O

R

O

Br

O

R

O O

R

OBr

NBS

NBS

B68a: R=Me b: R=Ph

c: R=OEt

d: R=NHPh

B69

(a: 92%, b: 98%,

c: 95%, d: 85%)

B71 (98%)

B73 (84%)

(CH2)n (CH2)n

B70: n=2, R=Me

B72: n=1, R=OEt

O

O

Conditionsa

SFRC

MeCN

Substrate Conversion

44%

8%

PO 86%

B65c

SFRC

MeCN

72%

5%

PO 91%

B65d

a React. cond.: 30 min, 20°C; PO: preorganisation of

reactants in MeCN.

(solid)

(liquid)


while further bromine addition is much faster than enoliza-tion. This expectation was also supported by Hammett corre-lation analysis of the process, revealing a slightly negative value of the reaction constant ( = -0.5), indicating moderate positive charge development in the rate determining step. An opposite association was observed for cyclic ketones (B75a-

d), where higher reactivity of substrates with a higher enoli-

zation constant (pKE) was established.

Scheme B18. Effect of enolisation of cycloalcanones and acetophe-

nones on bromination with NBS in the presence of PTSA.

NBS was also successfully employed for benzylic bromi-nation under SFRC using AIBN [102] or MW [103,104] as initiators (Scheme B19). Reactions of xylenes B78 with NBS under MW irradiation resulted in formation of mono (B79) and bis monobrominated (B80) products, while 20%

of dibrominated product B81 was also formed from 4-

nitrotoluene [103].

Scheme B19. Benzylic brominations with NBS.

High-speed vibration milling technology (HSVM) was employed for benzylic bromination of diquinoline com-pounds (B82, B83) with NBS and similar regio- and stereo-selectivity of the reaction performed under SFRC or in a

solvent (Scheme B20) was observed [105].

Scheme B20. HSVM induced benzylic brominations with NBS.

4.4. Functionalisation with HBr and Various Bromides

While trans-stilbene (B86) does not add gaseous HBr [60], some other olefinic compounds (B87, B88) could be hydrobrominated, whith the regioselectivity depending on the structure of substrate (Scheme B21) [52,55,60]. Hydro-bromination under SFRC was also studied using the inclu-sion complex of ethyl trans-cinnamate B90 with or -cyclodextrin (CD) and the formation of optically active S-(-)-3-bromo-3-phenylpropanoate (B91) in 31% e.e. when treated with -CD was observed, while after using -CD, 46% e.e of isomeric R-(+) product was isolated in only 17-21% yields

after 15-20 hours reaction at 20°C [53].

Addition of gaseous HBr to solid camphene (B92) quan-titatively gives isobornyl bromide (B93) as a result of the Wagner-Meerwein rearrangement (Scheme B22) [59]. Re-gio- and diastereospecific addition of gaseous HBr to choles-teryl oleate B94 and quantitative isolation of B95 after 10 hours at -30 to -20°C without the crystals melting was re-

ported [56].

N

Br

O O

PTSA

O

X

O

Ar

O

Br

O

BrB75a: c-pentanone

b: c-hexanone

c: c-heptanone

d: 1-indanone

B74 (a: R=H, b: R=4-Me,

c: R=3-Me, d: R=3-CF3,

e: R=4-CF3)

B76

B77

B74a

B74b

B74cB74d

B74e

B74a

B74b

B74c

B74d

B74e

Hammett correlation plot for the bromination of acetophenones:

B75a

B75b

B75c

B75d

Correlation between the enolization (pKE) of subst. acetophenones

and cyclic ketones and the rate of NBS bromination:

= - 0.4

N

N

H

H

N

N

H

H

Br

NBS

R

R

R

R

R

R

R

R

B82: R=H

B83: R=Br

B84 (85%)

B85 (88%)

Br

CH2Br

R

CH2Br

CH2Br

CHBr2

R

B79

B80 B81

R

B78

NBS


Reactions of solid epoxides (B96, Scheme B23) with gaseous hydrogen bromide were reported and quantitative ring opening was achieved after 16 hours at -60°C without melting the crystals [65]. Conversion of alcohols B98 to

bromides was also reported [61].

Scheme B23. Epoxide ring opening with HBr and conversion of

alcohols to bromides.

Alcohols could be converted to bromides using various imidazolium bromides (Scheme B24). The effect of the reac-tion conditions and structure of the substrates (B100) on room temperature transformation with 1-butyl-3-methylimi-dazolium bromide ([bmim][Br]) was studied. It was found that the reaction is most successful if an equimolar amount of H2SO4 is used, while no important effect of the length of the alkyl chain on the course of reaction was observed [64].

Scheme B22. Addition of HBr to camphene and cholesterol deriva-

tives.

Scheme B21. Effect of alkene structure on hydrobromination with gaseous HBr.

Scheme B24. Effect of reagent structure on the conversion of alco-hols to bromides.

H

Ph R

Y

Ph

Br O

Ph

PhPh

Me

Ph

OEt

O

PhO

Br H

OEt

B86: R=H, Y=PhB87: R=Me, Y=Ph

B88: R=H, Y=COPh

B89b

B89a

B90B91 (31% e.e.)

HBr

-CD / 20°C

Br

HBr

O

Cl

HBr

Br Cl

OH

-60°C

N

O

O

C96 C97

OH

HBr

N

O

O

Br

C98 C99

Br25°C

RO

C92 C93

O

C94 C95(CH2)7O

H3C(CH2)7

Br

HBr

HBr

C100 C101

R OH

N

N

Bu

Me

Br-

H-AR Br

Time [h] Yield [%]

24 57

Product

C100a n-C3H7

Sub. R H-A

CH3SO3H C101a

3 83H2SO4

20 95H2SO4

5.5 98C100b n-C7H15H2SO4 C101b

C102 C103

(CH2)n

N

N

R

Me

Br-

PTSA

Conditions Conv. [%]

110°C, 2h 98

Product

C102a 6

Sub. n

n-C4H9

R

C103a

HO OH (CH2)nBr Br

110°C, 2h 90n-C8H17

110°C, 2h 96i-C3H7

110°C, 2h 95C102b 8 n-C4H9C103b

110°C, 2h 95n-C8H17

MW, 50s 100

110°C, 2h 92i-C3H7

MW, 60s 99


Fatty diols B102 were transformed to dibromides with the 1-alkyl-3-methylimidazolium bromide/PTSA couple. Reaction was performed at 110°C for 2 hours under SFRC, but reac-tion times could be shortened drastically using MW irradia-

tion [106,107].

-Bromo substituted ketones can be prepared with mag-nesium dibromide through -tosyloxyketone intermediates in similar way as described for chlorination (Scheme C8) [66].

4.5. Transformation with the Bromide/Oxidant System

Hydrogen bromide treated silica gel in combination with iodosobenzene (2.2 equiv.) was used in transformations of olefins (B104, Scheme B25). 1,1-Diphenylethene was hy-drobrominated (B105a) in 27% yield, bromine addition to trans-stilbene B104b was observed in 39% yield, while oxi-dation, resulting in the formation of 47% of B105C was re-ported in the case of 1,1,2-triphenylethene B104c [69]. Bro-mination of 1,2-diphenylethyne resulted in the formation of the 1,2-dibromoethene derivative in 51% yield [69].

Scheme B25. Effect of alkene structure on functionalisation with

the HBr·SiO2/PhIO system.

Vapour phase aerobic bromination of aromatic com-pounds using the HBr/O2 system is usually performed in the presence of a catalysts containing an oxidizing metal and an inert support [108], but these systems exceed the scope of this account. The tandem of NaBr/(diacetoxyiodo)benzene was successfully used for room temperature bromination of activated benzene derivatives (B106, Scheme B26) and the formation of para brominated products was established [68], while the transformation of 2-methoxynaphthalene B108

gave 87% of 1-brominated product B109 [68].

Scheme B26. Bromination of activated aromatic molecules with

NaBr/PhI(OAc)2 system.

Cerium (IV) ammonium nitrate (CAN) [67] and urea-hydrogen peroxide (UHP) [109] were used as oxidizers in -bromination of ketones B110 under SFRC, while the acetic acid derivative of methylimidazolium bromide ([Acmim]Br) or NaBr with MW irradiation were used as the source of the bromide anion (Scheme B27).

Scheme B27. Bromination of ketones with a bromide/oxidant sys-

tem.

5. IODOFUNCTIONALISATION

5.1. Reactions with Iodine

Due to its low electrophilicity, the reactivity of iodine is rather low in comparison to other halogens and only the most reactive organic molecules can be directly iodofunctional-ised. Furthermore, the release of hydrogen iodide during the iodination process often causes the breakage of carbon-iodide bonds. Three main pathways are employed for activa-tion of iodine and modulation of its electrophilicity (Scheme I1) [110]: (a) a polarisation of the I-I bond by an electron deficient species (A) which acts as a Brønstead or Lewis

Scheme I1. Reaction pathways in functionalisation of organic molecules with molecular iodine.

Ph

R1 R2

Ph

Br

Ph

Ph

Ph

Br

B104a: R1=Ph, R2=H

b: R1=H, R2=Ph

c: R1=R2=Ph

B105b

B105a

Ph

Ph

O

Ph

B105c

PhI=O

SiO2 HBr.

HO

Br

Y Y

BrB106: Y=OMe, NMe2, NHCOMe B107

NaBr

PhI(OAc)2

OMe OMe

Br

NaBr

PhI(OAc)2

B108 B109

B110 B111

R1

O

R2R1

O

Br

R2

A

B

N

N

Me

Br-

COOH

/ CAN

NaBr / UHP

(MW, 20-120s)

80B110a

Substrate: R1 R2

H 80Ph

(3-6 min)

A: B:

72B110b H 854-MeC6H5

73B110c H 824-OMeC6H5

B110d Me 84Ph

B110e 90O

Reaction systema

a Yield [%]

I I

D H

I IA A

I I A

ab

c

-+

D H

D H

I I

I I

A

A

S

I

H

S

H

I

S I


acid; (b) an electron deficient activator A could interact with the organic substrate (D-H), generating its cation radical, which leads to iodinated substrate S-I after collapse with I2; (c) interaction of A with iodine generates an iodine cation radical, which collapse with D-H forming the final product (S-I). Iodine atom economy can be achieved using the latter

scenario, while half of the iodine is lost in paths a and b.

Three main reaction systems were applied for iodofunc-tionalisations with I2 under SFRC. Beside very limited use of iodine, various oxidizers, such as the urea/H2O2 complex, Oxone, and PhI(OAc)2) or supports, such as Al2O3, SiO2·Bi(NO3)3, and AgNO3) were used for its activation

(Scheme I2).

Scheme I2. Reaction systems applied in iodination with iodine.

Acetylenes are often reactive enough for iodination with molecular iodine without additional activation, so that trans-1,2-diiodoethene derivatives I2 were formed at room tem-perature, also under SFRC (Scheme I3) [111,112]. 1-Octene was iodinated with 1 equiv. of molecular iodine and 1,2-diiodooctane was isolated in 65% yield [111]. Sodium phe-nolate was functionalised with I2 yielding 2,4,6-triiodo-phenol (I4) [113], while an appropriate activator has usually to be used for aromatic ring iodination under SFRC. Azulene (I5) and some other aromatics were iodinated on alumina at

room temperature in 20 hours [114].

Scheme I3. Iodination of acetylenes and aromatic compounds with

iodine.

Silver nitrate [115] and silica supported bismuth(III) ni-trate pentahydrate [116] were also employed as supports for iodine activation. Iodination at the para position was achieved at room temperature with various monosubstituted benzene derivatives I7 and 2-substituted anisols I9 (Scheme I4). 9H-Carbazole (I11) was functionalised on position 3

(I12) in 70% yield using the I2/AgNO3 system [115].

Scheme I4. Iodination of aromatic compounds with the tandeme

iodine and AgNO3 or SiO2-Bi(NO3)3.

Higher iodine atom economy of a transformation could in some cases be achieved by the use iodine (0.5 equv.) and UREA-hydrogen peroxide (UHP) [111] or (diacetoxy-iodo)benzene (DIB) [68,117] as oxidisers (Scheme I5). In

Scheme I5. Iodination of aromatic compounds with the io-

dine/oxidant system.

Ph R

Ph

I R

I

OH OH

I I

I I

I

I2

I2

NaOH

r.t.

I2

I1 R=H, Me I2

I3

I4

I5 I6

Al2O3

I I

Al2O3

Bi(NO3)3

AgNO3

SiO2

I2Oxone

PhI(OAc)2

UREA

H2O2

Na2CO3

Y Y

I

I2

I7 R= OMe, SMe, Ph, NHAc I8

AgNO3 or

SiO2-Bi(NO3)3

OMe OMe

I

I2

I9 R= Me, Br, NO2, COOH I10

AgNO3 or

SiO2-Bi(NO3)3

RR

HN I2

AgNO3

HN

I11 I12 I

NR1R2NR1R2

I

0.5 I2

I14

[OXID.]

UHP PhI(OAc)2I13a: R1=R2=H

b: R1=R2=Me

c: R1=COMe, R2=H

OMe OMe

0.5 I2

[OXID.]

UHP PhI(OAc)2

(OMe)n (OMe)n

UHP

I16

90

91

2-OMe

3-OMe

894-OMe

PhI(OAc)2

I15

a

b

c

90

81

2,3-OMe

2,4-OMe

1003,5-OMe

d

e

f

4-I

5-I

2-I

4-I

5-I

2-I

Conv. [%]

I

n

1

2


this way aniline derivatives I13 were iodinated at the para position (I14) and various anisol (I15) and xylene deriva-

tives were also functionalised efficiently.

Alcohols were iodinated using the iodine/triphenyl-phosphine system under microwave irradiation and such a protocol was tested on derivatives of benzyl alcohol I17 and

some alky and cycloalkyl alcohols (Scheme I6) [118].

It has already been demonstrated that iodine is a very mild and useful catalyst for various functionalisations of organic compounds [119,120] and various transformations of aryl substituted alcohols I19 could be achieved a using small amount (3-10%) of iodine under SFRC. Acetates I21 were formed in the presence of acetanhydride [121], vinyl acetate [122] or isopropenyl acetate [123]. On the other hand, three different types of functionalisation have also been observed, usually at higher temperatures (70-90°C), forming ethers I20, alkenes I22 or substituted indenes I23, depending on the

structure of the substrate [124].

Scheme I6. Functionalisation of alcohols with iodine.

The solid state transformation of -Dicarbonyl com-

pounds to -iodo substituted derivatives (Scheme I7) was

reported using iodine (0.5 equiv.) and Oxone as catalyst (0.1

equiv.) at room temperature [125], but independent critical

evaluation of this method should be made, since the catalytic

role of Oxone is not clear.

Successful transformation of ketones to their -iodo de-rivatives was achieved at 45°C using an equimolar amount of iodine and UHP under SFRC. Acetophenone I26a, 4-methoxyacetophenone I26b and various other polymethoxy substituted acetophenones were iodinated regiospecifically on the side chain (Scheme I8) [111]. Higher iodine atom economy was observed in the case of benzocycloalkanones I28 where only 0.5 equiv. of I2 and 0.6 equiv. of UHP was sufficient for the formation of -iodinated products I29

[111].

5.2. Transformations with N-iodosuccinimide, ICl and

Various Iodides

N-iodosuccinimide (NIS) was used for SFRC iodofunc-tionalisation of ketones I30 (Scheme I9). Acetophenone was selectively -iodinated using NIS at room temperature in the presence of a catalytic (10%) amount of p-toluenesulfonic acid (PTSA), while reactions with -dicarbonyl derivatives also proceeded without a catalyst [58]. These transforma-tions using an equimolar amount of PTSA and MW irradia-tion was also reported [126], as well as iodination of aro-

matic compounds with NIS under SFRC [113].

For the transformation of ketones I30 to their -iodo de-rivatived the I

-/oxidiser system was used (Scheme I9). Simi-

lar to the introduction of chlorine or bromine, iodination could be performed using the acetic acid derivative of meth-ylimidazolium iodide [Acmim]I and CAN (2 eqiv.) [67] or MgBr2 through -tosyloxyketone intermediates [66]. Acety-lenes were iodinated using iodides and oxidisers, and only traces of 1,2-diiodoethene derivatives were observed after treating 1,2-diphenylethyne with silica supported HI and PhIO [69], while reaction of phenylacetylene with KI/HNO3

Scheme I7. Effect of structure of 1,3-diketones and -keto esters on

iodotransformation with iodine in the presence of catalytic amounts

of Oxone.

Scheme I8. Iodination of ketones using the iodine/UHP system.

OH

R1

R2

I

R1

R2

I2 / Ph3P

MW

I17 R1=H, R2=H, OMe, Me,

Cl, Br, NO2

R1=Me, R2=H

I18

I2

(3-10%)

Ar R2

OH

R1

SFRC

Ar

R1

R2

O

R2

R1

Ar Ar R2

OCOMe

R1

Ar

R1 R2 Ph

I19I20 I21

I22 I23

Oxone, r.t.R1

O

R2

O

R1

O

I

R2

O

I25

96

92

Me

Me

94Me

I24

a

b

c

95

94EtO

88Me

d

e

f

Yield [%]

OMe

Me

Ph

Ph

OEt

O

R1 R2

1

1

1.5

2

4

5

time [min]

Ph

I2

O

R

O

R

I2

I26a: R=H

b: R=OMe

I27

I

0.5

1

UHPOxone

O OI2

I28a: n=1

b: n=2

I29

0.1 Oxone

0.6 UHP I

(CH2)n (CH2)n


[112] was more efficient, but 1-iodo-2-nitroethene deriva-

tives were also formed besides 1,2-diodophenylethenes.

Scheme I9. Iodination of ketones using various iodination systems.

Metal iodides supported on clays were used for conver-sion of alcohols to iodides under SFRC (Scheme I10). Reac-tions in the presence of mineral acid (H2SO4) and under MW irradiation were used for successful transformation of ben-zylic substrates I34 [127]. The addition of acid was not nec-essary when iodine was supported on KSF-clay and MW irradiation [128] or heating (60°C) performed [129]. Effi-cient transformation was also achieved with the KI/PTSA [130] or NaI/SiO2/CeCl3·7H2O [131] combination and MW irradiation, heating diphosphorus tetraiodide under vacuum at 85°C [132] and in some cases also with gaseous hydrogen

iodide [61].

Scheme I10. Iodination of benzylic alcohols using metal iodides and natural or KSF clay.

Alkyl alcohols were successfully transformed to iodides using 1-n-butyl-3-methylimidazolium iodide at room tem-

perature in the presence of an equimolar amount of acid (CH3SO3H or H2SO4) [64]. Various other 1-alkyl-3-methyl-imidazolium iodides were used for transformation of fatty diols I36 under SFRC. PTSA was used as the acid (Scheme I11) and high yields of diiodides I37 were formed by either heating (110°C, 2h) or after a short MW irradiation

[106,107].

Scheme I11. Iodination of fatty diols using various imidazolium

iodides.

Dichloroiodates were shown to be effective reagents for iodination of aromatic compounds under mild SFRC (Scheme I12). The solid 1-benzyl-4-aza-1-azoniabicyclo [2.2.2]octane [133] and tetramethyammonium [134] dichlor-oiodate were used for functionalisation of activated and de-activated benzene derivatives I38. 4-Iodo and 3-iodo substi-tuted products were formed respectively at room temperature after 5-45 minutes. These reagents do not affect oxidizable groups, such as hydroxy, aldehyde or amino, and successful scale up was performed to obtain multigram quantities of 4-iodoanisole (I39a), 4-iodoaniline (I39b) and 3-(3-iodo-4-aminophenyl)propionic acid in good yield, while lower con-versions were observed when reactions are performed in organic solvents, even after a long reaction time [133,134]. Iodine(I)chloride was used for functionalisations of aromat-ics, but iodination and chlorination processes often compete. Durene (I40) was iodinated and product I41 was isolated in 40% yield after 1 hour reaction at room temperature with 2 equiv. of ICl, while 88% yield was observed with a lower amount of reagent (1.4 equiv.) supported on SiO2 [113]. In the case of anthracene (I42), chlorination to 9,10-dihlorinated product I43 in 55% yield was observed using 4

eqiv. of ICl after 30 minutes at 20°C.

Synthesis under SFRC of iodosubstituted aromatic com-pounds over diazonium salts was performed with potassium iodide (Scheme I13). Diazonium nitrate monohydrate I45, quantitatively transformed from 1-aminoanthraquinone (I44) using NO2 in a gas-solid reaction, was triturated with excess

I29a: n=1

b: n=2

I30R1

O

R2

O

I

O

R

IX

(CH2)n

O

I

(CH2)n

O

I

N

N

Bu

I-

COOH

NI

O

OMgI2

MW

HTIB

I33a: n=1

b: n=2

I31 I32

CAN

I34

CLAY

natural

+

H-A

KSF

CH2OH

R

KI NaI

CH2I

R

kT MWI35a: R=H

b: R=OMe

c: R=Cl

d: R=NO2

I37

(CH2)n

N

N

R

Me

I-

Conditions Conv. [%]

110°C, 2h 716

n

HO OH (CH2)nI I

MW, 95s 956

110°C, 2h 718

MW, 70s 988

PTSAkT

MW

I36

(a: n=6, b: n=8,

c: n=14, d: n=16)

n-C4H9

R

MW, 50s 9814

110°C, 2h 958

MW, 50s 988

110°C, 2h 918

n-C8H17

i-C3H7


KI and iodinated product I46 in quantitative yield was formed after 24 hours at room temperature [135]. The same

procedure, with some variations in strategies for the prepara-tion of precursor diazonium salts, was also used for iodina-tion of other aromatics (I47). The higher efficiency and se-lectivity of transformation under SFRC, compared to those

in solutions, was observed [135].

CONCLUSION

Solvent-free reaction conditions are becoming a widely used experimental technique for the selective and efficient introduction of halogen atoms into organic compounds. The environmental impact caused by the synthesis of organic compounds could be reasonably diminished by using this modern approach to chemical transformations. Avoiding volatile and toxic organic solvents during each particular phase of synthetic protocols should become the main goal of chemical synthesis designers in academia and particularly in the industrial research community.

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Scheme I12. Effect of substrate structure on transformations of

aromatic compounds using ICl and L+ICl2

-.

Scheme I13. Synthesis of iodosubstituted aromatic compounds

over diazonium salts using KI.

I44

O

O

NH2 O

O

N2+

NO3- . H2O

KIr.t.

24h

O

O

I

I45

I46 (100%)

R

N2+NO3

-.H2O

I47 R= Br, CN, NO2, COOH

KI

R

I

I48 (100%)

2NO2

I39

+NMe4Product

100

Y

I38

N N+Ph

Y Y

I

a 984-I

99b 874-I

90c 874-I

75d 503-I

92e 833-I

80f 803-I

NH2

Ph

CHO

COPh

NO2

Reaction systema:

I

Cl

Cl

ICl / SiO2

20°C, 1h

I40

I42

I41 (88%)

I43 (55%)

4ICl / SiO2

20°C, 0.5h

a Yield [%]

OMe

R4N ICl2


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Introduction of Halogen Atoms into Organic Compounds Under Solvent- Free Reaction Conditions

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