Synthesis of β-dicarbonyl compounds using 1-acylbenzotriazoles as regioselective C-acylating reagents

1564

Chem. Rev. 2010, 110, 1564–1610

Synthesis of Heterocycles Mediated by Benzotriazole. 1. Monocyclic Systems

Alan R. Katritzky* and Stanislaw Rachwal

Center for Heterocyclic Compounds, Department of Chemistry, University of Florida, Gainesville, Florida 32611-7200

Received May 22, 2009

9. Five-Membered Rings with Three or Four

Heteroatoms

1594

Contents

1. Introduction

2. Preparation of Simple Derivatives of Benzotriazole 1565

Used for Heterocyclic Synthesis

1564

9.1. 1,2,3-Triazole

9.2. 1,2,4-Triazole

1594

1595

1596

1597

1599

9.3. 1,2,4-Oxadiazole

9.4. 1,3,4-Oxadiazole

9.5. Tetrazole

2.1. By Nucleophilic Aliphatic Substitution

2.2. Addition to Multiple CC Bonds

1565

1566

2.3. By Adducts to Carbonyl Groups of Aldehydes 1567

and Their Conversions

10. Pyridine

10.1. Hexahydropyridine (Piperidine)

10.1.1. N-Substituent

10.1.2. Ring Formation

10.2. Tetrahydropyridine

10.3. Transformations of Ring Substituents

2.4. By Carbanions Stabilized by a Benzotriazolyl 1568

Substituent

3. Three-Membered Rings

3.1. Aziridine and Azirene

3.2. Oxirane

1568

1569

1570

1573

1574

10.4. Electrophilic and Nucleophilic Substitutions of 1600

the Aromatic Ring

4. Four-Membered Rings

5. Pyrrole

10.5. Aromatic Ring Formation

10.5.1. Pyridones and Thiopyridones

10.5.2. Pyridines

1600

1602

1603

1604

1605

5.1. Nonaromatic Rings

5.1.1. Pyrrolidines

5.1.2. Pyrrolidinones

11. Pyran and Thiopyran

11.1. Pyran

11.2. Thiopyran

5.1.3. Pyrrolines

5.2. Aromatic Ring Substituents

5.2.1. Substituents at the Nitrogen Atom

12. Six-Membered Rings with Two or More

Heteroatoms

5.2.2. Electrophilic Substitution at Ring Carbon 1574

Atoms

12.1. Pyridazine

12.2. Pyrimidine

12.3. Pyrazine

1605

1606

1607

1608

5.3. Aromatic Ring Formation

5.3.1. One Substituent at C-2

1576

1577

5.3.2. Two Substituents at C-2 and C-3

5.3.3. Two Substituents at C-2 and C-5

5.3.4. Two Substituents at C-3 and C-4

12.4. Oxazines

12.5. 1,4-Dithiin

12.6. 1,3,5-Triazine

12.7. 1,2,4,5-Tetrazine

13. Conclusion

5.3.5. Three Substituents at C-2, C-3, and C-4 1578

5.3.6. Four Substituents at Carbon Atoms

5.3.7. Benzotriazolyl Substituent at the Ring

1579

1580

14. References

6. Furan

6.1. Nonaromatic Rings

6.1.1. Tetrahydrofurans

6.1.2. 2,5-Dihydrofurans

1. Introduction

Throughout the years since our ﬁrst papers in the 1980s

on the application of benzotriazole derivatives in organic

synthesis,^1,2tremendous progress has been achieved in the

ﬁeld of benzotriazole chemistry. Benzotriazole intermediates

are now commonly used for introduction of a variety of

functional groups into molecules. Five major functions of

benzotriazole in organic transformations are illustrated in

Figure 1. Many aspects of the application of benzotriazole

methodology in organic synthesis have been reviewed;

however, there is only one outdated review^3dof a limited

scope that is speciﬁcally devoted to the synthesis of

heterocyclic molecules. With this paper, we ﬁll this existing

gap and hope to make the work of chemists who are

struggling with the construction and derivatization of het-

erocyclic systems a bit easier.

6.2. Electrophilic Substitution of the Aromatic Ring 1581

6.3. Aromatic Ring Formation

7. Thiophene

7.1. Nonaromatic Rings

1582

1583

7.2. Electrophilic Substitution of the Aromatic Ring 1583

7.3. Aromatic Ring Formation

8. Five-Membered Rings with Two Heteroatoms

8.1. Pyrazole

1583

1584

1586

1589

1590

1592

8.2. Imidazole

8.3. Isoxazole

8.4. Oxazole

8.5. Thiazole

10.1021/cr900204u

2010 American Chemical Society

Published on Web 10/02/2009

Synthesis of Heterocycles Mediated by Benzotriazole

Chemical Reviews, 2010, Vol. 110, No. 3 1565

Alan R. Katritzky is Kenan Professor of Chemistry and Director for the

Center of Heterocyclic Compounds at the University of Florida. He studied,

researched, and taught in the United Kingdom at the Universities of Oxford,

Cambridge, and East Anglia before crossing the Atlantic to take up his

present post in 1980. He has researched in diverse areas of organic and

physical-organic chemistry but none more deeply than in the chemistry

of benzotriazole, a topic which blossomed in his group after Stan Rachwal

joined him in 1983. Benzotriazole chemistry was ﬁrst summarized in

Chemical Reviews in 1998; that manuscript has since received 264

citations. It is a particular pleasure for him to have been asked by Stan

to share in the authorship of the present summary, which updates part of

the earlier review.

Figure 1. Reactivity proﬁle of benzotriazole.

Scheme 1

Scheme 2

Stanislaw Rachwal was born in Jodlowka and was raised in Krakow,

Poland. He received a Ph.D. in organic chemistry from Jagiellonian

University in Krakow and was nominated to the position of Adjunct

Professor at that university in 1980. His main research at that time was

focused on the chemistry of ferrocenophanes. During a sabbatical leave

in 1984, he joined Professor Alan R. Katritzky at the University of Florida

to lay a foundation for application of benzotriazole in organic synthesis.

He returned to the University of Florida in 1988, where as a group leader

he effectively contributed to the research on derivatives of benzotriazole.

His collaboration with Professor Katritzky resulted in over 40 scientiﬁc

papers on benzotriazole. Since 1993, he has worked in the pharmaceutical

industry specializing in CNS drugs with a primary focus on heterocyclic

compounds.

2. Preparation of Simple Derivatives of

Benzotriazole Used for Heterocyclic Synthesis

2.1. By Nucleophilic Aliphatic Substitution

Alkylation of benzotriazole (1) with alkyl halides or

sulfates in the presence of a base leads to mixtures of

1-alkylbenzotriazoles 2 and 2-alkylbenzotriazoles 3. The ratio

of product 2 to product 3 depends on the bulkiness of the

alkyl group and varies from 78:22 (R ) Et) to 50:50 (R )

C₆H₁₁CH₂) (Scheme 1).^4,5

Direct alkylation of benzotriazole with alcohols in the

presence of triphenylphosphine and NBS provides some

progress (Scheme 2). It is assumed that the ﬁrst step is the

formation of reactive intermediates 4, which are then attacked

by benzotriazole in the S_N2 fashion to give derivatives 5.

The reaction is regioselective and provides exclusively

1-alkyl-, 1-(arylmethyl)-, 1-(2-alken-1-yl)-, and 1-(2-alkyn-

The aim of this review is to provide practical guidance

for synthetic chemists. Bearing in mind that the major interest

in heterocycles is the synthesis of biologically active

compounds, we arranged the material systematically accord-

ing to the size and shape of the molecules. The nature of

the heteroatoms and their number and positions in the

molecule are used as secondary discriminators. This way,

any chemist searching for bioisosteres of a heterocyclic

scaffold or a heterocyclic substituent will ﬁnd a whole range

of useful structures.

1566 Chemical Reviews, 2010, Vol. 110, No. 3

Katritzky and Rachwal

Scheme 3

Scheme 4

1-yl)benzotriazoles in 60-84% yields. Secondary alcohols

give the corresponding alkyl derivatives in low yields, while

tertiary alcohols do not alkylate benzotriazole under these

conditions.⁶

Scheme 5

In an aqueous micellar medium with cetyltrimethylam-

monium bromide surfactant, benzotriazole is alkylated re-

gioselectively at N-1 with n-propyl and n-butyl bromides,

but activated alkylating agents (benzyl chloride, allyl bro-

mide, phenacyl chloride, etc.) produce mixtures of benzot-

rizol-1-yl and -2-yl isomers in ratios varying from 55:45 to

80:20.⁷Use of ionic liquids as media generally provides

higher regioselectivity; however, the trend is opposite to that

found under micellar conditions: phenacyl bromide and

similar compounds provide exclusively benzotriazol-1-yl

derivatives, and n-alkyl halides give mixtures of benzotriazol-

1-yl and -2-yl derivatives in a ratio of 15:1.⁸

Microwave irradiation can facilitate the alkylation. Thus,

compound 6 is cleanly prepared in 95% yield upon irradiation

of benzotriazole and the corresponding benzyl bromide in

DMF for 40 s.⁹Very often microwave-assisted alkylation

of benzotriazole works best when no solvent is used; for

example, derivative 7 is prepared in this way in 94% yield.¹⁰

In another example, benzotriazole with ethyl chloroacetate

and K₂CO₃in ethyl acetate catalyzed by polyethylene glycol

(PEG 400) gives a mixture of ethyl benzotriazol-1-ylacetate

(8; 56%) and its benzotriazol-2-yl isomer (15%).¹¹

protonation of the double bond with formation of the

corresponding carbocation is the ﬁrst step, Markovnikov’s

rule is followed, and derivatives with a benzotriazolyl

substituent at the terminal carbon atom are not observed.

Two examples of such additions are depicted in Scheme 4.

Thus, with styrene, benzotriazol-1-yl (13) and -2-yl (14)

isomers are formed in a ratio of 6.5:1 in a total yield of 46%.

Cyclohexene does not react with benzotriazole at 80 °C;

however, at 120 °C, a mixture of derivatives 15 and 16 is

obtained in a ratio of 1.1:1 and a total isolated yield of 56%.¹³

Mixing benzotriazole with acrolein (17) in equimolar

amounts results in an exothermic reaction leading to adducts

18 and 19 (R¹) R²) R³) H) in a ratio of 77:23. Addition

of benzotriazole to crotonaldehyde (R¹) R²) H, R³) Me)

requires initiation by heating the reagents to 60-80 °C. A

similar addition to methyl vinyl ketone gives 18 and 19 (R¹

) Me, R²) R³) H) in a 95:5 ratio. More sterically hindered

mesityl oxide generates equimolar amounts of 18 and 19 (R¹

) R²) R³) Me). In most cases, simple recrystallization

of the crude mixtures provides pure benzotriazol-1-yl deriva-

tives 18 (Scheme 5).¹⁴

In the presence of tetrabutylammonium bromide catalyst,

Benzotriazole with ethyl propiolate (20, R¹) H, R²)

Et) in reﬂuxing toluene gives a mixture of adducts 21a and

22a in a nearly quantitative yield with a cis:trans (21a:22a)

ratio of 39:61. A similar reaction with methyl 2-butynoate

(20, R¹) R²) Me) requires a CuI catalyst and results in a

1:1 mixture of 21b and 21b (Scheme 6).¹⁵

benzotriazole reacts with 1,2-dibromoethane in 40% NaOH

at 60 °C to give a mixture of 2-bromoethyl derivatives 9

and 10. When the reaction mixture is heated at 140 °C, HBr

is eliminated to provide a mixture of 1-vinylbenzotriazole

(11) and 2-vinylbenzotriazole (12). Column chromatography

of the mixture provides 11 in 34% yield and 12 in 10% yield

(Scheme 3).¹²

When the electron-deﬁcient alkene contains a good leaving

group X at the double bond, addition of benzotriazole may

be followed by elimination of X (or HX) with restoration of

the double bond. The total effect is a nucleophilic substitution

of group X by a benzotriazolide anion. Two examples of

such reactions are shown in Scheme 7. Thus, adduct 24 is

obtained from a low-temperature reaction of benzotriazole

with methyl 2-(triﬂuoroacetyl)vinyl sulfone (23). At slightly

elevated temperature, adduct 24 eliminates spontaneously

2.2. Addition to Multiple CC Bonds

Under strongly acidic conditions (10 molar equiv of

TsOH), benzotriazole adds to unactivated alkenes to afford

a mixture of 1-alkyl- and 2-alkylbenzotriazoles. Because

Synthesis of Heterocycles Mediated by Benzotriazole

Chemical Reviews, 2010, Vol. 110, No. 3 1567

Scheme 6

Scheme 9

Scheme 7

Scheme 10

Scheme 8

quantitative yields (Scheme 9).²¹Dialkylamines and N-

alkylarylamines also react with 29 to give 32 (R¹) alkyl,

R²) alkyl or aryl).²²In solutions, benzotriazol-1-yl deriva-

tives 32 obtained from secondary amines are in equilibria

with their benzotriazol-2-yl isomers 34.^23-26The intermediate

iminium cations 33 can be easily trapped in reactions with

nucleophiles.^1,22,27-30

methanesulﬁnic acid to give alkenone 25 in 88% yield.¹⁶

Addition of benzotriazolide anion to the R-carbon of (E)-

(2-phenylvinyl)phenyliodonium tetraﬂuoroborate (26) results

in unstable benzyl anion 27, which rapidly eliminates

iodobenzene to afford (E)-1-(2-phenylvinyl)benzotriazole

(28) in 64% yield.¹⁷

Reactions of primary aliphatic amines with 2 molar equiv

of 29 provide N,N-bis(benzotriazol-1-ylmethyl)amines 35 (R³

) alkyl), in mixtures with their benzotriazol-2-yl isomers.^21,22

Heating at reﬂux a toluene solution of 29 (2 molar equiv)

and an aromatic amine with azeotropic removal of water

allows the preparation of 35 (R³) aryl) as a mixture of

three isomers: Bt-1/Bt-1, Bt-1/Bt-2, and Bt-2/Bt-2.³¹29 reacts

also with amides to give the corresponding N-benzotriazol-

1-ylmethyl derivatives.^28,32In an example in Scheme 10,

reaction of 29 with formamide gives product 36 in 63% yield.

It is subsequently converted into isocyanide 37 in 66% yield

with phosphorus oxychloride and diisopropylamine.³²

The reactions described in Schemes 8-10 are not limited

to 1-(hydroxymethyl)benzotriazole. Higher aliphatic alde-

hydes and aromatic aldehydes with electron-deﬁcient rings

also give solid adducts with benzotriazole, 39, that are stable

enough to be recrystallized and their purity conﬁrmed by

CHN analysis. Condensation with alcohols further stabilizes

the molecule, allowing the preparation of alkoxy compounds

40 derived from a variety of aldehydes in pure form.³³

Condensation with primary aromatic amines converts 39 into

stable crystalline aminals 38 (R²) aryl, R³) H) that are

isolated in 76-98% yields.^21,34Dibenzylamine, pyrrolidine,

2.3. By Adducts to Carbonyl Groups of

Aldehydes and Their Conversions

Benzotriazole reacts eagerly with formaldehyde, even in

aqueous solutions, giving well-characterized 1-(hydroxym-

ethyl)benzotriazole (29) in practically quantitative yield.¹⁸

Treatment with thionyl chloride converts 29 into 1-(chlo-

romethyl)benzotriazole (30).¹⁸In a more practical one-pot

approach, a mixture of benzotriazole, 37% aqueous form-

aldehyde, and toluene is heated under a Dean-Stark trap to

remove water. Thionyl chloride is then added, and the

mixture is heated under reﬂux for 2 h to give a solution of

30 in toluene that can be directly used for further transforma-

tions.¹⁹

Substitution of the chlorine atom in 30 with nucleophiles

is an easy process giving rise to a variety of synthetically

valuable products 31. The yields are generally good; for the

examples given in Scheme 8, they vary from 44% (Nu )

PhSO₂) to 82% (Nu ) N₃).²⁰

Condensation of 29 with aromatic amines proceeds rapidly

in reﬂuxing ethanol and provides crystalline 1-(amino-

methyl)benzotriazoles 32 (R¹) aryl, R²) H) in practically

1568 Chemical Reviews, 2010, Vol. 110, No. 3

Katritzky and Rachwal

Scheme 11

Scheme 12

piperidine, morpholine, and thiomorpholine also give prod-

ucts 38 stable enough to be characterized.^22,35Thionyl

chloride converts 1-(1-hydroxyalkyl)benzotriazoles 39 into

1-chloroalkyl derivatives 42; in the presence of excess

benzotriazole, 1,1-bisbenzotriazol-1-ylalkanes 41 and their

benzotriazol-2-yl isomers are formed.³⁶Chlorides 42 react

readily with nucleophiles to give derivatives 43 in high

yields: 74% for R¹) t-Bu, Nu ) CN; 91% for R¹) n-Pr,

Nu ) PhCO₂; 88% for R¹) n-Pr, Nu ) PhS; 97% for R¹

) i-Pr, Nu ) i-PrO (Scheme 11).^19,36

Scheme 13

2.4. By Carbanions Stabilized by a Benzotriazolyl

Substituent

Table 1. Examples of Compounds 51 [E(2) ) H] and 52 [E(2) *

H]

Many synthetic applications of benzotriazole derivatives

are based on the ability of the benzotriazolyl substituent to

stabilize an adjacent carbanion. Even simple 1-(n-alkyl)ben-

zotriazoles 5 can be converted to anions 44 (R¹) H or alkyl)

by treatment with n-BuLi. The consecutive treatment with

alkyl halides converts 44 into 1-alkylbenzotriazoles 45

bearing secondary alkyl groups, e.g., R¹) Me, R²) Et (72%

yield), and R¹) Et, R²) n-C₁₀H₂₁(65% yield). Carbonyl

electrophiles can be used as well to trap 44. Thus, the anion

derived from 1-methylbenzotriazole (R¹) H) adds readily

to the carbonyl groups of benzaldehyde to give alcohol 46

(R¹) R⁴) H, R³) Ph) in 95% yield, acrylaldehyde to

give 46 (R¹) R⁴) H, R³) CH₂dCH) in 57% yield, or

benzophenone to give product 46 (R¹) H, R³) R⁴) Ph)

in 70% yield. In a reaction of 44 with ethyl benzoate, ketone

47 (R¹) H, R⁵) Ph) is obtained in 54% yield, whereas a

reaction of 44 with CO₂gives carboxylic acid 48 (R¹) H)

in 54% yield.⁴Reactions of lithiated 1-(arylmethyl)benzot-

riazoles 5 with electrophiles are even more effective; e.g.,

1-benzylbenzotriazole treated with n-BuLi and then n-BuI

gives 45 (R¹) Ph, R²) n-Bu) in 82% yield,³⁷1-(2-methoxy-

3-methylbenzyl)benzotriazole treated with n-BuLi followed

by p-tolualdehyde gives alcohol 46 (R¹) 2-methoxy-3-

methylphenyl, R³) p-tolyl, R⁴) H) in 87% yield, and when

the same 5 is lithiated and treated with ethyl benzoate, ketone

47 (R¹) 2-methoxy-3-methylphenyl, R⁵) Ph) is obtained

in 76% yield (Scheme 12).³⁸

X

E(1)

E(2)

yield (%) ref

Me₃Si

n-C₆H₁₃

H

80

70

80

91

95

87

95

86

89

73

39

40

41

42

43

45

47

3-oxocyclohexyl

n-C₆H₁₃

Me

carbazol-9-yl 1-hydroxycyclohexyl

carbazol-9-yl PhCH₂

indol-1-yl

PhS

H

PhS

CO₂Et

H

n-Bu

allyl

PhCHOH

n-PrCO

PhCH₂

n-Bu

MeS

EtO

PhCtC

more complex molecules 52.³⁹Derivatives 49 with X )

carbazol-9-yl readily form anions 50, which react with

electrophiles to generate derivatives 51, in which the

substituent BtCHX can be considered as a protected carbonyl

group of aldehydes.⁴⁰Their further lithiation and treatment

with other electrophiles generates 52 as protected forms of

complex ketones.⁴¹Other heterocycles, such as pyrrole,

indole, benzimidazole, imidazole, and 1,2,4-triazole, can also

be effective as substituents X in preparation of 51 and 52.⁴²

Aryl sulﬁdes 49 (X ) ArS) are also suitable for the chemistry

outlined in Scheme 13, providing interesting intermediates

for further transformations.^43-45Even alkoxy derivatives 51

(X ) RO) are acidic enough to be lithiated and converted

with electrophiles into 52.^46-50Examples of products syn-

thesized according to Scheme 13 are given in Table 1.

Anions 50 derived from compounds of the type BtCH₂X

(49), where X ) a heteroatom or a group attached by a

heteroatom, allow the generation of a variety of chemical

structures. Thus, compound 49 with X ) Me₃Si treated with

n-BuLi followed by electrophiles E(1)⁺gives molecules 51,

in which the trimethylsilyl group also can be substituted by

other electrophiles. Repeated lithiation of 51 followed by

treatment with another electrophile, E(2)⁺, generates even

3. Three-Membered Rings

3.1. Aziridine and Azirene

Bromination of 12 provides 2-(1,2-dibromoethyl)benzot-

riazole (53) in 93% yield. Reactions with amines convert

53 into 1-alkyl-2-benzotriazol-2-ylaziridines 55. Intermedi-

Synthesis of Heterocycles Mediated by Benzotriazole

Chemical Reviews, 2010, Vol. 110, No. 3 1569

Scheme 14

Scheme 17

Scheme 15

Scheme 18

Scheme 16

ates 54 can be observed in the reaction mixtures monitored

by NMR. The yields of aziridines 55 are high (80-96%)

except of that derived from benzylamine (30%) (Scheme

14).⁵¹The analogous reaction sequence of 11 does not give

aziridines but only 1-(1-bromovinyl)benzotriazole.⁵¹

water. They can be converted into their tosylates 62, but a

large excess ofKOH converts them directly into 2H-azirines

63 (58-66% yields). The benzotriazolyl moiety in azirines

63 is readily substituted by nucleophiles (organomagnesium

reagents, potassium phthalimide, or sodium thiophenoxide)

to give disubstituted azirines 64 in 50-79% yields (Scheme

17).⁵³

Treatment of 30 with lithium bis(trimethylsilyl)amide

results in very unstable anion 56, but when the reaction is

carried out in the presence of Schiff bases, anion 56 can be

effectively trapped, leading to aziridines 57 in high yields

(85-90%) (Scheme 15).⁵¹Due to their reactivity, aziridines

55 and 57 are convenient starting materials for the synthesis

of other heterocycles (see section 5 on pyrrole).

3.2. Oxirane

Oxiranes bearing a benzotriazol-1-yl substituent on the ring

can be prepared in practically quantitative yields by epoxi-

dation of benzotriazol-1-ylalkenes with dimethyldioxirane,

e.g., conversion of alkene 28 to oxirane 65 (Scheme 18). At

very low temperatures, substitution of the R-proton in oxirane

65 is possible; just its treatment with LDA at -116 °C

followed by benzyl bromide leads to R-benzyloxirane 67 in

51% yield, via lithiated intermediate 66. Using acyl chlorides

or benzophenone as an electrophile in this reaction provides

the corresponding oxiranes with acyl or diphenylhydroxy-

methyl substituents, respectively. At higher temperatures,

rearrangement of lithiated oxirane 66 to the appropriate

ketone is observed. The stereochemistry is preserved.⁵⁴

Condensation of 1-(azidomethyl)benzotriazole (31, Nu )

N₃) with triphenylphosphine provides [N-(benzotriazol-1-

ylmethyl)imino]triphenylphosphorane (betmip, 58) in a

practically quantitative yield. In a reaction of 58 with

methylmagnesium bromide, the benzotriazolyl moiety is

substituted by a methyl group to give phosphazene interme-

diate 59. Using a one-pot procedure, 59 is treated with

styrene oxide and heated at reﬂux in THF for 48 h to give

aziridine 60 in 55% yield (Scheme 16).⁵²

Oximes 61 are prepared in 91-93% yields from the

corresponding aryl benzotriazol-1-ylmethyl ketones, hy-

droxylamine hydrochloride, and NaOH in reﬂuxing ethanol/

1570 Chemical Reviews, 2010, Vol. 110, No. 3

Katritzky and Rachwal

Scheme 19

Scheme 21

Scheme 20

Scheme 22

77 that were unstable under the reaction conditions undergo-

ing ring-opening and rearrangement to the corresponding

R-phenoxy or R-alkoxy ketones (Scheme 21).⁵⁷

4. Four-Membered Rings

N-Substituted 1-(aminomethyl)benzotriazoles 78 treated

with ethyl bromodiﬂuoroacetate, zinc powder, and trimeth-

ylsilyl chloride (Reformatsky-type conditions) give N-

substituted ethyl 3-amino-2,2-diﬂuoropropionates 79a (89%

yield) and 79b (86% yield). Cyclization of 79 promoted by

tert-butylmagnesium chloride furnishes N-protected 3,3-

diﬂuoroazetidin-2-ones 80a (45% yield) and 80b (65% yield)

(Scheme 22). Several other attempts at the synthesis of such

compounds failed.⁵⁸

Anions generated from 1-acylbenzotriazoles 81 upon their

treatment with LDA add readily to the carbonyl groups of

aldehydes and ketones. Nucleophilic attack of the resultant

alkoxy anion 82 on the acyl carbonyl group followed by

elimination of a benzotriazolide anion results in formation

of oxet-2-one 83. This simple method allows the synthesis

of oxetane derivatives 83 in 42% (R¹) Et, R²) PhCH₂CH₂,

R³) H) to 90% (R¹) n-C₆H₁₃, R²) t-Bu, R³) H) yields

(Scheme 23).⁵⁹

1-Alkenylbenzotriazoles 68 are readily prepared by isomer-

ization of the corresponding allyl derivatives catalyzed by

t-BuOK. Reaction of lithiated 68 with electrophiles provides

R-substituted derivatives 69 in 41-80% yields. Epoxidation

of the double bond with m-chloroperbenzoic acid converts

69 into oxiranes 70 in 43% (R ) Me, E ) Ph₂COH) to 80%

(R ) H, E ) 1-hydroxycyclohexyl) yields. Oxiranes 70 can

be hydrolyzed to R-hydroxy ketones 71 in good yields

(Scheme 19).⁵⁵

30 can be converted into its anion by treatment with LDA

at -40 °C. The anion is trapped by ketones to provide a

convenient synthesis of benzotriazol-1-yloxiranes 72 (68-75%

yields). Treated with n-BuLi, oxiranes 72 give lithiated

intermediates 73 that react with various electrophiles to

provide tetrasubstituted oxiranes 74 in 68% (R¹) Ph, R²)

Et, E ) PhCO) to 92% (R¹) R²) Ph, E ) PhCHOH)

yields. Upon treatment with perchloric acid, benzoyl deriva-

tives 74 (E ) PhCO) undergo ring-opening with elimination

of benzotriazole to provide 3-hydroxy 1,2-diones, which

themselves are interesting starting materials for other het-

erocycles (Scheme 20).⁵⁶

5. Pyrrole

5.1. Nonaromatic Rings

5.1.1. Pyrrolidines

R-Benzotriazol-1-ylalkyl ethers 40 with n-BuLi generate

anions 75 that add readily to the carbonyl group of ketones

to give alkoxy anions 76. The presence of zinc bromide

promotes elimination of the benzotriazolide anion (as a zinc

complex) with the formation of phenoxy- or methoxyoxiranes

77 that are isolated in 56% (77a), 49% (77b), and 71% (77c)

yields. Several other ketones and aldehydes provided oxiranes

Pyrrolidines monosubstituted at C-2 are easily generated

from N-Boc-protected 3-chloropropanamine 84. In the ﬁrst

step, condensation with formaldehyde and benzotriazole

converts 84 into its N-benzotriazol-1-ylmethyl derivative 85.

In the second step, anion 86 generated from 85 and n-BuLi

undergoes cyclocondensation to pyrrolidine 89.⁶⁰In another

Synthesis of Heterocycles Mediated by Benzotriazole

Chemical Reviews, 2010, Vol. 110, No. 3 1571

Scheme 23

Scheme 26

Scheme 24

Scheme 27

Scheme 25

predominant S conﬁguration (80:20). The diastereomers can

be readily separated by chromatography. With DIBAL-H at

elevated temperature, derivative 94 is converted into (S)-1-

methyl-2-(tributylstannyl)pyrrolidine (95).⁶¹

approach, pyrrolidinone 87 is reduced by DIBAL-H to

2-hydroxypyrrolidine 88, which upon condensation with

benzotriazole is converted to 89.⁶¹With organomagnesium

reagents catalyzed by zinc chloride, the benzotriazolyl moiety

in 89 is readily substituted by an aryl or a phenylethynyl

group to furnish 2-substituted pyrrolidines 90 in 62-86%

yields.⁶⁰Treatment of 89 with (tributylstannyl)lithium affords

2-stannylpyrrolidine 91 in 78% yield (Scheme 24).⁶¹

The reaction can be carried out enantioselectively using a

chiral auxiliary instead of Boc. One such possibility is

depicted in Scheme 25. Derivative 92, obtained from

2-pyrrolidinone and 1S,2R-trans-2-cumylcyclohexyl chlo-

roformate, is reduced with DIBAL-H at low temperature and

then treated with benzotriazole to give compound 93. In a

reaction with (tributylstannyl)lithium, the benzotriazolyl

moiety is replaced by a tributylstannyl group to give

predominantly 2-(tributylstannyl)pyrrolidine 94 with the

N,N-Bis(benzotriazol-1-ylmethyl)amines 35, with their

benzotriazol-2-yl isomers, are readily prepared by condensa-

tion of 29 with primary amines.^21,62,63In solutions, they exist

in equilibria with ionic forms 96. Such mixtures treated with

samarium diiodide generate radicals 97 that are rapidly

trapped by vinyl groups of styrenes or vinyltrimethylsilane

to provide more stable radicals 98. Consecutive ionization

and reduction with samarium diiodide of the second benzo-

triazolylmethyl substituent provides a diradical that couples

intramolecularly to pyrrolidine 99. This simple process allows

preparation of 1,3-disubstituted pyrrolidines 99 in 49-85%

yields (Scheme 26).⁶⁴

When one of the substituents on the amine nitrogen atom

is able to trap a radical formed by treatment of N-(R-

aminoalkyl)benzotriazole with SmI₂, the intramolecular cy-

clization may occur (Scheme 27). Thus, condensation of the

5-(benzylamino) derivative of trans-2-pentenoic ester (100)

1572 Chemical Reviews, 2010, Vol. 110, No. 3

Katritzky and Rachwal

Scheme 28

Scheme 30

Scheme 29

Scheme 31

with an aldehyde and benzotriazole gives tertiary amine 101.

The R-aminoalkyl radical 102 generated by treatment of 101

with SmI₂is intramolecularly trapped by the double bond,

leading to the more stable radical 103. Final reduction by a

second molecule of SmI₂provides 1,2,3-trisubstituted pyr-

rolidine 104. Among the wide range of starting aldehydes,

the yields of products 104 vary from 29% (R ) PhCH₂OCH₂)

to 74% (R ) i-Pr). For pyridyl and aliphatic substituents,

cis stereoisomers strongly predominate (e.g., the cis:trans

ratio is 86:14 for R ) n-C₁₀H₂₁), but for most aromatic

substituents, the ratio is reversed (e.g., cis:trans ) 1:9 for R

) Ph).^65,66

The same method is effectively used to introduce three

substituents into positions 1, 2, and 4 of pyrrolidines. Thus,

condensation of the 5-(benzylamino) derivative of trans-2-

alkenoic ester 105 with 29 gives tertiary amine 106. The

aminomethyl radical generated from 106 by SmI₂is trapped

by the double bond, leading to pyrrolidine 107. Mixtures of

two stereoisomers in ratios 55:45 (107a), 64:36 (107b), and

65:35 (107c) are produced; however, their identities have

not been established (Scheme 28).⁶⁷

2-substituted and 2,5-disubstituted pyrrolidines. Thus, treat-

ment with organomagnesium reagents converts 112 into

mixtures of cis (113) and trans (114) pyrrolidines that can

be easily separated by chromatography. For aliphatic groups

R, the yields of cis isomers 113 vary from 53% to 60%,

whereas minor trans isomers 114 are obtained in 17-30%

yields. For R ) Ph, both isomers are equally abundant.

Hydrogenation of the intermediates readily removes the chiral

auxiliary to provide 2,5-disubstituted pyrrolidines 115 and

116; however, with R ) Ph, such a procedure causes opening

of the pyrrolidine ring (Scheme 30).⁶⁹

In a reaction with allyltrimethylsilane, the benzotriazolyl

moiety in 112 is substituted with an allyl group to provide

derivative 117 in 45% yield. Hydrogenation of 117 cleaves

the chiral auxiliary to give (2R)-2-propylpyrrolidine (118).

Alternatively, a reaction of 112 with triethyl phosphite leads

to chiral phosphonate 120, via intermediate 119, with 68%

overall yield (Scheme 31).⁶⁹

Alkylation of lithiated compounds 121 with 1-bromo-3-

chloropropane gives chloropropyl derivatives 122 in good

yields (80-89%). Subsequent substitution of the chlorine

atom by an alkylamino group is easily accomplished by

heating 122 and amine R²NH₂in DMF. Intramolecular

substitution of the benzotriazole moiety by the amino group

in amines 123 occurs at room temperature in the presence

of a palladium catalyst to furnish 2-vinylpyrrolidines 124 in

overall 65-85% yields for the last two steps (Scheme 32).⁷⁰

N-Derivatization of L-proline benzyl ester (125) provides

an example of application of benzotriazole methodology to

the synthesis of biologically important structures. Thus,

condensation of 125 with 29 provides intermediate 126,

which is subsequently subjected to reactions with organo-

N-(Benzotriazolylmethyl)-N-[(trimethylsilyl)methy-

l]amines 109 are readily prepared by condensation of

N-[(trimethylsilyl)methyl]amines 108 with formaldehyde and

benzotriazole. Thermally induced desilylation of 109 gener-

ates azomethine ylides 110. Electron-deﬁcient alkenes added

to the reaction mixture trap efﬁciently 110 to produce

pyrrolidines 111 in 71-90% yields. The cycloaddition

reaction proceeds stereospeciﬁcally with retention of the

oleﬁnic dipolarophile conﬁguration (Scheme 29).⁶⁸

Condensation of succinaldehyde (obtained by hydrolysis

of 2,5-dimethoxytetrahydrofuran) with benzotriazole and (S)-

2-phenylglycinol provides (3S,5R,7aR)-5-benzotriazol-1-yl-

3-phenyloxazolo[2,1-b]pyrrolidine (112). Oxazolopyrrolidine

112 is a convenient synthon for asymmetric syntheses of

Synthesis of Heterocycles Mediated by Benzotriazole

Chemical Reviews, 2010, Vol. 110, No. 3 1573

Scheme 32

Scheme 34

Scheme 33

Scheme 35

bismuth reagents generated from RX and BiCl₃/Al. Interest-

ingly, the reaction is carried out in aqueous solution to

provide N-substituted proline esters 127 in 18% (R ) Me)

to 70% (R ) allyl) yields (Scheme 33).⁷¹

Scheme 36

5.1.2. Pyrrolidinones

Condensation of 2,5-dimethoxy-2,5-dihydrofuran (128)

with benzotriazole and an amine carried out in reﬂuxing

acetic acid produces 5-benzotriazolylpyrrolidin-2-one in good

yield and with strong preference for the benzotriazol-1-yl

isomer 129. Substitution of the benzotriazole moiety in 129

with nucleophiles gives 5-substituted 2-pyrrolidinones

130-132. Since both benzotriazolyl isomers of 129 have

similar reactivity, the isomeric mixtures can be used directly

in this step. Thus, with organozinc reagents, pyrrolidinones

130 are obtained in 49-87% yields. The yields of pyrroli-

dinones 131 are 49-90% and those of 5-oxo-2-pyrrolidi-

nylphosphonates 132 49-85% (Scheme 34).⁷²

Michael addition of benzotriazole to N-methylmethacry-

lamide carried out at 150 °C provides ꢀ-benzotriazol-1-

ylpropionamide 133 in 45% yield. The dianion generated

from 133 by treatment with 2 molar equiv of n-BuLi is

trapped by methyl 4-methylbenzoate to give 2-pyrrolidinone

134 in 63% yield. The stereochemistry is not determined

(Scheme 35).⁷³

Acylation of 1 with N-protected L-glutamic acid 135 in

the presence of thionyl chloride readily provides derivative

136. Condensation with L-amino acids in aqueous acetonitrile

in the presence of triethylamine converts 136 into 2-pyrro-

lidinones 137. Washing the crude products with 4 N HCl

gives pure 137 in 58% (a), 88% (b), and 70% (c) yields

(Scheme 36).⁷⁴

white precipitate. Anion 139 derived from imine 138 upon

its treatment with n-BuLi adds readily to electron-deﬁcient

double bonds. In the case of methyl acrylate, pyrrolidine

anion 140 resulting from such an addition eliminates

spontaneously a benzotriazolide anion to give 1,2-pyrroline

141 in 96% yield (Scheme 37).⁷⁵According to NMR data,

the molecule of 141 has cis geometry. However, trans

substitution is found in pyrroline 142 (63% yield) derived

from a reaction of 139 with acrylonitrile. Reaction of 139

with dimethyl fumarate leads to pyrroline 143 (95% yield)

with trans,trans orientation of its substituents at C-3, C-4,

and C-5. A similar reaction with diethyl maleate gives a

mixture of stereoisomers (Scheme 38).⁷⁵

5.1.3. Pyrrolines

Condensation of benzotriazole with benzaldehyde and

ammonia in ethanol provides imine 138 in 92% yield as a

Alkylation of benzotriazole with 2,3-dichloro-1-propene

and Na₂CO₃in DMSO/H₂O provides 1-(2-chloropropen-3-

1574 Chemical Reviews, 2010, Vol. 110, No. 3

Katritzky and Rachwal

Scheme 37

Scheme 39

Scheme 38

Scheme 40

yl)benzotriazole (144) in 56% yield and its isomer 2-(2-

chloropropen-3-yl)benzotriazole in 30% yield. Stronger bases

smoothly convert 144 into 1-allenylbenzotriazole (145),

isolated in 90% yield when 20% NaOH is used. LDA is able

to remove an allenyl proton from 145, and the resultant anion

can be trapped by various electrophiles. In a useful approach,

144 is treated with 2 equiv of LDA followed by an

electrophile. Several R-substituted 1-allenylbenzotriazoles are

thus obtained. When N-(4-methoxybenzylidene)aniline is

used as an electrophile, allenyl product 146 rearranges

partially to its propargyl isomer, and both components can

be separated by column chromatography. Heating the allenyl

product in acetic anhydride results in its conversion to 3,4-

pyrroline 147, which is isolated in 30% overall yield (Scheme

39).⁷⁶

containing one carbon atom more than in the Grignard

reagent (Scheme 40).^42,77

Addition of an anion generated from 148 to the carbonyl

group of p-tolualdehyde results in alcohol 153, which is

separated in 35% yield. An analogous reaction with cyclo-

hexanone provides alcohol 154 in 76% yield. Treatment of

154 with phenylmagnesium bromide allows a convenient

removal of the benzotriazolyl auxiliary, providing alcohol

155 in 50% yield. A similar substitution of the benzotriazolyl

moiety with a phenyl ring in compound 153 gives the

corresponding alcohol in 60% yield (Scheme 41).^42,77

In a reaction of lithiated benzotriazolyl derivative 148 with

benzophenone, alcohol 156 is obtained in 72% yield. The

use of carboxylic esters as electrophiles is exempliﬁed by

synthesis of ketone 157 (R ) 4-MeC₆H₄, 53% yield). To

demonstrate the removal of the benzotriazolyl auxiliary from

such compounds, 157 is treated with activated zinc in acetic

acid to give ketone 160 in 50% yield. In a reaction of lithiated

148 with diphenyl disulﬁde, disubstituted product 158 is

obtained in 67% yield, whereas a reaction with trimethylsilyl

chloride leads to a mixture of monosubstituted (159) and

disubstituted products in an approximate ratio of 1:3 (Scheme

42).⁴²

5.2. Aromatic Ring Substituents

5.2.1. Substituents at the Nitrogen Atom

Introduction of a benzotriazol-1-ylmethyl substituent onto

the pyrrole nitrogen atom can be easily achieved on heating

a mixture of pyrrole, 30, and powdered NaOH in DMSO.

Product 148 treated with n-BuLi generates anion 150, which

is subsequently subjected to reactions with electrophiles. In

an example of such reactions, a solution of 148 in THF is

treated with n-BuLi at -78 °C followed by benzyl bromide

and is allowed to warm slowly to room temperature.

Chromatographic puriﬁcation provides derivative 151 in 47%

yield. The benzotriazolyl moiety can be easily removed from

151 by treatment with LiAlH₄to give 1-phenethylpyrrole

(152) in 96% yield. Reactions of 148 with RMgBr produce

N-substituted pyrroles 149 (42-73% yields) with the groups

5.2.2. Electrophilic Substitution at Ring Carbon Atoms

When the condensation of benzotriazole, formaldehyde

(aqueous solution), and aliphatic amines used in equimolar

Synthesis of Heterocycles Mediated by Benzotriazole

Chemical Reviews, 2010, Vol. 110, No. 3 1575

Scheme 41

Scheme 44

Scheme 45

Scheme 42

moiety in furyl and thienyl derivatives 163 with ZnCl₂

promotes their dissociation to cations 164 that readily attack

the C-2 atom of N-methylpyrrole to give products 165 in

56% (X ) O) and 52% (X ) S) yields (Scheme 44).⁷⁹

1-Acylbenzotriazoles 167, readily prepared in reactions of

the corresponding carboxylic acids with 1-(methanesulfo-

nyl)benzotriazole,⁸⁰are found to be convenient acylating

agents for pyrroles. Thus, in their reactions with unsubstituted

pyrrole catalyzed by TiCl₄, 2-acylpyrroles 166 are obtained

in 21% (R ) 4-Et₂NC₆H₄) to 91% (R ) 2-furyl) yields.

1-Methylpyrrole subjected to similar reactions gives 2-acyl-

1-methylpyrroles 168 in 51% (R ) 4-Et₂NC₆H₄) to 94% (R

) 2-furyl) yields. To direct the acylation reaction to C-3 of

pyrrole, N-protection with a bulky triisopropylsilyl group is

used. 3-Acylpyrroles 169 are isolated in generally good yields

(54-92%). To prove the protection concept, one of the

derivatives 169 (R ) 4-MeC₄H₄) was deprotected using

tetrabutylammonium ﬂuoride to give 3-acylpyrrole 170 in

98% yield (Scheme 45).⁸¹

The benzotriazole approach allows the introduction of

complex groups onto C-2 of pyrroles under mild conditions.

Thus, N-protected 1-(R-aminoacyl)benzotriazoles 171 derived

from chiral R-amino carboxylic acids can be conveniently

prepared by mixing benzotriazole with thionyl chloride

followed by N-protected R-amino carboxylic acid in a 4:1:1

ratio. Friedel-Crafts acylation of pyrrole with 171 in the

presence of AlCl₃provides chiral 2-(aminoacyl)pyrroles 172

in 45-82% yields (Scheme 46).⁸²

Scheme 43

amounts is carried out in diethyl ether or dichloromethane,

1-(aminomethyl)benzotriazoles 32 are obtained in high yields

(>90%). In solution, compounds 32 exist in equilibria with

their benzotriazol-2-yl isomers. This equilibration is expected

to proceed through iminium ion 161, and just this cation must

be involved in reactions of 32 with nucleophiles. In reactions

of 32 with pyrrole or 1-methylpyrrole, 2-substituted products

162 are obtained in 62-96% yields. With tertiary amines,

the reactions proceed well in the presence of AlCl₃; however,

a milder Lewis acid, ZnCl₂, has to be used for secondary

amines (Scheme 43).⁷⁸

1-Cyanobenzotriazole (173), prepared in 92% yield from

benzotriazole, NaH, and cyanogen bromide, is a convenient

reagent for introduction of CN groups onto nucleophilic

carbon atoms. With lithiated 1-methylpyrrole, an electrophilic

attack of 173 occurs at the ring C-2 atom, providing nitrile

174 in 55% yield (Scheme 47).⁸³

Not only amino, but also other electron-donating groups

at C-R of the benzotriazolyl substituents can facilitate

dissociation of the N-C bond, generating reactive carboca-

tions as well. Thus, complexation of the benzotriazolyl

1576 Chemical Reviews, 2010, Vol. 110, No. 3

Katritzky and Rachwal

Scheme 46

Scheme 49

Scheme 47

Scheme 48

Scheme 50

5.3. Aromatic Ring Formation

5.3.1. One Substituent at C-2

The anion delivered from 1-propargylbenzotriazole (175)

upon its treatment with n-BuLi readily adds to N-tosy-

larylimines to give sulfonamides 176 in 76-92% yields.

When heated with NaOH in ethanol, compounds 176 are

converted into 2-arylpyrroles 179 in 47-60% yields. The

proposed reaction mechanism involves isomerization of

alkyne 176 to allene 177 followed by intramolecular cy-

cloaddition to form pyrroline 178. Finally, under basic

conditions, the molecule eliminates benzotriazole and the

tosylate protecting group to furnish pyrrole 179 (Scheme

48).⁸⁴

are converted into 1,2-diarylpyrroles 183, isolated in 60-68%

yields (Scheme 49).⁸⁶

Alkoxy analogues of enamine 181 can be applied in such

reactions as well. Thus, R-ethoxy derivative 184, easily

prepared by condensation of benzotriazole with acrolein

diethyl acetal, undergoes a smooth rearrangement promoted

by ZnBr₂to (γ-ethoxyallyl)benzotriazole (185). After lithia-

tion, the anion is trapped by Schiff bases to give anions 186.

Catalyzed by ZnBr₂, intermediates 186 undergo cyclization

with elimination of benzotriazole and ethanol to furnish 1,2-

diarylpyrroles 187 in 55-63% yields (Scheme 50A).⁸⁷

Lithiated N-allylbenzotriazole (188) readily adds to the

CdN bond of Schiff bases derived from aromatic or

heteroaromatic aldehydes and amines to give amines 189 in

The reaction of acrolein with benzotriazole and morpholine

provides product 180 in 84% yield as a mixture with its

benzotriazol-2-yl isomers.¹⁴Upon treatment with sodium

hydride, one of the benzotriazolyl substituents is eliminated

to give enamine 181 in 74% yield as a stable crystalline

product.⁸⁵Additions of lithiated 181 to Schiff bases presum-

ably give unstable intermediate diamines 182 that by

cyclization and elimination of benzotriazole and morpholine

Synthesis of Heterocycles Mediated by Benzotriazole

Chemical Reviews, 2010, Vol. 110, No. 3 1577

Scheme 51

Scheme 52

Scheme 53

46-85% yields. In the presence of a palladium catalyst and

cupper(II) oxidizing agent, amines 189 are smoothly con-

verted to pyrroles 190 in 46-79% yields, except 190 with

Ar¹) 4-(MeO)C₆H₄and Ar²) Ph where the yield is only

21% (Scheme 50B).⁸⁸

5.3.2. Two Substituents at C-2 and C-3

N-(Benzotriazol-1-ylmethyl)thiobenzamide (191) is readily

prepared by condensation of benzotriazole with formaldehyde

and thiobenzamide.^89,90Treatment with n-BuLi followed by

iodomethane converts thiobenzamide 191 into S-methyl

thioimidate 192 in 87% yield. The anion generated from 192

adds to acrylonitrile to give pyrrolidine anion 193a, which

spontaneously eliminates benzotriazole and thiomethoxide

anion to give pyrrole 194a (88% yield). Similar reactions

with 2-vinyl- and 4-vinylpyridines provide 2-phenyl-3-

pyridinylpyrroles 194b (36% yield) and 194c (64% yield).

In the case of substituents X with moderate electron-

withdrawing power, the additions may occur in both modes,

giving rise to mixtures of regioisomers, as demonstrated in

a reaction with methyl vinyl ketone leading to 2,3-disubsti-

tuted pyrrole 195 (34% yield) and 2,4-disubstituted pyrrole

196 (18% yield) (Scheme 51).⁹¹

Scheme 54

Addition of 58 to PPh₃PdCH₂provides phosphonium salt

197, which is easily deprotonated by n-BuLi to give ylide

198. When the reaction mixture is quenched with 1,2-diaryl

1,2-diones, 2,3-disubstituted pyrroles 198a-c are obtained

in 67%, 75%, and 58% yields, respectively (Scheme 52).^92,93

riazole moiety is eliminated and the N-protection is removed

to provide 2,5-disubstituted pyrroles 204a (56% yield) and

204b (43% yield) (Scheme 53).⁸⁴

5.3.3. Two Substituents at C-2 and C-5

The synthetic method for pyrroles monosubstituted at C-2

shown in Scheme 48 can be modiﬁed for the preparation of

2,5-disubstituted pyrroles. Thus, treatment of 175 with 2

molar equiv of n-BuLi generates dianion 200, which is

subsequently alkylated with alkyl iodides to give alkynyl

anions 201. Consecutive addition of N-tosyl-1-naphthylm-

ethyleneimine provides adducts 202 in 72-77% yields.

Heated with an ethanolic solution of NaOH, compounds 202

tautomerize to their allene forms and undergo cyclization to

pyrrolines 203. Under the reaction conditions, the benzot-

5.3.4. Two Substituents at C-3 and C-4

In the presence of a base, isocyanide 37 adds readily to

electron-deﬁcient double bonds, and the resultant pyrroline

intermediates 205 spontaneously eliminate benzotriazole to

give 3,4-disubstituted pyrroles in 92% (206a), 81% (206b),

and 40% (206c) yields (Scheme 54).⁹⁴

Addition of lithiated allylbenzotriazoles 207 to the CdN

bond of isothiocyanates produces anions 208 that are

1578 Chemical Reviews, 2010, Vol. 110, No. 3

Katritzky and Rachwal

Scheme 55

Scheme 57

Scheme 56

Scheme 58

methylated in situ to provide methyl 2,2-disubstituted

3-buteniminothiates 209 in 59-80% yields. Treated with

Lewis acids, compounds 209 undergo cyclization to 2-

(methylthio)pyrroles 210. Yields of 210 determined by gas

chromatography are high (75-94%); however, the yields of

pure materials separated by column chromatography are

much lower (21-65%) due to the low stability of the

electron-rich pyrroles (Scheme 55).⁹⁵

In the [1 + 2 + 2] annulation process shown in Scheme

56, alkylation of 1-benzylbenzotriazoles 211 with 2-bro-

moacetaldehyde diethyl acetal to give intermediates 212 is

followed by a reaction with N-benzylideneaniline to produce

adducts 213. Subsequent treatment with formic acid causes

cyclization of 213 to 5-ethoxypyrrolidines 214 that then

eliminate ethanol and benzotriazole to give pyrroles 215 in

66-74% yields.⁹⁶

Due to the high strain energy of the three-membered ring,

aziridines are convenient starting materials for pyrroles. On

heating to 140 °C, the C-N bond in benzotriazol-2-

ylaziridines 55 is cleaved, and the dipolar species 216

undergo [3 + 2] cycloaddition to acetylenedicarboxylate to

form pyrrolines 217 that aromatize to pyrroles 218 by

elimination of benzotriazole (Scheme 57). The reaction is

relatively slow (72 h), providing products 218 in 25% (R )

n-C₁₀H₂₁) to 80% (R ) n-C₅H₁₁) yields.⁵¹

220 on treatment with sodium hydride add readily to electron-

poor double bonds to create unstable anions 221 that

spontaneously eliminate benzotriazole and thiomethoxide to

generate pyrroles 222 (Scheme 58).⁹¹Both reactions, me-

thylation and addition, can be conveniently carried out in

one pot when t-BuOK is used as a base.⁹⁷The yields of

pyrroles 222 are generally high (60-99%), except for the

case of R²) CF₃(20%).

A similar sequence is employed for the conversion of

N-(benzotriazol-1-ylmethyl)amides 223 into pyrroles 226.

Thus, in reactions with PCl₅, amides 223 give chloro imines

224 that on treatment with t-BuOK are converted to nitrile

ylides 225. Benzyl esters of R,ꢀ-unsaturated acids acting as

dipolarophiles trap 225 to generate pyrroles 226 in 81-90%

yield (Scheme 59).⁹⁸

In the presence of t-BuOK, benzotriazol-1-ylmethyl

isocyanide (BetMIC, 37) undergoes alkylation on the

methylene group to give isocyanide 227. The anion

derived from 227, upon treatment with t-BuOK, adds to

the electron-deﬁcient double bonds of R,ꢀ-unsaturated

ketones, esters, or nitriles to produce pyrroles 228 in

30-92% yields (Scheme 60).⁹⁴

Benzotriazol-1-ylaziridines 229 are thermally unstable. On

heating to 100 °C, the C-C bond of the aziridine ring is

cleaved to give azomethine ylides 230 that can be trapped

by diethyl acetylenedicarboxylate. The pyrroline intermedi-

ates that are formed in the ﬁrst step spontaneously eliminate

5.3.5. Three Substituents at C-2, C-3, and C-4

A 1 molar equiv of a base makes possible selective

methylation of the sulfur atom in thioamides 219 to give

thioimidates 220 in high yields. The anions derived from

Synthesis of Heterocycles Mediated by Benzotriazole

Chemical Reviews, 2010, Vol. 110, No. 3 1579

Scheme 59

Scheme 62

Scheme 63

Scheme 60

Scheme 61

Scheme 64

benzotriazole to furnish pyrroles 231 in 81-88% yield

(Scheme 61).⁵¹

5.3.6. Four Substituents at Carbon Atoms

Similarly to the addition of imine 138 to dimethyl fumarate

(Scheme 38), the anion generated from 138 adds readily to

dimethyl acetylenedicarboxylate to give quantitatively tet-

rasubstituted pyrrole 234. The reaction is believed to proceed

through pyrrolinyl anion 232, which spontaneously expels a

benzotriazolide anion to generate neutral molecule 233,

which eventually rearranges to the more stable aromatic

tautomer 234 (Scheme 62).⁷⁵

The synthetic method for 2,3,4-trisubstituted pyrroles based

on thioamides (Scheme 58) can be extended to 2,3,4,5-

tetrasubstituted pyrroles. Thus, as given in Scheme 63,

thioamide 235 is prepared in 92% yield by condensation of

thiobenzamide with 2,4-dichlorobenzaldehyde and benzot-

riazole. S-Methylthioimidate 236, obtained by methylation

of 235 with iodomethane in the presence of t-BuOK, is

treated in one pot with cinnamonitrile to give tetrasubstituted

pyrrole 237 in 63% yield.⁹⁷

5.3.7. Benzotriazolyl Substituent at the Ring

For most of the synthetic methods described in this

paragraph, pyrrole ring formation involves cycloaddition or

cyclocondensation reactions leading to unstable intermediate

pyrrolines or pyrrolidines that then spontaneously eliminate

benzotriazole and, in the case of pyrrolidines, also another

group to generate an aromatic system. However, under

special circumstances, the benzotriazolyl substituent may be

retained, and other groups leave. Thus, in Scheme 64,

vinamidinium salt 239, obtained in a reaction of benzotriazol-

1-ylacetic acid (238) with DMF and POCl₃, reacts with ethyl

esters of glycine and its N-methyl analogue to give 4-ben-

zotriazol-1-ylpyrrole derivatives 241a (89% yield) and 241b

(91% yield). Here, the presumed intermediate pyrrolidines

1580 Chemical Reviews, 2010, Vol. 110, No. 3

Katritzky and Rachwal

Scheme 65

Scheme 67

Scheme 66

Scheme 68

240 preferentially eliminate two molecules of dimethylamine,

leaving the benzotriazolyl substituent unaffected. The only

role for the benzotriazolyl group in this conversion is

activation of R-protons, making the condensation and

elimination easier.⁹⁹

6. Furan

6.1. Nonaromatic Rings

6.1.1. Tetrahydrofurans

Addition of benzotriazole to 1,2-dihydrofuran (242) pro-

duces a mixture of regioisomers 243 and 244 in a 7:1 ratio,

respectively. The mixture can be separated by chromatog-

raphy. Treatment with organomagnesium reagents smoothly

converts the mixture of 243 and 244 into 2-substituted furans

245 in 59-90% yields (Scheme 65).¹⁰⁰

Addition of N-(pyrrolidin-1-ylmethyl)benzotriazole (246)

to 242 results in a mixture of stereoisomers and regioisomers

247 and 248. The mixture can be separated by chromatog-

raphy; however, when treated with phenylmagnesium bro-

mide at elevated temperature, it is converted exclusively into

trans-1,2-disubstituted furan 250 in 75% yield. The stereo-

chemistry of 250 can be explained by formation of tricyclic

ionic intermediate 249 (Scheme 66).¹⁰¹

The method depicted in Scheme 66 can be extended to

relatively complex substituents at C-3. Thus, compound

251a, readily available from a reaction of benzotriazole with

benzaldehyde acetal, adds to 242 in the presence of an acidic

catalyst to produce a complex mixture of regio- and

stereoisomers 252a and 253a. Treatment with methylmag-

nesium iodide allows the substitution of benzotriazole to

252b and 253b. The separation of the four stereoisomers of

252b by chromatography is described. Conversions of the

individual stereoisomers 252b with methylmagnesium iodide

allows assignment of stereochemistry to the resultant deriva-

tives 254b-257b (Scheme 67).¹⁰²

6.1.2. 2,5-Dihydrofurans

The anion generated from 175 readily adds to diaryl

ketones to produce alcohols 258 in high yields. Treatment

with NaOH in ethanol at 60-80 °C allows the rearrangement

of alkynes 258 into allenes 259, which, under the reaction

conditions, undergo cyclization to 2,5-dihydrofurans 260,

isolated in 68-90% yields. On heating of 260 with Grignard

reagents in toluene, the benzotriazolyl moiety is replaced by

an alkyl or aryl group to provide 2,2,5-trisubstituted 2,5-

dihydrofurans 261 in 82-95% yields (Scheme 68).¹⁰³

The 1,1-disubstituted analogue of allene 259, product 262

(90% yield), forms on treatment of 144 with 2 molar equiv

of LDA followed by p-anisaldehyde. The ﬁrst equivalent of

LDA is used to generate 1-allenylbenzotriazole, which is

provide

2-methyl-3-(1-ethoxybenzyl)tetrahydrofurans

254a-257a. Isomers 254a-257a (each as a pair of enanti-

omers) are separated by column chromatography.¹⁰¹Addition

of morpholin-4-yl derivative 251b to 242 provides isomers

Synthesis of Heterocycles Mediated by Benzotriazole

Chemical Reviews, 2010, Vol. 110, No. 3 1581

Scheme 69

Scheme 71

Scheme 72

Scheme 70

deprotonated with the second equivalent of LDA, and the

resulting anion is ﬁnally trapped by the aldehyde. Similarly

to 259, allene 262 undergoes cyclization under basic condi-

tions to give 2,3-disubstituted 2,5-dihydrofuran 263 in 60%

yield (Scheme 69).⁷⁶

Scheme 73

The iminium cation generated from ethyl R-(dimethy-

lamino)-R-benzotriazol-1-ylacetate (264) upon treatment with

AlCl₃adds to C-5 of 2-[(trimethylsilyl)oxy]furan with

elimination of the (trimethylsilyl)oxy group to give unstable

2,5-dihydrofuran-2-one 265. Spontaneous elimination of

dimethylamine from 265 in reﬂuxing acetonitrile provides

ethyl (5-oxo-5H-furan-2-ylidene)acetate 266 in 83% yield.

The isomer ratio Z:E is 77:23. The isomers are readily

separated by column chromatography (Scheme 70).¹⁰⁴

presence of a Lewis acid provides 5-acylated derivatives 272

in 54% (R²) 2-pyridyl) to 98% (R²) 4-Me₂NC₆H₄) yields

(Scheme 72).¹⁰⁷

In a Mannich-type reaction of 2-methylfuran with 1-(pi-

peridinomethyl)benzotriazole (273a) catalyzed by ZnCl₂, 2,5-

disubstituted furan 274a is obtained in 87% yield. The

reaction can also be used for the introduction of N-

monoalkylated aminomethyl groups to C-5 of 2-methylfuran,

but the yields are somewhat lower: 58% for 274b and 47%

for 274c (Scheme 73).⁷⁸

Methyl N-(1-benzotriazol-1-ylalkyl)carbamates 275 are

conveniently prepared by condensation of aldehydes with

benzotriazole and methyl carbamate.¹⁰⁸With 2-methylfuran

in the presence of ZnCl₂, both the benzotriazolyl and the

carbamoyl groups in 275 are substituted to produce geminal

bis(5-methylfuran-2-yl)alkanes 276 in 88-90% yields (Scheme

74).⁷⁹

The substitution can be carried out stepwise using two

different heterocyclic systems. Thus, when 2-methylfuran

is subjected to a reaction with 1 molar equiv of carbamate

275a, a mixture of compounds 277 (42%), 278 (17%),

and 276a (15%) is obtained. Treatment of the crude

reaction mixture with 1-methylpyrrole and ZnCl₂provides

2-[1-(1-methylpyrrol-2-yl)-2-methylpropyl]-5-methylfu-

6.2. Electrophilic Substitution of the Aromatic

Ring

Furan can be lithiated at C-2 using n-BuLi in the presence

of TMEDA. The following treatment with ZnBr₂converts

the lithiated furan into 2-furylzinc bromide, a convenient

reagent for the preparation of furans monosubstituted at C-2.

Thus, condensation of N,N′-diphenylhydrazine with form-

aldehyde and benzotriazole provides trisubstituted hydrazine

267. In solutions, 267 exists in equilibrium with its benzo-

triazol-2-yl analogue, but both isomers are equally reactive.

With 2-furylzinc bromide, the benzotriazolyl moiety in 267

is substituted by a furyl group to give 2-[(N,N′-diphenylhy-

drazino)methyl]tetrahydrofuran (268) in 79% yield (Scheme

71).¹⁰⁵

2,5-Disubstituted furans can be readily obtained by C-5

lithiation of 2-substituted furans followed by reactions

with electrophiles. As an example, 2-ethylfuran is ﬁrst

treated with n-butyllithium and then with 1-(phenylsul-

fonyl)benzotriazole (269) to give derivative 270 in 80%

yield.¹⁰⁶When lithiated 2-ethylfuran is treated with 173,

5-ethyl-2-furonitrile (271) is obtained in 65% yield.⁸³Acy-

lation of 2-methylfuran with 1-acylbenzotriazoles 167 in the

1582 Chemical Reviews, 2010, Vol. 110, No. 3

Katritzky and Rachwal

Scheme 74

Scheme 77

Scheme 75

Scheme 78

Scheme 76

ran (279) in 56% yield. Obviously, both intermediates 277

and 278 have to react with 1-methylpyrrole to give the

same product (Scheme 75).⁷⁹

6.3. Aromatic Ring Formation

Under reﬂux in acetic acid, benzotriazole reacts with 128

to give 2-benzotriazol-1-ylfuran (280) in 67% yield (Scheme

76). In the presence of amines, N-substituted 2-benzotriazol-

1-ylpyrroles are formed instead, but the yields are low

(1-10%).¹⁰⁹

Alkylation of 185 occurs exclusively at the R-C, producing

derivatives 281, which, in their lithiated forms, add readily

to the carbonyl group of aldehydes. Upon treatment with

ZnBr₂, resultant anions 282 are rapidly converted to 2,3-

disubstituted furans 283 that are isolated in 46-52% overall

yields (Scheme 77).⁸⁸

In the presence of t-BuOK, oxiranes 285, obtained from

lithiated 175 and R-bromo ketones 284, undergo rearrange-

ment to furans 286, which are isolated in 51-61% yields.

When treated with electron-rich heterocycles and ZnCl₂, the

benzotriazolyl moiety in 286 is substituted by a heterocyclic

ring to provide derivatives 287 in 57-86% yields. Alterna-

tively, alkylation of the methylene carbon in 286 provides

derivatives 288, which in a reaction with heterocycles and

ZnCl₂are consecutively converted to products 289 in

55-95% yields. In this way, 2,4-disubstituted furans (R¹)

H) or 2,3,5-trisubstituted furans (R¹* H) are prepared

(Scheme 78).¹¹⁰

of DMF with 1-chlorobenzotriazole or 1-(trimethylsilyl)ben-

zotriazole, by triethylamine provides (dimethylamino)ben-

zotriazol-1-ylcarbene (291). In the presence of trans-1,2-

dibenzoylethylene, 1,4-cycloaddition of the carbene provides

2,3-dihydrofuran derivative 292, which in reﬂuxing benzene

eliminates benzotriazole to give 2,3,5-trisubstituted furan 293,

isolated in 15% yield. A more complex rearrangement

process leads to a side product, furan 294, which is isolated

from the reaction mixture in 6% yield (Scheme 79).¹¹¹

Benzotriazole with dibenzoylacetylene (295) and triph-

enylphosphine (equimolar amounts) gives a mixture of

compounds 296 (40%) and 297 (45%) (Scheme 80). No

open-chain benzotriazol-2-yl analogue of 296 or benzotriazol-

1-yl analogue of furan derivative 297 is detected.¹¹²Just steric

hindrance in the reaction intermediates may be responsible

for that. To make the cyclization possible, the molecule 296

must ﬁrst assume an E conﬁguration to bring the carbonyl

groups in close proximity. Isomerization between Z and E

conﬁgurations in 296 can be achieved by addition of another

molecule of benzotriazole to the double bond followed by

its elimination, but rotation of the R-benzoyl group imposes

too much strain due to the steric repulsion between its phenyl

and the benzotriazolyl benzenoid ring. The less bulky

Deprotonation of N,N-dimethylbenzotriazol-1-ylmethyl-

eneiminium chloride (290), readily available from a reaction

Synthesis of Heterocycles Mediated by Benzotriazole

Chemical Reviews, 2010, Vol. 110, No. 3 1583

Scheme 79

Scheme 81

Scheme 80

Scheme 82

Scheme 83

benzotriazol-2-yl substituent in the benzotriazol-2-yl ana-

logue of 296 allows for such transformations without high

energetic barriers.

7. Thiophene

7.1. Nonaromatic Rings

and subsequently treated with ZnBr₂to give 2-thienylzinc

bromide. The bromozinc group can be substituted by various

electrophiles. In an example in Scheme 83, 2-thienylzinc

bromide reacts with N-(benzotriazol-1-ylmethyl)-N,N′-diphe-

nylhydrazine (267) to give product 304 in 53% yield.¹⁰⁵

29 reacts with 2-methylthiophene in reﬂuxing glacial acetic

acid to give 2,5-disubstituted thiophene 305 in 50% yield.

The anion derived from 305 adds to the carbonyl group of

cyclohexanone to provide alkoxide anion 306. In situ

treatment with ZnBr₂promotes rearrangement of anion 306

with elimination of the benzotriazolide anion and expansion

of the cyclohexanone ring. 2-(5-Methylthien-2-yl)cyclohep-

tanone (307) so obtained is isolated in 67% yield (Scheme

84).¹¹⁴

Condensation of phenylpropargylaldehyde diethyl acetal

with benzotriazole readily provides 1-benzotriazol-1-yl-3-

phenylpropargyl ethyl ether (298). Treated with n-BuLi, 298

forms an anion that adds to a CdS bond in CS₂to give

dithiocarboxylate anion 299. An intramolecular attack of the

sulfur nucleophile on the triple bond in 299 leads to 3,3,5-

trisubstituted 2,3-dihydro-2-thiophenethione 300, isolated in

57% yield. A similar addition of lithiated 298 to the CdS

bond of 1-naphthyl isothiocyanate produces adduct 301,

which reacts further to provide 2,3-dihydro-2-(naphth-1-

ylimino)thiophene 302 in 64% yield (Scheme 81).¹¹³

7.2. Electrophilic Substitution of the Aromatic

Ring

7.3. Aromatic Ring Formation

Monosubstitution of thiophene at C-2 can be achieved

simply by acylation. 1-Acylbenzotriazoles 167 are efﬁcient

acylating agents under mild conditions (see section 5 on

pyrrole and section 6 on furan). Thus, 167 react smoothly

with thiophene in the presence of a Lewis acid catalyst to

give 2-acylthiophenes 303 in 58% (R ) 4-Et₂NC₆H₄) to 97%

(R ) 1-naphthyl) yields (Scheme 82).¹⁰⁷

R-Substituted 1-allylbenzotriazoles 121 are readily pre-

pared by treatment of 1-allylbenzotriazole with n-BuLi

followed by alkylating agents. Removal of the remaining

R-proton in 121 by n-BuLi and consecutive treatment with

isothiocyanates leads to thioamides 308. Without puriﬁcation,

thioamides 308 are then subjected to ZnBr₂, which causes

cyclization and elimination of benzotriazole to provide

2-aminothiophenes 309 in 25% (R¹) CH₂dCHCH₂, R²)

In another approach to monosubstituted thiophenes,

thiophene itself is lithiated at C-2 with n-BuLi and TMEDA

1584 Chemical Reviews, 2010, Vol. 110, No. 3

Katritzky and Rachwal

Scheme 84

Scheme 87

Scheme 85

Scheme 88

Scheme 86

compounds are not always readily available. Various deriva-

tives that can be considered to be synthetic equivalents of

ꢀ-dicarbonyl compounds may simplify the process. An

example of such reactions is given in Scheme 88. Thus, salt

290, a Vilsmeier-type reagent, reacts with N-propylimines

315 generated from simple ketones to give enamino-iminium

salts 316. In situ treatment with hydrazine converts salts 316

into 3,4-disubstituted pyrazoles 317. The synthesis proceeds

well when imines 315 are derived from symmetrical ketones,

when substituent R¹is unreactive (315b and 315c), or when

there is a signiﬁcant difference in steric hindrance between

both substituents (315d). In the last case, pyrazole 317d is

contaminated with a minor isomer (5%) formed by conden-

sation of salt 290 with the isobutylmethylene group. For

sterically less differentiated groups, regioselectivity is poor;

e.g., for 315e (R¹) n-Bu, R²) Et), the ratio of regioisomers

in the corresponding pyrazoles 317 is 55:45. Despite these

limitations and moderate yields, 31-83%, the simplicity of

this method makes it an attractive alternative in pyrazole

synthesis.¹¹⁶

4-ClC₆H₄) to 80% (R¹) 2-ClC₆H₄CH₂, R²) Ph) overall

yields for the two steps (Scheme 85).⁹⁵

By a different route to 2-aminothiophenes, benzotriazol-

1-ylacetone (310) is treated with phenyl isothiocyanate and

KOH to give adduct 311. Without separation, 311 is treated

in situ with phenacyl bromide to provide tetrasubstituted

thiophenes in 82% (312a) and 56% (312b) yields (Scheme

86).¹¹⁵

8. Five-Membered Rings with Two Heteroatoms

Condensation of equimolar amounts of 310 with p-

anisaldehyde in reﬂuxing DMF in the presence of a catalytic

amount of triethylamine gives benzotriazol-1-ylchalcone 318

in 81% yield. Chalcone 318 reacts readily with hydrazine to

provide 3,4,5-trisubstituted pyrazole 319 in 73% yield. This

addition/cyclocondensation process must proceed through a

corresponding pyrazoline that is oxidized under the reaction

conditions to pyrazole 319 without elimination of benzot-

riazole. When an excess of 4-nitrobenzaldehyde is used in

the condensation with 310, both the methylene and the

methyl groups react to give dibenzylideneacetone 320 in 81%

yield. In a reaction with hydrazine, the unsubstituted ben-

8.1. Pyrazole

Condensation of 1,4-diphenylsemicarbazide with formal-

dehyde and benzotriazole carried out in reﬂuxing benzene

with a Dean-Stark trap provides 1,1,4-trisubstituted semi-

carbazide 313. Using ZnBr₂catalyst, the iminium ion

generated from 313 by cleavage of the benzotriazolyl-C

bond is trapped by a vinyl group in CH₂dCHOEt, leading

to pyrazolidine 314, separated in 60% yield (Scheme 87).¹⁰⁵

The most popular method for the preparation of pyrazoles

unsubstituted at the nitrogen atoms involves condensation

of hydrazine with ꢀ-dicarbonyl compounds. However, such

Synthesis of Heterocycles Mediated by Benzotriazole

Chemical Reviews, 2010, Vol. 110, No. 3 1585

Scheme 89

Scheme 91

Scheme 92

Scheme 90

zylidene site in 320 is favored, providing pyrazole 321 in

61% yield (Scheme 89).¹¹⁷

2-Benzotriazol-1-ylvinamidinium salts 239 are convenient

reagents for the preparation of pyrazoles with a benzotriazolyl

substituent at C-4. In their reactions with arylhydrazines 322

and sodium carbonate in reﬂuxing methanol, salts 239 are

converted into pyrazoles 323 in 75% (R ) OMe) to 91% (R

) Br) yields (Scheme 90).⁹⁹

(75% yield). Alternatively, alkylation of lithiated pyrazolines

332 converts them to pyrazolines 331 that eliminate benzo-

triazole under basic conditions to furnish 1,4,5-trisubstituted

pyrazoles 334 (52-79% yields). The process is not limited

to aromatic aldehydes nor the benzotriazol-1-yl derivatives

shown in Scheme 92, since similarly good results are also

reported for R¹) phenethyl and benzotriazol-2-yl analogues

of compounds 328-332.¹¹⁸

R,ꢀ-Unsaturated ketones with a benzotriazolyl substituent

at the R-C can be easily prepared by condensation of

2-benzotriazol-1-ylacetophenone (335) with aldehydes in the

presence of a piperidine catalyst. The Z isomers of R,ꢀ-

unsaturated ketones 336 are formed exclusively and are

isolated in 55% (R¹) 3-pyridyl) to 71% (R¹) Ph) yields.

Treatment with hydrazines converts 336 into cis-substituted

pyrazolines 337 that are isolated in 51% (R¹) Ph, R²)

Me) to 80% (R¹) R²) Ph) yields. Elimination of

benzotriazole from pyrazolines 337 in the presence of bases

furnishes pyrazoles 340 in 81-94% yields. Lithiation of

pyrazolines 337 at C-4 followed by treatment with alkylating

agents provides pyrazolines 339 in 73-95% yields. Subse-

quent elimination of benzotriazole initiated by a base converts

In another approach to 4-benzotriazol-1-ylpyrazoles, 310

is treated with N,N-dimethylformamide dimethyl acetal

(DMFDMA) to give enaminone 324 (74% yield). Cyclo-

condensation of 324 with phenylhydrazine provides 1,4,5-

trisubstituted pyrazole 325 in 74% yield. Using the same

reagents but in the reversed order converts 310 into a

different regioisomer, 1,3,4-trisubstituted pyrazole 327 (70%

yield), via phenylhydrazone 326 (85% yield) (Scheme 91).^115a

When aldehydes replace ketones, pyrazoles unsubstituted

at C-3 result. Thus, condensation of benzotriazole with

chloroacetaldehyde dimethyl acetal provides benzotriazol-

1-yl derivative 328 as the main product (60% yield) and its

benzotriazol-2-yl analogue as a minor product (21% yield).

Treatment of lithiated acetal 328 with aldehydes results in

alcohols 329 (83-86% yields). Aqueous HCl converts

alcohols 329 to R,ꢀ-unsaturated aldehydes 330 in a practi-

cally quantitative manner. Addition/cyclocondensation reac-

tions of aldehydes 330 with methylhydrazine provide pyra-

zolines 332 (57-87% yields) that on treatment with bases

can be converted to 1,5-disubstituted pyrazoles, e.g., 333

1586 Chemical Reviews, 2010, Vol. 110, No. 3

Katritzky and Rachwal

Scheme 93

Scheme 95

Scheme 94

Scheme 96

pyrazolines 339 into 1,3,4,5-tetrasubstituted pyrazoles 338

in 85-95% yields (Scheme 93).¹¹⁹

For preparation of pyrazoles substituted at C-4 and

unsubstituted at C-3 and C-5, the method shown in Scheme

94 is a good option. Thus, addition of N-(benzotriazol-1-

ylmethyl)morpholine (341) to ethyl propiolate catalyzed by

ZnBr₂provides adduct 342 in 80% yield. Apart from the E

isomer 342, minor benzotriazol-2-yl analogues and Z isomers

are detected by NMR in the reaction mixture. Heating with

phenylhydrazine converts 342 into pyrazole 343 in 75%

yield. This step must involve oxidation by atmospheric

oxygen to convert the intermediate pyrazoline, which forms

ﬁrst by cyclocondensation of 342 with phenylhydrazine with

elimination of the benzotriazole and morpholine, into pyra-

zole 343 (Scheme 94).¹²⁰

reaction) that attacks the N-2 atom of benzotriazole. Hydro-

genation over Raney nickel cleaves the C-S bond and one

of the N-N bonds to generate 1-(2-aminophenyl)pyrazoles

350.¹²³

8.2. Imidazole

1,3-Dipolar cycloaddition of 1-(3-morpholin-4-ylallyl)ben-

zotriazole⁸⁵(181) to nitrilimine 344, generated in situ from

the corresponding phenylhydrazonyl bromide in reﬂuxing

benzene,¹²¹provides pyrazoline 345 in 70% yield. In the

following treatment with hydrochloric acid in ethanol at room

temperature, pyrazoline 345 eliminates morpholine to furnish

pyrazole 347 (90% yield). 1,3-Bisbenzotriazol-1-ylpropene

(346), prepared from epichlorohydrin and benzotriazole

followed by thionyl chloride and ﬁnally sodium hydride,

reacts with nitrilimine 344 to give directly pyrazole 347 in

80% yield; in this case, benzotriazole must be eliminated

from an unstable 5-benzotriazol-1-ylpyrazoline intermediate

(Scheme 95).¹²²

In the special case shown in Scheme 96, two of the

benzotriazolyl nitrogens are used to generate the pyrazole

ring. Thus, treated with triﬂuoroacetic anhydride, sulfoxides

348 undergo conversion to triazapentalenes 349 in high

yields. The process must involve acylation of the sulfoxide

oxygen atom and generation of a carbocation (Pummerer

Condensations of N-monosubstituted ethylenediamines 351

with 2 molar equiv of formaldehyde (as a 37% aqueous

solution) and 1 equiv of benzotriazole provide 1,3-disubsti-

tuted imidazolidines 352 in high yields (85-96%). For R¹

) Ph, the benzotriazol-1-yl isomer 352 is the only product;

in other cases, the benzotriazol-2-yl isomers are also present

as the minor components in crude product mixtures. Because

there is no signiﬁcant difference in their reactivity, both

isomers give the same products on treatment with nucleo-

philes. Thus, in reactions with Grignard reagents, the

benzotriazolyl moiety is replaced by an alkyl, vinyl, phe-

nylethynyl, or aryl group to give imidazolidines 354 in

63-96% yields. Similarly, compound 352 reacts with sodium

cyanide to form nitriles 355 (77-97% yields). Additional

reactions of one of the imidazolidines 352 (R¹) Ph) with

sodium borohydride, benzenethiol and sodium hydride, or

triethyl phosphite and ZnBr₂demonstrate easy substitution

of the benzotriazolyl moiety by a hydrogen atom (353, 96%

Synthesis of Heterocycles Mediated by Benzotriazole

Chemical Reviews, 2010, Vol. 110, No. 3 1587

Scheme 97

Scheme 99

Scheme 100

Scheme 98

Scheme 101

yield), a phenylthio group (356, 66% yield), or a phosphonate

group (357, 70% yield) (Scheme 97).¹²⁴

Condensation of ethylenediamine with 3 molar equiv of

formaldehyde and 2 equiv of benzotriazole provides 1,3-

bis(benzotriazol-1-ylmethyl)imidazolidine (358) together with

its minor benzotriazol-1-yl/2-yl isomer. The reaction of crude

358 with KCN in reﬂuxing acetonitrile gives dinitrile 359

in 88% yield. Treatment with Grignard reagents converts 358

into 1,3-dialkylimidazolidines 360 in 68-75% yields (Scheme

98).⁶³

Commercially available N-Boc-protected R-amino acids

can be converted in two easy steps into amides 361 by

coupling with p-toluidine and deprotection of the amino

group. Reduction of amides 361 with LiAlH₄gives optically

active diamines 362. Condensation of these diamines with

formaldehyde and benzotriazole provides single enantiomers

of 3-(benzotriazol-1-ylmethyl)imidazolidines 363 in 85-93%

yields. Subsequent reactions with nucleophiles allow sub-

stitution of the benzotriazole moiety by various functional

groups, resulting in chiral 1,3,4-trisubstituted imidazolidines

364 (Scheme 99).¹²⁴

Under forcing conditions, reﬂuxing under a Dean-Stark

trap of benzene solutions, amides 365 undergo condensation

with formaldehyde (generated by depolymerization of

paraformaldehyde in the presence of TsOH) and benzotria-

zole to give 1,3,4-trisubstituted imidazolidin-5-ones 366 that

are isolated as mixtures with their minor benzotriazol-2-yl

isomers (isomeric ratio of 3:1 to 5:1) in 91-94% yields

(Scheme 100).¹²⁵

N-Benzotriazol-1-ylmethyl derivatives of BOC-protected

amines behave similarly to amides. Thus, treatment of the

anion derived from compound 367 with N-benzylidene-p-

anisidine leads to imidazolidin-2-one 368 (82% yield) with

the substituents at C-4 and C-5 oriented trans. Subsequent

treatment with nucleophiles gives products 369 stereoselec-

tively in 64-68% yields (Scheme 101).¹²⁶

The aminocarbene generated by treatment of iminium

chloride 290 with triethylamine undergoes [1 + 2 + 2]

cycloaddition with phenyl isocyanate to give imidazolidine-

2,4-dione 370. Quenching the reaction mixture with tetra-

ethylammonium hydrogen sulﬁde results in reduction of the

C-5 functionality to give 1,3-diphenylimidazolidine-2,4-dione

(1,3-diphenylhydantoin, 371)in 35% yield. On treatment of

370 with sodium borohydride, only the benzotriazolyl moiety

is replaced by a hydride to give 5-(dimethylamino)hydantoin

372 in 51% yield. Similarly, hydantoin 373 (56% yield) is

generated in a reaction of 370 with ethylmagnesium bromide.

Analogous quenching of the reaction mixture with methanol

or morpholine replaces the benzotriazolyl moiety by a

1588 Chemical Reviews, 2010, Vol. 110, No. 3

Katritzky and Rachwal

Scheme 102

Scheme 103

Scheme 104

methoxy (57% yield) or morpholin-4-yl group, respectively,

without affecting the dimethylamino substituent. However,

when propylamine is used as a nucleophile, both the

benzotriazolyl and the dimethylamino groups are eliminated

to give 5-(N-propylimino) derivative 374 (54% yield). A

simple workup of the mixture containing intermediate 370

with water results in imidazolidine-2,4,5-trione 375 in 67%

yield (Scheme 102).¹¹¹

Scheme 105

1-(Chloroformyl)benzotriazole (377), prepared in a reac-

tion of benzotriazole with phosgene^127,128or more conve-

niently with triphosgene,¹²⁹reacts with amino acids 376 to

give derivatives 378. Treatment with thionyl chloride con-

verts acids 378 into acid chlorides 379 that are subsequently

treated with amines to give amides 380. Under mildly basic

conditions, sodium carbonate in acetone, amides 380 undergo

cyclocondensation with elimination of benzotriazole to

furnish hydantoins 381 in 24% (R¹) Ph, R²) Ph₂CH) to

88% (R¹) Me₂CHCH₂, R²) Ph₂CH) yields (Scheme

103).^130,131

Lithiation of bisbenzotriazol-1-ylmethane (382) followed

by treatment with tosyl azide gives diazide 383 in 22% yield.

In a reaction with triphenylphosphine, diazide 383 is

converted into bis(triphenylphosphoranylidene) derivative

384. Despite the fact that 384 is not stable enough to provide

an analytical sample, thorough NMR studies of the crude

material reveal that the benzotriazol-1-yl substituents have

rearranged to the sterically less hindered -2-yl forms.

Consecutive treatments of crude 384 with Grignard reagents

followed by benzil lead to 2H-imidazoles 385, although the

yields of isolated products are low (15-21%) (Scheme

104).¹³²

simple synthetic method provides 1,5-diarylimidazoles 387

in 23% (R ) Ph) to 85% (R ) H) yields (Scheme 105).⁹⁴

Displacement of benzotriazole in 58 by primary amines

provides derivatives 388 that are treated in situ with benzil

to give imidazoles 390 (X ) H) in 81-84% yields. With

4-chlorobenzil, the nucleophilic attack occurs primarily on

the carbonyl group attached to the 4-chlorophenyl ring,

leading to intermediates 389 that undergo cyclization with

elimination of water to give 4-(4-chlorophenyl)imidazoles

390 (X ) Cl). Identiﬁcation of the substituents in a molecule

of imidazole 390 with R ) PhCH₂and X ) Cl is provided

by X-ray crystallography (Scheme 106).¹³³

The anion derived from isocyanide 227, on treatment with

t-BuOK, adds readily to Schiff bases to form imidazolines

386. Under stronger basic conditions, imidazolines 386

eliminate benzotriazole to produce imidazoles 387. This

Synthesis of Heterocycles Mediated by Benzotriazole

Chemical Reviews, 2010, Vol. 110, No. 3 1589

Scheme 106

Scheme 108

Scheme 107

Scheme 109

8.3. Isoxazole

N,N-Bis(benzotriazol-1-ylmethyl)hydroxylamine (391) is

easily prepared by condensation of 1-(hydroxymethyl)ben-

zotriazole with hydroxylamine.²²At elevated temperatures,

in reﬂuxing toluene, 391 eliminates a molecule of benzot-

riazole to give nitrone 392, which can be readily trapped by

1,3-dipolarophiles. Thus, with methyl acrylate in reﬂuxing

toluene for 16 h, 391 gives isoxazolidine 393a quantitatively

and with acrylonitrile isoxazolidine 393b in 88% yield.

Pyridyl derivatives 393c (83% yield) and 393d (81% yield)

are obtained in the same manner from the corresponding

vinylpyridines. The electron-withdrawing ability of the alkene

substituent R seems to be a determining factor, as no such

reaction of 391 is observed with styrene. Use of 1,2-

disubstituted alkenes, e.g., dimethyl fumarate or N-methyl-

maleimide, allows preparation of 1,3,4-trisubstituted isox-

azolidines in this manner (Scheme 107).¹³⁴

Removal of the benzotriazol-1-ylmethyl substituent from

the isoxazolidine ring in 393 can be achieved by heating

their ethanolic solutions with perchloric acid. Thus, com-

pound 393d undergoes straightforward hydrolysis to 5-(4-

pyridyl)isoxazolidine (394) in 46% yield. Sodium borohy-

dride reduces the benzotriazol-1-ylmethyl group in 393d to

a methyl group, furnishing isoxazolidine 395 in 68% yield.

A similar reaction of 393c gives the corresponding 1-methyl-

isoxazolidine in 60% yield. However, involvement of the

pyridyl nitrogen atom during hydrolysis of 393c complicates

the process, leading to bridged tricyclic system 397, isolated

in 64% yield after 15 min of reﬂux. To prove its structure,

pyridinium salt 397 was reduced with sodium borohydride

to 12-oxa-1,3-diazatricyclo[7.2.1.0^3,8]dodec-5-ene (398). Pro-

longed heating of 393c with perchloric acid results in dimeric

product 396 (85% yield) (Scheme 108).¹³⁴

Treated with NCS, oximes 399 are readily converted

into benzhydroximoyl chlorides 400.^135,136Exposed to mild

bases, chlorides 400 eliminate HCl to give reactive

benzonitrile oxides 401.¹²¹When 188 is added, oxides 401

are trapped in a 1,3-dipolar cycloaddition reaction to give

isoxazolines 402 in 94-100% yields. A similar reaction with

ethoxy derivative 184 provides isoxazoline 403 in 81% yield.

In all these products, the benzotriazol-1-ylmethyl moiety is

located at C-5 of the isoxazoline ring (Scheme 109).¹³⁷

However, an opposite orientation of the reacting mol-

ecules is required in a 1,3-dipolar cycloaddition of

1-allylbenzotriazoles bearing an electron-donating sub-

stituent at C-3. Thus, 181⁸⁵adds to benzonitrile oxide to

provide isoxazoline 404 in 70% yield. Analogous reactions

of benzonitrile oxide with 185 and 346 give isoxazolines

405 (80% yield) and 406 (65% yield), respectively. For

1590 Chemical Reviews, 2010, Vol. 110, No. 3

Katritzky and Rachwal

Scheme 110

Scheme 112

Scheme 113

Scheme 111

stituent at C-R. In a reaction with hydroxylamine, chal-

cones 411 are converted to 4-benzotriazol-1-ylisoxazolines

412 that spontaneously eliminate benzotriazole to provide

3,5-disubstituted isoxazoles 413 in 55-81% yields (Scheme

112).¹¹⁹

Condensation of 310 with 2 molar-equivalents of

4-nitrobenzaldehyde provides 1,4-pentadien-3-one 414 in

81% yield. In a reaction with hydroxylamine, only the

double bond in derivative 414 without a benzotriazolyl

substituent is affected to give isoxazole 415 in 79% yield.

This process must involve an oxidation step (probably by

the atmospheric oxygen) of an isoxazoline intermediate

(Scheme 113).¹¹⁷

Condensation of 310 with N,N-dimethylformamide

dimethyl acetal in reﬂuxing xylene gives enaminone 416

in 74% yield. With an excess of hydroxylamine hydro-

chloride, enaminone 416 is converted into 5-aminoisox-

azole 420 in 68% yield. The process is assumed to go

through dioxime 417, which loses a molecule of water to

give R-cyanooxime 418. An intramolecular addition of

the OH to the CN group in 418 gives 5-iminoisoxazoline

419, which is converted to the more stable tautomeric form

420 (Scheme 114).¹¹⁵

isoxazolines 404-406, NMR spectra indicate a trans orienta-

tion of the substituents at C-4 and C-5. On treatment with

hydrochloric acid in ethanol at reﬂux, isoxazolines 404-406

eliminate the substituent at C-5 to furnish isoxazole 407 in

approximately 90% yield (Scheme 110).¹²²

In a simpliﬁed procedure, 175 is heated with benzal-

dehyde oximes, NCS, and wet KHCO₃to give directly in

one pot 3-aryl-5-(benzotriazol-1-ylmethyl)isoxazoles 408

in 52% (X ) 3-NO₂) to 100% (X ) H) yields. In this

conversion, the intermediate benzonitrile oxides, generated

by consecutive reactions of the oximes with NCS and

KHCO₃, undergo [3 + 2] cycloadditions with the prop-

argyl triple bond to generate the isoxazole ring. To test

possible pathways for the elimination of the benzotriazole

moiety from oxazoles 408, one of them (X ) 4-MeO) is

benzylated at C-R to give derivative 409, which is

subsequently treated with t-BuOK to furnish 4-styrylisox-

azole 410 in 63% yield (Scheme 111).¹³⁷

8.4. Oxazole

Similarly to the reaction shown in Scheme 26, the radicals

generated by treatment of N,N-bis(benzotriazolylmethy-

l)amines 35 with SmI₂are trapped by diethyl ketone, leading

to oxazolidines 421; however, the yields are low (30-38%)

(Scheme 115). In this case, generally better results are

obtained when N,N-bis(tosylmethyl)amines are used instead

of derivatives 35.¹³⁸

Condensation of 335 with aromatic aldehydes readily

provides chalcones 411 bearing a benzotriazol-1-yl sub-

Synthesis of Heterocycles Mediated by Benzotriazole

Chemical Reviews, 2010, Vol. 110, No. 3 1591

Scheme 114

Scheme 116

Scheme 115

Scheme 117

Cyclocondensation of (S)-2-phenylglycinol with ethyl

glyoxylate, benzotriazole, and formaldehyde provides ox-

azolidine 421 in 80% yield. In reactions with allyltrimeth-

ylsilane and (2-methylallyl)trimethylsilane catalyzed by

ZnBr₂, the benzotriazolyl moiety in oxazolidine 421 is readily

substituted to give corresponding oxazolidines 422 in 66%

and 69% yield, respectively. Similar reactions of 421 with

trimethylsilyl enolates provide ketones 423 in 56% (R²)

Me) and 70% (R ) Ph) yields. Phenylzinc bromide reacts

with 421 to give 3-benzyloxazolidine 424 in 57% yield;

however, aliphatic organozinc reagents fail to give analogous

products. In a similar manner, 421 reacts with triethyl

phosphite to give phosphate 425 in 78% yield and with

1-methoxy-2-methyl-1-[(trimethylsilyl)oxy]propene to give

ester 426 in 80% yield. In all these reactions, the chirality

at C-2 and C-4 is preserved (Scheme 116).¹³⁹

Scheme 118

1-(N-benzylthiocarbamoyl)benzotriazole (427) is prepared

from benzylamine and bisbenzotriazol-1-ylmethanethione in

97% yield.¹⁴⁰The isothiocyanate anion generated from 427

by 2 molar equiv of potassium tert-butoxide adds to carbonyl

groups of ketones to generate oxazolidinethiones 428, which

are isolated in 27% (R ) Ph) to 51% (R ) 2-thienyl) yields

(Scheme 117).¹⁴¹

Cyclocondensation of acylbenzotriazoles 167 with 2-amino-

2-methyl-1-propanol under microwave irradiation produces

2-oxazolines 429. To prevent hydrolysis leading to side

products, SOCl₂is added to the mixture after initial heating

at 80 °C for 10 min, and heating is then continued for an

additional 2 min. In this way, high yields of oxazolines 429

(85-97%) are obtained. Use of (S)-2-amino-3-phenyl-1-

propanol allows the preparation of chiral (S)-4-benzyl-2-

phenyl-2-oxazoline (430) in 82% yield (Scheme 118).¹⁴²

1-Imidoylbenzotriazoles 431 are prepared in a reaction of

1-acylbenzotriazoles 167 with isocyanates or a reaction of

thionyl benzotriazolide with amides. Lithiated 2-methyl-2-

oxazoline reacts readily with compounds 431 to give

enamines 433 in 82-96% yields. Imidoyl intermediates 432

are not detected by NMR in the product mixtures due to

their rapid tautomerization to forms 433 that are stabilized

by strong intramolecular hydrogen bonding between their

nitrogen atoms (Scheme 119).¹⁴³

The anion derived from isonitrile 37 (BetMIC) on treat-

ment with potassium tert-butoxide readily adds to the

carbonyl groups of ketones. The benzotriazolyl moiety in

the intermediates is substituted by an ethoxy group from the

added ethanol to give 4-ethoxyoxazolines 434. The reaction

provides high yields of the products derived from acyclic

ketones (93% for 434a and 92% for 434b) and moderate

1592 Chemical Reviews, 2010, Vol. 110, No. 3

Katritzky and Rachwal

Scheme 119

Scheme 122

Scheme 120

Scheme 123

Scheme 121

8.5. Thiazole

yields for the products derived from cycloalkanones (58-65%)

(Scheme 120).¹⁴⁴

As with the analogous reaction of 2-methyl-2-oxazoline

(Scheme 119), lithiated 2-methyl-2-thiazoline reacts with

imines 431 to give substituted 2-(ꢀ-enamino)-2-thiazolines

442 in good yields (79-98%). Due to possible hydrolysis

of the heterocyclic rings, thiazolines 442 and the previ-

ously described corresponding oxazolines 433 are con-

sidered as masked ꢀ-enamino carboxylic acids (Scheme

123).¹⁴³

Addition of 335 to phenyl isothiocyanate provides amino

thiol 443, which is trapped by phenacyl bromide to give

2,3-dihydro-2-(1′-benzotriazol-1-yl-1′-benzoylmethylidene)-

3,4-diphenylthiazole (444) in 85% yield (Scheme 124).¹¹⁵

Benzotriazol-1-ylacetonitrile (445) is easily prepared by

condensation of 30 with NaCN in DMSO.²⁰Hydrolysis of

nitrile 445 with H₂O₂/K₂CO₃/H₂O gives amide 446 (93%

yield), which is subsequently converted to thioamide 447

(83% yield) using Lawesson’s reagent. Cyclocondensation

of thioamide 447 with phenacyl bromide provides thiazole

448 in 84% yield. Treatment of lithiated 448 with alkyl

halides allows monoalkylation of the methylene group to give

derivatives 449 in 76-83% yields (Scheme 125).¹⁴⁶

As is illustrated by transformation of compound 449a, the

lithiation/alkylation process can be repeated to provide

thiazoles 450 (86-93% yields) with the methylene groups

dialkylated with the same or different substituents. In a

Addition of the anion derived from isonitrile 37 to the

carbonyl group of aromatic aldehydes results in oxazolines

435 that spontaneously eliminate benzotriazole to furnish

5-aryloxazoles 436. The reaction does not differentiate

between electron-rich and electron-poor aromatic rings, as

the yields of 436 obtained from benzaldehyde (69%),

4-ﬂuorobenzaldehyde (68%), and 4-methoxybenzaldehyde

(63%) are comparable, but heteroaromatic aldehydes give

signiﬁcantly lower yields: 35% for 2-furyl and 42% for

3-pyridyl (Scheme 121).¹⁴⁴

Condensation of benzotriazole with glyoxal in aqueous

acetic acid readily provides 1,2-bisbenzotriazol-1-yl-1,2-

ethanediol (437) almost quantitatively.³³When 437 is heated

with benzamides and a catalytic amount of Amberlyst 15

ion-exchange resin in reﬂuxing toluene with azeotropic

removal of water, diamides 438 are obtained in almost

quantitative yields. Deprotonation of 438 with NaH gives

anions 439 that in a nucleophilic attack on C-ꢀ repel the

benzotriazolide anion to provide oxazolines 440. Under the

reaction conditions, rapid elimination of the second benzo-

triazolyl substituent provides oxazoles 441 in 44-62% yields

(Scheme 122).¹⁴⁵

Synthesis of Heterocycles Mediated by Benzotriazole

Chemical Reviews, 2010, Vol. 110, No. 3 1593

Scheme 124

Scheme 126

Scheme 125

Scheme 127

Scheme 128

reaction with phenylmagnesium bromide in reﬂuxing toluene,

the benzotriazolyl moiety in thiazoles 450 is substituted by

phenyl to furnish 2-(R,R-dialkylbenzyl)-4-phenylthiazoles

452 in 54-75% yields. Thiazole 453 is obtained in 58% yield

in a similar reaction of 450c with methylmagnesium iodide.

Treatment of 450a with 2-methylfuran and ZnBr₂in reﬂuxing

1,2-dichloroethane substitutes the benzotriazolyl moiety by

furyl to provide thiazole 451 in 65% yield. 2-Methyl-

thiophene reacts similarly with 450c to give derivative 454

in 82% yield (Scheme 126).¹⁴⁶

The anion obtained from thiazole 448 can also be trapped

by other electrophiles. Thus, lithiated 448 is treated with

phenyl or tert-butyl isocyanate to provide amides 455 in

87-96% yields. Reduction with zinc/acetic acid in reﬂuxing

ethanol removes the benzotriazolyl group to give (4-

phenylthiazol-2-yl)acetamides 456 in 73-86% yields (Scheme

127).¹⁴⁶

Using higher R-bromo ketones in the reaction shown in

Scheme 125 allows substitution of C-5 of the ring. Thus,

condensation of thioamide 447 with 2-bromopropiophenone

gives thiazole 457 in 59% yield. Subsequent double lithiation/

methylation furnishes thiazole 458 in 56% yield. The

benzotriazolyl moiety in 458 can be substituted with a phenyl

or 5-methylfuryl ring to give thiazole 459 (59% yield) or

460 (70% yield), respectively (Scheme 128).¹⁴⁶

with benzotriazole in reﬂuxing toluene or dioxane convert

diimines 461 into imines 462 in 80-92% yields. Treatment

of 462 with n-butyllithium produces anions 463 that add

readily to isothiocyanates to give intermediate anions 464.

Loss of a benzotriazolide anion results in iminothiazole

systems 465 that undergo tautomerization to more stable

aminothiazoles 466. This way, 5-aminothiazoles 466 bearing

aryl or heteroaryl substituents at C-2 and C-4 are easily

Diimines 461 are prepared as precipitates in 75-90%

yields by stirring aromatic aldehydes with a 10-fold excess

of an aqueous or methanolic solution of ammonia. Reactions

Article Doi

Synthesis of β-dicarbonyl compounds using 1-acylbenzotriazoles as regioselective C-acylating reagents

DOI: 10.1021/jo991878f

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