Adventures with Benzotriazole An Overview of Some Recent Advances in Synthetic Methodology

Lecture presented at various locations in 2000 Alan R. Katritzky and Olga V. Denisko
Florida Center for Heterocyclic Compounds

For a review comprehensive through 1996 see: A. R. Katritzky, X. Lan, J. Yang, O. V. Denisko [98CR409] (includes 403 references of which 253 are from our group) For other recent relevant reviews see: (i) A. R. Katritzky and S. Belyakov [98AA33] Benzotriazole-based Reagents for Efficient Organic Synthesis; (ii) A. R. Katritzky, J. Li and L. Xie [99T8263] Benzannulations; (iii) A. R. Katritzky and M. Qi [98CCCC599] Michael additions of Benzotriazole-Stabilized Carbanions; (iv) A. R. Katritzky and M. Qi [98T2647] The Generation and Reactions of Non-Stabilized -Aminocarbanions. 1

Benzotriazole is Intrinsically Unreactive, Stable and Exhibits Desirable Physical and Innocuous Biological Properties
Chemical Stability of Benzotriazole Ring System

N N N R
Stable: thermally to 400 oC, to hot strong H2SO4, to fused KOH, to oxidation (KMnO4 oxidizes benzene ring) to reduction (e.g. LiAlH4; H2-Pd)

N N N H

Parent Benzotriazole acid pKa 8.2 for proton loss very weak Bronsted base (pKa < 0 for proton addition) Lewis base of appreciable strength non-volatile, crystalline, odorless, nontoxic almost insoluble in water, soluble in Na2CO3 solution hence easily recovered
2

Benzotriazole is Inexpensive ($47.55/500g) and Easily Inserted into a Molecule

By Substitution
RX + BtNa Bt-R
RCOX + BtNa R R OR' + OR' BtH R OR' Bt-COR R Bt also ortho esters and ortho carbonates ROH + BtH Bt-R (Mitsunobu)

By Addition
to C-heteroatom multiple bonds C=O, C=N, C=N+, C=S to electron deficient C-C multiple bonds by Michael addition

XH X + BtH Bt

e.g

CH

O + BtH

Bt

C CH2 C

to electron-rich C-C multiple bonds (enol ethers, enamines, enamides, vinyl sulfides)

C X

BtH

X CH C Bt

By Three Component Condensation (X = O, N, or S)

Bt C O + BtH + RXH C XR

A Benzotriazole Residue Conveys Multiple Activating Influences on Molecules to which it is Attached

R
Bt as a leaving group

Bt CH X

_ + RCH X Bt ion pair

e.g. R'MgBr (R'ZnBr is better)

R' CH X

Bt as an proton activator

CH2 Bt

n-BuLi

Bt CH Li

e.g. R'Br

Bt CH R'

Bt as a ambident anion directing group

OEt Bt

H+

_ Li+

OEt Bt

E+

E Bt

OEt

R
Bt as a cation stabilizer

Bt CH Y R

+ CH

_ Bt Y

e.g. PhNMe2 Me2N

CH

Bt

Bt as a radical precursor

CH2 Bt
_

+e

_ _

. RCH2
R' O

trapped

- Bt
+2e _ - Bt _

Bt as an anion precursor

CH2 Bt

RCH2

e.g. R'

R CH2 CR'2 OH

N-Acylbenzotriazoles: Neutral Acylating Reagents for the Preparation of Primary, Secondary and Tertiary Amides
NH3 RCONH2 72-100% (14 examples)

BtSO2CH3 RCOOH Et3N

N N N

R1NH2

RCONHR1

70-100% (10 examples)

COR 74-92% (17 examples)

R2R3NH

RCONR2R3

44-100% (9 examples)

OH i) BtSO2CH3, Et3N C COOH ii) RNH2 H

OH C CONHR H

R = Ph, 68% R = 4-MeC6H4, 72%

n-C3F7COCl

R1 = 4-MeC6H4, R2 = H, 90% 1 2 BtTMS R1R2NH n-C3F7CONR1R2 R = PhCHMe, R = H, 87% n-C3F7COBt R1 R2 = (CH2)4, 88% R1 R2 = (CH2)2O(CH2)2, 85% A. R. Katritzky, H.-Y. He, K. Suzuki, unpublished results 5

C-Acylation of Ketones
R O
2

O + R R N N N base

O R2 O R1

R1

Examples of -Diketones (% yield)

O O 82% Ph 71% O O

O O 78% Ph

O 81%

O Ph 92%

O O Ph 75% O 85%

O Ph 82%

O
75%

O 79% Ph

O
O O O O 93% Ph 63%

O Ph 78%

O Ph 69%

O 74% Ph

A. R. Katritzky, A. Pastor, 000JOCip

Imine Acylation: Preparation of Enaminones

O + Bt R
1

N Me

R3 R2

H O R
3

N R2

R1 = aryl, styryl, t-Bu, ClCH2 R2, R3 = alkyl, aryl 61-90% (16 examples) (except for R1 = ClCH2)

A. R. Katritzky, Y. Fang, A. Donkor, J. Xu, unpublished results

Synthesis of Guanidines
NH R1 R NH2
NH BrCN + 2 BtH Bt Bt
1

N H

Bt
NH R
1

THF rt

R1 = Ph, PhCH2, n-C5H11

R NH2

R1R2NH THF rt R1 N R2

NH Bt

THF,

N R2 H

N H

R1, R2 = alkyl; R3 = PhCH2, aryl yields 68-80% (5 examples)

PhNHMe THF, Me

N N O 85%
7

R1, R2 = alkyl 68-71% (3 examples)

A. R. Katritzky, B. V. Rogovoy, C. Chaissang, V. Vvedensky, unpublished results

Regioselective Reactions of Bt-Stabilized Propargylic Anions

OEt R OEt BtH R Bt BuLi THF OEt R Bt Li R'Br OEt R C C H+ O R C C C R' C Bt R' -78oC
iii C6H13 Bt

R R
1

PhCH3 OEt

ii

Ph

(i) R1CHO, 73-75%; OH (ii) RC(O)R, R 66-77%; Bt 84-98% 1 78%; (iii) Me3SiCl, R OH R = Ph, R1 = p-tolyl (iv) p-Tol-CH=N(p-Tol), 85%; R = C6H13, R1 = Ph (v) EtOAc, 65%; O OEt (vi) EtOCOOEt, 35%; Ph (vii) t-BuNCO, 54% Bt 98-100% OH R R = Ph R OH R R R = Me
OEt SiMe3 H+ 88% C6H13 SiMe3 O

OEt

H+

OEt iv Ph p-tolyl
v OEt Ph Me vi
OEt Ph t-BuNH Bt O

O NH(p-tolyl)

Bt NH(p-tolyl)
H+ Ph 92% OEt Ph
H+ 99%

H+ 90%
O

Ph p-tolyl

Bt O

O Me H+ 90%
O O t-BuNH

O Ph O EtO

vii

OEt Ph

Bt O

A. R. Katritzky, H. Lang, 95JOC7612

Preparation of Symmetrical and Unsymmetrical 1,6-Diketones

PhOCH2Bt + R Br
1

n-BuLi / THF -78 0C (81-92%)

Bt R1

OPh

R1 = (CH3)2CHCH2CH3, PhCH2, Et

OR n-BuLi (2 equiv) /THF 2 Bt

1

OR2 R
1

Bt R 2O

Br(CH2)4Br

R1

1N HCl / MeOH or H2C2O4/H2O/SiO2 R

1

O R1

Bt

R = Ph, H2C CH, PhC C R2 = Me or Et

O R1 = (CH3)2CHCH2CH2 ( 82%), PhCH2 (83%), (81%) Ph (82%), H2C=CH (83%), Ph

OR2 OR4 R
3

OR4 R
3

Bt

Br

Br 1.5-2.0 equiv

n-BuLi/THF -78 0C (82-91%) Bt

Br

R Bt n-BuLi/THF -78 0C

OR2 R1 Bt

Bt R3 OR4
1 N HCl / MeOH or H2C2O4 / H2O / SiO2

R3 = Et, Ph, Ph R4 = Me, Et, Ph

R1 = (CH3)2CHCH2CH2, R3 = Et, 86% R1 = PhCH2, R3 = Et, 82% R1 = H2C=CH, R3 = Ph, 82% , R1 = Ph R3 = Et, 82%

O R1 O

R3

A. R. Katritzky, Z. Huang, Y. Fang, I. Prakash, 99JOC2124

Synthesis of -Alkoxy Ketones

Bt Ph OEt
Ph Ph OEt O Ph OEt Bt H3O OH Ph Ph OPh Ph R2CO OH

OEt Bt Ph OEt O SiMe H3O OPh Ph SiMe3

PhO OEt Bt

Me3SiCl

OEt O OH Ph Ph

Ph

OPh

BuLi Ph

OEt Bt OPh

PhNCS Ph

OEt Bt

H3O Ph

OEt O S Ph NH

NHPh OPh

PhCHO

H3O
OEt Bt OH Ph OPh Ph Ph OEt O

TolCH=NHPh

i-PrNCO

NHPh Tol

H3O Ph

OEt Bt

NHPh Tol OPh Ph

OEt Bt O OPh

H3O Ph

O O NHPr-i

NHPr-i

A. R. Katritzky, D. Feng, M. Qi, 98JOC1473

10

Masked Formylation: Formyl Cation Equivalent

O OEt O + N H N N PF 5080 reflux 75% O
O
Cl O 70% O O O Cl O O 85% O 84% 86%

N N N O

RZnBr THF 20 oC

O R O

O
O

94% O O O O 54% O CN CN O
O O

50%

57%

64% O

O 72%

65%
O O O 73%

O O

83%

A. R. Katritzky, H. H. Odens, M. V. Voronkov, 000JOC1886

11

Conversion of Bt-Derivatives into Carbanions

Preparation of 5-Alkoxypent-3-ynols
BtCH2C CH i. n-BuLi, THF, -78 0C R1 1 2 ii. R COR BtCH2C C C OCH3 iii. MeI,rt R2 Li/LiBr/THF -78 0C R3 R1 HO C CH2 C C C OCH3 3 4 R COR R4 R2 Four examples: overall yields 60-72%

A. R. Katritzky, W. Bao, Y. Fang, M. Qi, I. Prakash, 99TL253

Synthesis of Alkoxybut-3-enols
H HO R -attack Ar OEt ArCHO Li/LiBr THF, -78 0C R Bt OEt R1COR2 Li/LiBr THF, -78 0C R R1 OEt OH R2

-attack

A. R. Katritzky, W. Bao, M. Qi, C. N. Fali, I. Prakash, 98TL6437

12

Pd-Catalyzed Preparation of Allylamines from Allylbenzotriazoles

Bt + N H Pd(OAc)2 (1 mol %), Ph3P MeOH, K2CO3, 80 oC, 4h N

R R
R1 H H CH3 C2H5 n-C4H9
2

Bt

Pd(OAc)2/Ph3P, K2CO3 R4R5NH, MeOH, reflux

R2 H H H H H H n-C4H9 R4 C6H5CH2 n-C8H17 R5 C6H5CH2 n-C8H17

R R

R N 5 R

Yield(%) 80 87 85 80 70 70 75

CH2-CH2-C6H4-CH2 n-C8H17 C6H5CH2 C 2H 5 -(CH2)4CH3 C6H5CH2 C 2H 5

C6H5CH2 n-C4H9

A. R. Katritzky, J. Yao, M. Qi, 98JOC5232

13

Preparation of Functionalized Allylamines

Bt i) n-BuLi ii) R1COR2 R
2

R1 OH R1 R4R5NH (i) Pd(OAc)2, PPh3 K2CO3, MeOH, reflux R4 N R2 R3

R1 = H, Me R2 = n-Pr, Ph, Me, cyclo-C6H11

HO R5 R4R5NH, Pd(OAc)2, PPh3, K2CO3, MeOH

[R4R5 = (CH2)2O(CH2)2, 65%]

Bt i) n-BuLi ii) n-BuBr

Bt Bu
n

Bt i) n-BuLi ii) n-PrCHO

R1 = H, n-Bu Bun 2 OH R3 = H, Me

Pr

R = Me, i-Pr, n-Pr, cyclo-C6H11 R4 = R5 = PhCH2, n-C8H17, n-C6H13 R4R5 = (CH2)5, (CH2)2O(CH2)2

Bt i) n-BuLi ii) O OH i) (PhCH2)2NH Pd(OAc)2, PPh3 K2CO3, MeOH, reflux ii) SiO2, EtOAc (PhCH2)2N 71% OAc

A. R. Katritzky, J. Yao, O. V. Denisko, 000JOCip

14

Synthesis of 2-Vinyl-pyrrolidines and -piperidines

R
1

Bt

R2 Cl

i. n-BuLi, -78 C
ii. BrCH2CHR CH2Cl
2

R1 Bt

i. n-BuLi, -78 0C ii. Br(CH2)4Cl

R1

Bt Cl

R1 = H, CH3, C6H5CH2 R2 = H, CH3

R1 = H, CH3, C6H5CH2

R3NH2, DMF K2CO3, 80 0C

i. R2NH2, DMF K2CO3 ii.Pd(OAc)2/Ph3P K2CO3/MeOH

R2
2 R1 Bt R

Pd(OAc)2/Ph3P NHR3 K2CO3/MeOH R1 N R3

R1 N R2
R1 = H, n-C4H9 R2 = C6H5CH2, n-C6H13, yields = 80%-85%

R = H, CH3, C6H5CH2 R2 = H, CH3 R3 = C6H5CH2, n-C12H25, c-C6H11, C6H5CH(CH3), EtOCH2CH2, Et2NCH2CH2

Katritzky, A. R.; Yao, J.; Yang, B. 99JOC6066

15

Stereoselective Synthesis of 4,5-Disubstituted Imidazolidin-2-ones

Bt N Boc 1. s-BuLi 2. R1CH=NC6H4-4-OMe Bt N O ~80% R1 N OMe
BF3. Et2O Si(CH3)3 R1 N O N OMe

~70% trans : cis = > 99:1

_ Boc

OSi(CH3)3 R2ZnBr R2 N O ~70% trans : cis = > 99:1 R1 N O OMe N O ~65% trans : cis = > 99:1
16

BF3 . Et2O

R1 N OMe

A. R. Katritzky, Z. Luo, Y. Fang, unpublished results

Asymmetrical Synthesis of 2,5-Di- and 2-Substituted Pyrrolidines

Ph NH2 80%
Ph SiMe3

OH

BtH

MeO +

H N

OMe

90-95% (3 examples) Pd(OH)2/C H2 Ph O RMgX N OH R

H N

Ph

Pd(OH)2/C H2
Bt

N BF3. Et2O 45%

95%

Me3SiO R Ph N O R 35-54% O MeO O 64% Ph N

OSiMe3 (EtO)3P ZnBr2 OMe

72-91% (4 examples) (R = Ph) Pd(OH)2 /C H2

Ph O Pd / C H2 H O N P EtO OEt 89%

O N P EtO OEt 77%

NH2 Ph

A. R. Katritzky, X.-L. Cui, B. Yang, P. J. Steel, 99JOC1979

17

Hexahydro-1H-pyrrolo[1,2-a]imidazoles and Octahydroimidazo[1,2-a]pyridines

OHC CHO + PhNH(CH2)2NH2 82%

BtH

RMgX R N N Ph

N N N

N Ph
R2

TMS

N Ph

OTMS R1

79%

R = alkyl, vinyl, alkynyl, aryl 86%-93% (6 examples)

(EtO)3P

R2

O R2
O EtO P EtO N N Ph

N Ph

R1 R2 ~85%

74%
CHO CHO + PhNH(CH2)2NH2 + BtH CH2Cl2 Bt N N Ph
R N N Ph

RMgX

R = alkyl, alkynyl, aryl 79-91% (5 examples)

A. R. Katritzky, G. Qiu, H.-Y. He, B. Yang, unpublished results

18

Preparation of 1,5-Disubstituted Pyrrolidin-2-ones

MeO + O OMe + BtH AcOH reflux
+ O N N N

R1NH2

N R1

N N N

N R1

60-74% (11 examples)

R2
O P OEt OEt (EtO)3P ZnBr2 CH2Cl2
O N R1
R3MgBr ZnCl2 THF

SiMe3
Bt1,2

R2 O N

N R
1

BF3 Et2O CH2Cl2

R1 = arylmethyl, 2-arylethyl 67-85% (5 examples)

R1 R1 = arylmethyl, 2-arylethyl R2 = H, Me 80-90% (6 examples)

50-80% (8 examples) O

N R1

R3

A. R. Katritzky, S. Mehta, H. -Y. He, X. Cui, unpublished results

19

Preparation of Naphthothiophenes
TMS N N N i) Cl ii) O Cl SH ZnCl2 Toluene reflux 0.5 h Bt S

56% S (R = PhCH2) t-BuOK t-BuOH / THF

BuLi, -78 C, 2h

O Bt S

Bt Li
RCl, -78 oC

R Bt R = Me3Si, 83% R = PhCH2, 76%

S
PhNCO -78 oC H N Ph O S Zn / AcOH THF S Bt H N Ph O
i)

S
O

ii) HCl Ph

S 48%

A. R. Katritzky, V. Yu. Vvedensky, D. O. Tymoshenko, unpublished results

20

Benzannulated and 2-Arylethenyl - Heterocycles

R1 R2 S N NH2

Bt N S N

R4
R1

R3COCH=CHR4 EtONa / EtOH S

N N

R2 59-86% (8 examples)

R1

Bt
R

R2 R3 59-74% (5 examples) Ar

O Bt Cl

NH2

N R

ArCH2Cl BuLi / t- BuOK

N R

43-76% (7 examples)
R

Bt
Me

71-74% (2 examples)
R R3COCH=CHR4 1) BuLi 2) HCl
4

N R

R 54-66% (5 examples) ArCH2Cl BuLi / t-BuOK Ar

54-57% (5 examples)

70% (2 examples) R

21

A. R. Katritzky, D. O. Tymoshenko, D. Monteux, V. Vvedensky, G. Nikonov, unpublished results

Regioselective Synthesis of Polysubstituted Pyrazoles and Isoxazoles

2

Bt RNHNH2 51-80% (5 examples) R1

R N

R2 NaH R1 N

Bt R1

N N 50-90% (7 examples) R R R = Me, Ph; R1, R2 = aryl, heteroaryl R = Me, Ph; R1, R2 = aryl, heteroaryl
n-BuLi

MeI Bt Me N R R N
2

Me NaH R1 N R

R2 N R = Me, Ph; R1= Ph, Tol; R2 = Ph 85-99% (3 examples)

R = Me, Ph; R1= Ph, Tol; R2 = Ph 71-95% (3 examples) R1

A. R. Katritzky, M. Wang, M. V. Voronkov, unpublished results.

22

Preparation of 2-Aminothiophenes and 2-Alkylthiopyrroles

Bt i) n-BuLi Bt ii) R X
1

i) n-BuLi ii) R NCS

2

Bt R1 H N R
2

R3I
S

Bt R1 N R2 S

R3

R1

EtO EtO

BtH (R1 = OEt)

ZnBr2 CH2Cl2 R1

R1 = alkyl, OEt R2 = aryl; R3 = Me 59-80% (10 examples)

R = alkyl, aryl R2 = aryl R2 N R3 = H, Me 41-80% (6 examples) R3

R1 S R1 = OEt R2 = aryl; R3 = Me R 3S 21-65% (6 examples) N R2

A. R. Katritzky, X. Wang, A. Denisenko, unpublished results

23

Preparation of 5-Aminothiazoles
Bt N R1 n-BuLi R1 THF -78 oC R _ + N Bt Li
1

R CHO

BtH NH3

R NCS
R1

R2

_ S N Bt R1
- BtLi

R1 + NLi

R1 R
2

N R1 S

R1 N R2

N R1 S

N H

R1 = aryl, thien-2-yl; R2 = aryl; 35-81% (13 examples)

A. R. Katritzky, X . Wang, R. Maimat, unpublished results

24

Preparation of Thiazolotriazoles
Earlier Methods:
(i) R1 N NH N H S + R
2

R3
Hal O R
3

PPA

N N R1 N S

R2

91EJMC929 97BMC57

(ii)

S NHCHO PPA + _ N OMes NH2

S N N N 74BSCB459

O R
1

R2

N N

O S

R2 N N toluene N 90 oC N N S N

O R1

R1 = aryl, aroyl; R2 = aryl, heteroaryl; 12-51% (12 examples)

A. R. Katritzky, A. Pastor, M. Voronkov, P. J. Steel, 000OL429

25

Regioselective Synthesis of Nicotinonitriles and Pyrazoles

_ Cl
Me O R R
1

+ N N Me N N NC R R1 50-75% (13 examples) N

NH2 + NC Me

TiCl4 59-84% (13 examples)

NC R R
1

NH2

THF, reflux

R = alkyl, aryl, benzyl R1 = H, alkyl, benzyl

_ Cl N N N

+ N + R1

Pr N THF, rt -benzotriazole R2

H + Pr _ N Cl R
1

N R
2

N2H4. H2O rt - PrNH2 - Me2NH. HCl

H N N R1 R2 R1, R2 = alkyl, benzyl 15-83% (12 examples)

A. R. Katritzky, A. Denisenko, M. Arend, 99JOC6076 and unpublished results

26

Synthesis of 1,2,3-Thiadiazoles
Bt OMe OMe TsNHNH2 Bt N Bt O Ph TsNHNH2 R
1

R SOCl2 N N S

R1 R2XH N N S X R2

NH Ts

Bt NaH

R1 = H, 78% R1 = Ph, 80%

R1 = H, 84% R1 = Ph, 85% DMF, (R = Ph) _ N S N+ 39%

X = O, S R1 = H, Ph; R2 = Ar, PhCH2 5 examples yields = 24 - 68%

Ph

A. R. Katritzky, D. O. Tymoshenko, G. Nikonov, unpublished results

27

Applications in Solid-Phase Synthesis of Pyridines and Pyrimidines

R4 = H BtCH2CN + 3 R NHR4 Bt NH NR3R4 i) H3COC2H4OH 80 oC 24 h O ii) R
H
2

H N

R3

50% TFA CH2Cl2 rt, 1h

HO

H N

R3

R4
N R N
4

R2

R3

HO 50% TFA CH2Cl2 rt, 1h

O O R2 THF

R4 = Alkyl
R4

R4 N

R3

MeONa

R2

O DMA 100 oC 24 h R1 O R2 HN NH2 R2

50% TFA CH2Cl2 rt, 1 h

R1 N R2 N

N N R1

79-93%

OH

A. R. Katritzky, L. Serdyuk, C. Chassaing, D. Toader, X. Wang, B. Forood, B. Flatt, C. Sun, K. Vo, 000JCC182

28

Solid-Phase Synthesis of 2-Pyridones

O HO Me

O O Me

OH DIAD PPh3 NMM

R1C6H4CHO MeOH THF

O O

R1

O Bt O
O HN HO R2 50% TFA DCM
HO
2

NH2
50% TFA DCM O

R NaOH / EtOH / THF

HN O
R1 R1 = Me, OMe, F; R2 = H, Me, Et purity 90-95% yields 79-87%

R2

R1
Purity 95% Yields 81-92% (3 examples)

R1

A. R. Katritzky, C. Chassaing, S. J. Barrow, Z. Zhang, V. Vvedensky, B . Forood, et. al., unpublished results
29

Homologation of Carboxylic Acids

Arndt-Eistert Reaction
O R OH i) SOCl2 or PCl3 ii) CH2N2 / ether R O N2 cat. Ag+ R OH O

Bt-Assisted Homologation
O R Cl O R
1
OMe R'OH 4 Bt HCl

OTf Bt Tf2O lutidine R

2

Bt

SiMe3

H Bt

MeONa

R 3

Bt

Isolated yields, %

MeONa CH3CN

O R 5 R' = Me, Et OR'

R Ph 4-ClC6H4 n-C7H15

1 85 83 95

2 95

3 98

4 86

5 89

81 97 90

94 98

--* --* 49

A. R. Katritzky, S. Zhang, Y. Fang, unpublished results

* the intermediates 3 and 4 were not isolated

30

Acknowledgments
Australia Darren Cundy Scott Henderson Richard Musgrave Nassem Peerzada Paul Savage Adam Wells Austria Isolde Puschmann Belgium Annie Mayence Chris Stevens J.-J. Vanden Eynde Columbia Rodrigo Abonia Egypt Saad El-Zemity Fatma Mahni Ashraf Abdel-Fattah Samia Agamy France Catherine Garot Olivier Lingibe Jean-Luc Moutou David Pleynet Delphine Semenzin Christophe Chassaing Daphne Monteux Sophie Busont Ghana Augustine Donkor China Weilang Bao He-Xi Chang Jie Chen Yaxing Chen Dai Cheng Xilin Cui Weihong Du Wei-Qiang Fan Yunfeng Fang Daming Feng Hai Ying He Qing-Mei Hong Tan Bao Huang Zhizhen Huang Fu Bao Ji Jinlong Jiang Xiangfu Lan Hengyuan Lang Kam Wah Law Jinqung Li Qiu-He Long Ping Lue Zhushou Luo Rexiat Maimait Ming Qi Guofang Qiu Huimin Song Jin Wang Junquan Wang Xiaojin Wang Zuoquan Wang Hong Wu Jiaxing Wu Jing Wu Linghong Xie Baozhen Yang UK Slovenia Poland Peter Leeming Sonja Strah Zbigniew Najzarek Julian Levell Maria Paluchowska Julie Thomson So. Africa Juliusz Pernak Jaco Breytenbach Boguslaw Pilarski Jamaica Ukraine Nazira Karodia Keisha Gay Hylton Bogumila Rachwal Sergei Belyakov Stanislaw Rachwal Anna Denisenko So. Korea Danuta Rasala Japan Sergei Denisenko Young-Seuk Hong Kunihiko Akutagawa Frank Saczewski Boris Rogovoy Yasuhisa Matsukawa Jadwiga Soloducho Alina Silina Kazuyuki Suzuki Mirek Szafran Spain Germany Larisa Serdyuk Ichiro Takahashi Maria Szajda Pilar Cabildo Michael Arend Leszek Wrobel Justo Cobo-Domingo Alexander Sorochinsky Torsten Blitzke Dmytro Tymoshenko Jordan Balbino Mancheno Peter Czerney Pakistan Shibli Bayyuk Alfredo Pastor-del-Castillo Aldo Jesorka Amir Afridi Olga Rubio-Teresa USA Simona Jurczyk Muhammad Latif Ken Caster New Zealand Jens Koeditz Sudan Peter Steel Terry Davis Romania Ahmad Yagoub M. Drewniak-Deyrup Greece Diana Aslan Nigeria Kenny Heck John Gallos Switzerland Mircea Darabantu Clara Fali Craig Hughes K. Yannakopoulou Frederick Brunner Ion Ghiviriga Glen Noble Daniela Oniciu Palestine Rick Offerman Hungary Syria Dorin Toader Abd Ferwanah Daniel Nicols Ferenc Soti Mohammed Soleiman Ioan Silberg John Stevens Laszlo Urogdi Panama Doug Tatham UK Russia Herman Odens India Steve Allin Olga Denisko M. Balasubramanian Richard Barcock Mikhail Gordeev Poland Vandana Gupta Mike Black Alexy Ignatchenko Piotr Barczynski Jamshed Lam Andy Briggs Alexander Lesin Joanna Borowiecka Negeshwar Malhotra Martin Button Valery Mortikov Jacek Brzezinski T. Mayelvaganan Kevin Doyle George Nikonov Zofia Dega-Szafran Subbu Perumal John Greenhill Irina Scherbakova Barbara Galuszka Mungala Rao Philip Harris Sergei Verin Andrzej Jizwiak Shamal Mehta Gregory Hitchings W. Kuzmierkiewicz Michael Voronkov India Navayath Shobana Sutha Vellaichamy China Zhijun Yang Guo-Wei Yao Jiangchao Yao Gui-Fen Zhang Lianhao Zhang Yongmin Zhang Zhongxing Zhang Xiaohong Zhao Lie Zhu

31

Financial Support
3M Corporation St. Paul, MN; Austin, TX Harlow, UK; Ferrania, Italy Abbott Laboratories, Chicago, IL Agrevo, Germany Aldrich/Sigma-Aldrich, WI Arcadia, Denmark Army Research Office Athena, San Francisco, CA BASF, Ludwigshafen, Germany Bayer, West Haven, CT Boehringer, Ingelheim, CT Bristol-Meyers Squibb, CT Centaur, CA Ciba-Geigy, Greensboro, NC COR Therapeutics, CA Cyanamid, Princeton, NJ Dow-Elenco, Indianapolis, IN Dupont Agro, DE Exxon Corporation, Baton Rouge, LA; Linden, NJ Clinton, NJ; Abingdon, UK Flexsys, Akron, OH Fisons, Rochester, NY FMC Corporation, Princeton, NJ Glaxo-Wellcome, UK & France Geo-Centers, Hopatcong, NJ Lancaster, UK and Gainesville, FL Merck, Rahway, NJ Monsanto, Nutrasweet, Chicago, IL New Technology, Chicago, IL Nippon Soda, japan NSF, Washington, DC Organon, Netherlands Parke-Davis, MI Pfizer, CN Pharmos, Alachua, FL Procter and Gamble, OH Reilly Industries, Indianapolis, IN Rhone-Poulenc, Research Triangle, NC Rohm and Haas RW Johnson Research, NJ Sandoz, Charlotte, NC Schering-Plough, NJ SDS Biotech, Tokyo, Japan Sigma-Aldrich, WI Solutia, St. Louis, MO SPECS, Holland Sterling Wintrop, Malvern, PA Trega, San Diego, CA Tularik Upjohn Corp., Kalamazoo, MI Warner-Lambert, Ann Arbor, MI Zenneca, UK 32

The Magic of Benzotriazole

N N N H

1. Inexpensive and easily introduced into organic molecules. 2. Conveys multiple activating influences on molecule to which it is attached. 3. Benzotriazole is intrinsically unreactive and stable. 4. Benzotriazole exhibits desirable physical and innocuous biological properties. 5. Readily removed from the molecules and can be easily recovered and recycled. 6. Adaptable to solid phase synthesis: resin available for Novabiochem.

33