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Acylation and Related Transformations

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1 Acylation and Related Transformations
1 Acylation and Related Transformations Alan R. Katritzky, Kazuyuki Suzuki, Ashraf A. Abdel-Fattah, Rachel Witek, Chunming Cai University of Florida, Center for Heterocyclic compounds Lecture presented in 2005 Reviews of Benzotriazole Chemistry Early Reviews: [91T2683] “Benzotriazole: A novel Synthetis Auxiliary” [94ACA31] “Benzotriazole-Stabilized Carbanions: Generation, Reactivity, and Synthetic Utility [94Sip] “Benzotriazole as a Synthetic Auxiliary: Benzotriazolylalkylations and Benzotriazole Mediated Heteroalkylation” [94CSRsub] “Benzotriazole Mediated Arylalkylation and Heteroalkylation” Review Comprehensive through 1996: [98CR409] “Properties and Synthetic Utility of N-Substituted Benzotriazoles” (includes 403 references of which 253 are from our group) More Recent Reviews: [98AA33] “Benzotriazole-Based Reagents for Efficient Organic Synthesis” [99T8263] “Benzannulations [98CCCC599] “Michael Additions of Benzotriazole-Stabilized Carbanions” [98T2647] “ The Generation and Reactions of Non-Stabilized a-Aminocarbanions” [00PAC1597] “Designing Efficient Routes to Polyfunctionality” [01SL458] “The preparation of Mono-, 1,1-Di-, trans-1,2-Di- and Tri-Substituted Ethylenes by Benzotriazole Methodology” [03CEJ4586] “Benzotriazole:An Ideal Synthetic Auxiliary”

2 Acylation in Organic Synthesis
2 Scope: on Nitrogen  Amides, especially peptides Sulfur  Thiol esters Oxygen  Esters Carbon  Ketones Reagents for Acylation — Activated Derivatives of Carboxylic Acid Acid chloride or Anhydride Activated ester or Amide From acid via non-isolated activated derivatives Disadvantages of Common Acylation Agents Sensitivity to water — precludes use of aqueous solutions Problems in handling, storage, weighing Lack of chiral stability Incompatibility of other functionality Acylazoles or Azolides — Staab ca. 1961 Especially acylimidazoles

3 Preparation of N-Acylbenzotriazoles direct from Carboxylic Acids
3 Preparation of N-Acylbenzotriazoles direct from Carboxylic Acids 1. Use of Counter-attack reagent (00JOC8210) 2. Via Sulfinyl-bisbenzotriazole (03S2795)

4 N-Acylbenzotriazoles: Aliphatic,
Aromatic, Heteroaromatic 4 RCOBt mp Yield HCOBt 94-96 71 CH3COBt 49-51 92 C2H5COBt 73-74 C3H7COBt 62-63 79 n-C4H9COBt 42-44 83 Me2CHCOBt Oil 91 tBuCOBt 71-72 94 tBuCH2COBt 56-57 C5H11COBt 96 n-C15H31COBt 54-55 89 tBuCH2CHMeCH2COBt 86 PhCH2COBt 65-66 84 Ph2CHCOBt 88-89 PhCH2CH2COBt 63-64 PhCOBt 93 4-CH3C6H4COBt 2-CH3OC6H4COBt 96-97 72 4-CH3OC6H4COBt 104 RCOBt mp Yield 4-ClC6H4CH2COBt 90-91 64 3-ClC6H4COBt 74 4-ClC6H4COBt 4-BrC6H4COBt 93 4-FC6H4COBt 119 98 4-NO2C6H4COBt 83 4-Et2NC6H4COBt 86-87 85 4-HOC6H4COBt 84 RCOBt mp Yield 87-89 88 84 76 90 92 205 82 191 189 54 95 CCl3COBt 78 98 CF3COBt 89-91 70 CF3CF2CF2COBt oil 86 BtCOCOBt 92 BtCOBt 90 92 97 75 98-100 91

5 N-Acylbenzotriazoles From Unsaturated, Functionalized and Bis-acids
5 RCOBt mp Yield oil 83 CH3CH=CHCOBt 87-88 86 PhCH=CHCOBt 96 HC≡ CCOBt 99-100 PhC≡ CCOBt 92 BrCH2COBt 91-92 87 Cl2CHCOBt CH3OCH2COBt PhSCH2COBt 90 PhCOCOBt 72-73 72 82 BtCO(CH2)4COBt 75 BtCO(CH2)18COBt 63 MeO2C(CH2)3COBt 51-52 300 77 RCOBt mp Yield 95 98 96 90 183 65 56 91-92 86 59 RCOBt mp Yield 94 247 16 60 80 98-100 40 98 87

6 N-Acylbenzotriazole Derivatives from N-Protected Amino Acids
(No Extra Functionality)-All solid, m.p.s in range of 50~180 oC. 6 Amino Acid N-Protecting Group Structure of N-Acylbenzotriazole Yield ee.* L-Gly Cbz Cbz-Gly-Bt 99 >97 L-Ala Boc Boc-Ala-Bt 61 Cbz-L-Ala-Bt 95 Fmoc Fmoc-L-Ala-Bt 79 Tfa Tfa-L-Ala-Bt 76 D-Ala Cbz-D-Ala-Bt 90 DL-Ala Cbz-DL-Ala-Bt 94 L-Val Boc-L-Val-Bt 83 Cbz-L-Val-Bt 91 Amino Acid N-Protecting Group Structure of N-Acylbenzotriazole Yield ee.* L-Phe Boc Boc-L-Phe-Bt 81 >97 Cbz Cbz-L-Phe-Bt 88 Fmoc Fmoc-L-Phe-Bt 83 Tfa Tfa-L-Phe-Bt 82 L-Leu Cbz-L-Leu-Bt 66 95 L-Ileu Cbz-L-Ileu-Bt L-Pro Cbz-L-Pro-Bt 74 * e.e. values were estimated in NMR and HPLC analysis by preparing a dipeptide for each N-aminoacylbenzotriazoles. (04S2645)(04S1806)(05S397)(In Preparation)

7 N-Acylbenzotriazole Derivatives from N-Protected Amino Acids with Functionality
7 Structure of N-Acylbenzotriazole Functionality Yield ee.a Cbz-L-Trp-Bt Indole NH 95 >97 Cbz-L-Tyr-Bt Phenol OH 86 Cbz-L-Gln-Bt Amide NH2 72 Cbz-L-Cys-Bt SH 76 Cbz-L-Asn-Bt Cbz-L-Asp(OMe)-Bt CO2Me 82 Cbz-L-Met-Bt CH2SMe >99 Cbz-L-His-Bt Imidazole NH 70b >95c Structure of N-Acylbenzotriazole Functionality Yield ee.a Fmoc-L-Trp-Bt Indole NH 90 >97 Fmoc-L-Met-Bt CH2SMe 87 Fmoc-L-Ser-Bt Alcoholic OH 68 Tfa-L-Asp(OMe)-Bt CO2Me 80 Tfa-L-Glu(OMe)-Bt 82 Di-Bt derivatives Structure of N-Acylbenzotriazole Functionality Yield ee.a Z-L-Cystine-Bt S-S dimer 90 >97 Z-L-Asp-diBt Two COBt 87 Z-L-Glu-diBt 68 a: e.e. values were estimated in NMR and HPLC analysis by preparing a dipeptide for each N-aminoacylbenzotriazoles. b; Characterized as amides. c; Determined on amides in NMR (05S397) (In Preparation)

8 N-Acylbenzotriazole Derivatives from N-Protected Dipeptides
8 N-Acylbenzotriazole Derivatives from N-Protected Dipeptides Entry Product Yield (%) Mp (oC) e.e.* 1 Z-L-Ala-L-Phe-Bt 90 148149 95 2 Z-L-Phe-L-Ala-Bt 85 180181 3 Z-L-Phe-D-Ala-Bt 156157 4 Z-L-Trp-L-Ala-Bt 78 176177 5 Z-L-Trp-L-Trp-Bt 76 152154 6 Z-L-Met-L-Ala-Bt 104105 7 Z-L-Met-D-Ala-Bt 87 135137 *e.e. was estimated in 1H NMR. (04S2645)(04S1806)(05S397)

9 Virtues of Acylbenzotriazoles
9 Preparation: (i) RCOCl + BtH + base  RCOBt (ii) RCO2H + NEt3 + BtSO2Me  [RCOOSO2Me + Bt]  RCOBt (iii) RCO2H + BtH (3 equiv) + SOCl2  RCOBt (via BtSOBt) Scope  Prepared from a very wide range of Acids (see previous slides) Advantages: (i) Solids, highly crystalline compounds (ii) Soluble in organic solvents (iii) Non-hydroscopic, stable in air, can be weighed out, and stored indefinitely (iv) Can be used in aqueous media (v) Compatible with wide range of functionality (vi) Chirally stable for long periods (vii) Selectivity (e.g.  diketones, not vinyl esters) (viii) Prepared directly from RCO2H in near quantitative yields (ix) Benzotriazole reagent easily recovered and recycled Utility: (i) Peptide synthesis in aqueous media (ii) Peptide synthesis with diverse unprotected functionality (iii) Efficient S-acylation (iv) O-Acylation (v) Wide range of C-acylation

10 N-Acylation: Amides from N-acylbenzotriazoles
Secondary amides RCONHR R R’ Yield(%) 4-ClC6H EtCH(CH3) 4-ClC6H C6H 4-Et2C6H n-C4H C6H t-C4H 2-Furanyl n-C4H 1-Naphthyl n-C4H 2-Pyridyl CH3OC6H 4-Pyridyl EtCH(CH3) 2-Pyrazinyl (CH3)3C Ph2CH C6H 10 Primary amides RCONH2 R Yield(%) C6H 2-CH3OC6H 3-ClC6H 4-NO2C6H 2-Furanyl 1-Naphthyl 2-Pyridyl 3-Pyridyl 4-Pyridyl 2-Pyrazinyl PhCH PhCH2CH Ph2CH n-C4H Tertiary amides RCONRR R R’ R” Yield(%) 4-CH3C6H C2H C2H 4-NO2C6H (CH2)4 C6H (CH2)4 2-CH3OC6H (CH2)4 2-Furanyl C2H C2H 1-Naphthyl (CH2)4 4-Pyridyl (CH2)4 PhCH (CH2)4 Ph2CH (CH2)5 (00JOC8210) For reactions with Wang resin linked amines see 02BMCL1809

11 Chiral Integrity of Peptide Synthesis
Preparation of N-(Boc acylamino)amides 11 1. The NMR method 2. The chiral column method HPLC: Performed on Beckman system gold with Chirobiotic T column, detection at 254 nm, flow rate of 1.0 mL/min, and MeOH/H2O (50:50) L,L R.Time L,D Cbz-L-Tyr-L-Phe-OH 10.8 Cbz-L-Tyr-D-Phe-OH 11.7 Cbz-L-Trp-L-Ala-OH 11.0 Cbz-L-Trp-D-Ala-OH 12.9 Fmoc-L-Trp-L-Ala-OH 11.1 Fmoc-L-Trp-D-Ala-OH 13.6 Cbz-L-Cys-L-Phe-OH 11.5 Cbz-L-Cys-D-Phe-OH 24.3 Cbz-L-Met-L-Ala-OH 10.9 Cbz-L-Met-D-Ala-OH 15.9 Cbz-L-Gln-L-Phe-OH Cbz-L-Gln-D-Phe-OH 1H NMR of Boc-Valine derivatives (02Arkivoc(viii)134) R.Time = Retention Time (05S397)

12 Methods of Peptide Preparation
12 Stepwise coupling: Fragment coupling: (04S2645)

13 Preparation of Dipeptides
13 Cbz-L-Met-L-Ala-OH 95 >97 Cbz-L-Met-D-Ala-OH Cbz-L-Met-L-Met-OH Cbz-L-Met-L-Trp-OH 82 Cbz-L-Met-L-Glu-OH 60 Cbz-L-Gln-L-Phe-OH 72 Cbz-L-Gln-L-Gln-OH 47 Cbz-L-Gln-L-Val-OH Fmoc-L-Trp-L-Ala-OH 70 Fmoc-L-Trp-L-Ser-OH 87 Fmoc-L-Met-L-Ser-OH 88 Fmoc-L-Met-L-Glu-OH 93 Chiral Dipeptides Yield(%) ee.a Cbz-L-Ala-L-Phe-OH 90 >97 Cbz-L-Ala-L-Ser-OH 85 Cbz-L-Ala-L-Trp-OH 97 Cbz-L-Val-L-Phe-OH 98 Cbz-L-Val-L-Trp-OH 96 Cbz-L-Phe-L-Ala-OH Cbz-L-Phe-L-Val-OH 95 Cbz-L-Phe-L-Phe-OH Cbz-L-Phe-L-Ser-OH Cbz-L-Tyr-L-Phe-OH 86 Cbz-L-Tyr-L-Trp-OH 60 Cbz-L-Trp-L-Ala-OH Cbz-L-Trp-L-Cys-OH Cbz-L-Trp-L-Ser-OH Cbz-L-Trp-L-Trp-OH Cbz-L-Cys-L-Ala-OH Diastereomeric mixture of Dipeptide Yield Cbz-L-Tyr-DL-Phe-OH 86 Cbz-L-Trp-DL-Ala-OH 98 Cbz-L-Cys-DL-Ala-OH 71 Cbz-L-Met-DL-Ala-OH 72 Cbz-L-Gln-DL-Phe-OH 74 Fmoc-L-Trp-DL-Ala-OH 68 a:e.e. value was estimated by 1H NMR and HPLC analysis. (05S397) (In Preparation)

14 and Tetra -Peptides Preparation of Tri-, (04S2645) (In progress) 14
Tripeptides Yield (%) ee.a Cbz-L-Ala-L-Gly-L-Leu-OH 93 >97 Cbz-L-Ala-L-Phe-L-Trp-OH 95 Cbz-L-Val-L-Gly-L-Leu-OH 85 Cbz-L-Phe-L-Gly-L-Gly-OH 98 Cbz-L-Phe-L-Ala-L-Ala-OH 92 Cbz-L-Phe-L-Ala-L-Ser-OH 94 Cbz-L-Trp-L-Ala-L-Cys-OH 86 Cbz-L-Trp-L-Trp-L-Try-OH 87 33 Cbz-L-Met-L-Ala-L-Ala-OH Cbz-L-Met-L-Ala-L-Ser-OH 83 64 Cbz-L-Met-L-Ala-L-Trp-OH 60 Cbz-DL-Ala-L-Gly-L-Leu-OH b Cbz-L-Met-DL-Ala-L-Ala-OH (04S2645) (In progress) Tetrapeptides Yield (%) ee.* Cbz-L-Phe-L-Ala-L-Gly-L-Leu-OH 86 >97 Cbz-L-Ala-L-Phe-L-Gly-L-Leu-OH 85 a:The ee. value was estimated by 1H NMR and HPLC analysis. b; Diastereomeric mixture

15 Synthesis of Weinreb amides and Hydroxamic acids
(02ARK39) (03S2777) Synthesis of Chiral 1,2,4-Oxadiazoles (05ARK, In press)

16 N-Acylation of Sulfonamides
15b (02ARK14) Microwave-assisted Preparation of Oxazolines and Thiazolines (04JOC811)

17 S-Acylation Previous methods and their difficulties
16 S-Acylation Previous methods and their difficulties Acyl halides with thiol sodium salts  low yields Couplings of acyl halides and thiols with catalysts (thallium, tin mercaptides, or Zinc)  limited by substrate specificity Activation of RCO2H by diphosgene or polyphosphate ester  low yield, harsh conditions Use of thiocyanate, instead of thiol  limited by availability of S.M. Couplings of RCO2H and thiols with carbodiimides (e.g. DCC)  difficulty in removal of urea.

18 S-Acylation Synthesis of Thiol esters
17 *The crude product was obtained in 90% yield. Pg-Phe-SR Yield (%) mp (oC) Boc-Phe-SPh 76 102103 Boc-Phe-SCH2Ph 97 9293 Boc-Phe-SCH2CO2Et 85 7778 Cbz-Phe-SPh 86 100101 Cbz-Phe-SCH2Ph 93 119120 Cbz-Phe-SCH2CO2Et 84 5556 Cbz-Phe-SCH2CO2H 94 9899 (04S1806)

19 O-Acylation O-Acylated steroids, terpenes, sugars, and lipids
18 O-Acylation O-Acylated steroids, terpenes, sugars, and lipids (Unpublished work)

20 C-Acylation (i) Aryl and Heteroaryl Rings
19 C-Acylation (i) Aryl and Heteroaryl Rings (03JOC5720)(04CCA175) (In progress)

21 C-Acylation (ii) Ketones,
20 C-Acylation (ii) Ketones, Sulfones, Nitrocompounds and Imines (00JOC3679) 16 examples (Average isolated yield 75%) R1 = alkyl or aryl R2 +R3 = alkyl or alicyclic R1 = alkyl or (hetero)aryl R2 = hydrogen, alkyl, vinyl or aryl R3 = alkyl or aryl (03JOC1443) 18 examples (Average isolated yield 80%) (In Progress) 14 examples (Average isolated yield 67%) R1 = alkyl or (hetero)aryl R2 = hydrogen, or alkyl (00S2029) 16 examples (Average isolated yield 62%) R1 = alkyl, alkenyl or aryl R2 = alkyl, or aryl R3 = alkyl (acyclic or alicyclic)

22 C-Acylation (iii) Heteroaryl Alkyl Groups
21 C-Acylation (iii) Heteroaryl Alkyl Groups (In Progress)

23 C-Acylation (iv) -Keto Esters
and -Diketones 22 (04JOC6617)

24 Thioamides 23 Drawbacks of Route A: Drawbacks of Route B:
(i) Lawesson’s reagent is expensive, and the large amount of reagent-derived byproducts which accompany its reactions can only be removed by chromatography. (ii) 1,1-thiocarbonyl diimidazole is unstable and decomposes after 28 days of storage at room temperature. Drawbacks of Route B: (i) Necessity of synthesizing thiocarbamic acid thioanhydride. (ii) Instability of alkyl isothiocyanates. (iii) Use of expensive metal catalyst and lack of commercially available thiocarbamoyl chlorides with substituents other than N,N-dimethyl.

25 Benzotriazole-Based Thioacylation Reagents
Rapoport’s method for the 24 Benzotriazole-Based Thioacylation Reagents Preparation of Thiocarbonyl-1H-6-nitrobenzotriazoles RCSBt: Synthesis of Thioacylbenzotriazoles from Grignards (96JOC9045) 6 examples:56-67 % yields (99JOC1065) 9 examples: % yields (Unpublished results) 7 examples: 44-78% yields R % Yield 4-Tolyl 63 4-Methoxyphenyl 89 Phenyl 76 RR1NCSBt: Preparation of Thiocarbamoylbenzotriazoles ROCSBt: Synthesis of Alkyl/Aryloxythiocarbonylbenzotriazoles 2 R R1 % Yield MP (oC) a Cyclohexyl H 85 128–130a b Furfuryl 94 119–120a c (R)-Methylbenzyl 87 oila d Phenethyl 89 112–113 e t-Butyl 60 61–63 f 1,5-Dimethylhexyl g -CH2CO2CH3 76 129–130 h 2,3-Dihydroindolyl =R1 84 123–124 i Pyrrolidinyl 86–87 j Phenyl Methyl 92 137–138 k Ethyl 98 oil l n-Butyl RSCSBt: Synthesis of Alkyl/Arylthiothiocarbonylbenzotriazoles

26 Thioacylations with Benzotriazole Reagents
25 Thioacylations with Benzotriazole Reagents ([04JOC2976] and unpublished work) Synthesis of Thioureas from Thiocarbamoylbenzotriazoles Synthesis of Thioamides from Thioacylbenzotriazoles 15 examples: average yield 89 % 6 Examples: average isolated yield 87 % Bis-(benzotriazolyl)methanethione One-pot Syntheses of Thioureas: Synthesis of Thioamides, Thiocarbamates, and Dithiocarbamates from Thiocarbamoylbenzotriazoles 17 examples: average yield 84 % 9 examples: average isolated yield 71% 2 examples: 59 and 60 % yields Thionesters and Thiocarbamates from Aryloxythioacylbenzotriazoles 73% yield 4 examples: average yield 84 % R =R1 Morpholinyl 70% R = Benzyl R1 = H 85%

27 Imidoylation-Scope Scope: on - Nitrogen ---Amidines, Guanidines
26 Scope: on - Nitrogen ---Amidines, Guanidines - Carbon Imines - Sulfur Imidothioformate Agents for imidoylation - Imidolyating agents Imidoyl chlorides, imidate fluoroborates, and iminium triflates - Guanidylating agents Will be discussed in detail later Benzotriazole derivatives for imidoylations - (a) Imidoylbenzotriazoles - (b) (bis-benzotriazol-1-yl-methylene)amines - (c) benzotriazole-1-carboxamidines

28 Reagents for the Preparation of Amidines
27 Reagents for the Preparation of Amidines Conventional methods Preparation of Imidoylbenzotriazoles 99OL577, 12 examples Yield: 20-87% 01JOC1043 6 examples Yield: 71-99% Imidoyl chlorides are generally prepared in situ, but they are extremely labile toward hydrolysis and side reactions have been reported at elevated temperatures. Iminium triflates and imidate fluoroborates require handling under inert atmosphere and cannot be isolated or purified. 95H231, 10 examples Yield: 15-75% 01JOC2865 11 examples Yield: 87-99% 04JOC5108, 9 examples Yield: 40-90% Imidoylbenzotriazoles are good substitutes for imidoyl chlorides. 90CB1545, 8 examples Yield: 38-96%

29 A Facile Preparation Method for Imidoylbenzotriazoles
28 Entry R1 R2 Yield (%) 6a Me Ph 75 (B) 6j 88 (A) 6b p-Tolyl 65 (B) 6k 82 (A) 6c Bn 62 (B) 6l 2-furyl 84 (A) 6d 56 (B) 6m p-MeOC6H4 6e PhCH2CH2 64 (B) 6n 93 (A) 6f PhCH2 57 (B) 6o 78 (A) 6g n-C6H13 6p 2-Furylmethyl 6h 2-Pyridyl 76 (A) 6q Cyclohexyl 95 (A) 6i p-O2NC6H4 6r 79 (A) Conditions for Route A and B Route A: amide (1 eq) + SOCl2 (2 eq) + BtH (4 eq); Solvent, CHCl3; Microwave, 80 oC, 80 W, 10 min. Route B: 1) amide (1 eq) + (COCl)2 + pyridine (1 eq), 0 oC, 15 min; solvent, CH2Cl2 2) BtH (2 eq), room temperature, 4 h

30 Preparation of Polysubstituted Amidines
29 Preparation of Polysubstituted Amidines Entry R R1 R2 R3 Yield (%) 7a Ph Me -(CH2)2O(CH2)2- 76 7b 74 7c Et 88 7d Bn H 77 7e p-Tolyl 89 7f 71 7g 63 7h 72 7i 66 7j 2-Furyl 7k 7l 86 7m 90 7n n-C6H13 78 7o 7p 75 Reaction took place under microwave irradiation, and just needed 10 minutes to finish. Acetic acid acts as a solvent, catalyst, and reactant. 15 amidines are listed here with good to excellent yields. Most amidines were isolated as acetic acid salts. The examples obtained showed the versatility of the method.

31 Literature and First Bt- Guanidylating Agents Literature reagents
30 Literature reagents Early Bt derivatives 95SC1173 01JOC2854 Reagents 6–7 both guanylate primary and secondary amines under mild conditions in high yields. Benzotriazole-1-carboxamidinium tosylate 6 afforded guanidines under mild conditions, in moderate to good yields (55-86%). Benzotriazolylcarboximidoyl chlorides 7 are stable, odorless, and convenient to handle. They afforded guanidines in moderate yields (68-69%). Disadvantages: These reagents must be synthetically prepared, most of them in a multi-step sequence. Harsh reaction conditions are required in some cases to deprotect the protecting groups A large excess of starting amines is in need at times to reach completion of the reaction. Low reactivity at times

32 Second Generation Bt-Mediated Preparation of Guanidines
31 Entry R1 R2 Yield (%) a H Ph 80 b n-C5H11 74 c Bn 68 d -(CH2)4- 71 e -(CH2)2O(CH2)2- f ipr Entry R1 R2 R3 R4 R5 Y (%) a’’ -(CH2)5- Ph 4-MeOC6H4 H 68 b’’ (CH2)2O(CH2)2 78 c’’ 76 d’’ n-Bu 84 e’’ iPr Et PhC2H4 51 f’’ Bn 50 g’’ i-Bu 56 h’’ 70 i’’ 60 j’’ k’’ l’’ 2-Furyl 81 m’’ p-Tolyl 79 n’’ 4-ClC6H4 MeO2CCH(Ph) o’’ -(CH2)4- Entry R1 R2 R3 R4 Yield a’ -(CH2)2O(CH2)2- Ph H 64 b’ p-Tolyl 74 c’ Bn 71 d’ Me 85 e’ -(CH2)4- 68 f’ 4-MeOC6H4 60 g’ iPr 48 (00JOC8080) (01S897)

33 Recent Bt-based Guanidylating Agents
32 Preparation of symmetrical and cyclic trisubstituted guanidines Preparation 5 examples, 77-96% 5 examples, 79-91% Preparation of substituted unsymmetrical guanidines 6 examples, % Starting materials 11 and 13 were prepared through a novel method with good yields 8 examples, 71-99%

34 Imidolylation at Sulfur
33 (01JOC2865) R1 R2 R3 R4 R5 Yield (%) a H -(CH2)2O(CH2)2- 2,5-Cl2C6H3 4-MeC6H4 44 b C6H5CH2 53 c Me Ph 92 d 4-NO2C6H4 e 46 f 4-tBu-2-MeC6H3 75 g iBu 3-NO2C6H4 4-Me C6H4 59 (95H231) R1 R2 R3 Yield (%) a 4-MeC6H4 Ph iPr 90 b Me 77 c 4-MeC6H4 4 PhCH2 91 d 94

35 Imidoylation at Carbon (Ketones)
34 01JOC4041 entry R1 R2 X Yield (%) 3a Ph O 85 3b S 79 3c 4-ClC6H4 87 3d 88 3e 4-BrC6H4 89 3f 98 3g 4-MeC6H4 82 3h 91 3i 96 3j 3k 4-MeOC6H4 84 3l 3m 3n

36 A Safe and Convenient Source of +CN
35 1-Cyanobenzotriazole A Safe and Convenient Source of +CN Preparation of 1-Cyanobenzotriazole 76% 90% (91RRC573) Whitten et al. (88S470) 1-Cyanobenzotriazole as a C-Cyanating Reagent 1-Cyanobenzotriazole as a N-Cyanating Reagent Hughes et al. (98JOC401) 5 examples: % (91RRC573) 7 examples: % yields Drechsler et al. (01JCSPT(2)581) 70% yield

37 Preparation of Sulfonylbenzotriazoles (04JOC1849)
36 Preparation of Sulfonylbenzotriazoles (04JOC1849) Classical Preparation of Sulfonamides: Sulfonylbenzotriazoles: Preparation Disadvanges of Using Sulfonyl Chlorides: Highly reactive and hygroscopic  Problematic to store Requires a base for reactions Many are difficult to access. Synthetic Equivalents to sulfonyl chlorides: O’Connell, J. F. and Rapoport, H. (92JOC4775)

38 Generation of Sulfonamides from Sulfonylbenzotriazoles
Benzotriazole-Assisted Sulfonylation ([94SC205] and [04JOC1849]) 37 3 examples: 87-93% yields 4 examples: 64-99% yields 10 examples: 51-99% yields Generation of Sulfonamides from Sulfonylbenzotriazoles Advantages over existing methods: no need for added base • reaction proceeds at ambient temperatures • Less reactive and more selective than sulfonyl chlorides Selectively sulfonylate a 10 amine over the • Selectively sulfonylate aliphatic amines over aromatic amines

39 Coworkers in Benzotriazole Chemistry 1987-2005
38 Argentina Laura Moyano Australia Darren Cundy Scott Henderson Richard Musgrave Nassem Peerzada Paul Savage Adam Wells Stuart Barrow Austria Isolde Puschmann Azerbaijan Novruz Akhmedov Rena Akhmedova Belgium Annie Mayence Chris Stevens J.-J. Vanden Eynde Brazil Alessandro Soares China Weilang Bao Chunming Cai Xiaohong Cai He-Xi Chang Jie Chen Jun Chen Ke Chen Yaxing Chen Dai Cheng Xilin Cui Weihong Du Wei-Qiang Fan Yunfeng Fang Daming Feng Hai Ying He Qing-Mei Hong Xiang Hong Tan Bao Huang Zhizhen Huang Fu Bao Ji Yu Ji Jinlong Jiang Rong Jiang Xiangfu Lan Hengyuan Lang Kam Wah Law Jinqung Li Lingfei Liu Qiu-He Long Ziwei Lu Ping Lue Zhushou Luo Rexiat Maimait Ming Qi Guofang Qiu Huimin Song Hui Tao Hongbin Tu Jin Wang Junquan Wang Mingyi Wang Xiaoling Wang Zuoquan Wang Hong Wu Jiaxing Wu Jing Wu Linghong Xie Yongjiang Xu Baozhen Yang Hongfang Yang Zhijun Yang Guo-Wei Yao Jiangchao Yao Yeyi Yin Yanhua Yu Gui-Fen Zhang Lianhao Zhang Suoming Zhang Yongmin Zhang Yuming Zhang Zhongxing Zhang Hongyan Zhao Xiaoming Zhao Dazhi Zhong Lie Zhu Columbia Rodrigo Abonia Henry Insuasty Egypt Ahmed El-Sayed Saad El-Zemity Abdel Haleem Hussein Fatma Mahni Ashraf Abdel-Fattah Samia Agamy France Sophie Busont Christophe Chassaing Catherine Garot Jeremy Kister Stephane Ledoux Yves LeGall Olivier Lingibe Daphne Monteux Jean-Luc Moutou David Pleynet Delphine Semenzin Geoffroy Sommen Germany Michael Arend Torsten Blitzke Nicole Clemens Peter Czerney Sebastian Hoffman Aldo Jesorka Simona Jurczyk Jens Koeditz Thomas Kurz Ghana Augustine Donkor Greece John Gallos K. Yannakopoulou Hungary Ferenc Soti Laszlo Urogdi India Parul Angrish M. Balasubramanian Vandana Gupta Ritu Jain Jamshed Lam Suman Majumder Negeshwar Malhotra Kavita Manju T. Mayelvaganan Nabin Meher Shamal Mehta Prabhu Mohapatra Satheesh Nair Subbu Perumal Mungala Rao Navayath Shobana Sandeep Singh Sanjai Singh Shaleindra Singh Srinivasa Rao Tala Ajith Dain Thomas Sutha Vellaichamy Akhilesh Verma Jamaica Keisha Gay Hylton Japan Kunihiko Akutagawa Yasuhisa Matsukawa Kazuyuki Suzuki Ichiro Takahashi Jordan Shibli Bayyuk Lebanon Niveen Khashab New Zealand Peter Steel Nigeria Clara Fali Palestine Abd Ferwanah Panama Herman Odens Poland Piotr Barczynski Joanna Borowiecka Jacek Brzezinski Zofia Dega-Szafran Jacek Doskocz Barbara Galuszka Krzysztof Indzik Andrzej Jizwiak W. Kuzmierkiewicz Zbigniew Najzarek Maria Paluchowska Juliusz Pernak Boguslaw Pilarski Bogumila Rachwal Stanislaw Rachwal Danuta Rasala Frank Saczewski Jadwiga Soloducho Mirek Szafran Maria Szajda Leszek Wrobel Pakistan Amir Afridi Muhammad Latif Romania Diana Aslan Mircea Darabantu Ion Ghiviriga Daniela Oniciu Dorin Toader Ioan Silberg Russia Sergey Bobrov Zoya Demyanets Olga Denisko Mikhail Gordeev Anna Gromova Alexy Ignatchenko Yekaterina Kovalenko Alexander Lesin Valery Mortikov Georgiy Nikonov Irina Scherbakova Alexander Shestopalov Sergei Verin Michael Voronkov Vladimir Vvedensky Slovenia Sonja Strah So. Africa Jaco Breytenbach Nazira Karodia So. Korea Young-Seuk Hong Young Soo Gyong Spain Pilar Cabildo Justo Cobo-Domingo Balbino Mancheno Alfredo Pastor-del-Castillo Olga Rubio-Teresa Sudan Ahmad Yagoub Switzerland Frederick Brunner Syria Mohammed Soleiman Togo Rufine Akue-Gedu Turkey Alaettin Guven Deniz Hur UK Steve Allin Richard Barcock Mike Black Andy Briggs Martin Button Kevin Doyle John Greenhill Dennis Hall Philip Harris Gregory Hitchings Peter Leeming Julian Levell Julie Thomson Ukraine Sergei Belyakov Anna Denisenko Sergei Denisenko Konstantin Kirichenko Natalie Kirichenko Alexander Mitrokhin Boris Rogovoy Alina Silina Larisa Serdyuk Alexander Sorochinsky Dmytro Tymoshenko Anatoly Vakulenko USA Ken Caster Janet Cusido Terry Davis Chris Diebert M. Drewniak-Deyrup Rachel Fuller-Witek Kenny Heck Amy Hayden Craig Hughes Glen Noble Rick Offerman Philip Phelphrey Daniel Nicols Valerie Rodriguez James Rogers John Stevens Doug Tatham Adam Vincek Chavon Wilkerson

40 Katritzky Group Financial Support 1987-2005
39 3M Corporation St. Paul, MN; Austin, TX Harlow, UK; Ferrania, Italy Abbott Laboratories, IL Affymax Agrevo, Germany Aldrich/Sigma-Aldrich, WI Aldrich Zeneca Amgen, CA Arcadia, Denmark Army, Research Office, NJ Athena, CA Aventis Crop Science BASF, Ludwigshafen, Germany Bayer, CT BioVitrum Boehringer, Ingelheim, CT Bristol-Myers Squibb, CT Centaur, CA Ciba-Geigy, NC Coelacanth, NJ COR Therapeutics, CA Cyanamid, NJ Dow Agroscience Dow-Elanco, IN Dupont Agro Chem, DE Dupont Pharma Eli Lilly Exxon Corporation, now ExxonMobil Baton Rouge, LA; Linden, NJ Clinton, NJ; Abingdon, UK Fisons, NY Flexsys, OH FMC Corporation, NJ Geo-Centers, NJ Glaxo-Wellcome, UK & France ImClone, NY Inspire Pharmaceuticals, NC Jansen Lancaster, UK and Gainesville, FL Lion Biosciences, CA L’Oreal Paris, France Maxim Pharmaceuticals Merck, NJ Millenium Monsanto, Nutrasweet, IL New Technology, IL Namiki Shoji, Japan NeurogesX, CA Nippon Soda, Japan Novartis Crop Protection, NC NSF, Washington DC Nutrasweet, IL Organon, Netherlands Parke-Davis, MI Pfizer, CN Pharmacia-Upjohn, MI Pharmos, Alachua, FL Procter and Gamble, OH, FL; UK Reilly Industries, IN Renovis, S. Francisco, CA Rhone-Poulenc, Research Triangle, NC Rohm and Haas, PA RW Johnson Research, NJ Samsung, Korea Sandoz, NC Schering-Plough, NJ Scriptgen SDS Biotech, Japan Senomyx Smith Klein Beecham SPECS, Holland Solutia, St. Louis, MO Sterling Winthrop Inc., PA Trega Biosciences, CA Tularik, CA Univ Alabama Upjohn Corp., MI US Navy, Research Office, CA US Army US Department of Agriculture Warner-Lambert, MI Zeneca, UK

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