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Acylation and Related Transformations Alan R. Katritzky, Kazuyuki Suzuki, Ashraf A. Abdel- Fattah, Rachel Witek, Chunming Cai University of Florida, Center.

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Presentation on theme: "Acylation and Related Transformations Alan R. Katritzky, Kazuyuki Suzuki, Ashraf A. Abdel- Fattah, Rachel Witek, Chunming Cai University of Florida, Center."— Presentation transcript:

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” 1

2 Acylation in Organic Synthesis 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 2 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 – Especially acylimidazoles

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

4 RCOBt mpYield RCOBtmpYield HCOBt CH 3 COBt C 2 H 5 COBt C 3 H 7 COBt n-C 4 H 9 COBt Me 2 CHCOBtOil91 t BuCOBt t BuCH 2 COBt C 5 H 11 COBtOil96 n-C 15 H 31 COBt t BuCH 2 CHMeCH 2 COBt PhCH 2 COBt Ph 2 CHCOBt PhCH 2 CH 2 COBt PhCOBt CH 3 C 6 H 4 COBt CH 3 OC 6 H 4 COBt CH 3 OC 6 H 4 COBt10493 N-Acylbenzotriazoles: Aliphatic, HeteroaromaticAromatic, RCOBtmpYield 4-ClC 6 H 4 CH 2 COBt ClC 6 H 4 COBt ClC 6 H 4 COBt BrC 6 H 4 COBt FC 6 H 4 COBt NO 2 C 6 H 4 COBt Et 2 NC 6 H 4 COBt HOC 6 H 4 COBt CCl 3 COBt7898 CF 3 COBt CF 3 CF 2 CF 2 COBtoil86 BtCOCOBt BtCOBt

5 N-Acylbenzotriazoles From Unsaturated, Functionalized and Bis-acids RCOBtmpYield oil83 CH 3 CH=CHCOBt PhCH=CHCOBt HC≡ CCOBt PhC≡ CCOBt BrCH 2 COBt Cl 2 CHCOBt CH 3 OCH 2 COBt PhSCH 2 COBt PhCOCOBt BtCO(CH 2 ) 4 COBt BtCO(CH 2 ) 18 COBt MeO 2 C(CH 2 ) 3 COBt RCOBtmp Yield RCOBtmp Yield

6 6 N-Acylbenzotriazole Derivatives from N-Protected Amino Acids (No Extra Functionality)-All solid, m.p.s in range of 50~180 o C. Amino Acid N-Protecting Group Structure of N- Acylbenzotriazole Yieldee.* L-GlyCbzCbz-Gly-Bt99>97 L-AlaBocBoc-Ala-Bt61>97 L-AlaCbzCbz-L-Ala-Bt95>97 L-AlaFmocFmoc-L-Ala-Bt79>97 L-AlaTfaTfa-L-Ala-Bt76>97 D-AlaCbzCbz-D-Ala-Bt90>97 DL-AlaCbzCbz-DL-Ala-Bt94>97 L-ValBocBoc-L-Val-Bt83>97 L-ValCbzCbz-L-Val-Bt91>97 * e.e. values were estimated in NMR and HPLC analysis by preparing a dipeptide for each N-aminoacylbenzotriazoles. Amino Acid N-Protecting Group Structure of N- Acylbenzotriazole Yieldee.* L-PheBocBoc-L-Phe-Bt81>97 L-PheCbzCbz-L-Phe-Bt88>97 L-PheFmocFmoc-L-Phe-Bt83>97 L-PheTfaTfa-L-Phe-Bt82>97 L-LeuBocCbz-L-Leu-Bt66>97 L-LeuCbzCbz-L-Leu-Bt95>97 L-IleuCbzCbz-L-Ileu-Bt95>97 L-ProCbzCbz-L-Pro-Bt74>97 (04S2645)(04S1806)(05S397)(In Preparation)

7 N-Acylbenzotriazole Derivatives from N-Protected Amino Acids with Functionality (05S397) (In Preparation) Structure of N- Acylbenzotriazole FunctionalityYieldee. a Cbz-L-Trp-BtIndole NH95>97 Cbz-L-Tyr-BtPhenol OH86>97 Cbz-L-Gln-BtAmide NH 2 72>97 Cbz-L-Cys-BtSH76>97 Cbz-L-Asn-BtAmide NH 2 72>97 Cbz-L-Asp(OMe)-BtCO 2 Me82>97 Cbz-L-Met-BtCH 2 SMe95>99 Cbz-L-His-BtImidazole NH70 b >95 c Structure of N- Acylbenzotriazole FunctionalityYieldee. a Fmoc-L-Trp-BtIndole NH90>97 Fmoc-L-Met-BtCH 2 SMe87>97 Fmoc-L-Ser-BtAlcoholic OH68>97 Tfa-L-Asp(OMe)-BtCO 2 Me80>97 Tfa-L-Glu(OMe)-BtCO 2 Me82>97 Di-Bt derivatives Structure of N- Acylbenzotriazole FunctionalityYieldee. a Z-L-Cystine-BtS-S dimer90>97 Z-L-Asp-diBtTwo COBt87>97 Z-L-Glu-diBtTwo COBt68>97 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 7

8 N-Acylbenzotriazole Derivatives from N-Protected Dipeptides EntryProductYield (%)Mp ( o C)e.e.* 1Z-L-Ala-L-Phe-Bt  149  95 2Z-L-Phe-L-Ala-Bt  181  95 3Z-L-Phe-D-Ala-Bt  157  95 4Z-L-Trp-L-Ala-Bt  177  95 5Z-L-Trp-L-Trp-Bt  154  95 6Z-L-Met-L-Ala-Bt  105  95 7Z-L-Met-D-Ala-Bt  137  95 *e.e. was estimated in 1 H NMR. 8 (04S2645)(04S1806)(05S397)

9 Virtues of Acylbenzotriazoles Preparation: (i) RCOCl + BtH + base  RCOBt (ii) RCO 2 H + NEt 3 + BtSO 2 Me  [RCOOSO 2 Me + Bt  ]  RCOBt (iii) RCO 2 H + BtH (3 equiv) + SOCl 2  RCOBt (via BtSOBt) Scope  Prepared from a very wide range of Acids (see previous slides) 9 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 N-Acylation: Amides from N-acylbenzotriazoles Primary amides RCONH 2 R Yield(%) C 6 H CH 3 OC 6 H ClC 6 H NO 2 C 6 H Furanyl Naphthyl Pyridyl Pyridyl Pyridyl Pyrazinyl 100 PhCH PhCH 2 CH 2 85 Ph 2 CH 90 n-C 4 H 9 72 Secondary amides RCONHR R R’ Yield(%) 4-ClC 6 H 5 EtCH(CH 3 ) 95 4-ClC 6 H 4 C 6 H Et 2 C 6 H 4 n-C 4 H 9 92 C 6 H 5 t-C 4 H Furanyl n-C 4 H Naphthyl n-C 4 H Pyridyl 4-CH 3 OC 6 H Pyridyl EtCH(CH 3 ) Pyrazinyl (CH 3 ) 3 C 100 Ph 2 CH C 6 H 5 70 Tertiary amides RCONRR  R R’ R” Yield(%) 4-CH 3 C 6 H 4 C 2 H 5 C 2 H NO 2 C 6 H 4  (CH 2 ) 4  96 C 6 H 5  (CH 2 ) 4  CH 3 OC 6 H 4  (CH 2 ) 4  98 2-Furanyl C 2 H 5 C 2 H Naphthyl  (CH 2 ) 4  94 4-Pyridyl  (CH 2 ) 4  100 PhCH 2  (CH 2 ) 4  99 Ph 2 CH  (CH 2 ) 5  68 (00JOC8210) For reactions with Wang resin linked amines see 02BMCL

11 11 Chiral Integrity of Peptide Synthesis Preparation of N-(Boc acylamino)amides 1 H NMR of Boc-Valine derivatives (02Arkivoc(viii)134) 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/H 2 O (50:50) L,LR.TimeL,DR.Time Cbz-L-Tyr-L- Phe-OH 10.8Cbz-L-Tyr-D- Phe-OH 11.7 Cbz-L-Trp-L- Ala-OH 11.0Cbz-L-Trp-D- Ala-OH 12.9 Fmoc-L-Trp- L-Ala-OH 11.1Fmoc-L-Trp- D-Ala-OH 13.6 Cbz-L-Cys-L- Phe-OH 11.5Cbz-L-Cys-D- Phe-OH 24.3 Cbz-L-Met-L- Ala-OH 10.9Cbz-L-Met- D-Ala-OH 15.9 Cbz-L-Gln-L- Phe-OH 12.9Cbz-L-Gln-D- Phe-OH 15.9 R.Time = Retention Time (05S397)

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

13 Preparation of Dipeptides Chiral DipeptidesYield(%)ee. a Cbz-L-Ala-L-Phe-OH90>97 Cbz-L-Ala-L-Ser-OH85>97 Cbz-L-Ala-L-Trp-OH97>97 Cbz-L-Val-L-Phe-OH98>97 Cbz-L-Val-L-Trp-OH96>97 Cbz-L-Phe-L-Ala-OH98>97 Cbz-L-Phe-L-Val-OH95>97 Cbz-L-Phe-L-Phe-OH98>97 Cbz-L-Phe-L-Ser-OH96>97 Cbz-L-Tyr-L-Phe-OH86>97 Cbz-L-Tyr-L-Trp-OH9860 Cbz-L-Trp-L-Ala-OH90>97 Cbz-L-Trp-L-Cys-OH86>97 Cbz-L-Trp-L-Ser-OH86>97 Cbz-L-Trp-L-Trp-OH85>97 Cbz-L-Cys-L-Ala-OH98>97 13 Cbz-L-Met-L-Ala-OH95>97 Cbz-L-Met-D-Ala-OH95>97 Cbz-L-Met-L-Met-OH95>97 Cbz-L-Met-L-Trp-OH82>97 Cbz-L-Met-L-Glu-OH60>97 Cbz-L-Gln-L-Phe-OH72>97 Cbz-L-Gln-L-Gln-OH47>97 Cbz-L-Gln-L-Val-OH95>97 Fmoc-L-Trp-L-Ala-OH70>97 Fmoc-L-Trp-L-Ser-OH87>97 Fmoc-L-Met-L-Ser-OH88>97 Fmoc-L-Met-L-Glu-OH93>97 a:e.e. value was estimated by 1 H NMR and HPLC analysis. ( 05S397 ) ( In Preparation ) Diastereomeric mixture of Dipeptide Yield Cbz-L-Tyr-DL-Phe-OH86 Cbz-L-Trp-DL-Ala-OH98 Cbz-L-Cys-DL-Ala-OH71 Cbz-L-Met-DL-Ala-OH72 Cbz-L-Gln-DL-Phe-OH74 Fmoc-L-Trp-DL-Ala-OH68

14 Preparation of Tri-, TripeptidesYield (%)ee. a Cbz-L-Ala-L-Gly-L-Leu-OH93>97 Cbz-L-Ala-L-Phe-L-Trp-OH95>97 Cbz-L-Val-L-Gly-L-Leu-OH85>97 Cbz-L-Phe-L-Gly-L-Gly-OH98>97 Cbz-L-Phe-L-Ala-L-Ala-OH92>97 Cbz-L-Phe-L-Ala-L-Ser-OH94>97 Cbz-L-Trp-L-Ala-L-Cys-OH86>97 Cbz-L-Trp-L-Trp-L-Try-OH8733 Cbz-L-Met-L-Ala-L-Ala-OH86>97 Cbz-L-Met-L-Ala-L-Ser-OH8364 Cbz-L-Met-L-Ala-L-Trp-OH9260 Cbz-DL-Ala-L-Gly-L-Leu-OH94b Cbz-L-Met-DL-Ala-L-Ala-OH86b TetrapeptidesYield (%)ee.* Cbz-L-Phe-L-Ala-L-Gly-L-Leu-OH86>97 Cbz-L-Ala-L-Phe-L-Gly-L-Leu-OH85>97 a:The ee. value was estimated by 1 H NMR and HPLC analysis. b; Diastereomeric mixture 14 (04S2645) (In progress) and Tetra -Peptides

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

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

17 S-Acylation Previous methods and their difficulties (i)Acyl halides with thiol sodium salts  low yields (ii)Couplings of acyl halides and thiols with catalysts (thallium, tin mercaptides, or Zinc)  limited by substrate specificity (iii)Activation of RCO 2 H by diphosgene or polyphosphate ester  low yield, harsh conditions (iv)Use of thiocyanate, instead of thiol  limited by availability of S.M. (v)Couplings of RCO 2 H and thiols with carbodiimides (e.g. DCC)  difficulty in removal of urea. 16

18 S-Acylation S-Acylation Synthesis of Thiol esters *The crude product was obtained in 90% yield. Pg-Phe-SR Yield (%) mp ( o C) Boc-Phe-SPh  103 Boc-Phe-SCH 2 Ph97 92  93 Boc-Phe-SCH 2 CO 2 Et85 77  78 Cbz-Phe-SPh  101 Cbz-Phe-SCH 2 Ph  120 Cbz-Phe-SCH 2 CO 2 Et84 55  56 Cbz-Phe-SCH 2 CO 2 H94 98  (04S1806)

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

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

21 C-Acylation (ii) Ketones, (00JOC3679) 16 examples (Average isolated yield 75%) (03JOC1443) 18 examples (Average isolated yield 80%) R 1 = alkyl or aryl R 2 +R 3 = alkyl or alicyclic (00S2029) 16 examples (Average isolated yield 62%) (In Progress) 14 examples (Average isolated yield 67%) 20 R 1 = alkyl or (hetero)aryl R 2 = hydrogen, alkyl, vinyl or aryl R 3 = alkyl or aryl R 1 = alkyl or (hetero)aryl R 2 = hydrogen, or alkyl R 1 = alkyl, alkenyl or aryl R 2 = alkyl, or aryl R 3 = alkyl (acyclic or alicyclic) Sulfones, Nitrocompounds and Imines

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

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

24 Thioamides 23 Drawbacks of Route A: (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 RCSBt: Synthesis of Thioacylbenzotriazoles from Grignards R % Yield 4-Tolyl63 4-Methoxyphenyl89 Phenyl76 RR 1 NCSBt: Preparation of Thiocarbamoylbenzotriazoles 2RR1R1 % YieldMP ( o C) aCyclohexylH85128–130 a bFurfurylH94119–120 a c(R)-MethylbenzylH87oil a dPhenethylH89112–113 et-ButylH6061–63 f1,5-DimethylhexylH87oil a g-CH 2 CO 2 CH 3 H76129–130 h2,3-Dihydroindolyl=R –124 iPyrrolidinyl=R –87 jPhenylMethyl92137–138 kEthyl 98oil ln-ButylMethyl76oil RSCSBt: Synthesis of Alkyl/Arylthiothiocarbonylbenzotriazoles ROCSBt: Synthesis of Alkyl/Aryloxythiocarbonylbenzotriazoles 24 Preparation of Thiocarbonyl-1H-6-nitrobenzotriazoles (96JOC9045) 6 examples:56-67 % yields (99JOC1065) 9 examples: % yields (Unpublished results) 7 examples: 44-78% yields Rapoport’s method for the

26 Thioacylations with Benzotriazole Reagents ([04JOC2976] and unpublished work) Synthesis of Thioureas from Thiocarbamoylbenzotriazoles 6 Examples: average isolated yield 87 % Synthesis of Thioamides from Thioacylbenzotriazoles 15 examples: average yield 89 % Bis-(benzotriazolyl)methanethione One-pot Syntheses of Thioureas: 17 examples: average yield 84 % Synthesis of Thioamides, Thiocarbamates, and Dithiocarbamates from Thiocarbamoylbenzotriazoles 4 examples: average yield 84 % 2 examples: 59 and 60 % yields 9 examples: average isolated yield 71% 73% yield R =R 1 Morpholinyl 70% R = Benzyl R 1 = H 85% Thionesters and Thiocarbamates from Aryloxythioacylbenzotriazoles 25

27 Imidoylation-Scope Scope: on - Nitrogen ---Amidines, Guanidines - Carbon Imines - Sulfur Imidothioformate 26 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 Conventional methodsPreparation of Imidoylbenzotriazoles 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% 90CB1545, 8 examples Yield: 38-96% 04JOC5108, 9 examples Yield: 40-90% 01JOC examples Yield: 87-99% 01JOC examples Yield: 71-99% 99OL577, 12 examples Yield: 20-87% 27  Imidoylbenzotriazoles are good substitutes for imidoyl chlorides.

29 A Facile Preparation Method for Imidoylbenzotriazoles EntryR1R1 R2R2 Yield (%)EntryR1R1 R2R2 Yield (%) 6aMePh75 (B)6jPh 88 (A) 6bMep-Tolyl65 (B)6kp-Tolyl 82 (A) 6cBnp-Tolyl62 (B)6l2-furylp-Tolyl84 (A) 6dBn 56 (B)6mPhp-MeOC 6 H 4 82 (A) 6ePhCH 2 CH 2 p-Tolyl64 (B)6nPhBn93 (A) 6fPhCH 2 CH 2 PhCH 2 57 (B)6op-MeOC 6 H 4 Bn78 (A) 6gn-C 6 H 13 p-Tolyl57 (B)6pPh2-Furylmethyl84 (A) 6hPh2-Pyridyl76 (A)6q2-furylCyclohexyl95 (A) 6ip-O 2 NC 6 H 4 Ph88 (A)6rp-O 2 NC 6 H 4 Bn79 (A) Conditions for Route A and B Route A: amide (1 eq) + SOCl 2 (2 eq) + BtH (4 eq); Solvent, CHCl 3 ; Microwave, 80 o C, 80 W, 10 min. Route B: 1) amide (1 eq) + (COCl) 2 + pyridine (1 eq), 0 o C, 15 min; solvent, CH 2 Cl 2 2) BtH (2 eq), room temperature, 4 h 28

30 EntryRR1R1 R2R2 R3R3 Yield (%) 7aPhMe-(CH 2 ) 2 O(CH 2 ) bPhMePhMe74 7cPhMeEt 88 7dPhMeBnH77 7ePhMep-TolylH89 7fPh Et 71 7gPh -(CH 2 ) 2 O(CH 2 ) hPh Me72 7iPh p-TolylH66 7j2-Furylp-Tolyl-(CH 2 ) 2 O(CH 2 ) k2-Furylp-TolylEt 77 7lBnp-TolylEt 86 7mBnp-Tolyl H90 7nn-C 6 H 13 p-Tolyl-(CH 2 ) 2 O(CH 2 ) on-C 6 H 13 p-TolylEt 88 7pBn -(CH 2 ) 2 O(CH 2 ) Preparation of Polysubstituted Amidines 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. 29

31 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%). Literature reagents 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 Early Bt derivatives 95SC117301JOC Guanidylating Agentsand First Bt-Literature

32 Second Generation Bt-Mediated Preparation of Guanidines EntryR1R1 R2R2 Yield (%) aHPh80 bHn-C 5 H cHBn68 d-(CH 2 ) e-(CH 2 ) 2 O(CH 2 ) fipr 68 EntryR1R1 R2R2 R3R3 R4R4 Yield a’-(CH 2 ) 2 O(CH 2 ) 2 -PhH64 b’-(CH 2 ) 2 O(CH 2 ) 2 -p-TolylH74 c’-(CH 2 ) 2 O(CH 2 ) 2 -BnH71 d’-(CH 2 ) 2 O(CH 2 ) 2 -PhMe85 e’-(CH 2 ) 4 -PhH68 f’-(CH 2 ) 4 -4-MeOC 6 H 4 H60 g’iPr 4-MeOC 6 H 4 H48 (00JOC8080) EntryR1R1 R2R2 R3R3 R4R4 R5R5 Y (%) a’’-(CH 2 ) 5 -Ph4-MeOC 6 H 4 H68 b’’-(CH 2 ) 5 -Ph (CH 2 ) 2 O(CH 2 ) 2 78 c’’-(CH 2 ) 5 -Ph H76 d’’-(CH 2 ) 5 -Phn-BuH84 e’’iPr EtPhC 2 H 4 H51 f’’iPr EtBnH50 g’’iPr Eti-BuH56 h’’iPr Et4-MeOC 6 H 4 H70 i’’iPr Ph H60 j’’iPr PhBnH78 k’’(CH 2 ) 2 O(CH 2 ) 2 4-MeOC 6 H 4 (CH 2 ) 2 O(CH 2 ) 2 84 l’’(CH 2 ) 2 O(CH 2 ) 2 2-FurylPhC 2 H 4 H81 m’’(CH 2 ) 2 O(CH 2 ) 2 2-Furylp-TolylH79 n’’(CH 2 ) 2 O(CH 2 ) 2 4-ClC 6 H 4 MeO 2 CCH(Ph)H70 o’’(CH 2 ) 2 O(CH 2 ) 2 4-ClC 6 H 4 -(CH 2 ) (01S897) 31

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

34 Imidolylation at Sulfur R1R1 R2R2 R3R3 R4R4 R5R5 Yield (%) aH-(CH 2 ) 2 O(CH 2 ) 2 -2,5-Cl 2 C 6 H 3 4-MeC 6 H 4 44 bH-(CH 2 ) 2 O(CH 2 ) 2 -2,5-Cl 2 C 6 H 3 C 6 H 5 CH 2 53 cHMePh2,5-Cl 2 C 6 H 3 Ph92 dH-(CH 2 ) 2 O(CH 2 ) 2 -4-NO 2 C 6 H 4 4-MeC 6 H 4 44 eH-(CH 2 ) 2 O(CH 2 ) 2 -C 6 H 5 CH 2 4-MeC 6 H 4 46 fH-(CH 2 ) 2 O(CH 2 ) 2 -C 6 H 5 CH 2 4- t Bu-2-MeC 6 H 3 75 g i Bu-(CH 2 ) 2 O(CH 2 ) 2 -3-NO 2 C 6 H 4 4-Me C 6 H 4 59 (01JOC2865) R1R1 R2R2 R3R3 Yield (%) a4-MeC 6 H 4 Ph i Pr90 bMePh i Pr77 c4-MeC 6 H 4 4PhPhCH 2 91 dMePhPhCH 2 94 (95H231) 33

35 Imidoylation at Carbon (Ketones) 01JOC4041 entryR1R1 R2R2 XYield (%) 3aPh O85 3bPh S79 3cPh4-ClC 6 H 4 O87 3dPh4-ClC 6 H 4 S88 3ePh4-BrC 6 H 4 O89 3fPh4-BrC 6 H 4 S98 3g4-MeC 6 H 4 PhO82 3h4-MeC 6 H 4 PhS91 3i4-MeC 6 H 4 4-BrC 6 H 4 O96 3j4-MeC 6 H 4 4-BrC 6 H 4 S89 3kPh4-MeOC 6 H 4 O84 3lPh4-MeOC 6 H 4 S85 3m4-MeC 6 H 4 4-MeOC 6 H 4 O85 3n4-MeC 6 H 4 4-MeOC 6 H 4 S84 34

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

37 Classical Preparation of Sulfonamides: 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: Preparation of Sulfonylbenzotriazoles Preparation of Sulfonylbenzotriazoles (04JOC1849) Sulfonylbenzotriazoles: Preparation O’Connell, J. F. and Rapoport, H. (92JOC4775) 36

38 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 1 0 amine over the 2 0 Selectively sulfonylate aliphatic amines over aromatic amines Benzotriazole-Assisted Sulfonylation Benzotriazole-Assisted Sulfonylation ([94SC205] and [04JOC1849]) Generation of Sulfonamides from Sulfonylbenzotriazoles 3 examples: 87-93% yields 4 examples: 64-99% yields 10 examples: 51-99% yields 37

39 38 Coworkers in Benzotriazole Chemistry 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 39 Katritzky Group Financial Support M 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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