Acylation and Related Transformations Alan R. Katritzky, Kazuyuki Suzuki, Ashraf A. Abdel- Fattah,...
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Transcript of Acylation and Related Transformations Alan R. Katritzky, Kazuyuki Suzuki, Ashraf A. Abdel- Fattah,...
Acylation and Related TransformationsAcylation and Related TransformationsAlan 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
Acylation in Organic SynthesisAcylation 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. 1961
– Especially acylimidazoles
NN
O
RWidely used
Preparation of N-AcylbenzotriazolesPreparation of N-Acylbenzotriazoles direct from Carboxylic Acidsdirect from Carboxylic Acids
1. Use of Counter-attack reagent
2. Via Sulfinyl-bisbenzotriazole
3
RO
OMeSO2Bt R
O
O SO2MeBt R
O
Bt
+
(or p-CH3C6H4SO2Bt)Any salts
as Na+ or Et3NH+
+- MeSO3
BtH SOCl2 SO
BtBt
RO
OH
2BtH HCl
RO
BtSO2 BtH+
4 mols 1 mol
+
Unstable
+ +
(00JOC8210)
(03S2795)
RCOBt mp Yield
87-89 88
149-151 84
146-147 76
215-216 90
136-137 92
232-234 88
205 82
191 92
189 54
164-166 95
4
RCOBt mp Yield
HCOBt 94-96 71
CH3COBt 49-51 92
C2H5COBt 73-74 92
C3H7COBt 62-63 79
n-C4H9COBt 42-44 83
Me2CHCOBt Oil 91
tBuCOBt 71-72 94
tBuCH2COBt 56-57 83
C5H11COBt Oil 96
n-C15H31COBt 54-55 89
tBuCH2CHMeCH2COBt 157-158 86
PhCH2COBt 65-66 84
Ph2CHCOBt 88-89 89
PhCH2CH2COBt 63-64 84
PhCOBt 112-113 93
4-CH3C6H4COBt 123-124 91
2-CH3OC6H4COBt 96-97 72
4-CH3OC6H4COBt 104 93
N-AcylbenzotriazolesN-Acylbenzotriazoles: Aliphatic, : Aliphatic,
173-175 92
171-173 97
161-162 75
98-100 91
OCOBt
SCOBt
NCOBt
COBtNH
NCOBt
N COBt
COBtN
N
NH
COBt
COBt
COBtBtOC
COBtBtOC
N
COBtBtOC
COBt
COBt
MeO
COBt
HeteroaromaticHeteroaromaticAromatic,Aromatic,RCOBt mp Yield
4-ClC6H4CH2COBt 90-91 64
3-ClC6H4COBt 120-121 74
4-ClC6H4COBt 138-139 74
4-BrC6H4COBt 142-143 93
4-FC6H4COBt 119 98
4-NO2C6H4COBt 193-194 83
4-Et2NC6H4COBt 86-87 85
4-HOC6H4COBt 199-200 84CCl3COBt 78 98
CF3COBt 89-91 70
CF3CF2CF2COBt oil 86
BtCOCOBt 163-164 92
BtCOBt 182-184 90
N-AcylbenzotriazolesN-AcylbenzotriazolesFrom Unsaturated, Functionalized and Bis-acidsFrom Unsaturated, Functionalized and Bis-acids
RCOBt mp Yield
oil 83
CH3CH=CHCOBt 87-88 86
PhCH=CHCOBt 151-152 96
HC≡ CCOBt 99-100 83
PhC≡ CCOBt 124-125 92
87-88 86
BrCH2COBt 91-92 87
Cl2CHCOBt 87-88 86
CH3OCH2COBt 103-104 96
PhSCH2COBt 103-104 90
PhCOCOBt 72-73 72
174-175 82
BtCO(CH2)4COBt 170-171 75
BtCO(CH2)18COBt 121-122 63
MeO2C(CH2)3COBt 51-52 87
300 77
COBt
COBtCl
BtOC COBt
5
RCOBt mp Yield
223-225 94
247 16
188-189 60
158-160 80
98-100 40
142-144 98
159-160 87
104-105 98
Bt
O
Bt
O
BtS
O
Bt
O
BtO
O
Bt
O
Bt
O
Bt
O
Bt
O
Bt
O
Bt SS
OBt
O
Bt
OBt
O
O
BtO
Bt
RCOBt mp Yield
142-144
169-170
95
98
183-184 96
244-245 90
136-137 98
183 65
196-197 95
118-120 56
91-92
165-167
86
59
O COBt
S COBt
COBtCl
COBtO2N
COBtMeO
MeO
MeO
COBtO
HO
COBtS
SCOBt
OCOBt
COBtCOBtBtOC
6N-Acylbenzotriazole Derivatives from N-Protected Amino Acids (No Extra Functionality)-All solid, m.p.s in range of 50~180 oC.
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 >97
L-Ala Cbz Cbz-L-Ala-Bt 95 >97
L-Ala Fmoc Fmoc-L-Ala-Bt 79 >97
L-Ala Tfa Tfa-L-Ala-Bt 76 >97
D-Ala Cbz Cbz-D-Ala-Bt 90 >97
DL-Ala Cbz Cbz-DL-Ala-Bt 94 >97
L-Val Boc Boc-L-Val-Bt 83 >97
L-Val Cbz Cbz-L-Val-Bt 91 >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
Yield ee.*
L-Phe Boc Boc-L-Phe-Bt 81 >97
L-Phe Cbz Cbz-L-Phe-Bt 88 >97
L-Phe Fmoc Fmoc-L-Phe-Bt 83 >97
L-Phe Tfa Tfa-L-Phe-Bt 82 >97
L-Leu Boc Cbz-L-Leu-Bt 66 >97
L-Leu Cbz Cbz-L-Leu-Bt 95 >97
L-Ileu Cbz Cbz-L-Ileu-Bt 95 >97
L-Pro Cbz Cbz-L-Pro-Bt 74 >97
(04S2645)(04S1806)(05S397)(In Preparation)
NN-Acylbenzotriazole Derivatives-Acylbenzotriazole Derivatives from from NN-Protected -Protected Amino Acids with FunctionalityAmino Acids with Functionality
(05S397) (In Preparation)
Structure of N-Acylbenzotriazole
Functionality Yield ee.a
Cbz-L-Trp-Bt Indole NH 95 >97
Cbz-L-Tyr-Bt Phenol OH 86 >97
Cbz-L-Gln-Bt Amide NH2 72 >97
Cbz-L-Cys-Bt SH 76 >97
Cbz-L-Asn-Bt Amide NH2 72 >97
Cbz-L-Asp(OMe)-Bt CO2Me 82 >97
Cbz-L-Met-Bt CH2SMe 95 >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 >97
Fmoc-L-Ser-Bt Alcoholic OH 68 >97
Tfa-L-Asp(OMe)-Bt CO2Me 80 >97
Tfa-L-Glu(OMe)-Bt CO2Me 82 >97
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 >97
Z-L-Glu-diBt Two COBt 68 >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
NN-Acylbenzotriazole Derivatives-Acylbenzotriazole Derivatives from from NN-Protected Dipeptides-Protected Dipeptides
R1
Z
O
NHNHO
HO
R2R1
Z
O
NHNHO
Bt
R2BtH, SOCl2
THF, -10oC
Entry Product Yield (%) Mp (oC) e.e.*
1 Z-L-Ala-L-Phe-Bt 90 148149 95
2 Z-L-Phe-L-Ala-Bt 85 180181 95
3 Z-L-Phe-D-Ala-Bt 90 156157 95
4 Z-L-Trp-L-Ala-Bt 78 176177 95
5 Z-L-Trp-L-Trp-Bt 76 152154 95
6 Z-L-Met-L-Ala-Bt 85 104105 95
7 Z-L-Met-D-Ala-Bt 87 135137 95
*e.e. was estimated in 1H NMR.
8
(04S2645)(04S1806)(05S397)
Virtues of AcylbenzotriazolesVirtues of Acylbenzotriazoles
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)
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
N-AcylationN-Acylation:Amides from N-acylbenzotriazoles
Primary amides RCONH2
R Yield(%)
C6H5 100
2-CH3OC6H4 100
3-ClC6H4 87
4-NO2C6H4 1002-Furanyl 1001-Naphthyl 1002-Pyridyl 1003-Pyridyl 1004-Pyridyl 1002-Pyrazinyl 100
PhCH2 100
PhCH2CH2 85
Ph2CH 90
n-C4H9 72
Secondary amides RCONHRR R’ Yield(%)
4-ClC6H5 EtCH(CH3) 95
4-ClC6H4 C6H5 75
4-Et2C6H4 n-C4H9 92
C6H5 t-C4H9 75
2-Furanyl n-C4H9 94
1-Naphthyl n-C4H9 92
2-Pyridyl 4-CH3OC6H5 83
4-Pyridyl EtCH(CH3) 100
2-Pyrazinyl (CH3)3C 100
Ph2CH C6H5 70Tertiary amides RCONRRR R’ R” Yield(%)
4-CH3C6H4 C2H5 C2H5 100
4-NO2C6H4 (CH2)4 96
C6H5 (CH2)4 100
2-CH3OC6H4 (CH2)4 98
2-Furanyl C2H5 C2H5 51
1-Naphthyl (CH2)4 94
4-Pyridyl (CH2)4 100
PhCH2 (CH2)4 99
Ph2CH (CH2)5 68
(00JOC8210)For reactions with Wang resin linked amines see 02BMCL1809
10
11Chiral Integrity of Peptide SynthesisChiral Integrity of Peptide SynthesisPreparation of N-(Boc acylamino)amides
1H NMR of Boc-Valine derivatives (02Arkivoc(viii)134)
Boc NH
O
Bt
R
Me
PhH2N
Boc NH
O
HN
R
Ph
Me
1. The NMR method 2. The chiral column methodHPLC: 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 R.Time
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
12.9 Cbz-L-Gln-D-Phe-OH
15.9
R.Time = Retention Time
(05S397)
Methods of Peptide PreparationMethods of Peptide Preparation
O
BtNH
R1
Cbz
O
OHH2N
R2Et3N O
HNNH
R1
CbzO
HO
R2+
CH3CN/H2O
r.t. 0.5 h
85~98%
O
BtNH
R1
Cbz
O
HNH2N
R2Et3N O
HNNH
R1
CbzO
HN
R2+
CH3CN/H2O
r.t. 0.5~1.0hO
HO
R3
OHO
R3
85~98%
Stepwise coupling:
O
HNNH
R1
CbzO
Bt
R2
O
OHH2N
R3
O
HNNH
R1
CbzO
HO
R2
O
HNNH
R1
CbzO
HN
R2
OHO
R3
BtH, SOCl2
0 oC
R1 = CH2Ph, R2 = Me, 85%
R1 = Me, R2 = CH2Ph, 90% 92~95%
Fragment coupling:
O
HNNHO
Bt
Cbz
Ph O
HNH2NO
HO
Et3N
O
HNNHCbzO
HN
OHN
O
HO
Ph
+CH3CN/H2O
r.t. 2.0h
86%
12
(04S2645)
Preparation of DipeptidesPreparation of DipeptidesChiral Dipeptides Yield(%) ee.a
Cbz-L-Ala-L-Phe-OH 90 >97
Cbz-L-Ala-L-Ser-OH 85 >97
Cbz-L-Ala-L-Trp-OH 97 >97
Cbz-L-Val-L-Phe-OH 98 >97
Cbz-L-Val-L-Trp-OH 96 >97
Cbz-L-Phe-L-Ala-OH 98 >97
Cbz-L-Phe-L-Val-OH 95 >97
Cbz-L-Phe-L-Phe-OH 98 >97
Cbz-L-Phe-L-Ser-OH 96 >97
Cbz-L-Tyr-L-Phe-OH 86 >97
Cbz-L-Tyr-L-Trp-OH 98 60
Cbz-L-Trp-L-Ala-OH 90 >97
Cbz-L-Trp-L-Cys-OH 86 >97
Cbz-L-Trp-L-Ser-OH 86 >97
Cbz-L-Trp-L-Trp-OH 85 >97
Cbz-L-Cys-L-Ala-OH 98 >97
13
Cbz-L-Met-L-Ala-OH 95 >97
Cbz-L-Met-D-Ala-OH 95 >97
Cbz-L-Met-L-Met-OH 95 >97
Cbz-L-Met-L-Trp-OH 82 >97
Cbz-L-Met-L-Glu-OH 60 >97
Cbz-L-Gln-L-Phe-OH 72 >97
Cbz-L-Gln-L-Gln-OH 47 >97
Cbz-L-Gln-L-Val-OH 95 >97
Fmoc-L-Trp-L-Ala-OH 70 >97
Fmoc-L-Trp-L-Ser-OH 87 >97
Fmoc-L-Met-L-Ser-OH 88 >97
Fmoc-L-Met-L-Glu-OH 93 >97
a:e.e. value was estimated by 1H NMR and HPLC analysis.
(05S397) (In Preparation)
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
Preparation of Tri-, Preparation of Tri-,
Tripeptides Yield (%) ee.a
Cbz-L-Ala-L-Gly-L-Leu-OH 93 >97
Cbz-L-Ala-L-Phe-L-Trp-OH 95 >97
Cbz-L-Val-L-Gly-L-Leu-OH 85 >97
Cbz-L-Phe-L-Gly-L-Gly-OH 98 >97
Cbz-L-Phe-L-Ala-L-Ala-OH 92 >97
Cbz-L-Phe-L-Ala-L-Ser-OH 94 >97
Cbz-L-Trp-L-Ala-L-Cys-OH 86 >97
Cbz-L-Trp-L-Trp-L-Try-OH 87 33
Cbz-L-Met-L-Ala-L-Ala-OH 86 >97
Cbz-L-Met-L-Ala-L-Ser-OH 83 64
Cbz-L-Met-L-Ala-L-Trp-OH 92 60
Cbz-DL-Ala-L-Gly-L-Leu-OH 94 b
Cbz-L-Met-DL-Ala-L-Ala-OH 86 b
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 >97
a:The ee. value was estimated by 1H NMR and HPLC analysis. b; Diastereomeric mixture
14
(04S2645)(In progress)
and Tetraand Tetra-Peptides-Peptides
Synthesis of Weinreb amides and Hydroxamic acidsSynthesis of Weinreb amides and Hydroxamic acids15a
O
BtR1
O
NR1+ HN
R3
OR2OR2
R3
Et3N, THF
r.t.
R1: alkyl, aromatic
R2: H, Et, Bn
R3: H, Me
Weinreb amides: 24 examples (64-94%) Hydroxamic acids: 6 examples (61-91%)
O
BtNH
R1
N
R2H2N
HOEtOH
O
ONH
R1
NNH2
R2
EtOH
N
NO
R2NH25 oC
Pg = Boc, Cbz, Fmoc
Amino acid with R: alanine, valine, phenylalanine, methionine, tryptophan, and glutamine
R2: p-tolyl, benzyl, p-pyridyl
Bt = benzotriazol-1-yl
reflux
R
PgPg Pg
18 examples(average yield 88%)Can be isolated
5 min
Synthesis of Chiral Synthesis of Chiral 1,2,4-Oxadiazoles1,2,4-Oxadiazoles
(02ARK39) (03S2777)
(05ARK, In press)
15b
O
BtR1 R2 S
O
O
NH2
NaH
THF
O
NH
R1 SO
O
R2
+
R1: Aromatic and amino acid derivatives
R2SO2NH2: MeSO2NH2, p-MeC6H4SO2NH2, and acetazolamide
18 examples (78-98%)
O
BtR1 +
R1: Aromatic X = O, 10 examples (84-98%)X = S, 8 examples (85-97%)
HX NH2
X = O, R2 = Me
X = S, R2 = H
O
N
1) M.W. 80 oC, 10min
2) M.W. 80 oC, 2min
SOCl2
R2
R2R2
R2
R1
N-Acylation of SulfonamidesN-Acylation of Sulfonamides
Microwave-assisted Preparation of Oxazolines and ThiazolinesMicrowave-assisted Preparation of Oxazolines and Thiazolines
(02ARK14)
(04JOC811)
SS-Acylation -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 RCO2H 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 RCO2H and thiols with carbodiimides (e.g. DCC)
difficulty in removal of urea.
16
SS-Acylation-AcylationSynthesis of Thiol esters
RO
Bt
HS R'
Et3N
RO
S R'CH2Cl2, r.t.
*The crude product was obtained in 90% yield.
R of reactant
RCOBt R
O
S Ph
Yield %
RO
SPh
Yield %
RO
SCO2Et
Yield %
RO
SCO2H
Yield % C6H5 (1a) 92 98 93 97
2-MeOC6H4 (1b) 99 99 85 92
2-pyridyl (1c) 90 85 90 35*
2-indolyl (1d) 93 95 93 89
2-furyl (1e) 93 89 87 88
4-Et2NC6H4 (1f) 86 96 91 82
m-C6H4 (1g) 90 85 98 96
O
BtNH
Ph
Pg
HS RO
SNH
Ph
PgR
CH2Cl2 / Et3N (cat.)
1h., 25oC
Pg = Boc, Cbz
Pg-Phe-SR Yield (%) mp (oC)
Boc-Phe-SPh 76 102103
Boc-Phe-SCH2Ph 97 9293
Boc-Phe-SCH2CO2Et 85 7778
Cbz-Phe-SPh 86 100101
Cbz-Phe-SCH2Ph 93 119120
Cbz-Phe-SCH2CO2Et 84 5556
Cbz-Phe-SCH2CO2H 94 9899
17
(04S1806)
OO-Acylation -Acylation 18
O
H
HO
H
HO
H
OHOHH
H
OH
O
H
HO
H
HO
H
OHOHH H
O O
HN
PgR
D-Glucose
Pg = Fmoc, CBZ
Bt
O
NH
R
ZO
H
H HO
NH
R
Z
CholesterolMicrowaves
65 oC, 20 min+
Z = PhCH2OCO-
R = L-Me2CH- (88%), L-PhCH2- (82%) D-PheCH2- (84%)
Bt
O
NH
R
ZO
O
NH
R
Z
NerolMicrowaves
65 oC, 20 min+
R = L-3-IndolylCH2- (XX%) L-CH3SCH2CH2- (XX%)
(Unpublished work)
O-Acylated steroids, terpenes, sugars, and lipids
CC-Acylation (i) Aryl and Heteroaryl Rings-Acylation (i) Aryl and Heteroaryl Rings
O
O
BtR
TiCl4or ZnBr2O
R
O
5 examples54~98% (Average 79%)
S SR
O
5 examples58~97% (Average 80%)
N
X
TiCl4
N
X
R
O
X = H, Me
7 examples for X = H21~91% (Average 56%)7 examples for X = Me51~94% (Average 70%)
N
Si(i-Pr)3
TiCl4
N
Si(i-Pr)3
O
R
6 examples54~92% (Average 79%)
N
X
TiCl4
N
X
X = H, Me
7 examples for X = H15~92% (Average 66%)7 examples for X = Me27~92% (Average 69%)
R
O
(03JOC5720)(04CCA175)
19
R1
NH
Bt
O
PGN
R2
AlCl3
CH2Cl2, 20 °C
R1
NH O
PGN
R2
PG = Tfa, R1 = Phenyl
PG= Tfa, R1 = H
PG = Fmoc, R1 = Phenyl
PG = Fmoc, R1 = indol-3-yl
PG = Fmoc, R1 = CH2SMe
R2 = H
R2 = Me
5 examples for R2 = H
52~82% (Average 70%)
5 examples for R2 = Me
41~78% (Average 60%)
R1
NH
Bt
O
PGAlCl3
CH2Cl2, 20 °C
R1
NH O
PG
PG = Tfa, R1 = Phenyl
PG= Tfa, R1 = H
PG = Fmoc, R1 = Phenyl
PG = Fmoc, R1 = indol-3-yl
PG = Fmoc, R1 = CH2SMe
R2 = H
R2 = Me
5 examples for R2 = H
63~87% (Average 79%)
5 examples for R2 = Me
40~90% (Average 62%)
NR2
NR2
(In progress)
CC-Acylation (ii) Ketones, -Acylation (ii) Ketones, O
R2 R3
R1O
O
R2 R3
O
BtR1
LDA
(00JOC3679)
16 examples
(Average isolated yield 75%)
R3 SO2
R2
O
BtR1
n-BuLiO2S
R3
OR1
R2(03JOC1443)
18 examples
(Average isolated yield 80%)
R1 = alkyl or arylR2 +R3 = alkyl or alicyclic
NH
R1O
N
R2
O
BtR1
LDA
R3R2
R3 (00S2029)
16 examples
(Average isolated yield 62%)
NO2
R2
O
BtR1
t-BuOK
O
R1NO2
R2
(In Progress)
14 examples
(Average isolated yield 67%)
20
R1 = alkyl or (hetero)aryl
R2 = hydrogen, alkyl,
vinyl or aryl
R3 = alkyl or aryl
R1 = alkyl or (hetero)aryl
R2 = hydrogen, or alkyl
R1 = alkyl, alkenyl or aryl
R2 = alkyl, or aryl
R3 = alkyl (acyclic or alicyclic)
Sulfones,Sulfones, Nitrocompounds and IminesNitrocompounds and Imines
CC-Acylation (iii) Heteroaryl Alkyl Groups-Acylation (iii) Heteroaryl Alkyl Groups
R2
Het R1
O
Bt
LDA R2
Het O
R1 R2
Het OH
R1(In Progress)
21
Entry
Het
R1 of R1COBt
R2 of HetCH2R
2 Yield (%)
(keto +enol) Keto/ enol
(%)
1 Pyridin-2-yl (CH3)2CHCH2 H 65 69/ 31 2 Pyridin-2-yl CH3(CH2)2CH2 H 56 67/ 33 3 Pyridin-2-yl PhCH=CH H 65 50/ 50 4 Pyridin-2-yl Ph H 78 59/ 41 5 Pyridin-2-yl 4-ClC6H4 H 83 38/ 62 6 Pyridin-2-yl Furan-2-yl H 84 68/ 32 7 Pyridin-2-yl Thiophen-2-yl H 68 85/ 15 8 Pyridin-2-yl Pyridin-3-yl H 72 16/ 84 9 Pyridin-2-yl 4-ClC6H4 Ph 95 58/ 42 10 Quinolin-2-yl Ph H 91 8/ 92 11 Quinolin-4-yl 4-ClC6H4 H 87 100/ 0 12 Quinolin-4-yl 4-NO2C6H4 H 72 100/ 0 13 Quinolin-4-yl Thiophen-2-yl H 66 100/ 0 14 Pyrimidin-4-yl Thiophen-2-yl H 80 50/ 50 15 Pyrimidin-4-yl Furan-2-yl H 50 50/ 50
CC-Acylation (iv) -Acylation (iv) -Keto Esters-Keto Esters
O
H3CCO2Et
R2
BtR1
O
NaHCO2Et
R2
COCH3
R1CO
O
R1
R2
CO2Et
1
2
43
O
H3C
O
BtR1
R2
O
NaH
OH
R1 R2
OO
R1 R2
O
5
2
6
(04JOC6617)
22
Entry
R1
R2
Yield (%)
(keto +enol)
enol
(%)
6a Ph Me 55 94
6b 4-MeC6H4 4-MeC6H4 97 97
6c 2-Thienyl 2-Thienyl 100 88
6d 4-MeC6H4 2-Furyl 52 94
Entry
R1
R2
Yield (%) (keto +enol)
Keto (%)
4a Ph H 76 83 4b 4-ClC6H4 H 84 78 4c 4-MeC6H4 H 85 86 4d 2-Furyl H 70 93 4e 4-Pyridyl H 71 39 4f n-C5H11 H 58 92 4g 4-MeC6H4 Me 76 100 4h n-C5H11 Me 52 93 4i 2-Furyl Me 71 100 4j 2-Thienyl Me 60 100 4k 2-Pyridyl Me 60 100 4l Ph Me 54 100
4m (Ph)2CH Me 51 100 4n 2-Furyl Bn 69 100 4o 2-Thienyl Bn 71 100 4p Ph Bn 65 100 4q Ph- Bn 54 0 4r 4-ClC6H4 Bn 53 100
and and -Diketones-Diketones
ThioamidesThioamides
R
S
YHN
R1
R2+
Route C
Y= Cl, OEt, Im, Bt
S
R NR1
R2
Route A
Route B
Route C
O
R NR1
R2
(Im)2CS
P2S5 or Lawesson's Reagent
PhN+
O-
Me
S
R NR1
R2
Routes
A (i)
A (ii)RMgX
RLi
RMgX
S
NMe
MeCl
R2 N C S
S
S
S
NR1
R2N R1
R2
Routes
B (i)
B (ii)
B (iii)
NiCl2(dppe)
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.
Benzotriazole-Based Thioacylation Benzotriazole-Based Thioacylation ReagentsReagents
CS2R MgBrTHF R
S
SMgBr
BtCl
R
S
Bt
RCSBt: Synthesis of Thioacylbenzotriazoles from Grignards
R % Yield4-Tolyl 634-Methoxyphenyl
89Phenyl 76
RR1NCSBt: Preparation of Thiocarbamoylbenzotriazoles
S
ClCl NN
N
SiMe3
S
BtBt
+
1
NHRS
NBtR
R1
R1
2
2 R R1 % Yield MP (oC)
a Cyclohexyl H 85 128–130a
b Furfuryl H 94 119–120a
c (R)-Methylbenzyl H 87 oila
d Phenethyl H 89 112–113
e t-Butyl H 60 61–63
f 1,5-Dimethylhexyl H 87 oila
g -CH2CO2CH3 H 76 129–130
h 2,3-Dihydroindolyl =R1 84 123–124
i Pyrrolidinyl =R1 76 86–87
j Phenyl Methyl 92 137–138
k Ethyl Ethyl 98 oil
l n-Butyl Methyl 76 oil
S
Bt Bt SH R S
S
RBt Bt
S
Bt
S R
11
+ +
R1
a) Phenylb) Benzylc) Acetyl ethyl esterd) Isopropyl
46%42%63% 0%
21%44%trace90%
1RSCSBt: Synthesis of Alkyl/Arylthiothiocarbonylbenzotriazoles
S
Bt Bt OH R O
S
RBt
1
R1 = Ethyl (19%) 2-Naphthyl (87%) 3-Pyridinyl (66%) 1-Naphthyl (81%) Phenyl (83%)
1+
ROCSBt: Synthesis of Alkyl/Aryloxythiocarbonylbenzotriazoles
24
N
S
R
N N
NO2
NH2
NH2O2NNH
OR
NH2
NO2
RCOCl 1)P2S5
2) HONO
Preparation of Thiocarbonyl-1H-6-nitrobenzotriazoles
(96JOC9045) 6 examples:56-67 % yields(99JOC1065) 9 examples: 48-55 % yields(Unpublished results) 7 examples: 44-78% yields
Rapoport’s method for the
O
S
NR
RO
SnBuLi
O
S
BtRR2NH
1
Thioacylations with Benzotriazole Reagents Thioacylations with Benzotriazole Reagents ([04JOC2976] and unpublished work)
R
S
NR1
R2
R1R2NH
R
S
Bt
Synthesis of Thioureas from Thiocarbamoylbenzotriazoles
6 Examples: average isolated yield 87 %
S
NH
BtR NH
R2
R3
Et3N S
NH
NRR2
R3
+
Synthesis of Thioamides from Thioacylbenzotriazoles
15 examples: average yield 89 %
NHR2
S
NNH
R2
R1 R1
S
Bt Bt
R NH21)
2)
R
Bis-(benzotriazolyl)methanethione One-pot Syntheses of Thioureas:
17 examples: average yield 84 %
Synthesis of Thioamides, Thiocarbamates, and Dithiocarbamates from Thiocarbamoylbenzotriazoles
N
S
RBt
R
N
S
R
RR
R-M(X)
N
S
R
RRO
N
S
R
RRS
2
11
2 2
1
2
1ROH
RSH
2 Note: R2 = H,No Reaction
4 examples: average yield 84 %
2 examples: 59 and 60 % yields
9 examples: average isolated yield 71%
73% yield
R =R1 Morpholinyl 70%R = Benzyl R1 = H 85%
Thionesters and Thiocarbamates from Aryloxythioacylbenzotriazoles
25
Imidoylation-ScopeImidoylation-Scope• Scope: on
- Nitrogen ---Amidines, Guanidines
- Carbon ------Imines
- Sulfur ------Imidothioformate
RNH Bt
NR
R Bt
NR
Bt Bt
NR
a b c
NNH
R R''
R'
NNH
NH
R''
R'
R''
Amidines Guanidines
N
Cl
N
EtO
H
N
TfO
H
R2
R1
R2
R1
+
BF4-
R2
R1
+
OTf -
Imidoyl chlorides Imidate fluoroborates Iminium triflates
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
Reagents for the Preparation of AmidinesReagents for the Preparation of Amidines
• Conventional methods • Preparation of Imidoylbenzotriazoles
O
NH
N
Cl
N
EtO
H
N
TfO
H
N
N
NH
R2
R2
R1
R2
R1
+
BF4
_
R2
R1
+
OTf_
1
2
3
R2
R1R3
R4
R3 R4
R1
• 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.
N
Bt
NH
O
R1R2
NH
O
R1R2
NOH
R1 R2
O
BtR1
NH
O
R1R2
R2
R1
Bt2SO
PPh3/BtCl
BtTs
R2NCO
BtR1
R2NC/BF3
BtHPOCl3, NEt3
95H231, 10 examples Yield: 15-75%
90CB1545, 8 examples
Yield: 38-96%
04JOC5108, 9 examples
Yield: 40-90%
01JOC2865
11 examples
Yield: 87-99%
01JOC1043
6 examples
Yield: 71-99%
99OL577, 12 examples
Yield: 20-87%
27
Imidoylbenzotriazoles are good substitutesfor imidoyl chlorides.
A Facile Preparation Method for Imidoylbenzotriazoles
Entry R1 R2 Yield (%) Entry R1 R2 Yield (%)
6a Me Ph 75 (B) 6j Ph Ph 88 (A)
6b Me p-Tolyl 65 (B) 6k p-Tolyl p-Tolyl 82 (A)
6c Bn p-Tolyl 62 (B) 6l 2-furyl p-Tolyl 84 (A)
6d Bn Bn 56 (B) 6m Ph p-MeOC6H4 82 (A)
6e PhCH2CH2 p-Tolyl 64 (B) 6n Ph Bn 93 (A)
6f PhCH2CH2 PhCH2 57 (B) 6o p-MeOC6H4 Bn 78 (A)
6g n-C6H13 p-Tolyl 57 (B) 6p Ph 2-Furylmethyl 84 (A)
6h Ph 2-Pyridyl 76 (A) 6q 2-furyl Cyclohexyl 95 (A)
6i p-O2NC6H4 Ph 88 (A) 6r p-O2NC6H4 Bn 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
N
R1Bt
R2
N
R1Bt
R2
NHR2R1
O
BtH + SOCl2
route A
i (COCl)2, PyH ii BtH
route B
R1 = Alkyl R1 = Aryl
28
R1
NR
AcOH, microwaves
120 oC, 120 W, 10 minR1
NR
Bt
+R3R2
HN N
R2
R3
7a-p
Entry R R1 R2 R3 Yield (%)
7a Ph Me -(CH2)2O(CH2)2- 76
7b Ph Me Ph Me 74
7c Ph Me Et Et 88
7d Ph Me Bn H 77
7e Ph Me p-Tolyl H 89
7f Ph Ph Et Et 71
7g Ph Ph -(CH2)2O(CH2)2- 63
7h Ph Ph Ph Me 72
7i Ph Ph p-Tolyl H 66
7j 2-Furyl p-Tolyl -(CH2)2O(CH2)2- 74
7k 2-Furyl p-Tolyl Et Et 77
7l Bn p-Tolyl Et Et 86
7m Bn p-Tolyl p-Tolyl H 90
7n n-C6H13 p-Tolyl -(CH2)2O(CH2)2- 78
7o n-C6H13 p-Tolyl Et Et 88
7p Bn Bn -(CH2)2O(CH2)2- 75
Preparation of Polysubstituted AmidinesPreparation 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
ArHN
S
NHAr
R
N PPh3
BocHN
NHBoc
S
BocHN
NBoc
SMe
H2N
NHBoc
S
H2N
NR1
SMe
HgCl2 , TEA,
DMF, 60oC
N Me
Cl
I
N
NH
N NR2
R1
HN
R
N
N
Cl
O
Cl
NH2R
H2N
NR1
SO3H
R1HN
NH
SMe
R1HN
NR1
N N
R1HN
NTf
NHR1
R1N
O
NR1
2a-j
+aR1 = Alkyl
Et2O, 0oC
bR1 = Boc, Cbz
DCM, 20oC
cR1 = Boc, Cbz
THF, 20oC
dR1 = Ph, Pr
MeCN, 20oC
eR1 = Mtr, Pmc
Hg(ClO4)2 , TEA
f
g
hEDCl, TEA,
DCM, 20oC
iR1 = Ar
t-BuOH, heat
j
R = Ar, 4
R1= Ar, Alk;
R2 = H
THF, reflux
1 3 5
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
H2N
NH2+
Bt Bt
NR
Cl
TsO
6 7
• 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
95SC1173 01JOC2854
30Guanidylating Agents and First Bt- Literature
Second Generation Bt-Mediated Preparation of GuanidinesSecond Generation Bt-Mediated Preparation of Guanidines
Bt N
N O
N N
N O
8b
R1
R2
R3
R1
R2
R3
R4
R5
R4NHR5
a''-o''
Entry R1 R2 Yield (%)
a H Ph 80
b H n-C5H11 74
c H Bn 68
d -(CH2)4- 71
e -(CH2)2O(CH2)2- 68
f ipr ipr 68
Bt Bt
NHBt
NH
NR1
R2
R1NHR2
THF rt
8a (65%) a-f
Entry R1 R2 R3 R4 Yield
a’ -(CH2)2O(CH2)2- Ph H 64
b’ -(CH2)2O(CH2)2- p-Tolyl H 74
c’ -(CH2)2O(CH2)2- Bn H 71
d’ -(CH2)2O(CH2)2- Ph Me 85
e’ -(CH2)4- Ph H 68
f’ -(CH2)4- 4-MeOC6H4 H 60
g’ iPr iPr 4-MeOC6H4 H 48
(00JOC8080)
Entry R1 R2 R3 R4 R5 Y (%)
a’’ -(CH2)5- Ph 4-MeOC6H4 H 68
b’’ -(CH2)5- Ph (CH2)2O(CH2)2 78
c’’ -(CH2)5- Ph Ph H 76
d’’ -(CH2)5- Ph n-Bu H 84
e’’ iPr iPr Et PhC2H4 H 51
f’’ iPr iPr Et Bn H 50
g’’ iPr iPr Et i-Bu H 56
h’’ iPr iPr Et 4-MeOC6H4 H 70
i’’ iPr iPr Ph Ph H 60
j’’ iPr iPr Ph Bn H 78
k’’ (CH2)2O(CH2)2 4-MeOC6H4 (CH2)2O(CH2)2 84
l’’ (CH2)2O(CH2)2 2-Furyl PhC2H4 H 81
m’’ (CH2)2O(CH2)2 2-Furyl p-Tolyl H 79
n’’ (CH2)2O(CH2)2 4-ClC6H4 MeO2CCH(Ph)
H 70
o’’ (CH2)2O(CH2)2 4-ClC6H4 -(CH2)4- 78(01S897)
31
N
NH
NR1
R2
R3
R4
R3NHR4
THF, Reflux
a'-g'
Recent Bt-based Guanidylating AgentsRecent Bt-based Guanidylating Agents
Bt
Bt
S
Bt
RBt
N
BtS
R1 NH
RBtN
R1 NH
R N PPh3
R N PPh3
9
10
12
11a-f
13a-l
10
R1NH2
12a R1 = Bn, 98 %
12b R1 = i-Pr, 95 %
12c R1 = Ph, 90 %
12d R1 = n-Bu, 98 %
10a R = Ph
10b R = p-Tol
10c R = C6H4CN-m
10d R = C6H4CO2Et
10e R = C6H4Cl-p
10f R = COPh
10g R = C6H2(Me)3-2,4,6
12e R1 = (CH2)2Ph, 93 %
12f R1 = (CH2)5CH, 95 %
12g R1 = CH2CH(CH3)CH2CH3, 98 %
12h R1 = 2-furylmethyl, 91 %
Preparation
Bt
BtN
R Bt
NHN
R
R1
NH
NHN
R
R1
R1
R1NH2
HN
HNN
R
NH2
NH2
NN
N
BtR N C R1N
11
Toluene, reflux 1h
Toluene, reflux 1h
16a-e
= Bt
15a-e
R1NH2
Preparation of symmetrical and cyclic trisubstituted guanidines
5 examples, 79-91%
5 examples, 77-96%
R1HN
BtN
R R1HN
NN
R
R3
R2
R1HN
HNN
R
R2
R2NH2
R3NHR2
13
Toluene, reflux 12h
Toluene, reflux 1h
17a-f
18a-h
NN
N= Bt
6 examples, 67-96 %
8 examples, 71-99%
• Starting materials 11 and 13 were prepared through a novel method with good yields
Preparation of substituted unsymmetrical guanidines
32
Imidolylation at SulfurImidolylation at Sulfur
N
Bt
N
R1
R2
R3
R4
N
N
S
R1
R2
R3
R4 R5R5SHNaOMe
THF, Reflux16-18h
R1 R2 R3 R4 R5 Yield (%)
a H -(CH2)2O(CH2)2- 2,5-Cl2C6H3 4-MeC6H4 44
b H -(CH2)2O(CH2)2- 2,5-Cl2C6H3 C6H5CH2 53
c H Me Ph 2,5-Cl2C6H3 Ph 92
d H -(CH2)2O(CH2)2- 4-NO2C6H4 4-MeC6H4 44
e H -(CH2)2O(CH2)2- C6H5CH2 4-MeC6H4 46
f H -(CH2)2O(CH2)2- C6H5CH2 4-tBu-2-MeC6H3 75
g iBu -(CH2)2O(CH2)2- 3-NO2C6H4 4-Me C6H4 59
(01JOC2865)
R1 R2 R3 Yield (%)
a 4-MeC6H4 Ph iPr 90
b Me Ph iPr 77
c 4-MeC6H4 4 Ph PhCH2 91
d Me Ph PhCH2 94
N
Bt
N
SR3SHNaOMe
THF, Reflux16-18hR1
R2
R1
R2 R3
(95H231)
33
Imidoylation at Carbon (Ketones)Imidoylation at Carbon (Ketones)
N
BtN N
X
N
X
R1
R2
R1
R2
+
LDATHF, -78 oC
Overnight
12a: X=O2b: X=S
3
01JOC4041
entry R1 R2 X Yield (%)
3a Ph Ph O 85
3b Ph Ph S 79
3c Ph 4-ClC6H4 O 87
3d Ph 4-ClC6H4 S 88
3e Ph 4-BrC6H4 O 89
3f Ph 4-BrC6H4 S 98
3g 4-MeC6H4 Ph O 82
3h 4-MeC6H4 Ph S 91
3i 4-MeC6H4 4-BrC6H4 O 96
3j 4-MeC6H4 4-BrC6H4 S 89
3k Ph 4-MeOC6H4 O 84
3l Ph 4-MeOC6H4 S 85
3m 4-MeC6H4 4-MeOC6H4 O 85
3n 4-MeC6H4 4-MeOC6H4 S 84
34
1-Cyanobenzotriazole1-CyanobenzotriazoleA Safe and Convenient Source of +CNA Safe and Convenient Source of +CN
N
NMe2
NBr
N+
NMe2
N
Br-
BtHN
NN
N
NBrN-
NN
Na+
Preparation of 1-Cyanobenzotriazole1-Cyanobenzotriazole
76% 90%
1-Cyanobenzotriazole as a 1-Cyanobenzotriazole as a NN-Cyanating Reagent-Cyanating Reagent
1-Cyanobenzotriazole as a 1-Cyanobenzotriazole as a CC-Cyanating Reagent-Cyanating Reagent
Hughes et al. (98JOC401) 5 examples: 30-66 %
Bt CN2.
1. LDAAr
CN
CNAr
CN
NC Bt CN
CN
CCH CHN
nBuLi
Drechsler et al. (01JCSPT(2)581) 70% yield
Bt CN NCN
R1R+ NHR
R1 R = H
chlorobenzene
(91RRC573) 7 examples: 84-96 % yields
Whitten et al. (88S470)(91RRC573)
35
Classical Preparation of Sulfonamides:
RS
Cl
O
OR NH2 R
SNH
R
O
O
base+
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:
N N+
S
O
O
CH3
-OTfClS
O
ONH N
TfOCH3
+
Preparation of SulfonylbenzotriazolesPreparation of Sulfonylbenzotriazoles (04JOC1849)
MgBr
S Li
Li
N
Li
MgCl
R M
93
82
65
20
71
Mp(0C)
133-134
143-144
117-119
oil
131-132
of RSO2BtYield (%)
MgCl
N
N
Li
N Li
N
Li
O Li
R M Yield (%)
75
80
71
41
83
Mp(0C)
107-109
147-150
oil
132-135
128-129
of RSO2Bt
R M SO2R S
OMgBr
O
BtClR S
O
O
BtNEt3
+
Sulfonylbenzotriazoles: Preparation
O’Connell, J. F. and Rapoport, H. (92JOC4775)
36
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 20 • Selectively sulfonylate aliphatic amines over aromatic amines
S
O
O
NN N
Ph
NH2R
ArOH
SR
O
O
NH
R
SR
O
O
N R
R
SR
O
O
O Ar
NH
R R1
1
1
1
22
THF/RT
Benzotriazole-Assisted SulfonylationBenzotriazole-Assisted Sulfonylation ([94SC205] and [04JOC1849])
Generation of Sulfonamides from Sulfonylbenzotriazoles
SO
O NH
SO
O N
S SO
O N
NS
O
O
N
S
O
ON
89
72
85
Cyclohexylamine,THF/25 0C/18 h
N-Methylbenzyl-amine,
THF/25 0C/15 h
Piperidine,THF/25 0C/42 h
YieldAmine/Conditions Sulfonamide
99Piperidine,THF/25 0C/20 h
(%)
Piperidine,DMF/80 0C/48 h 99
R S
O
OBt
NH
R2R1
RS
O
ON
R1
R2
S SO
O NH
NO
N
N
S
O
O
N
N
SN
O
OH
O SO
O NH
91
64
80
Morpholine,DMF/80 0C/24 h
1, 5- dimethyl-hexylamine,
DMF/80 0C/24 h
Phenethylamine,DMF/80 0C/48 h
992-Aminopentane,DMF/80 0C/24 h
Yield (%) Amine/Conditions Sulfonamide
3 examples: 87-93% yields
4 examples: 64-99% yields
10 examples: 51-99% yields
37
38Coworkers in Benzotriazole Chemistry 1987-2005Argentina
Laura Moyano
Australia
Darren CundyScott HendersonRichard MusgraveNassem PeerzadaPaul SavageAdam WellsStuart Barrow
Austria
Isolde Puschmann
Azerbaijan
Novruz AkhmedovRena Akhmedova
Belgium
Annie MayenceChris StevensJ.-J. Vanden Eynde
Brazil
Alessandro Soares
China
Weilang BaoChunming CaiXiaohong CaiHe-Xi ChangJie ChenJun ChenKe ChenYaxing ChenDai ChengXilin CuiWeihong DuWei-Qiang FanYunfeng FangDaming FengHai Ying HeQing-Mei HongXiang HongTan Bao HuangZhizhen HuangFu Bao Ji
Yu JiJinlong JiangRong JiangXiangfu LanHengyuan LangKam Wah LawJinqung LiLingfei LiuQiu-He LongZiwei LuPing LueZhushou LuoRexiat MaimaitMing QiGuofang QiuHuimin SongHui TaoHongbin TuJin WangJunquan WangMingyi WangXiaoling WangZuoquan WangHong WuJiaxing WuJing Wu Linghong XieYongjiang XuBaozhen YangHongfang Yang Zhijun YangGuo-Wei YaoJiangchao YaoYeyi YinYanhua YuGui-Fen ZhangLianhao ZhangSuoming ZhangYongmin ZhangYuming ZhangZhongxing ZhangHongyan ZhaoXiaoming ZhaoDazhi ZhongLie Zhu
Columbia
Rodrigo AboniaHenry Insuasty
Egypt
Ahmed El-SayedSaad El-ZemityAbdel Haleem HusseinFatma MahniAshraf Abdel-FattahSamia Agamy
France
Sophie BusontChristophe ChassaingCatherine GarotJeremy KisterStephane LedouxYves LeGallOlivier LingibeDaphne MonteuxJean-Luc MoutouDavid PleynetDelphine SemenzinGeoffroy Sommen
Germany
Michael ArendTorsten BlitzkeNicole ClemensPeter CzerneySebastian HoffmanAldo JesorkaSimona JurczykJens KoeditzThomas Kurz
Ghana
Augustine Donkor
Greece
John GallosK. Yannakopoulou
Hungary
Ferenc SotiLaszlo Urogdi
India
Parul AngrishM. BalasubramanianVandana GuptaRitu JainJamshed LamSuman MajumderNegeshwar MalhotraKavita ManjuT. MayelvagananNabin MeherShamal MehtaPrabhu MohapatraSatheesh NairSubbu PerumalMungala RaoNavayath ShobanaSandeep SinghSanjai SinghShaleindra SinghSrinivasa Rao TalaAjith Dain ThomasSutha VellaichamyAkhilesh Verma
Jamaica
Keisha Gay Hylton
Japan
Kunihiko AkutagawaYasuhisa MatsukawaKazuyuki SuzukiIchiro Takahashi
Jordan
Shibli Bayyuk
Lebanon
Niveen Khashab
New Zealand
Peter Steel
Nigeria
Clara Fali
Palestine
Abd Ferwanah
Panama
Herman Odens
Poland
Piotr BarczynskiJoanna BorowieckaJacek BrzezinskiZofia Dega-SzafranJacek DoskoczBarbara GaluszkaKrzysztof IndzikAndrzej JizwiakW. KuzmierkiewiczZbigniew NajzarekMaria PaluchowskaJuliusz PernakBoguslaw PilarskiBogumila RachwalStanislaw RachwalDanuta RasalaFrank SaczewskiJadwiga SoloduchoMirek SzafranMaria SzajdaLeszek Wrobel
Pakistan
Amir AfridiMuhammad Latif
Romania
Diana AslanMircea DarabantuIon GhivirigaDaniela OniciuDorin ToaderIoan Silberg
Russia
Sergey BobrovZoya DemyanetsOlga DeniskoMikhail GordeevAnna GromovaAlexy IgnatchenkoYekaterina Kovalenko
Alexander LesinValery MortikovGeorgiy NikonovIrina ScherbakovaAlexander ShestopalovSergei VerinMichael VoronkovVladimir Vvedensky
Slovenia
Sonja Strah
So. Africa
Jaco BreytenbachNazira Karodia
So. Korea
Young-Seuk HongYoung Soo Gyong
Spain
Pilar CabildoJusto Cobo-DomingoBalbino ManchenoAlfredo Pastor-del-CastilloOlga Rubio-Teresa
Sudan
Ahmad Yagoub
Switzerland
Frederick Brunner
Syria
Mohammed Soleiman
Togo
Rufine Akue-Gedu
Turkey
Alaettin GuvenDeniz Hur
UK
Steve AllinRichard BarcockMike BlackAndy BriggsMartin ButtonKevin Doyle
John GreenhillDennis HallPhilip HarrisGregory HitchingsPeter LeemingJulian LevellJulie Thomson
Ukraine
Sergei BelyakovAnna DenisenkoSergei DenisenkoKonstantin KirichenkoNatalie KirichenkoAlexander MitrokhinBoris RogovoyAlina SilinaLarisa SerdyukAlexander SorochinskyDmytro TymoshenkoAnatoly Vakulenko
USA
Ken CasterJanet CusidoTerry DavisChris DiebertM. Drewniak-DeyrupRachel Fuller-WitekKenny HeckAmy HaydenCraig HughesGlen NobleRick OffermanPhilip PhelphreyDaniel NicolsValerie RodriguezJames RogersJohn StevensDoug TathamAdam VincekChavon Wilkerson
39Katritzky Group Financial Support 1987-20053M 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, NetherlandsParke-Davis, MIPfizer, 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