Acylation and Related Reactions

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Transcript Acylation and Related Reactions 

1
Acylation and Related Transformations
Alan R. Katritzky, Kazuyuki Suzuki, Ashraf A. AbdelFattah, 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 NSubstituted 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 BenzotriazoleStabilized Carbanions”
•
[98T2647] “ The Generation and Reactions of NonStabilized a-Aminocarbanions”
•
[00PAC1597] “Designing Efficient Routes to
Polyfunctionality”
•
[01SL458] “The preparation of Mono-, 1,1-Di-, trans-1,2Di- and Tri-Substituted Ethylenes by Benzotriazole
Methodology”
•
[03CEJ4586] “Benzotriazole:An Ideal Synthetic Auxiliary”
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
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
O
N
Widely used
N
R
2
3
Preparation of N-Acylbenzotriazoles
direct from Carboxylic Acids
1.
Use of Counter-attack reagent
O
+
R
O
MeSO2Bt
O
R
O
Any salts
(or p-CH3C6H4SO2Bt)
as Na+ or Et3NH+
O SO2Me
+ Bt
- MeSO3
R
Bt
(00JOC8210)
2.
Via Sulfinyl-bisbenzotriazole
O
BtH
4 mols
+
SOCl2
1 mol
Bt
O
S
R
OH
Bt
O
R
Bt
+ SO2 + BtH
Unstable
+ 2BtH HCl
(03S2795)
N-Acylbenzotriazoles: Aliphatic, Aromatic, Heteroaromatic
RCOBt
mp
HCOBt
94-96
Yield RCOBt
71
4-ClC6H4CH2COBt
mp
Yield
90-91
64
CH3COBt
49-51
92
3-ClC6H4COBt
120-121
74
C2H5COBt
73-74
92
4-ClC6H4COBt
138-139
74
C3H7COBt
62-63
79
4-BrC6H4COBt
142-143
93
n-C4H9COBt
42-44
83
4-FC6H4COBt
119
98
Me2CHCOBt
Oil
91
4-NO2C6H4COBt
193-194
83
tBuCOBt
71-72
94
4-Et2NC6H4COBt
86-87
85
tBuCH COBt
2
56-57
83
4-HOC6H4COBt
199-200
84
Oil
96
CCl3COBt
78
98
n-C15H31COBt
54-55
89
CF3COBt
89-91
70
tBuCH CHMeCH COBt
2
2
157-158
86
CF3CF2CF2COBt
oil
86
PhCH2COBt
65-66
84
BtCOCOBt
163-164
92
Ph2CHCOBt
88-89
89
BtCOBt
182-184
90
PhCH2CH2COBt
63-64
84
173-175
92
C5H11COBt
PhCOBt
4-CH3C6H4COBt
112-113
93
123-124
91
2-CH3OC6H4COBt
96-97
72
4-CH3OC6H4COBt
104
93
COBt
RCOBt
mp
4
Yield
COBt
87-89
88
COBt
149-151
84
COBt
146-147
76
215-216
90
136-137
92
232-234
88
205
82
191
92
189
54
164-166
95
N
N
N
N
COBt
N
H
COBt
BtOC
COBt
BtOC
COBt
COBt
S
COBt
COBt
O
COBt
N
H
COBt
N
171-173
97
161-162
75
98-100
91
N
BtOC
MeO
COBt
COBt
N-Acylbenzotriazoles
5
From Unsaturated, Functionalized and Bis-acids
RCOBt
mp
oil
COBt
CH3CH=CHCOBt
PhCH=CHCOBt
HC≡ CCOBt
86
151-152
96
124-125
83
COBt
O
83
87-88
99-100
PhC≡ CCOBt
Yield RCOBt
142-144
95
RCOBt
COBt
S
169-170
O
98
Cl
87-88
86
BrCH2COBt
91-92
87
Cl2CHCOBt
87-88
86
CH3OCH2COBt
103-104
96
PhSCH2COBt
103-104
90
PhCOCOBt
72-73
72
O2N
244-245
174-175
MeO
BtCO(CH2)4COBt
170-171
75
BtCO(CH2)18COBt
121-122
63
MeO2C(CH2)3COBt
COBt
51-52
87
300
77
Bt
136-137
Bt
S
65
Bt
O
O
COBt
118-120
158-160
80
98-100
40
Bt
142-144
98
159-160
87
95
O
S
60
O
O
Bt
196-197
188-189
O
Bt
183
16
98
COBt
HO
247
O
O
O
94
Bt
Bt
MeO
82
O
O
COBt
223-225
Bt
O
MeO
COBt
COBt
90
Yield
O
O
96
mp
Bt
Bt
COBt
183-184
O
COBt
COBt
BtOC
Yield
Bt
92
Cl
BtOC
mp
56
O
S
Bt
Bt
O
COBt
91-92
86
COBt
165-167
59
Bt
S
S
Bt
104-105
O
98
6
N-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 NAcylbenzotriazole
Yield
ee.*
Amino
Acid
N-Protecting
Group
Structure of NAcylbenzotriazole
Yield
ee.*
L-Gly
Cbz
Cbz-Gly-Bt
99
>97
L-Phe
Boc
Boc-L-Phe-Bt
81
>97
L-Ala
Boc
Boc-Ala-Bt
61
>97
L-Phe
Cbz
Cbz-L-Phe-Bt
88
>97
L-Ala
Cbz
Cbz-L-Ala-Bt
95
>97
L-Phe
Fmoc
Fmoc-L-Phe-Bt
83
>97
L-Ala
Fmoc
Fmoc-L-Ala-Bt
79
>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-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-Ileu
Cbz
Cbz-L-Ileu-Bt
95
>97
L-Val
Boc
Boc-L-Val-Bt
83
>97
L-Pro
Cbz
Cbz-L-Pro-Bt
74
>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.
(04S2645)(04S1806)(05S397)(In Preparation)
N-Acylbenzotriazole Derivatives from N-Protected
Amino Acids with Functionality
7
Structure of NAcylbenzotriazole
Functionality
Yield
ee.a
Structure of NAcylbenzotriazole
Functionality
Yield
ee.a
Cbz-L-Trp-Bt
Indole NH
95
>97
Fmoc-L-Trp-Bt
Indole NH
90
>97
Cbz-L-Tyr-Bt
Phenol OH
86
>97
Fmoc-L-Met-Bt
CH2SMe
87
>97
Cbz-L-Gln-Bt
Amide NH2
72
>97
Fmoc-L-Ser-Bt
Alcoholic OH
68
>97
Tfa-L-Asp(OMe)-Bt
CO2Me
80
>97
Cbz-L-Cys-Bt
SH
76
>97
Tfa-L-Glu(OMe)-Bt
CO2Me
82
>97
Cbz-L-Asn-Bt
Amide NH2
72
>97
Cbz-L-Asp(OMe)-Bt
CO2Me
82
>97
Structure of NAcylbenzotriazole
Functionality
Yield
ee.a
Cbz-L-Met-Bt
CH2SMe
95
>99
Z-L-Cystine-Bt
S-S dimer
90
>97
Cbz-L-His-Bt
Imidazole NH
70b
>95c
Z-L-Asp-diBt
Two COBt
87
>97
Z-L-Glu-diBt
Two COBt
68
>97
(05S397) (In Preparation)
Di-Bt derivatives
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
8
N-Acylbenzotriazole Derivatives
from N-Protected Dipeptides
R1
R1
O
2
R
Z NH
BtH, SOCl2
NH
O
o
O
R2
Z NH
NH
THF, -10 C
O
HO
Bt
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
95
3
Z-L-Phe-D-Ala-Bt
90
156157
95
4
Z-L-Trp-L-Ala-Bt
78
176177
95
5
Z-L-Trp-L-Trp-Bt
76
152154
95
6
Z-L-Met-L-Ala-Bt
85
104105
95
7
Z-L-Met-D-Ala-Bt
87
135137
95
*e.e. was estimated in 1H NMR.
(04S2645)(04S1806)(05S397)
Virtues 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)
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
9
N-Acylation:
Amides from N-acylbenzotriazoles
Primary amides RCONH2
R
Yield(%)
C6H5
100
2-CH3OC6H4
100
3-ClC6H4
87
4-NO2C6H4
100
2-Furanyl
100
1-Naphthyl
100
2-Pyridyl
100
3-Pyridyl
100
4-Pyridyl
100
2-Pyrazinyl
100
PhCH2
100
PhCH2CH2
85
Ph2CH
90
n-C4H9
72
(00JOC8210)
For reactions with Wang resin
linked amines see 02BMCL1809
Secondary amides RCONHR
R
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
70
Tertiary amides RCONRR
R
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
10
Chiral Integrity of Peptide Synthesis
11
Preparation of N-(Boc acylamino)amides
2. The chiral column method
1. The NMR method
Me
R
Boc NH
O
H2N
Ph
Bt
R
O
Me
Boc NH HN
Ph
1H
NMR of Boc-Valine derivatives
(02Arkivoc(viii)134)
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
R.Time
Cbz-L-Tyr-LPhe-OH
10.8
Cbz-L-Tyr-DPhe-OH
11.7
Cbz-L-Trp-LAla-OH
11.0
Cbz-L-Trp-DAla-OH
12.9
Fmoc-L-TrpL-Ala-OH
11.1
Fmoc-L-TrpD-Ala-OH
13.6
Cbz-L-Cys-LPhe-OH
11.5
Cbz-L-Cys-DPhe-OH
24.3
Cbz-L-Met-LAla-OH
10.9
Cbz-L-MetD-Ala-OH
15.9
Cbz-L-Gln-LPhe-OH
12.9
Cbz-L-Gln-DPhe-OH
15.9
R.Time = Retention Time
(05S397)
12
Methods of Peptide Preparation
Stepwise coupling:
R1
R2
O
Et3N
R1
CH3CN/H2O
Cbz NH HN
O
O
R2
+
Cbz NH
Bt
H2N
OH
r.t. 0.5 h
1
R
2
O
R
Cbz NH
Et3N
HO
R1
CH3CN/H2O
Cbz NH HN
O
3
R
+
Bt
H2N
HN
85~98%
O
O
O
R2
O
r.t. 0.5~1.0h
HO
HN
R3
HO
O
Fragment coupling:
85~98%
R3
1
R
1
R
O
R2
O
Cbz NH HN
OH
O
Cbz NH HN
Cbz NH HN
HO
H2N
O
R2
O
R2
BtH, SOCl2
R1
O
HN
O
0 oC
R3
Bt
HO
R1 = CH2Ph, R2 = Me, 85%
O
R1 = Me, R2 = CH2Ph, 90%
92~95%
Ph
O
Ph
O
O
Et3N
Cbz NH HN
O
+
Cbz NH HN
H2N
(04S2645)
CH3CN/H2O
HN
O
Bt
O
HO
HN
r.t. 2.0h
HO
86%
HN
O
O
13
Preparation of Dipeptides
Chiral Dipeptides
Yield(%)
ee.a
Cbz-L-Met-L-Ala-OH
95
>97
Cbz-L-Ala-L-Phe-OH
90
>97
Cbz-L-Met-D-Ala-OH
95
>97
Cbz-L-Ala-L-Ser-OH
85
>97
Cbz-L-Met-L-Met-OH
95
>97
Cbz-L-Ala-L-Trp-OH
97
>97
Cbz-L-Met-L-Trp-OH
82
>97
Cbz-L-Val-L-Phe-OH
98
>97
Cbz-L-Met-L-Glu-OH
60
>97
Cbz-L-Val-L-Trp-OH
96
>97
Cbz-L-Gln-L-Phe-OH
72
>97
Cbz-L-Phe-L-Ala-OH
98
>97
Cbz-L-Gln-L-Gln-OH
47
>97
Cbz-L-Phe-L-Val-OH
95
>97
Cbz-L-Gln-L-Val-OH
95
>97
Cbz-L-Phe-L-Phe-OH
98
>97
Fmoc-L-Trp-L-Ala-OH
70
>97
Cbz-L-Phe-L-Ser-OH
96
>97
Fmoc-L-Trp-L-Ser-OH
87
>97
Cbz-L-Tyr-L-Phe-OH
86
>97
Fmoc-L-Met-L-Ser-OH
88
>97
Cbz-L-Tyr-L-Trp-OH
98
60
Fmoc-L-Met-L-Glu-OH
93
>97
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
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-, and Tetra -Peptides
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
14
(04S2645)
(In progress)
a:The ee. value was estimated
by 1H NMR and HPLC
analysis.
b; Diastereomeric mixture
15a
Synthesis of Weinreb amides and Hydroxamic acids
O
R1
Bt
HN
R3
+
OR2
O
Et3N, THF
R
r.t.
R1: alkyl, aromatic
R2: H, Et, Bn
1
N
R3
OR2
Weinreb amides: 24 examples (64-94%)
Hydroxamic acids: 6 examples (61-91%)
R3: H, Me
(02ARK39) (03S2777)
Synthesis of Chiral 1,2,4-Oxadiazoles
R1
1
R
O
Pg NH
Bt
HO
H2N
N
EtOH
R2
25 oC
R
O
Pg NH
reflux
O N
R2
Can be isolated
O N
EtOH
NH2
Pg NH
N
5 min
Pg = Boc, Cbz, Fmoc
Amino acid with R: alanine, valine, phenylalanine, methionine, tryptophan, and glutamine
R2
18 examples
(average yield 88%)
R2: p-tolyl, benzyl, p-pyridyl
Bt = benzotriazol-1-yl
(05ARK, In press)
15b
N-Acylation of Sulfonamides
O
1
R
+
Bt
R2
O
S NH2
O
NaH
R1
THF
O O
R2
S
18 examples
N
O
(78-98%)
H
R1: Aromatic and amino acid derivatives
2
R SO2NH2: MeSO2NH2, p-MeC6H4SO2NH2, and acetazolamide
(02ARK14)
Microwave-assisted Preparation of Oxazolines and Thiazolines
O
R1
1
Bt
+
R : Aromatic
HX
R2
R2
NH2
2
X = O, R = Me
2
X = S, R = H
1) M.W. 80 oC, 10min
2) M.W. 80 oC, 2min
R2
R2
O
R1
N
SOCl2
X = O, 10 examples (84-98%)
X = S, 8 examples (85-97%)
(04JOC811)
16
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 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.
17
S-Acylation
Synthesis of Thiol esters
O
O
R
R of reactant
RCOBt
R
CH2Cl2, r.t.
Bt
S R'
O
O
O
HS R'
Et3N
R
R
O
R
S
S
S Ph
R
Ph
S
CO2Et
CO2H
C6H5 (1a)
Yield %
92
Yield %
98
Yield %
93
Yield %
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
*The crude product was obtained in 90% yield.
Ph
HS R
CH2Cl2 / Et3N (cat.)
O
Pg NH
Bt
1h., 25oC
Pg = Boc, Cbz
(04S1806)
Pg-Phe-SR
Ph
Yield (%)
mp (oC)
O
Boc-Phe-SPh
76
102103
S
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
Pg NH
R
18
O-Acylation
O-Acylated steroids, terpenes, sugars, and lipids
R
O
Microwaves
+
Z NH
H
Cholesterol
O
o
Bt
65 C, 20 min
H
R
Z = PhCH2OCO-
H
O
NH
Z
R = L-Me2CH- (88%), L-PhCH2- (82%)
D-PheCH2- (84%)
R
O
+
Z NH
O
Microwaves
Bt
R
Nerol
65 C, 20 min
Z
H
N
R
H OH
HO
HO
HO
H
H
H
OH
OH
HO
HO
HO
NH
R = L-3-IndolylCH2- (XX%)
L-CH3SCH2CH2- (XX%)
Pg
O
HO
H
H
D-Glucose
O
o
H
OH
OH
Pg = Fmoc, CBZ
(Unpublished work)
19
C-Acylation (i) Aryl and Heteroaryl Rings
O
R
O
Bt
TiCl4or ZnBr2
R
5 examples
54~98% (Average 79%)
O
O
R1
N
R2
R
5 examples
58~97% (Average 80%)
S
S
O
R1
AlCl3
R2 = H
R2 = Me
PG
Bt
N
H
CH2Cl2, 20 °C
O
PG = Tfa, R1 = Phenyl
N
X
N
X
X = H, Me
O
R
TiCl4
52~82% (Average 70%)
5 examples for R2 = Me
N
Si(i-Pr)3
N
X
R2 = Me
O
TiCl4
N
X
7 examples for X = H
15~92% (Average 66%)
7 examples for X = Me
27~92% (Average 69%)
R
1
1
R
AlCl3
PG
R2 = H
R
41~78% (Average 60%)
PG = Fmoc, R1 = CH2SMe
6 examples
54~92% (Average 79%)
N
Si(i-Pr)3
N
H
Bt
CH2Cl2, 20 °C
O
PG
N
H
R2
N
O
PG = Tfa, R1 = Phenyl
5 examples for R2 = H
PG= Tfa, R1 = H
63~87% (Average 79%)
PG = Fmoc, R1 = Phenyl
5 examples for R2 = Me
1
PG = Fmoc, R = indol-3-yl
40~90% (Average 62%)
PG = Fmoc, R1 = CH2SMe
X = H, Me
(03JOC5720)(04CCA175)
O
PG = Fmoc, R1 = Phenyl
R2
N
O
N
R2
PG= Tfa, R = H
PG = Fmoc, R = indol-3-yl
7 examples for X = H
21~91% (Average 56%)
7 examples for X = Me
51~94% (Average 70%)
R
N
H
5 examples for R2 = H
1
1
TiCl4
PG
(In progress)
20
C-Acylation (ii) Ketones, Sulfones, Nitrocompounds and Imines
O
O
1
R
3
R
R2
O
R3
R2
Bt
LDA
(00JOC3679)
16 examples
R1
O
R1 = alkyl or aryl
R2 +R3 = alkyl or
alicyclic
(Average isolated yield 75%)
O
R2
3
1
R
S
O2
R
R2
O2S
Bt
R3
(03JOC1443)
1
R
n-BuLi
O
18 examples
(Average isolated yield 80%)
R1 = alkyl or (hetero)aryl
R2 = hydrogen, alkyl,
vinyl or aryl
R3 = alkyl or aryl
O
2
O
1
R
R
Bt
NO2
1
R
t-BuOK
NO2
(In Progress)
14 examples
R2
R1 = alkyl or (hetero)aryl
R2 = hydrogen, or alkyl
(Average isolated yield 67%)
O
3
N
2
R
R
1
R
LDA
Bt
R2
R3
N
H
O
R1
(00S2029)
R1 = alkyl, alkenyl or aryl
16 examples
R2 = alkyl, or aryl
(Average isolated yield 62%)
R3 = alkyl (acyclic or
alicyclic)
21
C-Acylation (iii) Heteroaryl Alkyl Groups
O
Het
R1
R2
Bt
LDA
Het
O
2
R
Het
1
2
R
Entry
Het
R1 of
R1COBt
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Pyridin-2-yl
Pyridin-2-yl
Pyridin-2-yl
Pyridin-2-yl
Pyridin-2-yl
Pyridin-2-yl
Pyridin-2-yl
Pyridin-2-yl
Pyridin-2-yl
Quinolin-2-yl
Quinolin-4-yl
Quinolin-4-yl
Quinolin-4-yl
Pyrimidin-4-yl
Pyrimidin-4-yl
(CH3)2CHCH2
CH3(CH2)2CH2
PhCH=CH
Ph
4-ClC6H4
Furan-2-yl
Thiophen-2-yl
Pyridin-3-yl
4-ClC6H4
Ph
4-ClC6H4
4-NO2C6H4
Thiophen-2-yl
Thiophen-2-yl
Furan-2-yl
OH
R
(In
Progress)
1
R
R2 of
HetCH2R2
Yield (%)
(keto +enol)
Keto/ enol
(%)
H
H
H
H
H
H
H
H
Ph
H
H
H
H
H
H
65
56
65
78
83
84
68
72
95
91
87
72
66
80
50
69/ 31
67/ 33
50/ 50
59/ 41
38/ 62
68/ 32
85/ 15
16/ 84
58/ 42
8/ 92
100/ 0
100/ 0
100/ 0
50/ 50
50/ 50
C-Acylation (iv) -Keto Esters and -Diketones
22
O
R1
O
CO2Et
H3C
Bt
2
1
R CO
NaH
R2
1
Entry
R1
R2
Yield (%)
(keto +enol)
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
Ph
4-ClC6H4
4-MeC6H4
2-Furyl
4-Pyridyl
n-C5H11
4-MeC6H4
n-C5H11
2-Furyl
2-Thienyl
2-Pyridyl
Ph
(Ph)2CH
2-Furyl
2-Thienyl
Ph
Ph-
4-ClC6H4
H
H
H
H
H
H
Me
Me
Me
Me
Me
Me
Me
Bn
Bn
Bn
Bn
Bn
76
84
85
70
71
58
76
52
71
60
60
54
51
69
71
65
54
53
Keto
(%)
83
78
86
93
39
92
100
93
100
100
100
100
100
100
100
100
0
100
O
COCH3
CO2Et
2
R
CO2Et
R1
R2
3
4
O
O
R1
O
2
H3C
R
Bt
2
NaH
O
R1
5
OH O
O
R1
R2
R2
6
Yield (%)
enol
Entry
R1
R2
(keto +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
(04JOC6617)
Thioamides
Route A
23
Route C
S
R1
R
N
R2
Route B
Routes
O
A (i)
R
1
R
N
R2
Routes
S
P2S5 or
Lawesson's
Reagent
1
R
RLi
R
A (ii)
Ph
1
N R
R2
S
B (i)
S
R1
Me
N+
O-
N
2
R
S
RMgX
N
(Im)2CS
R2 N C S
B (ii)
R2
RMgX
NiCl2(dppe)
S
S
R
+
HN
Y
R1
R2
Me N
Me
Cl
B (iii)
Y= Cl, OEt, Im, Bt
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.
Route C
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.
Rapoport’s method for the
Benzotriazole-Based Thioacylation
Reagents
24
Preparation of Thiocarbonyl-1H-6-nitrobenzotriazoles
NO2
NH2
RCSBt: Synthesis of Thioacylbenzotriazoles from Grignards
CS2
R MgBr
R
THF
R
SMgBr
R
4-Tolyl
4-Methoxyphenyl
Phenyl
NO2 2) HONO R
HN
R
S
BtCl
1)P2S5
RCOCl
NH2
O2N
S
H2N
O
S
N
N N
(96JOC9045) 6 examples:56-67 % yields
(99JOC1065) 9 examples: 48-55 % yields
(Unpublished results) 7 examples: 44-78% yields
Bt
RR1NCSBt: Preparation of Thiocarbamoylbenzotriazoles
% Yield
63
89
76
N
S
+
Cl
S
N
Cl
N
SiMe3
R1
R NH
Bt
S
Bt
Bt
N
R1
2
1
ROCSBt: Synthesis of Alkyl/Aryloxythiocarbonylbenzotriazoles
S
Bt
S
Bt
+
1
HO R
Bt
O
R1 =
R
1
Ethyl (19%)
2-Naphthyl (87%)
3-Pyridinyl (66%)
1-Naphthyl (81%)
Phenyl (83%)
RSCSBt: Synthesis of Alkyl/Arylthiothiocarbonylbenzotriazoles
S
S
1
Bt
Bt
+ HS R
S
1
Bt
S
R +
Bt
S R
Bt
R1
a) Phenyl
b) Benzyl
c) Acetyl ethyl ester
d) Isopropyl
46%
42%
63%
0%
21%
44%
trace
90%
1
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
R
25
Thioacylations with Benzotriazole Reagents
([04JOC2976] and unpublished work)
Synthesis of Thioureas from Thiocarbamoylbenzotriazoles
Synthesis of Thioamides from Thioacylbenzotriazoles
S
R
S
1 2
S
R R NH
Bt
1
R
Bt
N
R2
R
N
H
R
1) R NH2
S
N
R
R
1
R-M(X)
Bt
2
R
1
N
2
2 R
9 examples:
average isolated yield 71%
RO
Note:
= H,
No Reaction
2)
R
R2
1
R1
NH
RS
N
2
R
R
4 examples: average yield 84 %
N
H
N
R1
R2
S
nBuLi
1
R
Thionesters and Thiocarbamates from Aryloxythioacylbenzotriazoles
S
S
N
H
17 examples: average yield 84 %
N
2
R
2 examples:
59 and 60 % yields
RSH
Bt
S
ROH
R2
N
R3
S
R
Bt
R
R
NH
Bis-(benzotriazolyl)methanethione One-pot Syntheses
of Thioureas:
Synthesis of Thioamides, Thiocarbamates, and
Dithiocarbamates from Thiocarbamoylbenzotriazoles
S
R3
2
15 examples: average yield 89 %
6 Examples: average isolated yield 87 %
S
+
S
Et3N
2
R
O
Bt
O
RR2NH
R
S
1
N
O
R
73% yield
R =R1 Morpholinyl 70%
R = Benzyl R1 = H 85%
26
Imidoylation-Scope
•
•
Scope: on
- Nitrogen ---Amidines, Guanidines
- Carbon ------Imines
- Sulfur ------Imidothioformate
Agents for imidoylation
- Imidolyating agents
Imidoyl chlorides, imidate fluoroborates,
and iminium triflates
H
R' N
R
H
R' N
N
R''
N
R'' N
R''
H
Guanidines
Amidines
N
H + R2
N
R2
R1
Cl
TfO
R1
EtO
Imidoyl chlorides
BF4-
H + R2
N
Imidate fluoroborates
OTf -
R1
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
N
R
R
Bt
a
N
Bt
R
Bt
b
N
RNH
R
Bt
c
27
Reagents for the Preparation of Amidines
•
•
Conventional methods
N
Preparation of Imidoylbenzotriazoles
R2
R1
Cl
1
O
R1
N
H
R2
H + R2
N
_
BF4
R1
EtO
R3
H
N
HO
N
R4
R3
N
R2
99OL577, 12 examples
N
Yield: 20-87%
R2
R1
R1
O
R4
2
O
H + R2
N
_
OTf
R1
TfO
N
H
R1
R2
Bt2SO
• Iminium triflates and imidate fluoroborates
require handling under inert atmosphere and
cannot be isolated or purified.
R2
95H231, 10 examples
Yield: 15-75%
R1
R2NCO 6 examples
N
R1
N
H
Yield: 71-99%
Bt
PPh3/BtCl
O
R2
Imidoylbenzotriazoles are good substitutes
for imidoyl chlorides.
R2NC/BF3
BtH
POCl3, NEt3
04JOC5108, 9 examples
R1
BtR1
01JOC2865
11 examples
O
Yield: 40-90%

Bt
01JOC1043
3
• Imidoyl chlorides are generally prepared in
situ, but they are extremely labile toward
hydrolysis and side reactions have been
reported at elevated temperatures.
R1
BtTs
N
H
R2
90CB1545, 8 examples
Yield: 38-96%
Yield: 87-99%
A Facile Preparation Method for Imidoylbenzotriazoles
R2
i (COCl)2, PyH
ii BtH
N
R2
R
1
NHR2
route B
Bt
R
N
BtH + SOCl2
route A
1
R1
Bt
O
R1 = Aryl
R1 = Alkyl
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
28
Preparation of Polysubstituted Amidines
N
R
AcOH, microwaves
H
N
+
Bt
R1
N
R2
R3
120
oC,
R3
120 W, 10 min
29
R
R1
N
R2
7a-p
Entry
R
R1
R2
R3
7a
Ph
Me
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
7h
Ph
Ph
Ph
Me
72
7i
Ph
Ph
p-Tolyl
H
66
7j
2-Furyl
p-Tolyl
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
7o
n-C6H13
p-Tolyl
7p
Bn
Bn
-(CH2)2O(CH2)2-
-(CH2)2O(CH2)2-
-(CH2)2O(CH2)2-
-(CH2)2O(CH2)2-
Et
Et
-(CH2)2O(CH2)2-
Yield (%)
76
63
74
78
88
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.
Literature and First Bt- Guanidylating Agents
Literature reagents
2a-j
R NH2
1
O
a
b
R1N
2a
R1HN
2b
c
1
R HN
O
R1 = Alkyl
NTf
NHR1
NR1
N N
Cl
ArHN
R = Ar, 4
3
Et2O, 0oC
R1 = Boc, Cbz
DCM, 20oC
2f
g
2d
e
R1HN
2e
Cl
N Me
S
I
1
o
THF, 20 C
NHBoc
h
H2N
EDCl, TEA,
DCM, 20oC
S
NH
SMe
NR1
1
R = Ph, Pr
SO3H
H2N
NR
TsO
Bt
6
95SC1173
Bt
Cl
7
01JOC2854
2g
2h
NR
H2N
DMF, 60oC
NHBoc
BocHN
NH2+
HgCl2 , TEA,
SMe
R1 = Boc, Cbz
2c
d
BocHN
NHAr
5
NBoc
f
Early Bt derivatives
S
N PPh3
N
N
+
NR1 Cl
R
R
HN
30
MeCN, 20oC
i
H2 N
2i
R1 = Mtr, Pmc
Hg(ClO4)2 , TEA
j
R1
N
2
2j R
R1 = Ar
t-BuOH, heat
SMe
NH
N
N
R1= Ar, Alk;
R2 = H
THF, reflux
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
• 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%).
Second Generation Bt-Mediated Preparation of Guanidines
31
R3
NH
Bt
Bt
NH
NH
R1NHR2
R1
Bt
THF
rt
N
R3NHR4
R3
THF, Reflux
R2
R1
N
N
R4
R2
Yield (%)
Entry
a
H
Ph
80
a’’
b
H
n-C5H11
74
c
H
Bn
Y (%)
-(CH2)5-
Ph
4-MeOC6H4
H
68
b’’
-(CH2)5-
Ph
(CH2)2O(CH2)2
78
68
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
(CH2)2O(CH2)2
84
e
-(CH2)2O(CH2)2-
68
ipr
ipr
68
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
4-MeOC6H4
H
48
(00JOC8080)
R2
R2
a''-o''
R5
71
R1
R1
R4
-(CH2)4-
iPr
N
R3
d
iPr
N
R5
R2
R1
R4
R1
N
O
N
R4NHR5
2
8b R
R1
Entry
g’
Bt
Entry
f
O
N
a'-g'
a-f
8a (65%)
R3
k’’
(CH2)2O(CH2)2
4-MeOC6H4
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
(01S897)
-(CH2)4-
78
Recent Bt-based Guanidylating Agents
32
Preparation of symmetrical
and cyclic trisubstituted guanidines
Preparation
Bt
S
Bt
R
Bt
R N PPh3 10
N
Bt
Bt
9
11a-f
R
Bt
R N PPh3 10
1
NH
R
1
12c R = Ph, 90 %
12d R1 = n-Bu, 98 %
10b R = p-Tol
10c R = C6H4CN-m
R
N
Toluene,
reflux 1h
R
Toluene,
reflux 1h
1
NH
Bt
N
R
Bt
R1NH2
N
N = Bt
HN
R1 NH
N
HN
N
R 16a-e
R1 NH
5 examples,
77-96%
1
12g R = CH2CH(CH3)CH2CH3, 98 %
Preparation of substituted unsymmetrical
guanidines
12h R1 = 2-furylmethyl, 91 %
Bt
3
N
R
1
R HN
• Starting materials 11 and 13 were
prepared through a novel method with
good yields
N
R 15a-e
5 examples,
79-91%
12e R1 = (CH2)2Ph, 93 %
12f R1 = (CH2)5CH, 95 %
R N C N R1
NH2
NH2
10g R = C6H2(Me)3-2,4,6
13a-l
R1NH2
11
10f R = COPh
NH
12
12a R1 = Bn, 98 %
12b R1 = i-Pr, 95 %
10a R = Ph
10e R = C6H4Cl-p
S
1
Bt
10d R = C6H4CO2Et
1
R NH2
Bt
N
R
2
R NHR
Toluene,
reflux 12h
2
R
R3
N
1
R HN
13
Toluene,
reflux 1h
N
R
17a-f
6 examples,
67-96 %
R2NH2
N
N = Bt
R2
N
HN
R1HN
N
R 18a-h
8 examples, 71-99%
33
Imidolylation at Sulfur
R4
R5SH
NaOMe
Bt
R2
N
N
R1
R1
R2
a
H
b
R4
THF, Reflux
16-18h
R3
R5
R2
N
S
N
R1
R3
R4
R5
Yield (%)
-(CH2)2O(CH2)2-
2,5-Cl2C6H3
4-MeC6H4
44
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
R2
R3
(01JOC2865)
R3SH
NaOMe
Bt
N
R1
R2
S R3
(95H231)
N
THF, Reflux
16-18h
R1
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
34
Imidoylation at Carbon (Ketones)
X
R2
Bt
+
N
R1
1
X
LDA
THF, -78 oC
N
Overnight
2a: X=O
2b: X=S
R2
N
N
01JOC4041
R1
3
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
35
1-Cyanobenzotriazole
A Safe and Convenient Source of +CN
Preparation of 1-Cyanobenzotriazole
NMe2
NMe2
Br
BtH
N
+
N
N
Whitten et al. (88S470)
Br-
76%
N N
N
Br
N
N N
N-
N
Na+
90%
(91RRC573)
N
1-Cyanobenzotriazole as a C-Cyanating Reagent
1-Cyanobenzotriazole as a N-Cyanating Reagent
Ar
CN
chlorobenzene
R
Bt
CN
+
R1
NH
R=H
CN
1. LDA
2. Bt
Ar
CN
CN
Hughes et al. (98JOC401) 5 examples: 30-66 %
CN
R N 1
R
(91RRC573) 7 examples: 84-96 % yields
nBuLi
N
C CH
Bt
CN
CN
N
C CH
Drechsler et al. (01JCSPT(2)581) 70% yield
36
Preparation of Sulfonylbenzotriazoles (04JOC1849)
Classical Preparation of Sulfonamides:
O
R
S
O
OMgBr
O
Cl
+
R NH2
base
R
Sulfonylbenzotriazoles: Preparation
R
S
N
OH
R M
+
R S
SO2
O
Yield (%)
of RSO2Bt
M
R
Disadvanges of Using Sulfonyl Chlorides:
Mp(0C)
93
S
NEt3
133-134
82
143-144
71
117-119
65
oil
O
R S Bt
O
Mp(0C)
Li
N
Li
Yield (%)
of RSO2Bt
M
R
O
MgBr
• Highly reactive and hygroscopic  Problematic to store
• Requires a base for reactions
• Many are difficult to access.
BtCl
83
107-109
80
147-150
75
oil
71
132-135
41
128-129
Li
N
MgCl
MgCl
Synthetic Equivalents to sulfonyl chlorides:
Li
O
S Cl
O
+
HN
N
TfOCH3
O
S N
O
O’Connell, J. F. and Rapoport, H. (92JOC4775)
N
+ CH3
N
-OTf
Li
N
Li
Li
20
131-132
N
Benzotriazole-Assisted Sulfonylation ([94SC205] and [04JOC1849])
O
1
R S N R
H
O
1
R NH2
1
O
Ph S N
N N
O
THF/RT
R N R
H
ArOH
Amine/Conditions
Generation of Sulfonamides
from Sulfonylbenzotriazoles
R
O
R S Bt
O
1
N
H
Sulfonamide
O
Cyclohexylamine,
THF/25 0C/18 h
S
N
O H
O
S
N
O
O
R1
S N
R
O R2
Piperidine,
THF/25 0C/42 h
S
O
S
N
O
O
S
N
O
Piperidine,
THF/25 0C/20 h
O
S N
O
Piperidine,
DMF/80 0C/48 h
Advantages over existing methods:
4 examples: 64-99% yields
O
R S O Ar
O
N-Methylbenzylamine,
THF/25 0C/15 h
R2
3 examples: 87-93% yields
O R1
R S N R2
O
2
37
10 examples: 51-99% yields
Yield (%)
89
72
Amine/Conditions
N
Morpholine,
DMF/80 0C/24 h
1, 5- dimethylhexylamine,
DMF/80 0C/24 h
Yield (%)
Sulfonamide
N
N
N
O
S N
O
O
O
S
ON
H
91
64
85
Phenethylamine,
DMF/80 0C/48 h
S
O
S
N
O H
80
99
2-Aminopentane,
DMF/80 0C/24 h
O
O
S
NH
O
99
N
• no need for added base
• reaction proceeds at ambient temperatures
• Less reactive and more selective than sulfonyl chlorides
0
0
• Selectively sulfonylate a 1 amine over the 2
• Selectively sulfonylate aliphatic amines over aromatic amines
99
Coworkers in Benzotriazole Chemistry 1987-2005
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
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
Germany
Michael Arend
Torsten Blitzke
Nicole Clemens
Peter Czerney
Sebastian Hoffman
Aldo Jesorka
Simona Jurczyk
Jens Koeditz
Thomas Kurz
Jamaica
Keisha Gay Hylton
Ghana
Augustine Donkor
Lebanon
Niveen Khashab
Greece
John Gallos
K. Yannakopoulou
New Zealand
Peter Steel
Hungary
Ferenc Soti
Laszlo Urogdi
Japan
Kunihiko Akutagawa
Yasuhisa Matsukawa
Kazuyuki Suzuki
Ichiro Takahashi
Jordan
Shibli Bayyuk
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
38
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. DrewniakDeyrup
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
Katritzky Group Financial Support 1987-2005
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
39