Research Summary
Prabhu Mohapatra
1999-2007
Center for Heterocyclic Compounds, Department of Chemistry,
University of Florida, Gainesville, FL 32611-7200
1
Problem: Low yields of 1,3,4-oxadiazoles with unsaturated or nucleophilic substituent [06TL4827]
O
O
O
CDI
+
Ph
NHNH2
R
1
Ph
OH
N
H
2
H
N
PPh3, CBr4,
CH2Cl2, RT
R
Ph
3
O
R
N N
- H2O
O
O
diacylated hydrazides
N
CDI =
4
N
N
N
1,3,4-oxadiazoles
PPh3 and CBr4 are dehydrating agents
low yields
R = unsaturated or
nucleophilic
Solution: N-acylbenzotriazoles are activated derivatives of carboxylic acids
R
SOCl2
N
O
O
N
+
N
H
(3 equiv.)
OH
2
R
CH2Cl2 or THF, RT
- BtH.HCl
N
Bt
5
6
O
Bt
S
Bt
O
Bt
O
Yield = 99%
mp 151-152 oC
6b
98%
169-170 oC
H3C
OH O
Ph
6c
95%
142-144 oC
OH O
Bt
Bt
OH
Bt
Bt
Bt
O
O
6a
N
N-acylbenzotriazoles
OH O
Ph
N
Bt =
92%
124-125 oC
O
Br
6d
6e
92%
124-126 oC
6f
87%
108-109 oC
6g
6h
90%
150-151oC
95%
157-158 oC
2
Efficient One Pot Synthesis of 1,3,4-Oxadiazoles from N-acylbenzotriazoles and Acyl Hydrazides
[in progress]
O
Ph
O
NaH
NHNH2 CH2Cl2
RT
30 min
-H2
1
Ph
Ph
N N
+
NHNH
R
Ph
Bt -BtNa
7
N
H
6
Ph
O
O
O
Na
Ph
O
Ph
Ph
O
Me
Ph
4c
82%
novel
110-114 oC
OH
OH
O
Ph
4d
79%
[95CHC208] = 71%
115-117 oC
Ph
O
73%
novel
129-130 oC
Ph
OH
O
N N
N N
N N
N N
O
N N
O
4b
R
4
N N
4a
OH
O
O
N N
RT, 24 h
- H2O
O
S
Yield = 84%
lit. [06TL4827] yield = 23%
mp 245-248 oC
R
PPh3, CBr4, Ph
3
N N
Ph
H
N
Br
4e
4f
Yield = 94%
novel
89%
novel
146-148 oC
4g
66%
novel
196-198 oC
4h
73%
novel
3
Synthesis of ortho-Sulfamidotriazobenzenes from 1,1’-Sulfonylbis(benzotriazole) [07JOC5805]
Problem: Sulfuryl chloride is a toxic liquid, corrosive, and acts as a lachrymator
Solution: Stable benzotriazole derivative of sulfuryl chloride
O
N
N
N
H
5
N
(Me3Si)2NH
140 oC
12 h
8
O
S
N
N
SiMe3
Cl
Cl
toluene
0 oC, 24 h
O
S
N
N
N N
N N
9
O
-Me3SiCl
99%
97%
m.p. 165-166 oC
CH3CN
RT, 5 h
O
S
N
N
N
N
O
ORTEP diagram of Bt2SO2
NH
N N
N
expected product 11a
unexpected
ring-opening
NH
S N
O
O
10 a
55%
o
m.p. 109-111 C
ORTEP diagram of
ring opened product
ortho-Sulfamidotriazobenzenes of type 10 were unknown; however, closely related orthosulfonamidotriazobenzenes are known and have been used as color formers. [11CB2694]
4
Synthesis of ortho-Sulfamidotriazobenzenes from 1,1’-Sulfonylbis(benzotriazole) [07JOC5805]
N N
N
N
N
N
S N
O
O
+
N
NH
S N
O
O
N
N
S N
O
O
N
H
N
H
RT, 5 h
O
Reflux,
12 h
11f
O
S
N
N
N N
N N
O
73%
No ring opening
In case of
alkyl-aryl
or diaryl amines
N
H
Thermodynamically
controlled
Me
RT, 5 h
11b
53%
7%
N N
N
N
H
Me
N
H
Reflux,
12 h
N
N
N
S N
O
O Me
O
N
+
NH
S N
O
O
RT, 5 h
Me
9
10b
N
N
S N
O
O
O
O
10c
11c
63%
11%
Me
N N
N
11e
NH
S N
O
O
70%
10d
Me
Me
Me
ring opening
In case of
dialkyl amines
Kinetically
controlled
75%
ortho-Sulfamidotriazobenzenes 10 combine both the features of a triazine and a sulfamide group.
Many triazines are known to display potent antitumor activity. [06Pharmazie511]
5
Synthesis of ortho-Sulfamidotriazobenzenes from 1,1’-Sulfonylbis(benzotriazole) [07JOC5805]
H
N
R .. R2
1
+
N2
_
N
N
S N
N
O
O
N
N
N
N
S N
N
O
O
N
N
S N
N
O
O
-BtH
R2
N N 1
R
N
NH
R2
S N
O
O R1
R1 .. R2
N
H
9'
9
N2
10
diazonium betaine structure
Possible mechanism for the ring opening
O
N N
N Et
N
S
Ph
O O
12
NH2
H
N
S
O O
13
NaNO2
N
N
N
S
O O
14
N NH
N
N
H
O
S N
O
O
15
color formers
Literature synthesis of ortho-sulfonamidotriazobenzenes [11CB2694]
6
Synthesis of unsymmetrical sulfamides from N-sulfonylbenzotriazoles [07JOC5805]
N
S N
O
O
16a
90%
novel
m.p 53-54 oC
O
NH
Me
N
Me
N
N
S N
O
O
16c
88%
oil
MW 120 W,
120 oC, 10 min.
N
N
H
O
N
N
S N
O
O
O
11b
N
H
MW 120 W,
120 oC, 10 min.
N
S N
O
O
O
16b
88%
novel
m.p 70-72 oC
Sulfamides are of interest as
(i) components stable to enzymatic hydrolysis in peptidomimetics, [00T9781]
(ii) active components in epinephrine analogues, [81JMC1300]
(iii) agonists of the 5-HT1D receptor (regulating serotonin levels), [94JMC3023] and
(iv) HIV protease inhibitors. [97JMC898]
7
1-Benzotriazol-1-yl-3,3,3-trifluoro-2-methoxy-2-phenyl-propan-1-one: Mosher-Bt [07JOC4268]
F3C
COCl
OCH3
OCH3
OCH3
F3C
COCl
F3C
COCl
(Rac)-
(R)-
(S)-
17a
17b
17c
SOCl2
OCH3
F3C
COOH
(Rac)-MTPA
18a
a-Methoxy-a-Trifluoromethyl Phenyl Acetic acid chloride
(MTPA acid chloride): Mosher’s reagent
chiral derivatizing agents for determining both ee and
absolute configuration of chiral alcohols and amines
OCH3
reflux, 50 h
F3C
CO
N
N
N
N
N
N
H
rt, 12 h
95%
19a
(Rac)-MTPA Bt
m.p. 99-100 oC
ORTEP diagram of (rac)-MTPA Bt, 19a,
showing one enantiomer
SOCl2
SOCl2
OCH3
F3C
COOH
(R)-MTPA
18b
OCH3
reflux, 50 h
F3C
CO
N
N
N
N
N
N
H
rt, 12 h
OCH3
19b
(R)-MTPA Bt
oil
F3C
COOH
(S)-MTPA
95%
18c
OCH3
reflux, 50 h
N
N
N
H
rt, 12 h
F3C
CO
N
N
N
95%
19c
(S)-MTPA Bt
oil
8
1-Benzotriazol-1-yl-3,3,3-trifluoro-2-methoxy-2-phenyl-propan-1-one: Mosher-Bt [07JOC4268]
O
CF3
N
H
CO2H
O
H
N
MeO
N
H
O
O
(R)-Bt +
H3CO
Gly-(S)-Phe-(S)-Phe
91%
(R,S,S)-20e
m.p. 169-170 oC
CF3
(rac)-Bt +
N
H
CO2H
96%
(R,R) and (S,R)-20a
oil
(R)-Phe
(R)-Bt +
(R)-Bt +
O
H3CO
CF3
N
H
H
N
Gly-(R)-Phe
CO2H
O
97%
(R,R)-20e
m.p. 84-86 oC
OCH3
F3C
CO
N
N
N
(R)-Bt +
(R)-Trp
19 a-c
(R)-Phe
O
H3CO
CF3
(S)-Bt +
O
H3CO
NH
O
H3CO
CF3
CF3
N
H
CO2H
98%
(R,R)-20d
m.p. 78-80 oC
CO2H
96%
(R,R)-20b
m.p. 110-112 oC
(R)-Phe
Reaction conditions:
Et3N, CH3CN:H2O (2:1),
RT, 12 h
N
H
N
H
CO2H
96%
(S,R)-20c
m.p. 107-108 oC
Reactions of Mosher-Bt reagents with aminoacids and peptides, products 20b-f are single diastereomers
as proved by chiral HPLC analysis (using Chirobactic T column, detection at 254 nm,
flow rate 0.1 mL/min, solvent MeOH)
9
1-Benzotriazol-1-yl-3,3,3-trifluoro-2-methoxy-2-phenyl-propan-1-one: Mosher-Bt [07JOC4268]
shielded
3.24, 3.06 ppm
less shielded
3.28, 3.14 ppm
O
H3CO
CF3
H
H
O
N
CO2H
H H
shielded
4.93 ppm
H3CO
H
H
assignment of
absolute configuration
N
CO2H
H H
CF3
less shielded
5.03 ppm
MTPA plane
(R, R)-20b
(S, R)-20c
(a)
(b)
MTPA amides of (R)-Phenylalanine.
Chemical shift (d) values in the 1H, 13C and 19F NMR of MTPA amides of (R)-Phenylalanine
entry
productMosher
amide
abs.
config.
d-values
(1H NMR)
d-values
(13C NMR)
d-values
(19F NMR)
methylene
methine
methylene
methine
CF3
1
(R,R)-2a
(R,R)
3.28, 3.14
4.93
37.6
55.4, 55.3
-69.37
2
(S,R)-2a
(S,R)
3.24, 3.06
5.03
37.4
55.0, 55.0
-69.31
0.04, 0.08
0.1
0.2
0.4, 0.3
0.06
difference
10
1-Benzotriazol-1-yl-3,3,3-trifluoro-2-methoxy-2-phenyl-propan-1-one: Mosher-Bt [07JOC4268]
F3C
CO
N
N
N
19a
OCH3
OCH3
OCH3
F3C
19b
CO
N
N
N
F3C
CO
N
N
N
19c
Compared to the corresponding acid chlorides of Mosher-Bt reagents have the following advantages:
•
•
•
•
•
•
they are non-corrosive, stable to moisture and heat, and can be stored at room temperature indefinitely; and
thus easy to handle as compared to corrosive and moisture sensitive MTPA chloride,
the carboxyl groups of the aminoacids, di and tripeptides need no protection prior to making their MTPA
amides,
high yields of corresponding Mosher’s amides are obtained,
their reactions can be carried out in aqueous conditions,
unlike MTPA chloride the absolute configuration of the Mosher-Bt reagent and the Mosher’s ester or amide
are the same simplifying assignment of absolute configuration and
they are easily prepared in quantitative yield from the corresponding MTPA (250 mg, $36) using 1Hbenzotriazole (100 g, $25) and are thus more cost-effective as compared to commercially available MTPA
chloride (250 mg, $100).
11
Problem: Reaction of acid chlorides with Grignard reagents gives low yields of ketones due to many
side reactions including formation of undesired tertiary alcohols [05OL5593]
Solution: N-acylbenzotriazoles are stable alternatives of acid chlorides
O
O
Me
Bt
Bt
Bt
1a
Bt
Bt
N
O
1d
Me
O
N
H
O
1k
Me
O
(D,L)-1m
N
H
1j
1i
Bt
Cbz
O
Me
Bt
O
N
H
Cbz
Cbz
Bt
O
(D)-1m
1l
Cbz
O
Me
Bt
Bt
1e
Bt
Bt
1h
Bt
S
Me
O
1g
1f
O
O
S
O
Bt
1c
Bt
HO
Bt
Me
1b
O
O
O
CH2Ph
Cbz
N
H
Bt
O
(D)-1n
CH2Ph
Cbz
N
H
(L)-1n
N
H
(L)-1m
Bt
O
CH2Ph
Cbz
N
H
(D,L)-1n
N
Bt =
N
N
12
Alkyl, Unsaturated, (Hetero)aryl and N-Protected a-Amino Ketones by Acylation of Organometallic
Reagents [06JOC9861]
R1COBt + R2MgBr
R1COBt
O
Me
THF
R1COR2
R2MgBr
T (oC)
t (h)
TolMgBr
0
1.5
Product structure
O
Yield
89
Me
Bt
Me
TolMgBr
O
0
O
2.0
72
Bt
Me
Bt
O
TolMgBr
65
6.0
65
O
Me
TolMgBr
65
3.0
Bt
63
O
O
O
O
TolMgBr
O
Me
Me
65
6.0
66
O
Me
Bt
Me
Bt
O
TolMgBr
0
4.0
O
50
Me
13
Alkyl, Unsaturated, (Hetero)aryl and N-Protected a-Amino Ketones by Acylation of Organometallic
Reagents [06JOC9861]
R1COBt + R2M
R1COBt
Me
R2MgBr/R2Li
OH
Bt
Me
THF
R1COR2
T (oC)
t (h)
Product structure
25
4.0
O
OH
O
novel
Me
65
4.0
53
MgBr
S
80
Me
MgBr
Bt
Yield
S
O
O
Bt
25
6.0
-78
1.0
69
O
MgBr
O
O
Bt
S
70
Li
S
O
-78
Bt
1.0
Li
S
32
S
O
O
-78
N
Bt
N
O
1.0
S
48
S
Li
O
O
Me
Bt
-78
Li
N
Li
1.0
Me
N
H
72
14
O
Alkyl, Unsaturated, (Hetero)aryl and N-Protected a-Amino Ketones by Acylation of Organometallic
Reagents [06JOC9861]
R
Cbz
N
H
R
p-TolMgBr
Bt
O
R1COBt
Cbz
N
H
THF
0oC, 2h
Tol
O
Product structure
Yield
Me
Cbz
N
H
Cbz
N
H
O
Me
Cbz
N
H
(D)-
Cbz
Me
(L)-
Cbz
O
Cbz
Cbz
Cbz
N
H
N
H
N
H
N
H
N
H
O
CH2Ph
Bt
(D)-
Cbz
O
40
CH2Ph
Me
(L)-
CH2Ph
Me
(D,L)-
No racemization
56
No racemization
(L)-
CH2Ph
Me
O
50
novel
O
Cbz
HN
(D)novel
O
Cbz
HN
67
O
Cbz
HN
O
CH2Ph
Bt
No racemization
Me
(D,L)-
N
H
O
CH2Ph
Bt
55
O
Me
(D,L)-
Me
No racemization
proved by
chiral HPLC analysis
(L)-
Me
Bt
50
O
Me
Bt
Me
(D)-
N
H
O
N
H
O
Me
Bt
Cbz
Cbz
64
Bt
(D,L)novel
15
Efficient Synthesis of Hydroxyaryl-aliphatic and -(Hetero)aryl Ketones by acylation of Organometallic
Reagents [07S3141]
O
Problem: Conventional Friedel-Crafts acylation of phenols and
naphthols with acyl chlorides in the presence of Lewis acid
catalysts and Fries type rearrangement of suitable aryl esters are
frequently used for the preparation of hydroxyaryl ketones.
However, these reactions often suffer a lack of selectivity. Usually
both ortho- and para-acylation of phenols and naphthols takes
place to give a mixture.
HO
Me
Bt
R1COBt =
Bt
O
Bt
R1
R M
R2
R1
2A-C, 3D-G
4aA-dG
HO
O
O
+
1a-d
Bt
HO
OH O
2
OH
N
Bt
Bt =
N
N
O
Br
1a
1b
1c
1d
N-acylbenzotriazoles 1a-d
R2M =
Me
Br
Mg
MgBr
MgBr
Li
N
S
Li
Li
Li
Li
2A
2B
2C
3D
3E
3F
3G
Grignard reagents 2A-C and heteroaryllithium reagents 3D-F
16
Efficient Synthesis of Hydroxyaryl-aliphatic and -(Hetero)aryl Ketones by Acylation of Organometallic
Reagents [07S3141]
THF
O
R1
+
R MgBr
HO
T (oC)
t (h)
Bt
1a-d
R1COBt
R2MgBr
O
2
2A,B
T (oC)
t (h)
R2
4aA-dB
product structure
Me
Me
R1
O
yield (%)
OH
Bt
Me
1a
2A
25
4
O
O
Me
HexMgBr
4aB
53
4bA
66
4cA
63
4dB
70
OH
Me
Bt
1a
74
Me
MgBr
HO
4aA
2B
25
Me
2
O
Me
HO
O
OH
Bt
2A
1b
25
4
O
Me
Br
MgBr
Bt
Me
O
Br
O
2A
65
12
OH 1c
Me
MgBr
O
HO
Bt
O
OH
HexMgBr
1d
2B
25
5
Me
OH
17
Efficient Synthesis of Hydroxyaryl-aliphatic and -(Hetero)aryl Ketones by Acylation of Organometallic
Reagents [07S3141]
THF
O
R1
+
R1COBt
HO
3C-F
R2Li
T (oC)
R1
-78 oC
0.5 h
Bt
1a-d
O
R2Li
R2
4
t (h)
product structure
Me
O
Bt
OH
Me
1a
BuLi
3C
-78
yield (%)
Me
0.5
4aC
94
4aE
86
4bE
83
4cE
90
4cF
51
4dD
72
O
HO
Me
O
OH
Bt
1a
Me
Ph
Li
3E
-78
0.5
Ph
O
HO
O
Bt
1b
Ph
Li
3E
-78
0.5
O
Ph
Br
Br
Bt
O
O
Ph
Li
3E
-78
OH
0.5
OH 1c
Ph
Bt
Li
N
O
O
Li
OH 1c
3F
-78
0.5
OH
NH
HO
O
Bt
O
OH
1d
S
Li
3D
-78
0.5
S
HO
18
Efficient Synthesis of Hydroxyaryl-aliphatic and -(Hetero)aryl Ketones by Acylation of Organometallic
Reagents [07S3141]
OH OH
R'
R
R''
R''M
R
tertiary alcohol
OH O M
OH O
N
N
N
R'M
R
R'
N
N
N
NH4Cl
Proposed
Tetrahedral
Intermediate
OH O
R'
R
ketone
Possible mechanism of ketone synthesis
• Stable alternatives of acid chlorides
• Yields – high
• Selectivity - Ketone vs. tertiary alcohols
• Reactivity - Li reagents are more reactive (better
nucleophiles) than Grignard reagents
• Convenience – No need to protect the OH group
• single product vs. mixture (ortho + para) in case of
Friedal Craft acylation and Fries rearrangement to
obtain hydroxyaryl ketones
19
Efficient N-Aroylation of Substituted Indoles with N-Aroylbenzotriazoles [07S3141]
MeO
NaH
Bt
+
N
THF
25 oC
24 h
N
H
1a,b
indole
MeO
O
MeO
OMe
O
2a-d
3
RCOBt
product structure
yield (%)
lit. yield (%)
3a
81
32
3b
91
46
3c
90
34
3d
87
O
Bt
1a
N
H
N
2a
O
O
Bt
1a
N
H
N
2b
O
MeO
OMe
OMe O
Bt
1a
N
H
N
2c
O
MeO
O
MeO
1b
N
H
MeO
Bt
2a
N
15
O
20
Lit. Bremner, J. B.; Samosorn, S.; Ambrus, J. I. Synthesis 2004, 2653. (DCC/DMAP mediated coupling of indoles with carboxylic acids)
Efficient N-Aroylation of Substituted Indoles with N-Aroylbenzotriazoles [07S3141]
MeO
O
MeO
MeO
NaH
Bt
+
1a,b
indole
O
3
product structure
Bt
1b
yield (%)
3e
77
9
3f
42
0
OMe
3g
60
new
OMe
3h
36
new
N
2b
MeO
O
OMe
MeO
OMe O
Bt
1b
lit. yield (%)
MeO
O
MeO
MeO
OMe
2a-d
RCOBt
N
H
N
THF
25 oC
24 h
N
H
N
H
N
2c
O
MeO
proved by X-ray str.
OMe O
Bt
1a
N
H
N
2d
OMe
O
MeO
MeO
OMe O
MeO
1b
N
H
Bt
OMe
2d
N
O
MeO
21
Benzotriazole-Based Thioacylation Reagents [05JOC7866]
S
R
R1R2NH
CS2
BtCl
S
R
SMgBr
R
RT
12h
R1
6 examples
avarage yield 87%
S
R MgBr
THF
Reflux
3h
N
R2
Bt
R'OH
4 examples
42-89%
S
R
OR'
5 examples
60-99%
Thioamides and Thiolesters from Thiocarbonylbenzotriazole (RCSBt)
S
10 examples
52-99%
NR R
1 2
HNR
R1R2NH
S
S
Cl
S
BtTMS
Cl
RNH2
Bt
98%
Bt
1
Het NH
Het2NH
DCM
RT
18 h
DCM
reflux
R'M
S
Bt
R'
NHR
R'OH
9 examples
91-99%
S
R'O
Het HN
NHHet
2
7 examples
78-85 %
NHR
2 examples
59-60%
NHR
4 examples
60-99%
R'SH
S
1
NHR
9 examples
35-99%
S
R'S
Thioureas, Thioamides, Thiocarbamates and Dithiocarbamates from Thiocarbamoylbenzotriazoles (RNHCSBt)
22
Benzotriazole-Based Thioacylation Reagents [05JOC7866]
S
OR1
Bt
1
R OH
R1 = Ethyl (19%)
2-Naphthyl (87%)
3-Pyridinyl (66%)
1-Naphthyl (81%)
Phenyl (83%)
S
Bt
Bt
R1SH
S
Bt
R1
a) Phenyl
b) Benzyl
c) Acetyl ethyl ester
d) Isopropyl
SR1
46%
42%
63%
0%
S
+
Bt
SR1
Bt
21%
44%
trace
90%
Alkyl/Aryloxythiocarbonylbenzotriazoles (ROCSBt) and Alkyl/Arylthiothiocarbonylbenzotriazoles (RSCSBt)
S
nBuLi
S
O
R1R2NH
S
Bt
O
R1
N
R2
O
Thionesters and Thiocarbamates from ROCSBt
23
New Synthesis of N-Functionalized Dithiocarbamates [05ARK63]
S
HN
S
R
OH
BF3.Et2O
N
R1S
N
Bt
R1 = Et, t-Bu, Ph,
4-OCH3C6H4
89-99 %
S
THF
R = H, Me, Et, Pr
P(OR1)3
ZnBr2, Et2O
Reflux
73-93 %
S
R
O
N
RO P 1
OR
S
1
R1 = Et, i-Pr
76-88 %
neat
R
S
Reflux
S
R
Bt
S
R
R1SH
ZnBr2, Et2O
+ BtH
O
R
R1SH
ZnBr2, Et2O
S
HN
OH
BF3.Et2O
R1S
N
S
Reflux
S
R
R
Bt
S
Bt
S
N
R, R1 = Me, Ph; Et, Et; Et, Ph.
S
77-79 %
THF
R = Me, Et, Pr
65-70 %
P(OR1)3
ZnBr2, Et2O
Reflux
R
S
1
R O
P
R1O
O
N
S
R, R1 = Me, Et; Pr, Et.
72-77 %
24
Synthesis of a-Amino Amides [05JSCS319]
R1
R4
N
+ BtH + HNR2R3
O
4
R1
Bt
R NC
NR2R3
R4
N
NR R
1
R
NR2R3
BF3.Et2O
R4
HN
R1
THF
18 examples
79-96 %
earlier work
2 3
R5SH
Bt
SR5
Conc. HCl
EtOH/H2O
O
10 examples
75-92 %
NR2R3
R1
Synthesis of a-Benzotriazolyl Ketones [04ARK22]
Bt
HO
O
n-BuLi (2 eq.)
RX (a-c)
a: CH3I
b: AllylBr
c: 4-CH3C6H4CH2Br
R
HO
Bt
O
50-89 %
n-BuLi (2 eq.)
R1COCl (a-d)
a: CH3I
b: 4-CH3C6H4
c: 2-furyl
d: Bn
R
R1
Bt
O
56-84 %
25
Synthesis of Hexagonal Terpyridine-Ruthenium and -Iron Macrocycles by Step-wise or Self-assembly
procedures [02CEJ2946]
R
R
NaOH, EtOH
O
O
+
N
N
Me
N
NH4OAc
AcOH
reflux
24 h
O
R = Me, Br
N
N
N
N
Yield 40%
R
N
N
Fe
N
R
R
N
N
N
N
N
N
Fe
N
N
Ru
N
N
N
N
Fe
N
N
R
R
N
N
N
N
N
N
N
Fe
N
N
N
R
N
N
Fe
N
N
N
N
N
N
N
Fe
N
R
N
N
N
N
N
N
N
Ru
N
N
N
R
N
Ru
N
N
N
N
N
N
N
N
N
R
N
Ru
R
N
N
N
N
N
Ru
N
N
N
N
N
N
Ru
N
R
R
N
N
26
Comparison of HNMR spectra of the monomer and hexamer [02CEJ2946]
Monomer
Hexamer
27
Synthesis of a family of hetero-metallomacrocycles by step-wise procedure [04CEJ1493]
CH3
CH3
N
N
N
H3C
N
N
N
N
CH3
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
H3C
CH3
N
CH3
H3C
N
N
N
N
N
N
N
CH3
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
H3C
N
N
N
N
N
N
N
N
N
N
N
N
N
H3C
CH3
N
N
N
N
N
N
N
N
N
N
N
N
H3C
N
N
N
N
N
N
N
N
N
CH3
CH3
N
N
N
N
N
N
CH3
N
CH3
N
N
N
CH3
CH3
N
N
N
H3C
N
N
N
N
N
N
N
N
N
CH3
= Fe
N
N
N
N
N
N
N
N
N
N
= Ru
N
N
= Os
H3C
N
N
N
N
N
N
N
N
N
CH3
N
N
N
CH3
28
Synthesis of phenyl acetylene dendrons for antenna macrocycles [unpublished]
2-Methyl-3-butynol
Br
Pd(dba)2, CuI,
Br NEt3, PPh3
Br
Br
KOH,
Toluene
Br
Br
Br
Br
Br
Me3SiCl
H
EtMgBr,
THF
SiMe3
OH
2-Methyl-3-butynol
Pd(dba)2, CuI,
NEt3, PPh3
CF3SO2)2O
Pyr
OH
KOH,
Toluene
OSO2CF3
A
OH
H
2 eqiv.
Br
Br
SiMe3
K2CO3,
MeOH
H
Pd(dba)2, CuI,
NEt3, PPh3
B
SiMe3
H
29
Synthesis of antenna dendron substituted bis-terpyridine by Sonagashira coupling [unpublished]
Pd(dba)2, CuI,
NEt3, PPh3
Br
+
N
N
N
N
N
N
N
H
N
N
N
N
N
A
80%
Pd(dba)2,
NEt3,
CuI,
PPh3
Br
N
N
N
N
N
N
+
H
B
N
N
N
N
N
N
73%
30
Synthesis of Antenna G1 homo-metallomacrocycles [unpublished]
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
= Ru
= Fe
Possible use in photonics (light harvesting and storage applications)
31
Synthesis of Antenna G2 homo-metallomacrocycles [unpublished]
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
= Ru
= Fe
Possible use in photonics (light harvesting and storage applications)
32
Nanoassembly of a Fractal Polymer: A molecular “Sierpinski” Hexagonal gasket [06Science1782]
33
Nanoassembly of a Fractal Polymer: A molecular “Sierpinski” Hexagonal gasket [06Science1782]
Images of gasket 6. (A) AFM images at 1.12 x 1.12 µm and 100 x 100 nm. (B) TEM pictures with 50- and 20-nm
scale bars for the lower- and higher-resolution images, respectively (all images were obtained unstained). (C)
UHV-STM images (100 x 100 nm) on a Au(111) surface at 6 K, revealing a line of gaskets settled on a ridge on the
gold surface and a color-enhanced and magnified image of a single molecule (scale bar, 3 nm).
34
Synthesis of next generation non-nutritive sweetener Neotame C-7 [NS]
Cl
Cl
OH
LAH
CO2H
H2SO4
NaOCl
OH
O
TEMPO
96%
89%
o
2-3 C
+
60%
Ph
MeO2C
MeO2C
O
NH
N
H
CO2H
Me
Me
Ph
O
30 psi H2,
Pd/C,MeOH,
24 h, 97%
NH
Me
N
O
TEMPO
CO2H
H2N
Aspartame
Neotame C-7
Synthesis of 2,6,7-trimethyl-5-nitrosopyrrolo[1,2-b]pyridazine [L]
O
Me
N
N
Me
Br
+
Me
Me
Me
O
Me
Acetone
reflux
N
N
Me
Me NaHCO3
Br
N
N
Me
47%
Me
Me
ON
Me
NaNO2
N
N
Me
Me
67%
35
Me
Synthesis of 4-(2,6-dimethylpyrrolo[1,2-b]pyridazin-7-ylazo)benzenesulfonic acid [L]
N
N
O
Me
N
N
SO3H
Me
Me
Me
Br
N
N
O
+
Acetone
reflux
Me
Me
Me
NaHCO3
Me
SO3
N
N
N
N
EtOH / AcOH
Me
60%
99%
N
N
1.5 H2O
Me
55%
Synthesis of 2-methyl-1-nitrosoindolizine-3-carboxylic acid methyl ester [L]
O
Me
Cl
N
Me
Cl
NaHCO3
+
N
Me
Me
O
OMe
4h, reflux
N
Me
ON
OMe
NaNO2
AcOH
O
N
OMe
O
62%
80%
70%
Synthesis of 2-methylamino-1-nitrosoindolizine-3-carboxylic acid ethyl ester [L]
MeHN
O
Br
N
OEt
25oC, 12h
EtOAc
SMe
NHMe O
NO2
N
OEt
Br
O
75%
Et3N (10eq.)
EtOH, reflux
12h
N
OEt
NaNO2 / AcOH
0oC, 1h
NHMeO
ON
N
OEt
56%
90%
1-(methylamino)-1-(methylthio)-2-nitroethene is commercially available (Aldrich)
36
Synthesis of 2-methanesulfonyl-1-nitrosoindolizine-3-carboxylic acid ethyl ester [L]
MeS
N
OEt
O
NO
SMe
NO2
Et3N (10eq.)
EtOH, reflux
12h
SMe NaNO2 / AcOH
0oC, 1h
O
N
EtO
SMe
N
O
EtO
85%
80%
Br
MCPBA
NO2
NO
N
EtO
0oC to 25oC,
overnight
SO2Me +
N
O
EtO
SO2Me
Not separable by column
chromatography
O
90% [85:15]
Synthesis of 7-dimethylamino-2-methylsulfanyl-1-nitroso-indolizine-3-carboxylic acid ethyl ester [L]
MeS
SMe
NMe2
NaNO2
NO2
N+
BrCO2Et
O
N
SMe
N
EtOH,
reflux (1 d)
Me2N
CO2Et
AcOH
0 oC, 1 h
SMe
N
CO2Et
Me2N
20%
80%
Nitroketene dithioacetal is commercially available (Aldrich)
37
Synthesis of (6,7-dimethyl-5-nitrosopyrrolo[1,2-b]pyridazin-2-yl)diethylamine [L]
O
Me
Me
N
N
HNEt2
Br
sealed tube,
180oC, 16h
Cl
Me
Me
N
N
Me
NEt2
N
N
neat, 80oC
NaHCO3
H2O, reflux,5h
Me
Me
N
O
N
Me Br
NEt2
NEt2
90%
NO
NO2
Not separable by column
chromatography
Et2N
N
Me
N
Me
50%
+
Et2N
N
Me
N
i) NaNO2, AcOH, 0 oC,1h
ii) NaOH (2N)
Me
61%, (ratio of NO:NO2 is 65:35)
Synthesis of 2-methyl-1-nitroindolizine [L]
Cl
+
N
Me
Me
O
Me
i) neat, 80 oC, 4h
ii) H2O, NaHCO3
N
80%
HNO3
H2SO4
Me
O2N
N
45%
38
Synthesis of 2,3-dimethyl-1-nitroindolizine [L]
Me
Br
O
Me
N
Me
Br
Me
Me
N
Me MeCN, reflux,
Me
overnight
NaHCO3
Me
N
H2O, reflux
O
70%
NaNO2
N
Me
ON
Me
O2N
5N HCl
Me
+
N
Not separable by column
chromatography
Me
Total yield: 86% [35:65]
Synthesis of 5-nitrosopyrrolo[1,2-c]pyrimidine [L]
Me
Br
Me
Me
neat, 80 oC, 8h
o
Me
+
N
N
Me
Me
O
Me
ON
NaNO2, HCl
0 C, 1h
N
NaHCO3, H2O
Me
N
N
Me
Me
N
14%
70%
39
Synthesis of 7-substituted-3-methyl-5,6,7,8-tetrahydro-[2,7]naphthyridine-4-carbonitrile [R]
NMe2
Me
O
NC
NC
Me
TiCl4, Et3N
NH2
CH2Cl2,
25 oC, 24 h
Cl
SOCl2
THF
N
N
N
1)
BtTMS + DMF
92%
CH2Cl2,
25 oC, 24h
NH2
CN
Me
+
N
R
2) 2N NaOH, 25 oC
N
R
R
N
N
53 %
R = Bn, 70%
R = Boc, 40%
R = Bn, 53%
R = Boc, 7%
Synthesis of 6-benzyl-5,6,7,8-tetrahydro-2H-[2,6]naphthyridin-1-one [R]
OMe
Me
+
N
O-
Me
EtI
Neat
25 oC
1h
quant.
N+ IOEt
CN
KCN
Water
55 oC
6h
40%
Me
Me2N
CN
OMe
NMe2
Autoclave
180 oC
30 h
45%
N
N
HBr
H
N
O
N
Bn
80% overall
NaBH4
EtOH
0 oC, 1.5 h
RT, 16 h
O
H
N
N Br
Bn
BnBr
CH3CN
Refulx
2h
EtOH
Refulx
18 h
quant.
H
N
O
N
40
Synthesis of 3-fluoroadamantanylmethylamine hydrochloride [R]
OH
1 d, RT
H2N
DAST, CH2Cl2,
-78 oC to 25 oC,
1h
OH
(BOC)2O,
K2CO3, DMF
76% overall
HN
F
F
N S F
F
HN
BOC
BOC
DAST
HNO3 (60 %)
4 N HCl/Dioxane
conc. H2SO4
RT / 3 h
22%
10-15 oC, 6 h
100%
F
. HCl
H2N
H2N
Synthesis of 3-fluoroadamantane-1-carboxylic acid [R]
OH
HO2C
H2SO4
MeOH
OH
F
DAST
MeO2C
79%
overall
MeO2C
F
NaOH
HO2C
Synthesis of novel 3-noradamantylmethylamine BH3 salt [R]
OH
O
1.0 g
SOCl2 (10 mL)
80 oC, 1h
29% aq. NH4OH (5 mL)
CH2Cl2 (10 mL)
-78 oC to rt/ 12 h
NH2
O
0.94 g (100%)
BH3.THF (30 mL)
RT / 24 h
NH2
.BH3
0.24 g
41
Synthesis of novel 5-amino-isochromen-1-one [R]
NO2
Me
Me
N
DMF
115 oC
20 h
Me
SnCl2.2H2O
DMF
RT / 12h
NO2
+
CO2Me
MeO
NH2
O
OMe
O
O
O
500 g
Synthesis of novel 6-bromo-5-nitro-isochromen-1-one [R]
Br
Me
HNO3
NO2
Me
Br
Me
Br
+
HO2C
HO2C
HO2C
NO2
SOCl2/MeOH
Me
NO2
O
O
Me
NO2
Br
Br
N
MeO
+
OMe
Me
O
O2N
O
Regioisomers difficult to separate by
column chromatography
DMF
MeO2C
Br
Me
Br
+
MeO2C
NO2
Regioisomers are separable by
recrystallization
42
Synthesis of 3-ethoxy-4-ethoxycarbonyl phenylacetic acid, a key synthon of Repaglinide [R]
CO2H
Me
OH
CO2Et
EtBr
K2CO3
Me
CO2Et
CO2
HO2C
LDA/DMPU
-78 oC
2h
67%
OEt
DMSO
40 oC
10 h
99.6%
O
Me
N
N
OEt
DMPU
Preparation of Repaglinide [R]
Me
Me
H
NH2
N
CO2Et
HO2C
OEt
TEA, Tolune
o
-5 C, 1 h
O
O
t-BuCOCl
Me
Me
OEt
O
Me
Me
Me
30 oC, 12 h
73%
Me
H
N
H
N
CO2Et
O
CO2Et
1N NaOH
Me
H
N
H
OEt
EtOH
60-65 oC, 2 h
94%
O
CO2H
OEt
N
Repaglinide
43
Me
Synthesis of Chiral Metabolites of Pioglitazone [R]
O
Et
O
MCPBA
Et
NH
N
S
O
NH
CH2Cl2
N
O
O
O
S
O
96%
1. TFAA, CH2Cl2
O
2. Aq NaHCO3, THF
Et
NH
N
O
S
O
OH
O
Et
separated by making
diasreromeric esters
with mandelic acid
O
Et
NH
N
O
OH
S
O
74%
NH
N
O
OH
S
O
Boekel-heide rearrangement
chiral metabolites
of pioglitazone
44
Preparation of midazolam maleate [R]
SH
NH2
SH
O
Cl
F
H2N
NH2
CH3CN
Cl
S F
AlCl3
Reflux
2d
o
52-55 C
8h
N
S
Cl
S F
N
EtOH
RT
0.5h
H2N
Cl
MeOH
RT
12h
S F
N
F
Me Ce(NH4)2(NO3)6
Cl
S F
CH3CN/H2O
COOH
COOH
MeOH
S
N
COOH
N
N
N
NaCNBH3
Me
S
N
Cl
i-PrOH
AcOH
TEA
Reflux
6h
S F
N
N
Me NH2OH.HCl
O
Cl
N
N
O
S
HO
O
Br
N
S
TiCl4
Me
Cl
N
.
COOH
F
45
Thanks
46
Thank you.
47