research summary
DESCRIPTION
Research Summary. Prabhu Mohapatra 1999-2007 Center for Heterocyclic Compounds, Department of Chemistry, University of Florida, Gainesville, FL 32611-7200. Problem: Low yields of 1,3,4-oxadiazoles with unsaturated or nucleophilic substituent [06TL4827]. - PowerPoint PPT PresentationTRANSCRIPT
1
Research Summary
Prabhu Mohapatra
1999-2007
Center for Heterocyclic Compounds, Department of Chemistry, University of Florida, Gainesville, FL 32611-7200
2
Problem: Low yields of 1,3,4-oxadiazoles with unsaturated or nucleophilic substituent [06TL4827]
Solution: N-acylbenzotriazoles are activated derivatives of carboxylic acids
N N
NN
O
CDI =
PPh3 and CBr4 are dehydrating agents
R
O
OH+
Ph NHNH2
O
N N
OPhR
PPh3, CBr4, CH2Cl2, RTCDI
Ph NH
O HN R
O
diacylated hydrazides 1,3,4-oxadiazoles low yields R = unsaturated or nucleophilic
1 2 3 4
- H2O
NN
NBt =
R
O
OH
SOCl2+
NH
NN
CH2Cl2 or THF, RT R
O
Bt
2 5 6
(3 equiv.) - BtH.HCl N-acylbenzotriazoles
O
Ph Bt
O
S Bt
O
BtO PhBt
O
Yield = 99% 98% 95% 92%mp 151-152 oC 169-170 oC 142-144 oC 124-125 oC
6a 6b 6c 6d
OH
Bt
OH
Br
BtOH
Bt
OHH3C
92% 87% 90% 95% 124-126 oC 108-109 oC 150-151oC 157-158 oC
6e 6f 6g 6h
O
Bt
O O
O
3
Efficient One Pot Synthesis of 1,3,4-Oxadiazoles from N-acylbenzotriazoles and Acyl Hydrazides [in progress]
R
O
Bt+
Ph NHNH2
O
N N
OPhR
NaH PPh3, CBr4,
RT, 24 h
1 7 6 3 4
Ph NHNH
O
CH2Cl2 RT30 min
NaPh N
H
O HN R
O
-H2
-BtNa- H2O
Yield = 84% 82% 79% 73%lit. [06TL4827] yield = 23% novel [95CHC208] = 71% novel mp 245-248 oC 110-114 oC 115-117 oC 129-130 oC
4a 4b 4c 4d
N N
OPh
Ph N N
OPh
SN N
OPh
ON N
OPhPh
Yield = 94% 89% 66% 73% novel novel novel novel 146-148 oC 196-198 oC
4e 4f 4g 4h
N N
OPhOH Me
N N
OPhOH
Br
N N
OPhOH
N N
OPhOH
4
Synthesis of ortho-Sulfamidotriazobenzenes from 1,1’-Sulfonylbis(benzotriazole) [07JOC5805]
Problem: Sulfuryl chloride is a toxic liquid, corrosive, and acts as a lachrymatorSolution: Stable benzotriazole derivative of sulfuryl chloride
ORTEP diagram of Bt2SO2
ORTEP diagram of ring opened product
NN N
SO
N
O
N N toluene0 oC, 24 h
NN
N
SiMe3
SO
Cl Cl
O
NH
NN (Me3Si)2NH
140 oC 12 h
5 8 9
99% 97%-Me3SiCl
m.p. 165-166 oC
CH3CN RT, 5 h
NH
N
SO N
O
N N
10 a
NH
55%
NS
O
N
O
N N
m.p. 109-111 oC
expected product 11a
unexpectedring-opening
ortho-Sulfamidotriazobenzenes of type 10 were unknown; however, closely related ortho-sulfonamidotriazobenzenes are known and have been used as color formers. [11CB2694]
5
Synthesis of ortho-Sulfamidotriazobenzenes from 1,1’-Sulfonylbis(benzotriazole) [07JOC5805]
No ring openingIn case of alkyl-aryl or diaryl amines
Thermodynamicallycontrolled
ring openingIn case of dialkyl amines
Kineticallycontrolled
NN N
SO
N
O
N N
9
RT, 5 h
NH
N
SO N
O
N N
10b 11bNH 53% 7%
+ NN
N
SO NO
NH
O
NH
N
SO N
O
N N
10c 11c
O
O
+ NN
N
SO NO O
Me
NH
Me
NH
N
SO N
O
N N
Me
Me
Me
Me
10d
75%
NH
Me
NN
N
SO NO Me
Reflux, 12 h
11e
70%
RT, 5 h
63% 11%RT, 5 h
NH
NN
N
SO NO
11f
73%
Reflux, 12 h
ortho-Sulfamidotriazobenzenes 10 combine both the features of a triazine and a sulfamide group. Many triazines are known to display potent antitumor activity. [06Pharmazie511]
6
Synthesis of ortho-Sulfamidotriazobenzenes from 1,1’-Sulfonylbis(benzotriazole) [07JOC5805]
Possible mechanism for the ring opening
Literature synthesis of ortho-sulfonamidotriazobenzenes [11CB2694]
NN N
SN
O OPh
Et
12
N
SO N
O
N NH
SNN
N
OO O
NH
O
SHN
NH2
OO
NaNO2
13 14 15
color formers
10
R1HN
R2..
R1NH
R2..
NH
N
SO N
O R1
R2
N NR2
R1
9
NN
N
SO NO
NN
9'
N
N2
SO NO
NN
_
+
N
N2
SO NO
NN
-BtH
diazonium betaine structure
7
Synthesis of unsymmetrical sulfamides from N-sulfonylbenzotriazoles [07JOC5805]
NH
MW 120 W, 120 oC, 10 min.
NSO NO O
16a 90% novelm.p 53-54 oC
NH
MW 120 W, 120 oC, 10 min.
NSO NO O
16b 88% novelm.p 70-72 oC
NN
N
SO NO O
11b
NH
NMe
NSO NO O
NMe
16c 88% oil
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]
8
1-Benzotriazol-1-yl-3,3,3-trifluoro-2-methoxy-2-phenyl-propan-1-one: Mosher-Bt [07JOC4268]
ORTEP diagram of (rac)-MTPA Bt, 19a, showing one enantiomer
-Methoxy--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
F3C COCl
(R)-
OCH3
F3C COCl
(S)-
OCH3
F3C COCl
(Rac)-
17a 17b 17c
OCH3
F3C COOH
SOCl2
(R)-MTPA
NN
NH
OCH3
F3C CO
oil
N
NN
(R)-MTPA Bt
95%
reflux, 50 h
rt, 12 h18b 19b
OCH3
F3C COOH
SOCl2
(Rac)-MTPA
NN
NH
OCH3
F3C CON
NN
(Rac)-MTPA Bt
95%
reflux, 50 h
rt, 12 h
m.p. 99-100 oC
18a 19a
OCH3
F3C COOH
SOCl2
(S)-MTPA
NN
NH
OCH3
F3C CO
oil
N
NN
(S)-MTPA Bt
95%
reflux, 50 h
rt, 12 h18c 19c
9
1-Benzotriazol-1-yl-3,3,3-trifluoro-2-methoxy-2-phenyl-propan-1-one: Mosher-Bt [07JOC4268]
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)
NH
CO2H
O
CF3
H3CO
(rac)-Bt +
(R)-Phe
96%(R,R) and (S,R)-20a oil
NH
CO2H
O
CF3
H3CO
96% (R,R)-20bm.p. 110-112 oC
(R)-Bt +
(R)-Phe
NH
CO2H
O
CF3
H3CO
96% (S,R)-20cm.p. 107-108 oC
(S)-Bt +
(R)-Phe
NH
CO2H
O
CF3
H3CO
NH
98% (R,R)-20dm.p. 78-80 oC
(R)-Bt +
(R)-Trp
OCH3
F3C CON
NN
19 a-c
Reaction conditions:Et3N, CH3CN:H2O (2:1),RT, 12 h
NH
O
CF3
H3CO CO2HHN
O
97% (R,R)-20em.p. 84-86 oC
(R)-Bt +
Gly-(R)-Phe
NH
O
CF3
MeO HN
ONH
O CO2H
(R)-Bt +
Gly-(S)-Phe-(S)-Phe 91% (R,S,S)-20e m.p. 169-170 oC
10
1-Benzotriazol-1-yl-3,3,3-trifluoro-2-methoxy-2-phenyl-propan-1-one: Mosher-Bt [07JOC4268]
entry product-Mosheramide
abs.config.
-values(1H NMR)
-values(13C NMR)
-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
difference 0.04, 0.08 0.1 0.2 0.4, 0.3 0.06
Chemical shift () values in the 1H, 13C and 19F NMR of MTPA amides of (R)-Phenylalanine
MTPA amides of (R)-Phenylalanine.
assignment ofabsolute configurationN
HCO2H
O
CF3
H3CO
HH
NH
CO2H
O
CF3H3CO
HH
less shielded3.28, 3.14 ppm
shielded3.24, 3.06 ppm
(R, R)-20b (S, R)-20c
MTPA plane
H Hshielded4.93 ppm less shielded
5.03 ppm
(a) (b)
11
1-Benzotriazol-1-yl-3,3,3-trifluoro-2-methoxy-2-phenyl-propan-1-one: Mosher-Bt [07JOC4268]
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 1H-
benzotriazole (100 g, $25) and are thus more cost-effective as compared to commercially available MTPA chloride (250 mg, $100).
OCH3
F3C CON
NN
19a 19b 19c
OCH3
F3C CON
NN
OCH3
F3C CON
NN
12
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
BtMe
OBt
O Bt O
OO
Bt
Me Bt
O Bt
ON
O
Bt
S
Bt
O
Bt
O
MeHO
SBt
O
NN
N
Bt
OMe
NH
Bt
ONH
Bt
O
Me
NH
Bt
O
Me
NH
Bt
O
Me
NH
Bt
O
CH2Ph
NH
Bt
O
CH2Ph
NH
Bt
O
CH2Ph
1a
(D,L)-1m
Bt =
1k
1e1d1c1b
1j1i1h1g1f
Cbz CbzCbz
(L)-1m(D)-1m1l
Cbz Cbz Cbz Cbz
(D,L)-1n(L)-1n(D)-1n
13
Alkyl, Unsaturated, (Hetero)aryl and N-Protected -Amino Ketones by Acylation of Organometallic Reagents [06JOC9861]
504.00TolMgBr
666.065TolMgBr
633.065TolMgBr
656.065TolMgBr
722.00TolMgBr
891.50TolMgBr
YieldProduct structure t (h)T (oC)R2MgBrR1COBt
504.00TolMgBr
666.065TolMgBr
633.065TolMgBr
656.065TolMgBr
722.00TolMgBr
891.50TolMgBr
YieldProduct structure t (h)T (oC)R2MgBrR1COBt
R1COBt + R2MgBr R1COR2THF
14
Alkyl, Unsaturated, (Hetero)aryl and N-Protected -Amino Ketones by Acylation of Organometallic Reagents [06JOC9861]
R1COBt + R2M R1COR2THF
721.0-78
481.0-78
321.0-78
701.0-78
696.025
534.065
804.025
YieldProduct structuret (h)T (oC)R2MgBr/R2LiR1COBt
721.0-78
481.0-78
321.0-78
701.0-78
696.025
534.065
804.025
YieldProduct structuret (h)T (oC)R2MgBr/R2LiR1COBt
15
Alkyl, Unsaturated, (Hetero)aryl and N-Protected -Amino Ketones by Acylation of Organometallic Reagents [06JOC9861]
NH
Bt
O
RNH O
TolR
THF0oC, 2h
p-TolMgBrCbz Cbz
56
50
40
67
55
50
64
YieldProduct structureR1COBt
56
50
40
67
55
50
64
YieldProduct structureR1COBt
No racemizationproved by chiral HPLC analysis
No racemization
No racemization
No racemization
16
Efficient Synthesis of Hydroxyaryl-aliphatic and -(Hetero)aryl Ketones by acylation of Organometallic Reagents [07S3141]
Bt
O
MeHO
NN
NBt
O
HO
OH
O
Bt
Bt
O
HO
Br 1a 1b 1c 1d
Bt =
N-acylbenzotriazoles 1a-d
MgBrMeS Li
MgBr
Li
NLi
Li
Li
2A 2B 2C 3D 3E 3F 3G
MgBr
Grignard reagents 2A-C and heteroaryllithium reagents 3D-F
R1COBt =
R2M =
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.
O
Bt R2M
O
R2
1a-d 2A-C, 3D-G 4aA-dG
+R1
OH
R1
17
Efficient Synthesis of Hydroxyaryl-aliphatic and -(Hetero)aryl Ketones by Acylation of Organometallic Reagents [07S3141]
O
BtR2MgBr
R1
O
R2
1a-d 2A,B 4aA-dB
R1+
R1COBt R2MgBr T (oC) t (h) product structure yield (%)
Bt
O
MeHO
MgBr
Me
25 4Me
OHOMe
74
Bt
O
MeHO
HexMgBr 25 2
OHOMeMe
53
OH
O
Bt
Bt
O
HO
Br MgBr
Me O OH
MeBr
25 4 66
MgBr
Me
Me
O OH
65 12 63
THF
T (oC) t (h)
Bt
O
HO
HexMgBr
OHOMe25 5 70
1a 2A 4aA
1a 2B 4aB
1b 2A 4bA
1c2A 4cA
1d
2B 4dB
18
Efficient Synthesis of Hydroxyaryl-aliphatic and -(Hetero)aryl Ketones by Acylation of Organometallic Reagents [07S3141]
O
BtR2Li
R1
O
R2
1a-d 3C-F 4
R1+
R1COBt R2Li T (oC) t (h) product structure yield (%)
Bt
O
MeHO
-78 0.594
Bt
O
MeHO
86
OH
O
Bt
Bt
O
HO
Br
83
90
THF
-78 oC0.5 h
Bt
O
HO
72
1a 3C 4aC
1a 4aE
1b 4bE
1c4cE
1d
3D 4dD
BuLi
O OHMeMe
Ph Li 3E -78 0.5
OHOMe
Ph
Ph Li 3E -78 0.5
OHO
Ph
Br
Ph Li 3E -78 0.5OHO
Ph
OH
O
Bt
1c
NLi
Li 3F -78 0.5
OHO
NH514cF
S Li-78 0.5
O
HO
S
19
Efficient Synthesis of Hydroxyaryl-aliphatic and -(Hetero)aryl Ketones by Acylation of Organometallic Reagents [07S3141]
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
N
O
R'MN
N N
O
ProposedTetrahedral Intermediate
NN
M
R'
R'
O
NH4Cl
R''M
OH
R'R''
tertiary alcohol
ketone
R
OH OH
R
OH
R
OH
R
20
Efficient N-Aroylation of Substituted Indoles with N-Aroylbenzotriazoles [07S3141]
O
Bt
1a,b 2a-d 3
+
indole RCOBt product structure yield (%) lit. yield (%)
NaH
25 oC24 h
NH
MeO
THFN
MeO
O
MeO
OMe
NH
N
O
1a 81 323a
NH
1a
O
Bt
MeO
2bN
O OMe
3b 91 46
NH
1a
O
Bt 2cN
O
3c 90 34OMe
MeO
NH
1b
O
Bt 2a N
O
3d 87 15
MeO
O
Bt 2a
MeO
Lit. Bremner, J. B.; Samosorn, S.; Ambrus, J. I. Synthesis 2004, 2653. (DCC/DMAP mediated coupling of indoles with carboxylic acids)
21
Efficient N-Aroylation of Substituted Indoles with N-Aroylbenzotriazoles [07S3141] O
Bt
1a,b 2a-d 3
+
indole RCOBt product structure yield (%) lit. yield (%)
NaH
25 oC24 h
NH
MeO
THFN
MeO
O
MeO
OMe
NH
1b
O
Bt 2b N
O
3e 77 9MeO
MeO
MeO OMe
NH
1b
O
Bt 2c N
O
3f 42 0MeO
MeOOMe
proved by X-ray str.
MeO
NH
1a
O
Bt 2d N
O
3g 60 new
OMe
MeO
OMe
OMe
NH
1bMeO O
Bt 2d N
O
3h 36 new
OMe
MeO
OMe
OMe
MeO
22
Benzotriazole-Based Thioacylation Reagents [05JOC7866]
Thioamides and Thiolesters from Thiocarbonylbenzotriazole (RCSBt)
CS2R MgBr
R
S
SMgBr
BtCl
R
S
Bt THFReflux 3h
RT12h
4 examples 42-89%
R
S
NR1
R2R1R2NH
6 examplesavarage yield 87%
R'OH
R OR'
S
5 examples 60-99%
Bt Bt
S
7 examples 78-85 %
BtTMS
98%
RNH2
Bt NHR
S
R1R2NH
9 examples 91-99%
DCM RT 18 h
HNR NR1R2
S 10 examples 52-99%
R'MR' NHR
S 9 examples 35-99%
R'OH
R'O NHR
S2 examples 59-60%
R'SH
R'S NHR
S4 examples 60-99%
Het1NHHet2NH
Het1HN NHHet2
S
DCMreflux
Cl Cl
S
Thioureas, Thioamides, Thiocarbamates and Dithiocarbamates from Thiocarbamoylbenzotriazoles (RNHCSBt)
23
Benzotriazole-Based Thioacylation Reagents [05JOC7866]
Alkyl/Aryloxythiocarbonylbenzotriazoles (ROCSBt) and Alkyl/Arylthiothiocarbonylbenzotriazoles (RSCSBt)
S
Bt Bt
OR1
S
Bt
R1 = Ethyl (19%) 2-Naphthyl (87%) 3-Pyridinyl (66%) 1-Naphthyl (81%) Phenyl (83%)
SR1
S
Bt Bt
S
Bt
SR1
+
R1a) Phenylb) Benzylc) Acetyl ethyl esterd) Isopropyl
46%42%63% 0%
21%44%trace90%
R1OH
R1SH
Thionesters and Thiocarbamates from ROCSBt
O
S nBuLi R1R2NH
O
S
BtO
S
NR1
R2
24
New Synthesis of N-Functionalized Dithiocarbamates [05ARK63]
HN S
S
BF3.Et2O
THF
N S
S
P(OR1)3
ZnBr2, Et2O
R = H, Me, Et, Pr 73-93 %
R1 = Et, t-Bu, Ph, 4-OCH3C6H4 89-99 %
R1 = Et, i-Pr 76-88 %
R1SH
Bt OH
R
N S
S
Bt
R
R1S
R
N S
S
P
R
R1O OR1
O
Reflux
RefluxZnBr2, Et2O
BF3.Et2O
THF
P(OR1)3
ZnBr2, Et2O
R = Me, Et, Pr 65-70 %
R, R1 = Me, Ph; Et, Et; Et, Ph. 77-79 %
R1SH
Bt OH
RReflux
RefluxZnBr2, Et2O
HN S
S
N S
S
Bt
R
N S
S
R1S
R
N S
S
P
RR1O
OR1O
R, R1 = Me, Et; Pr, Et. 72-77 %
BtHO
R +neat
25
Synthesis of -Amino Amides [05JSCS319]
NBt
R1NR2R3
R4
Conc. HClEtOH/H2O
BF3.Et2O
79-96 %
75-92 %
18 examples
10 examplesTHF
Bt NR2R3
R1 R4NC
HNO
R1NR2R3
R4
NSR5
R1NR2R3
R4earlier work
R5SH
BtHR1
O HNR2R3+ +
Synthesis of -Benzotriazolyl Ketones [04ARK22]
Bt
HO O
Bt
HO O
RBt
R1O
Rn-BuLi (2 eq.)RX (a-c)
a: CH3Ib: AllylBrc: 4-CH3C6H4CH2Br
n-BuLi (2 eq.)R1COCl (a-d)
a: CH3Ib: 4-CH3C6H4c: 2-furyld: Bn 50-89 % 56-84 %
26
Synthesis of Hexagonal Terpyridine-Ruthenium and -Iron Macrocycles by Step-wise or Self-assembly procedures [02CEJ2946]
R
OO+ N
Me
O
NaOH, EtOH
NH4OAc AcOH reflux 24 h
Yield 40%
NN
R
N
N
N
N
R = Me, Br
R
NNN
N N
N
Ru Ru
R
N
N
NN
N
N
R
N
N
N N
N
N
Ru Ru
R
NNN
N N
N
Ru Ru
R
N
N
NN
N
N
R
N
N
N N
N
N
R
NNN
N N
N
Fe Fe
R
N
N
NN
N
N
R
N
N
N N
N
N
Fe Fe
R
NNN
N N
N
Fe Fe
R
N
N
NN
N
N
R
N
N
N N
N
N
27
Monomer
Hexamer
Comparison of HNMR spectra of the monomer and hexamer [02CEJ2946]
28
N
NN
N
NN
CH3
NN
NN
N
N
CH3
NN
N
NN
N
CH3
N
NN
N
NN
CH3
NN
NN
N
N
H3C
NN
N
NN
N
H3C
N
NN
N
NN
CH3
NN
NN
N
N
CH3
NN
N
NN
N
CH3
N
NN
N
NN
CH3
NN
NN
N
N
H3C
NN
N
NN
N
H3C
= Fe
= Ru
= Os
N
NN
N
NN
CH3
NN
NN
N
N
CH3
NN
N
NN
N
CH3
N
NN
N
NN
CH3
NN
NN
N
N
H3C
NN
N
NN
N
H3C
N
NN
N
NN
CH3
NN
NN
N
N
CH3
NN
N
NN
N
CH3
N
NN
N
NN
CH3
NN
NN
N
N
H3C
NN
N
NN
N
H3C
Synthesis of a family of hetero-metallomacrocycles by step-wise procedure [04CEJ1493]
29
Br
BrBrBrBr
OH
BrBr
H SiMe3
BrBr
H
2-Methyl-3-butynolPd(dba)2, CuI,NEt3, PPh3
KOH,Toluene Me3SiCl
SiMe3
OH
OSO2CF3OH
CF3SO2)2O
2-Methyl-3-butynolPd(dba)2, CuI,NEt3, PPh3
H
KOH,Toluene
H
SiMe3
BrBr
Pd(dba)2, CuI,NEt3, PPh3
K2CO3,MeOH
2 eqiv.
EtMgBr,THF
Pyr
A
B
Synthesis of phenyl acetylene dendrons for antenna macrocycles [unpublished]
30
Synthesis of antenna dendron substituted bis-terpyridine by Sonagashira coupling [unpublished]
NN
NN
N
N
Br
HNN
NN
N
N
+
Pd(dba)2, CuI,NEt3, PPh3
A
N
N
NN
N
N
Br
HNN
N
N
N
N
+
Pd(dba)2,NEt3,CuI,PPh3
B
NN
NN
N
N
Br
HNN
NN
N
N
+
Pd(dba)2, CuI,NEt3, PPh3
A
NN
NN
N
N
Br
HNN
NN
N
N
+
Pd(dba)2, CuI,NEt3, PPh3
A
N
N
NN
N
N
Br
HNN
N
N
N
N
+
Pd(dba)2,NEt3,CuI,PPh3
B
N
N
NN
N
N
Br
HNN
N
N
N
N
+
Pd(dba)2,NEt3,CuI,PPh3
B
31
Synthesis of Antenna G1 homo-metallomacrocycles [unpublished]
= Ru
N
N
NN
N
N NN
N
NNN
NN
N
NN N
N
N
NN
N
N NN
N
NNN
NN
N
NN N
= Fe
N
N
NN
N
N NN
N
NNN
NN
N
NN N
N
N
NN
N
N NN
N
NNN
NN
N
NN N
N
N
NN
N
N NN
N
NNN
NN
N
NN N
N
N
NN
N
N NN
N
NNN
NN
N
NN N
Possible use in photonics (light harvesting and storage applications)
32
= Ru
NN
N
N
N
N
N
NN
N
N NN
NN
N
NN
NN
N
N
N
N
N
NN
N
N NN
NN
N
NN
= Fe
NN
N
N
N
N
N
NN
N
N NN
NN
N
NN
NN
N
N
N
N
N
NN
N
N NN
NN
N
NN
Synthesis of Antenna G2 homo-metallomacrocycles [unpublished]
Possible use in photonics (light harvesting and storage applications)
33
Nanoassembly of a Fractal Polymer: A molecular “Sierpinski” Hexagonal gasket [06Science1782]
34
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).
35
Synthesis of next generation non-nutritive sweetener Neotame C-7 [NS]
Synthesis of 2,6,7-trimethyl-5-nitrosopyrrolo[1,2-b]pyridazine [L]
NO
Me
MeMe
Me
TEMPO
Cl
Cl
H2SO4
2-3 oC
LAH
TEMPO
60%
96%89%
NaOCl
OHCO2H OH O
30 psi H2,Pd/C,MeOH,24 h, 97%
H2NCO2H
O NH
MeO2CPh
+
NH
CO2H
O NH
MeO2CPh
Aspartame
Neotame C-7
NN
Me
Me
MeO
Br
MeNN
Me
Me
Me
MeO
NN
Me
Me
Me
NaNO2
NN
Me
Me
Me
ON
+Acetonereflux
47%67%
NaHCO3
Br
36
Synthesis of 4-(2,6-dimethylpyrrolo[1,2-b]pyridazin-7-ylazo)benzenesulfonic acid [L]
Synthesis of 2-methyl-1-nitrosoindolizine-3-carboxylic acid methyl ester [L]
Synthesis of 2-methylamino-1-nitrosoindolizine-3-carboxylic acid ethyl ester [L]
1-(methylamino)-1-(methylthio)-2-nitroethene is commercially available (Aldrich)
NN
Me
Me
OBr
MeNN
MeMeO
Me
NaHCO3
NN
Me
Me
+Acetonereflux
99% 60%
SO3
NN
NN
Me
NN
SO3H
Me
EtOH / AcOH1.5 H2O
55%
N Me
Cl
OMe
NaHCO3+
80%
N
Me
Cl
O
OMe
N
MeO
OMe
NaNO2
AcOH
ON
N
MeO
OMe4h, reflux
62%70%
N
BrO
OEt
EtOAcBr
N
O
OEt
MeHN SMe
NO2
Et3N (10eq.) N
NHMeO
OEtON
N
NHMeO
OEt25oC, 12h
EtOH, reflux 12h
NaNO2 / AcOH 0oC, 1h
75% 56% 90%
37
Synthesis of 2-methanesulfonyl-1-nitrosoindolizine-3-carboxylic acid ethyl ester [L]
Synthesis of 7-dimethylamino-2-methylsulfanyl-1-nitroso-indolizine-3-carboxylic acid ethyl ester [L]
Nitroketene dithioacetal is commercially available (Aldrich)
Not separable by column chromatography
N
O
OEt
MeS SMe
NO2
BrMCPBA
NSO2Me
OEtO
NO
Et3N (10eq.)
NSO2Me
OEtO
NO2
NSMe
OEtO
NO
NSMe
OEtO
NaNO2 / AcOH 0oC, 1h
85% 80%
90%
0oC to 25oC, overnight
EtOH, reflux 12h
+
[85:15]
N+
NMe2
CO2EtBr-
MeS SMe
NO2
N
SMe
CO2Et
Me2NN
SMe
CO2Et
Me2N
NO
EtOH, reflux (1 d)
AcOH0 oC, 1 h
NaNO2
20%
80%
38
Synthesis of (6,7-dimethyl-5-nitrosopyrrolo[1,2-b]pyridazin-2-yl)diethylamine [L]
Synthesis of 2-methyl-1-nitroindolizine [L]
Not separable by column chromatography
NN
Me
Me
NEt2
NN
O
Me
Me
NEt2
Br
BrO
MeMe
NN
Me
MeEt2N
NO
NN
Me
NEt2
HNEt2
NN
Me
MeEt2N
NO2
NN
Me
Cl
neat, 80oC
i) NaNO2, AcOH, 0 oC,1h ii) NaOH (2N)
50%
sealed tube,180oC, 16h
90%
NaHCO3 H2O, reflux,5h
+
61%, (ratio of NO:NO2 is 65:35)
Me O
Cl
Me N
Me HNO3 H2SO4
N
MeO2N
+
i) neat, 80 oC, 4hii) H2O, NaHCO3
45%80%
N
39
Synthesis of 2,3-dimethyl-1-nitroindolizine [L]
Synthesis of 5-nitrosopyrrolo[1,2-c]pyrimidine [L]
Not separable by column chromatography
N Me
BrO
Me
Me
N Me
O
MeMe
N
Me
Me
O2N
BrNaHCO3
NaNO2
N
Me
Me
ON
N
Me
Me
5N HCl
MeCN, reflux, overnight
H2O, reflux
70%
+
Total yield: 86% [35:65]
N
N Me
Me
O
Me
Me
Br
N
N
Me
Me
Me N
N
MeON
Me
Me
neat, 80 oC, 8h
14%
NaNO2, HCl 0 oC, 1h
NaHCO3, H2O+
70%
40
Synthesis of 7-substituted-3-methyl-5,6,7,8-tetrahydro-[2,7]naphthyridine-4-carbonitrile [R]
Synthesis of 6-benzyl-5,6,7,8-tetrahydro-2H-[2,6]naphthyridin-1-one [R]
NR
ONC Me
NH2NR
NCMe
NH2
NN
N
NMe2 Cl
2N NaOH, 25 oC NR
N
MeCN
1)
2)
TiCl4, Et3N
CH2Cl2, 25 oC, 24 h
CH2Cl2, 25 oC, 24h
53 %
+
R = Bn, 70% R = Bn, 53%R = Boc, 40% R = Boc, 7%
BtTMS + DMF
SOCl2 THF
92%
N+
O-N+
OEtI- N
MeCN
Me2N OMe
OMe
N
CNNMe2
N
HNO
N
HNO
Bn
Water 55 oC6 h40%
Neat25 oC1 hquant.
Autoclave180 oC30 h45% EtOH
Refulx18 hquant.
CH3CNRefulx2 h
EtOH0 oC, 1.5 hRT, 16 h
EtI KCN
HBr
BnBrNaBH4
Me Me
80% overall
N
HNO
BnBr
41
Synthesis of 3-fluoroadamantanylmethylamine hydrochloride [R]
Synthesis of 3-fluoroadamantane-1-carboxylic acid [R]
Synthesis of novel 3-noradamantylmethylamine BH3 salt [R]
N S FF
F
DAST
F
HN
OH
HN
(BOC)2O, K2CO3, DMF
OH
H2N
H2N
F
. HCl
conc. H2SO4
H2N
10-15 oC, 6 h 100%
DAST, CH2Cl2, -78 oC to 25 oC, 1 h
76% overall
HNO3 (60 %)
1 d, RT
4 N HCl/DioxaneRT / 3 h 22%
BOC BOC
HO2C
OH H2SO4
MeO2C
OH
MeO2C
FMeOH
HO2C
F DAST NaOH
79% overall
OH
O
NH2
O
NH2
.BH3
1.0 g
29% aq. NH4OH (5 mL)CH2Cl2 (10 mL)-78 oC to rt/ 12 h
SOCl2 (10 mL)80 oC, 1h
0.94 g (100%)
BH3.THF (30 mL)
0.24 g
RT / 24 h
42
Synthesis of novel 5-amino-isochromen-1-one [R]
Synthesis of novel 6-bromo-5-nitro-isochromen-1-one [R]
Regioisomers are separable by recrystallization
Regioisomers difficult to separate by column chromatography
NO2
Me
CO2Me+
MeO OMe
NMe Me
O
NO2
O
DMF115 oC20 h
O
NH2
O
SnCl2.2H2O DMF RT / 12h
500 g
BrMe
HO2C
BrMeNO2
HO2C
BrMe
NO2HO2C
BrMeNO2
MeO2C
BrMe
NO2MeO2C
SOCl2/MeOH
NMeMe
OMeMeOBr
O
O
NO2Br
O
OO2N
HNO3
+
++
DMF
43
Synthesis of 3-ethoxy-4-ethoxycarbonyl phenylacetic acid, a key synthon of Repaglinide [R]
Preparation of Repaglinide [R]
N NMe Me
O
DMPU
Me OH
CO2H
K2CO3
DMSOMe OEt
CO2Et
LDA/DMPU
CO2
OEt
CO2Et
HO2CEtBr
40 oC 10 h 99.6%
-78 oC2 h67%
OEt
CO2Et
HO2C
t-BuCOCl
TEA, Tolune
NH2
H
N
NH
Me
MeH
N
O
OEt
CO2Et
-5 oC, 1 h30 oC, 12 h 73%
1N NaOH
EtOH60-65 oC, 2 h 94%
Me
Me
Repaglinide
OEt
CO2Et
O
OOMe
MeMe
NH
Me
MeH
N
O
OEt
CO2H
44
Synthesis of Chiral Metabolites of Pioglitazone [R]
Boekel-heide rearrangement
N
Et
OS
NH
O
OCH2Cl2 N
Et
OS
NH
O
OO
N
Et
OS
NH
O
OOH
MCPBA
1. TFAA, CH2Cl2
2. Aq NaHCO3, THF
separated by making diasreromeric esterswith mandelic acid
chiral metabolitesof pioglitazone
N
Et
OS
NH
O
OOH
96%
74%
N
Et
OS
NH
O
OOH
45
Preparation of midazolam maleate [R]
NH2
ClO
F
NH2
ClS
SSH
SH
TiCl4
N
ClF
S
S
MeH2N
CH3CN
AlCl3
N
ClF
S
S
NO
Me
Br
O
O
N
ClF
S
S
N
Me
NHO
NH2OH.HCl
EtOH
N
ClF
S
S
N
Me
H2N
NaCNBH3
MeOH
N
Cl
F
N
N
Ce(NH4)2(NO3)6
CH3CN/H2O
COOH
COOH
MeOH
N
Cl
F
N
N
COOH
COOH
52-55 oC 8h
Reflux 2d
i-PrOHAcOHTEAReflux6h
RT0.5h
RT12h
.
F
46
Thanks
47
Thank you.