Laura Carroccia, Leonardo Degennaro, Arianna
Giovine, Maddalena De Renzo, Flavio Fanelli and
Renzo Luisi
http://www.farmchim.uniba.it/chimica_organica/Luisi2.html
Bari, 28 Febbraio 2014
FLAME – Lab
Flow Chemistry and
Microreactor Technology
Laboratory
Department of Pharmacy
Drug Sciences
Project financially supported by:
PON – R.A.I.S.E.
Reasearch,
Application,
Innovation, Services in
Bioimaging
Meeting the Green Chemistry Principles
1. Prevention *
2. Atom Economy *
3. Less Hazardous Chemical Syntheses *
4. Design Safer Chemicals
5. Safer Solvents and Auxiliaries *
6. Design for Energy Efficiency *
7. Use Renewable Feedstocks
8. Reduce Derivatives *
9. Catalysis *
10. Design for Degradation
11. Real-time Analysis for Pollution Prevention
12. Inherently Safer *
* Principles addressed by the Microreactor Technology
Contacts:
Prof. Renzo Luisi
Department of Pharmacy – Drug Sciences
University of Bari “A. Moro”
VIA E. ORABONA 4 – I-70125 BARI, Italy
tel: +390805442762
fax: +390805442539,
e-mail: [email protected]
Batch chemistry
Microreactor technology
Faster
Cleaner
Cheaper
Safer
K. Jhnisch, V. Hessel, H. Lwe, M. Baerns Angew. Chem. Int. Ed. 2004, 406.
T. Wirth Microreactors in Organic Synthesis and Catalysis 2008, Wiley – VCH
Time-dependent
transformation
Angew. Chem. Int. Ed. 2012, 3245
CH3
N
(S)
R
H3C
N
s-BuLi, TMEDA
Toluene, -78 °C
N
(S)
Li
Li
Li
R N
CH3
E+
E+
E
R
N
Racemic
(S)
E
Main product at -78 °C
in toluene
R N
Main product at -30 °C
in toluene
A. Giovine, B. Musio, L. Degennaro, A. Flacicchio, A. Nagaki, J-i Yoshida, R. Luisi Chem. Eur. J. 2013, 1672
Me
N
Me
N
-48 °C
0.1 M in
toluene/TMEDA
-48 °C
0.1 M in
toluene/TMEDA
P1
tR
M1
s-BuLi
R1
E
N
P2
M2
0.3 M in hexane
+
Me
s-BuLi
P1
M1
P3
tR2
R1
R2
P2
0.3 M in hexane
M2
E+
R2
E
tR1
0 °C
E
R3
N
tR3
P3
Me
0.4 M in toluene
ELECTROPHILE
YIELD (%)a
ClSiMe3
60
0.4 M in toluene
ELECTROPHILE
YIELD (%)a
C6H10O
58
ClSiMe3
90
PhCOPh
60
C6H10O
48
MeCOPh
75 (dr=52:48)
t-BuCHO
90 (dr=82:18)
EtCOPh
77 (dr=82:18)
p-CF3-PhCHO
54 (dr=45:55)
t-BuCOH
70 (dr=70:30)
PhCHO
95 (dr=45:55)
2,6-(CH3)2PhNCO
58
2,4,6-(Me)3-PhCHO
63 (dr=70:30)
C6H11NCS
73
2,6-(Me)2PhNCO
95
a : isolated yield
Reaction conditions: tR = 20.9 s; Flow rate:
aziridine 1a 3 mL/min; s-BuLi 1.5 mL/min
A. Giovine, B. Musio, L. Degennaro, A.
Flacicchio, A. Nagaki, J-i Yoshida, R.
Luisi Chem. Eur. J. 2013, 1672
a : isolated yield
Reaction conditions: tR1 = 20.9 s; tR2 = 41.9 s;
flow rates: aziridine1a 3 mL/min; s-BuLi 1.5
mL/min; electrophile 1.5 mL/min.
Me
Me
N
N
0 °C
Me
0 °C
0.05 M in
toluene/TMEDA
N
P1
tR
M1
s-BuLi
s-BuLi
R1
P2
M2
0.15 M in hexane
E+
0.05 M in
toluene/TMEDA
R2
1
P1
M1
N
tR2
R1
R2
P2
0.15 M in hexane
E Me
tR1
60 °C
E
R3
M2
E+
N
P3
Me
0.2 M in toluene
P3
E
0.2 M in toluene
2
E+
Yield (%)[a,b]
dr
SiMe3Cl
78
50:50
MeI
57[e]
56:44
Cyclohexanone
50
60:40
93:7
Acetone
60
50:50
74
10:90
C6H5CON(CH3)(OCH3)
53
55:45
68
5:95
2,6-(CH3)2-C6H3NCO
51
50:50
E+
Yield
(%)[a]
1:2 ratios
CD3OD
98
80:20
EtI
90[c]
62:38
Acetone
86
65:35
iPrI
53
Ph2CO
SiMe3Cl
a: Overall isolated yield
Reaction conditions: tR = 5.24 s; flow
rate: aziridine1a 3 mL/min; s-BuLi
1.5 mL/min; electrophile 1.5 mL/min
a: Overall isolated yields. b: Relative stereochemistry not assigned
Reaction conditions: tR1 = 5.24 s; tR2 = 10.5 s; flow rate:
aziridine1a 3 mL/min; s-BuLi 1.5 mL/min; electrophile 1.5
mL/min.
A. Giovine, B. Musio, L. Degennaro, A. Flacicchio, A. Nagaki, J-i Yoshida, R. Luisi Chem. Eur. J. 2013, 1672
In line with the principles of ‘‘green’’ chemistry, organocatalysis seeks to reduce energy
consumption and to optimize the use of the available resources, aiming to become a
sustainable strategy in chemical transformations.
Organocatalysts consist of small, low-molecular-weight organic compounds,
containing carbon, hydrogen, nitrogen, sulfur and phosphorus. The benefits of
using organocatalysts is that they are inexpensive, easily available, and nontoxic. Furthermore, the organocatalyst are often insensitive toward moisture
and oxygen, and hence, no special reaction conditions are required.
Aldol reaction
Angew. Chem. Int. Ed. 2009, 48, 2699 – 2702
Baylis-Hilman reaction
Chin. J. Chem. 2011, 29, 2385 – 2388.
L. Carroccia, B. Musio, L. Degennaro, G. Romanazzi, R.Luisi, J. Flow Chem., 2013, 29-33
O
N
N
N
H HN N
1a
10% catalyst
95%
yield
er:
66/34
dr:
90:10
25 °C, 3h
DMSO
soluble
Ph
P
N
H
t
H
N
Ph
N
H
OTMS
SO2Ph
N
H Ph Ph
1d
O
1c
1b
10% catalyst
56%
yield
er:
93/7
dr:
95:5
40 °C, 28h
CH2Cl2
soluble
Ph
R2
N
H
N
S
N
H
Ph
N
1f
N
H
N
H
1g
10%
catalyst
<1%
yield
suspension in
CH2Cl2, toluene
10%
catalyst
<1%
yield
suspension in
CH2Cl2, toluene
R2
R1
O
O
(1 equiv.)
+
NH2
O
Bu S
O
R1
+
R
80 °C, 100 min
DMSO
N
H
10%
catalyst
<1%
yield
suspension in
CH2Cl2, toluene
R2
N
HN N
8%
N
H
1e
N
N
H
H
N
Bu S
O
10% catalyst
<1%
yield
suspension in
CH2Cl2, THF,
toluene
10%
catalyst
40%
yield
er:
53:47
dr:
88/12
80 °C, 1.5h
EtOH/iPrOH 1:1
soluble
t
Me
N
NO2
NO2
R
A+ ent A
NO2
R
B+ ent B
R1
(1 equiv.)
CH3
Br
Br
inlet
O
O
NO2
O
NO2
Ph
88 %
dr: 87:13
er: 61:39
87 %
dr: 90:10
er: 68/32
O
NO2
CH3
92 %
dr: 90:10
er: 67:33
O
NO2
OMe
NO2
CH3
98 %
dr: 81:19
er: 70:30
93 %
dr: 91:9
er: 85:15
L. Carroccia, B. Musio, L.
Degennaro, G. Romanazzi,
R.Luisi, J. Flow Chem.,
2013, 29-33
output
N
N
H
N
HN N
12%
80 °C, 100 min
DMSO
O
O
Ar
N
+
(1 equiv.)
+
NO2
Ar
(1 equiv.)
NO2
Ph
CHO
+
DIPEA
(1 equiv.)
N
H
N
HN N
80 °C, 76 min
DMSO
Ph
OHC
NO2
HO
Ph
OHC
+
NO2
HO
Ar
Ar
A
er : 76:24
L. Carroccia, B. Musio, L. Degennaro, G. Romanazzi, R.Luisi, J. Flow Chem., 2013, 29-33
B
er : 89:11
Ar = 4-BrC6H4
Yield 89 %
dr (A:B) = 46:54
UNIVERSITÀ DEGLI STUDI DI BARI “A. Moro”
Prof. Renzo Luisi
Dr. Leonardo Degennaro
Dr. Arianna Giovine
Dr. Biagia Musio
Dr. Piera Trinchera
Dr. Marina Zenzola
Dr. Paolo Pace
Dr. Vito Costanza
Dr. Flavio Fanelli
Dr. Vanna Parisi
Mara Anelli
Maddalena De Renzo
Sara Pellicano
KYOTO UNIVERSITY
Prof. Jun-ichi Yoshida
Dr. Aichiro Nagaki
POLITECNICO DI BARI
Dr. Giuseppe Romanazzi
IC CNR BARI
Dr. Aurelia Falcicchio
Dr. Angela Altomare - IC CNR Bari