The Mannich Reaction:
New Light On An Old Story
Literature meeting
Julie Côté
November 27, 2007
The Mannich ReactionThe Mannich Reaction
H H
O+ R2NH + R
R'
OO
R'
R2N
R
Mannich base
Applications:
• Polymer chemistry (hardeners, cross-linkers and reaction accelerators)
• Plant protections
• Pharmaceutical area
Cribrochalina
Potent cytotoxic agent
Chan, C.; Heid, R.; Zheng, S.; Guo, J.; Zhou, B.; Furuuchi, T.; Danishefsky, S.J. J. Am. Chem. Soc. 2005, 127,4596-4598.
Dr. Ulrich Franz Carl Mannich Dr. Ulrich Franz Carl Mannich
Mechanism was discover in 1912
HNR2 HCl
-HCl
+HClHNR2
-CH2O
+ CH2O
HO NR2
-HCl, +H2O
+HCl, -H2ONR2
CH2
Cl
1
1 R1
O
R2
R1
OH
R2R1
O
R2
NR2HCl
Organic chemists in this area argue that this reaction has become the most important C-C bond-forming reaction!
Arend, M.; Westermann, B.; Risch, N. Angew. Chem. Int. Ed. 1998, 37, 1044-1070.
Limitation of the Mannich Reaction Limitation of the Mannich Reaction
R1
O
H R2
O+ +
R3
NH2
OR(NR2)
R1 H
N
R2
R3
R1
O HN
R2
R3
direct
indirect
This type was first used in early 20th century but neaded drastic reaction and long reaction time
The first methods developed were non-catalytic and employed preformed enolates and enamine with chiral
auxiliary control
O N
O
Bn
O
Arend, M.; Westermann, B.; Risch, N. Angew. Chem. Int. Ed. 1998, 37, 1044-1070. Enders, D.; Ward, D.; Adam, J.; Raabe, G. Angew. Chem. Int. Ed. Engl. 1996, 35, 981.
PresentationPresentation
Organocatalytic Mannich reaction• Proline catalyst• Cinchona alkaloids catalyst • Thiourea catalyst • Bronsted acid catalyst
Avancement in direct asymmetric mannich reaction• Aldimine MR• Anti-selective MR• Quaternary carbon center MR • Nitro MR• One pot three component MR
Indirect MR with Bronsted acid catalyst
Vinylogous MR
Aldimine in Direct Asymmetric Mannich Aldimine in Direct Asymmetric Mannich Reaction : Unmodified Ketones Reaction : Unmodified Ketones
O
20 vol% N
MeO
R
S
NH
CO2H
(20 mol%)
DMSO, rt, 24-48h
O
R
HN
MeO
O HN
MeO
45 %, 16 ee%
O HN
MeO
56 %, 88 ee%
O HN
MeO
NO248 %, 80 ee%
Very low yields and ee’s High amount of catalyst long reaction time
Notz, W. Sakthivel, K.; Bui, T.; Zhong, G.; Barbas, III, C.F. Tetrahedron Lett. 2001, 42, 199-201.
Aldimine in direct asymmetric Mannich Aldimine in direct asymmetric Mannich Reaction : Unmodified Aldehyde Reaction : Unmodified Aldehyde
H
O
R H CO2Et
NPMP (L)-Proline (5 mol%)
Dioxane
2-24h,rt
H
O
CO2Et
R
HNPMP
(S)(S)
(1,5 eq)
H
O
CO2Et
HNPMP
H
O
CO2Et
HNPMP
H
O
CO2Et
HNPMP
H
O
CO2Et
HNPMP
H
O
CO2Et
HNPMP
81%, dr: 10:1, 93 ee% 72%, dr: 1.1:1, 99 ee% 81%, dr: 3:1, 99 ee%
71%, dr: 19:1, 99 ee% 89%, dr: 19:1, 99 ee%
H
O
CO2Et
HNPMP
MeO
O
CO2Et
HNPMP
NPMPO
CO2EtH H1) NaClO2, KH2PO4 2-methyl-2-butene t-BuOH/H2O
2) CH2N2, Et2O, 89%
1) LHMDS, THF, -20C 96%
B-lactam
NO
HN
Benzylpenicillin(Penicillin G)
NO SO3
HN
ON
N
S
OO
OH
Monobactams(Azactam®)
NH2
S
HOO
NO
S
HOO
O
H
HHO
Carbapenems(Faropenem)Proceed smoothly with excellent enantioselectivity
Higher diastereoselectivities were achived with increased bulkiness of the substituents on the aldehyde
Cordova, A.; Watanabe. S. I.; Tanaka, F.; Notz, W.; Barbas, III, C. F. . J. Am. Chem. Soc. 2002, 124, 1866-1867.
Aldimine in Direct Asymmetric Mannich Aldimine in Direct Asymmetric Mannich Reaction : Ionic LiquidsReaction : Ionic Liquids
N N BF4[bmin]BF4 =
- non volatile- Tunable polarity - High thermal stability- Great abily to dissolve catalyst- « Green » solvent
Faster reaction in ionic liquids: result from ionic based activation of the imine electrophile.
Solvent and catalyst are readily recycled
Can be performed on a multi-gram scale
R1
O
R2 H
N
CO2Et
PMP (L)-proline (5 mol%)
[bmim] BF4
30 min
R1
O
R2
HN
CO2Et
PMP
Chowdari, N.S.; Ramachary, D.B.; Barbas, III, C. F. Synlett, 2003, 12, 1906-1909.
H
O HN
CO2Et
PMP
90 %, dr: 5:1, 93 ee%
H
O HN
CO2Et
PMP
96 %, dr: 19:1, 99 ee%
Me
O
Me
HN
CO2Et
PMP
77 %, dr: 19:1, 99 ee%
H
O
CO2Et
HNPMP
81%, dr: 10:1, 93 ee%
87%, dr: 13:1, 99 ee%
81%, dr: 3:1, 99 ee%
Aldimine in Direct Asymmetric Mannich Aldimine in Direct Asymmetric Mannich Reaction : Protecting GroupReaction : Protecting Group
R1
O
R2 H R2
NBoc (S)-proline (20 mol%)
CH3CN, 0C
8-12 h
R1
O
R3
R2
NHBoc
H
O NHBoc
91%, d.r. 99:1, e.r. 99:1
H
O NHBoc
OMe
80%, d.r. 99:1, e.r. 99:1 59%, d.r. 99:1, e.r. 98,5:1,5
H
O NHBoc
Cl
O NHBoc
73%, e.r. 99:1
R
HN
R2
PMP
R
HN
R2
BocR
NH2
R2
A
B
A
Drastic oxidative condition Harmful reagents: (NH4)Ce(NO3)6,
(CAN)
B
Easy clivage of Boc Provides stable crystalline compounds without purification
Initially homogenous
reaction mixture
After consumption of the starting
material : precipitation
Yang, J. W.; Stadler, M. List, B. Angew. Chem. Int. Ed. 2007, 46, 609-611.
Aldimine in Direct Asymmetric Aldimine in Direct Asymmetric Mannich Reaction :Anti-SelectiveMannich Reaction :Anti-Selective
H
O
R H
N
CO2Et
PMPNH
OMe
(20 mol%)
DMSO24-48h, rt
H
O
R
HN
CO2Et
PMP
(R)
(S)
H
O HN
CO2Et
PMP
H
O HN
CO2Et
PMP
H
O HN
CO2Et
PMP
52 %, dr: 10:1, 82 ee% 68 %, dr: 19:1, 76 ee%78 %, dr: 10:1, 76 ee%
VS
Proline catalyst SMP catalyst
Plausible transition-states
Moderate yields and ee
Cordova, A.; Barbas, III, C.F. Tetrahedron Lett. 2002, 43, 7749-7752.
(E)-Enamine predominate
Si-face of imine is attacked by enamine si-face
Facial selection is controlled by proton transfer
Lacking the stereodirecting carboxylate of proline, the topicity is altered
Si-face of imine is now attacked by re-face of the enamine
Aldimine in Direct Asymmetric Mannich Aldimine in Direct Asymmetric Mannich Reaction :Anti-SelectiveReaction :Anti-Selective
H
O
R H CO2Et
NPMP
NH
CO2H3
5
H
O
R
CO2Et
NHPMP
N
CO2H
HH
R
N
CO2H
R
HH
Structural features at the 5-position were installed to fix the enamine conformation
Acid position to affect control of enamine and imine facial selection
To avoid steric interaction between the substituents at the 5 the imine, substituents 3- and 5- are in trans -configuration
H
O
R1 H CO2R2
NPMP N
H
CO2H
H
O
R
CO2R2
NHPMP
H
O
R
CO2R2
NHPMP(1-5mol%)
DMSO
Entry R1 R2Time(h)
Yield( %)
dranti :syn
ee(%)
1 i-Pr Et 3 85 98 :2 992 n-Bu Et 1 71 97 :3 993 n-Pent Et 3 80 97 :3 >994 i-Pr i-Pr 1 92 97 :3 985 n-Pent i-Pr 1 85 96 :4 >99
Zhang, H.; Mifsud, M. Tanaka, F.; Barbas, III, C. F. J. Am. Chem. Soc. 2006, 128, 9630-9631.
N
H CO2Et
H
O
O
H
PMPH
Aldimine in direct asymmetric Mannich Aldimine in direct asymmetric Mannich Reaction :Anti-SelectiveReaction :Anti-Selective
R1
O
R2
NH
CO2H3
5
N
CO2H
R1H
R2
N
CO2H
R2
HR1
Ineffective in MR with ketones . Hypothesis: origined from the relatively slow formation of the enamine intermediates due to steric interaction with Me group of the catalyst
E1
O
R2 H
N
CO2R3
PMP
R1
O
R2
NHPMP
CO2R30.1 eq
2-PrOH, rt
NH
CO2H
Et
O
Me
NHPMP
CO2t-Bu
93%, dr: 99:1, 95 ee%
O NHPMP
CO2Et
96%, dr: 99:1, 96 ee%
Me
O NHPMP
CO2Et
85%, dr: 95:5, 91 ee%
S
O NHPMP
CO2Et
O
O NHPMP
CO2Et
78%, dr: 99:1, 99 ee% 82%, dr: 95:1, 86 ee%
Zhang, H.; Mifsud, M. Tanaka, F.; Barbas, III, C. F. J. Am. Chem. Soc. 2006, 128, 9630-9631.
Aldimine in Direct Asymmetric Mannich Aldimine in Direct Asymmetric Mannich Reaction :Anti-SelectiveReaction :Anti-Selective
R
O
HNH
H HEtO2C CO2Et
NH
Ph
OTMSPh
(10mol%)
benzoic acid (10 mol%)
CHCl3, -20 °C
R H
O
NH
CO2EtEtO2C
R
O
HNH
H HEtO2C CO2Et
NH
Ph
OTMSPh
(10mol%)
benzoic acid (10 mol%)
CHCl3, -20 °C
R H
O H CO2Et
NPMP
R CO2Et
HNPMP
OH
4°C, 24 hDMSO:CHCl3
(R)-proline
(35mol%) 80 %, 5:1 dr, 96% eeR= 2-naphtyl
Furnish three contiguous stereocenters in one step in good %The asymmetric reductive MTR proceed via a catalytic asymmetric domino reaction and furnish amino acid
Zhao, G. L.; Cordova, A.; Tetrahedron Lett. 2006, 47, 7417-7421.
Aldimine in Direct Asymmetric Mannich Aldimine in Direct Asymmetric Mannich Reaction :Anti-SelectiveReaction :Anti-Selective
Zhao, G. L.; Cordova, A.; Tetrahedron Lett. 2006, 47, 7417-7421.
N
H
R1 R2
Ar
ORAr
N
H
R1 R2
Ar
ORAr
N
H HEtO2C CO2Et
NH
EtO2C CO2Et
N
H
R1 R2
Ar
ORAr
NH
Ar
ORAr
H2O
O
H
R1 R2
H2O
O
H
R1 R2
Aldimine in Direct Asymmetric Mannich Aldimine in Direct Asymmetric Mannich Reaction :Anti-SelectiveReaction :Anti-Selective
N
H
R1 R2
Ar
ORAr
N
H
R1 R2
Ar
ORAr
N
H
R1 R2
Ar
ORAr
NH
Ar
ORAr
H2O
O
H
R1 R2
H2O
O
H
R1 R2
+ H+
NPMP
HEtO2C
NH
O
EtO
NH
O
EtOPMP
PMP
R1
NH
O
EtO
PMP
O H
R2
1,3-Dicarbonyls and Acyl Aldimines with 1,3-Dicarbonyls and Acyl Aldimines with Cinchona Alkaloids Catalyst Cinchona Alkaloids Catalyst
R1
O
OR2O
R3O N
O
PhH
R1
O
Ph
HN
OR2O
OR3
O
10 mol%
cinchonine
CH2Cl2-35 °C, 16h
N
H
HN
HO
cinchonine
O
Ph
HN
OO
OCH3
O
R1
O
Ph
HN
OCH3O
O
O
O
Ph
HN
OO
Ot-Bu
O
99%, 3:1 dr, 92% ee 85%, 3:1 dr, 80% ee 91%, 2:1 dr, 90% ee
H3C
O
Ph
N
OCH3O
O
O N NH
O
OCH3O
Bn
Ph
1) Pd(PPh3)4
BnNCOdimethylbarbituric acid
2) AcOH, EtOHmicrowave, 120°C
10 mins
Brandon, M. Lou, S.; Ting, A.; Schaus, S. E. J. Am. Chem. Soc. 2005, 127, 11256-11257.
Malonates and Acyl Aldimines with Malonates and Acyl Aldimines with Bifunctional Cinchona Alkaloids Catalyst Bifunctional Cinchona Alkaloids Catalyst
R H
NBoc
OR2
O
O OR2R
NH
COOR2
COOR2
Boc
(20 mol%)
-60 C, acetone36 h
catalyst
R2 = CH3, Bn, allyl up to 99 %, 99 ee%
R2 COOR
COOR
HNBoc
1) Pd/C, H2 MeOH, 10h
2) Toluene, reflux 2h
COOR
HNBoc
1) Pd(PPh3)4, THF morpholine, r.t., 3h
2) Dioxane, reflux 3h
COOR
HNBoc
R=Bn, R2= H, 96%ee
R=allyl, R2= vinyl, 96%ee
76%, 94 ee%72%, 96 ee%
Cinchona alkaloid derivatives bearing a thiourea functionnality might act as efficient bifunctional catalysts for malonates with simple imines
N
N
H3CO
HN
HN
S
CF3
CF3
thiourea cinchona alkaloid derivative
bridgehead nitrogen for activation of nucleophilic substrate
thiourea moiety for organisation/activation ofelectrophilic imine
Song, J.; Wang, Y.; Deng, L. J. Am. Chem. Soc. 2006, 128, 6048-6049.
Asymmetric Mannich Reaction Adducts Asymmetric Mannich Reaction Adducts with Quaternary Carbon Centerswith Quaternary Carbon Centers
H
O
R2
R1 H CO2Et
NPMP L-proline (30 mol%)
DMSO, rt H
O
CO2Et
R1 R2
HNPMP
0,25-48h
H
O
CO2Et
Me Ph
HNPMP
66%, syn/anti: 85:15, ee (syn:anti) 86/25
H
O
CO2Et
HNPMP
99%, syn/anti: 96/4ee(syn/anti) 93/5
H
O
CO2Et
Me
HNPMP
82%, syn/anti: 75:25, ee (syn:anti) 96/64
S
H
O
CO2Et
Me
HNPMP
OO
91%, syn/anti: 70:30, ee (syn:anti) 88/52
H
O HN
CO2Et
PMP
94%, ee (syn:anti) 88/52
H
O HN
CO2Et
PMP1) NaClO2, NaH2PO4 2h
2) NaOH (1 eq)
3) HCl (1.1 eq) 5 min
NO PMP
CO2Et
80 %
spiro lactam
Chowdari, N. S.; Suri, J. F.; Barbas, III, C. F. Org. Lett. 2004, 6, 2507-2510.
R1 and R2 need to be very diffirent to access good syn/anti ratio
Asymmetric Mannich Reaction Adducts Asymmetric Mannich Reaction Adducts with Quaternary Carbon Centerswith Quaternary Carbon Centers
Ar
CN
CO2Bn
N
CO2R2
Boc(DHQD)2PYR
(5mol%)
-78° C, CH2Cl2Ar
HN
CO2R2NC CO2Bn
Boc
(DHQD)2PYRHN
CO2EtNC CO2Bn
Boc
98%, 89:11 dr, 97 ee%
HN
CO2EtNC CO2Bn
BocCl
99%, 80:20 dr, 91 ee%
HN
CO2EtNC CO2Bn
BocMeO
97%, 85:15 dr, 96 ee%
HN
CO2EtNC CO2Bn
Boc
95%, 18:82 dr, 11 ee%
Br
HN
CO2iPrNC CO2Bn
Boc
98%, 85:15 dr, 98 ee%
Br
Interesting solvent effect was demonstrated which gave drastic changes in stereoselectivity CH2Cl2 Toluene
Poulsen, T. B.; Alemparte, C.; Saaby, S.; Bella, M. Jorgensen, K. A. Angew. Chem. Int. Ed. 2005, 44, 2896-2899.
Asymmetric Mannich Reaction Adducts Asymmetric Mannich Reaction Adducts with Quaternary Carbon Centerswith Quaternary Carbon Centers
X
O O
YH
N
Ar
H3CO
O
CH2Cl2
5 mol%X
O HN
Ar
OCH3
O
O
Y
cinchonine
O HNOCH3
O
O
H3CO
98%, 90 de%, 99 ee%
O HNOCH3
O
O
H3CH2CO
98%, 94 de%, 98 ee%
O HNOCH3
O
O
H3C
98%, 95 de%, 99 ee%
Ting, A.; Lou, S.; Schaus, S. E. Org. Lett. 2006, 8, 2003-2006.
N
H
HN
HO
cinchonine
Asymmetric Nitro-Mannich Reaction Asymmetric Nitro-Mannich Reaction
Ar N PPh2
O CH3NO2
(5 eq)
[YbK(binaphoxide)2] (20mol%)
toluene/THF (7:1) -40 C
Ar NH
NO2
PPh2
O
41-93%, 69-91ee%15 h
Metal-free of the nitro-Mannich reaction have recently evolved
Limitations: proceeded smoothly with imine which contains an electron-withdrawing substituent and need prolonged reaction time with electron-donating group.
Aza-Henry Reaction
Yamada, K. I.; Harwood, S. J.; Gröger, H.; Shibasaki, M. Angew. Chem. Int. Ed. 1999, 38, 3504-3506.
Asymmetric Nitro-Mannich Reaction Asymmetric Nitro-Mannich Reaction
Ar
NP(O)Ph2 RCH2NO2 (10 eq)
CH2Cl2, rt
Catalyst (0,1 eq)
Ar
HN
R
NO2
P(O)Ph2 F3C
CF3
HN
S
HN
N
thiourea derivative
HN
NO2
P(O)Ph2 HN
NO2
P(O)Ph2 HN
NO2
P(O)Ph2
87%, 67 ee%
O
85%, 76 ee%
N
91%, 68 ee%
HN
NO2
P(O)Ph2
83%, 67 ee%
Ar
NBoc
H ArNO2RCH3NO2
CH2Cl2, -20 °C, 24h
catalyst (10mol%) NHBoc
R
NO2
NHBoc
O
92%, 90/10 dr (syn/anti) 93 ee%
NO2
NHBoc
O
82%, 93/7 dr (syn/anti) 99%
NO2
NHBoc
94%, 97/3 dr (syn/anti) 92 %
F3C
Okino, T.; Nakamura, S.; Furukawa, T.; Takemoto, Y. Org Lett. 2004, 6, 625-627. Xu, X.; Furukawa, T.; Okino, T.; Miyabe, H.; Takemoto, T. Chem. Eur. J. 2006, 12, 466-476.
Asymmetric Nitro-Mannich Reaction Asymmetric Nitro-Mannich Reaction
Future work includes the expansion of the methodology to different substrates and investigation of the synthetic utility of the addition products.
Ar
NBoc
H ArNO2RCH3NO2
CH2Cl2, -20 °C
catalyst (10mol%) NHBoc
R
Xu, X.; Furukawa, T.; Okino, T.; Miyabe, H.; Takemoto, T. Chem. Eur. J. 2006, 12, 466-476.
The Thiourea moiety play a role in activation of N-Boc imine in the nucleophilic addition step and in nitroalkane deprotonation
Three-Component Mannich Reaction Three-Component Mannich Reaction
O
H R
O
NH2
OMe
(L)-Proline (35 mol%)
12-48 h1.1 eq
O
R
HNPMP
O HNPMP
NO2
O HNPMP
O HNPMP
O HNPMP
O
O HNPMP O HN
PMP
50%, 94 ee% 35%, 96 ee% 82%, 75 ee%
90%, 93 ee% 74%, 73 ee% 56%, 70 ee%
List, B. J. Am. Chem. Soc. 2000, 122, 9336-9337.
Three-Component Mannich Reaction Three-Component Mannich Reaction
JACS, 2002, 124 827
(S)-Proline (20 mol%)O
OHH
O
R
NH2
OMe1.1 eq
O
OH
HN
R
PMP
DMSO, rt, 3-24 h
10 vol% 1 eq
92%, dr = 20:1, 99 ee%
O
OH
HNPMP
NO2
O
OH
HNPMP
Br
90%, dr = 15:1, 98 ee%
O
OH
HNPMP
83%, dr = 9:1, 93 ee%
O
OH
HNPMP
OMe
88%, dr = 9:1, 61 ee%
O
OH
HNPMP
57%, dr = 17:1, 65 ee%
R H
ORNH2
OH
O
R
O
(S)-Proline
Sharpless AA
R
ONHR
OH
List, B.; Pojarliev, P.; Biller, W. T.; Martin, H. J. J. Am. Chem. Soc. 2002, 124, 827-833.
Mechanism of the Proline catalized Mechanism of the Proline catalized Mannich Reaction Mannich Reaction
N CO2H
XR
NAr
H R
O
H
N CO2
X
ArHN
R
H2O
O
X
ArHN
R
NH
CO2H
H2O
X
O
List, B.; Pojarliev, P.; Biller, W. T.; Martin, H. J. J. Am. Chem. Soc. 2002, 124, 827-833.
Mechanism of the Proline catalized Mechanism of the Proline catalized Mannich Reaction Mannich Reaction
N
X
OO
H
N CO2H
X
R
O
H
AldolMannich
N
H R
MeO
ArNH2
H
O
X
ArHN
R
N
X
OO
H
O
R H
H
O
X
ArHN
R
antisyn
enamine siimine si
enamine sialdehyde re
List, B.; Pojarliev, P.; Biller, W. T.; Martin, H. J. J. Am. Chem. Soc. 2002, 124, 827-833.
Three-Component Mannich Reaction Three-Component Mannich Reaction Optimization Optimization
O
H R
O
NH2
OMe
(L)-Proline (30 mol%)
4-96 h1.1 eq
O
R
HNPMP
Water-Freezing (-20 C, 200 MPa)
DMSO
O HNPMP
NO2
O HNPMP
O HNPMP
O HNPMP
O HNPMP
50%, 94 ee% 35%, 96 ee% 0%, 0 ee%
0%, 0 ee% 23%, 4 ee%
58%, 91 ee% 64%, 91 ee% 65%, 95 ee%
OMe
OMe
NH
O
82%, 92 ee% 90%, 84 ee%
Accelerates the reaction but also suppresses side
reactions
Hayashi, Y.; Tsuboi, W.; Shoji, M.; Suzuki, N. J. Am. Chem. Soc. 2003, 125, 11208-11209.
Three-Component Mannich Reaction Three-Component Mannich Reaction Optimization Optimization
O
H
O
H
R
H2N
(S)-proline
DMSO
O
NH
R
microwave
Entry Rmol % of catalyst
Power (W)
Temp(°C)
Time(h)
Yield( %)
ee(%)
1 H 20 15 47 2 80 972 H 10 15 46 2,5 96 983 H 5 15 45 2,5 93 984 H 1 15 48 4 89 975 H 0,5 15 46 3 83 986 OMe 10 15 47 2,5 71 957 OMe 10 10 45 2,5 81 958 Ome 1 10 47 3 84 949 i-Pr 10 10 45 3 71 9710 i-Pr 5 15 51 3,5 88 9711 i-Pr 0,5 15 49 4 86 97
Reducing the time of reaction
Rodriguez, B.; Bolm, C. J. Org. Chem. 2006, 71, 2888-2891.
Access to Chiral 1,2- and 1,4 DiaminesAccess to Chiral 1,2- and 1,4 Diamines
O
N3
CO2Et
ONH2
PMP
NH
N N
NN
30 mol %
DMSO, rt, 0.5 h
O
CO2Et
HN
N3
PMP
96%syn/anti 91/9, 99/99 ee%
O
NPhtCO2Et
ONH2
PMP
NH
N N
NN
30 mol %
DMF, 4°C, 40h
O
CO2Et
HNPMP
83%90 % ee%
NPht
NN N
NN
N
N
N
H
H R
N
MeO
NN N
NN
N
H
OOH R
N
MeO
NN N
NN
H
N OOH R
N
MeO
Protecting group dependent
regioselectivity
Chowdari, N. S.; Ahmad, M.; Albertshofer, K.; Tanaka, F.; Barbas, III, C. F. Org Lett. 2006, 8, 2839-2842.
Green Green Three-Component Mannich Three-Component Mannich Reaction Reaction
R1
O
HR2NH2
O
H2O (5 mL), rt, 3-16 h
H3PW12O40 (10 mg)
O NHR2
R1
O NHR2
R1
syn anti
O HN
Cl
anti/syn 62 / 38
80 %
O HN
OMe
OMe72 / 28
88 %
O HN
Cl
68 / 32
83 %
Cl
Low loading of catalyst Good yields Clean reactionNeed vigourous stirringEnvironmentally benign
The reaction might take place at the
interface of organic materiels with water
in heterogeneous system.
Azizi, N.; Torkiyan, L.; Saidi, M.R. Org. Lett. 2006, 8, 2079-2082.
Synthesis of interesting 1,3-Diaryl-5-Synthesis of interesting 1,3-Diaryl-5-spirohexahydropyrimidinesspirohexahydropyrimidines
O
R1
NH2
R2
H H
O (S)-proline (20mol %)
DMSO, rt, 30 h
O
N
N
R2
R2
R1
O
N
N
OMe
OMe
O
N
N
N
N
O
N
N
OMe
OMeO O
80 % 67 %65 %
Wei, H. L.; Yan, Z. Y.; Niu, Y. N.; Li, Q. G.; Liang, M. Y. J. Org. Chem. 2007, 72, 8600.
Mechanism Mechanism
Wei, H. L.; Yan, Z. Y.; Niu, Y. N.; Li, Q. G.; Liang, M. Y. J. Org. Chem. 2007, 72, 8600.
N COOH
R1 R2
N COOH
R1 R2
NAr
CH2O ArNH2
H2ONAr
NH
COOH
H2O
O
R1 R2
H2O
O
R1 R2
NH
Ar
MechanismMechanismO
R1 R2
NH
Ar
NH
COOH
N COOH
R1 R2
NH
Ar
N COOH
R1 R2
NH
Ar
N ArH2O
O
R1 R2
HN
NH
Ar
Ar
CH2O
H2O
O
R1 R2
N
N
Ar
Ar
CH2O ArNH2
H2ONAr
Application in SynthesisApplication in Synthesis
HO
OH
CH3
NH3
O
NH
CO2
O
HO OH
N NH
O
O
Nikkomycin
HO
OH
CH3
NH3
O
OH
OMeO
O
H3C NHBz
Antibiotic that inhibits the biosynthesis of chitin in cell wall by competitively
inhibiting chitin synthase
OH
OOTBS
NH2
O(L)- proline (10 mol%)
pyridine, NMP, -20 °C
NH
Me
O
H
TBSO
O
Without pyridine: 87%, 84 ee%
With pyridine: 94%, 92 ee%
Hayashi, Y.; Urushima, T.; Shin, M.; Shoji, M. Tetrahedron 2005, 61, 11393-11404.
Bifunctional Bronsted Acid Activation of Bifunctional Bronsted Acid Activation of the Mannich Reaction the Mannich Reaction
R1
NR2XnM
Lewis acid catalysis
R1
NR2H
X
Bronsted acid catalysis
O
OP
O
OH
Chiral phosphoric acid
NO2
NO2
N
Ph
OMe
OTMS
Ph OMe
OArHNcatalyst (30 mol%)
toluene, -78 C
(3.0 eq)
X
Entry X Time (h) Yields (%) ee (%)1 2-OH 13 98 892 4-OH 33 28 203 2-OMe 46 56 34 H 43 76 35
Yamanaka, M.; Itoh, J.; Fuchibe, K.; Akiyama, T. J. Am. Chem. Soc. 2007, 21, 6756-6761.
Bifunctional Bronsted Acid Activation of Bifunctional Bronsted Acid Activation of the Mannich Reaction the Mannich Reaction
Ph
NAr OTMS
OMe
catalyst (5mol%)
Toluene, -78 CPh OMe
ONHAr
O
P
O
ArAr
ArAr
O
O
O
OH
Ar- p-CF3C6H4
TADDOL-derived phosphoric acid catalyst
O
OP
O
O
H
H
N
O
HO
O
F
F FF3C
F
FF
Nu
Akiyama, T.; Saitoh, Y.; Morita, H.; Fuchibe, K. Adv. Synth. Catal. 2005, 347, 1523.
Bifunctional Bronsted Acid Activation of Bifunctional Bronsted Acid Activation of the Mannich Reaction the Mannich Reaction
Possible intramolecular hydrogen bonding
OMOM OMOM
BrNBS (1.1 eq)
AIBN (10 mol%)
CCl4reflux 5h
CF3SO2Na
(2.0 eq)
pyridine (0.1 eq)
DMA100 C, 12h
OMOM
Tf
57 % in two step
1) BuLi (1.1 eq)
Et2O, -78 C, 0,5h
2) Tf2O (0.6eq)
-78 C to rt, 2h
3) repeat 1 and two
OMOM
TfTf
Hconc. HCl
MeOH
50 C, 12h
47 % in three step
Hasegawa, A.; Naganawa, Y.; Fushimi, M.; Ishihara, K.; Yamamoto, H. Org. Lett. 2006, 15, 3175-3178.
Bifunctional Bronsted Acid Activation of Bifunctional Bronsted Acid Activation of the Mannich Reaction the Mannich Reaction
OH
TfTf
H
Chiral 2-bis(trifly)methyl-2'-hydroxy-1,1'-
binaphthyl
R
N OMe
OSiR33
(1.5 eq)
R1 OMe
ONHR4OSiR3
3
catalyst (10mol%)
tBuOH (100 mol%)
PrCl, -78 C, 24 h99% yield, 77 ee %
The addition of a stoichiometric achiral proton source is required to accomplish a
catalytic cycle of chiral bronsted acid catalyts
Hasegawa, A.; Naganawa, Y.; Fushimi, M.; Ishihara, K.; Yamamoto, H. Org. Lett. 2006, 15, 3175-3178.
Vinylogous Mannich Reaction Vinylogous Mannich Reaction
The VMR is rapidly emerging as an important process for the construction of derivatives of –aminocarbonyl compounds
Because the iminium and dienol components employed in this addition may be either acyclic or cyclic, a wide variety of adducts may be converted into a broad array of alkaloids and nitrogen heterocyclicles.
N
R1
nOR2
Z
OOR2
N
R1
n
N
R1
n
H
Z
O
O OH
N
n
O
X
H
X= H, OH
HON
O
N
Vinylogous Mannich Reaction
OHN
O
N
Basic Mannich Reaction
Martin, S. F. Acc. Chem. Res. 2002, 35, 895-904.
Vinylogous Mannich Reaction Vinylogous Mannich Reaction
OTBSO O
O
NHBn
OOH
NBn
OO
TBSOTf
CH2Cl2, -80°C
83%, 1:9
1) H2, Pd/C, THF
2) DBU, 80 °C
NH
O
OH OOH
NHBn
L.A
OO
O OTBS
Felkin-anh
Addition to the si-face of the imine
Access to lactam
Battistini, L.; Rassu, G.; Pinna, L.; Zanardi, F.; Casiraghi, G. Tetrahedron Asymmetry, 1999, 10, 765-773.
Vinylogous Mannich Reaction Vinylogous Mannich Reaction
Ar
N
MeO
O
Me
OTMS
catalyst (5mol%)
AgOAc (5mol%)
undistilled iPrOH (1.1eq)
undistilled THF, -78 °C, 18 h
in air
Ar
NH
O
Me
O
OMe
PPh2
N
sBu
O
HN
OMe
easily accessible chiral phosphine
NH
O
Me
O
OMe
NH
O
Me
O
OMe
NH
O
Me
O
OMe
MeOCl
85%, 98% de, 87ee% 70%, 98% de, 83ee% 97%, 98% de, 90ee%
NH
O
O
OMe
PhI(OAc)2, MeOH, 0 °C, 45 min;
1.0 M HCl, 0 °C to 22 °C, 1h;
Na2CO3; CH2Cl2
PhI(OAc)2, MeOH, 0 °C, 45 min;
1.0 M HCl, 0 °C to 22 °C, 1h;
Na2CO3; CH2Cl2,CbzCl, 4h
NH2
O
O
NHCbz
O
O
76%
76%
NH
O
O
OMe
2) PhI(OAc)2, MeOH, 0 °C, 45 min;
1.0 M HCl, 0 °C to 22 °C, 1h;
Na2CO3; CH2Cl2 71%
1) H2, 10% w/w Pd/C, EtOAc
2 h; 95%
3) DBU, 120 C, 18h, 70%
HN
O
OH
Ph
Carswell, E. L.; Snapper, M. L.; Hoveyda, A. H. Angew. Chem. Int. Ed. 2006, 45, 7230-7233.
Lactam
Vinylogous Mannich Reaction Vinylogous Mannich Reaction
Carswell, E. L.; Snapper, M. L.; Hoveyda, A. H. Angew. Chem. Int. Ed. 2006, 45, 7230-7233.
1-Bidentate chelation with aldimine
2-The catalyst-bond imine may react with the siloxyfuran by an endo type addition
3- Intramolecular desilylation by the lewis basic amide
4-Product release is facilited by iPrOH
Vinylogous Mannich Reaction Vinylogous Mannich Reaction
O
vinyloxirane
Vinyloxirane is a valuable and highly reactive species
Ring-opening and/or rearrangement processes are promoted by Lewis acids or transition-metal catalysts.
OLewis acid
ring opening
H
OLA
(1,2-hydride shift)
O
H
OH
aldehyde
(electrophile)
dienol(nucleophile)
Lautens, M.; Tayama, E.; Nguyen, D. Org. Lett. 2004, 6, 345-347.
Vinylogous Mannich Reaction Vinylogous Mannich Reaction
R H
NCHPh2
Sc(OTf)3 (10mol%)
O (1.5 eq)
THF, 0 addition to 50 °C, 10-30 minR
HNCHPh2
CHO
EtOOC
HNCHPh2
CHO
74 %
HNCHPh2
CHO
70 %Cl
HNCHPh2
CHO
35 %MeO
EtOOC
HNCHPh2
CHO
Pd/CH2 (1atm)
N COOEt
RN COOEt
CHPh2
solvent, rt
time
unnatural amino acidC
A=H, B=CHPh2
Entry Solvent Time (h) A B C 1 MeOH 4 84 0 0 2 Benzene 24 trace 77 53 Benzene 1 0 trace 53
Lautens, M.; Tayama, E.; Nguyen, D. Org. Lett. 2004, 6, 345-347.
Vinylogous Mannich Reaction: Application Vinylogous Mannich Reaction: Application in Synthesis in Synthesis
HN
NMe
H
CO2H
HN
NMe
H
Me OH
HN
NHMe
H
O
OMe
lysergic acid setoclavine rugulovasines A and B
A=ß-HB=a-H
The indole alkaloids of Ergot family have attracted the attention of synthetic chemists for decades
The most well-known representative of this class is lysergic acid and rugulovasines A and B represent novel types within this family
HN
NHMe
H
O
OMe
rugulovasines A
HN
NHMe
H
O
OMe
HN
OO
Me
NHMe
rugulovasines B
Liu, T. Y.; Cui, H. L.; Long, J.; Li, B. J.; Wu, Y.; Ding, L. S. Chen, Y. C. J. Am. Chem. Soc. 2007, 129, 1878-1879.
SummarySummary
Significant advancements have been reported in the direct asymmetric MR.
• High yields, dr and ee are possible using organocatalysis with relatively mild reaction conditions.
• Highly functionallized products are possible (ie. Nitro-Mannichs, quaternary carbon centers, 3 contiguous chiral centers).
•Usage in total synthesis still relatively rare.
•The use of the PMP protecting group remains widespread, although some work has been done to develop relatively <PMP-free protocols>.
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