Boronic Acids and Esters in
the Petasis-Borono Mannich
Multicomponent
Reaction
Wu Hua
2010-9-25
B.S., 1978, Aristotelian University of Thessaloniki, Greece
Ph.D., 1983, University of Pennsylvania
Research:
• New chemistry of organotitanium
compounds
• New chemistry of organoboron
compounds
• New Synthetic Methods and Strategies
• Lipoxins and other Lipids
Mechanism of the Mannich Reaction :
R
H
O
N R
H
H
HO
H
R
N
H
R
O
R
HH
H+
H
H O
H
N
H
R
N
R
H
- H2O
R
H
R
R
H
H
O
O
-H+
R'
+ H+/ - H-
O R
N R
H
H H
R
R'
R'
H
H
H
R
N
H
O
R
R2N
R'
R
R
N
R
Major advantage of this MCR:
a.Immense potential scaffold variability.
b.Large variety of organoboronic acids are readily available.
c.Most of these compounds are also air- and water-stable as well as low-toxic
and environmentally friendly .
d.boronic acids also tolerate many functional groups, thereby allowing the facile
synthesis of multifunctional molecules without the excessive use of protecting groups.
Reaction of vinyl boronic acids with the adducts of secondary amines and
paraformaldehyde gives tertiary allylamines. This simple and practical method was
used for the synthesis of geometrically pure naftifine, a potent antifungal agent.
N
H
(a) (CHO)2
dioxane, 90¡æ, 1h
(b) HO
B
N
Ph
Ph
HO
90¡æ, 30min
This 3-CR (3-component reaction) can also been described as a
boronic acid Mannich variant.
N. A. Petasis, I. Akritopoulou, Tetrahedron Lett. 1993, 34, 583.
General Mechanism:
R2
N
H
R3
O
+
R2
R4
H
N
R3
R4
HO
OH
-H2O
R2
N
R3
R4
H
OH
O
HO
R2
B(OH)3
+
R1
N
R3
H2O
R4
OH
R2
N
R4
O
H
R1
OH
HO
R1
HO B
R2
R3
N
R3
R4
B
O
OH
B
R1
OH
OH
O
O
O
OH
H
O
salicylaldehyde
glyoxylic acid
H
R
OH
glycolaldehyde
a. A complete study of three different aldehydes demonstrated the following order of
reactivity: glycolaldehyde > glyoxylic acid > salicylaldehyde.
b. Regarding the nature of the boronic acids employed in the reaction, vinyl boronic
acids are in general more reactive than their aryl counterparts.
A new, general, and practical method forthe synthesis of β,γunsaturated α-amino acids.
R3
R2
OR
B
OR
R5
N R6
H
R4
O
O
R3
R2
R5
R4 N R
6
O
R1
OH
OH
Nicos A. Petasis. J. Am. Chem. Soc. 1997, 119, 445-446
R2
N
H
R1
O
B
+
R2
O
CH2Cl2, r.t.
OH
R3
R1
COOH
O
H
N
R3
O
Koolmeister, Scobie, M. Tetrahedron Lett. 2002, 43, 5965.
R2
N
H
R1
O
B
+
R2
H
R3
R1
COOH
O
O
OH
N
R3
O
Jourdan, Piettre, S. R. Tetrahedron Lett. 2005, 46, 8027.
Analogously to the condensation with phenyl boronic acid derivatives, heteroaryl
amino acids were also obtained in good yields from heteroaryl boronic acids.
More reactive than their aryl counterparts.
OMe
Ph
Ph
NH
HN
COOH
S
92%
Ph
Ph
O
79%
NH
HN
COOH
COOH
S
Ph
81%
Ph
COOH
O
84%
Petasis, N. A.; Goodman, A.; Zavialov, I. A. Tetrahedron 1997, 53, 16463.
O
+
HO
O
OH
+
B
Ar
OH
HN
R1
R2
O
a, b
R2
N
O
R1
Ar
(a) microwave irradiation, 120 C, 10 min, DCM; (b)TMS–diazomethane, THF, rt, 3 h.
O
Ar
+
OH
OH
+
B
Ar
OH
HN
R1
R2
a
N
R2
R1
OH
(a) microwave irradiation, 120 C, 10 min, DCM
Electron-poor (hetero-)anilines often gave unsatisfactory yields and conversions.
However, Sanofi-Aventis chemists could show that even these problematic
cases can be easily mastered under microwave conditions.
N. J. McLean. Tetrahedron Letters, 2004, 45, 993–995
The presence of a substituent in the nitrogen atom of the indole ring was observed to
be crucial to success of the reaction. In the absence of such a substituent, low yields
of the corresponding product were obtained.
HOOC
OH
+
N
O
O
H
HO
R
OH
B
HOOC
OH
H
N
N
HO
O
R
O
OH
B
O
O
HO
R
OH
B
OH
OH
H B OH
R = aryl
O
O
OH2
N
N
N
HO
OH
B
O
O
O
HO
R
N
R
N
Naskar, D.; Neogi, S.; Roy, A.; Mandal, A. B. Tetrahedron Lett. 2008, 49, 6762.
Salicylaldehyde and Derivatives
R3
OH
B OH
R2
+
R4
O
N
H
R5
+
R
R
R3 4 N 5 OH
OH
H
R1
R2
R6
R1
R6
H2O
- B(OH)3
R3
R2
OH OH
R4 N
R5
- H2O
R1
R4 N
R5
OH
OH
B O
R6
N. A. Petasis, Tetrahedron Letters, 42 (2001) 539–542
O
R
O
Ph
N
H
Ph
H
OH
Ph
N
Ph
O
H
R
Ph
N
Ph
H
OH
Ph
N
Ph
R
O
R
B(OH)2
Ph
N
Ph
HO B
OH
H
O
(HO)2B
R
Wang, Q.; Finn, M. G. Org. Lett. 2000, 2, 4063.
Water as the solvent
Pedro M. P. Gois. Eur. J. Org. Chem. 2009, 1859–1863
R3BF3K
BF3.OEt
-KBF4
N
Cl
Cl
R2
R3BF2
F
F
R3
B
Cl
F2B
Cl
N
R2
Cl
N
Cl
R2
HN
NaOH
R3
Stas, S.; Tehrani, K. A. Tetrahedron 2007, 63, 8921.
Cl
Cl
R2
R3
Aza-cope rearragement
Cl
Cl
RBF3K
BF3.Et2O
H
Cl Cl
N
D
Cl
D
Cl
F
N
D
F B
D
R
F B
F
R
Cl
Cl Cl
N
D
F B
F
R
D
Cl
Aqueous
Workup
F
N
F B
D
D
R
N
D
Cl
D
Cl
HN
D
D
R
Stas, S.; Abbaspour Tehrani, K.; Laus, G. Tetrahedron 2008, 64, 3457.
Asymmetric Petasis-Borono Mannich Reaction
Petasis reaction has been tested for this proposal in three different approaches.
a. The first comprises the use of a stereogenic carbon in the amine that can induce
some regioselectivity on the formation of the new carbon-nitrogen bond.
b. Enantiopure or enantioenriched boronic ester, resulting in the formation of an
enantiomerically pure side product.
c. A more elegant process is the use of a chiral ligand that can complex
with the boronic ester.
The first report in the asymmetric version of this reaction was made by Petasis,
using an enantiomerically pure aminewith two different boronic acids.
Ph
Ph
OH
B
OH
Ph
HN
H2N
Ph
COOH
CH2Cl2, r.t.
88% ( 66%de)
O
OH
H
O
Ph
H2N
Ph
OH
CH2Cl2, r.t.
HN
Ph
OH
COOH
78% (>99%de)
Petasis, N. A.; Goodman, A.; Zavialov, I. A. Tetrahedron 1997, 53, 16463.
N-tosyl-3-indolylboronic acid reacted with glyoxylic acid using chiral
methylbenzylamine as the chiral auxiliary and the secondary amines were obtained
exclusively as one diastereoisomer in reasonable yields
Ph
HN
B(OH)2
+
R
N
Ts
O
Ph
+
NH2
H
COOH
CH2Cl2
r.t., 12h
COOH
R
N
Ts
Jiang, B.; Yang, C.-G.; Gu, X.-H. Tetrahedron Lett. 2001, 42, 2545.
Ph
OH
OH
Oi-Pr
i-PrO B
R1
+
O
Ph
N
H
R2
Molecular Sieves
C6H5CH3, r.t.
up to 94% Yield
>99% ee
R1
15 mol%
HN
O
R2
Ph
B
O
O
OH
Ph
Lou, S.; Moquist, P. N.; Schaus, S. E. J. Am. Chem. Soc. 2007, 129, 15398.
The best enantioselectivities were reported by Takemoto and co-workers in the
addition of boronic acids to N-acylated quinoline salts.
R1
R2
PhOCOCl
Catalyst
H2O,NaHCO3,DCM
R1
R2
N
R4
R4
N
COOPh
B(OH)2
R3
R3
CF3
S
F3C
Catalyst
N
H
N
H
N
HO
Yamaoka, Y.; Miyabe, H.; Takemoto, Y. J. Am. Chem. Soc. 2007, 129, 6686.
CF3
S
F3C
Electrophile
Activation
N
H
N
H
O
N
N
HO
B
OR
Ph
O
Nucleophile
Activation
Ph
OEt
B
OEt
R1
N
H
R1
15mol% (S)-VAPOL
Ph
O
H
R2
COOEt
N
R2
COOEt
Ph
Ph
OH
OH
Molecular sieves
Toluene
(S)-VAPOL
Lou, S.; Schaus, S. E. J. Am. Chem. Soc. 2008, 130, 6922.
Application
O
HO
Ph
OH
HN
HO
+
Ph
Et2O, r.t.
H3C(H2C)7
HO
NH2
(CH2)7CH3
NH2
HO
HO
(CH2)7CH3
FTY720
28% overal yield
Ph
B(OH)2
OH
OH
O
allyl-amine
OH OH
Et2O
r.t., 16h
HO
HO
HO
H
RN
OR
HO
Ph
HO
H
OH
OH
N
OH
Uniflorine A
Oi-Pr
i-PrO B
F
F
1. Oxalyl Chloride
DMF, CH2Cl2
2.
N
O
F
F
(S)-3,3'-Ph2-BINOL 15mol%
OH
O
Ph
Molecular Sieves
C6H5CH3, r.t.
TMS
N
H
H
F
HN
Ph
F
F
O
Ph
HN
Ph
F
O
N
N
N
N
75% Yield
>91% ee
Maraviroc
A new class of compounds for HIV therapy.
Summary
a. Typically Pt-3CR works satisfactorily with secondary or hindered primary amines,
hydrazines and anilines in solvents such as DCM at room temperature.
Alkenyl, electron-rich and electron-neutral (hetero-)aryl boronic acids can be employed.
b. The use of secondary amines is desirable when compared to primary ones, since
the latter usually results in low yields because of the lower reactivity of the imine
compared to the iminium formed from the former.
c. As a result of this exquisite reactivity, the Petasis reaction (Scheme 1) has become
an attractive method for the preparation of an assortment of compounds, among
which amino acids, heterocycles and alkylaminophenols are the most easily
accessible.
Problem
OH
O
O
O
OH
H
O
salicylaldehyde
glyoxylic acid
H
R
OH
glycolaldehyde
a. Regarding the asymmetric version, no suitable chiral catalyst
has been developed for the general reaction.
b. One other aspect that seems to be prominent is the discovery of substitutes for
each component of the reaction, particularly the discovery of new suitable
aldehydes without the need of a hydroxyl group for the boron activation.