Dr. Douglas C. Schmidt d.schmidt@vanderbilt dre.vanderbilt/~schmidt
Highlights of Schmidt Reaction in the Last Ten Years
45
Highlights of Schmidt Reaction in the Last Ten Years Dendrobates histrionicus Jack Liu Nov. 18, 2003
Transcript of Highlights of Schmidt Reaction in the Last Ten Years
Highlights of Schmidt Reactionin the Last Ten Years
Dendrobates histrionicus
Jack LiuNov. 18, 2003
• Introduction• Classical Schmidt reaction of aldehydes
and carboxylic acids• Classical Schmidt reaction of ketones• Inter- and intramolecular Schmidt reaction
with ketones using alkyl azides– Total Synthesis of alkaloid 251F
• Inter- and intramolecular Schmidt reactionof carbocations using alkyl azides– Formal Synthesis of gephyrotoxin
• Conclusion
How it all began
HN3 + H2SO4 N2 + " NH"
R H
O+ " NH"
NH
H
OR
Schmidt reaction: insertion of N into carbonyl group
Schmidt, K. F. Z. Angew. Chem. 1923, 36, 511.Schmidt, K. F. Ber. 1924, 57, 704.
O
+ " NH" NH
O
Me
O
+ " NH"NH
Me
OEtO2C
REtO2C
R
Migration of Carbon to an Electron Deficient Heteroatom
R N
OBr
RN
O+ Br -
R N
OOAc
RN
O+ OAc-
R N
O
RN
O+ N2
N2
R NH
ON2
RN
O+ N2
H
R
ON2
R
O+ N2
R'R'
R R'
N
+ MLnOH
OMLn
NR'
R R'
N
+ N2
N2
R R' + ArCO2-
OOO2CAr
R O
OR'
R
NR'
R
Hofmann
Lossen
Curtius
Schmidt
Wolff
Beckmann
Schmidt
Baeyer-Villager
Schmidt Reaction of Aldehydes
H
ONaN3 (2.3 equiv)H2SO4 (5.4 equiv)benzene, 10-15 oC
HN
O
H
59%
H
ONaN3 (2.3 equiv)H2SO4 (5.4 equiv)benzene, 10-15 oC
HN
O
H
48%
ClCl
Schmidt reaction of aldehydes results in formamides
McEwen, W. E. et al. J. Am. Chem. Soc. 1952, 74, 1168.
Schmidt Reaction of Carboxylic Acids
Datta, S. K. et al. J. Chem. Soc (C) 1970, 2058.
CO2HNaN3, H2SO4, CHCl3,40 oC, 1 h NH2
CO2HNaN3, H2SO4, CHCl3,40 oC, 1 h NH2
70-90%
Schmidt reaction of carboxylic acids results in amines with loss of carboxyl group
Drawback: One carbon lost; not atom economic
Acid Promoted Schmidt Reaction of Ketones
R1 R2
O
R1 R2R1 R2
OHHO N3
R1 R2
HO HNR1 R2
H2O N3 N2
R1 R2
N
R1 R2
NN2N2
N
HN3 H+
H+ HN3
N2N2
NH
R2
O
R1 NH
OR2 R1
R2
NR1
+
H2O H2O
R2R1
Smith, P. A. S. in Molecular Rearrangements Part I. de Mayo, P. ed. New York: Wiley, 1963. p. 512.
Studies on Migratory Aptitude—Electronic Effect
ONaN3 (3 equiv)H2SO4 (3.6 equiv)Cl3CCO2H, 50-60 oC
HN
OX
NH
+
X
A B
O
X
52:48Ph61:39OMe54:56Me49:41Cl51:49NO2
A:BX
Smith, P. A. S. et al. J. Am. Chem. Soc. 1950, 72, 3718.
No clear correlation between migratory aptitude and electronic nature of aryl group
Studies on Migratory Aptitude—Steric Effect
R
ONaN3 (3 equiv)H2SO4 (3.6 equiv)Cl3CCO2H, 50-60 oC
HN
O
RNH
R+
A B
O
11578081
yield(%)
0:100t-Bu
51:49i-Pr
85:15Et
95:5MeA:BR
Smith, P. A. S. et al. J. Am. Chem. Soc. 1950, 72, 3718.
Larger substituent has greater migratory aptitude
Origin of Selectivity
Migrating substituent is proposed to be antiperiplanar to azido group
RL RS
O
RL RS
N
RL RS
NN2
N2
HN3, H+
N2
NH
RS
O
RL NH
ORS
RL
N2
HN3, H+
Smith, P. A. S. in Molecular Rearrangements Part I. de Mayo, P. ed. New York: Wiley, 1963. p. 510-511.
major
minor
Intermolecular Schmidt Reaction of Ketoneswith Alkyl Azides—Acid Effect
Aubé, J. et al. J. Am. Chem. Soc. 2000, 122, 7226.
O
+ Ph N3 N
OPh
NH
O
+
85% 15%
TiCl4 (2.5 equiv), CH2Cl2, 0 oC to rt Ph
TfOH (1.1 equiv), CH2Cl2, 0 oC to rt
O
+ Ph N3 N NH
O
79%
Ph
Schmidt favored when TiCl4 used, Mannich favored when TfOH used
Proposed Mechanism of Mannich Reaction
Aubé, J. et al. J. Am. Chem. Soc. 2000, 122, 7226.
Origin of Mannich side-reaction: generation of iminium ion in situ
N3H+
NH
NN
NH
N2
OH
+ NH N
H
OPh
Substitution Effect of Cyclohexanones
Aubé, J. et al. J. Am. Chem. Soc. 2000, 122, 7226.
TiCl4 (3.5 equiv),BnN3
5
TiCl4 (3.5 equiv),BnN3
4
TiCl4 (3.5 equiv),BnN3
3
TiCl4 (3.5 equiv),BnN3
2
TiCl4 (3.5 equiv),BnN3
1
product(s), yieldconditionssubstrate
entry
O
O
t-Bu
O
Me
O
MeMe
OMe
N
OPh
88%
N
OPh
65%t-Bu
N
OPh
44%
N
OPh
Me
+Me
NH
O
11%
Ph
Me
NH
OPh
Me
+
N
OPh
52%
Me
Me
NH
O
35%
Ph
Me Me
NH
O
100%
PhMe
Substrate Scope—Cyclic Ketones
Aubé, J. et al. J. Am. Chem. Soc. 2000, 122, 7226.
product(s),yield
BnN3
BnN3
n-HexN3
azidesubstrate
6
5
4
entry
n-HexN3
3
n-HexN3
2
n-HexN3
1
product(s), yieldazidesubstrate
entry
O
Ph
N
On-Hex
Ph51%
n-HexO
< 5%
O
O N
O
n-Hex
Nn-Hex
O32% 8%
OO
n-Hex
100%
O
O
O
NH
Ph
93%
ONH
Ph
33%
Behavior of 3-Pentanone
Aubé, J. et al. J. Am. Chem. Soc. 2000, 122, 7226.
O
+ Ph N3
62%
TiCl4 (2.5 equiv), CH2Cl2, 0 oC to rt
O
NH
Ph
TfOH (1.1 equiv), CH2Cl2, 0 oC to rt
O
+ Ph N3
84%
O
NH
Ph
Acyclic ketones give exclusively Mannich product
Trends of Chemoselectivity
Aubé, J. et al. J. Am. Chem. Soc. 2000, 122, 7226.
Good substrate for Schmidt reaction: not hindered and conformationally less flexible
ClnTi NN2
R
Proposed key intermediate of TiCl4 mediated Schmidt reaction
good Mannich substratesgood Schmidt substratesO
Ph
O
O
O OMe
O
O
Intramolecular Schmidt Reaction of Ketoneswith an Alkyl Azide Tether
O
N3
ON3 N
N2OH
H
N
O
N2
N
OTFA, CH2Cl2, 10 min., rt
90%
Aubé, J. et al. J. Am. Chem. Soc. 1991, 113, 8965.
Intramolecular Schmidt reaction of ketones gives bicyclic amides
Substrate Scope
Aubé, J. et al. J. Am. Chem. Soc. 1991, 113, 8965.
77TFA6
91TFA, 20min.5
91TiCl4, 16 h4
0—TFA, 24 h3
90TFA, 10min.2
83TFA, 40min.1
yield(%)productconditionssubstrateentr
yO
N3
O
N3
ON3
O
N3
ON3
Ph
O
N3
N
O
N
O
N
O
N
O
Ph N
O
Intramolecular Schmidt Reaction of Ketoneswith in situ Tethering of Hydroxyalkyl Azides
Aubé, J. et al. J. Am. Chem. Soc. 1995, 117, 8047.Aubé, J. et al. Tetrahedron 1997, 53, 16241.
O
N3HO+NO
N2
X-
X-
OH-
OH-
O NHO
N
O
N
OOH
BF3 Et2OO N3
Intermolecular Schmidt Reaction of Ketones withHydroxyalkyl Azides—Substrate Scope
Aubé, J. et al. Tetrahedron 1997, 53, 16241.
796
735
904
983
982
961
yield(%)productazidesubstrateentr
yO
O
O
O
N
O
MeO
OO
N3HO
N3HO
N3HO
N3HO
HO N3
HO N3
N
OOH
N
O OH
N
O
OH
N
OOH
N
N
O
Me
OH
N
OOH
OO
Azides with longer carbon chain give no product.
Effect of Subsitution
Aubé, J. et al. J. Org. Chem. 2000, 65, 3771.
83:0:1751Br6
90:0:1068OMe5
>95:592Ph4
23:54:2340i-Pr3
57:4394Et2
55:4595Me1
by-productA:B:by-productyield (%)Rentry
O
N
OOH
1.BF3 Et2O, CH2Cl2, 0 oC
2. NaOH
R R+ N
OOH
R
HO N33
+ by-product
A B
O
O
HN
i-Pr
N
O
O
N
OOH
Proposed Origin of Selectivity
Aubé, J. et al. J. Org. Chem. 2000, 65, 3771.
NO
N
ORR N2
N
OOHR
A
ON
N
OR N
OOH
R
B
R
N2
N2
N2
Disfavored whenR = i-Pr
Reversal of regioselectivity caused by steric interaction between i-Pr and diazo group
Synthetic Utility—Macrocyclic Lactames and Lactones
Aubé, J. et al. J. Org. Chem. 1999, 64, 4381.
8
7
6
5
entry
6
4
3
1
n
NaHCO3
NaHCO3
NaHCO3
NaHCO3
base
29
30
40
12
time (h)
8:79
30:64
26:64
27:43
yieldA:B
30
30
40
12
time (h)
KOH
KOH
KOH
KOH
base
50:3064
51:1943
88:032
68:011
yieldA:Bnentry
1.BF3 Et2O, CH2Cl2, 0 oC
2. reflux, 73 h3. base, time
+
HO N32
A B
O
n
N
nn
O
OO
NH
OH
Lactams favoured when KOH used; lactones favoured when NaHCO3 used
Origin of Chemoselectivity—KOH Work-Up
Aubé, J. et al. J. Org. Chem. 1999, 64, 4381.
HO+
X-
OH-
OH-
O
N
HO
N
O
N
OBF3 Et2O
N3
OHO
OH-O
N
O
H2O
pH ~ 14
Origin of Chemoselectivity—NaHCO3 Work-Up
Aubé, J. et al. J. Org. Chem. 1999, 64, 4381.
pH ~ 9
HO+
X-
OH-
N
OBF3 Et2O
N3
O
H2O
O
N
HO
H
X-
ONH
O
OH-
pKa ~ 11
Asymmetric Intramolecular Schmidt Reaction
Aubé, J. et al. J. Am. Chem. Soc. 2003, 125, 7914.
O
N
OOH
1.BF3 Et2O, (3.5 equiv)CH2Cl2, -82 oC
2. KOH+
A BR
R1
R2
R3
R
N
OHO
R1
R2
R3
R
N3 OH
R1
R2
R3
+
98
93
94
96
100
98
yield(%)
60:40HPhHt-
Bu6
60:40HPhHMe5
90:10HHPh
t-Bu4
89:11HHPhMe3
95:5PhHHt-
Bu2
93:7PhHHMe1
A:BR3R2R1Rentry
Proposed Origin of Selectivity
Aubé, J. et al. J. Am. Chem. Soc. 2003, 125, 7914.
ON
N
OOH
major
NO
N
OHO
minor
N2
N2t-Bu
t-Bu
t-Bu
ON3
Ph Ph Ph
? ?
t-Bu t-Bu
PhPh
equatorial addition ofazide
Origin of selectivity: phenyl group preferentially occupieds equatorial position
Scope of Chiral Hydroxyalkyl Azide
Aubé, J. et al. J. Am. Chem. Soc. 2003, 125, 7914.
O
N
OOH
1.BF3 Et2O, (3.5 equiv)CH2Cl2, -82 oC
2. KOH+
A BR
R1
R2
R3
R
N
OHO
R1
R2
R3
R
N3 OH
R1
R2
R3
+
98
93
94
96
100
98
yield(%)
60:40HPhHt-
Bu6
60:40HPhHMe5
90:10HHPh
t-Bu4
89:11HHPhMe3
95:5PhHHt-
Bu2
93:7PhHHMe1
A:BR3R2R1Rentry
Proposed Cation-p Interaction
Aubé, J. et al. J. Am. Chem. Soc. 2003, 125, 13948.
ON
N
OOH
NO
N
OHO
N2
N2t-Bu
t-Bu
t-Bu
ON3
? ?
t-Bu t-Bu
equatorial addition ofazide
ArAr
ArAr
X
Aryl group occupying axial position is proposed to be stabilized by cation-p interaction
Effect of Substituents on Aryl Group
Aubé, J. et al. J. Am. Chem. Soc. 2003, 125, 13948.
O
N
OOH
1.BF3 Et2O2.KOH
+
A B
t-Bu t-Bu
N
OHO
t-Bu
N3 OH
+
XX X
NO2
F
H
OMe
X
86
73
99
99
yield(%)
76:244
69:313
64:362
43:571
A:Bentry
Electron-withdrawing substituents increase diastereoselectivity
Another Asymmetric Schmidt Reagent
Aubé, J. et al. J. Am. Chem. Soc. 2003, 125, 7914.
Origin of low diastereoselectivity: one methyl group axial and the other equatorial
O
N
OOH
1.BF3 Et2O, (3.5 equiv)CH2Cl2, -82 oC
2. KOH
A B
R
Me Me
R
N
OHO
MeMe
R
N3 OH
Me Me
+O
NNO
N2
N2R
RMe Me
?Me Me
98
98
yield(%)
60:40t-Bu2
59:41Me1
A:BRentry
Another Asymmetric Schmidt Reagent
Aubé, J. et al. J. Am. Chem. Soc. 2003, 125, 7914.
Origin of high diastereoselectivity: both methyl groups occupy equatorial position
O
N
OOH
1.BF3 Et2O, (3.5 equiv)CH2Cl2, -82 oC
2. KOH
A B
R
Me Me
R
N
OHO
MeMe
R
N3 OH
Me Me
+O
NNO
N2
N2R
RMe Me
?
MeMe
94
98
yield(%)
94:6t-Bu2
98:2Me1
A:BRentry
Scope of Substrate
Aubé, J. et al. J. Am. Chem. Soc. 2003, 125, 7914.
57
82
96
86
yield(%)
60:40
65:35
96:4
98:2
dr
4
3
2
1
productsazidesubstrateentry
O
Me
O
MeMe
O
Ph
N3 OH
Ph
N3 OH
Ph
N3 OH
Ph
N3 OH
Ph
N
OOH
+
Ph
N
OHO
Ph
Me Me
major minor
N
OOH
+
Ph
N
OHO
Ph
Me Me
major minor
Me Me
HH
O
N OH
PhO
Ph
N OH
PhO
H
H NHO
Ph O
H
H+
Total Synthesis of Alkaloid 251FH
H
Me
OOBn
Me1. Na/NH3
2. Zn(N3)2 2Pyr DEAD, PPh3
H
H
Me
O
N3
Me
50% (2 steps)a:b = 4:1
1. O3/DMS
2. NaBH4
OHH
H
Me
O
N3
Me
50-55% (2 steps)
N
O
Me Me
Me Me
MeH H
HMe
OHTfOH
79%
N
Me
MeH H
HMe
OHLiAlH4
86-100%Alkaloid 251F
Aubé, J. et al. J. Am. Chem. Soc. 2002, 124, 9974.
Intermolecular Schmidt Reaction ofCarbocations with Alkyl Azides
R1 R2
Ar OH acid
R1 R2
Ar NR
N2
R1 R2
Ar
R1 R2
Ar RN3
N2
R1 R2
H NR
Ar
R1 R2
Ar NR
H+ +H R2
Ar NR
R1
aryl migration H migration alkyl migration
Pearson, W. H. et al. Tetrahedron Lett. 1992, 37, 5291.Pearson, W. H. et al. J. Org. Chem. 1995, 60, 4960.
Substrate Scope—Acyclic Benzylic Alcohols
Pearson, W. H. et al. J. Org. Chem. 1995, 60, 4960.
R1 R2
Ar OH1. n-BuN3, CH2Cl2,TfOH (2 equiv)
2. NaBH4 (6 equiv),MeOH
R1 R2
H NBu
Ar
R1 R2
Ar NBu
H+ +H R2
Ar NBu
R1
aryl migration H migration alkyl migration
A B C
4-MeOPh
4-MeOPh
Ph
4-MeOPh
4-MePh
Ar
91
97
81
97
61
yield(%)
3.6:0:1Hn-Pr5
12.3:2.5:1HMe4
4.3:1:1.2HMe3
1:1.94:0HH2
1:5.8:0HH1
A:B:CR2R1entry
Migratory aptitude is related to the ability to stabilize positive charge
Substrate Scope—Cyclic Benzylic Alcohols
Pearson, W. H. et al. J. Org. Chem. 1995, 60, 4960.
substrate
82
66
97
yield(%)
3
2
1
Products, ratioentry
Aryl migration slightly favoured except for the case of cyclobutanol
Ph OH
OHPh
OHPh
NPh Bu
N
Ph
Bu+
NPh Bu
N
PhBu+
NPh Bu
NBu
Ph
+
1:5.1
1.1:1
2.4:1
R1 R2
Ph OH1. n-BuN3, CH2Cl2,TfOH (2 equiv)
2. NaBH4 (6 equiv),MeOH
R1 R2
H NBu
Ph+
H R2
Ph NBu
R1
Intramolecular Schmidt Reaction ofCarbocations with Alkyl Azide Tether
Pearson, W. H. et al. J. Am. Chem. Soc. 1993, 22, 10183.Pearson, W. H. et al. J. Org. Chem. 2000, 65, 8327.
Mercury promoted Schmidt reaction proceeds with much higher regioselectivity
N3
1. TfOH (2 equiv),benzene, 5 oC, 45 min.
2. NaBH4 (4 equiv), MeOH, 10 h
N
Me
H
N
H
+
Me1:1
79% isolatedyield
N3
1. Hg(OTf)2 (1 equiv),THF, rt, 15 min.
2. NaBH4 (4 equiv), NaOH, H2O, 2 h
N
Me
H
84% GCyield
Difference in Brønstead Acid and Lewis AcidPromoted Pathway
Pearson, W. H. et al. J. Am. Chem. Soc. 1993, 22, 10183.Pearson, W. H. et al. J. Org. Chem. 2000, 65, 8327.
A spirocyclic intermediate generates two isomers in Brønstead acid promoted reaction
XHg
N
Me
N
Me
N3
Me
N3
Me
N3
H+
Me
NN2
+
N
Me
H
N
HMe
+H-
HgX2 N3
XHgN
N2
XHg N N
Me
H
H-
more reactivecarbocation
N2
N2
Formal Synthesis of Gephyrotoxin
BrN3
TfOH
OMe
N
OMe
N
Br
OMe
+
1.L-Selectride2.Bu4NOAc3.LiAlH4
N
HO
OMe
N
OMe
+H
H
45%10%
N
HO
H
gephyrotoxin
H
H
Br
Br
Pearson, W. H. et al. J. Org. Chem. 2000, 65, 7158.
Conclusion
• Alkyl azides can be used in Schmidt reaction inthe present of a strong acid
• Intramolecular Schmidt reaction useful insynthesis of amides of different ring size
• Asymmetric Schmidt reaction achieved byemploying chiral hydroxy azides
• Schmidt reaction of carbocations is promoted byacids; useful in synthesis of bicyclic heterocycles
• Much work needed to improve selectivity
Analysis of Selectivity
TfOH
OMe
N
OMe
N
R
OMe
R
N3
OMe
R
N3
N
HHMeO
N
H
R
N2
OMe
H
RN2
N2
N2
alkyl migrationminor
aryl migrationmajor
R
Aryl migration favoured
First Half of the Synthesis of Alkaloid 251F
Synthesis of Alkyl Azide Advanced Intermediate
Pearson, W. H. et al. J. Org. Chem. 2000, 65, 7158.
Ito Formal Synthesis of gephyrotoxin
Ito, Y. Tetrahedron Lett. 1983, 24, 2881.
Hydrogenation catalyst: 5% Rh on alumina
