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Recent Developments of the Nazarov Reaction
Banibrata GhoshMichigan State University
January 14, 2004
Directed Nazarov reactions
Asymmetric Nazarov reactions
Other recent variants of the Nazarov reaction
Outline
Introduction
Acid (protic or Lewis) induced cationic 4π conrotatoryelectrocyclic ring closure reaction of divinyl ketone to form cyclopentenones
aNazarov, I. N.; Zaretskaya, I. I. Bull. Acad. Sci. (USSR) 1942, 200-209.bBraude, E. A.; Coles, J. A. J. Chem. Soc. 1952, 1430-1433.cShoppee, C. W.; Lack, R. E. J. Chem. Soc. 1969, 1346-1348.
Carbocation intermediateb
Proceeds via α,α’-divinyl ketoneb
Intramolecular electrocyclization reactionc
Definition of the classical acid-catalyzed Nazarov reaction:
Named after the eminent Russian chemist I. N. Nazarov (1906–1957)
Discovered in 1942a
O
OCH3OH, H2O
HgSO4, H2SO4
O
Mechanism of Classical Nazarov Reaction
Smith, D. A.; Ulmer, C. W. J. Org. Chem. 1991, 56, 4444-4447.
OH
R
OH
R
OH
R
Comments:
1. Stabilization of the positive chargeon the terminal carbons increasesthe energy of activation and lowersthe heat of cyclization
2. Stabilization of the positive charge on the carbons β to the hydroxyl groupdecreases the energy of activation andincreases the heat of cyclization
3. Steric effects should also be considered
Transition state
Reactant cationProduct cation
O OH OH OH OH O
- H++ H+
- H-
4
CON(RDS)
π
Stereochemistry
Mechanism and stereochemistry are coupled
O
AcOH/H3PO4
50°C(Conrotatory)
benzene
254 nm(Disrotatory)
O
O
Duality of the Electrocyclization Pathway: Torquoselectivitya
O
R
R1
+
aThis term was coined by K. N. Houk.
Houk, K. N. In Strain and Its Implications in Organic Chemistry; de Meijere, A.; Blechert, S. Ed.; Kluwer Academic: Boston, 1989, Vol. 1, pp 25-37.
Origin: Steric or Electronic ???
O
R1
R
+
Clockwise
O
R1
RH
H
(Conrotatory)
O
R1
R
Anticlockwise(Conrotatory)
R1
R
H
H
O
Limitations of the Classical Nazarov Reaction
1. Lack of control over torquoselectivity
2. Lack of positional control of the double bond
3. Strong acidic media leading to some undesirable rearrangements
OH3C
R1
OH2C
R1
OH3C
R1
Motoyoshia, J.; Yazaki, T.; Hayashi, S. J. Org. Chem. 1991, 56, 735-740.
R
O
R
OH OH
RH
OH
R
OH
H
R
+ H+ - H+ + H+
OH
H
R
O
R
O
R
Directed Nazarov Reactions
Silicon-directed Nazarov reactions
Tin-directed Nazarov reactions
Fluorine-directed Nazarov reactions
OR1
R2
Silicon-Directed Nazarov Reactions
Denmark, S. E.; Jones, T. K. J. Am. Chem. Soc. 1982, 104, 2642-2645.
FeCl3
CH2Cl2 R2
R1
SiMe3
OFeCl2
Cl-
R2
R1
OFeCl2
- Me3SiCl
R2
R1
SiMe3
O
R2
R1 CHO
Me3Si
MgBr+
R2
R1
SiMe3
OH
R2
R1
SiMe3
O
1) THF, - 20 °C
2) NH4Cl
NiO2
Et2O, 0°C(71-94%)overall
a
R2
R1
O
(55-95%)
Advantages:
1. Controlled introduction of a double bond
2. Ready isomerization of the double bond to the most substituted position or its transformation to other functionalities if needed
Tin-Directed Nazarov Cyclization
Peel, M. R.; Johnson, C. R. Tetrahedron Lett. 1986, 27, 5947-5950.
R2
R1
E
O a
b
E = Electrofuge
OHC n-C5H11
OBn
SnBu3
On-C7H15
SnBu3
On-C7H15
n-C5H11 OHOBn
1) LDA, - 78°C
(83%)
2)
MsCl, Et3N, r.t. (85%)
SnBu3
On-C7H15
n-C5H11
O
OBn
1) BF3•OEt2 CH2Cl2, r.t.
(56%)
2) Basic Al2O3 CH2Cl2, r.t. 24 hOBn
Fluorine-Directed Nazarov Reaction
Ichikawa, J.; Miyazaki, S.; Fujiwara, M.; Minami, T. J. Org. Chem. 1995, 60, 2320-2321.
CF2
CH3n-BuO O
n-Bu
F
TMSOTf
r.t., 0.1- 0.2 h (73%)
CH2Cl2-HFIP (1:1)
CF2
n-BuO
CH3
TMS
FF
n-Bu
OTMS
H
- TMSF- TfOHTMSOTf
Note: HFIP = Hexafluoroisopropanol
Another Variant of Fluorine-Directed Nazarov Reaction
Ichikawa, J.; Fujiwara, M.; Okauchi, T.; Minami, T. Synlett 1998, 927-929.
OCH3
CH3
F3CO
CH3
F3C CH3TMSOTf
CH2Cl2-HFIP (1:1)r.t., 0.1 h
(86%)
OF3C R1
R2
TMS
R1
R2H
F3C
OTMS
- TMSF- TfOHTMSOTf
Conclusions on Directed-Nazarov Reactions
Regiocontrol is possible through directed-Nazarov reactions
Silicon and tin can function as a β-cation stabilizer and also as electrofuge to control the
introduction of the double bond of the cyclopentenone product in a position depending on the
placement of silicon or tin
Fluorine can function as a β-cation destabilizer and as a nucleofuge to control the introduction
of a double bond away from fluorine in the cyclopentenone product
Miesch, M.; Gross, L. M.; Neumann, M. F. Tetrahedron 1997, 53, 2111-2118.
OMe3Si
1) BF3•OEt2, C6H5Et, 125°C
2) TBAF, THF, 25°C
O
OHOR R = SiMe2Thexyl
Asymmetric Nazarov Reactions
Substrate control
Reagent control
O
H
H
H
O
H
H
H
Clockwise
Electronic Control of Torquoselectivity
Denmark, S. E.; Wallace, M. A.; Walker, C. B. J. Org. Chem. 1990, 55, 5543-5545.
(R)-(+)-1 (+)-2
(S)-(-)-1 (-)-2
Anticlockwise
OMe3Si
CH2Cl2- 50°CCH2Cl2
FeCl3
HH
OFeCl2Me3Si
anti SE'
H H
OFeCl2Me3Si
Cl-
(86%ee)
(88%ee)
OMe3Si
CH2Cl2- 50°CCH2Cl2
FeCl3
HH
OFeCl2Me3Si
antiSE'
H H
OFeCl2Me3Si
Cl-
Anti-SE' pathway in the electrocyclization Stereospecific reaction
Asymmetric Nazarov: Axial to Tetrahedral Chirality Transfer
Hu, H.; Smith, D.; Cramer, R. E.; Tius, M. A. J. Am.Chem. Soc. 1999, 121, 9895-9896.
N O
OMOM
O
H
n-Bu
Li
Me
OTBS+
1) THF, -78°C, 0.5 h
2) aq. work up
HO
Me
O
OTBS
H
HO
Me
O
HOTBS
H
H
+50%, 78%ee
9%, 64%ee
OH
R3
H
O OMeR1
R2
OH
OR1
H R3
H
favored
OH
H
O OMeR1
R2
disfavored
OH
OR1
R2 H
R3
R2
H
Clockwise
Anticlockwise
R3
OMe OMOM
n-BuH
TBSO
Chiral Auxiliary on Non-Stereogenic Allenes
OH
H
H
O OMeR1
R2HO
R1
O
HH
R2
nonselective conrotation
For synthesis of chiral cyclopentenone here we need an asymmetricenvironment!
Carbohydrate-Derived Auxiliaries
Harrington, P. E.; Tius, M. A. Org. Lett. 2000, 2, 2447-2450.
52%, 68%ee
71%, 82%ee
O
OMe
MeOMeO
OO
H
H
H
H
Me
1) n-BuLi, LiCl, THF - 78°C
2)
N
O
LiOOXc
HH
NO
O
R
O
OMe
MeOMeO
OMeH
O
S
H
H
H1) n-BuLi, LiCl, THF - 78°C
2)N
O
O
N
O
LiOOXc
HH
HCl, EtOH
- 78°C
O
HO
HCl, HFIP
0°C
O
HO
Stereospecific reaction
Summary of the Results
Harrington, P. E.; Tius, M. A. Org. Lett. 2000, 2, 2447-2450.
Entry Amide Product Yield (%) ee (%)
NO
i-Pr
O
NO
O
NO
t-Bu
O
NO
O
NO
Ph
O
MeO
O
HO
i-PrO
HO
t-BuO
HO
PhO
HO
OMe
45
67
71
65
56
1
2
3
4
5
O
HO 41
67
57
42
<5
(61)
(52)
(61)
(58)
(69)
(66)
(68)
(73)
(67)
(63)
O
OMe
MeOMeO
OO
H
Li
H
H
Me
NO
OR1
R2
O
HO
R1
R2
(HCl, HFIP, 0°C)
2) HCl, EtOH, - 78°Cor
1)
Possible Reason: Mechanistic Insight
Harrington, P. E.; Tius, M. A. Org. Lett. 2000, 2, 2447-2450.
N
O
LiOOXc
Me
HH
H+
MeO
OXcMe
HHMeO
O
H+ OXcMe
HHMeO
OXcMe
HHMeO
O H
O HO
HO
Me
OMe
OOMe
OMeOMe
MeO
O
HO
Me
OMe
OOMe
OMeOMe
MeO
Xc = Auxiliary
Origin of Stereoselection!!!
Direction of conrotation is governed by the anomeric carbon atom and that might involve the interaction of pyran oxygen atom
Harrington, P. E.; Tius, M. A. J. Am. Chem. Soc. 2001, 123, 8509-8514.
R
R
Xc = auxiliary
O
HO
HCl, EtOH, - 78°C 61%, 61%ee
HCl, HFIP, 0°C 48%, 81%ee
O
OMe
MeOMeO
O
H
H
H
H
1) n-BuLi, LiCl THF, -78°C
2)
N
O
LiOOXc
HH
O
MeOMeO
Me O
H
HH H
OMe
1) n-BuLi, LiCl THF, -78°C
2)
N
O
LiOOXc
HH
NO
O
NO
O
Limitations of the Carbohydrate-Derived Auxiliary Approach
Nucleophilicity of the lithiated allenes was unsatisfactory
Erosion of the %ee took place upon scale up of the reaction
Preparation of carbohydrate-derived auxiliary was tedious on large scale
Camphor-Derived Auxiliary
Harrington, P. E.; Murai, T.; Chu, C.; Tius, M. A. J. Am. Chem. Soc. 2002, 124, 10091-10100.
OOLi
HH
NO
R1
R2
O
2) HCl, HFIP/TFE (1:1) - 78°C
O
HO
R1
R2
1)
Entry Amide Product Yield (%) ee (%)
NO
O
NO
O
NO
t-Bu
O
NO
TBS
n-C5H11
O
NO
F
Ph
O
O
HO
O
HO
O
HO
t-Bu
O
HO
F Ph
O
HO
TBS n-C5H11
1
2
3
4
5
67
69
84
55
62
65
74
87
58
76
Auxiliary on Stereogenic Allenes: Matched and Mismatched Cases!!!
OOH
RH
auxiliary and allenefavor the same conrotation
higher %ee
auxiliary and allenefavor opposite conrotation
lower %ee
Matched caseMismatched case
1. If auxiliary directs the conrotation, two allene enantiomers would give products with samestereogenic center β to the carbonyl group
2. If allene directs the conrotation, different allene enantiomers would give enantiomericallydifferent products
Outcome:
An Example Where Auxiliary Controls the Conrotation
Harrington, P. E.; Murai, T.; Chu, C.; Tius, M. A. J. Am. Chem. Soc. 2002, 124, 10091-10100.
67%, 79%ee
O
HO
CH3
CH3
67%, 71%ee
Matched
Mismatched
+ 1
4:3 mixture
1) n-BuLi, THF, - 78°C
2)N
O
H3CO
3) HCl, HFIP/TFE, -78°C
O
H
O δ
OH
CH3
PhH3C
H
δ
O
H
O δ
OH
CH3
PhH
CH3
δ
OO
OO
H
CH3
H
H
H3C
H
1) n-BuLi, THF, - 78°C
2)N
O
H3CO
3) HCl, HFIP/TFE, -78°C
1
2
65%ee from pure 2
An Example Where Allene Controls the Conrotation
Harrington, P. E.; Murai, T.; Chu, C.; Tius, M. A. J. Am. Chem. Soc. 2002, 124, 10091-10100.
Matched
Mismatched
O
HO
H3CCH3
O
HO
H3CCH3
56%, 94%ee 3%, 92%ee
+
O
HO
H3CCH3
O
HO
H3CCH3
33%, 72%ee 15%, 61%ee
+
OOH
H
1) n-BuLi, THF, - 78°C
NO
O
2)
3) HCl, HFIP/TFE
OO
H
H
1) n-BuLi, THF, - 78°C
NO
O
2)
3) HCl, HFIP/TFE
O
H
O δ
OH
CH3
CH3H
O
H
O δOH
CH3
CH3
δ
δ
H
N
O
SEM
Application of Chiral Auxiliary Approach: Synthesis of Roseophilin
Harrington, P. E.; Tius, M. A. J. Am. Chem. Soc. 2001, 123, 8509-8514.
O
N
Cl
H
OMeN O
HO
N
O
OOOLi
HH
+
Some Other Auxiliaries
Kerr, D. J.; Metje, C.; Flynn, B. L. Chem. Commun. 2003, 1380-1381.
Pridgen, L. N. et al. Synlett 1999, 1612-1614.
O
O O
O
Xc
PrO
H
N O
O
i-Pr
Xc =
Ph
O
NO
OO
Phkinetic product
Ph
O
NO
OO
Phthermodynamic product
N O
O
Ph
O O
Ph
MeSO3H
- 78 to 0°C (77%)
MeSO3H
r.t.(76%)
MeSO3H (5 equiv)
CH2Cl2, 0°C(88%, 70%de)
OPrO
Xc
O
OO
Ligand *, CuBr2AgSbF6, CH2Cl2, r.t.
* Ligand = 3 when R3 = OEt = 4 when R3 = NEt2
Reagent Controlled Nazarov: Catalytic Asymmetric Nazarov Cyclization
Aggarwal, V. K.; Belfield, A. J. Org. Lett. 2003, 5, 5075-5078.
R2
R3R1
Ph
O O
N N
CO O
t-But-Bu
N N
O O
i-Pri-Pr
N
4
3
Ligands
Me Me
OR1
Ph
O
R3
R2
R
R
Entry Substrate R1 R2 R3 Yield (%) ee (%)
1
2
3
4
5
6
1a
1b
1c
1d
1e
1f
Me
Ph
Me
Ph
Me
Ph
Ph
Ph
Me
Me
Ph
Ph
OEt
OEt
OEt
OEt
NEt2
NEt2
42
96
27
86
56
56
78
86
01
35
87
85
Origin of the Stereoselection: Stereochemical Model
Aggarwal, V. K.; Belfield. A. J. Org. Lett. 2003, 5, 5075-5078.
O
OEt
O
Ph
R1
R2
OO
R1
H
R2
Ph
Et2NCu
NN
O
O
H t-Bu
Ht-Bu O
NEt2
O
Ph
R1
R2
O
O
R2
Ph
R1
CuN
Oi-Pr
N
O N
i-PrEtO
Steric push from i-Pr group
Catalytic Asymmetric Nazarov Cyclization: Another Example
Liang, G.; Gradl, S. N.; Trauner, D. Org. Lett, 2003, 5, 4931-4934.
OO
NO
N N
O
Ph Ph
Sc(OTf )3
( 20 mol %)
THF
53%, 61%ee
OO
H
H
Probably Sc is binding to both oxygens forming a distorted complex structure and predisposing the orbital lobes to favor
clockwise conrotation
Conclusions on Asymmetric Nazarov Reaction
Both substrate and reagent controlled asymmetric induction is possible
Chiral auxiliaries induce asymmetry by favoring one mode of conrotation
Chiral catalysts distort the divinyl ketone to favor one conrotation over the other
Other Recent Variants of the Nazarov Reaction
Polarized Nazarov reactions
Pd(II)-catalyzed Nazarov reactions
Intercepted Nazarov reactions
Retro-Nazarov reactions
Polarized Nazarov Reaction
He, W.; Sun, X.; Frontier, A. J. J. Am. Chem. Soc. 2003, 125, 14278-14279.
OO
CO2Me
R
OO
CO2Me
R
Cu(OTf)2, (2 mol%) Cl(CH2)2Cl (0.06 M) 25°C
Entry Ketone R Time Yield (%)
1
2
3
4
5
3a
3b
3c
3d
3e
2,4,6-trimethoxyphenyl
4-methoxyphenyl
3-methoxyphenyl
phenyl
cyclohexyl
5 min
3.5 h
48 h
108 h
240 h
> 99
99
96
99
< 50
OE
R2
D
R1
Lewis AcidED
R1 R2
OLA
OH
ED
R1 R2
Cyclization
Vinyl Electrophile
Vinyl Nucleophile
δ− δ+
D = Electron donating groupE = Electron withdrawing group
Role of Vinyl Nucleophile and Vinyl Electrophile
Cu(OTf)2 (2 mol%) Cl(CH2)2Cl (0.06 M)A =
He, W.; Sun, X.; Frontier, A. J. J. Am. Chem. Soc. 2003, 125, 14278-14279.
OCO2Me
TMP
OCO2Me
TMP
A
40°C0.25 h(86%)
OO
H OO
A
55°C0.5 h(60%)
OH
DecompositionA
65°C4 h
TMP = 2,4,6-trimethoxyphenyl
OO
LAregioselective elimination
R
CO2Me
OLA
nonselective elimination
R2
R1R4
R3
Palladium(II) Catalyzed Nazarov Reaction
O
Ph
OEt + H Pd OAcL
L
Bee, C.; Leclerc, E.; Tius, M. A. Org. Lett. 2003, 5, 4927-4930.
OOEtH3C
Ph
O
OEt
Ph
OH
OH3C
Ph
PdCl2(MeCN)2 (1 mol%)
Pd(OAc)2(20 mol%)
acetone (H2O) r.t., 1 d, (91%)
DMSO80°C, 1 d, (50%)
O
OEt
H3C
Ph
PdX
XL
O
OEt
H3C
Ph PdX2L
OH3C
Ph
slow
H2OO
OH3C
Ph
OEt
PdLLX
O
O
H3C
Ph
Pd
X = Cl H2O
X = OAc
OH
OH3C
Ph
L2PdCl2 HCl EtOH+ + +
O
H3C
Ph
OEt
PdLLAcO
HOAc
ClL
L
+X-+
Intercepted Nazarov Reactions: Intramolecular
Mechanistic Rationale:
Bender, J. A.; Blize, A. E.; Browder, C. C.; Giese, S.; West, F. G. J. Org. Chem. 1998, 63, 2430-2431.
Me
O
Et
H
H
MeOBF3
EtMeH
Me
Me
EtH
MeOBF3
Me
HO O
Et
H
H
MeH3O+
OEt
Me
Me
Me
HO O
Et
H
H H
MeBF3•OEt2, CH2Cl2
-78°C, r.t., H2O(73%)
OEt
Me
Me
H
OEt
Me
Me
H
BF3
BF3
Intercepted Nazarov reactions help to conserve the stereocenters formed from the electrocyclic
ring closure
OBF3
Me H
Et Me
OH
oxyallylicintermediate
Domino-Nazarov Reaction
Bender, J. A.; Arif, A. M.; West, F. G. J. Am. Chem. Soc. 1999, 121, 7443-7444.
Me
Me
Et
MeO
Me
Me
Et
OTiCl4
MeTiCl4
H
MePh(CH2)2
MeMe
Et
EtH
MeMe
H Me
TiCl4, CH2Cl2 - 78°C (73%)
+
O
O
EtH
Me
MeMe
PhCH2CH2 H
Me
OCl4Ti H EtMe
Me
OTiCl4
- TiCl4
Intermolecular Trapping of Nazarov Intermediate: Reductive Nazarov Cyclization
A
B
H3C
H3C
F3BOPh
H
HEt3Si H
Path A
Path B
Giese, S.; West, F. G.; Tetrahedron 2000, 56, 10221-10228.
H3C
H3C
F3BOPh
H
H
H
H3C
H3CF3BO
Ph
H
H
H
Ph
HH3C
H
Ph
HH
H3C
δ
δ
δ
δ
δ
δ
O
Me
Ph
Me
Ph
BF3O
Me
PhPh
Me1.1 equiv. BF3•OEt
10 equiv. Et3SiHH2O
O
Ph
H
Ph
BF2
Et3SiH
Et3SiF
MeMe
O
Ph
Me
Ph
Me
O
Ph
Me
Ph
SiEt3
Me
+
(44%)
(54%)
H2O
[4+3] Capture of Oxyallyl Intermediate: Another Intermolecular Case
Wang, Y.; Schill, B. D.; Arif, A. M.; West, F. G. Org. Lett, 2003, 5, 2747-2750.
Me MePh Ph
O
Me
Me
Ph
PhMe
MeOBF3
Me MePh Ph
O
not seen
Me
Me
Ph
Ph
MeOBF3
Me
Me MePh Ph
O
not seen
MeO
Me
Ph
Me
Ph
Me BF3•OEt2
- 25°C, 2.5 hCH2Cl2(20%)
Me MePh Ph
O+
Me
Stepwise cycloaddition?
Retro-Nazarov Reaction
Probable Mechanism !!!
Harmata, M.; Lee, D. R. J. Am. Chem. Soc. 2002, 124, 14328-14329.
Retro-Nazarov: misnomer?
TFEO Ot-Bu
O
Ph+
O
t-BuO PhOCH2CF3
TFEO Ot-Bu
O
PhH+
(65%) (9%)
O
Br
Pht-BuO
TEA, TFE
reflux
O
Br
t-BuO
Ph2CuLi
O
t-BuO Ph(66%)
O
Br
t-BuO Ph
O
Br
t-BuO Ph
Et3NH
O-
t-BuO Ph
O
t-BuO Ph
RETRO
NAZAROV
- Br-
Conclusions
Classical acid catalyzed Nazarov cyclization reaction is a 4π conrotatoryelectrocyclic ring closure reaction of divinyl ketones
Directed Nazarov reactions attempt to overcome the problems related to regiocontrol of the double bond in the product
Asymmetric Nazarov reactions provide a means to selectively favor one modeof conrotation in the electrocyclic ring closure
Polarization of the precursor divinyl ketone gives the Nazarov product with regiocontrol under milder conditions
Trapping of the oxyallylic intermediate of the reaction can be done both intra and intermolecularly and that helps to conserve the stereocenters created by the electrocyclic ring closure
Dr. Robert Maleczka
Edith
Jill
Ron
Andrea
Feng
Kyoungsoo
Kim
Sanjit
Jill
Manish
Vijay
Manasi
Mahesh
All other friends!
Dr. Wagner
Dr. Tepe
Dr. Jackson
Dr. Reusch
Acknowledgements