reich organometallic reagents in synthesis · smith, a. b.; adams, c. m.; barbosa, s. a. l.;...
TRANSCRIPT
Organometallic Reagents in Synthesis
Isoamijiol (14-deoxy)Majetich, G.; Song, J. S.; Ringold, C.; Nemeth, G. A.
Tetrahedron Lett. 1990, 31, 2239
HOH
Li
CuSi
R
R = Radical
Li
HN
O
O
NHMe
K
Pd/Sn Si
Ruguluvasines A and BLiras, S.; Lynch, C. L.; Fryer, A. M.; Vu, B. T.; Martin, S. F.
J. Am. Chem. Soc 2001, 123, 5918.
Shahamin KLebsack, A. D.; Overman, L. E.; Valentkovitch, R. J.
J. Am. Chem. Soc. 2001, 123, 4851.
AcO
H
H
OAc
O
O
LiCu
Li
LiH
LiCationic cyclization olefin
PironetinDias, L. C.; Oliveira, L. G.; Sousa, M. A.
Org. Lett. 2003, 5, 265
OHOMe O
O
BB
Li
Li
B
P/Na
Penostatin A (Deoxy)Snider, B. B.; Liu, T.
J. Org. Chem. 2000, 65, 8490-8498.
C7H15
OH
O
H
P/LiP
Diels Alder (hetero)
Li
P/Li
MorphineTaber, D. F.; Neubert, T. B.; Rheingold, A. L.
J. Am. Chem. Soc. 2002, 124, 12416
OO
OH
OH
Li Li Cr Pd/Zn
Zr/AlSi
Mg
Okinellin BSchmitz, W. D.; Messerschmidt, N. B.
J. Org. Chem. 1998, 63, 2058
LaurenyneOverman, L. E.; Thompson, A. S. J. Am. Chem. Soc.
1988, 110, 2248
O
ClLi
K/PCationic
cyclization olefin K
Li/Si
HirsuteneD. P. Curran, D. M. Rakiewicz
J. Am. Chem. Soc., 1985, 107, 1448.
H
H H53%
Claisen
Li
LiRR R = Radical cyclization
N
O
OH
OH
HLi
CarbeneK
K
LI
LI
•
O OHO
OH
LiPd
Cu
CuLi
DysidiolideMadnuson, S. R.; Sepp-Lorenzino, L.; Rosen, N.;
Danishefsky, S. J. J. Am. Chem. Soc. 1998, 120, 1615.
LI
Organometallic and other C-C bond forming reactions in some representative syntheses: Li = lithium reagent, Mg =Grignard reagent, Cu = organocopper reagent, P = Wittig reagent, Li/P Na/P K/P Horner-Wadsworth-Emmons, Pd/Sn = Stillecoupling, Pd/Zn = Negishi coupling, Li/Si = Peterson olefination, Zr/Al = Tebbe reagent, B = organoboron reagent, R = Radicaladdition/cyclization.
ReichChem 547
Tedanolide (13-deoxy)Smith, A. B.; Adams, C. M.; Barbosa, S. A. L.; Degnan, A. P. J. Am. Chem. Soc 2003, 125, 350
PPh3
CO2Me
+
PPh3
+
H
PPh3
Br
+
Br
NO
O O
Ph
B-Enolate
BO
OCO2iPr
CO2iPr
NO
O O
Ph
B-Enolate
S
S
Li
S
S
Li
OMe
OTIPS
SS
OPMB
OO
Li
B1B2
Li1Li2 P1
P2
P3
B3
Li3
P1P1Li1
B(Ipc)2
Li
SS
OO OBn
SS
Li
PhSO2 Li
PhSO2
OPMB
OTBS
LiSiMe2
tBu
SS
Li
Li
B(Ipc)2 (Mg)
PhSO2 OTES
SS
OO
OTBS
TESO
H
H Li
BnO
Organometallic Reactions in Partial Synthesis of Spongistatin 1Smith, A. B. et al Tetrahedron Lett. 1997, 38, 8667, 8761, 8675
O
O
OH
H
OH
HOO
HO
H
OH
Cl
OO
OH
O
O
AcO
H
OAc
O
OMe
HO
H
O
H
H
BLi
B
Li Li
Li
LiLi
Li(Cu)
BLi
Li
LiLi
Li
B
Spongistatin 1
B O
OCO2iPr
CO2iPr
Major disconnections
PhSO2 OTES
SS
Li
L
LI
OH
O
O
OH
OMe
OH
O
O O
O
Li3
Li1Li2
P1
B2 B2
B1 B3
P2
P3
Classes of Nucleophilic Organometallic Reagents
C M+ Strong Carbanion, M+ Weak Lewis Acid
R_Li, R_Na, R_K, (R_MgX)
C_M Weak Carbanion, M+ Lewis Acid
R_B, R_Al, R_Zn, R_Ti, R-SiX3, (R_MgX)
C_M Weak Carbanion, M+ Non-Lewis Acidic
R_Si, R_Sn, R_Hg, various ate complexes
C_M Weak Carbanion, M+ Lewis Base
R2Cu , Pd°
:High nucleophilicity
Stereochemical controlNucleophilic catalysisCyclic transition states
Regiochemical controlIsomerically stable
Unusual Reactivity patternsHigh selectivity towards electrophiles
Balancing the Reactivity of Nucleophile and Electrophile
N + E+ N_E
H +
+
X R
O
R
O
+ HX
Activate the nucleophile:
Li
Br
BuLi
Activate the electrophile:
Me2N R
O
R
O
Cl R
O
R
OH +
O
R+
AlCl3
Assemble on a transition metal (mildly activate both E and N):
+SnMe3Cl R
O
R
O
+ Me3SnClPd(0)
+ HCl
Preparation of Organolithium Reagents1. Reduction of carbon-X bonds with lithium metal
R-X + 2Li° R-Li + LiX
2. Metalation (Li/H exchange)
R-H + R'Li R-Li + R'-H
3. Lithium-metalloid exchange (Li/M)
R-M + R'Li R-Li + R'M
MeLi n-Bu-LiPhLi t-BuLi s-Bu-Li
OMe
Li O LiPh
SOO
Li
LiRO Li O
BnOBnO
OBn
Li
H
R-C≡C-Li
X = Cl, Br, I, SPh
M = Br, I, SnBu3, HgCl, SePh, TePh
4. Addition of RLi to C-C multiple bonds.
RR'Li
RR'
Li
5. Metalation of N-sulfonylhydrazones (Shapiro)
N NHSO2Ar 2 n-BuLiLi
PhR
Li
PhSO2R
Li
Effect of Substituents on Carbanion Stability
Type: -CH2-X pKa of H-CH2-X Typical Metalating Agents
Very Strong
-NO2 -N +≡N
10-20 NaOH, KO-t-Bu, DBU
Strong 20-30 KO-t-Bu, NaH, LDA
KH, LiN(TMS)3
R ORS
R
R'
+
SO2CF3
PR3+
Intermediate 30-40 LDA, n-BuLi, KH
O- N-R-
NR2
CN
SR
OP
O
RRSe
R
O
Weak*** 40-50 n-BuLi, sec-BuLi, LiTMP
SR PR2 SeR
CH=CH2
BR2
-C≡C-R -Halogen -Ph
Very Weak** 50-60 sec-BuLi, n-BuLi/TMEDAn-BuLi/tBuOK
-OR -NR2 -SiR3
Destabilizing (compared to H)* >60 None available-CH3
Need two of these (X-CH2-X') for easy metalation with LDA.
These types are not usually prepared by metalation, but by other techniques (Li/Sn, Li/Halg exchange, reduction of
halogen or SR).
Alkyl groups are invariably kinetically deactivating.
***
***
OO O
R
OS
O
O O
-80
-70
-60
-50
-40
-30
-20
-10
0
10
CH3CH2:
(CH3)2CH:
CH3:
H:
H2C=CH:
Ph:
H2C-CH-CH2:
PhCH2:
HC≡C:
(Ph)3C:
H-
H:NH2:
HO:
CH3O:
F:
CH3S:
HS:
Me3SiCH2:MeSCH2:
Cl2CH:
Me2PCH2:
ClCH2:
(Me2P)2CH:
Me3Sn:
Me3Si:
Gas Phase Acidity (kcal/mol)
Brauman J. Am. Chem. Soc.1995, 117, 4908.
416.6
Effect of Substituents on Carbanion Stability
1. HybridizationIn almost all areas of organometallic chemistry the primary subdivision of reactivity types is by the hybridization of the
C-M carbon atom (methyl/alkyl, vinyl/aryl, alkynyl). A key second subdivision is the presence of conjugating substituents(allyl/allenyl/propargyl/benzyl).
The fractional s-character of the C-H bonds has a major effect on the kinetic and thermodynamic acidity of the carbonacid. Only s-orbitals have electron density at the nucleus, and a lone pair with high fractional s character has its electrondensity closer to the nucleus, and is hence stabilized. This can be easily seen in the gas-phase acidity of theprototypical C-H types, ethane, ethylene and acetylene, as well as for cyclopropane, where the hybridization of the C-Hbond is similar to that in ethylene.
CH3-CH3 CH2=CH2 HC≡CH
ΔH°acid (kcal/mol) 420 406 375
These effects are also clearly evident in solution, with terminal acetylenes and highly strained hydrocarbons easilymetalated by strong bases.
411
Li
JACS-72-7735
n-BuLi
2. Inductive EffectsElectron-withdrawing substituents will inductively stabilize negative charge on nearby carbons. These effects are
complex, since electronegative substituents interact with carbanions in other ways as well (e.g. O and F substituentshave lone pairs, which tend to destabilize adjacent carbanion centers).
Ph
OS
OH
H
Ph
OS
OCH3
H
Ph
OS
OOMe
H
Ph
OS
OF
H
Ph
OS
ON +
Me3
HpKa (DMSO) 29.0 31.0 30.7 28.5 19.4
3. Conjugation - π DelocalizationDelocalization of negative charge, especially onto electronegative atoms, provides potent stabilizations of carbanionic
centers. Since almost all conjugating substituents are also more electronegative than H or CH3, there is usually asignificant inductive contribution to the stabilization.
CH3
H
43
CH4
~55
A special case is the aromatic stabilization of cyclopentadienide and related indenide and fluorenide anions (Huckel4n + 2 π electron rule) .
HO
26.5
t-BuO
O
30.3
NC H
31.3
H
pKa (DMSO)
K
22.620.1 30.118.0pKa (DMSO)
ΔH°acid (kcal/mol) 356.1 373.9
The aromatic anions (6e π system)show a level of stabilization far abovethat of normal conjugated systems
4. Second and Third Row Element Effects ("d-orbital" effects)All measures of acidity show that there is an unusual level of carbanion stabilization for all second row elements (Cl,
S, P, Si, as well as higher elements) when these are bonded to a carbanion center.
R
n
S C
RS C
RS C
H
R H R
σ bond is stronger in S-substitutedcarbanions because of better orbital sizematch (negative charge increases size ofC-S orbital)
Negative hyperconjugation
The origin of this stabilization has several components. Classical overlap of the lone pair with the empty d-orbitals isat best a minor contributor, since the d-orbitals are too diffuse and too high in energy. For the electronegative elements(Cl and S) there is an inductive component. For those bearing substituents (SR, PR2, SiR3) there is a major contributionof σ-hyperconjugation (delocalization of charge into X-R σ* orbitals).
CH3 SCH3
OCH3
NCH3CH3
Kinetic acidityIsotopic exchangeKNH2/NH3
300
0.25
0.45
0.41
106
330
24
6
0.25
500
1
0.25
0.013
14
0.2
0.07
5. Lone Pair EffectsFor the first row elements N, O, F, and perhaps also for higher elements, the presence of lone pairs has a strong
destabilizing effect on a directly bonded carbanion center. This has several effects on carbanion structure: there aresubstantial rotational barriers around the C-X bond and the carbanion center is usually more pyramidalized.
d-orbital interaction
Rσ*
RO C
RO C
H
R H R
σ bond is weaker in O-substituted carbanionbecause of poorer orbital size match
S
A factor comparable in size to σ-hyperconjugation is the σ bond strength effect. There is a size difference between the3p orbitals of the S and 2p orbitals in the C-H compound. In the carbanion the C orbital increases in size, resulting in astronger sigma bond. In an oxygen-substituted system the orbital mismatch is in the opposite direction (the p orbital atoxygen is smaller than that at carbon, and this size difference is excacerbated in the carbanion). Superimposed on theseeffects are possible lone pair effects (Cl, S, P).
K
pKa (DMSO)Ph
OX
X Me
24.4
OMe OPh SPh SePh
22.9 21.1 17.1 18.6
Me-CH3
Me3SiCH3MeSCH3ClCH3
FCH3 MeOCH3420.1409 407
390.9393.2395.6
ΔH°acid (kcal/mol)
ΔH°acid (kcal/mol)
Gas phase acidity
13.4 13.8 19.2ΔΔH°acid
Bordwell J. Org. Chem.1976, 41, 1885
-80
-70
-60
-50
-40
-30
-20
-10
0
10
CH3-CH3 (420.1)2
Me2CH2 (419.4)2
CH4 (416.6)1
H2C=CH2 (407)7
Ph-H (400.7)4
H2C=CH-CH3 (387.2)1
PhCH3 (379.0)1
HC≡C-H (375.4)1
(Ph)3C-H
H2 (400.4)1
NH3 (399.6)1
HO-H (390.8)1
MeO-H (380.6)2
F-H (371.5)1
MeS-H (356.9)2
HS-H (351.2)2
Me3SiCH3 (390.9)3
MeSCH3 (393.2)3
Cl2CH2 (374.1)3
Me2PCH3 (384)3
ClCH3 (395.6)3
(Me2P)2CH2 (370)3
Me3Sn-H (349)2
Me3Si-H (383)2
400
390
380
370
360
350
340
330
320
(N≡C)2CH2 (331.7)5
410
420
1. Bartmess J. Am. Chem. Soc. 1979, 101, 60462. Braumann, J. Am. Chem. Soc. 1995, 117, 4905
NC-H (353.1)1
3. Braumann J. Am. Chem. Soc. 1998, 120, 2919
PH3 (370.4)1
HSe-H (338.7)1
-100
-90
310
H
PhS-H (338.9)1
Cl3C-H (356.7)3
F3CH (377)3
F2CH2 (389)7
FCH3 (409)3
PhO-H (351.4)1
Cl-H (333.3)1
Br-H (323.6)1
I-H (314.3)1
CH3OCH3 (407)3
(Me3Si)2CH2 (373)3
Me3CH (413.1)2
Me3Ge-H (361.5)2
SiH4 (372.8)2
GeH4 (359)2
H
N≡CCH3 (369)7
CH3COCH3 (368.8)1
Gas Phase Acidities
ΔH°acid (kcal/mol)
PhNH2 (367.1)1
Ph2CH2 (364.5)1PhCOCH3 (363.2)1
CH3SOCH3 (372.7)1
CH3SO2CH3 (366.6)1
O2NCH3 (358.7)1NH
(360.7)1
(356.1)1
(348.5)5
4. Tetrahedron Lett. 1997, 0, 8519
H
F(386.9)4
5. Kebarle J. Am. Chem. Soc. 1976, 98, 3399 (add 3-4?)
(CH3CO)2CH2 (342.6)5
(CH2=CH)2CH2 (359.7)5
EtCO2H (345.2)5
PhCO2H (337.7)5
ClCH2CO2H (333.6)5FCH2CO2H (335.6)5
F2CHCO2H (328.4)5
CF3COCH3 (347.1)5
δΔH°acid (kcal/mol)
MeOO-H (374.6)6
6. Ellison
HOO-H (376.5)6
7. Squires J. Am. Chem. Soc. 1990, 112, 2517
(408)7
PhCH2CH2-H (406)7
CH2C(O)-H (387)7
Organolithium Reagents Usually Prepared by Metalation
PhS Li
O O
PhS Li
ONC Li
PhSe
Li
PhS
Li
RO
Li
PhS Li S S
Li
SLi
OLi
OCH3
Li
CH2NMe2
Li
CONR2
Li
(EtO)2P Li
O
LiO
OLi R2N
OLi
Li
OR R'
R Li
H
O Li PhS Li R Li
Li
Li
NLi
R
NN
Li
N
OtBuO
Li
SPh
Li
PhS OMe
Li
Li Reagents by Metalation
Metalations by Organolithium Compounds, Mallan, J. M.; Bebb, R. L. Chem. Rev. 1969, 69, 693.
Allylic and Benzylic Carbanions Substituted by Heteroatoms, Biellmann, J. F.; Ducep, J. -B. Org. React. 1982, 27, 1.
Polar Allyl Type Organometallics as Key Intermediates in Regio- and Stereocontrolled Reactions: ConformationalMobilities and Preferences,
Schlosser, M.; Desponds, O.; Lehmann, R.; Moret, E.; Rauchschwalbe, G. Tetrahedron 1993, 49, 10175. Silylallyl Anions in Organic Synthesis: A Study in Regio- and Stereoselectivity,
Chan, T.H.; Wang, D. Chem. Rev. 1995, 95, 1279-92. Delocalized Carbanions in Synthesis,
Barry, C. E. III, Bates, R. B.; Beavers, W. A.; Camou, F. A.; Gordon, B. III; Hsu, H. F. J.; Mills, N. S. Synlett 1991,207. Regioselectivity of the Reactions of Heteroatom-Stabilized Allyl Anions with Electrophiles,
Katritzky, A. R.; Piffl, M.; Lang, H.; Anders, E. Chem. Rev. 1999, 99, 665-722.Heteroatom-Faciliated Lithiations,
H. W. Gschwend and H. R. Rodriguez Org. React. 1979, 26, 1. Lateral Lithiation Reactions Promoted by Heteroatomic Substituents,
Clark, R. D.; Jahangir, A. Org. React. 1995, 47, 1-314. α-Heteroatom Substituted 1-Alkenyllithium Reagents: Carbanions and Carbenoids for C-C Bond Formation,
Braun, M. Angew. Chem. Int. Ed. Engl. 1998, 37, 430-51.Lewis Acid Complexation of Tertiary Amines and Related Compounds: A Strategy for α-Deprotonation andStereocontrol,
Kessar, S.V.; Singh, P. Chem. Rev. 1997, 97, 721-38.Dipole Stabilized Carbanions,
P. Beak Chem. Rev. 1978, 78, 275.Stereo and Regiocontrol by Complex Induced Proximity Effects-Organolithium Compounds, P. Beak, A. I. Meyers Acc. Chem. Res. 1986, 356.
Selected Metalation AgentsA variety of metalation agents are used to deprotonate C-H acidic compounds. For materials with pK values above ca 37only alkyllithium reagents are effective. For more acidic protons these may also work, but various lithium amides(especially LiNiPr2) are often faster and give cleaner products.
n-BuLi n-Butyllithium in solvents like ether or THF, sometimes with activating cosolvents like TMEDA, PMDTA,or HMPA is by far the most extensively utilized metalation agent. Alkyllithiums fail to metalate mostcarbonyl compounds because of competing addition to the carbonyl group, and some heteroatomsubstituted compounds of the 3rd, 4th and 5th period (e.g, I, Se, Te, Sn) where attack at the heteroatom caninterfere (Li/I, Li/Se, Li/Te, Li/Sn exchange).
s-BuLi sec-Butyllithium is usually more active than n-BuLi and sometimes will successfully perform metalationsnot possible with the other alkyllithiums.
n-BuLi/KOtBu This combination, sometimes referred to as the Schlosser-Lochmann base or LIKOR base, is perhapsthe most powerful metalating combination available. The active reagent is believed to be a complex ofbutylpotassium. Some electrophiles are incompatible with the metalating agent, and conversion of theorganometallic to an intermediate Sn compound may be required, for subsequent Li/Sn exchange toprepare the lithium reagent under milder conditions.
t-BuLi tert-Butyllithium. A more aggressive base than either n-BuLi or s-BuLi, t-BuLi can perform metalations notpossible with these. It is more dangerous to handle (e.g., its solutions inflame spontaneously in air) andmore expensive. Steric effects may be a problem, but can also result in different selectivity.
LiMesityllithium. A special purpose hindered organolithium base with very low propensity to add tocarbonyl compounds. Used for deprotonations of relatively acidic compunds (pKa < 40) where the presenceof amines (if lithium amides would normally be used) is deleterious, where exceptional steric selectivity isdesired, or where carbonyl addition or reduction is a problem with alkyllithium bases.
LiN
Lithium diisopropylamide (LDA, pKa 36). Prepared by reaction of nBuLi with HNiPr2. This is thecheapest and most convenient base for deprotonations of compounds whose pKa is less than 36, includingall carbonyl compounds, alkyl sulfoxides, sulfones, and some aromatic compounds. Hindered and certainheterosubstituted ketones are sometimes reduced.[1] In this case use LiTMP or LiN(SiMe3)2. The amine isvolatile and can be removed even from enolate solutions by distillation. LDA can be prepared from Li .
LiN
Lithium 2,2,6,6-Tetramethylpiperidide (LiTMP, pKa 37).[4] This is the most potent and least nucleophilicof the amide bases. It is kinetically faster than LDA, and will smoothly do many deprotonations notpossible with LDA. Interference by the amine (e.g. in acylations) is minimal because of high sterichindrance. Disadvantage: the amine precursor is expensive. CAUTION: The reaction between n-BuLi andthe amine is slow at -78 °C and is best done at 0°C.[5]
Lithium Bis(trimethylsilyl)amide (aka Hexamethyldisilazide) (LiN(SiMe3)2, LiHMDS).[2] A considerablyweaker (pKa ca 30) base than the dialkylamides above. Used where a delicate touch is needed (e.g. forenolate alkylation when halide is part of the molecule[3]) and where hydride reduction occurs with LNiPr2. LiN(SiMe3)2 will give the thermodynamic enolate under appropriate conditions. Several more hinderedanalogs (such as (PhMe2Si)2NLi) have found some uses in stereoselective deprotonations
LiNSi
Si
1. a) C. Kowalski, S. Creary, A. J. Rollin and M. C. Burke J. Org. Chem. 1978, 43, 2602. (b) M. T. Reetz Ann.1980, 1471.
2. (a) M. W. Rathke J. Am. Chem. Soc. 1970, 92, 3222. (b) "Structure of Lithium Hexamethyldisilazide (LiHMDS): Spectroscopic Study of Ethereal Solvation in the Slow-Exchange Limit," Lucht, B. L.; Collum, D. B. J. Am. Chem. Soc.1994, 116, 6009-6010.
3. S. Danishefsky, K. Vaughan, R. C. Gadwood, K. Tsuzuki J. Am. Chem. Soc. 1980, 102, 4262; 1981, 103, 4136.4. M. W. Rathke and R. Kow J. Am. Chem. Soc. 1972, 94, 6854. R. A. Olofson and C. M. Dougherty J. Am. Chem.
Soc. 1973, 95, 582.5. I. E. Kopka, Z. A. Fataftah, M. W. Rathke J. Org. Chem. 1987, 52, 448.
N
Organolithium Reagents
Lithium Amides
0.0
2.0
4.0
6.0
8.0
10.0
12.0
14.0
16.0
18.0
20.0
22.0
24.0
26.0
28.0
30.0
32.0
34.0
36.0
38.0
40.0
42.0
44.0
46.0
48.0
50.0
52.0
54.0
56.0
0.0
2.0
4.0
6.0
8.0
10.0
12.0
14.0
16.0
18.0
20.0
22.0
24.0
26.0
28.0
30.0
32.0
34.0
36.0
38.0
40.0
42.0
44.0
46.0
48.0
50.0
52.0
54.0
56.0
H2O
NaOAc
NEt3Na2CO3
DBU/DBN
NaOH
NaOMe
KO-t-Bu
LiN(SiMe3)2
Ph3CLiNaNH2 NaCH2-S
O-CH3
PhLi
MeLi
DBU
N
N
CH2(NO2)2
CH3NO2
O OCH2(C≡N)2
RO OR
O O
OH-C≡C-PhCH3-CO2Et
CH3C≡N
CH3-SO2Ph
CH3PhCH2=CH2
Bases(pKa of Conjugate Acid)
Substrates(pKa)
HCPh3
LiN(i-Pr)2
N
H2O
DM
SO
CH3-P +
Ph3
ReichChem 547
pKa pKa
NH2Ph
NaOPhH-C≡N
NLi
H-S-Ph
H-S-CH3
n-BuLi, t-BuLi
CH2(SPh)2
OH
H-O-Ph
Pyridine
LiTMP
CH4
KH (?)
Acidity of Conjugate Bases and Substrates
Metalated Sulfones
Preparation. Sulfones are easily prepared by a variety of synthetic procedures:
Oxidation of sulfides and sulfoxides Nucleophilic substitution of halides and tosylates by sodium arenesulfinate
Alkylation of lithiosulfones Conjugate addition to vinyl and alkynyl sulfones Cycloaddition of SO2 to dienes
Metalation. All types of sulfones (1°, 2°, 3°, allyl, vinyl) which have σ-hydrogens metalate easily with n-BuLi or LiNiPr2, and theanions show good nucleophilicity. Commonly used electrophiles are alkyl halides and tosylates, epoxides, aldehydes, ketones andesters.
Subsequent Transformations. The products of reaction of metalated sulfones with electrophiles can be used in various ways: Reductive elimination of β-oxy and β-halo sulfones (Julia olefination)
Reductive desulfonylation with Al/Hg Metalation/oxidation to form ketones If cleavage of the C-S bond gives a stabilized cation, some sulfones can behave as C-electrophiles
Conjugate addition of sodium arenesulfinate to α,β-unsaturated carbonyl compounds
β-Elimination to give olefins if β-hydrogens are acidic
Oxidation of β-oxy sulfones to β-keto sulfones and desulfonylation to ketones
Sultone ChemistryD. W. Roberts, D. L. Williams, Tetrahedron 1987, 43, 1027.
The Chemistry of Vinyl Sulfones,Simpkins, N. S. Tetrahedron 1990, 46, 6951.
The Use of Sulfonyl 1,3-Dienes in Organic Synthesis,Baeckvall, J.-E.; Chinchilla, R.; Najera, C.; Yus, M. Chem. Rev. 1998, 98, 2291-312.
Recent Progress on Rearrangements of Sulfones,Braverman, S.; Cherkinsky, M.; Raj, P. 1999, 22, 49-84.
Desulfonylation Reactions: Recent Developments,Najera, C.; Yus, M. Tetrahedron 1999, 55, 10547-658.
The Chemistry of Acetylenic and Allenic Sulfones.Back, T. G. Tetrahedron 2001, 57, 5263-301.
Stereoselective and Enantioselective Synthesis of Five-Membered Rings via Conjugate Additions of Allylsulfone Carbanions, Hassner, A.; Ghera, E.; Yechezkel, T.; Kleiman, V.; Balasubramanian, T.; Ostercamp, D. Pure. Appl. Chem. 2000, 72, 1671-83.
SO2
OS
O
X
PhSM
PhSO2M
S
Ph
OS
O
Ph
Ox
RR
R
Ph
OS
ORM
Ph
OS
O1. base2. RCH2X
R
PhSM
BuLior
LiNiPr2
Ph
OS
O
R
Li
Otera JACS 84-3670
Heathcock JOC 95-1120
R'
Julia
2. base
[base]
[red][oxid]R'CHO
[red]
1. [base]2. [oxid]
R'
H
Ph
OS
O
R
Li
R
Ph
OS
O
R
R'HO
Ph
OS
O
R
R'O
R
R'O
1. Ac2O
Ph
OS
O
R
R'
[Acyl anion]
R
R
[Alkyl anion]
[Alkynyl anion]
R'
O
R'
R
R'HO
[red]
H
R
[Alkyl anion]
R'X
Ph
OS
O
R
R'
BuLi; CH2I2,iPrMgCl
R
R'
Julia II
1. Ac2O2. Na/Hg
Metalated Sulfone Reactions
OPMB
O1. PhSO2CH2Li
THF, HMPA2. TBSOTf OPMB
OTBS
PhSO2
O
OBn
OTBSI
H
OTBS
OBn
TBSOO
MeO
H
BuLi, HMPA
O
OBn
OTBS
H
OTBS
OBn
TBSOO
MeO
H
PhSO2
OTBS
OPMB
BuLi; CH2I2,iPrMgCl O
OBn
OTBS
H
OTBS
OBn
TBSOO
MeO
H
OTBS
OPMB
Smith, A. B. et al Tetrahedron Lett. 1997, 38, 8667, 8761, 8675
Spongistatin 1
Synthetic Uses of Lithiosulfones - Coupling by alkylation of sulfones
PhSO2
OPivOTESTBSO
LiMeO
I
OBn
1. THF/HMPA
2. Na/Hg
OPivOTESTBSO
MeOOBn
Coupling using a-Lithio-sulfone Alkylation - alkyl sulfones can be reductively cleaved: Synthesis of Aplyronines: Yamada, et al. J.Org. Chem. 1996, 61, 5326
+
Synthetic Uses of Lithiosulfones - The Julia Olefin SynthesisCoupling using Julia Olefination. The original Julia reaction involved a reductive elimination of a β-acetoxy sulfone,formed by addition of a metalated sulfone to an aldehyde or ketone.
OPiv
H
O
OR'TBSO
MeO
OMe
+
PhSO2
Li
OOTES OTES OROMe
1. Rx
2. Ac2O, DMAP3. Na/Hg, HaHPO4
OPivOR'TBSO
MeO
OMe OOTES OTES OROMe
R = CH2OCH2-C6H3(OMe)2-3,4
R' = CH2OCH2-C6H4OMe-4
Aplyronines
OHO
MeO
OMe O OH O
Aplyronine AO
O
NMe2
OAc
CHON
Me
O OMe
NMe2
Synthesis of Aplyronine: Yamada, et al. J. Org. Chem. 1996, 61, 5326
PhSO2
Li
H
O+
PhSO2
OH
PhSO2
OAc
Ac2O Na / Hg
LIN
Acyl Anions
The acyl anion equivalents most widely used are:
Metalated Dithianes:
S S
R Li
O O CN
R Li
Protected Cyanohydrins
O
Li
Metalated Enol EthersSeebach, JOC 75-231 Stork, JACS 74-5272 Baldwin, JACS 74-7125
Li
O=
A Compilation of References on Formyl and Acyl Anion Synthons,Hase,T.A.; Koskimies, J.K. Aldrichim. Acta 1981, 14, 73; 1982, 15, 35.
New Formyl Anion and Cation Equivalents,Dondoni, A.; Colombo, L. Adv. Use of Synthons in Org. Chem. Vol. 1 , Jai Press, 1993.
Acylvinyl and Vinylogous Synthons.Chinchilla, R.; Najera, C. Chem. Rev. 2000, 100, 1891-928.
Metalation of Cyanohydrins: Reactions of Acyl Anion Equivalent Derived from Cyanohydrins, Protected Cyanohydrins, and α-Dialkylamino Nitriles,
Albright, J.O. Tetrahedron 1983, 39, 3207. Cyanohydrins in Nature and the Laboratory: Biology, Preparations, and Synthetic Applications,
Gregory, R. J. H. Chem. Rev. 1999, 99, 3649-82.
Metalated Dithianes: Synthetic Uses of the 1,3-Dithiane Grouping from 1977-1988,
P. C. B. Page, M. B. van Niel, J. C. Prodger Tetrahedron 1989, 45, 7643. Ketene Dithioacetals in Organic Synthesis: Recent Developments,
M. Kolb Synthesis 1990, 171. Synthesis of Heterocycles from Ketene Dithioacetals,
Yokoyama, M.; Togo, H.; Kondo, S. Sulfur Reports, 1990, 10, 23. New Synthetic Applications of the Dithioacetal Functionality,
Luh, T.Y. Acc. Chem. Res. 1991, 24, 257.The Development and Application of 1,3-Dithiane 1-Oxide Derivatives as Chiral Auxiliaries and Asymmetric BuildingBlocks for Organic Synthesis. A Review,
Allin, S. M.; Page, P. C. B.Org. Prep. Proc. Int. 1998, 30, 145-76.The Role of 1,3-Dithianes in Natural Product Synthesis,
Yus, M.; Najera, C.; Foubelo, F. Tetrahedron 2003, 59, 6147-212. Evolution of Dithiane-Based Strategies for the Construction of Architecturally Complex Natural Products,
Smith, A. B. III; Adams, C. M. Acc. Chem. Res. 2004, 37, 365.
Metalated Vinyl EthersGeneration and Reactivity of α-Metalated Vinyl Ethers.
Friesen, R. W. JCS Perk. I 2001, 1969-2001.
S S
tBuMe2Si
1. tBuLi
BnO
OTBSO
OO
O
BnO
TBSO2.
3.
TBSOO
OOHS S
Silyl Dithiane as a LynchpinSpongistatin: Smith, A. B. et al Tetrahedron Lett. 1997, 38, 8667, 8761, 8675
S Sn-BuLi; TBS-Cl
S S
RLiO
tBuMe2Si
S S
RtBuMe2SiO
Li
Spongistatin 1
HMPA
Mycoticin A: Smith, A. B. et al Org. Lett. 1999, 1, 2001.
S S
tBuMe2Si Li
BnOO
1.
2. O O
HMPA
BnO OBn
TBSOSS
OH OHSS
OTBS
59%
Mycoticin A
HMPA
Metalated Dithianes
Monicillin I: Garbachio, R. M.; Stachel, S. J.; Baeschln, D. K.; Danishefsky, S. J. J. Am. Chem. Soc. 2001, 123, 10903 01-19
O
HO
OTBDMS
Cl
OO
Li
S
S
O
HO
OTBDMS
OO
S S
O
HO
OH
OO
O
Monocillin 1
L
α/γ 6/1
Hispidospermidine: Frontier, A. J.; Raghavan, S.; Danishevsky, S. J. J. Am. Chem. Soc. 2000, 122, 6151. 00-14
H
H
SS
S S
1, nBuLi
2.
Br
SiMe3
H
SS
S S
SiMe3
CAN, acetone
H
SiMe3O
O
NaOH
O
[Dithiane alkylation]
L
N
Recutive desulfurization of DithianeOkinellin B: Schmitz, W. D.; Messerschmidt, N. B. J. Org. Chem. 1998, 63, 2058.
Li
SS OBn
t-BuLi
OOBn
O SS
W-2 RaneyNickel
OBnIBr
H
SS
OBnO
OO
OH
O
Okinellin B
Roflamycoin: Rychnovsky, S. D.; Khire, U. R.; Yang, G. J. Am. Chem. Soc. 1997, 119, 2058
Li OBn
Li
SnBu3
S
S
SnBu3
S
S
OH
OH
97-07
BnO
O
O1.
2.
SnBu3
S
S
O
OBnO
BuLi, DMPU
Br
Br
O
O S
S
O
OBnO
Br
O
O
Roflamycoin
LIN
L
Amide Metalations
NtBuO
O
Li
Beak JOC 93-1109
Ph ON
O
Gawley JOC 89-3002
NH
N
Li
Meyers TL 84-939tBuLi, THFsBuLi, TMEDA
ether
nBuLi, THF
LitBu
Synthesis of Solenopsin: Reding, Buchwald J. Org. Chem. 1998, 63, 6344.
N
OtBuO
C11H23
1. s-BuLi, TMEDA
2. Me2SO4 N
OtBuO
C11H23Me
NLi
tBuO
O
H
R
NRtBuO O
LiSolenopsin
TFA
N
H
C11H23Me
N-nitrosocompounds canalso be metalated
Metalation and Electrophilic Substitution of Amine Derivatives Adjacent to Nitrogen: α-Metallo Amine SyntheticEquivalents,
P. Beak, W. J. Zadjel, D. B. Reitz Chem. Rev. 1984, 84, 471. New Metalation and Synthetic Applications of Isonitriles,
Ito, Y. Pure & Appl. Chem. 1990, 62, 583. Metalation of Isocyanides,
Ito, Y. Synlett 1990, 245. Generation and Reactions of sp2-Carbanionic Centers in the Vicinity of Heterocyclic Nitrogen Atoms,
Rewcatle, G. W.; Katritzky, A. R. Adv. Heterocyclic Chem. 1993, 56, 157. Benzotriazole-stabilized Carbanions: Generation, Reactivity, and Synthetic Utility,
Katritzky, A. R.; Yang, Z.; Cundy, D. J. Aldrichimica Acta, 1994, 27, 31-8. The Generation and Reactions of Non-Stabilized α-Aminocarbanions,
Katritzky, A. R.; Qi, M. Tetrahedron 1998, 54, 2647-68.
SteG
Metalation α to Nitrogen
Chiral Organolithium Reagents - Asymmetric Metalation.Hoppe, Hintze, Tebben Angew. Chem. Int Ed. 1990, 29, 1422, 1424.
NO O R
OsBuLi, Sparteine
5h, -78 °C NO O R
O LiCO2
HO R
CO2H
>95% ee
The carbamate group is strongly activating - good coordination to Li The organolithium reagents are configurationally stable at -78 °C Derivatizations occur with retention of configuration, unless R = Ph.
Kerrick, Beak J. Am. Chem. Soc. 1991, 113, 9708.
N
OtBuO
sBuLi, Sparteine
Et2O, -78 °C N
OtBuO
Li
N
NH
H
HH
Sparteine This is an asymmetric deprotonation.
N
OtBuO
CH3
76% yield, 95%ee
CH3I
Chelation Control in Metalation ReactionsSlocum, D. W.; Jennings, C. A. J. Org. Chem., 1976, 41, 3653.
N
OCH3
n-BuLi
TMEDAEt2O
N
OCH3
Li
n-BuLi
Et2O
N
OCH3
Li
Mills, R. J.; Snieckus, V. Tetrahedron Lett. 1984, 25, 479, 483.ortho-Metalation of Aromatic Amides - Synthesis of ERYTHROLACCIN
NEt2
O
OMe
MeO
1. s-BuLi, TMEDA
2. Me3SiCl
NEt2
O
OMe
MeO SiMe3
1. n-BuLi
2. MeI
NEt2
O
OMe
MeO SiMe3
Me
Br2
NEt2
O
OMe
MeO Br
Me
1. n-BuLi
2. OMe
OMeH CO
O
OMe
MeO
MeO
OMe
OMe
OMe
MeO
Me O
O
OMe
OMe
ERYTHROLACCIN
1. Zn, NaOH
2. TFAA3. CrO3
84-2
CsF
RCHO
Note the use of N,N-diethyl amide, N,N-dimethyl amide is too reactive
Aromatic ortho MetalationsDirected Lithiation of Aromatic Tertiary Amides: An Evolving Synthetic Methodology for Polysubstituted Aromatics,
P. Beak and V. Snieckus Acc. Chem. Res. 1982, 15, 306. Heteroatom Directed Aromatic Lithiation,
N. S. Narasimhan, R. S. Mali Top. Curr. Chem. 1987, 138, 63. The Directed Ortho Metalation Reaction. Methodology, Applications, Synthetic Links, and a Non-aromatic Ramification,
V. Snieckus, Pure Appl. Chem. 1990, 62, 2047. Directed Ortho Metalation. Tertiary Amide and O-Carbamate Directors in Synthetic Strategies for Polysubstituted Aromatics,
Snieckus, V. Chem. Rev. 1990, 90, 879. Combined Directed Ortho Metalation-Cross Coupling Stategies. Design for Natural Product Synthesis,
Snieckus, V. Pure App. Chem. 1994, 66, 2155-8.
Ortho-Metalation Directed by α-Amino AlkoxideComins D. L.; Brown, J. D. J. Org. Chem., 1984, 49, 1078.
Cl
HO
1. LiN
N
2. n-BuLi, -78°C Cl
N
Li
O-
N
1. CH3I
2. H2O Cl
HO
CH3
NLi
(CHO)
Cl
D. L. CominsTL., 1989, 30, 4337.
NMeO (CHO)
Li
JOC, 1990, 55, 69
Metalation of Pyridines - Synthesis of CamptothecinComins, Baevsky, Hong J. Am. Chem. Soc. 1992, 114, 10971; Fand, Xie, Lowery J. Org. Chem. 1994, 59, 6142;Curran, Ko, Josien Angew. Chem., Int. Ed. Engl. 1995, 34, 2683.
N
OMe
Me3Si
1. tBuLi
2. Me2N N H
O
3. n-BuLi4. I2
N
OMe
Me3Si
H
O
I49%
N O
Et OH
O
ON
Camptothecin
N Cl
1. LDA
2. CH2ON Cl
OH PBr3
N Br
Br
A
B
C D E
N
MeO
Me3Si
1. tBuLi2. Me2N N H
O
3. n-BuLi
4. I2
N
MeO
Me3Si
N
MeO
Me3Si
Li OLi
N
NMe
N
MeO
Me3Si
OLi
N
NMe
Li
N
OMe
Me3Si
H
O
I
49%
N
MeO
Me3Si
OLi
N
NMe
I
H2O
Heteroatom Directed Aromatic Lithiation. Reactions for the Synthesis of Condensed Heterocyclic Compounds,N.S. Narasimhan, R.S. Mali, Top, Curr. Chem. 1987, 138, 63.
Directed ortho-Metalation of Pyridines,Queguiner, G.; Marsais, F.; Snieckus, V.; Epsztajn, L. Adv. Heterocycl. Chem. 1991, 52, 187.
Metalation and Metal-Assisted Bond Formation in π-Electron Deficient Heterocycles,Undheim, K.; Benneche, T. Act. Chem. Scand. 1993, 47, 102.
Syntheses of Heterocyclic Compounds Involving Aromatic Lithiation Reactions in the Key Step,Narasimhan,N. S.; Mali, R. S. Synthesis 1983, 957.
Synthesis and reactions of lithiated Isoxazoles,Iddon, B. Heterocycles 1994, 37, 1263.
Synthesis and reactions of lithiated Oxazoles,Iddon, B. Heterocycles 1994 37, 1321.
Synthesis and Reactions of Lithiated Pyrazoles,Grimmett, M. R.; Iddon, B. Heterocycles, 1994, 37, 2087.
Synthesis and Reactions of Lithiated Imidazoles,Iddon, B.; Ngochindo, R. I. Heterocycles, 1994, 38, 2487.
Synthesis and Reactions of Lithiated Isothiazoles and Thiazoles,Iddon, B. Heterocycles 1995, 41, 533.
Metalation of Diazines,Turck, A.; Plé, N.; Quéguiner, G. Heterocycles, 1994, 37, 2149.
Synthesis and Reactions of Lithiated Triazoles, Tetrazoles, Oxadiazoles, and Thiadiazoles,Grimmett, M. R.; Iddon, B. Heterocycles, 1995, 41, 1525-74.
The Directed Ortho Metalation Cross-Coupling Symbiosis in Heteroaromatic Synthesis,Green, L.; Chauder, B.; Snieckus, V. J. Heterocycl. Chem. 1999, 36, 1453-68.
Synthesis of Substituted Quinazolin-4(3H)-ones and Quinazolines via Directed Lithiation.El-Hiti, G. A. Heterocycles 2000, 53, 1839-68.
Metallation of Pyridines, Quinolines and Carbolines.Mongin, F.; Queguiner, G. Tetrahedron 2001, 57, 4059-90.
Metalation of Pyrimidines, Pyrazines, Pyridazines and Benzodiazines.Turck, A.; Ple, N.; Mongin, F.; Queguiner, G. Tetrahedron 2001, 57, 4489-505.
Ortho Metalation of Heterocycles
The Lithium-Metalloid Exchange
A number of the heavy main-group elements (I, Br, Te, Se, Sn and others) undergo transmetallation reactions. The secondrow elements Cl, S, P, Si can only be used in exceptional circumstances.
R
R'
MBu
R
R'
MBuLi + - Li+
R'
MBu
R
MBu
R-Li+
+ R'-Li
This reaction is an equilibration: the lithiumcation attacks the R group in the atecomplex which carries the most charge(i.e., the one that best stabilizes negativecharge).ate
complex
I > Te > Sn > Br > Se >> Cl, S, P, Si, Ge
The reactions of the more commonly used metalloids (I, Br, Sn, Hg) are characteristically very fast, allowing lithium reagentsto be prepared at low temperatures under mild conditions (Reich, Green, Phillips, Borst, Reich Phosphorus Sulfur 1992, 67,83).
6 7 8 9Period
-8
-6
-4
-2
0
2
4
6
8
Log
k 2 (P
h nM
+ A
rLi)
THF,
0 °
C
S Cl
SeBr
Sn
Te I
Pb
M + Li Li + Mk2
PAs
SiGe
BiSb
Ate complexes have been spectroscopically characterized asintermediates in these exchanges (Reich, Green, Phillips J. Am.Chem. Soc. 1991, 113, 1414; Reich, Gudmundsson, Dykstra J.Am. Chem. Soc. 1992, 114, 7937; Reich, Phillips J. Am. Chem.Soc. 1986,108, 2102).
I Li+- Te Li+- Se- Li+ Sn CH3CH3
CH3Li+
The Halogen-Metal Interconversion Reaction with organolithium Compounds. Jones, R. B.; Gilman, H. Org. React. 1951, 6, 339.
Aromatic Organolithium Reagents Bearing Electrophilic Groups. Preparation by Halogen-Lithium Exchange,Parham, W. E.; Bradsher, C. K. Acc. Chem. Res. 1982, 15, 300.
Synthetic Methods using α-Heterosubstituted Organometallics,A. Krief Tetrahedron 1980, 36, 2531.
The Mechanism of the Lithium Halogen Interchange Reaction - A Review of the Literature,Bailey, W.F.; Patricia, J. J. J. Organomet. Chem. 1988, 352, 1.
Selenium Stabilized Carbanions,H. J. Reich in "Organoselenium Chemistry," D. Liotta, Ed. Wiley, 1987.
Selenium-Stabilized Carbanions,Ponthieux, S.; Paulmier, C. Top. Curr. Chem. 2000, 208, 113-42.
Preparation and some Applications of Functionalized Organo-Lithium Compounds in Organic Synthesis,Barluenga, J. Pure & Appl. Chem. 1990, 62, 595.
Nucleophilic Perfluoroalkylation Using Perfluoroalkyllithiums,Uno, H.; Suzukib, H. Synlett 1993, 91-6.
Polyfluorovinyl Lithium Reagents and Their Use in Synthesis. Coe, P. L. J. Fluor. Chem. 1999, 100, 45-52.
Primary allkyl iodides usually work, but primary bromides rarely do. McGarvey J. Org. Chem. 1995, 60, 778.
BnO IO O
1. 2 tBuLi
O O
H
O2.
BnO O O
OH
O O
Synthesis of Bafilomycin: K. Toshima Tetrahedron Lett. 1996, 37, 1069.
OO
OMe
n-BuLiLi
OO
OMe
Bu3SnClBu3Sn
OO
OMe
The Li/Br exchange is slow enough that side reactions such as α- and β-metalation can compete (Meyers, J. Org.Chem. 1985, 50, 4872). This is generally not a problem with the Li/I, Li/Sn and Li/Te exchanges.
Br OEt
OEt
n-BuLi
THF
Br OEt
OEtLi
1. PhCHO
2. tBuLi
Li OEt
OEtPh OLi OPh
1. MeI
2. H+
Li/H Li/Br
The Li/I exchange is several orders of magnitude faster than the Li/Br exchange, and so ist much less susceptible to sidereactions. Selective reactions to be performed (Evans J. Am. Chem. Soc. 2000, 122, 10035).
I
OMe
Br
2 tBuLi, Et2O
-105 °C
Li
OMe
Br>20/1 selectivity infavor of Li/I exchange
I
The Li/I Exchange
Amide bases such as LDA or LiTMP are poor transmetalating reagents, and will often perform deprotonations evenwhen a halide is present (Schlosser Helv. Chim. Acta 1977, 60, 2085). In both cases below, the Li/Br exchange is fastenough that BuLi does not perform a Li/H exchange to make the more stable lithium reagent.
S
S
BrO
O n-BuLi S
S
LiO
OS
S
BrO
OLi
LiN(iPr)2
O
Br
n-BuLiLiN(iPr)2
O
Li
O
Br
Li
Takano Tetrahedron Lett. 1985, 26, 1659
tBuLi with RBr or RI isessentially irreversible -tBuX is destroyed byexcess tBuLi
Several coupling methods were tried, includingLi-sulfone and Li-dithiane. This one worked best.
Fastest of all Li/M exchanges Products are reactive alkylating agentsExpensive, usually have to prepareWorks with primary iodideUsually fails with 2° or 3° halidesExchange can be made irreversible (t-BuLi)
Often tBuLi is best transmetalating reagent
Pro Con
The Li/Br Exchange Pro ConCheapestOften commercially availableStable enough to survive reactionsBest for vinyl and aryl bromides
Fairly slowSide reactions such as α- and β-metalationProducts may be reactive alkylating agentsDoesn't work with most alkyl bromides
Pro ConModestly stable compoundsReasonable methods for preparationNot a leaving group - can have in β-positionNot much likelihood of α and β-metalationEspecially widely used for vinyllithiumsR4Sn compounds relatively inertNMR active nucleus
NeurotoxinsExpensive - must prepareContamination of products with R4Sn Cannot be made irreversibleSensitive to steric effects
The Li/Sn Exchange
D. Seyferth, S. C. Vick, J.Organomet. Chem. 1978, 144, 1.
Bu3SnSnBu3
n-BuLiBu3Sn
Li
α-Aminoalkyllithium reagents cannot usually be prepared by the metal-halogen exchange, and the Li/Sn exchange is thebest method. D. J. Peterson, J. Am. Chem. Soc. 1971, 93, 4027.
N-CH2-SnBu3
Ph
Me
n-BuLi
0oCN-CH2-Li
Ph
Meα-Alkoxy lithium reagents are also very commonly prepared by Li/Sn exchange. The α-alkoxy tin compounds are easilyprepared by reaction of R3SnLi with aldehydes or ketones, or with α-haloethers. N. Meyer, D. Seebach, Chem. Ber.1980, 113, 1290.
Bu3Sn-CH2-OH2n-BuLi
hexaneLi-CH2-OLi
PhCHOPh
OH
OH
This reagent is the syntheticequivalent of1,2-dilithioethylene.
LiLi
" "
Pro ConEasy to prepareSpecial purpose - α-lithioSe, S
Not commercially availableToo slow for general aplicationToxic
The Li/Se Exchange
TBSO
TBSO
H
SeMe
SeMe
n-BuLi
Br TBSO
TBSO
H
SeMe
Pro ConVery fastPerhaps most general of all metalloidsEven secondary systems work
Difficult to prepareNot commercially availableSomewhat air and light sensitive
The Li/Te Exchange
s-BuLi, -78°
Ph
Ph
TePh
HPh
Ph
Li
HPh
Ph
H
Lis-BuLi, -78°
Ph
Ph
H
TePh
Ph
Ph
SMe
HPh
Ph
H
SMe
Me2S2Me2S2
Tetrahedron Lett. 1987, 28, 1337. J. Lucchetti, A. Krief, Tetrahedron Lett. 1981, 22, 1623.
Reich, H. J.; Medina, M. A.; Bowe, M. D. J. Am. Chem. Soc. 1992, 114, 11003-11004.
Functionalized Organolithium Reagents Prepared by Li/M ExchangeM. P. Cooke, Jr. J. Org Chem. 1993, 58, 2910; 1984, 49, 1144.
n-BuLi
-78°C
95%I
MeO
O I
MeO
O
B. M. Trost, S. R. Pulley, J. Am. Chem. Soc. 1995, 117, 10143 (Pancristitatin synthesis)
In Situ trapping of ArLi Reagents - Mesityllithium as Transmetallating agentKondo Org. Lett. 2001, 3, 13
O O
LiBuLi, -100 °C
Taxol Synthesis: G. Stork et al J. Am. Chem. Soc. 1998, 120, 1337
O O
Me3Sn H
TBSO
TBSO
O
O OOH
TBSO
TBSO
Taxol (partial)
N
I
O
O
O
Li
N
O
O
HO
OMe OMe
In situ Trapping of an Isocyanate
Flann, Overman J. Am. Chem. Soc. 1987, 109, 6115.
N
EtO2C OMe
CO2Et
OMe
Br
H
s-BuLi
THF, -78°CN
EtO2CH
O
OMe
OMe
NH
OH
H
OO
Streptazolin
O
O
MeO
O
O
OTES
TESO
N
OCBr
2 tBuLi, Et2O,
-78 °C O
O
MeO
O
O
OTES
TESO
N
O
H
Use of 2 equiv. of t-BuLi in themetal-halogen exchange results inan essentially irreversible process(t-BuLi + t-BuBr → t-BuH + Me2C=CH2)
Vinyllithium Reagents from TosylhydrazonesChamberlin, A. R.; Stemke, J. E.; Bond, F. T. JOC, 1979, 43, 147. This is a modification of the Shapiroolefin synthesis to allow efficient trapping of the organolithium intermediates. Tosylhydrazones and theirdecomposition products (p-toluenesulfinates) can behave as proton sources. The solution is to use2,4,6-triisopropylphenylsulfonylhydrazones (trisyl hydrazones).
NN
H
SO O
2 n-BuLiN
N
Li
SO O
Li Δ Li+ S
O
LiO+ N2
C6H13
O Li
C6H13
O Li
O Li
+
Li
9:1
Barrett, A. G. M.; Adlington, R. M. Chem. Comm., 1979, 1122; Acc. Chem. Res. 1983, 16, 55
NN
Li
SO2ArLi
O
OLi NN
Li
SO2Ar
1. n-BuLi, -3 °C2. CO2
3. H3O+O
O
Δ
550° O
O83%61%
Martin, S. F. J. Org. Chem., 1992, 57, 2523.
NNHSO2Ar
1. 2 n-BuLi
2.H
O
OTBS
OTBS
OH
O Li
Vinyllithium Reagents from Tosylhydrazones
Ar
The Bamford-Stevens and Shapiro Reactions
NN
H
SO O
Ar NaHN
N
Na
SO O
Ar Δ : Carbeneproducts
2 BuLi
NN
Li
SO O
Li Ar Δ Li [H+] H
Bamford-Stevens
Shapiro
-65 °C
-ArSO2Na-N2
Chem 547Reich
NN
Li
N
N+
LiLiO
Stable at -65 °C
Ar =
Lithioalkenes from Arylsulphonylhydrazones,Chamberlin, A. R.; Bloom, S. H. Org. React. 1990, 39, 1.
Recent Applications of the Shapiro Reaction,A. G. M. Barrett, Acc. Chem. Res. 1983, 16, 55.
Pros and cons of Using non-Alkali Metal Organometallic Reagents
AdvantagesPrepare and use functionalized reagents
Less basic reaction conditions
Wider range of solvents may be used (even protic)
Presence of β-leaving groups may be tolerated
Better stereochemical and regiochemical control
Different reactivity patterns
Chiral reagents easier to work with
Compatibilty with electrophilic catalysts
In situ reactions (Barbier processes)
Wider range of synthetic methods to prepare R-M
DisadvantagesUsually much more expensive (R-Li → R-M)
Some elements are quite toxic, disposal problems
Separation from the M-debris can be problematic
Usually much less reactive than RLi or RMgX
Narrower range of R groups are nucleophilic
Some Things We Would Like to be Able to do with Carbon Nucleophiles
1. Functionalized Reagents:E
M XM
Intramolecular β-Leavinggroups
M
O
Acyl Anion
M
O
Homoenolate
2. Control Allylic and Propargylic Regioselectivity in Donor and Acceptor.
-M+
E+
Eor
E
O R-M+ ORor
ROH
3. Control Diastereoselectivity in Donor and Acceptor.
OR-M+
OH
R or
R
OH
4. Control Enantioselectivity in Donor and Acceptor.
R H
O
+R
OH
or R
OH
PhR-M+
Ph
HO Ror
Ph
R OH
+ M R
X
HO
R
X
HO
R
X
or
5. Control Side Reactions.•Enolization vs. nucleophilic addition.•Substitution vs. elimination.•Selectivity among functional groups.
M
O
O
( )n
Ph
R-M+
Ph
RHN Ror
Ph
R NHRNR
"Softer" Organometallic Reagents
*
Boron in Organic Synthesis
Chem Reic
E
O1. BPhSe
2. RCHO
R
OH
PhSe
H2O2 R
OH
RB
RH B H
R
RR-
R
B-Y-X
B YR-
X
BY
R Y = O, N, S, C, etc.X = leaving group
B YR
BY
R+
BR - E+
BR-
E+ B
R
E
E+ = H+, PhSe+, R3Sn+, epoxide, carbonyl
BO O
B
1. Lewis Acidic Oxophilic Metal. Many boron reagents provide for simultaneous activation of acceptor and donorportions of substrate, e.g., in conjugate addition reactions:
2. Boron hydrides can serve as both electrophilic and nucleophilic H- donor. Borohydrides have powerful nucleophilicproperties, boranes are weak electrophiles.
3. Carbanion donor: Enol, allyl and propargyl boranes will transfer the group on boron to suitable electrophiles. Othertypes show little tendency to behave as carbanion sources.
-
O O
5. Organic groups on anionic boron readily migrate to electrophilic sites on adjacent atoms:
Essential Chemical Properties of Organoboron Compounds
4. Transmetalation of organoboron compounds to organocopper and organopalladium (Suzuki coupling) provides apowerful method for C-C bond formation (Miyaura, N.; Suzuki, A. Chem. Rev., 1995, 95, 2457).
OR'
R'O
Br
Pd(PPh3)4
R2B C5H11
OR'
R'O
C5H11
O
BO
O
OB
Organoborates in New Synthetic Reactions,Suzuki, A. Acc. Chem. Res. 1982, 15, 178; Top. in Current Chem. 1983, 112.
Carbon-Carbon Formation Involving Boron Reagents,A. Pelter Chem. Soc. Rev. 1982, 11, 191.
Formation of Carbon-Carbon and Carbon-Heteroatom Bonds via Organoboranes and Organoborates,E.-I. Negishi, M. J. Idacavage Org. React. 1985, 33, 1.
Organoboron Compounds in Organic Synthesis,R. M. Mikhailov, Harwood Academic, 1984.
Reactions of Group 13 Alkyls with Dioxygen and Elemental Chalcogens: from Carelessness to Chemistry,Barron, A. R. Chem. Soc. Rev. 1993, 22, 93.
Stereodirected Synthesis with Organoboranes,Trost, B.M. Ed., Springer: Berlin, Germany, 1995.
Contemporary Boron Chemistry,Davidson, M.; Hughes, A. K.; Marder, T. B.; Wade, K. Royal Society of Chemistry: Cambridge, U.K., 2000.
Rhodium-Catalyzed Asymmetric 1,4-Addition of Organoboronic Acids and Their Derivatives to Electron Deficient Olefins.Hayashi, T. Synlett 2001, 879-87.
"Organoboranes as a Source of Radicals."Ollivier, C.; Renaud, P. Chem. Rev. 2001, 101, 3415-34.
Pure Enantiomers via Chiral Organoboranes,H. C. Brown, B. Singram Accounts Chem. Res. 1988, 21, 287.
Boronic Esters in Stereodirected Synthesis,D. S. Matteson Tetrahedron 1989, 45, 1859.
Recent Advances in Asymmetric Synthesis with Boronic Esters,Matteson, D. S. Pure & Appl. Chem. 1991, 63, 339.
Stereodirected Synthesis with Organoboranes,D. S. Matteson, Springer, 1995.
Asymmetric Syntheses via Chiral Organoboranes Based on α-Pinene,by Brown, H.C. Adv. in Asymm. Synth. Vol. 1, Hassner, A., Ed. JAI: Greenwich, CT, 1995.
α-Halo Boronic Esters in Asymmetric Synthesis,Matteson, D. S. Tetrahedron 1998, 54, 10555-607.
Vinyl Boranes: Synthetic Applications of Vinylic Organoboranes,
H. C. Brown and J. B. Campbell, Jr. Aldrichim. Acta 1981, 14, 3. Haloboration of 1-Alkynes and Its Synthetic Application [Vinyl Boranes],
Suzuki, A. Rev. Heteroatom Chem. 1997, 17, 271-314.
Recent Developments in the Chemistry of Amine- and Phosphine-Boranes,Carboni, B.; Monnier, L. Tetrahedron 1999, 55, 1197-248.
Useful Synthetic Transformations Via Organoboranes. 1. Amination Reactions,Carboni, B.; Vaultier, M. Bull. Soc. Chim. Fr. 1995, 132, 1003-8.
Organoboron Reviews
R
B-Y-X
B YR
RR X
BY
R Y = O, N, S, C, etc.X = leaving group
-
Migration of Groups from Boron to Carbon - α Leaving Groups
R
B BR
RR
-
R R
-O-OHO
OH
BR
RO
R
Oxidation of Boranes
Reaction with α-X Organolithium Reagents. Hoffman, Stiasny Tetrahedron Lett. 1995, 36, 4595.
Br
BrTBSOn-BuLi
-110 °CLi
BrTBSO
3:1 dr
BO
OBrTBSO
OOB-
TBSOTBSO OHMe3N
+-O
-O O
B-
Serricornin - Boronic Ester HomologationMatteson, D. S.; Singh, R. P. J. Org. Chem. 1998, 63, 4467
• The process is repeatable, adding one chiral center at a time.
• The diastereoselectivity is very high.
BO
OLiCHCl2ZnCl2
Cl
B
O
OCy
Cy
LiCH2Cl
BO
O
Cy
Cy
1. LiCHCl22. MeMgCl
98-04
MgBr
BO
O
Cy
Cy B
O
OCy
Cy
1. LiCHCl2
2. EtMgCl
BOO
Cy Cy
1. H2O2
2. OsO4, NaIO4
O OH
Serricornin
BO
O Cy
CyH
ClCl-
BO
O Cy
CyMe H
MeCl
BO
O Cy
CyMe
ClH
Allyl-Metal Species
Ionic, contact or separated ion pairs:
M+
Li, Na, K
Covalent, but rapidly equilibrating: Mg, Al, Zn, Hg, B, Ti, Cr
M M ΔG = 10 - 25 kcal/mole
Covalent, slow equilibration: Sn, Ge, Si
M M ΔG > 25 kcal/mole
The reactivity decreases as C M bond becomes more covalent.
Lithium reagents are aggressive nucleophiles, react with weak electrophiles such as alkyl halides.Grignard reagents react well with carbonyl compounds.Allyl silanes react only with good electrophiles such as carbonium ions or halogens.
Allylic rearrangement also causes cis-trans isomerization of double bonds.
Lewis-Acidic metals (Mg, B) usually react by a cyclic "Zimmerman-Traxler" type of transition state.
If covalently bound, the stable structure has the metal on the less-substituted side of the allyl system.For such systems, reactions usually occur at the site remote from the metal (SE2').
For extensive comparative studies of crotyl-M species see:Yamamoto, J. Orgmet Chem., 1985, 284, C45.Martin, J. Org. Chem., 1989, 54, 6129.
Allyl-Metal Species: Reactivity
Transition metal π-complexes Pd, Pt, Ni, Co, Mo
M(L)n
Transition metal allyl π-complexes can show either nucleophilic or electrophilic reactivity,depending on the metal and ligands.
E / Z Isomerization rate
Slow
Fast
Slow
Depends on rate ofσ-allyl to π-allylinterconversion
Some Uses of Allyl Adducts
O
+
MR
R
OH
R
OH
R
OH
R
OH
OH
H
OEquivalent of aldolcondensation
Stereocontrol for netaddition of sec-alkyl
Functionalizedsec-alkyl
Structure Metals
MM
[O]
[H2]
M(L)n
1. H-BR'22. [O]
Structure and Dynamics
Reactivity towards (MeC6H4)2C +
Hin acetonitrile at 20 °C
1
2
3
4
5
6
7
8
9
10
11
log
k
RS-, X-
OSiMe3
8.3 OMe
8.8
7.7EtOH
6.6 H2O
6.1
10.3
SiCl3
SnBu3
8.3 OEt
7.6OMe
6.8 OEtSnPh3
SiMe36.3
SiMe3
OSiMe3 OMe
2.7 : 1
OSiMe3 OEt
1 : 0.19
BuSiMe3
1 : 7216
SiMe3 OEt
1 : 15
O O
1 : 4.8
SiMe3 SiMe3
1 : 37
Bartl, Steenken. Mayr, J. Am. Chem. Soc. 1991, 113, 7710; Mayr. Kempf, Ofial Acc. Chem. Res. 2003, 36, 66Reactivity of π-Nucleophiles with Carbenium ions
hνH+
SiMe3
HCl
H
Reactions of Allylsilanes with ElectrophilesFleming, I.; Langley, J. A. J. Chem. Soc. Perk. Trans 1, 1981, 26, 1421.
Me3Si SiMe2Ph
Me3Si SiMe2Ph
H+ Me3Si SiMe2Ph
H
+
SiMe2Ph
Me3Si
41
Both starting allyl silanes give the same product ratio.
Allyl Silanes
G.Majetich, C.Ringold, Heterocycles, 1987, 25, 271.
PERFORENONE
Aratani, M. Tetrahedron Lett., 1982, 23, 3921.
N
Cl
OCO2PNB
O
CO2CH3
SiR3
CO2PNB
AgBF4 N
OCO2PNB
O
CH3O2C
CO2PNB
69%
Overman, L. E. JACS, 1991, 113, 5378.
1. (Siamyl)2BH
2. LiTMPR2B
Li
1. Me3SiCl
2. HOAcSiMe3
O
O
O
CHOH
H
HSiMe3
BF3 OEt2
O
O
O
HH
H
OHCram
73%
EtAlCl2
94%O O
SiMe3
O
Epoxide Cyclization of Allyl Silane - Phorbol SynthesisPettersson, Frejd Chem. Commun. 1993, 1823.
O
O
TBSO
SiMe3
OMe3SiO
BF3 OEt2 O
O
TBSO
Me3SiO OH
Phorbol
H
Schmidt, R.; Huesmann, P. L.; Johnson, W. S. J. Am. Chem. Soc. 1980, 102, 5122.
EtO
EtO Cl
Li H EtO
EtO
1. NaNH2
2. Me3SiCH2Cl EtO
EtO
SiMe3
1. HCl, H2O
2. CH=C(CH3)MgBr
HO
SiMe3
CH3-C(OEt)3
EtCO2H, 130 °C SiMe3
EtO O
1. LiAlH4
2. CrO3
SiMe3
H O
PPh3HO O
OO
SiMe3
O O
OO
1.
2. PhLi
1. HCl, H2O2. NaOH3. MeLi
SiMe3
OH
CF3CO2H H
H
H
58%
1. O3; Zn
2. NaOH
O
H
H
H
O
4-Androstene-3,17-dione
80-7
+
SiMe3SiMe3
+
Synthesis of Steroids by Propargylsilane Cationic Cyclization
Akuammicine Synthesis by Propargylsilane CyclizationBonjoch, Sole, Garcia-Rubio, Bosch J. Am. Chem. Soc. 1997, 119, 7230
N SiMe3
O
ArBF3 OEt3
1. LDA; N≡CCO2Me
2. H2, PdN
H CO2Me
Akuammicine
Ar = o-NO2C6H4O
ArN N
Efficient termination ofcationic cyclization
[Wittig - trans]
[Claisen - Johnsom]
Stereochemistry of Allyl-M Carbonyl Reactions
B O R
H
H
Me
R H
O
H Me
SnBu3
Acyclic - Metal is not coordinated to carbonyl group. Configuration of product is more or less independent ofdouble bond configuration. Reaction may be highlyStereoselective.
Cyclic - Metal is coordinated to carbonyl group.Configuration of product is determined byconfiguration of double bond. Reaction isStereospecific.
Y. Yamamoto, JOMC 1985, 284,C45Martin, JOC, 1989, 54, 6129Roush, JOC, 1990, 55, 4109.
Stereochemistry of Crotyl Stannane Addition to AldehydesYamamoto, Yatagai, Naruta, Maruyama J. Am. Chem. Soc., 1980, 102, 7109.Keck, Savin, Cressman, Abbott J. Org. Chem. 1994, 59, 7889.
SnBu3 + RH
O BF3 OEt2
CH2Cl2 R
OH
+ R
OH
syn : anti
SnBu3
SnBu3 R = Ph 42.8 : 1R = cHex
R = Ph
Yamamoto explanation: antiperiplanar transition state.Focus on interaction between R and CH3 groups(place these anti to each other)
H CH3
SnBu3
R H
O
H CH3R H
O
syn
(85%)(88%)
(80%)(82%)
BF3
+BF3
Keck explanation: Synclinal transition states.Focus on interactions between the BF3 group and theallyl stannane, as well as on secondary orbital interactions which favor synclinal transition states.
H CH3R
H
OF3B
+
SnBu3
H CH3R
H
OF3B
E
Z
E : Z
90 : 1090 : 10
12 : 88R = cHex 12 : 88
14.9 : 1
4.2 : 11.41 : 1
syn
Stereochemistry of the Allyl Tin Reaction with Aldehydes - Intramolecular Case.Denmark, S. E.; Weber, E. J. J. Am. Chem. Soc. 1984, 106, 7970.
OHC
SnBu3
H OH
+
HO H
Et2O BF3 87 : 13CF3CO2H 99 : 1
O
HH
SnBu3 O H
H
SnBu3
Keck, JOC, 1994, 59, 7889.
AVERMECTIN A1a
Danishefsky, S.J.; et. al. J. Am. Chem. Soc., 1989, 111, 2967.
O
O
O
t-Bu
Ot-Bu
O
Ot-Bu
O
H
Ph3Si
CH3
BF3.Et2O
O
PvO
PvOH H
Me Me2CuLi
O
PvOH H
Me
Me
HOMe O
OMe
OMe O
OMe
O O
OO
O
HO
HMe
Me
OH
Me
Me
Me
OMe
HMe
O H
H
Me
H
SiPh3
cis-silane3/1 to 5/1
O HH Me
H
SiPh3trans-silane
1/3
Synthesis of Avermectin
Reaction is stereospecific, to some extent.
Allyl Borane Equilibration: The Curtin-Hammett PrincipleWang, Gu, Liu J. Am. Chem. Soc. 1990, 112, 4425.
Me3Si B
Me3Si
B
Me3Si
B
THF 25% 75% <2%All reactions occur from
this isomer.
OR
H
Me
Me3Si H
Me
B OR
H
Me
Me3Si Me
H
B
R
R
A B
A; NaOH 94 1 4 1
A; H2SO4 1 90 3 6
B; NaOH 0 0 98 2
B; H2SO4 0 0 8 92
R = n-C5H11
In the Peterson Olefination, treatment of the β-hydroxy silane with NaOH gives a syn elimination, whereas H2SO4 givesan anti elimination.
Interconversion among the isomers is faster than reaction of the major isomer with the aldehyde.
OR
H
Me
Me3Si Me
H
B
R
R
H2SO4Me
Crotyl Borane Addition to Aldehydes - Zimmerman-Traxler Type Transition StatesHoffmann, R. W. Ang. Chem. Int. Ed., 1982, 21, 255.
KCl-B(NMe2)2
B(NMe2)2HO
HO
B
O
O
O R
H
Me
HB
O
OO R
H
Me
HB
O
OR
OH
Me
R
OH
Me
+
syn (erythro)cis-Olefin syn (erythro)
trans-Olefin anti (threo) syn/anti = 97/3
Electrophilic Allylboranes will even add to Olefins.Singleton Org. Lett. 1999, 1, 485.
BBr2
BBr2
1.
2. NaOH, H2O2
OH
90%
Sn( )4
BBr3
0 °C, hexaneTo get high yields olefin needs to be somewhat activated -norbornene, styrene, 1,1-dialkylethylenes, cyclohexadiene andcyclopentadiene all work. 1-Nonene gives only 33% yield.
NaOH
Chiral Allyl and Crotylboronate Reagents
Synthesis of Rutamycin B: White et al. J. Org. Chem. 2001, 66, 5217
TBDPSO H
O
+ BO
OCO2iPr
CO2iPr
RO
OH9 : 1
80% dsmatched
RO
TBSO
H
O
BO
OCO2iPr
CO2iPr
+ RO
TBSO OH>98 : 2
>96% dsmatched
Allylborane - stereoselectivity poorer than for crotylboranes: Smith, A. B. et al Tetrahedron Lett. 1997, 38, 8667, 8761, 8675
BPSOCHO 1. Ipc2B-Allyl
2. NaOH, H2O2
BPSO
OH
92/8 er Ipc2B-Allyl
B)2
Crotylboronates
Crotylboronates
Roush, W. R.; Palkowitz, A. D. J. Am. Chem. Soc., 1987, 109, 953; 1990, 112, 6339.
TBDPSO H
O
+B
O
OCO2iPr
CO2iPr
RO
OH
1. Et3SiCl, Et3N, DMF2. O3, MeOH; Me2S
RO
Et3SiO
+B
O
OCO2iPr
CO2iPr
RO
Et3SiO OH
88% dsmismatched
H
O
98% dsmatched
-78 °C
75%
O O
OMe
OMeAcO
H
O+
BO
OCO2iPr
CO2iPr
O O
OMe
OMeAcOHO
91% ds
C-19 to C29 of Rifamycin S
BO
OCO2iPr
CO2iPrH
R O
BO
OCO2iPr
CO2iPr
H
R O
Transition state model
Allenylboronic Ester: Synthesis of (-)-IpsenolN. Ikeda, A. Arai, H. Yamamoto, J. Am. Chem. Soc., 1986, 108, 483.
Br
1. Mg(Hg)
2. B(OMe)3
3. H2O
B(OH)2
HO
HO
CO2R
CO2R
OB
O CO2R
CO2R
CHO
HO78%, >99% ee
1. 9-BBN-Br
2. HOAc3. H2O2, NaOH4. DHP,H+
THPO Br
CH2=CHBr
Pd(PPh3)4HO
(-)-Ipsenol H+, MeOH
86-2
Allenyl and Propargyl BoranesCorey, Yu, Lee J. Am. Chem. Soc. 1990, 112, 878.
N N SO2TolTolSO2 B
Br
PhPh
SnBu3
H
N N SO2TolTolSO2 B
PhPhPh
CHOPh
H
OH>99% ee, 74%
N N SO2TolTolSO2 B
PhPh
H
SnPh3
PhCHO Ph
OH98% ee, 79%
Trost, Doherty J. Am. Chem. Soc. 2000, 122, 3801.
HO
N N SO2TolTolSO2 B
PhPh
H
+
HO
Roseophilin
-78 °C, 2.5 h
-78 °C, 2.5 h
23 °C
23 °C
MgBr
1. Bu3SnCl2. Reflux, MeOH
SnBu3
H
78%
Ph3SnCl, Et2OSnPh3
71%
SO2TolTolSO2
PhPh
H HNN
BBr3 N N SO2TolTolSO2 B
Br
PhPhH
MgBr
H
"propargylmagnesium bromide"
NB
N
SO2Tol
SO2
O
HR
Allenyl Borane
Allenyl StannanesRousch, et al. J. Am. Chem. Soc. 2002, 124, 6981
BifilomycinH
OTESO OTBS
BuSnCl3, -40 °C
TESO OTBS OHBu3Sn
SiMe3
OMe
OMe
SiMe3
5 equiv.
20:1 ds (4:1 with 1.2 equiv)85% Kineticresolution
Stereochemistry of the Allyl FragmentHayashi, Konishi, Ito, Kumada, J. Am. Chem. Soc. 1982, 104, 4662, 4963.
Br + Me3Si MgBr
Ph
Cat* Pd PhSiMe3
H
85% ee
O
O O TiCl4
PhCH3
HHO
86% ee
Me3CCl, TiCl4
Pht-BuCH3
H 87% ee
CH3CO
Cl, AlCl3
PhCH3
H 53% ee
O
CH3H
Ph
SiMe3
E+
Me3CCOH, TiCl4 Pht-Bu
OH
99/1 syn
O
CH3
H
H
R
Ph
HSiMe3
Buckle, Fleming, Tetrahedron Lett. 1993, 34, 2383.
Me
Me3SiHMe
Cl
TiCl4, -78°+
CH3H
99:1
Product ofanti addition
Me
Me3SiHMe
+ H
O
TiCl4, -78°
OH
+
OH95:5
98% ee
89%
30%
Stereochemistry of the Allenyl Fragment
Me
Me3SiHMe
OiPrH TiCln
CH3H
OHHiPr
Chelation and Felkin-Anh Controlled Additions of Allyl Stannanes to AldehydesKeck, Boden, Tetrahedron Lett. 1984, 25, 265.
OBn
H
O
SnBu3
MgBr2, CH2Cl2-23 °C
OBn
OH
OBn
OH+
85% >250:1
OSiMe2tBu
H
O
SnBu3
2 BF3 OEt2CH2Cl2, -78 °C
OSiMe2tBu
OH
OSiMe2tBu
OH+
83%5:95
H
OBn
H
O
attack
MgBr2
threo
Chelation control Felkin-Anh control (Cram)
H H
O
attackOSiMe2tBu erythro
threo (syn) erythro (anti)
BF3 should not beable to chelate -monodentate Lewisacid
BF3+