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Electrophilic CarbenesThe reaction of so-called stabilized diazo compounds with late transition metals produces a metal carbene intermediate that is electrophilic. The most common catalysts are Cu(I) triflate and Rh(II) aceate and related complexes. Others include Pd(II) salts and Rh6(CO)16. These intermediates engage in very rich chemistry, often as part of cascade processes.
N2
R1 EWG + LnM
– N2 MLn
R1 EWG
no change inoxidation state
R2
R2
EWGR1
R C RO
MLn
R1 EWGO
R1 EWG
R
R
RZ HZ = C, O, N, S, Si
R1 EWG
H ZR
cyclopropanation
carbonylylide
formation
insertionreactions
O
N2
R
R
+ LnM
– N2
O
MLn
R
R
OR
MLn
R
a new carbene forfurther reactions
This resonance structureshows why these carbenesare electrophilic
Diazo FormationWhile diazo alkanes are normally reactive and unstable, those that are conjugated to electron-withdrawing groups (typically carbonyls) are often quite stable. Several methods available for their production.
Diazo transfer reactions
EWGEWG
EWG = ketone, nitro ester, amide
RSO2N3
Et3N
sulfonyl azide
EWGEWG
N2 N2
Me
O
OR
O
N2
OR
OK2CO3
MeOH
R1
OR2
LHMDS, THFCF3CO2CH2CF3
–78 ºC R1
O
R2
CF3
O MsN3, Et3N
H2O, CH3CN R1
OR2
N2J. Org. Chem. 1990, 55, 1959.
R Cl
O CH2N2
CaO R
ON2
R OH
Oa. EtO2CCl, Et3N
b. CH2N2
CyclopropanationIf formed in the presence of an olefin, the carbene can form cyclopropanes. Both inter- and intramolecular reactions are possible. Because the carbenes are electrophilic, the react much faster with electron-rich olefins.
X N2 CO2Et+catalyst
X
CO2Et
X = CH2Br, CH2Cl, OPh, Bu, OAc, OEt, OBu, i-Pr, t-Bu, CH2=CPh, CH2=CMe, CH2=Ct-Bu, CH=CHOMe, CH=CHCl, CH=CHPh, CH=CHMecatalyst = Rh2(OAc)4, CuCl–P(Oi-Pr)3, Rh6(CO)16, PdCl2(PhCN)2
Order of reactivity: electron-rich > "neutral" >> electron poor β-substitution on olefin slows reactivity & cis > trans
Alkene geometry is maintained, but little stereoselectivity for diazo-bearing carbon
Other reactive groups: dienes, alkynes, aromatic rings, and heteroaromatic rings
Asymmetric reactions are possible with chiral ligands on Rh and Cu catalysts.
Intramolecular reactions usually prefer to form 5-membered rings. With polyenes, the regioselectivity is usually good, but can depend on catalyst choice.
Cyclopropanation
N2
O
TBDPSO
Me
CO2Et
O
TBDPSOMe
CO2Et
1% Rh2(Oct)4
CH2Cl2, rt70%
J. Org. Chem. 1997, 62, 194.
O
Ph
OK2CO3Bu4NBr
BrCH2CH=CHR
PhCH3, 40 ºC82%
O
Ph
O
R
pNBSA, DBU
CH2Cl2, 0 ºC83%
O
N2
R
a. KHMDS, THF RCHO, LiBr –78 ºC
b. TBDPSCl DMAP, imidazole 38%
83:17 dr
thiophenolBF3•OEt2
CH2Cl2–78 ºC
90%, 10:1 dr
O
TBDPSOH
CO2Et
SPhH
Cyclopropanation
Me
Me MeMe
O
N2
Me
Me Me
Me
Ph
O
Me
CuSO4
cyclohexane, Δ52% (from acid)
J. Chem. Soc., Perkin Trans 1 2000, 2583
O
Me
O
N2
Rh2[5(S)-MEPY]4
CH2Cl2, 80%, 92% eeO
O
Me
H
HJ. Am. Chem. Soc. 2001, 123 ,12432.
NRh
O
Rh
MeO2C4
Rh2[5(S)-MEPY]4
Me
Me MeMe
OH a. CH3C(OEt)3 EtCO2H, Δ 65%
b. aq. NaOH 90%
Me
Me MeMe
OH
O
a. (COCl)2
b. CH2CHN2
Li
NH381%
Me Me
Me
Ph
O
Me
CyclopropanationWith appropriate substitution patterns, cascade reactions are possible
O
Me
N2
MeO2C
OTBS+ Rh2(OAc)4
CH2Cl2, Δ94%
OMe
MeO2C
OTBS
J. Org. Chem. 1991, 56, 723.
O
TBDPSO
CO2MeMe
O
N2
Rh2(OAc)4
CH2Cl250%
Me
CHOTBDPSO
CO2Me
O
Org. Lett. 2003, 5, 4113.
MeO2C
H
HMe
OTBSO
H H
N Me
Boc
OTBSCO2Me
N2
+1% Rh2(S-PTAD)4
2,2-dimethylbutane50 ºC
69%, 96% ee
NBoc
CO2Me
OTBSMe
J. Am. Chem. Soc. 2007, 129, 10312.
Ylide FormationThe electrophilic nature of the carbenes means they are also capable of reacting with Lewis basic groups such as carbonyls, ethers, and sulfides. This will form an ylide structure. If appropriate functionality is present, other reactions will take place (cycloadditions, rearrangements). Intramolecular formation of ylides are most common.
N2
EWG
Xcat.
X
EWG
ylide
OTBDPSO O
[2,3]-rearrangements
Cu(acac)2
THF, Δ75%
OO
OTBDPS
Me
oxonium ylide
O
O
OTBDPSHH
Me
Org. Lett. 2004, 6, 1773.N2
Me
>95:5
O
O
H
TBDPSO
Me
H δ+
δ–
S
Ylide Formation
Stevens-type rearrangement
N
O
SPh
CO2EtN2
Rh2(OAc)4
C6H6, Δ55%
Chem. Commun. 1986, 651.
N
O
SPh
CO2Et
N
O
PhS CO2Et
O
MeOO
CO2Me
N2SPh
Rh2(OAc)4
C6H6, Δ77%
O
MeOH
OSPh
CO2Me
J. Chem. Soc., Perkin Trans. 1 1995, 2989.
H
O
MeO2C
Ph
R
OH
racemic
Ph CO2Me
N2+
1% Rh2(S-DOSP)4
pentane, 0 ºC50–70% yield92–98% ee
Ph CO2Me
HOR
J. Am. Chem. Soc. 2010, 132, 396.
Ylide Formation
Rh2(OAc)4
PhCF3, 100 ºC73%
Angew. Chem. Int. Ed. 2006, 45, 6532.
O
N2 O
O
OTBDPS
OPMP
t-BuO2COTBDPS
N2 O
O
TMSO CO2t-Bu
OMOM Rh2(OAc)4
C6H6, Δ72%
O+
Angew. Chem. Int. Ed. 2003, 42, 5351.
Dipolar Cycloadditions – Addition of carbonyls will for a carbonyl ylide. These are 1,3-dipoles that can undergo cycloaddition reactions with electron deficient olefins/alkynes.
N
O
O
NMe Et
ON2
CO2Et
Rh2(OAc)4
C6H6, 50 ºC95%
N
NMe
OEt
CO2Et
O
O
H
J. Org. Chem. 1998, 63, 556.
onediastereomer
O
O
H
H
O
OPMP
OTBDPS
OO
OTMSt-BuO2C
t-BuO2C
OTBDPS
OMOMAc
Insertion Reactions
Rh(II) catalysts promote the insertion of diazoalkanes into C–H, O–H, N–H, S–H, and Si–H bonds. Likely involves a three-center transition state. Chiral ligands can be used for enantioselective reactions. Intramolecular reactions generally favor 5-membered ring formation. Fluorinated carboxylate ligands on the metal promote insertion into aromatic C–H bonds.
General order of reactivity for C–H bonds: 2º > 1º ≈ 3º, but is catalyst dependent
Electron-withdawing groups deactivate C–H bonds, electron-donating groups activate
C H
R
RR
MLn
C
EWG
+ C
R
RR
C
MLn
EWG
H
C
R
RR
C
H
EWG
Proposed transition state: J. Am. Chem. Soc. 1993, 115, 958.
This mechanism implies that the insertion reaction is stereospecific
MeO N
Ph
O
N2 CO2Et
MeO N
Ph
OTIPS
CO2EtRh2(NHCOC3F7)4CH2Cl2, rt
then Et3N, TIPSOTf91%
With Rh2(OAc)4a mixture was obtained
with benxylix C–H insertion.
Insertion Reactions
O O
N2
n
Rh2(4(S)-MACIM)4
cis:trans = 99:196–97% ee n
OO
62–75%
N
NO
AcCO2Me
4(S)-MACIM
J. Am. Chem. Soc. 1994, 116, 450.
P(O)(OMe)2
N2
Rh2(S-PTAD)4
2,2-di-Me-butane, Δ83%, 92% ee
+
P(O)(OMe)2Ph
Org. Lett. 2006, 8, 3437.
5 equiv
CO2Me
N2+Rh2(S-DOSP)4
2,2-di-Me-butane50 ºC
56%, 94% ee
MeOBr
CO2Me
MeO BrJ. Org. Chem. 2002, 67, 4165.
Insertion ReactionsN–H insertions
O–H insertions
Si–H insertions
CO2Me
N2
Z/E = 96:4CO2Me
PhMe2Si
Z/E = 95:5
Rh2(OAc)4PhMe2SiH
CH2Cl2, rt75%
Tetrahedron Lett. 1994, 35, 9549.
O
H
O Me
OH
1. Rh2(OAc)4 C6H6, 80 ºC 96%
2. H2CrO4 Et2O, rt
EtO2CP(O)(OEt)2
OH
H
OH Me
OHH
Tetrahedron Lett. 1995, 36, 8347.
O
H
MeH
NaH
THF, rt86%
(2 steps)
OCO2Et
NHO
CO2HO
MeHH
O
N2
NO
HOHH
O
Me
CO2
Rh2(Oct)4
EtOAc/hexaneΔ
J. Org. Chem. 1991, 56, 3183.
Metathesis with Alkynes
MeO
N2
Me
Rh2(OAc)4
CH2Cl2, rt95%
O
Me
MeTetrahedron Lett. 1991, 32, 4103.
Once formed, Rh carbenoids can undergo "metathesis"-type chemistry with alkynes. This generates a new Rh carbene that can undergo other processes, such as those we have already discussed.
MeO
N2
Rh2(OAc)4
CH2Cl2, rt97%
OMe
O
O
Tetrahedron Lett. 1993, 34, 7853.
RhLn
O
R
RhLn
R
O
R
O
RhLn
Nitrenoid IntermediatesMuch like metal-catalzyed decomposition of diazo compounds produces carbenoid intermediates, it is also possible to generate nitrenoid intermediates. This typically involves the in situ oxidation of a non-basic primary nitrogen atom (sulfonamide, amide, carbamate, urea, etc.).
CO2t-BuO
H2NO
5% Rh2(OAc)4PhI(OAc)2, MgO
CH2Cl2, 40 ºC82%
OHN
O
CO2t-Bu
MeMe
O NH2
O
5% Rh2(OAc)4PhI(OAc)2, MgO
CH2Cl2, 40 ºC
one enantiomer
MeMe
OHN
O
one enantiomerAngew. Chem. Int. Ed. 2001, 40, 598.
intermolecular are possible:J. Am. Chem. Soc. 2007, 129, 562.
HN OS
Me
O O
H2N OS
Me
O O 5% Rh2(esp)2PhI(OAc)2, MgO
CH2Cl2, 40 ºC90%
J. Am. Chem. Soc. 2004, 126, 15378.
carbonyl groups prefer 5 membered rings, sulfonyls prefer 6 membered rings.
CO2HHO2C
Me MeMe Me
esp
Nitrenoid Intermediates
MeO
OS
H2N
O O
OTBSTBSO
Rh2(OAc)4PhI(OAc)2
MgO
CH2Cl2quant.
MeO
OS
HN
O O
OTBSTBSO
OS
HN
O OH
OO
BF3•OEt2
CH2Cl268%
Org. Lett. 2007, 9, 5465.
Other types of reactions are possible besides C–H insertions
N NH
N
NH
NTces
H2N OTBDPS
CCl3
O
N NH
N
NH OTBDPS
CCl3
O
HN
TcesN
AcO
Rh2(esp)2PhI(OAc)2
MgO
CH2Cl2, 40 ºC61%
J. Am. Chem. Soc. 2008, 130, 12630.
