Carbenoids 2

Electrophilic Carbenes
The 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) triate 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.
R1 EWG
cyclopropanation This resonance structure shows why these carbenes are electrophilic
R2 R2 O R R1 N2 EWG C R R1 O R EWG R
+ LnM N2
R1
EWG MLn
R1
EWG MLn RZ H R1 H EWG ZR
carbonyl ylide formation
no change in oxidation state
Z = C, O, N, S, Si
O R MLn R R R MLn
insertion reactions
O R N2 R
+ LnM N2
a new carbene for further reactions
Diazo Formation
While 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 sulfonyl azide RSO2N3 Et3N EWG = ketone, nitro ester, amide
O EWG N2 EWG Me N2 O OR O OR N2
EWG
EWG
K2CO3 MeOH
O R1 R2
LHMDS, THF CF3CO2CH2CF3 78 C

R1
O CF3 R2
MsN3, Et3N H2O, CH3CN

R1
O R2 N2
J. Org. Chem. 1990, 55, 1959.
O R Cl
CH2N2 CaO
R
O N2
a. EtO2CCl, Et3N b. CH2N2

R
O OH
Cyclopropanation
If formed in the presence of an olen, the carbene can form cyclopropanes. Both inter- and intramolecular reactions are possible. Because the carbenes are electrophilic, the react much faster with electron-rich olens. catalyst
N2 CO2Et 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=CHMe catalyst = Rh2(OAc)4, CuClP(Oi-Pr)3, Rh6(CO)16, PdCl2(PhCN)2 Order of reactivity: electron-rich > "neutral" >> electron poor !-substitution on olen 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
O O Ph
K2CO3 Bu4NBr BrCH2CH=CHR PhCH3, 40 C 82%
O Ph
pNBSA, DBU CH2Cl2, 0 C 83%
N2
a. KHMDS, THF RCHO, LiBr 78 C b. TBDPSCl DMAP, imidazole 38%

TBDPSO
O CO2Et N2 Me
1% Rh2(Oct)4 CH2Cl2, rt 70% 83:17 dr
O CO2Et TBDPSO Me H
thiophenol BF3OEt2 CH2Cl2 78 C 90%, 10:1 dr

TBDPSO H SPh
CO2Et
J. Org. Chem. 1997, 62, 194.
Cyclopropanation
O O Me N2 O H Me H
J. Am. Chem. Soc. 2001, 123 ,12432.
Rh2[5(S)-MEPY]4
O
MeO2C
N Rh
O Rh
4
CH2Cl2, 80%, 92% ee
Rh2[5(S)-MEPY]4
OH Me
a. CH3C(OEt)3 EtCO2H, ! 65% b. aq. NaOH 90%
Me
a. (COCl)2
OH Me Me Me O
Me Me Me Me N2 Me
b. CH2CHN2
Me
Me O
Me
Me O
CuSO4 52% (from acid)

Me Me Ph
Li NH3 81%
Me Me Ph
Me
Me
Me cyclohexane, !
J. Chem. Soc., Perkin Trans 1 2000, 2583
Cyclopropanation
With appropriate substitution patterns, cascade reactions are possible
MeO2C N2 OTBS MeO2C H OTBS TBSO MeO2C H H Me H O
+
Me O
Rh2(OAc)4 CH2Cl2, ! 94%

Me O
J. Org. Chem. 1991, 56, 723.
Boc OTBS N Boc Me
+
N2
CO2Me
1% Rh2(S-PTAD)4 2,2-dimethylbutane 50 C 69%, 96% ee
N CO2Me OTBS
Me
J. Am. Chem. Soc. 2007, 129, 10312.
Me
O CO2Me N2 Me
Rh2(OAc)4 CH2Cl2 50%

TBDPSO CHO
O CO2Me
TBDPSO O
Org. Lett. 2003, 5, 4113.
Ylide Formation
The electrophilic nature of the carbenes means they are also capable of reacting with Lewis basic groups such as carbonyls, ethers, and suldes. 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.
EWG
cat.
X
EWG
N2
[2,3]-rearrangements
Me O O OTBDPS N2
Org. Lett. 2004, 6, 1773.
ylide
OTBDPS O
Cu(acac)2 THF, ! 75%

O O Me Me H O H OTBDPS
oxonium ylide
O TBDPSO
>95:5
"
H Me O + " H
Ylide Formation
O MeO O N2 SPh CO2Me Rh (OAc) 2 4 MeO O H MeO2C O CO2Me SPh S Ph H O
C6H6, ! 77%
J. Chem. Soc., Perkin Trans. 1 1995, 2989.
N2
OH
+
Ph CO2Me R
1% Rh2(S-DOSP)4 pentane, 0 C 5070% yield 9298% ee

Ph
R HO CO2Me
racemic
J. Am. Chem. Soc. 2010, 132, 396.
Stevens-type rearrangement
Ph S N2 N O CO2Et Ph S CO2Et PhS CO2Et
Rh2(OAc)4 C6H6, ! 55%

N O O N
Chem. Commun. 1986, 651.
Ylide Formation
Dipolar Cycloadditions Addition of carbonyls will for a carbonyl ylide. These are 1,3-dipoles that can undergo cycloaddition reactions with electron decient olens/alkynes.
O O N N Me O N2 CO2Et O OPMP N Et O N Me OPMP H O CO2Et
Rh2(OAc)4
Et O
J. Org. Chem. 1998, 63, 556.
C6H6, 50 C 95%
one diastereomer
OTBDPS N2 O
Rh2(OAc)4
O
PhCF3, 100 C 73%
H O
O H
O OTBDPS
Angew. Chem. Int. Ed. 2006, 45, 6532.
O N2 t-BuO2C TMSO O OMOM OTBDPS CO2t-Bu O
Ac
OMOM
Rh2(OAc)4 C6H6, ! 72%
t-BuO2C t-BuO2C
O O OTMS OTBDPS
Angew. Chem. Int. Ed. 2003, 42, 5351.
Insertion Reactions
Rh(II) catalysts promote the insertion of diazoalkanes into CH, OH, NH, SH, and SiH 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 CH bonds. General order of reactivity for CH bonds: 2 > 1 ! 3, but is catalyst dependent Electron-withdawing groups deactivate CH bonds, electron-donating groups activate Proposed transition state: J. Am. Chem. Soc. 1993, 115, 958.
R C R R H MLn R C EWG R R H C EWG MLn R R C R C EWG H
This mechanism implies that the insertion reaction is stereospecic Rh2(NHCOC3F7)4 CH2Cl2, rt then Et3N, TIPSOTf 91% MeO
CO2Et
N2 MeO N Ph
CO2Et O
With Rh2(OAc)4 a mixture was obtained OTIPS with benxylix CH insertion.
Ph
Insertion Reactions
N2 O O
Rh2(4(S)-MACIM)4 cis:trans = 99:1 9697% ee

O
n
Ac O O
N N
CO2Me
6275%
J. Am. Chem. Soc. 1994, 116, 450.
4(S)-MACIM
+ 5 equiv
Rh2(S-PTAD)4
N2 P(O)(OMe)2
2,2-di-Me-butane, ! 83%, 92% ee

Org. Lett. 2006, 8, 3437.
Ph
P(O)(OMe)2
Br MeO
CO2Me
Rh2(S-DOSP)4
N2 CO2Me
2,2-di-Me-butane 50 C 56%, 94% ee
J. Org. Chem. 2002, 67, 4165.
MeO
Br
Insertion Reactions
NH insertions
H HO NH O O H Me N2 CO2
Rh2(Oct)4 EtOAc/hexane !
H HO
Me O CO2
N O
J. Org. Chem. 1991, 56, 3183.
OH insertions
OH OH Me H P(O)(OEt)2
1. Rh2(OAc)4 C6H6, 80 C OH 96% 2. H2CrO4 Et2O, rt
EtO2C O O Me O H O
CO2Et O Me H
NaH THF, rt 86% (2 steps)
Tetrahedron Lett. 1995, 36, 8347.
SiH insertions
N2 CO2Me
Rh2(OAc)4 PhMe2SiH CH2Cl2, rt 75%
PhMe2Si CO2Me
Z/E = 96:4
Z/E = 95:5
Metathesis with Alkynes

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.
O RhLn R R O Me N2 R O RhLn O RhLn
Rh2(OAc)4 CH2Cl2, rt 95%

Me
Me
Me
O Me N2
Rh2(OAc)4 CH2Cl2, rt 97%

O
Me O
Nitrenoid Intermediates
Much 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.).
O H2N O CO2t-Bu O
5% Rh2(OAc)4 PhI(OAc)2, MgO CH2Cl2, 40 C 82% 5% Rh2(OAc)4 PhI(OAc)2, MgO CH2Cl2, 40 C

O
HN O CO2t-Bu
O HN O Me Me
Me Me O NH2
carbonyl groups prefer 5 membered rings, sulfonyls prefer 6 membered rings.
one enantiomer
one enantiomer intermolecular are possible: J. Am. Chem. Soc. 2007, 129, 562.
Angew. Chem. Int. Ed. 2001, 40, 598.
O H2N Me S
O O
5% Rh2(esp)2 PhI(OAc)2, MgO CH2Cl2, 40 C 90%

Me
O HN S
O O
Me HO2C
Me
Me
Me CO2H
J. Am. Chem. Soc. 2004, 126, 15378.
esp
Nitrenoid Intermediates
O H2N MeO S O O O O S O O O S HN O
Rh2(OAc)4 PhI(OAc)2 MgO CH2Cl2 quant.
HN MeO
BF3OEt2 CH2Cl2 68%
TBSO
OTBS
TBSO
OTBS
Org. Lett. 2007, 9, 5465.
OH
Other types of reactions are possible besides CH insertions

NTces H2N NH OTBDPS TcesN
Rh2(esp)2 PhI(OAc)2 MgO CH2Cl2, 40 C 61%
NH HN N AcO N O NH
OTBDPS
N N
NH CCl3 O
CCl3
J. Am. Chem. Soc. 2008, 130, 12630.

Carbenoids 2

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Electrophilic Carbenes

EWG MLn RZ H R1 H EWG ZR

carbonyl ylide formation

no change in oxidation state

a new carbene for further reactions

LHMDS, THF CF3CO2CH2CF3 78 C

MsN3, Et3N H2O, CH3CN

J. Org. Chem. 1990, 55, 1959.

a. EtO2CCl, Et3N b. CH2N2

K2CO3 Bu4NBr BrCH2CH=CHR PhCH3, 40 C 82%

pNBSA, DBU CH2Cl2, 0 C 83%

a. KHMDS, THF RCHO, LiBr 78 C b. TBDPSCl DMAP, imidazole 38%

1% Rh2(Oct)4 CH2Cl2, rt 70% 83:17 dr

thiophenol BF3OEt2 CH2Cl2 78 C 90%, 10:1 dr

J. Org. Chem. 1997, 62, 194.

CH2Cl2, 80%, 92% ee

a. CH3C(OEt)3 EtCO2H, ! 65% b. aq. NaOH 90%

CuSO4 52% (from acid)

J. Chem. Soc., Perkin Trans 1 2000, 2583

Rh2(OAc)4 CH2Cl2, ! 94%

J. Org. Chem. 1991, 56, 723.

Boc OTBS N Boc Me

1% Rh2(S-PTAD)4 2,2-dimethylbutane 50 C 69%, 96% ee

J. Am. Chem. Soc. 2007, 129, 10312.

Rh2(OAc)4 CH2Cl2 50%

Org. Lett. 2003, 5, 4113.

Cu(acac)2 THF, ! 75%

J. Chem. Soc., Perkin Trans. 1 1995, 2989.

1% Rh2(S-DOSP)4 pentane, 0 C 5070% yield 9298% ee

Rh2(OAc)4 C6H6, ! 55%

Chem. Commun. 1986, 651.

PhCF3, 100 C 73%

Angew. Chem. Int. Ed. 2006, 45, 6532.

O N2 t-BuO2C TMSO O OMOM OTBDPS CO2t-Bu O

Rh2(OAc)4 C6H6, ! 72%

Angew. Chem. Int. Ed. 2003, 42, 5351.

With Rh2(OAc)4 a mixture was obtained OTIPS with benxylix CH insertion.

Rh2(4(S)-MACIM)4 cis:trans = 99:1 9697% ee

2,2-di-Me-butane, ! 83%, 92% ee

2,2-di-Me-butane 50 C 56%, 94% ee

J. Org. Chem. 2002, 67, 4165.

J. Org. Chem. 1991, 56, 3183.

1. Rh2(OAc)4 C6H6, 80 C OH 96% 2. H2CrO4 Et2O, rt

NaH THF, rt 86% (2 steps)

Tetrahedron Lett. 1995, 36, 8347.

Rh2(OAc)4 PhMe2SiH CH2Cl2, rt 75%

Tetrahedron Lett. 1994, 35, 9549.

Metathesis with Alkynes

Rh2(OAc)4 CH2Cl2, rt 95%

Tetrahedron Lett. 1991, 32, 4103.

Rh2(OAc)4 CH2Cl2, rt 97%

5% Rh2(OAc)4 PhI(OAc)2, MgO CH2Cl2, 40 C 82% 5% Rh2(OAc)4 PhI(OAc)2, MgO CH2Cl2, 40 C

carbonyl groups prefer 5 membered rings, sulfonyls prefer 6 membered rings.

Angew. Chem. Int. Ed. 2001, 40, 598.

5% Rh2(esp)2 PhI(OAc)2, MgO CH2Cl2, 40 C 90%

J. Am. Chem. Soc. 2004, 126, 15378.

Rh2(OAc)4 PhI(OAc)2 MgO CH2Cl2 quant.

BF3OEt2 CH2Cl2 68%

Other types of reactions are possible besides CH insertions