Reductions
General Resource: Trost, Comp. Org. Syn. 1991, vol 8
March,1992, chap 19
Carey and Sundberg, vol B, Chap 5
Smith, Organic Synthesis, Chap 4
Material organized (roughly) by transformation
From March, 1992, p1208
H
H
5% Pd/C
Supported metal b/c Pd $$$ and tends to clump.
Two general classes: Transition metal hydrogenation
and dissolving metal reduction
Hydrogenation: Covered in much more detail in
Advanced Synthesis and Catalysis.
CH3
CH3
H2
5% Pd/C
O
O
no carbonyl reduction
M
H
H
H2
5% Pd/C
H2
NC
General trends:
NC
Ph
more substituted = slower
relationship of pressure:rate often not simple
many systems pose fire risk!
HOAc/HClO4
AcOH
HOH
EtOH
CH2Cl2
EtOAc
N
N
Ph
Benzyl survives
10% Pd/C
-Same deal as 5%, just more reactive
-Often used for hydrogenolysis and more difficult
hydrogenations
-Mechanism of hydrogenolysis unknown
increasing activity
Olefin isomerization sometimes a problem
MeO
N
MeO
Ph
H2
MeO
10% Pd/C
MeO
NH
90%
Note:
O2 + H2
Pd/C
Fire
5% Pd/ BaSO4
and
5% Pd/CaCO3/Pb(OAc)2 (Lindlar's cat.)
and
5% Pd/C/quinoline
PtO2 (Adams catalyst)
general hydrogenation cat; more active than Pd/C
reduced
activity
H2/PtO2
AcOH/Benzene
N
quinoline
8
O
N
N
H2
H
Raney Nickel (RaNi)
-various types available that differ in preparation
-sold as 50% wt. dispersion in water
-usually wash 5x water, 5x solvent (usually MeOH)
-Dry solid is pyrophoric!!!
-Remove by filtration under N2 or Ar (pretty good idea for
all hydrogenation catalysts)
alkyne semi-reduction most common use:
H2
5% Pd/CaCO3/Pb(OAc)2
97% Ph
Wasserman, TL, 1988, 4977
5% Pd/ BaSO4
Ph
8
Ph
O
Cl
Ph
H
Ph
Ph
87%
stereospecific
Ni/Al
NaOH
Ni/H2
+ NaAl(OH)4
complementary method:
slurry has hydrogenation
activity without added H2
Na/NH3
97%
stereoselective
(more on Na to come)
For some applications, can use Ni/Al in 1M NaOH/MeOH
Raney Ni Applications
OH
Ni2B (Nickel boride)
Brown, JACS, 1963, 1004, 1005
H2 (275 atm)
Ra-Ni
OH
NaBH4
Ni(OAc)2
Ni2B + H2
(future fuel cell technology??)
86%
H2
Ra-Ni
vegtable oil
in water:
More reactive than Ra-Ni
Less double bond rearragement
margarine
in EtOH:
Highly selective:
Ni2B
H2
other uses:
O
desulfurization
Ra-Ni
EtOH
S
97%
TL 1994, 5594
S
61%
O
Triazene reduction
O
O
H
O
H
HO
N
N
N
O
Ra-Ni
MeOH
no added H2
H
O
H
HO
H2N
95%
Wood, ACIEE, 2004, 1270
Ni2B
H2
O
45%
Can. J. Chem. 1991, 1554
Diimide Reductions
Examples
general trends: rate
H
H
N N
diimide
Unstable
-generate in situ
-use excess
No reaction with -CN, -NO2,
Not poisioned by heteroatoms
Generation
KO2C
N
N
CO2K
H2N NH2
(hydrazine)
S
R
R
Corey JACS,
2004, 15664
HN
KO2CN=NCO2K
O
II
Δ or base
NH O
Mechanism
88%
N
HOAc also promotes
E-Z isomerization
JOC, 1965, 3985
Cu , O2
NH2NH2
CuSO4
5 O2 EtOH/MeOH
H
N
-2 CO2
HO2C
as substitution
O
NH
O
O
JOC, 1977, 3987
Tol
O
H2N
H
HOAc
rate
as strain
-HTs
R
H
N N
concerted hydrogen transfter
ΔGo ~ -50kcal/mol
R
H
HN
NH2NH2
O2, Cu(II)
NH
R
Org. Syn. 1969, 30
R
N
Corey, JACS,
1961, 2957
OAc
OAc
+
N
KO2CN=NCO2K
CD3OD/CD3CO2D
D
D
syn-exo addition!
JACS, 1967, 410
Dissolving Metal Reductions
Enones
polar solvent
M+
M
e-
+
Most common solvents: NH3 (b.p. = -33 oC),
MeNH2 (b.p. = -6.3 oC)
Li, NH3,
2 equiv EtOH
O
O
+e-
Competing process:
2 e-
+ 2NH3
slow
2NH2- + H2
(rxn mixture is basic)
O
Birch Reduction
review: Rabideau, Marcinov, Org. React, 1992, 42, 1
CN
H
EtOH
vs.
CN
Li, NH3,
2 equiv EtOH
H
good overlap
EtOH
H
poor overlap
-
+e
EtOH
CN
CN
EtOH
CN
+e-
+eO
explain:
OMe
OMe
Li, NH3,
2 equiv EtOH
LiO
H
Regioselective enolate generation:
Li, NH3;
H
MeI
~50%
O
Deprotonation here
R
O
Ph
Na/NH3
R
OH
O
H
H
O
H
Stork, JACS, 1965, 275
Carbonyl Reductions
Metal Hydrides-General
RCO2H
RCH2OH
RCO2R
RCH2OH
RCONR2
RCH2NR2
Ionic Metal Hydrides (LiAlH4, NaBH4, etc)
LiAlH4
-very strong reducing agent
-flammable
-Workup can be trouble b/c Al salts; Feiser workup:
for ng LiAlH4, add n mL H2O, n mL 15% NaOH, then
3n mLH2O, filter ppt.
-related: Red-Al [NaH2Al(OCH2CH2OMe)2; similar reactivity but
greater solubility
2
H M L3
O
H
1 2
+ M M HL3
O
M1
OH
Reactivity increases with:
-increasing electronegative M1 (Li > Na)
-increasing electropositive M2 (Al > B)
-increasing e- donation of L (Et > H)
-increasing electrophilicity of substrate (RCHO > RCOR)
OH
MeO2C
MeO2C
H
O
O
O
THF, reflux
72%
L
H
+ MHL2
CO2H
M
O
H
L
O
OH
Reactivity increases with:
-increasing electropositive M (Al > B)
-increasing donor ability of substrate (RCO2R > RCOR)
H
O
H
H
O
H
OH
H
LiAlH4
H
Neutral Metal Hydrides (i-Bu2AlH, AlH3, B2H6)
HO
C(CH3)3
H
OH
Helmchen, JOC, 2000, 5072
OBn
O
H
O
CO2Me
LiAlH4
O
H
OBn
O
OH
O
H
Nicolaou, JACS, 1995, 10252
H
O
H
H
92%
O
Directed reduction proceeds through
intramolecular hydride delivery:
H
N
N
LiAlH4
88%
H
H
H
Al
Ts
O
O
N
H
O
N
H
H2
Al
+
H
R
Overman, JACS, 1999, 700
R
LiAlH4 can also reduce alkynes:
THPO
LiAlH4, Δ
73%
OH
LiAlH4
120 - 150 oC
HO
H
LiAlH4, Δ
70%
Nearby alcohol accelerates
OH LiAlH
4
n
R
Acta. C. Scan. 1073, B27, 2941
90%
TMS
H
H
H
allylic leaving group leads to allene:
forcing conditions are required for unactivated alkynes
OH
TMS
OH
n
n = 1, 1h, 66 oC, 68%
JOC, 1984, 4092
n = 2, 48h, 85 oC, 84%
JOC, 1985, 4014
OH
OH
TL, 1974, 1593
OH
LiAlH4
OMe
?????
LiBH4
-Seletive reduction of esters and lactones in presence
of acids
-acids 'protected' as Li salt
-solvent effects: ether>thf>iPrOH
HO
MeO2C
CO2H
O
O
BH3-THF
H
Br
HO
O
H
CO2H
Br
HO
LiBH4
O
OH
Corey, JOC, 1975, 579
CO2H
81%
JACS, 1075, 4144
hypothetical example:
O
O
H
N
O
O
N
O
O
S
HO
LiBH4
BH3-THF
HO
LiBH4
HO
O
I
Williams, JOC, 2004, 1028
Borane complexes (BH3-L)
-selective reduction of acids in presence of
esters, amides, lactones. Will reduce ketones,
aldehydes and olefins
-BH3-THF and BH3-Me2S available
+
ester
dibal alcohol
O
B2H6
O
OEt
B
O
+
R
3
OH
i-Bu2AlH (aka DIBAL or DIBAL-H)
-low temp, 1 equiv, ester -> aldehyde
-with XS, get alcohol
-gives 1,2 reduction of unsaturated esters
-commonly:
O
O
OEt
O
I
OH
OH
O
OEt
O
O
N O
S
O
45%
O
HO
H
N
HO
LiAlH4
OH
Ph
[O]
aldehyde
CO2Et
O
H
H
OTBS
DIBAL, -78 oC
95%
O
Ph
Brown, JACS, 1960,3866
OH
O
OEt
O
OTBS
H H
Nicolaou, Tetrahedron, 1990, 4517
Weinreb's amide to aldehyde
S
MeO2C
H
S
OHC
DIBAL
-78 oC
H
PO
NH
NH
O
OP
PO
H
O
DIBAL
O
N
OMe
Al
R
R
OP
OAlR2
R
H
OMe
O
JACS, 1982, 6460
O
O
N
OMe
stable at low T
stable intermediate
aminal decomposes to
aldehyde on workup
PO
biotin
>70%
O
OP
O
PO
OP
O
lactone to lactol
Evans, JACS, 1990, 7001
O
O
3o amides to aldehydes
3 equiv. DIBAL
H
Cl
NC
OTIPS
78%
H
Cl
NC
O
O
OTIPS
O
O
O
NMe2
OH
LiAlH(OtBu)3
LiAlH(OEt)3
note: nitrile survives
4 steps!!
Nitrile to aldehyde
xs tBuOH
O
O
O
TMSO
OTIPS
63%
92%
NC
DIBAL
>71% TMSO
O
O
OTIPS
Corey, JACS, 1993, 8871
LiAlH(OtBu)3
LiAlH4
1.5 EtOAc
LiAlH(OEt)3
Brown, JACS, 1964, 1089
O
Directed Reductions
OH
general reference for directed rxn: Hoveyda, Evans, Chem
Rev. 1993, 1307
many many many ways. Focus here on selectivity issues
2 common modes
OH
H
O
R
H
OH
D
99
89
80
3
7
Li/NH3
LiAlH4
NaBH4
LiBH(s-Bu)3 (L-selectride)
(i-Bu)2AlH
1
11
20
97
93
O
D
R
R
H
R'
O
D
M
R'
H-
R'
D = donor
D
M
D
R
O
OH
OH
R'
MBH(OAc)3; M usually NMe4
Evans, JACS, 1988, 3560
ax
H
O
O
eq disfavored for small H- donors
b/c interaction with C2 axial H
H eq
ax disfavored for large H- donors
b/c interaction with C3 axial H
H
LiAlH4
OH
OH
H
OH O
MBH(OAc)3 R
-HOAc
R'
OH O
MBH(OAc)3
-HOAc
83
17
O
O LiAlH4
?
?
?
92
8
?
acyclic cases usually follow Felkin-Ahn model or chelate
model (if chelating group nearby) to varying degrees. For
a chronological presentation, see Smith, Organic
Synthesis, chap 4.
O
OH
E
Me
O
H
50:1
O
H
R'
MBH(OAc)3
OH OH
OAc
B OAc
O
R
OH OH
OAc
B OAc
O
50:1
O
HO
H
OH
E
Me
one isomer
OH O
O
O
MBH(OAc)3
OR
OH OH OH O
OR
6:1
MeOB(Et)2/NaBH4
MeOB(Et)2
NaBH4
OH O
R
R
Tishchenko Reductions: Evans, Hoveyda, JACS, 1990,
6447
O
Prasad, TL, 1987, 155
H-
Et
B Et
O
-MeOH
OH O
OH OH
R
O
R
H
cat. SmI2
O
R, R' = alkyl, aryl
generally >97:3
OH O
O
R
OEt
O
OEt
R
O
Sm
Ln
OEt
MeOB(Et)2
NaBH4
OH O
CH3CHO
OH OH O
5
OEt
R
R = Me, Aryl
OAc OH
cat. SmI2
5
96%
>99:1
R = Me, Aryl
O
O
O
OH O
Zn(BH4)2 Oishi, Nakata, Accts. Chem. Res. 1984, 338;
Evans JACS 1984, 1154
OH
cat. SmI2
L
Zn L
O
O
95%
>99:1
BnO
OBn
OP
OH O
OP
OH O
OP
CH3CHO
OAc OH
cat. SmI2
Zn(BH4)2
Me4NBH(OAc)3
OP
OH OH OP
19:1
OP
OP
OH OH OP
4:1
95%
>99:1
OP
OH
directed reduction +
monoprotection
OH OH O
R
H-
O
R
likely Sm+3
MeOB(Et)2
NaBH4
98:2
OH O
R
O
R'CHO
Enantioselective reductions. For metal-catalyzed, see Advanced Synthesis and Catalysis notes.
CBS Reduction: from Corey, Bakshi, and Shibata
Reviews: Corey, ACIEE, 1998, p1986; Srebnik, Chem Rev, 1993, 763.
H Ph
NH
H Ph
Ph MeB(OH)2 (1.1 equiv)
OH
N
Ph
O
B
(10 mol%)
CH3
CBS Catalyst
O
R
BH3-THF (0.6 equiv)
R'
OH
OH
RL
R = CH3: 97%ee
R = Et: 97% ee
R = CH2Cl: 95%ee
R = (CH2)2CO2Me: 94% ee
OH
N
NO2 MeO
RS
95% ee
RS
93%ee
RL
OTBS O
O
O
BF3
R
S
CH3
94% ee
OH
MeO
H3C
Br
99% ee
N
OH
TBDPSO
OEt
MeO
84% ee
O
91% ee
91% ee
O
OH
O
Hex
~95% ee
MeO
OH
OH
RO
HO OR
R
OH
R
CH3
note: some data with
alternative boranes or
R' B-R groups
HO H
CH3
CH3
SnBu3
94% ee
O
Bu3Sn
CH3
93% ee
95% ee
91% ee
OH
H3C
OH
CH3
85% ee
R'
R
OEt
R = Ph, R' = n-alk: 70-90 % ee
R = Ph, R' = s-alky: 95% ee
R = H, R' = alk: ~96% ee
R = TIPS, R' = alk: >90% ee
Proposed mechanism for CBS reduction
Important points:
• Borane in catalyst is Lewis acid; Nitrogen is Lewis base to coordinate second borane
• Borane coordination forms cis-5,5 system (a-face in 5)
• Borane coordination increases Lewis acidity of catalyst (at B) and activates BH3 as hydride donor
• Carbonyl coordination trans to bulky or electron rich group
• Hydride transfer via 6-membered TS
• Disproportionation between 8 and BH3 + (RO)2BH allows <1 equiv BH3
Enantioselective reduction: Alpine borane and Dip-Cl
Review: Brown, JOMC, 500, 1995, p1.
Background: asymmetric hydroboration of olefins.
An improved reagent: DIP-Cl; Review, Brown, JOMC, 1995, v500, p1.
Conjugated systems:
1,4 addition
-recall Na/NH3
1,2 vs. 1,4
Luche reduction (original report: JACS, 1978, 2226;
review Molander, Chem Rev. 1992, 29)
O
OH
H-
Selectrides: MBH(s-Bu)3; M = K, Na, Li available
-useful for regioselective enolate generation
O
TIPSO
+
NaBH4
NaBH4/CeCl3
49
1
51
99
TfO
O
O
O
O
NaBH4,
CeCl3
O
O
OBn
Cl
OBn
O
OPMB
N3
O
O
75%
1,2 addtion expanded:
2.
O
OH O
Ar-CeIII
O
H
AcO
H
Wood, unpublished
Ph O O
1. CeCl3
O
75%, 1 diastereomer
Ph
Ph O O
Li
H
L-Selectride;
NCS
OH
NaBH4,
CeCl3
Ph
H
AcO
>80%
O
Overman, JACS, 1993, 9293
OH
O
O
>80%
O
O
OPMB
N3
N3
OtBu
OtBu
-Ce(+3) coordinates to carbonyl; promotes selective 1,2
addition.
-Requires stoichiometric quantity of ANHYDROUS CeCl3
N3
TIPSO
L-selectride;
PhNTf2
OtBu
OtBu
75%
Heterocycles, 1989, 703
Ionic Reductions
Reductive amination
-Usually with NaCNBH3 or NaBH(OAc)3
-Usually in presence of acid to promote imium ion
formation
-Alternative to amine alkylation (often get over
alkylation)
-reduction of cation (usually from protonation)
-need to avoid H- + H+
-CF3CO2H/Et3SiH is most common combination
OH
OH
CF3CO2H
Et3SiH
O
OH
OH
O
+
TBSO
O
93%
Chem Comm. 1986, 1568
O
CHO
+
OAc
N
H
NaBH(OAc)3, Sn(OTf)2,
4A MS
TBSO
OP
O
O
OAc
TMSOTf
Et3SiH
OAc
O
+
OP
O
O
N
H
H
N
OAc
OMe O
O
CO2Me
CF3CO2H
Et3SiH
N
OMe
O
O
H
OAc
TL, 2000, 6435
JACS, 2004, 516
N
CO2Me
N
N
N
H
N
H
H
OH
O
Nicolaou, JACS, 2004, 613
2
+
HN
NH NaBH3CN,
AcOH
95%
H
N
HN
O
O
BocHN
2
O
BocHN
N
H
HN
JACS,
2004, 557
α,β-unsaturated ketones give olefin migration:
O
R
R
R
R
O
Reduction of Tosylhydrazones
Maryanoff, JACS, 1973, 3662
Baker, JOC, 1975, 1834
O
R
H2N-NHTs
R
Ts
HN
DMF/sulfolane
AcOH/NaCNBH3
N
R
H2NNHTs, HCl, NaCNBH3
Ts
HN
R
NNHTs
NH
R
NaCNBH3, AcOH
R
-TsH (pKa=7.1)
~75%
JOC 1978, 2299
-N2
R
HN
R
N
R
R
2 possible mechanisms:
O
H2NNHTs, TsOH, NaCNBH3
DMF/sulfolane
N
Bn
Ts
HN
N
Bn
H-
79%
O
O
3
O
CN
O
3
5
NNHTs
H
H
R
O
"
CN
-N2
R
H
R
-N2
N
H
R
How would you distinguish between them?
HO
Boeckman, JACS, 1989, 2737
N
R
ZnCl2, NaCNBH3
~50%
H
H N
5
75%
HO
HN
N
H
H
Related chemistry:
TBS
N
N
SO2Ar
Li
R'Li
R
R
Wolf-Kishner
Brutal conditions
TBS
N
N
SO2Ar
R'
R
N
TBS
N
AcOH
-N2, -AcOTBS
R'
3
O
R
R'
3
synthesis of unfunctionalized sp -sp bonds
EtO2C
N2H4, NaOEt
170 oC
N
H
N
H
Myers, JACS, 1998, 8891
50-58%
Org. Syn. 1995, Coll vol 3, 513
OMOM
R
Li
O
1.MeO
MeO
C4H9
OMe
OMe
C4H9
NN(TBS)Ts
AcO
2. HCl, MeOH
73%
R
N2H4
NaOH
(HOCH2CH2)2O
reflux, then
HO
210 oC
O
69%
Barton, J. Chem. Soc., 1955, 2056
C4H9
MeO
cylindrocyclophane F
MeO
Smith, JACS, 1999, 7423
C4H9
OMe
HO
OMe
H2N
B
N
HN
N
H
H
-N2
H
H
Shapiro reaction
useful for difficult olefins; usually low yielding with
side products
review: Shapiro, Org. Rxns. 1976, 405
TsHN
2 equiv RLi
N
Li
TsN
Li
N
N
H
Other Methods
Clemmensen Reduction
review: Vedejs, Org. Rxns. 1975, 22, 401
O
Cl
N
Li
Cl
Zn(Hg)
HCl
56%
-N2
H
generally poor E/Z
selectivity in acylic cases
TsHN
Li
BuLi
JOC, 1969, 1109
A fine method if low yields of unfunctionalized products are
needed.
Review: Org. Rxns. 1962, 356
Ph
Ph
MeO
Ph
low yield
Swenton, JACS, 1971, 4808
N(CHO)Me
H
SMe
SMe
H
N
O
H
O
TsHNN
TsHNN
Cl
Desulfurization
See hydrogenation above.
Ra-Ni/H2 almost always used
N
Ph
Cl
Ra-Ni/H2
N(CHO)Me
H
H
N
O
H
O
Woodward, JACS, 1948,
2107
MeLi
NNHTs
MeO
20%
bullvalene
TL 1972, 2589
OH
Generally useful method, but:
-lota tin
-3o thiocarbamates can be difficult to make
-1o radicals difficult to form
common methods we won't cover:
-alkyl tosylate + LiAlH4
-conversion to halide/dehalogenation
-elimination/hydrogenation
S
O
O
S
O
O
Barton deoxygenation
N
N
AIBN, Bu3SnH
140 oC
HO
O
O
O
CN
CN
H
CN
N N
AIBN
NC
Bu3SnH
temp
50
70
100
40%
t1/2
74h
4.8h
7.2min
TL, 1988, 281
Im
S
S
Bu3Sn
H
O
R
AIBN, Bu3SnH
90 oC
O
C10H21
91%
O
O
O
C10H21
OH
O
JOC, 2000, 6035
Bu3SnH
S
O
SnBu3
R
AIBN, Bu3SnH
O
O
O
PO
S
O
SnBu3
R
Barton: Tet, 1983, 2609;
1987, 3541; 1991, 8969
Synthesis, 1988, 417, 489
S
75%
JOC, 1989, 5678
O
O
"NBSH"
Myers Diazene method
O2
S
N
H
NO2
PPh3/DEAD/
R
OH
Barton Decarboxylation
Barton, Chem. Comm. 1983, 939; Tet, 1987, 2733
NH2
NH2
N
SO2Ar
R
O
R
O
N
H
R
S
-HSO2Ar
R
H
-N2
-CO2
R
N
NH
O
R
N
O
S
Very useful for unhindered alcohols
SSnBu3
-
N
SnBu3
note: thiohydroxamic acid often labile enough that no Sn
is needed, just ambient light. Photolysis works too.
OH
MeO
H3C
PPh3/DEAD/NBSH
N
O
S
N
N
O
O
MeO
O
Cl
Cl
N
OH
PPh3/DEAD/NBSH;
O2 ;
Me2S
Eaton, ACIEE, 1992, 1421
O
1. i-BuOCOC
2. S
CO2H
O
H
N
N
O
N H
H
N
ONa
N
O
3. tBuSH, hν
O
H
N H
H
Martin, JOC, 1995, 3236
65%
OH
Holy cow! How does this happen?
quant.
O
N
Myers, JACS, 1997, 8572
O
S
AIBN, Bu3SnH
O
Reductive couplings and related reactions.
Reductive cleavage of strained rings:
electron transfer-promoted reductions (part II)
OSmX2
O
SmI2
I
from:
-CH2CH2
O
O
SmI2
+ Sm(0)
PMP
O
SmI2
HMPA
PMP
O
I
-almost always in THF (can do in Me3CCN)
-Very air sensitive
-reactivity modulated by additives (JACS 2004, 44; JACS 2000, 7718,
SYLETT, 1996, 633)
-Kagan discovered, Molander exploited, Flowers studied
-Rxns usually psycho fast
-Reviews: Molander, Chem Rev. 1992, 29; 1996, 307 (example from here).
O
+2
Sm
OSm+3
+2
ROH
OH
Sm
X2Sm
from [2+2]
O
AcO
O
O
SePh
OH
Sm
OH ROH
O
Guanacastepene A
OH
Sorensen, JACS, 2006, 7025
O
OSm+3
OTBS
CO2Me
O
SmI2, HMPA
5 min
TMS
TMS
HO
SmI2
79%
Intermolecular additions of ketyl radicals
97%
93:7
OTBS
O
CO2Me
Corey, JACS, 1987, 6187
+
CO2Et
SmI2
tBuOH
O
n-C7H15
O
>99:1 dr
ketyl can be intercepted:
S
O
OCN
OH
S
S
SmI2, LiCl
S
X2SmO
X2Sm
OCN
or radical addition
PMP
+3
_
O
O
OH
_
Less likely: via
SePhBr
50%
S
Ph
S
O
+
H
CN
SmI2
THF, MeOH
O
R
H
OH
O
N
H
Wood, ACIEE, 2004, 1270
O
CN
Ph
H3C OH
99:1 dr
M
O
CN
Intramolecular couplings:
Pinacol Couplings with SmI2
O
SmI2, HMPA
THF, tBuOH
CO2Me
O
2 Mn
2
OMn+1
OH
2
CO2Me
HO
OH
80%
H
H
SmI2,
HMPA
O
O
OH
O
2 SmI2
-PhS
OP
H
HO
H
OH
80%
poor dr
SmI2,
HMPA
78%
N
H
Ph
HN
2 SmI2
Ph
O
PO
OP OP
Ph
Ph
Ph
Ph
O
n-Hex
n-Hex
OP OP
OP
H
OH
O
OH OH
O
PO
With SmI2 (Chem Rev, 1996, 307)
H
O
86%
O
PhS
NH
93%; 4:1
OP OP
OP
SmI2
O
O
O
O
54%
OP
H
PO
HO
OH
OH
O
OH
OP
92:8
OMe
N
HO
OP OP
OH
O
OP
OH
H
HO
OP
2.5 SmI2
tBuOH, THF
OH OH
O
O
SmI2
~65%
N
Cbz
H2N
O
Grayanotoxin III
Shirahama, JOC, 1994, 5532
Note cleavage of N-OMe
Nicolaou, en route to diazonamide
JACS, 2004, 12897.
N
HO
OBn
NBn
NMOM
Cr-mediated reductive coupling of Sp2-X with aldehydes: the Nozaki-Hiyama-Kishi (NHK) reaction
X
+
CrCl2 (>2 equiv)
Ni(II) cat.
DMSO or DMF
O
OH
X = Br, I, OTf
Ni(II)
2Cr(II)
2Cr(III)
2Cr(III)
X
Ni(0)
2Cr(II)
Ni(II)
NiX
General characteristics
Reliable for late-stage coupling
Broad functional group compatibility (ketones, ester, nitriles)
Nuclophile formed in presence of electrophile (Barbier), so
intramolecular (cyclizations) possible
Often poor diastereoselectivity
Catalytic conditions (in Cr) have been developed: Furstner,
JACS, 1996, 12349
Enantioselective versions have been developed: Kishi, JACS,
2004, 12248; OL, 2008, 3073.
Review: Furstner, Chem Rev. 99, 991
Cr(III)
O
CrCl2 +
OCrCl2
Intermolecular additions: From Chem. Rev. 1999, 991
Intramolecular additions:
Allylations and alkynylations: