Transcript Seminar

Indium Mediated Allylations in
Aqueous Media
Lauren Huffman
Stahl Group
28 September 2006
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Why Water?
Advantages
• Not flammable, toxic or explosive
• Cheapest solvent on the planet
• Highest heat capacity of all liquids (4.19 J/gC˚)
• Isolation of organics facile through extraction
• Low volatility aids recycling
Drawbacks:
• Metals difficult to remove
• Removing organics before disposal can also be difficult
• High heat capacity = lots of energy for distillation
Li, C.J.; Chan, T.H. Organic Reactions In Aqueous Media; Wiley & Sons: New York, 1997.
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Water in Industry: Hydroformylation
Rurchemie / Rhone-Poulenc hydroformylation oxo process
(RCH/RP)
+
[cat]
CO / H2
[cat] = [Rh(CO)(TPPTS)3]
O
H2O
H
96
Homogeneous process where water aids in:
• Economic heat management
• Avoiding complicated catalyst recycling
• Product separation
> 600,000 tons/year production
H
+
:
O
4
SO3Na
NaO3S
P
SO3Na
TPPTS
Cornils, B.; Kuntz, E.G. Hydroformylation. In Aqueous-Phase Organometallic Catalysis; 2nd Ed; Cornils, B.;
Herrmann, W.A., Eds.; Wiley-VCH: Weinheim 2004; pp 351-363.
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Water in Industry: Palladium Processes
Wacker process
–
–
–
–
H
Biphasic process
Cu re-oxidizes Pd
O2 stoichiometric oxidant
Higher alkenes still being investigated
H
PdCl2/CuCl2
H
O
H
H2O, O2
H
Telomerization (Kuraray 1-octanol process)
– Biphasic process
– Ni catalyzed hydrogenation yields octanol
Pd/TPPMS
H2O
+
2
H2O/sulfolane
(Et)3NHHCO3
OH
OH
90
+
:
4
Aqueous-Phase Organometallic Catalysis; Cornils, B.; Herrmann, W.A., Eds.; Wiley-VCH: Weinheim 2004; pp
481-487, pp 545-546.
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Water in Industry: Electrochemistry
Synthesis of Adiponitrile (Monsanto)
– Quaternary ammonium salts (QASs) essential for selectivity
– Sodium phosphate-borate electrolyte
2
CN
+
2H2O
QAS, 2e-
NC
CN
+ OH-
90%
Asahi’s Sebacic Acid Process
– 92% yields, 85% to 90% current efficiency
– 20% aqueous solution of monomethyl adipate neutralized by NaOH
Electrolysis,
Hydrolysis
MeOH
HOOC
COOH
MeOOC
COOH
HO2C(CH2)8CO2H
Li, C.J.; Chan, T.H. Organic Reactions In Aqueous Media; Wiley & Sons: New York, 1997.
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Laboratory Scale Interest in Water
Diels Alder - rate acceleration due to hydrophobic effect
+
COCH3
H2O
H3COC
Olefin Metathesis - promising for bio-molecule synthesis
OPEG-Me
MesN NMes
Cl Ru
Cl
O
-Cl+Me N
3
Ph
H2O, 12h
-Cl+Me
3N
>95%
Rideout, D.C.; Breslow, R.; J. Am. Chem. Soc. 1980, 102, 7816.
Hong, S.H.; Grubbs, R.H.: J. Am. Chem. Soc. 2006, 128, 3508-3509.
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Indium Mediated Reactions
•
•
•
•
Grignard and Barbier Allylations
Indium Facts
Indium in Organic Solvent
Stoichiometric Indium
– Selectivity
– Mechanism
– Synthetic Applications
• Catalytic Indium
• Summary
• Future Directions
7
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Barbier and Grignard
• Grignard reaction pre-generates the RMgX compound
• Barbier is the “one pot” equivalent, (Li and Mg)
O
+
Br
[M]
anh. solvent
OH
• Enolization and reduction side reactions occur
• Proposed single electron transfer (SET) at
metal surface to form organometallic intermediate
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http://nobelprize.org/nobel_prizes/chemistry/laureates/1912/
Molle, G.; Bauer, P., J. Am. Chem. Soc. 1982, 104, 3481-3487.
Smith, M. B.; March, J. Advanced Organic Chemistry; 5th Ed; Wiley: New York 2001; pp 1205-1209.
8
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•
•
•
•
•
•
•
Meet Indium
Discovered in 1863
63rd most abundant element
Canada produces the majority of the world’s supply
Named for the brightest line in its spectrum
111In (t
1/2 = 2.8d) used for -ray imaging
Used in dental work and low melting alloys
Electron Configuration: [Kr] 5s24d105p1
III A
5
B
10.811
13
Al
26.982
31
Ga
69.723
49
In
114.818
81
Tl
204.59
LANL Chemistry Division http://periodic.lanl.gov/elements/49.html (Accessed Sep 2006)
Chandler, J.E.; Messer, H.H.; Ellender, G. J. Dent. Res. 1994, 73, 1554-1559.
Cotton, F.A.; Wilkinson, G., Murillo, C.A.; Bochman, M. Advanced Inorganic Chemistry, 6th Ed. Wiley & Sons:
New York, 1999; pp 175-207.
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In Mediated Allylations in Organic Solvent
• First Allylation mediated by Indium
O
+
1 eq In0
I
OH
DMF, 1h rt
1 eq
1.5 eq
84%
• Allylation of aromatic and aliphatic aldehydes and ketones
with allyl, crotyl and propargyl halides and phosphonates
• Proposed a sesquiiodide intermediate based on the
stoichiometry of the best conditions (2:3:2)
I
In
In
I
I
Araki, S.; Ito, H.; Butsugan, Y. J. Org. Chem. 1988, 53, 1833-1835.
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In Mediated Allylations in Organic Solvent
Ongoing field with success in selective imine allylation
N
COOMe
H
Br
In,
HN
COOMe
*
DMF, rt, 12h
(S,S):(S,R) = 99:1
75% yield
(2R,3S) 4,4,4,-Trifluoroisleucine synthesis
NBz
O
H
O
F3C
NHBz
Br
In, DMF, rt. 12h
O
NHCbz
HO
O
CF3
> 95% de
61% yield
4 steps
O
CF3
60% yield
(over 4 steps)
Loh, T.P.; Ho, D.S.C.; Xu, K.C.; Sim, K.Y. Tetrahedron Lett. 1997, 38, 865-868.
Chen, Q.; Qiu, X.L.; Qing, F.L. J. Org. Chem., 2006, 71, 3762-3767.
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Why Indium in Water?
• Does not form oxides readily in air
• Not sensitive to boiling water or alkali
• Low first ionization energy (5.79 eV)
• Believed to be non-toxic
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Li, C.J.; Chan, T.H. Organic Reactions In Aqueous Media, Wiley & Sons: New York, 1997.
http://www.webelements.com/webelements/elements/text/In/key.html
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Indium Mediated Allylations in Water
X
1.5 eq
+
1 eq
O
R1
OH
1 eq In
R2
H2O, rt
R1
R2
Entry
R1
R2
X
Time
Yield
1
Ph
H
Br
3h
97%
2
Ph
H
I
3h
95%
3
Ph
H
Cl
3h
60%
4
p-Cl-Ph
H
Br
1h
94%
5
CH3CHOH
H
Br
3h
85%
6
Ph
CH3
Br
5h
72%
7
HO(CH2)4
H
Br
3h
95%
Li, C.J; Chan, T.H. Tetrahedron Lett. 1991, 48, 7017-7020.
13
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Regioselectivity
Crotyl bromide and other substituted allyls give a rearranged ()
product
OH
Br
H
+
O
1 eq
1.5 eq
1.1 eq In
OH
OH
+
2h, H2O, rt
OH
OH
syn:anti (1:8.5), 77% yield
Methyl (2-bromomethyl) acrylate and other 1,1 disubstituted
alkenes do not rearrange
O
O
Br
O
1 eq
+
1 eq In
H
1 eq
OH
O
H2O, 5h, rt
O
96% yield
Paquette, L.A.; Mitzel, T.M. J. Org. Chem. 1996, 61, 8799-8804.
Li, C.J; Chan, T.H. Tetrahedron Lett. 1991, 48, 7017-7020.
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Diastereoselectivity
Non-chelating substrates follow Felkin-Ahn T.S.
SPh
H
Me
H
Br
SPh
In
PhS
In, H2O
O
H
SPh
+ Me
Me
Me
OH
O
OH
1:4 (syn:anti)
82% yield
Chelating substrates follow a chelated T.S.
Me
NMe2
H
O
Br
In, H2O
H
In NMe2
H
O
Me
NMe2
NMe2
+ Me
Me
OH
OH
>99:1 (syn:anti)
55% yield
Paquette, L.A.; Mitzel, T.M.; Issac, M.B.; Crasto, C.F.; Schomer, W.W. J. Org. Chem. 1997, 62, 4293-4301.
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Diastereoselectivity: 1,2 Induction
O
O
CH3
1.6 eq
Br
1.6 eq In,
rt, H2O
O
O
H3C
HO
OH
OCH3
In
OCH3
+
:
3
80% yield
97
1 eq
O CH3
H
OH
OCH3
1.6 eq
O
Br
Š 2.7 kcal/mol 1.6 eq In,
O
O
H CH
3
1 eq
rt, H2O
O
O
H
HO
OCH3
+
In
CH3
6
:
1
83% yield
Paquette, L.A.; Lobben, P.C. J. Am. Chem. Soc. 1996, 118, 1917-1930.
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Diastereoselectivity: 1,3 Induction
R O
1.6 eq
O
Br
H
1 eq
OR OH
1.1 eq In,
OR OH
+
solvent, rt
R
time
solvent
yield
syn
anti
H
-
THF
nr
-
-
H
2h
H2O
77%
1
8.5
CH3
8.5 h
THF
69%
1
3.3
CH3
3.5 h
H2O
84%
1
4
CH2Ph
2.5 h
H2O
80%
1
1
SiMe2tBu
2.7 h
H2O
78%
1
1
H
H3C
In
R
O
O
Paquette, L.A.; Mitzel, T.M. J. Am. Chem. Soc. 1996, 118, 1931-1937.
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Diastereoselectivity: 1,4 Induction
O
CH3
Si O
Br
CH3
In, H2O
+
TBSO
OH
TBSO
OH
67:33
91%
O
MeO
Br
In, H2O
+
MeO
OH
MeO
OH
58:42
85%
O
HO
Br
In, H2O
+
HO
OH
HO
13:87
84%
OH
O
HO
Br
HO
In, H2O
+
OH
13:87
79%
HO
OH
Paquette, L.A.; Bennett, G.D.; Issac, M.B.; Chhatriwalla, A. J. Org. Chem. 1998, 63, 1836-1845.
18
Diastereoselectivity: 1,4 Induction
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Sterics - of protecting group, R group and substituent on
allylbromide - are defining factor
O
R1H
H
LnIn
OPG
Ph
R1CHO
In, H2O
H
Ph
PGO
H-H interaction
(favorable)
HO R1
H
Ph
OH
R1
H
OPG
Ph
OPG
Br
H
H
H
H
R'
H
Ph
R'
InLn
OH
H
OPG
Ph-H interaction
(unfavorable)
OH
R1 OH
InLn
Ph
O
O
Ph
H
H
OPG
R1
OPG
Ph
Paquette, L.A.; Bennett, G.D.; Issac, M.B.; Chhatriwalla, A., J. Org. Chem. 1998, 63, 1836-1845.
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-product vs. -product
 - homoallylic alcohols also useful building blocks

O

OH
OH
Br
H
+
In, solvent
 adduct
(major product)
 adduct
(minor product)
solvent
amount (eq)
time (h)
yield % (
CH2Cl2
6
72
no rxn.
THF
6
72
20 (0:100)
H2O
2 mL
72
90 (0:100)
H2O
6
24
85 (99:1)
THF/H2O (1:1)
6:6
72
95 (0:100)
CH2Cl2/H2O (1:1)
6:6
24
86 (>99:1)
aldehyde:bromide:In = 1:1.2:1.5
Tan, K.T.; Chng, S.S.; Cheng, H.S.; Loh, T.P. J. Am. Chem. Soc. 2003, 125, 2958-2963.
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•
Spectroscopic Study of Product Selectivity
1H
NMR spectroscopy study
– Spectra taken at 2, 4, and 24 hour intervals.
– Reaction proceeded rapidly to  product, which slowly converted to 
product
• Crossover experiment
OH
OH
O
OH
H
+
Ph
Ph
Br
In, 6 eq H2O
Ph
10%
OH
OH
Ph
Ph
Ph
11%
Tan, K.T.; Chng, S.S.; Cheng, H.S.; Loh, T.P. J. Am. Chem. Soc. 2003, 125, 2958-2963.
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Proposed Mechanism of Rearrangement
O
R1
R2
Br
H
Metal
R1
R2
O
OH
R2
R1
OH
R1
R1
R2
path A
R1
H
O
R1
path B
O
OH
R1
R2
- H+
OH
R2
+ H+
R1
R1
O
O
R1
R1
OH2
R2
- H2O
O
O
R1
R2
R1
R1
+ H2O
OH2
R1
R2
R2
Tan, K.T.; Chng, S.S.; Cheng, H.S.; Loh, T.P. J. Am. Chem. Soc. 2003, 125, 2958-2963.
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E - Z Isomerization
Regioselectivity independent of initial double bond geometry sterics may be determining factor
O
OH
In
H2O
Br
+
E:Z (55:45)
O
OH
Br
+
In
H2O
E:Z (100:0)
Another route by which scrambling can occur
R1
X
R2
In
R1
InLn
R2
R1
R2
R2
InLn
InLn
R1
Tan, K.T.; Chng, S.S.; Cheng, H.S.; Loh, T.P. J. Am. Chem. Soc. 2003, 125, 2958-2963.
Li, C.J.; Chan, T.H. Tetrahedron 1999, 55, 11149 - 11176.
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Selectivity Recap
• 1,2 diastereoselectivity - Felkin-Ahn transition state
trajectory if chelation not favored or possible
• 1,3 diastereoselectivity - chelation increases selectivity and
sometimes rate
• 1,4 diastereoselectivity - chelation increases rate and
erodes selectivity
•  vs.  substitution -  substitution requires more time, a
specific amount of water, and excess aldehyde to rearrange
• E/Z isomerization - mostly dependent on sterics, not degree
of substitution or conjugation with substituent
24
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Accepted Mechanisms for Grignard
• Four membered transition state
R - Mg - Br
R MgBr
R2C O
R2C O
• Homogeneous SET
R - Mg - X
O
+
Ar
OMgX
+
R
Ar
Ar
Ar
OMgX
Ar
Ar
R
solvent cage
• Heterogeneous SET
R"
R"
O
R'
O
R'
R
Li
R" OH
R
R'
Molle, G.; Bauer, P. J. Am. Chem. Soc. 1982, 104, 3481-3487.
Smith, M. B.; March, J. Advanced Organic Chemistry; 5th Ed; Wiley: New York 2001; pp 1205-1209.
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Aqueous Mg Barbier and Mechanism
Barbier-Grignard allylation in water with Mg
O
OH
H
+
I
Mg
0.1N NH4Cl
12 h, rt
HO OH
+
58%
OH
+
34%
8%
Also observed 1,5 hexadiene as a by-product and complete
conversion of aldehyde.
I
RCHO
Mg
OH
Mg
R
RCHO
I
Mg
Li, C.J.; Zhang, W.C. J. Am. Chem. Soc. 1998, 120, 9102-9103.
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Postulated Mechanism: SET
Chan and Li postulate a radical anion, generated by single
electron transfer (SET) is coordinated to the metal surface,
and then a subsequent SET occurs
R
R'
O
Br
Br
In
In
R
R'
O
Br
SET
In
R
R'
OH
This mechanism is like the mechanism for both the Barbier
allylations
Li, C.J.; Chan, T.H. Organic Reactions In Aqueous Media; Wiley & Sons: New York, 1997.
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Organometallic Complex
• A discrete organometallic complex is thought to form
• Debate about whether an In(I) or In(III) complex
• Proposed mechanism:
O
H
In, H2O
Br
O
In
OH
+ [In]
H
In
1
X
In
In
In
3
2
3
X
In
X
X
4
In
X
InX
2
5
Kim, E.; Gordon, D.M.; Schmid, W.; Whitesides, G.M. J. Org. Chem. 1993, 58, 5500-5507.
Chan, T.H.; Yang, Y.; J. Am. Chem. Soc. 1999, 121, 3228-3229.
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NMR Spectroscopic Study
1
X
In
In
In
3
2
3
X
In
X
In
X
X
4
InX
2
5
• Allyl bromide with In in D2O studied by NMR spectroscopy
• Resonance at 1.7ppm grew in quickly and disappeared
overnight
• Signal at a maximum (30 min), quenched with benzaldehyde
and obtained 99% yield of homoallylic alcohol
• Formed same species by reaction with allyl mercury with In in
water - ruled out intermediates 3,4 and 5
• Allyl mercury with InBr3 did not form same complex by NMR ruled out 2 as well
Chan, T.H.; Yang, Y. J. Am. Chem. Soc. 1999, 121, 3228-3229.
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Stereochemical Support
Setting contiguous stereogenic centers in water - would be
difficult to predict if there were no organo-indium
intermediate.
TBSO CH O
TBSO CH O
3
OCH3
O
H
OTBS
H
O
OCH3
OH
5
OCH3
H3C
3
OH
95
Br
In, H2O
92%
TBSO
CH3 O
TBSO
OCH3
OCH3
OH
0
H3COOC
H
TBSO
H3C
Ph
H
OH
0
TBSO
H
InLn
O
CH3 O
Major
Product
H COOCH3
Ph
O
InLn
H
Minor
Product
CH3
Issac, M.B.; Paquette, L. A.; J. Org. Chem. 1997, 62, 5333-5338.
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Radical Inhibition in THF
Although run in THF, seems to support a non-radical pathway
for allylation
O
HInCl2
R
In
OH
H+
H
R
Radical inhibitor experiments
O
HInCl2
TEMPO
Ph
rt, 5h
OH
H
rt, 3h
Ph
43%
O
N
OH
TEMPO
O
TEMPO
HInCl2
rt, 5h
Ph H
rt, 3h
Ph
71%
Hayashi, N.; Honda, H.; Yasuda, M.; Shibata, I.; Baba, A. Org. Lett. 2006, 8, 4553-4556.
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Most Likely Mechanism
A discrete organometallic intermediate
• Helps to explain selectivity
• NMR spectroscopic evidence
• Able to be generated separately and still affect allylation
• Radical inhibitor does not affect allylation of carbonyl
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Synthetic Application: KDO
O
O
CHO
O
O
O
O
COOEt
In, Br
CO2Et
OH
O
O
10% formic acid
aq. CH3CN, 61%
O
1) O3, MeOH, -78ÞC
2) Me2S, MeOH,
-78Þto rt, 92%
O
erythro:threo=2:1
CO2Et
OH
O
O
O
aq.TFA,
55%
HO
HO OH
O COOH
HO
OH
3-Deoxy-D-manno-2-octulosinic acid
(KDO)
Gao, J.; H ärter, R.; Gordon, D.M.; Whitesides, G.M. J. Org. Chem. 1994, 59, 3714-3715.
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Synthetic Applications: KDN
O
OH OH O
HO
OH OH OH
Br
H
OCH3
OH OH
D-mannose
HO
In, H2O
OH OH
O
syn:anti
6:1
OMe
62% yield
syn diastereomer
1) O3, CH2Cl2, -78ÞC
2) Na2CO3
HOHO
OH
OH
O
HO
CO2H
HO
49% overall
3-deoxy-D-glycero-D-galacto-2-nonulosonic acid
(KDN)
KOH
MeOH
rt
OH OH OH O
OMe
HO
OH OH
Chan, T.H.; Li, C.J.; J. Chem. Soc., Chem. Commun. 1992, 747-748.
O
34
Qui ckTime™ and a
TIFF (LZW) decompressor
are needed to see this pi cture.
Synthetic Application: Neu5Ac analogs
Indium allylation easily scaled to >5 g with no loss of yield.
Comparable to isolation from edible birds nests or chemo-enzymatic
synthesis.
HO
HO
HO
NH2HCl
O
OH
1) Amine protection
2) In, EtOH:0.1M HCl
(7:1) 55ÞC, 36h
Br
NHBoc
HO
HO
HO
S/R = 4
88%
CO2Et
CO2Et
OH
*
OH
2 steps
HO
Quic kTime™ and a
TIFF (Unc ompres sed) dec ompres sor
are needed t o s ee t his pict ure.
OH
OH
HO
BocHN
O
CO2Et
HO
70%
Edible bird’s nest
Choi, S.K.; Lee, S.; Whitesides, G.M. J. Org. Chem. 1996, 61, 8739-8745.
35
Synthetic Applications: (+) Cyclophellitol
Qui ckTime™ and a
TIFF (LZW) decompressor
are needed to see this pi cture.
O
O
OH
HO
HO
OH
D-xylose
I
1) MeOH, HCl, 5ÞC
BnO
2) I2, PPh3, imidazole,
THF, 65ÞC
3) BnOC(NH)CCl3,
TfOH, dioxane, rt
In
Zn, THF/H2O
40ÞC
Sonication
OMe
OBn
H
Br
O
Bn
H
HO
BnO
CO2Et
OBn
CO2Et
CO2Et
O
OH
HO OH
(+) cyclophellitol
14% yield
OH
2 steps
BnO
OBn
OBn
In, H2O
La(OTf)3
48 h
CO2Et
O
CHO
Grubbs 2nd gen
CH2Cl2
OH
BnO OBn
85% yield
single diastereomer
Hansen, F.G.; Bundgaard, E.; Madsen, R. J. Org. Chem. 2005, 70, 10139-10142.
36
Qui ckTime™ and a
TIFF (LZW) decompressor
are needed to see this pi cture.
Synthetic Application: -Lactams
• Diastereofacial selectivity linked to amido substituent
• Chiral auxiliary allows for high stereoselectivity - only two of
four possible isomers are isolated
• Anhydrous conditions lead to enolization side reactions
• Route to highly functionalized, enantiomerically pure 
lactams
O
O
N
Me
H
Ph
Br
In, H2O/THF
+
Ph
HO
O
N Me
H
Ph
HO
O
N Me
H
+
20ÞC, 79%
71 : 29
Paquette, L.A.; Rothhaar, R.R.; Issac, M.B.; Rogers, L.M.; Rogers, R.D. J. Org.Chem. 1998, 63, 5463-5472.
37
Qui ckTime™ and a
TIFF (LZW) decompressor
are needed to see this pi cture.
Synthetic Applications: Carbocyclic Ring
Expansion
•Water found to be crucial for reaction to proceed
•Prepared 7,8,9,10 and 14 membered rings this way
O
O
H
O
Br
In, 10h
0.1N HCl/MeOH
(3:1)
CO2Me
O
H CO2Me
N
N
O
O
DBU
+
O
O
H CO Me
2
H CO Me
2
63% overall
2.5:1 de
Li, C.J.; Chen, D.L.; Lu, Y.Q.; Haberman, J.X.; Mague, J.T. J. Am.Chem. Soc. 1996, 118, 4216-4217.
38
Qui ckTime™ and a
TIFF (LZW) decompressor
are needed to see this pi cture.
Catalysis with Indium: Stoichiometric Mn
Need mild reductant (Mn) and oxophile (TMSCl) to complete
catalytic cycle. Cannot rule out activation of Mn by In.
10% [In]
O
H
1 eq
Br
+
OH
5 eq Mn
5 eq TMSCl
anh. THF
2.5 eq
[In]
yield
In0
88%
InBr3
61%
InBr
67%
Predictable stereochemistry
OBn
H
O
Br
+
In
Mn/TMSCl
anh. THF
22h, rt
O
BnO
H H
OBn
H
InLn
OH
68% yield
33:67 syn:anti
Augé, J.; Lubin-Germain, N.; Marque, S.; Seghrouchni, L. J. Organomet. Chem. 2003, 679, 79-83.
39
Qui ckTime™ and a
TIFF (LZW) decompressor
are needed to see this pi cture.
Catalysis with Indium: Stoichiometric Al
Need stoichiometric aluminum as reductant, water is oxophile
O
Br
H + 1.6 eq
1eq
1.6 eqAl,
6 mol% InCl3
OH
H
Ph
91%
(2:5) H2O/THF
InLn
O
Br
H
Al
AlCl3
OInLn
H
Ph
In(0)
InCl3
Ph
H2O
AlOH
Al(OH)3
HO InLn
Al
OH
Ph
H
Araki, S.; Jin, S.J.; Idou, Y.; Butsugan, Y. Bull. Chem. Soc. Jpn. 1992, 65, 1736-1738.
40
Qui ckTime™ and a
TIFF (LZW) decompressor
are needed to see this pi cture.
Catalysis with Indium: Electrochemistry
Can regenerate indium electrochemically
InCl3 (5 mol %)
O
+
–
–
–
–
Br
Al Anode
Pt Cathode
THF, 25ÞC
OH
96%
Uses an undivided cell
Reduction takes place at the sacrificial Al anode
Also get bis-allylation of methyl esters, in low conversion
Side reactions are problematic
Hilt, G.; Smolko, K.I. Angew. Chem., Int. Ed., 2001, 40, 3399-3402.
41
Qui ckTime™ and a
TIFF (LZW) decompressor
are needed to see this pi cture.
Summary
Allylating with indium in water is advantageous:
– Carbohydrates do not have to be protected
– Reactive without many by-products
– Selective and predictable reactions
• Stereochemistry relative to another stereocenter can be set
•  or  product can be had depending on conditions
• E vs. Z is still a little hard to predict, but large groups favor E
– Indium is able to be regenerated
– Scalable
– Water helps make separation of product from metal facile
– Homoallylic alcohol product can be further functionalized or utilized
with ease
42
Qui ckTime™ and a
TIFF (LZW) decompressor
are needed to see this pi cture.
Next Steps
• Further exploration of the intermediate indium complexes
would be exciting - organometallic chemistry in water
• Further kinetic study of the reaction will aid in understanding
which indium species is used in allyation
• Continue to couple aqueous RCM and this methodology to
make a two step organometallic sequence in water
43
Acknowledgements
• Shannon Stahl
• Stahl Group
• Practice talk attendees
–
–
–
–
–
Joe Binder
Brian Popp
Michelle Rogers
Mike Konnick
Chris Scarborough
• DOE
–
–
–
–
–
Dr. Tetsuya Hamada
Dr. Guosheng Liu
Dr. Denis Kissounko
Nattawan Decharin
James Hrovat
Qui ckTime™ and a
TIFF (LZW) decompressor
are needed to see this pi cture.
Indium vs. Zinc and Tin
• Tin
– Requires heat or sonication
– Reactive toward allyl halides but does not reduce aldehyde
• Zinc
– Requires sonication or heat
– Poorer selectivity and yield in the same reactions as Sn or In
– De-halogenation by-product seen
• Indium
– Reacts as well as tin, only at room temp without sonication
– More reactive toward allyl halides, does not reduce aldehyde
– No by-products observed
Kim, E., Gordon, D.M., Schmid, W., Whitesides, G.M. J. Org. Chem. 1993, 58, 5500-5507
45
Qui ckTime™ and a
TIFF (LZW) decompressor
are needed to see this pi cture.
Allenylation vs. propargylation
• Allenyl is generally preferred product
• Propargyl product favored when bromo-2-propyne used
OH
O
H
+
•
In / H2O
Br
O
5 to 7 h
O
OH
+
O
• NMR spectroscopy study shows intermediate depends on
solvent and substitution
H
•
In
H
H
aqueous and
organic media
HH
H
•
H
H
Br In
Br
organic media
Me
HH
Me
In
aqueous media,
more reactive to
aldehyde
In Br
Br
aqueous media,
less stable to H2O
Issac, M.B., Chan, T.H., J.Chem.Soc. Chem. Commun., 1995, 1003-1004
Miao, W., Chung, L.W., Wu, Y.-D., Chan, T.H. J.Am.Chem.Soc. 2004, 126, 13326-13334
46
Qui ckTime™ and a
TIFF (LZW) decompressor
are needed to see this pi cture.
HO
HO
Total Synthesis of (+)-Goniofurone
O H
H O
1) H2SO4
OH acetone
2)Tf2O,
O pyridine
DCM -40ÞC
O
O
O H
H O
OTf
LiBr
acetone
O
97%
O
O
O H
H O
Br
O
CF3CO2H
H2O, rt
98%
86%, 94%
HO
HO
O H
H O
Br
O
Br
32%
Key step: 56% yield, >10:1 favoring syn diastereomer
OH
O
AcO
OAc
H
H
HO H O
O
1) NaHSO3/Na2SO3/
MeOH/H2O
2) HCl(g)/MeOH
44%
AcOAcO H
In, (1:9)
0.1N HCl/EtOH
HO
OH
Br
O
O
1) O3/MeOH/Me2S
2)NaBH4/MeOH/ -10ÞC
3)H2SO4/Ac2O
• HO H
Br
O
O
75%
Yi, X.Y., Meng, Y., Hua, X.G., Li, C.J., J. Org. Chem. 1998, 63, 7472-7480
47
Qui ckTime™ and a
TIFF (LZW) decompressor
are needed to see this pi cture.
Other allylations
Addition to cylopropene - solvent and protecting groups affect
syn:anti ratio
OH
OH
H
H
OH
H
In2I3
OH
OH
H2O, rt, 2h
Cyclization of tethered haloenynes
Br
H
+
OH
cis:trans = 6:94, 75% yield
In (1eq), rt
X
X=C(CO2R), C(CN)2, NR, O
THF:H2O (1:1)
15 to 18 h
X
45% to 90% yield
Araki, S., et.al. Chem. Eur. J. 2001, 7, 2784-2790
Goeta, A., Salter, M.M., Shah, H., Tetrahedron, 2006, 62, 3582-3599
48