Indium Mediated Allylations in Aqueous Media

1
Indium Mediated Allylations in Aqueous Media

• Lauren Huffman
• Stahl Group
• 28 September 2006

2
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.
3
Water in Industry Hydroformylation

• Rurchemie / Rhone-Poulenc hydroformylation oxo
  process (RCH/RP)
• Homogeneous process where water aids in
• Economic heat management
• Avoiding complicated catalyst recycling
• Product separation
• 600,000 tons/year production

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.
4
Water in Industry Palladium Processes

• Wacker process
• Biphasic process
• Cu re-oxidizes Pd
• O2 stoichiometric oxidant
• Higher alkenes still being investigated
• Telomerization (Kuraray 1-octanol process)
• Biphasic process
• Ni catalyzed hydrogenation yields octanol

Aqueous-Phase Organometallic Catalysis Cornils,
B. Herrmann, W.A., Eds. Wiley-VCH Weinheim
2004 pp 481-487, pp 545-546.
5
Water in Industry Electrochemistry

• Synthesis of Adiponitrile (Monsanto)
• Quaternary ammonium salts (QASs) essential for
  selectivity
• Sodium phosphate-borate electrolyte
• Asahis Sebacic Acid Process
• 92 yields, 85 to 90 current efficiency
• 20 aqueous solution of monomethyl adipate
  neutralized by NaOH

Li, C.J. Chan, T.H. Organic Reactions In Aqueous
Media Wiley Sons New York, 1997.
6
Laboratory Scale Interest in Water

• Diels Alder - rate acceleration due to
  hydrophobic effect
• Olefin Metathesis - promising for bio-molecule
  synthesis

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.
7
Indium Mediated Reactions

• Grignard and Barbier Allylations
• Indium Facts
• Indium in Organic Solvent
• Stoichiometric Indium
• Selectivity
• Mechanism
• Synthetic Applications
• Catalytic Indium
• Summary
• Future Directions

8
Barbier and Grignard

• Grignard reaction pre-generates the RMgX compound
• Barbier is the one pot equivalent, (Li and Mg)
• Enolization and reduction side reactions occur
• Proposed single electron transfer (SET) at
• metal surface to form organometallic intermediate

http//nobelprize.org/nobel_prizes/chemistry/laure
ates/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.
9
Meet Indium

• Discovered in 1863
• 63rd most abundant element
• Canada produces the majority of the worlds
  supply
• Named for the brightest line in its spectrum
• 111In (t1/2 2.8d) used for ?-ray imaging
• Used in dental work and low melting alloys
• Electron Configuration Kr 5s24d105p1

LANL Chemistry Division http//periodic.lanl.gov/e
lements/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.
10
In Mediated Allylations in Organic Solvent

• First Allylation mediated by Indium
• 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 (232)

Araki, S. Ito, H. Butsugan, Y. J. Org. Chem.
1988, 53, 1833-1835.
11
In Mediated Allylations in Organic Solvent

• Ongoing field with success in selective imine
  allylation
• (2R,3S) 4,4,4,-Trifluoroisleucine synthesis

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.
12
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

Li, C.J. Chan, T.H. Organic Reactions In Aqueous
Media, Wiley Sons New York, 1997. http//www.we
belements.com/webelements/elements/text/In/key.htm
l
13
Indium Mediated Allylations in Water
Li, C.J Chan, T.H. Tetrahedron Lett. 1991, 48,
7017-7020.
14
Regioselectivity

• Crotyl bromide and other substituted allyls give
  a rearranged (?) product
• Methyl (2-bromomethyl) acrylate and other 1,1
  disubstituted alkenes do not rearrange

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.
15
Diastereoselectivity

• Non-chelating substrates follow Felkin-Ahn T.S.
• Chelating substrates follow a chelated T.S.

Paquette, L.A. Mitzel, T.M. Issac, M.B.
Crasto, C.F. Schomer, W.W. J. Org. Chem. 1997,
62, 4293-4301.
16
Diastereoselectivity 1,2 Induction
Paquette, L.A. Lobben, P.C. J. Am. Chem. Soc.
1996, 118, 1917-1930.
17
Diastereoselectivity 1,3 Induction
Paquette, L.A. Mitzel, T.M. J. Am. Chem. Soc.
1996, 118, 1931-1937.
18
Diastereoselectivity 1,4 Induction
Paquette, L.A. Bennett, G.D. Issac, M.B.
Chhatriwalla, A. J. Org. Chem. 1998, 63,
1836-1845.
19
Diastereoselectivity 1,4 Induction

• Sterics - of protecting group, R group and
  substituent on allylbromide - are defining factor

Paquette, L.A. Bennett, G.D. Issac, M.B.
Chhatriwalla, A., J. Org. Chem. 1998, 63,
1836-1845.
20
?-product vs. ?-product

• ? - homoallylic alcohols also useful building
  blocks

Tan, K.T. Chng, S.S. Cheng, H.S. Loh, T.P. J.
Am. Chem. Soc. 2003, 125, 2958-2963.
21
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

Tan, K.T. Chng, S.S. Cheng, H.S. Loh, T.P. J.
Am. Chem. Soc. 2003, 125, 2958-2963.
22
Proposed Mechanism of Rearrangement
Tan, K.T. Chng, S.S. Cheng, H.S. Loh, T.P. J.
Am. Chem. Soc. 2003, 125, 2958-2963.
23
E - Z Isomerization

• Regioselectivity independent of initial double
  bond geometry - sterics may be determining factor
• Another route by which scrambling can occur

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.
24
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

25
Accepted Mechanisms for Grignard

• Four membered transition state
• Homogeneous SET
• Heterogeneous SET

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.
26
Aqueous Mg Barbier and Mechanism

• Barbier-Grignard allylation in water with Mg
• Also observed 1,5 hexadiene as a by-product and
  complete conversion of aldehyde.

Li, C.J. Zhang, W.C. J. Am. Chem. Soc. 1998,
120, 9102-9103.
27
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
• 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.
28
Organometallic Complex

• A discrete organometallic complex is thought to
  form
• Debate about whether an In(I) or In(III) complex
  
• Proposed mechanism

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.
29
NMR Spectroscopic Study

• 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.
30
Stereochemical Support

• Setting contiguous stereogenic centers in water -
  would be difficult to predict if there were no
  organo-indium intermediate.

Issac, M.B. Paquette, L. A. J. Org. Chem. 1997,
62, 5333-5338.
31
Radical Inhibition in THF

• Although run in THF, seems to support a
  non-radical pathway for allylation
• Radical inhibitor experiments

Hayashi, N. Honda, H. Yasuda, M. Shibata, I.
Baba, A. Org. Lett. 2006, 8, 4553-4556.
32
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

33
Synthetic Application KDO
Gao, J. Härter, R. Gordon, D.M. Whitesides,
G.M. J. Org. Chem. 1994, 59, 3714-3715.
34
Synthetic Applications KDN
Chan, T.H. Li, C.J. J. Chem. Soc., Chem.
Commun. 1992, 747-748.
35
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.

Choi, S.K. Lee, S. Whitesides, G.M. J. Org.
Chem. 1996, 61, 8739-8745.
36
Synthetic Applications () Cyclophellitol
Hansen, F.G. Bundgaard, E. Madsen, R. J. Org.
Chem. 2005, 70, 10139-10142.
37
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

Paquette, L.A. Rothhaar, R.R. Issac, M.B.
Rogers, L.M. Rogers, R.D. J. Org.Chem. 1998, 63,
5463-5472.
38
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

Li, C.J. Chen, D.L. Lu, Y.Q. Haberman, J.X.
Mague, J.T. J. Am.Chem. Soc. 1996, 118, 4216-4217.
39
Catalysis with Indium Stoichiometric Mn

• Need mild reductant (Mn) and oxophile (TMSCl) to
  complete catalytic cycle. Cannot rule out
  activation of Mn by In.
• Predictable stereochemistry

Augé, J. Lubin-Germain, N. Marque, S.
Seghrouchni, L. J. Organomet. Chem. 2003, 679,
79-83.
40
Catalysis with Indium Stoichiometric Al
Need stoichiometric aluminum as reductant, water
is oxophile
Araki, S. Jin, S.J. Idou, Y. Butsugan, Y.
Bull. Chem. Soc. Jpn. 1992, 65, 1736-1738.
41
Catalysis with Indium Electrochemistry

• Can regenerate indium electrochemically
• 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.
42
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

43
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

44
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

45
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
46
Allenylation vs. propargylation

• Allenyl is generally preferred product
• Propargyl product favored when bromo-2-propyne
  used
• NMR spectroscopy study shows intermediate depends
  on solvent and substitution

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
47
Total Synthesis of ()-Goniofurone
Yi, X.Y., Meng, Y., Hua, X.G., Li, C.J., J. Org.
Chem. 1998, 63, 7472-7480
48
Other allylations

• Addition to cylopropene - solvent and protecting
  groups affect synanti ratio
• Cyclization of tethered haloenynes

Araki, S., et.al. Chem. Eur. J. 2001, 7,
2784-2790 Goeta, A., Salter, M.M., Shah, H.,
Tetrahedron, 2006, 62, 3582-3599