Novel stabilized organoboron partners for the Suzuki-Miyaura cross-coupling reaction

By Olga Dykhno

BOH

OHR

BR OO

MeN

O

O

R-B(MIDA)

R B

N

N

H

H

R-B(dan)

OO

B

H

Pinacolborane

BF3KR1

Organotrifluoroborate

Palladium catalyzed cross coupling reactions

1Metal- Catalyzed Cross- Coupling Reactions. 2nd ed. Ed. De Meijere, A.; Diederich, F. Wiley- VCH. Weinheim, 2004.

Early observations of Suzuki cross-coupling

Miyaura, N.; Suzuki, A. J. Chem. Soc., Chem. Commun. 1979, 866 - 867.Miyaura, N.; Yanagi, T.; Suzuki, A. Synth. Commun. 1981, 11, 513 - 519. 2

Suzuki- Miyaura Cross Coupling

3Walker, S.D.; Barber, T.W.; Martinelli, J.R.; Buchwald, S.L. Angew. Chem. Int. Ed. 2004, 43, 1871-1876 – 867; Bhayanna, B.; Fors, B.P.;Buchwald, S.L. Org. Lett., 2009, 11, 3954-3957.

Natural product synthesis of Vancomycin Aglycon

4Nicolaou, K.C.; Bulger, P.G.; Sarlah, D. Angew. Chem. Int. Ed. 2005, 44, 4442- 4489.

General routes to prepare boronic acids

5

Boronic acids. Ed. Hall, D.G, Wiley-VCH. Weinheim, 2005;

Molander, G.A.; Canturk, B. Angew. Chem. Int. Ed., 2009, 48, 9240-9262.;

Organoboron coupling parners

6

Boronic acid and boronic ester properties

• Boronic acids are trivalent boron-containing organic compounds• Mild organic Lewis acids• Low toxicity and degrades into environmentally friendly boric acid• Products of second oxidation of boranes

• Formation of boronic esters – loses hydrogen bond donor capabilities• Boronic esters are less polar, easier to handle• Boronic esters are non atom economical

7Boronic acids. Ed. Hall, D.G, Wiley-VCH. Weinheim, 2005.

Boronic acids and boronic esters

Limitations

• Boronic acids are not monomeric species, but rather exist as dimeric and cyclic trimeric anhydrides.

• Due to easy protodeboronation, excess (20-50%) of boronic acid is needed.

•Sensitivity to reagents commonly used in organic synthesis

8Boronic acids. Ed. Hall, D.G, Wiley-VCH. Weinheim, 2005.

• First report of convenient synthesis of organotrifluoroborates using boronic acid and derivatives using KHF2

• First to utilize organotrifluoroborates in coupling reactions with arenediazonium tetrafluoroborates.

Early observations of organotrifluoroborates

Vedejs, E.;Chapman, R.W.; Fields, S.C.; Lin, S.; Schrimpf, M.R. J. Org. Chem. 1995, 60, 3020-3027;Darses, S.; Genet, J.P.; Brayer, J.L.; Demoute, J.P. Tetrahedron Lett. 1997, 38, 4393-4396. 9

Advantages

• Monomeric, crystalline compounds that are easily handled and indefinitely stable to moisture and air.

• BF3K moiety is compatible with sensitive functional groups

• Tolerant to reaction conditions.

Organotrifluoroborate properties

10Darses,S.; Michaud, G.; Genet, J.-P. Eur.J.Org.Chem., 1999, 1875-1883.

Organotrifluoroborate stability

Molander, G.A.; Cooper, D.J. J. Org. Chem. 2007, 72, 3558-3560;Molander, G.A.; Petrillo, D.E. J. Am. Chem. Soc. 2006, 128, 9634-9635. 11

Advances over the years

• Potassium heteroaryl trifluoroborates with aryl chlorides.

• Electron poor aryl bromide with electron-deficient aryltrifluoroborates.

Molander, G.A.; Biolatto, B. J. Org. Chem. 2003, 68, 4302-4306; Molander, G. A.;Rivero, M.R. Org. Lett. 2002, 4, 107-111;

Molander, G.A.; Canturk, B. Org.Lett. 2008,10, 2135-2138; Barber, T.E.; Buckwald, S.L. Org.Lett. 2004, 6, 2649-2652.12

• Coupling of vinyl trifluoroborates with aryl triflates

Molander, G.A.; Canturk, B. Org.Lett. 2008,10, 2135-2138.

Preparation of potassium alkoxymethyltrifluoroborates

13

Molander, G.A.; Canturk, B. Org.Lett. 2008,10, 2135-2138.

Cross - coupling of potassium benzyloxytrifluoroborates

14

Hydroboration and Suzuki - Miyaura cross coupling

Molander, G.A.; Sandrock, D.L. J. Am. Chem. Soc. 2008,130,15792-15793. 15

One-pot hydroboration and bidirectional SMC

Molander, G.A.; Sandrock, D.L. J. Am. Chem. Soc. 2008,130,15792-15793. 16

Boronic acid "protecting group"

17

Iterative Cross-Coupling

Iterative Cross-Coupling criteria

• Building blocks are readily available and inexpensive• Coupling and Protection/deprotection are high yielding, functional group tolerant and do not produce toxic by-products• Handling, separation, and purification are facile

18Madabe, K.; Ishikawa, S. Chem.Comm 2008, 3829-3838.

Boron - Masking Strategy

Noguchi, H.; Hojo, Kosho.; Suginome, M. J. Am. Chem. Soc. 2007,129,758-759.

• Coupling of arylboronic acid A with haloboronic acid C – no desired product.• Formation of mixture of oligoarenes

• Coupling of arylboronic acid A with “masked” haloboronic acid C’- desired product.

19

Development of the Boron Masking Group

Masking Group Requirements

• Easy installation• High stability during coupling and isolation process• Easy unmasking

Noguchi, H.; Hojo, Kosho.; Suginome, M. J. Am. Chem. Soc. 2007,129,758-759. 20

Cross - coupling of arylboronic acids

Noguchi, H.; Hojo, Kosho.; Suginome, M. J. Am. Chem. Soc. 2007,129,758-759. 21

Divalent Cross - Coupling Module

Noguchi, H.; Shioda, T.; Chou, C.-M.;Suginome, M. Org.Lett. 2008, 10, 377-380.. 22

Noguchi, H.; Shioda, T.; Chou, C.-M.;Suginome, M. Org.Lett. 2008, 10, 377-380..

Synthesis of boron - substituted oligoarene derivatives

23

Boronic acid "protecting groups"

24

Design strategy of MIDA protected boronates

Boron masking strategy

Gillis, E.P.; Burke, M.D. J. Am. Chem. Soc. 2007, 129, 6716-6717. 25

Synthesis of MIDA protected bifunctional building blocks

Gillis, E.P.; Burke, M.D. J. Am. Chem. Soc. 2007, 129, 6716-6717. 26

Cross-coupling of MIDA haloboronic acids

Gillis, E.P.; Burke, M.D. J. Am. Chem. Soc. 2007, 129, 6716-6717. 27

•MIDA boronate functional group is stable to a wide range of common synthetic reagents• Further elaboration or increase in molecular complexity is possible with MIDA boronates

MIDA boronates stability

Gillis, E.P.; Burke, M.D. J. Am. Chem. Soc. 2008, 130, 14084-14085. 28

MIDA boronates stability

Gillis, E.P.; Burke, M.D. J. Am. Chem. Soc. 2008, 130, 14084-14085. 29

Benchtop stability of boronic acids and MIDA boronates

Knapp, D.M.; Gillis, E.P.; Burke, M.D. J. Am. Chem. Soc. 2009, 131, 6961- 6963. 30

Slow- release cross-coupling

31Knapp, D.M.; Gillis, E.P.; Burke, M.D. J. Am. Chem. Soc. 2009, 131, 6961- 6963.

32

Retrosynthetic Analysis of Ratanhine

Gillis, E.P.; Burke, M.D. J. Am. Chem. Soc. 2007, 129, 6716-6717. 33

Synthesis of Ratanhine

Gillis, E.P.; Burke, M.D. J. Am. Chem. Soc. 2007, 129, 6716-6717. 34

35

Conclusions and future directions

• Unmasking requires harsh conditions• Functional group tolerance was not illustrated

• Solubility issues are present

• Expensive protecting group• Loss of atom economy

36

Acknowledgements

Professor Tehshik Yoon

Kat Myhre

Steve Burke

Yoon Group

Kevin WilliamsonTamas Benkovics

Juana DuElliot Farney

Michael IschayShishi LinDr. Zic Lu

Dr. David MichaelisDr. Katie Partridge

Jon ParrishLaura Ruiz Espelt

Liz Tyson

Additional practice talk attendees

Teresa BearyJ.P. Gerdt

Brad RylandNicky StephensonAdam Weinstein