Recent Developments of the Morita-Baylis-Hillman Reactionfranklin.chem.colostate.edu/emferr/Ferreira_Research...Recent Developments of the Morita-Baylis-Hillman Reaction Erin Stache

Recent Developments of the Morita-Baylis-Hillman Reaction

Erin StacheDecember 6, 20103rd Year Seminar

EWG CatalystX

R2R1

X = O, NR

! EWGR2

R1

XH

Basavaiah, D.; Rao, A. J.; Satyanarayana, T. Chem. Rev. 2003, 103, 811-891.Basavaiah, D.; Reddy, B. S.; Badsara, S. S. Chem. Rev. 2010, 110, 5447-5674.

Origins of the Morita-Baylis-Hillman (MBH) Reaction

Me H

OCO2Et

NN

Morita 1968

CO2Et

HO Me

93% conversion

Baylis and Hillman 1972

5 mol %

neat, 7d, 23 °C

Morita, K.; Kobayashi, T. Bull. Chem. Soc. Jpn. 1968, 42, 2732.Baylis, A. B.; Hillman, M. E. D. German patent 2155113, 1972.

H Me

OCO2Me

CO2Me

HO MePCy3, 0.6 mol %

dioxane, 125 °C, 2h

23% conversion

DABCO

Features of the MBH Reaction

• 2 component coupling to form carbon-carbon bonds

EWG CatalystX

R2R1

X = O, NR

! EWGR2

R1

XH

• activated alkene component

• electrophiles are typically carbonyl components, but can also be Michael acceptors

• catalysts consist of trialkyl amines or trialkyl, -aryl phosphines, although some Lewis acids are used in conjunction


CO2R COR CN CONR2 SO2RX

O

n

X = CH2, O, S

O

R2RR2 = H or C

NR

R2Raza-MBH

EWG

Complications Associated with MBH

• Very slow reaction rates

• Reactive substrates lead to dimerized products

CO2Me DABCO

neat, 23 °C, 6 d

O

PhCO2Me

Ph

OH

89%

Caubere, P.; Fort, Y.; Berthe, M. C. Tetrahedron 1992, 48, 6371-6384.Shi, M.; Ma, G.-N.; Jiang, J.-J.; Wei, Y. Chem. Commun. 2009, 5496-5514.

COPh DABCO

DMF, 20 °C60-70 h

O

p-NO2Ph

OH

p-NO2PhCOPh

COPh

COPh COPh

76%15%

• No traditional MBH product observed

• More electron rich aromatic aldehydes less reactive

Synthetic Challenges Associated with MBH• Asymmetric Induction

• Esoteric substrates give high selectivity

• Previous attempts with chiral amines, aldehydes, and acrylates unsuccessful

SO

O

N

OMeCHO, DABCO

CH2Cl2, 0 °C, 12 h

O

O

O

MeMe85%, 99% ee

Leahy, J. W.; Brzezinski, L. J.; Rafel, S. J. Am. Chem. Soc. 1997, 119, 4317-4318Fráter, G.; Roth, F.; Gygax, P. Tetrahedron Lett. 1992, 33, 1045-1048.

• Intramolecular MBH

CO2Et

OMe PBu3, 23 °C, 1 d

CO2Et

OH

75% conversion

• First example of an intramolecular MBH

• Employing different electrophiles and exploring scope of the reaction

Mechanism of the MBH Reaction

O

OR1NR3 O

OR1

R3N

O

R2HR3N O

OR1

R2O

H

O

OR1

R2HO

Initial Mechanistic Hypothesis

RDS

• RDS is addition into aldehyde, followed by an intermolecular proton transfer and catalyst expulsion

Hill, J. S.; Isaacs, N. S. Tetrahedron Lett. 1986, 41, 5007-5010. Kaye, P. T.; Bode, M. L. Tetrahedron Lett. 1991, 32, 5611-5614.Caubere, P.; Fort, Y.; Berthe, M. C. Tetrahedron, 1992, 48, 6371-6384.

• 1° KIE of 1.3 observed with D-hydroxyquinuclidine in CDCl3

NN

NOH(D)

krel = 7.4krel = 1O

OR

N

OH

• stabilizing effect

Mechanistic Rationale Does Not Explain...

O

OR'

O

RH

O

OR'

OH

RDABCO (15 mol %)

neat, 23 °C

O

Ot-Bu

OH

Me

7 d, 89%

O

OMe

OH

Cl3C

20 h, 55%

O

OMe

OH

Ph

6 d, 39%

• Reaction rates dependent upon electronics and size of components

Hoffmann, H. M. R.; Rabe, J. Angew. Chem. Int. Ed., Engl. 1983, 22, 795-796.Ikegami, S.; Yamada, Y. M. A. Tetrahedron Lett. 2000, 41, 2165-2169.

O

Ph

O PBu3 (20 mol %)

THF, 23 °C, 1 h Ph

OHO

1.5 equiv 23%

• Yield quantitative with addition of 2-naphthyl alcohol (20 mol %)

Mechanism Also Does not Explain...

CO2PhN

NO

R

(cat)OH

R

CO2Ph

O

OO R

RR = Me 0% 57%

0% 95%

neat, 2-24 h, 23 °C

R = i-Pr

• Observation of dioxanone product questions proton transfer

CO2Ph NR3R3N O

OPhR3N O

OPh

Me O

R3N O

OPh

Me O

OMe

O

OPh

Me O

OHMe

OH

Me

CO2Ph

O

OO Me

Me-NR3

MeCHO

MeCHO

Perlmutter, P.; Puniani, E.; Westman, G. Tetrahedron Lett. 1996, 37, 1715-1718.

-HOPh

5 equiv

R = Me(1 equiv)

0% 52%

NN

HOMe

OO

OMe

NN

Ar H

O

Ar

OH

O

OMe

NN

Ar

OH

O

OMe

NN

O

Ar

Ar

OH

O

OMe

NN

ArO

Ar

O

O

OMe

OH

Ar RDS

Revised MBH Mechanism Supported by Data• 2nd order in aldehyde-2 equivalents in RDS

• 1st order in acrylate-1 equivalent in RDS

• 1st order in DABCO-1 equivalent in RDS

Ar H

O

McQuade, D. T.; Price, K. E.; Broadwater, S. J.; Jung, H. M. Org. Lett. 2005, 7, 147-150.McQuade, D. T.; Price, K. E.; Broadwater, S. J.; Walker, B. J. J. Org. Chem. 2005, 70, 3980-3987.

NN

(D)HOMe

OO

OMe

NN

Ar H

O

Ar

OH

O

OMe

NN

Ar

OH

O

OMe

NN

O

Ar

Ar

OH

O

OMe

NN

ArO

Ar

O

O

OMe

OH

Ar RDS

Revised MBH Mechanism Supported by Data• 1° KIE of 5.2 in DMSO with p-nitrobenzaldehyde

• 1° KIE of 2.2 in CHCl3 with p-nitrobenzaldehyde

• Decrease of 1° KIE a function of !pKa of alkoxide and "-proton

Ar H

O

McQuade, D. T.; Price, K. E.; Broadwater, S. J.; Jung, H. M. Org. Lett. 2005, 7, 147-150.McQuade, D. T.; Price, K. E.; Broadwater, S. J.; Walker, B. J. J. Org. Chem. 2005, 70, 3980-3987.

1° KIE

Another Look at the MBH Mechanism

HOR1

O NR3 HOR1

O

R3N

PhCHO

OR1

O

R3N

H

OPh

HO

R2

R3N

Ph

OH

EWGHO

R2

R3N

Ph

O

OR1

O

Ph

OH

OR1

O

or

Ikegami, S.; Yamada, Y. M. A. Tetrahedron Lett. 2000, 41, 2165-2169.Aggarwal, V. K.; Lloyd-Jones, G. C.; Fulford, S. Y. Angew. Chem. Int. Ed. 2005, 44, 1706-1708.

O

Ph

O PBu3 (20 mol %)

THF, 23 °C 1 h Ph

OHO

1.5 equiv 23%

• Yield quantitative with addition of 2-naphthyl alcohol (20 mol %)

RDS step 2

RDS step 3


(D)HOEt

OH

OEt

O

R3N

PhCHO

OR1

O

R3N

H

OPh

HO

R2

R3N

Ph

OH

EWGHO

R2

R3N

Ph

O

OEt

O

Ph

OH

OEt

O

or

Aggarwal, V. K.; Lloyd-Jones, G. C.; Fulford, S. Y. Angew. Chem. Int. Ed. 2005, 44, 1706-1708.

RDS step 2RDS step 3

• Competition experiment between d-ethyl acrylate/ethyl acrylate

• Suggests RDS is step 3 until 20% conversion, then RDS is step 2

N

-NR3

RDSlate

stage

RDS early stage



CO2Me DABCO

neat, 23 °C, 6 d

O

PhCO2Me

Ph

OH

89%

Caubere, P.; Fort, Y.; Berthe, M. C. Tetrahedron 1992, 48, 6371-6384.


• Without limiting substrate scope, 3 ways to enhance rate

• Find most reactive nucelophile to initiate reaction

• Use Lewis acid catalysts to promote nucleophilic addition

• Employ protic additives or solvents to assist in RDSR3N

Ph

OH

EWGHO

R2

OR

O O

R2OR

OOH

R2

DABCO (30 mol %)

La(OTf)3 (1.5 mol %)chiral diamine (3 mol %)

CH3CN, 23 °C, 10 h

Lewis Acid for Rate Enhancement of MBH

OMe

OOH

MeO55%

OPh

OOH

Ph

97%

OBn

OOH

Ph

75%

OR

OOH

Ph

R = naphthyl, 20 min88%

Chen, K.; Yang, K.-S.; Lee, W.-D.; Pan, J.-F. J. Org. Chem. 2003, 68, 915-919.Connell, B. T.; Bugarin, A. J. Org. Chem. 2009, 74, 4638-4641.

N N

MeMe

MeMeCO2H

HO2C

• Bulky aryl acrylates give faster reaction times by stabilization of enolate

OO

HR

TMEDA (10 mol %)MgCl2 (10 mol %)

DMAP (10 mol%)MeOH, 23 °C

O

R

OH

1.1 equiv

R = (CH3)2CH 15 h, 62%

R = p-NO2Ph 5 h, 94%

R = Ph 15 h, 91%

R = p-OMePh 15 h, 67%48 h, 83%

Ph O

OOH

Ph S

OOH

2h, 53% 1h, 92%

• MgCl2/TMEDA work as Lewis acid, with DMAP as nucelophile

Urea Catalyst for MBH Rate EnhancementO

CO2Mecatalyst (20 mol %)DABCO (1 equiv)

23 °C, neatCO2Me

OH

(10 equiv)

X

NH

NH

R

R R

RR = H, X = S

R = F, X = S

R = F, X = O

R = CF3, X = S

R = CF3, X = O

krel

none

Catalyst1.0

1.7

5.7

5.4

3.7

6.7

• EWG urea promotes reaction

88%, 20 h

CO2MeOH

MeO71%, 4 d

CO2MeOHNO2

93%, 1 h

O

OHCO2Me

88%, 2 h

CO2MeOHOMe

81%, 3 d

Connon, S. J.; Maher, D. J. Tetrahedron Lett. 2004, 45, 1301-1305.

• Urea catalyst enhances reaction rate through H-bonding

• Reactions employing MVK and catalyst resulted in decomposition

Exploration of MBH Amine Catalysts

Aggarwal, V. K.; Emme, I.; Fulford, S. Y. J. Org. Chem. 2003, 68, 692-700.

NN

N N N N NOH OAc Cl O

pKa

krel

11.3

9.0

8.7

1

9.9

4.3

9.3

0.15

8.9

0.04

6.9

0.006

• Reactions run neat; pKa measured in H2O• More basic catalyst gives higher concentration of ammonium enolate

CO2Me

R

O

1.2 equiv

quinuclidine (25 mol %)methanol (75 mol %)

23 °CCO2Me

OH

RR = Et 7 h, 83%R = 2-furyl 1 h, 84%R = cinnamyl 3 h, 62%R = p-MePh 9 h, 82%

• Catalytic MeOH aids in initial conversion and solubility of reactants

NN

pKa

krel

8.7

1

N NOAc Cl

9.3

0.15

8.9

0.04

• DABCO higher pKa in aprotic solvents, higher rate of reaction

time (h), yield previous best

14h, 83%20h, 85%24h, 43%24h, 61%

Exploration of MBH Amine Catalysts

Aggarwal, V. K.; Emme, I.; Fulford, S. Y. J. Org. Chem. 2003, 68, 692-700.

CN

R

O

1.2 equiv

quinuclidine (25 mol %)methanol (75 mol %)

23 °CCN

OH

R

CNOH

3 h, 81%5 min, 5kbar, 70%

CNOH

1 h, 87%4 h, 97%

CNOH

O20 min, 78%

5d, 74%

CNOH

6 h, 76%40 h, 66%

CONH2

R

O quinuclidine (50 mol %)methanol (7.5-14M)

23 °CCONH2

OH

R

CONH2

OHN

5 h, 83%24 h, 89%

CONH2

OH

O5 h, 66%

48 h, 61%

CONH2

OH

O2N4 h, 65%

24 h, 95%

CONH2

OH

3 d, 55%n/a

conditionsprevious best

• Very few acrylamide examples in literature

conditionsprevious best

Octanol for Rate Enhancement of MBH

COMeO

Me

DABCO (15 mol %)

23 °C, 12 hCOMe

Me OH

COMe

OH

7% : 7%COMe

OH

MeO

0% : 8%COMe

OH

F3C

20% : 0%COMe

OH

NO2

16% : 0%

Chong, Y.; Choo, H.; Park, K.-S.; Kim, J. Synlett 2007, 395-398.

Me

O

Me

OH2OMeOHBuOHoctanolCH3(CH2)11OHcyclohexanol

0% : 0%28% : 12%50% : 10%65% : 8%50% : 9%

68% : 10%• 2 equiv of octanol provided 90% yield MBH adduct

3 mL MeOHoctanol (2 equiv) 100% : 0% 100% : 0% 18% : 43% 91% : 9%

• Reactions with MVK and challenging aldehydes unsuccessful

O

MeH

R3N

Me

O

OHO

H

• stabilization of transition state through van der Waals

p-Nitrophenol as a Promoter with PPh3

H

OO PPh3 (20 mol %)

p-nitrophenol (30 mol %)

DMSO, 18 h, 23 °C

OOH

• p-nitrophenol acts as Lewis acid, promoting the conjugate addition step and proton transfer

Shi, M.; Liu, Y.-H. Org. Biomol. Chem. 2006, 4, 1468-1470.

52%25% no additive

OOH

MeO35%

OOH

O2N98%

OOH

72%

OOO

Ph3P

H B

PPh3

H B

enolate stabilization assisted deprotonation

H




CO2Me DABCO

neat, 23 °C, 6 d

O

PhCO2Me

Ph

OH

89%


COPh DABCO

DMF, 20 °C60-70 h

O

p-NO2Ph

OH

p-NO2PhCOPh

COPh

COPh COPh

76%15%

• No traditional MBH product observed


The Double MBH Reaction

Shi, M.; Ma, G.-N.; Jiang, J.-J.; Wei, Y. Chem. Commun. 2009, 5496-5514.

Ph

ONR3 Ph

O

R3N

R1CHO Ph

O

R3N

R1

O

Ph

O

R1

O

Ph

O

R3N

Ph

O

R1

O

Ph

O

R1

O

Ph

O

R1CHO Ph

O

R1

O

NR3

NR3

HH

HH

COPhCOPh

R3N

COPh

Ph

O

R3N

• Treating PVK dimer with nucelophile and aldehyde does not provide double MBH adduct

R3N

Ph

O

R1

OH

COPhCOPh

R3N

The Double MBH ReactionO

PhO

RH

DABCO (10 mol %)

DMF, 20 °C60-70 h Ph

OCOPh

OH

RPh

O

Ph

O

R = m-NO2Ph2 equiv

76% 15%R = Ph trace 33%

O

OPh

O

RH

DABCO (10 mol %)

DMF, 20 °C40-50 h

2 equiv

OPh

O

R

OH

R = m-NO2Ph 74%R = Ph 79%

• No MBH product observed; challenging aldehydes give only PVK dimer

• No dimerization or double MBH adductsShi, M.; Li, C.-Q.; Jiang, J.-K. Molecules 2002, 7, 721-733.Shi, M.; Ma, G.-N.; Jiang, J.-K.; Wei, Y. Chem. Commun. 2009, 5496-5514.

O

Me

O

H

NO22 equiv

NR3 (10 mol %)

DMF, 20 °C40-60 h Me

OCOMe

OH

RMe

O

R

OH

DMAPDABCO

85% 0%63% 23%

• Nucelophile used can affect formation of double MBH adducts

Avoiding Dimerization: The Sila-MBH

Gevorgyan, V.; Trofimov, A. Org. Lett. 2009, 11, 253-255.

TMSAr

O

Ar2

O

H

TTMPP (5 mol %)

C3H7CN, 23 °C

1.5 equiv

Ar

O

Ar2

TMSO

O

R

TMSOO

Ph

TMSO

OMe69%

O

Ph

TMSO

Cl72%

P

MeO

OMe

MeO 3TTMPP

TMSAr

O

PR3

TMSAr

O

PR3

Ar2

O

TMS Ar

O

PR3

OAr2

Ar

O

Ar2

TMSO

R = p-ClPh

R = Ph

R = p-OMePh

99%

81%

55%

• Normal MBH adducts achieved with electron rich vinyl ketones

-PR3

• 1,3-Brook rearrangement triggers elimination to provide product

Avoiding Dimerization: The Sila-MBH

MeO2C CO2Me

TMS

TTMPP (1 mol %), RCHO (2 equiv)

dioxane, 23 °C

MeO2C CO2Me

R

OTMS

MeO2C CO2Me

Ph

OTMS

MeO2C CO2Me

OTMS

MeO2C CO2Me

OTMS75%

OMe

65%

Ph

76%

MeO2C CO2Me

OTMSPh

69%

MeO2C CO2Me

Ph

OTMSn-Bu

86%

MeO2C CO2Me

PhOTMSCF3

53%

• Steric bulk not an issue due to highly reactive substrate

Gevorgyan, V.; Chuprakov, S.; Malyshev, D. A.; Trofimov, A. J. Am. Chem. Soc. 2007, 129, 14868-14869.

• Inspiration for sila-MBH of aryl vinyl ketones

• !-substitution well-tolerated; ketones function as electrophiles




CO2Me DABCO

neat, 23 °C, 6 d

O

PhCO2Me

Ph

OH

89%


COPh DABCO

DMF, 20 °C60-70 h

O

p-NO2Ph

OH

p-NO2PhCOPh

COPh

COPh COPh

76%15%

• Sila-MBH or change nucleophile

• Use protic additives to assist RDS of proton transfer

R3N

Ph

OH

EWGHO

R2


• Esoteric substrates give high selectivity

• Previous attempts with chiral amines, aldehydes, and acrylates unsuccessful

SO

O

N

OMeCHO, DABCO

CH2Cl2, 0 °C, 12 h

O

O

O

MeMe85%, 99% ee



CO2Et


CO2Et

OH

75% conversion




HOEt

OH

OEt

O

R3N

PhCHO

OR1

O

R3N

H

OPh

HO

R2

R3N

Ph

OH

EWGHO

R2

R3N

Ph

O

OEt

O

Ph

OH

OEt

O

or


RDS step 2RDS step 3

• Competition experiment between d-ethyl acrylate/ethyl acrylate

• Demonstrates RDS step 3 until 20% conversion, then RDS step 2

N

-NR3

RDSlate

stage

RDS early stage

Mechanism Explains Difficulties in Asymmetric Induction

O

OR

Nu!

OH R1CHO R1

O

Nu!

OR

OH

OH

!

!

RLSR1

! OR

OOHfast

slow

slow

slow


• 4 diastereomeric intermediates possible before proton transfer/elimination

• Past attempts unsuccessful due to incomplete understanding of mechanism

• Chiral amines or chiral lewis acids unlikely to control proton transfer step

• With properly designed chiral catalysts, only one diastereomeric intermediate will proceed to product

O

O CF3

CF3 catalyst (10 mol %)

THF or DMF, -55 °C p-NO2Ph O

O

CF3

CF3OH

Early Example of Asymmetric MBH

O O

p-NO2Ph

Op-NO2Ph

Hatakeyama, S.; Iwabuchi, Y.; Nakatani, M.; Yokoyama, N. J. Am. Chem. Soc. 1999, 121, 10219-10220.

N

N

OMe

OH

(+)-quinidine

N

N

OMe

ON

N

OMe

OH

OH

O

O2N3 equiv

N

N

OH

O

A B

A : 12%, ee ndB : 22%, 33% ee

A : 2%, ee ndB : 32%, 35% ee

A : 63%, 35% eeB : 10%, 33% ee

A : 58%, 91% eeB : 11%, 04% ee

• Less sterically hindered amine enhances rate of reaction

R O

O

CF3

CF3OHO O

R

OR

R = Ph A : 57%, 95% eeB : n/a

R = isobutyl A : 51%, 99% eeB : 18%, 85% ee

• High enantioselectivities for electron rich aromatic and aliphatic aldehydes

N

O

Et

N

OH

H

N

O

Et

N

O H

H

CO2RHHRO

Mechanistic Rationale for Stereoinduction

N

O

Et

N

O H

H

CO2RHHRO

OR

OOCH(CF3)2

Ocatalyst

R1CHO

R1CHO

OH

R1

O

ORO O

R1

R1 O

OH

R1

O

ORO O

R1

R1 O

R1CHOR1CHO

Hatakeyama, S.; Iwabuchi, Y.; Nakatani, M.; Yokoyama, N. J. Am. Chem. Soc. 1999, 121, 10219-10220.

NR2

H HH

CO2RYX

OHO

N

Thiourea Catalyst for Asymmetric MBH

NH

NH

S CF3

CF3N

OO catalyst (10 mol %)

solvent, 0 °C, 48 h

O OH

Wang, W.; Wang, J.; Li, H.; Yu, X.; Zu, L. Org. Lett. 2005, 7, 4293-4296.

PhPh

5 equiv

NH

NH

S CF3

CF3

NMe2

21%, 39% ee

NH

NH

S CF3

CF3N

56%, 73% ee 83%, 71% ee

• Binaphthyl amine essential for yield and enantioselectivity

• Optimized conditions with CH3CN provide 80% yield, 83% ee

O OH

63%, 94% ee

O OH

71%, 90% ee

O OH

n-Bu

84%, 81% ee

O OH

Cl55%, 60% ee

• Increased sterics improves enantioselecitivity; aromatic aldehydes provide moderate ee's

Simple Thiourea for Asymmetric MBH

S

NH

NH

CF3

CF3Ph

OH

S

NH

NH

CF3

CF3Ph

OH

Me

Ph

S

NH

NH

CF3

CF3Ph

OH

Ph

Ph

O Ocatalyst (20 mol %)

DABCO (20 mol %)23 °C

O OH

48h, 32%, 9% ee 65h, 56%, 46% ee 88h, 50%, 63% ee

• Removal of hydroxyl group results in lower conversion• Optimized conditions use 4 equiv cyclohexenone, 20 mol% catalyst and 20 mol% Et3N

O OH

147h, 61%, 88% ee

O OH

120h, 45%, 81% ee

O OH

119h, 74%, 64% ee

O OH

OMe119h, 86%, 56% ee

Lattanzi, A. Synlett 2007, 2106-2110.

Thiourea Catalyst for MBH with Aromatic Aldehydes

HN

NH

S

NH

R

S

HN

R

O2N

CHO catalyst (20 mol %)DABCO (20 mol %)

PhCH3, 23 °C, 3 d

O OOH

O2N

Shi, M.; Liu, X.-B. Org. Lett. 2008, 10, 1043-1046.

• Aromatic aldehydes have proven difficult in asymmetric reactions

R = 3,5-(CF3)2Ph67%, 5% ee

HN

NH

S

NH

R

S

HN

RR'

R'R' = Ph

R' = 3,5-(CH3)2Ph

R' = 3,5-(CF3)2Ph

53%, 39% ee

65%, 35% ee

67%, 72% ee

• More electron deficient thiourea provides highest levels of selectivity

OOH

99%, 81% ee

OOH

Cl

90%, 85% ee

OOH

F79%, 88% ee

Schaus, S. E.; McDougal, N. T. J. Am. Chem. Soc. 2003, 123, 12094-12095.Schaus, S. E.; McDougal, N. T.; Trevellini, W. L.; Rodgen, S. A.; Kilman, L. T. Adv. Synth. Catal. 2004, 346, 1231-1240.

X

X

OHOH

Ph H

OO

X =

Me

Me

O

Ph

OHcatalyst (2 mol %)PEt3 (0.5 equiv)

THF, 0 °C, 36 h

Chiral Brønsted Acid Catalyzed MBH

OHOH

74%, 32% ee X = HX = Ph

X =

CF3

CF3

73%, 48% ee69%, 86% ee

70%, 88% ee 84%, 86% ee

OMeOH

43%, 3% ee

• Removal of one Brønsted acid lowers catalyst activity and selectivity

O

Et3P

H BO

Et3P

O

R

HBOOH

71%, 96% ee

OOH

82%, 95% ee 72%, 96% ee

• stabilization of enolate and assisted deprotonation

OOHEt

NMeMe

MeMe

Me

N

NMe2N

Fe PhPhPh

PhPh

Fe FePh2P

Ph2P

NMe2

Lewis Acid Enhanced MBH with Chiral Amine Catalyst

Fu (+)-PPY Fu (+)-DMAP Taniaphos

O

Ph

O catalyst (10 mol %)MgI2 (50 mol %)

i-PrOH, -20 °C, 24 h

O

Ph

OH

98%, 81% ee 96%, 94% ee 45%, 54% ee

• Less nucelophilic catalyst provides highest selectivity

Connell, B. T.; Bugarin, A. Chem. Commun. 2010, 46, 2644-2646.

OOH

MeO73%, 95% ee

OOH

87%, 94% ee

OOH

94%, 98% ee

• Electron deficient aromatic and aliphatic aldehydes gave moderate results

• All other Michael acceptors failed to produce product

1.5 equiv

OOH

O2N75%, 89% ee

OMe

O O

Ph OMe

OOH

PhDABCO (30 mol %)

La(OTf)3 (1.5 mol %)chiral diamine (3 mol %)

CH3CN, 23 °C, 10 h

Lewis Acid for Asymmetric MBH

Chen, K.; Yang, K.-S.; Lee, W.-D.; Pan, J.-F. J. Org. Chem. 2003, 68, 915-919.

N N

MeMe

MeMeCO2H

HO2C

N N

MeMe

MeMeCO2H

HO2C

75%, 84% ee 70%, 67% ee

N N

Me Me

O

O

Me

Me

O

O La

OO

R3N

O

H R

• Stereochem rationalization

OR

OOH

O2N82%, 93% ee

OR

OOH

MeO

R = !-naphthyl

35%, 95% ee

• Aliphatic aldehydes gave moderate selectivity

N

O

N

OH

NH

O

OCHO (10 mol %)

CH2Cl2, - 20 °C, 4 dNH

O

HOCHO

79%, 98% ee

NO

HOCHO

Me96%, 98% ee

NO

HOCHO

Bn97%, 96% ee

NO

HOCHO

Me

F

92%, 96% ee

NO

HOCHO

Me

MeO

91%, 97% ee

N

HO

MeBr

Br

96%, 93% ee

Asymmetric Synthesis of Substituted Oxindoles

Zhou, J.; Liu, Y.-L.; Wang, B.-L.; Cao, J.-J.; Chen, L.; Zhang, Y.-X.; Wang, C. J. Am. Chem. Soc. 2010, 132, 15176-15178.

LiAlH4 (5.0 equiv)

THF, 23 °CN

HO

Me75%, 98% ee

NaBH4 (5.0 equiv)

THF/H2O (9:1 v/v)0 °C

OO

HOHMe

NHMe

81%, 98% ee3 : 1 dr

• Differential substitution does not effect selectivity

• In previous examples, ketones unsuccessful

• One step derivatization of oxindole products

O

H

O

CHO


• Use bifunctional catalyst to control stereochemistry of addition into aldehyde and proton transfer

SO

O

N

OMeCHO, DABCO

CH2Cl2, 0 °C, 12 h

O

O

O

MeMe85%, 99% ee



CO2Et


CO2Et

OH

75% conversion



Early Demonstrations of Intramolecular MBH

Keck, G. E.; Welch, D. S. Org. Lett. 2002, 4, 3687-3690.Koo, S.; Yeo, J. E.; Yang, X.; Kim, H. J. Chem. Commun. 2004, 236-237.

O

HO

SEt

OH O

SEt

solvent temp °C time (h) additive yield %

CHCl3 65 24 48

25CH2Cl2 23 3 DBU (1 equiv)DMF 78 5 43EtOH 78 1 DMAP, DMAP!HCl (1.0, 0.25 equiv) 87EtOH 78 1 DABCO (1 equiv) 18

CH2Cl2 23 15 PMe3 (0.1 equiv) 82

DMAP, DMAP!HCl (1.0, 0.25 equiv)

DMAP, DMAP!HCl (1.0, 0.25 equiv)

• DMAP!HCl assists in stabilization of resulting alkoxide, pushing equilibrium to product

O

HO

R

OH O

RPPh3 (1.0 equiv)

MeCN or t-BuOH20-30 °C

OH O

H

12 h, 98%

OH O

Ph

22 h, 99%

OH O

Me

24 h, 83%

OH O

Bu

25 h, 83%

• DABCO ineffective at inducing transformation

Intramolecular Asymmetric MBH

Ph

O Ocatalyst (10 mol %)

CDCl325 °C, 48h

Ph

O OH

N

N

O OH

82%, 80% ee

O OH

Cl92%, 79% ee

O OH

Me94%, 51% ee

O OH

S

83%, 74% ee

Miller, S. J.; Aroyan, C. E.; Vasbinder, M. M. Org. Lett. 2005, 7, 3849-3851.

• Co-catalyst conditions necessary for reaction and selectivity

NH

CO2H NH

CO2Me NH

CO2HMe

NH

CO2H

60% ee <10% ee <10% ee 60% ee

• Change of solvent to THF/H2O (3:1)32% ee 80% ee

• Ortho substitution lowers enantioselectivity

Thiourea Catalyzed Intramolecular Asymmetric MBH

Wu, X.-Y.; Gong, J.-J.; Yuan, K.; Song, H.-L. Tetrahedron 2010, 66, 2439-2443.

S

NH

NH

Ph

PPh2

i-Pr

O

Ph

O OH

Ph

Ocatalyst (10 mol %)

CH2Cl2, 25 °C

48 h, 72%, 18% ee

S

NH

NH

Ph

PPh2

Bn

60 h, 50%, 67% ee

S

NH

NH

PPh2

Bn

CF3

CF3

12 h, 83%, 76% ee

S

NH

NH

PPh2

BnOMe

84 h, 45%, 56% ee

• Electronics of thiourea have large effect on activity and selectivity

S

N NR

Ph2P

Bn

H HO

HO

Arre-attack

OHO

MeO77%, 84% ee

OHO

Me99%, 45% ee

OHO

F76%, 75% ee

• Ortho substitution effects enantioselectivity

Cyclization via MBH PathwayO

Cl1. PBu3 (1 equiv) t-BuOH, 5h, 23 °C

2. KOH, BnEt3NCl, 2h

O

80%

O

94%, >10 : 1

Krafft, M. E.; Haxell, T. F. J. Am. Chem. Soc. 2005, 127, 10168-10169.

OCl O

Cl

1 : 2

OCl

PBu3

OCl

Bu3P

O

Bu3P

OKOH

-PBu3Cl

• Second step needed to displace catalyst in absence of alkoxide

• Treatment of allylic alcohol with SOCl2 provided mixture of regioisomersCl

PBu3

t-BuOH, 23 °C, 5 h

Cl

>90% recovery

• Suggests no allylic isomerization, SN2' or SN2 mechanism likely

Cyclization via MBH PathwayO

RO

R2PMe3 (1 equiv)

t-BuOH, 23 °C

O

ROH

R2 O

R

R2HO

endo exo

O

Ph

OH

30h, 66%

O

Me OH

72h, 60%

O

MeOH

18h, 76%

O

R

OH

10 equiv PR372h, 92%

• Sterics govern endo/exo selectivity

Krafft, M. E.; Wright, J. A. Chem. Commun. 2006, 2977-2979. Krische, M. J.; Jellerichs, B. G.; Kong, J.-R. J. Am. Chem. Soc. 2003, 125, 7758-7759.

O

R

OCO2CH3

PBu3 (1 equiv)

Pd(PPh3)4 (1 mol %)t-BuOH, 60 °C

O

R

O

Ph

92%

O

76%

O

EtS

73%

O

66%

nn

• Cyclopropanes untouched under these conditions

Synthetic Applications of MBH

EWG CatalystX

R2R1

X = O, NR

! EWGR2

R1

XH

EWGR1

XH

• New method development using MBH adducts

Conditions

EWG CatalystX

R2R1

! EWGR2

R1

XHcomplex

products


• Use MBH adducts as synthetic intermediates en route to complex products

simplestarting

materials

EWGR1

X• Formation of tri-substituted olefins

X = OH, OR X = C, Cl, Br, I, N, O

Synthesis of Tri-substituted Olefins from MBH Adducts

Ph

OHCO2Me

N

N

N

Cl

ClCl(2.5 equiv)

DMF (2 M), CH2Cl223 °C, 1.5 h

Ph

CO2Me

Cl89%

CO2Me

Cl

Cl 94%

CO2Me

Cl

O2N 97%

CO2Me

ClO

85%

• Z-selective synthesis

CO2Et

Cl

92%

Li, J.; Li, S.; Jia, X.; Zhang, Y. J. Chem. Res. 2008, 48-49.Das, B.; Majhi, A.; Banerjee, J.; Chowdhury, N.; Venkateswarlu, K. Tetrahedron Lett. 2005, 46, 7913-7915.

• Formation of Villsmeier reagent followed by attack and elimination provides Z-isomer

Ph

OHCN

I2/PPh3

CH2Cl2, 23 °C0.5-6 h

Ph CN

I92%

• E-selective synthesis

CNI

Cl90%

n-heptCN

I

89%

CNI

NO2 58%

Applications of Modified MBH AdductsOAc

CO2Me Na2S (1.5 equiv)

DMSO/H2O, 40 °C10 min - 1.5 h S

CO2Me

R X R

R =5-OMe, X = FR = H, X = FR = H, X = NO2

34%41%43%

CO2Me

X S S

MeO2C

X

S2-

S

CO2Me

• Thiochromenes have shown variable biological activity

Lee, K.-J.; Cha, M. J.; Song, Y. S.; Han, E.-G. J. Heterocyclic Chem. 2008, 45, 235-240.Basavaiah, D.; Aravindu, K. Org. Lett. 2007, 9, 2453-2456.

NO2

OAcCO2Et

OO 1. K2CO3, THF 23 °C, 2-6 h

2. Fe/AcOH reflux, 1.5 h

HN

O

CO2Et

HN

O

CO2Me

62%

68%

HN

O

CO2Et

64%

MeO

MeO HN

O

CO2Me

63%

Br

Butenolide Synthesis From an MBH Adduct

O

R

OAc

R2

2-trimethylsiloxy furan(200 mol %)

PPh3 (20 mol %)THF

O

R R2

O

O

H H

O

Me

O

O

H H

88%, >95:5 drNO2

O

Me

O

O

H H

80%, 20:1 dr

O

Me

O

O

H H

Ph88%, 24:1 dr

O

MeO

O

O

H H

86%, >95:5 dr

Krische, M. J.; Cho, C.-W. Angew. Chem. Int. Ed. 2004, 43, 6689-6691.Shi, M.; Jiang, Y.-Q.; Shi, Y.-L. J. Am. Chem. Soc. 2008, 130, 7202-7203.

62-94%, >95 : 5 dr

O

Me

O

O

H H

94%, 96% ee36h

O

Me

O

O

H H

Br85%, 95% ee

24h

O

Me

O

O

H H

NO2

98%, 91% ee24h

O

Me

O

O

H Hn-Pr

60%, 72% ee96h

• Chiral phosphine used to induce asymmetry

Asymmetric Butenolide Synthesis from an MBH Adduct

NHCOMe

PPh2

O

R2

OAc

R O

OTMS10 mol % catalyst

PhCH3, H2O (6 equiv)23 °C

O

R2R

O

O

H H

2.5 equiv

Shi, M.; Jiang, Y.-Q.; Shi, Y.-L. J. Am. Chem. Soc. 2008, 130, 7202-7203.

PPhPh

R2

O RN

OMe H

PPhPh

R2

O RN

OMe H

OH

OSiMe3

HO

H

O

OTMS

PPhPh

R2OH

OSiMe3

HO

HMeOCHN

O

R2R

O

O

H HGrob-type ROC

• [4+2] cycloaddition with Grob-type fragmentation

[4+2]

MBH in Total Synthesis

NPMB

OBnO

O Me

Corey 2004 - Salinosporamide A

quinuclidine (1 equiv)

DME, 0 °C, 7 d90%

NO

PMBCO2Me

OBn

MeOH

NO

PMBCO2Me

OBn

OHMe

1 : 9HN

OO

O

ClMe

H

OH

steps

Corey, E. J.; Reddy, L. R.; Saravanan, P. J. Am. Chem. Soc. 2004, 126, 6230-6231.Porco Jr., J. A.; Lei, X. J. Am. Chem. Soc. 2006, 128, 14790-14791.

• Diastereoselective intramolecular MBH

Porco Jr. 2006 - (-)-Kinamycin C

OO

OTBSO

Br (CH2O)n, La(OTf)3

N(CH2CH2OH)3PEt3, CH2Cl2

-20 °C, 6 h, 70%

OO

OTBSO

Br

OH

steps

O

OOH NN

AcOOH

OAc

Me

OAc

• Triethanolamine sequesters lewis acid to liberate nucleophile

Concluding Remarks

• Morita-Baylis-Hillman reaction is an atom economical process that results in high levels of molecular complexity

• Despite the slow nature of the reaction, many methods have been developed to enhance reaction rate

• Asymmetric induction can be achieved using bifunctional catalysts or combinations of organocatalysts and lewis acids

• MBH products have many applications in total synthesis as well as new method development

EWG CatalystX

R2R1

X = O, NR

! EWGR2

R1

XH

Concluding Remarks



• Asymmetric induction can be achieved using bifunctional catalysts or combinations of organocatalysts and lewis acids


Concluding Remarks



• Asymmetric induction can be achieved using bifunctional catalysts or combinations of organocatalysts and Lewis acids


NH

NH

S CF3

CF3N

OO

i-Pr

catalyst (10 mol %)

CH3CN, 0 °C, 48-120h

O OH

i-Pr

94% ee

Concluding Remarks



• Asymmetric induction can be achieved using bifunctional catalysts or combinations of organocatalysts and Lewis acids

• MBH products have many applications in new method development and total synthesis

NHCOCH3

PPh2

O

R2

OAc

R O

OTMS10 mol % catalyst

PhCH3, H2O (6 equiv)23 °C

O

p-TolMe

O

O

H H

96% ee

• A general method for asymmetric induction still needed

• Current methods are very specific to substrates

• !-substitution very limited to special substrates

•PhMe2SiO

R1 R

HO

R1

R

R2

OH1. Sc(OTf)3 (10 mol %) CH2Cl2, -78 °C, 15min-18h

2. HCl, THF

20:1 Z:E

O

R2

• Compatible with extremely hindered and electron rich substrates

Scheidt, K. A.; Reynolds, T. E.; Bharadwaj, A. R. J. Am. Chem. Soc. 2006, 128, 15382-15383.

Future Outlook

• Intramolecular variant still in infancy

Acknowledgements

Eric Ferreira

Ferreira Group

Documents

Recent Developments of the Morita-Baylis-Hillman Reactionfranklin.chem.colostate.edu/emferr/Ferreira_Research...Recent Developments of the Morita-Baylis-Hillman Reaction Erin Stache