Phosphine Oxide-Catalysed Chlorination Reactions of Alcohols Under Appel conditions

Denton, R. M.; An, J.; Adeniran, B. Chem. Commun. 2010, 46, 3025-3027

A Concise Synthesis of HonokiolDenton, R. M.; Scragg, J. T.; Galofré, A. M.; Gui, X.; Lewis, W. Tetrahedron 2010, 66, 8029-8035

Catalysis of Phosphorus(V)-Mediated Transformations: Dichloronation Reactions of Epoxides Under Appel Conditions

Denton, R. M.; Tang, X.; Przeslak, A. Org. Lett. 2010, 12, 4678-4681

R1 R2

OH+ Cl

OCl

O

PO

PhPhPh

catalytic

R1 R2

Cl+ CO

CO2

R1R2

O+ Cl

OCl

O

PO

PhPhPh

catalytic

+ COCO2R1

R2

Cl

Cl

OHOH

Ross M. Denton

2001 - 2004: PhD with Professor J.C. Anderson (University of Nottingham)

2005 - 2007: Postdoctoral studies with K.C. Nicolaou (Scripps Research Institute)

2007 - 2009: Postdoctoral studies with Steven Ley (University of Cambridge)

June 2009: Appointed to a permanent lectureship (University of Nottingham)

Research Interests

New Chemistry and catalysis: Atom efficient and environmentally friendly construction of chemical bonds. New catalytic organophosphorus chemistry

Natural Products and Biological Study: Construction of plant derived natural products (>10 steps) for study of neurodegenerative diseases.

Appel Reaction

R

OH

R'

CX4, PPh3

X= Br, Cl R

X

R'

Mechanism

Ph3PBr

Br BrBr

P BrPhPhPh

+ CBr3

R

O

R'

H

P BrPhPhPh R

O

R'

R

O

R'

PPh

PhPh

BrR

Br

R'+ P

PhPhPh

O

Development of a Catalytic Chlorination Reaction

C9H19 OH5

X mol % Ph3PO,

1 equiv (COCl)2 CHCl3

C9H19 OH6

+ C9H19 O

7

+

O

O

ClC9H19 O

O

O

O C9H19

8

Entry Ph3PO (mol %) Addition protocol/addition time (% of 6) (% of 7) (% of 8) 1 100 5 added to (COCl)2 + Ph3PO 80 - -

2 0 5 added to (COCl)2 - 78 22

3 30 5 added to (COCl)2 + Ph3PO 46 44 10

4 25 5 added to (COCl)2 + Ph3PO over 2 hrs 65 - -

5 15 5 and (COCl)2 added to (COCl)2 + Ph3PO over 7hrs 83 - -

6 0 5 and (COCl)2 added to (COCl)2 over 7hrs - 89 -

7 10 5 and (COCl)2 added to (COCl)2 + Ph3PO over 7hrs 75 - -

8 18 5 and (COCl)2 added to (COCl)2 + Ph3PO over 5hrs 73 - -

Substrate Scope

R OH15 mol % Ph3PO,

1 equiv (COCl)2 CHCl3

R Cl

C9H19 Cl

83%

Ph Cl

80%

Ph Cl

73%

Me Cl

70%

C9H19 Br

48% 67%

Ph Cl

88%

C6H15Cl

Substrate Scope Continued

R OH

15 mol % Ph3PO,

1 equiv (COCl)2 CHCl3

R Cl

R' R'

Cl

7%

MeMe

Cl

69%

Me

Cl

64%

Mechanistic Studies

Cycle 1

PCl

PhPhPh

Cl

CO + CO2

PO

PhPhPh

Cl

R

R OH

R Cl

Cycle 2

PO

PhPhPh

Cl

COCOCl

PO

PhPhPh Cl

O

ClO P

O

PhPhPh

PO

PhPhPh

R OHO

O

ClO

R

OO

OPPh3

O

RCl

R Cl

1H NMR Study

C9H19 OH(COCl)2CDCl3

OO

ClO

C9H191 eq. PPh3

23°C, 16 hrs; reflux 2hrs

C9H19 Cl!!

Catalysis of Phosphorus(V)-Mediated Transformations: Dichloronation Reactions of Epoxides Under Appel Conditions

R1R2

O+ Cl

OCl

O

PO

PhPhPh

catalytic

+ COCO2R1

R2

Cl

Cl

Denton, R. M.; Tang, X.; Przeslak, A. Org. Lett. 2010, 12, 4678-4681

Previous Dichloronation of Epoxides

BnOOTBDPS

O O PPh3/NCS

toluene, 90°C BnOOTBDPS

Cl

ClCl

Cl

42% yield

Yoshimitsu, T.; Fukumoto, N.; Tanaka, T. J. Org. Chem. 2009, 74, 696-702

Croft, A. P.; Bartsch, R. A. J. Org. Chem. 1983, 48, 3353-3354

n(H2C) OPh3P, CCl4

reflux 2-5 daysn =1, 2, 6

n(H2C)Cl

Cl70-80% yield

shorter reaction times

MeO

9

Ph3PO, (COCl)2

2,6-tBuPyCHCl3

Me9

ClCl

Entry Ph3PO (mol %) (COCl)2 (mol %) 2,6-tBuPy (mol %) time (h) yield (%) 1 100 100 0 6 84

2 20 100 0 6 58

3 20 100 0 16 73

4 20 100 150 6 69

5 15 100 150 16 56

6 15 130 150 6 91

7 0 130 150 6 0

Reaction Optimization

Substrate Scope

R1

15 mol % Ph3PO,

1.3 equiv (COCl)2 1.5 equiv 2,6-tBuPy

6h

R2R1 R2O

Cl

Cl

81%

Cl

78%

PhCl

57%

Ph Cl

66%

Me

Cl

Cl

9 Cl4

Cl

Cl

62% 57% 66%

ClCl

TBDPSO 2 MeCl

MeCl

Me

Cl Cl

4 7CO2Et7

Mechanistic Studies

PO

PhPhPh

Cl

COCOCl

PCl

PhPhPh

Cl

Cl

PO

PhPhPh Cl

O

CO + CO2

Cl

O

R1 R2O

R1 R2

OPPh3

Cl

R1 R2

Cl

Cl

A Concise Synthesis of Honokiol

• Family or biaryl neolignans isolated from Magnoliae officinalis in 1972

• Extracts from this bark used for traditional Chinese and Japanese medicine

• Honokiol used a muscle relaxant as early as 1975

• Obtained by extraction from magnolia bark

• Anticancer activity and neurotrophic activity

• 1986 first total synthesis (4 steps, 16% yield)

• 2004 second total synthesis (14 steps, 21% yield)

OH

OH

honokiolOH

chavicol

OH

magnololHO

Initial Retrosynthetic Approach

OH

OHhonokiol

sigmatropicrearrangements

retro FriedelCrafts alkylation

O

O

MeMeMe

alkylation demethylation

OH

OMe

MeMeMe

directarylation

OH OMeMeMe

Me

Br

+

Forward Synthesis, First Approach

OH OMeMe

Me

Me

Br

+[RhCl(COD)]2 (10 mol%)

P(NMe2)3 (30 mol%),Cs2CO3, toluene,

reflux, 18 hrs45% yield

OH

OMe

MeMeMe

O

O

MeMeMe

1) BCl3·SMe2, DCE, reflux, 18 hrs, 66% yield2) Allyl bromide, Cs2CO3 DMF, 23°C, 15 hrs 92% yield

DMF, MW, 200°C, 1hr

49%

OH

OH

MeMeMe

Retro Friedel-Crafts Alkylation

OH

OH

MeMeMe

AlCl3, toluene:MeNO2 (10:1)

60°C, 2 hrs63% yield

OH

OH

OH

OH

MeMeMe

AlCl3, toluene:MeNO2 (10:1)

60°C, 2 hrsdecomposition

OH

OH

OH

OH

MeMeMe

AlCl3, toluene:MeNO2 (10:1)

23°C, 2 hrsno reaction

OH

OH

Revised Retrosynthetic Approach

OH

OHhonokiol

lithiation

OMe

Claisenrearrangement

deprotection

OMe

O

Suzukicoupling allylation

OMe OH

Br

+(HO)2B

Forward Synthesis, Second Approach

PCy2OMeMeO

S-Phos

OMe OH

Br

+(HO)2B

OMe

OH

Pd(dba)3 (10 mol%)

S-Phos (30 mol%)KF (5 equiv.)

THF/H2O, 15 hrs 94% yield

allyl bromide, K2CO3acetone, reflux, 18 hr

99% yield

OMe

O

BCl3·SMe2, DCE,reflux, 18 hrs,

47% yield

OH

OH

+OH

OH

honokiol

Forward Synthesis, Second Approach

PCy2OMeMeO

S-Phos

OMe OH

Br

+(HO)2B

OMe

OH

Pd(dba)3 (10 mol%)

S-Phos (30 mol%)KF (5 equiv.)

THF/H2O, 15 hrs 94% yield

allyl bromide, K2CO3acetone, reflux, 18 hr

99% yield

OMe

O

1) 1,2-dichlorobenzene200°C, MW, 15 min

86% yield

OH

OHhonokiol

2) BCl3·SMe2, DCE,reflux, 18 hrs,

91% yield