applicaons+of+ silylenesin...

Applica'ons of Silylenes in Organic Synthesis

Njamkou N. Nouc' The University of North Carolina at Chapel Hill

Literature Seminar 17 February 2012

1

Silylenes

2 Skell, P. S.; Goldstein, E. J. J. Am. Chem. Soc. 1964, 86, 1442–1443.

Si

First observed by P.S. Skell and E.J. Goldstein in 1964

Short–lived intermediate

Inser9on into Si–H bond

Me SiMe

MeH

Me SiMe

MeSiMeH

Me

MeSi

Me

MeSiCl

Me Cl Na–K

260–280 °CSiMeMe

Silacyclo– propane

MeSiCl

Me Cl

Reac'ons of Free Silylenes

3

–Dimeriza'on to disilenes

–Inser'on into polar bonds

–Reac'ons with olefins

SiMeMe

2 Si SiMe

Me Me

Me

SiMeMe MeOH Si

Me

Me

MeO

H

protectedsilylene

H2C CH2 SiMeMe

SiMeMe

4 4

R1 R2

SitBu tBu

R1 R2

•R3R4

R1R2

SitBu tBu

R1

R2R3

R4

R1 R2O

SiO R2

R1tButBu

R1R2

SitBu tBu

R1 R1

R1O

O

OR2

R1

HO2C

R2

OH

OR2

R1

O Si

R2R1

tButBu

SitBu tBu

Silylenes

5

– No electrical charge � Non–octet species

– Divalent silicon atom � Unshared electrons � Vacant p orbital

Si

Transi'on Metal Bonding

– Back–dona'on much weaker in a metal–silylene complex rela've to metal–carbene complex

� Silicon remains Lewis acidic

� Silicon o^en stabilized with Lewis base

M Si

dσ

6

M Si

dπ

Ground State

– Silylenes react via singlet ground state

7 Balasubramanian, K. J. Chem. Phys. 1986, 9, 5117–5119. Gaspar et. al. J. Organomet. Chem. 2002, 646, 68–79.

– Larger orbital size on silicon lowers pairing energy

ENERGY

8–10 kcal/mol

Singlet

Triplet

CR2

21 kcal/mol

Singlet

Triplet

SiR2ENERGY

Synthesis of Silylenes

8 Zybill, C.; Müller, G. Angew. Chem. Int. Ed. 1987, 26, 669–670. Straus, D.; Tilley, D.; Geib, S.; Rheingold, A. J. Am. Chem. Soc. 1987, 109, 5872–5873.

– Products used mainly for structural and characteriza'on studies – Synthe'c applica'ons of silylenes remains largely underexplored

Cp*Ru

SiMe3PMe3P NaBPh4

+ MeCN-NaOTf

Ph Ph

OTf BPh4

Cp*Ru

SiMe3PMe3P Ph

Ph

NC

Me

(tBuO)2SiCl2 Na2Fe(CO)4 (OC)4Fe SiOtBu

OtBuTHF- 2 NaCl

THF

Synthesis of Silylenes

9

Masked Silylene

Boudjouk P.; Chrusciel, J. et. al. J. Am. Chem. Soc. 1991, 10, 2095–2096.

High reac9vity and short life9me of silylene

intermediate limits further explora9on

Harsh thermal condi9ons and long reac9on 9mes greatly limits substrate

scope

tBuSi

Cl

tBu Cl2 Li0

THF SitButBu

2 LiCl

R R1

- EthyleneSi

tButBu

R

R1

SitButBu

SitButBu

- Ethylenehν or Δ

Cataly'c Variant

10 Cirakovic, J.; Driver, T.; Woerpel, K. A. J. Am. Chem. Soc. 2002, 124, 9370–9371.

Entry MXn T (°C) Time (h) Yield (%)

1 -- 130 36 85

2 Zn(OTf)2 55 12 60

3 Cu(OTf)2 25 0.28 96

4 CeCl3 25 15 87

5 AgOTf -27 2 90

6 AgCO2CF3 -27 2 86

7 Ag3PO4 25 16 94

Si(tBu)2 RMXn (10 mol %)

PhMeR

Si(tBu)2

Silylene Transfer

11

Si(tBu)2AgOTf (2 mol %)PhMe, -27 °C

(1.06 eq)R1R1Si(tBu)2 R2

R2

•

R3

R4

R1

R2

(0.5 eq)

Ag3PO4 (21 mol %)PhMe, -19 °C to rt

SitButBu

R1

R2

R3R4

R1

R2

Ag3PO4 (12 mol %)PhMe, rt

Si(tBu)2R1

R2

(1 eq)

Clark, T. B.; Woerpel, K. A. J. Am. Chem. Soc. 2004, 126, 9522–9523. Cirakovic, J.; Driver, T.; Woerpel, K. A. J. Am. Chem. Soc. 2002, 124, 9370–9371. Buchner, K. M.; Clark, T. B.; Loy, J. M. N.; Nguyen, T. X.; Woerpel, K. A. Org. LeL. 2009, 11, 2173–2175.

Proposed Mechanism

12 Cirakovic, J.; Driver, T.; Woerpel, K. A. J. Org. Chem. 2004, 69, 4007–4012.

SiAgX

tButBu

R

R

β–silyl elimination

RSi(tBu)2

Elimination

Si [Ag]tButBu

X

R

R

1,2–addition

AgX Si(tBu)2

Si

[Ag]

X

tButBu

Transmetallation

Ter'ary α–Hydroxy Acids

13 Howard, B. E.; Woerpel K. A. Org. LeL. 2007, 9, 4651–4653.

PhnBu

HO CO2H

yield: 72%

tBuPh

HO CO2H

yield: 47%

PhPh

HO CO2H

yield: 71%

PhCH2OTBDMS

HO CO2H

yield: 71%

EtPh

HO CO2H

yield: 84%

R1

OO

O

R2 R1

R2

HO CO2HAgOTs (10 mol %)-25 °C

2) HF•Pyr, rt

SiMeMe

tButBu1)

≥97% diastereoselectivity

Ter'ary α–Hydroxy Acids

14 Howard, B. E.; Woerpel K. A. Org. LeL. 2007, 9, 4651–4653.

[3,3]SiO

O

tButBu

R1O

R2

R1

OO

O

R26π electro–cyclization

OR2

OSiO

tButBu

R1

HF•Pyr, rtR1

R2

HO CO2H

R1

OO

O R2

SitBu tBu

AgOTs (10 mol %)-25 °C

SiMeMe

tButBu

1,2–Oxasilacyclopentanes

Franz, A. K.; Woerpel, K. A. J. Am. Chem. Soc. 1999, 121, 949–957.

yield: 82%d.r.: 91:9

(tBu)2SiO

Ph

iPr

H

yield: 74%d.r.: 98:2

(tBu)2SiO

iPr

H

Me

yield: 75%d.r. > 99:1

(tBu)2SiO

iPr

H

Me

Me

NO REACTION

(tBu)2Si OnPr

iPr

H

yield: 78%d.r.: 62:38

(tBu)2Si O

iPr

Me

MeMe

Si(tBu)2

AgOTf (5–10 mol %)

PhMe-27 °C

Si(tBu)2iPr R1 R2

O

CuBr2 (10 mol %)-78 °C to rt

(tBu)2Si OiPr R1

iPr

R2(3 eq)

(1.3 eq)

15

Proposed Mechanism

16 Franz, A. K.; Woerpel, K. A. J. Am. Chem. Soc. 1999, 121, 949–957.

Si(tBu)2iPr CuX

Cu

Si

X

tButBuiPr

Si

iPr

CutBu

tBuX Si

iPr

CutBu

tBuX

O

Me

Cu

OSi

iPr

MeX

tBu tBu

(tBu)2Si O

iPr

H

Me

-CuXSi

iPr

CutBu

tBuX

O

Me

1,3–Oxasilacyclopentanes

17 Cirakovic, J.; Driver, T. G.; Woerpel, K. A. J. Org. Chem. 2004, 69, 4007–4012.

(tBu)2SiO

OMenBu

yield: 87%regioselectivity: >99:1

d.r.: 76:24

(tBu)2SiO

OMeiPr


d.r.: 70:30

(tBu)2SiO

OMetBu

yield: 75%regioselectivity: 74:26

d.r.: 70:30 (major) 91:9 (minor)

(tBu)2Si O

iPr


EtEt

(tBu)2Si O

iPr


d.r.: 55:45

Me

Si(tBu)2

AgOTf (2 mol %)

PhMe-27 °C

Si(tBu)2R1 H R2

O

ZnBr2 (15 mol %)-78 °C to rt

(tBu)2Si O

R1R1 R2

(1 eq)

(1.06 eq)

(3 eq)

Proposed Mechanism

18 Franz, A. K.; Woerpel, K. A. Angew. Chem. Int. Ed. 2000, 39, 4295–4299.

H R2

OBr2Zn

(tBu)2Si

R1 (tBu)2Si O

R1 R2

Br ZnBr

Preferred orienta9on of aLack

Disfavored approach

SitBu

tBu

R1

H H

HBr

BrZnO

H R2

(tBu)2Si O

R2R1-ZnBr2

SitBu

tBu

H

H H

R1Br

BrZnO

H R2

SitBu

tBu

H

H H

R1Br

BrZnO

H R2

Oxasilacyclopentenes

19 Clark, T. B.; Woerpel, K. A. J. Am. Chem. Soc. 2004, 126, 9522–9523.

(tBu)2Si O

yield: 83%

MePh

Ph

(tBu)2Si O

yield: 94%

MePh

PhMe

(tBu)2Si O

yield: 54%

nPr

PhMe

(tBu)2Si O

yield: 68%

HOEt

Ph

(tBu)2Si O

yield: 78%

nPr

SiMe3

R1

R2

Si(tBu)2

Ag3PO4 (12 mol %)

PhMert

Si(tBu)2R1

R2

R3 R4

O

CuXn (15 mol %)-22 °C

(tBu)2Si O

R1R3

R4

R2

(1 eq)

(1 eq)Xn = I, Br2, OTf

(tBu)2Si O

yield: 72%

MePh

NBn

Me

(tBu)2Si O

yield: 90%

MePh

OTIPS

Product Diversifica'on

20

(tBu)2SiO

MeMe

X

X = NR2, OMe, OAc

Nu

Lewis Acid

(tBu)2SiO

MeMe

Nu

Me Nu

OH

Me

OH

[O]

Clark, T. B.; Woerpel, K. A. J. Am. Chem. Soc. 2004, 126, 9522–9523. Bear, T. J.; Shaw, J. T.; Woerpel, K. A. J. Org. Chem. 2002, 67, 2056–2064.

(tBu)2Si O MePh

Ph

KOtBu, nBu4NFOHMePh

PhMe

Me84%

SiO

tBu

tBuMePh

nPr 1) H2, Pd(OH)2

2) tBuOOH, KH, nBu4NF, 75 °C

Me nPr

OH

Ph

OH(tBu)2Si O

PhMe

nPr

Nucleophilic Subs'tu'on

21 Bear, T. J.; Shaw, J. T.; Woerpel, K. A. J. Org. Chem. 2002, 67, 2056–2064.

Nu

1

3

2

O(tBu)2Si

MeMe

O(tBu)2Si

MeMeNu

1

3

"inside" attack

favored2

Nu

"outside" attack

disfavored

1

3

2

O(tBu)2Si

MeMe

Nu

1

3

2

O(tBu)2Si

MeMe

NuH

eclipsed product

=

(tBu)2SiO

MeMe

OAcMe

O SiMe3(tBu)2Si

O

MeMe

MeO

yield: 60%d.r.: 98:2 SnBr4

DCM, -78 °CSnBr4

DCM, -78 °C

(tBu)2SiO

MeMe

Ph

O SiMe3

PhO

yield: 79%d.r.: 96:4

1

3

2

O(tBu)2Si

MeMe Nu

=

staggered product


22

ENER

GY

PATH OF REACTION

B

A

A

B

Bear, T. J.; Shaw, J. T.; Woerpel, K. A. J. Org. Chem. 2002, 67, 2056–2064.

(tBu)2Si O

MeMe

MeO

(tBu)2SiO

MeMe

OAcMe

O SiMe3(tBu)2Si

O

MeMe

MeO


DCM, -78 °CSnBr4

DCM, -78 °C

(tBu)2SiO

MeMe

Ph

O SiMe3

PhO

yield: 79%d.r.: 96:4

tBu

Si OtBu

Me

Me

OSi

Me

tButBu

Me

A

B

small nucleophile


23

ENER

GY

PATH OF REACTION

B

A

A

B

Bear, T. J.; Shaw, J. T.; Woerpel, K. A. J. Org. Chem. 2002, 67, 2056–2064.

(tBu)2Si O

MeMe

MeO

(tBu)2SiO

MeMe

PhO

(tBu)2SiO

MeMe

OAcMe

O SiMe3(tBu)2Si

O

MeMe

MeO


DCM, -78 °CSnBr4

DCM, -78 °C

(tBu)2SiO

MeMe

Ph

O SiMe3

PhO

yield: 79%d.r.: 96:4

tBu

Si OtBu

Me

Me

OSi

Me

tButBu

Me

A

B

small nucleophile

large nucleophile

(+/-‐)–1’–epi–stegobinone

24

Stegobinium Paniceum (drugstore beetle)

− Natural isomer readily isomerizes to epi–stegobinone � Epimer is a repellent to male species

Calad, S. A.; Cirakovic, J.; Woerpel, K. A. J. Org. Chem. 2007, 72, 1027–1030.

O

Me

O

Et

OMe

Me

Me

Naturally occuringstegobinone

* O

Me

O

Et

OMe

Me

Me

1'–epi–stegobinone

*

Retrosynthesis

25

O

Me

O

Et

OMe

Me

Me


MeMe

OH

Me Me

OPGOH

Me

O

acid promotedcyclization

Si

MeMe

tBu tBu

carbonyl insertion

Calad, S. A.; Cirakovic, J.; Woerpel, K. A. J. Org. Chem. 2007, 72, 1027–1030.

Si OEt

O

MeMe

Me

tButBu

oxasilacyclopentaneoxidation

stereoselective aldol

Forward Synthesis

26 Calad, S. A.; Cirakovic, J.; Woerpel, K. A. J. Org. Chem. 2007, 72, 1027–1030.

MeEt

OSiMe3

SnBr4, 95%

Si O

Et

O

MeMe

Me

tBu

tBu

Me Et

OH

Me

OH

Me

CH21. Ph3PCH3Br, nBuLi, 79%

2. PhMe2C(OOH)

KF, CsF, 94%

1. tBu2Si(OTf)2,

2,6–lutidine, 80%

2. O3; PPh3, 99% Me Et

O

Me

O

Me

OSi

tBu tBu Sn(OTf)2,

-15 °C, 2 h;

N Et

EtCHO, -78 °C, 2h97%

Me

O

Me

O

Me

OSi

tBu tBu

Me

Et

OH

Si

MeMe

tBu tBu

Me Me AgOCOCF3(1–2 mol%)

Si(tBu)2Bn N

CHO

MeCuI (20 mol %);

CuSO4 (aq); Ac2O74%, 4 steps

Si O

Me

Me

tButBu

OAc

Forward Synthesis

27 Calad, S. A.; Cirakovic, J.; Woerpel, K. A. J. Org. Chem. 2007, 72, 1027–1030.

1. (COCl)2, DMSO, Et3N2. CF3CO2H

87%, 2 stepsO

Me

O

Et

OAcMe

Me

Me

iBu2AlH

93%O

Me

OH

Et

OHMe

Me

Me

OI

O

(OAc)3

O

Me

O

Et

OMe

Me

Me

48%

17 steps8.8% overall yield


Me

O

Me

O

Me

OSi

tBu tBu

MeEt

OH

1. Ac2O, 97 %2. HF.pyridine3. TBDMSCl

Me

TBDMSO

Me

OH

Me

O

MeEt

OAc

58%, 2 steps

Conclusion

Metal catalysts facilitate silylene transfer to olefins and

acetylenes

28

SiR

R""

Si

R R

Silacyclopropanes readily insert into carbonyl

electrophiles

Allylic alcohols and 1,3–diols

[O]HO

R2R1

R4

R3R1 R3

OH

R2

OHH2/Pd

[O]

(tBu)2SiO

R2R1

R4

R3R4

O

MeO

Et

OMe

MeMe

(+/-‐)–1’–epi–stegobinone

SiR R R2Si O R2

R1

O

R1 R2

Thank You

El Jefe Erik J. Alexanian

Post-‐Doc

Rahul Edwankar

Graduate Students Kayla S. Bloome Andy T. Brusoe Benjamin Giglio

Brendan C. Lainhart Rebecca McMahen Caitlin McMahon

Ryan Quinn Valerie A. Schmidt

Undergraduate James Lancaster

29

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