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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
yield: 92%regioselectivity: >99:1
d.r.: 70:30
(tBu)2SiO
OMetBu
yield: 75%regioselectivity: 74:26
d.r.: 70:30 (major) 91:9 (minor)
(tBu)2Si O
iPr
yield: 58%regioselectivity: >99:1
EtEt
(tBu)2Si O
iPr
yield: 70%regioselectivity: >99:1
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
Nucleophilic Subs'tu'on
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
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
tBu
Si OtBu
Me
Me
OSi
Me
tButBu
Me
A
B
small nucleophile
Nucleophilic Subs'tu'on
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
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
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
1'–epi–stegobinone
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
1'–epi–stegobinone
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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