enabling synthetic organic transformations · include a number of lewis acid catalysts such as tin...
TRANSCRIPT
11 East Steel Rd.Morrisville, PA 19067Phone: 215-547-1015Fax: [email protected]
Gelest, Inc.The core manufacturing technology of Gelest is silanes, silicones and metal-organics with the capability to handle flammable, corrosive and air sensi-tive liquids, gases and solids. Headquartered in Morrisville, PA, Gelest isrecognized worldwide as an innovator, manufacturer and supplier of commer-cial and research quantities serving advanced technology markets through amaterials science driven approach. The company provides focused technicaldevelopment and application support for: semiconductors, optical materials,pharmaceutical synthesis, diagnostics and separation science, and specialtypolymeric materials.
Offering Selective and
Versatile Reagents for:
Enabling Synthetic Organic
Transformations
For additional information on Gelest’s Silicon and Metal-Organic based products or to inquire how we may assist in Enabling Your Technology, please contact:
Enabling Synthetic Organic Transformations
© 2014 Gelest, Inc.
• Reductions• Functional Group Protection
• Synthetic Organic Transformations• Cross-Coupling C-C Bond Formation
www.gelest.com
Organosilicon Basedand
Metal-Organic Synthetic Reagents
Gelest offers a number of other organosilane reagents that are of high use in the organic syntheticarea. These include, among others, trimethyliodosilane, trimethylbromosilane, trimethylsilyl triflate, cyanotrimethylsilane, a number of silyl enol ethers and silyl ketene acetals, in addition to anextensive variety of organosilanes that are attached to inorganic surfaces for the purpose of finalpurification of desired products. Gelest also offers several non-silicon-based synthetic reagentsthat complement and, oftentimes, assist in the reactions of the silicon-based reagents. These include a number of Lewis acid catalysts such as tin tetrachloride, tetraisopropyltitanate, tris(penta-fluorophenyl)boron, and a variety of metal diketonates. In addition Gelest offers several metal-organic reagents for various synthetic transformations.
Other Gelest Synthetic Reagents
H3C Si ICH3
CH3
SIT8564.0
H3C Si BrCH3
CH3
SIT8430.0
H3C Si OTfCH3
CH3
SIT8620.0
H3C Si CNCH3
CH3
SIT8585.0 SIT8580.0
H3C Si N3
CH3
H3C
OSi(CH3)3
SIC2462.0
OSi(CH3)3
SIT8571.0
(H3C)3SiO
SIT8171.2
O OSi(CH3)3
SIT8571.3
H3COSi(CH3)3
H3C
OCH3
SIM6496.0
NMe
Si
Ph
Cl
SIA0433.0
Si(CH3)3
SIA0555.0
H3C Si CH2ClCH3
CH3
SIC2305.0
H3C Si OLICH3
CH3SIL6469.7
(H3C)3SiN
Li
Si(CH3)3
SIL6467.0
(H3C)3SiN
K
Si(CH3)3
SIP6890.0
CH3CH2 Zn CH2CH3
OMZN017(CH3)2CHCH2
AlCH2CH(CH3)3
H
OMAL021.2
CH3CH2Al
Cl
Cl
OMAL033.2
i-PrO Ti ClOi-Pr
Oi-Pr
AKT851
BF
FF
F
F FF
F
F
FF
F
F
FF
OMBO087
Zn
OMZN040
FePPh2
PPh2
OMFE022
i-PrOB
Oi-Pr
Oi-Pr
AKB156.5
H3COB
OCH3
OCH3
AKB157
H3CO Mg OCH3
AKM503
SNT7930
Cl Sn ClCl
Cln-Bu Sn H
n-Bu
n-Bu
SNT8130
H3C Sn CH3
CH3
CH3
SNT7560
OCH2CH3
Sn(nBu)3
SNE4620 SNT7906
Sn
Enabling Synthetic Organic Transformations
Silicon-BasedBlocking Agents
Silicon-BasedBlocking Agents
Reagents For:-Functional Group Protection
-Synthetic Transformation-Derivatization
Enabling Your Technology
Silicon-Based
Cross-Coupling Reagents
Pd
Si(OEt)3
ONEt2
O
Si(OEt)3
ONEt2
O
H2N
Si(OMe)3
SiOH
n-C5H11
OMe
Si(OEt)3
Si(OEt)3
Me
MeSiMe3
N
Si(OEt)3
N
Br
N
Br
OTf
CF3
Cl
MeO
OMe
O
O
Br
OMe
Br
I
Me
Br
ONEt2
O
Br
ONEt2
O
Si(OMe)3
CF3
Version 2.0
1093_Vasanti brochure_Layout 1 10/24/14 9:53 PM Page 1
Organosilane reductions are very commonplace in synthetic organic chemistry with the Si-H bond,being weakly polarized such that the hydrogen is hydridic in nature. Because the Si-H bond is onlyweakly hydridic, the silanes have the potential to be highly selective reducing agents, reducing anumber of functionalities with excellent tolerance for other reducible functionalities. Organosilaneshave further advantages in terms of low toxicity, ease of handling, and ease of final product purifi-cation. In addition, a number of enantioselective organosilane reductions have been reported. Ionicand organometalic-catalyzed organosilane reductions have been extensively reviewed.1,2
The extensive electronic and steric diversity of organosilanes offers a large range of selectivities in reactivity. For example, the homopolymeric methylhydrogensiloxane, HMS-992, and related homopolymers represent a high molecular weight silane reducing agent that can offer significantproduct isolation advantages.3 Diphenylsilane, SID4559.0, has been shown to selectively reduceamides to aldehydes.4 Triisopropylsilane, SIT8385.0, has been shown to offer a steric advantageleading to a higher degree of the β-aryl glucoside from the hemiketal precursor.5
Tetramethyldisiloxane, TMDS, SIT7546.0, has recently been shown to be highly useful in the reduction of hemiketals to the corresponding ether. This has been applied to successful synthesesof the pharmaceutically important gliflozin family of diabetes 2 Specific Glucose Transport 2 (SGLT2)inhibitor drugs, such as canagliflozin, (Invokana) and dapagliflozin (Farxiga) among others.6 TMDS has also been shown to very effectively reduce nitroaryls to anilines7 and is an improvement over triethylsilane in the reduction of a ketone to a methylene in the production of a key intermediate in the preparation of ziprasidone.8
Organosilane Reducing Agents
CH3CH2 Si HCH3CH2
CH3CH2
SIT8330.0
SiCH3
CH3
H
SIP6729.0
HC Si H
HC
CH
CH3H3CH3C
H3CH3C CH3
SIT8385.0
Si HH
H
SIP6750.0
SiH
H
SID4559.0
CH3CH2 Si HCH3
CH3
SIE4894.0
CH3CH2O Si HCH3CH2O
CH3CH2O
SIT8185.0
Si H
SIT8665.0
(CH3)3Si Si H
(CH3)3Si
(CH3)3Si
SIT8724.0
Cl Si HCl
Cl
SIT8155.0
H Si OCH3
CH3
Si HCH3
CH3
SIT7546.0
SiO Si
OSi
OSiO
H3CH
CH3
H
CH3H
H
H3C
SIT7530.0
O Si HO
O
Si(CH3)3
(CH3)3Si
Si(CH3)3
SIT8721.0
H Si HCH3CH2
CH3CH2
SID3415.0
Si CH3
H
H
SIP6742.0
References:1. Larson, G. L.; Fry, J. L. “Ionic and Organometallic-Catalyzed Organosilane Reductions”, Organic Reactions, Vol. 71, 2008,
Denmark, S. E. Ed. Wiley and Sons, Hoboken, NJ.2. Larson, G. L. “Silicon-Based Reducing Agents” Version 2.0, Gelest, Inc. 2008.3. Chandrasekhar, S.; Reddy, Ch. R.; Ahmed, M. Synlett. 2000, 1655.4. Bower, S.; Kreutzer, K. A.; Buchwald, S. L. Angew. Chem. Int. Ed. 1996, 35, 1515.5. Elsworth, B. A. et al. Tetrahedron: Asymmetry 2003, 14, 3243.6. a. Lemaire, S. et al. Org. Lett. 2102, 14, 1480. b. Nomura, S. et al. J. Med. Chem. 2010, 53, 6355. c. Lee, J. et al. Bioorg.
Med. Chem. 2010, 18, 2178.7. Nagashima, H. et al. J. Am. Chem. Soc. 2009, 131, 15032.8. Nadkarni, D.; Hallissey, J. F. Org. Proc. Res. Dev. 2008, 12, 1142.
Cross-coupling reactions are usually associated with the metals of boron (Suzuki-Miyaura), zinc(Negishi), tin (Stille), and copper (Sonogashira) along with magnesium (Kumada).1 As a viable alternative to these metals the Hiyama-Denmark cross-coupling reactions involve organosiliconreagents as the nucleophilic partner in C-C bond forming cross-coupling protocols. The organosilaneshave several advantages, including being readily prepared by a variety of approaches, excellent storage stability, ease of removal or recycling of the organosilane by-products, good functional grouptoleration, and low to non-toxicity profiles. The organosilane cross-coupling chemistry has been thoroughly reviewed.2 The use of sodium and potassium silanolates as the nucleophilic partner in thesilicon-based cross-coupling transformations has been shown to be of practical utility.3
Organosilane Cross-Coupling Reagents Organosilane Protecting Groups
Si(OMe)
SIP6822.0
Si(OMe)
H2N
SIA0599.1
Si(OMe)3H2N
SIA0599.0
Si(OMe)3
MeO
SIM6492.55
Si(OMe)3
O
SIT8177.0
FF
FF
F
Si(OEt)3
SIP6716.7
Si(OEt)3
SIN6596.8
N
Si(OEt)3
SIP6934.0
SiMe2ONa
SIS6986.1
S SiMe2ONa
SIS6987.0
O SiMe2ONa
SIS6980.6
Si(OMe)3
SIV9220.0 SIP6905.0
SiMe3
OO
SiSi
OO
Si
Si
SIT7900.0
SiMe3
SIT8606.5
H SiMe3
SIE4904.0
SIT8604.0
SiMe3
HOSiMe3
Me3SiO
OSIT8623.0 SIP6903.0
HMe3SiO Me3Si-O-K
SIP6901.0
Me3Si CN
SIT8579.0
OSiMe2ONa +
TBSO
Br(t-Bu3P)2Pd (2.5 mol%)
toluene, 90°
99%
OOTBS
References:1. a. De Meijre, A.; Diederich, F. Eds. Metal-Catalyzed Cross-Coupling Reactions; Wiley-VCH: Weinheim, 2004. b. Bringmann, G.; Walter, R.;
Weirich, R. Angew. Chem. Int. Ed. 1990, 29, 977. c. Negishi, E. “Handbook of Organopalladium Chemistry for Organic Synthesis” Wiley-Interscience: New York, 2002.
2. a. Hiyama, T. in “Metal-Catalyzed Cross-Coupling Reactions” Diederich, F.; Stang, P. J. Eds. Wiley-VCH: Weinheim, 1998; chapter 10. b. Den-mark, S. E. Sweis, R. F. Acct. Chem. Res. 2002, 35, 835. c. Chang, W-T. T.; Smith, R. C.; Regens, C. S.; Bailey, A. D.; Werner, N. S.; Denmark,S. E. “Cross-Coupling with Organosilicon Compounds” Organic Reactions 2011, Vol. 75, pp d. Denmark, S. E. in “Silicon Compounds: Silanesand Silicones” Arkles, B. and Larson, G. L. Eds. Gelest, Inc. 2013, pp 63-70.
3. a. Denmark, S. E.; Baird, J. D. Chem. Eur. J. 2006, 8, 793. b. Denmark, S. E.; Smith, R. C.; Chang, W-T. T.; Muhuhi, J. M. J. Am. Chem. Soc.2009, 131, 3104. c. Denmark, S. E.; Smith, R. C.; Tymonko, S. A. Tetrahedron 2007, 63, 5730.
4. a. Smith, A. B. III; Hoye, A. T.; Martinez-Solorio, D.; Kim, W.-S.; Tong, R. J. Am. Chem. Soc. 2012, 134, 4533. b. Nguyen, M. H.; Smith, A. B.III Org. Lett. 2014, 16, 2070.
It is very common that in a multi-step synthetic sequence the protection of one or more functional groupswill be required. The most common groups that fall into this class are alcohols, amines, thiols, acids, and carbonyls, in particular ketones and aldehydes. For the protection of functional groupswith active hydrogens, such as alcohols and amines, organosilanes have proven to be among the bestand most favored alternatives.1 The reasons for this are that the silyl groups can be both introduced and removed in high-yield, facile processes. In addition, the organosilanes have the ability to be modified bothsterically and electronically, thus giving them excellent selectivity and versatility in their reactivity, stabil-ity, and ease of deprotection. Indeed, in many of the more complicated and lengthy synthetic sequencesit is common to have a requirement to remove one organosilyl-protected group in the presence of othersimilar groups. A thorough presentation on the selective deprotection of one organosilyl-protected groupin the present of another has been compiled.2 Gelest offers an extensive range of organosilanes designedfor the protection of various functional groups including alcohols, diols, amines, thiols, carboxylic acidsand terminal alkynes. Of particular note is the use of the trimethylsilylenol ether of acetone, SII6264.0,for the protection of diols as their acetonides in a very fast and high-yield reaction.3 Gelest is proud tooffer the E. J. Corey BIBS reagent for the protection of alcohols, amines, and carboxylic acids and the formation of highly stable enol silyl ethers.4
H3C Si CICH3
CH3
SIT8510.0
H3C Si OTfCH3
CH3
SIT8620.0 SID3605.0
H3C Si N(CH3)2
CH3
CH3
Si NN
H3CH3C
H3C
SIT8590.0
NH3C
O
Si
SiH3C
H3CH3C
CH3
CH3
CH3
SIB1846.0
NF3C
O
Si
SiH3C
H3CH3C
CH3
CH3
CH3SIB1876.0
Si ClCH3
CH3
SII6462.0
CH3CH2 Si ClCH3CH2
CH3CH2
SIT8250.0
CH3CH2 Si OTfCH3CH2
CH3CH2
SIT8335.0
SiCH3
CH3
Cl
SIP6828.0
t-Bu Si ClCH3
CH3
SIB1935.0
H3CSi
NH
SiCH3
CH3H3CCH3
CH3
SIH6110.0
C Si ClCH3
CH3
Pht-Bu
Ph
SIB1968.0
t-Bu Si OTfCH3
CH3
SIB1967.0
t-Bu Si OTfOTf
t-Bu
SID3345.0
Si Cl
SIT8645.0
t-Bu Si Clt-Bu
CH3
SID3255.0
Si Cl
SIT8384.0
Si OTf
SIT8387.0
SiO
SiCl Cl
SIT7273.0
Et3N ( 2 eq.)
CH2Cl2, rt, 12 h
94%
reference SID3226.0 4
t-Bu Si OTft-Bu
+ HOOH
O
OOH
OH
BIBSOOBIBS
O
OOH
OH
References:1. Wuts, P. G. M.; Greene, T. W. “Greene’s Protective Groups in Organic Syntheses” Wiley and Sons, 2007.2. Larson, G. L. “Silicon-Based Blocking Agents” Gelest, Inc. 2014.3. Larson, G. L.; Hernández, A. J. Org. Chem. 1973, 38, 3935.4. Liang, H.; Hu, L.; Corey, E. J. Org. Lett. 2011, 13, 4120.
1093_Vasanti brochure_Layout 1 10/24/14 9:53 PM Page 2
11 East Steel Rd.Morrisville, PA 19067Phone: 215-547-1015Fax: [email protected]
Gelest, Inc.The core manufacturing technology of Gelest is silanes, silicones and metal-organics with the capability to handle flammable, corrosive and air sensi-tive liquids, gases and solids. Headquartered in Morrisville, PA, Gelest isrecognized worldwide as an innovator, manufacturer and supplier of commer-cial and research quantities serving advanced technology markets through amaterials science driven approach. The company provides focused technicaldevelopment and application support for: semiconductors, optical materials,pharmaceutical synthesis, diagnostics and separation science, and specialtypolymeric materials.
Offering Selective and
Versatile Reagents for:
Enabling Synthetic Organic
Transformations
For additional information on Gelest’s Silicon and Metal-Organic based products or to inquire how we may assist in Enabling Your Technology, please contact:
Enabling Synthetic Organic Transformations
© 2014 Gelest, Inc.
• Reductions• Functional Group Protection
• Synthetic Organic Transformations• Cross-Coupling C-C Bond Formation
www.gelest.com
Organosilicon Basedand
Metal-Organic Synthetic Reagents
Gelest offers a number of other organosilane reagents that are of high use in the organic syntheticarea. These include, among others, trimethyliodosilane, trimethylbromosilane, trimethylsilyl triflate, cyanotrimethylsilane, a number of silyl enol ethers and silyl ketene acetals, in addition to anextensive variety of organosilanes that are attached to inorganic surfaces for the purpose of finalpurification of desired products. Gelest also offers several non-silicon-based synthetic reagentsthat complement and, oftentimes, assist in the reactions of the silicon-based reagents. These include a number of Lewis acid catalysts such as tin tetrachloride, tetraisopropyltitanate, tris(penta-fluorophenyl)boron, and a variety of metal diketonates. In addition Gelest offers several metal-organic reagents for various synthetic transformations.
Other Gelest Synthetic Reagents
H3C Si ICH3
CH3
SIT8564.0
H3C Si BrCH3
CH3
SIT8430.0
H3C Si OTfCH3
CH3
SIT8620.0
H3C Si CNCH3
CH3
SIT8585.0 SIT8580.0
H3C Si N3
CH3
H3C
OSi(CH3)3
SIC2462.0
OSi(CH3)3
SIT8571.0
(H3C)3SiO
SIT8171.2
O OSi(CH3)3
SIT8571.3
H3COSi(CH3)3
H3C
OCH3
SIM6496.0
NMe
Si
Ph
Cl
SIA0433.0
Si(CH3)3
SIA0555.0
H3C Si CH2ClCH3
CH3
SIC2305.0
H3C Si OLICH3
CH3SIL6469.7
(H3C)3SiN
Li
Si(CH3)3
SIL6467.0
(H3C)3SiN
K
Si(CH3)3
SIP6890.0
CH3CH2 Zn CH2CH3
OMZN017(CH3)2CHCH2
AlCH2CH(CH3)3
H
OMAL021.2
CH3CH2Al
Cl
Cl
OMAL033.2
i-PrO Ti ClOi-Pr
Oi-Pr
AKT851
BF
FF
F
F FF
FF
FF
FF
FF
OMBO087
Zn
OMZN040
FePPh2
PPh2
OMFE022
i-PrOB
Oi-Pr
Oi-Pr
AKB156.5
H3COB
OCH3
OCH3
AKB157
H3CO Mg OCH3
AKM503
SNT7930
Cl Sn ClCl
Cln-Bu Sn H
n-Bu
n-Bu
SNT8130
H3C Sn CH3
CH3
CH3
SNT7560
OCH2CH3
Sn(nBu)3
SNE4620 SNT7906
Sn
Enabling Synthetic Organic Transformations
Silicon-BasedBlocking Agents
Silicon-BasedBlocking Agents
Reagents For:-Functional Group Protection
-Synthetic Transformation-Derivatization
Enabling Your Technology
Silicon-Based
Cross-Coupling Reagents
Pd
Si(OEt)3
ONEt2
O
Si(OEt)3
ONEt2
O
H2N
Si(OMe)3
SiOH
n-C5H11
OMe
Si(OEt)3
Si(OEt)3
Me
MeSiMe3
N
Si(OEt)3
N
Br
N
Br
OTf
CF3
Cl
MeO
OMe
O
O
Br
OMe
Br
I
Me
Br
ONEt2
O
Br
ONEt2
O
Si(OMe)3
CF3
Version 2.0
1093_Vasanti brochure_Layout 1 10/24/14 9:53 PM Page 1
Organosilane reductions are very commonplace in synthetic organic chemistry with the Si-H bond,being weakly polarized such that the hydrogen is hydridic in nature. Because the Si-H bond is onlyweakly hydridic, the silanes have the potential to be highly selective reducing agents, reducing anumber of functionalities with excellent tolerance for other reducible functionalities. Organosilaneshave further advantages in terms of low toxicity, ease of handling, and ease of final product purifi-cation. In addition, a number of enantioselective organosilane reductions have been reported. Ionicand organometalic-catalyzed organosilane reductions have been extensively reviewed.1,2
The extensive electronic and steric diversity of organosilanes offers a large range of selectivities in reactivity. For example, the homopolymeric methylhydrogensiloxane, HMS-992, and related homopolymers represent a high molecular weight silane reducing agent that can offer significantproduct isolation advantages.3 Diphenylsilane, SID4559.0, has been shown to selectively reduceamides to aldehydes.4 Triisopropylsilane, SIT8385.0, has been shown to offer a steric advantageleading to a higher degree of the β-aryl glucoside from the hemiketal precursor.5
Tetramethyldisiloxane, TMDS, SIT7546.0, has recently been shown to be highly useful in the reduction of hemiketals to the corresponding ether. This has been applied to successful synthesesof the pharmaceutically important gliflozin family of diabetes 2 Specific Glucose Transport 2 (SGLT2)inhibitor drugs, such as canagliflozin, (Invokana) and dapagliflozin (Farxiga) among others.6 TMDS has also been shown to very effectively reduce nitroaryls to anilines7 and is an improvement over triethylsilane in the reduction of a ketone to a methylene in the production of a key intermediate in the preparation of ziprasidone.8
Organosilane Reducing Agents
CH3CH2 Si HCH3CH2
CH3CH2
SIT8330.0
SiCH3
CH3
H
SIP6729.0
HC Si H
HC
CH
CH3H3CH3C
H3CH3C CH3
SIT8385.0
Si HH
H
SIP6750.0
SiH
H
SID4559.0
CH3CH2 Si HCH3
CH3
SIE4894.0
CH3CH2O Si HCH3CH2O
CH3CH2O
SIT8185.0
Si H
SIT8665.0
(CH3)3Si Si H
(CH3)3Si
(CH3)3Si
SIT8724.0
Cl Si HCl
Cl
SIT8155.0
H Si OCH3
CH3
Si HCH3
CH3
SIT7546.0
SiO Si
OSi
OSiO
H3CH
CH3
H
CH3H
H
H3C
SIT7530.0
O Si HO
O
Si(CH3)3
(CH3)3Si
Si(CH3)3
SIT8721.0
H Si HCH3CH2
CH3CH2
SID3415.0
Si CH3
H
H
SIP6742.0
References:1. Larson, G. L.; Fry, J. L. “Ionic and Organometallic-Catalyzed Organosilane Reductions”, Organic Reactions, Vol. 71, 2008,
Denmark, S. E. Ed. Wiley and Sons, Hoboken, NJ.2. Larson, G. L. “Silicon-Based Reducing Agents” Version 2.0, Gelest, Inc. 2008.3. Chandrasekhar, S.; Reddy, Ch. R.; Ahmed, M. Synlett. 2000, 1655.4. Bower, S.; Kreutzer, K. A.; Buchwald, S. L. Angew. Chem. Int. Ed. 1996, 35, 1515.5. Elsworth, B. A. et al. Tetrahedron: Asymmetry 2003, 14, 3243.6. a. Lemaire, S. et al. Org. Lett. 2102, 14, 1480. b. Nomura, S. et al. J. Med. Chem. 2010, 53, 6355. c. Lee, J. et al. Bioorg.
Med. Chem. 2010, 18, 2178.7. Nagashima, H. et al. J. Am. Chem. Soc. 2009, 131, 15032.8. Nadkarni, D.; Hallissey, J. F. Org. Proc. Res. Dev. 2008, 12, 1142.
Cross-coupling reactions are usually associated with the metals of boron (Suzuki-Miyaura), zinc(Negishi), tin (Stille), and copper (Sonogashira) along with magnesium (Kumada).1 As a viable alternative to these metals the Hiyama-Denmark cross-coupling reactions involve organosiliconreagents as the nucleophilic partner in C-C bond forming cross-coupling protocols. The organosilaneshave several advantages, including being readily prepared by a variety of approaches, excellent storage stability, ease of removal or recycling of the organosilane by-products, good functional grouptoleration, and low to non-toxicity profiles. The organosilane cross-coupling chemistry has been thoroughly reviewed.2 The use of sodium and potassium silanolates as the nucleophilic partner in thesilicon-based cross-coupling transformations has been shown to be of practical utility.3
Organosilane Cross-Coupling Reagents Organosilane Protecting Groups
Si(OMe)
SIP6822.0
Si(OMe)
H2N
SIA0599.1
Si(OMe)3H2N
SIA0599.0
Si(OMe)3
MeO
SIM6492.55
Si(OMe)3
O
SIT8177.0
FF
FF
F
Si(OEt)3
SIP6716.7
Si(OEt)3
SIN6596.8
N
Si(OEt)3
SIP6934.0
SiMe2ONa
SIS6986.1
S SiMe2ONa
SIS6987.0
O SiMe2ONa
SIS6980.6
Si(OMe)3
SIV9220.0 SIP6905.0
SiMe3
OO
SiSi
OO
Si
Si
SIT7900.0
SiMe3
SIT8606.5
H SiMe3
SIE4904.0
SIT8604.0
SiMe3
HOSiMe3
Me3SiO
OSIT8623.0 SIP6903.0
HMe3SiO Me3Si-O-K
SIP6901.0
Me3Si CN
SIT8579.0
OSiMe2ONa +
TBSO
Br(t-Bu3P)2Pd (2.5 mol%)
toluene, 90°
99%
OOTBS
References:1. a. De Meijre, A.; Diederich, F. Eds. Metal-Catalyzed Cross-Coupling Reactions; Wiley-VCH: Weinheim, 2004. b. Bringmann, G.; Walter, R.;
Weirich, R. Angew. Chem. Int. Ed. 1990, 29, 977. c. Negishi, E. “Handbook of Organopalladium Chemistry for Organic Synthesis” Wiley-Interscience: New York, 2002.
2. a. Hiyama, T. in “Metal-Catalyzed Cross-Coupling Reactions” Diederich, F.; Stang, P. J. Eds. Wiley-VCH: Weinheim, 1998; chapter 10. b. Den-mark, S. E. Sweis, R. F. Acct. Chem. Res. 2002, 35, 835. c. Chang, W-T. T.; Smith, R. C.; Regens, C. S.; Bailey, A. D.; Werner, N. S.; Denmark,S. E. “Cross-Coupling with Organosilicon Compounds” Organic Reactions 2011, Vol. 75, pp d. Denmark, S. E. in “Silicon Compounds: Silanesand Silicones” Arkles, B. and Larson, G. L. Eds. Gelest, Inc. 2013, pp 63-70.
3. a. Denmark, S. E.; Baird, J. D. Chem. Eur. J. 2006, 8, 793. b. Denmark, S. E.; Smith, R. C.; Chang, W-T. T.; Muhuhi, J. M. J. Am. Chem. Soc.2009, 131, 3104. c. Denmark, S. E.; Smith, R. C.; Tymonko, S. A. Tetrahedron 2007, 63, 5730.
4. a. Smith, A. B. III; Hoye, A. T.; Martinez-Solorio, D.; Kim, W.-S.; Tong, R. J. Am. Chem. Soc. 2012, 134, 4533. b. Nguyen, M. H.; Smith, A. B.III Org. Lett. 2014, 16, 2070.
It is very common that in a multi-step synthetic sequence the protection of one or more functional groupswill be required. The most common groups that fall into this class are alcohols, amines, thiols, acids, and carbonyls, in particular ketones and aldehydes. For the protection of functional groupswith active hydrogens, such as alcohols and amines, organosilanes have proven to be among the bestand most favored alternatives.1 The reasons for this are that the silyl groups can be both introduced and removed in high-yield, facile processes. In addition, the organosilanes have the ability to be modified bothsterically and electronically, thus giving them excellent selectivity and versatility in their reactivity, stabil-ity, and ease of deprotection. Indeed, in many of the more complicated and lengthy synthetic sequencesit is common to have a requirement to remove one organosilyl-protected group in the presence of othersimilar groups. A thorough presentation on the selective deprotection of one organosilyl-protected groupin the present of another has been compiled.2 Gelest offers an extensive range of organosilanes designedfor the protection of various functional groups including alcohols, diols, amines, thiols, carboxylic acidsand terminal alkynes. Of particular note is the use of the trimethylsilylenol ether of acetone, SII6264.0,for the protection of diols as their acetonides in a very fast and high-yield reaction.3 Gelest is proud tooffer the E. J. Corey BIBS reagent for the protection of alcohols, amines, and carboxylic acids and the formation of highly stable enol silyl ethers.4
H3C Si CICH3
CH3
SIT8510.0
H3C Si OTfCH3
CH3
SIT8620.0 SID3605.0
H3C Si N(CH3)2
CH3
CH3
Si NN
H3CH3C
H3C
SIT8590.0
NH3C
O
Si
SiH3C
H3CH3C
CH3
CH3
CH3
SIB1846.0
NF3C
O
Si
SiH3C
H3CH3C
CH3
CH3
CH3SIB1876.0
Si ClCH3
CH3
SII6462.0
CH3CH2 Si ClCH3CH2
CH3CH2
SIT8250.0
CH3CH2 Si OTfCH3CH2
CH3CH2
SIT8335.0
SiCH3
CH3
Cl
SIP6828.0
t-Bu Si ClCH3
CH3
SIB1935.0
H3CSi
NH
SiCH3
CH3H3CCH3
CH3
SIH6110.0
C Si ClCH3
CH3
Pht-Bu
Ph
SIB1968.0
t-Bu Si OTfCH3
CH3
SIB1967.0
t-Bu Si OTfOTf
t-Bu
SID3345.0
Si Cl
SIT8645.0
t-Bu Si Clt-Bu
CH3
SID3255.0
Si Cl
SIT8384.0
Si OTf
SIT8387.0
SiO
SiCl Cl
SIT7273.0
Et3N ( 2 eq.)
CH2Cl2, rt, 12 h
94%
reference SID3226.0 4
t-Bu Si OTft-Bu
+ HOOH
O
OOH
OH
BIBSOOBIBS
O
OOH
OH
References:1. Wuts, P. G. M.; Greene, T. W. “Greene’s Protective Groups in Organic Syntheses” Wiley and Sons, 2007.2. Larson, G. L. “Silicon-Based Blocking Agents” Gelest, Inc. 2014.3. Larson, G. L.; Hernández, A. J. Org. Chem. 1973, 38, 3935.4. Liang, H.; Hu, L.; Corey, E. J. Org. Lett. 2011, 13, 4120.
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Organosilane reductions are very commonplace in synthetic organic chemistry with the Si-H bond,being weakly polarized such that the hydrogen is hydridic in nature. Because the Si-H bond is onlyweakly hydridic, the silanes have the potential to be highly selective reducing agents, reducing anumber of functionalities with excellent tolerance for other reducible functionalities. Organosilaneshave further advantages in terms of low toxicity, ease of handling, and ease of final product purifi-cation. In addition, a number of enantioselective organosilane reductions have been reported. Ionicand organometalic-catalyzed organosilane reductions have been extensively reviewed.1,2
The extensive electronic and steric diversity of organosilanes offers a large range of selectivities in reactivity. For example, the homopolymeric methylhydrogensiloxane, HMS-992, and related homopolymers represent a high molecular weight silane reducing agent that can offer significantproduct isolation advantages.3 Diphenylsilane, SID4559.0, has been shown to selectively reduceamides to aldehydes.4 Triisopropylsilane, SIT8385.0, has been shown to offer a steric advantageleading to a higher degree of the β-aryl glucoside from the hemiketal precursor.5
Tetramethyldisiloxane, TMDS, SIT7546.0, has recently been shown to be highly useful in the reduction of hemiketals to the corresponding ether. This has been applied to successful synthesesof the pharmaceutically important gliflozin family of diabetes 2 Specific Glucose Transport 2 (SGLT2)inhibitor drugs, such as canagliflozin, (Invokana) and dapagliflozin (Farxiga) among others.6 TMDS has also been shown to very effectively reduce nitroaryls to anilines7 and is an improvement over triethylsilane in the reduction of a ketone to a methylene in the production of a key intermediate in the preparation of ziprasidone.8
Organosilane Reducing Agents
CH3CH2 Si HCH3CH2
CH3CH2
SIT8330.0
SiCH3
CH3
H
SIP6729.0
HC Si H
HC
CH
CH3H3CH3C
H3CH3C CH3
SIT8385.0
Si HH
H
SIP6750.0
SiH
H
SID4559.0
CH3CH2 Si HCH3
CH3
SIE4894.0
CH3CH2O Si HCH3CH2O
CH3CH2O
SIT8185.0
Si H
SIT8665.0
(CH3)3Si Si H
(CH3)3Si
(CH3)3Si
SIT8724.0
Cl Si HCl
Cl
SIT8155.0
H Si OCH3
CH3
Si HCH3
CH3
SIT7546.0
SiO Si
OSi
OSiO
H3CH
CH3
H
CH3H
H
H3C
SIT7530.0
O Si HO
O
Si(CH3)3
(CH3)3Si
Si(CH3)3
SIT8721.0
H Si HCH3CH2
CH3CH2
SID3415.0
Si CH3
H
H
SIP6742.0
References:1. Larson, G. L.; Fry, J. L. “Ionic and Organometallic-Catalyzed Organosilane Reductions”, Organic Reactions, Vol. 71, 2008,
Denmark, S. E. Ed. Wiley and Sons, Hoboken, NJ.2. Larson, G. L. “Silicon-Based Reducing Agents” Version 2.0, Gelest, Inc. 2008.3. Chandrasekhar, S.; Reddy, Ch. R.; Ahmed, M. Synlett. 2000, 1655.4. Bower, S.; Kreutzer, K. A.; Buchwald, S. L. Angew. Chem. Int. Ed. 1996, 35, 1515.5. Elsworth, B. A. et al. Tetrahedron: Asymmetry 2003, 14, 3243.6. a. Lemaire, S. et al. Org. Lett. 2102, 14, 1480. b. Nomura, S. et al. J. Med. Chem. 2010, 53, 6355. c. Lee, J. et al. Bioorg.
Med. Chem. 2010, 18, 2178.7. Nagashima, H. et al. J. Am. Chem. Soc. 2009, 131, 15032.8. Nadkarni, D.; Hallissey, J. F. Org. Proc. Res. Dev. 2008, 12, 1142.
Cross-coupling reactions are usually associated with the metals of boron (Suzuki-Miyaura), zinc(Negishi), tin (Stille), and copper (Sonogashira) along with magnesium (Kumada).1 As a viable alternative to these metals the Hiyama-Denmark cross-coupling reactions involve organosiliconreagents as the nucleophilic partner in C-C bond forming cross-coupling protocols. The organosilaneshave several advantages, including being readily prepared by a variety of approaches, excellent storage stability, ease of removal or recycling of the organosilane by-products, good functional grouptoleration, and low to non-toxicity profiles. The organosilane cross-coupling chemistry has been thoroughly reviewed.2 The use of sodium and potassium silanolates as the nucleophilic partner in thesilicon-based cross-coupling transformations has been shown to be of practical utility.3
Organosilane Cross-Coupling Reagents Organosilane Protecting Groups
Si(OMe)
SIP6822.0
Si(OMe)
H2N
SIA0599.1
Si(OMe)3H2N
SIA0599.0
Si(OMe)3
MeO
SIM6492.55
Si(OMe)3
O
SIT8177.0
FF
FF
F
Si(OEt)3
SIP6716.7
Si(OEt)3
SIN6596.8
N
Si(OEt)3
SIP6934.0
SiMe2ONa
SIS6986.1
S SiMe2ONa
SIS6987.0
O SiMe2ONa
SIS6980.6
Si(OMe)3
SIV9220.0 SIP6905.0
SiMe3
OO
SiSi
OO
Si
Si
SIT7900.0
SiMe3
SIT8606.5
H SiMe3
SIE4904.0
SIT8604.0
SiMe3
HOSiMe3
Me3SiO
OSIT8623.0 SIP6903.0
HMe3SiO Me3Si-O-K
SIP6901.0
Me3Si CN
SIT8579.0
OSiMe2ONa +
TBSO
Br(t-Bu3P)2Pd (2.5 mol%)
toluene, 90°
99%
OOTBS
References:1. a. De Meijre, A.; Diederich, F. Eds. Metal-Catalyzed Cross-Coupling Reactions; Wiley-VCH: Weinheim, 2004. b. Bringmann, G.; Walter, R.;
Weirich, R. Angew. Chem. Int. Ed. 1990, 29, 977. c. Negishi, E. “Handbook of Organopalladium Chemistry for Organic Synthesis” Wiley-Interscience: New York, 2002.
2. a. Hiyama, T. in “Metal-Catalyzed Cross-Coupling Reactions” Diederich, F.; Stang, P. J. Eds. Wiley-VCH: Weinheim, 1998; chapter 10. b. Den-mark, S. E. Sweis, R. F. Acct. Chem. Res. 2002, 35, 835. c. Chang, W-T. T.; Smith, R. C.; Regens, C. S.; Bailey, A. D.; Werner, N. S.; Denmark,S. E. “Cross-Coupling with Organosilicon Compounds” Organic Reactions 2011, Vol. 75, pp d. Denmark, S. E. in “Silicon Compounds: Silanesand Silicones” Arkles, B. and Larson, G. L. Eds. Gelest, Inc. 2013, pp 63-70.
3. a. Denmark, S. E.; Baird, J. D. Chem. Eur. J. 2006, 8, 793. b. Denmark, S. E.; Smith, R. C.; Chang, W-T. T.; Muhuhi, J. M. J. Am. Chem. Soc.2009, 131, 3104. c. Denmark, S. E.; Smith, R. C.; Tymonko, S. A. Tetrahedron 2007, 63, 5730.
4. a. Smith, A. B. III; Hoye, A. T.; Martinez-Solorio, D.; Kim, W.-S.; Tong, R. J. Am. Chem. Soc. 2012, 134, 4533. b. Nguyen, M. H.; Smith, A. B.III Org. Lett. 2014, 16, 2070.
It is very common that in a multi-step synthetic sequence the protection of one or more functional groupswill be required. The most common groups that fall into this class are alcohols, amines, thiols, acids, and carbonyls, in particular ketones and aldehydes. For the protection of functional groupswith active hydrogens, such as alcohols and amines, organosilanes have proven to be among the bestand most favored alternatives.1 The reasons for this are that the silyl groups can be both introduced and removed in high-yield, facile processes. In addition, the organosilanes have the ability to be modified bothsterically and electronically, thus giving them excellent selectivity and versatility in their reactivity, stabil-ity, and ease of deprotection. Indeed, in many of the more complicated and lengthy synthetic sequencesit is common to have a requirement to remove one organosilyl-protected group in the presence of othersimilar groups. A thorough presentation on the selective deprotection of one organosilyl-protected groupin the present of another has been compiled.2 Gelest offers an extensive range of organosilanes designedfor the protection of various functional groups including alcohols, diols, amines, thiols, carboxylic acidsand terminal alkynes. Of particular note is the use of the trimethylsilylenol ether of acetone, SII6264.0,for the protection of diols as their acetonides in a very fast and high-yield reaction.3 Gelest is proud tooffer the E. J. Corey BIBS reagent for the protection of alcohols, amines, and carboxylic acids and the formation of highly stable enol silyl ethers.4
H3C Si CICH3
CH3
SIT8510.0
H3C Si OTfCH3
CH3
SIT8620.0 SID3605.0
H3C Si N(CH3)2
CH3
CH3
Si NN
H3CH3C
H3C
SIT8590.0
NH3C
O
Si
SiH3C
H3CH3C
CH3
CH3
CH3
SIB1846.0
NF3C
O
Si
SiH3C
H3CH3C
CH3
CH3
CH3SIB1876.0
Si ClCH3
CH3
SII6462.0
CH3CH2 Si ClCH3CH2
CH3CH2
SIT8250.0
CH3CH2 Si OTfCH3CH2
CH3CH2
SIT8335.0
SiCH3
CH3
Cl
SIP6828.0
t-Bu Si ClCH3
CH3
SIB1935.0
H3CSi
NH
SiCH3
CH3H3CCH3
CH3
SIH6110.0
C Si ClCH3
CH3
Pht-Bu
Ph
SIB1968.0
t-Bu Si OTfCH3
CH3
SIB1967.0
t-Bu Si OTfOTf
t-Bu
SID3345.0
Si Cl
SIT8645.0
t-Bu Si Clt-Bu
CH3
SID3255.0
Si Cl
SIT8384.0
Si OTf
SIT8387.0
SiO
SiCl Cl
SIT7273.0
Et3N ( 2 eq.)
CH2Cl2, rt, 12 h
94%
reference SID3226.0 4
t-Bu Si OTft-Bu
+ HOOH
O
OOH
OH
BIBSOOBIBS
O
OOH
OH
References:1. Wuts, P. G. M.; Greene, T. W. “Greene’s Protective Groups in Organic Syntheses” Wiley and Sons, 2007.2. Larson, G. L. “Silicon-Based Blocking Agents” Gelest, Inc. 2014.3. Larson, G. L.; Hernández, A. J. Org. Chem. 1973, 38, 3935.4. Liang, H.; Hu, L.; Corey, E. J. Org. Lett. 2011, 13, 4120.
1093_Vasanti brochure_Layout 1 10/24/14 9:53 PM Page 2
11 East Steel Rd.Morrisville, PA 19067Phone: 215-547-1015Fax: [email protected]
Gelest, Inc.The core manufacturing technology of Gelest is silanes, silicones and metal-organics with the capability to handle flammable, corrosive and air sensi-tive liquids, gases and solids. Headquartered in Morrisville, PA, Gelest isrecognized worldwide as an innovator, manufacturer and supplier of commer-cial and research quantities serving advanced technology markets through amaterials science driven approach. The company provides focused technicaldevelopment and application support for: semiconductors, optical materials,pharmaceutical synthesis, diagnostics and separation science, and specialtypolymeric materials.
Offering Selective and
Versatile Reagents for:
Enabling Synthetic Organic
Transformations
For additional information on Gelest’s Silicon and Metal-Organic based products or to inquire how we may assist in Enabling Your Technology, please contact:
Enabling Synthetic Organic Transformations
© 2014 Gelest, Inc.
• Reductions• Functional Group Protection
• Synthetic Organic Transformations• Cross-Coupling C-C Bond Formation
www.gelest.com
Organosilicon Basedand
Metal-Organic Synthetic Reagents
Gelest offers a number of other organosilane reagents that are of high use in the organic syntheticarea. These include, among others, trimethyliodosilane, trimethylbromosilane, trimethylsilyl triflate, cyanotrimethylsilane, a number of silyl enol ethers and silyl ketene acetals, in addition to anextensive variety of organosilanes that are attached to inorganic surfaces for the purpose of finalpurification of desired products. Gelest also offers several non-silicon-based synthetic reagentsthat complement and, oftentimes, assist in the reactions of the silicon-based reagents. These include a number of Lewis acid catalysts such as tin tetrachloride, tetraisopropyltitanate, tris(penta-fluorophenyl)boron, and a variety of metal diketonates. In addition Gelest offers several metal-organic reagents for various synthetic transformations.
Other Gelest Synthetic Reagents
H3C Si ICH3
CH3
SIT8564.0
H3C Si BrCH3
CH3
SIT8430.0
H3C Si OTfCH3
CH3
SIT8620.0
H3C Si CNCH3
CH3
SIT8585.0 SIT8580.0
H3C Si N3
CH3
H3C
OSi(CH3)3
SIC2462.0
OSi(CH3)3
SIT8571.0
(H3C)3SiO
SIT8171.2
O OSi(CH3)3
SIT8571.3
H3COSi(CH3)3
H3C
OCH3
SIM6496.0
NMe
Si
Ph
Cl
SIA0433.0
Si(CH3)3
SIA0555.0
H3C Si CH2ClCH3
CH3
SIC2305.0
H3C Si OLICH3
CH3SIL6469.7
(H3C)3SiN
Li
Si(CH3)3
SIL6467.0
(H3C)3SiN
K
Si(CH3)3
SIP6890.0
CH3CH2 Zn CH2CH3
OMZN017(CH3)2CHCH2
AlCH2CH(CH3)3
H
OMAL021.2
CH3CH2Al
Cl
Cl
OMAL033.2
i-PrO Ti ClOi-Pr
Oi-Pr
AKT851
BF
FF
F
F FF
F
F
FF
F
F
FF
OMBO087
Zn
OMZN040
FePPh2
PPh2
OMFE022
i-PrOB
Oi-Pr
Oi-Pr
AKB156.5
H3COB
OCH3
OCH3
AKB157
H3CO Mg OCH3
AKM503
SNT7930
Cl Sn ClCl
Cln-Bu Sn H
n-Bu
n-Bu
SNT8130
H3C Sn CH3
CH3
CH3
SNT7560
OCH2CH3
Sn(nBu)3
SNE4620 SNT7906
Sn
Enabling Synthetic Organic Transformations
Silicon-BasedBlocking Agents
Silicon-BasedBlocking Agents
Reagents For:-Functional Group Protection
-Synthetic Transformation-Derivatization
Enabling Your Technology
Silicon-Based
Cross-Coupling Reagents
Pd
Si(OEt)3
ONEt2
O
Si(OEt)3
ONEt2
O
H2N
Si(OMe)3
SiOH
n-C5H11
OMe
Si(OEt)3
Si(OEt)3
Me
MeSiMe3
N
Si(OEt)3
N
Br
N
Br
OTf
CF3
Cl
MeO
OMe
O
O
Br
OMe
Br
I
Me
Br
ONEt2
O
Br
ONEt2
O
Si(OMe)3
CF3
Version 2.0
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