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Honors Projects Chemistry
2009
Green Chemistry Using Bismuth Compounds: Bismuth(III) Triflate Catalyzed Allylation of Cyclic Acetals
Matthew J. Spafford, '09 Illinois Wesleyan University
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Recommended Citation Spafford, '09, Matthew .,J "Green Chemistry Using Bismuth Compounds: Bismuth(III) Triflate Catalyzed Allylation of Cyclic Acetals" (2009). Honors Projects. 33. https://digitalcommons.iwu.edu/chem_honproj/33
This Article is protected by copyright and/or related rights. It has been brought to you by Digital Commons @ IWU with permission from the rights-holder(s). You are free to use this material in any way that is permitted by the copyright and related rights legislation that applies to your use. For other uses you need to obtain permission from the rights-holder(s) directly, unless additional rights are indicated by a Creative Commons license in the record and/ or on the work itself. This material has been accepted for inclusion by faculty at Illinois Wesleyan University. For more information, please contact [email protected]. ©Copyright is owned by the author of this document. Green Chemistry Using Bismuth Compounds: Bismuth(III) TriflateCatalyzed Allylation of Cyclic Acetals
Matthew J. Spafford
Advisor: Dr. Ram Mohan
Research Honors Senior Thesis
Illinois Wesleyan University
Spring 2009 Approval Page i Green Chemistry Using Bismuth Compounds: Bismuth(III) Triflate Catalyzed Allylation of Cyclic Acetals By Matthew Spafford 1.
A PAPER SUBMITTED AS PART OF THE REQUIREMENTFOR RESEARCH HONORS IN CHEMISTRY Approved:
Ram S. Mohan, Ph. D., Research Advisor !
Brian B. Brennan, Ph. D.
"�Rebeccaa� Roesner, Ph. D.
Nathan Frank,Ph. D.
Illinois Wesleyan University, April 20, 2009 Acknowledgements
I would first like to thank my research advisor and friend,Dr. Ram Mohan, for all his support and encouragement over the past years. He has instilled a passion for chemistry in me throughhis teaching and for that, I very much indebted to him. His guidance and support has am been instrumental in shaping me as a scientist. I also very gratefulfo r the countless hours he am has spent on my behalf, without which this dissertation would not have been possible.
I would also like to thank Dr. Brian Brennan, Dr. Rebecca Roesner, and Dr. Nathan Frank for serving on my thesis committee.
A special thanks is in order for the all members of the research group over the past years: Aaron Bailey and Erin Anderson for their especial patiertce while training me as a Sophomore; Scott Krabbe for his synthesis of dioxanes and his wonderfulcountry music collection; Dr.
Eeshwar Begari for his early work on the allylation of dioxanes; Jay Christensen, Matthew Huddle, and Josh Lacey for their work on the allylation of dioxolanes; Pash DeVore, JP Carolan,
Kendall Tasche, Jason Bothwell, Dan Podgorski, Maggie Olsen, Long Le, Jamie Rogers, Herbie
Yung, Justin Emat, Ashvin Bam, Ann Palma, Veronica Angeles, Paul Sierszulski, and Phil Lazzara for makingtime in lab over the past years such a great time.
I also need to acknowledge Cindy Honegger for all of her help in the stockroom over the past two years. None of this work would have been possible if not for her assistance.
11 The Twelve Principles of Green Chemistry
1. Prevention: It is better to prevent waste than to treat or clean up waste afterit has been created.
2. Atom Economy: Synthetic methods should be designed to maximize the incorporation of all materials used in the process into the final product.
3. Less Hazardous Chemical Syntheses: Wherever practicable, synthetic methods should be designed to use and generate substances that possess little or no toxicity to human health and the environment.
4. Designing Safer Chemicals: Chemical products should be designed to effect their desired function while minimizing their toxicity.
5. Safer Solvents and Auxiliaries: The use of auxiliary substances (e.g., solvents, separation agents, etc.) should be made unnecessary wherever possible and innocuous when used.
Design for Energy Efficiency: Energy requirements of chemical processes 6. should be recognized fo r their environmental and economic impacts and should be minimized. If possible, synthetic methods should be conducted at ambient temperature and pressure.
7. Use of Renewable Feedstocks: A raw material or feedstock should be renewable rather than depleting whenever technically and economically practicable.
8. Reduce Derivatives: Unnecessary derivatization (use of blocking groups, protection/deprotection, temporarymodifica tion of physical/chemical processes) should be minimized or avoided if possible, because such steps require additional reagents and can generate waste.
9. Catalysis: Catalytic reagents (as selective as possible) are superior to stoichiometric reagents.
10. Design for Degradation: Chemical products should be designed so that at the end oftheir function they break down into innocuous degradation products and do not persist in the environment.
11. Real-time analysis for Pollution Prevention: Analytical methodologies need to be furtherdeveloped to allow for real-time, in-process monitoring and control
111 prior to the formation of hazardous substances.
12. Inherently Safer Chemistry for Accident Prevention: Substances and the form of a substance used in a chemical process should be chosen to minimize the potential for chemical accidents, including releases, explosions, and fires.
Anastas, P. T.; Warner, J. C. Green Chemistry, Theory and Practice. Oxford University Press, New York, 1998, 30.
IV Abstract
Bi(OTfh (2.0 mol %) (1.7 �SiMe3 eq) x�) n R1.-lX
X=O, S n = 1,2
Cyclic acetals (dioxolanes, dioxanes, and dithianes) are common protecting groupsin organic synthesis but they can also be converted to other usefulfunctional group s. A bismuth(III)triflate-catalyzed multi component reaction involving the allylation of cyclic acetals followed by in situ derivatization with acid anhydrides to generate highlyfunctionalized esters and thioesters has been developed under solvent-free conditions. Most reagents used to date for the allylation of cyclic acetals are highly corrosive or toxic and are oftenrequired in stoichiometric amounts. In contrast, the use of a relatively non-toxic and non-corrosive bismuth(III) based catalyst makes this methodology benign and attractive.
v Table of Contents
I. Introduction...... 1
A. Green Chemistry ...... 1
B. Bismuth Compounds ...... 7 C. Literature Review: Allylation of Acetals ...... 21
II. Results and Discussion ...... 32 A. Bismuth(III) TriflateCatalyzed Allylation of 1,3-Dioxolanes ...... 32
B. Mechanistic Studies ...... 37 C. Bismuth(III) TriflateCatalyzed Allylation of 1,3-Dioxanes...... 39 D. Bismuth(III) Triflate Catalyzed Allylation of 1,3-Dithianes...... 41
III. Experimental...... 45
A. General Experimental...... 45 B. Bismuth(III) TriflateCatalyzed Allylation of 1,3-Dioxolanes ...... 46 C. Bismuth(III) TriflateCatalyzed Allylation of5,5-Dimethyl-1,3-Dioxanes ..... 53 D. Bismuth(III) TriflateCatalyzed Allylation of 1,3-Dithianes ...... 56
IV. References ...... 63
V. Appendix: Spectral Data ...... 70
VI. VB I. Introduction
A. Green Chemistry
The contributions ofthe phannaceuticalindustry, especially via synthetic organic chemistry, to medicine have significantly improved the quality and length of human life. The synthesis and commercial development of countless compounds now allow for the treatment of diseases that have otherwise overwhelmed mankind. Over the past century, the discovery of antibiotics and new medicines has contributed to prolonging the average human life span by nearly thirty years.! The development of new fertilizers and pesticides has allowed for more bountifulharvests. Despite the vast achievements of the chemical industry, the massive amounts of hazardous waste produced cannot be ignored, especially when considering current environmental issues and the hazards presented to human health. For example, in 1984 a Union Carbide pesticide plant in Bhopal, India released 42 tons of methyl isocyanate? Nearly 15,000 people have lost their lives as result of this toxic gas leak and many others have suffered health problems due to exposure. Environmental drinking water contamination has also been a major issue in the aftermathof the disaster.
The United States Congress has passed many laws to help reduce the amount of chemical waste released into the environment. The most significant of these is the "Pollution Prevention Act" (PP A) passed in 1990.3 The PPA provides guidelines and laws on pollution prevention through the proper use and disposal of chemicals. Also, source reduction and prevention have been stressed in this legislation. The governmenttracks the production and release of toxic 4 chemical waste in the Toxic Release Inventory (TRI). In 2006, the TRI indicated that the chemical industry ranks third in the amount of waste released by sector (figure 1.1). The only
1 industries that produce and release more waste are the relatively large metal mining and electricity sectors.
4 Figure 1.1: TID Total Disposal or Release of Waste by Industry 2006
Food
Hazardous Waste 5%
Paper 5%
Therefore, chemists need to be more concerned with pollution in terms of hazardous waste being released into the environment. This has prompted synthetic organic chemists to consider developing environmentally friendly chemistry or Green Chemistry. Green Chemistry involves the design of chemical syntheses and processes that are more environmentally friendly, reduce waste production, and avoid use of toxic reagents.2 The main goal of green chemistry is to minimize the use of toxic chemicals by finding safe, effective alternatives. This type of developmental strategy is an efficient way to reduce the chemical waste associated with a synthesis. Also, avoiding the use of toxic and corrosive reagents makes synthesis much safer for the chemists involved. The risk associated with the use of a chemical can be expressed as a function of both hazard and exposure (eq. 1.1)?
2 Equation 1.1
Risk = f [hazard, exposure]
Past strategies of reducing risk have involved limiting exposure to dangerous chemicals by taking safety precautions and exercising especial care when handling reagents. This strategy can be an effective way of increasing safety if exposure can truly be limited. However, due to human error and faults in protective laboratory equipment, exposure control measures often fail. Therefore, the Green Chemistry approach is to lower hazards by using inherently less toxic or non-toxic reagents. This reduces risk associated with syntheses and reduces hazardous waste overall. This concept can be accomplished through the practice of Green Chemistry where information about toxicity of chemicals is utilized to lower hazard and reduce waste. This has particular relevance to synthetic organic chemistry, a field in which many toxic, corrosive and difficultto dispose of chemicals continue to be used in large quantities.
One concept that can be used to reduce the amount of waste associated with a chemical synthesis is atom economy. Atom economy is a measure of the percent by mass of reactants that end up in the desired product, and hence, is a good indication of the amount of waste material associated with a process. The solvents and catalysts necessary for a synthesis are not considered. This concept was introduced by Trost in 1991.5
Equation 1.2
Molecular Weight of desired product tom conomy = 10070 Of A E Molecular Weight of all reactants x
Many synthetic methods currently used yield byproducts that increase the amount of waste associated with a synthesis. Also, if the byproducts are toxic this makes waste disposal
3 more difficultand costly. The Wittig synthesis of alkenes produces one equivalent of triphenylphosphine oxide as a byproduct for every equivalent of alkene formed (scheme 1.1).
Scheme 1.1
o II o A + + Ph/�'Ph Ph
In contrast to the Wittig reaction, a classic example of an atom-economic reaction is the Diels- Alder cycloaddition. All of the atoms present in the diene and dienophile are present in the final cyclized product. Thus, the only chemical waste involved with this synthesis comes fromany necessary solvents or catalysts (scheme 1.2).
Scheme 1.2
R heat (j
The designof atom-economic processes allows for reduction of the amount of raw materials needed and a decrease in waste generated. Thus, designing syntheses with this principal in mind could drastically reduce the amount of waste produced by the chemical industry while also reducing costs.
The concept of E (environmental) factor was introduced by Roger Sheldon in 1992 to evaluate the environmental impact of chemical processes.6a The E factor is defined in terms of the amount waste associated with a process and the amount of desired product produced (eq. 1.3).
4 Equation 1.3
mass oj waste produced
actor = __---"- __----0... ___ _ E fi mass of product produced
The E factor can be determined for either an individual chemical process or an entire industrial sector. Sheldon determined the E factors for a number of different chemical industries (table 1.1). He found that the E factors associated with finechemi cal and pharmaceutical synthesis were relatively high when compared with more efficient industries, such as oil refining and bulk chemical synthesis. Production of waste on such a grand scale poses a major environmental concernand also hurts the cost effectiveness of numerous commercial processes.
Table E Factors of Various Chemical Industries 1.1:
Industry Sector Product produced (Tons) E Factor (kg waste/kg product) Oil refining 106_108 0.1 < Bulk chemicals 104_106 1 - 5 < Fine chemicals 102 _104 5 - 50 Pharmaceuticals 10-103 25 - 100
The importance of considering E factors and other Green Chemistry metrics becomes readily apparent when considering synthetic processes that generate large amounts of waste. In the early 1980s, Oce Andeno closed a plant responsible for the synthesis ofphloroglucino1.6b Phloroglucinol is used as a raw material for the synthesis of explosives and pharmaceuticals.
Closure of the plant was necessary because the cost of disposing of the waste associated with the synthesis was approaching the profits associated with the sale of phloroglucinol. The synthetic strategy employed at Oce Andeno involved the oxidation of 2,4,6-trinitrotoluene (TNT) with
5 potassium dichromate in fumingsulfuric acid 6c (scheme 1.3). This was followed by reduction of the nitro substituents with iron and hydrochloric acid and anin situ decarboxylation. Heating an acidic solution ofthe resulting 1,3,5-triaminobenzene yielded phloroglucinol.
Scheme 1.3
CH3 'Q'C02H 'Q' 02N N02 02N N02 K2Cr207 Fe/ HCI
)110 )110 10 H2S04/ S03 10 - CO2 N02 N02 2,4,6-trinitrotoluene
H2N NH2 HO OH aq. HCI y10 )110 y10 Heat NH2 OH phloroglucinol
The E factor for this process was determined by Sheldon to be 40. Thus, for every kg of phloroglucinol produced, 40 kg of solid waste containing Cr2(S04h FeCh, KHS04, and NH4Cl was generated. The cost associated with the disposal of this waste made the process impractical and resulted in the eventual closing of the Oce Andeno plant.
Though Sheldon's E factor is a good indication of the relative amount of waste produced by a given process or industry, the nature of the waste produced should also be taken into account when evaluating synthetic viability. A kilogram of sodium chloride or a similarly benignsalt is not equivalent to a kilogram of a toxic compound such as a tin salt when considering the environmental implications of chemical waste disposal. All of these factors should be considered collectively when designingGreen Chemistry processes.
6 The approach to environmentally friendlyche mistry in our laboratory utilizes non-toxic reagents that are highly catalytic in nature. It is in this context that bismuth compounds arevery attractive as catalysts and reagents in organic synthesis.
B. Bismuth Compounds
Bismuth, the 83rd element in the periodic table, has a natural abundance of 0.008 ppm in the Earth's crust and 0.0002 ppm in sea water.7 It is a soft,cryst alline metal with a whitish-pink hue. Bismuth is the heaviest stable element and the most diamagnetic element known.
Bismuth is a remarkable element because despite its proximity on the periodic table to toxic heavy metals such as lead and antimony, it is relative non-toxic. Due to their non-toxicity, bismuth compounds have found numerous applications in cosmetics and medicine. For example, the active ingredient in the anti-diarrheal medication Pepto-Bismol™ is bismuth subsalicylate
(figure 1.2). Bismuth sub citrate is the only compound known to be active against Helicobacter pylori, a bacterium that cause ulcers.8 Bismuth subnitrate is used in medicine as a wound dressing and as a component in ointment for inflamedskin. Cosmetically, bismuth oxychloride is used to impart a shimmering effect to various makeup products. Bismuth is an environmentally friendlyalternative to lead as the main component of shotgun cartridges used for waterfowl hunting.
Figure 1.2 o
Bi O.. 'OH BismuthV�9 Subsalicylate
7 With increasing fo cus on developing environmentally friendlysynt hesis methods, bismuth compounds have also been used as catalysts in synthetic organic chemistry. Bismuth compounds have several attractive features in this respect.
There is no evidence to date to suggest that bismuth compounds are carcinogenic or mutagenic.9 The remarkable non-toxicity of bismuth compounds has earnedbi smuth the distinction of a "Green" element. IO This non-toxicity is primarily due to their insolubility in neutral aqueous solutions such as biological fluids. Bismuth compounds are poorly soluble in the blood plasma and are readily excreted via the urinary tract. The non-toxicity of bismuth's compounds is evident froma comparison of LD50 values for a range of common Lewis acids (table 1.2). As can be seen fromtable 1.2, most bismuth compounds are even less toxic than sodium chloride. Even organobismuth compounds such as triphenylbismuthine areremark ably non-toxic.
Table Values of Bismuth Compounds and Comparable SaltslO 1.2: LDso
Compound (glKg) Species and Route LDso Sodium Chloride, NaCl 3.8 Rat, Oral Bismuth oxide, Bh03 5.0 Rat, Oral Bismuth nitrate, Bi(N03k5H2O 4.4 Rat, Oral Bismuth oxychloride, BiOCl 22 Rat, Oral Triphenylbismuthine, Ph3Bi 180 Dog, Oral Mercury chloride, HgCh 0.001 Rat, Oral Cerium chloride, CeCh 2.1 Rat, Oral Indium chloride, InCh 1.1 Rat, Oral Samarium chloride, SmCh 2.9 Rat, Oral Scandium chloride, ScCb 3.9 Rat, Oral Ytterbium chloride, YbCh 4.8 Rat, Oral
8 Despite the fact that bismuth is not common in the Earth's crust, bismuth compounds are relatively inexpensive. This is because bismuth is a byproduct oflead, copper and tin refining.
Many bismuth(III) compounds are commercially available at a low cost (table 1.3), which makes bismuth compounds even more attractive as potential catalysts.
Table 1.3: Availability of Bismuth(III) Compounds and Comparable Lewis Acidsa
Compound Cost/g Cost/mol ($) ($) Bismuth chloride, BiCh 2.25 711 Bismuth nitrate, Bi(N03k5H20 0.32 153 Bismuth oxide, Bh03 0.49 228 Bismuth Acetate, Bi(C2H302)3 3 1097 Bismuth trifiuoromethanesulfonate, Bi(OTf)3 10.60 6960 Scandium trifiuoromethanesulfonate, SC(OTf)3 37 17,820 Ytterbium trifluoromethanesulfonate, Yb(OTf)3 36 22,390 Trimethylsilyltrifiate, TMSOTf 1.70 378 Titanium tetrachloride, TiCl4 0.05 9.96 aSigma-Aldrich.com
Althoughthe hydrolysis of Bi(III) salts in water has been reported (this is discussed in more detail later, see scheme 1.36), bismuth compounds are relatively stable and tolerate small amounts of air and moisture. This contrasts sharply with moisture-sensitive Lewis acid reagents and catalysts, such as BF3·Et20 and TiC14, that must be handled under an inert atmosphere to ensure safety and viability of the reagent.
The electron configuration of bismuth is [Xe]4/45io6i6p3. On account of weak shielding by the 4f electrons (Lanthanide contraction) bismuth(III) compounds exhibit Lewis
9 acidity. Thus, bismuth(III) compounds can be utilized as potential Lewis acidic catalysts for organic synthesis.
Bismuth can also exist in the +5 oxidation state. Organobismuth compounds with bismuth in the +5 oxidation state are known andhave been applied in organic synthesis. II
Bismuth(V) compounds are commonly employed as oxidizing agents. Sodium bismuthate has been used for the benzylic oxidation of aromatic compounds 12 (scheme 1.4).
Scheme 1.4
HOAc, Acetone, H20
Triphenylbismuth(V) dichloride has been employed as an oxidizing agent for a variety of functionalities,including the oxidative phenylation ofphenolsl3 (scheme 1.5).
Scheme 1.5
OH
R R electron donating = 6
Applications of Bismuth(III) Compounds as Catalysts in Organic Synthesis
A variety ofbismuth(III) compounds have been used as Lewis acid catalysts for synthetic transformations.14 Bismuth(III) chloride is one of the most thoroughly investigated bismuth- based Lewis acids. The Knoevenage1 condensationl5 (scheme 1.6), Reformatsky reactionl6
(scheme 1.7), Die1s-Alder cyclization17, Mukaiyama-aldol reactionl8 (scheme 1.8), deprotection
10 20 2 of acetals19 (scheme 1.9), and the allylation of acid chlorides (scheme 1.10) andaldehyd es 1
(scheme 1.11) have all been reported with BiCh as the catalyst.
Scheme 1.6
BiCI3 (10.0 mol %) R1 R2 + F< H R3
R2 = CN, COOEt, CONH2, COCH3 (65-78 %)
R3 = CN, COOEt
Scheme 1.7
o BiCI3, AI Br Ph� +
Scheme 1.8
BiCI3 (5.0 mol %) »
Scheme 1.9
o BiCI3 (0.5 eq) R
R�1 ��(70-92 %)
Scheme 1.10
BiCI3 - 1.5 Znl2 o + R R' CH3, Ph, CI = �
11 Scheme 1.11
R + Zn or OH BiCI3 �R1 R2
I (45 - 99 %) = Fe 3 x CI, Br, Bismuth(III) bromide has been reported as a catalyst for the oxidation of epoxides to cyclic carbonates22 (scheme 1.12), the deprotection of alkyl TBDMS ethers23 (scheme 1.13), the
synthesis of nucleosides24, the formation of ethers25 (scheme 1.14), and the synthesis of tetrahydroquinoline derivatives26 (scheme 1.15).
Scheme 1.12
Ph�o BiBr3 (10 mol %)
Scheme 1.13 � moI OSitBuMe2 .:..,.( 3 _ _ _ %_ ...:..., OSitBuMe2 ) �ositBuMe, _BiB_ .::.-3 OH )loll!>- _ r yBr wetCH3CN (81Br-85 %) Scheme 1.14
(1-3 mol %) BiBr3 rt )10 CH3CN,
12 Scheme 1.15
BiBr3 (5-20 mol %) OH
n = 1,2
Bismuth(III) nitrate has also received significant attention in the literature. Bismuth(III) 2 nitrate has been utilized as a catalyst for the oxidation of alcohols 7 (scheme 1.16), the oxidation 28 2 of sulfides to sulfoxides (scheme 1.17), the deprotection of acetals 9 (scheme 1.18) and 30 3! thioacetals , the synthesis of acylals fromaldehydes (scheme 1.19), and the Biginelli reaction. 32
Scheme 1.16
OH Bi(N03h5H2O 0 )10 )l R1A R2 Montmorillonite R1 R2 rt
Scheme 1.17
0 Bi(N03h5H2O S SII R( 'R2 ]100 R( 'R2 CH3COOH (50-85 %)
13 Scheme 1.18
EtO 0Et 0 H
Bi(N03h5H20 (0.25 eq) � � I I o o OSitBuMe2 OSitBuMe2 Q Q76% Scheme 1.19
Bi(N03h5H20 (3-1 0 mol %) ROC OCOR lP � (RCOhO,CH 3CN Ar H
Bismuth Trifluoromethanesulfonate [Bismuth Triflate, Bi(OTf)3] Metal triflateshave received significant attention in the literature as Lewis acid catalysts.33 Likewise, bismuth triflate isthe one of the most thoroughly investigated bismuth- based catalysts.34 Bismuth triflate is a hygroscopic white solid that exists in a hydrated form at room temperature (Bi(OTt) 'xH20 with 1 x 4). Attempts to synthesize the anhydrous salt by 3 < < 3 heating Bi(OTt)3'4H20 result in decomposition above temperatures of 100 °C. 5 The final products of this decomposition areBiF 3 and H2S04. X-ray powder diffraction35 studies on
Bi(OTt)3 show that the bismuth atom is coordinated to four water molecules and four oxygen atoms fromtriflate groups. It was also determined that the tetrahydrate of bismuth triflate condenses into dimers.
Because ofthe environmentally friendly nature of bismuth salts, bismuth triflate has
received significant attention in the literature. 10, 34 Bismuth triflatehas been used as a catalyst for Diels-Alder reactions 17, 36 (scheme 1.20), Mukaiyamaaldol reactions37 (scheme 1.34), Biginelli
14 reactions38 (scheme 1.21), Friedel-Craftsacylations 39 (scheme 1.22) and alkylations4o, Beckmann rearrangements4! (scheme 1.23), Michael-type reactions42 (scheme 1.24), synthesis43 and deprotection44 of acetals, and the Sakurai allylation of a variety of functionalgroup including aldehydes45 (scheme 1.25), acetals46 (scheme 1.26), epoxides47 (scheme 1.27), aziridines47
(scheme 1.28), and quinones48 (scheme 1.29). This rather vast body ofliterature highlightsthe wide applicability and versatility of bismuth triflate as a catalyst in organic synthesis.
Scheme 1.20
Bi(OTfh (0.1-10 mol %)
Scheme 1.21
Bi(OTfh
x=O, S
Scheme 1.22
R1COCI or (R1COhO
Bi(OTfh (1-10 mol %) 0COR1 R� (65-96 %)
15 Scheme 1.23
Polyphosphoric acid OMe Bi(OTfb � 100-1200C H �V-{N-OH o 30%
Scheme 1.24
�OMe Bi(OTfb (2.0 mol %) + o Q O �MeO 96 %
Scheme 1.25
�SnBU3 OH Bi(OTfb (2.0 mol %) R �(65-95 %)
Scheme 1.26
OR1 Bi(OTfb (1.0 mol %) + R CH2CI2> )to rt (66-96� %)
16 Scheme 1.27
S 4 n � R 0 Bi(OTfb( (2.0 mol %) )100 Ar Ar�R CH2CI2, rt �OH (85-92 %)
Scheme 1.28
Ts sn I 4 N BiOTfb(� (2.0 mol %) )100 Ar CH2CI2, Ar � rt C� Scheme 1.29
0 �SiMe3 OH R R3 R1 1 Bi(OTfb (2.0 mol %) � I I )100 R2 R2V CH2CI2, rt 0 OH // (75-91 %) '-':::
Bismuth triflatecan be synthesized in the laboratory by a variety of literature methods. Verma and co-workers were the first to report a synthesis of bismuth triflate frombi smuth(III) 4 trifluoracetate and triflic acid 9 (scheme 1.30).
Scheme 1.30
rt, 8 h Bi(OCOCF3b CF3S03H Bi(OS02CF3h + -----l)loo1O-- (3.6 eq)
17 Bismuth triflatehas also been synthesized by treatment of triphenylbismuth with triflicacid so
(scheme 1.3 1). This method exploits the weak bismuth-carbon bonds (Bi-C bond: 143 KJ/mols1;
C-C bond: 447 KJ/mol) in triphenylbismuth to generate bismuth triflate. This method is not, however, environmentally friendly because of the formation of three equivalents of benzene, a known carcinogen.
Scheme 1.31
+ 3 TfOH Bi(OTf)s -78°C
A greener method for the synthesis of bismuth triflateinvolves reaction of bismuth oxide and triflicacid in aqueous ethanols2 (scheme 1.32). this procedure, bismuth triflate is isolated In by freeze-dryingthe solution.
Scheme 1.32
EtOH/H20 (75125) + 6 TfOH ,., Bi(OTfb
The efficiency of bismuth triflateas a Lewis acid catalyst is especially obvious when it is compared to other rare-earth triflates that have received considerably more attention in the literature. Bismuth triflate is reported to be a more effective catalyst for the chlorosulfinylation of aromatics than other triflatesS3 (scheme 1.33). Bismuth triflatewas sucessfullyempl oyed as a catalyst for the chlorosulfinylation of electron-rich aromatic compounds in high yields. The use of other metal triflates, such as scandium triflate and cerium triflate, resulted in significant
amounts of sulfide byproduct 2.
18 Scheme 1.33
Catalyst �o Meo 1 2
Catalyst (2.0 mol %) Yield of 1 (% t Yield of2 (%t Bi(OTf)3 99 Trace SC(OTf)3 14 40 Ce(OTf)4 28 38 Yb(OTf)3 Trace not detected Sb(OTf)3 75 4 a Yield determinedby H NMR spectroscopy 1
Also, bismuth triflateis a more effective catalyst for the Mukaiyama-aldol reaction37 than other metal triflates (scheme 1.34). I-Trimethylsilyloxycyclohexene was successfullycoupled with benzaldehyde with a low loading (1.0 mol %) of bismuth triflate. Ytterbium(III) triflateand yttrium(III) triflatewere ineffective as catalysts for this reaction.
Scheme 1.34
0 0 OH H Catalyst .. aOSiMe,I + CH2CI2 CYD uY Catalyst mol % Temp. T Yield (%) Bi(OTf)3 1.0 -70 °C 0.5 h 95 SC(OTf)3 5.0 -78 °C 15 h 81 Yb(OTf)3 5.0 -78 °C 15 h trace Y(OTf)3 5.0 -78 °C 15 h trace
19 Bismuth triflateis prone to hydrolysis in water yielding triflicacid (scheme 1.35). Other rare-earth metal triflates, such as scandium triflateand lanthanum triflateare not hydrolyzed in water. This unique property of bismuth triflate must be considered while dealing with acid- sensitive functional groups or proposing reaction mechanisms.
Scheme 1.35
For example, Marko and coworkers have explored the role oftriflic acid in the metal triflate catalyzed acylation of alcohols54 (scheme 1.36). It was discovered that the rate of benzoylation of alcohols catalyzed by bismuth triflatewas greatly inhibited when the reaction was performed in the presence 2,6-di-t-butyl-4-methylpyridine (DTBMP), a very hindered organic base. Moreover, the reaction was successfullycatalyzed using triflicacid. These data suggest that the acylation of alcohols is actually triflicacid catalyzed. Similar observations have been made by our group.44
Scheme 1.36
�OH �O)lPho
Catalyst mol DTBMP t Conversion % (%) (%t Bi(OTf)3 5.0 7h 17 Bi(OTf)3 5.0 15.0 15 h 8 TfOH 8.0 5h 30 a Measured by capillary GC aftercalibration of the response for each component
20 Bismuth triflatecan also be used as a catalyst in aqueous solutions. For example, the synthesis of2,3-disubstituted quinoxalines catalyzed by bismuth triflate in water been reported. 55 The bismuth triflatecatalyzed deprotection of acyclic and cyclic acetals in aqueous THF has also been reported44 (scheme 1.37). This protocol also applicable to ketals and conjugated acetals with a low loading of bismuth triflate(0. 1-1.0 mol %).
Scheme 1.37
H3C OCH3 Bi(OTfh (0.1-1.0 mol %) ° .. )l RX1 R2 THF/H20 (80:20) R1 R2 0 Bi(OTfh (0.1 -1.0 mol %) ) ° O .. R RJ.- THF/H20 (80:20) )lH
Many reagents and catalysts are destroyed when exposed to small amounts of water. This makes the use of anhydrous solvents and reagents imperative in many cases. Catalysts and reagents must oftenbe handled under an inert atmosphere. In contrast, most reactions catalyzed by bismuth triflatedo not require dry solvents or inert atmosphere conditions.
The environmentally friendly nature of bismuth (III) triflate coupledwith its ease of handling and inexpensive nature have prompted us to explore its utility as a catalyst for a variety of synthetic transformations.
C. Literature Review: Allylation of Acetals
Hosomi-Sakurai Allylation of Acyclic Acetals
Some of most importantorgani c transformations involve the formation of carbon-carbon bonds. These methodologies are especially important in the synthesis of pharmaceuticals and
21 natural products. Methods that have been developed for the formation of carbon-carbon bonds include the Suzuki Cross-Coupling56, Friedel-Crafts acylation57 and alkylation58, the Michael reaction59, OlefinMetat hesis6o, and Diels-Alder cyclization.61 The nucleophilic allylation of various carbon electrophiles is also an efficient strategy for carbon-carbon bond formation. The
Hosomi-Sakurai reaction involves the Lewis or protic acid catalyzed allylation of various electrophiles using allyl silanes. This method is commonly regarded as a mild method for carbon-carbon bond formation. Hosomi and Sakuraifirst reported the TiCl4-promoted allylation 62 of aldehydes and ketones to yield homoallyl alcohols (scheme 1.38).
Scheme 1.38
TiCI4 (0.5 eq)
They also successfullyextended this methodologyto the allylation of acyclic acetals63 (scheme
1.39). This represents an efficient synthesis of homo allyl ethers fromreadily available acetal starting materials. Following their report, the allylation of acyclic acetals to yield homo allyl ethers has since been well studied with a number of different Lewis acid catalysts. These include diphenylboryl triflate68, bis(fluorosulfonyl)imide69, montmorillonite7 0, CuBr7 tris(p- \ 2 3 4 bromophenyl)aminium hexachloroantimonate7 , Sc(OTf)3 7 , and BiBr3.7 Many of the catalysts previously employed for this synthesis are corrosive, for example AICl], TiC14, and TMSOTf, or toxic, for exampleBF 3"Et20. Additionally, stoichiometric catalyst loadings are oftennecessary. Low temperatures and anhydrous conditions are also required in several of these reported
22 protocols. These conditions detract fromthe utility of these procedures in the industry because of environmental and safety concerns.
Scheme 1.39
Our grouphas reported the bismuth(III) triflate-catalyzedallylation of acyclic acetals and ketals to yield homoallyl ethers in good yields75 (scheme 1.40). The allylation reactions proceeded smoothly at room temperature with a low catalyst loading (1.0 mol %).
Scheme 1.40
Bi(OTf)s (1.0 mol %)
..
This procedure provides a highly catalytic and environmentally friendly route to homoallyl ethers compared to previously reported methodologies.
Hosomi-Sakurai Allylation of Aldehydes
In contrast to the allylation of acyclic acetals, the allylation of aldehydes and carbonyl compounds to yield homoallyl ethers has received relatively little attention in the literature. Sakurai and co-workers reported the allylation of aldehydes and ketones catalyzed by iodotrimethylsilane in the presence of alkoxysilanesto yield homo allyl ethers 76 (scheme 1.41).
Trimethylsilyl triflate has also been used as a catalyst for the allylation of aldehydes in the
23 presence of alkoxysilanes to yield benzyl homo allyl ethers and n-hexyl homoallyl ethers.77 Two
disadvantages of this method are the utilization of a corrosive catalyst and the use of carbon tetrachloride, a carcinogenic and environmentally harmful solvent.
Scheme 1.41
Me3SiI (10.0 mol %)
�
We have recently reported the iron(III) p-toluenesulfonate catalyzed allylation of aldehydes and acetals to yield homoallyl ethers78 (scheme 1.42). The direct conversion of aldehydes to the corresponding homo allyl ether is advantageous because few acetals are
commercially available and must be typically synthesized fromthe corresponding aldehyde. In
addition, many acetals have poor shelflife due to their acid-sensitive nature. Moreover, most a methods in the literature for the allylation of acetals only report the synthesis of homo allyl
methyl or ethyl ethers. These compounds are not very amenable to further synthetic
manipulation since the alkyl groupap pended to the homo allyl ether oxygen is an inert methyl or ethyl group. A one-pot procedure utilizing alkoxysilanes allows for the installation of functional groupsthat are more amenable to further synthetic manipulation. This is possible because a wide range of alkoxysilanes is commercially available including benzyloxytrimethylsilane, ethoxytrimethylsilane, and allyloxytrimethylsilane.
24 Scheme 1.42
o R(,ll H �SiMe3 Fe(OTsh6H20 CH3CN, rt
We reported the allylation of aldehydes and ketones under mild conditions to yield homo allyl methyl ethers, homo allyl ethyl ethers, homoallyl allyl ethers, and homoallyl benzyl ethers. This protocol was applicable to both aliphatic and aryl aldehydes with low catalyst loadings (1.0-10.0 mol This method is especially attractive because ofthe utilization of %). iron(III) tosylate, an inexpensive and non-corrosive Lewis acid catalyst.
Our grouphas also reported the one-pot synthesis of homoallyl ethers from aldehydes catalyzed by bismuth(III) triflate79 (scheme 1.43). Trialkylorthoforrnatesor alkoxysilanes were employed to generate acetals or oxenium ions respectively, which can then undergo allylation to yield homoallyl ethers.
Scheme 1.43
HC(OR1b or R10SiMe3
�SiMe3 Bi(OTfb (0.1-5.0 mol %)
CH3CN or CH2CI2 27-82 %
This methodology was applicable to a variety of aryl aldehydes with a low catalyst loading. The use of alkoxytrimethylsilanes is particularly attractive because it allows for the installation of synthetically usefulallyl or benzyl groups at the homo allyl ether oxygen.
25 The one-pot synthesis of homo allyl acetates from aldehydes catalyzed by bismuth triflatehas also been reported (scheme 1.44). This procedure utilized acetic anhydride to generate the corresponding acylals, which canthen undergo allylation to yield homo allyl acetates. Aldehydes with strongly electron-donating groups (p-methoxy) underwent diallylation under the reaction conditions. The use of a relatively non-corrosive and non-toxic catalyst coupled with the wide availability of aldehydes makesthi s an attractive route to homo allyl acetates
Scheme 1.44
(CH3COhO
�SiMe3 OAe Bi(OTf)s (1.0 mol %) R� CH3CN 57-66 %
Hosomi-Sakurai Allylation of 1,3-Dioxolanes and 1,3-Dioxanes
Dioxolanes and dioxanes (fig. 1.3) have been primarily utilized as acid-labile protecting groups in organic synthesis. 80
Figure 1.3
1,3-dioxolane 1,3-dioxane
However, cyclic acetals can also be converted to other usefulfunctional groupsin the course of a
synthesis. For example, the synthesis of hydroxy esters by oxidation of cyclic acetals with m- chloroperbenzoic acid has been reported81 (scheme 1.45).
26 Scheme 1.45
BF3·Et20 (10 mol %) R2 R3 � mCPBA (1 eq) ° R2 R3 ° O ------i· R 0 OH b en z en e, rt R XH -- - .... 1 (1l � n = 0, 1
Cyclic acetals have received very little attention in the literature as substrates in the Hosomi- Sakurai reaction. Nevertheless, the ring-opening allylation of cyclic acetals ought to lead to the
synthesis of highly functionalized alcohols (scheme 1.46).
Scheme 1.46
SiMe3 �
._------..... Lewis Acid
Kuwajima and co-workers reported the allylationof a substituted 1,3-dioxolane catalyzed 2 by TiCI4, AICh, and SnC14.8 They found that the regioselectivity of ring-opening of a 4,4- dimethyl substituted 1 ,3-dioxolane was dependent on the Lewis acid used and the order of
addition of reagents (scheme 1.47). When TiC14 was employed as the Lewis acid,
regioselectivity was dependent on the order of addition of allyltrimethylsilane and TiC14. When AICh and SnC14 were used, isomer 4 was the major product (1 :99, 3:4). They also reported that the allylation did not proceed with TMSOTf as the catalyst and allyltrimethylsilane as the allyl
source. Instead, allyltributyltin, a highly toxic organotin reagent, was necessary to afford the
desired allylated product under these conditions.
27 Scheme 1.47
Lewis Acid OH OH �SiMe3 O� O� + C6H13 )Po 3 --Z� CH2CI2 C6H1 � C6H13� 3 4
Mead and co-workers have reported the allylation ofspiroketals using BF3'EhO, TiC14, and TMSOTf as Lewis acid catalysts83 (scheme 1.48). Stoichiometric catalyst loadings and low temperature conditions were necessary to promote the reaction. A mixture ofmonoallylated (5) and diallylated (6) products was obtained in most cases. Because of these factors, this procedure is not very attractive within the context of Green Chemistry.
Scheme 1.48
�SiMe3 TMSOTf, TiCI4, BF3'OEt2 or
The allylation of a cyclic acetal derived from �-D-ribo-hexopyranose has been reported84
(scheme 1.49). The allylation required stoichiometric loadings of both TMSOTf (3 eq) and
BF3'EhO (3 eq) with allyltrimethylsilane (12.3 eq) as the allylating agent. Moreover, the
allylation yielded a mixture of isomers, only one of which, 7, was carried on in the synthesis.
28 Scheme 1.49
7:8=10:1
Morelli and co-workers have reported the TiCl4 promoted allylation of 4-trifluoromethyl- 1 ,3-dioxolanes85 (scheme 1.50). This protocol was extended to only three aliphatic dioxolanes. Furthermore, highly toxic allyltributyltin was used as the source of the allyl group and a stoichiometric loading of TiCl4 was necessary to afford the desired homo allyl ether product.
Scheme 1.50
Me)--(CF3 CF3 TiCI4 OH SnBu3 J�Me � o .. R R 0 CH2CI2• OoC �62% - 85% 15 min
The allylation of 1,3-dioxolanes catalyzed by Sn(OTf)2 in the presence of alkoxysilanes has been reported86 (scheme 1.51). This synthesis yielded homo allyl ethers as a result of exchange between the alkoxysilane and the 1,3-dioxolane. The authors propose that the allylation of the acyclic acetal resulting fromthe exchange is faster than the allylation of the cyclic acetal. This reaction was applicable to a number of aliphatic and aryl dioxolanes in good yields, but a stoichiometric catalyst loading was necessary.
29 Scheme 1.51
�SiMe3 (1.4 eq) R30SiMe3 (2.0 eq) OR3 )10 Sn(OTfh (1.0 eq) R1 CH3CN, -20 DC 41�-97%
OR3
R1 fast exchange obse�rved product
The allylation of a number of 1,3-dioxolanes and 1,3-dioxanes catalyzed by TMSOTfhas been reported by Hunter and co-workers87 (scheme 1.52). This method utilized allyl borates as the source of the allyl group. The allyl borate reagents are not commercially available and must be synthesized in lab. A corrosive catalyst (TMSOTf) was employed in stoichiometric quantities and low temperature conditions were required (-78 °C). In a few cases, an alcohol byproduct arising from reduction of the cyclic acetal under the reaction conditions was also isolated in significantyield.
Scheme 1.52
TMSOTf (1.2 eq) + reduction product n = 1,2 THF, -78 DC to 0 DC 38-71%
Denmark and co-workers have reported one of the few Sakurai-Hosomi protocols utilizing 1,3- dioxanes as substrates88 (scheme 1.53). The allylation of4,6-d imethyl-2-hexyl-l,3-dioxane proceeded with a highdegree of diastereoselectivity (270:1) with a stoichiometric loading of
TiCLJTi(O-i-Pr)4 (11 eq) and allyltributyltin (8 eq) as the allylating agent. The
30 diastereoselectivity was much lower when allyltrimethylsilane was employed (56:1). The use of a corrosive Ti-based catalyst and a toxic organotincompound in superstoichiometric amounts detracts from the utility of this method.
Scheme 1.53
QH3 CH3 �SnBU3 eq) (8 O�OH TiCI41Ti(O-i-Pr)4 eq) + (11 n-C6H 3 CH2CI2 1 � QC -78 9 d r 100%= 9/10 270/1
QH3 CH3 �SiMe3 eq) (8 9�OH CI Ti 41Ti(O-i-Pr)4 eq) + � (11 n-C6H13 CH2CI2 QC -78 d r 100%= 9/10 56/1
The lack of a highly catalytic, widely applicable, and environmentally-friendlymetho d for the allylation of cyclic acetals prompted us to explore the bismuth(III) triflate-catalyzed allylation of cyclic acetals. The development of greener methods for allylation chemistry is of particularrelevance because of increasing environmental concernsand the importanceof carbon- carbon bond forming reactions in organic synthesis. Bismuth-based Lewis acids are particularly attractive in this respect because they are relatively non-toxic, non-corrosive, and inexpensive.
31 II. Results and Discussion
A. Allylation of 1,3-Dioxolanes followed by Derivitization with Acid Anhydrides in situ Catalyzed by Bismuth(III) Triflate
The lack of a highly catalytic and environmentally benign method for the ring-opening allylation of 1,3-dioxolanes (scheme 2.1) prompted our interest in investigating the utility of bismuth(III) triflateas a catalyst for this transformation. In contrast to the Hosomi-Sakurai allylation of aldehydes62, 76-79 and acyclic acetals63-7S, the allylation of cyclic acetals has received very little attention.
Scheme 2.1
�x Catalyst Solvent
Bismuth triflatewas not anef fective catalyst for the allylation of 1 ,3-dioxolanes to yield the expected alcohol products (scheme 2.2). Instead, a mixture of starting material and the corresponding aldehyde was isolated.
Scheme 2.2
Bi(OTfh
were isolated
32 It was reasoned that one way to push the reaction mightbe to trap the putative alkoxide intermediate that results fromaddi tion of the allyl group withan electrophile (scheme 2.3). This method would represent a multicomponent reaction in which the alkoxide is derivatized in a one- pot process.
Scheme 2.3
�SiMe3 Bi(OTf)3 �OE O Solvent R� ' R�
Attempts to capture the alkoxide with trimethylsilylchloride orp-toluenesul fonic anhydride were unsuccessful(s cheme 2.4). In both cases, a mixture of starting material and aldehyde was obtained.
Scheme 2.4
(1 .2 eq) TMSCI SiMe3 (1.2 eq) �OTMS � O work-up I / / ------�.� Bi(OTf)s (2.0 mol %) Ph� /7.
(1.7 eq) Ts20 �SiMe3 (1.7 eq)
Bi(OTf)s (2.0 mol %) 70 ,. CH3CN
Gratifyingly, we were able to trap the alkoxide intermediate with acetic anhydride (scheme 2.5), a protocol that allowed for the synthesis of highly functionalized esters in a one-
33 pot process. There are no literature reports for the allylation of cyclic acetals involving an in situ derivatization of the alkoxide, and thus, this new procedure is especially attractive. Such multi component reactions reduce the time and number of steps associated with a synthesis because isolation of intermediates is unnecessary.
Scheme 2.5
AC20 (1.7x)
�SiMe3 (1.7x)
Bi(OTfb (2.0 mol %) o�Oy CH3CN, 0 °C Ph�O
An efficient one-pot procedure for the synthesis of highly functionalized ester products was thus developed.89 The protocol was applied to the allylation of a number of aryl and aliphatic dioxolanes (table 2.1).
Although the initial work was performedusing acetonitrile as the solvent, the reactions were also found to proceed smoothly under solvent-freeconditi ons. This reduces the amount of waste associated with the reaction. Products were initially isolated by aqueous work-up followed by filtration througha silica column. The unacceptably low purity of crude products and the difficultyof removing anhydrides during work-up prompted us to consider a direct filtration of the reaction mixture througha silica gel column. This simple purification eliminates the need for a tedious aqueous work-up and reduces the total amount of organic waste associated with the
synthesis.
34 Table 2.1: Bismuth(III) Triflate Catalyzed Allylation of 1,3-Dioxolanes
�OCOR2 O 2.0 mol % Bi(OTfb .. �I R 1 �SiMe3 (1.7x) (R2COhO (1. 7x) DC o
R R2 t Yield I (%) p-CIC6H4 Me 40 min 67a p-CH3C6H4 Me 1 h 43b o-BrC6H4 Me 1 h 62b,c o-FC6H4 Me 1 h 61b m-BrC6H4 Me 45 min 73b CH3(CH2)8 Me 21 h 30 min 73b,c p-CIC6H4 iPr 35 min 36a O-BrC6H4 iPr 4 h 30 min 47a o-CIC6H4 iPr Ih 15 min 53a CH3(CH2)8 iPr 3 h 35 min 44a O-BrC6H4 tBu 2 h40 min 54a a Reaction mixture was loaded onto silica gel and eluted with EtOAc/ heptane b Product was isolated by aqueous work-up followed by flashchromatography c Reaction carried out in CH3CN at rt
This transformation was successfulwith a low catalyst loading (2.0 mol and under %) mild, solvent-freereaction conditions. This contrasts sharply with previous reports in which stoichiometric loadings of corrosive catalysts (TiC14, TMSOTf, SnCI4) were necessary to
35 promote allylation. Reaction times were relatively short (1-4 h), with the exception of aliphatic
dioxolanes which required longer reaction times. All reactions proceeded at 0 0 C andunder mild, solvent-freeconditions. Many methods reported to date require low temperature
conditions (-78 0 C).
Moreover, many of the previous procedures were only applied to a few dioxolanes. Our protocol was amenable to a variety of aliphatic and substituted aryl dioxolanes. Electron-rich aryl dioxolanes underwent allylation with a low catalyst loading (2.0 mol %).
A variety of acid anhydrides such as acetic anhydride, isobutyricanhy dride and trimethylacetic anhydride were successfullyempl oyed for the in situ derivatization of the alkoxide intermediate. However, the yield of the product dropped with use of hindered anhydrides. Thus, structural diversity can be introduced into the ester product by altering both the dioxolane and acid anhydride utilized. Furthermore, the highly functionalizedproduct is formed via a one-pot procedure from commercially available or readily accessible dioxolane starting materials.
Attempts to apply the protocol to the allylation of 1,3-dioxolanes derived fromketones were unsuccessful. A mixture of starting material and acetophenone was isolated when the 1,3- dioxolane derived fromacetophenone was subjected to the established reaction conditions (scheme 2.6).
36 Scheme 2.6
�SiMe3 (1.7 eq) AC20 (1.7 eq)
Bi(OTfh (2.0 mol %) /
oDe
B. Mechanistic Studies on the Bismuth(IH) Triflate-CatalyzedAllylation of Dioxolanes
In order to determine the mechanism by which bismuth(III) triflateis catalyzing the allylation of dioxolanes, a number of control experiments were performed (scheme 2.7). Though it was hypothesized that bismuth triflate is acting as a Lewis acid, it is also possible that the reaction is protic acid catalyzed. Triflic acid generated in solution by the hydrolysis of bismuth triflatecould potentially be catalyzing the allylation of dioxolanes.
As was already established, the allylation of 2-(2-bromophenyl)-1 ,3-dioxolane catalyzed by bismuth triflate(2.0 mol proceeded to completion in an hour. The allylation does not %) proceed in the absence of a catalyst. When triflicacid (5.0 mol was used as a catalyst for the %) allylation, a mixture of desired product and aldehyde was detected by GC analysis of the reaction mixture.
The bismuth triflate-catalyzed allylation was also conducted in the presence of 1,8-
(dimethylamino)napthalene (Proton Sponge™)90 (figure 2.1).
37 Figure 2.1 (CH�H3)' ProtonVU Sponge ™ 1 ,8-bis( dimethylamino)napthalene
Under these conditions, no product or aldehyde was observed by GC. While this mightsuggest
that the reaction is protic acid catalyzed, it is also possible that the amino functionalities of 1,8- (dimethyl amino )napthalene are strongly coordinating to bismuth triflate, rendering it unable to
catalyze the reaction. More studies arenecessa ry to determine bismuth triflate's role in catalyzing the allylation of dioxolanes.
Scheme 2.7 mol % Bi(OTfb 2.0 o� o� 1 h, 90% produ by II ct GC O-BrC6H4 � 0 No Catalyst No product SiMe3 (1.7x) o� � AC20 (1.7x) Vsr o 1 h, 40% product, 55% aldehyde by GC
mol % Bi(OTfb 2.0 No product 7 mol % proton sponge
38 A proposed mechanism for allylation involving activation of the dioxolane by bismuth triflateis shown (scheme 2.8).
Scheme 2.8
+ TfOSiMe3
/'... .0-Bi(OTfh O� ...... " •• Bi(OTfh Tf0 8 + ------�.� J.... .k,.>0 '" . R R )..� R <±>BI (OTf)2 � 3 1 ) �SiMe3
2
° + Bi(OTfh + �oSiMe3
C. Allylation of 1,3-Dioxanes followed by Derivitization with Acid Anhydrides in situ Catalyzed by Bismuth(III) Triflate
When compared to the allylation of 1,3-dioxolanes, there is very little precedent for the allylation of 1 ,3-dioxanes in the literature. Furthermore, the established methods utilize stoichiometric quantities of corrosive catalysts (TiCI4/Ti(O-i-Pr)4 or TMSOTf). Hunter and coworkers utilized allyl borates as the source of the allyl group87 (scheme 1.52). These compounds must be prepared in lab, detracting from the utility of this procedure. Denmark and coworkers utilized a large excess (8 eq) of allyltrimethylsilane or the highlytoxic allyltributylstannane as the allyl source88 (scheme 1.53). Thus, our goal was to apply the previously developed allylation methodology to the allylation of 1,3-dioxanes. This would constitute the firstcatalytic allylation of 1,3-dioxanes reported in the literature.
39 The previously developed procedure was applied to the allylation of a number of aryl and aliphatic 1,3-dioxanes (table 2.2). Thoughthe acetal center is more electron-rich in dioxanes than dioxolanes as supported by J3C NMR data, the allylations all proceeded to completion with a low catalyst loading (2.0 mol In all cases, acetic anhydride was used to derivatize the %). alkoxides in situ. The resulting functionalized esters were isolated in moderate to good yields.
Table 2.2: Bismuth(III) TriflateCatalyzed Allylation of 1, 3-Dioxanes
0 2.0 mol % Bi(OTf)s O�O)lGH3
(1.7x) R �SiMe3 R .. 1� ,1) (GH3GObO (1 .7x) ODG
R t Yielda (%) O-BrC6H4 1 h 30 min 79 p-BrC6H4 2h 65 p-CIC6H4 2h 70 p-CH3C6H4 1 h 30 min 60 m-CH3OC6H4 1 h 30 min 70 CH3(CH2)s 4h 75 BrCH2CH2 2 h 30 min 70 a Reaction mixture was loaded onto silica gel and eluted with EtOAcl heptane
The allylation of 5,5-dimethyl substituted 1,3-dioxanes was also explored using the
developed conditions. The allylation and in situ derivatization of aryl andaliphati c 5,5- dimethyl-l ,3-dioxanes was successfulunder mild conditions (table 2.3). The ester products were isolated in moderate to good yields in all cases.
40 Table 2.3: Bismuth(III) Triflate Catalyzed Allylation of 5, 5-Dimethyl -l, 3-Dioxanes
o 2.0 mol % Bi(OTfb O�O)lCH3
------!>-I>SiMe3 (1.7x) R1 � � (CH3CObO (1.7x) ODC
R t Yield (%) p-CIC6H4 10 min p-CH3C6H4 30 min CH3(CH2)s 3 h 30 min
a Reaction mixture was loaded onto silica gel and eluted with EtOAcI heptane. Product was b isolated by aqueous work-up followed by flash chromatography.
D. AUylation of 1,3-Dithianes followed by Derivitization with Acid Anhydrides in situ Catalyzed by Bismuth(III) Triflate
1,3-Dithianes have received significant attention in the literature as protecting groups for carbonyl compounds.80 Also, their application in the "Umpolung" chemistry pioneered by Seebach and Corey is well precedented91 (scheme 2.9).
Scheme 2.9 n-BuLi
THF, - 30 DC
41 Dithianes can be also be potentially converted to other usefulfunctional group s. To date, there has been no report of a Hosomi-Sakurai type allylation of dithianes to yield functionalized
thiols (scheme 2.10).
Scheme 2.10
S�SH
R Lewis Acid � Solvent
This total lack of literature precedent for the allylation of 1,3-dithianes prompted our interest in extending the established bismuth(III) triflate catalyzed allylationmet hodology to this
functionality. A one-pot allylation and in situ derivatization of 1 ,3-dithianes with acid anhydrides would constitute an efficient synthesis of functionalized thioesters (scheme 2.11).
Scheme 2.11
SiMe3 (1.7 eq) � (CH3COhO (1.7 eq)
Bi(OTfh (2.0 mol %)
OOC
Initial attempts to allylate 2-( 4-chlorophenyl)-1 ,3-dithiane to yield the corresponding
functionalized thiol were unsuccessful(sc heme 2.12). GC analysis of the reaction mixture indicated that no reaction was taking place.
42 Scheme 2.12
�SiMe3 (1.7 eq)
Bi(OTfh (10 mol %) 7 CH3CN, O OC
However, by using a protocol similar to the allylation of dioxolanes and dioxanes, the thiolate intermediatewas successfullytrapp ed with acetic anhydride to yield the corresponding
thioester. This strategy was applied to a handful of aryl and aliphatic dithianes, yielding the
corresponding thioesters in moderate to good yields (table 2.4).
Table 2.4: Bismuth(III) Triflate Catalyzed Allylation of 1,3-Dithianes
�SiMe3 (1.7 eq) 0 � (CH3CO)20 (1.7 eq) S SJl.CH3 R .. R J Bi(OTfh � ) OOC
b R mol % Bi(OTf)3 t Yield (%)
C6HS 2.0a 3 h45 min 78 p-CIC6H4 2.0 2 h45 min 65 m-CH3C6H4 4.0 4 h 30 min 74 CH3(CH2)8 10.0 3 h 30 min 63 b a An additional 2.0 mol % Bi(OTf)3 was added after 3 h. Reaction mixture was loaded onto silica gel and eluted with EtOAc/ heptane.
The allylation of 1,3-dithianes proceeded smoothly under mild, solvent-freeconditions with low
catalyst loadings (2.0 -10.0 mol %). Although allylation of dioxolanes and dioxanes proceeded
43 with a 2.0 mol % loading of bismuth (III) trifiate, electron-rich aryl dithianes and aliphatic dithianes required more catalyst (4.0 - 10.0 mol %) for the reactions to proceed to completion.
To the best of our knowledge, this procedure represents the firstexample ofthe application of 1,3-dithianes as substrates for the Hosomi-Sakurai reaction. Furthermore, the method utilizes a non-toxic and non-corrosive catalyst and solvent-free conditions.
Conclusions
A robust and highly catalytic method for the allylation and in situ derivatization of a number of cyclic acetals (dioxolanes, dioxanes, and dithianes) has been developed. There has been little precedent in the literature for the allylation ofthese functionalities. Most reagents used to date for the allylation of cyclic acetals are highly corrosive or toxic and are often required in stoichiometric amounts. In contrast, the use of a relatively non-toxic and non corrosive bismuth(III) based catalyst and the lack of anaqueous waste stream make the developed methodology environmentally benign and attractive.
44 III. Experimental
A. General Experimental:
Bismuth(III) triflate was purchased from Aldrich Chemical Company and stored under vacuum.
Allyltrimethylsilane was purchased from Acros Chemical Company or Aldrich Chemical Company. Acetic anhydride was purchased from Fisher Scientific. Dioxanes and dithianes were prepared in lab following procedures developed in our group or literature protocols.80 Products were analyzed using a lEOL Eclipse NMR Spectrometer at 270 MHz for lH NMR and 67.5 MHz for I3C NMR in CDCb as the solvent. GC analysis was performed on a Varian CP-3800
Gas Chromatograph equipped with a 30 m silica-packed column with a diameter of 0.25 mm (Conditions: hold at 100 °C for 1 min; ramp at 30 °C/min until 220 °c ; hold at 220 °C; flowrate; 2.0 mL/min of He). Thin-layer Chromatography was performed on alumina backed silica gel plates. Spots were visualized under UV light (when a UV active chromophore was present) and by spraying the plate with phosphomolybdic acid followed by heating. Purifications were performed by flash chromatography on silica gel.92 Products were characterized by lH NMR, I3C NMR, and GC. Satisfactory elemental analysis or High Resolution Mass Spectrometry (HRMS) data was obtained for all new compounds.
45 B. Bismuth(III) Triflate Catalyzed Allylation of 1,3-Dioxanes
Allylation of 2-(2-bromophenyl)-1,3-dioxane (MJS2057fr2051)
o (1 .7 eq) �SiMe3 O�O� AC20 (1.7 eq) 2.0 mol % Bi(OTf)s � Br DoC UO�
A homogeneous mixture of 2-(2-bromophenyl)-1,3-dioxane (0.2450 g, 1.008 mmol), allyltrimethylsilane (0.2723 0.1958 g, 1.713 mmol, 1.7 eq), and acetic anhydride (0.1620 mL, mL, 0.1749 g, 1.713 mmol, 1.7 eq) was stirred at 0 °C under N2 in a flame-dried three-neck rbf as bismuth(III) triflate (0.0132 g, 0.0202 mmol, 2.0 mol %) was added. The reaction mixture immediately acquired a light yellow color. Reaction progress was followed by gas chromatography. After 1 h 30 min, the reaction mixture was loaded onto 65 g of silica gel and eluted with EtOAc/heptane (5/95, v/v). Fifty-eight fractions (8 mL) were collected after a 100 mL prefraction. Fractions 20 to 51 were combined and concentrated to yield 0.26 g (79 %) of a clear, colorless liquid product that was determined to be 97 % pure by GC analysis and IH l3C & NMR spectroscopy. IH NMR: () 1.84-1.89 (m, 2 H), 1.99 (s, 3 H), 2.39-2.44 (m, 2 H), 3.34-3.38
(m, 2 H), 4.13-4.18 (t, 2 H, J= 6.43 Hz), 4.68-4.71 (m, 1 H), 5.00-5.07 (m, 2 H), 5.80-5.86 (m, 1 H). 7.10-7.51 (m, 4 H). l3C: (15 peaks) () 171.0, 141.2, 134.4 132.6, 128.7, 127.6, 127.6, 122.9,
117.0, 80.2, 65.4, 61.6, 41.1, 28.9, 20.9. HRMS-EI M+ calcd for C sH 9Br03Na, (mlz): l I 349.0415; found, 349.0423.
46 Allylation of 4-bromophenyl)-1,3-dioxane (MJSl185fr5069) 2-(
�SiMe3 (1.7 eq) AC20 (1.7 eq) 2.0 mol % Bi(OTf)s DoC
A homogenous mixture of2-(4-bromophenyl)-1,3-dioxane (0.2501 g, 1.029 mmol), allyltrimethylsilane (0.2779 0.1998 g, 1.749 mmol, 1.7 eq), and acetic anhydride (0.1653 mL, mL, 0.1785 g, 1.749 mmol, 1.7 eq) was stirred at 0 °C under N2 in a flame-driedthree-neck rbf as bismuth(III) triflate(0.0 135 g, 0.0206 mmol, 2.0 mol %) was added. The reaction mixture immediately acquired a light yellow color. Reaction progress was followed by gas chromatography. After2 h, the reaction mixture was loaded onto 65 g of silica gel and eluted with EtOAc/ heptane (5/95, v/v). Seventy-two fractions (8 were collected aftera 100 mL mL) prefraction. Fractions 50 to 69 were combined and concentrated to yield 0.22 g (65 %) of a clear, colorless liquid product that was determined to be 98 % pure by GC analysis and IH 13C & NMR spectroscopy. IH NMR: () 1.82-1.86 (m, 2 H), 1.98 (s, 3 H), 2.32-2.50 (m, 2 H), 3.31-3.34
(m, 2 H), 4.10-4.15 (m, 3 H), 4.96-5.02 (m, 1 H), 5.65-5.76 (m, 1 H), 7.1 1-7.14 (d, 2 H, J= 8.15
Hz), 7.42-7.45 (d, 2 H, J= 8.15 Hz). 13C: (13 peaks) () 171.0, 141.1, 134.2, 131.4, 128.3, 121.3,
117.2, 81.5, 65.0, 61.6, 42.4, 28.9, 20.9. HRMS-EI M+ calcd for C SH 9Br03Na, (mlz): I I 349.0415; found, 349.0417.
47 AHylation of 2-( 4-chlorophenyl)-1,3-dioxane (MJS 1179fr8099)
�SiMe3 (1.7 eq) AC20 (1 .7 eq) 2.0 mol % Bi(OTf)s
OOC
A homogenous mixture of 2-(4-chlorophenyl)-1,3-dioxane (0.2500 g, 1.259 mmol) , allyltrimethylsilane (0.3399 0.2445 g, 2.140 mmol, 1.7 eq), and acetic anhydride (0.2022 mL, mL, 0.2184 g, 2.140 mmol, 1.7 eq) was stirred at 0 °C under N2 in a flame-driedth ree-neck rbf as bismuth(III) triflate (0.0165 g, 0.0252 mmol, 2.0 mol %) was added. The reaction mixture immediately acquired a light yellow color. Reaction progress was followed by gas chromatography. After 2 h, the reaction mixture was loaded onto 66 g of silica gel and eluted with EtOAc/heptane (5/95, v/v). One hundred and six fractions (4 were collected. mL) Fractions 80 to 99 were combined and concentrated to yield 0.25 g (70 %) of a clear, colorless liquid product that was determined to be 98 % pure by GC analysis and IH 13C spectroscopy. & IH N R 1.82-1.89 (m, 2 H), 1.98 (s, 3 H), 2.32-2.54 (m, 2 H), 3.31-3.34 (m, 2 H), 4.11-4.20 M : 0 H), H), H), H). 13C: (m, 3 4.97-5.03 (m, 2 5.66-5.76 (m, 1 7.17-7.31 (m, 4 (13 peaks) 0 171.0, 140.6, 134.2, 133.1, 128.4, 128.0, 117.2, 81.4, 65.0, 61.5, 42.4, 28.9, 20.9. HRMS-EI (mlz) : M+ calcd for ClsHI9CI03Na, 305.0920; found, 305.0913.
48 Allylation of 2-(4-tolyl )-1,3-dioxane (MJS2051fr3052)
o (1.7 eq) �SiMe3 O�O� AC20 (1.7 eq) ----...... � � 2.0 mol % Bi(OTf)s I H3C ~h- OOC
A homogenous mixture of 2-(4-tolyl)-1,3-dioxane (0.2497 g, 1.402 mmol), allyltrimethylsilane
(0.3788 mL, 0.2723 g, 2.383 mmol, 1.7 eq), and acetic anhydride (0.2253 mL, 0.2433 g, 2.383 mmol, 1.7 eq) was stirred at 0 °C under N2 in a flame-driedthree-neck rbf as bismuth(III) triflate
(0.0184 g, 0.0280 mmol, 2.0 mol %) was added. The reaction mixture immediately acquired a bright pink color. Reaction progress was followed by gas chromatography. After 1 h 30 min, the reaction mixture was loaded onto 60 g of silica gel and eluted with EtOAc/heptane (5/95, v/v). Sixty fractions (8 mL) were collected. Fractions 30 to 52 were combined and concentrated to yield 0.22 g (60 %) of a clear, colorless liquid product that was determined to be 99 % pure by
GC analysis and IH l3C spectroscopy. IH NMR: 0 1.82-1.89 (m, 2 H), 1.98 (s, 3 H), 2.33 (s, 3 & H), 2.37-2.56 (m, 2 H), 3.29-3.35 (m, 2 H), 4.11-4.16 (m, 3 H), 4.97-5.05 (m, 2 H), 5.70-5.76 (m,
1 H). 7.1 1-7.17 (m, 4 H). l3C: (14 peaks) 0 171.1, 139.0, 137.2, 135.0, 129.0, 126.6, 116.7, 82.0,
64.8, 61.8, 42,6, 29.0, 21.1,20.9. Anal. Calcd for C16H2203: C, 73.25; H, 8.45. Found: C, 73.08; H, 8.45.
49 Allylation of 2-(3-methoxyphenyl)-1,3-dioxane (MJS119lfr2433)
o (1.7 eq) �SiMe3 O�O� AC20 (1.7 eq) 2.0 mol % Bi(OTf)s ODC rOCH3
A homogenous mixture of 2-(3-methoxyphenyl)-1 ,3-dioxane (0.2504 g, 1.289 mmol), allyltrimethylsilane (0.3483 0.2504 g, 2.192 mmol, 1.7 eq), and acetic anhydride (0.2072 mL, mL, 0.2237 g, 2.192 mmol, 1.7 eq) was stirred at 0 °C under N2 in a flame-driedrbf as bismuth(III) triflate(0 .0169 g, 0.0258 mmol, 2.0 mol %) was added. The reaction mixture immediately acquired a dark red color. Reaction progress was followed by gas chromatography and TLC. After 1 h 30 min, the reaction mixture was loaded onto 60 g of silica gel and eluted with EtOAc/hexanes (10190, v/v) for fractions 1-24 and EtOAc/hexanes (20/80, v/v) for fractions 24-57. Fifty-seven fractions (8 were collected after a 100 mL prefraction. Fractions 24 to mL) 33 were combined and concentrated to yield 0.25 g (70 %) of a clear, colorless liquid that was determined to be 99 % pure by GC analysis and IH J3C NMR spectroscopy. IH NMR: 0 1.83- & 1.87 (m, 2 H), 1.98 (s, 3 H), 2.35-2.52 (m, 2 H), 3.30-3.38 (m, 2 H), 3.79 (s, 3 H), 4.1 1-4.16 (m, 3 H), 4.97-5.05 (m, 2 H), 5.70-5.80 (m, 1 H), 6.78-6.85 (m, 3 H), 7.20-7.26 (m, 1 H). l3C: (16 peaks) 0 171.1, 159.7, 143.8, 134.8, 129.3, 119.0, 116.8, 112.9, 111.9, 82.0, 65.0, 61.7, 55.1,
42.5, 28.9, 20.9. Anal. Calcd for C16H2204: C, 69.04; H, 7.97. Found: C, 68.83; H, 7.94.
50 Allylation of 2-nonyl-l,3-dioxane (MJS2059fr3463)
(1.7 �SiMe3 eq) o O�O� mol 2.0 % Bi(OTfh OOC A homogenous mixture of2-nonyl-l,3-dioxane (0.2509 g, 1.176 mmol), allyltrimethylsilane
(0.3177 0.2284 g, 1.999 mmol, 1.7 eq), and acetic anhydride (0.2041 0.1889 g, 1.999 mL, mL, mmol, 1.7 eq) was stirred at 0 °C under N2 in a flame-dried rbf as bismuth(III) triflate (0.0154 g,
0.0235 mmol, 2.0 mol %) was added. The reaction mixture immediately acquired a light yellow color. Reaction progress was followed by gas chromatography and TLC. After 4 h, the reaction mixture was loaded onto 75 g of silica gel and eluted with EtOAclhexanes (3/97, v/v). Sixty-six fractions (8 mL) were collected after a 100 mL prefraction. Fractions 34 to 63 were combined and concentrated to yield 0.25 g (75 %) of a clear, colorless liquid that was determined to be 97
% pure by GC analysis and IH 13C NMR spectroscopy. IH NMR: 0.85 (t, 3 H, J = 6.91 Hz), & b 1.24 (s, 14 H), 1.39-1.43 (m, 2 H), 1.80-1.89 (m, 2 H), 2.02 (s, 3 H), 2.22 (t, 2 H, J= 6.18 Hz), 3.20-3.29 (m, 1 H), 3.40-3.57 (m, 2 H), 4.14 (t, 2 H, J= 6.42 Hz), 5.00-5.06 (m, 2 H), 5.71-5.86 (m, 1 H). 13C: (18 peaks) 171.1, 135.1, 116.7, 79.3, 65.2, 61.8, 38.3, 33.8, 31.9, 29.7, 29.6, b 29.6, 29.4, 29.3,25.4, 22.7, 21.0, 14.1. HRMS-EI M+ ca1cd for C sH3403Na, 321.2406; (mlz): 1 found, 321.2416.
51 Allylation of 2-(2-bromoethyl)-1,3-dioxane (MJS2107fr4460)
SiMe3 (1.7 eq) � o AC20 (1.7 eq) O�O� ,.. Br 2.0 mol % Bi(OTf)s Br Do � �) C A homogenous mixture of 2-(2-bromoethyl)-1,3-dioxane (0.2545 g, 1.305 mmol), allyltrimethylsilane (0.3525 0.2534 g, 2.218 mmol, 1.7 eq), and acetic anhydride (0.2097 mL, mL, 0.2264 g, 2.218 mmol, 1.7 eq) was stirred at 0 °C under N2 in a flame-dried rbfas bismuth(III) triflate (0.0171 g, 0.0261 mmol, 2.0 mol %) was added. The reaction mixture immediately acquired a light brown color. Reaction progress was followed by gas chromatography. After 2 h 30 min, the reaction mixture was loaded onto 60 g of silica gel and eluted with EtOAc/hexanes (5/95, v/v). Sixty fractions (8 were collected. Fractions 44 to mL) 60 were combined and concentrated to yield 0.2569 g (70 %) of a clear, colorless liquid that was determined to be 98 % pure by GC analysis and IH I3C NMR spectroscopy. IH NMR: 1.83- & b 1.96 (m, 4 H), 2.03 (s, 3 H), 2.24-2.29 (m, 2 H), 3.45-3.51 (m, 4 H), 3.60-3.66 (m, 1 H), 4.11-
4.16 (m, 2 H), 5.04-5.10 (m, 2 H), 5.71-5.81 (m, 1 H). 13C: (11 peaks) 171.1, 133.9, 117.6, b 76.5, 65.6, 61.6, 37.9, 37.3, 30.4, 29.2, 21.0. HRMS-EI [M H calcd for ClIH20Br03, (mlz): + t 279.0596; found, 279.0598.
52 C. Bismuth(III) Tritlate Catalyzed Allylation of5,5-Dimethyl-l,3-Dioxanes
AHylation of 2-( 4-chlorophenyl)-5,5-dimethyl-l,3-dioxane (EBl123fr3343)
�SiMe3 (1.7 eq) AC20 (1.7 eq) 2.0 mol % Bi(OTfh
OOC
A homogenous mixture of 2-( 4-chlorophenyl)-5,5-dimethyl-l ,3-dioxane (0.2500 g, 1.103 mmol), allyltrimethylsilane (0.2979 mL, 0.2142 g, 1.875 mmol, 1.7 eq), and acetic anhydride (0.1786 mL, 0.1929 g, 1.875 mmol, 1.7 eq) was stirred at 0 °c under N2 in a flame-driedthree-neck rbf as bismuth(III) triflate (0.0724 g, 0.110 mmol, 10.0 mol %) was added. The reaction mixture immediately acquired a bright orange color. Reaction progress was followed by gas chromatography. After 10 min, the reaction mixture was stirred with 10% Na2C03 (15 for mL) 25 minutes. The mixture was extracted with EtOAc (3 x 10 m:). The combined organic layers were washed with sat. NaCl (20 mL), dried (Na2S04), and concentrated to yield 0.3360 g (98 %) of a yellow liquid that was determined to be 90 % pure by GC and IH NMR. The crude product was loaded onto 22 g of silica gel and eluted with EtOAc/ heptane (2.5/97.5, v/v). Sixty-five fractions (4 mL) were collected. Fractions 35 to 51 were combined and concentrated to yield 0.2534 g (74 %) of a clear, colorless liquid product that was determined to be 95 % pure by GC analysis and IH spectroscopy. IH NMR: 0.87 (s, 3H), 0.89 (s, 3 H), 1.98 (s, 3 H), 2.24-2.53 (m, b 2 H), 2.95-3.05 (q, 2 H, J= 8.64 Hz), 3.87 (dd, 2 H, J= 10.63, 2.21 Hz), 4.11-4.16 (m, 1 H), 4.96-5.02 (m, 2 H), 5.66-5.81 (m, 1 H), 7.15-7.18 (m, 2 H), 7.26-7.30 (m, 2 H). BC: (14 peaks):
171 .2, 140.9, 134.5, 133.0, 128.4, 127.9, 117.0, 81.7, 74.4, 69.7, 42.6, 35.3, 21.9, 20.9. HRMS- b EI calcd for C H23CI03Na, 333.1233; found, 333.1247. (mlz): � 17
53 Allylation of 2-( 4-tolyl)-5,5-dimethyl-l,3-dioxane (MJS2063frl034)
�SiMe3 (1.7 eq)
2.0 mol % Bi(OTf)s
o De
A homogenous mixture of 2-( 4-tolyl)-5,5-dimethyl-1 ,3-dioxane (0.2590 1.256 mmol), g, allyltrimethylsilane (0.3392 mL, 0.2439 g, 2.135 mmol, 1.7 eq), and acetic anhydride (0.2018 mL, 0.2179 g, 2.135 mmol, 1.7 eq) was stirred at 0 °C under N2 in a flame-driedthree-neck rbf as bismuth(III) triflate (0.0165 g, 0.0251 mmol, 2.0 mol %) was added. The reaction mixture immediately acquired a light yellow color. Reaction progress was followed by gas chromatography. After 30 min, the reaction mixture was loaded onto 60 g of silica gel and eluted with EtOAc/heptane (5/95, v/v). Sixty fractions (8 mL) were collected aftera 50 mL prefraction. Fractions 10 to 34 were combined and concentrated to yield 0.30 g (83 %) of a clear, colorless liquid product that was determined to be 99 % pure by GC analysis and IH 13C & NMR spectroscopy. IH NMR: 0.88 (s, 3 H), 0.90 (s, 3 H), 1.99 (s, 3 H), 2.26-2.56 (m, 2 H), D 2.33 (s, 3 H), 2.94-3.09 (dd, 2 H, 17.08, 8.64 Hz), 3.85-3.94 (t, 2 H, 10.58 Hz), 4.1 1-4.l3 (m, J= 1 H), 4.96-5.00 (m, 2 H). 5.73-5.84 (m, 1 H), 7.l3 (s, 4 H). 13C: (15 peaks): 171.0, l39.3, D l36.9, l35.1, 128.8, 126.4, 116.4, 82.1, 74.1, 69.7, 42.8, 35.3, 21.9, 21.0, 20.8. Anal. Calcd for
ClsH2603: C, 74.45; H, 9.02. Found: C, 74.15; H, 9.08.
54 Allylation of 2-nonyl-5,5-dimethyl-l,3-dioxane (EB1125fr916)
SiMe3 eq) � (1.7 O� eq) AC20 (1.7 �O) -2 -.0-m- -l o-o----f --JSo"- O V Bi(OT )3 OOC A homogenous mixture of 2-nonyl-5,5-dimethyl-l,3-dioxane (0.2500 g, 1.031 mmol), allyltrimethylsilane (0.2786 mL, 0.2003 g, 1.754 mmol, 1.7 eq), and acetic anhydride (0.1676 mL, 0.1793 g, 1.754 mmol, 1.7 eq) was stirred at 0 °c under N2 in a flame-dried three-neck rbf as bismuth(III) triflate (0.0135 g, 0.0206 mmol, 2.0 mol %) was added. The reaction mixture immediately acquired a pale yellow color. Reaction progress was followed by gas chromatography. After 3 h 30 min, the reaction mixture was stirred with 10% Na2C03 (15 mL) for 25 minutes. The mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with sat. NaCl (25 dried (Na2S04), and concentrated to yield 0.3152 g mL), (98 %) of a dark brown liquid that was determined to be 83 % pure by GC and 1 H NMR. The crude product was loaded onto 12.5 g of silica gel and eluted with EtOAc/heptane (4/96, v/v). Twenty-fivefr actions (4 mL) were collected aftera 100 mL prefraction. Fractions 5 to 16 were combined and concentrated to yield 0.2315 g (72 %) of a clear, colorless liquid product that was determined to be 97 % pure by GC analysis and IH BC NMR spectroscopy. IH NMR: 0.85- & C 0.89 (m, 9 H), 1.24-1.41 (m, 16 H), 2.03 (s, 3 H), 2.19 (t, 2 H, 6.91 Hz), 3.08-3.22 (m, 3 H), J= 3.86 (s, 2 H), 4.97-5.01 (m, 2 H), 5.72-5.83 (m, 1 H). l3C (19 peaks): 171.0, 135.30, 116.48, C 79.34, 74.53, 69.91,38.29, 35.52, 33.80, 31.96, 29.81,29.69, 29.65, 29.39, 25.36, 22.73, 22.05,
20.91, 14.15. HRMS-EI calcd for C2 H3803Na, 349.2719; found, 349.2735. (mlz): � o
55 D. Bismuth(III) Triflate Catalyzed Allylation of 1,3-Dithianes
Allylation of 2-phenyl-l,3-dithiane (MJS2071frl135)
�SiMe3 (1.7 eq) o � AC20 (1.7 eq) s s� 4.0 mol % Bi(OTf)s r ooe
A homogenous mixture of 2-phenyl-l ,3-dithiane (0.2530 g, 1.289 mmol), allyltrimethylsilane
(0.3481 mL, 0.2503 g, 2.191 mmol, 1.7 eq), and acetic anhydride (0.2071 0.2236 g, 2.191 mL, mmol, 1.7 eq) was stirred at 0 °C under N2 in a flame-dried three-neck rbf as bismuth(III) triflate
(0.0169 g, 0.0258 mmol, 2.0 mol %) was added. The reaction mixture immediately acquired a
light yellow color. Reaction progress was followed by gas chromatography. After 3 h, additional bismuth(III) triflate (0.0169 g, 0.0258 mmol,2.0 mol %) was added to the reaction mixture because startingmaterial was detected by Gc. After 3 h 45 min, the reaction mixture was loaded onto 70 g of silica gel and eluted with EtOAc/heptane (3/97, v/v) for the prefraction and EtOAC/heptane (5/95, v/v) for the fractions. Forty-eight fractions (8 were collected mL) aftera 75 mL prefraction. Fractions 11 to 35 were combined and conc�ntrated to yield 0.28 g (78 %) of a clear, colorless liquid product that was determined to be 98 % pure by GC analysis
and IH spectroscopy. IHNMR: 1.67-1.73 (m, 2 H), 2.27-2.37 (m, 5 H), 2.56-2.61 (t, 2 H, b J= 7.43 Hz), 2.80-2.88 (m, 2 H), 3.78-3.84 (t, 1 H, 7.43 Hz), 4.95-5.05 (m, 2 H), 5.64-5.74 (m, 1 J = H), 7.24-7.30 (m, 5 H). 13C: (13 peaks) 195.5, 141.9, 135.2, 128.4, 127.8, 127.1, 116.9, 49.4, b 40.8, 30.5, 29.7, 29.0, 28.0. HRMS-EI calcd for C sH200S2, 280.0956; found, (mlz): M+ 1 280.0952.
56 Synthesis of 2-(4-chlorophenyl )-1,3-dithiane (MJS2095fr1444)
r'I o SH SH (1.2 x) H CH3S03H (10.0 mol %) CI N� CH2CI2. ODC
A solution ofp-chlorobenzaldehyde (0.5428 g, 3.861 mmol) and 1,3-propanedithiol (0.4661 mL, 0.5015 g, 4.634 mmol, 1.2 eq) in CH2Ch (10 was stirred at O °C in a three-neck rbfas mL) methane sulfonic acid (0.0250 0.371 g, 0.386 mmol, 10.0 mol %) was added. Reaction mL, progress was followed by gas chromatography. After 17 h 30 min, additional 1,3-propanedithiol (0.1942 0.2089 g, 1.930 mmol, 0.5 eq) and methane sulfonic acid (0.0125 0.0185 g, mL, mL, 0.193 mmol, 5.0 mol %) were added to the reaction mixture because SM was detected by GC.
After22 h, the reaction mixture was stirred with 2 M NaOH (20 mL) for 15 min. The mixture was extracted with CH2Ch (2 X 20 The combined organic layers were washed with H20 (2 mL). X 40 mL) and sat. NaCl (40 mL), dried (Na2S04), and concentrated to yield 0.8616 g (97 %) of a white solid that was determined to be 95 % pure by GC analysis and IH NMR. The crude product was loaded onto 50 g of silica gel and eluted with EtOAc/heptane (5/95, v/v). Sixty fractions (8 mL) were collected. Fractions 14 to 44 were combined and concentrated to yield 0.74 g (83 %) of a white solid that was determined to be >99 % pure by GC and IH NMR. IH
NMR: 1.82-1.98 (m, 1 H), 2.13-2.21 (m, 1 H), 2.85-3.10 (m, 4 H), 5.12 (s, 1 H), 7.25-7.38 (m, 6 4 H).
57 Allylation of 2-( 4-chlorophenyl)-1,3-dithiane (MJS2119fr2346)
�SiMe3 (1.7 eq)
2.0 mol % Bi(OTf)s
ooe
A homogenous mixture of 2-(4-chlorophenyl)-1,3-dithiane (02590 g, 1.122 mmol), allyltrimethylsilane (0.3032 0.2180 g, 1.908 mmol, 1.7 eq), and acetic anhydride (0.1 803 mL, mL, 0.1948 g, 1.908 mmol, 1.7 eq) was stirred at 0 °C under N2 in a flame-dried three-neck rbf as bismuth(III) triflate (0.0147 g, 0.0225 mmol, 2.0 mol %) was added. The reaction mixture immediately acquired a light yellow color. Reaction progress was followed by gas chromatography. After 2 h 45 min, the reaction mixture was loaded onto 60 g of silica gel and eluted with EtOAc/heptane (3/97, v/v). Forty-eight fractions (8 were collected aftera 100 mL) mL prefraction. Fractions 13 to 34 were combined and concentrated to yield 0.23 g (65 %) of a clear, colorless liquid product that was determined to be 98 % pure by GC analysis and IH spectroscopy. IH NMR: () 1.68-1.73 (m, 2 H), 2.26-2.31 (m, 5 H), 2.51-2.58 (m 2 H), 2.75-2.91
(m, 2 H), 3.75-3.81 (t, 3 H, 7.40 Hz), 4.96-5.03 (m, 2 H), 5.60-5.70 (m, 1 H), 7.24-7.26 (m, 4 J= H). l3C: (13 peaks) () 195.6, 140.5, 134.8, 132.7, 129.2, 128.6, 117.3, 48.8, 40.8, 30.6, 29.7, 29.0,
28.0. HRMS-EI M+ calcd for C sH19ClOS2, 314.0566; found, 314.0564. (mlz): l
58 Synthesis of 2-(3-tolyl)-1,3-dithiane (MJS2101crude)
(l SH SH (1.7 x)
CH3S03H (10.0 mol %) CH2CI2• ODC
A solution of m-tolualdehyde (0.5081 g, 4.229 mmol) and 1,3-propanedithiol (0.7231 mL, 0.7781 g, 7.189 mmol, 1.7 eq) in CH2Ch(10 was stirred at O°C in a three-neck rbfas mL) methane sulfonic acid (0.0274 0.0406 g, 0.423 mmol, 10.0 mol %) was added. The reaction mL, mixture immediately acquired a cloudy white color. Reaction progress was followed by gas chromatography. After 18 h, the reaction mixture was stirred with 2 M NaOH (40 mL) for 15 min. The mixture was extracted with CH2Ch (3 X 20 mL). The combined organic layers were washed with H20 (2 X 40 mL) and sat. NaCI (40 mL), dried (Na2S04), and concentrated to yield 0.76 g (85 %) of a yellow liquid that was determined to be 98 % pure by GC analysis and IH I NMR. H NMR: 0 1.84-2.00 (m, 1 H), 2.12-2.19 (m, 1 H), 2.33 (s, 3 H), 2.85-3.11 (m, 4 H), 5.12 (s, 1 H), 7.08-7.28 (m, 4 H).
Allylation of 2-(3-tolyl)-1,3-dithiane (MJS2097fr1334)
�SiMe3 (1 .7 eq) o S�S AC20 (1.7 eq) � 4.0 mol % Bi(OTfb ODC CH3 ~CH3
A homogenous mixtureof 2-(3-tolyl)-1 ,3-dithiane (0.2481 g, 1.179 mmol), allyltrimethylsilane
(0.3186 0.2291 g, 2.005 mmol, 1.7 eq), and acetic anhydride (0.1895 0.2047 g, 2.005 mL, mL,
59 mmol, 1.7 eq) was stirred at 0 °C under N2 in a flame-dried three-neck rbf as bismuth(III) triflate
(0.0310 g, 0.0472 mmol, 4.0 mol %) was added. Reaction progress was followed by gas chromatography. After3 h, the reaction mixture was stirred with 10% Na2C03 (20 mL) 15 minutes. The mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with sat. NaCl (40 mL), dried (Na2S04), and concentrated to yield 0.3263 g (94 %) of a dark brown liquid that was determined to be 83 % pure by GC and I H NMR. The crude compound was loaded onto 60 g of silica gel and eluted with EtOAc/heptane (3/97, v/v). Fifty- three fractions (8 were collected. Fractions 13 to 50 were combined and concentrated to mL) yield 0.2460 g (74 %) of a clear, colorless liquid product that was determined to be 97 % pure by GC analysis and IH spectroscopy. IH NMR: 6 1.66-1.76 (m, 2 H), 2.28 (S, 3 H), 2.33 (s, 3 H),
2.52-2.61 (t, 2 H, 14.34 Hz), 2.76-2.94 (m, 2 H), 3.74-3.79 (t, 1 H, 7.37 Hz), 4.96-5.06 J= J= (m, 2 H), 5.64-5.74 (m, 1 H). 7.01-7.25 (m, 4 H). l3C: (16 peaks) 6 195.6, 141.9, 138.1, 135.4,
128.4, 128.3, 128.0, 124.9, 116.9, 49.5, 40.9, 30.6, 29.8, 29.0, 28.0, 21.5. HRMS-EI (mlz): � calcd for CI6H220S2Na, 317.1010; found, 317.1028.
Synthesis of 2-nonyl-l,3-dithiane (MJS2113crude)
(l SH SH (1.8 x) S o H CH3S03H (10.0 mol %) :)S CH2CI2. OoC
A solution of decanal (0.5662 g, 3.623 mmol) and 1,3-propanedithiol (0.6196 0.6666 g, mL, 6.169 mmol, 1.8 eq) in CH2Ch (10 was stirred at O °C in a three-neck rbf as methane mL) sulfonic acid (0.024 0.035 g, 0.36 mmol, 10.0 mol %) was added. Reaction progress was mL, followed by gas chromatography. After 18 h, the reaction mixture was stirred with 2 M NaOH
60 (40 mL) for 20 min. The mixture was extracted with CH2Ch (3 X 20 The combined mL). organic layers were washed with H20 (2 X 40 mL), 2 M NaOH (3 X 20 sat. NaCl (40 mL), mL), dried (Na2S04), and concentrated to yield 0.6959 g (78 %) of a clear,colorless liquid that was determined to be 97 % pure by GC analysis and IH NMR. IH NMR: 6 0.80-0.85 (t, 3 H, J = 6.91
Hz), 1.22 (s, 12 H), 1.36-1.46 (m, 2 H), 1.65-1.87 (m, 3 H) 2.03-2.10 (m, 1 H), 2.61-2.84 (m, 4 H), 3.98-4.02 (t, 1 H, J= 6.67 Hz).
AHylation of 2-nonyl-l,3-ditbiane (MJS2U 7fr1519)
SiMe3 (1.7 eq) � o AC20 (1.7 eq) � s s�s � 10.0 mol % Bi(OTfh s
OoC A homogenous mixture of 2-nonyl-l,3-dithiane (0.2522 g, 1.023 mmol), allyltrimethylsilane (0.2764 0.1988 g, 1.740 mmol, 1.7 eq), and acetic anhydride (0.1644 0.1776 g, 1.740 mL, mL, mmol, 1.7 eq) was stirred at 0 °c under N2 in a flame-driedrbf as bismuth(III) triflate (0.0671 g,
0.102 mmol, 10.0 mol %) was added. The reaction mixture immediately acquired a light yellow color. Reaction progress was followed by gas chromatograph. After 3 h 30 min, the reaction mixture was loaded onto 60 g of silica gel and eluted with EtOAc/heptane (3/97, v/v). Eighty- eight fractions (8 were collected after a 50 mL prefraction. Fractions 15 to 19 were mL) combined and concentrated to yield 0.2127 g (63 %) of a clear, colorless liquid that was determined to be 97 % pure by GC analysis and IH BC NMR spectroscopy. IH NMR: 6 0.83- & 0.88 (t, 3 H, J = 6.67 Hz), 1.24 (s, 14 H), 1.39-1.58 (m, 3 H), 1.79-1.85 (m, 2 H), 2.27-2.32 (m, 4 H), 2.51-2.64 (m, 3 H), 2.92-2.98 (t, 2 H, J= 7.15 Hz), 5.02-5.08 (m, 2 H), 5.77-5.87 (m, 1 H).
61 13 C: (15 peaks) 0 195.6, 135.7, 116.8, 45.3, 39.3, 34.2, 31.9, 30.6, 29.6, 29.3, 29.2, 28.1,26.7,
22.7, 14.1. HRMS-EI(ml z): � calcd for C18H340S2Na, 353.1949; found, 353.1963.
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69 IV. Appendix: Spectral Data
70 • ,_ ..-
(Millions) 24.0 25.0 26.0 27.0 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 9.0 10.0 11.0 12.0 13.0 14.0 15.0 16.0 17.0 18.0 19.0 20.0 21.0 22.0 23.0 . . . .l.L.I...L ..t..u..1. J.L.Ll. LLt.L .u. .u..L. .l.l,.l.. ..1.Lu. ..l.1.I...L ...Lu.JH J • . •. J...w.L...u....t..1.w.L.l.,1.J ILL.1.J,..t.l.J..w...L.lu..LLlLLW.J..)..L,.I .J..tJo t...t..J...d• l L L LLl Lt l d l J 1 �1 .d_L...Lw l..r_w. .d.J�� .l,J�Lu ... u...L I..L.I .d UJ....lJ...... r.�
.... til �..... x g ::rtv 'E 8: . a ..:.;1: ;;.. "" !?;; � o·:= co..... '"' )0'o ::tl j 1 o)=0 �
7.5073 7.4780 r. " . __ 'C 7.3947 � ----- _ _ _ ...... --'" (�- .. .. . 7.3022 . "'---- 7.1053 � 7.0989 - rJ1 /;c� \ "d ;", � � ...... , = = ....
5.8636 � ''-...... <:) :::r::: 5.8379 -� ...,/" 5.7995 .
o >-+, 5.0742 � " ', " 5.0375 U. /'Q �[/1 S.01}37 /' tv 4.7079 �� o 4.6978 ", VI 4.6795 ';'' --·I ;' -- -....) -�- tv . - 4.1804 '- .. - o::p [ 4. 1566 VI / ======---- /" ...... 4.1328 ... r·=iffiiE·····,, ------� ;",
;>�i �:�:g�3.3388 I
�
2.4377 2.4194 " .... 2.3928 ' " :';'- � 1.9899 ...... N 1.8883 � ..... �. 1.8654 . .. . �------. �l ,b " [� �----.------1.8425 //. L- �
..... - ;",
0.0549 0 -' T t"'57f"'51��2'" o�
8�0-]
MI MI . , ;"""", ,.., '"', '"", ""' TI ". .,-y ,"", ,-' ,..",, ", ,T' rl n, , ,,..,,.., ,M' ''''''' "I ''' 'T' '''' ' n. '' 'T''''' ,.., ,(",'''''''' n. ,, ,,,..,.,,-, '",'"""'" ...., ,M ', ",,"""" ,,,, ..,., .,-, """, , ''', ,",,, ,.., ,",, ,,",'T''''' n. ''T, T' '''' ,..",,",, ,T'''-, ,n,'T, ""'i"" ,,.., ....,,.. , M, ,-r'I TT'1 .n,-"''''' , ,n, ..,., ,.., n. ',"" , r, n. ''"1'' T' , ,n, ..,.,"",,",,,,,,,,,,, ,,,,,,,,,,,,,,,,,,,, n[ ,,.,, ,.., n. 1M, ""' ''''' n[ i"""', 'r' .r .,, ,,,,,,,, . ""1 11"'1'' '''''''' ,""''' '' ,"", ,.., ", ,,'T' , ,M, .",,.., n. ,nl"' ''''' M. ,-r'T' '''', .n' ''''I'''' ' ,,", ,"', ""• , ,, ,,.,.'TI ,-,... i,i- 200.0,'-"'TI "' 190.0 180.0-,. 170.0 160.0 150.0 140.0 ..,..,.130.0.,-. 120.0 100.0 .,..,""'90.0-"'TI 80.0.,.. .,.. 70.0 60.0 .,. 50.0 40.0 30.0 .... 2 .0 10.0 .,.. 0 no.o ,0 .'., i \'\ -M <:>- <:> '" '" III N M- "'<:> .... <:>.... til ,.., Q "" l"-_ ...... Co 1.0 ,� .","" QOl"- "" r-:::: � "" .,.. M ::::; "" "" "" N �N ':1 "';No:S� � :g :l .... ::::; !:!��:! � � parts per DC X : Million :
Spectru� 2 l3e NMR ofMJS2057fr2051 (Millions)
: 0 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 9.0 10.0 12.0 13.0 14.0 15.0 16.0 0 18.0 20.0 I. 17. 19.0 21.0 t j!J I t I!! I!. II.!I!! I.!!I j, III 11If, r I t fIr, J I I -Lu...l...l-Lw ! I,I I n.OI,! I I., f ! t!!.'I' I!,I I I, I I! I,I, t 11I! t I •• !.!,.1 I !
� ! .... '""' "<:I ,. � g OJ..... ::;0,. iii> 16... � 0 e; = ,; p ! ,... � � �
o � /=0
7.4524 ...... 7.4213 . 7.2464 . .._- .....
::r: , " � �� � :;;0� �'�i:�5 6886 = o 5.6529: ?-- >-i")
r:/1� ...... : L...... 5.0055, '"/..�<:\ 1 00 :4.9625:: ( Vl l
Vl o� 0'\ \0 4.1493 4.1255 �'" 4.1016 7"'ot. b "I
3.3269 ...... 3.3132 �,.:.; 3.3040 7"" w � <:>
2.5265 2.5000 2.4743 �;� 2.3434 ': 2.3177 ?� 1.9771 1.8590 ...... !" 1.8361 1.8132 >fjQ
1.2317 --......
,.. <:>
c:> mjs1185frac5069car-2.jdf
I I 200.0 190.0 180.0 170.0 160.0 150.0 140.0 130.0 120.0 1l0.n 100.0 70.0 60.0 50.0 40.0 30.0 2 .0 10.0 0 �O.O ,' p /\\ r--- tf"I�'>C N '" o.n o.n '" o ...... -t--- ... '" '=''O''''''' \Q � ""� � -Q�\C o.n ... '" C/C.,..; t"-- � t--I:'"-- t--= w \COvi � \CO M� N N5
: 13C X partsper Million :
Spectrum 4 I3C NMR ofMJS1185fr5069 mjs1185fr5069dept135-5.jdf
I
I I ' I I 200.0 190.0 180.0 170.0 160.0 150.0 140.0 130.0 120.0 110.0 100.0 90.0 80.0 70.0 60.0 50.0 .40.0 30.9 20.0 10.0 o
"" '" tTl ." \to N '" '" <::> "" '" "" ." '" "" tTl "" ....'" .... tTl '" .". .". 1Il "" '" M ,...... , -..; '=! �. :! '" "" � "" ." N N ..,; :2 00 ;; � � ;; :; :; � � Million : 13C X : parts per
Spectrum 5 DEPT-l35 ofMJSl1 85fr5069 , ,
, '
; 1
� �j�I4 t i ! :[i �' �l'�"�"�'�l '�"�' �"�'I�' �' �jj�jj�t1�'�i �j (�jj�' �" �" �'�"�'�"�il�' �' �li�"�l t�' �I I�j l�II�' �iI�"T! I�' �ll�"�"�' �I I�Ii�\I�' �ii�I I�I I�' �"�"�"�I �l i�Ii�"�' �llnj l�"�' �il�"�" �" �' �"�"�"�J �" �" �i1 �' �l'njl�1l�'�j'�lj�' j�' �" �i J�' �ii�'l�"�'iI �������� I j I j � : �.l; 170.0 160.0 150.0 140.0 130.0 120.0 110.0 100.0 90.0 80.0 70.0 60.0 50.0 40.0 30.0 20.0 100.0 : X partsper Million : l3e (Thousands)
Spectrum 6 HETCOR ofMJSl185fr5069 (Millions)
1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 9.0 10.0 11.0 12.0 13.0 14.0 l5.0 16.0 17.0 18.0 19.0 20.0 21.0 22.0 23.0 24.0 . .I..I..I,.L.l-L1..u...Lll...LL...J_L.J...l.l_Ll.J.....L_l.L....l_1..J.,.L'-t..w.J .l.J_l.1.J.J_I.l.,1,.L,�.J�J,.t..t.Lt.l • . .1,J..LIo .l-LI.J.J.J..f.Ld-.l.,L ,�.l,u .1,J .L.J. • .• • .u..LLl.l... L.-l.l..w....t...t..L,J..,.,l....l.. l ...... l.J..t�wJ..J...w..t.L1...L.J._.t...... t...U•.LLL..w....t.
...... x - 2.'"
't) p-<::> ., � Q ;i' it &, � � 'a:J.., § � iii 1
o ��; )=0
7.2976 " . .. 7.2665 --��-.,--� . -- --- "-. -. -� • .------7.1978 • •• --- �;.�'"W'h ------l 00 7.1658 --I "'0 ;> Q ee � .... ""i = :3 -...l '" ::r: 5.7546 "-, Q- . ,- 5.7189 z , .. . 5.6886 -;; 5.6529 ./ �o >-i') � 5.0174 . 5.0018 � !" 00...... 4.9588 ...... /.:Q -.) \.0
00 o::p OC=· . \.0 4.1483 -, ----·-··---·-----""'-�··- 4.1245 �I...,� ...... , ...... �_. __ .��N_�. \.0 -' .I>, . 4.1007 ,/ ,--� Q- C ------_., 3.3342 " " .. .. _-_.. __ .__ . 3.l2S 1 .__ . __._ . _._ _ __ . /" . . . 3.3123 ...... r' , w ' b -
2.5027 ""� 2.4762 � --.....-- 2.3461 .. ----.----.. - ..- ....__ ._--"'"'\.... 2.3196 ,..-"' � 1.9725 - � 1.8590 "'" c ------= .. �'" l" - _ -_ . 1.8351 -" _ L= L= ._ /;�. _ 1.8[23 _ �-; �,�:.. , . _.. ._ --'- ----)
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. "" '·'·'·" 'I" "'"·' '." .··I·l" '·,ililj ••••••• . . j.l ••. i.,.j'.,i ••. ji"il ""I" """I! III" ""I """"'( """II'1 ,,1, •. ,1 '1,•. 1.1" ' 1 ,.,.,,1" " """"1 '" ""i'X" """'l "" I I .. ,.111" ,1'1 200.0 190.0 180.0 170.0 160.0 150.0 140.0 130.0 120.0 . 110.0 100.0 90.0 80.0 . 70.0 60.0 50.0 .40.0 30.0 20.0 10.0 0
/\
,... M ...... - ." N'¢�O\ ... "" <::> <>-'<> ¢ON .". t-NQON M '" <>- ... .., 00"" <::> V1N"'=fOQ Q\ Spectrum 8 I3e NMR ofMJS1179fr8099 m,I!!20S1fr3052-4.jM I' . . ,-- ,-- i-J 0 O�O� r ~ r i • ...1 t 1 ...I.! J f j� ...... j'J�v � ' : 10.0 3.0 lit t? , 1.0 ,0 6.0 5,q 1\' '1\ \ 9.0 7.0 0 l \ 3.0 1/\ /1\ I ; I, , \ /;\ \· j;\ /11 j "..,.., 1 ")It>'" ...... "" 1 "' ...... ", ,,, ... '"'''S; �¢'\"'$�t!� "' .... $ ....ii�g .. ,.. !g;::! ... • _. i �..¢'lf!� "". �.il'...... ��" !�! "l"l"l"' ''' ''' NNN<"l"l"l"l"l ...ci�"'= ..,c..... 'I'!"'l : X : jIIlI1!Iper MiI&Ja 18 Spectrum 9 IH NMR ofMJS2051 fr3052 mjs20S1fr3 052car-2.jdf o O�O� ~ °NM��� 'T. r' r,.n""' n' ".,r,r"M""'T" ,n,n ",r,n,.M' ., r, r, n' In, T' �' n.n, ,r.n,.n" '.T' r' nlt ".'T. r' . · "'r,IM'n.,.""r,.M" ,.,.",r'jn" ,r,r'T'n.'n" "IT'rj.n.n" 'T'T'�'!n'n'T.�'�'n'·""T,r'n'. ��' �' rl.n" '�'�'�'MILn" ,"T' �1 1�'n"""'rln"r..""T,�.'n'n1"T'rl.n""'T'�'rl,n" 'T'�'r.,n""lr,n' in" 'T'T'r"�I" •. Tl r••n" "'T'�'rli�I ".'�'r'in'n" 'T'TI M. 'n" ,.,r,r•• nX j .• nl •. i •• • , Mln •• • 200.0 190.0 180.0 170.0 l60.0 150.0 140.0. 130.0 120.0 110.0 90.0 80.0 .' 70.0 60.0 50.0 .40.0 30.0 2,0.0 10.0 0 tOo.o i\ /F1\ /\ � "I!!f" 1:'"--1:' co t- _'d"O"'l:t '" "., ,",," "CW-",," <::> r- ".,� );; QlI'l_,¢ "., .,., �� ¢) � <;o r;--. :r;--..t:" "" "" '" '" "' Nr-:r-.:"&i ..". � ..". '" :1�.... 13C X : partsper Million : Spectrum 10 l3e NMR ofMJS205lfr3052 (Millions) 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 9.0 10.0 11.0 12.0 13.0 14.0 15.0 16.0 17.G 18.0 'IoI!, t!1.,. I w...l-J'1, t I J 1 I I! I!' / I' t,!,!! r!!'. L.I.R���l....L-1-l....l-..t..J ! t!,!.!t I!t! j. ".1" , J! LJ.....LJ.....l.l..J.-t..I-l....W...1... .E. � .... ::: <::> :::; ¢ 'g fS... it J, � o 1 o 0. is: V>I .., § g �<::> s 1 o (=0 r;; 7.2583 7.2280 CIl 7.1996 �.,," "0 /-..) � � ¢ t":) 6.8489 .... 6.8187 ,-- ... 6.7821 = /'" I = ...... "" ::r:: 5.8040 ¢ z 5.7665 5.7408 � - 5.7024 -j:/' o� >-l') 5.0495 � ,_ Ul L·�_. 5.0092 .-.' �; ___ --- CIl 4.9744 - ¢ "::::zss= � ...... /' ...... \0 ...... N ::p+:>. W 4.1621 W 4.1383 �;.. ,.... . 4.1145 / ¢' ") 3.7903 �:����3.3251 �§! 3.3031 /'"" w c� I ¢ 2.5220 ------;; 2.4954 �,�,'" 2.3754 , 2.3535 /''"' 1.9808 .. � 1.8718 � !;; 1.8480 �'" - 1.8251 - 7--:" I ... ¢ <::> o O�O� ~OCH3 '" � j Jj ...... ;-]oj ' j i 3 <:> ..., _1"'� i'"c: � :; � s o::> E- , , , , ., , , . " . . 't. , • ,i I • 1 • •• ••• I lit. j L j , 1 i . I, t" t I I. •• , •• , i I i. • I i , Ii ,j j •• ,I. II • j ii'i •••• •• I, ,j • [, ..• 'I. ..•I I t. j I I • 1 I ••• I I I I,j j I. 'j . I I i , , I ' •• i I I , j l, •• i • I. j 'i' .. I' i , [I• ,. I • .•I , i l' -:l' { t , , , \' , ii,ii, ! , i I • tit. I I' , t 200.0 190.0 180.0 170.0 160.0 150.0 140.0 130.0 120,0 100.0 90.0 ,80.0 ", 70.0 60.0 50.0 40.0 30.0. 20.0 10.0 0 HO.O / \ ! J/\ .... "" "" "" ...... "" to 00<'> Q .,.. ""00 .,..,<:0 "".... 0'" � .'" '"<:> '" _N <'l - �¢! "" -.i � ... 5 � ..; - �� :::: � .� :::l ;::: �� X : parts per Million : Be Spectrum 12 13e NMR of MJS119lfr2433 (Millions) 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 9.0 10.0 11.0 12.0 13.0 14.0 ",!" II,!,!Ilf .wl..w...t�.! , t!,I!!!., ,� I!! f'I!" I" ')'t I r _, ! o "!I!. J 1,...I u . .L.WJ ...LLLW. .1.J...I."UJili.l..U ..L J..l t ,1 ,." !'!t,! f t j 1,LJ...l..l..LLu..l.u...u..u..w..w.J.J.J...U , . . � . �. ... � 1 � � .:... s: e; I§ i § ill g 00 <:0 � o 7.2454 )=0 rJ). "0 ee .... � (:, ..... � e ..... f.H 0\ ::c: 5.8022 (:, z 5.7756 "'-..... 5.7381 . � ;;;::: � o >-i; 5.0678 '-. '" �\./J ' N o ;;:·(:,1 Vl �:�m r-·---1 \0 �w � 4.1648 '--- 0\ " w 4.1410 4.1172 ;'/."f>0:> 3.5137 3.4908 ':::-::i: 3.4597 -� --l 3.4368 /.".,> i F 3.2482 /_. � 2.2445 2.2188 '---- 2.0256 1.8745 1.8507 ;:::;,� 1.8278 /" 1.4386 1.2408 =� 0.8818 "'-,.....(:, . 0.8580 �- 0.8324 7' C -�l 0.0485 0::> (Thousands) 10.0 20.0 30.0 40.0 50.0 60.0 70.0 80.0 90.0 100.0 I I ! 1 I!I I ! ! () l-L.LJ...LJ_,•.l.J.J .LL,...L..i.-L..l.ll.l j I ! ! t, 1 ! • I , ,!t' r" , "'" f ••, , , I ' , ! .)!f ! .!1 I. I Itt!! ! , I •••! t t! I ! ! • I , ! ! • , ! ! I I I t-.> .. HO.O c . , , , , , , , , c .§. ? � x "" .... cr; \0 ] 5; a ?c t fiJ � .... co � a: lc f c ?- �..., -'" 171.1737 ("J .:::;c <::> .... ?<:> ... 1 ;!l-C ° � (=0 r.f1 "e 135.1666 � � "* .., c· = � 9 .... ,...t-.> ... C w 116.7850 ? (J g o H") C;. � gl-: r./J� N o Vl <:> • \0 ""? W ;:p... 79.3492 0\ 77.5691 � W � 77.0955 "'-. .:c . 76.6294 7 ' � 65.2536 61.9149 '• g �Q 38.4068 ._v"' .... �=� 33.9222 -... ' . 31.9816 .. . 29.8348 ,- :--- 29.7049 ---' � . Z9.6743 ... 29.4375 29.4070 �:'b 25.4647 <:> 22.7602 21.0565 �.r"?N 14.1958 -,- .... ?-c Q (Millions) 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 9.0 10.0 11.0 12.0 13.0 14.0 15.0 16.0 17.0 18.0 .J_LJ._L..I._l�lh.LLL_LLL....l.._Ll,J..J.....l..J._J.JJ.JM.J�.J o •..I�.J..J •..l.J_J •.. Lt.... .L.LI�LL..LL..1...... l.-.Il_.l.....t�l-1-l..i. LL.J._l...... L..LJ..•• t_l.,.L..J I ! 1 I ••• I r ,_.I,_Ll-J_W_,LL..L.J-.l-L.J.....J....l.. ,-..tJ....,�.L...L.I-j ... .. E. � x Q "" ii>. ....,::;- ."'" .... � OJ � .... � 19; = �. :.c<::> = IJ 1 co '" ° 0 >=0 7.2454 00 <:>;-l "0 � � """ ;:! 9 ..... u-. g; ::c: 5.7573 5.7354 '> . 5.6960 // ��� o 5.0852 L ...." � 5.0641 ., > 'tit .�:=- __ _ '-./' 5.0238 C � �r:/1 N " o ...... -..J �..j:::. 4.1483 "-. .. ..j:::. . . 0\ 4.1255 ...... """ . o 4.1016 0 /" --� 3.4972 3.4817 3.4734 3.4606 3.4377 �./ : ...---.-.-.-.. ------.------� ..., o· 2.2555 2.0210 1.9377 �. �� .- 1.9267 .. ----...... -� 1.8745 { -- 1.8516 �� $if- ---- 1.8278 ;; ..-� ....o· ¢ " gl-!m js2107fr44-6o-2.jdf o O�O� Br� .".; .:$-1 -1 �,-1 I i C> __ �__ ��· .�'rl�. 'n,�. �,�. �'r'inl�' �i T' �' �I.ni�j �' Tir, �,.n'�' T'T' r' �){r..�'�'�' r,rj,r.'�'�lr'r'rijn""'T.r'rljn,�" ,r'�'rijn'n. ,'r,�. r' .n.",'r' rlrl'n" 'T'r'r'r.'lnl"T'T.�' r,tn.n" 'T'Tirtin'n' ,'r,�,rjI�'n" 'T.T'r.•n,n" I,.r.r,r'in.""T'rlr,.n'r.."�'T.r'r"�" "'T'r.r"n'n'""r.rl.n,n" ,r.r.r:.r..""r.r.r.,'n" I�'T.T,r.r.,.n'T" 'Tjr'rjln.n" 'T,r,r'jr..n" 'T,r,r,r'IM" ,T'T'T'r,.n'T,T.T,�.rr" 200.0 190.0 180.0 170.0 160.0 150.0 140.0 130.0 120.0 110.0 100.0 90.0 80.0 70.0 60.0 50.0 40.0. 3"." 20.0 10.0 0 \ / iI I \ ! \ \ '" "" t- ""t- o."" '"...... on 00'" .....on "" ..... '" "" .., ""'"-00 .... Spectrum 16 l3e NMR ofMJS2107fr4460 (Millions) o 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 9.0 10.0 11.0 12.0 " '!" " I..J..J...l..J.. J..L..LJ..t.J..I ,.,." .I,·" ",'t'" "fl" '!" ! I'!" '!" '!!I,!,!.,!,., !" I.!t!tlt!jl , t. .l.!fl •••"I •• .•. !,.,! .• •• ,I ... ,.,." 'III" �' '"'C;! .... >< el .- l:I' 1 1; Il1 o S � - L . ..t i1:1 " e; :.: �: �,! ;1- = � ff�o o � /=0 00- � 7.3004 � 7.2692 ·s � .... ______...... �.::. .1850 "l �._ 77.1539 ;.,/ � ----7 9 0 I==' -l ::r: 0\ � 5.7903 <:> :;;0 5 7546 '-'''-',.:: o 5 �._. I-+) 7244 m 5.6886: ;/'" ...... tv W 5.0192 5,0055 ::::::" .� 4.9615 /.- . -l � W 4.1410 4.1337 " 4.1126 :::::"" ---l 3.8864 /� ?c ...: 3.8782 -I 3.0265 ''''' 2.9780 ...;;....-.:.:�::: 2.9460 -� 2.4780 . 2.4496 ...... 2.4249 2.3452 2.3187 2.2976 ' N ��j :� 0 1.9890 / ' 1.5879 .... . 0.8992 '_.-;,,, 0.8763 }::> 0.0549 "" EB1123fl"l'lc37-43car-2.jdf "" .;; "" .;;Q ..... "" .;; -.0 "" .;; on "" � .;;Q ,.., Ji "" ..... �i -= g �" <:> . u. � <::> , , , ' , , , • , , ) , , , , , , , , ( , , • I ••I [ •• t , j • , , , • l , • j •• • I •••I • I It, • . l t t • l I • I , I I •• I i •.j It. ( • 1 .• I I .• I • •••j •• • I I I I I I Ii. I : i I It' I ,1 , • I j , I iii , I , , i ' i I ' .1 • ii, • 1 t •• l I ii,i IJO' • i J I • l ••• I •. i I \ J I , , i • i i iii ' . i •• , j ••• . • • [ I J • , ••••• I . 200.0 190.0 180.0 170.0 160.0 150.0 140.0 130.0 120.0 110.0 100.0 90.0 80.0 .... . 70.0 60.0 50.0 .40.0 30.0 20.0 10.0 0 i, i , , ,\�" f \ !\" '\ "" '" """"e-."" ",e-...."" "" -"" "'-0"'" >0O """" "'" '" 5 �M... - Q606- ... :! : X parts perMillion : 13C Spectrum 18 J3e NMR ofEBl123fr3743 (Millions) 11.0 12.0 13.0 14.0 15.0 16.0 17.0 18.0 19.0 20.0 21.0 22.0 23.0 24.0 o 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 9.0 10.0 I t , r ! I • r , ! , , ! ! I ....1 _I...w..J...LJ.J..lu..w..L.t..J...I.J...l.J • ••1 ] , • ! I ! ! t , I I I ! • , ! I ! ! ! , I Ll..t..l...w...1.J..LLI_.l_d_.1 ••LJ.J..LJ.., l •.t-i.LJ. ...l..-,I....l....1...L�u..L..Lu....wJ.Lw I r ! f , ! I , , , , , , , , J ...... at ',I '1;;' � :> 7.2445 ,g'eo 7.1365 � a� = e ,... \0 ::c � z':7,:::., '.M5.8077" �.� 5.7821 -< � 5.7436 "/ � I o H-, [ <-<� 5.0430 = ' C/lN 5.0064 - ----I o 4.9716 0\ I W I ::p...... f\.1456 " 8 4.1355 �, --l. ..- // !>- C=_. Q /' 1 �:;��i3.901 1 . [_ ••. ..� 3.104 ")71 2.978:9 '::,•.. "w• c:' -- ==-'-- ____ � 2."" / .. . '\ 2.5339 2.5064 � 2.4789 '.r-7.'..... '." C;; 2.4533 (_ '-=- .__ � 2.3645 /J:; .: 2.3370 //N C .__ 1.9945 - ... 0 - , .. r \ I- :-' 0.9111 '--. Q 0.8901 ----.- � .' .0769 0 "" :j 2(1);0 180.0 120.0 11{l.() 90.0 0. 0 ... 1 . 190;0 170.0 16M 1S0.0 14().0 13(),O I So.o . 70.0 6 0 50.0 40.0 30.0 211·0 0 0 1 ; , : /'0\ \ /!\ ..,...... 000 "" 00 'C'CO\c:>o.. 00 ...... ""- --eo- -,", .., 00 0 on 000\0 ""'<>- <'>= N "" '<> -<'>"" on""'" ""'" �n���� "": ,. �:,...o!.,...... t'<,;.'.... ,.,:::;; <>') '" "":��...... = <'><'>'"c;:: t-=� ...... ¢:-6 "" ,-('., �... � ..... � �'.� 00 t'w l""-- t"-- I:""-'o.O '" "' ''' ... -.-<- -- '"' � � ;::!��� '!J X : partsper Million : Be Spectrum 20 l3e NMR ofMJS2063fr1034 (Millions) 2.0 3.0 4.0 5.0 6.0 7.0 8.0 9.0 10.0 11.0 12.0 13.0 14.0 15.0 16.0 17.0 18.0 19.0 20.0 21.0 22.0 23.0 1 • o • to I I I .w .w�w..l.WJ. d ..t..L.I...L.!.1...1....L...LL,l .J .Lw..• w.J"i..l.. ,-d-'-1.J,...t..1.1 Lw...LJ_J_J.J...LJ_.LL.l ! 1 ! ! I t W ..w w .LL.Lu 1 I ! ! t ! ! , , • ..t..LJ...t..J , , J..J....l...J.,J...Lw...l ! f w...t..l..u..w...Lu_.u.l...... , , , , trl I;!;I ...... , :><: '" ." .. g; ;r 'f'.... a "" � is: -g(ll f 1.. �.." � s 0 �� I ( � 7.2464 ...... 0 iJ1 � � I (=0 "0 � � �..... '"'l = = N i-' 0\ ::c 5.7930 � .. 5.7674 Z 5.7299 /'" � � 0 >-+-, 5.0467 '" tr:I 5.0156 '-...... 4.9780 . . --b:i /' � --tv Vl \0i:t' 0'\-- "'" 3.8654 � 3.2253 3.1932 3.1218 �" 3.0897 7-··� . 2.2234 2.1978 � 2.1758 /"." N 2.0339 /'".. � 1.5943 1.4176 1.2829 1.2408 .....--�------�-��=====------ 0.8956 � -... . 0.8608 '-...... ,,'".. � 0.8351 /' ----; <:> (Thollsands) 10.0 20.0 30.0 40.0 50.0 60.0 70.0 80.0 90.0 100.0 110.0 120.0 130.0 1." ' ...... I I o • • • • , ••L.J Lt ..LLWJ..LLI..lu...w..w-U."L..!...J..M w..u.L..U II!!111,1 1.J..I. .1.t....w..l.I-U..L1 ,!,I I" III!' 1.1 II" !' III J I t.•• u ... u_u d. .l.J..L.I..I..1..I...L.I." " I! . .! t'!!'" !!I tv .� .,.,! ><: � � ... "" 51 'g ;t a 1; g-! l .... � � a; 8,... g ,... 171.0896 ...:t . <::> , )l) "<:> � .... g � ,... �<::> o 135.3042 00 )=0 '"d � � � - '"'l = Q-W 9 "<:> 1f6.4870 N N ,... w n g Z �o ',:'. >-i; tr:1 ...... s?' ...... OJ � N Vl 00 • 79.3416 \.0 77.5997 - Pc:> �...... , 0\ 77.1260 76.6523 ;; :' . 74.5361 69.9139 / pC>...:t " "" p-C> '" P¢ 38.2922 <::> 35.5265 ...... � 33.8076 '" 31.9663 --" 29.8119 . 29.6973 .;' � . 29.6591 29.3917 ?';"<:> 25.3654 %::; '" 22.7373 <::> • 22.0573 P 20.9113 ?l...... - - 14.1576 ::; "<:> <::> - (Millions) o 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 9.0 10.0 11.0 12.0 13.0 14.0 15.0 16.0 17.0 IS.0 • , I I I ! 1.-'-.l.�.J�L..1..J...J...... L.l....t...J....L.L..i• ..1�l..J...... i-J•• •LL.L.J._L.,r�,.l-J �.!•• LJ.. ..L.l�l.,.L.I l .i-•. L Lw I-L..LLJ I , I, ,t I I • t 1-�.L...... l...I-.l.J,�I_.t....J."""�L•.J....J- ...... a. :-;.. >< .... s.... g 'E 5:.... � � 1 J. .,� � § = � II 1 (f) )=0 00 e:, 7.2985 7.2839 �... rJ) 7.2436 ;;:: "0 fj) ( !':)'""" � "1 =: = N W tI: � 5.7015 5.6758 � .. 5.6383 7::· : o -I �>-+, 5.0467 •. �C/) 4.9890 "-'''' :.:;:'/Jl ------/" N 4.9524 . o -.....l IIi � .-� ...... �...... W Vl "" 3.8352 e:,- 3.8068 � . 3.7793 ;;------l 2.8516 ?' 2.8214 .,�. "-" o 2.6145 � � 2.5879 . ====--�._"'" �'------. 2.5604 �., ./ e: 2.3177 '-- � 2.2939 �o:::ca="""'2!t!Q:z: �__ - -=-== C �. 2.2720 , .. ,------:-- /' [� =, 1.7271 � 1.7005 �,., 1.6740 7'''' _��- �±E:��==�------[ �l ;; c- mjs2071fd 135car-2.jdf "" .:;OQ o S�S� r "'I """"'I" """'I """"'j """"''.1.,III,I[.I.,,·•• .· •• ·[·.·l••••••• ,. ],.,II•••• j" .1.1I,'I' •••••" .III,'I,'.'I" ••• ·.,·I·I,.I •. ··I" '.·;, •• ••••••••• I'.'." •• 'I •• I.llil,!" II" ·" I'··'·" ·'I' I I ! 180.0 160.0 0 50.0 20.0 o 200.0 190.0 170.0 15 .0 140.0 130.0. 120.0 , 110.0 100.0 90.0 80.0 , , 70.0 60.0 .O 10.0 : ! � 39�P /1\ /:\ 11\\ 00 00"'"" 00 N �('t")'¢"'" ... "' ''' ''' "" '<> U') (/')Q\f"'l '"on � '" 1;cl ",r-.-"' ''' ''' "" "" Q\C-t")N '" M '" ��tt<0<:1\.. '" r-- oo -,....( .... \f) '" vi 06 r-:: r--: '" ���r-- r-- \Q '" "') .� .. "'l r-- r-- r-- ." c)�c\OO('f'}�<"l'!"'l "'M'" ..."" ..". i :�.� � � --'"' -� X : partsper Million ; Be ! -"-'7" '�"" :---'-" '-" -" ''-'''�''--- ,.-� Spectrum J3e NMR ofMJS207lfr1135 l 24 (Millions) 1.0 2.0 3.0 4.0 5,0 6.0 7.0 8.0 9.0 10.0 11.0 12.0 13.0 14.0 16.0 17.0 18.0 19.0 20.0 21.0 22.0 23.0 24.0 25.0 26.0 27.0 " !.,!! ..d1 'I.I o •••• 1!·,.sJ-t...u..l�L1.W... .!,l" .!1111.!" " I., I,I" "I•..t.J..J..i...u i,tt.I., •• I ••,!! '�.J I, •••. I,! ,.1.,[,1, • •• 1" " It••• ft! 1.1.,.,1 .,1.' , d IS.O . lllll I..T � .... ' <:> Q ::;> ¢, ) 1 :;:; J, � ;;: � 5: s; 0'= en .... ::t: � � � en )=0 9"<:> 7.2876 7.2564 "'.� 7 354 ..:=,....,,;;;:;��"'"""'======--===�- 00 7:'"'-l 'e .� r -r f'D.. � ¢, � '\ ; 2 ;: 51 (;: N til ::c: g; z � 5.5989 / :::0 o H) 5.0284 " , ?, � 4.9927 / ---"-,.----., �:�m >::I;>J� .--� 4.9579 C;i:ltv / I o I \0 -....l L I-' �W W ..,. � ¢, 3.8104 '" 3.7820 " , . 3.7546 ./ 2.8553 !" .2.8223 ��r ·2.5522 2.5339 , .2.3104 o-, 2.3013 � '2.2839 '2.2573 ):; '" ¢, 1.7289 1.7024 '->,,'.; /-' 1.6758 1 l.2344 -¢,- <::> .. I i ' I I I 200.0 190.0 ISM 170.0 160.0 150.0 140.0 120.0 110.0 100.0 90.0 60.0 50.0 40.0 30.0 20.0 1 .0 0 ,1301 SO.O 70.0 0 9 iI i, /\ ; \ \ /\ 1\ j!\\ I.f)ClO1'0'\ ,., .... 00 Ii'l .... r-'¢"t-\C to-- QO <1\= '" 0\'<>0 tiH"'-l. C""it'-- MN N- .". "' ... '<> C>"'&<:\:t'-- ¢\oo t"'>t- ..,. Spectrum I3C NMR ofMJS2097fr1334 26 r II o I s�s� J I (r r I I I II r ( I I i I I , I( I I I Co"'; ,"' 1 i r -��.:j � "'��.j ------� , I • , I ' , I ' • I ' ) ! L j� , Iii.I I I ' I I , I j • • I • , ':C' 3 0 2,0 � , .:[, :, : 10,0 9,0 S,O ,7,0 6,0 4,0 1,0 .." 5,� . o \ I i /\ /I /;! ; 1\\ /\ ji \ ,1 , /! / " /! I /\ \ Qf')�('f'l.QO 'C¢\'o::!" t.n "'r-"' '''.... "' .... '" QClIl�"I!!" ,,'''',,::, """ _¢oec "' ''' ''' "'''' ''' t-!.� r--! r..! "'."."��� .i)�� X : partsper Million : IH Spectrum 27 IH NMR ofMJS2119fr2346 (Thousands) 1M 4M �o ao �� �o �o .L II'I!!.! I" !'!'!" !'!!I!." .!.,!!,!" ,I, !" '!IJ'�-.1-'-L,..J L¥l J-..f.-J-Wjjltlll!ll'I!II!'!l t!,!!ll" ' J..J..J. •.• o l__ W� �O ... - e �o "'" 195.7055 ��- X .... � '" � II:l'" 't> � � !l1 l is: ... � == � �' � ... w (") --.l ., """- � Q Cf) ... '" � >=0 th·o "'" 142.0044 ...... rJ2 138.1539 "C('t> g r':> 135.5257 ...."'l 128.5428 t;; = -: 128.3824 "'--.,.,-;/¢P 9 128.0539 ,/ N 125.0284 /.- 00 ....N w <::> 116.9912 "'" (1 ...... g o foot) � ....<:> 0 �C/J "'" tv - \Q ...... \0 g tv t:Pw ..j::>. eo 0\ Q - 77.5997 77.1260 "'-. "'" 76.6600 /" -.l , 0::>P '" g th 49.5688 g 40.9509 'Q.... "'" 30.6981 29.9035 �w ." 29.1472 .... ,P 28.1464 :,;::. Q -4 21.5684 " IV 0 "'" ?0 0 -' (Millions) o to 2.0 3.0 4.0 5.0 6.0 7.0 8.0 9.0 10.0 11.0 12.0 13.0 .rl l.j. .!lltll!. ··,·,···· '..L..J....L..1.. .J..1J....tJ..J-lJ..J J....W....LJ I. (l lltl' 1" ' I J •• •• 111111.1" 1'!111111 U l...LJ. I !" """.1" "", ••• " ••1" """,1" " 111•• � 't! .. PQ.... �::;>...., til a ... �... 1. is: I: S; §' "" 53 b" <» b- 1 (J) 1J). 7.2454 )=0 "0 � Q � :-' - "'I = 9 N \0 '" 5.8352 b ::c: ' 5.8123 �-. ,� .. , ' 5.7738 ; / � o �>-I-) 5.0842 "-, 5.0623 "' ... �. 'Vt: � // 5.0229 'Q 1J)...... IV -.....l...... VI� ...... \C! � 2.9231 :?:>� i:��;�2.6199 61 �=,-._---. : 32 �" i2.5366:�� ;/" =, 2.5101 ��' L== 2.3242 2.3077 1 N -j 2.2747 _._._. :::'-b 1.8470 _ 1.8205 "7-c": 1.7939 __ 1.5073 __._ : 1.4606 :/:;; : 1.4139 ;/ - 1.2417 ./" � .--�-==--. 0.8809 b- \ 0.8571 �, __ 0.8324 :...---- E c-= =� --l <::> o s�s� I 00 I , 1.-.0 130.1 !lU 110.1 100.0 MJI .0 ;1 70.0 at !IU 10.1 t ! ' .-.p il\� I I /i\ I I ... '� f:! ...... ! .S � ,:.;'.-� - 'S.," ' .-' !;it:: � .....: ...... , :.. • :':, :�, ' , :: ..:: .... �1U;��M��iG;a " ... �S �... '-t ; :; ::.. ;;;:; �1=:"" � � ������ :tt � : : X pu1I ,.r MIIm 13(; Spectrum 30 l3C NMR ofMJS2117fr1519