FLORIDA THE STATE UNIVERSITY COLLEGE OF ARTS AND SCIENCES
THE MORITABAYLISHILLMAN CYCLOALKYLATION REACTION
By KIMBERLY A. BROOKOVER
A Thesis submitted to the Department of Chemistry in partial fulfillment of the requirements for the degree of Master of Science
Degree Awarded: Summer Semester, 2005
The members of the committee approve the thesis of Kimberly A. Brookover defended on July 1, 2005. ________________________ Marie E. Krafft Professor Directing Thesis ________________________ Robert A. Holton Committee Member ________________________ Greg Dudley Committee Member ________________________ Kenneth Goldsby Committee Member
Approved: ______________________________ Naresh Dalal, Chair, Department of Chemistry
The Office of Graduate Studies has verified and approved the above named committee members.
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I would like to dedicate this Thesis to my parents, Jim and Wendy Brookover for all their encouragement and sacrifices over the years. I would not be who and where I am today without their support. I would also like to dedicate this to my fianc, Greg Seibert, who has been so supportive and encouraging throughout this entire process. With love and gratitude Kimberly
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ACKNOWLEDGMENTS
I would like to express my sincerest gratitude to my major professor, Dr. Marie E. Krafft, for her guidance and support. I would also like to thank the members of the Krafft group, most notable Dr. Thomas F. N. Haxell, for their support and enthusiasm. Lastly I would like to thank the MDS Research Foundation and NSF for their funding.
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TABLE OF CONTENTS List of Tables .............................................................................................................vi List of Figures ............................................................................................................vii Standard List of Abbreviations ..................................................................................xi Abstract ......................................................................................................................xvii 1. INTRODUCTION Organocatalysis Amine and Phosphine Catalysts.......................................1 Rauhut Currier Reaction ................................................................................4 Baylis-Hillman Reaction................................................................................7 Summary ........................................................................................................15 2. RESULTS AND DISCUSSION Optimization of Reaction Conditions ............................................................17 Synthesis of test substrates.................................................................17 Screening of different nucleophiles, solvent systems, and bases.......18 Study of the effects of halides............................................................20 Preparation and Reaction of Additional Substrates .......................................23 Synthesis and reactions of hetero-substituted enones........................28 Conclusion .....................................................................................................31 3. EXPERIMENTAL General Considerations..................................................................................32 Synthesis of Substrates ..................................................................................33 APPENDIX................................................................................................................52 REFERENCES ..........................................................................................................119 BIOGRAPHICAL SKETCH .....................................................................................123
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LIST OF TABLES
Table 1. Screening Nucleophiles and Bases in the IMBH Reaction..........................19 Table 2. Comparison of Halogens as Alternate Electrophiles ...................................21 Table 3. Cyclization of Sterically Hindered Enones..................................................24 Table 4. Results of Bicycle Cycloalkylation..............................................................27 Table 5. Additional Five- and Six-membered Ring Substrate Results ......................28 Table 6. Results of Heterocycle Formation ...............................................................30
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LIST OF FIGURES
Figure 1. 500 MHz 1H NMR Spectrum of Ester 50.......................................53 Figure 2. 75 MHz 13C Spectrum of Ester 50..................................................54 Figure 3. IR Spectrum of Ester 50 .................................................................55 Figure 4. 500 MHz 1H NMR Spectrum of Ester 52.......................................56 Figure 5. 75 MHz 13C Spectrum of Ester 47..................................................57 Figure 6. IR Spectrum of Ester 52 .................................................................58 Figure 7. 500 MHz 1H NMR Spectrum of Ester 59.......................................59 Figure 8. 75 MHz 13C Spectrum of Ester 59..................................................60 Figure 9. IR Spectrum of Ester 59 .................................................................61 Figure 10. 500 MHz 1H NMR Spectrum of Ester 61.....................................62 Figure 11. 75 MHz 13C Spectrum of Ester 61................................................63 Figure 12. IR Spectrum of Ester 61 ...............................................................64 Figure 13. 500 MHz 1H NMR Spectrum of Ester 60.....................................65 Figure 14. 75 MHz 13C Spectrum of Ester 60................................................66 Figure 15. IR Spectrum of Ester 60 ...............................................................67 Figure 16. 500 MHz 1H NMR Spectrum of Ester 62.....................................68 Figure 17. 75 MHz 13C Spectrum of Ester 62................................................69 Figure 18. IR Spectrum of Ester 62 ...............................................................70
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Figure 19. 500 MHz 1H NMR Spectrum of Enone 70...................................71 Figure 20. 75 MHz 13C Spectrum of Enone 70..............................................72 Figure 21. IR Spectrum of Enone 70 .............................................................73 Figure 22. 500 MHz 1H NMR Spectrum of Bicycle 72.................................74 Figure 23. 75 MHz 13C Spectrum of Bicycle 72............................................75 Figure 24. IR Spectrum of Bicycle 72 ...........................................................76 Figure 25. 500 MHz 1H NMR Spectrum of Alkene 69 .................................77 Figure 26. 75 MHz 13C Spectrum of Alkene 69 ............................................78 Figure 27. IR Spectrum of Alkene 69............................................................79 Figure 28. 500 MHz 1H NMR Spectrum of Enone 71...................................80 Figure 29. 75 MHz 13C Spectrum of Enone 71..............................................81 Figure 30. IR Spectrum of Enone 71 .............................................................82 Figure 31. 500 MHz 1H NMR Spectrum of Enone 73...................................83 Figure 32. 75 MHz 13C Spectrum of Enone 73..............................................84 Figure 33. IR Spectrum of Enone 73 .............................................................85 Figure 34. 500 MHz 1H NMR Spectrum of Ester 51.....................................86 Figure 35. 75 MHz 13C Spectrum of Ester 51................................................87 Figure 36. IR Spectrum of Ester 51 ...............................................................88 Figure 37. 500 MHz 1H NMR Spectrum of Ester 53.....................................89 Figure 38. 75 MHz 13C Spectrum of Ester 53................................................90 Figure 39. IR Spectrum of Ester 53 ...............................................................91 Figure 40. 500 MHz 1H NMR Spectrum of Enone 77...................................92 Figure 41. 75 MHz 13C Spectrum of Enone 77..............................................93
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Figure 42. IR Spectrum of Enone 77 .............................................................94 Figure 43. 500 MHz 1H NMR Spectrum of Enone 75...................................95 Figure 44. 75 MHz 13C Spectrum of Enone 75..............................................96 Figure 45. IR Spectrum of Enone 75 .............................................................97 Figure 46. 500 MHz 1H NMR Spectrum of Enone 89...................................98 Figure 47. 75 MHz 13C Spectrum of Enone 89..............................................99 Figure 48. IR Spectrum of Enone 89 .............................................................100 Figure 49. 500 MHz 1H NMR Spectrum of Enone 90...................................101 Figure 50. 75 MHz 13C Spectrum of Enone 90..............................................102 Figure 51. IR Spectrum of Enone 90 .............................................................103 Figure 52. 500 MHz 1H NMR Spectrum of Sulfonamide 84 ........................104 Figure 53. 75 MHz 13C Spectrum of Sulfonamide 84 ...................................105 Figure 54. IR Spectrum of Sulfonamide 84 ...................................................106 Figure 55. 500 MHz 1H NMR Spectrum of Sulfonamide 85 ........................107 Figure 56. 75 MHz 13C Spectrum of Sulfonamide 85 ...................................108 Figure 57. IR Spectrum of Sulfonamide 85 ...................................................109 Figure 58. 500 MHz 1H NMR Spectrum of Enone 64...................................110 Figure 59. 75 MHz 13C Spectrum of Enone 64..............................................111 Figure 60. IR Spectrum of Enone 64 .............................................................112 Figure 61. 500 MHz 1H NMR Spectrum of Enone 65...................................113 Figure 62. 75 MHz 13C Spectrum of Enone 65..............................................114 Figure 63. IR Spectrum of Enone 65 .............................................................115 Figure 64. 500 MHz 1H NMR Spectrum of Phosphonium Salt 54................116
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Figure 65. 75 MHz 13C Spectrum of Phosphonium Salt 54...........................117 Figure 66. IR Spectrum of Phosphonium Salt 54 ..........................................118
x
STANDARD LIST OF ABBREVIATIONS
Ac acac AIBN anhyd Ar atm 9-BBN Bn BOC bp br Bu i-Bu s-Bu t-Bu C calcd Cbz
acetyl acetylacetonate 2,2-azobisisobutyronitrile anhydrous aryl atmosphere(s) 9-borabicyclo[3.3.1]nonyl benzyl tert-butoxycarbonyl boiling point broad (spectral) butyl iso-butyl sec-butyl tert-butyl degrees Celsius calculated benzyloxycarbonyl
xi
CI cm concd COSY COT Cp Cy-hexyl d DABCO DBN DBU DCB DCC DCM DDQ DEAD DEPT DIBALH DMAP DME DMF DMPU
chemical ionization (in mass spectrometry) centimeter(s) concentrated correlation spectroscopy cyclooctatetraene cyclopentadienyl cyclohexyl chemical shift in parts per million downfield from tetramethylsilane day(s); doublet (spectral) 1,4-diazabicyclo[2.2.2]octane 1,5-diazabicyclo[4.3.0]non-5-ene 1,8-diazabicyclo[5.4.0]undec-7-ene 2,6-dichlorobenzyl N,N-dicyclohexylcarbodiimide dichloromethane 2,3-dichloro-5,6-dicyano-1,4,benzoquinone diethyl azodicarboxylate distortionless enhancement by polarization transfer diisobutylaluminum hydride 4-(dimethylamino)pyridine 1,2-dimethoxyethane dimethylformamide dimethylpropylene urea
xii
DMSO E1 E2 ee EI Et FAB FT g GC H HMO HMPA HOMO HPLC HRMS Hz IP IR J k KOH L
dimethyl sulfoxide unimolecular elimination bimolecular elimination enantiomeric excess electron impact (in mass spectrometry) ethyl fast action bombardment (in mass spectrometry) Fourier transform gram(s) gas chromatography hours(s) Hckel molecular orbital hexamethylphosphoric triamide highest occupied molecular orbital high-performance liquid chromatography high-resolution mass spectrometry hertz ionization potential infrared coupling constant (in NMR) kilo potassium hydroxide liter(s)
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LAH LDA LHMDS LTMP LUMO m M MBH m-CPBA m/e Me MEM Mes MHz min mM MO mol MOM mp Ms MS
lithium aluminum hydride lithium diisopropylamide lithium hexamethyldisilazane lithium 2,2,6,6-tetramethylpiperidide lowest occupied molecular orbital micro multiplet (spectral), meter(s), milli moles per liter Morita-Baylis-Hillman m-chloroperoxybenzoic acid mass to charge ratio (in mass spectrometry) methyl (2-methoxyethoxy)methyl mesityl, 2,4,6-trimethylphenyl megahertz minute(s) millimoles per liter molecular orbital mole(s) methoxymethyl melting point Methanesulfonyl (mesyl) mass spectrometry
xiv
MVK m/z NBS NCS NMO NMR NOE Nu OD ORD PCC PDC PEG Ph PMB PPA ppm PPTS Pr i-Pr q re Rf
methyl vinyl ketone mass to charge ratio (in mass spectrometry) N-bromosuccinimide N-chlorosuccinimide N-methylmorpholine-N-oxide nuclear magnetic resonance nuclear Overhauser effect nucleophile optical density optical rotary dispersion pyridinium chlorochromate pyridinium dichromate polyethylene glycol phenyl p-methoxybenzyl polyphosphoric acid parts per million (in NMR) pyridinium p-toluenesulfonate propyl isopropyl quartet (spectral) rectus (stereochemistry) retention factor (in chromatography)
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rt s si SN1 SN2 SN t TBAB TBDMS Tf TFA TFAA THF THP TIPS TLC TMEDA TMS Tr Ts TS tR UV
room temperature singlet (spectral); second(s) sinister (stereochemistry) unimolecular nucleophilic substitution bimolecular nucleophilic substitution nucleophilic substitution with allylic rearrangement triplet (spectral) tetrabutylammonium bromide tert-butyldimethylsilyl trifluoromethanesulfonyl (triflyl) trifluoroacetic acid trifluoroacetic anhydride tetrahydrofuran tetrahydropyran triisopropylsilyl thin layer chromatography N,N,N,N-tetramethyl-1,2-ethylenediamine trimethysilyl, tetramethylsilane triphenylmethyl (trityl) tosyl, p-toluenesulfonyl transition state retention time (in chromatography) ultraviolet
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ABSTRACT
The Morita-Baylis-Hillman reaction dates back to German and Japanese patents where both Morita, and Baylis and Hillman, discovered a new carbon-carbon bond forming reaction involving a nucleophilic catalyst, an activated alkene, and an electrophile. Although this reaction was discovered in the early 1970s, it was not until over a decade later that researchers took notice and began to thoroughly investigate this reaction. Since then, this reaction has seen tremendous growth in all three components to now include several activated alkenes such as acrylates, vinyl ketones, vinyl nitriles, vinyl sulfones, vinyl sulfoxides, vinyl phosphonates, allenic esters and acrolein. Furthermore, while a range of sp2 hybridized electrophiles, including aldehydes, -keto esters, 1,2-diketones, aldimines, bromo methyl enoates, allylic acetates under Pd catalysis, and allylic halides have been studied extensively in this intriguing reaction, the application of simple unactivated alkyl halides as the electrophilic partner has never been reported. A new version of the Morita-Baylis-Hillman reaction has been discovered that uses unactivated sp3 hybridized halides as the electrophilic partner. It has also been shown that this reaction tolerates alterations on the tether as well as the increase of steric bulk on the enone moiety. This reaction is a convenient and simple route for the synthesis of five- and six-memebered ring compounds in extremely high yields.
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CHAPTER I
INTRODUCTION
1. Organocatalysis Amine and Phosphine Catalysts Discovering new high-yielding, selective reactions is vital for the advancement of synthetic organic chemistry. Even more noteworthy are the developments of new carbon carbon bond forming reactions, which are fundamental for the construction of organic molecular frameworks. Reactions that facilitate carbon-carbon bond formation have been well documented and include many different organocatalyzed reactions. Organocatalysis is defined as the acceleration of chemical reactions using substoichiometric amounts of a metal-free organic compound.1 Organocatalyzed reactions have a broad application and have been used extensively in the Mannich, Wittig,2 and Strecker reactions and have more recently been applied to the Suzuki,3 Sonagashira,4 Ullmann,5 and Heck-type coupling reactions6 as well as the Tsuji-Trost7 reaction now demonstrating that they proceed under metal-free conditions. In 2003, Leadbeater demonstrated a Suzuki-coupling of aryl halides with boronic acids in water under transition metal free conditions.3 After screening many different phase transfer catalysts it was found that tetrabutylammonium bromide (TBAB) was the optimal phase transfer catalyst. With further optimization of the reaction conditions, treatment of bromobenzene and 1.3 eq of boronic acid 2 in 2 mL of water with 1 eq of TBAB and 3.8 eq of Na2CO3 and heating at 150 C for 5 min gave desired product 3 in 1
90% yield (eq 1). This method has been extended to accept many different types of aryl halides including p-bromonitrobenzene, p-bromoacetophenone, p-tolyl bromide and pbromoanisole. However, in 2005, Leadbeater found small amounts of Pd present in the reaction mixture which assisted the reaction; albeit in amounts less than 2.5 ppm.8
Br
B(OH)2
TBAB, Na2CO3 H2O, w, 90%
(1) 3
1
2
Leadbeater also demonstrated Sonogashira-type couplings of aryl bromides and iodides with terminal alkynes without transition metal catalysis.4 Following optimization of the phase transfer catalyst as well as the base, he showed that after treatment of piodoacetophenone, 4, and 1.2 eq of phenylacetylene, 5, in 1 mL of water with 2 eq of NaOH and 1 mL of polyethylene glycol (PEG) followed by heating at 170 C for 5 min, desired product 6 was obtained in 91% yield (eq 2). This method has been extended to accept several different types of aryl halides and alkynes in moderate to good yields.
COMe Ph I 4 5
w H2O, NaOH, PEG 91%
Ph 6
COMe
(2)
Ikushima et al demonstrated noncatalytic Heck-coupling reactions of iodobenzene and styrene using supercritical water in the presence of KOAc to give both cis- and transstilbene in 56% yield.6 Muzart and coworkers have shown a Tsuji-Trost-type reaction 2
that proceeds in the absence of transition-metal catalysts.7 They have shown that when acetic acid 1,3-diphenyl-allyl ester was treated with acetylacetone and potassium carbonate in water/methanol the desired coupled product was observed in 92% yield. This ongoing development of new organocatalytic reactions is important in that it provides the organic chemical community with a new range of simple catalysts that are easily employed in otherwise complicated reactions. Organocatalysts mainly react as heteroatom-centered Lewis bases and more recently as Brnsted acids.9 Because of this, the organic catalyst can now activate either the donor or the acceptor thus speeding up the overall rate of the reaction. Although phosphorous and sulfur compounds have been used as organic catalysts, amines, in general, are the most commonly employed organocatalysts.10 Amine catalyzed reactions generally proceed via an enamine cycle with the most successful amine of this type being
L-Proline, one of a few natural amino acids exhibiting a secondary amine functionality. L-
Proline, 9, has been used successfully as an enantioselective catalyst in a wide range of reactions such as the Mannich reaction (eq 3),11 aldol condensations (eq 4),12 amination reactions, and alkylation reactions.
O O H R R = alkyl, allyl 7 8 H CO2Et PMP N N H 9 OH 5 mol% H O NH PMP (3)
dioxane, r.t. (57-89%)
CO2Et R d.r. up to 19:1 up to 99% ee 10
Although amines tend to be employed most often in reactions as the organocatalyst, they are not the only successful catalysts utilized by organic chemists. Organophosphorus compounds have been widely used in synthetic organic chemistry in more recent times. When compared with amines, phosphines exhibit many similarities. 3
Both, tertiary phosphines and tertiary amines have a pyramidal geometry, although at room temperature amines invert their geometry whereas the phosphine geometry is stable at room temperature. The chemistry of both phosphine and amine catalysts are centered on the non-bonded lone pair of electrons, which may be used to form bonds between the catalysts and a range of electrophilic species. However when compared with the more basic amines, phosphines are generally more nucleophilic, exhibiting greatest nucleophilicity with alkyl substituents.13
O H Me
O H
Me Me
O N H 9 OH 10 mol% DMF, 4 C (88%) H
O
OH
Me Me (4)
Me anti/syn 3:1 97% ee
11
12
13
The Staudinger and Mitsunobu reactions are known to employ the use of stoichiometric amounts of phosphines while the Wittig reaction makes use of phosphorous ylids to promote the olefination of carbonyls. Although phosphines as catalysts have been around since the 1960s with the discovery of the Rauhut-Currier and Morita-Baylis-Hillman reactions, it was not until more recently, when these reactions began to be studied in depth, that the application of phosphines as a nucleophilic catalyst has seen tremendous growth. 2. Rauhut Currier Reaction The Rauhut-Currier (RC) reaction dates back to a patent in 1963 where Rauhut and Currier reported a phosphine-catalyzed reaction involving the dimerization of activated alkenes, acrylonitrile, 14, and ethyl acrylate, 15, (Scheme 1).14 4
2
EWG
P(alkyl)3 or P(Ar)3 EWG = CN, CO2R
EWG EWG
SCHEME 1
A couple of years later the groups of McClure15 and Baizer and Anderson16 independently investigated this transformation concluding that the reaction involves a reversible Michael addition of phosphine onto the activated alkene followed by a Michael reaction of the enolate with the second equivalent of activated alkene. Subsequent proton migration followed by release of the catalyst generated the observed product as well as regenerated the catalyst. Five years later, in 1970, McClure reported the first crosscoupling reaction between ethyl acrylate and acrylonitrile, giving 2-ethoxycarbonyl-4cyano-1-butene, 18, in moderate yield while also observing the homocoupled adducts, 16 and 17 (eq 5).17
CN CO2Et 18 CN 1 mol % Bu3P CO2Et 100 C t-butanol CO2Et CO2Et 17 CN CN 16
48%
22%
(5)
14
15
25%
Despite these early findings, little research was carried out on the phosphinecatalyzed intermolecular Rauhut-Currier reaction until recently.18 Meanwhile, in the late 5
80s to early 90s, several groups investigated a variant of this reaction using tertiary amines to catalyze the dimerization of several different activated alkenes.19 Unfortunately, when attempting the cross-coupling reaction they reported difficulty with the control of the cross-coupling. It wasnt until more recently that the groups of Krische and Roush addressed the problem with lack of control when attempting an intermolecular cross-coupling reaction. Krische and co-workers20 solved this problem by developing an intramolecular reaction in which the activated alkenes were tethered by a 2- or 3-atom chain. This new intramolecular reaction involving the cycloisomerization of bis-enones using a catalytic amount of a tertiary phosphine provided five- and six-membered ring adducts in good overall yield (Scheme 2). At the same time Roush and co-workers reported similar trialkyl phosphine-mediated intramolecular Rauhut-Currier reactions for diactivated 1,5 heptadienes, and 1,6 hexadienes to give the densely functionalized vinylogous MoritaBaylis-Hillman products.21
O R
O
R' Bu3P (cat.) solvents 75-96% R
O O R'
R = aryl or alkyl R' = aryl, alkyl or Oalkyl
SCHEME 2
In 2003, Verkade reported the intermolecular head-to-tail dimerization of methyl acrylate, 19, to form 2-methylene-pentanedioic acid dimethyl ester, 20,22 a useful monomer for the synthesis of polymers as well as a building block for the construction of larger molecules. The dimerization had been previously reported using elevated temperatures with phosphines as well as transition metal trialkyphosphine complexes as catalysts. However using milder conditions, Verkade has successfully shown the 6
dimerization of methyl acrylate giving product 20 in 82% and 85% yield when treated with catalytic amounts of P(RNCH2CH2)3N (R = i-Bu and Bn respectively) in THF at room temperature (eq 6).
O OMe 19
P(i-BuNCH2CH2)3N THF, r.t., 4 h 82% MeO
O
O OMe 20 (6)
Along with these advances in the RC reaction, it was observed that the smaller phosphines, tributylphosphine and even more so trimethylphosphine, exhibited optimal activity over tricyclohexylphosphine, while triphenylphosphine was completely inactive. It was also noted in the intramolecular Rauhut-Currier reaction, phosphines were far better nucleophiles than amines such as DABCO, DBU, quinuclidine, and DMAP. This may be a result of the phosphines being softer nucleophiles than amines, therefore making them able to add to the soft activated alkene. 3. Baylis-Hillman Reaction Equally important in the development of organocatalyzed reactions was the Baylis-Hillman reaction.23 The Baylis-Hillman reaction dates back to a German patent24 published in 1972 where Baylis and Hillman reported an organocatalytic three-
O + H 21
O OEt 22
Nucleophilic Organocatalyst
OH
O OEt 23 (7)
Nucleophilic Catalyst: DABCO, r.t., 7d, 76% (Baylis-Hillman) Cy3P, 130C, 2h, 23% (Morita)
7
component process involving the -position of an activated alkene, ethyl acrylate, with an electrophilic partner, acetaldehyde, using a catalytic amount of the tertiary amine DABCO at room temperature for seven days giving the Baylis-Hillman product 23 in 76% yield (eq 7). However, it was Morita who five years earlier reported the same reaction using tricyclohexylphosphine as the catalyst at 130 C for two hours affording the same product in 26% yield.25 Thus it is more appropriately called the Morita-Baylis-Hillman (MBH) reaction. This reaction possesses two important requirements in organic synthesis, atom economy and generation of functional groups, making it increasingly important as a method for carboncarbon bond formation. The currently accepted reaction mechanism (Scheme 3 for MVK and benzaldehyde using DABCO) is believed to proceed through a Michael addition to the position of the activated alkene to produce a zwitterionic enolate. This enolate then attacks the carbon electrophile in an aldol fashion generating a second zwitterionic intermediate. Subsequent proton migration followed by release of the catalyst affords the product while regenerating the catalyst.
O conjugate N: N OH R N N addition N O H O N
O R aldol
O R N N
H O
OH O R
SCHEME 3
8
More recently McQuade reported a new interpretation of the Morita-BaylisHillman mechanism based on rate data and two different kinetic isotope experiments (Scheme 4). He has shown that his proposed hemiacetal intermediate in the MBH mechanism is consistent with the results where the rate-determining step was determined to be second order in aldehyde and first order in DABCO and acrylate. The proposed mechanism has been extended to include aryl aldehydes under polar, nonpolar and protic conditions.26
Me O
Ar O H O Ar Ar O H N Me O N N O H O Ar O Me O N
O O H O
Ar
Ar BH Product
N N
SCHEME 4
Unfortunately, the MBH reaction has been limited with respect to applications to more complex synthetic problems due to low rates and conversions as well as highly substrate-dependent yields. Because the coupling of the enolate with the aldehyde was accepted as the rate-determining step, the MBH reaction remained underdeveloped many years after its initial discovery despite its obvious synthetic potential.27 However during the last 15 years, the intermolecular MoritaBaylisHillman reaction has seen tremendous growth in terms of all three components and now encompasses a wide variety of activated alkenes, electrophiles and nucleophilic catalysts (Scheme 5).
9
XH X R R' + EWG nucleophilic organocatalyst R R' EWG
X = O, NCO2R, NTs, NSO2Ph R = aryl, alkyl, heteroaryl; R' = H, CO2R, alkyl EWG = COR, CHO, CN, CO2R, PO(OEt)2, SO2Ph, SO3Ph, SOPh
SCHEME 5
A range of sp2 hybridized electrophiles has been successfully used in the MBH reaction. The electrophiles that have been used are predominantly aldehydes both aryl, alkyl, and heteroaryl, but also -keto esters, 1,2-diketones, and aldimine derivatives, however simple ketones have failed as alternate electrophiles in the MBH reaction. Several different alkenes have also been examined expanding the method to now include acrylates, vinyl ketones, vinyl nitriles, vinyl sulfones, vinyl sulfoxides, vinyl phosphonates, allenic esters and acrolein. Unfortunately, for the intermolecular MBH reaction the activated alkene must be ,-unsubstituted in order for the reaction to take place thus limiting the scope of this method. Similarly, the nucleophilic catalysts still tend to be limited to primarily tertiary phosphines or tertiary amines.
O O N SO O H 3 eq. DABCO, DCM 0 C O
O
O
O MeOH MeO CSA, 85% HO
(8)
24
25
26
Furthermore, this reaction has been done asymmetrically where chiral versions of all three components have been used28 although, due to its termolecular nature, the reaction tends to be slow taking anywhere from days to weeks to complete as more 10
complex substrates were utilized. In 1997, Leahy and co-workers performed an asymmetric Baylis-Hillman reaction of chiral Michael acceptors using Oppolzers sultam 24 as the chiral auxiliary in their DABCO-catalyzed Baylis-Hillman reaction (eq 8).29 Two years later, Hatakeyama and co-workers extended the scope of the asymmetric Baylis-Hillman reaction using chiral catalyst 29 to promote enantioselectivity (eq 9).30
H N O O 27 CF3 CF3 R 28 O H 29
O N OH OH R O O 30 CF3 CF3 (9)
DMF, -55 C
In spite of the high degree of growth the intermolecular MBH reaction has seen in all three essential components, the intramolecular Morita-Baylis-Hillman (IMBH) reaction has not been studied in depth. The intramolecular variant of this reaction was first reported by Frater31 in 1992 where he found that N-bases were ineffective in forming the five-membered ring cyclization product. However upon use of phosphine catalysts he observed up to 75% of the product with 25% recovery of starting material (eq 10).
O COOC2H5 31
25 mol % Bu3P neat, 1d, 75%(GLC)
OH COOC2H5 (10)
32
11
Further investigation was carried out by Murphy coworkers32 who studied tandem intramolecular addition Michael-aldol reactions using both activated alkenes and electrophiles. They screened several catalysts including amines, phosphines and thiols and it was found that when tributylphosphine was used as a catalyst, five-, six-, and seven-membered rings were formed with aryl enones and esters although the reaction time varied from 2 h to 28 days (eq 11). They also reported that use of a catalytic amount of piperidine with phenyl enones the Baylis-Hillman adducts were formed in moderate yields. Koo and coworkers reported similar results of intramolecular Baylis-Hillman reactions efficiently providing five- and six-membered ring adducts.33 They used aldehydes as well as methyl, ethyl, butyl, and phenyl ketones for the activated alkenes and treated the enone with triphenylphosphine in various solvents including THF, DCM, acetone, MeCN, t-BuOH, and EtOAc at temperatures ranging from room temperature to 80 C. These reactions took as little as 2 hours to complete and as long as 2 days giving the desired product in 14 - 99% yield.
O R ( )n R = Ph, OMe n = 1, 2 33 O Bu3P (0.2-0.4 eq.) CHCl3, r.t. 2h - 28d. 20-75% R
O
OH (11) ( )n
34
Keck also investigated the intramolecular MBH reaction using unsaturated esters and thioesters and a catalytic amount of trimethylphosphine.34 With esters, he observed slow cyclizations; however with thiol esters, Keck observed that both cyclopentene and cyclohexene derivatives were formed efficiently with a catalytic amount trimethylphosphine. After optimization, the desired cyclization products were formed upon treatment of dicarbonyl compound with 1 eq. of N, N-dimethylaminopyridine (DMAP) and 0.25 eq. of DMAPHCl in EtOH and with heating at 78 C for 1h. Similar 12
success was observed when thiol ester 35 was treated with 0.1 eq. of Me3P in DCM at room temperature for 15 h (eq 12).
H O O 35
DMAP, DMAPHCl EtOH 87% SEt or PMe3, CH2Cl2 82%
OH
O SEt 36 (12)
Not only has the substitution on the carbonyl been altered to test the tolerance of this reaction, but several research groups have looked at alternate electrophiles as a way to expand the scope of this method. The groups of Basavaiah, Krische, and Krafft have accomplished this by examining specialized allylic leaving groups as alternate electrophiles. For instance, bromo methyl enoates have recently been used in the Baylis-Hillman reaction. In 2001, Basavaiah demonstrated the use of activated allylic halides where 2 eq. of DABCO were necessary for the reaction to take place. The first equivalent initially formed the allylic ammonium salt and the second then added in a Michael fashion to the activated alkene resulting in the formation of the densely functionalized BaylisHillman product 39 (eq 13).35
O RO
Br + Ar 37 CN DABCO (2 eq.) r.t. 7 days 3767% 38 RO
O
Ar (13) CN 39
13
O R ( )n n = 1,2 40
OCO2CH3 Bu3P (100 mol%) (Ph3P)4Pd (1 mol%) t-BuOH (0.1 M), 60 C R
O (14) ( )n 64-92% Yield 41
The following year, building on previous success in the Rauhut-Currier reaction where electron-deficient 1,5- and 1,6-dienes were used, Krische36 cleverly blended organomediated and transition metal catalyzed reactions in a complexation reaction where formation of the -allyl complex was necessary to promote reaction with the zwitterionic enolate to give the BaylisHillman adducts (eq 14).
R O R Cl + 1 : 2 42, R = H 45, R = Me 43, R = H 46, R = Me O Cl R (i) Bu P (1 eq), t-BuOH 3 r.t. 5 h (ii) KOH, BnEt3NCl CH2Cl2H2O (1:1) r.t. 2 h O (15) 78% 44, R = H 47, R = Me
Lastly, allylic halides have recently been shown to serve as a viable electrophiles in the IMBH reaction and undergo intramolecular cyclization using only trialkylphosphines as the catalyst. Krafft and coworkers37 have shown that allylic halides 42 and 43 readily cyclize upon the addition of stoichiometric amounts of tributylphosphine or trimethylphosphine followed by the addition of base under phase transfer conditions, yielding the desired MBH adducts after 2-10 hours in excellent yields. This method has been demonstrated to work with aryl and alkyl enones as well as primary and secondary halides. They reported that when secondary halides were used as 14
substrates, a regioisomeric mixture of chlorides was subjected to the optimized MBH reaction conditions to give the desired cycloallylation product 44 in excellent yields (eq 15). Summary Organocatalysis is an important tool for making carboncarbon bonds, and possibly one of the most fundamental and important processes for the construction of organic molecular frameworks. Recently, two such reactions, the Rauhut-Currier and Morita-Baylis-Hillman reactions, which utilize amine and phosphine catalysts, have rocketed to the forefront leading the way for new methods of creating carboncarbon bonds without the use of transition metals. These reactions have been studied extensively to now include a wide variety of electrophiles and activated alkenes. However, with respect to the Morita-Baylis-Hillman reaction, the electrophiles that have been successfully and in the reaction have all been limited to those bearing sp2 hybridized carbons at the reacting center. It should also be noted that with the MBH reaction, the intermolecular reaction has seen far greater research than the intramolecular version. This overall lack of research in the IMBH reaction as well as the limited scope of electrophiles previously used has led us to expand this synthetically useful reaction to now include sp3 hybridized carbons at the reacting center.
15
CHAPTER II
RESULTS AND DISCUSSION
The Morita-Baylis-Hillman reaction, dating back to both German and Japanese patents, is a three component reaction involving an activated alkene, a nucleophilic catalyst, and an electrophile. The intermolecular version of this reaction has been thoroughly investigated while the IMBH reaction has not been studied extensively. This lack of progress is in part due to the additional substitution at the beta carbon of the activated alkene, which completely stops the intermolecular reaction. Several activated alkenes that have been shown to be successful in the MBH reaction include acrylates, vinyl ketones, vinyl nitriles, vinyl sulfones, vinyl sulfoxides, vinyl phosphonates, allenic esters and acrolein. Furthermore, while a range of sp2 hybridized electrophiles, including aldehydes, -keto esters, 1,2-diketones, aldimines, bromo methyl enoates, allylic acetates under Pd catalysis, and allylic halides have been studied extensively in this intriguing reaction, the application of simple unactivated alkyl halides as the electrophilic partner in the MoritaBaylisHillman reaction has never been reported.38 In view of the previously developed simple method for the formation of cycloallylation products originating from either allylic halide regioisomers (eq 15), a natural extension of this work was to explore the feasibility of the corresponding cycloalkylation chemistry. Several requirements important to this extension were that the reaction needed to be entirely organomediated, to use simple nucleophilic initiators and leaving groups, and to tolerate a wide variety of activated alkenes and structural alterations at the leaving group moiety. Variables considered with this reaction were the choice of halide leaving 16
group, choice of nucleophile whether it be an amine or a trialkylphosphine, and choice of solvent including EtOAc, acetone, THF, and alcoholic solvents (Scheme 6).
O R R' X
Organic nucleophilic catalyst solvent
O R
R'
n R = alkyl, aryl or Oalkyl R' = H or alkyl X = halide or tosylate
n
SCHEME 6
1. Optimization of Reaction Conditions 1.1 Synthesis of test substrates To assess the feasibility of the proposed reaction, initial studies were performed using various enones bearing a halide leaving group. A test substrate, enone 50, was readily prepared in two steps beginning with diethyl allylmalonate (eq 16).39
E E
Br NaH, THF
X
X E E X = Br, 48 X = Cl, 49
O
(16)
O Grubbs II CH2Cl2, reflux
X E E
Yield (2 steps) 50, X=Br, 48% 51, X=Cl, 48%
17
Deprotonation of diethyl allylmalonate using NaH in THF followed by reaction of the resultant anion with dibromoethane gave the alkylated malonate 48. Subsequent cross metathesis with 3-penten-2-one using Grubbs 2nd generation catalyst40 in DCM at reflux overnight furnished desired cycloalkylation precursor 50 in good overall yield. 1.2 Screening of different nucleophiles, solvent systems, and bases Having the desired test substrate, enone 50, in hand, amine nucleophiles, DABCO, DBU and quinuclidine,41 which are commonly employed in the traditional BaylisHillman reaction, were found to be ineffective at promoting cycloalkylation of 50. Various solvents were used in this reaction such as EtOAc, THF, CHCl3, MeOH, and tBuOH, at temperatures from ambient to 63 C, but the conditions were still unsuccessful at promoting cyclization. In these cases decomposition of starting material was observed. Accordingly, after treatment of 50 in t-BuOH at r. t. with tributylphosphine for 2 h, all starting material was consumed leaving a more polar material. After, reviewing the BH reaction mechanism (Scheme 3), it was noted that the alkoxide anion formed after conjugate addition with the electrophile was needed to deprotonate alpha to the carbonyl allowing for eventual release of the catalyst. In our case no alkoxide anion was formed to facilitate the release of the catalyst, and upon further consideration, it was determined that addition of a base may be necessary for the reaction to proceed to completion. Several bases were screened by adding 1 eq of various bases in 0.1 M of different solvent systems and monitoring by TLC analysis to determine whether the polar intermediate could be converted to the desired product (Table 1). In most cases the more polar material was not affected upon addition of base in the various solvent systems. However, when adding 1 eq of KOH with 0.01 eq of BnEt3NCl in 0.1 M DCM/H2O (1:1) product 52 was generated in excellent yield regardless of whether the nucleophile was tribuyl- or trimethyl-phosphine. It must be noted that KOH in DMSO also worked in equivalent yield when compared to KOH under phase transfer conditions, but due to the removal of DMSO being quite time consuming, the phase transfer conditions were optimal. These results may be explained by noting that the hydroxide anion formed is made more basic when the phase transfer conditions are employed.
18
TABLE 1. Screening Nucleophiles and Bases in the IMBH reaction
O Me E 50 Step 1 Nu DBU DABCO Quinuclidine Bu3P Me3P Bu3P Bu3P Bu3P Bu3P Bu3P Bu3P Bu3P Bu3P Bu3P
a
Br (i) Nucleophile (1eq) (ii) Base Me
O
E 52 Step 2 E
E
Solvent THF t-BuOH THF t-BuOH t-BuOH t-BuOH t-BuOH t-BuOH t-BuOH t-BuOH t-BuOH t-BuOH t-BuOH t-BuOH
Base
Solvent
Yield (%) NR NR NR
KOH/BnEt3NCl KOH/BnEt3NCl NaOH/BnEt3NCl MeONa/BnEt3NCl MeONa EtONa t-BuOK KH NaH KOH KOH
DCM/H2O DCM/H2O t-BuOH MeOH MeOH EtOH t-BuOH THF THF t-BuOH DMSO
99 96 0a 0a 0a 0a 0a 0a 0a traces 99
In these cases a reaction took place upon addition of phosphine catalyst, however following addition of base no
product was formed leaving the more polar intermediate.
19
1.3 Study of the effect of halides Having optimized the reaction conditions, it was important to observe the effect of changing the electrophilic partner to the corresponding chloride or iodide. These substrates were readily prepared in two steps beginning with diethylallyl malonate. Deprotonation of diethylallyl malonate using NaH in THF followed by reaction of the resultant anion with 1-bromo-2-chloroethane gave alkylated malonate 49. Subsequent cross metathesis with 3-penten-2-one using Grubbs 2nd generation catalyst in DCM, at reflux overnight furnished the desired cycloalkylation precursor 51 in good overall yield (eq 16). Iodide 53 was prepared from 51 via halogen exchange using NaI in acetone (eq 17).
O
Cl NaI E E 51 Acetone, reflux 95%
O
I
E E 53 (17)
Treatment of 51 in t-BuOH with either tributylphosphine or trimethylphosphine followed by addition of KOH under phase transfer conditions gave none of the desired product. Reaction of iodide 53 with tributylphosphine under the same conditions as before resulted in cycloalkylation product 52 in a somewhat diminished yield when compared to that of the bromide. When the nucleophilic catalyst was trimethylphosphine no product was formed (Table 2).
20
TABLE 2. Comparison of Halogens as Alternative Electrophiles
O Me E E Halide 51 51 50 50 53 53 X Cl Cl Br Br I I X (i) Nucleophile (1eq) t-BuOH, r.t. (ii) KOH, BnEt 3NCl CH2Cl2/H2O (1:1) Nucleophile Bu3P Me3P Bu3P Me3P Bu3P Me3P Time (h) 24 24 3 5 3 24 Product 52 52 52 52 52 52 Me E E Yield (%) 0 0 99 96 87 0 O
With these results in hand, test reactions were performed in order to understand the different outcomes with the different alkyl halides. To discount the idea that the phosphine was initially reacting with the bromide to form a salt, a control reaction was performed. Treatment of phenethyl bromide with 1 eq. of either Bu3P or Me3P in t-BuOH at r.t. for 5 hours gave quantitative recovery of the starting material (eq 18). This
Br
Bu3P, t-BuOH r.t. 5h 99% recovered starting material Me3P, t-BuOH r.t. 5h (18)
21
suggested that the phosphine was not forming a salt by reaction with the halide and was in fact adding in a Michael fashion to the enone giving the more polar material, which was observed after the first step. Next, in order to understand why with iodide 53, reaction with Bu3P afforded the desired product whereas with Me3P no product was produced, a test reaction was carried out using 1-iodo hexane. Trimethylphosphine was added to 1-iodo hexane in t-BuOH and stirred for 5 h generating the corresponding salt, 54, in 95% yield (eq 19).
I
Me3P, t-BuOH r.t. 5h, 95%
P I 54
(19)
Looking further into the MBH reaction with alkyl chloride 51 one would expect to see a homo coupling product 55 with a slow reaction and a less reactive leaving group (eq 20). However the homo coupling product was not observed and instead it was noted that initial studies had provided a mixture of the desired product and the intermediate. With a longer reaction time, over 48 h, the product was obtained in 43% yield with 10% recovery of starting material as well as decomposition of starting material.
O
Cl Me3P or Bu3P E E 51 t-BuOH, r.t. 5h
Cl E E O
O
E
E Cl (20)
55
22
2. Preparation and Reaction of Additional Substrates Having established bromide as the optimal leaving group, the tolerance of this method was further probed by varying the substitution at the enone moiety. Enones 59 and 60 were selected as representative substituted compounds for further study (eq 21).
E E
Br NaH, THF
Br
Br E E 48 R
O
(21)
O Grubbs II CH2Cl2, reflux R
Br E E
Yield (2 steps) 59, R=Ph 48% 60, R=CH2CH2Ph 39%
In order to synthesize cycloalkylation precursor 59, 1-phenyl-but-2-en-1-one, 56, was needed for the cross metathesis reaction. Enone 56 was prepared via a Friedel-Crafts reaction of trans crotonyl chloride and benzene (eq 22).42
O Cl Benzene AlCl3 r.t. 60%
O (22)
56
23
Enone 58, used in the synthesis of 60, was prepared in 2 steps starting with a vinyl Grignard addition to hydrocinnamaldehyde in THF to give allylic alcohol 57. Subsequent Jones oxidation gave desired enone 58 in good yield (eq 23).
O vinyl Grignard ether, 50% 57
OH Na2Cr2O7H2O H2SO4, 72% 58
O (23)
Finally cross metathesis of 1-phenyl-hex-4-en-3-one, 58, and 1-phenyl-but-2-en1-one, 56, with alkyl malonate 48 using Grubbs 2nd generation catalyst in DCM at reflux overnight gave good yields of the desired products 60 and 59 respectively (eq 21). Remarkably, increasing the steric bulk of the enone had little consequence on the isolated yield of the six-membered cycloalkylation adducts (Table 3).
TABLE 3. Cyclization of Sterically Hindered Enones
O R E E Enone 50 50 59 59 60 60 R Me Me Ph Ph PhCH2CH2 PhCH2CH2 Br O R E E Product 52 52 61 61 62 62 Yield (%) 99 96 90 69 79 68
(i) Nucleophile (1eq) t-BuOH, r.t. (ii) KOH, BnEt 3NCl CH2Cl2/H2O (1:1) Nucleophile Bu3P Me3P Bu3P Me3P Bu3P Me3P Time (h) 3 5 10 6 17 19
24
Driven by these outstanding results, precursors for five-membered ring analogues were synthesized to demonstrate the scope of this method. Thus these cycloalkylation precursor was readily prepared in two steps starting with diethyl allylmalonate. Deprotonation of diethyl allylmalonate using NaH in THF followed by reaction of the resultant anion with dibromomethane gave alkylated malonate 63 in 99% yield.43 Subsequent cross metathesis with either 3-penten-2-one or 1-phenyl-but-2-en-1-one using Grubbs 2nd generation catalyst in DCM, at reflux overnight furnished the desired cycloalkylation precursors 64 and 65, respectively, in good overall yield (eq 24).
Br E E 63 R
O
O Grubbs II CH2Cl2, reflux R
Br E E
64, R=Me 75% 65, R=Ph 23%
(24)
Unfortunately, when enones 64 and 65 were treated with either Me3P or Bu3P in tBuOH followed by KOH under phase transfer conditions no products were observed. It was not surprising that these substrates failed to cyclize when compared to the ease of cyclization of their six-membered ring analogues. The loss of one carbon on the tether placed the alkyl bromide at a neopentyl center, increasing the steric hindrance adjacent to the halide and therefore stopping the cyclization altogether. Realizing that the neopentyl center had completely stopped the MBH reaction, a new five-membered ring analogue without this center was sought. Hoping to assist in the cyclization process a cis-fused bicycle was targeted. Thus the cycloalkylation precursor 70 was readily prepared in five steps starting with cis-1,2-cyclohexane-dicarboxylic anhydride (eq 25). Reduction of cis-1,2-cyclohexane-dicarboxylic anhydride using NaBH4 gave lactone 66 in 85% yield. Further reduction of 66 using DIBAL in DCM 25
yielded lactol 67 followed by olefination with the methyltriphenylphosphorane in DCM afforded allylic alcohol 68 in good overall yield. The alcohol was then converted to bromide 69 in 76% yield using CBr4 and Ph3P in DCM from 0 C to room temperature. Finally cross metathesis of 69 using Hoveyda-Grubbs catalyst44 and 3-penten-2-one afforded the desired substrate 70 in 55% yield.
H O O H O NaBH4 THF, 0 C 85%
H O O H 66 DIBAL-H CH2Cl2, -78 C 91%
H OH O H 67
Ph3P=CH2 THF, reflux 62%
H CBr4, Ph3P OH H 68 O CH2Cl2, 0 C - r.t. 76%
H Br R
O (25)
H 69
HoveydaGrubbs CH2Cl2, reflux
H Br H
R
70, R=Me 55% 71, R=H 56%
As expected, treatment of 70 with tributylphosphine in t-BuOH followed by the addition of KOH under phase transfer conditions afforded cis-fused bicycle 72 in good yield. Delightfully, use of crotonaldehyde instead of 3-penten-2-one in the cross metathesis reaction afforded aldehyde 71 in 56% yield, and upon subjection to the previously optimized MBH conditions, enal 73 was formed in similarly high yield (Table 4). Having now established that five- and six-memebered rings could be made with great efficiency, more substrates were targeted to demonstrate the scope of the method. Additional five- and six-membered ring precursors were synthesized in one step starting 26
from either 1-bromopentene or 1-bromohexene. The brominated alkenes were treated with either 3-penten-2-one or 1-phenyl-but-2-en-1-one, 56, in DCM at reflux with 5 mol% Grubbs 2nd generation catalyst to give the desired substrates 74 77 (eq 26).
TABLE Results 4. of Bicycle Cycloalkylation
O H Br H Entry 70 70 71 71 R Me Me H H R (i) Bu3P (1 eq) t-BuOH, r.t (ii) KOH, BnEt3NCl CH2Cl2/H2O (1:1) Nucleophile Bu3P Me3P Bu3P Me3P Time (h) 5 3 7 6 H O R
H Product 72 72 73 73
Yield (%) 90 74 83 70
Br R ( )n
O
5 mol % Grubbs II CH2Cl2, reflux
O R ( )n Br
74, n=1, R=Me 75% 75, n=1, R=Ph 23% 76, n=2, R=Me 47% 77, n=2, R=Ph 28%
(26)
n= 1,2; R= Ph, Me
Enones 74 77 underwent cyclization with trimethylphosphine or tributylphosphine to give the cycloalkylation adducts, 78 81, in excellent yields (Table 5).
27
TABLE 5. Additional Five- and Six-membered Ring Substrate Results
O R ( )n Entry 74 74 75 75 76 76 77 77 R Me Me Ph Ph Me Me Ph Ph n 1 1 1 1 2 2 2 2 Br (i) Nucleophile (1eq) t-BuOH, r.t (ii) KOH, BnEt 3NCl CH2Cl2/H2O (1:1) Nucleophile Bu3P Me3P Bu3P Me3P Bu3P Me3P Bu3P Me3P Product 78 78 79 79 80 80 81 81 O R ( )n Yield (%) 0 81 87 95 0 80 100 92
2.1 Synthesis and reactions of hetero-substituted enones Probing further the tolerance of this method to alterations on the tether, substrates with a heteroatom in the tether were synthesized. Allyl sulfonamide 83 was synthesized in two steps starting from the commercially available allyl amine. The amine was tosylated using 1 eq of TsCl and Et3N, in DCM at 0 C to give the desired sulfonamide 82 in quantitative yield.45 Potassium hydroxide was then added to the sulfonamide 82 in THF with dibromoethane and tetrabutylammonium bromide to give alkylated amine 83 in good yield (eq 27).46
NH2 TsCl, Et3N DCM, 0 C 99%
H N 82
Ts
Br Br KOH, Bu4NBr THF 76%
Br N 83 (27) Ts
28
N-Allyl-N-(2-bromo-ethyl)-4-methyl benzenesulfonamide, 83, was then subjected to a cross metathesis reaction with 3-penten-2-one or 1-phenyl-but-2-en-1-one, 56, using Grubbs 2nd generation catalyst in DCM at reflux overnight to give the corresponding enones 84 and 85 in good yield (eq 28). Unfortunately, treatment of enones 84 and 85 with either Me3P or Bu3P in t-BuOH gave none of the desired product yielding only decomposition of starting material (Table 6).
O R
Br N
Ts
5 mol % Grubbs II DCM, reflux o.n.
O R
Br N 84, R = Me 48% 85, R = Ph 64% Ts (28)
R = Me, Ph
83
3-(2-Bromo-ethoxy)-propene, 88, was prepared from readily available 2(allyoxy)ethanol (eq 29).47 A mixture of 2-(allyloxy)ethanol and dry pyridine were added to neat PBr3 at -10 C to give the desired substrate 88.
OH PBr3 O Pyridine, -10 C 62%
Br O (29)
88
Ozonolysis of ether 88 at -78 C in DCM followed by treatment with acetylmethylene triphenylphosphorane and warming to room temperature gave enone 89 29
in moderate yield. Enone 90 was prepared in similar fashion except the ozonide was reduced with triphenylphosphine and the solution was warmed to room temperature before benzoylmethylene triphenylphosphorane was added to the reaction mixture (eq 30). Unfortunately, treatment of both enones with either trimethylphosphine or tributylphosphine in t-BuOH gave decomposition of staring material (Table 6).
O R PPh3 R = Me, Ph (step 2)
Br 1) O3, DCM, -78 C O 88 2) DCM, -78 C to r.t. R
O
Br O 89, R = Me 31% 90, R = Ph 24% (30)
TABLE 6. Results of Heterocycle Formation
O R
Br X
(i) Nucleophile (1eq) t-BuOH, r.t. (ii) KOH, BnEt 3NCl CH2Cl2/H2O (1:1) X NTs NTs NTs NTs O O O O Nucleophile Bu3P Me3P Bu3P Me3P Bu3P Me3P Bu3P Me3P
O R X Product 86 86 87 87 91 91 92 92 Yield (%) 0 0 0 0 0 0 0 0
Entry 84 84 85 85 89 89 90 90
R Me Me Ph Ph Me Me Ph Ph
30
The unfortunate results regarding the substrates involving a heteroatom in the tether are not surprising. Nitrogen and oxygen atoms have very different electronic properties than carbon, which has proved to be detrimental to this MBH reaction. Conclusion The intramolecular Morita-Baylis-Hillman reaction allows for the synthesis of densely functionalized products. Until recently the IMBH reaction has been limited to only specialized allylic electrophiles and more recently unactivated allylic halides as the electrophilic partner. However, this method has now been expanded to accept unactivated alkyl halides as the electrophilic partner allowing for the facile formation of five- and sixmembered rings in excellent yields.
31
CHAPTER III
EXPERIMENTAL
General Considerations Solvents were reagent grade and in most cases dried prior to use. All other commercially available reagents were used as received unless otherwise noted. The organic extracts were dried over anhydrous Na2SO4. Tetrahydrofuran (THF) was distilled from lithium aluminum hydride (LiAlH4) prior to use. Methylene chloride (DCM), and triethylamine (Et3N) were distilled from calcium hydride. Diethyl ether (Et2O) was distilled from sodium-benzophenone ketyl. Infrared (IR) spectra were recorded as thin films on sodium chloride plates using a Perkin-Elmer FT-IR Paragon 1000 Fourier Transform spectrometer with frequencies given in reciprocal centimeters (cm 1). Elemental Analysis was performed by Atlantic Microlab Inc, Northcross, GA. Proton nuclear magnetic resonance spectroscopy (1H NMR) was recorded on a Varian Fourier Transform 500 (500 MHz) spectrometer. Chemical shifts are reported in units, parts per million (ppm) relative to the singlet at 7.26 ppm for chloroform-d or in ppm relative to the singlet at 7.15 ppm for benzene-d6. The following abbreviations are used to describe peak patterns where appropriate: br = broad, s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet. Coupling constants, J are reported in Hertz unit (Hz). Carbon-13 nuclear magnetic resonance spectroscopy (13C NMR) was recorded on a Varian Fourier Transform 300 (75 MHz) and was fully decoupled by broad-band decoupling. Chemical shifts are reported in ppm with centerline 32
of the triplet for chloroform-d set at 77.0 ppm or that for benzene-d6 set at 128.0 ppm. Mass spectra were obtained on a Jeol JMS-600. Synthesis of substrates
Br O O O O
Synthesis of 2-Allyl-2-(2-bromo-ethyl)-malonic acid diethyl ester (48). A solution of diethyl allylmalonate (9.9 mL, 0.05 mol) in dry THF (14 mL) was added dropwise at room temperature to a stirred suspension of sodium hydride (60% dispersion in mineral oil, 2.40 g, 0.06 mol) in dry THF (14 mL) over a period of 30 min. The mixture was stirred for 1 h at room temperature, and a solution of 1,2-dibromoethane (5.2 mL, 0.06 mol) in dry THF (14 mL) was added dropwise over 30 min. The mixture was stirred for 15 h at room temperature and then poured into water. The mixture was extracted with ether and washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield ester 48 as a yellow oil. Excess 1,2-dibromoethane and unreacted diethyl allylmalonate were removed by Kugelrohr distillation to yield the bromoester as a colorless oil (14.76 g, 96%).39
Cl O O O O
Synthesis of 2-Allyl-2-(2-chloro-ethyl)-malonic acid diethyl ester (49). A solution of diethyl allylmalonate (3.95 mL, 20 mmol) in dry THF (12 mL) was added dropwise at room temperature to a stirred suspension of sodium hydride (60% dispersion in mineral oil, 0.96 g, 24 mmol) in dry THF (5 mL) over a period of 30 min. The mixture was stirred for 1 h at room temperature, and a solution of 1-bromo-2-chloroethane (2.0 mL, 24 mmol) was added dropwise over 30 min. The mixture was stirred for 15 h at room temperature and then poured into water. The mixture was extracted with ether and 33
washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield a yellow oil. Excess 1-bromo-2-chloroethane and unreacted diethyl allylmalonate were removed by Kugelrohr distillation (110 C, high vacuum) to yield the chloroester 49 as a colorless oil (1.73 g, 33%).48
O H3C E Br E
Synthesis of 2-(2-Bromo-ethyl)-2-(4-oxo-pent-2-enyl)-malonic acid diethyl ester (50). A flame-dried round-bottom flask equipped with reflux condenser was charged with alkylated malonate 48 (2.14 g, 7 mmol), 3-penten-2-one (2.1 mL, 7 mmol), and dichloromethane (35 mL). Grubbs 2nd generation catalyst (219 mg, 0.35 mmol) was subsequently added as a solid, producing a light brown/green solution which was refluxed for 12 h. The mixture was then plugged through a pad of silica gel and concentrated in vacuo. Purification of the residue via distillation at maximum vacuum at 125 C afforded the desired ester 50 in 48% yield. 1H NMR (500 MHz, CDCl3): 6.64 (td, 1H, J = 7.93, 15.87 Hz, CH=CHCH2), 6.12 (br d, 1H, J = 15.87 Hz, CH=CHCH2), 4.22 (q, 4H, J = 7.1 Hz, CH2CH3) 3.36 (t, 2H, J = 8.1 Hz, CH2CH2C), 2.80 (dd, 2H, J = 1.2, 7.6 Hz, CH=CHCH2) 2.46 (t, 2H, J = 8.1 Hz, CH2CH2C), 2.24 (s, 3H, CH3), 1.27 (t, J = 7.1 Hz, CHCH3) 13C NMR (75 MHz, CDCl3): 197.6, 169.5, 140.7, 134.6, 61.9, 57.2, 36.7, 36.5, 27.0, 26.5, 13.9 HRMS (FAB+) Calcd. For C14H21O5BrNa (M + Na): 371.0470, Found: 371.0467 FTIR (neat): 2981, 2938, 1701, 1677, 1630, 1446, 1366, 1300, 1253, 1194, 1176 cm-1 Anal. Calcd. For C14H21O5Br: C, 48.15; H, 6.06. Found: C, 48.18; H, 6.16.
O H3C E Cl E
Synthesis of 2-(2-Chloro-ethyl)-2-(4-oxo-pent-2-enyl)-malonic acid diethyl ester (51). 2-(2-Chloro-ethyl)-2-(4-oxo-pent-2-enyl)-malonic acid diethyl ester was prepared in 77% yield by following the same procedure used to prepare 2-(2-bromo-ethyl)-2-(4-oxopent-2-enyl)-malonic acid diethyl ester, 50. 1H NMR (500 MHz, CDCl3): 6.64 (td, J = 34
7.6, 15.9 Hz, 1H, CH=CHCH2), 6.12 (br d, J = 15.9 Hz, 1H, CH=CHCH), 4.22 (q, J = 7.3 Hz, 4H, CH2CH3), 3.54 (t, J = 7.6 Hz, 2H, CH2CH2C), 2.82 (dd, J = 1.5, 7.6 Hz, 2H, CH=CHCH2) 2.38 (t, J = 7.6 Hz, 2H, CH2CH2C), 2.24 (s, 3H, CH3), 1.27 (t, J = 7.1 Hz, 6H, CH2CH3) 13C NMR (75 MHz, CDCl3): 197.5, 169.6, 140.7, 134.5, 61.8, 56.2, 39.4, 36.4, 36.2, 26.8, 13.8. HRMS (FAB+) Calcd. For C14H21O5NaCl (M+Na): 327.0980, Found: 327.0975. FTIR (neat): 2982, 2908, 1731, 1700, 1678, 1632, 1446, 1254, 1180 cm-1. Anal. Calcd. For C14H21O5Cl: C, 55.17; H, 6.95. Found: C, 54.94; H, 7.01.
O H3C E E
Synthesis of 4-Acetyl-cyclohex-3-ene-1,1-dicarboxylic acid diethyl ester (52). A flame-dried round bottom flask was charged with 2-(2-Bromo-ethyl)-2-(4-oxo-pent-2enyl)-malonic acid diethyl ester, 50, (49 mg, 0.14 mmol) and tert-butanol (0.28 mL). Tributylphosphine (0.04 mL, 0.14 mmol) was then added to reaction mixture and stirred until all starting material was consumed (TLC analysis). At this time, dichloromethane (0.07 mL), water (0.07 mL), potassium hydroxide (8 mg, 0.14 mmol), and benzyltriethylammonium chloride (3 mg, 0.014 mmol) were added to reaction mixture which was allowed to stir until product was formed (TLC analysis). The mixture was extracted with DCM, washed with water, dried with sodium sulfate, plugged through a pad of silica gel, and concentrated in vacuo affording the cyclized product 52 (0.037 g, 99%). 1H NMR (500 MHz, CDCl3): 6.84 (tt, J = 2.2, 3.9 Hz, 1H, CHCH2), 4.187 (ABq, J = 7.3, 7.3 Hz, 2H, CHHCH3), 4.182 (ABq, J = 7.3, 7.3 Hz, 2H, CHHCH3) 2.78 (td, J = 2.2, 3.9 Hz, 2H, CH2CH), 2.29 (m, 2H, CH2C=) 2.28 (s, 3H, CH3), 2.16 (t, J = 6.4, Hz, 2H, CH2CH2C=), 1.24 (t, J = 7.3 Hz, 6H, CH3CH2). 13C NMR (75 MHz, CDCl3): 198.1, 170.9, 138.2, 137.1, 61.5, 52.4, 31.3, 26.9, 25.1, 20.1, 13.9 HRMS (FAB+) Calcd. For C14H20O5Na (M+Na): 291.1211, Found: 291.1208 FTIR (neat): 2980, 1731, 1668, 1258, 1175, 1068, 1021 cm-1. Anal. Calcd. For C14H20O5: C, 62.67; H, 7.51. Found: C, 62.50; H, 7.65.
35
O H3C
I E E
Synthesis of 2-(2-Iodo-ethyl)-2-(4-oxo-pent-2-enyl)-malonic acid diethyl ester (53). A mixture containing excess sodium iodide (30 mg, 0.2 mmol) in acetone (0.8 mL and 2-(2-chloro-ethyl)-2-(4-oxo-pent-2-enyl)-malonic acid diethyl ester, 51, (50 mg, 0.16 mmol) was stirred under reflux for 24 h. The reaction mixture was extracted with dichloromethane, washed with water, NaHSO3, brine, and then dried with Na2SO4. The solvent was removed under reduced pressure affording ester 53 as a thick oil (0.045 g, 71%). 1H NMR (500 MHz, CDCl3): 6.63 (dt, J = 7.6, 15.6 Hz, 1H, CH=CHCH2), 6.11 (d, J = 15.6 Hz, 1H, CH=CHCH2), 4.22 (q, J = 7.2, 4H, OCH2CH3), 3.10 (m, 2H, ICH2CH2 or ICH2), 2.77 (dd, J = 1.0, 7.6 Hz, 2H, CH=CHCH2), 2.48 (m, 2H, ICH2CH2 or ICH2), 2.23 (s, 3H, -CH3), 1.26 (t, J = 7.2 Hz, 6H, OCH2CH3). 13C NMR (75 MHz, CDCl3): 197.4, 169.2, 140.6, 134.3, 61.7, 58.6, 31.2, 36.0, 26.8, 13.8, -3.3. HRMS (FAB+) Calcd. For C14H21O5INa (M+Na): 419.03312, Found: 419.0335. FTIR (neat): 2980, 1729, 1676, 1253, 1188 cm-1. Anal. Calcd. For C14H21O5I: C, 42.44; H, 5.35. Found: C, 42.41; H, 5.44.
I
P
Synthesis of Hexyltrimethyl-phosphonium iodide (54): A flame-dried round
bottom flask was charged with 1-iodohexane (0.15 mL g, 1 mmol) and tert-butanol (2 mL). Trimethylphosphine (0.09 mL, 1 mmol) was then added to reaction mixture which was stirred until all starting material was consumed by TLC analysis. At this time a solid precipitate was formed and the reaction mixture was concentrated in vacuo affording the phosphonium salt 54 (151 mg, 94%). 1H NMR (500 MHz, CDCl3): 2.48 (m, 2H, PCH2), 2.21 (d, J = 13.9 Hz, 9H, PCH3), 1.58 (m, 2H, PCH2CH2), 1.52 (m, 2H, PCH2CH2CH2), 1.33 (m, 4H, CH2CH2CH3), 0.89 (t, J = 6.6 Hz, 3H, CH2CH3). 13C NMR (75 MHz, CDCl3): 30.8, 29.9, 24.0, 23.3, 22.0, 21.3, 13.7, 9.6, 8.8. HRMS (FAB+) Calcd. For C9H22PNa (M+Na): 161.1462, Found: 161.1459. FTIR (neat): 2959, 1298, 985, 776 cm-1. Anal. Calcd. For C9H22PI: C, 37.51; H, 7.70. Found: C, 37.40; H, 7.79.
36
O
Synthesis of 1-Phenyl-but-2-en-1-one (56). Aluminum trichloride (10.96 g, 82.2
mmol) was suspended in benzene (40 mL), and stirred vigorously at room temperature while trans-crotonyl chloride (6.18 mL, 64.2 mmol) was added dropwise over 5 min. After a further 15 min the resulting clear solution was poured onto a mixture of ice (100 mL) and hydrochloric acid solution (2 M; 50 mL). The resulting mixture was extracted with ether, washed with sodium hydroxide solution (3 M), dried with magnesium sulfate, and concentrated in vacuo. The crude material was purified by distillation (125 C, max vacuum) to give phenyl enone 56 as a clear oil (6.467 g, 69%).42
OH
Synthesis of 1-Phenyl-hex-4-en-3-ol (57). Magnesium metal (1.458 g, 60 mmol) was
added to a heat dried round bottom flask containing 50 mL ether and heated until all the metal had dissolved. After allowing the reaction mixture to cool to room temperature, 1bromo-1-propene (5.11 mL, 60 mmol) was added and the mixture was stirred for 2 hours or until all the 1-bromo-1-propene was consumed by TLC analysis. After the Grignard reagent was formed, hydrocinnamaldehyde (5.16 mL, 39 mmol) was added dropwise and stirred for an additional hour. The reaction mixture was then diluted with ethyl acetate, washed with ammonium chloride solution, dried with magnesium sulfate, and concentrated in vacuo. Purification by distillation afforded 1-phenyl-hex-4-en-3-ol (3.59 g, 52%).49
O
Synthesis of 1-Phenyl-hex-4-en-3-one (58). Sodium dichlorochromate and water
(0.6 mL) was added to a vial and cooled to 0 C. Sulfuric acid was added to the reaction mixture slowly and stirred for 3 min. To a separate reaction vial 1-phenyl-hex-4-en-3-ol,
57, (176 mg, 1 mmol) and diethyl ether (0.6 mL) were added and the resulting mixture
37
was cooled in an ice bath and allowed to stir for 5 min. To this reaction mixture half of the oxidizing agent was added with vigorous stirring. The rest of the oxidizing agent was added dropwise over 10 min and stirring was continued for an additional 0.5 h before partitioning the mixture between ether and water, washing with sodium carbonate, drying with magnesium sulfate and concentrating in vacuo to afford the desired enone 58 (157 mg, 90%).50
O Br E E
Synthesis of 2-(2-Bromo-ethyl)-2-(4-oxo-4-phenyl-but-2-enyl)-malonic acid diethyl ester (59). A flame-dried round-bottom flask equipped with a reflux condenser
was charged with phenyl enone 56 (964 mg, 6.6 mmol), alkylated ester 48 (925 mg, 3 mmol), and dichloromethane (15 mL). Grubbs 2nd generation catalyst (127 mg, 0.15 mmol) was subsequently added as a solid, producing a light brown/green solution which was refluxed for 12 h. The mixture was then plugged through a pad of silica gel and concentrated in vacuo. Purification of the residue via column chromatography afforded ester 59 (592 mg, 48%). 1H NMR (500 MHz, CDCl3): 7.90 (d, J = 7.9 Hz, 2H, aromatic H), 7.57 (t, J = 7.4 Hz, 1H, aromatic H), 7.47 (t, J = 7.9 Hz, 2H, aromatic H) 6.94 (d, J = 15.2 Hz, 1H, CH=CHCH2), 6.85 (td, J = 7.4, 15.2 Hz, 1H, CH=CHCH2) 4.23 (q, J = 7.4 Hz, 4H, CH2CH3), 3.40 (t, J = 7.9, Hz, 2H, CCH2CH2), 2.92 (d, J = 7.4 Hz, 2H, CH=CHCH2) 2.50 (t, J = 7.9 Hz, 2H, CCH2CH2) 1.27 (t, J = 7.4 Hz, 6H, CH2CH3) 13C NMR (75 MHz, CDCl3): 189.8, 169.6, 141.9, 137.3, 132.9, 129.6, 128.5, 128.4, 62.9, 57.4, 36.8, 36.7, 26.6, 14.0 HRMS (FAB+) Calcd. For C19H23O5NaBr (M+Na): 433.0626, Found: 433.0644. FTIR (neat): 2980, 2937, 1730, 1674, 1624, 1447 cm-1. Anal. Calcd. For C19H23O5Br: C, 55.49; H, 6.99. Found: C, 55.39; H, 6.95.
O Br E E
Synthesis of 2-(2-Bromo-ethyl)-2-(4-oxo-6-phenyl-hex-2-enyl)-malonic acid diethyl ester (60). A flame-dried round-bottom flask equipped with reflux condenser was
38
charged with alkylated malonate 48 (616 mg, 2 mmol), benzyl enone 58 (766 mg, 4.4 mmol), and dichloromethane (15 mL). Grubbs 2nd generation catalyst (85 mg, 0.1 mmol) was subsequently added as a solid, producing a light brown/green solution which was refluxed for 12 h. The mixture was then plugged through a pad of silica gel and concentrated in vacuo. Purification of the residue via column chromatography afforded ester 60 (342 mg, 39%). 1H NMR (500 MHz, CDCl3): 7.28 (m, 2H, aromatic), 7.20 (m, 3H, aromatic), 6.64 (td, J = 7.6, 15.6 Hz, 1H, CH=CHCH2), 6.15 (d, J = 15.6 Hz, 1H, CH=CHCH2), 4.21 (q, J = 7.1 Hz, 4H, OCH2CH3), 3.35 (t, J = 8.0 Hz, 2H, CH2Br), 2.92 (m, 2H, PhCH2CH2, or PhCH2), 2.85 (m, 2H, PhCH2CH2, or PhCH2), 2.78 (dd, J = 1.2, 7.6 Hz, 2H, CH=CHCH2), 2.43 (t, J = 8.0 Hz, 2H, CH2CH2Br), 1.25 (t, J = 7.1 Hz, 6H, OCH2CH3). 13C NMR (75 MHz, CDCl3): 198.9, 169.9, 141.2, 140.2, 133.9, 128.8, 128.6, 126.4, 62.2, 57.5, 42.1, 37.0, 36.8, 30.1, 26.8, 14.3. HRMS (FAB+) Calcd. For C21H27O5NaBr (M+Na): 461.0940, Found: 461.0945. FTIR (neat): 2980, 1729, 1445, 1260 cm-1. Anal. Calcd. For C21H27O5Br: C, 57.41; H, 6.19. Found: C, 57.03; H, 6.28.
O E E
Synthesis of 4-Benzoyl-cyclohex-3-ene-1,1-dicarboxylic acid diethyl ester (61). 4-
Benzoyl-cyclohex-3-ene-1,1-dicarboxylic acid diethyl ester was obtained in 90% yield following the same procedure used to prepare 4-acetyl-cyclohex-3-ene-1,1-dicarboxylic acid diethyl ester, 52, using tributylphosphine as the nucleophile. 1H NMR (500 MHz, CDCl3): 7.62 (m, 2H, aromatic), 7.53 (m, 1H, aromatic), 7.41 (m, 2H, aromatic), 6.53 (br s, 1H, CH2CHC), 4.24 (q, J = 7.1 Hz, 4H, CH2CH3), 2.79 (m, 2H, CH2CH), 2.50 (m, 2H, CH2C=), 2.27 (t, J = 6.4 Hz, 2H, CH2CH2C=), 1.27 (t, J = 7.1 Hz, 6H, CH3CH2) 13C NMR (75 MHz, CDCl3): 197.0, 171.0, 139.8, 138.1, 137.2, 131.6, 129.2, 128.1, 61.6, 52.6, 31.4, 27.2, 21.2, 14.0 HRMS (FAB+) Calcd. For C19H22O5Na (M+Na): 353.1358, Found: 353.1365. FTIR (neat): 1729, 1245, 708 cm-1. Anal. Calcd. For C19H22O5: C, 69.07; H, 6.71. Found: C, 69.06; H, 6.55.
39
O E E
Synthesis of 4-(3-Phenyl-propionyl)-cyclohex-3-ene-1,1-dicarboxylic acid diethyl ester (62). 4-(3-Phenyl-propionyl)-cyclohex-3-ene-1,1-dicarboxylic acid diethyl ester
was obtained in 79% yield following the same procedure used to prepare 4-acetylcyclohex-3-ene-1,1-dicarboxylic acid diethyl ester, 52, using tributylphosphine as the nucleophile. 1H NMR (500 MHz, CDCl3): 7.27 (m, 3H, aromatic), 7.18 (m, 2H, aromatic), 6.82 (tt, 1H, J = 1.9, 3.9 Hz, CH2CHC), 4.187 (ABq, J =7.1, 7.1 Hz, 2H, CHHCH3), 4.182 (ABq, J = 7.1, 7.1 Hz, 2H, CHHCH3), 2.96 (m, 2H, ArCH2CH2), 2.91 (m, 2H, ArCH2CH2), 2.75 (td, J = 2.2, 3.9 Hz, 2H, CH2CH), 2.31 (dtt, J = 1.9, 2.2, 6.4 Hz, 2H, CH2CCH), 2.15 (t, J = 6.4 Hz, 2H, CH2CH2CCH), 1.24 (t, J = 7.1 Hz, 6H, CH3CH2) 13C NMR (75 MHz, CDCl3): 199.3, 171.0, 141.4, 137.8, 136.2, 128.4, 128.4, 126.0, 61.6, 52.5, 39.0, 31.3, 30.3, 27.1, 20.4, 14.0. HRMS (FAB+) Calcd. For C21H26O5Na (M+Na): 381.1693, Found: 381.1678. FTIR (neat): 2981, 1731, 1668, 1252 cm-1. Anal. Calcd. For C21H26O5: C, 70.37; H, 7.31. Found: C, 70.44; H, 7.21.
Br O O O O
Synthesis of 2-Allyl-2-bromomethyl-malonic acid diethyl ester (63): 2-Allyl-2-
bromomethyl-malonic acid diethyl ester was prepared in 99% yield by following the same procedure used to prepare 2-allyl-2-(2-bromo-ethyl)-malonic acid diethyl ester using dibromo methane instead of dibromo ethane.43
O H3C E Br E
Synthesis of 2-Bromomethyl-2-(4-oxo-pent-2-enyl)-malonic acid diethyl ester (64): A
flame-dried round-bottom flask equipped with reflux condenser was charged with 2-allyl2-bromomethyl-malonic acid diethyl ester, 63, (690 mg, 2.3 mmol), 3-penten-2-one (0.35 40
mL, 2.3 mmol), and dichloromethane (11.5 mL). Grubbs 2nd generation catalyst (98 mg, 0.115 mmol) was subsequently added as a solid, producing a light brown/green solution which was refluxed for 12 h. The mixture was then plugged through a pad of silica gel and concentrated in vacuo. Purification of the residue via column chromatography afforded enone 64. (342 mg, 44%). 1H NMR (500 MHz, CDCl3): 6.59 (td, J = 8.1, 16.1 Hz, 1H, CH2CH=CH), 6.20 (td, J = 1.5, 16.1 Hz, 1H, CH2CH=CH), 4.26 (ABq, J = 7.0, 10.3 Hz 2H, CH2CH3), 4.23 (ABq, J = 7.0, 10.3 Hz 2H, CH2CH3), 3.76 (s, 2H, CH2Br), 2.97 (dd, J = 1.5, 8.1 Hz, 2H, CH2CH=CH), 2.24 (s, 3H, CH3), 1.27 (t, J = 7.3 Hz, 6H, CH2CH3). 13C NMR (75 MHz, CDCl3): 197.5, 167.8, 139.8, 134.9, 62.2, 58.1, 34.6, 32.8, 27.0, 13.9. HRMS (FAB+) Calcd. For C13H19O5BrNa (M+Na): 357.0317, Found: 357.0314. FTIR (neat): 2982, 2938, 1732, 1678, 1631, 1465, 1432, 1365, 1256, 1095 cm1
. Anal. Calcd. For C13H19O5Br: C, 46.58; H, 5.71. Found: C, 46.49; H, 5.63.
O Br E E
Synthesis of 2-Bromomethyl-2-(4-oxo-4-phenyl-but-2-enyl)-malonic acid diethyl ester (65): 2-Bromomethyl-2-(4-oxo-4-phenyl-but-2-enyl)-malonic acid diethyl ester was
prepared in 40% yield by following the same procedure used to prepare 2-bromomethyl2-(4-oxo-pent-2-enyl)-malonic acid diethyl ester, 64, using 1-phenyl-but-2-en-1-one. 1H NMR (500 MHz, CDCl3): 7.92 (d, J = 8.6 Hz, 2H, aromatic H), 7.57 (dd, J = 7.3, 7.3 Hz, 1H, aromatic H), 7.48 (dd, J = 7.6, 8.1 Hz, 2H, aromatic H), 7.05 (d, J = 15.5 Hz, 1H, CH=CHCH2), 6.79 (dt, J = 7.8, 15.5 Hz, 1H, CH=CHCH2), 4.252 (ABq, J = 3.9, 7.3 Hz, 2H, CH2CH3), 4.248 (ABq, J = 3.9, 7.3 Hz, 2H, CH2CH3), 3.80 (s, 2H, CH2Br), 3.09 (dd,
J = 0.7, 7.8 Hz, 2H, CH=CHCH2), 1.28 (t, J = 7.3 Hz, 6H, CH2CH3). 13C NMR (75 MHz,
CDCl3): 189.8, 168.0, 140.9, 137.4, 132.4, 132.9, 130.2, 128.6, 128.5, 62.3, 58.2, 34.9, 33.0, 14.0. HRMS (FAB+) Calcd. For C18H21O5BrNa (M+Na): 419.0481, Found: 419.0470. FTIR (neat): 2980, 2937, 1731, 1673, 1625, 1447, 1264, 1191 cm-1. Anal. Calcd. For C18H21O5Br: C, 54.42; H, 5.44. Found: C, 54.41; H, 5.45.
41
O O
Synthesis of Hexahydro-isobenzofuran-1-one (66). To a solution of sodium
borohydride (1.19 g, 30.8 mmol) and THF (0.8 mL) at 0 C was added cis-1-2cyclohexane dicarboxylic anyhdride (5.0 g, 30.8 mmol) and THF (30 mL). The reaction mixture was stirred for 2 h followed by addition of HCl (6 M, 12 mL) and dilution with water (70 mL). Subsequent extraction with diethyl ether, drying with sodium sulfate, and concentration in vacuo afforded lactone 66 (3.65 g, 85%).51
O OH
Synthesis of 2-Hydroxymethyl-cyclohexanecarbaldehyde (67). To a solution of
hexahydro-isobenzofuran-1-one 66 (3.65 g, 26.1 mmol) in dichloromethane (131 mL) at 78 C was added DIBAL (31.3 mL, 31.3 mmol). After stirring for 2.5 h at -78 C the reaction mixture was quenched with methanol (0.188 mL), diluted with ether, and ground sodium sulfate decahydrate (8.41 g) was added. The reaction mixture was allowed to slowly warm to room temperature and stir overnight. Upon completion of the reaction the suspension was plugged through a pad of Celite and the filtrate was concentrated in
vacuo yielding 2-hydroxymethyl-cyclohexanecarbaldehyde (3.38 g, 91%).52
OH
Synthesis of (2-Vinyl-cyclohexyl)-methanol (68). A solution of
methyltriphenylphosphonium bromide (30.36 g, 85 mmol) and THF (85 mL) in a heat dried round bottom flask was cooled to 0 C. Then while stirring, n-butyllithium (53 mL, 1.6 M in hexane) was added slowly and the reaction mixture was allowed to warm to room temperature and stir for 0.5 h. Lactol 67 was added to the reaction mixture slowly and refluxed for an additional 2 h. Upon completion, the reaction mixture was quenched with water and extracted with ethyl acetate. The concentrated residue was then plugged through a pad of silica gel, concentrated in vacuo and purified by column chromatography (hexane:ethylacetate, 5:1) to yield product 68 (2.26 g, 95%).53 42
Br
Synthesis of 1-Bromomethyl-2-vinyl-cyclohexane (69). A solution of alcohol 68
(0.11 g, 0.79 mmol) and carbon tetrabromide (0.33 g, 1 mmol) in dichloromethane was cooled to 0 C. Then, triphenylphosphine (0.29 g, 1.1 mmol) was added and the reaction mixture was allowed to warm to room temperature. The reaction stirred for 5 h and the solvent was removed in vacuo. The bromo alkene was purified by column chromatography, eluting with hexane:ethyl acetate (5:1). The bromide was obtained as a clear oil (12 mg, 76%). 1H NMR (500 MHz, CDCl3): 5.92 (ddd, J = 8.1, 10.3, 16.1 Hz, 1H, CH=CH2), 5.14 (dd, J = 2.2, 16.1 Hz, 1H, CH2=CHCH), 5.09 (dd, J = 2.2, 10.3 Hz, 1H, CH2=CHCH), 3.26 (ABd, J = 7.3, 10.2 Hz, 1H, CH2Br), 3.23 (ABd, J = 7.3, 9.5 Hz, 1H, CH2Br), 2.60 (dddd , J = 3.7, 4.4, 4.4, 8.1 Hz, 1H, CHCH=CH2), 1.89 (ddddd , J = 3.8, 3.8, 7.3, 7.3, 11.1 Hz, 1H, CHCH2Br), 1.72 1.31 (m, 8H, cyclohexane ring). 13C NMR (75 MHz, CDCl3): 137.1, 116.4, 42.5, 41.8, 37.5, 30.8, 27.1, 25.0, 21.8. FTIR (neat): 3073, 3002, 2927, 2855, 1636, 1448, 1234, 918 cm-1. Anal. Calcd. For C9H15Br: C, 53.22; H, 7.44. Found: C, 52.82; H, 7.73.
O CH3 Br
Synthesis of 4-(2-Bromomethyl-cyclohexyl)-but-3-en-2-one (70). 4-(2-
Bromomethyl-cyclohexyl)-but-3-en-2-one was prepared in 97% yield by following the same procedure used to prepare 2-(2-bromo-ethyl)-2-(4-oxo-pent-2-enyl)-malonic acid diethyl ester, 50, using Hoveyda-Grubbs catalyst. 1H NMR (500 MHz, CDCl3): 6.90 (dd, J = 9.0, 15.9 Hz, 1H, CH=CHCH), 6.23 (dd, J = 0.7, 15.9 Hz, 1H, CH=CHCH), 3.25 (dd, J = 7.1, 10.3 Hz, 1H, BrCH2) 3.14 (dd, J = 8.1, 10.3 Hz, 1H, BrCH2), 2.80 (dddd, J = 4.2, 4.4, 4.4, 9.0 Hz, 1H, CH=CHCH) 2.26 (s, 3H, -CH3), 2.01 (ddddd, J = 4.0, 4.2, 7.1, 8.1, 11.8 Hz, 1H, CHCH2Br), 1.76-1.37 (m, 8H, cyclohexane ring). 13C NMR (75 MHz, CDCl3): 198.0, 146.2, 132.1, 42.5, 40.3, 36.5, 30.2, 27.5, 27.3, 24.7, 21.7. HRMS (FAB+) Calcd. For C11H17ONaBr (M+Na): 267.0352, Found: 267.0360. FTIR (neat): 43
2929, 2857, 1696, 1674, 1622, 1450, 1254 cm-1. Anal. Calcd. For C11H17OBr: C, 53.89; H, 5.64. Found: C, 53.76; H, 5.95.
O H Br
Synthesis of 3-(2-Bromomethyl-cyclohexyl)-propenal (71). A flame-dried round-
bottom flask equipped with reflux condenser was charged with 69 (1.21 g, 6 mmol), crotonaldehyde (0.49 mL, 6 mmol), and dichloromethane (30 mL). Hoveyda-Grubbs catalyst (188 mg, 0.3 mmol) was subsequently added as a solid, producing a light brown/green solution which was refluxed for 12 h. The mixture was then plugged through a pad of silica gel and concentrated in vacuo. Purification of the residue via column chromatography afforded enal 71 (1.33 g, 96%). 1H NMR (500 MHz, CDCl3): 9.54 (d, J = 7.8 Hz, 1H, aldehyde), 6.93 (dd, J = 8.6, 15.6 Hz, 1H, CHCH=CH), 6.25 (ddd, J = 1.0, 7.8, 15.6 Hz, 1H, CHCH=CH), 3.28 (dd, J = 7.1, 10.2 Hz, 1H, CH2CHCH=C), 3.14 (dd, J = 8.1, 10.2, 1H, CH2CHCH=C), 2.96 (dddd, J = 4.2, 4.4, 4.4, 8.6 Hz, 1H, CHCH=CH), 2.06 (ddddd, J = 4.0, 4.2, 7.1, 8.1, 12.0 Hz, 1H, BrCH2CH) 1.79-1.65 (m, 4H, CH2CH2CHCH=), 1.54 (m, 2H, CH2CHCH=), 1.41 (m, 2H, CH2CHCH2Br). 13C NMR (75 MHz, CDCl3): 193.3, 156.8, 133.9, 42.2, 40.4, 36.0, 29.6, 27.1, 24.4, 21.5. HRMS (FAB+) Calcd. For C10H15ONaBr (M+Na): 253.0204, Found: 253.0216. FTIR (neat): 2930, 2857, 1689, 1450, 1137, 1117, 978 cm-1. Anal. Calcd. For C10H15O: C, 51.97; H, 6.54. Found: C, 51.75; H, 6.41.
O CH3
Synthesis of 1-(3a,4,5,6,7,7a-Hexahydro-1H-inden-2-yl)-ethanone (72). 1-
(3a,4,5,6,7,7a-Hexahydro-1H-inden-2-yl)-ethanone was obtained in 90% yield following the same procedure used to prepare 4-acetyl-cyclohex-3-ene-1,1-dicarboxylic acid diethyl ester, 52, using tributylphosphine as the nucleophile. 1H NMR (500 MHz, CDCl3): 6.67 (br s, 1H, C=CH), 2.78 (m, 1H, CHCH=C), 2.49 (tdd, J = 2.0, 8.6, 16.9 Hz, 1H, CHHC), 2.30 (s, 3H, CH3), 2.28 (m, 1H, CHHC), 1.67 (dddd, J = 6.6, 6.6, 6.6, 13.0 Hz, 1H, CH2CHCH=C), 1.55-1.00 (m, 8H, cyclohexane ring). 13C NMR (75 MHz, CDCl3): 197.3, 44
149.4, 145.2, 45.3, 37.5, 35.4, 27.6, 27.5, 26.3, 23.3, 22.9. FTIR (neat): 2925, 2852, 1666, 1604, 1449, 1371 cm-1. Anal. Calcd. For C11H16O: C, 80.44; H, 9.82. Found: C, 80.82; H, 9.81.
O H
Synthesis of 3a,4,5,6,7,7a-Hexahydro-1H-indene-2-carbaldehyde (73).
3a,4,5,6,7,7a-Hexahydro-1H-indene-2-carbaldehyde was obtained in 90% yield following the same procedure used to prepare 4-acetyl-cyclohex-3-ene-1,1-dicarboxylic acid diethyl ester, 52, using tributylphosphine as the nucleophile. 1H NMR (500 MHz, CDCl3): 9.76 (s, 1H, CHO); 6.82 (br s, 1H, C=CH); 2.82 (m, 1H, CHCHC); 2.48 (br dd, J = 6.8, 15.5 Hz, 1H, CHHC); 2.34 (dddt, J = 6.6, 6.6, 6.6, 6.8 Hz, 1H, CHCH2C); 2.26 (br dd, J = 5.3, 15.5 Hz, 1H, CHHC); 1.71 (dddd, J = 5.8, 5.8, 5.8, 11.6 Hz, 1H, CH2CHCHC); 1.56-1.24 (m, 7H, cyclohexane ring). 13C NMR (75 MHz, CDCl3): 190.4, 158.0, 146.9, 45.2, 37.7, 33.3, 27.6, 27.3, 23.3, 22.8. For C10H14ONa (M+Na): 150.1042, Found: 150.1045. FTIR (neat): 2926, 2853, 1678, 1449 cm-1. Anal. Calcd. For C10H14O: C, 79.96; H, 9.39. Found: C, 79.78; H, 9.34.
O H3C Br
Synthesis of 7-Bromo-hept-3-en-2-one (74). 7-Bromo-hept-3-en-2-one was
prepared in 75% yield by following the same procedure used to prepare 2-(2-bromoethyl)-2-(4-oxo-pent-2-enyl)-malonic acid diethyl ester.54
O Br
Synthesis of 6-Bromo-1-phenyl-...