... undergo cleavage with the first three methods. The two periodate methods were allowed to stir for up to three days with little change. The. 39. 2 mofO/o Os04.
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I.
OXIDATIVE REACTIONS OF THE DOUBLE BOND OF IN SUBSTITUTED II
METHYLENECYCLOPROPANES
TI. A NOVEL RUTHENIUM CATALYZED REARRANGEMENT OF
METHYLENECYCLOPROPYL KETONES TO 2,5-DISUBSTITUTED FURANS by
Kevin J. Ruff B.A., Southern lllinoiSUniversity, 1993
Submitted to the Department of Chemistry and the Faculty of the Graduate School of the University of Kansas in partial fulfillment of the requirements for the degree of Doctor of Philosophy.
DtSS .:~LCC
Dissertation Committee:
r""' . 'l)f! 1---, U I~
Dissertation defended: August 2000
DEC 3 1 2000
UMI Number: 9998109
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Abstract Kevin J. Ruff, Ph.D. Department of Chemistry, August 2000 The University of Kansas
I.
Secondary and tertiary methylenecyclopropyl carbinols can readily be prepared by the
addition of 2-Iithiomethylenecyclopropane to various aldehydes and ketones. Methylenecyclopropyl ketones can then be prepared from the resultant secondary carbinols. Ozonolysis of both 2° and 3° methylenecyclopropyl carbinols produced complex mixtures of at least eight compounds, however ozonolysis of methylenecyclopropyl ketones produced 4-substituted-tetrahydro:furan-2-ones and 1-hydroxy-5-substituted-2,5-diones. Dihydroxylation of methylenecyclopropyl ketones with osmium tetraoxide and N-methylmorpholine-N-oxide produced the same 1-hydroxy-5-substituted-2,5-diones as above. Dihydroxylation of3° methylenecyclopropyl carbinols resulted in novel dials that, when subjected to protic acid, rearranged to dimers of 1-hydroxy-4-(1-hydroxycycloalkyl)butan-2-ones and 4-alkylylidene-1-hydroxy-butan-2-ones.
II.
Secondary methylenecyclopropyl carbinols can readily be prepared by the addition of
2-lithiomethylenecyclopropane to various aldehydes. Methylenecyclopropyl ketones can then be prepared from these carbinols. 2,5-Disubstituted furans can then be prepared catalytically by subjecting the methylenecyclopropyl ketones to ring-closing metathesis conditions with a ruthenium based modified Grubbs' catalyst having a 1,3-dimesityl-4,5dihydroimidazol-2-ylidene ligand.
ii
Acknowledgments
I would like to acknowledge the University of Kansas General Research Fund for their financial support and the Department of Chemistry of the University of Kansas for their 5-year Teaching Assistantship. I would also like to express my heartfelt gratitude to Dr. Robert G. Carlson for his patience and understanding throughout the trials and tribulations of my research projects. I will forever be indebted to him for the intangible knowledge that I gained from his mentorship that could not be attained in any coursework. I would also like to thank my wife Tara for her patience and understanding. She was invaluable in helping me to maintain my composure throughout the trials and tribulations of my research projects. I especially appreciate her understanding whenever I needed to take time away from her to complete my work and this dissertation. I would also like to thanks my parents for providing support and encouragement to help me make it to this point. Without them I surely couldn't have succeeded. I also must give thanks to God for the abiiities that He has given to me. I will spend the rest of my days trying to be deserving of those blessings.
iii
Table of Contents
Page(s) Abstract .................................................................................................................... ii Acknowledgments .................................................................................................. m Chapter I: Introduction L Historical ................................................................................................ .... 1 II. Proposed Research ....... ........................... ........... ........................... ....... .. .. .. 9 ill. Results and Discussion 1. Choice of Model Compounds ...................................................... 11 2. Synthesis and Metallation of Methylenecyclopropane ................. 11 3. Preparation ofMeth.ylenecyclopropyl Carbinols .......................... 13 4. Preparation ofMethylenecyclopropyl Ketones ............................ 14 5. Attempted Cleavage ofMethylenecyclopropanes to Cyclopropanones A. Ozonolysis 1. Methylenecyclopropyl Carbinols ................... 15 2. Methylenecyclopropyl Ketones ...................... 15 B. "One Pot" Cleavage: Osmium Tetraoxide I Sodium Periodate 1. Methylenecyclopropyl Carbinols ................... 22 C. Two Step Cleavage: Dihydroxylation Followed by Subsequent Diol Cleavage 1. Methylenecyclopropyl Ketones ...................... 22 2. Methylenecyclopropyl Carbinols ................... 23 6. Heterogeneous Protic Acid Rearrangement ofDihydroxycyclopropyl Carbinols .................................................................. 25 ExperbnentaiProcedure
Preparation of Methylenecyclopropane (1) ............................................................. 34 Preparation of2-lithiomethylenecyclopropane ....................................................... 35 General Procedure For The Addition of2-lithiomethylenecyclopropane to Ketones Addition of2-lithiomethylenecyclopropane to Cyclohexanone ............................. 35 Addition of2-lithiomethylenecyclopropane to Cyclopentanone ............................ 36
iv
General Procedure For Preparation ofMethylenecyclopropyl Ketones Preparation of 1-(2-methylenecyclopropyl)hexan.-1-one (40) ................................. 37 Preparation of 1-(2-meth.ylenecyclopropyl)cyclohexylm.ethanone (42) .................. 38 Preparation of 1-(2-meth.ylenecyclopropyl)-3-phenylpropan-1-one (43) ................ 39 General Procedure For The Hydroxylation of Tertiary Alcohols Hydroxylation of 1-(2-meth.ylenecyclopropyl)cyclohexan-1-ol (39) ...................... 40 Hydroxylation of 1-(2-methylenecyclopropyl)cyclopentan-1-ol (53) ..................... 41 General Procedure For The Hydroxylation of Ketones Hydroxylation of 1-(2-methylenecyclopropyl)hexan-1-one (41) ............................ 42 Hydroxylation of 1-(2-methylenecyclopropyl)-1-cyclohexylmethanone (42) ........ 43 Hydroxylation of 1-(2-methylenecyclopropyl)-3-phenylpropan-1-one (43) ........... 43 General Procedure For The Ozonolysis of Ketones Ozonolysis of 1-(2-meth.ylenecyclopropyl)hexan-1-one (41) ................................. 44 Ozonolysis of 1-(2-methylenecyclopropyl)-1-cyclohexylm.eth.anone (42) .............. 45 Ozonolysis of 1-(2-methylenecyclopropyl)-3-phenylpropan-1-one (43) ................ 46 Rearrangement of 1-(2-hydroxymeth.ylcyclopropan-2-ol)cyclohexan-1-ol (SO) ..... 4 7 Rearrangement of 1-(2-hydroxymeth.ylcyclopropan-2-ol)cyclopentan-1-ol (54) .... 49
Chapter II: Introduction I. Historical .................................................................................................. 51 II. Proposed Research ..... ...... ... ... .. .... .. .............. ..... ... ............... ... ...... ....... ..... 58 ill. Results and Discussion 1. Choice of Model Compounds ...................................................... 60 2. Synthesis and Metallation ofMethylenecyclopropane ................. 11 3. Preparation of Methylenecyclopropyl Carbinols .......................... 60 4. Preparation ofMethylenecyclopropyl Ketones ............................ 14 5. Attempted RCM ofMethylenecyclopropyl Carbinols and Ketones to Bridged Methylenecyclopropanes With Grubbs' Catalyst ............ .... ... ... ...... ........... .. .. ....... ....................... ......... ..... .. 6 3 6. Preparation of Modified Grubbs' Catalyst ................................... 63
v
7. Attempted RCM ofMethylenecyclopropyl Carbinols and Ketones to Bridged Methylenecyclopropanes With Modified Grubbs' Catalyst ........................................................................... 64
Experimental Procedure Preparation ofMethylenecyclopropane (1) ............................................................. 34 Preparation of2-lithiomethylenecyclopropane ....................................................... 35 Ozonolysis of cis-cyclooctene ................................................................................. 75 Addition ofMethyltriphenylphosphorane to 8,8-dimethoxyoctanal (66) ..•............ 76 Hydrolysis of9,9-dimethoxynonen (67) ................................................................. 77 Addition of2-lithiomethylenecyclopropane to 8-nonenal (68) ............................... 78 Oxidation of 1-(2-methylenecyclopropyl)-8-nonen-1-ol (64) ................................. 80 General Procedure For The Addition of2-lithiomethylenecyclopropane to Aldehydes Followed by Subsequent Oxidation to Ketones Preparation of 1-(2-methylenecyclopropyl)hexan-1-one (41) ................................. 81 Preparation of 1-(2-methylenecyclopropyl)-1-phenylmethanone (74) .................... 83 Preparation of 1-(2-methylenecyclopropyl)-3-methylbutan-1-one (72) .................. 83 Preparation of 1-(2-methylenecyclopropyl)2-ethylhexan-1-one (73) ..................... 84 Preparation of 1-(2-methylenecyclopropyl)octan-1-one (75) .................................. 84 Preparation of Modified Grubbs' Catalyst (62) ...................................................... 85 General Procedure For The Ruthenium Catalyzed Rearrangement of Methylenecyclopropyl Ketones to 2,5-Disubstituted Furans Rearrangement of 1-(2-methylenecyclopropyl)-8-nonen-1-one (64) ...................... 86 Rearrangement of 1-(2-methylenecyclopropyl)hexan-1-one (41) ........................... 87 Rearrangement of 1-(2-methylenecyclopropyl)-1-phenylmethanone (74) .............. 87 Rearrangement of 1-(2-methylenecyclopropyl)-3-methylbutan-1-one (72) ............ 88 Rearrangement of 1-(2-methylenecyclopropyl)2-ethylhexan-1-one (73) ................ 89 Rearrangement of 1-(2-methylenecyclopropyl)octan-1-one (75) ............................ 89
vi
Table of Figures and Tables Page(s) Table 1: Ozonolysis Products ofMethylenecyclopropyl Ketones .......................... 16 Table 2: Dihydroxylation Products ofMethylenecyclopropyl Ketones .................. 24 Table 3: Ruthenium Catalyzed Rearrangement Products of Methylenecyclopropyl Ketones ............. ...................... .....................................•........ 71 Figure 1: 1H-NMR. spectrum of 44 .......................•.................................................. 17 Figure 2: 1H-COSY spectrum of 44 ........................................................................ 18 Figure 3: IIMQC spectrum of 44 •........................................................................... 19 Figure 4: fiMBC spectrum of 44 ............. ............................................... ................ 19 Figure 5: 1H-NMR. spectrum of Sl .......................................................................... 26 Figure 6: 1H-COSY spectrum of Sl ........................................................................ 27 Figure 7: IIMQC spectrum of Sl ............................................................................ 28 Figure 8: fiMBC spectrum. of Sl .. ... ..... ..................... ............ ... ...... .............. .... ...... 28 Figure 9: ORTEP diagram of dimer Sl ................................................................... 29 Figure 10: 1H-N"MR. spectrum of 69 ........................................................................ 66 Figure 11: 1H-COSY spectrum of 69 ...................................................................... 67 Figure 12: HMQC spectrum of 69 .......................................................................... 68 Figure 13: IIMBC spectrum of 69 ......................................................................... 68 Figure 14: 1H-N"MR. spectrum ofmethylenecyclopropane (1) ................................ 91 Figure 15: 13C-NMR spectrum ofmethylenecyclopropane {1) ............................... 91 Figure 16: IR spectrum of 1-(2-methylenecyclopropyl)cyclohexan-1-ol (39) ........ 92 Figure 17: 1H-NMR spectrum of 1-(2-methylenecyclopropyl)cyclohexan-1-ol (39) ......................................................................................... 93 Figure 18: 13C-NMR spectrum of1-(2-methylenecyclopropyl)hexan-1-ol (39) ......................................................................................... 93 Figure 19: IR spectrum of 1-(2-hydroxymethylcyclopropan-2-ol)cyclohexan-1-ol (SO) ..•.....•.•......•............•..•.............•........................•.•..•.. 94 Figure 20: 1H-NMR spectrum of 1-(2-hydroxymethylcyclopropan-2-ol)cyclohexan-1-ol (SO) ..•..••••............••.•.•...•................•................................ 95 Figure 21: 13C-N"MR. spectrum of 1-(2-hydroxymethylcyclopropan-2-ol)cyclohexan-1-ol (SO) ..•..••...•..........•....•...•..........•.•...•........•...•................. .. 95 Figure 22: 1H-COSY spectrum of1-(2-hydroxymethylcyclopropan-2-ol)cyclohexan-1-ol (SO) ..•.•••...•...•.........•.....••..•......•••...•.........•..•.............•..... 96 Figure 23: HMQC spectrum of 1-(2-hydroxymethylcyclopropan-2-ol)cyclohexan-1-ol (SO) .••...••.........•..•••.....•..•..•.......•.........•....•.••..........•••...... 96 Figure 24: IR spectrum of 1-hydroxy-4-(1-hydroxycyclohexyl)butan-2-one dimer (Sl) ............................................................................ 97 Figure 25: 1H-NMR spectrum of 1-hydroxy-4-(1-hydroxycyclohexyl)butan-2-one dimer (Sl) ............................................................................ 98 vii
Figure 26: 13C-NMR. spectrum of 1-hydroxy-4-(1-hydroxycyclohexyl)butan-2-one dimer (51) ····················-······················································· 98 Figure 27: IR spectrum of 4-cyclohexylidene-1-hydroxybutan-2-one (52) ............ 99 Figure 28: 1H-NMR. spectrum of 4-cyclohexylidene-1-hydroxybutan-2-one (52) ..............................•...................................................... I 00 Figure 29: 13C-NMR. spectrum of4-cyclohexylidene-1-hydroxybutan-2-one (52) ..............................••..................................................... 100 Figure 30: IR spectrum of 1-(2-methylenecyclopropyl)cyclopentan-1-ol (53) ..... 101 Figure 31: 1H-NMR. spectrum of 1-(2-methylenecyclopropy1)cyclopentan-1-o1 (53) ...............................••..................................................... 102 Figure 32: 13C-NMR. spectrum of 1-(2-methylenecyclopropyl)cyclopentan-1-ol (53) ...............................••..................................................... I 02 Figure 33: IR spectrum of 1-(2-hydroxymethylcyclopropan-2-ol)cyc1opentan-1-ol (54) ·······················-····················································· I 03 Figure 34: 1H-NMR spectrum of 1-(2-hydroxymethy1cyclopropan-2-o1)cyc1opentan.-I-ol (54) ·······················-····················································· 104 Figure 35: 13C-NMR. spectrum of 1-(2-hydroxymethylcyclopropan-2-ol)cyc1opentan-1-ol (54) ·······················-····················································· 104 Figure 36: IR spectrum of 1-hydroxy-4-(1-hydroxycyclopentyl)butan-2-one dimer (55) ..................... ..................................................... I 05 Figure 37: 1H-NMR spectrum of 1-hydroxy-4-(I-hydroxycyclopentyi)butan-2-one dimer (55) ·····················-···················································· Figure 38: 13C-NMR. spectrum of 1-hydroxy-4-(I-hydroxycyclopentyl)butan-2-one dimer (55) ·····················-···················································· Figure 39: IR spectrum of 4-cyclopenty1idene-l-hydroxybutan-2-one (56) ......... Figure 40: 1H-NMR spectrum of 4-cyclopentylidene-1-hydroxybutan-2-one (56) ...............................•..................................................... Figure 41: 13C-NMR spectrwn of 4-cyc1opentylidene-1-hydroxybutan-2-one (56) ...............................••.................................................... Figure 42: IR spectrum of 1-(2-methylenecyclopropy1)hexan-I-one (41) ............ Figure 43: 1H-NMR spectrum of 1-(2-methy1enecyc1opropy1)hexan-I-one (41) ·······························-···················································· Figure 44: 13C-NMR spectrum of 1-(2-methy1enecyclopropyl)hexan-I-one (41) ·······························-···················································· Figure 45: IR spectrum of 4-(1-hexyloxo)tetrahydrofuran-2-one (44) ................. Figure 46: 1H-NMR spectrum of 4-(1-hexyloxo)tetrahydrofuran-2-one (44) ................................•.................................................... Figure 4 7: 13C-NMR spectrum of 4-(1-hexyloxo)tetrahydrofuran-2-one (44) ................................••................................................... Figure 48: IR spectrum of 1-hydroxy-2,5-decandione (47) .................................. Figure 49: 1H-NMR spectrum of 1-hydroxy-2,5-decandione {47) ........................
viii
106 I 06 I07 I 08 I 08 I09 I10 110 1I1 1I2 112 113 114
Figme 50: 13C-NMR spectrum of 1-hydroxy-2,5-decandione (47) ....................... 114 Figme 51: IR spectrum of 1-(2-methylenecyclopropyl)-1-cyclohexylmethanone ( 42) .............................................................................. 115 Figme 52: 1H-NMR spectrum of 1-(2-methylenecyclopropyl)-1-cyclohexylmethanone (42) .............................................................................. 116 Figure 53: 13C-NMR spectrum of 1-(2-methylenecyclopropyl)-1-cyclohexylmethanone (42) .. ......................................................................... ... 116 Figure 54: IR spectrum of 4-(1-cyclohexylmethoxo)tetrahydrofuran-2-one ( 4S) ...................................•................................................. 117 Figure 55: 1H-NMR spectrum of 4-(1-cyclohexylmethoxo)tetrahydrofuran-2-one ( 4S) ..................................................................................... 118 Figme 56: 13C-NMR spectrum of 4-(1-cyclohexylmethoxo)tetrahydrofuran-2-one ( 4S) ..................................................................................... 118 Figure 57: IR spectrum of 1-hydroxy-5-cyclohexyl-2,5-pentandione (49) ........... 119 Figure 58: 1H-NMR spectrum of 1-hydroxy-5-cyclohexyl-2,5-pentandione (49) ............................................................................................... 120 Figure 59: 13C-NMR spectrum of 1-hydroxy-5-cyclohexyl-2,5-pentandione (49) ............................................................................................... 120 Figme 60: IR spectrum of 1-(2-methylenecyclopropyl)-3-phenylpropan-1-one (43) ................................................................................... 121 Figure 61: 1H-NMR spectrum of 1-(2-methylenecyclopropyl)-3-phenylpropan-1-one (43) ................................................................................... 122 Figure 62: 13C-NMR spectrum of 1-(2-methylenecyclopropyl)-3-phenylpropan-1-one (43) ................................................................................... 122 Figure 63: IR spectrum of 4-(3-phenylpropanoxo)tetrahydrofuran-2-one ( 4S) .... 123 Figure 64: 1 H-~fR spectrum of 4-(3-phenylpropanoxo)tetrahydrofuran-2-one ( 45) ..................................................................................... 124 Figure 65: 13C-NMR spectrum of 4-(3-phenylpropanoxo)tetrahydrofuran-2-one ( 45) ..................................................................................... 124 Figure 66: IR spectrum of 1-hydroxy-7-phenyl-2,5-heptandione (48) .................. 125 Figure 67: 1H-NMR spectrum of 1-hydroxy-7-phenyl-2,5-heptandione (48) ....... 126 Figure 68: 13C-NMR spectrum of 1-hydroxy-7-phenyl-2,5-heptandione (48) ...... 126 Figure 69: IR spectrum of 8,8-dimethoxyoctanal (66) .......................................... 127 Figure 70: 1H-NMR spectrum of8,8-dimethoxyoctanal (66) ............................... 128 Figure 71 : 13C-NMR spectrum of 8,8-dimethoxyoctanal (66) .............................. 128 Figure 72: IR spectrum of9,9-dimethoxynonen (67) ............................................ 129 Figure 73: 1H-NMR spectrum of9,9-dimethoxynonen (67) ................................. 130 Figure 74: 13C-NMR spectrum of9,9-dimethoxynonen (67) ................................ 130 Figure 75: IR spectrum of 8-nonenal (68) ............................................................. 131 Figure 76: 1H-NMR spectrum of 8-nonenal (68) .................................................. 132 Figure 77: 13C-NMR spectrum of8-nonenal (68) ................................................. 132 Figure 78: IR spectrum of 1-(2-methylenecyclopropyl)-8-nonen-1-ol (64) .......... 133 ix
Figure 79: 1H-NMR spectrum of 1-(2-methylenecyclopropyl)8-nonen-1-ol (64) ................................................................................... 134 Figure 80: 13C-NMR spectrum of I -(2-methylenecyclopropyl)8-nonen-1-ol (64) ................................................................................... 134 Figure 8I: IR spectrum of 1-(2-methylenecyclopropyl)-8-nonen-I-one (65) ....... 135 Figure 82: 1H-NMR spectrum of 1-(2-methylenecyclopropyl)8-nonen-I -one (65) ................................................................................. 136 Figure 83: 13C-NMR spectrum of 1-(2-methylenecyclopropyl)8-nonen-1-one (65) .... ...................................... ..................................... .. 13 6 Figure 84: IR spectrum of2-methyl-5-(7-octenyl)furan (69) ................................ 137 Figure 85: 1H-NMR spectrum of2-methyl-5-(7-octenyl)furan (69) ..................... 138 Figure 86: 13C-NMR spectrum of2-methyl-5-(7-octeny1)furan (69) .................... 138 Figure 87: IR spectrum of2-methy1-5-pentylfuran (76) ....................................... 139 Figure 88: 1H-NMR spectrum of2-methyl-5-pentylfuran (76) ............................. 140 Figure 89: 13C-NMR spectrum of2-methyl-5-pentylfuran (76) ............................ 140 Figure 90: IR spectrum of 1-(2-methylenecyclopropyl)-1-phenylmethan.-1-one (74) .................................................................................. 141 Figure 91: 1H-NMR spectrum of 1-(2-methylenecyclopropyl)-1-phenylmethan.-1-one (74) .................................................................................. 142 Figure 92: 13C-NMR spectrum of 1-(2-methylenecyclopropyl)-1-phenylmethan.-1-one (74) .................................................................................. 142 Figure 93: IR spectrum of2-methyl-5-phenylfuran (79) ....................................... 143 Figure 94: 'H-NMR spectrum of2-methyl-5-phenylfuran (79) ............................ 144 Figure 95: 13C-NMR spectrum of2-methyl-5-phenylfuran (79) ........................... 144 Figure 96: IR spectrum of 1-(2-methylenecyclopropyl)-3-methylbutan-1-one (72) ..................................................................................... 145 Figure 97: 1H-NMR spectrum of 1-(2-methylenecyclopropyl)-3-methylbutan-1-one (72) .... .. ..... ...... ....... .............. ... ... ......... .................. .. ....... .. ... 146 Figure 98: 13C-NMR spectrum of 1-(2-methylenecyclopropyl)-3-methylbutan-1-one (72) ..................................................................................... 146 Figure 99: IR spectrum of2-methyl-5-(2-methylpropyl)furan (77) ...................... 147 Figure 100: 1H-NMR spectrum of2-methyl-5-(2-methylpropyl)furan (77) ......... 148 Figure 101: 13C-NMR spectrum of 2-methyl-5-(2-methylpropyl)furan (77) ......... 148 Figure 102: IR spectrum of 1-(2-methylenecyclopropyl)-2-ethylhexan.-1-one (73) ...... .... .. ... ......... .... .... ....... .... .. ......... ... .... ..... ..... ...... ....... 149 Figure 103: 'H-NMR spectrum of 1-(2-methylenecyclopropyl)-2-ethylhexan.-1-one (73) .................................................................................... 150 Figure 104: 13C-NMR spectrum of 1-(2-methylenecyclopropyl)-2-ethylhexan.-1-one (73) .................................................................................... 150 Figure 105: IR spectrum of2-methyl-5-(1-ethylpentyl)furan (78) ........................ 151 Figure 106: 1H-NMR spectrum of2-methyl-5-(1-ethylpentyl)furan (78) ............. 152 Figure 107: 13C-NMR spectrum of2-methyl-5-(1-ethylpentyl)furan (78) ............ 152 X
Figure 108: IR spectrum of 1-(2-methylenecyclopropyl)octan-1-one (75) ........... Figure 109: 1H-NMR spectrum of 1-(2-methylenecyclopropyl)octan.-1-one (75) ..................................................................................... Figure 110: 13C-NMR. spectrum of 1-(2-methylenecyclopropyl)octan.-1-one (75) ..................................................................................... Figure 111: IR spectrum of2-methyl-5-heptylfuran (80) ..................................... Figure 112: 1H-NMR. spectrum of2-methyl-5-heptylfuran (80) ........................... Figure 113: 13C-NMR spectrum of2-methyl-5-heptylfuran (80) ..........................
xi
153 154 154 155 156 156
1
Introduction
I. Historical Cycloaddition reactions of methylenecyclopropane (MCP) and MCP-derivatives are well established in the literature. 1•7 Transition metals, usually Ni(O) or Pd(O), catalyze [3+2] cycloaddition reactions ofMCP with various alkenes to form methylenecyclopentanes. Two different types of products are possible due to the different MCP ring opening intermediates (Scheme 1). Cleavage of the C 1-C2 bond results in proximal products, whereas cleavage of the C2-C3 bond results in distal products. Which bond is cleaved depends, in part, on which catalyst is present. Pd(O)
Scheme 1
! 1
+
X
Pd(O) or
+
Ni(O)
I./)( 2,3 cleavage
proximal
distal
A
catalysts tend to promote formation of only distal products. 5 Conversely, Ni(O) catalysts can form both proximal and distal products. 5 It is possible in some instances
2
to control product formation in the Ni(O) reactions. The use of either triphenylphosphine or triarylphosphite modified Ni(O) catalysts produces mainly distal products (equations 3 and 4), whereas phosphorus-free Ni(O) catalysts produce mainly proximal products (equations I and 2).
Ni(C00)2
1
(COD
=cyclooctadienyl)
46%
Ni(COD}2
1
+
9
1 78%
1
+
Ni(COD}2 PPh3
g
Me~
)l
~
+
c~
···~c~
MeIv'e
+
2
Pd
CO:tMe
3
C~t
20 mol% catalyst
~)
CO>
EtOzC 4
5 Cata~st
PdCI2/Ph3P
cat.: Ph~P
Yield
1:2
98%
1:0.5
74%
eq. 77
DiBAI-H Ni(COD)2 I Ph3P
Cyclopropanones can also undergo cycloaddition reactions. Cyclopropanones are known to undergo [2+2], [3+2], and [3+4] cycloadditions to form 4, 5, and 7 membered rings, respectively (Scheme 2).s- 16 [3+2] and [3+4] cycloaddition reactions of cyclopropanone (6) are believed to proceed through an oxyallyl cation (7) (Scheme 3). Based upon reactions of6 with various nucleophiles and electrophiles, it is
s Scheme2
~ ]
0
"=
!
[3+2]
~
FOR, 0
Q o
R2
YR.
evident that an equilibrium exists between the cyclic form of 6 and the open form of 7. 10 This equilibrium appears to significantly lie in favor of 6 but can be influenced
Scheme 3
6
7
by either the addition of substituents to 6 or by varying the nucleophile, electrophile, or solvent polarity. 10
6
There are numerous literature methods for forming cyclopropanones. One of these methods, often used due to mild reaction conditions, takes advantage of the
Scheme4
Y\ X
X=Br,l
0 F~COg
X
Cl
~r
10 Zn-Cu Cu I Nal or Zn-Ag 0
~00---
~ 8
9
:rC 14
0
~
;/ RO-/-ROH Favorskii Reaction
11
yLx12 H
X=CI, Br,l
R-HC=C=O
13
equilibrium between a cyclopropanone hemiketal (9) and 8.9 Another often used method, albeit not for cycloadditions, is that of the Favorskii reaction in which an enolizable a.-hydrogen of an a.-haloketone (12) is removed by a base, usually an alkoxide, to form 8. 10 A method, useful in certain instances, involves the photoelimination of carbon monoxide from a cyclobutadione (14) to form 8. 8 Another method with limited utility is the addition of diazomethane to a ketene (13) to form 8.9 More recently, a method that produces 8 from dehalogenation of an
7
a,a'-dihaloketone (10) with various metal reagents was developed}3 Some of the reductive metal reagents used are: couplings of zinc and copper (Zn-Cu) or zinc and silver (Zn-Ag), an iron complex (Fe2C09), or sodium iodide with copper metal (Nal/ Cu). 15 A rather novel method employs the fluoride-induced desilylation of a chlorosilylalleneoxide (11) to form 8. 14 As mentioned earlier, cyclopropanones are known to undergo [2+2], [3+2],
and [3+4] cycloadditions to form 4-, 5-, and 7-membered rings, respectively. Both
0
~+
H:5C, C=C=O
HJ(( 16 Et20/-?8°C
CH:i
c~
17
eq.8
19 90%
eq.9
HaC c~
15 oc~
15
H:sCO>= H:sCO 18 CH2CI2 I -78°C
OCH:i
HaC c~
dimethyl.ketene (16) and 1,1-dimethoxyethylene (18) undergo [2+2] cycloaddition reactions with 2,2-dimethylcyclopropanone (15) to form y-lactone (17) and orthoformate (19) (equations 8 and 9, respectively). 11 Various a-substituted styrenes (21-24) undergo [3+2] cycloaddition reactions with 2,4-dibromopentan-3-one (20) to
form substituted cyclopentanones (25-28) in good yield (60-95%) (equation 10). 18 A
8
0
0
~c~+)= Br
Cti:!
F~Og
benzene
Br 20
R
eq.10
R
=H (21), CH3 (22), Ph (23),
60-95%
cyclopropyl (24)
R = H (25), CH3 (26), Ph (27), cyciopropyl (28)
substituted furan (29) undergoes a [3+4] cycloaddition reaction with 15 to form the bicyclic adducts 30 and 31 in good yield (>70%) (equation 11 ). 12 The synthetic utility of cyclopropanone cycloadditions can be seen in the syntheses ofthe natural products a.-cuparenone (34) 19 (equation 12) and
15
eq. 11
29 30
~
31
0
~
0
7.5: 1
karahanaenone (37) 20 (equation 13). A regiospecific [3+2] cycloaddition reaction combined with simple starting materials (dihalobutanone (32) and substituted styrene (33)) is a convenient route to a moderately complex natural product (34).
9
~Br
+
17 hr. 55°C
Br
eq.12
34 18%
benzene
32 33
f-t:3C
0
0
~ +y Cl Me
35
Me
Me
AgCI04 THF/Et~ 0
Me
+
eq. 13
o c. 1 tr
36
Me
37
38
71:29 65%
While not regiospecific, the (3+4] cycloaddition reaction of chlorosilyl enol ether (35) and isoprene (36) to form 37 and 38 (71 : 29) is also a convenient route to a somewhat complex natural product.
II. Proposed Research At the outset of this research, cycloadditions were being reported for cyclopropanone synthons 1&-20 as well as for cyclopropanones themselves 11 • 12• It was our goal to develop new methodology to generate substituted cyclopropanones in situ that could either undergo inter or intramolecular cycloadditions depending upon the substituents.
10
The reaction ofMCP with tert-butyllithium followed by subsequent treatment with aldehydes and ketones to give secondary and tertiary methylenecyclopropylcarbinols (Scheme 5), is a very general method for the preparation of substituted MCPs.21 "25 These substituted MCPs could then be utilized
SchemeS
!
aldehydes
t-Buli
or
THF
ketones
directly in a cycloaddition reaction or could be modified and then allowed to react in a cycloaddition reaction (Scheme 6).
Scheme 6
JU:R, R2
Y8rious methods
uR, R2
~
0
\\0
COOH
~ Rt;
»~ Re
Rs
various methods
){~a
0
R7 Re
Re
R4
The purpose of this research was to investigate the preparation of these cyclopropanones and their subsequent [3+2] or (3+4] cycloaddition reactions.
11
m. Results and Discussion 1. Choice of Model Compounds The model compounds that were chosen for this study are: 1-(2-methylenecyclopropyl)cyclohexan-1-ol (39), 1-(2-methylenecyclopropyl)hexan-1-ol (40), and 1-(2-methylenecyclopropyl)- hexan-1-one (41) (Scheme 7). These compounds were chosen because the starting materials were readily available and procedures for their preparation were previously determined in our group. 21 In addition, these compounds provide for the determination of the importance of neighboring functionality (tertiary alcohol, secondary alcohol, or ketone).
Scheme 7
39
40
41
2. Synthesis and Metallation of Methylenecyclopropane (MCP) A modification of the Organic Synthesis procedure for the preparation of MCP24 was followed. This preparation requires the addition of 1 equivalent of methallyl chloride to a mixture of 1.5 equivalents of sodium tert-butoxide and 3.0 equivalents of sodium amide in anhydrous tetrahydrofuran (THF). The addition is done very slowly over 8 hours. The MCP produced is bubbled through a sulfuric acid
12
wash to remove liberated ammonia, followed by passage through a silica gel drying tube. The dry MCP is then collected in a cold trap at -78°C, protected from the atmosphere by a calcium chloride drying tube. This procedure was modified by replacing the silica gel drying tube with a calcium chloride drying tube. This helped to minimize back pressure which would lead to loss of the gaseous MCP at some apparatus joints. Another modification was to protect the cold trap from the atmosphere with an oil bubbler rather than a calcium chloride drying tube. This allowed for closer monitoring ofMCP collection. That is, one could visually follow the amount of gas passing through the sulfuric acid wash and compare that to the volume passing through the bubbler. While this procedure generates a modest yield (- 40% based on methallyl chloride) ofMCP, it can easily be carried out on a large scale (250-gram quantities). A modification of the procedure determined by Graber 1 for the metallation of MCP was followed. Graber's method called for the addition of tert-butyllithium to MCP at -78°C in the presence of N,.N,N',N'-tetramethylethylenediamine (TMEDA). The reaction was maintained at -78°C for 24 hr. and then allowed to warm to 0°C for 2 hr. At that point, metallation was complete based upon Graber's method of analysis. This method was modified, in part, because of the publication of a study of the half-lives oforganolithium reagents in ethereal solvents.25 The halflife of tert-butyllithium in THFffMEDA was reported as 338 minutes at -400C or 45 minutes at -20°C. The study also reported a 42-minute half-life for tert-butyllithium in only THF at -20°C. Based on these data, it was assumed that TMEDA would have
13
little effect on the reaction at warmer temperatures and that the half-life would continue to decrease drastically at warmer temperatures. The resultant procedure required the addition oftitra.ted53 tert-butyllithium to MCP in TIIF at -78°C with a small amount(- 2%) ofbipyridyl as an indicator. This red solution was immediately allowed to warm to 0°C over 45 minutes. The carbonyl compounds would subsequently be added until the indicator color faded to pale yellow and the reaction would be allowed to warm to room temperature over 20 minutes. After workup, crude yields of 68-94% were obtained for various carbonyl compounds. These yields were slightly better than those reported by Graber and resulted from a reaction time of less than 1 hour as compared to 26 hours previously.
3. Preparation of Methylenecyclopropyl Carbinols The methylenecyclopropyl carbinols were prepared from lithiomethylenecyclopropane and various ketones and aldehydes. The reactions were quenched with aqueous 5% hydrochloric acid solution. The crude yellow carbinols could be purified by flash column chromatography (hexanes I ethyl acetate). Purified yields ranged from 56-86%. Because of the use of the bipyridyl indicator, many of the resultant carbinols had only minor impurities and, in some instances, could be used without further purification.
Several of the carbinols that were prepared from aldehydes had NMR spectra that were rather complex due to the formation of diastereomers and, consequently, diastereotopic centers. As a result, it was prudent to oxidize the crude carbinols to methylenecyclopropyl ketones which produced greatly simplified NMR. spectra.
14
4. Preparation of Methylenecyclopropyl Ketones
Various methods were explored for the oxidation of the secondary methylenecyclopropyl carbinols to ketones. We explored the use of: pyridinium chlorocbromate (PCC)26, catalytic tetrapropylammonium perruthenate (TPAP)27·29 with N-methylmorpholine- N-oxide (NMO) as co-oxidant, and the heterogeneous Brown oxidation30 - ether with aqueous chromic acid. Yields with all three methods were comparable (67-87% with PCC, 34-79% with TPAP, and 67-74% by Brown's procedure), however, the reaction times were much shorter for the Brown oxidation. This combined with the ease of workup of the Brown method, made this the procedure of choice. A modification to the Brown method was made in which saturated sodium bisulfite was added 15 minutes prior to any extraction. This aided in the removal of any chromium salts from the ethereal phase. With this modification, the crude ketones were quite pure and required little further purification. S. Attempted Oxidative Cleavage of Methylenecyclopropanes to Cyclopropanones A. Ozonolysis
Various procedures are available for the ozonolysis of alkenes40-43 and most of them differ primarily in the reductive workup. Initially, the procedure of van den Heuvel43 , which had no reductive workup, was followed due to the high degree of similarity between their alkenes (alkylidenecyclopropanes) and our methylenecyclopropanes. Ozone was bubbled through the MCPs in dry methanol (or CH2Ch) at -78°C. After removal of excess ozone and warming to room temperature, the solvent
IS
was evaporated. TLC, GC/MS, 1H-NMR., and 13C-NMR data were obtained for the crude mixtures. 1. Methylenecyclopropyl Carbinols
Secondary carbinol 40 and tertiary carbinol39 were subjected to ozonolysis and both reactions resulted in complex mixtures of products (at least eight compounds for 39 and at least ten compounds for 40). The ozonolysis reactions were repeated with the addition of a reductive workup and extraction with aqueous 10% sodium thiosulfate solution. The reactions, as before, resulted in complex mixtures of products that were not identified. Due to the complexity of the product mixtures, this methodology for the preparation of cyclopropanones from methylenecyclopropyl carbinols was abandoned.
2. Methylenecyclopropyl Ketones The methylenecyclopropyl ketones (41- 43) were subjected to ozonolysis without a reductive workup. While cyclopropanones were not formed, it is interesting to note that the novel :furanones 44-46 were formed, as well as the hydroxydiones 47 and 48 that had also been obtained in the dihydroxylation rearrangement sequence (see Section 5, Part C). This may imply that both the dihydroxylation reaction and ozonolysis share a common intermediate. It is also interesting to note that the furanones were formed whether or not a reductive workup was utilized. In addition, the ozonolysis also leads to furanones in both protic (MeOH) and aprotic (CH2Ch)
16
solvents. The mechanistic implications of these facts remain unclear. The results of the ozonolysis reactions are summarized in Table 1.
Table 1 Startfng Compound
Product
Product
8%
viQOI'OUSiy shaken for 5 minutes.
The structure of 51 was not easily established, even with advanced 2D-NMR techniques (IH-COSY, HMQC, and HMBC). There were no stretching frequencies for either a hydroxyl group or a carbonyl in the infrared spectrum. The 1H-NMR (Figure 5) had only two distinct signals, an apparent one hydrogen doublet at 3.38 ppm and an apparent one hydrogen doublet at 4.15 ppm. These signals are consistent
'
'
I
I
I
v I
,,,'1
-
-
/' ~ ij~ l~J~ ~.
I-
II
...
I
u
\
..a
2.S
:to
t.S
Figure 5: 1H-NMR spectrum of 51.
l t.D
D.5
.....
27
with a hydrogen on a carbon bearing at least one oxygen atom. There were eight 13
C-NMR signals, two of which were a quaternary carbon at 85.9 ppm and a
quaternary carbon at 102.6 ppm (as determined by DEPT). These signals were consistent with carbons attached to one and two oxygen atoms, respectively. From
•• t .•
I
.~ :
D!
• c:
DDII
DDII
Figure 6: 1H-COSY spectrum of 51.
the 1H-COSY, coupling between the two doublets at 3.38 ppm (J =11Hz) and 4.15 ppm (J = 11 Hz) was evident. It was also evident that the remaining signals from 1.1 ppm to 1.8 ppm coupled with each other. This was expected as the starting material contained a cyclohexyl ring that would produce a similar pattern in this region. The
28
30
I
I
0
0 70
...
...
Figure 7: HMQC spectrum of 51.
&4~·· 0
'
60
·'' eo
I •
Cl 1:1
Figure 8: HMBC spectrum of 51.
100
29
HMQC (Figure 7) showed that the apparent one hydrogen doublets at 3.38 ppm and 4.15 ppm were actually on the same carbon (66.5 ppm) and so were a result of a diastereotopic methylene. In the HMBC (Figure 8) the diastereotopic methylene (3.38 ppm and 4.15 ppm) correlated to the quaternary ketal carbon at 102.6 ppm. This carbon and the other quaternary carbon at 85.9 ppm correlated with most of the remaining signals. At this point, only very small fragments of the structure had been deduced from the spectral data. Ultimately, the overall structure was determined by X-Ray crystallography (Figure 9) and shown to be a dimer.
•
=Oxygen
Figure 9: ORTEP diagram of dimer 51.
30
With the dimeric structure in hand, the spectral data could be correlated without question. From the absolute structure it was now evident that the doublet signals at 3.38 ppm and 4.15 ppm were indeed the diastereotopic methylenes attached to the quaternary ketal carbons (102.6 ppm) that comprised the central dioxane ring of the dimer. The great dissimilarity in the proton shifts of these signals arises from the fact that the system is rigid, resulting in one hydrogen being cis to the adjacent oxygen atom and the other hydrogen being trans to the adjacent oxygen atom. The trans hydrogen is inductively deshielded to a greater extent than the cis hydrogen, and thus results in a lower field chemical shift of 4.15 ppm. This premise is supported by the assignment of a similar methylene in the system, 2,3,4-tri-0-benzoyl-PL -lyxopyranoside.66
Structural assignment of 52 was again much simpler. This compound had also been previously characterized in our group by Nachtigall23 from a related protic acid rearrangement of the epoxide of 1-(2-methylenecyclopropyl)cyclohexan-1-ol. The different products arise mechanistically from the differing sites where protonation is possible. That is, if cyclopropyl bond protonation occurs, dimer 51 will result (Scheme II), whereas, if hydroxyl group protonation occurs, dehydration product 52 will result (Scheme 12). As described earlier, the formation of the products could be controlled by varying the experimental conditions. This control may be a result of the heterogeneous reaction conditions. This theory may be supported by the fact that only one isomer of the dimer is formed.
31
Scheme 11
-H20
Scheme 12
-~ 6H L~ \
OH
w
H..,_e 0
OH~
0 OH
OH
Diol 54 was subjected to the same dihydroxylation procedure. As before, dimer (55) and dehydration product (56) were formed in good overall yield (80%) (equation 16). The structures of 55 and 56 were assigned by analogy to the spectral data of 51 and 52, respectively.
32
OH OH
45% HBF.c
eq.16
CHzC~
54 ~Vigorously shaken
for 5 minutes.
We attempted to explore the chemical properties of the unique dimer with limited success. Dim.er Sl was subjected to aqueous acid hydrolysis conditions (2: I
THFIH20, cat. H 2S04 ) for three days with no effect. When this reaction was heated at 40°C for three hours, decomposition occurred.
33
Experimental Procedure
All research was completed using the research facilities at The University of
Kansas, Lawrence, Kansas. Nuclear Magnetic Resonance (NMR) spectra were obtained at 400MHz on a Broker A vance DRX 400 spectrometer using tetramethylsilane (TMS) as an internal standard. Deuterochloroform, deuteroacetone, or deuteromethanol were utilized as solvents. Infrared spectra were determined using a Nicolet Impact 410 FT-IR using Teflon film as a support. Melting points were determined in capillary tubes using a Thomas Hoover Uni-melt and are uncorrected. Ozonolysis was done using a Welsbach Ozonator. 3-Chloro-2-methylpropene, sodium metal, cyclohexanone, n-hexanal, cyclohexanecarboxaldehyde, N-methylmorpholine-N-oxide (NMO), t-butyllithium, pyridinium chlorochromate (PCC), osmium tetraoxide, tetrahydro:furan (THF), and deuterated chloroform, acetone, and methanol were purchased from Aldrich Chemical Company - Milwaukee, Wisconsin. Thin layer chromatography was accomplished using silica gel plates with fluorescent indicator purchased from AnalTech, Inc.-Newark, Delaware. Silica Gel 60 (70-270 mesh) for flash column chromatography was purchased from Brinkmann Instruments, Inc.-- Westbury, New Jersey. Tetrahydrofuran was dried and distilled from sodium I benzophenone. Any other chemicals not mentioned specifically were commercially available or prepared as described in the experimental section. All chemicals were used without further purification unless otherwise indicated.
34
Preparation of methylenecyclopropane {1) A modified Organic Synthesis procedure was used. 24 To a 1-L resin flask equipped with a Dry-Ice™ condenser, a Vibromixer, and a gas inlet tube, was added approximately 450 mL of distilled anhydrous ammonia. Ferric nitrate nonahydrate, 575 mg (1.42 mmol), was added with vigorous mixing. Sodium metal, 52.7 g (2.28 moles), cut into small pieces(- 1.5 em diameter), was added to the rust-orange solution with continued mixing. As the sodium reacted, the solution became purple. After complete addition of the sodium metal, the Dry-Ice™ condenser was replaced by a water-cooled condenser and 400 mL of anhydrous THF was slowly added. The excess ammonia was allowed to evaporate overnight. To the sodium amide was added dropwise a solution of56.7 g (0.76 moles) of tert-butyl alcohol in 50 mL of anhydrous THF via a pressure equalizing addition
funnel. Upon completion of the addition, the reaction mixture was heated to 65°C in an oil bath for 1 h. 3-Chloro-2-methylpropene, 45.6 g (0.50 moles), in 100 m.L of anhydrous THF was added dropwise via a pressure equalizing addition funnel. The reaction apparatus was fitted with a 5.0 N H2S04 gas washing bottle, a CaCh drying tube, and two Dry-Ice™ cooled gas traps, all connected in series. Addition was
complete after- 5 h. The reaction was maintained at 65°C for 18 h. The crude liquid from the cold traps was distilled from bulb to bulb and yielded 10.69 g (39%) of methylenecyclopropane24 (1); 1H-NMR (CDCh) o 1.1 (triplet, 4H, J =2Hz, cyclopropyl methylenes), 5.4 (quintet, 2H, J =2Hz, terminal olefinic methylene);
35
13
C-NMRo 2.8 (triplet, C-2 cyclopropyl methylenes), 103.1 (triplet, C-1 ~terminal
olefinic methylene), 131.1 (singlet, C-1 cyclopropyl olefin).
Preparation of 2-litbiomethylenecyclopropane
Anhydrous tetrahydrofuran (25 mL) and -3 mg ofbipyridyl indicator were placed in a 100-mL round-bottomed flask equipped with a rubber septum, a gas inlet needle, and a magnetic stirrer, under a nitrogen atmosphere. The flask was cooled to -78°C ina Dry-IceTM/acetone bath. Methylenecyclopropane, 1.5 g (27.7 mmol), was distilled into the cold flask. 1.2M tert-Butyllithium in hexanes (23.0 mL, 27.6 mmol), was added by syringe over 15 minutes. The solution immediately became red-orange. After the addition, the Dry-IceTM bath was replaced with a water ice bath and the reaction was allowed to stir at 0°C for 45 min.
General Procedure For The Addition of 2-lithiomethylenecyclopropane to Ketones Addition of 2-lithiomethylenecyclopropane to cyclohexanone
To a 50.9 mmol solution (at 0°C) of2-lithiomethylenecyclopropane in 55 mL of anh. THF was added by syringe a solution of 5.0 g (50.9 mmol) of cyclohexanone in 20 mL of anh. THF over 20 min. Upon completion of the addition, the red-orange color changed to bright yellow. The reaction mixture was allowed to warm to room temperature over 30 minutes. To this was added 25 mL of an aqueous 5% HCl
36
solution and the reaction mixture was allowed to stir vigorously for 5 min. The mixture was transferred to a separatory funnel, 30 mL of diethyl ether was added, and the organic layer was removed. The aqueous layer was extracted three times with 30 mL portions of diethyl ether. The organic layers were combined and were extracted two times with 35 mL portions of saturated NaHC03 solution. The organic solution was dried over anhydrous Na2S04, and the solvent was removed. The resulting crude yellow liquid was distilled using a Kugelrohr apparatus to afford 5.69 g (73%) of 1-(2-methylenecyclopropyl)cyclohexan-1-ol23 (39) as a clear colorless oil.; b.p. 45-50°C at 0.007 Torr; IR (Teflon film) 3450, 3060, 2990-2855, 1449, 898 em·•; 1H-NMR (CDCh) o 1.12-1.38 (multiplet, 4H), 1.42-1.88 (multiplet, 10H), 5.44 (doublet, 2H, J =12Hz);
13
C-NMR o 4.8 (triplet), 21.9 and 22.1 (triplets),
25.7 (triplet, C-4), 26.3 (doublet), 36.5 and 37.6 (triplets), 69.6 (singlet), 104.0 (triplet), 133.2 (singlet).
Addition of 2-lithiomethylenecyclopropane to cyclopentanone
Using the above procedure, 2.3 g (27.7 mmol) of cyclopentanone gave a crude yellow liquid which was distilled using a Kugelrohr apparatus to afford 2.6 g (68%) of 1-(2-methylenecyclopropyl)cyclopentan-1-ol23 (53) as a clear colorless oil.; b.p. 40-45°C at 0.007 Torr; IR (Teflon film) 3388, 3060, 2960-2870, 1439, 898 em·•; H-NMR (CDCh) o 1.12 (multiplet, 1H), 1.19 (multiplet, 1H), 1.41-1.95 (multiplet,
1
37
10H), 5.43 (doublet, 2H, J = 8 Hz); 13C-NMR o6.6 (triplet), 24.1 and 24.2 (triplets), 25.1 (doublet), 38.4 and 39.4 (triplets), 81.7 (singlet), 104.3 (triplet), 133.9 (singlet).
General Procedure For Preparation of Methylenecyclopropyl Ketones Preparation of 1-(2-methylenecyclopropyl)hexan-1-one (40) To a 64.7 mmol solution (at 0°C) of2-lithiomethylenecyclopropane in 60 mL of anh. THF was added by syringe a solution of 6.5 g (64. 7 mmol) of n-hexanal in 25 mL of anh. THF over 20 min. Upon completion of the addition, the red-orange color
changed to bright yellow. The reaction mixture was allowed to warm to room temperature over 30 minutes. To this was added 30 mL of an aqueous 5% HCl solution and the reaction mixture was allowed to stir vigorously for 5 min. The mixture was transferred to a separatory funnel, 35 mL of diethyl ether was added, and the organic layer was removed. The aqueous layer was extracted three times with 35 mL portions of diethyl ether. The organic layers were combined and were extracted
two times with 40 mL portions of saturated NaHC03 solution. The organic solution was dried over anhydrous Na2S04, and the solvent was removed to provide 6.8 g of 1-(2-methylenecyclopropyl)hexan-1-ol (40) as a crude yellow liquid. The oxidation was carried out using Brown's method30• A portion of the crude alcohol (0.53g, 3.4 mmol) was dissolved in 7 mL of diethyl ether (Et20). To this was added 4.7 mL (3.1 mmol, -3 eq) of 0.66M H2Cr04 solution with vigorous stirring.
38
The addition was done slowly to maintain a temperature of 25°C. The reaction mixture became dark brown as the reaction proceeded. The reaction mixture was
allowed to stir for 1.5 h. Et20 (15 m.L) was added and the solution was transferred to a separatory funnel. The layers were separated and the aqueous layer was extracted 3 times with 15 mL portions ofEt20. The Et20 layers were combined and washed 2 times with 25 mL portions of sat. NaHC03 solution and once with 25 mL of sat. NaCl solution. The
Et20 was dried over anh. Na2S04 and the solvent was removed by rotary evaporation to afford a dark yellow oil which was purified by flash column chromatography (20: 1 hexanes/EtOAc) to afford 0.46 g (87%) of 1-(2-methylenecyclopropyl)hexan-1-one23
(41) as a clear colorless oil.; IR (Teflon film) 3083, 2960,2933, 2860, 1697, 898 cm-1; H-NMR (CDCh) o0.93 (triplet, 3H, J = 7 Hz), 1.34 (multiplet, 4H}, 1.61 (multiplet,
1
3H}, L82 (multiplet, 1H), 2.44 (triplet, 2H, J = 7.5 Hz), 2.50 (multiplet, 1H), 5.44 (doublet, 2H, J =23Hz); 13C-NMR o 12.4 (triplet}, 14.3 (quartet), 22.8 (triplet), 24.1 (triplet), 26.9 (doublet), 3L7 (triplet), 41.4 (triplet), 104.2 (triplet), 132.3 (singlet), 208.3 (singlet).
Preparation of 1-(2-methylenecyclopropyl)-1-cyclohexylmethanone ( 42) Using the above procedure, 3.1 g (28.0 mmol) of cyclohexanecarboxaldehyde gave 3.3 g of 1-(2-methylenecyclopropyl)-1-cyclohexylmethanol as a crude yellow liquid.
39
A portion of the crude alcohol (0.55 g, 3.3 mmol) was oxidized using the above procedure to provide a crude dark yellow liquid which was purified by flash column chromatography (20:1 hexanes/EtOAc) to afford 0.43 g (79%) of 1-(2-methylenecyclopropyl)-1-cyclohexylmethanone23 (42) as a clear colorless oil.; IR (Teflon film) 3083, 2937, 2855, 1699, 1452, 1099, 898 cm-1; 1H-NMR (CDCh) o 1.11-1.52 (multiplet, 4H), 1.63-2.05 (multiplet, 8H), 2.43 (multiplet, 1H), 2.66 (multiplet, 1H), 5.45 (doublet, 2H, J =32Hz); 13C-NMR o 12.1 (triplet), 25.3 (doublet), 25.9, 26.1, and 26.3 (triplets), 28.8 and 28.9 (triplets), 50.6 (doublet), 103.8 (triplet), 132.9 (singlet), 210.7 (singlet).
Preparation of 1-(2-methylenecyclopropyl)-3-phenylpropan-1-one (43) Using the above procedure, 2.86 g (21.3 mmol) of dihydrocinammaldehyde gave 3.1 g of 1-(2-methylenecyclopropyl)-2-phenylpropanol as a crude yellow liquid. A portion of the crude alcohol (2.5 g, 13.5 mmol) was oxidized using the above procedure to provide a crude dark yellow liquid which was distilled using a Kugelrohr apparatus to afford 1.7 g (67%) of 1-(2-methylenecyclopropyl)-3-phenylpropan-1-one (43) as a clear colorless oil.; b.p. 68-70°C at 0.007 Torr; IR (Teflon film) 3085,3060,3030,2930, 1697, 1604, 1499, 1102, 898 cm-1; 1H-NMR (CDCh) o 1.63 (triplet of triplets, 1H, J = 10 and 2Hz), 1.82 (multiplet, 1H), 2.50 (multiplet, 1H), 2.74 (multiplet, 2H), 2.91 (multiplet, 2H), 5.45 (doublet, 2H, J =40Hz), 7.11-7.35 (multiplet, 5H); 13C-NMR o 12.7 (triplet), 27.2 (doublet), 30.4 (triplet), 42.7
40
(triplet), 104.7 (triplet), 126.5, 128.8, 128.9 (doublets), 132.0 (singlet), 141.4 (singlet), 207.3 (singlet). Mass Spectrum mlz (relative intensity) M+1 187 (100), 105 (28), 91 (85), 65 (16); High Res. Mass Spectrum calcd. for C 13H1sO: 187.1123, Obsvd. 187.1124.
General Procedure For The Hydroxylation of Tertiary Alcohols Hydroxylation of 1-(2-methylenecyclopropyl)cyclohexan-1-ol (39) To a solution of 1.7 g (11.5 mmol) of 1-(2-methylenecyclopropyl)cyclohexan-1-ol (39) in 50 mL of acetone was added 6.9 mL (0.34 mmol, 3 mol%) of an aqueous 0.05 M solution of Os04. The reaction mixture immediately became black. The reaction mixture was allowed to stir for 10 min. and 1.3 g (11.5 mmol, 1 eq.) of N-methylmorpholine-N-oxide (NMO) was added in portions, over several minutes. The reaction mixture was allowed to stir for 1 h. A second equivalent of NMO was added and the reaction mixture was allowed to stir for an additional 1.5 h. The reaction mixture was transferred to a separatory funnel and 10 mL each of saturated sodium thiosulfate and water were added. This solution was extracted three times with 25 mL portions of 1:1 CH2Ch/EtOAc. The organic layers were combined and dried over anhydrous sodium sulfate. The solvent was removed by rotary evaporation to afford 1.8 g of a dark brown semi-solid which was recrystallized from methylene chloride resulting in 1.1 g (52%) of 1-(2-hydroxymethylcyclopropan2-ol)cyclohexan-1-ol (SO) as an off-white solid.; m.p. 142-143°C; IR (Teflon film)
41
3255,3015,2935,2860, 1040 cm· 1; 1H-NMR (CD30D) o 0.75 (doublet of doublets, IH, J =5Hz and 10Hz), 0.80 (doublet of doublets, IlL J =5Hz and 8Hz), 1.24 (doublet of doublets, 1H, J =8Hz and 10Hz), 1.30-1.73 (multiplet, 10H), 3.83 (doublet, 1H, J =12Hz), 4.02 (doublet, IH, J =12Hz); 13C-NMR o 13.0 (triplet), 22.1 and 22.3 (triplets), 25.8 (triplet), 35.5 (doublet), (2) 38.6 (triplets), 58.7 (singlet), 64.6 (triplet), 69.2 (singlet); Mass Spectrum: mlz (relative intensity) [M+-!8] 168 (2), 99 (30), 81 (100), 67 (57), 55 (58), 41 (43); High Res. Mass Spectrum calcd. for C10Ht903: 187.1334, Obsvd. 187.1357.
Hydroxylation of l-(2-methylenecyclopropyl)cyclopentan-1-ol (53) Using the above procedure, 0.5 g (3.6 mmol) of 1-(2-methylenecyclopropyl)cyclopentan-1-ol (53) gave a crude dark brown semi-solid which was recrystallized from methylene chloride to afford 293 mg (47%) of 1-(2-hyd.roxymethylcyclopropan-2-ol)cyclopentan-1-ol (54) as an off-white solid.; m.p. 128-130°C.; IR (Teflon film) 3275, 3005, 2965, 2870, 1040 cm-1; 1H-NMR (CD30D)
o0.83 (multiplet, 2H), 1.36 (doublet of doublets, 1H, J =8Hz and 10Hz), 1.53-1.87 (multiplet, 8H), 3.75 (doublet, 1H, J =12Hz), 4.01 (doublet, IH, J =12Hz); 13C-NMR o 14.9 (triplet), 23.3 and 23.6 (triplets), 34.5 (doublet), 39.4 and 40.8 (triplets), 58.9 (singlet), 65.1 (triplet), 80.1 (singlet); Mass Spectrum: m/z(relative intensity) [M+] 172 (12), 155 (100), 95 (24), 67 (20), 55 (20); High Res. Mass Spectrum calcd. for C9Ht60 3 : 172.1099, Obsvd. 172.1116.
42
General Procedure For The Hydroxylation of Ketones
Hydroxylation of 1-(2-methylenecyclopropyl)hexan-1-one (41)
To a solution of I 50 mg (0.98 mmol) of I-(2-methylenecyclopropyl)hexan-I-one (41) in4 mL of acetone was added 0.6 mL (0.03 mmol, 3 mol%) of an aqueous 0.05 M solution of Os04. The reaction mixture immediately became black. The reaction mixture was allowed to stir for I 0 min. and N-methylmorpholineN-oxide (NMO), (1I5 mg, 0.98 mmol, I eq.), was added in portions, over several minutes. The reaction mixture was allowed to stir for I h. A second equivalent of NMO was added and the reaction mixture was allowed to stir for an additional I.5 h. The reaction mixture was transferred to a separatory funnel and I 0 mL each of saturated sodium thiosulfate and aqueous 5% HCl solution were added. This solution was extracted three times with 5 mL portions of I: I CH2Ch/EtOAc. The organic layers were combined and dried over anh. sodium sulfate. The solvent was removed by rotary evaporation and the dark brown oil was purified by flash column chromatography (2:I hexanes/acetone) to afford 84 mg (46%) of I-hydroxy-2,5decandione23 (47) as a white solid.; m.p. 56-58°C; IR. (Teflon film) 3230, 2955, 2930, 2865, I705 cm·1; 1H-NMR (CDCh) o 0.90 (triplet, 3H, J =8Hz), 1.30 (multiplet, 4H), 1.60 (quintet, 2H, J =8Hz), 2.45 (triplet, 2IL J =8Hz), 2.63 (triplet, 2H, J = 8 Hz), 2.8I (triplet, 2H, J =8Hz), 3.04 (broad singlet, IH), 4.34 (singlet, 2H); 13
C-NMR o I4.3 (quartet), 22.8 (triplet), 23.9 (triplet), 31.7 (triplet), 32.I (triplet),
36.4 (triplet), 43.0 (triplet), 68.6 (triplet}, 209.I (singlet), 209.6 (singlet); Mass
43
Spectrum: mlz (relative intensity) [M+] 186 (1), 155 (100), 99 (32), 71 (36), 55 (39), 43 (75), 31 (63).
Hydroxylation of 1-(2-methylenecyclopropyl)-1-cyclohexylmethanone (42)
Using the above procedure, 0.5 g (3.0 mmol) of 1-(2-methylenecyclopropyl)-1-cyclohexylmethanone (42) gave a crude dark brown oil which was purified by flash column chromatography (3:1 hexanes/EtOAc) to afford 312 mg (52%) of 1-hydroxy-5-cyclohexyl-2,5-pentandione (49) as a clear colorless oil.; b.p. 78-80°C at 0.1 Torr; IR. (Teflon film) 3465, 2935, 2860, 1705 cm·1; 1H-NMR (CDCb) n R
52
these, ruthenium based catalysts have the greatest functional group tolerance, and thus the widest application. The most widely used ruthenium based catalyst is Grubbs' catalyst 61.56 The use of 61, however, is limited mainly to reactions forming disubstituted alkenes and those starting materials not containing protic functional groups in close proximity(< 3 atoms) to the site of metathesis (see Scheme 15, entry 1). A more reactive ruthenium based catalyst is the modified Grubbs' catalyst 62,
1 \N-Mes
Mes-N
PCy3 Clr.,,
I
'·R
c,..,...,~Ph PCy3
61
Cb.Y
··~
Cl_,...l
PCy3
Mes
Ph
=(
3o>-~ )
62
which can be synthesized from 61 in one step (after ligand synthesis) (Scheme 16).60 This catalyst does not have the limitations of its predecessor 61, and can catalyze reactions forming tri- and tetrasubstituted alkenes in> 90% yield (see Scheme 15, entries 2 and 4). Protic functional groups do not hinder metathesis even in close proximity to the active site (see Scheme 15, entry 3). Due to unexpected experimental results from the metathesis reactions, some additional background is needed.
53
Scheme 1560 Yield of Product Using: Product
Substrate E
E
E
E
E
Me
quant.
quant.
20%
quant.
N.P.
quant.
N.P.
90%
E
Q
~
2.
62
E
6
E
~
1.
61
Me
OH
OH
0
~
3.
E
E
4. Me
Me Me
E = -C0 2 Et; quant. =quantitative conversion; N.P. =no product observed by 1 H-NMR
Scheme 16
JyH
Mes-N~
~
Mes-N
NaB~.
1:1 THF/
N-Mes
MeOH
0
1\
1. KOtBu
2. 61, 80°C
1200C
Mes-~N-Mes
cr...... Rl
CI~I~Ph PCy3
63
1 \N-Mes
Mes-N
62
\
H
I
H
54
There are innumerable biologically active compounds that contain cyclopentane systems. As a result, much emphasis has been placed on developing new methodologies for generating these cyclopentane systems. One such method is the vinylcyclopropane-cyclopentene (VCP-CP) rearrangemen~ and a related rearrangement is the vinylmethylenecyclopropane-methylenecyclopentene (VMCP-MCP) rearrangement'7 (Scheme 17). As can be discerned from the reaction
Scheme 17
6)1
!J
3600C, 10 Torr
96%44
aooc 90%47
[6] 0 [=6] 0
conditions of the two reactions, the VMCP-MCP rearrangement is much more facile. The facility of the rearrangement is believed to arise from the diradical intermediate of the reaction. That is, the VCP-CP rearrangement proceeds through a primary and allylic diradical, whereas the VMCP-MCP rearrangement proceeds through a diallylic diradical. This stability results in a much lower activation energy of27 kcallmole48 for the VMCP-MCP reaction as compared to 49.7 kcallmole44 for the VCP-CP reaction. Examples of the utility of the VMCP-MCP rearrangement can be found in equations 17 and 18.
55
&~
Ph
135-140°C hexane 65-80%
Ph
[o:5=]- ~ toluene, reflux 4h
eq. 1850
90%
A variation of the VMCP-MCP rearrangement exists in which the terminal vinylic carbon is replaced with a heteroatom such as oxygen51 or nitrogen23 • Consequently, methylenecyclopropyl ketones and methylenecyclopropyl imines can undergo rearrangement to give substituted furans (equation 19) and substituted pyrroles (equation 20), respectively. The substituents in the furans and pyrroles are at
CHJ
flash vacuum pyrolysis
360°C, 1.5 To,.S
or 2 eq. TMS-GI, 2 eq. pyridine
DMF, 135°C, 23 hb
42
3.5 eq.
PhCH~~
0.75 eq.1iCf4 90% toluene, reflux, 6.5h
42
57
eq. 2023
S6
the 2 and 4 positions. It is possible to generate unprotected substituted pyrroles by cleaving theN-benzyl group via a lithium/ammonia reduction (equation 21)52•
OMe
OMe 1) U I NH3, THF 2) NH4CI
I
CHi'hOH
Furan formation with trimethylsilyl chloride and pyridine probably proceeds through a Lewis acid catalyzed rearrangement (Scheme 18)23 • Furan formation via flash vacuum pyrolysis is believed to follow a diradical mechanism51 • Evidence in
Scheme 18
o
II
R~
~iCI
pyridine
RYO'Il
~CHa
support of this mechanism was established in our lab by Dufi67 via an NMR experiment. In this experiment, the exomethylene dihydrofuran 59 (Scheme 19) was detected by 1H-NMR spectroscopy, and after 15 minutes at a probe temperature of 34.6°C the tautomerization to the furan was complete.
57
Scheme 19 H flash vacuum
n-8
pyrolysis
Et
58
59
o5.73 15 minutes 34.6°C
n-Bu H o6.96 Et
60
The mechanism for the formation of the substituted pyrroles (Scheme 20) is analogous to the mechanism for the formation of the substituted furans in Scheme 18.
Scheme20
---PhC~-~N== ~ ~ -PhC~ liCb PhC~/~
~
liC~
58
Generation of the benzyl imine most certainly occurs before the Lewis acid catalyzed rearrangement proceeds.
n.
Proposed Research Highly straine562 ~
l~
,ca·· /' ~tj~ ~RtStrong
~=~ n f153
=
~
~
. BU
R,=H, ~=~ n 3, 4 64
=
59
Reaction ofMCP with tert-butyllithium followed by subsequent treatment with aldehydes to give secondary methylenecyclopropyl carbinols (Scheme 22), is a very general method for the preparation of substituted MCPs.21 •25 If the aldehydes Scheme22
!
II
t-BuU
~u
THF
UH
aldehydes
R
employed are chosen so that an alkene is present, these substituted MCPs could then be utilized either directly or after oxidation in RCM reactions to form bridged methylenecyclopropanes (Scheme 23).
Scheme 23
,,'l_,
~00
l[O]
RCM
4(CH,1 H
00
H
II ~(CH,1 ~0
RCM
~(CH,1 0
60
The purpose ofthis research was to investigate the preparation of these methylenecyclopropyl carbinols and methylenecyclopropyl ketones and their subsequent ring-closing metathesis reactions. ffi. Results and Discussion
1. Choice of Model Compounds
The model compounds that were chosen for this study were 1-(2-methylenecyclopropyl)-8-nonen-1-ol (64), and 1-(2-methylenecyclopropyl)-8-nonen-1-one (65) (Scheme 24). These compounds were chosen because they would generate bridged methylenecyclopropanes ([11.1.0]) that should be stable and isolable.
Scheme 24
64
65
2. Synthesis and Metallation of Methylenecyclopropane (MCP)
See Chapter I, Results and Discussion, Section 2. 3. Preparation of Methylenecyclopropyl Carbinols In order to generate the model compounds 64 and 65, the proper starting
aldehyde 68 was synthesized by the route shown in Scheme 25. The first step involved the ozonolysis of cyclooctene following the procedure developed by SchreiberD8. This procedure, which produces terminally differentiated products,
61
requires the addition ofp-toluenesulfonic acid to the reaction mixture to catalyze acetal formation, followed by stirring for 90 min. while warming to 25°C. When this procedure was used, the major product(- 65%) was the bis-acetal of 1,8-octandial. The analogous problem was not reported by Hart and coworkers69 in the Schreiber
Scheme25
0
0
1. 03 2. TsOH
9
PI'\3PCH:le Br H
(CH:l0)2CH 3. NaHC03 4.M~S
66
97%
n-BlL.i 0
5moi%TsOH H
(CH:lO)~H
67
32%
10:5:1 THFIH 2 0/i-PrOH
68
79%
ozonolysis of cycloheptene. By monitoring the ozonolysis reaction mixture by GC/MS, it was found that bis-acetal formation occurred as the reaction mixture warmed to 25°C. Although the reason for this unwanted bis-acetal formation was unclear, the formation needed to be avoided. By modifying the temperature and length of reaction time, bis-acetal formation could be kept to a minimum ( < 5%). The resultant procedure required the addition ofp-TsOH while warming to ooc over a period of 25 min. The resultant functionally differentiated acetal-aldehyde 66 was converted to the acetal-olefin 67 in a modest yield (32%) by a Wittig reaction. The reaction conditions for this conversion were varied in an attempt to improve the yield. Both
62
butyllithium and potassium hexamethyldisilazide (KHMDS) were utilized as the base during ylide formation. The yields from these reactions were 32% and 30%, respectively. Ylide formation was attempted at both ooc and 25°C with no effect on yield. Differing reaction times for ylide formation were also employed at both temperatures. These ranged from 30 min. to 3 h. The relative ratios ofylide to aldehyde were also varied. Ratios of 1: 1 ylide to aldehyde and 2:1 ylide to aldehyde were employed with BuLi as the base. The yields from these reactions were 32% and 23%, respectively. Various reaction times for the Wittig reaction {25°C) were also employed with no effect on yield. The hydrolysis of 67 was attempted under a variety of conditions, including 10 mol% TsOH in THF, 10% HCl in THF70, 10% oxalic acid on silica geF 1 in CH2Ch, 15% H2S04 on silica geF 1 in CH2Ch, and 5 mol% TsOH in 10:5:1
THF/H20/i-Pr0If72, all carried out at reflux. The first four methods produced no detectable hydrolysis product by either TLC or GC/MS. The last method accomplished the desired transformation to afford 8-nonenal (68) in a moderate yield (79%). With aldehyde 68 in hand, compound 64 was generated from the addition of 2-lithiomethylenecyclopropane in a moderate yield (75%). 4. Preparation of Methylenecyclopropyl Ketones From Methylenecyclopropyl Carbinols
See Chapter I, Results and Discussion, Section 4.
63
5. Attempted RCM of Methylenecyclopropyl Carbinols and Ketones to Bridged Methylenecyclopropanes With Grubbs' Catalyst
The standard procedure developed by Grubbs55 for RCM was followed. Dry methylene chloride, 0.01 Min alkene, was degassed with nitrogen for 15 min. Grubbs' catalyst 61 (5 mol%) was added under nitrogen and the reaction mixture was heated at 45°C for up to 8 hours. No product from 64 or 65 could be detected by TLC orGC/MS. At this time, Grubbs published a papeto describing a more reactive catalyst and we decided to see if it would catalyze the RCM of methylenecyclopropanes. 6. Preparation ofModified Grubbs' Catalyst
Several attempts were made to synthesize modified Grubbs' catalyst following Grubbs' procedure60 • This procedure required the addition of a solution of potassium tert-butoxide in anhydrous tetrahydrofuran to tetrafluoroborate salt 63 (see Scheme 16). Because the reactions were not proceeding as expected, it was thought that the solid potassium tert-butoxide we used might have partially decomposed. A 1.0 M solution of KOtBu in THF was purchased. Several attempts were made to synthesize the catalyst following the same procedure utilizing this fresh solution. In one instance, a small amount of product was crystallized from methanol (the solvent evaporated very slowly overnight). All attempts to reproduce this crystallization failed. In the interim, a procedure to synthesize a related catalyst was published by Grubbs.61 The relative concentrations of reagents and reaction times were drastically different from the original procedure. It was decided that the two procedures would
64
be combined. The original procedure required a 0.034 M (1.4 eq.) solution of tetrafluoroborate salt 63 (previously synthesized61 •65) and KOtBu to be stirred for 1 h. In the second procedure, these compounds were 0.13 M (1.6 eq.) and were stirred for
30 min. Both procedures called for the addition of this solution to - 0.02 M Grubbs' catalyst (61) in benzene (or toluene) followed by heating to 80°C. The time of heating in the original procedure was 30 min. and was shortened to 15 min. in the second procedure. The resultant combined procedure utilized a 0.10 M (1.6 eq.) solution of the tetrafluoroborate salt 63 in anh. TIIF and KOtBu with a 30 min reaction time. This solution was transferred to a 0.02 M solution of Grubbs' catalyst in benzene followed by heating at 80°C for 15 min. The volatiles were removed under vacuum and -7 mL of dry methanol per mmole was added to the crude tar-like product with vigorous swirling. The methanol was then removed under vacuum. This procedure was repeated (usually three times) until crystaUization appeared complete. Recrystallization of the crude product from dry methanol afforded modified Grubbs' catalyst 62 in moderate yield (48%). The catalyst was characterized by 1H-NMR and was analogous to data published by Grubbs60 • 7. Attempted RCM of Methylenecyclopropyl Carbinols and Ketones to Bridged Methylenecyclopropanes With Modified Grubbs' Catalyst Initially, the standard procedure developed by Grubbs55 for RCM was followed. Dry methylene chloride, 0.01 M in alkene, was degassed with nitrogen for 15 min. Modified Grubbs' catalyst 62 (5 mol%) was added under nitrogen and the reaction mixture was heated at 45°C for up to 8 hours. No products from either 64 or
65
65 could be detected by TLC or GC/MS, so the reaction times were extended to 24 h. There was still no indication of any reaction occurring, so an additional equivalent of
62 was added. Heating was continued for an additional 24 h. 1LC indicated some product formation from 65. The 1H-NMR spectrum of the crude product showed the signal at 5.4 ppm for the olefinic methylene of the methylenecyclopropane was reduced to about half of its integration relative to the other olefinic signals (4.95 ppm and 5.82 ppm). Integration of the terminal alkene of the alkyl chain, however, remained the same. The crude reaction mixture was again subjected to metathesis with 62. After an additional 24 h., the proton signal for the methylenecyclopropane alkene was absent. GC/MS analysis of the reaction mixture confirmed that the starting material (65) had indeed been consumed. It also indicated that the mixture largely consisted of only one new compound. This compound was purified and was eventually identified as 2-methyl-5-(7-octenyl)furan (69). Not only was this product unexpected, it was formed in good yield as well (71 %).
69
Structural assignment of 69 was accomplished primarily with advanced 2D-NMR techniques (H-COSY, HMQC, and HMBC). The first indication that metathesis had not occurred was obtained from the mass spectral data. The mass
spectrum of 69 exhibited a parent ion at mlz 192, whereas the metathesis product should have had a parent ion at mlz 164. Another indication of an unsuccessful metathesis arose from the infrared spectrum. The carbonyl stretching frequency from the starting material (170 1 cm·1) was no longer present. This was confirmed by the absence of the carbonyl signal from the starting material (208.4 ppm) in the 13C-NMR spectrum of69. There were also new signals in the 1H-NMR. spectrum (figure 10). These were a 3H singlet at 2.25 ppm and a 3H multiplet at 5.82 ppm. The 3H singlet at 2.25 ppm indicated the presence of an isolated methyl group attached to a double
I
!
I
i
( . fI
~~'-------"'{..____ _ _1JJJI~_j._-...___......I__Jj Figure 10: 1H-NMR spectrum of69.
or aromatic ring and the 3H multiplet at 5.82 ppm indicated the presence of new olefinic protons. In addition, the proton signal from the methylene alpha to the
67
carbonyl in the starting material (2.4 ppm) had shifted to 2.55 ppm (triplet, J =8Hz) in 69. This picture was somewhat clarified by the 1H-COSY spectrum (Figure 11 ). That is, the 3H multiplet at 5.82 ppm coupled to both of the doublets at 4.9 ppm (from the terminal olefinic methylene). Since it was impossible for three hydrogens to
, _...,.·
,.
_
I ---
•
...+··---•
I-··
+.
-
.__.
I
-·
I ...& oc•
Figure 11: 1H-COSY spectrum of69.
couple to a terminal olefinic methylene, the multiplet at 5.82 ppm had to be at least two overlapping signals. The 1H-COSY also indicated, albeit not very clearly, coupling between the 5.82 ppm multiplet and a 2H multiplet at 2.03 ppm as would be expected from the tennina1 olefinic methine. The HMQC spectrum (Figure 12) confinned the overlapping proton signals at 5.82 ppm by exhibiting a correlation
68
0
. ...
20
fT
.. •
100
•
120
• aa~L
A'
~·
1
Figure 12: HMQC spectrum of69.
0
I
.
•
.' •
I
..
•e•·o·....,_~
•
0
....
•
.
100
'
0
,. 0
0
go-
6
s
'
Cl
•
Figure 13: HMBC spectrum of69.
ISO
...
69
between that signal and carbon signals at 105.5 ppm, 106.1 ppm, and 139.5 ppm. The HMBC spectrum (Figure 13) was the most informative. It showed a correlation between the methyl proton signal at 2.25 ppm and a quaternary carbon signal at 150.4 ppm. This quaternary carbon signal correlated to the proton signal at 5.82 ppm. The proton signal at 5.82 ppm correlated to another quaternary carbon signal at 155.1 ppm. This quaternary carbon signal correlated to the methylene proton signal at 2.55 ppm. Based on these data, and the fact that the shifts of the quaternary carbons were within the region for quaternary a.-furan carbons, the presence of a 2,5-disubstituted furan system was secure and the structure of 69 was confirmed.
Based on the structure of 69, it was unclear why two equivalents of catalyst were required for reaction to occur. The reaction was repeated several times with only one equivalent of 62 and was heated for 48 h. The results were inconsistent. That is, one reaction would lead to the expected product (69), whereas only starting material would be recovered from another reaction. The starting material and catalyst were from the same batches as had been previously used and the solvent was from the same source, as well. This led us to believe that the degassing process was inadequate and that 62 was probably very sensitive to oxygen. The reaction was repeated as before except that the solvent was vacuum filtered twice through a fritted funneL Subsequent reactions consistently produced the furan product. Once the reaction was reproducible, we turned to the question of the necessity ofthe terminal alkene of the alkyl chain. Based on the structure of the furan, it would
70
appear that it is unneeded. Indeed, this proved to be the case. 1-(2-Methylenecyclopropyl)hexan-1-one (41) was subjected to metathesis conditions and the expected furan {76) was formed in moderate yield (56%). We next attempted to optimize the reaction and test its generality. Since no intramolecular metathesis reaction was involved, cross-metathesis was not a conce~ and it was thought that the dilute conditions (0.01 Min alkene) were unnecessary. The reaction was carried out with 5 mol% of62 and a 0.1 M solution of 41. This resulted in a complex mixture of at least eight compounds, including the expected product 76. The reaction was then carried out with 10 mol% 62 and a 0.0 I M solution of 41. The reaction time was reduced to approximately 16 h. The fact that only 5 or 10 mol% of 62 was necessary for reaction to occur indicated that the process was catalytic (Scheme 26).
Scheme 26
+
Mes-,n.. . .
~Mes
c~ ... T
c,;~Ph PCy,j
62
71
Methylenecyclopropyl ketones 72-75 were subjected to the same reaction conditions as above and afforded :furans 77-80 in moderate to good yield (57-71%). The results are summarized in Table 3.
Table 3 Startins Compound
o
II
~~J(L 64
Product
Yield
~'0~~ ~ h
71%
69 56%
41
~ 72
76
~
57%
n 70%
73
78
0 67%
74
CH,(CH,lsu 75
69%
80
72
Although we have no definitive evidence, a possible mechanism for this novel rearrangement is shown in Scheme 27. Several NMR experiments were performed in an attempt to provide evidence for the existence of the cyclopropylidene intermediate.
Scheme27
1\
L)lR .~0::CI_....., ~Ph II
o
PCYJ
1\ Mes-yN-Mes CH~I2. 45°C Cl
''···~
Cl~
-PCy3 metathesis
62
1\
bJ(l_
1\
Mes-~N-Mes
Cl•····k~
CI_.....V 0
~c~
Ph
R
Mes-~N--Mes
Clo ••..
+
Cl_.,...·-~
R
R
71
1\
Mes-~N-Mes
~ c~ ~ CL ••..
1\
II o +A)l
R
metathesis
R
--:~. Cl""'==
w-~ H
~
0 0.88
~
0 14.8
H 0 2.41 0 1.62
0 24.4 0 29.6 0 41.5
H
0 1.85 & 2.56
154
r
,
'
.r
I
-
.J
I
t--l'
Jl.
'
~~
.
ILU~.
-
2
'
1
Figure 109: H-NMR spectrum of 1-(2-methyleoecyclopropyl)octan-1-one (75)
'
II III I I I
I
i
I
,I
I
I L
. I
""'
...
UD
..
Figure 110: 13C-NMR spectrum of 1-(2-methylenecyclopropyl)octan-1-one (75)
-
155
4000
3500
3000
2000 2500 Waveoombers
1500
1000
Figure 111: Infrared spectrum of2-methyl-5-heptylfuran (80)
0 1.30-1.36 8 2.58 ,---.....__-......, H H H H H H
0 0.91 c~
8 1.30-1.36
013.9 c~
8 105.5 0 106.1
500
156
[,
I--
r-
.
.
L1
.
'
A_J~
-
~
.
2
1
Figure 112: H-NMR spectrum of2-methyl-5-heptylfuran (80)
,,I
I
II
II
i/I· ·I I!
I
I I
!
I
I
II
1
J
I
...
...
'
""
...
.,
.
..
!!. .,
Cl
211
Figure 113: 13C-NMR spectrum of 2-methyl-5-heptylfuran (80)
-
157
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