Massachusetts Institute of Technology Organic Chemistry 5.511
September, 2007 Prepared by Julia Robinson
Problem Set 1 Functional Group Transformations Study Guide SOLUTIONS
Part I - Functional Group Interconversions and Protective Group Chemistry
(1) Tosylate formation
O O R-OH R Cl S Me O+ S Me ROTs O H O N
Mesylate formation O O O R Cl S CH 2 H2C S HO R H2C S O MsOR O H O NEt3 O H
(2) In order to convert a primary alcohol to the corresponding nitrile, the alcohol must first be converted to a sulfonate or halide. DMSO is superior to ethanol as a solvent for the conversion of primary sulfonates or halides to the corresponding nitriles because DMSO solvates cations selectively, resulting in more nucleophilic anions.
O O (3) (COCl)2 When the pre-formed carboxylate salt is used, these conditions are essentially neutral. R OH R Cl
O O O O O O Cl Cl + Cl Cl- R O Cl O R Cl O O R O O
- CO2 + CO + Cl O Cy Cy Cy (4) N C N N C N- N C NH R OR' HO Cy Cy O Cy O + R R R' O H O+ O O R OH HN NH Cy Cy
(5) OH CH2N2 OCH3 Alcohols do not work for this reaction because their pKa is too high... they do not protonate the diazomethane as phenol does in order to make the activated methylating N species. N+ Ph H - + C H3C N N PhOCH3 + N2 H O H Ph O-
(6) OCH3 OH BBr3 CH2Cl2
Br-
CH3 CH3 CH3 Ph O Ph O+ Br Ph O+ BBr 3 - B Br BBr2 Br
3 H O + 2 Ph O H3CBr Ph OH + B(OH)3 + 2 HBr
BBr2
O Cl CN (7) Cl CN O R O R OH H2O OMe O Cl CN O OH Cl CN Cl CN Cl CN R OH H2O O Cl CN Cl CN + OH OH H O OH R O Ar H Ar R O Ar R O Ar Provide conditions for effecting each of the following transformations. In this and related problems in 5.511, you will be expected to indicate reagents, an appropriate solvent, and in cases where it is critical to the success of the reaction, the number of equivalents of reagents and the reaction temperature.
OH MsCl OMs Et3N CH2Cl2 0-25 oC
OH DEAD Br Ph3P LiBr THF
OH DEAD OMs Ph3P MsOH THF
1. Ph P, DEAD, THF OH 3 OH p-nitrobenzoic acid
2. NaOH, THF
OH DEAD NHTs Ph3P H2NTs THF
DEAD OH 1) Na NHCO2t-Bu Ph3P liq. NH3 H NBoc 2 2) Boc2O THF (EtCO)2O OH O Me3SiOTf (cat.) THF O
CN HCl CO2H
H2O
1. NH2OH, PhH CHO 2. POCl3, Et3N CN
1. NaN3, DMSO 2. Ph P Ph 3 Ph Br NH2
1. NaCN Ph DMSO Ph NH2 Br 2. LiAlH4
O
Ph CO2H DCC Ph NH + N 2 DMAP H THF
CO H NHCO t-Bu 2 (PhO)2P(O)N3 2 tBuOH, Δ
Provide conditions for the formation of each of the following protected functional groups and for their deprotection. Me Si 3 O Cl OH iPr2NEt, CH2Cl2 O O SiMe3 TBAF, THF SEM ether NaH, NaI, ClCH2SCH3, OH DME O SMe
HgCl2, H2O, CH3CN MTM ether
TBSCl, DMAP, Et N, CH Cl OH 3 2 2 OSit-BuMe2
TBAF, THF TBDMS ether
OH . O BF3 Et2O, CH2Cl2 OMe acetonide OH pTsOH, MeOH O
MeO OMe , CH2Cl2 BF .Et O, 4A sieves OH 3 2 O O CH3 PPTS, tBuOH, Δ MOM ether
OH BOMCl, iPr2NEt, CH2Cl2 O OCH2Ph
BOM ether H2, Pd/C, EtOAc
OMe
OMe OH Cl , iPr2NEt, CH2Cl2 O
DDQ, CH2Cl2 PMB ether
. HS OH, BF3 OEt2, CH2Cl2 O hemithioketal O HgCl2, H2O, CH3CN S
NH2 Boc2O, NaOH, H2O NHCO2t-Bu
TFA, CH2Cl2 Part II - Oxidation Methods
(1) Swern oxidation of a secondary alcohol O O NEt Cl 3 Cl Cl Me Cl Me O S+ S+ H O + + - S O Me Me O Me + O Me Me S OH R R' Me - Cl R R'
Me Me + + S O O H S -CH O C O 2 + S H2 R R' Me Me NEt H R' 3 R R' R
(2) Transition state for epoxidation of an alkene with a peracid O R
H O O
(3) Reaction of enol ethers with peracids such a m-CPBA (the “Rubottom Oxidation”) produce α-silyloxy ketones (usually hydrolyzed in situ or during workup to the α-hydroxy derivatives). However, oxidation with DMDO often allows isolation of the epoxides. Provide a mechanism for each transformation and explain the different outcome of the reactions. Rubottom oxidation: OTMS TMSO R' R R' OTMS SiMe3 O R R' O OH O R' R O O+ O R OTMS H O H R R' Ar O H O Ar O R' Oxidation with DMDO: TMSO R' R OH TMSO R' O R + Peracid epoxidation results in the formation of a O carboxylic acid which protonates the epoxide, R O Me Me Me O leading to epoxide-opening and 1,4-silyl migration. Me Epoxidation with DMDO occurs under neutral conditions, so the epoxide does not open. . . (4) Oxone = 2 KHSO5 KHSO4 K2SO4 (5) Ground state oxygen Excited state "singlet" oxygen
O O O O
(6) A photosensitizer is a compound that absorbs light and is promoted to an excited state, then transfers that excitation to triplet oxygen in order to form singlet oxygen and regenerate the ground-state photosensitizer. This is the most common method for generation of singlet oxygen.
(7) Selenium dioxide oxidation of alkenes to allylic alcohols
R ene reaction R R R CH solvolysis O 2 = Se H O Se HO Se O OSeOH O H O [2,3] sigmatropic R rearrangement
OH
(8) Ozonolysis of a simple alkene in dichloromethane
O+ O- O O O O O O O O
O O [4+2] cycloaddition [4+2] cycloreversion [4+2] cycloaddition
PPh3
PPh3 PPh3 O O O O O O
O O O (9) Org. Syn. 1986, 64, 150
O3, MeOH, CH2Cl2; then add TsOH; OMe then add NaHCO ; 3 OMe then add Me2S CHO
O3 MeOH MeO MeO MeO O+ O O O O- OH TsOH OH OH CHO + H-O-Me OMe O O + O H2 H MeO MeO MeO O O O Me MeO OH OH HCO - OH S OH 3 + DMSO Me + OMe O Me + OMe OMe O Me OMe OMe H-O-Me H
CHO
OMe OMe
O3, MeOH, CH2Cl2; CO2Me then add Ac2O, Et3N CHO
O3 MeOH Et N O MeO O O 3 H O+ O O O- OH O O MeO CHO CHO CHO O3, MeOH, CH2Cl2; then add TsOH; then add NaHCO3; then add Ac2O, Et3N CO2Me
OMe OMe see above O3, MeOH, CH2Cl2; for mech. of then add TsOH; these steps then add NaHCO3
Et N O MeO O O 3 H O O OH O O MeO OMe OMe OMe OMe
(10) Migratory aptitude in the Baeyer-Villiger oxidation: tert-alkyl, sec-alkyl > benzyl, phenyl > cyclopropyl > methyl
Migratory aptitude is based on the ability of a group to accomodate partial positive charge. In the transition state of the reaction, one of the alkyl groups develops a partial positive charge. O δ+ δ- R1 O O Ar
R2 OH
(11) Dess Martin reagent IBX
AcO OAc - OAc HO O I I+ O O
O O
(12) H2O2 works for B-V oxidation in this case (even though it doesn't work for cyclohexanone) because the ring strain of the cyclobutanone makes it more reactive. H O H O O
H H Provide detailed conditions for effecting each of the following transformations.
NaOCl2, NaH2PO4 aq. tBuOH CHO CO2H
5 methods:
CH OH CHO 2 1. PCC, CH2Cl2 2. (COCl)2, DMSO, CH2Cl2; Et3N . 3. CrO3 pyr2, CH2Cl2 4. Dess-Martin periodinane*, CH2Cl2 5. TEMPO (cat), NaOCl, CH2Cl2
AcO OAc * OAc OH PCC I O CH2Cl2
O O
cat. PdCl 2 O Ph CuCl2 H2O, O2 Ph DMF
O O KHMDS;
O N OH Ph SO2Ph Part III - Reduction Methods (1) Crabtree's catalyst is especially useful for hydroxyl-directed hydrogenations because the hydroxyl group coordinates very strongly to the cationic iridium center. + - PF6
Ir PCy3 N
(2) O Amines are the products of this reaction LiAlH - R' 4 R' because R2N is a terrible leaving group R N R N compared to HO-, so the iminium is formed rather than the aldehyde, and the iminium is R'' R'' reduced to the amine. - O OH H - H R' R' R' + R' R N R N R N R N R'' R'' R'' R''
(3) In reduction of ketones and aldehydes the reactivity order is Zn(BH4)2 > NaBH4 > NaBH3CN because zinc is a stronger Lewis acid than sodium, and the cyano group of NaBH3CN reduces the nucleophilicity of the hydrides due to its electron-withdrawing effect.
(4) Diborane reduces carboxylic acids to alcohols but reacts very slowly with carboxylic esters because diborane reacts with carboxylic acids to give a triacyloxyborane intermediate via protonolyis of the B-H bonds. In this intermediate the carbonyl exhibits enhanced reactivity towards the reducing agent because the ester oxygen donates some electron 3 RCO2H + BH3 (RCO2)3B + 3H2 density to the boron, decreasing donation to the carbonyl, and thus increasing the electrophilicity of the carbonyl compared to O CO R O CO2R 2 an ester carbonyl. B B R O CO2R R O CO2R
(5) DIBAL reduction of esters to aldehydes without over-reduction to alcohols
iBu O + iBu Al O- O OR OR workup H H
H At low temperatures the hemi-acetal intermediate is stable and does not Al collapse to the aldehyde until workup, preventing over-reduction. (6) Esters react slowly with borane and alane (AlH3) but tertiary amides and lactams are reduced smoothly to amines because borane and alane form a Lewis acid-base complex with the carbonyl of the amide or lactam and then deliver the hydride in an intramolecular fashion. The carbonyl oxygen of tertiary amides and lactams are more Lewis basic than the carbonyl oxygens of esters because nitrogen is more electron-donating than oxygen, so the Lewis acid-base adduct forms more readily with tertiary amides and lactams.
(7) Suggest several reagents that effect selective 1,2-reduction of conjugated enones to produce allylic alcohols and explain why these reagents favor 1,2-reduction while the use of NaBH4 and LiAlH4 often leads to mixtures of 1,2 and 1,4-addition products. NaBH4 + CeCl2 (Luche reduction), DIBAL, and 9-BBN all give exclusive carbonyl reduction because the reactivity of the carbonyl group is enhanced by Lewis acid complexation at oxygen, and these reagents are more Lewis acidic than sodium borohydride and lithium aluminum hydride. (8) The reduction of propargylic alcohols with Red-Al to (E)-allylic alcohols:
H NaH2Al(OR)2 OH H2O - trans addition RO Al O H HO
(9)
OH 1. NaH, CS2, MeI 2. nBu3SnH, AIBN, PhH, reflux
- OH O- O S NaH S C S S H3C I
O SMe O SMe
S S Sn(nBu)3 Sn(nBu)3
H Sn(nBu)3
Sn(nBu)3
O SMe
S Sn(nBu)3 (10) Birch reduction of anisole: explain regiochemical course of reaction
OCH3 OCH3
Li, NH3 EtOH
OCH OCH3 OCH 3 3 OCH3 OCH3 Li EtOH Li EtOH
protonation kinetic control: occurs ortho protonation of pentadienyl to EDG anions occurs at central carbon
Provide conditions for effecting the following transformations.
O Li OSiMe3 liq. NH3, Et2O; TMSCl
O Et3SiH 1) NH2NHTs, EtOH OH . BF3 OEt2 2) NaBH3CN
O NH2 NH4OAc;
NaBH3CN
LiAlH4 THF OH OH OH 1. NaH, CS2, MeI 2. nBu3SNH, AIBN, PhH, reflux