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 to the corresponding , the alcohol must first be converted to a sulfonate or halide. DMSO is superior to as a solvent for the conversion of primary sulfonates or halides to the corresponding 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 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 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 (usually hydrolyzed in situ or during workup to the α-hydroxy derivatives). However, oxidation with DMDO often allows isolation of the . 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 which protonates the , 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 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 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 R N R N compared to HO-, so the iminium is formed rather than the , 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 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 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 because the 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 is enhanced by Lewis acid complexation at oxygen, and these reagents are more Lewis acidic than 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) 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