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Home , Acylation, Aldehyde, Epoxide, Functional group, Ketone, Pyridine

14C synthesis strategies, Chem 315/316 / Beauchamp 1 Reactions

O O : Make O from R Br OH R Br R H R R R H S H haloalkanes aldehydes O H2SO4 1. LiAlH4 & & ketones H2O 1. Mg (LiAlD4) Wolff-Kishner Clemmenson H /Pd H2 /Pd 2 2. workup 2. workup NH NH /ROH/ Zn / HCl 2 2 aromatic sulfonic

y:\files\classes\316\special handouts\316_FG_syn.doc 14C synthesis strategies, Chem 315/316 / Beauchamp 2 O O O O O O O Make R OH ROH R OH R R' from R O R OH R Cl ketones R' H2SO4 (-H2O) RBr RBr R O ROH mCPBA Fischer syn Baeyer-Villigar SN2 SN1 H SO acyl substitution acyl substitution 2 4 rxn O Aldehydes O OH N R R O C Make R R O R Cl R R from R esters chlorides 1o alkenes alkynes 1. HCON(CH ) /POCl R H 1. R AlH 3 2 3 CrO 1. R2AlH 1. R2AlH 2 2. workup 3 1. O , -78oC 1. R BH 3 2 (DIBAH) (DIBAH) (DIBAH) 2. H O , HO Vilsmeier Rxn (PCC) 2. CH3SCH3 2 2 2. workup 2. workup 2. workup

Ketones R O O O OH N R O O O C Make R' R R NR R 2 R' Cl R R' R OH from R R' 3o 2o alcohols R' alkynes nitriles acid chlorides ketals acids R R' CrO3 alkenes deprotect 1. 2 eqs. R'Li H2SO4/H2O 1. R'MgBr 1. R'MgBr 1. R2Cu Li 2. workup pyridine o 1. O , -78 C +2 2. workup 2. workup 2. workup + (PCC) 3 Hg cat. H O /H O (2 ways) (2 ways) (2 ways) 3 2 (2 ways) 2. CH3SCH3 O O O 1o, 2o, 3o amides N C O Make from R' Cl R' O R R R acid chlorides anhydrides nitriles R N o from from (1 amides) NH , 1o, 2o amides o o R = C, H R 3 NH3, 1 , 2 amides HCl / H2O

O Reactions of Acid Chlorides O R' O O O O R N R O O O R" aromatic R' R H R R R O R' 1o,2o,3o amides R' ketones R Cl R O anhydrides esters R S aldehydes ketones H R R AlCl O Cu 3 O N Al H SH R Li R' H R' R Friedel-Crafts R' R DIBAH cuprates R' OH R=CorH

y:\files\classes\316\special handouts\316_FG_syn.doc 14C synthesis strategies, Chem 315/316 / Beauchamp 3 Reactions of Alkenes OH OH Br Br OH OH Br Br Br + HBr / ROOR H3O / H2O 1. Hg(OAc)2/H2O 1. BH3 2. NaBH or (poss. rearrangement) 4 2. H2O2 / HO HBr Br2 Br2 / H2O (no rearrangement) (anit-Markovnikov) 1. BH3 OH 2. Br2 / CH3O (anit-Markovnikov) NaOH OH (mild) O O OH O OH O HO O OH OH CH 2 CH3 C O + OsO or KMnO H / Pd o o H H O / H O 4 4 2 1. O3 , -78 C 1. O , -78 C o OH 2 2 mCPBA syn 3 1. O3 , -78 C or 2. CH3SCH3 2. NaBH4 2. H O , HO 2 2 anti diol H2O / HO

Alkynes H R Br Br R H H R R X O Make R R R alkynes haloalkanes from alkene alkynes R R dihaloalkane 1. NaNR 1. Br 2 O 2 1. NaNR 1. NaNR2 2. NaNR 2 excess/zipper aldehydes excess/zipper excess/zipper excess/zipper 2. & ketones R 2. workup 2. workup 3. workup 3. workup Reactions of Alkynes OH O O Br OH H 1. R BH + 2 H3O / H2O 2. H O HO +2 2 2 / 1. NaNR2 1. NaNR Hg cat. (anit-Markovnikov) HBr 2 1. NaNR2 2. 2. O 2. Br O H 3. workup 3. workup Reactions of Alkynes O start O over H Pd, H2 1. excess NaNR 1. R BH Na / NH / ROH Pd, H 2 2 3 2 2. workup 2. H O HO H O+ / H O E alkenes 2 2 / 3 2 (Lindlar's Cat.) (zipper reaction) (anit-Markovnikov) Hg+2 cat. Z alkenes O

R R R H O aldehydes & ketones Make from alkene alkene H3C H3C R epoxides S CH n-butyl 1. Br2 /H2O 2 S CH3 mCPBA 2. mild NaOH H C ylid H C I 3 3 anhydrides acid chlorides & acids O O O O Make from R O R' R Cl R' OH (2 ways)

Organometallics (Li, Mg, Cu)

2 eqs. Make R X Make R X R Cu R Make from from R Li R Li from haloalkanes R (MgBr) haloalkanes Li Mg CuBr Li y:\files\classes\316\special handouts\316_FG_syn.doc 14C synthesis strategies, Chem 315/316 / Beauchamp 4 Mg and Li Organometallics Reactions OH OH OH OH O O OH

R Li R R" R R' R R R R' R' R' R OH R R' R (MgBr) O O O O O N O similar C C R O R' H H R' H R' R" R' O 1. make R-Metal 1. make R-Metal 1. make R-Metal 1. make R-Metal 1. make R-Metal 1. make R-Metal 1. make R-Metal 2. electrophile 2. electrophile 2. electrophile 2. electrophile 2. electrophile 2. electrophile 2. electrophile 3. workup 3. workup 3. workup 3. workup 3. workup 3. workup 3. workup Mg and Li Organometallics Reactions OH O OH OH

R Li R R R" R' R R R' R' R R R' O (MgBr) O similar O O R' R" chemistry R' NR R' Cl 2 R' 1. make R-Metal 1. make R-Metal 1. make R-Metal 1. make R-Metal o 2. electrophile 2. electrophile 2. electrophile 2. 3 amides 3. workup 3. workup 3. workup 3. workup Cuprate Reactions Li Li Li R Cu R R Cu R O R Cu R R O Make Make Make O from from O R R' R' X from R R' haloalkanes (2 ways) (2 ways) conjugate addition R' Cl Dithiane Synthesis of Aldehydes and Ketones S R S S S S O O R Make R Make from R' Li from S S S S S R R' R H 1. n-BuLi HgBr HgBr2 Aldehydes 2 Br n-BuLi Ketones R H2O 2. R'Br H2O OH S Dithiane Synthesis S S S OH O Make S Li S S HO from S O OH 1. 2 eqs. n-BuLi 1. OH HgBr2 2. H2C=O 2. workup n-BuLi H2O 3. workup Wittig Reactions Ph R Ph O Ph Ph Make P Ph Ph R' from P makes very C HC P R Br specific alkenes R H n-butyl lithium H C Br Ph Ph (usually Z) R (very strong ) 2 carbonyl R (2 ways) ylid (Wittig ) Ph compound Chemistry electrophiles O O O R X E haloalkanes o 1. LDA,-78 C aldehydes or 2. electrophile (E) O (aldol rxns) 3. workup O O & ketones epoxides (Claisen rxns) R R E O O

y:\files\classes\316\special handouts\316_FG_syn.doc 14C synthesis strategies, Chem 315/316 / Beauchamp 5

Acetoacetic Ester Synthesis + O H3O /H2O/ O 1. RO Na O O O or 2. electrophile (E) R HO /H O/ R 3. workup O 2 O O E (-CO2) E O R X substituted electrophiles haloalkanes epoxides aldehydes & ketones

y:\files\classes\316\special handouts\316_FG_syn.doc 14C synthesis strategies, Chem 315/316 / Beauchamp 6 O O Electrophilic Aromatic Substitution Reactions (aromatic ring is a  ) 1. CO 2 NaOH, second 2. WK OH RX OR Reaction 1 1 o/p dibromo Br2 Br 2 o/p bromo / FeBr3 1. H2CO 3 o/p bromo / keto 2. WK OH HBr Br ortho/para director 4 o/p bromo / nitro Organometallic O 5 o/p bromo / reactions 1. C R R H Reaction 2 1 o/p alkyl / bromo (MgBr) NaCN R 2. WK OH RCl 2 o/p alkyl / alkyl AlCl Br 3 Mg O 3 o/p alkyl / keto CN 1. alkyl 4 o/p alkyl / nitro C RR ortho/para director R R O 5 o/p alkyl / sulfonic acid the aromatic ring 2. WK is a nuclephile, OH O 1 meta keto / bromo  Reaction 3 the donation O Cl R poor reaction R 2 comes from an sp2 AlCl3 1. C 1. (1.LAH, 2. WK) 3 poor reaction orbital not the  R OR' 2. (HCl, H O) 4 meta keto / nitro 2. WK 2 aromatic ketones R 3. acid (H SO , H O) meta director 5 meta keto / sulfonic acid reacts 2 4 2 4. (1.RMgBr, 2. WK) twice OH Reaction 4 1 meta nitro / bromo 5. (1.DIBAH, 2. WK) HNO3 NO O 2 2 1. H2SO4 poor reaction HBr OH OH Ph 3 poor reaction 2. WK CrO 4 meta dinitro 3 O meta director (PCC) Ph 5 meta nitro / sulfonic acid 1. O CrO3 H Reaction 5 meta director 1 meta sulfonic acid / bromo OH R H2O H SO SO3H 2 poor reaction 2. WK O 2 4 (Jones) Ph 3 poor reaction R OH sulfonic acids and this reaction 4 meta sulfonic acid / nitro 1. CuBr R CrO can be reversed with the addition of water. meta disulfonic acid 2. RX 3 5 (PCC) O the aromatic ring Cl CuCl 1. CuBr Ph is a  electrophile Diazonium chemistry O O R 2. compare to T > 5oC Br Fe / HCl CuBr R Cl Friedel -Crafts NO R 2 or NH NaNO2 N reactions 2 N SnCl / HCl HCl 2 N diazonium C 1. CuBr reduction CuCN O O chemistry 2.

complete ortho/para substitution with some electophiles (NH2 I meta is too reactive) or the complexes with acid becoming KI substitution positively charged and a meta director; an alternative strategy conjugate forms the amide to make the substituent less reactive and then addition hydrolyze amide back to the amine (aniline) when done OH H H2O acetanilide controlled ortho/para substitution NO is possible and the amide can be cleaved in acid or base back to Diazonium chemistry provides our HF the amine (aniline ) F only route to some aromatic : BF 3 such as CN, I, OH and F. There are reactions alternative options for Cl, Br and H. The polarity of the joining groups is O R H completely backwards from the other CrO3 H3PO2 aromatic reactions. The aromatic ring  OH is the electrophile. oxidation at least one benzylic

Clemmenson NH NH / RO /  Br2 / h Br O 2 2 HH O Reduction HH Wolff-Kishner C C C C free R Reduction R R Zn, HCl R substitution at least one of sp3 CH benzylic hydrogen

y:\files\classes\316\special handouts\316_FG_syn.doc 14C synthesis strategies, Chem 315/316 / Beauchamp 7 Combination Problems – Two structures (or more) in one target .

Esters Make R and acyl substitution Fischer ester synthesis O 1 SN2 R2 skeletons. O O O C R 2 R2 C C C R2 R2 R1 O HO R OH R1 Cl R1 OH Br 1 HO (NaOH) (TsOH / -H O) 2

Ketones Make R1 and approach cuuprate approach traditional approach R skeletons. O 2 N N O R O OH C C 2 R1 Other approaches C R Br Br are possible (like 1 R2 R1 R2 C C CH R1 R2 alkynes, etc.) Br Br R1 Cl Cl R1 R1 R2

Alkynes Wittig Reactions

R1 O R2 O R R Make R1CH2- and 1 2 R1 R2 R2CH2-skeletons. (must be primary) Alkynes Ph P Ph P 3 Br H R2 3 Br H R1

Ethers Amides Cuprate Couplings

2o and 3o Alcohols

y:\files\classes\316\special handouts\316_FG_syn.doc 14C synthesis strategies, Chem 315/316 / Beauchamp 8 Electrophiles (Lewis acids)

aldehydes and ketones, RX derivatives carboxylic acids and derivatives, carbonyl addition reactions e dioxide SN2 / E2 and SN1 / E1 carbonyl substitution reactions k O O O CO O H3C Br pqu Br a C R' C methyl RX C R OH R O H H l Br methanal nitriles carboxylic acids esters N benzylic RX O f 1o RX O O C r v b R unreactive RX patterns C Br C C H R H m Br R Cl R N simple vinyl RX acid chlorides o aldehydes Br s 1 amides H derivatives 2o RX O O O O O w c C C g n Br C R O R C R' R R anhydrides R N simple O phenyl RX ketones o t O o h 3 RX 2 amides H O o Br Br O R' C R' x O O O allylic RX neopentyl RX C R' d i dialkyl R N

Other Lewis acids used: FeX3, AlX3, BH3, o 3 amides R' BF3, HgX2, etc. conjugated j O Occasional weak Lewis acids:Br2, Cl2, H2O2 carbonyl (also react in free radical reactions) compounds Strong Bronsted acids: H2SO4, H3PO4, HCl, HBr, HI

Nucleophiles (Bases) nitrogen weak nucleophiles nucleophiles nucleophiles (and/or bases) nucleophiles (and/or bases) (and/or bases) (and/or bases) + (and/or bases) Na 15 8 1. LiAlH4 H-O-H 1. O 20 1 NC (LAH) H O 5 2. workup N 16 R-O-H Na 1. NaBH4 21 Na+ imidate O 9 2. workup 2 O R O 2. NaOH HC C 22 17 1. H OH 6 Li 10 Al N 1. (Ph)3PCH2 3 O And any K ylid (make) DIBAH functional lithium 2.WK group with a t-butoxide of diisopropylamide 11 2.WK (LDA) 1. R-MgX electrons 4 O Na 2. WK (e.g. oxygen always 18 Grignard NaH and nitrogen) O a base reagents always 7 12 1. R-Li a base miscillaneous neutral 1. Na R2N 2. WK nucleophiles 2. workup KH organolithium 19 (and/or bases) NH amide reagents always 3 R3P (always a base) 13 O a base Li R NH2 neutral carbon CH H S 2 1o amines 2 nucleophiles S Ph hydrogen C C 2. WK R Ph PCH CC 2 R NH H CC 14 S Li alkynes Ph 2o amines R S alkenes R-Cu-R Li dithiane Wittig ylid aromatic cuprates R comounds R R N R S R O Occasional weak Lewis R N 3o amines CC bases: R-Cl, R-Br, R-I, CC Br2, Cl2 with strong Lewis acids like: FeX , and 3 AlX3, etc. y:\files\classes\316\special handouts\316_FG_syn.doc 14C synthesis strategies, Chem 315/316 / Beauchamp 9 Use clues in the target molecule to determine what the last step could have been. Once you work back one step, use clues in that molecule to determine how you could work back one additional step. Repeat this process until you get 14 to the necessary starting conditions, i.e. allowable C starting units (*CH4, *CO2, Na*CN where “*” indicates a radioactive 14C isotope). Until aromatic chemistry is covered bromobenzene is also available.

Starting Structures: Br

CH4

Examples – Target (TM - #)

Straight chain C5 alcohols 1 2 3 4 56 * * * * * OH OH OH OH OH OH

78OH OH 9OH 10 OH 11 OH 12 OH * * * * * 13 14 * 15 16 * * OH OH OH OH

y:\files\classes\316\special handouts\316_FG_syn.doc 14C synthesis strategies, Chem 315/316 / Beauchamp 10 TM - 3 1. Mg HBr 1. Mg 2. O 2. H *C=O * or * 2 3. workup * Br PBr3 HO Br OH 3. workup

Pd / H2 1. NaNR2 HO 2. H2*C=O 3. workup *

TM - 4 1. Mg * HBr 1. Li HBr 2. O 1. Mg or 2. H C=O * or * 2 2. H *C=O Br Br PBr HO 3. workup Br PBr 2 3. workup * 3 * 3 HO 3. workup OH CH3 1. Mg 2. O

* HBr 1. Li 3. workup or 2. H2C=O * PBr3 OH 3. workup Br HO

TM - 7 1. Mg 1. Li OH 2. O CrO / pyridine OH 2. O O Br 3 (PCC) Br H H 3. workup CH3 * 3. workup *

CrO3 / pyridine 1. NaNR2 (PCC) 2. O OH HO Pd / H2 3. workup

O 1. NaNR2 1. R2BH 2. 2. H O /HO Br H 2 2

y:\files\classes\316\special handouts\316_FG_syn.doc 14C synthesis strategies, Chem 315/316 / Beauchamp 11 TM - 8 1. Mg OH O CrO3 OH 1. Mg Br H2O 2. H2*C=O 2. CH H*C=O 3 (Jones) 3. workup CH * 3. workup Br * H * 3 OH 1. NaNR2 Pd / H2 * 2. CH3H*C=O * 3. workup HO

1. Mg 1. Mg OH CrO3 2. H *C=O 2. CH3CH2CH2H*C=O O 2 OH Br H O Br 3. workup 2 3. workup (Jones) * CH * 3 H * 1. NaNR2 Pd / H2 2. H2*C=O * 3. workup

HO 1. Mg 1. Mg 2. O 2. O 2eqs. OH OH O H2SO4 * C R Br * mCPBA * H O 3. workup Br * 3. workup * * CH3

TM - 11 1. Mg 2. O HBr OH or 1. Mg 2. H2C=O Br 3. workup PBr3 Br HO 3. workup * * CH * * 3

y:\files\classes\316\special handouts\316_FG_syn.doc 14C synthesis strategies, Chem 315/316 / Beauchamp 12

1. Mg TM - 13 2. 1. NaNR2 Pd / H O Br mCPBA 2 2. 3. workup quinoline Br * O CH3 OH *

1. Mg 2. O O 1. R2BH 2. H2O2/HO H 3. workup * 3. workup H OH Br * CrO3 (see TM-11) pyridine

(PCC) 1. H3B 2. H2O2/HO HO 3. workup

TM - 14 1. Mg O 2. O * HBr * H or H 3. workup OH (above, TM-13) * PBr3 OH (above, TM-10) Br

y:\files\classes\316\special handouts\316_FG_syn.doc 14C synthesis strategies, Chem 315/316 / Beauchamp 13 Examples – Target Molecules (TM - #)

4C chain with methyl branch alcohols – Many approaches. Ran out of time to write them out. Ask, if questions. There are “hints” at possibilities that follow, but not ever step is shown.

* 1 2 3 4 56 * * * * OH OH OH OH OH OH

7 8 9 10 11 * * * * OH OH OH OH OH

12 13 14 15 16

* * * * OH OH OH OH OH

17 OH 18 OH 19 OH 20 OH 21 OH

* * * *

O TM-2 * O Br O HO CH CH * * * H 2 3 * * CH2 Br HO Br OH

TM-3 * * O * O Br

CH CH2 Br HO 3 H * OH

y:\files\classes\316\special handouts\316_FG_syn.doc 14C synthesis strategies, Chem 315/316 / Beauchamp 14

TM-6 O Br

CH HO CH3 2 Br O O OH

H Br O

H

TM-7 Br * CH3 O HO OH * (above, TM-6) Br

CH3

Br O * Br CH OH * O * OH 3 * H

y:\files\classes\316\special handouts\316_FG_syn.doc 14C synthesis strategies, Chem 315/316 / Beauchamp 15

TM-12 Br O Br

CH3 CH * * 3 OH

O O Br * Br H OH CH3 OH * * * H

y:\files\classes\316\special handouts\316_FG_syn.doc 14C synthesis strategies, Chem 315/316 / Beauchamp 16

TM-19 OH O O Br OH CH2 CH2 * * Br * *

In our course every carbon-carbon bond made with asterisked OH OH carbon must be made with a nucleophile/electrophile reaction. * *C C C C

nucleophile (Nu) = ? *C C Nu E E Nu electrophile (E) = ? clue: COH group could have been C=O group (aldehyde or ketone).

OH E E OH * * OH E E OH CC C C

*C C C* C * C C O O Nu Nu Nu Nu clue: COH group could have been C=O group (ester). clue: COH group could have been C=O group (carbon dioxide).

O OH O O O O * C C C C electrophiles = C C C R H R H R H O Nu E Mg or 2Li clue: COH group could have been an epoxide group. nucleophiles = R Br R (MgBr) or Li

y:\files\classes\316\special handouts\316_FG_syn.doc 14C synthesis strategies, Chem 315/316 / Beauchamp 17 Products from reactions of carbon nucleophiles and carbon electrophiles used in the 14C Game and our course: Carbon and hydrogen nucleophiles R O Al H Li R Li R (MgBr) Na CN R Cu Li Li AlH4 Na BH4 Carbon RCC Na 2 R electrophiles organolithium organolithium acetylides cyanide cuprates (LAH) diisobutylaluminium reagents reagents hydride (DIBAH) enolates

H3C Br 2 RX coupling NR NR alkynes nitriles alkyls NR SN2 methyl RX reaction

2 RX coupling R Br NR NR alkynes nitriles alkyls alkyls NR SN2 alkylation reaction primary RX

R 2 RX coupling NR NR nitriles E2 reaction alkyls alkyls NR SN2 alkylation R Br secondary RX

O S 2 - like o N o o 1 ROH o o 1 ROH 1 ROH 1 ROH 1o ROH 1o ROH 1 ROH NR opens epoxide alkynes nitriles O SN2 - like o o o o o o o 2 ROH 2 ROH 2 ROH 2 ROH 2 ROH 2 ROH 2 ROH NR opens epoxide alkynes nitriles O S 2 - like o o o N 3 ROH 3o ROH 3o ROH 3o ROH 3o ROH 3 ROH 3 ROH NR opens epoxide alkynes nitriles isobutylene oxide

O

o o 1o ROH acyl addition C 1 ROH 1 ROH NR methanol NR adds to C=O H H alkynes methanal

O acyl addition o o o cyanohydrin o C 2 ROH 2 ROH 2 ROH NR 1o ROH 1 ROH NR adds to C=O R H alkynes simple aldehydes

O cyanohydrin acyl addition 3o ROH o o unless o o NR C 3 ROH 3 ROH sterically NR 2 ROH 2 ROH adds to C=O R R alkynes hindered simple ketones O 3o ROH o 3 ROH o o acyl substitution C R NR NR 1 ROH 1 ROH aldehydes (Nu: twice) (Nu: twice) NR at C=O R O (Nu: twice) simple esters

O ketones acid/base C acid/base acid/base acid/base acid/base acid/base acid/base no net rxn no net rxn NR no net rxn no net rxn no net rxn no net rxn no net rxn R OH (B: once simple Nu: once) carboxylic acids O

C 3o ROH 3o ROH acyl substitution NR NR ketones 1o ROH 1o ROH NR at C=O R Cl (Nu: twice) (Nu: twice) simple acid chlorides

1o amines aldehydes R C N ketones ketones NR NR NR NR ketones simple nitriles (also amines (also aldehydes from amides) from 3o amides)

O CO carboxylic carboxylic carboxylic carboxylic NR NR NR acids acids acids NR NR acids carbon dioxide

O conjugate conjugate 3o ROH o C 3 ROH NR NR addition alcohols alcohols NR addition R ,-unsaturated ketones + WK = normal workup to neutralize the reaction conditions. For the basic reactions (like above) above this would require mild acid neutralization (H3O ). NR = no reaction or no productive result or not emphasized y:\files\classes\316\special handouts\316_FG_syn.doc 14C synthesis strategies, Chem 315/316 / Beauchamp 18 Key strategies in a 14C synthesis problem? Use clues in the target molecule to determine what the last step could have been. Once you work back one step, use clues in that molecule to determine how you could work back one additional step. Repeat this process until you get 14 to the necessary starting conditions, i.e. allowable C starting units (*CH4, *CO2, Na*CN). These can be converted into other C1 molecules such as: *CH3Br, *CH3OH, *CH2=O, H*CO2H, H*CO2R.. Until aromatic chemistry is covered bromobenzene is also available.

1. Which carbon could have been a carbonyl (C=O) functional group? (methanal, general aldehyde, ketone, ester, carbon dioxide)? Or, some other functional group (alkene, RX compound, epoxide)? 2. To start from some “functional group”, what features have to be retained from the target structure, or regenerated in the starting structure? 3. What features can be taken away from the target structure (that were originally in the starting structure, but are now lost)? 4. Draw a possible starting structure. 5. What portion has to be added and how can we do that?

Starting possibilities to produce alcohols. O O O O O O Br C C C C R' C CC HH RH RR CC RO O C methanal general carbon () aldehyde ketone ester alkene epoxide dioxide RX compound

Some useful interconversions in 14C syntheses (using 1C transformations).

NaOH HBr H3C Br H3C OH H3C Br

1. NaBH4 PCC H2C O H3C OH H2C O 2. WK CrO3, no H2O

O O

1. LiAlH4 Jones C H3C OH + C 2. WK CrO3, H , H2O H OH H OH

1. NaOH 2. CH3CH2Br

O 1. LiAlH4 2. WK C Mg H OCH CH H3C Br H3C MgBr 2 3 There are many C-C bond Li forming reactions possible 1. DIBAH H C Br 3 H3C Li using these reagents 2. WK Na CN H3C Br H3C CN H2C O Na CN H C CN H3C Br 3 WK = workup (neutralization) Sample Reactions of Nitriles - further transformations to: amines, amides, carboxylic acids, aldehydes, ketones NH O O 1. LiAlH 2 H SO 1. R'Li RNC 4 RNC 2 4 R C RNC R C R CH2 2. WK 2. WK H2O,  OH R O O RNC HCl R C 1. DIBAH H O RNC R C 2 NH2 2. WK H y:\files\classes\316\special handouts\316_FG_syn.doc 14C synthesis strategies, Chem 315/316 / Beauchamp 19 X X X C1 - C6 skeletons X X X 89 3 4 5 6 1 2 7 X X H C X 3 1C 2C 3C 3C4C 4C 4C 4C 5C X X X 13 X 14 15 16 17 10 X 11 X 12 X

5C 5C 5C 5C 5C 5C X 5C 6C

X 21 22X 23 18 X 19 X 20 X

X 6C 6C 6C 6C 6C 6C

X X 25 X 29 30 24 26 27 28 31 X

X 6C 6C 6C X 6C 6CX 6C 6C X 6C O 32 33 34 35 36 O O Li X Br C R X C C R MgBr N NH2 N 6C X Cu X 6C H R R Some skeletal patterns above are more difficult to fit with these functional group patterns than others. R O N O O O NH2 SH C X= Br OH O S C C R R C C C R O R OH Cl O

ketone (C=O) - when in an internal position and not tertiary aldehyde (-CH=O) - when X is on a terminal position (-CO2H) - when X is on a terminal position alkene skeletons 345 8 9 10 1 2 67

10 13 14 16 11 12 15

20 21 17 18 19 22 23

26 29 27 28 30 31 24 25

Every one of these alkenes could be transformed into epoxides, ROH and RBr (Markovnikov and anti-Markovnikov). Other typical alkene reactions conditions are listed in the first part of this document (along with many, many other reactions). skeletons - remember that terminal acetylides do not react well with 2o RX compounds 7 123 4 5 6 8

12 13 15 9 10 11 14

allylic alcohols allylic carbonyls made from epoxides and LDA (can make , -unsaturated carbonyl compounds). Just a few examples are shown. OH O OH OH O O OH O

y:\files\classes\316\special handouts\316_FG_syn.doc