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14C synthesis strategies, Chem 315/316 / Beauchamp 1 Products from reactions of carbon and carbon electrophiles used in the 14C Game and our course: Carbon and hydrogen nucleophiles Ph R Ph Al H N R Li R (MgBr) P Li AlH R Cu Li Na CN RCC Na Ph 4 Li Carbon 2 H C R organolithium organolithium cyanide acetylides 2 ylid Na BH4 diisobutylaluminium lithium diisopropy- electrophiles cuprates (LAH) o reagents reagents Wittig reagents hydride (DIBAH) (LDA), -78 C H C Br 3 not useful not useful 2 RX coupling nitrilesalkynes not useful alkyls alkyls not useful methyl RX reaction

R Br not useful not useful 2 RX coupling alkynes not useful alkyls alkyls not useful primary RX reaction

R

2 RX coupling nitriles alkyls not useful E2 not useful alkyls not useful not useful reaction R Br secondary RX

O 1o ROH 1o ROH 1o ROH 1o ROH not useful 1o ROH o not useful not useful 1o ROH 1 ROH oxide nitriles alkynes O o o o o o o 2 ROH 2 ROH 2 ROH 2 ROH 2o ROH 2 ROH 2 ROH not useful not useful E2, make nitriles alkynes allylic alcohols propylene oxide

O

o 3 ROH 3o ROH o 3o ROH o not useful o 3o ROH not useful E2, make 3 ROH 3 ROH 3 ROH allylic alcohols nitriles alkynes isobutylene oxide

O

o o specific methanol methanol C 1 ROH 1 ROH not used cyanohydrin 1o ROH not useful not useful in our course H H alkynes methanal

O

specific o enolate o o cyanohydrin o 1 ROH o C 2 ROH 2 ROH not useful 2 ROH alkenes 1 ROH not useful R H alkynes simple aldehydes

O cyanohydrin o unless specific o enolate C 3 ROH 3o ROH o 2o ROH 2 ROH not useful sterically 3 ROH alkenes not useful chemistry R R hindered simple alkynes

O o o 3 ROH 3 ROH not used enolate C R not useful not useful 1o ROH not useful aldehydes (Nu: twice) (Nu: twice) not useful in our course chemistry R O simple esters

O ketones /base acid/base acid/base acid/base acid/base enolate C use 2 equivalents acid/base acid/base no net rxn no net rxn no net rxn not useful no net rxn no net rxn no net rxn chemistry R OH no net rxn HCN = danger simple (B: once carboxylic Nu: once) O

C o o 3 ROH 3 ROH not useful o o E2, make ketones not useful not useful 1 ROH 1 ROH aldehydes ketenes R Cl (Nu: twice) (Nu: twice) simple acid chlorides

o R C N 1 amines aldehydes ketones simple nitriles ketones enolate not useful not useful not useful not useful (also amines not useful chemistry RCONR' (also aldehydes 2 ketones ketones 3o from amides) from 3o amides) ketones O CO use 2 equivalents carboxylic not useful not useful carboxylic not useful not useful not useful not useful not useful (B: once acids acids Nu: once) O

conjugate C o o not useful 3 ROH 3 ROH conjugate addition not useful alcohols alcohols not useful R addition α,β-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

Z:\classes\316\special handouts\316 Syn & C14 strategies.doc 14C synthesis strategies, Chem 315/316 / Beauchamp 2

* (Nu) = ? In our course every carbon-carbon bond made C C with asterisked carbon must be made with a electrophile (E) = ? nucleophile/electrophile reaction.

OH OH OH E E OH

* * * * C C C C CC C C

* C C Nu E E Nu Nu clue: COH group could have been an electrophilic Nu C=O group (aldehyde or ) + nucleophilic clue: COH group could have been an electrophilic C=O Grignard or lithium reagent. group (ester) + nucleophilic Grignard or lithium reagent (2x).

OH E E OH H E E H * * C C C C *C C C* C

O O O O Nu Nu Nu Nu clue: COH group could have been an electrophilic C=O group clue: CHO (aldehyde) group can be made from (carbon dioxide) + nucleophilic Grignard or lithium reagent. nucleophilic Grignard or lithium reagents + electrophilic dimethylformamide (DMF). OH O O O O O *C C C O electrophiles = C C C C C H H R H R R R OR Nu E O clue: COH group could have been an electrophilic Mg or 2Li group + nucleophilic Grignard or lithium nucleophiles = R Br R (MgBr) or Li reagent.

O O O E O N * C C C C C C electrophiles = R OH R NR' R Cl R R 2 carboxylic nitriles3o amides acid chlorides Nu acids clue: C=O group could have been 2 equivalents a ( + Grignard or lithium reagent), R Cu R o nucleophiles = (MgBr) or Li a ( 3 amide + Grignard or lithium reagent), R R Li R Li an (acid chloride + cuprate) or Mg and Li organometallics cuprates organolithium a (carboxylic acid + 2 eqs. of R-Li). reagents

O α β α α O O β O α C β β electrophiles = * C

R OR α,β-unsaturated C=O Nu clue: C=O group could have been an electrophilic α,β-unsaturated cuprate R Cu R C=O (+ nucleophilic cuprate = conjugate addition). nucleophiles = Li

Z:\classes\316\special handouts\316 Syn & C14 strategies.doc 14C synthesis strategies, Chem 315/316 / Beauchamp 3

Carbon skeletons from C1 – C7

aba b c

CH4

C1 skeleton C2 skeleton C3 skeleton C4 skeletons C5 skeletons

a b c d e

C6 skeletons

d a b c e

f g h i

C7 skeletons

Seven carbon skeleton – “isomer c” with variable 14C labels 2 4 6 * * 1 3 5 * * C2-star 7 C1-star C3-star C4-star * *

C7-star no 14C label C5-star C6-star *

Seven carbon skeleton - “isomer c” with variable “OH”, no 14C labels 2 6 OH OH 4 OH HO 3 5 1 7 C1-OH C2-OH C3-OH C4-OH

OH

C5-OH OH C6-OH C7-OH OH

Seven carbon skeleton – “isomer c” with 14C label on first carbon (C1-star) and variable “OH” 2 6 OH OH 4 OH HO * 3 5 * 1 * * 7 C1-star, C1-OH C1-star, C2-OH C1-star, C3-OH C1-star, C4-OH

* * * OH

OH C1-star, C5-OH C1-star, C6-OH C7-star, C1-OH OH

Z:\classes\316\special handouts\316 Syn & C14 strategies.doc 14C synthesis strategies, Chem 315/316 / Beauchamp 4 The following carbon skeletons represent parts of structures that can be made with or without 14C labeled positions. C1 – C4 carbon skeletons are all shown, with “*” to indicate the location of any 14C label. In structures with 5 carbon atoms, or more, the first structure drawn represents the parent skeleton and the second structure shows all of the different positions that a single 14C label could be inserted (a number indicates each different possibility). "X" represents a simple functional group or a point of attachment in a functional group pattern that could have more than one carbon portion. (See example page with several examples of functional group patterns that could have 2 or more branches.) Synthetic targets can be randomly generated by drawing out a number for the carbons in the skeleton (1-7), then picking a random pattern, then picking a random isomer with or without a 14C label. This can be done once, twice or 3 times for each branch in the selected functional group pattern (which can also be picked at random). The possibilities are effectively endless for organic synthesis problems (there are about 420 skeletal patterns, including 14C labels). These problems are relatively straight forward because there is only 1 functional group. More than one functional group may require protection/deprotection steps and the difficulty of such synthetic problems can rapidly go up. Some patterns may have limitations due to steric crowding. (X = OH, Br, OR, O2CR, NH2, CN, CCR and many other possibilities)

1 carbon 2 carbons 3 carbons 4 carbons pattern 1 pattern 2 pattern 4 pattern 1 pattern 3 pattern 2 1 1 1 1 X 1 3 X 1 1 X * 4 X X H3C X 2 * 2 X * * * 1 2 2 2 2 X 2 X * X X 3 * X X H C X * X 3 X X * 3 X 2 4 * 3 5 * * * 3 4 * X X 3 X 3 * * X * * X 5 X 4 * X X X * X * X

5 carbons: 1 = parent skeleton without any 14C label, numbers = skeleton location with a 14C label at that position (for reference in synthesis problems) pattern 1 pattern 2 pattern 3 pattern 4 pattern 5 pattern 6 pattern 7 pattern 8 1 = parent skeleton 1 X 1 1 1 1 1 X 1

X X X X X 3 5 X 3 6 X 2 4 6 2 4 X 5 3 2 4 5 2 4 6 5 3 2 4 3 2 4 3 5 2 3 X X 3 5 4 X X 2 4 X X

6 carbons: 1 = parent skeleton without any 14C label, numbers = skeleton location with a 14C label at that position (for reference in synthesis problems) pattern 1 pattern 2 pattern 3 pattern 4 pattern 5 pattern 6 pattern 7 1 = parent skeleton 1 1 1 X 1 1 1 X

X X X X 3 5 7 7 X X 3 5 7 2 4 6 2 4 6 X 5 5 5 7 2 3 2 4 6 2 4 6 3 5 2 4 6 3 3 X X 4 6 X 3 5 X X 2 4 6 pattern 8 pattern 9 pattern 10 pattern 11 pattern 12 pattern 13 pattern 14 pattern 15 1 1 1 X 1 1 X 11 1

X X X X X X X X 3 3 5 2 3 2 4 4 5 6 2 4 6 4 5 4 4 4 3 3 5 2 3 5 3 3 5 2 4 2 2 6 2 5 X 5 X X X 7 7 6 X X

Z:\classes\316\special handouts\316 Syn & C14 strategies.doc 14C synthesis strategies, Chem 315/316 / Beauchamp 5 7 carbons: 1 = parent skeleton without any 14C label, numbers = skeleton location with a 14C label at that position (for reference in synthesis problems)

pattern 1 pattern 2 pattern 3 pattern 4 pattern 5 1 = parent skeleton 1 11 X 1 X X

X 3 5 7 X 8 2 4 6 8 X X X 3 2 2 3 5 7 2 6 8 4 5 7 X 2 4 6 8 3 5 7 5 4 6 3 4 X pattern 6 pattern 8 pattern 7 pattern 9 pattern 10 pattern 11 X 1 1 11 1 1 X

X X X X X X 3 5 7 5 5 7 3 7 4 6 6 2 4 6 4 6 3 3 5 7 3 5 7 4 2 4 2 2 2 6 3 5 7 X 2 4 6 X X X 8

pattern 12 pattern 13 pattern 14 pattern 15 pattern 16 pattern 17 1 X 1 X 1 X 1 X 1 1

X X X X 3 X X 3 5 2 4 4 2 6 5 7 4 6 4 6 3 5 3 7 3 5 7 7 7 5 3 5 7 2 2 6 2 4 6 2 4 6 8 8 8 8 8 X 8 X

pattern 19 pattern 18 pattern 20 pattern 21 pattern 22 pattern 23 pattern 24 1 1 1 1 X 1 1 X 1

X X 7 X X X 8 X X 3 5 3 4 6 2 2 5 4 6 3 5 3 5 3 5 3 4 6 4 5 2 6 3 2 4 6 4 6 X 5 2 X 2 X 2 4 6 X X 7 7 7

pattern 25 pattern 26 pattern 27 pattern 28 pattern 29 pattern 30 pattern 31 X 1 11 1 1 1 1

X X X X X X 7 X 4 3 5 3 5 6 2 2 4 4 6 2 6 3 4 5 3 5 3 3 4 2 4 3 5 6 2 4 6 2 7 5 2 X X 6 X 7 7 X X X 7

pattern 32 pattern 33 pattern 34 X pattern 35 pattern 36 pattern 37 pattern 38 pattern 39 X X 11 1 1 1 1 X 1 1

X X X X X X X 3 X 6 2 4 6 5 2 4 4 6 5 3 5 5 3 4 6 3 4 4 5 4 4 3 2 2 2 3 3 3 5 2 5 X 2 X 2 X 6 7 X 6

Z:\classes\316\special handouts\316 Syn & C14 strategies.doc 14C synthesis strategies, Chem 315/316 / Beauchamp 6

O O * * * * * O N O * either side either side 2 problems in one structure (ester) H joined (acid + RX) by SN chemistry, 2 problems in one structure (amide) 2 problems in one structure (ether) (acid-Cl + alcohol),(acid + alcohol) (joined acid-Cl + amine) by acyl (alcohol/alkoxide + RX), by acyl substitution substitution, amine = NH3,RNH2,R2NH (alcohol + alcohol) by SN chemistry O * * * * * both sides Wittig all sides * 2 problems in one structure (alkyne) 2 problems in one structure () from reduction of alkyne or Wittig * by terminal acetylide + Me or 1o RX, reaction SN chemistry * all sides Up to 4 problems in one structure, O can have 1, 2, 3 or 4 branches N * * * * Multiple problems in one. either side * 2 problems in one structure (ketone) Up to 3 problems in one structure, can How can one cut up these (acid chloride + cuprate),(aldehyde + RX) have 1, 2, or 3 branches, by Gabriel molecules into simpler parts? (cyanide to nitrile to ketone) amine syn and imine reduction chemistry Some of the Synthetic Strategies in 14C Game

1. Every *C-C (carbon-carbon) bond to a *C must be made. If atoms have been joined together, is there an obvious nucleophile (alkyne, cyanide, Mg or Li reagent) and/or electrophile (an OH that was a C=O or an epoxide)? You need one of each. If one part is obvious, can you think of how the other part might be made? Could you join the atoms in the opposite fashion ()? Think in both directions. 2. Functional Group Interconversions (FGI) are often used (i.e. ketone to alcohol, or alcohol to ketone, or alcohol to bromoalkane, which can be a for an SN reaction or made into Grignard or Lithium reagents). Which carbon could have been a carbonyl (C=O) functional group and altered by the reactions shown? (such as methanal, general aldehyde, ketone, ester, carbon dioxide)? Or, could have been some other functional group (alkene, RX compound, epoxide)? 3. Alcohols are often oxidized to carbonyls (alcohols Æ aldehydes, ketones, carboxylic acids) (carboxylic acids Æ esters, acid chlorides) (acid chlorides Æ esters, 1o,2o,3o amides, ketones, aldehydes, thiolesters), which can be used as electrophiles (etc.). 4. Many organic groups can be reduced (alkene Æ alkane, alkyne Æ Z-alkene, E-alkene, alkane, carbonyl Æ alcohol, alkane, etc.) 5. Additional special reactions of course (Wittig, Wolff-Kishner, Clemmenson, enamine, imines, cuprates, etc.). 6. Protections are sometimes necessary (acetals, ketals “C=O” protected with ethylene glycol or “ROH” protected as THP ether). There are many other kinds of protections besides those discussed in our course. 7. If starting from some “functional group”, what features are retained in the target structure? 8. If thinking back from the product, what features need to be generated in the product? 9. Draw a possible starting structure and consider what reactions possible reactions that we have studied could make the target functional group? Does one seem better suited than another?

Z:\classes\316\special handouts\316 Syn & C14 strategies.doc 14C synthesis strategies, Chem 315/316 / Beauchamp 7 Connecting 2 or 3 patterns from above in the functional groups below.

Several of the patterns below may require an additional 1 or 2 carbon atoms at the connecting point, in addition to the R1 and R2 patterns. O OH O OH O R2 R1 R2 R R R1 R3 R1 O 1 2 ketones R o R1 R2 2 esters ethers oxidation of 2 ROH o 2o alcohols 3 alcohols carboxylate + RBr ROH + RBr (S 1) nitrile + R-Li/R-MgBr acid chloride + ROH N ketone + LAH ketone + R-Li/R-MgBr RO + RBr (S 2) acid chloride + cuprate Fischer ester synthesis N epoxide + LAH alkene + ROH 3o amide + R-Li/R-MgBr aldehyde + R-Li/R-MgBr epoxide + R-Li/R-MgBr carboxylic acid + 2 eqs. R-Li epoxide + LAH ester + R-Li/R-MgBr (2 eqs.) alkyne hydrolysis epoxide + R-Li/R-MgBr alkene hydrolysis dithiane (react twice), alkene hydrolysis, S 2, S 1and more Friedel Crafts SN2, SN1and more N N O O O R R3 R 2 H 2 R R1 N N 1 R1 N N H R1 R2 X R1 R2 R3 o o R2 2o amides 3o amides 2 amines 3 amines o o o o acid chlorides + 1 amines acid Cl + 2 amines, use ald / ket + 1 amine, then use ald / ket + 2 amine, then two couplings using imine reduction with NaH3BCN, imine reduction with NaH3BCN, enolate chemistry of LAH reduction of 2o amide LAH reduction of 3o amide various carbonyl patterns, enamines or ethers too

R2

R1 R2 R3 R1 R 3 3 R1 R1 R2 2 cuprate coupled sp /sp all carbon linkagess, disubstituted alkynes R R cis disubstituted alkenes 1 2 reduction or other (R1 and R2 must be using Wittig reaction trans disubstituted alkenes primary or methyl trisubstituted alkene functional groups or reduction of alkyne (Lindlar's) using reduction of alkyne (Na/NH3) when RX = SN2), (alkynes have some limitations), (alkynes have some limitations), using Wittig reaction, (aldehyde, ketone, alkene, open , some E1 or E2 reactions some E1 or E2 reactions some E1 or E2 reactions alkyne, etc.) (hard to see) or attack carbonyls

O X = single groups (a few examples) O O R2 R OH R Br alcohols = many possibilities

R1 O R2 many possibilities SN2, SN1 at RX R-H + Br /hν; addition to alkenes R1 2 SN2, SN1 at ROH + HBr/PBr3/SOBr2 (Markovnikov, anti-Markovnikov) cuprate conjugate addition a. TsCl/py, b. NaBr (avoids rearrangement) LAlH or NaBH reduction followed by reaction anhydrides from 4 4 of carbonyls and epoxides, with enolate intermediate acid chlorides HBr addition to alkenes (tandom reaction) + carboxylates (Markovnikov, anti-Markovnikov) ozonolysis of alkenes (WK = NaBH4); etc. O R C N R NH nitriles O 2 R C o RX + NaCN 1 amines R C o R H o o Gabriel amine syn (1 ) aldehydes SN2 at Me, 1 , 2 RX o NH2 use ald / ket + NH3, then E2, E1 with RX o 1 amide + SOCl2 oxidation of 1 ROH o ROH/H SO /∆ Sandmeyer rxn 1 amides imine reduction with NaH3BCN, 2 4 DIBAH reduction of o reduction of alkynes acid (HCl/H O) or LAH reduction of 1 amide ester, nitrile, acid Cl, makes aromatic nitriles 2 Wittig reactions base hydrolysis anti-Markovnikov addition of nitriles; O to alkyne; dithianes (1x); R C CH acid Cl + NH oxonolysis of alkenes alkynes 3 R C R (WK = CH SCH ); etc. RX + NaCCR (make) 3 3 O OH (S 2 at Me, 1o RX) O N carboxylic acids aromatic derivatives zipper reaction R C RMgBr or RLi + CO2 Friedel Crafts or o R1 double elimination (E2) Cl Jones oxidation of 1 ROH acylation; cuprate coupling; X carboxylic acid + acid or base hydrolysis of esters, Ar-MgBr or Ar-Li reactions, single coupling using SOCl or PCl or acid or base hydrolysis of nitriles and more enolate chemistry of R SH 2 3 oxalyl chloride various carbonyl patterns, thiols ozonolysis of alkenes etc. (ethers, sulfides,...) enamines or enol ethers too RX + HS (WK = H2O2); etc.

Z:\classes\316\special handouts\316 Syn & C14 strategies.doc 14C synthesis strategies, Chem 315/316 / Beauchamp 8 Use clues in the target molecule (TM) to determine what the last step could have been. Once you work back one step, use clues in that molecule (TM-1) to determine how you could work back one additional step (TM-2). Repeat 14 this process until you get to the necessary starting conditions (TM-n), i.e. allowable C starting units (*CH4, *CO2, Na*CN where “*” indicates a radioactive 14C isotope) and other allowed starting materials. Until aromatic chemistry is covered bromobenzene is also available. You may use any reagents learned in our course. Many of the simpler starting structures below were prepared in the above reactions (1C, 2C and 3C examples).

Starting Structures: Br

CH4

Examples – Target Molecules (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

TM - 1 1. NaNR2 2. O 1. NaNR2 HO 2. H2 / Pd Br * * CH2 * OH 3. WK 1. Mg or Li HBr or 2. O PBr 3 Br 1. Mg or Li HO 2. O 3. WK * Br * CH2 1. Mg or Li OH 3. WK HBr or 2. O PBr3 Br CH = C-C bond formed with nucleophile/electrophile strategy HO 2 3. WK

TM - 2 1. Mg or Li 1. Mg or Li 2. * O 2. O * HBr or * CH2 PBr Br 3 * CH2 Br HO OH 3. WK 3. WK HBr or 1. NaNR PBr3 2 2. O HO * H / Pd 2 * CH2 HO * 3. WK

Z:\classes\316\special handouts\316 Syn & C14 strategies.doc 14C synthesis strategies, Chem 315/316 / Beauchamp 9

1. Mg or Li 1. Mg or Li 2. O TM - 3 2. O * HBr or * * CH2 Br PBr Br 3 HO 3. WK * 3. WK OH HBr or 1. NaNR PBr 2 3 2. O HO H2 / Pd * * CH2 * HO 3. WK

TM - 4 1. Mg or Li 1. Mg or Li 1. Mg or Li 2. O 2. O * 2. O HBr or HBr or * Br PBr PBr3 * 3 CH2 * CH2 Br Br HO HO 3. WK 3. WK 3. WK CH3 OH * *

TM - 5 1. Mg or Li 1. Mg or Li 2. O HBr or 2. O Br PBr3 * Br * HO * CH3 3. WK OH 3. WK *

1. NaNR2 1. NaNR2 2. 2. Br O H / Pd HO * 2 * CH3 OH * 3. WK * 3. WK

TM - 6 1. Mg or Li 2. O

Br OH 3. WK

1. NaNR2 2. HO O

H2 / Pd

OH 3. WK

TM - 7 1. Mg or Li OH O CrO OH 1. Mg + *CH -Br 3 2. O 3 2. aldehyde (PCC) 3. WK Br H * 3. WK

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

1. NaNR2 O 2. 1. R2BH 2. H2O2/HO Br H (see above) 3. WK

Z:\classes\316\special handouts\316 Syn & C14 strategies.doc 14C synthesis strategies, Chem 315/316 / Beauchamp 10

TM - 8 1. Mg or Li O OH 2. O OH 1. Mg + Br CrO3 2. aldehyde pyridine Br 3. WK (PCC) * CH2 H CH * * * 3. WK 3

1. NaNR2 O OH 2.

H2 / Pd * * * H HO 3. WK

1. Mg or Li OH O OH 2. O 1. Mg + CH -Br CrO3 3 Br 2. aldehyde pyridine 3. WK (PCC) * CH2 * H * * 3. WK

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

OH OH 1. 2 equivalents 1. Mg + Br O O Mg + CH -Br 2. epoxide * H2SO4/∆ 3 1. NaOH O mCPBA 2. aldehyde 3. WK (-H2O) C R 2. R-Br * 3. WK C * * H * O H * OH

TM - 9 1. Mg or Li 1. Mg or Li 2. O 2. O OH HBr or * PBr * CH2 * 3 Br H HO 3. WK Br * 3. WK

1. NaNR2 Br 1. BH3 2. H / Pd 2. Br2/CH3O 2 quinoline * * CH3 * (Lindlar's) 3. WK

TM - 10 1. Mg or Li 1. Mg or Li OH 2. 2. O O Br HBr or * * * PBr3 * CH2 CH3 Br HO 3. WK 3. WK

TM - 11 1. Mg or Li 1. Mg or Li OH 2. O 2. O HBr or Br PBr 3 HO CH2 Br * * CH3 3. WK * 3. WK *

Z:\classes\316\special handouts\316 Syn & C14 strategies.doc 14C synthesis strategies, Chem 315/316 / Beauchamp 11 TM - 12 1. Mg or Li OH 2. O

Br 3. WK

1. NaNR OH OH 2 2. O H2 / Pd

3. WK

TM - 13 1. NaNR2 H / Pd 1. Mg + *CH3-Br 2 2. mCPBA quinoline 2. epoxide Br 3. WK (Lindlar's) * O OH (above, TM-11) * O 1. Mg + Br 1. R BH 2. aldehyde 2 3. WK 2. H2O2/HO * H OH CrO3 pyridine (PCC) 1. BH3 2. H2O2/HO HO

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

TM - 15 2 eqs. O 1. NaOH O * 1. Mg + Br 2. ester 2. R-Br R 3. WK H H O OH * H * O

TM - 16 2 eqs. O 1. NaOH O 1. Mg + Br 2. ester 2. R-Br R 3. WK H H O OH H O

1 eqs. O

1. Mg + Br 1. R2BH 2. aldehyde 2. H2O2/HO 3. WK H OH

Z:\classes\316\special handouts\316 Syn & C14 strategies.doc 14C synthesis strategies, Chem 315/316 / Beauchamp 12 Examples – Target Molecules (TM - #)

4C chain with methyl branch alcohols * 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

* * * *

TM-1 1. Mg or Li 1. Mg or Li 2. O 2. O HBr or PBr3 Br * * CH2 H Br HO 3. WK 3. WK OH 1. Mg or Li 2. O HBr or Br PBr3 CH Br HO H 3 3. WK

1. Mg or Li HBr or 2. O PBr3 Br Br HO 3. WK CH3

TM-2 1. Ts-Cl Br 1. Mg or Li 1. Mg or Li 2. pyridine O CrO O Br * 2. O 2. NaBr 1. Mg + 3 * 2. aldehyde pyridine (S 2) * N * 3. WK (PCC) HO * CH2 CH3 CH2 Br HO * H 3. WK OH 3. WK (avoids rearrangement)

TM-3 1. Ts-Cl 1. Mg or Li * 1. Mg or Li 2. O pyridine 2. O * Br 2. NaBr * (SN2) CH2 H CH3 Br HO 3. WK * (avoids rearrangement) 3. WK OH

Z:\classes\316\special handouts\316 Syn & C14 strategies.doc 14C synthesis strategies, Chem 315/316 / Beauchamp 13 TM-4 1. Ts-Cl 1. Mg or Li 1. Mg or Li Br pyridine O 2. O 2. O * CrO3 2. NaBr 1. Mg + Br 2. aldehyde pyridine (S 2) N (PCC) CH2 * CH2 3. WK HO Br HO H CH3 OH 3. WK * * 3. WK (avoids rearrangement)

TM-5 1. Mg or Li 1. Ts-Cl 2. O pyridine 1. Mg or Li 2. NaBr 2. O Br (S 2) * CH2 N Br * HO * CH3 3. WK 3. WK * OH (avoids rearrangement)

TM-6 1. Mg or Li 2. O 1. Mg or Li 2. HBr or O Br PBr3 CH2 Br HO CH3 3. WK (without * label OH 3. WK rearrangement is not a concern) same 1. Mg or Li 2. O

H HO Br 3. WK

H2 / Pd 1. NaNR2 2. O

H HO 3. WK

TM-7 (above, TM-6) HO CrO3 + H3O /H2O 1. NaNR2 Br 1. Mg + *CH3-Br O (Jones) 2. 2. ketone H2SO4 / H2O * +2 3. WK (Hg cat.) CH3 OH 3. WK

1. Mg or Li 2. O CrO3 Br * 1. Mg + Br pyridine 2. ketone (PCC) CH OH 3. WK * O * OH 3 H * 3. WK

1. NaNR2 2.

H / Pd 2 HO * * O OH * 3. WK

Z:\classes\316\special handouts\316 Syn & C14 strategies.doc 14C synthesis strategies, Chem 315/316 / Beauchamp 14 TM-8 1. 2 equivalents O * 1. Mg + Br CrO3 O 2. aldehyde pyridine Mg + CH3-Br 1. NaOH 2. ester 3. WK * (PCC) * R 2. R-Br H OH 3. WK H O O OH H * O *

TM-10 1. Mg or Li 2. O Br 1. Mg + *CH -Br * 3 H2SO4/∆ 2. aldehyde mCPBA (-H2O) CH3 3. WK * OH O OH 3. WK

TM-11 (above, TM-6) HO

CrO3 + 1. NaNR H3O /H2O 2 Br 1. Mg + CH3-Br O (Jones) 2. 2. ketone H2SO4 / H2O +2 3. WK (Hg cat.) CH3 OH 3. WK

1. Mg or Li 2. O CrO3 Br 1. Mg + Br pyridine 2. ketone (PCC) OH 3. WK O CH3 OH H 3. WK

1. NaNR2 2.

H / Pd 2 HO O OH 3. WK

1. NaNR2 TM-12 2. Br 1. Mg + *CH -Br H / Pd 3 O 2 mCPBA quinoline 2. epoxide CH3 * 3. WK (Lindlar's) 3. WK OH Z alkenes

1. Mg + *CH3-Br O 2. epoxide mCPBA Na / NH3 3. WK

E alkenes

1. Mg or Li 1. Mg or Li 2. O 2. O HBr or Br H PBr3 * H Br OH CH3 OH 3. WK * * * 3. WK

TM-13 1. Mg or Li 1. Mg or Li 2. O 2. O TM-8 2 eqs. HBr or R Br PBr3 * H * * H * O Br OH CH3 OH 3. WK 3. WK

Z:\classes\316\special handouts\316 Syn & C14 strategies.doc 14C synthesis strategies, Chem 315/316 / Beauchamp 15

TM-14 1. Mg or Li O CrO OH 2. O Br 1. Mg + Br 3 * 2. aldehyde pyridine CH 3. WK (PCC) * CH2 3 * H * OH 3. WK

TM-15 1. Mg or Li 2. O 1. Mg + *CH3-Br H CrO3 * 2. aldehyde pyridine 3. WK (PCC) CH 2 Br OH O OH 3. WK

TM-16 1. Mg or Li 2. O

H Br OH 3. WK

TM-17 1. Mg or Li 1. Mg or Li 2. O OH 2. O HBr or Br PBr3 H Br OH CH * 3. WK * 3 * * 3. WK

TM-18 1. Mg or Li 1. 2 equivalents O OH 2. O O HBr or Mg + CH3-Br 1. NaOH 2. ester * PBr3 * R 2. R-Br 3. WK H OH H O * 3. WK Br * H * O

TM-19 1. Mg or Li 1. Mg or Li OH 2. O 2. O HBr or Br OH CH2 PBr3 * CH2 3. WK * * 3. WK Br *

TM-20 1. Mg or Li 1. Mg or Li 2. 2. O OH O HBr or Br OH * CH2 PBr3 CH2 * 3. WK 3. WK Br

TM-21 1. Mg or Li 2. O OH

Br 3. WK

Z:\classes\316\special handouts\316 Syn & C14 strategies.doc 14C synthesis strategies, Chem 315/316 / Beauchamp 16 Some important 1C, 2C and 3C building blocks that are used in the C-14 syntheses that follow.

1 Carbon – some examples of reagents that allow synthetic transformations among these structures. O N R O O Br Br SN2 OH O SH NH2 OH 2 C O R hν (Nu: ) oxidation CH4 C C CH3 CH3 CH CH CH 3 3 3 CH CH CH3 H OH 3 3 CH3 H H 1. O (HO ) (RO ) (HS ) CrO (NC ) (HCC ) (RCO2 ) 3 CrO3 available make available + N available make make pyridine H3O /H2O PCC Jones make O 2. NaOH Mg/Li organometallic reactions anhydride (RCO H) H C (MgBr) 2 3 O O H3C O ester (ROH) (from CH3Br + Mg) H C OH o 3 OH 1 amide (NH3) or E C C O C 2o amide (RNH ) O 2 H C OH H3C CH3 H C Cl o 3 3 3 amide (R2NH) H3C Li 2. workup CH (from (CO2) 2 H3CCN aldehyde (R2AlH = DIBAH) (from CH Br + Li) + 3 available RCO2H + SOCl2) ketone (R2Cu Li = cuprate) cuprate reactions 3. coupling with α,β-unsaturated carbonyl (3 reaction types for us) 1. coupling with other RX compounds 2. coupling with RCOCl = acid chloride O O O O H C Cu CH cuprate cuprate 3 3 Br R H3CR cuprate C C Li R CH makes alkane-like structure R Cl 3 (from 2 CH Li + CuI) β addition to conjugated 3 makes ketones carbonyl compound CH3

Wittig reactions Ph Ph 2. carbonyl Ph Ph Ph Ph P 1. n-butyl lithium compound R Br P S 2 P Ph Ph N (very strong base) O CH Br makes very CH 3 CH2 3 Ph C specific alkenes (Wittig salt) ylid nucleophile R H

2 Carbons – some examples of reagents that allow synthetic transformations among these structures.

S 2 Br2 N O hν (Nu: ) NH C Br OH OR SH 2 1. O N (HO ) (RO ) (HS ) O R (NC ) (HCC ) available make available N (RCO2 ) available make make make O 2. NaOH

O O 3 equivalents OH O K+ t-butoxide Br2 Br 1. NaNR oxidation Br 2 Br 2. next OH C NaCN H Na CrO3 CrO3 O pyridine + O H SO /∆ H3O /H2O OH 2 4 2. react with various available mCPBA PCC Jones electrophiles (or WK)

OH Mg/Li organometallic reactions O (MgBr) OH O OH H3C H2C (or Li+) OH E O from Mg (or Li) OH O O + + O 2. workup E = + E = + E = H3CCN E = (E+ = CO ) R 2 E+ = O Br H H H Z:\classes\316\special handouts\316 Syn & C14 strategies.doc 14C synthesis strategies, Chem 315/316 / Beauchamp 17

organocuprate reactions coupling with coupling with RCOCl coupling with other RX compounds (acid chloride) α,β-unsaturated carbonyl O O O Li + 0.5 CuBr Cu E H3C H2C cuprate + Li E = + Li cuprate nucleophiles R-Br = E O (3 reaction types for us) E+ = Br Cl E+ = electrophile makes alkane-like structure conjugate addition Br makes ketones

CrO3 / pyridine (PCC) α α O β O β OH OH 1. NaOH O HBr OH 2. R-Br α 1. E O (1 eq.) Li O O β Br Li OR CO2 2. WK CH2 H N(CH3)2 E+ = electrophile E+ E+ =E+ = DMF E+ = α,β-unsaturated carbonyl compounds

OH acid chloride reactions make (with) OH anhydride (RCO2H) O O ester (ROH) o 1. E 1 amide (NH3) (SOCl2) o O O 2 amide (RNH2) Na 2. workup o OH Cl 3 amide (R2NH) Br aldehyde (R AlH = DIBAH) + 2 + E+ = H E = ketone (R Cu Li+ = cuprate) E = electrophile E+ = 2

Ph Wittig reactions Ph 2. carbonyl nBu Li Ph Ph compound Ph Ph P P P 1. n-butyl lithium Ph Ph O SN2 (very strong base) CH Br + Ph Br E = acid/base H3C makes very specific (Wittig salt) reaction ylid nuclephile H alkenes (usually Z)

O makes iminium o o o 1. , then reduced imines and amines (1 , 2 and 3 ) O 1. H B CN 3 E+ = E+ = Na H H NH 2. workup 2 H N N pH≈5 (-H O) 1o amine N 2 o pH≈5 (-H O) 2. (from Gabriel 1 amine 2 reduced H imine H B CN 2o amine3 3o amine synthesis or LAH reduction 3. workup Na of nitrile)

O enamines H2SO4/H2O (Hg+2) H O alkylation Markovnikov E+ = O N + N E = Br O H 1. R2BH 2. workup H 2. H2O2/HO pH≈5 (-H2O) (regenerates H 2o amine enamine anit-Markovnikov C=O group)

Z:\classes\316\special handouts\316 Syn & C14 strategies.doc 14C synthesis strategies, Chem 315/316 / Beauchamp 18 protection of aldehyde as acetal and ketone as ketal Reaction occurs at Could attack with RBr, not ketone. Grignard here in another reaction. TsO-H dilute O O (-H2O) NaCN H SO N O O O N 2 4 O C Br C HO Br Ketone is ketal ketone regenerated ketone OH ketal (deprotected). Could also make Grignard here.

protection of alcohol as THP acetal THP = (MgBr) THP = dilute O H SO 2 4 OH TsO-H H3C H2C OH O O O O Alcohol is addition regenerated OH O reaction 2. workup alcohol DHP O acetal OH acetal (deprotected).

3 Carbons – Just a few selective examples. There are too many possibilities to be comprehensive.

NH2 O 1. O Doesn't work because N RX is secondary Br2 SN2 NaOH hν (Nu: ) O R C (E2 instead). OH make O Br (RCO2 ) N + make 2o alcohols 2. NaOH (NC ) (HCC ) E = make esters

3 equivalents 2. react with various OH O O K+ t-butoxide 1. NaNR2 Br2 Br Na electrophiles oxidation 2. next (or WK) Br Br Li N CrO3 α CrO H SO /∆ O 3 CrO3 2 4 mCPBA pyridine O β pyridine R R HO water OH (PCC) PCC Jones LDA

Mg/Li organometallic reactions O OH O OH (MgBr) E OH OH 2. workup or O from Li O E+ = O (E+ = CO ) E+ = 2 H CCN 2 equivalents E+ = 3 organometallic R + O (from R-Br) H E =

coupling with coupling with RCOCl organocuprate reactions other RX compounds (acid chloride) coupling with O α,β-unsaturated carbonyl O O (H3C)2HC + 0.5 CuBr E Li Cu cuprate Li Li O + E = + + cuprate reactions Br E = E = (3 reaction types for us) Cl conjugate addition Br makes alkane-like structure makes ketones

Z:\classes\316\special handouts\316 Syn & C14 strategies.doc 14C synthesis strategies, Chem 315/316 / Beauchamp 19

O O 1. BH3 2. H2O2, HO OH H OH CrO CrO HBr or 3 3 pyridine + H3O /H2O PBr3 NaOH, DMSO PCC Jones O 1. BH3 2. Br , CH O 2 3 SN2 NH C O R Br (Nu: ) OR SH 2 N (HS ) 1. O 1. Mg or Li (RO ) (NC ) (HCC ) (RCO2 ) 2. electrophile N 3. WK organometallic O reactions 2. NaOH

acid chloride reactions OH make (with) OH Na anhydride (RCO2H) O O ester (ROH) (SOCl2) o 1 amide (NH3) o E 2 amide (RNH2) O O OH Cl o 3 amide (R2NH) 2. workup E+ = Br aldehyde (R AlH = DIBAH) + 2 E+ = E = ketone (R Cu Li+ = cuprate) H 2

Ph Wittig reactions Ph Ph Ph 2. carbonyl Ph Ph Bu Li P compound P P SN2 1. n-butyl lithium Ph Ph O (very strong base) H3C CH Br Br C + + Ph E = E = acid/base H2 makes very specific reaction alkenes (usually Z) (Wittig salt) ylid nucleophile H

o o o make iminium salt imines and amines (1 , 2 and 3 ) 1. O E+ = O E+ = 1. H3B CN H H N N NH 2 H Na pH≈5 (-H2O) o N 2. workup 2. 1 amine from H pH≈5 (-H2O) H B CN Gabriel amine o 3 imine 2 amine o synthesis (reduced) 3. workup Na 3 amine

enamines O H2SO4/H2O +2 H alkylation (Hg ) O O Markovnikov + N E = N Br + E = O 1. R2BH 2. workup 2. H2O2/HO pH≈5 (-H2O) regenerates o 2 amine enamine anti-Markovnikov H C=O compound

Z:\classes\316\special handouts\316 Syn & C14 strategies.doc 14C synthesis strategies, Chem 315/316 / Beauchamp 20 Key strategies in a 14C synthesis problem?

1. How do you prepare RX compounds? (Use bromides as a consistent, reliable target.)

a. from alkenes (Markovnikov reaction)

Br HBr R R

b. from alkenes (anti-Markovnikov reaction)

1. BH3 OH HBr Br 2. H2O2, HO R R R

1. BH3 2. Br2, CH3O

o o o c. from alcohols (HBr or PBr3), SN2 at 1 ROH and SN1 at 2 ,3 ROH, use 1. make tosylate, 2. NaBr to avoid rearrangement 1. Ts-Cl / pyridine 2. NaBr (S 2) HBr PBr3 N R OH R Br R OH R Br R OH R Br possible rearrangement at 2o RX possible rearrangement at 2o RX avoids rearrangements

2. Generation of an organometallic nucleophile from an RX compound

a. organomagnesium reagents (Grignard reactions) and organolithium reagents (mostly interchangeable in our course).

R Br Mg R (MgBr) R Br 2 Li R Li

3. Organometallic nucleophiles + organic electrophiles (e- pair acceptors), WK = work up = acidic neutralization

a. formaldehyde (methanal) = 1C extension of R:-- with 1o alcohol functionality at the end

O H2 C (MgBr) R C R OH H H 2. WK 1o alcohol

b. ethylene oxide (epoxides) = 2C extension of R:-- with alcohol functionality

R R R O H O 2 R CH R C O R C C OH C OH C OH R Li R H H2 R H2 2 R 2. WK 2. WK Li 2. WK o Li 3o alcohol 1o alcohol R 2 alcohol R

c. general aldehydes = extension of R:-- with 2o alcohol functionality

O OH

C o R (MgBr) CH 2 alcohol R' H 2. WK R R'

Z:\classes\316\special handouts\316 Syn & C14 strategies.doc 14C synthesis strategies, Chem 315/316 / Beauchamp 21 d. general ketone = extension of R:-- with tertiary alcohol functionality

OH O

o C 3 alcohol (MgBr) C R R R" R' R" 2. WK R'

e. general ester = extension of R:-- with tertiary alcohol functionality (at least two identical R' groups)

OH O 3o alcohol with two 2 equivalents identical R groups, C C R"O is lost during R R R (MgBr) R' OR" 2. WK R' the reaction.

f. carbon dioxide = extension of R: -- with carboxylic acid functionality (can be converted into ester with RX)

O Carbon dioxide is like having two carbonyl groups on one carbon, where R (MgBr) O C O C carboxylic only one actually reacts. Organolithium 2. WK R OH acids reagents can react twice and form ketones.

4. Remember additional reactions of alcohols, RX compounds, alkenes, alkynes, carbonyls (aldehydes, ketones, esters, acids and others will accumulate).

a. alcohols can be made into RX compounds (above, chlorides, bromides, iodides, tosylates). Reactions occur by SN2 at methyl and primary and SN1 at secondary and tertiary (with possibility of rearrangement) in our course.

HCl or PCl HBr or PBr 3 3 1. Ts-Cl / pyridine or SOCl2 or SOBrl2 HI R OH R Cl R OH R Br R OH R I R OH 2. NaBr (SN2) R Br (avoids rearrangement)

o o o o b. RX compounds can react with nucleophiles in SN2 (methyl, 1 and 2 ) and SN1 (2 and 3 ) reactions

i. cyanide (nitriles at methyl, 1o and 2o RX) O H2SO4 H O/∆ 2 R

OH HCl O H2O R

NH2 Na CN R CN R Br 1. LiAlH nitriles 4 2. WK (SN2) R

NH2 1. DIBAH O (R2Al-H) 2. WK R

H

1. R'Li O 2. WK R

R'

Z:\classes\316\special handouts\316 Syn & C14 strategies.doc 14C synthesis strategies, Chem 315/316 / Beauchamp 22 ii. terminal acetylides (react at methyl and 1o RX, epoxides, ketones and aldehydes), and can be converted into aldehydes, ketones, alkanes, and E/Z-alkenes.

R' Br H2 / Pd quinoline (SN2) R CCR' R (Lindlar's cat.) O R' OH 1. Z alkenes 2. WK R CC O R CCH1. NaNR2 Na CCR C Na / NH3 R' OH terminal alkynes 1. H H R acid/base 2. WK E alkenes R CC O

C 1. R BH H2SO4/H2O 2 1. R H OH (Hg+2) 2. H2O2/HO 2. WK Markovnikov anti-Markovnikov R CC O R O R C 1. R R OH R O 2. WK R CC R H methyl ketones aldehydes R

iii. triphenylphosphine (makes phosphonium salts, used in Wittig reactions with aldehydes/ketones to make alkenes)

Wittig reaction P O R R Ph Ph Br R Ph 1. nBuLi C P (acid/base) R Br PH P R' H 2 PH2 SN2 H P PH2 PH aldehydes R' 2 H2P 2 and Z alkenes Wittig salt ylid nucleophile ketones

o iv. phthalimide anion (make 1 amines after hydrolysis with aqueous hydroxide, or , H2NNH2)

O O O O R

1. NaOH Br 2. NaOH O (acid/base) N R N H N O SN2 R NH2 o O O 1 amine O O throw away

v. esters (acetates), then hydrolyze to form alcohols (most useful at 2o RX), additional chemistry is possible.

R' O O O 1. NaOH Br NaOH R' (acid/base) R' R OH SN2 R O R O OH carboxylic acids carboxylates esters alcohols RX compounds

c. primary alcohols can be oxidized to aldehydes or carboxylic acids (…which can be made into esters, see above)

1. NaOH CrO3 / HCl (acid/base) O O O 2. R' N CrO R OH R OH 3 + R' H3O / H2O Br R H R OH R O o (PCC) o 1 alcohols aldehydes 1 alcohols (Jones) carboxylic acids SN2 esters

Z:\classes\316\special handouts\316 Syn & C14 strategies.doc 14C synthesis strategies, Chem 315/316 / Beauchamp 23 d. secondary alcohols can be oxidized to ketones with either of our “Cr+6” oxidizing reagents

OH CrO / HCl OH 3 O O CrO N 3 + R R R R H3O / H2O R R R R o 2o alcohols (PCC) ketones 2 alcohols (Jones) ketones

o o e. aldehydes/ketones reduced to alcohols (1 and 2 ) by LiAlH4 and NaBH4 after acid workup

O OH O OH 1. Na BH 4 1. Li AlH4 2. WK R H R R R' 2. WK R R' aldehydes 1o alcohols ketones 2o alcohols

f. esters and acids are only reduced by LiAlH4 (not NaBH4), to primary alcohols after acid workup

OH O R' O HO 1. Na BH4 R' 1. Li AlH4 R' No reaction 2. WK R maybe keep or 2. WK R O maybe throw R O (slow reaction) esters 1o alcohols away esters

Obviously not ever reaction cannot be covered in this short handout, but this hopefully gives you a sample of reactions for approaching these kinds of problems.

Points to ponder when considering a retrosynthetic step.

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 (and skeletal parts) 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 (or structures). 5. What portion has to be added and how can we do that (usually nucleophile/electrophile or functional group interconversion) 6. Is protection required to keep some part of the starting structure from reacting (often more advanced than we consider)?

Starting possibilities to produce alcohol OH or carboxylic acid OH (only CO2).

O O Br O O O O

C C C C C C R' C C CC R H R R" R H R R' R O methanal O R' (formaldehyde) aldehydes ketones esters carbon dioxide alkenes epoxides RX compounds

Z:\classes\316\special handouts\316 Syn & C14 strategies.doc 14C synthesis strategies, Chem 315/316 / Beauchamp 24 Combination Problems – Two (or more) 14C structures in one target molecule.

Esters Alcohols acyl substitution Fischer ester synthesis OH O Make R1 and SN2 O O O R2 skeletons.

C R2 R1 C R3 R2 C C R2 C R R1 O HO 2 R Cl R OH Br R1 OH 1 1 HO R2 (NaOH) o o o (TsOH / -H2O) 1 , 2 or 3 ROH

Ketones Make R and o 1 nitrile approach traditional 2 alcohol R2 skeletons. cuuprate approach approach (oxidize with O 2 eqs. 1. R2 O N N CrO3) alkynes O O OH Li R2 R C C 1 C Br Br C R1 R R R2 2 1 C C CH R R1 OH R1 R2 Br Br + R1 Cl Cl R1 R1 R2 H3O /H2O 2. workup Alkynes Wittig Reactions

R1 O R2 O R1 R2 Make R1CH2- and R1 R2 R2CH2-skeletons. (must be primary) Terminal Ph3P Ph3P Alkynes Br H R2 Br H R1 S 2 N Ethers Amines Amides Cuprate Couplings O O R3 O R1 R2

R1 R2 H C R C R2 N N 2 Both R1 and R2 come from R-Br R N Join in SN1, SN2 and R1 N 1 compounds. One is made into lithium R1 R2 R1 R2 H addition reactions to Use amine/carbonyl synthesis of imine and reagent to react with other as RBr. alkenes. R reduce with cyanoborohydride. Use acid chlorides and amines. 3 Hard to see, because there are no clues.

Generic examples of 4C patterns with one C-14 label and specific patterns using above functional groups

Example 4C patterns with C-14 labels

* * * * X X * X X * * X X * * X X * * * X X X

X X * Esters - S 2, Fischer syn, Ketones - from cuprates, nitriles, o N Alkynes - Me, 1 RX Alkenes (Wittig) acid chlorides + alcohol alcohols, carboxylic acids O O * * * * * * O * * Amines - Gabriel, reductive amination Alcohols - C=O + organometallic Amides - acid chloride Ethers - S 2, S 1, alkene addition + amine N N * OH * * * * * N N * O O * * H H

Cuprates - conjugate addition Anhydrides - use acid chloride Cuprates - coupling (2 x RX) * O O O Construct two (or more) 4 carbon patterns, then join them together * using one of the above functional * O groups. * * O *

Z:\classes\316\special handouts\316 Syn & C14 strategies.doc