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Synthetic Methodology > Clarke > Flashcards

Clarke Flashcards

1
Q

what features do you want in a protecting group

A

stability, improving stereo-selectivity and purification, orthogonal protection

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2
Q

list some silicon protecting groups in order of stability

A

Me3Si (TMS) < Ph3Si < MetBuSi (TBS) < iPr3Si (TIPS) < Ph2tBuSi (TBDPS)

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3
Q

What group is usually attached to a Si protecting group to act as a good leaving group for a reaction to happen?

A

Cl (or OTf)

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4
Q

What two solvents are regularly used with silicon protecting groups

A

Triethylamine and imidazole

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5
Q

What does a silicon group protect?

A

OH

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6
Q

How do you remove a silicon protecting group?

A

F- ions. So HF is good for most «< but TBAF removes any

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7
Q

What is orthogonal protection?

A

When two different protecting groups (of different strengths and removed by different molecules) are used in one molecule to preferentially react to one or the other OH -

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8
Q

Name some other OH protecting groups

A

benzyl // MOM // MTM // MEM

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9
Q

what’s the relationship between MOM, MTM and MEM?

A

MOM is methoxymethyl ether, MTM is methyl thiomethyl ether - so the same as MOM but with a sulfur, MEM is methoxyethoxymethyl ether - same as MOM but with an extra O bridged with ethyl.

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10
Q

What is the main aim of an amine protecting group?

A

need to prevent basic/nucleophilic properties affecting other reagents

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11
Q

Name some amine protecting groups

A

benzyl (Bn) // Tert-butylcarbonyl (BOC) // carboxybenzyl (Cbz) // fluorenylmethyloxycarbonyl (Fmoc)

(phthalimide, tosyl and tert-butyl as well).

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12
Q

What would you deprotect an amine group with?

A

varies with different groups

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13
Q

What amine protecting groups would you deprotect with Pd/C and H2?

A

Bn and Cbz

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14
Q

What amine protecting groups would you deprotect with HCl or TFA?

A

BOC (TFA = trifluoroaceticacid)

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15
Q

What amine protecting groups would you deprotect with NR3?

A

Fmoc

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16
Q

What reagent do you use to add a protecting group to an amine?

A

Et3N

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17
Q

What molecules can you use to ortholithiate a benzene ring?

A

oxazoline and bulky amide

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18
Q

How does an oxazoline bond to a benzene with CO2H? + SOCl3

A

SOCl3 turns CO2H into COCl which is then attached by the nitrogen and another SOCl3 is used to cyclise the structure.

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19
Q

Why do you need a bulky amide to ortholithiate a benzene ring? cf a dimethyl amino

A

a dimethyl amino would just results in an addition elimination reaction

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20
Q

which is better at directing ortholithiation?
CONHR2 vs Oxazoline?
diether vs SO2R
OR vs C(=NR)R

A

CONHR2
SOR2
C(=NR)R

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21
Q

How would you remove an oxazoline group?

A

hydrolyse with any acid

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22
Q

What properties do multiple directing groups have on a benzene ring

A

they work together

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23
Q

What ethers are good directing groups?

A

MOM and MEM

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24
Q

how would you make an aniline a better ortholithiator?

A

convert to n-BOC aniline

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25
Q

What reagents would you do a halogen-lithium exchange with?

A

nBuLi in Et2O or pentane

or 2:1 tBuLi

26
Q

What is a superbase?

What special property does it have regarding directing groups?

A

tBuOK - strong ligand for Li.

they have little influence - the most acidic proton will be removed.

27
Q

Name some reactions to make organometallic nucleophiles

A

transmetallation // grignard-exchange reaction // insertion/oxidative addition

28
Q

Which organometallic metals have problems with reactivity?

A

Mg and Zn - particle size too large and oxide layers present

29
Q

What are some methods of activating unreactive metals for organometallic reagents?

A

Stir under argon, iodine catalyse, dibromoethane catalyst, Reike (lithium in Napthalene)

30
Q

benefit of orangozinc?

A

more tolerant than organolithium and Mg and has good functional group tolerance

31
Q

What is the reformatsky reagent?

A

Br-ester + Zn —> ester-CH2ZnBr

32
Q

What does the reformatsky reagent do?

A

ROOCBr –> reagent + ketone –> ROOCCH2[tertalcohol].

33
Q

How would a lewis base increase Zn reactivity?

A

organozinc donates electron density and breaks up aggregates

34
Q

How would a lewis acid increase Zn reactivity?

A

eg using MgCl2 - electrons can be removed from a C=O bond to make it more reactive to ZnBr reagent

35
Q

Name some reactions of organocuprates

A

Sn2 alkylations // Sn2’ with allylic halides // limiting addition elimination // conjugate addition

36
Q

Where does Cu react in a conjugate addition reaction?

A

1,4

37
Q

Where are copper reagents normal made?

A

in situ

38
Q

Explain what you would do if you were using the Felkin-Anh model

A

put the large R group perpendicular to the C=O and then attack at the hydrogen which ‘should’ be around 107 degrees. Then rotate to put the large R group app to the nucleophile.

39
Q

Explain what you would do if you were using the chelation control model?

A

‘think of the chelated intermediate’ so put whatever would chelate with in line with the C=O then redraw staggered and nucleophilic attack where the H is 90 degrees to the C=O.

40
Q

Why would you use the chelation control model instead of the felkin-anh?

A

if there is a relatively unhindered heteroatom present that can form a 5/6 membered ring with the C=O and the metal ion. Or if chelation is unlikely but heteroatoms are present - the most stable configuration is the heteroatom 90 degrees to the C=O

41
Q

What is the optimal angle called for attacking the C=O

A

Burgi-Dunitz

42
Q

what are the 3 reactions in a Pd-cross-coupling catalytic cycle?

A

oxidative addition, transmetallation, reductive elimination

43
Q

Order aryl halides for reactivity

A

Ar-I > Ar-Br ~ Ar-OTf > Ar-Cl&raquo_space;> Ar-F

44
Q

Order steric effects of subsitutents for reactivity

A

p-EWG > m-EWG > o-EWG > p-EDG > o-EDG > o-EDG+o-R

45
Q

when reacting a Pd catalyst with an Ar-I compound, which reacts faster L2Pd or L1Pd (with bulky ligands)

A

L1Pd

46
Q

What is significant about cross coupling with ArCl?

A

can only react if highly activated

47
Q

To activate a reasonably unreactive ArX compound what ligands could you put on the L1Pd?

A

bulky: John-Phos or tri-tBuphosphine

48
Q

What does the Suzuki coupling do?

A

Ar-B(OH)2 + ArX –> Ar-Ar

49
Q

How would you improve nucleophile strength in a Suzuki coupling?

A

use base additives eg CsF, KF, NAOH, NaOMe

50
Q

What is Negishi coupling?

A

cross-coupling reaction with organozinc - ArZnI + ArX —> Ar-Ar

51
Q

How do Negishi and Suzuki and Stille coupling compare with regards to functional group tolerance?

A

Negishi is the least (but most reactive)

52
Q

What type of reagents are used in Stille coupling reactions

A

(Ar- )Tin (-R3)

53
Q

How would you improve the reactivity of a Stille coupling

A

add CuCl or LiCl

54
Q

Why would you use Stille over Suzuki or Negishi?

A

extreme f.g.t. and good for diene synthesis

vs biaryl and aryl-alkene synthesis of Suzuki and Negishi

55
Q

What does the sonogashira coupling do?

A

couples alkynes and X groups using copper species in situ

56
Q

What is Pd catalysed amination?

A

RRNH + ArX —> RRN-Ar

only needs mild conditions and has good f.g.t. (weaker base better f.g.t.)

57
Q

applications of Pd-catalysed amination?

A

cross-coupling secondary amines // primary amine synthesis “ammonia equivalents”

58
Q

what is amidocarbonylation?

A

substitution of ArX to Ar-C=O(NHR) using a Pd catalyst, CO and RNH2 and base

59
Q

What is the Heck reaction?

A

complexes alkene to Pd complex, migratory insertion, B-hydride elimination, reductive elimination, oxidative addition

60
Q

What isomer product is preferred from the Heck reaction?

A

trans - due to the syn elimination

61
Q

what is ring closing metathesis?

A

way of making cyclic alkenes by combining two alkenes

Synthetic Methodology (2 decks)

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