Clarke Flashcards
what features do you want in a protecting group
stability, improving stereo-selectivity and purification, orthogonal protection
list some silicon protecting groups in order of stability
Me3Si (TMS) < Ph3Si < MetBuSi (TBS) < iPr3Si (TIPS) < Ph2tBuSi (TBDPS)
What group is usually attached to a Si protecting group to act as a good leaving group for a reaction to happen?
Cl (or OTf)
What two solvents are regularly used with silicon protecting groups
Triethylamine and imidazole
What does a silicon group protect?
OH
How do you remove a silicon protecting group?
F- ions. So HF is good for most «< but TBAF removes any
What is orthogonal protection?
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 -
Name some other OH protecting groups
benzyl // MOM // MTM // MEM
what’s the relationship between MOM, MTM and MEM?
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.
What is the main aim of an amine protecting group?
need to prevent basic/nucleophilic properties affecting other reagents
Name some amine protecting groups
benzyl (Bn) // Tert-butylcarbonyl (BOC) // carboxybenzyl (Cbz) // fluorenylmethyloxycarbonyl (Fmoc)
(phthalimide, tosyl and tert-butyl as well).
What would you deprotect an amine group with?
varies with different groups
What amine protecting groups would you deprotect with Pd/C and H2?
Bn and Cbz
What amine protecting groups would you deprotect with HCl or TFA?
BOC (TFA = trifluoroaceticacid)
What amine protecting groups would you deprotect with NR3?
Fmoc
What reagent do you use to add a protecting group to an amine?
Et3N
What molecules can you use to ortholithiate a benzene ring?
oxazoline and bulky amide
How does an oxazoline bond to a benzene with CO2H? + SOCl3
SOCl3 turns CO2H into COCl which is then attached by the nitrogen and another SOCl3 is used to cyclise the structure.
Why do you need a bulky amide to ortholithiate a benzene ring? cf a dimethyl amino
a dimethyl amino would just results in an addition elimination reaction
which is better at directing ortholithiation?
CONHR2 vs Oxazoline?
diether vs SO2R
OR vs C(=NR)R
CONHR2
SOR2
C(=NR)R
How would you remove an oxazoline group?
hydrolyse with any acid
What properties do multiple directing groups have on a benzene ring
they work together
What ethers are good directing groups?
MOM and MEM
how would you make an aniline a better ortholithiator?
convert to n-BOC aniline
What reagents would you do a halogen-lithium exchange with?
nBuLi in Et2O or pentane
or 2:1 tBuLi
What is a superbase?
What special property does it have regarding directing groups?
tBuOK - strong ligand for Li.
they have little influence - the most acidic proton will be removed.
Name some reactions to make organometallic nucleophiles
transmetallation // grignard-exchange reaction // insertion/oxidative addition
Which organometallic metals have problems with reactivity?
Mg and Zn - particle size too large and oxide layers present
What are some methods of activating unreactive metals for organometallic reagents?
Stir under argon, iodine catalyse, dibromoethane catalyst, Reike (lithium in Napthalene)
benefit of orangozinc?
more tolerant than organolithium and Mg and has good functional group tolerance
What is the reformatsky reagent?
Br-ester + Zn —> ester-CH2ZnBr
What does the reformatsky reagent do?
ROOCBr –> reagent + ketone –> ROOCCH2[tertalcohol].
How would a lewis base increase Zn reactivity?
organozinc donates electron density and breaks up aggregates
How would a lewis acid increase Zn reactivity?
eg using MgCl2 - electrons can be removed from a C=O bond to make it more reactive to ZnBr reagent
Name some reactions of organocuprates
Sn2 alkylations // Sn2’ with allylic halides // limiting addition elimination // conjugate addition
Where does Cu react in a conjugate addition reaction?
1,4
Where are copper reagents normal made?
in situ
Explain what you would do if you were using the Felkin-Anh model
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.
Explain what you would do if you were using the chelation control model?
‘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.
Why would you use the chelation control model instead of the felkin-anh?
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
What is the optimal angle called for attacking the C=O
Burgi-Dunitz
what are the 3 reactions in a Pd-cross-coupling catalytic cycle?
oxidative addition, transmetallation, reductive elimination
Order aryl halides for reactivity
Ar-I > Ar-Br ~ Ar-OTf > Ar-Cl»_space;> Ar-F
Order steric effects of subsitutents for reactivity
p-EWG > m-EWG > o-EWG > p-EDG > o-EDG > o-EDG+o-R
when reacting a Pd catalyst with an Ar-I compound, which reacts faster L2Pd or L1Pd (with bulky ligands)
L1Pd
What is significant about cross coupling with ArCl?
can only react if highly activated
To activate a reasonably unreactive ArX compound what ligands could you put on the L1Pd?
bulky: John-Phos or tri-tBuphosphine
What does the Suzuki coupling do?
Ar-B(OH)2 + ArX –> Ar-Ar
How would you improve nucleophile strength in a Suzuki coupling?
use base additives eg CsF, KF, NAOH, NaOMe
What is Negishi coupling?
cross-coupling reaction with organozinc - ArZnI + ArX —> Ar-Ar
How do Negishi and Suzuki and Stille coupling compare with regards to functional group tolerance?
Negishi is the least (but most reactive)
What type of reagents are used in Stille coupling reactions
(Ar- )Tin (-R3)
How would you improve the reactivity of a Stille coupling
add CuCl or LiCl
Why would you use Stille over Suzuki or Negishi?
extreme f.g.t. and good for diene synthesis
vs biaryl and aryl-alkene synthesis of Suzuki and Negishi
What does the sonogashira coupling do?
couples alkynes and X groups using copper species in situ
What is Pd catalysed amination?
RRNH + ArX —> RRN-Ar
only needs mild conditions and has good f.g.t. (weaker base better f.g.t.)
applications of Pd-catalysed amination?
cross-coupling secondary amines // primary amine synthesis “ammonia equivalents”
what is amidocarbonylation?
substitution of ArX to Ar-C=O(NHR) using a Pd catalyst, CO and RNH2 and base
What is the Heck reaction?
complexes alkene to Pd complex, migratory insertion, B-hydride elimination, reductive elimination, oxidative addition
What isomer product is preferred from the Heck reaction?
trans - due to the syn elimination
what is ring closing metathesis?
way of making cyclic alkenes by combining two alkenes
