1
Functional Group Interconversions
1. The most important thing to remember is any functional group can be converted to any other functional
group
a) Organize by oxidation state changes and C addition or deletion
b) Alcohols, aldehydes/ketones, carboxylic acids are central
2. Alcohols, aldehydes/ketones, carboxylic acids
a) oxidation and reductions
i) 1° alcohols → aldehydes by PCC, oxidant and catalytic TPAP, Dess–Martin reagent
ii) aldehydes → carboxylic acids by Ag2O, NaClO2
iii) 1° alcohols → carboxylic acids by Jones reagent (CrO3, aq. H2SO4)
iv) acids → 1° alcohols by BH3
v) esters → 1° alcohols by LiAlH4, DIBAL (i-Bu2AlH)
vi) aldehydes → 1° alcohols by NaBH4, LiAlH4, DIBAL, BH3
vii) esters → aldehydes by DIBAL (not always!)
viii)CH2O → 1° alcohols by RLi, RMgBr, RCeCl2, in some cases RZnCl
ix) CO2 → acids by RLi, RMgBr
x) 2° alcohols → ketones by PCC, oxidant and catalytic TPAP, Dess–Martin reagent
xi) ketones → 2° alcohols by NaBH4, LiAlH4, DIBAL, BH3, etc.
xii) aldehydes or HCO2Et → 2° alcohols by RLi, RMgBr, RCeCl2, in some cases RZnCl
xiii)RCON(Me)OMe (Weinreb amides) → ketones by RLi or RMgBr
xiv)ketones or esters → 3° alcohols by RLi, RMgBr, RCeCl2
OH
Increasing Substitution
Increasing Oxidation State
R
OH
R
O
R
H
R
1
O
R´´
R´
R
R´
2
3
O
OH
R
O
1
R
R´
OH
1
X
1
From the ester
From the formate ester
3
From the Weinreb amide
2
O C O
b) Carboxylic acids, carboxylic esters, carboxylic amides, nitriles, and acyl halides are all interconvertible
i) any RCOX or RC≡N → RCO2H with aq. base or aq. acid
ii) RCO2H or RCO2Et → RCO2Et or RCONR2 via acyl halide, with a carbodiimide, with catalytic
acid, or in some cases with no extra reagent
iii) RCONH2 → RC≡N with POCl3 or other inorganic acyl halides
c) Stereoselective reductions
i) rigid cyclohexanones
a) equatorial alcohols with small reagents (NaBH4, LiAlH4)
(1) axial attack on electrophile is stereoelectronically favored
b) axial alcohols with very bulky reagents (Li(s-Bu)3BH)
(1) axial approach to electrophile is sterically hindered
2
O
O
Me
O
Me
equatorial approach
sterically favored
NaH
O
H
R 3B
CN
axial approach
sterically disfavored,
stereoelectronically
favored
O–
Me
LiBH(s-Bu)3
Me H CN
H
H
R 3B
Me
Me
HO
O
O
O
CN
ii) acyclic ketones
a) neighboring OH groups can H-bond to carbonyl O and bias conformation of compound
O
H
OH H
H
O NaBH4
O
meso only
Ph
Ph
Ph H
Ph H
b) neighboring group can deliver reagent to one face of carbonyl
OH Me
OH Me
H
H
MeO2C
MeO2C
O
OH
NaBH(OAc)3
O
O
reduction from
concave face
Me
Me
O
O
OH
O
OH OH
O
O
NaBH(OAc)3
N
N
Ph
Ph
O
O
Me
Me
Me
Me
i-Pr
i-Pr
c) Cram or Felkin or Felkin–Anh selectivity in addition to aldehydes
O
Nu OH
HO Nu
–
H
RS
RS
Nu
R
R OR RL
R ?
RL
Ph
Me
RM
RM
(1) major stereoisomer has RL at 90° angle to carbonyl in reactive conformer
(2) two such conformers exist
(3) more reactive conformer has C–H bond nearly anti to C=O so that approach of nucleophile in
normal trajectory is least hindered
O RS
RM O
RL
RM
RL
R RM
RS R
OH
Nu
R
RL = R L
M
Nu
RS
R
Nu–
(4) major product has Nu anti to RL and OH anti to H
(5) diastereoselectivity is usually not very high (ca. 70:30)
(6) depending on identity of Nu and R, can make either diastereomer!
OH
R
RS
3
H OH
H
Ph
Me
O
H
Ph
HO H
Me
H
Ph
Me
O
H
Ph
H
Me
Me
Me
Me
iii) stoichiometric asymmetric reductions
a) BINOL + LiAlH4
b) (Ipc)BBN and related reagents
iv) catalytic asymmetric reductions (Noyori, Asymmetric Catalysis in Organic Synthesis, 1994)
a) CBS procedure
(1) stoichiometric BH3 (gives background reaction problem) or (catechol)BH (no background
reaction)
(2) catalyst derived from prolinol and MeB(OH)2
(3) works best on ketones with two very different groups
(4) used industrially!
O
OH
Ph Ph
Br
Br
H
(catechol)BH
cat. =
O
10 mol% cat.
N
Me3Si
Me3Si
B
Me
97% ee
b) Noyori hydrogenation (Noyori, Ohkuma, Angew. Chem. Intl. Ed. 2001, 40, 40)
(1) stoichiometric H2 — the absolute best! — no background reaction
(2) catalyst derived from (BINAP)Ru catalyst
(3) huge numbers of turnovers possible
(4) some catalysts selective for ketone over C=C π bonds!
(5) in early versions, an anchoring group (C=C, OH, C=O) had to be present in substrate, but this
is no longer necessary
O
H2
0.2 mol% cat.
Me 0.4 mol% KOH
PPh2
OH
cat. =
Me
RuCl2 +
PPh2
Ar
Ar
NH2
i-Pr
NH2
Ar = 4-MeOC6H4
c) enzyme-catalyzed (Faber, Biotransformations in Organic Chemistry)
(1) most often done with baker’s yeast
(2) actual reductant is NADH — needs to be used catalytically for cost-effectiveness
(a) in whole yeast reductions, organism recycles NADH itself (reducing power from sugar)
(b) in isolated enzymatic reductions, HCO2– or EtOH and another enzyme can be used to
reduce NAD
(3) highly substrate-dependent
(a) more than one reducing enzyme is present in cell
(b) different enzymes compete for different substrates
(c) different enzymes have different stereoselectivities
(d) particular ketone can be reduced with selectivity from >95% R to 0% ee to >95% S!
(e) other organisms can give other selectivities
4
OH
OH
H D
CH3
H3C
OH
H3C
O
OEt
>95% ee
96% ee
>96% ee
v) asymmetric allylations and crotylations
a) allylboron compounds react with aldehydes in a six-membered TS, giving high
diasteroselectivity when allylic group is diastereopure
OH
H
H
BR2
BR2 H2O
Rt
Rt
O
O
R1
R1
R1
Rc
Rc
Rt Rc
b) synthesis of geometrically pure crotylboron compounds is not hard
BuLi, t-BuOK;
MeHC
MeHC
Me
stereospecific
BR2
R2B–X
c) chiral substituents on B give enantiopure products
Me
Me
OH
Me
CH
MeCHO
Me 1/2 BH3;
2
)2 B
Me
MeOH
Me H
(–)-α-pinene
(1) Brown method: use (+)- or (–)-α-pinene (both very cheap); very high ee’s
(2) Roush method: use diisopropyl (+)- or (–)-tartrate (both again very cheap); lower ee’s but a
little more convenient
(3) other B ligands can be used
d) products are common motifs in natural products and can be ozonized to aldols
e) more highly substituted allylic groups can be used if you can make them diastereopure
f) metals other than B can be used (Si, Al, Sn, Ti, Al) according to personal preference; some need
Lewis acid activation, but a chiral Lewis acid can be used in catalytic quantities
vi) catalytic asymmetric alkylations of aldehydes (Knochel, Perea, Jones, Tetrahedron 1998, 54, 8275)
a) aldehydes react with R2Zn only in presence of certain catalysts (ligand-accelerated catalysis)
b) chiral catalysts give asymmetric reactions
Ar Ar
OH
NHTf
O
R´2Zn
OH
RCHO
cat. =
R´
Ti(O-i-Pr)4 or R
OH
O
NHTf
Ti(O-t-Bu)4
8–10% cat.
Ar Ar
c) Et2Zn is the only commercial dialkylzinc that generally undergoes reaction, but Knochel has
been developing ways of making other R2Zn
(1) HBEt2
Zn
X
X
X
(2) Et2Zn
1/2 Et2Zn
X
I
d) problems:
(1) Et2Zn is pyrophoric
X
Zn
X
5
(2) excess of R2Zn is required
(3) R almost always 1° alkyl
e) advantages:
(1) R can be functionalized (esters, acetals, amides, alkenes, etc.)
(2) very convergent and retrosynthetically straightforward
(3) no other way to do it: asymmetric addition not possible with RLi or RMgBr!
3. Amines
a) 1°, 2°, 3° amines refer to number of groups attached to N, not substitution of C attached to N
i) So t-BuOH is a 3° alcohol but t-BuNH2 is a 3°-alkyl 1° amine
b) By N-alkylation
i) In general, NH3 → RNH2 → R2NH → R3N → R4N+ is hard to control
a) sometimes stops at intermediate stages when at least one R is 2° or 3°
b) not possible to control by stoichiometry
c) amines are good nucleophiles/good bases, so works well with 1° alkyl halides only
d) best for making 3° amines
ii) NH2– synthetic equivalents: NaN3, KNPhth, NaNO2
a) work well with 1° and 2° halides
b) cleavage
(1) RN3 → RNH2 with LiAlH4, H2 and Pd/C, or Ph3P
(2) RNPhth → RNH2 with N2H4 or KOH
(3) RNO2 → RNH2 with H2 and catalyst, LiAlH4, SmI2
c) each has disadvantages
(1) RN3 explosive for small R
(2) NaNO2 alkylation gives moderate-to-low yields, both N- and O-alkylation
(3) harsh cleavage conditions for RNPhth
iii) Controlled alkylation with carbonyls
a) acylation and reduction
(1) 1° amines: RCONH2 or RC≡N → RCH2NH2 (with LiAlH4, BH3)
(2) 2° amines: RNH2 → RNHCOR´ → RNHCH2R´
(3) 3° amines: R2NH → R2NCOR´ → R2NCH2R´
(4) always introduces new 1° alkyl group
b) reductive alkylation
(1) aldehydes give 1°-alkyl amines, ketones give 2°-alkyl amines
(2) 1° amines by HONH2 + O=CRR´ → HON=CRR´ → H2NCHRR´ (with catalytic
hydrogenation)
(3) 2° amines by RNH2 + O=CRR´ → [RN=CRR´] → RNHCHRR´
(a) reduction with NaBH3CN or catalytic hydrogenation
(b) imine usually not isolated
(c) ketones + 1° amines usually stop at 2° amine
(d) aldehydes + 1° amines can give 2° or 3° amines (depends on substitution)
(4) 2° amines by RNH2 + N≡CR → [RN=CRR´] → RNHCHRR´
(a) proceeds via HN=CHR
(b) best for intramolecular reactions (formation of 5- and 6-membered azacycles)
(c) serious side reaction in RC≡N hydrogenation
(5) 3° amines by R2NH + O=CRR´ → [R2N=CRR´]+ → R2NCHRR´
(a) use removable R like Bn or DBS to reliably make 2° amine
(6) works really well in intramolecular sense
c) neither method can be used to make 3°-alkyl amines
6
Br
NaN3,
KNPhth,
NaNO2
H H
N
R
+
R
NH
H R
R
O
Cl
O
N
N
R´
NaN3,
KNPhth,
NaNO2
Br
+
R´
R
R´
NH
R
O
R
R
c) By C-alkylation with –CH2NH2 synthetic equivalents (d1 synthons)
i) NaCN
a) works well with 1°, some 2° halides (esp. in polar aprotic solvents or phase transfer)
b) RC≡N → RCH2NH2 with LiAlH4 or BH3 or catalytic hydrogenation
ii) CH3NO2
a) Undergoes Michael, aldol (Henry) reactions
b) alkylation reactions can be very tricky due to competing N- and O-alkylation
c) RCH2NO2 and R2CHNO2 work too
d) RNO2 → RNH2 with LiAlH4 or catalytic hydrogenation or SmI2
iii) CH3CO2t-Bu and CH2(CO2Et)2
a) regular alkylation, Michael, aldol chemistry of carbonyls
b) RCH2CO2t-Bu or RCH(CO2Et)2→ RCH2CO2H
c) RCH2CO2H → RCH2CON3 → RCH2N=C=O → RCH2NH2 (Curtius reaction)
d) Can make 1°-alkyl or 2°-alkyl 1° amines
NaCN
(1°-alkyl amine)
R X
R
H2N
R´
O
R´
EtO2C
CO2Et
+
R
H
H2N
(1°- or 2°-alkyl amine)
R´
H2N
R´´
R´´
R
R´
NO2
(1°-, 2°-, or 3°-alkyl amine)
Z
d) Arylamines by aromatic substitution
i) Nitration of ArH with HNO3, then reduction (LiAlH4, catalytic hydrogenation, Fe, Sn)
ii) Pd-catalyzed substitution reactions of ArX (Hartwig, Buchwald)
e) By degradation of RCO2H
i) Especially useful for making 3° alkyl or aryl amines
ii) RCO2H → RCON3 → RN=C=O → RNH2 (Curtius reaction) (also Hofmann, Beckmann work)
iii) Add a C in the retrosynthetic direction, and you lose a C in the forward direction!
R CO2H
Ar H
R NH2
Ar NH2
R COMe
Ar X
f) Other N synthons
i) a2 — CH2=CHNO2, ClCH2CH=NOMe
ii) a3 — CH2=CHCN
iii) d2 — RCH2CH=NNMe2, RCH2CN
4. Additions to C=C bonds
7
a) to alcohols, ethers, and esters
i) Markovnikov addition
a) Direct addition of ROH or RCO2H catalyzed by HX works for 1,1-disubstituted or enol ethers
b) RCH=CH2 + ROH, Hg(OAc)2 → RCH(OH)–CH2HgOAc + NaBH4 → RCH(OH)–CH3
c) RCH=CH2 + ROH, NBS → RCH(OH)–CH2Br + Bu3SnH → RCH(OH)–CH3
d) both methods suffer from toxic by-products
e) neither can be done enantioselectively
f) but intramolecular cyclizations proceed with high diastereselectivity, and with chiral auxiliaries
can give very high enantioselectivity
ii) anti-Markovnikov addition
a) hydroboration is the way to go
b) can be done asymmetrically with boranes derived from pinene such as Ipc2BH
c) addition of less reactive boranes like (catechol)BH catalyzed by Rh complexes — asymmetric
modification possible
b) to epoxides
i) peracids
a) concerted transfer of O to same face of alkene at both C’s
b) gives preservation of stereochemistry
c) strongly directed by neighboring OH groups by H-bonding
O
O
HO
HO
AcO
AcO
mCPBA
mCPBA
ii) Sharpless epoxidation
a) asymmetric synthesis
(1) works well on allylic alcohols only
(2) stoichiometric oxidant is t-BuOOH; catalyst made from Ti(O-i-Pr)4 and diethyl tartrate
(3) essentially no background reaction (ligand-accelerated catalysis)
(4) very predictable stereochemistry
Rt O
Rt
t-BuOOH, cat. Ti(O-i-Pr)4
Rc
Rc
D-(–)-diethyl tartrate
Rg
Rg
OH
OH
(unnatural isomer)
(5) allylic alcohols prepared from α,β-unsaturated esters, themselves prepared by Wittig reaction
b) kinetic resolution
(1) 2° chiral allylic alcohol can be resolved
(2) one enantiomer of alcohol reacts quickly with chiral catalyst (matched case), other reacts
slowly (mismatched case)
(3) half of material is wasted, but high value-added sometimes makes it useful
OH
OH
O
(matched)
Me
C6H11 t-BuOOH, cat. Ti(O-i-Pr) Me
C6H11
4
+
+
L-(+)-diisopropyl tartrate
OH
OH
(mismatched)
Me
Me
C6H11
C6H11
iii) Jacobsen epoxidation (Jacobsen, Comprehensive Organometallic Chemistry II, Vol. 12, Chap. 11.1
(1995))
a) stoichiometric oxidant is NaOCl
b) catalyst is chiral (salen)MnCl (salen is diimine derived from 1,2-cyclohexanediamine and 4,6-dit-butylsalicylaldehyde)
c) catalyst is cheap and is easily tuned sterically and electronically
d) essentially no background reaction (ligand-accelerated catalysis)
8
e) works best for cis alkenes, enynes, and styrenes, but also works for other substrate classes
f) no requirement for allylic alcohols!
R
R
Ph
Ph
NaOCl
Ph
R
cat.
R´
t-Bu
H
N
O
Mn
N
O
Ph
H (S,S)
t-Bu
O
R O R´
Cl
t-Bu
t-Bu
g) proceeds through radical intermediate, so reaction is not diastereospecific, but enantioselectivites
can be very high
iv) Sharpless asymmetric dihydroxylation (Kolb, VanNieuwenhze, Sharpless, Chem. Rev. 1994, 94,
2483)
a) converts alkene to 1,2-diol, with OH groups adding syn to alkene
b) history
(1) done stoichiometrically with KMnO4 or OsO4 followed by aqueous hydrolysis
(2) reaction of OsO4 accelerated by amines like pyridine or quinuclidine (ligand-accelerated
catalysis)
(3) carried out catalytically with stoichiometric oxidants like R3NO or K3Fe(CN)6
(a) requires that hydrolysis of osmate ester occurs at a reasonable rate
(b) can use nonvolatile, reduced form of Os (K2OsO2(OH)4)
(4) observations (c) and (d) combined to make catalytic asymmetric dihydroxylation
c) O-aryldihydroquinidines or O-aryldihydroquinines used as cocatalysts: bis(DHQD)phthalazine,
bis(DHQD)-2,5-Ph2pyrimidine, etc.
d) very low catalyst loadings used — as little as 0.05 mol% Os (expensive, toxic)
e) works well for a large variety of alkene substitution patterns
(1) best for trans-alkenes
(2) can vary aryl group on amine catalyst for different alkene substitution patterns
f) predictable stereochemistry — RL = aryl or large lipophilic alkyl works best
Dihydroquinidine derivatives
Dihydroquinine derivatives
Et
OMe
H
Et
RO
H
H
N
H OR
RM
RS
H
MeO
N
H
RL
N
H
N
g) reagent mixture commercially available as AD-mix-α (contains dihydroquinine-PHAL) and ADmix-β (dihydroquinidine-PHAL)
9
Et
N
N
H
OMe
N
N N Et
H
N
H
H
N
H
H
Et
H
H
O
O
H
H
OMe
N
N
O
O
O
O
Et
N
H
MeO
MeO
H
(DHQ)2AQN (component of AD-mix-α)
(DHQD)2PHAL (component of AD-mix-β)
h) diol products can be converted to epoxides (inversion at one center!) or cyclic sulfates (retention
at both centers!) to make one end electrophilic for SN2 substitutions
v) Sharpless asymmetric aminohydroxylation (leading ref: Goossen, Liu, Dress, Sharpless, Angew.
Chem. Int. Ed. 1999, 38, 1080)
a) converts alkene to 1,2-aminoalcohol, with OH and NH2 groups adding syn to alkene
b) stoichiometric oxidant is ZNX– Na+, where Z = RO2C, RSO2, and RCO and X = Cl or Br
c) source of O is H2O
d) same facial selectivity as asymmetric dihydroxylation
e) regioselectivity generally puts N β to EWG, reversed for anthraquinone-based ligands, but
mixtures of regioisomers usually obtained
c) to carbonyls
i) ozonolysis
a) NaBH4 workup gives alcohols
b) Me2S or Ph3P workup gives aldehydes/ketones
c) H2O2 and AcOH workup gives carboxylic acids
d) need O3-generating machine, but very convenient if you have one
e) best for electron-rich alkenes
f) will attack other oxidizable groups (e.g. amines) and can overoxidize
g) ozonolysis of terminal alkenes loses one C!
ii) hydroformylation (Breit & Seiche, Synthesis 2001, 1)
a) R2CH=CH2 → R2CHCH2CHO (aldehyde with one more C)
b) use H2, CO, and a Co or Rh catalyst
(1) industrially, originally used HCo(CO)4 in molten Ph3P — required high T and P
(2) now can use (bulky phosphite)Rh catalysts at room temperature under 1–5 atm
c) highly regioselective and chemoselective
d) adds one C!
Me
Me
O
O
800 psi H2, CO
O
O
0.5 mol% Rh(acac)(CO)2
2 mol% Ph3P
Me
Me
e) traditional method for this transformation
(1) hydroborate/oxidize
(2) tosylate
(3) –C≡N substitution
(4) DIBAL and hydrolysis
f) enantioselective variants are on their way!
iii) Wacker oxidation
a) R2CH=CH2 → R2CHCOCH3 (ketone with same number of C’s)
CHO
14:1 dr
80%
10
b) Use O2, aq. AcOH, and catalytic CuCl2 and PdCl2
c) mechanism
(1) attack of H2O on PdII–alkene complex to give (β-hydroxyalkyl)PdII
(2) β-hydride elimination to give enol and PdII–H
(3) deprotonation of PdII–H to give Pd0
(4) CuCl2 oxidizes Pd0 back to PdII
(5) O2 oxidizes CuI back to CuII
d) no change in number of C’s!
e) useful only for terminal alkenes — retron is methyl ketone!
O
O
Wacker
CH3
H3C
H3C
O
f) traditional method
(1) oxymercuration
(2) NaBH4 reduction of C–Hg bond
(3) oxidation with Cr
5. Protecting groups (Greene & Wuts, Protective Groups in Organic Synthesis)
a) most common groups to protect
i) aldehydes and ketones (carbonyl group)
a) acetals and ketals (OCH2CH2O)
ii) alcohols (acidic H)
a) ArCH2 (Bn, PMB)
b) esters (Ac, Piv, Bz)
c) silyl ethers (TMS, TES, TBS, TBDPS, TIPS)
d) acetals (MOM, THP)
iii) 1,2-diols (acidic H’s)
a) carbonate
b) acetal
iv) carboxylic acids (acidic H)
a) Bn ester
b) t-Bu ester
c) allyl ester
v) carboxylic esters (carbonyl)
a) not very many ways, but IBO is one
vi) amines (lone pair, H)
a) carbamates (Boc, Z, Fmoc, Alloc, Teoc, ...)
b) Ar (PMP)
c) ArCH2 (Bn, DBS)
d) imines (=CPh2)
vii) miscellaneous groups: thiols, phosphines, C acids
b) things to think about when using protecting groups (PG)
i) can you avoid the PG altogether by choosing later reaction conditions carefully?
a) addition and removal of PG requires two steps — costs time, money, material!
b) avoid if at all possible!
ii) can PG be introduced without “damaging” other parts of the compound?
iii) is PG stable to the reaction conditions to which the compound will be subjected before the group is
removed?
a) don’t use Ac to protect OH if LDA is going to be used to deprotonate an ester
b) don’t use Bn if Pd/C required for hydrogenation later
c) PG can be adjusted to require more or less robust conditions for removal
d) orthogonal protection — compounds with more than one OH may require different kinds of OH
PGs that can be removed independently of one another: R3Si with F–, Bn with H2 and Pd/C,
Mom with cat. H+, Ac with NaOMe.
iv) can PG be removed without “damaging” other parts of the compound?
11
a) Hint: remove PG at the same time as an essential reaction — saves a step!
b) unpredictable things can happen when trying to remove PG!
v) does PG introduce new stereocenters that will create diastereomeric mixtures?
a) THP and EE groups for alcohols
b) rotational barriers in amides and carbamates create NMR problems
vi) will PG alter physical properties (solubilities, molecular weight) in undesirable ways?
a) organic chemists often can’t handle water-soluble compounds
b) PGs often used to make hydrophilic compounds (e.g., carbohydrates) hydrophobic