Stoichiometric Enamine Chemistry
Baran Group Meeting
Jonathan Lockner
Vinylamine reactivity known since 1884...
Collie, Liebigs Ann. Chem. 1884, 226, 294-322
Benary, Ber. Dtsch. Chem. Ges. 1909, 42, 3912-3925
Robinson, J. Chem. Soc. 1916, 109, 1038-1046
Wittig coined "enamine" as nitrogen analog of enol...
NR2
OH
Wittig, Ber. Dtsch. Chem. Ges. 1927, 60, 1085-1094
Enamine preparation was first made practical by Mannich...
Mannich, Ber. Dtsch. Chem. Ges. 1936, 69, 2106-2112
But no one seized the opportunity for nearly two decades ! until Stork...
Stork, Terrell, Szmuszkovicz, J. Am. Chem. Soc. 1954, 76, 2029
Stork, Landesman, J. Am. Chem. Soc. 1956, 78, 5128
Stork, Landesman, J. Am. Chem. Soc. 1956, 78, 5129
Stork, Brizzolara, Landesman, Szmuszkovicz, Terrell, J. Am. Chem. Soc. 1963, 85, 207
Until silyl enol ethers emerged in the early 1970s, enamines enjoyed a unique status
as noncharged enolate equivalents...
Asymmetric induction ! as early as 1969 with (S)-proline...
Yamada, Tet. Lett. 1969, 10, 4233 & 4237
Today, enamine chemistry remains a powerful tool in the synthetic chemist's
armamentarium...
Silyl enol ethers: superior stability
N
Enamines: neutral conditions mitigate self-condensation side reactions
Enolates: quick/easy generation; predictable regioselectivity
Metalloenamines: low levels of proton transfer; hence little polyalkylation
Reviews:
Szmuszkovicz, Adv. Org. Chem. 1963, 4, 86
Kuehne, Synthesis 1970, 510
Valentine, Synthesis 1978, 329
Hickmott, Tetrahedron 1982, 38, 1975 & 3363
Whitesell, Synthesis 1983, 517
November 3, 2007
Books:
Enamines: Synthesis, Structure, and
Reactions; Cook, A.G., Ed.; Marcel
Dekker: New York, 1988
The Chemistry of Enamines;
Rappoport, Z., Ed.; John Wiley & Sons:
New York, 1994
www.colby.edu/chemistry/CH432/Lecture8.pdf
also Evan's Chem 206 (Harvard)
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Stoichiometric Enamine Chemistry
Baran Group Meeting
Enamine chemistry complements other methods, e.g.:
Enamines are ambident nucleophiles: nitrogen and "-carbon(s)
O
O
MVK
Me
acid or base
Ketone enamines are more reactive than aldehyde enamines:
(Robinson)
NR2
Me
NR2
>
R
O
R
H
NR2
>
R
opportunity for selectivity;
e.g. "-tetralones...
(Stork)
neutral cond.
Me
R
NR2
>
Me
MVK
N
Jonathan Lockner
R
H
R
tend to react preferentially at N;
therefore try metalloenamine chemistry...
Cyclic ketone enamines ! general reactivity order:
Enamine chemistry offers significant enhancements in selectivity, e.g.:
LDA
O
tBu
O
tBu
MeI
tBu
NR2
NR2
>
O
Me
Me
NR2
NR2
>
>
"Structure!Nucleophilicity Relationships for Enamines" H. Mayr, Chem. Eur. J. 2003, 9, 2209
55 : 45
MeI
N
90 : 10
H3O+
tBu
Stork enamine
1. LDA
NNMe2 2. MeI
tBu
Corey
dimethylhydrazone
97 : 3
3. CuCl2
H2O, pH=7
Enamine chemistry has been exploited in asymmetric methods, e.g.:
O
Bn
Bn
Bn
OMe
NH2
LDA
N
OMe
!30°C
N
Li
OMe
EtI
O
Et
H3O+
1970s: A.I. Meyers (e.g. above, later chiral oxazolines), see also D. Enders (SAMP/RAMP)
November 3, 2007
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Baran Group Meeting
November 3, 2007
Stoichiometric Enamine Chemistry
Jonathan Lockner
Page 3
Stoichiometric Enamine Chemistry
Baran Group Meeting
Jonathan Lockner
Pyramidalization, induction, pπ-conjugation:
Reactivity/Outcome depends on many parameters:
(1) solvent (hexanes vs. THF vs. HMPA)
(2) temperature (equilibration...)
(3) amine moiety (steric/electronic issues)
(4) amount of base used
(5) proportion of reagents, and order of addition
(6) number and type (e.g. acyl vs. alkyl) of substituents present on the enamine
(7) type of electrophile
Case in point:
Hickmott, J. Chem. Soc. Perkin Trans. I 1975, 1885; ibid 1974, 2544; ibid 1973, 2063;
ibid 1973, 1514; Tetrahedron 1967, 3151
OH O
R
O
O
O
R
80°C
20°C
Z Z
Z Z
O
R
R
O
R
Cl
NR2
O
Z
crotonyl chloride
methacryloyl chloride
O
Degree of pyramidalization influences extent to which N lone pair can donate electron
density into the π orbital of the alkene (pπ-conjugation). Better orbital alignment means
greater pπ-conjugation, and hence greater nucleophilicity at β-carbon of the alkene...
Nature of substituents on amine influences same (e.g. inductive withdrawal by oxygen)...
O
O
O
N
Z Z
(Z = CO2Et, CN, H)
N
O
N
O
N
O
N
← a really bad situation
(see 19c above); N lone
pair orthogonal, ∴ zero
pπ-conjugation
OH O
R
acryloyl chloride
Z
Nature of substituents on amine influences isomer distribution:
(∝ of less-substituted isomer increases with increasing pπ-conjugation)
R
80°C
O
NR2
O
OH O
Me
Me
R'
NR2
O
Me
+
A
B
pyrrolidine (90% A)
dimethylamine (60% A)
morpholine (52% A)
piperidine (46% A)
diethylamine (25% A)
2,5-dimethylpyrrolidine (10% A)
N-methylaniline (0% A)
Nature of substituents on amine can also "tune" E/Z ratio:
decreasing pyramidalization
increasing p-character
increasing pπ-conjugation
Et
Et
Me
NR2
(E)
NR2
Me
(Z)
pyrrolidine (98:2)
dimethylamine (97:3)
piperidine (90:10)
morpholine (88:12)
diethylamine (86:14)
diisopropylamine (55:45)
pπ- vs. ππ-conjugation:
C6H11(Me)N (83:17)
Ph(Me)N (20:80)
o-MeC6H4(Me)N (83:17)
(A1,3- and A1,2-strain vs. pπ-conjugation)
November 3, 2007
Page 4
inc.
pπ-conj
Baran Group Meeting
Stoichiometric Enamine Chemistry
Ground states vs. transition states in enamine chemistry...
(gs enamine isomer distribution, governed by factors described on the previous
pages, is not necessarily a reliable predictor of product distribution)
Jonathan Lockner
Valentin, Tetrahedron, 1974, 30, 2741
Curtin−Hammett: product distribution reflects ts energies rather than gs populations
November 3, 2007
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Stoichiometric Enamine Chemistry
Baran Group Meeting
Enamine preparation:
Jonathan Lockner
A process paper on optimization of morpholine enamine preparation: Carlson, OPRD 2005 321
via condensation of carbonyl with amine, aided by a dehydrating agent/mechanism
"In the original procedure, TiCl4 is
added dropwise to a solution of the
ketone, and the amine and the mixture
are then stirred for several hours. We
found that the reaction time could be
considerably shortened by a modified
procedure: TiCl4 is added at 0 °C to a
solution of the amine in petroleum ether
to form a solid TiCl4-amine complex.
The mixture is then heated to reflux with
vigorous stirring, and the ketone is
rapidly added. For nonhindered
ketones, the reaction is completed
within minutes. It was, however, found
that the amounts of TiCl4/ketone and
amine/ketone to be used for a rapid
conversion were dependent on the
structure of the ketone. For this reason,
the amounts of titanium tetrachloride
and amine to be used have to be
determined for each ketone."
chemically inert dehydrating agents: MS, K2CO3, MgSO4, Na2SO4
aldehydes: Mannich & Davidsen 1936 (2 eq amine to generate aminal, which yields
enamine upon destructive distillation)
enamines of aldehydes are often unstable, being readily hydrolyzed, oxidized, polymerized
"new" method for aldehydes: JOC 2006 7481 (cf. White, JACS 1981 1813)
1.2 eq amine
4A MS
R
O
R
CHCl3
0 °C 1 h
good yields
NR2
ketones: Stork 1963 (Dean-Stark azeotropic removal of H2O; w/ Bronsted acids: AcOH,
PTSA; in refluxing solvent: PhH, PhMe, xylene)
methyl ketones problematic (self-condensation under these conditions), so TiCl4 as water
scavenger is typically employed (White, JOC 1967 213; Carlson, Acta Chem. Scand.
1983, B 37, 7)
As a function of amine nucleophilicity:
• if strong (pKa of conj. acid 6-10), then addition may proceed without acid catalysis, and
dehydration is rate-determining
• if weak (pKa of conj. acid 3-5), then addition and dehydration both require acid catalysis
Other methods of enamine preparation:
O
N
H
(pKa 11.26)
N
ACIE 2006 5194
via allyl amines:
Chem. Ber. 1969 1917
quant.
PhH, reflux
94%
O
N
cat. PTSA
or cat. ZnCl2
PhMe or neat
reflux
Ph
N
Me
KOtBu
DMSO
"
Ph
O
Me
N
H
(pKa 4.70)
cat. PhCO2H
O
N
via terminal epoxides:
JACS 2004 6870
Me
O LTMP-analog
C4H9
THF
N
89 : 11
JOC 1990 2317
or K-10 Mont. clay, 56% yield:
J. Chem. Res. Synopses 1995, 1, 21
O
+
C4H9
tBu
N
R
RX
tBu
MeCN
C4H9
O
no N-alkylation; provides !-substituted aldehydes (including nBu and iPr); cf. JOC 1975 607
November 3, 2007
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Stoichiometric Enamine Chemistry
Baran Group Meeting
O
Representative Sampling of Synthetic Uses:
O
Cycloadditions:
[2+2] with vinylketenes (HCA 1982 2230)
O
Generating 1,3-dicarbonyl: Acylation
Me
NR2
Generating 1,4-dicarbonyl: Alkylation
O
Generating 1,5-dicarbonyl: Michael Addition
O
O
O
Ph
O
Cl
Cl
−78 °C
N
NO2 (EWG)
(EDG) R2N
+
Et
O
Me
H2O
N
Me
Me
R'
R"
R'
O
R"
N
O
R'
R"
100%
Ph
R2N
NO2
Et
Ph
[4+2] with pyrones (JOC 1983 4869)
Halogenation:
α−chlorination (Chem. Ber. 1979 1670)
N
+
O
H
NR2
H
H
NR2
strong preference for axial attack (Tetrahedron 1974 2741
Cl2
Ph
H2O
Ph
Me
Me
O
•
[2+2] with nitrostyrenes (JOC 1965 4280)
H
H
Me
N
O
Cascade of bond-forming events is sometimes possible:
(β-carbon nucleophilic, then α-carbon electrophilic)
H
Jonathan Lockner
CO2R
Me
Δ
O
− CO2
Me
CO2R
Me
Me
CO2R
Me
R'
R'
N R"
O
R"
O
65%
Spiroannulation via homologation-alkylation sequence:
(Martin, JOC 1976 3337; ibid 1978 3792)
next page: chemoselective α−bromination enabled by enamine chemistry
Oxygenation:
(Chem. Comm. 1969 314)
O2
cat. CuCl
N
O
O
Michael-Stork addition:
(Silvestri, JOC 2005 8239)
Cyclopropanation:
(Org. Lett. 2006 2261
N
CH2Cl2
N
TiCl4/Mg/THF
chemoselective
50%
November 3, 2007
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Stoichiometric Enamine Chemistry
Baran Group Meeting
Enamines in Natural Product Synthesis:
Review: Kuehne, Synthesis 1970 510
vitamin B12 (Woodward, Classics I)
intramolecular imino-ester-enamine condensation mediated by pyrrolidinium acetate
Jonathan Lockner
pyrazine metabolite (Heathcock, JOC 1993 6155)
hetero-[4+2]; enamine tactic was vital
ecteinascidin 743 (Corey, Classics II)
Ru-catalyzed asymmetric hydrogenation
vinblastine (Fukuyama, Classics II)
intramolecular Diels−Alder
(+)-mesembrine (Yamada, Chem. Pharm. Bull. 1973 2130)
asymmetric enamine Michael into MVK; then condensation (cf Woodward above)
camptothecin (Kametani, JCS Perkin I 1981 1563)
enamine annulation
diterpene resin acids (Kuehne, JACS 1961 1492)
chemoselective bromination of ketone in presence of anisole ring through enamine activation
analog of steganone (Becker, JCS Chem Comm 1974 430)
November 3, 2007
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