(E)-4-CHLORO-3-BUTEN-2-ONE 1

(E)-4-Chloro-3-buten-2-one1 precursors to vitamin D in 56% overall yield and with high

diastereoselectivity (eq 2).5b

Cl
R2 O
O
R1 O Et HCl
Cl CO2Et AcOH, ∆
R1 = R2 =H
(1) O

(1; R1
= R2
= H)
[7119-27-9] C4 H5 ClO (MW 104.52)
O Et
InChI = 1/C4H5ClO/c1-4(6)2-3-5/h2-3H,1H3/b3-2+
Et
InChIKey = HTPABEPAZTWGPP-NSCUHMNNBZ (1)
CO2Et
(2; R1 = Me, R2 = H) H O O
[57982-323-8] C5 H7 ClO (MW 118.56) 71% from the ketoester
InChI = 1/C5H7ClO/c1-4(6)3-5(2)7/h3H,1-2H3/b4-3+
InChIKey = WLEFTWHIDSWPNV-ONEGZZNKBU O OLi
OLi O
(3; R1 = H, R2 = Me)
t-Bu Cl
[105-32-8] C5 H7 ClO (MW 118.56) P
Ph O
InChI = 1/C5H7ClO/c1-2-5(7)3-4-6/h3-4H,2H2,1H3/b4-3+
H P t-Bu
InChIKey = CFMFGANUEMXVTA-ONEGZZNKBS Ph

(ketovinylation reagent which reacts with a variety of O

O
nucleophiles; used as a methyl vinyl ketone equivalent under O 1. H2, Pd/C
medium pressure P t-Bu
H
aprotic conditions; precursor to dienol borinates) 2. 2% KOH, MeOH Ph
(2)
Alternate Name: 2-chlorovinyl methyl ketone. O 70%
O
Physical Data: (1) bp 21 ◦ C/21 mmHg; d 1.130 g cm−3 ;2a (2) H P t-Bu
Ph
bp 38–40 ◦ C/11 mmHg; (3) bp 43–45 ◦ C/14 mmHg; d 1.076 80%
g cm−3 .
Solubility: insol water; sol most organic solvents.
Preparative Method: from acetylene and acetyl chloride
catalyzed by aluminum chloride.2 Substitution with Hetero Nucleophiles. Chloride may be
Purification: distillation in vacuo. replaced by SR,1c NR2 , OR, C5 H5 N+ Cl− ,4 and RNH in a con-
Handling, Storage, and Precautions: the chloro enone is lachry- jugate addition–elimination.6 In particular, (1) has been utilized
matory and corrosive to the skin. Therefore handling with extensively in synthetic approaches to the indole alkaloids
gloves in a fume hood is essential. The compound has in which the key step is vinylic substitution by tryptamine
limited stability at room temperature and should be stored under (eq 3).6 The coupling of substituted homoallylic amines to
nitrogen at 4 ◦ C or lower; it solidifies at ca. 5 ◦ C. Under these 4-chlorobutenone followed by intramolecular photocycloaddi-
conditions, darkening and HCl loss is minimized, enabling the tion affords fused cyclobutanes, which undergo retro-Mannich
chloro enone to be stored for several weeks. fragmentation to ketoimines followed by Mannich ring closure
to give perhydroindoles in good yields.6b By using this method-
ology, synthetic routes to mesembrine6b and vindorosine6d have
been achieved.
Ketovinylation of Carbonyl Compounds. (E)-4-Chloro-3-
buten-2-one (1) is a vinylogous acyl chloride and as such is highly
O NH2
reactive towards nucleophiles. Reaction with the enolates of NEt3, EtOH
substituted malonic esters, β-keto esters, and 1,3-diketones leads +
Cl 92%
N
to highly functionalized products which may be utilized in a (1) Me
variety of synthetic schemes.1a For example, the enolates of
substituted β-keto esters undergo conjugate addition to the chloro N H Ac2O, NEt3
enone followed by loss of chloride ion to give ketovinyl substituted O C6H6, ∆
keto esters. Treatment of these products with Hydrochloric Acid N 64%
in acetic acid with heating affords substituted α-pyrones (eq 1).1a,3 Me
The ketovinylation of enolates derived from cyclic ketones4
provides an alternative to the use of methyl vinyl ketone as an Ac
entry to 1,4-diketones required for the Robinson annulation.5 N
For example, (1) efficiently traps the enolate derived from the N Ac O
BF3·Et2O (3)
conjugate addition of lithiated (E)-butenyl(t-butyl)phenyl phos-
N 38% H
phine oxide to 2-methylcyclopentenone. Hydrogenation of the N
double bonds followed by aldol cyclization affords hydrindenone Me Me
O

Avoid Skin Contact with All Reagents

2 (E)-4-CHLORO-3-BUTEN-2-ONE

Substitution with Organometallic Reagents. Lithium A route to α,β-unsaturated aldehydes has been reported in
dialkylcuprates and organocopper reagents readily undergo conju- which the vinyl chloride moiety is converted into a dimethyl
gate addition to (1) with predominant retention of the double bond acetal and the carbonyl group can then react with Grignard
geometry.7 For example, the conjugate addition of bis(trimethyl- reagents to form γ-hydroxy acetals. These are then hydrolyzed
silylmethyl)copperlithium to (E)-4-chloropent-3-en-2-one (2) and dehydrated to the unsaturated aldehydes (eq 7).2a
affords the silylmethyl derivative in 51% yield (E:Z = 74:26). Irra-
diation at −76 ◦ C isomerizes the product to the (Z) isomer which
O
upon heating at 38 ◦ C undergoes a 1,5-shift of the silyl group MeOH
O OMe R′MgX
to give a trimethylsilyloxy-substituted butadiene, a compound of R Cl NaOH, –10 °C R OMe
general use in Diels–Alder chemistry (eq 4).7a Normally alkenyl-
copper reagents are too unreactive to add to β-chloro enones.
OH OMe
However, in the presence of 3% Tetrakis(triphenylphosphine)- R′ oxalic acid, ∆ R′
(7)
palladium(0) coupling with (1) proceeds with high stereoselectiv- R OMe
R O
ity and in high yield. For example, the formation of (E,Z)-dienones
is readily achieved (eq 5).7b

(Me3SiCH2)2CuLi O hν 1. (a) Kochetkov, N. K.; Kudryashov, L. J.; Gottich, B. P., Tetrahedron

O
–15 °C –76 °C
1961, 63. For a general discussion on vinyl substitution see: (b) Patai, S.;
Cl 51% Rappoport, Z. In The Chemistry of Alkenes, Patai, S., Ed.; Interscience:
SiMe3
(2) London, 1964; Chapter 8, p 525 and (c) Modena, G., Acc. Chem. Res.
(E):(Z) = 74:26 1971, 4, 73. (d) Smith, A. B.; Kilényi, S. N., Tetrahedron Lett. 1985, 26,
4419 and references cited.
Me3Si
O OSiMe3 2. (a) Price, C. C.; Pappalardo, J. A., J. Am. Chem. Soc. 1950, 72, 2613.
38 °C
(4) (b) Benson, W. R.; Pohland, A. E., J. Org. Chem. 1964, 29, 385.
3. Kochetkov, N. K.; Gottich, B. P., J. Gen. Chem. USSR (Engl. Transl.)
Pd(PPh3)4
1959, 29, 1297.
Cl
+ Cu·MgBr2 (5) 4. Hills, P. R.; McQuillin, F. J., J. Chem. Soc. 1953, 4060.
84%
O Bu Bu O 5. (a) Dancer, R. J.; Haynes, R. K.; Loughlin, W. A.; Vonwiller, S. C., Aust.
(1) >99% isomeric purity J. Chem. 1990, 43, 1375. (b) Haynes, R. K.; Stokes, J. P.; Hambley, T. W.,
J. Chem. Soc., Chem. Commun. 1991, 58.
6. (a) Büchi, G.; Matsumoto, K. E.; Nishimura, H., J. Am. Chem. Soc. 1971,
93, 3299. Ando, M.; Büchi, G.; Ohnuma, T., J. Am. Chem. Soc. 1975, 97,
4-Chlorobut-3-en-2-one as a Bifunctional Reagent. The
6880. (b) Winkler, J. D.; Muller, C. L.; Scott, R. D., J. Am. Chem. Soc.
ability to form dienol borinates while retaining the chloro func- 1988, 110, 4831. (c) Blowers, J. W.; Brennan, J. P.; Saxton, J. E., J. Chem.
tionality enables the reagent to react as a dipolar synthon. Thus Soc., Perkin Trans. 1 1987, 2079. (d) Winkler, J. D.; Scott, R. D.; Williard,
treatment of the β-chloro enone (3) with generates the dienol P. G., J. Am. Chem. Soc. 1990, 112, 8971.
borinate, which undergoes addition to aldehydes with high syn 7. (a) Casey, C. P.; Jones, C. R.; Tukada, H., J. Org. Chem. 1981, 46,
diastereoselectivity to give substituted hydroxy-β-chloro enones. 2089. (b) Jabri, N.; Alexakis, A.; Normant, J. F., Tetrahedron 1986, 42,
These can then undergo an intramolecular conjugate addition 1369.
in the presence of Trimethylsilyl Trifluoromethanesulfonate to 8. Paterson, I.; Osborne, S., Tetrahedron Lett. 1990, 31, 2213. Paterson, I.;
afford dihydropyrones in good yields (eq 6).8 Smith, J. D., J. Org. Chem. 1992, 57, 3261.

Cl Bu2BOTf Cl BnOCH2CHO Richard K. Haynes

(i-Pr)2NEt Hong Kong University of Science Technology, Vowloon,
O OBBu2
(3) Hong Kong
Simone C. Vonwiller
O
The University of Sydney, Sydney, New South Wales, Australia
Me3SiOTf
Cl (6)
BnO (i-Pr)2NEt BnO
HO O O
84% 62%
syn:anti = 97:3 cis:trans = 74:26

A list of General Abbreviations appears on the front Endpapers