Access to diversely α-substituted cyclopentenones from α-chlorocyclopentenones

Article abstract of DOI:10.1016/j.tetlet.2004.07.049

α-Chlorocyclopentenones can readily be transformed into a variety of I?±-substituted cyclopentenones via their dimethyltrimethylene acetals.

Full text of DOI:10.1016/j.tetlet.2004.07.049

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 6749–6751
Access to diversely a-substituted cyclopentenones from
a-chlorocyclopentenones
*
´
Audrey Giannini, Yoann Coquerel, Andrew E. Greene and Jean-Pierre Depres
´
Chimie Recherche (LEDSS), Universite Joseph Fourier, BP 53X, 38041 Grenoble Cedex, France
Received 28June 2004; accepted 12 July 2004
Available online 30 July 2004
Abstract—a-Chlorocyclopentenones can readily be transformed into a variety of a-substituted cyclopentenones via their dimethyl-
trimethylene acetals.
Ó 2004 Elsevier Ltd. All rights reserved.
The development of effective new approaches to substi-
tuted cyclopentenones constitutes a worthwhile syn-
thetic pursuit because of their ubiquitousness in nature
and their usefulness as synthetic building blocks. The se-
quence developed several years ago in our laboratory,
consisting of regio- and stereoselective [2 + 2] cycloaddi-
tion of dichloroketene with olefins, followed by diazo-
Scheme 2.
methane ring expansion and dehydrochlorination,
leads efficiently to a-chlorocyclopentenones (Scheme
required methylation.2 The extension of this procedure
for the preparation of a variety of a-substituted conju-
1);1 however, a proven procedure for replacing the a-
gated cyclopentenones is now described.
chloro group in cyclopentenones by other a-substituents
has not been available.
In early optimization studies it was found that when the
ethylene acetal of a-chlorocyclopentenone 1a1b,c
Recently, in the context of the total synthesis of several
(Scheme 2) was allowed to react for 1h at ꢀ78°C with
a preformed solution of LDBB3 (Yus and co-workersÕ
standard metallation conditions2b) and then treated with
excess iodomethane for 20min, followed by dilute HCl,
the desired a-methylcyclopentenone (3a, CH3)1b,4 could
be obtained in 59% yield, together with 5% of the a-un-
substituted cyclopentenone (3a, H). Some improvement
was realized by using LDMAN5 instead of LDBB; opti-
mal results were ultimately achieved with in situ gener-
ated LDMAN as the electron transfer reagent at
ꢀ65°C in combination with the dimethyltrimethylene
acetal, which is known to be more stable to6a (and
in6b) organometallics than the ethylene acetal. With
these modifications, the above methylation could be rep-
roducibly achieved in 90% isolated yield.
guaiane sesquiterpenes,1d it became necessary to effect
the transformation of an a-chlorocyclopentenone into
an a-methylcyclopentenone. Since no effective method
could be found for the conversion of an a-chloro enone
into an a-alkyl enone, a procedure was developed for the
Scheme 1.
Keywords: Lithiation; Acetals; Electron transfer; Cyclopentenones;
Carbanions.
Various electrophiles can be used in the sequence to give
the corresponding a-substituted cyclopentenones (Table
1). For example, the vinyllithium intermediate derived
from dimethyltrimethylene acetal 2a7 on treatment with
three primary alkyl iodides produces the corresponding
*
Corresponding author. Tel.: +33-(0)476-514345; fax: +33-(0)476-
514494; e-mail: jean-pierre.depres@ujf-grenoble.fr
´ ´
Present address: SymBio UMR CNRS 6178, Universite Paul Cezan-
´ ˆ ˆ
ne, Centre Universitaire de St Jerome, Boıte D12, 13397 Marseille
Cedex 20, France.
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.07.049

6750
A. Giannini et al. / Tetrahedron Letters 45 (2004) 6749–6751
Table 1. Synthesis of diversely a-substituted cyclopentenones
Entry
1
Substrate
Electrophile
CH3I
Product
Yielda (%)
90 (6)
O
O
O
CH
Cl
2a
3
3aab
O
2
2a
CH3CH2I
77 (17)
CH CH
2
3
3abc
3
4
2a
2a
CH3CH2OSO2CF3
CH3(CH2)4I
3ab
51 (14)
66 (28)
O
(C H ) CH
2 4
3
3
3acd
O
5
6
2a
2a
CH3(CH2)7I
(CH3)3SiCl
75 (15)
67 (12)
(C H ) CH
2 7
3ad
O
Si(CH )
3 3
3aee
O
7
8
9
2a
2a
2a
(CH3)2CO
51 (35)f
63g (4)
51h
C(CH ) OH
3 2
3af
O
(CH3)2NCHO
O
CHO
2ag
O
O
CH CH(OH)CH
2
3
3ah
O
O
10
CH3I
88 (5)
O
CH
3bai
Cl
3
2b
O
O
O
11
12
CH3I
CH3I
66 (8)
77 (4)
CH
3caj
3
Cl
2c
O
O
O
CH (CH )
3
2 7
CH (CH )
3
2 7
CH
3
Cl
3da
2d
a Yields are for isolated, homogeneous products. Except for entry 1, yield optimization was not attempted. Yields in parentheses are for
a-unsubstituted enone side products.
b Refs. 1b and 4.
c Ref. 8.
d Ref. 9.
e Ref. 10.
f 4-Hydroxy-4-methylpentan-2-one was also isolated.
g Acetal 2ag was not hydrolyzed.
h Hydroxy enone 3ah (dr=1:1) suffered partial decomposition on silica gel chromatography.
i Ref. 4.
j Ref. 11.

A. Giannini et al. / Tetrahedron Letters 45 (2004) 6749–6751
6751
a-alkyl cyclopentenones 3ab,8 3ac,9 and 3ad (entries
2,4,5) in good overall yields, despite some protonation
of the vinyllithium through elimination in the halides
(and, perhaps, adventitious introduction of moisture).
Triflates appear to be inferior to iodides (entries 2 and
3). Chlorotrimethylsilane, acetone, and dimethylform-
amide have also been used to produce, respectively, a-
trimethylsilyl cyclopentenone 3ae10 (entry 6), tertiary
alcohol 3af (entry 7), and aldehyde 2ag (entry 8); the
reaction with propylene oxide yields selectively the ex-
pected secondary alcohol 3ah (entry 9). In addition,
two other bicyclic a-chloro enone acetals, bicyclo-
[5.3.0]decenone derivative 2b and bicyclo[3.3.0]octenone
derivative 2c, as well as a monocyclic a-chloro enone
acetal, cyclopentenone derivative 2d, have also been
found to undergo facile lithiation–alkylation–hydrolysis
to give in good yields enones 3ba,4 3ca,11 and 3da
(entries 10–12), respectively.12
Freeman, L. L.; Hutchinson, L. L. J. Org. Chem. 1980, 45,
1924–1930.
4. Jacobson, R. M.; Abbaspour, A.; Lahm, G. P. J. Org.
Chem. 1978, 43, 4650–4652.
5. Lithium 1-(dimethylamino)naphthalenide. See: Cohen, T.;
Kreethadumrongdat, T.; Liu, X.; Kulkarni, V. J. Am.
Chem. Soc. 2001, 123, 3478–3483, Lithium powder
provided better results than lithium wire.
6. (a) McOmie, J. F. W. Protective Groups in Organic
Chemistry; Plenum: London, 1973; Chapter 9; (b) Stowell,
J. C. J. Org. Chem. 1976, 41, 560–561; Stowell, J. C.;
Keith, D. R.; King, B. T. Org. React. 1984, 62, 140–147,
and references cited therein.
7. The dimethyltrimethylene acetals used in this work have
been obtained from the corresponding a-chlorocyclopent-
enones1a–c in yields of 50–70% (100% based on recovered
a-chloro enone). See Ref. 12.
8. Frejaville, C.; Jullien, R. Tetrahedron Lett. 1971,
2039–2041.
´
9. Malacria, M.; Gore, J. J. Org. Chem. 1979, 44, 885–886.
10. Urabe, H.; Suzuki, K.; Sato, F. J. Am. Chem. Soc. 1997,
119, 10014–10027.
In summary, it has been shown that a-chlorocyclopent-
enones can readily be transformed, via their dimethyltri-
methylene acetals, into a variety of a-substituted
cyclopentenones. The LDMAN-mediated metal–chlo-
rine exchange, the key step, is effected through in situ
generation of the reagent, which is both convenient
and efficient. Since a-chlorocyclopentenones themselves
are easily prepared, this methodology provides a simple
route to a-substituted cyclopentenones and nicely com-
plements other procedures for accessing these useful
compounds.
11. Piers, E.; Marais, P. C. J. Org. Chem. 1990, 55, 3454–3455.
12. General procedure for preparation of chloro acetals: A
mixture of the a-chloro enone (11.7mmol), 2,2-dimethyl-
1,3-propanediol (175.0mmol), trimethyl orthoformate
(31.6mmol), p-toluenesulfonic acid hydrate (4.7mmol),
and molecular sieves was vigorously stirred in dichloro-
methane (50mL) at 20°C for 15h, whereupon solid
K2CO3 was added. The crude reaction product was
isolated in the usual way and purified by flash chroma-
tography on silica gel (treated with 2.5% v/v of triethyl-
amine) with ethyl acetate in pentane to give unreacted
a-chloroenone and the desired acetal (50–70% yield, 100%
brsm). Selected physical data for acetal 2a: mp 58°C. IR
Acknowledgements
1720, 1303, 1109cmꢀ1 1H NMR (CDCl3, 300MHz):
.
d = 0.75 (s, 3H), 0.94–1.09 (m, 1H), 1.15–1.41 (m, 2H),
1.28(s, 3H), 1.61 (dd, J = 13.0, 4.9Hz, 1H), 1.73–1.89 (m,
3H), 1.90–2.03 (m, 1H), 2.41–2.74 (m, 3H), 3.49–3.64 (m,
4H). 13C NMR (CDCl3, 75MHz): d = 22.3, 22.7, 25.8,
25.9, 26.2, 30.4, 35.3, 36.5, 41.4, 72.5, 72.7, 108.0, 124.1,
145.4. MS (DCI) m/z 257 (MH+, 100%). Anal. Calcd for
C14H21ClO2: C, 65.49; H, 8.24. Found: C, 65.33; H, 8.47.
General procedure for preparation of a-substituted cyclo-
pentenones: To a suspension of Li powder in mineral oil
(6.0mmol) was added a solution of the chloro acetal
(1.0mmol) in THF (4.0mL), followed by N,N-dimethyl-1-
naphthylamine (1.0mmol). The mixture was cooled to
ꢀ65°C, stirred for 2h (complete metallation, by TLC),
and then treated with the electrophile (5mmol; 20mmol
for CH3I). After being stirred for an additional 30min at
ꢀ65°C, the mixture was allowed to warm slowly to 20°C
and then treated with 1N HCl (2mL). The resulting
mixture was extracted twice with ether/pentane (3:2) and
the combined organic layers were washed successively with
2% Na2S2O3, satd NaHCO3, water, and brine, dried over
anhydrous Na2SO4, and concentrated under reduced
pressure. The resulting crude product was purified by
flash chromatography on silica gel with ether in pentane.
Selected physical data for 3-methyl-1,4,5,6,7,7a-hexa-
We thank Prof. P. Dumy for his interest in our work,
The Research Ministry for fellowship awards to A.G.
´
and Y.C., and the Universite Joseph Fourier and the
CNRS (UMR 5616, FR 2607) for financial support.
References and notes
´
1. (a) Greene, A. E.; Depres, J.-P. J. Am. Chem. Soc. 1979,
101, 4003–4005; (b) Depres, J.-P.; Greene, A. E. J. Org.
´
Chem. 1980, 45, 2036–2037; See, also: (c) Mehta, G.; Rao,
K. S. Tetrahedron Lett. 1984, 25, 1839–1842; For a recent
´
example, see: (d) Coquerel, Y.; Greene, A. E.; Depres J.-P.
Org. Lett. 2003, 5, 4453–4455.
2. However, vinylsamarium reagents had been generated
from acyclic (Z)-a-chloroenones with samarium diiodide
and treated with (reactive) aldehydes and ketones, and
lithium reagents had been formed from ethylene acetals of
a-chlorocyclohexenone with lithium and di-tert-butylbi-
´
phenyl and similarly treated. See: (a) Concellon, J. M.;
´
´
Bernad, P. L.; Huerta, M.; Garcıa-Granda, S.; Dıaz, M.
R. Chem. Eur. J. 2003, 9, 5343–5347; (b) Bachki, A.;
Foubelo, F.; Yus, M. Tetrahedron 1997, 53, 4921–4934;
For the preparation of vinyllithium reagents from the
ethylene acetal of a-bromoenones by treatment with
hydro-inden-2-one (3aa):1b,4 IR 1700, 1653cmꢀ1
.
1H
NMR (CDCl3, 300MHz): d = 0.97–1.11 (m, 1H), 1.24–
1.39 (m, 1H), 1.42–1.58(m, 1H), 1.67 (s, 3H), 1.80–2.18
(m, 5H), 2.49–2.58 (m, 2H), 2.80–2.88 (m, 1H). 13C NMR
(CDCl3, 75MHz): d = 7.8, 25.8, 26.8, 28.9, 35.3, 40.5, 41.6,
133.0, 176.1, 209.3. MS (DCI) m/z 151 (MH+, 100%).
`
n-BuLi, see: (c) Chinchilla, R.; Najera, C. Chem. Rev.
2000, 100, 1891–1928.
3. Lithium 4,40-di-tert-butylbiphenylide. See: Freeman, P.
K.; Hutchinson, L. L. Tetrahedron Lett. 1976, 1849–1852;