A convenient synthesis of 2-chlorophenyl methylidene-5,5- dimethylcyclopentanone, a key intermediate for a potent fungicide against Botrytis cinera

Full text of DOI:10.1021/jo972199c

J . Org. Chem. 1998, 63, 3793-3794
3793
Sch em e 1
A Con ven ien t Syn th esis of 2-Ch lor op h en yl
Meth ylid en e-5,5-d im eth ylcyclop en ta n on e, a
Key In ter m ed ia te for a P oten t F u n gicid e
a ga in st Botr ytis cin er a
Yannick Quesnel, Laure Bidois-Sery,
J ean-Marie Poirier,† and Lucette Duhamel*
Universite´ de Rouen, UPRES-A 6014, Laboratoire des
Fonctions Azote´es et Oxyge´ne´es Complexes, IRCOF, 76821
Mont Saint Aignan Cedex, France
Received December 3, 1997
Compound 1 is an efficient fungicide used to protect
tomatoes against Botrytis cinera (efficiency >80%). In
the reported synthesis of 1, the key intermediate, 2-[(chlo-
rophenyl)methylidene]-5,5-dimethylcyclopentanone (2a )
has been obtained by aldolization of 2,2-dimethylcyclo-
pentanone (4) with p-chlorobenzaldehyde followed by
dehydration in situ of the aldol (Scheme 1, path A).1
Then, ketone 2a was condensed with dimethyloxosul-
foxonium methylide (Corey ylide), and the resulting
epoxide was opened with triazole.1
The drawback of this procedure is the access to the
starting 2,2-dimethylcyclopentanone (4). Indeed, all
methods using the monomethylation of 2-methylcyclo-
pentanone (5)2 and dimethylation of cyclopentanone3
result in mixtures of polyalkylated cyclopentanones from
which the wanted ketone 4 is very difficult to separate.
Thus, many multistep procedures to prepare this ketone
4 have been reported. They either require the cyclization
of 2,2-dimethyladipic acid,4 5-iodo-2,2-dimethylpentani-
trile,5 or 2-dimethylpent-4-enal6 or pinacolic transposition
reactions.7 Our recent findings8,9 led us to test another
pathway to 2a involving as a key step the synthesis of
enone 3a via the regioselective aldolization with p-
chlorobenzaldehyde of commercial 2-methylcyclopen-
tanone 5 (Scheme 1, path B).
Sch em e 2a
* To whom correspondence should be addressed. Tel.: 02 35 52 29
10. Fax: 02 35 52 29 71. E-mail: lucette.duhamel@univ-rouen.fr.
† Deceased on May 7, 1997.
(1) (a) Mugnier, J .; Greiner, A.; Hutt, J .; Pepin, R. (Rhoˆne Poulenc
Agrochimie) French patent 2 662 911 (12/06/90). (b) Hutt, J .; Mugnier,
J .; Pepin, R.; Greiner, A. (Rhoˆne Poulenc Agrochimie), European patent
378 953 (29/12/88).
a
Reagents and conditions: (a) M ) K:t-BuOK (1 equiv), THF,
-15 °C, 45 min; M ) Li: t-BuOK (1 equiv), THF, -15 °C, 45 min,
then LiBr (5 equiv), THF, -15 °C, 15 min; (b) (i) RCHO, -78 °C,
THF, 1 h, (ii) H2O, -78 °C.
(2) (a) Haller, A.; Cornubert, R. Bull. Soc. Chim. Fr. 1926, 39, 1724.
(b) Bouveault, L.; Locquin, R. Bull. Soc. Chim. Fr. 1908, 3, 437. (c)
House, H. O.; Trost, B. M. J . Org. Chem. 1965, 30, 2505.
(3) (a) Gault, F. G.; Germain, J . E.; Conia, J . M. Bull. Soc. Chim.
Fr. 1957, 1064. (b) House, H. O.; Kramar, V. J . Org. Chem. 1963, 28,
3362. (c) Coates, R. M.; Sowerby, R. L. J . Am. Chem. Soc. 1971, 93,
1027.
(4) (a) Blanc, G. Bull. Soc. Chim. Fr. 1865, 3, 780. (b) Blanc, G. Bull.
Soc. Chim. Fr. 1908, 3, 780. (c) Wilcox, C. F., J r.; Mesirov, M. J . Org.
Chem. 1960, 25, 1841. (d) Meerwein, H.; Unkel, W. Ann. 1910, 376,
152. (e) King, F. E.; King, T. J .; Topliss, J . G. J . Chem. Soc. 1957, 919.
(f) Kopecky, K. R.; Levine, C. Can. J . Chem. 1981, 59, 3273.
(5) Larcheveˆque, M.; Debal, A.; Cuvigny, Th. J . Organomet. Chem.
1975, 87, 25. (b) Larcheveˆque, M.; Debal, A.; Cuvigny, Th. Bull. Soc.
Chim. Fr. 1974, 1710.
(6) Fairly, D. P.; Bosnich, B. Organometallics 1988, 7, 936.
(7) (a) Bartlett, P. D.; Bavley, A. J . Am. Chem. Soc. 1938, 60, 2416.
(b) Conley, R. T. Rec. Trav. Chim. 1962, 81, 198. (c) Krief, A.;
Laboureur, J . L.; Dumont, W. Tetrahedron Lett. 1987, 28, 1549.
(8) Duhamel, P.; Cahard, D.; Quesnel, Y.; Poirier, J . M. J . Org.
Chem. 1996, 61, 2232.
We have recently reported that the condensation of
potassium enolates 7 and 10 (M ) K) with carbonyl
compounds leads to the thermodynamically most stable
aldols 11, whereas the corresponding lithium enolates 7
and 10 (M ) Li) yield the expected aldols 8 and 11,
respectively.8 The potassium enolates can be easily
generated from the corresponding enoxy silanes 6 and 9
and potassium tert-butoxide (Scheme 2).9
We studied the methodology of pathway B with two
aromatic aldehydes. Our first approach required a
two-step procedure: aldol 11b (R ) Ph) obtained
from enoxy silanes 6 or 9 according to Scheme 28 (82%
yield) was successively treated with potassium tert-
butoxide and methyl iodide, yielding directly ketone 2b
(R ) Ph, 60% yield from 11b, 49% overall yield from 6
or/and 9). The dehydration of the aldol occurred in situ.
(9) Duhamel, P.; Cahard, D.; Poirier, J . M. J . Chem. Soc., Perkin
Trans. 1 1993, 2509.
S0022-3263(97)02199-3 CCC: $15.00 © 1998 American Chemical Society
Published on Web 05/29/1998

3794 J . Org. Chem., Vol. 63, No. 11, 1998
Notes
Potassium tert-butoxide was purchased from Aldrich and sub-
limed prior to use. Lithium bromide was dried by heating under
reduced pressure. Silyl enol ethers 6 and 9 were prepared
according to literature procedures12,13 (according to ref 12, 6/9
) 95/5, and to ref 13, 6/9 ) 1/99). NMR spectra were recorded
on a Bruker A. C. spectrometer in chloroform-d (200 MHz for
1H and 50 MHz for 13C).
Sch em e 3
P r ep a r a tion of Keton e 2b fr om 11b. To a solution of
hydroxy ketone 11b (5 mmol, 1.02 g, T/E ) 1.4/1, cis/trans )
2.6/1) in THF (10 mL) under argon was added a solution of
potassium tert-butoxide (10 mmol, 1 equiv, 1.12 mg) in THF (5
mL) at -20 °C, and the mixture was then stirred for 1 h.
A
solution of methyl iodide (2 equiv, 7.5 mmol, 412 µL) was added
dropwise, and the mixture was stirred for additional 1 h. The
mixture was quenched with water (10 mL) at -20 °C and
extracted with diethyl ether. The extract was dried over
anhydrous MgSO4 and concentrated in vacuo. Ketone 2b was
obtained in 60% yield after purification by flash chromatography
using petroleum ether/ether ) 96/4 as eluent.
We then developed a one-pot synthesis. Mixtures of
enoxy silanes 6 and 9 (6/9 ) 95/5, 50/50, 1/99) were
treated with potassium tert-butoxide, and corresponding
mixtures of potassium enolates 7 and 10 (M ) K) were
condensed with p-chlorobenzaldehyde or benzaldehyde.
Reaction of the resulting potassium aldolates with potas-
sium tert-butoxide allowed their transformation into
enones 3a or 3b which yielded, after enolization and
alkylation with methyl iodide, ketones 2a (R ) p-ClC6H4)
or 2b (R ) Ph) with an overall yield of 80% (2a ) and 79%
(2b) after a single crystallization (Scheme 3).
Ketone 2b was already reported in the literature by a
three-step procedure: reaction of benzaldehyde with the
kinetic lithium enolate 10 of 2-methylcyclopentanone 5,
dehydration of aldol 11b (R ) Ph) via its mesylate, and
methylation of the resulting enone 3b (overall yield
72%).10 It is to be noted that in our case the potassium
aldolates of 11 were spontaneously transformed into
enones 3 at -15 °C, whereas this reaction did not occur
at -78 °C.8,11
P r ep a r a tion of Keton es 2a a n d 2b in On e P ot fr om 6 or
9. To a solution of silyl enol ether 6 or 9 (or any mixture of 6
and 9) (5 mmol, 0.85 g) in THF (10 mL) under argon was added
a solution of potassium tert-butoxide (5 mmol, 0.56 g) in THF (5
mL) at -15 °C, and the mixture was then stirred for 45 min.
The aromatic aldehyde (5 mmol) in THF (5 mL) was added and
stirred for 1 h at this temperature. A solution of potassium tert-
butoxide (2 equiv, 10 mmol, 1.12 g) in THF (10 mL) was then
added, and the resulting mixture was stirred for 2 h. A solution
of methyl iodide (1.5 equiv, 7.5 mmol, 412 µL) in THF (5 mL)
was added dropwise, and the mixture was stirred for additional
2 h at this temperature. The mixture was quenched with water
(10 mL) and extracted with diethyl ether. The extract was dried
over anhydrous MgSO4 and concentrated in vacuo to provide a
pale yellow solid. A single crystallization in pentane afforded a
white solid in 80% yield (2a , 0.94 g, 4 mmol) and 79% yield (2b,
0.79 g, 3.95 mmol).
2-Ben zylid en e-5,5-d im et h ylcyclop en t a n on e (2b ):10 mp
1
134 °C; H NMR δ 7.53-7.30 (m, 6H), 2.84 (d, 2H, J ) 2.8, 6.9
Hz), 1.80 (t, 2H, J ) 6.9 Hz), 1.09 (s, 6H); 13C NMR δ 210.0,
125.5, 135.4, 133.2, 130.4, 129.1, 128.6, 44.7, 35.8, 25.8, 23.8;
IR (neat) 2963, 1725, 1649, 1578, 1452; MS (EI, m/z) 200, 185,
116, 91. Anal. Calcd for C14H16O: C, 83.95; H, 8.05. Found:
C, 83.82; H, 7.82.
In conclusion, the highly regioselective condensation
of carbonyl compounds with potassium enolates 7 or 10
led to an expeditious synthesis of the key ketone 2a in
one pot from enoxy silanes 6 or 9. The other advantages
of this procedure are that we can start from any mixture
of enoxysilanes 6/9 obtained from 2-methylcyclopen-
tanone 5 and avoid the laborious preparation of 2,2-
dimethylcyclopentanone 4.
2-[(p-Ch lor op h en yl)m eth ylid en e]-5,5-d im eth ylcyclop en -
ta n on e (2a ):1 mp 122 °C (lit.1 mp 121 °C); 1H NMR δ 7.44-
7.33 (4H, 2d, J ) 8.6, 12.6 Hz), 7.32 (s, 1H), 2.83 (2H, d, J )
2.7, 7.3 Hz), 1.83 (2H, t, J ) 7.3 Hz), 1.10 (s, 6H); 13C NMR δ
210.9, 135.8, 134.9, 134.0, 131.6, 131.5, 128.8, 44.7, 35.6, 25.7,
23.8; IR 2958, 1704, 1622, 1458, 1100, 834 cm-1. Anal. Calcd
for C14H15ClO: C, 71.64; H, 6.44. Found: C, 71.59; H, 6.59.
Exp er im en ta l Section
Gen er a l Meth od s. Prior to use, tetrahydrofuran (THF) was
distilled from sodium benzophenone ketyl and kept under argon.
Ack n ow led gm en t. We thank the Ministe`re de la
Recherche et de la Technologie for a grant (Y.Q.) and
Rhoˆne Poulenc Industrialization for a financial support
(L.B.S).
(10) Fleming, I.; Higgins, D.; Lawrence, N. J .; Thomas, A. P. J .
Chem. Soc., Perkin Trans. 1 1992, 24, 3331.
(11) The transformation of initial potassium aldolate into enone 3
can occur via the following equilibrium:
J O972199C
(12) (a) Cazeau, P.; Moulines, F.; Laporte, O.; Duboudin, F. J .
Organomet. Chem. 1980, 201, 2075. (b) Cazeau, P.; Duboudin, F.;
Moulines, F.; Babot, O.; Dunogue`s, J . Tetrahedron 1987, 43, 2085.
(13) House, H. O.; Czuba, L. Z.; Gall, M.; Olmstead, H. D. J . Org.
Chem. 1969, 34, 2324.