Titanocene(II)-promoted desulfurizative acylation of thioacetals with alkanenitriles

Article abstract of DOI:10.1016/S0040-4039(99)02001-8

Ketones were obtained in good yields by titanocene(II)-promoted reaction of thioacetals with alkanenitriles. The regioselective formation of α-substituted ketone was observed when the reaction was carried out in the presence of methyl iodide or benzyl bro

Full text of DOI:10.1016/S0040-4039(99)02001-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 65–68
Titanocene(II)-promoted desulfurizative acylation of thioacetals
with alkanenitriles
Takeshi Takeda,∗ Haruhiko Taguchi and Tooru Fujiwara
Department of Applied Chemistry, Tokyo University of Agriculture and Technology, Koganei, Tokyo 184-8588, Japan
Received 16 September 1999; revised 15 October 1999; accepted 18 October 1999
Abstract
Ketones were obtained in good yields by titanocene(II)-promotedreaction of thioacetals with alkanenitriles. The
regioselective formation of α-substituted ketone was observed when the reaction was carried out in the presence
of methyl iodide or benzyl bromide. © 1999 Elsevier Science Ltd. All rights reserved.
Keywords: acylation; alkylation; thioacetal; titanium; titanium compounds.
Recently, the chemistry of carbene complexes of transition metals has been extensively studied and
a number of useful synthetic reactions have been developed.1 A methylidene complex of titanium
formed from Tebbe reagent,2 Grubbs reagent,3 or dimethyltitanocene4 is a synthetically useful metal
carbene and is reactive toward carbon–carbon and carbon–heteroatom multiple bonds. Its reaction with
alkanenitrile was first reported by Eisch and Piotrowski.5 They obtained acetophenone by the reaction
of methylidenetitanocene with benzonitrile. Doxsee and his co-workers investigated the reactions of
intermediary vinylimido complexes of titanium and reported the formal [4+2] cycloadditions with
ketones, nitriles, and imines.6 Recently, we found that the desulfurization of thioacetals 1 with a low-
valent titanium reagent Cp2Ti[P(OEt)3]2 2 gave an organotitanium species which reacted with organic
molecules having a multiple bond.7 These results suggest that the active species formed from thioacetals
are alkylidenetitanocenes 3. We then investigated the reaction of these organotitanium species with
alkanenitriles 4 (Eq. 1).
(1)
Thioacetals 1 were treated with the low-valent titanium reagent 2 at room temperature for 15 min. The
reaction of the resulting organotitanium compounds with alkanenitriles 4 for 1–3 h and the following
hydrolysis produced the corresponding ketones 5 (Table 1). It is well known that the preparation
∗
Corresponding author. Tel: +81 42 388 7034; fax: +81 42 388 7034; e-mail: takeda-t@cc.tuat.ac.jp
0040-4039/00/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(99)02001-8

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Table 1
Desulfurizative acylation of thioacetals 1 with alkanenitriles 4a
of ketones by addition of organometallic compounds such as Grignard reagents to alkanenitriles is
often affected by steric hindrance, and the yields are generally low in the case of α,α-disubstituted
alkanenitriles.8 The most remarkable feature of the present acylation is the generality in the choice of
substrates. As shown in Table 1, ketones were obtained in good yields even when the sterically hindered
alkanenitriles were employed.
The following is a typical experimental procedure. Finely powdered molecular sieves 4 A (180 mg),
magnesium turnings (53 mg, 2.2 mmol; purchased from Nacalai Tesque Inc., Kyoto, Japan) and Cp2TiCl2
(448 mg, 1.8 mmol) were placed in a flask and dried by heating with a heat gun under reduced pressure

67
(2–3 mmHg). During this procedure, care is taken not to sublime Cp2TiCl2. After cooling, THF (4 ml)
and P(OEt)3 (0.61 ml, 3.6 mmol) were added successively with stirring at room temperature under argon.
After 3 h, a THF (1 ml) solution of 3-phenyl-1,1-bis(phenylthio)propane (1b) (202 mg, 0.6 mmol) was
added and the reaction mixture was stirred for 15 min. Valeronitrile (4d) (42 mg, 0.5 mmol) in THF (1.5
ml) was added and the mixture was stirred for a further 1.5 h. The reaction was quenched by addition of
1 M NaOH and the insoluble materials were filtered off through Celite. The filtrate was extracted with
ether and the organic phase was dried over Na2SO4. After removal of the solvent, the residue was purified
by PTLC (hexane:AcOEt 9:1) to yield 69 mg (68%) of 1-phenyloctan-4-one (5a).
(2)
We tentatively propose that this reaction proceeds via the formation of vinylimido complex 6 similarly
to the reaction of methylidenetitanocene (Eq. 2). Unlike the unsubstituted vinylimido complex (R1=H),
however, the intermediate of the present reaction showed no reactivity toward carbonyl compounds,
nitrile, and imine. We further investigated its reaction with electrophiles and found that alkylation
proceeded to give the monoalkylated ketones 7 on treatment with reactive alkyl halides such as methyl
iodide or benzyl bromide (Table 2).9 This acylation–alkylation sequence was successfully applied to the
preparation of cyclic ketones; α-substituted cyclohexanones 7e and h were obtained by the reaction using
5-halovaleronitrile (entries 5 and 8).
In summary, we have developed a new method for the preparation of ketones from thioacetals and
alkanenitriles. Further study on the reaction of the organotitanium intermediates is currently under way.
Acknowledgements
This work was supported by a Grant-in-Aid for Scientific Research from the Ministry of Education,
Science, Sports, and Culture, Japan (Nos. 11119214 and 11440213).
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