Titanocene(II)-promoted reductive alkylation of anilides with thioacetals

Article abstract of DOI:10.1016/j.tetlet.2005.03.062

Titanocene(II)-promoted reaction of anilides with thioacetals followed by treatment with a small amount of water gave reductive alkylation products, anilines with a secondary alkyl group.

Full text of DOI:10.1016/j.tetlet.2005.03.062

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 3157–3160
Titanocene(II)-promoted reductive alkylation
of anilides with thioacetals
Takeshi Takeda,* Yasutaka Yatsumonji and Akira Tsubouchi
Department of Applied Chemistry, Graduate School of Engineering, Tokyo University of Agriculture and Technology,
Koganei, Tokyo 184-8588, Japan
Received 20 January 2005; revised 5 March 2005; accepted 14 March 2005
Available online 26 March 2005
Abstract—Titanocene(II)-promoted reaction of anilides with thioacetals followed by treatment with a small amount of water gave
reductive alkylation products, anilines with a secondary alkyl group.
Ó 2005 Elsevier Ltd. All rights reserved.
In the course of study on the carbonyl olefination utiliz-
ing a thioacetal–titanocene(II) system,1 we observed the
unusual formation of pyrrolidines when N-[3,3-bis(phen-
ylthio)propyl]anilides were treated with titanocene(II)
Cp2Ti[P(OEt)3]2 1.2 We were intrigued with the reduc-
Scheme 1.
tion of carbon–carbon double bond of enamine involved
in the above transformation, and further investigated
the titanocene(II)-promoted carbonyl olefination of
amides with thioacetals. Here, we report a convenient
method for the reductive alkylation of anilides 2 using
a titanocene(II) 1–thioacetal 3 system (Scheme 1). The
substituted enamine 6 is produced by the isomerization
of the enamine 8 initially formed by the intramolecular
carbonyl olefination of the intermediary titanium car-
method consists of the carbonyl olefination of 2 and
bene complex 9 (Scheme 2). The disubstituted enamine,
reduction of the resulting enamines, giving alkylated
anilines 4.
formed from 5c, would be rather susceptible to hydroly-
sis hence the cyclopentanone 7 was obtained.
We initially made a detailed study of the titanocene(II)-
promoted intramolecular reaction of 5,5-bis(phenyl-
Contrary to these results, cyclopentylamines 10 were
obtained when the reaction mixture was treated with
thio)pentanilides 5 and found that the reaction gave
a small amount of water (entries 4–8). The yield of 10
two types of products depending on the work-up condi-
is dependent on the position of the substituent of the
tions. Reaction of 5,5-bis(phenylthio)-1-phenylpentan-
ilide 5a with the titanocene(II) species 1 under reflux
in THF for 1h and an alkaline work-up produced the
amide 5. Although the reactions of a-substituted amides
5a and 5b gave the cyclic amines 10 in moderate yields
(entries 4 and 5), the amines 10 were obtained in good
trisubstituted enamine 6a in high yield (Table 1, entry
yields when a-unsubstituted amides 5c–e were subjected
1). The highly substituted enamine 6b was also obtained
to the reaction (entries 6–8). Since the enamines 6 are
by the reaction of a-substituted anilide 5b (entry 2).
produced by the reaction of the anilides 5 with 1 fol-
lowed by the alkaline aqueous work-up, it is reasonable
to assume that the amines 10 are produced by reduction
of the enamines 6 or 8.3
When the b-substituted anilide 5c was treated with the
titanocene(II) reagent 1, the cyclopentanone 7 was iso-
lated (entry 3). It is reasonable to assume that the highly
The typical experimental procedure for the preparation
Keywords: Anilides; Carbonyl olefination; Reduction; Anilines; Tita-
nocene(II); Thioacetals.
of cyclopentylamines is as follows: finely powdered
molecular sieves 4 A (120 mg), magnesium turnings
(35 mg, 1.4 mmol) and Cp2TiCl2 (299 mg, 1.2 mmol)
*
Corresponding author. Tel./fax: +8142 388 7034; e-mail: takeda-t@
cc.tuat.ac.jp
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.03.062

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T. Takeda et al. / Tetrahedron Letters 46 (2005) 3157–3160
Table 1. Titanocene(II)-promoted intramolecular reaction of 5,5-
bis(phenylthio)pentanilides 5a
and the reaction mixture was stirred for 3 h. A THF
(6 mL) solution of 5b (154 mg, 0.3 mmol) was added
dropwise to the mixture over 20 min, and the mixture
was refluxed for 1h. After cooling to 25 °C, water
(0.3 mL) was added to the reaction mixture, which was
stirred for 30 min. The reaction was quenched by addi-
tion of 1M NaOH. The insoluble materials were filtered
off through Celite and washed with ether. The organic
materials were extracted with ether and dried over
Na2SO4. After removal of the solvent, the residue was
purified by PTLC (silica gel, hexane–AcOEt = 9:1) to
give 10b (41mg, 49%).
Entry
Anilide 5
Product (yield/%)
1b
5a
6a (89)c
2b
To investigate the mechanism for the reduction of the
double bond, the reaction mixture of 5b with 1 was trea-
ted with D2O (1mL/1mmol of 5b) at 25 °C for 1h. The
formation of the 1,2-dideuteriocyclopentylamine 11, in
which lesser extent of deuterium incorporation was ob-
served at the position b to the amino group in the major
isomer (Scheme 3), suggests that the reduction proceeds
via the b-aminoalkyltitanium species 12 (Scheme 4).
Two pathways for the formation of such species would
be plausible: partial deuteration of a titanacyclopropane
intermediate 13 generated by the reaction of the enam-
ine 6b with a titanocene(II) species and deuteriotitana-
tion of 6b with a titanium deuteride 14. Considering
that the conditions of aqueous work-up determines,
which product is formed, the latter pathway seems to
be likely. Similar reduction of enamines with metal
hydrides has been well documented4 and Brown and
co-workers reported that the hydroboration of enamines
with borane–methyl sulfide complex proceeds regioselec-
tively to produce b-amino alkylboranes.4f
5b
6b (75)c
3b
5c
5a
7 (54)
4
10a (20)d
5
6
5b
5c
10b (49)e
On the basis of the above consideration, we expected
that acyclic amines would be produced by the reductive
alkylation of anilides using a thioacetal–titanocene(II)
system (Scheme 1). After the carbonyl olefination of ani-
lide 2 with thioacetal 3 and the titanocene(II) reagent 1
at 30 °C or under reflux in THF, the reaction mixture
was treated with water to produce acyclic amine 4.
Using different thioacetals, a variety of anilines bearing
a secondary alkyl group were obtained in good overall
yields (Table 2).
10c (71)f,g
7
8
10d (76)f
5d
5e
Various Wittig-like olefinations of amides using tita-
nium based reagents, such as the Tebbe and related
reagents,5 dialkyltitanocenes,6 and gem-dihalides–
Zn(Pb)–TiCl4,7 have been developed. Although prepara-
tion of 1-benzyl-2-methylpyrrolidine by methylenation
of 1-benzyl-2-pyrrolidinone with dimethyltitanocene
and subsequent reduction of the crude enamine with
CF3CO2H–NaBH4 was reported,7b no one-pot proce-
dure for the carbonyl olefination of amide and reduction
of the resulting enamine has ever been reported. There-
fore, since thioacetals are readily prepared from various
starting materials, the present one-pot procedure using
the same reagent for both the processes is a facile and
convenient way for the preparation of amines.
10e (72)
a All the reactions were performed with a similar procedure as
described in the text, unless otherwise noted.
b Without treatment with water before quenching.
c Isolated by column chromatography on aluminia (eluted with 1%
triethylamine in hexane).
d Only the cis-isomer was produced. Compound 3a was obtained in
46% yield.
e cis:trans = 81:19.
f Obtained as a mixture of stereoisomers.
g Compound 4 was obtained in 13% yield.
were placed in a flask and dried by heating with a heat
gun under reduced pressure (2–3 mmHg). After cooling,
THF (3.6 mL) and P(OEt)3 (0.41mL, 2.4 mmol) were
added successively with stirring at 25 °C under argon,
In summary, we have developed a one-pot procedure for
the reductive alkylation of anilides by the combination
of titanocene(II)-promoted carbonyl olefination of

T. Takeda et al. / Tetrahedron Letters 46 (2005) 3157–3160
3159
Scheme 2.
amides and reduction of the resulting enamines. Further
study on the reduction of carbon–carbon double bonds
with low-valent titanium reagents is currently underway.
Acknowledgements
This research was supported by a Grant-in-Aid for Sci-
entific Research (No. 14340228) from the Ministry of
Education, Culture, Sports, Science, and Technology,
Japan. This work was carried out under the 21st Cen-
tury COE program of ÔFuture Nano-materialsÕ in Tokyo
University of Agriculture and Technology.
Scheme 3.
References and notes
1. (a) Horikawa, Y.; Watanabe, M.; Fujiwara, T.; Takeda, T.
J. Am. Chem. Soc. 1997, 119, 1127; (b) Takeda, T.;
Scheme 4.
Table 2. Preparation of acyclic amines 10a
Entry
Thioacetal 3
Anilide 2
Temp/°C
Acyclic amine 4 (yield/%)
1
30
3a
3a
2a
4a (56)
2
3
4
5
30
2b
2b
4b (66)
4c (52)
4d (55)
30
3b
3c
3d
2b
Reflux
Reflux
2c
4e (54)
(continued on next page)

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T. Takeda et al. / Tetrahedron Letters 46 (2005) 3157–3160
Table 2 (continued)
Entry
Thioacetal 3
Anilide 2
Temp/°C
Acyclic amine 4 (yield/%)
6
7
8
3d
2a
Reflux
4f (51)
2b
Reflux
Reflux
3e
3f
4g (54)
4h (56)
2d
a All the reactions were performed with a similar procedure as described in Ref. 8.
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8. The experimental procedure for the preparation of 4b is as
follows: after the treatment of 3a (198 mg, 0.45 mmol)
with the titanocene(II) reagent 1, prepared from magne-
sium turnings (39 mg, 1.6 mmol), Cp2TiCl2 (336 mg,
1.4 mmol), molecular sieves 4 A (135 mg), and P(OEt)3
(0.46 mL, 2.7 mmol), at 25 °C for 15 min, a THF (0.9 mL)
solution of 2b (72 mg, 0.3 mmol) was added to the
reaction mixture, which was stirred for 3 h at 30 °C. After
addition of water (0.3 mL), the mixture was further stirred
for 30 min at 25 °C. The usual work-up and purification
by PTLC (silica gel, hexane–AcOEt = 95:5) gave 4b
(88 mg, 66%).
3. The treatment of enamine 6b with a mixture of titano-
cene(II) reagent 1 (2 equiv) and water (1mL/1mmol of 6b)
at 25 °C for 30 min produced the amine 10b in 61% yield. It
is of interest that 10b was obtained in better yield (74%)
when a THF solution of 1 was refluxed for 15 min before
use. This fact implies that a certain low-valent titanium
species other than the titanocene(II) species 1 also acts as a
reducing agent in the one-pot reaction.
4. For examples (a) Borch, R. F.; Bernstein, M. D.; Durst, H.
D. J. Am. Chem. Soc. 1971, 93, 2897; (b) Bach, R. D.;
Mitra, D. K. J. Chem. Soc., Chem. Commun. 1971, 1 43
3; (c) Barieux, J. J.; Gore, J. Tetrahedron 1972, 28,
1537; (d) Mitsudo, T.; Watanabe, Y.; Tanaka, M.; Atsuta,
S.; Yamamoto, K.; Takegami, Y. Bull. Chem. Soc. Jpn.
1975, 48, 1506; (e) Kim, S.; Oh, C. H.; Ko, J. S.; Ahn, K.