Free radical-promoted conjugate addition of activated bromo compounds using titanocene(III) chloride as the radical initiator

Article abstract of DOI:10.1016/j.tetlet.2005.07.007

Free radical-promoted conjugate addition of activated bromo compounds to α,β-unsaturated ketones and reactive α,β-unsaturated esters has been described using titanocene(III) chloride (Cp₂TiCl) as the radical initiator. Cp₂TiCl was prepared in situ from commercially available Cp₂TiCl₂ and activated zinc dust in THF.

Full text of DOI:10.1016/j.tetlet.2005.07.007

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 6115–6117
Free radical-promoted conjugate addition of
activated bromo compounds using titanocene(III)
chloride as the radical initiator
Samir Kumar Mandal, Samaraesh Jana and Subhas Chandra Roy*
Department of Organic Chemistry, Indian Association for the Cultivation of Science, Jadavpur, Kolkata 700 032, India
Received 12 May 2005; revised 21 June 2005; accepted 29June 2005
Available online 18 July 2005
Abstract—Free radical-promoted conjugate addition of activated bromo compounds to a,b-unsaturated ketones and reactive a,b-
unsaturated esters has been described using titanocene(III) chloride (Cp
2
TiCl) as the radical initiator. Cp
2
TiCl was prepared in situ
from commercially available Cp TiCl and activated zinc dust in THF.
2
2005 Elsevier Ltd. All rights reserved.
2
ꢀ
O
Carbon–carbon bond formation through conjugate
O
Br Cp2TiCl / THF
rt, 4 h, 68%
addition to a,b-unsaturated carbonyl compounds is a
+
Ph
Ph
1
Ph
Ph
powerful synthetic tool in organic chemistry. Typically,
1
a
1
b
an ionic species or an organocopper reagent is used as
the nucleophile for this purpose. Only recently have con-
jugate addition reactions of free radicals to a,b-unsatu-
rated carbonyl compounds, including carbohydrate
derivatives, been successfully studied mainly using tin
Scheme 1.
2
in THF. In a preliminary experiment, treatment of the
enone 1a with allyl bromide in the presence of Cp TiCl
in THF at room temperature under argon for 4 h affor-
ded the 1,4-addition product 1b in 68% yield (Scheme
hydrides as the radical initiator. Some other reagents
2
have also been reported in the literature for conjugate
3
additions. However, the radical initiator titanocene(III)
8
species, Cp TiCl, has not been explored in detail for
2
1
).
conjugate addition of nucleophiles to a,b-unsaturated
carbonyl compounds. To our knowledge, only one
report on the titanium(III)-promoted C-glycosidation
of a,b-unsaturated carbonyl compounds with glycosyl
Thus, a series of a,b-unsaturated ketones and reactive
a,b-unsaturated esters were treated with various acti-
vated bromo compounds in the presence of Cp
4
2
TiCl
halides has appeared very recently. In continuation of
5
and the results are summarized in Table 1.
our studies towards radical-promoted carbon–carbon
bond formation using Cp TiCl as the radical initiator,
2
Three types of bromo compounds, for example, allyl
bromide, propargyl bromide and benzyl bromide
were chosen for the conjugate addition. Cyclic ketone
we recently reported an excellent method for the allyla-
6
tion of aldehydes. We wish to report here a mild and
efficient method for the titanium(III)-induced conjugate
addition of activated bromo compounds to a,b-unsatu-
9
1
a, acyclic ketone 10a and b-aryl substituted ketones
a–8a underwent smooth conjugate addition. While
rated ketones and reactive a,b-unsaturated esters. The
7
reactive esters 11a and 12a took part in the reaction
satisfactorily, less reactive esters such as methyl cinna-
mate remained unchanged under the reaction condi-
tions even after prolonged stirring. It is noteworthy
that the results of the conjugate addition of benzyl
bromide only to compounds 9a–12a are shown in
Table 1. Conjugate addition of the other bromo
compounds (allyl bromide and propargyl bromide) to
radical initiator Cp TiCl was generated in situ from
2
commercially available Cp TiCl and activated zinc dust
2
2
Keywords: Free radical; Titanocene(III) chloride; Conjugate addition;
a,b-Unsaturated carbonyl compounds; Bromo compounds.
*
Corresponding author. Tel.: +91 33 2473 4971; fax: +91 33 2473
805; e-mail: ocscr@mahendra.iacs.res.in
2
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.07.007

6116
S. K. Mandal et al. / Tetrahedron Letters 46 (2005) 6115–6117
Table 1. 1,4-Conjugate addition of activated bromo compounds to a,b-unsaturated ketones and reactive esters
a
b
Entry
1
Enone
RBr
Time (h)
Product
Yield (%)
O
O
Br
5
65
Ph
Ph
Ph
Ph
Ph
Ph
Ph
2
a
2
b
O
O
O
2
3
PhCH
2
Br
Br
4.5
4.5
69
67
Ph
Ph
Ph
3
a
3
b
Ph
O
O
PhCH
2
Ph
Ph
Me
4
a
4
b
Me
O
4
5
6
7
8
9
5
66
66
72
69
71
78
73
70
Ph
Br
OMe
OMe
5
a
5
b
Ph
O
O
PhCH
2
Br
6
Ph
Ph
6
a
6
b
O
O
O
O
4.5
5.5
4.5
4
Br
Ph
Ph
Ph
Ph
7
a
7
b
Ph
O
O
O
PhCH
2
2
2
2
2
Br
Br
Br
Br
Br
O
8
a
8
b
O
O
PhCH
PhCH
PhCH
PhCH
CH Ph
2
9
a
9b
O
O
CH Ph
2
1
0a
1
0b
O
O
1
1
0
1
5
MeO
MeO
MeO
MeO
CH2Ph
1
1a
11b
O
O
6
CH2Ph
1
2a
12b
a
Products were characterized by IR, NMR and HRMS.
Yield refers to pure isolated product.
b
9
a–12a have also been attempted, however, due to their
In conclusion, a free radical-promoted mild and efficient
method for conjugate addition of activated bromo com-
pounds to a,b-unsaturated ketones and reactive a,b-
high volatility, the products could not be isolated after
usual work-up.

S. K. Mandal et al. / Tetrahedron Letters 46 (2005) 6115–6117
6117
unsaturated esters in good yields using titanocene(III)
chloride has been developed.
Beattie, M. S. J. Am. Chem. Soc. 1990, 112, 6408; (c)
Rajanbabu, T. V.; Nugent, W. A. J. Am. Chem. Soc. 1994,
1
16, 986; For a catalytic version see: (d) Gansauer, A.;
Bluhm, H.; Pierobon, M. J. Am. Chem. Soc. 1998, 120,
2849.
. Typical procedure: A solution of titanocene dichloride
249mg, 1 mmol) in dry THF (10 mL) was stirred with
1
Acknowledgements
8
(
S.K.M. and S.J. thank CSIR, New Delhi, for awarding
the fellowships.
activated zinc dust (196 mg, 3 mmol) (activated zinc dust
was prepared by washing 20 g of commercially available
zinc dust with 60 mL of 4 N HCl followed by thorough
washing with water until the washings became neutral and
finally washed with dry acetone and then dried in vacuo) for
References and notes
1
h under argon. The resulting green solution was added
1
2
. (a) Perlmutter, P. Conjugate Addition Reactions in Organic
Synthesis; Pergamon: Oxford, UK, 1992; (b) Leonard, J.;
Diez-Barra, F.; Merino, S. Eur. J. Org. Chem. 1998,
slowly to a stirred solution of the enone 1a (104 mg,
0.5 mmol) and allyl bromide (60 mg, 0.5 mmol) in dry THF
(5 mL) at room temperature over 1.5 h. The reaction
mixture was then stirred for an additional 2.5 h and finally
2
051.
. (a) Jeon, Y. T.; Lee, C.-P.; Mariano, P. S. J. Am. Chem.
Soc. 1991, 113, 8847; (b) Sibi, M. P.; Ji, J.; Sausker, J. B.;
Jasperse, C. P. J. Am. Chem. Soc. 1999, 121, 7517; (c)
Mirakata, M.; Tsutsui, H.; Hoshino, O. Org. Lett. 2001, 3,
decomposed with 10% aqueous H SO solution (5 mL).
2 4
Most of the solvent was removed under reduced pressure
and the residue obtained was extracted with diethyl ether
(4 · 25 mL). The ether layer was successively washed with
water (2 · 10 mL), brine (2 · 10 mL) and finally dried
2
99; (d) Sibi, M. P.; Manyem, S. Org. Lett. 2002, 4, 2929;
(
e) Sibi, M. P.; Liu, P.; Ji, J.; Hajra, S.; Chen, J.-X. J. Org.
2 4
(Na SO ). After removal of the solvent, the crude residue
Chem. 2002, 67, 1738; (f) Srikanth, G. S. C.; Castle, S. L.
Org. Lett. 2004, 6, 449.
obtained was purified by column chromatography over
silica gel (5% ethyl acetate in petroleum ether) to afford 1b
3
. (a) Iserloh, U.; Curran, D. P.; Kanemasa, S. Tetrahedron:
Asymmetry 1999, 10, 2417; (b) Liu, J.-Y.; Jang, Y.-J.; Lin,
W.-W.; Liu, J.-T.; Yao, C.-F. J. Org. Chem. 2003, 68, 4030.
. Spencer, R. P.; Schwartz, J. Tetrahedron 2000, 56, 2103.
. (a) Mandal, P. K.; Maiti, G.; Roy, S. C. J. Org. Chem.
(85 mg, 68%) as a crystalline solid mp 50–51 ꢁC. IR (neat):
À1
2927, 1678, 1639, 1595, 1494, 1448, 1352, 1261, 1215 cm
;
1
3
H NMR (300 MHz, CDCl ): d 2.38 (dd, J = 7.2, 6.9Hz,
4
5
2H), 3.21 (d, J = 6.6 Hz, 2H), 3.35–3.45 (m, 1H), 4.88 (d,
J = 9.9 Hz, 1H), 4.92 (d, J = 16.5 Hz, 1H), 5.54–5.68 (m,
1H), 7.07–7.23 (m, 5H), 7.34 (dd, J = 8.1, 7.5 Hz, 2H), 7.44
1
998, 63, 2829; (b) Roy, S. C.; Rana, K. K.; Guin, C. J.
1
3
Org. Chem. 2002, 67, 3242.
(t, J = 7.5 Hz, 1H), 7.81 (d, J = 8.1 Hz, 2H); C NMR
(75 MHz, CDCl ): d 40.5, 40.6, 44.4, 116.6, 126.2, 127.4,
128.3, 128.4, 128.8, 132.8, 136.1, 137.0, 144.2, 198.8. HRMS
6
7
. Jana, S.; Guin, C.; Roy, S. C. Tetrahedron Lett. 2004, 45,
3
6
575.
. (a) Nugent, W. A.; RajanBabu, T. V. J. Am. Chem. Soc.
988, 110, 8561; (b) RajanBabu, T. V.; Nugent, W. A.;
+
(ESI) calcd for
251.1430.
18 19
C H O (M +H): 251.1436; found
1