Mild and efficient allylation of aldehydes mediated by titanium(III) chloride

Article abstract of DOI:10.1016/j.tetlet.2004.07.045

A mild, chemoselective and efficient method for the allylation of aldehydes is described. Ketones remained unreacted under the reaction conditions.

Full text of DOI:10.1016/j.tetlet.2004.07.045

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 6575–6577
Mild and efficient allylation of aldehydes mediated by
titanium(III) chloride
Samaresh Jana, Chandrani Guin and Subhas Chandra Roy*
Department of Organic Chemistry, Indian Association for the Cultivation of Science, Jadavpur, Kolkata 700032, India
Received 12 May 2004; revised 28 June 2004; accepted 9 July 2004
Available online 24 July 2004
Abstract—A mild, chemoselective and efficient method for the allylation of aldehydes is described. Ketones remained unreacted un-
der the reaction conditions.
ꢀ 2004 Elsevier Ltd. All rights reserved.
The allylation of carbonyl compounds is a well-estab-
lished procedure for the preparation of homoallyl alco-
hols. Homoallyl alcohols have attracted significant
attention due to their versatile uses as important build-
ing blocks for natural product synthesis.1 Various types
of procedures have been reported1c for the allylation of
carbonyl compounds using metals such as magnesium,2a
zinc,2b tin,2c indium,2d aluminium,2e manganese,2f and
cadmium.2g Lewis acid catalyzed and environmentally
friendly green methodologies have also been reported.3
However, many of these methods suffer from limitations
such as lack of selectivity, extended reaction times, poor
yields, harsh reaction conditions and the use of costly or
toxic reagents. Therefore, a mild and efficient method is
still desirable. In this report, we wish to disclose a mild
and efficient methodology for chemoselective allylation
of aldehydes mediated by titanium(III) chloride that
overcomes many of the aforementioned complications.
by radical cyclization of epoxides, we have developed
a mild and efficient method for allylation of aldehydes
using 2equiv of Cp2TiCl as the radical initiator in excel-
lent yields (Scheme 1). Cp2TiCl was prepared4 in situ
from commercially available titanocene dichloride and
zinc dust in THF under argon. In the optimized proce-
dure,11 a green solution of the reagent in THF was
added slowly to the mixture of the aldehyde and allyl
bromide at room temperature under argon. After com-
pletion of the reaction (monitored by TLC) an aqueous
solution of sodium dihydrogen phosphate was added
followed by usual work-up and purification.
Thus, a series of aldehydes were subjected to the allyl-
ation reaction10 and the results are summarized in
Table 1.
While aliphatic and aromatic aldehydes reacted smoothly,
ketones for example, acetophenone, benzophenone and
cyclopentanone remained unreacted under the reaction
conditions. In a separate experiment, a 1:1 mixture of
benzaldehyde and acetophenone was treated with allyl
bromide in the presence of excess Cp2TiCl in THF under
the same reaction conditions. Benzaldehyde reacted com-
pletely to afford the desired allylated product (94%) but
Titanium(III) chloride has been extensively used as a
mild and useful reagent for various chemical transfor-
mations such as reduction of aromatic aldehydes,5 gly-
cosyl halides,6 vicinal dihalides,7 sulfoxides,8 etc. In
particular, titanium(III)-promoted homolytic cleavage
of epoxides4 forming a carbon-centred radical opened
a new era in synthetic organic chemistry. Radical cycli-
zation reaction of epoxides using titanium(III) species
has attracted much attention in recent years leading to
the synthesis of a number of naturally occurring com-
pounds and related products.9,10 In continuation of
our efforts towards the synthesis of natural products10
OH
Cp TiCl (2 eq)
2
Br
+
RCHO
R
THF, rt, 1.5 h
76-94%
2
1
R = aryl, alkyl
*
Scheme 1.
Corresponding author. E-mail: ocscr@mahendra.iacs.res.in
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.07.045

6576
S. Jana et al. / Tetrahedron Letters 45 (2004) 6575–6577
Table 1. Allylation of aldehydes using allyl bromide and Cp2TiCl
Entry
Substrate
CHO
Product
OH
Yield (%)a
1
2
94
92
OH
CHO
MeO
MeO
OH
CHO
3
4
94
94
OMe
OH
CHO
OMe
MeO
MeO
OMe
CHO
OMe
OH
5
6
93
93
O
O
O
OH
O
CHO
BnO
BnO
OMe
CHO
OMe
OH
7
8
80
94
Cl
Cl
OH
CHO
9
76
88
O
CHO
O
OH
OH
10
C5H11CHO
C5H11
a Yield refers to pure isolated product.
acetophenone did not undergo allylation at all and was
recovered unchanged (95%) (Scheme 2). It is noteworthy
that p-nitrobenzaldehyde did not react at all.
the cases, about 15–17% of the pinacol product was iso-
lated.
It is noteworthy that 2equiv of Cp2TiCl with respect to
the aldehyde are essential for complete conversion. We
presume that the bromine from allyl bromide 1 is ab-
stracted via a single electron transfer by 1equiv of Cp2
TiCl to produce the allylic radical 3, which is stabilized
by another equivalent of Cp2TiCl through the complex
4. Trapping of this radical complex with an aldehyde
Substituted allyl bromide namely, crotyl or cinnamyl
bromide was also used as allylating agent. In both cases,
the reaction was found to be regioselective, giving
mainly the c-regioisomer (Scheme 3). The reaction
was, however, less diastereoselective, giving an insepara-
ble 1:1 mixture of syn- and anti-diastereomers. In all
OH
Allyl bromide (2.5 eq)
Cp TiCl (4 eq)
2
CHO
COCH3
COCH3
CH
+
+
THF, rt, 1.5 h
94%
95%
Scheme 2.

S. Jana et al. / Tetrahedron Letters 45 (2004) 6575–6577
6577
R
OH
Ph
H
Cp TiCl / THF
2
Ph
Br
R
Ph
+
O
+
+
Ph
R
rt
Ph
OH
OH
γ- (syn:anti)
OH
α-
0%
17%
15%
77% (approx. 1:1)
40% (approx. 1:1)
R = Me
R = Ph
34%
Scheme 3.
Bosco, M.; Giuliani, A.; Markantoni, E.; Palmieri, A.;
Petrini, M.; Sambri, L. J. Org. Chem. 2004, 69, 1290–1297;
(c) Lu, J.; Ji, S.-J.; Qian, R.; Chen, J.-P.; Liu, Y.; Loh,
T.-P. Synlett, 2004, 534–536; (d) Masuyama, Y.; Suga, T.;
Watabe, A.; Kurusu, Y. Tetrahedron Lett. 2003, 44,
2845–2847; (e) Aspinall, H. C.; Bissett, J. S.; Greeves, N.;
Levin, D. Tetrahedron Lett. 2002, 43, 319–321; (f) Satashi,
K. A.; Keiji, M. Tetrahedron Lett. 2001, 42, 1935–1939; (g)
Aspinall, H. C.; Bissett, J. S.; Meiver, E. G. Tetrahedron
Lett. 1998, 39, 9283–9286; (h) Miyamoto, H.; Daikawa,
N.; Tanaka, K. Tetrahedron Lett. 2003, 44, 6963–6964; (i)
Andrews, P. C.; Peatt, A. C.; Raston, C. L. Tetrahedron
Lett. 2004, 42, 243–248; (j) Zha, Z.; Xie, Z.; Zhou, C.;
Chang, M.; Wang, Z. New J. Chem. 2003, 27, 1297–1300.
4. (a) Rajanbabu, T. V.; Nugent, W. A. J. Am. Chem. Soc.
1994, 116, 986–997; (b) Gansauer, A.; Bluhm, H. Chem.
Rev. 2000, 100, 2771–2788.
.
Cp TiCl
Cp TiCl / THF
2
Br
2
Ti
-Cp TiClBr
2
Cl
Cp
1
3
Cp
4
Cp
OH
NaH PO
Cl
Cp
2
4
RCHO
Ti
R
O
H O
2
2
R
5
Scheme 4.
leads to the observed product 2 via the six-membered
transition complex 5 (Scheme 4).
5. Gansauer, A.; Bauer, D. J. Org. Chem. 1998, 63,
2070–2071.
6. Spencer, R. P.; Cavalloro, C. L.; Schwartz, J. J. Org.
Chem. 1999, 64, 3987–3995.
In conclusion, we have developed a mild, chemoselective
and efficient methodology for allylation of aldehydes
using titanium(III) chloride and allyl bromide in THF.
7. Qian, Y.; Li, G.; Zheng, X.; Huang, Y. Z. Synlett 1991,
489–490.
8. Zhang, Y.; Yu, Y.; Bao, W. Synth. Commun. 1995, 25,
1825.
Acknowledgements
9. (a) Clive, D. L. J.; Magnuson, S. R. Tetrahedron Lett.
1995, 36, 15–18; (b) Gansauer, A.; Pierobon, M.; Bluhm,
H. Synthesis 2001, 2500–2520, and references cited
therein.
S.J. and C.G. thank CSIR, New Delhi for awarding the
fellowships.
10. (a) Mandal, P. K.; Maiti, G.; Roy, S. C. J. Org. Chem.
1998, 63, 2829–2834; (b) Roy, S. C.; Rana, K. K.; Guin, C.
J. Org. Chem. 2002, 67, 3242–3248.
References and notes
11. General procedure: A solution of titanocene dichloride
(2mmol) in dry THF (15mL) was stirred with activated
zinc dust10a (7mmol) for 1h under argon. The resulting
green solution was then added dropwise to a stirred
solution of the aldehyde (1mmol) and allyl bromide
(1.1mmol) in dry THF (5mL) at room temperature under
argon over 30min. The reaction mixture was then stirred
for an additional 1.5h and finally decomposed with
saturated aqueous sodium dihydrogen phosphate solution
(5mL). Most of the volatiles were removed under reduced
pressure and the residue obtained was extracted with
diethyl ether (4 · 25mL). The ether layer was washed with
brine (2 · 10mL) and dried (Na2SO4). After removal of
solvent the crude residue obtained was purified by column
chromatography over silica gel eluting with ethyl acetate
and light petroleum to afford the desired product.
1. (a) Kim, E.; Gordon, D. M.; Schmid, W.; Whitesides, G.
M. J. Org. Chem. 1993, 58, 5500–5507; (b) Kadota, I.;
Matsukawa, Y.; Yamamoto, Y. J. Chem. Soc., Chem.
Commun. 1993, 1638; (c) Yamamoto, Y.; Asao, N. Chem.
Rev. 1993, 2207–2293, and references cited therein.
2. (a) Blomberg, C.; Hartog, F. A. Synthesis 1977, 18–36; (b)
Jubert, C.; Knochel, P. J. Org. Chem. 1992, 57, 5425–5431;
(c) Jhou, J.-Y.; Chen, Z.-G.; Wu, S.-H. J. Chem. Soc.,
Chem. Commun. 1994, 2783; (d) Yi, X.-H.; Haberman, J.
X.; Li, C.-J. Synth. Commun. 1998, 28, 2933; (e) Araki, S.;
Jin, S. J.; Idou, Y.; Butsugen, Y. Bull. Chem. Soc. Jpn.
1992, 65, 1736; (f) Li, C.-J.; Meng, Y.; Yi, X.-H.; Ma, J.;
Chan, T.-H. J. Org. Chem. 1997, 62, 8632; (g) Kobayashi,
S.; Aoyama, N.; Manabe, K. Synlett 2002, 483–485.
3. (a) Tan, X.-H.; Shen, B.; Deng, W.; Jhao, H.; Liu, L.;
Guo, Q.-X. Org. Lett. 2003, 5, 1833–1835; (b) Bartoli, G.;