High-yielding and rapid carbon-carbon bond formation from alcohols: Allylation by means of TiCl4

Article abstract of DOI:10.1055/s-0033-1338746

TiCl₄ efficiently promotes high yield (80-99%) replacement of OH in tertiary, benzylic, and allylic alcohols, and even nonactivated secondary alcohols, by an allyl group. The reaction usually proceeds within minutes at room temperature. Georg Thieme Verlag Stuttgart. New York.

Full text of DOI:10.1055/s-0033-1338746

LETTER
▌1275
letter
High-Yielding and Rapid Carbon–Carbon Bond Formation from Alcohols:
Allylation by Means of TiCl4
Carbon–Carbon Bond Formation from Alcohols
Alfred Hassner,* Chennakesava Reddy Bandi
Department of Chemistry, Bar-Ilan University, Ramat-Gan 52900, Israel
Fax +972(3)7384053; E-mail: hassna@biu.ac.il
Received: 17.01.2013; Accepted after revision: 18.04.2013
BuLi to convert the alcohol into the corresponding lithium
Abstract: TiCl4 efficiently promotes high yield (80–99%) replace-
alcoholate.2c,5a
ment of OH in tertiary, benzylic, and allylic alcohols, and even non-
activated secondary alcohols, by an allyl group. The reaction
usually proceeds within minutes at room temperature.
While TiCl4 has been used effectively in the Sakurai–
Hosomi allylation of aldehydes and ketones,1 to the best
Key words: alcohols, C–C bonds, allylation, allyltrimethylsilane, of our knowledge there has been only one report of the re-
Lewis acid, TiCl4
placement of OH by an allyl group in the presence of
TiCl4.13 We therefore examined the application of TiCl4 to
the displacement of an alcohol OH group by an allyl group
using allyltrimethylsilane 2 (see 4 to 5, Scheme 2).
Carbon–carbon bond-forming reactions are important
tools for the synthesis of organic compounds. Ketones and
alcohols are particularly useful substrates for the introduc-
tion of allyl functional groups. In addition to the reaction
of aldehydes or ketones with Grignard and other organo-
metallic reagents, the Lewis acid1 catalyzed allylation of
such compounds involving nucleophilic transfer of an al-
lyl group from an allyl silane (Sakurai–Hosomi allylation,
Scheme 1)1 has been of major importance.
R1
R3
OH
R2
TiCl4
SiMe3
+
R1
R3
R2
2
4
5
R1 = R2, R3 = alkyl, aryl, H
Scheme 2
First we examined the reaction of 1-methylcyclohexanol
(4a), a tertiary alcohol as a substrate in the reaction with
allyltrimethylsilane 2, and compared TiCl4 with several
other Lewis acids and with TsOH. We found TiCl4 to be
superior not only in terms of the yield of allylated product
5 but also in that it requires shorter reaction times and pro-
ceeds at room temperature (Table 1 and Scheme 3). Allyl-
trichlorosilane was much less effective.
OH
O
R1
Lewis acid
SiMe3
+
R1
R2
R2
1
2
3
Scheme 1
Recently, the Sakurai–Hosomi allylation has inspired the
development of C-allylation of alcohols (replacement of
OH by an allyl group), especially of benzylic or tertiary
alcohols using allyltrimethylsilane 2.2–12
OH
Lewis acid
SiMe3
+
CH2Cl2
r.t.
Generation of allylated carbon from alcohols by means of
allylsilanes has been reported in the presence of a variety
Lewis acids based on B,2 In,3 Bi,4 Fe,5 Al,6 Ca,7 Zr,8 Re,9
Rh,10 as well as montmorillonites11 and phosphomolybdic
acid (PMA),12 used either in catalytic or stoichiometric
amounts. The yields are variable, and the reactions some-
times required hours and/or heating. Thus, using InCl3 and
allylsilanes, Baba et al.3a have successfully converted ben-
zylic alcohols into allyl derivatives in 50–90% yield with
reaction times of ten minutes to 7.5 hours. They further
showed that by first converting the alcohols into silyl
ethers3e and using InCl3/I2 or InCl3/TMSBr,3d,e the OTMS
group was more readily displaced than the OH group by
an allyl moiety. Allyl-group introduction using allyltri-
methylsilane and FeCl3 was also carried out by first using
2
4a
5a
Scheme 3
We then examined several other alcohols and report (Ta-
ble 2) that TiCl4 is very effective in converting activated
alcohols (tertiary or benzylic) 4 in high yield (80–99%)
into allyl derivatives 5 in 1–5 minutes at room tempera-
ture. Benzhydryl alcohols and triphenylmethanol, which
can form a highly stabilized carbocation, reacted even
faster (1–2 min) and provided products 5 in excellent
yields while requiring only 0.1 equivalents of TiCl4. Ter-
tiary alcohols and secondary benzylic alcohols gave al-
lylated products in over 90% yield within minutes. Allylic
alcohol 4h and even the primary benzyl alcohol 4b react-
ed within 10–15 minutes and gave 5 in over 80% yield.
SYNLETT 2013, 24, 1275–1279
Advanced online publication: 15.05.2013
DOI: 10.1055/s-0033-1338746; Art ID: ST-2013-B0058-L
© Georg Thieme Verlag Stuttgart · New York
Allylation of nonactivated sec-alcohols, except for nor-
borneol,3a,d (which can form a nonclassical carbocation),
has not been reported. Using TiCl4, we were able to con-
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6

1276
A. Hassner, C. R. Bandi
LETTER
Highlighting the effectiveness of TiCl4 over other Lewis
acids, we found: 1) formation of 5f from 4f using BF3 pro-
ceeded only in 36% yield2a (vs. 98% within 1 min using
TiCl4, Table 2); 2) benzyl alcohol 4b was not allylated at
all to 5b by a Brønsted acid14 nor by means of BCl32c (vs.
83% with TiCl4 in 10 min, Table 2); 3) 4a, after conver-
sion into its TMS ether, gave 5a in 70% yield after three
hours using InCl33e (vs. 92% directly from 4a with TiCl4
within 5 min, Table 2); and 4) 5f was obtained in 69%
yield after five hours reaction with phosphomolybdic
acid7 or in 84% yield after three hours using BiCl34a (vs.
98% within 1 min using TiCl4).
Table 1 TiCl4 Compared to Other Lewis Acids in the Conversion of
4a (1 mmol) into 5a Using Allyltrimethylsilane 2a
Entry Lewis acid 6 6 (mmol)
Time (min) Yield of 5a (%)b
1
2
3
4
5
6
BF3·OEt2
AlCl3
1
1
1
1
1
30
30
30
30
30
30
38
60
10
75
InCl3
BiBr3
FeCl3
Ti(Oi-Pr)4
1
3
30
30
trace
10
Aldehydes and ketones can be readily alkylated by Gri-
gnard or related reagents to alcohols. Allylation of the lat-
ter provides for an overall transformation of a C=O to a
quaternary carbon containing an olefinic group.
c
7
8
9
TiCl4
0.8
1
5
2
92
92
c
SbCl5
1
1
5
30
70
80
NMR of the crude products of the reaction of 4g–j (Table
2, entries 7–10) indicated only traces of any side products,
the major products 5g–j having formed without rearrange-
ment or elimination of water. In order to ascertain if the al-
lylation, mediated by the strong Lewis acid TiCl4,15
proceeds via carbocations, we examined the reaction of
phenylethenyl alcohol (4k) where a rearrangement is pos-
sible. Indeed a 3:1 mixture of 5k and rearranged 5k′ was
obtained. This observation, together with the fact that the
reaction of allylic alcohols 4m,n with 2 and TiCl4 led to a
nonseparable mixture of isomeric products, indicate the
involvement of carbocations16 in these reactions with the
more stable product usually being favored. A likely path-
way is shown in Scheme 4.
PTSA
1
30
trace
a Conditions: 1.2 mmol of allyltrimethylsilane 2.
b Further reaction time did not improve the yield significantly.
c Conditions: 1 M in CH2Cl2.
vert nonactivated secondary alcohols 2-adamantanol (4i)
and cyclohexanol (4j) into allylated products 5i and 5j, re-
spectively, in good yield on warming. Menthol (4l) react-
ed readily at room temperature but gave an inseparable
mixture of allylated product and menthol ether.
Table 2 TiCl4-Mediated Allylation of Alcohols 4 to 5 Using Allyltrimethylsilane 2 at Room Temperature17
Entry
Alcohol 4
Product 5
TiCl4 (equiv)
0.8
Time (min)
5
Yield (%)
92
OH
1
4a
4b
5a
5b
OH
2
3
1.05
0.1
10
1
83
96
OH
4c
5c
OH
4
0.1
1
95
Cl
Cl
Cl
Cl
4d
5d
Synlett 2013, 24, 1275–1279
© Georg Thieme Verlag Stuttgart · New York

LETTER
Carbon–Carbon Bond Formation from Alcohols
1277
Table 2 TiCl4-Mediated Allylation of Alcohols 4 to 5 Using Allyltrimethylsilane 2 at Room Temperature17 (continued)
Entry
Alcohol 4
Product 5
TiCl4 (equiv)
Time (min)
Yield (%)
OH
5
0.1
1
98
MeO
OMe
MeO
OMe
4e
5e
OH
6
7
0.1
1
98
82
4f
5f
OH
1.05
10
4g
5g
OH
8
9
1.1
1.1
1.1
10
15
15
83
4h
4i
5h
5i
OH
80a
OH
10
70a
4j
5j
OH
5k
11
0.5
4
90b
4k
5k′
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 1275–1279

1278
A. Hassner, C. R. Bandi
LETTER
Table 2 TiCl4-Mediated Allylation of Alcohols 4 to 5 Using Allyltrimethylsilane 2 at Room Temperature17 (continued)
Entry
12
Alcohol 4
Product 5
TiCl4 (equiv)
Time (min)
Yield (%)
1.05
12
85c
HO
5l:4l-ether
63:37
4l
HO
mixture of isomers
65:35
13
14
1.0
1.0
5
8
80c
80c
4m
OH
mixture of isomers
75:25
4n
a Required warming to 50 °C for best yield.
b A 3:1 separable mixture.
c Inseparable mixture.
(4) Using bismuth derivatives: (a) Surya, K. D.; Richard, A. G.
Tetrahedron Lett. 2005, 46, 8345. (b) Kumar, G. G. K. S. N.;
Laali, K. K. Org. Biomol. Chem. 2012, 10, 7347.
(5) Using iron derivatives: (a) Kabalka, G. W.; Yao, M. L.;
Borella, S.; Goins, L. K. Organometallics 2007, 26, 4112.
(b) Han, J.; Cui, Z.; Wang, J.; Liu, Z. Synth. Commun. 2010,
40, 2042.
(6) Using montmorillonite derivatives: (a) Motokura, K.;
Nakagiri, N.; Mizugaki, T.; Ebitani, K.; Kaneda, K. J. Org.
Chem. 2007, 72, 6006. (b) Wang, J.; Masui, Y.; Onaka, M.
Tetrahedron Lett. 2010, 51, 3300.
(7) Kadam, S. T.; Lee, H.; Kim, S. S. Appl. Organomet. Chem.
2010, 24, 67.
(8) Mahoney, S. J.; Lou, T.; Bondarenko, G.; Fillon, E. Org.
Lett. 2012, 14, 3474.
(9) Meyer, V. J.; Niggemann, M. Eur. J. Org. Chem. 2011,
3671.
SiMe3
TiCl3 Cl–
OH
Cl–
R1
1HO+
TiCl4
2
2
R
Ti(OH)Cl3
+
+
TMSCl
+
R
5
R1
H
R2
R2
H
4
H
V
VI
Scheme 4
In conclusion, we showed that TiCl4 is an efficient Lewis
acid promoting high yield and rapid formation of allyl
products 5 by reaction of 2 with benzylic, allylic, or tertia-
ry alcohols 4, including for the first time nonactivated sec-
ondary alcohols, though formation of rearranged products
were sometimes observed.
(10) Sharma, G. V. M.; Reddy, K. L.; Lakshmi, P. S.; Ravi, R.;
Kunwar, A. C. J. Org. Chem. 2006, 71, 3967.
(11) Kuninobu, Y.; Ishii, E.; Takai, K. Angew. Chem. Int. Ed.
2007, 46, 3296.
(12) Onodera, G.; Yamamoto, E.; Tonegawa, S.; Iezumi, M.;
Takeuchi, R. Adv. Synth. Catal. 2011, 353, 2013.
(13) Claremon, D. A.; Zhuang, L.; Ye, Y.; Singh, S. B.; Tice, C.
M.; Xu, Z.; Simpson, R. D. WO 2009/088997, 2009; report
the allylation of a tert-benzylic alcohol in low yield by
means of 2 in refluxing CH2Cl2.
Acknowledgment
Support of this research by the Marcus Center for Medicinal and
Pharmaceutical Chemistry at Bar-Ilan University is gratefully
acknowledged.
References and Notes
(1) (a) Sakurai, H.; Hosomi, A. J. Org. Chem. 1969, 34, 1764.
(b) Sakurai, H. Pure Appl. Chem. 1083, 54, 1. (c) Fleming,
I.; Dunogues, J.; Smithers, R. Org. React. 1989, 37, 57.
(2) Using boron derivatives: (a) Cella, J. A. J. Org. Chem. 1982,
47, 2125. (b) Rubin, M.; Gevorgyan, V. Org. Lett. 2001, 3,
2705. (c) Kabalka, G. W.; Yao, M. L.; Borella, S. J. Am.
Chem. Soc. 2006, 128, 11320.
(3) Using indium derivatives: (a) Yasuda, M.; Saito, T.; Ueba,
M.; Baba, A. Angew. Chem. Int. Ed. 2004, 43, 1414.
(b) Kim, S.; Shin, C.; Pae, A.; Koh, H.; Chang, M.; Chung,
B.; Cho, Y. Synthesis 2004, 1581. (c) Saito, T.; Yasuda, M.;
Baba, A. Synlett 2005, 1737. (d) Saito, T.; Nishimoto, Y.;
Yasuda, M.; Baba, A. J. Org. Chem. 2006, 71, 8516.
(e) Saito, T.; Nishimoto, Y.; Yasuda, M.; Baba, A. J. Org.
Chem. 2007, 72, 8588.
(14) Kaur, G.; Kaushik, M.; Trehan, S. Tetrahedron Lett. 1997,
38, 2521.
(15) That the reactive species is Ti(OH)n rather than TiCl4 is less
likely since a whole equivalent of TiCl4 was required in most
of the examples and Ti(Oi-Pr)4 was not effective.
(16) The facile allylation of benzhydryl alcohols 4c–e and of
triphenylmethanol (4f) is indicative of formation of cationic
species. Furthermore, allylations of allyl alcohols, e.g., 4k,
with 2 catalyzed by Brønsted acids are reported to lead to
rearrangements.14 Rearrangements were also observed in
allylations of allyl silyl ethers using ZnCl2, see: Yokozawa,
T.; Furuhashi, K.; Natsume, H. Tetrahedron Lett. 1995, 36,
5243.
Synlett 2013, 24, 1275–1279
© Georg Thieme Verlag Stuttgart · New York

LETTER
Carbon–Carbon Bond Formation from Alcohols
reaction was indicated by TLC, excess of solvent was
1279
(17) Typical Experimental Procedure
To a stirred solution of alcohol 4 (1 mmol) in CH2Cl2 (2 mL)
at r.t. was added TiCl4 (0.8 mmol, 1 M in CH2Cl2) and
allyltrimethylsilane 2 (1.2 mmol). The mixture was stirred
for the indicated time (see Table 2). After completion of the
evaporated, and the product was flash chromatographed
using EtOAc–hexane as eluents (1:99) to afford pure
allylated product 5. NMR spectra were identical to those
reported.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 1275–1279