Regioselective carbon-carbon bond formation in titanium mediated reaction of ethylmagnesium bromide with allylic alcohols and allylic ethers

Article abstract of DOI:10.1055/s-2001-9707

In the presence of Ti(Oi-Pr)₄ reaction of EtMgBr with allylic alcohols and allylic ethers affords the products of formal S_N2′ substitution of hydroxy or alkoxy groups with ethyl groups in moderate to good yields and excellent regiose

Full text of DOI:10.1055/s-2001-9707

LETTER
49
Regioselective Carbon-Carbon Bond Formation in Titanium Mediated
Reaction of Ethylmagnesium Bromide with Allylic Alcohols and Allylic Ethers
Oleg G. Kulinkovich,* Oleg L. Epstein, Vladimir E. Isakov, Ekaterina A. Khmel‘nitskaya
Department of Organic Chemistry, Belarussian State University, 4, Skoriny av., Minsk, Belarus
Fax +375-17-226-4998; E-mail: kulinkovich@chem.bsu.unibel.by
Received 6 October 2000
formal SN2’ allylic ethylation.7 As shown in Scheme 1,
Abstract: In the presence of Ti(Oi-Pr)4 reaction of EtMgBr with al-
when 2-undecen-4-ol (1a) or its methyl (1b) and THP (1c)
lylic alcohols and allylic ethers affords the products of formal SN2’
ethers are treated with 3-4 equiv EtMgBr in the presence
substitution of hydroxy or alkoxy groups with ethyl groups in mod-
erate to good yields and excellent regioselectivity. The mechanism
of 1 equiv Ti(Oi-Pr)4 at room temperature in Et2O, alkene
of the reaction includes the formation of titanacyclopropanes as the 2 is obtained in good yields.8 Carbon-carbon bond forma-
key organometallic intermediates. Promoting action of EtMgBr on
the process of C-C bond formation in the transformation of titana-
cyclopropane-olefin complex 5 into the titanacyclopentane ate com-
plex 6 is proposed.
tion occurred exclusively at the g-carbon and no forma-
tion of regioisomeric olefins, the a-attack products, was
detected by GC-MS analysis.
As illustrated in the Table, the reaction of the allylic alco-
Key words: titanium alkoxides, Grignard reagents, allylic com-
hol 1a with EtMgBr in the presence of equimolecular
amounts of Ti(Oi-Pr)4 provided much better yields of sub-
stitution product 2 in comparison with catalytic conditions
(entry1-4). Full consumption of substrate occurred after
addition of 4 equiv of the Grignard reagent. When the
ethers 1b and 1c were used, 3 equiv of EtMgBr were suf-
ficient for their full involvement in the reaction (entries 5-
11). Under similar reaction conditions, the primary allylic
alcohol with disubstituted double bond (entry 12) as well
as primary and tertiary allylic alcohols and 2-tetrahydro-
pyranyl ethers with mono- (entries 13-17) and trisubstitut-
ed (entries 18 and 19) double bonds are also involved in
this transformation. However, in the case of allylic alco-
hols with monosubstituted double bond9 and, especially,
their THP ethers, reaction was accompanied with the for-
mation of appreciable amounts of hydroxyl group reduc-
tive elimination products derived from the corresponding
allyltitanium species.10 It is also noteworthy that in the
case of linalool (entry 16), the product of allylic substitu-
tion in geraniol was obtained in good yield only in the
presence of excess of reagents (entries 18 and 19).
pounds, alkylations, alkenes
Alkene complexes of the Group IV transition metals show
properties of metallacyclopropane reagents in the reac-
tions with electrophiles.1 Until now, the properties of ti-
tanocene and zirconocene derivatives are the most
studied. Some years ago, we found that the reaction of eth-
ylmagnesium bromide with carboxylic esters in the pres-
ence of titanium alkoxides smoothly results in formation
of 1-substituted cyclopropanols.2 It was supposed that the
key organometallic intermediate in this reaction is diiso-
propoxytitanacyclopropane (diisopropoxytitanium-ethyl-
ene complex) which acts like a 1,2-dicarbanionic
equivalent. To the best of our knowledge, it was the first
synthetically useful transformation for the generation of
titanacyclopropane reagents where inexpensive and easy-
to-use titanium alkoxides were used instead of titanocene
derivatives. Later, it was shown that dialkoxytitanacyclo-
propane reagents react with N,N-dialkylcarboxamides to
form the corresponding aminocyclopropanes,3 and are in-
volved in the ligand exchange4 as well as in inter- and in-
tramolecular olefins and acetylenes coupling reactions.5
Dialkoxytitanacyclopropane 1,2-dicarbanionic equiva-
lents have also been successfully used in consecutive re-
actions with two different electrophiles.6
Substitution of hydroxyl group in allylic alcohols occurs
with low cis/trans stereoselectivity (entries 1-4, 13-16).
Predominant formation of trans-alkenes is observed in ti-
tanium-mediated reaction of EtMgBr with allylic ethers
(entries 5-11, 17), especially in the case of 2-tetrahydro-
pyranyl ethers with disubstituted and monosubstituted
double bond (entries 8-11, 17) where up to 95% of trans-
isomer is formed (entry 8-11).
We report herein the titanium alkoxide mediated reaction
of ethylmagnesium bromide with allylic alcohols and al-
lylic ethers, resulting in the formation of the products of
R = H (a), Me (b), 2-tetrahydropyranyl (c)
Scheme 1
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50
O. G. Kulinkovich et al.
LETTER
Table Yields of Substitution Products in the Reaction of Allylic Alcohols and Allylic Ethers with EtMgBr in the
Presence of Ti(Oi-Pr)4.
a) Isolated yield.
b) Near 10% (GC-MS) of reductive elimination products are formed as a mixture of regioisomers.
c) Near 20% (GC-MS) of reductive elimination products are formed as a mixture of regioisomers.
d) Near 20% (GC-MS) of ethane addition product is formed (M/e = 200).
e) Near 50%(GC-MS) of reductive elimination products are formed as a mixture of regioisomers.
A plausible mechanism for this reaction is shown in Our supposition that titanacyclopropane-olefin complex-
Scheme 2. Ethylation of Ti(Oi-Pr)4 with EtMgBr affords es 5 under the reaction conditions do not transform direct-
diethyltitanium derivative 3, which disproportionates to ly into titanacyclopentane derivatives 87 is grounded on
give diisopropoxytitanacyclopropane 4.2 If each of the the fact that all our efforts to fix any organometallic prod-
isopropoxy groups are considered as six-electron ligand, ucts of this reaction were unsuccessful. In fact, sequential
then titanacyclopropane 4 is formally a 16e organometal- cleavage of Ti-C and C-O bonds in the intermediate 8
lic species. Its coordination with substrate 1 gives an 18e would lead to bis-homoallylic organometallic species 9,
olefin complex 5. We propose that EtMgBr addition to the which like analogous zirconocene intermediates could be
complex 5 possibly induces its transformation into titana- fixed by the reactions with electrophiles.7 However, pass-
cyclopentane ate complex 6. Sequential Ti-C and C-O ing an excess of gaseous oxygen through a reaction mix-
bond cleavages of 6 afford dialkylated titanium species 7, ture derived from the reaction of allylic alcohol 1a with
which easily undergoes ethane elimination to provide the 3 equiv EtMgBr and 1 equiv Ti(Oi-Pr)4 as well as addition
alkene 2 and titanacyclopropane 4.
of I2 or benzaldehyde does not lead to a considerable de-
Synlett 2001, No. 1, 49–52 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Regioselective Carbon-Carbon Bond Formation in Titanium Mediated Reaction
51
R = H, Me, THP, MgBr, Ti(OR’)3
R’ = Oi-Pr, OC12H23
Scheme 2
crease of the yield of 2, as compared with the yield ob- generation and one more equivalent for the initiation of ti-
tained by treatment with water. We suppose that the tanacyclopentane ate complex formation step.
substitution product 2 forms before treatment of the reac-
In summary, high regioselective ethylation of allylic alco-
tion mixture with the electrophile (Scheme 2). Easier for-
hols and allylic ethers by the action of EtMgBr in the pres-
mation of titanacyclopentane ate complex
6
in
ence of titanium(IV) isopropoxide have been found.
comparison with the parent titanacyclopentane 8 can be
explained by the fact that the titanacyclopropane-olefin
complex 5 is an 18e species whereas the titanacyclopen-
tane ate complex 8 is a 16e species.
Acknowledgement
This work was carried out with support of the Belarussian Republi-
can Fund for Fundamental Research (Project X98-123).
Within the framework of this mechanism the necessity to
use different relative amounts of EtMgBr and Ti(Oi-Pr)4
for full consumption of the substrate (Table) can also be
explained. Near equimolar amounts of Ti(Oi-Pr)4 in the
case of allylic alcohols are necessary because of the cor-
responding titanium oxides formation which, probably,
could not be involved into a catalytic cycle.3 Full con-
sumption of the substrate in the reaction of alcohol 1a
with 4 equiv of EtMgBr (entry 4) can be explained by
spending of 1 equiv of Grignard reagent for magnesium
alkoxide 1 (R = MgBr) and i-PrOMgBr formation, addi-
tional 2 equivalents for titanacyclopropane intermediate 4
References and Notes
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Kulinkovich, O. G.; Sviridov, S. V.; Vasilevskii, D. A.
Synthesis 1991, 234.
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52
O. G. Kulinkovich et al.
LETTER
(3) Chaplinski, V.; de Meijere, A. Angew. Chem. Int. Ed. Engl.
1996, 35, 413. Chaplinski, V.; Winsel, H.; Kordes M.; de
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(7) Zr-catalysed addition of EtMgBr to the nonactivated double
carbon-carbon bond (ethylmagnesation reaction) was
discovered by Dzhemilev et al. See: Dzhemilev, U. M.;
Vostrikova, O. S.; Sultanov, R. M. Izv. Akad. Nauk SSSR, Ser.
Khim. 1983, 32, 218. Dzhemilev, U. M.; Vostrikova, O. S.;
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Organomet. Chem. 1986, 304, 17. When allylic alcohols were
used in this reaction, C-C bond formation proceeded at the b-
carbon of the allylic compound. With allylic ethers C-C bond
was formed both in b-position and in g-position with
elimination of the alkoxy group. See: Hoveyda, A. H.; Xu, Z.
J. Am Chem. Soc. 1991, 113, 5079. Houri, A. F.; Didiuk, M.
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(8) Typical procedure for (E)-3-methyl-4-tridecene (2). To a
solution of allylic ether 1c (1.38 g, 5 mmol) and Ti(Oi-Pr)4
(1.5 mL, 5 mmol) in Et2O (15 mL), EtMgBr (15 mL of 1 M
solution in Et2O) was added dropwise in 1 h at room
temperature, and the mixture was stirred for an additional
30 min. After acidic work up (20 mL of 10% aq. H2SO4) and
extraction with ether, organic layers were washed with
saturated NaHCO3 and brine, dried over MgSO4 and
evaporated. (E)-3-Methyl-4-tridecene ((E)-2) (containing less
than 5% of Z-isomer by GC-MS-analysis) (0.69 g, 71%) was
isolated by column chromatography on silica gel (eluent -
cyclohexane). NMR 1H (200 MHz, CDCl3): 0.86 (t, J = 7.2
Hz, 3H), 0.90(t, J = 7.2 Hz, 3H), 0.96(d, J = 6.9 Hz, 3H), 1.18-
1.41 (m, 14H), 1.88-2.06 (m, 3H), 5.14-5.23 (m, 2H). NMR
13C (50 MHz, CDCl3): 11.63, 14.16, 20.56, 22.81, 29.29,
29.46, 29.64, 29.87, 30.01, 32.74, 33.51, 38.56, 128.79,
136.19. MS (70eV), m/z 196(M+), 167, 154, 139, 125, 111, 97,
83, 70, 55(100%), 41, 29. IR (CCl4), n, cm-1: 2973, 2853,
1453, 1373, 1200, 1026, 973.
(9) In the case of 1-undecen-3-ol (entries 13 and 14) in the
reaction mixture by GC-MS analysis the alcohol with
M/z = 200 (product of ethane addition to the allylic alcohol)
was fixed. Its formation can be explained by the b-attack of
titanacyclopropane reagent on the double bond of substrate
following by protolytic cleavage of titanacyclopentane
intermediate. See ref. 7.
(10) The formation of allyltitanium compounds from allylic esters
and allyl halides by the action 2 i-PrMgCl/Ti(Oi-Pr)4 have
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Sato, F. Angew. Chem. Int. Ed. Engl. 1996, 35, 2848. Matsuda,
S.; An, D. K.; Okamoto, S.; Sato, F. Tetrahedron Lett. 1998,
39, 7513.
Article Identifier:
1437-2096,E;2001,0,01,0049,0052,ftx,en;G21500ST.pdf
Synlett 2001, No. 1, 49–52 ISSN 0936-5214 © Thieme Stuttgart · New York