DOI: 10.1002/anie.201104331
Alkylation
Stereoselective Alkylation of Allylic Alcohols: Tandem Ethylation and
Functionalization**
Pragna Pratic Das, Ivan L. Lysenko, and Jin Kun Cha*
Transition metal catalyzed allylic substitution is used fre-
quently in organic synthesis. A high level of regio- and
Table 1: Titanium-mediated ethylation of acyclic allylic alcohols and
in situ functionalization using three different scavengers.
stereocontrol of asymmetric allylic alkylation is made possi-
ble by a judicious choice of substrates, late-transition-metal
catalysts, and chiral ligands.[1,2] Outside the domain of late
transition metal catalyzed reactions the use of group IVA
metals can also be effective for allylic substitution of readily
available allylic alcohols.[3] For example, treatment of acyclic
and cyclic allylic alcohols with the ethyl Grignard reagent in
the presence of titanium isopropoxide provides stereoselec-
tive SN2’-type ethylation products [Eq. (1); El = H].[4–6] The
Yield [%][a]
TiCl4
5 (R2)
TMSCl[b]
ClTi(OiPr)3[d]
[c]
Entry
1
2
3
4
5
6
7
5a (iPr)
5b (Ph)
5c (PhCH CH)
5d (CH2 CH)
5e (CH2 CMe)
52
56
52
56
48
52
45
58
60
70
73
n.d.
n.d.
69
=
n.d.
n.d.
n.d.
n.d.
n.d.
=
=
synthetic utility of the low-valent titanium (Kulinkovich
reagent)[4] mediated alkylation would be greatly enhanced
by an in situ introduction of a functionalized side chain (El ¼
H). We report herein a stereoselective alkylation reaction of
allylic alcohols by trapping of the presumed alkyltitanium
intermediates with suitable electrophiles.
=
5 f (MeCH CH)
5g (H)
73
48
[a] Yields of the isolated products are given for each of the three
scavengers used. [b] Used 3 equiv. [c] Used 0.75 equiv. [d] Used 3 equiv.
n.d.=not determined.
This formal SN2’ ethylation reaction by the ethyl Grignard
reagent was first reported by the Kulinkovich group,[5] and the
stereochemical studies revealed the overall suprafacial
stereochemical outcome is due to syn addition of the Kulin-
and ClTi(OiPr)3] examined, ClTi(OiPr)3 afforded the most
satisfactory yields of the products. The reaction conditions
were found to be general for aliphatic, unsaturated, and
aromatic aldehydes. Halogenation and oxidation of the alkyl–
titanium bond of 4 were also effected by electrophilic
halogenation reagents (I2 and CF3SO2Cl) and O2, respectively,
to provide 6, 7, and 8 (Scheme 1).
As expected, cyclic substrates are also well suited for
allylic ethylation and in situ functionalization (Table 2 and
Scheme 2).
ꢀ
kovich reagent through a Ti O tether and subsequent
syn b elimination.[5d,e,6] Our mechanistic analysis implicated
the generation of an alkyltitanium intermediate 4 by way of
b elimination of 3 at the penultimate stage, which prompted
us to investigate in situ elaboration of 4 to broaden the scope
of this allylation reaction (Table 1).[7] In light of the known
instability of alkyl homologues of MeTi(OiPr)3,[8] the temper-
ature control of the reaction was first examined, and it was
optimal to warm the reaction mixture from ꢀ788C up to ꢀ10
or ꢀ58C, to set the stage of the trapping step. The presence of
a scavenger for magnesium alkoxides in the reaction mixture
was necessary prior to addition of an aldehyde to prevent an
aldol condensation. Among three scavengers [TMSCl, TiCl4,
[*] Dr. P. P. Das, Dr. I. L. Lysenko, Prof. Dr. J. K. Cha
Department of Chemistry, Wayne State University
Detroit, MI 48236 (USA)
E-mail: jcha@chem.wayne.edu
[**] We thank the NSF (CHE-0615604) for generous financial support.
Scheme 1. Halogenation and oxidation of the alkyl–titanium bond of 4.
[a] Yields of the isolated products when using 3 equiv ClTi(OiPr)3.
[b] Yields of the isolated products in absence of ClTi(OiPr)3.
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2011, 50, 9459 –9461
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
9459