Angewandte
Chemie
Table 4: Chemoselectivity of titanium(IV) reactions with substrates
containing two sulfonate leaving groups.
new titanium(IV) reactions has been the use of new chelating
leaving groups (NALGs). The extension of this reagent class
to new reactions including stereoretentive carbon-carbon
bond formation is currently underway.
Entry
1
Substrate
T [8C]
Product Yield (Reaction Time)[a]
RT
81% (1.5 h)[b]
88% (1 h)
20% (15 h)[b]
75% (2 h)
Experimental Section
General Procedure for bromination reactions: A cold (À788C)
solution of quisylate ester (1.0 equiv) in dichloromethane (1.5m)
was added to a cold (À788C) solution of TiBr4 (2.0 equiv) in
dichloromethane (0.15m). Following completion (usually within
15 min,monitored by thin-layer chromatography),the reaction
mixture was quenched with water and extracted three times with
dichloromethane. The collected organic extracts were concentrated
and the resulting oil was purified by silica gel chromatography
(usually using pure hexanes as eluent). For spectroscopic data,see
Supporting Information.
2
3
4
5
À78
RT
76% (1 h)
45% (2 h)
61% (2 h)
74% (1 h)
54% (2 h)
85% (2.5 h)
RT
À78
General Procedure for azidation reactions: Azidotrimethylsilane
(25 equiv) was added to a solution of TiF4 (6.0 equiv) in 1,2-
dichloroethane (0.2m) at room temperature. After stirring for
30 min,the reaction slurry was cooled to 0 8C and quisylate ester
(1.0 equiv) was added as a dichloroethane solution (1.5m). The
reaction was maintained at 08C until completion (< 8 h). Following
completion,the reaction mixture was quenched with water and
extracted three times with dichloromethane. The collected organic
extracts were concentrated and the resulting residue was purified by
silica gel chromatography (usually using pure hexanes as eluent). For
spectroscopic data,see Supporting Information.
General Procedure for azidation reactions with mixed Lewis acid:
Trimethylsilyl triflate (9.0 equiv) was added to a room temperature
solution of TiF4 (6.0 equiv) in dichloromethane (0.5m). The resulting
slurry was stirred for 15 min followed by the addition of azidotrime-
thylsilane (18.0 equiv) which was allowed to stir for an additional
15 min. The reaction slurry was then cooled (08C) and quisylate ester
(1.0 equiv) was added as a dichloromethane solution (0.2m). The
reaction was maintained at 08C until completion (< 2 h). Following
completion the reaction mixture was quenched with water and
extracted three times with dichloromethane. The collected organic
extracts were concentrated and the resulting oil was purified by silica
gel chromatography (using pure hexane as eluent). For spectroscopic
data,see Supporting Information.
[a] Yields of isolated product. All starting materials and products are
racemic [b] Note that halogen position shifted relative to substrate.
Titanium(IV) reactions with 1,2-butanediol bistosylate gave
the 3-halogenated products,presumably as a result of a
hydride shift (Table 4,entry 1),whereas the 12,-bisquisylate
substrate led to 2-halogenated products in good yields
(Table 4,entry 2). No rearrangement occurred in the reaction
of the 1,3-bistosylate with titanium(IV) chloride and bromide,
leading to the corresponding 3-halogenated products
(Table 4,entry 3). Reasonable yields were also obtained
with diol systems containing an unprotected tertiary alcohol
with quisylates affording significantly better yields than
tosylates (Table 4,entries 4 and 5).
In terms of formulating a mechanistic rationale for these
titanium(IV)reactions,two reactivity trends described in this
communication are revealing. Firstly,the poor reactivity of
primary alcohol (Table 3,entry 8), a-hydroxy ester (Table 3,
entry 9),and primary sulfonate moieties (Table 4) can be
rationalized in terms of partial positive charge formation at
the carbinol carbon in the transition state,the argument being
that carbons of primary alcohols and a-hydroxy esters are less
able to stabilize positive charge build-up,relative to secon-
dary carbinol carbon centers. Secondly,we hypothesize that
the aromatic nitrogen of the quisylate group stabilizes a
concerted SNi-type (or non-solvent-separated SN1) mecha-
nism with titanium(IV) reagents. By comparison,tosylate
substrate 2 (devoid of an aromatic nitrogen) underwent
Received: May 27,2008
Published online: August 19,2008
Keywords: azides · halogenation · leaving groups ·
.
nucleophilic substitution · titanium
[1] Some recent examples include: a) L. X. Liu,P. Q. Huang,
P. L. Bernad,J. R. Suarez,S. Garcia-Granda,M. R. Diaz, J. Org.
[2] Some recent examples include: a) G. C. Lloyd-Jones,S. W.
Krska,D. L. Hughes,L. Gouriou,V. D. Bonnet,K. Jack,Y.
significant ionization,leading to elimination product
8
(Table 2,entries 1–3). The quisylate nitrogen also appears to
increase the rate of substitution in most cases (for example,
compare entries 3 and 4 of Table 1). A possible transition
state,involving a quisylate nitrogen coordinated to titaniu-
m(IV),involves a stable six-membered-ring geometry (see
Figure).
[3] Some examples include: a) I. Lee,H. Y. Kim,H. K. Kang,H. W.
Cayzergues,C. Georgoulis,G. J. Ville, J. Chem. Res. Synop. 1978,
9,325.
In conclusion,a series of titaniu-
m(IV) reagents have been shown to
give alkyl bromides,iodides,and azides
from sulfonates in reasonable yields
and with complete retention of config-
uration. Critical to the design of these
[5] N. T. Ahn,C. Minot, J. Am. Chem. Soc. 1980, 102,103.
Angew. Chem. Int. Ed. 2008, 47, 7511 –7514
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