Titanium-mediated oxidative arylation of homoallylic alcohols

Article abstract of DOI:10.1002/anie.201007244

E-Substituted styrene derivatives are synthesized from terminal olefins and aryl Grignard reagents through Ti^IV-mediated oxidative coupling (see scheme). Substrates include homoallylic alcohols containing a range of functional groups and substituted aryl Grignard reagents. The reaction may proceed through aryltitanation followed by β-hydride elimination; reductive elimination of arene occurs from a Ti^IVH(aryl) intermediate.

Full text of DOI:10.1002/anie.201007244

DOI: 10.1002/anie.201007244
Oxidative Arylation
Titanium-Mediated Oxidative Arylation of Homoallylic Alcohols**
Kathleen S. Lee and Joseph M. Ready*
The addition of aryl groups to unactivated olefins represents a
and ClTi(OiPr)3 could be used interchangeably with compa-
rable results, but the order of addition of reaction components
proved essential for reproducibility. Optimally, the Mg-
alkoxide was formed by treating 1a in CH2Cl2 with PhMgBr
(1 equiv, solution in Et2O) prior to the addition of TiIV.
Subsequent addition of stoichiometric ArMgBr initiated
arylation. Use of THF as the reaction medium or Grignard
solvent greatly decreased conversion.[10] The product ratio is
also heavily dependent on the titanium and Grignard
stoichiometry: a 1:1:1 ratio of 1a:Ti:ArMgBr yielded a ca.
1:1 ratio of 2a and 3a (Table 1, entry 1) while a 1:2:2 ratio
improved selectivity to 18:1 (entry 2). Ultimately, the opti-
mized conditions employed 2 equiv Ti(OiPr)4 and 3 equiv
PhMgBr and provided 2a in 91% yield (entry 3; 2a:3a >
99:1).[11]
Several homoallylic alcohols were subjected to the
oxidative arylation. Silyl ethers, acids, amides, amines, and
heterocycles were stable to the standard conditions. Sub-
strates with an additional acidic proton required an extra
equivalent of base prior to addition of titanium and the
remaining Grignard reagent (Table 1, entries 6, 8, 10–11). A
tert-butyl ester was partially hydrolyzed under the reaction
conditions, but arylation efficiency was still high (entry 9).
Notably, only alkenes with a proximal alcohol reacted,[12]
diene 2b was isolated in good yield, and no arylation of the
remote olefin was observed (entry 4).
The oxidative arylation proved sensitive to the steric
environment of both the olefin and the alcohol. A substrate
containing a geminal dimethyl group (1k) yielded a 1.7:1
mixture of 2k:3k (Table 1, entry 13). Tertiary alcohol 1l
reacted with similarly poor selectivity at room temperature,
but the product ratio could be favorably increased to a 4.8:1
mixture of 2l:3l at 408C (entry 14). Moderately hindered
substrates syn- and anti-1m both reacted with high selectivity
(entries 15 and 16). In contrast, 1,1-disubstituted alkenes were
unreactive under these reaction conditions. However, the
method was successfully expanded to accommodate sub-
strates containing disubstituted olefins. For example, trans-
1,2-disubstituted alkene 1n was successfully arylated in good
yield at a slightly elevated temperature (entry 17). A single
regio- and stereoisomeric trisubstituted olefin was isolated in
good yield. In contrast, cis-1n failed to react at room
temperature; higher temperatures resulted in a complex
mixture of products. In all cases, only (E)-olefins were
observed. Finally, allylic alcohols provided intractable mix-
tures of regioisomeric and stereoisomeric substitution and
addition products when submitted to the reaction conditions.
The generality of the oxidative arylation was further
demonstrated by the incorporation of substituted aryl
Grignards, which were freshly prepared in Et2O prior to
use. Methyl-substitution had little electronic effect on the
overall yield, but the increased steric hindrance of an o-
À
direct approach to C C bond construction. Pd-catalyzed
coupling of aryl halides with alkenes, the Heck reaction,
offers a viable approach to arylation.[1] However, terminal
unactivated olefins often display low reactivity in Heck
reactions and can yield mixtures of styrenes and allyl arenes
owing to poor regiocontrol in the b-hydride elimination.[2]
High selectivity for styrene products has been observed with
oxidative couplings between aryl boronic acids and terminal
olefins.[3] In this context, we wondered if inexpensive Group 4
transition metals could promote oxidative couplings between
olefins and aryl organometallic reagents. Indeed zirconocene
and titanocene catalysts as well as stoichiometric titani-
um(IV) reagents are capable of effecting the carbometalation
of terminal alkenes with a variety of nucleophilic partners,
including alkylaluminum species[4] and alkyl Grignard
reagents.[5] However these methodologies are limited to the
addition of simple alkyl groups and cyclization reactions.[6]
More recently, titanacyclopropanes and titanacyclopro-
penes[7] have been shown to effect alkylation and vinylation
of alkenols and alkynols.[8] These methods involved the
generation of low-valent titanium complexes through b-
hydride elimination/reductive elimination pathways. There-
fore, we were uncertain if substrates lacking this ability, for
example, aryl groups, would participate in addition reactions.
Here we report an oxidative coupling of homoallylic alcohols
and aryl Grignards [Eq. (1)]. This work demonstrates the
ability of aryl titanium complexes to add to unactivated
olefins and therefore reveals a new reaction manifold for
Group 4 transition metals.
Initial experiments revealed that Ti(OiPr)4 and ClTi-
(OiPr)3 promote the addition of PhMgBr to homoallylic
alcohol 1a to provide mixtures of products arising from
oxidative arylation (2) and carbometalation (3).[9] Ti(OiPr)4
[*] K. S. Lee, Prof. J. M. Ready
Department of Biochemistry
The University of Texas Southwestern Medical Center
5323 Harry Hines Boulevard, Dallas, TX 75390-9038 (USA)
Fax: (+1)214-648-0320
E-mail: joseph.ready@utsouthwestern.edu
Homepage: http://www4.utsouthwestern.edu/readylab
[**] Financial support was provided by the NSF (CAREER), the Welch
Foundation (I-1612), and Amgen. J.M.R. is a fellow of the A. P. Sloan
Foundation.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201007244.
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Communications
Table 1: Oxidative arylation of homoallylic alcohols.[a]
Table 2: Scope of substituted aryl Grignard reagents.[a]
Entry Substrate
Major product
2:3
Yield
[%][b]
Entry
Ar
Yield
[%][b]
Entry
Ar
Yield
[%]
1a
1
2
3
4
89
6
7
8
9
73[f]
1a:Ti:Mg
1:1:1
1:2:2
1
2
3
1:1
18:1
>99:1
(32)
(82)
91
89[c]
69
60 (74)
66 (75)
50 (78)
1:2:3
4
1b
1c
>99:1
74
5
>99:1
69
83[d,e]
6
7
1d
1e
>99:1
>99:1
80[c]
83
5
75[d]
10
55 (74)
[a] 1 Equiv PhMgBr as base, 2 equiv Ti(OiPr)4, 3 equiv ArMgBr, 0.17m in
CH2Cl2, RT overnight. [b] Yields of isolated product. Yields based on
recovered starting material in parenthesis. [c] Isolated as a 1:2 mixture of
2p:3p. [d] Reaction time was 3 h. [e] Isolated as a 1:1 mixture of 2r:3r.
[f] Isolated as a 5.3:1 mixture of 2t:3t.
8
9
1 f
1g
1h
4:1
>99:1
>99:1
74[c]
2g: 38
2 f: 36
electron-poor Grignards due to incomplete conversion
(entries 7–10). Neither longer reaction times nor excess
reagents were able to bring the reaction to completion. Of
the electron-poor Grignards, p-fluorophenylmagnesium bro-
mide alone resulted in a mixture of oxidative arylation and
carbometalation products under the standard conditions
(entry 6).
Two sets of experiments revealed aspects of the mecha-
nism of oxidative arylation. First, as foreshadowed by the
reactivity of 1n (Table 1, entry 17), the transformation is
stereospecific. Thus, [D1]-trans-1a reacted with (2-naph-
thyl)MgBr to give [D1]-2q which completely retained the
deuterium label; in contrast, deuterium was completely
eliminated from [D1]-cis-1a to provide unlabeled 2q and
[D1]naphthalene, revealing the final destination of the
eliminated hydrogen (Scheme 1).[13] Secondly, time course
experiments indicated that the oxidative arylation (2) and
carbometalation products (3) likely arise from a common
intermediate. For example, under conditions that provide
10
78[c]
11
12
13
1i
1j
>99:1
>99:1
1.7:1
94[c]
91
1k
85
14
15
1l
4.8:1
75[d]
syn-1m
17:1[e] 68[d]
16
17
anti-1m
>99:1
>99:1
81
1n
75[d]
[a] 1 Equiv PhMgBr as base, 2 equiv Ti(OiPr)4, 3 equiv PhMgBr, 0.17m in
CH2Cl2, RT overnight. [b] Combined yields of 2 and 3 after product
isolation. GC yields of 2 in parenthesis. [c] Used 2 equiv PhMgBr as base.
[d] Overnight at 408C. [e] Ratio of crude product 6:1.
methyl substituent resulted in a 1:2 mixture of 2p:3p (Table 2,
entries 1 and 2). Reactions with electron-rich Grignards were
complete within 3 h (entries 4 and 5); longer reaction times
resulted in arylation of 2. Lower yields were observed for
Scheme 1. Stereospecificity of oxidative arylation.
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solution was removed from the ice bath and stirred at room
temperature for 1 h. The reaction was then brought to À788C, and
PhMgBr (3.0m in Et2O, 1.0 mL, 3.0 equiv) was added slowly dropwise.
When the addition was complete, the reaction was removed from the
ice bath and allowed to stir overnight at room temperature. The
reaction was quenched with 1m HCl (15 mL) and stirred until both
phases became clear. The aqueous layer was extracted 3 times with
Et2O (20 mL). The combined organic extracts were washed with brine
(30 mL), dried over Na2SO4, and concentrated under reduced
pressure to yield the crude oxidative arylation product.
mixtures of products, the ratio of 2:3 evolved from 0.9:1 at
40 min (100% conversion) to 6.4:1 at 40 h.
Under the reaction conditions, transmetalation of magne-
sium alkoxide A to titanium[14] and addition of aryl Grignard
may yield the aryltitanium alkoxide C (Scheme 2).[15] The
aryltitanation is then directed to the proximal olefin to form
Received: November 18, 2010
Published online: January 25, 2011
À
Keywords: alcohols · C C coupling · Grignard reagents ·
oxidative arylation · titanium reagents
.
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Experimental Section
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[11] See Supporting Information for optimization details.
[16] A similar mechanism is proposed in Ref. [4a].
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