Improvements and Applications of the Transition Metal-Free Asymmetric Allylic Alkylation using Grignard Reagents and Magnesium Alanates

Article abstract of DOI:10.1002/adsc.201500495

Two new N-heterocyclic carbene (NHC) ligands have been synthesized and employed in the transition metal-free asymmetric allylic alkylation (AAA) mediated by Grignard reagents and magnesium alanates. The employment of these ligands showed high yields and improved regio- and enantioselectivity in the formation of tertiary and quaternary stereocenters. Moreover, the low catalyst loading (up to 0.3 mol%) and high scalability (up to 10 mmol) of this improved methodology provide a convenient access to biologically active compounds and synthetically valuable intermediates.

Full text of DOI:10.1002/adsc.201500495

FULL PAPERS
DOI: 10.1002/adsc.201500495
Improvements and Applications of the Transition Metal-Free
Asymmetric Allylic Alkylation using Grignard Reagents and
Magnesium Alanates
David Grassia and Alexandre Alexakisa,*
a
DØpartement de Chimie Organique, UniversitØ de Gen›ve, 30 quai Ernest-Ansermet, CH-1211 Gen›ve-4, Switzerland
Fax: (+41)-2-2379-6522; e-mail: alexandre.alexakis@unige.ch
Received: May 22, 2015; Revised: July 24, 2015; Published online: September 25, 2015
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201500495.
Abstract: Two new N-heterocyclic carbene (NHC) li- (up to 0.3 mol%) and high scalability (up to
gands have been synthesized and employed in the 10 mmol) of this improved methodology provide
transition metal-free asymmetric allylic alkylation a convenient access to biologically active compounds
(AAA) mediated by Grignard reagents and magnesi- and synthetically valuable intermediates.
um alanates. The employment of these ligands
showed high yields and improved regio- and enantio- Keywords: alanates; Grignard reagents; N-heterocyl-
selectivity in the formation of tertiary and quaterna- ic carbene (NHC) ligands; transition metal-free con-
ry stereocenters. Moreover, the low catalyst loading ditions
Introduction
albeit in poor substrate scope.[9] Indeed limitations of
this methodology involved the use of an ester deriva-
The asymmetric allylic alkylation (AAA) has been tive whereas the use of common cinnamyl bromide
highly explored over the past decade. The use of derivatives yielded poor values of enantioselectivity,
chiral ligands such as NHC (N-heterocyclic car- regioselectivity and reactivity. The authors proposed
benes),[1] phosphoramidites, or ferrocene-based li- that the strong s donation of the NHC ligand in-
gands in combination with a transition metal such as creased the electron density on the alkyl fragment
copper, palladium and iridium has allowed the effi- linked to the organometallic species.[10] Thus the
À
cient construction of C C bonds in a highly regiose- change of electronic properties promoted an unusual
lective and enantioselective fashions.[2] Various hard highly selective SN2’ attack in the absence of a transi-
nucleophiles such as Grignard reagents,[3] triorganoa- tion metal. Hoveyda reported the transition metal-
luminium,[4] diorganozinc,[5] organolithium,[6] and or- free AAA addition of trimethylaluminium and di-
ganoboron[7] reagents have been successfully em- organozinc on cinnamyl phosphate derivatives using
ployed with copper as transition metal. The efficiency L2.[11] Despite the possibility to construct quaternary
of the AAA has clearly been demonstrated in total centres the applicability of this methodology was lim-
synthesis. The syntheses of representative and struc- ited by the low nucleophile scope inherent to the use
turally diverse biologically active compounds have of triorganoaluminium and diorganozinc reagents.
been disclosed in the literature using the AAA as key
Several groups relying on the design of structurally
step (sporochnol A, indolizine, faranal, bacopyridone diverse NHC ligands L3–L8 (Scheme 1) studied the
C, lasiol, ibuprofen, naproxen, elenic acid).[8] If the transition metal-free AAA using Grignard reagents
transition metal was removed and the ligand was on cinnamyl type substrates. The combination of an
solely used, the formation of an unselective SN2’/SN2 excellent regioselectivity and enantioselectivity could
adduct or an absence of reactivity has been always not be achieved so far and the ligand L8 developed in
observed. Nonetheless the seminal work of Hoveyda our laboratory has the best balance between regiose-
in 2006 demonstrated that the association of a catalytic lectivity and enantioselectivity.[12,13] Development of
amount of an NHC ligand L1 which acted as a Lewis transition metal-free enantioselective protocols is of
base and a stoichiometric amount of a Lewis acid great interest because in recent years an intense push
(Grignard reagent) may promote the unexpected se- towards a more environmentally friendly chemistry
lective formation of the enantioenriched SN2’ adduct has been impulsed by organocatalysis.[14] Transition
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David Grassi and Alexandre Alexakis
Table 1. Solvent screening.
Entry
Solvent
O(Et)2
O(n-Pr)2
O(i-Pr)2
MTBE
Reaction time[a]
1 h
1 h
1 h
1 h
SN2’/SN2 (ee [%])[b]
1
73/27 (90)
68/32 (90)
30/70 (90)
75/25 (72)
2
3
4
[a]
[b]
Time necessary to reach full conversion.
Enantiomeric value measured by chiral GC.
the only efficient solvent.[12b] In the ethereal solvent
screening the enantioselectivity is constant except
when MTBE was used but the SN2’/SN2 regioselectivi-
ty was clearly affected by the nature of the ethereal
solvent (Table 1, entries 1–4). However, we did not
find the optimal solvent and we kept Et2O as a solvent
Scheme 1. Ligands used in transition metal-free AAA.
metal-free protocols are valuable even in cases where of choice.
a metal-catalysed variant is available.[15] The two reac-
Hence, we turned our attention to the modification
tions differ by different and distinct mechanistic path- of the ligand L8 backbone. Our ligand is composed of
ways. Therefore it can give rise to complementary re- a chelating part (left part) and of a blocking part
activity and selectivity patterns. The scope of a defined (right part). Several new ligands bearing new and rep-
reaction is becoming wider and new valuable sub- resentative blocking parts were synthesised and tested
strates could be explored. Pursing this goal in the con- in our benchmark reaction (addition of EtMgBr to
text of the transition metal-free AAA we recently re- cinnamyl bromide). The other corresponding sub-
ported the construction of quaternary fluoroalkyl cen- strates were either commercially available or synthes-
tres, quaternary cyclic centres, vicinal tertiary/quater- ised using literature procedures.[17] The results are
nary centres via kinetic resolution and the construc- summarised in the Table 2. To begin with, two imida-
tion of tertiary centres bearing a trisubstituted zolium salts L9 and L10 with a substitution ortho/
olefin.[16] Crucially we were able to outperform the meta pattern were subjected into classical reaction
copper-catalysed versions which are inefficient on conditions (Table 2, entries 2 and 3). In the case of L9
these interesting substrates. In contrast the modest re- a good excess of 89% ee was obtained in spite of
gioselectivity obtained with the presence of L8 a low regioselectivity of 33/67 SN2’/SN2. On increasing
prompted us to design novel NHC ligands and investi- the steric bulk, L10 led to a decrease of enantioselec-
gate their effect in the stereoselectivity of the AAA tivity while affording the same level of regioselectivity
between cinnamyl bromide derivatives and Grignard as L9. Similarly an imidazolium L11 salt with a 1-
reagents.[12b] In this article we report the design of two naphthyl group having a methyl group in the ortho
new highly efficient NHC ligands and show their abil- position provided a good ee value but low regioselec-
ity in the context of transition metal-free AAA.
tivity (Table 2, entry 4). The low regioselectivity ob-
tained with ligands L9–L11 indicates that double
ortho-substution on the blocking arene was essential
for a good regioselectivity in the allylic alkylation.
Ligand L12 was then synthesised (Table 2, entry 5).
However this ligand provided low regio- and enantio-
selectivity, probably in the light of an unproductive
Results and Discussion
Design of the Third Generation Catalyst
Before carrying on the design of novel NHC ligands, coordination between magnesium and OMe groups in
we investigated the effect of several ethereal solvents the transition state. With employment of two chlorine
in the AAA in the presence of ligand L8. As previ- atoms, L13 yielded 87% ee and a regioselectivity of 4/
ously reported, the solvent has a crucial role in gener- 1 in favour of the desired adduct (Table 2, entry 6).
ating the active species. This was fully proved by The use of phenyl/methyl in the ortho position as in
1H NMR and 13C NMR spectroscopy and ether was L14 (Table 2, entry 7) did not provide any improve-
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Improvements and Applications of the TM-Free Asymmetric Allylic Alkylation
Table 2. Optimization on the blocking part of the ligand
(right part).
Table 3. Optimization on the chelating part of the ligand
(left part).
Entry
Ligand
Conv. [%][a]
SN2’/SN2[a] (ee [%])[b]
1[c]
2
3
4
5
L8
L9
L10
L11
L12
L13
L14
100
100
100
100
100
100
100
73/27 (91)
33/67 (89)
30/70 (63)
33/67 (88)
50/50 (10)
82/18 (87)
83/17 (60)
Entry
L
Conv. [%][a]
SN2’/SN2[a] (ee [%])[b]
1[c]
2
3
4
5
6
7
8
9
10
11
12
13
14
L8
100
100
100
100
100
100
100
100
100
100
100
100
100
100
73/27 (91)
55/45 (94)
67/33 (90)
61/39 (95)
76/24 (96)
62/38 (95)
82/18 (92)
70/30 (95)
82/18 (92)
85/15 (92)
82/18 (95)
87/13 (96)
92/8 (96)
85/15 (94)
L15
L16
L17
L18
L19
L20
L21
L22
L23
L24
L25
L26
L27
6
7
[a]
1
By H NMR.
[b]
[c]
Enantiomeric value measured by chiral GC.
Results from ref.[12b]
ments in terms of selectivity. In view of the negligible
effect provided by the screening of the blocking part
on the regioselectivity of the process, we envisioned
that an increased p–p stacking interaction between li-
gands and cinnamyl derivative could enhance the re-
gioselectivity of the AAA. These interactions can be
tuned by the addition of aryl groups in the para posi-
tion of the phenol group of the chelating part.
[a]
1
By H NMR.
[b]
[c]
Enantiomeric value measured by chiral GC.
Results from ref.[12b]
Consequently we decided to synthesise new NHC duction of a fluorine atom in the para position of the
ligands in order to tune the steric and the electronic second phenyl ring as in L18 (Table 3, entry 5) deter-
properties of the chelating part of the ligand. By ap- mined a drastic improvement in terms of enantiose-
plying the general synthetic sequence of NHC ligands lectivity (from 90% ee to 96% ee) and a moderate re-
L15–L31 could be synthesised in good yield and gioselectivity was reached (76/24 SN2’/SN2). Then we
purity. In previous publications by our group, we introduced several hindered aryl groups in the para
showed how the introduction of para-substituent on position to give L20–L24 (Table 3, entries 6-11) that
the directing phenol moiety of the NHC ligand could increased the steric hindrance in the vicinity of the re-
significantly enhance the stereoselectivity of the active centre of the ligand. We noticed the positive in-
asymmetric AAA reaction. For example, on introduc- fluence effect when a 2-naphthyl substituted aryl
tion of the second phenyl group, L17 with a para posi- group was utilised. Hence, L24 bearing a 2-naphthyl
tion of the phenol group gave a positive effect on the group provided the best balance between regio- and
stereoselectivity of the transition metal-free AAA re- enantioselectivity (Table 3, entry 11). The combina-
action for dibromo and fluoroalkyl substrates.[16a,b] tion of best chelating part and blocking part provided
Consequently the electronic properties were screened good level of regioselectivity and excellent level of
by the addition of strong electron-withdrawing and enantioselectivity with ligands L25 and L26 (Table 3,
electron-donating groups to give L15 and L16 entries 12 and 13). These ligands provide an optimal
(Table 3, entries 2 and 3). The results obtained were balance of steric and electronics factors. For the 4-F-
deleterious in terms of regioselectivity. Similarly the C6H4 the electronic parameter prevailed over the
introduction of a phenyl group as in L17 (Table 3, steric ones.[17] On the other hand, for the 2-naphthyl
entry 4) provided low results. To our delight the intro- moiety the steric parameter prevailed.
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David Grassi and Alexandre Alexakis
Table 4. Exploring more the fluorine effect.
Entry
Ligand
Conv. [%][a]
SN2’/SN2[a] (ee [%])[b]
1[c]
2
3
4
5
L8
100
100
100
100
100
100
73/27 (91)
87/13 (96)
90/10 (94)
89.5/10.5 (92)
91/9 (94)
L25
L28
L29
L30
L31
6
90/10 (94)
[a]
1
By H NMR.
[b]
[c]
Enantiomeric value measured by chiral GC.
Results from ref.[12b]
The positive effect that a fluorine atom on the
second phenyl ring has was then investigated by syn-
thesising a series of fluorine-containing ligands. The
introduction of the fluorine atom on the meta posi-
tion, L28 (Table 4, entry 3), gave a slightly better re-
gioselectivity with a decrease in ee to 94%. Further-
more, the introduction of the fluorine atom on ortho
position, L29 (Table 4, entry 4), gave a slightly better
regioselectivity and a lower ee. The introduction of
two or three fluorine atoms, L30 and L31 (Table 4,
entries 5 and 6) did not provide any appreciable im-
provement. Regarding the results and the synthetic
accessibility, the best ligands were L25 and L26.
Scheme 2. Nucleophile scope for the construction of tertiary
centres in transition metal-free AAA using L25 and L26 on
cinnamyl bromide.
enantioselectivity when a methyl Grignard was em-
ployed. Noteworthy, bulky secondary Grignard re-
agents 14 could be introduced with excellent regiose-
Nucleophiles and Substrates Scope
Employment of ethylmagnesium bromide as nucleo- lectivity. On using a sterically hindered substrate bear-
phile provided the adduct 1 in 75% isolated yield, ing a methyl in the ortho position, 15, once again
a regioselectivity of 92/8 SN2’/SN2 and 96% ee a perfect regioselectivity was observed with an excel-
(Scheme 2). The utilisation of other primary nucleo- lent value of 96% ee (Scheme 3).
philes afforded the desired adducts 2–7 with regiose-
The nucleophile scope was further explored using
lectivity greater than 90/10 SN2’/SN2 with excellent aliphatic substrates. Several nucleophiles 16–18 could
enantioselectivity values and isolated yields. To our be introduced with good to excellent regioselectivity
delight the introduction of the challenging methyl and 75 to 88% ee when a bulky cyclohexyl group was
moiety, 9, worked in a very efficient manner as also next to the reactive centre. Paradoxically on using
did the use of bulkier Grignard reagents such as that even a bulkier substrate with a t-Bu group, 19, excel-
with a cyclopentyl group, 8.
lent regioselectivity and ee value could be obtained
The introduction of Grignard reagents when a mod- (Scheme 4). With a substrate bearing the less sterical-
erately electron-donating group 10 and 11 was present ly hindered methyl group 20 the regioselectivity was
on the aromatic ring gave similar results as when em- decreased to 86% in favour of the SN2’ adduct with
ploying the model substrate (cinnamyl bromide). The a lower ee value of 56% ee.
introduction of
a
strongly electron-withdrawing
A comparison between the transition metal-free
group, 12 and 13, afforded the desired products with AAA versus Cu-catalysed protocols is illustrated in
perfect regioselectivity but at the expense of the Scheme 5.[18] Copper-catalysed procedures did not tol-
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Improvements and Applications of the TM-Free Asymmetric Allylic Alkylation
Scheme 3. Aromatic substrate scope for the construction of
tertiary centres in transition metal-free AAA using L25.
Scheme 5. Transition metal-catalysed versus transition
metal-free reactions.
omatic ring showed how the transition metal-free pro-
tocol constituted the best method for the achievement
of high regioselectivity and enantioselectivity.
Transition Metal-Free AAA using Magnesium
Alanates
Trialkylaluminium species has been scarcely studied
as nucleophiles in the copper-catalysed AAA when
compared to arylaluminium, allylaluminium and
alkenylaluminium species.[4b–f] The use of copper in
combination with a BINOL-derived ligand has been
reported by Woodward but only reactive trimethylalu-
minium has been employed with complete regioselec-
tivity albeit in racemic form.[19] Furthermorew, the
combination of a phosphoramidite-type ligand and
copper salts provided low selectivity and reactivity
(Scheme 6).[19b] The use of copper and NHC ligands
Scheme 4. Alipathic substrate scope for the construction of
tertiary centres in transition metal-free AAA using L25 and
L26.
erate sterically hindered substrate while the transition has been also applied using trimethylaluminium as
metal-free methodology provided impressive results. nucleophile in the total synthesis of bacopyridone C
The use of the bulky cyclopentyl nucleophile afforded with good results in terms of enantioselectivity and
a higher enantioselectivity with a similar level of re- regioselectivity (95/5 SN2’/SN2, 89% ee) but as a draw-
gioselectivity as the copper-catalysed version. Finally back high ligand and metal catalyst loadings
the use of electron-withdrawing substituent on the ar- (15 mol% each) were required.[20]
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David Grassi and Alexandre Alexakis
Table 5. Relationship versus conversion and generation of
the magnesium alanate species.
Scheme 6. Copper-catalysed AAA using trialkylaluminium
reagent.
Our aim was to develop of an efficient transition
metal-free methodology involving the use of trialkyl-
aluminium as nucleophiles in a similar manner to the
previously developed protocol with Grignard re-
agents. Previous results from our group indicated that
direct addition of trimethylaluminium under our tran-
sition metal-free condition did not lead to any reason-
able conversion or regioselectivity. In turn we hypoth-
esised that magnesium alanates, that have enhanced
nucleophilicity, might show higher reactivity in the
AAA. The magnesium alanates were readily prepared
by the addition of one equivalent of Grignard reagent
to a solution of triorganoaluminium in ether at
À158C as described in the literature.[21] Initial experi-
ments investigated the optimal ratio between trime-
thylaluminum and organomagnesium reagent in order
to get high yield and selectivity in the AAA. When
only trimethylaluminium was present in the reaction
mixture a poor conversion (less than 5% conversion)
was observed and only the SN2 adduct resulting from
the attack of the trimethylaluminium (Table 5,
entry 1). Interestingly when 0.15 equiv. of ethylmagne-
sium bromide was used 15% conversion was reached
with the selective transfer of the methyl moiety with
encouraging values of enantioselectivity and perfect
regioselectivity (Table 5, entry 2). If the amount of
the magnesium alanate was increased gradually from
0.30 to 1.50 equiv. high conversions were achieved
without any cost in terms of regio- and enantioselec-
tivity. Noteworthy the utilisation of 1.50 equiv. of
EtMgBr allowed the reaction to go to completion in
4 h with 84% ee and >99/1 SN2’/SN2 regioselectivity
(Table 5, entry 4). In addition no Et adduct was ob-
served! As a control experiment when 1.50 equiv. of
magnesium alanate were added to the imidazolium
salt full conversion was reached but only the SN2
product was observed. This illustrates the fact that the
NHC-Mg complex needs to be preformed to ensure
transmetallation with the magnesium alanate species.
In Table 6 a catalyst survey has been performed
Entry x equiv. of Conv.
Ratio 1/9/21/ SN2’/SN2 (ee
A[d]
[%][a]
22[a]
[%])[b]
[c]
1
2
3
4
5
–
5
0/0/1/0
1/0/0/0
1/0/0/0
1/0/0/0
1/0/0/0
–
0.15
0.30
0.60
1.50
15
30
60
100
>99/1 (84)
>99/1 (84)
>99/1 (84)
>99/1 (84)
[a]
[b]
[c]
1
By H NMR.
Enantiomeric value measured by chiral GC.
2 equiv. of trimethylalumium are used on NHC-Mg com-
plex.
[d]
A=MgBrAlMe3Et.
Table 6. Ligand screening.
Entry
L
Conv. [%][a]
SN2’/SN2 (ee [%])[b]
1
2
3
4
5
6
7
8
L25
L16
L15
L17
L19
L26
L7
55
40
19
51
20
42
92
100
82/18 80)
80/20 (72)
82/18 (81)
84/16 (79)
72/28 (78)
85/15 (79)
88/12 (71)
93/7 (80)
L8
[a]
1
By H NMR.
[b]
Enantiomeric value measured by chiral GC.
using our best conditions. The electronic properties The introduction of electron-withdrawing or electron-
on the left part of the ligand were investigated. The donating groups did not provide the desired results
use of a 4-F-C6H4 moiety on the para position from (Table 6, entries 2 and 3). Playing on the steric hin-
the hydroxy group led to modest conversion with drance of the ligand by introducing 2-naphthyl or 1-
modest regioselectivity and 80% ee (Table 6, entry 1). naphthyl was not the key modification to reach full
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Improvements and Applications of the TM-Free Asymmetric Allylic Alkylation
Table 7. Substrate and nucleophile scope.
Formation of Quaternary Centres using Grignard
Reagents
The two best ligands for the construction of tertiary
centres L25 and L26 were selected as potential candi-
dates to improve the results on the formation of qua-
ternary centres previously achieved using ligand
L8.[12b] The ligand L25 had a beneficial effect on both
the regioselectivity and the enantioselectivity when
substrates bearing a phenyl group 24 and 25 were em-
ployed (Table 8, entries 1–6). On the other hand L26
bearing a 2-naphthyl group was the ligand of choice
for the construction of quaternary centres when an
alkyl group is present on the substrate (Table 8, en-
tries 7–12) providing products 29–30 with excellent re-
sults. The construction of quaternary fluoroalkyl qua-
ternary centres in the context of AAA has been al-
ready reported by our group.[16b] Therefore ligands
L18 and L24 were tested and adducts 31 and 32 were
obtained with good results (Table 8, entries 13–18)
albeit L17 remained the optimal ligand for such types
of substrates (see Scheme 12).
Entry R1
R
Yield [%][a] SN2’/SN2 (ee [%])[b]
1
2
3
Ph
Ph
Ph
Ph
Me 9 65
Et 1 65
n-Bu 3 70
93/7 (83)
87/13 (91)
92/8 (90)
85/15 (86)
82/18 (86)
92/8 (94)
89/11 (81)
96/4 (76)
93/7 (96)
89/11 (84)
4
i-Bu 6 67
5
6
7
8
4-Me-C6H4 Et 10 60
4-F3C-C6H4 Et 12 69
4-Me-C6H4 Me 11 70
4-F3C-C6H4 Me 13 72
2-Me-C6H4 Et 15 68
9
10
Cy
Et 16 55
[a]
[b]
Isolated yield after column chromatography.
Enantiomeric value measured by chiral GC.
Table 8. Optimization reactions.
conversion (Table 6, entries 5 and 6). Gratifyingly the
use of L7 led to almost full conversion with good
regio- and enantioselectivity (Table 6, entry 7). The
switch from two methyl to two ethyl groups in L8
gave the best ligand yielding the desired adduct with
100% conversion, 93/7 SN2’/SN2, 80% ee (Table 6,
entry 8).
The scope of trialkylaluminiums via the corre-
sponding magnesium alanate (R is the same alkyl
group on the magnesium alanate and the Grignard re-
agent used to activate the imidazolium salt) was then
explored. Alkyl groups could be introduced with good
yield, good level of regioselectivity and promising
enantioselectivity (Table 7, entries 1–4). Introduction
of an electron-withdrawing group was beneficial for
the system considering the level of regioselectivity ob-
tained (Table 7, entries 6 and 8) compared to a moder-
ate electron-donating group (Table 7, entries 5 and 7).
The developed conditions worked equally well for an
ortho substituted substrate with both high levels of re-
gioselectivity and enantioselectivity (Table 7, entry 9).
Finally with an aliphatic derivative the addition of
magnesium alanate in a transition metal-free AAA
afforded satisfactory results (Table 7, entry 10). These
results were particularly interesting since the presence
of a sulphonate group on the ligand scaffold is com-
pulsory to reach good results with aluminium-based
reagents in the transition metal-free AAA.[11]
Entry
L
Product
SN2’/SN2[a]
ee [%][b]
1[c]
2
L8
24
24
24
25
25
25
29
29
29
30
30
30
31
31
31
32
32
32
>99/1
>99/1
>99/1
92/8
95/5
92/8
>99/1
>99/1
>99/1
>99/1
>99/1
>99/1
>99/1
>99/1
>99/1
>99/1
>99/1
>99/1
90
94
85
86
90
84
79
82
88
83
80
89
94
91
89
95
92
90
L25
L26
L8
L25
L26
L8
L25
L26
L8
L25
L26
L17
L18
L24
L17
L18
L24
3
4[c]
5
6
7[c]
8
9
10[c]
11
12
13[d]
14
15
16[d]
17
18
[a]
1
By H NMR.
[b]
[c]
[d]
Enantiomeric value measured by chiral GC.
Results from ref.[12b]
Results from ref.[16b]
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Scheme 8. Stereoselective transformations of quaternary ad-
ducts.
centre in the a position. Additionally the formation
of E or Z vinyl iodide 35, 36 can be achieved through
either Takai[22] reaction or Zhao–Stork reaction on
the latter aldehyde.[23] This is a formal selective for-
mation of E or Z quaternary adducts via the AAA re-
action. The accessibility of the substrate (purification
issue) and the control of the E/Z ratio on a represen-
tative scope of substrates and nucleophiles are ex-
tremely challenging and therefore remain undisclosed
(Scheme 8).
The pivotal aldehyde 37 was transformed into
adduct 38. The reported derivatisation of compound
38 allowed the construction of two vicinal tertiary/
quaternary stereocentres in a completely diastereso-
Scheme 7. Nucleophile and substrate scope for the construc-
tion of quaternary centers in transition metal-free catalysed
AAA using L25 and L26 with Grignard reagents.
With the optimised conditions the reaction was selctive manner (Scheme 9).[24] The adduct 38 was hy-
scaled up to 0.5 mmol and the desired adducts 24–30 drogenated providing the formation of ester 39 bear-
and 33–34 were isolated Scheme 7. The reaction toler- ing a quaternary stereocentre on the g position
ated arene substituents, 24–28, while generally afford- (Scheme 9). Our group has made strong efforts to
ing compounds with good yields, perfect regioselectiv-
ity and high ee values. The formation of quaternary
centres worked equally well with bulky aliphatic sub-
strates 29 and 30. Different Grignard reagents could
be used with again perfect levels of regioslectivity and
good enantiomeric excess 33 and 34. It is crucial to
highlight that no transition metal-catalysed protocols
are able to construct quaternary centres with
Grignard reagents.
Applications of the Transition Metal-Fee AAA to the
Synthesis of Relevant Synthetic Intermediates
To further demonstrate the utility of our methodology
we used our catalysis adducts towards the stereoselec-
tive synthesis of synthetic intermediates. The catalysis
adducts could undergo further transformation and be
converted into an aldehyde bearing a quaternary ducts.
Scheme 9. Stereoselective transformations of quaternary ad-
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Scheme 11. Formal synthesis of (S)-dehydrocurcumene, (S)-
curcumene and ar-tumerone.
Scheme 10. Stereoselective transformations of quaternary
adducts.
create such a framework on a tertiary centre using methyl analogues of bioactive compounds or com-
copper/BINAP-type ligand and trimethylaluminium, pounds used in the fragrance industry were carried
on keto amides. However, the construction of a qua- out. A hydroboration/oxidation sequence afforded the
ternary centre using this methodology was impossi- desired alcohol which could be easily transformed
ble.[25]
into difluoromethyl analogue of curcumone 45 or
Starting again from catalysis adduct 38, reduction monofluoromethyl analogue of florhydral 43
was performed to provide compound 40.The alcohol (Scheme 12). Simple oxidative cleavage of the termi-
derivative 40 was itself a product which is the result nal double bond provided the difluoromethyl ana-
of
a selective 1,4 addition to an epoxide via logue of ibuprofen 47 (Scheme 12). Those new ana-
a DYKAT process. In our hands the reaction failed logues may exhibit increased activity because of the
on tertiary centres leading to a complicated mixture incorporation of the fluoroalkyl moieties.[29]
of compounds and a poor level of enantioselectivity
(Scheme 10).[26] The alcohol 40 was oxidised with
Dess–Martin reagent followed by Wittig olefination
to give the product 41. This is a selective 1,6-AAA
skipped diene (Scheme 10). The 1,4 attack was always
observed when a tertiary centre was constructed.[27]
The selective 1,6-attack is even less favourable when
a more congested quaternary centre is present on the
starting material making that transformation valuable.
Applications of the Transition Metal-Free AAA to
the Synthesis of Biologically Active Compounds
The opportunity to decrease the catalyst loading for
more convenient and scalable protocols has been in-
vestigated. With the third generation NHC ligand L25
the catalyst loading could be reduced to 0.3 mol%
without any erosion in yield, regioselectivity or enan-
tioselectivity. The synthesis of pivotal catalysis adduct
11 in good yield, regioselectivity and enatioselectivity
could be performed on a 10 mmol scale. The inter-
mediate 11 can be derived into three bioactive com-
pounds with interesting medicinal properties
(Scheme 11).[28]
In addition, using transition metal-free AAA the
syntheses of several monofluoromethyl or difluoro- yl analogues of florhydral, curcumone and ibuprofen.
Scheme 12. Synthesis of monofluoromethyl or difluorometh-
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time 2.The glassware for catalysis, preparation of Grignard
reagent, substrates and catalyst were washed with aqua
regia (1/1 v/v HCl/H2SO4) prior to use to remove any traces
of metals. The Grignard reagents were prepared by using
>99.99% pure magnesium powder. After column chroma-
tography the solvent was filtered over a pad of cotton to
remove any traces of silica gel.
Conclusions
In this article we have described the design of the two
NHC ligands L25 and L26 (easy to synthesise from
commercially available sources in three steps) with
both prevalent steric control and electronic control el-
ements. These ligands could be applied to the transi-
tion metal-free AAA using Grignard reagent and
magnesium alanates. When using Grignard reagents
excellent selectivities and enantioselectivities were ac-
cessed on both tertiary and quaternary centres com-
pared to the previously described ligand L8. Of inter-
est, reactive magnesium alanates could be employed
to construct tertiary centres with good results. Impor-
tantly the catalyst loading can be decreased to
0.3 mol% and the reaction can be scaled up to
Procedure for the Synthesis of Ligand L25
Pd(OAc)2 (22.5 mg, 0.1 mmol, 0.1 equiv.), sublimed sodium
tert-butoxide (154 mg, 1.6 mmol, 1.6 equiv.), rac-BINAP
(124.5 mg, 0.2 mmol, 0.2 equiv.) were stirred for one hour in
15 mL of degassed toluene. The diamine (212 mg, 1 mmol,
1 equiv.) solubilised in 10 mL of degassed toluene and bro-
mide derivative (234 mg, 1.1 mmol, 1.1 equiv.) were added.
The Young valve Schlenk tube was sealed and the mixture
10 mmol. Consequently as applications the formal was vigorously stirred at 1108C for 48 h. The mixture was
filtered over celite and the plug washed with dichlorome-
thane. The mixture was concentrated and purified by deacti-
vated silica gel (15% to 50% mixture of EtOAc/cyclohex-
ane). The compound was recovered as a yellow viscous oil;
syntheses of (S)-dehydrocurcumene, (S)-curcumene
and ar-tumerone were carried out. In addition, the
synthesis of highly challenging synthons bearing enan-
tioenriched quaternary centres and fluoroalkyl ana-
logues of florhydral, curcumone and ibuprofen have
been synthesised.
1
yield: 251 mg (75%). H NMR (300 MHz, CDCl3): d=7.1–
7.4 (m, 17H), 6.80 (t, 1H, J=7.3 Hz), 4.60 (d, 1H, J=
9.2 Hz), 4.40 (d, 1H, J=9.4 Hz), 4.05 (d, 1H, J=13.3 Hz),
3.90 (d, 1H, J=13.3 Hz), 2.65 (q, 4H, J=7.3 Hz), 1.30 (t,
6H, J=7.5 Hz); 13C NMR (75 MHz, CDCl3, carbon-fluorine
decoupled): d=157.6, 143.0, 142.2, 141.6, 129.7, 129.4, 129.3,
128.4, 128.3, 128.0, 127.9, 127.3, 127.0, 126.8, 123.3, 121.1,
115.7, 66.8, 61.1, 23.7, 20.3, 14.5; 19F NMR (376 MHz,
CDCl3): d=51.79; HR-MS (ESI+ mode): m/z=450.2676,
calcd.: 450.2671.
Experimental Section
General Remarks
All reactions were carried out under nitrogen or argon at-
mosphere in flame-dried glassware and with dry solvents.
Solvents (THF, Et2O, toluene, DCM, MTBE and CH3CN)
were dried over alumina (activated at 3508C under nitrogen
The Buchwald amination product (114 mg, 0.3 mmol,
1 equiv.) was dissolved in 5 mL of dry methanol. The alde-
hyde (238 mg, 0.33 mmol, 1.1 equiv.) solubilised in the same
amount of THF was added. A strong change of colour from
pale yellow to bright yellow was observed. Activated 4Š
molecular sieves (100 mg), sodium cyanoborohydride
(30 mg, 0.45 mmol, 1.5 equiv.) and glacial acetic acid
(0.045 mL, 0.75 mmol, 2.5 equiv.) were added and the result-
ing mixture stirred at room temperature for 24 h. The mix-
ture was filtered over Celite and concentrated. The residue
was taken up into ethyl acetate and washed with saturated
aqueous sodium hydrogen carbonate solution. The water
phase was extracted two times with ethyl acetate. The or-
ganic phases were combined dried over sodium sulphate
and concentrated under vacuum to give the crude com-
pound. The crude compound was purified by deactivated
silica gel (5% to 20% mixture of EtOAc/cyclohexane). The
compound was obtained as a white foam; yield: 112 mg
(69%). 1H NMR (300 MHz, CDCl3): d=11.05 (bs, 1H),
7.49–6.96 (m, 10H), 4.54 (d, 1H, J=9.5 Hz), 4.34 (d, 1H,
J=9.5 Hz), 4.05 (d, 1H, J=14.3 Hz), 3.94 (d, 1H, J=
13.3 Hz), 2.58 (q, 4H, J=7.6 Hz), 1.23 (t, 6H, J=7.5 Hz);
13C NMR (dept135, 75 MHz, CDCl3): d=162.3, 128.5, 128.4,
128.2, 128.1, 128, 127.9, 127.7, 127.4, 127.2, 126.9, 126.8,
122.7, 116.8, 115.6, 115.3, 68.3, 67.8, 50, 25 2 14.7; 19F NMR
(376 MHz, CDCl3): d=51.79.
1
atmosphere for 12 h). Yields refer to H NMR homogeneous
materials, unless otherwise stated. Reactions were moni-
tored by GC-MS on a Hewlet Packard (EI mode) HP6890–
5973 on an HP6890 or by TLC carried out on 0.25 mm E.
Merck silica gel plates (60F-254) using UV lamp as visualis-
ing agent and KMnO4 solution as developing agents. Flash
chromatography was performed using silica gel (particle size
32–63 mm, 60 Š). 1H (300, 400 MHz or 500 MHz) and 13C
(75 or 100 MHz) NMR spectra were recorded on Bruker
AMX-300 or 400 instrument in CDCl3 and calibrated using
residual undeuterated solvent as an internal reference.
Chemical shift values (d) are given in ppm relative to tetra-
methylsilane (0 ppm). Multiplicity is indicated as follows:
s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet),
dd (doublet of doublet), br s (broad singlet). Coupling con-
stants J are reported in Hz. Mass spectra (MS) and high res-
olution mass spectra (HR-MS) were obtained by electro-
spray ionisation (ESI) or by electronic impact (EI, 70 eV).
Optical rotations were measured at 208C in a 10 cm cell in
the stated solvent; [a] values are given in 10À1 degcm2 gÀ1
(concentration c given as g/100 mL). Enantiomeric excesses
were determined either by chiral GC measurement on an
HP6890 (H2 as vector gas) or HP6850 (He or H2 as vector
gas).Temperature programmes are described as follows: ini-
tial T (8C) – initial times (min) – temperature gradient (8C/
min) – final T (8C); retention times (RT) are given in min.
Retention times are given as retention time 1 and retention
The diamine (82 mg, 0.15 mmol, 1 equiv.) was solubilised
into 5 mL of dry toluene and placed into a Young valve
Schlenk tube. Ammonium chloride (10.5 mg, 0.2 mmol,
1.3 equiv.) and trimethyl orthoformate (0.330 mL, 3 mmol,
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Improvements and Applications of the TM-Free Asymmetric Allylic Alkylation
20 equiv.) were added and the flask was sealed. The mixture
was refluxed at 1108C for 16 h and then cooled to room
temperature. The mixture was concentrated and the carbene
was precipitated by addition of ether. The solid was triturat-
ed in ether using an ultrasound bath and filtered. The solid
was washed with three portions of ether and dried under
high vacuum. The compound was obtained as a white solid;
(3”3 mL). The combined organic fractions were dried over
Na2SO4, filtered and concentrated under vacuum. The resi-
due was purified by flash column chromatography using
100% pentane as eluting solvent to offer a mixture of SN2’
and SN2 products.
(S)-But-3-en-2-ylbenzene (9): The product was obtained
as a colourless oil after column chromatography (100% pen-
tane) in 93/7 SN2’/SN2 regioselectivity with 83% ee; yield:
26 mg (65%). GC (HYDRODEX B3P: 60–10–1–85–20–
170–5): t1=19.2 min, t2=19.8 min. Spectral data in accord-
ance with the literature.[12a]
1
yield: 66 mg (75%). H NMR (500 MHz, CDCl3): d=10.76
(bs, 1H), 9.83 (s, 1H), 7.72 (d, 1H, J=8.4 Hz), 7.47 (t, 3H,
J=3.3 Hz), 7.39 (dd, 1H, J=2.3 Hz and J=8.4 Hz), 7.29–
7.20 (m, 10H), 7.09 (d, 2H, J=8.3 Hz), 7.02 (d, 2H, J=
6.7 Hz), 6.97 (t, 2H, J=8.8 Hz), 5.92 (d, 1H, J=14.3 Hz),
5.29 (d, 1H, J=8.7 Hz), 5.12 (d, 1H, J=8.7 Hz), 4.11 (d,
1H, J=14.3 Hz), 2.83 (q, 1H, J=7.5 Hz), 2.63 (q, 1H, J= Procedure for Quaternary Centres using Grignard
7.5 Hz), 2.48 (q, 1H, J=7.5 Hz), 2.1 (q, 1H, J=7.5 Hz), 1.38
(t, 3H, J=7.5 Hz), 0.88 (t, 3H, J=7.5 Hz); 13C NMR
(126 MHz, CDCl3): d=162.9, 160.9, 158.9, 156.7, 143.4,
140.4, 136.4 (d, J=3.1 Hz), 135.1, 132.8, 131.3, 130.2 (d, J=
3.5 Hz), 130, 129.9 (d, J=11.8 Hz), 129.2, 129.1, 129, 128.8,
128.7 (d, J=8 Hz), 128.6, 128.5, 128.4, 128.3, 128.2, 128.1,
128, 127.9, 127.8, 127.6, 127.3, 127, 126.8, 126.7, 126.6, 126.1,
118.3 (d, J=10.8 Hz), 115.4 (d, J=21.3 Hz), 76.2, 69.3, 48.7,
24.5, 23.7, 15.28 15; 19F NMR (376 MHz, CDCl3): d=51.79;
[a]: +150.5 (c 0.5, CHCl3); HR-MS (ESI+ mode): m/z=
590,2499, calcd.: 590,2500.
Reagents
In a flame-dried Schlenk tube, under an N2 atmosphere, the
substrate (105 mg, 0.5 mmol, 1 equiv.) and L25 (3.1 mg,
0.005 mmol, 0.01 equiv.) were suspended in dry Et2O (2 mL)
and cooled to À158C. EtMgBr Et2O (3M, 0.3 mL, 0.9 mmol,
1.8 equiv.) was added dropwise over 4 min. After complete
conversion, the mixture was quenched by addition of a satu-
rated solution of NH4Cl (2 mL) and stirred at room temper-
ature during 10 min. The aqueous layer was separated and
extracted with Et2O (3”3 mL). The combined organic frac-
tions were dried over Na2SO4, filtered and concentrated
under vacuum. The residue was purified by flash column
chromatography to offer a mixture of SN2’ and SN2 products.
(S)-(3-Methylpent-1-en-3-yl)benzene (24): The product
was obtained as a colourless oil after column chromatogra-
phy (100% pentane) in >99/1 SN2’/SN2 regioselectivity with
94% ee; yield: 65%. GC (CP-CHIRASIL DEX CB: 80–1–
120–20–170–5): t1=22.5 min, t2=23.1 min. Spectral data in
accordance with the literature.[12a]
Procedure for Tertiary Centres using Grignard
Reagents
In a flame-dried Schlenk tube, under an N2 atmosphere, cin-
namyl bromide (98 mg, 0.5 mmol, 1 equiv.) and L26 (3.1 mg,
0.005 mmol, 0.01 equiv.) were suspended in dry Et2O (2 mL)
and cooled to À158C. EtMgBr in Et2O (3M, 0.3 mL,
0.9 mmol, 1.8 equiv.) was added dropwise over 4 min. After
complete conversion, the mixture was quenched by addition
of a saturated solution of NH4Cl (2 mL) and stirred at room
temperature during 15 min. The aqueous layer was separat-
ed and extracted with Et2O (3”3 mL). The combined organ-
ic fractions were dried over Na2SO4, filtered and concentrat-
ed under vacuum. The residue was purified by flash column
chromatography to offer a mixture of SN2’ and SN2 products.
(S)-Pent-1-en-3-ylbenzene (1): Following the general pro-
cedure the product obtained as a colourless oil after column
chromatography (100% pentane) in 92/8 SN2’/SN2 regiose-
lectivity with 96% ee; yield: 75%. GC (CP-CHIRASIL
DEX CB: 75–35–20–170–5): t1=31.5 min, t2=32.5 min.
Spectral data in accordance with the literature.[12a]
35. (S,E)-(1-Iodo-3-methylpent-1-en-3-yl)benzene (35): To
well stirred solution of iodoform (243 mg,0.6 mmol,
a
2 equiv.) and chromium chloride (7 equiv.) in THF at 08C
the aldehyde (50 mg, 0.3 mmol, 1 equiv.) dissolved in 2 mL
of dry THF was added dropwise. After stirring for an addi-
tional 30 min at 08C the ice bath was removed and the re-
sulting mixture was stirred for 2 h at room temperature.
TLC showed completion of the reaction, the mixture was
then quenched with an aqueous solution of sodium thiosul-
phate. The mixture was extracted with two portions of
ether, dried over sodium sulphate and concentrated under
vacuum. The crude mixture was purified using 100% pen-
tane as eluting solvent. The compound was obtained with
>99/1% E isomer purity; yield: 60 mg (71%). 1H NMR
(300 MHz, CDCl3): d=7.35–7.28 (m, 5H), 6.74 (d, 1H, J=
13 Hz), 6.03 (d, 1H, J=16.1 Hz), 1.82 (m, 2H), 1.39 (s, 3H),
0.81 (t, 3H, J=7.3 Hz); 13C NMR (75 MHz, CDCl3): d=
154.3, 145.6, 128.2, 126.5, 126.1, 74.2, 48.5, 33.2, 24.1, 8.8;
[a]: +7.2 (c 1.33, CHCl3); HR-MS (ESI+ mode): m/z=
286.0219, calcd.: 286.0218.
(S,Z)-(1-Iodo-3-methylpent-1-en-3-yl)benzene (36): To
a well stirred solution of the methyltriphenylphosphonium
iodide (158 mg, 0.39 mmol, 1.3 equiv.) in 3 mL of dry THF
at À788C KHMDS in THF (2M, 0.384 mL, 0.48 mmol,
1.6 equiv.) was added dropwise. After stirring for an addi-
tionnal 10 min at À788C, an ice bath was placed and the re-
sulting mixture was stirred for 30 min at 08C. The solution
was cooled again to À788C. The aldehyde (55 mg, 0.3 mmol,
1 equiv.) in 1 mL of dry THF was added dropwise. After
Procedure for Tertiary Centres using Magnesium
Alanate
In a flame-dried Schlenk, under an N2 atmosphere, L8
(7.4 mg, 0.015 mmol, 0.05 equiv.) was suspended in dry Et2O
(0.8 mL) and cooled to À158C. MeMgBr in Et2O (3M,
0.180 mL, 0.54 mmol, 1.8 equiv.) was added dropwise over
4 min and stirred 10 min. Trimethylaluminium in hexane
(3M, 0.250 mL, 0.75 mmol, 2.5 equiv.) was added and the
mixture was stirred at À158C for 1 h. The allylic bromide
derivative (60 mg, 0.3 mmol, 1 equiv.) in dry ether (0.8 mL)
was added. After complete conversion the mixture was
quenched by addition of a solution of tartaric acid (2 mL).
The aqueous layer was separated and extracted with Et2O
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30 min at À788C TLC showed completion of the reaction,
the mixture was then quenched with an aqueous solution of
ammonium chloride. The mixture was extracted with two
portions of ether, dried over sodium sulfate and concentrat-
ed under vacuum. The crude mixture was purified using
100% pentane as eluting solvent. The product was obtained
as slightly yellow oil with 87% Z isomer purity; yield: 42 mg
toluene and added via syringe to a one-neck flask equipped
with a septum and a nitrogen balloon. The solution was
cooled down to À788C using an acetone/dry ice bath.
DIBAL-H in toluene (1M, 0.43 mL, 0.43 mmol, 2.4 equiv.)
was added dropwise. The mixture was stirred at À788C for
30 min and for 30 min at 08C. The mixture was then
quenched by addition of a solution of tartaric acid (5 mL).
EtOAc was added and the stirring was continued for an ad-
ditional 30 min. The mixture was extracted with two por-
tions of EtOAc, dried over sodium sulphate and concentrat-
ed under vacuum. The residue was purified using silica gel
chromatography with pentane/ether 1/1 as eluent. The prod-
uct was obtained as a colourless oil; yield: 37 mg (95%).
1H NMR (300 MHz, CDCl3): d=7.34 (m, 4H), 7.23 (m,
1H), 5.96 (d, 1H, J=15.8 Hz), 5.67 (dt, 1H, J=18 Hz and
J=6 Hz), 4.20 (d, 2H, J=5.8 Hz), 1.79 (m, 2H), 1.42 (s,
3H), 1.30–0.91 (m, 5H), 0.89 (t, 3H, J=7 Hz); 13C NMR
(75 MHz, CDCl3): d=147.5, 141.6, 128.1, 126.5, 126.1, 125.7,
64, 43.3, 41.3, 26.6, 25.2, 23.3, 14.1; [a]: +11.5 (c 1.33,
CHCl3); HR-MS (ESI+ mode): m/z=218,1673, calcd.:
218,1671.
1
(45%). H NMR (300 MHz, CDCl3): d=7.35 (m, 5H), 6.90
(d, 1H, J=8 Hz), 6.41 (d, 1H, J=8.3 Hz), 1.86 (m, 2H),
1.60 (s, 3H), 1.31–1.26 (m, 4H), 0.90 (t, 3H, J=7.4 Hz);
13C NMR (75 MHz, CDCl3): d=148.3, 146.4, 128.2, 128,
127.4, 126.4, 125.6, 79.1, 45.4, 44.2, 26.4, 24.5, 23.2, 14.1; [a]:
À30.1 (c 1.85, CHCl3); [a]: +5.6 (c 1.33, CHCl3); HR-MS
(ESI+ mode): m/z=314.0530, calcd.: 314,0531.
(S,E)-Ethyl 4-methyl-4-phenyloct-2-enoate (38): To a con-
ditioned one-neck flask equipped with a septum and a nitro-
gen balloon, NaH (60% in mineral oil, 18 mg, 0.45 mmol,
1.5 equiv.) was washed with pentane. Dry THF was added
(5 mL) and the resulting suspension was cooled to 08C using
an ice cooled bath. Triethyl phosphonacetate (80 mg,
0.36 mmol, 1.2 equiv.) was then added dropwise to the reac-
tion mixture. After the addition was finished the ice bath
was removed and the solution was stirred at room tempera-
ture for 30 min. The aldehyde (55 mg, 0.3 mmol, 1 equiv.)
dissolved in 1 mL of dry THF was added and the reaction
mixture was stirred at room tempeature overnight. The reac-
tion was quenched using saturated aqueous ammonium
chloride solution. The mixture was extracted using two por-
tions of EtOAc, dried over sodium sulphate and concentrat-
ed under vacuum. The residue was purified using silica gel
chromatography with pentane/ether 98/2 as eluent. The
product was obtained as colourless oil with >99/1% E
isomer purity; yield: 52 mg (66%). 1H NMR (300 MHz,
CDCl3): d=7.34–7.22 (m, 5H), 7.17 (d, 1H, J=15.9 Hz),
5.86 (d, 1H, J=15.9 Hz), 4.26 (q, 2H, J=7.3 Hz), 1.85 (m,
2H), 1.46 (s, 3H), 1.34 (t, 3H, J=8.9 Hz), 1.31–1.05 (m,
2H), 0.91 (t, 3H, J=7.1 Hz); 13C NMR (75 MHz, CDCl3):
d=167, 156.8, 145.6, 128.3, 126.5, 126.2, 118.7, 60.2, 44.2,
40.6, 26.5, 24.6, 23.2, 14.2, 13.9; [a]: +13.3 (c 1.33, CHCl3):
HR-MS (ESI+ mode): m/z=260.1175, calcd.: 260.1176.
(S)-Ethyl 4-methyl-4-phenyloctonoate (39): To a condi-
tioned one-neck flask equipped with a septum the starting
material (52 mg, 0.2 mmol, 1 equiv.) was dissolved in techni-
cal methanol. Pd/C (10 mg, 10 wt%in palladium) was added
and a hydrogen balloon was set up in the reaction. Two
gentle cycles of vacuum/H2 filling were performed to ensure
a complete H2 atmosphere. The mixture was stirred over-
night at room temperature. The palladium was removed
using filtration on Celite and the cake was washed with two
portions of methanol. The solvent was removed under
vacuum to afford the desired compound as colourless oil in;
yield: 50 mg (98%). 1H NMR (500 MHz, CDCl3): d=7.30
(m, 4H), 7.18 (m, 1H), 4.07 (q, 2H, J=7.2 Hz), 2.12 (m,
2H), 1.97 (m, 2H), 1.75 (m, 1H), 1.56 (m, 1H), 1.30 (s, 3H),
1.28 (t, 3H, J=7.1 Hz), 1.25–1.20 (m, 2H), 1.15–1.00 (m,
1H), 0.95–0.9 (m, 1H), 0.83 (t, 3H, J=7.1 Hz); 13C NMR
(126 MHz, CDCl3): d=174.1, 146.7, 128.1, 126.3, 125.5, 60.2,
43.1, 40.3, 37.9, 29.8, 26.3, 23.5, 23.3, 14.1, 14; [a]: +12.3 (c
1.33, CHCl3); HR-MS (ESI+ mode): m/z=262.1935, calcd.:
262.1933.
(S,E)-(5-Methylnona-1,3-dien-5-yl)benzene
(41):
The
starting material (37 mg, 0.17 mmol, 1 equiv.) was dissolved
in 2 mL of dry dichloromethane. Dess–Martin periodinane
(122 mg, 0.29 mmol, 1.7 equiv.) was added. After stirring for
1 h at room temperature TLC showed complete consump-
tion of the starting material. The reaction was quenched
with a 1/1 v/v aqueous solution of sodium thiosulphate and
sodium hydrogen carbonate. The aqueous phase was extract-
ed twice with dichloromethane. The combined organic
phases were dried over sodium sulphate and concentrated
under vacuum. The crude mixture was purified using a plug
of silica gel with pentane ether 90/10 as eluting solvent. The
product was obtained as a colourless oil; yield: 26 mg
(73%). 1H NMR (300 MHz, CDCl3): d=9.61 (s, 1H, J=
7.6 Hz), 7.39–7.26 (m, 5H), 7.03 (d, 1H, J=15.9 Hz), 6.19
(dd, 1H, J=15 Hz and J=6 Hz), 1.93–1.84 (m, 2H), 1.50 (s,
3H), 1.31 (m, 4H), 0.91 (t, 3H, J=7.1 Hz); 13C NMR
(75 MHz, CDCl3): d=194.3, 166.3, 144.9, 129.9, 128.5, 126.5,
126.4, 44.9, 40.3, 26.5, 24.4, 23.2, 13.9; [a]: +10.1 (c 1.33,
CHCl3); HR-MS (ESI+ mode): m/z=216,1513, calcd.:
216,1514.
Methyltriphenylphosphonium salt (73 mg, 0.18 mmol,
1.5 equiv.) was suspended in 3 mL of dry ether and added
via syringe to a one-neck flask equipped with a septum and
a nitrogen balloon. The flask was cooled to 08C using an ice
cooled bath. n-BuLi in pentane (1.6M, 0.120 mL, 0.2 mmol,
1.6 equiv.) was added and the yellow solution was stirred at
08C for 1 h. The starting material (26 mg, 0.12 mmol,
1 equiv.) in dry ether was added and the ice bath removed.
The solution was stirred overnight before water was added
to quench the reaction. The mixture was extracted twice
using ether, dried over sodium sulphate and concentrated
under vacuum. The crude mixture was purified using a plug
of silica gel with 100% pentane as eluting solvent; yield:
1
22 mg (85%). H NMR (300 MHz, CDCl3): d=7.39–7.23 (m,
5H), 6.41 (m, 1H), 6.11 (m, 1H), 5.99 (m, 1H), 5.18 (dd,
1H, J=3.4 Hz and J=16 Hz), 5.09 (dd, 1H, J=3.2 Hz and
J=10.9 Hz), 1.81 (m, 2H), 1.45 (s, 3H), 1.34–1.28 (m, 4H),
0.94 (t, 3H, J=7.1 Hz); [a]: +6.6 (c 1.33, CHCl3); HR-MS
(ESI+ mode): m/z=214.1721, calcd.: 214.1722.
(S,E)-4-Methyl-4-phenyloct-2-en-1-ol (40): The ester
(52 mg, 0.18 mmol, 1 equiv.) was dissolved into 5 mL of dry
3182
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FULL PAPERS
Improvements and Applications of the TM-Free Asymmetric Allylic Alkylation
(R)-1-(1-Fluoro-2-methylbut-3-en-2-yl)-3-isopropylben-
zene (42): In a flame-dried Schlenk tube , under an N2 at-
mosphere, the substrate (135 mg, 0.5 mmol, 1 equiv.) and
L17 (9 mg, 0.015 mmol, 0.03 equiv.) were suspended in dry
Et2O (4 mL) and cooled to À158C. EtMgBr in Et2O (3M,
0.3 mL, 0.9 mmol, 1.8 equiv.) was added dropwise over
4 min. After complete conversion, the mixture was
quenched by addition of a saturated solution of NH4Cl
(2 mL) and stirred at room temperature during 24 h. The
aqueous layer was separated and extracted with Et2O (3”
3 mL). The combined organic fractions were dried over
Na2SO4, filtered and concentrated under vacuum. The resi-
due was purified by flash column chromatography. The de-
sired compound was obtained as a colourless oil with >99/
1 SN2’/SN2 and 82% ee; yield: 64 mg (62%. 1H NMR
(300 MHz, CDCl3): d=7.31–7.15 (m, 4H), 6.08 (dd, 1H, J=
18 Hz and J=9 Hz), 5.27 (d, 1H, J=9 Hz), 5.24 (d, 1H, J=
11 Hz), 4.62 (dd, 1H, J=48 Hz and J=9 Hz), 4.56 (dd, 1H,
J=48 Hz and J=9 Hz), 2.94 (sext, 1H, J=6.5 Hz), 1.52 (s,
3H), 1.31 (d, 6H, J=6.8 Hz); 13C NMR (75 MHz, CDCl3):
d=148.8, 143.2, 142.4 (d, J=3.9 Hz), 128.2, 125.2, 124.5,
124.2, 114.2, 90.2 (d, J=179.7 Hz), 46.1 (d, J=17.6 Hz), 34.2,
24, 22.1 (d, J=4.7 Hz); [a]: À20.8 (c 1.85, CHCl3); HR-MS
(EI+ mode): m/z=206.1469, calcd.: 206.1471.
(R)-4-Fluoro-3-(3-isopropylphenyl)-3-methylbutanal (43):
The Young valve Schlenk tube was vacuumed and backfilled
three times with nitrogen. The terminal olefin (50 mg,
0.24 mmol, 1 equiv.) was added into 0.5 mL of dry THF. The
stirring was continued for an additional 10 min and BH3
THF complex in THF (1M, 0.300 mL, 0.27 mmol, 1 equiv.)
was added via syringe. A balloon of argon was fixed and the
resulting yellow solution was stirred at room temperature
for an additional 18 h. NaOH (1M, 0.2 mL) and H2O2
(0.15 mL) were added and the mixture was stirred at 608C
for 1 h. The mixture was diluted with diethyl ether and
water, extracted and dried over sodium sulphate. The result-
ing yellow liquid was purified via silica gel chromatography
using a mixture of pentane/ether 9/1 as eluting solvent. The
product was recovered as a colourless liquid with a >99/
1 linear/branched ratio; yield: 65%; [a]: À30.1 (c 1.85,
CHCl3); HR-MS (ESI+ mode): m/z=224.1575, calcd.:
224.1576.
J=5.2 Hz); [a]: À37.7 (c 1.85, CHCl3); HR-MS (ESI+
mode): m/z=222.1420, calcd.: 222.1420.
(R)-1-(1,1-Difluoro-2-methylbut-3-en-2-yl)-4-methylben-
zene (44): In a flame-dried Schlenk tube, under an N2 at-
mosphere, the substrate (130 mg, 0.5 mmol, 1 equiv.) and
L17 (9 mg, 0.015 mmol, 0.03 equiv.) were suspended in dry
Et2O (4 mL) and cooled to À158C. EtMgBr in Et2O (3M,
0.3 mL, 0.9 mmol, 1.8 equiv.) was added dropwise over
4 min. After complete conversion, the mixture was
quenched by addition of a saturated solution of NH4Cl
(2 mL) and stirred at room temperature during 24 h. The
aqueous layer was separated and extracted with Et2O (3”
3 mL). The combined organic fractions were dried over
Na2SO4, filtered and concentrated under vacuum. The resi-
due was purified by flash column chromatography. The de-
sired compound was obtained as a colourless oil with >99/
1
SN2’/SN2 in 77% ee; yield: 57 mg (58%). 1H NMR
(300 MHz, CDCl3): d=7.34 (t, 2H, J=7.2 Hz), 7.25 (t, 2H,
J=8 Hz), 6.23 (dd, 1H, J=18 Hz and J=12 Hz), 5.94 (t,
1H, J=5.6.3 Hz), 5.40 (d, 1H, J=11 Hz), 5.22 (d, 1H, J=
17.7 Hz), 2.39 (s, 3H), 1.56 (s, 3H); 13C NMR (75 MHz,
CDCl3): d=139.2 (t, J=3.2 Hz), 137.4 (t, J=2.6 Hz), 136.8,
129.4, 128.9, 127.4, 121.9, 118.6, 116.2, 115.3, 48.7 (t, J=
18.8 Hz), 20.9, 19.1 (t, J=4.1 Hz); [a]: À23.8 (c 1.85,
CHCl3); HR-MS (EI+ mode): m/z=196.1065, calcd.:
196.1064.
(R)-5,5-Difluoro-4-methyl-4-p-tolylpentan-2-one (45): The
starting material (38 mg, 0.18 mmol, 1 equiv.) was dissolved
in 2 mL of dry dichloromethane. Dess–Martin periodinane
(130 mg, 0.31 mmol, 1.7 equiv.) was added. After stirring for
1 h at room temperature, TLC showed complete consump-
tion of the starting material. The reaction was quenched
with a 1/1 v/v aqueous solution of sodium thiosulphate and
sodium hydrogen carbonate. The aqueous phase was extract-
ed twice with dichloromethane. The combined organic
phases were dried over sodium sulphate and concentrated
under vacuum. The crude mixture was purified using a plug
of silica gel with pentane/ether 95/5 as eluting solvent. The
product was obtained as a colourless oil; yield: 27 mg
1
(75%). H NMR (300 MHz, CDCl3): d=9.59 (s, 1H), 7.33
(d, 2H, J=7.9 Hz), 7.25 (d, 2H, J=7.8 Hz), 5.81 (t, 1H, J=
56.5 Hz), 3.10 (dd, 1H, J=16.5 Hz and J=2.7 Hz), 2.81 (dd,
1H, J=16.3 Hz and J=2.5 Hz), 2.38 (s, 3H), 1.62 (s, 3H);
13C NMR (75 MHz, CDCl3): d=200.3, 137.5, 135.7, 129.5,
126.9, 118.7 (t, J=248.8 Hz), 47.9 (t, J=3.1 Hz), 43.9 (t, J=
19.1 Hz), 20.9, 19.1 (t, J=4.2 Hz); [a]: À30.1 (c 1.85,
CHCl3); HR-MS (ESI+ mode): m/z=212,1013, calcd.:
212.1013.
The starting material (27 mg, 0.13 mmol, 1 equiv.) was dis-
solved into 4 mL of dry ether in a conditioned two-necked
flask. The flask was cooled using an ice/water bath and
MeMgBr in ether (3M, 0.066 mL, 0.2 mmol, 1.5 equiv.) was
added dropwise. The ice/water bath was removed and the
mixture was stirred for 1 h at room temperature. The reac-
tion was quenched with saturated ammonium chloride solu-
tion. The water phase was extracted two times with ether.
The organic phases were pooled and dried over magnesium
sulphate and concentrated under vacuum. The crude materi-
al was engaged without further purification in the next step.
The starting material (30 mg, 0.133 mmol, 1 equiv.) was
dissolved in 2 mL of dry dichloromethane. Dess–Martin pe-
riodinane (96 mg, 0.22 mmol, 1, 7 equiv.) was added. After
stirring for 1 h at room temperature, TLC showed complete
consumption of the starting material. The reaction was
quenched with a 1/1 v/v aqueous solution of sodium thiosul-
phate and sodium hydrogen carbonate. The aqueous phase
was extracted twice with dichloromethane. The combined
organic phases were dried over sodium sulphate and concen-
trated under vacuum. The crude mixture was purified using
a plug of silica gel with pentane/ether 9/1 as eluting solvent.
The product was obtained as a colourless oil; yield: 28 mg
1
(80%). H NMR (500 MHz, CDCl3): d=9.60 (s, 1H), 7.33 (t,
1H, J=7.6 Hz), 7.20 (m, 3H), 4.63 (dd, 1H, J=115.1 Hz
and J=9.1 Hz), 4.51 (dd, 1H, J=45.8 Hz and J=9 Hz),
2.94–2.90 (m, 2H), 2.81 (dd, 1H, J=0.8 Hz and J=15.6 Hz),
1.55 (d, 3H, J=1.8 Hz), 1.23 (d, 6H, J=6.9 Hz); 13C NMR
(126 MHz, CDCl3): d=201.7, 149.4, 141.9 (d, J=4.2 Hz),
128.7, 125.1, 124.5, 123.6, 90.9 (d, J=178.8 Hz), 51.2 (d, J=
2.8 Hz), 41.5 (d, J=17.3 Hz), 34.3, 24 (d, J=3.4 Hz), 22.4 (d,
To
a conditioned two-necked flask oxalyl chloride
(0.035 mL, 0.4 mmol, 3 equiv.) was dissolved into 4 mL of
dry DCM and cooled to À788C using an acetone/dry ice
Adv. Synth. Catal. 2015, 357, 3171 – 3186
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3183

FULL PAPERS
David Grassi and Alexandre Alexakis
bath. DMSO was added (0.063 mL, 0.88 mmol, 6.5 equiv.)
and the mixture was stirred for 20 min. The alcohol dis-
solved in 1 mL of dry DCM was added and five minutes
after dry triethylamine (0.25 mL, 1.8 mmol, 13.3 equiv.) was
added. After 30 min at À788C the mixture was heated up to
room temperature and quenched with saturated ammonium
chloride solution. The water phase was extracted two times
with ether. The organic phases were pooled and dried over
magnesium sulphate and concentrated under vacuum. The
residue was purified using silica gel chromatography (90/10
pentane/ether mixture). The desired compound was recov-
ered as a colourless oil; yield: 23 mg (79% over 2 steps).
1H NMR (500 MHz, CDCl3): d=7.28 (d, 2H, J=6.2 Hz),
7.19 (d, 2H, J=7.8 Hz), 6.00 (t, 1H, J=56.9 Hz), 3.14 (d,
1H, J=17.9 Hz), 2.92 (d, 1H, J=16.8 Hz), 2.35 (s, 3H), 2.03
(s, 3H), 1.56 (s, 3H); 13C NMR (126 MHz, CDCl3): d=
205.7, 136.9, 136.8, 129.2, 126.6, 118.7 (t, J=247.7 Hz), 48.3
(t, J=3.5 Hz), 44.4 (t, J=18.8 Hz), 31.5, 20.9, 18.7 (t, J=
4.9 Hz); [a]: À33.4 (c 1.85, CHCl3); HR-MS (ESI+ mode):
m/z=226.1170, calcd.: 226.1169.
CDCl3): d=7.39 (d, 2H, J=8.3 Hz), 7.24 (d, 2H, J=8.3 Hz),
6.43 (t, 1H, J=55.6 Hz), 2.54 (d, 2H, J=7.1 Hz), 1.92 (m,
1H), 1.79 (s, 3H), 0.97 (d, 6H, J=6.5 Hz); 13C NMR
(75 MHz, CDCl3): d=177.7 (t, J=8.6 Hz), 142.1, 132.8 (t,
J=5.6 Hz), 130.1, 129.6, 129.2, 126.2, 116.3 (t, J=245.8 Hz),
54.3 (t, J=21.9 Hz), 44.9, 30.1, 22.4, 22.3, 14.1 (t, J=4.2 Hz);
19F NMR (376 MHz, CDCl3): d=37.2 (d, J=277 Hz), 31.2
(d, J=277 Hz); [a]: À36.4 (c 1.85, CHCl3); HR-MS (ESI+
mode): m/z=275.1276, calcd.: 256.1275.
Acknowledgements
This work is supported by the Swiss National Research Foun-
dation (grant No. 200020-126663).
References
(R)-1-(1,1-Difluoro-2-methylbut-3-en-2-yl)-4-isobutylben-
zene (46): In a flame-dried Schlenk tube under an N2 atmo-
sphere, the substrate (49 mg, 0.25 mmol, 1 equiv.) and L17
(4.5 mg, 0.0075 mmol, 0.03 equiv.) were suspended in dry
Et2O (2 mL) and cooled to À158C. EtMgBr in Et2O (3M,
150 mL, 0.45 mmol, 1.8 equiv) was added dropwise over
4 min. After complete conversion, the mixture was
quenched by addition of a saturated solution of NH4Cl
(2 mL). The aqueous layer was separated and extracted with
Et2O (3”3 mL). The combined organic fractions were dried
over Na2SO4, filtered and concentrated under vacuum. The
residue was purified by flash column chromatography. The
desired compound was obtained as a colourless oil with
>99/1 SN2’/SN2 in 77% ee; yield: 36 mg (60%). 1H NMR
(300 MHz, CDCl3): d=7.34 (t, 2H, J=7.2 Hz), 7.25 (t, 2H,
J=8 Hz), 6.23 (q, 1H, J=6.6 Hz), 5.94 (t, 1H, J=56.3 Hz),
5.40 (d, 1H, J=11 Hz), 5.22 (d, 1H, J=17.7 Hz), 2.61 (d,
2H, J=7.2 Hz), 2.03–1.96 (m, 1H), 1.56 (s, 3H), 1.03 (d,
6H, J=6.7 Hz); 13C NMR (75 MHz, CDCl3): d=139.2 (t,
J=3.2 Hz) 137.4 (t, J=2.6 Hz) 136.8, 129.4, 128.9, 127.4,
121.9, 118.6, 116.2, 115.3, 48.7 (t, J=18.8 Hz), 45, 30, 22,
19.1 (t, J=4.1 Hz); [a]: À25.8 (c 1.85, CHCl3); HR-MS (EI+
mode): m/z=238.1532, calcd.: 238.1533.
[1] a) S. Tominaga, Y. Oi, T. Kato, D. K. An, S. Okamoto,
Tetrahedron Lett. 2004, 45, 5585; b) S. Okamoto, S. To-
minaga, N. Saino, K. Kase, K. Shimoda, J. Organomet.
Chem. 2005, 690, 6001; c) A. O. Larsen, W. Leu, C. N.
Oberhuber, J. E. Campbell, A. H. Hoveyda, J. Am.
Chem. Soc. 2004, 126, 11130; d) J. J. Van Veldhuizen,
J. E. Campbell, R. E. Giudici, A. H. Hoveyda, J. Am.
Chem. Soc. 2005, 127, 6877; e) H. Seo, D. Hirsch-Weil,
K. A. Abboud, S. Hong, J. Org. Chem. 2008, 73, 1983;
f) K. B. Selim, K. Yamada, K. Tomioka, Chem.
Commun. 2008, 5140; g) D. Hirsch-Weil, D. R. Snead,
S. Inagaki, H. Seo, K. A. Abboud, S. Hong, Chem.
Commun. 2009, 18, 2475; h) K. B. Selim, Y. Matsumoto,
K. Yamada, K. Tomioka, Angew. Chem. 2009, 121,
8889; Angew. Chem. Int. Ed. 2009, 48, 8733; i) K. B.
Selim, H. Nakanishi, Y. Matsumoto, Y. Yamamoto, K.
Yamada, K. Tomioka, J. Org. Chem. 2011, 76, 1398;
j) T. Jennequin, J. Wencel-Delord, D. Rix, J. Dau-
bignard, C. CrØvisy, M. Mauduit, Synlett 2010, 1661.
[2] For reviews see: a) A. Alexakis, C. Malan, L. Lea, K.
Tissot-Croset, D. Polet, C. Falciola, Chimia 2006, 60,
124; b) C. A. Falciola, A. Alexakis, Eur. J. Org. Chem.
2008, 3765; c) A. Alexakis, J. E. Bäckvall, N. Krause, O.
Pàmies, M. DiØguez, Chem. Rev. 2008, 108, 2796;
d) S. R. Harutyunyan, T. den Hartog, K. Geurts, A. J.
Minnaard, B. L. Feringa, Chem. Rev. 2008, 108, 2824.
[3] a) K. Tissot-Croset, A. Alexakis, Org. Lett. 2002, 4,
4147; b) K. Tissot-Croset, A. Alexakis, Angew. Chem.
2004, 116, 2480; Angew. Chem. Int. Ed. 2004, 43, 2426;
c) A. W. van Zijl, F. Lopez, A. J. Minnaard, B. L. Ferin-
ga, J. Org. Chem. 2007, 72, 2558; d) C. Falciola, A.
Alexakis, Angew. Chem. 2007, 119, 2673; Angew.
Chem. Int. Ed. 2007, 46, 2619; e) H. Seo, D. Hirsch-
Weil, K. A. Abboud, S. Hong, J. Org. Chem. 2008, 73,
1983; f) K. B. Selim, K. Yamada, K. Tomioka, Chem.
Commun. 2008, 5140; g) A. W. Van Zijl, W. Szymanski,
F. Lopez, A. J. Minnaard, B. L. Feringa, J. Org. Chem.
2008, 73, 6994; h) C. Falciola, A. Alexakis, Chem. Eur.
J. 2008, 14, 10615; i) D. Hirsch-Weil, D. R. Snead, S. In-
agaki, H. Seo, K. A. Abboud, S. Hong, Chem.
Commun. 2009, 18, 2475; j) K. B. Selim, Y. Matsumoto,
K. Yamada, K. Tomioka, Angew. Chem. 2009, 121,
(R)-3,3-Difluoro-2-(4-isobutylphenyl)-2-methylpropanoic
acid (47): The starting terminal olefin (36 mg, 0.15 mmol,
1 equiv.) was dissolved in 1 mL of technical acetonitrile and
1 mL of carbon tetrachloride (the use of other solvents,
even chloroform, poisoned the catalyst and gave low conver-
sion of undesired aldehyde). The solution was vigorously
stirred while sodium metaperiodate (161 mg, 0.75 mmol,
5 equiv.) was added portion-wise. Ruthenium trichloride hy-
drate (5 mg, 0.0105 mmol, 0.07 equiv.) dissolved in 1 mL of
distilled water was added to the reaction mixture. The re-
sulting slurry was vigorously stirred at room temperature for
3 h (complete conversion of the starting material monitored
by TLC analysis). The reaction mixture was diluted with
water and ether. The water phase was extracted two times
with ether. The combined organic phases were dried over
sodium sulphate, concentrated under vacuum and purified
using silica gel chromatography (mixture of 1/1 pentane/
ether as eluent). The compound was recovered as a yellow
1
oil with 77% ee; yield: 20 mg (52%). H NMR (400 MHz,
3184
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Adv. Synth. Catal. 2015, 357, 3171 – 3186

FULL PAPERS
Improvements and Applications of the TM-Free Asymmetric Allylic Alkylation
8889; Angew. Chem. Int. Ed. 2009, 48, 8733; k) T. den
Hertog, B. Macia, A. Minnaard, B. L. Feringa, Adv.
Synth. Catal. 2010, 352, 999; l) F. Giacomina, D. Riat,
A. Alexakis, Org. Lett. 2010, 12, 1156; m) J. F. Teichert,
S. Zhang, A. W. Van Zijl, J. W. Slaa, A. J. Minnaard,
B. L. Feringa, Org. Lett. 2010, 12, 4658; n) A. W. Van
Zijl, S. P. Fletcher, A. J. Minnaard, B. L. Feringa, Org.
Lett. 2011, 13, 948; o) H. Li, A. Alexakis, Angew.
Chem. 2012, 124, 1079; Angew. Chem. Int. Ed. 2012, 51,
1055; p) M. Fananas Mastral, B. ter Horst, A. J. Min-
aard, B. L. Feringa, Chem. Commun. 2011, 47, 5843;
q) M. Giannerini, M. Fananas Mastral, B. L. Feringa, J.
Am. Chem. Soc. 2012, 134, 4108; r) M. Magrez, Y.
Le Guen, O. Basle, C. Crevisy, M. Mauduit, Chem. Eur.
J. 2013, 19, 1199.
Hamilton, D. Sarlah, E. M. Carreira, J. Am. Chem. Soc.
2013, 135, 994.
[8] a) A. Alexakis, in: Transition Metal Catalyzed Enantio-
selective Allylic Substitution in Organic Synthesis, (Ed.:
U. Kazmaier), Topics in Organometallic Chemistry, Vol.
38, Springer, Berlin, Heidelberg, 2012; b) O. BaslØ, A.
Dennicourt-Nowicki, C. CrØvisy, M. Mauduit, in:
Copper-Catalyzed Asymmetric Synthesis. (Eds.: A.
Alexakis, N. Krause, S. Woodward), Wiley-VCH, Wein-
heim, 2014, p 85.
[9] Y. Lee, A. H. Hoveyda, J. Am. Chem. Soc. 2006, 128,
15604.
[10] G. L. Beutner, S. E. Denmark, Angew. Chem. 2008,
120, 1584; Angew. Chem. Int. Ed. 2008, 47, 1560.
[11] Y. Lee, B. Li, A. H. Hoveyda, J. Am. Chem. Soc. 2009,
131, 11625.
[12] a) O. Jackowski, A. Alexakis, Angew. Chem. 2010, 122,
3418; Angew. Chem. Int. Ed. 2010, 49, 3346; b) D.
Grassi, C. Dolka, O. Jackowski, Chem. Eur. J. 2013, 19,
1466.
[13] a) H. Ishikawa, Y. Shibata, Y. Suhura, S. Okamoto, Tet-
rahedron Lett. 2010, 51, 5704; b) R. Nomura, Y. Tsu-
chiya, H. Ishikawa, S. Okamoto, Tetrahedron Lett.
2013, 54, 1360; c) C. M. Latham, A. J. Blake, W. Lewis,
M. Lawrence, S. Woodward, Eur. J. Org. Chem. 2012,
699.
[14] a) M. Malhau, B. List, Angew. Chem. 2013, 125, 540;
Angew. Chem. Int. Ed. 2013, 52, 518; b) K. Brak, E. N.
Jacobsen, Angew. Chem. 2013, 125, 558; Angew. Chem.
Int. Ed. 2013, 52, 534; c) Y. Xi, X. Shi, Chem.
Commun. 2013, 49, 8583.
[15] a) S. Bräse, S. Hofener, Angew. Chem. 2005, 117, 8091;
Angew. Chem. Int. Ed. 2005, 44, 7879; b) K. S. Lee, A.
Zhugralin, A. H. Hoveyda, J. Am. Chem. Soc. 2009,
131, 7253; c) J. OꢁBrien, A. H. Hoveyda, J. Am. Chem.
Soc. 2011, 133, 7712; d) H. Wu, S. Radomkit, J.
OꢁBrien, A. H. Hoveyda, J. Am. Chem. Soc. 2012, 134,
8277.
[16] a) D. Grassi, A. Alexakis, Org. Lett. 2012, 14, 1568;
b) D. Grassi, H. Li, A. Alexakis, Chem. Commun. 2012,
48, 11404; c) D. Grassi, A. Alexakis, Angew. Chem.
2013, 125, 13887; Angew. Chem. Int. Ed. 2013, 52,
13642; d) D. Grassi, A. Alexakis, Chem. Sci. 2014, 5,
3803.
[17] a) C. Sparr, E. M. Tanzer, J. Bachmann, R. Gilmour,
Synthesis 2010, 1394; b) H. U. Vora, T. Rovis, J. Am.
Chem. Soc. 2010, 132, 2860; c) A. Quintard, J. B. Lan-
glois, D. Emery, J. Mareda, A. Alexakis, Chem. Eur. J.
2011, 17, 13433; d) X. Zhao, D. A. Di Rocco, T. Rovis,
J. Am. Chem. Soc. 2011, 133, 12466; e) D. A. Di Rocco,
E. L. Noey, K. N. Houk, T. Rovis, Angew. Chem. 2012,
124, 2441; Angew. Chem. Int. Ed. 2012, 51, 2391.
[18] a) K. Tissot-Croset, PhD thesis, University of Geneva,
2005; b) see ref.[3b]
[4] a) P. J. Goldsmith, S. J. Teat, S. Woodward, Angew.
Chem. 2005, 117, 2275; Angew. Chem. Int. Ed. 2005, 44,
2235; b) D. G. Gillingham, A. H. Hoveyda, Angew.
Chem. 2007, 119, 3934; Angew. Chem. Int. Ed. 2007, 46,
3860; c) Y. Lee, K. Akiyama, D. G. Gillingham, M. K.
Brown, A. H. Hoveyda, J. Am. Chem. Soc. 2008, 130,
446; d) J. A. Dabrowski, F. Gao, A. H. Hoveyda, J. Am.
Chem. Soc. 2011, 133, 4788; e) F. Gao, K. P. McGrath,
Y. Lee, A. H. Hoveyda, J. Am. Chem. Soc. 2010, 132,
14315; f) F. Gao, Y. Lee, K. Mandai, A. H. Hoveyda,
Angew. Chem. 2010, 122, 8548; Angew. Chem. Int. Ed.
2010, 49, 8370.
[5] a) F. Dubner, P. Knochel, Angew. Chem. 1999, 111, 391;
Angew. Chem. Int. Ed. 1999, 38, 379; b) F. Dubner, P.
Knochel, Tetrahedron Lett. 2000, 41, 9233; c) H. Malda,
A. W. Van Zijl, L. A. Arnold, B. L. Feringa, Org. Lett.
2001, 3, 1169; d) A. W. Van Zijl, L. A. Arnold, A. J.
Minaard, B. L. Feringa, Adv. Synth. Catal. 2004, 346,
413; e) W. J. Shi, L. X. Wang, Y. Fu, S. F. Zhu, Q. L.
Zhou, Tetrahedron: Asymmetry 2003, 14, 3867; f) P. J.
Goldsmith, S. J. Teat, S. Woodward, Angew. Chem.
2005, 117, 2275; Angew. Chem. Int. Ed. 2005, 44, 2235;
g) U. Piarulli, P. Daubos, C. Claverie, M. Roux, C. Gen-
nari, Angew. Chem. 2003, 115, 244; Angew. Chem. Int.
Ed. 2003, 42, 234; h) U. Piarulli, C. Claverie, P. Daubos,
C. Gennari, A. J. Minaard, B. L. Feringa, Org. Lett.
2003, 5, 4493.
[6] a) M. Perez, M. Fananas Mastral, P. H. Bos, A. Ru-
dolph, S. R. Harutyunyan, B. L. Feringa, Nat. Chem.
2011, 3, 397; b) M. Perez, M. Fananas Mastral, V. Horr-
nillos, A. Rudolph, P. H. Bos, S. R. Harutyunyan, B. L.
Feringa, Chem. Eur. J. 2012, 18, 1180; c) P. H. Bos, A.
Rudolph, M. Perez, M. Fananas Mastral, S. R. Haru-
tyunyan, B. L. Feringa, Chem. Commun. 2012, 48, 1748;
d) M. Fananas Mastral, M. Perez, P. H. Bos, A. Ru-
dolph, S. R. Harutyunyan, B. L. Feringa, Angew. Chem.
2012, 124, 1958; Angew. Chem. Int. Ed. 2012, 51, 1922.
[7] a) R. Shintani, K. Takatsu, M. Takeda, T. Hayashi,
Angew. Chem. 2011, 123, 8815; Angew. Chem. Int. Ed.
2011, 50, 8656; b) F. Gao, J. L. Carr, A. H. Hoveyda,
Angew. Chem. 2012, 124, 6717; Angew. Chem. Int. Ed.
2012, 51, 6613; c) P. Zhang, L. A. Brozek, J. P. Morken,
J. Am. Chem. Soc. 2010, 132, 10686; d) P. Zhang, H. Le,
R. E. Kyne, J. P. Morken, J. Am. Chem. Soc. 2011, 133,
9716; e) L. A. Brozek, M. J. Ardolino, J. P. Morken, J.
Am. Chem. Soc. 2011, 133, 16778; f) B. Jung, A. H.
Hoveyda, J. Am. Chem. Soc. 2012, 134, 1990; g) J. Y.
[19] C. Borner, J. Gimeno, S. Gladiali, P. J. Goldsmith, D.
Ramazotti, S. Woodward, Chem. Commun. 2000, 2433.
[20] D. Gillingham, A. H. Hoveyda, Angew. Chem. 2007,
119, 3934; Angew. Chem. Int. Ed. 2007, 46, 3860.
[21] D. Müller, C. Hawner, M. Tissot, L. Palais, A. Alexakis,
Synlett 2010, 1694.
[22] K. Takai, K. Nitta, K. Utimoto, J. Am. Chem. Soc.
1986, 108, 7408.
Adv. Synth. Catal. 2015, 357, 3171 – 3186
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
3185

FULL PAPERS
David Grassi and Alexandre Alexakis
[23] G. Stork, K. Zhao, Tetrahedron Lett. 1989, 2173.
[24] See refs.[3a,b,g]
[25] a) S. Goncalves-Contal, L. Gremaud, A. Alexakis,
Angew. Chem. Int. Ed. 2013, 52, 12701; b) L. Gremaud,
A. Alexakis, Angew. Chem. 2012, 124, 818; Angew.
Chem. Int. Ed. 2012, 51, 794.
[28] a) A. Zhang, T. V. Rajanbabu, Org. Lett. 2004, 6, 3159;
b) C. Fuganti, S. Serra, A. Dulio, J. Chem. Soc. Perkin
Trans. 1 1999, 279.
[29] a) Organofluorine Compounds: Chemistry and Applica-
tions, (Ed.: T. Hiyama), Springer, New York, 2000;
b) P. Kirsch, Modern Fluoroorganic Chemistry: Synthe-
sis Reactivity, Applications, Wiley-VCH, Weinheim,
2004; c) R. D. Chambers, Fluorine in Organic Chemis-
try, Blackwell, Oxford, 2004; d) K. Uneyama, Organo-
fluorine Chemistry, Blackwell, New Dehli, 2006;
e) A. M. Thayer, Chem. Eng. News 2006, 84, 15; f) K.
Muller, C. Faeh, F. Diedrich, Science 2007, 317, 1881.
[26] Unpublished results. For DYKAT in AAA see: J. B.
Langlois, A. Alexakis, Angew. Chem. 2011, 123, 1917;
Angew. Chem. Int. Ed. 2011, 50, 1877.
[27] a) See ref.[3o]; b) Y. Huang, M. Fananas Mastral, A. J.
Minaard, B. L. Feringa, Chem. Commun. 2013, 49,
3309; c) see ref.[3s]
3186
asc.wiley-vch.de
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2015, 357, 3171 – 3186