Al(OTf)3: An efficient lewis acid additive for domino addition-elimination of Grignard reagents to activated ketones

Article abstract of DOI:10.1055/s-0035-1561401

It has been demonstrated that aluminium triflate in either stoichiometric or catalytic quantities facilitates the addition-elimination of Grignard reagents to electron-rich ketones, such as methoxy substituted acetophenones, propiophenone and chromanone in a one-pot process, and that it has an enhancing effect on the addition of these reagents to the ketones. It has also been found that the reactions are highly stereoselective towards one regioisomer of the alkene in the case of oxygenated aryl-alkyl substituted substrates, but not when the elimination originates from a double benzylic alcohol intermediate.

Full text of DOI:10.1055/s-0035-1561401

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© Georg Thieme Verlag Stuttgart · New York
2016, 27, A–F
letter
A
T. Pieterse et al.
Letter
Synlett
Al(OTf)3: An Efficient Lewis Acid Additive for Domino Addition–
Elimination of Grignard Reagents to Activated Ketones
Tanya Pieterse
Melanie Visser
R2
R1
R4
Charlene Marais
R2
R1
Barend C. B. Bezuidenhoudt*
CHR3
CH2R3
Department of Chemistry, University of the Free State,
PO Box 339, Bloemfontein, 9300, South Africa
bezuidbc@ufs.ac.za
or
O
R1 = H or OMe
R2 = H, OMe or Me
R3 = H or Me
Al(OTf)3, –30 °C
R2
R1(H)
CHR5
R4MgX or R5CH2MgX
–30 °C to r.t.
R3
up to 97% yield
Received: 11.11.2015
Accepted after revision: 05.02.2016
Published online: 04.03.2016
example, was subjected to olefination with EDA over a
methyltrioxorhenium (MTO) catalyst system, reasonable
yields (ca. 70%) could only be obtained after 50 hours in the
presence of benzoic acid as co-catalyst.5g Under the same
conditions, 4-methoxyacetophenone gave a yield of only
30% after prolonged reaction time (132 h). In an effort to in-
crease the electrophilicity of the carbonyl carbon in ke-
tones, Lewis acids such as SbCl5 and Et3OBF4 were also test-
ed as co-catalysts, but unwanted side reactions meant that
the olefin yield remained below 10%. These results showed
that strong Lewis acids do not activate ketones towards ole-
fination under these conditions.5g
DOI: 10.1055/s-0035-1561401; Art ID: st-2015-d0886-l
Abstract It has been demonstrated that aluminium triflate in either
stoichiometric or catalytic quantities facilitates the addition–elimina-
tion of Grignard reagents to electron-rich ketones, such as methoxy
substituted acetophenones, propiophenone and chromanone in a one-
pot process, and that it has an enhancing effect on the addition of
these reagents to the ketones. It has also been found that the reactions
are highly stereoselective towards one regioisomer of the alkene in the
case of oxygenated aryl-alkyl substituted substrates, but not when the
elimination originates from a double benzylic alcohol intermediate.
Key words aluminium triflate, Grignard reagent, ketone, olefin, addi-
tion–dehydration, one-pot reaction
Reports on the transformation of aldehydes and ketones
into olefins utilizing Grignard reagents are limited to the
papers by the groups of Luh12 and Zhang.13 Luh and co-
workers utilized Grignard reagents and a nickel catalyst to
convert dithioacetals, prepared from the corresponding
carbonyl compounds, into alkenes, whereas Zhang and co-
workers were successful in reacting the aldehyde or ketone
directly with the Grignard reagent in the presence of dieth-
yl phosphite for generating the corresponding olefin
(Scheme 1). Although these methodologies are suitable to
prepare the corresponding alkenes in good to excellent
yields at room temperature from both aldehydes and ke-
tones, two equivalents of the Grignard reagent and stoi-
chiometric amounts of phosphite are needed.
Whereas strong Lewis acids did not lead to appreciable
amounts of olefinic products being formed when ketones
were subjected to MTO-catalysed reactions,5g it is well
known that cuprate additions to carbonyl compounds are,
in fact, enhanced by the addition of Lewis acids.14 CeCl3, for
example, has been used to improve the reactivity of various
carbonyl substrates toward Grignard addition reactions and
increased yields of the alcohol products.15
The olefination of carbonyl compounds represents an
important transformation in the preparation of many or-
ganic molecules. The quest for alkenes of various substitu-
tion patterns have furthermore been intensified by the de-
velopment of metathesis-based methodologies for the
preparation of a variety of organic compounds. While clas-
sical methods for the transformation of carbonyl com-
pounds into alkenes, such as the Wittig reaction and its
variants,1 Julia olefination,2 and Peterson olefination,3 do
exist, many of these protocols are hampered by the inher-
ent disadvantages of stoichiometric quantities of reagents
and strong basic reaction conditions being required, as well
as by the stepwise generation of the ylide or other interme-
diate. Although catalytic alternatives to the Wittig reaction
based on several metals (Mo,4 Re,5 Fe,6 Ru,7 Co,8 Rh,9 Cu,10
and Ir11) and ligands have been reported, these methods re-
quire the availability of diazocompounds, which, unlike
ethyl diazoacetate (EDA), are not always commercially avail-
able and have to be prepared. Furthermore, many of these
protocols are only high yielding when applied to aldehydes
and electron-deficient ketones. When cyclohexanone, for
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–F

B
T. Pieterse et al.
Letter
Synlett
CH2Cl2 with one equivalent aluminium triflate and allowing
the reaction mixture to warm to room temperature, did not
lead to the formation of any addition product (Table 1, entry
1).
R2
MeMgI
S
S
(a)
(b)
R1
NiCl2(PPh3)2
R1 R2
58–94% yield
R3
The use of Al(OTf)3 at –30 °C for 30 minutes, followed by
the addition of PhMgBr (2.0 equiv) in diethyl ether, and the
same reaction without Al(OTf)3, led to the expected tertiary
alcohol, 1,1-diphenylethanol, in 44% yield.17 When the sub-
strate was changed to 4-methoxyacetophenone (2), we
were delighted to observe that the desired product, α-(4-
methoxyphenyl)styrene (12), was formed in 71% yield (Ta-
ble 1, entry 2). To confirm that the product was indeed
formed during the reaction and not the work-up process,
and that Al(OTf)3 played an essential role during the reac-
tion leading to the product, the reaction with 2 was repeat-
ed at room temperature without the triflate. Under these
conditions, however, no alcohol or olefinic products were
observed (Table 1, entry 2). During the optimization of the
reaction conditions, the reaction of 2 with Al(OTf)3 (1 equiv)
was also repeated with only one equivalent of PhMgBr, but
although olefin 12 formation was still observed, the yield
dropped to 40%. Two equivalents of Grignard reagent was
therefore used throughout the rest of the investigation.
O
R3CH2MgX
(EtO)2P(O)H
R1
R2
R1
R2
R2MgX
O
R2
(EtO)2P(O)H
R1
R1
43–95% yield
Scheme 1 Methodologies of (a) Luh and co-workers12 and (b) Zhang
and co-workers13 to convert aldehydes, ketones or the protected ver-
sions thereof into olefins
In a continuation of our work on determining the scope
and limitations of aluminium triflate as Lewis acid reagent
and catalyst in synthesis,16 we decided to evaluate the ef-
fect, if any of aluminium triflate on Grignard reactions.
Treatment of a solution of acetophenone (1) in anhydrous
Table 1 Reaction of Ketones with Grignard Reagents in the Presence of Al(OTf)3 in CH2Cl2 at –30 °C to Room Temperaturea
Entry
Substrate
Grignard reagent
Product
Yield (%)
c
Al(OTf)3 (1 equiv)
No Al(OTf)3
44d,27
Ph
Ph
1
2
PhMgBr
PhMgBr
0
Ph
O
O
1
2
1120a
C6H4-4-OMe
C6H4-4-OMe
C6H4-4-OMe
C6H4-4-OMe
71 (72)b
0
0
Ph
1222
3
4
EtMgBr
BnMgBr
53
67
O
O
2
2
1320b
C6H4-4-OMe
C6H4-4-OMe
12
Ph
1421c
C6H3-2,4-(OMe)2
C6H3-2,4-(OMe)2
C6H3-2,4-(OMe)2
C6H3-2,4-(OMe)2
Ph
5
6
PhMgBr
EtMgBr
62 (45)b
0
0
O
O
3
4
1523
46
16
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–F

C
T. Pieterse et al.
Letter
Synlett
Table 1 (continued)
Entry
Substrate
Grignard reagent
Product
Yield (%)
c
Al(OTf)3 (1 equiv)
No Al(OTf)3
C6H3-2,4-Me2
C6H3-2,4-Me2
Ph
7
8
PhMgBr
PhMgBr
PhMgBr
PhMgBr
24
0
O
O
4
5
6
7
1724
C6H4-4-Cl
–
0
0e,28
22d,27
85d,29
Ph
O
Ph
9
0
Ph
18
C6H4-4-OMe
C6H4-4-OMe
10
97 (67)b
O
Ph
1921a
11
PhMgBr
–
0
0
O
O
8
9
O
12
13
PhMgBr
55 (39)b
0
O
Ph
2025
Ph
Ph
Ph
Ph
4-MeOC6H4MgBr
29
21
O
C6H4-4-OMe
O
2126
10
a Reaction conditions: A solution of ketone (200 mg) in anhydrous CH2Cl2 (2–5 mL) was cooled to –30 °C. Al(OTf)3 (1.0 equiv) was added and the reaction mix-
ture stirred for 30 min. Grignard reagent (2.0 equiv) in Et2O was added and the reaction allowed to warm up to r.t. with stirring for 24 h.
b Reaction with catalytic Al(OTf)3 (10 mol%).
c Ketone [200 mg in anhydrous CH2Cl2 (5–10 mL)], Grignard reagent in Et2O (2.0 equiv), r.t.
d Tertiary alcohol was obtained as product.
e Repeating the reaction in THF led to the tertiary alcohol [1-(4-chlorophenyl)-1-phenylethan-1-ol] being obtained in 51% yield.
Subsequently, the success of this one-pot, two-step pro-
cess for the formation of the olefin from acetophenone 2
prompted an evaluation of the applicability of this method-
ology to other acetophenones and carbonyl compounds
with different Grignard reagents. Subjecting 4-methoxy-ac-
etophenone (2) to ethyl and benzyl Grignard reagents un-
der the reaction conditions described above led to the for-
mation of the internal olefinic products 13 and 14 in 53 and
67% yields, respectively (Table 1, entries 3 and 4). While a
mixture of the cis- and trans-products was expected from
these reactions, only the E-isomers 13 and 14 were, in fact,
obtained, as was confirmed by GC and NMR analysis.18
Eliminating the Lewis acid from the reaction mixture in the
case of the ethyl Grignard gave no addition product at all,
whereas 12% of (E)-4-methoxy-α-methyl-β-phenylstyrene
(14) was obtained with the benzyl Grignard reaction in this
instance.19 The reactions of PhMgBr with 2,4-dimethoxyac-
etophenone (3) and 2,4-dimethylacetophenone (4) led to
the olefinic products 15 and 17 in 62 and 24% yield, respec-
tively (Table 1, entries 5 and 7). These yields, taken in con-
junction with the fact that acetophenone (1) and 4-chloro-
acetophenone (5) did not give any olefinic product at all
(Table 1, entries 1, 5, 7 and 8), serves as an indication that
an electron-rich aromatic ring is required for Grignard ad-
dition and subsequent alkene formation under these reac-
tion conditions. Although the aluminium triflate is used in
stoichiometric quantities, the fact that only the reactions of
oxygenated ketones are accelerated points towards some
complexation between the Lewis acid and the oxygen at-
tached to the aromatic ring. The reaction of 2,4-dimethoxy-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–F

D
T. Pieterse et al.
Letter
Synlett
acetophenone (3) with EtMgBr led to the formation of the
alkene product in 46% yield, but only the Z-isomer was ob-
tained in this case (Table 1, entry 6).
Finally, it was also shown that the inclusion of alumini-
um triflate has a slight enhancing effect on the 1,4-addition
of 4-MeOC6H9MgBr to the α,β-unsaturated substrate 10 un-
der the same reaction conditions (Table 1, entry 13). Inter-
estingly, no 1,2-addition product was found in either of the
reactions either with or without triflate.
Although Al(OTf)3 was used in stoichiometric amounts
in all of the reactions mentioned above, it was also deter-
mined that it could be used in catalytic quantities. In this
regard, repeating the reactions of 4-methoxyacetophenone
(2), 2,4-dimethoxy-acetophenone (3), 4-methoxypropio-
phenone (7) and chromanone (9) with PhMgBr in the pres-
ence of catalytic quantities (10 mol%) of Al(OTf)3 led to the
desired 1,1-disubstituted styrenes, 12, 15, 19, and 4-
phenylchromene (20) being formed in 72, 45, 67 and 39%
yield, respectively (Table 1, entries 2, 5, 10 and 12).
In conclusion, it is evident from the results presented in
this communication that aluminium triflate has an enhanc-
ing effect on the addition of Grignard reagents to electron-
rich ketones and that this reagent also facilitates the forma-
tion of the olefinic product from the initially formed tertia-
ry alkoxide in a one-pot process. It is also demonstrated
that the reaction is highly stereoselective towards one re-
gioisomer of the alkene in the case of oxygenated aryl-alkyl
substituted substrates, but not when the elimination origi-
nates from a double benzylic alcohol intermediate. Finally,
it has been found that aluminium triflate may be utilised in
less than molar quantities, rendering this methodology the
first Grignard based catalytic olefination process.
The formation of only the E-isomers during the reaction
of 4-methoxyacetophenone (2) with the ethyl and benzyl
Grignard reagents can be explained in terms of an alumini-
um triflate assisted E2-type elimination of the oxygen func-
tionality wherein transition states A and B are possible
during the elimination process (Figure 1). If it could be as-
sumed that complexation of the bulky aluminium triflate to
the Mg-alkoxide function would lead to it being in a per-
pendicular orientation towards the aromatic ring, steric in-
teraction between the methyl/phenyl entity and the ortho-
hydrogen atoms on the ring would lead to elimination from
the gauche conformation A rather than the anti-conformer
B. In the case of the 2,4-dimethoxy substrate 3, complex-
ation of the triflate to both the aromatic methoxy oxygen
and the magnesium alkoxide C would keep the aromatic
ring, benzylic carbon and alkoxide in the same plain, allow-
ing free rotation for the ethyl group and subsequent pre-
ferred antiperiplanar elimination of the oxygen function
from C. It may also be that the observed selectivity is a con-
sequence of the reaction taking place under thermodynam-
ic control.
(TfO)3Al
H
MgBr
R
(TfO)3Al
MgBr
H
O
H
O
H
R
Steric repulsion
Me
Me
MeO
MeO
A R = Me, Ph
B R = Me, Ph
Acknowledgment
(TfO)3Al
MgBr
H
Funding from SASOL Technology limited is gratefully acknowledged.
Me
O
O
H
Me
Me
Supporting Information
MeO
Supporting information for this article is available online at
C
http://dx.doi.org/10.1055/s-0035-1561401.
S
u
p
p
o
nrtIo
g
f
rmoaitn
S
u
p
p
ortiInfogrmoaitn
Figure 1 Possible TS conformations
References and Notes
The reaction of PhMgBr with propiophenone (6), 4-me-
thoxypropiophenone (7), α-tetralone (8), and chromanone
(9) confirmed activation of the aromatic ring to be a prereq-
uisite for the olefination reaction, with the formation of
only the 1,1-diphenyl-1-propene (19) and chromene 20
products in 97 and 55% yields, respectively (Table 1, entries
9, 10, 11, and 12). In this instance, an approximately 1:1
mixture of E- and Z-isomers was observed as product in the
propiophenone reaction, which is probably explicable in
terms of an E1-type elimination of the OH function from
the double benzylic position in the tertiary alcohol inter-
mediate.
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(17) General Procedure: A solution of carbonyl compound in anhy-
drous CH2Cl2 (2–5 mL) was cooled to –30 °C. Al(OTf)3 (1.0 equiv)
was added and the reaction mixture was stirred at –30 °C for
30 min under Ar. Grignard reagent (3.0 M in Et2O, 2.0 equiv) was
subsequently added and the reaction mixture was allowed to
warm to r.t. while being stirred. Once the reaction was deemed
complete (TLC analysis), the reaction mixture was neutralised
with aq NH4Cl and the product was extracted into EtOAc (3 × 50
mL). The organic layer was dried over Na2SO4, filtered and evap-
orated under reduced pressure. Purification by prep. TLC gave
the corresponding alkenes or alcohols (Table 1).
(Z)-2,4-Dimethoxy-α,β-dimethylstyrene (16): The general
procedure with 2′,4′-dimethoxyacetophenone (3; 0.217 g, 1.22
mmol) and Al(OTf)3 (0.531 g, 1.12 mmol, 0.9 equiv) in CH2Cl2 (5
mL) and ethylmagnesium bromide (3 M, 0.7 mL, 1.7 equiv)
yielded 16 (0.107 g, 46%) as a colourless oil. Rf = 0.61 (hexane–
acetone, 8:2). 1H NMR (600 MHz, CDCl3): δ = 7.06 (d, J = 8.2 Hz,
1 H, H-6), 6.48 (d, J = 2.4 Hz, 1 H, H-3), 6.46 (dd, J = 8.2, 2.4 Hz,
1 H, H-5), 5.55 (qq, J = 6.7, 1.3 Hz, 1 H, H-β), 3.83 (s, 6 H, OMe),
2.00–1.98 (m, 3 H, α-CH3), 1.80–1.78 (m, 3 H, β-CH3). 13C NMR
(151 MHz, CDCl3): δ = 159.8 (C-2/4), 157.6 (C-2/4), 135.3 (C-
1/α), 130.0 (C-6), 128.1 (C-1/α), 123.5 (C-β), 103.9 (C-5), 98.7
(C-3), 55.4 (-OMe), 17.0 (α-CH3), 14.0 (β-CH3). MS (EI, 70 eV):
m/z (%) = 192.1 (100) [M]+. HRMS (AP+): m/z = 193.1233 [MH]+.
(18) Chemical shift of the residual β-proton in the E-isomer of aryl
substituted 2-butenes of δ = 5.78 and 5.90 ppm vs. δ = 5.52–
5.58 ppm for the Z-isomer.20 Chemical shift of the residual β-
proton in the E-isomer of methyl substituted stilbenes was δ =
6.78 and 6.81 vs. δ ≈ 6.32 ppm for the Z-isomer.21
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