Fe(BF 4) 2 -Catalyzed Inter- and Intramolecular Carbonyl-Ene Reaction of Trifluoropyruvate

Article abstract of DOI:10.1055/s-0036-1591858

Inter- And intramolecular carbonyl-ene reactions have been developed using 5 mol% Fe(BF ₄) ₂ as catalyst, affording homoallylic alcohols in 36-87% isolated yields. This catalyst, prepared from FeCl ₂ and AgBF ₄,

Full text of DOI:10.1055/s-0036-1591858

SYNLETT
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© Georg Thieme Verlag Stuttgart · New York
2017, 28, A–E
letter
A
en
D. Meng, T. Ollevier
Letter
Synlett
Fe(BF4)2-Catalyzed Inter- and Intramolecular Carbonyl-Ene
Reaction of Trifluoropyruvate
Di Meng
5 mol% FeCl2
10 mol% AgBF4
O
HO CF3
OEt
Thierry Ollevier*
0
0
0
0
0-
0
0
2
6-
0
8
4
7-
9
5
4
OEt
+
R
F3C
R
CH2Cl2, 4 Å MS, rt, 48 h
O
O
Département de Chimie, Université Laval, 1045 Avenue de la Médecine,
Québec (Québec) G1V 0A6, Canada
Thierry.Ollevier@chm.ulaval.ca
R = aryl, alkyl
36–87%
Received: 10.11.2017
Accepted after revision: 14.11.2017
Published online: 13.12.2017
iron, which is inexpensive, ubiquitous, and relatively less
toxic in comparison with other metals, represents a major
advantage.18
DOI: 10.1055/s-0036-1591858; Art ID: st-2017-d0689-l
Following our studies on iron catalysis, such as in the
iron-catalyzed enantioselective Mukaiyama aldol reaction,
meso-epoxide opening, and aromatic sulfoxide oxidation
reactions,19 this article describes the study of the iron-cata-
lyzed carbonyl-ene reaction of ethyl 3,3,3-trifluoropyruvate
with various alkenes.
Abstract Inter- and intramolecular carbonyl-ene reactions have been
developed using 5 mol% Fe(BF4)2 as catalyst, affording homoallylic alco-
hols in 36–87% isolated yields. This catalyst, prepared from FeCl2 and
AgBF4, is the first FeII Lewis acid reported for the carbonyl-ene reaction
using ethyl trifluoropyruvate. The method was successfully applied to
the reaction of various 1,1-disubstituted alkenes with ethyl trifluoropy-
ruvate and to the cyclization of citronellal.
Table 1 Screening of Iron Salts in Carbonyl-Ene Reaction
Key words ene reaction, Lewis acids, iron, trifluoropyruvate, cycliza-
tion
HO CF3
O
5 mol% FeXn
OEt
OEt
+
F3C
CH2Cl2, rt, 48 h
O
O
The carbonyl-ene reaction is a very powerful C–C bond-
forming transformation.1a It readily converts available
alkenes and carbonyl compounds into homoallylic alcohols
via a synthetically economical route in an intra- or inter-
molecular fashion.1b,c The scope of the reaction has been
studied extensively in terms of the aldehyde scope used in
the carbonyl-ene reaction, and a variety of metal salts has
been investigated including Lewis acid catalysts, such as
AlMe2Cl,2 TiCl4,3 SnCl4,4 Sc(OTf)3,5 and chiral catalysts, such
as BINOL-Ti,6 BINAP-Pd/Pt,7 BOX-Cu,8 DPPF-Ni,9 and Salen-
Co,10 have been disclosed in enantioselective versions. To
the best of our knowledge, there are only two precedents of
iron salts used in the carbonyl-ene reaction, but they have
been employed in intramolecular cases and in a stoichio-
metric fashion.11 In the past decade, research has focused
on using trifluoropyruvates as activated ketones, since ke-
tones were usually more difficult to react as enophiles,12a
allowing the formation of chiral alcohols possessing tetra-
substituted stereogenic centers containing a trifluorometh-
yl group, which are important building blocks for pharma-
ceuticals and agrochemicals.12b Lewis acids, such as Ca,13
Pd,14 In,15 Ru16 complexes, and organocatalysts17 have
proved to be efficient catalysts in the trifluoropyruvate-ene
reaction. However, there is a need to develop a catalytic
iron-mediated carbonyl-ene reaction. From a green chemis-
try perspective, developing new synthetic methods using
1
2
3a
Entry
1/2
2:1
FeXn
Yield (%)a
1
2
FeCl3
–
2:1
Fe(OTf)3
–
3
2:1
FeCl2
58
4
2:1
Fe(OAc)2
44
5
2:1
Fe(NTf)2
63
6
2:1
Fe(ClO4)2·6H2O
Fe(BF4)2·6H2O
Fe(OTf)2
53b
75b
62 (66)c
68
7
2:1
8
2:1
9
4:1
Fe(OTf)2
10
11
12
13
14
15
1:1.5
1:2
Fe(OTf)2
72
Fe(OTf)2
73
1:1.2
1:1.5
1:1.5
1:1.5
Fe(OTf)2
54
Fe(BF4)2·6H2O
FeCl2 + 2 AgBF4
FeCl2 + 2 AgBF4
75b
83b
87b,d
a Isolated yield.
b With 4 Å molecular sieves (for entries 7 and 13, the yields were the same
without 4 Å MS).
c 10 mol% iron salt, 60 h.
d Using filtration on cotton and Celite.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

B
D. Meng, T. Ollevier
Letter
Synlett
The studies were initiated by selecting the model reac-
tion using α-methyl styrene (1) and ethyl trifluoropyruvate
(2) with various iron salts (Table 1). FeIII catalysts only led to
side reactions (Table 1, entries 1 and 2). Using FeII salts, the
products obtained were a mixture of the ene product and
side products (Table 1, entries 3–7). Fe(BF4)2·6H2O afforded
homoallylic alcohol 3a in a 75% yield, which encouraged us
to optimize the conditions further (Table 1, entry 7). The
yield decreased to 62% using Fe(OTf)2, and a longer reaction
time or an increased catalyst loading (10 mol%) had little ef-
fect on the reaction efficiency (Table 1, entry 8).
Optimization of the ratio of α-methyl styrene to ethyl
trifluoropyruvate was performed in both ways (Table 1, en-
tries 9–12). Using an excess of styrene (4 equivalents) did
not lead to appreciable increase in yield (Table 1, entry 9);
whereas using an excess of ethyl trifluoropyruvate afforded
a better yield (Table 1, entries 10 and 11). However, using
Fe(BF4)2·6H2O and changing the ratio of 1/2 from 2:1 to
1:1.5 had no impact on the yield (Table 1, entries 7 and 13).
When comparing Fe(OTf)2 with Fe(BF4)2·6H2O, the latter ex-
hibited a better catalytic activity (Table 1, entries 10 and
13). Anhydrous Fe(BF4)2, generated from FeCl2 and AgBF4,
was also tested and showed better catalytic efficiency than
Fe(BF4)2·6H2O (Table 1, entry 14). In order to suppress any
competing catalytic effect resulting from AgCl in the mix-
ture of FeCl2 and AgBF4; a control experiment, after filtering
off the AgCl, demonstrated that anhydrous Fe(BF4)2 in the
absence of silver salt was a more efficient catalyst than
Fe(BF4)2 in its presence, affording an 87% yield of 3a (Table
1, entry 15). However, Fe(BF4)2·6H2O, being a commercial
catalyst, was used for the screening of solvents (Table 2).
In MeCN, the carbonyl-ene reaction did not proceed and
starting materials were recovered (Table 2, entry 1). Et2O
and DCE gave moderate yields of 3a (Table 2, entries 2 and
3). Toluene led to higher yield of 3a (Table, entry 4). Both
THF and Me-THF afforded only traces of the product, and
ethyl trifluoropyruvate was recovered (Table 2, entries 6
and 7). Several ‘green’ solvents were considered (Table 2,
entries 8–10). Cyclopentyl methyl ether (CPME) afforded a
slightly lower yield than with dichloromethane (Table 2, en-
try 8). tert-Butyl methyl ether (TBME) and dimethyl car-
bonate (DMC) led to moderate yields (Table 2, entries 9 and
10). Among the list of selected solvents, CH2Cl2 provided the
highest yield (Table 2, entry 5) and it was consequently cho-
sen for studying the scope of the reaction using various
alkene substrates.
5 mol% FeCl2
10 mol% AgBF4
O
HO CF3
OEt
OEt
+
F3C
R
R
CH2Cl2, 4 Å MS, rt, 48 h
O
O
(1.5 equiv)
1
2
3
HO CF3
HO CF3
OEt
HO CF3
OEt
OEt
O
O
O
MeO
3b, 75%
3c, 60%
3a, 87%
HO CF3
HO CF3
OEt
HO CF3
MeO
OEt
OEt
Br
O
O
F
3d, 52%
3e, 46%
3f, 47%
HO CF3
HO CF3
OEt
OEt
Table 2 Optimization of the Reaction Solvents
O
S
O
3g, 36%
3h, 53%
HO CF3
O
5 mol% Fe(BF4)2·6H2O
solvent, rt, 48 h
OEt
OEt
HO CF3
+
HO CF3
F3C
OEt
OEt
O
O
O
1a
2
3a
O
3i, 60%
3j, 83%
Entry
Solvent
Yield (%)a
Scheme 1 Reaction scope of the Fe(BF4)2 catalyzed trifluoropyruvate
carbonyl-ene reaction
1
2
MeCN
Et2O
–
52
46
71
75
–
However, cyclopentyl methyl ether, which is a green
solvent, gave a very promising yield in the model reaction.
In order to demonstrate the reaction scope, various substi-
tuted α-methyl styrenes were selected (Scheme 1), using
the best conditions selected from Table 1 (5 mol% FeCl2, 10
mol% AgBF4, entry 15). Using substrates possessing an elec-
tron-donating group, such as a methyl group in the para po-
sition, the yield was good (3b). With a more electron-
donating group such as p-MeO, side competing reactions of
the alkene occurred and the yield of the adduct decreased
to 60% (Scheme 1, 3c). Steric hindrance was another factor
influencing the reaction. A methoxy group in the ortho po-
sition led to further decrease of the yield (3d). Moreover,
3
DCE
4
Toluene
CH2Cl2
THF
5
6
7
Me-THF
CPME
TBME
DMC
< 5b
72
42
59
8
9
10
a Isolated yield.
b Calculated by 1H NMR spectroscopy.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

C
D. Meng, T. Ollevier
Letter
Synlett
the presence of electron-withdrawing groups (Br, F) on the
aryl ring of the styrene derivatives led to moderate yields
(3e,f). Using less nucleophilic 2-isopropenylnaphthalene,
the yield dropped further (3g). A moderate yield was ob-
tained using 2-(prop-1-en-2-yl)thiophene as the nucleo-
phile (3h). More nucleophilic methylenecyclopentane and
methylenecyclohexane afforded the products in moderate
to good yields (3i,j). Only traces of product were obtained
when using 2-(1-methylethenyl)-pyridine as a hetero-
aromatic alkene, probably because the pyridine deactivated
the catalyst.20 Less nucleophilic noncyclic aliphatic alkenes,
such as 1-hexene, led only to traces of the desired product.
Indeed, 1-hexene has often been used in the literature with
a large excess of the enophile.12a Overall, the developed cat-
alytic system was efficient with 1,1-disubstituted aromatic
and aliphatic alkenes.
such as in the CuII-catalyzed carbonyl-ene reaction of ethyl
glyoxylate disclosed by Evans.12a FeII can be considered to
coordinate with the two carbonyl oxygens of the trifluoro-
pyruvate in a bidentate manner as shown in the proposed
mechanism (Scheme 3). The Lewis acid promoted ene reac-
tion is usually discussed in terms of a continuum from a
concerted to a cationic mechanism.1b,27 However, a stepwise
radical pathway could also be envisaged.28 A control experi-
ment using TEMPO as a radical scavenger [methylstyrene
(1), 1.5 equiv trifluoromethyl pyruvate 2, 5 mol% FeCl2, 10
mol% AgBF4, 5 mol% TEMPO] led to a signficant decrease in
the yield of 3a (43% instead of 83%).
FeCl2 + 2 AgBF4
O
OEt
Fe(BF4)2
+
HO CF3
F3C
OEt3
O
The intramolecular carbonyl-ene reaction is a useful
method for making C–C bonds in organic synthesis.1,21 The
cyclization of (R)-(+)-citronellal affording (–)-isopulegol (5)
is a known reaction. The latter is a desirable precursor to a
widely employed chemical (–)-menthol.22 Several catalysts
have been used for this process, including Sc(OTf)3,23a
SnCl4,23b BiCl3,23c and Bi(OTf)3·xH2O.23d FeCl3 (10 mol%) has
been reported in the literature but a low yield (20%) with a
76:24 ratio of isopulegol 5 to other diastereomers was
achieved.24 Hence, it was of interest to test Fe(BF4)2 in the
cyclization of citronellal, since iron salts have been less ex-
plored compared to other metal salts. Using the Fe(BF4)2
catalytic system with (S)-(–)-citronellal (4), a total yield of
70% was obtained in a 70:30 trans/cis ratio of (+)-isopulegol
to (–)-neo-isopulegol in the crude product while the isolat-
ed yields were: (+)-isopulegol 5, 45%, (–)-neo-isopulegol 6,
25%, with no (–)-iso-isopulegol or (–)-neo-iso-isopulegol
being identified (Scheme 2).25
O
2+
2 BF4
OEt
Fe
O
2 BF4
HO
2+
O
Fe
CF3
+
O
F3C
OEt
Fe2+
2 BF4
O
H
O
OEt
CF3
Scheme 3 Postulated mechanism for the Fe(BF4)2-catalyzed carbonyl-
ene reaction between ethyl trifluoropyruvate and α-methylstyrene
The observation that the reaction still occurs, although
less efficient, in the presence of TEMPO does not rule out
unambiguously that a radical process is involved in the pro-
cess, at least to some extent.
To sum up, we have reported the first iron catalytic sys-
tem for both inter- and intramolecular carbonyl-ene reac-
tions. Using a low catalytic loading of Fe(BF4)2, the reaction
proceeds smoothly to afford ene products in 36–87% isolat-
ed yields.29 The method was also applied to 1,1-disubstitut-
ed alkenes with trifluoropyruvate and to the cyclization of
citronellal. The carbon–carbon bond-forming process was
affected by the electronic and steric properties of the sub-
stituents on the arene ring in the intermolecular carbonyl-
ene reaction. A good yield of and selectivity for isopulegol
were obtained in the intramolecular carbonyl-ene reaction.
Further development of iron catalysis in the carbonyl-ene
reaction will be reported in due course.
5 mol% FeCl2
10 mol% AgBF4
+
O
CH2Cl2, 4 Å MS, rt, 48 h
OH
OH
4
5, 45%
6, 25%
Scheme 2 Intramolecular Fe(BF4)2-catalyzed carbonyl-ene reaction of
(S)-citronellal
Through the evaluation of a variety of iron salts, we
have found that the FeII salts were more appropriate to cat-
alyze the carbonyl-ene reaction. Indeed, FeIII salts, such as
FeCl3 and Fe(OTf)3, failed to catalyze the carbonyl-ene reac-
tion of α-methyl styrene and trifluoropyruvate (Table 1, en-
tries 1 and 2). Secondly, it was found that the counterion
had a marked effect on the conversion of the Lewis acid cat-
alyzed reaction between methylenecyclohexane and ethyl
trifluoropyruvate.26 Anhydrous Fe(BF4)2, generated from
FeCl2 and AgBF4, led to higher yields than Fe(BF4)2·6H2O.
Furthermore, a bidentate coordination can be postulated
Funding Information
We are grateful to the Natural Sciences and Engineering Research
Council of Canada (NSERC), the Centre in Green Chemistry and Catal-
ysis (CGCC), and Université Laval for financial support of our program.)(
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

D
D. Meng, T. Ollevier
Letter
Synlett
Acknowledgment
(19) (a) Plancq, B.; Ollevier, T. Chem. Commun. 2012, 48, 3806.
(b) Lafantaisie, M.; Plancq, B.; Mirabaud, A.; Ollevier, T. Chem-
CatChem 2014, 6, 2244. (c) Jalba, A.; Régnier, N.; Ollevier, T. Eur.
J. Org. Chem. 2017, 1628.
D. M. thanks the China Scholarship Council (CSC) for a doctoral schol-
arship.
(20) Interestingly, the reaction of 2-methyl quinoline and ethyl tri-
fluoropyruvate was reported to occur thermally using Fe(OAc)2;
the trifluoropyruvate being activated by an FeII-enamide
acetate species: Pi, D.; Jiang, K.; Zhou, H.; Sui, Y.; Uozumi, Y.;
Zou, K. RSC Adv. 2014, 4, 57875.
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Hiersemann, M. Org. Lett. 2014, 16, 4062. (c) Okamoto, R.;
Takeda, K.; Tokuyama, H.; Ihara, M.; Toyota, M. J. Org. Chem.
2013, 78, 93.
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S. In Chirality in Industry; Collins, A. N.; Sheldrack, G. N.; Crosby,
J., Eds.; John Wiley: New York, 1992, 313.
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rahedron Lett. 1998, 39, 1997. (b) Nakatani, Y.; Kawashima, K.
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Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1591858.
S
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ortiInfogrmoaitn
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p
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with Ethyl 3,3,3-Trifluoropyruvate
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3
V
o.
l
Jacobsen, E.
FeCl2 (1.7 mg, 0.0125 mmol) and AgBF4 (5 mg, 0.025 mmol)
were added into a flame-dried test tube. The test tube was
placed under high vacuum and purged with argon three times.
Afterwards, distilled THF (1 mL) was added, and the resulting
solution was stirred for 0.3 h, then filtered under argon atmo-
sphere through a pre-dried pipet plugged with cotton and
Celite® to remove the precipitated AgCl. To the resulting solu-
tion was added 4 Å MS (50 mg), and the solution was then evap-
orated under reduced pressure. The test tube was then placed
under high vacuum (1 Torr) for 0.3 h. Under an argon atmo-
sphere freshly distilled CH2Cl2 (0.5 mL) was then added, and the
solution stirred for 0.1 h. Then, α-methyl styrene (30 mg, 0.25
mmol) and ethyl 3,3,3-trifluoropyruvate (64 mg, 0.375 mmol)
were added via syringe into the solution. The solution was then
stirred for 48 h under an argon atmosphere. Then, the crude
reaction mixture was directly purified by silica flash chroma-
tography (eluent: hexane/ethyl acetate) to give pure carbonyl-
ene product 3a (63 mg, 87%).
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Ethyl
2-Hydroxy-4-phenyl-2-(trifluoromethyl)pent-4-enoate
(18) Bauer, I.; Knölker, H.-J. Chem. Rev. 2015, 115, 3170.
(3a)30
1H NMR (400 MHz, CDCl3): δ = 7.35–7.26 (m, 5 H), 5.39 (d, J =
1.3 Hz, 1 H), 5.28 (d, J = 1.3 Hz, 1 H), 4.03 (dq, J = 10.6, 7.2 Hz, 1
H), 3.76 (d, J = 0.9 Hz, 1 H), 3.64 (dq, J = 10.6, 7.2 Hz, 1 H), 3.28
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

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D. Meng, T. Ollevier
Letter
Synlett
(d, J = 14.0 Hz, 1 H), 3.04 (d, J = 14.0, 1.0 Hz, 1 H), 1.11 (t, J = 7.2
Hz, 3 H). 13C NMR (100 MHz, CDCl3): δ = 168.9, 141.0, 128.1,
127.9, 126.8, 123.4 (q, J = 286.2 Hz), 119.4, 77.09 (q, J = 28.9 Hz),
63.5, 37.0, 13.5. IR (NaCl): 3491, 2985, 1741, 1629, 1446, 1370,
(30) Luo, H.-K.; Woo, Y.-L.; Schumann, H.; Jacob, C.; Meurs, M. V.;
Yang, H.-Y.; Tan, Y.-T. Adv. Synth. Catal. 2010, 352, 1356.
1312, 1227, 1184, 1136, 1050, 911, 778, 701 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E