Facile synthesis of 1-trifluoromethylalkenes via the decarboxylation of α-trifluoromethyl-β-lactones

Article abstract of DOI:10.1039/c5cc03230j

DCC-mediated cyclodehydration of α-trifluoromethyl-β-hydroxy acids provides α-trifluoromethylated β-lactone intermediates, without loss of stereoselectivity. These lactones undergo facile decarboxylation providing a simple route to obtain both alkyl and aryl trifluoromethylated alkenes in excellent yields and stereoselectivity.

Full text of DOI:10.1039/c5cc03230j

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Facile synthesis of 1-trifluoromethylalkenes via
the decarboxylation of a-trifluoromethyl-
b-lactones†
Cite this:DOI: 10.1039/c5cc03230j
Received 18th April 2015,
Accepted 26th June 2015
P. Veeraraghavan Ramachandran* and Barnabas Otoo
DOI: 10.1039/c5cc03230j
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DCC-mediated cyclodehydration of a-trifluoromethyl-b-hydroxy acids
provides a-trifluoromethylated b-lactone intermediates, without loss of
stereoselectivity. These lactones undergo facile decarboxylation
providing a simple route to obtain both alkyl and aryl trifluoro-
methylated alkenes in excellent yields and stereoselectivity.
The extreme rarity of fluorine in natural products1 makes the
synthesis of fluoro-organic molecules inevitable for their examina-
tion in medicinal and materials chemistry.2 Accordingly, develop-
ment of novel methodologies for the preparation of fluorinated
building blocks has for long attracted synthetic chemists.3 Conver-
sion of fluorinated substrates to useful synthons is a preferred
alternative to cumbersome and often non-selective late-stage
Scheme 1 Preparation of trifluoromethyl olefins from aldehydes.
fluorination techniques. As part of our program on fluoroorganic presence of pyridine and allowed to stand overnight in CHCl3
synthesis via boranes,4 we had recently reported the preparation at 0 1C. However, none of the expected b-lactone, 4-phenyl-3-
of a-trifluoromethyl-b-hydroxy acids (1) in high stereoselectivity (trifluoromethyl)oxetan-2-one (2a), was observed. Fortunately,
via the enolization–aldolization of 3,3,3-trifluoropropanoic after scanning a variety of reagents, we achieved the dehydration–
acids.5 This development opened the door for the preparation cyclization, within 15 min, using dicyclohexylcarbodiimide (DCC)13
of hitherto unknown a-trifluoromethyl-b-lactones and a ready in CHCl3 at 0 1C (Scheme 2). Unfortunately, the separation of 2a
synthesis of 1-trifluoromethylalkenes (Scheme 1).6
from the N,N0-dicyclohexylurea (DCU) byproduct was difficult.
The chemistry of b-lactones has been reviewed several times A modified workup was used, whereby the solvent was replaced
in the literature.7 They have been converted to several classes with ethyl acetate and cooled to ꢀ78 1C, when the precipitated DCU
of functional derivatives, including olefins.8,9 Yet, surprisingly, could be filtered cold to yield 88% of 2a as a yellow oil (Scheme 2).‡
a-trifluoromethyl-b-lactones have not been reported thus far.10 Spectroscopic (PMR and FMR) analysis revealed that the anti-
Considering the importance of trifluoromethylated alkenes in a stereochemistry of 1a is retained in 2a.
variety of fields,6,11 their ready synthesis from these lactones
should be beneficial. Accordingly, we undertook such a project a trifluoromethyl group at the a-position on the preparation as well
and the results are reported herein. as the stability of such b-lactones (Table 1). Lactone 2a was stable for
The successful synthesis of 2a led us to examine the effect of
We began the project by examining the lactonization of anti- a few minutes at room temperature (rt), after which the decarboxyla-
3,3,3-trifluoro-2-(hydroxy(phenyl)methyl)propanoic acid (1a) via tion to the corresponding olefin, (E)-b-trifluoromethylstyrene (3a),
the most common method for this transformation.12 Thus, 1a initiated. The decarboxylation was complete within 12 h, at rt
was allowed to react with p-toluenesulfonyl chloride in the (Scheme 2). The stereochemistry of 3a and all other olefins
subsequently discussed was determined by comparing their
1H NMR spectra with those reported.14 The preparation of the
olefins are summarized in Table 2.
The b-hydroxy acid bearing a b-tolyl group, (with the mildly
electron-donating p-methyl group, (1b)), underwent lactonization
under similar conditions (0 1C, 15 min) to provide 2b, which
Herbert C. Brown Center for Borane Research, Purdue University, 560 Oval Drive,
West Lafayette, IN 47907-2084, USA. E-mail: chandran@purdue.edu
† Electronic supplementary information (ESI) available: Further details on the
synthesis and characterization data of the compounds and 1H, 13C, and 19F NMR
spectra. See DOI: 10.1039/c5cc03230j
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Table 2 Preparation of 1-trifluoromethylalkenes
Scheme 2 Synthesis of b-lactone and trifluoromethyl styrene.
Table 1 Preparation of a-trifluoromethyl-b-lactones
Aldol/lactone Alkene
Entry
1
R
3
Methoda Yieldb (%) E : Zc
1
2
3
4
5
6
7
8
1a
2a
1b
2b
1c
2c
1d
2e
1f
C6H5
C6H5
3a
3a
3b
3b
3c
3c
A
B
A
B
A
B
B
C
B
B
C
C
C
98d
99 : 1
99 : 1
99 : 1
99 : 1
99 : 1
99 : 1
99 : 1
96 : 4
99 : 1
99 : 1
98 : 2
92 : 8
99 : 1
94
4-Me-C6H4
4-Me-C6H4
4-F-C6H4
4-F-C6H4
4-MeO-C6H4 3d
4-NO2-C6H4 3e
2-Thioph
Ph-CHQCH 3g
Chx
i-Pr
t-Bu
98e
95
97 f
93
96
72
98
Aldol
b-Lactone
Entry
1
R
anti : syn
2
Yielda (%)
anti : synb
9
3f
10
11
12
13
1g
2h
2i
79
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
1g
1h
1i
Ph
99 : 1
99 : 1
99 : 1
99 : 1
96 : 4
99 : 1
99 : 1
98 : 2
92 : 8
99 : 1
2a
2b
2c
2d
2e
2f
2g
2h
2i
88
85
80
99 : 1
99 : 1
99 : 1
3h
3i
3j
52, (99)g
48, (99)g
58, (99)g
4-Me-C6H4
4-F-C6H4
4-MeO-C6H4
4-NO2-C6H4
2-Thioph
Ph-CHQCH
Chx
c
c
2j
—
—
80d
—
a
A: allow neat b-lactone to stand at rt for periods mentioned: see d–f
below. B: stir aldol with DCC in chloroform for 15 min at 0 1C, followed
by warming to rt and stirring for 4–48 h. C: heat b-lactone in quinoline
c
c
—
—
c
c
—
—
97
97
98
98 : 2
92 : 8
99 : 1
b
c
at 200 1C for 2–6 h. Isolated yields. E/Z ratio determined by 19F NMR
i-Pr
t-Bu
d
e
spectroscopy. Overnight decarboxylation. Decarboxylation complete
10
1j
2j
f
in 2 h. Decarboxylation takes place within 4–14 days. g 19F NMR yields
a
b
Isolated yield. E/Z ratio determined by 19F NMR spectroscopy.
with PhCOCF3 as an internal standard.
c
d
Unstable lactones convert to olefins immediately. The stable lactone
bearing the 4-nitrophenyl group (2e) was isolated in 80% yield as a
mixture containing 20% unidentified impurities, which was carried to
the olefination step without purification.
respectively), were converted to the lactones in 15 min at 0 1C and
were very stable. They could be stored at rt for several weeks without
any noticeable decomposition, similar to 2e. The stable aromatic
lactone 2e and aliphatic lactones 2h–j failed to decarboxylate at
rt and formed amides with DCU upon heating. Refluxing 2h in
pyridine for 5 d resulted in partial decarboxylation to the olefin
and olefinic acid, (E)-3-cyclohexyl-2-(trifluoromethyl)acrylic acid.
Olefin (3h) was the sole product when the bath temperature was
maintained at 140 1C for 3 d. Quinoline as the solvent allowed
the decarboxylation to be conducted at 200 1C (Method C,
Table 2) (entry 11) and the lower boiling olefin was isolated in
52% yield within 2 h (Scheme 3). This process was then extended
to 2e, 2i and 2j (Table 2, entries 8, 12, and 13).
In all of the cases, we obtained (E)-olefins with very high
diastereoselectivity from the anti-hydroxy acids/lactones. The
enolboration–aldolization protocol has not been standardized for
the preparation of pure syn-a-trifluoromethyl-b-hydroxy acids.5
However, when such b-hydroxy acids with lower diastereo-
selectivities (syn :anti::7 : 3)5 are decarboxylated under this protocol,
the dr was transferred to the corresponding olefin (Z:E::7 : 3). Thus,
the new protocol could be extended to prepare syn-a-trifluoromethyl-
b-lactones and (Z)-trifluoromethyl olefins.
decarboxylated over 30 min at rt (Table 2, entry 3). In comparison, a
mildly electron-withdrawing b-4-fluorophenyl substituent (1c)
provided the corresponding lactone (2c), which was stable, at rt,
for 3 d. A slow decarboxylation which sets in after 3 d takes 2–3
weeks for completion at rt (Table 2, entry 5). The b-lactone from
the hydroxy acid bearing a 4-anisyl group at the b-position
(a stronger electron donating substituent (1d)) was not isolable
and immediately decarboxylated to the corresponding olefin 3d
under the same reaction conditions (0 1C, 15 min) (Table 2, entry 7).
As expected, the hydroxyl acid with a stronger electron-withdrawing
4-nitrophenyl group at the b-position (1e) underwent cyclization
only at rt and the isolated lactone 2e was stable for several months.
All of these observations are consistent with both theoretical and
practical studies reported by various groups.8,10,15,16 It has been
reported that while p-donors at the b-position destabilize b-lactones,
p-acceptors stabilize them.15 Hydroxy acids bearing 2-thiophenyl
and cinnamyl groups (1f and 1g) at the b-position underwent
cyclization as soon as they were treated with DCC at 0 1C and the
anti-lactones (2f and 2g, respectively) underwent ready decarboxyla-
tion to the E-olefins (3f and 3g, respectively, Table 2, entries 9
and 10) without any further delay. The lactones could not be isolated
in these cases as well.
In conclusion, the first synthesis of anti-a-trifluoromethyl-b-
lactone intermediates via a DCC-mediated cyclodehydration of
Indeed, it is also possible to conveniently convert all of the
aromatic hydroxy acids, except 1e, directly to the olefins by allowing
the DCC-mediated reaction to proceed for longer periods at rt,
without isolating the lactones (Method B, Table 2).
Hydroxy acids bearing aliphatic groups, such as cyclohexyl,
isopropyl, and tert-butyl substituents at the b-position (1h, 1i, and 1j,
Scheme 3 Preparation of aliphatic (E)-trifluoromethyl olefins.
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2 I. Ojima, ChemBioChem, 2004, 5, 628.
anti-a-trifluoromethyl-b-hydroxy carboxylic acids has been described.
b-Substituted a-trifluoromethyl lactones with b-aliphatic groups and
b-p-acceptors are stable while those with b-p-donors are transient. A
simple synthesis of trifluoromethylated (E)-olefins has also been
developed. The preparation of pure syn-lactones and (Z)-olefins is in
progress. Also, further transformations of the stable novel trifluoro-
methyl b-lactones are in progress.
3 For recent examples, see: (a) T. Liang, C. N. Neumann and T. Ritter,
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2015, 56, 3019.
Notes and references
6 For selected synthesis of trifluoromethyl alkenes, see: (a) T. Kobayashi,
T. Eda, O. Tamura and H. Ishibashi, J. Org. Chem., 2002, 67, 3156–3159;
(b) P. V. Ramachandran and W. Mitsuhashi, Org. Lett., 2015, 17, 1252,
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‡ General procedure for the dehydration of b-hydroxyacids: anti-3,3,3-
trifluoro-2-(hydroxy(phenyl)methyl)propanoic acid,5 (1a), (0.47 g,
2 mmol) was weighed into an oven dried 50 mL round-bottom flask
and dissolved in 5 mL of chloroform (additional amounts of chloroform
and longer periods of stirring may be required to completely dissolve some
of the aldols). The solution was cooled to 0 1C and N,N0-dicyclohexyl-
carbodiimide (DCC) (0.412 g, 2 mmol) was added. The mixture was stirred
for 15 min at 0 1C, when the clear solution turned into a white suspension
indicating the formation of N,N0-dicyclohexylurea (DCU). The solvent was
removed on a rotovap at room temperature and 20 mL of ethyl acetate (pre-
cooled to ꢀ78 1C) was added to the slurry. The suspension was filtered
carefully while keeping it cold and concentrated at room temperature to
obtain 2a (0.39 g, 88%). For characterization data and NMR spectra, see
ESI.†
General procedure for the one-pot preparation of trifluoromethyl olefins from
b-hydroxy acids: anti-3,3,3-trifluoro-2-(hydroxy(phenyl)methyl)propanoic acid
(1a), (0.47 g, 2 mmol) was weighed into a 50 mL round-bottom flask and
dissolved in 5 mL of chloroform (additional amounts of chloroform and
longer periods of stirring may be required to fully dissolve some of the
aldols). The solution was cooled to 0 1C and N,N0-dicyclohexylcarbodiimide
(DCC) (0.412 g, 2 mmol) was added. The mixture was stirred for 15 min at
0 1C, warmed to rt and stirred for 12 h. (Other hydroxyacids may require
longer times. See text for details.) The solvent was removed on a rotovap and
10% ethyl acetate/hexane solution (50 mL) was added to the slurry, filtered
through a silica pad and concentrated on a rotary evaporator to afford 3a
(0.33 g, 98%). For characterization data and NMR spectra, see ESI.†
General procedure for the decarboxylation of aliphatic b-lactones: prepara-
tion of (E)-(3,3,3-trifluoroprop-1-en-1-yl)cyclohexane (3h) is representative.
anti-4-Cyclohexyl-3-(trifluoromethyl)oxetan-2-one (2h), (4.0 g, 10 mmol)
was dissolved 15 mL of quinoline, contained in a 50 mL round-bottom flask
fitted with a reflux condenser. The solution was maintained in an oil bath at
200 1C. The reaction, followed by 19F nmr spectroscopy, was complete
within 2 h. The cooled mixture was dissolved in Et2O, washed with aq. 6 N
HCl, water, and dried (Na2SO4). Removal of ether and distillation provided
0.85 g (52%) of 3h. For characterization data and NMR spectra, see ESI.†
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