Alkylation and ring opening of perfluoroalkyl- and perfluoroaryl- substituted 2-siloxycyclopropanecarboxylates yielding fluorinated γ-oxo esters or β,γ-unsaturated ketones

Article abstract of DOI:10.1055/s-0033-1338892

Deprotonation of perfluoroalkyl- and perfluorophenyl-substituted methyl 2-siloxycyclopropanecarboxylates and subsequent reaction with alkyl halides furnished C-1 alkylated cyclopropanes with high diastereoselectivities. Smooth triethylamine trishydrofluor

Full text of DOI:10.1055/s-0033-1338892

PAPER
▌2179
paper
Alkylation and Ring Opening of Perfluoroalkyl- and Perfluoroaryl-Substituted
2-Siloxycyclopropanecarboxylates Yielding Fluorinated γ-Oxo Esters or
β,γ-Unsaturated Ketones
Fluorinated γ-Oxo Esters or β,γ-Unsaturated Ketones
Daniel Gladow, Hans-Ulrich Reissig*
Institut für Chemie und Biochemie, Freie Universität Berlin, Takustr. 3, 14195 Berlin, Germany
Fax +49(30)83855367; E-mail: hans.reissig@chemie.fu-berlin.de
Received: 10.04.2013; Accepted after revision: 30.04.2013
nucleophilicity,5 their cyclopropanation reactions pro-
Abstract: Deprotonation of perfluoroalkyl- and perfluorophenyl-
ceeded with high yields. One-pot procedures afforded tri-
substituted methyl 2-siloxycyclopropanecarboxylates and subse-
fluoromethyl-, perfluoropentyl-, or perfluorophenyl-
quent reaction with alkyl halides furnished C-1 alkylated cyclopro-
panes with high diastereoselectivities. Smooth triethylamine
substituted 4,5-dihydropyridazin-3(2H)-ones, γ-hydroxy
trishydrofluoride mediated desilylation and ring opening afforded esters, and γ-lactones with potential biological activity.4
the corresponding γ-oxo esters in good to excellent yields. Treat-
ment of methyl 2-siloxycyclopropanecarboxylates with Grignard
In these transformations cyclopropanes 1 served as
masked γ-oxo esters that were not isolated and immediate-
reagents and subsequent ring opening in the presence of acid pro-
ly converted into the products under the reaction condi-
vided β,γ-unsaturated ketones with fluorine-containing substitu-
tions employed.6
ents.
In this current report we present our results on the depro-
tonation and diastereoselective alkylation7 of typical 2-sil-
oxycyclopropanecarboxylates bearing strongly electron-
withdrawing perfluorinated substituents. Their subse-
quent ring opening by triethylamine trishydrofluoride
(Et3N·3HF)8,9 or under alternative conditions will also be
discussed. These methods allow the preparation of func-
tionalized esters, e.g. with formyl or vinyl ketone moi-
eties, that are otherwise difficult to obtain.10 One purpose
of this study is to reveal whether the fluorine-containing
substituents cause different reactivity patterns, e.g. in de-
protonation and alkylation. More importantly, because of
the relevance of fluorinated building blocks, we aimed to
establish new and versatile routes to functionalized ke-
tones with perfluoroalkyl and perfluoroaryl substitu-
ents.11,12
Key words: donor–acceptor cyclopropanes, fluorine, γ-oxo esters,
ring opening, defluorination
Among the small-ring building blocks available in organ-
ic synthesis, donor–acceptor cyclopropanes (d–a cyclo-
propanes) are extremely versatile precursors. The donor
and acceptor moieties in vicinal positions render them es-
pecially reactive and allow their participation in processes
involving nucleophiles, electrophiles, or radicals, but they
also serve as components in a variety of [3+2] or [3+3] cy-
cloadditions. As a consequence, d–a cyclopropanes have
found numerous applications in the preparation of acyclic,
carbocyclic, or heterocyclic compounds, including the
synthesis of natural products.1 Due to the unique proper-
ties of fluorine-containing compounds, the preparation of
organofluorine compounds, especially trifluoromethyl-
containing motifs, has attracted great attention from
chemists over the last few decades.2 Perfluorinated sub-
stituents are strongly electron-withdrawing and cause hy-
drophobicity. As a consequence, fluorinated compounds
exhibit significantly higher volatility, different reactivity,
and altered bioavailability.3
Methyl 2-siloxycyclopropanecarboxylates 1a–c were
smoothly deprotonated at C-1 by lithium diisopropyl-
amide. Subsequent addition of methyl iodide or allyl bro-
mide to the generated lithium ester enolate at –78 °C and
warming to –40 °C afforded alkylated cyclopropanes 2a–d
in moderate to good yields (Table 1). Compared to our
previous results,7 the replacement of the methyl group by
a trifluoromethyl or perfluorophenyl group slightly low-
ers the yields. This may be attributed to the reduced nu-
cleophilicity of the generated enolates due to the electron-
withdrawing nature of the fluorinated substituents. How-
ever, in all cases the precursors 1 were not recovered and,
hence, we assumed that the higher volatility of fluorinated
compounds 2 leads to the loss of material. The perfluoro-
alkyl-substituted cyclopropanes 2a–c were isolated with
diastereomeric ratios of 97:3 and 95:5 (entries 1–3),
whereas product 2d with the perfluorophenyl substituent
was obtained with only 80:20 d.r. (entry 4). The trans con-
figuration of the major diastereomer of 2a was confirmed
by an NOE experiment, and we assume the same relative
configuration for the other major products 2. Steric hin-
These features motivated us to investigate the properties
of d–a cyclopropanes containing perfluorinated groups
and to study their subsequent chemistry, which should
lead to a variety of products containing these unique sub-
stituents. We disclosed in an earlier report that perfluoro-
substituted alkyl 2-siloxycyclopropanecarboxylates 1a–c
are smoothly accessible by the Rh2(OAc)4-mediated cy-
clopropanation of the corresponding silyl enol ethers with
diazo esters.4 Although perfluoroalkyl- and perfluoroaryl-
substituted silyl enol ethers have remarkably reduced
SYNTHESIS 2013, 45, 2179–2187
Advanced online publication: 17.06.2013
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0033-1338892; Art ID: SS-2013-T0284-OP
© Georg Thieme Verlag Stuttgart · New York

2180
D. Gladow, H.-U. Reissig
PAPER
drance induced by the perfluorinated substituents presum- readily open to the corresponding carbonyl compounds.
ably directs the incoming electrophile to the opposite face The reactions were very fast whereas the conversions of
of the lithium enolate. In addition, a previously discussed 1c and 1e were slightly slower (entries 3 and 5).
stereoelectronic effect7 of the siloxy group may lead to the
Table 2 Ring Opening of Alkyl 2-Siloxycyclopropanecarboxylates
1 and 2 by Triethylamine Trishydrofluoride Leading to γ-Oxo Esters 3
observed ‘syn-siloxy addition’. At the moment we have
no explanation for the low diastereoselectivity in the al-
kylation of perfluorophenyl-substituted cyclopropane 1c.
O
R2
Et3N⋅3HF
Me3SiO
R2
OR3
R1
CH2Cl2, r.t., time
R1 CO2R3
Table 1 Diastereoselective Alkylation of Donor–Acceptor Cyclo-
propanes 1 with Alkyl Halides
O
1 or 2
3
1) LDA, THF,
–78 °C, 2 h
Entry
1
R1
R2
R3
Time
(min)
3
Yield
(%)
Me3SiO
CO2Me
Me3SiO
R2
2) R2–X, –78 °C, 8 h,
–40 °C
R1
R1 CO2Me
1
2
1aa
1ba
1ca
1da
1ea
1fa
2a
CF3
H
Me
Me
Me
Et
10
10
60
30
60
15
10
10
10
30
3a
3b
3c
3d
3e
3f
72b
91
1
2
C5F11
C6F5
C5F11
CF3
H
Entry
1
R1
R2
X
2
Yield d.r.
(%)
3
H
96
4
CF3
CF3
CF3
Me
allyl
Me
allyl
90b
94b
84
1
2
3
4
1a
1a
1b
1c
CF3
CF3
Me
I
2a
2b
2c
2d
81
71
65
57
97:3
5
Et
allyl
Me
Br
I
95:5
95:5
80:20
6
H
Et
C5F11
C6F5
7
CF3
Me
Me
Me
Me
3g
3h
3i
81b
93b
93
allyl
Br
8
2b
2c
CF3
The results summarized in Table 1 reveal that perfluori-
nated substituents at C-2 do not prevent functionalization
at C-1. Even cyclopropane 1c underwent smooth alkyla-
tion, although it bears a highly electrophilic perfluorophe-
nyl group that is prone to attack by nucleophiles.13 An
intermolecular attack of the generated enolate could lead
to self-destruction of this species. However, no fluoride
formation was detected by 19F NMR spectroscopy under
the fairly mild conditions for deprotonation and alkylation
of 1c.
9
C5F11
C6F5
10
2d
3j
93
a Mixture of cis/trans isomers.
b Product contained ca. 10% of the corresponding carbonyl hydrate 4.
We could not detect remaining starting material or any by-
products in the unpurified mixture after the given reaction
time by 19F NMR spectroscopy. However, in several cases
the partial formation of carbonyl hydrates 4 was observed
after aqueous workup (Scheme 1).
We next studied the ring opening of alkyl 2-siloxycyclo-
propanes 1 and 2 to the corresponding γ-oxo esters 3. In
general, the trimethylsiloxy group is stable under a variety
of reaction conditions, however, in protic solvents, e.g.
methanol, this group is slowly cleaved. This slow, in situ
deprotection is often desirable since it prevents side reac-
tions of the highly reactive carbonyl compounds. Under
stronger acidic or basic conditions (usually 2 M HCl or 2
M NaOH) desilylation occurs rapidly and, hence, func-
tional group tolerance is limited.8 The use of fluoride
sources such as triethylamine trishydrofluoride (Et3N·3
HF)9 has several advantages: it is only slightly acidic, it
can be used in standard glassware (in contrast to Olah’s
reagent14 or HF), it is less sensitive towards moisture, and
it enables facile workup.
O
H2O
HO OH
RF
CO2Me
CO2Me
RF
3
4
Scheme 1 Equilibrium of perfluoroalkyl ketones 3 and carbonyl hy-
drates 4
Trifluoromethyl ketones are highly activated, due to
strongly electron-withdrawing fluorine atoms, and their
tendency to form adducts with nucleophiles is mirrored by
their biological activity as enzyme inhibitors.11 In water
these compounds predominantly exist as the carbonyl hy-
drate. We observed the presence of about 10% of the cor-
responding carbonyl hydrate in CDCl3 for the
perfluoroalkyl ketones 3a,d,e,g,h.
Ring opening of siloxycyclopropanes 1 and 2 was com-
plete within 10–60 minutes on treatment with stoichio-
metric amounts of triethylamine trishydrofluoride in
dichloromethane to give the γ-oxo esters 3 (Table 2). The
yields of purified products are generally good to excellent
(72–96%). Despite the strong electron-withdrawing na-
ture of perfluorinated substituents, which could possibly
interfere with ring opening, all examined cyclopropanes
We also tried to perform the ring opening of compound 1f
in methanol with potassium carbonate. Surprisingly, we
observed a defluorination process leading to the two γ-lac-
tones 5 and 6 in moderate yields (Scheme 2); both com-
pounds were obtained as cis/trans mixtures. Traces of a
Synthesis 2013, 45, 2179–2187
© Georg Thieme Verlag Stuttgart · New York

PAPER
Fluorinated γ-Oxo Esters or β,γ-Unsaturated Ketones
2181
third product were observed by NMR spectroscopy, but
its structure could not be elucidated.
F
F
F
Me3SiO
CO2Et
CF3
1f
K2CO3, MeOH
– Me3SiOMe
O
H
CO2Et
K2CO3
MeOH
O
MeO
O
Me3SiO
CO2Et
CF3
1f
– F
r.t., 48 h
R
OMe
64%
(5/6 = 1:2)
5 R = C(OMe)3
6 R = CO2Me
F
F
F
F
MeO
O
O
H
CO2Et
H
CO2Et
Scheme 2 Ring opening of cyclopropane 1f under basic reaction
conditions leading to defluorinated lactones 5 and 6.
– F
We were not able to isolate intermediates from this trans-
formation; however, based on literature evidence, we pro-
pose the mechanism depicted in Scheme 3. Compounds
with trifluoromethyl groups at acidic CH units activated
by an adjacent electron-withdrawing group undergo anal-
ogous defluorination reactions.15 Upon treatment of 1f
with base in methanol the siloxy group is cleaved off and
the ring-opened compound 3f is formed; it is in equilibri-
um with its well-stabilized carbanion under the reaction
conditions. Subsequent fluoride elimination affords a re-
active difluoro olefin, which in turn is attacked by metha-
nolate.16 A second fluoride elimination leads to a
monofluoro olefin. A third displacement of fluoride may
occur more slowly, resulting in the long reaction time.
Monitoring the reaction progress by 19F NMR spectrosco-
py gave clear evidence for the formation of potassium
fluoride (δ = –150.4). Additionally, hemiacetal formation
takes place to enable cyclization to the corresponding lac-
tone 5. In view of the lability of ortho esters under acidic
conditions, the partial conversion into ester 6 may have
occurred during aqueous workup or purification on silica
gel.
F
OMe
O
CO2Et
C(OMe)3
MeO
H
O
H
CO2Et
– EtO
O
O
O
MeO
O
MeO
H
CO2Me
C(OMe)3
6
5
Scheme 3 Proposed mechanism leading to lactones 5 and 6.
Ph Ph
OH
a
Me3SiO
CO2Me
Me3SiO
F3C
F3C
1a
61%
(2 steps)
b
To demonstrate the synthetic versatility of the perfluoro-
alkyl- and perfluoroaryl-substituted cyclopropanes, com-
pound 1a was converted in a one-pot procedure into β,γ-
unsaturated ketone 7 (Scheme 4).17 In the first step 1a was
treated with excess phenylmagnesium bromide for three
hours at room temperature affording the corresponding
O
O
c
Ph
Ph
Ph
Ph
F3C
F3C
91%
8
7
tertiary alcohol, which was confirmed by NMR spectros- Scheme 4 Transformation of siloxycyclopropane 1a into the β,γ-un-
saturated ketone 7 and subsequent hydrogenation to ketone 8. Re-
agents and conditions: (a) PhMgBr (3 equiv), Et2O, –78 °C, then r.t.
3 h; (b) aq HCl, MeOH, r.t., 3 h; (c) 10% Pd/C, MeOH, r.t., 7 h.
copy. The crude addition product was exposed to 37%
aqueous hydrochloric acid in methanol to furnish ketone
7 in 61% overall yield. This step involves cleavage of the
siloxy group, ring opening, and elimination of water. The
conversion of the trifluoromethyl-substituted alcohol was
very slow in a biphasic system (pentane–2 M HCl) previ-
ously employed for the synthesis of β,γ-unsaturated ke-
tones.17 Under the described conditions no isomerization
to the possible α,β-unsaturated ketone was observed. Hy-
drogenation of 7 under standard conditions afforded the
saturated trifluoromethyl ketone 8 in excellent yield.
even more pronounced on reacting methylmagnesium
bromide with 1c; quantitative conversion of 1c required
the temperature to be raised to 50 °C and afforded, after
acidic treatment, the ketone 10 in 52% overall yield. In
view of the ready substitution of fluoride in pentafluoro-
toluene by methyllithium at –78 °C, the yields are remark-
able.13
Perfluorophenyl-substituted cyclopropane 1c was similar-
ly converted into ketone 9 in good yield (Scheme 5). In
this case longer reaction times were necessary, since the
addition of phenylmagnesium bromide as well as subse-
quent ring opening/elimination was much slower (19F
NMR spectroscopic monitoring). This behavior became
We also examined the addition of Grignard reagents to α-
substituted cyclopropane 1f (Scheme 6). The addition of
phenylmagnesium bromide occurred very slowly, even at
elevated temperature, as shown by 19F NMR monitoring.
Full conversion of the starting material required the mix-
ture to be heated under reflux for six hours. After treat-
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 2179–2187

2182
D. Gladow, H.-U. Reissig
PAPER
In summary, we have shown that d–a cyclopropanes with
perfluorinated substituents are smoothly deprotonated by
lithium diisopropylamide and addition of the generated
lithium enolate to alkyl halides afforded the alkylated cy-
clopropanes in moderate to good yields with high diaste-
reoselectivities. Independent of the substitution pattern of
the cyclopropane core, fluoride-mediated ring opening af-
forded the corresponding carbonyl compounds in good to
excellent yields. The trifluoromethyl group in the vicinity
of an adjacent ester group led, under basic methanolic re-
action conditions, to complete substitution of fluorine
atoms by methoxy groups. Care must be taken while plan-
ning synthesis if this substitution pattern is given. Reac-
tion of the cyclopropanes with Grignard reagents and
subsequent ring opening/elimination to provide β,γ-unsat-
urated ketones with perfluorinated substituents under-
score the versatility of donor–acceptor cyclopropanes as
building blocks in organic synthesis.
O
O
a, b
Me3SiO
CO2Me
Ph
C6F5
73%
(2 steps)
F5C6
1c
Ph
9
c, b
Me3SiO
CO2Me
Me
C6F5
52%
(2 steps)
F5C6
1c
Me
10
Scheme 5 Transformation of siloxycyclopropane 1c into the β,γ-un-
saturated ketones 9 and 10. Reagents and conditions: (a) PhMgBr (3
equiv), Et2O, r.t., 16 h; (b) aq HCl, MeOH, r.t., 3 h; (c) MeMgBr (3
equiv), THF, 50 °C, 3 h.
ment with p-toluenesulfonic acid, which proved to be
more efficient in this case, the product was not the expect-
ed β,γ-unsaturated ketone but the 1,4-dicarbonyl com-
pound 11, which was isolated in 45% yield. This
compound is an interesting intermediate for the prepara-
tion of various trifluoromethyl-substituted heterocycles.18
Treatment of the intermediate with hydrochloric acid in-
stead of p-toluenesulfonic acid led to simultaneous con-
version of aldehyde 11 into its dimethyl acetal in about
35% yield. Apparently, only one equivalent of the
Grignard reagent underwent addition to 1f giving a phenyl
ketone intermediate, which, after ring opening, provided
the 1,4-dicarbonyl compound or its acetal. Addition of
methylmagnesium bromide to 1f under the conditions de-
scribed for preparation of 11 resulted in a complex prod-
uct mixture and the expected methyl ketone was not
isolated.
Reactions were generally performed under argon in flame-dried
flasks. Solvents and reagents were added by syringes. Solvents were
dried by standard procedures. Reagents were purchased and were
used as received without further purification. Bulb-to-bulb distilla-
tions were performed with a glass oven (Büchi, B-585). Column
chromatography: silica gel (230–400 mesh, Merck or Macherey &
Nagel). Yields refer to analytically pure samples. IR Spectra were
recorded with a Jasco FT/IR-4100 spectrophotometer. Several car-
bonyl compounds showed O–H bands due to the partial formation
of carbonyl hydrates under the recording conditions. 1H NMR
[CHCl3 (δ = 7.26), TMS (δ = 0.00) as internal standard], 19F NMR
[frequency calibrated lock with ±1 ppm deviation] and 13C NMR
spectra [CDCl3 (δ = 77.2) as internal standard] were recorded with
Jeol (ECS 400, ECX 400, and Eclipse 500) or Bruker (AC 250 and
AVIII 700) instruments in CDCl3 solutions. In some cases 13C{19F}
NMR spectra were recorded to enable correct assignment. HRMS
analyses were performed with an Agilent 6210 (ESI-TOF) or a
Finnigan MAT 711 (EI) instrument. The elemental analyses were
recorded with Perkin Elmer CHN-Analyzer 2400 and Elementar
Vario EL Elemental Analyzer. Due to the high volatility of many
compounds and the formation of hydrates, elemental analyses were
only reported if feasible. Cyclopropanes 1a–f were synthesized ac-
cording to literature procedures.4
Ph
a
Me3SiO
CO2Et
CF3
Me3SiO
OEt
OMgBr
CF3
1f
b
Methyl 1-Methyl-2-(trifluoromethyl)-2-(trimethylsiloxy)cyclo-
propanecarboxylate (2a); Typical Procedure (TP1)
A 1 M LDA solution was freshly prepared: 2.5 M n-BuLi in hexanes
(0.70 mL, 1.76 mmol) was added at –78 °C to a solution of i-Pr2NH
(178 mg, 1.76 mmol) in THF (1.76 mL) and the resulting mixture
was stirred for 20 min. A THF solution (1 mL) of 1a (300 mg, 1.17
mmol) was added and stirred for 2 h at –78 °C, followed by the ad-
dition of MeI (415 mg, 2.93 mmol). Stirring was continued for 8 h
at –78 °C, whereupon the mixture was warmed to –40 °C and
quenched with sat. aq NH4Cl solution (1 mL). The mixture was di-
luted with Et2O (50 mL) and sat. aq NH4Cl solution (50 mL). The
organic layer was washed with brine (50 mL), dried (Na2SO4), and
concentrated under reduced pressure. Distillation of the crude prod-
uct afforded the alkylated siloxycyclopropane 2a as a colorless liq-
uid; yield: 256 mg (81%); bp 100–110 °C (10 mbar); trans/cis 97:3.
O
O
CF3
Me3SiO
Ph
Ph
H
45%
(2 steps)
CF3
O
11
Scheme 6 Formation of 1,4-dicarbonyl compound 11. Reagents and
conditions: (a) PhMgBr (3 equiv), THF, reflux, 6 h; (b) PTSA,
MeOH, r.t., 1 h.
We can currently only speculate about the different reac-
tivity of 1a and 1f. The ethoxycarbonyl group of 1f is ste-
rically more hindered than the methoxycarbonyl group of
1a causing slower addition of the Grignard reagent. The
formation of 11 indicates that the primary addition prod-
uct to the ester (a metallated hemiacetal, see Scheme 6) is
stable and further transformation of this intermediate oc-
curs only after aqueous workup.
IR (neat): 3155–2745 (C–H), 1740 (C=O), 1335, 1285, 1255, 1160
cm–1 (C–F).
1H NMR (400 MHz, CDCl3): δ = 0.12* (s, 9 H, SiMe3), 0.18 (s, 9
H, SiMe3), 0.82–0.86* (m, 1 H, 3-H), 0.88 (qd, J = 1.7, 7.2 Hz, 1 H,
3-H), 1.25* (d, J = 7.2 Hz, 1 H, 3-H), 1.39 (s, 3 H, 1-Me), 1.80 (d,
J = 7.2 Hz, 1 H, 3-H), 3.66 (s, 3 H, CO2Me), 3.66* (s, 3 H, CO2Me);
* signals of cis-2a.
Synthesis 2013, 45, 2179–2187
© Georg Thieme Verlag Stuttgart · New York

PAPER
Fluorinated γ-Oxo Esters or β,γ-Unsaturated Ketones
2183
13C NMR (101 MHz, CDCl3): δ = 0.6 (qq, JCF = 0.9 Hz, SiMe3),
16.4 (t, 3-C), 21.1 (q, 4JCF = 1.9 Hz, 1-Me), 29.8 (q, 3JCF = 1.2 Hz,
Major diastereomer
1H NMR (400 MHz, CDCl3): δ = 0.03 (s, 9 H, SiMe3), 1.34, 2.10 (2
d, J = 6.7 Hz each, 2 H, 3-H), 2.39 (dd, J = 7.0, 15.5 Hz, 1 H, 1-
CH2), 2.98 (dd, J = 6.1, 15.5 Hz, 1 H, 1-CH2), 3.51 (s, 3 H, CO2Me),
5.03–5.15 (m, 2 H, CH=CH2), 5.85–6.02 (m, 1 H, CH=CH2).
2
1-C), 52.5 (q, CO2Me), 61.8 (q, JCF = 37.8 Hz, 2-C), 124.3 (q,
1JCF = 277 Hz, 2-CF3), 171.2 (s, CO2Me); signals of cis-2a were not
detected.
19F NMR (376 MHz, CDCl3): δ = –79.3* (s, CF3), –72.3 (s, CF3);
* signal of cis-2a.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C10H17F3NaO3Si:
13C NMR (101 MHz, CDCl3): δ = 0.33 (q, SiMe3), 25.7 (td,
J
CF = 6.7 Hz, 3-C), 32.0 (t, 1-CH2), 35.6 (d, JCF = 1.7 Hz, 1-C), 52.2
(q, CO2Me), 58.2 (mc, 2-C), 116.9 (tt, JCF = 1.2 Hz, CH=CH2),
135.8 (dt, JCF = 1.7 Hz, CH=CH2), 114.3, 137.47, 137.49, 141.2,
145.7, 146.0 (6 mc, Ar), 172.4 (s, CO2Me).
19F NMR (376 MHz, CDCl3): δ = –162.2 (mc, 2 F, Ar–F), –153.8
293.0791; found: 293.0792.
Methyl 1-Allyl-2-(trifluoromethyl)-2-(trimethylsiloxy)cyclo-
propanecarboxylate (2b)
Starting from 1a (300 mg, 1.17 mmol) gave 2b (246 mg, 71%) as a
colorless oil; bp 45–50 °C (0.05 mbar); d.r. 95:5.
(mc, 1 F, Ar–F), –141.1 (mc, 1 F, Ar–F), –140.2 (mc, 1 F, Ar–F).
Minor diastereomer
1H NMR (400 MHz, CDCl3): δ = 0.00 (s, 9 H, SiMe3), 1.03, 1.30 (2
d, J = 7.2 Hz each, 2 H, 3-H), 2.23, 3.06 (2 d, J = 7.5 Hz each, 2 H,
1-CH2), 3.75 (s, 3 H, CO2Me), 4.92–5.05 (m, 2 H, CH=CH2), 5.71–
5.60 (m, 1 H, CH=CH2).
IR (neat): 3645–3195 (=C–H), 3195–2745 (C–H), 1740 (C=O),
1645 (C=C), 1340, 1285, 1255, 1220, 1180, 1155 cm–1 (C–F).
1H NMR (CDCl3, 250 MHz): δ = 0.21 (s, 9 H, SiMe3), 1.00 (qd,
4JHF = 1.6, J = 7.3 Hz, 1 H, 3-H), 1.84 (dd, J = 1.1, 7.3 Hz, 1 H, 3-
H), 2.20–2.08, 2.76–2.92 (2 m, 2 H, 1-CH2), 3.68 (s, 3 H, CO2Me),
3.71* (s, 3 H, CO2Me), 4.93–5.20 (m, 2 H, CH=CH2), 5.78 (tdd,
J = 6.8, 10.1, 17.1 Hz, 1 H, CH=CH2); * signal of the minor diaste-
reomer.
13C NMR (101 MHz, CDCl3): δ = 0.25 (q, SiMe3), 23.2 (td,
J
CF = 7.0 Hz, 3-C), 34.3 (td, JCF = 1.2 Hz, 1-CH2), 35.1 (d, JCF = 2.0
Hz, 1-C), 52.9 (q, CO2Me), 57.2 (mc, 2-C), 116.3 (tt, JCF = 2.1 Hz,
CH=CH2), 133.8 (dt, JCF = 1.6 Hz, CH=CH2), 113.5, 137.6, 137.9,
141.5, 145.4, 146.5 (6 mc, Ar), 170.1 (s, CO2Me).
19F NMR (376 MHz, CDCl3): δ = –161.1 (mc, 2 F, Ar–F), –152.8
13C NMR (101 MHz, CDCl3): δ = 0.7 (qq, JCF = 1.1 Hz, SiMe3),
19.9 (tq, 3JCF = 2.0 Hz, 3-C), 34.2 (q, 3JCF = 1.0 Hz, 1-C), 34.7 (t, 1-
CH2), 52.5 (q, CO2Me), 61.8 (q, 2JCF = 37.7 Hz, 2-C), 117.5–117.6
(mc, 1 F, Ar–F), –141.5 (mc, 1 F, Ar–F), –137.4 (mc, 1 F, Ar–F).
1
(m, CH=CH2), 124.1 (q, JCF = 277 Hz, CF3), 133.8 (dt, JCF = 3.0
Hz, CH=CH2), 170.1 (s, CO2Me); signals of the minor diastereomer
were not detected.
Methyl 5,5,5-Trifluoro-4-oxopentanoate (3a); Typical Proce-
dure (TP2)
Precursor 1a (230 mg, 0.844 mmol) was dissolved in CH2Cl2 (5
mL) and treated with Et3N·3HF (37% in Et3N, 404 mg, 0.928 mmol)
at r.t. for 10 min. The mixture was diluted with CH2Cl2 (50 mL),
washed with brine (2 × 50 mL), dried (Na2SO4), and concentrated
under reduced pressure. Distillation of the crude product afforded
γ-oxo ester 3a as a colorless liquid; yield: 113 mg (72%); mixture
containing approximately 10% of its carbonyl hydrate 4a; bp 80–
85 °C (10 mbar).
19F NMR (376 MHz, CDCl3): δ = –79.1* (s, CF3), –72.6 (s, CF3);
* signal of the minor diastereomer.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C12H19F3NaO3Si:
319.0948; found: 319.0935.
Methyl 1-Methyl-2-(perfluoropentyl)-2-(trimethylsiloxy)cyclo-
propanecarboxylate (2c)
Starting from 1b (300 mg, 0.66 mmol) gave 2c (202 mg, 65%) as a
colorless liquid; bp 110–120 °C (10 mbar); d.r. 95:5.
1H NMR (400 MHz, CDCl3): δ = 2.07–2.12, 2.75–2.70 (2 m, 4 H,
2-H, 3-H), 3.68 (s, 3 H, CO2Me).
IR (neat): 3180–2730 (C–H), 1740 (C=O), 1320, 1235, 1200, 1150,
1110 cm–1 (C–F).
The NMR data are consistent with reported values; the carbonyl hy-
drate form was not reported.19
1H NMR (400 MHz, CDCl3): δ = 0.13* (s, 9 H, SiMe3), 0.19 (s, 9
H, SiMe3), 0.95 (dd, JHF = 2.2 Hz, J = 7.3 Hz, 1 H, 3-H), 1.27* (d,
J = 7.3 Hz, 1 H, 3-H), 1.42 (d, JHF = 1.4 Hz, 3 H, 1-Me), 1.94 (d,
J = 7.3 Hz, 1 H, 3-H), 3.66 (s, 3 H, CO2Me), 3.70* (s, 3 H, CO2Me);
* signals of the minor diastereomer.
Analytical data for carbonyl hydrate 4a:
1H NMR (400 MHz, CDCl3): δ = 2.07–2.12, 2.75–2.84 (2 m, 4 H,
2-H, 3-H), 3.75 (s, 3 H, CO2Me).
13C NMR (101 MHz, CDCl3): δ = 27.2 (t, 3-C), 31.5 (t, 2-C), 52.7
(q, OMe), 92.9 (q, 2JCF = 32.0 Hz, 4-C), 123.5 (q, 1JCF = 287 Hz, 5-
C), 177.2 (s, 1-C).
13C NMR (101 MHz, CDCl3): δ = 0.9 (qd, JCF = 2.0 Hz, SiMe3),
16.4 (td, 3JCF = 0.7 Hz, 3-C), 20.0 (q, 1-Me), 30.5 (d, 3JCF = 5.9 Hz,
1-C), 52.4 (q, CO2Me), 62.4–63.1 (m, 2-C), 108.8, 110.7, 111.7,
19F NMR (376 MHz, CDCl3): δ = –86.7 (s, 5-F).
2
1
116.0 [4 mc, (CF2)4CF3], 117.5 [tq, JCF = 32.8 Hz, JCF = 288 Hz,
(CF2)4CF3], 170.9 (s, CO2Me); signals for the minor diastereomer
were not detected.
Methyl 5,5,6,6,7,7,8,8,9,9,9-Undecafluoro-4-oxononanoate (3b)
Starting from 1b (1.01 g, 2.20 mmol) gave 3b (774 mg, 91%) as a
colorless liquid; bp 90–95 °C (4 mbar). Complete ring opening was
observed within 10 min.
19F NMR (376 MHz, CDCl3): δ = –127.6 to –117.0 [m, 7 F,
(CF2)4CF3], –109.7 to –108.3 [m, 1 F, (CF2)4CF3], –80.8 [t, J = 9.9
Hz, 3 F, (CF2)4CF3], –80.7* [t, J = 8.9 Hz, 3 F, (CF2)4CF3]; * signal
of the minor diastereomer.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C14H17F11NaO3Si:
493.0664; found: 493.0663.
IR (neat): 3155–2790 (C–H), 1760, 1745 (C=O), 1360, 1230, 1200,
1140 cm–1 (C–F).
1H NMR (400 MHz, CDCl3): δ = 2.71, 3.07 (2 t, J = 6.4 Hz each, 4
H, 2-H, 3-H), 3.70 (s, 3 H, CO2Me).
13C NMR (101 MHz, CDCl3): δ = 26.9, 33.3 (2 t, 3-C, 2-C), 52.2 (q,
Methyl 1-Allyl-2-(perfluorophenyl)-2-(trimethylsiloxy)cyclo-
propanecarboxylate (2d)
Starting from 1c (500 mg, 1.41 mmol) of 2d (316 mg, 57%) as a col-
orless oil; bp 125–130 °C (0.5 mbar); d.r. 80:20.
OMe), 109.3, 110.4, 110.9 (4 mc, 5-C, 6-C, 7-C, 8-C), 117.3 (ttq,
2
1
3JCF = 1.1 Hz, JCF = 33.1 Hz, JCF = 288 Hz, 9-C), 171.8 (s, 1-C),
192.8 (t, 2JCF = 26.7 Hz, 4-C).
19F NMR (376 MHz, CDCl3): δ = –126.3 (mc, 2 F, 8-F), –122.5 (mc,
4 F, 5-F, 6-F), –120.4 (t, J = 11.7 Hz, 2 F, 7-F), –80.9 (t, J = 9.1 Hz,
3 F, 9-F).
IR (neat): 3685–3210 (=C–H), 3210–2710 (C–H), 1720 (C=O),
1650, 1520, 1490 (C=C), 1325, 1255, 1210, 1140 cm–1 (C–F).
Anal. Calcd for C17H19F5O3Si (394.4): C, 51.77; H, 4.86; found: C,
51.52; H, 4.64.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 2179–2187

2184
D. Gladow, H.-U. Reissig
PAPER
1
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C10H7F11NaO3:
407.0112; found: 407.0134.
1JCF = 280 Hz, 5-C), 124.5* (q, JCF = 280 Hz, 5-C), 165.5 (q,
3
3JCF = 2.8 Hz, 1-C), 169.4* (q, JCF = 2.6 Hz, 1-C), 188.1 (q,
2JCF = 37.4 Hz, 4-C); * signals of carbonyl hydrate 4e.
Anal. Calcd for C10H7F11O3 (384.1): C, 31.27; H, 1.84; found: C,
31.11; H, 1.92.
19F NMR (376 MHz, CDCl3): δ = –86.8* (s, 3 F, 5-F), –78.9 (s, 3 F,
5-F), –67.6 (d, J = 8.2 Hz, 3 F, CF3), –67.6* (d, J = 8.2 Hz, 3 F,
CF3); * signals of carbonyl hydrate 4e.
Methyl 4-Oxo-4-(perfluorophenyl)butanoate (3c)
Starting from 1c (500 mg, 1.41 mmol) gave 3c (384 mg, 96%) as a
colorless liquid; bp 120–125 °C (0.1 mbar). Complete ring opening
was observed within 60 min.
Anal. Calcd for C8H10F6O4 (284.2) 4e: C, 33.81; H, 3.55; found: C,
34.34; H, 3.22.
IR (neat): 3130–2715 (C–H), 1740, 1715 (C=O), 1650, 1520, 1490
(C=C), 1355, 1310, 1210, 1140 cm–1 (C–F).
1H NMR (400 MHz, CDCl3): δ = 2.78, 3.18 (2 mc, 4 H, 2-H, 3-H),
Ethyl 4-Oxo-2-(trifluoromethyl)butanoate (3f)
Starting from 1f (500 mg, 1.85 mmol) gave 3f (309 mg, 84%) as a
colorless liquid; bp 80–85 °C (10 mbar). Complete ring opening
was observed within 15 min.
1H NMR (400 MHz, CDCl3): δ = 1.30 (t, J = 7.1 Hz, 3 H, OEt), 2.89
(dd, J = 3.5, 18.9 Hz, 1 H, 3-H), 3.28 (dd, J = 10.4, 18.9 Hz, 1 H, 3-
H), 3.69 (qdd, 3JHF = 8.8 Hz, J = 3.5, 10.3 Hz, 1 H, 2-H), 4.26, 4.28
(AB part of an ABX3 system, JAX = JBX = 7.1 Hz, JAB = 9.4 Hz, 2 H,
OEt), 9.76 (s, 1 H, 4-H).
3.70 (s, 3 H, CO2Me).
13C NMR (101 MHz, CDCl3): δ = 27.9, 39.7 (2 t, 3-C, 2-C), 52.1 (q,
CO2Me), 114.6, 137.8, 143.1, 144.7 (4 mc, Ar), 172.5 (s, 4-C), 192.4
(s, 1-C).
19F NMR (376 MHz, CDCl3): δ = –159.8 (mc, 2 F, Ar–F), –148.6
(mc, 1 F, Ar–F), –140.4 (mc, 2 F, Ar–F).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C11H7F5NaO3:
305.0208; found: 305.0252.
13C NMR (CDCl3, 176 MHz): δ = 14.0 (q, OEt), 39.9 (tq, 3JCF = 2.0
2
Hz, 3-C), 44.2 (dq, JCF = 28.7 Hz, 2-C), 62.6 (t, OEt), 124.6 (q,
3
1JCF = 280 Hz, CF3), 166.3 (q, JCF = 3.2 Hz, 1-C), 196.7 (q,
4JCF = 1.8 Hz, 4-C).
Anal. Calcd for C11H7F5O3 (282.2): C, 46.82; H, 2.50; found: C,
46.88; H, 2.52.
19F NMR (CDCl3, 471 MHz): δ = –67.8 (d, 3JHF = 8.8 Hz, CF3).
The NMR data are consistent with reported values; however, 13C
Ethyl 5,5,6,6,7,7,8,8,9,9,9-Undecafluoro-4-oxo-2-(trifluoro-
methyl)nonanoate (3d)
NMR data were not reported.12
Starting from 1d (400 mg, 0.74 mmol) gave 3d (310 mg, 90%) as a
colorless liquid; bp 80–85 °C (0.1 mbar). Complete ring opening
was observed within 30 min.
Methyl 5,5,5-Trifluoro-2-methyl-4-oxopentanoate (3g)
Starting from 2a (220 mg, 0.81 mmol) gave 3g (130 mg, 81%) as a
colorless liquid; bp 70–72 °C (7–10 mbar). Complete ring opening
was observed within 10 min.
IR (neat): 3100–2820 (C–H), 1760, 1750 (C=O), 1320, 1225, 1205,
1140, 1120 cm–1 (C–F).
IR (neat): 3730–3065 (O–H), 3065–2730 (C–H), 1765, 1730
(C=O), 1305, 1265, 1175, 1150 cm–1 (C–F).
1H NMR (400 MHz, CDCl3): δ = 1.30 (t, J = 7.2 Hz, 3 H, CO2Et),
1.34* (t, J = 7.2 Hz, 3 H, CO2Et), 3.11 (dd, J = 3.2, 19.4 Hz, 1 H, 3-
H), 3.56 (dd, J = 10.4, 19.4 Hz, 1 H, 3-H), 3.64–3.81 (m, 1 H, 2-H),
4.27 (q, J = 7.2 Hz, 2 H, CO2Et), 4.35* (q, J = 7.2 Hz, 2 H, CO2Et);
* signals of carbonyl hydrate 4d.
1H NMR (400 MHz, CDCl3): δ = 1.26 (d, J = 7.2 Hz, 3 H, Me),
1.28* (d, J = 7.6 Hz, 3 H, Me), 1.93* (dd, J = 2.4, 14.9 Hz, 1 H, 3-
H), 2.16* (dd, J = 10.5, 14.9 Hz, 1 H, 3-H), 2.74 (dd, J = 5.1, 18.9
Hz, 1 H, 3-H), 2.97–3.09 (m, 1 H, 2-H), 3.19 (dd, J = 8.3, 18.9 Hz,
1 H, 3-H), 3.69 (s, 3 H, CO2Me), 3.76* (s, 3 H, CO2Me); * signals
of carbonyl hydrate 4g.
13C NMR (101 MHz, CDCl3): δ = 17.0 (q, Me), 34.1 (d, 2-C), 39.6
(t, 3-C), 52.4 (q, OMe), 115.5 (q, 1JCF = 292 Hz, 5-C), 174.9 (s, 1-
C), 190.0 (q, 2JCF = 35.8 Hz, 4-C).
13C NMR (101 MHz, CDCl3): δ = 13.8 (q, OEt), 35.0 (mc, 3-C),
45.0 (dq, 2JCF = 28.9 Hz, 2-C), 63.0 (t, OEt), 63.8* (t, OEt), 108.5,
109.3, 110.4, 110.8 (4 mc, 5-C, 6-C, 7-C, 8-C), 117.3 (tq, 2JCF = 33.5
1
1
Hz, JCF = 288 Hz, 9-C), 124.1 (q, JCF = 280 Hz, CF3), 165.3 (q,
3JCF = 2.7 Hz, 1-C), 190.7 (t, 2JCF = 27.7 Hz, 4-C); * signals of car-
bonyl hydrate 4d.
19F NMR (376 MHz, CDCl3): δ = –86.9* (s, 5-F), –79.3 (s, 5-F);
* signal of carbonyl hydrate 4g.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C7H9F3O3 (3g):
19F NMR (376 MHz, CDCl3): δ = –126.2 (mc, 2 F, 8-F), –122.2 (mc,
4 F, 6-F, 7-F), –120.0 (mc, 2 F, 5-F), –80.7 (t, J = 6.8 Hz, 3 F, 9-F),
–67.7 (d, 3JHF = 8.6 Hz, 3 F, CF3).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C12H8F14NaO3:
489.0142; found: 489.0150.
199.0577; found: 199.0597.
HRMS (ESI-TOF): m/z [M + K]+ calcd for C7H10F3KO4 (4g):
255.0241; found: 255.0270.
Ethyl 5,5,5-Trifluoro-4-oxo-2-(trifluoromethyl)pentanoate (3e)
Starting from 1e (200 mg, 0.59 mmol) gave 1e (148 mg, 94%) as a
colorless liquid; bp 90–95 °C (4 mbar). Complete ring opening was
observed within 60 min.
Methyl 2-(3,3,3-Trifluoro-2-oxopropyl)pent-4-enoate (3h)
Starting from 2b (173 mg, 0.58 mmol) gave 3h (122 mg, 93%) as a
colorless liquid; bp 50–55 °C (0.5 mbar). Complete ring opening
was observed within 10 min.
IR (neat): 3720–3075 (O–H), 3075–2710 (C–H), 1770, 1745
(C=O), 1375, 1340, 1280, 1225, 1175, 1150, 1120 cm–1 (C–F).
1H NMR (400 MHz, CDCl3): δ = 1.30 (t, J = 7.1 Hz, 3 H, OEt),
1.33* (t, J = 7.1 Hz, 3 H, OEt), 3.07 (dd, J = 3.4, 19.2 Hz, 1 H, 3-
H), 3.51 (dd, J = 10.5, 19.2 Hz, 1 H, 3-H), 3.72 (qdd, 3JHF = 8.5 Hz,
J = 3.4, 10.5 Hz, 1 H, 2-H), 4.26, 4.28 (AB part of an ABX3 system,
IR (neat): 3740–3135 (=C–H), 3135–2765 (C–H), 1765, 1735
(C=O), 1440, 1395 (C=C), 1290, 1205, 1145 cm–1 (C–F).
1H NMR (400 MHz, CDCl3): δ = 2.29–2.56 (2 m, 2 H, 2-CH2), 2.78
(dd, J = 3.8, 18.6 Hz, 1 H, 3-H), 3.00–3.13 (m, 1 H, 2-H), 3.16 (dd,
J = 9.1, 18.6 Hz, 1 H, 3-H), 3.71 (s, 3 H, CO2Me), 3.78* (s, 3 H,
CO2Me), 5.05–5.16 (m, 2 H, 5-H), 5.60–5.77 (m, 1 H, 4-H); * signal
of carbonyl hydrate 4h.
J
AX = JBX = 7.1 Hz, JAB = 9.4 Hz, 2 H, OEt), 4.27* (mc, 2 H, OEt);
* signals of carbonyl hydrate 4e.
13C NMR (101 MHz, CDCl3): δ = 13.8* (q, OEt), 13.9 (q, OEt),
13C NMR (101 MHz, CDCl3): δ = 35.6 (t, 3-C), 37.0 (d, 2-C), 38.8
(t, 2-CH2), 52.3 (q, OMe), 115.5 (q, JCF = 292 Hz, CF3), 118.7–
3
3
1
33.3* (tq, JCF = 2.0 Hz, 3-C), 33.3 (tq, JCF = 2.3 Hz, 3-C), 44.8
2
2
(dq, JCF = 29.0 Hz, 2-C), 45.2* (dq, JCF = 28.5 Hz, 2-C), 63.1 (t,
118.8 (m, 5-C), 133.6–134.0 (m, 4-C), 173.8 (s, 1-C), 190.1 (q,
2
2JCF = 35.8 Hz, COCF3).
OEt), 63.2* (t, OEt), 92.5* (q, JCF = 32.7 Hz, 4-C), 115.4 (q,
1JCF = 291 Hz, CF3), 123.0* (q, JCF = 287 Hz, CF3), 124.1 (q,
1
Synthesis 2013, 45, 2179–2187
© Georg Thieme Verlag Stuttgart · New York

PAPER
Fluorinated γ-Oxo Esters or β,γ-Unsaturated Ketones
2185
19F NMR (376 MHz, CDCl3): δ = –86.8* (s, CF3), –79.2 (s, CF3);
* signal of carbonyl hydrate 4h.
H), 3.31 [s, 9 H, C(OMe)3], 3.44 (s, 3 H, 5-OMe), 5.34 (dd, J = 2.6,
6.0 Hz, 1 H, 5-H).
HRMS (EI): m/z [M]+ calcd for C9H11F3O3: 224.0660; found:
224.0650.
13C NMR (CDCl3, 176 MHz): δ = 31.5 (t, 4-C), 43.5 (d, 3-C), 50.7
[q, C(OMe)3], 56.8 (q, 5-OMe), 103.8 (d, 5-C), 113.1 [s, C(OMe)3],
173.2 (s, 2-C).
Methyl 5,5,6,6,7,7,8,8,9,9,9-Undecafluoro-2-methyl-4-oxo-
nonanoate (3i)
Minor diastereomer
1H NMR (CDCl3, 700 MHz): δ = 2.22 (ddd, J = 4.5, 7.8, 14.3 Hz, 1
H, 4-H), 2.43–2.58 (m, 1 H, 4-H), 3.10 (dd, J = 7.8, 10.9 Hz, 1 H,
3-H), 3.30 [s, 9 H, C(OMe)3], 3.49 (s, 3 H, 5-OMe), 5.32 (dd,
J = 4.5, 6.6 Hz, 1 H, 5-H).
13C NMR (CDCl3, 176 MHz): δ = 30.3 (t, 4-C), 43.6 (d, 3-C), 50.5
[q, C(OMe)3], 57.4 (q, 5-OMe), 103.7 (d, 5-C), 113.2 [s, C(OMe)3],
172.5 (s, 2-C).
Starting from 2c (200 mg, 0.425 mmol) gave 3i (158 mg, 93%) as a
colorless liquid; bp 70–72 °C (1–2 mbar). Complete ring opening
was observed within 10 min.
IR (neat): 3100–2725 (C–H), 1760, 1740 (C=O), 1240, 1210, 1140
cm–1 (C–F).
1H NMR (400 MHz, CDCl3): δ = 1.24 (d, J = 7.3 Hz, 3 H, Me), 2.77
(dd, J = 5.0, 19.2 Hz, 1 H, 3-H), 2.96–3.06 (m, 1 H, 2-H), 3.22 (dd,
J = 8.2, 19.2 Hz, 1 H, 3-H), 3.67 (s, 3 H, CO2Me).
13C NMR (101 MHz, CDCl3): δ = 16.9 (q, Me), 34.2 (d, 2-C), 41.4
(t, 3-C), 52.4 (q, OMe), 108.5, 109.2, 110.4, 110.9 (4 mc, 5-C, 6-C,
7-C, 8-C), 117.3 (mc, 9-C), 174.8 (s, 1-C), 192.6 (t, 2JCF = 26.4 Hz,
4-C).
19F NMR (376 MHz, CDCl3): δ = –126.2, –122.3 (2 mc, 3 F, 6-F,
7-F, 8-F), –120.3 (t, J = 11.5 Hz, 2 F, 5-F), –80.7 (t, J = 8.4 Hz, 3 F,
9-F).
Methyl 5-Methoxy-2-oxotetrahydrofuran-3-carboxylate (6)
IR (neat): 3180–2830 (C–H), 1785, 1740 cm–1 (C=O).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C7H10NaO5: 197.0420;
found: 197.0404.
Major diastereomer
1H NMR (400 MHz, CDCl3): δ = 2.34 (ddd, J = 1.5, 9.0, 13.6 Hz, 1
H, 4-H), 2.74 (ddd, J = 5.8, 9.8, 13.6 Hz, 1 H, 4-H), 3.45 (s, 3 H, 5-
OMe), 3.71 (dd, J = 9.0, 9.8 Hz, 1 H, 3-H), 3.76 (s, 3 H, CO2Me),
5.45 (dd, J = 1.5, 5.8 Hz, 1 H, 5-H).
13C NMR (101 MHz, CDCl3): δ = 33.0 (t, 4-C), 45.0 (d, 3-C), 53.1
(q, 5-OMe), 56.9 (q, CO2Me), 104.0 (d, 5-C), 168.1 (s, CO2Me),
171.4 (s, 2-C).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C11H9F11NaO3:
421.0268; found: 421.0272.
Methyl 2-[2-Oxo-2-(perfluorophenyl)ethyl]pent-4-enoate (3j)
Starting from 2d (200 mg, 0.51 mmol) gave 3j (152 mg, 93%) as a
colorless liquid; bp 135–140 °C (0.1 mbar). Complete ring opening
was observed within 30 min.
Minor diastereomer
1H NMR (400 MHz, CDCl3): δ = 2.43–2.58 (m, 1 H, 4-H), 2.64
(ddd, J = 5.8, 10.3, 14.0 Hz, 1 H, 4-H), 3.48 (s, 3 H, 5-OMe), 3.55
(dd, J = 6.5, 10.3 Hz, 1 H, 3-H), 3.76 (s, 3 H, CO2Me), 5.41 (dd,
J = 3.6, 5.8 Hz, 1 H, 5-H).
13C NMR (101 MHz, CDCl3): δ = 32.3 (t, 4-C), 45.7 (d, 3-C), 53.2
(q, 5-OMe), 57.4 (q, CO2Me), 104.6 (d, 5-C), 167.7 (s, CO2Me),
170.6 (s, 2-C).
IR (neat): 3740–3225 (=C–H), 3225–2805 (C–H), 1735, 1715
(C=O), 1520, 1490 (C=C), 1350, 1320, 1270, 1140 cm–1 (C–F).
1H NMR (400 MHz, CDCl3): δ = 2.27–2.57 (2 m, 2 H, 2-CH2), 2.95
(tdd, J = 1.5, 4.1, 17.9 Hz, 1 H, 3-H), 3.09–3.23 (m, 1 H, 2-H), 3.27
(tdd, J = 1.2, 9.3, 17.9 Hz, 1 H, 3-H), 3.70 (s, 3 H, CO2Me), 5.03–
5.15 (2 m, 2 H, 5-H), 5.63–5.77 (m, 1 H, 4-H).
13C NMR (101 MHz, CDCl3): δ = 35.7 (t, 3-C), 39.9 (d, 2-C), 45.5
(t, JCF = 2.4 Hz, 2-CH2), 52.1 (mc, OMe), 117.6–118.7 (m, 5-C),
133.7–134.8 (m, 4-C), 137.7, 142.9, 144.5 (3 mc, Ar), 173.8–174.7
(m, 1-C), 192.3 (s, COAr).
19F NMR (376 MHz, CDCl3): δ = –159.8, –149.0, –140.5 (3 mc, 5
F, Ar–F).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C14H11F5NaO3:
345.0521; found: 345.0531.
1,1,1-Trifluoro-5,5-diphenylpent-4-en-2-one (7)
A 2.8 M PhMgBr in Et2O solution (1.25 mL, 3.50 mmol) was added
at –78 °C to a solution of 1a (300 mg, 1.17 mmol) in anhyd Et2O (5
mL). The mixture was allowed to warm to r.t. and was stirred for 3
h. After the addition of sat. aq NH4Cl solution (50 mL), the mixture
was diluted with Et2O (50 mL) and the aqueous layer was extracted
with another portion of Et2O (50 mL). The combined organic layers
were washed with brine (50 mL) and dried (Na2SO4). After removal
of the solvent the residue was taken up in MeOH (5 mL) and treated
with 37% aq HCl (464 μL, 4.68 mmol) at r.t. for 3 h. After evapo-
ration of the volatiles the crude product was purified by column
chromatography (silica gel, 15% EtOAc–hexane) to afford 7 (206
mg, 61%) as a colorless oil.
Anal. Calcd for C14H11F5O3 (322.2): C, 52.18; H, 3.44; found: C,
51.80; H, 3.22.
5-Methoxy-3-(trimethoxymethyl)dihydrofuran-2(3H)-one (5)
and Methyl 5-Methoxy-2-oxotetrahydrofuran-3-carboxylate
(6)
IR (neat): 3740–3150 (O–H), 3150–2810 (C–H), 1760 (C=O),
1645, 1600, 1495, 1445 (C=C), 1280, 1190, 1145 cm–1 (C–F).
1H NMR (400 MHz, CDCl3): δ = 3.56 (d, J = 7.0 Hz, 2 H, 3-H),
6.22 (t, J = 7.0 Hz, 1 H, 4-H), 7.06–7.61 (m, 10 H, Ph).
13C NMR (101 MHz, CDCl3): δ = 37.7 (t, 3-C), 115.7 (q, 1JCF = 292
Hz, 1-C), 116.2 (d, 4-C), 127.6, 128.00, 128.04, 128.4, 128.8, 129.5,
138.8, 141.4 (6 d, 2 s, Ph), 147.4 (s, 5-C), 189.7 (q, 2JCF = 35.1 Hz,
2-C).
To a solution of 1f (500 mg, 1.85 mmol) in anhyd MeOH (10 mL),
K2CO3 (511 mg, 3.70 mmol) was added and the suspension was
stirred at r.t. for 48 h. At this point the mixture became clear and a
19F NMR spectrum showed the disappearance of the starting mate-
rial and formation of KF (δ = –150.4). The solution was diluted with
CH2Cl2 (40 mL) and washed with water (2 × 50 mL). After drying
(Na2SO4) and removal of the solvents, the crude product was puri-
fied by column chromatography (silica gel, 50% Et2O–pentane) to
afford a mixture of 5 and 6 (213 mg, 64%, 5/6 1:2).
19F NMR (376 MHz, CDCl3): δ = –78.7 (s, 1-F).
5-Methoxy-3-(trimethoxymethyl)dihydrofuran-2(3H)-one (5)
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C9H16NaO6: 243.0839;
found: 243.0814.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C17H14F3O: 291.0991;
found: 291.0998.
1,1,1-Trifluoro-5,5-diphenylpentan-2-one (8)
Major diastereomer
Compound 7 (850 mg, 2.24 mmol) was dissolved in anhyd MeOH
(30 mL) and 10% Pd/C (72 mg, 0.067 mmol) was added. Under vig-
orous stirring the suspension was saturated with H2 for 15 min and
1H NMR (CDCl3, 700 MHz): δ = 2.10 (ddd, J = 2.6, 9.5, 13.9 Hz, 1
H, 4-H), 2.43–2.58 (m, 1 H, 4-H), 3.20 (dd, J = 7.6, 9.5 Hz, 1 H, 3-
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 2179–2187

2186
D. Gladow, H.-U. Reissig
PAPER
was then stirred at r.t. for 7 h under an atmosphere of H2. Filtration
through a short pad of celite and purification of the crude product
by column chromatography (silica gel, 0–10% EtOAc–hexane) af-
forded 8 (597 mg, 91%) as a colorless oil.
HRMS (EI): m/z [M + Na]+ calcd for C12H9F5O: 264.0574; found:
264.0576.
Anal. Calcd for C12H9F5O (264.2): C, 54.55; H, 3.43; found: C,
54.55; H, 3.44.
IR (neat): 3700–3195 (O–H), 3195–2735 (C–H), 1760 (C=O),
1600, 1495, 1450 (C=C), 1285, 1205, 1165, 1135 cm–1 (C–F).
1H NMR (CDCl3, 500 MHz): δ = 2.44 (td, J = 7.3, 8.0 Hz, 2 H, 4-
H), 2.69 (t, J = 7.3 Hz, 2 H, 3-H), 3.95 (t, J = 8.0 Hz, 1 H, 5-H),
7.19–7.34 (m, 10 H, Ph).
13C NMR (CDCl3, 125.8 MHz): δ = 28.1, 35.0 (2 t, 3-C, 4-C), 50.1
(d, 5-C), 115.6 (q, 1JCF = 292 Hz, 1-C), 126.8, 127.8, 128.8, 143.6
(3 d, s, Ph), 191.4 (q, 2JCF = 35.1 Hz, 2-C).
3-Benzoyl-4,4,4-trifluorobutanal (11)
A 2.8 M PhMgBr in Et2O solution (1.19 mL, 3.33 mmol) was added
to a solution of 1f (300 mg, 1.11 mmol) in anhyd THF (5 mL) and
the mixture was stirred under reflux for 6 h. After the addition of sat.
aq NH4Cl solution (50 mL), the mixture was diluted with Et2O (50
mL) and the aqueous layer was extracted with another portion of
Et2O (50 mL). The combined organic layers were washed with brine
(50 mL) and dried (Na2SO4). After removal of the solvent the resi-
due was taken up in hexane (5 mL) and a white precipitate was fil-
tered off. This procedure was repeated twice to obtain a yellow oil.
The crude oil was taken up in MeOH (5 mL) and treated with
PTSA·H2O (422 mg, 2.22 mmol) for 1 h at r.t. After evaporation of
the solvent, the crude product was purified by column chromatog-
raphy (silica gel, 5% EtOAc–hexane) to afford 11 (115 mg, 45%) as
a yellow oil. The product was slightly contaminated with biphenyl,
which was removed by preparative HPLC (nucleosil 50-5 column,
Macherey-Nagel; 3% EtOAc–hexane; 96 mL/min; UV detection at
254 nm) to obtain an analytically pure sample.
19F NMR (376 MHz, CDCl3): δ = –79.1 (s, 1-F).
Anal. Calcd for C17H15F3O (292.3): C, 69.85; H, 5.17; found: C,
69.82; H, 5.13.
1-(Perfluorophenyl)-4,4-diphenylbut-3-en-1-one (9)
A 2.8 M PhMgBr in Et2O solution (910 μL, 2.54 mmol) was added
to a solution of 1c (300 mg, 0.847 mmol) in anhyd Et2O (5 mL) and
the mixture was stirred at r.t. for 16 h. After the addition of sat. aq
NH4Cl solution (50 mL) the mixture was diluted with Et2O (50 mL)
and the aqueous layer was extracted with another portion of Et2O
(50 mL). The combined organic layers were washed with brine (50
mL) and dried (Na2SO4). After removal of the solvent, the residue
was taken up in MeOH (5 mL) and treated with 37% aq HCl (335
μL, 3.39 mmol) for 3 h at r.t. After evaporation of the solvent, the
crude product was purified by column chromatography (silica gel,
15% EtOAc–hexane) to afford 9 (240 mg, 73%) as a yellow oil,
which slowly solidified upon standing; mp 43–45 °C.
IR (neat): 3185–2590 (C–H), 1725, 1690 (C=O), 1595, 1580, 1450
(C=C), 1295, 1265, 1230, 1165, 1115 cm–1 (C–F).
1H NMR (400 MHz, CDCl3): δ = 3.04 (dd, J = 3.0, 19.2 Hz, 1 H, 2-
H), 3.61 (dd, J = 10.4, 19.2 Hz, 1 H, 2-H), 4.75 (ddq, J = 3.0, 10.4
Hz, 3JHF = 8.6 Hz, 1 H, 3-H), 6.91–8.16 (m, 5 H, Ph), 9.72 (s, 1 H,
1-H).
13C NMR (101 MHz, CDCl3): δ = 41.0 (t, 2-C), 43.6 (dq,
1
2JCF = 26.6 Hz, 3-C), 124.6 (q, JCF = 280 Hz, 4-C), 129.0, 134.3,
IR (neat): 3595–3175 (O–H), 3175–2760 (C–H), 1735 (C=O),
1650, 1520, 1495, 1445 (C=C), 1215, 1200, 1135 cm–1 (C–F).
136.2 (2 d, s, Ph), 192.7 (mc, 3-COPh), 197.3 (d, 1-C).
1H NMR (400 MHz, CDCl3): δ = 3.69 (d, J = 7.3 Hz, 2 H, 2-H),
6.28 (t, J = 7.3 Hz, 1 H, 3-H), 7.05–7.45 (m, 10 H, Ph).
13C NMR (101 MHz, CDCl3): δ = 46.0 (mc, 2-C), 118.0 (d, 3-C),
115.0, 137.6 142.7, 144.1 (4 mc, Ar), 127.5, 127.79, 127.84, 128.3,
128.6, 129.5, 139.1, 141.6 (6 d, 2 s, Ph), 146.9 (s, 4-C), 191.9 (mc,
1-C).
19F NMR (376 MHz, CDCl3): δ = –159.7 (mc, 2 F, Ar–F), –149.3
(mc, 1 F, Ar–F), –140.8 (mc, 2 F, Ar–F).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C22H13F5NaO:
411.0779; found: 411.0782.
19F NMR (376 MHz, CDCl3): δ = –65.9 (d, 3JFH = 8.7 Hz, 4-F).
HRMS (ESI-TOF): m/z [M
+ Na +
MeOH]+ calcd for
C12H13F3NaO3: 285.0709; found: 285.0710.
Acknowledgment
We gratefully acknowledge support by the Deutsche Forschungs-
gemeinschaft (GRK 1582 ‘Fluorine as Key Element’) and Bayer
HealthCare. We also thank M.Sc. V. Rohde and D. Reich (Freie
Universität Berlin) for preliminary studies of the ring-opening reac-
tions and Dr. R. Zimmer (Freie Universität Berlin) for assistance
during the preparation of this manuscript.
4-Methyl-1-(perfluorophenyl)pent-3-en-1-one (10)
A 3 M MeMgBr in Et2O solution (847 μL, 2.54 mmol) was added
to a solution of 1c (300 mg, 0.847 mmol) in anhyd THF (5 mL) and
the mixture was stirred at 50 °C for 3 h. After the addition of sat. aq
NH4Cl solution (50 mL), the mixture was diluted with Et2O (50 mL)
and the aqueous layer was extracted with another portion of Et2O
(50 mL). The combined organic layers were washed with brine (50
mL) and dried (Na2SO4). After removal of the solvent the residue
was taken up in MeOH (5 mL) and treated with 37% aq HCl (335
μL, 3.39 mmol) at r.t. for 3 h. After evaporation of the solvent, the
crude product was purified by column chromatography (silica gel,
15% EtOAc–hexane) to afford 10 (117 mg, 52%) as a yellow oil.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
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© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 2179–2187