The reaction of carboxylic acid esters with RfMgBr: A convenient synthesis of perfluoroalkyl ketones

Article abstract of DOI:10.1002/ejoc.201000887

An efficient method for the preparation of the synthetically attractive perfluoroalkyl ketones through the reaction of readily available alkenoates, alkynoates, or regular carboxylic esters with perfluoroalkyl Grignard reagents at -70 to -60 °C in diethyl

Full text of DOI:10.1002/ejoc.201000887

FULL PAPER
DOI: 10.1002/ejoc.201000887
The Reaction of Carboxylic Acid Esters with RfMgBr: A Convenient Synthesis
of Perfluoroalkyl Ketones
Can Xue,[a] Guangke He,[a] Chunling Fu,[a] Liqin Xue,[b] Zhenyang Lin,*[b] and
Shengming Ma*[a]
Keywords: Esters / Grignard reaction / Fluorine / Perfluoroalkanes / Ketones
An efficient method for the preparation of the synthetically
attractive perfluoroalkyl ketones through the reaction of
readily available alkenoates, alkynoates, or regular carbox-
ylic esters with perfluoroalkyl Grignard reagents at –70 to
–60 °C in diethyl ether with moderate to good yields was de-
veloped. The reaction stopped at the ketone stage, with no
further reaction to form the tertiary alcohols being observed.
DFT calculations confirmed that the perfluoroalkyl-substi-
tuted ketones are less electrophilic as compared to ordinary
ketones.
have focused our attention on the reactions of alkenoates,
alkynoates, and nonfluorinated carboxylic esters with
RfMgBr and on a theoretical study on the reactivities of
perfluoroalkyl ketones (Scheme 1).
Introduction
Perfluoroalkyl ketones are important intermediates in or-
ganic synthesis, materials science, and the pharmaceutical
industry.[1] A literature survey shows that perfluoroalk-
yllithium reagents (RfLi) have been extensively used in per-
fluoroalkylation reactions with amides, anhydrides, and carb-
oxylic esters, etc.[2–6] In most cases, a mixture of perfluoro-
alkyl ketones and diperfluoroalkyl-substituted tertiary
alcohols were obtained.[2,7] Reports on the preparation of
perfluoroalkyl ketones through the reactions of perfluoro-
alkyl Grignard reagents (RfMgX) with carboxylic esters are
very limited.[8–10] Recently, we have developed an efficient
method for the synthesis of perfluoroalkyl allenyl ketones
through the 1,2-addition/elimination reaction of allenoates
with RfMgX.[11] As a meaningful extension of this field, we
Results and Discussion
According to the established reaction conditions,[11] we
conducted the reaction of ethyl (E)-2-methyl-3-phenyl-2-
propenoate [(E)-1a] with 3.5 equiv. of n-C4F9MgBr in anhy-
drous Et2O at –60 °C. As a result, perfluorobutyl (1E)-1-
phenylprop-1-en-2-yl ketone [(E)-2a] was formed in an iso-
lated yield of 85% (Table 1, Entry 1). n-C4F9MgBr was pre-
pared by the I/Mg exchange reaction of n-C4F9I with
EtMgBr in anhydrous Et2O at –70 °C.[12] We attempted to
reduce the amount of RfMgBr, but the reaction with 2.0,
2.5 and 3.0 equiv. of the Grignard reagents led to incom-
plete conversions (Table 1, Entries 2–4). Furthermore, it is
interesting to note that only 5% of ketone (E)-2a was ob-
served when tetrahydrofuran (THF) was used as the solvent
1
(determined by H NMR spectroscopic analysis); the reac-
tion in toluene afforded ketone (E)-2a in 74% yield with
26% recovery of (E)-1a.
As the starting materials are easily available, we then
started to explore the scope of this reaction with the opti-
mized reaction conditions (Table 2). A conjugated carbon–
carbon double bond in the starting material remained un-
touched in the reaction. The experimental results showed
that for 2-monosubstituted (Table 2, Entries 3 and 4) and
2,3-disubstituted (Table 2, Entries 1 and 2) ethyl 2-alk-
enoates, the reaction proceeded smoothly with yields rang-
ing from 82 to 85%. However, when 3-monosubstituted
ethyl 2-alkenoate (1c) was subjected to the same reaction
conditions, considerable amounts of starting material were
also recovered (Table 2, Entry 5).
Scheme 1. Reactions of RfMgBr with allenoates (previous work[11]
and alkenoates, alkynoates, and nonfluorinated carboxylic esters
(this work).
)
[a] Laboratory of Molecular Recognition and Synthesis,
Department of Chemistry, Zhejiang University,
Hangzhou 310027, Zhejiang, P. R. China
Fax: +86-216-260-9305
E-mail: masm@sioc.ac.cn
[b] Department of Chemistry, Hong Kong University of Science
and Technology,
Clear Water Bay, Hong Kong, P. R. China
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201000887.
7012
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Synthesis of Perfluoroalkyl Ketones
Table 1. Optimization of the reaction of ethyl (E)-2-methyl-3-phenyl-2-propenoate with n-C4F9MgBr.
Entry
x [equiv.]
Solvent
Time [h]
NMR yield of (E)-2a [%]
Recovery of (E)-1a [%]
1
2
3
4
5
6
3.5
2.0
2.5
3.0
3.5
3.5
Et2O
Et2O
Et2O
Et2O
THF
11
48
48
48
24
24
85[a]
51
68
81
5
0
39
30
14
94
26
toluene
74
[a] Isolated yield.
Table 2. Reaction of alkenoates with perfluoroalkyl Grignard reagents.
Entry
R1
R2
Rf (equiv.)
Time [h]
Yield of 2 [%][a]
1
2
3
4
5
Ph
Ph
H
H
Ph
Me [(E)-1a]
Me [(E)-1a]
Bn (1b)
n-C4F9 (3.5)
n-C6F13 (4.0)
n-C4F9 (3.5)
n-C6F13 (4.0)
n-C4F9 (3.5)
11
11
11
11
24
85 [(E)-2a]
85 [(E)-2b]
82 (2c)
Bn (1b)
84 (2d)
H [(E)-1c]
51 [(E)-2e][b]
[a] Isolated yield. [b] Starting material [(E)-1c] was recovered (28%).
We then explored the reaction of a range of substituted expected target products could also be obtained in yields
ethyl 2-alkynoates with RfMgBr. Alkyl- and aryl-substi- ranging from 87 to 94% (Table 3, Entries 10 and 11).
tuted ethyl 2-alkynoates could be readily converted into the
As reported previously, usually, a mixture of ketones and
corresponding 1-alkynyl perfluoroalkyl ketones upon ad- tertiary alcohols are produced when perfluoroalkyllithium
dition of RfMgBr with good to excellent yields (Table 3, reagents are added to normal carboxylic esters.[7,8] We
Entries 1–3). The substituents on the aryl ring had no sig- therefore attempted to carry out the reaction of ethyl n-
nificant effect on the reaction (Table 3, Entries 4–9). It octanoate (1j) with 3.5 equiv. of n-C4F9MgBr under our re-
should be noted that for substrates substituted with a het- action conditions (Table 4, Entry 1) and were surprised to
eroaromatic group (e.g., ethyl 3-thienylpropiolate; 1i), the find that the starting material was converted into n-heptyl
nonafluorobutyl ketone (2q) completely. Aryl and alkyl
carboxylates could readily be transformed into the corre-
sponding perfluoroalkyl ketones without the formation of
Table 3. Reaction of alkynoates with perfluoroalkyl Grignard rea-
gents.
Table 4. Reaction of nonfluorinated carboxylic esters with perfluo-
roalkyl Grignard reagents.
Entry
R
Rf (equiv.)
Time [h] Yield of 2 [%][a]
1
2
3
4
5
6
7
8
9
n-C4H9 (1d)
Ph (1e)
Ph (1e)
n-C6F13 (4.0)
n-C4F9 (3.5)
n-C6F13 (4.0)
11
14.5
11
18
18
11
21.5
17
17
12
94 (2f)
91 (2g)
89 (2h)
83 (2i)
75 (2j)
97 (2k)
96 (2l)
79 (2m)
75 (2n)
87 (2o)
94 (2p)
Entry
R
Rf (equiv.)
Time [h]
Yield of 2 [%][a]
4-MeOC6H4 (1f) n-C4F9 (4.0)
4-MeOC6H4 (1f) n-C6F13 (4.0)
4-n-PrC6H4 (1g) n-C4F9 (3.5)
4-n-PrC6H4 (1g) n-C6F13 (4.5)
4-FC6H4 (1h)
4-FC6H4 (1h)
3-thienyl (1i)
3-thienyl (1i)
1
2
3
4
5
6
7
n-C7H15 (1j)
n-C7H15 (1j)
Ph (1k)
n-C4F9 (3.5)
n-C6F13 (4.0)
n-C4F9 (3.5)
n-C6F13 (4.0)
16.5
15.5
14.5
16
24
13
87 (2q)
82 (2r)
61 (2s)
86 (2t)[b]
77 (2u)
86 (2v)
82 (2w)
n-C4F9 (3.5)
n-C6F13 (4.0)
n-C4F9 (3.5)
n-C6F13 (4.0)
Ph (1k)
cyclohexyl (1l) n-C6F13 (4.0)
cumyl (1m) n-C4F9 (3.5)
adamantyl (1n) n-C4F9 (3.5)
10
11
21.5
24
[a] Isolated yield.
[a] Isolated yield. [b] Starting material was also recovered (3.5%).
Eur. J. Org. Chem. 2010, 7012–7019
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Z. Lin, S. Ma et al.
FULL PAPER
tertiary alcohols (Table 4, Entries 2–4). The reactions of
RfMgBr with secondary and tertiary alkyl carboxylates,
such as cyclohexyl, cumyl, and adamantyl carboxylates
(Table 4, Entries 5–7) also afforded the expected products
2u–w in rather good yields. These results indicate that the
relatively weaker nucleophilicity of RfMgBr compared to
RfLi enables the reaction to stop at the ketone stage com-
pletely.
The reaction could also be carried out on a scale of 4.0–
20 mmol to afford the corresponding perfluoroalkyl
ketones (E)-2a, 2g, and 2x in 92, 87, and 55% yields, respec-
tively (Scheme 2).
Scheme 3. Comparsion of methyl ketones with trifluoromethyl
ketones.
ketones A1 and B1, respectively. The greater conjugation in
A2 or B2 increases the inertness of their carbonyl moieties
toward nucleophiles.
Conclusions
We have developed an efficient method with which to
prepare perfluoroalkyl ketones through the reaction of alk-
enoates, alkynoates, or nonfluorinated carboxylic esters
with perfluoroalkyl Grignard reagents. The results of the
DFT calculations are consistent with the experimental ob-
servation of less electrophilic carbonyl moieties in the per-
fluoroalkyl ketones as compared to those of nonfluorinated
ketones. In the perfluoroalkyl ketones, the charge density
loss at the carbonyl carbon atom to the perfluoroalkyl
group is apparently more compensated for by π-electron do-
nation from the carbonyl oxygen atom, leading to a more
inert carbonyl moiety. Due to the ready availability of the
starting materials and to the relative convenience of
RfMgBr compared to the corresponding RfLi reagents, this
approach will provide a convenient method for introducing
perfluoroalkyl groups into organic molecules.
Scheme 2. Larger scale reactions of 1a, 1e, and 1o with n-
C4F9MgBr.
Theoretical Studies on the Reactivity of Methyl Ketones
versus Trifluoromethyl Ketones
The experimental results presented above, together with
our previous observations,[11] point to the fact that the per-
fluoroalkyl group in a perfluoroalkyl ketone RfC(O)R helps
stabilize the carbonyl moiety, preventing it from further re-
actions towards the RfMgBr reagent. To better understand
this stabilization effect, we performed density functional
theory (DFT) calculations by using the B3LYP functional
on four different perfluoroalkyl ketones (Scheme 3).
Scheme 3 shows the bond lengths, atomic charges, and
bond orders calculated for two methyl ketones, A1 and A2,
as well as two trifluoromethyl ketones, B1 and B2. The
atomic charges and bond orders, which are Wiberg bond
indices[13] and a measure of bond strength, were obtained
by using the natural bond orbital (NBO) analysis.[14] The
DFT results clearly show that the trifluoromethyl group en-
hances the C=O bonding interaction. The C=O bond in B1
is noticeably shorter than that in A1, and its bond order is
larger. A similar trend can also be observed for B2 when
compared with A2. The atomic charges calculated for the
carbonyl carbon atoms in B1 and B2 are less positive than
those in A1 and A2, respectively, implying that the carbonyl
carbon atoms in the perfluoroalkyl ketones are less electro-
philic. The atomic charges calculated for the carbonyl car-
bon atom in the allenyl ketones A2 and B2 were determined
Experimental Section
General: Et2O was distilled from Na/benzophenone. EtMgBr was
produced freshly just before the reaction. The other commercially
available chemicals were purchased and used without additional
purification. Petroleum ether with a boiling range of 30–60 °C was
used. Flash-column chromatography was carried out on silica gel
1
H (10–40 µm). H, 13C and 19F NMR spectra were recorded with
a Bruker AM-300 spectrometer. IR spectra were recorded with a
Perkin–Elmer 983 spectrometer. Mass spectra were recorded with
an HP 5989A spectrometer.
n-Perfluorobutyl (1E)-1-Phenylprop-1-en-2-yl Ketone [(E)-2a]. Typi-
cal Procedure I: To a dried Schlenk tube were added n-C4F9I
(0.36 mL, d = 2.01 g/mL, 0.72 g, 2.09 mmol) and anhydrous Et2O
(2.5 mL). The resulting mixture was cooled to –70 °C with a cool-
to be less positive than those in their corresponding alkyl ing bath, and a solution of EtMgBr (0.48 mL, 3.0 m in Et2O,
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Synthesis of Perfluoroalkyl Ketones
1.44 mmol) was added dropwise at –70 °C with stirring. After the
addition, anhydrous Et2O (0.75 mL) was applied to rinse the re-
maining EtMgBr. The resulting mixture was stirred at –70 °C for
1.5 h. A solution of (E)-1a (76.5 mg, 0.40 mmol) in anhydrous Et2O
(1 mL) was then added to this resulting mixture dropwise at –70 °C
within 10 min with stirring, and the mixture was warmed to –60 °C
within 10 min and stirred at –60 °C for 11 h (reaction monitored by
TLC analysis). The mixture was quenched with saturated aqueous
NH4Cl (5 mL) at –60 °C. After warming slowly to room temp.,
n-Perfluorobutyl 3-Phenylprop-1-en-2-yl Ketone (2c): According to
Typical Procedure I, the reaction of n-C4F9I (0.36 mL, d = 2.01 g/
mL, 0.72 g, 2.09 mmol) with EtMgBr (0.48 mL, 3.0 m in Et2O,
1.44 mmol) in Et2O (3.25 mL) at –70 °C, afforded the Grignard
reagent, which was treated with 1b (76.5 mg, 0.40 mmol) in Et2O
(1 mL) at –60 °C for 11 h to afford 2c (120.0 mg, 82%) as a liquid.
1H NMR (300 MHz, CDCl3): δ = 7.36–7.20 (m, 3 H, ArH), 7.19–
7.13 (m, 2 H, ArH), 6.43 (d, J = 0.6 Hz, 1 H, =CH), 6.05 (s, 1 H,
=CH), 3.66 (s, 2 H, CH2) ppm. 13C NMR (75 MHz, CDCl3): δ =
H2O (5 mL) was added, and the mixture was extracted with Et2O 183.7 (app. td, J1 = 25.1, J2 = 1.3 Hz), 143.2 (t, J = 2.2 Hz), 137.1,
(3ϫ20 mL). The combined organic extracts were washed with
brine (5 mL) and dried with anhydrous Na2SO4. Filtration, concen-
tration, and purification by chromatography on silica gel (petro-
leum ether, boiling range 30–60 °C) afforded (E)-2a (124.0 mg,
132.6 (app. tt, J = 3.7 Hz), 129.1, 128.7, 126.8, 37.7 ppm. 19F NMR
(282 MHz, CDCl3): δ = –80.9 to –81.1 (m, 3 F), –112.0 to –112.2
(m, 2 F), –121.9 to –122.1 (m, 2 F), –125.2 to –125.5 (m, 2 F) ppm.
IR (neat): ν = 3033, 2928, 1706, 1497, 1455, 1439, 1355, 1238, 1138,
˜
1
85%) as a liquid. H NMR (300 MHz, CDCl3): δ = 7.78 (s, 1 H,
1096, 1075, 1047 cm–1. MS (EI, 70 eV): m/z (%) = 365 (6.47) [M+
C=CH), 7.50–7.38 (m, 5 H, ArH), 2.17 (s, 3 H, CH3) ppm. 13C + 1], 364 (45.01) [M]+, 145 (100). HRMS: calcd. for C14H9F9O
NMR (75 MHz, CDCl3): δ = 184.7 (t, J = 24.3 Hz), 145.8 (app. tt,
J = 5.4 Hz), 134.8, 132.7 (t, J = 2.1 Hz), 130.3, 129.9, 128.7,
13.7 ppm. 19F NMR (282 MHz, CDCl3): δ = –81.0 to –81.1 (m, 3
F), –110.2 to –110.3 (m, 2 F), –121.6 to –121.9 (m, 2 F), –125.0 to
[M]+ 364.0510; found 364.0519.
n-Perfluorohexyl 3-Phenylprop-1-en-2-yl Ketone (2d): According to
Typical Procedure I, the reaction of n-C6F13I (0.54 mL, d = 2.063 g/
mL, 1.11 g, 2.50 mmol) with EtMgBr (0.54 mL, 3.0 m in Et2O,
1.62 mmol) in Et2O (3.0 mL) at –70 °C, afforded the Grignard rea-
gent, which was treated with 1b (77.6 mg, 0.41 mmol) in Et2O
(1 mL) at –60 °C for 11 h to afford 2d (158.7 mg, 84%) as a liquid:
1H NMR (300 MHz, CDCl3): δ = 7.36–7.12 (m, 5 H, ArH), 6.42
(s, 1 H, =CH), 6.05 (s, 1 H, =CH), 3.66 (s, 2 H, CH2) ppm. 13C
NMR (75 MHz, CDCl3): δ = 183.7 (t, J = 25.2 Hz), 143.3 (t, J =
1.8 Hz), 137.1, 132.6 (app. tt, J = 6.5 Hz), 129.2, 128.7, 126.8,
37.8 ppm. 19F NMR (282 MHz, CDCl3): δ = –80.8 to –81.1 (m, 3
F), –111.8 to –112.1 (m, 2 F), –120.9 to –121.5 (m, 4 F), –122.7 to
–125.2 (m, 2 F) ppm. IR (neat): ν = 1690, 1616, 1577, 1492, 1449,
˜
1395, 1354, 1327, 1236, 1164, 1137, 1066, 1006 cm–1. MS (EI,
70 eV): m/z (%) = 365 (6.34) [M+ + 1], 364 (38.19) [M]+, 117 (100).
HRMS: calcd. for C14H9F9O [M]+ 364.0510; found 364.0512.
Large-Scale Reaction for the Synthesis of n-Perfluorobutyl (1E)-1-
Phenylprop-1-ene-2-yl Ketone [(E)-2a]. Typical Procedure II: To an
oven-dried, three-necked, round-bottom flask were added n-C4F9I
(5.0 mL, d = 2.01 g/mL, 10.05 g, 29.05 mmol) and anhydrous Et2O
(34 mL). After the mixture was cooled in a –70 °C cooling bath, a
solution of EtMgBr (6.4 mL, 3.0 m in Et2O, 19.2 mmol) was added
dropwise at –70 °C with stirring for 15 min. After the addition,
anhydrous Et2O (12 mL) was applied to rinse the remaining
EtMgBr. The resulting mixture was stirred at –70 °C for 1.5 h. A
solution of (E)-1a (1.0467 g, 5.5 mmol) in Et2O (12 mL) was then
added dropwise with stirring at –70 °C within 10 min, and the mix-
ture was warmed to –60 °C within 5 min and stirred at –60 °C for
18 h (reaction monitored by TLC, eluted with pure petroleum ether
twice). The mixture was quenched with saturated aqueous NH4Cl
(25 mL) at –60 °C, and, after the mixture had been warmed slowly
to room temp., H2O (15 mL) was added. The organic layer was
separated, and the aqueous layer was extracted with Et2O
(5ϫ20 mL). The combined organic extracts were washed with
brine (15 mL) and dried with anhydrous Na2SO4. Filtration, con-
centration, and purification by chromatography on silica gel (petro-
leum ether, boiling range 30–60 °C) afforded (E)-2a (1.8434 g, 85%)
as a liquid.
–123.1 (m, 2 F), –126.1 to –126.4 (m, 2 F) ppm. IR (neat): ν =
˜
3067, 3033, 2927, 1705, 1605, 1497, 1455, 1439, 1364, 1316, 1241,
1206, 1146, 1075, 1031, 1008 cm–1. MS (EI, 70 eV): m/z (%) = 465
(5.86) [M+ + 1], 464 (32.76) [M]+, 145 (100). HRMS: calcd. for
C16H9F13O [M]+ 464.0446; found 464.0452.
n-Perfluorobutyl (E)-Styryl Ketone [(E)-2e]:[3b] According to Typical
Procedure I, the reaction of n-C4F9I (0.46 mL, d = 2.01 g/mL,
0.92 g, 2.67 mmol) with EtMgBr (0.60 mL, 3.0 m in Et2O,
1.80 mmol) in Et2O (3.0 mL) at –70 °C, afforded the Grignard rea-
gent, which was treated with (E)-1c (70.6 mg, 0.40 mmol) in Et2O
(1 mL) at –60 °C for 24 h, to afford (E)-2e (72.3 mg, 51%) as a
liquid, with recovery of (E)-1c (28% by 1H NMR analysis). 1H
NMR (300 MHz, CDCl3): δ = 8.00 [d, J = 15.6 Hz, 1 H, =C(Ph)-
H], 7.72–7.63 (m, 2 H, ArH), 7.55–7.41 (m, 3 H, ArH), 7.13 [d, J
= 15.9 Hz, 1 H, =C(CO)H] ppm. 13C NMR (75 MHz, CDCl3): δ
= 182.0 (t, J = 25.3 Hz), 150.0, 133.3, 132.4, 129.4, 129.2,
116.9 ppm. 19F NMR (282 MHz, CDCl3): δ = –80.8 to –81.1 (m,
3 F), –121.1 to –121.4 (m, 2 F), –123.2 to –123.5 (m, 2 F), –125.7
n-Perfluorohexyl (1E)-1-Phenylprop-1-en-2-yl Ketone [(E)-2b]: Ac-
cording to Typical Procedure I, the reaction of n-C6F13I (0.54 mL,
d = 2.063 g/mL, 1.11 g, 2.50 mmol) with EtMgBr (0.54 mL, 3.0 m
in Et2O, 1.62 mmol) in Et2O (3.0 mL) at –70 °C, afforded the Grig-
nard reagent, which was treated with (E)-1a (74.9 mg, 0.39 mmol)
in Et2O (1 mL) at –60 °C for 11 h to afford (E)-2b (156.2 mg, 85%)
to –126.0 (m, 2 F) ppm. IR (neat): ν = 3066, 3032, 1712, 1609,
˜
1577, 1497, 1452, 1339, 1306, 1235, 1206, 1136, 1084, 1012 cm–1.
MS (EI, 70 eV): m/z (%) = 351 (4.31) [M+ + 1], 350 (29.66)
[M]+, 131 (100). HRMS: calcd. for C13H7F9O [M]+ 350.0353; found
350.0355.
1
as a liquid. H NMR (300 MHz, CDCl3): δ = 7.79 (s, 1 H, =CH),
7.51–7.37 (m, 5 H, ArH), 2.17 (s, 3 H, CH3) ppm. 13C NMR n-Hex-1-yn-1-yl n-Perfluorohexyl Ketone (2f): According to Typical
(75 MHz, CDCl3): δ = 184.6 (t, J = 24.5 Hz), 145.8 (app. tt, J =
Procedure I, the reaction of n-C6F13I (0.53 mL, d = 2.063 g/mL,
6.2 Hz), 134.8, 132.7 (t, J = 2.1 Hz), 130.3, 129.9, 128.6 (d, J = 1.09 g, 2.45 mmol) with EtMgBr (0.53 mL, 3.0 m in Et2O,
5.7 Hz), 13.7 ppm. 19F NMR (282 MHz, CDCl3): δ = –80.9 to
1.59 mmol) in Et2O (3.0 mL) at –70 °C, afforded the Grignard rea-
–81.2 (m, 3 F), –110.0 to –110.3 (m, 2 F), –120.7 to –121.3 (m, 4
gent, which was treated with 1d (62.6 mg, 0.41 mmol) in Et2O
F), –122.8 to –123.1 (m, 2 F), –126.1 to –126.4 (m, 2 F) ppm. IR (1 mL) at –60 °C for 11 h, to afford 2f (164.4 mg, 94%) as a liquid.
(neat): ν = 3064, 3031, 2931, 1690, 1617, 1577, 1493, 1449, 1395, 1H NMR (300 MHz, CDCl3): δ = 2.52 (t, J = 6.9 Hz, 2 H,
˜
1363, 1313, 1240, 1145, 1124, 1070, 1024, 1006 cm–1. MS (EI, CϵCCH2), 1.70–1.58 (m, 2 H, CH2), 1.53–1.39 (m, 2 H, CH3CH2),
70 eV): m/z (%) = 465 (4.37) [M+ + 1], 464 (22.73) [M]+, 117 (100).
0.95 (t, J = 7.4 Hz, 3 H, CH3) ppm. 13C NMR (75 MHz, CDCl3):
δ = 169.0 (t, J = 30.3 Hz), 106.2, 77.0, 29.1, 21.8, 19.2, 13.3 ppm.
HRMS: calcd. for C16H9F13O [M]+ 464.0446; found 464.0438.
Eur. J. Org. Chem. 2010, 7012–7019
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Z. Lin, S. Ma et al.
FULL PAPER
19F NMR (282 MHz, CDCl3): δ = –80.7 to –80.9 (m, 3 F), –118.4
to –118.7 (m, 2 F), –121.4 to –122.0 (m, 4 F), –122.7 to –123.1 (m,
2.063 g/mL, 1.11 g, 2.50 mmol) with EtMgBr (0.54 mL, 3.0 m in
Et2O, 1.62 mmol) in Et2O (3.0 mL) at –70 °C afforded the Grignard
reagent, which was treated with 1f (76.2 mg, 0.40 mmol) in Et2O
(1 mL) at –60 °C for 18 h, to afford 2j (144.2 mg, 75%) as a liquid.
1H NMR (300 MHz, CDCl3): δ = 7.67–7.60 (m, 2 H, ArH), 6.99–
6.92 (m, 2 H, ArH), 3.88 (s, 3 H, CH3) ppm. 13C NMR (75 MHz,
CDCl3): δ = 168.6 (t, J = 30.4 Hz), 163.4, 136.4, 114.8, 109.8, 103.5,
85.1, 55.5 ppm. 19F NMR (282 MHz, CDCl3): δ = –80.8 to –81.1
(m, 3 F), –118.2 to –118.6 (m, 2 F), –121.4 to –122.1 (m, 4 F),
–122.7 to –123.1 (m, 2 F), –126.1 to –126.5 (m, 2 F) ppm. IR (neat):
2 F), –126.1 to –126.4 (m, 2 F) ppm. IR (neat): ν = 2932, 2215,
˜
1708, 1458, 1240, 1205, 1147 cm–1. MS (ESI): m/z = 427 [M –
H]–. HRMS (ESI): calcd. for C13H8F13O– [M – H]– 427.0373; found
427.0357.
n-Perfluorobutyl Phenylacetylenyl Ketone (2g): According to Typi-
cal Procedure I, the reaction of n-C4F9I (0.36 mL, d = 2.01 g/mL,
0.72 g, 2.09 mmol) with EtMgBr (0.48 mL, 3.0 m in Et2O,
1.44 mmol) in Et2O (3.25 mL) at –70 °C, afforded the Grignard
reagent, which was treated with 1e (69.8 mg, 0.40 mmol) in Et2O
(1 mL) at –60 °C for 14.5 h, to afford 2g (127.3 mg, 91%) as a li-
ν = 3010, 2961, 2941, 2847, 2186, 1694, 1602, 1568, 1511, 1466,
˜
1445, 1364, 1240, 1145, 1083, 1035 cm–1. MS (EI, 70 eV): m/z (%)
= 479 (2.40) [M+ + 1], 478 (13.47) [M]+, 159 (100). HRMS: calcd.
for C16H7F13O2 [M]+ 478.0238; found 478.0241.
1
quid. H NMR (300 MHz, CDCl3): δ = 7.71–7.66 (m, 2 H, ArH),
7.62–7.55 (m, 1 H, ArH), 7.50–7.43 (m, 2 H, ArH) ppm. 13C NMR
(75 MHz, CDCl3): δ = 168.9 (t, J = 30.8 Hz), 134.0, 132.6, 129.0,
118.1, 101.5, 84.3 ppm. 19F NMR (282 MHz, CDCl3): δ = –80.8 to
–81.0 (m, 3 F), –118.5 to –118.7 (m, 2 F), –122.6 to –122.8 (m, 2
n-Perfluorobutyl [4-(n-Propyl)phenyl]acetylenyl Ketone (2k): Ac-
cording to Typical Procedure I, the reaction of n-C4F9I (0.36 mL,
d = 2.01 g/mL, 0.72 g, 2.09 mmol) with EtMgBr (0.48 mL, 3.0 m in
Et2O, 1.44 mmol) in Et2O (3.25 mL) at –70 °C afforded the Grig-
nard reagent, which was treated with 1g (87.0 mg, 0.40 mmol) in
Et2O (1 mL) at –60 °C for 11 h, to afford 2k (152.2 mg, 97%) as a
liquid. 1H NMR (300 MHz, CDCl3): δ = 7.62–7.55 (m, 2 H, ArH),
7.29–7.23 (m, 2 H, ArH), 2.65 (t, J = 7.7 Hz, 2 H, ArCH2), 1.73–
1.59 (m, 2 H, CH3CH2), 0.95 (t, J = 7.4 Hz, 3 H, CH3) ppm. 13C
NMR (75 MHz, CDCl3): δ = 168.8 (t, J = 30.5 Hz), 148.6, 134.1,
129.2, 115.2, 102.6, 84.5, 38.3, 24.1, 13.6 ppm. 19F NMR
(282 MHz, CDCl3): δ = –81.0 to –81.1 (m, 3 F), –118.6 to –118.7
(m, 2 F), –122.7 to –123.0 (m, 2 F), –125.7 to –126.0 (m, 2 F) ppm.
F), –125.6 to –125.8 (m, 2 F) ppm. IR (neat): ν = 2927, 2855,
˜
2200, 1701, 1597, 1491, 1446, 1354, 1310, 1238, 1138, 1084, 1028,
1008 cm–1. MS (EI, 70 eV): m/z (%) = 348 (3.34) [M]+, 129 (100).
HRMS: calcd. for C13H5F9O [M]+ 348.0197; found 348.0197.
Large-Scale Preparation of n-Perfluorobutyl Phenylacetylenyl
Ketone (2g): According to Typical Procedure II, the reaction of n-
C4F9I (3.6 mL, d = 2.01 g/mL, 7.24 g, 20.91 mmol) with EtMgBr
(4.8 mL, 3.0 m in Et2O, 14.4 mmol) in Et2O (32 mL) at –70 °C, af-
forded the Grignard reagent, which was treated with 1e (0.6975 g,
4.0 mmol)/Et2O (10 mL) at –60 °C for 16.5 h, to afford 2g
(1.2186 g, 87%) as a liquid.
IR (neat): ν = 3036, 2966, 2937, 2877, 2195, 1698, 1605, 1508, 1467,
˜
1414, 1382, 1355, 1311, 1237, 1138, 1083, 1021, 1007 cm–1. MS (EI,
70 eV): m/z (%) = 391 (1.82) [M+ + 1], 390 (10.43) [M]+, 171 (100).
HRMS: calcd. for C16H11F9O [M]+ 390.0666; found 390.0667.
n-Perfluorohexyl Phenylacetylenyl Ketone (2h): According to Typi-
cal Procedure I, the reaction of n-C6F13I (0.53 mL, d = 2.063 g/mL,
1.09 g, 2.45 mmol) with EtMgBr (0.53 mL, 3.0 m in Et2O,
1.59 mmol) in Et2O (3.0 mL) at –70 °C, afforded the Grignard rea-
gent, which was treated with 1e (67.9 mg, 0.39 mmol) in Et2O
(1 mL) at –60 °C for 11 h, to afford 2h (154.8 mg, 89%) as a liquid.
1H NMR (300 MHz, CDCl3): δ = 7.71–7.64 (m, 2 H, ArH), 7.61–
7.54 (m, 1 H, ArH), 7.50–7.41 (m, 2 H, ArH) ppm. 13C NMR
(75 MHz, CDCl3): δ = 168.9 (t, J = 30.7 Hz), 134.0, 132.6, 129.0,
118.1, 101.5, 84.2 ppm. 19F NMR (282 MHz, CDCl3): δ = –80.9 to
–81.1 (m, 3 F), –118.4 to –118.7 (m, 2 F), –121.4 to –122.0 (m, 4
F), –122.8 to –123.2 (m, 2 F), –126.2 to –126.5 (m, 2 F) ppm. IR
n-Perfluorohexyl [4-(n-Propyl)phenyl]acetylenyl Ketone (2l): Accord-
ing to Typical Procedure I, the reaction of n-C6F13I (0.60 mL, d =
2.063 g/mL, 1.24 g, 2.78 mmol) with EtMgBr (0.60 mL, 3.0 m in
Et2O, 1.80 mmol) in Et2O (3.0 mL) at –70 °C afforded the Grignard
reagent, which was treated with 1g (87.0 mg, 0.40 mmol) in Et2O
(1 mL) at –60 °C for 21.5 h, to afford 2l (190.1 mg, 96%) as a li-
1
quid. H NMR (300 MHz, CDCl3): δ = 7.64–7.53 (m, 2 H, ArH),
7.31–7.21 (m, 2 H, ArH), 2.65 (t, J = 7.7 Hz, 2 H, ArCH2), 1.74–
1.59 (m, 2 H, CH3CH2), 0.95 (t, J = 7.4 Hz, 3 H, CH3) ppm. 13C
NMR (75 MHz, CDCl3): δ = 168.8 (t, J = 30.6 Hz), 148.6, 134.1,
129.2, 115.2, 102.6, 84.5, 38.3, 24.1, 13.6 ppm. 19F NMR
(282 MHz, CDCl3): δ = –80.9 to –81.2 (m, 3 F), –118.3 to –118.6
(m, 2 F), –121.5 to –122.0 (m, 4 F), –122.8 to –123.0 (m, 2 F),
(neat): ν = 3068, 2957, 2930, 2197, 1701, 1597, 1491, 1446, 1364,
˜
1319, 1240, 1146, 1084, 1037 cm–1. MS (EI, 70 eV): m/z (%) = 448
(1.53) [M]+, 129 (100). HRMS: calcd. for C15H5F13O [M]+
448.0133; found 448.0135.
–126.1 to –126.5 (m, 2 F) ppm. IR (neat): ν = 3036, 2966, 2937,
˜
(4-Methoxyphenyl)acetylenyl n-Perfluorobutyl Ketone (2i): Accord-
ing to Typical Procedure I, the reaction of n-C4F9I (0.42 mL, d =
2.01 g/mL, 0.84 g, 2.44 mmol) with EtMgBr (0.54 mL, 3.0 m in
Et2O, 1.62 mmol) in Et2O (3 mL) at –70 °C, afforded the Grignard
reagent, which was treated with 1f (77.1 mg, 0.41 mmol) in Et2O
(1 mL) at –60 °C for 18 h, to afford 2i (126.9 mg, 83%) as a liquid.
1H NMR (300 MHz, CDCl3): δ = 7.66–7.60 (m, 2 H, ArH), 6.98–
6.92 (m, 2 H, ArH), 3.88 (s, 3 H, CH3) ppm. 13C NMR (75 MHz,
CDCl3): δ = 168.6 (t, J = 30.6 Hz), 163.4, 136.4, 114.8, 109.7, 103.5,
85.1, 55.5 ppm. 19F NMR (282 MHz, CDCl3): δ = –80.9 to –81.1
(m, 3 F), –118.5 to –118.6 (m, 2 F), –122.7 to –123.0 (m, 2 F),
2877, 2192, 1698, 1605, 1508, 1467, 1414, 1364, 1319, 1240, 1146,
1083, 1035, 1021 cm–1. MS (EI, 70 eV): m/z (%) = 490 (4.21)
[M]+, 171 (100). HRMS: calcd. for C18H11F13O [M]+ 490.0602;
found 490.0603.
(4-Fluorophenyl)acetylenyl n-Perfluorobutyl Ketone (2m): According
to Typical Procedure I, the reaction of n-C4F9I (0.36 mL, d =
2.01 g/mL, 0.72 g, 2.09 mmol) with EtMgBr (0.48 mL, 3.0 m in
Et2O, 1.44 mmol) in Et2O (3.25 mL) at –70 °C afforded the Grig-
nard reagent, which was treated with 1h (72.0 mg, 0.40 mmol) in
Et2O (1 mL) at –60 °C for 17 h, to afford 2m (117.4 mg, 79%) as a
liquid. 1H NMR (300 MHz, CDCl3): δ = 7.76–7.65 (m, 2 H, ArH),
7.22–7.10 (m, 2 H, ArH) ppm. 13C NMR (75 MHz, CDCl3): δ =
168.8 (t, J = 30.9 Hz), 165.2 (d, J = 255.7 Hz), 136.5 (d, J =
8.4 Hz), 116.7 (d, J = 22.1 Hz), 114.3 (d, J = 3.5 Hz), 100.3,
84.3 ppm. 19F NMR (282 MHz, CDCl3): δ = –80.9 to –81.2 (m, 3
F), –102.3 to –102.5 (m, 1 F), –118.6 to –118.8 (m, 2 F), –122.7 to
–125.7 to –126.0 (m, 2 F) ppm. IR (neat): ν = 3014, 2939, 2847,
˜
2188, 1691, 1601, 1567, 1511, 1466, 1444, 1421, 1355, 1301, 1237,
1172, 1138, 1083, 1030 cm–1. MS (EI, 70 eV): m/z (%) = 379 (2.09)
[M+ + 1], 378 (13.49) [M]+, 159 (100). HRMS: calcd. for
C14H7F9O2 [M]+ 378.0302; found 378.0302.
(4-Methoxyphenyl)acetylenyl n-Perfluorohexyl Ketone (2j): Accord-
ing to Typical Procedure I, the reaction of n-C6F13I (0.54 mL, d =
–123.0 (m, 2 F), –125.7 to –126.0 (m, 2 F) ppm. IR (neat): ν =
˜
7016
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 7012–7019

Synthesis of Perfluoroalkyl Ketones
2201, 1699, 1600, 1509, 1408, 1355, 1311, 1240, 1158, 1138, 1083,
(m, 2 F), –123.3 to –123.6 (m, 2 F), –125.8 to –126.1 (m, 2 F) ppm.
1008 cm–1. MS (EI, 70 eV): m/z (%) = 366 (1.46) [M]+, 147 (100). IR (neat): ν = 2960, 2932, 2861, 1759, 1467, 1405, 1354, 1237, 1137,
˜
HRMS: calcd. for C13H4F10O [M]+ 366.0102; found 366.0103.
1073 cm–1. MS (ESI): m/z = 345 [M – H]–. HRMS (ESI): calcd. for
C12H14F9O– [M – H]– 345.0906; found 345.0892.
(4-Fluorophenyl)acetylenyl n-Perfluorohexyl Ketone (2n): According
to Typical Procedure I, the reaction of n-C6F13I (0.54 mL, d =
2.063 g/mL, 1.11 g, 2.50 mmol) with EtMgBr (0.54 mL, 3.0 m in
Et2O, 1.62 mmol) in Et2O (3.0 mL) at –70 °C afforded the Grignard
n-Heptyl n-Perfluorohexyl Ketone (2r): According to Typical Pro-
cedure I, the reaction of n-C6F13I (0.53 mL, d = 2.063 g/mL, 1.09 g,
2.45 mmol) with EtMgBr (0.53 mL, 3.0 m in Et2O, 1.59 mmol) in
reagent, which was treated with 1h (73.0 mg, 0.41 mmol) in Et2O Et2O (3.0 mL) at –70 °C afforded the Grignard reagent, which was
(1.5 mL) at –60 °C for 17 h, to afford 2n (144.2 mg, 75%) as a li-
treated with 1j (69.8 mg, 0.41 mmol) in Et2O (1 mL) at –60 °C for
1
quid. H NMR (300 MHz, CDCl3): δ = 7.75–7.65 (m, 2 H, ArH),
15.5 h, to afford 2r (148.6 mg, 82%) as a liquid. 1H NMR
7.21–7.11 (m, 2 H, ArH) ppm. 13C NMR (75 MHz, CDCl3): δ = (300 MHz, CDCl3): δ = 2.75 (t, J = 7.2 Hz, 2 H, COCH2), 1.73–
168.8 (t, J = 30.6 Hz), 165.2 (d, J = 255.6 Hz), 136.5 (d, J =
10.3 Hz), 116.7 (d, J = 22.4 Hz), 114.3 (d, J = 3.5 Hz), 100.3,
84.3 ppm. 19F NMR (282 MHz, CDCl3): δ = –80.8 to –81.1 (m, 3
F), –102.3 to –102.5 (m, 1 F), –118.4 to –118.6 (m, 2 F), –121.4 to
–122.0 (m, 4 F), –122.7 to –123.4 (m, 2 F), –126.1 to –126.5 (m, 2
1.60 (m, 2 H, CH2), 1.38–1.20 [m, 8 H, (CH2)4], 0.93–0.82 (m, 3
H, CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 194.1 (t, J =
25.8 Hz), 37.9, 31.6, 28.9, 28.7, 22.6, 22.5, 13.9 ppm. 19F NMR
(282 MHz, CDCl3): δ = –80.8 to –81.0 (m, 3 F), –120.3 to –120.6
(m, 2 F), –121.5 to –121.8 (m, 2 F), –122.2 to –122.5 (m, 2 F),
–122.7 to –123.1 (m, 2 F), –126.1 to –126.4 (m, 2 F) ppm. IR (neat):
F) ppm. IR (neat): ν = 2198, 1703, 1601, 1509, 1240, 1158, 1146,
˜
1083, 1034 cm–1. MS (EI, 70 eV): m/z (%) = 466 (2.24) [M]+, 147 ν = 2967, 2931, 2865, 1759, 1241, 1206, 1146, 1017 cm–1. MS (ESI):
˜
(100). HRMS: calcd. for C15H4F14O [M]+ 466.0039; found m/z = 445 [M – H]–. HRMS (ESI): calcd. for C14H14F13O– [M –
466.0040.
H]– 445.0843; found 445.0823.
n-Perfluorobutyl 3-Thienylacetylenyl Ketone (2o): According to
Typical Procedure I, the reaction of n-C4F9I (0.36 mL, d = 2.01 g/
n-Perfluorobutyl Phenyl Ketone (2s):[4] According to Typical Pro-
cedure I, the reaction of n-C4F9I (0.36 mL, d = 2.01 g/mL, 0.72 g,
mL, 0.72 g, 2.09 mmol) with EtMgBr (0.48 mL, 3.0 m in Et2O, 2.09 mmol) with EtMgBr (0.48 mL, 3.0 m in Et2O, 1.44 mmol) in
1.44 mmol) in Et2O (3.25 mL) at –70 °C afforded the Grignard rea-
Et2O (3.25 mL) at –70 °C afforded the Grignard reagent, which was
gent, which was treated with 1i (70.7 mg, 0.39 mmol) in Et2O
treated with 1k (61.6 mg, 0.41 mmol) in Et2O (1 mL) at –60 °C for
(1 mL) at –60 °C for 12 h, to afford 2o (121.0 mg, 87%) as a liquid. 14.5 h, to afford 2s (81.5 mg, 61%) as a liquid. 1H NMR
1H NMR (300 MHz, CDCl3): δ = 8.00–7.96 (m, 1 H, =CH), 7.43–
7.39 (m, 1 H, =CH), 7.33–7.29 (m, 1 H, =CH) ppm. 13C NMR
(75 MHz, CDCl3): δ = 168.8 (t, J = 30.9 Hz), 137.5, 130.4, 126.9,
117.6, 96.9, 84.9 ppm. 19F NMR (282 MHz, CDCl3): δ = –80.9 to
–81.1 (m, 3 F), –118.5 to –118.7 (m, 2 F), –122.7 to –122.9 (m, 2
(300 MHz, CDCl3): δ = 8.08 (d, J = 7.5 Hz, 2 H, ArH), 7.77–7.67
(m, 1 H, ArH), 7.60–7.50 (m, 2 H, ArH) ppm. 13C NMR (75 MHz,
CDCl3): δ = 183.2 (t, J = 25.8 Hz), 135.4, 131.5 (t, J = 2.1 Hz),
130.2 (t, J = 3.2 Hz), 129.0 ppm. 19F NMR (282 MHz, CDCl3): δ
= –80.8 to –81.1 (m, 3 F), –112.8 to –113.1 (m, 2 F), –121.8 to
F), –125.7 to –125.9 (m, 2 F) ppm. IR (neat): ν = 3116, 2191,
–122.1 (m, 2 F), –125.2 to –125.4 (m, 2 F) ppm. IR (neat): ν = 1712,
˜
˜
1698, 1512, 1356, 1237, 1199, 1138, 1089, 1077, 1011 cm–1. MS (EI,
70 eV): m/z (%) = 354 (12.92) [M]+, 135 (100). HRMS: calcd. for
C11H3F9OS [M]+ 353.9761; found 353.9761.
1599, 1451, 1356, 1304, 1237, 1137, 1025 cm–1. MS (EI, 70 eV): m/z
(%) = 324 (0.04) [M]+, 305 (2.59) [M+ – F], 277 (6.48) [M+ – F –
CO], 105 (100). HRMS: calcd. for C11H5F9O [M]+ 324.0197; found
324.0187.
n-Perfluorohexyl 3-Thienylacetylenyl Ketone (2p): According to
Typical Procedure I, the reaction of n-C6F13I (0.54 mL, d = 2.063 g/
n-Perfluorohexyl Phenyl Ketone (2t):[5] According to Typical Pro-
mL, 1.11 g, 2.50 mmol) with EtMgBr (0.54 mL, 3.0 m in Et2O, cedure I, the reaction of n-C6F13I (0.54 mL, d = 2.063 g/mL, 1.11 g,
1.62 mmol) in Et2O (3.0 mL) at –70 °C afforded the Grignard rea-
gent, which was treated with 1i (71.7 mg, 0.40 mmol) in Et2O
(1 mL) at –60 °C for 21.5 h, to afford 2p (169.9 mg, 94%) as a li-
2.50 mmol) with EtMgBr (0.54 mL, 3.0 m in Et2O, 1.62 mmol) in
Et2O (3.0 mL) at –70 °C afforded the Grignard reagent, which was
treated with 1k (59.1 mg, 0.39 mmol) in Et2O (1 mL) at –60 °C for
16 h, to afford 2t (144.5 mg, 86%) as a liquid together with recov-
1
quid. H NMR (300 MHz, CDCl3): δ = 8.00–7.96 (m, 1 H, =CH),
7.43–7.39 (m, 1 H, =CH), 7.33–7.29 (m, 1 H, =CH) ppm. 13C
ery of 1k (3.5%). H NMR (300 MHz, CDCl3): δ = 8.13–8.04 (m,
1
NMR (75 MHz, CDCl3): δ = 168.9 (t, J = 31.2 Hz), 137.4, 130.4, 2 H, ArH), 7.76–7.67 (m, 1 H, ArH), 7.60–7.50 (m, 2 H, ArH)
126.9, 117.6, 96.8, 84.9 ppm. 19F NMR (282 MHz, CDCl3): δ =
–80.9 to –81.1 (m, 3 F), –118.4 to –118.6 (m, 2 F), –121.5 to –122.0
(m, 4 F), –122.8 to –123.1 (m, 2 F), –126.2 to –126.5 (m, 2 F) ppm.
ppm. 13C NMR (75 MHz, CDCl3): δ = 183.3 (t, J = 25.6 Hz),
135.4, 131.6 (t, J = 2.0 Hz), 130.2 (t, J = 3.6 Hz), 129.0 ppm. 19F
NMR (282 MHz, CDCl3): δ = –80.8 to –81.0 (m, 3 F), –112.7 to
–112.9 (m, 2 F), –120.9 to –121.4 (m, 4 F), –122.7 to –123.1 (m, 2
IR (neat): ν = 3117, 2193, 1698, 1513, 1363, 1318, 1240, 1145, 1089,
˜
1078, 1038, 1020 cm–1. MS (EI, 70 eV): m/z (%) = 454 (7.01) F), –126.1 to –126.3 (m, 2 F) ppm. IR (neat): ν = 1713, 1600, 1452,
˜
[M]+, 135 (100). HRMS: calcd. for C13H3F13OS [M]+ 453.9697;
found 453.9699.
1365, 1312, 1240, 1205, 1144, 1126 cm–1. MS (EI, 70 eV): m/z (%)
= 424 (0.02) [M]+, 405 (6.10) [M+ – F], 377 (3.37) [M+ – F – CO],
105 (100). HRMS: calcd. for C13H5F13O [M]+ 424.0133; found
424.0151.
n-Heptyl n-Perfluorobutyl Ketone (2q): According to Typical Pro-
cedure I, the reaction of n-C4F9I (0.36 mL, d = 2.01 g/mL, 0.72 g,
2.09 mmol) with EtMgBr (0.48 mL, 3.0 m in Et2O, 1.44 mmol) in
Et2O (3.25 mL) at –70 °C afforded the Grignard reagent, which was
treated with 1j (68.4 mg, 0.40 mmol) in Et2O (1 mL) at –60 °C for
16.5 h, to afford 2q (119.6 mg, 87%) as a liquid. 1H NMR
(300 MHz, CDCl3): δ = 2.74 (t, J = 7.2 Hz, 2 H, COCH2), 1.74–
1.60 (m, 2 H, CH2), 1.41–1.20 [m, 8 H, (CH2)4], 0.88 (t, J = 6.8 Hz,
Cyclohexyl n-Perfluorohexyl Ketone (2u): According to Typical Pro-
cedure I, the reaction of n-C6F13I (0.54 mL, d = 2.063 g/mL, 1.10 g,
2.50 mmol) with EtMgBr (0.54 mL, 3.0 m in Et2O, 1.62 mmol) in
Et2O (3 mL) at –70 °C afforded the Grignard reagent, which was
treated with 1l (62.7 mg, 0.41 mmol) in Et2O (1 mL) at –60 °C for
24 h, to afford 2u (132.5 mg, 77%) as a liquid after purification by
3 H, CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 194.1 (t, J = column chromatography (n-hexane). 1H NMR (300 MHz, CDCl3):
25.9 Hz), 37.9, 31.6, 28.9, 28.7, 22.6, 22.4, 14.0 ppm. 19F NMR
δ = 2.97–2.83 (m, 1 H, COCH), 1.96–1.78 (m, 4 H, CH2CH2), 1.77–
(282 MHz, CDCl3): δ = –81.0 to –81.2 (m, 3 F), –120.6 to –120.8 1.67 (m, 1 H, CH), 1.53–1.17 (m, 5 H, C2H4CH) ppm. 13C NMR
Eur. J. Org. Chem. 2010, 7012–7019
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7017

Z. Lin, S. Ma et al.
FULL PAPER
(75 MHz, CDCl3): δ = 197.4 (t, J = 25.0 Hz), 46.1, 28.2, 25.4,
25.2 ppm. 19F NMR (282 MHz, CDCl3): δ = –80.8 to –81.0 (m, 3
F), –119.6 to –119.9 (m, 2 F), –121.4 to –121.8 (m, 2 F), –121.9 to
–122.2 (m, 2 F), –122.7 to –123.1 (m, 2 F), –126.0 to –126.4 (m, 2
identify all stationary points as minima (zero imaginary frequency).
The 6-31G* basis set was used for C, O, F, and H atoms. All the
calculations were performed with the Gaussian 03 software pack-
age.[15] The natural bond orbital (NBO) program,[16] as im-
plemented in Gaussian 03, was also used to obtain the natural pop-
F) ppm. IR (neat): ν = 2941, 2864, 1751, 1453, 1364, 1316, 1241,
˜
1207, 1146, 1075 cm–1. MS (EI, 70 eV): m/z (%) = 430 (0.07) ulation of atoms.
[M]+, 411 (2.37) [M+ – F], 131 (7.95) [C3F5+], 111 (30.08) [M+
–
Supporting Information (see footnote on the first page of this arti-
C6F13], 83 (100). HRMS: calcd. for C13H11F13O [M]+ 430.0602;
found 430.0581.
1
cle): Copies of H, 13C, and 19F NMR spectra of all compounds.
Cumyl n-Perfluorobutyl Ketone (2v): According to Typical Pro-
cedure I, the reaction of n-C4F9I (0.36 mL, d = 2.01 g/mL, 0.72 g,
2.09 mmol) with EtMgBr (0.48 mL, 3.0 m in Et2O, 1.44 mmol) in
Et2O (3.2 mL) at –70 °C afforded the Grignard reagent, which was
treated with 1m (76.5 mg, 0.40 mmol) in Et2O (1 mL) at –60 °C for
13 h to afford 2v (125.9 mg, 86%) as a liquid after purification by
column chromatography (n-hexane). 1H NMR (300 MHz, CDCl3):
δ = 7.42–7.34 (m, 2 H, ArH), 7.33–7.26 (m, 1 H, ArH), 7.26–7.20
(m, 2 H, ArH), 1.61 (s, 6 H, CH3) ppm. 13C NMR (75 MHz,
CDCl3): δ = 196.6 (app. tt, J = 24.1 Hz), 139.8, 129.0, 127.7, 125.8,
51.8 (t, J = 1.8 Hz), 24.8 ppm. 19F NMR (282 MHz, CDCl3): δ =
–81.0 to –81.3 (m, 3 F), –111.3 to –111.6 (m, 2 F), –121.5 to –122.0
Acknowledgments
Financial support from the National Natural Science Foundation
of China (No. 20732005, 20972135) and the Zhejiang Provincial
Natural Science Foundation of China (No. Y4090217) is greatly
appreciated. We thank Binjie Guo for reproducing the results pre-
sented in Table 2 (Entry 2), Table 3 (Entry 6), and Table 4 (Entry 3].
S. M. is a Qiu Shi Adjunct Professor at Zhejiang University.
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[3] For the reaction of nonfluorinated carboxylates with RfI in the
presence of MeLi/LiBr affording perfluoroalkyl ketones, see: a)
R. J. Cregge, T. T. Curran, W. A. Metz, J. Fluorine Chem. 1998,
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reagents to afford perfluoroalkyl ketones, see: P. Moreau, N.
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[6] For the reaction of perfluoroalkylated esters or carboxylic ac-
ids with organometallic reagents (LDA, PhLi, Al/HgCl2,
CH3MgBr, and NaOCH3) to afford the perfluoroalkyl ketones,
see: a) J. T. Reeves, J. J. Song, Z. Tan, H. Lee, N. K. Yee, C. H.
Senanayake, J. Org. Chem. 2008, 73, 9476–9478; b) X. Jiang,
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(m, 2 F), –125.7 to –126.1 (m, 2 F) ppm. IR (neat): ν = 3065, 3030,
˜
2985, 2938, 1739, 1497, 1475, 1449, 1355, 1295, 1238, 1215, 1136,
1090, 1076 cm–1. MS (EI, 70 eV): m/z (%) = 366 (0.05) [M]+, 347
(0.45) [M+ – F], 277 (1.10) [M+ – CF3 – HF], 219 (1.26) [C4F9+],
119 (100). HRMS: calcd. for C14H11F9O [M]+ 366.0666; found
366.0653.
Adamantyl n-Perfluorobutyl Ketone (2w): According to Typical Pro-
cedure I, the reaction of n-C4F9I (0.36 mL, d = 2.01 g/mL, 0.72 g,
2.09 mmol) with EtMgBr (0.48 mL, 3.0 m in Et2O, 1.44 mmol) in
Et2O (3.2 mL) at –70 °C afforded the Grignard reagent, which was
treated with 1n (84.9 mg, 0.41 mmol) in Et2O (1 mL) at –60 °C for
24 h to afford 2w (128.0 mg, 82%) as a liquid. 1H NMR (300 MHz,
CDCl3): δ = 2.14–2.05 (m, 3 H, CH2CH), 1.99 (d, J = 3 Hz, 6 H,
3ϫ CCH2), 1.84–1.68 (m, 6 H, 3ϫ CH2) ppm. 13C NMR (75 MHz,
CDCl3): δ = 198.1 (app. tt, J = 23.9 Hz), 47.5 (t, J = 2.2 Hz), 36.8
(t, J = 1.9 Hz), 36.2, 27.6 ppm. 19F NMR (282 MHz, CDCl3): δ =
–81.1 to –81.3 (m, 3 F), –113.4 to –113.7 (m, 2 F), –121.6 to –121.9
(m, 2 F), –125.0 to –125.3 (m, 2 F) ppm. IR (neat): ν = 2913, 2859,
˜
2683, 2663, 1731, 1455, 1353, 1321, 1236, 1134, 1060, 1036 cm–1.
MS (EI, 70 eV): m/z (%) = 382 (0.04) [M]+, 363 (0.78) [M+ – F], 219
(0.05) [C4F9+], 163 (1.44) [M+ – C4F9], 135 (100). HRMS: calcd. for
C15H15F9O [M]+ 382.0979; found 382.0963.
tert-Butyl n-Perfluorobutyl Ketone (2x): According to Typical Pro-
cedure II, the reaction of n-C4F9I (18.1 mL, d = 2.01 g/mL, 36.4 g,
105 mmol) with EtMgBr (23.4 mL, 3.0 m in Et2O, 70.2 mmol) in
Et2O (140 mL) at –70 °C afforded the Grignard reagent, which was
treated with 1o (2.6012 g, 20 mmol) in Et2O (10 mL) at –60 °C for
24 h to afford 2x (3.3239 g, 55%) as a liquid after distillation (b.p.
1
107–109 °C/760 Torr). H NMR (300 MHz, CDCl3): δ = 1.31 (t, J
= 1.1 Hz, 9 H, 3 CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 199.0
(app. tt, J = 24.5 Hz), 44.6 (t, J = 2.4 Hz), 25.6 (t, J = 2.0 Hz) ppm.
19F NMR (282 MHz, CDCl3): δ = –81.0 to –81.2 (m, 3 F), –112.8
to –113.2 (m, 2 F), –121.7 to –122.0 (m, 2 F), –125.1 to –125.4 (m,
2 F) ppm. IR (neat): ν = 2981, 2926, 2886, 2858, 1739, 1484, 1468,
˜
1372, 1355, 1240, 1138, 1090, 1067 cm–1. MS (EI, 70 eV): m/z (%)
= 289 (2.18) [M+ – CH3], 219 (1.96) [C4F9+], 131 (4.75) [C3F5+],
119 (4.47) [C2F5+], 100 (5.03) [C2F4+], 84(100). HRMS: calcd. for
C9H9F9O [M]+ 304.0510; found 304.0513.
Computational Details: Molecular geometries were optimized at the
Becke3LYP (B3LYP) level of density functional theory. Frequency
calculations at the same level of theory were also performed to
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Received: June 21, 2010
Published Online: November 9, 2010
Eur. J. Org. Chem. 2010, 7012–7019
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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