Easy access to CF2-containing molecules based on the reaction of 2,2,3,3-tetrafluorooxetane with various nucleophiles

Article abstract of DOI:10.1039/c1ob05545c

2,2,3,3-Tetrafluorooxetane reacted easily with organolithium reagents to give 1,1,3-trisubstituted 2,2-difluoropropan-1-ols in good to excellent yields. On the other hand, the reaction with Grignard reagent led to 3-bromo-1,1-disubstituted 2,2-difluoropro

Full text of DOI:10.1039/c1ob05545c

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PAPER
Easy access to CF2-containing molecules based on the reaction of
2,2,3,3-tetrafluorooxetane with various nucleophiles†
Shigeyuki Yamada, Masahiro Kato, Yudai Komori, Tsutomu Konno and Takashi Ishihara*
Received 7th April 2011, Accepted 13th May 2011
DOI: 10.1039/c1ob05545c
2,2,3,3-Tetrafluorooxetane reacted easily with organolithium reagents to give 1,1,3-trisubstituted
2,2-difluoropropan-1-ols in good to excellent yields. On the other hand, the reaction with Grignard
reagent led to 3-bromo-1,1-disubstituted 2,2-difluoropropan-1-ols in good yields. On treating with
lithium enolates, generated from enol silyl ethers and MeLi/LiBr, the corresponding
1-bromo-2,2-difluoro-3,5-dicarbonyl compounds were obtained in fair to good yields.
3-Iodo-2,2-difluoropropanoate, prepared readily from 2,2,3,3-tetrafluorooxetane and NaI, reacted
successfully with various silyl enol ethers in the presence of a radical initiator to provide the
corresponding coupling products in good yields.
Introduction
Incorporation of fluorine atom(s) into organic molecules often
changes their structure, stability, reactivity, and biological activity,
and thereby frequently leads to the discovery of novel potent
applications in various domains from liquid crystalline materials
to biologically active substances, peptide isosteres or enzyme
inhibitors.1 Consequently, a wide variety of synthetic methods
have hitherto been developed for the preparation of various types
of fluorine-incorporated compounds.2
Among such compounds, organic molecules containing an a,a-
difluorinated carbonyl backbone have recently been recognized as
one of the most important units for the application to a potent HIV
protease inhibitor, etc.3 Generally, it is well-known that molecules
A having a heteroatom substituent, such as a hydroxyl or an amino
group, at the b position can easily be prepared via the Reformatsky
reaction or its variant using commercially available a-halo-a,a-
difluoroacetate 1 (Scheme 1).4 However, the fluorinated molecules
B, without any heteroatom substituent at the b position, are very
difficult to be constructed by the above methods (Scheme 2). To
the best of our knowledge, there have been only a few reports on
the preparation of B so far.5
Scheme 2 Intended programs.
Therefore, the development of easy and effective synthetic
methods for such molecules are highly desirable. Herein we
wish to disclose easy access to various types of CF2-containing
molecules, including a,a-difluorinated carbonyl compounds with-
out a heteroatom substituent at the b position, based on the
nucleophilic reaction with 2,2,3,3-tetrafluorooxetane (2)6,7 or the
radical reaction of 3, which can easily be prepared from 2, in detail.
Results and discussion
Reaction of 2,2,3,3-tetrafluorooxetane with organolithium reagents
Initially, we attempted a nucleophilic ring-opening reaction of
2,2,3,3-tetrafluorooxetane (2) with organolithium reagents (R–Li)
(4) as shown in Table 1.
Thus, on treating 2 with 1.1 equiv of freshly prepared
PhLi (4a) in THF/Et2O at -78 ◦C for 2 h, 2,2-difluoro-1,1,3-
triphenylpropan-1-ol (5a) was obtained in 21% yield, together
with a large amount of the unreacted starting oxetane 2 (Entry
1). As shown in Entries 2 and 3, increasing the amount of 4a
led to satisfactory results, and the best yield of 5a (78%) was
obtained when 2 was treated with 4.4 equiv of 4a in THF at -78 ◦C
for 2 h (Entry 3). However, (Z)-2-fluoroallyl alcohol 6a was also
Scheme 1 Reformatsky reaction.
Department of Chemistry and Materials Technology, Kyoto Institute of
Technology, Matsugasaki, Sakyo-ku, Kyoto, 606-0962, Japan. E-mail:
ishihara@kit.ac.jp
† Electronic supplementary information (ESI) available: NMR spectra.
See DOI: 10.1039/c1ob05545c
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Table 1 Reaction of 2 with various organolithium reagents 4
Table 2 Reaction of 2 with various Grignard reagents 7
Temp./◦
C
Yielda/%
of 8
Organolithium
Entry reagents (RLi)
Equiv Temp./◦ Yielda/% Yielda/%
Grignard reagents
(RMgBr)
Equiv
of 7
of 4
C
of 5
of 6
Entry
1b
2b
3c
PhLi (4a)
1.1
2.2
4.4
4.4
4.4
5.5
4.4
4.4
4.4
4.4
-78
-78
-78
-20
r.t.
21
41
78
49
33
11
55
38
25
—
0
0
1
2
3
4
5
6
PhMgBr (7a)
2.2
2.2
4.4
4.4
4.4
4.4
4.4
4.4
4.4
4.4
4.4
0
18
16
87 (78)
24
69 (69)
92 (78)
—
—
—
—
33
PhLi (4a)
PhMgBr (7a)
r.t.
r.t.
reflux
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
PhLi (4a)
18
43
58
71
10
58
43
—
PhMgBr (7a)
PhMgBr (7a)
4c
PhLi (4a)
5c
PhLi (4a)
4-MeOC6H4MgBr (7b)
4-CH3C6H4MgBr (7c)
1-NpMgBr (7d)
n-BuMgBr (7e)
s-BuMgBr(7f)
6c,d
7c
PhLi (4a)
r.t.
7b
8b
9b
10b
11
4-MeOC6H4Li (4b)
4-CF3C6H4Li (4c)
n-BuLi (4d)
-78
-78
-78
-78
8c
9c
10e
c-HexMgBr(7g)
11d
12
13
4.4
4.4
4.4
-78
-20
-20
6
0
0
0
12
4.4
r.t.
(91)
91 (77)
a Determined by 19F NMR. Values in parentheses are of isolated yield. b
complex mixture was obtained.
A
quant.
(78)
14
15
4.4
4.4
-20
-20
99 (78)
99 (73)
0
0
Thus, treatment of 2 with 2.2 equiv of freshly prepared phenyl-
magnesium bromide (7a) in THF at 0 ◦C or room temperature for
20 h did not provide any trace of 2,2-difluoropropanol derivative
5a, but led to 3-bromo-2,2-difluoropropanol derivative 8a in low
yield (Entries 1 and 2). The reaction with 4.4 equiv of 7a in THF
at room temperature for 20 h took place smoothly to give 8a in
87% yield as a sole product (Entry 3), though the reaction at
the reflux temperature did not afford a satisfactory result (Entry
4). Aromatic Grignard reagents, such as 4-methoxyphenyl- (7b)
and 4-methylphenylmagnesium bromide (7c), could participate
nicely in the reaction, leading to the corresponding 8b and 8c in
good to excellent yields (Entries 5 and 6). However, neither 1-
naphthylmagnesium bromide (7d) nor alkylmagnesium bromides
(7e, 7f and 7g) were found to be effective for the present
reaction (Entries 7–10). While alkenylmagnesium bromide 7h was
somewhat less reactive (Entry 11), alkynylmagnesium bromide 7i
reacted well with 2 to afford 8i in 91% yield (Entry 12).
a Determined by 19F NMR. Values in parentheses are of isolated yield. b
A
large amount of the starting oxetane 2 remained unreacted. c The products,
5 and 6 were obtained as an inseparable mixture. d Carried out for 20 h.
e A complex mixture was obtained.
observed in 18% yield as byproduct, and we found that both were
inseparable. Raising the reaction temperature caused an increase
in the amount of 6a (Entries 3–5). When 2 was treated with 5.5
equiv of 4a at room temperature for 20 h, the corresponding (Z)-
6a was formed in 71% yield (Entry 6). In this case, 11% of 5a still
remained unreacted. Various sorts of organolithium reagents were
also applied to this reaction under the conditions as described in
Entry 3. 4-Methoxyphenyllithium (4b) was found to be effective for
this reaction, leading to 2,2-difluoropropanol derivative 5b in 55%
yield, along with 10% of (Z)-2-fluoroallyl alcohol 6b (Entry 7). By
contrast, 4-(trifluoromethyl)phenyllithium (4c) and n-BuLi (4d)
provided the corresponding (Z)-2-fluoroallyl alcohols 6c and 6d
in 58% and 43% yields as a major product, respectively (Entries 8
and 9). The use of alkenyllithium 4e did not result in a satisfactory
result (Entry 10). While phenyl◦ethynyllithium (4f) also did not
react with the oxetane 2 at -78 C (Entry 11), a higher reaction
temperature (-20 ◦C) resulted in a quantitative formation of 5f
(Entry 12). Various lithium acetylides 4g, 4h and 4i could also
participate successfully in the nucleophilic ring-opening reaction
to give the corresponding 2,2-difluoropropanol derivatives 5g, 5h
and 5i in excellent yields, respectively (Entries 13–15).
A possible reaction mechanism
As shown in Scheme 3, 2,2,3,3-tetrafluorooxetane (2) may be
opened by nucleophilic attack of the organolithium reagent at
the methylene carbon to form 3-substituted 2,2-difluoropropanoyl
fluoride (Int-A), which undergoes double nucleophilic attack by
the organolithium reagent, followed by hydrolysis, affording 3-
substituted 2,2-difluoropropanol derivative 5. (Z)-2-Fluoroallyl
alcohol 6 would be obtained by E2-type H–F elimination from
lithium alkoxide Int-B through a preferable conformation Int-
B¢. In the case of the Grignard reaction, MgBr2 species, which
would be formed from RMgBr via Schlenk equilibrium, might
attack the methylene carbon of 2 much faster than RMgBr, leading
to 3-bromo-2,2-difluoropropanoyl fluoride (Int-C). The resulting
Int-C would be immediately transformed into the alkoxide Int-D
Reaction of 2,2,3,3-tetrafluorooxetane with Grignard reagents
Similarly, we examined the reaction of 2,2,3,3-tetrafluorooxetane
(2) with Grignard reagents (7) as tabulated in Table 2.
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Scheme 4 MgX2-induced ring-opening reaction of 2.
Scheme 5 MgBr2-induced ring-opening/nucleophilic attack sequence
leading to 3-bromo-2,2-difluoropropanoates.
Scheme 3 A possible reaction mechanism.
by double nucleophilic attack of the Grignard reagent, providing
the 3-bromo-2,2-difluoropropanol derivative 8 after hydrolysis.
MgX2-induced ring-opening reaction of 2
The above results of the reaction with Grignard reagents led us to
be interested in the MgX2-induced ring-opening reaction of 2.
On treatment of 2 with 0.6 equiv of MgBr2 in THF at room tem-
perature for 3 h, not only 3-bromo-2,2-difluoropropanoyl fluoride
(Int-C) but also 4-bromobutyl 3-bromo-2,2-difluoropropanoate
(9) were observed in 53% and 29% yields, respectively. The use
of 1.2 equiv of MgBr2 caused a significant improvement of the
yield, 9 being obtained in 76% yield. MgI2 was also found to be
very effective for this reaction, the corresponding iodinated ester
10 being afforded in 89% yield. These esters would be formed as
shown in Scheme 4. Thus, MgX2 activates the carbonyl group of
acid fluoride Int-C, followed by simultaneous nucleophilic attack
by THF–oxygen, leading to an oxonium ion intermediate, which
may be attacked by X- to form the corresponding ester 9 or 10.
This ring-opening reaction could also be employed for the
one-pot preparation of ethyl 3-bromo-2,2-difluoropropanoates 11.
Thus, treatment of 2,2,3,3-tetrafluorooxetane (2) with 2.0 equiv
of MgBr2 in Et2O at room temperature for 3 h provided the
corresponding ethyl ester in 81% yield (Scheme 5).
Scheme 6 One-pot preparation of 2,2-difluorinated carbonyl compound
from 2.
Reaction of 2,2,3,3-tetrafluorooxetane with enolates
Next, we attempted to address the reaction of 2,2,3,3-
tetrafluorooxetane (2) with enolates. The results are summarized
in Table 3.
Thus, treatment of 2 with 2.0 equiv of lithium enolate 13a, pre-
pared from LDA and acetophenone, in THF at room temperature
for 2 h gave the enol 14a in only 19% yield (Entry 1). Prolonged
reaction time (20 h) did not lead to a dramatic change (Entry 2).
Additionally, the use of 3.0–4.0 equiv of 14a caused only a slight
increase of the yield of 15a (Entries 3 and 4).
The reaction with lithium enolate 13a, generated from a-
silyloxystyrene and MeLi/LiBr, was also performed as listed in
Entries 5–9. On treating 2 with 1.1 equiv of 13a, generated from
1.1 equiv each of a-silyloxystyrene and MeLi/LiBr, in THF at
Additionally, the MgBr2-induced ring-opening reaction was
applied to the one-pot preparation of 2,2-difluoroketones as
illustrated in Scheme 6. Thus, on treating 2 with MgBr2 in Et2O
at room temperature for 3 h, followed by addition of 3.0 equiv of
PhMgBr (7a) at -40 ◦C, 3-bromo-2,2-difluoropropiophenone (12)
was obtained in 48% a two-step yield.
0
◦C for 2 h, b-brominated adduct 15a was given in 39% yield,
instead of 14a (Entry 5). Increasing the amount of lithium enolate
as well as raising the reaction temperature resulted in a significant
improvement of the yield (Entries 6 and 7), and the best result was
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Table 3 Reaction of 2 with lithium enolate derived from acetophenone
Table 4 Reaction of 2 with various lithium enolates 13 using Method B
Entry
1
Product
Yielda/% of 15
(15a)
79 (66)
2
3
4
5
(15b)
86 (45)
83 (60)
84 (65)
93 (40)
Equiv Temp/◦ Time/ Yieldb/% Yieldb/%
Entry Methoda
1c
of 13a C
h
of 14a
of 15a
2.0
r.t.
2
19
0
(15c)
(15d)
(15e)
2c
2.0
3.0
4.0
1.1
r.t.
r.t.
r.t.
0
20
2
2
21
39
43
0
0
0
0
39
3c
4c
5c,d
2
6b
7c
8c
(15f)
95 (59)
quant. (64)
40
6d
7d
8d
9
2.2
2.2
2.2
3.3
0
2
2
20
2
0
0
0
0
49
70
73
79 (66)
r.t.
r.t.
r.t.
(15g)
(15h)
a Method A: Lithium enolate was generated from LDA and acetophenone
in THF. Method B: Lithium enolate was generated from a-silyloxystyrene
and MeLi/LiBr in Et2O. b Determined by 19F NMR. Value in parentheses
is of isolated yield. c The unreacted starting oxetane 2 was observed.
d Unknown product was observed.
obtained (79% yield) when 2 was subjected to 3.3 equiv of 13a at
room temperature for 2 h (Entry 9).
9c
(15i)
35
As shown in Entries 2–5 of Table 4, lithium enolates 13, prepared
from various types of acetophenone derivatives having an electron-
donating as well as an electron-withdrawing group, were found to
be very effective for this reaction, the corresponding products 15b–
e being provided in 83–93% yields. 2-Acetyl furan or thiophene-
derived enolates could also participate successfully in the reaction,
giving the corresponding furan- or thiophene-containing product
15f and 15g in almost quantitative yields (Entries 6 and 7).
However, the lithium enolates derived from propiophenone and
pinacolone were somewhat less reactive, the desired adducts being
afforded in moderate yields (Entries 8 and 9).
a Determined by 1◦9F NMR. Values in parentheses are of isolated yield.
b Carried out at 0 C. c Unknown product was observed.
ethyl benzoylacetate and ethyl diethylphosphonoacetate, brought
about a preferential formation of the bis-adducts 17a and 17b in
13% and 42% yields, together with a small amount of 16b and 16c.
Unfortunately, these products were found to be inseparable from
unknown products.
Additionally, the reaction of 2 with various stabilized carban-
ions were also attempted as shown in Fig. 1.
Radical reaction using 2,2-difluoro-3-iodopropanoate
Thus, treatment of 2 with 3.3 equiv of sodium diethyl malonate
in THF at room temperature for 2 h, followed by the addition of
sat. NH4Cl aqueous solution, led to 2,2-difluorinated amide 16a
in 81% yield as the sole product. In sharp contrast, the use of
other stabilized carbanions, such as the carbanions derived from
We next investigated the radical reaction8 of methyl 2,2-difluoro-3-
iodopropanoate (18),9 which could easily be prepared via the ring-
opening reaction of 2,2,3,3-tetrafluorooxetane (2). The results are
collated in Table 5.
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Table 6 Radical coupling reaction of 18 with various silyl enol ethers 19
Yielda/
% of 20
Recoverya/
% of 18
Entry Product
1
(20a)
73 (65)
23
2b
3
(20b)
52 (44)
30
(20c)
77 (58)
22
33
4b
(20d) 22
5
(20e)
76 (34)
48 (40)
23
40
Fig. 1 Reaction of 2 with various stabilized carbanions.
Table 5 Radical coupling reaction of 18 with silyl enol ether 19a
6b
(20f)
7
8
(20g)
80 (54)
54 (20)
18
45
Equiv
of 19a
Temp/◦
C
Yieldb/
% of 20a
Recoveryb/
% of 18
(20h)
Entry
Solventa
1c
2
1.1
2.2
2.2
2.2
3.3
3.3
DMF/H2O
DMF/H2O
DMF
DMF/H2O
DMF/H2O
DMF/H2O
r.t.
r.t.
r.t.
40
r.t.
40
52
55
0
55
73 (65)
61
34
43
quant.
0
23
0
3
a Determined by 19F NMR. Values in parentheses are of isolated yield. b In
Entries 2, 4 and 6, reduction product 21 was obtained in 17%, 38% and
10% yields, respectively.
4c
5
6
a Ratio of DMF/H2O was 4 : 1. b Determined by 19F NMR. Value in
parentheses is of isolated yield. c 2-Fluoroacrylate was observed in the
reaction mixture.
Reaction of 1.1 equiv of silyl enol ether 19a in the presence of 1.1
equiv each of Na2S2O4 and NaHCO3 in DMF/H2O (4 : 1) at room
temperature for 20 h proceeded relatively smoothly to give the
corresponding coupling product 20a in 52% yield, together with
34% recovery of the starting ester 18 (Entry 1). The use of 2.2 equiv
of 19a did not improve the yield at all. As can be seen in Entry 3,
H2O was found to be crucial. Though increasing the temperature
did not lead to a satisfactory result (Entry 4), the reaction using 3.3
equiv of 19a at room temperature gave the best yield, the coupling
adduct 20a being obtained in 73% yield (Entry 5).
Subsequently, various types of silyl enol ethers were applied
to the present radical coupling reaction under the conditions
of Entry 5 in Table 5, and the results are summarized in
Table 6.
As shown in Entries 1–3, 5 and 6, various silyl enol ethers
derived from acetophenones containing an electron-donating
as well as an electron-withdrawing group at the 4-position,
like 4-methoxy (19b), 4-methyl- (19c), or 4-fluoroacetophenone
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(19e), could participate well in the reaction, giving rise to the
corresponding adducts 20b, 20c, and 20e in 52–77% yields.
Additionally, the silyl enol ethers derived from 1-acetonaphthone,
2-acetylfuran, and 2-acetylthiophene were also found to be good
radical coupling partners, the desired adducts 20f, 20g, and 20h
being obtained in good to high yields. However, incorporation of
a dimethylamino group into the phenyl ring of the acetophenone
led to a decrease in the reactivity of the corresponding silyl
enol ether, the coupling product 20d being provided in only 22%
yield.
Similarly, the radical coupling reaction of 18 with alkenes, like 1-
octene, vinylcyclohexane, and 5-hexen-1-ol was attempted (Fig. 2).
Thus, the reaction of 18 with 3.3 equiv of 1-octene in DMF/H2O
(4 : 1) at room temperature for 20 h did not lead to a satisfactory
result (the coupling product 22a was obtained in only 5%), while
the reaction using Et3B (10 mol%, 3 times) as a radical initiator in
hexane at 0 ◦C for 4.5 h resulted in a significant improvement of
the yield of 22a (64% yield). The reaction with vinylcyclohexane
or 5-hexen-1-ol also gave the corresponding adducts 22b, 22c in
fair to good yields.
Experimental section
Typical procedure for the preparation of 2,2-difluoro-1,1,3-
triphenylpropan-1-ol (5f)
A 50 mL three-necked round-bottomed flask equipped with a
magnetic stirrer bar, a thermometer, a rubber septum and an
inlet tube for argon was charged with a solution of 4.4 equiv of
phenylacetylene in THF. To this solution was added 4.4 equiv of n-
BuLi in hexane at -20 ◦C, and the solution was stirred for 15 min.
Then, 0.130 g (1.0 mmol) of 2,2,3,3-tetrafluorooxetane (2) in THF
(4.0 mL) was slowly added to the mixture via a syringe at -20 ◦C,
and the solution was stirred for additional 2 h at -20 ◦C. The
reaction mixture was poured into a saturated aqueous solution
of NH4Cl (30 mL), followed by extraction with ether (20 mL,
5 times). The organic layers were dried over anhydrous Na2SO4,
filtered and concentrated in vacuo. Column chromatography of
the residue using hexane/ethyl acetate gave the pure product, 2,2-
difluoro-1,1,3-tris(2-phenylethynyl)propan-1-ol (5f) in 77% yield.
2,2-Difluoro-1,1,3-tris(2-phenylethynyl)propan-1-ol (5f)
1H NMR (CDCl3) d 3.12 (s, 1H), 3.53 (t, J = 16.9 Hz, 2H), 7.25–
7.53 (m, 15H); 13C NMR (CDCl3) d 24.62 (t, J = 25.2 Hz), 67.51 (t,
J = 30.9 Hz), 80.20, 83.30, 84.10, 86.34, 119.17 (t, J = 255.8 Hz),
120.93, 122.81, 128.14, 128.28, 129.35, 131.75, 132.01; 19F NMR
(CDCl3) d -110.01 (t, J = 16.9 Hz, 2F); IR (neat) 3543, 3061, 1495,
1448, 1217, 1192, 1167, 1042 cm-1; HRMS (FAB) m/z (M+) Calcd
for C27H18F2O 396.1326, found 396.1328.
2,2-Difluoro-1,1,3-tris(3-benzyloxypropyn-1-yl)propan-1-ol (5g)
1H NMR (CDCl3) d 3.22 (t, J = 16.9 Hz, 2H), 4.13 (s, 2H), 4.14
(s, 4H), 4.54 (s, 4H), 4.57 (s, 2H), 4.96 (s, 1H), 7.22–7.33 (m, 15H);
13C NMR (CDCl3) d 23.41 (t, J = 24.6 Hz), 56.52, 56.90, 65.97 (t,
J = 31.1 Hz), 70.95, 71.41, 77.47, 79.57, 81.18, 82.02, 118.84 (t, J =
255.4 Hz), 127.22, 127.60, 127.77, 127.96, 128.13, 128.21, 136.52,
136.93; 19F NMR (CDCl3) d -110.52 (brs, 2F); IR (neat) 3310,
3065, 3032, 2934, 2856, 1497, 1456, 1354, 1258, 1184, 1088, 1028
cm-1; HRMS (FAB) m/z (M+) Calcd for C33H29F2O4 527.2034,
found: 527.2040.
Fig. 2 Radical coupling reaction of 18 with various alkenes.
2,2-Difluoro-1,1,3-tris(2-trimethylsilylethynyl)propan-1-ol (5h)
1H NMR (CDCl3) d 0.15 (s, 9H), 0.17 (s, 18H), 3.12 (t, J = 16.9 Hz,
2H), 3.22 (s, 1H); 13C NMR (CDCl3) d -0.61, -0.20, 24.52 (t, J =
24.7 Hz), 66.78 (t, J = 30.8 Hz), 89.12, 91.82, 96.54, 98.70, 118.41
(t, J = 256.2 Hz); 19F NMR (CDCl3) d -111.60 (t, J = 16.9 Hz);
IR (neat) 3472, 2963, 2901, 2189, 1418, 1337, 1252, 1151, 1067,
1030, 937 cm-1; HRMS (FAB) m/z (M+) Calcd for C18H31F2OSi3
385.1651, found 385.1654.
Conclusions
In summary, we have demonstrated easy access to various
sorts of the CF2-containing molecules including a,a-difluorinated
carbonyl compounds without a heteroatom substituent at the
b position. Fluorinated oxetane 2 reacted easily with organo-
lithium reagents to give 1,1,3-trisubstituted 2,2-difluoropropanols
5 in good to excellent yields. On the other hand, the reaction
with Grignard reagents led to 3-bromo-1,1-disubstituted 2,2-
difluoropropanols 8 in good yields. Additionally, lithium eno-
lates from silyl enol ethers were found to be a good nucle-
ophiles. Furthermore, it was revealed that methyl 3-iodo-2,2-
difluoropropanoate (18) also reacted successfully with various
types of alkenes in the presence of a radical initiator to afford
the corresponding radical coupling products 20 and 22 in fair to
good yields.
2,2-Difluoro-1,1,3-trihexyn-1-ylpropan-1-ol (5i)
1H NMR (CDCl3) d 0.83–0.87 (m, 9H), 1.35–1.47 (m, 12H), 2.12–
2.20 (m, 6H), 2.99–3.05 (m, 3H); 13C NMR (CDCl3) d 13.22, 13.27,
18.07, 18.19, 21.65, 23.37 (t, J = 25.1 Hz), 29.92, 30.56, 66.44 (t,
J = 31.0 Hz), 70.45, 75.52, 83.87, 86.58, 118.98 (t, J = 254.5 Hz);
19F NMR (CDCl3) d -112.22 (t, J = 16.9 Hz, 2F); IR (neat) 3479,
2959, 2936, 2864, 2241, 1697, 1466, 1086 cm-1; HRMS (FAB) m/z
(M+) Calcd for C21H39F2O 335.2186, found 335.2188.
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Typical procedure for the preparation of 3-bromo-2,2-difluoro-1,1-
diphenylpropan-1-ol (8a)
tube for argon was charged with a suspension of 1.2 equiv of
MgBr2 in THF. To this suspension, 0.130 g (1.0 mmol) of 2,2,3,3-
tetrafluorooxetane (2) in THF (2 mL) was added slowly via a
A 50 mL three-necked round-bottomed flask equipped with a
magnetic stirrer bar, a thermometer, a rubber septum and an
inlet tube for argon was charged with a solution of 4.4 equiv
of phenylmagnesium bromide in THF. To this solution, 0.130 g
(1.0 mmol) of 2,2,3,3-tetrafluorooxetane (2) in THF (4.0 mL) was
slowly added via a syringe at -20 ◦C. After being stirred for 20
h at room temperature, the reaction mixture was poured into
a saturated aqueous solution of NH4Cl (30 mL), followed by
extraction with ether (20 mL, 5 times). The organic layers were
dried over anhydrous Na2SO4, filtered and concentrated in vacuo.
Column chromatography of the residue using hexane/benzene
(5 : 1) gave pure product 8a.
◦
syringe at 0 C. After being stirred for 3 h at room temperature,
the reaction mixture was poured into a saturated aqueous solution
of NH4Cl (30 mL). The resultant mixture was extracted with
ether (50 mL, 3 times) and the organic layers were dried over
anhydrous Na2SO4, filtered and concentrated in vacuo. Column
chromatography of the residue using hexane/benzene (1 : 2) gave
pure product 9.
4-Bromobutyl 3-bromo-2,2-difluoropropanoate (9)
1H NMR (CDCl3) d 1.89–2.00 (m, 4H), 3.44 (t, J = 6.29 Hz, 2H),
3.73 (t, J = 12.88 Hz, 2H), 4.35 (t, J = 6.23 Hz, 2H); 13C NMR
(CDCl3) d 28.88, 28.37 (t, J = 30.16 Hz), 28.79, 32.64, 66.38, 112.44
(t, J = 253.15 Hz), 161.87 (t, J = 31.94 Hz); 19F NMR (CDCl3) d
-105.58 (t, J = 12.41 Hz, 2F); IR (neat) 3042, 2966, 2851, 1774,
1422, 1331, 1223, 1169, 1051, 881, 772, 716.
3-Bromo-2,2-difluoro-1,1-diphenylpropan-1-ol (8a)
1H NMR (CDCl3) d 2.96 (brs, 1H), 3.66 (t, J = 16.11 Hz, 2H),
7.33–7.38 (m, 6H), 7.57–7.58 (m, 4H); 13C NMR (CDCl3) d 31.35
(t, J = 26.32 Hz), 79.59 (t, J = 26.53 Hz), 120.77 (t, J = 254.79 Hz),
127.30 (t, J = 2.26 Hz), 128.21, 128.28, 140.78; 19F NMR (CDCl3)
d -108.08 (t, J = 16.94 Hz, 2F); IR (neat) 3543, 3061, 3038, 2991,
1601, 1495, 1423, 1340, 1271, 1126; HRMS (FAB) m/z (M+) Calcd
for C15H13BrF2O 326.0118, found 326.0129.
4-Iodobutyl 3-iodo-2,2-difluoropropanoate (10)
1H NMR (CDCl3) d 1.78–1.92 (m, 4H), 3.18 (t, J = 6.57 Hz, 2H),
3.56 (t, J = 14.72 Hz, 2H), 4.29 (t, J = 6.29 Hz, 2H); 13C NMR
(CDCl3) d 0.00 (t, J = 27.30 Hz), 5.77, 28.90, 29.28, 65.98, 112.42
(t, J = 252.02 Hz), 161.15 (t, J = 32.95 Hz); 19F NMR (CDCl3) d
-100.49 (t, J = 15.59 Hz, 2F); IR (neat) 3523, 3033, 2962, 2844,
1767, 1414, 1295, 1228, 1163, 1058, 909, 768, 730; HRMS (FAB)
m/z (M+Na) Calcd for C7H10F2I2NaO2 440.8631, found 440.8638.
3-Bromo-2,2-difluoro-1,1-bis(4-methoxyphenyl)propan-1-ol (8b)
1H NMR (CD3COCD3) d 2.67 (brs, 1H), 3.66 (s, 6H), 3.66 (m, 2H),
6.74–6.78 (m, 4H), 7.32–7.36 (m, 4H); 13C NMR (CD3COCD3) d
32.74 (t, J = 26.46 Hz), 55.46, 79.65 (t, J = 24.80 Hz), 113.83, 121.96
(t, J = 253.76 Hz), 129.55, 134.71, 159.91; 19F NMR (CD3COCD3)
d -105.18 (t, J = 15.80 Hz, 2F); IR (neat) 3437, 3001, 2958, 2636,
2837, 1706, 1582, 1442, 1419, 1128, 1111; HRMS (FAB) m/z (M+)
Calcd for C17H17BrF2NaO3 409.0227, found 409.0218.
Ethyl 3-bromo-2,2-difluoro propanoate (11)
1H NMR (CDCl3) d 1.37 (t, J = 7.18 Hz, 3H), 3.73 (t, J = 13.01
Hz, 2H), 4.38 (q, J = 7.11 Hz, 2H); 13C NMR (CDCl3) d 13.88,
28.47 (t, J = 30.12 Hz), 63.54, 112.39 (t, J = 252,90 Hz), 161.91 (t,
J = 32.07 Hz); 19F NMR (CDCl3) d -105.80 (t, J = 12.03, 2F); IR
(neat) 3580, 3399, 1763, 1703, 1420, 1375, 1225, 1051.
3-Bromo-2,2-difluoro-1,1-bis(4-methylphenyl)propan-1-ol (8c)
1H NMR (CD3COCD3) d 2.12 (s, 6H), 2.62 (brs, 1H), 3.61 (t,
J = 16.19 Hz, 2H), 6.95–7.00 (m, 4H), 7.23–7.30 (m, 4H); 13C
NMR (CD3COCD3) d 21.08, 32.80 (t, J = 26.06 Hz), 80.04 (t,
J = 25.20 Hz), 122.01 (t, J = 253.76 Hz), 128.30, 129.47, 138.27,
139.94; 19F NMR (CD3COCD3) d -105.16 (t, J = 15.99 Hz, 2F); IR
(neat) 3535, 3030, 2923, 1707, 1670, 1511, 1426, 1364, 1270, 1111.
Typical procedure for the preparation of 3-bromo-2,2-difluoro-1-
phenyl-propane-1-one (12)
A 50 mL three-necked round-bottomed flask equipped with a
magnetic stirrer bar, a thermometer, a rubber septum and an inlet
tube for argon was charged with a suspension of 1.2 equiv of
MgBr2 in THF. To this suspension, 0.130 g (1.0 mmol) of 2,2,3,3-
tetrafluorooxetane (2) in THF (2 mL) was added slowly via a
3-Bromo-2,2-difluoro-1,1-bis(phenylethynyl)propan-1-ol (8i)
◦
syringe at 0 C. After being stirred for 3 h at room temperature,
1H NMR (CDCl3) d 3.22 (s, 1H), 4.09 (t, J = 15.68 Hz, 2H), 7.34–
7.42 (m, 6H), 7.52–7.54 (m, 4H); 13C NMR (CDCl3) d = 29.20 (t,
J = 25.89 Hz), 66.94 (t, J = 31.26 Hz), 82.88, 86.74, 117.24 (t, J =
254.54 Hz), 120.72, 128.39, 129.57, 132.07; 19F NMR (CDCl3) d
-111.99 (t, J = 16.94 Hz, 2F); IR (neat) 3408, 3057, 2926, 2853,
2361, 2235, 1599, 1576, 1491, 1445, 1360, 1329, 1269, 1229, 1217,
1043; HRMS (FAB) m/z (M+) Calcd for C19H14BrF2O 375.0196,
found 375.0197.
the reaction mixture was allowed to cool to -40 ◦C, then 3.0 equiv
of PhMgBr, which was prepared from PhBr and Mg in THF, was
added to this mixture. After being stirred for 20 h, the reaction
mixture was poured into a saturated aqueous solution of NH4Cl
(30 mL). The solution was extracted with ether (50 mL, 3 times)
and the organic layers were dried over anhydrous Na2SO4, filtered
and concentrated in vacuo. Column chromatography of the residue
using hexane/EtOAc gave the product 12.
Typical procedure for the preparation of 4-bromobutyl
3-bromo-2,2-difluoropropanoate (9)
3-Bromo-2,2-difluoro-1-phenyl-propane-1-one (12)
1H NMR (CDCl3) d 3.92 (t, J = 14.57 Hz, 2H), 7.52 (t, J = 7.98
A 50 mL three-necked round-bottomed flask equipped with a
magnetic stirrer bar, a thermometer, a rubber septum and an inlet
Hz, 2H), 7.67 (t, J = 8.78 Hz, 1H), 8.11 (d, J = 7.38 Hz, 2H); 13
C
NMR (CDCl3) d 29.14 (t, J = 28.02 Hz), 115.14 (t, J = 256.57 Hz),
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128.83, 130.17 (t, J = 3.40 Hz), 131.44 (t, J = 2.64 Hz), 134.80,
187.54 (t, J = 30.94 Hz); 19F NMR (CDCl3) d -100.27 (t, J = 12.03
Hz, 2F) IR (neat) 3379, 3062, 2987, 2929, 2854, 1971, 1913, 1773,
1697, 1598, 1450, 1422, 1309, 1206, 1033, 929, 898, 713, 686, 578;
HRMS (FAB) m/z (M+H) Calcd for C9H8BrF2O 248.9751, found
248.9727.
5-Bromo-4,4-difluoro-1-hydroxy-1-(4-chlorophenyl)-pent-1-en-
3-one (15d)
◦
1
M.P. 46–47 C; H NMR (CDCl3) d 3.80 (t, J = 13.44 Hz, 2H),
6.62 (s, 1H), 7.46 (d, J = 8.45 Hz, 2H), 7.88 (d, J = 8.45 Hz, 2H),
15.38 (s, 1H); 13C NMR (CDCl3) d 28.35 (t, J = 30.43 Hz), 92.81
(t, J = 3.61 Hz), 114.37 (t, J = 250.77 Hz), 128.82, 129.32, 131.69,
140.11, 183.39 (t, J = 30.43 Hz), 184.15; 19F NMR (CDCl3) d
-107.05 (t, J = 13.44 Hz, 2F); IR (KBr) 3124, 3037, 2980, 1922,
1795, 1592, 1489, 1217, 1094, 1044, 845, 807; HRMS (FAB) m/z
(M+H) Calcd for C11H9BrClF2O2 324.9443, found 324.9443.
Typical procedure for the preparation of 5-bromo-4,4-
difluoro-1-hydroxy-1-phenylpent-1-en-3-one (15a)
A 50 mL three-necked round-bottomed flask equipped with a
magnetic stirrer bar, a thermometer, a rubber septum and an
inlet tube for argon was charged with 3.3 equiv. of 1-phenyl-1-
(trimethylsilyloxy)ethylene, prepared from acetophenone in THF.
To this solution, 3.32 mL (3.30 mmol) of 1.04 M methyl-lithium
in ether was slowly added via a syringe at -78 ◦C. After being
stirred for 0.5 h at 0 ◦C, to this solution 0.130 g (1.0 mmol) of
2 was slowly added via a syringe at -78 ◦C. After being stirred
for 2 h at room temperature, the reaction mixture was poured
into a saturated aqueous solution of NH4Cl (30 mL), followed
by extraction with ether (20 mL ¥ 5). The organic layers were
dried over anhydrous Na2SO4, filtered and concentrated with a
rotary evaporator. Column chromatography of the residue using
hexane/benzene (5 : 1) gave pure product, 5-bromo-4,4-difluoro-
1-hydroxy-1-phenylpent-1-ene-3-one (15a).
5-Bromo-4,4-difluoro-1-hydroxy-1-(4-fluorophenyl)-pent-1-en-
3-one (15e)
◦
1
M.P. 39–41 C; H NMR (CDCl3) d 3.80 (t, J = 13.45 Hz, 2H),
6.61 (s, 1H), 7.17 (t, J = 8.65 Hz, 2H), 7.98 (dd, J = 8.65, 8.65 Hz,
2H), 15.49 (s, 1H); 13C NMR (CDCl3) d 28.41 (t, J = 30.18 Hz),
92.68 (t, J = 2.48 Hz), 114.41 (t, J = 250.39 Hz), 116.07, 116.24,
131.69, 140.11, 183.39 (t, J = 30.43 Hz), 184.15; 19F NMR (CDCl3)
d -107.10 (t, J = 13.45 Hz, 2F), -104.12 (d, J = 8.65 Hz, 1F);
IR (KBr) 3124, 3041, 2984, 1918, 1600, 1507, 1418, 1219, 1090,
1049, 809, 570; HRMS (FAB) m/z (M+H) Calcd for C11H9BrF3O3
308.9745, found 308.9739.
5-Bromo-4,4-difluoro-1-hydroxy-1-(2-furyl)-pent-1-en-3-one (15f)
1H NMR (CDCl3) d 3.78 (t, J = 13.38 Hz, 2H), 6.55 (s, 1H), 6.62–
6.63 (m, 1H) 7.32 (d, J = 3.61 Hz, 2H), 7.67 (s, 1H), 14.88 (s, 1H).;
13C NMR (CDCl3) d 28.54 (t, J = 30.69 Hz), 93.26 (t, J = 2.70 Hz),
112.36, 113.14, 114.37, 118.11, 147.57 (t, J = 219.95 Hz), 176.50,
179.25 (t, J = 31.44 Hz).; 19F NMR (CDCl3) d -107.32 (t, J =
13.38 Hz, 2F); IR (neat) 3174, 1604, 1543, 1466, 1272, 1269, 1092,
1040, 1015, 931, 884, 806, 761; HRMS (FAB) Found: m/z (M+H)
Calcd for C9H8BrF2O3 280.9628, found 280.9626.
5-Bromo-4,4-difluoro-1-hydroxy-1-phenylpent-1-en-3-one (15a)
◦
1
M.P. 31–33 C; H NMR (CDCl3) d 3.83 (t, J = 13.66 Hz, 2H),
6.67 (s, 1H), 7.47 (t, J = 6.67 Hz, 2H), 7.60 (t, J = 6.67 Hz, 1H),
7.94 (d, J = 6.91 Hz, 2H), 15.46 (s, 1H); 13C NMR (CDCl3) d 28.49
(t, J = 29.29 Hz), 92.79 (t, J = 2.55 Hz), 114.39 (t, J = 250.77 Hz),
127.50, 128.84, 133.21, 133.65, 183.34 (t, J = 29.29 Hz), 185.43;
19F NMR (CDCl3) d -107.21 (t, J = 13.66 Hz, 2F); IR (KBr) 3140,
3033, 2971, 1811, 1600, 1227, 1050, 1035, 927, 775; HRMS (FAB)
m/z (M+) Calcd for C11H1079BrF2O2 290.9833, found 290.9838.
5-Bromo-4,4-difluoro-1-hydroxy-1-(2-thionyl)-pent-1-en-3-one
(15g)
5-Bromo-4,4-difluoro-1-hydroxy-1-(4-metoxyphenyl)-pent-1-en-
3-one (15b)
1H NMR (CDCl3) d 3.79 (t, J = 13.36 Hz, 2H), 6.51 (s, 1H), 7.19
(t, J = 4.36 Hz, 1H), 7.73 (d, J = 4.36 Hz, 2H), 7.83 (d, J = 4.36 Hz,
2H), 15.21 (s, 1H); 13C NMR (CDCl3) d 28.60 (t, J = 30.95 Hz),
93.91 (t, J = 3.42 Hz), 114.52 (t, J = 248.38 Hz), 128.71, 133.05,
134.68, 139.95, 176.71 (t, J = 30.95 Hz), 182.52; 19F NMR (CDCl3)
d -107.23 (t, J = 13.36 Hz, 2F); IR (neat) 3109, 3040, 2961, 1775,
1584, 1414, 1255, 1046, 860, 801, 727; HRMS (FAB) m/z (M+H)
Calcd for C9H8BrF2O2S 296.9395, found 296.9397.
M.P. 49–50 ◦C; 1H NMR (CDCl3) d 3.80 (t, J = 13.60 Hz, 2H), 3.88
(s, 3H), 6.58 (s, 1H), 6.96 (d, J = 8.95 Hz, 2H), 7.93 (d, J = 8.95 Hz,
2H), 15.76 (s, 1H); 13C NMR (CDCl3) d 28.74 (t, J = 30.74 Hz),
55.50, 91.99 (t, J = 2.91 Hz), 114.47 (t, J = 250.01 Hz), 114.21,
125.71, 129.86, 164.24, 181.52 (t, J = 30.74 Hz), 185.59; 19F NMR
(CDCl3) d -107.31 (t, J = 8.95 Hz, 2F); IR (KBr) 3046, 2984, 2844,
1600, 1509, 1423, 1315, 1261, 1171, 1030, 792; HRMS (FAB) m/z
(M+H) Calcd for C12H12BrF2O3 320.9940, found 320.9939.
Typical procedure for the preparation of 4,4-bis(ethoxycarbonyl)-
2,2-difluorobutanamide (16a)
5-Bromo-4,4-difluoro-1-hydroxy-1-(4-methylphenyl)-pent-1-en-
3-one (15c)
A 50 mL three-necked round-bottomed flask equipped with a
magnetic stirrer bar, a thermometer, a rubber septum and an inlet
tube for argon was charged with a suspension of 3.3 equiv of
NaH in THF. To this suspension, 0.529 g (3.3 mmol) of diethyl
malonate was added dropwise via a syringe at 0 ◦C and then stirred
for 30 min. at 0 ◦C. To the resulting solution 0.130 g (1.0 mmol) of
2,2,3,3-tetrafluorooxetane (2) in THF (2 mL) was slowly added via
a syringe at 0 ◦C. After being stirred for 2 h at room temperature,
the reaction mixture was poured into a saturated aqueous solution
of NH4Cl (30 mL). The resultant mixture was extracted with ethyl
M.P. 53–54 ◦C; 1H NMR (CDCl3) d 2.40 (s, 3H), 3.79 (t, J = 13.61
Hz, 2H), 6.61 (s, 1H), 7.26 (d, J = 7.99 Hz, 2H), 7.82 (d, J = 7.99
Hz, 2H), 15.59 (s, 1H); 13C NMR (CDCl3) d 21.59, 28.59 (t, J =
30.36 Hz), 92.33 (t, J = 2.33 Hz), 114.37 (t, J = 250.26 Hz), 127.54,
139.53, 130.43, 144.82, 182.73 (t, J = 30.36 Hz), 185.60; 19F NMR
(CDCl3) d -107.26 (t, J = 13.61 Hz, 2F); IR (KBr) 3037, 2977,
1606, 1504, 1421, 1229, 1187, 1050, 1029, 800; HRMS (FAB) m/z
(M+H) Calcd for C12H12BrF2O2 304.9988, found 304.9989.
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acetate (50 mL, 3 times) and the organic layers were dried over
anhydrous Na2SO4, filtered and concentrated in vacuo. Column
chromatography of residue using ethyl acetate gave pure product
16a.
7.88 Hz, 2H), 7.86 (ABq, J = 7.88 Hz, 2H); 13C NMR (CDCl3)
d 21.60, 28.95 (t, J = 23.66 Hz), 30.48 (t, J = 3.61 Hz), 53.37,
115.90 (t, J = 249.92 Hz), 128.09, 129.34, 133.76, 144.30, 164.42
(t, J = 32.88 Hz), 196.58; 19F NMR (CDCl3) d -106.53 (t, J =
16.94 Hz, 2F); IR (KBr) 2962, 1770, 1679, 1606, 1441, 1334, 1296,
1211, 1197, 1097, 1045, 974; HRMS (FAB) m/z (M+H) Calcd for
C13H15F2O3 257.0990, found 257.0988.
4,4-Bis(ethoxycarbonyl)-2,2-difluorobutanamide (16a)
◦
1
M.P. 65–66 C; H NMR (CDCl3) d 1.20 (t, J = 7.12 Hz, 6H),
2.70 (t, J = 17.32 Hz, 2H), 3.63 (t, J = 7.12 Hz, 1H), 4.11–4.17
(m, 4H), 6.69 (s, 1H), 6.97 (s, 1H); 13C NMR (CDCl3) d 13.68,
32.65 (t, J = 23.72 Hz), 45.62 (t, J = 2.68 Hz), 61.94, 116.10 (t, J =
253.15 Hz), 165.92 (t, J = 23.72 Hz), 167.94; 19F NMR (CDCl3) d
-105.20 (t, J = 14.12 Hz, 2F); IR (KBr) 3427, 3185, 2991, 1716,
1471, 1339, 1228, 1007, 974, 861, 663; HRMS (EI) m/z (M+H)
Calcd for C10H16F2NO5 268.0995, found 268.0997.
Methyl 2,2-difluoro-5-(4-fluorophenyl)-5-oxopentanoate (20e)
M.P. 42–44 ◦C; 1H NMR (CDCl3) d 2.50–2.64 (m, 2H), 3.19–3.24
(m, 2H), 3.89 (s, 3H), 7.12–7.19 (m, 2H), 7.97–8.03 (m, 2H); 13C
NMR (CDCl3) d 28.86 (t, J = 23.76 Hz), 30.56 (t, J = 3.69 Hz),
53.41, 115.77 (t, J = 250.17 Hz), 115.80 (d, J = 22.01 Hz), 130.65
(d, J = 9.18 Hz), 132.66 (d, J = 2.77 Hz), 164.35 (t, J = 32.88 Hz),
165.90 (d, J = 255.40 Hz), 195.36; 19F NMR (CDCl3) d -104.50–
-105.05 (m, 1F), -106.57 (t, J = 16.94 Hz, 2F); IR (neat) 2960,
2361, 1770, 1689, 1508, 1443, 1292, 1159, 1097; HRMS (FAB) m/z
(M+H) Calcd for C12H12F3O3 261.0739, found 261.0745.
Typical procedure for the preparation of methyl 2,2-difluoro-5-
oxo-5-phenylpentanoate (20a)
A 50 mL three-necked round-bottomed flask equipped with a
magnetic stirrer bar, a thermometer, a rubber septum and an inlet
tube for argon was charged with 0.67 g (3.3 mmol) of Na2S2O4
and 0.28 g (3.3 mmol) of NaHCO3 in DMF/H2O (1 mL). To this
solution 0.190 g (0.99 mmol) of 1-(trimethylsilyloxy)styrene in
DMF/H2O (2 mL) and 0.075 g (0.3 mmol) of methyl 2,2-difluoro-
3-iodopropanoate (18) in DMF/H2O (2 mL) was added slowly via
a syringe at room temperature. After being stirred for 20 h at room
temperature, the reaction mixture was poured into a saturated
aqueous solution of NH4Cl (40 mL). The resultant mixture was
extracted with ether (50 mL, 3 times) and the organic layers were
dried over anhydrous Na2SO4, filtered and concentrated in vacuo.
Column chromatography of the residue using hexane/ethyl acetate
(11 : 1) gave pure product 20a.
Methyl 2,2-difluoro-5-(1-naphthyl)-5-oxopentanoate (20f)
1H NMR (CDCl3) d 2.65 (tt, J = 17.08, 7.45 Hz, 2H), 3.33 (t,
J = 7.45 Hz, 2H), 3.89 (s, 3H), 7.46–7.66 (m, 3H), 7.84–7.93 (m,
2H), 7.98–8.07 (m, 1H), 8.58–8.64 (m, 1H); 13C NMR (CDCl3)
d 29.24 (t, J = 23.86 Hz), 33.77 (t, J = 2.55 Hz), 53.43, 115.85
(t, J = 250.24 Hz), 124.31, 125.61, 126.54, 127.88, 128.13, 128.45,
130.05, 133.16, 133.94, 134.81, 164.43 (t, J = 32.94 Hz), 200.76;
19F NMR (CDCl3) d -106.59 (t, J = 17.08 Hz, 2F); IR (neat)
2959, 2924, 1770, 1689, 1591, 1574, 1442, 1290, 1176, 1093, 982;
HRMS (FAB) m/z (M+H) Calcd for C16H15F2O3 293.0997, found
293.0990.
Methyl 2,2-difluoro-5-oxo-5-phenylpentanoate (20a)
◦
1
M.P. 48–50 C; H NMR (CDCl3) d 2.50–2.62 (m, 2H), 3.20–
3.26 (m, 2H), 3.87 (s, 3H), 7.44–7.49 (m, 2H), 7.54–7.60 (m, 1H),
7.92–7.97 (m, 2H); 13C NMR (CDCl3) d 28.88 (t, J = 23.78 Hz),
30.61 (t, J = 3.69 Hz), 53.37, 115.83 (t, J = 249.86 Hz), 127.96,
128.65, 133.42, 136.17, 164.38 (t, J = 32.94 Hz), 196.98; 19F NMR
(CDCl3) d -106.53 (t, J = 16.94 Hz, 2F); IR (KBr) 3352, 2968,
1770, 1686, 1448, 1431, 1334, 1294, 1199, 1045, 970; HRMS (FAB)
m/z (M+H) Calcd for C12H18F2O3 243.0840, found 243.0834.
Methyl 2,2-difluoro-5-(2-furyl)-5-oxopentanoate (20g)
1H NMR (CDCl3) d 2.53 (tt, J = 17.02, 7.76 Hz, 2H), 3.10 (t, J =
7.76 Hz, 2H), 3.89 (s, 3H), 6.57 (dd, J = 3.57, 1.08 Hz, 1H), 7.24 (d,
J = 3.57 Hz, 1H), 7.61 (d, J = 1.08 Hz, 1H); 13C NMR (CDCl3) d
28.44 (t, J = 23.95 Hz), 30.35 (t, J = 3.97 Hz), 53.39, 112.35, 115.66
(t, J = 250.24 Hz), 117.29, 146.57, 152.06, 164.29 (t, J = 32.88 Hz),
186.10; 19F NMR (CDCl3) d -106.66 (t, J = 17.02 Hz, 2F); IR
(neat) 3138, 2960, 1770, 1682, 1572, 1470, 1308, 1211, 1084, 905,
766; HRMS (FAB) m/z (M+H) Calcd for C10H11F2O4 233.0629,
found 233.0626.
Methyl 2,2-difluoro-5-(4-methoxyphenyl)-5-oxopentanoate (20b)
M.P. 54–56 ◦C; 1H NMR (CDCl3) d 2.49–2.61 (m, 2H), 3.18 (t, J =
7.40 Hz, 2H), 3.87 (s, 3H), 3.88 (s, 3H), 6.94 (ABq, J = 8.81 Hz,
2H), 7.95 (ABq, J = 8.81 Hz, 2H); 13C NMR (CDCl3) d 29.05 (t,
J = 23.51 Hz), 30.24 (t, J = 3.48 Hz), 53.39, 55.47, 113.81, 115.94
(t, J = 250.05 Hz), 129.32, 130.29, 163.73, 164.46 (t, J = 33.07 Hz),
195.48; 19F NMR (CDCl3) d -106.56 (t, J = 16.94 Hz, 2F); IR
(KBr) 2945, 2847, 1774, 1674, 1577, 1421, 1336, 1255, 1186, 1074,
1024; HRMS (FAB) m/z (M+H) Calcd for C13H15F2O4 273.0933,
found 273.0939.
Methyl 2,2-difluoro-5-oxo-5-(2-thienyl)pentanoate (20h)
1H NMR (CDCl3) d 2.55 (tt, J = 17.02, 7.81 Hz, 2H), 3.17 (t,
J = 7.81 Hz, 2H), 3.88 (s, 3H), 7.14 (dd, J = 4.96, 3.78 Hz, 1H),
7.66 (d, J = 4.96 Hz, 1H), 7.75 (d, J = 3.78 Hz, 1H); 13C NMR
(CDCl3) d 28.92 (t, J = 23.85 Hz), 31.19 (t, J = 3.91 Hz), 53.44,
115.68 (t, J = 250.36 Hz), 120.20, 132.14, 134.02, 143.28, 164.31 (t,
J = 32.95 Hz), 189.85; 19F NMR (CDCl3) d -106.63 (t, J = 17.02
Hz, 2F); IR (neat) 2959, 1770, 1668, 1416, 1356, 1211, 1097, 1063,
966, 858, 729; HRMS (FAB) m/z (M+H) Calcd for C10H11F2O3S
249.0389, found 249.0398.
Methyl 2,2-difluoro-5-(4-methylphenyl)-5-oxopentanoate (20c)
◦
1
M.P. 71–73 C; H NMR (CDCl3) d 2.41 (s, 3H), 2.55 (tt, J =
16.94, 7.85 Hz, 2H), 3.20 (t, J = 7.85 Hz, 2H), 7.27 (ABq, J =
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Typical procedure for the preparation of methyl 2,2-difluoro-5-
iodo-undecanoate (22a)
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A 50 mL three-necked round-bottomed flask equipped with a
magnetic stirrer bar, a thermometer, a rubber septum and an inlet
tube for argon was charged with 0.224 g (2.0 mmol) of 1-octene in
hexane (1 mL). To this solution, 0.250 g (1.0 mmol) of methyl 2,2-
difluoro-3-iodopropanoate (18) in hexane (1 mL) was added slowly
via a syringe at room temperature and then 0.1 mL (0.1 mmol) of
1.01 M Et3B in n-hexane was added slowly via a syringe at 0 ◦C.
The whole was stirred for 1.5 h at 0 ◦C and then 0.1 mL (0.1 mmol)
of 1.01 M Et3B in n-hexane was added slowly via a syringe at 0 ◦C
2 times. After being stirred for 4.5 h at 0 ◦C, the reaction mixture
was poured into a saturated aqueous solution of NH4Cl (40 mL).
The resultant mixture was extracted with ether (50 mL, 3 times)
and the organic layers were dried over anhydrous Na2SO4, filtered
and concentrated in vacuo. Column chromatography of the residue
using hexane/benzene (5 : 1) gave pure product 22a.
Methyl 2,2-difluoro-5-iodo-undecanoate (22a)
1H NMR (CDCl3) d 1.20–1.41 (m, 10H), 1.41–1.53 (m, 1H), 1.65–
1.72 (m, 1H), 1.85–2.02 (m, 3H), 2.09–2.23 (m, 1H), 2.31–2.44 (m,
1H), 3.87 (s, 3H), 4.04–4.10 (m, 1H); 13C NMR (CDCl3) d 14.02,
22.54, 28.39, 29.36, 29.36, 31.59, 32.17 (t, J = 3.92 Hz), 34.72 (t, J =
23.42 Hz), 36.79, 40.59, 53.41, 115.73 (t, J = 250.39 Hz), 164.48;
19F NMR (CDCl3) d -107.00–-105.50 (m, 2F); IR (neat) 2957,
2929, 2857, 1771, 1445, 1349, 1303, 1201, 1081, 948, 827.
Methyl 5-cyclohexyl-2,2-difluoro-5-iodo-pentanate (22b)
1H NMR (CDCl3) d 1.04–1.35 (m, 7H), 1.62–1.81 (m, 5H), 1.90–
1.92 (m, 1H), 2.04–2.13 (m, 2H), 2.38–2.45 (m, 1H), 3.89 (s, 3H),
4.03 (dt, J = 9.84 Hz, 1H); 13C NMR (CDCl3) d 25.89, 25.95,
26.17, 29.66 (t, J = 3.97 Hz), 31.32, 32.39, 35.17 (t, J = 23.44 Hz),
45.10, 46.85, 53.41, 115.73 (t, J = 250.51 Hz), 164.50; 19F NMR
(CDCl3) d -105.00–-107.10 (m, 2F); IR (neat) 2928, 2854, 1770,
1447, 1299, 1222, 1087, 952, 827, 659.
Methyl 2,2-difluoro-9-hydroxy-5-iodo-nonanate (22c)
1H NMR (CDCl3) d 1.40–1.45 (m, 1H), 1.47–1.60 (m, 3H), 1.81–
1.98 (m, 3H), 2.05–2.19 (m, 1H), 2.27–2.39 (m, 1H), 2.28 (s, 1H),
3.58 (t, J = 6.26 Hz, 2H), 3.84 (s, 3H), 4.00–4.06 (m, 1H); 13C
NMR (CDCl3) d 25.65, 31.51, 32.02 (t, J = 3.85 Hz), 34.52 (t, J =
23.11 Hz), 36.42, 40.12, 53.35, 62.17, 115.56 (t, J = 250.77 Hz),
164.31 (t, J = 32.95 Hz); 19F NMR (CDCl3) d -107.20–-105.40 (m,
2F); IR (neat) 3368, 2938, 2863, 2354, 1766, 1445, 1309, 1201, 1076,
913, 828, 734; HRMS (FAB) m/z (M+H) Calcd for C10H18F2IO3
351.0242, found 351.0269.
6 For the preparation of 2, see: S. Ikeda and T. Sonoi, PCT Int. Appl.
WO2005080365, 2005.
7 For related reports on the synthetic applications starting from 2. For
the preparation of fluoroalkylated 2-nitroimidazoles, see: (a) Daikin
co. Ltd. JP S64-79159; For the preparation of 5-fluorothiouracil, see:
(b) Daikin co. Ltd. JP S63-22566; For the preparation of fluorine-
containing thioglycolic acid derivatives, see: (c) Daikin co. Ltd. JP S61-
280468; For the preparation of fluorine-containing amineamides, see:
(d) Daikin co. Ltd. JP S61 100554.
8 For radical reactions of fluoroalkyl halides in the presence of various
radical initiators, see: (a) W. Dmowski and J. Ignatowsk, J. Fluorine
Chem., 2003, 123, 37–42; (b) A.-Y. Long and Q.-Y. Chen, J. Org. Chem.,
1999, 63, 4775–4782; (c) T. Morikawa, M. Uejima, Y. Kobayashi and T.
Taguchi, J. Fluorine Chem., 1993, 65, 79–89; (d) K. Miura, Y. Takeyama,
K. Oshima and K. Utimoto, Bull. Chem. Soc. Jpn., 1991, 64, 1542–
1553; (e) T. Ishihara, M. Kuroboshi and Y. Okada, Chem. Lett., 1986,
1895–1896; (f) S.-K. Chung and Q.-Y. Hu, Synth. Commun., 1982, 12,
261–266.
Acknowledgements
The authors thank Daikin Industries, Ltd. for supplying 2,2,3,3-
tetrafluorooxetane (2) and methyl 3-iodo-2,2-difluoropropanoate
(18).
Notes and references
1 (a) T. Hiyama, K. Kanie, T. Kusumoto, Y. Morizawa and M. Shimizu,
Organofluorine Compounds, Springer-Verlag, Berlin-Heidelberg, 2000;
(b) V. A. Soloshonok, (ed.), Enanthiocontrolled Synthesis of Fluoro-
Organic Compounds, Wiley, Chichester, 1999; (c) R. D. Chambers,
(ed.), Organofluorine Chemistry, Springer, Berlin, 1997; (d) I. Ojima,
9 For related reports on the preparation of b-halo-a,a-difluoropro-
panoates, see: (a) Daikin co. Ltd. Japanese Patent H02-223538;
(b) Daikin co. Ltd. JP S61-130254; (c) Daikin co. Ltd. JP S60-136536;
(d) Daikin co. Ltd. JP S60-078940.
5502 | Org. Biomol. Chem., 2011, 9, 5493–5502
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The Royal Society of Chemistry 2011
©