Nucleophilic 5- Endo - Trig cyclization of 3,3-difluoroallylic metal enolates and enamides: Facile synthesis of ring-fluorinated dihydroheteroles

Article abstract of DOI:10.1055/s-0033-1340857

Metal enolates and enamides bearing difluoroallylic moieties underwent nucleophilic 5-endo-trig cyclization, a process considered to be disfavored according to Baldwin's rules. Whereas no C-cyclization was observed in these reactions, O- and N-cyclization proceeded exclusively to afford 5-fluorinated 2-alkylidene-2,3-dihydrofurans and -2,3-dihydropyrroles, respectively. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1340857

PAPER
▌1493
paper
Nucleophilic 5-endo-trig Cyclization of 3,3-Difluoroallylic Metal Enolates and
Enamides: Facile Synthesis of Ring-Fluorinated Dihydroheteroles
5-endo-trig Cyclization of 3,3-Difluoroallylic Metal Enolates and Enamides
Takeshi Fujita,a Masahiro Ikeda,a Masahiro Hattori,a Kotaro Sakoda,b Junji Ichikawa*a
a
Division of Chemistry, Faculty of Pure and Applied Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8571, Japan
Fax +81(29)8534237; E-mail: junji@chem.tsukuba.ac.jp
b
Department of Chemistry, Graduate School of Science, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Received: 20.12.2013; Accepted after revision: 02.02.2014
neously installed on the resulting cyclized product.5,6 The
Abstract: Metal enolates and enamides bearing difluoroallylic
unique properties of 1,1-difluoro-1-alkenes make even a
moieties underwent nucleophilic 5-endo-trig cyclization, a process
nucleophilic 5-endo-trig approach feasible. Specifically,
it seems that (i) the highly polarized difluorovinylidene
considered to be disfavored according to Baldwin’s rules. Whereas
no C-cyclization was observed in these reactions, O- and N-cycliza-
tion proceeded exclusively to afford 5-fluorinated 2-alkylidene-2,3- double bond permits initial ring formation by electrostatic
dihydrofurans and -2,3-dihydropyrroles, respectively.
attraction between the CF2 carbon and the internal nucleo-
phile, and (ii) the successive elimination of fluoride ion
suppresses the reverse ring opening, thereby functioning
as a ‘lock’ to afford the 5-endo-trig product. In a series of
our studies, hydroxy (–OH), sulfonylamino (–NHSO2R),
and sulfanyl (–SH) groups have been successfully em-
ployed as nucleophiles under basic conditions to afford a
variety of fluorine-containing five-membered heterocy-
cles (Scheme 1, a).
Key words: cyclizations, fluorine, heterocycles, furans, pyrroles,
ring closure
According to Baldwin’s rules, the 5-endo-trig cyclization
is a disfavored process, because the transition state of this
cyclization mode involves a profound distortion of the
bond angles.1 Although the number of reported examples
of the 5-endo-trig cyclization is gradually increasing,
well-designed cyclization precursors are still required in
most cases.2–5 As a result, in practice, the 5-endo-trig cy-
clization process is rarely adopted for the construction of
five-membered rings. Therefore, a version of this anti-
Baldwin process with wider application is highly desir-
able.
We recently reported the 5-endo-trig cyclization of rota-
tionally restricted 3,3-difluoroallylic metal enolates
(Scheme 1, b).7 In this reaction, 5-endo-trig ring closure is
exclusively effected in an O-cyclization fashion to pro-
vide 2-alkylidene-2,3-dihydrofurans,8 despite the extra
steric constraint associated with the planarity of enolates.
Furthermore, we have achieved 5-endo-trig cyclization of
3,3-difluoroallylic imines via their metal enamides, pre-
pared in situ by treatment with an appropriate base
(Scheme 1, b). Notably, the 3,3-difluoroallylic metal en-
amides appear to be more restricted than the correspond-
ing metal enolates because of the presence of an extra
substituent on the nitrogen atom. Intriguingly, the 5-endo-
We have previously achieved nucleophilic 5-endo-trig
cyclization of gem-difluoroalkenes (1,1-difluoro-1-al-
kenes).5 The high reactivity of 1,1-difluoro-1-alkenes,
arising from their electron-deficient and highly polarized
nature, facilitates intramolecular nucleophilic vinylic sub-
stitution (SNV), in which a fluorine substituent is simulta-
(a) with OH, NHTs, and SH nucleophiles (previous work)
F
F
F2C
Y–
F2C
YH
F
Y
Y
base
R
R
R
– F–
R
Y = O, NTs, S
(b) with metal enolates and enamides (this work)
F2C F2C
F
F
Y
Y
F
Y
Y
base
R3
R3
R3
R4
R3
R1 R2 R4
– F–
R1 R2
R1 R2
R4
R4
R1 R2
1: Y = O
2: Y = NTs
Scheme 1 The 5-endo-trig cyclization of 1,1-difluoro-1-alkenes
SYNTHESIS 2014, 46, 1493–1505
Advanced online publication: 08.05.2014
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0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0033-1340857; Art ID: SS-2013-F0685-OP
© Georg Thieme Verlag Stuttgart · New York

1494
T. Fujita et al.
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trig cyclization of enamides bearing 1,1-difluoro-1-al- (Table 1). When the 1,3-keto aldehydes 3 were treated
kene moieties readily proceeds in an N-cyclization fash- with a triaminophosphonium difluoromethylide generated
ion, similar to the O-cyclization of enolates, to give 2- by the reaction of dibromodifluoromethane with tris(di-
alkylidene-2,3-dihydropyrroles. Here, we report the full methylamino)phosphine,9 the corresponding 3,3-difluoro-
details of the 5-endo-trig cyclization of 3,3-difluoroallylic allylic ketones 1 were obtained in moderate to high yields
ketones 1 and imines 2, and we discuss the stereochemis- (Table 1).11 Furthermore, the enamide precursors, the 3,3-
try of exocyclic double-bond formation in both products.
difluoroallylic N-(4-methylbenzenesulfonyl)(tosyl)im-
ines 2, were prepared by treating the ketones 1 with 4-tol-
uensulfonamide in the presence of titanium(IV) chloride
and triethylamine (Table 1).12
The enolate precursors, the 3,3-difluoroallylic ketones 1,
were synthesized by a Wittig-type difluoromethylenation
of 1,3-keto aldehydes 3 (Table 1),9 which, in turn, were
prepared either by acylation of the N-tert-butyl enamides The resulting 3,3-difluoroallylic ketones 1 were subjected
generated by deprotonation of the imines 4 (method A) or to basic conditions to effect the normally disfavored 5-
by acylation of the morpholine enamines 5 (method B), endo-trig cyclization (Table 2). When sodium hydride and
with subsequent hydrolysis in each case.10 Keto aldehydes sodium methoxide were used as bases in tetrahydrofuran,
3a, 3c–g, and 3j were obtained by method A, whereas no cyclization occurred (Table 2, entries 1 and 2). Upon
keto aldehydes 3b, 3h, and 3i were prepared by method B treatment with an equimolar amount of lithium diisopro-
Table 1 Preparation of 3,3-Difluoroallylic Ketones 1 and Imines 2a
method A
1) LDA (1.1 equiv)
Et2O, –78 to 0 °C, 2 h
t-Bu
N
R1
2)
O
R2
R3
Cl
4
R4
(1.0 equiv)
Et2O, r.t., 12 h
3) (COOH)2•2H2O (1.0 equiv)
CH2Cl2/H2O (5:3), r.t., 1 h
CF2Br2 (2.0 equiv)
(Me2N)3P (4.0 equiv)
4 Å MS
TsNH2 (1.0 equiv)
TiCl4 (1.0 equiv)
Et3N (2.0 equiv)
F2C
O
F2C
NTs
O
O
R3
R3
R3
DCE, reflux
time 2
THF, –78 °C to r.t.
time 1
R1 R2
R1 R2
R1 R2
R4
R4
R4
method B
1
2
3
1)
O
R3
Cl
O
N
R4
(1.0 equiv)
Et2O, 0 °C to reflux, 10–12 h
R1
2) sat. aq NaHCO3
Et2O/H2O (2:3), 0 °C, 1 h
R2
5
Entry
R1
R2
R3
R4
Method Yield of 3 (%)
Time 1 (h) Yield of 1 (%) Time 2
Yield of 2 (%)
1
2
Me
Me
Me
Me
Me
Me
Me
Me
(CH2)7Me
Bn
H
H
H
H
H
H
A
B
3a 32
3b 58
3c 45
3d 85
3e 44
3f 54
3g 90
3h –18
3i 29
3j 41
10
16
7
1a 86
1b 87
1c 82
1d 58
1e 63
1f 58
1g 71
1h 66
1i 68
1j 27
3 d
1 d
7 h
–
2a 61
2b 68
2c 82
Me
3
Me
Cy
A
A
A
A
A
B
4
Me
t-Bu
10
10
5
5
Me
Ph
1 d
2 d
–
2e 60
2f 54
6
Me
4-MeOC6H4
–(CH2)5–
H
7
Me
12
10
8
8
–(CH2)5–
–(CH2)5–
–(CH2)5–
H
H
1 d
–
2h 67
9
t-Bu
B
10
–(CH2)5–
Aa
10
–
a Reaction conditions: 1. 4, t-BuLi (1.0 equiv), pentane–THF, –78 °C to 0 °C, 1 h; 2. CyCOCl (1.0 equiv), pentane–THF, –78 °C to reflux, 2 h;
3. AcOH (50 equiv), NaOAc (50 equiv), H2O–pentane–THF, 0 °C, 1 h.
Synthesis 2014, 46, 1493–1505
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5-endo-trig Cyclization of 3,3-Difluoroallylic Metal Enolates and Enamides
1495
pylamide (LDA), 1a gave the 5-fluorinated 2-alkylidene-
2,3-dihydrofuran 6a in 29% yield (entry 3) as a single
diastereomer (Z-form; see below). O-Cyclization of the
enolate generated from 1a proceeded exclusively in a 5-
endo-trig fashion, and the C-cyclized product, the 3-fluo-
ro-2-octylcyclopent-3-en-1-one 7a, was not detected. The
use of two equivalents of LDA improved the yield of di-
hydrofuran 6a to 42% (entry 4). Potassium tert-butoxide
Table 3 5-endo-trig Cyclization of 3,3-Difluoroallylic Ketones 1 via
Their Metal Enolates
F
F2C
O
KH (2.0 equiv)
THF, reflux
O
R3
R4
R3
R1 R2
R4
R1 R2
1
6
and potassium hydride were found to be much more effec- Entry
tive bases than LDA (entries 5 and 6). Finally, the use of
two equivalents of potassium hydride led to a 91% yield
Time (h) Product
Yield (%)
91
F
F
F
F
O
O
O
O
of dihydrofuran 6a without the formation of cyclopenten-
one 7a (entry 7).
n-C8H17
1
2
6a
Table 2 Optimization of Base-Mediated 5-endo-trig Cyclization of
Ketone 1aa
2
2
2
2
2
6b
6c
6d
6e
97
83
75
98
F
F
R
F2C
O
base
THF
O
+
R
R
O
1a
6a
7a
3
4
5
R = n-C8H17
Entry
Base
(equiv)
Time
(h)
Yield
Yield
(%) of 6a (%) of 7a
t-Bu
b
b
b
b
b
b
b
b
b
1
2
3
4
5
6
7
NaH (1.0)
NaOMe (1.0)
LDA (1.0)
LDA (2.0)
t-BuOK (1.0)
KH (1.0)
2
2
5
4
2
2
2
–
–
–
–
–
–
–
–
–
F
O
29
42
63
79
91
OMe
F
F
O
O
6
7
2
6f
97
94
KH (2.0)
a Reaction conditions: THF, reflux.
b Not detected.
21
6g
Having identified the optimal conditions, we then investi-
gated the substrate scope for the 5-endo-trig cyclization of
3,3-difluoroallylic ketones 1 (Table 3). Ketones 1b–f and
1i bearing benzyl (entry 2), secondary alkyl (entry 3), ter-
tiary alkyl (entries 4 and 9), or aryl groups (entries 5 and
6) on the α-carbon participated in the cyclization to pro-
duce the corresponding 2-alkylidene-5-fluoro-2,3-dihy-
drofurans 6b–f and 6i in high to excellent yields with
exclusive stereoselectivity. The reaction was therefore un-
affected by substituents on the α-carbon of the carbonyl
group distal to the difluoroalkene moiety. In addition, the
cyclization proceeded successfully even when the α-car-
bon was disubstituted (entries 7 and 10) or unsubstituted
(entry 8). When ketones 1h–j bearing a cyclohexane ring
F
F
F
O
O
O
8
9
5
2
3
6h
6i
91
94
97
t-Bu
at the allylic position were used, the corresponding spiro- 10a
cyclic products 6h–j were obtained (entries 8–10). In all
cases, the 5-endo-trig cyclization afforded the appropriate
5-fluorinated 2-alkylidene-2,3-dihydrofuran 6 without the
6j
a Pyridine was used as the solvent instead of THF.
formation of a C-cyclization product. As Baldwin previ-
ously noted, in the intramolecular nucleophilic cyclization
© Georg Thieme Verlag Stuttgart · New York
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1496
T. Fujita et al.
PAPER
of enolates, C-cyclization requires a perpendicular ap-
proach of the electrophilic moiety to the plane of the eno-
late, whereas O-cyclization allows the electrophilic
moiety to approach in the plane of the enolate, so that the
reaction can proceed more readily.13
Table 4 Optimization of the Base-Mediated 5-endo-trig Cyclization
of Imine 2b
F
Ts
F2C
NTs
N
base
Ph
In this series of experiments, the 2-alkylidene-2,3-dihy-
drofurans 6a–f and 6i were obtained as single stereoiso-
mers. To determine the configuration of the alkylidene
moieties of 6, we performed nuclear Overhauser effect
(NOE) experiments with dihydrofuran 6b (Figure 1). A
substantial correlation was observed between the vinylic
proton (Ha in Figure 1) and the protons of the two methyl
groups attached to the dihydrofuran ring, whereas no
NOE correlation was detected between the allylic protons
(Hb in Figure 1) and the methyl protons. Therefore, the
stereochemistry of dihydrofurans 6a–f and 6i was deter-
mined to be Z. This can be rationalized as follows: steric
repulsion between the substituents on both the α-carbons
of the ketone 1 facilitates selective formation of the Z-
enolate, which undergoes subsequent cyclization without
inversion to give (Z)-6.
Ph
2b
8b
Entry Base
(equiv)
Conditions
Yield of 8b E/Z
(%)
a
1
2
3
4
5
6
7
KH (2.0)
KH (1.2)
THF, reflux, 2 h
DMF, 90 °C, 3 h
DMF, 90 °C, 4 h
–
–
68
69
74:26
61:39
75:25
79:21
78:22
80:20
NaH (1.2)
NaOMe (1.2)
t-BuOK (1.2)
t-BuOK (1.2)
t-BuOK (2.0)
DMF, 90 °C, 5.5 h 57
DMF, 90 °C, 4 h
DMF, 100 °C, 3 h
DMF, 90 °C, 4 h
78
69
59
a Not detected.
F
2-alkylidene-5-fluoro-2,3-dihydropyrroles 8 (Table 5).
Imines 2a and 2c bearing primary and secondary alkyl
substituents on the α-carbon of the imino group distal to
the difluoroalkene moiety readily underwent the 5-endo-
trig cyclization to give dihydropyrroles 8a and 8c, respec-
tively (Table 5, entries 1 and 3). Note that the cyclization
of α-arylated imines 2e and 2f proceeded with exclusive
stereoselectivity to afford products 8e and 8f, respectively
(entries 4 and 5). Furthermore, in the case of imine 2h
bearing a cyclohexane ring in the allylic position, the cor-
responding spirocyclic product 8h was obtained almost
quantitatively (entry 6).
Hb
Hb
O
Ha
Me
Me
(Z)-6b
Figure 1 Stereochemistry of 6b determined by NOE experiments
In an attempt to broaden the range of applicability of the
5-endo-trig cyclization of 1,1-difluoro-1-alkenes, we at-
tempted a similar reaction with the 3,3-difluoroallylic im-
ines 2 in the hope of obtaining the corresponding ring-
fluorinated dihydropyrroles (Table 4). However, when we
initially applied the optimal conditions determined for the
cyclization of 3,3-difluoroallylic ketones 1 to the reaction
of the 3,3-difluoroallylic imine 2b, we obtained no cy-
clized products (Table 4, entry 1). Instead, the corre-
sponding Z-enamine was formed, presumably through
protonation of the intermediary metal enamide (See be-
low; Scheme 2). However, the use of N,N-dimethylform-
amide instead of tetrahydrofuran as the solvent induced
the desired 5-endo-trig cyclization at 90 °C to afford the
5-fluorinated 2-alkylidene 2,3-dihydropyrrole 8b in 68%
yield with a diastereomeric ratio of 74:26 (entry 2). As
with ketones 1, no C-cyclized product was obtained and
N-cyclization occurred exclusively. Among the bases ex-
amined, potassium tert-butoxide was found to be the most
effective, and the use of 1.2 equiv at 90 °C gave the high-
est yield of 8b (78%) with a diastereomeric ratio of ap-
proximately 4:1 (entry 5).
As in the case of the 2-alkylidene-2,3-dihydrofurans 6, the
stereochemistry of 8 was determined by NOE experi-
ments using an E/Z mixture of dihydropyrrole 8b (Figure
2). The major product exhibited a correlation between the
allylic protons (Hb in Figure 2) and the protons of the two
methyl groups attached to the dihydropyrrole ring, where-
as the minor product exhibited correlation between the vi-
nylic proton (Ha in Figure 2) and the methyl protons.
These observations suggested that the major and minor
products were the E- and Z-isomers of 8b, respectively,
which is in sharp contrast to the Z-selectivity observed in
the O-cyclization of ketones 1. The change in stereoselec-
Ts
Ts
Hb
F
F
Hb
N
N
Ha
Ha
Me
Me
Me
Hb
Me
Hb
The optimal conditions for the cyclization of imine 2b
were successfully applied to other 3,3-difluoroallylic im-
ines 2. This resulted in the formation of the corresponding
(E)-8b (major)
(Z)-8b (minor)
Figure 2 Stereochemistry of 8b determined by NOE experiments
Synthesis 2014, 46, 1493–1505
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5-endo-trig Cyclization of 3,3-Difluoroallylic Metal Enolates and Enamides
1497
sion between the tosyl group and the aryl substituents on
the carbon α to the imino groups is of sufficient magnitude
to induce exclusive formation of the E-isomers as a result
of the planarity of the enamide system.
Table 5 5-endo-trig Cyclization of 3,3-Difluoroallylic Imines 2 via
Their Metal Enamides
F
F2C
NTs
NTs
t-BuOK (1.2 equiv)
R3
DMF, 90 °C
R1 R2
R3
F2C
NTs
F2C
NHTs
R1 R2
KH (2.0 equiv)
THF, reflux, 2 h
2
8
Ph
Ph
Entry Time (h) Product
Yield (%) E/Z
2b
(Z)-9b 61%
Scheme 2 Confirmation of the stereochemistry of the metal enamide
F
F
NTs
NTs
1
2
4
4
8a
8b
74
78
89:11
In summary, we succeeded in cyclizing 3,3-difluoroallyl-
ic ketones 1 and imines 2 in a 5-endo-trig fashion, a pro-
cess predicted to be disfavored by Baldwin’s rules. The
corresponding metal enolates and enamides undergo ex-
clusive O- and N-cyclization to afford 2-alkylidene-5-
fluoro-2,3-dihydrofurans 6 and 2-alkylidene-5-fluoro-
2,3-dihydropyrroles 8, respectively. The 5-endo-trig cy-
clization of 1,1-difluoro-1-alkenes therefore has broad ap-
plicability. Note that this protocol simultaneously
introduces a fluorine substituent and an exo-alkylidene
unit onto the dihydroheterole rings. Because ring-fluori-
nated compounds bearing such unique heteronuclei are
unprecedented, these compounds have significant poten-
tial as key synthetic intermediates for the preparation of
fluorinated functional heteroles, which constitute an im-
portant class of bioactive molecules.14
n-C8H17
79:21
Ph
F
F
F
NTs
NTs
NTs
3
4
6
4
8c
8e
63
86
93:7
–
Cy
Ph
1H NMR, 13C NMR, and 19F NMR spectra were recorded on a Bruk-
er Avance 500 or a Bruker DRX 500 spectrometer. Chemical shift
values are given in ppm relative to internal TMS (for 1H NMR: δ =
0.00 ppm), CDCl3 (for 13C NMR: δ = 77.0 ppm), or C6F6 (for 19F
NMR: δ = 0.00 ppm). IR spectra were recorded on a Horiba FT-
300S spectrometer by the attenuated total reflectance (ATR) meth-
od. Mass spectra were measured on a JEOL MS-700M or a JEOL
JMS-T100GCV spectrometer. Elemental analyses were carried out
at the Elemental Analysis Laboratory, Division of Chemistry, Fac-
ulty of Pure and Applied Sciences, University of Tsukuba. All reac-
tions were carried out under argon. THF and DMF were purified by
using a solvent-purification system (GlassContour) equipped with
columns of activated alumina and supported copper catalyst (Q-5)
before use. Column chromatography was performed on Silica Gel
60 (Kanto Chemical Co. Inc.). Preparative TLC was performed on
B5-F silica gal (Wako Pure Chemical Industries, Ltd. 4-(Cyclohex-
ylidenemethyl)morpholine,15 4-(2-methylprop-1-en-1-yl)morpho-
line,15 2-methyl-N-(2-methylpropylidene)propan-2-amine,16 N-
(cyclohexylmethylene)-2-methylpropan-2-amine,17 and 1-acetylcy-
clohexanecarbaldehyde (3h)18 were prepared according to literature
procedures.
5a
3
4
8f
77
99
–
–
OMe
F
NTs
6a
8h
a Amount of t-BuOK used was increased to 1.3 equiv.
tivity can be explained as follows. It is likely that the Z-
enamides are initially formed by deprotonation of 3,3-
difluoroallylic imines 2, presumably as a result of steric
repulsion between the substituents on the two α-carbons
of imines 2. This speculation is supported by the fact that
the reaction of 2b with potassium hydride in tetrahydrofu-
ran gave the Z-enamine 9b exclusively (Scheme 2; see
also Table 4, entry 1). The stereochemistry of 9b was con-
firmed by NOE experiments. Cyclization of the Z-en-
amide derived from 2b appears to be retarded by the
presence on the nitrogen atom of the tosyl group, which is
repelled by the benzyl group, thereby hindering the reac-
tion. As a result, cyclization occurs preferentially from the
E-enamide after stereo inversion, leading to the selective
formation of dihydropyrrole 8b bearing an E-alkylidene
moiety. In particular, for imines 8e and 8f, the steric repul-
2,2-Dimethyl-3-oxododecanal (3a); Typical Procedure A (Meth-
od A)
A 2.4 M solution of BuLi in hexane (16.4 mL, 43.3 mmol) was add-
ed to a solution of i-Pr2NH (6.35 mL, 45.3 mmol) in Et2O (98 mL)
at –78 °C, and the mixture was stirred for 10 min at –78 °C and then
for 10 min at 0 °C. 2-Methyl-N-(2-methylpropylidene)propan-2-
amine (5.01 g, 39.4 mmol) was added dropwise at –78 °C, and the
solution was stirred for 10 min at –78 °C, warmed to 0 °C, and
stirred for 2 h at 0 °C. Me(CH2)8COCl (8.00 mL, 39.4 mmol) was
added at –78 °C, and the mixture was stirred for 15 min at –78 °C,
warmed to r.t., and stirred for 12 h. Phosphate buffer (pH 7; 50 mL)
was added, and the organic materials were extracted with Et2O (3 ×
150 mL). The combined extracts were washed with brine (300 mL),
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 1493–1505

1498
T. Fujita et al.
PAPER
dried (Na2SO4), and concentrated under reduced pressure. The res-
idue was dissolved in CH2Cl2 (78 mL) and the solution was treated
with a solution of oxalic acid dihydrate (4.91 g, 39.4 mmol) in H2O
(47 mL) with stirring for 1 h at r.t. Organic materials were extracted
with CH2Cl2 (3 × 150 mL), and the extracts were combined, washed
with brine (300 mL), dried (MgSO4), and concentrated under re-
duced pressure. The residue was purified by column chromatogra-
phy [silica gel, EtOAc–hexane (1:5)] to give a colorless oil; yield:
2.47 g (32%).
hydrate (1.03 g, 8.19 mmol) in H2O (9.8 mL), and the mixture was
stirred for 1 h at r.t. Purification by column chromatography [silica
gel, EtOAc–hexane (1:3)] gave a colorless liquid; yield: 716 mg
(45%).
IR (neat): 2973, 2924, 2852, 2715, 1731, 1701, 1658, 1448, 1365,
1286, 1195, 1045, 914, 827 cm–1.
1H NMR (500 MHz, CDCl3): δ = 0.88 (m, 2 H), 1.07–1.18 (m, 1 H),
1.20–1.34 (m, 2 H), 1.31 (s, 6 H), 1.60–1.70 (m, 5 H), 1.82–1.95 (m,
1 H), 2.31 (d, J = 6.7 Hz, 2 H), 9.61 (s, 1 H).
13C NMR (126 MHz, CDCl3): δ = 19.0, 26.0, 26.1, 26.1, 33.1, 46.6,
60.5, 201.2, 208.8.
IR (neat): 2924, 2854, 1734, 1700, 1466, 1366, 1072, 1035, 914,
838, 722 cm–1.
1H NMR (500 MHz, CDCl3): δ = 0.88 (t, J = 7.0 Hz, 3 H), 1.21–
1.32 (m, 12 H), 1.33 (s, 6 H), 1.45 (tt, J = 7.3, 7.3 Hz, 2 H), 2.44 (t,
J = 7.3 Hz, 2 H), 9.62 (s, 1 H).
HRMS (EI): m/z [M – CO]+ calcd for C11H20O: 168.1514; found:
168.1515.
13C NMR (126 MHz, CDCl3): δ = 14.0, 19.1, 22.6, 23.3, 29.0, 29.2,
29.3, 29.3, 31.8, 39.0, 60.3, 201.1, 209.3.
HRMS (FAB): m/z [M + H]+ calcd for C14H27O2: 227.2011; found:
227.2006.
2,2,5,5-Tetramethyl-3-oxohexanal (3d)
Compound 3d was prepared by following typical procedure A from
i-Pr2NH (4.61 mL, 32.9 mmol), Et2O (71 mL), a 2.64 M soln of
BuLi in hexane (11.5 mL, 31.4 mmol), 2-methyl-N-(2-methylpro-
pylidene)propan-2-amine (3.64 g, 28.6 mmol), and t-BuCH2COCl
(4.00 mL, 28.6 mmol). The mixture was stirred at r.t. for 12 h, and
then pH 7 phosphate buffer (40 mL) was added. After workup, the
crude product was treated with CH2Cl2 (28 mL) and oxalic acid di-
hydrate (1.80 g, 14.3 mmol) in H2O (17 mL). The reaction mixture
was stirred for 1 h at r.t. Purification by column chromatography
[silica gel, EtOAc–hexane (1:4)] gave a colorless liquid; yield: 2.04
g (85%).
1-(3,3-Dimethylbutanoyl)cyclohexanecarbaldehyde (3i); Typi-
cal Procedure B (Method B)
t-BuCH2COCl (3.65 g, 27.1 mmol) was dissolved in Et2O (7 mL)
with vigorous stirring at 0 °C. 4-(Cyclohexylidenemethyl)morpho-
line (4.92 g, 27.1 mmol) was added over 1 h at 0 °C, and the solution
was then refluxed for 10 h. Sat. aq NaHCO3 (10 mL) was added at
0 °C and the mixture was stirred for 1 h at 0 °C. Organic materials
were extracted with Et2O (3 × 100). The combined were combined,
washed with brine (150 mL), dried (Na2SO4), and concentrated un-
der reduced pressure. The residue was purified by column chroma-
tography [silica gel, EtOAc–hexane (1:20)] to give a colorless oil;
yield: 1.65 g (29%).
IR (neat): 2954, 2870, 2715, 1731, 1703, 1466, 1365, 1246, 1061,
912, 835 cm–1.
1H NMR (500 MHz, CDCl3): δ = 1.01 (s, 9 H), 1.30 (s, 6 H), 2.35
(s, 2 H), 9.61 (s, 1 H).
13C NMR (126 MHz, CDCl3): δ = 19.0, 29.4, 30.7, 50.6, 61.0,
201.3, 208.3.
IR (neat): 2935, 2866, 1730, 1699, 1450, 1363, 1217, 1124, 1016,
908, 829, 741, 690 cm–1.
HRMS (EI): m/z [M – CO]+ calcd for C9H18O: 142.1358; found:
142.1356.
1H NMR (500 MHz, CDCl3): δ = 0.99 (s, 9 H), 1.26–1.42 (m, 3 H),
1.47–1.61 (m, 3 H), 1.78–1.87 (m, 2 H), 2.04–2.11 (m, 2 H), 2.32
(s, 2 H), 9.48 (s, 1 H).
13C NMR (126 MHz, CDCl3): δ = 22.3, 25.1, 28.4, 29.4, 30.6, 50.7,
66.7, 201.9, 206.8.
2,2-Dimethyl-3-oxo-4-phenylbutanal (3e)
Compound 3e was prepared by following typical procedure A from
i-Pr2NH (0.371 mL, 2.64 mmol), Et2O (5.8 mL), a 2.64 M soln of
BuLi in hexane (0.93 mL, 2.5 mmol), 2-methyl-N-(2-methylpropyl-
idene)propan-2-amine (293 mg, 2.30 mmol), and PhCH2COCl
(0.31 mL, 2.3 mmol). The mixture was stirred at r.t. for 12 h, and
then pH 7 phosphate buffer (5 mL) was added. After workup, the
crude product was treated with CH2Cl2 (4.6 mL) and oxalic acid di-
hydrate (290 mg, 2.30 mmol) in H2O (2.8 mL), and the mixture was
stirred for 1 h at r.t. Purification by column chromatography [silica
gel, EtOAc–hexane (1:5)] gave a colorless liquid; yield: 192 mg
(44%).
LRMS (FAB): m/z (%) = 211 (11) [M + H]+.
2,2-Dimethyl-3-oxo-5-phenylpentanal (3b)
This was prepared by following the typical procedure B from
Ph(CH2)2COCl (4.41 mL, 28.3 mmol) and 4-(2-methylprop-1-
enyl)morpholine (4.00 g, 28.3 mmol) in Et2O (7.0 mL). The mixture
was refluxed for 12 h, and sat. aq NaHCO3 (10 mL) was added. Pu-
rification by column chromatography [silica gel, EtOAc–hexane
(1:5)] gave a colorless oil; yield: 3.34 g (58%).
IR (neat): 3028, 2975, 2935, 2823, 2717, 1726, 1699, 1604, 1496,
1454, 1365, 1065, 987, 912, 819, 748, 698 cm–1.
IR (neat): 2978, 1729, 1700, 1497, 1455, 1051, 827, 728, 696, 549
cm–1.
1H NMR (500 MHz, CDCl3): δ = 1.29 (s, 6 H), 2.77 (t, J = 7.4 Hz,
2 H), 2.89 (t, J = 7.4 Hz, 2 H), 7.15–7.23 (m, 3 H), 7.26–7.29 (m, 2
H), 9.55 (s, 1 H).
1H NMR (500 MHz, CDCl3): δ = 1.36 (s, 6 H), 3.77 (s, 2 H), 7.14
(d, J = 7.4 Hz, 2 H), 7.24 (tt, J = 7.4, 1.7 Hz, 1 H), 7.30 (dd, J = 7.4,
7.4 Hz, 2 H), 9.56 (s, 1 H).
13C NMR (126 MHz, CDCl3): δ = 19.1, 29.5, 40.8, 60.2, 126.2,
128.3, 128.5, 140.7, 201.0, 208.4.
13C NMR (126 MHz, CDCl3): δ = 19.1, 45.5, 60.5, 127.0, 128.5,
129.5, 133.0, 200.6, 206.3.
HRMS (FAB): m/z [M + H]+ calcd for C12H15O2: 191.1072; found:
191.1077.
Anal. Calcd for C13H16O2: C, 76.44; H, 7.90. Found: C, 76.31; H,
8.14.
4-Cyclohexyl-2,2-dimethyl-3-oxobutanal (3c)
4-(4-Methoxyphenyl)-2,2-dimethyl-3-oxobutanal (3f)
Compound 3c was prepared by following typical procedure A from
i-Pr2NH (1.30 mL, 9.28 mmol), Et2O (71 mL), a 2.64 M soln of
BuLi in hexane (3.40 mL, 8.98 mmol), 2-methyl-N-(2-methylpro-
pylidene)propan-2-amine (1.04 g, 8.20 mmol), and CyCH2COCl
(1.32 g, 8.20 mmol). The mixture was stirred at r.t. for 12 h, and
then pH 7 phosphate buffer (40 mL) was added. After workup, the
crude product was treated with CH2Cl2 (16 mL) and oxalic acid di-
Compound 3f was prepared by following typical procedure A from
i-Pr2NH (5.19 mL, 37.0 mmol), Et2O (80 mL), a 2.64 M soln of
BuLi in hexane (13.0 mL, 35.5 mmol), 2-methyl-N-(2-methylpro-
pylidene)propan-2-amine (4.09 g, 32.2 mmol), and 4-
MeOC6H4CH2COCl (5.94 g, 32.2 mmol). The mixture was stirred
at r.t. for 12 h, and then pH 7 phosphate buffer (50 mL) was added.
After workup, the crude product was treated with CH2Cl2 (64 mL)
Synthesis 2014, 46, 1493–1505
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5-endo-trig Cyclization of 3,3-Difluoroallylic Metal Enolates and Enamides
1499
and oxalic acid dihydrate (4.06 g, 32.2 mmol) in H2O (39 mL), and
the mixture was stirred for 1 h at r.t. Purification by column chro-
matography [silica gel, EtOAc–hexane (1:3 to 1:2 to 1:1)] gave a
colorless liquid; yield: 3.85 g (54%).
quenched with pH 7 phosphate buffer (20 mL) at 0 °C. After suction
filtration, the organic materials were extracted with EtOAc (3 × 50
mL). The combined extracts were washed with brine (100 mL),
dried (Na2SO4), and concentrated under reduced pressure. The res-
idue was purified by TLC [silica gel, EtOAc–hexane (1:5)] to give
a colorless oil; yield: 2.07 g (86%).
IR (neat): 2972, 2935, 2836, 2717, 1701, 1612, 1512, 1464, 1246,
1033, 815, 787 cm–1.
IR (neat): 2925, 2854, 1738, 1716, 1508, 1456, 1331, 1223, 1001,
771 cm–1.
1H NMR (500 MHz, CDCl3): δ = 0.88 (t, J = 6.9 Hz, 3 H), 1.26–
1.31 (m, 18 H), 1.56 (tt, J = 7.1, 7.1 Hz, 2 H), 2.49 (t, J = 7.1 Hz, 2
H), 4.37 (dd, JHF = 27.9, 4.4 Hz, 1 H).
13C NMR (126 MHz, CDCl3): δ = 14.0, 22.6, 24.1, 24.9 (d, JCF = 3
Hz), 29.2, 29.2, 29.4, 29.4, 31.8, 37.0, 45.1 (dd, JCF = 4, 4 Hz), 83.9
(dd, JCF = 23, 15 Hz), 155.7 (dd, JCF = 294, 287 Hz), 211.7.
1H NMR (500 MHz, CDCl3): δ = 1.37 (s, 6 H), 3.72 (s, 2 H), 3.79
(s, 3 H), 6.73 (d, J = 8.6 Hz, 2 H), 7.06 (d, J = 8.6 Hz, 2 H), 9.55 (s,
1 H).
13C NMR (126 MHz, CDCl3): δ = 19.3, 44.8, 55.2, 60.6, 114.1,
124.8, 130.6, 158.7, 200.6, 206.6.
HRMS (EI): m/z [M+] calcd for C13H16O3: 220.1099; found:
220.1106.
19F NMR (470 MHz, CDCl3): δ = 76.9 (dd, JFF = 44 Hz, JFH = 4 Hz,
1 F), 78.2 (dd, JFF = 44 Hz, JFH = 28 Hz, 1 F).
3-Cyclohexyl-2,2-dimethyl-3-oxopropanal (3g)
Compound 3g was prepared by following typical procedure A from
i-Pr2NH (4.60 mL, 32.9 mmol), Et2O (71 mL), a 2.64 M soln of
BuLi in hexane (11.5 mL, 31.4 mmol), 2-methyl-N-(2-methylpro-
pylidene)propan-2-amine (3.64 g, 28.6 mmol), and CyCOCl (4.00
mL, 28.6 mmol). The mixture was stirred at r.t. for 12 h, and then
pH 7 phosphate buffer (50 mL) was added. After workup, the crude
product was treated with CH2Cl2 (57 mL) and oxalic acid dihydrate
(3.60 g, 28.6 mmol) in H2O (34 mL), and the mixture was stirred for
1 h at r.t. Purification by column chromatography [silica gel,
EtOAc–hexane (1:4)] gave a colorless liquid; yield: 4.70 g (90%).
Anal. Calcd for C15H26F2O: C, 69.20; H, 10.07. Found: C, 69.10; H,
10.14.
6,6-Difluoro-4,4-dimethyl-1-phenylhex-5-en-3-one (1b)
Compound 1b was prepared by following typical procedure C from
CF2Br2 (2.37 mL, 25.7 mmol), microwave-dried 4 Å MS (1.3 g),
THF (40 mL), P(NMe2)3 (9.32 mL, 51.3 mmol), and aldehyde 3b
(2.62 g, 12.8 mmol). The mixture was stirred for 16 h and then the
reaction was quenched with pH 7 phosphate buffer (20 mL) at 0 °C.
Purification by column chromatography [silica gel, EtOAc–hexane
(1:10)] gave a colorless oil; yield: 2.28 g (87%).
IR (neat): 2975, 2931, 2856, 2715, 1732, 1699, 1450, 1367, 1141,
1066, 987, 831, 733, 667 cm–1.
1H NMR (500 MHz, CDCl3): δ = 1.17–1.29 (m, 3 H), 1.33 (s, 6 H),
1.35–1.41 (m, 2 H), 1.64–1.79 (m, 5 H), 2.65 (tt, J = 11.4, 3.3 Hz, 1
H), 9.62 (s, 1 H).
IR (neat): 3028, 2979, 2937, 1736, 1712, 1329, 1227, 997, 700 cm–1.
1H NMR (500 MHz, CDCl3): δ = 1.25 (dd, JHF = 1.0, 0.6 Hz, 6 H),
2.80–2.83 (m, 2 H), 2.87–2.90 (m, 2 H), 4.30 (dd, JHF = 27.8, 4.4
Hz, 1 H), 7.17–7.20 (m, 3 H), 7.26–7.30 (m, 2 H).
13C NMR (126 MHz, CDCl3): δ = 19.0, 25.4, 25.5, 29.1, 47.1, 60.9,
201.1, 212.2.
13C NMR (126 MHz, CDCl3): δ = 24.8 (d, JCF = 2.2 Hz), 30.2, 39.1,
45.2 (dd, JCF = 4, 3 Hz), 83.8 (dd, JCF = 24, 15 Hz), 126.1, 128.4,
128.5, 141.3, 155.8 (dd, JCF = 294, 288 Hz), 210.6.
HRMS (EI): m/z [M – CO]+ calcd for C10H18O: 154.1358; found:
154.1362.
19F NMR (470 MHz, CDCl3): δ = 77.2 (dd, JFF = 43 Hz, JFH = 4 Hz,
1 F), 78.3 (dd, JFF = 43 Hz, JFH = 28 Hz, 1 F).
1-(Cyclohexanecarbonyl)cyclohexanecarbaldehyde (3j)
N-(Cyclohexylmethylene)-2-methylpropan-2-amine (983 mg, 5.87
mmol) was dissolved in THF (35 mL) and t-BuLi (1.59 M, 3.69 mL,
5.87 mmol) was added over 1 min at –78 °C. The mixture was
stirred at 0 °C for 1 h then CyCOCl (861 mg, 5.87 mmol) was added
at –78 °C. The mixture was refluxed for 2 h, and then treated with
AcOH (17.6 g, 293 mmol), NaOAc (24.1 g, 293 mmol), and H2O
(70 mL) at 0 °C with stirring for 1 h. The organic materials were ex-
tracted with Et2O (3 × 20 mL), and the organic layers were com-
bined and washed sequentially with aq NaHCO3 (10 × 30 mL) and
brine (50 mL), then dried (Na2SO4). Purification by column chro-
matography [silica gel, Et3N–EtOAc–hexane (1:2:50)] gave a col-
orless liquid; yield: 533 mg (41%).
Anal. Calcd for C14H16F2O: C, 70.57; H, 6.77. Found: C, 70.24; H,
6.96.
1-Cyclohexyl-5,5-difluoro-3,3-dimethylpent-4-en-2-one (1c)
Compound 1c was prepared by following typical procedure C from
CF2Br2 (2.7 mL, 29 mmol), microwave-dried 4 Å MS (4.5 g), THF
(48 mL), P(NMe2)3 (10.9 mL, 57.6 mmol), and aldehyde 3c (2.82 g,
14.4 mmol). The mixture was stirred for 7 h and then the reaction
was quenched with pH 7 phosphate buffer (20 mL) at 0 °C. Purifi-
cation by column chromatography [silica gel, EtOAc–hexane (1:5)]
gave a colorless oil; yield: 2.71 g (82%).
IR (neat): 2978, 2923, 2852, 1735, 1712, 1469, 1448, 1328, 1286,
1226, 1136, 1045, 1001, 962, 943, 906 cm–1.
IR (neat): 2927, 2854, 1728, 1701, 1450, 1367, 1246, 1163, 1132,
987, 893, 773 cm–1.
1H NMR (500 MHz, CDCl3): δ = 0.84–0.92 (m, 2 H), 1.11–1.17 (m,
1 H), 1.24–1.32 (m, 3 H), 1.27 (dd, JHF = 1.0, 0.6 Hz, 6 H), 1.61–
1.69 (m, 4 H), 1.85–1.90 (m, 1 H), 2.36 (d, J = 6.7 Hz, 2 H), 4.35
(dd, JHF = 28.0, 4.5 Hz, 1 H).
13C NMR (126 MHz, CDCl3): δ = 24.8 (dd, JCF = 3, 1 Hz), 26.1,
26.2, 33.1, 33.4, 44.8, 45.2 (dd, JCF = 4, 4 Hz), 83.8 (dd, JCF = 23,
15 Hz), 155.8 (dd, JCF = 294, 288 Hz), 211.0.
1H NMR (500 MHz, CDCl3): δ = 1.18–1.69 (m, 14 H), 1.72–1.80
(m, 2 H), 1.80–1.90 (m, 2 H), 2.05–2.13 (m, 2 H), 2.67 (tt, J = 12.7,
3.3 Hz, 1 H), 9.53 (s, 1 H).
13C NMR (126 MHz, CDCl3): δ = 22.4, 25.1, 25.4, 25.5, 28.2, 29.1,
46.9, 66.4, 201.6, 211.0.
HRMS (FAB): m/z [M + H]+ calcd for C14H23O2: 223.1698; found:
223.1693.
19F NMR (470 MHz, CDCl3): δ = 77.0 (dd, JFF = 44 Hz, JFH = 4 Hz,
1 F), 77.8 (dd, JFF = 44 Hz, JFH = 28 Hz, 1 F).
1,1-Difluoro-3,3-dimethyltridec-1-en-4-one (1a); Typical Proce-
dure C
Anal. Calcd for C13H20F2O: C, 67.80; H, 8.75. Found: C, 67.57; H,
8.78.
P(NMe2)3 (7.0 mL, 37.0 mmol) was added to a mixture of CF2Br2
(1.77 mL, 18.6 mmol) and microwave-dried 4 Å MS (3.0 g) in THF
(31 mL) at –78 °C. The mixture was stirred for 15 min at –78 °C and
then warmed to r.t. Aldehyde 3a (2.10 g, 9.28 mmol) was added,
and the mixture was stirred for 10 h. The reaction was then
1,1-Difluoro-3,3,6,6-tetramethylhept-1-en-4-one (1d)
Compound 1d was prepared by following typical procedure C from
CF2Br2 (0.80 mL, 8.4 mmol), microwave-dried 4 Å MS (0.42 g),
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 1493–1505

1500
T. Fujita et al.
PAPER
THF (3.2 mL), P(NMe2)3 (3.2 mL, 17 mmol), and aldehyde 3d (714
mg, 4.20 mmol). The mixture was stirred for 10 h, and then the re-
action was quenched with pH 7 phosphate buffer (5 mL) at 0 °C.
Purification by column chromatography [silica gel, EtOAc–hexane
(1:5)] gave a colorless oil; yield: 500 mg (58%).
18.7 mmol). The mixture was stirred for 12 h and then the reaction
was quenched with pH 7 phosphate buffer (20 mL) at 0 °C. Purifi-
cation by column chromatography [silica gel, EtOAc–hexane
(1:10)] gave a colorless oil; yield: 2.86 g (71%).
IR (neat): 2977, 2933, 2857, 1736, 1709, 1452, 1331, 1227, 1134,
1063, 989, 933, 798 cm–1.
1H NMR (500 MHz, CDCl3): δ = 1.22–1.28 (m, 3 H), 1.30 (dd,
JHF = 0.6, 0.6 Hz, 6 H), 1.38–1.46 (m, 2 H), 1.62–1.65 (m, 2 H),
1.76–1.79 (m, 3 H), 2.76 (tt, J = 11.6, 3.3 Hz, 1 H), 4.39 (dd,
IR (neat): 2956, 2927, 2856, 1738, 1716, 1466, 1365, 1330, 1225,
1128, 1061, 1005 cm–1.
1H NMR (500 MHz, CDCl3): δ = 1.02 (s, 9 H), 1.26 (dd, JHF = 1.3,
0.8 Hz, 6 H), 2.40 (s, 2 H), 4.34 (dd, JHF = 28.0, 4.5 Hz, 1 H).
JHF = 27.8, 4.6 Hz, 1 H).
13C NMR (126 MHz, CDCl3): δ = 24.9 (d, JCF = 2 Hz), 29.6, 30.6,
45.7 (dd, JCF = 4, 4 Hz), 48.8, 83.9 (dd, JCF = 23, 15 Hz), 155.7 (dd,
13C NMR (126 MHz, CDCl3): δ = 24.6 (d, JCF = 2 Hz), 25.6, 25.7,
30.2, 45.6 (dd, JCF = 4, 3 Hz), 46.0, 83.3 (dd, JCF = 23, 15 Hz), 155.9
(dd, JCF = 295, 288 Hz), 214.4.
19F NMR (470 MHz, CDCl3): δ = 77.5 (dd, JFF = 44 Hz, JFH = 4 Hz,
1 F), 78.2 (dd, JFF = 44 Hz, JFH = 28 Hz, 1 F).
JCF = 295, 288 Hz), 210.9.
19F NMR (470 MHz, CDCl3): δ = 76.9 (dd, JFF = 44 Hz, JFH = 4 Hz,
1 F), 77.8 (dd, JFF = 45 Hz, JFH = 28 Hz, 1 F).
Anal. Calcd for C11H18F2O: C, 64.68; H, 8.88. Found: C, 64.67; H,
9.10.
Anal. Calcd for C12H18F2O: C, 66.64; H, 8.39. Found: C, 66.40; H,
8.34.
5,5-Difluoro-3,3-dimethyl-1-phenylpent-4-en-2-one (1e)
Compound 1e was prepared by following typical procedure C from
CF2Br2 (491 mg, 2.34 mmol), microwave-dried 4 Å MS (0.23 g),
THF (1.8 mL), P(NMe2)3 (763 mg, 4.68 mmol), and aldehyde 3e
(222 mg, 1.17 mmol). The mixture was stirred for 10 h, and then the
reaction was quenched with pH 7 phosphate buffer (5 mL) at 0 °C.
Purification by TLC [silica gel, EtOAc–hexane (1:5)] gave a color-
less oil; yield: 166 mg (63%).
1-[1-(2,2-Difluorovinyl)cyclohexyl]ethanone (1h)
Compound 1h was prepared by following typical procedure C from
CF2Br2 (5.12 g, 24.4 mmol), microwave-dried 4 Å MS (1.89 g),
THF (55 mL), P(NMe2)3 (7.99 g, 49.0 mmol), and aldehyde 3h
(1.89 g, 12.3 mmol). The mixture was stirred for 10 h, and then the
reaction was quenched with pH 7 phosphate buffer (30 mL) at 0 °C.
Purification by column chromatography [silica gel, Et2O–hexane
(1:20)] gave a colorless oil; yield: 1.52 g (66%).
IR (neat): 2964, 1809, 1682, 1211, 1192, 1174, 1055, 935, 771, 694
cm–1.
1H NMR (500 MHz, CDCl3): δ = 1.34 (s, 6 H), 3.81 (s, 2 H), 4.41
(dd, JHF = 27.8, 4.3 Hz, 1 H), 7.18 (d, J = 7.2 Hz, 2 H), 7.25 (t,
J = 7.2 Hz, 1 H), 7.30 (dd, J = 7.2, 7.2 Hz, 2 H).
13C NMR (126 MHz, CDCl3): δ = 24.9, 43.8, 45.6 (dd, JCF = 4, 4
Hz), 83.8 (dd, JCF = 23, 15 Hz), 126.8, 128.4, 129.4, 134.4, 155.8
(dd, JCF = 294, 288 Hz), 208.5.
IR (neat): 2935, 2858, 1732, 1709, 1333, 1211, 1180, 1136, 987,
920, 887, 798, 590 cm–1.
1H NMR (500 MHz, CDCl3): δ = 1.29–1.40 (m, 1 H), 1.44–1.62 (m,
5 H), 1.68–1.80 (m, 4 H), 2.15 (s, 3 H), 4.21 (dd, JHF = 28.2, 4.8 Hz,
1 H).
13C NMR (126 MHz, CDCl3): δ = 22.2, 25.2, 25.4, 32.8 (d, JCF = 1
Hz), 49.4 (dd, JCF = 3, 3 Hz), 82.0 (dd, JCF = 23, 16 Hz), 155.7 (dd,
J
CF = 295, 289 Hz), 209.0.
19F NMR (470 MHz, CDCl3): δ = 77.5 (dd, JFF = 43 Hz, JFH = 4 Hz,
1 F), 78.3 (dd, JFF = 43 Hz, JFH = 28 Hz, 1 F).
HRMS (FAB): m/z [M + H]+ calcd for C13H15F2O: 225.1091; found:
19F NMR (470 MHz, CDCl3): δ = 78.3 (dm, JFF = 41 Hz, 1 F), 78.6
(dd, JFF = 41 Hz, JFH = 29 Hz, 1 F).
HRMS (FAB): m/z [M + H]+ calcd for C10H15F2O: 189.1091; found:
225.1087.
189.1100.
5,5-Difluoro-1-(4-methoxyphenyl)-3,3-dimethylpent-4-en-2-
one (1f)
1-[1-(2,2-Difluorovinyl)cyclohexyl]-3,3-dimethylbutan-1-one
(1i)
Compound 1f was prepared by following typical procedure C from
CF2Br2 (3.5 mL, 37 mmol), microwave-dried 4 Å MS (6.0 g), THF
(62 mL), P(NMe2)3 (13.5 mL, 71.3 mmol), and aldehyde 3f (4.1 g,
19 mmol). The mixture was stirred for 5 h, and then the reaction was
quenched with pH 7 phosphate buffer (10 mL) at 0 °C. Purification
by column chromatography [silica gel, EtOAc–hexane (1:4)] gave
a colorless oil; yield: 2.72 g (58%).
Compound 1i was prepared by following typical procedure C from
CF2Br2 (452 mg, 2.15 mmol), microwave-dried 4 Å MS (0.22 g),
THF (1.6 mL), P(NMe2)3 (702 mg, 4.30 mmol), and aldehyde 3i
(226 mg, 1.08 mmol). The mixture was stirred for 8 h, and then the
reaction was quenched with sat. aq NaHCO3 (5 mL) at 0 °C. Purifi-
cation by TLC [silica gel, EtOAc–hexane (1:20)] gave a colorless
oil; yield: 178 mg (68%).
IR (neat): 2978, 2939, 1736, 1726, 1514, 1248, 1178, 1047, 1003
cm–1.
1H NMR (500 MHz, CDCl3): δ = 1.34 (dd, JHF = 1.0, 0.7 Hz, 6 H),
3.76 (s, 2 H), 3.79 (s, 3 H), 4.41 (dd, JHF = 27.8, 4.3 Hz, 1 H), 6.85
(d, J = 8.7 Hz, 2 H), 7.09 (d, J = 8.7 Hz, 2 H).
13C NMR (126 MHz, CDCl3): δ = 25.1 (dd, JCF = 3, 1 Hz), 42.9,
45.6 (dd, JCF = 4, 3 Hz), 55.2, 83.9 (dd, JCF = 24, 15 Hz), 113.9,
126.5, 130.4, 155.8 (dd, JCF = 295, 288 Hz), 158.5, 209.0.
IR (neat): 2937, 1732, 1711, 1363, 1333, 1223, 1184, 1009, 908,
812 cm–1.
1H NMR (500 MHz, CDCl3): δ = 0.94 (s, 9 H), 1.15–1.24 (m, 2 H),
1.31–1.41 (m, 2 H), 1.42–1.53 (m, 2 H), 1.55–1.64 (m, 2 H), 1.59–
1.69 (m, 2 H), 2.29 (s, 2 H), 4.09 (dd, JHF = 28.8, 4.6 Hz, 1 H).
13C NMR (126 MHz, CDCl3): δ = 22.3, 25.5, 29.5, 30.5, 32.7, 49.0,
49.9 (dd, JCF = 4, 3 Hz), 81.9 (dd, JCF = 23, 15 Hz), 155.7 (dd,
J
CF = 295, 288 Hz), 210.0.
19F NMR (470 MHz, CDCl3): δ = 77.4 (dd, JFF = 43 Hz, JFH = 4 Hz,
1 F), 78.2 (dd, JFF = 43 Hz, JFH = 28 Hz, 1 F).
19F NMR (470 MHz, CDCl3): δ = 78.2 (d, JFF = 41 Hz, 1 F), 78.9
(dd, JFF = 41 Hz, JFH = 29 Hz, 1 F).
LRMS (FAB): m/z (%) = 245 (11) [M + H]+.
Anal. Calcd for C14H16F2O2: C, 66.13; H, 6.34. Found: C, 66.19; H,
6.46.
1-Cyclohexyl-4,4-difluoro-2,2-dimethylbut-3-en-1-one (1g)
Compound 1g was prepared by following typical procedure C from
CF2Br2 (3.6 mL, 37 mmol), microwave-dried 4 Å MS (1.9 g), THF
(15 mL), P(NMe2)3 (14 mL, 75 mmol), and aldehyde 3g (3.40 g,
Cyclohexyl[1-(2,2-difluorovinyl)cyclohexyl]methanone (1j)
Compound 1j was prepared by following typical procedure C from
CF2Br2 (897 mg, 4.27 mmol), microwave-dried 4 Å MS (0.43 g),
THF (3.2 mL), P(NMe2)3 (1.39 g, 8.53 mmol), and aldehyde 3j (823
Synthesis 2014, 46, 1493–1505
© Georg Thieme Verlag Stuttgart · New York

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5-endo-trig Cyclization of 3,3-Difluoroallylic Metal Enolates and Enamides
1501
mg, 3.70 mmol). The mixture was stirred for 10 h, and then the re-
action was quenched with pH 7 phosphate buffer (5 mL) at 0 °C.
Purification by column chromatography [silica gel, EtOAc–hexane
(1:20)] gave a colorless oil; yield: 252 mg (27%).
Anal. Calcd for C21H23F2NO2S: C, 64.43; H, 5.92. Found: C, 64.43;
H, 6.00.
N-[1-(Cyclohexylmethyl)-4,4-difluoro-2,2-dimethylbut-3-en-1-
ylidene]-4-methylbenzenesulfonamide (2c)
IR (neat): 2929, 2854, 1728, 1705, 1450, 1331, 1225, 1186, 1151,
985, 901, 804, 735 cm–1.
1H NMR (500 MHz, CDCl3): δ = 1.12–1.25 (m, 4 H), 1.29–1.42 (m,
4 H), 1.45–1.74 (m, 12 H), 2.63 (tt, J = 11.6, 3.3 Hz, 1 H), 4.14 (dd,
JHF = 28.5, 4.6 Hz, 1 H).
Compound 2c was prepared by following typical procedure D from
ketone 1c (538 mg, 2.34 mmol), TsNH2 (400 mg, 2.34 mmol), DCE
(23 mL), Et3N (0.65 mL, 4.66 mmol), and TiCl4 (0.22 mL, 2.00
mmol). Purification by column chromatography [silica gel, EtOAc–
hexane (1:5)] gave a pale-yellow oil; yield: 733 mg (82%).
13C NMR (126 MHz, CDCl3): δ = 22.3, 25.5, 25.6, 25.7, 30.3, 32.4,
46.5, 49.8 (dd, JCF = 3, 3 Hz), 81.3 (dd, JCF = 23, 15 Hz), 155.9 (dd,
IR (neat): 2927, 2852, 1739, 1616, 1448, 1319, 1218, 1157, 1093,
1004, 813, 738, 678, 584 cm–1.
1H NMR (500 MHz, CDCl3): δ = 1.05–1.20 (m, 3 H), 1.25–1.33 (m,
8 H), 1.65–1.67 (m, 1 H), 1.73–1.75 (m, 4 H), 2.11–2.18 (m, 1 H),
2.43 (s, 3 H), 2.83 (d, J = 7.5 Hz, 2 H), 4.28 (dd, JHF = 27.2, 5.0 Hz,
1 H), 7.31 (d, J = 8.2 Hz, 2 H), 7.83 (d, J = 8.2 Hz, 2 H).
13C NMR (126 MHz, CDCl3): δ = 21.5, 26.0, 26.4, 26.8 (d, JCF = 3
Hz), 33.7, 38.2, 41.6, 44.7 (dd, JCF = 5, 3 Hz), 84.6 (dd, JCF = 24, 14
Hz), 126.9, 129.4, 138.8, 143.2, 155.7 (dd, JCF = 295, 288 Hz),
193.6.
J
CF = 296, 289 Hz), 214.0.
19F NMR (470 MHz, CDCl3): δ = 78.6 (d, JFF = 40 Hz, 1 F), 79.2
(dd, JFF = 40 Hz, JFH = 28 Hz, 1 F).
LRMS (FAB): m/z (%) = 257 (17) [M + H]+.
N-(4,4-Difluoro-2,2-dimethyl-1-nonylbut-3-en-1-ylidene)-4-
methylbenzenesulfonamide (2a); Typical Procedure D
Et3N (110 μL, 0.79 mmol) was added to a solution of ketone 1a (104
mg, 0.40 mmol) and TsNH2 (68 mg, 0.40 mmol) in DCE (4 mL) at
0 °C, and the mixture was stirred for 5 min at 0 °C. TiCl4 (44 μL,
0.40 mmol) was added dropwise at 0 °C, and the mixture was re-
fluxed for 3 d then cooled to r.t. The reaction was quenched with pH
7 phosphate buffer (5 mL), and the mixture was filtered through a
pad of Celite under reduced pressure. The organic materials were
extracted with EtOAc (3 × 10 mL). The extracts were combined,
washed with brine (20 mL), dried (Na2SO4), and concentrated under
reduced pressure. The residue was purified by column chromatog-
raphy [silica gel, EtOAc–hexane (1:5)] to give a pale-yellow oil;
yield: 101 mg (61%).
19F NMR (470 MHz, CDCl3): δ = 77.9 (dd, JFF = 43 Hz, JFH = 5 Hz,
1 F), 78.4 (dd, JFF = 43 Hz, JFH = 27 Hz, 1 F).
Anal. Calcd for C20H27F2NO2S: C, 62.64; H, 7.10. Found: C, 62.72;
H, 7.33.
N-(1-Benzyl-4,4-difluoro-2,2-dimethylbut-3-en-1-ylidene)-4-
methylbenzenesulfonamide (2e)
Compound 2e was prepared by following typical procedure D from
ketone 1e (132 mg, 0.59 mmol), TsNH2 (101 mg, 0.59 mmol), DCE
(6 mL), Et3N (165 μL, 1.2 mmol), and TiCl4 (65 μL, 0.59 mmol).
Purification by TLC [silica gel, EtOAc–hexane (1:5)] gave pale-
yellow crystals; yield: 133 mg (60%); mp 75.0–76.0 °C.
IR (neat): 2954, 2925, 2871, 2854, 1735, 1616, 1467, 1458, 1319,
1303, 1290, 1222, 1157, 1093, 1004, 813, 746, 680 cm–1.
1H NMR (500 MHz, CDCl3): δ = 0.88 (t, J = 7.0 Hz, 3 H), 1.26–
1.35 (m, 16 H), 1.43 (tt, J = 7.4, 7.4 Hz, 2 H), 1.73–1.80 (m, 2 H),
2.43 (s, 3 H), 2.85–2.89 (m, 2 H), 4.30 (dd, JHF = 27.4, 4.8 Hz, 1 H),
7.31 (d, J = 8.2 Hz, 2 H), 7.84 (d, J = 8.2 Hz, 2 H).
13C NMR (126 MHz, CDCl3): δ = 14.1, 21.5, 22.6, 26.3 (d, JCF = 3
Hz), 29.0, 29.0, 29.2, 29.4, 30.5, 31.8, 34.2, 44.5 (dd, JCF = 5, 3 Hz),
84.3 (dd, JCF = 24, 14 Hz), 126.9, 129.4, 138.6, 143.3, 155.8 (dd,
JCF = 295, 288 Hz), 193.8 (dd, JCF = 2, 2 Hz).
19F NMR (470 MHz, CDCl3): δ = 77.9 (dd, JFF = 42 Hz, JFH = 5 Hz,
1 F), 78.5 (dd, JFF = 42 Hz, JFH = 27 Hz, 1 F).
IR (neat): 2983, 2927, 1738, 1616, 1321, 1240, 1155, 1092, 914,
687 cm–1.
1H NMR (500 MHz, CDCl3): δ = 1.24 (d, JHF = 1.4 Hz, 6 H), 2.45
(s, 3 H), 4.13 (dd, JHF = 27.4, 5.0 Hz, 1 H), 4.44 (s, 2 H), 7.24 (m, 3
H), 7.33 (m, 4 H), 7.88 (d, J = 8.4 Hz, 2 H).
13C NMR (126 MHz, CDCl3): δ = 21.6, 27.5 (d, JCF = 4 Hz), 40.2,
44.7 (dd, JCF = 5, 4 Hz), 84.9 (dd, JCF = 25, 14 Hz), 126.9, 127.1,
128.8, 129.0, 129.5, 134.6, 138.3, 143.7, 155.5 (dd, JCF = 295, 288
Hz), 191.0.
19F NMR (470 MHz, CDCl3): δ = 77.9 (dd, JFF = 42 Hz, JFH = 5 Hz,
1 F), 78.5 (dd, JFF = 42 Hz, JFH = 27 Hz, 1 F).
Anal. Calcd for C22H33F2NO2S: C, 63.89; H, 8.04. Found: C, 63.78;
H, 8.24.
Anal. Calcd for C20H21F2NO2S: C, 63.64; H, 5.61. Found: C, 63.89;
H, 5.76.
N-[4,4-Difluoro-2,2-dimethyl-1-(2-phenylethyl)but-3-en-1-yli-
dene]-4-methylbenzenesulfonamide (2b)
N-[4,4-Difluoro-1-(4-methoxybenzyl)-2,2-dimethylbut-3-en-1-
ylidene]-4-methylbenzenesulfonamide (2f)
Compound 2b was prepared by following typical procedure D from
ketone 1b (213 mg, 0.895 mmol), TsNH2 (153 mg, 0.89 mmol),
DCE (9 mL), Et3N (249 μL, 1.79 mmol), and TiCl4 (98 μL, 0.89
mmol). Purification by TLC [silica gel, EtOAc–hexane (1:5)] gave
a pale-yellow solid; yield: 238 mg (68%); mp 43.2–44.5 °C.
Compound 2f was prepared by following typical procedure D from
ketone 1f (679 mg, 2.67 mmol), TsNH2 (457 mg, 2.67 mmol), DCE
(26 mL), Et3N (0.744 mL, 5.34 mmol), and TiCl4 (0.293 mL, 2.67
mmol). Purification by column chromatography [silica gel, EtOAc–
hexane (1:4)] gave a pale-yellow oil; yield: 584 mg (54%).
IR (neat): 3064, 3028, 2981, 2938, 2873, 1736, 1614, 1496, 1456,
1317, 1219, 1155, 1092, 1002, 814, 760, 737, 681, 584, 551 cm–1.
1H NMR (500 MHz, CDCl3): δ = 1.33 (s, 6 H), 2.45 (s, 3 H), 3.09–
3.20 (m, 4 H), 4.28 (dd, JHF = 27.2, 4.7 Hz, 1 H), 7.22–7.25 (m, 1
H), 7.32–7.34 (m, 6 H), 7.89 (d, J = 8.3 Hz, 2 H).
13C NMR (126 MHz, CDCl3): δ = 21.6, 26.2 (d, JCF = 3 Hz), 34.9,
36.4, 44.7 (dd, JCF = 5, 3 Hz), 84.1 (dd, JCF = 24, 14 Hz), 126.5,
127.0, 128.4, 128.7, 129.4, 138.4, 140.5, 143.6, 155.9 (dd,
JCF = 295, 289 Hz), 192.1 (dd, JCF = 2, 2 Hz).
19F NMR (470 MHz, CDCl3): δ = 78.3 (dd, JFF = 42 Hz, JFH = 5 Hz,
1 F), 78.8 (dd, JFF = 42 Hz, JFH = 27 Hz, 1 F).
IR (neat): 2983, 2937, 2836, 1738, 1614, 1511, 1465, 1319, 1247,
1180, 1155, 1092, 1034, 1004, 814, 782, 683 cm–1.
1H NMR (500 MHz, CDCl3): δ = 1.23 (d, JHF = 1.3 Hz, 6 H), 2.45
(s, 3 H), 3.79 (s, 3 H), 4.15 (dd, JHF = 27.4, 5.0 Hz, 1 H), 4.36 (s, 2
H), 6.86 (d, J = 8.7 Hz, 2 H), 7.18 (d, J = 8.7 Hz, 2 H), 7.34 (d,
J = 8.2 Hz, 2 H), 7.88 (d, J = 8.2 Hz, 2 H).
13C NMR (126 MHz, CDCl3): δ = 21.6, 27.6 (d, JCF = 3 Hz), 39.5,
44.6 (dd, JCF = 5, 3 Hz), 55.2, 85.0 (dd, JCF = 25, 14 Hz), 114.1,
126.5, 127.1, 129.4, 130.2, 138.4, 143.6, 155.5 (dd, JCF = 295, 288
Hz), 158.5, 191.6 (dd, JCF = 2, 2 Hz).
19F NMR (470 MHz, CDCl3): δ = 77.8 (dd, JFF = 43 Hz, JFH = 5 Hz,
1 F), 78.5 (dd, JFF = 43 Hz, JFH = 27 Hz, 1 F).
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 1493–1505

1502
T. Fujita et al.
PAPER
Anal. Calcd for C21H23F2NO3S: C, 61.90; H, 5.69. Found: C, 62.14;
H, 5.82.
Anal. Calcd for C14H15FO: C, 77.04; H, 6.93. Found: C, 76.80; H,
7.16.
N-{1-[1-(2,2-Difluorovinyl)cyclohexyl]ethylidene}-4-methyl-
benzenesulfonamide (2h)
(2Z)-2-(Cyclohexylmethylene)-5-fluoro-3,3-dimethyl-2,3-dihy-
drofuran (6c)
Compound 2h was prepared by following typical procedure D from
ketone 1h (209 mg, 1.11 mmol), TsNH2 (190 mg, 1.11 mmol), DCE
(11 mL), Et3N (0.309 mL, 2.22 mmol), and TiCl4 (0.122 mL, 1.11
mmol). Purification by column chromatography [silica gel, EtOAc–
hexane (1:5)] gave a yellow solid; yield: 253 mg (67%); mp 59.1–
61.0 °C.
Compound 6c was synthesized by typical procedure E from difluo-
roallylic ketone 1c (194 mg, 0.84 mmol), THF (15 mL), and KH
(oil-free, 68 mg, 1.7 mmol). The mixture was refluxed for 2 h. Pu-
rification by column chromatography [silica gel, Et2O–pentane
(1:10)] gave a colorless oil; yield: 147 mg (83%).
IR (neat): 2962, 2923, 2850, 1724, 1689, 1448, 1342, 1309, 1280,
1255, 1227, 1138, 1039, 993, 890, 730 cm–1.
IR (neat): 2935, 2860, 1730, 1614, 1315, 1149, 1092, 696, 552 cm–1.
1H NMR (500 MHz, CDCl3): δ = 1.18–1.28 (m, 1 H), 1.36–1.46 (m,
2 H), 1.50–1.66 (m, 5 H), 1.74–1.79 (m, 2 H), 2.43 (s, 3 H), 2.52 (s,
3 H), 4.19 (dd, JHF = 28.1, 4.6 Hz, 1 H), 7.32 (d, J = 8.4 Hz, 2 H),
7.85 (d, J = 8.4 Hz, 2 H).
1H NMR (500 MHz, CDCl3): δ = 1.01–1.09 (m, 2 H), 1.10–1.19 (m,
1 H), 1.21 (d, JHF = 1.2 Hz, 6 H), 1.25–1.40 (m, 2 H), 1.61–1.70 (m,
5 H), 2.32–2.37 (m, 1 H), 4.13 (d, JHF = 5.3 Hz, 1 H), 4.38 (dd,
J = 9.1, JHF = 3.6 Hz, 1 H).
13C NMR (126 MHz, CDCl3): δ = 20.2, 21.5, 22.2, 25.3, 47.9 (dd,
JCF = 4, 3 Hz), 81.9 (dd, JCF = 23, 15 Hz), 126.9, 129.3, 138.5,
143.4, 156.0 (dd, JCF = 296, 290 Hz), 190.6.
13C NMR (126 MHz, CDCl3): δ = 25.9, 26.1, 30.3 (d, JCF = 2 Hz),
33.4, 34.2, 43.9 (d, JCF = 2 Hz), 79.3 (d, JCF = 8 Hz), 106.7, 157.6
(d, JCF = 275 Hz), 158.5 (d, JCF = 3 Hz).
19F NMR (470 MHz, CDCl3): δ = 79.3 (dd, JFF = 39 Hz, JFH = 5 Hz,
1 F), 79.7 (dd, JFF = 39 Hz, JFH = 28 Hz, 1 F).
HRMS (EI): m/z [M+] calcd for C17H21F2NO2S: 341.1261; found:
19F NMR (470 MHz, CDCl3): δ = 46.0 (s).
Anal. Calcd for C13H19FO: C, 74.25; H, 9.11. Found: C, 74.37; H,
9.24.
341.1265.
(2Z)-2-(2,2-Dimethylpropylidene)-5-fluoro-3,3-dimethyl-2,3-di-
hydrofuran (6d)
(2Z)-5-Fluoro-3,3-dimethyl-2-nonylidene-2,3-dihydrofuran
(6a); Typical Procedure E
Compound 6d was synthesized by typical procedure E from difluo-
roallylic ketone 1d (115 mg, 0.56 mmol), THF (11 mL), and KH
(oil-free, 45 mg, 1.1 mmol). The mixture was refluxed for 2 h. Pu-
rification by column chromatography [silica gel, Et2O–pentane
(1:10)] gave a colorless oil; yield: 77 mg (75%).
KH (oil-free, 38 mg, 0.94 mmol) was added to a solution of difluo-
roallylic ketone 1a (122 mg, 0.47 mmol) in THF (9 mL) at r.t. The
mixture was refluxed for 2 h and then cooled to r.t. The reaction was
quenched with pH 7 phosphate buffer (5 mL), and the organic ma-
terials were extracted with Et2O (3 × 10 mL). The extracts were
combined, washed with brine (20 mL), dried (MgSO4), and concen-
trated under reduced pressure. The residue was purified by TLC
[silica gel, Et2O–pentane (1:10)] to give a colorless oil; yield: 102
mg (91%).
IR (neat): 2952, 2927, 2868, 1705, 1464, 1363, 1247, 1059, 808
cm–1.
1H NMR (500 MHz, CDCl3): δ = 1.12 (s, 9 H), 1.19 (d, JHF = 1.2
Hz, 6 H), 4.12 (d, JHF = 5.3 Hz, 1 H), 4.42 (d, JHF = 3.7 Hz, 1 H).
13C NMR (126 MHz, CDCl3): δ = 30.5, 30.5, 30.5, 44.8 (d, JCF = 2
Hz), 79.0 (d, JCF = 8 Hz), 110.4 (d, JCF = 1 Hz), 157.6 (d, JCF = 274
Hz), 158.1 (d, JCF = 3 Hz).
19F NMR (470 MHz, CDCl3): δ = 46.2 (s).
HRMS (EI): m/z [M – CH3]+ calcd for C10H14FO: 169.1029; found:
IR (neat): 2922, 2854, 1726, 1689, 1458, 1327, 1281, 1138, 993,
731 cm–1.
1H NMR (500 MHz, CDCl3): δ = 0.88 (t, J = 7.0 Hz, 3 H), 1.22 (d,
JHF = 1.1 Hz, 6 H), 1.24–1.36 (m, 12 H), 2.07 (td, J = 7.3, 7.3 Hz, 2
H), 4.14 (d, JHF = 5.2 Hz, 1 H), 4.50 (td, J = 7.3 Hz, JHF = 3.6 Hz, 1
H).
169.1032.
13C NMR (126 MHz, CDCl3): δ = 14.1, 22.7, 24.7, 29.1, 29.3, 29.4,
29.6, 30.3 (d, JCF = 3 Hz), 31.9, 44.0 (d, JCF = 3 Hz), 79.4 (d, JCF = 8
Hz), 100.8, 157.7 (d, JCF = 274 Hz), 159.8.
19F NMR (470 MHz, CDCl3): δ = 46.1 (dd, JFH = 5, 4 Hz).
HRMS (FAB): m/z [M + H]+ calcd for C15H26FO: 241.1968; found:
(2Z)-2-Benzylidene-5-fluoro-3,3-dimethyl-2,3-dihydrofuran
(6e)
Compound 6e was synthesized by typical procedure E from difluo-
roallylic ketone 1e (51 mg, 0.23 mmol), THF (5 mL), and KH (30%
dispersion in mineral oil, 60 mg, 0.45 mmol). The mixture was re-
fluxed for 2 h. Purification by TLC [silica gel, EtOAc–pentane
(1:5)] gave a colorless oil; yield: 45 mg (98%).
241.1966.
IR (neat): 2925, 1724, 1682, 1279, 1261, 1059, 989, 750, 692 cm–1.
(2Z)-5-Fluoro-3,3-dimethyl-2-(2-phenylethylidene)-2,3-dihy-
drofuran (6b)
1H NMR (500 MHz, CDCl3): δ = 1.35 (d, JHF = 1.1 Hz, 6 H), 4.30
(d, JHF = 5.5 Hz, 1 H), 5.47 (d, JHF = 3.3 Hz, 1 H), 7.17 (tt, J = 7.6,
1.1 Hz, 1 H), 7.32 (dd, J = 7.6, 7.6 Hz, 2 H), 7.53 (dd, J = 7.6, 1.1
Hz, 2 H).
Compound 6b was synthesized by typical procedure E from difluo-
roallylic ketone 1b (138 mg, 0.58 mmol), THF (11 mL), and KH
(oil-free, 46 mg, 1.2 mmol). The mixture was refluxed for 2 h. Pu-
rification by TLC [silica gel, EtOAc–pentane (1:5)] gave a colorless
oil; yield: 122 mg (97%).
13C NMR (126 MHz, CDCl3): δ = 29.9 (d, JCF = 2 Hz), 45.9 (d,
J
CF = 2 Hz), 80.0 (d, JCF = 7 Hz), 101.0, 126.2, 128.0, 128.4, 134.5,
IR (neat): 3028, 2970, 2931, 1801, 1726, 1703, 1454, 1279, 1219,
1126, 1088, 993, 976, 748, 698 cm–1.
1H NMR (500 MHz, CDCl3): δ = 1.26 (d, JHF = 1.1 Hz, 6 H), 3.45
(d, J = 7.5 Hz, 2 H), 4.20 (d, JHF = 5.4 Hz, 1 H), 4.73 (td, J = 7.5,
JHF = 3.4 Hz, 1 H), 7.18–7.22 (m, 3 H), 7.27–7.30 (m, 2 H).
157.4 (d, JCF = 277 Hz), 160.6 (d, JCF = 3 Hz).
19F NMR (470 MHz, CDCl3): δ = 46.5 (m).
HRMS (FAB): m/z [M + H]+ calcd for C13H14FO: 205.1029; found:
205.1022.
13C NMR (126 MHz, CDCl3): δ = 30.1 (d, JCF = 2 Hz), 30.9, 44.2
(d, JCF = 2 Hz), 79.7 (d, JCF = 8 Hz), 99.4, 125.9, 128.2, 128.4,
141.0, 157.5 (d, JCF = 276 Hz), 160.6 (d, JCF = 3 Hz).
(2Z)-5-Fluoro-2-(4-methoxybenzylidene)-3,3-dimethyl-2,3-di-
hydrofuran (6f)
Compound 6f was synthesized by typical procedure E from difluo-
roallylic ketone 1f (105 mg, 0.41 mmol), THF (8 mL), and KH (oil-
free, 33 mg, 0.83 mmol). The mixture was refluxed for 2 h. Purifi-
19F NMR (470 MHz, CDCl3): δ = 46.2 (s).
Synthesis 2014, 46, 1493–1505
© Georg Thieme Verlag Stuttgart · New York

PAPER
5-endo-trig Cyclization of 3,3-Difluoroallylic Metal Enolates and Enamides
1503
cation by TLC [silica gel, EtOAc–hexane (1:10)] gave a colorless
oil; yield: 93 mg (97%).
13C NMR (126 MHz, CDCl3): δ = 23.2, 25.7, 29.7, 30.6, 40.3 (d,
JCF = 2 Hz), 49.9 (d, JCF = 3 Hz), 75.1 (d, JCF = 9 Hz), 111.0, 158.4
(d, JCF = 274 Hz), 158.4 (d, JCF = 3 Hz).
IR (neat): 3134, 2964, 2929, 1809, 1720, 1674, 1606, 1510, 1458,
1350, 1245, 1176, 1140, 1059, 1030, 989, 844, 733 cm–1.
19F NMR (470 MHz, CDCl3): δ = 46.9 (dd, JFH = 5, 3 Hz).
1H NMR (500 MHz, CDCl3): δ = 1.34 (d, JHF = 0.3 Hz, 6 H), 3.80
(s, 3 H), 4.28 (d, JHF = 5.5 Hz, 1 H), 5.42 (d, JHF = 3.3 Hz, 1 H), 6.87
(d, J = 8.8 Hz, 2 H), 7.47 (d, J = 8.8 Hz, 2 H).
HRMS (FAB): m/z [M + H]+ calcd for C14H22FO: 225.1655; found:
225.1649.
1-Cyclohexylidene-3-fluoro-2-oxaspiro[4.5]dec-3-ene (6j)
Compound 6j was synthesized by typical procedure E from difluo-
roallylic ketone 1j (25 mg, 0.099 mmol), pyridine (5 mL), and KH
(30% dispersion in mineral oil, 49 mg, 0.36 mmol). The mixture
was refluxed for 3 h. Purification by TLC [silica gel, EtOAc–
hexane (1:10)] gave a colorless oil; yield: 23 mg (97%).
13C NMR (126 MHz, CDCl3): δ = 29.9 (d, JCF = 2 Hz), 45.7 (d,
JCF = 2 Hz), 55.2, 79.8 (d, JCF = 8 Hz), 100.4, 113.8, 127.3, 129.2,
157.4 (d, JCF = 277 Hz), 157.9, 159.0 (d, JCF = 3 Hz).
19F NMR (470 MHz, CDCl3): δ = 46.4 (s).
Anal. Calcd for C14H15FO2: C, 71.78; H, 6.45. Found: C, 71.61; H,
6.70.
IR (neat): 2921, 2852, 1793, 1685, 1446, 1335, 1261, 1198, 1161,
1146, 1113, 1041, 1014, 847 cm–1.
1H NMR (500 MHz, CDCl3): δ = 1.17–1.40 (m, 5 H), 1.49–1.60 (br
s, 4 H), 1.60–1.75 (m, 5 H), 1.80–1.89 (m, 2 H), 2.16–2.21 (m, 2 H),
2.25–2.30 (m, 2 H), 4.51 (d, JHF = 4.9 Hz, 1 H).
13C NMR (126 MHz, CDCl3): δ = 23.1, 25.7, 26.6, 27.4, 28.1, 28.2,
28.3, 29.7, 36.6 (d, JCF = 2 Hz), 75.1 (d, JCF = 9 Hz), 115.6, 150.1
(d, JCF = 2 Hz), 157.9 (d, JCF = 272 Hz).
2-Cyclohexylidene-5-fluoro-3,3-dimethyl-2,3-dihydrofuran
(6g)
Compound 6g was synthesized by typical procedure E from difluo-
roallylic ketone 1g (67 mg, 0.31 mmol), THF (8 mL), and KH (oil-
free, 25 mg, 0.62 mmol). The mixture was refluxed for 21 h. Purifi-
cation by column chromatography [silica gel, Et2O–pentane (1:10)]
gave a colorless oil; yield: 57 mg (94%).
19F NMR (470 MHz, CDCl3): δ = 45.7 (dt, JFH = 4, 3 Hz).
HRMS (FAB): m/z [M + H]+ calcd for C15H22FO: 237.1655; found:
IR (neat): 2966, 2925, 2854, 1724, 1687, 1327, 1313, 1047, 725,
584 cm–1.
1H NMR (500 MHz, CDCl3): δ = 1.36 (d, JHF = 1.3 Hz, 6 H), 1.51–
1.56 (m, 6 H), 2.14–2.23 (m, 4 H), 4.01 (d, JHF = 4.9 Hz, 1 H).
237.1646.
(2E)-5-Fluoro-2-(4-methoxybenzylidene)-3,3-dimethyl-1-[(4-
tolyl)sulfonyl]-2,3-dihydro-1H-pyrrole (8f); Typical Procedure
F
13C NMR (126 MHz, CDCl3): δ = 26.5, 27.2, 27.9 (d, JCF = 1 Hz),
27.9, 28.3, 28.4, 44.2 (d, JCF = 3 Hz), 79.8 (d, JCF = 9 Hz), 115.1,
150.1 (d, JCF = 2 Hz), 157.1 (d, JCF = 273 Hz).
t-BuOK (32 mg, 0.28 mmol) was added to a solution of difluoroal-
lylic imine 2f (87 mg, 0.21 mmol) in DMF (5 mL) at r.t., and the
mixture was heated to 90 °C for 3 h then cooled to r.t. The reaction
was quenched with pH 7 phosphate buffer (5 mL), and the organic
materials were extracted with EtOAc (3 × 10 mL). The extracts
were combined, washed with brine (20 mL), dried (Na2SO4), and
concentrated under reduced pressure. The residue was purified by
TLC [silica gel, EtOAc–hexane (1:2)] to give a colorless solid;
yield: 63 mg (77%); mp 108.1–109.8 °C.
19F NMR (470 MHz, CDCl3): δ = 45.0 (d, JHF = 5 Hz).
Anal. Calcd for C12H17FO: C, 73.44; H, 8.73. Found: C, 73.64; H,
8.95.
3-Fluoro-1-methylene-2-oxaspiro[4.5]dec-3-ene (6h)
Compound 6h was synthesized by typical procedure E from difluo-
roallylic ketone 1h (50 mg, 0.27 mmol), THF (5 mL), and KH (30%
dispersion in mineral oil, 71 mg, 0.53 mmol). The mixture was re-
fluxed for 2 h. Purification by TLC [silica gel, Et2O–hexane (1:10)]
gave a colorless oil; yield: 41 mg (91%).
IR (neat): 3103, 2966, 2931, 2868, 2837, 1703, 1608, 1510, 1464,
1371, 1290, 1248, 1171, 1082, 1034, 814, 673, 615, 557, 540 cm–1.
1H NMR (500 MHz, CDCl3): δ = 0.62 (d, JHF = 0.9 Hz, 6 H), 2.48
(s, 3 H), 3.81 (s, 3 H), 4.41 (d, JHF = 2.6 Hz, 1 H), 6.84 (d, J = 8.5
Hz, 2 H), 7.07 (d, J = 8.5 Hz, 2 H), 7.18 (s, 1 H), 7.40 (d, J = 8.1 Hz,
2 H), 7.79 (d, J = 8.1 Hz, 2 H).
13C NMR (126 MHz, CDCl3): δ = 21.7, 28.1 (d, JCF = 3 Hz), 43.6,
55.2, 97.5 (d, JCF = 9 Hz), 113.3, 121.1, 127.8, 128.5, 129.5, 130.3,
132.8, 144.9, 144.9, 149.6 (d, JCF = 280 Hz), 158.7.
IR (neat): 2922, 2852, 1716, 1684, 1647, 1458, 1375, 1294, 1230,
997, 721, 667 cm–1.
1H NMR (500 MHz, CDCl3): δ = 1.29–1.46 (m, 6 H), 1.68 (d,
J = 11.5 Hz, 2 H), 1.74 (d, J = 11.5 Hz, 2 H), 4.22 (dd, JHF = 3.1 Hz,
J = 3.0 Hz, 1 H), 4.34 (d, JHF = 5.4 Hz, 1 H), 4.60 (d, J = 3.0, 1 H).
13C NMR (126 MHz, CDCl3): δ = 23.0, 25.6, 29.7, 39.7 (d, JCF = 2
Hz), 76.0 (d, JCF = 8 Hz), 84.7, 158.0 (d, JCF = 275 Hz), 167.9 (d,
19F NMR (470 MHz, CDCl3): δ = 43.2 (s).
JCF = 3 Hz).
19F NMR (470 MHz, CDCl3): δ = 46.7–46.8 (m).
HRMS (FAB): m/z [M + H]+ calcd for C10H14FO: 169.1029; found:
Anal. Calcd for C21H22FNO3S: C, 65.10; H, 5.72. Found: C, 65.22;
H, 5.90.
169.1034.
5-Fluoro-3,3-dimethyl-2-nonylidene-1-[(4-tolyl)sulfonyl]-2,3-
dihydro-1H-pyrrole (8a)
(1Z)-1-(2,2-Dimethylpropylidene)-3-fluoro-2-oxaspiro[4.5]dec-
3-ene (6i)
Compound 8a was synthesized by typical procedure F from difluo-
roallylic imine 2a (53 mg, 0.13 mmol), DMF (3 mL), and t-BuOK
(18 mg, 0.16 mmol). The mixture was heated to 90 °C for 4 h. Pu-
rification by TLC [silica gel, EtOAc–hexane (1:5)] gave a pale-
yellow oil; yield: 38 mg (74%; E/Z = 89:11).
Compound 6i was synthesized by typical procedure E from difluo-
roallylic ketone 1i (49 mg, 0.20 mmol), THF (2 mL), and KH (30%
dispersion in mineral oil, 53 mg, 0.40 mmol). The mixture was re-
fluxed for 2 h. Purification by TLC [silica gel, Et2O–hexane (1:10)]
gave a colorless oil; yield: 42 mg (94%).
IR (neat): 2958, 2925, 2856, 1705, 1664, 1599, 1458, 1377, 1298,
1174, 1081, 910, 813, 706, 667, 619, 561 cm–1.
IR (neat): 2924, 2854, 1724, 1684, 1462, 1346, 1283, 1225, 995,
731 cm–1.
1H NMR (500 MHz, CDCl3): δ = 1.12 (s, 9 H), 1.18–1.37 (m, 6 H),
1.61–1.72 (m, 4 H), 4.42 (d, JHF = 3.4 Hz, 1 H), 4.50 (d, JHF = 5.0
Hz, 1 H).
1H NMR (500 MHz, CDCl3): δ (major) = 0.82 (d, JHF = 1.2 Hz, 6
H), 0.90 (t, J = 7.0 Hz, 3 H), 1.26–1.36 (m, 12 H), 2.15 (dt, J = 8.0,
7.7 Hz, 2 H), 2.43 (s, 3 H), 4.40 (d, JHF = 2.4 Hz, 1 H), 6.06 (t,
J = 8.0 Hz, 1 H), 7.31 (d, J = 8.2 Hz, 2 H), 7.66 (d, J = 8.2 Hz, 2 H);
δ (minor) = 0.89 (d, JHF = 1.2 Hz, 6 H), 0.88 (t, J = 7.0 Hz, 3 H),
1.39–1.46 (m, 12 H), 2.32 (td, J = 7.3, 7.2 Hz, 2 H), 2.43 (s, 3 H),
© Georg Thieme Verlag Stuttgart · New York
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T. Fujita et al.
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4.59 (d, JHF = 2.9 Hz, 1 H), 5.16 (td, J = 7.2, JHF = 2.1 Hz, 1 H), 7.33
(d, J = 8.2 Hz, 2 H), 7.76 (d, J = 8.2 Hz, 2 H).
Anal. Calcd for C20H26FNO2S: C, 66.09; H, 7.21. Found: C, 65.93;
H, 7.35.
13C NMR (126 MHz, CDCl3): δ (mixture) = 14.1, 21.6, 22.7, 27.2
(d, JCF = 3 Hz), 27.4, 28.6 (d, JCF = 3 Hz), 28.9, 29.2, 29.3, 29.4,
29.4, 29.4, 29.6, 30.1, 31.9, 42.6 (d, JCF = 2 Hz), 43.5 (d, JCF = 1
Hz), 97.5 (d, JCF = 9 Hz), 98.5 (d, JCF = 9 Hz), 119.9, 120.4, 128.5,
129.2, 129.4, 132.2, 134.2, 142.5, 144.3, 144.7, 149.8 (d, JCF = 279
Hz), 151.2 (d, JCF = 279 Hz).
(2E)-2-Benzylidene-5-fluoro-3,3-dimethyl-1-[(4-tolyl)sulfonyl]-
2,3-dihydro-1H-pyrrole (8e)
Compound 8e was synthesized by typical procedure F from difluo-
roallylic imine 2e (49 mg, 0.13 mmol), DMF (3 mL), and t-BuOK
(20 mg, 0.18 mmol). The mixture was heated to 90 °C for 4 h. Pu-
rification by TLC [silica gel, EtOAc–hexane (1:5)] gave a colorless
solid; yield: 40 mg (86%); mp 124.0–126.0 °C.
19F NMR (470 MHz, CDCl3): δ (major) = 43.9 (s); δ (minor) = 45.3
(s).
IR (neat): 2983, 2931, 2867, 1704, 1652, 1597, 1373, 1292, 1174,
1088, 1026, 706, 673, 621 cm–1.
1H NMR (500 MHz, CDCl3): δ = 0.61 (d, JHF = 1.2 Hz, 6 H), 2.48
(s, 3 H), 4.40 (d, JHF = 2.7 Hz, 1 H), 7.14 (d, J = 7.9 Hz, 2 H), 7.24–
7.32 (m, 4 H), 7.41 (d, J = 8.1 Hz, 2 H), 7.80 (d, J = 8.1 Hz, 2 H).
13C NMR (126 MHz, CDCl3): δ = 21.7, 28.2 (d, JCF = 3 Hz), 43.7
(d, JCF = 2 Hz), 97.3 (d, JCF = 9 Hz), 121.1, 127.2, 127.9, 128.5,
129.1, 129.5, 132.8, 135.5, 145.0, 145.4, 149.6 (d, JCF = 280 Hz).
Anal. Calcd for C22H32FNO2S: C, 67.14; H, 8.20. Found: C, 67.21;
H, 8.37.
5-Fluoro-3,3-dimethyl-1-2-(2-phenylethylidene)-[(4-tolyl)sulfo-
nyl]-2,3-dihydro-1H-pyrrole (8b)
Compound 8b was synthesized by typical procedure F from difluo-
roallylic imine 2b (47 mg, 0.12 mmol), DMF (3 mL), and t-BuOK
(17 mg, 0.15 mmol). The mixture was heated to 90 °C for 4 h. Pu-
rification by TLC [silica gel, EtOAc–hexane (1:5)] gave a colorless
solid; yield: 35 mg (78%; E/Z = 79:21); mp 103.2–105.8 °C.
19F NMR (470 MHz, CDCl3): δ = 43.2 (s).
Anal. Calcd for C20H20FNO2S: C, 67.20; H, 5.64. Found: C, 67.16;
H, 5.77.
IR (neat): 3027, 2964, 2927, 2868, 1705, 1670, 1597, 1496, 1454,
1373, 1273, 1172, 1089, 800, 700, 586, 540 cm–1.
1H NMR (500 MHz, CDCl3): δ (major) = 0.92 (s, 6 H), 2.43 (s, 3 H),
3.54 (d, J = 8.4 Hz, 2 H), 4.45 (d, JHF = 2.6 Hz, 1 H), 6.29 (t, J = 8.4
Hz, 1 H), 7.18–7.37 (m, 7 H), 7.55 (d, J = 8.3 Hz, 2 H); δ
(minor) = 0.92 (s, 6 H), 2.44 (s, 3 H), 3.71 (d, J = 6.9 Hz, 2 H), 4.65
(d, JHF = 2.4 Hz, 1 H), 5.35 (td, J = 6.9, JHF = 1.8 Hz, 1 H), 7.18–
7.37 (m, 7 H), 7.80 (d, J = 8.3 Hz, 2 H).
13C NMR (126 MHz, CDCl3): δ (major) = 21.6, 27.6 (d, JCF = 3 Hz),
33.2, 42.7 (d, JCF = 2 Hz), 97.2 (d, JCF = 9 Hz), 117.7, 126.4, 128.3,
128.5, 128.6, 129.3, 132.1, 139.8, 143.4, 144.7, 149.8 (d, JCF = 280
Hz); δ (minor) = 21.6, 28.5 (d, JCF = 3 Hz), 35.1, 43.7, 98.6 (d,
JCF = 9 Hz), 118.9, 126.1, 128.4, 128.5, 128.5, 129.5, 134.1, 141.0,
144.9, 145.2, 151.1 (d, JCF = 279 Hz).
3-Fluoro-1-methylene-2-[(4-tolyl)sulfonyl]-2-azaspiro[4.5]dec-
3-ene (8h)
Compound 8h was synthesized by typical procedure F from difluo-
roallylic imine 2h (65 mg, 0.19 mmol), DMF (5 mL), and t-BuOK
(27 mg, 0.24 mmol). The mixture was heated to 90 °C for 4 h. Pu-
rification by column chromatography [silica gel, EtOAc–hexane
(1:5)] gave a pale-yellow solid; yield: 61 mg (99%); mp 88.3–
89.4 °C.
IR (neat): 2929, 2858, 1699, 1647, 1367, 1288, 1171, 677, 559 cm–1.
1H NMR (500 MHz, CDCl3): δ = 0.92–0.99 (m, 2 H), 1.08–1.21 (m,
5 H), 1.45–1.52 (m, 2 H), 1.58–1.63 (m, 1 H), 2.42 (s, 3 H), 4.67
(dd, JHF = 2.3 Hz, J = 2.0 Hz, 1 H), 4.89 (br s, 1 H), 5.61 (d, J = 2.0
Hz, 1 H), 7.31 (d, J = 8.3 Hz, 2 H), 7.68 (d, J = 8.3 Hz, 2 H).
13C NMR (126 MHz, CDCl3): δ = 21.6, 22.7, 25.4, 39.2 (d, JCF = 3
Hz), 47.5 (d, JCF = 2 Hz), 90.8 (d, JCF = 8 Hz), 97.3, 128.0, 129.4,
132.7, 144.8, 150.4 (d, JCF = 280 Hz), 152.9.
19F NMR (470 MHz, CDCl3): δ (major) = 44.0 (s); δ (minor) = 45.3
(s).
Anal. Calcd for C21H22FNO2S: C, 67.90; H, 5.97. Found: C, 67.82;
H, 6.09.
19F NMR (470 MHz, CDCl3): δ = 42.8 (s).
HRMS (EI): m/z [M+] calcd for C17H20FNO2S: 321.1199; found:
2-(Cyclohexylmethylene)-5-fluoro-3,3-dimethyl-1-[(4-tolyl)sul-
fonyl]-2,3-dihydro-1H-pyrrole (8c)
321.1198.
Compound 8c was synthesized by typical procedure F from difluo-
roallylic imine 2c (77 mg, 0.20 mmol), DMF (5 mL), and t-BuOK
(27 mg, 0.24 mmol). The mixture was heated to 90 °C for 6 h. Pu-
rification by TLC [silica gel, EtOAc–hexane (1:5)] gave a pale-
yellow oil; yield: 46 mg (63%; E/Z = 93:7).
N-[(1Z)-4,4-Difluoro-2,2-dimethyl-1-(2-phenylethylidene)but-
3-en-1-yl]-4-methylbenzenesulfonamide [(Z)-9b]
KH (30% dispersion in mineral oil, 25 mg, 0.19 mmol) was added
to a solution of difluoroallylic imine 2b (37 mg, 0.095 mmol) in
THF (2 mL) at r.t., and the mixture was refluxed for 2 h then cooled
to r.t. The reaction was quenched with pH 7 phosphate buffer (5
mL), and the organic materials were extracted with Et2O (3 × 10
mL). The extracts were combined, washed with brine (20 mL),
dried (MgSO4), and concentrated under reduced pressure. The resi-
due was purified by TLC [silica gel, EtOAc–hexane (1:5)] to give a
colorless solid; yield: 23 mg (61%); mp 87.5–90.2 °C.
IR (neat): 2960, 2927, 2850, 1705, 1662, 1448, 1377, 1290, 1174,
1141, 1089, 1062, 673, 579, 542 cm–1.
1H NMR (500 MHz, CDCl3): δ (major) = 0.80 (d, JHF = 1.1 Hz, 6
H), 1.18–1.29 (m, 5 H), 1.63–1.68 (m, 3 H), 1.76 (br s, 2 H), 2.24–
2.27 (m, 1 H), 2.43 (s, 3 H), 4.41 (d, JHF = 2.5 Hz, 1 H), 5.93 (d,
J = 11.4 Hz, 1 H), 7.32 (d, J = 8.1 Hz, 2 H), 7.65 (d, J = 8.1 Hz, 2
H); δ (minor) = 0.84 (d, JHF = 0.9 Hz, 6 H), 0.97–1.05 (m, 2 H),
1.13–1.34 (m, 3 H), 1.66–1.75 (m, 3 H), 1.79–1.83 (m, 2 H), 2.43
(s, 3 H), 2.64–2.72 (m, 1 H), 4.58 (d, JHF = 2.9 Hz, 1 H), 4.96 (dd,
J = 10.4, JHF = 2.1 Hz, 1 H), 7.33 (d, J = 8.2 Hz, 2 H), 7.76 (d,
J = 8.2 Hz, 2 H).
IR (neat): 3267, 3028, 2976, 1736, 1414, 1329, 1221, 1153, 1092,
995, 771, 677, 557 cm–1.
1H NMR (500 MHz, CDCl3): δ = 1.23 (d, JHF = 0.7 Hz, 6 H), 2.40
(s, 3 H), 3.35 (d, J = 6.9 Hz, 2 H), 4.05 (dd, JHF = 27.2, 5.3 Hz, 1 H),
5.60 (br s, 1 H), 5.62 (t, J = 6.9 Hz, 1 H), 7.07 (d, J = 7.5 Hz, 2 H),
7.19 (t, J = 7.3 Hz, 1 H), 7.25–7.28 (m, 4 H), 7.78 (d, J = 8.3 Hz, 2
H).
13C NMR (126 MHz, CDCl3): δ = 21.5, 27.6 (d, JCF = 3 Hz), 34.8,
38.6 (dd, JCF = 5, 3 Hz), 85.7 (dd, JCF = 22, 13 Hz), 125.2, 126.1,
126.8, 128.4, 128.4, 129.5, 138.7, 138.9, 140.4, 143.5, 155.5 (dd,
13C NMR (126 MHz, CDCl3): δ (major) = 21.6, 25.7, 25.8, 27.7 (d,
JCF = 3 Hz), 33.3, 36.9, 42.7 (d, JCF = 2 Hz), 97.4 (d, JCF = 9.2 Hz),
125.2, 128.6, 129.2, 131.8, 141.4, 144.7, 149.7 (d, JCF = 279 Hz); δ
(minor) = 21.6, 25.8, 26.2, 28.7 (d, JCF = 3 Hz), 32.8, 37.0, 43.3,
98.7 (d, JCF = 9 Hz), 125.9, 128.5, 129.4, 134.2, 142.6, 144.6, 151.1
(d, JCF = 279 Hz).
19F NMR (470 MHz, CDCl3): δ (major) = 43.9 (s); δ (minor) = 45.6
JCF = 296, 287 Hz).
(s).
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5-endo-trig Cyclization of 3,3-Difluoroallylic Metal Enolates and Enamides
1505
19F NMR (470 MHz, CDCl3): δ = 77.8 (dd, JFF = 44 Hz, JFH = 27
Hz, 1 F), 78.2 (dd, JFF = 44 Hz, JFH = 5 Hz, 1 F).
HRMS (EI): m/z [M+] calcd for C21H23F2NO2S: 391.1418; found:
111. (f) Ichikawa, J. Org. Synth. 2011, 88, 162. (g) Ichikawa,
J.; Wada, Y.; Okauchi, T.; Minami, T. Chem. Commun.
1997, 1537. (h) Ichikawa, J.; Fujiwara, M.; Wada, Y.;
Okauchi, T.; Minami, T. Chem. Commun. 2000, 1887.
(i) Tanabe, H.; Ichikawa, J. Chem. Lett. 2010, 39, 248.
(j) Fuchibe, K.; Takahashi, M.; Ichikawa, J. Angew. Chem.
Int. Ed. 2012, 51, 12059.
391.1405.
Acknowledgment
(6) For recent reviews, see: (a) Uneyama, K. Organofluorine
Chemistry; Blackwell: Oxford, 2006, Chap 2.3. (b) Amii,
H.; Uneyama, K. Chem. Rev. 2009, 109, 2119.
(7) Fujita, T.; Sakoda, K.; Ikeda, M.; Hattori, M.; Ichikawa, J.
Synlett 2013, 24, 57.
(8) For selected examples of conventional synthetic
methodologies for 2-alkylidene-2,3-dihydrofurans, see:
(a) Tiecco, M.; Testaferri, L.; Tingoli, M.; Marini, F. J. Org.
Chem. 1993, 58, 1349; and references cited therein.
(b) Lattanzi, A.; Sagulo, F.; Scettri, A. Tetrahedron:
Asymmetry 1999, 10, 2023. (c) Fang, Y.; Li, C. Chem.
Commun. 2005, 3574. (d) Chen, Y.-F.; Wang, H.-F.; Wang,
Y.; Luo, Y.-C.; Zhu, H.-L.; Xu, P.-F. Adv. Synth. Catal.
2010, 352, 1163. (e) Montel, S.; Bouyssi, D.; Balme, G. Adv.
Synth. Catal. 2010, 352, 2315.
(9) For difluoromethylenation of aldehydes with CF2Br2 and
P(NMe2)3, see: (a) Naae, D. G.; Burton, D. J. Synth.
Commun. 1973, 3, 197. (b) Vinson, W. A.; Prickett, K. S.;
Spahic, B.; de Montellano, P. R. O. J. Org. Chem. 1983, 48,
4661.
(10) For the synthesis of 1,3-ketoaldehydes from enamines, see:
Kuhlmey, S.-R.; Adolph, H.; Rieth, K.; Opitz, G. Liebigs
Ann. Chem. 1979, 617.
(11) 1,3-Ketoaldehydes 3 underwent chemoselective
difluoromethylenation of the formyl groups to afford 3,3-
difluoroallylic ketones 1.
(12) For the synthesis of N-[(4-tolyl)sulfonyl] imines, see:
(a) Sandrinelli, F.; Perrio, S.; Beslin, P. J. Org. Chem. 1997,
62, 8626. (b) Esquivias, J.; Arrayás, R. G.; Carretero, J. C.
J. Org. Chem. 2005, 70, 7451.
(13) Baldwin, J. E.; Kruse, L. I. J. Chem. Soc., Chem. Commun.
1977, 233.
(14) Müller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881.
(15) Martin, S. F. J. Org. Chem. 1976, 41, 3337.
(16) De Kimpe, N.; De Smaele, D.; Hofkens, A.; Dejaegher, Y.;
Kesteleyn, B. Tetrahedron 1997, 53, 10803.
This research was partially supported by MEXT/JSPS KAKENHI.
We acknowledge a generous gift of CF2Br2 from Tosoh F-Tech, Inc.
Supporting Information for this article is available online
at
http://www.thieme-connect.com/products/ejournals/journal/
10.1055/s-00000084.SunpfgIpi
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Synthesis 2014, 46, 1493–1505