Regio- and diastereoselective nickel-catalyzed allylation of aromatic aldehydes with α-halo-β,β-difluoropropene derivatives

Article abstract of DOI:10.1021/jo301688d

A one-pot nickel-catalyzed allylation of aromatic aldehydes with α-halo-β,β-difluoropropene-containing compounds promoted by ZnEt₂ under mild conditions was described. The reaction displays moderate to good regio- and diastereoselectivity, tole

Full text of DOI:10.1021/jo301688d

Article
pubs.acs.org/joc
Regio- and Diastereoselective Nickel-Catalyzed Allylation of
Aromatic Aldehydes with α‑Halo-β,β-difluoropropene Derivatives
Xiaowei Lin,† Feng Zheng,† and Feng-Ling Qing*,†,‡
†Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling
Lu, Shanghai 200032, China
‡College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, 2999 North Renmin Lu, Shanghai 201620,
China
S
* Supporting Information
ABSTRACT: A one-pot nickel-catalyzed allylation of aro-
matic aldehydes with α-halo-β,β-difluoropropene-containing
compounds promoted by ZnEt2 under mild conditions was
described. The reaction displays moderate to good regio- and
diastereoselectivity, tolerates a wide range of functional groups,
and provides an efficient method for the synthesis of γ-
fluorinated homoallylic alcohols.
the proposed transition state.9a−c,12i,13b,15 Cyclohexadiene is
one exception among the dienes examined so far and undergoes
INTRODUCTION
■
Fluoroorganic compounds have attracted increased interest as
1,4-addition instead of 1,2-addition under the catalysis of Ni-
pharmaceutical agents in recent years since it has been found
Et2Zn.13b The steric repulsion in the syn-cis dienes-Nickel
that fluorine modifies biological activity by altering the
physicochemical properties of organic compounds.1 Fluoroole-
transition state was suggested to explain the unusual 1,4-
addition regioselectivity.9a,13b
fins, one of the most important classes of organofluorine
compounds, have received great attention in material2 and life
Inspired by this body of work, we envisioned that the
sciences.3 For example, the fluoroolefins have been widely
extremely electron-deficient 3-fluoro-1,3-dienes could be
employed as the substrates of the Ni-catalyzed reductive
utilized in mimicking the peptide bonds, because the trans-
coupling of dienes and carbonyl compounds for the efficient
fluoroolefin dipeptide isostere ψ[CFCH], compared to the
synthesis of fluoroolefinic alcohols.
natural peptide, not only has the same orientation of the dipole
moment, but also can increase the lipophilicity of the target
peptide.3d,4 Given its widespread use, many efforts have been
made to develop practical and efficient methods for the
preparation of functionalized fluoroolefins;4c,f,5,6 however, the
stereoselective control of the olefin configuration and the use of
readily available starting material are still challenging subjects.
Furthermore, the methodology for the construction of versatile
γ-fluorinated homoallylic alcohol structural moieties is in great
demand.7
RESULTS AND DISCUSSION
■
Initial experiments surveyed the Ni-catalyzed reaction of (4-
fluorohexa-3,5-dienyl)benzene 2 and benzaldehyde at room
temperature. Surprisingly, the unusual 1,4-addition product (γ-
fluorinated homoallylic alcohol) 3a was obtained in 30% yield
(Scheme 2a). However, the further utilization of 3-fluoro-1,3-
diene 2 was restricted due to its polymerization.16 Since 3-
fluoro-1,3-diene 2 was prepared from (3-bromo-4,4-difluor-
ohex-5-enyl)benzene 1a via reductive debromodefluorination
by treatment with Mg (Scheme 2b).17 We speculated that the
vicinal bromodifluoride 1 could be used as the equivalent of 3-
fluoro-1,3-dienes that can be generated in situ and coupled with
aldehydes under the reductive conditions of Ni-ZnEt2 (Scheme
2c).
The allylation of carbonyl compounds is among the most
efficient methodologies for the construction of C−C bond and
well developed to furnish synthetically useful homoallylic
alcohols motif.8 Recently, Ni-promoted coupling of dienes with
carbonyls,9,10 first discovered by Wilke11 and subsequent
pioneering studies in catalysis by Mori12 and Tamaru,13
provided a new method for the synthesis of homoallylic
alcohols or bishomoallylic alcohols. Mechanistic studies by
Ogoshi14 showed that the Ni-promoted reaction of dienes with
aldehydes is initiated by cyclometalation of the substrates,
subsequent σ-bond metathesis and reductive elimination
generate 1,2-addition (homoallylation) or 1,4-addition (allyla-
tion) product (Scheme 1). In most cases, the 1,2-addition was
much more favored because of the easy-accessible β-agostic
interaction of the H-donor group with the vacant site on Ni in
To probe the hypothesis, the Ni-catalyzed debromodefluori-
nation of compound 1a was first investigated. As expected, 3-
fluoro-1,3-diene 2 was produced in 83% yield with good
selectivity (Z/E = 11/1) under the reductive conditions of Ni-
ZnEt2 using P(OiPr)3 as ligand (eq 1).
Received: August 9, 2012
Published: September 8, 2012
© 2012 American Chemical Society
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Scheme 1
Scheme 2
Table 1. Optimization of the Ni-Catalyzed Allylation of
Benzaldehyde with (3-Bromo-4,4-difluorohex-5-
a
enyl)benzene 1a
b
entry
ligand
PPh3
ZnEt2 (equiv)
additive
yield 3a (%)
1
2
3
4
5
6
7
8
2.5
3.5
4.5
5.5
4.5
4.5
4.5
4.5
4.5
4.5
4.5
4.5
4.5
4.5
4.5
4.5
4.5
18
40
48
45
60
31
48
73
20
49
35
20
70
56
90
60
PPh3
PPh3
PPh3
PPh3
ZnCl2
ZnCl2
ZnCl2
ZnCl2
ZnCl2
ZnCl2
ZnCl2
ZnCl2
ZnCl2
ZnCl2
ZnCl2
ZnCl2
ZnCl2
P(OMe)3
P(OEt)3
P(OiPr)3
P(o-Tol)3
P(m-Tol)3
P(p-Tol)3
PPh2-Me
PPh2-OEt
PPh2-Cy
PCy2-Ph
PCy3
c
9
c
10
c
11
12
13
Having achieved the Ni-catalyzed reductive elimination, we
focused on the cascade dehalogenation−coupling reaction and
chose the reaction outlined in Table 1 to screen the catalyst
system. Treatment of vicinal bromodifluoride 1a with Ni-
(acac)2/PPh3 (10 mol %) and ZnEt2 (2.5 equiv) in THF gave
desired coupling product 3a in 18% yield (Table 1, entry 1). In
consideration of the fact that ZnEt2 serves not only as a formal
hydride source as usual, but also as a reducing reagent to
participate in the dehalodefluorination, the reaction would
perform better with increasing amount of ZnEt2. As expected,
the yield of 3a was improved to 48% when 4.5 equiv of ZnEt2
were used (entries 2−4). Recently, Ikeda and co-workers18
illustrated that ZnCl2 can promote the Ni-catalyzed domino
coupling of enones, alkynes and alkenes. Experimentally, the
yield of product 3a was increased to 60% in the presence of
ZnCl2 (2.0 equiv) (entry 5). Exploration of phosphorus ligands
revealed that PCy2-Ph was the best active ligand, affording
product 3a in 90% yield (entries 6−16). None of the desired
product was detected in the absence of nickel catalyst (entry
17).
With the optimized conditions in hand (Table 1, entry 15),
the substrate scope (aromatic aldehydes and α-halo-β,β-
difluorides) of this transformation was then examined. As
shown in Table 2, 3-bromo-, 3-iodo-, and 3-chloro-4,4-difluoro-
5-enyl-benzenes (1a, 1a′, 1a″) reacted with benzaldehyde
smoothly to afford product 3a in moderate yields. Benzalde-
hydes bearing electron-donating groups were competent
coupling partners to give the desired products in moderate to
good yields (3b−3h). Benzaldehydes carrying Br and Cl
substituents exhibited high chemoselectivity for the coupling
process to give products 3i and 3j, respectively, and no
products arising from the Negish-type coupling were observed.
However, the reaction of 4-(trifluoromethyl)benzaldehyde and
d
14
d
15
d
16
de
,
f
17
PCy2-Ph
0
a
Reactions were carried out on a 0.2 mmol scale. acac = acetylacetone.
b
Yield determined by 19F NMR using fluorobenzene as an internal
c
d
e
f
standard. Tol = tolyl. Cy = cyclohexyl. Without Ni(acac)2. 1a was
recovered completely.
methyl 4-formylbenzoate with (3-bromo-4,4-difluorohex-5-
enyl)benzene 1a under the optimized conditions gave only
trace amount of the desired products. Instead, the direct
ethylation of aldehydes took place. This is apparently owing to
the high reactivity of electron-deficient aldehydes, which
resulted in the first direct ethylation of aldehydes with ZnEt2
and retardation of the debromodefluorination of (3-bromo-4,4-
difluorohex-5-enyl)benzene 1a. We anticipated that the desired
product should be formed if (4-fluorohexa-3,5-dienyl)benzene
2 was formed first in situ from 1a and then aldehydes were
added to the reaction mixture. To our delight, treatment of (3-
bromo-4,4-difluorohex-5-enyl)benzene 1a with ZnEt2 and
followed by addition of the aldehydes gave the desired products
3k and 3l in 57 and 54% yields, respectively. Furthermore, the
Ni-catalyzed allylation of 2-naphthaldehyde and furan-2-
carbaldehyde performed well to give compounds 3m and 3n
in good yields. Finally, our attention was turned to the
compatibility of α-bromo-β,β-difluorides 1. It was found that
the allylation of benzaldehyde with octyl- and benzyl-
substituted α-bromo-β,β-difluorides (1b, 1c) gave compounds
3o and 3p, respectively, in moderate yields. It should be noted
that the 1,2-anti-γ-fluorinated homoallylic alcohols were
obtained exclusively in most cases.
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a
Table 2. Ni-Catalyzed Allylation of Aromatic Aldehydes with α-Halo-β,β-difluorides
a
Unless stated otherwise, the reaction was performed using 1 (0.2 mmol), R2CHO (2 equiv), ZnEt2 (4.5 equiv), Ni(acac)2 (10 mol %), PCy2-Ph (20
mol %) and ZnCl2 (2 equiv) in THF (1.5 mL) at room temperature for 1.5 h under Argon. The ratios of Z/E in parentheses were determined by 19
NMR spectra of crude mixtures. The reaction was performed according to the General Procedure B. See the Experimental Section for details.
F
b
Scheme 3. Determination of the Configuration of the Double Bond in 3g
The relative configuration of the major isomer (anti, Z) of
homoallylic alcohol 3a was determined by single crystal X-ray
diffraction analysis (see the Supporting Information).19 The
configuration of the double bond in 3g was confirmed by the
formation of Z-ketone 4a and E-ketone 4b (Scheme 3). The
stereochemical assignments of other γ-fluorinated homoallylic
alcohols were based on comparison spectra data with 3g.
To learn whether the Z/E ratio of diene in situ generated by
the Ni-catalyzed elimination matched the Z/E ratio of product
3 and the diene was isomerized during the reaction, diene 2 (Z/
E = 11/1, prepared by Ni-catalyzed reductive elimination) was
subjected to the optimized coupling conditions with
benzaldehyde and 4-trifluoromethylbenzaldehyde respectively.
Interestingly, the Z/E ratio of product 3a was the same as that
of diene 2 (Scheme 4a). However, in case of 4-trifluorome-
thylbenzaldehyde, the Z/E ratio of product 3k was decreased to
3/1 (Scheme 4b). These results indicated that the coordination
ability of the aldehyde to the Lewis acid ZnCl2 played an
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Scheme 4
important role in determining the Z/E ratio of the product. For
the relative electron-rich benzaldehyde with good affinity to
Zn(II), the coupling reaction underwent faster than the diene
isomerization, and the Z/E ratio remained unchanged in
product. While, on the other hand, the electron-deficient 4-
trifluoromethylbenzaldehyde could not be activated by Zn(II)
efficiently, and thus the coupling proceeded slowly and the
diene isomerization occurred.
In view of the similar reaction conditions, a possible
mechanistic scenario, which is similar to the mechanisms
suggested by Tamaru9a,13b and Mori,12i is proposed to
understand the unusual 1,4-addition regiochemical course of
this coupling process. As depicted in Scheme 5, the ethyl
diene B. Subsequently, oxidative cyclization of the zerovalent
nickel complex across 3-fluoro-1,3-diene B and aldehyde
generated the intermediate D, in which R1 and Ar groups
properly occupied the anti vicinal pseudoequatorial positions.
After that, σ-bond metathesis with ZnEt2 would then deliver π-
allyl intermediate E that may engage in π−σ−π isomerization
prior to β-H elimination and reductive elimination. Then, β-H
elimination of the intermediate F led to the intermediate G.
Finally, reductive elimination of the intermediate G provided
the product 3 and completed the catalytic cycle. It is
conceivable that with a 3-fluoro substituted π-allyl, the
π−σ−π isomerization could proceed more smoothly, leading
to a less hindered intermediate F. The release of the
nonbonding repulsion in η1-π-allyl nickel complex could
narrow down the energy gap between η1- and η3-π-allyl nickel
complexes, which may facilitate their interconversion.
Scheme 5. Proposed Mechanism
CONCLUSION
■
In conclusion, we have demonstrated an efficient one-pot
allylation of aromatic aldehydes with α-halo-β,β-difluoropro-
pene-containing compounds promoted by Ni(acac)2/PCy2-Ph/
ZnCl2/ZnEt2 system. This protocol provided a useful method
for the synthesis of γ-fluorinated homoallylic alcohols. The
reaction shows moderate to good regio- and stereoselectivity
and tolerates a wide range of functional groups.
EXPERIMENTAL SECTION
■
General Experimental Methods. 1H NMR (TMS as the internal
standard) and 19F NMR spectra (CFCl3 as the external standard and
low field is positive) were recorded on a 300 or 400 MHz
spectrometer. 13C NMR were recorded on a 400 MHz spectrometer.
Chemical shifts (δ) are reported in ppm, and coupling constants (J)
are in Hertz (Hz). The following abbreviations were used to explain
the multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, m =
multiplet, br = broad. Reagents were either purchased from
commercial sources and used without further purification, unless
specified otherwise, or prepared as described in the literature. Dry
THF was distilled from sodium and benzophenone immediately
before use. 4,4-Difluoro-1-phenylhex-5-en-3-ol was prepared according
to the published procedure.20
General Procedure for the Preparation of α-Hydroxy-β,β-
difluoroethylene-Containing Compounds.20 A vigorously stirred
suspension of indium powder (1.38 g, 12 mmol), aldehyde (10 mmol),
tetrahydrofuran (5 mL) and water (20 mL) was cooled to 0 °C in an
ice bath, and 3-bromo-3,3-difluoropropene (1.88 g, 12 mmol) was
slowly added via a dropping funnel. After the addition was completed,
the reaction mixture was allowed to warm to room temperature, and
stirring was continued overnight. To work up, 10% aqueous
hydrochloric acid (15 mL) was added to the reaction mixture, excess
transfer from ZnEt2 to Ni(acac)2, accompanied with reductive
elimination from bis(ethyl)nickel intermediate, led to a
zerovalent nickel complex A. Oxidative addition of α-halo-
β,β-difluoropropene-containing compound with the zerovalent
nickel complex and β-fluorine elimination of the nickel(II)-alkyl
intermediate generated the 3-fluoro-1,3-diene B and a two-
valent nickel complex. The latter was reduced to a zerovalent
complex again and coordinated to the formed 3-fluoro-1,3-
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3
indium was removed by suction filtration, and the residues were
washed with ether (30 mL). The organic layer was separated, and the
aqueous layer was extracted with ether (2 × 50 mL). The combined
organic extracts were washed with brine (50 mL), then dried over
anhydrous sodium sulfate, filtered and concentrated in vacuo. The
residues were purified by column chromatography to give the desired
compound.
9.3 Hz, 1F), −103.3 (AB, JAB = 242.8 Hz, JHF = 11.6 Hz, 1F); 13C
NMR (100.7 MHz, CDCl3, 293 K, TMS) δ ppm 130.1 (t, J = 26.2
Hz), 121.0 (t, J = 9.5 Hz), 118.7 (t, J = 242.1 Hz), 54.3 (t, J = 30.6
Hz), 31.8 (t, J = 2.9 Hz), 29.0, 28.7, 27.3, 22.6, 14.0; IR (thin film) υmax
2957, 2928, 2858, 1466, 1419, 1307, 999, 952 cm−1. Anal. Calculated
for C11H19BrF2: C 49.08, H 7.11. Found: C 48.79, H 6.96.
(2-Bromo-3,3-difluoropent-4-en-1-yl)benzene (1c). Prepared
3,3-Difluoroundec-1-en-4-ol (1b-OH). Prepared from octanal
from 3,3-difluoro-1-phenylpent-4-en-2-ol 1c-OH using general
procedure to afford 1c as a colorless oil (2.01 g, 77%): H NMR
1
using general procedure to afford 1b-OH as a colorless oil (1.57 g,
1
76%): H NMR (400 MHz, CDCl3, 293 K, TMS) δ ppm 6.04−5.91
(400 MHz, CDCl3, 293 K, TMS) δ ppm 7.34−7.21 (m, 5H), 6.18−
6.06 (m, 1H), 5.79 (dt, J = 17.6 Hz, J = 2.0 Hz, 1H), 5.60 (d, J = 11.2
Hz, 1H), 4.22−4.13 (m, 1H), 3.49 (dd, J = 14.8 Hz, J = 2.8 Hz, 1H),
2.94 (dd, J = 14.8 Hz, J = 11.2 Hz, 1H); 19F NMR (282 MHz, CDCl3)
δ ppm −99.1 (AB, JAB = 242.8 Hz, 3JHF = 8.2 Hz, 1F), −104.6 (AB, JAB
= 242.8 Hz, 3JHF = 12.4 Hz, 1F); 13C NMR (100.7 MHz, CDCl3, 293
K, TMS) δ ppm 137.0, 130.1 (t, J = 23.1 Hz), 129.3, 128.6, 127.2,
122.1 (t, J = 9.4 Hz), 118.7 (t, J = 243.4 Hz), 54.8 (t, J = 29.9 Hz),
38.2 (t, J = 2.2 Hz); IR (thin film) υmax 3088, 3065, 3031, 3005, 2960,
2922, 2849, 1604, 1496, 1455, 1419, 1303, 1200, 748, 697 cm−1; MS
(EI) m/z (%) 262, 260 (M+), 184, 182, 91 (100), 77, 65, 51, 41;
HRMS (EI-TOF) Calculated for C11H11BrF2 260.0012, found
260.0012.
(m, 1H), 5.73−5.67 (m, 1H), 5.54−5.51 (m, 1H), 3.79−3.71 (m, 1H),
2.15 (br, 1H), 1.63−1.55 (m, 2H), 1.47−1.28 (m, 10H), 0.88 (t, J =
6.4 Hz, 3H); 19F NMR (282 MHz, CDCl3) δ ppm −108.2 (AB, JAB
=
248.2 Hz, 3JHF = 10.4 Hz, 1F), −111.8 (AB, JAB = 248.2 Hz, 3JHF = 10.2
Hz, 1F); 13C NMR (100.7 MHz, CDCl3, 293 K, TMS) δ ppm 129.9
(t, J = 26.2 Hz), 121.0 (t, J = 9.5 Hz), 120.4 (t, J = 241.3 Hz), 73.6
(dd, J = 29.9 Hz, J = 28.4 Hz), 31.8, 30.1 (dd, J = 2.9 Hz, J = 1.5 Hz),
29.4, 29.1, 15.5, 22.6, 14.0; IR (thin film) υmax 3602, 3415, 2927, 2858,
1466, 1421, 1075, 989, 949, 723 cm−1; MS (ESI) m/z 229 [M + Na]+;
HRMS (ESI-FT) Calculated for C11H20F2NaO [M + Na]+ 229.1374,
found 229.1374.
3,3-Difluoro-1-phenylpent-4-en-2-ol (1c-OH). Prepared from
2-phenylacetaldehyde using general procedure to afford 1c-OH as a
colorless oil (1.59 g, 80%): 1H NMR (400 MHz, CDCl3, 293 K, TMS)
δ ppm 7.33−7.23 (m, 5H), 6.11−5.97 (m, 1H), 5.80−5.74 (m, 1H),
5.59−5.56 (m, 1H), 3.99 (ddd, J = 19.6 Hz, J = 10.0 Hz, J = 2.4 Hz),
3.01−2.97 (m, 1H), 2.71−2.65 (m, 1H), 1.96 (br, 1H); 19F NMR (282
MHz, CDCl3) δ ppm −106.8 (AB, JAB = 249.0 Hz, 3JHF = 9.3 Hz, 1F),
(4,4-Difluoro-3-iodohex-5-en-1-yl)benzene (1a′). A dry 250
mL flask, equipped with a mechanical stirrer and a septum, was
charged with 4,4-difluoro-1-phenylhex-5-en-3-ol (2.12 g, 10 mmol),
PPh3 (10.49 g, 40 mmol), imidazole (1.84 g, 27 mmol), iodine (6.85 g,
27 mmol) in toluene (100 mL), and the resulting mixture was stirred
at 110 °C for 3 h. The reaction was quenched with water (50 mL).
The aqueous layer was extracted with hexane (2 × 50 mL). The
combined organic extracts were washed with brine (50 mL), dried
over anhydrous sodium sulfate, filtered and concentrated in vacuo. The
residues were purified by column chromatography to give (4,4-
difluoro-3-iodohex-5-en-1-yl)benzene 1a′ as a colorless oil (2.25 g,
3
−112.1 (AB, JAB = 249.0 Hz, JHF = 10.4 Hz, 1F); 13C NMR (100.7
MHz, CDCl3, 293 K, TMS) δ ppm 137.3, 129.8 (t, J = 25.5 Hz), 129.4,
128.7, 126.9, 121.4 (t, J = 9.4 Hz), 119.9 (t, J = 241.3 Hz), 74.6 (t, J =
29.9 Hz), 36.6 (t, J = 2.9 Hz); IR (thin film) υmax 3442, 3087, 3064,
3004, 2930, 1604, 1496, 1420, 1219, 1165, 1065, 740, 699 cm−1; MS
(EI) m/z (%) 198 (M+), 121, 107, 103, 91 (100), 77, 65, 51, 41;
HRMS (EI-TOF) Calculated for C11H12F2O 198.0856, found
198.0856.
1
70%): H NMR (400 MHz, CDCl3, 293 K, TMS) δ ppm 7.31−7.20
(m, 5H), 6.07−5.94 (m, 1H), 5.68 (dt, J = 17.2 Hz, J = 2.4 Hz, 1H),
5.51−5.49 (m, 1H), 4.03−3.94 (m, 1H), 3.01−2.94 (m, 1H), 2.70−
2.62 (m, 1H), 2.18−2.00 (m, 2H); 19F NMR (282 MHz, CDCl3) δ
ppm −95.5 to −97.4 (m, 2F); 13C NMR (100.7 MHz, CDCl3, 293 K,
TMS) δ ppm 139.9, 130.4 (t, J = 26.2 Hz), 128.7, 128.6, 126.5, 121.9
(t, J = 8.7 Hz), 118.8 (t, J = 242.1 Hz), 35.6, 34.7 (t, J = 2.9 Hz), 33.3
(t, J = 28.4 Hz); IR (thin film) υmax 3085, 3062, 3027, 3002, 2940,
2858, 1603, 1496, 1454, 1418, 784, 749, 699 cm−1; MS (EI) m/z (%)
322 (M+), 195, 91 (100), 77, 65, 51; HRMS (EI-TOF) Calculated for
C12H13F2I 322.0030, found 322.0030.
General Procedure for the Preparation of α-Bromo-β,β-
difluoropropene-Containing Compounds. A dry 250 mL flask,
equipped with a mechanical stirrer and a septum, was charged with
4,4-difluoro-1-phenylhex-5-en-3-ol (2.12 g, 10 mmol), PPh3 (5.25 g,
20 mmol), CBr4 (6.63 g, 20 mmol) and toluene (100 mL); the
resulting mixture was stirred at 110 °C for 3 h. The reaction was
quenched with water (50 mL). The organic layer was separated and
the aqueous layer was extracted with hexane (2 × 50 mL). The
combined organic extracts were washed with brine (50 mL) and then
dried over anhydrous sodium sulfate, filtered and concentrated in
vacuo. The residues were purified by column chromatography to give
the desired compound.
(3-Chloro-4,4-difluorohex-5-en-1-yl)benzene (1a″). To a
solution of 4,4-difluoro-1-phenylhex-5-en-3-ol (636 mg, 3 mmol) in
CH2Cl2 (40 mL) was added DMAP (1.10 g, 9 mmol), followed by p-
toluenesulfonyl chloride (1.71 g, 9 mmol) at 0 °C. The reaction
mixture was allowed to warm to room temperature and stirred for 16
h. The solvent was concentrated in vacuo, and the residues were
purified by column chromatography to give 4,4-difluoro-1-phenylhex-
5-en-3-yl 4-methylbenzenesulfonate 1a″-Ts as a white solid (1.01 g,
(3-Bromo-4,4-difluorohex-5-en-1-yl)benzene (1a). Prepared
from 4,4-difluoro-1-phenylhex-5-en-3-ol using general procedure to
afford 1a as a colorless oil (2.34 g, 85%): 1H NMR (400 MHz, CDCl3,
293 K, TMS) δ ppm 7.32−7.20 (m, 5H), 6.09−6.00 (m, 1H), 5.71 (dt,
J = 17.2 Hz, J = 2.4 Hz, 1H), 5.56−5.53 (m, 1H), 4.00−3.88 (m, 1H),
3.30−3.00 (m, 1H), 2.76−2.69 (m, 1H), 2.35−2.27 (m, 1H), 2.11−
1
92%): mp 69−71 °C; H NMR (400 MHz, CDCl3, 293 K, TMS) δ
ppm 7.80−7.13 (m, 9H), 5.86−5.73 (m, 1H), 5.62−5.58 (m, 1H),
5.47−5.45 (m, 1H), 4.84−4.76 (m, 1H), 2.81−2.63 (m, 2H), 2.43 (s,
2.01 (m, 1H); 19F NMR (282 MHz, CDCl3) δ ppm −99.2 (AB, JAB
=
243.9 Hz, 3JHF = 9.3 Hz, 1F), −103.0 (AB, JAB = 243.9 Hz, 3JHF = 11.3
Hz, 1F); 13C NMR (100.7 MHz, CDCl3, 293 K, TMS) δ ppm 140.0,
129.9 (t, J = 25.6 Hz), 128.7, 128.6, 126.5, 121.9 (t, J = 9.0 Hz), 118.7
(t, J = 242.8 Hz), 53.3 (t, J = 30.6 Hz), 33.4, 33.1; IR (thin film) υmax
3063, 3028, 2927, 2861, 1603, 1496, 1454, 1419, 985, 754, 749, 700
cm−1; MS (EI) m/z (%) 276, 274 (M+), 195, 91 (100), 77, 65, 51;
HRMS (EI-TOF) Calculated for C12H13BrF2 274.0169, found
274.0169.
3H), 2.08−1.90 (m, 2H); 19F NMR (282 MHz, CDCl3) δ ppm
3
−104.1 (AB, JAB = 253.2 Hz, JHF = 9.3 Hz, 1F), −109.0 (AB, JAB
=
253.2 Hz, 3JHF = 12.3 Hz, 3JHF = 8.2 Hz, 1F); 13C NMR (100.7 MHz,
CDCl3, 293 K, TMS) δ ppm 145.1, 140.4, 134.1, 129.8, 129.1, 128.8,
128.6, 128.5, 127.9, 126.3, 122.3 (t, J = 9.5 Hz), 118.1 (t, J = 244.3
Hz), 80.7 (dd, J = 32.5 Hz, J = 30.7 Hz), 31.1, 21.7; IR (thin film) υmax
3087, 3063, 3029, 3003, 2964, 2933, 2866, 1598, 1469, 1372, 1190,
814, 748, 701, 668 cm−1; MS (EI) m/z (%) 366 (M+), 194, 117 (100),
91, 77, 65, 51, 41; HRMS (EI-TOF) Calculated for C19H20F2O3S
366.1101, found 366.1101.
4-Bromo-3,3-difluoroundec-1-ene (1b). Prepared from 3,3-
difluoroundec-1-en-4-ol (1b-OH) using general procedure to afford 1b
1
as a colorless oil (2.18 g, 81%): H NMR (400 MHz, CDCl3, 293 K,
A dry 25 mL flask, equipped with a mechanical stirrer and a septum,
was charged with the sulfonate 1a″-Ts (547 mg, 1.5 mmol), LiCl (252
mg, 6 mmol) and DMF (10 mL); the resulting mixture was stirred at
130 °C for 24 h. The reaction was quenched with water (10 mL), and
the organic layer was separated. The aqueous layer was extracted with
TMS) δ ppm 6.11−6.00 (m, 1H), 5.73 (dt, J = 17.2 Hz, J = 2.0 Hz,
1H), 5.56−5.54 (m, 1H), 4.03−3.95 (m, 1H), 2.02−1.94 (m, 1H),
1.78−1.63 (m, 2H), 1.42−1.29 (m, 9H), 0.89 (t, J = 6.4 Hz, 3H); 19F
3
NMR (282 MHz, CDCl3) δ ppm −99.2 (AB, JAB = 242.8 Hz, JHF
=
8700
dx.doi.org/10.1021/jo301688d | J. Org. Chem. 2012, 77, 8696−8704

The Journal of Organic Chemistry
Article
hexane (2 × 20 mL). The combined organic extracts were washed with
brine (10 mL), then dried over anhydrous sodium sulfate, filtered and
concentrated in vacuo. The residues were purified by column
chromatography to give (3-chloro-4,4-difluorohex-5-en-1-yl)benzene
1a″ as a colorless oil (235 mg, 71%): 1H NMR (400 MHz, CDCl3, 293
K, TMS) δ ppm 7.32−7.19 (m, 5H), 6.05−5.92 (m, 1H), 5.71 (dt, J =
17.2 Hz, J = 2.0 Hz, 1H), 5.56−5.53 (m, 1H), 3.93−3.85 (m, 1H),
3.01−2.94 (m, 1H), 2.76−2.68 (m, 1H), 2.29−2.21 (m, 1H), 2.02−
= 8.8 Hz, 1H), 2.70−2.63 (m, 1H), 2.44−2.30 (m, 2H), 1.95 (br, 1H),
1.77−1.67 (m, 1H), 1.70 (dd, J = 6.8 Hz, J = 2.0 Hz, 3H), 1.41−1.32
(m, 1H); 19F NMR (282 MHz, CDCl3) δ ppm −117.9 (dd, J = 32.2
Hz, J = 23.69 Hz, 0.06 F), −122.9 (dd, J = 38.1 Hz, J = 28.8 Hz, 0.94
F); 13C NMR (100.7 MHz, CDCl3, 293 K, TMS) δ ppm 157.8 (d, J =
253.8 Hz), 157.2, 157.1, 141.6, 136.7, 129.8, 128.4, 128.3, 128.2, 125.9,
123.4, 118.9, 118.8, 104.8 (d, J = 15.3 Hz), 74.2, 51.0 (d, J = 24.1 Hz),
33.2, 29.1, 8.9 (d, J = 6.6 Hz); IR (thin film) υmax 3564, 3445, 3061,
3026, 2925, 2865, 1707, 1589, 1505, 1488, 1454, 1243, 1024, 872, 749,
694 cm−1; MS (ESI) m/z 399 [M + Na]+; HRMS (ESI-FT)
Calculated for C25H25FNaO2 [M + Na]+ 399.1736, found 399.1731.
anti-3-Fluoro-2-phenethyl-1-p-tolylpent-3-en-1-ol (3d). Pre-
pared from 1a and 4-methylbenzaldehyde using general procedure A
to afford 3d as a white solid (44.8 mg, 75%): mp 90−92 °C; 1H NMR
(400 MHz, CDCl3, 293 K, TMS) δ ppm 7.25−7.00 (m, 9H), 4.75 (dq,
J = 38.2 Hz, J = 13.6 Hz, J = 6.8 Hz, 1H), 4.57 (d, J = 9.2 Hz, 1H),
2.68−2.61 (m, 1H), 2.45−2.36 (m, 2H), 2.33 (s, 3H), 2.01 (br, 1H),
1.74−1.64 (m, 1H), 1.69 (dd, J = 7.0 Hz, J = 2.0 Hz, 3H), 1.39−1.31
(m, 1H); 19F NMR (282 MHz, CDCl3) δ ppm −118.1 (dd, J = 32.0
Hz, J = 21.4 Hz, 0.05 F), −122.8 (dd, J = 38.2 Hz, J = 29.0 Hz, 0.95
F); 13C NMR (100.7 MHz, CDCl3, 293 K, TMS) δ ppm 158.1 (d, J =
254.5 Hz), 141.7, 138.9, 137.7, 129.2, 128.4, 128.2, 126.9, 125.8, 104.5
(d, J = 16.1 Hz), 74.5, 50.9 (d, J = 24.1 Hz), 33.3, 29.1, 21.2, 89 (d, J =
6.5 Hz); IR (thin film) υmax 3366, 3059, 3024, 2999, 2924, 2861, 1713,
1600, 1515, 1495, 1452, 1308, 823, 756, 697 cm−1; MS (ESI) m/z 321
[M + Na]+; HRMS (ESI-FT) Calculated for C20H23FNaO [M + Na]+
321.1631, found 321.1625.
1.93 (m, 1H); 19F NMR (282 MHz, CDCl3) δ ppm −101.5 (AB, JAB
=
245.9 Hz, 3JHF = 9.3 Hz, 1F), −106.7 (AB, JAB = 245.9 Hz, 3JHF = 11.3
Hz, 1F); 13C NMR (100.7 MHz, CDCl3, 293 K, TMS) δ ppm 140.1,
129.5 (t, J = 26.2 Hz), 128.7, 128.6, 126.4, 121.9 (t, J = 9.5 Hz), 118.9
(t, J = 242.8 Hz), 61.2 (t, J = 31.4 Hz), 32.9 (t, J = 2.2 Hz), 32.0; IR
(thin film) υmax 3087, 3064, 3028, 3004, 2960, 2930, 2864, 1603, 1496,
1455, 1420, 800, 750, 700 cm−1; MS (EI) m/z (%) 230 (M+), 195,
107, 91 (100), 77, 65, 51, 41; HRMS (EI-TOF) Calculated for
C12H13ClF2 230.0674, found 230.0674.
General Procedure A for the Nickel-Catalyzed Coupling of
Aldehydes with α-Halo-β,β-difluoropropene-Containing Com-
pounds. To a solution of Ni(acac)2 (5.1 mg, 10 mol %), PCy2-Ph
(11.0 mg, 20 mol %) and ZnCl2 (54.4 mg, 0.4 mmol) in THF (2 mL)
was added PhCHO (42.5 mg, 0.4 mmol) and (3-bromo-4,4-
difluorohex-5-en-1-yl)benzene 1a (55.0 mg, 0.2 mol) in THF (1
mL) at room temperature under argon by syringe. Then ZnEt2 (0.9
mL of 1.0 M hexane solution, 0.9 mmol) was added dropwise to the
resulting mixture. The reaction mixture was stirred at room
temperature for an additional 1.5 h. The reaction was quenched
with 2 mL of 1 M HCl. The organic layer was separated, and the
aqueous layer was extracted with Et2O (2 × 2 mL). The combined
organic extracts were washed with brine (5 mL) and then dried over
anhydrous sodium sulfate, filtered and concentrated in vacuo. The
residues were purified by column chromatography to give 3-fluoro-2-
phenethyl-1-phenylpent-3-en-1-ol 3a.
anti-3-Fluoro-2-phenethyl-1-m-tolylpent-3-en-1-ol (3e). Pre-
pared from 1a and 3-methylbenzaldehyde using general procedure A
to afford 3e as a white solid (38.2 mg, 64%): mp 47−49 °C; 1H NMR
(400 MHz, CDCl3, 293 K, TMS) δ ppm 7.24−6.99 (m, 9H), 4.75 (dq,
J = 38.0 Hz, J = 13.8 Hz, J = 7.2 Hz, 1H), 4.56 (d, J = 9.2 Hz, 1H),
2.68−2.61 (m, 1H), 2.45−2.34 (m, 2H), 2.32 (s, 3H), 1.90 (br, 1H),
1.75−1.66 (m, 1H), 1.69 (dd, J = 6.8 Hz, J = 2.0 Hz, 3H), 1.39−1.31
(m, 1H); 19F NMR (282 MHz, CDCl3) δ ppm −118.4 (dd, J = 32.0
Hz, J = 22.8 Hz, 0.05 F), −123.2 (dd, J = 38.1 Hz, J = 28.8 Hz, 0.95
F); 13C NMR (100.7 MHz, CDCl3, 293 K, TMS) δ ppm 158.0 (d, J =
254.5 Hz), 141.8, 141.6, 138.2, 128.8, 128.4, 128.3, 128.2, 127.6, 125.8,
124.2, 104.6 (d, J = 15.3 Hz), 74.7, 50.8 (d, J = 24.0 Hz), 33.2, 29.0,
21.4, 8.9 (d, J = 6.6 Hz); IR (thin film) υmax 3566, 3447, 3060, 3026,
2924, 2865, 1707, 1605, 1495, 1453, 1380, 1296, 1030, 978, 787, 749,
699 cm−1; MS (ESI) m/z 321 [M + Na]+; HRMS (ESI-FT)
Calculated for C20H23FNaO [M + Na]+ 321.1631, found 321.1625.
anti-3-Fluoro-2-phenethyl-1-o-tolylpent-3-en-1-ol (3f). Pre-
pared from 1a and 2-methylbenzaldehyde using general procedure A
anti-3-Fluoro-2-phenethyl-1-phenylpent-3-en-1-ol (3a). Pre-
pared from 1a and benzaldehyde using general procedure A to afford
1
3a as a white solid (35.8 mg, 63%): mp 89−91 °C; H NMR (400
MHz, CDCl3, 293 K, TMS) δ ppm 7.34−7.00 (m, 10 H), 4.79 (dq, J =
38.0 Hz, J = 13.6 Hz, J = 6.8 Hz, 1H), 4.60 (d, J = 8.8 Hz, 1H), 2.67−
2.61 (m, 1H), 2.45−2.32 (m, 2H), 1.94 (br, 1H), 1.76−1.66 (m, 1H),
1.69 (dd, J = 6.8 Hz, J = 2.0 Hz, 3H), 1.39−1.31 (m, 1H); 19F NMR
(282 MHz, CDCl3) δ ppm −118.2 (dd, J = 32.9 Hz, J = 23.7 Hz, 0.05
F), −122.9 (dd, J = 38.0 Hz, J = 28.8 Hz, 0.95 F); 13C NMR (100.7
MHz, CDCl3, 293 K, TMS) δ ppm 157.9 (d, J = 253.7 Hz), 141.9,
141.6, 128.5, 128.4, 128.3, 128.1, 126.9, 125.8, 104.6 (d, J = 15.3 Hz),
74.7, 50.9 (d, J = 24.8 Hz), 33.3, 29.1, 8.9 (d, J = 6.6 Hz); IR (thin
film) υmax 3565, 3445, 3062, 3027, 2924, 2865, 1708, 1602, 1453, 1301,
1188, 1028, 978, 754, 699 cm−1; MS (ESI) m/z 307 [M + Na]+;
HRMS (ESI-FT) Calculated for C19H21FNaO [M + Na]+ 307.1474,
found 307.1468.
1
to afford 3f as a colorless oil (32.8 mg, 55%): H NMR (400 MHz,
CDCl3, 293 K, TMS) δ ppm 7.27−6.99 (m, 9H), 4.93 (d, J = 9.2 Hz,
1H), 4.73 (dq, J = 37.8 Hz, J = 13.8 Hz, J = 6.8 Hz, 1H), 2.70−2.63
(m, 1H), 2.51−2.36 (m, 2H), 2.31 (s, 3H), 1.85 (br, 1H), 1.83−1.73
(m, 1H), 1.70 (dd, J = 6.8 Hz, J = 2.4 Hz, 3H), 1.39−1.31 (m, 1H);
19F NMR (282 MHz, CDCl3) δ ppm −117.8 (dd, J = 30.7 Hz, J = 23.7
anti-1-(Biphenyl-4-yl)-3-fluoro-2-phenethylpent-3-en-1-ol
(3b). Prepared from 1a and [1,1′-biphenyl]-4-carbaldehyde using
general procedure A to afford 3b as a white solid (43.9 mg, 61%): mp
Hz, 0.04 F), −122.9 (dd, J = 37.5 Hz, J = 28.8 Hz, 0.96 F); 13C NMR
(100.7 MHz, CDCl3, 293 K, TMS) δ ppm 157.9 (d, J = 255.0 Hz),
141.5, 140.0, 135.7, 130.5, 128.4, 128.3, 127.6, 126.4, 126.3, 125.9,
104.7 (d, J = 16.1 Hz), 70.4, 50.6 (d, J = 24.1 Hz), 33.3, 28.6, 19.5, 8.9
(d, J = 6.5 Hz); IR (thin film) υmax 3564, 3454, 3062, 3026, 2925,
2865, 1707, 1603, 1495, 1454, 1380, 1300, 979, 799, 756, 699 cm−1;
MS (ESI) m/z 321 [M + Na]+; HRMS (ESI-FT) Calculated for
C20H23FNaO [M + Na]+ 321.1631, found 321.1625.
1
96−98 °C; H NMR (400 MHz, CDCl3, 293 K, TMS) δ ppm 7.58−
6.90 (m, 14H), 4.75 (dq, J = 38.2 Hz, J = 14.0 Hz, J = 6.8 Hz, 1H),
4.64 (d, J = 8.8 Hz, 1H), 2.70−2.63 (m, 1H), 2.49−2.36 (m, 2H), 2.05
(br, 1H), 1.79−1.72 (m, 1H), 1.70 (dd, J = 6.4 Hz, J = 2.0 Hz, 3H),
1.43−1.37 (m, 1H); 19F NMR (282 MHz, CDCl3) δ ppm −117.9 (dd,
J = 32.4 Hz, J = 23.7 Hz, 0.10 F), −122.7 (dd, J = 36.9 Hz, J = 28.7 Hz,
0.90 F); 13C NMR (100.7 MHz, CDCl3, 293 K, TMS) δ ppm 157.9
(d, J = 254.2 Hz), 141.6, 141.0, 140.9, 140.8, 128.8, 128.4, 128.3,
127.5, 127.4, 127.2, 127.1, 125.9, 104.7 (d, J = 15.5 Hz), 74.5, 50.9 (d,
J = 24.1 Hz), 33.3, 29.1, 9.0 (d, J = 6.9 Hz); IR (thin film) υmax 3565,
3434, 3061, 3027, 2925, 2864, 1708, 1589, 1506, 1488, 1453, 1287,
1029, 871, 748, 696 m−1; MS (ESI) m/z 383 [M + Na]+; HRMS (ESI-
FT) Calculated for C25H25FNaO [M + Na]+ 383.1787, found 383.
anti-3-Fluoro-2-phenethyl-1-(4-phenoxyphenyl)pent-3-en-
1-ol (3c). Prepared from 1a and 4-phenoxybenzaldehyde using general
procedure A to afford 3c as a white solid (50.4 mg, 67%): mp 72−74
°C; 1H NMR (400 MHz, CDCl3, 293 K, TMS) δ ppm 7.35−6.95 (m,
14 Hz), 4.76 (dq, J = 38.0 Hz, J = 13.6 Hz, J = 6.8 Hz, 1H), 4.59 (d, J
anti-3-Fluoro-1-(4-methoxyphenyl)-2-phenethylpent-3-en-
1-ol (3g). Prepared from 1a and 4-methoxybenzaldehyde using
general procedure A to afford 3g as a white solid (44.6 mg, 71%): mp
1
66−68 °C; H NMR (400 MHz, CDCl3, 293 K, TMS) δ ppm 7.24−
6.83 (m, 9H), 4.75 (dq, J = 38.0 Hz, J = 13.6 Hz, J = 6.8 Hz, 1H), 4.55
(d, J = 9.2 Hz, 1H), 3.79 (s, 3H), 2.68−2.60 (m, 1H), 2.42−2.29 (m,
2H), 1.99 (br, 1H), 1.72−1.63 (m, 1H), 1.69 (dd, J = 6.8 Hz, J = 1.2
Hz, 3H), 1.37−1.28 (m, 1H); 19F NMR (282 MHz, CDCl3) δ ppm
−118.1 (dd, J = 31.9 Hz, J = 22.6 Hz, 0.06 F), −122.8 (dd, J = 38.2 Hz,
J = 28.8 Hz, 0.94 F); 13C NMR (100.7 MHz, CDCl3, 293 K, TMS) δ
ppm 159.4, 158.1 (d, J = 254.4 Hz), 141.7, 134.1, 128.3, 128.2, 128.1,
8701
dx.doi.org/10.1021/jo301688d | J. Org. Chem. 2012, 77, 8696−8704

The Journal of Organic Chemistry
Article
125.8, 113.9, 104.5 (d, J = 15.3 Hz), 74.2, 55.3, 51.0 (d, J = 24.8 Hz),
33.3, 29.1, 8.9 (d, J = 6.6 Hz); IR (thin film) υmax 3461, 3061, 3026,
2928, 2865, 2836, 1708, 1611, 1585, 1515, 1454, 1249, 835, 750, 700
cm−1; MS (ESI) m/z 337 [M + Na]+; HRMS (ESI-FT) Calculated for
C20H23FNaO2 [M + Na]+ 337.1580, found 337.1574.
anti-3-Fluoro-1-(furan-2-yl)-2-phenethylpent-3-en-1-ol (3n).
Prepared from 1a and furan-2-carbaldehyde using general procedure A
to afford 3n as a yellow oil (38.4 mg, 70%): H NMR (400 MHz,
1
CDCl3, 293 K, TMS) δ ppm 7.38−6.23 (m, 8H), 4.77 (dq, J = 38.0
Hz, J = 13.6 Hz, J = 6.8 Hz, 1H), 4.66 (d, J = 9.6 Hz, 1H), 2.71−2.57
(m, 2H), 2.48−2.41 (m, 1H), 1.92 (br, 1H), 1.80−1.72 (m, 1H), 1.68
(dd, J = 7.0 Hz, J = 2.0 Hz, 3H), 1.44−1.36 (m, 1H); 19F NMR (282
MHz, CDCl3) δ ppm −118.8 (dd, J = 32.0 Hz, J = 23.7 Hz, 0.08 F),
−124.3 (dd, J = 37.5 Hz, J = 27.9 Hz, 0.92 F); 13C NMR (100.7 MHz,
CDCl3, 293 K, TMS) δ ppm 157.5 (d, J = 253.8 Hz), 154.2, 142.3,
141.6, 128.4, 128.3, 125.9, 110.2, 108.0, 104.8 (d, J = 15.3 Hz), 68.1,
48.6 (d, J = 24.8 Hz), 33.2, 29.3, 8.9 (d, J = 6.6 Hz); IR (thin film) υmax
3467, 3084, 3061, 3026, 2924, 2864, 1708, 1603, 1496, 1453, 740, 700
cm−1; MS (ESI) m/z 297 [M + Na]+; HRMS (ESI-FT) Calculated for
C17H19FNaO2 [M + Na]+ 297.1267, found 297.1261.
anti-3-Fluoro-1-(2-methoxyphenyl)-2-phenethylpent-3-en-
1-ol (3h). Prepared from 1a and 2-methoxybenzaldehyde using
general procedure A to afford 3h as a colorless oil (34.6 mg, 55%): 1H
NMR (400 MHz, CDCl3, 293 K, TMS) δ ppm 7.26−6.83 (m, 9H),
4.86 (d, J = 8.8 Hz, 1H), 4.64 (dq, J = 38.0 Hz, J = 13.6 Hz, J = 7.2 Hz,
1H), 3.73 (s, 3H), 2.70−2.50 (m, 2H), 2.45−2.34 (m, 1H), 2.28 (br,
1H), 1.84−1.75 (m, 1H), 1.66 (dd, J = 6.8 Hz, J = 2.0 Hz, 1H), 1.45−
1.37 (m, 1H); 19F NMR (282 MHz, CDCl3) δ ppm −117.3 (dd, J =
33.6 Hz, J = 22.6 Hz, 0.10 F), −121.9 (dd, J = 37.7 Hz, J = 29.9 Hz,
0.90 F); 13C NMR (100.7 MHz, CDCl3, 293 K, TMS) δ ppm 158.6
(d, J = 255.0 Hz), 156.9, 141.9, 130.1, 128.7, 128.4, 128.3, 128.2,
125.7, 120.8, 110.7, 103.7 (d, J = 16.3 Hz), 71.7, 55.2, 49.3 (d, J = 23.3
Hz), 33.3, 29.5, 8.9 (d, J = 6.8 Hz); IR (thin film) υmax 3565, 3459,
3061, 3026, 2936, 2864, 2837, 1707, 1601, 1588, 1493, 1455, 1241,
1029, 797, 754, 699 cm−1; MS (ESI) m/z 337 [M + Na]+; HRMS
(ESI-FT) Calculated for C20H23FNaO2 [M + Na]+ 337.1580, found
337.1574.
anti-1-(4-Bromophenyl)-3-fluoro-2-phenethylpent-3-en-1-ol
(3i). Prepared from 1a and 4-bromobenzaldehyde using general
procedure A to afford 3i as a white solid (44.3 mg, 61%): mp 80−82
°C; 1H NMR (400 MHz, CDCl3, 293 K, TMS) δ ppm 7.46−7.00 (m,
9H), 4.72 (dq, J = 37.8 Hz, J = 13.6 Hz, J = 6.8 Hz, 1H), 4.56 (d, J =
8.8 Hz, 1H), 2.69−2.62 (m, 1H), 2.43−2.26 (m, 2H), 1.95 (br, 1H),
1.77−1.71 (m, 1H), 1.68 (dd, J = 7.0 Hz, J = 2.0 Hz, 3H), 1.39−1.31
(m, 1H); 19F NMR (282 MHz, CDCl3) δ ppm −117.9 (dd, J = 32.4
Hz, J = 22.6 Hz, 0.10 F), −122.6 (dd, J = 38.1 Hz, J = 28.8 Hz, 0.90
F); 13C NMR (100.7 MHz, CDCl3, 293 K, TMS) δ ppm 157.5 (d, J =
254.4 Hz), 141.4, 140.9, 131.6, 128.6, 128.3, 125.9, 121.8, 105.0 (d, J =
15.3 Hz), 74.1, 50.9 (d, J = 24.1 Hz), 33.2, 28.9, 8.9 (d, J = 7.3 Hz); IR
(thin film) υmax 3564, 3444, 3061, 3026, 2925, 2864, 1706, 1602, 1488,
1453, 1406, 832, 749, 719, 699 cm−1; MS (ESI) m/z 385 [M + Na]+;
HRMS (ESI-FT) Calculated for C19H20BrFNaO [M + Na]+ 385.0579,
found 385.0574.
anti-1-(4-Chlorophenyl)-3-fluoro-2-phenethylpent-3-en-1-ol
(3j). Prepared from 1a and 4-chlorobenzaldehyde using general
procedure A to afford 3j as a white solid (40.2 mg, 57%): mp 78−80
°C; 1H NMR (400 MHz, CDCl3, 293 K, TMS) δ ppm 7.31−6.99 (m,
9H), 4.72 (dq, J = 37.8 Hz, J = 13.6 Hz, J = 6.8 Hz, 1H), 4.58 (d, J =
8.8 Hz, 1H), 2.69−2.62 (m, 1H), 2.43−2.26 (m, 2H), 2.00 (br, 1H),
1.76−1.71 (m, 1H), 1.68 (dd, J = 6.8 Hz, J = 2.0 Hz, 3H), 1.38−1.30
(m, 1H); 19F NMR (282 MHz, CDCl3) δ ppm −117.8 (dd, J = 30.3
Hz, J = 22.8 Hz, 0.10 F), −122.5 (dd, J = 36.0 Hz, J = 28.8 Hz, 0.90
F); 13C NMR (100.7 MHz, CDCl3, 293 K, TMS) δ ppm 157.5 (d, J =
255.2 Hz), 141.4, 140.4, 133.7, 128.6, 128.4, 128.3, 125.9, 105.0 (d, J =
14.6 Hz), 74.0, 50.9 (d, J = 24.1 Hz), 33.2, 29.0, 8.9 (d, J = 7.3 Hz); IR
(thin film) υmax 3565, 3455, 3062, 3026, 2925, 2865, 1706, 1601, 1493,
1454, 1387, 1089, 834, 750, 699 cm−1; MS (ESI) m/z 341 [M + Na]+;
HRMS (ESI-FT) Calculated for C19H20ClFNaO [M + Na]+ 341.1084,
found 341.1079.
anti-3-Fluoro-1-(naphthalen-2-yl)-2-phenethylpent-3-en-1-
ol (3m). Prepared from 1a and 2-naphthaldehyde using general
procedure A to afford 3m as a white solid (44.1 mg, 66%): mp 63−65
°C; 1H NMR (400 MHz, CDCl3, 293 K, TMS) δ ppm 7.82−6.95 (m,
12H), 4.84−4.69 (m, 2H), 2.68−2.61 (m, 1H), 2.56−2.34 (m, 2H),
2.06 (br, 1H), 1.80−1.71 (m, 1H), 1.70 (dd, J = 6.8 Hz, J = 2.0 Hz,
3H), 1.41−1.33 (m, 1H); 19F NMR (282 MHz, CDCl3) δ ppm
−118.0 (dd, J = 32.6 Hz, J = 21.7 Hz, 0.07 F), −122.9 (dd, J = 37.8 Hz,
J = 28.8 Hz, 0.93 F); 13C NMR (100.7 MHz, CDCl3, 293 K, TMS) δ
ppm 157.9 (d, J = 255.2 Hz), 141.5, 139.3, 133.3, 133.2, 128.4, 128.3,
128.1, 127.7, 126.4, 126.2, 126.1, 125.9, 124.5, 104.8 (d, J = 16.1 Hz),
74.9, 50.8 (d, J = 24.8 Hz), 33.3, 29.2, 9.0 (d, J = 6.5 Hz); IR (thin
film) υmax 3565, 3445, 3058, 3026, 2924, 2864, 1707, 1602, 1568, 1496,
1453, 1360, 978, 859, 819, 746, 699 cm−1; MS (ESI) m/z 357 [M +
Na]+; HRMS (ESI-FT) Calculated for C23H23FNaO [M + Na]+
357.1631, found 357.1625.
anti-2-(1-Fluoroprop-1-enyl)-1-phenylnonan-1-ol (3o). Pre-
pared from 1b and benzaldehyde using general procedure A to afford
1
3o as a white solid (31.2 mg, 56%): mp 42−45 °C; H NMR (400
MHz, CDCl3, 293 K, TMS) δ ppm 7.36−7.24 (m, 5H), 4.71 (dq, J =
37.6 Hz, J = 13.6 Hz, J = 7.2 Hz, 1H), 4.56 (d, J = 8.8 Hz, 1H), 2.40−
2.27 (m, 1H), 2.08 (br, 1H), 1.65 (dd, J = 6.6 Hz, J = 2.0 Hz, 3H),
1.43−0.90 (m, 12H), 0.84 (t, J = 6.8 Hz, 3H); 19F NMR (282 MHz,
CDCl3) δ ppm −117.9 (dd, J = 32.4 Hz, J = 23.7 Hz, 0.11 F), −122.7
(dd, J = 37.5 Hz, J = 28.7 Hz, 0.89 F); 13C NMR (100.7 MHz, CDCl3,
293 K, TMS) δ ppm 158.3 (d, J = 255.2 Hz), 142.3, 128.4, 127.9,
126.9, 126.8, 104.0 (d, J = 15.3 Hz), 74.8, 51.6 (d, J = 24.1 Hz), 31.8,
29.2, 29.1, 27.6, 27.2, 22.6, 14.0, 8.8 (d, J = 6.6 Hz); IR (thin film) υmax
3445, 3026, 2926, 2857, 1708, 1607, 1455, 1305, 1043, 789, 761, 700
cm−1; MS (ESI) m/z 301 [M + Na]+; HRMS (ESI-FT) Calculated for
C18H27FNaO [M + Na]+ 301.1944, found 301.1938.
anti-2-Benzyl-3-fluoro-1-phenylpent-3-en-1-ol (3p). Prepared
from 1c and benzaldehyde using general procedure A to afford 3p as a
1
colorless oil (24.3 mg, 45%): H NMR (400 MHz, CDCl3, 293 K,
TMS) δ ppm 7.40−6.98 (m, 10H), 4.70 (d, J = 8.4 Hz, 1H), 4.44 (dq,
J = 38.2 Hz, J = 14.0 Hz, J = 7.2 Hz, 1H), 2.72−2.42 (m, 3H), 2.04 (br,
1H), 1.51 (dd, J = 6.8 Hz, J = 2.4 Hz, 3H); 19F NMR (282 MHz,
CDCl3) δ ppm −117.8 (dd, J = 31.3 Hz, J = 23.7 Hz, 0.14 F), −121.7
(dd, J = 37.5 Hz, J = 27.9 Hz, 0.86 F); 13C NMR (100.7 MHz, CDCl3,
293 K, TMS) δ ppm 157.1 (d, J = 253.0 Hz), 142.1, 139.5, 128.9,
128.6, 128.2, 126.9, 126.1, 105.0 (d, J = 16.0 Hz), 74.5, 54.1 (d, J =
24.0 Hz), 34.5, 8.8 (d, J = 7.3 Hz); IR (thin film) υmax 3565, 3445,
3085, 3062, 3028, 2923, 2865, 1708, 1603, 1494, 1454, 1386, 763, 700
cm−1; MS (ESI) m/z 293 [M + Na]+; HRMS (ESI-FT) Calculated for
C18H19FNaO [M + Na]+ 293.1318, found 293.1312.
Gerneral Procedure B for the Nickel-Catalyzed Coupling of
Electron-Deficient Aldehydes with α-Halo-β, β-difluoropro-
pene-Containing Compounds. To a solution of Ni(acac)2 (5.1 mg,
10 mol %), PCy2-Ph (11.0 mg, 20 mol %) in THF (2 mL) was added
(3-bromo-4,4-difluorohex-5-en-1-yl)benzene 1a (55.0 mg, 0.2 mol) in
THF (1 mL) and ZnEt2 (0.6 mL of 1.0 M hexane solution, 0.6 mmol).
The resulting mixture was stirred for an additional 1 h. Then 4-
(trifluoromethyl)benzaldehyde (69.6 mg, 0.4 mmol) and ZnEt2 (0.9
mL of 1.0 M hexane solution, 0.9 mmol) were added dropwise to the
resulting mixture. The reaction mixture was stirred at room
temperature for an additional 1.5 h. The reaction was quenched
with 2 mL of 1 M HCl. The organic layer was separated, and the
aqueous layer was extracted with Et2O (2 × 2 mL). The combined
organic extracts were washed with brine (5 mL) and then dried over
anhydrous sodium sulfate, filtered and concentrated in vacuo. The
residues were purified by column chromatography to give 3-fluoro-2-
phenethyl-1-(4-(trifluoromethyl)phenyl)pent-3-en-1-ol 3k.
anti-3-Fluoro-2-phenethyl-1-(4-(trifluoromethyl)phenyl)-
pent-3-en-1-ol (3k). Prepared from 1a and 4-(trifluoromethyl)-
benzaldehyde using general procedure B to afford 3k as a white solid
1
(40.2 mg, 57%): mp 57−59 °C; H NMR (400 MHz, CDCl3, 293 K,
TMS) δ ppm 7.58−6.98 (m, 9H), 5.45−4.64 (m, 2H), 2.82−2.29 (m,
3H), 2.20 (br, 1H), 1.91−1.71 (m, 1H), 1.68 (dd, J = 6.8 Hz, J = 2.4
Hz, 1.9H), 1.39 (dd, J = 7.0 Hz, J = 2.4 Hz, 1.1H), 1.49−1.31 (m, 1H);
19F NMR (282 MHz, CDCl3) δ ppm −62.0 (s, 8.4F), −117.3 (dd, J =
31.6 Hz, J = 23.7 Hz, 0.36 F), −122.0 (dd, J = 37.5 Hz, J = 27.6 Hz,
8702
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The Journal of Organic Chemistry
Article
0.64 F); 13C NMR (100.7 MHz, CDCl3, 293 K, TMS) δ ppm 157.5
(d, J = 245.7 Hz), 157.3 (d, J = 254.5 Hz), 146.1, 145.9, 141.3, 141.2,
130.2 (q, J = 32.8 Hz, J = 29.9 Hz), 128.4, 128.3, 127.3, 127.1, 126.1,
126.0, 125.4 (t, J = 3.0 Hz), 124.2 (t, J = 269.7 Hz), 105.6 (d, J = 23.4
Hz), 105.3 (d, J = 15.3 Hz), 74.7, 74.2, 50.8 (d, J = 24.1 Hz), 45.6 (d, J
= 24.8 Hz), 33.2, 33.1, 29.0, 28.9, 10.2 (d, J = 9.5 Hz), 8.9 (d, J = 6.5
Hz); IR (thin film) υmax 3444, 3063, 3028, 2928, 2867, 1705, 1620,
1603, 1496, 1454, 1420, 1327, 1125, 845, 748, 700 cm−1; MS (ESI) m/
z 375 [M + Na]+; HRMS (ESI-FT) Calculated for C20H20F4NaO [M
+ Na]+ 375.1348, found 375.1343.
2.4 Hz, 3H); 19F NMR (282 MHz, CDCl3) δ ppm −111.3 (dd, J =
37.5 Hz, J = 20.6 Hz); 13C NMR (100.7 MHz, CDCl3, 293 K, TMS) δ
ppm 195.9, 163.7, 157.5 (d, J = 255.9 Hz), 141.3, 130.9, 129.4, 128.6,
128.5, 126.1, 113.9, 103.1, 55.5, 48.9 (d, J = 25.5 Hz), 44.3, 31.2, 9.0
(d, J = 6.5 Hz); IR (thin film) υmax 3061, 3026, 2933, 2864, 1702,
1678, 1600, 1574, 1496, 1455, 1313, 1261, 1172, 841, 751, 700 cm−1;
MS (EI) m/z (%) 312 (M+), 193, 135 (100), 107, 77, 65, 47; HRMS
(EI-TOF) Calculated for C20H21FO2 312.1526, found 312.1526.
(E)-3-Fluoro-1-(4-methoxyphenyl)-2-phenethylpent-3-en-1-
one (4b). White solid; 5.6 mg, 6% yield: mp 84−86 °C.1H NMR (400
MHz, CDCl3, 293 K, TMS) δ ppm 7.85−6.88 (m, 9H), 5.22 (dq, J =
21.2, J = 14.3 Hz, J = 7.6 Hz, 1H), 4.21 (dq, J = 30.0 Hz, J = 8.4 Hz, J
= 6.0 Hz, 1H), 3.86 (s, 3H), 2.80−2.64 (m, 2H), 2.39−2.30 (m, 1H),
2.23−2.14 (m, 1H), 1.56 (dd, J = 7.4 Hz, J = 2.8 Hz, 3H); 19F NMR
Methyl 4-(anti-3-Fluoro-1-hydroxy-2-phenethylpent-3-
enyl)benzoate (3l). Prepared from 1a and methyl 4-formylbenzoate
using general procedure B to afford 3l as a colorless oil (37.0 mg,
1
54%): H NMR (400 MHz, CDCl3, 293 K, TMS) δ ppm 8.00−6.98
(282 MHz, CDCl3) δ ppm −110.1 (dd, J = 29.9 Hz, J = 21.2 Hz); 13
C
(m, 9H), 5.45−4.64 (m, 2H), 3.91 (s, 3H), 2.84−2.74 (m, 1H), 2.43−
2.26 (m, 2H), 2.19 (br, 1H), 1.91−1.72 (m, 1H), 1.68 (dd, J = 6.8 Hz,
J = 2.0 Hz, 2.4H), 1.40 (dd, J = 7.2 Hz, J = 2.0 Hz, 0.6H), 1.49−1.30
(m, 1H); 19F NMR (282 MHz, CDCl3) δ ppm −117.7 (dd, J = 31.0
Hz, J = 23.7 Hz, 0.22 F), −122.4 (dd, J = 37.1 Hz, J = 28.8 Hz, 0.78
F); 13C NMR (100.7 MHz, CDCl3, 293 K, TMS) δ ppm 157.7 (d, J =
244.2 Hz), 157.4 (d, J = 254.5 Hz), 147.3, 147.1, 147.1, 141.3, 141.2,
129.8, 129.7, 129.6, 128.4, 128.3, 126.9, 126.8, 126.0, 125.9, 105.5 (d, J
= 23.3 Hz), 105.1 (d, J = 15.3 Hz), 74.8, 74.3, 52.1, 50.9 (d, J = 24.0
Hz), 45.6 (d, J = 24.7 Hz), 33.2, 33.1, 29.1, 29.0, 10.3 (d, J = 10.2 Hz),
8.9 (d, J = 6.5 Hz); IR (thin film) υmax 3488, 3026, 2951, 2925, 2864,
1723, 1611, 1496, 1454, 1436, 1281, 801, 749, 700 cm−1; MS (ESI) m/
z 365 [M + Na]+; HRMS (ESI-FT) Calculated for C21H23FNaO3 [M
+ Na]+ 365.1529, found 365.1523.
NMR (100.7 MHz, CDCl3, 293 K, TMS) δ ppm 195.4, 163.8, 157.1
(d, J = 248.7 Hz), 141.3, 130.5, 129.3, 128.6, 128.5, 126.1, 113.8, 103.2
(d, J = 24.0 Hz), 55.5, 45.9 (d, J = 27.0), 33.2, 29.9, 10.4 (d, J = 9.5
Hz); IR (thin film) υmax 3026, 2926, 2850, 1680, 1600, 1510, 1496,
1455, 1419, 1314, 1260, 1171, 1030, 840, 746, 700 cm−1; MS (EI) m/z
(%) 312 (M+), 208, 135 (100), 107, 77, 65, 51; HRMS (EI-TOF)
Calculated for C20H21FO2 312.1526, found 312.1526.
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Copies of H NMR and 13C NMR spectra of all the new
compounds, and crystallographic data for compound 3a (CIF).
This material is available free of charge via the Internet at
http://pubs.acs.org.
(4-Fluorohexa-3,5-dienyl)benzene (2). To a solution of Ni-
(acac)2 (5.1 mg, 10 mol %), P(OiPr) (16.6 mg, 40 mol %) in THF (2
mL) was added (3-bromo-4,4-difluorohex-5-en-1-yl)benzene 1a (55.0
mg, 0.2 mol) in THF (1 mL) at room temperature under argon by
syringe. Then ZnEt2 (0.9 mL of 1.0 M hexane solution, 0.9 mmol) was
added dropwise to the resulting mixture. The reaction mixture was
stirred at room temperature for an additional 2 h. The reaction was
quenched with 2 mL of 1 M HCl. The organic layer was separated, and
the aqueous layer was extracted with Et2O (2 × 2 mL). The combined
organic extracts were washed with brine (5 mL) and then dried over
anhydrous sodium sulfate, filtered and concentrated in vacuo. The
residues were purified by column chromatography to give (4-
fluorohexa-3,5-dienyl)benzene 2 as a colorless oil (21.1 mg, 81%):
1H NMR (400 MHz, CDCl3, 293 K, TMS) δ ppm 7.28−7.20 (m, 5H),
6.14−5.97 (m, 1H), 5.44 (d, J = 17.1 Hz, 1H), 5.09 (d, J = 11.1 Hz,
1H), 4.80 (dt, J = 36.6 Hz, J = 6.6 Hz, 1H), 2.69 (d, J = 6.9 Hz, 2H),
2.49 (d, J = 6.9 Hz, 2H); 19F NMR (282 MHz, CDCl3) δ ppm −120.1
(dd, J = 27.4 Hz, J = 20.6 Hz, 0.08F), −125.5 (dd, J = 36.1 Hz, J = 26.8
Hz, 0.92F); 13C NMR (100.7 MHz, CDCl3, 293 K, TMS) δ ppm
156.7 (d, J = 247.9 Hz), 141.5, 129.0 (d, J = 26.2 Hz), 128.5, 128.4,
126.0, 113.6 (d, J = 4.3 Hz), 110.0 (d, J = 16.0 Hz), 35.4 (d, J = 1.4
Hz), 25.8 (d, J = 4.4 Hz); IR (thin film) υmax 3085, 3062, 2926, 2858,
1675, 1604, 1495, 1453, 1316, 981, 913, 746, 698 cm−1; MS (EI) m/z
(%) 176 (M+), 104, 91 (100), 85, 77, 65, 51, 41; HRMS (EI-TOF)
Calculated for C12H13F 176.1001, found 176.1001.
AUTHOR INFORMATION
Corresponding Author
*E-mail: flq@mail.sioc.ac.cn.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
National Natural Science Foundation of China (21072028,
20832008) and National Basic Research Program of China
(2012CB21600) are greatly acknowledged for funding this
work.
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