One-pot cross-enyne metathesis (CEYM)-Diels-Alder reaction of gem-difluoropropargylic alkynes

Article abstract of DOI:10.3762/bjoc.9.305

Propargylic difluorides 1 were used as starting substrates in a combination of cross-enyne metathesis and Diels-Alder reactions. Thus, the reaction of 1 with ethylene in the presence of 2^nd generation Hoveyda-Grubbs catalyst generates a diene moiety which in situ reacts with a wide variety of dienophiles giving rise to a small family of new fluorinated carbo- and heterocyclic derivatives in moderate to good yields. This is a complementary protocol to the one previously described by our research group, which involved the use of 1,7-octadiene as an internal source of ethylene.

Full text of DOI:10.3762/bjoc.9.305

One-pot cross-enyne metathesis (CEYM)–Diels–Alder
reaction of gem-difluoropropargylic alkynes
Santos Fustero*1,2, Paula Bello1, Javier Miró1, María Sánchez-Roselló1,2,
Günter Haufe3 and Carlos del Pozo*1
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2013, 9, 2688–2695.
1Departamento de Química Orgánica, Universidad de Valencia,
E-46100 Burjassot, Spain, 2Laboratorio de Moléculas Orgánicas,
Centro de Investigación Príncipe Felipe, E-46012 Valencia, Spain and
3Organisch-Chemisches Institut, Westfälische Wilhelms-Universität,
Corrensstraße 40, D-48149 Münster, Germany
doi:10.3762/bjoc.9.305
Received: 01 September 2013
Accepted: 06 November 2013
Published: 28 November 2013
Email:
This article is part of the Thematic Series "Organo-fluorine chemistry III".
Guest Editor: D. O'Hagan
Santos Fustero* - santos.fustero@uv.es; Carlos del Pozo* -
carlos.pozo@uv.es
* Corresponding author
© 2013 Fustero et al; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
cross metathesis; Diels–Alder; one-pot reaction; organo-fluorine;
propargylic difluorides
Abstract
Propargylic difluorides 1 were used as starting substrates in a combination of cross-enyne metathesis and Diels–Alder reactions.
Thus, the reaction of 1 with ethylene in the presence of 2nd generation Hoveyda–Grubbs catalyst generates a diene moiety which in
situ reacts with a wide variety of dienophiles giving rise to a small family of new fluorinated carbo- and heterocyclic derivatives in
moderate to good yields. This is a complementary protocol to the one previously described by our research group, which involved
the use of 1,7-octadiene as an internal source of ethylene.
Introduction
In recent years the number of applications of olefin metathesis Furthermore, a sequential use of EYM and Diels–Alder reac-
as a mild and competitive synthetic method for the creation of tions generates highly functionalized carbo- and heterocyclic
carbon–carbon bonds has exponentially increased, due to the frameworks [7-11].
availability of well-defined catalysts [1-3]. Particularly, enyne
metathesis (EYM) is a powerful synthetic tool for generating The intramolecular version of this process, the ring closing
1,3-dienes by redistributing unsaturated functionalities between enyne metathesis (RCEYM) reaction, has found wide applica-
an alkene and an alkyne moiety via vinylalkylidene intermedi- tion, and several examples can be found in the literature
ates [4-6]. This is an atom economical process since it is an [12,13]. However, the intermolecular version, i.e. the cross-
addition reaction and non-olefin byproducts are formed. enyne metathesis (CEYM) reaction, has been much less
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exploited probably due to its inherent problems of selectivity,
which results in the formation of a mixture of E- and Z-isomers
[14]. The discovery of the beneficial effect of ethylene has
changed this tendency allowing the straightforward preparation
of 1,3-dienes [15,16]. Thus, during the ethylene gas promoted
CEYM reaction, ethylene does not incorporate into the product
but intercepts the secondary metathesis pathways avoiding the
formation of secondary products during the process [17,18].
Among organic fluorine compounds, propargylic fluorides
constitute a relevant class of fluorinated building blocks. The
transformational diversity of the alkynyl group converts them
into versatile synthetic intermediates. Additionally, propargylic
fluorides are prevalent motifs in life sciences, such as medic-
inal chemistry or crop protection. In this context, the prepar-
ation of monofluorinated propargylic compounds has been the
subject of intense research, and efficient methodologies to
access these derivatives have been devised [19,20]. However,
the analogues bearing the gem-difluoro moiety next to unsatu-
rated bonds have not received comparable attention, probably
Scheme 1: Sequential CEYM–Diels–Alder reaction.
due to the limited availability of the starting materials. In this observed. This newly formed diene was isolated in 70% yield
context, the recent introduction of difluoropropargyl bromide as and it reacted smoothly with 4-phenyl-3H-1,2,4-triazole-
fluorinated building block gave access to a wide variety of gem- 3,5(4H)-dione as dienophile at room temperature to afford, after
difluoro-containing alkyne derivatives [21,22]. Recently, we chromatographic purification, the corresponding Diels–Alder
have employed these fluorinated triple bond scaffolds in adduct 3a in 60% yield (Scheme 2). It was interesting to find
several types of cyclization reactions for the preparation of that this sequence can be performed as a one-pot procedure.
different difluoropropargylamides and ketones, having been Thus, when the formation of the diene intermediate 2a was
subjected to intramolecular hydroaminations [23], cascade completed (determined by TLC), the dienophile was added to
RCEYM–Diels–Alder reactions [24], [2 + 2 + 2] cycloaddi- the reaction mixture and was allowed to react for two addition-
tions and gold-mediated dimerization reactions [25].
al hours. Flash chromatography of the crude product afforded
the desired tandem derivative 3a in 60% overall yield
Although the CEYM reaction has been found to be very fruitful (Scheme 2).
for the preparation of 1,3-dienes, this protocol has remained
almost unexplored for propargyl fluorides [26]. In this context, Next, the one-pot protocol was extended to other starting difluo-
we have recently established a tandem multicomponent protocol ropropargylic alkynes and dienophiles, affording a new family
CEYM–Diels–Alder reaction of several difluoropropargylic of carbo- and heterocyclic derivatives in moderate to good
derivatives [27,28] mediated by 1,7-octadiene as an internal yields (Table 1).
source of ethylene [29]. Following our ongoing interest in the
use of these fluorinated building blocks, we decided to evaluate A wide variety of nucleophiles is compatible with the one-pot
the CEYM reaction of several difluoropropargylamides and protocol (Table 1, method A, entries 1–6). Ethyl fumarate gave
ketones in combination with a Diels–Alder reaction under the desired product 3b in 55% yield (Table 1, method A, entry
Mori´s conditions, in order to compare this protocol with the 2). It is interesting to point out that diethyl acetylenedicarboxy-
aforementioned one (Scheme 1).
late (DEAD) afforded adduct 3c in 51% yield, and no aromati-
zation was observed during the process (Table 1, method A,
entry 3). When maleic anhydride was used as dienophile, the
Results and Discussion
In order to prove the efficiency of ethylene-mediated cross- corresponding diacid 3f, arising from the anhydride ring
enyne metathesis on our fluorinated alkynes, substrate 1a was opening under the reaction conditions, was observed as the
chosen as a model substrate. As expected, when a toluene solu- major product (Table 1, method A, entries 6 and 9). With chiral
tion of alkyne 1a and 5 mol % of 2nd generation starting material 1b, in all cases a 1:1 mixture of diastereoiso-
Hoveyda–Grubbs catalyst I was heated under ethylene atmos- mers was obtained which could not be separated. This indicates
phere (1 atm) for 2 h, the clean formation of diene 2a was that the chiral information is not close enough to the reacting
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Scheme 2: One-pot CM–Diels–Alder reaction with fluorinated alkyne 1a.
Table 1: Preparation of compounds 3 by one-pot CEYM–Diels–Alder reaction of substrates 1 (method A).
entry
1
R1
dienophile
product
% yield
method Aa
(time, h)
% yield
method Bb
(time, h)
1
1a
Bn–NH
60 (2 h)c
–
3a
3b
3c
2
3
1a
1a
Bn–NH
Bn–NH
55 (8 h)
51 (6 h)
70 (20 h)
55 (6 h)
4
1a
Bn–NH
50 (4 h)
63 (24 h)
3d
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Table 1: Preparation of compounds 3 by one-pot CEYM–Diels–Alder reaction of substrates 1 (method A). (continued)
5
6
1a
1a
Bn–NH
Bn–NH
47 (24 h)
50 (24 h)
3e
3f
85 (120 h)c
–
3g
+
7
1b (R)-Ph(Me)–CHNH
87 (4 h)d
73 (24 h)d
3g’
3h
+
8
1b (R)-Ph(Me)–CHNH
74 (2 h)d
70 (10 h)d
3h’
3i
+
9
1b (R)-Ph(Me)–CHNH
74 (20 h)c,d
–
3i’
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Table 1: Preparation of compounds 3 by one-pot CEYM–Diels–Alder reaction of substrates 1 (method A). (continued)
10
1b (R)-Ph(Me)–CHNH
63 (10 h)
60 (24 h)
3j
11
12
13
14
1c
1d
1d
1d
PropylNH
40 (5 h)
48 (4 h)
28 (8 h)
58 (12 h)
–
3k
3l
Ph
Ph
Ph
55 (15 h)
–
3m
3n
70 (17 h)
15
1e
Cy
54 (12 h)
–
3o
aMethod A: One-pot protocol with Mori´s conditions. The formation of the corresponding diene 2 with ethylene was complete after 2 h at 90 °C for all
substrates. bMethod B: Tandem multicomponent protocol mediated by 1,7-octadiene [29]. cWhen maleic anhydride or 4-phenyl-3H-1,2,4-triazole-
3,5(4H)-dione were used as dienophiles, the Diels–Alder reaction was performed at rt. With maleic anhydride final products were isolated as the
corresponding diacid derivatives. dIn all cases, adducts were obtained as an inseparable 1:1 mixture of diastereoisomers.
centre (Table 1, method A, entries 7–10). Finally, fluorinated and heterocyclic derivatives bearing a gem-difluoro moiety in
ketones could also be used as substrates for the sequential an efficient manner. However, at this point it is important to
process (Table 1, method A, entries 12–15) and again with mention that when the 1,7-octadiene protocol was applied using
alkynes as dienophiles, no aromatization of the final products maleic anhydride or 4-phenyl-3H-1,2,4-triazole-3,5(4H)-dione
was detected (Table 1, method A, entry 12).
as dienophiles (Table 1, method B, entries 1, 6 and 9), a com-
plex mixture was obtained. This is probably due to the fact that
The yields that appear in Table 1 in the last column (method B) under those thermal conditions, it is not possible to use these
represent the reaction performed under the tandem-multicompo- types of dienophiles since they decompose while being heated.
nent conditions mediated by 1,7-octadiene (Scheme 1). In The sequential generation of the dienic intermediate 2 and the
general, yields are comparable using either methodology, indi- Diels–Alder reaction allow performing the second step at rt,
cating that they are applicable for the synthesis of new carbo- avoiding these problems. Thus, although a tandem-multicompo-
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Beilstein J. Org. Chem. 2013, 9, 2688–2695.
nent protocol is more desirable, the use of the one-pot protocol raphy affording 41 mg of 2a (70% yield) as a yellow oil starting
expand the utility and scope of this methodology, since milder from 52 mg of 1a. 1H NMR (CDCl3, 300 MHz) δ 4.52 (d, J =
conditions can be employed in the cyclization step.
5.8 Hz, 2H), 5.25 (d, J = 11.3 Hz, 1H), 5.52 (d, J = 17.9 Hz,
1H), 5.64 (d, J = 15.9 Hz, 2H), 6.32 (dd, J1 = 11.3 Hz, J2 = 17.7
Hz, 1H), 6.65 (br s, 1H), 7.26–7.39 (m, 5H); 13C NMR (CDCl3,
Conclusion
In conclusion, a tandem one-pot enyne-cross metathesis- 300 MHz) δ 43.61, 114.40 (t, 1JCF = 253.2 Hz), 118.17, 119.33
Diels–Alder reaction of difluoropropargylic alkynes with a (t, 3JCF = 8.6 Hz), 127.81, 127.93, 128.84, 131.02 (t, 3JCF = 2.3
variety of dienophiles has been described. The process took Hz), 136.75, 138.82 (t, 2JCF = 22.3 Hz), 163.23 (t, 2JCF = 29.9
place in moderate to good yields, giving rise to a new family of Hz); 19F NMR (CDCl3, 282 MHz) δ −105.57 (s, 2F); HRMS:
fluorinated carbo- and heterocyclic derivatives in a very simple [M + 1]+ calcd for C13H14F2NO, 238.1038; found, 238.1042.
manner. In comparison with the tandem multicomponent
protocol, the one-pot sequence is a complementary method- N-Benzyl-2-(1,3-dioxo-2-phenyl-2,3,5,8-tetrahydro-1H-
ology, since although comparable yields of the final adducts can [1,2,4]triazolo[1,2a]pyridazin-6-yl)-2,2-difluoroacetamide
be obtained, this methodology is compatible with a greater (3a). Following the general procedure described above, 61 mg
variety of dienophiles.
of 3a (60% yield) were obtained as a white solid starting from
52 mg of 1a. mp = 148–150 °C; 1H NMR (CDCl3, 300 MHz) δ
4.26–4.29 (m, 2H), 4.34 (s, 2H), 4.5 (d, J = 5.7 Hz, 2H), 6.46
Experimental
General experimental methods. Reactions were carried out (m, 1H), 6.86 (br s, 1H), 7.16–7.53 (m, 10H); 13C NMR
under argon atmosphere unless otherwise indicated. The (CDCl3, 300 MHz) δ 41.8 (t, 3JCF = 4 Hz), 43.1, 43.8, 113.3 (t,
solvents were purified prior to use: THF, diethyl ether and 1JCF = 253.8 Hz), 123.7 (t, 3JCF = 8.7 Hz), 125.4, 126.8 (t, 2JCF
toluene were distilled from sodium/benzophenone; = 25.2 Hz), 127.9, 128.2, 128.4, 129.0, 129.2, 130.8, 136.3,
dichloromethane and acetonitrile were distilled from calcium 152.3, 152.4, 162.2 (t, 2JCF = 29.9 Hz); 19F NMR (CDCl3, 282
hydride. The reactions were monitored with the aid of thin-layer MHz) δ −106.9 (s, 2F); HRMS: [M]+ calcd for C21H18F2N4O3,
chromatography (TLC) on 0.25 mm precoated silica gel plates. 412.1347; found, 412.1344.
Visualization was carried out with UV light and aqueous ceric
ammonium molybdate solution or potassium permanganate Diethyl 4-(2-(benzylamino)-1,1-difluoro-2-oxoethyl)cyclo-
stain. Flash column chromatography was performed with hex-4-ene-1,2-dicarboxylate (3b). Following the general
the indicated solvents on silica gel 60 (particle size procedure described above, 30 mg (55% yield) of 3b were
0.040–0.063 mm). 1H and 13C NMR spectra were recorded on obtained as a white solid starting from 26 mg of 1a.
300 or 400 MHz spectrometers. Chemical shifts are given in
ppm (δ), with reference to the residual proton resonances of the Diethyl 4-(2-(benzylamino)-1,1-difluoro-2-oxoethyl)cyclo-
solvents. Coupling constants (J) are given in Hertz (Hz). The hexa-1,4-diene-1,2-dicarboxylate (3c). Following the general
letters m, s, d, t, and q stand for multiplet, singlet, doublet, procedure described above, 52 mg (51% yield) of 3c were
triplet and quartet, respectively. The letters br indicate that the obtained as a dark brown oil starting from 52 mg of 1a.
signal is broad. Starting fluorinated amides 1 [23-25] and com-
pounds 3b,c,e,g,h,j,l,n [29] were previously described.
N-Benzyl-2-(1,3-dioxo-2-phenyl-2,3,3a,4,7,7a-hexahydro-
1H-isoindol-5-yl)-2,2-difluoroacetamide (3d). Following the
General procedure for the one-pot process. Ethylene was general procedure described above, 25 mg of 3d (50% yield)
bubbled through a solution of catalyst I (5 mol %) in dry were obtained as a dark brown oil starting from 26 mg of 1a. 1H
toluene (2.4 mL) for 3 minutes at room temperature in a sealed NMR (CDCl3, 300 MHz) δ 2.32–2.47 (m, 2H), 2.82–2.93 (m,
tube. Substrate 1 (0.12–0.25 mmol) was added next and it was 2H), 3.27–3.38 (m, 2H), 4.46 (d, J = 5.7 Hz, 2H), 6.49–6.55 (m,
heated at 90 °C for 2 hours. Once the intermediate diene was 1H), 6.68 (br s, 1H), 7.27–7.47 (m, 10H); 13C NMR (CDCl3,
formed (by TLC), it was cooled to room temperature and the 300 MHz) δ 22.8, 23.9, 38.7, 39.1, 43.7, 114.2 (t, 1JCF = 251.0
corresponding dienophile was added. The reaction mixture was Hz), 126.5, 127.9, 128.0, 128.7, 128.9, 129.1, 129.9 (t, 3JCF =
stirred at temperatures and times given in Table 1. Finally, after 8.9 Hz), 131.8, 131.9 (t, 2JCF = 24.4 Hz), 136.6, 162.8 (t, 2JCF =
removal of solvents, the reaction mixture was purified by flash 30.1 Hz), 177.7, 178.1; 19F NMR (CDCl3, 282 MHz) δ −106.5
chromatography in hexanes/ethyl acetate (3:1).
(d, JFF = 258.1 Hz, 1F), −108.7 (d, JFF = 258.4 Hz, 1F); HRMS:
[M]+ calcd for C23H20F2N2O3, 410.1442; found, 410.1445.
N-Benzyl-2,2-difluoro-3-methylenepent-4-enamide (2a).
Following the procedure described above and before adding the N-Benzyl-2-(9,10-dioxo-1,4,4a,9,9a,10-hexahydroanthracen-
dienophile, the crude mixture was subjected to flash chromatog- 2-yl)-2,2-difluoroacetamide (3e). Following the general proce-
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Beilstein J. Org. Chem. 2013, 9, 2688–2695.
dure described above, 24 mg of 3e (47% yield) were obtained as Diethyl 4-[1,1-difluoro-2-oxo-2-(propylamino)ethyl]cyclo-
a dark brown oil starting from 26 mg of 1a.
hex-4-ene-1,2-dicarboxylate (3k). Following the general
procedure described above, 27 mg of 3k (40% yield) were
4-[2-(Benzylamino)-1,1-difluoro-2-oxoethyl]cyclohex-4-ene- obtained as a dark brown oil starting from 30 mg of 1c. 1H
1,2-dicarboxylic acid (3f). Following the general procedure NMR (CDCl3, 300 MHz) δ 0.93 (t, J = 7.5 Hz, 3H), 1.23 (t, J =
described above, 71 mg of 3f (85% yield) were obtained as a 6.9 Hz, 3H), 1.24 (t, J = 7.2 Hz, 3H), 1.57 (m, 2H), 2.22–2.37
dark brown oil starting from 52 mg of 1a. 1H NMR (CDCl3, (m, 2H), 2.50–2.62 (m, 2H), 2.86 (m, 2H), 3.27 (q, J = 6.0 Hz,
300 MHz) δ 2.46–2.52 (m, 2H), 2.68–2.75 (m, 2H), 3.07 (m, 2H), 4.13 (q, J = 6.9 Hz, 4H), 6.18–6.20 (br m, 1H); 13C NMR
1H), 3.17 (m, 1H), 4.47 (d, J = 5.7 Hz, 2H), 6.21 (s, 1H), (300 MHz) δ 11.2, 14.0, 22.4, 25.0 (t, 4JCF = 2.3 Hz), 27.3,
6.80–6.84 (m, J = 5.4 Hz, 1H), 7.25–7.37 (m, 5H), 7.77 (br s, 40.4, 40.6, 41.2, 60.8, 60.9, 114.7 (t, 1JCF = 250.9 Hz), 127.6 (t,
2H); 13C NMR (CDCl3, 300 MHz) δ 23.1, 25.0, 38.5, 38.9, 3JCF = 8.6 Hz), 129.0 (t, 2JCF = 24.1 Hz), 163.2 (t, 2JCF = 30.2
43.6, 114.8 (t, 1JCF = 251.1 Hz), 127.8, 127.9, 128.8, 136.6, Hz), 173.7, 173,9; 19F NMR (CDCl3, 282 MHz) δ −106.8 (d,
163.6 (t, 2JCF = 30.6 Hz), 178.3, 178.5; 19F NMR (CDCl3, 282 JFF = 257.8 Hz, 1F), −107.9 (d, JFF = 258.4 Hz, 1F); HRMS:
MHz) δ −117.0 (d, JFF = 258.9 Hz, 1F), −118.0 (d, JFF = 258.7 [M + 1]+ calcd for C17H26F2NO5, 362.1774; found, 362.1779.
Hz, 1F); HRMS: [M + Na]+ calcd for C17H17F2NO5, 376.0972;
found, 376.0969.
Diethyl 4-(1,1-difluoro-2-oxo-2-phenylethyl)cyclohexa-1,4-
diene-1,2-dicarboxylate (3l). Following the general pro-
Diethyl 4-(1,1-difluoro-2-oxo-2-[(R)-1-phenylethyl- cedures described above, 20 mg (48% yield) of 3l were
amino)ethyl]cyclohex-4-ene-1,2-dicarboxylate (3g + 3g’). obtained as a dark brown oil starting from 20 mg of 1d.
Following the general procedure described above, 41 mg (87%
yield) of a inseparable mixture of 3g and 3g’ were obtained as a 5-(1,1-Difluoro-2-oxo-2-phenylethyl)-2-phenyl-3a,4,7,7a-
dark brown oil starting from 25 mg of 1b.
tetrahydro-1H-isoindole-1,3(2H)-dione (3m). Following the
general procedure described above, 15 mg of 3m (28% yield)
2-(1,3-Dioxo-2-phenyl-2,3,3a,4,7,7a-hexahydro-1H-isoindol- were obtained as a dark brown oil starting from 25 mg of 1d.
5-yl)-2,2-difluoro-N-[(R)-1-phenylethyl]acetamide 1H NMR (CDCl3, 300 MHz) δ 2.26–2.41 (m, 2H), 2.73–2.84
(3h + 3h’). Following the general procedure described above, (m, 2H), 3.18–3.30 (m, 2H), 6.33–6.38 (m, 1H), 7.09–7.14 (m,
34 mg (74% yield) of a inseparable mixture of 3h and 3H), 7.23–7.35 (m, 5H), 7.47–7.52 (m, 1H), 7.91–7.94 (m, 2H);
3h’ were obtained as a dark brown solid starting from 25 mg of 13C NMR (CDCl3, 300 MHz) δ 23.2 (t, 3JCF = 2.6 Hz), 23.8,
1b.
38.8, 39.0, 116.2 (t, 1JCF = 253.0 Hz), 126.4, 128.6, 128.7,
129.1, 129.7 (t, 3JCF = 8.9 Hz), 130.2 (t, 4JCF = 3.0 Hz), 131.8,
4-[1,1-difluoro-2-oxo-2-((R)-1-phenylethylamino)- 133.2 (t, 2JCF = 23.9 Hz), 134.4, 177.7, 178.2, 188.3 (t, 2JCF =
ethyl]cyclohexa-4-ene-1,2-dicarboxylate (3i + 3i’). Following 32.1 Hz); 19F NMR (CDCl3, 282 MHz) δ −112.367 (d, JFF =
the general procedure described above, 24.3 mg of an insepa- 284.6 Hz, 1F), −111.2 (d, JFF = 284.4 Hz, 1F); HRMS: [M +
rable mixture of 3i and 3i’ were obtained as a dark brown oil 1]+ calcd for C22H18F2NO3, 382.1255; found, 382.1258.
starting from 25 mg of 1b. 1H NMR (CDCl3, 300 MHz) δ1.53
(dd, J = 6.9 Hz, J = 4.8 Hz, 3H), 2.46–2.51 (m, 2H), 2.67–2.74 Diethyl 4-[1,1-difluoro-2-oxo-2-(phenylamino)-
(m, 2H), 3.02–3.07 (m, 1H), 3.15–3.17 (m, 1H), 5.08–5.17 (m, ethyl]cyclohex-4-ene-1,2-dicarboxylate (3n). Following the
1H), 6.17 (d, J = 13.5 Hz, 1H), 6.63–6.68 (br m, 1H), 7.28–7.38 general procedure described above, 24.5 mg (58% yield) of 3n
(m, 5H); 13C NMR (CDCl3, 300 MHz) δ 21.2, 23.4, 25.2, 49.2, were obtained as a yellow oil starting from 20 mg of 1d.
114.7 (t, 1JCF = 255.0 Hz), 126.1, 127.7, 128.7, 141.7, 162.5 (t,
2JCF = 30.7 Hz), 177.6, 177.9; 19F NMR (CDCl3, 282 MHz) δ Diethyl 4-(2-cyclohexyl-1,1-difluoro-2-oxoethyl)cyclohexa-
−106.6 (d, JFF = 258.9 Hz, 1F), −106.8 (d, JFF = 256.4Hz, 1F), 1,4-diene-1,2-dicarboxylate (3o). Following the general proce-
−107.8 (d, JFF = 255.6 Hz, 1F), −107.9 (d, JFF = 257.5 Hz, 1F); dure described above, 28 mg of 3o (54% yield) were obtained
HRMS: [M + Na]+ calcd for C18H19F2NO5, 390.1129; found, as a dark oil starting from 25 mg of 1e. 1H NMR (CDCl3, 300
390.1133.
MHz) δ 1.11–1.41 (m, 5H), 1.63–1.84 (m, 5H), 2.30–2.46 (m,
5H), 2.71–2.92 (m, 3H), 3.26–3.36 (m, 2H), 6.37–6.41 (m, 1H),
(R)-Diethyl 4-[1,1-difluoro-2-oxo-2-(1-phenylethyl- 7.25–7.29 (m, 2H), 7.35–7.49 (m, 3H); 13C NMR (300 MHz) δ
amino)ethyl]cyclohexa-1,4-diene-1,2-dicarboxylate (3j). 30.0 (t, 4JCF = 2.7 Hz), 23.8, 25.3, 25.4, 28.3, 38.7, 45.1, 115.1
Following the general procedure described above, 59.5 mg (t, 1JCF = 253.7 Hz), 126.4, 128.6, 129.1, 129.5 (t, 3JCF = 9.1
(63% yield) of 3j were obtained as a dark brown oil starting Hz), 132.2 (t, 2JCF = 24.2 Hz), 177.7, 178.2, 202.7 (t, 2JCF =
from 50 mg of 1b [29].
31.7 Hz); 19F NMR (CDCl3, 282 MHz) δ −109.9 (d, JFF =
2694

Beilstein J. Org. Chem. 2013, 9, 2688–2695.
23.Fustero, S.; Fernández, B.; Bello, P.; del Pozo, C.; Arimitsu, S.;
Hammond, G. B. Org. Lett. 2007, 9, 4251. doi:10.1021/ol701811z
24.Arimitsu, S.; Fernández, B.; del Pozo, C.; Fustero, S.; Hammond, G. B.
J. Org. Chem. 2008, 73, 2656. doi:10.1021/jo7025965
25.Fustero, S.; Bello, P.; Fernández, B.; del Pozo, C.; Hammond, G. B.
J. Org. Chem. 2009, 74, 7690. doi:10.1021/jo9013436
26.Pujari, S. A.; Kaliappan, K. P.; Valleix, A.; Grée, D.; Grée, R. Synlett
2008, 2503. doi:10.1055/s-2008-1078179
276.7 Hz, 1F), −106.0 (d, JFF = 276.7 Hz, 1F); HRMS: [M]+
calcd for C22H23F2NO3, 387.1646; found, 387.1656.
Acknowledgements
We would like to thank MICINN (CTQ2010-19774) of Spain
and Generalitat Valenciana (PROMETEO/2010/061) for their
financial support. P.B. and J.M. express their thanks to the
University of Valencia for a predoctoral fellowship.
As far as we know, only one example of CEYM involving fluorinated
alkynes have been reported.
27.Qing, F.-L.; Zheng, F. Synlett 2011, 1052. doi:10.1055/s-0030-1259947
See for a recent review that highlights the importance of gem-difluoro
moiety-containing derivatives.
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