1,7-octadiene-assisted tandem multicomponent cross-enyne metathesis (CEYM)-diels-alder reactions: A useful alternative to Mori's conditions

Article abstract of DOI:10.1002/chem.201200835

The use of 1,7-octadiene as an in situ source of ethylene led us to develop a novel multicomponent tandem cross-enyne metathesis (CEYM)-Diels-Alder reaction. The process can be considered a relay metathesis, in which the ethylene liberated in the ring-closing metathesis (RCM) of 1,7-octadiene initiates the tandem sequence. Aliphatic, aromatic, and fluorinated alkynes and several dienophiles are compatible with the process, which is particularly efficient with aromatic alkynes. This methodology constitutes a useful variant of Mori's conditions in CEYM-related reactions. El empleo de 1,7-octadieno como una fuente in situ de etileno nos ha permitido desarrollar un nuevo proceso tandem multicomponente metatesis cruzada de enino-reaccion de Diels-Alder. El proceso puede considerarse como una metatesis por relevos, donde el etileno liberado en la metatesis con cierre de anillo del 1,7-octadieno inicia la secuencia tandem. Alquinos alifaticos, aromaticos y fluorados y varios dienofilos son compatibles con el proceso, que es particularmente eficiente con alquinos aromaticos. Esta metodologia constituye una variante stil de las condiciones desarrolladas por Mori en reacciones de metatesis cruzada de eninos. Ruthenium catalysis: A new, multicomponent, tandem cross-enyne metathesis (CEYM)-Diels-Alder reaction that is mediated by 1,7-octadiene is described. The ethylene liberated in the ring-closing metathesis of this diene initiates the enyne metathesis and, in the presence of a dienophile, the tandem process takes place in an efficient manner (see scheme). Copyright

Full text of DOI:10.1002/chem.201200835

FULL PAPER
DOI: 10.1002/chem.201200835
1,7-Octadiene-Assisted Tandem Multicomponent Cross-Enyne Metathesis
(CEYM)-Diels–Alder Reactions: A Useful Alternative to Moriꢀs Conditions
Santos Fustero,* Paula Bello, Javier Mirꢁ, Antonio Simꢁn, and Carlos del Pozo*[a]
Abstract: The use of 1,7-octadiene as an in situ source of ethylene led us to devel-
op a novel multicomponent tandem cross-enyne metathesis (CEYM)-Diels–Alder
reaction. The process can be considered a relay metathesis, in which the ethylene
liberated in the ring-closing metathesis (RCM) of 1,7-octadiene initiates the
tandem sequence. Aliphatic, aromatic, and fluorinated alkynes and several dieno-
philes are compatible with the process, which is particularly efficient with aromatic
alkynes. This methodology constitutes a useful variant of Moriꢀs conditions in
CEYM-related reactions.
Keywords: cross
metathesis
·
Diels–Alder reactions · multicom-
ponent reactions · octadienes · tan-
dem reactions
Introduction
the molecular complexity with minimal added cost or
waste.[10]
Metathesis has become one of the most powerful tools for
the creation of carbon–carbon bonds.[1] With the advent of
stable ruthenium catalysts, metathesis processes have
become the transformation of choice for the creation of a
wide variety of carbo- and heterocycles.[2] Among them,
enyne metathesis (EYM) is a singular process as a new func-
tionality in the product that is different from that of the
starting materials is generated.[3] This reorganization of an
alkene and alkyne to produce a 1,3-diene was first reported
in 1985.[4] However, its development has lagged behind its
diene counterpart, probably due to the less predictable
nature of its regio- and stereoselectivity.[5]
In this context, during the course of an on-going project
in our laboratory aimed at the development of a new
CEYM-Diels–Alder protocol, we discovered that the ethyl-
ene generated in the RCM of 1,7-octadiene can serve as an
in situ source of ethylene and initiates the aforementioned
sequence. This serendipitous finding led us to develop a
multicomponent cascade reaction that allows for the synthe-
sis of new carbo- and heterocyclic derivatives in a tandem
protocol. This methodology was further extended to fluori-
nated alkynes (Scheme 1).
EYM has been used in both intra- (ring-closing enyne
metathesis, RCEYM) and intermolecular (cross-enyne
metathesis, CEYM) applications. Whereas examples of
RCEYM are well-documented in the literature,[6] the inter-
molecular CEYM has seen fewer applications because of its
greater difficulty (the first example of CEYM was reported
in early 1997).[7] The discovery of the beneficial effect of
ethylene by Mori et al. has changed this tendency, allowing
for the preparation of 1,3-dienes[8] suitable for either inter-
or intramolecular Diels–Alder reactions in a sequential or
tandem manner.[9] This metathesis cascade chemistry is a
powerful tool for the synthesis of skeletally diverse small
molecules, converting the diene created through enyne
metathesis into other useful functionalities and increasing
Scheme 1. 1,7-Octadiene promoted tandem multicomponent CEYM-
Diels–Alder reaction.
Results and Discussion
Our initial idea was the development of a new triple tandem
protocol: a combination of a CEYM/CM/Diels–Alder reac-
tion.[11] Thus, CEYM of an alkyne and an 1,n-diene would
render a new 1,3-diene functionality bearing an additional
double bond suitable for a subsequent CM reaction that
would convert this olefin into a good dienophile for an in-
tramolecular Diels–Alder reaction (Scheme 2, pathway A).
To this end, phenyl acetylene 1a was chosen as a model sub-
strate and was subjected to the tandem protocol by treat-
ment with ruthenium catalyst I (5 mol%) in the presence of
[a] Prof. Dr. S. Fustero, P. Bello, J. Mirꢁ, Prof. Dr. A. Simꢁn,
Prof. Dr. C. del Pozo
Departamento de Quꢂmica Orgꢃnica
Universidad de Valencia
46100-Burjassot, Valencia (Spain)
Fax : (+34)963-544-939
E-mail: santos.fustero@uv.es
carlos.pozo@uv.es
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fashion, generating a new carbene that in turn would react
with the previously formed ethylene to afford intermediate
diene 2a. Under the reaction conditions, in the presence of
ethyl acrylate, diene 2a would be trapped in a Diels–Alder
fashion to afford regioisomers 3a and 3a’. This would be
similar to a relay metathesis process,[12] in which the remote
initiating site is used to release both the ruthenium carbene
as the active catalyst and the ethylene for the subsequent
CEYM by extruding cyclohexene. The overall process con-
stitutes a novel tandem multicomponent CEYM-Diels–
Alder reaction and, therefore, we decided to evaluate this
protocol in more detail.
In the first step of our study we evaluated the formation
of 1,3-diene 2a in the presence of 1,7-octadiene. Thus, when
phenylacetylene 1a was heated with 1,7-octadiene as the in-
ternal source of ethylene in the presence of ruthenium cata-
lyst I in toluene at 908C, complete formation of the diene
was observed after two hours (determined by TLC analysis).
Under these conditions, diene 2a was isolated in 98% yield
after flash chromatography (Scheme 3).
With these data in hand we decided to identify suitable
conditions for the tandem multicomponent CEYM-Diels–
Scheme 3. Formation of diene 2a.
Scheme 2. Reaction of 1a with 1,7-cyclooctadiene and ethyl acrylate in
the presence of ruthenium catalyst Ru-I.
1,7-octadiene and ethyl acrylate. However, when this mix-
ture was heated in toluene at 908C for 6 h, instead of the ex-
pected bicyclic derivative (Scheme 2, pathway A) a regioiso-
meric mixture of compounds 3a and 3a’ was isolated in an
excellent yield (90%) in a 82:18 ratio (Scheme 2, pathway
B). This result indicates that the ring-closing metathesis re-
action of 1,7-octadiene is more favorable than the cross-
metathesis protocol. Therefore, after the RCM of 1,7-octa-
diene, cyclohexadiene and ethylene are liberated and the
ruthenium carbene as the catalytic species is released. This
carbene reacts with the triple bond in a cross-metathesis
Abstract in Spanish: El empleo de 1,7-octadieno como una
fuente in situ de etileno nos ha permitido desarrollar un
nuevo proceso tꢀndem multicomponente metꢀtesis cruzada
de enino-reacciꢁn de Diels–Alder. El proceso puede conside-
rarse como una metꢀtesis por relevos, donde el etileno libera-
do en la metꢀtesis con cierre de anillo del 1,7-octadieno inicia
la secuencia tꢀndem. Alquinos alifꢀticos, aromꢀticos y fluora-
dos y varios dienꢁfilos son compatibles con el proceso, que
es particularmente eficiente con alquinos aromꢀticos. Esta
metodologꢂa constituye una variante ffltil de las condiciones
desarrolladas por Mori en reacciones de metꢀtesis cruzada de
eninos.
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A Useful Alternative to Moriꢀs Conditions
FULL PAPER
Alder reaction by trapping the dienic intermediate with a
variety of dienophiles present in the reaction vessel. The re-
action described in Scheme 2 with ethyl acrylate as a dieno-
phile was employed as the starting point. When this reaction
mixture was heated in toluene at 908C and allowed to react
for 20 h, a mixture of the regioisomers 3a/3a’ was obtained
in quantitative yield (Table 1, entry 1). Therefore, these con-
ditions were further extended to different starting alkynes 1
and dienophiles. The results are summarized in Table 1.
Several dienophiles were tested in the tandem protocol;
besides ethyl acrylate, ethyl fumarate and 1,4-benzoquinone
gave the desired products 3b and 3e, respectively, also in
quantitative yield (Table 1, entries 2 and 5). Diethyl acet-
ing the final adducts in excellent yields; either phenyl acet-
AHCTUNGTREGyNNNU lene (entry 2) or aromatic alkynes with electron-donating
(entries 6 and 7) or -withdrawing substituents (entries 8–12)
reacted with ethyl fumarate in almost quantitative yields in
most cases. However, with heteroaromatic alkynes
(entry 13), aliphatic alkynes (entry 14), or electronically de-
ficient alkynes (entry 15) the overall process was less effec-
tive affording the final products in moderate yields. It is
worth mentioning that the reaction also took place with the
very sterically demanding triisopropylsilyl acetylene, albeit
the desired adduct was isolated in a modest 31% yield after
72 h (entry 16).
When methyl propiolate was used as the starting alkyne
in the tandem protocol, together with the desired product
ACHTUNGTRENNUNG
3o (46%), compound
4 was isolated in 30% yield
ACHTUNGTRENNUNG
(Scheme 4). This product arises from the highly regioselec-
also a good partner for the tandem process, affording cyclo-
adduct 3d in 62% yield (entry 4). With aromatic alkynes the
tandem protocol proceeded with excellent efficiency, afford-
Table 1. Preparation of cycloadducts 3 by tandem multicomponent CEYM-Diels–
Alder reactions of substrates 1 and 1,7-octadiene.
Entry
1
Substrate
R
Dienophile
t
Product
Yield
[%][a]
[h]
1a
Ph
20
3a+3a’
99[b]
2
3
1a
1a
Ph
Ph
20
20
3b
3c
98
70
Scheme 4. Multicomponent reaction with methyl propiolate 1k.
tive Diels–Alder reaction of two molecules of the
dienic intermediate , initially formed by CEYM re-
action of methyl propiolate with the ethylene gener-
ated in situ, one of them acting as the diene coun-
terpart and the other one as a dienophile for the
most electronically deficient olefin (Scheme 4). In
the presence of ethyl fumarate, this process com-
petes with the Diels–Alder reaction of this diene in-
termediate with ethyl fumarate, which generates
adduct 3o. With this data in hand, we decided to
perform the process in the absence of ethyl fuma-
rate. Thus, after 22 h under the optimized condi-
tions, compound 4 was isolated in 70% yield in a
regioselective fashion (Scheme 4).[13] This unexpect-
ed reaction extends the utility of this tandem proto-
col.
The results summarized in Table 1 showed that
this multicomponent tandem protocol is a useful al-
ternative to Moriꢀs conditions in CEYM-type proc-
esses.[8] The use of 1,7-octadiene as an in situ source
of ethylene gas represents a logistical improvement.
Following our ongoing interest in the use of fluori-
nated building blocks,[14] we decided to extend the
scope of this transformation to fluorinated deriva-
4
1a
Ph
20
3d
62
5
1a
Ph
20
3e
99
6
1b
1c
1d
1e
1 f
1g
1h
1i
4-MeO-C6H4
2-MeO-C6H4
4-F-C6H4
20
20
20
20
20
20
30
22
28
20
72
3 f
3g
3h
3i
99
99
99
86
99
99
95
50
42
46[c]
31
7
8
9
2,4-F2-C6H3
3,4-F2-C6H3
4-CF3-C6H4
3,5-(CF3)2-C6H3
3-pyridyl
10
11
12
13
14
15
16
3j
3k
3l
3m
3n
3o
3p
1j
CH2OAc
1k
1l
MeO2C
TIPS
[a] The yields shown in the table were obtained with 4 equivalents of 1,7-octadiene.
[b] Compounds 3a/3a’ were obtained as a 82:18 mixture of regiosiomers, as deter-
mined by GC-MS. [c] When methyl propiolate was used as the starting alkyne com-
pound 4 (see Scheme 4) was isolated in 30% yield together with the desired product.
TIPS=triisopropylsilyl.
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S. Fustero, C. del Pozo et al.
tives 5.[15] In this context, several fluorinated terminal al-
kynes were subjected to the optimized reaction conditions.
The results obtained in this study are depicted in Table 2.
Difluoropropargyl amide 5a[16] reacted with ethyl fuma-
rate to give adduct 6a in 70% yield (Table 2, entry 1).
DEADC afforded diene 6b in its reaction with 5a in moder-
ate yield, and no aromatization was observed during the pu-
rification process (entry 2). N-Phenyl maleimide and p-ben-
zoquinone were also good partners for the tandem process,
affording the cycloadducts 6c and 6d in 62 and 50% yields,
respectively (entries 3 and 4). With chiral starting material
5b, an 1:1 inseparable mixture of diastereoisomers was ach-
ieved in all cases, which indicates that the chiral information
is too far away from the reacting center (entries 5–7). Final-
ly, fluorinated ketones were also adequate substrates for the
sequential process (entries 8 and 9) and again the reaction
with DEADC afforded product 6h without aroma-
tization. Therefore, by following this methodology,
Table 2. Preparation of difluorinated cycloadducts
CEYM-Diels–Alder reactions of substrates 5 and 1,7-octadiene.
6 by tandem multicomponent
a new family of fluorinated carbo- and heterocycles
can be created in a simple manner.[17]
Conclusion
A novel multicomponent tandem enyne cross-meta-
thesis-Diels–Alder reaction of terminal alkynes
with a variety of nucleophiles was developed. The
process relies on the use of 1,7-octadiene as an in
situ source of ethylene by RCM, allowing the initial
formation of the 1,3-diene by its reaction with the
starting alkyne and initiating the tandem sequence.
The developed methodology was particularly effi-
cient with aromatic alkynes. This protocol consti-
tutes an alternative to the Moriꢀs conditions avoid-
ing the use of ethylene gas. Further applications of
this tandem protocol are currently underway.
Entry Substrate
R
Dienophile
t
Product Yield
[%][a]
[h]
1
2
5a
5a
PhCH2NH
PhCH2NH
20
6
6a
6b
70
55
3
5a
PhCH2NH
24
6c
63
4
5a
PhCH2NH
24
6d
50
5
6
5b
5b
(R)-Ph(Me)CHNH
(R)-Ph(Me)CHNH
24
10
6e+6e’ 73[b]
6 f+6 f’
70[b]
Experimental Section
7
8
5b
5c
(R)-Ph(Me)CHNH
Ph
24
15
6g
6h
60
55
General methods: Reactions were carried out under an argon
atmosphere unless otherwise indicated. The solvents were puri-
fied prior to use: THF, diethyl ether, and toluene were distilled
from sodium/benzophenone; dichloromethane was distilled
from calcium hydride. The reactions were monitored with the
aid of TLC on 0.25 mm precoated silica gel plates. Visualiza-
tion was carried out with UV light and aqueous ceric ammoni-
um molybdate solution or potassium permanganate stain.
Flash column chromatography was performed with the indicat-
9
5c
Ph
17
6i
70
[a] The yields shown in the table were obtained with 4 equiv of 1,7-octadiene. [b] In
these cases, adducts were obtained as an inseparable 1:1 mixture of diastereoisomers.
ed solvents on silica gel 60 (particle size: 0.040–0.063 mm). Melting
points were measured on a Bꢅchi B-540 apparatus and are uncorrected.
Optical rotations were measured on a Jasco P-1020 polarimeter. 1H, 19F,
and 13C NMR spectra were recorded on a 300 or 400 MHz spectrometer.
Chemical shifts are given in ppm (d), with reference to the residual
proton resonances of the solvents. Coupling constants (J) are given in
Hertz (Hz). The letters m, s, d, t, and q stand for multiplet, singlet, dou-
blet, triplet, and quartet, respectively. The letters br indicate that the
signal is broad.
General procedure for the multicomponent tandem protocol: A solution
of catalyst I (5 mol%), 1,7-octadiene (4 equiv), alkyne 1 (0.5 mmol), or 5
(0.12 mmol) and the corresponding dienophile (3 equiv) in dry toluene
(0.05m) was heated at 908C in a sealed tube. The reaction mixture was
stirred at this temperature until TLC analysis showed total consumption
of the starting material (times are shown in Tables 1 and 2). The solvents
were then removed under reduced pressure and the crude mixture was
purified by flash chromatography in hexanes/ethyl acetate.
2-Phenyl-1,3-butadiene (2a): By following the general procedure de-
AHCTUNGERTGsNNUN cribed above and before adding the dienophile, the crude mixture was
subjected to flash chromatography affording 2a[18] (65 mg, 98% yield) as
a colorless oil by starting from 51 mg of phenyl acetylene 1a.
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A Useful Alternative to Moriꢀs Conditions
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Ethyl 3-phenyl-3-cyclohexene carboxylate and ethyl 4-phenyl-3-cyclohex-
174.3 (s, C), 174.4 ppm (s, C); 19F NMR (CDCl3, 282 MHz): d=
À115.9 ppm (s, 1F); HRMS: m/z: calcd for C18H22FO4: 321.1497 [M+1]+;
found: 321.1491.
ene carboxylate (3a/3a’): By following the general procedure described
[19]
above, an inseparable mixture of regioisomers 3a/3a’
(115 mg, 82:18,
99% yield) were obtained as a yellowish oil by starting from 51 mg of
1a.
(trans)-Diethyl
4-(2,4-difluorophenyl)-4-cyclohexene-1,2-dicarboxylate
(3i): By following the general procedure described above, 3i (145 mg,
86% yield) was obtained as a yellowish oil by starting from 69 mg of 1e.
1H NMR (CDCl3, 300 MHz): d=1.23 (t, J=7.0 Hz, 3H), 1.24 (m, J=
7.2 Hz, 3H), 2.29–2.40 (m, 1H), 2.49–2.70 (m, 3H), 2.87–3.02 (m, 2H),
4.10–4.19 (m, 4H), 5.84–5.85 (m, 1H), 6.71–6.82 (m, 2H), 7.11–7.19 ppm
(m, 1H); 13C NMR (CDCl3, 300 MHz): d=14.1, (s, 2CH3), 28.3 (s, CH2),
ACHTUNGTRENNUNG(trans)-Diethyl 4-phenyl-4-cyclohexene-1,2-dicarboxylate (3b): By fol-
lowing the general procedure described above, 3b[19] (148 mg, 98% yield)
was obtained as a yellowish oil by starting from 51 mg of 1a.
Diethyl 4-phenyl-1,4-cyclohexadiene dicarboxylate (3c): By following the
general procedure described above, 3c (105 mg, 70% yield) was obtained
as a yellowish oil by starting from 51 mg of 1a. 1H NMR (CDCl3,
300 MHz): d=1.24 (t, J=6 Hz, 3H), 1.25 (t, J=6 Hz, 3H), 3.11–3.19 (m,
2H), 3.29–3.35 (m, 2H), 4.19 (q, J=6 Hz, 2H), 4.20 (q, J=6 Hz, 2H),
6.00–6.03 (m, 1H), 7.16–7.34 ppm (m, 5H); 13C NMR (CDCl3, 300 MHz):
d=14.0 (s, 2CH3), 29.1 (s, CH2), 29.7 (s, CH2), 61.1 (s, CH2), 61.2 (s,
CH2), 119.2 (s, CH), 125.0 (s, 2CH), 127.5 (s, CH), 128.4 (s, 2CH), 131.8
(s, C), 132.5 (s, C), 132.6 (s, C), 139.9 (s, C), 167.8 (s, C), 167.9 ppm (s,
C); HRMS: m/z: calcd for C18H19O4: 209.1278 [MÀ2]+; found: 209.1287.
31.0 (d, 5J
60.7 (s, CH2), 104.0 (t, 2J
AHCTUNGTRENNUNG
ACHTUNGTRENNUNG
4JCF =3.8 Hz, CH), 125.6 (d, JCF =2.3 Hz, CH), 125.9 (d, JCF =3.8 Hz, C),
129.9 (dd, 3J(C,F)=9.1, 3J(C,F)=6.0 Hz, CH), 131.0 (d, 3J
(C,F)=1.5 Hz,
C), 159.2 (dd, J
4
2
A
A
ACHTUNGTRENNUNG
1
3
1
AHCTUNGTRENGU(NN C,F)=160.1, JACHTNURTGEG(NNNU C,F)=12.1 Hz, CF), 162.5 (dd, JACHTUNGTRENNUNG(C,F)=
158.5, 3J (C,F)=12.1 Hz, CF), 174.3 (s, C), 174.5 ppm (s, C); 19F NMR
(CDCl3, 282 MHz): d=À111.5 (d, 4J
(F,F)=7.3 Hz, 1F), À112.4 ppm (d,
R
4J
ACTHUNRGTEN(UNG F,F)=7.3 Hz, 1F); HRMS: m/z: calcd for C18H21F2O4: 339.1402
[M+1]+; found: 339.1410.
2,5-Diphenyl-3a,4,7,7a-tetrahydro-1H-isoindole-1,3-2H-dione (3d): By
following the general procedure described above, 3d (94 mg,[19] 62%
yield) was obtained as a yellowish oil by starting from 51 mg of 1a.
AHCTUNGTERG(NNUN trans)-Diethyl 4-(3,4-difluorophenyl)-4-cyclohexene-1,2-dicarboxylate
(3j): By following the general procedure described above, 3j (167 mg,
99% yield) was obtained as a yellowish oil by starting from 69 mg of 1 f.
1H NMR (CDCl3, 300 MHz): d=1.23 (t, J=7.1 Hz, 3H), 1.24 (t, J=
7.1 Hz, 3H), 2.28–2.74 (m, 3H), 2.82–3.01 (m, 2H), 4.10–4.18 (m, 4H),
5.99–6.00 (m, 1H), 7.01–7.14 ppm (m, 3H); 13C NMR (CDCl3, 300 MHz):
d=14.0, (s, 2CH3), 28.3 (s, CH2), 29.7 (s, CH2), 40.7 (s, CH), 41.6 (s, CH),
60.6 (s, CH2), 60.7 (s, CH2), 113.9 (d, J
R
2-Phenyl-1,4,4a,9a-tetrahydroanthracene-9,10-dione (3e): By following
the general procedure described above, 3e (143 mg, 99% yield) was ob-
tained as a yellowish oil by starting from 51 mg of 1a. 1H NMR (CDCl3,
300 MHz): d=2.36 (d, J=18 Hz, 1H), 2.53 (d, J=17 Hz, 1H), 2.64 (d,
J=18 Hz, 1H), 2.85 (d, J=17 Hz, 1H), 3.35 (dd, J1 =11 Hz; J2 =6 Hz,
1H), 3.46 (dd, J1 =11; J2 =6 Hz, 1H), 5.98 (s, 1H), 7.11–7.28 (m, 5H),
7.65 (dd, J1 =5; J2 =3 Hz, 2H), 7.96 ppm (d, J=3 Hz, 2H); 13C NMR
(CDCl3, 300 MHz): d=25.3 (s, CH2), 26.7 (s, CH2), 46.1 (s, CH), 47.0 (s,
CH), 121.5 (s, CH), 125.2 (s, 2CH), 126.8 (s, CH), 126.9 (s, CH), 127.1 (s,
CH), 128.2 (s, 2CH), 133.9 (s, C), 133.9 (s, C), 134.3 (s, 2CH), 134.7 (s,
C), 141.0 (s, C), 197.7 (s, C), 198.0 ppm (s, C); HRMS: m/z: calcd for
C20H17O2: 289.1223 [M+1]+; found: 289.1232.
2
G
(C,F)=6.0, 4J
ACHUTGTNRENNUG CAHTUNGTRENNUNG
N
ACHTUNGTRENNUNG
1
2
A
ACHTUNGTRENNUNG
(1J(C,F)=49.0, 2J
ACTHNUTRGENNUG AHCUTNGTREN(NUGN C,F)=13.3 Hz, CF), 174.2 (s, C), 174.3 ppm (s, C);
19F NMR (CDCl3, 282 MHz): d=À138.4 ppm (d, 3J
ACHTUNGTREN(NUGN F,F)=21.5 Hz, 1F),
À140.4 ppm (d, 3J (F,F)=21.5 Hz, 1F); HRMS: m/z: calcd for
C18H21F2O4: 339.1402 [M+1]+; found: 339.1400.
A
4-(4-methoxyphenyl)-4-cyclohexene-1,2-dicarboxylate
R
ACHTUNGTRENNUNGyl-
(3 f): By following the general procedure described above, 3 f (164 mg,
99% yield) was obtained as a yellowish oil by starting from 66 mg of 1b.
1H NMR (CDCl3, 300 MHz): d=1.26 (t, J=7.1 Hz, 3H), 1.27 (t, J=
7.1 Hz, 3H), 2.29–2.41 (m, 1H), 2.47–2.66 (m, 2H), 2.76–2.84 (m, 1H),
2.85–3.04 (m, 2H), 3.79 (s, 3H), 4.16 (q, J=7.1 Hz, 2H), 4.17 (q, J=
7.1 Hz, 2H), 5.97 (t, J=2.4 Hz, 1H), 6.85 (d, J=8.4 Hz, 2H), 7.29 ppm
(d, J=8.7 Hz, 2H); 13C NMR (CDCl3, 300 MHz): d=14.1, 1 (s, 2CH3),
28.6 (s, CH2), 30.2 (s, CH2), 41.1 (s, CH), 42.0 (s, CH), 55.2 (s, CH3), 60.6
(s, CH2), 60.6 (s, CH2), 113.7 (s, 2CH), 120.3 (s, CH), 126.2 (s, 2CH),
133.5 (s, C), 134.5 (s, C), 158.9 (s, C), 174.6 (s, C), 174.7 ppm (s; C);
HRMS: m/z: calcd for C19H25O5: 333.1697 [M+1]+; found: 333.1700.
AHCTUNGTRENNUNG
(183 mg, 99% yield) was obtained as a yellowish oil by starting from
85 mg of 1g. 1H NMR (CDCl3, 300 MHz): d=1.24 (t, J=7.2 Hz, 3H),
1.25 (t, J=7.2 Hz, 3H), 2.32–2.44 (m, 1H), 2.51–2.69 (m, 2H), 2.73–2.81
(m, 1H), 2.86–3.04 (m, 2H), 4.11–4.20 (m, 4H), 6.12–6.13 (m, 1H), 7.42
(d, J=8.3 Hz, 2H), 7.53 ppm (d, J=8.2 Hz, 2H); 13C NMR (CDCl3,
300 MHz): d=14.0, (s, 2CH3), 28.4 (s, CH2), 29.7 (s, CH2), 40.7 (s, CH),
41.6 (s, CH), 60.6 (s, CH2), 60.7 (s, CH2), 124.1
CF3), 124.1 (s, CH), 125.1 (q, 3J
(C,F)=3.7 Hz, 2CH), 125.2 (s, 2CH),
128.9 (q, 2J
ACTHNUGTRNE(NUG C,F)=32.6 Hz, C), 134.0 (s, C), 144.1 (s, C), 174.2 (s, C),
(q, 1J
ACHUTGTNRENNUG ACHUTNTGREN(NUGN C,F)=271.5 Hz,
AHCTUNGTRENNUNG
174.3 ppm (s, C); 19F NMR (CDCl3, 282 MHz): d=À62.9 ppm (s, 3F);
A
4-(2-methoxyphenyl)-4-cyclohexene-1,2-dicarboxylate
HRMS: m/z: calcd for C19H22F3O4: 371.1465 [M+1]+; found: 371.1462.
(3g): By following the general procedure described above, 3g (165 mg,
99% yield) was obtained as a yellowish oil by starting from 66 mg of 1c.
1H NMR (CDCl3, 300 MHz): d=1.24 (t, J=7.2 Hz, 3H), 1.26 (t, J=
7.1 Hz, 3H), 2.29–2.39 (m, 1H), 2.53–2.75 (m, 3H), 2.90–3.03 (m, 2H),
3.78 (s, 3H), 4.09–4.21 (m, 4H), 5.72–5.74 (m, 1H), 6.83–6.91 (m, 2H),
7.09 (dd, J1 =7.4, J2 =1.9 Hz, 1H), 7.19–7.25 ppm (m, 1H); 13C NMR
(CDCl3, 300 MHz): d=14.0, (s, 2CH3), 28.5 (s, CH2), 31.4 (s, CH2), 41.0
(s, CH), 41.9 (s, CH), 55.2 (s, CH3), 60.3 (s, CH2), 60.4 (s, CH2), 110.5 (s,
CH), 120.4 (s, CH), 123.4 (s, CH), 128.3 (s, CH), 129.4 (s, CH), 131.6 (s,
C), 135.7 (s, C), 156.5 (s, C), 174.7 (s, C), 174.8 ppm (s, C); HRMS: m/z:
calcd for C19H25O5: 333.1697 [M+1]+; found: 333.1703.
AHCTUNGTERG(NNUN trans)-Diethyl 4-[3,5-bis(trifluoromethyl)phenyl]-4-cyclohexene-1,2-di-
carboxylate (3l): By following the general procedure described above, 3l
(207 mg, 95% yield) was obtained as a yellowish oil by starting from
119 mg of 1h. 1H NMR (CDCl3, 300 MHz): d=1.27 (t, J=7.1 Hz, 3H),
1.28 (t, J=7.1 Hz, 3H), 2.39–2.51 (m, 1H), 2.58–2.83 (m, 3H), 2.92–3.10
(m, 2H), 4.18 (q, J=7.1 Hz, 2H), 4.19 (q, J=7.1 Hz, 2H), 6.21–6.23 (m,
1H), 7.74 (s, 1H), 7.76 ppm (s, 2H); 13C NMR (CDCl3, 300 MHz): d=
14.1, (s, 2CH3), 28.2 (s, CH2), 29.5 (s, CH2), 40.6 (s, CH), 41.5 (s, CH),
60.9 (s, CH2), 61.0 (s, CH2), 120.7 (sept, 3J
1J(C,F)=272.5 Hz, 2CF3), 125.2 (s, CH), 125.8 (s, 2CH), 131.7 (q, 2J-
ACHTUNGTNER(NUNG C,F)=3.8 Hz, CH), 123.3 (q,
AHCTUNGTRENNUNG
AHCTUNGERTG(NNUN C,F)=33.2 Hz, 2C), 133.1 (s, C), 142.9 (s, C), 174.0 (s, C), 174.1 ppm (s,
ACHTUNGTRENNUNG(trans)-Diethyl 4-(4-fluorophenyl)-4-cyclohexene-1,2-dicarboxylate (3h):
C); 19F NMR (CDCl3, 282 MHz): d=À63.4 ppm (s, 6F); HRMS: m/z:
By following the general procedure described above, 3h (159 mg, 99%
yield) was obtained as a yellowish oil by starting from 60 mg of 1d.
1H NMR (CDCl3, 300 MHz): d=1.27 (t, J=7.1 Hz, 3H), 1.27 (t, J=
7.1 Hz, 3H), 2.32–2.42 (m, 1H), 2.49–2.67 (m, 2H), 2.73–2.81 (m, 1H),
2.86–3.05 (m, 2H), 4.17 (q, J=7.1 Hz, 2H), 4.18 (q, J=7.1 Hz, 2H), 6.00
(t, J=2.4 Hz, 1H), 6.99 (dd, J1 =J2 =8.7 Hz, 2H), 7.31 ppm (dd, J1 =8.7,
J2 =5.4 Hz, 2H); 13C NMR (CDCl3, 300 MHz): d=14.0, (s, 2CH3), 28.4
(s, CH2), 30.1 (s, CH2), 40.9 (s, CH), 41.8 (s, CH), 60.8 (s, CH2), 60.6 (s,
calcd for C20H21F6O4: 439.1339 [M+1]+; found: 439.1341.
AHCTUNGTERG(NNUN trans)-Diethyl 4-(3-pyridyl)-4-cyclohexene-1,2-dicarboxylate (3m): By
following the general procedure described above, 3m (76 mg, 50% yield)
was obtained as a yellowish oil by starting from 52 mg of 1i. 1H NMR
(CDCl3, 300 MHz): d=1.26 (t, J=7.1 Hz, 3H), 1.27 (t, J=7.1 Hz, 3H),
2.35–2.46 (m, 1H), 2.52–2.71 (m, 2H), 2.75–2.83 (m, 1H), 2.89–3.07 (m,
2H), 4.16 (q, J=7.1 Hz, 2H), 4.19 (q, J=7.1 Hz, 2H), 6.09–6.13 (m, 1H),
7.23 (ddd, J1 =8.0, J2 =4.8, J3 =0.6 Hz, 1H), 7.62 (ddd, J1 =8.0, J2 =2.2,
J3 =1.7 Hz, 1H), 8.47 (dd, J1 =4.7, J2 =1.1 Hz, 1H), 8.61 ppm (d, J=
2
3
CH2), 115.0 (d, J
G
ACHTUNGTRNE(NUNG C,F)=
7.9 Hz, 2CH), 134.1 (s, C), 136.8 (s, C), 162.0 (d, 1J
AHCTUNGTRENNUNG
Chem. Eur. J. 2012, 00, 0 – 0
ꢄ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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S. Fustero, C. del Pozo et al.
1.8 Hz, 1H); 13C NMR (CDCl3, 300 MHz): d=14.1, (s, 2CH3), 28.4 (s,
CH2), 29.6 (s, CH2), 40.8 (s, CH), 41.6 (s, CH), 60.8 (s, CH2), 60.8 (s,
CH2), 123.1 (s, CH), 123.9 (s, CH), 132.3 (s, CH), 132.5 (s, C), 136.2 (s,
C), 146.7 (s, CH), 148.4 (s, CH), 174.3 (s, C), 174.4 ppm (s, C); HRMS:
m/z: calcd for C17H22NO4: 304.1543 [M+1]+; found: 304.1538.
13C NMR (CDCl3, 300 MHz): d=14.4 (s, CH3), 14.4 (s, CH3), 25.7 (t, 3J-
AHCTUNGTRENNUNG
A
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
2CH), 131.6 (s, C), 131.8 (s, C), 137.1 (s, C), 163.5 (t, 2J
ACHTNUTRGNE(NUG C,F)=30.4 Hz,
C), 167.5 (s, C), 167.8 ppm (s, C); 19F NMR (CDCl3, 282 MHz): d=
À108.6 ppm (s, 2F); HRMS (EI+): m/z: calcd for C21H23F2NO5: 407.1544
[M]+; found: 407.1546.
ACHTUNGTRENNUNG(trans)-Diethyl 4-acetoxymethyl-4-cyclohexene-1,2-dicarboxylate (3n):
By following the general procedure described above, 3n (64 mg, 43%
yield) was obtained as a yellowish oil by starting from 49 mg of 1j.
1H NMR (CDCl3, 300 MHz): d=1.25 (t, J=7.1 Hz, 3H), 1.26 (t, J=
7.1 Hz, 3H), 2.07 (s, 3H), 2.18–2.28 (m, 2H), 2.36–2.53 (m, 2H), 2.78–
2.93 (m, 2H), 4.14 (q, J=7.1 Hz, 2H), 4.16 (q, J=7.1 Hz, 2H), 4.46 (s,
2H), 5.74–5.75 ppm (m, 1H); 13C NMR (CDCl3, 300 MHz): d=14.1, (s,
2CH3), 20.9 (s, CH3), 27.8 (s, CH2), 28.6 (s, CH2), 41.0 (s, CH), 41.3 (s,
CH), 60.7 (s, CH2), 60.7 (s, CH2), 67.6 (s, CH2), 124.0 (s, CH), 131.3 (s,
C), 170.8 (s, C), 174.4 (s, C), 174.5 ppm (s, C); HRMS: m/z: calcd for
C15H23O6: 299.1489 [M+1]+; found: 299.1492.
N-Benzyl-2-(1,3-dioxo-2-phenyl-2,3,3a,4,7,7a-hexahydro-1H-isoindol-5-
yl)-2,2-difluoroacetamide (6c): By following the general procedure A de-
scribed above, 6c (31 mg, 63% yield) was obtained as a dark-brown oil
by starting from 25 mg of 5a. 1H NMR (CDCl3, 300 MHz): d=2.32–2.47
(m, 2H), 2.82–2.93 (m, 2H), 3.27–3.38 (m, 2H), 4.46 (d, J=5.7 Hz, 2H),
6.49–6.55 (m, 1H), 6.68 (brs, 1H), 7.27–7.47 ppm (m, 10H); 13C NMR
(CDCl3, 300 MHz): d=22.8 (s, CH2), 23.9 (s, CH2), 38.7 (s, CH), 39.1 (s,
CH), 43.7 (s, CH2), 114.2 (t, 1J
127.9 (s, 2CH), 128.0 (s, CH), 128.7 (s, CH), 128.9 (s, 2CH), 129.1 (s,
2CH), 129.9 (t, 3J(C,F)=8.9 Hz, CH), 131.8 (s, C), 131.9 (t, 2J
(C,F)=
ACHTUNGTERN(NGNU C,F)=251.0 Hz, CF2), 126.5 (s, 2CH),
ACHTUNGTRENNUNG(trans)-Diethyl 4-methoxycarbonyl-4-cyclohexene-1,2-dicarboxylate (3o):
A
ACHTUNGTRENNUNG
By following the general procedure described above, 3o (65 mg, 46%
yield) was obtained as a yellowish oil by starting from 42 mg of 1k.
1H NMR (CDCl3, 300 MHz): d=1.24 (t, J=7.1 Hz, 3H), 1.25 (t, J=
7.1 Hz, 3H), 2.30–2.42 (m, 2H), 2.57–2.68 (m, 1H), 2.74–2.89 (m, 3H),
3.73 (s, 3H), 4.15 (q, J=7.1 Hz, 2H), 4.15 (q, J=7.1 Hz, 2H), 6.93–
6.95 ppm (m, 1H); 13C NMR (CDCl3, 300 MHz): d=13.9, (s, 2CH3), 26.5
(s, CH2), 28.0 (s, CH2), 40.2 (s, CH), 40.9 (s, CH), 51.6 (s, CH3), 60.6 (s,
2CH2), 128.3 (s, C), 136.7 (s, CH), 166.4 (s, C), 173.8 (s, C), 173.9 ppm (s,
C); HRMS: m/z: calcd for C14H21O6: 285.1333 [M+1]+; found: 285.1327.
24.4 Hz, C), 136.6 (s, C), 162.8 (t, 2J
ACTHNUTRGNE(NUG C,F)=30.1 Hz, C), 177.7 (s, C),
178.1 ppm (s, C); 19F NMR (CDCl3, 282 MHz): d=À106.5 ppm (d, JFF
=
258.1 Hz, 1F), À108.7 ppm (d, JFF =258.4 Hz, 1F); HRMS (EI+): m/z:
calcd for C23H20F2N2O3: 410.1442 [M]+; found: 410.1445.
N-Benzyl-2-(9,10-dioxo-1,4,4a,9,9a,10-hexahydroanthracen-2-yl)-2,2-di-
fluoroacetamide (6d): By following the general procedures described
above, 6d (24 mg, 50% yield) was obtained as a dark-brown oil by start-
ing from 25 mg of 5a. 1H NMR (CDCl3, 300 MHz): d=2.35–2.45 (m,
2H), 2.57–2.70 (m, 2H), 3.37–3.43 (m, 1H), 3.45–3.50 (m, 1H), 4.50 (d,
J=5.8 Hz, 2H), 6.23–6.28 (m, 1H), 6.8 (brs, 1H), 7.27–7.38 (m, 5H),
7.73–7.79 (m, 2H), 7.99–8.07 ppm (m, 2H); 13C NMR (CDCl3, 300 MHz):
d=22.0 (s, CH2), 24.3 (s, CH2), 43.6 (s, CH2), 45.6 (s, CH), 45.8 (s, CH),
ACHTUNGTRENNUNG(trans)-Diethyl 4-(triisopropylsilyl)-4-cyclohexene-1,2-dicarboxylate (3p):
By following the general procedure described above, 3p (44 mg, 31%
yield) was obtained as a yellowish oil by starting from 112 mg of 1l.
1H NMR (CDCl3, 300 MHz): d=1.03–1.05 (m, 21H), 1.25 (t, J=7.1 Hz,
3H), 1.25 (t, J=7.1 Hz, 3H), 2.14–2.32 (m, 2H), 2.41–2.57 (m, 2H), 2.73–
2.90 (m, 2H), 4.14 (q, J=7.1 Hz, 2H), 4.15 (q, J=7.1 Hz, 2H), 5.94–
5.97 ppm (m, 1H); 13C NMR (CDCl3, 300 MHz): d=14.2 (s, 2CH3), 17.7
(s, 3CH), 18.7 (s, 6CH3), 29.7 (s, CH2), 31.5 (s, CH2), 41.3 (s, CH), 41.9 (s,
CH), 60.5 (s, 2CH2), 132.3 (s, C), 135.5 (s, CH), 175.0 (s, C), 175.2 ppm (s,
C); HRMS: m/z: calcd for C21H39O4Si: 383.2612 [M+1]+; found:
283.2623.
114.6 (t, 1J
(C,F)=8.6 Hz, CH),127.8 (CH), 127.9 (CH), 128.6 (t, 2J
C), 128.8 (CH), 133.6 (C), 133.7 (C), 134.6 (CH), 136.1 (C), 163.1 (t, 2J-
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
(C,F)=30.6 Hz, C), 197.0 (s, C), 197.1 ppm (s, C); 19F NMR (CDCl3,
282 MHz): d=À107.5 ppm (s, 2F); HRMS (ES+): m/z: calcd for
C23H20F2NO3: 396.1406 [M+1]+; found: 396.1404.
AHCTUNGTRENGN(UN trans)-Diethyl 4-{1,1-difluoro-2-oxo-2-[(S)-1-phenylethylamino]ethyl}-4-
Dimethyl 1-vinyl-3-cyclohexene-1,4-dicarboxylate (4): By following the
general procedure described above, 4 (75 mg, 67% yield) was obtained
as a yellowish oil by starting from 42 mg of 1k. 1H NMR (CDCl3,
300 MHz): d=1.75–1.84 (m, 1H), 2.03–2.12 (m, 1H), 2.26–2.39 (m, 3H),
2.74–2.83 (m, 1H), 3.67 (s, 3H), 3.70 (s, 3H), 5.08 (d, J=17.5 Hz, 1H),
5.14 (d, J=10.7 Hz, 1H), 5.85 (dd, J1 =17.4, J2 =10.7 Hz, 1H), 6.92–
6.96 ppm (m, 1H); 13C NMR (CDCl3, 300 MHz): d=21.7 (s, CH2), 29.4
(s, CH2), 32.1 (s, CH2), 47.2 (s, C), 51.5 (s, CH3), 52.2 (s, CH3), 115.2 (s,
CH2), 129.3 (s, C), 137.0 (s, CH), 139.3 (s, CH), 167.3 (s, C), 174.8 ppm (s,
C); HRMS: m/z: calcd for C12H17O4: 225.1121 [M+1]+; found: 225.1110.
cyclohexene-1,2-dicarboxylate (6e+6e’): By following the general proce-
dures described above, 6e+6e’ (37 mg, 73% yield) were obtained as a
dark-brown oil by starting from 27 mg of 5b.[20] 1H NMR (CDCl3,
300 MHz): d=1.23 (t, J=7.2 Hz, 6H), 1.54 (d, J=6.9 Hz, 3H), 2.20–2.31
(m, 2H), 2.52- 2.58 (m, 2H), 2.79–2.92 (m, 2H), 4.13 (q, J=7.2 Hz, 4H),
5.08–5.18 (m, 1H), 6.17 (brs, 1H), 6.64 (d, J=6.64 Hz, 1H), 7.27–
7.39 ppm (m, 5H); 13C NMR (CDCl3, 300 MHz): d=14.1 (CH3), 21.3
(2CH3), 24.9 (CH2), 27.2 (CH2), 40.3 (CH), 40.6 (CH), 49.2 (CH), 60.8
(CH2), 60.9 (CH2), 114.6 (t, 1J
(CH), 127.8 (t, 3J(C,F)=8.7 Hz, CH), 128.8 (2CH), 128.9 (t, 2J
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
G
24.0 Hz, C), 141.7 (C), 162.3 (t, 2J
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
173.8 ppm (C); 19F NMR (CDCl3, 282 MHz): d=À106.7 (d,
JACHTUNGTRENNUNG
258.7 Hz, 1F), À106.8 (d, J
(F,F)=258.1 Hz, 1F), À107.9 (d, J
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
258.9 Hz, 1F), À107.9 ppm (d, J
(F,F)=258.7 Hz, 1F); HRMS (ES+): m/
ACHTUNGTRENNUNG
starting from 25 mg of 5a.{20] M.p. 61–638C; H NMR (CDCl3, 300 MHz):
d=1.24 (t, J=7.2 Hz, 3H), 1.25 (t, J=7.2 Hz, 3H), 2.23–2.38 (m, 2H),
2.51–2.61 (m, 2H), 2.81–2.95 (m, 2H), 4.14 (q, J=7.11 Hz, 4H), 4.50 (d,
J=5.8 Hz, 2H), 6.22 (brs, 1H), 6.70 (brs, 1H), 7.27–7.39 ppm (m, 5H);
13C NMR (CDCl3, 300 MHz): d 14.1=(s, 2CH3), 25.0 (s, CH2), 27.3 (s,
CH2), 40.3 (s, CH), 40.6 (s, CH), 43.6 (s, CH2), 60.9 (s, CH3), 60.9 (s,
1
z: calcd for C22H28F2NO5: 424.1936 [M+1]+; found: 424.1940.
2-(1,3-Dioxo-2-phenyl-2,3,3a,4,7,7a-hexahydro-1H-isoindol-5-yl)-2,2-di-
fluoro-N-[(S)-1-phenylethyl]acetamide (6 f+6 f’): By following the gener-
al procedures described above, 6 f+6 f’ (36 mg, 70% yield) were ob-
tained as a dark-brown solid by starting from 27 mg of 5b. M.p. 113–
1158C; 1H NMR (CDCl3, 300 MHz): d=1.53 (d, J=6.9 Hz, 3H), 2.31–
2.46 (m, 2H), 2.76–2.91 (m, 2H), 3.25–3.36 (m, 2H), 5.04–5.16 (m, 1H),
6.45–6.51 (m, 1H), 6.65 (brs, 1H), 7.22–7.48 ppm (m, 10H); 13C NMR
(CDCl3, 300 MHz): d=21.1 (CH3), 21.3 (CH3), 22.7 (CH2), 23.8 (CH2),
CH3), 114.7 (t, 1J
128.0 (s, CH), 128.9 (s, 2CH), 128.9 (t, 2J
AHCTUNGTRENNUNG
ACHTUNGTRENNUNG
C), 163.2 (t, 2J
ACHTUNGTRENNUNG(C,F)=30.9 Hz, C), 173.7 (s, C), 173.9 ppm (s, C);
19F NMR (CDCl3, 282 MHz): d=À136.4 (d,
J (F,F)=258.2 Hz, 1F),
ACHTUNGTRENNUNG
(F,F)=258.2 Hz, 1F); HRMS (ES+): m/z: calcd for
38.7 (CH), 39.0 (CH), 49.2 (CH), 49.3 (CH), 114.0 (t, 1J
CF2), 114.1 (t, 1J
(C,F)=252 Hz, CF2), 126.1 (2CH), 126.2 (2CH), 126.4
(2CH), 126.5 (2CH), 127.7 (CH), 127.8 (CH), 128.6 (CH), 128.7 (CH),
128.8 (2CH), 129.1 (2CH), 129.8 (t, 3J(C,F)=8.7 Hz, CH), 129.8 (t, 3J-
(C,F)=8.8 Hz, CH), 131.7 (C), 131.8 (C), 131.8 (t, 2J
(C,F)=24.6 Hz, C),
131.9 (t, 2J(C,F)=24.6 Hz, C), 141.5 (C), 141.7 (C), 161.9 (t, 2J
(C,F)=
30 Hz, C), 177.7 (C), 177.8 (C), 178.1 (C), 178.2 ppm (C); 19F NMR
(CDCl3, 282 MHz): d=À105.9 (d, J(F,F)=259.7 Hz, 1F), À106.4 (d, J-
AHCTUNGTREG(NNUN C,F)=251.6 Hz,
À137.5 ppm (d, J
C21H27F2NO5: 410.1774 [M+1]+; found: 410.1776.
AHCTUNGTRENNUNG
Diethyl 4-[2-(benzylamino)-1,1-difluoro-2-oxoethyl]-1,4-cyclohexadiene-
1,2-dicarboxylate (6b): By following the general procedures described
above, 6b (27 mg, 55% yield) was obtained as a dark-brown oil by start-
AHCTUNGTRENNUNG
A
ACHTUNGTRENNUNG
1
A
ACHTUNGTRENNUNG
ing from 25 mg of 5a. H NMR (CDCl3, 300 MHz): d=1.29 (t, J=7.2 Hz,
3H), 1.30 (t, J=7.2 Hz, 3H), 3.10 (s, 4H), 4.23 (q, J=7.2 Hz, 4H), 4.50
(d, J=6 Hz, 2H), 6.22 (brs, 1H), 6.70 (brs, 1H), 7.26–7.39 ppm (m, 5H);
AHCTUNGTRENNUNG
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www.chemeurj.org
ꢄ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!

A Useful Alternative to Moriꢀs Conditions
FULL PAPER
A
E
makar, T. Biswas, K. C. Majumdar, H. Rahaman, B. Roy, Tetrahe-
dron 2007, 63, 3919.
[3] a) S. T. Diver, A. J. Giessert, Chem. Rev. 2004, 104, 1317; b) C. S.
Poulsen, R. Madsen, Synthesis 2003, 1.
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b) T. M. Sivavec, T. J. Katz, M. Y. Chiang, G. X.-Q. Yang, Organo-
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[5] E. C. Hansen, D, Lee, Acc. Chem. Res. 2006, 39, 509.
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b) S. V. Maifeld, D. Lee, Chem. Eur. J. 2005, 11, 6118.
JACHTUNGTRENNUNG
(F,F)=257.6 Hz, 1F); HRMS (EI+): m/z calcd for C24H22F2N2O3:
424.1598 [M]+; found: 424.1599.
(R)-Diethyl 4-[1,1-difluoro-2-oxo-2-(1-phenylethylamino)ethyl]ciclohexa-
1,4-diene-1,2-dicarboxylate (6g): By following the general procedures de-
scribed above, 6g (30 mg, 60% yield) was obtained as a dark-brown oil
by starting from 27 mg of 5b. [a]D25 =À88.9 (c=1.0 in CHCl3); 1H NMR
(CDCl3, 300 MHz): d=1.29 (t, J=7.2 Hz, 6H), 1.56 (d, J=6.9 Hz, 3H),
3.12 (s, 4H), 4.23 (q, J=7.2 Hz, 4H), 5.14 (quint, J=7.2 Hz, 1H), 6.17–
6.19 (m, 1H), 6.58 (brs, 1H), 7.29–7.39 ppm (m, 5H); 13C NMR (CDCl3,
300 MHz): d=14.4 (s, CH3), 14.4 (s, CH3), 21.8 (s, CH3), 25.7 (t, J
2.6 Hz, CH2), 28.5 (s, CH2), 49.7 (s, CH), 61.8 (s, CH2), 62.4 (s, CH2),
114.9 (t, J
[7] R. Stragies, M. Schuster, S. Blechert, Angew. Chem. 1997, 109, 2628;
Angew. Chem. Int. Ed. Engl. 1997, 36, 2518.
[8] For selected examples, see: a) G. C. Lloyd-Jones, R. G. Margue, J. G.
de Vries, Angew. Chem. Int. Ed. 2005, 44, 7442; b) A. Kinoshita, N.
Sakakibara, M. Mori, Tetrahedron 1999, 55, 8155; c) A. Kinoshita,
N. Sakakibara, M. Mori, J. Am. Chem. Soc. 1997, 119, 12388.
[9] a) C. O’Leary-Steele, P. J. Pedersen, T. James, T. Lanyon-Hogg, S,
Leach, J. Hayes, A. Nelson, Chem. Eur. J. 2010, 16, 9563; b) S.
Kotha, M. Meshram, A. Tiwari, Chem. Soc. Rev. 2009, 38, 2065.
[10] For a very recent review, see: J. Li, D. Lee, Eur. J. Org. Chem. 2011,
4269.
[11] Several examples of a tandem CEYM-Diels–Alder reaction have
been reported, but only few of them are involved in a triple tandem
process. For selected examples of tandem CEYM-Diels–Alder reac-
tion, see: a) A. V. Subrahmanyam, K. Palanichamy, K. P. Kaliappan,
Chem. Eur. J. 2010, 16, 8545; b) R. S. Nandurdikar, A. V. Subrahma-
nyam, K. P. Kaliappan, Eur. J. Org. Chem. 2010, 2788; c) R. J.
Spandl, H. Rudyk, D. R. Spring, Chem. Commun. 2008, 3001; d) M.
Rosillo, G. Domꢂnguez, L. Casarrubios, U. Amador, J. Pꢆrez-Cas-
tells, J. Org. Chem. 2004, 69, 2084; e) H.-J. Lee, H. Y. Kim, H. Tae,
B. G. Kim, J. Lee, Org. Lett. 2003, 5, 3439; f) C. S. Poulsen, R.
Madsen, J. Org. Chem. 2002, 67, 4441.
2CH), 127.3 (t, JACHTUNGTRENNUNG
(s, C), 131.8 (s, C), 142.1 (s, C), 162.6 (t, 3J
ACTHNUTRGNE(UNG C,F)=30.4 Hz, C), 167.5 (s,
C), 167.8 ppm (s, C); 19F NMR (CDCl3, 282 MHz): d=À106.8 (d, J-
N
A
(EI+): m/z: calcd for C22H26F2NO5: 422.1774 [M+1]+; found: 422.1753.
Diethyl 4-(1,1-difluoro-2-oxo-2-phenylethyl)-1,4-cyclohexadiene-1,2-dicar-
boxylate (6h): By following the general procedures described above, 6h
(25 mg, 55% yield) was obtained as a dark-brown oil by starting from
22 mg of 5c[20] 1H NMR (CDCl3, 300 MHz): d=1.23 (t, J=7.2 Hz, 3H),
.
1.24 (t, J=7.2 Hz, 3H), 3.16 (s, 4H), 4.17 (q, J=7.2 Hz, 2H), 4.17 (q, J=
7.2 Hz, 2H), 6.19–6.20 (brm, 1H), 7.47 (dd, J1 =J2 =6 Hz, 2H), 7.63 (tt,
J1 =7.2 Hz, J2 =1.5 Hz, 1H), 8.03 ppm (d, J=7.2 Hz, 2H); 13C NMR
(CDCl3, 300 MHz): d=13.9 (s, CH3), 14.0 (s, CH3), 25.3 (t, 4J
ACHTUNGTRENNUNG
N
ACHTUNGTRENNUNG
188.5 ppm (t, 2J(C,F)=30.6 Hz, C); 19F NMR (CDCl3, 282 MHz): d=
À103.2 ppm (s, 2F); HRMS (EI+): m/z: calcd for C20H20F2O5: 378.1269
[12] The concept of relay metathesis was first introduced by Hoye: T. R.
Hoye, C. S. Jeffrey, M. A. Tennakoon, J. Wang, H. Zhao, J. Am.
Chem. Soc. 2004, 126, 10210.
[M]+; found: 378.1279.
ACHTUNGTRENNUNG(trans)-Diethyl 4-[1,1-difluoro-2-oxo-2-(phenylamino)ethyl]-4-cyclohex-
ene-1,2-dicarboxylate (6i): By following the general procedures described
above, 6i (32 mg, 70% yield) was obtained as a yellow oil by starting
from 22 mg of 5c. 1H NMR (CDCl3, 300 MHz): d=1.24 (t, J=7.2 Hz,
3H), 1.25 (t, J=7.2 Hz, 3H), 2.23–2.41 (m, 2H), 2.51–2.64 (m, 2H), 2.84–
2.98 (m, 2H), 4.14 (q, J=7.2 Hz, 4H), 6.17–6.22 (m, 1H), 7.48 (dd, J1 =
J2 =7.8 Hz, 2H), 7.63 (tt, J1 =7.2, J2 =1.5 Hz, 1H), 8.03 ppm (d, J=
7.2 Hz, 2H); 13C NMR (CDCl3, 300 MHz): d=14.1 (s, 2CH3), 25.0 (s,
CH2), 27.3 (s, CH2), 40.4 (s, CH), 40.6 (s, CH), 60.9 (s, CH2), 61.0 (s,
[13] In the tandem protocol with methyl propiolate, a 93:7 mixture of re-
gioisomers was observed, as was determined by GCMS. The regio-
chemistry of the final product was deduced by means of a COSY ex-
periment.
[14] S. Fustero, J. F. Sanz-Cervera, J. L. AceÇa, M. Sꢃnchez-Rosellꢁ, Syn-
lett 2009, 525.
[15] As far as we know only one example of CEYM involving fluorinat-
ed alkynes has been reported. The resulting diene was combined
with a Diels–Alder reaction in a two-step sequence: S. A. Pujari,
K. P. Kaliappan, A. Valleix, D. Grꢆe, R. Grꢆe, Synlett 2008, 2503.
[16] For the preparation of substrates 5, see: a) X. Xu, M. Mae, J. A.
Hong, J. Y. Li, G. B. Hammond, Synthesis 2006, 803; b) G. B. Ham-
mond, J. Fluorine Chem. 2006, 127, 476.
[17] For a recent review that highlights the importance of gem-difluoro
moiety-containing derivatives, see: F.-L. Qing, F. Zheng, Synlett
2011, 1052.
CH2), 116.4 (t, 1J
128.7 (s, 2CH), 130.1 (t, 2J
2CH), 132.2 (s, C), 134.4 (s, CH), 173.7 (s, C), 173.9 (s, C), 188.8 ppm (t,
2J
A
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
A
JACTHNGUTRENNU(G F,F)=272.2 Hz, 1F); HRMS
(EI+): m/z: calcd for C20H23F2O5: 381.1508 [M+1]+; found: 381.1514.
[18] J. Lindh, J. Sꢇvmarker, P. Nilsson, P. J. R. Sjçber, M. Larhed, Chem.
Eur. J. 2009, 15, 4630.
Acknowledgements
[19] R. R. Pidaparthi, C. S. Junker, M. E. Welker, C. S. Day, M. W.
Wright, J. Org. Chem. 2009, 74, 8290.
[20] a) S. Arimitsu, B. Fernꢃndez, C. del Pozo, S. Fustero, G. B. Ham-
mond, J. Org. Chem. 2008, 73, 2656; b) S. Fustero, P. Bello, B.
Fernꢃndez, C. del Pozo, G. B. Hammond, J. Org. Chem. 2009, 74,
7690.
This work was supported by the Ministerio de Ciencia e Innovaciꢁn of
Spain (CTQ2010–19774-C02) and Generalitat Valenciana (GV/PROME-
TEO/2010/061). P.B. thanks the University of Valencia for a predoctoral
fellowship.
[1] A. H. Hoveyda, A. R. Zugralin, Nature 2007, 450, 243.
[2] For recent reviews see: a) T. J. Donohoe, L. P. Fishlock, P. A. Proco-
piou, Chem. Eur. J. 2008, 14, 5716; b) S. K. Chattopadhyay, S. Kar-
Received: March 13, 2012
Published online: && &&, 0000
Chem. Eur. J. 2012, 00, 0 – 0
ꢄ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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7
&
ÞÞ
These are not the final page numbers!

S. Fustero, C. del Pozo et al.
Ruthenium catalysis: A new, multi-
component, tandem cross-enyne meta-
thesis (CEYM)-Diels–Alder reaction
that is mediated by 1,7-octadiene is
described. The ethylene liberated in
the ring-closing metathesis of this
diene initiates the enyne metathesis
and, in the presence of a dienophile,
the tandem process takes place in an
efficient manner (see scheme).
Relay Metathesis
S. Fustero,* P. Bello, J. Mirꢁ, A. Simꢁn,
C. del Pozo* ................... &&&& — &&&&
1,7-Octadiene-Assisted Tandem Multi-
component Cross-Enyne Metathesis
(CEYM)-Diels–Alder Reactions: A
Useful Alternative to Moriꢀs Condi-
tions
&
8
&
www.chemeurj.org
ꢄ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!