Access to cyclic α-CF3-substituted α-amino acid derivatives by ring-closing metathesis of functionalized 1,7-enynes

Article abstract of DOI:10.1002/ejoc.201300619

An efficient method for the preparation of new α-CF₃ α-amino acid 1,7-enynes that contain electron-donating and electron-withdrawing groups on the triple bond has been developed that proceeds through a Sonogashira-type coupling reaction. The ring-closing enyne methathesis (RCEYM) of the obtained 1,7-enynes with commercially available Grubbs and Hoveyda catalysts provides access to a series of new cyclic α-amino acids. The latter compounds that contain the 1,3-diene moiety are attractive building blocks for the construction of trifluoromethylated polycyclic systems. An efficient method to prepare new α-CF₃ α-amino acid 1,7-enynes that contain different substituents on the triple bond has been developed that proceeds by a Sonogashira-type coupling reaction. The ring-closing enyne methathesis (RCEYM) of the obtained 1,7-enynes with commercially available Grubbs and Hoveyda catalysts provides access to a series of new cyclic α-amino acids. Copyright

Full text of DOI:10.1002/ejoc.201300619

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FULL PAPER
Fluorinated α-Amino Acids
A. K. Mailyan, I. M. Krylov, C. Bruneau,
P. H. Dixneuf, S. N. Osipov* ........... 1–12
Access to Cyclic α-CF3-Substituted α-
Amino Acid Derivatives by Ring-Closing
Metathesis of Functionalized 1,7-Enynes
An efficient method to prepare new α-CF3
α-amino acid 1,7-enynes that contain
different substituents on the triple bond
has been developed that proceeds by a
Sonogashira-type coupling reaction. The
ring-closing enyne methathesis (RCEYM)
of the obtained 1,7-enynes with commer-
cially available Grubbs and Hoveyda cat-
alysts provides access to a series of new
cyclic α-amino acids.
Keywords: Amino acids / Enynes / Metath-
esis / Cyclization / Cross-coupling / Fluor-
ine
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FULL PAPER
DOI: 10.1002/ejoc.201300619
Access to Cyclic α-CF3-Substituted α-Amino Acid Derivatives by Ring-Closing
Metathesis of Functionalized 1,7-Enynes
Artur K. Mailyan,[a,b] Ivan M. Krylov,[a] Christian Bruneau,[c] Pierre H. Dixneuf,[c] and
Sergey N. Osipov*[a]
Keywords: Amino acids / Enynes / Metathesis / Cyclization / Cross-coupling / Fluorine
An efficient method for the preparation of new α-CF3 α-
amino acid 1,7-enynes that contain electron-donating and
electron-withdrawing groups on the triple bond has been de-
veloped that proceeds through a Sonogashira-type coupling
reaction. The ring-closing enyne methathesis (RCEYM) of
the obtained 1,7-enynes with commercially available Grubbs
and Hoveyda catalysts provides access to a series of new
cyclic α-amino acids. The latter compounds that contain the
1,3-diene moiety are attractive building blocks for the con-
struction of trifluoromethylated polycyclic systems.
proves the profile of bioactive peptides, the synthesis of
fluorinated α-amino acids is currently attracting atten-
tion.[8]
Introduction
Cyclic α-amino acids that contain a piperidine ring are
present in many biologically important compounds.[1]
Pipecolic acid derivatives[2] are nonproteogenic α-amino
acids that are found as metabolites in several biological sys-
tems (e.g., plants, fungi, and human physiological fluids)
and often exhibit interesting pharmacological activities. The
immunosuppressors rapamycin[3] and FK506[4] as well as
the antitumor antibiotic sandramycin[5] are examples of
compounds with a pipecolic acid fragment in their struc-
ture. Although several methods may be envisioned for the
synthesis of such structures, the ring-closing metathesis
(RCM) of α-amino acids that incorporates a 1,7-diene/en-
yne skeleton must surely rank as one of the more direct and
potentially efficient methods.
Because of the unique properties of substances with
fluorine substituents, such as high electronegativity and
hydrophobicity, fluorinated compounds have become very
important in the field of medicinal chemistry and pharma-
ceuticals.[6] Among them, fluorinated amino acids are inter-
esting building blocks that can be used to design the folds
of hyperstable proteins or obtain highly specific
protein···protein interactions.[7] Moreover, 19F NMR spec-
troscopy is an effective tool for conformational studies of
fluorine-containing peptides. As fluorine considerably im-
In past decades, ruthenium alkylidene-catalyzed alkene
metathesis has emerged as a powerful tool of synthetic or-
ganic and biomedical chemistry for the preparation of vari-
ous biologically active molecules, including natural prod-
ucts.[9] The ring-closing enyne metathesis (RCEYM) was re-
vealed as one of the most versatile methods in terms of
efficiency and atom-economy to afford functionalized cyclic
and heterocyclic products that contain the synthetically use-
ful 1,3-diene moiety for a cross-metathesis or Diels–Alder
reaction.[10] Recent examples of biologically relevant com-
pounds that were synthesized by sequences utilizing the
RCEYM as a key step include the antitumor and antiviral
agents acylfulvene and irofulven[11] as well as nucleoside an-
alogues to the agent stavudine.[12]
The development of efficient methods for the preparation
of functionally substituted 1,7-enynes and their catalytic cy-
clization to access new representatives of the pipecolic acid
family, including their fluorinated derivatives, is of current
interest. Although the RCEYM of N-tethered 1,7-enynes
has successfully afforded a variety of functionalized piper-
idines, which include pipecolic acid derivatives,[13] this cata-
lytic cyclization is still a capricious transformation that de-
pends on the steric and electronic effects of the substituents
of 1,7-enyne structure. Furthermore, there is a lack of
straightforward methods to access functionalized enynes,
and only α-H-α-amino acid 1,7-enynes that contain ter-
minal triple bonds have been utilized for the synthesis of
pipecolic acid derivatives. In this case, a high loading of the
Grubbs catalyst (20 mol-%) was required to afford appro-
priate yields of the metathesis products.[13e–13g]
[a] A. N. Nesmeyanov Institute of Organoelement Compounds,
Russian Academy of Sciences,
Vavilov str. 28, 119991 Moscow, Russia
E-mail: osipov@ineos.ac.ru
Homepage: http://www.ineos.ac.ru/en/staff4/osipov.html
[b] National Research Centre “Kurchatov Institute”,
Akademika Kurchatova pl., 1, 123182 Moscow, Russia
[c] Centre of Catalysis and Green Chemistry, UMR 6226 CNRS,
Universite de Rennes 1,
Campus de Beaulieu, 35042 Rennes Cedex, France
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300619.
We have previously described a convenient one-step
method for the synthesis of trifluoromethylated 1,7-enynes
2
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Ring-Closing Metathesis of Functionalized 1,7-Enynes
Figure 1. Synthesis and transformations of fluorinated 1,7-enynes (acac = acetylacetonate).
that incorporates α-aminocarboxylic and α-aminophos- the cyclic product as a result of the poisoning of the active
phonic acids and utilizes a highly selective CuII-catalyzed catalyst through a secondary metathesis of the diene prod-
[2,3] sigmatropic rearrangement of the allyl group of an uct, which leads to a stable and unreactive Ru-carbene spe-
allylpropargyl-containing nitrogen CF3-ylides[14] [see Fig- cies.[16] The utilization of ethylene gas in a RCEYM usually
ure 1, Equation (1a)]. Herein, we disclose the synthesis of prevents the latter process and provides significant improve-
α-CF3-α-amino acid 1,7-enynes with electron-donating and ments to the yields of cyclic 1,3-dienes,[13c,17] and the nature
electron-withdrawing aryl, acyl, and aroyl groups on the of the catalyst can significantly affect the outcome of the
triple bond and their RCEYM with commercially available metathesis reaction.[18]
Grubbs II and Hoveyda II catalysts to afford new fluor-
Taking into account the electronic and steric effects of
inated pipecolic acid derivatives that contain the syntheti- the substituents of 1,7-enyne 1, we first investigated its reac-
cally useful 1,3-diene moiety [see Figure 1, Equation (1b)].
tion with commercially available Ru-based metathesis cat-
alysts (see Scheme 1). In the absence of ethylene, full con-
version of the starting enyne 1 was only achieved by treat-
ment with 5 mol-% of Grubbs I catalyst and heating at
Results and Discussion
Amine-containing compounds generally inhibit an alk- 80 °C in toluene for 8 h (monitored by TLC). This reaction,
ene metathesis by coordinating to the metal site. The use of however, afforded metathesis product 2 in low yield (15%)
sterically hindered amines, acceptor-substituted amines along with a complicated mixture of byproducts (monitored
(e.g., amides), or acidic additives [e.g., Ti(OiPr)4] are the by 19F NMR spectroscopy). Unexpectedly, the application
main solutions to overcome this problems.[15] Furthermore, of Grubbs II and Hoveyda II catalysts under the same con-
the RCEYM of terminal alkynes often gives low yields of ditions for 2 h resulted in the formation of compound 3,
Scheme 1. RCM of terminal 1,7-enyne 1 (Mes = 2,4,6-trimethylphenyl).
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S. N. Osipov et al.
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which arose from the self-metathesis of 2. In these cases, no initiated by the addition of piperidine to the activated triple
trace amounts of 1,3-diene 2 were detected in the reaction bond. After screening several organic bases, we found that
mixtures. The best yield of 3 (63%) was obtained by using the best yields of the corresponding enynes 4g and 4h (see
5 mol-% of Grubbs II in toluene at 80 °C. It is noteworthy Table 1, Entries 7 and 8) were obtained within 3 h by using
that varying the substrate concentration to within a range NEt3 (20-fold excess amount). This result could be ex-
of 0.03–0.2 m did not significantly affect the outcome of all plained by the enhanced reactivity of NO2-substituted iodo-
above-mentioned reactions.
benzenes.
The yield of 2 was significantly improved by performing
the reaction under an ethylene atmosphere. In this case, the
reaction proceeded at 70 °C for 2 h with Grubbs II or Hov-
eyda II catalysts (5 mol-%) to give a mixture of 2 and 3 in
a ratio of approximately 2:1, respectively. Compounds 2 and
3 were easily separated by column chromatography to af-
ford the desired 1,3-diene 2 in 45% yield (see Scheme 1).
As the self-metathesis of 1,1-disubstituted alkenes is not
a trivial task, which generally requires either forcing condi-
tions or more active catalytic systems,[18] we decided to in-
troduce an additional substituent on the triple bond of the
starting enyne 1 to generate a 1,1-disubstituted exocyclic
olefin moiety after the RCEYM step and, thus, to suppress
the undesirable formation of self-metathesis products such
as 3. We performed a Sonogashira Pd-catalyzed cross-cou-
pling reaction between 1 and different aryl iodides. The re-
action of 1 with iodobenzene proceeded at room tempera-
ture in tetrahydrofuran (THF) in the presence of a 5-fold
excess amount of Et3N using a PdCl2(PPh3)2/CuI catalytic
system (5 mol-%) to afford the corresponding internal alk-
yne 4a in poor yield (22%). Comparable amounts of the
homocoupled derivative 5 (32%), which presumably re-
sulted from a Cu-mediated Glaser-type coupling,[19] were
also isolated as a byproduct (see Scheme 2). In the case of
4-iodoanisole, even after 24 h, the formation of a significant
amount of 5 along with the incomplete conversion of 1
(68%) was detected (monitored by 19F NMR spec-
troscopy).[20]
Table 1. Synthesis of aryl-substituted 1,7-enynes 4.
Entry
Ar
Product
% Yield[a]
1
2
3
4
5
6
7
8
Ph
4a
4b
4c
4d
4e
4f
81
79
87
93
95
4-MeOC6H4
4-MeC6H4
4-BocNHC6H4
2-MeC6H4
2-MeOC6H4
2-NO2C6H4
4-NO2C6H4
[b]
86
4g
4h
70[c]
80[c]
[a] After column chromatography on silica gel (hexanes/ethyl acet-
ate). [b] Boc = tert-butoxycarbonyl. [c] Reactions were performed
using NEt3 as a base.
For the preparation of 1,7-enynes that contain electron-
withdrawing groups on the triple bond, the cross-coupling
reaction between 1 and different acyl chlorides was success-
fully performed by using PdCl2(PPh3)2/CuI as the catalyst.
Table 2. Synthesis of acyl-substituted 1,7-enynes 6.
We were pleased that the formation of homocoupled de-
rivative 5 could be completely suppressed by performing the
reaction with 5 mol-% of PdCl2(PPh3)2/CuI with a 20-fold
excess amount of piperidine, as a base, in N,N-dimethyl-
formamide (DMF). The reactions were completed within
4 h at ambient temperature to give cross-coupling products
4a–4f in good yields (79–95%, see Table 1, Entries 1–6).
The only exceptions were the reactions with NO2-substi-
tuted iodobenzenes, in which there was rapid degradation/
Entry
R
Product
% Yield[a]
1
2
3
4
5
C6H5
6a
6b
6c
6d
6e
71
64
74
76
83
4-FC6H4
2-FC6H4
4-ClC6H4
tBu
resinification of the starting enyne 1, which was probably [a] After column chromatography on silica gel (hexanes/ethyl acetate).
Scheme 2. Sonogashira coupling of 1,7-enyne 1 with iodobenzene and 4-iodoanisole.
4
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Ring-Closing Metathesis of Functionalized 1,7-Enynes
The reactions readily occurred at room temperature in THF tures. An explanation for this unusual finding is the strong
and went to completion in only 25 min to give internal α- shielding effect of the ortho substituent, which prevents the
keto alkynes 6a–6e in high yields (see Table 2). The forma- coordination of a ruthenium carbene species to the triple
tion of byproduct 5 was not observed because of the higher bond during the catalytic cycle.
activity of the acyl chlorides in comparison to the aryl iod-
Until now, some aspects of the RCEYM mechanisms
ides.
with regard to the competition between the yne-then-ene
The ring-closing metathesis reactions of the new 1,7-en- and ene-then-yne pathways as well as the exo and endo
ynes 4 and 6, which were comprised of an internal triple selectivity[21] remain unknown. There is, however, evidence
bond, was then investigated with Grubbs II and Hoveyda II that enyne metathesis reactions with substrates that have a
catalysts. The cyclization reactions of 4a–4d proceeded sterically demanding alkyne moiety prefer the yne-then-ene
smoothly with 5 mol-% of Grubbs II catalyst in toluene at pathway.[22] In the formation of small- to medium-sized
80 °C for 2 h to afford the desired products 7a–7d in good rings, the ruthenium-catalyzed RCEYM reactions generally
isolated yields (see Scheme 3). Indeed, in all cases, the self- follow an exo-mode pathway, whereas tungsten- and
metathesis of compounds 7, analogous to the process that molybdenum-catalyzed reactions with similar precursors
formed 3 (see Scheme 1), was not observed.
commonly follow an endo-mode pathway.[23] In the case of
Unexpectedly, 1,7-enynes 4e–4g that contain an ortho- 4h, which contains a para-nitro group on the benzene ring,
substituted aryl moiety on the triple bond (2-MeC6H4, 2- the reaction led to a mixture of exo- and endo-cyclic
MeOC6H4, 2-NO2C6H4) proved to be inert with respect to metathesis products 7h and 8 in a ratio of 2:1, respectively
both Grubbs II and Hoveyda II catalysts, even with in- (see Scheme 4). Both products were easily separated by
creased catalyst loading (up to 10%), elevated temperatures using column chromatography and fully characterized by
(boiling toluene), and an ethylene atmosphere. The starting NMR spectroscopy, MS, and elemental analysis (see Exp.
materials were completely recovered from the reaction mix- Sect.).
Scheme 3. RCM of aryl-substituted 1,7-enynes 4.
Scheme 4. RCM of 1,7-enyne 4h.
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Figure 2. Proposed mechanism for the formation of endo- and exo-cyclic products.
The appearance of a significant amount of endo-cyclic
We have further investigated the RCEYM reaction of
isomer 8 can be rationalized by the formation of a β-ruth- 1,7-enynes 6 that contain electron-withdrawing acyl groups
enacyclobutene intermediate in the first step of the catalytic on the triple bond. The first attempt to perform the reac-
cycle (see Figure 2, Route B), whereas the formation of de- tion by applying the same conditions as those for 4 led to a
rivatives 7 is explained by Route A. Presumably, the elec- complicated mixture of products. We found that 6 smoothly
tron-withdrawing impact of the NO2 group contributes to underwent cyclization by treatment with Hoveyda II cata-
this process.
lyst (5 mol-%) under an ethylene atmosphere in toluene at
80 °C for 3 h to afford the desired products 9 in moderate
to good yields (see Scheme 5). The formation of self-me-
tathesis products, similar to 3, was not observed.
To demonstrate a further synthetic application of these
new cyclic α-amino acid 1,3-dienes, we studied the Diels–
Alder reaction of dienes 7a and 7c with N-phenylmaleimide
(see Scheme 6) to construct functionalized polycyclic com-
pounds. The cycloaddition occurred in toluene at reflux for
24 h to afford the corresponding tricyclic derivatives 10a
Scheme 6. Diels–Alder reaction of 1,3-dienes 7a and 7c with N-
phenylmaleimide to afford 10 (relative configurations).
Scheme 5. RCM of acyl-substituted 1,7-enynes 6.
6
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Ring-Closing Metathesis of Functionalized 1,7-Enynes
interface temperature was set at 180 °C. 1,7-Enyne 1 was prepared
and 10b in 78 and 74% isolated yield, respectively. Products
10a and 10b were formed as diastereomeric mixtures (ca.
3:2, determined by 19F NMR analysis), which could be
easily separated by column chromatography on silica gel.
by a previously published protocol.[14]
Methyl 1-Methyl-2-(trifluoromethyl)-5-vinyl-1,2,3,6-tetrahydropyr-
idine-2-carboxylate (2):
A solution of 1,7-enyne 1 (100 mg,
0.402 mmol) in dry toluene (14 mL) was placed in a flame-dried
two-necked flask that was equipped with a bubbling tube, a bubble
counter, a magnetic stirring bar, and a reflux condenser. Ethylene
gas was bubbled through the toluene solution for 15 min at room
temperature. Then Grubbs’ second-generation catalyst (17 mg,
0.02 mmol) was added, and the resulting wine-red solution was
heated to 80 °C for 2 h with continuous bubbling. The resulted
solution was cooled to room temp., and the solvent was removed
under reduced pressure. The residual oil was chromatographed
(EtOAc/petroleum ether, 1:20) to furnish compound 2 (45 mg,
45%) as a colorless oil. 1H NMR (300 MHz, CDCl3, 25 °C): δ =
6.01 (s, 2 H, 2 CH), 5.75 (s, 2 H, 2 CH), 3.83 (s, 6 H, 2 CO2CH3),
3.65 (d, J = 16.3 Hz, 2 H, 2 NCH2), 3.53 (d, J = 17.3 Hz, 2 H, 2
NCH2), 2.94 (dd, J = 17.9, 5.1 Hz, 2 H, 2 CH2), 2.79–2.64 (m, 8
H, 2 NCH3, 2 CH2) ppm. 13C NMR (101 MHz, CDCl3, 25 °C): δ
= 168.53, 133.69, 126.01, 124.92 (q, J = 288.2 Hz), 121.68, 68.01 (q,
J = 25.3 Hz), 52.74, 51.73, 40.05, 30.57 ppm. 19F NMR (282 MHz,
CDCl3, 25 °C): δ = 8.66 (s, 3 F, CF3) ppm. C11H14F3NO2 (249.23):
calcd. C 53.01, H 5.66, N 5.62; found C 53.22, H 5.32, N 5.98.
Conclusions
An efficient method for the preparation of new α-CF3-α-
amino acid 1,7-enynes that contain electron-donating and
electron-withdrawing groups on the triple bond has been
developed that proceeds through a Sonogashira-type cou-
pling reaction of terminal enynes. Although the RCEYM
of terminal enynes is not efficient, the RCEYM of the ob-
tained 1,7-enynes with commercially available Grubbs and
Hoveyda catalysts have led to the corresponding pipecolic
acid derivatives that contain the synthetically useful 1,3-
diene moiety. As a result, we found that the RCEYM of
1,7-enynes that contain para-substituted aryl groups on the
triple bond proceeded smoothly by treatment with Grubbs
II catalyst. In contrast, their ortho-substituted counterparts
proved to be absolutely inert with respect to both Grubbs
II and Hoveyda II catalysts. 1,7-Enynes with electron-with-
drawing acyl groups displayed low activity in the metathesis
process. In these cases, acceptable yields of the correspond-
ing cyclization products were obtained only by treatment
with Hoveyda II catalyst under an ethylene atmosphere.
Furthermore, the Diels–Alder cycloaddition of the synthe-
sized 1,3-dienes with N-phenylmaleimide as the dienophile
opened access to the hitherto unknown trifluoromethylated
polycyclic amino acid derivatives. These simple and envi-
ronmentally benign reactions extend the potential applica-
tions of cyclic amino acid derivatives to synthetic and me-
dicinal chemistry.
Dimethyl
5,5Ј-(Ethene-1,2-diyl)bis[1-methyl-2-(trifluoromethyl)-
1,2,3,6-tetrahydropyridine-2-carboxylate] (3): A solution of 1,7-en-
yne 1 (0.1 g, 0.402 mmol) in dry toluene (2 mL) was placed in a
flame-dried Schlenk tube under argon, and Grubbs’ second-genera-
tion catalyst (17 mg, 0.02 mmol) was added. The resulting solution
was heated to 80 °C for 2 h. The mixture was cooled to room temp.,
and TLC showed complete disappearance of the starting material.
The solvent was removed under reduced pressure, and the residual
oil was chromatographed (EtOAc/petroleum ether, 1:3) to furnish
compound 3 (57 mg, 60%, 3:2 mixture of isomers) as a yellowish
1
oil. H NMR (300 MHz, CDCl3, 25 °C): δ = 6.01 (s, 2 H, 2 CH),
5.75 (s, 2 H, 2 CH), 3.83 (s, 6 H, 2 CO2CH3), 3.65 (d, J = 16.3 Hz,
2 H, 2 NCH2), 3.53 (d, J = 17.3 Hz, 2 H, 2 NCH2), 2.94 (dd, J =
17.9, 5.1 Hz, 2 H, 2 CH2), 2.79–2.64 (m, 8 H, 2 NCH3, 2
CH2) ppm. 13C NMR (101 MHz, CDCl3, 25 °C): δ = 168.53,
133.69, 126.01, 124.92 (q, J = 288.2 Hz), 121.68, 68.01 (q, J =
25.3 Hz), 52.74, 51.73, 40.05, 30.57 ppm. 19F NMR (282 MHz,
CDCl3, 25 °C): δ = 8.69 (s, 3 F, CF3), 8.58 (s, 3 F, CF3) ppm.
HRMS: calcd. for C20H24F6N2O4 [M + 1]+ 471.4061; found
471.4087. C20H24F6N2O4 (470.41): calcd. C 51.07, H 5.14, N 5.96;
found C 50.77, H 5.29, N 5.74.
Experimental Section
General Methods: All solvents were freshly distilled from the appro-
priate drying agents prior to use. All other reagents were recrys-
tallized or distilled as necessary. The Sonogashira and metathesis
reactions were performed under argon. Analytical TLC was per-
formed with Merck silica gel 60 F254 plates. Visualization was
achieved by using UV light and by spraying with a Ce(SO4)2 solu-
tion in 5% H2SO4 or a KMnO4 solution in water. Column
chromatography was carried out with Merck silica gel 60 (230–
400 mesh ASTM) and a mixture of ethyl acetate/petroleum ether
as the eluent. The NMR spectroscopic data were recorded at room
temperature with Bruker AV-200, AV-300, and AV-600 spectrome-
ters that operated at 300, 400, and 600 MHz, respectively (TMS
General Procedure for Sonogashira Coupling of 1,7-Enyne 1 with
Aryl Iodides: To a flame-dried Schlenk tube was placed a solution
of the corresponding aryl iodide (3 mmol) in dry dimethylform-
amide (17 mL). The solution was cooled to –50 °C, and the air was
replaced by argon. Then, PdCl2(PPh3)2 (70 mg, 0.1 mmol), piperi-
dine (3 mL), and a solution of 1,7-enyne 1 (0.5 g, 2 mmol) in dry
dimethylformamide (3 mL) were sequentially added under an argon
flow. The resulting mixture was again degassed and warmed to
room temperature. CuI (19 mg, 0.1 mmol) was added under an ar-
gon flow, and the reaction mixture immediately became colorless
and was stirred for 4 h. The resulting solution was poured into
brine (200 mL), and the product was extracted with EtOAc (3ϫ
70 mL). The organic fractions were combined, washed with water
(2ϫ), and dried with MgSO4. The solvents were evaporated to dry-
ness under reduced pressure. The crude product was purified by
column chromatography with the appropriate mixture of EtOAc
and petroleum ether.
1
reference) for H NMR, at 75, 101, and 151 MHz for 13C NMR,
and 282 MHz for 19F NMR (CF3COOH reference). High resolu-
tion mass spectra were measured with a Bruker micro TOF II in-
strument using electrospray ionization. The measurements were
performed either in a positive ion mode (interface capillary voltage:
4500 V) or in a negative ion mode (3200 V) with a mass range from
m/z = 50 to 3000 Da, and the external or internal calibration was
done with an Electrospray Calibrant Solution (Fluka). Syringe in-
jection was used for solutions in acetonitrile, methanol, and water
(flow rate: 3 μL/min). Nitrogen was applied as a dry gas, and the
Methyl 2-[Methyl(3-phenylprop-2-yn-1-yl)amino]-2-(trifluorometh-
yl)pent-4-enoate (4a): Column chromatography (EtOAc/petroleum
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S. N. Osipov et al.
CF3) ppm. C18H20F3NO2 (339.36): calcd. C 63.71, H 5.94, N 4.13;
FULL PAPER
ether, 1:20) afforded 4a (0.53 g, 81%) as a colorless oil. H NMR
1
(400 MHz, CDCl3, 25 °C): δ = 7.45–7.38 (m, 2 H, Ar), 7.32–7.25 found C 63.55, H 6.21, N 4.27.
(m, 3 H, Ar), 5.90–5.75 (m, 1 H, CHallyl), 5.23–5.10 (m, 2 H,
Methyl 2-{[3-(2-Methoxyphenyl)prop-2-yn-1-yl](methyl)amino}-2-
CH2allyl), 3.84–3.68 (m, 5 H, CO2CH3, NCH2), 2.88–2.74 (m, 2 H,
CH2), 2.67 (q, J = 1.1 Hz, 3 H, NCH3) ppm. 13C NMR (101 MHz,
CDCl3, 25 °C): δ = 168.23, 131.70, 130.97, 128.24, 128.11, 125.98
(q, J = 294.1 Hz), 123.18, 119.62, 85.58, 84.14, 72.76 (q, J =
23.9 Hz), 52.68, 42.66 (q, J = 1.8 Hz), 36.55, 36.53 ppm. 19F NMR
(trifluoromethyl)pent-4-enoate (4f): Column chromatography
(EtOAc/petroleum ether, 1:10) afforded 4f (0.61 g, 86%) as a color-
less oil. 1H NMR (300 MHz, CDCl3, 25 °C): δ = 7.31 (dd, J = 7.5,
1.6 Hz, 1 H, Ar), 7.26–7.10 (m, 1 H, Ar), 6.87–6.70 (m, 2 H, Ar),
5.87–5.65 (m, 1 H, CHallyl), 5.18–5.01 (m, 2 H, CH2allyl), 3.85–3.61
(m, 8 H, CO2CH3, OCH3, NCH2), 2.88–2.64 (m, 2 H, CH2), 2.61 (s,
3 H, NCH3) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ = 167.90,
159.77, 133.29, 130.82, 129.22, 125.65 (q, J = 293.9 Hz), 120.05,
119.16, 112.03, 110.30, 89.37, 80.25, 72.51 (q, J = 23.8 Hz), 55.36,
52.27, 42.50, 36.28, 36.12 ppm. 19F NMR (282 MHz, CDCl3,
25 °C): δ = 11.24 (s, 3 F, CF3) ppm. C18H20F3NO3 (355.35): calcd.
C 60.84, H 5.67, N 3.94; found C 60.97, H 5.81, N 3.88.
(282 MHz, CDCl3, 25 °C):
δ = 11.41 (s, 3 F, CF3) ppm.
C17H18F3NO2 (325.33): calcd. C 62.76, H 5.58, N 4.31; found C
63.01, H 5.75, N 4.48.
Methyl 2-{[3-(4-Methoxyphenyl)prop-2-yn-1-yl](methyl)amino}-2-
(trifluoromethyl)pent-4-enoate (4b): Column chromatography
(EtOAc/petroleum ether, 1:15) afforded 4b (0.56 g, 79%) as a yel-
lowish oil. 1H NMR (300 MHz, CDCl3, 25 °C): δ = 7.42 (d, J =
8.8 Hz, 2 H, Ar), 6.88 (d, J = 8.8 Hz, 2 H, Ar), 6.01–5.80 (m, 1 H,
CHallyl), 5.32–5.15 (m, 2 H, CH2allyl), 3.95–3.73 (m, 8 H, CO2CH3,
OCH3, NCH2), 2.99–2.80 (m, 2 H, CH2), 2.74 (s, 3 H, NCH3) ppm.
13C NMR (75 MHz, CDCl3, 25 °C): δ = 167.89, 159.17, 132.78,
130.73, 125.70 (q, J = 294.1 Hz), 119.20, 114.98, 113.53, 83.75,
83.67, 72.44 (q, J = 23.8 Hz), 54.85, 52.27, 42.35, 36.21, 36.20 ppm.
19F NMR (282 MHz, CDCl3, 25 °C): δ = 11.38 (s, 3 F, CF3) ppm.
C18H20F3NO3 (355.35): calcd. C 60.84, H 5.67, N 3.94; found C
60.71, H 5.88, N 3.82.
General Procedure for Sonogashira Coupling of 1,7-Enyne 1 with 1-
Iodo-4-nitrobenzene or 1-Iodo-2-nitrobenzene: The same synthetic
protocol at that for 4a–4f was applied, but NEt3 was used instead
of piperidine.
Methyl
2-{Methyl[3-(2-nitrophenyl)prop-2-yn-1-yl]amino}-2-(tri-
fluoromethyl)pent-4-enoate (4g): Column chromatography (EtOAc/
petroleum ether, 1:10) afforded 4g (0.52 g, 70%) as a yellow oil. 1H
NMR (400 MHz, CDCl3, 25 °C): δ = 7.99 (dd, J = 8.2, 0.9 Hz, 1
H, Ar), 7.60 (dd, J = 7.8, 1.4 Hz, 1 H, Ar), 7.53 (td, J = 7.6, 1.2 Hz,
Methyl 2-{Methyl[3-(p-tolyl)prop-2-yn-1-yl]amino}-2-(trifluorometh- 1 H, Ar), 7.42 (td, J = 11.2, 1.5 Hz, 1 H, Ar), 5.91–5.66 (m, 1 H,
yl)pent-4-enoate (4c): Column chromatography (EtOAc/petroleum
ether, 1:20) afforded 4c (0.56 g, 87%) as a colorless oil. H NMR
(300 MHz, CDCl3, 25 °C): δ = 7.39 (d, J = 7.8 Hz, 2 H, Ar), 7.17
(d, J = 7.8 Hz, 2 H, Ar), 6.01–5.81 (m, 1 H, CHallyl), 5.31–5.18 (m,
CHallyl), 5.30–5.03 (m, 2 H, CH2allyl), 3.93–3.68 (m, 5 H, CO2CH3,
NCH2), 2.88–2.73 (m, 2 H, CH2), 2.69 (s, 3 H, NCH3) ppm. 13C
NMR (101 MHz, CDCl3, 25 °C): δ = 168.17, 149.86, 134.92,
132.73, 130.79, 128.55, 125.94 (q, J = 294.0 Hz), 124.52, 119.72,
1
2 H, CH2allyl), 3.92–3.73 (m, 5 H, CO2CH3, NCH2), 2.98–2.80 (m, 118.54, 94.23 (q, J = 1.4 Hz), 79.26, 72.76 (q, J = 23.9 Hz), 52.73,
2 H, CH2), 2.75 (s, 3 H, NCH3), 2.40 (s, 3 H, CH3) ppm. 13C NMR 42.89 (q, J = 2.0 Hz), 36.63 (q, J = 1.5 Hz), 36.44 ppm. 19F NMR
(75 MHz, CDCl3, 25 °C): δ = 167.94, 137.85, 131.29, 130.74, (282 MHz, CDCl3, 25 °C): 11.61 (s, F, CF3) ppm.
δ
=
3
128.69, 125.70 (q, J = 294.1 Hz), 119.83, 119.26, 84.52, 83.95, 72.47
C17H17F3N2O4 (370.33): calcd. C 55.14, H 4.63, N 7.56; found C
55.22, H 4.76, N 7.49.
(q, J = 23.8 Hz), 52.34, 42.39, 36.26, 36.24, 21.12 ppm. 19F NMR
(282 MHz, CDCl3, 25 °C):
C18H20F3NO2 (339.36): calcd. C 63.71, H 5.94, N 4.13; found C
64.03, H 5.72, N 4.33.
δ = 11.36 (s, 3 F, CF3) ppm.
Methyl
2-{Methyl[3-(4-nitrophenyl)prop-2-yn-1-yl]amino}-2-(tri-
fluoromethyl)pent-4-enoate (4h): Column chromatography (EtOAc/
petroleum ether, 1:10) afforded 4h (0.59 g, 80%) as a yellow oil. 1H
NMR (300 MHz, CDCl3, 25 °C): δ = 8.23 (d, J = 8.9 Hz, 2 H, Ar),
7.62 (d, J = 8.9 Hz, 2 H, Ar), 5.99–5.76 (m, 1 H, CHallyl), 5.33–
5.17 (m, 2 H, CH2allyl), 3.87 (s, J = 4.7 Hz, 5 H, CO2CH3, NCH2),
2.87 (d, J = 7.0 Hz, 2 H, CH2), 2.75 (s, 3 H, NCH3) ppm. 13C
NMR (75 MHz, CDCl3, 25 °C): δ = 167.65, 146.61, 132.01, 130.30,
129.70, 125.55 (q, J = 294.0 Hz), 123.08, 119.32, 91.15, 81.97, 72.31
(q, J = 24.0 Hz), 52.31, 42.28, 36.22, 36.09 ppm. 19F NMR
Methyl
2-[(3-{4-[(tert-Butoxycarbonyl)amino]phenyl}prop-2-yn-1-
yl)(methyl)amino]-2-(trifluoromethyl)pent-4-enoate (4d): Column
chromatography (EtOAc/petroleum ether, 1:15) afforded 4d (0.52 g,
93%) as a colorless oil. 1H NMR (300 MHz, CDCl3, 25 °C): δ =
7.41 (d, J = 8.8 Hz, 2 H, Ar), 7.36 (d, J = 8.8 Hz, 2 H, Ar), 6.58
(s, 1 H, NH), 6.03–5.77 (m, 1 H, CHallyl), 5.37–5.13 (m, 2 H,
CH2allyl), 3.96–3.66 (m, 5 H, CO2CH3, NCH2), 2.98–2.81 (m, 2 H,
CH2), 2.73 (s, 3 H, NCH3), 1.57 (s, 9 H, 3 CH3) ppm. 13C NMR
(75 MHz, CDCl3, 25 °C): δ = 167.96, 152.28, 138.15, 132.12,
130.67, 125.67 (q, J = 294.1 Hz), 119.26, 117.73, 117.02, 84.29,
83.69, 80.39, 72.42 (q, J = 23.8 Hz), 52.32, 42.36, 36.24, 36.22,
27.95 ppm. 19F NMR (282 MHz, CDCl3, 25 °C): δ = 11.41 (s, 3 F,
CF3) ppm. C22H27F3N2O4 (440.46): calcd. C 59.99, H 6.18, N 6.36;
found C 59.81, H 6.29, N 6.55.
(282 MHz, CDCl3, 25 °C):
C17H17F3N2O4 (370.33): calcd. C 55.14, H 4.63, N 7.56; found C
55.38, H 4.82, N 7.39.
δ = 11.36 (s, 3 F, CF3) ppm.
Dimethyl 2,2Ј-[Hexa-2,4-diyne-1,6-diylbis(methylazanediyl)]bis[2-
(trifluoromethyl)pent-4-enoate] (5): Compound 5 (yellowish oil) was
isolated as a byproduct of the Sonogashira coupling of 1,7-enyne
1 with iodobenzene or 4-iodoanisole. 1H NMR (600 MHz, CDCl3,
25 °C): δ = 5.93–5.65 (m, 2 H, 2 CHallyl), 5.31–5.07 (m, 4 H, 2
CH2allyl), 3.80 (s, 6 H, 2 CO2CH3), 3.64 (d, J = 17.5 Hz, 2 H, 2
NCH2), 3.59 (d, J = 17.5 Hz, 2 H, 2 NCH2), 2.89–2.69 (m, 4 H, 2
CH2), 2.62 (s, 6 H, 2 NCH3) ppm. 13C NMR (151 MHz, CDCl3,
25 °C): δ = 168.01, 130.67, 125.82 (q, J = 293.8 Hz), 119.67, 74.67,
72.56 (q, J = 24.0 Hz), 68.45, 52.67, 42.57, 36.41, 36.42 ppm. 19F
NMR (282 MHz, CDCl3, 25 °C): δ = 11.00 (s, 6 F, 2 CF3) ppm.
C22H26F6N2O4 (496.45): calcd. C 53.23, H 5.28, N 5.64; found C
53.49, H 5.56, N 5.77.
Methyl
2-{Methyl[3-(o-tolyl)prop-2-yn-1-yl]amino}-2-(trifluoro-
methyl)pent-4-enoate (4e): Column chromatography (EtOAc/petro-
leum ether, 1:15) afforded 4e (0.64 g, 95%) as a colorless oil. 1H
NMR (300 MHz, CDCl3, 25 °C): δ = 7.49 (d, J = 7.4 Hz, 1 H, Ar),
7.39–7.14 (m, 3 H, Ar), 6.05–5.81 (m, 1 H, CHallyl), 5.41–5.16 (m,
2 H, CH2allyl), 4.02–3.78 (m, 5 H, CO2CH3, NCH2), 3.02–2.84 (m,
2 H, CH2), 2.78 (s, 3 H, NCH3), 2.52 (s, 3 H, CH3) ppm. 13C NMR
(75 MHz, CDCl3, 25 °C): δ = 167.96, 139.88, 131.74, 130.73,
129.09, 127.82, 125.73 (q, J = 294.0 Hz), 125.19, 122.72, 119.21,
89.26, 82.71, 72.48 (q, J = 24.0 Hz), 52.30, 42.43, 36.21, 36.23,
General Procedure for Sonogashira Coupling of 1,7-Enyne 1 with
20.39 ppm. 19F NMR (282 MHz, CDCl3, 25 °C): δ = 11.15 (s, 3 F, Acyl Chlorides: In a flame-dried Schlenk tube, a solution of 1,7-
8
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Job/Unit: O30619
/KAP1
Date: 09-07-13 16:56:24
Pages: 12
Ring-Closing Metathesis of Functionalized 1,7-Enynes
enyne 1 (0.3 g, 1.2 mmol) with the corresponding acyl chloride
(1.8 mmol) in dry tetrahydrofuran (5 mL) was mixed together. The
reaction mixture was cooled to –78 °C, and the air was replaced by
argon. Then, PdCl2(PPh3)2 (42 mg, 0.06 mmol) and CuI (11 mg,
0.06 mmol) were sequentially added under an argon flow. The re-
sulting suspension was warmed to room temperature, and NEt3
(0.21 mL, 1.8 mmol) was injected through a rubber septum. After
stirring for 5 min, much of the white precipitate appeared, and the
reaction mixture was stirred for an additional 20 min. TLC analysis
showed full conversion of the starting 1,7-enyne. The resulting mix-
ture was filtered to remove the NEt3·HCl, and the solvents were
evaporated to dryness under reduced pressure. The crude product
was purified by column chromatography with the appropriate mix-
ture of EtOAc and petroleum ether as the eluent.
= 8.6 Hz, 2 H, Ar), 7.51 (d, J = 8.7 Hz, 2 H, Ar), 5.97–5.73 (m, 1
H, CHallyl), 5.33–5.18 (m, 2 H, CH2allyl), 3.93 (s, 2 H, NCH2), 3.86
(s, 3 H, CO2CH3), 2.86 (d, J = 6.9 Hz, 2 H, CH2), 2.76 (s, 3 H,
NCH3) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ = 175.97,
167.51, 140.36, 134.71, 130.49, 130.04, 128.58, 125.49 (q, J =
293.5 Hz), 119.48, 91.42, 81.44, 72.17 (q, J = 24.3 Hz), 52.40, 42.05,
36.52, 35.99 ppm. 19F NMR (282 MHz, CDCl3, 25 °C): δ = 10.78
(s, 3 F, CF3) ppm. C18H17ClF3NO3 (387.78): calcd. C 55.75, H 4.42,
N 3.61; found C 55.59, H 4.63, N 3.72.
Methyl 2-[(5,5-Dimethyl-4-oxohex-2-yn-1-yl)(methyl)amino]-2-(tri-
fluoromethyl)pent-4-enoate (6e): Column chromatography (EtOAc/
petroleum ether, 1:10) afforded 6e (0.33 g, 83%) as a yellowish oil.
1H NMR (300 MHz, CDCl3, 25 °C): δ = 5.91–5.70 (m, 1 H, CHal-
lyl), 5.37–5.08 (m, 2 H, CH2allyl), 3.82 (s, 3 H, CO2CH3), 3.80 (s, 2
H, NCH2), 2.80 (d, J = 6.9 Hz, 2 H, CH2), 2.67 (s, 3 H, NCH3),
1.23 (s, 9 H, 3 CH3) ppm. 13C NMR (151 MHz, CDCl3, 25 °C): δ
= 193.83, 167.89, 130.47, 125.83 (q, J = 293.8 Hz), 119.72, 90.12,
81.42, 72.48 (q, J = 24.2 Hz), 52.69, 44.64, 42.10, 36.63, 36.30,
25.85 ppm. 19F NMR (282 MHz, CDCl3, 25 °C): δ = 10.66 (s, 3 F,
CF3) ppm. C16H22F3NO3 (333.35): calcd. C 57.65, H 6.65, N 4.20;
found C 57.92, H 6.77, N 4.48.
Methyl 2-[Methyl(4-oxo-4-phenylbut-2-yn-1-yl)amino]-2-(trifluoro-
methyl)pent-4-enoate (6a): Column chromatography (EtOAc/petro-
leum ether, 1:15) afforded 6a (0.3 g, 71%) as a yellow oil. 1H NMR
(300 MHz, CDCl3, 25 °C): δ = 8.21 (d, J = 7.5 Hz, 2 H, Ar), 7.68
(t, J = 7.4 Hz, 1 H, Ar), 7.55 (t, J = 7.5 Hz, 2 H, Ar), 5.94–5.75
(m, 1 H, CHallyl), 5.35–5.16 (m, 2 H, CH2allyl), 3.94 (s, 2 H, NCH2),
3.87 (s, 3 H, CO2CH3), 2.87 (d, J = 6.9 Hz, 2 H, CH2), 2.78 (s, 3
H, NCH3) ppm. 13C NMR (101 MHz, CDCl3, 25 °C): δ = 177.74,
167.97, 136.78, 134.15, 130.58, 129.62, 128.63, 125.93 (q, J =
293.5 Hz), 119.82, 91.23, 82.23, 72.65 (q, J = 24.2 Hz), 52.76, 42.46
(q, J = 1.9 Hz), 36.96, 36.45 ppm. 19F NMR (282 MHz, CDCl3,
25 °C): δ = 10.77 (s, 3 F, CF3) ppm. C18H18F3NO3 (353.34): calcd.
C 61.19, H 5.13, N 3.96; found C 61.03, H 5.31, N 4.15.
General Procedure for Ruthenium-Catalyzed RCEYM of Aryl-Sub-
stituted 1,7-Enynes 4a–4d and 4h: A solution of corresponding aryl-
substituted 1,7-enyne 4 (1.5 mmol) in dry toluene (15 mL) was
placed in a flame-dried Schlenk tube under argon, and Grubbs’
second-generation catalyst (64 mg, 0.075 mmol) was added. The re-
sulting solution was heated to 80 °C for 2 h. Then, the reaction
mixture was cooled to room temp., and 19F NMR analysis indi-
cated full conversion of the starting material. The solvent was re-
moved under reduced pressure, and the residual oil was chromato-
graphed with the appropriate mixture of EtOAc and petroleum
ether to furnish the desired product.
Methyl 2-{[4-(4-Fluorophenyl)-4-oxobut-2-yn-1-yl](methyl)amino}-2-
(trifluoromethyl)pent-4-enoate (6b): Column chromatography
(EtOAc/petroleum ether, 1:10) afforded 6b (0.28 g, 64%) as a yellow
oil. 1H NMR (300 MHz, CDCl3, 25 °C): δ = 8.34–8.07 (m, 2 H,
Ar), 7.29–7.10 (m, 2 H, Ar), 5.97–5.68 (m, 1 H, CHallyl), 5.39–5.09
(m, 2 H, CH2allyl), 3.90 (s, 2 H, NCH2), 3.84 (s, J = 5.6 Hz, 3 H,
CO2CH3), 2.84 (d, J = 6.9 Hz, 2 H, CH2), 2.74 (s, 3 H,
NCH3) ppm. 13C NMR (101 MHz, CDCl3, 25 °C): δ = 176.08,
167.92, 166.51 (d, J = 256.6 Hz), 133.30 (d, J = 2.7 Hz), 132.28 (d,
J = 9.6 Hz), 130.52, 125.92 (q, J = 293.5 Hz), 119.83, 115.84 (d, J
= 22.2 Hz), 91.55, 81.91, 72.62 (q, J = 24.3 Hz), 52.77, 42.45 (q, J
= 1.9 Hz), 36.93, 36.42 ppm. 19F NMR (282 MHz, CDCl3, 25 °C):
δ = 10.75 (s, 3 F, CF3), –25.53 (s, 1 F, CFAr) ppm. C18H17F4NO3
(371.33): calcd. C 58.22, H 4.61, N 3.77; found C 58.39, H 4.49, N
3.93.
Methyl 1-Methyl-5-(1-phenylvinyl)-2-(trifluoromethyl)-1,2,3,6-tetra-
hydropyridine-2-carboxylate (7a): Column chromatography
(EtOAc/petroleum ether, 1:30) afforded 7a (0.33 g, 67%) as a color-
1
less oil. H NMR (600 MHz, CDCl3, 25 °C): δ = 7.39–7.30 (m, 3
H, Ar), 7.29–7.25 (m, 2 H, Ar), 5.61 (br. s, 1 H, CH), 5.19 (s, 1 H,
CH2), 5.12 (s, 1 H, CH2), 3.84 (s, 3 H, CO2CH3), 3.70 (d, J =
17.5 Hz, 1 H, NCH2), 3.58 (d, J = 17.5 Hz, 1 H, NCH2), 2.88 (d,
J = 17.9 Hz, 1 H, CH2), 2.71 (q, J = 1.3 Hz, 3 H, NCH3), 2.67 (d,
J = 17.9 Hz, 1 H, CH2) ppm. 13C NMR (151 MHz, CDCl3, 25 °C):
δ = 168.61, 147.85, 140.67, 135.58, 128.50, 128.07, 127.51, 125.03
(q, J = 288.7 Hz), 121.25, 112.60, 67.53 (q, J = 25.1 Hz), 53.10,
52.68, 39.95, 30.38 ppm. 19F NMR (282 MHz, CDCl3, 25 °C): δ =
8.83 (s, 3 F, CF3) ppm. C17H18F3NO2 (325.33): calcd. C 62.76, H
5.58, N 4.31; found C 62.57, H 5.43, N 4.59.
Methyl 2-{[4-(2-Fluorophenyl)-4-oxobut-2-yn-1-yl](methyl)amino}-2-
(trifluoromethyl)pent-4-enoate (6c): Column chromatography
(EtOAc/petroleum ether, 1:15) afforded 6c (0.32 g, 74%) as a
1
brownish oil. H NMR (300 MHz, CDCl3, 25 °C): δ = 8.09 (td, J
= 7.7, 1.8 Hz, 1 H, Ar), 7.77–7.48 (m, 1 H, Ar), 7.36–7.26 (m, 1
H, Ar), 7.20 (ddd, J = 11.0, 8.3, 0.8 Hz, 1 H, Ar), 6.02–5.66 (m, 1
H, CHallyl), 5.42–5.07 (m, 2 H, CH2allyl), 3.90 (s, 2 H, NCH2), 3.85
(s, 3 H, CO2CH3), 2.85 (d, J = 6.9 Hz, 2 H, CH2), 2.74 (s, 3 H,
NCH3) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ = 173.66,
167.55, 161.66 (d, J = 262.0 Hz), 135.20 (d, J = 9.1 Hz), 131.64,
130.12, 125.46 (q, J = 293.6 Hz), 125.01 (d, J = 7.6 Hz), 123.77 (d,
J = 4.0 Hz), 119.32 (d, J = 10.8 Hz), 116.66 (d, J = 21.8 Hz), 90.76,
83.08, 72.18 (q, J = 24.1 Hz), 52.33, 42.04, 36.42, 35.98 ppm. 19F
NMR (282 MHz, CDCl3, 25 °C): δ = 10.76 (s, 3 F, CF3), –33.87 (s,
1 F, CFAr) ppm. C18H17F4NO3 (371.33): calcd. C 58.22, H 4.61, N
3.77; found C 58.05, H 4.82, N 4.01.
Methyl 5-[1-(4-Methoxyphenyl)vinyl]-1-methyl-2-(trifluoromethyl)-
1,2,3,6-tetrahydropyridine-2-carboxylate (7b): Column chromatog-
raphy (EtOAc/petroleum ether, 1:15) afforded 7b (0.29 g, 68%) as
1
a colorless oil. H NMR (300 MHz, CDCl3, 25 °C): δ = 7.24 (d, J
= 8.6 Hz, 2 H, Ar), 6.91 (d, J = 8.6 Hz, 2 H, Ar), 5.68 (br. s, 1 H,
CH), 5.16 (s, 1 H, CH2), 5.12 (s, 1 H, CH2), 3.87 (s, 3 H, CO2CH3),
3.86 (s, 3 H, OCH3), 3.73 (d, J = 16.4 Hz, 1 H, NCH2), 3.59 (d, J
= 16.4 Hz, 1 H, NCH2), 2.93 (d, J = 18.1 Hz, 1 H, CH2), 2.74 (s,
3 H, NCH3), 2.64 (d, J = 18.1 Hz, 1 H, CH2) ppm. 13C NMR
(75 MHz, C6D6, 25 °C): δ = 168.58, 159.18, 147.42, 136.00, 132.99,
129.50, 125.07 (q, J = 288.6 Hz), 120.90, 113.47, 111.69, 67.54 (q,
Methyl 2-{[4-(4-Chlorophenyl)-4-oxobut-2-yn-1-yl](methyl)-amino}- J = 25.2 Hz), 55.15, 53.29, 52.57, 39.86, 30.37 ppm. 19F NMR
2-(trifluoromethyl)pent-4-enoate (6d): Column chromatography
(EtOAc/petroleum ether, 1:15) afforded 6d (0.35 g, 76%) as a
brownish oil. 1H NMR (300 MHz, CDCl3, 25 °C): δ = 8.13 (d, J
(282 MHz, CDCl3, 25 °C): δ = 8.79 (s, 3 F, CF3) ppm.
C18H20F3NO3 (355.35): calcd. C 60.84, H 5.67, N 3.94; found C
61.15, H 5.95, N 3.76.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
9

Job/Unit: O30619
/KAP1
Date: 09-07-13 16:56:24
Pages: 12
S. N. Osipov et al.
FULL PAPER
Methyl
1-Methyl-5-[1-(p-tolyl)vinyl]-2-(trifluoromethyl)-1,2,3,6- for C17H17F3N2O4 [M
+
1]+ 371.3232; found 371.3214.
tetrahydropyridine-2-carboxylate (7c): Column chromatography
(EtOAc/petroleum ether, 1:30) afforded 7c (0.3 g, 74%) as a color-
less oil. H NMR (300 MHz, CDCl3, 25 °C): δ = 7.20 (s, 4 H, Ar),
C17H17F3N2O4 (370.33): calcd. C 55.14, H 4.63, N 7.56; found C
55.51, H 4.37, N 7.88.
1
General Procedure for Ruthenium-Catalyzed RCEYM of Acyl-Sub-
stituted 1,7-Enynes 6a–6e: A solution of the corresponding acyl-
substituted 1,7-enyne 6 (0.8 mmol) in dry toluene (40 mL) was
placed in flame-dried Schlenk tube under argon. The Hoveyda–
Grubbs’ second-generation catalyst (25 mg, 0.04 mmol) was added,
and the argon atmosphere was replaced by ethylene gas. The re-
sulting solution was heated to 80 °C for 3 h. Then, the reaction
mixture was cooled to room temp., and 19F NMR analysis showed
full conversion of the starting material. The solvent was removed
under reduced pressure, and the crude product was purified by col-
umn chromatography with the appropriate mixture of EtOAc and
petroleum ether as the mobile phase.
5.67 (br. s, 1 H, CH), 5.19 (s, 1 H, CH2), 5.14 (s, 1 H, CH2), 3.88
(s, 3 H, CO2CH3), 3.73 (d, J = 16.8 Hz, 1 H, NCH2), 3.60 (d, J =
16.8 Hz, 1 H, NCH2), 2.91 (d, J = 17.9 Hz, 1 H, CH2), 2.80–2.64
(m, 4 H, NCH3, CH2), 2.42 (s, 3 H, CH3) ppm. 13C NMR
(75 MHz, CDCl3, 25 °C): δ = 168.33, 147.45, 137.44, 137.01,
135.44, 128.69, 128.09, 124.73 (q, J = 288.8 Hz), 120.75, 111.92,
67.28 (q, J = 25.2 Hz), 52.94, 52.45, 39.68, 30.08, 20.89 ppm. 19F
NMR (282 MHz, CDCl3, 25 °C): δ = 8.79 (s, 3 F, CF3) ppm.
C18H20F3NO2 (339.36): calcd. C 63.71, H 5.94, N 4.13; found C
63.92, H 5.81, N 4.29.
Methyl 5-(1-{4-[(tert-Butoxycarbonyl)amino]phenyl}vinyl)-1-methyl-
2-(trifluoromethyl)-1,2,3,6-tetrahydropyridine-2-carboxylate
(7d):
Methyl
1-Methyl-5-(3-oxo-3-phenylprop-1-en-2-yl)-2-(trifluoro-
Column chromatography (EtOAc/petroleum ether, 1:10) afforded
7d (0.37 g, 70%) as a white powder; m.p. 43–45 °C. 1H NMR
(400 MHz, CDCl3, 25 °C): δ = 7.32 (d, J = 8.0 Hz, 2 H, Ar), 7.17
(d, J = 8.3 Hz, 2 H, Ar), 6.61 (s, J = 29.1 Hz, 1 H, NH), 5.60 (br.
s, 1 H, CH), 5.10 (s, 1 H, CH2), 5.06 (s, 1 H, CH2), 3.81 (s, 3 H,
CO2CH3), 3.64 (d, J = 16.6 Hz, 1 H, NCH2), 3.52 (d, J = 16.6 Hz,
1 H, NCH2), 2.84 (d, J = 15.1 Hz, 1 H, CH2), 2.73–2.58 (m, 4 H,
NCH3, CH2), 1.52 [s, 9 H, C(CH3)3] ppm. 13C NMR (101 MHz,
CDCl3, 25 °C): δ = 168.59, 152.79, 147.28, 137.79, 135.70, 135.29,
129.03, 124.98 (q, J = 288.5 Hz), 121.06, 118.16, 112.07, 80.60,
67.49 (q, J = 25.1 Hz), 53.20, 52.71, 39.92, 30.32, 28.32 ppm. 19F
NMR (282 MHz, CDCl3, 25 °C): δ = 8.83 (s, 3 F, CF3) ppm.
C22H27F3N2O4 (440.46): calcd. C 59.99, H 6.18, N 6.36; found C
60.19, H 5.94, N 6.71.
methyl)-1,2,3,6-tetrahydropyridine-2-carboxylate (9a): Column
chromatography (EtOAc/petroleum ether, 1:8) afforded 9a (0.14 g;
50%) as a colorless oil. 1H NMR (300 MHz, CDCl3, 25 °C): δ =
7.92 (d, J = 7.3 Hz, 2 H, Ar), 7.61 (t, J = 7.3 Hz, 1 H, Ar), 7.49
(t, J = 7.3 Hz, 2 H, Ar), 5.75 (br. s, 1 H, CH), 5.54 (s, 1 H, CH2),
5.30 (s, 1 H, CH2), 3.86–3.73 (m, 4 H, CO2CH3, NCH2), 3.66 (d,
J = 16.2 Hz, 1 H, NCH2), 2.86 (dd, J = 18.0, 4.8 Hz, 1 H, CH2),
2.76 (s, 3 H, NCH3), 2.64 (dd, J = 18.0, 2.8 Hz, 1 H, CH2) ppm.
13C NMR (75 MHz, CDCl3, 25 °C): δ = 197.05, 167.85, 145.98,
136.21, 133.20, 131.57, 129.54, 128.19, 124.49 (q, J = 288.2 Hz),
122.27, 115.23, 67.02 (q, J = 25.3 Hz), 52.44, 51.46, 39.61 (q, J =
2.0 Hz), 30.05 ppm. 19F NMR (282 MHz, CDCl3, 25 °C): δ = 9.19
(s, 3 F, CF3) ppm. C18H18F3NO3 (353.34): calcd. C 61.19, H 5.13,
N 3.96; found C 60.95, H 5.29, N 4.15.
Methyl
1-Methyl-5-[1-(4-nitrophenyl)vinyl]-2-(trifluoromethyl)-
Methyl 5-[3-(4-Fluorophenyl)-3-oxoprop-1-en-2-yl]-1-methyl-2-(tri-
fluoromethyl)-1,2,3,6-tetrahydropyridine-2-carboxylate (9b): Col-
umn chromatography (EtOAc/petroleum ether, 1:8) afforded 9b
1,2,3,6-tetrahydropyridine-2-carboxylate (7h): Column chromatog-
raphy (EtOAc/petroleum ether, 1:12) afforded 7h (0.26 g, 60%) as
a yellowish solid; m.p. 94–95 °C. 1H NMR (600 MHz, CDCl3,
25 °C): δ = 7.87 (d, J = 8.8 Hz, 2 H, Ar), 6.94 (d, J = 8.8 Hz, 1 H,
Ar), 5.29 (br. s, J = 2.1 Hz, 1 H, CH), 5.03 (s, 1 H, CH2), 4.88 (s,
1 H, CH2), 3.67 (d, J = 16.5 Hz, 1 H, NCH2), 3.40 (d, J = 16.5 Hz,
1 H, NCH2), 3.33 (s, 3 H, CO2CH3), 2.85 (dd, J = 17.7, 5.4 Hz, 1
H, CH2), 2.70 (q, J = 1.4 Hz, 3 H, NCH3), 2.62 (dq, J = 17.7,
3.0 Hz, 1 H, CH2) ppm. 13C NMR (151 MHz, C6D6, 25 °C): δ =
168.04, 147.30, 146.75, 146.18, 135.13, 128.99, 125.44 (q, J =
288.2 Hz), 123.18, 122.22, 114.27, 67.48 (q, J = 25.8 Hz), 52.91,
51.86, 39.56, 30.84 ppm. 19F NMR (282 MHz, CDCl3, 25 °C): δ =
8.82 (s, 3 F, CF3) ppm. MS (EI): m/z (%) = 370 (15) [M]+, 311 (100)
1
(0.22 g, 75%) as a yellow oil. H NMR (600 MHz, CDCl3, 25 °C):
δ = 7.90 (dd, J = 8.9, 5.4 Hz, 2 H, Ar), 7.10 (t, J = 8.6 Hz, 2 H,
Ar), 5.68 (br. s, 1 H, CH), 5.48 (s, 1 H, CH2), 5.24 (s, 1 H, CH2),
3.77 (s, 3 H, CO2CH3), 3.72 (d, J = 16.5 Hz, 1 H, NCH2), 3.60 (d,
J = 16.5 Hz, 1 H, NCH2), 2.81 (dd, J = 18.1, 5.2 Hz, 1 H, CH2),
2.70 (q, J = 1.1 Hz, 3 H, NCH3), 2.59 (dd, J = 18.2, 2.9 Hz, 1 H,
CH2) ppm. 13C NMR (151 MHz, CDCl3, 25 °C): δ = 195.73,
168.10, 165.98 (d, J = 255.7 Hz), 146.05, 132.87 (d, J = 2.1 Hz),
132.52 (d, J = 9.4 Hz), 131.76, 124.78 (q, J = 288.5 Hz), 122.69,
115.66 (d, J = 22.0 Hz), 115.32, 67.27 (q, J = 25.4 Hz), 52.73, 51.65,
39.88, 29.68 ppm. 19F NMR (282 MHz, CDCl3, 25 °C): δ = 8.85
(s, 3 F, CF3), –26.12 (s, 1 F, CFAr) ppm. C18H17F4NO3 (371.33):
calcd. C 58.22, H 4.61, N 3.77; found C 58.45, H 4.52, N 3.95.
[M – CO2Me]+, 163 (20) [M – CO2Me – CH2=CH-C6H4-NO2]2+
.
HRMS: calcd. for C17H17F3N2O4 [M + 1]+ 371.3232; found
371.3210. C17H17F3N2O4 (370.33): calcd. C 55.14, H 4.63, N 7.56;
found C 55.30, H 4.29, N 7.81.
Methyl 5-[3-(2-Fluorophenyl)-3-oxoprop-1-en-2-yl]-1-methyl-2-(tri-
fluoromethyl)-1,2,3,6-tetrahydropyridine-2-carboxylate (9c): Col-
umn chromatography (EtOAc/petroleum ether, 1:10) afforded 9c
Methyl 1-Methyl-6-methylene-5-(4-nitrophenyl)-2-(trifluoromethyl)-
2,3,6,7-tetrahydro-1H-azepine-2-carboxylate
(8):
Column
1
chromatography (EtOAc/petroleum ether, 1:12) afforded 8 (0.12 g,
28%) as a yellowish oil. 1H NMR (600 MHz, C6D6, 25 °C): δ =
7.94 (d, J = 8.8 Hz, 2 H, Ar), 7.02 (d, J = 8.8 Hz, 2 H, Ar), 5.33–
5.29 (m, 1 H, CH), 4.82 (s, 1 H, CH2), 4.56 (s, 1 H, CH2), 3.92 (d,
J = 16.3 Hz, 1 H, NCH2), 3.44 (d, J = 16.3 Hz, 1 H, NCH2), 3.40
(s, 3 H, CO2CH3), 2.87 (dd, J = 16.1, 5.7 Hz, 1 H, CH2), 2.75 (dd,
(0.14 g, 48%) as a yellow oil. H NMR (300 MHz, CDCl3, 25 °C):
δ = 7.71 (t, J = 7.4 Hz, 1 H, Ar), 7.63–7.46 (m, 1 H, Ar), 7.25 (t,
J = 7.5 Hz, 1 H, Ar), 7.17–7.06 (m, 1 H, Ar), 5.81 (br. s, 1 H, CH),
5.60 (s, 1 H, CH2), 5.46 (s, 1 H, CH2), 3.82 (s, 3 H, CO2CH3), 3.72
(d, J = 16.8 Hz, 1 H, NCH2), 3.60 (d, J = 16.8 Hz, 1 H, NCH2),
2.87 (dd, J = 18.0, 4.8 Hz, 1 H, CH2), 2.72 (s, 3 H, NCH3), 2.62
J = 16.1, 8.2 Hz, 1 H, CH2), 2.65 (s, 3 H, NCH3) ppm. 13C NMR (dd, J = 18.0, 2.6 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3,
(151 MHz, C6D6, 25 °C): δ = 168.10, 148.48, 147.13, 145.06, 25 °C): δ = 193.66, 168.02, 160.81 (d, J = 255.9 Hz), 147.71, 134.01
143.29, 129.51, 126.09 (q, J = 290.0 Hz), 125.00, 123.14, 116.52, (d, J = 8.7 Hz), 131.36, 130.75, 126.22 (d, J = 12.0 Hz), 124.55 (q,
73.37 (q, J = 24.8 Hz), 57.40, 51.73, 39.26, 30.78 ppm. 19F NMR
(282 MHz, CDCl3, 25 °C): δ = 6.40 (s, 3 F, CF3) ppm. MS (EI):
m/z (%) = 370 (15) [M]+, 311 (100) [M – CO2Me]+. HRMS: calcd.
J = 288.1 Hz), 124.03 (d, J = 3.6 Hz), 121.61, 118.85, 116.24 (d, J
= 22.1 Hz), 67.16 (q, J = 25.5 Hz), 52.40, 52.17, 39.56, 29.87 ppm.
19F NMR (282 MHz, CDCl3, 25 °C): δ = 8.46 (s, 3 F, CF3), –34.52
10
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Job/Unit: O30619
/KAP1
Date: 09-07-13 16:56:24
Pages: 12
Ring-Closing Metathesis of Functionalized 1,7-Enynes
(s, 1 F, CFAr) ppm. C18H17F4NO3 (371.33): calcd. C 58.22, H 4.61, 7.28 (t, J = 6.8 Hz, 1 H, Ar), 7.13 (d, J = 7.2 Hz, 2 H, Ar), 7.08
N 3.77; found C 58.50, H 4.73, N 3.59.
(d, J = 7.0 Hz, 2 H, Ar), 3.87 (s, 3 H, CO2CH3), 3.83 (d, J =
14.7 Hz, 1 H, NCH2), 3.47–3.41 (m, 1 H, NCH2), 3.34–3.28 (m, 2
H, CH2), 3.17–3.07 (m, 2 H, CH2), 2.86–2.73 (m, 2 H, 2 CH), 2.57
(dd, J = 14.8, 4.1 Hz, 1 H, CH), 2.52 (q, J = 1.7 Hz, 3 H,
NCH3) ppm. 13C NMR (151 MHz, CDCl3, 25 °C): δ = 178.20,
176.81, 169.79, 139.48, 134.26, 131.65, 130.86, 129.23, 128.77,
128.29, 127.99, 127.39, 126.40, 126.07 (q, J = 294.6 Hz), 69.07 (q,
J = 24.6 Hz), 53.14, 50.09, 42.19, 40.02, 39.27, 31.80, 30.56,
29.09 ppm. 19F NMR (282 MHz, CDCl3, 25 °C): δ = 7.69 (s, 3 F,
CF3) ppm. C27H25F3N2O4 (498.50): calcd. C 65.05, H 5.05, N 5.62;
found C 65.31, H 5.33, N 5.43.
Methyl 5-[3-(4-Chlorophenyl)-3-oxoprop-1-en-2-yl]-1-methyl-2-(tri-
fluoromethyl)-1,2,3,6-tetrahydropyridine-2-carboxylate (9d): Col-
umn chromatography (EtOAc/petroleum ether, 1:10) afforded 9d
1
(0.22 g, 71%) as a yellow oil. H NMR (300 MHz, CDCl3, 25 °C):
δ = 7.83 (d, J = 8.5 Hz, 2 H, Ar), 7.44 (d, J = 8.5 Hz, 2 H, Ar),
5.70 (br. s, 1 H, CH), 5.53 (s, 1 H, CH2), 5.28 (s, 1 H, CH2), 3.86–
3.70 (m, 4 H, CO2CH3, NCH2), 3.62 (d, J = 16.3 Hz, 1 H, NCH2),
2.84 (dd, J = 18.1, 4.9 Hz, 1 H, CH2), 2.73 (q, J = 1.2 Hz, 3 H,
NCH3), 2.68–2.56 (m, 1 H, CH2) ppm. 13C NMR (75 MHz,
CDCl3, 25 °C): δ = 195.53, 167.69, 145.57, 139.55, 134.50, 131.39,
130.77, 128.42, 127.36 (q, J = 288.2 Hz), 122.36, 115.36, 66.90 (q,
Methyl 7-Methyl-1,3-dioxo-2-phenyl-5-(p-tolyl)-8-(trifluoromethyl)-
J = 25.4 Hz), 52.27, 51.32, 39.49, 29.96 ppm. 19F NMR (282 MHz, 2,3,3a,4,6,7,8,9,9a,9b-decahydro-1H-pyrrolo[3,4-f]isoquinoline-8-
CDCl3, 25 °C): δ = 8.65 (s, 3 F, CF3) ppm. C18H17ClF3NO3
(387.78): calcd. C 55.75, H 4.42, N 3.61; found C 55.61, H 4.65, N
3.83.
carboxylate (10b): Column chromatography (gradient of EtOAc/
petroleum ether, from 1:8 to 1:5 and 1:1) afforded 10b (0.91 g, 74%)
as a diasteromeric mixture (A/B, 2:1). Data for diastereomer A: 1H
NMR (600 MHz, CDCl3, 25 °C): δ = 7.46 (t, J = 7.6 Hz, 2 H, Ar),
7.40 (t, J = 7.4 Hz, 1 H, Ar), 7.16 (d, J = 7.8 Hz, 2 H, Ar), 7.13
(d, J = 7.2 Hz, 2 H, Ar), 7.00 (d, J = 8.0 Hz, 2 H, Ar), 3.85 (s, 3
H, CO2CH3), 3.75 (dt, J = 14.1, 2.6 Hz, 1 H, NCH2), 3.47 (t, J =
14.1 Hz, 1 H, NCH2), 3.44–3.39 (m, 1 H, CH2), 3.34 (d, J =
14.0 Hz, 1 H, CH2), 3.29 (dd, J = 8.9, 5.8 Hz, 1 H, CH2), 3.13 (dd,
J = 14.5, 1.1 Hz, 1 H, CH2), 2.95–2.87 (m, 1 H, CH), 2.82–2.75
(m, 1 H, CH), 2.47 (dd, J = 15.3, 4.8 Hz, 1 H, CH), 2.38 (s, 3 H,
NCH3), 2.37 (s, 3 H, CH3) ppm. 13C NMR (151 MHz, CDCl3,
25 °C): δ = 178.23, 176.94, 168.94, 137.13, 136.49, 133.62, 131.73,
131.34, 129.24, 129.02, 128.76, 127.96, 126.49, 125.97 (q, J =
286.6 Hz), 69.00 (q, J = 25.4 Hz), 52.25, 50.73, 42.43, 40.44, 40.18,
31.71, 31.04, 28.33, 21.20 ppm. 19F NMR (282 MHz, CDCl3,
25 °C): δ = 5.11 (s, 3 F, CF3) ppm. C28H27F3N2O4 (512.53): calcd.
C 65.62, H 5.31, N 5.47; found C 65.43, H 5.53, N 5.34. Data for
Methyl 5-(4,4-Dimethyl-3-oxopent-1-en-2-yl)-1-methyl-2-(trifluoro-
methyl)-1,2,3,6-tetrahydropyridine-2-carboxylate (9e): Column
chromatography (EtOAc/petroleum ether, 1:8) afforded 9e (0.18 g;
70%) as a yellow oil. 1H NMR (600 MHz, CDCl3, 25 °C): δ = 5.45
(br. s, 1 H, CH), 5.10 (s, 1 H, CH2), 4.88 (s, 1 H, CH2), 3.72 (s, 3 H,
CO2CH3), 3.56 (d, J = 16.5 Hz, 1 H, NCH2), 3.47 (d, J = 16.5 Hz, 1
H, NH2), 2.82 (dd, J = 18.0, 5.4 Hz, 1 H, CH2), 2.64 (d, J = 1.3 Hz,
3 H, NCH3), 2.60–2.54 (m, 1 H, CH2), 1.12 [s, 9 H, C(CH3)3] ppm.
13C NMR (151 MHz, CDCl3, 25 °C): δ = 213.53, 168.09, 147.45,
131.50, 124.69 (q, J = 288.3 Hz), 121.44, 109.95, 67.31 (q, J =
25.4 Hz), 52.64, 51.39, 44.40, 39.79, 30.21, 27.01 ppm. 19F NMR
(282 MHz, CDCl3, 25 °C):
δ = 8.61 (s, 3 F, CF3) ppm.
C16H22F3NO3 (333.35): calcd. C 55.65, H 6.65, N 4.20; found C
55.41, H 6.39, N 4.11.
1
General Procedure for Diels–Alder Reaction of Compounds 7a and
7c with N-Phenylmaleimide: A mixture of the corresponding 1,3-
diene (2.4 mmol) and N-phenylmaleimide (0.44 g, 2.52 mmol) in
dry toluene (10 mL) was placed in a flame-dried Schlenk tube un-
der argon. The resulting mixture was heated at 110 °C for 24 h.
TLC analysis showed full conversion of the starting material. The
solvent was evaporated to dryness under reduced pressure, and the
crude mixture was purified by column chromatography with the
appropriate mixture of EtOAc/petroleum ether to give the desired
product as a mixture of diastereomers.
diastereomer B: H NMR (600 MHz, CDCl3, 25 °C): δ = 7.44 (t,
J = 7.6 Hz, 2 H, Ar), 7.38 (t, J = 7.4 Hz, 1 H, Ar), 7.14 (d, J =
7.8 Hz, 2 H, Ar), 7.12 (d, J = 7.2 Hz, 2 H, Ar), 6.96 (d, J = 8.0 Hz,
2 H, Ar), 3.87 (s, 3 H, CO2CH3), 3.82 (d, J = 14.6 Hz, 1 H, NCH2),
3.42 (t, J = 8.3 Hz, 1 H, NCH2), 3.33–3.26 (m, 2 H, CH2), 3.15–
3.07 (m, 2 H, CH2), 2.83–2.72 (m, 2 H, 2 CH), 2.56 (dd, J = 14.8,
4.1 Hz, 1 H, CH), 2.51 (q, J = 1.4 Hz, 3 H, NCH3), 2.36 (s, 3 H,
CH3) ppm. 13C NMR (151 MHz, CDCl3, 25 °C): δ = 178.24,
176.87, 169.86, 137.11, 136.60, 133.67, 131.67, 130.72, 129.20,
128.96, 128.74, 127.89, 126.42, 126.10 (q, J = 294.9 Hz), 69.08 (q,
J = 24.4 Hz), 53.12, 50.13, 42.21, 40.04, 39.27, 31.79, 30.63, 29.13,
21.19 ppm. 19F NMR (282 MHz, CDCl3, 25 °C): δ = 7.70 (s, 3 F,
CF3) ppm. C28H27F3N2O4 (512.53): calcd. C 65.62, H 5.31, N 5.47;
found C 65.82, H 5.45, N 5.79.
Methyl
7-Methyl-1,3-dioxo-2,5-diphenyl-8-(trifluoromethyl)-
2,3,3a,4,6,7,8,9,9a,9b-decahydro-1H-pyrrolo[3,4-f]isoquinoline-8-
carboxylate (10a): Column chromatography (gradient of EtOAc/
petroleum ether, from 1:8 to 1:5 and 1:1) afforded 10a (0.93 g, 78%)
as a mixture of diasteromers (A/B, 2:1). Data for diastereomer A:
1H NMR (600 MHz, CDCl3, 25 °C): δ = 7.46 (t, J = 7.6 Hz, 2 H,
Ar), 7.40 (t, J = 7.4 Hz, 1 H, Ar), 7.35 (t, J = 7.5 Hz, 2 H, Ar),
7.29 (t, J = 7.4 Hz, 1 H, Ar), 7.14 (d, J = 7.4 Hz, 1 H, Ar), 7.10
(d, J = 7.1 Hz, 2 H, Ar), 3.85 (s, 3 H, CO2CH3), 3.75 (dt, J = 14.1,
2.5 Hz, 1 H, NCH2), 3.51–3.40 (m, 2 H, NCH2, CH2), 3.35–3.28
(m, 2 H, CH2), 3.15 (d, J = 13.8 Hz, 1 H, CH2), 2.96–2.89 (m, 1
H, CH), 2.85–2.77 (m, 1 H, CH), 2.48 (dd, J = 15.3, 4.8 Hz, 1 H,
CH), 2.38 (s, 3 H, NCH3) ppm. 13C NMR (151 MHz, CDCl3,
25 °C): δ = 178.18, 176.86, 168.90, 139.38, 134.21, 131.71, 131.45,
129.25, 128.78, 128.35, 128.05, 127.39, 126.46, 125.94 (q, J =
286.4 Hz), 68.99 (q, J = 25.8 Hz), 52.25, 50.66, 42.41, 40.43, 40.17,
31.72, 30.96, 28.33 ppm. 19F NMR (282 MHz, CDCl3, 25 °C): δ =
5.38 (s, 3 F, CF3) ppm. C27H25F3N2O4 (498.50): calcd. C 65.05, H
5.05, N 5.62; found C 64.81, H 5.21, N 5.77. Data for diastereomer
Supporting Information (see footnote on the first page of this arti-
1
cle): H and 13C NMR spectroscopic data for representative com-
pounds.
Acknowledgments
This work was financially supported by the Russian Foundation of
Basic Research (grant number 12-03-00557) and Groupe de Re-
cherche International (grant number 12-03-93111) in the frame of
a bilateral collaboration between CNRS France and the Russian
Academy of Sciences.
[1] For example, see: a) J. P. Shilvock, R. J. Nash, J. D. Lloyd,
A. L. Winters, N. Asano, J. W. Fleet, Tetrahedron: Asymmetry
1998, 9, 3505; b) B. Ho, T. M. Zabriskie, Bioorg. Med. Chem.
Lett. 1998, 8, 739; c) I. Ninomiya, T. Kiguchi, T. Naito, in: The
1
B: H NMR (600 MHz, CDCl3, 25 °C): δ = 7.45 (t, J = 7.6 Hz, 2
H, Ar), 7.39 (t, J = 7.4 Hz, 1 H, Ar), 7.34 (t, J = 7.5 Hz, 2 H, Ar),
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
11

Job/Unit: O30619
/KAP1
Date: 09-07-13 16:56:24
Pages: 12
S. N. Osipov et al.
FULL PAPER
Alkaloids (Ed. G. A. Cordell), Academic Press, New York,
1998, vol. 50, p. 317; d) D. Lamarre, G. Croteau, L. Bourgon,
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Received: April 29, 2013
Published Online: ᭿
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