Intramolecular alkene–alkyne metathesis and 1,4-cis-hydrogenation as a stereocontrolled route to compounds with exocyclic double bonds

Article abstract of DOI:10.1007/s11172-020-2739-1

Intramolecular alkene-alkyne metathesis of diethyl (but-3-en-1-yl)(propargyl)malonate affords diethyl 3-vinylcyclohex-3-ene-1,1-dicarboxylate whose conjugated diene system was 1,4-cis-hydrogenated in the presence of η⁶-(naphthalene)chromium tri

Full text of DOI:10.1007/s11172-020-2739-1

Russian Chemical Bulletin, International Edition, Vol. 69, No. 1, pp. 169—171, January, 2020
169
Brief Communications
Intramolecular alkene—alkyne metathesis and 1,4-cis-hydrogenation
as a stereocontrolled route to compounds with exocyclic double bonds
A. A. Vasil´ev,a L. Engman,b E. P. Serebryakova†
aN. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (499) 135 5328. E-mail: vasiliev@ioc.ac.ru
bDepartment of Chemistry, Uppsala University,
BMC Box 576, 751 23 Uppsala, Sweden.
E-mail: Lars.Engman@kemi.uu.se
Intramolecular alkene—alkyne metathesis of diethyl (but-3-en-1-yl)(propargyl)malonate
affords diethyl 3-vinylcyclohex-3-ene-1,1-dicarboxylate whose conjugated diene system was
1,4-cis-hydrogenated in the presence of 6-(naphthalene)chromium tricarbonyl. The exocyclic
double bond of thus formed diethyl 3-ethylidenecyclohexane-1,1-dicarboxylate is strictly
(E)-configured.
Key words: enynes, dienes, metathesis, 1,4-cis-hydrogenation, stereocontrolled synthesis.
Stereospecific 1,4-cis-hydrogenation of conjugated
dienes performed over chromium carbonyl complexes (see
priority reports1,2 and reviews3,4) and more rarely over
special ruthenium catalysts5—7 is a convenient strategy for
formation of olefins with specified configuration of the
double bond. The expedience of its employment in target
synthesis of complex compounds is largely determined by
the availability of the corresponding diene precursors (see
review8). Since the late 1990s promising procedures for
performing alkene—alkyne (enyne) metathesis affording
conjugated dienes were developed (see review9). Therefore,
the sequence of such metathesis and 1,4-cis-hydrogenation
seems to be a good protocol for stereocontrolled synthesis
of olefins restricted only by the accessibility of the required
precursors. In the late 1990s, the preparation of 2,3-di-
substituted butadienes by intermolecular metathesis of
alkynes and ethylene10,11 in the presence of Grubbs I
catalyst was proposed. Using this procedure, we converted
1-acetoxy-5-benzyloxypent-2-yne into the corresponding
2-acetoxymethyl-3-(2-benzyloxyethyl)buta-1,3-diene,
which was further 1,4-cis-hydrogenated into a Z-configured
tetrasubstituted olefin,12 a potent precursor for the phero-
mones faranal and lasiol. It is noteworthy that only in 2018
other scientists13 turned their attention to the possibility
of employing the enyne metathesis—cis-hydrogenation
sequence for the alkene stereosynthesis.
At the same time, 1,4-cis-hydrogenation of dienes of
the 1-(alk-1-en-1-yl)cycloalk-1-ene type can serve as
† Deceased.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 1, pp. 0169—0171, January, 2020.
1066-5285/20/6901-0169 © 2020 Springer Science+Business Media, Inc.

Vasil´ev et al.
170
Russ. Chem. Bull., Int. Ed., Vol. 69, No. 1, January, 2020
a practically non-competitive strategy to obtain com-
pounds with exocyclic double bonds of required configu-
ration (see review3 and original works14,15). The necessary
alkenylcycloalkenes were prepared by complicated multi-
step synthesis. In 1998, an interesting access to such dienes
by intramolecular alkene—alkyne metathesis was re-
ported,16 the model enyne precursors being rather avail-
able. Hence, extension of the enyne metathesis—cis-
hydrogenation protocol onto compounds bearing both
multiple bonds in one molecule seems to be an expedient
route to alkylidenecycloalkanes with specified configura-
tion of the double bond.
Herein, with model enyne 1 the possibility of accom-
plishing such a protocol is demonstrated (Scheme 1).
Enyne 1 was subjected to intramolecular metathesis in the
presence of Grubbs I catalyst under an ethylene atmo-
sphere following the earlier described procedure16 (the
positive effect of ethylene to promote the reaction was
reported16). In our hands, the reaction proceeded rather
slowly (within 1—4 days); however, the yield of vinyl-
cyclohexene 2 was essentially quantitative. Apparently,
the full conversion was due to a higher thermodynamic
stability of the cyclization product.
(see Scheme 1). In particular, irradiation of an olefin
proton at  5.24 caused response on the singlet of C(2)H2
group at  2.59 (7%) and on the doublet of the CH3 group
at  1.54 (13%). Irradiation of this methyl group produced
no effect on the C(2)H2 group but had a weak (~1%) cor-
relation with the other 4-positioned methylene group of
the cycle at  2.10 along with that of the olefin proton
(~3%). This result is in agreement with a mechanism
comprising formation of intermediate A (see Scheme 1
and works1,2).
Concerning the positive effect of ethylene to promote
metathesis,16 we anticipated to obtain some other more
complex dienes from the starting enynes by replacing
ethylene for other alkenes. In particular, it seemed intrigu-
ing to access dienes with chlorine atoms at the double
bonds. In our experiments, metathesis of enyne 1 in the
presence of trans-1,2-dichloroethylene (10 mmoles) gave
quantitatively the same diene 2. According to the balance,
transformation 12 is an isomerization and there is no
demand to incorporate or release any species. Therefore,
the role of dichloroethylene in the course of 12 metath-
esis and its promotion in view of full conversion of reactant 1
remains unclear.
In conclusion, the sequence of intramolecular alkene—
alkyne metathesis and 1,4-cis-hydrogenation can serve as
a convenient protocol for the stereocontrolled preparation
of olefins with exocyclic double bond. We believe that
extension of this approach to more complex compounds
can simplify schemes for the total synthesis of physiolo-
gically valuable compounds (see, e.g., review3).
Scheme 1
Experimental
NMR spectra were recorded on a Varian Unity-400 spectro-
meter (working frequencies of 399.95 (1H) and 100.57 MHz
(
13C)) in CDCl3. High resolution electrospray ionization mass
spectrometry was performed with a Bruker micrOTOF II instru-
ment operating on a positive ion mode (capillary voltage was
4500 V), the mass scanning range (m/z) was 50—3000 Da with
internal calibration using Electrospray Calibrant Solution (Fluka).
Acetonitrile solutions of the samples were injected via a syringe
at a flow rate of 3 L min–1. Nitrogen was used as the nebulizer gas
(4 L min–1), the interface temperature was 180 C. High resolu-
tion mass spectra were recorded in the Department of Structural
Studies of the N. D. Zelinsky Institute of Organic Chemistry
of the Russian Academy of Sciences (Moscow, Russia).17
6-(Naphthalene)chromium tricarbonyl was synthesized as earlier
reported.18 Hydrogenation was carried out in a 250 mL stainless
steel Parr autoclave equipped with a mechanical stirrer. Benzyl-
idenebis(tricyclohexylphosphine)dichlororuthenium (Grubbs I
catalyst) was purchased from Fluka. Silica gel MATREX LC
60/A/35-70 MY 80/25 85040 (GRACE Davison) was used for
column chromatography in amounts of 30—40 mL in volume
per 1 g of the material to be separated, the column diameter was
selected to provide silica layer height of 15—20 cm.
i. H2 (40 atm), THF, 45—50 C, 3 h.
Subsequent 1,4-cis-hydrogenation of diene 2 employ-
ing 6-(naphthalene)chromium tricarbonyl at 40 atm and
45-50 C within 3 h afforded alkene 3 with the exocyclic
double bond in quantitative yield (1H NMR data). Its
configuration was established based on NOE experiments
Diethyl (but-3-en-1-yl)(propargyl)malonate (1). To a solution
of diethyl malonate (4.01 g, 25 mmol) and 4-bromobut-1-ene

Stereoconfigured exocyclic double bond
Russ. Chem. Bull., Int. Ed., Vol. 69, No. 1, January, 2020
171
(3.38 g, 25 mmol) in DMSO (35 mL), freshly powdered K2CO3
(13.8 g, 100 mmol) was added and the mixture was stirred at
55 C for 5 h. An aliquot was treated with water, extracted with
ether, dried with CaCl2, evaporated, and dissolved in CDCl3.
The 1H NMR spectrum of thus prepared sample contained sig-
nals of diethyl (but-3-en-1-yl)malonate (cf. Ref. 19), ca 5% of
the starting diethyl malonate, and no dialkylated product. Then
propargyl bromide (3.27 g, 27.5 mmol) was added. After 4 h
stirring at 50 C, another portion of propargyl bromide (0.5 g,
4.2 mmol) was added and the reaction was continued for 2 h. The
mixture was treated with water (100 mL), extracted with diethyl
ether (320 mL), dried with CaCl2, concentrated, and the resi-
due was co-evaporated with toluene. The residue was subjected
to silica gel column chromatography (gradient elution with
3.55% EtOAc in pentane) to afford along with mixed fractions
(the major impurity was diethyl dipropargylmalonate) 2.5 g (39%)
of pure title compound 1. 1H NMR (400 MHz, CDCl3), : 1.24
(t, 6 H, J = 7.1 Hz); 1.96 (m, 2 H); 1.99 (t, 1 H, J = 2.7 Hz);
2.14 (m, 2 H); 2.82 (d, 2 H, J = 2.7 Hz); 4.19 (q, 4 H, J = 7.1 Hz);
4.96 (d, 1 H, J = 10.1 Hz); 5.04 (d, 1 H, J = 17.2 Hz); 5.78
(m, 1 H). The 1H NMR spectrum is in accord with that re-
ported previously.20
C(5)H2); 2.03 (t, 2 H, C(6)H2, J = 6.1 Hz); 2.10 (t, 2 H, C(4)
H2, J = 6.4 Hz); 2.59 (s, 2 H, C(2)H2); 4.08—4.21 (m, 4 H,
OCH2); 5.24 (br.q, =CH, J = 6.9 Hz). 13C NMR (100 MHz,
CDCl3), : 12.8 (=CCH3), 14.0 (CH3), 23.5 (CH2), 26.9 (CH2),
31.6 (CH2), 41.0 (CH2), 56.6 (C), 61.0 (OCH2), 119.2 (=CH),
134.2 (=C), 171.4 (C=O). HRMS (ESI), m/z: found 255.1591
[M + H]+, 277.1410 [M + Na]+; C14H22O4; calculated: [M + H] =
= 255.1596, [M + Na] = 277.1416.
References
1. M. Cais, E. N. Frankel, A. Rejoan, Tetrahedron Lett.,
1968, 1919.
2. E. N. Frankel, E. Selke, C. A. Glass, J. Am. Chem. Soc., 1968,
90, 2446.
3. M. Sodeoka, M. Shibasaki, Synthesis, 1993, 643.
4. A. A. Vasil´ev, E. P. Serebryakov, Russ. Chem. Bull, 2002,
51, 1341.
5. S. Steines, U. Englert, B. Driessen-Hölscher, Chem. Commun.,
2000, 217.
6. Ch. Fehr, I. Magpantay, M. Vuagnoux, Ph. Dupau, Chem.
Eur. J., 2011, 17, 1257.
7. A. A. Birkbeck, X. Marquet, P. Millet, H. Pamingle, Eur. J.
Org. Chem., 2014, 7582.
8. A. A. Vasil´ev, E. P. Serebryakov, Russ. Chem. Rev., 2001,
70, 735.
9. S. T. Diver, A. J. Giessert, Chem. Rev., 2004, 104, 1317.
10. A. Kinoshita, N. Sakakibara, M. Mori, J. Am. Chem. Soc.,
1997, 119, 12388.
Diethyl 3-vinylcyclohex-3-ene-1,1-dicarboxylate (2). A solu-
tion of enyne 1 (0.65 g, 2.6 mmol) in CH2Cl2 (12 mL) was stirred
with Cl2Ru=CHPh(PCy3)2 catalyst (50 mg) under an ethylene
atmosphere at room temperature for 18 h. An aliquot was
evaporated, the residue was dissolved in CDCl3 (0.5 mL), passed
through silica (ca. 0.1 mL), the silica pad was rinsed with CDCl3
1
(0.2 mL), and the filtrate was analyzed by H NMR, which re-
vealed 91% conversion. The reaction mixture was left for 3 days,
which provided full conversion. In another experiment with 2.5 g
of enyne 1, 46 mL of CH2Cl2, and 70 mg of the catalyst, the
conversion in 18 h was 14%. Additional 50 mg portion of the
catalyst was added, the conversion reached 87% in 1 day and
100% in 4 days in total. The combined reaction mixtures were
concentrated, co-evaporated with toluene, and the residue was
purified by silica gel column chromatography (gradient elution
with 13.5% EtOAc in pentane). Overall yield 2.9 g (92%).
1H NMR (400 MHz, CDCl3), : 1.24 (t, 6 H, J = 7.1 Hz); 2.13
(m, 2 H); 2.22 (m, 2 H); 2.68 (br.q, 2 H, J = 1.7 Hz); 4.19 (q, 4 H,
J = 7.1 Hz); 4.96 (d, 1 H, J = 11.0 Hz); 5.15 (d, 1 H, J = 17.7 Hz);
5.70 (br.t, 1 H, J = 1.7 Hz); 6.35 (dd, 1 H, J = 11.0 Hz, J = 17.7 Hz).
13C NMR (100 MHz, CDCl3), : 14.0 (CH3), 22.8 (CH2), 27.3
(CH2), 29.3 (CH2), 53.1 (C), 61.3 (OCH2), 110.7 (=CH2), 127.7
(=CH of the cycle), 133.1 (=C), 138.8 (=CH vinyl), 171.5
(C=O). The spectrum is in accord with that reported previously.16
Diethyl (E)-3-ethylidenecyclohexane-1,1-dicarboxylate (3).
Diene 2 (2.9 g, 11.5 mmol) was hydrogenated in the presence of
6-(naphthalene)chromium tricarbonyl (0.2 mg) in THF at
45—50 C for 3 h under an initial hydrogen pressure of 40 atm,
which provided a complete conversion of the starting compound
(1H NMR data). The product was purified by silica gel column
chromatography (gradient eluton with 23.5% EtOAc in pentane)
to afford 2.7 g (93%) of the title compound as a thick colorless
oil. 1H NMR (400 MHz, CDCl3), : 1.21 (t, 6 H, CH2CH3,
J = 7.1 Hz); 1.54 (d, 3 H, =CCH3, J = 6.7 Hz); 1.62 (m, 2 H,
11. A. Kinoshita, N. Sakakibara, M. Mori, Tetrahedron, 1999,
55, 8155.
12. A. A. Vasil´ev, L. Engman, E. P. Serebryakov, Mendeleev
Commun., 2000, 10, 101.
13. F. Ratsch, H.-G. Schmalz, Synlett, 2018, 29, 785.
14. M. Shibasaki, M. Sodeoka, Y. Ogawa, J. Org. Chem., 1984,
49, 4096.
15. M. Sodeoka, Y. Ogawa, Y. Kirio, M. Shibasaki, Chem. Pharm.
Bull., 1991, 39, 309.
16. M. Mori, N. Sakakibara, A. Kinoshita, J. Org. Chem., 1998,
63, 6082.
17. A. M. Tsedilin, A. N. Fakhrutdinov, D. B. Eremin, S. S.
Zalesskiy, A. O. Chizhov, N. G. Kolotyrkina, V. P. Ananikov,
Mendeleev Commun., 2015, 25, 454; DOI: 10.1016/j.mencom.
2015.11.019.
18. M. Uemura, T. Minami, K. Hirotsu, Y. Hayashi, J. Org.
Chem., 1989, 54, 469.
19. G. A. Molander, C. R. Harris, J. Am. Chem. Soc., 1996,
118, 4059.
20. R. Singh, R. R. Schrock, P. Müller, A. H. Hoveyda, J. Am.
Chem. Soc., 2007, 129, 12654.
Received September 18, 2019;
in revised form October 24, 2019;
accepted November 1, 2019