Consecutive enolate addition/cyclization of Fischer enynyl carbene complexes: facile access to cyclopentenoids

Article abstract of DOI:10.1016/j.tetlet.2009.03.058

Functionalized cyclopentenoids were synthesized from Fischer enynyl carbene complexes by a sequence that involves regioselective nucleophilic 1,4-addition of enolates and anionic electrocyclization of the resulting intermediate. Moreover, the method is ef

Full text of DOI:10.1016/j.tetlet.2009.03.058

Tetrahedron Letters 50 (2009) 3606–3608
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Consecutive enolate addition/cyclization of Fischer enynyl carbene
complexes: facile access to cyclopentenoids
*
José Barluenga , Ana Álvarez-Fernández, Silvia Martínez, Ángel L. Suárez-Sobrino, Miguel Tomás
Instituto Universitario de Química Organometálica, ‘Enrique Moles’, Unidad Asociada al CSIC, Universidad de Oviedo, Julian Clavería 8, 33071 Oviedo, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Functionalized cyclopentenoids were synthesized from Fischer enynyl carbene complexes by a sequence
that involves regioselective nucleophilic 1,4-addition of enolates and anionic electrocyclization of the
resulting intermediate. Moreover, the method is effective for the C2–C3 annulation of heterocyclic rings
like benzofuran and indole. The methoxycyclopentadiene thus obtained can be hydrolyzed to substituted
cyclopentenones, which are not straightforwardly accessible by other methods.
Received 20 February 2009
Revised 9 March 2009
Accepted 10 March 2009
Available online 14 March 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Carbene
Chromium
Cyclopentannulation
Cyclopentenone
Enolate
Developing new strategies for cyclopentane-based molecules
continues to stimulate synthetic chemists. Currently, the Pauson–
Khand reaction (alkyne + alkene + CO) is a reference for synthesis
of cyclopentenones.1 Although the cyclopentannulation reaction
of functionalized dienyl systems, like dienyl ketones for the Naza-
rov cyclization, appears to represent an attractive synthetic tool, it
remains much less exploited and development of new strategies of
this type would be beneficial for cyclopentane-based molecules.2
ethyl acetate 5:1) to give the cyclopentadiene enolether 3 as a sin-
gle compound in 82% yield (Scheme 1). The structure of 3 was
ascertained on the basis of its NMR spectroscopic and HRMS data,6
and confirmed by an X-ray analysis.7 The formation of 3 can be ex-
plained by nucleophilic 1,4-addition of the enolate to the alkynyl
carbene functionality (intermediate I) followed by anionic electro-
cyclization (intermediate II) and hydrolysis (Scheme 1).
The usefulness of this reaction was further expanded to the syn-
thesis of bicyclic ethers 6–12 (65–92%) by using chromium cyclo-
alkenylalkynyl carbenes 4a,b, and various lithium enolates
derived from mono and dicarbonyl compounds 5 (Scheme 2). The
reaction was found to work well for unsubstituted and substituted
malonate substrates (compounds 6, 8, 9) as well as for ethyl aceto-
acetate (compound 7). On the other hand, simple lithium enolates
derived from di- and trisubstituted esters also promote efficiently
the cyclopentannulation reaction (compounds 10, 11).8 In the same
way, using 1-phenylpropan-1-one yields the cycloadduct 12 as a
2:1 mixture of diastereoisomers.9
In the last years,
a,b-unsaturated Fischer carbene complexes
have demonstrated high potential in the area of carbocyclization
reactions.3 One can realize that not only that linear-conjugated die-
nylcarbenes (1-metalla-1,3,5-hexatrienes) are attractive candidates
for the construction of the cyclopentane skeleton, but also their
cyclopentannulation would complement the Nazarov reaction
which involves the cyclization of
a cross-conjugated system
(Fig. 1).4 We also envisioned that the Michael-type addition to read-
ily available, highly electrophilic enynyl carbenes would give easy
access to the required cis-dienyl carbenes. Therefore, we report
herein on the synthesis of functionalized cyclopentenoids from
Fischer enynyl carbene complexes of chromium(0) by a tandem
sequence involving addition of enolates and cyclopentannulation.5
First, chromium 4-phenyl-3-buten-1-ynyl carbene 1 was trea-
ted with lithium enolate 2 at À78 °C in THF for ca. 15 min until
complete disappearance of the carbene. The mixture was warmed
up to room temperature, worked-up (aqueous ammonium chlo-
ride), and the resulting crude chromatographed (SiO2, hexanes/
The chance that an aromatic C–C double-bond might participate
in the cyclization was then taken in mind. However, the reaction of
_
Nu
O
Nu
M
_
RO
RO
M
Nazarov
cyclization
This work
* Corresponding author. Tel./fax: +34 985 510 3450.
E-mail address: barluenga@uniovi.es (J. Barluenga).
Figure 1.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.03.058

J. Barluenga et al. / Tetrahedron Letters 50 (2009) 3606–3608
3607
OMe
OMe
OMe
OMe
E
1) THF, -78°C- rt
2) NH4Cl, H2O
OLi
H
H
1) THF, -78°C -rt
2) NH4Cl, H2O
[Cr]
[Cr]
Ph
N
+
E
OMe
+
2
E
89%
82%
E
N
Ph
E
1
2
3
15
14
_
OMe
OMe
_
E
Ph
[Cr]
[Cr]
E
OMe
E
E
OMe
1) THF, -78°C-rt
2) NH4Cl, H2O
[Cr]
Ph
E
II
+
2
O
I
78 %
E = CO2Me; [Cr] = Cr(CO)5
E
O
Scheme 1. Cyclopentannulation of chromium enynyl carbene
conjugated addition and cyclization.
1
by sequential
16
E = CO2Me; [Cr] = Cr(CO)5
17
phenylethynyl(methoxy)carbene of chromium with various eno-
lates resulted in the formation of complex mixtures of unidentified
compounds. Fortunately, replacing the phenyl group with hetero-
aryl substituents led to success. Thus, the reaction of (1-methylin-
dol-3-yl)ethynyl carbene 14 with the lithium enolate derived from
dimethyl malonate gave rise, under the reaction conditions and
after purification (SiO2, hexanes/ethyl acetate, 5:1), to dihydroin-
dole derivative 15 in 89% yield (Scheme 3). The benzofuran-2-yl
substituted carbene 16 also underwent the cyclopentannulation
with malonate diester enolate 2 to furnish the benzofuran-fused
cyclopentene 17 in 78% yield. The structures of these tricyclic
adducts were assigned by means of mono- and bidimensional 1H
and 13C NMR experiments, as well as X-ray analysis for 15.10
Finally, the hydrolysis of the methoxycyclopentadiene system
was accomplished with aqueous HCl. For instance, the treatment
of cycloadducts 6, 11 with 6 N HCl in THF at room temperature
provided the cyclopentenone derivatives 18, 19 in 79–88% yield.11
In summary, we have described a facile access to functionalized
cyclopentenoids from Fischer enynyl carbene complexes that in-
volves regioselective addition of enolates and cyclization. Interest-
ingly, the method has proven to serve for the C2–C3 annulation of
the benzofuran and indole rings, irrespective of the carbon (C2 or
Scheme 3. Cyclopentannulation reaction of heteroaryl-substituted alkynyl carb-
enes 14 and 16.
OMe
O
H
H
H
H
6N HCl
F
88%
E
E
E
E
6
18
OMe
O
H
6N HCl
F
79%
E
H
E
11
E = CO2Me
19
Scheme 4. Hydrolysis of enolethers 6 and 11 to cyclopentenones 18 and 19.
C3) bonded to the alkynyl carbene ligand. These types of cyclopen-
tenones are not at all straightforwardly accessible by the intermo-
lecular Pauson–Khand reaction because of
a lack of either
reactivity (in particular for unstrained alkenes) or regioselectivity
(2,5-disubstituted cyclopentenones are generally formed) (see
Scheme 4).
OMe
1) THF, -78°C-rt
2) NH4Cl, H2O
OMe
OLi
R1
[Cr]
R2
R3
+
n
Acknowledgments
O
R1
65-92%
R2
R3
n
This research was partially supported by the Governments of
Spain (CTQ2007-61048) and Principado de Asturias (IB08-088;
predoctoral fellowship to A.A.-F).
5
6-12
4a (n =1)
4b (n = 2)
OMe
OMe
O
OMe
OMe
E
H
H
H
H
Supplementary data
E
E
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.03.058.
E
E
E
E'
6 (81%)
7 (65%)
8 (76%)
OMe
E
9 (77%)
References and notes
E/Z =1.4:1
OMe
O
1. (a) Gibson, S. E.; Mainolfi, N. Angew. Chem., Int. Ed. 2005, 44, 3022–3037; (b)
Strübing, D.; Beller, M. Top. Organomet. Chem. 2006, 18, 165–178.
2. (a) Pellisier, H. Tetrahedron 2005, 61, 6479–6517; (b) Frontier, A. J.; Collison, C.
Tetrahedron 2005, 61, 7577–7606.
OMe
E
3. Recent reviews: (a) de Meijere, A.; Wu, Y.-T. Top. Organomet. Chem. 2004, 13,
21–57; (b) Barluenga, J.; Rodríguez, F.; Fañanás, F. J.; Flórez, J. Top. Organomet.
Chem. 2004, 13, 59–121; (c) Barluenga, J.; Santamaría, J.; Tomás, M. Chem. Rev.
2004, 104, 2259–2284; (d) Barluenga, J.; Fernández-Rodríguez, M. A.; Aguilar, E.
J. Organomet. Chem. 2005, 690, 539–587; (e) Herndon, J. W. Coord. Chem. Rev.
2009, 253, 86–179.
Ph
12 (92%)
dr = 2:1
11 (66%)
10 (67%)
dr = 1:1
E= CO2Me; E' = CO2Et; [Cr] = Cr(CO)5
4. The [3+2] cyclization of alkenylcarbenes and alkynes is thought to involve the
cyclization of a metallahexatriene: Wulff, W. D.; Bax, B. M.; Brandvold, T. A.;
Chan, K. S.; Gilbert, A. M.; Hsung, R. P. Organometallics 1994, 13, 102–126.
Scheme 2. Cyclopentannulation of chromium enynyl carbenes 4a,b using different
lithium enolates 5.

3608
J. Barluenga et al. / Tetrahedron Letters 50 (2009) 3606–3608
5. The cyclization of 4-amino-1-metalla-1,3,5-trienes to 1,3-cyclopentadienes
was reported: Auman, R.; Fröhlich, R.; Prigge, J.; Meyer, O. Organometallics
1999, 18, 1369–1380.
9. The reaction of the enynyl carbene 4b with lithium acetone enolate led to
trienone 20 as a result of, (i) initial 1,2-addition of the enolate to the metal-
carbene functionality, (ii) 1,3-shift of the metal fragment, and (iii) hydrolytic
metal elimination. This behavior of Fischer carbene complexes toward carbon
nucleophiles has been described. Barluenga, J.; Trabanco, A. A.; Flórez, J.;
García-Granda, S.; Llorca, M.-A. J. Am. Chem. Soc. 1998, 120, 12129–12130.
6. Synthesis of 3, typical procedure: Dimethyl malonate (85.9 mg, 0.65 mmol) was
added to a solution of lithium diisopropyl amide (0.715 mmol) in THF (1 mL) at
À78 °C and the mixture was stirred for 15 min at that temperature. A solution
of the enynylcarbene 1 (235.5 mg, 0.65 mmol) in THF (0.5 mL) was added and
the solution was allowed to warm to room temperature. The resulting mixture
was stirred for 15 min, treated with saturated aqueous ammonium chloride
(20 mL), and the mixture extracted with ether (3 Â 10 mL). After solvent
removal the resulting crude was purified (SiO2, hexanes/ethyl acetate 5:1) to
give cyclopentadiene enolether 3 (161 mg, 82% yield). Spectroscopic data of 3:
1H NMR (300 MHz, C6D6): d 2.93 (s, 3H), 3.48 (s, 6H), 3.58 (s, 3H), 6.49 (s, 1H),
6.88–6.90 (m, 2H), 6.97–7.02 (m, 3H). 13C NMR (75 MHz, C6D6): d 40.2 (CH2),
40.9 (CH), 51.0 (CH3), 51.1 (CH3), 57.6 (CH3), 103.1 (CH), 111.4 (C), 127.0 (CH),
126.4 (2 Â CH), 128.7 (2 Â CH), 141.4 (C), 166.7 (C), 167.0 (C), 181.1 (2 Â C).;
HRMS calcd for C17H18O5 [M+] 302.1149, found: 302.1144.
O
OMe
OLi
[Cr]
+
MeO
20
4b
7. Crystallographic data for
3
have been deposited with the Cambridge
10. Crystallographic data for 15 have been deposited with the Cambridge
Crytallographic Data Centre as supplementary publication CCDC 721067.
Copies of the data can be obtained, free of charge on application to CCDC,
12 Union Road, Cambridge CB2 1EZ, UK (fax + 44-(0)1223-336033 or e-
mail: deposit@ccdc.cam.ac.uk).
Crytallographic Data Centre as supplementary publication CCDC 721068.
Copies of the data can be obtained, free of charge on application to CCDC, 12
Union Road, Cambridge CB2 1EZ, UK (fax + 44-(0)1223-336033 or e-mail:
deposit@ccdc.cam.ac.uk).
8. All new compounds isolated gave satisfactory analytical figures and were
11. For cyclopentenone-containing natural and bioactive compounds, see: Gibson,
S. E.; Lewis, S. E.; Mainolfi, N. J. Organomet. Chem. 2004, 689, 3873–3890.
characterized by spectroscopic means (IR, HRMS, 1H, and 13C NMR).