Regioselective synthesis of trisubstituted cyclopentadienyl ligands from furans

Article abstract of DOI:10.1055/s-2002-34148

1,2,3- And 1,2,4-trisubstituted cyclopentadienyl manganese tricarbonyl compounds have been synthesized regioselectively from furans following a common synthetic strategy. The key steps include the transformation of furylcarbinols into hydroxycyclopentenones followed by the conjugate addition of Grignard reagents under chelation directed conditions. This affords hydroxycyclopentanones which can be dehydrated to cyclopentenones. These compounds are further elaborated into the final targets by the 1,2-addition of organolithium reagents.

Full text of DOI:10.1055/s-2002-34148

LETTER
1451
Regioselective Synthesis of Trisubstituted Cyclopentadienyl Ligands from
Furans
Synthesis of
Trisuu
r
lopenta
d
e
ienyl
L
igan
l
ds io G. Csákÿ,* Claudia Contreras, Myriam Mba, Joaquín Plumet
Departamento de Química Orgánica I. Facultad de Química, Universidad Complutense, 28040 Madrid, Spain
E-mail: csaky@quim.ucm.es
Received 29 May 2002
Among the different procedures for the assembly of cy-
clopentenones, we were particularly interested in the use
of simple furan derivatives as starting material. This
method is characterized by the ready availability of the
Abstract: 1,2,3- And 1,2,4-trisubstituted cyclopentadienyl manga-
nese tricarbonyl compounds have been synthesized regioselectively
from furans following a common synthetic strategy. The key steps
include the transformation of furylcarbinols into hydroxycyclo-
pentenones followed by the conjugate addition of Grignard reagents precursors and the simplicity of the synthetic procedures,6
under chelation directed conditions. This affords hydroxycyclo-
which may be of interest from a large-scale synthesis
pentanones which can be dehydrated to cyclopentenones. These
standpoint. We report herein the regioselective prepara-
compounds are further elaborated into the final targets by the 1,2-
tion of 1,2,3- and 1,2,4-trisubstituted cyclopentadienes by
addition of organolithium reagents.
means of a common synthetic strategy starting from fur-
Key words: cyclopentadienes, furans, metallocenes, manganese,
organometallic reagents
fural and simple Grignard and organolithium reagents.
Furylcarbinols 1 can be prepared by a variety of proce-
dures.7 Among these methods, the nucleophilic addition
of organolithiums or Grignard compounds (R1M) to inex-
Cyclopentadienyls constitute one of the most important
pensive furfural is particularly attractive. Compounds 1
types of ligands in organometallic chemistry.1 It is well
known that the substitution pattern of the cyclopentadi-
can be rearranged to the 4-hydroxycyclopentenones 2 by
acid treatment, and the latter can be isomerized to the 4-
enyl moiety can significantly modify the properties of
hydroxycyclopentenones 3 (Scheme 1). This first step al-
metallocenes.2 Therefore, the development of new effi-
lows for the introduction of the first substituent (R1) of the
cient approaches for the easy generation of polysubstitut-
final cyclopentadienyl.
ed cyclopentadienyls in a regioselective fashion is of
continuing importance.3
R1MgBr
R1
OH
Trisubstituted cyclopentadienyl ligands can be conve-
niently prepared either by the deprotonation of the corre-
sponding cyclopentadienes or by the addition of hydride
or carbon nucleophiles to fulvenes.3 Both approaches re-
quire the functionalization of simpler disubstituted cyclo-
pentadienes, which are used as starting materials.
However, in most cases the deprotonation of disubstituted
cyclopentadienes followed by reaction with alkyl halides
or carbonyl compounds suffers from poor regioselectivi-
ty, giving rise to mixtures of isomeric trisubstituted cyclo-
pentadienes or fulvenes. Also, the alkylation of
disubstituted cyclopentadienes cannot be used for the in-
troduction of aryl groups on the cyclopentadienyl moiety.
Therefore, alternative synthetic strategies must be de-
vised. The functionalization of cyclopentenones appears
particularly attractive in this context, and different proce-
dures have been reported for the synthesis of this kind of
compounds.4 However, most of these methods either do
not allow for the introduction of three different aryl
groups, or are limited to only one type of substitution pat-
tern (1,2,3- or 1,2,4) in the final cyclopentadiene.5
H
O
O
O
1
ZnCl2
1,4-dioxane / H2O
O
O
R1
OH
R1 Al O
2
3
HO
3
2
Scheme 1
The introduction of the second substituent (R2) has
been accomplished by addition of Grignard reagents to
hydroxycyclopentenones 2 or 3 (Scheme 2). The reaction
takes place regioselectively in a 1,4-fashion when carried
out in THF solution, with no need of the presence of Cu(I)
salts or co-solvents.8 This step is crucial in determining
the regiochemistry of the final trisubstituted cyclopentadi-
enyl ligand: when the reaction was carried out starting
from 4-hydroxycyclopentenones 2, substituents R1 and R2
ended up in a 1,3-relative disposition giving rise to com-
pounds 4; while starting from compounds 3, allowed for
a 1,2-relative disposition between R1 and R2 affording
compounds 5.9
Synlett 2002, No. 9, Print: 02 09 2002.
Art Id.1437-2096,E;2002,0,09,1451,1454,ftx,en;G14902ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

1452
A. G. Csákÿ et al.
LETTER
R3
O
O
O
O
R3
OH
OH
R1
R1
R1
R1
R1
R1
R2MgBr
THF
R3Li
THF
AcOH
AcOH
TsOH
Et2O
R2
OH
R2
R2
R2
R2
OH
2
6
4
10
6
8
9
O
O
O
O
R3
R3
R1
R1
R2
R1
R2
R2MgBr
THF
R1
R2
R1
R1
R3Li
THF
TsOH
Et2O
HO
HO
R2
R2
3
7
5
7
11
Scheme 2
Scheme 3
However, partial dehydration of compounds 4 to 6 was
The addition of organolithiums to the carbonyl group of
observed either upon standing in CHCl3 solution or under compounds 6 took place with high diastereoselectivity in
silica gel chromatography conditions.10 This spontaneous favor of the products 8 with 1,4-cis stereochemistry.8
Only in those cases where R2 was alkyl (6b, Table 2, en-
dehydration was not observed for the regioisomeric com-
tries 3 and 4) minor amounts of the 1,4-trans isomers were
detected in the H NMR spectra of the crude reaction
products. These could be separated by chromatography.
pounds 5. Both types of hydroxycyclopentanones could
be quantitatively dehydrated to cyclopentenones 6 and 7
in HOAc solution. Therefore, the synthesis of compounds
6 and 7 could be conveniently carried out in a one pot pro-
cedure starting from hydroxycyclopentenones 2 and 3
without isolation of the intermediate hydroxycyclopen-
tanones 4 and 5. The results of the overall transformation
of compounds 2 and 3 to cyclopentenones 6 and 7 are giv-
en in Table 1.11
1
Similarly, the addition of R3M to the carbonyl group of
cyclopentenones 7 led to major formation of the corre-
sponding compounds 9 with 1,5-cis-4,5-trans stereo-
chemistry in those cases where R3 was aryl.15 However,
the reaction was found to be sensitive to the nature of R3,
as the addition of MeLi to 7c (Table 2, entry 13) led to
compound 9d as a 1:1 mixture of 1,5-cis-4,5-trans and
1,5-trans-4,5-trans isomers. Dehydration of hydroxycy-
clopentenes 8 and 9 with calalytic amounts of TsOH in
Et2O solution gave rise to cyclopentadienes 11 and 12
(Scheme 3).
Table 1 Synthesis of Compounds 6 and 7 from Furylcarbinols 1
No.
1
1
2
R1
Ph
Ph
Ph
Ph
Me
Ph
Ph
Ph
Ph
R2
6, 7 (%)a
6a (55)
6b (55)
6c (60)
6d (60)
7a (75)
7b (65)
7c (70)
7d (70)
7e (75)
1b
1b
1b
1b
1a
1b
1b
1b
1b
2b
2b
2b
2b
3a
3b
3b
3b
3b
Ph
2
Me
The use of these compounds as ligands in organometallic
chemistry has been tested in the case of the synthesis of
the cyclopentadienylmanganesetricarbonyl compounds
12 and 13. In this way, metalation of 10 and 11 was car-
ried out (Scheme 4) by treatment with Mn2(CO)10 in re-
fluxing xylene for 24 h, giving rise to the corresponding
trisubstituted cyclopentadienyl mangansese compounds
12 and 13.16 The scope of the transformation of furyl-
carbinols 1 into the trisubstituted cyclopentadienyl man-
ganese tricarbonyls 13 and 14 is given in Table 2.17
3
p-MeO-Ph
p-CF3-Ph
Ph
4
5
6
Me
7
Ph
8
p-MeO-Ph
p-CF3-Ph
9
R3
R3
a Isolated yields.
R1
R1
Mn2(CO)10
xylene, ∆
R2
R2
Mn(CO)3
The introduction of the third substituent (R3) of the final
trisubstituted cyclopentadienyl ligand was carried out by
the 1,2-nucleophilic addition of organolithium or Grig-
nard reagents to the carbonyl group of compounds 6 and
7 (Scheme 3). Dehydration of the intermediate vinyl-
carbinols 8 and 9 with catalytic amounts of TsOH in Et2O
solution gave rise to cyclopentadienes 10 and 11.12 The re-
sults of the synthesis of compounds 8–11 are gathered in
Table 2.13,14
10
12
R3
R3
R1
R1
Mn2(CO)10
xylene, ∆
2
R2
Mn
(CO)3
R
13
11
Scheme 4
Synlett 2002, No. 9, 1451–1454 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Synthesis of Trisubstituted Cyclopentadienyl Ligands
1453
Table 2 Synthesis of Trisubstituted Cyclopentadienyls
No
6, 7
6a
6a
6b
6b
6c
R1
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Me
Ph
Ph
Ph
Ph
Ph
Ph
R2
R3
8, 9 (%)a
8a (70)
8b (80)
8c (80)
8d (70)
8e (65)
8f (65)
8g (55)
8h (65)
9a (90)
9b (90)
9c (85)
9d (70)
9e (90)
9f (85)
9g (50)
10, 11 (%)a
10a (95)
10b (95)
10c (90)
10d (90)
10e (80)
10f (80)
10g (80)
10h (80)
11a (50)
11b (80)
11c (95)
11a (90)
11d (75)
11e (70)
11f (65)
12, 13 (%)a
12a (85)
12b (80)
12c (85)
12d (80)
12e (85)
12f (80)
12g (80)
12h (75)
13a (75)
13b (90)
13c (85)
13a (75)
13d (60)
13e (55)
13f (50)
1
Ph
Ph
2
Ph
Me
3
Me
Ph
4
Me
Me
5
p-MeO-Ph
p-MeO-Ph
p-CF3-Ph
p-CF3-Ph
Ph
p-MeO-Ph
p-CF3-Ph
p-MeO-Ph
p-CF3-Ph
Ph
6
6c
7
6d
6d
7a
7b
7c
8
9
10
Me
Ph
11
Ph
Ph
12
7c
Ph
Me
13
7d
7d
7e
p-MeO-Ph
p-MeO-Ph
p-CF3-Ph
p-MeO-Ph
p-CF3-Ph
p-CF3-Ph
14
15
a Isolated yields.
(7) General methods for the preparation of furylcarbinols
In summary, we have developed a procedure, which al-
lows for regioselective synthesis of 1,2,3- and 1,2,4-cyc-
lopentadienyl manganese compounds starting from the
same precursors and making use of a common synthetic
strategy. This method allows the introduction of different
alkyl or aryl groups at will on a trisubstituted cyclopenta-
nyl ring in a completely regioselective fashion.
include the reduction of furfuryl ketones, which in turn are
obtained from the Friedel–Crafts reaction on furans, or by
the reaction of metallated furans with electrophiles. See:
Sargent, M. V.; Dean, F. M. In Comprehensive Heterocyclic
Chemistry, Vol. 4; Katritzky, A. R.; Rees, C. W., Eds.;
Pergamon Press: Oxford, 1984, Chap. 3.11.
(8) Csákÿ, A. G.; Mba, M.; Plumet, J. J. Org. Chem. 2001, 66,
9026.
(9) The addition of the organomagnesium reagent to the
hydroxycyclopentenones 3 took place in a completely
diastereoselective fashion giving rise to a 2,3-trans-3,4-cis
stereochemistry for compounds 4. See ref. 8.
(10) All compounds described throughout this work are racemic.
(11) General procedure for the synthesis of cyclopentenones 6
and 7: To a solution of the corresponding
Acknowledgement
Ministerio de Ciencia y Tecnología (Project BQU2000-0653) and
REPSOL-YPF are gratefully thanked for financial support.
References
hydroxycyclopentenone 2 or 3 (5 mmol) in THF (25 mL) at
0 ºC was dropwise added a solution of ArMgX (11.0 mmol,
1 M solution in THF) or MeMgI (11.0 mmol, 3 M solution
in Et2O). The mixture was heated at reflux for 2 h, cooled to
r.t., and hydrolyzed with saturated NH4Cl solution (10 mL).
After extraction with EtOAc (3 25 mL) the combined
extracts were dried on MgSO4 and the solvent was
evaporated under reduced pressure. The resulting oil was
dissolved in HOAc (20 mL) and the solution was heated at
reflux for 2 h. The mixture was cooled to r.t. and the solvent
was evaporated under reduced pressure. The remaining oil
was taken in Et2O (20 mL) and washed with saturated
NaHCO3 (2 10 mL) and brine (1 15 mL). The solution
was dried on MgSO4 and the solvent evaporated under
reduced pressure to afford an oil which was purified by
chromatography (hexane–EtOAc, 8:1).
(1) Jutzi, P. J. Organometal. Chem. 1990, 400, 1.
(2) See for example: (a) Janiak, C.; Schumann, H. Adv.
Organomet. Chem. 1991, 33, 291. (b) Okuda, J. Top. Curr.
Chem. 1992, 160, 97. (c) Coville, N. J.; du Plooy, K. E.;
Pickl, W. Coord. Chem. Rev. 1992, 116, 97. (d) Okuda, J.
Nachr. Chem. Tech. Lab. 1993, 41, 8.
(3) (a) Halterman, R. L. Chem. Rev. 1992, 92, 965.
(b) Metallocenes, Vol. 1; Togni, A.; Halterman, R. L., Eds.;
Wiley-VCH: Weinheim, 1998. (c) Metallocenes, Vol. 2;
Togni, A.; Halterman, R. L., Eds.; Wiley-VCH: Weinheim,
1998.
(4) (a) Ellison, R. A. Synthesis 1973, 397. (b) Theil, F. Chem.
Rev. 1995, 95, 2203.
(5) See the example: Lee, B. Y.; Moon, H.; Chung, Y. K. J. Am.
Chem. Soc. 1994, 116, 2163.
(6) Piancatelli, G.; D´Auria, M.; D´Onofrio, F. Synthesis 1994,
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(12) Compounds 10 and 11 were obtained as mixtures of double
bond isomers.
Synlett 2002, No. 9, 1451–1454 ISSN 0936-5214 © Thieme Stuttgart · New York

1454
A. G. Csákÿ et al.
LETTER
(13) General procedure for the synthesis of cyclopentenols 8 and
9: To a solution of cyclopentenone 6 or 7 (1 mmol) in THF
(10 mL) at –78 ºC was dropwise added a solution of R3Li
(1.6 mmol, 1.6 M solution of MeLi in THF, 1.8 M solution
of PhLi in cyclohexane–Et2O, or 1.0 M solution of ArLi in
THF). The temperature was slowly raised to r.t. and was
further stirred for 18 h. The mixture was hydrolyzed with
saturated NH4Cl (10 mL) and extracted with Et2O (3 15
mL). The combined extracts were dried on MgSO4 and the
solvent was eliminated under reduced pressure to afford an
oil which was purified by silica gel chromatography
(hexane–EtOAc, 8:1).
The mixture was diluted with Et2O (20 mL) and washed with
saturated NaHCO3 (2 10 mL) and brine (1 15 mL). The
organic layer was dried on MgSO4 and the solvent was
eliminated under reduced pressure. The resulting oil was
purified by chromatography (hexane–Et2O, 40:1).
(15) The stereochemistry of 9d was determined by NOE
experiments.
(16) No dealkylation of the methyl-substituted cyclopentadienes
was observed under these reaction conditions. See ref. 5.
(17) General procedure for the synthesis of 12 and 13: A solution
of 10 or 11 (1.8 mmol) and Mn2(CO)10 (2.0 mmol) in xylene
(80 mL) was heated at reflux for 24 h. The solvent was
eliminated under reduced pressure and the crude reaction
product was purified by chromatography (hexane–Et2O,
10:1).
(14) General procedure for the synthesis of cyclopentadienes 10
and 11: To a solution of 8 or 9 (3 mmol) in Et2O (6 mL) was
added TsOH (0.6 mmol) and the solution was stirred at r.t.
until disappearance of the starting material by TLC (1–6 h).
Synlett 2002, No. 9, 1451–1454 ISSN 0936-5214 © Thieme Stuttgart · New York