Synthesis of a novel ethylene-bis(tetrahydroindenyl) ligand containing a functionalized four-carbon tether

Article abstract of DOI:10.1016/S0040-4039(03)00827-X

In this work we present an efficient synthesis of a novel ethylene-bis(2-methyl-tetrahydroindenyl) ligand, 2b, containing a tethered functional group. The tethered functional group may enable heterogenization of the homogeneous ligand on various solid sup

Full text of DOI:10.1016/S0040-4039(03)00827-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 4095–4098
Synthesis of a novel ethylene-bis(tetrahydroindenyl) ligand
containing a functionalized four-carbon tether
Anthony P. Panarello and Johannes G. Khinast*
Department of Chemical and Biochemical Engineering, 98 Brett Road, Piscataway, NJ 08854, USA
Received 13 February 2003; revised 26 March 2003; accepted 28 March 2003
Abstract—In this work we present an efficient synthesis of a novel ethylene-bis(2-methyl-tetrahydroindenyl) ligand, 2b, containing
a tethered functional group. The tethered functional group may enable heterogenization of the homogeneous ligand on various
solid supports. This strategy is the first attempt of incorporating a functional tether into a bridged metallocene ligand without
disrupting the ethane bridge and represents a new approach to heterogenizing metallocene ligands. A practical synthesis was
achieved by selective alkylation of the starting material and the Pauson–Khand cyclization. In addition, this strategy offers a new
synthetic pathway for the preparation of the ethylene-bis(2-methyl-tetrahydroindenyl) ligand, 1b. © 2003 Elsevier Science Ltd. All
rights reserved.
Metallocenes are a subgroup of organometallic com-
plexes, which are used for various catalytic reactions.1
One particularly promising class of metallocene ligands
are ethylene-bis(tetrahydroindenyl) and derivatives, e.g.
1a and 1b, (in Fig. 1). First developed by Brintzinger,2
this chiral complex, whose chirality is derived from the
ligand–metal linkage, proved to be effective for poly-
merization,3 as well as for asymmetric hydrogenation
catalysis.4
The extraordinary effectiveness of metallocenes has
lead to a considerable effort in developing a strategy for
anchoring these complexes onto solid supports. While
the ethylene-bis(tetrahydroindenyl) ligand has not yet
been heterogenized, researchers have attempted to het-
erogenize similar cyclopentadienyl ligands resulting in
catalysts with lower activity and selectivity.5 In this
work we sought to develop novel ethylene-bis(tetra-
hydroindenyl) ligands that contain a functional tether
distant from the active catalytic site in order not to
disrupt the ethane bridge. Herein, we report the first
successful attempt at attaching a functionalized tether
onto the ethylene-bis(2-methyl-tetrahydroindenyl) lig-
and, 2b, through the cyclohexane ring, as shown in
Figure 1. Our synthesis also represents a useful syn-
thetic pathway for the preparation of the homogeneous
ethylene-bis(2-methyl-tetrahydroindenyl) ligand, 1b.
After reviewing the literature, we determined that the
most effective strategy to attach a tethered functional
group was to modify the synthesis presented by Halter-
man.6 This approach utilizes a double alkylation of
1,5-hexadiyne, a Pauson–Khand cyclization to form the
ethylene-bis(hydroindeneone) followed by a Shapiro
elimination reaction. The five-step synthesis represents
the most efficient synthetic pathway for preparing the
ethylene-bis(tetrahydroindenyl) ligand. However, for
our purposes it was necessary to modify this procedure
in order to accommodate a carbon tether containing an
alcohol group. Subsequent heterogenization could then
occur at this site.
Figure 1. The homogeneous ethylene-bis(tetrahydroindenyl)
ligand (1) and the functionalized ethylene-bis(tetra-
hydroindenyl) ligand (2). Configuration of the conjugated
double bonds depends on the substituent, R.
Keywords:
ethylene-bis(tetrahydroindenyl); alkyne alkylation;
cyclopentadiene; heterogenization.
* Corresponding author. Tel.: (732) 445-2970; fax: (732) 445-2581;
e-mail: khinast@sol.rutgers.edu
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00827-X

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A. P. Panarello, J. G. Khinast / Tetrahedron Letters 44 (2003) 4095–4098
Our selective alkylation strategy is presented in Scheme
1. Before the alkylations were undertaken, it was neces-
sary to generate alkyl-electrophiles by converting alco-
double alkylation products were only observed when
alkyl-iodide was used for the alkylation with yields less
then 20%. Using the same alkylation procedure, com-
pound 5 was alkylated with 4a or 4b to form 15-allyl-
19-methoxymethoxy-nonadec-1-ene-7,11-diyne, 6. This
provided the desired asymmetric enyne. Success with
reversing the alkylation sequence indicates either a mild
steric or electronic limitation on the alkyne alkylations.
hols
into
the
appropriate
leaving
group.
3-Allyl-7-methoxymethoxy-heptan-1-ol, 3, and 6-hexen-
1-ol, 4, were converted to alkyl-iodides by reaction with
imidazole (2 mol. equiv.), triphenyl phosphine (2 mol.
equiv.), and I2 (2 mol. equiv.) in ethyl ether and aceto-
nitrile.7 While the halogenation is straightforward and
very favorable, the formation of hydriodic acid may
cleave the MOM-alcohol protecting group, resulting in
low yields of 4-(2-iodo-ethyl)-8-methoxymethoxy-oct-1-
ene, 3a. This did not appear to influence the 6-iodo-1-
hexene, 4a, even when the reaction was extended. In
order to minimize the loss of the starting alcohol,
alkyl-tosylates were also prepared. The alcohols were
treated with pyridine (2 mol. equiv.) and tosylate chlo-
ride (2 mol. equiv.) in methylene chloride to obtain
alkyl-tosylates, 3b and 4b in good yields.8
With our enyne, 6, the double Pauson–Khand cycliza-
tion reaction was used to synthesize the branched ethyl-
ene-bis(hydroindeneone), as shown in Scheme 1.6
Dicobalt octacarbonyl (2.2 mol equiv.) complexes with
alkyne at ambient temperature to form a stable metal-
alkyne bond. When the bubbling ceased, the reaction
mixture was heated under reflux overnight to give 7 in
80% yield.13 Although literature showed some steric
limitations of the reaction,14 the lack of any significant
by-products and yields greater than 75%, led us to
conclude that the tethered functional group did not
result in steric inhibition with the reaction.
In an attempt to selectively alkylate a single terminal
alkyne, we first synthesized 1-trimethylsilane-1,5-
hexadiyne (pathway not shown).9 The unprotected ter-
minal alkyne was then alkylated via an SN2 mechanism
with 4a.10 A carbanion was first generated at −78°C by
using n-butyllithium (1.1 mol. equiv.) with small
amounts of HMPA to minimize lithium clustering.
After 45 min, dilute 4a was slowly added. The reaction
was then allowed to warm up to room temperature over
4 h. Next, the alkyne-protecting group was removed
using TBAF.11 Unfortunately, all further attempts to
alkylate dodec-11-ene-1,5-diyne with 3a or 3b failed.12
Quenching the lithiated alkyne with deuterated water—
as opposed to addition of the alkyl-halide—showed
that nearly complete lithiation had occurred. As a
result, the alkylation sequence was reversed. With the
lack of available 1-trimethylsilane-1,5-hexadiyne, 1,5-
hexadiyne was alkylated with 3a or 3b, as previously
described, to obtain 9-allyl-13-methoxymethoxy-
trideca-1,5-diyne, 5. Alkylation with alkyl-iodide was
more favorable with a 70% yield, compared to a 45%
yield when alkyl-tosylates were used. Surprisingly, the
Reduction of the hydroindeneone, 7, to a hydroindenyl,
2a, can be carried out by forming a tosylhydrazone (2.2
mol equiv. p-toluenesulfonyl hydrozide) followed by
the Shapiro elimination6,15 (5.0 mol equiv. s-butyl-
lithium) or by reducing the enone to an alcohol with
LiAlH4 (2.2 mol. equiv.) followed by treating it with a
mild acid,16 as shown in Scheme 2. Reduction with
LiAlH4 offered higher yields (>90% compared to <50%
for reaction with tosylhydrazide), shorter reaction
times, lower reaction temperatures and simpler work-
ups. While both approaches were successful, the insta-
bility of the ethylene-bis(tetrahydroindenyl), 1a and 2a,
prevented us from obtaining quantitative analytical
data.17
Either trimethylsilane,18 or a methyl group,19 can be
attached to cyclopentadienyl to help stabilize tetra-
hydroindenyl, 2a. Since 2b is more stable and easier to
prepare as well as to separate, we chose methyl addi-
tion. As shown in Scheme 3, methyllithium was slowly
Scheme 1. Reagents and conditions: (i) I2, TPP, imidazole, (4/1) EE and acetonitrile, rt; (ii) TsCl, Me2Cl2, 0°C; (iii) 1. n-BuLi,
−78°C, THF, 2. HMPA, 3. Electrophile+THF, 4. rt, 8 h; (iv) Co2CO8, acetonitrile, reflux 16 h.

A. P. Panarello, J. G. Khinast / Tetrahedron Letters 44 (2003) 4095–4098
4097
overall yield of 65%.23 The hydroindeneone intermedi-
ate was also converted into the TMS-stabilized ethyl-
ene-bis(2-trimethylsilane-tetrahydroindenyl), 1c, by
reacting with LiAlH4 followed by Amberlyst 15 to yield
ethylene-bis(tetrahydroindenyl), 1a. Next, 1a was lithi-
ated with n-butyllithium at 0°C and after 12 h
quenched with chlorotrimethylsilane to afford 1c.
It is noteworthy that the alcohol-protecting group
(MOM) has not yet been removed. A strong base will
be used to attach the metal to the ligand, which will
most likely react with an unprotected alcohol. There-
fore, it was decided to remove the alcohol-protecting
group after the attachment of the metal. Several strate-
gies for removing the MOM protecting group will be
investigated.11
In conclusion, we have presented a practical and
efficient synthesis for incorporating a tethered func-
tional group into the ethylene-bis(2-methyl-tetra-
hydroindenyl), 2b, ligand in 15% overall yield. The
addition of the tethered group may enable anchoring
the homogeneous organometallic ligand onto various
heterogeneous supports. The five-step synthesis benefits
from steric or electronic limitations by inhibiting the
double alkylation of 1,5-hexadiyne using a alkyl-elec-
trophile with minimal steric bulk, which selectively
alkylates a single terminal alkyne in good yields. Selec-
tive alkylation of 1,5-hexadiyne also demonstrates the
ability to incorporate a tethered functional group in the
Scheme 2. Formation of the ethylene-bis(tetrahydroindenyl)
ligand.
ethylene-bis(tetrahydroindenyl)
synthesis
without
increasing the complexity of the synthesis and elimi-
nates the need for alkyne protecting groups. Lastly, the
presented synthesis is also a novel and efficient synthe-
sis for the preparation of the untethered ethylene-bis(2-
methyl-tetrahydroindenyl), 1b.
Acknowledgements
Scheme 3. Reduction of the hydroindeneone by stabilizing
the cyclopenta-dienyl to form two cycloalkene isomers.
Reagents and conditions: (i) MeLi, EE, 0°C; (ii) H+ or sponta-
neous.
We would like to thank Dr. Yongkui Sun (Merck &
Co. Inc.), Dr. Jennifer Albaneze-Walker (Merck & Co.
Inc.), Professor Eleonora Polo (Univ. of Ferrara), Pro-
fessor Alan Goldman (Rutgers University) and Dr.
Riga Misra (BMS) for their helpful suggestions.
added to 7 in ethyl ether at 0°C. The reaction was kept
in an ice bath for 1 h and was then allowed to warm up
to ambient temperature over 2 h. During the reaction,
spontaneous dehydration was observed, forming the
References
1. Tegni, A. Halterman, R. Metallocenes; Wiley-VCH: New
York, 1998; Vols. I and II.
desired
tethered
ethylene-bis(2-methyl-tetrahydro-
indenyl), 2b. Several cyclopentadienyl isomers20 were
2. (a) Wild, F. R. W. P.; Zsolnai, L.; Huttner, G.;
Brintzinger, H. H. J. Organomet. Chem. 1982, 232, 233–
240; (b) Wild, F. R. W. P.; Zsolnai, L.; Huttner, G.;
Brintzinger, H. H. J. Organomet. Chem. 1985, 288, 63–67.
3. (a) Leclerc, M. C.; Brintzinger, H. H. J. Am. Chem. Soc.
1997, 118, 9024–9032; (b) Imanishi, Y.; Naga, N. Prog.
Poly. Sci. 2001, 26, 1147–1198.
4. (a) Willoughby, C. A.; Buchwald, S. L. J. Am. Chem.
Soc. 1994, 116, 8952–8965; (b) Verdaguer, X.; Lange, U.
E. W.; Reding, M. T.; Buchwald, S. T. J. Am. Chem. Soc.
1996, 118, 6784–6785.
observed in 55% yield and an overall yield of 15%.21
An analogous method can be applied to the synthesis of
the ethylene-bis(2-methyl-tetrahydroindenyl) ligand, 1b.
Hydroindeneone was easily prepared using a double
alkylation of 1,5-hexadyine with 6-iodo-1-hexene, 4a,
followed by the double Pauson–Khand cyclization.22
Reduction of the hydroindeneone with methyllithium
was followed by spontaneous dehydration. Two
cyclopentadienyl isomers of 1b were observed with an

4098
A. P. Panarello, J. G. Khinast / Tetrahedron Letters 44 (2003) 4095–4098
5. (a) Lee, D. H.; Lee, H. B.; Noh, S. K.; Song, B. K.;
17. Product + isomers were observed using LC/MS and UV
analysis but were not stable or pure enough for accurate
1H or 13C NMR analysis. (a) Mironov, V. A.; Ivanov, A.
P.; Kimelfeld, Y. M.; Petrovskaya, L. I.; Akhrem, A. A.
Tetrahedron Lett. 1969, 39, 3347–3350; (b) Dare, L. M.;
de Haan, J. W.; Kloosterziel, H. Tetrahedron Lett. 1970,
11, 2755–2758.
Hong, S. M. J. Appl. Pol. Sci. 1999, 71, 1071–1080; (b)
Ribeiro, M. R.; Deffieux, A.; Portela, M. F. Ind. Eng.
Chem. Res. 1997, 36, 1224–1237.
6. Halterman, R. L.; Ramsey, T. M.; Pailes, N. A.; Khan,
M. A. J. Organomet. Chem. 1995, 497, 43–53.
7. (a) Lange, G. L.; Gottardo, C. Synth. Commun. 1990, 20,
1473–1479; (b) Spino, C.; Barriault, N. J. Org. Chem.
1999, 64, 5292–5298.
18. Llina´s, G. H.; Mena, M.; Palacios, F.; Royo, P.; Serrano,
R. J. Organomet. Chem. 1988, 340, 37–43.
19. Csa´ky¨, A. G.; Mba, M.; Plumet, J. J. Org. Chem. 2001,
66, 9026–9029.
20. Desired isomer, 8a, was only seen in 10% yield Austin, R.
N.; Clark, T. J.; Dickson, T. E.; Killian, C. M.; Nile, T.
A.; Schabacker, D. J.; McPhail, A. T. J. Org. Chem.
1995, 491, 11–18.
8. (a) Kametani, T.; Aizawa, M.; Nemoto, H. Tetrahedron
1981, 37, 2547–2554; (b) Wender, P. A.; Cooper, C. B.
Tetrahedron Lett. 1987, 28, 6125–6128.
9. Hillard, R. L.; Vollhardt, K. P. C. J. Am. Chem. Soc.
1977, 99, 4058–4065.
10. (a) Sugimoto, T.; Ishihara, J.; Murai, A. Tetrahedron
Lett. 1997, 38, 7379–7382; (b) Llerena, D.; Buisine, O.;
Aubert, C.; Malacria, M. Tetrahedron 1998, 54, 9373–
9392.
21. 5 - (4 - Methoxymethoxy-butyl)-2-methyl-1-[2-(2-methyl-
4,5,6,7-tetrahydro-1H-inden-1-yl)-ethyl]-4,5,6,7-tetra-
1
hydro-1H-indene, 10% yield as a colorless oil. H NMR
(CDCl3) isomer protons for the desired isomer seen at
5.85 ppm. MS m/z (appi, ion trap) 410.2+ (frag., Int.)
378.3 (100), 276.5 (12), 262.5 (27), 230.6 (14), 160.8 (34),
158.8 (10), 146.9 (36), 144.8 (11). UV ads. 315, 326 and
346 nm peaks adsorption.
11. Greene, T. W.; Wuts, P. G. M. Protective Groups in
Organic Synthesis, 3rd ed.; John-Wiley & Sons: New
York, 1999; pp. 654–659.
12. Altered reaction solvent, reaction temperature, base and
various alkyl-halide addition strategies.
22. 1,2,-Ethylene-bis(9-bicyclo [4.3.0]-non-1(9)-en-8-one), 80%
isolated yield as a off-white solid. 1H NMR (400 MHz,
CDCl3): l=2.8 (t, 2H), 2.5 (d, 4H), 2.3–2.4 (b. s, 3), 2.23
(d, 1H), 2.12 (d, 2H), 1.75–2.05 (m, 8H), 1.4–1.55 (q, 2H),
1.1–1.35 (m, 2H), 95–1.1 (m, 2H). 13C NMR: 208, 178,
136, 41, 40, 35, 28, 27, 21. MS m/z (appi, ion trap):
298.4+ (frag., Int.): 280.4 (40), 263.5 (15), 262.5 (100),
260.4 (18), 1663.7 (12), 142.8 (17), 132.8 (30), 130.8 (51).
23. 1,2-Ethylene-bis(10-methyl bicyclo [5.3.0] dec-7,9 diene),
13. 5-(4-Methoxymethoxy-butyl)-3-[2-(2-oxo-3,3a,4,5,6,7-hexa-
hydro-2H-inden-1-yl)-ethyl]-1,4,5,6,7,7a-hexahydro-in-
1
den-2-one, 80% isolated yield as a colorless oil. H NMR
(400 MHz, CDCl3): l=4.65 (s, 2H), 3.55 (t, 2H), 3.35 (s,
3H), 2.8 (t, 2H), 2.45–26 (dd, 4H) 2.3–2.4 (b. s, 3H), 2.23
(d, 1H), 2.15 (d, 2H), 1.75–2.1 (m, 6H), 1.35–1.65 (m,
6H), 1.25 (b. s, 4H), 8–1.1 (m, 2H), 6–8 (m, 1H). 13C
NMR: 208, 178, 136, 96, 68, 55, 41, 40, 37, 35, 33.5, 30,
28, 26.5, 25.5, 24, 21. MS m/z (appi, ion trap): 414.2+
(frag., Int.): 382.2 (100), 381.3 (2), 380.2 (1), 352.3 (11),
350.6 (1), 346.3 (1), 162.8(1).
1
50% isolated yield as yellow crystals. H NMR (CDCl3):
l=5.95 (s, 2H), 5.9 (s, 2H), 2.95–3.15 (m, 4H), 2.6–2.75
(d, 4H), 2.1 (s, 16H), 1.85–1.95 (d, 4H), 1.6–1.75 (s, 16H),
1.05–1.2 (t, 12H). 13C NMR: 152.6, 152.8, 143.4, 143.6,
135.7, 135.6, 111.9, 111.7, 111.5, 111.2, 44.4, 44.2, 44, 39,
39.5, 27.4, 27.2, 27, 23.3, 22.8, 22.7, 22.6, 22.5, 22.3, 22.1.
MS m/z (appi, ion trap) 294.4+ (frag., Int.) 278.3 (25),
236.4 (35), 196.6 (23), 184.7 (28), 170.8 (29), 161.8 (23),
160.7 (100), 158.7 (66), 147.6 (38), 146.8 (63), 144.8 (29),
134.9 (43), 130.9 (48), 118.9 (69), 105 (44).
14. Chung, Y. K. Coord. Chem. Rev. 1999, 188, 297–341.
15. Kurek-Tyrlik, A.; Marczak, S.; Michalak, K.; Wicha, J.;
Zarecki, A. J. Org. Chem. 2001, 66, 6994–7001.
16. (a) Mengele, W.; Diebold, J.; Troll, C.; Roll, W.;
Brintzinger, H. H. Organometallics 1993, 12, 1931–1935;
(b) Polo, E.; Bellabarba, R. M.; Prini, G.; Traverso, O.;
Green, M. L. H. J. Organomet. Chem. 1999, 577, 211–
218.