Diastereoselective synthesis of highly substituted five-membered-ring oxygen heterocycles by zirconocene-mediated C - C coupling reactions

Article abstract of DOI:10.1002/(SICI)1521-3773(19980703)37:12<1673::AID-ANIE1673>3.0.CO;2-A

As homoenolate equivalents, zirconocene-1-aza-1,3-diene complexes were used for the first time in stereoselective synthesis. By insertion of an unsymmetrical ketone in the Zr-C σ bond, sterically demanding trisubstituted dihydro- and tetrahydrofuran derivatives were prepared in good overall yields and with high diastereoselectivities (see below).

Full text of DOI:10.1002/(SICI)1521-3773(19980703)37:12<1673::AID-ANIE1673>3.0.CO;2-A

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Diastereoselective Synthesis of Highly
Substituted Five-Membered-Ring Oxygen
Heterocycles by Zirconocene-Mediated
C ± C Coupling Reactions**
Dieter Enders,* Manfred Kroll, Gerhard Raabe, and
Jan Runsink
The synthetic potential of unsaturated compounds has been
extended considerably in the last few years by their con-
version into the corresponding transition metal complexes.[1]
The use of ªCp2Zrº (Cp ˆ cyclopentadienyl) as a complexing
group has brought forth a number of new synthetic methods
during the last ten years,[2, 3] and the chemistry of zirconocene-
imine complexes in particular has led to a series of important
innovations in this field.[4]
In this context we present a new synthesis of highly
substituted five-membered-ring oxygen heterocycles, with a
high degree of diastereoselectivity. Starting from a,b-unsatu-
rated imines and unsymmetrical ketones highly substituted
sterically demanding g-butyrolactols 6 were synthesized.
These could be easily converted into the corresponding g-
butyrolactones 7, dihydrofurans 8, and tetrahydrofurans 9.
This new practical route to the heterocycles in the
title provides building blocks for the synthesis of natural
products and biologically active substances such as alkaloids,
macrocyclic antibiotics, lignans, pheromones, and fragran-
ces.[5]
Inspired by the work of Whitby et al.[6] and Scholz et al.,[7]
we investigated the use of zirconocene-1-aza-1,3-diene com-
plexes as homoenolate equivalents[8] in stereoselective syn-
thesis. Scholz et al. had shown that acetophenone inserts into
the Zr± C s bond of 2,2-bis(h5-cyclopentadienyl)-1-(2-meth-
ylphenyl)-3-phenyl-1-aza-2-zircona-4-cyclopentene (2). By
extending this principle to other substrates and developing a
method for the isolation of the b-substituted carbonyl
compounds from the corresponding insertion products (3),
we were able to use complexes 2 as homoenolate equivalents
for the first time (Scheme 1).
Scheme 1. Diastereoselective insertion of unsymmetrical ketones into the
Zr± C s bond of zirconocene-1-aza-1,3-diene complexes (2) as a new
homoenolate equivalent for the synthesis of trisubstituted five-membered-
ring oxygen heterocycles (Arˆ 2-methylphenyl or 2-methoxyphenyl):
a) 16 ± 78% over six steps; b) ArNH2, molecular sieves; c) [Cp2Zr], ªnBuLi
routeº, quantitative over two steps; d) R1COR2, toluene, D; e) C5H5NO,
H2O; f) HCl/THF, 51 ± 78% over four steps; g) Ag2CO3, toluene, D, 94 ±
100%; h) pyridinium-p-toluenesulfonate (PPTS), toluene, 1 h, >90%;
i) BH3 ´ Me2S, THF, 69 ± 94%.
Scholz et al.[7] emphasized the high degree of cis-stereo-
selectivity achieved in the insertion reaction of acetophenone
into the 1-aza-2-zircona-4-cyclopentene (2, Arˆ 2-methyl-
phenyl), which was also obtained under drastic experimental
conditions. In contrast to this, we were only able to reproduce
the stereoselective insertion in ether under reflux conditions
(85% de); a lower selectivity was observed in boiling toluene
(68% de).
Using sterically demanding aliphatic ketones (such as 3,3-
dimethyl-2-butanone, 1-acetyladamantane, etc.) we observed
a reaction that differed greatly from that mentioned above.
When the zirconocene-1-aza-1,3-diene complexes 2 (Arˆ 2-
methylphenyl or 2-methoxyphenyl) were mixed with
1.05 equivalents of the ketones in boiling toluene, the
corresponding 3-aza-1-oxa-2-zircona-4-cycloheptenes 3a ± e
(see Table 1) were formed cleanly within 30 to 60 minutes.
In contrast to the situation with the aromatic ketone, very
high diastereomeric excesses were reached under these
conditions (>80 de and in some ones higher than 98%).
Additionally NOE experiments and X-ray structural analysis
of the resulting products showed that the trans insertion
products were formed in every aliphatic case (as opposed to
cis in the aromatic case). This big difference in selectivity can
be explained by steric effects for the aliphatic ketones and by
attractive p ± p interactions for the aromatic ketones. When
the symmetric ketones (g and h) were investigated under
these reaction conditions the yields were also nearly quanti-
tative. The zirconocene fragment was removed oxidatively
In the synthesis of the zirconocene-1-aza-1,3-diene com-
plexes (2) we used the nBuLi-route introduced by Negishi et
al.[9] and further investigated by Dioumaev and Harrod[10] in
order to generate the zirconocene equivalent. Following this
method [Cp2Zr(nBu)2] is formed in situ by the reaction of two
equivalents of nBuLi with [Cp2ZrCl2] ( 788C). By warming
up the solution the generated Cp2Zr fragment can form the
desired 1-aza-2-zircona-4-cyclopentene 2 through ligand ex-
change reactions with the a,b-unsaturated imine added to the
reaction mixture.[11]
[*] Prof. Dr. D. Enders, Dipl.-Chem. M. Kroll, Dr. G. Raabe,
Dr. J. Runsink
Institut für Organische Chemie der Technischen Hochschule
Professor-Pirlet-Strasse 1, D-52074 Aachen (Germany)
Fax: (‡49)241-8888127
E-mail: enders@rwth-aachen.de
[**] This work was supported by the Deutsche Forschungsgemeinschaft
(Leibniz prize and Sonderforschungsbereich 380) and by the Fonds
der Chemischen Industrie. We thank BASF AG, Bayer AG, and
Hoechst AG for their donation of chemicals.
ˆ
from the insertion products 3 as [Cp2Zr O]n by the addition of
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pyridinium-N-oxide/H2O. During the course of the reaction
an imine ± enamine tautomerization took place to yield g-
hydroxyimines (4), followed by an intramolecular nucleophil-
whereas their reaction with catalytic amounts of pyridinium-
p-toluenesulfonate (PPTS) under the same conditions gave
the dihydrofurans 8 in very good yield. The series of five-
membered-ring oxygen heterocycles could finally be com-
pleted by the reduction of the g-butyrolactols 6 with two
equivalents of BH3 ´ Me2S to form the corresponding tetrahy-
drofurans 9 (Table 2).
ˆ
ic attack of the hydroxy group on the C N bond leading
to 5,5-disubstituted N-aryl(4-phenyltetrahydrofuran-2-yl)-
amines (5, 1:1 mixture of diastereomers; Figure 1). To obtain
Table 2. Yields and diastereoisomeric excesses of the resulting five-membered-
ring oxygen heterocycles.
7 ± 9 R1
R2
7
8
9
yield [%] yield [%] yield [%] de [%][a]
a
b
c
Me
Me
Me
Me
tBu
cyclohexyl
1-adamantyl
64
59
60
69
65
59
57
58
68
> 98
> 96
> 96
> 96
66[b]
74
d
3-neoadamantyl 72
e
Me
78
70
54
> 96
f
g
h
Ph
Et
Ph
Me
Et
Ph
51
78
67
47[c]
72
62
16
71
±
> 95
±
±
Figure 1. Structure of N-(2-methoxyphenyl)(5-methyl-4-phenyl-5-tricy-
clo[3.3.1.03, 7]non-3-yltetrahydrofuran-2-yl)amine (5d).[14±16]
[a] The de values were determined by 1H NMR spectroscopy with a Varian
Gemini 300 MHz spectrometer. [b] 84% de. [c] 81% de, as the starting material
was not enriched.
optimum yields we refrained from the purification of the a-
anilinotetrahydrofurans (5) as they tended to decompose,
even on deactivated silica. Any impurities present had no
negative influence on the following steps (cleavage of the
aniline unit). If complex 3a is treated with two equivalents of
a freshly prepared ethereal solution of HCl, a-anilinotetrahy-
drofuran (5a) is formed, and the zirconocene fragment is
recovered as [Cp2ZrCl2]. Nevertheless our less complicated
pyridinium-N-oxide method was applied in general.
We have succeeded in using zirconocene-1-aza-1,3-diene
complexes 2 as homoenolate equivalents in stereoselective
synthesis for the first time. The high degree of flexibility in the
range of products as well as the steric demand of the
diastereoselectively obtained trisubstituted five-membered-
ring oxygen heterocycles must be emphasized. Although they
contain quaternary centers adjacent to one another or to
tertiary centers, the title compounds could be synthesized in
good overall yields and can be broadly used as building blocks
for organic synthesis.[17]
The chemistry of a-anilinotetrahydrofurans 5 is rather
unknown apart from their pyrolysis reactions in which the
resulting dihydrofurans tend to polymerize.[12] A method had
to be developed, therefore, to cleave the aniline unit from
these compounds as efficiently as possible. By reaction with
five equivalents of 0.1n HCl we managed to prepare the g-
butyrolactols 6 (Table 1). No spectroscopic evidence for their
existence as open-chain g-hydroxyaldehydes could be found.
The lactols 6 could be quantitatively transformed into
Experimental Section
trans-3a ± e and 3g ± h: To a solution of the aza-zirconacyclopentene 2
(Arˆ 2-methoxyphenyl; 2-methylphenyl in the case of 3h) (1.0 mmol) in
toluene (20 mL) under an atmosphere of argon was added and the
appropriate unsymmetric aliphatic ketone (1.05 equiv), and the mixture
heated to reflux. On warming a darkening (red) of the original luminous
orange solution took place followed by a further change to yellow. As soon
as no further color change was observed the solution was cooled to room
temperature (RT) and the solvent evaporated in vacuo. The insertion
products were obtained as yellow or orange amorphous solids or oils in
greater than 95% purity and were used in this form for the subsequent
transformations. A further purification could be achieved by recrystalliza-
tion from toluene/hexane.
[13]
lactones 7 by oxidation with Ag2CO3 in boiling toluene,
Table 1. Yields and diastereoisomeric excesses of g-butyrolactols 6.
6[a]
R1
R2
Yield [%]
de [%][b]
6a
6b
6c
6d
Me
Me
Me
Me
tBu
cyclohexyl
1-adamantyl
64
66
74
> 98
84
> 96
> 96
3-neoadamantyl 72
6e
Me
78
> 95[c]
5:Pyridinium-N-oxide (0.114 g, 1.2 mmol) was added to solutions of 3 (each
1 mmol) in THF (20 mL). Under vigorous stirring H2O (1 mL) was added,
6 f
6g
6h
Ph
Et
Ph
Me
Et
Ph
51
78
67
> 95[c]
ˆ
whereupon an intense clouding caused by the precipitation of [Cp2Zr O]n
±
±
appeared immediately. After stirring for 8 h at RT the reaction mixture was
diluted with ether (40 mL), dried over MgSO4, and the MgSO4 filtered off
ˆ
[a] The data for 6 f und 6h relate to 2 (Arˆ 2-methylphenyl) as the starting
material. In all other cases 2 (Arˆ 2-methoxyphenyl) was used. Compound
6f was synthesized according to the procedure of Scholz et al.[7] [b] The de
values were determined by 1H NMR spectroscopy on a Varian Gemini 300
MHz or a Varian Unity 500 MHz spectrometer (6b ± f: 300 MHz; 6a:
500 MHz). [c] After flash chromatography (SiO2, diethyl ether/pentane,
1/4).
together with the [Cp2Zr O]n. Evaporation of the solvent led to yellow oils
or solids that were used in the subsequent manipulations without further
purification. Possible impurities do not affect the course of the following
steps. In the case of N-(2-methoxyphenyl)-N-(5-methyl-4-phenyl-5-tricy-
clo[3.3.1.03,7]non-3-yltetrahydro-2-furanyl)amine (5d) recrystallization
(ether/pentane 1/1) resulted in crystals suitable for X-ray structural
analysis (see Figure 1).
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Â
6: To solutions of the crude a-anilinotetrahydrofurans 5 (1 mmol) in THF
(50 mL) was added 0.1n HCl (50 mL) dropwise under vigorous stirring.
After completion of the reaction (monitored by TLC, about 6 h) extraction
with ether, drying over MgSO4, and removal of the solvent in vacuo, the
crude product was purified by chromatography (SiO2, ether/pentane 1/4).
The g-butyrolactols 6 were obtained as colorless liquids or solids.
Pedrosa, M. Vicente, S. García-Granda, A. Gutierrez-Rodríguez,
ibid. 1996, 52, 10761; d) J. D. Armstrong, F. W. Hardner, A. E.
DeCamp, R. P. Volante, I. Shinkai, Tetrahedron Lett. 1992, 6599; e) H.
Ahlbrecht, G. Bonnet, D. Enders, G. Zimmermann, Tetrahedron Lett.
1980, 21, 3175. Homoenolates in the syntheses of b,g,g-trisubstituted
five-membered-ring oxygen heterocycles: e) A. R. Katritzky, D. Feng,
Â
H. Lang, J. Org. Chem. 1997, 62, 706; f) E. Alonso, D. J. Ramon, M.
Yus, Tetrahedron 1997, 53, 2641.
8: Lactols 6 were dissolved in toluene (each 20 mLmmol 1) and heated to
reflux in the presence of a catalytic amount of pyridinium-p-toluenesul-
fonate (water separator). As soon as no further conversion was detected (as
monitored by TLC) the solution was cooled to RT and washed with pH 7
buffer (10 mL). The aqueous phase was extracted with pentane (10 mL),
the combined organic layers dried over MgSO4, and the solvent evaporated
in vacuo. The reddish to orange crude syrups were purified by chromatog-
raphy (SiO2, pentane). Dihydrofurans 9 were obtained as colorless oils.
[9] E.-I. Negishi, S. J. Holmes, J. M. Tour, J. A. Miller, F. E. Cederbaum,
D. R. Swanson, T. Takahashi, J. Am. Chem. Soc. 1989, 111, 3336.
[10] V. K. Dioumaev, J. F. Harrod, Organometallics 1997, 16, 1452; see also
D. R. Swanson, E.-I. Negishi, Organometallics 1991, 10, 825.
[11] Two equivalents of volatile C4-hydrocarbons are formed during the
decomposition of the initialy formed [Cp2Zr(nBu)2]. This amount
3
equals a gas volume of more than 2000 cm when the reaction is
9: A solution of BH3 ´ Me2S (2n in THF; 1 mL) was added to the
appropriate lactol 6 (1 mmol) at 08C under an atmosphere of argon. After
removal of the cooling bath the mixture was stirred until the evolution of
gas ceased and then heated slowly to 608C. As soon as no further
conversion was detected (monitored by TLC), the solution was cooled to
08C. After the addition of methanol (2 mLmmol 1) to hydrolyze any excess
borane, the solution was warmed to reflux temperature before removing
the volatile components in vacuo. The colorless residue was purified by
chromatography (SiO2, pentane) to yield the corresponding tetrahydrofur-
ans 9 as colorless liquids or solids.
performed on a scale of 50 mmol. Among these volatile compounds
are unsaturated species like butene, which are able to undergo diverse
C ± C-coupling reactions in the presence of ªCp2Zrº.[2] A gas outlet for
the removal of these by-products should, therefore, have a positive
effect on the driving force of the complexation as well as on the
prevention of side reactions. This is proved by obtaining near
quantitative yields when a stream of argon is passed over the reaction
mixture.
[12] C. Glacet, Bull. Soc. Chim. Fr. 1952, 990, 994.
[13] a) Y. Koga, M. Sodeoka, M. Shibasaki, Tetrahedron Lett. 1994, 35,
1227; b) T. Sakamoto, Y. Kondo, H. Yamanaka, Heterocycles 1993, 36,
2437.
Received: February 3, 1998 [Z11429IE]
[14] Substance 5d (C27H33NO2) crystallizes from ether/pentane 1/1 (crystal
dimensions ca. 0.3 Â 0.3 Â 0.3 mm3). Orthorhombic, space group Pbcn
(No. 60), a ˆ 31.362(1), b ˆ 10.366(1), c ˆ 13.618(2) Š, Vˆ 4427.3 Š3,
Z ˆ 8, Mr ˆ 403.57, 1calcd ˆ 1.211 gcm 3. Enraf-Nonius CAD4 diffrac-
tometer, CuKa radiation (graphite monochromator, l ˆ 1.54179 Š).
The structure has been solved with direct methods (Gensin, Gentan,
from Xtal3.2).[15] Some of the hydrogen positions could be localized,
the remaining have been calculated. Reflections observed [I > 2s(I)]:
2136, parameters refined: 272, R ˆ 0.070, Rw ˆ 0.049; residual electron
density 0.6/ ‡ 0.5 eŠ 3. Crystallographic data (excluding structure
factors) for the structure reported in this paper have been deposited
with the Cambridge Crystallographic Data Centre as supplementary
publication no. CCDC-101110. Copies of the data can be obtained free
of charge on application to CCDC, 12 Union Road, Cambridge
CB21EZ, UK (fax: (‡44)1223-336-033; e-mail: deposit@ccdc.cam.
ac.uk).
[15] S. R. Hall, H. D. Flack, J. M. Stewart, XTAL3.2 Reference Manual,
Universities of West-Australia, Genf and Maryland, Lamb, Perth,
1992.
[16] Software for ball-and-stick plot: Ball & Stick Ver. 2.2, A. Falk, N.
Müller, G. Schoppel, L. Webb, Linz (Austria), Stafford (UK).
[17] All isolated new compounds showed suitable spectroscopic data (IR,
NMR, MS) and correct elemental analysis or high resolution mass
spectra.
German version: Angew. Chem. 1998, 110, 1770 ± 1773
Keywords: asymmetric syntheses ´ heterocycles ´ homoeno-
lates ´ insertions ´ zirconium
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Angew. Chem. Int. Ed. 1998, 37, No. 12
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