Pentadienylzirconium compounds: Easily accessible new reagents for selective pentadienylation reactions

Article abstract of DOI:10.1016/S0040-4039(00)02353-4

2,4-Pentadienylzirconium complexes are generated from 2,4- or 2,2′-pentadienyl ethers in turn. These compounds react in situ with aldehydes and ketones in a totally γ-regioselective manner and with predominant anti stereoselectivity to produce bis(homoall

Full text of DOI:10.1016/S0040-4039(00)02353-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 1677–1680
Pentadienylzirconium compounds: easily accessible new reagents
for selective pentadienylation reactions
Philippe Bertus, Franck Cherouvrier and Jan Szymoniak*
Re´actions Se´lectives et Applications, CNRS and Universite´ de Reims, 51687 Reims Cedex 2, France
Received 13 November 2000; accepted 22 December 2000
Abstract—2,4-Pentadienylzirconium complexes are generated from 2,4- or 2,2%-pentadienyl ethers in turn. These compounds react
in situ with aldehydes and ketones in a totally g-regioselective manner and with predominant anti stereoselectivity to produce
bis(homoallylic) alcohols in good yields. Iodocyclization of one of these alcohols represents regio- and stereocontrolled short entry
to functionalized tetrahydrofurans. © 2001 Elsevier Science Ltd. All rights reserved.
Whereas the addition of allylmetals to carbonyl com-
pounds is a well-known reaction,1 the analogous reac-
tion involving pentadienylmetals has been much less
developed. The use of lithium-, magnesium-, zinc-, tin-,
silicon- and indium-based reagents have been reported.2
These reagents, which are usually generated from 5-
bromo-1,3-pentadienyl derivatives or by metalation of
dienes, add to aldehydes with varying degrees of a (o)
versus g regioselectivity (Scheme 1). Moreover, almost
nothing is known about the stereoselectivity of these
pentadienylation reactions.3
(‘Cp2Zr’)4 to allylic ethers.5 We anticipated that new
pentadienylzirconium compounds could be generated in
an analogous fashion from dienyl ethers. Since the
Cp2Zr residue in organozirconocenes tends to migrate
to the least hindered terminal position,4,6 we reasoned
that isomeric pentadienyl ethers 1 or 2 could be
employed to produce regioselectively the unique 2,4-
pentadienylzirconium species 3 (Scheme 2). In this man-
ner, one synthetic advantage of the method would be
the possible use of different substrates. To test the
aforementioned hypothesis, compounds 1 and 2 were
easily prepared by reaction of acroleine with vinylmag-
nesium bromide (followed by acidic isomerization to
form the dienol precursor of 1) and etherification
An efficient procedure for preparing allylzirconium spe-
cies involves the oxidative addition of zirconocene
Scheme 1.
Scheme 2.
Keywords: zirconium; g-pentadienylation reaction; homoallylic alcohols; regiocontrol; tetrahydrofurans.
* Corresponding author.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)02353-4

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P. Bertus et al. / Tetrahedron Letters 42 (2001) 1677–1680
(NaH, BnBr).7 Thereafter, the oxidative addition reac-
tion was investigated. In an initial experiment, the
Taguchi protocol for the generation of allylzirconiums
from allylic ethers was applied.5c Compound 1 or 2 (1
equiv.) was added to the mixture of Cp2ZrCl2 (1.3
equiv.) and 2.6 equiv. of n-BuLi at −78°C, the tempera-
ture was raised to 20°C (3 h), benzaldehyde (1.5 equiv.)
was added at 0°C and the reaction carried out at rt for
2 h. Alternatively, the following simplified procedure
has been developed.8 To a solution of 1 (or 2) (1 mmol)
and Cp2ZrCl2 (1.1 mmol) in THF (4 mL) n-BuLi (2.2
mmol, 2.5 M in hexane) was added slowly via syringe at
0°C. The reaction mixture was then refluxed for 0.5 h.
Benzaldehyde (1.2 equiv.) was added and the reaction
carried out at rt for 1 h. After a conventional hydrolytic
workup (1 M HCl) followed by flash chromatography,
the dienol 4 was obtained as a sole product, in 60–70%
yields, by using each of the two procedures (Scheme 2).
Also, noteworthy was the unique formation of 4 start-
ing from the isomeric pentadienyl ethers 1 or 2. Clearly,
irrespective of the substrate structure, the coupling with
benzaldehyde occurred regioselectively at the g-position
of the same zirconium species 3. In this manner, the
overall transformation appeared as doubly regioselective,
both in the formation of the organozirconium reagent
and in its successive addition to aldehyde.
simplified procedure, as above. As shown in Table 1, in
all cases the reaction occurred in a g-regioselective
manner to afford solely the branched alcohols 12–17.
Benzaldehyde, aliphatic and unsaturated aldehydes
gave good yields (entries 1–5). The a,b-unsaturated
aldehydes 9 and 10 afforded the unique 1,2-addition
products 15 and 16 (entries 4 and 5). The reaction
employing acetone also proceeded smoothly to give the
terpene 17 (santolina alcohol) (entry 6). Starting from
the aldehydes 6, 8 and 9 similar good diastereoselectiv-
ities were obtained. Particularly, the reaction of ben-
zaldehyde afforded 12, as an 86:14 mixture of
diastereomers (12a and 12b).10 Attempts to separate
these isomers and to determine the anti/syn configura-
tion failed.
To establish the stereochemistry, we therefore turned to
the use of a cyclization method. The iodocyclization of
homoallylic alcohols was reported to proceed generally
via a 5-endo-trig pathway, leading to substituted tetra-
hydrofurans.11 Using I2/NaHCO3 in acetonitrile as sol-
vent, high stereoselectivities were obtained.12 However,
there have been no reports on the analogous reactions
employing bis(homoallylic) alcohols such as 12. Partic-
ularly, in this case, the level of regioselection with
regard to different CꢀC double bonds remained uncer-
tain. We were pleased to find that the iodocyclization
reaction of 12 (using the I2–NaHCO3–MeCN method)
occurred with a total regioselectivity, in a 5-endo-trig
manner and exclusively on the more substituted CꢀC
To further investigate the regio- and stereochemical
outcome of the reaction we next used pentadienyl ether
5 as a substrate.9 Several carbonyl compounds were
employed and the reactions carried out according to the
Table 1. Reaction of 5 (1 mmol) and Cp2ZrCl2 (1.1 mmol) with n-BuLi (2.2 mmol) in THF, followed by the addition of a
carbonyl compound (1.2 mmol)

P. Bertus et al. / Tetrahedron Letters 42 (2001) 1677–1680
1679
Scheme 3.
double bond. Furthermore, the reaction appeared as
totally stereoselective. Only two diastereomeric tetra-
hydrofurans 18a and 18b were formed in 85:15 ratio,
i.e. the same as the initial ratio of 12a and 12b.10 The
regio- and stereochemical outcome of the iodocycliza-
tion reaction made the configurational assignment pos-
sible, directly on 18. The 2,3-cis-and 2,3-trans
relationship (Ph, vinyl) was assigned to 18a and 18b,
respectively, on the basis of NOE experiments, as indi-
cated in Scheme 3. These attributions were confirmed
by the marked difference in the 1H NMR chemical
shifts of the vinyl a-hydrogen (-CHꢀCH2), upfield-
shifted for 18a (l 4.84) in comparison with 18b (l 5.65).
Consequently, the anti configuration was assigned to
the major diastereomer 12a while the syn configuration
was assigned to the minor diastereomer 12b. The pre-
dominant anti diastereoselection can be rationalized by
assuming a conventional chair-like six-membered tran-
sition state for these g-pentadienylation reactions.13 The
overall reaction sequence leading to 18 exemplifies a
short and stereoselective synthesis of a tetrahydrofuran
derivative with functionalized end groups at C3 and
C4.14
Chem. 1997, 549, 305. (i) Melekhov, A.; Fallis, A. G.
Tetrahedron Lett. 1999, 40, 7867.
3. Only the reactions with prochiral aldehydes were studied,
see Ref. 2g.
4. For reviews of ‘Cp2Zr’ chemistry, see: (a) Negishi, E.;
Takahashi, T. Bull. Chem. Soc. Jpn. 1998, 71, 755. (b)
Negishi, E.; Kondakov, D. Y. Chem. Soc. Rev. 1996, 26,
417. (c) Negishi, E.; Takahashi, T. Acc. Chem. Res. 1994,
27, 124.
5. (a) Rousset, C. J.; Swanson, D. R.; Lamaty, F.; Negishi,
E. Tetrahedron Lett. 1989, 30, 5105; (b) Ito, H.; Taguchi,
T.; Hanzawa, Y. Tetrahedron Lett. 1992, 33, 1295; (c) Ito,
H.; Nakamura, T.; Taguchi, T.; Hanzawa, Y. Tetra-
hedron 1995, 51, 4507.
6. Wipf, P.; Jahn, H. Tetrahedron 1996, 52, 12853 and
references cited therein.
7. The pentadienyl ethers are quite stable compounds, in
contrast to the more sensitive pentadienyl bromides.
8. We have proved that this new procedure is also useful for
the preparation of allylzirconiums from allylic ethers.
9. Compound 5 was easily prepared in two steps by reaction
of 3-methyl-2-butenal with vinylmagnesium bromide fol-
lowed by etherification with BnBr.
1
10. Spectral data for 12 and 18. Major isomer 12a (anti ): H
In summary, 2,4-pentadienylzirconium compounds
have been generated in a regioconvergent manner from
the easily available 2,4- or 2,2%-pentadienyl ethers.
These new reagents have been demonstrated to react
with aldehydes and ketones with complete g-regioselec-
tivity and predominant anti stereoselectivity. Because a
wide variety of 2,4-pentadienylzirconiums may be easily
prepared, the method should be convenient for the
synthesis of various bis(homoallylic) alcohols.
NMR (500 MHz, CDCl3) l 1.33 (s, 3H), 1.61 (s, 3H),
2.25 (s, 1H), 3.24 (q, J=8.3 Hz, 1H), 4.49 (d, J=7.6 Hz,
1H), 5.02 (d, J=9.4 Hz, 1H), 5.16 (d, J=16.0 Hz, 1H),
5.17 (d, J=11.3 Hz, 1H), 5.78 (ddd, J=16.0, 11.3, 8.0
Hz, 1H), 7.20–7.35 (m, 5H); 13C NMR (125 MHz,
CDCl3) l 17.9 (CH3), 26.8 (CH3), 51.6 (CH), 76.4 (CH),
117.0 (CH2), 122.0 (CH), 126.7 (CH), 127.3 (CH), 127.8
(CH), 134.5 (C), 138.0 (CH), 142.1 (C); MS (EI): m/z
(%)=184 (4, M−H2O), 169 (10), 106 (48), 105 (52), 94
(39), 77 (100). Minor isomer 12b (syn): 1H NMR (500
MHz, CDCl3) l 1.61 (s, 3H), 1.78 (s, 3H), 2.25 (s, 1H),
3.27 (masked, 1H), 4.48 (masked, 1H), 4.93 (d, J=17.2
Hz, 1H), 4.96 (d, J=10.4 Hz, 1H), 5.15 (masked, 1H),
5.60 (ddd, J=17.2, 10.4, 6.9 Hz, 1H), 7.20–7.35 (m, 5H);
13C NMR (125 MHz) l 18.3 (CH3), 26.1 (CH3), 51.0
(CH), 77.0 (CH), 116.1 (CH2), 122.3 (CH), 127.0 (CH),
127.5 (CH), 128.0 (CH), 136.6 (C), 137.4 (CH), 141.9 (C).
References
1. (a) Yamamoto, Y.; Asao, N. Chem. Rev. 1993, 93, 2207;
(b) Roush, W. In Comprehensive Organic Synthesis;
Trost, B. M.; Fleming, I.; Heathock, C. W., Eds.; Perga-
mon: Oxford, 1991; Vol. 2, p. 1.
1
2. Li: (a) Ge´rard, F.; Miginiac, P. Bull. Soc. Chim. Fr. 1974,
1924. Mg: (b) Yasuda, H.; Yamauchi, M.; Nakamura,
A.; Sei, T.; Kai, Y.; Yasuoka, N.; Kasai, N. Bull. Chem.
Soc. Jpn. 1980, 53, 1089. Zn: (c) Ghosez, L.; Marko, I.;
Hesbain-Frisque, A. M. Tetrahedron Lett. 1986, 27, 5211.
(d) Jung, M. E.; Nichols, C. J. Tetrahedron Lett. 1996, 37,
7667. Sn: (e) Nishigaichi, Y.; Fujimoto, M.; Takuwa, A.
Synlett 1994, 731. Si: (f) Kobayashi, S.; Nishio, K. Chem.
Lett. 1994, 1773. (g) Valle´e, Y.; Pelloux-Le´on, N.; Minas-
sian, F. Synlett 2000, 242. In: (h) Hirashita, T.; Inoue, S.;
Yamamura, H.; Kawai, M.; Araki, S. J. Organomet.
Major isomer 18a: H NMR (500 MHz, CDCl3) l=1.55
(s, 3H), 1.56 (s, 3H), 3.43 (dt, J=11.3, 9.6 Hz, 1H), 3.82
(d, J=11.3 Hz, 1H), 4.84 (ddd, J=16.7, 9.8, 9.8 Hz, 1H),
4.97 (dd, J=10.0, 1.7 Hz, 1H), 5.08 (dd, J=16.7, 1.3 Hz,
1H), 5.16 (d, J=9.4 Hz, 1H), 7.18–7.32 (m, 5H); 13C
NMR (125 MHz, CDCl3) l 24.8 (CH3), 25.8 (CH3), 38.1
(CH), 57.9 (CH), 80.7 (CH), 82.7 (C), 118.8 (CH2), 126.8
(CH), 127.4 (CH), 128.0 (CH), 135.0 (CH), 139.5 (C).
1
Minor isomer 18b: H NMR (500 MHz, CDCl3) l 1.47
(s, 3H), 1.61 (s, 3H), 2.96 (dt, J=11.3, 9.2 Hz, 1H), 4.02
(d, J=10.9 Hz, 1H), 4.67 (d, J=9.4 Hz, 1H), 5.06 (d,

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P. Bertus et al. / Tetrahedron Letters 42 (2001) 1677–1680
J=17.0 Hz, 1H), 5.24 (dd, J=10.2, 0.9 Hz, 1H), 5.65
12. Barks, J. M.; Knight, D. W.; Seaman, C. J.; Weingarten,
G. G. Tetrahedron Lett. 1994, 35, 6511.
13. The stereochemical assignments for 14–16 were estab-
lished by analogy to 12.
14. Such types of THF derivatives are rare. For the recent
syntheses of tetrahydrofurans, see (a) Elliott, M. C. J.
Chem. Soc., Perkin Trans. 1 1998, 4175. (b) Micalizio, G.
C.; Roush, W. R. Org. Lett. 2000, 2, 461 and references
cited therein.
(ddd, J=17.0, 10.2, 8.7 Hz, 1H), 7.22–7.35 (m, 5H); 13C
NMR (125 MHz, CDCl3) l 26.7 (CH3), 29.5 (CH3), 39.0
(CH), 61.5 (CH), 82.5 (C), 83.6 (CH), 120.2 (CH2), 125.9
(CH), 127.7 (CH), 128.2 (CH), 134.2 (CH), 140.5 (C).
11. (a) Bedford, S. B.; Bell, K. E.; Fenton, G.; Hayes, C. J.;
Knight, D. W.; Shaw, D. Tetrahedron Lett. 1992, 33,
6511; (b) Lipshutz, B. H.; Tirado, R. J. Org. Chem. 1994,
59, 8307.
.
.