Reactions of acylzirconocene chloride with nucleophiles: Bimodal reactivity at β- and acyl carbons of α,β-unsaturated acylzirconocene chloride

Article abstract of DOI:10.1016/S0040-4039(00)01291-0

Reactions of α,β-unsaturated acylzirconocene chloride with nucleophiles showed novel bimodal reactivity at the β- and acyl carbons depending upon the nucleophile employed, and the formation of ketone α,β-dianionic species was also observed. (C) 2000 Elsev

Full text of DOI:10.1016/S0040-4039(00)01291-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 7525–7528
Reactions of acylzirconocene chloride with nucleophiles:
bimodal reactivity at b- and acyl carbons of a,b-unsaturated
acylzirconocene chloride
Yuji Hanzawa,* Kensuke Narita, Akito Kaku-uchi and Takeo Taguchi*
School of Pharmacy, Tokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji,
Tokyo 192-0392, Japan
Received 3 July 2000; revised 21 July 2000; accepted 24 July 2000
Abstract
Reactions of a,b-unsaturated acylzirconocene chloride with nucleophiles showed novel bimodal reactiv-
ity at the b- and acyl carbons depending upon the nucleophile employed, and the formation of ketone
a,b-dianionic species was also observed. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: acylzirconocene chloride; ketone a,b-dianion; metallacycles; Michael additions; cuprate.
Recent studies on the reactivity of acylzirconocene chloride derivatives (1 and 2) indicated
their usefulness as an ‘unmasked’ acyl anion donor in organic synthesis.1 Herein we report the
reactions of a,b-unsaturated acylzirconocene chloride 2 with nucleophiles and the bimodal
(nucleophilic or electrophilic) reactivity at both the acyl and b-carbons in 2 (Fig. 1).
Reactions of 2 with stable carbon nucleophiles (sodium salt of dimethyl malonate and
malononitrile) at 0°C in THF afforded Michael addition products 4 in good yields (Eq. (1))
Figure 1. Electronic duality of a,b-unsaturated acylzirconocene chloride 2
* Corresponding authors. Tel: +81 426 76 3274; fax: +81 426 76 3257; e-mail: hanzaway@ps.toyaku.ac.jp
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01291-0

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(entries 1–5, Table 1).2 Direct treatment of the intermediate 3 with allyl bromide in the presence
of a catalytic amount of CuI·2LiCl (10 mol%) at 0°C gave allylic ketone 5 in one-pot (Eq. (1))
(entries 6–8, Table 1).3,4 In the reaction of 2a with dimethyl malonate anion, D2O-work-up gave
a-deuterated deutero aldehyde 6 in 88% yield (>95 D%). The transformation of 2 into 5 implies
that the electronic nature of 2 is to be A shown in Fig. 1.
(1)
Table 1
Reactions of 2 with stable carbon nucleophiles and the subsequent Cu(I)-catalyzed coupling reaction with allyl
bromidea
Entry
2
Nucleophile
X
Yield (%)b
R2
4
5
1
2
3
4
5
6
7
8
2a
2a
2b
2b
2b
2a
2b
2b
H
CH3
H
CH3
H
H
COOCH3
88
84
81
72
52
COOCH3
COOCH3
COOCH3
CN
COOCH3
COOCH3
COOCH3
81
75
68
H
CH3
a Reaction conditions for the formation of 4:2 1.5 equiv.; NAH (1.1–1.5 equiv.); R2CHX2 (1 equiv.); 0°C, 2 h.
Reaction conditions for 5:2 1.5 equiv.: (i) NaH (1.1–1.5 equiv.); R2CHX2 (1 equiv.); 0°C, 2 h and (ii) CuI·2LiCl (10
mol%), allyl bromide (1.3 equiv.) 0°C, 1 h.
b Isolated yield.
However, the reaction of 2 with a higher-order cyanocuprate reagent,5 R2Cu(CN)Li2, at
−78°C in THF afforded, contrary to our expectation, saturated ketone 7 by aqueous work-up
(Eq. (2)). No trace of a Michael addition product was observed in the reaction mixture. In the
reaction of 2a and (CH3)2Cu(CN)Li2, D2O treatment of the reaction mixture gave a,b-didueter-
ated ketone 8 (the undetermined stereochemistry) in 69% yield, and the deuterium content at
each position was over 95%. The formation of 8 suggests the presence of ketone a,b-dianion
equivalent6 from 2 under the reaction conditions. An addition of an excess of organic halides to
the reaction mixture of 2 and R2Cu(CN)Li2 afforded ketone derivatives 9. D2O-treatment of the
reaction mixture, which is derived from 2a, (CH3)2Cu(CN)Li2 and CH3I, afforded a-deuterated
10 in 65% yield (Eq. (2)). Attempts to react the a-carbanion with electrophiles, however, ended
with synthetically little success.7 The results of the reactions of 2a with higher-order
cyanocuprate and the following reaction with organic halides are shown in Table 2.
The facts that (i) the reaction of saturated acylzirconocene chloride 1a with (CH3)2Cu(CN)Li2
gave alcohol 12 (73%), and (ii) D2O work-up of the reaction gave d-12 suggest the formation of

7527
(2)
Table 2
The formation of 9 by the treatment of 2a with R2Cu(CN)Li2 and R2Ia
Entry
R2X
R
9 Yield (%)b
1
2
3
4
5
6
CH3I
CH3
CH3
CH3
CH3
CH3
n-C4H9
68
71
22c
68
46
50
allyl chloride
Propargyl chloride
PhCOCl
CH3COCl
2-Naphthoyl chloride
a Reaction conditions: 2a 1.5 equiv., R2Cu(CN)Li2 (2.0 equiv.) in THF, −78°C, 0.5 h then R2X (3 equiv.) −78°C,
0.5 h.
b Isolated yield.
c Allenyl product.
ketone–zirconocene intermediate 11 (Eq. (3)).8 Thus, in the case of 2, oxazirconacyclopentene
14,9 a ketone a,b-dianion equivalent, would be formed through the formation of unsaturated
ketone–zirconocene complex 13 followed by 1,3-rearrangement of the zirconocene moiety (Eq.
(4)). Although the intermediate 14 proved difficult to isolate and characterize,10 the 1,3-rear-
rangement of the zirconocene portion in the nitrogen analogue of 11 has been well established
in the formation of zirconaazacycle, the nitrogen analogue of 14.9b The formation of ketone 15
or d2-15 (Eq. (5)) by the reaction of saturated acylzirconocene chloride 1a with higher-order
vinyl cyanocupurate would support the postulated process.
In the present reactions of 2 with nucleophiles, the dichotomous reactivity (A and B in Fig.
1) at both the b- and acyl carbons in 2 was brought about by our choice of nucleophilic reagents
(stable carbon nucleophiles or R2Cu(CN)Li2).
(3)
(4)
(5)

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In summary, we have shown that an electronic nature at the b- and acyl carbons of the
a,b-unsaturated acylzirconocene chloride 2 depends on the employed nucleophile. Generation of
the ketone a,b-dianion species, oxazirconacyclopentene derivative 14, through the reaction of
a,b-unsaturated acylzirconocene chloride 2 with R2Cu(CN)Li2 and the efficient reaction of 14
toward electrophiles has opened up a new synthetic possibility of the acylzirconocene complex.
Preparation of 9: To a solution of 2a (2.0 mmol) in THF (5 mL) [prepared by (i) stirring with
Cp2Zr(H)Cl (1.3 mmol) and 4-phenyl-1-butyne (2.1 mmol) in CH2Cl2 (4 mL) at ambient
temperature for 0.5 h, (ii) stirring under CO atmosphere (1 atm) for 2 h and (iii) concentration
to dryness in vacuo and addition of THF (5 mL)] was added a solution of (CH3)2Cu(CN)Li2 (4
mmol) in THF–ether (8: 5) (13 mL) at −78°C. After the mixture was stirred for 0.5 h at the same
temperature, CH3I (6 mmol) was added and the stirring was continued for 0.5 h at −78°C. The
reaction was quenched by the addition of sat. aq. NH4Cl and extracted with ether. After the
usual procedures, the crude material was purified by silica gel column chromatography (hex-
ane:ethyl acetate=80:1) to give 9 [R1=Ph(CH2)2, R2=CH3, R=CH3] (68%).
References
1. (a) Harada, S.; Taguchi, T.; Tabuchi, N.; Narita, K.; Hanzawa, Y. Angew. Chem. Int. Ed. Engl. 1998, 37, 1696.
(b) Hanzawa, Y.; Tabuchi, N.; Taguchi, T. Tetrahedron Lett. 1998, 39, 6249. (c) Hanzawa, Y.; Tabuchi, N.;
Taguchi, T. Tetrahedron Lett. 1998, 39, 8141. (d) Hanzawa, Y.; Tabuchi, N.; Saito, K.; Noguchi, S.; Taguchi, T.
Angew. Chem. Int. Ed. Engl. 1999, 38, 2395.
2. Michael addition reaction of lithium amide to a,b-unsaturated acyliron complex has been reported; Davis, S. G.;
Garrido, N. M.; McGee, P. A.; Shilvock, J. P. J. Chem. Soc., Perkin Trans. 1 1999, 3105.
3. According to Grubbs’ report, the formation of ketene–Zr complex as an intermediate through the intramolecular
substitution of the chloride on zirconocene species 2 with enolate oxygen might be possible: Waymouth, R. M.;
Santarsiero, B. D.; Coots, R. J.; Bronikowski, M. J.; Grubbs, R. H. J. Am. Chem. Soc. 1986, 108, 1427 and the
references cited therein. A clear NMR spectrum of the intermediate could not be obtained.
4. Transmetalation from Zr to Cu, see Xi, C.; Kotora, M.; Takahashi, T. Tetrahedron Lett. 1999, 40, 2375 and the
references cited therein. See also the Cu(I)-catalyzed cross-coupling reaction of acylzirconocene complexes;
Hanzawa, Y.; Narita, K.; Taguchi, T. Tetrahedron Lett. 2000, 41, 109.
5. For reviews, see: (a) Lipshutz, B. H. Synthesis 1987, 325. (b) Lipshutz, B. H.; Wilhelm, R. S.; Kozlowski, J. A.
Tetrahedron 1984, 40, 5005. Other organometallic reagents (MeLi, Me2CuLi and MeMgBr) gave lower yield
(35%) of 6 or a complex mixture (Grignard reagent).
6. (a) Ryu, I.; Nakahira, H.; Ikebe, M.; Sonoda, N.; Yamato, S.; Komatsu, M. J. Am. Chem. Soc. 2000, 122, 1219.
(b) Nakahira, H.; Ryu, I.; Ikebe, M.; Kambe, N.; Sonoda, N. Angew. Chem. Int. Ed. Engl. 1991, 30, 177.
7. The reaction of 2 with Me2Cu(CN)Li2 followed by the addition of MeI and HCHO (gas) afforded a low yield
(ꢀ10%) of a-hydoxymethyl, b-methyl ketone.
8. The reaction of acylzirconocene chloride with Al(CH3)3 has been reported to give ketone–zirconocene complex:
Waymouth, R. M.; Grubbs, R. H. Organometallics 1988, 7, 1631. We were unable to prove the structure of 11
by a spectroscopic method probably due to the presence of an excess of cuprate reagent.
9. Preparation and reactions of an azaanalogue of 14, zirconaazacycle, have been reported; (a) Enders, D.; Kroll,
M.; Raabe, G.; Runsink, J. Angew. Chem. Int. Ed. Engl. 1998, 37, 1673. (b) Davis, J. M.; Whitby, R. J.;
Jaxa-Chamiec, A. J. Chem. Soc., Chem. Commun. 1991, 1743. (c) Scholz, J.; Nolte, M.; Kru¨ger, C. Chem. Ber.
1993, 126, 803.
10. Titanocene analogue of 14 has been reported to be impossible to characterize because of its instability, see Ref.
(9b).
.