Cu(I)-assisted carbon-carbon bond forming reactions of γ,γ-dialkoxyallylic zirconium species: A new versatile homoenolate equivalent of propionate

Article abstract of DOI:10.1016/S0040-4039(00)01822-0

In the presence of CuCN, reaction of γ,γ-dialkoxyallylic zirconium species 1 with acyl chloride or allylic phosphates proceeded at the α-position of 1 to give alkanoates 3 after aqueous work-up. The ketene dialkylacetal moiety in the coupling products 2 can be used for further bond forming reaction with electrophiles such as nitrosobenzene, nitrostyrene or trichloroacetylisocyanate. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01822-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 10239–10243
Cu(I)-assisted carbonꢀcarbon bond forming reactions of
g,g-dialkoxyallylic zirconium species: a new versatile
homoenolate equivalent of propionate
Azusa Sato, Hisanaka Ito, Yusuke Yamaguchi and Takeo Taguchi*
Tokyo University of Pharmacy & Life Science, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
Received 8 September 2000; revised 10 October 2000; accepted 12 October 2000
Abstract
In the presence of CuCN, reaction of g,g-dialkoxyallylic zirconium species 1 with acyl chloride or allylic
phosphates proceeded at the a-position of 1 to give alkanoates 3 after aqueous work-up. The ketene
dialkylacetal moiety in the coupling products 2 can be used for further bond forming reaction with
electrophiles such as nitrosobenzene, nitrostyrene or trichloroacetylisocyanate. © 2000 Elsevier Science
Ltd. All rights reserved.
Keywords: g,g-dialkoxyallylic zirconium; allyl cuprate; homoenolate; ketene acetal.
We have reported an efficient generation and the characterization of g,g-dialkoxyallylic
zirconium species 1 and its reaction with a variety of carbonyl compounds. That is; the
zirconium species 1, easily formed in situ by treating orthoester of acrylate with zirconocene–
butene complex, reacted with aldehyde at the g-position as a typical allylic metal to give the
gem-dialkoxylated homoallyl alcohol derivative,1 while in the presence of more than 1 equiva-
lent of Lewis acid 1 reacted firstly at the b-position (nucleophilic attack of ketene acetal moiety),
followed by carbonꢀzirconium bond cleavage to give the dialkoxycyclopropane derivative.2
Furthermore, 1 showed a different reaction pathway in the reaction with acrylamide derivative
to give the dialkoxy cyclobutane compounds.3 As a further development of the synthetic utility
of the zirconium species 1, we focused on examining the cross-coupling reaction at the
a-position of 1 leading to a new homoenolate equivalent of propionate.4–6 In this paper, we
report that copper(I) assisted cross-coupling reaction of the zirconium species 1 with acyl
chlorides and allylic phosphates proceeds at the a-position of 1 to give the alkanoate derivative
3. Furthermore, the ketene dialkylacetal moiety in the coupling product 2 can be used for a
further bond forming reaction with electrophiles or via cycloaddition reaction (Scheme 1).
* Corresponding author. Tel: +81 426 76 3257; fax: +81 426 76 3257; e-mail: taguchi@ps.toyaku.ac.jp
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01822-0

10240
E
E
OEt
H2O
β
γ
OEt
α
CuCN, E-X
O
O
E
OEt
OEt
3
4
Cp2Zr
OEt
(X-YH)
OEt
E'-X
E'
OEt
2
1
X = Y
OEt
OEt
1
O
O
Scheme 1.
Reaction of the zirconium species 1, generated from triethyl orthoacrylate and zirconocene–
butene complex in toluene,1 with benzoyl chloride was conducted to find a suitable copper salt
for the coupling reaction. While copper salt such as CuCl, CuBr, CuBr·Me2S, CuCN·2LiCl,
which often work well in the transmetalation of the carbonꢀzirconium bond,7 did not give a
satisfactory result (mostly giving rise to a complex mixture), CuCN was found to effect the
cross-coupling at the a-position of 1 to provide the g-keto ester 3a after aqueous work-up.8
Without CuCN any bond forming product between 1 and benzoyl chloride was not detected.
The reaction proceeded by using a catalytic amount of CuCN (20 mol%, 3a 53%), but the yield
of the coupling product 3a increased to 65% when 1 equiv. of CuCN was used. Not only
aromatic acid chloride but also an aliphatic one gave the coupling products, although sterically
hindered pivaroyl chloride resulted in low yield (27%) of product 3d (Scheme 2).
β
O
γ
OEt
α
1) CuCN, RCOCl
2) H2O
Cp2Zr
OEt
OEt
OEt
R
Cp2Zr
OEt
OEt
toluene
O
OEt
3
1
3b
3d
3a
3c
n-C7H15
57
R
p-NO2Ph
50
Ph
65
t-Bu
27
Yield %
Scheme 2.
CuCN catalyzed coupling reaction of 1 also proceeded with allylic bromides or preferably
with allylic phosphates. Coupling reactions were carried out in toluene–THF (2:1) using 1 equiv.
of CuCN. Results are summarized in Table 1. Allyl bromide and allyl diethyl phosphate gave
the coupling product 3e in 72 and 83% yield, respectively, but 3e was not obtained with allyl
acetate (entries 1–3). Substituted allylic bromides were not always suitable substrates in the
present coupling reaction. For example, in the case of cinnamyl bromide a complicated mixture
resulted, probably partly due to a halogen–metal exchange reaction. On the other hand,
cinnamyl phosphate gave the SN2% product 3h in 65% yield along with the formation of the
coupling product 5 (15% yield) reacted between the g-position of 1 and a-position of the
phosphate (entries 6, 7).8 As shown in Table 1, with the other substituted allylic phosphates
examined here, SN2% products reacted at the a-position of the allylic zirconium 1 were exclusively
formed in good yields, even in the case of terminally disubstituted primary allylic phosphates
(entries 8, 9).8,9 Thus, low regioselectivity (SN2% versus SN2 pathway) in the reaction with

10241
Table 1
CuCN-Assisted coupling reaction of 1 with allylic substratea
O
OEt
R1
1) CuCN
2) H2O
X
R3
OEt
Cp2Zr
OEt
OEt
R2 R3
R1 R2
1
3
Entry
R1
R2
R3
X
3
Yield (%)b
1
2
3
4
5
6
7
8
9
H
H
H
H
CH3
Ph
Ph
CH3
PhCH2CH2
H
H
H
H
H
H
H
CH3
CH3
H
H
H
CH3
H
H
H
H
H
Br
3e
3e
3e
3f
3g
3h
3h
3i
72c
83
OP(O)(OEt)2
OAc
OP(O)(OEt)2
OP(O)(OEt)2
OP(O)(OEt)2
Br
0
75d
74
65e,f
Trace
81
OP(O)(OEt)2
OP(O)(OEt)2
3j
96
a Solvent; toluene–THF (2:1), 1 equiv. CuCN.
b Isolated yield.
c 68% yield when 20 mol% CuCN was used.
d E/Z=2.5.
e Solvent; toluene.
f Isomeric coupling product 5 was isolated in 15% yield.
EtO OEt
Ph
5
15%
cinnamyl phosphate may be an exceptional case. Since coupling reaction of 1 with allylic
phosphates did not proceed without CuCN as in the cases of acyl chlorides, in these reactions
allylic copper species should be formed through the Zr-to-Cu transmetalation.10
Under similar reaction conditions, alkyl iodide (butyl iodide), alkenyl iodide (E-1-iodohex-
ene), aryl iodide (iodobenzene), benzyl bromide and benzyl diethylphosphate did not give the
coupling products.
To utilize the ketene acetal moiety in the coupling product, we examined the further reaction
with electrophiles or with electron deficient unsaturated compounds.11 Some examples are shown
in Scheme 3. Quenching the coupling product 2a formed from allyl bromide with D2O provided
the a-deuterated ester 6 (71% yield, 95%-D) as expected. Introduction of amino group to the
a-position could be achieved by reaction with nitrosobenzene to give the anilino derivative 7 in
60% yield.12 Furthermore, nitrostyrene gave the corresponding adduct 8 in 35% yield
(diastereomer ratio 1.5:1)11b and trichloroacetylisocyanate11c gave the malonate derivative 9 in
50% yield after the purification of the crude product by silica gel column chromatography.
In conclusion, we have shown that in the presence of CuCN reaction of g,g-dialkoxyallylic
zirconium species 1 with acyl chloride and allylic phosphates proceeds at the a-position of 1 to

10242
E
(X-YH)
COOEt
CuCN
Br
E-X
OEt
OEt
1
or X=Y
2a
PhCH=CHNO2
Ph
D2O
PhNO
Cl3CCONCO
O
NH2
D
NHPh
COOEt
60 %
NO2
COOEt
71% (95%-D)
COOEt
35 %
COOEt
6
7
8
9 50 %
Scheme 3.
give the alkanoates in SN2% manner with the allylic phosphates. Furthermore, the ketene
diethylacetal moiety in the coupling product can be used for further bond forming reaction with
electron-deficient unsaturated compounds. Thus, g,g-dialkoxyallylic zirconium species 1 can
serve as a homoenolate and a,b-dianion equivalents of propionate.13
References
1. (a) Ito, H.; Taguchi, T. Tetrahedron Lett. 1997, 38, 5829. (b) Sato, A.; Ito, H.; Taguchi, T. J. Org. Chem. 2000,
65, 918.
2. (a) Ito, H.; Kuroi, H.; Ding, H.; Taguchi, T. J. Am. Chem. Soc. 1998, 120, 6623. (b) Ito, H.; Sato, A.; Taguchi,
T. Tetrahedron Lett. 1999, 40, 3217.
3. Ito, H.; Sato, A.; Kusanagi, T.; Taguchi, T. Tetrahedron Lett. 1999, 40, 3397.
4. For reviews on homoenolate anions and homoenolate anions equivalents, see: (a) Werstiuk, N. H. Tetrahedron
1983, 39, 205. (b) Hoppe, D. Angew. Chem., Int. Ed. Engl. 1984, 23, 932. (c) Ryu, I.; Sonoda, N. J. Org. Synth.
Chem. Jpn. 1985, 43, 112. (d) Kuwajima, I.; Nakamura, E. In Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 2, Chapter 1.14.
5. For the pioneering studies on metal homoenolate of ester, see: (a) Nakamura, E.; Kuwajima, I. J. Am. Chem.
Soc. 1984, 106, 3368. (b) Nakamura, E.; Aoki, S.; Sekiya, K.; Oshino, H.; Kuwajima, I. J. Am. Chem. Soc. 1987,
109, 8056 and references cited therein.
6. For recent examples of homoaldol reactions, see: (a) Martin, E. O.; Gleason, J. L. Org. Lett. 1999, 1, 1643. (b)
Ahlbrecht, H.; Beyer, U. Synthesis 1999, 365. (c) Hanazawa, T.; Okamoto, S.; Sato, F. Org. Lett. 2000, 2, 2369.
7. For examples of transmetalation of vinylic zirconium to copper, see: (a) Lipshutz, B. H.; Segi, M. Tetrahedron
1995, 51, 4407. (b) Takahashi, T.; Shen, B.; Nakajima, K.; Xi, Z. J. Org. Chem. 1999, 64, 8706.
8. For examples of allylic cuprate reactions, see: (a) Lipshutz, B. H.; Elworthy, T. R. J. Org. Chem. 1990, 55, 1695.
(b) Lipshutz, B. H.; Ellsworth, E. L.; Dimock, S. H.; Smith, R. A. J. J. Am. Chem. Soc. 1990, 112, 4404. (c)
Yanagisawa, A.; Noritake, Y.; Nomura, N.; Yamamoto, H. Synlett 1991, 251. See also: (d) Yamamoto, Y.; Asao,
N. Chem. Rev. 1993, 93, 2207.
9. For the copper-catalyzed reactions of allylic phosphates and chlorides with titanium, zinc and aluminum
reagents, see: (a) Arai, M.; Nakamura, E.; Lipshutz, B. H. J. Org. Chem. 1991, 56, 5489. (b) Nakamura, E.;
Sekiya, K.; Arai, M.; Aoki, S. J. Am. Chem. Soc. 1989, 111, 3091. (c) Flemming, S.; Kabbara, J.; Nickisch, K.;
Westermann, J.; Mohr, J. Synlett 1995, 183.
10. Typical procedure for coupling reaction with allylic phosphate (Table 1, entry 5): Under an argon atmosphere,
a mixture of Cp2ZrCl2 (351 mg, 1.2 mmol) and n-BuLi (1.42 M hexane solution, 1.69 mL, 2.4 mmol) in toluene
(5 mL) was stirred at −78°C for 1 h, and then to this was added triethyl orthoacrylate (174 mg, 1 mmol). After
being stirred for 3 h at room temperature, the mixture was cooled at −78°C. To this was added CuCN (90 mg,
1 mmol), THF (5 mL) and crotyl diethyl phosphate (174 mg, 1.2 mmol) and the whole mixture was stirred for
4 h at room temperature. Extractive work-up (addition of sat. NH4Cl (aq) and extraction with AcOEt), followed
by silica gel column chromatography (hexane:AcOEt, 50:1) gave 3g (116 mg, 0.74 mmol, 74% yield).

10243
11. (a) Baldwin, J. E. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford,
1991; Vol. 5, Chapter 2.1. (b) Scheeren, J. W. Recl. Trav. Chim. Pays-Bas 1986, 105, 71. (c) Arbuzov, B. A.;
Zobova, N. N. Synthesis 1982, 433.
12. Mechanistic detail for the formation of the anilino derivative 7, instead of the expected N-hydroxyl-N-phenyl
compound is not clear. Report on the reaction of ketene silyl acetal with nitrosobenzene, see: Sasaki, T.; Mori,
K.; Ohno, M. Synthesis 1985, 280.
13. Recently, generation of a,b-dianion of ketone and its reaction with electrophiles was reported. See: Ryu, I.;
Nakahira, H.; Ikebe, M.; Sonoda, N.; Yamato, S.; Komatsu, M. J. Am. Chem. Soc. 2000, 122, 1219.
.
.