Highly regioselective coupling reactions of allylic and propargylic alcohol derivatives with γ,γ-dialkoxyallylic zirconium species via Zr-to-Cu transmetalation

Article abstract of DOI:10.1021/jo0489216

(Chemical Equation Presented) In the presence of CuCN, reaction of γ,γ-dialkoxyallylic zirconium species 4, generated in situ by treating triethyl orthoacrylate with zirconocene-butene complex, with allylic and propargylic phosphates proceeded at the α-po

Full text of DOI:10.1021/jo0489216

â-phenylsulfonyl ketone 24 or allylic anion of dithioacetal
3 and allyl sulfides5 (Scheme 1). However, in this sulfur-
Highly Regioselective Coupling Reactions
of Allylic and Propargylic Alcohol
Derivatives with γ,γ-Dialkoxyallylic
Zirconium Species via Zr-to-Cu
Transmetalation
SCHEME 1
Azusa Sato, Hisanaka Ito,† and Takeo Taguchi*,†
Tokyo Women’s Medical University,
8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan, and
Tokyo University of Pharmacy and Life Science,
1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
taguchi@ps.toyaku.ac.jp
Received June 25, 2004
based chemistry there exists several disadvantages, in
particular, due to the lack of regioselectivity (γ vs R
position of the allyl system) in the reactions with elec-
trophiles and due to the requirement of the cleavage of
carbon-sulfur bond under specific conditions, which often
affects on the yields of the products.
In our preliminary report, we have shown that γ,γ-
dialkoxyallylic zirconium species 4,6 easily formed in situ
by treating triethyl orthoacrylate with zirconocene-
butene complex, can serve as a new homoenolate or R,â-
dianion equivalent of propionate in the CuCN-mediated
cross-coupling reaction with allylic phosphates or acid
chlorides (Scheme 2).7 Thus, the Cu(I)-mediated reaction
In the presence of CuCN, reaction of γ,γ-dialkoxyallylic
zirconium species 4, generated in situ by treating triethyl
orthoacrylate with zirconocene-butene complex, with allylic
and propargylic phosphates proceeded at the R-position of
4 in a highly SN2′-selective manner to give the corresponding
5-alkenoates and 4,5-alkadienoates, respectively. In the
present Cu(I)-mediated coupling reaction, the γ,γ-dialkoxy-
allylic zirconium species 4 serves as a synthetically useful
homoenolate anion equivalent of propionate.
SCHEME 2
Homoenolate anion and its equivalent organometals,
which function as an inverse polarity of Michael acceptor,
are important synthons in organic synthesis.1 In this
area, the zinc homoenolate of propionate 1 has been
demonstrated to have versatile reactivity with general
synthetic utility.2,3 Another typical example developed as
homoenolate anion equivalents may be the conceptually
important umpolung of carbonyl reactivity with sulfur-
substituted nucleophiles such as the carbonyl-protected
of γ,γ-dialkoxyallylic zirconium species 4 proceeded re-
gioselectively at its R-position, while we had already
reported both γ-selective and â-selective reactions of this
allylic zirconium species 4 with carbonyl compounds
(Scheme 3).6,8 The results obtained from the reactions
with carbonyl compounds indicated that depending on
† Tokyo University of Pharmacy and Life Science.
(1) For reviews on homoenolate anions and homoenolate anion
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.; Pergmon Press: Oxford, 1991; Vol. 2, Chapter 1.14.
(2) (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.
(3) 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.
(4) (a) Kondo, K.; Tunemoto, D. Tetrahedron Lett. 1975, 1007, 1397
and 2275. (b) Julia, M.; Badet, B. Bull. Soc. Chim. Fr. 1975, 1363.
(5) (a) Grobel, B.-T.; Seebach, D. Synthesis 1977, 357. (b) Seebach,
D. Angew. Chem., Int. Ed. Engl. 1979, 18, 239. (c) Hoppe, D. Angew.
Chem., Int. Ed. Engl. 1984, 23, 932. (d) Ziegler, F. E.; Tam, C. C. J.
Org. Chem. 1979, 44, 3428. (e) Bellato, R.; Gatti, A.; Venturello, P.
Tetrahedron 1992, 48, 2501.
(6) (a) Ito, H.; Taguchi, T. Tetrahedron Lett. 1997, 38, 5829. (b) Sato,
A.; Ito, H.; Taguchi, T. J. Org. Chem. 2000, 65, 918.
(7) Sato, A.; Ito, H.; Yamaguchi, Y.; Taguchi, T. Tetrahedron Lett.
2000, 41, 10239.
10.1021/jo0489216 CCC: $30.25 © 2005 American Chemical Society
Published on Web 12/14/2004
J. Org. Chem. 2005, 70, 709-712
709

SCHEME 3
which gave the coupling product 6a, substituted allylic
bromides such as cinnamyl bromide gave a complex
mixture under the similar reaction conditions.7 Thus,
allylic phosphates rather than bromides are recom-
mended as the partner for the present coupling reaction
not only due to the reactivity but also due to availability
and ease of preparation.10 As shown in Table 1, with the
substituted allylic phosphates, SN2′ products 6 reacted
at the R-position of the zirconium species 4 were exclu-
sively formed in good yields, even in the case of termi-
nally disubstituted primary allylic phosphates (entries
4-6).9d,11,12 A moderate E selectivity of the coupling
product 6b (E/Z ) 2) was observed with the secondary
allylic phosphate (entry 4). No coupling product was
obtained with primary alkyl iodides, benzyl bromide and
alkenyl iodides. Sterically bulky geminal alkoxyl substi-
tutents in the dialkoxyallyic copper species effects the
selective coupling at the R-position and at the same time
its relatively low reactivity. This would be a sharp
contrast to monosubstituted allylic cuprate such as
cinnamyl derivative, which reacted with primary alkyl
halide exclusively at the γ-position.9g
TABLE 1. CuCN-Mediated Coupling Reaction of 4 with
Allylic Substratea
yieldb
entry
R1
R2
R3
X
6
(%)
1
2
3
4
5
6
H
H
H
H
H
Br
6a
72
83
0
H
H
H
H
H
OP(O)(OEt)2 6a
OAc or OBz 6a
H
H
CH3
PhCH2CH2 OP(O)(OEt)2 6b
81c
74
96
H
H
OP(O)(OEt)2 6c
OP(O)(OEt)2 6d
PhCH2CH2 CH3
a Solvent: toluene-THF (1:3); 1 equiv of CuCN. b Isolated yield.
c E/Z ) 2.0.
In these coupling reactions conducted in a mixture of
THF and toluene (3-4:1 v/v) or in THF, the efficiency of
CuCN as compared with the other commonly used Cu(I)
salts such as CuI, CuI‚2LiCl, CuBr, CuBr‚Me2S, or CuCl
was remarkable to obtain the desired products 6.13
Furthermore, the reaction temperature seemed to be a
crucial factor for the Cu(I)-mediated coupling reactions
examined here. When the temperature rose to about -20
°C after addition of CuCN (1 equiv) to a yellowish solution
of dialkoxyallylic zirconium 46 in THF-toluene at -78
°C, the reaction mixture changed to a green-colored clear
solution. When this green solution stood at room tem-
perature (ca 25 °C), the color gradually changed from
green to dark deep yellow and at the same time black
precipitates such as copper mirror appeared on the flask
wall. Addition of allyl phosphate at this stage resulted
in the recovery of the phosphate without the formation
of the coupling product. Thus, the observed color change
may indicate that the copper species has a short lifetime
at room temperature. With allylic phosphates 5, coupling
reaction hardly proceeded at low temperature below -30
°C and very slowly at -10 to 0 °C. Thus, the reactivity
of the copper species formed from 4 by Zr-to-Cu trans-
metalation using CuCN (1 equiv) seemed considerably
low, and finally, for the coupling reaction we optimized
the reaction temperature at 0-15 °C and reaction time
within about 10 h. According to Lipshutz’s report on
cuprate-mediated coupling reaction of allylic zirconium,9g
we examined transmetalation by higher order cuprate
the reaction conditions the zirconium species 4 can act
as an R,â-unsaturated acyl anion equivalent and gem-
dialkoxycyclopropyl anion equivalent, respectively.6,8 Since
the coupling reaction of 4 with allylic phosphates or acid
chlorides did not proceed without CuCN, we believe that
the cross-coupling reaction should proceed through Zr-
to-Cu transmetalation generating dialkoxyallylic copper
species as the plausible intermediate.9 Further study of
the present coupling reaction has been made to see the
reactivity and regioselectivity with propargylic and al-
lenyl alcohol derivatives as well as stereochemical out-
come with chiral allylic and propargylic phosphates. The
results are reported in this paper.
Reaction with Allylic Substrates. Treatment of γ,γ-
dialkoxyallylic zirconium species 4, generated from tri-
ethyl orthoacrylate and zirconocene-butene complex in
toluene, with CuCN followed by the reaction with allylic
phosphates 5 in toluene-THF (1:3-4 v/v) proceeded at
the R-position of 4 in a highly SN2′ manner to give the
5-alkenoate 6 in good yields.7 Typical results are sum-
marized in Table 1. Allyl bromide and allyl diethyl
phosphate gave the coupling product 6a in 72% and 83%
yield, respectively, but allyl acetate or benzoate did not
afford the coupling product 6a; instead the starting ester
was recovered (entries 1-3). Contrary to allyl bromide
(8) For reaction of γ,γ-dialkoxyallylic zirconium species 4 with
carbonyl compounds, see: (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. (c) Ito, H.; Sato, A.; Kusanagi, T.;
Taguchi, T. Tetrahedron Lett. 1999, 40, 3397. See also ref 6.
(9) For examples of zirconium to copper transmetalation, see: (a)
Yoshifuji, M.; Loots, M. J.; Schwartz, J. Tetrahedron Lett. 1977, 1303.
(b) Wipf, P.; Smitrovitch, J. H. J. Org. Chem. 1991, 56, 6494. (c)
Lipshutz, B. H.; Dimock, S. H. J. Org. Chem. 1991, 56, 5761. (d)
Venanzi, L. M.; Lehmann, R.; Keil, R.; Lipshutz, B. H. Tetrahedron
Lett. 1992, 33, 5857. (e) Wipf. D. Synthesis 1993, 537. (f) Lipshutz, B.
H.; Wood, M. R. J. Am. Chem. Soc. 1993, 115, 12625. (g) Lipshutz, B.
H.; Bhandari, A.; Lindsley, C.; Keil, R.; Wood, M. R. Pure Appl. Chem.
1994, 66, 1493. (h) Lipshutz, B. H.; Segi, M. Tetrahedron 1995, 51,
4407. (i) Fleming, S.; Kabbara, J.; Nickiseh, K.; Westermann,; Mohr,
J. Synlett 1995, 183. (j) Wipf, P.; Jahn, H. Tetrahedron 1996, 52, 12853.
(k) Takahashi, T.; Shen, B.; Nakajima, K.; Xi, Z. J. Org. Chem. 1999,
64, 8706. (l) Hanzawa, Y.; Narita, K.; Taguchi, T. Tetrahedron Lett.
2000, 41, 109.
(10) Miller, J. A.; Wood, H. C. S. J. Chem. Soc. 1968, 1837.
(11) 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.
(12) For reviews of organocopper reagents, see: (a) Lipshutz, B. H.;
Sengupta, S. Org. React. 1992, 41, 135. (b) Posner, G. H. Org. React.
1975, 22, 253.
(13) Efficiency of CuCN as a precursor for cuprate formation was
reported. (a) Bertz, S. H.; Gibson, C. P.; Dabbagh, G. Tetrahedron Lett.
1987, 28, 4251. (b) Tseng, C. C.; Paisley, S. D.; Goering, H. L. J. Org.
Chem. 1986, 51, 2884. (c) Tseng, C. C.; Yen, S.-J. D.; Goering, H. L. J.
Org. Chem. 1986, 51, 2892. See also ref 9i.
710 J. Org. Chem., Vol. 70, No. 2, 2005

SCHEME 5
[Me2Cu(CN)Li2] in stead of CuCN, but lower yield of the
product 6 was the result. It should be noted that the
coupling products 6 can be obtained in good yields even
on using nearly equal amount of the allylic zirconium 4
relative to the phosphates (see the Supporting Informa-
tion), since generally an excess amount of allylic metals
is used in such coupling reactions to obtain the products
in good yields.12
The stereochemical outcomes of the present coupling
reactions with chiral allylic substrates, cis-carvyl phos-
phate 7 and 4-alkoxy-2-alkenyl phosphate 9, were also
examined. Reaction of 1-deuterated cis-carvyl phosphate
711c,14,15 with 4 in the presence of CuCN in THF at 0 °C
proceeded in completely regioselective manner to give the
SN2′ product 8 in 54% yield, but with moderate anti-
selectivity (anti/syn ) 3) (Scheme 4).
TABLE 2. CuCN-Mediated Coupling Reaction of 4 with
Propargylic Substratea
SCHEME 4
With racemic 4-tert-butyldimethylsilyloxy-2-pentenyl
phosphate derivative 9a, reaction proceeded in com-
pletely SN2′ manner to obtain the product 10a in 89%
yield as a mixture of diastereomers in a ratio of 3:1. For
the determination of relative stereochemistry, 10a was
converted to the lactone form by treating with 50%
aqueous trifluoroacetic acid to give the 5,6-disubstituted
δ-varelolactone 11a (91% yield, ratio 3:1) (Scheme 5).
1
From the H NMR spectrum of each isomer, the major
isomer was confirmed to be cis-11a having vicinal
coupling constant JH(5)-H(6) ) 3.6 Hz, whereas 6.3 Hz for
the minor isomer trans-11a. Thus, the major diastere-
omer of 10a was assigned as an anti isomer. Under
similar conditions, the phenyl derivative 9b showed a
slightly higher anti selectivity to give the coupling
product 10b in 70% yield (anti/syn ) 5). Conversion to
the lactone compound 11b also proceeded in a good yield
(Scheme 5). It is well documented that in reactions of
organocopper reagents with a chiral allylic substrate
having an oxygen-substituted stereogenic center at 4-po-
sition and the leaving group at 1-position such as
phosphates 9 or the corresponding chloride, regioselec-
tivity (SN2 vs SN2′) strongly depends on the nature of
organocopper reagent, but a high to excellent anti dias-
tereoselectivity in the SN2′ product is observed regardless
a Solvent: toluene-THF (1:3); 1 equiv of CuCN. b Solvent:
toluene.
the nature of the copper reagent.14 Contrary to these,
with allylic phosphates such as 7 and 9, the present
copper reagent formed from CuCN and the dialkoxyallylic
zirconium 4 in THF showed an excellent regioselectivity
reacting at the R-position of 4 in a complete SN2′ manner,
but with moderate diastereoselectivity.
Reaction with Propargylic Substrates. Substitu-
tion reaction of propargylic substrates with organocopper
reagents or with organometallics in the presence of Cu-
(I)X provides the corresponding allenyl products in an
SN2′ manner.12 Not surprisingly, CuCN-mediated cou-
pling reaction of the dialkoxyallylic zirconium 4 with
propargylic phosphates 12 also proceeded at the R-posi-
tion of 4 in a completely SN2′ manner to give the 4,5-
alkadienoates 13 in good yields (Table 2). Propargyl
phosphate as well as bromide or tosylate can be used
giving rise to the coupling product 13a (entries 1-3).
With the substrates having alkyl substituents, the cou-
pling reaction also proceeded smoothly to give the allenyl
(14) (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. (b) Corey, E. J.; Boaz, N. W. Tetrahedron Lett.
1985, 26, 6019. (c) Alexakis, A.; Berlan, J.; Besace, Y. Tetrahedron Lett.
1986, 27, 1047.
(15) Itoh, A.; Ozawa, S.; Oshima, K.; Sasaki, S.; Yamamoto, H.;
Hiyama, T.; Nozaki, H. Bull Chem. Soc. Jpn. 1980, 53, 2357.
(16) Matsuzawa, S.; Horiguchi, Y.; Nakamura, E.; Kuwajima, I.
Tetrahedron 1989, 45, 349.
(17) Negishi, E.; Cederbaum, F. E.; Takahashi, T. Tetrahedron Lett.
1986, 27, 2829.
(18) (a) Ochiai, H.; Tamaru, Y.; Tsubaki, K.; Yoshida, Z. J. Org.
Chem. 1987, 52, 4418. (b) Kasatkin, A.; Kobayashi, K.; Okamoto, S.;
Sato, F. Tetrahedron Lett. 1996, 37, 1849.
(19) Stepanyan, A. N.; Oganyan, G. B.; Badanyan, Sh. O. Arm.
Khim. Zh. 1987, 40, 122.
J. Org. Chem, Vol. 70, No. 2, 2005 711

SCHEME 7
compounds 13b-e in good yields regardless of the alkyl-
substitution pattern (entries 4-7). Each diastereomeri-
cally pure phosphate (12f and 12g) derived from (R)-
glyceraldehyde acetonide gave the corresponding allenyl
compound (13f and 13g) as a single isomer, respectively.
The absolute stereochemistry of 13g was determined by
X-ray analysis of amide 14 which was easily obtained in
three steps from 13g (Scheme 6).
In conclusion, we have shown that in the presence of
CuCN reaction of γ,γ-dialkoxyallylic zirconium species
4 with allylic and propargylic phosphates proceeds at the
R-position of 4 in an SN2′ manner to give the 5-alkenoate
or 4,5-alkadienoate derivatives in good yield. In this
reaction, the zirconium species 4 acts as a synthetically
useful homoenolate anion equivalent of propionate.
SCHEME 6
Supporting Information Available: Experimental pro-
cedure and characterization of new compounds 9a,b, 12f,g,
15, 6b-d, 8, 10a,b, 13b-g, 16, 11a,b, and 14. This material
is available free of charge via the Internet at http://pubs.acs.org.
With allenyl phosphate 15, the 1,3-dienyl compound
16 was exclusively formed in 80% yield with little
stereoselectivity (Z/E ) 2) (Scheme 7).
JO0489216
712 J. Org. Chem., Vol. 70, No. 2, 2005