Stereoselective olefination of unfunctionalized ketones via ynolates

Article abstract of DOI:10.1021/jo0497813

Ynolates react with ketones at room temperature to afford α,β,β,-trisubstituted acrylates (tetra-substituted olefins) with 2:1-8:1 geometrical selectivities. This can be regarded as a new olefination reaction of ketones giving tetrasubstituted olefins in good yield, even in the case of sterically hindered substrates. The reaction mechanism involves cycloaddition of ynolates with a carbonyl group and subsequent thermal electrocyclic ring-opening of the resulting β-lactone enolates. The stereoselectivity is determined in the ring-opening, which is regulated by torquoselectivity. In this paper, we describe the scope and limitations of olefination of ketones via ynolates and discuss the stereocontrol mechanism.

Full text of DOI:10.1021/jo0497813

Ster eoselective Olefin a tion of Un fu n ction a lized Keton es via
Yn ola tes
Mitsuru Shindo,* Yusuke Sato, Takashi Yoshikawa, Ryoko Koretsune, and Kozo Shishido
Institute for Medicinal Resources, University of Tokushima, Sho-machi 1, Tokushima 770-8505, J apan
shindo@ph.tokushima-u.ac.jp
Received February 7, 2004
Ynolates react with ketones at room temperature to afford R,â,â-trisubstituted acrylates (tetra-
substituted olefins) with 2:1-8:1 geometrical selectivities. This can be regarded as a new olefination
reaction of ketones giving tetrasubstituted olefins in good yield, even in the case of sterically hindered
substrates. The reaction mechanism involves cycloaddition of ynolates with a carbonyl group and
subsequent thermal electrocyclic ring-opening of the resulting â-lactone enolates. The stereoselec-
tivity is determined in the ring-opening, which is regulated by torquoselectivity. In this paper, we
describe the scope and limitations of olefination of ketones via ynolates and discuss the stereocontrol
mechanism.
In tr od u ction
SCHEME 1
Olefination of carbonyl compounds is a fundamental
carbon-carbon bond-forming reaction in synthetic or-
ganic chemistry.1 Although conventional olefinations,
2
such as the Wittig and the Horner-Wadsworth-Em-
3
mons reactions, are generally effective in providing di-
and trisubstituted olefins from aldehydes, the low reac-
tivity and/or stereoselectivity of these methods make
them less desirable in the olefination of ketones to furnish
have already demonstrated the synthetic utility of the
unique anions, including tandem reactions providing
11
polysubstituted carbocycles, cycloaddition with aldi-
4
tetrasubstituted olefins, which serve as important syn-
12
mines giving â-lactams, and 1,3-dipolar cycloadditions
thetic intermediates and useful units in medicinal chem-
13
with nitrones leading to â-amino acids.
5
6
istry and material science. Considering how difficult it
is to achieve high stereoselectivity in the olefination of
ketones using phosphorus reagents, development of a
novel reaction with a new mechanism would be extremely
useful.7
In a previous paper, we reported an olefination of
14
aldehydes using the ynolate anions 3, via ring-opening
of the â-lactone enolates 4 derived from the cycloaddition
(7) For recent examples of stereoselective construction of tetrasub-
We have reported a novel methodology for the genera-
tion of ynolate anions 3 via cleavage of ester dianions 2
stituted olefins via carbometalation of alkynes, see: (a) Itami, K.;
Kamei, T.; Yoshida, J . J . Am. Chem. Soc. 2003, 125, 14670-14671.
(
1
b) Zhou, C.; Emrich, D. E.; Larock. R. C. Org. Lett. 2003, 5, 1579-
8
9
derived from R,R-dibromo esters 1 (Scheme 1). Since
582. (c) Zhu, N.; Hall. D. G. J . Org. Chem. 2003, 68, 6066-6069. (d)
ynolate anions are ketene anion equivalents, they are
Tessier, P. E.; Penwell, A. J .; Souza, F. E. S.; Fallis, A. G. Org. Lett.
2003, 5, 2989-2992. (e) Tietze, L. F.; Kahle, K.; Raschke, T. Chem.
Eur. J . 2002, 8, 401-407. (f) Marino, J . P.; Nguyen, H. N. J . Org. Chem.
expected to act as multifunctional reactive species.10 We
2
002, 67, 6291-6296. (g) Hojo, M.; Murakami, Y.; Aihara, H.; Sakuragi,
(
1) Kelly, S. E. In Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Schreiber, S. L., Eds.; Pergamon: Oxford, 1991; Vol. 1, pp
29-817.
2) For
Maryanoff, B. E.; Reitz, A. B. Chem. Rev. 1989, 89, 863.
3) For a representative review for Horner-Wadsworth-Emmons
reaction, see: Wadsworth, W. S. Org. React. 1977, 25, 73-253.
4) For recent examples of olefination of ketones leading to tetra-
R.; Baba, Y.; Hosomi, A. Angew. Chem., Int. Ed. 2001, 40, 621-623.
For other approaches, see: (h) Maciagiewicz, I.; Dybowski, P.; Skow-
ronska, A. Tetrahedron 2003, 59, 6057-6066. (i) Shimizu, M.; Fujimoto,
T.; Minezaki, H.; Hata, T.; Hiyama, T. J . Am. Chem. Soc. 2001, 123,
6947-6948. (j) Kakiya, H.; Shinokubo, H.; Oshima, K. Tetrahedron
2001, 57, 10063-10069. (k) Ide, M.; Nakata, M. Synlett 2001, 1511-
1515.
(8) Shindo, M.; Sato, Y.; Koretsune, R.; Yoshikawa, T,; Matsumoto,
K.; Itoh, K.; Shishido, K. Chem. Pharm. Bull. 2003, 51, 477-478.
(9) (a) Shindo, M. Tetrahedron Lett. 1997, 38, 4433-4436. (b)
Shindo, M.; Sato, Y.; Shishido, K. Tetrahedron 1998, 54, 2411-2422.
(c) Shindo, M.; Koretsune, R.; Yokota, W.; Itoh, K.; Shishido, K.
Tetrahedron Lett. 2001, 42, 8357-8360.
(10) For reviews, see: (a) Shindo, M. Synthesis 2003, 2275-2288.
(b) Shindo, M. J . Synth. Org. Chem. J pn. 2000, 58, 1155-1166. (c)
Shindo, M. Yakugaku Zasshi 2000, 120, 1233-1246. (d) Shindo, M.
Chem. Soc. Rev. 1998, 27, 367-374.
(11) (a) Shindo, M.; Sato, Y.; Shishido, K. J . Am. Chem. Soc. 1999,
121, 1, 6507-6508. (b) Shindo, M.; Matsumoto, K.; Sato, Y.; Shishido,
K. Org. Lett. 2001, 3, 2029-2031. (c) Shindo, M.; Sato, Y.; Shishido,
K. J . Org. Chem. 2001, 66, 7818-7824.
7
(
a representative review of the Wittig olefination, see:
(
(
substituted olefins, see: (b) Sano, S.; Yokoyama, K.; Teranishi, R.;
Shiro, M.; Nagao, Y. Tetrahedron Lett. 2002, 43, 281-284. (c) Sano,
S.; Takehisa, T.; Ogawa, S.; Yokoyama, K.; Nagao, Y. Chem. Pharm.
Bull. 2002, 50, 1300-1302. (d) Mantani, T.; Shiomi, K.; Konno, T.;
Ishihara, T.; Yamanaka, H. J . Org. Chem. 2001, 66, 3442-3448.
(
5) For an example, see: Levenson, A. S.; J ordan, V. C. Eur. J .
Cancer 1999, 35, 1628-1639.
6) For recent examples, see: (a) Valliant, J . F.; Schaffer, P.;
(
Stephenson, K. A.; Britten, J . F. J . Org. Chem. 2002, 67, 383-387. (b)
Rathore, R.; Deselnicu, M. I.; Burns, C. L. J . Am. Chem. Soc. 2002,
1
24, 14832-14833. (c) Harada, N.; Saito, A.; Koumura, N.; Uda, H.;
de Lange, B.; J ager, W. F.; Wynberg, H.; Feringa, B. L. J . Am. Chem.
Soc. 1997, 119, 7241-7248.
1
0.1021/jo0497813 CCC: $27.50 © 2004 American Chemical Society
Published on Web 05/06/2004
3
912
J . Org. Chem. 2004, 69, 3912-3916

Stereoselective Olefination via Ynolates
SCHEME 2
TABLE 1. Olefin a tion of Sym m etr ica l Keton es via
Yn ola tes
yield
ketone (R1) conditionsa product (%)
entry
ynolate (R)
3a (Bu)
3a (Bu)
3a (Bu)
3b (Me)
3e (Ph)
3f (i-Pr)
3d (t-Bu)
1
2
3
4
5
6
7
8
9
Ph
Me
-(CH2)5-
Ph
Ph
Ph
Ph
A
A
A
A
B
B
B
B
A
5
6
7
8
9
10
11
12
13
82
51
68
>99
94
99
85
94
98
of aldehydes with ynolates, with excellent E selectivity
(
Scheme 2), and briefly mentioned the preliminary
1
5
results of olefination of ketones. In the next paper, we
presented a stereoelectronic effect on the E/ Z selectivity
in the olefination of acetophenone and benzophenone.16
Although we have achieved high Z-selectivity in the
olefination of acylsilanes to give vinylsilanes,17 the gen-
erality including the mechanistic considerations in the
olefination of unfunctionalized ketones have not been
known. The development of general methods for the
efficient olefination of ketones is, therefore, still a chal-
lenge. In this paper, we describe the scope and limitations
of the olefination of unfunctionalized ketones via ynolates
with mechanistic considerations on the stereocontrol.
3f (PhCH2CH2) Ph
3g (Me3Si) Ph
b
a
After ketones were added to a THF solution of Ynolates at
room temperature, the mixture was stirred for 0.5 h. Condition
A: Ynolates were prepared with t-BuLi. Condition B: ynolates
b
were prepared with naphthalene-catalyzed lithiation. Isolated as
methyl ester.
SCHEME 3
Resu lts
Olefination of ketones providing tetrasubstituted ole-
fins was investigated under the conditions used in
olefination of aldehydes. Table 1 shows the olefination
of symmetrical ketones. As expected, the tetrasubstituted
olefins were synthesized in good yields. The sterically
hindered ynolate 3d , aromatic ynolate 3e, and trimeth-
ylsilyl-substituted ynolate 3g afforded the tetrasubsti-
tuted olefins in good yields. It was also demonstrated that
not only the lithium-halogen exchange method (method
A) but also the reductive lithiation method (method B)
for the generation of the ynolates were applicable to the
olefination.9
Next, we examined the stereoselective olefination of
unsymmetrical ketones. As shown in Table 2, the reac-
tions of methyl-, butyl-, cyclohexyl-, and phenyl-substi-
tuted ynolates with aryl alkyl ketones gave the desired
olefins in good yield and in unprecedented E-selectivities
late was unsuccessful (entry 5), probably due to enoliza-
tion of the ketone by the sterically hindered ynolate.
Olefination of chalcone preferred the (E,E)-diene, where
the aryl group is cis to the carboxylate (entry 12). The
stereochemical preference for olefination of pinacolone
(
(
tert-butyl methyl ketone) is the production of the Z-olefin
entry 13). Since the E-selectivity using 2-methylcyclo-
hexanone was poor, the recognition between the second-
3
ary and tertiary carbons on sp carbons is not very good
(entry 14). Table 2 also demonstrates that the one-pot
c
methyl esterification can be applicable to this olefination
of ketones.
For comparison, olefination of tert-butyl phenyl ketone
via the Wittig and Horner-Wadsworth-Emmons reac-
tions was attempted, but no reaction occurred (Scheme
3
). It can be seen from these results that ynolates turn
(
entries 1-4, 6-10) except for indanone, which afforded
out to be much better reagents than conventional re-
agents for the olefination of ketones, especially sterically
hindered ones.
18
the Z-olefin preferentially (entry 11). These results
indicate that aryl groups and alkyl groups of ketones
were recognized efficiently in the olefination. Olefination
of acetophenone with the trimethylsilyl-substituted yno-
During the course of this research, we also observed a
16
stereoelectronic effect, which has already been reported.
The elucidation of this effect, as well as that of the
stereoselectivity, requires theoretical calculations and
will be published elsewhere.
(
12) (a) Shindo, M.; Oya, S.; Sato, Y.; Shishido, K.Heterocycles 1998,
9, 113-116. (b) Shindo, M.; Oya, S.; Murakami, R.; Sato, Y.; Shishido,
K. Tetrahedron Lett. 2000, 41, 5943-5946.
13) (a) Shindo, M.; Itoh, K.; Tsuchiya, C.; Shishido, K. Org. Lett.
002, 4, 3119-3121. (b) Shindo, M.; Itoh, K.; Ohtsuki, K.; Tsuchiya,
C.; Shishido, K. Synthesis 2003, 1441-1445.
14) Shindo, M.; Sato, Y.; Shishido, K. Tetrahedron Lett. 1998, 39,
857-4860.
15) For a pioneering work, see: Kowalski, C. J .; Fields, K. W. J .
Am. Chem. Soc. 1982, 104, 321-323.
16) Shindo, M.; Sato, Y.; Shishido, K. J . Org. Chem. 2000, 65, 5443-
445.
17) Shindo, M.; Matsumoto, K.; Mori, S.; Shishido, K. J . Am. Chem.
Soc. 2002, 124, 6840-6841.
18) The configurations of the unknown olefins were determined by
4
(
2
Discu ssion
(
The olefination of ketones via ynolates consists of the
two steps of cycloaddition and ring-opening as shown in
Scheme 2. This olefination has two notable features, the
first being high reactivity toward sterically hindered
ketones. Ynolates can react with phenyl tert-butyl ketone
at room temperature to provide the tetrasubstituted olefin
in good yield. It would be probably due to the fact that
ynolates are highly nucleophilic compact nucleophiles
4
(
(
5
(
(
1
NOE experiments. The E/Z ratios were determined by H NMR spectra.
See the Supporting Information.
J . Org. Chem, Vol. 69, No. 11, 2004 3913

Shindo et al.
TABLE 2. Olefin a tion of Un sym m etr ica l Keton es via Yn ola tes
a
The ynolate was prepared via naphthalene-catalyzed lithiation.
3
914 J . Org. Chem., Vol. 69, No. 11, 2004

Stereoselective Olefination via Ynolates
F IGURE 1. Torquoselectivity for conrotatory electrocyclic
ring-opening of a cis-3-donor-4-acceptor-cyclobutene.
F IGURE 2. Electrocyclic ring-opening of 3-alkylcyclobutenes
and â-lactone enolates derived from aldehydes.
bearing linear sp-hybridized carbons at the reaction site.
In addition, although it is not clear that the first step
giving â-lactone enolates is the concerted cycloaddition
or the stepwise addition-cyclization, the reverse reaction,
which is frequently found in aldol reactions of ketones,
is constrained by the spontaneous conversion of the
highly labile adduct, the â-lactone enolate, into the R,â-
unsaturated carboxylate at room temperature. As de-
scribed above, the conventional phosphorus ylide meth-
ods, like the Wittig reaction, are sensitive to steric
congestion, presumably due to the steric hindrance of the
triphenylphosphorus unit and their moderate nucleophi-
licity.
The second feature is the stereoselectivity. The E/ Z
stereochemistry of the olefination products is determined
in the thermal conrotatory electrocyclic ring-opening of
the â-lactone enolates. Since this ring-opening would be
an exothermic irreversible reaction, the transition state
also should be “reactant-like”. Thus, the relative energy
of the transition states should take precedence over the
relative thermodynamic stability of the products. The
ring-opening of â-lactone enolates should be similar to
that of oxetenes. It is known that cycloadditions of
aldehydes or ketones with alkynyl ethers are promoted
by Lewis acids to give alkoxyoxetenes, which are con-
verted to R,â-unsaturated esters via ring-opening.19 There
have been, however, few reports on the E/ Z selectivity,
especially for the olefination of ketones. Thermal ring-
alkenes,23 which is in good agreement with our results.
In both cases, alkyl substituents rotate outward exclu-
sively. Houk and co-workers interpret this finding, based
on theoretical calculations, as a steric effect, which, in
part, involves repulsion between filled orbitals of R′ and
24
the σ-orbital of the breaking C-C bond. In the case of
â-lactone enolates, it can be similarly suggested that the
alkyl and the aryl groups (R′) derived from aldehydes
rotate outward, partially due to repulsion between filled
orbitals of the alkyl (or aryl) group (R′) and the σ-orbital
of the breaking C-O bond. This repulsion would be larger
than the steric repulsion between the alkyl group (R′)
and the substituent (R) derived from the ynolate, unless
the transition state is late. This would be one reason the
thermodynamically unstable (E)-olefins were generated
exclusively.
The olefination of ketones via ynolates corresponds to
the ring-opening of 3,3-dialkyl(or aryl)cyclobutenes, which
was extensively studied by Stevens20 and Houk. Stevens
reported that 3-tert-butyl-3-methylcyclobutenes prefer-
entially gave the E-isomer as the major isomer, which is
not in accord with our results (Figure 3). In his case, since
the transition state occurs at a relatively late stage, if
the tert-butyl group rotates inwardly, the steric repulsion
between the tert-butyl group and the methylene group
would be critical and thus the E-isomer would be favored.
In our case, because the transition state would occur at
an early stage, the steric repulsion between the tert-butyl
and oxygen atom would be expected to be smaller than
in Stevens’ case. According to Houk’s torquoselectivity,
the electron-donating groups rotate outward and the
electron-accepting substituents inward (Figure 1). In our
case, although the obvious electron-accepting substitu-
ents are not present, some orbital interactions should
nonetheless participate in the selectivity. Recently, the
role of σ* orbitals as acceptors has been discussed by
25
opening of cyclobutenes giving butadienes has been well
studied experimentally2
0,21
and theoretically. In particu-
lar, Houk’s torquoselectivity22 provides a reasonable
explanation for our results (Figure 1).
The olefination of aldehydes corresponds to the ring-
opening of 3-alkyl(or 3-aryl)cyclobutenes (Figure 2). It has
been reported that 3-methylcyclobutene gives only E-
(19) (a) Vieregge, H.; Bos, H. J . T.; Arens, J . F. Recl. Trav. Chim.
Pays-Bas 1959, 78, 664-666. (b) Vieregge, H.; Schmidt, H. M.; Renema,
J .; Bos, H. J . T.; Arens, J . F. Recl. Trav. Chim. Pays-Bas 1966, 85,
9
8
1
29-951. (c) Bos, H. J . T.; Boleij, J . Recl. Trav. Chim. Pays-Bas 1969,
8, 465-473. (d) Pornet, J .; Khouz, B.; Miginiac, L. Tetrahedron Lett.
985, 26, 1861-1862. (e) Pornet, J .; Rayadh, A.; Miginiac, L. Tetra-
26
27
Murakami and Houk. If the σ* orbital of the C-C bond
is supposed to be more electron accepting than that of
the C-H bond,28 the inward rotation of the tert-butyl
hedron Lett. 1986, 27, 5479-5482. (f) Zakarya, D.; Rayadh, A.; Samih,
M: Lakhlifi, T. Tetrahedron Lett. 1994, 35, 405-408. (g) Zakarya, D.;
Rayadh, A.; Samih, M.; Lakhlifi, T. Tetrahedron Lett. 1994, 35, 2345-
2
2
348. (h) Crich, D.; Crich, J . Z., Tetrahedron Lett. 1994, 35, 2469-
472. (i) Oblin, M.; Parrain, J .-L.; Rajzmann, M.; Pons, J .-M. Chem.
(23) Frey, H. M.; Marshall, D. C. Trans. Faraday Soc. 1965, 61,
1715.
Commun. 1998, 1619-1620. (j) Hayashi, A.; Yamaguchi, M.; Hirama,
M. Synlett 1995, 195-196. (k) Kowalski, C. J .; Sakdarat, S. J . Org.
Chem. 1990, 55, 1977-1979. Theoretical calculations for the ring-
opening of oxetene, see: (l) Yu, H.; Chan, W.-T.; Goddard, J . D. J . Am.
Chem. Soc. 1990, 122, 7529-7537.
(24) (a) Kallel, E. A.; Wang, Y.; Spellmeyer, D. C.; Houk, K. J . Am.
Chem. Soc. 1990, 112, 6759-6763. (b) Niwayama, S.; Kallel, E. A.;
Spellmeyer, D. C.; Sheu, C.; Houk, K. N. J . Org. Chem. 1996, 61, 2813-
2825.
(25) Kallel, E. A.; Wang, Y.; Spellmeyer, D. C.; Houk, K. N. J . Am.
Chem. Soc. 1990, 112, 6759-6763.
(26) Murakami, M.; Miyamoto, Y.; Ito, Y. Angew. Chem., Int. Ed.
2001, 40, 189-190. We also reported the same effect as with the vacant
orbitals on silicon, see ref 17.
(27) Lee, P. S.; Zhang, X.; Houk, K. N. J . Am. Chem. Soc. 2003, 125,
5072-5079.
(28) Theoretical calculations have been reported; see: Alabugin, I.
V.; Zeidan, T. A. J . Am. Chem. Soc. 2002, 124, 3175-3185.
(
20) Curry, M. J .; Stevens, D. R. J . Chem. Soc., Perkin Trans. 2 1980,
391-1398.
21) Dolbier, W. R., J r.; Koroniak, H.; Burton, D. J .; Bailey, A. R.;
Shaw, G. S.; Hansen, S. W.J . Am. Chem. Soc. 1984, 106, 1871-1872.
22) (a) Kirmse, W.; Rondan, N. G.; Houk, K. N. J . Am. Chem. Soc.
1
(
(
1
1
984, 106, 7989. (b) Rondan, N. G.; Houk, K. N. J . Am. Chem. Soc.
985, 107, 2099. (c) Dolbier, J r. W. R.; Koroniak, H.; Houk, K. N.; Sheu,
C. Acc. Chem. Res. 1996, 29, 471-477.
J . Org. Chem, Vol. 69, No. 11, 2004 3915

Shindo et al.
F IGURE 4. Electrocyclic ring-opening of 3-methyl-3-phenyl-
cyclobutene and the â-lactone enolate derived from acetophe-
none.
In conclusion, we have developed a new olefination
reaction of ketones via ynolates. The reaction mechanism,
involving cycloaddition of the ynolate with a carbonyl,
followed by thermal electrocyclic ring-opening of the
resulting â-lactone enolates, is quite different from the
conventional ylide and metal carbenoid methods. Thus,
it would constitute a new category of olefination. The
stereoselectivity is determined in the ring-opening, which
is mainly regulated by stereoelectronic effects and tor-
quoselectivity, which can be predicted theoretically. Since
ynolates are highly reactive, even sterically hindered
ketones can be olefinated under mild conditions to give
tetrasubstituted olefins in good yield and in unprec-
edented E/ Z selectivity. Although the detailed stereo-
control mechanism is still unclear, this reaction can be
applied to a wide variety of organic syntheses, especially
sterically congested systems.
F IGURE 3. Electrocyclic ring-opening of 3-tert-butyl-3-me-
thylcyclobutene and â-lactone enolate derived from pinacolone.
group might be expected. Further theoretical calculations
are still needed before a more precise explanation of these
results can be forthcoming.
In contrast, the results of olefination of phenyl alkyl
ketones are consistent with that of 3-methyl-3-phenyl-
cyclobutene; that is, the phenyl group rotates outward
preferentially in both cases (Figure 4). In this case, since
the phenyl group has an electron-rich π-orbital, it can
be regarded as an electron-donating group compared with
the alkyl group. The stereoelectronic factor would over-
come the steric factor. Our findings are consistent with
those indicating that a phenyl group bearing an electron-
donating substituent at the para position rotates outward
Ack n ow led gm en t. This work was supported in part
by a Grant-in-Aid for Scientific Research in the Priority
Area (A) “Exploitation of Multi-Element Cyclic Mol-
ecules” from the Ministry of Education, Culture, Sports,
Science and Technology, J apan, and PRESTO, J ST
more preferentially and that the one bearing an electro-
withdrawing group rotates inward.16 In the olefination
Su p p or tin g In for m a tion Ava ila ble: General experimen-
tal procedures and spectral data of the products. This material
is available free of charge via the Internet at http://pubs.acs.org.
of indanone and chalcone, however, the phenyl group
prefers to rotate inward. As the reason is unclear, more
detailed theoretical calculations are required.
J O0497813
3
916 J . Org. Chem., Vol. 69, No. 11, 2004