Gosteli-claisen rearrangement: Substrate synthesis, simple diastereoselectivity, and kinetic studies

Article abstract of DOI:10.1021/jo802303m

The results of kinetic studies on the uncatalyzed [3,3]-sigmatropic rearrangement of 2-alkoxycarbonyl- substituted allyl vinyl ethers are reported. Apparently first reported by Gosteli in 1972, this variation of a Claisen rearrangement enjoyed a shadowy existence for three decades until its potential for the development of a catalytic asymmetric Claisen rearrangement was discovered. Inspired by this development, we have studied substituent and solvent rate effects, and we provide evidence that a chairlike transition state is highly favorable for the uncatalyzed Gosteli-Claisen rearrangement.

Full text of DOI:10.1021/jo802303m

Gosteli-Claisen Rearrangement: Substrate Synthesis, Simple
Diastereoselectivity, and Kinetic Studies
Julia Rehbein,* Sabine Leick, and Martin Hiersemann*
Fakulta¨t Chemie, Technische UniVersita¨t Dortmund, Germany
julia.rehbein@udo.edu; martin.hiersemann@udo.edu
ReceiVed October 15, 2008
The results of kinetic studies on the uncatalyzed [3,3]-sigmatropic rearrangement of 2-alkoxycarbonyl-
substituted allyl vinyl ethers are reported. Apparently first reported by Gosteli in 1972, this variation of
a Claisen rearrangement enjoyed a shadowy existence for three decades until its potential for the
development of a catalytic asymmetric Claisen rearrangement was discovered. Inspired by this
development, we have studied substituent and solvent rate effects, and we provide evidence that a chairlike
transition state is highly favorable for the uncatalyzed Gosteli-Claisen rearrangement.
Introduction
(iii) geometry of the transition-state structure,5b,7 and (iv)
substituent5c,8 and solvent8b,9 effects on the nature of the
transition-state structure. Historically, the aliphatic Claisen
rearrangement has been classified according to the substrate
structure (Figure 1). Many of these Claisen rearrangements are
named reactions and possess significant synthetic importance.10,11
Aliphatic Claisen rearrangements are thermally allowed [3,3]-
sigmatropic rearrangements of allyl vinyl ethers to γ,δ-unsatur-
ated carbonyl compounds. The rearrangement is characterized
by a concerted but asynchronous bond reorganization process
via a cyclic, usually chairlike transition-state structure.1-3
Substituent and solvent rate effects have been quantified by first-
order kinetic studies.4 Furthermore, a fairly large number of
studies during the past two decades have been concerned with
the elucidation of the mechanistic details of Claisen rearrange-
ments by computational methods. Important topics have been
studied at various levels of theory: (i) diradicaloid or dipolar
character of the transition-state structure,5 (ii) extension of bond
making and bond breaking in the transition state structure,5b,e,6
(4) (a) Frey, H. M.; Pope, B. M. J. Chem. Soc. B 1966, 209–210. (b) Burrows,
C. J.; Carpenter, B. K. J. Am. Chem. Soc. 1981, 103, 6983–6984. (c) Curran,
D. P.; Suh, Y. G. J. Am. Chem. Soc. 1984, 106, 5002–5004. (d) Koreeda, M.;
Luengo, J. I. J. Am. Chem. Soc. 1985, 107, 5572–5573. (e) Wilcox, C. S.;
Babston, R. E. J. Am. Chem. Soc. 1986, 108, 6636–6642. (f) Coates, R. M.;
Rogers, B. D.; Hobbs, S. J.; Curran, D. P.; Peck, D. R. J. Am. Chem. Soc. 1987,
109, 1160–1170. (g) Gajewski, J. J.; Jurayj, J.; Kimbrough, D. R.; Gande, M. E.;
Ganem, B.; Carpenter, B. K. J. Am. Chem. Soc. 1987, 109, 1170–1186. (h)
Brandes, E.; Grieco, P. A.; Gajewski, J. J J. Org. Chem. 1989, 54, 515–516. (i)
Gajewski, J. J.; Gee, K. R.; Jurayj, J. J. Org. Chem. 1990, 55, 1813–1822. (j)
Wood, J. L.; Moniz, G. A. Org. Lett. 1999, 1, 371–374. (k) Craig, D.; Slavov,
N. K. Chem. Commun. 2008, 6054–6056.
(1) (a) Gajewski, J. J.; Conrad, N. D. J. Am. Chem. Soc. 1979, 101, 2747–
2748. (b) Gajewski, J. J.; Conrad, N. D. J. Am. Chem. Soc. 1979, 101, 6693–
6704. (c) Kupczyk-Subotkowska, L.; Saunders, W. H.; Shine, H. J.; Subotkowski,
W. J. Am. Chem. Soc. 1993, 115, 5957–5961. (d) Gajewski, J. J.; Brichford,
N. L. J. Am. Chem. Soc. 1994, 116, 3165–3166.
(2) (a) Schuler, F. W.; Murphy, G. W. J. Am. Chem. Soc. 1950, 72, 3155–
3159. (b) Stein, L.; Murphy, G. W. J. Am. Chem. Soc. 1952, 74, 1041–1043. (c)
Ralls, J. W.; Lundin, R. E.; Bailey, G. F. J. Org. Chem. 1963, 28, 3521–3526.
(d) Frey, H. M.; Montague, D. C. Trans. Faraday Soc. 1968, 64, 2369–2374.
(3) (a) Vittorelli, P.; Winkler, T.; Hansen, H.-J.; Schmid, H. HelV. Chim.
Acta 1968, 51, 1457–1461. (b) Faulkner, D. J.; Petersen, M. R. Tetrahedron
Lett. 1969, 10, 3243–3246. (c) Perrin, C. L.; Faulkner, D. J. Tetrahedron Lett.
1969, 10, 2783–2786. (d) Hansen, H.-J.; Schmid, H. Tetrahedron 1974, 30, 1959–
1969.
(5) (a) Dewar, M. J. S.; Healy, E. F. J. Am. Chem. Soc. 1984, 106, 7127–
7131. (b) Vance, R. L.; Rondan, N. G.; Houk, K. N.; Jensen, F.; Borden, W. T.;
Komornicki, A.; Wimmer, E. J. Am. Chem. Soc. 1988, 110, 2314–2315. (c)
Dewar, M. J. S.; Jie, C. J. Am. Chem. Soc. 1989, 111, 511–519. (d) Wiest, O.;
Black, K. A.; Houk, K. N J. Am. Chem. Soc. 1994, 116, 10336–10337. (e) Yoo,
H. Y.; Houk, K. N J. Am. Chem. Soc. 1994, 116, 12047–12048.
(6) (a) Wiest, O.; Houk, K. N. J. Org. Chem. 1994, 59, 7582–7584. (b) Meyer,
M. P.; DelMonte, A. J.; Singleton, D. A. J. Am. Chem. Soc. 1999, 121, 10865–
10874.
(7) (a) Khaledy, M. M.; Kalani, M. Y. S.; Khuong, K. S.; Houk, K. N.;
Aviyente, V.; Neier, R.; Soldermann, N.; Velker, J. J. Org. Chem. 2003, 68,
572–577. (b) Ozturk, C.; Aviyente, V.; Houk, K. N. J. Org. Chem. 2005, 70,
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10.1021/jo802303m CCC: $40.75
Published on Web 01/16/2009
2009 American Chemical Society
J. Org. Chem. 2009, 74, 1531–1540 1531

Rehbein et al.
TABLE 1. Structure of Allyl Vinyl Ethers (TPS ) t-BuPh2Si, Bn
) CH2Ph)
compd
1a
1b
R1
R2
Me
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
H
R3
H
H
Me
Me
H
H
H
H
H
H
H
(E)-1c
(Z)-1c17
(E)-1d
CH2OTPS
CH2OTPS
Me
FIGURE 1. Classification of aliphatic Claisen rearrangements.
(Z)-1d
(Z)-1e
SCHEME 1. Claisen Rearrangement of
2-Alkoxycarbonyl-Substituted Allyl Vinyl Ethers
(Z)-1f
Me
Me
Me
Me
Me
Me
Me
Me
CH2CF3
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
Me
H
(E,E)-1g
(Z,E)-1g
(E,Z)-1g
(Z,Z)-1g
(Z,E)-1h13
(E,Z)-1i31
(Z,Z)-1i31
Me
Me
Me
Me
n-Pr
CH2OBn
CH2OBn
Me
thereafter.14 Subsequent studies led to the discovery of efficient
chiral Lewis acid catalysts and organocatalysts for enantiose-
lective Gosteli-Claisen rearrangements.15-17
Here, we report an experimental study on the uncatalyzed
Gosteli-Claisen rearrangement. Various 2-alkoxycarbonyl-
substituted allyl vinyl ether 1 have been synthesized and
pyrolized to provide product diastereoselectivities and activation
parameters which enable us to draw conclusions about sub-
stituent and solvent rate effects as well as the stereochemical
course of the Gosteli-Claisen rearrangement.
Each variant is characterized by the substrate synthesis, the rate
range of the rearrangement, and the structure of the product.
The Claisen rearrangement of acyclic 2-alkoxycarbonyl-
substituted allyl vinyl ethers (1) to δ,ꢀ-unsaturated R-keto esters
(2) has so far found very limited attention (Scheme 1). The
original study of Gosteli was followed by only isolated reports
in the literature.12 The first kinetic study on the Gosteli-Claisen
rearrangement by Gajewski and co-workers was performed in
the context of the chorismate-mutase research field.4g A general
synthetic access to acyclic 2-alkoxycarbonyl-substituted allyl
vinyl ethers was published in 2000,13 and the first Lewis acid
catalyzed Gosteli-Claisen rearrangement was revealed shortly
Results and Discussion
Allyl Vinyl Ether Synthesis. The allyl vinyl ethers 1a-i
utilized to study the simple (syn/anti) diastereoselectivity and
the kinetics of the Gosteli-Claisen rearrangement are illustrated
in Table 1. Synthesis of 1c and 1g could be accomplished in a
concise manner as outlined in Scheme 2. Hydrometalation/
protonation or hydrogenation of 2-butyn-1-ol provided (E)- or
(Z)-2-buten-1-ol (3).18 Subsequent etherification of the allylic
alcohols 3 and 4 with bromoacetic acid afforded the R-allyloxy
acetates 5 and 6, which were converted to the isopropyl esters
7 and 8 utilizing Steglich’s conditions.19 Treatment of the esters
7 and 8 with LDA and freshly distilled acetaldehyde afforded
the ꢀ-hydroxy esters 9 and 10,20 which were mesylated and
(8) (a) Davidson, M. M.; Hillier, I. H. J. Chem. Soc., Perkin Trans. 2 1994,
1415–1417. (b) Sehgal, A.; Shao, L.; Gao, J. J. Am. Chem. Soc. 1995, 117,
11337–11340. (c) Aviyente, V.; Yoo, H. Y.; Houk, K. N. J. Org. Chem. 1997,
62, 6121–6128. (d) Yoo, H. Y.; Houk, K. N. J. Am. Chem. Soc. 1997, 119,
2877–2884. (e) Khanjin, N. A.; Snyder, J. P.; Menger, F. M. J. Am. Chem. Soc.
1999, 121, 11831–11846. (f) Aviyente, V.; Houk, K. N. J. Phys. Chem. A 2001,
105, 383–391.
(9) (a) Severance, D. L.; Jorgensen, W. L. J. Am. Chem. Soc. 1992, 114,
10966–10968. (b) Cramer, C. J.; Truhlar, D. G. J. Am. Chem. Soc. 1992, 114,
8794–8799. (c) Davidson, M. M.; Hillier, I. H.; Hall, R. J.; Burton, N. A. J. Am.
Chem. Soc. 1994, 116, 9294–9297. (d) Gao, J. J. Am. Chem. Soc. 1994, 116,
1563–1564. (e) Davidson, M. M.; Hillier, I. H. J. Phys. Chem. 1995, 99, 6748–
6751. (f) Hu, H.; Kobrak, M. N.; Xu, C.; Hammes-Schiffer, S. J. Phys. Chem.
A 2000, 104, 8058–8066.
(10) (a) Hurd, C. D.; Pollack, M. A. J. Am. Chem. Soc. 1938, 60, 1905–
1911. (b) Claisen, L. Chem. Ber. 1912, 45, 3157–3167. (c) Gosteli, J. HelV.
Chim. Acta 1972, 55, 451–460. (d) Carroll, M. F. J. Chem. Soc. 1940, 704–706.
(e) Arnold, R. T.; Searles, S. J. Am. Chem. Soc. 1949, 71, 1150–1151. (f) Wick,
A. E.; Felix, D.; Steen, K.; Eschenmoser, A. HelV. Chim. Acta 1964, 47, 2425–
2429. (g) Johnson, W. S.; Werthemann, L.; Bartlett, W. R.; Brocksom, T. J.; Li,
T.-T.; Faulkner, D. J.; Petersen, M. R. J. Am. Chem. Soc. 1970, 92, 741–743.
(h) Ireland, R. E.; Mueller, R. H. J. Am. Chem. Soc. 1972, 94, 5897–5898.
(11) For selected review articles, see: (a) Tarbell, D. S. Chem. ReV. 1940,
27, 495–546. (b) Tarbell, D. S. Org. React. 1944, 2, 1–48. (c) Rhoads, S. J.;
Raulins, N. R. Org. React. 1975, 22, 1–252. (d) Bennett, G. B. Synthesis 1977,
589–606. (e) Ziegler, F. E. Acc. Chem. Res. 1977, 10, 227–232. (f) Pereira, S.;
Srebnik, M. Aldrichim. Acta 1993, 26, 17–29. (g) Ganem, B. Angew. Chem.,
Int. Ed. 1996, 35, 936–945. (h) Ito, H.; Taguchi, T. Chem. Soc. ReV. 1999, 28,
43–50. (i) Chai, Y.; Hong, S.-p.; Lindsay, H. A.; McFarland, C.; McIntosh, M.
C Tetrahedron 2002, 58, 2905–2928. (j) Nubbemeyer, U. Synthesis 2003, 961–
1008. (k) Castro, A. M. M. Chem. ReV. 2004, 104, 2939–3002. (l) Majumdar,
K. C.; Alam, S.; Chattopadhyay, B. Tetrahedron 2008, 64, 597–643.
(12) (a) Hase, T. A.; Ourila, A.; Holmberg, C. J. Org. Chem. 1981, 46, 3137–
3139. (b) Berryhill, S. R.; Price, T.; Rosenblum, M. J. Org. Chem. 1983, 48,
158–162. (c) Sleeman, M. J.; Meehan, G. V. Tetrahedron Lett. 1989, 30, 3345–
3348. (d) Shi, G.-q.; Cao, Z.-y.; Cai, W.-l. Tetrahedron 1995, 51, 5011–5018.
(13) Hiersemann, M. Synthesis 2000, 1279–1290.
(14) (a) Hiersemann, M.; Abraham, L. Org. Lett. 2001, 3, 49–52. (b)
Hiersemann, M.; Abraham, L. Eur. J. Org. Chem. 2002, 1461–1471. (c) Ollevier,
T.; Mwene-Mbeja, T. M Can. J. Chem. 2008, 86, 209–212.
(15) Uyeda, C.; Jacobsen, E. N. J. Am. Chem. Soc. 2008, 130, 9228–9229.
(16) For the chiral Lewis acid catalyzed Gosteli-Claisen rearrangement, see:
(a) Abraham, L.; Czerwonka, R.; Hiersemann, M. Angew. Chem., Int. Ed. 2001,
40, 4700–4703. (b) Abraham, L.; Ko¨rner, M.; Schwab, P.; Hiersemann, M. AdV.
Synth. Catal. 2004, 346, 1281–1294. (c) Abraham, L.; Ko¨rner, M.; Hiersemann,
M. Tetrahedron Lett. 2004, 45, 3647–3650. (d) Pollex, A.; Hiersemann, M. Org.
Lett. 2005, 7, 5705–5708.
(17) Kirsten, M.; Rehbein, J.; Hiersemann, M.; Strassner, T. J. Org. Chem.
2007, 72, 4001–4011.
(18) Balduzzi, S.; Brook, M. A.; McGlinchey, M. J Organometallics 2005,
24, 2617–2627, To avoid over-reduction and E/Z isomerization, it was pivotal
to monitor the progress of the hydrogenation by GC.
(19) Neises, B.; Steglich, W. Angew. Chem. 1978, 90, 556–557, Attempts
to perform the esterification under acidic conditions (H2SO4, i-PrOH, reflux)
were unsuccessful.
(20) Isolated as inseparable mixtures of diastereomers. The relative config-
uration of the major and minor diastereomer was not assigned.
1532 J. Org. Chem. Vol. 74, No. 4, 2009

Gosteli-Claisen Rearrangement
SCHEME 2. Synthesis of the Allyl Vinyl Ethers 1c,g
SCHEME 3. Synthesis of the Allyl Vinyl Ethers 1a,b
SCHEME 4. Synthesis of the Allyl Vinyl Ethers 1e,f
subsequently treated with DBU to provide the allyl vinyl ether
1c,g as a mixture of double-bond isomers. Separation of the
E/Z-diastereomers was accomplished by automated preparative
HPLC on multigram scale.
The synthesis of 1a,b required the hydroxymethylation of
the ester enolate of 11 to provide the ꢀ-hydroxy esters 12 and
13 (Scheme 3).21 After some experimentation with gaseous
formaldehyde, we found the application of a procedure reported
by Bischoff and co-workers more convenient and high yield-
ing.22 In the event, commercially available benzotriazolylmetha-
nol was used for the in situ formation of formaldehyde. The
synthesis of the unsubstituted parent allyl vinyl ether 1a,b for
the Gosteli-Claisen rearrangement was completed in two steps
with the mesylation of the ꢀ-hydroxy esters 12 and 13 and base-
mediated elimination of the crude mesylates.
The carboxyl-substituted allyl vinyl ether (Z)-1e was syn-
thesized according to Scheme 4. (E/Z)-1j was prepared by the
aldol condensation approach and subsequently treated with
LiOH in a polar protic solvent system to afford the carboxylic
acid (E/Z)-1e. Because of the well-established rate acceleration
of the Claisen rearrangement in aqueous solution, the success
of the saponification is noteworthy.23 To avoid the undesired
Claisen rearrangement of 1j,e, particularly at prolonged reaction
times, the progress of the reaction was carefully monitored by
Tlc, and using optimized reaction times, the allyl vinyl ether
1e was isolated in good yields. Notably, the double-bond isomers
of 1e were separable by flash chromatography, and (Z)-1e was
then elaborated to the 2,2,2-trifluoroethyl ester (Z)-1f as
described above. This route provides a strategically novel and
expeditious access to carboxyl-derived functional groups at the
2-position of allyl vinyl ethers.
We have been able to prepare functionalized allyl vinyl ethers
(1) by employing the aldol condensation approach.16 In the
present study, the aldol reaction between the lithium enolate of
8 and a siloxyacetaldehyde delivered the ꢀ-hydroxyester 15
which was further elaborated to the 1-siloxymethyl-substituted
allyl vinyl ether 1d (Scheme 5).
Simple Diastereoselectivity. The uncatalyzed Claisen rear-
rangement of achiral allyl vinyl ethers containing two stereo-
genic double bonds provides racemic γ,δ-unsaturated carbonyl
compounds featuring two chiral carbon atoms. The relative
configuration of the rearrangement products depends on the
geometry of the corresponding transition-state structures (chair
versus boat) as well as the double-bond configuration of the
allyl vinyl ethers. Experimental results indicate a strong prefer-
ence for a chairlike transition-state structure for the Claisen
rearrangement of acyclic, aliphatic allyl vinyl ethers;3 however,
an unambiguous and general verification of this observation was
not available for the Gosteli-Claisen rearrangement. Therefore,
1g-i were pyrolized, and the syn/anti diastereoselectivities of
the rearrangement were determined (Table 2). The rearrange-
(21) Care must be taken during the purification and isolation of the allyl
vinyl ether 1a and 1b because of their volatility at reduced pressure.
(22) Deguest, G.; Bischoff, L.; Fruit, C.; Marsais, F. Org. Lett. 2007, 9, 1165–
1167.
(23) Grieco, P. A.; Brandes, E. B.; McCann, S.; Clark, J. D. J. Org. Chem.
1989, 54, 5849–5851.
J. Org. Chem. Vol. 74, No. 4, 2009 1533

Rehbein et al.
SCHEME 5. Synthesis of the Allyl Vinyl Ether 1d (TPS )
t-BuPh2Si)
Eyring equations to provide the activation parameters. The
experimentally determined rate constants (k) and free energies
of activation (∆Gq) at 80 °C are summarized in Tables 3 and 4.
For comparison, the kinetic parameters for the Claisen rear-
rangement of allyl vinyl ether (Table 3, entry 1) and the four
double-bond isomers of crotyl propenyl ether 16 (Table 4, entries
2, 4, 6, and 8) are also included. The accuracy of the
experimentally determined activation parameters is supported
by the resemblance of our ∆G‡ value for 1a and the value
reported by Gajewski and co-workers (Table 3, entries 2 and
3).
We elected to initially determine the substituent rate effect
of an ester group at the 2-position of an allyl vinyl ether (Table
3, entries 1-3). The 2-CO2Me substituent in 1a lowers the
activation barrier by 2.7 kcal/mol at 80 °C; this corresponds to
a 35-fold rate acceleration compared to the unsubstituted allyl
vinyl ether. Replacing the methyl ester (1a) by an isopropyl
ester (1b) has only a small effect on the rate of the rearrangement
(Table 3, entries 3 and 4). We next investigated the rate effect
of an additional methyl substituent at the vinyl ether double
bond and the influence of the double-bond configuration (Table
3, entries 5-10). For (E)-1c, the methyl substituent causes a
rate-accelerating effect in benzene-d6 (krel ) 3.2) and 1,2-
dichloroethane (DCE, krel ) 4.8) compared to 1b. For (Z)-1c,
the rate-accelerating effect is attenuated but still evident for the
rearrangement in DCE (krel ) 1.3) and CD3CN (krel ) 1.6). The
significant rate accelerating influence of TFE (krel ) 15.2) on
the Gosteli-Claisen rearrangement of (Z)-1c is remarkable
(Table 3, entry 10).25,26 In order to evaluate the responsiveness
of the krel to the steric bulk of the substituent at C1 and the
double-bond configuration, the methyl group (1c) was replaced
by the t-BuPh2SiOCH2 group (1d). Somewhat surprisingly, we
determined identical ∆Gq values for the rearrangement of (E)-
1d and (E)-1c in DCE at 80 °C (Table 3, entries 6 and 11).
Even more surprising was our finding that (Z)-1d (krel ) 8.6)
rearranges faster than (E)-1d (krel ) 4.8) and (E)-1c (krel ) 4.8)
in DCE (Table 3, entries 6, 11, and 12). This result is difficult
to interpret because intrinsic ground- or transition-state stabiliz-
ing or destabilizing effects of the substituents may be respon-
sible. Therefore, the rate effects cannot be predicted or explained
based solely on conventional resonance or steric effects. We
next turned our attention to the influence of the nature of the
ester alcohol on the rate of the rearrangement (Table 3, entries
13-15). We expected that a CO2CH2CF3 substitutent should
affect the rate of the rearrangement because of the electron
withdrawing effect of the CF3 group. However, a significant
rate difference for the rearrangement of the trifluoroethyl ester
(Z)-1f (krel ) 2.1) and the isopropyl ester (Z)-1c (krel ) 2.7) in
CD3CN at 80 °C was not observed (Table 3, entries 9 and 15).
Consequently, and considering the results of a computational
work (BLYP/6-31G*) by Houk and Wiest,27 we expected a
comparable reactivity of the acid (Z)-1e and the ester (Z)-1c.
However, the acid (Z)-1e was more reactive than the ester (Z)-
1c in DCE (krel ) 11.4 versus 1.6) and CD3CN (krel ) 5.6 versus
2.7) (Table 3, entries 13, 14 versus 8, 9). Surprisingly, the more
polar solvent CD3CN (dielectric constant ꢀ ) 35.9) has a rate
TABLE 2. Simple Diastereoselectivity of the Gosteli-Claisen
Rearrangement
entry substrate
R
main product solventa syn/antib yield [%]c
1
2
3
4
5
6
7
(E,E)-1g Me
(()-syn-2g
(()-anti-2g
(()-anti-2g
(()-syn-2g
(()-anti-2h
DCE
DCE
DCE
DCE
DCE
TFE
TFE
>95/5
97/3
>95/5
>95/5
97/3
95
96
95
90
99
99
95
(Z,E)-1g Me
(E,Z)-1g Me
(Z,Z)-1g Me
(Z,E)-1h n-Pr
(E,Z)-1i CH2OBn (()-anti-2i
(Z,Z)-1i CH2OBn (()-syn-2i
95/5
95/5
a DCE
)
1,2-dichloroethane, TFE
)
2,2,2-trifluoroethanol.
b Determined from 1H NMR spectra. >95/5 ) minor diastereomer not
detectable. c Yield of isolated and purified material.
ment of the 1g and 1h proceeded in 1,2-dichloroethane (DCE)
at 80 °C with a reasonable reaction rate (Table 2, entries 1-5)
but was very slow for 1i. We hoped to take advantage of the
rate accelerating effect of polar protic solvents on the Claisen
rearrangement,4h and a useful rate for the rearrangement of 1i
was finally achieved in 2,2,2-trifluoroethanol (TFE) at 80 °C
(Table 2, entries 6 and 7). Generally, we obtained a complete
mass balance and very high diastereoselectivities (g95/5) for
the uncatalyzed Gosteli-Claisen rearrangement of 1g-i. Sig-
nificant impurities were not detectable; the product diastereomers
1
syn- and anti-2g-i are distinguishable in the H NMR. The
assignment of the relative configuration of syn-2g and syn-2i
was corroborated by crystal structure analyses of synthetic
derivatives.24 The observed diastereoselectivities correspond to
a difference in free energy (∆∆Gqchair/boat) of g2.2 kcal/mol
between the chair- and the boatlike transition states at 80 °C, a
value that correlates well with the ∆∆Gqchair/boat reported for the
uncatalyzed Claisen rearrangement of crotyl propenyl ethers in
heptane at 143 °C (2.9-3.1 kcal/mol, depending on the double-
bond configuration).3a
Kinetic Studies. Kinetic measurements were conducted in a
sealed glass tube. The degree of conversion was determined by
1H NMR from the crude reaction mixture. The collected NMR
data fitted to a first-order rate law over several half-life periods.
No products other than the R-keto esters 2 could be detected.
The first-order rate constants were determined from double
experiments and analyzed according to the Arrhenius and the
(25) A 25-fold rate acceleration in TFE compared to benzene has been
experimentally determined for a Claisen rearrangement, see: Brandes, E.; Grieco,
P. A.; Gajewski, J. J. J. Org. Chem. 1989, 54, 515–516.
(26) Strassner and co-workers have calculated a gas-phase ∆Gq for (Z)-1c
of 27.4 kcal/mol at the DFG B3LYP/6-311++G** level of theory; see ref 17.
This value is in very good agreement with our experimentally determined values
in benzene-d6 (28.1 kcal/mol) or DCE (27.9 kcal/mol).
(24) (a) Gille, A.; Schu¨rmann, M.; Preut, H.; Hiersemann, M. Acta Crys-
tallogr. 2008, E64, o1835. (b) Ko¨rner, M.; Schu¨rmann, M.; Preut, H.; Hierse-
mann, M. Acta Crystallogr. 2008, E63, o3012.
(27) Wiest, O.; Houk, K. N. J. Am. Chem. Soc. 1995, 117, 11628–11639.
1534 J. Org. Chem. Vol. 74, No. 4, 2009

Gosteli-Claisen Rearrangement
TABLE 3. Kinetic Data for the Costeli-Claisen Rearrangement of Disubstituted Allyl Vinyl Ethers at 80 °C (TPS ) t-BuPh2Si).
c
entry
compd
R1
R2
Me
Me
i-Pr
i-Pr
solventa
Tb (°C)
∆G‡
kd
krel
1
2
3
4
5
6
7
8
parente
C6D6
CCl4
C6D6
C6D6
C6D6
DCE
C6D6
DCE
CD3CN
TFE
DCE
DCE
DCE
CD3CN
CD3CN
118-153
41-80
60-80
71-103
60-90
60-100
60-90
80-100
70-100
55-82
66-92
66-94
70-100
70-91
72-103
30.7
28.0
28.0
28.2
27.4
27.1
28.1
27.9
27.5
26.3
27.1
26.7
26.5
27.0
27.7
0.07
3.4
3.4
2.5
7.9
12.1
2.9
3.4
0.03
1.4
1.4
1
3.2
4.8
1.2
1.3
1.6
15.2
4.8
8.6
11.4
5.6
2.1
1af
H
H
H
Me
1a
1b
(E)-1c
(Z)-1c
Me
i-Pr
9
3.9
10
11
12
13
14
15
38.0
12.1
21.5
28.6
14.0
5.2
(E)-1d
(Z)-1d
(Z)-1e
CH2OTPS
CH2OTPS
Me
i-Pr
i-Pr
H
(Z)-1f
Me
CH2CF3
a DCE ) 1,2-dichloroethane, TFE ) 2,2,2-trifluoroethanol. b Temperature range of the kinetic measurements (temperature fluctuation ( 1 °C). c kcal
d
mol-1 at 353.15 K. Determined from the Eyring plot and adjusted to one decimal place. × 10-5 s-1 at 353.15 K. Calculated according to the Eyring
equation and adjusted to one decimal place. e All-hydrogen-substituted, parent allyl vinyl ether. Value taken from ref 4i. f Value taken from ref 4i.
TABLE 4. Kinetic Data for the Costeli-Claisen Rearrangement of
Trisubstituted Allyl Vinyl Ethers at 80°C. See Table 2 for Simple
Diastereoselectivities
c
e
entry compd
R
solventa Tb (°C) ∆G‡
kd
60-90 26.7 21.5
nr 30.5 0.095 (17.2)
60-80 27.2 10.5
nr 31.5 0.029
60-80 27.4 7.9
nr 31.8 0.015
60-80 28.2 2.5
nr
krel
8.6
1
2
3
4
5
6
7
8
(E,E)-1g Me
DCE
gas phase
DCE
gas phase
DCE
gas phase
DCE
(E,E)-16f
(Z,E)-1g Me
4.2
(5.3)
3.2
(2.7)
1
(Z,E)-16f
(E,Z)-1g Me
(E,Z)-16f
(Z,Z)-1g Me
FIGURE 2. Substrate-reactivity relationship.
(Z,Z)-16f
gas phase
32.5 0.0053 (1)
--------------------------------------
9
(Z,E)-1h n-Pr
10 (E,Z)-1i CH2OBn TFE
11 EtOH
12 (Z,Z)-1i CH2OBn TFE
DCE
68-103 27.6 6.0
50-80 27.1 12.1
50-80 27.7 5.2
50-80 27.9 3.9
50-80 28.5 1.7
2.4
7.1
2.3
3.0
1.0
state structure is required. Computational studies at an adequate
level of theory could contribute crucial structural and energetic
data for the analysis of the experimentally observed substituent
and solvent rate effects.
13
EtOH
We expanded our kinetic study of the Gosteli-Claisen
rearrangement to take trisubstituted allyl vinyl ethers into
consideration. Table 4 summarizes the experimentally deter-
mined activation parameters for 1g-i. For comparison, the
reported kinetic data for crotyl propenyl ether (16) are
included.3a We begin our discussion in reminiscence of some
instructive results from Table 3. The relative rate constants
enable a quantification of the rate effect of a CO2i-Pr and a
methyl group at the vinyl ether double bond. According to
Figure 2, the CO2i-Pr group has a significant rate accelerating
influence which is further amplified by the additional methyl
group in (E)-1c. The amplification effect is strongly dependent
on the double-bond configuration, as (Z)-1c and 1b show a
comparable reactivity.
a DCE
)
1,2-dichloroethane, TFE
)
2,2,2-trifluoroethanol.
b Temperature range of the kinetic measurements (temperature
c
fluctuation ( 1 °C). nr ) not reported. kcal mol-1 at 353.15 K.
Determined from the Eyring plot and adjusted to one decimal place.
d
×10-5 s-1 at 353.15 K. Calculated according to the Eyring equation
and adjusted to one decimal place. e Values in parentheses refer only to
the relative reactivity of 16. f Value taken from ref 3a.
decelerating effect on the rearrangement of the acid (Z)-1e (krel
) 5.6) compared to DCE (krel ) 11.4, ꢀ ) 10.4), which is in
contrast to the experimental result for the ester (Z)-1c (krel
1.6 in CD3CN and 1.3 in DCE). So far, we have determined
predictable and, more interestingly, less predictable rate con-
stants for the Gosteli-Claisen rearrangement of 1a-f. To
explain the unexpected reactivity of 1d (t-BuPh2SiOCH2 at C1)
and 1e (CO2H at C2) and the remarkable solvent effect of 2,2,2-
trifluoroethanol, knowledge of the relative product and transi-
tion-state stability as well as the detailed nature of the transition-
)
Using (E)-1c for comparison (krel ) 1), the rate effect of a
methyl at C6 was then studied and the results are illustrated in
Figure 3. In the event, we found a small rate acceleration for
J. Org. Chem. Vol. 74, No. 4, 2009 1535

Rehbein et al.
FIGURE 5. Qualitative transition-state model for the Gosteli-Claisen
rearrangement of (E,Z)- and (Z,Z)-1i.
FIGURE 3. Substrate-reactivity relationship.
the allyl vinyl ethers 1g. Although this simple qualitative
analysis neglects the relative stability of substrates (1g) and
products (2g) and does not account for the exact electronic
nature of the transition state (polarization because of the
asynchronous bond reorganization process) and solvent rate
effects, it in fact predicts the relative reactivity of the four allyl
vinyl ether 1g correctly.
It is instructive to compare the kinetic data of 1g with those
of the crotyl propenyl ether 16 (Table 4, entries 1-8).
Comparing the difference in the free energy of activation of
allyl vinyl ethers with an identical double-bond configuration,
the barrier for the Gosteli-Claisen rearrangement of 1g is lower
than for the Claisen rearrangement of 16 by 3.8-4.4 kcal/mol.
The decreased barrier for the rearrangement of 1g can be
attributed to the substituent rate effect of the CO2i-Pr group
and the rate-accelerating solvent effect of DCE. The krel of the
four crotyl propenyl ethers 16 obeys the same trend as observed
for the Gosteli-Claisen rearrangement of 1g. The analogy of
krel for the (Z,E)-, (E,Z)-, and (Z,Z)-configured ethers 16 and 1g
is striking (Table 4, entries 3-6). However, the krel (8.6) of
(E,E)-1g is less pronounced than the krel (17.2) for (E,E)-16
(Table 4, entries 1 and 2). This discrepancy may be interpreted
as experimental evidence for an increased “loosness” of the
transition-state structure for the rearrangement of 1g compared
to 16. A looser transition-state structure would attenuate
transanular interactions and increase the relative reactivity of
the allyl vinyl ethers that contain at least one Z-configured
double bond.
We concluded our study by modifying the C6 substituent at
the allylic ether double bond (Table 4, entries 9-13). Replacing
the methyl group in (Z,E)-1g for a propyl group provides (Z,E)-
1h (Table 4, entry 9). As anticipated for steric reasons, the
propyl group has a rate decelerating effect ((Z,E)-1h: krel ) 2.4)
compared to the methyl group ((Z,E)-1g: krel ) 4.3).28 We further
increased the steric bulk of the C6 substituent by introducing a
BnOCH2 group (Table 4, entries 10-13). In the event, we found
that the rate of the rearrangement of (E,Z)- and (Z,Z)-1i in DCE
was too slow to provide useful kinetic data. Therefore, the rate
constants were experimentally determined in TFE and ethanol,
again taking advantage of the rate accelerating effect of polar
protic solvents. We than found in accordance with the simplified
reactivity model discussed above, that (E,Z)-1i is more reactive
FIGURE 4. Qualitative transition-state model for the Gosteli-Claisen
rearrangement of 1g.
(E,E)-1g (krel ) 1.8) and a small rate retardation for (E,Z)-1g
(krel ) 0.6) (Table 4, entries 1 and 5). A related statement is
applicable for (Z)-1c (krel ) 1) if compared to (Z,E)-1g (krel
)
2.7) and (Z,Z)-1g (krel ) 0.7) (Table 4, entries 3 and 7). These
data support the conclusion that a C6 methyl group has a general
rate accelerating effect, providing that the allylic ether double
bond is E-configured.
We continued our study by comparing the relative reactivity
of the double-bond isomers of 1g (Table 4, entries 1, 3, 5, and
7). The experimentally determined substrate-reactivity relation-
ship can be rationalized by a qualitative steric model that
considers only the relative stability of the transition-state
structures [1g]q to predict the relative reactiVity of the corre-
sponding substrates 1g (Figure 4). Judging from the minimiza-
tion of transanular interactions in the chairlike transition-state
structure [1g]‡ as single qualitative criteria, [(E,E)-1g]q is the
most stable transition state. The transition state structures [(E,Z)-
1g]q and [(Z,E)-1g]q are less favorable because of the axial
methyl group that causes 1,3-diaxial interactions. Therefore,
(E,Z)-1g (krel ) 3.2) and (Z,E)-1g (krel ) 4.2) are less reactive
than (E,E)-1g (krel 8.6). The slightly higher reactivity of (Z,E)-
1g (krel ) 4.2) compared to (E,Z)-1g (krel ) 3.2) can be explained
by the assumption that [(E,Z)-1g]q is less stable than [(Z,E)-
1g]q due to the additional 1,3-diaxial interaction between the
methyl and the CO2i-Pr group. Unfavorable transanular 1,3-
diaxial interactions are maximized in the transition state [(Z,Z)-
1g]q and, therefore, (Z,Z)-1g is the least reactive (krel ) 1) of
than (Z,Z)-1i in TFE (krel ) 7.1 versus 3.0) and ethanol (krel
)
2.3 versus 1.0) (Figure 5). The relative reactivity of (E,Z)- and
(Z,Z)-1i at 80 °C (krel ) 2.3) is independent of the solvent and
(28) The ∆Gq (29.6 kcal/mol) for the uncatalyzed Gosteli-Claisen rear-
rangement of (E,Z)-7h was predicted at the IEFPCM(solvent ) CH2Cl2)//B3LYP/
¨
6-31G* level of theory; see: Oztu¨rk, C.; Balta, B.; Aviyente, V.; Vincent, M. A.;
Hillier, I. H. J. Org. Chem. 2008, 73, 4800–4809.
1536 J. Org. Chem. Vol. 74, No. 4, 2009

Gosteli-Claisen Rearrangement
mL, 44.7 mmol, 1.3 equiv), n-BuLi (2.0 M in hexanes, 20.6 mL,
41.3 mmol, 1.2 equiv), and acetaldehyde (9.6 mL, 172 mmol, 5
equiv). (E)-9 was isolated after chromatographic purification
(cyclohexane/ethyl acetate 10/1) as a yellowish oil (6.8 g, 92%,
7/3 mixture of diastereomers): Rf ) 0.7 (cyclohexane/ethyl acetate
1/1); 1H NMR (400 MHz, CDCl3, mixture of diastereomers) δ 1.18
(d, J ) 7.0 Hz, 3H) 1.25 (d, J ) 6.2, 6H), 1.68 (d, J ) 6.78, 3H),
3.63 (dminor, J ) 6.02, 1H), 3.83 (dmajor, J ) 4.52 Hz, 1H) 3.85-3.95
(m, 1H), 4.01-4.15 (m, 2H), 5.09 (sept, J ) 6.2, 1H), 5.50-5.59
(m, 1H), 5.65-5.75 (m, 1H); 13C NMR (100 MHz, CDCl3, mixture
of diastereomers) δ 18.2, 18.8, 21.9, 68.4, 68.8, 72.0, 81.8, 82.5,
118.5, 118.7, 133.8, 133.9, 170.4, 170.8; IR (film on KBr) 3480
(broad), 1740 cm-1. Anal. Calcd for C11H20O4: C, 61.09; H, 9.32.
Found: C, 61.0; H, 9.3.
corresponds well with the relative reactivity (krel ) 3.2) of the
methyl-substituted derivatives (E,Z)- and (Z,Z)-1g. In accordance
with an experimental study of Grieco and Gajewski, we found
that the rate accelerating influence of TFE is more pronounced
compared to ethanol.4h Whether the observed solvent rate effects
are attributable to a selective transition-state stabilization by
increased dipole stabilization, hydrogen bonding to the ether
oxygen atom, or by the hydrophobic effect can not be deduced
from our experimental data.29
Conclusion
The Gosteli-Claisen rearrangement has lately attracted
attention in connection with the development of catalyzed
Claisen rearrangements. Lewis acids and organocatalysts have
been successfully utilized to establish a catalytic asymmetric
aliphatic Claisen rearrangement,15,16 an elusive quest for many
decades. Computational studies have emerged that provide
structural models for the stereodifferentiation of the catalyzed
Gosteli-Claisen rearrangement.15,17 The present work has
collectedfundamentalinformationontheuncatalyzedGosteli-Claisen
rearrangement. We provide experimental details for a general
synthetic strategy to 2-alkoxycarbonyl-substituted allyl vinyl
ethers (1), the simple diastereoselectivity of the rearrangement,
and experimental activation parameter that should be useful for
the validation of future computational studies on the catalyzed
Gosteli-Claisen rearrangement. A computational study on the
uncatalyzed Gosteli-Claisen rearrangement could be a crucial
step forward to a fundamental understanding of the experimen-
tally observed substituent and solvent rate effects. Success in
this venture will be reported in due course.
ꢀ-Hydroxy Ester (Z)-9. Prepared according to general procedure
A from (Z)-7 (1.1 g, 6.2 mmol, 1 equiv), diisopropylamine (1.1
mL, 8 mmol, 1.3 equiv), n-BuLi (2.1 M in hexanes, 3.5 mL, 7.4
mmol, 1.2 equiv), and acetaldehyde (0.7 mL, 12.4 mmol, 2 equiv).
(Z)-9 was isolated after chromatographic purification (cyclohexane/
ethyl acetate 10/1) as a yellowish oil (1.2 g, 89%, 65/35 mixture
1
of diastereomers): Rf ) 0.6 (cyclohexane/ethyl acetate 1/1); H
NMR (400 MHz, CDCl3, mixture of diastereomers) δ 1.20 (dd, J
) 6.4, 3.7 Hz, 3H) 1.27 (d, J ) 6.3, 6H), 1.65 (d, J ) 6.8 Hz, 3H)
2.17 (broad s, 1H), 3.65 (dminor, J ) 5.7 Hz, 1H) 3.84 (dmajor, J )
4.4 Hz, 1H), 4.06 (m, 2H), 4.24 (m, 1H), 5.12 (sept, J ) 6.1, 1H),
5.53 (m, 1H), 5.70 (m, 1H); 13C NMR (75.475 MHz, CDCl3,
mixture of diastereomers) δ 13.1, 18.2, 18.7, 21.8, 65.8, 68.4, 68.7,
81.4, 82.4, 125.6, 125.8, 129.2, 129.4, 170.4, 170.6; IR (film on
KBr) 3460 (broad), 1730 cm-1. Anal. Calcd for C11H20O4: C, 61.09;
H, 9.32. Found: C, 61.2; H, 9.3.
ꢀ-Hydroxy Ester 12.30 Prepared according to general procedure
B from 11 (1.3 g, 10 mmol, 1 equiv), diisopropylamine (4.2 mL,
30 mmol, 3 equiv), n-BuLi (2.0 M in hexanes, 15 mL, 30 mmol,
2.1 equiv), and benzotriazolylmethanol (3 g, 20 mmol, 2 equiv).
Compound 12 was isolated after chromatographic purification
(hexanes/ethyl acetate 10/1) as a colorless oil (1.34 g, 84%): Rf )
0.4 (hexanes/ethyl acetate 1/1); 1H NMR (CDCl3, 400 MHz) δ 2.13
(broad s, 1H), 3.75 (s, 3H), 3.80-3.90 (m, 2H), 3.96-4.06 (m,
2H), 4.26 (dd, J ) 12.4, 5.4 Hz, 1H), 5.21 (d, J ) 9.5, 1H), 5.28
(dd, J ) 17.2, 1.4, 1H), 5.84-5.96 (m, 1H); 13C NMR (100.6 MHz,
CDCl3) δ 52.0, 63.3, 71.8, 78.2, 118.3, 133.5, 170.9; IR (film on
KBr) 3445 (broad), 1740 cm-1. Anal. Calcd for C7H12O4: C, 52.5;,
H, 7.6. Found: C, 52.3; H, 7.7.
Experimental Section
General Procedure A: Aldol Addition. A cooled (-78 °C)
solution of the ester (1 equiv) in THF (3 mL/mmol of the ester)
was added to a solution of LDA [prepared in situ from diisopro-
pylamine (1.3 equiv) and n-BuLi (2.3 M in hexanes, 1.2 equiv) in
THF (3 mL/mmol of the ester) at -78 °C] at -78 °C. The solution
was stirred for 15 min at -78 °C before freshly distilled and cooled
(-78 °C) acetaldehyde (5 equiv) was added. After the reaction
mixture was stirred for 15 min at -78 °C, a saturated aqueous
NH4Cl solution (5 mL/mmol of the ester) was added at -78 °C,
the reaction mixture was warmed to ambient temperature, the layers
were separated, and the aqueous phase was extracted with CH2Cl2
(3×). The combined organic phases were dried (MgSO4) and
concentrated at reduced pressure, and the residue was purified by
chromatography (silica gel).
ꢀ-Hydroxy Ester 13. Prepared according to general procedure
B from 8 (0.64 g, 4 mmol, 1 equiv), diisopropylamine (1.7 mL, 12
mmol, 3 equiv), n-BuLi (2.0 M in hexanes, 6 mL, 12.0 mmol, 2.1
equiv), and benzotriazolylmethanol (1.2 g, 8 mmol, 2 equiv).
Compound 13 was isolated after chromatographic purification
(hexanes/ethyl acetate 10/1) as a colorless oil (0.75 g, 98%): Rf )
0.4 (hexanes/ethyl acetate 1/1); 1H NMR (CDCl3, 400 MHz) δ 1.25
(d, J ) 6.3 Hz, 3H), 1.26 (d, J ) 6.3 Hz, 3H), 2.21 (broad s br,
1H), 3.74-3.90 (m, 2H), 3.95-4.02 (m, 2H), 4.24 (d, J ) 5.3 Hz,
1H), 5.08 (sept, J ) 6.3 Hz, 1H), 5.20 (d, J ) 10.0, 1H), 5.29 (dd,
J ) 17.1, 1.5 Hz, 1H), 5.85-5.95 (m, 1H); 13C NMR (100.6 MHz,
CDCl3) δ 21.7, 63.4, 68.8, 71.7, 78.4, 118.2, 133.7, 170.0; IR (film
General Procedure B.22 A cooled (-78 °C) solution of the ester
(1 equiv) in THF (1 mL/mmol of the ester) was added to a solution
of LDA in THF [prepared from diisopropylamine (3.0 equiv) and
n-BuLi (2.0 M in hexanes, 2.1 equiv) in THF (1 mL/mmol of the
ester) at -78 °C] at -78 °C. The solution was stirred for 15 min
at -78 °C before benzotriazolylmethanol (2 equiv) in THF (2 mL/
mmol of ester) was added at -78 °C over a period of 20 min.
After 2 h at -78 °C, saturated aqueous NH4Cl solution was added,
and the resulting suspension was warmed to room temperature. The
organic phase was separated, and the aqueous layer was extracted
with CH2Cl2 (4×). The combined organic phases were dried
(MgSO4), the solvents were removed under reduced pressure, and
the residue was purified by chromatography (silica gel).
on KBr) 3465 (broad), 1725 cm-1
.
ꢀ-Hydroxy Ester 14. Prepared according to general procedure
A from 11 (4.3 g, 33.4 mmol, 1 equiv), diisopropylamine (7.4 mL,
43.4 mmol, 1.3 equiv), n-BuLi (2.0 M in n-hexanes, 20.1 mL, 40.1
mmol, 1.2 equiv), and acetaldehyde (9.4 mL, 167 mmol, 5 equiv).
Compound 14 was isolated after chromatographic purification
(cyclohexane/ethyl acetate 10/1) as a colorless oil (5.7 g, 98%, 65/
35 mixture of diastereomers): Rf ) 0.4 (cyclohexane/ethyl acetate
1/1); 1H NMR (400 MHz, CDCl3, mixture of diastereomers) δ 1.19
(dmajor, J ) 6.5 Hz, 3H) 1.21 (dminor, J ) 7.0, 3H), 2.31 (broad
ꢀ-Hydroxy Ester (E)-9. Prepared according to general procedure
A from (E)-7 (5.9 g, 34.4 mmol, 1 equiv), diisopropylamine (6.3
(30) Eichelberger, U.; Mansourova, M.; Hennig, L.; Findeisen, M.; Giesa,
S.; Mu¨ller, D.; Wetzel, P. Tetrahedron 2001, 57, 9737–9742.
(31) Ko¨rner, M.; Hiersemann, M. Org. Lett. 2007, 9, 4979–4982.
(29) For an insightful discussion on this topic, see: Gajewski, J. J. Acc. Chem.
Res. 1997, 30, 219–225.
J. Org. Chem. Vol. 74, No. 4, 2009 1537

Rehbein et al.
smajor, 1H), 2.43 (broad sminor, 1H), 3.74 (s, 3H) 3.90 (d, J ) 4.5
Hz, 1H), 3.91-4.98 (m, 1H), 4.00-4.10 (m, 1H), 4.17-4.24 (m,
1H), 5.2 (m, 1H), 5.20 (dd, J ) 17.3, 1.5 Hz), 5.83-5.94 (m, 1H);
13C NMR (100 MHz, CDCl3, mixture of diastereomers) 18.2, 18.7,
51.8, 51.9, 68.1, 68.2, 72.0, 72.3, 81.6, 82.0, 118.0, 118.3, 133.4,
133.5, 171.1, 171.3; IR (film on KBr) 3425 (broad), 2880, 1740
cm-1. Anal. Calcd for C8H14O4: C, 55.2; H, 8.1. Found: C, 55.5;
H, 8.1.
dried (MgSO4), the solvents were evaporated under reduced
pressure, and the residue was purified by chromatography (silica
gel).
Allyl Vinyl Ether 1a.4g Prepared according to general procedure
C from 12 (1.21 g, 7.6 mmol, 1 equiv), Et3N (1.4 mL, 9.9 mmol,
1.3 equiv), MsCl (0.7 mL, 9.1 mmol, 1.2 equiv), and DBU (3.4
mL, 22.8 mmol, 3 equiv). Chromatographic purification (hexanes/
ethyl acetate 100/1) delivered 1a as a colorless liquid (0.89 g, 82%):
Rf ) 0.8 (hexanes/ethyl acetate 1/1); 1H NMR (400 MHz, CDCl3)
δ 3.80 (s, 3H), 4.33(d, J ) 5.8 Hz, 2H), 4.61 (d, J ) 2.7 Hz, 1H),
5.27 (dd, J ) 10.5, 1.2 Hz, 1H), 5.33-5.39 (m, 2H), 5.93-6.03
(m, 1H); 13C NMR (100 MHz, CDCl3) δ 52.3, 69.3, 94.8,
118.4,131.9, 150.6, 163.4; IR (thin film) 1740, 1625 cm-1. Anal.
Calcd for C7H10O3: C, 59.14; H, 7.09. Found: C, 59.19; H, 7.14.
Allyl Vinyl Ether 1b. Prepared according to general procedure
C from 13 (0.83 g, 4.7 mmol, 1 equiv), Et3N (0.86 mL, 6.1 mmol,
1.3 equiv), MsCl (0.4 mL, 5.6 mmol, 1.2 equiv), and DBU (2.2
mL, 14.1 mmol, 3 equiv). Chromatographic purification (hexanes/
ethyl acetate 100/1) provided 1b as a colorless liquid (0.55 g, 74%):
Rf ) 0.7 (hexanes/ethyl acetate 1/1); 1H NMR (300 MHz, CDCl3)
δ 1.29 (d, J ) 6.3 Hz, 6H), 4.33 (dt, J ) 5.3, 1.4 Hz, 2H), 4.58 (d,
J ) 2.5 Hz, 1H), 5.09 (sept, J ) 6.3 Hz, 1H), 5.25-5.33 (m, 3H),
5.93-6.03 (m, 1H); 13C NMR (80 MHz, CDCl3) δ 21.7, 69.0, 69.2,
ꢀ-Hydroxy Ester 15. Imidazole (0.55 g, 8 mmol, 1 equiv) and
t-BuPh2SiCl (2.2 g, 8 mmol, 1 equiv) were successively added to
a solution of ethylene glycol (2.60 g, 42 mmol, 6 equiv) in THF
(21 mL) at 0 °C. The reaction mixture was allowed to warm to
room temperature overnight and then diluted by the addition of
saturated aqueous NaHCO3 solution. The layers were separated,
the aqueous phase was extracted with CH2Cl2 (3 × 20 mL), and
the solvents were evaporated at reduced pressure. The residue was
purified by chromatography (cyclohexane/ethyl acetate 5/1) to
provide the mono-TPS-protected diol as colorless oil (87%, 2.1 g,
7 mmol): 1H NMR (400 MHz, CDCl3) δ 1.05 (s, 9H), 2.31 (broad
s, 1H), 3.67 (d, J ) 4.8 Hz, 2H), 3.75 (d, J ) 4.8 Hz, 2H),
7.35-7.45 (m, 6H), 7.66 (d, J ) 6.3 Hz, 4H); 13C NMR (100 MHz,
CDCl3) δ 19.1, 26.7, 63.6, 64.8, 127.6, 129.5, 133.1, 134.7, 135.4;
IR (film on KBr) ν 3425 (broad) cm-1. To a solution of the mono-
TPS-protected alcohol (3 g, 10 mmol, 1 equiv) in DMSO (8.5 mL,
120 mmol, 12 equiv) and CH2Cl2 (10 mL) were added Et3N (5.6
mL, 40 mmol, 4 equiv) and SO3 · pyridine complex (3.18 g, 20
mmol, 2 equiv) at 0 °C. The reaction mixture was stirred at 0 °C
for 10 min and at ambient temperature for 2.5 h. The progress of
reaction was monitored by TLC (heptane/ethyl acetate 1/1; alcohol:
Rf ) 0.5, white spot; aldehyde: Rf ) 0.6, blue spot; anisaldehyde
staining). The reaction mixture was diluted with water (10 mL),
the layers were separated, and the aqueous phase was extracted
with CH2Cl2 (3 × 20 mL). The combined organic phases were dried
(MgSO4), the solvents were evaporated at reduced pressure, and
the residue was purified by flash chromatography (heptane/ethyl
acetate 5/1) to provide the aldehyde as a pale yellow oil (92%,
94,0, 118.0, 132.0, 151.0, 162.0; IR (film on KBr) 2980, 1730 cm-1
.
Anal. Calcd for C9H14O3: C, 63.51; H, 8.29. Found: C, 63.58; H,
8.22.
Allyl Vinyl Ether 1d. Prepared according to general procedure
C from 15 (2.62 g, 5.8 mmol, 1 equiv), Et3N (1.1 mL, 7.5 mmol,
1.3 equiv), MsCl (0.5 mL, 6.9 mmol, 1.2 equiv), and DBU (2.7
mL, 17.4 mmol, 3 equiv). Chromatographic purification (heptane/
ethyl acetate 20/1) delivered 1d (2.17 g, 86%, Z/E ) 70/30) as a
colorless liquid. The double-bond diastereomers were separated by
preparative HPLC: Nucleosil 50-7, 32 mm × 250 mm, heptane/
ethyl acetate 98/2, flow 25 mL/min, 32 × 10-1 MPa, (Z)-1d )
11.6 min, (E)-1d ) 12.9 min. Rf ) 0.7 (heptane/ethyl acetate 1/1).
1
(Z)-1d: H NMR (300 MHz, CDCl3) δ 1.05 (s, 9H), 1.30 (d, J )
1
2.76 g, 9.2 mmol): H NMR (400 MHz, CDCl3) δ 1.09 (s, 9H),
6.2 Hz, 6H), 4.21 (ddd, J ) 5.9, 1.2 Hz, 2H), 4.44 (d, J ) 5.8 Hz,
2H), 5.21 (m, 3H), 5.83 (ddt, J ) 17.0, 10.4, 6.2 Hz, 1H), 5.25 (t,
J ) 6.0 Hz, 1H), 7.33-7.44 (m, 6H), 7.64-7.71 (m, 4H); 13C NMR
(75 MHz, CDCl3) δ 19.2, 21.8, 26.8, 59.1, 67.5, 68.7, 72.8, 118.1,
127.0, 129.7, 133.6, 135.6, 144.4, 162.9; IR (film on KBr) 1720
cm-1. Anal. Calcd for C26H34O4Si: C, 71.19; H, 7.81. Found: C,
4.20 (s, 2H), 7.40 (m, 6H), 7.65 (dd, J ) 7.7, 1.7 Hz, 4H), 9.71 (s,
1H). According to general procedure A, the ester 8 (1.33 g, 8.6
mmol, 1 equiv) was treated with diisopropylamine (1.6 mL, 11.1
mmol, 3 equiv), n-BuLi (2.16 M in hexanes, 4.8 mL, 10.3 mmol,
2.1 equiv), and the freshly prepared aldehyde (2.8 g, 9.4 mmol,
1.1 equiv). The residue was purified by chromatography (heptane/
ethyl acetate 20/1) to provide the ꢀ-hydroxy ester 15 as a colorless
oil (2.25 g, 88%, 7/3 mixture of diastereomers): Rf ) 0.5 (heptane/
ethyl acetate 1/1); 1H NMR (300.1 MHz, CDCl3, mixture of
diastereomers) δ 1.10 (s, 9H), 1.22 (d, J ) 6.2 Hz, 3H), 1.27 (d, J
) 6.2 Hz, 3H), 3.65-4.17 (series of m, 6H), 5.10 (sept, J ) 6.3,
1H), 5.19 (ddt, J ) 10.4, 1.5 Hz, 1H), 5.26 (ddt, J ) 17.2, 1.6 Hz,
1H), 5.88 (ddt, J ) 17.2, 10.4, 5.9 Hz, 1H), 7.33-7.44 (m, 6H),
7.61-7.69 (m, 4H); 13C NMR (75.5 MHz, CDCl3, mixture of
diastereomers) δ 19.1, 21.7, 21.8, 26.6, 26.9, 64.0, 68.7, 71.7, 72.5,
78.8, 117.9, 127.7, 129.8, 133.1, 133.8, 134.8, 135.5, 170.5; IR
(film on KBr) 3430 (broad), 1740 cm-1. Anal. Calcd for C26H36O5Si:
C, 68.39; H, 7.95. Found: C, 68.59; H, 7.99.
1
71.30; H, 7.79. (E)-1d: H NMR (300 MHz, CDCl3) δ 1.06 (s,
9H), 1.15 (d, J ) 6.2 Hz, 6H), 4.26 (ddd, J ) 5.3, 1.2 Hz, 2 H),
4.65 (d, J ) 5.2 Hz, 2H), 4.97 (sept, J ) 6.3 Hz, 1H), 5.27 (ddt,
J ) 10.4, 1.3 Hz, 1H), 5.32 (ddt, J ) 17.2, 1.5 Hz, 1H), 5.40 (t, J
) 5.4 Hz, 1H), 6.01 (ddt, J ) 17.2, 10.5, 5.2 Hz, 1H), 7.33-7.42
(m, 6H), 7.62-7.69 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 19.2,
21.7, 26.9, 61.1, 68.8, 69.6, 72.8, 117.6, 127.7, 129.6, 132.8, 133.8,
135.6, 143.8, 162.8; IR (film on KBr) 1720 cm-1. Anal. Calcd for
C26H34O4Si: C, 71.19; H, 7.81. Found: C, 71.17; H, 8.19.
Allyl Vinyl Ether (E,Z)- and (Z,Z)-1g. Prepared according to
general procedure C from (Z)-9 (0.84 g, 3.9 mmol, 1 equiv), Et3N
(0.7 mL, 5 mmol, 1.3 equiv), MsCl (0.4 mL, 4.6 mmol, 1.2 equiv),
and DBU (1.7 mL, 11.6 mmol, 3 equiv). Chromatographic
purification (heptane/ethyl acetate 100/1) afforded (E/Z,Z)-1g (0.62
g, 87%, Z/E ) 60/40) as a colorless liquid. The double-bond
diastereomers were separated by automated preparative HPLC
(Nucleosil 50-7, 32 mm × 250 mm, heptane/ethyl acetate 99/1,
flow 20 mL/min, pressure 31 × 10-1 MPa, (Z,Z)-1g ) 23.5 min
(48%), (E,Z)-1g ) 27.3 min (32%), baseline separation with 100
General Procedure C: Mesylation and Elimination. To a
solution of the ꢀ-hydroxy ester (1.0 equiv) in CH2Cl2 (3 mL/mmol
of ꢀ-hydroxy ester) at 0 °C were added Et3N (1.3 equiv) and MsCl
(1.2 equiv). The ice bath was removed, and the white suspension
was stirred at ambient temperature for 30 min. The reaction mixture
was then diluted with saturated aqueous NaHCO3 solution, the
layers were separated, the aqueous phase was extracted with CH2Cl2
(3×), the combined organic phases were dried (MgSO4), and the
solvents were evaporated under reduced pressure. The residue was
then dissolved in THF (2 mL/mmol of the ꢀ-hydroxy ester) and
cooled to 0 °C, and DBU (3 equiv) was added. The reaction mixture
was allowed to warm to room temperature overnight and then
diluted with water. The layers were separated, the aqueous layer
was extracted with CH2Cl2 (3×), the combined organic phases were
1
mg/injection). Rf ) 0.84 (heptane/ethyl acetate 1/1). (Z,Z)-1g: H
NMR (400 MHz, CDCl3) δ 1.26 (d, J ) 6.3 Hz, 6H), 1.65 (d, J )
6.3 Hz, 3H), 1.74 d, J ) 7.1 Hz, 3H), 4.39 (d, J ) 6.3 Hz, 2H),
5.06 (sept, J ) 6.3 Hz, 1H), 5.58-5.74 (m, 1H), 6.31 (q, J ) 7.1
Hz, 1H); 13C NMR (100.6 MHz, CDCl3) δ 11.3, 13.0, 21.8, 66.8,
68.1, 123.9, 125.7, 129.0, 145.9, 163.5; IR (film on KBr) 1720,
1
1650 cm-1. (E,Z)-1g: H NMR (300 MHz, CDCl3) δ 1.30 (d, J )
6.3 Hz, 6H), 1.65 (d, J ) 6.3 Hz, 3H), 1.92 (d, J ) 7.4 Hz, 3H),
1538 J. Org. Chem. Vol. 74, No. 4, 2009

Gosteli-Claisen Rearrangement
1
4.30 (d, J ) 6.3 Hz, 2H), 5.11 (sept, J ) 6.3 Hz, 1H), 5.38 (q, J
) 7.4 Hz, 3H), 5.55-5.72 (m, 1H); 13C NMR (75.5 MHz, CDCl3)
δ 9.2, 12.6, 21.8, 68.4, 70.1, 112.6, 126.2, 130.1, 145.7, 163.6; IR
(film on KBr) 1725, 1645 cm-1. Anal. Calcd for C11H18O3: C, 66.6;
H, 9.2. Found: C, 66.6; H, 9.2.
C7H10O3: C, 59.14; H, 7.09. Found: C, 59.19; H, 7.14. (E)-7e: H
NMR (300 MHz, CDCl3) δ 2.06 (d, J ) 7.0 Hz, 3H), 4.29 (dt, J
) 5.6, 1.2 Hz, 2H), 5.25 (d, J ) 1.2 Hz, 2H), 5.37 (dd, J ) 10.1,
1.2 Hz, 1H), 5.50 (q, J ) 7.0 Hz, 1H), 5.92-6.04 (m, 1H); 13C
NMR (100 MHz, CDCl3) δ 12.4, 69.7, 112.8, 117.8, 132.8, 151.3,
162.0; IR (film on KBr) 1725, 1640 cm-1. Anal. Calcd for C7H10O3:
C, 59.14; H, 7.09. Found: C, 59.13; H, 7.16.
Allyl Vinyl Ether (Z)-1f. A solution of the acid (Z)-1e (0.30 g,
2.1 mmol, 1 equiv) in CH2Cl2 (5 mL) was treated with DCC (0.47
g, 2.3 mmol, 1.1 equiv), DMAP (0.01 g, 0.1 mmol, 0.05 equiv),
and 2,2,2-trifluoroethanol (0.52 mL, 4.2 mmol, 2 equiv) at 0 °C.
The reaction mixture was allowed to warm to room temperature
overnight; the white precipitate was removed by filtration and rinsed
with CH2Cl2. The filtrate was concentrated under reduced pressure
(40 °C, 620 mbar), and the residue was purified by flash chroma-
tography (heptane/ethyl acetate 20/1) to deliver the ester (Z)-1f
Allyl Vinyl Ether (Z,E)-1g and (E,E)-1g. Prepared according
to general procedure C from (E)-9 (3.1 g, 14.3 mmol, 1 equiv),
Et3N (2.6 mL, 18.6 mmol, 1.3 equiv), MsCl (1.3 mL, 17.2 mmol,
1.2 equiv), and DBU (6.5 mL, 42.9 mmol, 3 equiv). Chromato-
graphic purification (isohexanes/ethyl acetate 100/1) furnished (Z/
E,E)-1g (2.71 g, 96%, Z/E ) 60/40) as a colorless liquid. The
double-bond diastereomers were separated by automated preparative
HPLC: Nucleosil 50-7, 32 mm × 250 mm, heptane/ethyl acetate
99/1, flow 20 mL/min, pressure 31 × 10-1 MPa, (Z,E)-1g ) 23.5
min (62%), (E,E)-1g ) 27.3 min (34%), baseline separation with
100 mg/injection. Rf ) 0.9 (isohexanes/ethyl acetate 1/1). (Z,E)-
1g: 1H NMR (300 MHz, CDCl3) δ 1.26 (d, J ) 6.0 Hz, 6H), 1.65
(d, J ) 5.8 Hz, 3H), 1.73 (d, J ) 7.2 Hz, 3H), 4.22 (d, J ) 6.27
Hz, 2H), 5.05 (sept, J ) 6.3 Hz, 1H), 5.60-5.78 (m, 2H), 6.29 (q,
J ) 7.2 Hz, 1H); 13C NMR (75.5 MHz, CDCl3) δ 11.3, 17.7, 21.6,
21.8, 68.2, 72.7, 123.7, 126.8, 130.7, 145.9, 163.5; IR (film on KBr)
1720, 1650, 1450 cm-1. Anal. Calcd for C11H18O3: C, 66.6; H, 9.2.
1
(67%, 0.3 g, 1.4 mmol) as a pale yellow liquid: H NMR (300
MHz, CDCl3) δ 1.80 (d, J ) 7.16 Hz, 3H), 4.32 (dt, J ) 6.2, 1.1
Hz, 2H), 4.53 (q, J ) 8.4 Hz, 1H), 5.22 (dd, J ) 10.3 1.2 Hz, 1H),
5.28 (dd, J ) 17.2, 5.3 Hz, 1H), 5.97 (m, 1H), 6.44 (q, J ) 7.2 Hz,
1H); 13C NMR (100 MHz, CDCl3) δ 11.8, 60.7, 73.3, 118.7, 127.6,
133.4, 144.1, 162.2; IR (film on KBr) 1740 cm-1. Anal. Calcd for
C9H11F3O3: C, 48.22; H, 4.95. Found: C, 48.2; H, 4.9.
1
Found: C, 66.6; H, 9.1. (E,E)-1g: H NMR (400 MHz, CDCl3) δ
1.29 (d, J ) 6.3 Hz, 6H), 1.69 (dq, J ) 6.3, 0.7 Hz, 3H), 1.90 (d,
J ) 7.3 Hz, 3H), 4.14 (d, J ) 5.8 Hz, 2H), 5.10 (sept, J ) 6.27
Hz, 1H), 5.36 (q, J ) 7.3 Hz, 1H), 5.58-5.66 (m, 1H), 5.69-5.79
(m, 1H); 13C NMR (75.5 MHz, CDCl3) δ 9.2, 12.6, 21.8, 68.4,
70.1, 112.6, 126.2, 130.1, 145.7, 163.6; IR (film on KBr) 1725,
1645 cm-1. Anal. Calcd for C11H18O3: C, 66.6; H, 9.2. Found: C,
66.6; H, 9.1.
General Procedure F: Kinetic Measurements. A solution of
the allyl vinyl ether (0.4 mmol) in the specified solvent (2 mL) in
a commercially available glass pressure tube was submerged into
a preheated oil bath. The time measurement was started with a delay
of 30 s for temperature equilibration (measured with a commercially
available internal thermometer). The maximum temperature fluctua-
tion during the kinetic measurements was ( 0.5 °C. Samples were
taken by syringe (0.3 mL) and were immediately transferred into
a cooled (0 °C) flask (1,2-dichloroethane, 2,2,2-trifluoroethanol,
EtOH) or NMR tube (C6D6, CD3CN). Nondeuterated solvents were
evaporated at reduced pressure and ambient temperature. The
Allyl Vinyl Ether 1j.15 Prepared according to general procedure
C from 14 (5.3 g, 30.4 mmol, 1 equiv), Et3N (5.2 mL, 36.5 mmol,
1.3 equiv), MsCl (2.8 mL, 39.5 mmol, 1.2 equiv), and DBU (13.7
mL, 91.2 mmol, 3 equiv). Chromatographic purification (cyclo-
hexane/ethyl acetate 100/1) furnished 1j (3.8 g, 80%, Z/E ) 60/
40) as a colorless liquid. The double-bond diastereomers were
separated by automated preparative HPLC: Nucleosil 50-7, 32 mm
× 250 mm, heptane/ethyl acetate 95/5, flow 20 mL/min, pressure
31 × 10-1 MPa, (Z)-1j ) 12.3 min (51%), (E)-1j ) 13.1 min (34%),
baseline separation with 100 mg/injection. Rf ) 0.9 (cyclohexane/
1
substrate/product ratio was determined from the H NMR spectra
of the crude product. The obtained data were analyzed according
to a first-order rate law. Eyring and Arrhenius parameters were
generated from the resulting k values.
r-Keto ester 2a: 1H NMR (400 MHz, CDCl3) δ 2.36 (dd, J1 )
J2 ) 6.9 Hz, 2H), 2.93 (t, J ) 7.3 Hz, 2H), 3.84 (s, 3H), 4.99 (dd,
J ) 10.3, 1.25 Hz, 1H), 5.05 (m, J ) 17.3, 1.51 Hz, 1 H), 5.74-5.85
(m, 1H); 13C NMR (100.6 MHz, CDCl3) δ 26.9, 38.5, 53.1, 116.0,
136.1; IR (film on KBr) 1725 cm-1. Anal. Calcd for C7H10O3: C,
59.14; H, 7.09. Found: C, 59.31; H, 7.16.
1
ethyl acetate 1/1). (Z)-1j: H NMR (300 MHz, CDCl3) δ 1.76 (d,
J ) 7.0 Hz, 3H), 3.75 (s, 3H), 4.31 (d, J ) 6.0 Hz, 2H), 5.20 (dt,
J ) 10.1, 0.5 Hz, 1H), 5.30 (dd, J ) 17.1, 1.5 Hz, 1H), 5.92-6.04
(m, 1H), 6.35 (q, J ) 7.0 Hz, 1H); 13C NMR (100 MHz, CDCl3)
δ 11.3, 51.7, 72.9, 118.0, 124.7, 133.6, 145.2, 162.0; IR (thin film)
1
r-Keto ester 2b: H NMR (400 MHz, CDCl3) δ 1.32 (d, J )
1
1725, 1650 cm-1. (E)-1j: H NMR (300 MHz, CDCl3) δ 1.76 (d,
6.3 Hz, 6H), 2.36 (dd, J1 ) J2 ) 6.7 Hz, 2H), 2.91 (t, J ) 7.4 Hz,
2H), 4.99 (dd, J ) 10.3, 1.3 Hz, 1H), 5.04 (dd, J ) 17.1, 1.3 Hz,
1H), 5.10 (sept, J ) 6.3 Hz, 1H), 5.70-5.85 (m, 1H); 13C NMR
(100 MHz, CDCl3) δ 21.5, 26.9, 38.3, 70.6, 115.7, 136.1; IR (film
on KBr) 1730 cm-1. Anal. Calcd for C9H14O3: C, 63.5; H, 8.3.
Found: C, 64.7; H, 8.3.
J ) 7.0 Hz, 3H), 3.75 (s, 3H), 4.31 (d, J ) 6.0 Hz, 2H), 5.20 (dt,
J ) 10.1, 0.5 Hz, 1H), 5.30 (dd, J ) 17.1, 1.5 Hz, 1H), 5.92-6.04
(m, 1H), 6.35 (q, J ) 7.0 Hz, 1H); 13C NMR (100 MHz, CDCl3)
δ 12.4, 51.7, 69.7, 112.8, 117.8, 132.8, 151.3, 162.0; IR (film on
KBr) 1725, 1640 cm-1
.
Allyl Vinyl Ether (Z)-1e. To a cooled solution (0 °C) of 1j (1.28
g, 8.2 mmol, 1 equiv) in THF (5 mL) and H2O (2.5 mL) was added
LiOH ·H2O (0.69 g, 16.4 mmol, 2 equiv). The resulting suspension
was stirred vigorously for 30 min at 0 °C and then at room
temperature (∼6 h) until TLC indicated complete consumption of
the ester (1j: Rf ) 0.9, 1e: Rf ) 0.1-0.4, cyclohexane/ethylacetate
1/1). The yellow reaction mixture was then cooled to 0 °C, acidified
with diluted aqueous HCl (pH 4), and extracted with CHCl3 (6 ×
10 mL). The combined organic phases were dried (MgSO4) and
concentrated under reduced pressure, and the residue was purified
by flash chromatography (cyclohexane/ethyl acetate 100/1 to 1/1)
to afford (Z)-1e as white solid (0.5 g, 3.5 mmol, 43%) and (E)-1e
r-Keto ester (()-2c: 1H NMR (300 MHz, CDCl3) δ 1.19 (d, J
) 7.1 Hz, 3H), 1.34 (d, J ) 6.2 Hz, 6H), 2.09-2.22 (m, 1H),
2.39-2.51 (m, 1H), 3.28 (tq, J ) 17.5, 7.3 Hz, 1H), 5.00-5.09
(m, 2H), 5.14 (sept, J ) 6.3 Hz, 1H), 5.72 (m, 1H); 13C NMR (75
MHz, CDCl3) δ 14.8, 21.6, 36.1, 41.9, 70.5, 117.4, 134.8, 161.5,
197.8; IR (film on KBr) 1725 cm-1. Anal. Calcd for C10H16O3: C,
65.19; H, 8.75. Found: C, 65.22; H, 8.84.
1
r-Keto ester (()-2d: H NMR (400 MHz, CDCl3) δ 1.00 (s,
9H), 1.31 (d, J ) 6.2 Hz, 3H), 1.32 (d, J ) 6.2 Hz, 3H), 2.20-2.32
(m, 1H), 2.40-2.51 (m, 1H), 3.59 (dt, J ) 12.9, 6.5 Hz, 1H), 3.88
(d, J ) 5.8 Hz, 2H), 4.93-5.03 (m, 2H), 5.11 (sept, J ) 6.3, 1H),
5.69 (ddt, J ) 17.1, 10.2, 7.0 Hz, 1H), 7.33-7.46 (m, 6H),
7.58-7.64 (m, 4H); 13C NMR (75.5 MHz, CDCl3) δ 19.2, 21.5,
26.7, 31.5, 49.7, 63.7, 70.4, 117.2, 127.7, 129.7, 134.6, 135.5, 160.9,
184.5; IR (film on KBr) 1730 cm-1. Anal. Calcd for C26H34O4Si:
C, 71.19; H, 7.81. Found: C, 71.01; H, 7.84.
1
as yellowish oil (0.31 g, 2.5 mmol, 26%). (Z)-1e: H NMR (300
MHz, CDCl3) δ 1.76 (d, J ) 7.2 Hz, 3H), 4.34 (d, J ) 6.0 Hz,
2H), 5.20 (d, J ) 10.4 Hz, 1H), 5.32 (dd, J ) 17.2, 1.2 Hz, 1H),
5.92-6.04 (m, 1H), 6.53 (q, J ) 7.2 Hz, 1H); 13C NMR (apt, 75
MHz, CDCl3) δ 11.5, 73.3, 118.4, 127.2, 133.5, 144.7, 168.1; IR
(film on KBr) 3450, 2925, 1710, 1650 cm-1. Anal. Calcd for
1
r-Keto acid (()-2e: H NMR (400 MHz, CDCl3) δ 1.15 (d, J
) 7.0 Hz, 3H), 2.19 (ddd, J1 ) J2 ) J3 ) 7.2 Hz, 1H), 2.47 (ddd,
J. Org. Chem. Vol. 74, No. 4, 2009 1539

Rehbein et al.
J1 ) J2 ) J3 ) 6.8 Hz, 1H), 3.4 (tq, J1 ) J2 ) 7.8 Hz, 1H), 5.0 (s,
1H), 5.05 (d, J) 4.0 Hz, 1H), 5.64-5.75 (m, 1H), 6.3-7.0 (broad
s, 1H); 13C NMR (100 MHz, CDCl3) δ 15.1, 25.6, 68.0, 117.8,
134.5, 160.5, 199.0; IR (film on KBr) 3020, 1720 cm-1. Anal. Calcd
for C7H10O3: C, 59.1; H, 7.1. Found: C, 58.8; H, 7.1.
186.9, 198.1; IR (film on KBr) 1720, 1640 cm-1. Anal. Calcd for
C11H18O3: C, 66.6; H, 9.1. Found: C, 66.7; H, 9.2.
r-Keto ester (()-anti-2h: 1H NMR (300 MHz, CDCl3) δ 0.88
(t, J ) 6.7 Hz, 3H), 1.11 (d, J ) 6.1 Hz, 3H), 1.19-1.43 (m, 4H),
1.34 (d, J ) 6.3 Hz, 3H), 1.35 (d, J ) 7.3 Hz, 3H), 2.42-2.54 (m,
1H), 3.22 (dq, J1 ) J2 ) 6.8 Hz, 1H), 4.98 (ddd, J ) 16.9, 1.9, 0.8
Hz, 1H), 5.07 (dd, J ) 10.2, 1.8 Hz, 1H), 5.16 (sept, J ) 6.3 Hz,
1H), 5.46 (ddd, J ) 17.1, 10.1, 9.3 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ 12.4, 13.9, 20.1, 21.5, 21.6, 34.8, 44.9, 46.0, 70.4, 117.2,
138.1, 161.6, 184.0; IR (film on KBr) 1720 cm-1. Anal. Calcd for
C13H22O3: C, 68.78; H, 9.70. Found: C, 68.79; H, 9.80.
1
r-Keto ester (()-2f: H NMR (400 MHz, CDCl3) δ 1.16 (d, J
) 7.0 Hz, 3H), 2.13-2.25 (m, 1H), 2.41-2.52 (m, 1H), 3.28 (dq,
J1 ) J2 ) 6.9 Hz, 1H), 4.61 (q, J ) 8.1 Hz, 2H), 5.02-5.10 (m,
2H), 5.64-5.75 (m, 1H); 13C NMR (100 MHz, CDCl3) δ.14.3, 35.9,
42.1, 60.9, 117.9, 134.1, 159.7; IR (film on KBr) 1730 cm-1
.
1
r-Keto ester (()-syn-2g: H NMR (300 MHz, CDCl3) δ 0.96
(d, J ) 7.0 Hz, 3H), 1.05 (d, J ) 6.7 Hz, 3H), 1.31 (dd, J ) 6.0,
5.0 Hz, 6H), 2.55 (m, 1H), 3.23 (m, J ) 6.8 Hz, 1 H), 4.99 (d, J
) 9.8 Hz, 2H), 5.11 (sept, J ) 6.2 Hz, 1H), 5.68-5.78 (m, 1H);
13C NMR (100.6 MHz, CDCl3) δ 11.3, 15.5, 21.4, 39.0, 46.3, 70.4,
114.8, 141.0, 161.4, 198.1; IR (film on KBr) 1720 cm-1. Anal.
Calcd for C11H18O3: C, 66.6; H, 9.1. Found: C, 66.6; H, 9.1.
Acknowledgment. Financial Support by the DFG (HI 628/
4) and by the Technische Universita¨t Dortmund is gratefully
acknowledged. J.R. thanks Miss Sarah Jansing (TU Dortmund)
for her skillful technical assistance.
Supporting Information Available: Additional experimental
1
1
procedures, copies of H NMR and 13C NMR spectra for new
r-Keto ester (()-anti-2g: H NMR (300 MHz, CDCl3) δ 1.04
(d, J ) 7.0 Hz, 3H), 1.02 (d, J ) 6.8 Hz, 3H), 1.32 (d, J ) 6.2 Hz,
6H), 2.57 (m, 1H), 3.14 (m, 1H), 4.98 (d, J ) 6.8, 2H), 5.13 (sept,
J ) 6.2 Hz, 1H), 5.61 (ddt, J ) 18.7, 13.5, 8.3 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ 12.5, 18.2, 21.6, 39.5, 47.0, 70.4, 115.5, 139.9,
compounds, and Arrhenuis and Eyring plots. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO802303M
1540 J. Org. Chem. Vol. 74, No. 4, 2009