On the mechanism of DABCO-catalyzed isomerization of γ-hydroxy- α,β-alkynoates to γ-oxo-α,β(E)-alkenoates

Article abstract of DOI:10.1021/ol052376t

Since the discovery of organic base-catalyzed isomerization of γ-hydroxy-α,β-acetylenic esters to γ-oxo-α,β- trans-alkenyl esters in 1949, the mechanism has not been elucidated. This study shows that the mechanism involves cumulene formation, protonation

Full text of DOI:10.1021/ol052376t

ORGANIC
LETTERS
2006
Vol. 8, No. 2
199-202
On the Mechanism of DABCO-Catalyzed
Isomerization of
γ
γ
-Hydroxy-
r,â-alkynoates to
-Oxo- -(E)-alkenoates
r,â
John P. Sonye and Kazunori Koide*
Department of Chemistry, UniVersity of Pittsburgh, 219 Parkman AVenue,
Pittsburgh, PennsylVania 15260
koide@pitt.edu
Received October 1, 2005
ABSTRACT
Since the discovery of organic base-catalyzed isomerization of
γ
-hydroxy-
r,
â
-acetylenic esters to
γ
-oxo-r
,
â
-trans-alkenyl esters in 1949, the
mechanism has not been elucidated. This study shows that the mechanism involves cumulene formation, protonation with the conjugate acid
of the amine, and protonation of the resulting allenol with water.
γ-Oxo-R,â-trans-alkenyl esters (B, Scheme 1) are substrates
of such an isomerization was reported by the Raphael group
(Scheme 2),6 whereby 1 was subjected to excess Et3N at 23
for various types of organic reactions1 and part of peptido-
Scheme 2. Redox Isomerization of 1 to E2 and Z2
Scheme 1. Redox Isomerization of A to B
°C and the subsequent distillation afforded E2. The high
E-selectivity is presumably due to the isomerization of Z2
mimetic2 and some natural products.3 Compounds B can be
formed via the redox isomerization of readily accessible4,5
γ-hydroxy-R,â-alkynyl esters A. In 1949, the first example
(3) (a) Nozoe, S.; Hirai, K.; Tsuda, K. Tetrahedron Lett. 1965, 6, 4675.
(b) Hayashi, M.; Kim, Y. P.; Hiraoka, H.; Natori, M.; Takamatsu, S.;
Kawakubo, T.; Masuma, R.; Komiyama, K.; Omura, S. J. Antibiot. 1995,
48, 1435. (c) Takamatsu, S.; Kim, Y. P.; Hayashi, M.; Hiraoka, H.; Natori,
M.; Komiyama, K.; Omura, S. J. Antibiot. 1996, 49, 95.
(4) Midland, M. M.; Tramontano, A.; Cable, J. R. J. Org. Chem. 1980,
45, 28.
(1) (a) Angell, E. C.; Fringuelli, F.; Guo, M.; Minuti, L.; Taticchi, A.;
Wenkert, E. J. Org. Chem. 1988, 53, 4325. (b) Kowalski, C. J.; Lal, G. S.
J. Am. Chem. Soc. 1988, 110, 3693. (c) Molander, G. A.; Harris, C. R. J.
Org. Chem. 1998, 63, 812. (d) Hirayama, T.; Oshima, K.; Matsubara, S.
Angew. Chem., Int. Ed. 2005, 44, 3293.
(2) Vabeno, J.; Brisander, M.; Lejon, T.; Luthman, K. J. Org. Chem.
2002, 67, 9186.
(5) Shahi, S. P.; Koide, K. Angew. Chem., Int. Ed. 2004, 43, 2525.
(6) Nineham, A. W.; Raphael, R. A. J. Chem. Commun. 1949, 118.
10.1021/ol052376t CCC: $33.50
© 2006 American Chemical Society
Published on Web 12/15/2005

to E2 at an elevated temperature in the presence of Et3N as
suggested in more recent literature.7 The pathway of the
Raphael reaction was “conjectured” to go through an allenol
intermediate, PhC(OH)dCdCHCO2Me (3). Although the
Raphael reaction has been used for many decades for the
conversion of A to B,7,8 neither the intermediacy of 3 nor
the mechanism have been studied.
To determine whether this E-selective isomerization is
thermodynamically controlled, compound Z2 was subjected
to 10 mol % of DABCO in DMSO-d6 at 23 °C (Scheme 3).
Scheme 3. DABCO-Catalyzed Isomerization of Z2 to E2
We have recently reported a more convenient transforma-
tion of 1 to E2 using 1,4-diazabicyclo[2.2.2]octane (DABCO)
as a catalyst (10 mol %) at 23 °C,9 and this method has been
found to be applicable to other substrates A.10 We have
become interested in the mechanism of this DABCO-
catalyzed isomerization because it could also be related to
the mechanism of the Raphael reaction. Herein, we report
our mechanistic studies of the Raphael-like reaction catalyzed
by DABCO.
By monitoring the DABCO-catalyzed isomerization of 1
by H NMR spectroscopy, we found that the half-life of 1
1
1H NMR analysis showed that the reaction mixture rapidly
(t1/2 < 5 min) reached nearly the same E:Z ratio (30:1),
indicating that the origin of the high E-selectivity was a
thermodynamic preference. A plausible mechanism for the
isomerization between Z2 and E2 may involve intermediate
4, which can be formed by the conjugate addition of DABCO
toward Z2 and E2.
was approximately 90 min under the reaction conditions (10
mol % of DABCO, initial [1] ) 0.25 M, DMSO-d6, 23 °C).
The yield of E2 was approximately 95% based on the internal
standard (Bn2O) and the E2:Z2 ratio was 33:1. The kinetic
1
studies of the isomerization of 1 by H NMR analysis
revealed that the reaction rate was second order overall
(Figure 1a) and first order with respect to DABCO (Figure
At this point, we speculated that the DABCO-catalyzed
isomerization of 1 proceeded in two steps (Scheme 4). In
Scheme 4. Two Steps in the Isomerization of 1 to E2
Step 1, 1 is transformed to the mixture of E2 and Z2 in an
unknown ratio. In Step 2, the DABCO-catalyzed equilibrium
between E2 and Z2 (see Scheme 3) is established to
predominantly yield E2. Throughout the transformation of
1 to E2, compound Z2 was hardly detectable by NMR
analysis, which is consistent with the notion that the second
step is much faster than the first step (t1/2 ) ∼90 min for
the overall process, whereas t1/2 < 5 min for the isomeriza-
tion of Z2 to E2). Even though we cannot exclude the
possibility that the high E-selectivity is due to a kinetic
control, an alternative thermodynamic control is more likely
because the kinetic pathway should involve the protonation
of allenol 3 from the less hindered face to form Z2 (see
Scheme 7).
To address this, we hypothesized that the intermediacy of
4 might be supported if the conversion of Z2 to E2 in the
presence of D2O resulted in the deuterated E2. To determine
the position of the deuterium atom in E2, we required the
unambiguous assignment of olefinic protons in the 1H NMR
spectrum (Figure 2). Toward this objective, an HMBC
experiment proved to be informative, which revealed a
coupling between the methyl hydrogens and C2 (see the
Figure 1. Kinetic studies of DABCO-catalyzed isomerization. (a)
Conversion of the isomerization of 1 to E2 catalyzed by 5.6 mol
% ([), 10 mol % (9), and 37 mol % (2) of DABCO in DMSO-d6
at 23 °C; (b) initial reaction rate vs DABCO in mol % of the
isomerization of 1 to E2 in DMSO-d6 at 23 °C. R2 ) 0.999.
1b), indicating that the rate-determining step involves one
molecule of DABCO and one molecule of 1 in the transition
state.
(7) Bernotas, R. C. Synlett 2004, 2165.
(8) Coelho, A.; Sotelo, E.; Ravina, E. Tetrahedron 2003, 59, 2477.
(9) Sonye, J. P.; Koide, K. Synth. Commun. Accepted for publication.
(10) Sonye, J. P.; Koide, K. Manuscript in preparation.
200
Org. Lett., Vol. 8, No. 2, 2006

Scheme 6. Deuterium Incorporation Experiment
Figure 2. Key HMBC signal to assign 2-H and 3-H.
Supporting Information). On the basis of these results, the
chemical shifts of 2-H and 3-H were assigned to be 6.89
and 7.93 ppm, respectively. With the proton assignment, we
proceeded to study the isomerization of Z2 to E2 (Scheme
5); however, treatment of Z2 with 10 mol % of DABCO in
DMSO-d6/D2O (16:1) afforded E2 and not 3-d-E2 after 3 h.
This experiment neither supports nor excludes the interme-
diacy of 4, but indicates that the putative intermediate 4
undergoes the bond rotation-E1cb reaction (pathway a; 4 f
4′) faster than protonation (pathway b). Importantly, this
result suggested that deuterium incorporation in the isomer-
ization of 1 to E2 in DMSO-d6/D2O would elucidate the
mechanism of Step 1 shown in Scheme 4.
Scheme 5. No Deuterium Incorporation in the Isomerization
of Z2 to E2
1 (or a deuterium from D2O) in the less sterically hindered
face11 to generate 3-d-Z2. Finally, as described in Scheme
3, this intermediate isomerizes in the presence of DABCO
to form 3-d-E2.
Scheme 7. Proposed Mechanism
Encouraged by this perspective, we turned our attention
to Step 1. We treated 1 with 10 mol % of DABCO in DMSO-
d6/D2O (16:1), which exclusively generated 3-d-E2 (Scheme
6a). This result ruled out any mechanisms invoking a 1,2-
hydride shift from C4 to C3 induced by the 4-OH deproto-
nation by DABCO (Scheme 6b). As an alternative mecha-
nism, DABCO could undergo a conjugate addition toward
acetylenic esters to generate intermediate 6 (Scheme 6c). This
intermediate would be quenched by D2O to form 2-d-E2 via
7. However, 2-d-E2 was not observed; therefore, although
6 may be formed in a reversible manner, the subsequent
pathway does not proceed in the DABCO-catalyzed isomer-
ization of 1 to E2.
On the basis of the results described thus far, we postulated
the mechanism shown in Scheme 7: the 4-H of 1 is
abstracted by DABCO to form intermediate 8 and the
protonated DABCO. The protonated DABCO species is far
more acidic (pKa ) 9 in DMSO) than H2O (or D2O; pKa )
32 for H2O in DMSO), providing the source of the proton
in the next step to form allenol 3. The following tautomer-
ization occurs by abstracting a proton from residual H2O or
If the above mechanism is correct and the deprotonation
of 4-H is the rate-determining step, the substitution of 4-H
of 1 with a deuterium atom should substantially retard the
reaction by virtue of a primary isotope effect. Additionally,
the product formed in DMSO-H2O should be 2-d-E2
(11) (a) Zimmerman, H. E. J. Org. Chem. 1955, 20, 549. (b) Smadja,
W. Chem. ReV. 1983, 83, 263. (c) Ikeda, I.; Honda, K.; Osawa, E.; Shiro,
M.; Aso, M.; Kanematsu, K. J. Org. Chem. 1996, 61, 2031. (d) Trost, B.
M.; Oi, S. J. Am. Chem. Soc. 2001, 123, 1230. (e) Vanderwal, C. D.;
Vosburg, D. A.; Sorensen, E. J. Org. Lett. 2001, 3, 4307. (f) Wipf, P.;
Soth, M. J. Org. Lett. 2002, 4, 1787.
Org. Lett., Vol. 8, No. 2, 2006
201

Scheme 8. Deuterium Transfer and Kinetic Isotope Effect
Scheme 9. Crossover Experiment
because the N-deuterated DABCO would quench cumulene
7 at the C2 position (Scheme 8). To test this hypothesis,
4-d-1, prepared by coupling PhCDO with Ag-CtC-CO2-
Me,5 was subjected to 20 mol % of DABCO in DMSO-d6/
H2O (16:1) at 23 °C to find that 2-d-E2 was indeed formed
as the sole product. Furthermore, similarly to the enolization
of 2,4-dimethyl-3-pentanone with NaOH (kH/kD ) 6.1) at
25 °C,12 a large kinetic isotope effect, kH/kD ) 6.4, was
observed at 23 °C. Thus, the proposed mechanism shown in
Scheme 4 is consistent with this experiment and the dramatic
reaction-rate acceleration in DMSO (the isomerization does
not occur in nonpolar solvents such as CHCl3 and benzene),
a solvent that facilitates the formation of charged species
such as 8 and the protonated DABCO. The results shown in
Schemes 6a and 8 also indicate that the protonated DABCO
does not undergo proton exchange with H2O, which is not
surprising because H2O is far less acidic than the protonated
DABCO in DMSO (∆pKa ≈ 23).
Despite these observations, we cannot entirely exclude an
alternative mechanism in which DABCO undergoes a
conjugate addition with 1 to form intermediate 6. To be
consistent with our results, both the OH deprotonation of
7 by an additional DABCO molecule and a disrotatory 1,3-
hydride shift from C4 to C2 occur at the same time. Alter-
natively, the conjugate addition of DABCO and the hydride
shift occur simultaneously. Although we do not have any
evidence to exclude these mechanisms, the stringent require-
ment for the timing of either of the two processes involving
the kinetically unfavorable hydride shift would be less likely
than the mechanism described above.
In conclusion, we have gained significant mechanistic
insight into the DABCO-catalyzed isomerization of γ-hy-
droxy-R,â-alkynyl esters to γ-oxo-R,â-trans-alkenyl esters.
The order of proton additions and the sources of each olefinic
proton determined in this study could facilitate the develop-
ment of related synthetic methods with various electrophiles.
An unanswered question at this point was whether
intermediate 8 formed a tight ion pair with the protonated
DABCO. To address this question, a mixture of 4-d-1 and 9
(7.2:1) in DMSO-d6 was treated with 10 mol % of DABCO
at 23 °C (Scheme 9). After the reaction, it was found that
12% of the methyl ester product contained H and 32% of
the ethyl ester product contained D at their 2-positions. Due
to the formation of protonated E2 and deuterated 2-d-E10,
it is deduced that intermediate 8 does not form a strong ion
pair with the protonated DABCO.
Acknowledgment. Financial support was provided by the
University of Pittsburgh. We thank a reviewer for suggesting
the crossover experiment.
Supporting Information Available: NMR spectra for
3-d-E2, 2-d-E2, and the crossover experiment. This material
is available free of charge via the Internet at http://pubs.acs.org.
(12) Lynch, R. A.; Vincenti, S. P.; Lin, Y. T.; Smucker, L. D.; Subba
Rao, S. C. J. Am. Chem. Soc. 1972, 94, 8351.
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