TABLE 3. E-Redox Isomerization Revisiteda
NaOAc gave a shorter time scale (0.5 h) for the redox
isomerization but with poor E/Z selectivity (entry 2). From these
results, we hypothesized that the combination of DABCO and
NaOAc would accelerate the redox isomerization without a loss
of E/Z selectivity. In effect, treatment of 1 with 20 mol % of
DABCO and 20 mol % of NaOAc gave E2 in slightly lower
62% yield but in a much shorter reaction time (0.8 h; entry 3).
We postulate that the stronger base, NaOAc, accelerates the rate-
determining methine deprotonation step while the DABCO
facilitates the Z to E isomerization to give excellent E/Z
selectivity.15
entry
base
DABCO
NaOAc
DABCO/NaOAc
time (h)
yield (%)
E2/Z2
1
2
3
7
0.5
0.8
70
n/ab
62
33:1
1:2.4
30:1
a Conditions: 20 mol % of base in DMSO at 23 °C. b Not isolated.
In conclusion, we have developed a convenient method
to isomerize γ-hydroxy-R,â-alkynyl esters to γ-oxo-R,â-(E)-
alkenyl esters using catalytic DABCO. The modified methods
were applied to propargylic alcohols conjugated with an amide
and phosphonate, respectively. The corresponding highly Z-
selective isomerization method will be reported in due course.16
longer (25 h) reaction times compared to that in entry 1 (4 h)
are consistent with the proposed mechanism due to the lower
and higher pKa values for the hydrogen atoms abstracted by
DABCO. In addition to these para-substituted derivatives, ortho-
substituted compounds were examined; unexpectedly, treatment
of aryl bromide 11 (entry 4) with catalytic DABCO gave 12
only in 34% isolated yield and the reaction was slow (23 h).
We are currently investigating side reactions of the 11 f 12
conversion. We postulate that steric hindrance posed by the
bromide atom toward DABCO may be the cause of the longer
reaction time. Aryl fluoride 13 (entry 5) underwent the isomer-
ization in 20 h to give 14 in 60% isolated yield. According to
the recent work of Bernotas,8 this product is capable of
undergoing a cascade sequence with 1,2-diamines (1,4-addition,
lactamization, and intramolecular SNAr-type reaction) to form
medicinally important arylpyrazine derivatives.
The furan derivative 15 (entry 6) generated the corresponding
product 16 in 78% yield, showing that the reaction is amenable
to heteroaromatics. Interestingly, the isomerization of the
cinnamyl alcohol derivative 17 (entry 7) was rapid (0.5 h),
affording diene 18 in quantitative yield. However, the treatment
of aliphatic alkene 19 (entry 8) with 20 mol % of DABCO in
DMSO at 23 °C generated an intractable mixture with no
detectable 20. Compound 21 (entry 9) could not be transformed
into 22 in the presence of DABCO; instead, the starting material
was recovered even when the reaction was heated to 95 °C in
the presence of 20 mol % of DABCO. Treatment of 21 with 75
mol % of NaHCO3 in DMSO at 23 °C resulted in a complex
mixture with no detectable olefin.
Experimental Section
Alkynes were synthesized by one of the two following methods.
Preparation of 7 (Method A). Using the procedure as shown
in ref 17, silica gel chromatography (5 f 20% EtOAc in hexanes)
afforded 7 (303.0 mg, 61%) as a yellow oil: Rf ) 0.33 (30% EtOAc
in hexanes); IR (film) 3420 (br, OH), 3011, 2959, 2242 (CtC),
1
1717 (CdO), 1438, 1329, 1260, 1167, 1128, 1017, 857 cm-1; H
NMR (300 MHz, 293 K, CDCl3) δ 7.65 (br s, 4H), 5.61 (br s, 1H),
3.80 (s 3H); 13C NMR (125 MHz, 293 K, CDCl3) δ 153.8, 142.4,
130.7 (q, J ) 32.3 Hz), 126.8, 125.6 (q, J ) 3.8 Hz), 123.8 (q, J
) 270.4 Hz), 86.2, 77.5, 63.1, 52.9; HRMS (EI+) calcd for
C12H9F3O3 (M+) 258.0503, found 258.0500.
Preparation of 11 (Method B). Using the procedure as shown
in ref 18, silica gel chromatography (5 f 20% EtOAc in hexanes)
afforded 11 (459.0 mg, 46%) as a yellow oil: Rf ) 0.40 (30% EtOAc
in hexanes); IR (film) 3411 (br, OH), 2954, 2923, 2238 (CtC),
1
1716 (CdO), 1436, 1255, 1019, 942, 751 cm-1; H NMR (500
MHz, 293 K, CDCl3) δ 7.72 (dd, 1H, J ) 7.8, 1.5 Hz), 7.57 (d,
1H, J ) 8.0 Hz), 7.38 (t, 1H, J ) 7.6 Hz), 7.22 (td, 1H, J ) 7.8,
1.6 Hz), 5.87 (s, 1H), 3.79 (s, 3H); 13C NMR (125 MHz, 293 K,
CDCl3) δ 153.8, 137.7, 132.9, 130.2, 128.4, 127.9, 122.4, 86.0,
76.9, 63.4, 52.9; HRMS (EI+) calcd for C11H9BrO3 (M+) 267.9735,
found 267.9742.
General Procedure for the Formation of Trans Olefins.
Preparation of 8. To a solution of 7 (64.5 mg, 0.2500 mmol) in
DMSO (1.25 mL) at 23 °C was added DABCO (5.6 mg, 0.050
mmol) in one portion, and the resulting solution was stirred at the
same temperature for 2 h. The reaction was then diluted with water
(25 mL) and then acidified to pH 3 with pH 3 phosphate buffer.
The resulting aqueous mixture was extracted with Et2O (25 mL ×
3). The combined organic layers were then washed with water (25
mL) and brine (25 mL), dried over Na2SO4, filtered, and concen-
trated under reduced pressure. The resulting residue was purified
by silica gel chromatography (5 f 20% EtOAc in hexanes) to afford
8 (40.0 mg, 62%) as a pale yellow solid: Rf ) 0.41 (20% EtOAc
in hexanes); mp ) 73.5-74.0 °C; IR (film) 3079, 2927, 1731
(CdO), 1669 (CdO), 1628, 1410, 1319, 1306, 1164, 1126, 970,
In addition to alkynoic esters, other electron-deficient alkynes
were examined. Under the conditions used in entry 1-9 (20
mol % of DABCO in DMSO, 23 °C), diethyl phosphonate 23
(entry 11) was isomerized to 24 and its Z-isomer in an E/Z )
6:1 ratio. This ratio was improved to E/Z ) 10:1 at 40 °C in
95% yield as a mixture of the stereoisomers. It is noteworthy
that 50 mol % of CsHCO3 was also capable of producing 24
with no detectable Z-isomer, but the isolated yield was moderate
(50%).
The amide derivative 25 (entry 10) did not isomerize to 26
under the above conditions (20 mol % DABCO in DMSO at
23 °C), which is not surprising because the propargylic proton
of 25 is not as acidic as that of the ester derivatives shown above.
However, after screening efforts, we found that the isomerization
proceeded under the modified conditions (20 mol % of NaOAc
and 20 mol % of DABCO in DMSO, 23 °C, 22 h) to form 26
in 76% yield. To the best of our knowledge, this is the first
example of the redox isomerization of an electron-deficient
propargylic alcohol conjugated to an amide.
1
773, 722 cm-1; H NMR (300 MHz, 293 K, CDCl3) δ 8.11 (br d,
2H, J ) 8.8 Hz), 7.90 (d, 1H, J ) 15.6 Hz), 7.79 (br d, 1H, J )
8.8 Hz), 6.93 (d, 1H, J ) 15.6 Hz), 3.87 (s, 3H); 13C NMR (125
MHz, 293 K, CDCl3) δ 188.6, 165.6, 139.1, 135.7, 135.0 (q, J )
32.5 Hz), 133.0, 129.0, 125.9, 123.4 (q, J ) 273.8 Hz), 52.4; HRMS
(ES+) calcd for C12H9F3O3 (M+) 258.0504, found 258.0538.
(16) Sonye, J. P.; Koide, K. Submitted for publication.
(17) Shahi, S. P.; Koide, K. Angew.Chem., Int. Ed. 2004, 43, 2525-
2527.
The facile reaction of amide 25 with NaOAc prompted us to
apply these conditions to 1. Our optimized conditions using
DABCO gave E2 selectively in 7 h (Table 3, entry 1) while
(18) Krause, N. Liebigs Ann. Chem. 1990, 603-604.
6256 J. Org. Chem., Vol. 71, No. 16, 2006