Convenient synthesis of electron deficient dienes via Pd(0) catalyzed coupling

Article abstract of DOI:10.1055/s-1998-1885

The convenient preparation of 1,6-dicarbonyl-2,4-butadienes by the coupling of enol triflates with α,β-unsaturated carbonyls in the presence of Pd(PPh₂)₂Cl₂ is described.

Full text of DOI:10.1055/s-1998-1885

October 1998
SYNLETT
1059
Convenient Synthesis of Electron Deficient Dienes via Pd(0) Catalyzed Coupling
,a
a
a
a,b
Hwa-Ok Kim,* Cyprian O. Ogbu, Sherry Nelson and Michael Kahn
a
b
Molecumetics Ltd., 2023 120th Ave. N.E. Suite 400, Bellevue, WA 98005-2199. University of Washington, Department of Pathobiology, SC-38,
Seattle, WA 98195.
Received 20 May 1998
Abstract: The convenient preparation of 1,6-dicarbonyl-2,4-butadienes
by the coupling of enol triflates with α,β-unsaturated carbonyls in the
presence of Pd(PPh ) Cl is described.
2 2
2
As a part of our continuing research in the area of peptide secondary
1
structure mimetics, we required a facile method for the preparation of
dienes of type 1 (Eq. 1). Electron-deficient dienes can serve as 4π
donors in the inverse electron demand Diels-Alder reaction. With
differentiable terminal functionality, these dienes and their correponding
cycloadducts can be selectively transformed into useful synthetic
intermediates.
Although there are several preparative methods available in the
2
literature, we sought a more direct and efficient alternative to
3
synthesizing these dienes. Drawing upon Pd(0) catalyzed coupling
methodology, which has been extensively investigated for the coupling
of enol triflates 2 and β-stannyl-α,β-unsaturated carbonyls 4, we were
able to join 2 with the readily available α,β-unsaturated carbonyl
compounds 3 to provide the desired dienes. This particular approach
serves to simplify the laborious workup associated with stannyl reagents
and led to the desired coupled products.
ketone functional group in 5i can be protected through the formation of
the ketal 7 in 29% yield.
Enol triflates 2 were prepared from methyl acetoacetate or methyl 2-
oxocyclopentane carboxylate by the reaction with NaH and triflic
o
anhydride in dichloromethane at 0 C (Eq.2). The resulting enol triflates
2
were then coupled with tert-butyl acrylate (3a) under Stille
3a
conditions. These coupling reactions resulted in the formation of the
desired dienoic diesters 5a-e in moderate to excellent yields.
Deprotection of the t-butyl group of 5 by treatment with TFA in
4
dichloromethane afforded the dienoic acids 1a-e in quantitative yields.
The coupling of enol triflates with methyl vinyl ketone and acrolein
were also examined. These reactions proceeded smoothly to give the
corresponding 1,6-dicarbonyl dienes in good yields (Eq. 3, 4). In the
case of 1f-h, the coupled products were the orthogonally protected keto
diesters.
While these dienoic esters could be used directly in the Diels-Alder
reaction, we desired to transform either the ketone or ester functional
groups prior to cycloaddition. For example, when the dienoic methyl
Among the dienes examined, 1f displayed unexpected reactivity when
the t-butyl group was cleaved. Dienoic ester 1f upon treatment with TFA
underwent an intramolecular cyclization (presumably catalyzed by
TFA) to provide lactone 8 (Eq.6).
ester of 5i was treated with NaBH /CeCl , the corresponding hydroxy
4
3
ester 6a was afforded in 95% yield (Eq.5). The resulting hydroxy ester
6a was then protected with either THP or TBDMS groups to form
dienes 6b and 6c in 73% and 93% yield respectively. Furthermore, the

1060
LETTERS
SYNLETT
30 min, 1N HCl (50 mL) was added and the solution was extracted
with dichloromethane (100 mL). The organic extract was then
dried (MgSO ), passed through a short pad of SiO , and
4
2
1
concentrated to provide an oil in quantitative yield. H NMR (500
MHz, CDCl ) δ 2.17 (s, 3H), 3.77 (s, 3H), 5.77 (s, 1H). Without
3
further purification the oil was used for the next reaction.
To a stirred solution of above triflate in DMF (30 mL) was added
t-butyl acrylate (3a) (3 mL, 20 mmol), followed by Pd(PPh ) Cl
3 2
2
(140 mg, 0.2 mmol) and TEA (4.2 mL, 30 mmol) at rt. The
o
In summary, we have demonstrated facile synthesis of a wide variety of
electron deficient dienes through the reaction of enol triflates with α,β-
unsaturated carbonyls in the presence of Pd(II).
solution was heated at 80 C for 22h. After dilution with Et O
2
(100 mL) and H O (100 mL), the aqueous phase was separated
2
and extracted with Et O (100 mL). The combined organic extracts
2
were washed with H O (100 mL), dried (MgSO ), and
2
4
concentrated to give an oil. The crude product was purified by
flash chromatography (hexane:EtOAc = 95:5 to 90:10 to 80:20) to
Acknowledgment. The authors thank Dr. Tomas Vaisar for obtaining
the mass spectra.
provide an oil (560 mg, 25 % for two steps). Less Polar fraction:
1
H NMR (500 MHz, CDCl ) δ 1.46 (s, 9H), 2.23 (d, 3H,
3
Reference and Notes
J=1.5Hz), 3.69 (s, 3H), 5.97 (d, 1H, J=0.5Hz), 6.10 (d, 1H,
J=16Hz), 7.14 (dd, 1H, J=16, 1Hz). More polar fraction: H NMR
1.
a) Peptide Secondary Structure Mimetics. Tetrahedron Symposia-
in-print no. 50, Kahn, M. Ed., 1993, 49, 3444. b) Kahn, M. Synlett
1993, 821. c) Kim, H. -O.; Lum, C.; Lee, M. S. Tetrahedron Lett.
1997, 38, 4935.
1
(500 MHz, CDCl ) δ 1.50 (s, 9H), 2.01 (d, 3H, J=1.5Hz), 3.73 (s,
3
3H), 5.90 (d, 1H, J=0.5Hz), 6.08 (dd, 1H, J=16, 1Hz), 8.50 (d, 1H,
J=16Hz). The ratio was about 3:1.
A solution of above diene diester (550 mg, 2.4 mmol) in
dichloromethane (2 mL) was treated with TFA (2 mL) at rt for
2.
3.
4.
Houpis, I. N.; DiMichele, L.; Molina, A. Synlett 1993, 365 and
references cited therein.
a) Scott, W. J.; Pena, M. R.; Sward, K.; Stoessel, S.; Stille, J. K. J.
Org. Chem. 1985, 50, 2302. b) Ritter, K. Synthesis 1993, 735.
1.5h. Concentration gave 1a as a pale yellow solid (420 mg, 100
1
%). Minor: H NMR (500 MHz, CDCl ) δ 2.07 (s, 3H), 3.77 (s,
3
3H), 6.00 (s, 1H), 6.18 (d, 1H, J=16Hz), 8.72 (d, 1H, J=16Hz).
Major : 2.03 (d, 3H, J=1 Hz), 3.77 (s, 3H), 6.10 (s, 1H), 6.23 (d,
Typical Procedure for 1: Synthesis of 1a: To a stirred solution of
methyl acetoacetate (1.1 mL, 10 mmol) in dichloromethane (30
mL) was added NaH (400 mg of 60%/oil, 10 mmol) at 0 C. After
-
o
1H, J=16Hz), 7.38 (d, 1H, J=16Hz), 9.92 (br). MS ES m/z 169.5
+
+
+
10 min, Tf O (2 mL, 12 mmol) was added at the same temp. After
(M-H ); ES m/z 171.6 (M+H ).
2