Synthesis of 1,5-dicarbonyl and related compounds from Baylis-Hillman adducts via Pd-mediated decarboxylative protonation protocol

Article abstract of DOI:10.1016/j.tetlet.2008.08.051

We prepared various 1,5-dicarbonyl and related compounds from Baylis-Hillman adducts by using a Pd-mediated decarboxylative protonation protocol.

Full text of DOI:10.1016/j.tetlet.2008.08.051

Tetrahedron Letters 49 (2008) 6241–6244
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Synthesis of 1,5-dicarbonyl and related compounds from Baylis–Hillman
adducts via Pd-mediated decarboxylative protonation protocol
*
Saravanan Gowrisankar, Ko Hoon Kim, Sung Hwan Kim, Jae Nyoung Kim
Department of Chemistry and Institute of Basic Science, Chonnam National University, Gwangju 500-757, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
We prepared various 1,5-dicarbonyl and related compounds from Baylis–Hillman adducts by using a
Pd-mediated decarboxylative protonation protocol.
Received 22 July 2008
Revised 8 August 2008
Accepted 11 August 2008
Available online 19 August 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
1,5-Dicarbonyls
Baylis–Hillman adducts
Palladium
Decarboxylative protonation
.
Baylis–Hillman adducts have been used as effective precursors
for the synthesis of various 1,5-dicarbonyl compounds.1–4 Previous
syntheses of these compounds from Baylis–Hillman adducts were
carried out by using (carbethoxymethylene)triphenylphospho-
rane,1 or via the Johnson–Claisen rearrangement with trialkyl
orthoacetate.2 However, these methods have some drawbacks
including the limitations of substituents.1,2 Due to the importance
of 1,5-dicarbonyl and related moieties in both natural product
chemistry and synthetic organic chemistry, a new and efficient
synthetic approach is highly desirable.1–3,5
tonation and allylation of allyl esters have also been reported.7,8
In a continuation of our studies on Pd-mediated reactions using
the Baylis–Hillman adducts,9 we theorized that various 1,5-dicar-
bonyl and related compounds could be synthesized easily from
Baylis–Hillman adducts, as shown in Scheme 1, by using the
Pd-mediated decarboxylative protonation as the key step.
Initially, we synthesized the starting material 3a (EWG1 =
COOMe, EWG2 = COOEt, R = H) from the reaction between the ace-
tate of Baylis–Hillman adduct and allyl ethyl malonate (2a). How-
ever, 3a was obtained as a mixture of E/Z (9:1). Thus, we used
cinnamyl bromide 1a, which can be synthesized as a pure E form
by the treatment of Baylis–Hillman adduct with aqueous HBr,10
and obtained 3a-E in good yield (92%, vide infra, entry 1 in Table
2). With this compound 3a, we examined the reaction conditions
Baylis–Hillman acetates themselves can be used as effective
substrates in the Pd-mediated reactions via the corresponding
p-
allylpalladium complex, and many papers using this concept have
already been reported.6 Palladium-assisted decarboxylative pro-
K2CO3
CH3CN, rt
EWG1
EWG2
EWG1
EWG2
Ph
Ph
EWG1
Br
Pd(OAc)2, PPh3
EWG2
O
Ph
+
R
O
Et3N, CH3CN/H2O (9:1)
R
R
O
O
3a-h
1
2
4a-h
2a: R = H, EWG2 = COOEt
1a: EWG1 = COOMe
1b: EWG1 = COOEt
1c: EWG1 = COCH3
2b: R = H, EWG2 = COOallyl
2c: R = CH2Ph, EWG2 = COOallyl
2d: R = H, EWG2 = COMe
2e: R = H, EWG2 = CN
Scheme 1.
* Corresponding author. Tel.: +82 62 530 3381; fax: +82 62 530 3389.
E-mail address: kimjn@chonnam.ac.kr (J. N. Kim).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.08.051

6242
S. Gowrisankar et al. / Tetrahedron Letters 49 (2008) 6241–6244
Table 1
Table 2
Optimization of reaction conditions for the conversion of 3a to 4a
Synthesis of 1,5-dicarbonyl and related compounds 4
Conditionsa
4a (%)
Entry
1 + 2
3 (%)
Time (h)
4a (%)
Entry
1
2
3
4
5
6
7
8
1a + 2a
1a + 2b
1a + 2c
1a + 2d
1b + 2a
1b + 2b
1b + 2e
1c + 2d
3a (92)
3b (86)
3c (78)
3d (85)
3e (89)
3f (87)
3g (71)
3h (74)
2
6
6
5
3
4
2
2
4a (90)
4b (88)
4c (89)
4d (86)
4e (88)
4f (91)
4g (66)b
4h (88)
1
2
HCOOH (1.2 equiv)/Et3N (1.2 equiv)/CH3CN/reflux/1 h
HCOOH (1.2 equiv)/Et3N (1.2 equiv)/THF/60 ºC/6 h
65
50
3
Et N (1.2 equiv)/CH CN—H O (9:1)/70 ºC
h
90
/2
3
3
2
4
5
a
CH3CN—H2O (9:1)/70 ºC/8 h
Et3N (1.2 equiv)/dry CH3CN/60 ºC/12 h
67
<5
In all cases, Pd(OAc)2 (5 mol %) and PPh3 (10 mol %) were used.
a
Conditions: Pd(OAc)2 (5 mol %), PPh3 (10 mol %), Et3N (1.2 equiv), CH3CN–H2O
(9:1), 70 °C, 2–6 h.
b
Decarboxylative allylation product was isolated in 16%.
for the selective Pd-mediated decarboxylative protonation. As
shown in Table 1, the conditions comprised of Pd(OAc)2/PPh3/
HCOOH/Et3N in CH3CN (entry 1) afforded 4a in 65%. The reaction
in THF was less effective (entry 2). When the reaction was carried
out under aqueous CH3CN in the presence of Et3N, the highest yield
of 4a (90%) was obtained (entry 3).11 Although the role of Et3N is
not clear at this stage, the reaction without Et3N gave diminished
yield of product (67%, entry 4). The reaction in dry CH3CN was
very sluggish as expected due to the absence of proton source
(entry 5).
Encouraged by the results, we prepared substrates 3b–h from
the reaction of cinnamyl bromides 1a–c and allyl malonates 2a–e
in 71–89% yields. These compounds were subjected to the opti-
mized conditions (entry 3 in Table 1) and we obtained good to
excellent yields of products 4b–h (66–91%), as summarized in
Table 2. It is interesting to note that decarboxylation-allylation
product was also isolated in 16% for the starting material 3g
(entry 7).8
Table 3
Synthesis of 1,5-dicarbonyl compounds 7
O
EWG2
OAc
conditionsa
EWG2
Ph
EWG2
O
(i) DABCO, aq THF
O
COOMe
R
+
COOMe
Ph
COOMe
(ii) Compound 2
Ph
O
5a
2
7
6
Entry
5a + 2
6 (%)
Time (h)
7 (%)
1
2
3
5a + 2a
5a + 2b
5a + 2d
6a (46)
6b (53)
6c (50)
2
3
3
7a (82)
7b (87)
7c (96)
a
Conditions: Pd(OAc)2 (5 mol %), PPh3 (10 mol %), Et3N (1.2 equiv), CH3CN–H2O (9:1), 70 °C, 2–3 h.
Pd(OAc)2 + PPh3
Pd(0)
COOMe
OEt
Ph
OH
O
O
O
3a
COOMe
Ph
OEt
PdII-OH
O
PdII
O
O
(I)
COOMe
COOEt
Ph
4a
COOMe
OEt
Ph
O
PdII
H2O
CO2
(II)
Figure 1. Postulated mechanism.

S. Gowrisankar et al. / Tetrahedron Letters 49 (2008) 6241–6244
6243
COOMe
COOEt
Ph
COOMe
Pd(OAc)2, PPh3
Ph
4a (79%)
COOEt
O
Et3N, CH3CN/H2O (9:1)
Ph
Ph
OH
O
(28%)
3i
Scheme 2.
without Pd(OAc)2
(i) PPh3, Et3N, aq CH3CN, 70 o
COOMe
COOMe
COOEt
Ph
C
Ph
+
4a (12%)
COOEt
COOH
8 (69%)
O
(ii) H3O+
O
3a
H3O+
H3O+
H2O
- allyl alcohol
COOMe
COOMe
OEt
Ph
Ph
COOMe
OEt
- CO2
Et3N
Ph
COOEt
OH
O
less effective
Et3NH
O
O
O
Et3NH
O
(IV)
(III)
Scheme 3.
Introduction of allyl malonates at the secondary position of the
Baylis–Hillman adducts was carried out according to the reported
conditions involving the use of DABCO in aqueous THF.12 Actually,
we prepared three compounds 6a–c in moderate yields (46–53%)
and then examined the Pd-mediated decarboxylative protonation
reaction (Table 3). As expected 1,5-dicarbonyl compounds 7a–c
were obtained similarly in good yields (82–96%).
Acknowledgments
This work was supported by the Korea Research Foundation
Grant funded by the Korean Government (MOEHRD, KRF-2007-
313-C00417). Spectroscopic data were obtained from the Korea
Basic Science Institute, Gwangju branch.
The reaction mechanism for the conversion of 3a into 4a can be
postulated as shown in Figure 1. Oxidative addition of Pd(0) to 3a
affords the Pd-carboxylate (I), which is converted to Pd-enolate (II)
after decarboxylation.7a The Pd-enolate reacts with water to give
References and notes
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Tetrahedron Lett. 2006, 47, 7619–7623; (b) Basavaiah, D.; Pandiaraju, S.
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product 4a and the
p-allylpalladium complex, which regenerates
Pd(0) and liberates allyl alcohol.7a The detection of liberated allyl
alcohol was somewhat difficult, thus we made the cinnamyl deriv-
ative 3i and carried out decarboxylative protonation under the
same conditions (Scheme 2). We did not observe the formation
of b-methyl styrene. Instead, we isolated cinnamyl alcohol (28%),
cinnamyl acetate (7%), and product 4a (79%). The low yield of cin-
namyl alcohol must be due to the instability of cinnamyl alcohol
itself under the reaction conditions. The mechanism of HCOOH/
Et3N system (entries 1 and 2 in Table 1) might involve the libera-
tion of propene instead of allyl alcohol.7b–e
3. For the synthesis of 1,5-dicarbonyl compounds from Baylis–Hillman adducts
using different approach, see: Garrido, N. M.; Garcia, M.; Diez, D.; Sanchez, M.
R.; Sanz, F.; Urones, J. G. Org. Lett. 2008, 10, 1687–1690.
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Reactions; Paquette, L. A., Ed.; John Wiley & Sons: New York, 1997; Vol. 51, pp
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8062; (d) Kim, J. N.; Lee, K. Y. Curr. Org. Chem. 2002, 6, 627–645; (e) Lee, K. Y.;
Gowrisankar, S.; Kim, J. N. Bull. Korean Chem. Soc. 2005, 26, 1481–1490; (f)
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The reaction of 3a using PPh3/Et3N/aqueous CH3CN/70 °C/5 h
also produced 4a, albeit in lower yield (12%), even in the absence
of Pd(OAc)2 (Scheme 3). In the reaction, carboxylic acid 8 was iso-
lated in 69% yield. The results demonstrate that hydrolysis of allyl
ester can occur in part without the aid of Pd catalyst, but the sub-
sequent decarboxylation of triethylammonium carboxylate (III) to
triethylammonium enolate (IV) is somewhat difficult.
In summary, we disclose an efficient protocol for the synthesis
of various 1,5-dicarbonyl and related compounds from Baylis–Hill-
man adducts by using the sequential introduction of allyl malo-
nates followed by a Pd-mediated decarboxylative protonation
strategy.
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W.; Dong, G.; Venkataiah, B.; Chen, C. J. Org. Chem. 2005, 70, 9207–9210; (b)
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Martin, R. Helv. Chim. Acta 1991, 74, 1213–1220; (f) Mazdiyasni, H.; Konopacki,
D. B.; Dickman, D. A.; Zydowsky, T. M. Tetrahedron Lett. 1993, 34, 435–438.
11. Typical experimental procedure for the synthesis of 4a: To a stirred solution of
3a (346 mg, 1.0 mmol), Pd(OAc)2 (11 mg, 0.05 mmol), PPh3 (26 mg, 0.1 mmol)
in CH3CN–H2O (3 mL, 9:1) was added Et3N (122 mg, 1.2 mmol), and the
reaction mixture was heated to 70 °C for 2 h. After usual aqueous workup and
column chromatographic purification process (hexanes/ether, 95:5),
compound 4a was isolated as colorless oil, 236 mg (90%). Other compounds
were synthesized similarly and the representative spectroscopic data of 4a, 4d,
and 7a are as follows.
Chattopadhyay, K.; Jana, R. Tetrahedron Lett. 2007, 48, 3847–3850; (e) Park, J.
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J. A. J. Am. Chem. Soc. 2007, 129, 4138–4139; (b) Tsuji, J.; Yamada, T.; Minami, I.;
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Compound 4a:2a 90%, colorless oil; IR (film) 1710, 1635, 1254 cmÀ1 1H NMR
;
(CDCl3, 300 MHz) d 1.24 (t, J = 7.0 Hz, 3H), 2.55 (t, J = 8.0 Hz, 2H), 2.88 (t,
J = 8.0 Hz, 2H), 3.83 (s, 3H), 4.11 (q, J = 7.0 Hz, 2H), 7.32–7.42 (m, 5H), 7.74 (s, 1H).
Compound 4d: 86%, colorless oil; IR (film) 1713, 1634, 1254 cmÀ1 1H NMR
;
(CDCl3, 300 MHz) d 2.14 (s, 3H), 2.65–2.71 (m, 2H), 2.77–2.84 (m, 2H), 3.82 (s,
3H), 7.21–7.42 (m, 5H), 7.72 (s, 1H); 13C NMR (CDCl3, 75 MHz) d 21.80, 29.68,
42.67, 51.98, 128.57 (2C), 129.02, 131.42, 135.20, 140.06, 168.34, 207.54.
Compound 7a: 82%, colorless oil; IR (film) 1723, 1634, 1142 cmÀ1 1H NMR
;
(CDCl3, 300 MHz)
d
1.53 (t, J = 7.0 Hz, 3H), 2.74–2.83 (m, 1H),
2.87–2.95 (m, 1H), 3.67 (s, 3H), 4.06 (q, J = 7.0 Hz, 2H), 4.41 (t, J = 8.1 Hz, 1H),
5.66 (s, 1H), 6.32 (s, 1H), 7.16–7.31 (m, 5H); 13C NMR (CDCl3, 75 MHz) d 14.04,
39.58, 42.68, 51.86, 60.44, 124.49, 126.78, 127.76, 128.41, 141.14, 142.36,
166.70, 171.36.
9. For our recent contributions on Pd-mediated reactions with Baylis–Hillman
adducts, see: (a) Gowrisankar, S.; Lee, H. S.; Kim, J. M.; Kim, J. N. Tetrahedron
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K. Y.; Lee, J.-E.; Kim, J. N. Tetrahedron Lett. 2007, 48, 8619–8622.
12. For the regioselective introduction of nucleophiles at the secondary positions
of Baylis–Hillman adducts by using the DABCO salt concept, see: (a) Kim, J. N.;
Kim, J. M.; Lee, K. Y.; Gowrisankar, S. Bull. Korean Chem. Soc. 2004, 25, 1733; (b)
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