Studies on K2CO3-Catalyzed 1,4-Addition of 1,2-Allenic Ketones with Diethyl Malonate: Controlled Selective Synthesis of β,γ-Unsaturated Enones and α-Pyrones

Article abstract of DOI:10.1021/jo034633i

The K₂CO₃ (10 mol%)-catalyzed 1,4-addition reaction of diethyl malonate with various substituted 1,2-allenic ketones leading to polyfunctionalized β,γ-unsaturated enones 3 or 4 was studied. With 3-unsubstituted 1-substituted-1,2-alle

Full text of DOI:10.1021/jo034633i

Stu d ies on K2CO3-Ca ta lyzed 1,4-Ad d ition of 1,2-Allen ic Keton es
w ith Dieth yl Ma lon a te: Con tr olled Selective Syn th esis of
â,γ-Un sa tu r a ted En on es a n d r-P yr on es
Shengming Ma,* Shichao Yu, and Shaohu Yin
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, P.R. China
masm@mail.sioc.ac.cn
Received May 13, 2003
The K2CO3 (10 mol %)-catalyzed 1,4-addition reaction of diethyl malonate with various substituted
1,2-allenic ketones leading to polyfunctionalized â,γ-unsaturated enones 3 or 4 was studied. With
3-unsubstituted 1-substituted-1,2-allenyl ketones, the highly selective formation of â,γ-unsaturated
enones 4 was observed; with 1,2-allenyl ketones bearing one or two 3-substituents in the allenyl
group, only â,γ-unsaturated enones 3 with an unmigrated carbon-carbon double bond were
produced; with 3-monosubstituted-1,2-allenyl ketones Z-â,γ-unsaturated enones 3 were formed with
excellent stereoselectivity (E:Z > 96:4); with propadienyl ketones, mixtures of â,γ-unsaturated
enones 3 and 4 were formed. R-Pyrone derivatives were synthesized via the K2CO3-catalyzed or
-promoted reaction of 1,2-allenic ketones with diethyl malonate via a sequential Michael addition-
carbon-carbon double bond migration-lactonization process.
In tr od u ction
thesis,6 showing high reactivities.7 Among them, the
nucleophilic 1,4-addition reactions have been most ex-
tensively investigated, in which the carbon-carbon double
bond of the initially formed â,γ-unsaturated enones would
like to migrate to form R,â-unsaturated enones or a
mixture of R,â- and â,γ-unsaturated enones.8
Recently, during the course of our study of the chem-
istry of allenes,9 we have demonstrated that electron-
deficient allenes can easily accept the nucleophilic attack
of a halide anion to afford â-halo-â,γ-unsaturated func-
â,γ-Unsaturated enones can be found in some natural
products1 and are important intermediate in organic
synthesis. However, due to the possible migration of the
carbon-carbon double bond from the â,γ-position to the
R,â-position, it is challenging to synthesize â,γ-unsatur-
ated enones selectively. â,γ-Unsaturated enones are
usually obtained indirectly by rather sophisticated long
and tedious procedures. Some typical methodologies for
the preparation of â,γ-unsaturated ketones are sum-
marized as follows: (1) acylation of olefins;2 (2) oxidation
of pent-4-en-2-ol with Corey’s oxidant;3 (3) Zn-Ag couple-
promoted reaction of allylic bromide with nitriles;4 and
(4) oxidative cleavage of phenylselenolates.5 Thus, it is
still highly desirable to develop new and efficient meth-
odologies for the synthesis of â,γ-unsaturated enones.
1,2-Allenic ketones constitute an important class of
compounds with numerous applications in organic syn-
(6) (a) Patai, S., Ed. The Chemistry of Ketenes, Allenes and Relate
Compounds; Wiley: New York, 1980. (b) Schuster, H. F., Coppola, G.
M., Ed. Allenes in Organic Syntheses; Wiley: New York, 1984. (c)
Landor, S. R., Ed. The Chemistry of the Allenes; Academic Press: New
York, 1982; Vols. 1-3.
(7) (a) Hashmi, A. S. K. Angew. Chem., Int. Ed. 2000, 39, 3590. (b)
Nagao, Y.; Lee, W. S.; Komaki, Y.; Sano, S.; Shiro, M. Chem. Lett. 1994,
597. (c) Nagao, Y.; Lee, W. S.; J eong, I.-Y.; Shiro, M. Tetrahedron Lett.
1995, 36, 2799. (d) Sanche´z-obrego´n, R.; Barrios, H.; Ort´ız, B.; Yuste,
F. Rev. Roum. Chim. 1986, 31, 709. (e) Bertrand, M.; Le Gras, J . Bull.
Soc. Chim. Fr. 1967, 4336.
* Corresponding author.
(1) (a) Noda, Y.; Hashimoto, H.; Norizuki, T. Heterocycles 2001, 55,
1839. (b) Walker, R. P.; Thompson, J . E.; Faulkner, D. J . J . Org. Chem.
1980, 45, 4976. (c) Thompson, J . E.; Walker, R. P.; Wratten, S. J .;
Faulkner, D. J . Tetrahedron 1982, 38, 1865. (d) Paterson, I.; Hulme,
A. N. Tetrahedron Lett. 1990, 31, 7513. (e) Uotani, K.; Naganawa, H.;
Konda, S.; Aogagi, T.; Umezawa, H. J . Antibiotics 1982, 135, 1495. (f)
Thomas, A. F.; Thommen, W.; Willhalm, B.; Hagaman, E. W.; Wenkert,
E. Helv. Chim. Acta 1974, 57, 2055. (g) Appendino, G.; Nano, G. M.;
Viterbo, D.; De Munno, G.; Cisero, M.; Palmisano, G.; Aragno, M. Helv.
Chim. Acta 1991, 74, 495.
(2) (a) Newman, M. S.; Both, W. T. J . Am. Chem. Soc. 1945, 67,
154. (b) Calas, R.; Dunogue`s, J .; Pillot, J .-P.; Biran, C.; Pisciotti, F.;
Arreguy, B. J . Orgnomet. Chem. 1975, 85, 149. (c) Kosugi, M.; Shimizu,
Y.; Migita, T. J . Orgnomet. Chem. 1977, 129, C36.
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Chem. 1972, 37, 776.
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Am. Chem. Soc. 1980, 102, 3904. (b) Scarborough, R. M.; Smith, A. B.,
III. Tetrahedron Lett. 1977, 4361.
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B 2000, 39, 643. (b) Lu, X. Y.; Zhang, C. M. Tetrahedron Lett. 1997,
38, 4831. (c) Marshall, J . A.; Tang, Y. J . Org. Chem. 1993, 58, 3233.
(d) Bol’shedvorskaya, R. L.; Pavlova, G. A.; Garrilov, L. D.; Alekseeva,
N. V.; Vereschagin, L. I. J . Org. Chem. USSR 1992, 27, 1927. (e) Sujita,
T.; Eida, M.; Ito, H.; Komatsu, N.; Abe, K.; Suama, M. J . Org. Chem.
1987, 52, 3789. (f) Cristau, H.-J .; Viala, J .; Chritol, H. Bull. Soc. Chim.
Fr. 1985, 980. (g) Gras, J .-L.; Galle´dou, B. S. Bull. Soc. Chim. Fr. 1983,
II-89. (h) Walsh, C. Tetrahedron 1982, 38, 871. (i) Cristau, H. J .; Viala,
J .; Chritol, H. Tetrahedron Lett. 1982, 23, 1569. (j) Santelli, C.
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(9) For some of our recent work in this area, see: (a) Ma, S.; Wu, S.
Chem. Commun. 2001, 441. (b) Ma, S.; Zhao, S. J . Am. Chem. Soc.
2001, 123, 5578. (c) Ma, S.; Shi, Z. Chem. Commun. 2002, 540. (d)
Ma, S.; Gao, W. Synlett 2002, 65. (e) Ma, S.; Yin, S.; Li, L.; Tao, F.
Org. Lett. 2002, 4, 505. (f) Ma, S.; J iao, N.; Zhao, S.; Hou, H. J . Org.
Chem. 2002, 67, 2837. (g) Ma, S.; Duan, D.; Wang, Y. J . Comb. Chem.
2002, 4, 239. (h) Ma, S.; Yu, Z. Angew. Chem., Int. Ed. 2002, 41, 1775.
(i) Ma, S.; Gao, W. Org. Lett. 2002, 4, 2989. (j) Ma, S.; Gao, W. J . Org.
Chem. 2002, 67, 6104.
10.1021/jo034633i CCC: $25.00 © 2003 American Chemical Society
Published on Web 10/24/2003
8996
J . Org. Chem. 2003, 68, 8996-9002

Synthesis of â,γ-Unsaturated Enones and R-Pyrones
SCHEME 1
SCHEME 2
SCHEME 3
SCHEME 4
tionalized alkenes.10 Of particular interest, we observed
that â-halo-â,γ-unsaturated enones can be formed highly
selectively from 1,2-allenic ketones.11 On the basis of
these results, we reasoned that in principle 1,2-allenic
ketones may accept any nucleophilic attack. However, for
the reaction with malonates, due to the existence of three
carbonyl groups, there is a great tendency that the
carbon-carbon double bond may migrate to form com-
pounds with a conjugated carbon-carbon double bond
(Scheme 1). Thus, the challenge is how to control the
extent of migration of the â,γ carbon-carbon double bond
and the stereoselectivity of the reaction. In a previous
communication, we have demonstrate that 1,2-allenic
ketones can react with malonates to afford R-pyrones.12
In this paper, we wish to disclose the details of this
nucleophilic conjugate addition.
SCHEME 5
SCHEME 6
Resu lts a n d Discu ssion
Syn th esis of th e Sta r tin g Ma ter ia ls. A number of
methods13 were reported for the preparation of 1,2-allenic
ketones and all of the starting 1,2-allenic ketones used
in this study were prepared through the application of
known procedures (in some cases, with slight modifica-
tion). 1-Substituted 1,2-allenyl ketones 1a -e and 1,2-
propadiennyl ketone 1w were synthesized via the elimi-
nation of the corresponding 4-bromo-3-penten-2-ones
(Scheme 2).14 1f was obtained by the oxidation of the
corresponding allenic alcohol15 with the Swern oxidation
procedure (Scheme 3).16 3,3-Disubstituted-1,2-allenyl
ketones 1g-h (Scheme 4),17 3-monosubstituted-1,2-allen-
yl ketone 1i-k (Scheme 5),17 and 1,3-disubstituted-1,2-
allenyl ketones 1l-r (Scheme 6) were prepared via the
SCHEME 7
reaction of the corresponding 1,2-allenyllithiums with
N,N-dimethyl amides. 1,3-Nonsubstituted-1,2-allenyl ke-
tones 1s-v were prepared by the addition of allenic
magnesium bromide to an aldehyde,18 followed by the
oxidation with DMP19 (Scheme 7). 1,2-Propadienyl ke-
tones 1x20 and 1y21 were prepared by the addition of
allenic magnesium bromide with the corresponding esters
at -78 °C (Scheme 8).
(10) For some of our recent work in this area, see: (a) Ma, S.; Wei,
Q. Eur. J . Org. Chem. 2000, 1939. (b) Ma, S.; Li, L.; Wei, Q.; Xie, H.;
Wang, G.; Shi, Z.; Zhang, J . Pure Appl. Chem. 2000, 9, 1739. (c) Ma,
S.; Li, L.; Wei, Q.; Xie, H.; Wang, G.; Shi, Z.; Zhang, J . Synthesis 2001,
5, 713. (d) Ma, S.; Li, L. Synlett 2001, 1206. (e) Ma, S.; Wei, Q. J . Org.
Chem. 1999, 64, 1026.
(11) Ma, S.; Li, L.; Xie, H. J . Org. Chem. 1999, 64, 5325.
(12) Ma, S.; Yin, S.; Li, L.; Tao, F. Org. Lett. 2002, 4, 505.
(13) (a) For recent reviews, see: Li, L.; Ma, S. Chin. J . Org. Chem.
2000, 20, 850. (b) Hashmi, A. S. K.; Ruppert, T. L.; Kno¨fel, T.; Bats, J .
W. J . Org. Chem. 1997, 62, 7295. (c) Marshall, J . A.; Wang, X.-j. J .
Org. Chem. 1992, 57, 3387. (d) Fukuda, Y.; Shiragami, H.; Utimoto,
K.; Nozaki, H. J . Org. Chem. 1991, 56, 5816. (e) Cazes, B.; J ulia, S.
Synth. Commun. 1977, 7, 273. (f) Aksnes, G.; Frøyen, P. Acta Chem.
Scand. 1968, 22, 2347.
(17) (a) Ma, S.; Li, L.; Xie, H. J . Org. Chem. 1999, 64, 5325. (b)
Clinet, J . C.; Linstumelle, G. Nouv. J . Chem. 1977, 1, 373. (c) Ma, D.;
Yu, Y.; Lu, X. J . Org. Chem. 1989, 54, 1105.
(14) (a) Buono, G. Synthesis 1981, 872. (b) Ma, S.; Li, L. Org. Lett.
2000, 2, 941.
(15) (a) Mukayama, T.; Hurada, T. Chem. Lett. 1981, 621. (b) Place,
P.; Vernie´re, C.; Gore´, J . Tetrahedron 1981, 37, 1359.
(16) Omura, K.; Swern, D. Tetrahedron 1978, 34, 1651.
(18) (a) Speicher, A.; Bomm, V.; Eicher, T. J . Prakt. Chem. 1996,
338, 588. (b) Hashmi, A. S. K.; Ruppert, T. L.; Kno¨fel, T.; Bats, J . W.
J . Org. Chem. 1997, 62, 7295.
(19) Dess, D. B.; Martin, J . C. J . Am. Chem. Soc. 1991, 113, 7277.
(20) Nagao, Y.; Lee, W.-S.; Kim, K. Chem. Lett. 1994, 389.
J . Org. Chem, Vol. 68, No. 23, 2003 8997

Ma et al.
SCHEME 8
4 (entries 6, 8, and 9, Table 1) indicates that the malonate
moiety in the products can stabilize the carbon-carbon
double bond under conditions A.
Encouraged by the above results, we envisioned that
any substitutes at the 3-position of the allenyl group
might also contribute to the control of the isomerization
of the â,γ-unsaturated carbon-carbon double bond. In
fact, to our surprise, 3,3-disubstituted-1,2-allenyl ketones,
i.e., 5-methylhexa-3,4-dien-2-one 1g and 2-methylundeca-
2,3-dien-5-one 1h , reacted with diethyl malonate forming
â,γ-unsaturated enones 3g and 3h , respectively. In these
two compounds the carbon-carbon double bond was kept
at the original position (entries 1-3, Table 2). It is
interesting to observe that 3-monoalkyl-substituted-1,2-
allenyl ketones (1i to 1r ) reacted smoothly with diethyl
malonate to afford the corresponding â,γ-unsaturated
enones 3 in good yields highly stereoselectively (E:Z >
96:4) (entries 4-13, Table 2). The configurations of the
carbon-carbon double bond of the products 3i-r (entries
TABLE 1. K2CO3-Ca ta lyzed 1, 4-Ad d ition of
r-Su bstitu ted γ-Non su bstitu ted Allen ic Keton es w ith
Dieth yl Ma lon a te
1
yield (%)
temp
entry
R3
R4
solvent (°C) time
4
6
1
2
3
4
5
6
7
8
9
n-C4H9 CH3 (1a )
n-C4H9 CH3 (1a )
n-C4H9 CH3 (1a )
n-C4H9 CH3 (1a )
n-C4H9 CH3 (1a )
n-C4H9 CH3 (1a )
n-C6H13 CH3 (1c)
CH3CN rt
CH2Cl2 60
16 h 48 (4a ) 25 (6a )
2.5 d 57 (4a ) 28 (6a )
10 h 36 (4a ) 34 (6a )
24 h 65 (4a ) 27 (6a )
1
4-13, Table 2) were determined by the H-1H NOESY
DMF
EtOH
a
rt
rt
rt
spectra of E/ Z-3j and E-3o (Figure 1).
The most reactive unsubstituted propadienyl ketones
1s-v also underwent conjugate addition with diethyl
malonate. The results are shown in Table 3. In contrast
to the reaction discussed above, the formation of a
mixture of carbon-carbon double bond isomers was
observed. The general ratio of â,γ-unsaturated enones 3
to R,â-unsaturated enones 4 was ∼3/1 (determined by 1H
NMR spectra) whereas in dichloromethane the ratios
drop to ∼1/1. Efforts such as other combinations of
weaker bases (KHCO3, KF, KOAc, NaHCO3, NaOAc)
with solvents (CH3CN, CH2Cl2, acetone) were made to
improve the stereoselectivity of the reaction, but failed.
A rationale for the observed regio- and stereochemistry
is shown in Scheme 9. In this mechanism, a dienolate
intermediate is produced by the attack of the anionic
nucleophile from the less hindered side at the â-carbon
of the allenic ketones. Thus, the configuration of the
carbon-carbon double bond in the pertinent final product
3i-r is E. The two π systems in the resulting dienolate
are orthogonal to each other.22 Selective protonation at
the R-carbon afforded â,γ-unsaturated enones 3.22 When
groups R1 and R2 in the substrate are hydrogens, due to
the lack of stabilization effect of substituents to the
unreacted carbon-carbon double bond, it has a tendency
to migrate to form thermodynamically more stable prod-
ucts 4, especially in the basic environment. What is
surprising is that with propadienyl ketones 1s-v the
carbon-carbon double bond in the initially formed 1,4-
adduct did not completely transform to product 4 as
1-substituted-3-unsubstituted-1,2-allenyl ketones did.
4 d
8 h
47 (4a )
57 (4a ) 3 (6a )
acetone 60
acetone reflux 12 h 67 (4c) 27 (6c)
acetone reflux 8 h 56 (4e)
n-C5H11 n-C8H17 (1f) acetone reflux 24 h 85 (4f)
Bn
CH3 (1e)
a
A mixture of DMF and CH2Cl2 (1:1) was used as the solvent.
K2CO3-Ca ta lyzed 1,4-Ad d ition of 1,2-Allen ic Ke-
ton es w ith Dieth yl Ma lon a te. We examined the reac-
tion of 1-(n-butyl)-1,2-propadienyl methyl ketone (1a )
with diethyl malonate using K2CO3 as a catalyst in
different solvents (entries 1-6, Table 1). The reactions
in DMF, EtOH, and CH3CN at room temperature af-
forded a mixture of â,γ-unsaturated enone 4a with the
carbon-carbon double bond conjugated with the two
ethoxycarbonyl groups and R-pyrone 6a in good combined
yields and low selectivities. The reaction in DMF was
faster than those in EtOH and CH3CN (entries 1, 3, and
4, Table 1). In dichloromethane, it took 2.5 days for the
reaction to produce 57% of 4a and 28% of 6a at 60 °C
(entry 2, Table 1). However, it is interesting to observe
that the corresponding reaction in acetone at 60 °C
afforded 4a with modest yields highly selectively together
with only 3% of 6a (entry 6, Table 1). In acetone, the
concentration of active nucleophile may be kept level to
ensure the 1,4-addition reaction while at the same time
inhibit the isomerization-lactonization reaction. Thus,
the key point in carrying out this experiment is to choose
a modest polar solvent and control the reaction time. In
the following cases we carried out the reaction in acetone
with heating using 10% K2CO3 as the catalyst (conditions
A).
The new synthetic method has several noteworthy
features: (1) for 3-mono- or disubstituted-1,2-allenyl
ketones, only â,γ-unsaturated enones with an unmigrated
carbon-carbon double bond were produced; (2) for 3-mono-
substituted-1,2-allenyl ketones the corresponding 3 were
formed with an excellent stereoselectivity (E:Z > 96:4);
(3) polyfunctionalities in the products made them ready
for further transformation; (4) the present catalytic
The results of other 1-substituted-3-unsubstituted-1,2-
allenyl ketones with diethyl malonate catalyzed by K2-
CO3 in acetone affording â,γ-unsaturated enones 4 are
given in Table 1 (entries 7-9). The highly selective
migration of the carbon-carbon double bond leading to
(21) (a) Couffignal, R.; Gaudemar, M. Bull. Soc. Chim. Fr. 1970,
3157. (b) Couffignal, R.; Gaudemar, M. Bull. Soc. Chim. Fr. 1969, 898.
(c) Couffignal, R.; Gaudemar, M. Bull. Soc. Chim. Fr. 1969, 3218. (d)
Couffignal, R.; Gaudemar, M. Acad. Sci. Paris 1968, 266, 224. (e)
Kumar, K.; Kapur, A.; Ishar, M. P. S. Org. Lett. 2000, 2, 787.
(22) A similar pathway has been used to explain the regioselectivity
of the addition of thioe and amines to the conjugated allenic ketones
and esters: Sugita, T.; Eida, M.; Ito, H.; Komatsu, N.; Abe, K.; Suama,
M. J . Org. Chem. 1987, 52, 3789.
8998 J . Org. Chem., Vol. 68, No. 23, 2003

Synthesis of â,γ-Unsaturated Enones and R-Pyrones
TABLE 2. K2CO3-Ca ta lyzed 1,4-Ad d ition of γ-Su bstitu ted Allen ic Keton es w ith Dieth yl Ma lon a te
1
3
temp
(°C)
entry
R1
R2
R3
R4
time
yield (%)
E:Zb
1
2a
3
CH3
CH3
CH3
CH3
H
H
H
H
H
H
H
CH3 (1g)
reflux
55
9 h
75 (3g)
83 (3g)
58 (3h )
75 (3i)
81 (3j)
58 (3k )
84 (3l)
71 (3m )
76 (3n )
47 (3o)
83 (3p )
78 (3q)
75 (3r )
CH3
CH3 (1g)
11 h
21 h
12 h
12 h
24 h
4 d
CH3
n-C6H13 (1h )
CH3 (1i)
CH3 (1j)
n-C7H15 (1k )
CH3 (1l)
n-C7H15 (1m )
Ph (1n )
Toyl (1o)
CH3 (1p )
n-C7H15 (1q)
Ph (1r )
reflux
reflux
reflux
reflux
55
4
n-C7H15
n-C4H9
n-C7H15
n-C5H11
n-C5H11
n-C5H11
n-C5H11
n-C5H11
n-C5H11
n-C5H11
>99:1
98:2
5
H
6
H
96:4
7
H
n-C4H9
n-C4H9
n-C4H9
n-C4H9
n-C5H11
n-C5H11
n-C5H11
>99:1
95:5
8
H
55
2 d
9
H
55
3 d
>99:1
98:2
>99:1
>99:1
>99:1
10
11
12
13
H
60
2 d
H
55
2.5 d
3 d
H
55
H
55
3 d
a
b
DMF was used as the solvent. Determined by 1H NMR spectra.
SCHEME 9
F IGURE 1. NOE study of 3j and 3o.
TABLE 3. K2CO3-Ca ta lyzed 1,4-Ad d ition of
r,γ-Non su bstitu ted Allen ic Keton es w ith Dieth yl
Ma lon a te
environment, unsaturated enones can cyclize to form
R-pyrone. Thus, combining the three sequential processes
we can develop an efficient method for the synthesis of
R-pyrone with diversity and regioselectivity since the
allenic ketones can accommodate four different substi-
tuents at the different locations ready for assembly into
the different locations of R-pyrones.
As revealed in Table 4, 1-substituted-3-unsubstituted-
1,2-allenyl ketones can undergo this K2CO3-catalyzed
sequential Michael addition-carbon-carbon double bond
migration-lactonization readily with diethyl malonate
in acetone, ethanol, and DMF. Structural variation in the
1
temp
solvent (°C)
entry
R4
time
yield (%) (3:4)a
1
2
3
4
5
6
7
8b
n-C4H9 (1s) acetone 55 55 min 88 (3s:4s ) 2.9:1)
n-C5H11 (1t) acetone 55 50 min 89 (3t:4t ) 3.5:1)
n-C6H13 (1u ) acetone 55 50 min 86 (3u :4u ) 3.7:1)
n-C8H17 (1v) acetone 55 50 min 74 (3v:4v ) 3.6:1)
n-C4H9 (1s) CH2Cl2
n-C5H11 (1t) CH2Cl2
n-C6H13 (1u ) CH2Cl2
50 11 h
50 11 h
50 10 h
66 (3s:4s ) 2.7:1)
66 (3t:4t ) 1.1:1)
69 (3u :4u ) 0.9:1)
71 (3t:4t ) 3.5:1)
n-C5H11(1t) acetone 55 8 h
a
b
Determined by the 300-MHz 1H NMR spectra; 10% Na2CO3
(23) (a) Corey, E. J .; Kozikowski, A. P. Tetrahedron Lett. 1975, 2389.
(b) Bloomer, J . L.; Zaidi, S. M. H.; Strupczewski, J . T.; Brosz, C. S.;
Gudzyk, L. A. J . Org. Chem. 1974, 39, 3615. (c) Bryson, T. A.; Donelson,
D. M. J . Org. Chem. 1977, 42, 2930. (d) For a review see: Money, T.
Chem. Rev. 1970, 70, 553.
(24) For a discussion of the chemistry of R-pyrone, see also: Stauton,
J . Comprehensive Organic Chemistry; Samnes, P. G., Ed.; Pergamon
Press: Oxford, UK, 1979; Vol. 4, pp 629-646.
(25) (a) Hayashi, Y.; Yuki, Y.-i.; Matsumoto, T.; Sakan, T. Tetrahe-
dron Lett. 1977, 3637. (b) Chen, K. K.; Kovarikova, A. J . Pharm.
Sci.1967, 56, 1535. (c) Kupchan, S. M.; Moniot, J . L.; Sigel, C. W.;
Hemingway, R. J . J . Org. Chem. 1971, 36, 2611.
(26) For a synthesized R-pyrone with anti-HIV activity, see: Prasad,
J . V. N. V.; Para, K. S.; Lunney, E. A.; Ortwine, D. F.; Dunbar, J . B.;
Ferguson, D., J r.; Tummino, P. J .; Hupe, D.; Tait, B. D.; Domagala, J .
M.; Humblet, C.; Bhat, T. N.; Liu, B.; Guenin, D. M. A.; Baldwin, E.
T.; Erickson, J . W.; Sawyer, T. K. J . Am. Chem. Soc. 1994, 116, 6989.
was used as the catalyst.
reaction is operationally simple; and (5) commercial
solvents are good enough for this reaction.
Seq u en t ia l Mich a el Ad d it ion -Ca r b on -Ca r b on
Dou ble Bon d Migr a tion -La cton iza tion Syn th esis
of r-P yr on es. R-Pyrones are a class of important inter-
mediates utilized in organic synthesis23,24 and a com-
monly observed structural unit in many naturally occur-
ring products, which show a broad range of biological
activities.25,26 During the course of our study of transfor-
mation of the above products, we found that in a basic
J . Org. Chem, Vol. 68, No. 23, 2003 8999

Ma et al.
TABLE 4. K2CO3-Ca ta lyzed or -P r om oted Sequ en tia l Mich a el Ad d ition -Ca r bon -Ca r bon Dou ble Bon d
Migr a tion -La cton iza tion of Allen ic Keton es w ith Dieth yl Ma lon a te
1
R3
temp
(°C)
yield (%)
entry
R1
R2
R4
solvent
time
(6)
1
2
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
n-C4H9
n-C4H9
n-Et
n-Et
n-Et
n-C6H13
allyl
allyl
Bn
Me (1a )
acetone
DMF
reflux
80
reflux
80
reflux
55
reflux
reflux
reflux
60
48 h
7 h
12 h
12 h
20 h
3 d
64a (6a )
55 (6a )
53 (6b)
50 (6b)
33 (6b)
81 (6c)
54 (6d )
90 (6d )
92 (6e)
90 (6e)
56 (6f)
65 (6s)
63 (6u )
69 (6v)
74 (6w )
71 (6x)
56 (6x)
69 (6y)
Me (1a )
3
Me (1b)
EtOH
4
Me (1b)
DMF
5
Me (1b)
acetone
acetone
EtOH
6
Me (1c)
7
Me (1d )
15 h
20 h
21 h
2.5 h
2 d
8
Me (1d )
acetone
acetone
DMF
acetone
acetone
acetone
acetone
EtOH
9
Me (1e)
10
11
12
13
14
15
16
17
18
Bn
Me (1e)
n-C5H11
H
n-C8H17 (1f)
n-C4H9 (1s)
n-C6H13 (1u )
n-C8H17 (1v)
Me (1w )
Ph (1x)
reflux
55
9 h
H
55
9 h
H
55
9 h
H
60
1.5 h
4 h
H
acetone
EtOH
CH2Cl2
reflux
reflux
reflux
H
Ph (1x)
Bn (1y)
1.5 h
40 h
H
a
1 equiv of K2CO3 was used.
SCHEME 10
SCHEME 11
1,2-allenic ketone component has also been examined. As
showed in Table 4, R3 can be alkyl, allyl, and benzyl
groups and R4 can be alkyl, phenyl, and benzyl groups.
Propadienyl butyl ketone (1s) reacted smoothly with
diethyl malonate in the presence of 10% K2CO3 as the
catalyst giving the corresponding R-pyrone (6s) in 65%
yield (entry 12, Table 4). Changing R4 from methyl to
octyl and benzyl, the yields are almost the same (entries
14 and 16, Table 4). The sequential reaction of 1y even
proceeds in dichloromethane to yield R-pyrone 6y with
prolonged time (entry 18, Table 4).
Next we examined the cyclization reaction of other 1,2-
allenyl ketones with diethyl malonate. Generally speak-
ing, the yields of the reactions of 3-substituted-1,2-allenyl
ketones with diethyl malonate were notably low. The
reaction of nona-3,4-dien-2-one 1j with diethyl malonate
in EtOH yielded 6j in 38% yield, whereas in DMF the
yield of 6j is 54% (Scheme 10). When it comes to 1,3-
disubstituted-1,2-allenyl ketone, R-pyrone was not formed.
According to the results of 1,4-addition, instead of the
intermediacy of 5, it is believed that R-pyrone was formed
via keto-ester cyclization of â,γ-unsaturated enones 4
(Scheme 11).
sequential carbon-carbon double bond migration-cy-
clization protocol for the synthesis of various substituted
R-pyrones starting from the easily available 1,2-allenic
ketones with diethyl malonate. We found that the sub-
stituent of substrates has a great effect on the reaction.
The 3-substituent of the allenyl group can stabilize the
carbon-carbon double bond of the 1,4-addition product.
The reaction shows good 1,4-regio- and E-stereoselecivity.
Further investigation in this area is being intensively
carried out in our laboratory.
Exp er im en ta l Section
Sta r tin g Ma ter ia ls. Compounds 3-butylpenta-3,4-dien-2-
one (1a ),11a 3-ethylpenta-3,4-dien-2-one (1b),11a 3-allylpenta-
3,4-dien-2-one (1d ),11b 3-benzylpenta-3,4-dien-2-one (1e),11b
5-methylhexa-3,4-dien-2-one (1g),14b 2-methylundeca-2,3-dien-
5-one (1h ),14 dodeca-3,4-dien-2-one (1i),14a,c nona-3,4-dien-2-
one (1j),14a,b octa-1,2-dien-4-one (1s),15 nona-1,2-dien-4-one
Con clu sion
In conclusion, we have developed an efficient method-
ology for the synthesis of â,γ-unsaturated ketones and a
9000 J . Org. Chem., Vol. 68, No. 23, 2003

Synthesis of â,γ-Unsaturated Enones and R-Pyrones
(1t),15 penta-3,4-dien-2-one (1w ),11a 1-phenylbuta-2,3-dien-1-
one (1x),17 and 1-phenylpenta-3,4-dien-2-one (1y)18 are pre-
pared as reported.
1.52 (m, 2 H), 1.18-1.41 (m, 16 H), 0.78-0.91 (m, 6 H); 13C
NMR (75 MHz, CDCl3) δ 213.0, 202.3, 97.6, 95.6, 39.2, 32.0,
31.9, 29.5, 29.3, 29.3, 29.3, 29.2, 28.1, 25.1, 22.8, 14.3; MS m/z
(%) 264 (M+, 1.80), 57 (100); HRMS m/z (EI) calcd for C18H32
O
Syn th esis of 3-h exylp en ta -3,4-d ien -2-on e (1c):11 A mix-
ture of acetoacetone (10.0 g, 0.1 mol), 1-bromohexane (15.5 mL,
18.2 g, 0.11 mol), potassium carbonate (15.2 g, 0.11 mol), and
potassium iodide (8.3 g, 0.05 mol) in acetone (50 mL) was
refluxed for 43 h. After filtration and evaporation, the resulting
crude 3-hexylpenta-2,4-dione was directly added dropwise into
an ice-cold solution of PPh3Br2 (prepared from PPh3 (21.6 g,
83 mmol) and Br2 (17.8 g, 80 mmol)) in dichloromethane (100
mL). The mixture was stirred until the evolution of hydrogen
bromide ceased. After removal of triphenylphosphine oxide by
addition of ether, the residue was dissolved in 100 mL of
acetonitrile followed by the addition of triethylamine (7.5 g,
75 mmol). After being stirred for 23 h at 80 °C, the precipitate
was removed by filtration and the resulting mixture was
washed with diluted hydrochloric acid (2 × 30 mL) and
saturated NaCl solution (2 × 50 mL). The combined organic
phase was dried over magnesium sulfate. After evaporation,
the residue was purified by chromatography on silica gel
(eluent, hexane/ether 100/1) to afford 4.5 g (36%) of 1c: liquid;
264.24532, found 264.25030.
P r ep a r a tion of 1,2-Allen ic Keton es 1l-r . Typ ica l P r o-
ced u r e. Syn th esis of 3-bu tyld eca -3,4-d ien -2-on e (1l): To
a solution of oct-1-en-3-yne (1.1 g, 10 mmol) in tetrahydrofuran
(60 mL) was added 4 mL of 2.5 M n-BuLi at -40 °C under
argon. After being stirred at -25 °C for 0.5 h, the solution
was recooled to -78 °C and treated with a solution of N,N-
dimethyl acetamide (5.1 g, 30 mmol) in tetrahydrofuran (10
mL) for another 2 h. Then the reaction mixture was trans-
ferred to 400 mL of 0.2 N HCl solution. After the usual workup,
the residue was purified by flash chromatography on silica gel
(eluent: hexane/ether 100/1) to afford 3.2 g (55%) of 1l: liquid;
IR (neat) 1944, 1680 cm-1; 1H NMR (300 MHz, CDCl3) δ 5.59-
5.39 (m, 1 H), 2.17 (s, 3 H), 2.20-2.07 (m, 4 H), 1.50-1.11 (m,
10 H), 0.95-0.82 (m, 6 H); 13C NMR (75 MHz, CDCl3) δ 212.4,
199.6, 109.6, 95.5, 31.3, 30.1, 28.7, 28.2, 26.9, 26.2, 22.4, 22.3,
14.0, 13.9; MS m/z (%) 208 (2.77), 43 (100); HRMS m/z (EI)
calcd for C14H24O 208.1827, found 208.1795.
IR (neat) 1933, 1682, 1466, 1358, 1242, 1020, 843, 725 cm-1
;
P r ep a r a tion of 1,2-Allen ic Keton es 1u -v. Typ ica l
P r oced u r e. Syn th esis of d eca -1,2-d ien -4-on e (1u ):16 To a
suspension of magnesium turnings (3.6 g, 0.15 mol) in dry Et2O
(60 mL) was added HgCl2 (0.1 g). After being stirred for 2.5 h
at room temperature, the mixture was cooled to 0 °C followed
by the addition of propargyl bromide (10.7 mL, 0.12 mol). After
an additional 1 h, the mixture was cooled to -40 °C and
treated with heptanal (16.0 mL, 0.11 mol). After 1 h, the
mixture was warmed to room temperature naturally and
poured into a solution of NH4Cl. After the usual workup, the
residue was distilled under reduced pressure to give dec-1-
yn-4-ol (bp 99-100 °C/20 mmHg) (15.9 g, 93%).
1H NMR (300 MHz, CDCl3) δ 5.18 (t, J ) 3.2 Hz, 2 H), 2.29 (s,
3 H), 2.12-2.20 (m, 2 H), 1.22-1.40 (m, 8 H), 0.86 (t, J ) 7.2
Hz, 3 H); 13C NMR (75 MHz, CDCl3) δ 217.1, 199.1, 109.4, 79.7,
31.9, 29.1, 28.0, 27.2, 26.3, 22.8, 14.3; MS m/z (%) 166 (M+,
0.18), 43 (100); HRMS m/z (EI) calcd for C11H18O 166.13576,
found 166.13514.
Syn th esis of 3-p en tyld od eca -1,2-d ien -4-on e (1f):12,13
A
suspension of stannous chloride (2.39 g, 12.6 mmol), 1-bro-
mooct-2-yne (1.8 g, 10.1 mmol), and sodium iodide (1.85 g, 12.4
mmol) in DMF (20 mL) was stirred at room temperature for 1
h. After the reaction mixture was cooled to 0 °C, a solution of
1.4 g (9.9 mmol) of nonanal in 10 mL of DMF was added and
the mixture was stirred at 0 °C for another 24 h followed by
quenching with water. Extraction, drying, evaporation, and
flash chromatography on silica gel (hexane/ether 15:1) afforded
1.04 g of the crude alcohol. To a solution of 0.7 mL (6.2 mmol)
of oxalyl chloride in 10 mL of dichloromethane was added 1.1
mL (12.4 mmol) of DMSO in 10 mL of CH2Cl2 at -78 °C. After
5 min, a solution of 1.04 g of the alcohol in 10 mL of
dichloromethane was added. The mixture was stirred at -78
°C for another 30 min followed by the addition of 6.0 mL (40
mmol) of triethylamine. Then the mixture was warmed to 0
°C and stirred at 0 °C for another 10 min. The mixture was
diluted with ether, washed with 10% HCl solution, extracted
with ether, and dried over anhydrous magnesium sulfate.
Evaporation and flash chromatography on silica gel (petroleum
ether/ethyl acetate 100/1) afforded 0.84 g (82%) of 1f: liquid;
A solution of the above prepared alcohol (8.8 g, 57 mmol) in
dichloromethane (100 mL) was added to a solution of DMP
(29.5 g, 69 mmol) in dichloromethane (400 mL) with stirring.
After 2 h, the homogeneous reaction mixture was diluted with
500 mL of ether and the resulting suspension was added to
200 mL of 1 N sodium hydroxide. After the usual workup, the
residue was purified by flash chromatography on silica gel
(eluent: hexane/ethyl acetate 100/1) to afford 4.7 g (54%) of
1u : liquid; IR (neat) 3066, 1961, 1934, 1684, 849 cm-1 1H
;
NMR (300 MHz, CDCl3) δ 5.63 (t, J ) 6.6 Hz, 1 H), 5.15 (d, J
) 6.6 Hz, 2 H), 2.52 (t, J ) 8.4 Hz, 2 H), 1.51 (t, J ) 7.2 Hz,
2 H), 1.12-1.29 (m, 6 H), 0.79 (t, J ) 6.6 Hz, 3 H); 13C NMR
(75 MHz, CDCl3) δ 216.8, 201.2, 96.8, 79.5, 39.4, 31.8, 29.0,
24.7, 22.7, 14.2; MS m/z (%) 153 (M+ + 1, 2.20), 43 (100);
HRMS m/z (EI) calcd for C10H16O 152.12012, found 152.11928.
IR (neat) 1934, 1681, 1466, 1378, 1171, 1091, 841 cm-1 1H
;
Gen er a l P r oced u r e for K2CO3-Ca ta lyzed 1,4-Ad d ition
of 1,2-Allen ic Keton es w ith Dieth yl Ma lon a te. A solution
of 1 (1.2 mmol), diethyl malonate (1.0 mmol), and 15.8 mg (10
mol %) of K2CO3 in 2 mL of acetone was heated to 60 °C with
stirring. After the reaction was over as monitored by TLC, the
solvent was evaporated and the crude product was purified
by chromatography on silical gel (petroleum ether/ethyl acetate
10/1) to afford 3 or 4 or 6 or their mixture.
NMR (300 MHz, CDCl3) δ 5.13 (t, J ) 2.9 Hz, 2 H), 2.60 (t, J
) 7.5 Hz, 2 H), 2.08-2.18 (m, 2 H), 1.42-1.60 (m, 2 H), 1.18-
1.41 (m, 16 H), 0.84 (t, J ) 6.5 Hz, 6 H); 13C NMR (75 MHz,
CDCl3) δ 216.4, 201.8, 108.8, 79.6, 39.4, 32.0, 31.6, 29.6, 29.5,
29.4, 27.7, 26.4, 25.3, 22.9, 22.6, 14.3, 14.2; MS m/z (%) 250
(M+, 3.28), 57 (100); HRMS m/z (EI) calcd for C17H30
O
250.22966, found 250.22745.
Syn th esis of octa d eca -9,10-d ien -8-on e (1k ):14 To a solu-
tion of deca-1,2-diene (4.4 g, 32 mmol) in THF (100 mL) was
added n-BuLi (2.5 M in cyclohexane, 12 mL, 30 mmol) at -70
°C. Then the mixture was stirred for 1 h at -50 to -40 °C
followed by the dropwise addition of N,N-dimethyl octamide
(5.1 g, 30 mmol) at -78 °C. After 2 h at this temperature, the
resulting solution was slowly transferred into an ice-cold
aqueous HCl solution (0.2 N, 200 mL). Extraction with ether,
drying over anhydrous magnesium sulfate, rotary evaporation,
and flash chromatography on silica gel (eluent: hexane/ether
40/1) afforded 3.1 g (39%) of 1k : liquid; IR (neat) 1947, 1737,
Syn th esis of eth yl 2-(eth oxyca r bon yl)-3-m eth yl-4-bu -
t yl-5-oxo-2-h exen oa t e (4a ) a n d 3-(et h oxyca r b on yl)-4,6-
d im eth yl-5-bu tyl-2-p yr a n on e (6a ): A solution of 1a (169.7
mg, 1.2 mmol), diethyl malonate (164.5 mg, 1.0 mmol), and
16.7 mg (10 mol %) of K2CO3 in 2 mL of acetone was heated to
60 °C with stirring. After the reaction was over as monitored
by TLC, the solvent was evaporated and the crude product
was purified by chromatography on silical gel (petroleum ether/
ethyl acetate 10/1) to afford 172.4 mg (57%) of 4a and 9.1 mg
(3%) of 6a . 4a : liquid; IR (neat) 1732, 1628, 1227, 1058, 869,
1
783 cm-1; H NMR (300 MHz, CDCl3) δ 4.21-4.31 (m, 4 H),
1682, 1466, 1377, 1092, 879, 723 cm-1 1H NMR (300 MHz,
;
4.14-4.20 (m, 1 H), 2.18 (s, 3 H), 1.87 (s, 3 H), 1.81-1.86 (m,
1 H), 1.47-1.54 (m, 1 H), 1.22-1.33 (m, 8 H), 1.10-1.19 (m, 2
H), 0.86 (t, J ) 7.2 Hz, 3 H); 13C NMR (75 MHz, CDCl3) δ
CDCl3) δ 5.68-5.73 (m, 1 H), 5.59 (q, J ) 6.8 Hz, 1H), 2.55 (t,
J ) 7.5 Hz, 2 H), 2.12-2.20 (m, 2 H), 1.52-1.60 (m, 2 H), 1.41-
J . Org. Chem, Vol. 68, No. 23, 2003 9001

Ma et al.
206.8, 165.3, 165.3, 153.8, 128.0, 61.5, 61.4, 57.5, 29.7, 29.5,
28.1, 22.8, 16.5, 14.2, 14.0; MS m/z (%) 298 (M+, 0.47), 181
(100); HRMS m/z (EI) calcd for C16H26O5 298.17802, found
Major State Basic Research Development Program
(Grant No. G2000077500) was greatly appreciated.
Shengming Ma is the recipient of a 1999 Qiu Shi Award
for Young Scientific Workers issued by Hong Kong Qiu
Shi Foundation of Science and Technology (1999-2003).
1
298.18169. 6a : yellow oil; H NMR (300 MHz, CDCl3) δ 4.42
(q, J ) 7.1 Hz, 2 H), 2.25-2.50 (m, 2 H), 2.26 (s, 3 H), 2.17 (s,
3 H), 1.38-1.25 (m, 7 H), 0.94 (t, J ) 7.1 Hz, 3 H); MS m/z (%)
253 (M+ + 1, 9), 252 (M+, 52), 181 (100); IR 1718, 1635, 1552,
1236 cm-1. Elemental Anal. Calcd for C14H20O4: C 66.65, H
7.99. Found: C 66.67, H 7.70.
Su p p or tin g In for m a tion Ava ila ble: Analytical data for
compounds 1, 3, 4, and 6 and 1H NMR and 13C NMR spectra
of these compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
Ack n ow led gm en t. Financial support from the Na-
tional Natural Science Foundation of China and the
J O034633I
9002 J . Org. Chem., Vol. 68, No. 23, 2003