Lactones, part 28: A new approach for the synthesis of α-methylene lactones from alkenes

Article abstract of DOI:10.1055/s-2006-941598

A facile two-step procedure for synthesis of α-methylene lactones from alkenes and cycloalkenes is presented. Reactions carried out on some monoterpene alkenes afforded corresponding lactones in enantiomerically pure forms. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-941598

LETTER
1523
1
Lactones, Part 28: A New Approach for the Synthesis of a-Methylene
Lactones from Alkenes
S
A
ynthesis of
a
-Me
n
thylene Lacto
t
nes fro
o
m
A
lkenes ni Szumny,* Czeslaw Wawrzenczyk
Department of Chemistry, Agricultural University, Norwida 25, 50-375 Wroclaw, Poland
E-mail: antjasz@o2.pl
Received 23 January 2006
1
4
scribed earlier by Murta. Here we present a simple two-
step procedure for the synthesis of a-methylene-g-lac-
tones from alkenes. The first step, the addition of Mel-
drum’s acid to alkenes or cycloalkenes mediated by
cerium(IV) ammonium nitrate (CAN)15 afforded corre-
sponding a-carboxylactones (Scheme 1). They, without
purification, were subjected to decarboxylative methyl-
enation in the second step. In this way, following the sim-
ple procedure,20 a-methylene lactones were obtained in
Abstract: A facile two-step procedure for synthesis of a-methylene
lactones from alkenes and cycloalkenes is presented. Reactions
carried out on some monoterpene alkenes afforded corresponding
lactones in enantiomerically pure forms.
Key words: a-methylene lactone, CAN, Meldrum’s acid
a-Methylene-g-butyrolactones exhibit a broad range of
biological activities. The intensive studies have been fo-
3
5–50% yields (Table 1). The structures of products were
2
3
4
cused on their cytotoxic, antitumoral, antibacterial and
1
established on the basis of their H NMR, IR and MS (EI)
5
plant growth inhibitory activities. They are also known as
insect feeding deterrents. In recent years it has been
data.21
6
recognized that a-methylene group is essential for these
O
O
R3
O
7
activities. Because of that it is not surprising that
O
O
O
OH
CAN (2 equiv)
O
R3
R2
chemists elaborated many methods for the synthesis of
R2
+
8
–10
a-methylene-g-lactones.
R1
O
R1
Our research interest in the synthesis of lactones and their
O
methylenation
R3
a-methylene analogues was inspired by antifeedant ac-
R2
1
1
tivity of natural a-methylene sesquiterpenoid lactones.
R1
1
2a–d
We obtained many isoprenoid lactones,
including
1
3
Scheme 1
some a-methylene-g-lactones. The two-step procedure
via a-carboxylactones was applied for synthesis of a-
methylene lactones. The carboxy group was introduced The analysis of data presented in the Table 1 allows us to
into the lactone ring by using of methoxymagnesium draw up several features of this reaction. In this analysis
methyl carbonate (MMC). The decarboxylative methyl- the following mechanism for the formation of a-carboxyl-
enation was performed with solution of formaldehyde, N- actone F (Scheme 2) was considered.
methylaniline, acetic acid and sodium acetate, as was de-
R3
O
O
R2
O
O
O
O
R3
O
O
O
O
O
R1
R3
2 +
CAN
O
O
CAN
R2
O
R1
R
O
R1
O
O
C
A
B
H
O
O
O
H
O
+
O
R3
R2
O
OH
O
R3
R2
R3
R2
O
+
– AcMe
H+
O
O
O
R1
–
R1
R1
F
E
D
Scheme 2
SYNLETT 2006, No. 10, pp 1523–1526
2
1
.0
6
.2
0
0
6
Advanced online publication: 12.06.2006
DOI: 10.1055/s-2006-941598; Art ID: G02506ST
Georg Thieme Verlag Stuttgart · New York
©

1
524
A Szumny, C. Wawrzenczyk
LETTER
The reaction begins with a formation of Meldrum’s acid Table 1 Yields of a-Methylene Lactones
radical A and its addition to a double bond. The radical B
Substrate
Product
Yield (%)
in the reaction with CAN is converted into carbocation C
which via the next carbocations D and E rearranges into
a-carboxylactone F and acetone.
O
O
40
1
The process of addition of Meldrum’s acid radical to a
double bond is highly regioselective and chemoselective.
The reaction of b-myrcene (3) and limonene (5) with one
equivalent of Meldrum’s acid afforded lactones 3a and
1
a
11
3
3
5
9
6
0
O
11
O
O
5
a, respectively, as the only products. It is a result of both
2
2
3
a
a
electronic and steric requirements of this process. In the
case of b-myrcene (3), the higher stability of the radical
formed after Meldrum’s acid radical addition to alkene is
the determining factor. In the case of limonene the
regioselectivity can be explained taking into consider-
ation the steric interactions in the process of addition of
Meldrum’s acid radical. Such analysis indicates that the
approach and addition of this radical to a less-hindered
double bond of isopropenyl group is preferred.
O
3
4
O
O
4
a
The lactone ring formation step in the reaction of cyclo-
alkenes in which the ring’s double bond is involved is
highly diastereoselective. In the reactions of 1-methyl-
cyclohexene (4), (+)-3-carene (6), and (+)-a-pinene (8)
and (–)-a-pinene (9) the respective bi- or tricyclic lactones
O
3
3
8
5
O
5
5a
H
4
a, 6a, 8a, 9a with a cis-fused lactone ring were formed.
H
Such junction of the lactone and cyclohexane rings is con-
firmed by spectral data of the corresponding products.
O
H
O
The spectral data of lactone 4a, obtained by us, are the
same as those of the cis lactone synthesized by Cam-
6
6
a
1
6
paigne. The cis junction of the lactone ring to cyclohex-
ane in the pinane system and its trans orientation towards
the gem-dimethyl group was indirectly confirmed by
spectral data of saturated lactone 8c obtained by thermal
decarboxylation in pyridine of the crude carboxy lactone
40
7
2
0
20
8
b (Scheme 3). The physical ([a]D , nD ) and spectral
7a
data of lactone 8c are the same as those determined for the
9
8
1
7
H
lactone obtained earlier by Paruch et al.1
2d
6
4
4
2
2
2
5
1
0
O
3
4
O
T, Py
8
9
H
8a
9a
O
H
O
O
O
O
6b
6c
HOOC
O
H
H
O
T, Py
COOH
O
O
8c
O 8b
by us is a diastereoisomer of the lactone obtained earlier
by Dulcère et al.17 The configuration of a-methylene
lactone 6a was also indirectly proven by the structure of
saturated lactone 6c, the product of thermal decarboxyl-
ation of lactone 6b (Scheme 3). The spectral data of this
product were identical with data of the pure enantiomer of
Scheme 3
The spectral data of lactone 6a obtained from (+)-3-carene
6) suggest also the cis-junction of the lactone ring and its
(
trans-orientation towards the cyclopropane ring. The
trans-orientation of the lactone ring towards the gem-di-
methylcyclopropane ring could be supposed from the
small difference in chemical shifts (Dd = 0.01 ppm) of
gem-dimethyl groups. a-Methylene lactone (6a) obtained
6
c obtained by Lamarque.18
The formation of (+)-a-methylene lactone 8a from (–)-a-
pinene and (–)-a-methylenelactone 9a from (+)-a-pinene
indicates the stereoselectivity of the lactone ring-closing
Synlett 2006, No. 10, 1523–1526 © Thieme Stuttgart · New York

LETTER
Synthesis of a-Methylene Lactones
1525
process. High stereoselectivity of this process was also
observed in the reaction of racemic camphene, where the
racemic a-methylene lactone 7a was obtained as a prod-
uct. The structure of lactone 7a was established on the ba-
sis of NMR spectral data, especially those obtained from
(7) Zhang, S.; Won, Y. K.; Ong, C. N.; Shen, H. M. Curr. Med.
Chem.: Anti-Cancer Agents 2005, 5, 239.
(8) Grieco, A. Synthesis 1975, 67.
(
9) Hoffmann, H. M. R.; Rabe, J. Angew. Chem., Int. Ed. Engl.
1
985, 24, 94.
10) Petragnani, N.; Ferraz, H. M. C.; Silva, G. V. J. Synthesis
986, 157.
(
1
3
1
C– H COSY method. The exo orientation of lactone ring
1
was indicated by relatively large difference (Dd = 0.99
(11) Datta, S.; Saxena, D. Pest. Manag. Sci. 2001, 57, 95.
(12) (a) Paruch, E.; Ciunik, Z.; Wawrzeńczyk, C. Eur. J. Org.
Chem. 1998, 2677. (b) Dams, I.; Białońska, A.; Ciunik, Z.;
Wawrzeńczyk, C. J. Agric. Food Chem. 2004, 54, 1630.
ppm) of chemical shifts of protons of CH -7 group and
2
much smaller difference of chemical shifts of CH -6 pro-
2
tons (Dd = 0.25 ppm). The large difference of chemical
(c) Dams, I.; Białońska, A.; Ciunik, Z.; Wawrzeńczyk, C.
shifts of CH -7 protons indicates that one of them is much
2
Eur. J. Org. Chem. 2004, 12, 2662. (d) Paruch, E.; Ciunik,
Z.; Wawrzeńczyk, C. Liebigs Ann./Recl. 1997, 2341.
(13) Szumny, A.; Olejniczak, T.; Gabryś, T.; Halarewicz-Pacan,
A.; Dancewicz, K.; Krystkowiak, K.; Wawrzeńczyk, C.
Arthropods. Chemical, Physiological and Environmental
Aspects; Konopińska, D., Ed.; University of Wrocław:
Poland, 2001, 234.
closer to the lactone moiety than the other three protons
(
CH -6 and one of CH -7).
2 2
We have also tried to replace Meldrum’s acid by ethyl
acetoacetate to synthesize from alkenes, proper a-acetyl
lactones. They could be next transformed via a-hydroxy-
ethyl derivative into a,b-unsaturated lactone with exocy-
clic double bond. Unfortunately instead of a-acetyl
lactone ethyl 2-methyl-5-neopentyl-4,5-dihydrofuran-3-
carboxylate (10) was obtained in 70% yield (Scheme 4).
It is a result of a nucleophilic attack of the more reactive
ketone carbonyl group and easy proton abstraction from
the obtained carbocation A. Similar types of compounds
were obtained in the reaction of alkenes with ethyl ace-
toacetate in the presence of manganese(III) acetate.19
(14) Murta, M. M.; de Azevedo, M. B. M.; Greene, A. E. J. Org.
Chem. 1993, 58, 7537.
(15) Solabannavar, S. B.; Helavi, V. B.; Desai, U. V.; Mane, R.
B. Tetrahedron Lett. 2002, 43, 4535.
(16) Campaigne, E.; Beckman, J. C. Synthesis 1978, 385.
(
17) Dulcère, J. P.; Mihoubi, M. N.; Rodriguez, J. J. Org. Chem.
1
993, 58, 5709.
18) Lamarque, L.; Mèou, A.; Brun, P. Tetrahedron 1998, 54,
497.
(19) Heiba, E. A. I.; Dessau, R. M. J. Org. Chem. 1974, 39, 3456.
(
6
(
20) General Procedure.
CAN (20 mmol) was slowly added to a cooled (ice bath) and
vigorously stirred solution of alkene (10 mmol) and
Meldrum’s acid (or ethyl acetoacetate for compound 10)
O
OEt
O
OEt
CAN
+
1
+
(
10 mmol) in 50 mL MeCN. The reaction was complete
when the orange color of the mixture turned to pale-yellow
usually after 1 h). Then the solvent was evaporated (below
0 °C, because of possible decarboxylation reaction). Then,
O
O
(
5
H O (100 mL) was added to the residue and the product was
2
extracted with EtOAc (3 × 40 mL). Combined ethereal
H-O-H
+
–
solutions were washed with brine. The purification of crude
O
O
O
OEt
product via NaHCO –HCl procedure significantly decreased
+
3
the yield of this reaction. So in the next step crude a-car-
boxylactone was stirred overnight with 3 mL of stock
A
O
H+
O
solution containing Et NH (3 mL), 30% formaldehyde (6
2
mL), NaOAc (0.2 g) and AcOH (8 mL). The reaction
mixture was acidified with 10% HCl (50 mL) and extracted
O
O
O
with Et O. Crude product was purified by column
2
OEt
chromatography (eluent hexane–Et O, starting from 20:1
2
and next 2:1).The physical and spectral data of compounds
obtained are presented below.
O
O
10
not observed
(
21) Analytical Data for Compounds Obtained.
2
0
1
Compound 1a: nD 1.4605. H NMR (300 MHz, CDCl ):
3
Scheme 4
d = 6.19 (1 H, t, J = 2.8 Hz, =CH ), 5.57 (1 H, t, J = 2.4 Hz,
2
=
CH ), 2.72 (1 H, dt, J = 16.8, 2.8 Hz, CH in lactone), 2.68
2
2
(
1 H, dt, J = 16.8, 2.4 Hz, CH in lactone), 1.71 and 1.65 [2
2
References and Notes
H, 2 d, J = 14.8 Hz ,(CH ) CCH , AB system], 1.44 [3 H, s,
3
3
2
(
1) Gładkowski, W.; Grabarczyk, M.; Wińska, K.; Białońska,
(CH )CO], 1.00 [9 H, s, (CH ) CCH ]. IR (film): 1778 (s),
1675 (m), 1290 (m), 1108 (m) cm . MS (EI): m/z (%) = 183
3 3 3 2
–
1
A.; Ciunik, Z.; Wawrzeńczyk, C. J. Mol. Catal. B: Enzym.
2
006, 39, 31.
[M + H](7), 167 (1), 126 (4), 111 (100), 83 (18), 68 (5).
1
(
(
2) Lee, K. H.; Huang, B. R. Eur. J. Med. Chem. 2002, 37, 333.
3) Kupchan, S. M.; Fessler, D. C.; Eakin, M. A.; Giacobbe, T.
J. Science 1970, 168, 376.
Compound 2a: mp 86 °C. H NMR (300 MHz, CDCl ): d =
3
6.21 (1 H, t, J = 2.9 Hz, =CH ), 5.61 (1 H, t, J = 2.4 Hz,
2
=CH ), 4.50 [1 H, tt, J = 7.6, 5.6 Hz, >CH(O)], 3.01 (1 H,
2
(
(
4) Neerman, M. F. Int. J. Aromather. 2003, 13, 114.
5) Ohno, S.; Tomita-Yokotani, K.; Kosemura, S.; Node, M.;
Suzuki, T.; Amano, M.; Yasui, K.; Goto, T.; Yamamura, S.;
Hasegawa, K. Phytochemistry 2001, 56, 577.
ddt, J = 17.0, 7.6, 2.5 Hz, CH in lactone), 2.56 (1 H, ddt,
2
J = 17.0, 5.9, 2.9 Hz, CH in lactone), 1.52–1.76 [2 H, m,
2
CH (CH ) CH ], 1.16–1.44 [20 H, m, CH (CH ) CH ],
3
2 10
2
3
2
10
2
0.86 [3 H, t, J = 6.9 Hz, CH (CH ) CH ]. IR (KBr): 1776
3
2 10
2
–
1
(
6) Picman, A. K. Biochem. System. Ecol. 1986, 14, 255.
(s), 1676 (w), 1284 (m), 1124 (m), 944 (m) cm . MS (EI):
Synlett 2006, No. 10, 1523–1526 © Thieme Stuttgart · New York

1
526
A Szumny, C. Wawrzenczyk
LETTER
1
m/z (%) = 267 (72) [M + H], 249 (13), 227 (13), 221 (25),
Compound 7a: mp 73–74 °C; H NMR (600 MHz, CDCl ):
3
1
71 (23), 123 (34), 109 (52), 97 (100), 83 (31), 69 (69).
d = 6.13 (1 H, t, J = 2.8 Hz, =CH ), 5.57 (1 H, t, J = 2.7 Hz,
2
2
0
1
Compound 3a: nD 1.4885. H NMR (300 MHz, CDCl ):
=CH ), 2.91 (1 H, dt, J = 17.0, 2.7 Hz, CH in lactone), 2.80
3
2
2
d = 6.22 (1 H, m, >C=CH ), 5.85 (1 H, dd, J = 17.2, 11.0 Hz,
(1 H, dt, J = 17.0, 2.8 Hz, CH in lactone), 2.15 (1 H, dd,
J = 6.4, 1.1 Hz, H-1), 2.10 (1 H, dd, J = 10.4, 1.8 Hz, CH2-
7), 1.85 (1 H, d, J = 1.8 Hz, H-4), 1.58 (1 H, ddd, J = 12.4,
2
2
CH =CH), 5.60 (1 H, m, =CH ), 5.22 (1 H, d, J = 17.2 Hz,
2
2
CH =CH), 5.17 (1 H, d, J = 11.0 Hz, CH =CH), 5.06 [1 H, t,
2
2
J = 5.6 Hz, (CH ) C=CH], 2.82 (2 H, s, CH in lactone), 2.06
10.1, 3.2 Hz, CH -6), 1.52 (1 H, ddd J = 13.2, 6.5, 3.2 Hz,
3
2
2
2
(
2 H, m, =CHCH CH ), 1.76 (2 H, t, J = 8.2 Hz,
CH -5), 1.33 (1 H, ddd, J = 12.4, 6.5, 1.3 Hz, CH -6), 1.25
2
2
2
2
=
CHCH CH ), 1.67 [3 H, s, =C(CH ) ], 1.59 [3 H, s,
(1 H, ddd, J = 13.2, 10.1, 1.3 Hz CH -5), 1.21 (1 H, d,
2
2
3
2
2
=
C(CH ) ]. IR (film,): 1766 (s), 1665 (w), 1276 (m), 1072
J = 10.4 Hz, CH -7), 0.99 [3 H, s, C(CH ) ], 0.95 [3 H, s,
3
2
2
3 2
–
1
13
(w), 934 (w) cm . MS (EI): m/z (%) = 207 [M + H] (59), 189
(54), 173 (8), 161 (100), 145 (35), 133 (18), 121 (80), 105
(29), 93 (48), 67 (4).
C(CH ) ]. C NMR (CDCl ): 169.9, 136.5, 120.5, 93.7,
3 2 3
49.2, 49.1, 44.0, 34.8, 32.1, 25.7, 24.4, 24.1, 22.2. The NMR
1
3
1
1
13
1
assignments were aided by C DEPT, H– H and C– H
COSY spectroscopy. IR (KBr): 1759 (s), 1667 (w), 1120
2
0
1
Compound 4a: nD 1.4962. H NMR (300 MHz, CDCl ):
3
–
1
d = 6.20 (1 H, d, J = 3.0 Hz, =CH ), 5.44 (1 H, d, J = 2.7 Hz,
(w), 975 (w) cm . MS (EI): m/z (%): 207 (40) [M + H], 191
(13), 133 (24), 138 (72), 123 (100), 121 (67), 108 (56), 95
(64), 79 (45), 67 (94).
2
=CH ), 2.73 (1 H, m, >CHCH ), 1.71–1.25 [m, 8 H, (CH )
2 2 2 4
in cyclohexyl], 1.46 (3 H, s, CH ). IR (film): 1776 (s), 1676
3
–
1
20
(
+
6
m), 1168 (m), 936 (m) cm . MS (EI): m/z = 167 (100) [M
H], 151 (14), 138 (10), 123 (61), 108 (9), 95 (18), 79 (8),
7 (10).
Compound 8a: [a] +35 (c 2.01 CHCl ); mp 73–75 °C.
D
3
1
H NMR (300 MHz, CDCl ): d = 6.25 (1 H, d, J = 2.9 Hz,
3
=CH ), 5.61 (1 H, d, J = 2.5 Hz, =CH ), 2.95 (1 H, dq,
2
2
2
0
1
Compound 5a: nD 1.5085. H NMR (600 MHz, CDCl ):
J = 10.8, 2.8 Hz, H-6), 2.54 (1 H, ddt, J = 13.5, 10.8, 2.2 Hz,
3
d = 6.20 (1 H, t, J = 2.8 Hz, =CH ), 5.58 (1 H, m, =CH ),
CH -7), 2.22 (1 H, ddd, J = 12.0, 6.0, 2.2 Hz H-8), 2.21 (1 H,
2
2
2
5
.35 (1 H, m, >C=CH), 2.87 (dt, J = 17.1, 2.8 Hz, CH in
d, J = 5.4 Hz, H-1), 1.93 (1 H, dddd, J = 11.0, 6.0, 5.4, 2.2
Hz, CH -10), 1.76 (1 H, dt, J = 13.5, 3.3 Hz, CH -7), 1.47 (3
2
lactone, diastereomer A), 2.86 (dt, J = 17.0, 3.1 Hz, CH in
2
2
2
lactone, diastereomer B), 2.57 (1 H, dt, J = 17.0, 2.8 Hz, CH2
in lactone, diastereomer B), 2.56 (1 H, dt, J = 17.1, 2.4 Hz,
CH in lactone, diastereomer A), 1.70–2.12 (7 H, m, CH and
H, s, CH , C-2), 1.28 [3 H, s, (CH ) C<], 1.02 (1 H, dd,
3
3
2
J = 12.0, 11.0 Hz, CH -10), 0.90 [3 H, s, (CH ) C<]. IR
2
3 2
(KBr): 1758 (s), 1655 (m), 1288 (m), 1066 (m), 1016 (m)
2
2
–
1
>
CH in cyclohexyl), 1.61 [3 H, s, =C(CH )], 1.35 and 1.34
cm . MS (EI): m/z (%) = 207 (100) [M + H], 191 (16), 136
3
[
3 H, 2 s, >C(O)CH for both diastereomers]. IR (film): 1768
(41), 151 (21), 135 (22), 121 (26), 107 (25), 91 (34), 79 (44).
3
–
1
20
(
2
(
s), 1668 (w), 1296 (s), 1060 (m) cm . MS (EI): m/z (%) =
07 (40) [M + H], 189 (9), 161 (15), 121 (100), 111 (37), 93
27), 93 (27), 83 (19).
Compound 9a: [a]D –30 (c 1.29 CHCl ).
3
1
2
0
Compound 10: yield 70%; nD 1.4673. H NMR (300 MHz,
CDCl ): d = 4.14 (2 H, q, J = 7.1 Hz, CH CH O-), 2.80 (1 H,
3
3
2
2
0
20
5
Compound 6a: [a]D –46 (c 1.85 CHCl ); nD 1.5321.
dq, J = 11.3 Hz, J = 1.5 Hz, CH ), 2.57 (1 H, dq, J = 11.3,
1.5 Hz, CH ), 2.14 [3 H, t, J = 1.5 Hz, C(O)CH ], 1.70 and
3
2
1
5
H NMR (300 MHz, CDCl ): d = 6.25 (1 H, d, J = 2.7 Hz,
3
2
3
=
CH ), 5.54 (1 H, d, J = 2.3 Hz, =CH ), 2.69 (1 H, m, CH<
1.63 [2 H, two d, J = 14.6 Hz (CH ) CCH , AB system], 1,37
2
2
3 3 2
in lactone), 2.07 (1 H, dd, J = 14.6, 6.8 Hz, >CHCH ), 1.88
[3 H, s, (CH )CO], 1.26 (3 H, t, J = 7.1 Hz, CH CH O), 0.99
3 3 2
2
1
3
(
(
1 H, dd, J = 14.6, 5.1 Hz, >CHCH ), 1.30 [3 H, s,
[9 H, s, (CH ) CCH ]. C NMR (CDCl ): 166.7, 166.6,
2
3 3 2 3
CH )CO<], 1.10 (1 H, m, >CHCH CH<), 0.93 and 0.94 [6
101.0, 89.2, 59.3, 53.2, 43.5, 31.2, 28.2, 14.5. IR (film):
2960 (s), 1708 (s), 1660 (s), 1268 (m), 1224 (m), 1096 (m)
3
2
H, two s, (CH ) C<], 0.81 (1 H, m, >CHCH CH<), 0.44–
3
2
2
–
1
0
1
1
.56 (2 H, m, cyclopropyl). IR (film): 1768 (s), 1668 (w),
296 (s), 1060 (m) cm . MS (EI): m/z (%) = 206 (53) [M ],
91 (23), 177 (13), 163 (53), 145 (25), 121 (22), 110 (98), 96
cm . MS (EI): m/z (%) = 241 (11) [M + H], 222 (21), 207
(20), 198 (42), 166 (43), 141 (100), 111 (56), 95 (70), 67
(43).
–
1
+
(
73), 82 (100), 67 (30).
Synlett 2006, No. 10, 1523–1526 © Thieme Stuttgart · New York