of rove beetles,6 fruits,7 butterfat,8 and the territorial marking
fluid of the Bengal tiger,9 dodecan-4-olide is a small natural
product which plays a role in many different biological
processes.10 Due to this compound’s abundance in nature,
dodecan-4-olide is one of the most common butanolides
targeted for small-molecule synthesis.11
Recently, in our research directed toward the utility of
cyclopropane hemimalonates, we reported the synthesis of
a variety of 3-azidobutyric acid esters 5 from cyclopropane
hemimalonates and sodium azide (Scheme 1).12 During
the development of this chemistry, it was noted that in the
presence of substituted unreactive azide sources, such as
benzyl azide, the cyclopropane (4a) was able to undergo a
unimolecular transformation to produce a mixture of bu-
tanolides 6 and 7. The organoazide is not incorporated into
the products and is thus unnecessary toward the forma-
tion of butanolides. Herein, we report the development
and generalization of a γ-substituted butanolide synthesis
from cyclopropane hemimalonates and its application to
the synthesis of naturally occurring (R)-dodecan-4-olide.
Initial attempts to optimize this cyclopropane reorgani-
zation proved quite fruitful, allowing access to butanolide
6 in an 82% yield upon heating in 2-methoxyethanol in the
presence of a slight excess of ammonium chloride (Table 1,
entry 1). In the absence of the salt, the reaction failed to
proceed. Although the use of ammonium chloride gave a
high yield of 6, it also led to a trace amount of inseparable
butanolide 7, a product of a dealkoxycarbonylation. While
a variety of salts promoted the reaction, ammonium
chloride salts seemed to be superior. It was never possible
to obtain 6 as the sole product in our hands.
Table 1. Reaction Optimization
additive
entry
(1.4 equiv)
solvent/temp (°C)
timea
product (%)
1
NH4Cl
2-MeO(CH2)2OH/reflux 2 h
82% 6, trace 7
87% 6, trace 7
mixtureb
mixtureb
mixtureb
mixtureb
no rxn
2
NH4Cl
NH4Cl
NaCl
KCl
DMSO/135 °C 1 h
5:1 DMSO:H2O/135 °C 1 h
Scheme 1. Previous Work with Cyclopropane Hemimalonates
3
4
DMSO/135 °C
DMSO/135 °C
DMSO/135 °C
DMSO/135 °C
DMSO/135 °C
DMSO/135 °C
1 h
5
1 h
6
LiCl
24 h
24 h
24 h
1/6 h
24 h
24 h
7
NaCN
8
Me3N HCl
mixtureb
3
9
NH4Cl/NaCN
65% 7
10
11
12c
13c
LiCl/Me3N HCl DMSO/135 °C
LiCl/Me3N HCl DMSO/reflux
mixtureb
mixtureb
3
3
3
3
LiCl/Me3N HCl DMSO/150 °C
LiCl/Me3N HCl DMF/150 °C
40 min 71% 7
40 min 82% 7
40 min 45% 7
14c,d LiCl/Me3N HCl DMF/150 °C
3
a Time to complete consumption of starting material by TLC analy-
sis. b A 1:1 mixture of compounds 6 and 7. c Performed in microwave
reactor. d The corresponding methyl diester was used.
(6) Wheeler, J. W.; Happ, G. M.; Araujo, J.; Pasteels, J. M. Tetra-
hedron Lett. 1972, 13, 4635.
(7) Tang, C. S.; Jennings, W. G. J. Agric. Food Chem. 1968, 16, 252.
(8) Jurriens, G.; Olele, J. M. J. Am. Oil. Chem. Soc. 1965, 42, 857.
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N.; Fourie, W. B.; Weibchen, G. J. Chem. Ecol. 2008, 34, 695.
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J. Agric. Food Chem. 1967, 15, 29.
Frustrated with the inability to form 6 cleanly, it was
decided to focus on pushing the reaction toward the
formation of 7 as the sole product. Reaction conditions
were modified by using DMSO, a solvent commonly used
in Krapcho dealkoxycarbonylation reactions. The use of
ammonium chloride in DMSO (entries 2 and 3) with and
without water improved the overall reaction time and
yield; however, both 6 and 7 were still obtained as an
inseparable mixture. A variety of additives were explored
in hopes to promote the smooth conversion to 7, but to no
avail (entries 4À8). It is noteworthy that, with the excep-
tion of sodium cyanide, all additives induced the initial
lactone formation, but the dealkoxycarbonylation step
was sluggish and incomplete. It was at this point that a
one-pot, two-step process was engaged, using ammonium
chloride to promote initial butanolide formation followed
by the addition of sodium cyanide to facilitate the
dealkoxycarbonylation (entry 9). We were pleased to find
thatthe two-stepprocessworked, giving 7 ina 65% yield as
the sole product.
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T. Synth. Commun. 2010, 40, 1607. (b) Habel, A.; Boland, W. Org.
€
Biomol. Chem. 2008, 6, 1604. (c) Gansauer, A.; Fan, C.-A.; Keller, F.;
Keil, J. J. Am. Chem. Soc. 2007, 129, 3484. (d) Pollock, J. A.; Clark,
K. M.; Martynowicz, B. J.; Pridgeon, M. G.; Rycenga, M. J.; Stolle,
K. E.; Taylor, S. K. Tetrahedron: Asymmetry 2007, 18, 1888. (e)
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grance J. 2007, 22, 421. (f) Sabitha, G.; Reddy, E. V.; Yadagiri, K.;
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Pagliarini, E.; Ratti, S.; Giuseppe, C.; de Ferra, L.; Sannicolo, F.
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Spurred by this success, we next examined the use of
standard dealkoxycarbonylation salt systems, which could
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B
Org. Lett., Vol. XX, No. XX, XXXX