The Grob/Eschenmoser fragmentation of cycloalkanones bearing β-electron withdrawing groups: A general strategy to acyclic synthetic intermediates

Article abstract of DOI:10.1039/c0ob00632g

Introduction of a β-electron withdrawing group to cycloalkanones allows facile C-C bond fragmentation. The reaction has been demonstrated with a large range of ring sizes, bearing various leaving and electron withdrawing groups, and using a variety of nitrogen and oxygen containing nucleophiles (>30 examples). The application of fragmentation products to the preparation of substituted γ-lactones has been demonstrated. Mechanistic studies are reported which are suggestive of a Grob/Eschenmoser type reaction.

Full text of DOI:10.1039/c0ob00632g

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
The Grob/Eschenmoser fragmentation of cycloalkanones bearing b-electron
withdrawing groups: a general strategy to acyclic synthetic intermediates†
Judith Hierold, Tina Hsia and David W. Lupton*
Received 27th August 2010, Accepted 12th October 2010
DOI: 10.1039/c0ob00632g
Introduction of a b-electron withdrawing group to cycloalkanones allows facile C–C bond
fragmentation. The reaction has been demonstrated with a large range of ring sizes, bearing various
leaving and electron withdrawing groups, and using a variety of nitrogen and oxygen containing
nucleophiles (>30 examples). The application of fragmentation products to the preparation of
substituted g-lactones has been demonstrated. Mechanistic studies are reported which are suggestive of
a Grob/Eschenmoser type reaction.
ring-opening (vide infra).9–11 In the event, fragmentation—up to
24 times in a single transformation—enabled a novel approach to
the synthesis of dendrimers, for example [G4]-ene24 (Scheme 2).12
Introduction
Organic synthesis requires control over bond making and breaking
events. Within the latter class fragmentations, as studied by
Grob,1 have lasting significance. In a large part this is due to the
observation that cyclic structures can be fashioned, with chemo-
and stereoselectively, then converted in a predictable manner to
acyclic products.2 This has been demonstrated in total synthesis,3,4
and in the preparation of synthetic intermediates.5 In the context
of a program into the preparation of hyperbranched polymers we
envisaged the use of C–C bond fragmentation with non-carbon
nucleophiles to assemble a diverse modular array of materials.
This strategy was inspired by the seminal studies of Eschenmoser
who investigated the fragmentation of cyclopentyl tosylate 1(n =
0)→2 (Scheme 1).6 Unfortunately due to the narrow scope of
this reaction (i.e. 1(n = 1)→3+4)7 it required modification to be
useful for our studies. We felt that by introducing a b-electron
withdrawing group (i.e. 1, X EWG) inductive weakening of the
fragmentable C–C bond should allow ring opening under mild
conditions.
Scheme 1
Scheme 2
Inspection of the literature supported this hypothesis with a
number of undesired ring openings reported as minor side reac-
Concurrent to studies on the synthesis of dendrimers more
general investigations into the fragmentation of b-ketoesters of
type 1, and the application of this reaction in organic synthesis,
tions with related substrates.8 In addition the ester functionality
introduces an equally conceivable retro-Dieckmann pathway for
were undertaken. Herein we report an extensive survey of the
nucleophilic C–C bond fragmentation of cycloalkanones bearing
a b-electron withdrawing group. Exploration of the reaction
mechanism and potential applications in synthesis are also
described.
Monash University, Clayton, 3800, Melbourne, Australia. E-mail: david.
lupton@monash.edu; Fax: +61 2 9905 4597; Tel: +61 3 99020327
† Electronic supplementary information (ESI) available: 1H- and 13C-
NMR spectra of all reported compounds as well as additional experimental
procedures. See DOI: 10.1039/c0ob00632g
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Table 1 Optimisation of fragmentation of cyclohexanone 1a
temperature providing diester 5a in 93% isolated yield (Table 1,
entry 6).
Having developed conditions for the fragmentation of
b-ketoester 1a with ethanol, we targeted non-symmetrical diesters,
materials better suited to subsequent chemoselective transforma-
tions. When examining alternate primary alcohols we found that
iso-butanol fragmented 1a effectively (Table 2, entry 1), while less
hindered alcohols were plagued by concomitant transesterification
reactions. This was eliminated, with benzylalcohol and n-butanol,
by using a single equivalent of K2CO3 (Table 2, entries 2–3), while
with methanol, the reaction had to be conducted at 0 ◦C (Table 2,
entry 4a). When secondary alcohols were examined more forcing
conditions were required to reach completion. For instance,
iso-propanol fragmented cyclohexanone 1a only after 96 h at 82 ◦C
(Table 2, entry 5a). Finally, tert-butanol proved to be unsuitable
(Table 2, entry 6).
Entry
Base (equiv.)
Additive
Temp.
70 ◦C
Yield%a
1
2
3
4
5
6
Et3N (4)
Et3N (4)
Pyridine (4)
Imidazole (4)
K2CO3 (4)
K2CO3 (2)
5 mol% DMAP
81
(52)
(3)
(32)
(100)
(100) 93
—
—
—
—
—
70 ◦
70 ◦
70 ◦
70 ◦
rt
C
C
C
C
a Isolated yield, conversion in parentheses as judged by 1H-NMR analysis.
Rather than avoiding transesterification it was possible to
conduct the reaction under conditions that favoured the one-
pot fragmentation transesterification. In the case of methanol this
was achieved with 2 equivalents of K2CO3 at room temperature
providing the dimethyl ester in 82% isolated yield (Table 2, entry
4b). With iso-propanol the reaction gave reasonable yields of the
diester after extended heating at 82 ◦C (Table 2, entry 5b).
Next the capacity of amines to fragment b-ketoester 1a was
explored. Previously optimised conditions used 40 equivalents
of alcohol, however using these conditions it was difficult to
separate the product from unreacted amine. This problem was
circumvented by conducting the reaction with one equivalent
of amine in dichloromethane at reflux, thus providing benzyl
amide 5a (Y NH, R1 Bn, R2 Et) in 61% yield (Table 2,
Results and discussion
Reaction development and scope of nucleophiles
Studies commenced with the fragmentation of b-ketoester 1a13
using 5 mol% DMAP, triethylamine as the stoichiometric base,
and ethanol as the nucleophile. To our satisfaction these conditions
proved adequate providing diester 5a in 81% isolated yield (Table 1,
entry 1). To clarify the role of DMAP it was omitted and the
reaction found to proceed, albeit more slowly, achieving 52%
conversion after 14 h of heating at 70 ◦C (Table 1, entry 2). Pyridine
and imidazole were not suitable bases (Table 1, entries 3 and 4),
while K2CO3 gave complete conversion within 14 h (Table 1, entry
5). Further optimization revealed that two equivalents of K2CO3
were required, and that the reaction could be conducted at room
Table 2 Fragmentation of cyclohexanone 1a with alcohol and amines
Conditions
Product
Entrya
Base (equiv.)
Temp.
R1
Y
R2
Yield%b
1
2
3
4a
4b
5a
5b
6
K2CO3 (2)
K2CO3 (1)
K2CO3 (1)
K2CO3 (1)
K2CO3 (2)
K2CO3 (1)
K2CO3 (2)
K2CO3 (2)
K2CO3 (4)
K2CO3 (4)
K2CO3 (4)
NaOH (2)
NaOH (4)f
NaBH4 (2.5)f
rtc
rt
i-Bu
PhCH2
n-Bu
Me
Me
i-Pr
i-Pr
t-Bu
PhCH2
PMB
MeBn
H
O
O
O
O
O
O
O
O
NH
NH
NH
O
Et
Et
Et
Et
Me
Et
i-Pr
Et
Et
Et
Et
Et
H
63
71
65
81
82
57
63
trace
61
62
86
68
63
60
rtc
0 ◦
rt
C
82 ◦◦Cc
82 Cd
83 ◦
40 ◦
40 ◦
40 ◦
40 ◦
70 ◦
rt
C
C
C
C
C
C
7ae
7be
7ce
8a
8b
9
H
O
a 40 equivalents of R1YH used except as noted. b Isolated yield following flash column chromatography. c 96 h to reach completion. d Conducted for 168 h.
e 1 equivalent of R1YH in CH2Cl2. f Conducted in ethanol.
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entry 7a). The transformation could also be achieved using
p-methoxybenzylamine and methylbenzylamine (Table 2, entries
7b-c).
To demonstrate this in a racemic context, studies commenced
with the monoprotection of cyclohexan-1,4-diol 6 and oxidation
using PCC to afford the symmetrical ketone 7. Formation of the
b-ketoester and introduction of the iodomethyl group then
provided 1p, which fragmented with NaOH (Table 2, entry 8a) to
give the acid 5r in 60% isolated yield (Scheme 3). When TBAF was
used to remove the silyl protecting group spontaneous cyclisation
with loss of ethanol gave the a-methylene g-butyrolactone 9. While
deprotection using CAN delivered the isomeric g-lactone 8 in high
yield and selectivity.
Finally, hydrolytic and reductive fragmentation was investi-
gated. Using NaOH in dichloromethane it was possible to
fragment b-ketoester 1a to give the expected acid in 68% yield
(Table 2, entry 8a). Increased stoichiometry of the hydroxide and
temperature promoted subsequent hydrolysis, providing diacid 5a
(R1 R2 H, Y O) in 63% isolated yield (Table 2, entry 8b).
Extending the capacity to provide products with differentiated
functionality we found that the reduction of ketone 1a with NaBH4
provided alcohol 5b in 60% isolated yield (Table 2, entry 9).
Scope with regard to carbocycles
Attention now moved to the cycloalkanones suited to this
reaction, of particular interest were ring systems incompatible
with Grob/Eschenmoser type fragmentations.14 Examining the
scope of this reaction was intended to aid future studies in natural
product15 and novel dendrimer synthesis. To commence we probed
the type of leaving group, finding that when the iodide was
replaced by a bromide the reaction proceeded in similar yield, while
the mesylate required elevated temperature to reach completion
(Table 3, entries 1a–c). Similarly diiodide 1d fragmented well, but
only when heated at 70 ◦C (Table 3, entry 2).
Scheme 3 Application of fragmentation in the synthesis of g-lactones.
The type of electron-withdrawing group in the b-position was
examined with substrates 1e and f. Replacing the ester with a nitrile
(1a cf. 1e) had no effect on the reaction (Table 3, entry 3), while
fragmentation of the phenyl ketone 1f proceeded more slowly and
gave a lower isolated yield (Table 3, entry 4). The modest yield
arose due to competing cleavage of the benzoyl group.
Cyclopentanone 1g was fragmented by both ethanol (Table 3,
entry 5a) and secondary amines such as benzylmethylamine,
providing amide 5h (Table 3, entry 5b), and dibenzylamine,
providing amide 5i (Table 3, entry 5c). Cycloheptanone 1j reacted
readily at room temperature to provide ester 5j in 81% yield
(Table 3, entry 6), while cyclododecanone 1k gave the expected
product 5k in good yield (Table 3, entry 7). The bicyclic indanone
1l fragmented under the general reaction conditions (Table 3,
entry 8), while tetralone 1m required heating (Table 3, entry 9a).
Fragmentation of tetralone 1m could also be achieved using amine
nucleophiles to provide amide 5n (Table 3, entry 9b).
One-pot alkylation/fragmentation
Through the course of our studies we found that traces of
water caused fragmentation to proceed during the alkylation
of the b-ketoester starting material. Exploiting this process we
decided to investigate a one-pot alkylation fragmentation. When 3
equivalents of NaH were used in the alkylation, and an appropriate
alcohol added after 14 h, this could be achieved in acceptable
yields, and examples using cyclopentyl and cyclohexyl substrates
are shown (Scheme 4).
Scheme 4 One-pot alkylation fragmentation.
Finally, cyclohexyl derivatives bearing an alkyl (1o), or protected
alcohol (1p) functionality reacted readily under the standard
conditions (Table 3, entries 10 and 11). The starting material
for the latter reaction is accessible in enantiopure form,16 thus
providing a useful approach to homochiral intermediates, a
possible application of which is introduced below.
Mechanistic observations
Following examination of the scope of the reaction, studies into the
reaction mechanism were undertaken. This reaction is most likely
to resemble either a Grob-fragmentation or a retro-Dieckmann
followed by elimination. In order to investigate these possibilities,
competitive rate studies, monitored by 1H-NMR, were undertaken
(Fig. 1). When the reaction of the six membered b-ketoester 1a
with d4-MeOH was compared to that of the seven membered 1j,
it was found that the former fragmented in less than 5 min, while
the latter required 50 min (Fig. 1, graph A). A similar comparison
of cyclohexanone 1a to cyclopentanone 1g was undertaken. At
Application to the synthesis of lactone building blocks
Substituted g-lactones are well-represented motifs in bioactive
and naturally occurring materials.17 The capacity to fragment
TBS protected cycloalkanone 1p, provides the opportunity to
develop the synthesis of such materials. In addition, since the
de-symmetrisation of ketone 7 and subsequent acylation has
been demonstrated16 it should be possible to access optically
pure fragmentation precursors, and hence g-lactones, from this
intermediate.18
◦
room temperature this was too fast to monitor, however at 0 C
we found that cyclopentanone 1g reacted in under two minutes,
and cyclohexanone 1a in under four (Fig. 1, graph B). These
studies demonstrate that the rate of reaction is related to ring size,
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Table 3 Scope of Grob/Eschenmoser fragmentation with cycloalkanones 1a–p bearing b-electron withdrawing groups
Starting material
Product
Entry
Nucleophile
LG
Y
R
Yield%a
1a
1b
1cb
EtOH
¢¢
¢¢
I (1a)
Br (1b)
OMs (1c)
—
—
—
—
—
—
93
92
73
2b,c
EtOH
EtOH
EtOH
—
—
—
—
—
—
—
—
—
Et
80
3
79
4b,e
60f
5a
EtOH
BnMeNH2
Bn2NH
—
—
—
O
N
N
83 (5g)
80 (5h)
15 (5i)
5bg
5cg
BnMe
Bn2
6
7
MeOH
EtOH
—
—
—
—
81
68
—
—
8
EtOH
—
—
—
70
9ab
9bg
EtOH
PMB-NH2
—
—
O
NH
Et
PMB
84 (5m)
52 (5n)
10
11
EtOH
EtOH
—
—
—
—
—
—
65
63
a Isolated yield following flash column chromatography. b Conducted under reflux. c Reaction time 4 h. d Stereoisomeric ratio determined by 1H-NMR.
e 48 h to reach completion. f 35% ethyl benzoate isolated. g 4 equiv. of amine and K2CO3, 20 mol% DMAP, CH2Cl2, D, 72 h.
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Fig. 1 Graph A: Cyclohexanone 1a, ꢀ Cycloheptanone 1j. Graph B: Cyclohexanone 1a, ꢀ Cyclopentanone 1g. Graph C: Iodide 1a, ꢀ Bromide
᭹
᭹
᭹
1b.
as expected with a Grob-fragmentation, or a retro-Dieckmann
reaction followed by rapid elimination. If the reaction proceeds
by a rate determining retro-Dieckmann reaction, then bromide 1b
would react more quickly than iodide 1a, due to its greater capacity
to stabilise the developing negative charge. This was not the case
with iodide 1a reacting more quickly (Fig. 1, graph C) as expected
with a process that involves concomitant departure of the leaving
group. Thus it was observed that the rate is proportional to both
ring size and leaving group in a fashion most supportive of a Grob
fragmentation.
case of some liquids, distilled. Tetrahydrofuran (THF) was distilled
from sodium benzophenone ketyl. Ethanol and dichloromethane
˚
were distilled from calcium hydride. DMSO was dried over 4 A
molecular sieves.
Experimental procedures for the preparation of fragmentation
precursors (1)
All fragmentation precursors (1) were prepared by alkylation of
the corresponding 1,3-dicarbonyls. When the starting materials
where not commercially available they where prepared from
the corresponding ketone. Precursors 1a,19a 1b,19b 1g, 1j,13 1l,12
1m19c and 1p12 were synthesised as reported previously, while
new precursors were accessed following either the procedures of
Beckwith13 in the case of 1d, 1k, and 1o, Mu20 in the case of 1f
or Bolm21 followed by mesylation in the case of 1c and 1e. The
generalised procedures can be found in the ESI†.
Conclusions
Fragmentation reactions have widespread applications in or-
ganic synthesis. We have demonstrated that, by introducing an
electron-withdrawing group to an Eschenmoser fragmentation
precursor, substrates formerly unreactive undergo facile reaction.
The application of the products to the synthesis of substituted
g-lactones has been demonstrated, while previously we have used
this reaction to prepare fourth generation dendrimers. Mechanisti-
cally, the reaction appears to occur by Grob-fragmentation, rather
than a retro-Dieckmann/E1cb sequence. Studies exploiting the
applications of this reaction in total synthesis and hyperbranched
polymer synthesis are ongoing.
Ethyl 1-(((methylsulfonyl)oxy)methyl)-2-oxocyclohexane-
carboxylate (1c)
Rf 0.4 (3 : 2, v/v EtOAc–hexane); IR nmax 2944, 2871, 1714,
1
1453, 1359, 1209, 1178; H-NMR (400 MHz, CDCl3) d 1.28 (t,
J = 7.0 Hz, 3H), 1.62–1.84 (m, 4H), 2.04–2.09 (m, 1H), 2.42–
2.48 (m, 1H), 2.50–2.59 (m, 2H), 3.04 (s, 3H), 4.24 (q, J =
7.0 Hz, 2H), 4.36 (d, J = 10.0 Hz, 1H), 4.48 (d, J = 10.0 Hz,
1H); 13C-NMR (100 MHz, CDCl3) d 14.16, 21.90, 27.00, 33.20,
37.41, 40.85, 60.61, 62.36, 70.77, 168.86, 205.22; HRMS found
(M+H)+ 279.0900, C11H18O6S requires (M+H)+ 279.0902; found
(M+NH4)+ 296.1167, requires (M+NH4)+ 296.1168.
Experimental
General experimental
Proton (1H) and carbon (13C) NMR spectra were recorded on a
Bruker DRX400 operating at 400 MHz for proton and 100 MHz
for carbon nuclei. Infrared spectra (nmax) were recorded on a
Perkin–Elmer RXI FTIR spectrometer. Low resolution mass
spectrometry (ESI) was performed on a Micromass Platform
QMS spectrometer. High resolution mass spectra (HRMS) were
recorded on a Bruker BioApex 47e FTMS fitted with an analytical
electrospray source using NaI for accurate mass calibration.
Melting points were measured on a Stuart hot-stage microscope
apparatus. Flash column chromatography was performed on silica
gel (Davisil LC60A, 40–63 mm silica media) using compressed air
or nitrogen. Thin layer chromatography (TLC) was performed
using aluminium-backed plates coated with 0.2 mm silica (Merck,
DC-Platten, Kieselgel; 60 F254 plates). Eluted plates were visualized
using a 254 nm UV lamp and/or by treatment with a suitable
stain followed by heating. Starting materials and reagents were
purchased from Sigma–Aldrich and were used as supplied or, in the
Ethyl 1-(diiodomethyl)-2-oxocyclohexanecarboxylate (1d)
Rf 0.5 (1 : 4, v/v EtOAc–hexane); IR nmax 2944, 2867, 1715, 1648,
1597, 1451, 1251, 1200; 1H-NMR (400 MHz, CDCl3) d 1.28 (t, J =
7.0 Hz, 3H), 1.58–1.74 (m, 1H), 1.90–2.02 (m, 3H), 2.04–2.15 (m,
1H), 2.24–2.32 (m, 1H), 2.42–2.47 (m, 1H), 2.77–2.82 (m, 1H),
4.14–4.29 (m, 2H), 5.72 (s, 1H); 13C-NMR (100 MHz, CDCl3)
d -25.82, 14.16, 22.55, 25.80, 35.01, 41.36, 62.96, 66.72, 165.34,
201.89; HRMS Found (M+H)+, 436.9107, C10H14I2O3 requires
(M+H)+, 436.9111.
(1-Cyano-2-oxocyclohexyl)methyl methanesulfonate (1e)
Rf 0.4 (1 : 1, v/v EtOAc–hexane); IR nmax 2943, 2872, 2241, 1731,
1452, 1360, 1315, 1178, 999; 1H-NMR (400 MHz, CDCl3) d 1.68–
1.83 (m, 2H), 1.94–2.01 (m, 1H), 2.03–2.12 (m, 1H), 2.17–2.25
(m, 1H), 2.48–2.56 (m, 2H), 2.82–2.91 (m, 1H), 3.11 (s, 3H),
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4.33 (d, J = 10.5 Hz, 1H), 4.53 (d, J = 10.5 Hz, 1H); 13C-NMR
(100 MHz, CDCl3) d 21.78, 27.59, 31.66, 35.58, 37.84, 50.71, 68.29,
117.07, 200.53; HRMS found (M+H)+ 232.0635, C9H13NO4S
requires (M+H)+ 232.0644; found (M+NH4)+ 249.0900, requires
(M+NH4)+ 249.0909.
1-Ethyl 7-isobutyl 2-methyleneheptanedioate (5a, Table 2, entry 1)
Rf 0.5 (CH2Cl2); IR nmax 2961, 2875, 1736, 1719, 1471, 1370, 1178,
1135; 1H-NMR (400 MHz, CDCl3) d 0.91 (d, J = 7.0 Hz, 6H), 1.29
(t, J = 7.0 Hz, 3H), 1.46–1.54 (m, 2H), 1.62–1.69 (m, 2H), 1.91
(nonet, J = 7.0 Hz, 1H), 2.29–2.34 (m, 4H), 3.84 (d, J = 7.0 Hz, 2H),
4.19 (q, J = 7.0 Hz, 2H), 5.51 (d, J = 1.0 Hz, 1H), 6.13 (d, J = 1.0 Hz,
1H); 13C-NMR (100 MHz, CDCl3) d 14.33, 19.21, 24.69, 27.85,
28.04, 31.63, 34.26, 60.71, 70.56, 124.67, 140.68, 167.32, 173.78;
HRMS found (M+H)+, 257.1752, C14H24O4 requires (M+H)+,
257.1753.
2-Benzoyl-2-(iodomethyl)cyclohexanone (1f)
Rf 0.5 (1 : 4, v/v EtOAc–hexane); IR nmax 2957, 2928, 2873, 1747,
1
1713, 1682, 1465; H-NMR (400 MHz, CDCl3) d 1.45–1.51 (m,
1H), 1.72–1.83 (m, 2H), 1.93–2.09 (m, 2H), 2.19–2.30 (m, 1H),
2.46–2.54 (m, 1H), 2.99–3.04 (m, 1H), 3.58 (d, J = 10.5 Hz, 1H),
3.79 (d, J = 10.5 Hz, 1H), 7.39–7.44 (m, 2H), 7.52–7.55 (m, 1H),
7.81–7.84 (m, 2H); 13C-NMR (100 MHz, CDCl3) d 10.87, 22.67,
29.58, 40.33, 43.31, 66.09, 128.97, 129.27, 133.60, 134.01, 195.00,
210.04; HRMS found (M+Na)+ 365.0010, C14H15IO2 requires
(M+Na)+ 365.0014.
7-Benzyl 1-ethyl 2-methyleneheptanedioate (5a, Table 2, entry 2)
Rf 0.5 (CH2Cl2); IR nmax 2981, 2940, 2868, 1736, 1716, 1631, 1456,
1
1179; H-NMR (400 MHz, CDCl3) d 1.20 (t, J = 7.0 Hz, 3H),
1.39–1.47 (m, 2H), 1.56–1.64 (m, 2H), 2.23 (t, J = 7.5 Hz, 2H),
2.30 (t, J = 7.5 Hz, 2H), 4.11 (q, J = 7.0 Hz, 2H), 5.03 (s, 2H),
5.42 (q, J = 1.0 Hz, 1H), 6.05 (t, J = 1.0 Hz, 1H), 7.19–7.27 (m,
5H); 13C-NMR (100 MHz, CDCl3) d 14.23, 24.49, 27.88, 31.51,
34.07, 60.58, 66.11, 124.58, 128.18, 128.19, 128.56, 136.14, 140.53,
167.14, 173.33; HRMS found (M+NH4)+, 308.1857, C17H22O4
requires (M+NH4)+, 308.1862.
Ethyl 1-(iodomethyl)-2-oxocyclododecanecarboxylate (1k)
Rf 0.6 (1 : 1, v/v CH2Cl2–hexane); IR nmax 2923, 2861, 1743, 1706,
1
1468, 1441, 1242, 1149, 1027; H-NMR (400 MHz, CDCl3) d
1.21–1.37 (m, 18H), 1.96–2.16 (m, 4H), 3.01–3.09 (m, 1H), 3.49
(d, J = 11.0 Hz, 1H), 3.62 (dd, J = 11.0 Hz, 1.5 Hz, 1H), 4.15–
4.30 (m, 2H); 13C-NMR (100 MHz, CDCl3) d 8.13, 14.22, 18.40,
21.68, 21.90, 22.06, 22.73, 23.51, 26.27, 26.43, 30.08, 34.90, 62.13,
64.54, 170.45, 204.88; HRMS found (M+H)+, 395.1072, C16H27IO3
requires (M+H)+, 395.1083.
7-Butyl 1-ethyl 2-methyleneheptanedioate (5a, Table 2, entry 3)
Rf 0.5 (CH2Cl2); IR nmax 2960, 2937, 2873, 1734, 1718, 1631, 1464,
1
1178, 1136; H-NMR (400 MHz, CDCl3) d 0.91 (t, J = 7.5 Hz,
3H), 1.28 (t, J = 7.0 Hz, 3H), 1.36 (sext, J = 7.5 Hz, 2H), 1.45–
1.53 (m, 2H), 1.55–1.68 (m, 4H), 2.30 (t, J = 7.5 Hz, 4H), 4.05 (t,
J = 6.5 Hz, 2H), 4.18 (q, J = 7.0 Hz, 2H), 5.50 (d, J = 1.0 Hz,
1H), 6.12 (d, J = 1.0 Hz, 1H); 13C-NMR (100 MHz, CDCl3) d
13.79, 14.30, 19.25, 24.64, 28.00, 30.81, 31.61, 34.23, 60.68, 64.26,
124.64, 140.66, 167.29, 173.78; HRMS found (M+H)+, 257.1749,
C14H24O4 requires (M+H)+, 257.1753.
Ethyl 1-(iodomethyl)-3-methyl-2-oxocyclohexanecarboxylate (1o)
Rf 0.4 (1 : 9, v/v EtOAc–hexane); IR nmax 2979, 2935, 2871, 1739,
1
1710, 1454, 1372, 1275; H-NMR (400 MHz, CDCl3) d 1.04 (d,
J = 6.5 Hz, 3H), 1.30 (t, J = 7.0 Hz, 3H), 1.45–1.53 (m, 1H),
1.62–1.74 (m, 1H), 1.77–1.85 (m, 1H), 2.04–2.17 (m, 2H), 2.32–
2.40 (m, 1H), 2.59–2.68 (m, 1H), 3.64 (d, J = 10.0 Hz, 1H), 3.77
(dd, J = 10.0 Hz, 1.0 Hz, 1H), 4.24 (qd, J = 7.0 Hz, 2.0 Hz, 2H);
13C-NMR (100 MHz, CDCl3) d 7.44, 14.22, 15.27, 19.71, 35.25,
35.63, 42.68, 61.83, 62.25, 169.85, 207.43; HRMS found (M+H)+
325.0295, C11H17IO3 requires (M+H)+ 325.0301.
1-Ethyl 7-methyl 2-methyleneheptanedioate (5a, Table 2, entry
4a)23
Rf 0.5 (CH2Cl2); IR nmax 2982, 2952, 2868, 1740, 1717, 1631, 1438,
1
1178, 1136; H-NMR (400 MHz, CDCl3) d 1.25 (t, J = 7.0 Hz,
3H), 1.42–1.50 (m, 2H), 1.57–1.65 (m, 2H), 2.25–2.30 (m, 4H),
3.61 (s, 3H), 4.15 (q, J = 7.0 Hz, 2H), 5.47 (d, J = 1.0 Hz, 1H), 6.09
(d, J = 1.0 Hz, 1H); 13C-NMR (100 MHz, CDCl3) d 14.22, 24.49,
27.91, 31.54, 33.85, 51.46, 60.60, 124.59, 140.56, 167.17, 173.99.
General experimental procedure for fragmentation with alcohols
A magnetically stirred solution of b-ketoester 1 (0.5 mmol) in dry
alcohol (20 mmol), was reacted at the specified temperature with
K2CO3 (1–2 equiv.) for a given period of time (for details see Ta-
bles 1, 2 and 3). The reaction mixture was filtered then evaporated
and the resultant oil purified via flash column chromatography.
Dimethyl 2-methyleneheptanedioate (5a, Table 2, entry 4b)19a
Rf 0.4 (CH2Cl2); IR nmax 2995, 2953, 2866, 1723, 1631, 1438, 1198,
1
1167, 1138; H-NMR (400 MHz, CDCl3) d 1.44–1.51 (m, 2H),
1.59–1.66 (m, 2H), 2.27–2.32 (m, 4H), 3.63 (s, 3H), 3.72 (s, 3H),
5.51 (q, J = 1.0 Hz, 1H), 6.11 (t, J = 1.0 Hz, 1H); 13C-NMR
(100 MHz, CDCl3) d 24.52, 27.92, 31.61, 33.89, 51.53, 51.84,
124.96, 140.28, 167.69, 174.05.
Diethyl 2-methyleneheptanedioate (5a, Table 1, entry 6)22
Rf 0.5 (CH2Cl2); IR nmax 2982, 2939, 2869, 1718, 1631, 1464, 1446,
1
1370, 1237, 1136; H-NMR (400 MHz, CDCl3) d 1.18 (t, J =
1-Ethyl 7-isopropyl 2-methyleneheptanedioate (5a, Table 2, entry
5a)
7.0 Hz, 3H), 1.23 (t, J = 7.0 Hz, 3H), 1.42–1.46 (m, 2H), 1.55–1.61
(m, 2H), 2.22–2.27 (m, 4H), 4.05 (q, J = 7.0 Hz, 2H), 4.13 (q, J =
7.0 Hz, 2H), 5.45 (q, J = 1.0 Hz, 1H), 6.07 (t, J = 7.0 Hz, 1H);
13C-NMR (100 MHz, CDCl3) d 14.17, 14.21, 24.47, 27.85, 31.49,
34.09, 60.18, 60.54, 124.52, 140.52, 167.16, 173.55.
Rf 0.4 (CH2Cl2); IR nmax 2981, 2936, 2871, 1731, 1632, 1466, 1373,
1
1179, 1110; H-NMR (400 MHz, CDCl3) d 1.21 (d, J = 6.5 Hz,
6H), 1.28 (t, J = 7.0 Hz, 3H), 1.45–1.53 (m, 2H), 1.59–1.67 (m,
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2H), 2.25–2.32 (m, 4H), 4.19 (q, J = 7.0 Hz, 2H), 4.98 (sept, J =
6.5 Hz, 1H), 5.50 (q, J = 1.0 Hz, 1H), 6.12 (t, J = 1.0 Hz, 1H);
13C-NMR (100 MHz, CDCl3) d 14.32, 21.96, 24.68, 27.98, 31.64,
34.58, 60.69, 67.53, 124.64, 140.70, 167.31, 173.23; HRMS found
(M+H)+, 243.1592, C13H22O4 requires (M+H)+, 243.1596.
7.5 Hz, 2H), 4.10 (q, J = 7.0 Hz, 2H), 5.05 (quint, J = 7.0 Hz,
1H), 5.42 (q, J = 1.0 Hz, 1H), 5.95 (br d, J = 7.0 Hz 1H), 6.05 (t,
J = 1.0 Hz, 1H), 7.14–7.26 (m, 5H); 13C-NMR (100 MHz, CDCl3)
d 14.24, 21.82, 25.28, 28.05, 31.51, 36.46, 48.62, 60.63, 124.69,
126.21, 127.28, 128.64, 140.56, 143.46, 167.30, 171.98; HRMS
found (M+H)+ 304.1911, C18H25NO3 requires (M+H)+ 304.1913.
Diisopropyl 2-methyleneheptanedioate (5a, Table 2, entry 5b)
6-(Ethoxycarbonyl)hept-6-enoic acid (5a, Table 2, entry 8a)
Rf 0.5 (CH2Cl2); IR nmax 2981, 2938, 2871, 1732, 1715, 1631, 1374,
1180, 1109; H-NMR (400 MHz, CDCl3) d 1.22 (d, J = 6.0 Hz,
1
A magnetically stirred solution of b-ketoester 1a (310 mg, 1 mmol)
in CH2Cl2 (8 mL) was treated with NaOH (80 mg, 2 mmol) and
then refluxed for 14 h. After cooling to room temperature the
mixture was washed with HCl (3 ¥ 10 mL of a 1 M aqueous
solution). The combined aqueous fractions were extracted with
CH2Cl2 (3 ¥ 10 mL) and the combined organic fractions dried
(MgSO4) and concentrated under reduced pressure. The resultant
oil was purified via flash column chromatography to yield the title
compound (136 mg, 68%).
6H), 1.26 (d, J = 6.5 Hz, 6H), 1.45–1.53 (m, 2H), 1.60–1.68 (m,
2H), 2.26–2.32 (m, 4H), 4.99 (sept, J = 6.5 Hz, 1H), 5.05 (sept, J =
6.0 Hz, 1H), 5.48 (d, J = 1.0 Hz, 1H), 6.11 (d, J = 1.0 Hz, 1H);
13C-NMR (100 MHz, CDCl3) d 21.95, 21.98, 24.71, 28.03, 31.64,
34.62, 67.55, 68.04, 124.36, 141.10, 166.86, 173.26; HRMS found
(M+H)+ 257.1749, C14H24O4 requires (M+H)+ 257.1753.
General experimental procedure for fragmentation with amines
Rf 0.2 (3 : 7, v/v EtOAc–hexane); IR nmax 2982, 2940, 2871, 1714,
1630, 1412, 1301, 1180, 1136; 1H-NMR (400 MHz, CDCl3) d 1.29
(t, J = 7.0 Hz, 3H), 1.49–1.57 (m, 2H), 1.66 (quint, J = 7.5 Hz,
2H), 2.32 (t, J = 7.5 Hz, 2H), 2.37 (t, J = 7.5 Hz, 2H), 4.20 (q, J =
7.0 Hz, 2H), 5.52 (d, J = 1.5 Hz, 1H), 6.14 (d, J = 1.5 Hz, 1H),
10.25 (br s, 1H); 13C-NMR (100 MHz, CDCl3) d 14.32, 24.30,
27.92, 31.63, 33.91, 60.78, 124.84, 140.56, 167.36, 179.81; HRMS
found (M+H)+, 201.1122, C10H16O4 requires (M+H)+, 201.1127.
A magnetically stirred solution of b-ketoester 1 (0.5 mmol) in
CH2Cl2 (5 mL) was treated with amine (1–4 equiv.), K2CO3 (4
equiv.) and DMAP (0–20 mol%) then brought to reflux for a given
period of time (for details see Table 2, entry 7 and Table 3, entries
5b–c, 9b). The reaction mixture was filtered then evaporated and
the resultant oil purified via flash column chromatography.
Ethyl 7-(benzylamino)-2-methylene-7-oxoheptanoate (5a, Table 2,
entry 7a)
2-Methyleneheptanedioic acid (5a, Table 2, entry 8b)24
A magnetically stirred solution of b-ketoester 1a (310 mg, 1 mmol)
and NaOH (160 mg, 4 mmol) in ethanol (3 mL) was refluxed for
14 h. After cooling to room temperature the mixture was acidified
with HCl (5 mL of a 2 M aqueous solution) and extracted with
EtOAc (3 ¥ 7 mL). The combined organic fractions were dried
(MgSO4) and concentrated under reduced pressure. Recrystallisa-
tion from H2O afforded the pure product (108 mg, 63%).
Mp. 89–90 ◦C; IR nmax 2946, 2903, 1677, 1627, 1427, 1406, 1257,
925; 1H-NMR (400 MHz, CDCl3) d 1.52–1.60 (m, 2H), 1.64–1.71
(m, 2H), 2.33 (t, J = 7.0 Hz, 2H), 2.40 (t, J = 7.0 Hz, 2H), 5.66
(d, J = 1.0 Hz, 1H), 6.30 (d, J = 1.0 Hz, 1H), 11.62 (br s, 1H);
13C-NMR (100 MHz, CDCl3) d 24.01, 27.66, 31.26, 33.72, 127.49,
139.61, 172.69, 180.09.
Rf 0.4 (1 : 1, v/v EtOAc–hexane); IR nmax 3292, 2933, 2865, 1715,
1651, 1548, 1455, 1369, 1245, 1179, 1135; H-NMR (400 MHz,
1
CDCl3) d 1.21 (t, J = 7.0 Hz, 3H), 1.40–1.48 (m, 2H), 1.62
(quint, J = 7.5 Hz, 2H), 2.16 (t, J = 7.5 Hz, 2H), 2.22–2.26 (m,
2H), 4.11 (q, J = 7.0 Hz, 2H), 4.36 (d, J = 5.5 Hz, 2H), 5.45
(q, J = 1.0 Hz, 1H), 5.77 (br s, 1H), 6.06 (t, J = 1.0 Hz, 1H),
7.17–7.28 (m, 5H); 13C-NMR (100 MHz, CDCl3) d 14.32, 25.36,
28.18, 31.60, 36.53, 43.72, 60.73, 124.81, 127.61, 127.95, 128.82,
138.53, 140.63, 167.38, 172.80; HRMS found (M+H)+, 290.1753,
C17H23NO3 requires (M+H)+, 290.1756.
Ethyl 7-(4-methoxybenzylamino)-2-methylene-7-oxoheptanoate
(5a, Table 2, entry 7b)
Ethyl 7-hydroxy-2-methyleneheptanoate (5b)
Rf 0.3 (1 : 1, v/v EtOAc–hexane); IR nmax 3286, 2977, 2933, 2867,
1715, 1641, 1545, 1370, 1301, 1179, 1139; H-NMR (400 MHz,
1
A magnetically stirred solution of b-ketoester 1a (155 mg,
0.5 mmol) in EtOH (5 mL) was treated with NaBH4 (47.5 mg,
1.25 mmol) for 14 h. The mixture was diluted with HCl (10 mL
of a 0.5 M aqueous solution) and extracted with CH2Cl2 (3 ¥
10 mL). The combined organic fractions were dried (MgSO4)
and concentrated under reduced pressure. The resultant oil was
purified via flash column chromatography to yield the title
compound (56 mg, 60%).
CDCl3) d 1.26 (t, J = 7.0 Hz, 3H), 1.44–1.52 (m, 2H), 1.62–1.69
(m, 2H), 2.19 (t, J = 7.5 Hz, 2H), 2.28 (t, J = 7.5 Hz, 2H), 3.76 (s,
3H), 4.15 (q, J = 7.0 Hz, 2H), 4.32 (d, J = 5.5 Hz, 2H), 5.49 (q, J =
1.0 Hz, 1H), 5.95 (br s, 1H), 6.11 (t, J = 1.0 Hz, 1H), 6.82 (d, J =
8.5 Hz, 2H), 7.16 (d, J = 8.5 Hz, 2H); 13C-NMR (100 MHz, CDCl3)
d 14.26, 25.32, 28.11, 31.54, 36.44, 43.08, 55.34, 60.66, 114.11,
124.72, 129.20, 130.65, 140.57, 159.05, 167.31, 172.71; HRMS
found (M+H)+, 320.1856, C18H25NO4 requires (M+H)+, 320.1862.
Rf 0.3 (3 : 7, v/v EtOAc–hexane); IR nmax 3390, 2982, 2936, 2863,
1715, 1633, 1302, 1181; 1H-NMR (400 MHz, CDCl3) d 1.30 (t, J =
7.0 Hz, 3H), 1.37–1.43 (m, 2H), 1.47–1.52 (m, 3H), 1.55–1.62 (m,
2H), 2.31 (td, J = 7.5 Hz, 1.0 Hz, 2H), 3.64 (t, J = 7.0 Hz, 2H),
4.20 (q, J = 7.0 Hz, 2H), 5.51 (q, J = 1.0 Hz, 1H), 6.12 (t, J =
1.0 Hz, 1H); 13C-NMR (100 MHz, CDCl3) d 14.34, 25.48, 28.37,
31.97, 32.67, 60.71, 63.02, 124.49, 141.06, 167.49; HRMS found
(M+H)+ 187.1329, C10H18O3 requires (M+H)+ 187.1334.
Ethyl 2-methylene-7-oxo-7-(1-phenylethylamino)heptanoate (5a,
Table 2, entry 7c)
Rf 0.4 (1 : 1, v/v EtOAc–hexane); IR nmax 3232, 2983, 2915, 1711,
1620, 1555, 1510, 1242, 1145, 1022; 1H-NMR (400 MHz, CDCl3)
d 1.20 (t, J = 7.0 Hz, 3H), 1.39 (d, J = 7.0 Hz, 3H), 1.37–1.44
(m, 2H), 1.54–1.62 (m, 2H), 2.11 (t, J = 7.5 Hz, 2H), 2.22 (t, J =
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Diethyl 2-(iodomethylene)heptanedioate (5d)
1H), 7.13–7.37 (m, 5H); 13C-NMR (100 MHz, CDCl3) d major:
14.28, 23.83, 31.46, 32.83, 34.80, 50.85, 60.69, 124.97, 127.36,
128.08, 128.63, 137.59, 140.40, 167.23, 172.69 minor: 14.26, 24.00,
31.39, 32.42, 34.00, 53.38, 60.66, 124.90, 126.35, 127.65, 128.99,
136.78, 140.33, 167.19, 173.06. HRMS found (M+H)+, 290.1750,
C17H23NO3 requires (M+H)+, 290.1756.
Rf E-isomer: 0.67, Z-isomer: 0.62 (1 : 4, v/v EtOAc–hexane); IR
nmax 2934, 1736, 1714, 1594, 1368, 1295, 1214, 1095; H-NMR
1
(400 MHz, CDCl3) d E-isomer: 1.25 (t, J = 7.0 Hz, 3H), 1.30 (t,
J = 7.0 Hz, 3H), 1.46–1.54 (m, 2H), 1.66–1.73 (m, 2H), 2.34 (t,
J = 7.5 Hz, 2H), 2.49–2.53 (m, 2H), 4.13 (q, J = 7.0 Hz, 2H), 4.20
(q, J = 7.0 Hz, 2H), 7.77 (s, 1H) Z-isomer: 1.25 (t, J = 7.0 Hz,
3H), 1.35 (t, J = 7.0 Hz, 3H), 1.45–1.53 (m, 2H), 1.60–1.67 (m,
2H), 2.30 (t, J = 7.5 Hz, 2H), 2.42 (td, J = 7.5 Hz, 1.0 Hz, 2H),
4.12 (q, J = 7.0 Hz, 2H), 4.28 (q, J = 7.0 Hz, 2H), 6.71 (s, 1H);
13C-NMR (100 MHz, CDCl3) d E-isomer: 14.31, 14.42, 24.82,
27.40, 33.68, 34.29, 60.39, 61.44, 98.55, 143.62, 163.58, 173.65
Z-isomer: 14.31, 14.39, 24.33, 27.79, 34.08, 36.49, 60.46, 61.35,
81.48, 144.41, 167.15, 173.49; HRMS found (M+H)+, 355.0400,
C12H19IO4 requires (M+H)+, 355.0406.
Ethyl 6-(dibenzylamino)-2-methylene-6-oxohexanoate (5i)
Rf 0.4 (3 : 7, v/v EtOAc–hexane); IR nmax 3030, 2980, 2934, 1713,
1
1650, 1605, 1495, 1452, 1366, 1182, 1028; H-NMR (400 MHz,
CDCl3) d 1.19 (t, J = 7.0 Hz, 3H), 1.81–1.86 (m, 2H), 2.72 (t, J =
7.5 Hz, 2H), 2.35 (t, J = 7.5 Hz, 2H), 4.11 (q, J = 7.0 Hz, 2H), 4.35
(s, 2H), 4.52 (s, 2H), 5.44 (q, J = 1.0 Hz, 1H), 6.05 (t, J = 1.0 Hz,
1H), 7.04–7.28 (m, 10H); 13C-NMR (100 MHz, CDCl3) d = 14.33,
24.12, 31.46, 32.65, 48.34, 50.05, 60.75, 125.04, 126.51, 126.86,
127.51, 127.74, 128.27, 128.42, 128.73, 129.09, 129.11, 136.71,
137.62, 139.89, 140.38, 167.26, 173.25; HRMS found (M+Na)+,
388.1882, C23H27NO3 requires (M+Na)+, 388.1889.
Ethyl 6-cyanohept-6-enoate (5e)
Rf 0.8 (3 : 7, v/v EtOAc–hexane); IR nmax 2983, 2940, 2223, 1732,
Dimethyl 2-methyleneoctanedioate (5j)15a
1
1622, 1251, 1185; H-NMR (400 MHz, CDCl3) d 1.25 (t, J =
7.0 Hz, 3H), 1.56–1.70 (m, 4H), 2.27 (t, J = 7.5 Hz, 2H), 2.33 (t,
J = 7.5 Hz, 2H), 4.13 (q, J = 7.0 Hz, 2H), 5.72 (q, J = 1.0 Hz, 1H),
5.85 (d, J = 1.0 Hz, 1H); 13C-NMR (100 MHz, CDCl3) d 14.37,
24.02, 27.09, 33.96, 34.44, 60.53, 118.66, 122.96, 130.60, 173.35;
HRMS found (M+H)+ 182.1182, C10H15NO2 requires (M+H)+
182.1181; found (M+Na)+ 204.0997, requires (M+Na)+ 204.1000.
Rf 0.4 (CH2Cl2); IR nmax 2996, 2951, 2862, 1723, 1631, 1438, 1334,
1290, 1263, 1198, 1167; 1H-NMR (400 MHz, CDCl3) d 1.28–1.35
(m, 2H), 1.41–1.49 (m, 2H), 1.61 (quint, J = 7.5 Hz, 2H), 2.25–2.29
(m, 4H), 3.63 (s, 3H), 3.71 (s, 3H), 5.48 (d, J = 1.0 Hz, 1H), 6.09
(d, J = 1.0 Hz, 1H); 13C-NMR (100 MHz, CDCl3) d 24.76, 28.09,
28.71, 31.76, 34.03, 51.50, 51.81, 124.73, 140.61, 167.77, 174.17.
Ethyl 6-benzoylhept-6-enoate (5f)
Diethyl 2-methylenetridecanedioate (5k)
Rf 0.6 (1 : 4, v/v EtOAc–hexane); IR nmax 2937, 2866, 1732, 1658,
1597, 1448, 1177, 982, 754, 708; H-NMR (400 MHz, CDCl3) d
Rf 0.7 (3 : 7, v/v EtOAc–hexane); IR nmax 2928, 2856, 1737, 1719,
1631, 1466, 1370, 1252, 1179; H-NMR (400 MHz, CDCl3) d
1
1
1.24 (t, J = 7.0 Hz, 3H), 1.51–1.60 (m, 2H), 1.67–1.74 (m, 2H),
2.33 (t, J = 7.5 Hz, 2H), 2.49 (tt, J = 7.5 Hz, 1.0 Hz, 2H), 4.12
(q, J = 7.0 Hz, 2H), 5.60 (d, J = 1.0 Hz, 1H), 5.84 (q, J = 1.0 Hz,
1H), 7.41–7.45 (m, 2H), 7.51–7.55 (m, 1H), 7.73–7.74 (m, 2H); 13C-
NMR (100 MHz, CDCl3) d 14.25, 24.64, 27.67, 31.96, 34.12, 60.25,
125.60, 128.20, 129.51, 132.19, 137.90, 147.91, 173.58, 198.25;
HRMS found (M+H)+ 261.1486, C16H20O3 requires (M+H)+
261.1491, found (M+Na)+ 283.1305, requires (M+Na)+ 283.1310.
1.23–1.32 (m, 18H), 1.41–1.47 (m, 2H), 1.59–1.63 (m, 2H), 2.38
(t, J = 7.5 Hz, 4H), 4.12 (q, J = 7.0 Hz, 2H), 4.20 (q, J =
7.0 Hz, 2H), 5.50 (q, J = 1.0 Hz, 1H), 6.11 (t, J = 1.0 Hz,
1H); 13C-NMR (100 MHz, CDCl3) d 14.37, 14.41, 25.14, 28.56,
29.29, 29.35, 29.39, 29.54, 29.57, 29.64, 32.00, 34.55, 60.29, 60.66,
124.23, 141.34, 167.58, 174.05; HRMS found (M+H)+, 313.2366,
C18H32O4 requires (M+H)+, 313.2379.
Ethyl 2-(2-(ethoxycarbonyl)allyl)benzoate (5l)23
Diethyl 2-methylenehexanedioate (5g)15b
Rf 0.4 (1 : 9, v/v EtOAc–hexane); IR nmax 2982, 2938, 2906, 1719,
1633, 1602, 1578, 1448, 1367, 1259; 1H-NMR (400 MHz, CDCl3)
d 1.26 (t, J = 7.0 Hz, 3H), 1.34 (t, J = 7.0 Hz, 3H), 4.01 (s, 2H), 4.19
(q, J = 7.0 Hz, 2H), 4.31 (q, J = 7.0 Hz, 2H), 5.19 (q, J = 1.5 Hz,
1H), 6.19 (q, J = 1.5 Hz, 1H), 7.23 (dd, J = 7.5 Hz, 1.0 Hz, 1H),
7.29 (td, J = 7.5 Hz, 1.0 Hz, 1H), 7.43 (td, J = 7.5 Hz, 1.5 Hz, 1H),
7.90 (dd, J = 7.5 Hz, 1.5 Hz, 1H); 13C-NMR (100 MHz, CDCl3)
d 14.26, 14.29, 36.04, 60.81, 60.97, 125.50, 126.62, 130.64, 130.85,
131.66, 131.97, 140.01, 140.56, 167.07, 167.52.
Rf 0.6 (1 : 4, v/v EtOAc–hexane); IR nmax 2982, 2939, 2875, 1735,
1630, 1463, 1447, 1372, 1180; 1H-NMR (500 MHz, CDCl3) d 1.25
(t, J = 7.0 Hz, 3H), 1.29 (t, J = 7.0 Hz, 3H), 1.78–1.84 (m, 2H),
2.30–2.35 (m, 4H), 4.12 (q, J = 7.0 Hz, 2H), 4.18 (q, J = 7.0 Hz,
2H), 5.54 (q, J = 1.0 Hz, 1H), 6.17 (t, J = 1.0 Hz, 1H); 13C-NMR
(125 MHz, CDCl3) d 14.17, 14.21, 23.56, 31.16, 33.60, 60.27, 60.65,
125.12, 139.93, 167.00, 173.37.
Ethyl 6-(benzyl(methyl)amino)-2-methylene-6-oxohexanoate (5h)
Ethyl 2-(3-(ethoxycarbonyl)but-3-enyl)benzoate (5m)
3 : 2 Ratio of rotamers; Rf 0.6 (1 : 1, v/v EtOAc–hexane); IR nmax
2932, 1715, 1648, 1452, 1406, 1265, 1183, 1139, 1028; H-NMR
1
Rf 0.6 (1 : 4, v/v EtOAc–hexane); IR nmax 2982, 2937, 2874, 1718,
1
(400 MHz, CDCl3) d major: 1.29 (t, J = 7.0 Hz, 3H), 1.82–1.92
(m, 2H), 2.31–2.41 (m, 4H), 2.89 (s, 3H), 4.19 (q, J = 7.0 Hz,
2H), 4.58 (s, 2H), 5.56 (d, J = 1.0 Hz, 1H), 6.17 (d, J = 1.0 Hz,
1H), 7.13–7.37 (m, 5H) minor: 1.26 (t, J = 7.0 Hz, 3H), 1.82–1.92
(m, 2H), 2.31–2.41 (m, 4H), 2.94 (s, 3H), 4.19 (q, J = 7.0 Hz,
2H), 4.51 (s, 2H), 5.52 (d, J = 1.0 Hz, 1H), 6.13 (d, J = 1.0 Hz,
1630, 1448, 1367, 1255, 1186, 1145, 1078; H-NMR (400 MHz,
CDCl3) d 1.31 (t, J = 7.0 Hz, 3H), 1.38 (t, J = 7.0 Hz, 3H), 2.62 (td,
J = 8.0 Hz, 0.5 Hz, 2H), 3.14 (t, J = 8.0 Hz, 2H), 4.21 (q, J = 7.0 Hz,
2H), 4.35 (q, J = 7.0 Hz, 2H), 5.51 (q, J = 1.0 Hz, 1H), 6.15 (t, J =
1.0 Hz, 1H), 7.23–7.27 (m, 2H), 7.41 (td, J = 7.5 Hz, 1.5 Hz, 1H),
7.88 (dd, J = 7.5 Hz, 1.0 Hz, 1H); 13C-NMR (100 MHz, CDCl3)
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d 14.37, 14.45, 33.51, 33.85, 60.74, 60.96, 125.20, 126.18, 130.11,
130.74, 131.30, 131.95, 140.40, 143.23, 167.31, 167.76; HRMS
found (M+H)+, 277.1437, C16H20O4 requires (M+H)+, 277.1440.
EtOAc (3 ¥ 7 mL). The combined organic fractions were dried
(MgSO4) and concentrated under reduced pressure. The resultant
residue was purified via flash column chromatography to produce
the title compound (198 mg, 60%).
Ethyl 4-(2-(4-methoxybenzylcarbamoyl)phenyl)-2-methylene-
butanoate (5n)
Rf 0.13 (1 : 4, v/v EtOAc–hexane); IR nmax 2957, 2930, 2858,
1713, 1631, 1256, 1181, 1085; 1H-NMR (400 MHz, CDCl3) d 0.03
(s, 6H), 0.87 (s, 9H), 1.29 (t, J = 7.0 Hz, 3H), 1.64–1.73 (m, 1H),
1.79–1.87 (m, 1H), 2.36–2.51 (m, 4H), 3.91–3.97 (m, 1H), 4.20 (q,
J = 7.0 Hz, 2H), 5.59 (d, J = 1.0 Hz, 1H), 6.21 (d, J = 1.0 Hz, 1H);
13C-NMR (100 MHz, CDCl3) d -4.62, -4.34, 14.33, 18.12, 25.97,
29.66, 31.40, 40.32, 60.84, 69.75, 128.10, 137.40, 167.11, 180.02;
HRMS found (M+H)+ 331.1930, C16H30O5Si requires (M+H)+
331.1941; found (M+Na)+ 353.1752, requires (M+Na)+ 353.1760.
Rf 0.3 (3 : 7, v/v EtOAc–hexane); IR nmax 3245, 2931, 1709, 1634,
1511, 1452, 1251, 1178, 1028; 1H-NMR (400 MHz, CDCl3) d 1.28
(t, J = 7.0 Hz, 3H), 2.60–2.63 (m, 2H), 2.95–2.99 (m, 2H), 3.80 (s,
3H), 4.17 (q, J = 7.0 Hz, 2H), 4.55 (d, J = 5.5 Hz, 2H), 5.50 (d,
J = 1.5 Hz, 1H), 6.09 (br s, 1H), 6.13 (d, J = 1.5 Hz, 1H), 6.88 (d,
J = 9.0 Hz, 2H), 7.17–7.23 (m, 2H), 7.29 (d, J = 9.0 Hz, 2H), 7.32–
7.36 (m, 2H); 13C-NMR (100 MHz, CDCl3) d 14.37, 32.56, 33.84,
43.62, 55.46, 60.79, 114.33, 125.43, 126.25, 126.97, 129.44, 130.02,
130.48, 130.57, 136.61, 139.67, 140.24, 159.28, 167.34, 169.91;
HRMS found (M+H)+, 368.1862, C22H25NO4 requires (M+H)+,
368.1862.
Ethyl 2-((5-oxotetrahydrofuran-2-yl)methyl)acrylate (8)
A magnetically stirred solution of 5r (83 mg, 0.25 mmol) in dry
ethanol (3 mL) was reacted with ceric ammonium nitrate (206 mg,
0.38 mmol) at room temperature for 40 h. The solvent was removed
under reduced pressure, the residue re-dissolved in diethyl ether
(10 mL) and washed with NaHCO3 (10 mL of a saturated aqueous
solution), H2O (10 mL) and brine (10 mL). The organic fraction
was dried (MgSO4) and concentrated under reduced pressure. The
resultant oil was purified via flash column chromatography to
produce the title compound (40 mg, 81%).
Rf 0.7 (1 : 1, v/v Et2O–CH2Cl2); IR nmax 2984, 1774, 1713, 1633,
1179, 914, 732; 1H-NMR (400 MHz, CDCl3) d 1.31 (t, J = 7.0 Hz,
3H), 1.86–1.96 (m, 1H), 2.29–2.38 (m, 1H), 2.51–2.56 (m, 2H),
2.67–2.70 (m, 2H), 4.22 (q, J = 7.0 Hz, 2H), 4.72 (quint, J =
7.0 Hz, 1H), 5.74 (d, J = 1.0 Hz, 1H), 6.32 (J = 1.0 Hz, 1H); 13C-
NMR (100 MHz, CDCl3) d 14.33, 27.79, 28.82, 38.05, 61.18, 79.03,
128.75, 135.48, 166.74, 176.91; HRMS found (M+H)+ 199.0964,
C10H14O4 requires (M+H)+ 199.0970.
Diethyl 2-methyl-6-methyleneheptanedioate (5o)
Rf 0.6 (CH2Cl2); IR nmax 2980, 2938, 2874, 1731, 1632, 1464, 1371,
1
1301, 1267, 1153; H-NMR (400 MHz, CDCl3) d 1.14 (d, J =
7.0 Hz, 3H), 1.25 (t, J = 7.0 Hz, 3H), 1.29 (t, J = 7.0 Hz, 3H), 1.42–
1.52 (m, 3H), 1.64–1.72 (m, 1H), 2.28–2.31 (m, 2H), 2.39–2.47 (m,
1H), 4.12 (q, J = 7.0 Hz, 2H), 4.20 (q, J = 7.0 Hz, 2H), 5.51 (q, J =
1.0 Hz, 1H), 6.13 (t, J = 1.0 Hz, 1H); 13C-NMR (100 MHz, CDCl3)
d 14.35, 14.40, 17.19, 26.14, 31.84, 33.38, 39.51, 60.29, 60.72,
124.65, 140.75, 167.36, 176.83; HRMS found (M+H)+, 243.1589,
C13H22O4 requires (M+H)+, 243.1596.
Diethyl 4-(tert-butyldimethylsilyloxy)-2-methyleneheptanedioate
(5p)
Rf 0.5 (1 : 9, v/v EtOAc–hexane); IR nmax 2957, 2931, 2858, 1736,
1718, 1630, 1255, 1178, 1084; 1H-NMR (400 MHz, CDCl3) d 0.02
(s, 3H), 0.03 (s, 3H), 0.87 (s, 9H), 1.24 (t, J = 7.0 Hz, 3H), 1.30 (t,
J = 7.0 Hz, 3H), 1.63–1.72 (m, 1H), 1.77–1.86 (m, 1H), 2.30–2.50
(m, 4H), 3.91 (quint d, J = 6.5 Hz, 1.5 Hz, 1H), 4.11 (q, J = 7.0 Hz,
2H), 4.21 (q, J = 7.0 Hz, 2H), 5.59 (d, J = 1.5 Hz, 1H), 6.21 (d,
J = 1.5 Hz, 1H); 13C-NMR (100 MHz, CDCl3) d -4.48, -4.31,
14.37 (2XC), 18.16, 26.00, 29.98, 31.79, 40.38, 60.39, 60.80, 69.87,
128.03, 137.48, 167.13, 173.89; HRMS found (M+H)+, 359.2242,
C18H34O5Si requires (M+H)+, 359.2254.
3-(4-Methylene-5-oxotetrahydrofuran-2-yl)propanoic acid (9)
A magnetically stirred solution of 5r (60 mg, 2 mmol) in dry THF
(3 mL) was reacted with TBAF (0.2 mL of a 1 M solution in
THF) at room temperature for 14 h. The reaction mixture was
diluted with NH4Cl (10 mL of a saturated aqueous solution) and
extracted with EtOAc (3 ¥ 10 mL). The combined organic fractions
were washed with brine (10 mL), dried (MgSO4) and concentrated
under reduced pressure. The resultant oil was purified via flash
column chromatography to provide the title compound (17 mg,
49%).
1-Ethyl 6-methyl 2-methylenehexanedioate (5q)15b
Rf 0.03 (1 : 1, v/v EtOAc–hexane); IR nmax 2928, 1758, 1696,
1
1629, 1420, 1359, 1172, 1026; H-NMR (400 MHz, CDCl3) d
Rf 0.5 (CH2Cl2); IR nmax 2985, 2954, 1712, 1631, 1438, 1370, 1265,
909; 1H-NMR (400 MHz, CDCl3) d 1.30 (t, J = 7.0 Hz, 3H), 1.82
(quint, J = 7.5 Hz, 2H), 2.32–2.36 (m, 4H), 3.67 (s, 3H), 4.20 (q,
J = 7.0 Hz, 2H), 5.54 (q, J = 1.0 Hz, 1H), 6.17 (t, J = 1.0 Hz, 1H);
13C-NMR (100 MHz, CDCl3) d 14.34, 23.73, 31.34, 33.51, 51.66,
60.81, 125.25, 140.10, 167.16, 173.93.
1.87–1.97 (m, 1H), 2.32–2.40 (m, 1H), 2.53–2.58 (m, 2H), 2.68–
2.70 (m, 2H), 4.74 (quint, J = 7.0 Hz, 1H), 5.89 (s, 1H), 6.48 (s,
1H); 13C-NMR (100 MHz, CDCl3) d 27.81, 28.83, 37.60, 78.90,
122.87, 131.53, 171.59, 177.05; HRMS found (M+H)+ 171.0653,
C8H10O4 requires (M+H)+ 171.0657; found (M+Na)+ 193.0474,
requires (M+Na)+ 193.0477.
4-((tert-Butyldimethylsilyl)oxy)-6-(ethoxycarbonyl)hept-6-enoic
acid (5r)
General procedures for kinetic analysis
A magnetically stirred solution of b-ketoester 1p (440 mg, 1 mmol)
and NaOH (160 mg, 4 mmol) in ethanol (3 mL) was refluxed for
14 h. After cooling to room temperature the mixture was acidified
with HCl (5 mL of a 2 M aqueous solution) and extracted with
A magnetically stirred solution of the competing b-ketoesters 1
(0.7 mmol of each) in dry CD3OD (56 mmol) was reacted with
K2CO3 (2.8 mmol) at the specified temperature (see Fig. 1). At the
specified times aliquots (100 mL) were removed and quenched by
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addition of HCl (100 mL of a 3 M aqueous solution). The mixtures
Kitazume, K. Suzuki and E. Tosaka, Tetrahedron Lett., 1998, 39, 4059;
(c) E. Charonnet, M.-H. Filippini and J. Rodriguez, Synthesis, 2001,
788.
were extracted with CDCl3 (0.7 mL) and analyzed by 1H-NMR.
9 For early examples see: (a) L. N. Owen and A. G. Peto, J. Chem. Soc.,
1956, 1146; (b) H. Gedes, H. Marschall and P. Weyerstahl, Chem. Ber.,
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10 For selected examples see: (a) R. G. Salomon and M. F. Salomon, J. Org.
Chem., 1975, 40, 1488; (b) A. P. Kozikowski and A. Ames, J. Am. Chem.
Soc., 1981, 103, 3923; (c) M.-H. Filippini and J. Rodriguez, Synth.
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Pons, M. Rajman, R. Faure and J. Rodriguez, Chem.–Eur. J., 2001, 7,
1056; (e) A. Avenoza, J. I. Barriobero, J. H. Busto and J. M. Peregrina,
J. Org. Chem., 2003, 68, 2889; (f) S. Sano, H. Shimizu and Y. Nagao,
Tetrahedron Lett., 2005, 46, 2883; (g) J. R. Goodell, J. P. McMullen,
N. Zaborenko, J. R. Maloney, C.-X. Ho, K. F. Jensen, J. A. Porco and
A. B. Beeler, J. Org. Chem., 2009, 74, 6169.
11 For related retro-aldol see: K. Xu, G. Lalic, S. M. Sheehan and M. D.
Shair, Angew. Chem., Int. Ed., 2005, 44, 2259.
12 J. Hierold, A. Gray-Weale and D. W. Lupton, Chem. Commun., 2010,
46, 6789.
13 For a synthetic approach to b-ketoesters 1 see: A. L. J. Beckwith, D. M.
O’Shea and S. W. Westwood, J. Am. Chem. Soc., 1988, 110, 2565.
14 In addition to limitations already introduced see: D. Bo¨ttger and P.
Welzel, Liebigs Ann. Chem., 1985, 1985, 837.
15 For recent applications of related materials in synthesis see: (a) J. Le
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17 For a review on a-methylene-g-butyrolactones see: H. M. R. Hoffmann
and J. Rabe, Angew. Chem., Int. Ed. Engl., 1985, 24, 94.
18 It is unlikely that following desymmetrisation diastereoselective alky-
lation will be possible, however it is of no consequence since the
fragmentation removes this chiral centre.
19 (a) B. C. Ranu, P. Dutta and A. Sarkar, J. Chem. Soc., Perkin Trans.
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Acknowledgements
The authors thank the ARC (DP0881137) and Monash University
(ECR program) for financial support and Konrad Gebauer for
preliminary experimental contributions.
Notes and references
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792 | Org. Biomol. Chem., 2011, 9, 783–792
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The Royal Society of Chemistry 2011
©