Construction of Polycyclic β-Ketoesters Using a Homoconjugate Addition/Decarboxylative Dieckmann Annulation Strategy

Article abstract of DOI:10.1021/acs.joc.8b00754

The construction of arene-fused cyclic β-ketoesters from 2-iodoaryl esters and 1,1-cyclopropane diesters is detailed. The synthetic method takes advantage of a CuI·SMe₂-mediated homoconjugate addition followed by a decarboxylative Dieckmann cyclization to afford valuable polycyclic building blocks. Various iodoaryl esters and 1,1-cyclopropane diesters were evaluated, and the limitations of both reactions are discussed. Several mechanistic probes are detailed and synthetic applications are described.

Full text of DOI:10.1021/acs.joc.8b00754

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Note
Construction of Polycyclic #-Ketoesters using a Homoconjugate
Addition / Decarboxylative Dieckmann Annulation Strategy
Zhiwei Chen, Allen Y. Hong, and Xin Linghu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00754 • Publication Date (Web): 16 May 2018
Downloaded from http://pubs.acs.org on May 16, 2018
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Page 1 of 12
The Journal of Organic Chemistry
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Construction of Polycyclic β-Ketoesters Using a Homoconjugate
Addition / Decarboxylative Dieckmann Annulation Strategy
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Zhiwei Chen, Allen Y. Hong,* and Xin Linghu
Department of Small Molecule Process Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080,
United States
Supporting Information Placeholder
O
homoconjugate
addition
O
O
O
CO2R2
OR1
+
R2O
OR2
X
X
decarboxylative
cyclization
I
ABSTRACT: The construction of arene-fused cyclic β-ketoesters from 2-iodoaryl esters and 1,1-cyclopropane diesters is detailed.
The synthetic method takes advantage of a CuI·SMe2-mediated homoconjugate addition followed by a decarboxylative Dieckmann
cyclization to afford valuable polycyclic building blocks. Various iodoaryl esters and 1,1-cyclopropane diesters were evaluated and
the limitations of both reactions are discussed. Several mechanistic probes are detailed and synthetic applications are described.
Fused cyclic ketones are integral motifs in biologically ac-
tive molecules. In particular, α-tetralones and their derivatives
are important motifs in natural products and pharmaceuticals,
such as nimbiol, tetrahydroaltersolanol B, and tetracycline
(Scheme 1A). During the course of an internal research pro-
gram in our laboratories, rapid access to a variety of tetralone
derivatives became critical for future studies. Synthetic routes
often had to be redesigned for different substitution patterns
because no satisfactory general synthetic route was available
for access to diverse arene and heteroarene scaffolds.1 To
remedy this deficiency, we reasoned that a homoconjugate
addition of an organometallic intermediate (generated from
metal-halogen exchange of an 2-halobenzoate ester 1) to a
cyclopropyl ester electrophile 2 could provide an intermediate
diester 3, which could then undergo a Dieckmann cyclization
to form a polycyclic β-ketoester 4 (Scheme 1B). We envi-
sioned that this would provide the basis for the preparation of
numerous building blocks for analog synthesis.
Our approach was marked by a number of foreseeable chal-
lenges. For the first transformation, chemoselective homocon-
jugate addition over carbonyl addition would be critical. For
the second cyclization stage, intramolecular annulation over
intermolecular pathways such as ester exchange (R1≠R2)
would be an important consideration.
For the metal-halogen exchange and homoconjugate addi-
tion processes, we were encouraged by the work of Knochel,
which showed that functionalized Grignard reagents can be
generated using i-PrMgCl·LiCl and aryl halides.2a,3 Subse-
quent transmetallation to form an organocuprate could enable
, ,6
coupling with various cyclopropyl electrophiles.4 5 The
diesters 3 formed in this manner could cyclize in a straight-
forward fashion to provide cyclic β-ketoester products 4.
As a starting point, we attempted the coupling of ethyl 2-
bromobenzoate 1b with cyclopropanecarboxylate esters 2
(Scheme 1B), but avoiding carbonyl addition side reactions
during formation of the corresponding Grignard reagent
proved difficult.2a However, the analogous aryl iodide 1a un-
derwent facile metal-halogen exchange2 after 30 min at –40
°C. Transmetallation of Grignard reagent 5 with CuCN gener-
ated the corresponding organocuprate, but no homoconjugate
addition was observed with ethyl cyclopropanecarboxylate,
even in the presence of Lewis acids.4,6
SCHEME 1. Natural Products Containing Tetralone Core
Structures and Annulation Design Strategy
A.
O
O
O
OH
OH
O
OH
O
OH
H
Me
OH
HO
HO
H2N
H
Me
Me
HO
OMe
Next, we performed the reaction with the more electrophilic
doubly activated diethyl cyclopropane-1,1-dicarboxylate (6a)
and were encouraged upon isolating desired triester 7aa in
28% yield (Scheme 2). However, in addition to the desired
triester product 7aa, ethyl benzoate (8), anthraquinone (9), and
biaryl dimer 10 were formed. Presumably, ethyl benzoate
arose from protonation of the organocuprate during aqueous
quench of the reaction aliquot. Anthraquinone and the biaryl
side product 10 were generated from dimerization via ketone
formation and oxidative coupling, respectively, and these hy-
potheses were confirmed through control experiments.
H
H
H
Me
H
OH
Me
Me2N
OH
nimbiol
tetracycline
tetrahydroaltersolanol B
B.
O
i) metal-halogen
exchange
O
O
CO2R2
cyclization
OR1
OR1
CO2R2
ii)
CO2R2
X
2
1
3
4
homoconjugate
addition
1b R1 = Et, X = Br
1a R1 = Et, X = I
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Page 2 of 12
SCHEME 3. Formation of β-Ketoester Mixtures During
the Unoptimized Cyclization of Mixed Ester Substrates
1
2
3
4
5
6
7
8
SCHEME 2. Side Products in an Unoptimized Homocon-
jugate Addition Reaction
O
O
O
CO2Me
CO2Et
NaOMe
CO2Et
OEt
+
6a
CO2Me
THF
O
CO2Et
O
70 °C
O
CuCN·2LiCl
CO2Me
7ab
4b
4a
i-PrMgCl•LiCl
OEt
OEt
OEt
CO2Et
5.4 : 1 ratio
(HPLC)
THF, –40 °C
(1.2 equiv)
–40→23 °C
MgCl
·LiCl
I
CO2Et
1a
7aa
28% yield
5
9
side products formed:
For our optimization studies, we investigated the cyclization
of triester 7aa to β-ketoester 4a. An initial survey of bases
showed that using an excess of Mg(Ot-Bu)2 in 2-MeTHF af-
forded the cyclic β-ketoester 4a in 51% yield. Motivated by
the promise of milder organic bases, the use of Et3N with
MgCl2 as an additive increased the yield to 78%. Notably, no
reactivity was observed when MgCl2 was omitted or dosed in
substoichiometric (0.2 equiv) quantities. Replacing MgCl2
with MgBr2 led to a further increase in the yield to 94%. Grati-
fyingly, application of the optimal conditions (Et3N, MgBr2, 2-
MeTHF) to mixed ester substrates such as 7ab led to no ob-
servable ester exchange.10
O
O
O
CO2Et
O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
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49
50
51
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60
OEt
OEt
H
CO2Et
EtO2C
CO2Et
ethyl benzoate (
8
)
anthraquinone (
16 A% HPLC
9
)
biaryl (10
)
desired product (7aa)
25 A% HPLC
29 A% HPLC
28 A% HPLC
To improve this challenging transformation, we considered
the introduction of additives for controlling the reaction pro-
file. Wicha and co-workers5c studied the homoconjugate addi-
tion of a methallylcopper intermediate (generated from a me-
thallyl Grignard reagent and CuI·SMe2) to cyclopropane
diesters and found that the addition of HMPA led to selective
homoconjugate addition over carbonyl addition. HMPA may
alter the aggregation state of the organocuprate intermediates
and influence their reactivity. Introduction of HMPA additive
to our system proved beneficial, and replacement of CuCN
with CuI·SMe2 led to an increase in reactivity and selectivity
(69% yield, 80:20 homoconjugate addition:biaryl formation).
Furthermore, the elimination of hazardous cyanide waste was
a positive feature of employing CuI·SMe2. Substitution of
HMPA with the less toxic 1,3-dimethyl-2-imidazolidinone
(DMI)7 slightly increased the selectivity (83:17 ratio), but de-
creased product formation (44% yield). Performing the metal-
halogen exchange at –78 °C with DMI additive further in-
creased the selectivity (96:4 ratio) while maintaining good
yield. This positive result was attributed to the suppression of
oxygen-mediated homodimerization of the organocuprate rela-
tive to the desired homoconjugate addition reaction. An evalu-
ation of solvents revealed that 2-MeTHF was superior to THF
and CPME, providing product 7aa in an optimal manner (79%
yield, 98:2 ratio homoconjugate addition:biaryl formation).
After our optimization studies, we turned our attention to
the substrate scope of the Cu-mediated homoconjugate addi-
tion step (Table 1). We were pleased to find that most sub-
strates performed well in the reaction with variations in the
ester and arene. The initial Mg/I exchange was well-tolerated
by a range of sensitive functionality, including aryl bromides
and esters (7be and 7bj). Nitro groups at the 5-position of the
arene, however, did not appear to be tolerated (7bg).11
Transmetallation to copper and addition to diethyl 1,1-
cyclopropane dicarboxylate (6a) proceeded smoothly in most
cases. Electron-rich and electron-deficient arenes afforded
product in comparably high yields. We were pleased to see
that heterocycles such as pyridine, thiophene, and indole-
based starting materials also furnished the corresponding ad-
ducts 7bl (57% yield), 7bm (73% yield) and 7bn (90% yield).
To further probe the substrate scope of the transformation,
we evaluated cyclopropyl electrophile partners with various
esters (Table 2). Increasing the steric demand of the ester
components had a clear and detrimental effect on the reaction
yield (7aa–7ad). In these transformations, Cu-mediated ho-
modimerization of the aryl fragment became competitive with
productive coupling, leading to the decrease in yield. Phenyl-
substituted cyclopropane 12 was also tested and the transfor-
mation was completely selective for addition at the electroni-
cally more activated benzylic cyclopropane position.12 Lac-
tone-fused cyclopropane 13 was also evaluated and provided
adduct in 94% yield. Exploration of diallyl diester cyclopro-
pane 14, a substrate with competing reactive sites, provided no
cyclopropyl addition. Instead, arene allylation product (not
shown) was isolated in 58% yield. In contrast to other cyclo-
propane diesters 6, Meldrum’s acid-derived cyclopropane 15
showed no productive bond formation. Several other cyclo-
propane electrophiles (2, 16–17), which lacked dicarbonyl
functionality capable of chelation, showed no reactivity under
our developed reaction conditions.
Next, we turned our attention toward the Dieckmann cy-
clization8 with triesters 7. While our original design planned
for the use of diesters 3, the triesters 7 were expected to be
more challenging for our desired cyclization. Several reports
showed that this decarboxylative transformation is feasible for
6-membered ring formation, but also suggested that the alkox-
ide bases and alcohol solvents in the transformation needed to
be matched with the ester moieties of the molecule.9 These
constraints appeared to be a key limitation for the mixed ester
substrates we possessed (such as 7ab) because application of
such conditions led to a mixture of methyl and ethyl β-
ketoester products (4b and 4a) (Scheme 3). Additionally, liter-
ature examples were isolated and did not delve into a broader
study of reaction scope.9 Clearly, new reaction conditions
were needed to accomplish our goal.
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The Journal of Organic Chemistry
TABLE 2. Cu-Mediated Homoconjugate Addition
TABLE 1. Cu-Mediated Homoconjugate Addition
1
Iodoester Substrate Scope
Cyclopropyl and Other Electrophile Scope
2
3
4
5
6
7
O
O
O
O
i-PrMgCl•LiCl (1.8 equiv)
CuI•SMe2 (1.5 equiv)
i-PrMgCl•LiCl (1.8 equiv)
CuI•SMe2 (1.5 equiv)
X
X
O
O
OR
OR
OEt
OEt
+
+
acceptor
EtO
OEt
CO2Et
CO2R
DMI (3.0 equiv)
2-MeTHF (0.33 M)
–78 to 23 °C
DMI (3.0 equiv)
2-MeTHF (0.33 M)
–78 to 23 °C
I
I
CO2Et
CO2R
1
6a
7
1a
7
RO2C
CO2R
EtO2C
CO2Et
X
O
O
O
8
9
Me
CO2Et
OMe
OEt
OEt
A =
6
11
poor coupling partners:
O
CO2Et
A
A
A
O
O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
X = Me 7ba 99% yield
X = Ph 7bb 99% yield
7aa
79% yield
7ae
97% yield
O
OEt
OEt
O
O
CO2R
O
O
O
CO2R
14
X
EtO2C
CO2Et
OMe
OMe
A
OMe
A
R = Me 7ab 90% yield
R = Et 7aa 79% yield
R = i-Pr 7ac 78% yield
R = t-Bu 7ad 47% yield
Me Me
A
X
19
73% yield
Me
X = Me 7bc
X = F 7bd
X = Br 7be
X = OMe 7bf
X = NO2 7bg
94% yield
95% yield
98% yield
99% yield
0% yield
X = Me
X = Cl
7bh
7bi
99% yield
85% yield
95% yield
O
O
H
CO2R
7bk
74% yield
O
O
X = CO2Me 7bj
O
O
15
2a R = Et
2b R = Me
EtO2C
Ph
CO2Et
EtO
O
O
O
Me
O
NC
CN NC
CO2Me
N
S
12
13
OMe
OMe
A
OMe
O
A
16
17
N
A
OEt
O
7bl
57% yield
7bm 73% yield
7bn
90% yield
EtO2C
CO2Et
OEt
CO2Et
CO2Et
O
18
Our interests also extended beyond cyclopropane acceptors
because we were also interested in the corresponding analo-
gous indanone and benzosuberone products in addition to our
primary tetralone targets. Toward this end, we tested diethyl
methylidene malonate 11 and obtained adduct 19 in 73%
yield. In contrast, attempted coupling with diethyl 1,1-
cyclobutane dicarboxylate (18) did not lead to any desired
adduct.
Ph CO2Et
O
20
65% yield
21
94% yield
TABLE 3. Decarboxylative Dieckmann Cyclization Scope
O
O
Et3N (3.0 equiv)
MgBr2 (1.5 equiv)
X
X
CO2R'
OR
CO2R'
2-MeTHF (0.5 M)
80 °C
With a variety of adducts in hand, we turned our attention to
the cyclization step to evaluate the substrate scope (Table 3).
The cyclization of triesters 7 containing various malonate and
aryl esters proceeded smoothly in most cases to give bicyclic
β-ketoesters 4 in good yield. In the cases of mixed esters such
as 7ab and 7ba, no ester scrambling was observed and the
product β-ketoester always retained one of the original malo-
nate esters. For the 6-substituted triester starting materials, a
significant drop in yield was apparent with a large phenyl sub-
stituent (18% yield) compared to a smaller methyl substituent
(94% yield) (cf. 4e and 4f). Placing various electronically di-
verse substituents further away at the arene 5-position, as
shown by examples 4g–4j, had a beneficial effect on reaction
yields. Excellent results were also obtained with 3-substituted
and 4-substituted triesters, as shown by β-ketoesters 4k–4n.
Substitution on the aliphatic chain, as shown by product 4o,
also translated to good cyclization yields. Unfortunately, the
attempted cyclization of lactone substrate 21 did not provide
desired product under these conditions and instead led to
gradual decomposition during extended reaction times.
CO2R'
7
4
O
O
X
O
X
CO2Et
CO2R3
CO2Et
R' = Me 4a
78% yield
91% yield
68% yield
74% yield
X = Me 4e
X = Ph 4f
94% yield
18% yield
X = Me 4g
75% yield
84% yield
91% yield
80% yield
R' = Et
4b
X = F
4h
4i
R' = i-Pr 4c
R' = t-Bu 4d
X = Br
X = OMe 4j
O
O
CO2Et
O
CO2Et
CO2Et
X
Me
X = Me
X = Cl
4k
4l
82% yield
97% yield
4n
99% yield
22
90% yield
X = CO2Me 4m 97% yield
O
OH
O
Me
O
CO2Et
CO2Et
CO2Et
N
S
CO2Et
N
Ph
89% yield
4o
46% yield
58% yield
72% yield
4p
23
4q
With the substrate scope of two key transformations ex-
plored in detail,14 we devoted attention to developing working
hypotheses for the two transformations based on the observed
trends. Chelation appears to be an important feature of both
transformations as a means of activating the key reactive func-
tionality for productive bond formation (Scheme 4). In the
case of the Cu-mediated homoconjugate addition, activation of
both carbonyls greatly facilitates arylcuprate coupling6
(Scheme 4A). Monoesters 2, dinitrile 16, nitrile ester 17, and
Finally, heterocyclic scaffolds were also evaluated. Cycliza-
tion to the indanone scaffold13 in 22 proceeded efficiently in
90% yield. Pyridines, indoles, and benzothiophenes could all
be incorporated into cyclization products, but the pyridine 4p
was isolated in relatively low yield while carbazole 23 was
formed as a result of facile air oxidation during handling and
isolation. Thiophene 4q was formed efficiently under the reac-
tion conditions and was isolated without aromatization.
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Meldrum’s acid derivative 15 that do not benefit from this
Page 4 of 12
O
O
6a
OEt
1
2
3
4
5
6
7
8
EtO
type of activation remain unreactive. In a similar manner, the
cyclization step benefits from chelation interactions to facili-
tate enolization of the malonate ester in triester 7 and promote
intramolecular nucleophilic attack on the aryl ester (Scheme
4B). Extrusion of diethyl carbonate appeared to be a likely
step for the formation of final β-ketoester 4. We were pleased
to observe diethyl carbonate by 13C NMR (δ 156.1, 64.1, 14.8
ppm) when the reaction was carried out in THF-d8.
O
i-PrMgCl•LiCl (1.8 equiv)
CuI•SMe2 (1.5 equiv)
Et3N (3.0 equiv)
MgBr2 (1.5 equiv)
O
I
OEt
OEt
CO2Et
2-MeTHF (0.5 M)
80 °C
DMI (3.0 equiv)
2-MeTHF (0.33 M)
–78 to 23 °C
CO2Et
1a
7aa
85% yield
5.9 mmol scale
79% yield
30 mmol
O
O
HCl
CO2Et
To provide a gram scale demonstration of our synthetic
method, we converted 30 mmol of diethyl cyclopropane-1,1-
dicarboxylate 6a to the homoconjugate adduct 7aa in 79%
yield (Scheme 5). Subsequent decarboxylative Dieckmann
cyclization of triester 7aa on 5.9 mmol scale provided 85%
yield of β-ketoester 4a. Additionally, a simple thermal decar-
boxylation in the presence of HCl and i-PrOH provided 93%
yield of tetralone.
9
i-PrOH
85 °C
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
4a
30
93% yield
SCHEME 5. Gram-Scale Demonstration and Synthetic
Applications of β-Ketoester Products
The synthetic versatility of β-ketoester building blocks in
complexity-generating transformations has been well docu-
mented. Through a variety of methods, compound 4a has been
elaborated to more complex products, including ring expan-
EXPERIMENTAL SECTION
General Methods and Materials. All reactions were car-
ried out in heat gun-dried screw-cap vials with Teflon septa
equipped with Teflon stir bars under a nitrogen atmosphere
unless otherwise noted. Thin-layer chromatography (TLC)
was conducted with EMD silica gel 60 F254 pre-coated plates
and visualized using UV light (254 nm) or stained with
KMnO4. Flash column chromatography was performed with
pre-packed RediSep silica gel Standard or Gold columns on a
CombiFlash ISCO system using i-PrOAc in heptane (0−50%
gradient) as eluent. Reported yields correspond to isolated
sion
products,
heterocycles,
and
chiral
pounds.15,16,17,18,19,20,,21,22
SCHEME 4. Mechanistic Working Hypotheses and the
Role of Chelation in the Addition and Cyclization Steps
O
A.
EtO
OEt
1
OEt OEt
material. All new compounds were characterized by H NMR,
O
O
1
13C NMR, IR, and HRMS. H and 13C Nuclear Magnetic Res-
O
O
[M]
[M]
[Cu]
EtO
26
O
onance spectra were recorded on a Bruker 300 or Bruker 500
MHz instrument at ambient temperature. All H NMR spectra
EtO
1
24
25
[M] = Mg or Cu
were measured in parts per million (ppm) relative to the resid-
ual chloroform signal in deuterated solvent, unless otherwise
B.
O
O
Et3N (3.0 equiv)
1
CO2Et
MgBr2 (1.5 equiv)
stated. Data for H NMR were reported in ppm relative to re-
OEt
sidual chloroform (δ 7.26 ppm) as follows: chemical shift,
multiplicity (br = broad signal, s = singlet, d = doublet, t =
triplet, q = quartet, sept = septet, m = multiplet), coupling con-
stants, and integration. All 13C NMR spectra are reported in
ppm relative to residual chloroform (δ 77.16 ppm) or THF (δ
CO2Et
THF-d8 (0.5 M)
80 °C
CO2Et
7aa
4a
O
EtO
OEt
observed by
13C NMR
Mg
1
O
67.57 ppm), and were obtained with complete H decoupling
O
O
O
unless otherwise stated. All 19F NMR spectra were obtained on
a Bruker 300 MHz instrument at ambient temperature, with
OEt
OEt
CO2Et
MgX2
EtO–
CO2Et
OEt OEt
CO2Et
– EtO–
O
1
Mg
complete H decoupling. When the reported spectra contain
EtO
O
27
28
29
diastereomers, terms such as “major” and “minor” were used
to indicate peaks respectively. IR spectra were recorded on a
Bruker Alpha Platinum-ATR spectrometer and are reported in
frequency of absorption (cm−1). HRMS data was obtained on a
LTQ Orbitrap Discovery (Thermo Fisher Scientific) at Genen-
tech, Inc. High-resolution mass spectrometry (HRMS) data
was acquired on a Thermo Scientific Orbitrap Fusion mass
spectrometer. HPLC analyses were performed on an Agilent
1260 Infinity HPLC system with a UV detector at 220, 254,
and 280 nm using a Waters SL XBRIDGE column.
In summary, we have developed a novel homoconjugate ad-
dition / decarboxylative Dieckmann annulation strategy for the
efficient formation of a variety of polycyclic β-ketoesters from
readily accessible 2-iodoaryl esters and 1,1-cyclopropane
diesters. Both transformations appear to benefit from chelation
interactions based on reactivity trends. Further evaluation of
the substrate scope, exploration of the mechanism of these
transformations, and synthetic applications of the β-ketoester
building blocks will be reported in due course.
General Procedure for the Homoconjugate Addition. In
a heat-gun dried 2-dram vial was added 2-iodoester 1 (0.90
mmol, 1.5 equiv) and anhydrous 2-MeTHF (0.60 mL). The
solution was cooled to –78 °C, and i-PrMgCl·LiCl (0.83 mL,
1.1 mmol, 1.8 equiv, 1.3 M in THF) was added. The resulting
mixture was stirred at –78 °C for 30 min. CuI·SMe2 (228 mg,
0.90 mmol, 1.5 equiv) was added as a suspension in anhydrous
2-MeTHF (1.2 mL), followed by DMI (0.20 mL, 1.8 mmol,
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The Journal of Organic Chemistry
3.0 equiv) and diethyl 1,1-cyclopropane dicarboxylate 6 (0.11
1500, 1447, 1367, 1265, 1138, 1022, 863 cm-1. HRMS calcu-
lated for C19H26O6H [M+H]+ 351.1802, found 351.1803.
1
2
3
4
5
6
7
8
mL, 0.6 mmol, 1 equiv). The resulting mixture was allowed to
stir overnight, slowly warming to ambient temperature. The
reaction mixture was quenched with saturated aqueous NH4Cl
and extracted with i-PrOAc (3 × 5 mL). The combined organic
layers were dried over MgSO4 and concentrated in vacuo. The
residue was purified by column chromatography (SiO2) to
afford the triester.
Triester 7bc: The title compound was synthesized accord-
ing to the general procedure (0.60 mmol of cyclopropane start-
ing material 6a and iodoester partner SI-1bc) and isolated by
column chromatography (SiO2, 15% i-PrOAc in heptane) as a
1
colorless oil (190.2 mg, 94% yield). H NMR (300 MHz,
CDCl3) δ 7.69 (s, 1H), 7.22 (dd, J = 8.1, 2.2 Hz, 1H), 7.13 (d,
J = 7.8 Hz, 1H), 4.24 – 4.12 (m, 4H), 3.86 (s, 3H), 3.37 (t, J =
7.5 Hz, 1H), 3.00 – 2.91 (m, 2H), 2.32 (s, 3H), 2.25 – 2.12 (m,
2H), 1.25 (t, J = 7.1 Hz, 6H). 13C NMR (75 MHz, CDCl3) δ
169.4, 167.9, 139.7, 135.9, 132.9, 131.3, 131.2, 129.3, 61.3,
51.9, 51.8, 31.6, 30.5, 20.8, 14.1. IR (ATR): 2981, 2949,
1723, 1460, 1369, 1259, 1177, 1148, 1067, 761, 701 cm-1.
HRMS calculated for C18H24O6H [M+H]+ 337.1646, found
337.1648.
Triester 7aa: The title compound was synthesized accord-
ing to the general procedure (0.20 mmol of cyclopropane start-
ing material 6a and iodoester partner 1a) and isolated by col-
umn chromatography (SiO2, 15% i-PrOAc in heptane) as a
colorless oil (53.1 mg, 79% yield). 1H NMR (300 MHz,
CDCl3) δ 7.90 (dd, J = 8.1, 1.5 Hz, 1H), 7.43 (td, J = 7.3, 1.5
Hz, 1H), 7.31 – 7.23 (m, 2H), 4.36 (q, J = 7.1 Hz, 2H), 4.20
(q, J = 6.9 Hz, 4H), 3.40 (t, J = 7.5 Hz, 1H), 3.09 – 2.94 (m,
2H), 2.32 – 2.13 (m, 2H), 1.40 (t, J = 7.1 Hz, 3H), 1.28 (t, J =
7.1 Hz, 6H). 13C NMR (75 MHz, CDCl3) δ 169.5, 167.5,
142.7, 132.1, 131.3, 130.9, 130.0, 126.4, 61.5, 61.0, 51.9,
32.1, 30.5, 14.4, 14.2. IR (ATR): 2981, 1716, 1447, 1367,
1250, 1149, 1131, 1081, 1037, 754 cm-1. HRMS calculated for
C18H24O6H [M+H]+ 337.1646, found 337.1647.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Triester 7bd: The title compound was synthesized accord-
ing to the general procedure (0.60 mmol of cyclopropane start-
ing material 6a and iodoester partner SI-1bd) and isolated by
column chromatography (SiO2, 15% i-PrOAc in heptane) as a
1
colorless oil (193.5 mg, 95% yield). H NMR (300 MHz,
CDCl3) δ 7.58 (dd, J = 9.5, 2.8 Hz, 1H), 7.23 (dd, J = 8.5, 5.5
Hz, 1H), 7.12 (td, J = 8.2, 2.8 Hz, 1H), 4.19 (q, J = 7.1, 6.6
Hz, 4H), 3.88 (s, 3H), 3.37 (t, J = 7.4 Hz, 1H), 3.02 – 2.92 (m,
2H), 2.23 – 2.11 (m, 2H), 1.26 (t, J = 7.1 Hz, 6H). 13C NMR
(75 MHz, CDCl3) δ 169.4, 166.6 (d, J = 2.7 Hz), 160.9 (d, J =
245.7 Hz), 138.8 (d, J = 3.5 Hz), 132.9 (d, J = 7.5 Hz), 130.9
(d, J = 7.1 Hz), 119.2 (d, J = 20.8 Hz), 117.6 (d, J = 23.2 Hz),
61.5, 52.3, 51.8, 31.3, 30.5, 14.2. 19F NMR (282 MHz,
CDCl3) δ -116.0. IR (ATR): 2982, 2955, 1724, 1582, 1497,
1437, 1266, 1208, 1182, 1148, 1071 cm-1. HRMS calculated
for C17H21FO6H [M+H]+ 341.1395, found 341.1398.
Triester 7ba: The title compound was synthesized accord-
ing to the general procedure (0.60 mmol of cyclopropane start-
ing material 6a and iodoester partner SI-1ba) and isolated by
column chromatography (SiO2, 15% i-PrOAc in heptane) as a
1
colorless oil (200.1 mg, 99% yield). H NMR (300 MHz,
CDCl3) δ 7.22 (t, J = 7.6 Hz, 1H), 7.06 (dd, J = 7.6, 2.4 Hz,
2H), 4.19 (q, J = 6.9 Hz, 4H), 3.91 (s, 3H), 3.35 (t, J = 7.3 Hz,
1H), 2.70 – 2.58 (m, 2H), 2.30 (s, 3H), 2.24 – 2.11 (m, 2H),
1.26 (t, J = 7.1 Hz, 6H). 13C NMR (75 MHz, CDCl3) δ 170.3,
169.2, 137.9, 135.2, 133.8, 129.6, 128.2, 127.0, 61.4, 52.0,
51.6, 31.5, 30.4, 19.8, 14.1. IR (ATR): 2982, 2953, 1725,
1596, 1464, 1369, 1265, 1218, 1146, 1074 cm-1. HRMS calcu-
lated for C18H24O6NH4 [M+NH4]+ 354.1911, found 354.1913.
Triester 7be: The title compound was synthesized accord-
ing to the general procedure (0.60 mmol of cyclopropane start-
ing material 6a and iodoester partner SI-1be) and isolated by
column chromatography (SiO2, 15% i-PrOAc in heptane) as a
Triester 7bb: The title compound was synthesized accord-
ing to the general procedure (0.60 mmol of cyclopropane start-
ing material 6a and iodoester partner SI-1bb) and isolated by
column chromatography (SiO2, 15% i-PrOAc in heptane) as a
1
colorless oil (236.3 mg, 98% yield). H NMR (300 MHz,
CDCl3) δ 8.02 (d, J = 2.3 Hz, 1H), 7.53 (dd, J = 8.2, 2.2 Hz,
1H), 7.14 (d, J = 8.2 Hz, 1H), 4.19 (q, J = 7.2, 6.6 Hz, 4H),
3.88 (s, 3H), 3.37 (t, J = 7.4 Hz, 1H), 3.02 – 2.90 (m, 2H),
2.25 – 2.10 (m, 2H), 1.26 (t, J = 7.1 Hz, 6H). 13C NMR (75
MHz, CDCl3) δ 169.3, 166.4, 141.9, 135.1, 133.8, 132.9,
131.2, 120.0, 61.5, 52.3, 51.7, 31.5, 30.3, 14.2. IR (ATR):
2981, 1722, 1480, 1391, 1215, 1190, 1138, 1080, 1041, 967
cm-1. HRMS calculated for C17H21BrO6H [M+H]+ 403.0574,
found 403.0576.
1
colorless oil (236.6 mg, 99% yield). H NMR (300 MHz,
CDCl3) δ 7.43 – 7.30 (m, 6H), 7.28 – 7.21 (m, 2H), 4.20 (q, J
= 7.1 Hz, 4H), 3.56 (s, 3H), 3.40 (t, J = 7.3 Hz, 1H), 2.79 –
2.68 (m, 2H), 2.23 (dt, J = 10.7, 7.7 Hz, 2H), 1.27 (t, J = 7.1
Hz, 6H). 13C NMR (75 MHz, CDCl3) δ 170.0, 169.2, 140.9,
140.5, 138.5, 133.2, 129.7, 128.6, 128.33, 128.29, 127.9,
127.5, 61.5, 51.9, 51.6, 31.4, 30.4, 14.2. IR (ATR): 2981,
2953, 1720, 1435, 1369, 1266, 1198, 1138, 1080, 1043 cm-1.
HRMS calculated for C23H26O6NH4 [M+NH4]+ 416.2068,
found 416.2070.
Triester 7bf: The title compound was synthesized accord-
ing to the general procedure (0.60 mmol of cyclopropane start-
ing material 6a and iodoester partner SI-1bf) and isolated by
column chromatography (SiO2, 15% i-PrOAc in heptane) as a
yellow oil (209.9 mg, 99% yield). 1H NMR (300 MHz,
CDCl3) δ 7.40 (d, J = 2.9 Hz, 1H), 7.15 (d, J = 8.5 Hz, 1H),
6.96 (dd, J = 8.5, 2.9 Hz, 1H), 4.18 (qd, J = 7.1, 0.8 Hz, 4H),
3.87 (s, 3H), 3.79 (s, 3H), 3.36 (t, J = 7.5 Hz, 1H), 2.99 – 2.86
(m, 2H), 2.22 – 2.08 (m, 2H), 1.25 (t, J = 7.1 Hz, 6H). 13C
NMR (75 MHz, CDCl3) δ 169.4, 167.6, 157.8, 134.8, 132.4,
130.3, 118.4, 115.5, 61.3, 55.5, 52.1, 51.8, 31.2, 30.6, 14.1. IR
(ATR): 2981, 2953, 1720, 1609, 1501, 1435, 1280, 1219,
1076, 1039 cm-1. HRMS calculated for C18H24O7H [M+H]+
353.1595, found 353.1595.
Triester 7ae: The title compound was synthesized accord-
ing to the general procedure (0.60 mmol of cyclopropane start-
ing material 6a and iodoester partner SI-1ae) and isolated by
column chromatography (SiO2, 15% i-PrOAc in heptane) as a
1
colorless oil (203.4 mg, 97% yield). H NMR (300 MHz,
CDCl3) δ 7.68 (d, J = 2.0 Hz, 1H), 7.24 – 7.17 (m, 1H), 7.12
(d, J = 7.8 Hz, 1H), 4.34 (q, J = 7.1 Hz, 2H), 4.18 (q, J = 6.7
Hz, 4H), 3.37 (t, J = 7.5 Hz, 1H), 3.02 – 2.88 (m, 2H), 2.32 (s,
3H), 2.26 – 2.12 (m, 2H), 1.38 (t, J = 7.1 Hz, 3H), 1.25 (t, J =
7.1 Hz, 6H). 13C NMR (75 MHz, CDCl3) δ 169.4, 167.6,
139.5, 135.9, 132.7, 131.2, 131.1, 129.7, 61.3, 60.8, 51.8,
31.6, 30.5, 20.8, 14.3, 14.1. IR (ATR): 2981, 2937, 1716,
Triester 7bh: The title compound was synthesized accord-
ing to the general procedure (0.60 mmol of cyclopropane start-
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The Journal of Organic Chemistry
Page 6 of 12
ing material 6a and iodoester partner SI-1bh) and isolated by MHz, CDCl3) δ 169.5, 166.9, 161.8, 152.1, 138.7, 125.6,
1
2
3
4
5
6
7
8
column chromatography (SiO2, 15% i-PrOAc in heptane) as a
colorless oil (199.9 mg, 99% yield). H NMR (300 MHz,
121.3, 61.4, 52.5, 51.9, 34.4, 28.3, 14.2. IR (ATR): 2982,
2954, 1722, 1569, 1432, 1262, 1132, 1084, 1029, 774 cm-1.
HRMS calculated for C16H21NO6H [M+H]+ 324.1442, found
324.1440.
1
CDCl3) δ 7.79 (d, J = 8.6 Hz, 1H), 7.03 (d, J = 7.1 Hz, 2H),
4.18 (q, J = 7.1 Hz, 4H), 3.83 (s, 3H), 3.38 (t, J = 7.5 Hz, 1H),
3.03 – 2.92 (m, 2H), 2.32 (s, 3H), 2.24 – 2.12 (m, 2H), 1.25 (t,
J = 7.1 Hz, 6H). 13C NMR (75 MHz, CDCl3) δ 169.3, 167.6,
143.0, 142.6, 132.0, 131.1, 127.0, 126.4, 61.3, 51.8, 51.7,
32.0, 30.4, 21.3, 14.1. IR (ATR): 2981, 2953, 1717, 1612,
1435, 1262, 1136, 1083, 1025, 813 cm-1. HRMS calculated for
C18H24O6H [M+H]+ 337.1646, found 337.1647.
Triester 7bm: The title compound was synthesized accord-
ing to the general procedure (0.60 mmol of cyclopropane start-
ing material 6a and iodoester partner SI-1bm) and isolated by
column chromatography (SiO2, 15% i-PrOAc in heptane) as a
yellow oil (163.7 mg, 73% yield). 1H NMR (300 MHz,
CDCl3) δ 7.71 (d, J = 8.0 Hz, 1H), 7.40 – 7.33 (m, 2H), 7.16
(ddd, J = 8.0, 4.9, 3.0 Hz, 1H), 4.21 (q, J = 7.1 Hz, 4H), 4.01
(s, 3H), 3.96 (s, 3H), 3.43 (t, J = 7.3 Hz, 1H), 3.23 – 3.12 (m,
2H), 2.36 – 2.20 (m, 2H), 1.28 (t, J = 7.1 Hz, 6H). 13C NMR
(75 MHz, CDCl3) δ 169.5, 163.2, 138.9, 126.6, 125.5, 124.9,
123.7, 120.8, 120.1, 110.2, 61.4, 51.8, 51.6, 32.2, 30.0, 23.3,
14.2. IR (ATR): 2981, 2951, 1746, 1728, 1529, 1440, 1367,
1241, 1102, 969, 740 cm-1. HRMS calculated for C20H25NO6H
[M+H]+ 376.1755, found 376.1754.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Triester 7bi: The title compound was synthesized accord-
ing to the general procedure (0.60 mmol of cyclopropane start-
ing material 6a and iodoester partner SI-1bi) and isolated by
column chromatography (SiO2, 15% i-PrOAc in heptane) as a
1
colorless oil (182.8 mg, 85% yield). H NMR (300 MHz,
CDCl3) δ 7.89 – 7.82 (m, 1H), 7.29 – 7.22 (m, 2H), 4.21 (q, J
= 7.1 Hz, 4H), 3.89 (s, 3H), 3.39 (t, J = 7.4 Hz, 1H), 3.06 –
2.95 (m, 2H), 2.26 – 2.15 (m, 2H), 1.28 (t, J = 7.1 Hz, 6H).
13C NMR (75 MHz, CDCl3) δ 169.3, 166.9, 145.1, 138.4,
132.6, 131.3, 127.9, 126.7, 61.6, 52.2, 51.8, 32.0, 30.2, 14.2.
IR (ATR): 2982, 2954, 1720, 1593, 1564, 1435, 1251, 1149,
1024, 779 cm-1. HRMS calculated for C17H21ClO6H [M+H]+
357.1099, found 357.1100.
Triester 7bn: The title compound was synthesized accord-
ing to the general procedure (0.60 mmol of cyclopropane start-
ing material 6a and iodoester partner SI-1bn) and isolated by
column chromatography (SiO2, 15% i-PrOAc in heptane) as a
red solid (204.8 mg, 90% yield). 1H NMR (300 MHz, CDCl3)
δ 7.98 – 7.92 (m, 1H), 7.87 – 7.80 (m, 1H), 7.52 – 7.41 (m,
2H), 4.22 (q, J = 7.2, 6.6 Hz, 4H), 3.93 (s, 3H), 3.50 (t, J = 7.3
Hz, 1H), 3.45 – 3.34 (m, 2H), 2.34 – 2.19 (m, 2H), 1.27 (d, J =
7.1 Hz, 6H). 13C NMR (75 MHz, CDCl3) δ 169.4, 163.5,
144.2, 140.8, 139.4, 127.4, 127.3, 124.8, 123.9, 122.8, 61.6,
52.3, 51.9, 28.8, 25.1, 14.2. IR (ATR): 3017, 2917, 2849,
1713, 1531, 1445, 1231, 1194, 1029, 738 cm-1. HRMS calcu-
lated for C19H22SO6H [M+H]+ 379.1210, found 379.1217.
Triester 7bj: The title compound was synthesized accord-
ing to the general procedure (0.60 mmol of cyclopropane start-
ing material 6a and iodoester partner SI-1bj) and isolated by
column chromatography (SiO2, 20% i-PrOAc in heptane) as a
1
colorless oil (216.0 mg, 95% yield). H NMR (300 MHz,
CDCl3) δ 7.91 (d, J = 6.3 Hz, 3H), 4.19 (q, J = 7.1 Hz, 4H),
3.92 (s, 3H), 3.90 (s, 3H), 3.38 (t, J = 7.4 Hz, 1H), 3.09 – 2.97
(m, 2H), 2.29 – 2.15 (m, 2H), 1.27 (t, J = 7.1 Hz, 6H). 13C
NMR (75 MHz, CDCl3) δ 169.3, 167.2, 166.3, 142.8, 133.6,
133.1, 132.2, 130.9, 127.4, 61.5, 52.43, 52.35, 51.8, 31.9,
30.3, 14.2. IR (ATR): 2981, 2954, 1719, 1435, 1369, 1251,
1192, 1112, 1023, 754 cm-1. HRMS calculated for C19H24O8H
[M+H]+ 381.1544, found 381.1545.
Triester 7ab: The title compound was synthesized accord-
ing to the general procedure (0.60 mmol of cyclopropane start-
ing material SI-6ab and iodoester partner 1a) and isolated by
column chromatography (SiO2, 15% i-PrOAc in heptane) as a
yellow oil (166.5 mg, 90% yield). 1H NMR (300 MHz,
CDCl3) δ 7.95 – 7.86 (m, 1H), 7.47 – 7.38 (m, 1H), 7.30 –
7.23 (m, 2H), 4.37 (q, J = 7.1 Hz, 2H), 3.75 (s, 6H), 3.45 (t, J
= 7.5 Hz, 1H), 3.07 – 2.96 (m, 2H), 2.32 – 2.17 (m, 2H), 1.40
(t, J = 7.1 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 169.8,
167.4, 142.5, 132.0, 131.2, 130.9, 129.9, 126.4, 60.9, 52.5,
51.5, 32.0, 30.6, 14.4. IR (ATR): 2954, 1733, 1715, 1435,
1251, 1150, 1131, 1082, 755, 710 cm-1. HRMS calculated for
C16H20O6H [M+H]+ 309.1333, found 309.1332.
Triester 7bk: The title compound was synthesized accord-
ing to the general procedure (0.60 mmol of cyclopropane start-
ing material 6a and iodoester partner SI-1bk) and isolated by
column chromatography (SiO2, 0–30% i-PrOAc in heptane) as
1
a colorless oil (148.4 mg, 74% yield). H NMR (500 MHz,
CDCl3) δ 7.65 (d, J = 7.9 Hz, 1H), 7.33 – 7.24 (d, J = 7.9 Hz,
1H), 7.15 (dd, J = 7.7, 7.7 Hz, 1H), 4.22 (qd, J = 7.1, 1.2 Hz,
4H), 3.88 (s, 3H), 3.49 (dd, J = 7.4, 7.4 Hz, 1H), 3.02 – 2.89
(m, 2H), 2.39 (s, 3H), 2.20 – 2.07 (m, 2H), 1.28 (dd, J = 7.1,
7.1 Hz, 6H). 13C NMR (125 MHz, CDCl3) δ 169.3, 168.6,
140.4, 137.7, 134.0, 130.6, 128.2, 125.9, 61.3, 52.2, 52.0,
52.0, 28.9, 28.0, 20.0, 19.6, 19.6, 14.1. IR 2981, 2954, 2375,
1719, 1686, 1459, 1438, 1369, 1266, 1250, 1220, 1188, 1174,
1151, 1130, 1094, 1078, 1049, 1022, 975, 910, 861, 811, 759,
643, 592, 460 cm-1. HRMS calculated for C18H24O6H [M+H]+
337.3195, found 337.1653.
Triester 7ac: The title compound was synthesized accord-
ing to the general procedure (0.60 mmol of cyclopropane start-
ing material SI-6ac and iodoester partner 1a) and isolated by
column chromatography (SiO2, 15% i-PrOAc in heptane) as a
1
colorless oil (170.5 mg, 78% yield). H NMR (300 MHz,
CDCl3) δ 7.89 (dd, J = 8.1, 1.5 Hz, 1H), 7.42 (td, J = 7.4, 1.5
Hz, 1H), 7.25 (ddd, J = 8.5, 4.0, 1.8 Hz, 2H), 5.06 (sept, J =
6.3 Hz, 2H), 4.36 (q, J = 7.1 Hz, 2H), 3.33 (t, J = 7.5 Hz, 1H),
3.07 – 2.95 (m, 2H), 2.27 – 2.13 (m, 2H), 1.39 (t, J = 7.1 Hz,
3H), 1.25 (d, J = 6.3 Hz, 12H). 13C NMR (75 MHz, CDCl3) δ
168.9, 167.4, 142.7, 132.0, 131.2, 130.8, 130.0, 126.3, 68.8,
60.9, 52.2, 32.0, 30.3, 21.7, 21.6, 14.3. IR (ATR): 2981, 2937,
1717, 1453, 1366, 1250, 1100, 1017, 755, 710 cm-1. HRMS
calculated for C20H28O6H [M+H]+ 365.1959, found 365.1960.
Triester 7bl: The title compound was synthesized accord-
ing to the general procedure (0.60 mmol of cyclopropane start-
ing material 6a and iodoester partner SI-1bl) and isolated by
column chromatography (SiO2, 50% i-PrOAc in heptane) as a
yellow oil (109.6 mg, 57% yield). 1H NMR (300 MHz,
CDCl3) δ 8.65 (dd, J = 4.8, 1.9 Hz, 1H), 8.17 (dd, J = 7.9, 1.8
Hz, 1H), 7.22 (dd, J = 7.9, 4.8 Hz, 1H), 4.25 – 4.15 (m, 4H),
3.92 (s, 3H), 3.48 (t, J = 7.5 Hz, 1H), 3.30 – 3.18 (m, 2H),
2.43 – 2.31 (m, 2H), 1.27 (t, J = 7.1 Hz, 6H). 13C NMR (75
Triester 7ad: The title compound was synthesized accord-
ing to the general procedure (0.60 mmol of cyclopropane start-
ing material SI-6ad and iodoester partner 1a) and isolated by
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The Journal of Organic Chemistry
column chromatography (SiO2, 15% i-PrOAc in heptane) as a
colorless oil (110.0 mg, 47% yield). H NMR (300 MHz,
equiv), MgBr2 (55.8 mg, 0.30 mmol, 1.5 equiv), 2-MeTHF
(0.40 mL, 0.50 M), and Et3N (84.5 mL, 0.60 mmol, 3.0 equiv).
The resulting mixture was stirred at 80 °C for 4 h. The reac-
tion mixture was quenched with 2 M HCl and extracted with i-
PrOAc (3 × 2 mL). The combined organic layers were dried
over MgSO4 and concentrated in vacuo. The residue was puri-
fied by column chromatography (SiO2) to afford the β-
ketoester.
1
1
2
3
4
5
6
7
8
CDCl3) δ 7.88 (d, J = 7.6 Hz, 1H), 7.43 (td, J = 7.5, 1.5 Hz,
1H), 7.28 (d, J = 5.8 Hz, 2H), 4.47 – 4.29 (m, 2H), 3.20 (t, J =
7.5 Hz, 1H), 3.05 – 2.95 (m, 2H), 2.13 (q, J = 7.7 Hz, 2H),
1.48 (s, 18H), 1.40 (t, J = 7.1 Hz, 3H). 13C NMR (75 MHz,
CDCl3) δ 168.9, 167.6, 143.0, 132.0, 131.3, 130.9, 130.1,
126.3, 81.5, 61.0, 53.9, 32.1, 30.5, 28.1, 14.5. IR (ATR):
2978, 2934, 1718, 1455, 1367, 1249, 1129, 1081, 849, 743 cm-
1. HRMS calculated for C22H32O6Na [M+Na]+ 415.2091,
found 415.2094.
β-Ketoester 4a: The title compound was synthesized ac-
cording to the general procedure (from 0.30 mmol of starting
material 7aa) and isolated by column chromatography (SiO2,
10% i-PrOAc in heptane) as a colorless oil (59.3 mg, 91%
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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Triester 19: The title compound was synthesized according
to the general procedure (0.60 mmol of diethyl 2-
methylenemalonate (11) and iodoester partner 1a) and isolated
by column chromatography (SiO2, 15% i-PrOAc in heptane)
1
yield, 2:1 enol:keto). H NMR (300 MHz, CDCl3) δ 12.48 (s,
1H), 7.80 (dd, J = 7.3, 1.8 Hz, 1H), 7.38 – 7.26 (m, 2H), 7.16
(ddd, J = 7.3, 1.7, 0.8 Hz, 1H), 4.28 (q, J = 7.1 Hz, 2H), 2.78 –
2.83 (m, 2H), 2.63 – 2.51 (m, 2H), 1.34 (t, J = 7.1 Hz, 3H).
Minor peaks corresponding to the keto tautomer observed at δ
8.04 (dd, J = 7.9, 1.5 Hz, 1H), 7.48 (td, J = 7.5, 1.5 Hz, 1H),
7.25 (td, J = 6.7, 6.2, 3.2 Hz, 2H), 4.26 – 4.19 (m, 2H), 3.59
(dd, J = 10.3, 4.8 Hz, 1H), 3.02 (dt, J = 9.7, 5.3 Hz, 2H), 2.52
– 2.43 (m, 1H), 2.41 – 2.28 (m, 1H), 1.29 (t, J = 7.1 Hz, 3H).
13C NMR (75 MHz, CDCl3) of the enol and keto tautomers, δ
193.4, 172.9, 170.3, 165.1, 143.8, 139.5, 134.0, 131.9, 130.6,
130.2, 128.9, 127.9, 127.5, 127.0, 126.7, 124.4, 97.2, 61.4,
60.7, 54.7, 27.9, 27.8, 26.5, 20.7, 14.5, 14.3. IR (ATR): 2980,
2935, 1737, 1686, 1643, 1617, 1569, 1296, 1156, 1022 cm-1.
HRMS calculated for C13H14O3H [M+H]+ 219.1016, found
219.1013.
1
as a colorless oil (140.6 mg, 73% yield). H NMR (300 MHz,
CDCl3) δ 7.96 (dd, J = 7.7, 1.5 Hz, 1H), 7.40 (td, J = 7.5, 1.6
Hz, 1H), 7.33 – 7.23 (m, 2H), 4.37 (q, J = 7.1 Hz, 2H), 4.14
(qd, J = 7.1, 2.4 Hz, 4H), 3.89 (t, J = 7.7 Hz, 1H), 3.55 (d, J =
7.7 Hz, 2H), 1.39 (t, J = 7.1 Hz, 3H), 1.19 (t, J = 7.1 Hz, 6H).
13C NMR (75 MHz, CDCl3) δ 169.1, 167.2, 139.6, 132.14,
132.06, 131.2, 129.9, 127.1, 61.4, 61.1, 53.3, 33.8, 14.3, 14.1.
IR (ATR): 2982, 1713, 1447, 1367, 1294, 1256, 1151, 1134,
855, 753 cm-1. HRMS calculated for C17H22O6H [M+H]+
323.1489, found 323.1490.
Triester 20: The title compound was synthesized according
to the general procedure (0.60 mmol of cyclopropane starting
material 12 and iodoester partner 1a) and isolated by column
chromatography (SiO2, 0–30% i-PrOAc in heptane) as a color-
less oil (161.1 mg, 65% yield). 1H NMR (500 MHz, CDCl3) δ
7.76 (d, J = 7.3 Hz, 1H), 7.49 – 7.40 (m, 2H), 7.32 – 7.20 (m,
5H), 7.21 – 7.13 (m, 1H), 5.12 (dd, J = 8.0, 8.0 Hz, 1H), 4.31
(qd, J = 7.1, 2.2 Hz, 2H), 4.23 – 4.02 (m, 4H), 3.26 (dd, J =
7.3, 7.3 Hz, 1H), 2.71 (ddd, J = 13.9, 7.7, 7.7 Hz, 1H), 2.61
(ddd, J = 13.9, 8.1, 7.2 Hz, 1H), 1.34 (t, J = 7.1 Hz, 3H), 1.23
(q, J = 7.0 Hz, 6H). 13C NMR (125 MHz, CDCl3) δ 169.4,
169.2, 167.8, 144.1, 143.4, 131.7, 131.1, 130.3, 128.4, 128.2,
128.1, 126.4, 126.2, 61.4, 61.4, 61.0, 50.4, 42.6, 34.7, 14.2,
14.0, 14.0. IR 2981, 2938, 2906, 2873, 2373, 2258, 2163,
1718, 1686, 1599, 1453, 1466, 1458, 1447, 1389, 1367, 1262,
1224, 1150, 1133, 1093, 1074, 1044, 1023, 910, 860, 787,
729, 700, 648, 591, 562, 478 cm-1. HRMS calculated for
C24H28O6H [M+H]+ 413.1959, found 413.1965.
β-Ketoester 4b: The title compound was synthesized ac-
cording to the general procedure (from 0.20 mmol of starting
material 7ab) and isolated by column chromatography (SiO2,
10% i-PrOAc in heptane) as a colorless oil (32.0 mg, 78%
1
yield, 1.5:1 enol:keto). H NMR (300 MHz, CDCl3) δ 12.40
(s, 1H), 7.80 (dd, J = 7.0, 2.2 Hz, 1H), 7.38 – 7.26 (m, 2H),
7.22 – 7.11 (m, 1H), 3.82 (s, 3H), 2.80 (dd, J = 8.9, 6.5 Hz,
2H), 2.64 – 2.54 (m, 2H). Minor peaks corresponding to the
keto tautomer observed at δ 8.04 (dd, J = 7.9, 1.5 Hz, 1H),
7.49 (td, J = 7.5, 1.5 Hz, 1H), 7.28 – 7.22 (m, 1H), 7.20 – 7.12
(m, 1H), 3.77 (s, 3H), 3.62 (dd, J = 10.2, 4.8 Hz, 1H), 3.02 (dt,
J = 10.0, 5.2 Hz, 2H), 2.48 (ddd, J = 10.2, 8.1, 4.3 Hz, 1H),
2.42 – 2.28 (m, 1H). 13C NMR (75 MHz, CDCl3) of the enol
and keto tautomers, δ 193.2, 173.2, 170.7, 165.2, 143.8, 139.5,
134.0, 131.8, 130.7, 130.1, 128.9, 127.9, 127.5, 127.0, 126.7,
124.5, 96.9, 54.6, 52.4, 51.7, 27.9, 27.7, 26.5, 20.7. IR (ATR):
2951, 2847, 1742, 1684, 1645, 1618, 1568, 1438, 1360, 1263,
1084 cm-1. HRMS calculated for C12H12O3H [M+H]+
205.0859, found 205.0855.
Triester 21: The title compound was synthesized according
to the general procedure (0.60 mmol of cyclopropane starting
material 13 and iodoester partner 1a) and isolated by column
chromatography (SiO2, 0–50% i-PrOAc in heptane) as a color-
less oil (180.1 mg, 94% yield). 1H NMR (500 MHz, CDCl3) δ
7.98 (dd, J = 7.9, 1.5 Hz, 1H), 7.46 (ddd, J = 7.5, 7.5, 1.5 Hz,
1H), 7.32 (ddd, J = 7.6, 7.6, 1.3 Hz, 1H), 7.22 (dd, J = 7.6, 1.2
Hz, 1H), 4.52 – 4.44 (m, 1H), 4.36 (qd, J = 7.1, 0.9 Hz, 2H),
4.10 – 3.96 (m, 3H), 3.44 – 3.35 (m, 2H), 3.34 – 3.27 (m, 1H),
3.23 – 3.14 (m, 1H), 1.40 (t, J = 7.1 Hz, 3H), 1.16 (t, J = 7.2
Hz, 3H). 13C NMR (125 MHz, CDCl3) δ 172.1, 167.3, 166.9,
139.5, 132.3, 131.5, 131.4, 129.6, 127.2, 71.6, 61.9, 61.1,
52.1, 41.7, 35.9, 14.3, 13.9. IR (ATR) 2982, 2934, 2908,
2873, 1778, 1733, 1710, 1601, 1576, 1447, 1368, 1347, 1258,
1244, 1208, 1139, 1083, 1015, 932, 855, 799, 712, 693, 665,
638, 598, 552, 519, 479 cm-1. HRMS calculated for
C17H20O6H [M+H]+ 321.1333, found 321.1337.
β-Ketoester 4c: The title compound was synthesized ac-
cording to the general procedure (from 0.20 mmol of starting
material 7ac) and isolated by column chromatography (SiO2,
10% i-PrOAc in heptane) as a colorless oil (31.6 mg, 68%
1
yield, 3:1 enol:keto). H NMR (300 MHz, CDCl3) δ 12.57 (s,
1H), 7.90 – 7.74 (m, 1H), 7.39 – 7.27 (m, 2H), 7.23 – 7.10 (m,
1H), 5.18 (sept, J = 6.2 Hz, 1H), 2.82 (dd, J = 8.9, 6.5 Hz,
2H), 2.63 – 2.53 (m, 2H), 1.34 (d, J = 6.2 Hz, 6H). Minor
peaks corresponding to the keto tautomer observed at δ 8.06
(dd, J = 7.8, 1.5 Hz, 1H), 7.50 (td, J = 7.5, 1.5 Hz, 1H), 7.27
(td, J = 6.9, 6.1, 3.3 Hz, 2H), 5.16 – 5.08 (m, 1H), 3.57 (dd, J
= 10.4, 4.8 Hz, 1H), 3.22 – 2.95 (m, 2H), 2.52 – 2.43 (m, 1H),
2.42 – 2.29 (m, 1H), 1.29 (d, J = 6.3 Hz, 6H). 13C NMR (75
MHz, CDCl3) of the enol and keto tautomers, δ 193.5, 172.5,
169.9, 165.0, 143.7, 139.5, 133.9, 132.0, 130.5, 130.3, 128.9,
General Procedure for the Decarboxylative Dieckmann
Reaction. In a 2-dram vial was added triester (0.20 mmol, 1.0
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127.8, 127.5, 127.0, 126.7, 124.4, 97.5, 68.9, 68.1, 54.9, 27.9, material 7ae) and isolated by column chromatography (SiO2,
1
2
3
4
5
6
7
8
27.8, 26.5, 22.1, 21.9, 20.7. IR (ATR): 2980, 2936, 1734,
1687, 1641, 1615, 1570, 1382, 1266, 1103, 1082 cm-1. HRMS
calculated for C14H16O3H [M+H]+ 233.1172, found 233.1170.
10% i-PrOAc in heptane) as a colorless oil (35.0 mg, 75%
yield, 1:1 enol:keto). H NMR (300 MHz, CDCl3) δ 12.52 (s,
1
1H), 7.68 – 7.57 (m, 1H), 7.14 (d, J = 7.7 Hz, 2H), 4.29 (q, J =
7.1 Hz, 2H), 2.77 (dd, J = 8.9, 6.5 Hz, 2H), 2.63 – 2.51 (m,
2H), 2.37 (s,3H), 1.36 (t, J = 7.1 Hz, 3H). Minor peaks corre-
sponding to the keto tautomer observed at δ 7.92 – 7.82 (m,
1H), 7.31 (dd, J = 7.9, 2.0 Hz, 1H), 7.07 (d, J = 7.7 Hz, 1H),
4.30 – 4.17 (m, 2H), 3.58 (dd, J = 10.2, 4.8 Hz, 1H), 3.07 –
2.91 (m, 2H), 2.52 – 2.41 (m, 1H), 2.37 (s, 3H), 1.30 (t, J = 7.1
Hz, 3H). 13C NMR (75 MHz, CDCl3) of the enol and keto
tautomers, δ 193.6, 172.9, 170.4, 165.4, 140.9, 136.7, 136.6,
136.2, 135.0, 131.7, 131.3, 130.0, 128.8, 127.9, 127.4, 124.9,
97.1, 61.3, 60.6, 54.8, 27.5, 27.4, 26.7, 21.2, 21.0, 20.8, 14.5,
14.3. IR (ATR): 2980, 2930, 1738, 1685, 1642, 1597, 1573,
1269, 1215, 1086, 814 cm-1. HRMS calculated for C14H16O3H
[M+H]+ 233.1172, found 233.1171.
β-Ketoester 4d: The title compound was synthesized ac-
cording to the general procedure (from 0.20 mmol of starting
material 7ad) and isolated by column chromatography (SiO2,
10% i-PrOAc in heptane) as a colorless oil (36.3 mg, 74%
1
yield, 2:1 enol:keto). H NMR (300 MHz, CDCl3) δ 12.62 (s,
1H), 7.78 (dd, J = 7.2, 1.9 Hz, 1H), 7.35 – 7.21 (m, 3H), 2.78
(dd, J = 8.9, 6.6 Hz, 2H), 2.51 (dd, J = 8.8, 6.3 Hz, 2H), 1.55
(s, 9H). Minor peaks corresponding to the keto tautomer ob-
served at δ 8.04 (dd, J = 7.9, 1.5 Hz, 1H), 7.47 (td, J = 7.5, 1.5
Hz, 1H), 7.19 – 7.11 (m, 2H), 3.49 (dd, J = 9.8, 4.8 Hz, 1H),
3.24 – 2.91 (m, 2H), 2.46 – 2.38 (m, 1H), 2.38 – 2.20 (m, 1H),
1.48 (s, 9H). 13C NMR (75 MHz, CDCl3) of the enol and keto
tautomers, δ 193.9, 172.7, 169.6, 164.6, 143.7, 139.4, 133.8,
132.2, 130.5, 130.3, 128.9, 127.7, 127.4, 126.9, 126.6, 124.3,
98.5, 81.9, 81.4, 55.5, 28.5, 28.2, 28.0, 27.7, 26.6, 21.1. IR
(ATR): 2980, 2936, 1734, 1687, 1641, 1615, 1570, 1382,
1266, 1103, 1082 cm-1. HRMS calculated for C15H18O3Na
[M+Na]+ 269.1148, found 269.1147.
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60
β-Ketoester 4h: The title compound was synthesized ac-
cording to the general procedure (from 0.20 mmol of starting
material 7bd) and isolated by column chromatography (SiO2,
10% i-PrOAc in heptane) as a white solid (39.7 mg, 84%
1
yield, 4:1 enol:keto). H NMR (300 MHz, CDCl3) δ 12.42 (s,
1H), 7.49 (dd, J = 9.5, 2.7 Hz, 1H), 7.13 (dd, J = 8.3, 5.4 Hz,
1H), 7.01 (td, J = 8.4, 2.7 Hz, 1H), 4.30 (q, J = 7.1 Hz, 2H),
2.84 – 2.72 (m, 2H), 2.67 – 2.53 (m, 2H), 1.36 (t, J = 7.1 Hz,
3H). Minor peaks corresponding to the keto tautomer observed
at δ 7.71 (dd, J = 9.0, 2.6 Hz, 1H), 7.28 – 7.17 (m, 2H), 4.27 –
4.20 (m, 2H), 3.59 (dd, J = 10.0, 4.8 Hz, 1H), 3.00 (dt, J =
13.8, 5.2 Hz, 2H), 2.53 – 2.43 (m, 1H), 2.37 (ddt, J = 8.8, 6.2,
4.7 Hz, 1H), 1.30 (t, J = 7.2 Hz, 3H). 13C NMR (75 MHz,
CDCl3) of the enol and keto tautomers, δ 192.4 (d, J = 1.5 Hz),
172.7, 170.0, 163.9 (d, J = 2.4 Hz), 161.7 (d, J = 246.7 Hz),
161.9 (d, J = 243.9 Hz), 139.5 (d, J = 3.0 Hz), 134.9 (d, J =
3.3 Hz), 133.5 (d, J = 6.3 Hz), 131.9 (d, J = 7.9 Hz), 130.8 (d,
J = 7.0 Hz), 128.8 (d, J = 7.6 Hz), 121.4 (d, J = 22.2 Hz),
117.1 (d, J = 21.6 Hz), 113.7 (d, J = 22.1 Hz), 111.4 (d, J =
23.5 Hz), 98.0, 61.5, 60.9, 54.3, 27.1, 27.0, 26.6, 20.8, 14.4,
14.3. 19F NMR (282 MHz, CDCl3) δ -114.62 (keto), -115.82
(enol). IR (ATR): 2927, 2852, 1644, 1604, 1573, 1493, 1278,
1219, 972, 811 cm-1. HRMS calculated for C13H13 FO3H
[M+H]+ 237.0921, found 237.0919.
β-Ketoester 4e: The title compound was synthesized ac-
cording to the general procedure (from 0.20 mmol of starting
material 7ba) and isolated by column chromatography (SiO2,
10% i-PrOAc in heptane) as a colorless oil (43.6 mg, 94%
1
yield, 1:2 enol:keto). H NMR (300 MHz, CDCl3) δ 7.33 (t, J
= 7.6 Hz, 1H), 7.12 (d, J = 3.4 Hz, 1H), 7.09 (d, J = 3.9 Hz,
1H), 4.25 (q, J = 7.1 Hz, 2H), 3.60 (dd, J = 10.6, 5.0 Hz, 1H),
3.04 (dt, J = 10.3, 5.2 Hz, 2H), 2.64 (s, 3H), 2.58 – 2.41 (m,
2H), 1.30 (t, J = 7.2 Hz, 3H). Minor peaks corresponding to
the enol tautomer observed at δ 13.03 (s, 1H), 7.18 (t, J = 7.5
Hz, 1H), 7.08 – 6.97 (m, 2H), 4.33 – 4.27 (m, 2H), 2.74 (dd, J
= 8.9, 5.9 Hz, 2H), 2.64 (s, 3H), 2.39 – 2.26 (m, 2H), 1.36 (t, J
= 7.2 Hz, 3H). 13C NMR (75 MHz, CDCl3) of the enol and
keto tautomers, δ 195.2, 173.2, 170.7, 168.8, 144.8, 142.1,
141.4, 138.0, 132.8, 130.8, 130.7, 130.6, 130.0, 128.8, 126.9,
125.5, 98.2, 61.3, 60.6, 56.4, 29.8, 28.9, 26.2, 23.3, 23.0, 20.7,
14.5, 14.3. IR (ATR): 2978, 2932, 1736, 1677, 1634, 1593,
1563, 1309, 956, 774 cm-1. HRMS calculated for C14H16O3H
[M+H]+ 233.1172, found 233.1171.
β-Ketoester 4i: The title compound was synthesized ac-
cording to the general procedure (from 0.20 mmol of starting
material 7be) and isolated by column chromatography (SiO2,
10% i-PrOAc in heptane) as a white solid (53.8 mg, 91%
yield, 17:1 enol:keto). 1H NMR (300 MHz, CDCl3) δ 12.42 (s,
1H), 7.92 (d, J = 2.1 Hz, 1H), 7.42 (d, J = 2.2 Hz, 1H), 7.05
(d, J = 8.0 Hz, 1H), 4.30 (q, J = 7.1 Hz, 2H), 2.76 (dd, J = 8.9,
6.7 Hz, 2H), 2.62 – 2.50 (m, 2H), 1.36 (t, J = 7.1 Hz, 3H).
Minor peaks corresponding to the keto tautomer observed at δ
8.17 (d, J = 2.2 Hz, 1H), 7.60 (dd, J = 8.2, 2.2 Hz, 1H), 7.14
(d, J = 8.2 Hz, 1H), 4.29 – 4.21 (m, 2H), 3.59 (dd, J = 9.9, 4.7
Hz, 1H), 3.11 – 2.98 (m, 1H), 2.93 (ddd, J = 16.7, 9.0, 4.5 Hz,
1H), 2.49 (dq, J = 9.4, 4.7 Hz, 1H), 2.36 (ddt, J = 11.1, 6.3, 3.2
Hz, 1H), 1.36 – 1.30 (m, 3H). 13C NMR (75 MHz, CDCl3) of
the enol and keto tautomers, δ 192.1, 172.6, 169.9, 163.6,
142.4, 138.1, 136.7, 133.2, 132.0, 130.7, 130.6, 129.1, 127.4,
121.0, 120.4, 98.0, 61.6, 60.9, 54.2, 32.0, 27.4, 22.8, 20.5,
14.4, 14.2. IR (ATR): 2940, 2853, 1615, 1586, 1556, 1475,
1349, 1271, 1025, 814 cm-1. HRMS calculated for
C13H13BrO3H [M+H]+ 297.0121, found 297.0121.
β-Ketoester 4f: The title compound was synthesized ac-
cording to the general procedure (from 0.20 mmol of starting
material 7bb) and isolated by column chromatography (SiO2,
10% i-PrOAc in heptane) as a colorless oil (10.4 mg, 18%
1
yield, 1:1 enol:keto). H NMR (300 MHz, CDCl3) δ 12.34 (s,
1H), 7.51 – 7.12 (m, 8H), 4.26 (q, J = 7.0 Hz, 2H), 2.82 (dd, J
= 8.8, 5.8 Hz, 2H), 2.58 (dd, J = 8.8, 5.8 Hz, 2H), 1.35 (t, J =
7.1 Hz, 3H). Minor peaks corresponding to the keto tautomer
observed at δ 7.73 – 6.51 (m, 8H), 4.24 – 4.16 (m, 2H), 3.59
(dd, J = 9.1, 5.1 Hz, 1H), 3.24 – 3.10 (m, 1H), 3.09 – 2.94 (m,
1H), 2.50 (dd, J = 8.9, 4.9 Hz, 1H), 2.45 – 2.29 (m, 1H), 1.27
(t, J = 7.2 Hz, 3H). 13C NMR (75 MHz, CDCl3) of the enol
and keto tautomers, δ 193.8, 172.8, 170.3, 167.0, 144.6, 144.4,
143.2, 142.4, 141.9, 141.4, 132.3, 130.9, 130.7, 130.6, 129.7,
128.6, 128.4, 128.18, 128.17, 128.0, 127.6, 127.0, 126.8,
126.6, 98.6, 61.4, 60.6, 55.8, 29.7, 28.4, 26.6, 20.7, 14.5, 14.3.
IR (ATR): 3057, 2981, 2929, 1735, 1687, 1634, 1609, 1259,
1232, 938, 757 cm-1. HRMS calculated for C19H18O3H
[M+H]+ 295.1329, found 295.1310.
β-Ketoester 4g: The title compound was synthesized ac-
cording to the general procedure (from 0.20 mmol of starting
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β-Ketoester 4j: The title compound was synthesized ac-
material 7bj) and isolated by column chromatography (SiO2,
10% i-PrOAc in heptane) as a white solid (53.7 mg, 97%
yield, 4:1 enol:keto). H NMR (300 MHz, CDCl3) δ 12.41 (s,
1
2
3
4
5
6
7
8
cording to the general procedure (from 0.20 mmol of starting
material 7bf) and isolated by column chromatography (SiO2,
10% i-PrOAc in heptane) as a colorless oil (44.9 mg, 80%
1
1H), 7.98 – 7.89 (m, 1H), 7.85 (s, 1H), 7.87 – 7.79 (m, 1H),
4.29 (q, J = 7.1 Hz, 2H), 3.92 (s, 3H), 2.85 (dd, J = 9.0, 6.6
Hz, 2H), 2.59 (dd, J = 8.8, 6.4 Hz, 2H), 1.35 (t, J = 7.1 Hz,
3H). Minor peaks corresponding to the keto tautomer observed
at δ 8.09 (d, J = 8.6 Hz, 1H), 7.92 (d, J = 1.7 Hz, 2H), 4.26 –
4.20 (m, 2H), 3.94 (s, 3H), 3.63 (dd, J = 10.0, 4.8 Hz, 1H),
3.07 (dq, J = 8.8, 5.2, 4.8 Hz, 2H), 2.54 – 2.45 (m, 1H), 2.43 –
2.33 (m, 1H), 1.29 (t, J = 7.1 Hz, 3H). 13C NMR (75 MHz,
CDCl3) of the enol and keto tautomers, δ 192.8, 172.6, 169.9,
166.8, 166.3, 163.7, 143.6, 139.3, 134.9, 134.5, 134.2, 131.5,
130.3, 128.5, 128.0, 127.9, 127.7, 124.4, 99.1, 61.5, 60.9,
54.6, 52.6, 52.3, 27.7, 27.6, 26.3, 20.6, 14.4, 14.3. IR (ATR):
2947, 2923, 2852, 1714, 1637, 1603, 1561, 1258, 1024, 786
cm-1. HRMS calculated for C15H16 O5H [M+H]+ 277.1071,
found 277.1070.
1
yield, 1:1 enol:keto). H NMR (300 MHz, CDCl3) δ 12.53 (s,
1H), 7.35 (d, J = 2.8 Hz, 1H), 7.08 (d, J = 8.2 Hz, 1H), 6.88
(dd, J = 8.3, 2.8 Hz, 1H), 4.29 (q, J = 7.1 Hz, 2H), 3.83 (s,
3H), 2.74 (dd, J = 9.0, 6.4 Hz, 2H), 2.68 – 2.50 (m, 2H), 1.35
(t, J = 7.1 Hz, 3H). Minor peaks corresponding to the keto
tautomer observed at δ 7.52 (d, J = 2.8 Hz, 1H), 7.16 (d, J =
8.4 Hz, 1H), 7.07 (d, J = 8.4 Hz, 1H), 4.27 – 4.19 (m, 2H),
3.83 (s, 3H), 3.57 (dd, J = 10.2, 4.8 Hz, 1H), 3.06 – 2.84 (m,
2H), 2.51 – 2.41 (m, 1H), 2.40 – 2.28 (m, 1H), 1.30 (t, J = 7.1
Hz, 3H). 13C NMR (75 MHz, CDCl3) of the enol and keto
tautomers, δ 193.3, 172.9, 170.4, 165.0, 158.6, 158.5, 136.4,
132.6, 131.7, 131.0, 130.1, 128.4, 122.4, 117.0, 109.6, 108.9,
97.4, 61.3, 60.7, 55.6, 55.5, 54.5, 27.00, 26.95, 26.8, 21.0,
14.4, 14.3. IR (ATR): 2935, 1737, 1683, 1644, 1596, 1570,
1497, 1219, 1026, 811 cm-1. HRMS calculated for C14H16O4H
[M+H]+ 249.1121, found 249.1121.
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β-Ketoester 4n: The title compound was synthesized ac-
cording to the general procedure (from 0.20 mmol of starting
material 7bk) and isolated by column chromatography (SiO2,
10% i-PrOAc in heptane) as a colorless oil (45.8 mg, 99%
yield, 1:1.5 enol:keto). 1H NMR (500 MHz, CDCl3) δ 7.92 (d,
J = 8.0 Hz, 1H), 7.37 (d, J = 7.3 Hz, 1H), 7.27 – 7.15 (m, 1H),
4.28 – 4.21 (m, 2H), 3.58 (dd, J = 10.7, 4.6 Hz, 1H), 3.00
(ddd, J = 17.4, 5.2, 5.2 Hz, 1H), 2.82 (ddd, J = 17.4, 9.6, 4.9
Hz, 1H), 2.53 – 2.43 (m, 1H), 2.41 – 2.34 (m, 1H), 2.31 (s,
3H), 1.29 (t, J = 7.1 Hz, 3H). Minor peaks corresponding to
the enol tautomer observed at δ 12.46 (s, 1H), 7.69 (dd, J =
7.4, 1.8 Hz, 1H), 7.27 – 7.15 (m, 2H), 4.29 (q, J = 7.1 Hz, 2H),
2.75 (dd, J = 8.8, 6.9 Hz, 2H), 2.56 (dd, J = 8.8, 6.8 Hz, 2H),
2.30 (s, 3H), 1.35 (t, J = 7.1 Hz, 3H). 13C NMR (125 MHz,
CDCl3) δ 193.6, 172.7, 170.2, 165.3, 141.9, 137.7, 136.4,
135.2, 134.9, 132.4, 132.0, 130.0, 126.4, 125.9, 125.6, 122.3,
96.4, 61.2, 60.5, 53.9, 25.5, 24.8, 23.8, 20.1, 19.4, 19.4, 14.4,
14.2. IR 3070, 2970, 2953, 2871, 2851, 1736, 1686, 1649,
1617, 1595, 1580, 1464, 1398, 1376, 1348, 1323, 1275, 1220,
1201, 1140, 1095, 1077, 1032, 934, 903, 827, 796, 764, 740,
592, 580, 544, 528 cm-1. HRMS calculated for C14H16O3H
[M+H]+ 233.1172, found 233.1174.
β-Ketoester 4k: The title compound was synthesized ac-
cording to the general procedure (from 0.20 mmol of starting
material 7bh) and isolated by column chromatography (SiO2,
10% i-PrOAc in heptane) as a colorless oil (38.0 mg, 82%
1
yield, 3:1 enol:keto). H NMR (300 MHz, CDCl3) δ 12.51 (s,
1H), 7.70 (d, J = 7.9 Hz, 1H), 7.07 (d, J = 8.5 Hz, 1H), 7.00 (s,
1H), 4.29 (q, J = 7.1 Hz, 2H), 2.84 – 2.73 (m, 2H), 2.62 – 2.53
(m, 2H), 2.37 (s, 3H), 1.36 (t, J = 7.1 Hz, 3H). Minor peaks
corresponding to the keto tautomer observed at δ 7.96 (d, J =
8.0 Hz, 1H), 7.12 – 7.15 (m, 2H), 4.27 – 4.21 (m, 2H), 3.58
(dd, J = 10.3, 4.8 Hz, 1H), 2.98 (dt, J = 9.7, 5.3 Hz, 2H), 2.54
– 2.40 (m, 2H), 2.39 (s, 3H), 1.31 (t, J = 7.1 Hz, 3H). 13C
NMR (75 MHz, CDCl3) of the enol and keto tautomers, δ
193.0, 172.9, 170.5, 165.5, 144.9, 143.8, 141.0, 139.6, 129.6,
129.3, 128.3, 128.0, 128.0, 127.5, 127.4, 124.4, 96.3, 61.3,
60.5, 54.7, 28.0, 27.7, 26.6, 21.8, 21.6, 20.8, 14.5, 14.3. IR
(ATR): 2979, 2906, 1737, 1682, 1640, 1610, 1561, 1268,
1208, 1090, 1022 cm-1. HRMS calculated for C14H16O3H
[M+H]+ 233.1172, found 233.1172.
β-Ketoester 4l: The title compound was synthesized ac-
cording to the general procedure (from 0.20 mmol of starting
material 7bi) and isolated by column chromatography (SiO2,
10% i-PrOAc in heptane) as a colorless oil (49.0 mg, 97%
β-Ketoester 22: The title compound was synthesized ac-
cording to the general procedure (from 0.20 mmol of starting
material 19) and isolated by column chromatography (SiO2,
10% i-PrOAc in heptane) as a yellow oil (36.6 mg, 90% yield,
1
yield, 4:1 enol:keto). H NMR (300 MHz, CDCl3) δ 12.46 (s,
1
1H), 7.72 (d, J = 8.3 Hz, 1H), 7.25 (dd, J = 8.2, 2.0 Hz, 1H),
7.19 – 7.15 (m, 1H), 4.29 (q, J = 7.1 Hz, 2H), 2.79 (dd, J =
8.8, 6.7 Hz, 2H), 2.58 (dd, J = 8.9, 6.7 Hz, 2H), 1.36 (t, J = 7.1
Hz, 3H). Minor peaks corresponding to the keto tautomer ob-
served at δ 7.99 (d, J = 8.4 Hz, 1H), 7.30 (dd, J = 8.4, 2.0 Hz,
1H), 7.28 – 7.23 (m, 1H), 4.28 – 4.22 (m, 2H), 3.59 (dd, J =
10.0, 4.7 Hz, 1H), 3.05 (dt, J = 17.1, 5.4 Hz, 1H), 2.97 (ddd, J
= 17.1, 9.3, 4.7 Hz, 1H), 2.50 (ddt, J = 14.1, 9.5, 4.4 Hz, 1H),
2.36 (ddt, J = 13.5, 6.2, 4.6 Hz, 1H), 1.30 (t, J = 7.2 Hz, 3H).
13C NMR (75 MHz, CDCl3) of the enol and keto tautomers, δ
192.3, 172.7, 170.0, 164.2, 145.3, 141.2, 140.3, 136.4, 130.4,
129.5, 128.8, 128.7, 127.63, 127.60, 126.9, 125.8, 97.3, 61.5,
60.8, 54.4, 27.8, 27.6, 26.3, 20.5, 14.4, 14.3. IR (ATR): 2980,
2850, 1739, 1689, 1644, 1615, 1592, 1559, 1262, 1195, 1022
cm-1. HRMS calculated for C13H13ClO3H [M+H]+ 253.0626,
found 253.0624.
<1:20 enol:keto). H NMR (300 MHz, CDCl3) δ 7.77 (d, J =
7.7 Hz, 1H), 7.62 (td, J = 7.4, 1.3 Hz, 1H), 7.53 – 7.47 (m,
1H), 7.43 – 7.36 (m, 1H), 4.31 – 4.19 (m, 2H), 3.71 (dd, J =
8.3, 4.1 Hz, 1H), 3.62 – 3.48 (m, 1H), 3.37 (dd, J = 17.3, 8.3
Hz, 1H), 1.31 (t, J = 7.1 Hz, 3H). 13C NMR (75 MHz, CDCl3)
δ 199.6, 169.2, 153.7, 135.5, 135.4, 127.9, 126.7, 124.8, 61.8,
53.5, 30.4, 14.3. IR (ATR): 2981, 2934, 1737, 1709, 1572,
1255, 1150, 1091, 1007, 760 cm-1. HRMS calculated for
C12H12O3H [M+H]+ 205.0859, found 205.0857.
β-Ketoester 4o: The title compound was synthesized ac-
cording to the general procedure (from 0.20 mmol of starting
material 20) and isolated by column chromatography (SiO2,
50% i-PrOAc in heptane) as a white solid (52.5 mg, 89%
1
yield, >20:1 enol:keto). H NMR (500 MHz, CDCl3) δ 12.48
(s, 1H), 7.89 (dd, J = 7.6, 1.7 Hz, 1H), 7.38 – 7.15 (m, 7H),
6.86 (ddd, J = 7.7, 1.2, 1.2 Hz, 1H), 4.34 – 4.19 (m, 2H), 4.15
(dd, J = 10.5, 6.6 Hz, 1H), 2.94 (dd, J = 15.7, 6.7 Hz, 1H),
2.83 (dd, J = 15.7, 10.5 Hz, 1H), 1.30 (t, J = 7.1 Hz, 3H). 13C
β-Ketoester 4m: The title compound was synthesized ac-
cording to the general procedure (from 0.20 mmol of starting
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NMR (125 MHz, CDCl3) δ 172.6, 164.6, 143.3, 141.6, 130.7, ambient temperature. The reaction mixture was quenched with
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7
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130.1, 128.6, 128.5, 127.7, 126.8, 126.8, 124.4, 95.9, 60.6,
44.1, 29.1, 14.2. IR 3060, 3025, 2981, 2972, 2928, 2902,
2852, 1734, 1717, 1698, 1684, 1647, 1617, 1568, 1541, 1521,
1507, 1496, 1489, 1473, 1454, 1400, 1378, 1345, 1321, 1268,
1241, 1181, 1137, 1082, 1025, 969, 953, 932, 914, 823, 766,
749, 701, 527, 614, 588, 563, 505, 458, 419 cm-1. HRMS cal-
culated for C19H18O3H [M+H]+ 295.1329, found 295.1332.
saturated aqueous NH4Cl and extracted with i-PrOAc (2 × 60
mL). The combined organic layers were dried over MgSO4
and concentrated in vacuo. The residue was purified by col-
umn chromatography (SiO2, 0–20% i-PrOAc in heptane) to
afford the triester 7aa (8.01 g, 23.8 mmol, 79% yield) as a tan
oil.
Decarboxylative Dieckmann Step. In a 60 mL scintillation
vial was added triester 7aa (2.0 g, 5.94 mmol, 1.0 equiv),
MgBr2 (1.66 g, 8.92 mmol, 1.5 equiv), 2-MeTHF (12 mL, 0.50
M), and Et3N (2.51 mL, 17.84 mmol, 3.0 equiv). The resulting
mixture was stirred at 80 °C for 1 h. The reaction mixture was
quenched with 2 M HCl (9 mL) and extracted with i-PrOAc (3
× 15 mL). The combined organic layers were dried over
MgSO4 and concentrated in vacuo. The residue was purified
by column chromatography (SiO2, 0–20% i-PrOAc in heptane)
to afford the b-ketoester 4a (1.10 g, 5.04 mmol, 85% yield) as
a pale tan oil.
Deuterated Solvent 13C NMR Experiment for the Obser-
vation of Diethyl Carbonate. To a 2 dram vial was added
MgBr2 (55.8 mg, 0.30 mmol, 1.5 equiv), stir bar, triester 7aa,
Et3N (84.5 mL, 0.60 mmol, 3.0 equiv), and THF-d8 (0.40 mL,
0.50 M). The resulting mixture was stirred at 80 °C for 5 h.
The reaction mixture was transferred to an NMR tube and
analyzed by 13C NMR. The crude spectrum was compared to
the spectrum of an authentic sample of diethyl carbonate in
THF-d8.
β-Ketoester 4p: The title compound was synthesized ac-
cording to the general procedure (from 0.20 mmol of starting
material 7bl) and isolated by column chromatography (SiO2,
50% i-PrOAc in heptane) as a white solid (20.0 mg, 46%
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yield, >20:1 enol:keto). H NMR (300 MHz, CDCl3) δ 12.39
(s, 1H), 8.49 (dd, J = 5.0, 1.8 Hz, 1H), 8.04 (dd, J = 7.8, 1.8
Hz, 1H), 7.23 (dd, J = 7.8, 4.9 Hz, 1H), 4.31 (q, J = 7.1 Hz,
2H), 3.03 (dd, J = 8.9, 7.0 Hz, 2H), 2.70 (dd, J = 8.8, 7.1 Hz,
2H), 1.37 (t, J = 7.1 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ
172.6, 163.3, 159.5, 150.5, 131.6, 126.0, 122.0, 97.9, 61.0,
30.6, 20.1, 14.4. IR (ATR): 2922, 2853, 1736, 1647, 1621,
1563, 1270, 1207, 751, 723 cm-1. HRMS calculated for
C12H13NO3H [M+H]+ 220.0968, found 220.0965.
Carbazole 23: The title compound was synthesized accord-
ing to the general procedure (from 0.20 mmol of starting mate-
rial 7bm) and isolated by column chromatography (SiO2, 15%
i-PrOAc in heptane) as a yellow solid (31.7 mg, 59% yield).
1H NMR (300 MHz, CDCl3) δ 11.79 (s, 1H), 8.07 (d, J = 7.8
Hz, 1H), 7.67 (d, J = 8.4 Hz, 1H), 7.59 – 7.49 (m, 2H), 7.43
(d, J = 8.3 Hz, 1H), 7.26 (ddd, J = 8.0, 5.7, 1.0 Hz, 1H), 4.47
(q, J = 7.1 Hz, 2H), 4.26 (s, 3H), 1.48 (t, J = 7.1 Hz, 3H). 13C
NMR (75 MHz, CDCl3) δ 171.8, 151.1, 142.5, 128.8, 128.7,
127.1, 122.4, 121.1, 119.7, 119.4, 111.0, 109.3, 108.2, 61.4,
32.2, 14.4. IR (ATR): 2922, 1660, 1632, 1461, 1370, 1310,
1105, 787, 716 cm-1. HRMS calculated for C16H15NO3H
[M+H]+ 270.1125, found 270.1124.
Diallyl cyclopropane-1,1-dicarboxylate (14): To a 40 mL
vial with cross-shaped stir bar and septum fitted screw cap was
added cyclopropane-1,1-dicarboxylic acid (500 mg, 3.7 mmol,
1.0 equiv), K2CO3 (5.2 g, 37 mmol, 10 equiv), DMF (5 mL),
and allyl bromide (2.0 mL, 22 mmol, 6.0 equiv). The tan sus-
pension was stirred vigorously. After stirring for 19 h, the
reaction was diluted with MTBE (80 mL) and water (20 mL).
The phases were separated and the aqueous phase was extract-
ed with MTBE (2 x 60 mL). The combined organic phases
were dried over Na2SO4, filtered, and concentrated under re-
duced pressure. The crude product was purified by purified by
column chromatography (SiO2, 15% i-PrOAc in heptane) to
afford the cyclopropane diester 14 (689 mg, 3.28 mmol, 88%
yield) as a colorless oil. 1H NMR (500 MHz, CDCl3) δ 5.99 –
5.83 (m, 2H), 5.35 (ddd, J = 17.3, 1.5, 1.5 Hz, 2H), 5.24 (dq, J
= 10.5, 1.3, 1.3 Hz, 2H), 4.64 (dq, J = 5.8, 1.4 Hz, 4H), 1.49
(s, 2H). 13C NMR (125 MHz, CDCl3) δ 169.4, 131.7, 118.3,
66.0, 28.1, 16.8. IR (ATR) 1720, 1421, 1366, 1314, 1197,
1164, 1123, 1043, 984, 928, 881, 829, 795, 752, 711, 645,
588, 556, 487 cm-1. HRMS calculated for C11H14O4H [M+H]+
211.0965, found 211.0967.
β-Ketoester 4q: The title compound was synthesized ac-
cording to the general procedure (from 0.20 mmol of starting
material 7bn) and isolated by column chromatography (SiO2,
10% i-PrOAc in heptane) as a yellow oil (39.8 mg, 72% yield,
1
<1:20 enol:keto). H NMR (300 MHz, CDCl3) δ 7.88 (d, J =
7.6 Hz, 1H), 7.82 (d, J = 7.3 Hz, 1H), 7.51 (ddd, J = 8.1, 7.1,
1.5 Hz, 1H), 7.44 (td, J = 7.5, 1.3 Hz, 1H), 4.33 – 4.18 (m,
2H), 3.71 (dd, J = 9.0, 4.8 Hz, 1H), 3.24 (ddd, J = 17.5, 6.5,
4.9 Hz, 1H), 3.05 (ddd, J = 17.4, 8.0, 5.0 Hz, 1H), 2.79 – 2.61
(m, 1H), 2.52 (ddt, J = 13.7, 6.4, 4.9 Hz, 1H), 1.30 (t, J = 7.1
Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 188.3, 169.8, 147.8,
143.0, 138.0, 135.3, 128.5, 125.0, 124.0, 123.6, 61.6, 54.2,
27.3, 22.6, 14.3. IR (ATR): 2979, 2936, 1729, 1660, 1526,
1382, 1218, 1148, 1008, 756 cm-1. HRMS calculated for
C15H14SO3H [M+H]+ 275.0736, found 275.0716.
ASSOCIATED CONTENT
Gram Scale Procedure for Homoconjugate Addition and
Cyclization:
Supporting Information
Homoconjugate Addition Step. In a heat-gun dried 500
mL round-bottom flask was added ethyl 2-iodobenzoate (1a)
(12.81 g, 45 mmol, 1.5 equiv) and anhydrous 2-MeTHF (30
mL). The solution was cooled to –78 °C, and i-PrMgCl·LiCl
(42 mL, 1.1 mmol, 1.8 equiv, 1.3 M in THF) was added. The
resulting mixture was stirred at –78 °C for 30 min. CuI·SMe2
(11.14 g, 11.4 mmol, 1.5 equiv) was added as a suspension in
anhydrous 2-MeTHF (60 mL), followed by DMI (9.9 mL, 90
mmol, 3.0 equiv) and diethyl 1,1-cyclopropane dicarboxylate
(6a) (5.59 g, 5.30 mL, 30 mmol, 1 equiv). The resulting mix-
ture was allowed to stir overnight (19.5 h), slowly warming to
The Supporting Information is available free of charge on the
ACS Publications website.
Reagent information, reaction optimization information, substrate
table compound structures, and NMR spectra (1H, 13C, and 19F)
for isolated compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
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The Journal of Organic Chemistry
* Email: hong.allen@gene.com
1
2
ORCID
Zhiwei Chen: 0000-0001-5380-6284
Xin Linghu: 0000-0002-8095-3244
Allen Y. Hong: 0000-0002-4691-548X
3
4
5
6
7
8
9
Copper-Catalyzed Addition of Methallyl Grignard Reagent to
Activated Cyclopropanes. Synthesis 2001, 145–149.
6. For mechanistic discussion of mono and diactivated cyclopro-
pane homoconjugate additions, see: Bertz, S. H.; Dabbagh, G.;
Cook, J. M.; Honkan, V. Organocuprate Reactions with Cyclo-
propanes. Evidence for Three types of Mechanism. J. Org.
Chem. 1984, 49, 1739–1743.
ACKNOWLEDGMENT
We thank the Genentech Summer Internship Program for support-
ing Z.C. during the project. Kenji Kurita and J. Levi Knippel are
thanked for experimental assistance. Filip Petronijević, Ian S.
Young, Cheol K. Chung, C. Greg Sowell, Haiming Zhang, and
Francis Gosselin (Genentech, Inc.) are thanked for helpful discus-
sions.
7. For several examples of the use of DMI as an additive in transi-
tion metal-mediated reactions, see:
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(a) Lo, C.-C.; Chao, P. M. Replacement of Carcinogenic Solvent
HMPA by DMI in Insect Sex Pheromone Synthesis. J. Chem.
Ecol. 1990, 16, 3245–3253.
(b) Zhou, Q.-L.; Pfaltz, A. Chiral Mercaptoaryl-Oxazolines as
Ligands in Enantioselective Copper-Catalyzed 1,4-Additions of
Grignard Reagents to Enones. Tetrahedron 1994, 50, 4467–
4478.
(c) Wefelscheid, U. K.; Reissig, H.-U. Pentacyclic Compounds
by Samarium Diiodide‐Induced Cascade Cyclizations of Naph-
thyl‐Substituted 1,3‐Diones. Adv. Synth. Catal. 2008, 350, 65–
69.
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Kopp, F.; Korn, T.; Sapountzis, I.; Vu, V. A. Highly Functional-
ized Organomagnesium Reagents Prepared through Halogen-
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10. Attempting the reaction in EtOH led to partial ester exchange for
mixed ester substrate 7ab.
11. Sapountzis, I.; Knochel, P. General preparation of functionalized
o-nitroarylmagnesium halides through an iodine-magnesium ex-
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