Tandem ring-opening decarboxylation of cyclopropane hemimalonates with sodium azide: A short route to γ-aminobutyric acid esters

Article abstract of DOI:10.1021/jo3010606

Cyclopropane hemimalonates, when treated with sodium azide, undergo a tandem ring-opening decarboxylation to produce γ-azidobutyric acids in good yields. These adducts were hydrogenated to form γ-aminobutyric acid (GABA) methyl esters.

Full text of DOI:10.1021/jo3010606

Note
pubs.acs.org/joc
Tandem Ring-Opening Decarboxylation of Cyclopropane
Hemimalonates with Sodium Azide: A Short Route to γ-Aminobutyric
Acid Esters
Michael R. Emmett, Huck K. Grover, and Michael A. Kerr*
Department of Chemistry, Western University, London, Ontario, Canada N6A 5B7
S
* Supporting Information
ABSTRACT: Cyclopropane hemimalonates, when treated with
sodium azide, undergo a tandem ring-opening decarboxylation
to produce γ-azidobutyric acids in good yields. These adducts
were hydrogenated to form γ-aminobutyric acid (GABA)
methyl esters.
Scheme 1. Opening of Epoxides and Cyclopropanes with
Azide
γ-Aminobutyric acid (GABA) is an inhibitory neurotransmitter
in the central nervous system.1 Though the roles of GABA are
varied and complex, in humans GABA plays a central part in
the regulation of muscle tone. With its many roles in the human
body, it is not surprising that many drugs which mimic or
interfere with GABA have been investigated. Both pregabalin
(Lyrica) and gabapentin (Neurontin) were developed by Pfizer
for the treatment of fibromyalgia-related pain and migraine
pain, respectively (Figure 1).
solvents also gave unsatisfactory results. The fact that the
diester was unreactive is interesting due to the report that the
Meldrum’s acid derived cyclopropane underwent ring-opening
at subambient temperatures in less than an 1 h.5
Figure 1. GABA and GABA-inspired drugs.
Entry 1 from Table 1 represents a duplication of the Backvall
̈
conditions which led to a 70% isolated yield of the azido adduct
which had concurrently undergone decarboxylation. In the
absence of ammonium chloride (entries 2 and 3), an alternative
(and unidentified) product was formed in low yield in the
presence of water and the expected adduct was formed in low
yield in the absence of water. Other solvents which, in previous
work, have been compatible with cyclopropane ring openings
(entries 4−6) where unsatisfactory in this instance. A further
tuning of the reaction conditions (entries 7−12) revealed our
optimal conditions (entry 7).
With our best conditions in hand, we set out to survey the
range of cyclopropanes6 which would effectively undergo this
transformation.7 Table 2 shows the substrate scope (see ref 3
for preparation of cyclopropanes 4). For the most part, the
reaction seems to proceed effectively with aromatic or
heteroaromatic substituents on the cyclopropane. Note that
electron-withdrawing groups on the phenyl ring attenuated the
reactivity and resulted in lower yields (adducts 5g and 5h).
Electron-donating groups had the opposite effect, producing
During our work involving the ring-opening reactions of
donor−acceptor cyclopropanes,2 specifically the recently
discovered special reactivity of cyclopropane hemimalonates,3
we were compelled to attempt the ring-opening of cyclo-
propane diesters and hemimalonates with the azido anion in
order to complement the existing toolbox of nucleophiles for
this type of reaction. Herein we report the smooth tandem ring-
opening/decarboxylation of cyclopropane hemimalonates in
the absence of a Lewis acid catalyst to provide a variety of 3-
azidobutyric acid esters (Scheme 1) as well as the reduction to
GABA methyl esters.
The reaction conditions which ultimately proved to be the
best (after optimization for our substrates) were inspired by
Backvall,4 who reported that a mixture of sodium azide and
̈
ammonium chloride in a solvent mixture of 2-methoxyethanol
and water was effective in preparing azidoethanols from
epoxides (Scheme 1). Table 1 shows the fine-tuning of these
conditions for our needs, as well as a brief examination of other
conditions. It is of note that the diesters (which were
investigated first) were unreactive under these reaction
conditions and that the use of Lewis acids in alternative
Received: June 8, 2012
© XXXX American Chemical Society
A
dx.doi.org/10.1021/jo3010606 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Table 1. Optimization of Tandem Ring-Opening/
Decarboxylation
Table 2. Reaction Scope
azide
NH4Cl
(equiv)
a
b
entry
1
(equiv)
solvent
yield (%)
1
1.4
2-MeO(CH2)2OH/H2O
(10:1)
70
2
1
0
2-MeO(CH2)2OH/H2O
(10:1)
N/A
30
3
4
1
1
0
2-MeO(CH2)2OH
C6H6
1.4
no
reaction
5
6
1
1.4
1.4
1.4
1.4
3
CH3CN
THF
no
reaction
1
no
reaction
7
1.2
2
2-MeO(CH2)2OH/H2O
(10:1)
78
73
74
8
2-MeO(CH2)2OH/H2O
(10:1)
9
2
2-MeO(CH2)2OH/H2O
(10:1)
c
10
11
12
1.2
1.2
1.2
1.2
1.4
1.4
1.4
1.4
2-MeO(CH2)2OH/H2O
(10:1)
50
2-MeO(CH2)2OH/H2O
(5:1)
74
60
50
2-MeO(CH2)2OH/H2O
(1:1)
d
13
2-MeO(CH2)2OH/H2O
(10:1)
a
b
c
Reactions performed at 125 °C for 2 h. Isolated yield. Performed in
d
a microwave reactor at 150 °C for 0.5 h. 20 mol % of Yb(OTf)3 was
a
b
For 2 h. For 30 min.
added.
Scheme 2. Possible Involvement of an Acyl Azide
adducts in excellent yields (adducts 5c and 5d). While a
styrenyl substituent was well tolerated (adduct 5i), the vinyl
cyclopropane (R = CHCH2) was not, resulting in the
formation of an inseparable mixture of the expected adduct and
the product resulting from SN2′ opening. It is of note that the
optically enriched phenyl cyclopropane (S)-4a8 (90% ee)
underwent this transformation with full retention of enantio-
purity (vide infra) to give (S)-5a. Finally, cyclopropanes where
R = aliphatic or R = H were unreactive under these conditions,
and starting material was recovered intact.
The fact that the hemimalonates are effective substrates and
the diesters are not is surprising to us. In our previous report in
which we described the nucleophilic opening of these species
with indoles,3 we were able to rationalize the results by
invoking a high pressure induced intramolecular hydrogen
bond between the carboxylic acid and the ester. The effect of
this would be to stereoelectronically align the carbonyls for the
ring-opening event. It is hard to make such a rationalization in
this case since the reaction takes place in a refluxing protic
medium. It puzzles us then, why the carboxylic acid moiety is a
requirement for this reaction. One explanation (Scheme 2) is
that the reaction was proceeding via an acyl azide 6 which could
undergo a [3,3]-sigmatropic rearrangement to yield ketene 7,
which in turn would be intercepted by water to regenerate the
acid. Decarboxylation of the resulting monoester 8 could then
ensue, yielding the observed product 5. We have attempted to
prepare and isolate the acylazide, and subject it to the reaction
conditions in order to prove this hypothesis; however, the
results were inconclusive due to extensive decomposition.9
As proof that the azidoesters 5 could be viable precursors to
GABA esters, a representative example (5a) was subjected to
reduction under a balloon of hydrogen gas with catalysis by
palladium on carbon. GABA ester 9 was produced in 93% yield
(Scheme 3).
The conversion of (S)-5a, the product of enantioenriched
(S)-4a (90% ee), to 9 also served to determine the
Scheme 3. Reduction to a GABA Ester and a γ-Lactam
B
dx.doi.org/10.1021/jo3010606 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
132.7, 120.7, 108.3, 106.9, 101.2, 65.1, 51.7, 31.3, 30.5; IR (thin film)
3459, 3323, 2953, 2101, 1739, 1505, 1490, 1443, 1342, 1328, 1252,
1170, 1102, 1042, 933, 863, 813, 661; HRMS (EI) calcd for
C12H13N3O4 263.0906, found 263.0905.
stereochemical course of the cyclopropane ring-opening.
Aminoester 9 was derivatized as the Mosher amide (as was
the racemate prepared from racemic 4a). Analysis of the 19F
NMR spectrum indicated that no loss of enantiomeric purity
had occurred. To rule out a double inversion involving the
carboxylic acid moiety (a net retention of configuration), 9 was
lactamized to 10 (see the Supporting Information) and the
optical rotation compared to the reported value for this known
compound.10 Indeed, 5a is the result of inversion of
configuration upon cyclopropane ring-opening.
In summary, we have reported a technically simple and
catalyst-free method for the nucleophilic ring-opening of
cyclopropane hemimalonates with azides. The products
underwent concomitant decarboxylation to yield 4-azido
carboxylic acid esters. Simple reduction yields γ-aminobutyric
acid (GABA) methyl esters.
Methyl 4-Azido-4-(4-methoxyphenyl)butanoate (5d). Reagents
employed: 1-(methoxycarbonyl)-2-(4-methoxyphenyl)-
cyclopropanecarboxylic acid (4d) (100 mg, 0.40 mmol), sodium
azide (31 mg, 0.48 mmol), ammonium chloride (30 mg, 0.56 mmol),
2-methoxyethanol/water: yield 95% (95 mg) as a clear oil; Rf = 0.54,
1
30% EtOAc in hexanes; H NMR (400 MHz, CDCl3) δ = 7.25−7.21
and 6.92−6.89 (m, AA′BB′, 4H), 4.47 (dd, J = 7.8, 6.3 Hz, 1H), 3.80
(s, 3H), 3.66 (s, 3H), 2.36 (t, J = 7.4, 2H), 2.15−1.98 (m, 2H); 13C
NMR (100 MHz, CDCl3) δ = 173.1, 159.6, 130.8, 128.1, 114.2, 64.8,
55.2, 51.6, 31.2, 30.5; IR (thin film) 3451, 3319, 2953, 2839, 2482,
2101, 1739, 1611, 1529, 1438, 1245, 1174, 1034, 832, 545; HRMS
(EI) calcd for C12H15NO3 221.1052, found 221.1050 (M − N2).
Methyl 4-Azido-4-(4-bromophenyl)butanoate (5e). Reagents
employed: 2-(4-bromophenyl)-1-(methoxycarbonyl)-
cyclopropanecarboxylic acid (4e) (95 mg, 0.32 mmol), sodium azide
(25 mg, 0.38 mmol), ammonium chloride (24 mg, 0.45 mmol), 2-
methoxyethanol/water: yield 62% (59 mg) as a clear oil; Rf = 0.53,
EXPERIMENTAL SECTION
■
General Information. All solvents for routine isolation of
products and chromatography were reagent grade. Flash chromatog-
raphy was performed using silica gel (230−400 mesh) with indicated
solvents. All reactions were monitored by thin-layer chromatography
on 0.25 mm silica plates (60F-254) visualizing with UV light and
1
30% EtOAc in hexanes; H NMR (400 MHz, CDCl3) δ = 7.53−7.50
and 7.20−7.17 (m, AA′BB′, 4H), 4.52 (dd, J = 8.2, 6.3 Hz, 1H), 3.66
(s, 3H), 2.37 (ddd, J = 9.8, 7.8, 3.1 Hz, 2H), 2.12−1.97 (m, 2H); 13C
NMR (100 MHz, CDCl3) δ = 173.0, 183.0, 132.0, 128.5, 122.4, 64.6,
51.7, 31.3, 30.3; IR (thin film) 3455, 3319, 2951, 2101, 1737, 1489,
1437, 1250, 1201, 1171, 1044, 1011, 822, 532; HRMS (EI) calcd for
C11H13BrN3O2 298.0191, found 298.0185 (M + H).
developed using acidic anisaldehyde. H, 19F, and 13C NMR spectra
1
were recorded either on a 400 MHz or on a 600 MHz NMR
spectrometer. Chemical shifts, multiplicity (s, singlet; d, doublet; t,
triplet; q, quartet; m, multiplet), coupling constant in hertz (Hz), and
number of protons. HRMS were measured with electron impact (EI)
ionization and quadrupolar mass analyzer.
General Experimental Procedure for the Synthesis of
Azidoesters 5a−l. Sodium azide (1.2 equiv) and ammonium
chloride (1.4 equiv) were added to a solution of cyclopropane
hemimalonate (1.0 equiv) in 2-methoxyethanol:water (5.0 mL:0.5
mL). The mixture was stirred at reflux (125 °C) until the reaction was
complete (as determined by TLC analysis). The reaction was then
quenched with water and extracted with ether (3 times). The organic
layers were then combined and dried with magnesium sulfate.
Following filtration, the solvent was removed under reduced pressure
and the crude mixture purified by flash chromatography (EtOAc/
hexanes, 20:80) to yield the desired products 5a−l.
Methyl 4-Azido-4-phenylbutanoate (5a). Reagents employed: 1-
(methoxycarbonyl)-2-phenylcyclopropanecarboxylic acid (4a) (104
mg, 0.47 mmol), sodium azide (37 mg, 0.57 mmol), ammonium
chloride (36 mg, 0.66 mmol), 2-methoxyethanol/water: yield 78% (81
mg) as a clear oil. The data for this compound matched that previously
reported.11
Methyl 4-Azido-4-(naphthalen-1-yl)butanoate (5b). Reagents
employed: 1-(methoxycarbonyl)-2-(naphthalen-1-yl)-
cyclopropanecarboxylic acid (4b) (119 mg, 0.44 mmol), sodium
azide (35 mg, 0.53 mmol), ammonium chloride (33 mg, 0.62 mmol),
2-methoxyethanol/water: yield 76% (90 mg) as a clear oil; Rf = 0.58,
30% EtOAc in hexanes; 1H NMR (400 MHz, CDCl3) δ = 8.16 (d, J =
8.6, 1H), 7.90 (dd, J = 7.8, 1.6 Hz, 1H), 7.84 (d, J = 7.8 Hz, 1H),
7.60−7.48 (m, 4H), 5.37 (dd, J = 8.6, 5.8 Hz, 1H), 3.69 (s, 3H), 2.60−
2.43 (m, 2H), 2.36−2.16 (m, 2H); 13C NMR (100 MHz, CDCl3) δ =
173.3, 134.7, 134.0, 130.6, 129.1, 128.95, 126.6, 125.9, 125.3, 124.3,
122.9, 62.0, 51.7, 30.71, 30.6; IR (thin film) 3050, 2953, 2926, 2852,
2101, 1736, 1437, 1364, 1325, 1252, 1201, 1173, 801, 779; HRMS
(EI) calcd for C15H15N3O2 269.1164, found 269.1159.
Methyl 4-Azido-4-(4-chlorophenyl)butanoate (5f). Reagents
employed: 2-(4-chlorophenyl)-1-(methoxycarbonyl)-
cyclopropanecarboxylic acid (4f) (105 mg, 0.41 mmol), sodium
azide (32 mg, 0.50 mmol), ammonium chloride (30 mg, 0.58 mmol),
2-methoxyethanol/water: yield 60% (63 mg) as a clear oil; Rf = 0.56,
1
30% EtOAc in hexanes; H NMR (400 MHz, CDCl3) δ = 7.38−7.35
and 7.26−7.23 (m, AA′BB′, 4H), 4.53 (dd, J = 7.8, 6.3 Hz, 1H), 3.67
(s, 3H), 2.38 (ddd, J = 9.4, 7.4, 2.3 Hz, 2H), 2.13−1.98 (m, 2H); 13C
NMR (100 MHz, CDCl3) δ = 173.0, 137.5, 134.2, 129.1, 128.2, 64.5,
51.7, 31.3, 30.3; IR (thin film) 2952, 2101, 1739, 1493, 1437, 1325,
1249, 1202, 1171, 1092, 1015, 826, 534; HRMS (EI) calcd for
C11H13ClN3O2 254.0696, found 254.0710 (M + H).
Methyl 4-Azido-4-(4-cyanophenyl)butanoate (5g). Reagents
employed: 2-(4-cyanophenyl)-1-(methoxycarbonyl)-
cyclopropanecarboxylic acid (4g) (116 mg, 0.47 mmol), sodium
azide (37 mg, 0.57 mmol), ammonium chloride (35 mg, 0.66 mmol),
2-methoxyethanol/water: yield 56% (65 mg) as a clear oil; Rf = 0.46,
1
30% EtOAc in hexanes; H NMR (400 MHz, CDCl3) δ = 7.69−7.66
and 7.44−7.41 (m, AA′BB′, 4H), 4.63 (dd, J = 7.0, 7.0 Hz, 1H), 3.66
(s, 3H), 2.46−2.32 (m, 2H), 2.07−2.02 (m, 2H); 13C NMR (100
MHz, CDCl3) δ = 172.7, 144.4, 132.7, 127.5, 118.2, 112.3, 64.4, 51.7,
31.3, 30.0; IR (thin film) 2953, 2230, 2100, 1734, 1609, 1438, 1417,
1308, 1252, 1200, 1174, 1019, 835, 566; HRMS (EI) calcd for
C12H13N4O2 245.1039, found 245.1045 (M + H).
Methyl 4-Azido-4-(4-nitrophenyl)butanoate (5h). Reagents em-
p l o y e d : 1 - ( m e t h o x y c a r b o n y l ) - 2 - ( 4 - n i t r o p h e n y l ) -
cyclopropanecarboxylic acid (4h) (116 mg, 0.44 mmol), sodium
azide (34 mg, 0.53 mmol), ammonium chloride (33 mg, 0.61 mmol),
2-methoxyethanol/water: yield 46% (53 mg) as a clear oil; Rf = 0.44,
1
30% EtOAc in hexanes; H NMR (400 MHz, CDCl3) δ = 8.26−8.23
and 7.52−7.49 (m, AA′BB′, 4H), 4.71 (dd, J = 7.0, 7.0 Hz, 1H), 3.68
(s, 3H), 2.49−2.34 (m, 2H), 2.08 (q, J = 7.0 Hz, 2H); 13C NMR (100
MHz, CDCl3) δ = 172.7, 147.8, 146.4, 127.7, 124.1, 64.3, 51.8, 31.5,
30.0; IR (thin film) 2953, 2926, 2100, 1735, 1607, 1522, 1437, 1348,
1253, 1200, 1172, 853, 700; HRMS (EI) calcd for C11H13N4O4
265.0937, found 265.0935 (M + H).
Methyl 4-Azido-4-(benzo[d][1,3]dioxol-5-yl)butanoate (5c). Re-
agents employed: 2-(benzo[d][1,3]dioxol-5-yl)-1-(methoxycarbonyl)-
cyclopropanecarboxylic acid (4c) (97 mg, 0.37 mmol), sodium azide
(29 mg, 0.44 mmol), ammonium chloride (27 mg, 0.51 mmol), 2-
methoxyethanol/water: yield 87% (84 mg) as a clear oil; Rf = 0.58,
30% EtOAc in hexanes; 1H NMR (400 MHz, CDCl3) δ = 6.80 (d, J =
1.6 Hz, 1H), 6.78 (s, 1H) 6.76 (d, J = 1.6 Hz, 1H) 5.97 (s, 2H), 4.44
(dd, J = 7.8, 6.25 Hz, 1H), 3.66 (s, 3H), 3.76 (t, J = 7.4, 2H), 2.11−
1.94 (m, 2H); 13C NMR (100 MHz, CDCl3) δ = 173.1, 148.2, 147.7,
(E)-Methyl 4-Azido-6-phenylhex-5-enoate (5i). Reagents em-
ployed: (E)-1-(methoxycarbonyl)-2-(4-styrylphenyl)-
cyclopropanecarboxylic acid (4i) (101 mg, 0.41 mmol), sodium
azide (32 mg, 0.49 mmol), ammonium chloride (30 mg, 0.57 mmol),
2-methoxyethanol/water: yield 78% (78 mg) as a clear oil; Rf = 0.50,
30% EtOAc in hexanes; 1H NMR (400 MHz, CDCl3): δ = 7.37 (d, J =
C
dx.doi.org/10.1021/jo3010606 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
7.4 Hz, 2H), 7.31 (t, J = 7.4 Hz, 2H), 7.26−7.22 (m, 1H), 6.60 (d, J =
15.6 Hz, 1H), 6.06 (dd, J = 16.0, 8.2 Hz, 1H) 4.08 (dd, J = 14.9, 7.4
Hz, 1H), 3.64 (s, 3H), 2.41 (t, J = 7.4 Hz, 2H), 1.94−1.88 (m, 2H);
13C NMR (100 MHz, CDCl3) δ = 173.2, 135.7, 133.9, 128.6, 128.2,
126.7, 126.1, 63.9, 51.7, 30.2, 29.8; IR (thin film) 3027, 2952, 2105,
1739, 1493, 1437, 1239, 1170, 1112, 1071, 969, 888, 751, 694; HRMS
(EI) calcd for C13H14NO2 216.1030, found 216.1030 (M − N2, H).
Methyl 4-Azido-4-(1-tosyl-1H-indol-3-yl)butanoate (5j). Reagents
employed: 1-(methoxycarbonyl)-2-(4-(1-tosyl-1H-indol-3-yl)phenyl)-
cyclopropanecarboxylic acid (4j) (98 mg, 0.24 mmol), sodium azide
(18 mg, 0.28 mmol), ammonium chloride (18 mg, 0.33 mmol), 2-
methoxyethanol/water: yield 58% (57 mg) as a clear oil; Rf = 0.54,
30% EtOAc in hexanes; 1H NMR (400 MHz, CDCl3) δ = 7.99 (d, J =
8.2 Hz, 1H), 7.75 (d, J = 8.6 Hz, 2H), 7.61 (d, J = 1 Hz, 1H), 7.58 (s,
1H), 7.35 (ddd, J = 8.6, 7.4, 1.2 Hz, 1H), 7.26 (ddd, J = 8.2, 8.2, 0.8
Hz, 1H), 7.23−7.21 (m, 2H), 4.76 (dd, J = 7.0, 7.0 Hz, 1H), 3.68 (s,
3H), 2.51−2.38 (m, 2H), 2.33 (s, 3H), 2.27−2.17 (m, 2H); 13C NMR
(100 MHz, CDCl3) δ = 173.0, 145.2, 135.5, 134.8, 129.9, 128.4, 126.8,
125.3, 124.0, 123.5, 120.2, 120.0, 113.9, 57.8, 51.7, 30.4, 29.4, 21.5; IR
(thin film) 2953, 2925, 2109, 1735, 1448, 1372, 1256, 1178, 1123,
1089, 749, 669, 574, 538; HRMS (EI) calcd for C20H20N4O4S
412.1205, found 412.1190.
Methyl 4-Azido-4-(furan-2-yl)butanoate (5k). Reagents employed:
2-(4-(furan-3-yl)phenyl)-1-(methoxycarbonyl)cyclopropanecarboxylic
acid (4k) (126 mg, 0.60 mmol), sodium azide (47 mg, 0.72 mmol),
ammonium chloride (45 mg, 0.84 mmol), 2-methoxyethanol/water:
yield 63% (79 mg) as a clear oil; Rf = 0.54, 30% EtOAc in hexanes; 1H
NMR (400 MHz, CDCl3) δ = 7.42 (d, J = 1 Hz, 1H), 6.36 (dd, J = 3.1,
1.8 Hz, 1H), 6.33 (d, J = 3.1 Hz, 1H), 4.53 (dd, 7.2, 7.2 Hz, 1H), 3.68
(s, 3H), 2.43 (ddd, J = 7.6, 7.6, 0.8 Hz, 2H), 2.25−3.12 (m, 2H); 13C
NMR (100 MHz, CDCl3) δ = 172.9, 151.5, 143.0, 110.2, 108.1, 57.9,
51.7, 30.2, 27.8; IR (thin film) 2954, 2102, 1736, 1438, 1338, 1239,
1210, 1173, 1013, 745; HRMS (EI) calcd for C9H11NO3 181.0739,
found 181.0739 (M − N2).
(0.0041 mmol). The solution was stirred at room temperature
overnight. The solution was filtered and the solvent was removed
under reduced pressure, to which the mixture was purified by flash
chromatography (EtOAc/hexanes, 20:80) to yield Mosher’s amide.
Mosher’s Amide. Reagents employed: methyl 4-amino-4-phenyl-
butanoate (9) (13 mg, 0.068 mmol), Mosher’s acid (17 mg, 0.071
mmol), DCC (17 mg, 0.081 mmol), DMAP (1 mg, 0.0041 mmol):
1
yield 61% (17 mg); H NMR (400 MHz, CDCl3) δ = 7.56−7.54 (m,
2H), 7.42−7.41 (m, 3H), 7.37−7.34 (m, 2H), 7.31−7.29 (m, 3H),
7.19 (d, J = 8.2 Hz, 1H), 5.01 (br dd J = 15.2, 7.8 Hz, 1H), 3.67 (s,
0.19H), 3.59 (s, 3H), 3.40 (s, 0.22H), 3.37 (s, 3H), 2.30−2.26 (m,
3H), 2.17−2.11 (m, 2H); 19F NMR (376 MHz, CDCl3) δ = −68.8 (s,
3F), −68.9 (s, 0.16F). The enantiomeric excess was determined to be
90% by Mosher’s amide (1H, 19F NMR).
ASSOCIATED CONTENT
■
S
* Supporting Information
Complete experimental procedures as well as 1H NMR and 13
C
NMR, IR, MS, data for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: makerr@uwo.ca.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Natural Sciences and Engineering Research
Council of Canada for generous funding of this research. We
are grateful to Mr. Doug Hairsine of the Western University
Mass Spectroscopy facility for performing MS analyses.
Methyl 4-Azido-4-(thiophen-2-yl)butanoate (5l). Reagents em-
ployed: 1-(methoxycarbonyl)-2-(4-(thiophen-3-yl)phenyl)-
cyclopropanecarboxylic acid (4l) (135 mg, 0.60 mmol), sodium
azide (47 mg, 0.72 mmol), ammonium chloride (45 mg, 0.84 mmol),
2-methoxyethanol/water: yield 79% (106 mg) as a clear oil; Rf = 0.47,
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■
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C. A.; Kerr, M. A. Chem. Soc. Rev. 2009, 38, 3051. (b) Rubin, M.;
Rubina, M.; Gevorgyan, V. Chem. Rev. 2007, 107, 3117. (c) Yu, M.;
Pagenkopf, B. L. Tetrahedron 2005, 61, 321. (d) Reissig, H.-U.;
Zimmer, R. Chem. Rev. 2003, 103, 1151. (e) Wong, H. N. C.; Hon, M.
Y.; Tse, C. W.; Yip, Y. C.; Tanko, J.; Hudlicky, T. Chem. Rev. 1989, 89,
165. (f) Danishefsky, S. Acc. Chem. Res. 1979, 12, 66.
1
30% EtOAc in hexanes; H NMR (400 MHz, CDCl3) δ = 7.30 (dd, J
= 5.0, 1.2 Hz, 1H), 7.04−7.03 (m, 1H), 7.01−6.98 (m, 1H), 4.9 (dd, J
= 7.0, 7.0 Hz, 1H), 3.67 (s, 3H), 2.44 (dd, J = 7.4, 1.2 Hz, 2H), 2.23−
2.10 (m, 2H); 13C NMR (100 MHz, CDCl3) δ = 172.8, 141.7, 126.8,
125.8, 125.6, 60.3, 51.6, 31.6, 30.4; IR (thin film) 2952, 2099, 1736,
1437, 1367, 1328, 1240, 1173, 854, 835, 707; HRMS (EI) calcd for
C9H11NO2S 197.0510, found 197.0511 (M − N2).
Experimental Procedure for the Azide Reduction to GABA
Esters 9. To a solution of azide (1 equiv) in MeOH was added 10%
palladium on activated carbon. The solution was stirred under a
balloon of hydrogen for two hours. The mixture was then passed
through Celite, and the solvent was removed under reduced pressure
to give GABA ester 9.
(3) Emmett, M. R.; Kerr, M. A. Org. Lett. 2011, 13, 4180.
(4) Jonsson, S. Y.; Lofstrom, C. M. G.; Backvall, J.-E. J. Org. Chem.
̈
̈
̈
2000, 65, 8454.
(5) Izquierdo, M. L.; Arenal, I.; Bernabe, M.; Alvarez, E. F.
Tetrahedron 1985, 41, 215.
(6) Perreault, C.; Goudreau, S. R.; Zimmer, L. E.; Charette, A. B. Org.
Lett. 2008, 10, 689.
(7) The relative stereochemistry of the cyclopropane hemimalonates
4b−l is assumed by analogy to the known compound 4a.
(8) Sapeta, K.; Kerr, M. A. J. Org. Chem. 2007, 72, 8597.
(9) As suggested by a reviewer, it would be enlightening to attempt
the reaction using the diasteromeric hemimalonate with the carboxylic
acid cis to the vicinal substituent. Absence of reaction would lend
support to an intramolecular reaction mechanism. This work will be
undertaken in the near future.
Methyl 4-Amino-4-phenylbutanoate (9). Reagents employed:
methyl 4-azido-4-phenylbutanoate (5a) (66 mg, 0.30 mmol), 10%
palladium on activated carbon (3 mg): yield 93% (54 mg) as a yellow
oil. The data for this compound matched that previously reported.12
Lactamization Procedure. To a solution of optically enriched
methyl 4-amino-4-phenylbutanoate 9 (0.26 mmol) in MeOH, was
added 1.7 M NaOH (0.39 mmol) dropwise. The solution was stirred
for 2 h and then diluted with EtOAc and water to separate layers. The
aqueous layer was then acidified with 5% HCl to reach pH 2, then
extracted three times with EtOAc. The combined organic layers were
washed with brine, dried of MgSO4, filtered and concentrated.
(S)-5-Phenylpyrrolidin-2-one (10). Reagents employed: methyl 4-
amino-4-phenylbutanoate (9) (50 mg, 0.26 mmol), 1.7 M NaOH (0.5
mL, 0.39 mmol): yield 98% (40 mg) as a yellow oil. The data for this
compound matched that previously reported.7
(10) Camps, P.; Gomez, T.; Munoz-Torrero, D.; Rull, J.; Sanchez, L.;
́
́
̃
Boschi, F.; Comes-Franchini, M.; Ricci, A.; Calvet, T.; Font-Bardia,
M.; De Clerq, E.; Naesens, L. J. Org. Chem. 2008, 73, 6657.
(11) Benati, L.; Leardini, R.; Minozzi, M.; Nanni, D.; Spagnolo, P.;
Strazzari, S.; Zanardi, G. Org. Lett. 2002, 4, 3079.
(12) Morlacchi, F.; Losacco, V.; Tortorella, V. Gazz. Chim. Ital. 1975,
105, 349.
Mosher’s Amide Procedure. To a solution of methyl 4-amino-4-
phenylbutanoate (9) (0.068 mmol) in THF (1 mL) was added
Mosher’s Acid (0.071 mmol), DCC (0.081 mmol) and DMAP
D
dx.doi.org/10.1021/jo3010606 | J. Org. Chem. XXXX, XXX, XXX−XXX