Facile preparation of tert-butyl 1-tert-butoxycarbonylaminocyclopent-3- enecarboxylate from inexpensive starting materials

Article abstract of DOI:10.1055/s-2004-831218

1,5-C,C-Cycloalkylation of tert-butyl acetoacetate (1) with cis-1,4-dichloro-2-butene (2) followed by the haloform reaction of the product in NaOH solution and subsequent Curtius degradation in tert-butyl alcohol furnished tert-butyl 1-tert-butoxycarbonyl

Full text of DOI:10.1055/s-2004-831218

158
PRACTICAL SYNTHETIC PROCEDURES
Facile Preparation of tert-Butyl 1-tert-Butoxycarbonylaminocyclopent-3-
enecarboxylate from Inexpensive Starting Materials
Preparationof tert
-Butyl
1
e
-
tert-Buto
g
xycarbonylaminocy
V
clopent-3-enecarb
.
oxylate Larionov, Sergei I. Kozhushkov, Armin de Meijere*
Institut für Organische and Biomolekulare Chemie, Georg-August-Universität Göttingen,
Tammannstrasse 2, 37077 Göttingen, Germany
Fax +49(551)399475; E-mail: Armin.deMeijere@chemie.uni-goettingen.de
PSP
Received 30 March 2004; revised 24 May 2004
No36
Abstract: 1,5-C,C-Cycloalkylation of tert-butyl acetoacetate (1) with cis-1,4-dichloro-2-butene (2) followed by the haloform reaction of
the product in NaOH solution and subsequent Curtius degradation in tert-butyl alcohol furnished tert-butyl 1-tert-butoxycarbonylaminocy-
clopent-3-enecarboxylate (5) in 32% overall yield.
Key words: alkenes, cyclizations, excitatory amino acids, haloform reaction, Curtius rearrangement
Scheme 1
Since the important role of excitatory amino acids in the by appropriate modification of the protective groups
regulation of processes in the central nervous system pro- (overall yields 53–63%).5 However, the corresponding
cesses was recognized, considerable efforts have been starting materials for both of these approaches like tert-
made to develop efficient synthetic approaches to these butyl N-(diphenylmethylene)glycinate6 are rather expen-
structurally diverse compounds as a treatment option sive.7 Alternatively, the target compound 5 has recently
against various neurological disorders.1
been prepared in six steps2 from methyl tert-butyl mal-
onate in close analogy to the other known approaches.8
While this is a viable method, the high price of the differ-
entiated dialkyl malonate9 may be prohibitive to apply it
for the preparation of larger quantities of 5. At least in this
respect it should be advantageous to prepare the target
molecule 5 from inexpensive tert-butyl acetoacetate (1),10
which can indeed be achieved in three steps with 32%
overall yield (Scheme 1).
The title compound 5 is an important intermediate for the
preparation of excitatory amino acid prodrugs.2 Every
possible synthetic approach to 5 may comprise essentially
two parts: (a) elaboration of the 4,4-disubstituted cyclo-
pentene ring, and (b) transformation of the substituents
into the protected amino acid fragment. The first part can
be realized via two-fold allylation of compounds with
C,H-acidic methylene group followed by a ring-forming
metathesis reaction (49–90% yield in the metathesis step, It is known that upon treatment of 1 with cis-1,4-dichloro-
while the overall yields for the protected amino acids 2-butene (2)11 in the presence of a base, 1,3- and 1,5-C,C-
range from 19–33%)3 or by cycloalkylation of such com- cycloalkylations compete with each other as well as with
pounds.4 Among the latter group of reactions, the most C,O-cycloalkylations.4 However, upon appropriate choice
convenient method known to date is by cycloalkylation of of conditions, the cyclopentene derivative 3 is obtained
an appropriately substituted glycine equivalent followed exclusively in 61% yield (Scheme 1). In the first experi-
ments, the rather toxic hexamethylphosphoric acid tri-
amide (HMPT) was used as an additive (cf. ref.4). It was
found later, however, that the same yield of 3 could be ob-
tained by employing the non-toxic dimethylpropyl-
SYNTHESIS 2005, No. 1, pp 0158–0160
Advanced online publication: 16.09.2004
DOI: 10.1055/s-2004-831218; Art ID: T03404SS
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© Georg Thieme Verlag Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
tert-Butyl 1-tert-Butoxycarbonylaminocyclopent-3-enecarboxylate 159
13C NMR: d = 27.7 (3 × CH3), 41.0 (2 × CH2), 59.3 (C), 82.2 (C),
eneurea (DMPU). The haloform reaction of 3 with 10
equivalents, 15 equivalents and 30 equivalents of bromine
127.8 (2 × CH), 171.0 (C), 178.1 (C).
in NaOH solution furnished the diacid monoesters 4 in Anal. Calcd for C11H16O4 (212.24): C, 62.25; H, 7.60. Found: C,
62.09; H, 7.44.
75%, 90% and 100% yield, respectively. No reaction was
observed with a stoichiometric quantity of bromine in
NaOH solution as well as with freshly prepared sodium
hypochlorite. With the half ester 4 available, the protected
tert-Butyl 1-tert-Butoxycarbonylaminocyclopent-3-enecarbox-
ylate (5)
Variant A: To a stirred solution of the monoester 4 (2.8 g, 13.2
amino acid 5 could easily be obtained by a Curtius degra-
dation. This was achieved in tert-butyl alcohol employing
the Weinstock protocol12 under activation with tin
tetrachloride8a,13 to give the protected amino acid 5 in 53%
yield (Scheme 1, Variant A). Curtius degradation of 4
with diphenylphosphoryl azide (DPPA)14 in tert-butyl al-
cohol according to the Jamada protocol15 furnished the de-
sired product 5 in only 29% yield.
mmol) in anhydrous acetone (50 mL), Et3N (1.7 g, 16.8 mmol) was
added dropwise at –5 °C. After stirring for an additional 15 min at
this temperature, a solution of ethyl chloroformate (2.32 g, 21.4
mmol) in acetone (14 mL) was added over a period of 1 h, and the
resulting mixture was stirred for 1.5 h at this temperature. Then a so-
lution of NaN3 (1.46 g, 22.4 mmol) in H2O (6 mL) was added over
a period of 1 h. The mixture was stirred at 0 °C for 1.5 h, poured into
ice-cold water (200 mL) and extracted with Et2O (5 × 50 mL). The
combined ethereal solutions were washed with ice-cold water (100
mL) and dried at 0 °C for 1 h under intensive stirring. After concen-
tration under reduced pressure at 0 °C, the residue was taken up with
anhydrous t-BuOH (45 mL) and heated at 85 °C for 5 h; SnCl4 (0.2
g, 0.77 mmol) was added after the first 2 h of heating. After cooling
to 20 °C and concentration under reduced pressure, the residue was
taken up with EtOAc (10 mL) and subjected to column chromatog-
raphy (250 g of silica gel, 6 × 15 cm column, hexane–Et2O, 5:1) to
give 5 (1.99 g, 53%) as a colorless solid (Rf = 0.41). An analytical
sample was obtained by recrystallization from hexane and had mp
72–73 °C (lit. 87–89 °C2).
1H and 13C NMR spectra were measured at 250 MHz (for 1H NMR),
and 62.9 MHz [for 13C NMR, additional DEPT (Distortionless En-
hancement by Polarization Transfer)] on a Bruker AM 250 instru-
ment in CDCl3 solution, if not otherwise specified, with CHCl3/
CDCl3 as internal reference. Anhydrous tert-butyl alcohol was ob-
tained by storing the commercial quality reagent over molecular
sieves 4 Å, and anhydrous acetone by distillation from anhydrous
K2CO3. All other chemicals were used as commercially available.
Organic extracts were dried over MgSO4.
Variant B: A solution of acid 4 (2.8 g, 13.2 mmol), diphenylphos-
phoryl azide (DPPA) (3.67 g, 13.37 mmol) and Et3N (1.36 g, 13.5
mmol) in anhydrous t-BuOH (33 mL) was heated under reflux for a
period of 10 h. After cooling, the solution was concentrated under
reduced pressure, taken up with Et2O (100 mL), washed with 5%
citric acid solution (100 mL), 5% aq NaHCO3 solution (2 × 100
mL), brine (100 mL), dried and concentrated under reduced pres-
sure. The product (1.10 g, 29%) was purified by column chromatog-
raphy as described above.
1H NMR: d = 1.45 (s, 9 H, 3 × CH3), 1.46 (s, 9 H, 3 × CH3), 2.57 (d,
J = 17.2 Hz, 2 H, CH2), 3.00 (d, J = 17.2 Hz, 2 H, CH2), 5.09 (br s,
1 H, NH), 5.63 (s, 2 H, 2 × =CH).
13C NMR: d = 27.8 (3 × CH3), 28.3 (3 × CH3), 44.8 (2 × CH2), 64.5
(C), 81.1 (C), 82.1 (C), 127.7 (2 × CH), 154.9 (C), 173.3 (C).
tert-Butyl 1-Acetylcyclopent-3-enecarboxylate (3)
To a stirred solution of the tert-butyl acetoacetate (1) (15.8 g, 16.6
mL, 0.1 mol) in a mixture of anhydrous dimethoxyethane (186 mL)
and anhydrous dimethylpropyleneurea (DMPU, 28.5 mL) at 0 °C
under N2 was added lithium hydride (1.92 g, 0.24 mol) in one por-
tion. The mixture was stirred at this temperature for 2 h and then,
after the evolution of H2 had ceased, the dichlorobutene 2 (14.2 g,
12 mL, 0.114 mol) was added in one portion. The resulting mixture
was heated under stirring at 65 °C for 72 h, then cooled, poured into
ice-cold water (500 mL) and extracted with a hexane–Et2O (3:1)
mixture (3 × 150 mL). The combined organic layers were washed
with water (4 × 100 mL), brine (100 mL), dried, concentrated under
reduced pressure and distilled in vacuo to give the keto ester 3 (12.8
g, 61%) as a colorless oil, bp 85–88 °C/2 mbar.
1H NMR: d = 1.42 (s, 9 H), 2.14 (s, 3 H), 2.84 (s, 4 H), 5.52 (s, 2 H).
13C NMR: d = 27.7 (3 × CH3), 25.9 (CH3), 39.0 (2 × CH2), 66.0 (C),
61.7 (C), 127.6 (2 × CH), 171.9 (C), 202.7 (C).
Acknowledgment
This work was supported by the State of Niedersachsen as well as
the Fonds der Chemischen Industrie. The authors are grateful to the
companies BASF AG, Bayer AG, Chemetall GmbH, and Degussa
AG for generous gifts of chemicals, and particularly to Dr. B. Knie-
riem, Göttingen, for his careful proofreading of the final manus-
cript.
Cyclopent-3-ene-1,1-dicarboxylic Acid tert-Butyl Ester (4)
To a stirred solution of NaOH (26.6 g, 665 mmol) in water–dioxane
mixture (226/146 mL), cooled in an ice bath, was added slowly bro-
mine (27.4 g, 8.78 mL, 171 mmol). The resulting mixture was
stirred for an additional 10 min and then added in one portion to a
stirred solution of the keto ester 3 (2.1 g, 10 mmol) in a water–diox-
ane mixture (20/65 mL). The reaction mixture was stirred at 0 °C for
3 h. The reaction was then quenched by carefully adding a solution
of Na2SO3 (17.70 g) in water (200 mL) under ice-bath cooling, and
the mixture was washed with Et2O (2 × 100 mL). The aqueous
phase was acidified to pH 2 with 12 N HCl solution at 5 °C and ex-
tracted with Et2O (4 × 50 mL). The combined organic layers were
dried and concentrated under reduced pressure to give the half ester
4 (1.90 g, 90%) as a colorless solid. An analytical sample was ob-
tained by recrystallization from hexane and had mp 114–116 °C (lit.
119 °C2).
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Synthesis 2005, No. 1, 158–160 © Thieme Stuttgart · New York

160
O. V. Larionov et al.
PRACTICAL SYNTHETIC PROCEDURES
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Synthesis 2005, No. 1, 158–160 © Thieme Stuttgart · New York