A convenient access to variously substituted spiro[cyclopropane-1,4′- oxazoline]

Article abstract of DOI:10.1002/ejoc.200800333

Michael additions of carboxamides 2a-d under basic conditions onto methyl 2-chloro-2-cyclopropylideneacetate (1) with subsequent ring closure furnished the 4-spirocyclopropanated methyl oxazolinecarboxylates 3a-d (51-81%yields), from which the corresponding free carboxylic acids 4a-d were obtained by hydrolysis in excellent yield (89-93%). Coupling reactions of 4a-d with different o-hydroxyaniline derivatives in the presence of HOAt/EDC and 2,4,6-collidine gave the anilides 5 in good to very good yields (55-92%). The latter under Mitsunobu reaction conditions (Ph₃P/DEAD) furnished the benzoxazole derivatives 6 (81-88%). The bromine substituent in the N-methylated 4-spirocyclopropanated 2-(bromophenyl)oxazoline-5-carboxanilides 8c,d were aminated with various secondary amines under Buchwald-Hartwig reaction conditions to give the 2-(aminophenyl)-oxazolinecarboxanilides 9 (12-90%). Suzuki cross-couplings of 8c with arene- and hetareneboronic acids provided the oxazolines with 2-biaryl substituents 10-13 (65-90%). Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200800333

FULL PAPER
DOI: 10.1002/ejoc.200800333
A Convenient Access to Variously Substituted Spiro[cyclopropane-1,4Ј-
oxazoline]s[‡]
Suryakanta Dalai,[a] Mazen Es-Sayed,[b] Marcus Nötzel,[a] and Armin de Meijere*[a]
Keywords: Amides / Nitrogen heterocycles / Michael addition / Buchwald–Hartwig amination / Suzuki coupling / Cyclo-
propanes / Spiro compounds
Michael additions of carboxamides 2a–d under basic condi-
tions onto methyl 2-chloro-2-cyclopropylideneacetate (1)
with subsequent ring closure furnished the 4-spirocyclopro-
panated methyl oxazolinecarboxylates 3a–d (51–81 % yields),
from which the corresponding free carboxylic acids 4a–d
were obtained by hydrolysis in excellent yield (89–93 % ).
Coupling reactions of 4a–d with different o-hydroxyaniline
derivatives in the presence of HOAt/EDC and 2,4,6-collidine
gave the anilides 5 in good to very good yields (55–92 % ).
The latter under Mitsunobu reaction conditions (Ph3P/DEAD)
furnished the benzoxazole derivatives 6 (81–88 % ). The bro-
mine substituent in the N-methylated 4-spirocyclopropan-
ated 2-(bromophenyl)oxazoline-5-carboxanilides 8c,d were
aminated with various secondary amines under Buchwald–
Hartwig reaction conditions to give the 2-(aminophenyl)-
oxazolinecarboxanilides 9 (12–90 % ). Suzuki cross-couplings
of 8c with arene- and hetareneboronic acids provided the
oxazolines with 2-biaryl substituents 10–13 (65–90 % ).
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
alogue of Imidacloprid® is virtually as potent an insecticide
as the commercial Imidacloprid itself,[8] made this a reason-
able endeavor.
Introduction
As has recently been demonstrated, the highly electro-
philic Michael acceptor methyl 2-chloro-2-cyclopropyl-
ideneacetate (1)[1–3] in the presence of sodium hydride un-
dergoes addition of arenecarboxamides with subsequent in-
tramolecular nucleophilic substitution of the chlorine atom
to yield methyl 2Ј-arylspiro[cyclopropane-1,4Ј-oxazoline]-
5Ј-carboxylates 3.[4] The latter essentially are protected cy-
clic derivatives of β-(N-acylamino)-α-hydroxycarboxylic ac-
ids and have been employed as such to prepare various ana-
logues of Taxol (4);[5,6] yet in more general terms they can
be regarded as mimics of aryl-substituted hetarenes. Since
a large number of biologically active compounds are com-
posites of heterocycles including oxazolines[7] and hetero-
substitued arenes, we set out to develop a set of methods
to further diversify the 4-spirocyclopropanated 2-aryl-
oxazolinecarboxylates 3 in order to make a library of po-
tentially biologically active derivatives accessible, since one
such compound had previously exhibited an interesting in-
secticidal activity. The fact that a spirocyclopropanated an-
Results and Discussion
By employing the previously published procedure,[4]
methyl 2-chloro-2-cyclopropylideneacetate (1)[1,2] in aceto-
nitrile upon reaction with benzamide (2a) in the presence
of sodium hydride gave methyl 2Ј-phenylspiro[cyclopro-
pane-1,4Ј-oxazoline]-5-carboxylate (3a) in 54% isolated
yield after column chromatography. Analogously, 4-(tri-
fluoromethyl)- as well as 4-bromo- and 3-bromobenzamide
(2b–d) furnished the corresponding oxazolinecarboxylates
3b–d in yields ranging from 51 to 81% (Scheme 1 and
Table 1). The bromobenzamides 2c,d were specifically cho-
sen in order to provide an opportunity for further derivati-
zation of the products 3c and 3d by cross-coupling reac-
tions. The hydrolyses of the esters 3a–d to the correspond-
ing oxazolinecarboxylic acids 4a–d were brought about
more efficiently than previously reported by treatment with
[‡] Cyclopropyl Building Blocks for Organic Synthesis, 148. Part
147: B. Yucel, M. Noltemeyer, A. de Meijere, Eur. J. Org. Chem. 1  aqueous sodium hydroxide in methanol/tetrahydrofuran
2008, 1072–1078. Part 146: J. Revuelta, S. Cicchi, A. de Meijere,
A. Brandi, Eur. J. Org. Chem. 2008, 1085–1091.
[a] Institut für Organische und Biomolekulare Chemie der Georg-
August-Universität, Göttingen,
Tammannstrasse 2, 37077 Göttingen, Germany
Fax: + 49-551-399475
E-mail: Armin.deMeijere@chemie.uni-goettingen.de
[b] Bayer CropScience AG,
(4:1). Thus, the free carboxylic acids were isolated after pu-
rification by column chromatography in 89–93% yield.
With the 5-(benzoxazolyl)oxazoline derivatives as targets
in mind, conversion of the oxazolinecarboxylic acids to the
corresponding amides with substituted o-hydroxyanilines
were intended. First attempts were made with the 3Ј-phen-
ylspiro[cyclopropane-1,4Ј-oxazoline]-5Ј-carboxylic acid (4a)
and 5-chloro-2-hydroxyaniline by employing dicyclohexyl-
Alfred-Nobel-Strasse 50, 40789 Monheim, Germany
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Eur. J. Org. Chem. 2008, 3709–3713
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3709

S. Dalai, M. Es-Sayed, M. Nötzel, A. de Meijere
FULL PAPER
Table 2. Amide coupling of oxazolinecarboxylic acids 4a,b with o-
hydroxyanilines and dehydrative cyclization of the products to 5-
(benzoxazolyl)oxazoline derivatives 6 (see Scheme 2).
4
Ar1
X in
Product Yield Product Yield
Ar2NH2
(%)
(%)
4a
Ph
5-Cl
5-Cl
5aa
5ba
5bb
5bc
5bd
92
85
55
79
78
6aa
6ba
6bb
6bc
6bd
83
85
81
88
81
4b 4-F3CC6H4
4b 4-F3CC6H4 5-F3CO
4b 4-F3CC6H4 3,5-Cl2
4b 4-F3CC6H4 5-F3C
Scheme 1. 2Ј-Arylspiro[cyclopropane-1,4Ј-oxazoline]carboxylic acids
4a–d from arenecarboxamides and methyl 2-chloro-2-cyclopropyl-
ideneacetate (1). For details see Table 1.
An attempted dehydrative cyclization of 5aa with phos-
phorus pentoxide in carbon tetrachloride at 80 °C also left
the starting material unchanged, and with pyridinium p-
toluenesulfonate (PPTs) in dichloroethane after 12 h at
85 °C only a small amount (12%) of the product 6aa was
isolated. The desired product 6aa was also not observed
when the same reaction was carried out in toluene by em-
ploying a Dean–Stark trap. Finally, under Mitsunobu con-
ditions[10] (Ph3P, DEAD), the product 6aa was formed from
5aa in 83% isolable yield. Analogously, the other anilides 5
were converted into the corresponding (benzoxazolyl)-
oxazolines 6ba, 6bb, 6bc, 6bd in 81–88% yield (Scheme 2,
Table 2).
Table 1. Methyl 2Ј-arylspiro[cyclopropane-1,4Ј-oxazoline]-5Ј-car-
boxylates 3a–d and the corresponding oxazolinecarboxylic acids
4a–d from 1 (see Scheme 1).
Amide
Ar1
Product
Yield
(%)
Product
Yield
(%)
2a
2b
2c
2d
Ph
3a
3b
3c
3d
54
81
51
64
4a
4b
4c
4d
89
93
91
90
4-F3CC6H4
4-BrC6H4
3-BrC6H4
The spiro[cyclopropane-1,4Ј-oxazoline]-5Ј-carboxylic ac-
ids 4c,d were further diversified with heteroatom-containing
substituents by conversion to 3-(trifluoromethyl)anilides
7c,d under the same conditions as employed for 4a,b, subse-
quent N-methylation with dimethyl sulfate and final Buch-
wald–Hartwig amination[11,12] of the N-methylanilides 8c,d
with various secondary amines. An attempted amide coup-
ling of the 4-bromophenyl derivative 4c with N-methyl-3-
(trifluoromethyl)aniline in the presence of HOAt, EDC·HCl
and 2,4,6-collidine did not give any of the desired product,
but with 3-(trifluoromethyl)aniline under the same reaction
conditions the anilide 7c was obtained in 92% yield, and
methylation with dimethyl sulfate in the presence of potas-
sium carbonate furnished the desired N-methyl derivative 8c
as the precursor for the envisioned Pd-catalyzed aminations.
Analogously, the (3-bromophenyl)oxazolinecarboxanilide
8d was prepared in 73% overall yield. By employing well-
established conditions [Pd2(dba)3, BINAP, NatOBu], the
cross coupling of 8c with morpholine in toluene furnished
the product 9ca in 71% yield within 16 h. The conditions
as optimized with respect to the amount of catalyst called
for 2 mol-% of Pd2(dba)3 and 3 mol-% of (Ϯ)-BINAP to
give best yields. The same oxazoline 9c with pyrrolidine un-
der these conditions gave the product 9cb in 90% yield, but
the N-methyl- and N-benzylpiperazine derivatives 9cc and
9cd were obtained in only 59 and 62%, respectively
(Scheme 3 and Table 3).
carbodiimide (DCC) and 4-(dimethylamino)pyridine
(DMAP) in dichloromethane. However, after 18 h at 20 °C,
the unchanged starting materials were completely reco-
vered, and the same result was achieved with DCC and 1-
hydroxybenzotriazole (HOBT) in dichloromethane.[9] An
attempted conversion of the carboxylic acid 4a to the acyl
chloride by treatment with thionyl chloride and subsequent
reaction with the aniline led to complete decomposition of
the starting material 4a. Eventually, the amide coupling suc-
ceeded in the presence of 1-hydroxy-7-azabenzotriazole
(HOAt),
N-[3-(dimethylamino)propyl]-NЈ-ethylcarbodi-
imide (EDC) and 2,4,6-collidine to furnish the oxazoline-
carboxanilide 5aa in 92% yield. Under these conditions, the
reactions of the 2-[4-(trifluoromethyl)phenyl]oxazolinecar-
boxylic acid 4b with different mono- and disubstituted o-
hydroxyanilines gave the corresponding anilides 5ba, 5bb,
5bc, 5bd in 55–85% yield (Scheme 2, Table 2).
The cross coupling of 8c with the bicyclic secondary
amine 3,3-dibenzyl-3-azabicyclo[3.1.0]hexane[13] also pro-
ceeded smoothly to afford the product 9ce in 67% yield.
The same five amines were also coupled with the 3-bro-
mophenyl derivative 8d to give the corresponding 2-(3-ami-
nophenyl)oxazolinecarboxamides 9da–9de; however, 5 mol-
% of Pd2(dba)3 and 7.5 mol-% of (Ϯ)-BINAP had to be
Scheme 2. Amide coupling of oxazolinecarboxylic acids 4a,b with
o-hydroxyanilines followed by dehydrative cyclization to yield 5-
(benzoxazolyl)oxazoline derivatives 6. For details see Table 2.
3710
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 3709–3713

Variously Substituted Spiro[cyclopropane-1,4Ј-oxazoline]s
Thienyl- and 2-naphthylboronic acid also formed the prod-
ucts 12c and 13c in 65 and 85% yield, respectively
(Scheme 4 and Table 4).
Scheme 4. Suzuki–Miyaura coupling of (bromophenyl)oxazoline-
carboxanilide 8c. For details see Table 4.
Table 4. 2Ј-Biarylspiro[cyclopropane-1,4Ј-oxazoline]-5Ј-carboxani-
lides 10c–13c by Suzuki–Miyaura coupling of the 2-(bromophenyl)-
oxazolinecarboxyamide derivative 8c (see Scheme 4).
Starting
material
Ar2 in
Product
Yield
(%)
Ar2B(OH)2
8c
8c
8c
8c
Ph
10c
11c
12c
13c
90
80
65
85
4-F3COC6H4
3-thienyl
2-naphthyl
Scheme 3. N-Methyl-N-[3-(trifluoromethyl)phenyl]anilides 7c,d from
2Ј-(bromophenyl)spiro[cyclopropane-1,4Ј-oxazoline]-5Ј-carboxylic
acids 4c,d and subsequent Buchwald–Hartwig amination of the
bromophenyl groups in the N-methylanilides 8c,d with various
secondary amines. For details see Table 3.
Experimental Section
General Remarks: All reagents were used as purchased without fur-
ther purification. All reactions in organic solvents were carried out
by using standard Schlenk techniques under dry nitrogen. The sol-
vents were purified and dried prior to use according to conven-
tional methods; tetrahydrofuran (THF) and toluene were freshly
distilled from sodium/benzophenone. Solvents and reagents are ab-
breviated as follows: CH2Cl2 = dichloromethane, EtOAc = ethyl
acetate, MeOH = methanol, C5H12 = pentane, Et2O = diethyl ether,
DEAD = diethyl azodicarboxylate, DCC = N,NЈ-dicyclohexylcar-
bodiimide, EDC = N-[3-(dimethylamino)propyl]-NЈ-ethylcarbodi-
imide, HOBt = 1-hydroxybenzotriazole, HOAt = 1-hydroxy-7-aza-
Table 3. Buchwald–Hartwig aminations of the bromophenyl sub-
stituents in the N-methyl-N-[3-(trifluoromethyl)phenyl]spiro[cyclo-
propane-1,4Ј-oxazoline]-5Ј-carboxamides 8c,d (see Scheme 3).
Starting
R2NH
Product Yield
material 8
9
(%)
8c
8c
8c
8c
8c
8d
8d
8d
8d
8d
morpholine
pyrrolidine
N-methylpiperazine
N-benzylpiperazine
9ca
9cb
9cc
9cd
9ce
9da
9db
9dc
9dd
9de
71
90
59
62
67
82
73
13
12
81
3,3-dibenzyl-3-azabicyclo[3.1.0]hexane
morpholine
1
benzotriazole. H and 13C NMR spectra were recorded at ambient
temperature with either Bruker AM 250 or Varian 200 or 300 MHz
instruments. Chemical shifts (δ) are given in ppm relative to resid-
ual resonances of solvents (1H: δ = 7.26 ppm for CDCl3 and δ =
3.31 ppm for CD3OD; 13C: δ = 77.0 ppm for CDCl3, and δ =
49.0 ppm for CD3OD). Coupling constants (J) are given in Hz.
Multiplicities of signals are described as follows: br. = broad, s =
singlet, d = doublet, t = triplet, m = multiplet, dt = doublet of
triplets. The multiplicities of signals were determined by the DEPT
technique: DEPT: + = primary (CH3) or tertiary (CH) (positive
DEPT signal), – = secondary (CH2) (negative DEPT signal), Cquat.
= quaternary C atoms. J values in 13C NMR spectra refer to
13C,19F couplings. “cPr” refers to cyclopropyl. IR: Bruker IFS 66.
MS: Finnigan MAT 95, 70 eV. Chromatographic separations were
carried out on Merck silica gel 60 (0.063–0.200 mm, 70–230 mesh
ASTM). The dimensions of the columns are given in cm as “dia-
meter ϫheight of the silica gel column”. TLC: Macherey–Nagel,
ready-to-use TLC plates Alugram® Sil G/UV254. Detection under
UV light at 254 nm. Melting points (uncorrected) were determind
in capillaries with a Büchi 510 apparatus. Elemental analyses:
Mikroanalytisches Laboratorium des Instituts für Organische und
pyrrolidine
N-methylpiperazine
N-benzylpiperazine
3,3-dibenzyl-3-azabicyclo[3.1.0]hexane
used in these cases. In spite of that, the yields of the N-
benzyl-N-methylpiperazines were rather poor (13 and 12%,
respectively), and the reactions did not go to completion
even after 40 h (Scheme 3 and Table 3).
The possibility to further diversify the library of 2Ј-aryl-
spiro[cyclopropane-1,4Ј-oxazoline]-5Ј-carboxanilides 7 by
palladium-catalyzed cross coupling with areneboronic acids
(Suzuki–Miyaura coupling)[14] was also tested. After several
conditions had been tried, it was found that the coupling
of 8c with benzeneboronic acid required 10 mol-% of
Pd(OAc)2 and 40 mol-% of Ph3P to go to completion within
16 h, and the product 10c could be isolated in 90% yield.
[p-(Trifluoromethoxy)phenyl]boronic acid under the same
reaction conditions gave the product 11c in 84% yield. 3- Biomolekulare Chemie der Universität Göttingen.
Eur. J. Org. Chem. 2008, 3709–3713
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3711

S. Dalai, M. Es-Sayed, M. Nötzel, A. de Meijere
FULL PAPER
General Procedure for the Preparation of Methyl 2Ј-Arylspiro[cyclo-
propane-1,4Ј-oxazoline]-5Ј-carboxylates 3 (GP1): A solution of
methyl 2-chloro-2-cyclopropylideneacetate (1)[1,2] and the respective
carboxamide (1 equiv.) in anhydrous acetonitrile was treated with
1 equiv. of NaH (60% dispersion in mineral oil) at 0 °C. The re-
sulting suspension was subsequently stirred at this temperature for
1 h and at 20 °C for an additional 1 h. After removal of the solvent,
the pale yellow residue was taken up with diethyl ether (300 mL)
and the solution washed with water (100 mL). The aq. layer was
extracted with diethyl ether (2ϫ100 mL), and the combined or-
ganic phases were dried with MgSO4. The solvents were evaporated
under reduced pressure, and the crude product was purified by col-
umn chromatography.
(185 mg, 0.85 mmol), H OAt (139 mg, 1.02 mmol), ED C·H Cl
(244 mg, 1.27 mmol), 2,4,6-collidine (206 mg, 1.70 mmol) and 5-
chloro-2-hydroxyaniline (146 mg, 1.1 mmol) in CH2Cl2 (15 mL) ac-
cording to GP3 was purified by column chromatography (Rf =
0.25; pentane/Et2O, 1:1) to yield 268 mg (92%) of 5aa as a colorless
solid, m.p. 211 °C. IR (KBr): ν = 3381 , 3052, 1668, 1558, 1431,
˜
1339, 1195, 1033 cm–1. 1H NMR (300 MHz, CDCl3): δ = 0.96–1.18
(m, 2 H, cPr-H), 1.34–1.50 (m, 2 H, cPr-H), 5.01 (s, 1 H, CH),
6.87–6.92 (m, 1 H, Ar-H), 7.05 (dd, 3J = 8.2, 4J = 2.5 Hz, 1 H,
aryl-H) 7.42–7.58 (m, 3 H, aryl-H), 7.77 (s, 1 H, aryl-H), 7.96–8.00
(m, 2 H, aryl-H), 8.27 (br. s, 1 H, NH) ppm. 13C NMR (75.5 MHz,
CDCl3, APT): δ = 10.6 (–, cPr-C), 14.5 (–, cPr-C), 53.7 (–, cPr-C),
80.2 (+, CH-C), 120.1 (+, aryl-C), 121.9 (+, aryl-C), 125.5 (–, aryl-
C), 126.6 (–, aryl-C), 127.0 (+, aryl-C), 127.9 (+, 2 C, aryl-C), 128.7
(+, 2 C, aryl-C), 131.9 (+, aryl-C), 146.8 (–, aryl-C), 161.5 (–, CN-
C), 168.2 (–, CO-C) ppm. MS (70 eV): m/z (%) = 344/342 (6/20)
[M+], 200 (55), 173 (100), 172 (58), 105 (54). C18H15ClN2O3 (342.8):
calcd. C 63.07, H 4.41, N 8.17; found C 63.32, H 4.18, N 8.02.
Methyl
5-Phenyl-6-oxa-4-azaspiro[2.4]hept-4-ene-7-carboxylate
(3a): The crude product obtained from 1 (2.50 g, 17.0 mmol),
benzamide (2a, 5.20 g, 17.0 mmol) and NaH (595 mg, 17.0 mmol)
in anhydrous acetonitrile (50 mL) according to GP1 was purified
by column chromatography (Rf
3ϫ10 cm) to yield 2.2 g (54%) of 3a as a colorless solid, m.p.
48 °C. IR (KBr): ν = 2948, 1732, 1449, 1284, 1057, 694 cm–1 1H
= 0.38; pentane/Et2O, 4:1;
General Procedure (GP4) for the Preparation of (Benzoxazolyl)-
oxazolines 6: A solution of DEAD (2.2 equiv.) was added drop-
wise to a solution of the respective anilide 5 (1 equiv.) and Ph3P
(2.2 equiv.) in anhydrous THF (10 mL) in an ice bath, and the mix-
ture was stirred at 20 °C for 10 h. To the reaction mixture were
added Et2O (25 mL) and H2O (80 mL), and the organic layer was
separated. The aq. layer was extracted with Et2O (2ϫ25 mL), the
combined ethereal layers were dried with MgSO4 and concentrated,
and the residue was purified by column chromatography to yield
the corresponding benzoxazoles.
.
˜
NMR (250 MHz, CDCl3): δ = 0.91–1.08 (m, 2 H, cPr-H), 1.18–
1.27 (m, 1 H, cPr-H), 1.32–1.42 (m, 1 H, cPr-H), 3.80 (s, 3 H, CH3),
4.93 (s, 1 H, CH), 7.39–7.54 (m, 3 H, aryl-H), 7.91–7.99 (m, 2 H,
aryl-H) ppm. 13C NMR (50.3 MHz, CDCl3, APT): δ = 10.4 (–,
cPr-C), 14.7 (–, cPr-C), 52.3 (+, CH3), 53.3 (–, cPr-C), 79.7 (+, CH-
C), 127.0 (–, aryl-C), 128.0 (+, 2 C, aryl-C), 128.4 (+, 2 C, aryl-C),
131.5 (+, aryl-C), 163.5 (–, CN-C), 169.5 (–, CO-C) ppm. MS
(70 eV): m/z (%) = 231 (35) [M+], 172 (100) [M+ – CO2Me], 144
(60), 105 (26).
5-Chloro-2-(5-phenyl-6-oxa-4-azaspiro[2.4]hept-4-en-7-yl)benz-
oxazole (6aa): The crude product obtained from 5aa (103 mg,
0.3 mmol), Ph3P (173 mg, 0.66 mmol) and D EAD (115 mg,
0.66 mmol) according to GP4 was purified by column chromatog-
raphy (Rf = 0.35; pentane/Et2O, 5:1) to yield 83 mg (85%) of 6aa
General Procedure for the Hydrolysis of Methyl Spiro[cyclopropane-
1,4Ј-oxazoline]carboxylates 3 (GP2): Aq. NaOH (1 , 5 equiv.) was
added to a solution of the respective methyl oxazolinecarboxylate 3
(1 equiv.) in MeOH/THF (4:1) at room temperature. The resulting
solution was stirred for 30 min, then glacial AcOH (10 equiv.) was
added, the mixture stirred for an additional 15 min, and the solvent
evaporated in vacuo. The residue was filtered through a pad of SiO2
gel (Et2O/AcOH, 50:1) and the product crystallized from ether/hex-
ane.
as a colorless solid, m.p. 129 °C. IR (KBr): ν = 3077 , 2971, 1653,
˜
1569, 1427, 1335, 1293, 1078, 698 cm–1 1H N MR (300 MH z,
.
CDCl3): δ = 0.54–0.63 (m, 1 H, cPr-H), 0.98–1.06 (m, 1 H, cPr-H),
1.18–1.28 (m, 1 H, cPr-H), 1.36–1.45 (m, 1 H, cPr-H), 5.70 (s, 1 H,
CH), 7.28–7.39 (m, 1 H, aryl-H), 7.40–7.57 (m, 4 H, aryl-H), 7.69
(s, 1 H , aryl-H ), 7.95–8.02 (m, 2 H , aryl-H ) ppm. 13C N M R
(75.5 MHz, CDCl3, APT): δ = 11.1 (–, cPr-C), 14.7 (–, cPr-C), 54.2
(–, cPr-C), 77.8 (+, CH-C), 111.9 (+, aryl-C), 120.4 (+, aryl-C),
126.1 (+, aryl-C), 126.8 (–, aryl-C), 128.1 (+, 2 C, aryl-C), 128.5
(+, 2 C, aryl-C), 130.2 (–, aryl-C), 131.6 (+, aryl-C), 141.5 (–, aryl-
C), 149.5 (–, aryl-C), 163.2 (–, CN-C), 163.7 (–, CN-C) ppm. MS
(70 eV): m/z (%) = 325/323 (2/8) [M+], 172 (16), 155 (100), 105 (18),
91 (82). C18H13ClN2O2 (324.8): calcd. C 66.57, H 4.03, N 8.63;
found C 66.58, H 3.84, N 8.55.
5-Phenyl-6-oxa-4-azaspiro[2.4]hept-4-ene-7-carboxylic Acid (4a):
From 3a (3.40 g, 14.7 mmol), NaOH (2.96 g, 74 mmol) and AcOH
(8.80 g, 147 mmol) in MeOH/THF (200 mL) according to GP2 (Rf
= 0.40; Et2O/AcOH, 50:1), 5.10 g (93%) of 4a was obtained as a
colorless solid, m.p 182 °C. IR (KBr): ν = 3061 , 3009, 1717, 1638,
˜
1
1457, 1364, 1211, 1069, 735 cm–1. H NMR (250 MHz, CD3OD):
δ = 0.95–1.03 (m, 1 H, cPr-H), 1.05–1.34 (m, 3 H, cPr-H), 4.99 (s,
1 H, CH), 7.40–7.59 (m, 3 H, aryl-H), 7.86–7.98 (m, 2 H, aryl-H)
ppm. 13C NMR (62.9 MHz, CD3OD, DEPT): δ = 11.0 (–, cPr-C),
15.3 (–, cPr-C), 54.0 (Cquat., cPr-C), 81.3 (+, CH-C), 128.3 (Cquat.
,
General Procedure (GP5) for the Buchwald–Hartwig Amination of
(Bromophenyl)oxazolinecarboxanilides 8: An oven-dried Schlenk
flask purged with nitrogen, was charged with Pd2(dba)3 and (Ϯ)-
BINAP in toluene (5 mL). The mixture was heated at 80 °C with
stirring for 5 min to dissolve the BINAP. After cooling, the respec-
tive (bromophenyl)oxazolinecarboxanilide 8 (1 equiv.), the respec-
tive secondary amine (1.5 equiv.), and NaOtBu (1.5 equiv.) were
added, and the mixture was heated at 80 °C for 16 h. After cooling
to room temperature, it was diluted with Et2O (25 mL), filtered,
and concentrated in vacuo. The crude product was purified by col-
umn chromatography.
aryl-C), 129.3 (+, 2 C, aryl-C), 129.9 (+, 2 C, aryl-C), 133.3 (+,
aryl-C), 166.2 (–, CN-C), 172.4 (–, CO-C) ppm. MS (70 eV): m/z
(%) = 217 (48) [M+], 172 (100) [M+ – CO2H], 144 (57), 104 (28).
General Procedure for the Preparation of Oxazolinecarboxanilides 5
and 7 (GP3): To an ice-cold solution of the respective oxazoline-
carboxylic acid 4 (1 equiv.) and HOAt (1.2 equiv.) in anhydrous
CH2Cl2 was added EDC·HCl (1.5 equiv.) in one portion, the mix-
ture was stirred for 15 min, then 2,4,6-collidine (2.0 equiv.) and the
respective aniline (1.3 equiv.) were added. The cooling bath was
removed, and the resulting pale yellow reaction mixture was stirred
at 20 °C for 12 h and filtered through a pad of silica gel. The crude
product was purified by column chromatography.
N-Methyl-5-[4-(morpholin-4-yl)phenyl]-N-[3-(trifluoromethyl)-
phenyl]-6-oxa-4-azaspiro[2.4]hept-4-ene-7-carboxamide (9ca): The
crude product obtained from 8c (90.6 mg, 0.20 mmol), Pd2(dba)3
(3.65 mg), (Ϯ)-BI N A P (3.74 mg), mo r p h o lin e (26.0 m g,
N-(5-Chloro-2-hydroxyphenyl)-5-phenyl-6-oxa-4-azaspiro[2.4]hept-
4-ene-7-carboxamide (5aa): The crude product obtained from 4a
3712
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 3709–3713

Variously Substituted Spiro[cyclopropane-1,4Ј-oxazoline]s
0.30 mmol) and NaOtBu (28.8 mg, 0.30 mmol) according to GP5
was purified by column chromatography (Rf = 0.25; Et2O) to yield
65 mg (71%) of 9ca which crystallized from Et2O at 0 °C as a color-
of all the new compounds 3b–3d, 4b–4d, 5ba–5bd, 6ba–6bd, 7c, 7d,
8d, 9cb–9ce, 9da–9de, 11c, 12c, 13c.
less solid, m.p. 159–160 °C. IR (KBr): ν = 3084 , 2969, 2864, 1655,
˜
Acknowledgments
1607, 1521, 1335, 1228, 1119 cm–1 1H NMR (200 MHz, CDCl3):
.
δ = 0.62–0.83 (m, 1 H, cPr-H), 0.98–1.33 (m, 3 H, cPr-H), 3.02–
3.20 (m, 2 H), 3.28 (s, 3 H, CH3), 3.66–3.91 (m, 2 H), 4.97 (s, 1 H,
This work was supported by the Land Niedersachsen and the Bayer
CropScience AG. The authors are grateful to Stefan Beußhausen,
Göttingen, for technical assistance in assembling the final manu-
script.
3
CH), 6.62 (d, J = 8.2 Hz, 2 H, aryl-H) 7.03–7.50 (m, 6 H, aryl-H)
ppm. 13C NMR (75.5 MHz, CDCl3, APT): δ = 11.8 (–, cPr-C),
14.4 (–, cPr-C), 39.0 (+, CH3), 48.1 (–, 2 C, CH2-C), 53.4 (–, cPr-
C), 66.6 (–, 2 C, CH2-C), 80.8 (+, CH-C), 113.6 (+, 2 C, aryl-C),
1
[1] T. Liese, F. Seyed-Mahdavi, A. de Meijere, Org. Synth. 1990,
69, 148–153.
117.0 (–, aryl-C), 123.3 (–, q, JC–F = 264 Hz, CF3), 124.2 (+, q,
3
3JC–F = 4.3 Hz, aryl-C), 124.3 (+, q, JC–F = 3.2 Hz, aryl-C), 129.0
[2] For an advanced synthesis of 1, see: M. Limbach, S. Dalai, A.
de Meijere, Adv. Synth. Catal. 2004, 346, 760–766.
[3] For reviews see: a) A. de Meijere, L. Wessjohann, Synlett 1990,
20–32; b) A. de Meijere, S. Kozhushkov, L. P. Hadjiarapoglou,
Top. Curr. Chem. 2000, 207, 149–227.
2
(+, 2 C, aryl-C), 130.1 (+, aryl-C), 131.8 (–, q, JC–F = 32.5 Hz,
aryl-C), 143.2 (–, aryl-C), 153.1 (–, aryl-C), 162.4 (–, CN-C), 168.2
(–, CO-C) ppm. MS (70 eV): m/z (%) = 459 (22) [M+], 285 (16),
257 (20), 190 (100).
[4] M. W. Nötzel, M. Tamm, T. Labahn, M. Noltemeyer, M. Es-
Sayed, A. de Meijere, J. Org. Chem. 2000, 65, 3850–3852.
[5] C. Liu, M. Tamm, M. W. Nötzel, A. de Meijere, J. K. Schilling,
D. G. I. Kingston, Tetrahedron Lett. 2003, 44, 2049–2052.
[6] C. Liu, M. Tamm, M. W. Nötzel, K. Rauch, A. de Meijere,
J. K. Schilling, A. Lakdawala, J. P. Snyder, S. L. Bane, N.
Shanker, R. Rudravajhala, D. G. I. Kingston, Eur. J. Org.
Chem. 2005, 3962–3972.
[7] a) M. R. Prinsep, R. E. Moore, I. A. Levine, G. M. Patterson,
J. Nat. Prod. 1992, 55, 140–142; b) M. North, G. Pattenden,
Tetrahedron 1990, 46, 8267–8290; c) T. Ishida, M. Tanaka, M.
Nabae, M. Inoue, S. Kato, Y. Hamada, T. Shioiri, J. Org.
Chem. 1988, 53, 107–112.
[8] F. Brackmann, D. S. Yufit, J. A. K. Howard, M. Es-Sayed, A.
de Meijere, Eur. J. Org. Chem. 2005, 600–609.
[9] Adopted from a previously published procedure: L. Lebreton,
J. Annat, P. Derrepas, P. Dutarte, P. Renaut, J. Med. Chem.
1999, 42, 277–290.
[10] Adopted from previously published procedures: a) D. M.
Roush, M. M. Patel, Synth. Commun. 1985, 15, 675–679; b) P.
Wief, C. P. Miller, Tetrahedron Lett. 1992, 33, 6267–6270; c) P.
Jiao, J. Xu, Q. Zhang, M. C. K. Choi, A. S. C. Chan, Tetrahe-
dron: Asymmetry 2001, 12, 3081–3088.
[11] a) A. S. Guram, R. A. Rennels, S. L. Buchwald, Angew. Chem.
1995, 107, 1456–1459; Angew. Chem. Int. Ed. Engl. 1995, 34,
1348–1350; b) J. Louie, J. F. Hartwig, Tetrahedron Lett. 1995,
36, 3609–3612.
General Procedure (GP6) for the Suzuki–Miyaura Coupling of (Bro-
mophenyl)oxazolinecarboxanilide 8c: A 25 mL Schlenk flask was
charged with Pd(OAc)2 (4.5 mg, 10 mol-%) and P(Ph)3 (21 mg,
40 mol-%) in toluene (5 mL). The mixture was deoxygenated for
5 min by bubbling nitrogen through it. To this solution was added
8c (90.6 mg, 0.2 mmol), the respective boronic acid (0.30 mmol)
and aq. Na2CO3 (0.40 mmol, 2 ), and the mixture was stirred at
80 °C for 16 h. The reaction mixture was cooled to room tempera-
ture, taken up in Et2O (25 mL), washed with water (10 mL), and
the aq. layer was extracted with Et2O (2ϫ10 mL). The combined
organic phases were dried with MgSO4 and concentrated in vacuo.
The crude product was purified by column chromatography.
5-(Biphenyl-4-yl)-N-methyl-[3-(trifluoromethyl)phenyl]-6-oxa-4-aza-
spiro[2.4]hept-4-ene-7-carboxamide (10c): The crude product ob-
tained from 8c and phenylboronic acid (36.5 mg) according to the
GP6 was purified by column chromatography (Rf = 0.30; pentane/
Et2O, 1:2), to yield 81 mg (90%) of 10c as a colorless solid, m.p.
136–137 °C. IR (KBr): ν = 3081 , 1660, 1643, 1334, 1128, 1067, 705
˜
cm–1 1H NMR (200 MHz, CDCl3): δ = 0.74–0.83 (m, 1 H, cPr-
.
H), 1.03–1.38 (m, 3 H, cPr-H), 3.25 (s, 3 H, CH3), 5.02 (s, 1 H,
CH-H), 7.09–7.59 (m, 13 H, aryl-H) ppm. 13C NMR (75.5 MHz,
CDCl3, APT): δ = 12.0 (–, cPr-C), 14.7 (–, cPr-C), 39.1 (+, CH3),
1
53.7 (–, cPr-C), 81.0 (+, CH-C), 123.2 (–, q, JC–F = 262 Hz, CF3),
3
3
124.1 (+, q, JC–F = 3.8 Hz, aryl-C), 124.4 (+, q, JC–F = 3.8 Hz,
aryl-C), 125.2 (–, aryl-C), 126.6 (+, 2 C, aryl-C), 127.1 (+, 2 C,
aryl-C), 127.9 (+, aryl-C), 128.1 (+, 2 C, aryl-C), 128.9 (+, 2 C,
[12] For a recent review, see: L. Jiang, S. L. Buchwald, in Metal-
Catalyzed Cross-Coupling Reactions, 2nd ed. (Eds.: A. de Mei-
jere, F. Diederich), Wiley-VCH, Weinheim, 2004, pp. 699–760.
[13] A. de Meijere, C. M. Williams, A. Kourdioukov, S. V. Sviridov,
V. Chaplinski, M. Kordes, A. I. Savchenko, C. Stratmann, M.
Noltemeyer, Chem. Eur. J. 2002, 8, 3789–3801.
[14] For a recent review, see: N. Miyaura, in Metal-Catalyzed Cross-
Coupling Reactions, 2nd ed. (Eds.: A. de Meijere, F. Diederich),
Wiley-VCH, Weinheim, 2004, pp. 41–123.
2
aryl-C), 130.2 (+, aryl-C), 132.0 (–, q, JC–F = 33.2 Hz, aryl-C),
140.1 (–, aryl-C), 143.2 (–, aryl-C), 143.9 (–, aryl-C), 162.2 (–, CN-
C), 168.0 (–, CO-C) ppm. MS (70 eV): m/z (%) = 450 (92) [M+], 276
(91), 248 (61), 181 (100). C26H21F3N2O2 (450.5): calcd. C 69.33, H
4.70, N 6.22; found C 69.26, H 4.48, N 6.18.
Supporting Information (see footnote on the first page of this arti-
Received: April 1, 2008
cle): Detailed experimental procedures for and full characterization
Published Online: June 9, 2008
Eur. J. Org. Chem. 2008, 3709–3713
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3713