Synthesis of spirocyclopropanated analogues of iprodione

Article abstract of DOI:10.1002/ejoc.200400600

Methyl 1-(tert-butoxycarbonylamino)cyclopropanecarboxylate (9) was converted into the spirocyclopropanated five-membered ring analogue 7a of Iprodione (1) in five steps with an overall yield of 28%. The spirocyclopropanated five-membered ring analogue 8a was prepared from tert-butyl N-[1-(hydroxymethyl)cyclopropyl]carbamate (10) in five steps with an overall yield of 19%. En route to the spirocyclopropanated six-membered ring analogues of Iprodione (1), the oxalic acid diamides 5b and 6b could be obtained starting from 9 or 10 in 33 or 19% yield, respectively. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005.

Full text of DOI:10.1002/ejoc.200400600

FULL PAPER
Synthesis of Spirocyclopropanated Analogues of Iprodione[‡]
Farina Brackmann,[a] Mazen Es-Sayed,[b] and Armin de Meijere*[a]
Keywords: Cyclopropanes / Cyclization / Fungicides / Heterocycles / Small ring systems / Spiro compounds
Methyl 1-(tert-butoxycarbonylamino)cyclopropanecarboxyl-
ate (9) was converted into the spirocyclopropanated five-
membered ring analogue 7a of Iprodione (1) in five steps
with an overall yield of 28%. The spirocyclopropanated five-
membered ring analogue 8a was prepared from tert-butyl N-
[1-(hydroxymethyl)cyclopropyl]carbamate (10) in five steps
with an overall yield of 19%. En route to the spirocyclopro-
panated six-membered ring analogues of Iprodione (1), the
oxalic acid diamides 5b and 6b could be obtained starting
from 9 or 10 in 33 or 19% yield, respectively.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2005)
pathway. Encouraged by these results, we also set out to
modify Iprodione (1) by introducing a 1,1-disubstituted
three-membered ring to obtain the regioisomeric spirocy-
clopropanated five-membered analogues 7a and 8a as well
as the six-membered analogues 7b and 8b. It was especially
of interest to see, whether the substitution of the amide car-
bonyl group by a spiro-annelated cyclopropane ring, which
is known for its alkene-like properties,[11] causes any effect
upon fungicidal activity.
Introduction
For the last few decades substantial efforts of syntheti-
cally working scientists have been devoted to cyclopropane
analogues of biologically active compounds,[1] because the
incorporation of a cyclopropyl moiety in many cases had
proved to have a beneficial influence on the biological ac-
tivity.[2a] Introduction of a rigid three-membered ring into
a molecule can e. g. enforce a certain orientation of the sub-
stituents along the chain of a molecule.[2b] Numerous exam-
ples of biologically active naturally occurring[3] as well as
non-natural compounds rigidified by cyclopropane moieties
are known. Among the latter are the antidepressant Tranyl-
cypromin,[4] the antiinfectants Ciprofloxacin[5] and the once
successful antiinfective Trovafloxacin.[6] Naturally occur-
ring and synthetic pyrethroids are the best known cyclopro-
pane derivatives with a pesticide activity.[3b,7]
Fungicides become more and more important because
modern intensive agricultural procedures facilitate infes-
tation of crops with fungi. The contact fungicide Iprodione
(1), which was developed in 1970 by Rhône–Poulenc, and
used to control a variety of fungal diseases by inhibiting the
germination of spores and the growth of fungal mat,[8] has
found a widespread application throughout the world. As
we recently realized, biologically active motifs, like the one
found in the neonicotinergic acetylcholine receptor agonists
Imidacloprid[9] and Thiacloprid, may be modified by incor-
poration of spiroannelated cyclopropane rings,[10] with re-
tention of the activity, but a change in the overall metabolic
Several synthetic sequences have been tried out without
isolating and characterizing the intermediate products in an
effort to develop a protocol for combinatorial approaches
to libraries of such small molecules. Here we present our
successful endeavours.
Results and Discussion
The envisaged synthetic route was designed to allow ac-
cess to both the spirocyclopropanated five- as well as the
six-membered ring analogues 7 and 8 of Iprodione (1) re-
gioselectively from the same precursor of type 2, which
should be equipped in such a way as to permit selective
substitution on each amino group to form the arylamines 3
and 4, respectively. The latter then would be cyclized with
an appropriate carbonyl-group containing component to
afford the heterocycles 5 and 6, respectively, which, in turn,
would be converted into the biurets 7 and 8 (Scheme 1).
[‡] Cyclopropyl Building Blocks in Organic Synthesis, 111. Part
110: M. Knoke, A. de Meijere, Eur. J. Org. Chem. 2005, in press.
Part 109: T. Kurahashi, A. de Meijere, Synlett 2005, 805–808.
[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,
Alfred-Nobel-Strasse 50, 40789 Monheim, Germany
2250
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/ejoc.200400600
Eur. J. Org. Chem. 2005, 2250–2258

Synthesis of Spirocyclopropanated Analogues of Iprodione
FULL PAPER
in 2-propanol and subsequent cocyclization with phosgene,
applied as a solution in toluene according to a published
protocol,[15] provided the urea derivative 5a (Scheme 2).
This, after deprotonation with NaH, was treated again with
an excess of the phosgene solution and then with isopro-
pylamine. However, in contrast to published analogous re-
actions,[16] none of the desired product 7a was formed, but
exclusively the oligourea 13 arising by twofold substitution
on phosgene with 5a. This indicates that the intermediately
formed carbamoyl chloride reacts more rapidly with the de-
protonated 5a than with isopropylamine. The spirocyclic
urea 5a did not react with isopropyl isocyanate in the pres-
ence of 10 mol% of NEt3 (cf.[17]). Fortunately, the deproton-
ation of 5a with an ethereal solution of ethylmagnesium
bromide followed by treatment with a small excess of iso-
propyl isocyanate furnished the five-membered ring ana-
logue 7a (71% yield) of 1 along with some starting material
5a (Scheme 2).
Scheme 1. Retrosynthetic considerations of the spirocyclopropan-
ated analogues 7 and 8 of Iprodione (1).
The starting material chosen was methyl 1-(tert-butoxy-
carbonylamino)cyclopropanecarboxylate (9), which can be
prepared in 57% yield by monohydrolysis[12a] followed by
Curtius degradation[12b,12c] of the commercially available di-
methyl cyclopropane-1,1-dicarboxylate. Reduction of 9 with
lithium borohydride furnished tert-butyl N-[1-(hy-
droxymethyl)cyclopropyl]carbamate (10) in up to virtually
quantitative yield.[12d,12e]
Scheme 2. Synthesis of the spirocyclopropanated five-membered
ring analogue 7a of Iprodione (1). Reagents and conditions: i)
LiOH, THF/H2O/MeOH, 0 to 20 °C, 20 h, then citric acid to pH
Ϸ 4; ii) 3,5-dichloroaniline, DCC, HOBt, THF, 0 to 20 °C, 19 h;
iii) LiAlH4 (inverse addition of a solution in Et2O at 0 °C over 1 h),
Et2O, 0 °C, 4 h then 20 °C, 19 h; iv) TFA, 0 °C, 0.5 h, then HCl
(5 m solution in iPrOH), then COCl2 (20% solution in toluene),
NEt3, 0 to 20 °C, 2 h; v) NaH, THF, 20 °C, 10 min, then COCl2
(20% solution in toluene), 20 °C, 1.5 h, then iPrNH2, THF, 20 °C,
19 h; vi) EtMgBr, THF/Et2O, 0 °C, 15 min, then iPrN=C=O,
20 °C, 24 h.
Spirocyclopropanated Analogues of Iprodione (1) with a
Five-Membered Ring
Mild hydrolysis of the N-Boc-protected amino ester 9,
followed by peptide coupling of the intermediate 1-(tert-
butoxycarbonylamino)cyclopropanecarboxylic acid with
Deprotection of the N-Boc-protected aminoalcohol 10 as
3,5-dichloroaniline mediated by dicyclohexylcarbodiimide described above for compound 11 followed by a copper(i)
(DCC) and 1-hydroxybenzotriazole (HOBt) adopting a iodide catalyzed Buchwald coupling[18] of the free base (ob-
published procedure,[13] gave the amide 11 in 81% yield. tained from the hydrochloride by treatment with sodium
While reduction of the latter with borane–THF complex isopropanolate) with 3,5-dichloroiodobenzene[19] using eth-
(cf.[14]) furnished the corresponding amine 12 in less than ylene glycol as a ligand and K3PO4 as a base, afforded the
20% yield, careful reduction by slow addition of LiAlH4 as N-arylated aminoalcohol 14 (Scheme 3). The yield of this
an ethereal solution furnished 12 in 61% yield after column coupling went down upon scaling up the reaction, being
chromatography. The Boc protective group, under these 65% on a 2 mmol scale and only 53% on a 15–25 mmol
conditions, is affected to a minimal extent only. Deprotec- scale.[20] The obtained product 14 was contaminated with
tion of the cyclopropylamino moiety in 12 with trifluoro- up to 11 mol%[20] of 2-(3,5-dichlorophenoxy)ethanol (15)
acetic acid followed by treatment with hydrogen chloride which resulted from the O-arylation of ethylene glycol and
Eur. J. Org. Chem. 2005, 2250–2258
www.eurjoc.org
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2251

F. Brackmann, M. Es-Sayed, A. de Meijere
FULL PAPER
could not be removed by column chromatography. Such an pared by treatment of 6a with an ethereal solution of ethyl-
O-arylation has previously been reported only when magnesium bromide followed by addition of an excess of
Cs2CO3 was used as a base.[19a] The impure 14 was sub- isopropyl isocyanate in full analogy to the synthesis of 7a
jected to a Mitsunobu reaction[21] using hydrazoic acid[22] (Scheme 3).
as the nucleophile, and after purification by column
chromatography, the pure azide 16 was obtained in 79%
yield. Reduction of the latter with 1,3-propanedithiol[23]
furnished crude (1-aminomethylcyclopropyl)-(3,5-dichlo-
rophenyl)amine which was isolated as its dihydrochloride
Approach to Spirocyclopropanated Analogues of Iprodione
(1) with a Six-Membered Ring
17 and further converted without purification (Scheme 3).
Just as the attempted “shotgun” cocyclizations of the di-
amine 17 did not furnish any detectable quantity of the het-
erocycle 6a, treatment of 17 with diethyl oxalate only led to
the monoamide 19a by attack of the primary amino group
on the diester (90% yield), while the secondary arylamino
function remained as such, even after prolonged heating in
ethanol (cf.[25]) (Scheme 4). The analogous methyl ester 19b
was obtained from 17 upon treatment with methyl oxalyl
chloride (oxalic acid chloride mono methyl ester), and it
could not be cyclized even by prolonged heating in toluene
in the presence of molecular sieves 4 Å. The more reactive
oxalyl chloride[26] afforded the N,NЈ-disubstituted oxamide
20 in 69% yield as the sole product. However, a stepwise
proceeding turned out to be successful. Thus, mild hydroly-
sis of the methyl ester function in 19b with lithium hydrox-
ide followed by conversion of the carboxylic acid moiety
into the acid chloride with thionyl chloride, and finally
treatment with imidazole gave the desired six-membered
ring product 6b, albeit in an overall yield from the dihydro-
chloride 17 of only 18%.
With the intention in mind to acylate the less reactive
secondary arylamino group with the dicarbonyl building
block first, the free base of 17 was treated with di-tert-butyl
pyrocarbonate (Boc2O) to protect the primary amino
group, and the resulting Boc-protected diamine was allowed
to react with methyl oxalyl chloride in the presence of NEt3.
The obtained intermediate was directly treated with TFA to
remove the Boc group, and the resulting primary amine was
converted into its hydrochloride with hydrogen chloride in
2-propanol, and finally this in turn treated with sodium me-
thoxide in methanol at ambient temperature to provide the
desired pure product 6b in 51% overall yield starting from
the dihydrochloride 17 without any purification of the inter-
mediate products (Scheme 4).
Scheme 3. Synthesis of the spirocyclopropanated five-membered
ring analogue 8a of Iprodione (1). Reagents and conditions: i) TFA,
0 °C, 0.5 h, then HCl (5 m solution in iPrOH), then iPrONa, then
3,5-dichloroiodobenzene, CuI, K3PO4, HOCH2CH2OH, iPrOH,
80 °C, 22 h; ii) PPh3, DIAD, HN3 (solution in benzene), THF, –78
to 20 °C, 22 h; iii) HS(CH2)3SH, NEt3, MeOH, 20 °C, 1 d, then
HCl (satd. solution in Et2O), 0 °C; iv) COCl2 (20% solution in
toluene), NEt3, THF, 0 to 20 °C, 2.5 h; v) NaOH, then Boc2O,
CH2Cl2, DMAP, 20 °C, 0.5 h (variant A, 44%) or CDA, CH2Cl2,
0 to 20 °C, 1 d (variant B, 54%); vi) EtMgBr, THF/Et2O, 0 °C,
15 min, then iPrN=C=O, 20 °C, 3 h.
Surprisingly, contrary to the successful cocyclization of
This approach turned out to be successful also for the
deprotected 12 with phosgene in toluene solution (see precursor 5b of an Iprodione analogue with a six-membered
above), the attempted cocyclization of 17 under the same ring. Applying exactly the same sequence of operations to
conditions resulted in the quantitative formation of the the N-Boc-protected arylcyclopropyldiamine 12 – treatment
imidazolidinylimidazoline derivative 18. Presumably, the with methyl oxalyl chloride in the presence of NEt3, Boc-
initially formed desired product 6a, under these conditions, removal with TFA, conversion to the hydrochloride and fi-
reacts with excess phosgene to give a 2-chloroimidazoline nal treatment with NaOMe – gave the ring-closed product
derivative which can undergo formal nucleophilic substitu- 5b in 66% overall yield from 12 (Scheme 4).
tion with a second molecule of 6a. Alternatively, therefore,
Surprisingly, the attempted deprotonation of 5b and 6b
17 was cocyclized with di-tert-butyl pyrocarbonate[24] under with ethylmagnesium bromide in order to add the amide
4-(dimethylamino)pyridine (DMAP) mediation or with car- anion to isopropyl isocyanate, the sequence which had
bonyldiimidazole (CDA), respectively, to afford the spirocy- proved successful in the preparation of the spirocyclopro-
clopropanated heterocycle 6a, albeit in moderate yields (54 panated Iprodione analogues 7a and 8a with a five-mem-
and 44%, respectively). Finally, the spirocyclopropanated bered ring, failed and formed the products of Grignard ad-
five-membered ring analogue 8a of Iprodione (1) was pre- dition to either one of the carbonyl functions, 21a and 21b
2252
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2005, 2250–2258

Synthesis of Spirocyclopropanated Analogues of Iprodione
FULL PAPER
chain failed so far. The evaluation of the biological activity
of these analogues is currently in progress.
Experimental Section
General Remarks: NMR spectra were recorded with a Varian
UNITY-200 (200 MHz for 1H and 50.2 MHz for 13C NMR), a
Bruker AM 250 (250 MHz for 1H and 62.9 MHz for 13C NMR) or
a Varian UNITY-300 (300 MHz for 1H and 75.5 MHz for 13C
NMR) instrument. Proton chemical shifts are reported in ppm rela-
tive to residual peaks of deuterated solvents. Multiplicities were
determined by DEPT (Distortionless Enhancement by Polarisation
Transfer), APT (Attached Proton Test) measurements or HMQC
(Heteronuclear Multiple Quantum Coherence). Chemical shifts re-
fer to δTMS = 0.00 ppm according to the chemical shifts of residual
solvent signals. IR: Bruker IFS 66 (FT-IR) spectrophotometer,
measured as KBr pellets or oils between KBr plates. MS (EI at
70 eV or DCI with NH3): Finnigan MAT 95 spectrometer. MS
(HR-EI): pre-selected ion peak matching at R ϾϾ 10000 to be
within 2 ppm of the exact masses. Melting points: Büchi 510 cap-
illary melting point apparatus, values are uncorrected. TLC: Mach-
erey–Nagel precoated sheets, 0.25 mm Sil G/UV254
. Column
chromatography: Merck silica gel, grade 60, 230–400 mesh. Ele-
mental analyses: Mikroanalytisches Laboratorium des Instituts für
Organische und Biomolekulare Chemie, Universität Göttingen.
Starting materials: Methyl (1-tert-butoxycarbonylamino)cyclopro-
pane carboxylate (9),[11a–11c] tert-butyl (1-hydroxymethylcyclopro-
pyl)carbamate (10)[11d,11e] and hydrazoic acid[21] were prepared ac-
cording to published procedures. Anhydrous THF was obtained by
distillation from sodium benzophenone ketyl, CH2Cl2 and MeCN
from P4O10, MeOH from Mg, NEt3 from CaH2. All other chemi-
cals were used as commercially available. All operations in anhy-
drous solvents were performed under nitrogen in flame-dried glass-
ware. Organic extracts were dried with MgSO4.
Scheme 4. Synthesis of the spirocyclopropanated heterocycles 5b,
6b and en route to the spirocyclopropanated six-membered ring
analogues 7b and 8b. Reagents and conditions: i) NaOH, then
(CO2Et)2, EtOH, 78 °C, 21 h; ii) NEt3, then ClCOCO2Me, THF, 0
to 20 °C, 2.5 h; iii) NEt3, then (COCl)2, THF, 0 to 20 °C, 2 h; iv)
LiOH, THF/H2O, 0 to 20 °C, 1.5 h; v) SOCl2, DMF (cat.), CH2Cl2,
20 to 40 °C, then imidazole, MeCN, 20 to 80 °C, 20 h; vi) NaOH,
then Boc2O, CH2Cl2, 20 °C, 15 h; ix) TFA, 0 °C, 0.5 h, then HCl
(5 m solution in iPrOH); x) NaOMe, MeOH, 20 °C, 1 d; xi)
EtMgBr, THF/Et2O, 0 °C, 15 min, then iPrN=C=O, 20 °C, 2 h.
tert-Butyl [1-(3,5-Dichlorophenylcarbamoyl)cyclopropyl]carbamate
(11): To a solution of the N-Boc-amino ester 9 (7.43 g, 34.5 mmol)
in a mixture of THF/H2O/MeOH (30 mL/15 mL/15 mL) was added
at 0 °C LiOH (4.14 g, 173 mmol) in one portion, and the resulting
mixture was stirred at this temp. for 5 h and at ambient temp. for
an additional 15 h. After evaporation of the volatile components,
the residue was taken up with H2O (15 mL) and brought to pH 4
with a 10% aq. citric acid solution. The aqueous phase was ex-
tracted with Et2O (3×80 mL). The combined organic phases were
dried and evaporated under reduced pressure. The resulting crude
in a ratio of 6.5: 1[27] in 31% yield (Scheme 4, the regio-
chemistry is attributed arbitrarily). Any further attempts to
introduce the isopropylamide functionality into 5b, e. g. by
deprotonation with NaH or KF/aluminum oxide[28] and
subsequent treatment with isopropyl isocyanate, failed as
well.
1-(tert-butoxycarbonylamino)cyclopropanecarboxylic
acid[29]
(6.03 g, 30.0 mmol) was dissolved in THF (120 mL) and the solu-
tion cooled to 0 °C. 3,5-Dichloroaniline (4.86 g, 30.0 mmol), 1-hy-
droxybenzotriazol (4.54 g, 30.0 mmol, cont. 12% H2O) and dicy-
clohexylcarbodiimide (6.50 g, 31.5 mmol) were added in this order,
each in one portion. The reaction mixture was warmed to ambient
temp. and stirred for an additional 19 h. The suspension was fil-
tered through a pad of Celite and the filtrate was evaporated under
reduced pressure. The residue was taken up in EtOAc (120 mL),
and the organic layer was washed with satd. aq. NaHCO3 solution
(2×50 mL), aq. 0.2 n HCl solution (2×50 mL) and H2O (50 mL),
dried and concentrated under reduced pressure. Recrystallization
of the residue from EtOAc yielded 11 (9.60 g, 81%) as a colorless
Conclusions
An efficient route to novel Iprodione (1) analogues has
been developed in which a spiroannelated cyclopropane
ring occupies in position 4 or 5, respectively, of the cyclic
urea. In addition, precursors to the six-membered spirocy-
clopropanated Iprodione analogues have been synthesized,
containing an additional carbonyl group in the heterocycle.
voluminous solid, m.p. 150–153 °C. IR (KBr): ν = 3335 cm–1 (N–
˜
H), 3298 (N–H), 3084 (C–H) 2986 (C–H), 2976 (C–H), 2930 (C–
H), 1688 (C=O), 1583, 1168 (OtBu), 848, 670. 1H NMR (250 MHz,
CDCl3): δ = 1.06–1.15 (m, 2 H, Cpr-H), 1.46 [s, 9 H, C(CH3)3],
Unfortunately the introduction of the isopropyl urea side 1.59–1.67 (m, 2 H, Cpr-H), 5.43 (br. s, 1 H, CprNH), 7.02–7.08
Eur. J. Org. Chem. 2005, 2250–2258
www.eurjoc.org © 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 2253

F. Brackmann, M. Es-Sayed, A. de Meijere
FULL PAPER
(m, 1 H, Ar-H), 7.42–7.50 (m, 2 H, Ar-H), 8.68 (br. s, 1 H, ArNH)
ppm. 13C NMR (50.3 MHz, CDCl3, APT): δ = 18.2 (–, Cpr-C),
28.2 [+, C(CH3)3], 36.5 (–, Cpr-C), 81.6 [–, C(CH3)3], 117.9 (+, Ar-
C), 124.1 (+, Ar-C), 135.1 (–, Ar-C), 139.7 (–, Ar-C), 156.2 (–,
CprNCO), 170.6 (–, CprCON) ppm. MS (EI): m/z (%) = 348/346/
sure. The residue was again treated with water (20 mL), and the
mixture filtered. Column chromatography of the residue (85 g of
silica gel, 4×20 cm column, CHCl3/MeOH, 35:1) yielded 5a
(797 mg, 81%) as a colorless solid, m.p. 183–184 °C, Rf = 0.40. IR
(KBr): ν = 3295 cm–1 (N–H), 1724, 1708 (C=O), 1561, 1460, 1394.
˜
344 (Ͻ1:5:8) [M+], 292/290/288 (3:19:28) [M+ – C4H8], 275/273/271 1H NMR (250 MHz, CDCl3): δ = 0.78–0.90 (m, 2 H, Cpr-H), 0.90–
(Ͻ1:4:7) [M+ – OtBu], 248/246/244 (Ͻ1:5:9) [M+ – CO2tBu + H],
231/229/227 (Ͻ1:Ͻ1:2) [M+ – H2NCO2tBu], 199 (4), [M+ – Cl2Ar], 6.99–7.05 (m, 1 H, Ar-H), 7.45–7.50 (m, 2 H, Ar-H) ppm. 13C
1.02 (m, 2 H, Cpr-H), 3.87 (s, 2 H, CH2N), 5.24 (br. s, 1 H, NH),
165/163/161 (Ͻ1:4:8) [Cl2ArNH2+], 149/147/145 (Ͻ1:Ͻ1:1)
[Cl2Ar+], [H2NCOC3H4NHCO+],
127 (5) 100
NMR (50.3 MHz, CDCl3, APT): δ = 11.8 (–, Cpr-C), 34.5 (–, Cpr-
(3) C), 52.6 (–, CH2N), 115.5 (+, Ar-C), 122.3 (+, Ar-C), 135.1 (–, Ar-
[H2NCOC3H4NH2+, CO2tBu+ – H], 57 (100) [C4H9+], 41 (8) C), 141.8 (–, Ar-C), 158.1 (–, CO) ppm. MS (EI): m/z (%) = 260/
[C3H5+]. HRMS (EI) calcd. for C15H18Cl2N2O3 [M+] 344.0694,
258/256 (8:63:100) [M+], 245/243/241 (8:56:95), 232/230/228
correct mass. C15H18Cl2N2O3 (345.22): calcd. C 52.19, H 5.26, N (4:30:45) [M+ – CO], 178 (23), 174 (36), 149/147/145 (3:19:29)
8.11; found C 52.45, H 5.18, N 7.86.
[Cl2Ar+], 41 (62) [C3H5+]. HRMS (EI) calcd. for C11H10Cl2N2O
[M+] 256.0170, (correct HRMS) C11H10Cl2N2O (257.12): calcd. C
51.39, H 3.91, Cl 27.58, N 10.90; found C 51.40, H 3.78, Cl 27.41,
N 10.78.
tert-Butyl
[1-(3,5-Dichlorophenylaminomethyl)cyclopropyl]carba-
mate (12): LiAlH4 (8.52 mmol, 5.68 mL of a 1.50 m solution in
Et2O) was added to a stirred solution of 11 (1.96 g, 5.68 mmol) in
anhydrous Et2O (100 mL) at 0 °C over a period of 1 h. The reaction
mixture was stirred at 0 °C for 4 h, warmed to ambient temp. and
stirred at this temp. for an additional 19 h. A second portion of
LiAlH4 (2.65 mL, 3.98 mmol, 1.50 m in Et2O) was added dropwise
at 0 °C, and the reaction mixture was warmed up to ambient temp.,
stirred at this temp. for an additional 4 h and cooled to 0 °C again.
An aq. satd. Na2SO4 solution (3 mL) was added carefully at 0 °C,
and the resulting suspension was stirred for 13 h while warming up
to ambient temp., then filtered through a pad of Celite. The filtrate
was dried and evaporated under reduced pressure. Column
chromatography of the residue (105 g of silica gel, 4×25 cm col-
umn, CHCl3) yielded 12 (1.15 g, 61%) as a colorless voluminous
Bis[6-(3,5-dichlorophenyl)-4,6-diaza-5-oxospiro[2.4]hept-4-yl]meth-
anone (13): A solution of 5a (321 mg, 1.25 mmol) in anhydrous
THF (10 mL) was added dropwise to a suspension of NaH
(80.0 mg, 2.00 mmol, 60% suspension in mineral oil) in anhydrous
THF (10 mL), and the mixture stirred for 10 min at ambient temp.
Phosgene (4.00 mmol, 2.12 mL of a 20% solution in toluene) was
added, and the reaction mixture was stirred at the same temp. for
an additional 1.5 h. The suspension was filtered through a pad of
Celite, and the filtrate was evaporated under reduced pressure. The
residue was dissolved in anhydrous THF (20 mL), treated with iso-
propylamine (266 μL, 4.00 mmol) and stirred at ambient temp. for
an additional 19 h. The volatile compounds were evaporated under
reduced pressure. The residue was treated with water (30 mL), and
solid, m.p. 79–81 °C, R = 0.48. IR (KBr): ν = 3365 cm–1 (N–H),
˜
f
3057 (C–H), 2995 (C–H), 2972 (C–H), 2922 (C–H), 1676 (C=O), the mixture extracted with CH2Cl2 (4×30 mL). The combined or-
1596, 1576, 1506, 1368, 1270, 1256, 1161, 1081. 1H NMR ganic phases were dried and evaporated under reduced pressure.
(250 MHz, CDCl3): δ = 0.79–0.95 (m, 4 H, Cpr-H), 1.43 [s, 9 H,
C(CH3)3], 3.11 (d, J = 4.5 Hz, 2 H, CH2N), 5.01 (br. s, 1 H, NH), (321 mg, 95%) as a colorless solid, m.p. Ͼ250 °C. IR (KBr): ν =
Recrystallization of the residue from CHCl3/Et2O yielded 13
3
˜
5.24 (br. s, 1 H, NH), 6.35–6.43 (m, 2 H, Ar-H), 6.55–6.67 (m, 1
3088 cm–1 (C–H), 3004 (C–H), 2867 (C–H), 1722 (C=O), 1700
H, Ar-H) ppm. 13C NMR (62.9 MHz, CDCl3, DEPT): δ = 13.5 (C=O), 1593, 1556, 1461, 1437, 1336, 1305, 1211. 1H NMR
(–, Cpr-C), 28.3 [+, C(CH3)3], 32.3 (Cquat, Cpr-C), 52.4 (–, CH2N),
80.2 [Cquat, C(CH3)3], 110.3 (+, Ar-C), 116.2 (+, Ar-C), 135.3
(250 MHz, CDCl3): δ = 0.66–0.86 (m, 4 H, Cpr-H), 1.72–1.90 (m,
2
4 H, Cpr-H), 3.50 (d, J = 8.2 Hz, 2 H, CH2N), 4.21 (2J = 8.2 Hz,
(Cquat, Ar-C), 150.1 (Cquat, Ar-C), 156.6 (Cquat, NCO) ppm. MS 2 H, CH2N), 7.07–7.15 (m, 2 H, Ar-H), 7.40–7.50 (m, 4 H, Ar-H)
(EI): m/z (%) = 334/332/330 (1:9:14) [M+], 278/276/274 (1:10:15)
[M+ – C4H8], 178/176/174 (3:12:19) [M+ – C3H4NHCO2tBu], 57
(100) [C4H9+], 41 (15) [C3H5+]. HRMS (EI) calcd. for
C15H20Cl2N2O2 [M+] 330.0902, correct mass. C15H20Cl2N2O2
(331.24): calcd. C 54.39, H 6.09, Cl 21.41, N 8.46; found C 54.21,
H 5.87, Cl 21.61, N 8.31.
ppm. 13C NMR (50.3 MHz, CDCl3, APT): δ = 5.5 (–, Cpr-C), 13.7
(–, Cpr-C), 39.0 (–, Cpr-C), 52.1 (–, CH2N), 117.1 (+, Ar-C), 124.0
(+, Ar-C), 135.3 (–, Ar-C), 140.6 (–, Ar-C), 147.1 (–, CO), 152.2 (–,
CO) ppm. MS (EI): m/z (%) = 546/544/542/540/538 (Ͻ1:1:6:14:11)
[M+], 287/285/283 (2:16:29) [Cl2ArNCH2C3H4NCOCO+], 260/258/
256 (9:59:100) [Cl2ArNCH2C3H4NHCO+], 245/243/241 (2:17:25),
96 (53) [C3H4CH2NCO+], 68 (10), 53 (44), 41 (14) [C3H5+].
C23H18Cl4N4O3 (540.23): calcd. C 51.14, H 3.36, Cl 26.25, N 10.37;
found C 50.84, H 3.43, Cl 26.70, N 10.15.
Deprotection of N-Boc-protected Amines. General Procedure 1 (GP,
1): The indicated quantity of the respective carbamate was stirred
with TFA (5 mL) at 0 °C for 30 min. All volatile components of
the reaction mixture were removed under reduced pressure. To the
residue was added a solution of HCl (5 mL of a 5 m solution in
iPrOH), and the reaction mixture was concentrated. This operation
was repeated three times. The residual hydrochloride was used
without further purification.
Reactions with Isopropyl Isocyanate. General Procedure 2 (GP, 2):
A solution of the respective heterocycle (1.00 mmol) in anhydrous
THF (15 mL) was treated with an ethereal solution of ethylmages-
ium bromide (1.00 mmol) at 0 °C, and the resulting mixture was
stirred for an additional 15 min. Isopropyl isocyanate (1.10 mmol)
was added at the same temp., the resulting mixture was warmed up
to ambient temp. and stirred at this temp. for the indicated time.
The reaction was quenched with an aq. satd. NH4Cl solution
(20 mL), and the phases were separated. The aqueous phase was
extracted with Et2O (2×20 mL), the combined organic phases were
dried and evaporated under reduced pressure. The product was
purified by column chromatography on silica gel.
6-(3,5-Dichlorophenyl)-4,6-diazaspiro[2.4]heptan-5-one (5a): The hy-
drochloride obtained from the carbamate 12 (1.28 g, 3.85 mmol)
according to GP1 was dissolved in anhydrous THF (50 mL), the
solution cooled to 0 °C, treated with NEt3 (2.19 mL, 15.8 mmol)
and stirred for an additional 10 min. A 20% solution of phosgene
in toluene (5.78 mmol, 3.06 mL) was added dropwise at 0 °C over
a period of 30 min, the resulting mixture was warmed to ambient
temp. and stirred for an additional 2 h. Water (1 mL) was added,
and all volatile compounds were evaporated under reduced pres-
6-(3,5-Dichlorophenyl)-N-isopropyl-5-oxo-4,6-diazaspiro[2.4]hept-
ane-4-carboxamide (7a): Column chromatography (25 g of silica
2254
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2005, 2250–2258

Synthesis of Spirocyclopropanated Analogues of Iprodione
FULL PAPER
as well as 15 (309 mg, 1.50 mmol) according to its H NMR spec-
trum] in anhydrous THF (100 mL) at –78 °C. The reaction mixture
was warmed to ambient temp., stirred at this temp. for an ad-
ditional 22 h and concentrated under reduced pressure. The residue
was filtered through a pad of silica gel (200 g) eluting with chloro-
form, the solution concentrated under reduced pressure and the
1
gel, 2×25 cm column, CHCl3) of the residue obtained from 5a
(257 mg, 1.00 mmol), EtMgBr (1.00 mmol, 370 μL of a 2.70 m solu-
tion in Et2O) and isopropyl isocyanate (108 μL, 1.10 mmol) accord-
ing to GP2 (24 h stirring) yielded 7a (243 mg, 71%) and some start-
ing material 5a (44 mg, 17%). An analytical sample of 7a was ob-
tained by recrystallization from hexane/CH2Cl2. 7a: Colorless solid,
m.p. 122–123 °C, R = 0.60. IR (KBr): ν = 3301 cm–1 (N–H), 3118 residue then purified by column chromatography (100 g of silica
˜
f
(C–H), 3064 (C–H), 2993 (C–H), 2970 (C–H), 2930 (C–H) 2885
(C–H), 1718 (C=O), 1684 (C=O), 1590, 1560, 1547 (NC=O), 1449,
gel, 3×40 cm column, hexane/Et2O, 30:1) to yield 16 (2.40 g,
9.33 mmol, 79%) as a pale yellow oil which crystallized while kept
at –26 °C overnight, m.p. 49–50 °C, Rf = 0.16. IR (KBr): ν =
˜
1389, 1363, 1213, 1176, 671. 1H NMR (250 MHz, CDCl3): δ =
3
0.59–0.67 (m, 2 H, Cpr-H), 1.18 [d, J = 6.6 Hz, 6 H, CH(CH3)2], 3347 cm–1 (N–H), 3094 (C–H), 3008 (C–H), 2924 (C–H), 2858 (C–
3
2.03–2.17 (m, 2 H, Cpr-H), 3.74 (s, 2 H, CH2N), 3.94 [sept, J = H), 2100 (N3), 1590, 1572, 1451, 1338, 1236, 821, 674. 1H NMR
6.6 Hz, 1 H, CH(CH3)2], 7.06–7.13 (m, 1 H, Ar-H), 7.42–7.48 (m,
2 H, Ar-H), 8.21 (br. d, 3J = 7.0 Hz, 1 H, NH) ppm. 13C NMR
(62.9 MHz, CDCl3, DEPT): δ = 10.9 (–, Cpr-C), 22.8 [+, CH-
(250 MHz, CDCl3): δ = 0.87–0.91 (m, 4 H, Cpr-H), 3.38 (s, 2 H,
CH2N), 4.50 (br. s, 1 H, NH), 6.56–6.60 (m, 2 H, Ar-H), 6.71–6.75
(m, 1 H, Ar-H) ppm. 13C NMR (62.9 MHz, CDCl3, DEPT): δ =
(CH3)2], 38.8 [+, CH(CH3)2], 41.7 (Cquat, Cpr-C), 51.9 (–, CH2N), 13.3 (–, Cpr-C), 34.5 (Cquat, Cpr-C), 55.3 (–, CH2N), 111.6 (+, Ar-
116.7 (+, Ar-C), 123.8 (+, Ar-C), 135.3 (Cquat, Ar-C), 140.5 (Cquat C), 117.8 (+, Ar-C), 135.41 (Cquat, Ar-C), 147.7 (Cquat, Ar-C) ppm.
Ar-C), 151.6 (Cquat, CO), 155.3 (Cquat, CO) ppm. MS (EI): m/z (%) MS (EI): m/z (%) = 260/258/256 (2:10:14) [M+], 218/216/214
,
=
345/343/341 (Ͻ1:1:2) [M+], 260/258/256 (8:67:100) [M+
–
(10:66:100) [M+ – N3], 204/202/200 (10:38:49) [M+ – CH2N3], 181/
179 (19:66) [M+ – N3 – Cl], 164 (41), 145 (25), 130 (13), 111 (14),
109 (20), 75 (22), 56 (22) [CH2N3+], 41 (14) [C3H5+]. HRMS (EI)
calcd. for C10H10Cl2N4 [M+] 256.0283, (correct HRMS).
C10H10Cl2N4 (257.12): calcd. C 46.71, H 3.92, N 21.79; found C
46.61, H 3.63, N 21.74.
iPrNHCO + H], 245/243/241 (5:29:59). HRMS (EI) calcd. for
C15H17Cl2N3O2 [M+] 341.0698, correct mass. C15H17Cl2N3O2
(342.22): calcd. C 52.65, H 5.01, Cl 20.72, N 12.78; found C 52.68,
H 4.74, Cl 20.81, N 12.06.
[1-(3,5-Dichlorophenylamino)cyclopropyl]methanol (14): The residue
obtained from tert-butyl (1-hydroxymethylcyclopropyl)carbamate
(10) (3.09 g, 16.5 mmol) according to GP1 was added in small por-
tions to a solution of NaOiPr in iPrOH [freshly prepared by dis-
solving Na (380 mg, 16.5 mmol) in anhydrous iPrOH (40 mL)], and
the resulting mixture stirred for 15 min at ambient temp. Then
K3PO4 (6.37 g, 30.0 mmol), ethylene glycol (1.67 mL, 30.0 mmol),
3,5-dichloroiodobenzene (4.09 g, 15.0 mmol) and CuI (143 mg,
750 μmol) were added, and the resulting suspension was stirred at
80 °C for 22 h. After cooling to ambient temp., the reaction mixture
was diluted with water (40 mL), and the phases were separated. The
aqueous phase was extracted with Et2O (3×50 mL), the combined
organic layers were dried and evaporated under reduced pressure.
Column chromatography of the residue (150 g of silica gel,
4×25 cm column, CHCl3) yielded 14 (1.85 g, calculated yield 53%)
as a brown, viscous oil which was contaminated with 2-(3,5-dichlo-
rophenoxy)ethanol (15) (180 mg, calculated yield 6%), Rf = 0.15.
4,4Ј-Bis(3,5-dichlorophenyl)-5,6Ј-bi[4,6-diazaspiro[2.4]heptyl]-5-en-
5Ј-one (18): A solution of the azide 16 (573 mg, 2.23 mmol) in
MeOH (10 mL) was treated with NEt3 (773 μL, 5.58 mmol) and
1,3-propanedithiol (560 μL, 5.58 mmol), and the mixture stirred for
1 d. The reaction mixture was filtered through a pad of Celite, and
the filtrate was concentrated under reduced pressure. The residue
was taken up in Et2O (2.5 mL), and a satd. HCl solution in Et2O
(2.5 mL) was added. The volatile compounds were evaporated in
vacuo, and the residue was washed with Et2O to yield crude (1-
aminomethylcyclopropyl)-(3,5-dichlorophenyl)amine dihydrochlo-
ride (17) (587 mg, 1.93 mmol, 87%), slow decomp. Ͼ205 °C, m.p.
215–220 °C. 1H NMR (300 MHz, D2O): δ = 0.96–1.03 (m, 2 H,
Cpr-H), 1.03–1.12 (m, 2 H, Cpr-H), 3.20 (s, 2 H, CH2N), 6.76–
6.83 (m, 2 H, Ar-H), 6.86–6.90 (m, 1 H, Ar-H) ppm. 13C NMR
(75.5 MHz, CDCl3, APT): δ = 14.3 (–, Cpr-C), 32.7 (–, Cpr-C),
51.5 (–, CH2N), 112.6 (+, Ar-C), 118.1 (+, Ar-C), 136.1 (–, Ar-C),
149.2 (–, Ar-C) ppm. The crude 17 was dissolved in THF (20 mL),
treated with NEt3 (1.10 mL, 7.91 mmol) at 0 °C and stirred for
10 min. Phosgene (2.90 mmol, 1.53 mL of a 20% solution in tolu-
ene) was added over a period of 45 min at 0 °C. The resulting mix-
ture was warmed to ambient temp. and stirred for an additional
2.5 h. Water (15 mL) was added, and the reaction mixture was ex-
tracted with CH2Cl2 (2×20 mL). The combined organic layers were
dried and concentrated under reduced pressure. Column
chromatography of the residue (30 g of silica gel, 1×20 cm column,
CHCl3/MeOH, 35:1) yielded 18 (478 mg, 963 μmol, 100%) as a col-
orless solid, Rf = 0.35. An analytical sample was obtained by
recrystallization from CH2Cl2/Et2O and had m.p. 186–190 °C. IR
IR (KBr): ν = 3409 cm–1 (O–H, N–H), 2936 (C–H), 1592, 1572,
˜
1
1450, 1036, 838, 802. 14: H NMR (300 MHz, CDCl3): δ = 0.78–
0.88 (m, 4 H, Cpr-H), 1.64 (br. s, 1 H, OH), 3.61 (s, 2 H, CH2O),
4.52 (br. s, 1 H, NH), 6.53–6.60 (m, 2 H, Ar-H), 6.65–6.70 (m, 1
H, Ar-H) ppm. 13C NMR (75.5 MHz, CDCl3, APT): δ = 12.7 (–,
Cpr-C), 36.3 (–, Cpr-C), 65.4 (–, CH2OH), 111.8 (+, Ar-C), 117.5
(+, Ar-C), 135.35 (–, Ar-C), 148.5 (–, Ar-C) ppm. 15: 1H NMR
(300 MHz, CDCl3): δ = 1.56 (br. s, 1 H, OH), 3.90–3.98 (s, 2 H,
CH2O), 4.02–4.08 (s, 2 H, CH2O), 4.52 (br. s, 1 H, NH), 6.78–
6.82 (m, 2 H, Ar-H), 6.92–6.98 (m, 1 H, Ar-H) ppm. 13C NMR
(75.5 MHz, CDCl3, APT): δ = 61.1 (–, CH2OH), 69.8 (–, CH2OAr),
113.6 (+, Ar-C), 121.4 (+, Ar-C), 135.40 (–, Ar-C), 159.6 (–, Ar-C)
ppm. 14 and 15: MS (EI): m/z (%) = 235/233/231 (3:14:22) [M1+],
(KBr): ν = 3085 cm–1 (C–H), 2859 (C–H), 1737 (C=O), 1612, 1585,
˜
+
219/208/206 (2:13:22) [M2+], 204/202/200 (18:33:45) [M1
–
1
1572, 1402, 1376. H NMR (250 MHz, CDCl3): δ = 0.51–0.67 (m,
CH2OH], 166/164/162 (12:68:100) [Cl2ArNH3+], 149/147:145
(2:12:18) [Cl2Ar+], 109 (13), 99 (17), 75 (11), 63 (16), 45 (22), 41 (4)
[C3H5+]. This mixture was used in the next step without separation.
2 H, Cpr-H), 0.67–0.82 (m, 4 H, Cpr-H), 0.82–0.94 (m, 2 H, Cpr-
H), 3.94 (s, 2 H, CH2N), 4.03 (s, 2 H, CH2N), 6.78–6.88 (m, 2 H,
Ar-H), 6.88–6.95 (m, 2 H, Ar-H), 7.18–7.25 (m, 1 H, Ar-H), 7.25–
7.31 (m, 1 H, Ar-H) ppm. 13C NMR (62.9 MHz, CDCl3, DEPT):
(1-Azidomethylcyclopropyl)-(3,5-dichlorophenyl)amine (16): Diiso-
propyl azodicarboxylate (2.98 mL, 15.4 mmol) and hydrazoic acid
(15.2 mmol, 15.2 mL of a 1.0 m solution in benzene) were added
one after the other to a stirred solution of PPh3 (4.14 g, 15.8 mmol)
in a mixture of the amino alcohol 14 and the hydroxy ether 15
[prepared as described above and containing 14 (2.71 g, 11.7 mmol)
δ = 8.4 (–, Cpr-C), 10.9 (–, Cpr-C), 41.2 (Cquat, Cpr-C), 48.9 (Cquat
,
Cpr-C), 51.7 (–, CH2N), 60.4 (–, CH2N), 124.9 (+, Ar-C), 126.6
(+, Ar-C), 127.7 (+, Ar-C), 128.4 (+, Ar-C), 135.0 (Cquat, Ar-C),
135.3 (Cquat, Ar-C), 135.7 (Cquat, Ar-C), 142.8 (Cquat, Ar-C), 153.4
(Cquat, CO), 154.8 (Cquat, NNCN) ppm. MS (EI): m/z (%) = 502/
Eur. J. Org. Chem. 2005, 2250–2258
www.eurjoc.org
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2255

F. Brackmann, M. Es-Sayed, A. de Meijere
FULL PAPER
500/498/496/494 (Ͻ1:2:9:21:15) [M+], 339/337/335 (7:44:70) [M+
–
[Cl2ArNCH2C3H4NH+], 97 (94) [C3H4CH2NHCO+], 84 (42)
[HNC3H4CH2NH+], 43 (58). C15H17Cl2N3O2 (342.22): calcd. C
52.65, H 5.01, Cl 20.72, N 12.28; found C 52.54, H 4.88, Cl 20.90,
N 12.08.
Cl2ArN], 311/309/307 (9:59:92) [M+ – Cl2ArN – CO], 217/215/213
(13:62:100)
[Cl2ArNC3H4CH2+],
180/178
(27:89)
[ClArNC3H4CH2+]. C22H18Cl4N4O (496.22): calcd. C 53.25, H
3.66, Cl 28.58, N 11.29; found C 53.11, H 3.87, Cl 28.82, N 11.12.
N,NЈ-Bis[1-(3,5-dichlorophenylamino)cyclopropylmethyl]oxalamide
4-(3,5-Dichlorophenyl)-4,6-diazaspiro[2.4]heptan-5-one (6a). Variant (20): The crude dihydrochloride 17 [304 mg, 1.00 mmol; obtained
A: The crude 17 [152 mg, 500 μmol; obtained from 16 (148 mg,
575 mmol) as indicated above] was dissolved in a solution of NaOH
(3.5 mL of aq. 1 m solution), and the mixture extracted with
CH2Cl2 (5×3 mL). The combined organic layers were dried, con-
centrated under reduced pressure, and the residue taken up with
anhydrous CH2Cl2 (2.5 mL). In a second flask, a solution of Boc2O
from 16 (296 mg, 1.15 mmol) as indicated above] was dissolved in
anhydrous THF (10 mL), the solution treated with NEt3 (380 μL,
2.73 mmol) at 0 °C and the mixture stirred for 15 min. A solution
of oxalyl chloride (116 μL, 1.35 mmol) in THF (10 mL) was added
at 0 °C over a period of 1 h, the resulting mixture was warmed to
ambient temp. and stirred for an additional 2 h. Water (1 mL) was
(120 mg, 550 μmol) in anhydrous CH2Cl2 (1.5 mL) was treated with added, and the volatile components were evaporated in vacuo. The
DMAP (61.1 mg, 500 μmol) and stirred for 10 min at ambient
temp. before the solution of the free base from 17 was added. The
reaction mixture was stirred at ambient temp. for an additional
30 min, and the volatile components were evaporated under re-
duced pressure. Column chromatography of the residue (20 g of
silica gel, 1×15 cm column, CHCl3/MeOH, 40:1) yielded 6a
(57 mg, 222 μmol, 44%) as a colorless solid, Rf = 0.37. IR (KBr):
residue was triturated with H2O (8 mL), filtered off and washed
successively with water (5 mL), EtOH (5 mL) and Et2O (5 mL) to
yield 20 (179 mg, 347 μmol, 69%) as a pale grey solid, m.p. 245–
250 °C (decomp.). IR (KBr): ν = 3412 cm–1 (N–H), 3305 (N–H),
˜
1
1648 (C=O), 1592 (C=O), 1569, 1518, 1449. H NMR (300 MHz,
[D6]DMSO): δ = 0.52–0.63 (m, 4 H, Cpr-H), 0.80–0.93 (m, 4 H,
Cpr-H), 3.32 (d, 3J = 6.2 Hz, 4 H, CH2N), 6.61 (s, 2 H, NH), 6.62–
ν = 3239 cm–1 (N–H), 3113 (C–H), 2863 (C–H), 1696 (C=O), 1584, 6.69 (m, 4 H, Ar-H), 6.75–6.85 (m, 2 H, Ar-H), 8.74 (t, 3J = 6.2 Hz,
˜
1
1443, 1232, 854, 685. H NMR (300 MHz, CDCl3): δ = 0.60–0.68 2 H, CONH) ppm. 13C NMR (75.5 MHz, [D6]DMSO, APT): δ =
(m, 2 H, Cpr-H), 1.69–1.79 (m, 2 H, Cpr-H), 3.57 (s, 2 H, CH2N), 11.7 (–, Cpr-C), 33.2 (–, Cpr-C), 41.7 (–, CH2N), 110.7 (+, Ar-C),
5.95 (br. s, 1 H, NH), 7.04–7.08 (m, 2 H, Ar-H), 7.26–7.30 (m, 1
H, Ar-H) ppm. 13C NMR (50.2 MHz, CDCl3, APT): δ = 8.6 (–,
Cpr-C), 43.6 (–, Cpr-C), 47.7 (–, CH2N), 127.9 (+, Ar-C), 127.9
114.5 (+, Ar-C), 134.0 (–, Ar-C), 149.9 (–, Ar-C), 160.1 (–, CO)
ppm. MS (EI): m/z (%) = 522/520/518/516/514 (Ͻ1:2:14:27:18)
[M+], 306/304/302 (Ͻ1:6:13) [Cl2ArNHC3H4CH2NHCOCONH3+],
(+, Ar-C), 135.2 (–, Ar-C), 136.8 (–, Ar-C), 160.9 (–, CO) ppm. 304/302/300 (6:13:10) [Cl2ArNHC3H4CH2NHCOCONH+], 261/
MS (EI): m/z (%) = 260/258/256 (3:23:40) [M+], 216/214/212 259/257 (2:9:16) [Cl2ArNHC3H4CH2NHCO+], 219/217/215
(2:9:14), 180/178 (9:34) [ClArNC3H4CH2+], 149/147/145 (2:12:21) (4:29:100) [Cl2ArNHC3H4CH3+], 217/215/213 (29:100:100)
[Cl2Ar+], 97 (71) [C3H4CH2NHCO+], 84 (100) [HNCH2C3H4NH+]. [Cl2ArNC3H4CH2+], 204/202/200 (6:45:71) [Cl2ArNHC3H4+], 180/
C11H10Cl2N2O (257.12): calcd. C 51.39, H 3.92, Cl 27.58, N 10.90;
found C 51.23, H 3.74, Cl 27.33, N 10.77. Variant B: The crude
dihydrochloride 17 [152 mg, 500 μmol; obtained from 16 (148 mg,
575 mmol) as indicated above] was dissolved in anhydrous CH2Cl2
(50 mL), treated with NEt3 (281 μL, 2.03 mmol) at 0 °C and stirred
for an additional 15 min. Carbonyldiimidazole (81.1 mg, 500 μmol)
was added at 0 °C, the resulting mixture was stirred at this temp.
for an additional 20 min, warmed to ambient temp. and stirred
for an additional 1 d. The reaction mixture was washed with H2O
(30 mL), dried and concentrated in vacuo. Column chromatog-
raphy of the residue (20 g of silica gel, 1×15 cm column, CHCl3/
MeOH, 45:1) yielded 6a (69 mg, 268 μmol, 54%) as a colorless so-
lid, m.p. 196–198 °C, Rf = 0.33.
178 (14:35) [ClArNC3H4CH2+], 166/164 (8:16) [ClArNC3H4+].
4-(3,5-Dichlorophenyl)-4,7-diazaspiro[2.5]octane-5,6-dione
(6b).
Variant A: The crude dihydrochloride 17 [152 mg, 500 μmol; ob-
tained from 16 (148 mg, 575 μmol) as indicated above] was dis-
solved in anhydrous THF (10 mL), treated at 0 °C first with NEt3
(146 μL, 1.05 μmol) and then with methyl oxalyl chloride (46 μL,
500 μmol). The resulting mixture was stirred at 0 °C for 45 min,
warmed to ambient temp. and stirred for an additional 2.5 h. Water
(0.5 mL) was added, and all volatile components were evaporated
under reduced pressure. The residue was filtered through a pad
of silica gel (8 g, eluent CHCl3/MeOH, 50:1), and the filtrate was
concentrated in vacuo to yield crude 19b (149 mg, 470 μmol) as a
yellow oil. This oxalic acid ester was dissolved in THF/H2O (4 mL/
2 mL) and the mixture cooled to 0 °C. LiOH (56 mg, 2.35 mmol)
was added in one portion, and the resulting mixture was stirred at
0 °C for 15 min, warmed to ambient temp. and stirred for an ad-
4-(3,5-Dichlorophenyl)-N-isopropyl-5-oxo-4,6-diazaspiro-
[2.4]heptane-6-carboxamide (8a): Column chromatography (25 g of
silica gel, 2×25 cm column, hexane/CHCl3, 1:3) of the residue ob-
tained from 6a (210 mg, 817 μmol), EtMgBr (817 μmol, 303 μL of ditional 1 h. The volatile components were evaporated under re-
a 2.70 m solution in Et2O) and isopropyl isocyanate (100 μL,
1.02 mmol) according to GP2 (3 h stirring) yielded 8a (267 mg,
780 μmol, 95%) as a colorless solid, m.p. 131–134 °C, Rf = 0.19. An
analytical sample was obtained by recrystallization from hexane/
duced pressure, the residue was dissolved in H2O (10 mL), and the
pH was brought to 1–2 using an aq 2 m HCl solution. The aqueous
phase was extracted with Et2O (3×20 mL), the combined organic
phases were dried and concentrated under reduced pressure to yield
the crude N-[1-(3,5-dichlorophenylamino)cyclopropylmethyl]oxal-
CH Cl . IR (KBr): ν = 3312 cm–1 (N–H), 3063 (C–H), 2976 (C–
˜
2
2
H), 2895 (C–H), 1702 (C=O), 1672 (C=O), 1569, 1543 (N–CO), amic acid (121 mg, 399 μmol). This acid was dissolved in anhy-
1
1396 (iPr) ppm. H NMR (200 MHz, CDCl3): δ = 0.52–0.60 (m, 4
drous CH2Cl2 (20 mL), treated with SOCl2 (35 μL, 479 μmol) and
H, Cpr-H), 1.17 [d, 3J = 6.0 Hz, 6 H, CH(CH3)2], 3.97 (s, 2 H, DMF (1 drop). The reaction mixture was heated under reflux for
CH2N), 4.02 [sept, J = 6.0 Hz, 1 H, CH(CH3)2], 7.03–7.10 (m, 2 2.5 h, cooled to ambient temp. and concentrated in vacuo. The re-
3
3
H, Ar-H), 7.31–7.38 (m, 1 H, Ar-H), 7.88 (br. d, J = 7.0 Hz, 1 H, sidual crude {[1-(3,5-dichlorophenylamino)cyclopropylmethyl]-
NH) ppm. 13C NMR (50.3 MHz, CDCl3, DEPT): δ = 8.8 (–, Cpr-
C), 22.9 [+, CH(CH3)2], 40.5 (Cquat, Cpr-C), 42.1 [+, CH(CH3)2],
amino}oxoacetyl chloride was taken up with anhydrous MeCN
(20 mL), the mixture treated with imidazole (68 mg, 998 μmol) and
48.7 (–, CH2N), 128.0 (+, Ar-C), 128.9 (+, Ar-C), 135.1 (Cquat, Ar- stirred at ambient temp. for 2 h and at 80 °C for an additional 16 h.
C), 135.5 (Cquat, Ar-C), 152.1 (Cquat, CO), 156.0 (Cquat, CO) ppm. The reaction mixture was cooled to ambient temp., treated with
MS (EI): m/z (%) = 345/343/341 (2:9:13) [M+], 260/258/256 H2O (0.1 mL) and concentrated under reduced pressure. Column
(9:62:100) [M+
iPrNHCO H], 232/230/228 (9:58:92) chromatography of the residue (20 g of silica gel, 1×20 column,
–
+
2256
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2005, 2250–2258

Synthesis of Spirocyclopropanated Analogues of Iprodione
FULL PAPER
CHCl3/MeOH, 20:1) yielded 6b (25 mg, 87.7 μmol, 18%) as a yel-
low oil. Variant B: The crude dihydrochloride 17 [304 mg,
1.00 mmol; obtained from 16 (296 mg, 1.15 mmol) as indicated
above] was suspended in CH2Cl2 (5 mL), the mixture treated with
an aq. 1 m NaOH solution (3.5 mL) and stirred vigorously for
5 min. The phases were separated, and the aqueous phase was ex-
tracted with CH2Cl2 (3×2 mL). The combined organic phases were
dried and concentrated to a volume of 5 mL. Boc2O (218 mg,
1.00 mmol) was added in one portion, and the reaction mixture
was stirred for 15 h. All volatile components were removed under
reduced pressure, the residue was dissolved in CH2Cl2 (8 mL), the
solution cooled to 0 °C and treated first with NEt3 (146 μL,
1.05 mmol) and then with methyl oxalyl chloride (93 μL,
1.00 mmol). The reaction mixture was warmed to ambient temp.
and stirred for 2 h. Water (0.1 mL) was added, and all volatile com-
ponents were removed under reduced pressure. The residue was
filtered through a pad of silica gel (5 g, eluent CHCl3/MeOH, 50:1),
the filtrate was concentrated under reduced pressure, and the resi-
due was taken up with CH2Cl2 (2 mL). TFA (0.2 mL) was added,
and the resulting mixture was stirred for 45 min at ambient temp.
All volatile compounds were evaporated in vacuo. A solution of
HCl (5 m solution of HCl in iPrOH) (2 mL) was added and the
reaction mixture was evaporated under reduced pressure. This op-
eration was repeated three times. The residue was dissolved in anhy-
drous MeOH (10 mL), the mixture treated with NaOMe (54 mg,
1.00 mmol) and stirred for 1 d. The reaction mixture was concen-
trated in vacuo, and the residue purified by column chromatog-
raphy (30 g of silica gel, 1.5×30 cm column, CHCl3/MeOH, 20:1)
to yield 6b (145 mg, 509 μmol, 51%) as a pale grey solid, m.p. 222–
ν = 3260 cm–1 (N–H), 3065 (C–H), 1707 (C=O), 1669 (C=O), 1583,
˜
1575, 1452, 1339, 1128, 845, 674. 1H NMR (200 MHz, [D6]
DMSO): δ = 0.60–1.00 (m, 4 H, Cpr-H), 3.82 (s, 2 H, CH2N),
7.42–7.60 (m, 3 H, Ar-H), 9.00 (br. s, 1 H, NH) ppm. 13C NMR
(50.3 MHz, [D6]DMSO, APT): δ = 10.6 (–, Cpr-C), 32.5 (–, Cpr-
C), 54.4 (–, CH2N), 123.5 (+, Ar-C), 125.9 (+, Ar-C), 133.8 (–, Ar-
C), 143.0 (–, Ar-C), 157.2 (–, CO), 157.8 (–, CO) ppm. MS (EI):
m/z (%) = 288/286/284 (10:65:100) [M+], 260/258/256 (3:23:37)
[M+ – CO], 245/243/241 (5:39:66) [M+ – CONH], 232/230/228
(2:17:28) [M+ – 2CO], 149/147/145 (2:14:22) [Cl2Ar+], 41 (72)
[C3H5+]. C12H10Cl2N2O2 (285.13): calcd. C 50.55, H 3.53, N 9.82;
found C 50.26, H 3.76, N 9.77.
7-(3,5-Dichlorophenyl)-6-ethyl-6-hydroxy-4,7-diazaspiro[2.5]octan-
5-one (21a) and 7-(3,5-Dichlorophenyl)-5-ethyl-5-hydroxy-4,7-diaza-
spiro[2.5]octan-6-one (21b): Column chromatography (15 g of silica
gel, 1×15 cm column, CHCl3) of the residue obtained from 5b
(285 mg, 1.00 mmol), EtMgBr (1.00 mmol, 370 μL of a 2.7 m solu-
tion in Et2O) and isopropyl isocyanate (122 μL, 1.25 mmol) accord-
ing to GP2 (2 h stirring) yielded a mixture of 21a and 21b (97 mg,
308 μmol, 31%) in a ratio of 6.5:1[27] as the only product. 21a and
21b: Colorless solid, R = 0.47. IR (KBr): ν = 3376 cm–1 (N–H, O–
˜
f
H), 3353 (N–H, O–H), 3083 (C–H), 2979 (C–H), 2936 (C–H), 2876
(C–H), 1676 (C=O), 1579, 1522. 1H NMR (300 MHz, CDCl3,
major isomer): δ = 0.85–0.98 (m, 4 H, Cpr-H), 1.07 (t, 3J = 7.5 Hz,
3 H, CH3), 2.92 (q, 3J = 7.5 Hz, 2 H, CH2CH3), 3.18 (s, 2 H,
CH2N), 4.50 (br. s, 1 H, OH), 6.35–6.46 (m, 2 H, Ar-H), 6.70–6.75
1
(m, 1 H, Ar-H), 7.39 (br. s, 1 H, NH) ppm. H NMR (300 MHz,
CDCl3, minor isomer): δ = 0.68–0.78 (m, 4 H, Cpr-H), 1.00–1.13
(m, 3 H, CH3), 2.85–2,95 (m, 2 H, CH2CH3), 3.65 (s, 2 H, CH2N),
6.58–6.64 (m, 2 H, Ar-H), 6.78–6.84 (m, 1 H, Ar-H) ppm. The
signal of the OH proton could not be assigned. 13C NMR
(75.5 MHz, CDCl3, APT, HSQC, major isomer): δ = 7.0 (+,
CH2CH3), 12.8 (–, Cpr-C), 30.1 (–, CH2CH3), 32.1 (–, Cpr-C), 51.4
(–, CH2N), 110.6 (+, Ar-C), 116.9 (+, Ar-C), 135.4 (–, Ar-C), 149.5
(–, Ar-C), 161.7 (–, COH), 199.4 (–, CO) ppm. 13C NMR
(75.5 MHz, CDCl3, APT, HMQC, minor isomer): δ = 7.0 (+,
CH2CH3), 11.1 (–, Cpr-C), 30.1 (–, CH2CH3), 34.6 (–, Cpr-C), 55.3
(–, CH2N), 116.1 (+, Ar-C), 120.0 (+, Ar-C), 135.5 (–, Ar-C), 148.9
(–, Ar-C), 161.7 (–, COH), 199.4 (–, CO) ppm. MS (EI): m/z (%)
224 °C, R = 0.25. IR (KBr): ν = 3447 cm–1 (N–H), 3215 (C–H),
˜
f
1
3113 (C–H), 1689 (C=O), 1585, 1571, 1439, 1336, 1317. H NMR
(250 MHz, CDCl3): δ = 0.76–0.92 (m, 2 H, Cpr-H), 0.92–1.05 (m,
2 H, Cpr-H), 3.57 (s, 2 H, CH2N), 7.00–7.10 (m, 2 H, Ar-H), 7.32–
7.40 (m, 1 H, Ar-H), 8.20 (br. s, 1 H, NH) ppm. 13C NMR
(50.3 MHz, CDCl3, APT): δ = 11.2 (–, Cpr-C), 40.8 (–, Cpr-C),
48.1 (–, CH2N), 126.9 (+, Ar-C), 128.8 (+, Ar-C), 135.6 (–, Ar-C),
137.8 (–, Ar-C), 158.77 (–, CO), 158.84 (–, CO) ppm. MS (EI):
m/z (%) = 288/286/284 (2:19:27) [M+], 260/258/256 (1:14:18) [M+
–
CO], 245/243/241 (1:12:20) [M+ – CONH], 217/215/213 (3:22:37)
[Cl2ArNC3H4CH2+], 180/178 (26:100) [ClArNC3H4CH2+], 163/
161/159 (17:40:56) [Cl2ArN+], 149/147/145 (4:27:44) [Cl2Ar+], 112
(30) [HNC3H4CH2NHCO+], 111/109 (13:34), 97 (39)
[C3H4CH2NHCO+], 84 (54) [HNC3H4CH2NH+].
=
318/316/314 (7:61:100) [M+], 261/259/257 (8:50:77) [M+
–
C3H5O], 233/231/229 (1:14:22) [M+ – CO – C3H5O], 178/176/174
(10:18:33) [Cl2ArNCH3+], 96 (33), 57 (35) [C3H5O+].
Acknowledgments
7-(3,5-Dichlorophenyl)-4,7-diazaspiro[2.5]octane-5,6-dione (5b): To a
solution of compound 12 (1.32 g, 4.00 mmol) in CH2Cl2 (8 mL),
kept at 0 °C was added first NEt3 (582 μL, 4.20 mmol) and then
methyl oxalyl chloride (368 μL, 4.00 mmol). The reaction mixture
was warmed to ambient temp. and stirred for 2 h. H2O (0.2 mL)
was added and all volatile compounds were evaporated in vacuo.
The residue was filtered through silica gel (15 g, 2×15 cm, CHCl3/
MeOH, 50:1), and the filtrate was concentrated under reduced
pressure. The residue was taken up in CH2Cl2 (5 mL), the mixture
cooled to 0 °C, then treated with TFA (1 mL) and HCl (2 mL each
portion) according to GP1. The residue was dissolved in anhydrous
MeOH (40 mL), treated with NaOMe (432 mg, 8.00 mmol) and the
mixture stirred at ambient temp. for 1 d. After evaporation of all
volatile components, H2O (15 mL) and CH2Cl2 (15 mL) were
added. The resulting two-phase suspension was stirred for 10 min,
filtered off, and the filtrate was concentrated under reduced pres-
sure. The residue was dissolved in CH2Cl2 (5 mL), the mixture co-
oled to 0 °C and filtered again. The combined precipitates were
dried with P4O10 in vacuo overnight to furnish 5b (758 mg,
2.66 mmol, 66%) as a colorless solid, m.p. 244–246 °C. IR (KBr):
This work was supported by the State of Niedersachsen, Bayer
CropScience AG and the Fonds der Chemischen Industrie. The au-
thors are grateful to Chemetall GmbH for generous gifts of chemi-
cals, and particularly to Dr. B. Knieriem, Göttingen, for his careful
proofreading of the final manuscript. F. B. is indebted to Dr. S. I.
Kozhushkov and Dr. A. Leonov for helpful discussions and practi-
cal advice.
[1] a) The Chemistry of the Cyclopropyl Group (Ed.: Z. Rappo-
port), Wiley, Chichester, 1987; b) Carbocyclic Three-Mem-
bered Ring Compounds, Methods of Organic Chemistry
(Houben-Weyl), vol. E17a–c (Ed.: A. de Meijere), Thieme,
Stuttgart, 1997.
[2] a) C. J. Suckling, Angew. Chem. 1988, 100, 555–570; Angew.
Chem. Int. Ed. Engl. 1988, 27, 537–552; b) S. Abele, P. Seiler,
D. Seebach, Helv. Chim. Acta 1999, 82, 1559–1571; See also:
c) J.-F. Tocanne, Tetrahedron 1972, 28, 389–416; d) M. Pelissier,
A. Serafini, J. Devanneaux, J.-F. Labarre, J.-F. Tocanne, Tetra-
hedron 1971, 27, 3271–3284.
Eur. J. Org. Chem. 2005, 2250–2258
www.eurjoc.org
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2257

F. Brackmann, M. Es-Sayed, A. de Meijere
FULL PAPER
[3] Reviews: a) J. Salaün, M. S. Baird, Curr. Med. Chem. 1995, 2,
511–542; b) J. Salaün, Top. Curr. Chem. 2000, 207, 1–67; c) J.
Pietruszka, Chem. Rev. 2003, 103, 1051–1070; d) L. A.
Wessjohann, W. Brandt, T. Thiemann, Chem. Rev. 2003, 103,
1625–1647.
M. S. Pampulla, M. R. Schott, R. Chen, J. Med. Chem. 1994,
37, 3561–3578.
[16] a) U. Valcavi, A. Brandt, G. B. Corsi, S. Innocenti, F. Minoja,
G. Pascucci, Il Farmaco 1980, 35, 563–572; b) I. Tapia, L.
Alonso-Cires, P. L. López-Tudanca, R. Mosquera, L. Labeaga,
A. Innerárity, A. Orjales, J. Med. Chem. 1999, 42, 2870–2880;
c) W. H. Pirkle, K. A. Simmons, J. Org. Chem. 1983, 48, 2520–
2527.
[17] M. Shi, Y.-M. Shen, Heteroatom Chem. 2001, 12, 610–616.
[18] a) F. Y. Kwong, A. Klapars, S. L. Buchwald, Org. Lett. 2002,
4, 581–584; b) M. Wolter, G. Nordmann, G. E. Job, S. L. Buch-
wald, Org. Lett. 2002, 4, 973–976.
[4] T. Fujita, J. Med. Chem. 1973, 16, 923–930.
[5] a) D. M. Campoli-Richards, J. P. Monk, A. Price, P. Benfield,
P. A. Todd, A. Ward, Drugs 1988, 35, 373–447; b) R. Wise,
J. M. Andrews, L. J. Edwards, Antimicrob. Chemoter. 1983, 23,
559–564.
[6] a) K. E. Brighty, WO Patent 91/02526, 1991; EU Patent
413,455, 1991, Chem. Abstr. 1991, 115, 232216; b) K. E.
Brighty, US Patent 5,164,402, 1992, Chem. Abstr. 1993, 119,
117227; c) K. E. Brighty, M. J. Castaldi, Synlett 1996, 1097–
1099; d) E. Vilsmaier, T. Goerz, Synthesis 1998, 739–744.
[7] Recent Advances in the Chemistry of Insect Control (Ed.: N. F.
Janes), Royal Society of Chemistry, London, 1985.
[8] a) M. Sauli (Rhône–Poulenc S. A.), Ger. Offen 2,149,923, 1972,
Chem. Abstr. 1972, 77, 19647; b) Rhône–Poulenc S. A., FR
Patent 2,148,868, 1973, Chem. Abstr. 1973, 79, 78805; c) L.
Lacroix, M. Laurent, M. Buys in Anal. Methods Pestic. Plant
Growth Regul. (Ed.: G. Zweig), Academic Press 1980, 11, 247–
261.
[19] a) R. Bolton, C. Moore, J. P. B. Sandall, J. Chem. Soc. Perkin
Trans. 2 1982, 1593–1598; b) A. Ohno, A. Tsutsumi, N. Yama-
zaki, M. Okamura, Y. Mikata, M. Fujii, Bull. Chem. Soc. Jpn.
1996, 69, 1679–1685.
[20] The composition of this mixture was estimated by integrating
1
the signals in the H-NMR spectrum.
[21] Reviews: a) O. Mitsunobu, Synthesis 1981, 1–28; b) D. L.
Hughes, Org. React. 1992, 42, 335–656; c) D. L. Hughes, Org.
Prep. Proced. Int. 1996, 28, 127–164.
[22] H. Wolff, Org. React. 1947, 3, 307–336.
[23] H. Bayley, D. N. Standring, J. R. Knowles, Tetrahedron Lett.
1978, 3633–3634.
[24] a) H.-J. Knölker, T. Braxmeier, G. Schlechtingen, Angew. Chem.
1995, 107, 2746–2749; Angew. Chem. Int. Ed. Engl. 1995, 34,
2497–2500; b) H.-J. Knölker, T. Braxmeier, Tetrahedron Lett.
1998, 39, 9407–9410.
[9] P. Jeschke, K. Moriya, R. Lantzsch, H. Seifert, W. Lindner, K.
Jelich, A. Göhrt, M. E. Beck, W. Etzel, Pflanzenschutz-Nach-
richten Bayer 2001, 54, 147–160.
[10] F. Brackmann, D. S. Yufit, J. A. K. Howard, M. Es-Sayed, A.
de Meijere, Eur. J. Org. Chem. 2004, 600–609.
[11] a) A. de Meijere, Angew. Chem. 1979, 91, 867–884; Angew.
Chem. Int. Ed. Engl. 1979, 18, 809–826; b) Methods of Organic
Chemistry (Houben-Weyl), vol. E 17c (Ed.: A. de Meijere), Thi-
eme, Stuttgart, 1997.
[12] a) Z. Hell, Z. Finta, W. Dmowski, F. Faigl, Yu. M. Pustovit,
L. Toke, V. Harmat, J. Fluorine Chem. 2000, 104, 297–302; b)
Y. Kimura, S. Atarashi, M. Takahashi, I. Hayakawa, Chem.
Pharm. Bull. 1994, 42, 1442–1454; c) T. N. Wheeler, J. A. Ray,
Synth. Commun. 1988, 18, 141–150; d) M. P. Wentland, R. B.
Perni, P. H. Dorff, J. B. Rake, J. Med. Chem. 1988, 31, 1694–
1697; e) J. S. Kiely, M. C. Schroeder, J. C. Sesnie, J. Med. Chem.
1988, 31, 2004–2008.
[13] C. Pérollier, J. Pécaut, R. Ramasseul, J.-C. Marchon, Bull. Soc.
Chim. Fr. 1997, 134, 517–523.
[14] K. Kawakami, H. Takahashi, H. Ohki, K. Kimura, S. Miyau-
chi, R. Miyauchi, M. Takemura, Chem. Pharm. Bull. 2000, 48,
1667–1672.
[25] a) G. Hervé, H. Bernard, L. Toupet, H. Handel, Eur. J. Org.
Chem. 2000, 33–36; b) F. Bellouard, F. Chuburu, N. Kervarec,
L. Toupet, S. Triki, Y. Le Mest, H. Handel, J. Chem. Soc. Per-
kin Trans. 1 1999, 3499–3506; c) U. T. Mueller-Westerhoff, M.
Zhou, J. Org. Chem. 1994, 59, 4988–4992.
[26] E. E. Korshin, L. I. Sabirova, T. A. Ziablikova, I. E. Isamaev,
Y. A. Levin, Russ. Chem. Bull. 1994, 43, 439–444.
[27] The assignment of the regioisomers is uncertain.
[28] a) B. E. Blass, M. Drowns, C. L. Harris, S. Liu, D. E. Portlock,
Tetrahedron Lett. 1999, 40, 6545–6547; b) J. Yamawaki, T.
Ando, Chem. Lett. 1979, 755–758.
[29] For other preparations of this acid see ref. [11c] and also: a)
M. Suzuki, E. E. Gooch, C. H. Stammer, Tetrahedron Lett.
1983, 24, 3839–3840; b) P. Aufranc, J. Ollivier, A. Stolle, C.
Bremer, M. Es-Sayed, A. de Meijere, J. Salaün, Tetrahedron
Lett. 1993, 34, 4193–4196; c) M. C. Pirrung, J. Cao, J. Chen, J.
Org. Chem. 1995, 60, 5790–5794; d) M. Kordes, H. Winsel, A.
de Meijere, Eur. J. Org. Chem. 2000, 3235–3245.
[15] A. B. Reitz, M. G. Goodman, B. L. Pope, D. C. Argentieri,
S. C. Bell, L. E. Burr, E. Chourmouzis, J. Come, J. H. Good-
man, D. H. Klaubert, B. E. Maryanoff, M. E. Mc Donnell,
Received: August 23, 2004
(publication delayed at authors’ request)
2258
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2005, 2250–2258