Synthesis of spirocyclopropanated analogues of imidacloprid and thiacloprid

Article abstract of DOI:10.1002/ejoc.200400599

tert-Butyl N-[1-(hydroxymethyl)cyclopropyl]carbamate (8) was converted into spirocyclopropanated analogues 14-CP and 14-CT of the insecticide Thiacloprid (2) in six simple steps with overall yields of 24 % each, along with their regioisomers 13-CP and 13-CT in overall yields of 17 and 15 %, respectively. The spirocyclopropanated analogues 27-CP and 27-CT of the insecticide Imidacloprid (1) were prepared from 8 in five steps in an overall yield of 10 % each, along with their regioisomers 20-CP and 20-CT in an overall yield of 8 and 7 %, respectively. The key step in all preparations was a cocyclization of an appropiately protected (1-aminocyclopropyl)methyl derivative with S,S-dimethyl cyanodithioimino-carbonate (11) or nitroguanidine (22). The structures of several final products and by-products were verified by X-ray crystal structure analyses.

Full text of DOI:10.1002/ejoc.200400599

FULL PAPER
Synthesis of Spirocyclopropanated Analogues of Imidacloprid and
Thiacloprid[‡]
Farina Brackmann,[a] Dmitrii S. Yufit,[b] Judith A. K. Howard,[b] Mazen Es-Sayed,[c] and
Armin de Meijere*[a]
Keywords: Cyclopropanes / Pesticides / Ring contraction / Spiro compounds / Structure elucidation
tert-Butyl N-[1-(hydroxymethyl)cyclopropyl]carbamate (8)
was converted into spirocyclopropanated analogues 14-CP
and 14-CT of the insecticide Thiacloprid (2) in six simple
steps with overall yields of 24 % each, along with their re-
gioisomers 13-CP and 13-CT in overall yields of 17 and 15 %,
respectively. The spirocyclopropanated analogues 27-CP and
27-CT of the insecticide Imidacloprid (1) were prepared from
8 in five steps in an overall yield of 10 % each, along with
their regioisomers 20-CP and 20-CT in an overall yield of 8
and 7 %, respectively. The key step in all preparations was a
cocyclization of an appropiately protected (1-aminocyclopro-
pyl)methyl derivative with S,S-dimethyl cyanodithioimino-
carbonate (11) or nitroguanidine (22). The structures of sev-
eral final products and by-products were verified by X-ray
crystal structure analyses.
particularly useful in horticulture as well as in modern crop
protection systems.
Introduction
The relatively new non-natural insecticide Imidacloprid
(1) is the first chloronicotinyl insecticide (CNI)™ which
consists of the 2-(N-nitroimino)imidazolidine building
block coupled with a (6-chloropyridin-3-yl)methyl (CPM)
residue. Imidacloprid (1) was introduced to the market in
1991 and has become one of the most effective and widest
used insecticides worldwide in crop protection and veteri-
nary pest control in the last decade.[1] Encouraged by this
success, numerous analogues have been synthesized.[2] The
second example is the chloronicotinyl insecticide Thiaclop-
rid (2) which contains a (N-cyanoimino)thiazolidine group.
Thiacloprid (2) encompasses high insecticidal activity with
a favorable ecobiological profile and safety to bees. It is
In order to study the influence of spirocyclopropane-an-
nelation on the saturated heterocycle upon the biological
activities of these compounds, we have elaborated a syn-
thetic approach to spirocyclopropanated analogues of 1 and
2, and this paper summarizes our results.
Results and Discussion
The first goal was to develop a synthetic strategy which
offers a regioselective access to spirocyclopropanated ana-
logues 3 and 7 of Imidacloprid (1) and Thiacloprid (2)
(Scheme 1).
[‡]
Cyclopropyl Building Blocks in Organic Synthesis, 106. Part
105: A. P. Molchanov, V. V. Diev, J. Magull, D. Vidovic, S. I.
Kozhushkov, A. de Meijere, R. R. Kostikov, Eur. J. Org. Chem.
2005, 593–599. Part 104: M. Schelper, A. de Meijere, Eur. J.
Org. Chem. 2005, 582–592.
[a]
Institut für Organische und Biomolekulare Chemie der Georg-
August-Universität Göttingen,
Tammannstrasse 2, 37077 Göttingen, Germany
Fax: (internat.) +49-551-399475
E-mail: Armin.deMeijere@chemie.uni-goettingen.de
[b]
Department of Chemistry, University of Durham,
Durham, South Rd., DH1 3LE, England
[c]
Scheme 1. Retrosynthetic considerations concerning spirocyclopro-
panated analogues 3 and 7 of Imidacloprid (1) and Thiacloprid (2).
Bayer CropScience AG,
Alfred-Nobel-Strasse 50, 40789 Monheim, Germany
600
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/ejoc.200400599
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Synthesis of Spirocyclopropanated Analogues of Imidacloprid and Thiacloprid
FULL PAPER
The crucial point of this strategy is the appropriate (chloromethyl)pyridine (CCMP) required a longer reaction
choice of the building block 4, which should allow one to time (2 d) and elevated temperature (70 °C). Surprisingly,
selectively functionalize each of the two nitrogen atoms two isomeric products 13 and 14 in a ratio of about 1:1.5
(when X = N) or transform the functional group X into a were formed in both cases (Scheme 2) They could, however,
sulfur-containing group, respectively, before cyclization be separated by preparative thin layer chromatography.
with 5 followed by alkylation with 6. tert-Butyl N-[1-
By X-ray analyses of the chlorothiazole-substituted pro-
(hydroxymethyl)cyclopropyl]carbamate (8), which can be ducts 13-CT and 14-CT (Figure 1) they were proved to be
synthesized in three steps (40 % overall yield) from N,N- the regioisomers resulting from alkylation either on the
dibenzyl-2-benzyloxyacetamide[3] starting with its reductive amino function of the heterocycle (major compounds, 14-
cyclopropanation (the de Meijere variant of the so-called CP, 14-CT) or on the nitrogen atom of the imino function
Kulinkovich reaction[4]) was chosen as an appropriate start- (minor compounds, 13-CP, 13-CT).
ing material. Compound 8 can also be prepared in 56 %
overall yield by monohydrolysis[5a] of commercially avail-
able diethyl cyclopropane-1,1-dicarboxylate followed by
Curtius degradation[5b,5c] of the carboxylic acid residue and
subsequent reduction[5d,5e] of the ester moiety.
Spirocyclopropanated Analogues of Thiacloprid (2)
Towards the conversion of the N-Boc-protected (1-
aminocyclopropyl)methanol 8 into the spirocyclopropan-
ated analogues 14-CP and 14-CT of Thiacloprid (2), the
hydroxy function of 8 was transformed into the mesylate,
and this was substituted by thioacetic acid according to an
established procedure[6] to yield the thioester 9. The latter
was hydrolyzed using potassium carbonate[6] to furnish the
thiol 10. Deprotection of the amino group required heating
of 10 in 6 n aqueous hydrochloric acid under reflux to
cleave the intermediately formed tert-butyl thioether. Subse-
quent cyclization of the crude product with S,S-dimethyl
cyanodithioiminocarbonate (11) adopting a published pro-
tocol[7] afforded the heterocycle 12. Whereas alkylation of
the latter with 2-chloro-5-(chloromethyl)thiazole (CCMT)
under basic conditions succeeded upon stirring the reaction
mixture at 50 °C overnight, the reaction with 2-chloro-5-
Figure 1. Structures of the chlorothiazole-substituted 6-thia-4-aza-
spiro[2.4]heptanes 13-CT and 14-CT in the crystals.[8]
The overall yields of the spirocyclopropanated analogues
of Thiacloprid 14-CP and 14-CT were 24 % over six steps
in each case.
Spirocyclopropanated Analogues of Imidacloprid (1)
The transformation of the N-Boc-protected (1-amino-
cyclopropyl)methanol 8 into spirocyclopropanated ana-
logues 19 and 20 of Imidacloprid (1) was performed follow-
ing essentially the same logic as in the previous case
(Scheme 3). The hydroxy function of 8 was first converted
into an azido group by a Mitsunobu reaction[9] using hydra-
zoic acid as the nucleophile. The Boc group could be re-
moved from the resulting azide 15, and the deprotected am-
ine was alkylated under iodide catalysis at 50 °C for 1 d
with CCMP or CCMT, respectively, to yield the precursors
16-CP and 16-CT with an alkylated nitrogen on the three-
membered ring in 69 and 72 % yield, respectively. However,
after reduction of the azido to amino groups in 16-CP and
16-CT applying a Staudinger reaction,[10] the attempted
cyclizations with S,S-dimethyl cyanodithioiminocarbonate
(11) adopting a published protocol[11] (EtOH, 90 °C, 2 d)
only led to decomposition of the starting material. Another
Scheme 2. Synthesis of spirocyclopropanated analogues 14-CP and
14-CT of Thiacloprid (2).
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F. Brackmann, D. S. Yufit, J. A. K Howard, M. Es-Sayed, A. de Meijere
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portion of the N-Boc-protected primary amine obtained droxide and one equivalent of 11 in anhydrous EtOH at
from the azide 15 by reduction with triphenylphosphane 70 °C for 1.5 d gave a mixture of two products, which could
was alkylated with CCMP or CCMT on its amino group in not be separated by column chromatography. Slow evapora-
the α-position of the cyclopropane moiety. To prevent the tion of some solvent from a solution of this mixture in hex-
formation of undesired dialkylamino derivatives (cf.[12]), ane/Et2O produced two types of crystals, which could be
slightly substoichiometric amounts of CCMP or CCMT, picked apart. X-ray crystal structure analyses of these crys-
respectively, were used in these reactions. While only de- tals proved that the plate-like was the target product 19-CT,
composition of the starting material was observed at 70 °C, the wedge-like was the spirocyclic urea derivative 21-CT,
the alkylation proceeded smoothly at 50 °C, and gave only respectively (Figure 2).
the monoalkylated products 17-CP and 17-CT in 69 and
Table 1. Cocyclizations of 1-(aminomethyl)cyclopropylamines 18-
CP(CT) with S,S-dimethyl cyanodithioiminocarbonate (11) and
nitroguanidine (22). Compound 22 contained up to 20 % of water,
if not otherwise specified.
72 % yield, respectively (Scheme 3). In this case, the alky-
lation with CCMP required a longer reaction time (3 d)
than the alkylation with CCMT (1 d).
En-
try
Start-
ing ma- gent
terial
Rea-
Conditions
Product / Yield (%)
1
2
3
4
18-CP 11
18-CT 11
18-CT 11
18-CT 11
NEt3, EtOH, 19-CP / 0 21-CP / 0
80 °C, 3 d
KOH, EtOH, 19-CT / 25 21-CT / 36
125 °C, 2 d
NEt3, EtOH, 19-CT / 55 21-CT / 14
80 °C, 2.5 d[a]
NEt3, EtOH, 19-CT / 35 21-CT / 9
mol. sieves
4 Å,
80 °C, 1 d
5
18-CT 11
NEt3, DMF,
mol. sieves
4 Å, 100 °C, 2
d
19-CT /
Ͻ30
21-CT /
Ͻ10
6
7
8
18-CT 22
18-CT 22
18-CT 22
KOH, H2O,
100 °C, 2 d
KOH, H2O,
150 °C 5 d[a]
20-CT / 0 21-CT / 0
20-CT / 0 21-CT / 44
NEt3, MeCN/ 20-CT / 0 21-CT / 0
EtOH, 85 °C,
3 d[b]
[a]
[b]
The reaction was performed in a tightly screwed Pyrex tube.
Anhydrous nitroguanidine (22) was used.
The crystal of 19-CT contained two crystallographically
independent molecules, with virtually identical geometrical
parameters, but different orientations of the CT groups [the
corresponding SCCN torsional angles are to –96.1(1) and
56.0(2)° in the two independent molecules]. Whereas the
molecules of 13-CT and 14-CT in the crystals are connected
by a number of weak C–H···N(nitroamide) interactions (the
shortest H···N distances are in the range of 2.4–2.6 Å), the
Scheme 3. Preparation of substituted 1-aminocyclopropylmethyl
derivatives 16-CP(CT) as well as 18-CP(CT) and cyclizations of
the latter with S,S-dimethyl cyanodithioiminocarbonate (11) and
nitroguanidine (22).
Deprotection of the cyclopropylamino moiety in 17 with molecules of 19-CT and 21-CT are linked by hydrogen
trifluoroacetic acid (TFA) followed by treatment with hy- bonds. A pair of N–H···N(nitroamide) hydrogen bonds
drogen chloride in ethyl acetate led to the amines 18-CP [N···N 2.858(2), 2.980(2)Å, N–H···N 167(2), 168(2)°] com-
and 18-CT with a free primary amino group at the cyclo- bines independent molecules of 19-CT in dimers, and N–
propane ring. These compounds were used directly in the H···O hydrogen bonds [N···O 2.871(3)Å, N–H···O 170(3)°]
subsequent cocyclization reactions.
link the molecules of 21-CT in chains, orientated parallel to
Surprisingly, the cocyclizations of 18-CP(CT) with S,S- the b-axis.
dimethyl cyanodithioiminocarbonate (11) and nitroguani-
1H NMR spectra disclosed that 19-CT and 21-CT were
dine (22) differed significantly from known analogous reac- formed as a 1:1.4 mixture, which corresponds to yields of
tions of similar substrates, but without a 1,1-disubstituted 25 and 36 %, respectively (Entry 2). The urea derivative 21-
cyclopropane moiety (cf.[11]). Thus, an attempted cocycliza- CT must arise from hydrolysis of the imino moiety in 19-
tion of 18-CP with 11 failed completely (Table 1, Entry 1). CT during the course of the reaction or upon work-up in-
Stirring of 18-CT with two equivalents of potassium hy- cluding column chromatography. Switching from potassium
602
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Synthesis of Spirocyclopropanated Analogues of Imidacloprid and Thiacloprid
FULL PAPER
Since the (1-aminocyclopropyl)methanethiol generated
by deprotection of 10 could successfully be cocyclized with
11, an analogous reaction with the (aminocyclopropyl)-
methylamine 23 prepared from the N-Boc-protected (1-
aminocyclopropyl)methyl azide 15 in two simple steps, i.e.
hydrogenolysis under palladium catalysis followed by Boc
removal (Scheme 4) was attempted. Cocyclization with S,S-
dimethyl cyanodithioiminocarbonate (11) or aqueous nitro-
guanidine (22) furnished the spirocyclopropanated cyclic
guanidines 24 and 25 as the sole products in 50 and 28 %
yield, respectively, over three steps. Although the reaction
was performed in water, no products resulting from hydrol-
ysis of the imino group were detected.
Figure 2. Structures of the spirocyclopropanated analogue 19-CT
of Imidacloprid (1) and the spirocyclic urea derivative 21-CT in the
crystals.[8]
hydroxide to anhydrous triethylamine increased the yield of
19-CT to 55 %, yet, the undesired urea derivative 21-CT
was still formed in 14 % yield (Entry 3). Carrying out the
reaction in the presence of molecular sieves 4 Å decreased
the general yield, but the proportion of 19-CT : 21-CT was
almost the same as in the previous case (ca. 3.9:1, Entry 4).
Even more discouraging were the attempted cocycliza-
tions of 18-CP(CT) with nitroguanidine (22). Not only did
18-CP not react with 22 under different conditions, but the
heating of 18-CT with one equivalent of water-containing
22 and two equivalents of potassium hydroxide in water
also did not cause any transformation within two days (En-
try 6). Stirring of this reaction mixture at elevated tempera-
ture in a tightly screwed Pyrex tube for 5 d gave the urea
21-CT in 44 % yield as the sole product (Entry 7), but no
reaction was observed when the cocyclization was at-
tempted under anhydrous conditions (anhydrous triethyl-
amine and anhydrous nitroguanidine (22) in a mixture of
MeCN/EtOH, Entry 8).
Scheme 4. Preparation of spirocyclopropanated heterocycles 24, 25
and their N-alkylation with CCMP or CCMT.
N-Alkylations of the spirocyclic nitroguanidine 25 with
It is rather difficult to understand, why analogously sub- CCMP or CCMT, respectively, yielded mixtures of two iso-
stituted diamines, but without a 1,1-disubstituted cyclopro- meric products each in ratios of about 1:1.3, and in both
pane moiety, enter the cocyclization reactions with S,S-di- cases they could not be separated by column chromatogra-
methyl cyanodithioiminocarbonate (11) and with nitrogua- phy. Applying two-dimensional NMR spectroscopy
nidine (22),[11] but amines derived from 16-CP(CT) as well (HSQC, HMQC, NOE), these products were identified as
as 18-CP(CT) react to a small extent only or not at all. the regioisomers 27-CP(CT) and 20-CP(CT) resulting from
While the former failure may be due to low thermal stability alkylation of the two secondary amino functions. In con-
of diamines from 16-CP(CT), the low reactivity of 18- trast to the alkylation of the thiazolidine derivative 12, no
CP(CT) must be associated with the decrease of the nucleo- alkylation of the imino function was observed in the cases
philicity of its free amino group because of the significantly of 24 and 25. Analogous alkylations of the spirocyclic cya-
lower basicity of a cyclopropyl compared to a normal sec- noguanidine 24 gave mixtures of three chromatographically
alkylamine.[13] It is conceivable, that this decrease of basic- non-separable products, two-dimensional NMR spec-
ity of a nitrogen atom adjacent to a cyclopropane moiety troscopy of which revealed the two pairs of regioisomers
in the products 19-CT, 20-CT at the same time increases 26-CP(CT) and 19-CP(CT) (resulting from alkylation of the
the electrophilicity of the imino moiety and makes it par- different amino groups) as well as the twofold alkylation
ticularly susceptible to nucleophilic attack by water.
products 28-CP(CT). As in the previous cases, no products
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F. Brackmann, D. S. Yufit, J. A. K Howard, M. Es-Sayed, A. de Meijere
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ditional 19 h. The solvent was evaporated under reduced pressure,
water (60 mL) was added to the residue, and the aqueous layer was
extracted with EtOAc (3 × 60 mL). The combined organic extracts
were dried and concentrated under reduced pressure. The residue
was taken up with MeCN (90 mL), the mixture stirred with cesium
carbonate (6.78 g, 20.8 mmol) and thioacetic acid (1.58 g,
20.8 mmol) at 65 °C for 1 h, cooled to 25 °C, and the solvents evap-
orated under reduced pressure. Water (90 mL) was added, and the
aqueous layer was extracted with EtOAc (3 × 100 mL). The com-
bined organic phases were dried and concentrated under reduced
pressure. Recrystallization of the residue from hexane/Et2O yielded
resulting from alkylation of the imino function were formed
(Scheme 4).[14] The final separation and purification of
these compounds for biological testing was carried out by
preparative HPLC.[15]
Conclusions
The newly developed route to spirocyclopropanated ana-
logues of the chloronicotinyl insecticides Imidacloprid (1)
and Thiacloprid (2) led to numerous products of potentially
high biological activity. Further evaluation of the biological
potential of the described compounds is in progress.
9 (2.97 g, 61 %) as pale yellow needles, m.p. 89–90 °C. IR (KBr): ν
˜
= 3363 cm–1 (N–H), 3083 (C–H), 2992 (C–H), 2972 (C–H), 2934
(C–H), 1687 (C=O), 1508 (H–NCO), 1366 (tBu), 1254 (tBu), 1169
(O–tBu). 1H NMR (250 MHz): δ = 0.69–0.92 (m, 4 H, Cpr-H),
1.42 [s, 9 H, C(CH3)3], 2.33 (s, 3 H, CH3), 3.17 (s, 2 H, CH2S), 4.98
(br. s, 1 H, NH) ppm. 13C NMR (62.9 MHz, DEPT): δ = 14.7 (–,
Cpr-C), 28.3 [+, C(CH3)3], 30.6 (+, CH3), 33.5 (Cquat, Cpr-C), 36.6
Experimental Section
General Remarks: NMR spectra were recorded with a Bruker AM
250 (250 MHz for 1H and 62.9 MHz for 13C NMR), a Varian
UNITY-300 (300 MHz for 1H and 75.5 MHz for 13C NMR) Varian
Inova 500 (500 MHz for 1H and 128 MHz for 13C NMR) or a
(–, CH2S), 79.6 [Cquat, C(CH3)3], 155.4 (Cquat, NCO), 195.2 (Cquat
,
SCO) ppm. MS (DCI): m/z (%) = 508 (Ͻ 1) [2M + NH4+], 452 (Ͻ
+
+
1) [2M + NH4 – C4H8], 391 (Ͻ 1) [2M + NH4 – H2NCO2 tBu],
264 (12) [M + NH4 + H], 263 (100) [M + NH4+], 246 (6) [M +
+
1
Varian Inova 600 (600 MHz for H and 151 MHz for 13C NMR)
H+], 207 (34) [M + NH4 – C4H8]. C11H19NO3S (245.34): calcd. C
+
instrument in CDCl3, if not otherwise specified. Proton chemical
shifts are reported in ppm relative to residual peaks of deuterated
solvents. Multiplicities were determined by DEPT (Distortionless
Enhancement by Polarisation Transfer) or APT (Attached Proton
Test) measurements. For the mixtures of the compounds 26, 19,
28 and 27, 20, respectively, HMBC (Heteronuclear Multiple Bond
Connectivity), HMQC (Heteronuclear Multiple Quantum Coher-
ence) and NOE (Nuclear Overhauser Effect) spectra were also mea-
53.85, H 7.81, N 5.71; found C 54.04, H 7.73, N 5.53.
tert-Butyl [1-(Mercaptomethyl)cyclopropyl]carbamate (10): K2CO3
(3.34 g, 24.2 mmol) was added in one portion to a solution of the
carbamate 9 (2.96 g, 12.1 mmol) in anhydrous, deoxygenated
MeOH (100 mL) at 0 °C. After additional stirring at this temp.
for 1 h, the solvent was evaporated under reduced pressure. Water
(60 mL) was added to the residue, and the aqueous layer was ex-
tracted with EtOAc (4 × 55 mL). The combined organic layers were
dried and concentrated under reduced pressure. Column chroma-
tography of the residue (100 g of silica gel, 4 × 20 cm column, hex-
ane/Et2O, 3:1) yielded 10 (2.27 g, 93 %) as a colorless solid, m.p.
sured. Chemical shifts refer to δ
= 0.00 ppm according to the
TMS
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. HPLC:
Kromasil 100 C18, 5 µm, 250 × 20 mm. Melting points: Büchi 510
capillary melting point apparatus, values are uncorrected. TLC:
Macherey–Nagel precoated sheets, 0.25 mm Sil G/UV254. Prepara-
tive TLC: Macherey–Nagel, silica gel G/UV254, layer thickness
0.25 mm (200 × 200 mm). Column chromatography: Merck silica
gel, grade 60, 230–400 mesh. Elemental analyses: Mikroanalyti-
sches Laboratorium des Instituts für Organische und Biomolekul-
are Chemie, Universität Göttingen. Starting materials: tert-Butyl
[1-(hydroxymethyl)cyclopropyl]carbamate (8)[3a,5] and hydrazoic
acid[16] were prepared according to previously published pro-
cedures. Anhydrous THF was obtained by distillation from sodium
benzophenone ketyl, CH2Cl2 and MeCN from P4O10, EtOH and
MeOH from magnesium, triethylamine from CaH2. S,S-Dimethyl
cyanodithioiminocarbonate (11) was dried in vacuo over P4O10 and
nitroguanidine (22) was dried in a drying oven at 110 °C for 1 h.
2-Chloro-5-(chloromethyl)thiazole (CCMT) and 2-chloro-5-(chlo-
romethyl)pyridine (CCMP) were supplied by Bayer AG, nitroguani-
dine was supplied by NIGU GmbH. All other chemicals were used
as commercially available. All operations in anhydrous solvents
were performed under a nitrogen atmosphere in flame-dried glass-
ware. Organic extracts were dried with MgSO4.
62–63 °C, R = 0.39. IR (KBr): ν = 3423 cm–1 (N–H), 3078 (C–
˜
f
H), 3005 (C–H), 2979 (C–H), 2933 (C–H), 2564 (S–H), 1707, 1683
1
(C=O), 1524 (H–NCO), 1368 (tBu), 1276 (tBu), 1177 (O–tBu). H
NMR (250 MHz, CDCl3): δ = 0.63–0.77 (m, 2 H, Cpr-H), 0.77–
3
0.91 (m, 2 H, Cpr-H), 1.41 [s, 9 H, C(CH3)3], 2.70 (d, J = 8.2 Hz,
2 H, CH2S), 5.71 (br. s, 1 H, NH) ppm. The signal of the C(CH3)3-
proton overlapped the signal of the SH-proton. 13C NMR
(62.9 MHz, CDCl3, DEPT): δ = 14.8 (–, Cpr-C), 28.3 [+, C(CH3)3],
32.5 (Cquat Cpr-C), 35.5 (–, CH2S), 79.6 (Cquat, C(CH3)3], 155.4
(Cquat, NCO) ppm. MS (DCI): m/z (%) = 424 (2) [2M + NH4+],
+
368 (Ͻ 1) [2M + NH4 – C4H8], 238 (12) [M + NH3 + NH4+], 221
(100) [M + NH4+], 204 (15) [M + H+], 182 (8) [M + NH3 + NH4
–
+
+
C4H8], 165 (30) [M + NH4 – C4H8]. C9H17NO2S (203.30): calcd.
C 53.17, H 8.43, N 6.89; found C 53.42, H 8.18, N 6.80.
Cyclizations with S,S-Dimethyl Cyanodithioiminocarbonate (11) and
Nitroguanidine (22). General Procedure 1 (GP1) for the Preparation
of Spiroheterocycles 12, 19-CT, 21-CT, 24 and 25: To the solution
of the respective starting material in EtOH or H2O was added
KOH or NEt3 as well as 11 or 22, respectively, and the resulting
mixture was stirred at the indicated temp. for the indicated time.
After cooling to ambient temp., the mixture was filtered through a
pad of Celite, concentrated under reduced pressure, and the crude
product was purified by column chromatography or preparative
thin layer chromatography on silica gel, if not otherwise specified
(see preparation of compound 25).
tert-Butyl N-[1-(Acetylthiomethyl)cyclopropyl]carbamate (9): Meth-
anesulfonyl chloride (2.75 g, 24.0 mmol) was added dropwise at
0 °C to a stirred solution of tert-butyl N-[1-(hydroxymethyl)cyclo-
propyl]carbamate (8) (3.74 g, 20.0 mmol) and NEt3 (2.43 g,
24.0 mmol) in anhydrous CH2Cl2 (100 mL). The reaction mixture
was warmed to ambient temp. and stirred at this temp. for an ad-
N-Alkylation with 2-Chloro-5-(Chloromethyl)pyridine (CCMP) or 2-
Chloro-5-(chloromethyl)thiazole (CCMT). General Procedure
2
(GP2) for the Preparation of Compounds 13, 14, 17, 19, 20, 26–29:
604
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2005, 600–609

Synthesis of Spirocyclopropanated Analogues of Imidacloprid and Thiacloprid
FULL PAPER
A mixture containing the respective starting material, CCMP or
CCMT and potassium carbonate in anhydrous MeCN was stirred
at the indicated temp. for the indicated time. After cooling to ambi-
ent temp., the mixture was filtered through a pad of Celite, concen-
trated under reduced pressure, and the crude product was purified
by column chromatography or preparative thin layer chromatogra-
phy on silica gel.
N-(2-Chlorothiazol-5-ylmethyl)-N-(6-thia-4-azaspiro[2.4]hept-4-en-
5-yl)cyanamide (13-CT) and N-[4-(2-Chlorothiazol-5-ylmethyl)-6-
thia-4-azaspiro[2.4]hept-5-ylidene]cyanamide (14-CT): Preparative
TLC (CH2Cl2/MeOH, 50:1) of the residue obtained from 12
(76.6 mg, 500 µmol), CCMT (84.0 mg, 500 µmol) and K2CO3
(276 mg, 2.00 mmol) in MeCN (10 mL) according to GP2 (50 °C,
20 h) furnished 13-CT (47.0 mg, 33 %, Rf = 0.60) and 14-CT
(76.0 mg, 53 %, Rf = 0.28) as colorless solids. 13-CT: M.p. 105–
107 °C. IR (KBr): ν = 2135 cm–1 (CϵN), 1622 (C=N), 1413, 1264,
(6-Thia-4-azaspiro[2.4]hept-5-ylidene)cyanamide (12): Carbamate 10
(470 mg, 2.31 mmol) was stirred with aq. 6 n HCl solution (20 mL)
at 85 °C for 10 h. The volatile compounds were evaporated under
reduced pressure, and the residue was treated with 11 (338 mg,
2.31 mmol) and KOH (130 mg, 2.31 mmol) in EtOH (20 mL) ac-
cording to GP1 (20 °C, 1 d). Column chromatography of the resi-
due (25 g of silica gel, 2 × 20 cm column, CH2Cl2/MeOH, 35:1)
furnished 12 (283 mg, 1.85 mmol, 80 %) as a colorless solid, m.p.
˜
1
1054. H NMR (250 MHz): δ = 0.79–0.96 (m, 2 H, Cpr-H), 1.18–
1.32 (m, 2 H, Cpr-H), 3.59 (s, 2 H, CH2S), 4.87 (s, 2 H, CH2Ar),
7.56 (s, 1 H, Ar-4-H). 13C NMR (50.3 MHz, APT): δ = 14.8 (–,
Cpr-C), 43.2 (–, Cpr-C), 46.4 (–, CH2S), 55.2 (–, CH2Ar), 110.6 (–
, CϵN), 132.1 (–, Ar-C-5), 142.3 (+, Ar-C-4), 154.3 (–, Ar-C-2),
154.8 (–, NNCS) ppm. MS (EI): m/z (%) = 286/284 (1/4) [M+],
249 (Ͻ1) [M+ – Cl], 152 (16) [M+ – CH2ArCl], 134/132 (32/100)
[CH2ArCl+], 71 (8), 45 (6), 41 (Ͻ1) [C3H5+]. HRMS (EI) calcd. for
C10H9ClN4S2 [M+] 283.9957, found 283.9957. C10H9ClN4S2
(284.78): calcd. C 42.18, H 3.19, N 19.67, Cl 12.45; found C 42.22,
140–141 °C, Rf = 0.35. IR (KBr): ν = 3134 cm–1 (N–H), 2192
˜
1
(CϵN), 2161 (CϵN), 1586 (C=N), 1413, 1071, 958, 695, 670. H
NMR (250 MHz): δ = 0.88–1.07 (m, 2 H, Cpr-H), 1.08–1.24 (m, 2
H, Cpr-H), 3.51 (s, 2 H, CH2S), 8.15 (br. s, 1 H, NH) ppm. 13C
NMR (62.9 MHz, DEPT): δ = 12.3 (–, Cpr-C), 38.3 (–, CH2S),
43.7 (Cquat, Cpr-C), 116.0 (Cquat, CϵN), 178.2 (Cquat, NNCS) ppm.
MS (EI): m/z (%) = 153 (100) [M+], 152 (70) [M+ – H], 138 (26)
[M+ – NH], 125 (11), 120 (20), 111 (14) [M+ – H2NCN], 99 (4)
H 3.43, N 19.48, Cl 12.28. 14-CT: M.p. 103–105 °C, IR (KBr): ν =
˜
3085 cm–1 (C–H), 2934 (C–H), 2194 (CN), 1558 (CN), 1521, 1055.
1H NMR (250 MHz): δ = 0.91–1.05 (m, 2 H, Cpr-H), 1.13–1.27
(m, 2 H, Cpr-H), 3.39 (s, 2 H, CH2S), 4.40 (s, 2 H, CH2Ar), 7.38
(s, 1 H, Ar-4-H) ppm. 13C NMR (50.3 MHz): δ = 9.9 (–, Cpr-C),
37.2 (–, Cpr-C), 38.8 (–, CH2S), 47.0 (–, CH2Ar), 115.9 (–, CϵN),
134.8 (–, Ar-C-5), 140.1 (+, Ar-C-4), 153.5 (–, Ar-C-2), 174.8 (–,
NNCS) ppm. MS (EI): m/z (%) = 286/284 (9/24) [M+], 249 (16)
[M+ – Cl], 152 (4) [M+ – CH2ArCl], 134/132 (36/100) [CH2ArCl+],
71 (13), 45 (10), 41 (2) [C3H5+]. HRMS (EI) calcd. for
C10H9ClN4S2 [M+] 283.9957, correct mass. C10H9ClN4S2 (284.78):
calcd. C 42.18, H 3.19, N 19.67, Cl 12.45; found C 42.31, H 3.34,
N 19.55, Cl 12.34.
[HNCSNCN+], 85 (54) [HSCNCN+], 71 (23), 68 (19) [M+
–
HSCNCN], 54 (12) [M+ – HNCSNCN], 45 (22), 41 (51). HRMS
(EI) calcd. for C6H7N3S [M+] 153.0361, correct mass. C6H7N3S
(153.20): calcd. C 47.04, H 4.61, N 27.43; found C 47.02, H 4.58,
N 27.30.
N-(6-Chloropyridine-3-ylmethyl)-N-(6-thia-4-azaspiro[2.4]hept-4-en-
5-yl)cyanamide (13-CP) and N-[4-(6-Chloropyridine-3-ylmethyl)-6-
thia-4-azaspiro[2.4]-hept-5-ylidene]cyanamide (14-CP): Preparative
TLC (CH2Cl2/MeOH, 50:1) of the residue obtained from 12
(76.6 mg, 500 µmol), CCMP (81.0 mg, 500 µmol) and K2CO3
(276 mg, 2.00 mmol) in MeCN (10 mL) according to GP2 (70 °C,
2 d) furnished 13-CP (52.0 mg, 37 %, Rf = 0.60) and 14-CP
(73.0 mg, 52 %, Rf = 0.23) as high viscous oils. 13-CP: IR (KBr):
tert-Butyl [1-(Azidomethyl)cyclopropyl]carbamate (15): Diisopropyl
azodicarboxylate (5.76 g, 28.5 mmol), hydrazoic acid (28.5 mmol,
28.5 mL of a 1.0 m solution in benzene) and a solution of carba-
mate 8 (4.68 g, 25.0 mmol) in THF (50 mL) were added one after
the other at –78 °C to a stirred solution of PPh3 (7.87 g, 30.0 mmol)
in anhydrous THF (200 mL). The reaction mixture was warmed to
ambient temp., stirred at this temp. for an additional 18 h, and
concentrated under reduced pressure. Column chromatography of
the residue (200 g of silica gel, 4 × 30 cm column, hexane/CH2Cl2/
Et2O, 4:1:1, Rf = 0.46) gave 15 (4.57 g, 86 %) as a colorless oil
which crystallized while kept at –26 °C overnight, m.p. 45–46 °C.
ν = 2223 cm–1 (CϵN), 1617 (C=N), 1462, 1264, 1103. 1H NMR
˜
(200 MHz): δ = 0.75–1.07 (m, 2 H, Cpr-H), 1.10–1.21 (m, 2 H,
3
Cpr-H), 3.55 (s, 2 H, CH2S), 4.76 (s, 2 H, CH2Ar), 7.36 (d, J =
3
4
8.3 Hz, 1 H, Ar-5-H), 7.75 (dd, J = 8.3, J = 2.6 Hz, 1 H, Ar-4-
H), 8.40 (d, 4J = 2.6 Hz, 1 H, Ar-2-H) ppm. 13C NMR (50.3 MHz,
APT): δ = 14.8 (–, Cpr-C), 43.1 (–, Cpr-C), 50.6 (–, CH2S), 55.3
(–, CH2Ar), 111.1 (–, CϵN), 124.5 (+, Ar-C-5), 128.7 (–, Ar-C-3),
139.2 (+, Ar-C-4), 150.2 (+, Ar-C-2), 152.1 (–, Ar-C-6), 154.9
(–, NNCS) ppm. MS (DCI): m/z (%) = 561/559/557 (6/25/30) [2M
+ H+], 315/313 (5/12) [M + NH3 + NH4+], 298/296 (26/67) [M +
NH4+], 281/279 (41/100) [M + H+]. HRMS (EI) calcd. for
C12H11ClN4S [M+] 278.0393, found 278.0393. C12H11ClN4S
(278.76): calcd. C 51.70, H 3.98, N 20.10, Cl 12.72; found C 51.82,
IR (KBr): ν = 3350 cm–1 (N–H), 2985 (C–H), 2937 (C–H), 2874
˜
(C–H), 2099 (N3), 1690 (C=O), 1510 (H–NCO), 1369 (tBu), 1296
1
(tBu), 1174 (O–tBu). H NMR (250 MHz): δ = 0.71–0.79 (m, 2 H,
Cpr-H), 0.81–0.88 (m, 2 H, Cpr-H), 1.43 [s, 9 H, C(CH3)3], 3.55 (s,
2 H, CH2N3), 5.08 (br. s, 1 H, NH) ppm. 13C NMR (62.9 MHz,
DEPT): δ = 12.7 (–, Cpr-C), 28.3 [+, C(CH3)3], 33.3 (Cquat, Cpr-
C), 56.9 (–, CH2N3), 79.9 [Cquat, C(CH3)3], 155.4 (Cquat, NCO)
ppm. MS (DCI): m/z (%) = 247 (10) [M + NH3 + NH4+], 230 (100)
H 4.12, N 20.01, Cl 12.79. 14-CP: IR (KBr): ν = 2162 cm–1 (CϵN),
˜
[M + NH4+], 213 (18) [M + H+], 191 (6) [M + NH4 + NH3
–
+
1
1556 (CN), 1460, 1385. H NMR (200 MHz): δ = 0.86–1.01 (m, 2
+
C4H8], 174 (28) [M + NH4 – C4H8]. C9H16N4O2 (212.25): calcd.
C 50.93, H 7.60, N 26.40; found C 51.19, H 7.69, N 26.11.
H, Cpr-H), 1.01–1.18 (m, 2 H, Cpr-H), 3.42 (s, 2 H, CH2S), 4.34
3
3
(s, 2 H, CH2Ar), 7.33 (d, J = 8.4 Hz, 1 H, Ar-5-H), 7.61 (dd, J
4
4
= 8.4, J = 2.5 Hz, 1 H, Ar-4-H), 8.19 (d, J = 2.5 Hz, 1 H, Ar-2-
H) ppm. 13C NMR (50.3 MHz, APT): δ = 9.7 (–, Cpr-C), 37.0 (–,
Cpr-C), 42.6 (–, CH2S), 47.1 (–, CH2Ar), 116.2 (–, CϵN), 124.6
N-[1-(Azidomethyl)cyclopropyl]-N-[6-chloropy-ridin-3-yl)methyl]-
amine (16-CP): Azide 15 (425 mg, 2.00 mmol) was stirred with aq.
6 n HCl solution (20 mL) at ambient temp. for 16 h. The volatile
(+, Ar-C-5), 130.4 (–, Ar-C-3), 137.9 (+, Ar-C-4), 148.1 (+, Ar-C- compounds were evaporated under reduced pressure, and the resi-
2), 151.3 (–, Ar-C-6), 175.4 (–, NNCS) ppm. MS (EI), m/z (%) =
280/278 (5/16) [M+], 152 (12) [M+ – ClArCH2+], 128/126 (32/100)
[ClArCH2+]. HRMS (EI) calcd. for C12H11ClN4S [M+] 278.0393,
correct mass. C12H11ClN4S (278.76): calcd. C 51.70, H 3.98, N
20.10; found C 51.96, H 4.20, N 19.85.
due was treated with CCMP (316 mg, 1.95 mmol), potassium iod-
ide (33.2 mg, 200 µmol, 10 mol%) and K2CO3 (1.11 g, 8.00 mmol)
in MeCN (25 mL) according to GP2 (50 °C, 1 d). Column chroma-
tography of the residue (25 g of silica gel, 2 × 20 cm column,
CH2Cl2/MeOH, 50:1, Rf = 0.25), yielded 16-CP (339 mg, 73 %), as
Eur. J. Org. Chem. 2005, 600–609
www.eurjoc.org
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
605

F. Brackmann, D. S. Yufit, J. A. K Howard, M. Es-Sayed, A. de Meijere
(1.52 mg, 5.80 mmol) and H2O (90.0 mg, 5.00 mmol) was treated
FULL PAPER
a yellow oil. IR (KBr): ν = 3326 cm–1 (N–H), 3087 (C–H), 3008
˜
(C–H), 2926 (C–H), 2854 (C–H), 2097 (N3), 1587 1567, 1457, 1252, with CCMT (823 mg, 4.90 mmol) and K2CO3 (1.03 g, 7.50 mmol)
1105, 1022, 824. 1H NMR (250 MHz): δ = 0.49–0.62 (m, 2 H, Cpr-
in MeCN (25 mL) according to GP2 (50 °C, 1 d). Column chroma-
tography of the residue (80 g of silica gel, 3 × 35 cm column,
H), 0.62–0.75 (m, 2 H, Cpr-H), 1.86 (br. s, 1 H, NH), 3.30 (s, 2 H,
3
CH2N3), 3.79 (s, 2 H, CH2Ar), 7.23 (d, J = 8.2 Hz, 1 H, Ar-5-H), CH2Cl2/MeOH, 30:1, Rf = 0.15) yielded 17-CT (908 mg, 58 %), as
4
4
7.61 (dd, 3J = 8.2, J = 2.4 Hz, 1 H, Ar-4-H), 8.27 (d, J = 2.4 Hz, a pale yellow, highly viscous oil. IR (KBr): ν = 3326 cm–1 (N–H),
˜
1 H, Ar-2-H) ppm. 13C NMR (62.9 MHz, DEPT): δ = 12.7 (–, 3089 (C–H), 3005 (C–H), 2977 (C–H), 2930 (C–H), 2821 (C–H),
Cpr-C), 38.8 (Cquat, Cpr-C), 46.5 (–, CH2N3), 55.9 (–, CH2Ar),
123.8 (+, Ar-C-5), 134.8 (Cquat, Ar-C-3), 138.7 (+, Ar-C-4), 149.1
1702 (C=O), 1502 (H–NCO), 1365 (tBu), 1250 (tBu), 1170 (O–
tBu), 1047. H NMR (250 MHz): δ = 0.56–0.70 (m, 2 H, Cpr-H),
1
(+, Ar-C-2), 149.9 (Cquat, Ar-C-6) ppm. MS (DCI): m/z (%) = 479/ 0.70–0.82 (m, 2 H, Cpr-H), 1.38 [s, 9 H, C(CH3)3], 1.79 (br. s, 1 H,
477/475 (22/83/100) [2M + H+], 257/255 (3/8) [M + NH4+], 240/238 NHAlk), 2.64 (s, 2 H, CH2Alk), 3.93 (s, 2 H, CH2Ar), 5.12 (br. s,
(18/48) [M + H+]. C10H12ClN5 (237.69): calcd. C 50.53, H 5.09, N
29.46, Cl 14.92; found C 50.29, H 5.08, N 29.29, Cl 14.92.
1 H, NHBoc), 7.28 (s, 1 H, Ar-4-H) ppm. 13C NMR (62.9 MHz,
DEPT): δ = 12.6 (–, Cpr-C), 28.2 [+, C(CH3)3], 32.8 (Cquat, Cpr-
C), 45.6 (–, CH2Alk), 54.6 (CH2Ar), 79.4 [Cquat, C(CH3)3], 137.8
(+, Ar-C-4), 142.1 (Cquat, Ar-C-5), 150.9 (Cquat, Ar-C-2), 155.8
(Cquat, NCO) ppm. MS (EI): m/z (%) = 319/317 (Ͻ1/Ͻ1) [M+], 262/
N-[1-(Azidomethyl)cyclopropyl]-N-[2-chlorothiazol-5-yl)methyl]-
amine (16-CT): Column chromatography (25 g of silica gel, 2 ×
20 cm column, CH2Cl2/MeOH, 100:1, Rf = 0.20) of the residue
obtained from the same quantities of starting material and rea-
gents, and under the same conditions as in the preceding prepara-
tion, but with CCMT (328 mg, 1.95 mmol) as alkylating agent, fur-
260 (3/5) [M+ – tBu], 233/231 (Ͻ1/4), 202/200 (Ͻ1/1) [M+
–
H2NCO2 tBu], 163/161 (2/8), 148/146 (6/14) [NCH2ArCl+], 134/132
(16/40) [CH2ArCl+], 57 (100) [tBu+], 41 (28) [C3H5+]. HRMS (EI)
calcd. for C13H20ClN3O2S [M+] 317.0365, correct mass.
C13H20ClN3O2S (317.83): calcd. C 49.13, H 6.34, N 13.22, Cl 11.15;
found C 49.42, H 6.44, N 13.12, Cl 10.77.
nished 16-CT (376 mg, 79 %), as a yellow oil. IR (KBr): ν =
˜
3316 cm–1 (N–H), 3087 (C–H), 3007 (C–H), 2920 (C–H), 2834 (C–
1
H), 2098 (N3), 1422, 1328, 1264, 1049. H NMR (250 MHz): δ =
N-[4-(2-Chlorothiazol-5-ylmethyl)]-4,6-diazaspiro[2.4]heptan-5-one
(21-CT): Carbamate 17-CT (159 mg, 500 µmol) was stirred with
TFA (0.5 mL) at ambient temp. for 1 h. All volatile components of
the reaction mixture were removed in vacuo. To the residue was
added a 5–6 m solution of HCl in iPrOH (2.5 mL), and the reaction
mixture was evaporated. This operation was repeated three times.
The crude residual dihydrochloride 18-CT was treated with 22
(65.0 mg, 500 µmol, cont. 20 % of water) and KOH (56.1 mg,
1.00 mmol) in water (10 mL) according to GP1 (150 °C, 5 d). Col-
umn chromatography (15 g of silica gel, 1 × 15 cm column, CHCl3/
MeOH, 25:1) of the residue furnished 21-CT (54 mg, 44 %, Rf =
0.45–0.64 (m, 2 H, Cpr-H), 0.64–0.77 (m, 2 H, Cpr-H), 2.07 (br. s,
1 H, NH), 3.29 (s, 2 H, CH2N3), 3.97 (s, 2 H, CH2Ar), 7.32 (s, 1
H, Ar-4-H) ppm. 13C NMR (62.9 MHz, DEPT): δ = 12.6 (–, Cpr-
C), 38.8 (Cquat, Cpr-C), 42.6 (–, CH2N3), 56.1 (–, CH2Ar), 137.5
(+, Ar-C-4), 142.0 (Cquat, Ar-C-5), 151.1 (Cquat, Ar-C-2) ppm. MS
(DCI): m/z (%) = 491/489/487 (40/100/98) [2M + H+], 377/375 (14/
18), 246/244 (21/37) [M + H+], 208 (7) [M+ – Cl]. C8H10ClN5S
(243.71): calcd. C 39.43, H 4.14, N 28.74, Cl 14.55; found C 39.36,
H 4.09, N 28.55, Cl 14.77.
tert-Butyl 1-{[(6-Chloropyridin-3-yl)methylamino]methyl}cyclopro-
pylcarbamate (17-CP): A solution of the azide 15 (425 mg,
2.00 mmol), PPh3 (609 mg, 2.00 mmol) and water (36.0 mg,
2.32 mmol) in THF (20 mL) was stirred at ambient temp. for 1 d
and then evaporated. The residue was treated with CCMP (316 mg,
1.95 mmol) and K2CO3 (415 mg, 3.00 mmol) in MeCN (25 mL)
according to GP2 (50 °C, 3 d). Column chromatography of the resi-
due (40 g of silica gel, 2 × 25 cm column, CH2Cl2/MeOH, 25:1, Rf
= 0.16) yielded 17-CP (419 mg, 69 %) as a pale yellow solid, m.p.
0.30) as a light orange solid, m.p. 110–113 °C. IR (KBr): ν =
˜
3228 cm–1 (N–H), 1700 (C=O), 1658, 1415, 1047. 1H NMR
(250 MHz): δ = 0.50–0.75 (m, 2 H, Cpr-H), 0.75–1.00 (m, 2 H,
Cpr-H), 3.33 (s, 2 H, CH2Cpr), 4.46 (s, 2 H, CH2Ar), 5.90 (br. s, 1
H, NH), 7.37 (s, 1 H, 4-Ar-H) ppm. 13C NMR (50.3 MHz, APT):
δ = 11.4 (–, Cpr-C), 35.2 (–, Cpr-C), 39.8 (–, CH2NH), 51.8 (–,
CH2Ar), 136.6 (–, Ar-C-5), 139.8 (+, Ar-C-4), 152.2 (–, Ar-C-2),
161.4 (–, NNCN) ppm. MS (DCI): m/z (%) = 508/506/504 (2/8/10)
[2M + NH4+], 491/489/487 (6/24/33) [2M + H+], 280/278 (3/7) [M
+ NH3 + NH4+], 263/261 (37/100) [M + NH4+], 246/244 (48/18)
[M + H+]. C9H10ClN3OS (243.71): calcd. C 44.36, H 4.14, N 17.24;
found. C 44.71, H 4.31, N 17.16.
68–69 °C. IR (KBr): ν = 3367 cm–1 (N–H), 3077 (C–H), 3008 (C–
˜
H), 2986 (C–H), 2970 (C–H), 2934 (C–H), 1687 (C=O), 1504 (H–
1
NCO), 1365 (tBu), 1267 (tBu), 1169 (O–tBu), 754 (Ar). H NMR
(250 MHz): δ = 0.56–0.69 (m, 2 H, Cpr-H), 0.69–0.80 (m, 2 H,
Cpr-H), 1.38 [s, 9 H, C(CH3)3], 1.66 (br. s, 1 H, NHAlk), 2.64 (s,
2 H, CH2Alk), 3.79 (s, 2 H, CH2Ar), 5.08 (br. s, NHBoc), 7.23 (d,
3J = 8.1 Hz, 1 H, Ar-3-H), 7.63 (dd, 3J = 8.1, 4J = 2.1 Hz, 1 H,
Ar-4-H), 8.28 (d, 4J = 2.1 Hz, 1 H, Ar-6-H) ppm. 13C NMR
(62.9 MHz, DEPT): δ = 12.7 (–, Cpr-C), 28.3 [+, C(CH3)3], 33.0
{N-[4-(2-Chlorothiazol-5-ylmethyl)-4,6-diazaspiro[2.4]heptan-5-ylid-
ene}cyanamide (19-CT) and N-[4-(2-Chlorothiazol-5-ylmethyl)]-
4,6-diazaspiro[2.4]heptan-5-one (21-CT): a) The crude 18-CT ob-
tained as described in the previous preparation from 17-CT (159 g,
500 µmol), was treated with 11 (73.1 mg, 500 µmol) and KOH
(56.1 mg, 1.00 mmol) in EtOH (10 mL) according to GP1 (125 °C,
2 d, tightly screwed Pyrex tube). Column chromatography of the
residue (15 g of silica gel, 1 × 15 cm column, CH2Cl2/MeOH, 25:1,
Rf = 0.30) furnished an unseperable mixture of 19-CT (33 mg, cal-
culated yield 25 %) and 21-CT (44 mg, calculated yield 36 %)[14] as
a pale yellow solid. b) The crude 18-CT obtained as described in
the previous preparation from 17-CT (159 g, 500 µmol), was treated
with 11 (73.1 mg, 500 µmol) and NEt3 (146 mL, 1.05 mmol) in
EtOH (5 mL) according to GP1 (80 °C, 2.5 d). Column chromatog-
raphy of the residue (15 g of silica gel, 1 × 15 cm column, CH2Cl2/
(Cquat, Cpr-C), 49.9 (–, CH2Alk), 55.1 (–, CH2Ar), 79.4 [Cquat
,
C(CH3)3], 123.9 (+, Ar-C-5), 134.8 (Cquat, Ar-C-3), 138.6 (+, Ar-
C-4), 149.2 (+, Ar-C-2), 149.8 (Cquat, Ar-C-6), 155.9 (Cquat, NCO)
ppm. MS (EI): m/z (%) = 313/311 (2/6) [M+], 256/254 (4/10) [M+
–
tBu], 238/236 (2/8) [M+ – H2O – tBu], 227/225 (2/8), 157/155 (6/20)
[CH2NHCH2ArCl+], 143/141 (14/30) [HNCH2ArCl+], 128/126 (15/
38) [CH2ArCl+], 86/84 (31/48), 57 (100) [tBu], 41 (16) [C3H5+].
HRMS (EI) calcd. for C15H22ClN3O2 [M+] 311.1401, correct mass.
C15H22ClN3O2 (311.81): calcd. C 57.78, H 7.11, N 13.48, Cl 11.37;
found C 57.62, H 7.19, N 13.22, Cl 11.24.
tert-Butyl 1-{[(2-Chlorothiazol-5-yl)methylamino]methyl}cyclopro- MeOH, 25:1, Rf = 0.30) furnished an unseperable mixture of 19-
pylcarbamate (17-CT): The residue obtained under the conditions
of the previous preparation from 15 (1.06 g, 5.00 mmol), PPh3
CT (73 mg, calculated yield 55 %) and 21-CT (17 mg, calculated
yield 14 %)[14] as a pale yellow solid. The spectroscopic data were
606
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2005, 600–609

Synthesis of Spirocyclopropanated Analogues of Imidacloprid and Thiacloprid
FULL PAPER
consistent with those of independently prepared 21-CT (see above)
and 19-CT (see below).
(Cquat, Ar-C-6), 161.2 (Cquat, NNCN) ppm. MS (EI): m/z (%) =
283/281 (4/14) [M+], 237/235 (16/51) [M+ – NO2], 199 (32) [M+
–
NO2 – HCl], 128/126 (32/100) [ClArCH2+]. HRMS (EI) calcd. for
(4,6-Diazaspiro[2.4]hept-5-ylidene)nitroamide (25): A solution of the
azide 15 (2.12 g, 10.0 mmol) in MeOH (10 mL) was stirred with
10 % palladium on charcoal (212 mg, 2 mol%) under hydrogen at
ambient temp. for 2.5 h. The reaction mixture was filtered through
a pad of Celite, and the filtrate was concentrated. The residue was
stirred with TFA (7 mL) at ambient temp. for 30 min. All volatile
components of the reaction mixture were removed in vacuo. The
residue was treated with a 1 m solution of HCl in iPrOH (5 mL)
and the solvents evaporated. This operation was repeated four
times. The crude residual 1-(aminomethyl)cyclopropylamine dihy-
drochloride (1.59 g, 100 %) was treated with nitroguanidine (22)
(1.35 g, 13.0 mmol) and a solution of KOH [1.12 g, 20.0 mmol as
a solution in water (2 mL)] in H2O (20 mL) according to GP1
(70 °C, 6 h). The precipitate which was formed upon cooling of the
reaction mixture was filtered off to give 25 (440 mg, 28 %) as a pale
C11H12ClN5O2 [M+] 281.0680, correct mass. 20-CP: M.p. 180–
181 °C. IR (KBr): ν = 3343 cm–1 (N–H), 1547, 1463, 1446, 1287,
˜
1269, 1190, 1131, 1108. 1H NMR (600 MHz, add. HMBC, HMQC,
NOE): δ = 0.77–0.83 (m, 2 H, Cpr-H), 1.08–1.14 (m, 2 H, Cpr-H),
3
3.49 (s, 2 H, CH2Cpr), 4.54 (s, 2 H, CH2Ar), 7.31 (d, J = 8.2 Hz,
3
4
1 H, Ar-5-Ar), 7.67 (dd, J = 8.2, J = 2.5 Hz, 1 H, Ar-4-H), 8.04
(br.s, 1 H, NH), 8.27 (d, 4J = 2.5 Hz, 1 H, Ar-2-H) ppm. 13C NMR
(151 MHz, add. HMBC, HMQC, NOE): δ = 12.3 (Cpr-C), 38.9
(Cpr-Cquat), 45.2 (CH2Cpr), 52.0 (CH2Ar), 124.7 (Ar-C-5), 129.8
(Cquat, Ar-C-3), 139.0 (Ar-C-4), 149.2 (Ar-C-2), 151.4 (Cquat, Ar-
C-6), 160.3 (Cquat, NNCN) ppm. MS (EI): m/z (%) = 283/281 (22/
67) [M+], 237/235 (23/73) [M+ – NO2], 199 (39) [M+ – NO2 – HCl],
128/126 (31/100) [ClArCH2+]. HRMS (EI) calcd. for
C11H12ClN5O2 [M+] 281.0680, correct mass.
yellow solid, m.p. 225–227 °C (decomp.). IR (KBr): ν = 3397 cm–1
[4-(2-Chlorothiazol-5-ylmethyl)-4,6-diazaspiro[2.4]hept-5-ylidene]ni-
troamide (27-CT) and [6-(2-Chlorothiazol-5-ylmethyl)-4,6-diazaspi-
ro[2.4]hept-5-ylidene]nitroamide (20-CT): [17] Column chromatogra-
phy (15 g of silica gel, 2 × 15 cm column, CHCl3/MeOH, 50:1, Rf =
0.22) of the residue prepared from 25 (315 mg, 2.02 mmol), CCMT
(339 mg, 2.02 mmol) and K2CO3 (1.12 g, 8.10 mmol) in MeCN
(20 mL) according to GP2 (70 °C, 17 h) furnished a mixture of the
two regioisomers 27-CT (238 mg, calculated yield 41 %) and 20-CT
(176 mg, calculated yield 30 %)[14] as a light brown foam. 27-CT:
˜
(N–H), 3222, 3149 (C–H), 1588 (NO2) 1553, 1476, 1364, 1298
1
(NO2), 1101. H NMR (200 MHz, [D6]DMSO): δ = 0.65–0.85 (m,
2 H, Cpr-H), 0.85–1.05 (m, 2 H, Cpr-H), 3.62 (s, 2 H, CH2), 8.50
(br. s, 2 H, NH) ppm. 13C NMR (500 MHz, [D6]DMSO): δ = 11.1
(–, Cpr-C), 39.8 (Cquat, Cpr-C), 48.3 (–, CH2), 162.0 (Cquat
,
NNCN) ppm. MS (EI): m/z (%) = 156 (20) [M+], 110 (38) [M+
–
NO2], 94 (22) [M+ – NO2 – NH2], 55 (100) [C4H7+, C3H5N+].
HRMS (EI) calcd. for C5H8N4O2 [M+] 156.0647, correct mass.
M.p. 175–176 °C. IR (KBr): ν = 3304 cm–1 (N–H), 1565, 1547,
˜
1445, 1288, 1209, 1048. 1H NMR (600 MHz, add. HMBC, HMQC,
NOE): δ = 0.81–0.91 (m, 2 H, Cpr-H), 1.07–1.14 (m, 2 H, Cpr-H),
3.56 (s, 2 H, CH2Cpr), 4.64 (s, 2 H, CH2Ar), 7.64 (s, 1 H, Ar-4-
H), 8.00 (br.s, 1 H, NH) ppm. 13C NMR (151 MHz, CDCl3, add.
HMBC, HMQC, NOE): δ = 12.2 (Cpr-C), 40.7 (CH2Cpr), 42.0
(Cpr-Cquat), 50.0 (CH2Ar), 139.7 (Cquat, Ar-C-5), 140.9 (Ar-C-4),
153.1 (Cquat, Ar-C-2), 160.4 (Cquat, NNCN) ppm. MS (EI): m/z (%)
(4,6-Diazaspiro[2.4]hept-5-ylidene)cyanamide
(24):
1-(Amino-
methyl)cyclopropylamine dihydrochloride (811 mg, 5.10 mmol)
prepared as described in the previous experiment was treated with
S,S-dimethyl cyanodithioiminocarbonate (11) (819 mg, 5.60 mmol)
and KOH (572 mg, 10.2 mmol) in H2O (20 mL) according to GP1
(70 °C, 16 h). Column chromatography of the residue (25 g of silica
gel, 2 × 20 cm column, CHCl3/MeOH, 20:1, Rf = 0.30) furnished
24 (346 mg, 50 %) as a pale yellow solid, m.p. 170–171 °C. IR
= 289/287 (2/4) [M+], 252 (23) [M+ – Cl], 243/241 (10/27) [M+
–
(KBr): ν = 3183 cm–1 (N–H), 2183 (CϵN), 1635 (C=N), 1528,
NO2], 134/132 (36/100) [ClArCH2+]. HRMS (EI) calcd. for
˜
1416, 1255. 1H NMR (250 MHz, CD3OD): δ = 0.60–0.72 (m, 2 H,
Cpr-H), 0.72–1.88 (m, 2 H, Cpr-H), 3.53 (s, 2 H, CH2) ppm. 13C
NMR (75.5 MHz, CD3OD, DEPT): δ = 11.8 (–, Cpr-C), 41.2
C9H10ClN5O2S [M+] 287.0244, correct mass. 20-CT: M.p. 190–
192 °C. IR (KBr): ν = 3368 cm–1 (N–H), 1580, 1538, 1524, 1469,
˜
1444, 1289, 1247, 1230, 1199, 1058, 1030. 1H NMR (600 MHz,
add. HMBC, HMQC, NOE): δ = 0.73–0.81 (m, 2 H, Cpr-H), 1.14–
1.20 (m, 2 H, Cpr-H), 3.81 (s, 2 H, CH2Cpr), 4.28 (s, 2 H, CH2Ar),
7.34 (s, 1 H, Ar-4-H), 8.21 (br.s, 1 H, NH) ppm. 13C NMR
(151 MHz, CDCl3, add. HMBC, HMQC, NOE): δ = 8.7 (Cpr-C),
35.9 (CH2Cpr), 39.0 (Cpr-Cquat), 51.7 (CH2Ar), 139.6 (Cquat, Ar-
C-5), 140.9 (Ar-C-4), 153.4 (Cquat, Ar-C-2), 159.8 (Cquat, NNCN)
ppm. MS (EI): m/z (%) = 289/287 (Ͻ1/1) [M+], 243/241 (31/82)
[M+ – NO2], 205 (68) [M+ – NO2 – HCl], 134/132 (39/100)
[ClArCH2+]. HRMS (EI) calcd. for C9H10ClN5O2S [M+] 287.0244,
correct mass.
(Cquat, Cpr-C), 50.9 (–, CH2), 119.7 (Cquat, CϵN), 166.4 (Cquat
,
NNCN) ppm. MS (EI): m/z (%) = 136 (65) [M+], 121 (100) [M+
–
NH], 108 (26) [M+ – CNH2], 68 (26) [C4H6N+], 54 (18) [C3H4N+],
41 (24) [C3H5+]. HRMS (EI) calcd. for C6H8N4 [M+] 136.0749,
correct mass. C6H8N4 (136.16): calcd. C 52.93, H 5.92, N 41.15;
found. C 52.98, H 6.20, N 41.09.
[4-(6-Chloropyridin-3-ylmethyl)-4,6-diazaspiro[2.4]hept-5-ylidene]ni-
troamide (27-CP) and [6-(6-chloropyridin-3-ylmethyl)-4,6-diazaspi-
ro[2.4]hept-5-ylidene]nitroamide (20-CP): [17] Column chromatogra-
phy (15 g of silica gel, 2 × 15 cm column, CHCl3/MeOH, 40:1, Rf
= 0.23, 0.26) of the residue prepared from 25 (234 mg, 1.50 mmol),
CCMP (243 mg, 1.50 mmol) and K2CO3 (829 mg, 6.00 mmol) in
[4-(6-Chloropyridin-3-ylmethyl)-4,6-diazaspiro[2.4]hept-5-ylidene]cy-
anamide (26-CP), [6-(6-Chloropyridin-3-ylmethyl)-4,6-diazaspi-
MeCN (15 mL) according to GP2 (70 °C, 17 h) furnished a mixture ro[2.4]hept-5-ylidene]cyanamide (19-CP) and [4,6-Bis(6-chloropyri-
of the two regioisomers 27-CP (181 mg, calculated yield 43 %) and
din-3-ylmethyl)-4,6-diazaspiro[2.4]hept-5-ylidene]cyanamide
(28-
[17]
20-CP (139 mg, calculated yield 33 %)[14] as a yellow foam. 27-CP:
CP):
Column chromatography (15 g of silica gel, 2 × 15 cm
M.p. 134–135 °C. IR (KBr): ν = 3355 cm–1 (N–H), 1562, 1537, column, CHCl3/MeOH, 50:1, Rf = 0.18, 0.25) of the residue pre-
˜
1464, 1436, 1298, 1242, 1032. 1H NMR (600 MHz, add. HMBC, pared from 24 (190 mg, 1.40 mmol), CCMP (227 mg, 1.40 mmol)
HMQC, NOE): δ = 0.65–0.74 (m, 2 H, Cpr-H), 0.97–1.05 (m, 2 H,
and K2CO3 (774 mg, 5.60 mmol) in MeCN (15 mL) according to
3
Cpr-H), 3.84 (s, 2 H, CH2Cpr), 4.24 (s, 2 H, CH2Ar), 7.26 (d, J = GP2 (70 °C, 17 h) furnished a mixture of 26-CP (66 mg, calculated
3
4
8.2 Hz, 1 H, Ar-5-H), 7.60 (dd, J = 8.2, J = 2.5 Hz 1 H, Ar-4-
yield 18 %), 19-CP (44 mg, calculated yield 12 %) and 28-CP
(92 mg, calculated 34 %)[14] as a high viscous yellow oil. 26-CP:
4
H), 8.19 (d, J = 2.5 Hz, 1 H, Ar-2-H), 8.31 (br.s, 1 H, NH) ppm.
13C NMR (151 MHz, add. HMBC, HMQC, NOE): δ = 8.5 (Cpr- M.p. 190–191 °C. IR (KBr): ν = 3177 cm–1 (N–H), 2170 (CϵN),
˜
C), 39.8 (CH2Cpr), 42.3 (Cpr-Cquat), 50.0 (CH2Ar), 124.4 (Ar-C-
1603 (C=N), 1523, 1465, 1422, 1396, 1105, 811. 1H NMR
5), 131.5 (Cquat, Ar-C-3), 137.9 (Ar-C-4), 147.9 (Ar-C-2), 150.8 (600 MHz, add. HMBC, HMQC, NOE): δ = 0.55–0.65 (m, 2 H,
Eur. J. Org. Chem. 2005, 600–609
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© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
607

F. Brackmann, D. S. Yufit, J. A. K Howard, M. Es-Sayed, A. de Meijere
Table 2. Crystallographic data and parameters of the refinements of compounds 13-CT, 14-CT, 19-CT and 21-CT.
FULL PAPER
Identification code
13-CT
14-CT
19-CT
21-CT
Empirical formula
Formula weight (g/mol)
C10H9ClN4S2
284.78
C10H9ClN4S2
284.78
C10H10ClN5S
267.74
C9H10ClN3OS
243.71
Crystal system
Space group
monoclinic
P21/c
orthorhombic
Pna21
triclinic
P1
monoclinic
P21/n
¯
Unit cell dimensions
a (Å)
b (Å)
c (Å)
α (°)
β (°)
5.2823(2)
12.0185(4)
19.9117(7)
90
97.44(2)
90
1253.45(8)
4
1.509
0.619
584
13.4197(3)
13.1871(4)
6.9676(2)
90
90
90
1233.03(6)
4
1.534
0.630
584
5.7101(2)
14.0746(4)
14.9377(5)
101.29(1)
96.68(1)
94.01(1)
1163.9(7)
4
5.9702(3)
8.1798(5)
21.713(1)
90
95.64(2)
90
1055.2(1)
4
1.534
γ (°)
Volume (Å3)
Z
Density (calculated) (Mg/m3)
Absorption coefficient (mm–1)
Fo
1.528
0.491
552
0.535
504
Crystal size (mm)
θ range for data collection (°)
Reflections collected
0.46 × 0.14 × 0.07
1.98 to 30.00
10370
3655 [0.0222]
3655/0/190
1.046
0.37 × 0.13 × 0.04
2.17 to 29.99
14103
3577 [0.0249]
3577/1/190
1.036
0.28 × 0.24 × 0.06
1.82 to 30.00
11571
6623 [0.0190]
6623/0/387
1.032
0.32 × 0.16 × 0.14
1.88 to 27.49
8395
2427, [0.0336]
2427/0/176
1.037
Independent reflections [R
Data/restraints/parameters
Goof on F2
]
int
R1, wR2 indices [I Ͼ 2σ(I)]
R1, wR2 indices (all data)
0.0346, 0.0913
0.0458, 0.0989
0.492 and –0.472
0.0273, 0.0694
0.0301, 0.0716
0.309 and –0.199
0.0366, 0.0936
0.0509, 0.1025
0.455 and –0.270
0.0443, 0.1137
0.0597, 0.1218
0.760 and –0.385
Largest diff. peak and hole, e·Å–3
Cpr-H), 0.85–0.91 (m, 2 H, Cpr-H), 3.64 (s, 2 H, CH2Cpr), 4.10 (s, NNCN) ppm. MS (EI): m/z (%) = 390/388/386 (2/11/17) [M+], 262/
3
2 H, CH2Ar), 7.24 (d, J = 8.3 Hz, 1 H, Ar-5-H), 7.46 (br.s, 1 H,
260 (15/49) [M+ – ClArCH2], 128/126 (30/100) [ClArCH2+]. HRMS
(EI) calcd. for C18H16Cl2N6 [M+] 386.0814, correct mass.
3
4
4
NH), 7.56 (dd, J = 8.3, J = 2.5 Hz, 1 H, Ar-4-H), 8.17 (d, J =
2.5 Hz, 1 H, Ar-2-H) ppm. 13C NMR (151 MHz, add. HMBC,
HMQC, NOE): δ = 8.1 (Cpr-C), 37.9 (Cpr-Cquat), 39.5 (CH2Cpr), [4-(2-Chlorothiazol-5-ylmethyl)-4,6-diazaspiro[2.4]hept-5-ylidene]cy-
49.2 (CH2Ar), 118.4 (Cquat, CϵN), 124.3 (Ar-C-5), 132.0 (Cquat
Ar-C-3), 137.9 (Ar-C-4), 148.0 (Ar-C-2), 150.6 (Cquat, Ar-C-6),
,
anamide (26-CT), [6-(2-Chlorothiazol-5-ylmethyl)-4,6-diazaspi-
ro[2.4]hept-5-ylidene]cyanamide (19-CT) and [4,6-Bis(2-chlorothi-
163.6 (Cquat, NNCN) ppm. MS (EI): m/z (%) = 263/261 (20/64)
azol-5-ylmethyl)-4,6-diazaspiro[2.4]hept-5-ylidene]cyanamide
(28-
[M+], 135 (50) [M+ – ClArCH2], 128/126 (32/100) [ClArCH2+]. CT):
Column chromatography (15 g of silica gel, 2 × 15 cm
[17]
HRMS (EI) calcd. for C12H12ClN5 [M+] 261.0781, correct mass. column, CHCl3/MeOH, 35:1, Rf = 0.26, 0.29) of the residue pre-
19-CP: M.p. 205–206 °C. IR (KBr): ν = 3217 cm–1 (N–H), 2178
pared from 24 (136 mg, 1.00 mmol), CCMT (168 mg, 1.00 mmol)
and K2CO3 (553 mg, 4.00 mmol) in MeCN (10 mL) according to
GP2 (70 °C, 17 h) furnished a mixture of 26-CT (27 mg, calculated
˜
1
(CϵN), 1609 (C=N), 1536, 1387, 1112. H NMR (600 MHz, add.
HMBC, HMQC, NOE): δ = 0.55–0.65 (m, 2 H, Cpr-H), 0.98–1.05
(m, 2 H, Cpr-H), 3.40 (s, 2 H, CH2Cpr), 4.39 (s, 2 H, CH2Ar), 7.28 yield 10 %), 19-CT (17 mg, calculated yield 6 %) and 28-CT
3
3
4
(d, J = 8.3 Hz, 1 H, Ar-5-H), 7.61 (dd, J = 8.3, J = 2.5 Hz 1 H,
(106 mg, calculated yield 53 %)[14] as a high viscous yellow oil. 26-
4
Ar-4-H), 7.66 (br.s, 1 H, NH), 8.24 (d, J = 2.5 Hz, 1 H, Ar-2-H)
CT: M.p. 179–180 °C. IR (KBr): ν = 3170 cm–1 (N–H), 2183
˜
ppm. 13C NMR (151 MHz, add. HMBC, HMQC, NOE): δ = 11.4 (CϵN), 1616 (C=N), 1523, 1421, 1049. H NMR (600 MHz, add.
1
(Cpr-C), 43.1 (Cpr-Cquat), 44.9 (CH2Cpr), 53.3 (CH2Ar), 118.9
HMBC, HMQC, NOE): δ = 0.72–0.81 (m, 2 H, Cpr-H), 1.03–1.11
(Cquat, CϵN), 124.5 (Ar-C-5), 130.3 (Cquat, Ar-C-3), 138.8 (Ar-C- (m, 2 H, Cpr-H), 3.59 (s, 2 H, CH2Cpr), 4.15 (s, 2 H, CH2Ar), 7.28
4), 138.9 (Ar-C-2), 151.1 (Cquat, Ar-C-6), 163.0 (Cquat, NNCN)
(s, 1 H, Ar-4-H), 7.37 (br.s, 1 H, NH) ppm. 13C NMR (151 MHz,
add. HMBC, HMQC, NOE): δ = 8.1 (Cpr-C), 35.5 (CH2Cpr), 42.7
(Cpr-Cquat), 49.1 (CH2Ar), 117.8 (Cquat, CϵN), 137.0 (Cquat, Ar-
C-5), 139.3 (Ar-C-4), 152.7 (Cquat, Ar-C-2), 162.7 (Cquat, NNCN)
ppm. MS (EI): m/z (%) = 263/261 (24/74) [M+], 135 (19) [M+
–
ClArCH2], 128/126 (32/100) [ClArCH2+]. HRMS (EI) calcd. for
C12H12ClN5 [M+] 261.0781, correct mass. 28-CP: M.p. 142–144 °C.
IR (KBr): ν = 2172 cm–1 (CϵN), 1589 (C=N), 1566, 1507, 1453, ppm. MS (EI): m/z (%) = 269/267 (16/46) [M+], 232 (29) [M+ – Cl],
˜
1250, 1100, 819. 1H NMR (600 MHz, add. HMBC, HMQC,
134/132 (28/100) [ClArCH2+]. HRMS (EI) calcd. for C10H10ClN5S
NOE): δ = 0.55–0.65 (m, 2 H, Cpr-H), 0.91–0.65 (m, 2 H, Cpr-H), [M+] 267.0345, correct mass. 19-CT: M.p. 179–180 °C. IR (KBr): ν
˜
3.47 (s, 2 H, CH2Cpr), 4.34 (s, 2 H, CH2Ar), 4.78 (s, 2 H, CH2Ar),
3164 cm–1 (N–H), 2182 (CϵN), 1614 (C=N), 1522, 1421, 1049. 1H
NMR (600 MHz, add. HMBC, HMQC, NOE): δ = 0.62–0.70 (m,
3
3
7.26 (d, J = 8.3 Hz, 1 H, Ar-5-H), 7.32 (d, J = 8.3 Hz, 1 H, Ar-
3
4
3
5-H), 7.57 (dd, J = 8.3, J = 2.5 Hz 1 H, Ar-4-H), 7.72 (dd, J = 2 H, Cpr-H), 0.96–1.03 (m, 2 H, Cpr-H), 3.46 (s, 2 H, CH2Cpr),
4
4
8.3, J = 2.5 Hz 1 H, Ar-4-H), 8.20 (d, J = 2.5 Hz, 1 H, Ar-2-H),
4.46 (s, 2 H, CH2Ar), 7.36 (s, 1 H, Ar-4-H), 7.66 (br.s, 1 H, NH)
8.30 (d, 4J = 2.5 Hz, 1 H, Ar-2-H) ppm. 13C NMR (151 MHz, add. ppm. 13C NMR (151 MHz, add. HMBC, HMQC, NOE): δ = 11.2
HMBC, HMQC, NOE): δ = 8.4 (Cpr-C), 40.5 (Cpr-Cquat), 41.1 (Cpr-C), 37.9 (Cpr-Cquat), 40.3 (CH2Cpr), 52.9 (CH2Ar), 118.4
(CH2Cpr), 46.3 (CH2Ar), 53.6 (CH2Ar), 115.5 (Cquat, CϵN), 124.4
(Cquat, CϵN), 134.5 (Cquat, Ar-C-5), 140.4 (Ar-C-4), 152.4 (Cquat,
(Ar-C-5), 124.7 (Ar-C-5), 129.8 (Cquat, Ar-C-3), 131.7 (Cquat, Ar- Ar-C-2), 162.5 (Cquat, NNCN) ppm. MS (EI): m/z (%) = 269/267
C-3), 137.6 (Ar-C-4), 138.9 (Ar-C-4), 147.8 (Ar-C-2), 149.1 (Ar-C-
2), 150.8 (Cquat, Ar-C-6), 151.4 (Cquat, Ar-C-6), 157.9 (Cquat
(6/20) [M+], 232 (36) [M+ – Cl], 135 (11) [M+ – ClArCH2], 134/132
(37/100) [ClArCH2+]. HRMS (EI) calcd. for C10H10ClN5S [M+]
,
608
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2005, 600–609

Synthesis of Spirocyclopropanated Analogues of Imidacloprid and Thiacloprid
FULL PAPER
2789–2834; c) B. Breit, J. Prakt. Chem. 2000, 342, 211–214; d)
F. Sato, H. Urabe, S. Okamoto, Chem. Rev. 2000, 100, 2835–
2886; e) F. Sato, H. Urabe, S. Okamoto, Synlett 2000, 753–
777; f) A. de Meijere, S. I. Kozhushkov, A. I. Savchenko, in:
Titanium and Zirconium in Organic Synthesis (Ed.: I. Marek),
Wiley-VCH, Weinheim, 2002, pp. 390.; g) A. de Meijere, S. I.
Kozhushkov, A. I. Savchenko, J. Organomet. Chem. 2004, 689,
2033–2055.
267.0345, correct mass. 28-CT: M.p. 145–146 °C. IR (KBr): ν =
˜
1
3091 cm–1 (C–H), 2174 (CϵN), 1602 (C=N), 1515, 1420, 1037. H
NMR (600 MHz, add. HMBC, HMQC, NOE): δ = 0.62–0.81 (m,
2 H, Cpr-H), 0.96–1.11 (m, 2 H, Cpr-H), 3.50 (s, 2 H, CH2Cpr),
4.35 (s, 2 H, CH2Ar), 4.87 (s, 2 H, CH2Ar), 7.34 (s, 1 H, Ar-4-H),
7.44 (s, 1 H, Ar-4-H) ppm. 13C NMR (151 MHz, add. HMBC,
HMQC, NOE): δ = 8.6 (Cpr-C), 36.6 (CH2Cpr), 40.7 (Cpr-Cquat),
41.6 (CH2Ar), 53.3 (CH2Ar), 115.2 (Cquat, CϵN), 133.8 (Cquat, Ar-
C-5), 136.4 (Cquat, Ar-C-5), 139.6 (Ar-C-4), 140.9 (Ar-C-4), 152.5
(Cquat, Ar-C-2), 153.0 (Cquat, Ar-C-2), 157.1 (Cquat, NNCN) ppm.
MS (EI): m/z (%) = 402/400/398 (2/6/10) [M+], 365/363 (12/31)
[M+ – Cl], 268/266 (9/28) [M+ – ClArCH2], 134/132 (37/100)
[ClArCH2+]. HRMS (EI) calcd. for C14H12Cl2N6S2 [M+] 397.9942,
correct mass.
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[8] Crystallographic data (excluding structure factors) for the
structures reported in this paper have been deposited as supple-
mentary publication no. CCDC-246775 (for 13-CT), -246776
(for 14-CT), -246777 (for 19-CT), and -246774 (for 21-CT) con-
tain the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_r-
equest/cif.
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Crystal Structure Determination: Suitable crystals of the com-
pounds 13-CT, 14-CT, 19-CT and 21-CT for X-ray crystal structure
determinations were obtained by slow evaporation of solvents from
their solutions in hexane/Et2O mixtures. The X-ray data were col-
lected at 120.0 K with a Bruker SMART CCD 6000 diffractometer
(λMo-Kα, graphite monochromator, ω-scan, 0.3°/frame) equipped
with Oxford Cryostream LT-device. The structures were solved by
direct methods and refined by full-matrix least-squares on F2 for
all data. Non-hydrogen atoms were refined with anisotropic dis-
placement parameters, all H-atoms were located in the difference
Fourier maps and refined isotropically. Crystallographic data and
parameters of the refinements are listed in Table 2.[8]
Acknowledgments
This work was supported by the State of Niedersachsen, Bayer
CropScience AG as well as the Fonds der Chemischen Industrie.
The authors are grateful to the companies Chemetall AG and
NIGU Chemie GmbH for generous gifts of chemicals, and particu-
larly 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 practical advice.
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[14] All ratios and yields of compounds 19, 20, 21, 25–27 were cal-
culated from their 1H NMR spectra. All compounds were
about 85–95 % pure.
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[17] IR and mass spectra of the single compounds 19, 20, 25–27
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Received August 23, 2004
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www.eurjoc.org
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