Synthesis of 3-chloroanthranilates from α,γ,γ-trichloro-β-iminoesters

Article abstract of DOI:10.1016/S0040-4020(01)00750-5

3-Chloroanthranilates have been prepared by a short pathway involving dehydrohalogenation of α,γ,γ-trichloro-β-iminoesters, which were obtained by trihalogenation of the corresponding enaminoesters. This route opens the way to a number of previously unknown functionalised anthranilates, which are potential starting materials for a variety of heterocyclic and biologically interesting compounds.

Full text of DOI:10.1016/S0040-4020(01)00750-5

TETRAHEDRON
Pergamon
Tetrahedron 57 32001) 7685±7692
Synthesis of 3-chloroanthranilates from a,g,g-trichloro-b-
iminoesters
Christian V. Stevens,p Bart Kesteleyn, Erick Rosas Alonso and Norbert De Kimpep
Department of Organic Chemistry, Faculty of Agricultural and Applied Biological Sciences, Ghent University,
Coupure links 653, B-9000 Ghent, Belgium
Received 7 May 2001; accepted 16 July 2001
AbstractÐ3-Chloroanthranilates have been prepared by a short pathway involving dehydrohalogenation of a,g,g-trichloro-b-iminoesters,
which were obtained by trihalogenation of the corresponding enaminoesters. This route opens the way to a number of previously unknown
functionalised anthranilates, which are potential starting materials for a variety of heterocyclic and biologically interesting compounds.
q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
equivalents of dimethyl carbonate in benzene. The reaction
with dimethyl carbonate proceeds smoothly for cyclo-
hexanone itself, but results in the formation of a con-
siderable amount of side-products 3about 18%) for the
4-t-butyl derivative which had to be removed by a short
path high vacuum distillation. Distillation of all the alkoxy-
carbonyl cyclohexanones 1 is recommended before conden-
sation with primary amines in the next step.8
Chloroanthranilates and dichloroanthranilates proved to be
versatile building blocks for the synthesis of a variety
of heterocyclic compounds. They are used for the syn-
thesis of 1,2,3,4-tetrahydroquinoline-2,3,4-trione 3-oximes
3NMDA-glycine site antagonists),1 several kinds of 1,2,3,4-
tetrahydro-1,4-benzodiazepines,2,3 4-hydroxycarbostyril-3-
alkylcarboxylic acids and their esters 3aldosterone antago-
nists),4 benzo-separated xanthines,5 2-amino-3,1-benz-
oxazin-4-ones 3serine protease C1r inhibitors)6 and 9-oxo-
9,10-dihydroacridine-4-carboxylic acids.7
b-Keto esters 1 were then condensed with an excess of a
primary amine in re¯uxing benzene under azeotropic
removal of water and acid catalysis 3p-toluenesulfonic
acid) to obtain the N-alkyl enaminoesters 2 3Scheme 1).9,10
An excess of amine was necessary when using volatile
amines, whereas 1.2 equiv. were suf®cient for less volatile
amines, e.g. cyclohexylamine. The selectively formed
b-enaminoesters11,12 were obtained in almost quantitative
yield 398±100%) and can be used as such in the following
reaction step. However, when the compounds need to be
stored for a longer period, puri®cation is advisable since
small traces of p-toluenesulfonic acid stimulates hydrolysis.
The puri®ed b-enaminoesters 2 can be obtained in reason-
able to good yields 345±97%).
Despite the utility of chloroanthranilates in general, little
attention was paid to the synthesis of 3-chloroanthranilates,
which were seldomly reported in the literature.2 The lack of
straightforward synthetic methods probably led to the
absence of 3-chloro substituted derivatives in the screening
of the corresponding heterocyclic compounds reported. In
this communication, a straightforward method for regio-
speci®cally chlorinated anthranilates, i.e. 3-chloroanthrani-
lates 4, from a,g,g-trichloro-b-iminoesters 3 is reported.
Since very little work has been performed on chlorinated
b-enaminoesters or b-iminoesters,13±16 the chlorination of 2
was evaluated using different conditions suitable for the
chlorination of imines. During this study, it was observed
that the chlorination of 2 with NCS in tetrachloromethane
often produced complex mixtures of chlorinated products.
2. Results and discussion
The synthesis of 3-chloroanthranilates is described via
halogenation of N-alkyl enaminoesters, followed by base
induced dehydrohalogenation.
Alkoxycarbonylation of cyclohexanones was performed by
treatment with sodium hydride and reaction with two
Even an attempt to selectively chlorinate the monochloro
iminoester 8, synthesised by imination of a-chloro-b-keto-
ester 6 and thermal rearrangement, similar to the allylic
rearrangement of a-chloro-b-ketoesters to g-chloro-b-
ketoesters, did not lead to a good synthesis of the dichloro
Keywords: anthranilates; chloroanthranilates; iminoesters; chloroimines.
Corresponding authors. Fax: 132-9-264-6243; e-mail: chris.stevens@
rug.ac.be; Fax: 132-9-264-6243; e-mail: norbert.dekimpe@rug.ac.be
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020301)00750-5

7686
C. V. Stevens et al. / Tetrahedron 57 -2001) 7685±7692
Scheme 1.
derivative 9 3Scheme 2). Only mixtures could be obtained
containing up to 70% of the a,g-dichloro-b-iminoester 9.
However, if an excess of chlorinating agent 37 equiv. NCS)
was applied to 8, the trichloro derivative 3 could be obtained
but the reaction mixture was contaminated with some
starting material and some hydrolyzed starting material
3purity: 70%).
tetrachloromethane and reacted with 5 equiv. of N-chloro-
succinimide 3NCS) during 20 h of re¯ux in order to obtain
the trichlorinated derivative 3.
The same result could be achieved by adding 7 equiv. of
NCS and heating the reaction mixture vigorously by a
bunzen ¯ame for 30 s. The trichlorinated iminoesters 3
were obtained in almost quantitative yield 398±100%) and
could be used without further puri®cation. Because of the
E/Z-isomerism of the trichlorinated b-iminoesters, the
reaction mixtures always contained two isomers in a ratio
approximately 2:1, which cause the occurrence of two sets
of signals in the 13C NMR.
When the enaminoesters 2 were treated with an excess of
chlorinating reagent, a single reaction product could be
isolated. Therefore, the enaminoesters were dissolved in
Treatment of the a,g,g-trichloro-b-iminoesters with sodium
alkoxides in the corresponding alcohols led to the synthesis
of alkyl 3-chloroanthranilates 4 3or alkyl 3-chloro-2-amino-
benzoates) in moderate to good yields 3Table 1). The purity
of the reaction mixtures is better when using methyl
benzoates compared to ethyl benzoates, which also results
in higher yields after the chromatographic puri®cation.
Because of considerable loss of material during ¯ash
chromatography of the anthranilates, the solvent mixtures
for puri®cation were choosen so that the Rf-value of the
compounds 4 were high. However, in the case of the
t-butyl derivative 4e, the aromatised compound was present
but could not be obtained pure.
The mechanism of the formation of 3-chloroanthranilates
4 3Scheme 3) consists of a double dehydrochlorination
leading to
a
3chlorocyclohexadienylidene)amine 10,
Scheme 2.

C. V. Stevens et al. / Tetrahedron 57 -2001) 7685±7692
7687
Table 1. Yields for the synthesis of enaminoesters 2, a,g,g-trichloro-b-iminoesters 3 and 3-chloroanthranilates 4
Substituent compound
R1
R2
R3
Yield 2
Yield 3
Yield 4
a
b
c
d
e
f
g
h
i
Me
Me
Et
Et
Me
M
Me
Me
Et
i-Pr
c-Hex
i-Pr
c-Hex
i-Pr
2CH2C6HCH
5
s-Bu
Cyclopent.
Cyclopent.
s-Bu
H
H
H
H
t-Bu
H
H
H
H
81
87
79
45
77
90
97
70
±
.98
.98
98
.98
.98
.98
99
97
±
±
65 345)a
71 353)a
66 326)a
39 317)a
±
±
66
b
e
58
52c
35c
j
Et
H
±
a
Isolated yield after ¯ash chromatography.
The compound was present in the mixture, but could not be obtained pure.
Products obtained by dehydrohalogenation and transesteri®cation.
b
c
Scheme 3.
followed by proton abstraction giving rise to the formation
of the aromatic nucleus. A similar reactivity has been
reported during the formation of 2,6-dichloroanilines
from the imines derived from 2,2,6,6-tetrachlorocyclo-
hexanone.17,18
SI) and at 270 MHz 3Jeol PMX 270 SI) with CDCl3 as
solvent. 13C NMR spectra were recorded at 20 MHz 3Varian
FT-80) with CDCl3 as solvent. Mass spectra were obtained
on a Varian MAT 112 mass spectrometer 370 eV) using
direct inlet or GC-MS coupling 3RSL 200, 20 m capillary
column, i.d. 0.53 mm, He carrier gas). Diethyl ether and
tetrahydrofuran were distilled from sodium/benzophenone
ketyl.
Also, interesteri®cation could be performed during the
aromatisation when sodium methoxide or ethoxide was
used on the ethyl or methyl benzoate derivatives, respec-
tively 3conversion of 3g, 3h into 4j, 4i). The aromatisation
of the N-phenylethyl derivative 3f could not be performed
using different sodium alkoxides 3sodium methoxide,
potassium t-butoxide) and led to complicated reaction
mixtures, which were not characterised further.
3.1. General procedure for the synthesis of enamino-
esters 2
In a round bottom ¯ask of 250 ml, equipped with a Dean±
Stark aparatus and a re¯ux condenser, 50 mmol of alkoxy-
carbonylcyclohexanone 1 was dissolved in benzene and
100 mg of p-toluenesulphonic acid was added. The reaction
mixture was heated under re¯ux and 250 mmol of the
primary amine was added during one hour. After 4 h of
re¯ux, the solvent was evaporated in vacuo. Puri®cation
of the reaction mixture was performed by high vacuum
distillation 3yield: 45±87%).
The a,g,g-trichloro-b-iminoesters 3 were also hydrolysed
to the a,g,g-trichloro-b-ketoesters 5 after prolonged heating
3minimum 20 h) in a two phase system dichloromethane/
water in the presence of oxalic acid 3yield: 76±82%).
These derivatives could not be prepared by direct chlori-
nation of the b-ketoesters 1 since their treatment with an
excess of sulfuryl chloride 33.3 equiv., re¯ux 20 h) only
allowed the introduction of one chlorine atom. Therefore,
the synthesis of trichlorocyclohexanones was only possible
by chlorination of the iminoesters followed by hydrolysis.
3.1.1.
Methyl
2-)isopropylamino)-1-cyclohexen-1-
1
carboxylate )2a). H NMR 3270 MHz, CDCl3) d: 1.18
36H, d, Jˆ6.6 Hz, CH3Me)2); 1.54±1.69 34H, m, 3CH2)2);
2.26 32H, t, Jˆ6 Hz, CH2); 2.35 32H, t, Jˆ6 Hz, CH2); 3.65
33H, s, OCH3); 3.72 31H, m, CH3CH3)2); 8.93 31H, broad d,
Jˆ5.9 Hz, NH). 13C NMR 367.9 MHz, CDCl3) d: 22.39 and
22.82 and 23.83 and 26.24 34£CH2); 24.34 3CH3CH3)2);
43.23 3CH3CH3)2); 50.21 3OCH3); 88.82 3CvCN); 158.88
3CvCN); 171.21 3CvO). IR 3NaCl, n, cm21): 1650 3CO),
1600 3CvC). MS m/z 3%): 197 3M1, 68); 182 343); 166
342); 156 346); 150 3100); 138 362); 122 334); 110 313);
96 327); 81 327); 67 321); 58 326); 41 338). Bp: 678C/
In conclusion, this paper describes a convenient three-step
synthesis of 3-chloroanthranilates by dehydrohalogenation
of a,g,g-trichloro-b-iminoesters prepared by a straightfor-
ward halogenation of the easily accessible enaminoesters.
3. Experimental
1H NMR spectra were recorded at 60 MHz 3Jeol PMX 60

7688
C. V. Stevens et al. / Tetrahedron 57 -2001) 7685±7692
0.02 mmHg. Anal. Calcd for C11H19NO2: C, 66.97; H, 9.71;
N, 7.10. Found: C, 66.84; H, 9.86; N, 7.15.
23.81 and 26.33 34£CH2); 37.34 3CH2CH2N); 44.06
3CH2N); 50.26 3OCH3); 89.52 3CvCN); 126.47 3CH);
128.53 32C); 128.75 32C)3vCH); 138.99 3vCquat);
159.37 3CvCN); 171.10 3CvO). IR 3NaCl, n, cm21):
1645 3CO), 1595 3CvC). MS m/z 3%): 259 3M1, 26); 244
310); 230 340); 228 331); 212 318); 198 323); 168 316); 122
310); 91 399); 77 314); 67 331); 55 312); 41 332); 39 324).
This compound was not distilled and used as such ꢀpurity .
95%† in the next chlorination step.
3.1.2. Methyl 2-)cyclohexylamino)-1-cyclohexen-1-carb-
oxylate )2b). H NMR 3270 MHz, CDCl3) d: 1.23±1.35
1
36H, m, 3CH2)3); 1.53±1.87 38H, m, 3CH2)4); 2.26 32H, t,
Jˆ6.3 Hz, CH2); 2.35 32H, t, Jˆ6.3 Hz, CH2); 3.31 31H, m,
NHCH); 3.65 33H, s, OCH3); 9.06 31H, broad d, Jˆ8.6 Hz,
NH). 13C NMR 367.9 MHz, CDCl3) d: 22.39 and 22.84 and
23.85 32C) and 24.82 32C) and 25.57 32C) and 26.27
39£CH2); 34.59 3CHN); 50.22 3OCH3); 88.62 3CvCN);
158.88 3CvCN); 171.21 3CvO). IR 3NaCl, n, cm21):
1645 3CO), 1580 3CvC). MS m/z 3%): 237 3M1, 100);
222 312); 206 333); 204 320); 194 337); 178 367); 162
360); 156 382); 154 342); 124 345); 96 363); 81 330); 55
346); 41 349). Crystallised from diethyl ether/pentane; Mp:
638C. Anal. Calcd for C14H23NO2: C, 70.85; H, 9.77; N,
5.90. Found: C, 70.99; H, 9.64; N, 5.82.
3.1.7. Methyl 2-)1-sec-butylamino)-1-cyclohexen-1-carb-
oxylate )2g). H NMR 3270 MHz, CDCl3) d: 0.92 33H, t,
1
Jˆ7.4 Hz, CH2CH3); 1.14 33H, d, Jˆ6.6 Hz, CHCH3); 1.47
32H, m, CH2CH3); 1.48±1.69 34H, m, 3CH2)2); 2.24±2.38
34H, m, 3CH2)2); 3.38±3.49 31H, m, CHCH3); 3.66 33H, s,
OCH3); 8.95 31H, broad s, NH). 13C NMR 367.9 MHz,
CDCl3) d: 10.39 3CH2CH3); 21.89 3CHCH3); 22.30 and
22.72 and 23.76 and 26.33 34£CH2); 30.97 3CH2CH3);
48.66 3OCH3); 50.06 3CHN); 88.50 3CvCN); 159.12
3CvCN); 171.10 3CvO). IR 3NaCl, n, cm21) 1645 3CO),
1595 3CvC). MS m/z 3%): 211 3M1, 24); 182 346); 180
327); 164 313); 150 3100); 122 311); 96 311); 81 310); 40
324). Bp: 708C/0.05 mmHg. Anal. Calcd for C12H21NO2: C,
68.21; H, 10.02; N, 6.63. Found: C, 68.14; H, 9.94; N, 6.57.
3.1.3. Ethyl 2-)isopropylamino)-1-cyclohexen-1-carboxyl-
ate )2c). See Ref. 19 for details.
3.1.4. Ethyl 2-)cyclohexylamino)-1-cyclohexen-1-carbox-
ylate )2d).20 1H NMR 3270 MHz, CDCl3) d: 1.19±1.34 36H,
m, 3CH2)3); 1.26 33H, t, Jˆ7.3 Hz, MeCH2O); 1.55±1.87
310H, m, 3CH2)513CH2)2); 2.27 32H, t, Jˆ6 Hz, CH2); 2.35
32H, t, Jˆ6 Hz, CH2); 3.31 31H, m, NHCH); 4.11 32H, q,
Jˆ7.3 Hz, OCH2); 9.05 31H, broad d, Jˆ7.9 Hz, NH). 13C
NMR 367.9 MHz, CDCl3) d: 14.74 3MeCH2O); 22.43 32C)
and 22.84 and 23.88 and 24.87 32C) and 25.57 and 26.29
and 34.63 39£CH2); 50.30 3CHN); 58.53 3MeCH2O); 88.86
3CvCN); 158.69 3CvCN); 170.90 3CvO). IR 3NaCl, n,
cm21): 1645 3CO), 1595 3CvC). MS m/z 3%): 251 3M1,
100); 222 328); 208 334); 206 337); 104 334); 178 380); 170
370); 168 349); 162 360); 124 350); 122 332); 98 329); 96
367); 81 331); 55 321); 41 352). Bp: 125±127/0.001 mmHg.
Anal. Calcd for C15H25NO2: C, 71.67; H, 10.02; N, 5.57.
Found: C, 71.53; H, 10.13; N, 5.69.
3.1.8. Methyl 2-)cyclopentylamino)-1-cyclohexen-1-
carboxylate )2h). H NMR 3270 MHz, CDCl3) d: 1.43±
1
1.78 and 1.81±1.98 312H, m, 3CH2)2 and 3CH2)4-cyclo-
pentyl); 2.26 32H, ,t, CH2); 2.37 32H, ,t, CH2); 3.65
33H, s, OCH3); 3.81±3.91 31H, m, NCH); 9.06 31H, broad
s, NH). 13C NMR 367.9 MHz, CDCl3) d: 22.25 and 22.66
and 23.65 and 23.72 32C) and 26.63 and 34.39 32C) 3CH2)2-
cyclopentyl and 4£CH2); 50.06 3OCH3); 53.26 3NCH);
88.72 3CvCN); 159.26 3CvCN); 171.03 3CvO). IR
3NaCl, n, cm21): 3252 3NH); 1709 3CO); 1645 3CvC).
MS m/z 3%): 224 3M1 11, 15); 223 3M1, 100); 222 318);
192 338); 190 324); 178 315); 164 395); 162 328); 156 355);
149 332); 136 315); 124 338); 122 333); 96 366); 81 332); 79
334); 67 343); 55 330); 41 385). This compound was not
distilled and used as such ꢀpurity . 95%† in the next
chlorination step.
3.1.5. Methyl 5-tert-butyl-2-)isopropylamino)-1-cyclo-
hexen-1-carboxylate )2e). H NMR 3270 MHz, CDCl3) d:
1
0.90 39H, s, C3CH3)3); 1.17 33H, d, Jˆ6.6 Hz, CH3Me)2);
1.19 33H, d, Jˆ6.6 Hz, CH3Me)2); 1.13±1.25 32H, m, CH2);
1.82±1.94 32H, m, CH2); 2.22±2.60 33H, m); 3.67 33H, s,
OCH3); 3.64±3.76 31H, m, CH3CH3)2); 8.88 31H, broad d,
Jˆ8.3 Hz, NH). 13C NMR 367.9 MHz, CDCl3) d: 24.40 and
24.37 3CH3CH3)2; 23.50 and 25.18 and 27.53 and 32.29
33£CH2, 1£CH); 27.32 3C3CH3)3); 43.38 3CH3CH3)2);
44.29 3C3Me)3), 50.24 3OCH3); 88.80 3CvCN); 158.81
3CvCN); 171.31 3CvO). IR 3NaCl, n, cm21): 1650
3CO), 1595 3CvC). MS m/z 3%): 253 3M1, 63); 238 382);
222 327); 210 325); 206 330); 196 333); 194 327); 169 334);
154 3100); 122 334); 110 346); 94 325); 57 328); 43 322); 41
340). Bp: 85±908C/0.01 mmHg. Anal. Calcd for
C15H27NO2: C, 71.10; H, 10.74; N, 5.53. Found: C, 71.23;
H, 10.64; N, 5.45.
3.2. General procedure for the synthesis of a,g,g-tri-
chloro-b-iminoesters 3
To a solution of 25 mmol enaminoester 2 in 10 ml of tetra-
chloromethane, 175 mmol 37 equiv.) of N-chlorosuccini-
mide was added. The ¯ask was equipped with a re¯ux
condenser and the solution was re¯uxed by means of a
bunzen ¯ame for 30 s. After cooling the reaction mixture
to 08C, succinimide was ®ltered and washed with cold tetra-
chloromethane. After evaporation of the solvent, the
trichloroiminoesters were obtained in almost quantitative
yield 396±100%) and with high purity 3.96%).
3.2.1. Methyl 1,3,3-trichloro-2-)isopropylimino)cyclo-
hexanecarboxylate )3a). 3Ratio E/Z: 65/35) 1H NM R
3270 MHz, CDCl3) d: 1.13 36H, d, Jˆ5.9 Hz, CH3Me)2,
major); 1.18 36H, d, Jˆ5.9 Hz, CH3Me)2, minor); 1.96±
2.06 32H, m, CH2); 2.24±2.34 31H, m, CH3H)); 2.58±2.87
32H, m, CH2); 3.20±3.31 31H, m, CH3H)); 3.69 31H, sept.,
Jˆ5.9 Hz, CH3Me)2, minor); 3.78 33H, s, OCH3, major);
3.84 33H, s, OCH3, minor); 4.84 31H, sept., Jˆ5.9 Hz,
3.1.6. Methyl 2-)phenetylamino)-1-cyclohexen-1-carb-
oxylate )2f). H NMR 3270 MHz, CDCl3) d: 1.51±1.63
1
34H, m, 3CH2)2); 2.22±2.26 34H, m, 3CH2)2); 2.84 32H, t,
Jˆ7.6 Hz, NCH2CH2); 3.41 32H, t, Jˆ7.6 Hz, NCH2); 3.66
33H, s, OCH3); 7.19±7.36 35H, m, C6H5); 9.01 31H, broad s,
NH). 13C NMR 367.9 MHz, CDCl3) d: 22.28 and 22.69 and

C. V. Stevens et al. / Tetrahedron 57 -2001) 7685±7692
7689
CH3Me)2, major). 13C NMR 367.9 MHz, CDCl3) d: Major:
16.19 3CH2); 21.98 3CH3Me)2); 22.28 3CH3Me)2); 31.19
3CH2CCl); 43.52 3CH2CCl2); 51.81 3CH3Me)2); 53.31
3OCH3); 74.09 3CCl); 78.44 3CCl2); 155.43 3CvN);
168.91 3CvO). Minor: 16.73 3CH2); 21.51 3CH3Me)2);
22.43 3CH3Me)2); 36.32 3CH2CCl); 42.39 3CH2CCl2);
52.94 3CH3Me)2); 53.96 3OCH3); 64.06 3CCl); 87.69
3CCl2); 154.61 3CvN); 169.95 3CvO). IR 3NaCl, n,
cm21) 1750 3CO). MS m/z 3%): no M1; 284/86 36); 264/
66 310); 257/59 327); 225/27/29 333); 190/92/94 39); 177 34);
135 310); 89 38); 59 319); 43 3100). Anal. Calcd for
C11H16Cl3NO2: C, 43.95; H, 5.36; N, 4.66. Found: C,
43.92; H, 5.33; N, 4.68.
OCH2Me, major); 4.25 32H, m, OCH2Me, minor); 4.54
31H, br.s., CHN). 13C NMR 367.9 MHz, CDCl3) d: Major:
14.03 3OCH2Me);16.32 3CH2); 25.75 32£CH2); 31.63
32£CH2))3cyclohex.); 23.70 3CH2); 31.91 3CH2CCl); 43.70
3CH2CCl2); 59.93 3HCN); 62.62 3OCH2CH3); 73.89 3CCl);
78.40 3CCl2); 155.65 3CvN); 168.37 3CvO). Minor: 13.89
3OCH2Me); 16.75 3CH2); 25.66 32£CH2); 31.36 32£
CH2)3cyclohex.); 23.81 3CH2); 36.21 3CH2CCl); 42.25
3CH2CCl2); 61.24 3HCN); 63.36 3OCH2CH3); 64.24 3CCl);
87.99 3CCl2); 154.82 3CvN); 169.45 3CvO). IR 3NaCl, n,
cm21) 1750 3CO); 1650 3CvN). MS m/z 3%): no M1; 318/
20/22 336); 271/73/75 313); 225/27/29 39); 192 34); 164 34);
135 36); 101 33); 83 3100); 55 364); 41 331).
3.2.2. Methyl 1,3,3-trichloro-2-)cyclohexylimino)cyclo-
hexanecarboxylate )3b). 3Ratio E/Z: 65/35) 1H NM R
3270 MHz, CDCl3) d: 1.28±1.83 310H, m, 3CH2)5-cyclo-
hex.); 1.96±2.32 33H, m); 2.61±2.87 32H, m); 3.31±3.33
31H, m, CH3H)); 3.36 31H, br.s., CHN); 3.78 33H, s,
OCH3, major); 3.83 33H, s, OCH3, minor); 4.52 31H, br.s.,
CHN). 13C NMR 367.9 MHz, CDCl3) d: Major: 16.23
3CH2); 31.25 32£CH2); 31.57 32£CH2); 23.58 3CH2);
31.95 3CH2CCl); 43.54 3CH2CCl2); 53.35 3HCN); 59.69
3OCH3); 74.14 3CCl); 78.31 3CCl2); 155.74 3CvN);
169.00 3CvO). Minor: 16.77 3CH2); 25.76 32£CH2);
31.34 32£CH2); 23.76 3CH2); 36.30 3CH2CCl); 42.41
3CH2CCl2); 53.89 3HCN); 41.40 3OCH3); 64.00 3CCl);
87.87 3CCl2); 154.50 3CvN); 170.00 3CvO). IR 3NaCl,
n, cm21) 1755 3CO). MS m/z 3%): no M1; 304/06/08 334);
257/59/61 314); 225/27/29 36); 121 35); 83 3100); 55 362); 41
332).
3.2.5. Methyl 5-tert-butyl-1,3,3-trichloro-2-)isopropyl-
imino)cyclohexanecarboxylate )3e). 3Ratio E/Z: 59/41)
1H NMR 3270 MHz, CDCl3) d: 0.95 39H, s, C3CH3)3);
1.15 36H, d, Jˆ5.9 Hz, CH3Me)2, major); 1.19 36H, d, Jˆ
5.9 Hz, CH3Me)2, minor); 2.12±2.19 and 2.28±2.48 and
2.86±3.02 35H, each m, 3CH2)21CHring); 3.66 31H, sept.,
Jˆ5.9 Hz, CH3Me)2, major); 3.79 33H, s, OCH3, minor);
3.84 33H, s, OCH3, major); 4.95 31H, sept., Jˆ5.9 Hz,
CH3Me)2, minor). 13C NMR 367.9 MHz, CDCl3) d: Major:
21.42 3CH3Me)2); 21.98 3CH3Me)2); 27.13 3C3CH3)3); 31.95
and 38.74 and 41.78 and 48.30 3C3CH3)31CH2CHCH2);
53.14 3CH3Me)2); 53.99 3OCH3); 64.29 3CCl); 88.41
3CCl2); 155.43 3CvN); 170.40 3CvO). Minor: 21.64
3CH3Me)2); 22.21 3CH3Me)2); 27.13 3C3CH3)3); 31.88 and
39.17 and 39.30 and 51.36 3C3CH3)31CH2CHCH2); 51.64
3CH3Me)2); 53.48 3OCH3); 75.47 3CCl); 79.57 3CCl2);
155.29 3CvN); 169.81 3CvO). IR 3NaCl, n, cm21) 1750
3CO). MS m/z 3%): no M1; 340/42/44/46 319); 320/22/24
339); 304/06/08 312); 272/74 318); 248 38); 228 38); 177/79
320); 154 39); 135 312); 121/3 354); 112 313); 97319); 83
320); 70 327); 44 329); 43 340); 41 332); 40 3100).
3.2.3. Ethyl 1,3,3-trichloro-2-)isopropylimino)cyclohexane-
carboxylate )3c). 3Ratio E/Z: 62/38) H NMR 3270 MHz,
1
CDCl3) d: 1.15 33H, d, Jˆ5.9 Hz, CH3Me)2, major); 1.18
33H, d, Jˆ5.9 Hz, CH3Me)2, major); 1.14 33H, d, Jˆ5.9 Hz,
CH3Me)2, minor); 1.19 33H, d, Jˆ5.9 Hz, CH3Me)2, minor);
1.29 33H, t, Jˆ7.3 Hz, OCH2Me, major); 1.32 33H, t, Jˆ
7.3 Hz, OCH2Me, minor); 1.94±2.33 33H, m); 2.58±2.89
32H, m, CH2); 3.18±3.29 33H, m); 3.74 31H, sept., Jˆ
5.9 Hz, CH3Me)2, minor); 4.23 32H, m, OCH2Me, major);
4.33 32H, m, OCH2Me, minor); 4.86 31H, sept., Jˆ5.9 Hz,
CH3Me)2, major). 13C NMR 367.9 MHz, CDCl3) d: Major:
13.99 3OCH2Me); 16.30 3CH2); 22.01 3CH3Me)2); 22.23
3CH3Me)2); 31.43 3CH2CCl); 43.72 3CH2CCl2); 51.82
3CH3Me)2); 62.60 3OCH2Me); 73.82 3CCl); 78.54 3CCl2);
155.36 3CvN); 168.28 3CvO). Minor: 13.82 3OCH2Me);
16.71 3CH2); 21.56 3CH3Me)2); 22.43 3CH3Me)2); 36.21
3CH2CCl); 42.25 3CH2CCl2); 52.79 3CH3Me)2); 63.38
3OCH2Me); 64.26 3CCl); 87.81 3CCl2); 154.62 3CvN);
169.31 3CvO). IR 3NaCl, n, cm21) 1750 3CO), 1650
3CvN, w). MS m/z 3%): no M1; 298/00/02/04 37); 278/
80/82 331); 271/73/75 323); 242/44/46 318); 225/27/29
341); 190 323); 164 318); 135 331); 107 320); 89 318); 77
319); 43 3100). Anal. Calcd for C12H18Cl3NO2: C, 45.81; H,
5.77; N, 4.45. Found: C, 45.78; H, 5.82; N, 4.41.
3.2.6. Methyl 1,3,3-trichloro-2-)benzylimino)cyclohexane-
carboxylate )3f). 3Ratio E/Z: 64/36) H NMR 3270 MHz,
1
CDCl3) d: 1.96±2.07 32H, m, CH2); 2.23±2.33 31H, m,
CH3H)); 2.59±3.09 34H, m, CH2 and NCH2CH2); 3.20±
3.23 31H, m, CH3H)); 3.74 33H, s, OCH3, major); 3.78
33H, s, OCH3, minor); 4.25±4.35 32H, m, NCH2); 7.16±
7.30 35H, m, C6H5). 13C NMR 367.9 MHz, CDCl3)? d:
Major: 16.09 3CH2); 31.39 3NCH2CH2); 36.48 3CH2CCl);
43.43 3CH2CCl2); 53.15 3NCH2); 53.82 3OCH3); 73.51
3CCl); 87.67 3CCl2); 125.84 and 2£127.99 and 2£128.66
3vCH); 139.53 3vCquat); 157.45 3CvN); 168.43
3CvO). Minor: 16.57 3CH2); 35.65 3NCH2CH2); 36.19
3CH2CCl); 41.99 3CH2CCl2); 46.92 3NCH2); 53.59
3OCH3); 71.34 3CCl); 87.37 3CCl2); 126.01 and 2£127.99
and 2£128.75 3vCH); 139.26 3vCquat); 157.14 3CvN);
169.04 3CvO). IR 3NaCl, n, cm21) 1745 3CO), 1655
3CvN). MS m/z 3%): no M1; 254 310); 242/44 339); 210/
12 3100); 182 318); 154 332); 149/50 381); 126/27 325); 105
317); 99 311); 91 321); 85 311); 77 315); 70 315); 63 312); 57
330); 43 320); 41 322). Anal. Calcd for C15H16Cl3NO2: C,
51.67; H, 4.63; N, 4.02. Found: C, 51.62; H, 4.68; N, 3.98.
3.2.4. Ethyl 1,3,3-trichloro-2-)cyclohexylimino)cyclo-
hexanecarboxylate )3d). 3Ratio E/Z: 62/38) 1H NM R
3270 MHz, CDCl3) d: 1.29 33H, t, Jˆ6.9 Hz, OCH2Me,
major); 1.33 33H, t, Jˆ6.9 Hz, OCH2Me, minor); 1.30±
1.78 310H, m, 3CH2)5-cyclohex.); 1.94±2.33 33H, m);
2.57±2.90 32H, m); 3.22±3.30 33H, m); 4.21 32H, m,
3.2.7. Methyl 1,3,3-trichloro-2-)1-sec-butylimino)cyclo-
hexanecarboxylate )3g). 3Ratio E/Z: 53/47) 1H NM R
3270 MHz, CDCl3) d: 0.85±0.96 33H, m, CH2CH3); 1.09±
1.27 3CHCH3); 1.48±1.69 32H, m, CH2CH3); 1.88±2.07
32H, m, CH2); 2.24±2.33 31H, m, CH3H)); 2.59±2.89 32H,

7690
C. V. Stevens et al. / Tetrahedron 57 -2001) 7685±7692
m, CH2); 3.17±3.28 31H, m, CH3H)); 3.77 33H, s, OCH3,
major); 3.85 33H, s, OCH3, minor); 4.58±4.64 31H, m,
NCH). 13C NMR 367.9 MHz, CDCl3) d: Major: 10.52
3CH2CH3); 16.23 3CH2); 19.75 3CHCH3): 30.77
3CH2CH3); 31.00 3CH2); 43.42 3CH2); 53.39 3OCH3);
57.34 3NCH); 74.50 3CCl); 88.11 3CCl2); 156.14 3CvN);
168.98 3CvO). Minor: 10.42 3CH2CH3); 16.68 3CH2);
19.66 3CHCH3): 30.293CH2CH3); 32.42 3CH2); 44.71
3CH2); 53.94 3OCH3); 57.13 3NCH); 74.57 3CCl); 87.69
3CCl2); 155.87 3CvN); 169.16 3CvO). IR 3NaCl, n,
cm21): 1746 3CvO); 1653 3CvN). MS m/z 3%): 314
3M1, 1); 285/87 326); 283/85/87 328); 259/61 322); 257
325); 229 313); 227 330); 225 333); 189 312); 121/23 313);
59 319); 57 3100); 56 313); 55 313); 41 356). 3Purity: 65%).
80). Anal. Calcd for C11H14ClNO2: C, 58.03; H, 6.20; N,
6.15. Found: C, 58.21; H, 6.11; N, 6.06.
3.3.2. Methyl 3-chloro-2-cyclohexylaminoanthranilate
)4b). H NMR 3270 MHz, CDCl3) d: 1.14±1.37 36H, m,
1
cyclohex.); 1.57±1.73 32H, m, cyclohex.); 1.94±1.98 32H,
m, cyclohex.); 3.70±3.81 31H, m, CHN); 3.87 33H, s,OMe);
6.72 31H, dd, J1ˆ8.1, J2ˆ7.4 Hz, vCH); 7.02 31H, broad s,
NH); 7.41 31H, dd, J1ˆ7.8, J2ˆ1.7 Hz, vCH); 7.82 31H,
dd, J1ˆ8.1, J2ˆ1.7 Hz, vCH). 13C NMR 367.9 MHz,
CDCl3) d: 25.05 32£CH2); 25.79 32£CH2); 34.29
32£CH2); 52.04 3CHN); 54.75 3OCH3); 118.61 3CCOOMe);
118.81 3vCH); 124.72 3vCCl); 130.15 3vCH); 135.74
3vCH); 148.50 3vCNH); 168.39 3CvO). IR 3NaCl, n,
cm21): 3325 3NH); 1690 3CO); 1585; 1510; 1450. MS m/z
3%): 267/69 3M1, 62); 252/54 351); 236/38 319); 224/26
389); 192 3100); 166 321); 153 341); 98 329); 90 317); 55
326); 41 332). Rfˆ0.59 3EtOAc/Hex.: 20/80). Anal. Calcd
for C14H18ClNO2: C, 62.80; H, 6.78; N, 5.23. Found: C,
62.68; H, 6.88; N, 5.35.
3.2.8. Methyl 1,3,3-trichloro-2-)cyclopentylimino)cyclo-
hexanecarboxylate )3h). 3Ratio E/Z: 68/32) 1H NM R
3270 MHz, CDCl3) d: 1.49±2.06 310H, m, CH2 and
3CH2)4-cyclopentyl); 2.24±2.34 31H, m, CH3H)); 2.61±
2.93 32H, m, CH2); 3.21±3.33 31H, m, CH3H)); 3.77 33H,
s, OCH3, major); 3.83 33H, s, OCH3, minor); 4.98±5.10 31H,
m, NCH). 13C NMR 367.9 MHz, CDCl3) d: Major: 16.18
3CH2); 24.78 32£CH2-cyclohexyl); 31.25 3CH2); 34.11
32£CH2-cyclohexyl); 43.51 3CH2); 53.25 3OCH3); 61.62
3NCH); 65.77 3CCl); 74.13 3CCl2); 155.08 3CvN); 168.91
3CvO). Minor: 16.73 3CH2); 24.99 32£CH2-cyclohexyl);
32.92 3CH2); 33.68 32£CH2-cyclohexyl); 42.28 3CH2);
53.86 3OCH3); 62.46 3NCH); 65.77 3CCl); 74.13 3CCl2);
154.21 3CvN); 169.97 3CvO). IR 3NaCl, n, cm21): 1756
3CO); 1638 3CvN). MS m/z 3%): no M1; 290/92/94 331);
261 310); 259 326); 257 327); 254 310); 227 327); 225 328);
121/23 335); 101 310); 77 312); 69 399); 68 318); 66 336); 65
319); 59 316); 51 313); 41 3100).
3.3.3. Ethyl 3-chloro-2-isopropylaminoanthranilate )4c).
1H NMR 3270 MHz, CDCl3) d: 1.17 36H, d, Jˆ6.3 Hz,
CH3CH3)2); 1.39 33H, t, Jˆ6.9 Hz, OCH2Me); 4.15 31H,
sept., Jˆ6.3 Hz, CH3CH3)2); 4.34 32H, q, Jˆ6.9 Hz,
OCH2Me); 6.75 31H, t, Jˆ7.9 Hz, CH); 6.77 31H, broad s,
NH); 7.42 31H, dd, J1ˆ7.9, J2ˆ1.7 Hz, vCH); 7.85 31H,
dd, J1ˆ7.9, J2ˆ1.7 Hz, vCH). 13C NMR 367.9 MHz,
CDCl3) d: 14.25 3OCH2Me); 23.74 3CH3CH3)2); 47.65
3CH3CH3)2); 61.02 3OCH2CH3); 118.96 3CCOOMe);
119.60 3vCH); 125.10 3vCCl); 130.13 3vCH); 135.61
3vCH); 148.64 3vCNH); 167.92 3CvO). IR 3NaCl, n,
cm21): 3315 3NH); 1690 3CO); 1580; 1505; 1450. MS m/z
3%): 241/43 3M1, 24); 226/28 324); 212/14 324); 196 314);
194 327); 180/82 3100); 153 311); 117 35); 90 39); 58 312), 43
33). Rfˆ0.59 3EtOAc/Hex.: 20/80). Anal. Calcd for
C12H16ClNO2: C, 59.63; H, 6.67; N, 5.79. Found: C,
59.75; H, 6.63; N, 5.82.
3.3. General procedure for the synthesis of 3-chloro-
anthranilates 4
To a ¯ask, equiped with a re¯ux condenser and a drying
tube, 0.88 mmol of the a,g,g-trichloro-b-iminoester 3 was
treated with 5.28 mmol of sodium methoxide 32 M) in
methanol 3or sodium ethoxide 32 M), in case of trans-
esteri®cation 4i and 4j). The reaction mixture was re¯uxed
for 6 h, then poured into 20 ml of water and extracted three
times with dichloromethane. The combined organic extracts
were dried 3MgSO4), ®ltered and the solvent was evaporated
under reduced pressure. The crude products were puri®ed by
¯ash chromatography 3EtOAc/hex.:mostly 20/80) in order
to obtain the pure 3-chloroanthranilates 4.
3.3.4. Ethyl 3-chloro-2-cyclohexylaminoanthranilate
)4d). H NMR 3270 MHz, CDCl3) d: 1.12±1.34 36H, m,
1
cHex.); 1.56±1.64 31H, m, cHex.); 1.70±1.75 31H, m,
cHex.); 1.93±1.98 32H, m, cHex.); 1.38 33H,t, Jˆ7 Hz,
OCH2CH3); 3.77 31H, m, CHN); 4.34 32H, q, Jˆ7 Hz,
OCH2Me); 6.72 31H, t, Jˆ7.9 Hz, vCH); 7.00 31H, broad
s, NH); 7.40 31H, dd, J1ˆ7.9, J2ˆ1.6 Hz, vCH); 7.83 31H,
dd, J1ˆ7.9, J2ˆ1.7 Hz, vCH). 13C NMR 367.9 MHz,
CDCl3) d: 14.27 3OCH2Me); 25.07 32£CH2); 25.82
32£CH2); 34.29 32£CH2); 54.75 3CHN); 60.99
3OCH2CH3); 118.63 3CCOOMe); 119.28 3vCH); 124.81
3vCCl); 130.11 3vCH); 135.59 3vCH); 148.46
3vCNH); 167.94 3CvO). IR 3NaCl, n, cm21): 3320
3NH); 1690 3CO); 1580; 1510; 1450 3arom.). MS m/z 3%):
281/83 3M1, 42); 252/54 386); 238/40 359); 234/36 332);
192/94 3100); 153 329); 55 316); 41 322). Rfˆ0.65
3EtOAc/hex.:20/80). Anal. Calcd for C15H20ClNO2: C,
63.94; H, 7.15; N, 4.97. Found: C, 63.82; H, 7.14; N, 5.10.
3.3.1. Methyl 3-chloro-2-isopropylaminoanthranilate
)4a). 1H NMR 3270 MHz, CDCl3) d: 1.17 36H, d, Jˆ
6.6 Hz, CH3CH3)2); 3.87 33H, s,OMe); 4.14 31H, sept., Jˆ
6.6 Hz, CH3CH3)2); 6.73 31H, dd, J1ˆ8.1, J2ˆ7.8 Hz,
vCH); 6.87 31H, broad s, NH); 7.41 31H, dd, J1ˆ7.8, J2ˆ
1.7 Hz, vCH); 7.83 31H, dd, J1ˆ8.1, J2ˆ1.7 Hz, vCH).
13C NMR 367.9 MHz, CDCl3) d: 23.74 3CH3CH3)2); 47.64
3CH3CH3)2); 52.04 3OCH3); 118.88 3CCOOMe); 119.10
3vCH); 124.98 3vCCl); 130.17 3vCH); 135.74 3vCH);
148.68 3vCNH); 168.35 3CvO). IR 3NaCl, n, cm21): 3330
3NH); 1695 3CO); 1590; 1515; 1450. MS m/z 3%): 227/29
3M1, 31); 212/14 354); 194/96 320); 180/82 3100); 153/55
319); 117 310); 90 317); 58 319). Rfˆ0.6 3EtOAc/hex.:20/
3.3.5. Methyl 5-tert-butyl-3-chloro-2-isopropylamino-
anthranilate )4e). H NMR 3270 MHz, CDCl3) d: 1.15
1
36H, d, Jˆ6.3 Hz, CH3CH3)2); 1.29 39H, s, C3CH3)3); 3.89
33H, s,OMe); 4.07 31H, sept., Jˆ6.3 Hz, CH3CH3)2); 6.80
31H, broad s, NH); 7.46 31H, d, Jˆ2.3 Hz); 7.82 31H, d,

C. V. Stevens et al. / Tetrahedron 57 -2001) 7685±7692
7691
Jˆ2.3 Hz, vCH). IR 3NaCl, n, cm21): 3320 3NH); 1690
3CO); 1530; 1430 3arom.). MS m/z 3%): 283/85 3M1, 45);
268/70 3100); 252 314); 250 322); 238 335); 237 319); 236
398); 226 315); 196 320); 194 320); 166 38); 126 39); 117 39);
103 38); 97 313); 58 325); 57 325). This anthranilate could
not be obtained pure despite all chromatographic efforts,
this compound was only obtained with a purity of about
50%.
)4j). 1H NMR 3270 MHz, CDCl3) d: 0.88 33H, t, Jˆ
7.8 Hz, Me); 0.92 33H, t, Jˆ7.4 Hz, CH2CH3); 1.13 33H,
d, Jˆ6.3 Hz, CHCH3); 1.35±1.51 32H, m, CH2CH3);
3.89±3.98 31H, m, NCH); 4.33 32H, q, Jˆ6.9 Hz, OCH2);
6.72 31H, t, Jˆ7.9 Hz, vCH); 6.94 31H, broad s, NH); 7.40
31H, dd, J1ˆ1.6, J2ˆ7.9 Hz, vCH); 7.84 31H, dd, J1ˆ1.64,
J2ˆ7.9 Hz, vCH). 13C NMR 367.9 MHz, CDCl3) d: 10.39
3CH2CH3); 20.83 3CHCH3); 30.78 3CH2CH3); 52.85 3CHN);
60.97 3OCH2); 118.44 3vCH); 119.07 3vCCO2Et); 124.46
3vCCl); 130.17 3vCH); 135.69 3vCH); 148.81 3vCN);
167.98 3CvO). IR 3NaCl, n, cm21): 3314 3NH); 1687 3CO);
1580; 1510; 1450 3Arom.). MS m/z 3%): 255/57 3M1, 11);
226/28 347); 208/10 319); 194/96 311); 180/82 3100); 84/86
310); 67/69 325); 53 314); 49 312); 41 325).). Rfˆ0.19 3hex./
CH2Cl2: 80/20). Anal. Calcd for C13H18ClNO2: C, 61.05; H,
7.09; N, 5.48. Found: C, 61.18; H, 7.23; N, 5.41.
3.3.6. Methyl 3-chloro-2-)sec-butylamino)anthranilate
)4g). 1H NMR 3270 MHz, CDCl3) d: 0.93 33H, t, Jˆ
7.4 Hz, CH2CH3); 1.13 33H, d, Jˆ6.3 Hz, CHCH3); 1.43±
1.61 32H, m, CH2CH3); 3.88 33H, s, OCH3); 3.91±4.03 31H,
m, CHN); 6.71 31H, dd, J1ˆ6.9, J2ˆ7.9 Hz, vCH); 6.96
31H, broad s, NH); 7.41 31H, dd, J1ˆ1.3, J2ˆ6.9 Hz, vCH);
7.82 31H, dd, J1ˆ1.3, J2ˆ7.9 Hz, vCH). 13C NM R
367.9 MHz, CDCl3) d: 10.24 3CH2CH3); 20.74 3CHCH3);
30.69 3CH2CH3); 51.81 3OCH3); 52.67 3CHN); 118.22
3vCH); 121.13 3vCCO2CH3); 124.13 3vCCl); 130.09
3vCH); 135.72 3vCH); 148.77 3vCNH); 168.25 3CvO).
IR 3NaCl, n, cm21): 3318 3NH); 1692 3CO); 1580; 1510;
1440 3Arom.). MS m/z 3%): 241/43 3M1, 15); 212/14 364);
194 312); 180/82 3100); 153 310); 90 311). Rfˆ0.64 3EtOAc/
hex.:20/80). Anal. Calcd for C12H16ClNO2: C, 59.63; H,
6.67; N, 5.79. Found: C, 59.51; H, 6.55; N, 5.90.
3.4. General procedure for the synthesis of 1,3,3-tri-
chloro-2-oxocyclohexane-1-carboxylates 5
To a ¯ask containing 1 mmol of a,g,g-trichloro-b-imino-
ester 3 in 2.5 ml of dichloromethane was added a solution of
1 mmol of oxalic acid 33COOH)2´2H2O) in 2.5 ml of water.
The two phase system was re¯uxed during 20 h and the
aqueous layer was extracted afterwards three times with
dichloromethane. The combined organic extracts were
dried 3MgSO4), ®ltered and the solvent was evaporated in
vacuo. The alkyl 1,3,3-trichloro-2-oxocyclohexane-1-
carboxylates 5 were recrystallised from an ether/pentane
mixture.
3.3.7. Methyl 3-chloro-2-cyclopentylaminoanthranilate
)4h). H NMR 3270 MHz, CDCl3) d: 1.47±1.92 38H, m,
1
3CH2)4); 3.86 33H, s, OCH3); 4.42±4.46 31H, m, NCH);
6.68 31H, dd, J1ˆ1.6, J2ˆ7.9 Hz, vCH); 7.39 31H, dd,
J1ˆ1.6, J2ˆ7.9 Hz, vCH); 7.81 31H, dd, J1ˆ1.6, J2ˆ
7.3 Hz, vCH). 13C NMR 367.9 MHz, CDCl3) d: 23.43
32£CH2); 33.93 32£CH2); 51.95 3OCH3); 57.61 3NCH);
118.09 3vCH); 121.15 3vCCO2CH3); 123.74 3vCCl);
130.15 3vCH); 135.87 3vCH); 148.75 3vCN); 168.37
3CvO). IR 3NaCl, n, cm21): 3320 3NH); 1688 3CO);
1580; 1510; 1450. MS m/z 3%): 254/56 3M111, 7); 253/
55 3M1, 51); 238/40 353); 224/26 369); 220/22 341); 211
315); 192/94 3100); 179/81 313); 164/66 320); 153/55 342);
130 312); 111 310); 90 314); 84 336); 75 314); 67 312); 63
311); 55 314); 51 310); 41 338). Rfˆ0.2 3Hex./CH2Cl2: 80/
20). Anal. Calcd for C13H16ClNO2: C, 61.54; H, 6.36; N,
5.52. Found: C, 61.70; H, 6.25; N, 5.60.
3.4.1. Methyl 1,3,3-trichloro-2-oxocyclohexane-1-carb-
oxylate )5a). 3R1ˆMe, R3ˆH) 1H NMR 3270 MHz,
CDCl3) d: 1.87±2.26 33H, m, CH2); 2.50±2.62 31H, m);
2.83±2.90 31H, m); 3.01±3.07 31H, m); 3.81 33H, s,
OMe). 13C NMR 367.9 MHz, CDCl3) d: 20.38 3CH2);
39.41 3CH2CCl); 47.30 3CH2CCl2); 53.82 3OCH3); 71.55
3CCl); 87.51 3CCl2); 165.80 3COOMe); 185.48 3CvO).
IR 3KBr, n, cm21): 1735 3CO); 1245 3COOMe). MS m/z
3%): 258/60/62 312); 223 33); 191 33); 179/81 39); 136/38
385); 124 337); 123 348); 122 357); 121 3100); 108 315); 89
328); 75 329); 59 336); 40 323); 39 330). Mp: 80.18C, Yield:
76%. Anal. Calcd for C8H9Cl3O3: C, 37.03; H, 3.50. Found:
C, 37.19; H, 3.62.
3.3.8. Ethyl 3-chloro-2-cyclopentylaminoanthranilate
)4i). 1H NMR 3270 MHz, CDCl3) d: 0.89 33H, t, Jˆ
7.2 Hz, CH2CH3); 1.51±1.91 38H, m, 3CH2)4); 4.34 32H,
q, Jˆ7.1 Hz, CH2CH3); 4.44±4.48 31H, m, CHN); 6.70
31H, t, Jˆ7.8 Hz, vCH); 7.41 31H, dd, J1ˆ1.3, J2ˆ
7.8 Hz, vCH); 7.85 31H, dd, J1ˆ1.3, J2ˆ7.8 Hz, vCH).
13C NMR 367.9 MHz, CDCl3) d: 14.07 3CH2CH3); 23.49
32£CH2); 33.59 32£CH2); 57.67 3NCH); 60.94 3OCH3);
118.15 3vCH); 118.42 3vCCO2Et); 123.88 3vCCl);
130.15 3vCH); 135.78 3vCH); 148.81 3vCN); 167.98
3CvO). IR 3NaCl, n, cm21): 3318 3NH); 16853CO) 1590;
1515; 1450 3Arom.). MS m/z 3%): 267/69 3M1, 34); 238/40
3100); 220/22 354); 204 310); 192/94 373); 164/66 316); 153/
55 327); 90 314); 84 319); 75 312); 55 315); 41 331). Rfˆ0.26
3hex./CH2Cl2: 80/20); This anthranilate could not be
obtained pure despite all chromatographic efforts, this
compound was only obtained with a purity of about 85%.
3.4.2. Ethyl 1,3,3-trichloro-2-oxocyclohexane-1-carboxyl-
1
ate )5c). 3R1ˆEt, R3ˆH) H NMR 3270 MHz, CDCl3) d:
1.30 33H, t, Jˆ7 Hz, Me); 1.86±2.26 33H, m, CH2); 2.51±
2.62 31H, m); 2.83±2.90 31H, m); 2.88±3.07 31H, m); 4.26
32H, m, OCH2Me). 13C NMR 367.9 MHz, CDCl3) d: 13.66
3Me); 20.36 3CH2); 39.32 3CH2CCl); 47.30 3CH2CCl2);
63.47 3OCH2CH3); 71.77 3CCl); 87.53 3CCl2); 165.24
3COOMe); 185.55 3CvO). IR 3KBr, n, cm21): 1700±
1770 3CO). MS m/z 3%): 272/74/76 3M1, 12); 227/29 35);
200/02 313); 165/67/69 386); 150/52/54 3100); 135/37 362);
122/24/26 344); 107/09/11 397); 89 334); 75 339); 65 331); 39
344). Mp: 39.5±39.68C, yield: 82%. Anal. Calcd for
C9H11Cl3O3: C, 39.52; H, 4.05. Found: C, 39.71; H, 3.93.
3.4.3. Methyl 5-tert-butyl-1,3,3-trichloro-2-oxocyclo-
hexane-1-carboxylate )5e). 3R1ˆMe, R3ˆC3CH3)3) 1H
NMR 3270 MHz, CDCl3) d: 0.99 39H, s, C3CH3)3); 2.26±
2.55 34H, m, CH2); 2.95±3.02 31H, m); 3.88 33H, s, OMe).
3.3.9. Ethyl 3-chloro-2-)sec-butylamino)anthranilate

7692
C. V. Stevens et al. / Tetrahedron 57 -2001) 7685±7692
13C NMR 367.9 MHz, CDCl3) d: 27.28 3C3CH3)3); 32.02
3C3CH3)3); 39.17 3CH); 39.53 3CH2CCl); 48.75
3CH2CCl2); 54.27 3OCH3); 69.68 3CCl); 84.35 3CCl2);
167.24 3COOMe); 188.80 3CvO). IR 3KBr, n, cm21):
1730±1775 3CO). MS m/z 3%): 314/16/18/20 3M1, 2);
258/60/62/64 33); 223/25/27 34); 188/90 32); 164/66/68
32); 136 35); 121 35); 57 3100); 41 311). Mp: 98.68C,
yield: 81% 3purity: 87%).
Raser, K. J.; Stafford, D.; Watson, D.; Wang, K.; Jaen, J. C.
J. Med. Chem. 1998, 41, 1060±1067.
7. Stewart, G. M.; Rewcastle, G. W.; Denny, W. A. Aust.
J. Chem. 1984, 37, 1939±1950.
8. Unsubstituted 2-alkoxycarbonylcyclohexanones are commer-
cially available from Acros, Aldrich or Fluka. 4-t-Butyl-2-
alkoxycarbonylcyclohexanones can be prepared according
to: Kayser, R. H.; Brault, M.; Pollack, R. M.; Bantia, S.;
Sadoff, S. F. J. Org. Chem. 1983, 48, 4497±4502.
9. Parr, R. W.; Reiss, J. A. Aust. J. Chem. 1984, 37, 389±394.
10. Merck and Co. Jpn. Kokai Tokkyo JP 62 33,140 [87 33,140]
13 Feb 1987, US Appl. 760,423, 30 Jul 1985; Chem. Abstr.
1988, 108, 185853v.
Acknowledgements
The authors are indebted to the Fund for Scienti®c
Wetenschappelijk
Research-Flanders
3Fonds
voor
11. Hodgson, A.; Marshall, J.; Hallet, P.; Gallagher, T. J. Chem.
Soc., Perkin Trans. 1 1992, 2169±2174.
12. Labelle, M.; Gravel, D. Can. J. Chem. 1985, 63, 1884±1890.
Â
13. De Kimpe, N.; Verhe, R.; De Buyck, L.; Schamp, N.
Tetrahedron Lett. 1985, 26, 2709±2712.
14. De Kimpe, N.; Schamp, N. Org. Prep. Proced. Int. 1981, 13,
Onderzoek-Vlaanderen) and Ghent University for ®nancial
support. E. R. A. is indebted to the Mexican National
Council for Science and Technology 3CONACyT).
References
245±313.
15. De Kimpe, N.; Schamp, N. Org. Prep. Proced. Int. 1983, 15,
1. Cai, S. X.; Zhou, Z.-L.; Huang, J.-C.; Whittemore, E. R.;
Egbuwoku, Z. O.; LuÈ, Y.; Hawkinson, J. E.; Woodward,
R. M.; Weber, E.; Keana, J. F. W. J. Med. Chem. 1996, 39,
3248±3255.
71±135.
16. De Kimpe, N.; Verhe, R. In The Chemistry of a-Haloketones,
Â
a-Haloaldehydes and a-Haloimines, Patai, P., Rappoport, Z.,
Eds.; Wiley: Chichester, 1988.
2. Corral, C.; MadronÄero, R.; Vega, S. J. Heterocycl. Chem.
1977, 14, 99±102.
3. Lehmann, J.; Kraft, G. Arch. Pharm. 1984, 317, 595±606.
17. Saeki, T.; Ishikawa, H.; Oki, T. Eur. Pat. Appl. EP 313,740, 3
Aug. 1988; Chem. Abstr. 1989, 111, 173731c.
18. Leblond, B. PhD Thesis, University of Rouen, France, 1991.
19. De Kimpe, N.; Keppens, M. Tetrahedron 1996, 52, 3705±
3718.
È
4. Horlein, U. Arch. Pharm. 1971, 104, 81±98.
5. Schneller, S. W.; Ibay, A. C.; Christ, W. J.; Bruns, R. F. J. Med.
Chem. 1989, 32, 2247±2254.
20. Duerbeck, H. W.; Duttka, L. L. Tetrahedron 1973, 29, 4285±
4290.
6. Hays, S. J.; Caprathe, B. W.; Gilmore, J. L.; Amin, N.;
Emmerling, M. R.; Michael, W.; Nadimpalli, R.; Nath, R.;